77	33299129	Information includes mutations, variants, copy number, mRNA expression, protein expression, methylation and overall patient survival for 32 cancer types.	('patient', 'Species', '9606', (116, 123))	('protein expression', 'MPA', (72, 90))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('methylation', 'biological_process', 'GO:0032259', ('92', '103'))	('variants', 'Var', (32, 40))	('mRNA expression', 'MPA', (55, 70))	('copy number', 'Var', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('methylation', 'MPA', (92, 103))
109	33299129	The relative comparison of IC50s between different cancer cell lines treated with FGFR1 inhibitor (AZD4547, FGFR3861, Foretinib, PD173074, Ponatinib) with a significant difference in primary and metastatic cell lines are shown (Fig.	('Foretinib', 'Chemical', 'MESH:C544831', (118, 127))	('FGFR1', 'Gene', (82, 87))	('Ponatinib', 'Chemical', 'MESH:C545373', (139, 148))	('PD173074', 'Var', (129, 137))	('FGFR3861', 'Var', (108, 116))	('PD173074', 'Chemical', 'MESH:C115711', (129, 137))	('FGFR1', 'Gene', '2260', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('FGFR', 'molecular_function', 'GO:0005007', ('82', '86'))	('FGFR', 'molecular_function', 'GO:0005007', ('108', '112'))	('AZD4547', 'Var', (99, 106))	('AZD4547', 'Chemical', 'MESH:C572463', (99, 106))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
133	33299129	The bar graph for copy number variation allows the user to investigate alterations such as deletions or amplifications of the gene of interest in a given cancer cohort.	('deletions', 'Var', (91, 100))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('amplifications', 'Var', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
141	33299129	This research was supported by CPRIT (RP160710/RP170172), NSF (15-597-1605817), NIH/NCI (R01CA200970, 2R01CA155243, and 5P30CA016672), and the Bowes Foundation, (to S.A.M.	('5P30CA016672', 'Var', (120, 132))	('NSF', 'Gene', (58, 61))	('15-597-1605817', 'Var', (63, 77))	('RP160710/RP170172', 'Var', (38, 55))	('R01CA200970', 'Var', (89, 100))	('NSF', 'Gene', '4905', (58, 61))
144	33344043	Patient blood contained an increased content of CD14+HLA-DR-/low M-MDSCs and inflammatory CD16+ monocytes, while their dendritic cells expressed lower levels of activation markers.	('increased', 'PosReg', (27, 36))	('content', 'MPA', (37, 44))	('levels of', 'MPA', (151, 160))	('lower', 'NegReg', (145, 150))	('Patient', 'Species', '9606', (0, 7))	('CD14+HLA-DR-/low', 'Var', (48, 64))
148	33344043	Hence, while the immune system of patients with uveal melanoma shows signs of immunosuppression, the presence of activated immune cells may correlate to a longer survival, at least following IHP treatment.	('uveal melanoma', 'Disease', (48, 62))	('presence', 'Var', (101, 109))	('IHP', 'Chemical', '-', (191, 194))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('patients', 'Species', '9606', (34, 42))	('longer', 'PosReg', (155, 161))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (48, 62))
200	33344043	When correlating myeloid cell parameters and T cell parameters, it was found that patients with myeloid cells with high HLA-ABC expression also had CD8+ T cells expressing high levels of HLA-DR and PD-1 (Figure 2i,k).	('high', 'Var', (115, 119))	('CD8', 'Gene', '925', (148, 151))	('HLA-DR', 'MPA', (187, 193))	('PD-1', 'MPA', (198, 202))	('ABC', 'Gene', (124, 127))	('patients', 'Species', '9606', (82, 90))	('ABC', 'Gene', '10058', (124, 127))	('CD8', 'Gene', (148, 151))
206	33344043	Sections from these biopsies were analyzed for the presence of tumor-infiltrating CD8+, PD-1+, CD68+ and CD163+ cells (Figure 4e,h).	('CD163+', 'Var', (105, 111))	('tumor', 'Disease', (63, 68))	('CD8', 'Gene', (82, 85))	('CD8', 'Gene', '925', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('CD68+', 'Var', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
208	33344043	Similar analyses performed on PD-1+ and CD68+ tumor-infiltrating cells showed that patients with many PD-1+ and CD68+ cells had a longer overall survival after IHP (Figure 4b,c).	('longer', 'PosReg', (130, 136))	('CD68+ cells', 'Var', (112, 123))	('PD-1+', 'Var', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('IHP', 'Chemical', '-', (160, 163))	('patients', 'Species', '9606', (83, 91))	('overall', 'MPA', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
209	33344043	In contrast, no survival benefit was seen with the presence of CD163+ cells (Figure 4d), which generally is regarded to be an immunosuppressive myeloid cell population The treatment the patients received for the primary tumor in the eye was enucleation or radiotherapy (see Table 1).	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('CD163+ cells', 'Var', (63, 75))	('tumor', 'Disease', (220, 225))	('enucleation', 'biological_process', 'GO:0090601', ('241', '252'))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('patients', 'Species', '9606', (186, 194))
213	33344043	During recent years immunotherapy for the treatment of cutaneous malignant melanoma has been a success story with antibodies against CTLA-4 and PD-1 paving the way for a new era of immune checkpoint inhibitors.	('CTLA-4', 'Gene', '1493', (133, 139))	('malignant melanoma', 'Phenotype', 'HP:0002861', (65, 83))	('PD-1', 'Gene', (144, 148))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('malignant melanoma', 'Disease', 'MESH:D008545', (65, 83))	('malignant melanoma', 'Disease', (65, 83))	('CTLA-4', 'Gene', (133, 139))	('antibodies', 'Var', (114, 124))
217	33344043	Tumors with a high mutational load are more likely to contain neo-antigens that T cells may recognize, and the mutational burden is known to be much higher in cutaneous melanoma than in uveal melanoma.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('uveal melanoma', 'Phenotype', 'HP:0007716', (186, 200))	('uveal melanoma', 'Disease', (186, 200))	('uveal melanoma', 'Disease', 'MESH:C536494', (186, 200))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('cutaneous melanoma', 'Disease', (159, 177))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (159, 177))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (159, 177))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('Tumors', 'Disease', (0, 6))	('neo-antigens', 'MPA', (62, 74))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('high mutational load', 'Var', (14, 34))	('contain', 'Reg', (54, 61))
225	33344043	M-MDSCs have been shown to be enriched in blood and tumors in many cancer patients, including cutaneous melanoma, where they suppress T cell responses.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('T cell responses', 'CPA', (134, 150))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('suppress', 'NegReg', (125, 133))	('cancer', 'Disease', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('cutaneous melanoma', 'Disease', (94, 112))	('patients', 'Species', '9606', (74, 82))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (94, 112))	('tumors', 'Disease', (52, 58))	('M-MDSCs', 'Var', (0, 7))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (94, 112))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
227	33344043	CD16+ monocytes accumulate during inflammatory conditions and produce higher levels of pro-inflammatory cytokines, such as TNF-alpha and IL-1beta, compared with classical monocytes.	('IL-1beta', 'Gene', '3552', (137, 145))	('TNF-alpha', 'Gene', (123, 132))	('IL-1beta', 'Gene', (137, 145))	('CD16+', 'Var', (0, 5))	('IL-1', 'molecular_function', 'GO:0005149', ('137', '141'))	('higher', 'PosReg', (70, 76))	('levels of pro-inflammatory cytokines', 'MPA', (77, 113))	('TNF-alpha', 'Gene', '7124', (123, 132))
243	33344043	No connection could be found between high amounts of CD163+ cells and survival, suggesting that it was the presence of CD68+CD163- M1 stimulatory macrophages that correlated to a favorable IHP response.	('IHP', 'Chemical', '-', (189, 192))	('IHP response', 'CPA', (189, 201))	('CD68+CD163-', 'Var', (119, 130))
245	33344043	Radiotherapy may cause immunogenic cell death in cancer cells in a similar way as certain chemotherapeutic drugs.	('cell death', 'biological_process', 'GO:0008219', ('35', '45'))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Radiotherapy', 'Var', (0, 12))	('immunogenic cell death', 'Disease', (23, 45))	('immunogenic cell death', 'Disease', 'MESH:D003643', (23, 45))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
254	33324425	This review will summarize the studies describing MIF in tumor-specific innate and adaptive immune responses and attempt to reconcile these various pleiotropic functions in normal physiology.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('adaptive immune responses', 'CPA', (83, 108))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('MIF', 'Var', (50, 53))	('tumor', 'Disease', (57, 62))
255	33324425	Tumor immune responses are shaped and characterized by a number of factors including mutational burden, inflammatory response, differential expression of cytokines and chemokines, and the presence and/or activation of both tumoral and stromal immune suppressive checkpoint ligands and receptors.	('activation', 'PosReg', (204, 214))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('expression', 'MPA', (140, 150))	('inflammatory', 'CPA', (104, 116))	('tumoral', 'Disease', 'MESH:D009369', (223, 230))	('inflammatory response', 'biological_process', 'GO:0006954', ('104', '125'))	('tumoral', 'Disease', (223, 230))	('mutational', 'Var', (85, 95))
258	33324425	Because each of these cell types influences the initiation, growth, progression, and/or metastatic dissemination of tumors, we will attempt to summarize how MIF shapes tumor-associated immune responses focusing on individual cell effectors and their relative contributions to pro/anti-tumor immunity.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('shapes', 'Reg', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', (285, 290))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('influences', 'Reg', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (116, 121))	('MIF', 'Var', (157, 160))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
293	33324425	Conversely, anti-inflammatory/immunosuppressive "M2" TAMs promote wound healing and resolution of chronic inflammatory responses that would otherwise drive tumor initiation, but in the context of established tumors, M2-TAMs promote evasion of anti-tumor immunity, de novo neoangiogenesis, and extracellular matrix remodeling.	('evasion', 'MPA', (232, 239))	('tumor initiation', 'Disease', 'MESH:D009369', (156, 172))	('extracellular matrix remodeling', 'CPA', (293, 324))	('promote', 'PosReg', (224, 231))	('tumor', 'Disease', (156, 161))	('tumor initiation', 'Disease', (156, 172))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('tumor', 'Disease', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('TAMs', 'Chemical', '-', (53, 57))	('TAMs', 'Chemical', '-', (219, 223))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('de novo neoangiogenesis', 'CPA', (264, 287))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('wound healing', 'biological_process', 'GO:0042060', ('64', '77'))	('tumors', 'Disease', (208, 214))	('M2-TAMs', 'Var', (216, 223))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('291', '311'))
302	33324425	These findings were later confirmed using mouse models of both primary and metastatic melanoma in MIF+/+ and MIF-/- mice.	('MIF+/+', 'Var', (98, 104))	('mice', 'Species', '10090', (116, 120))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('mouse', 'Species', '10090', (42, 47))	('MIF-/-', 'Var', (109, 115))	('primary', 'Disease', (63, 70))
305	33324425	Combined, these findings indicate that loss or inhibition of MIF in solid tumor settings very efficiently re-polarizes intratumoral TAMs from an immunosuppressive/angiogenic pro-tumor phenotype to an immunostimulatory/non-angiogenic anti-tumor phenotype.	('inhibition', 'NegReg', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', (74, 79))	('loss', 'Var', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('TAMs', 'Chemical', '-', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumoral', 'Disease', (124, 131))	('tumoral', 'Disease', 'MESH:D009369', (124, 131))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (238, 243))	('MIF', 'Gene', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('rat', 'Species', '10116', (122, 125))
313	33324425	Interestingly, reconstitution of shRNA-resistant wildtype MIF largely reverts the slow growth and metastases-resistant phenotype of 4T1 MIF shRNA knockdown cells and restores M-MDSC numbers while an enzymatically inactive MIF mutant construct (MIF-P2G) does not.	('MIF', 'Var', (136, 139))	('slow growth', 'Phenotype', 'HP:0001510', (82, 93))	('4T1 MIF', 'Var', (132, 139))	('M-MDSC', 'MPA', (175, 181))	('metastases-resistant', 'Disease', (98, 118))	('metastases-resistant', 'Disease', 'MESH:D009362', (98, 118))	('M-MDSC', 'Chemical', '-', (175, 181))	('reverts', 'NegReg', (70, 77))	('restores', 'PosReg', (166, 174))
314	33324425	An additional example of paracrine-acting MIF driving MDSC phenotypes came from the Lathia group which identified that glioblastoma (GBM) cancer stem cell (CSC)-secreted MIF increases MDSC immune suppressive activity in an arginase 1-dependent manner.	('glioblastoma', 'Disease', (119, 131))	('increases', 'PosReg', (174, 183))	('cancer', 'Disease', (138, 144))	('MDSC immune suppressive activity', 'CPA', (184, 216))	('GBM', 'Phenotype', 'HP:0012174', (133, 136))	('glioblastoma', 'Disease', 'MESH:D005909', (119, 131))	('arginase 1', 'Gene', '383', (223, 233))	('glioblastoma', 'Phenotype', 'HP:0012174', (119, 131))	('MIF', 'Var', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('arginase 1', 'Gene', (223, 233))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
319	33324425	This requirement for stromal MIF in promoting tumor burden phenotypes is consistent with other reports showing that loss of stromal MIF reduces MDSC accumulation and/or tumor growth in de novo oral carcinogenesis and human melanoma.	('melanoma', 'Disease', (223, 231))	('oral carcinogenesis', 'Disease', (193, 212))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (193, 212))	('human', 'Species', '9606', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('stromal', 'Gene', (124, 131))	('tumor', 'Disease', (169, 174))	('MDSC accumulation', 'MPA', (144, 161))	('loss', 'Var', (116, 120))	('reduces', 'NegReg', (136, 143))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
321	33324425	However, the fact that MIF P2G mutants and 4-IPP-mediated MIF inhibition (4-IPP specifically interacts with and disrupts the Pro-2 in MIF) abolishes MIF-dependent effects on MDSCs suggests that the cognate MIF receptor CD74:which can still interact with and signal by MIF-P2G mutants and 4-IPP-inhibited MIF :is not centrally involved.	('mutants', 'Var', (31, 38))	('4-IPP', 'Chemical', '-', (43, 48))	('MIF-P2G', 'Gene', (268, 275))	('4-IPP', 'Chemical', '-', (288, 293))	('MIF P2G', 'Gene', (23, 30))	('mutants', 'Var', (276, 283))	('4-IPP', 'Chemical', '-', (74, 79))
324	33324425	Perhaps more importantly, exposure of patient MDSCs to 4-IPP for longer periods of time results in reductions in the expression of MDSC markers CD14 and PD-L1 and a simultaneous increase in the expression of dendritic cell (DC) markers CD80, CD83, CD86, and CD40.	('CD80', 'Gene', (236, 240))	('PD-L1', 'Gene', (153, 158))	('CD14', 'Gene', (144, 148))	('expression', 'MPA', (117, 127))	('CD80', 'Gene', '941', (236, 240))	('CD83', 'Gene', (242, 246))	('CD14', 'Gene', '929', (144, 148))	('reductions', 'NegReg', (99, 109))	('patient', 'Species', '9606', (38, 45))	('CD86', 'Gene', (248, 252))	('expression', 'MPA', (194, 204))	('increase', 'PosReg', (178, 186))	('CD40', 'Var', (258, 262))	('4-IPP', 'Chemical', '-', (55, 60))	('CD83', 'Gene', '9308', (242, 246))
328	33324425	Also consistent with a paracrine function for tumor-derived MIF, M-MDSC differentiation is induced by human pediatric rhabdomyosarcoma and multiple myeloma cell lines in a MIF-dependent manner and that MIF induces the recruitment and accumulation of M-MDSCs into bladder cancer lesions.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('induces', 'Reg', (206, 213))	('accumulation', 'PosReg', (234, 246))	('M-MDSC', 'Chemical', '-', (250, 256))	('bladder cancer', 'Phenotype', 'HP:0009725', (263, 277))	('bladder cancer lesions', 'Disease', 'MESH:D001749', (263, 285))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('multiple myeloma', 'Phenotype', 'HP:0006775', (139, 155))	('human', 'Species', '9606', (102, 107))	('rhabdomyosarcoma', 'Disease', (118, 134))	('M-MDSC', 'Chemical', '-', (65, 71))	('bladder cancer lesions', 'Disease', (263, 285))	('tumor', 'Disease', (46, 51))	('multiple myeloma', 'Disease', 'MESH:D009101', (139, 155))	('recruitment', 'MPA', (218, 229))	('M-MDSC differentiation', 'CPA', (65, 87))	('MIF', 'Var', (202, 205))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (118, 134))	('induced', 'Reg', (91, 98))	('multiple myeloma', 'Disease', (139, 155))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (118, 134))
331	33324425	It is also conceivable:given that the CD74-binding competent MIF-P2G mutant and 4-IPP-inhibited MIF :that intracellular MDSC MIF may be independently involved in dictating MDSC differentiation and immune-suppressive gene expression patterns.	('4-IPP', 'Chemical', '-', (80, 85))	('dictating', 'Reg', (162, 171))	('mutant', 'Var', (69, 75))	('gene expression', 'biological_process', 'GO:0010467', ('216', '231'))	('intracellular', 'cellular_component', 'GO:0005622', ('106', '119'))	('MIF-P2G', 'Gene', (61, 68))	('binding', 'molecular_function', 'GO:0005488', ('43', '50'))	('MDSC differentiation', 'CPA', (172, 192))
333	33324425	Several studies investigating potential roles for MIF in DC-dependent anti-tumor immunity suggest that MIF functionally impairs the ability of DCs to present TAAs to T cells leading to a dampening of anti-tumor responses.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('MIF', 'Var', (103, 106))	('impairs', 'NegReg', (120, 127))	('dampening', 'NegReg', (187, 196))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('present', 'Interaction', (150, 157))	('tumor', 'Disease', (75, 80))
334	33324425	One such study found that loss of tumor-derived MIF significantly enhances DC tumor accumulation, effector functions and, anti-tumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('MIF', 'Gene', (48, 51))	('effector functions', 'CPA', (98, 116))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('loss', 'Var', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('enhances', 'PosReg', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
337	33324425	The mechanism by which loss of tumor-derived MIF increased DC tumor accumulation was attributed to enhanced tumor cell cytolysis and ensuing tumor-associated antigen release.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('MIF', 'Gene', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('enhanced', 'PosReg', (99, 107))	('increased', 'PosReg', (49, 58))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (108, 113))	('loss', 'Var', (23, 27))	('cytolysis', 'biological_process', 'GO:0019835', ('119', '128'))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
340	33324425	Given the similarities, it is tempting to speculate that the requirement for MIF in maintaining M-MDSC differentiation/restraining spontaneous DC differentiation, described above, may also be participating in these observed increases in intratumoral DC functions upon loss of MIF.	('increases', 'PosReg', (224, 233))	('M-MDSC', 'Chemical', '-', (96, 102))	('loss', 'Var', (268, 272))	('MIF', 'Gene', (276, 279))	('spontaneous DC differentiation', 'CPA', (131, 161))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('rat', 'Species', '10116', (240, 243))	('tumoral', 'Disease', (242, 249))	('tumoral', 'Disease', 'MESH:D009369', (242, 249))	('M-MDSC differentiation/restraining', 'CPA', (96, 130))
344	33324425	Given that DCs cross-present antigens to CD8+ T cells via MHC-I, this finding indicates that MIF promotes immunosuppression, in part, by dampening DC cross-presentation of tumor antigens.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('MIF', 'Var', (93, 96))	('CD8', 'Gene', (41, 44))	('dampening', 'NegReg', (137, 146))	('immunosuppression', 'MPA', (106, 123))	('CD8', 'Gene', '925', (41, 44))	('cross-presentation', 'biological_process', 'GO:0002480', ('150', '168'))	('cross-presentation', 'biological_process', 'GO:0042590', ('150', '168'))	('promotes', 'PosReg', (97, 105))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('cross-presentation', 'biological_process', 'GO:0002479', ('150', '168'))
345	33324425	Additionally, studies that looked at DC MHC-II expression found that MIF promotes downregulation of MHC-II, which further suggests that MIF may also impair tumor antigen presentation of DCs to CD4+ T cells.	('MIF', 'Var', (136, 139))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('downregulation', 'NegReg', (82, 96))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('antigen presentation', 'biological_process', 'GO:0019882', ('162', '182'))	('MHC-II', 'Gene', (100, 106))	('impair', 'NegReg', (149, 155))	('tumor', 'Disease', (156, 161))	('tumor antigen', 'molecular_function', 'GO:0008222', ('156', '169'))
351	33324425	MIF-induced CCL4 and MMP9 production in TANs may have tumor autonomous effects by promoting lymphangiogenesis as well as tumor-stromal remodeling.	('MMP9', 'Gene', '4318', (21, 25))	('CCL4', 'Gene', '6351', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (121, 126))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('92', '109'))	('CCL4', 'Gene', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('CCL', 'molecular_function', 'GO:0044101', ('12', '15'))	('MMP9', 'molecular_function', 'GO:0004229', ('21', '25'))	('lymphangiogenesis', 'CPA', (92, 109))	('promoting', 'PosReg', (82, 91))	('tumor', 'Disease', (54, 59))	('MIF-induced', 'Var', (0, 11))	('MMP9', 'Gene', (21, 25))
353	33324425	Whether MIF-dependent CCL4 expression in TANs has pro- or anti-tumorigenic effects likely depends on which immune cells infiltrate and how the tumor microenvironment specifically activates these cells.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (143, 148))	('CCL', 'molecular_function', 'GO:0044101', ('22', '25'))	('MIF-dependent', 'Var', (8, 21))	('rat', 'Species', '10116', (126, 129))	('CCL4', 'Gene', '6351', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('CCL4', 'Gene', (22, 26))	('expression', 'Var', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
356	33324425	Further studies employing additional time points of MIF-dependent regulating TAN biology and effector functions will likely reveal additional examples by which MIF promotes TAN-dependent tumor initiation in early-stage tumors through chronic inflammation and, likely, as tumors progress and develop, this phenotype may switch to tumor-associated MIF in driving TAN-associated immune evasion.	('immune evasion', 'biological_process', 'GO:0051842', ('376', '390'))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('inflammation', 'Disease', 'MESH:D007249', (242, 254))	('tumor initiation', 'Disease', 'MESH:D009369', (187, 203))	('tumor', 'Disease', (219, 224))	('tumors', 'Disease', (271, 277))	('tumor', 'Disease', (187, 192))	('tumor initiation', 'Disease', (187, 203))	('MIF', 'Var', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Disease', (329, 334))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('inflammation', 'Disease', (242, 254))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('inflammation', 'biological_process', 'GO:0006954', ('242', '254'))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('promotes', 'PosReg', (164, 172))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumors', 'Disease', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (271, 276))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('TAN-associated immune evasion', 'MPA', (361, 390))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('immune evasion', 'biological_process', 'GO:0042783', ('376', '390'))
363	33324425	Subsequent validation experiments found that neutralizing anti-MIF attenuated the NK inhibitory activity in the AH and purified recombinant mouse MIF recapitulated the AH NK inhibitory activity.	('mouse', 'Species', '10090', (140, 145))	('AH', 'Disease', 'MESH:D007039', (112, 114))	('attenuated', 'NegReg', (67, 77))	('anti-MIF', 'Var', (58, 66))	('AH', 'Disease', 'MESH:D007039', (168, 170))	('NK inhibitory activity', 'MPA', (82, 104))	('neutralizing anti-MIF', 'Var', (45, 66))
368	33324425	MIF overexpression in ovarian cancer cell lines also promotes immune evasion in NK cells; in this case by inducing the transcriptional downregulation of ovarian tumor target cell NKG2D that triggers NK-mediated tumor cell cytolysis.	('inducing', 'Reg', (106, 114))	('ovarian cancer', 'Disease', (22, 36))	('tumor', 'Disease', (211, 216))	('transcriptional', 'MPA', (119, 134))	('tumor', 'Disease', (161, 166))	('ovarian cancer', 'Phenotype', 'HP:0100615', (22, 36))	('MIF', 'Gene', (0, 3))	('promotes', 'PosReg', (53, 61))	('ovarian tumor', 'Disease', (153, 166))	('cytolysis', 'biological_process', 'GO:0019835', ('222', '231'))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('overexpression', 'Var', (4, 18))	('ovarian tumor', 'Disease', 'MESH:D010051', (153, 166))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('immune evasion', 'biological_process', 'GO:0042783', ('62', '76'))	('immune evasion', 'biological_process', 'GO:0051842', ('62', '76'))	('NKG2D', 'Gene', (179, 184))	('immune evasion', 'MPA', (62, 76))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('NKG2D', 'Gene', '22914', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('ovarian cancer', 'Disease', 'MESH:D010051', (22, 36))	('ovarian tumor', 'Phenotype', 'HP:0100615', (153, 166))	('downregulation', 'NegReg', (135, 149))
373	33324425	These subtypes include: CD8+ cytotoxic T lymphocytes (CTL), CD4+ helper T cells, FOXP3+ regulatory T cells (Tregs), Th17 lymphocytes, and gammadelta T cells.	('Th17 lymphocytes', 'CPA', (116, 132))	('gammadelta T cells', 'CPA', (138, 156))	('Th17', 'Chemical', '-', (116, 120))	('CD8', 'Gene', (24, 27))	('FOXP3+', 'Var', (81, 87))	('CD8', 'Gene', '925', (24, 27))	('CD4+', 'Var', (60, 64))	('Tregs', 'Chemical', '-', (108, 113))
374	33324425	The first description of a functional role for MIF in T cell activation reported that murine splenocytes co-cultured with neutralizing anti-MIF antibody and activated by antigen, PMA/Ionomycin, or anti-CD3 exhibited significantly reduced IL-2 expression and concurrent reductions in T cell proliferation.	('reductions', 'NegReg', (269, 279))	('expression', 'MPA', (243, 253))	('CD3', 'Gene', (202, 205))	('T cell proliferation', 'biological_process', 'GO:0042098', ('283', '303'))	('Ionomycin', 'Chemical', 'MESH:D015759', (183, 192))	('antibody', 'cellular_component', 'GO:0019814', ('144', '152'))	('murine', 'Species', '10090', (86, 92))	('PMA', 'Chemical', '-', (179, 182))	('IL-2', 'molecular_function', 'GO:0005134', ('238', '242'))	('neutralizing anti-MIF antibody', 'Var', (122, 152))	('IL-2', 'Protein', (238, 242))	('antibody', 'Var', (144, 152))	('antibody', 'molecular_function', 'GO:0003823', ('144', '152'))	('reduced', 'NegReg', (230, 237))	('rat', 'Species', '10116', (297, 300))	('antibody', 'cellular_component', 'GO:0042571', ('144', '152'))	('T cell activation', 'biological_process', 'GO:0042110', ('54', '71'))	('CD3', 'Gene', '12503', (202, 205))	('T cell proliferation', 'CPA', (283, 303))	('antibody', 'cellular_component', 'GO:0019815', ('144', '152'))
376	33324425	A subsequent study looking at the re-activation and relative CTL activity of in vivo primed splenocytes found that anti-MIF specifically increases CTL activity against the same irradiated syngeneic tumor cell line in vitro while control mAb and rMIF had no effect.	('syngeneic tumor', 'Disease', (188, 203))	('CTL activity', 'MPA', (147, 159))	('rMIF', 'Gene', '81683', (245, 249))	('rMIF', 'Gene', (245, 249))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('syngeneic tumor', 'Disease', 'MESH:D009369', (188, 203))	('increases', 'PosReg', (137, 146))	('anti-MIF', 'Var', (115, 123))
377	33324425	While this study suggested that CTL-derived MIF directly inhibited anti-tumor CTL activity of primed lymphocytes, a separate finding indicated that tumor-derived MIF is similarly inhibitory to T cell activation and acts by inducing activation-induced T cell death via an IFN-gamma-dependent pathway.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('T cell activation', 'biological_process', 'GO:0042110', ('193', '210'))	('inducing', 'PosReg', (223, 231))	('MIF', 'Var', (162, 165))	('tumor', 'Disease', (72, 77))	('inhibited', 'NegReg', (57, 66))	('tumor', 'Disease', (148, 153))	('death', 'Disease', 'MESH:D003643', (258, 263))	('death', 'Disease', (258, 263))	('IFN-gamma-dependent pathway', 'Pathway', (271, 298))	('rat', 'Species', '10116', (120, 123))	('cell death', 'biological_process', 'GO:0008219', ('253', '263'))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
378	33324425	CD4+CD25+FOXP3+ effector regulatory T cells (Tregs) infiltrate into the tumor stroma as well as tumor-draining lymph nodes and potently suppress anti-tumor immunity.	('Tregs', 'Chemical', '-', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('CD4+CD25+FOXP3+', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor stroma', 'Disease', 'MESH:D009369', (72, 84))	('rat', 'Species', '10116', (58, 61))	('suppress', 'NegReg', (136, 144))	('tumor stroma', 'Disease', (72, 84))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
379	33324425	CD80 and CD86) on APCs resulting in T cell anergy, ectonucleotidases that hydrolyze ATP to adenosine and direct lysis of effector T cells through perforin-dependent cytotoxicity.	('lysis', 'biological_process', 'GO:0019835', ('112', '117'))	('T cell anergy', 'CPA', (36, 49))	('T cell anergy', 'biological_process', 'GO:0002870', ('36', '49'))	('CD80', 'Gene', (0, 4))	('cytotoxicity', 'Disease', (165, 177))	('CD86', 'Var', (9, 13))	('CD80', 'Gene', '941', (0, 4))	('adenosine', 'Chemical', 'MESH:D000241', (91, 100))	('lysis', 'CPA', (112, 117))	('cytotoxicity', 'Disease', 'MESH:D064420', (165, 177))	('ATP', 'Chemical', 'MESH:D000255', (84, 87))
380	33324425	In mouse models of mammary and colon carcinoma, MIF promotes the generation/expansion of CD4+CD25+FOXP3+ Tregs by increasing IL-2 expression in activated splenocytes.	('MIF', 'Gene', (48, 51))	('expression', 'MPA', (130, 140))	('mouse', 'Species', '10090', (3, 8))	('Tregs', 'Chemical', '-', (105, 110))	('CD4+CD25+FOXP3+', 'Var', (89, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('IL-2', 'molecular_function', 'GO:0005134', ('125', '129'))	('IL-2', 'Gene', (125, 129))	('generation/expansion', 'CPA', (65, 85))	('colon carcinoma', 'Disease', (31, 46))	('colon carcinoma', 'Disease', 'MESH:D003110', (31, 46))	('rat', 'Species', '10116', (69, 72))	('increasing', 'PosReg', (114, 124))
382	33324425	Interestingly, complete tumor rejection was observed in a subset of MIF-/- mice that coincided with significant decreases in Tregs and corresponding increases in splenic CD4+ and CD8+ lymphocytes.	('MIF-/-', 'Var', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mice', 'Species', '10090', (75, 79))	('tumor', 'Disease', (24, 29))	('CD8', 'Gene', (179, 182))	('increases', 'PosReg', (149, 158))	('CD8', 'Gene', '925', (179, 182))	('Tregs', 'CPA', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('Tregs', 'Chemical', '-', (125, 130))	('decreases', 'NegReg', (112, 121))
384	33324425	CTLA-4, GITR, IFN-gamma, TGF-beta, and IL-10) from MIF-deficient mice suggesting that MIF regulates Treg  viaexpansion/generation rather than modulation of Treg effector functions.	('MIF', 'Var', (86, 89))	('MIF-deficient', 'Disease', (51, 64))	('Treg', 'Chemical', '-', (156, 160))	('MIF-deficient', 'Disease', 'MESH:D007153', (51, 64))	('GITR', 'Gene', (8, 12))	('mice', 'Species', '10090', (65, 69))	('IL-10', 'molecular_function', 'GO:0005141', ('39', '44'))	('GITR', 'Gene', '21936', (8, 12))	('rat', 'Species', '10116', (123, 126))	('Treg', 'Chemical', '-', (100, 104))	('viaexpansion/generation', 'MPA', (106, 129))	('rat', 'Species', '10116', (130, 133))	('regulates', 'Reg', (90, 99))	('Treg', 'CPA', (100, 104))	('TGF-beta', 'Gene', (25, 33))
417	33324425	All things combined, MIF influences B cell activation pathways at multiple stages of development and maturation but whether these activation phenotypes occur during tumorigenesis and extrapolate to tumor immunity is largely unexplored.	('B cell activation', 'biological_process', 'GO:0042113', ('36', '53'))	('rat', 'Species', '10116', (105, 108))	('B cell activation pathways', 'Pathway', (36, 62))	('influences', 'Reg', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (198, 203))	('MIF', 'Var', (21, 24))	('tumor', 'Disease', (165, 170))
454	32992741	miR105 from exosome is shown to downregulate ZO1, a tight junction protein that increases vascular permeability and helps in metastasis.	('downregulate', 'NegReg', (32, 44))	('helps', 'PosReg', (116, 121))	('miR105', 'Var', (0, 6))	('metastasis', 'CPA', (125, 135))	('exosome', 'cellular_component', 'GO:0070062', ('12', '19'))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('increases', 'PosReg', (80, 89))	('miR105', 'Chemical', '-', (0, 6))	('ZO1', 'Gene', '7082', (45, 48))	('ZO1', 'Gene', (45, 48))	('tight junction', 'cellular_component', 'GO:0070160', ('52', '66'))	('vascular permeability', 'MPA', (90, 111))
466	32992741	Thus, the overproduction of ROS increases stress in cells, which influences the exosomal release and autophagic activity.	('overproduction', 'Var', (10, 24))	('autophagic activity', 'CPA', (101, 120))	('ROS', 'Chemical', '-', (28, 31))	('influences', 'Reg', (65, 75))	('stress in', 'MPA', (42, 51))	('ROS', 'Gene', (28, 31))	('exosomal release', 'MPA', (80, 96))	('increases', 'PosReg', (32, 41))
469	32992741	Any imbalance in stimuli or inflammation in the cornea may lead to neovascularization, causing opacity and vision loss.	('vision loss', 'Disease', 'MESH:D014786', (107, 118))	('inflammation', 'Disease', (28, 40))	('vision', 'biological_process', 'GO:0007601', ('107', '113'))	('vision loss', 'Disease', (107, 118))	('causing', 'Reg', (87, 94))	('lead to', 'Reg', (59, 66))	('inflammation', 'biological_process', 'GO:0006954', ('28', '40'))	('imbalance', 'Var', (4, 13))	('neovascularization', 'CPA', (67, 85))	('opacity', 'Disease', (95, 102))	('inflammation', 'Disease', 'MESH:D007249', (28, 40))	('vision loss', 'Phenotype', 'HP:0000572', (107, 118))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
485	32992741	The pathogenesis for UM involves genetic and molecular changes that include disruption in the Rb (retinoblastoma) tumor suppressor pathway, where cyclin D overexpression directly and the methylation and inactivation of the INK4A gene indirectly inactivate Rb by hyperphosphorylation.	('Rb (retinoblastoma) tumor', 'Disease', 'MESH:D012175', (94, 119))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('114', '130'))	('hyperphosphorylation', 'biological_process', 'GO:0048151', ('262', '282'))	('overexpression', 'PosReg', (155, 169))	('tumor suppressor', 'biological_process', 'GO:0051726', ('114', '130'))	('Rb', 'Gene', '5925', (256, 258))	('inactivation', 'Var', (203, 215))	('INK4A', 'Gene', '1029', (223, 228))	('methylation', 'Var', (187, 198))	('retinoblastoma', 'Phenotype', 'HP:0009919', (98, 112))	('disruption', 'Reg', (76, 86))	('hyperphosphorylation', 'MPA', (262, 282))	('cyclin', 'molecular_function', 'GO:0016538', ('146', '152'))	('INK4A', 'Gene', (223, 228))	('Rb', 'Gene', '5925', (94, 96))	('inactivate', 'NegReg', (245, 255))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('methylation', 'biological_process', 'GO:0032259', ('187', '198'))	('pathogenesis', 'biological_process', 'GO:0009405', ('4', '16'))	('UM', 'Phenotype', 'HP:0007716', (21, 23))
505	32992741	It occurs in two types: (1) Bilateral/multifocal (in both eyes), which is heritable, occurs because of germline mutation of the RB1 tumor suppressor gene in a developing retinal cell, and includes 25% of the total cases, and (2) Unilateral/unifocal (in one eye), which is non-heritable and includes 75% of all cases.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('132', '148'))	('RB1', 'Gene', (128, 131))	('eyes', 'Disease', 'MESH:D000853', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('eyes', 'Disease', (58, 62))	('tumor', 'Disease', (132, 137))	('RB1', 'Gene', '5925', (128, 131))	('germline mutation', 'Var', (103, 120))	('tumor suppressor', 'biological_process', 'GO:0051726', ('132', '148'))	('RB', 'Phenotype', 'HP:0009919', (128, 130))
506	32992741	Tumor formation is because of the loss of function mutation in both the alleles of the RB1 gene present in chromosome 13q.	('Tumor formation', 'CPA', (0, 15))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('formation', 'biological_process', 'GO:0009058', ('6', '15'))	('RB1', 'Gene', (87, 90))	('loss of function', 'NegReg', (34, 50))	('RB1', 'Gene', '5925', (87, 90))	('chromosome', 'cellular_component', 'GO:0005694', ('107', '117'))	('mutation', 'Var', (51, 59))	('RB', 'Phenotype', 'HP:0009919', (87, 89))
539	32992741	miR-182 alteration is related to cervical cancer pathogenesis and plays an oncogenic role involving apoptosis and cell cycle pathways.	('alteration', 'Var', (8, 18))	('cell cycle pathways', 'CPA', (114, 133))	('related', 'Reg', (22, 29))	('pathogenesis', 'biological_process', 'GO:0009405', ('49', '61'))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('cell cycle', 'biological_process', 'GO:0007049', ('114', '124'))	('miR-182', 'Gene', (0, 7))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('miR-182', 'Gene', '406958', (0, 7))	('apoptosis', 'CPA', (100, 109))
545	32992741	miR-30b-5p plays a role in the suppression of the tumor in esophageal squamous cell carcinoma.	('suppression', 'NegReg', (31, 42))	('miR-30b-5p', 'Chemical', '-', (0, 10))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('esophageal squamous cell carcinoma', 'Disease', (59, 93))	('miR-30b-5p', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (59, 93))
556	32992741	Another study has revealed the role of miR-582-5p as a tumor-suppressor in gastric cancer cell growth via targeting AKT3, suggesting it as a target for treatment as well as diagnosis of gastric cancer.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('55', '71'))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (186, 200))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('AKT3', 'Gene', '10000', (116, 120))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('55', '71'))	('miR-582-5p', 'Var', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cell growth', 'biological_process', 'GO:0016049', ('90', '101'))	('targeting', 'Reg', (106, 115))	('AKT3', 'Gene', (116, 120))	('gastric cancer', 'Disease', (186, 200))	('gastric cancer', 'Disease', (75, 89))	('miR-582-5p', 'Chemical', '-', (39, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (186, 200))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('tumor', 'Disease', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))
561	32992741	miR-483-5p, in coordination with miR-125-3p, is identified as a promoter of adipogenesis via the suppression of the RhoA/ROCK1/ERK1/2 pathway, and their studies may prove as a strategy to treat obesity or multiple symmetric lipomatosis (MSL).	('lipomatosis', 'Disease', 'MESH:D008068', (224, 235))	('miR-483-5p', 'Var', (0, 10))	('lipomatosis', 'Disease', (224, 235))	('suppression', 'NegReg', (97, 108))	('adipogenesis', 'biological_process', 'GO:0045444', ('76', '88'))	('miR-125-3p', 'Gene', (33, 43))	('obesity', 'Disease', (194, 201))	('lipomatosis', 'Phenotype', 'HP:0001012', (224, 235))	('RhoA', 'Gene', (116, 120))	('adipogenesis', 'biological_process', 'GO:0060612', ('76', '88'))	('ERK1/2', 'Gene', (127, 133))	('ROCK1', 'Gene', (121, 126))	('promoter', 'PosReg', (64, 72))	('obesity', 'Disease', 'MESH:D009765', (194, 201))	('ERK1/2', 'Gene', '5595;5594', (127, 133))	('miR-483-5p', 'Chemical', '-', (0, 10))	('adipogenesis', 'MPA', (76, 88))	('RhoA', 'Gene', '387', (116, 120))	('miR-125-3p', 'Gene', '100302208', (33, 43))	('ERK1', 'molecular_function', 'GO:0004707', ('127', '131'))	('ROCK1', 'Gene', '6093', (121, 126))	('obesity', 'Phenotype', 'HP:0001513', (194, 201))
576	32992741	ATP6V1C1 controls tumor growth and bone metastasis, and the silencing of the gene suggests treatment and prevention strategies against cancer.	('cancer', 'Disease', (135, 141))	('tumor', 'Disease', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('ATP6V1C1', 'Gene', (0, 8))	('ATP6V1C1', 'Gene', '528', (0, 8))	('silencing', 'Var', (60, 69))	('bone metastasis', 'CPA', (35, 50))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
579	32992741	Spectrin-associated protein 1 (Camsap1) is shown to be modulated by miR 26; this modulation alters the tumor microenvironment and inhibits metastasis.	('alters', 'Reg', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('miR', 'Gene', '220972', (68, 71))	('miR', 'Gene', (68, 71))	('tumor', 'Disease', (103, 108))	('Spectrin', 'cellular_component', 'GO:0008091', ('0', '8'))	('metastasis', 'CPA', (139, 149))	('iron', 'Chemical', 'MESH:D007501', (117, 121))	('Camsap1', 'Gene', '157922', (31, 38))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('modulation', 'Var', (81, 91))	('Camsap1', 'Gene', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('inhibits', 'NegReg', (130, 138))
586	32992741	KDM1B (flavin-dependent histone demethylases) knockdown shows to inhibit cellular proliferation and induce apoptotic activity in pancreatic cancer and suggests a role in prevention.	('cellular proliferation', 'CPA', (73, 95))	('knockdown', 'Var', (46, 55))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('KDM1B', 'Gene', (0, 5))	('inhibit', 'NegReg', (65, 72))	('KDM1B', 'Gene', '221656', (0, 5))	('induce', 'PosReg', (100, 106))	('flavin', 'Chemical', 'MESH:C024132', (7, 13))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('pancreatic cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('apoptotic activity', 'CPA', (107, 125))
595	32751097	Metastasis of Uveal Melanoma with Monosomy-3 Is Associated with a Less Glycogenetic Gene Expression Profile and the Dysregulation of Glycogen Storage The prolonged storage of glucose as glycogen can promote the quiescence of tumor cells, whereas the accumulation of an aberrant form of glycogen without the primer protein glycogenin can induce the metabolic switch towards a glycolytic phenotype.	('Melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('Monosomy-3', 'Var', (34, 44))	('tumor', 'Disease', (225, 230))	('quiescence', 'biological_process', 'GO:0044838', ('211', '221'))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('Gene Expression', 'biological_process', 'GO:0010467', ('84', '99'))	('promote', 'PosReg', (199, 206))	('quiescence', 'MPA', (211, 221))	('glycogen', 'Chemical', 'MESH:D006003', (286, 294))	('metabolic switch towards a glycolytic phenotype', 'MPA', (348, 395))	('Melanoma', 'Disease', 'MESH:D008545', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('Glycogen', 'Chemical', 'MESH:D006003', (71, 79))	('Glycogen', 'Chemical', 'MESH:D006003', (133, 141))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (14, 28))	('glycogen', 'Chemical', 'MESH:D006003', (322, 330))	('Melanoma', 'Disease', (20, 28))	('induce', 'Reg', (337, 343))	('glycogen', 'Chemical', 'MESH:D006003', (186, 194))	('storage', 'biological_process', 'GO:0051235', ('164', '171'))	('protein', 'cellular_component', 'GO:0003675', ('314', '321'))	('glucose', 'Chemical', 'MESH:D005947', (175, 182))
598	32751097	UMs with monosomy-3 exhibited a less glycogenetic and more insulin-resistant gene expression profile, together with the reduction of glycogen levels, which were associated with the metastases.	('glycogen levels', 'MPA', (133, 148))	('more', 'PosReg', (54, 58))	('less', 'NegReg', (32, 36))	('metastases', 'Disease', 'MESH:D009362', (181, 191))	('gene expression', 'biological_process', 'GO:0010467', ('77', '92'))	('monosomy-3', 'Var', (9, 19))	('glycogenetic', 'MPA', (37, 49))	('reduction of glycogen levels', 'Phenotype', 'HP:0012270', (120, 148))	('insulin', 'Gene', '3630', (59, 66))	('reduction', 'NegReg', (120, 129))	('insulin', 'molecular_function', 'GO:0016088', ('59', '66'))	('insulin', 'Gene', (59, 66))	('metastases', 'Disease', (181, 191))	('glycogen', 'Chemical', 'MESH:D006003', (37, 45))	('glycogen', 'Chemical', 'MESH:D006003', (133, 141))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
600	32751097	Remarkably, glycogen was more abundant in the monosomy-3 tumors of male versus female patients.	('monosomy-3', 'Var', (46, 56))	('patients', 'Species', '9606', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('glycogen', 'Chemical', 'MESH:D006003', (12, 20))	('glycogen', 'MPA', (12, 20))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
601	32751097	We therefore provide the first evidence to the dysregulation of glycogen metabolism as a novel factor that may be aggravating the course of UM particularly in males.	('dysregulation', 'Var', (47, 60))	('aggravating', 'PosReg', (114, 125))	('glycogen metabolism', 'biological_process', 'GO:0005977', ('64', '83'))	('glycogen', 'Chemical', 'MESH:D006003', (64, 72))	('glycogen metabolism', 'MPA', (64, 83))	('UM', 'Phenotype', 'HP:0007716', (140, 142))
605	32751097	The most critical prognostic factor for UM is the loss of one copy of chromosome 3 (monosomy-3), with the occurrence of metastatic disease almost exclusively in the patients having this anomaly in their primary tumor.	('anomaly', 'Disease', 'MESH:D000014', (186, 193))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('anomaly', 'Disease', (186, 193))	('metastatic disease', 'Disease', (120, 138))	('loss', 'Var', (50, 54))	('chromosome', 'cellular_component', 'GO:0005694', ('70', '80'))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('patients', 'Species', '9606', (165, 173))	('UM', 'Phenotype', 'HP:0007716', (40, 42))
606	32751097	Likewise, the presence of monosomy-3 in the circulating melanoma cells (CMCs) and metastasized UMs was associated with a higher metastatic risk and disease progression rate, respectively.	('disease progression rate', 'CPA', (148, 172))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('metastatic risk', 'CPA', (128, 143))	('monosomy-3', 'Var', (26, 36))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('higher', 'PosReg', (121, 127))
607	32751097	Monosomy-3 therefore serves as an independent prognostic factor for shorter survival following the diagnosis of metastases and the UMs with this anomaly are classified as high-risk tumors.	('UM', 'Phenotype', 'HP:0007716', (131, 133))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('Monosomy-3', 'Var', (0, 10))	('metastases', 'Disease', (112, 122))	('anomaly', 'Disease', (145, 152))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('anomaly', 'Disease', 'MESH:D000014', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('shorter', 'NegReg', (68, 75))
609	32751097	Remarkably, the presence of monosomy-3 in primary UMs was positively correlated with the metabolic activity of these tumors in positron emission tomography (PET) scans, which indicates a higher rate of glucose influx into the UM cells with monosomy-3.	('UM', 'Phenotype', 'HP:0007716', (226, 228))	('correlated', 'Reg', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('metabolic activity', 'MPA', (89, 107))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('monosomy-3', 'Var', (28, 38))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('glucose influx', 'MPA', (202, 216))	('glucose', 'Chemical', 'MESH:D005947', (202, 209))	('higher', 'PosReg', (187, 193))	('monosomy-3', 'Var', (240, 250))
624	32751097	Moreover, the BAP1 tumor suppressor, which is encoded by a gene on chromosome 3p21.1 and the loss of which is strongly associated with UM metastases, may also be positively regulating glycogen synthesis as demonstrated by the depletion of glycogen in the livers of mice with a conditional Bap1 deletion.	('tumor suppressor', 'biological_process', 'GO:0051726', ('19', '35'))	('deletion', 'Var', (294, 302))	('metastases', 'Disease', 'MESH:D009362', (138, 148))	('Bap1', 'Gene', (289, 293))	('depletion of glycogen in the livers', 'Phenotype', 'HP:0006568', (226, 261))	('glycogen', 'Chemical', 'MESH:D006003', (184, 192))	('tumor', 'Disease', (19, 24))	('glycogen', 'Chemical', 'MESH:D006003', (239, 247))	('regulating', 'Reg', (173, 183))	('associated', 'Reg', (119, 129))	('metastases', 'Disease', (138, 148))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('loss', 'Var', (93, 97))	('glycogen synthesis', 'biological_process', 'GO:0005978', ('184', '202'))	('depletion of glycogen', 'MPA', (226, 247))	('glycogen synthesis', 'MPA', (184, 202))	('UM', 'Phenotype', 'HP:0007716', (135, 137))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mice', 'Species', '10090', (265, 269))	('chromosome', 'cellular_component', 'GO:0005694', ('67', '77'))	('Bap1', 'Gene', '104416', (289, 293))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('19', '35'))
626	32751097	The silencing of the glycogenin-1 gene in Gyg1-knockout mice has also resulted in the unexpected accumulation of an aberrant type of protein-free glycogen with a larger molecular size, which led to the metabolic switch of muscle cells toward a more glycolytic and less oxidative phenotype despite the maintenance of normal mitochondria.	('glycogen', 'Chemical', 'MESH:D006003', (21, 29))	('mitochondria', 'cellular_component', 'GO:0005739', ('323', '335'))	('metabolic switch', 'MPA', (202, 218))	('led to', 'Reg', (191, 197))	('more', 'PosReg', (244, 248))	('glycogen', 'Chemical', 'MESH:D006003', (146, 154))	('glycogenin-1 gene', 'Gene', (21, 38))	('accumulation', 'PosReg', (97, 109))	('mice', 'Species', '10090', (56, 60))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('mitochondria', 'MPA', (323, 335))	('silencing', 'Var', (4, 13))
627	32751097	However, it is not explored yet, whether the depletion of the glycogenin isoforms GYG1 or GYG2 induces such a glycolytic switch in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('glycogen', 'Chemical', 'MESH:D006003', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('GYG2', 'Gene', (90, 94))	('tumor', 'Disease', (131, 136))	('GYG2', 'Gene', '8908', (90, 94))	('induces', 'Reg', (95, 102))	('depletion', 'Var', (45, 54))	('glycolytic switch', 'MPA', (110, 127))
629	32751097	Yet, it has remained unknown whether the UM cells can store the glucose as glycogen or the presence of monosomy-3 is associated with a gender-specific difference in this event that may be influencing the clinical outcome.	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('associated', 'Reg', (117, 127))	('presence', 'Var', (91, 99))	('glucose as glycogen', 'MPA', (64, 83))	('glucose', 'Chemical', 'MESH:D005947', (64, 71))	('influencing', 'Reg', (188, 199))	('monosomy-3', 'Gene', (103, 113))	('glycogen', 'Chemical', 'MESH:D006003', (75, 83))	('store', 'MPA', (54, 59))
637	32751097	Our findings highlight the dysregulation of glycogen storage as a novel pathomechanism that may be worsening the prognosis of UM with monosomy-3 particularly in the male patients.	('patients', 'Species', '9606', (170, 178))	('monosomy-3', 'Var', (134, 144))	('dysregulation', 'Var', (27, 40))	('UM', 'Phenotype', 'HP:0007716', (126, 128))	('storage', 'biological_process', 'GO:0051235', ('53', '60'))	('glycogen', 'MPA', (44, 52))	('worsening', 'PosReg', (99, 108))	('glycogen', 'Chemical', 'MESH:D006003', (44, 52))
645	32751097	Likewise, the major biological pathways involving these genes included the carbohydrate and glucose metabolism, as well as the glycogen synthesis (Figure 1).	('glucose metabolism', 'Disease', (92, 110))	('glycogen', 'Chemical', 'MESH:D006003', (127, 135))	('glucose metabolism', 'biological_process', 'GO:0006006', ('92', '110'))	('glucose metabolism', 'Disease', 'MESH:D044882', (92, 110))	('glycogen synthesis', 'biological_process', 'GO:0005978', ('127', '145'))	('glycogen synthesis', 'MPA', (127, 145))	('genes', 'Var', (56, 61))	('carbohydrate', 'Chemical', 'MESH:D002241', (75, 87))
650	32751097	Likewise, the upregulated genes were associated with the carbohydrate and energy reserve metabolic processes, glucose breakdown, and glycogen lysis (Figure 1).	('glucose', 'Chemical', 'MESH:D005947', (110, 117))	('glycogen lysis', 'MPA', (133, 147))	('glucose breakdown', 'MPA', (110, 127))	('genes', 'Var', (26, 31))	('glucose breakdown', 'biological_process', 'GO:0006007', ('110', '127'))	('lysis', 'biological_process', 'GO:0019835', ('142', '147'))	('upregulated', 'PosReg', (14, 25))	('glycogen', 'Chemical', 'MESH:D006003', (133, 141))	('carbohydrate', 'Chemical', 'MESH:D002241', (57, 69))
687	32751097	Monosomy-3 was detected in 46.7% (n = 14 of 30) of the primary tumors.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('Monosomy-3', 'Var', (0, 10))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
694	32751097	The objective quantifications demonstrated a significantly reduced level of glycogen in the tumors with a higher extent of monosomy-3 and lower nuclear BAP1 expression (Figure 6, Table 2).	('nuclear BAP1 expression', 'MPA', (144, 167))	('reduced', 'NegReg', (59, 66))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('lower', 'NegReg', (138, 143))	('glycogen', 'Chemical', 'MESH:D006003', (76, 84))	('reduced level of glycogen', 'Phenotype', 'HP:0012270', (59, 84))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('monosomy-3', 'Var', (123, 133))	('level of glycogen', 'MPA', (67, 84))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))
698	32751097	The percentage of CMCs with monosomy-3 was also elevated in the metastatic versus non-metastatic patients (Median: 37.5 vs. 10.8%, respectively, p = 0.03, Mann-Whitney U test).	('CMCs', 'Disease', (18, 22))	('metastatic', 'Disease', (64, 74))	('monosomy-3', 'Var', (28, 38))	('elevated', 'PosReg', (48, 56))	('patients', 'Species', '9606', (97, 105))
701	32751097	No association was observed between the glycogen levels and the remaining parameters including the affected eye, irradiation, tumor size, cytoplasmic BAP1 expression, presence or number of CMCs, presence of monosomy-3 in the CMCs, and patient gender (Table 2).	('patient', 'Species', '9606', (235, 242))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('monosomy-3', 'Var', (207, 217))	('CMCs', 'Gene', (189, 193))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('glycogen', 'Chemical', 'MESH:D006003', (40, 48))	('glycogen levels', 'MPA', (40, 55))	('tumor', 'Disease', (126, 131))
702	32751097	Remarkably, the further stratification of the female and male patients with regard to the monosomy-3 status, irradiation, or metastases revealed several gender-specific differences.	('monosomy-3 status', 'Var', (90, 107))	('metastases', 'Disease', (125, 135))	('patients', 'Species', '9606', (62, 70))	('metastases', 'Disease', 'MESH:D009362', (125, 135))
703	32751097	For instance, the levels of glycogen were higher in the monosomy-3 tumors of male versus female patients (n = 7 patients each, p = 0.03, Figure 7, Figure S1).	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('levels of glycogen', 'MPA', (18, 36))	('glycogen', 'Chemical', 'MESH:D006003', (28, 36))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('higher', 'PosReg', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('patients', 'Species', '9606', (96, 104))	('tumors', 'Disease', (67, 73))	('monosomy-3', 'Var', (56, 66))
705	32751097	In contrast, the percentage of CMCs with monosomy-3 was lower in the male patients (n = 14 females, n = 13 males, p = 0.02).	('lower', 'NegReg', (56, 61))	('patients', 'Species', '9606', (74, 82))	('CMCs', 'Disease', (31, 35))	('monosomy-3', 'Var', (41, 51))
706	32751097	CMCs with monosomy-3 were detected at a similar extent in the female patients without or with metastases (Median: 33.3% for each group, n = 9 and 5 patients, respectively, p = 0.74).	('metastases', 'Disease', (94, 104))	('patients', 'Species', '9606', (148, 156))	('monosomy-3', 'Var', (10, 20))	('CMCs', 'Disease', (0, 4))	('metastases', 'Disease', 'MESH:D009362', (94, 104))	('patients', 'Species', '9606', (69, 77))
707	32751097	However, the male patients with metastases exhibited significantly more CMCs with monosomy-3 compared to the non-metastatic patients (Median: 43.8% vs. 0.0%, n = 9 and 4 patients, respectively, p = 0.01).	('patients', 'Species', '9606', (170, 178))	('metastases', 'Disease', (32, 42))	('CMCs', 'Disease', (72, 76))	('monosomy-3', 'Var', (82, 92))	('patients', 'Species', '9606', (18, 26))	('metastases', 'Disease', 'MESH:D009362', (32, 42))	('patients', 'Species', '9606', (124, 132))
708	32751097	Accordingly, the prevalence of CMCs with monosomy-3 was higher in the female versus male patients without metastases (median: 33.3% vs. 0.0%, n = 9 patients per group, p = 0.01, Figure 7).	('metastases', 'Disease', 'MESH:D009362', (106, 116))	('patients', 'Species', '9606', (148, 156))	('CMCs', 'Disease', (31, 35))	('patients', 'Species', '9606', (89, 97))	('monosomy-3', 'Var', (41, 51))	('metastases', 'Disease', (106, 116))
714	32751097	Remarkably, the chromosome 3 harbors several genes that are directly involved in glycogen metabolism, but it has remained unknown whether the UM cells can store glycogen and how the presence of monosomy-3 influences this process.	('monosomy-3', 'Var', (194, 204))	('UM', 'Phenotype', 'HP:0007716', (142, 144))	('store glycogen', 'MPA', (155, 169))	('glycogen metabolism', 'biological_process', 'GO:0005977', ('81', '100'))	('chromosome', 'cellular_component', 'GO:0005694', ('16', '26'))	('influences', 'Reg', (205, 215))	('glycogen', 'Chemical', 'MESH:D006003', (161, 169))	('glycogen', 'Chemical', 'MESH:D006003', (81, 89))
715	32751097	In this study, we report the differential expression of n = 22 genes that regulate glycogen dynamics and provide the first evidence to the dysregulation of glycogen storage in the primary UMs with monosomy-3, which was associated with a worse prognosis.	('dysregulation', 'MPA', (139, 152))	('glycogen dynamics', 'MPA', (83, 100))	('glycogen storage', 'MPA', (156, 172))	('glycogen', 'Chemical', 'MESH:D006003', (83, 91))	('expression', 'MPA', (42, 52))	('storage', 'biological_process', 'GO:0051235', ('165', '172'))	('monosomy-3', 'Var', (197, 207))	('glycogen', 'Chemical', 'MESH:D006003', (156, 164))	('UM', 'Phenotype', 'HP:0007716', (188, 190))
718	32751097	Likewise, the targeted deletion of the BAP1 tumor suppressor (Locus: 3p21.1) resulted in the depletion of glycogen from the liver of knockout mice.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('resulted in', 'Reg', (77, 88))	('depletion of glycogen', 'MPA', (93, 114))	('deletion', 'Var', (23, 31))	('glycogen', 'Chemical', 'MESH:D006003', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mice', 'Species', '10090', (142, 146))	('depletion of glycogen from the liver', 'Phenotype', 'HP:0006568', (93, 129))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('tumor', 'Disease', (44, 49))	('BAP1', 'Gene', (39, 43))
723	32751097	It might be therefore very informative to focus further on the contribution of the EPM2A-depletion to the unfavorable prognosis of the UM tumors with the 6q loss and dysregulation of glycogenesis.	('UM', 'Phenotype', 'HP:0007716', (135, 137))	('EPM2A', 'Gene', (83, 88))	('glycogen', 'Chemical', 'MESH:D006003', (183, 191))	('tumors', 'Disease', (138, 144))	('EPM2A', 'Gene', '7957', (83, 88))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('dysregulation', 'Var', (166, 179))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
727	32751097	The downregulation of these genes in the UMs with monosomy-3 therefore indicates the impairment of normal insulin signaling in such samples.	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('insulin', 'Gene', (106, 113))	('monosomy-3', 'Var', (50, 60))	('insulin', 'Gene', '3630', (106, 113))	('downregulation', 'NegReg', (4, 18))	('insulin', 'molecular_function', 'GO:0016088', ('106', '113'))
731	32751097	We have also recently reported the lower expression of adiponectin (Locus: 3q27.3) and its receptor Adipor1 in the UM samples with monosomy-3, suggesting the occurrence of a local insulin resistance in such tumors.	('insulin resistance', 'Phenotype', 'HP:0000855', (180, 198))	('insulin', 'Gene', (180, 187))	('monosomy-3', 'Var', (131, 141))	('expression', 'MPA', (41, 51))	('insulin', 'Gene', '3630', (180, 187))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('adiponectin', 'Gene', (55, 66))	('UM', 'Phenotype', 'HP:0007716', (115, 117))	('insulin', 'molecular_function', 'GO:0016088', ('180', '187'))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('lower', 'NegReg', (35, 40))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('Adipor1', 'Gene', (100, 107))	('adiponectin', 'Gene', '9370', (55, 66))	('Adipor1', 'Gene', '51094', (100, 107))	('lower expression of adiponectin', 'Phenotype', 'HP:0030685', (35, 66))
732	32751097	In this study, we provide further support to the existence of an insulin-resistant state in the UMs with monosomy-3, which was associated with the onset of metastasis and reduced survival rate.	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('survival rate', 'CPA', (179, 192))	('insulin', 'molecular_function', 'GO:0016088', ('65', '72'))	('insulin-resistant state', 'Phenotype', 'HP:0000831', (65, 88))	('monosomy-3', 'Var', (105, 115))	('insulin', 'Gene', (65, 72))	('insulin', 'Gene', '3630', (65, 72))	('reduced', 'NegReg', (171, 178))
757	32751097	The less efficient upregulation of the GYG2 isoform in the male versus female patients in response to the loss of GYG1 (Locus: 3q24) in the monosomy-3 tumors may therefore be contributing to the worse prognosis of the former group by impairing the synthesis of normal glycogen, which deserves further investigation.	('contributing', 'Reg', (175, 187))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('glycogen', 'Chemical', 'MESH:D006003', (268, 276))	('patients', 'Species', '9606', (78, 86))	('synthesis', 'biological_process', 'GO:0009058', ('248', '257'))	('upregulation', 'PosReg', (19, 31))	('monosomy-3', 'Var', (140, 150))	('less', 'NegReg', (4, 8))	('GYG2', 'Gene', '8908', (39, 43))	('GYG2', 'Gene', (39, 43))	('GYG1', 'Gene', (114, 118))	('impairing', 'NegReg', (234, 243))	('loss', 'Var', (106, 110))	('synthesis of normal glycogen', 'MPA', (248, 276))
759	32751097	Nevertheless, the co-occurrence of such small changes that affect multiple steps of the glycogen metabolism might be exerting a cumulative effect on this event.	('affect', 'Reg', (59, 65))	('changes', 'Var', (46, 53))	('glycogen metabolism', 'biological_process', 'GO:0005977', ('88', '107'))	('glycogen', 'Chemical', 'MESH:D006003', (88, 96))	('glycogen metabolism', 'MPA', (88, 107))
762	32751097	Our differential PAS-stainings provided additional support to the findings of the gene expression analysis and demonstrated lower levels of the amylase-sensitive glycogen in the primary UMs with monosomy-3, which was also associated with the development of metastases.	('metastases', 'Disease', 'MESH:D009362', (257, 267))	('PAS', 'cellular_component', 'GO:0000407', ('17', '20'))	('UM', 'Phenotype', 'HP:0007716', (186, 188))	('glycogen', 'Chemical', 'MESH:D006003', (162, 170))	('levels', 'MPA', (130, 136))	('lower', 'NegReg', (124, 129))	('lower levels of the amylase', 'Phenotype', 'HP:0410289', (124, 151))	('gene expression', 'biological_process', 'GO:0010467', ('82', '97'))	('PAS', 'Chemical', '-', (17, 20))	('monosomy-3', 'Var', (195, 205))	('associated', 'Reg', (222, 232))	('metastases', 'Disease', (257, 267))
764	32751097	We were also not able to determine whether the formation of aberrant glycogen fibers and their possible exocytosis contributed to the extracellular vasculogenic mimicry patterns, which are usually visualized by a normal PAS staining without amylase pretreatment.	('glycogen', 'Chemical', 'MESH:D006003', (69, 77))	('exocytosis', 'MPA', (104, 114))	('formation', 'biological_process', 'GO:0009058', ('47', '56'))	('contributed', 'Reg', (115, 126))	('PAS', 'Chemical', '-', (220, 223))	('exocytosis', 'biological_process', 'GO:0006887', ('104', '114'))	('extracellular', 'cellular_component', 'GO:0005576', ('134', '147'))	('extracellular vasculogenic mimicry patterns', 'MPA', (134, 177))	('PAS', 'cellular_component', 'GO:0000407', ('220', '223'))	('aberrant', 'Var', (60, 68))
775	32751097	Aberrant forms of glycogen can indeed be generated due to the impairment of certain genes such as the GYG1 on chromosome 3q24, which encodes the glycogenin-1 protein that serves as the primer of glycogen synthesis by catalyzing the addition of glucose molecules on to itself.	('glucose', 'Chemical', 'MESH:D005947', (244, 251))	('glycogen', 'Chemical', 'MESH:D006003', (195, 203))	('GYG1', 'Gene', (102, 106))	('impairment', 'Var', (62, 72))	('glycogen', 'Chemical', 'MESH:D006003', (18, 26))	('glycogen', 'Chemical', 'MESH:D006003', (145, 153))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('protein', 'cellular_component', 'GO:0003675', ('158', '165'))	('glycogen synthesis', 'biological_process', 'GO:0005978', ('195', '213'))
776	32751097	Rather than preventing glycogen production, the silencing of Gyg1 has surprisingly led to the over-accumulation of an aberrant type of glycogen with a larger size.	('silencing', 'Var', (48, 57))	('glycogen production', 'MPA', (23, 42))	('over-accumulation', 'MPA', (94, 111))	('aberrant type of glycogen', 'MPA', (118, 143))	('Gyg1', 'Gene', (61, 65))	('glycogen', 'Chemical', 'MESH:D006003', (135, 143))	('glycogen', 'Chemical', 'MESH:D006003', (23, 31))
781	32751097	The female patients with monosomy-3 may be compensating for the deficiency of GYG1 to a certain extent by the upregulation of the Gyg2 homolog on chromosome X, while the male patients with monosomy-3 may be more restricted in this aspect, as suggested by the gene expression profiles.	('upregulation', 'PosReg', (110, 122))	('GYG1', 'Gene', (78, 82))	('Gyg2', 'Gene', '8908', (130, 134))	('deficiency', 'Var', (64, 74))	('chromosome', 'cellular_component', 'GO:0005694', ('146', '156'))	('patients', 'Species', '9606', (175, 183))	('gene expression', 'biological_process', 'GO:0010467', ('259', '274'))	('Gyg2', 'Gene', (130, 134))	('patients', 'Species', '9606', (11, 19))	('monosomy-3', 'Var', (25, 35))
782	32751097	The monosomy-3 tumors of the male patients would therefore be more inclined to store the glucose as a protein-free glycogen with an abnormal structure and accumulation rate compared to the females, that needs to be characterized in more detail.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('store', 'MPA', (79, 84))	('accumulation', 'MPA', (155, 167))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('structure', 'MPA', (141, 150))	('glucose', 'Chemical', 'MESH:D005947', (89, 96))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('glycogen', 'Chemical', 'MESH:D006003', (115, 123))	('patients', 'Species', '9606', (34, 42))	('monosomy-3', 'Var', (4, 14))	('tumors', 'Disease', (15, 21))
783	32751097	Remarkably, the aberrant, protein-free glycogen in the Gyg1-knockout mice could also induce functional consequences, such as the metabolic switch of the muscle cells towards a more glycolytic rather than oxidative phenotype despite the maintenance of normal mitochondria.	('aberrant', 'Var', (16, 24))	('mitochondria', 'cellular_component', 'GO:0005739', ('258', '270'))	('metabolic switch', 'MPA', (129, 145))	('mice', 'Species', '10090', (69, 73))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('Gyg1-knockout', 'Gene', (55, 68))	('mitochondria', 'MPA', (258, 270))	('glycogen', 'Chemical', 'MESH:D006003', (39, 47))	('induce', 'Reg', (85, 91))
786	32751097	Notably, the UM cells with monosomy-3 may be more capable of a higher rate of glucose influx, as suggested by their elevated PET-scan activity.	('elevated', 'PosReg', (116, 124))	('glucose influx', 'MPA', (78, 92))	('rate', 'MPA', (70, 74))	('glucose', 'Chemical', 'MESH:D005947', (78, 85))	('UM', 'Phenotype', 'HP:0007716', (13, 15))	('PET-scan activity', 'MPA', (125, 142))	('higher', 'PosReg', (63, 69))	('monosomy-3', 'Var', (27, 37))
787	32751097	Yet, it is still not known, how the intracellular glucose is metabolized in the UM cells and whether monosomy-3 induces a gender-specific effect on this process.	('induces', 'Reg', (112, 119))	('UM', 'Phenotype', 'HP:0007716', (80, 82))	('monosomy-3', 'Var', (101, 111))	('intracellular glucose', 'MPA', (36, 57))	('glucose', 'Chemical', 'MESH:D005947', (50, 57))	('intracellular', 'cellular_component', 'GO:0005622', ('36', '49'))
788	32751097	In our study, the prevalence of CMCs with monosomy-3 was higher in the female versus male patients who did not develop metastases, suggesting that the CMCs of the female patients may be possessing less metastatic potential despite the presence of monosomy-3.	('patients', 'Species', '9606', (170, 178))	('less', 'NegReg', (197, 201))	('metastases', 'Disease', (119, 129))	('patients', 'Species', '9606', (90, 98))	('monosomy-3', 'Var', (247, 257))	('metastatic potential', 'CPA', (202, 222))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
789	32751097	In contrast, the male patients with monosomy-3 positive CMCs were significantly more likely to develop metastases.	('metastases', 'Disease', 'MESH:D009362', (103, 113))	('patients', 'Species', '9606', (22, 30))	('monosomy-3 positive', 'Var', (36, 55))	('develop', 'PosReg', (95, 102))	('metastases', 'Disease', (103, 113))
791	32751097	A possible reason accounting for the more aggressive growth potential of the male UM cells with monosomy-3 may indeed be the storage of excessive glucose as an aberrant, protein-free glycogen due to the deficiency of both GYG1 and GYG2 on chromosomes 3 and X, respectively.	('monosomy-3', 'Var', (96, 106))	('storage', 'biological_process', 'GO:0051235', ('125', '132'))	('deficiency of both GYG1', 'Disease', 'OMIM:613507', (203, 226))	('glucose', 'Chemical', 'MESH:D005947', (146, 153))	('deficiency of both GYG1', 'Disease', (203, 226))	('glycogen', 'Chemical', 'MESH:D006003', (183, 191))	('UM', 'Phenotype', 'HP:0007716', (82, 84))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('GYG2', 'Gene', '8908', (231, 235))	('excessive glucose', 'Phenotype', 'HP:0003074', (136, 153))	('GYG2', 'Gene', (231, 235))
792	32751097	The over-accumulation of this abnormal glycogen might then be inducing a glycolytic switch that would enable the faster growth of the male UM cells with monosomy-3 particularly when the extracellular glucose is highly abundant such as during hyperglycemia, which urgently deserves further investigation.	('monosomy-3', 'Var', (153, 163))	('glucose', 'Chemical', 'MESH:D005947', (200, 207))	('hyperglycemia', 'Disease', (242, 255))	('inducing', 'Reg', (62, 70))	('UM', 'Phenotype', 'HP:0007716', (139, 141))	('extracellular', 'cellular_component', 'GO:0005576', ('186', '199'))	('hyperglycemia', 'Disease', 'MESH:D006943', (242, 255))	('hyperglycemia', 'Phenotype', 'HP:0003074', (242, 255))	('glycolytic switch', 'MPA', (73, 90))	('glycogen', 'Chemical', 'MESH:D006003', (39, 47))	('faster', 'PosReg', (113, 119))	('enable', 'PosReg', (102, 108))	('over-accumulation', 'PosReg', (4, 21))
797	32751097	Under such hyperglycemic conditions, the disseminated UM cells with monosomy-3 or their dormant micrometastases in the liver may become more activated due to their impaired ability to store glucose as normal glycogen.	('metastases', 'Disease', (101, 111))	('glucose', 'Chemical', 'MESH:D005947', (190, 197))	('monosomy-3', 'Var', (68, 78))	('store glucose', 'MPA', (184, 197))	('metastases', 'Disease', 'MESH:D009362', (101, 111))	('glycogen', 'Chemical', 'MESH:D006003', (208, 216))	('UM', 'Phenotype', 'HP:0007716', (54, 56))	('ability', 'MPA', (173, 180))	('activated', 'PosReg', (141, 150))	('impaired', 'NegReg', (164, 172))
798	32751097	The monosomy-3 positive UM cells of the male patients may acquire a further growth advantage by the induction of a glycolytic switch via the accumulation of an aberrant form of protein-free glycogen as suggested above.	('UM', 'Phenotype', 'HP:0007716', (24, 26))	('protein-free glycogen', 'MPA', (177, 198))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('glycogen', 'Chemical', 'MESH:D006003', (190, 198))	('patients', 'Species', '9606', (45, 53))	('accumulation', 'PosReg', (141, 153))	('growth', 'MPA', (76, 82))	('glycolytic switch', 'MPA', (115, 132))	('monosomy-3 positive', 'Var', (4, 23))
800	32751097	The dormant UM cells with monosomy-3 may thereby be benefiting from an abnormal glucose release from the liver in a gender-dependent manner and growing unproportionally faster via a glycolytic switch, which may also be accounting for the very short survival time of the UM-patients with clinically detectable (macro)-metastases in the liver.	('abnormal glucose', 'Phenotype', 'HP:0001952', (71, 87))	('patients', 'Species', '9606', (273, 281))	('metastases', 'Disease', (317, 327))	('glucose', 'Chemical', 'MESH:D005947', (80, 87))	('metastases', 'Disease', 'MESH:D009362', (317, 327))	('monosomy-3', 'Var', (26, 36))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('UM', 'Phenotype', 'HP:0007716', (270, 272))	('faster', 'PosReg', (169, 175))	('glucose release', 'MPA', (80, 95))
819	32751097	Image deconvolution was then performed using the Fiji software to separate the layers of PAS reaction and pigmentation with minimal overlap using the following, user-defined red (R), green (G), and blue (B) values: magenta for PAS (R1: 0.182, G1: 0.969, B1: 0.169); brown for the pigmentation (R3: 0.446, G3: 0.616, B3: 0.649); and blue-green for background (R2: 0.776, G2: 0.501, B2: 0.382).	('PAS', 'Chemical', '-', (227, 230))	('pigmentation', 'Disease', 'MESH:D010859', (106, 118))	('pigmentation', 'Disease', (106, 118))	('PAS', 'cellular_component', 'GO:0000407', ('227', '230'))	('PAS', 'Chemical', '-', (89, 92))	('pigmentation', 'biological_process', 'GO:0043473', ('280', '292'))	('pigmentation', 'biological_process', 'GO:0043473', ('106', '118'))	('pigmentation', 'Disease', 'MESH:D010859', (280, 292))	('R3', 'Var', (294, 296))	('pigmentation', 'Disease', (280, 292))	('PAS', 'cellular_component', 'GO:0000407', ('89', '92'))
839	32751097	In conclusion, our findings provide the first insight into the monosomy-3-dependent alterations in the glycogen metabolism of UM cells, which may be providing a growth advantage particularly in the male patients under hyperglycemic conditions.	('glycogen metabolism', 'MPA', (103, 122))	('growth advantage', 'PosReg', (161, 177))	('glycogen metabolism', 'biological_process', 'GO:0005977', ('103', '122'))	('glycogen', 'Chemical', 'MESH:D006003', (103, 111))	('alterations', 'Reg', (84, 95))	('patients', 'Species', '9606', (203, 211))	('UM', 'Phenotype', 'HP:0007716', (126, 128))	('monosomy-3-dependent', 'Var', (63, 83))
853	32781746	Other genetic aberrations, including gains of chromosome 8q, and inactivating mutations of BRCA1 associated protein (BAP1) gene have been correlated to a high metastatic risk and hence poor outcome.	('BRCA1 associated protein', 'Gene', (91, 115))	('BAP1', 'Gene', '8314', (117, 121))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('inactivating mutations', 'Var', (65, 87))	('gains', 'PosReg', (37, 42))	('BRCA1 associated protein', 'Gene', '8315', (91, 115))	('BAP1', 'Gene', (117, 121))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
854	32781746	Mutually exclusive mutations in two other genes, eukaryotic translation initiation factor 1A (EIF1AX) and splicing factor 3 subunit 1 (SF3B1), have allowed further subdivision of the low metastatic risk D3 group, with EIF1AX mutations associated with non-metastasising tumours, whereas SF3B1 mutations are associated with a delayed metastatic onset (intermediate risk).	('EIF1AX', 'Gene', '1964', (94, 100))	('non-metastasising tumours', 'Disease', (251, 276))	('EIF1AX', 'Gene', (94, 100))	('associated with', 'Reg', (235, 250))	('mutations', 'Var', (225, 234))	('EIF1AX', 'Gene', '1964', (218, 224))	('EIF1AX', 'Gene', (218, 224))	('SF3B1', 'Gene', '10291', (286, 291))	('SF3B1', 'Gene', (286, 291))	('non-metastasising tumours', 'Disease', 'MESH:D009369', (251, 276))	('tumour', 'Phenotype', 'HP:0002664', (269, 275))	('SF3B1', 'Gene', '10291', (135, 140))	('SF3B1', 'Gene', (135, 140))	('tumours', 'Phenotype', 'HP:0002664', (269, 276))	('splicing', 'biological_process', 'GO:0045292', ('106', '114'))	('splicing factor 3 subunit 1', 'Gene', (106, 133))	('splicing factor 3 subunit 1', 'Gene', '10291', (106, 133))	('translation initiation', 'biological_process', 'GO:0006413', ('60', '82'))
855	32781746	UM are initiated by a gain-of-function driver mutation in GNAQ or GNA11 G-protein coupled receptors in almost 80% of cases, most frequently at the Q209 position and less frequently at the R183 position.	('gain-of-function', 'PosReg', (22, 38))	('GNAQ', 'Gene', '2776', (58, 62))	('Q209', 'Var', (147, 151))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('GNA11', 'Gene', (66, 71))	('GNAQ', 'Gene', (58, 62))	('GNA11', 'Gene', '2767', (66, 71))	('G-protein coupled receptors', 'Protein', (72, 99))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
859	32781746	Aberrant microRNA (miRNA) expression, frequently observed in a myriad of cancers, is also reported in UM.	('miR', 'Gene', '220972', (19, 22))	('cancers', 'Disease', (73, 80))	('miR', 'Gene', (19, 22))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('microRNA', 'Protein', (9, 17))	('UM', 'Phenotype', 'HP:0007716', (102, 104))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
862	32781746	This review explores aberrant miRNA expression in UM and maps these to signalling pathways that appear to regulate UM growth and could be exploited as future drug targets.	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('aberrant', 'Var', (21, 29))	('UM', 'Phenotype', 'HP:0007716', (115, 117))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('signalling', 'biological_process', 'GO:0023052', ('71', '81'))
873	32781746	This can be attributed to genetic loss, epigenetic silencing and defects in signalling pathways, resulting in reduced mature miRNA levels.	('genetic loss', 'Disease', 'MESH:D030342', (26, 38))	('genetic loss', 'Disease', (26, 38))	('reduced', 'NegReg', (110, 117))	('signalling', 'biological_process', 'GO:0023052', ('76', '86'))	('miR', 'Gene', '220972', (125, 128))	('epigenetic silencing', 'Var', (40, 60))	('defects', 'NegReg', (65, 72))	('signalling pathways', 'Pathway', (76, 95))	('miR', 'Gene', (125, 128))
881	32781746	Most recently, a TCGA-UM study, which analysed 80 primary UM samples, identified four main miRNA clusters that were clearly associated with chromosome 3 status, metastatic risk and corresponding DNA methylation profile.	('miR', 'Gene', (91, 94))	('DNA methylation', 'biological_process', 'GO:0006306', ('195', '210'))	('associated', 'Reg', (124, 134))	('UM', 'Phenotype', 'HP:0007716', (22, 24))	('chromosome', 'Var', (140, 150))	('metastatic', 'Disease', (161, 171))	('chromosome', 'cellular_component', 'GO:0005694', ('140', '150'))	('DNA', 'cellular_component', 'GO:0005574', ('195', '198'))	('UM', 'Phenotype', 'HP:0007716', (58, 60))	('miR', 'Gene', '220972', (91, 94))
931	32781746	These provide evidence that epigenetic regulation of miRNAs by other mechanisms, adds an additional layer in the complexity of signalling pathway regulation.	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', (53, 56))	('regulation', 'biological_process', 'GO:0065007', ('39', '49'))	('signalling pathway', 'biological_process', 'GO:0007165', ('127', '145'))	('epigenetic regulation', 'Var', (28, 49))	('regulation', 'biological_process', 'GO:0065007', ('146', '156'))
932	32781746	When undertaking any miRNA scientific study, the ultimate goal will either be a functional outcome for potential epigenetic modification or drug targeting, or as a biomarker for prognosis and diagnosis.	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('drug targeting', 'Var', (140, 154))	('epigenetic modification', 'Var', (113, 136))
933	32781746	In UM, chromosomal mutations and genetic aberrations in the primary tumour can predict with relatively high accuracy whether a UM has a low or high risk of metastasis.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('chromosomal mutations', 'Var', (7, 28))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('tumour', 'Disease', (68, 74))	('genetic aberrations', 'Var', (33, 52))	('UM', 'Phenotype', 'HP:0007716', (127, 129))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
978	32827765	Amplification or overexpression of BET proteins has been identified in breast tumors highlighting their clinical significance.	('breast tumors', 'Phenotype', 'HP:0100013', (71, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('Amplification', 'Var', (0, 13))	('breast tumors', 'Disease', 'MESH:D001943', (71, 84))	('BET proteins', 'Protein', (35, 47))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('breast tumors', 'Disease', (71, 84))	('overexpression', 'PosReg', (17, 31))
989	32827765	During carcinogenesis, extensive epigenetic modifications occur, including aberrant acetylation and methylation patterns.	('aberrant', 'Var', (75, 83))	('acetylation', 'MPA', (84, 95))	('carcinogenesis', 'Disease', 'MESH:D063646', (7, 21))	('carcinogenesis', 'Disease', (7, 21))	('methylation patterns', 'MPA', (100, 120))	('methylation', 'biological_process', 'GO:0032259', ('100', '111'))
1026	32827765	Depletion of BRD4 disrupted the E2-dependent transcription, mimicking JQ1 activity.	('BRD4', 'Gene', (13, 17))	('Depletion', 'Var', (0, 9))	('E2-dependent transcription', 'MPA', (32, 58))	('transcription', 'biological_process', 'GO:0006351', ('45', '58'))	('disrupted', 'NegReg', (18, 27))	('E2', 'Chemical', 'MESH:D004958', (32, 34))
1029	32827765	Subsequently, WHSC1 methylates K36 on histone H3 so as to activate the transcription of ESR1, while estrogen binding to ERa stimulates the expression of WHSC1, creating a vicious cycle.	('WHSC1', 'Gene', (14, 19))	('transcription', 'biological_process', 'GO:0006351', ('71', '84'))	('stimulates', 'PosReg', (124, 134))	('methylates', 'Var', (20, 30))	('activate', 'PosReg', (58, 66))	('ER', 'Gene', '2069', (120, 122))	('ESR1', 'Gene', '2099', (88, 92))	('ESR1', 'Gene', (88, 92))	('WHSC1', 'Gene', '7468', (14, 19))	('WHSC1', 'Gene', '7468', (153, 158))	('K36', 'Gene', '8689', (31, 34))	('estrogen binding', 'molecular_function', 'GO:0099130', ('100', '116'))	('expression', 'MPA', (139, 149))	('WHSC1', 'Gene', (153, 158))	('transcription', 'MPA', (71, 84))	('K36', 'Gene', (31, 34))
1031	32827765	As a result, JQ1 efficiently inhibited proliferation of tamoxifen-resistant ER + cell lines as well as that of four long-term estrogen deprived lines (mimicking aromatase inhibitor resistance), mainly by inducing prolonged G1 cell cycle arrest.	('inhibited', 'NegReg', (29, 38))	('arrest', 'Disease', (237, 243))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('226', '243'))	('proliferation', 'CPA', (39, 52))	('JQ1', 'Var', (13, 16))	('tamoxifen', 'Chemical', 'MESH:D013629', (56, 65))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (226, 243))	('inducing', 'Reg', (204, 212))	('ER', 'Gene', '2069', (76, 78))	('arrest', 'Disease', 'MESH:D006323', (237, 243))
1033	32827765	Moreover, abundant BRD4 occupancy to MYC results in upregulation of MYC-related genes and drives resistance to mTOR inhibition BET inhibition reverses this BRD4-mediated resistance, sensitizing breast cells to mTOR inhibitors Furthermore, BRD3 is enriched at active ESR1 enhancers leading to significantly higher levels of transcription and E2 responsiveness.	('mTOR', 'Gene', (210, 214))	('ESR1', 'Gene', '2099', (266, 270))	('BRD4', 'Gene', (19, 23))	('occupancy', 'Var', (24, 33))	('BRD3', 'Gene', '8019', (239, 243))	('ESR1', 'Gene', (266, 270))	('mTOR', 'Gene', '2475', (210, 214))	('E2', 'Chemical', 'MESH:D004958', (341, 343))	('MYC', 'Gene', '4609', (37, 40))	('MYC', 'Gene', '4609', (68, 71))	('levels of transcription', 'MPA', (313, 336))	('higher', 'PosReg', (306, 312))	('transcription', 'biological_process', 'GO:0006351', ('323', '336'))	('mTOR', 'Gene', (111, 115))	('E2 responsiveness', 'MPA', (341, 358))	('upregulation', 'PosReg', (52, 64))	('mTOR', 'Gene', '2475', (111, 115))	('BRD3', 'Gene', (239, 243))	('MYC', 'Gene', (37, 40))	('MYC', 'Gene', (68, 71))
1034	32827765	Overall, high expression of BRDs seems to correlate with poor overall survival in ER + breast cancer.	('overall', 'MPA', (62, 69))	('poor', 'NegReg', (57, 61))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('ER', 'Gene', '2069', (82, 84))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('BRDs', 'Protein', (28, 32))	('high', 'Var', (9, 13))
1036	32827765	Providing in vivo evidence, JQ1-injected mice exhibited substantial decrease in uterine growth as a sign of reduced estrogen signaling.	('estrogen signaling', 'MPA', (116, 134))	('JQ1-injected', 'Var', (28, 40))	('reduced', 'NegReg', (108, 115))	('decrease', 'NegReg', (68, 76))	('mice', 'Species', '10090', (41, 45))	('uterine growth', 'CPA', (80, 94))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))
1039	32827765	JQ1 inhibited growth of TNBC lines either of the basal-like (HCC1143, MDA-MB-468, HCC70) or of the claudin-low (MDA-MB-231, BT549, HCC38) population in several studies.	('HCC1143', 'CellLine', 'CVCL:1245', (61, 68))	('BT549', 'CellLine', 'CVCL:1092', (124, 129))	('growth', 'CPA', (14, 20))	('inhibited', 'NegReg', (4, 13))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (70, 80))	('JQ1', 'Var', (0, 3))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (112, 122))
1041	32827765	JQ1 induces cell cycle arrest at G1 phase, as indicated by the elevated p21, p27 and cyclin D1, D3 levels.	('cyclin D1, D3', 'Gene', '595;896', (85, 98))	('arrest', 'Disease', (23, 29))	('G1 phase', 'biological_process', 'GO:0051318', ('33', '41'))	('cyclin', 'molecular_function', 'GO:0016538', ('85', '91'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (12, 29))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('12', '29'))	('p21', 'Gene', (72, 75))	('arrest', 'Disease', 'MESH:D006323', (23, 29))	('p21', 'Gene', '644914', (72, 75))	('JQ1', 'Var', (0, 3))	('p27', 'Gene', '3429', (77, 80))	('elevated', 'PosReg', (63, 71))	('p27', 'Gene', (77, 80))
1046	32827765	In consistence with these findings, either BCL-xL knockdown or combination of JQ1 and Obatoclax, an inhibitor of Bcl-2 family of proteins, reduced cell viability and increased the number of apoptotic cells.	('cell viability', 'CPA', (147, 161))	('knockdown', 'Var', (50, 59))	('increased', 'PosReg', (166, 175))	('BCL-xL', 'Gene', '598', (43, 49))	('Bcl-2', 'molecular_function', 'GO:0015283', ('113', '118'))	('reduced', 'NegReg', (139, 146))	('Bcl-2', 'Gene', (113, 118))	('Bcl-2', 'Gene', '596', (113, 118))	('BCL-xL', 'Gene', (43, 49))	('JQ1', 'Gene', (78, 81))
1049	32827765	However, JQ1 attenuated the expression of many transcription factors, as Forkhead box M1 (FOXM1), Lim domain only 4 (LM04) and DEP domain containing 1 (DEPDC).	('attenuated', 'NegReg', (13, 23))	('Forkhead box M1', 'Gene', '2305', (73, 88))	('FOXM1', 'Gene', '2305', (90, 95))	('FOXM1', 'Gene', (90, 95))	('DEP domain containing 1', 'Gene', '55635', (127, 150))	('JQ1', 'Var', (9, 12))	('expression', 'MPA', (28, 38))	('Forkhead box M1', 'Gene', (73, 88))	('DEP domain containing 1', 'Gene', (127, 150))	('transcription', 'biological_process', 'GO:0006351', ('47', '60'))	('Lim domain only 4', 'Gene', (98, 115))	('Lim domain only 4', 'Gene', '8543', (98, 115))
1054	32827765	However, LIN9 appears to be the most profound since knockdown of either FOXM1 or MYBL2 did not produce the same effect.	('FOXM1', 'Gene', (72, 77))	('LIN9', 'Gene', (9, 13))	('MYBL2', 'Gene', '4605', (81, 86))	('MYBL2', 'Gene', (81, 86))	('knockdown', 'Var', (52, 61))	('LIN9', 'Gene', '286826', (9, 13))	('FOXM1', 'Gene', '2305', (72, 77))
1060	32827765	An AURKA inhibitor, MLN8237 (Alisertib) also exhibited the same antiproliferative activity with JQ1 in TNBC cells.	('antiproliferative', 'MPA', (64, 81))	('AURKA', 'Gene', (3, 8))	('MLN8237', 'Chemical', 'MESH:C550258', (20, 27))	('MLN8237', 'Var', (20, 27))	('Alisertib', 'Chemical', 'MESH:C550258', (29, 38))	('AURKA', 'Gene', '6790', (3, 8))
1062	32827765	Moreover, JQ1 disrupts Twist and BRD4 interaction and Twist/BRD4/P-TEFb/RNA-PolII complex formation at the WNT5 promoter.	('Twist', 'Gene', (54, 59))	('BRD4', 'Protein', (33, 37))	('formation', 'biological_process', 'GO:0009058', ('90', '99'))	('disrupts', 'NegReg', (14, 22))	('RNA', 'cellular_component', 'GO:0005562', ('72', '75'))	('Twist', 'Gene', '7291', (23, 28))	('JQ1', 'Var', (10, 13))	('Twist', 'Gene', '7291', (54, 59))	('Twist', 'Gene', (23, 28))
1066	32827765	In the same context, BRD4 is essential for basal epithelial phenotype by promoting the expression of epithelial-specific genes, such as TP63 gene and GRHL3, a transcription factor of the Grainyhead-like family.	('transcription factor', 'molecular_function', 'GO:0000981', ('159', '179'))	('promoting', 'PosReg', (73, 82))	('transcription', 'biological_process', 'GO:0006351', ('159', '172'))	('TP63', 'Gene', '8626', (136, 140))	('TP63', 'Gene', (136, 140))	('expression', 'MPA', (87, 97))	('BRD4', 'Var', (21, 25))	('GRHL3', 'Gene', (150, 155))	('GRHL3', 'Gene', '57822', (150, 155))
1070	32827765	Homologous recombination (HR) efficiency and formation of single-stranded DNA by BRCA1 upon DNA damage are both impaired by BETi treatment Considering that BRCA1/2 mutated breast cancer patients demonstrated a better overall response rate to carboplatin in clinical trials, BETi treatment could synergize with platinum therapy.	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('platinum', 'Chemical', 'MESH:D010984', (310, 318))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('BETi', 'Chemical', '-', (124, 128))	('better', 'PosReg', (210, 216))	('BRCA1/2', 'Gene', (156, 163))	('breast cancer', 'Disease', (172, 185))	('carboplatin', 'Chemical', 'MESH:D016190', (242, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('formation', 'biological_process', 'GO:0009058', ('45', '54'))	('mutated', 'Var', (164, 171))	('BETi', 'Chemical', '-', (274, 278))	('BRCA1/2', 'Gene', '672;675', (156, 163))	('Homologous recombination', 'biological_process', 'GO:0035825', ('0', '24'))	('patients', 'Species', '9606', (186, 194))
1071	32827765	Not only BET inhibition leads to a BRCA-mutant like phenotype, but also BRCA1 mutation sensitizes TNBC tumors to BET inhibitors.	('sensitizes', 'Reg', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mutation', 'Var', (78, 86))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('BRCA', 'Gene', '672', (72, 76))	('TNBC tumors', 'Disease', 'MESH:D009369', (98, 109))	('BRCA', 'Gene', (35, 39))	('BRCA', 'Gene', '672', (35, 39))	('BRCA', 'Gene', (72, 76))	('TNBC tumors', 'Disease', (98, 109))
1075	32827765	As already established in prostate cancer, JQ1 disrupted interaction of BRD4 and androgen receptor (AR), providing an effect that could be exploited in AR + TNBC breast cancer treatment.	('BRD4', 'Gene', (72, 76))	('androgen receptor', 'Gene', '367', (81, 98))	('TNBC breast cancer', 'Disease', 'MESH:D001943', (157, 175))	('AR', 'Gene', '367', (100, 102))	('AR', 'Gene', '367', (152, 154))	('prostate cancer', 'Disease', (26, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('disrupted', 'NegReg', (47, 56))	('TNBC breast cancer', 'Disease', (157, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('androgen receptor', 'Gene', (81, 98))	('JQ1', 'Var', (43, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('interaction', 'Interaction', (57, 68))	('prostate cancer', 'Disease', 'MESH:D011471', (26, 41))	('prostate cancer', 'Phenotype', 'HP:0012125', (26, 41))
1076	32827765	Indeed, JQ1 demonstrated a dose-dependent antitumor efficacy in AR + TNBC cell lines and xenograft model, which was further enhanced by addition of enzalutamide in vitro but not in vivo.	('JQ1', 'Var', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('enzalutamide', 'Chemical', 'MESH:C540278', (148, 160))	('tumor', 'Disease', (46, 51))	('AR', 'Gene', '367', (64, 66))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
1077	32827765	JQ1 did not directly downregulate AR expression, but rather inhibited interactions between ATAD2, a co-activator of AR, with BRD4 and AR complex, suppressing the transcription of AR-induced genes.	('ATAD2', 'Gene', '29028', (91, 96))	('AR', 'Gene', '367', (116, 118))	('transcription', 'biological_process', 'GO:0006351', ('162', '175'))	('inhibited', 'NegReg', (60, 69))	('AR', 'Gene', '367', (134, 136))	('transcription', 'MPA', (162, 175))	('interactions', 'Interaction', (70, 82))	('JQ1', 'Var', (0, 3))	('AR', 'Gene', '367', (34, 36))	('suppressing', 'NegReg', (146, 157))	('ATAD2', 'Gene', (91, 96))	('AR', 'Gene', '367', (179, 181))
1078	32827765	Finally, BET inhibition disrupted hypoxia response and angiogenesis in triple negative breast cancer via downregulation of hypoxia-induced genes.	('hypoxia', 'Disease', 'MESH:D000860', (123, 130))	('downregulation', 'NegReg', (105, 119))	('inhibition', 'Var', (13, 23))	('angiogenesis', 'biological_process', 'GO:0001525', ('55', '67'))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('hypoxia', 'Disease', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('hypoxia', 'Disease', (34, 41))	('disrupted', 'NegReg', (24, 33))	('hypoxia', 'Disease', 'MESH:D000860', (34, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('angiogenesis', 'CPA', (55, 67))
1079	32827765	JQ1 altered the expression of multiple hypoxia-induced genes, including hypoxia-inducible factor (HIF) genes, carbonic anhydrase 9 (CA9) and vascular endothelial growth factor A (VEGF-A).	('HIF', 'Disease', 'None', (98, 101))	('vascular endothelial growth factor A', 'Gene', '7422', (141, 177))	('altered', 'Reg', (4, 11))	('hypoxia', 'Disease', (39, 46))	('hypoxia', 'Disease', 'MESH:D000860', (39, 46))	('vascular endothelial growth factor A', 'Gene', (141, 177))	('carbonic anhydrase 9', 'Gene', (110, 130))	('VEGF-A', 'Gene', '7422', (179, 185))	('VEGF-A', 'Gene', (179, 185))	('carbonic anhydrase 9', 'Gene', '768', (110, 130))	('CA9', 'Gene', (132, 135))	('hypoxia', 'Disease', (72, 79))	('hypoxia', 'Disease', 'MESH:D000860', (72, 79))	('JQ1', 'Var', (0, 3))	('HIF', 'Disease', (98, 101))	('CA9', 'Gene', '768', (132, 135))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('141', '175'))	('expression', 'MPA', (16, 26))
1081	32827765	As far as metastatic ability is concerned, JQ1 reduced migration of two TNBC cell lines via impairing Jagged/Notch1 signaling pathway.	('migration', 'CPA', (55, 64))	('impairing', 'NegReg', (92, 101))	('signaling pathway', 'biological_process', 'GO:0007165', ('116', '133'))	('JQ1', 'Var', (43, 46))	('reduced', 'NegReg', (47, 54))	('Notch1', 'Gene', '4851', (109, 115))	('Notch1', 'Gene', (109, 115))
1087	32827765	Clinical trials demonstrated an increased response to carboplatin in BRCA1/2 mutated TNBC population (41).	('BRCA1/2', 'Gene', (69, 76))	('TNBC', 'Gene', (85, 89))	('mutated', 'Var', (77, 84))	('BRCA1/2', 'Gene', '672;675', (69, 76))	('response to carboplatin', 'biological_process', 'GO:0097328', ('42', '65'))	('increased', 'PosReg', (32, 41))	('response', 'MPA', (42, 50))	('carboplatin', 'Chemical', 'MESH:D016190', (54, 65))
1090	32827765	BET inhibition increased sensitivity of BRCA wild-type TNBC cells to treatment with Olaparib both in vitro and in vivo via inducing a BRCA mutant-like phenotype.	('Olaparib', 'Chemical', 'MESH:C531550', (84, 92))	('BRCA', 'Gene', '672', (134, 138))	('sensitivity', 'MPA', (25, 36))	('BRCA', 'Gene', (134, 138))	('mutant-like', 'Var', (139, 150))	('increased', 'PosReg', (15, 24))	('BRCA', 'Gene', '672', (40, 44))	('BRCA', 'Gene', (40, 44))	('inhibition', 'NegReg', (4, 14))	('inducing', 'Reg', (123, 131))
1091	32827765	JQ1 attenuated proliferation of tamoxifen-resistant ER + cells at a greater extent comparing to parental cells, by reducing BRD3/4 recruitment to ERa promoter.	('tamoxifen', 'Chemical', 'MESH:D013629', (32, 41))	('ER', 'Gene', '2069', (146, 148))	('attenuated', 'NegReg', (4, 14))	('BRD3/4', 'Gene', '8019;23476', (124, 130))	('recruitment', 'MPA', (131, 142))	('BRD3/4', 'Gene', (124, 130))	('proliferation', 'CPA', (15, 28))	('JQ1', 'Var', (0, 3))	('reducing', 'NegReg', (115, 123))	('ER', 'Gene', '2069', (52, 54))
1092	32827765	In addition to this, ENST00000456526 is a long noncoding RNA, namely LOL (lncRNA of luminal), which is overexpressed in luminal breast cancer.	('ENST00000456526', 'Var', (21, 36))	('luminal breast cancer', 'Disease', 'MESH:D001943', (120, 141))	('RNA', 'cellular_component', 'GO:0005562', ('57', '60'))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('luminal', 'Chemical', 'MESH:D010634', (84, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('luminal breast cancer', 'Disease', (120, 141))	('luminal', 'Chemical', 'MESH:D010634', (120, 127))
1101	32827765	Resistance to PI3K inhibition is often mediated by feedback activation of alternative tyrosine kinase receptors (RTKs), like AKT and mTOR pathways, despite the initial response.	('PI3K', 'Var', (14, 18))	('PI3K', 'molecular_function', 'GO:0016303', ('14', '18'))	('mTOR', 'Gene', '2475', (133, 137))	('activation', 'PosReg', (60, 70))	('mTOR', 'Gene', (133, 137))	('AKT', 'Pathway', (125, 128))
1110	32827765	BET inhibition increased sensitivity to lapatinib in HER2+ cell lines and HER2+ xenograft models by decreasing lapatinib-induced MYC upregulation without affecting FOXO levels.	('sensitivity', 'MPA', (25, 36))	('HER2', 'Gene', (74, 78))	('MYC', 'Gene', '4609', (129, 132))	('lapatinib', 'Chemical', 'MESH:D000077341', (111, 120))	('HER2', 'Gene', (53, 57))	('increased', 'PosReg', (15, 24))	('inhibition', 'Var', (4, 14))	('HER2', 'Gene', '2064', (74, 78))	('HER2', 'Gene', '2064', (53, 57))	('lapatinib', 'Chemical', 'MESH:D000077341', (40, 49))	('MYC', 'Gene', (129, 132))	('decreasing', 'NegReg', (100, 110))
1113	32827765	This resistance mechanism was blocked by BET inhibition through dissociation of BRD4 and thus RNA PolII from lapatinib-induced kinase genes.	('lapatinib', 'Chemical', 'MESH:D000077341', (109, 118))	('RNA', 'cellular_component', 'GO:0005562', ('94', '97'))	('dissociation', 'Var', (64, 76))	('BRD4', 'Gene', (80, 84))
1115	32827765	On the other hand, inhibition of AKT suppresses FOXO3a phosphorylation, allowing its nuclear translocation and its interaction with BD2 domain of BRD4.	('phosphorylation', 'biological_process', 'GO:0016310', ('55', '70'))	('inhibition', 'Var', (19, 29))	('suppresses', 'NegReg', (37, 47))	('AKT', 'Pathway', (33, 36))	('BD2', 'Gene', (132, 135))	('BD2', 'Gene', '1673', (132, 135))	('FOXO3a', 'Gene', '2309', (48, 54))	('FOXO3a', 'Gene', (48, 54))	('phosphorylation', 'MPA', (55, 70))	('interaction', 'Interaction', (115, 126))	('nuclear translocation', 'MPA', (85, 106))	('BRD4', 'Gene', (146, 150))
1127	32827765	Combination treatment with GSK2801 and JQ1 exhibited increased efficacy in a series of TNBC cell lines, by causing BRD2 dissociation from promoter and enhancer regions additionally to JQ-1-induced BRD4 loss.	('BRD4 loss', 'Disease', 'MESH:D014786', (197, 206))	('BRD4 loss', 'Disease', (197, 206))	('GSK2801', 'Var', (27, 34))	('GSK', 'molecular_function', 'GO:0050321', ('27', '30'))	('dissociation', 'MPA', (120, 132))	('BRD2', 'Gene', '6046', (115, 119))	('BRD2', 'Gene', (115, 119))	('GSK2801', 'Chemical', 'MESH:C000609271', (27, 34))
1130	32827765	PIK3CA mutation is associated with resistance to BET inhibition.	('associated', 'Reg', (19, 29))	('resistance to BET inhibition', 'MPA', (35, 63))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutation', 'Var', (7, 15))
1131	32827765	A66, a PIK3CA inhibitor increased susceptibility to JQ1 treatment.	('PIK3CA', 'Gene', (7, 13))	('PIK3CA', 'Gene', '5290', (7, 13))	('increased', 'PosReg', (24, 33))	('susceptibility', 'MPA', (34, 48))	('A66', 'Var', (0, 3))
1133	32827765	ABT737, an anti-BCL-xL molecule sensitized cells to JQ1 and enhanced its activity.	('ABT737', 'Var', (0, 6))	('ABT737', 'Chemical', 'MESH:C501332', (0, 6))	('activity', 'MPA', (73, 81))	('sensitized', 'Reg', (32, 42))	('enhanced', 'PosReg', (60, 68))	('BCL-xL', 'Gene', (16, 22))	('BCL-xL', 'Gene', '598', (16, 22))
1135	32827765	Another mechanism of BETi resistance is the inactivation of the PP2A phosphatase tumor suppressor gene, which results in hyperphosphorylation of BRD4 and increased binding of BRD4 to MED1.	('binding', 'molecular_function', 'GO:0005488', ('164', '171'))	('inactivation', 'Var', (44, 56))	('MED1', 'Gene', '5469', (183, 187))	('PP2A', 'Gene', '5524', (64, 68))	('BRD4', 'Gene', (145, 149))	('phosphatase', 'molecular_function', 'GO:0016791', ('69', '80'))	('hyperphosphorylation', 'MPA', (121, 141))	('increased', 'PosReg', (154, 163))	('BETi', 'Chemical', '-', (21, 25))	('tumor', 'Disease', (81, 86))	('hyperphosphorylation', 'biological_process', 'GO:0048151', ('121', '141'))	('PP2A', 'Gene', (64, 68))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('81', '97'))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor suppressor', 'biological_process', 'GO:0051726', ('81', '97'))	('BRD4', 'Protein', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('MED1', 'Gene', (183, 187))	('binding', 'Interaction', (164, 171))
1140	32827765	Indeed, treatment with FGFR1 inhibitor PD173074 and JQ1 enhanced cytotoxic effect in ILC and IDC resistant cell lines.	('FGFR1', 'Gene', (23, 28))	('PD173074', 'Var', (39, 47))	('IDC', 'Disease', (93, 96))	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('PD173074', 'Chemical', 'MESH:C115711', (39, 47))	('FGFR1', 'Gene', '2260', (23, 28))	('JQ1', 'Gene', (52, 55))	('cytotoxic effect', 'CPA', (65, 81))	('enhanced', 'PosReg', (56, 64))	('ILC', 'Disease', (85, 88))
1143	32827765	Silence of VDAC1 in breast cancer cell lines increased sensitivity to JQ1 treatment.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('increased', 'PosReg', (45, 54))	('breast cancer', 'Disease', (20, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('VDAC1', 'Gene', (11, 16))	('VDAC1', 'Gene', '7416', (11, 16))	('sensitivity to JQ1 treatment', 'MPA', (55, 83))	('Silence', 'Var', (0, 7))
1148	32827765	OTX015/MK-8628 (Birabresib) is a triazolothienodiazepine selective inhibitor of BRD2, BRD3, BRD4 which has exhibited efficacy in hematological malignancies and solid tumors Moreover, OTX015 exhibited antitumor activity in different triple negative breast cancer cell lines as a single agent or in combination with everolimus.	('hematological malignancies', 'Disease', (129, 155))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('solid tumors', 'Disease', 'MESH:D009369', (160, 172))	('triazolothienodiazepine', 'Chemical', '-', (33, 56))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('MK-8628', 'Chemical', 'MESH:C000605331', (7, 14))	('everolimus', 'Chemical', 'MESH:D000068338', (314, 324))	('BRD2', 'Gene', '6046', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('BRD3', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('Birabresib', 'Chemical', 'MESH:C000605331', (16, 26))	('BRD2', 'Gene', (80, 84))	('BRD3', 'Gene', '8019', (86, 90))	('hematological malignancies', 'Disease', 'MESH:D019337', (129, 155))	('tumor', 'Disease', (166, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (248, 261))	('hematological malignancies', 'Phenotype', 'HP:0004377', (129, 155))	('solid tumors', 'Disease', (160, 172))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('OTX015', 'Var', (183, 189))	('breast cancer', 'Disease', 'MESH:D001943', (248, 261))	('tumor', 'Disease', (204, 209))	('breast cancer', 'Disease', (248, 261))
1149	32827765	Concomitant treatment with OTX015 and everolimus was effective in TNBC xenograft models and also more potent than either monotherapy or paclitaxel.	('potent', 'MPA', (102, 108))	('TNBC', 'Disease', (66, 70))	('paclitaxel', 'Chemical', 'MESH:D017239', (136, 146))	('OTX015', 'Var', (27, 33))	('everolimus', 'Chemical', 'MESH:D000068338', (38, 48))
1166	32827765	INCB057643 is a BET inhibitor effective in AML, MM, DLBCL and CRPC xenograft models.	('INCB057643', 'Var', (0, 10))	('INCB057643', 'Chemical', '-', (0, 10))	('AML', 'Disease', 'MESH:D015470', (43, 46))	('AML', 'Disease', (43, 46))	('DLBCL', 'Disease', (52, 57))
1172	32827765	Of 134 patients receiving INCB057643, 6 patients achieved objective response, with two patients exhibiting complete response (follicular lymphoma and relapsed AML), 4 patients exhibiting partial response (three patients with follicular lymphoma and one breast cancer patient in combination treatment with paclitaxel) and 27 patients achieved stable disease, 6 of whom remained on SD for more than six months.	('breast cancer', 'Phenotype', 'HP:0003002', (253, 266))	('lymphoma', 'Phenotype', 'HP:0002665', (137, 145))	('paclitaxel', 'Chemical', 'MESH:D017239', (305, 315))	('breast cancer', 'Disease', 'MESH:D001943', (253, 266))	('AML', 'Disease', 'MESH:D015470', (159, 162))	('breast cancer', 'Disease', (253, 266))	('lymphoma', 'Disease', (236, 244))	('patients', 'Species', '9606', (7, 15))	('patient', 'Species', '9606', (40, 47))	('patients', 'Species', '9606', (324, 332))	('AML', 'Disease', (159, 162))	('patients', 'Species', '9606', (211, 219))	('patient', 'Species', '9606', (7, 14))	('lymphoma', 'Disease', 'MESH:D008223', (236, 244))	('patient', 'Species', '9606', (167, 174))	('patient', 'Species', '9606', (87, 94))	('patient', 'Species', '9606', (324, 331))	('lymphoma', 'Disease', (137, 145))	('lymphoma', 'Disease', 'MESH:D008223', (137, 145))	('INCB057643', 'Var', (26, 36))	('patient', 'Species', '9606', (211, 218))	('one breast', 'Phenotype', 'HP:0012813', (249, 259))	('INCB057643', 'Chemical', '-', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('patient', 'Species', '9606', (267, 274))	('patients', 'Species', '9606', (40, 48))	('lymphoma', 'Phenotype', 'HP:0002665', (236, 244))	('patients', 'Species', '9606', (167, 175))	('patients', 'Species', '9606', (87, 95))
1186	32827765	INCB054329 exhibited a faster absorption and clearance rate and a shorter half-life than INCB057643.	('INCB057643', 'Chemical', '-', (89, 99))	('INCB054329', 'Var', (0, 10))	('INCB054329', 'Chemical', 'MESH:C000627927', (0, 10))	('absorption', 'MPA', (30, 40))	('clearance', 'MPA', (45, 54))	('faster', 'PosReg', (23, 29))
1187	32827765	However, treatment with INCB054329 was characterized by high interpatient variability in drug clearance of the same drug doses.	('INCB054329', 'Chemical', 'MESH:C000627927', (24, 34))	('drug clearance', 'MPA', (89, 103))	('INCB054329', 'Var', (24, 34))	('patient', 'Species', '9606', (66, 73))
1206	32827765	Another Phase I Study was designed to assess the combination of R06870810 BET inhibitor and Atezolizumab anti-PD-L1 antibody in advanced ovarian and triple negative breast cancer (NCT03292172).	('PD-L1', 'Gene', (110, 115))	('ovarian', 'Disease', (137, 144))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('Atezolizumab', 'Chemical', 'MESH:C000594389', (92, 104))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('antibody', 'cellular_component', 'GO:0019815', ('116', '124'))	('PD-L1', 'Gene', '29126', (110, 115))	('antibody', 'cellular_component', 'GO:0019814', ('116', '124'))	('antibody', 'molecular_function', 'GO:0003823', ('116', '124'))	('R06870810', 'Chemical', '-', (64, 73))	('R06870810', 'Var', (64, 73))	('antibody', 'cellular_component', 'GO:0042571', ('116', '124'))	('ovarian', 'Disease', 'MESH:D010049', (137, 144))
1207	32827765	The same BET inhibitor R06870810 is explored in the two-part, Phase I trial with a dose escalation cohort in solid tumors and a dose expansion cohort in selected malignancies (NCT01987362).	('solid tumors', 'Disease', (109, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('solid tumors', 'Disease', 'MESH:D009369', (109, 121))	('malignancies', 'Disease', 'MESH:D009369', (162, 174))	('R06870810', 'Var', (23, 32))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('R06870810', 'Chemical', '-', (23, 32))	('malignancies', 'Disease', (162, 174))
1224	32827765	BMS-986158 is another potent BET inhibitor which caused >70% tumor inhibition in patient derived xenograft models (triple negative breast cancer, lung and colorectal).	('patient', 'Species', '9606', (81, 88))	('BMS-986158', 'Var', (0, 10))	('lung', 'Disease', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('breast cancer', 'Disease', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('tumor', 'Disease', (61, 66))
1225	32827765	A Phase I/IIa trial is ongoing to assess BMS-986158 as monotherapy or in combination with nivolumab in selected advanced solid tumors (TNBC, SCLC, serous ovarian cancer BRCA1/2 wild type) and hematological malignancies (NCT02419417).	('ovarian cancer', 'Phenotype', 'HP:0100615', (154, 168))	('SCLC', 'Disease', (141, 145))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (147, 168))	('SCLC', 'Disease', 'MESH:D018288', (141, 145))	('BMS-986158', 'Var', (41, 51))	('hematological malignancies', 'Disease', (192, 218))	('BRCA1/2', 'Gene', (169, 176))	('solid tumors', 'Disease', 'MESH:D009369', (121, 133))	('hematological malignancies', 'Phenotype', 'HP:0004377', (192, 218))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('hematological malignancies', 'Disease', 'MESH:D019337', (192, 218))	('BRCA1/2', 'Gene', '672;675', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('solid tumors', 'Disease', (121, 133))	('serous ovarian cancer', 'Disease', (147, 168))	('nivolumab', 'Chemical', 'MESH:D000077594', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))
1238	32827765	BI 894999 is a novel potent, selective BET inhibitor with a greater affinity to BRD4-BD2 bromodomain and an established efficacy in AML cell lines.	('BD2', 'Gene', '1673', (85, 88))	('AML', 'Disease', (132, 135))	('BI 894999', 'Var', (0, 9))	('BD2', 'Gene', (85, 88))	('AML', 'Disease', 'MESH:D015470', (132, 135))
1255	32827765	Another BET degrader, BETd-246 effectively decreased BRD2, BRD3 and BRD4 protein levels and induced apoptosis in TNBC cell lines.	('BETd', 'Chemical', '-', (22, 26))	('induced', 'Reg', (92, 99))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('BRD4 protein levels', 'MPA', (68, 87))	('BETd-246', 'Var', (22, 30))	('BRD3', 'Gene', (59, 63))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('BRD3', 'Gene', '8019', (59, 63))	('decreased', 'NegReg', (43, 52))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('BRD2', 'Gene', '6046', (53, 57))	('BRD2', 'Gene', (53, 57))
1294	31731645	General characteristics of cancer cells are genome instability and mutation load that should in principle render them good targets for the host immune system.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('genome instability', 'CPA', (44, 62))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('mutation load', 'Var', (67, 80))
1295	31731645	Among the tumor types, melanoma is considered a highly immunogenic tumor due to its elevated mutation load.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('mutation', 'Var', (93, 101))
1337	31731645	In 1995, Cui and Bystryn showed the presence of autoantibodies to melanocytes in 80% of melanoma and in 83% of vitiligo patients.	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('vitiligo', 'Phenotype', 'HP:0001045', (111, 119))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('patients', 'Species', '9606', (120, 128))	('autoantibodies', 'Var', (48, 62))
1340	31731645	Other authors reported the presence of autoantibodies against melanocyte differentiation antigens, such as tyrosinase, in the sera of both vitiligo and melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('presence', 'Reg', (27, 35))	('tyrosinase', 'Gene', '7299', (107, 117))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('melanocyte differentiation', 'biological_process', 'GO:0030318', ('62', '88'))	('autoantibodies', 'Var', (39, 53))	('vitiligo', 'Phenotype', 'HP:0001045', (139, 147))	('tyrosinase', 'Gene', (107, 117))	('patients', 'Species', '9606', (161, 169))	('sera', 'molecular_function', 'GO:0004617', ('126', '130'))
1382	31731645	Development of autoimmune leukoderma was observed in mice treated with anti-CD4 to deplete regulatory T cells (Treg) followed by surgery to excise large B16 melanomas.	('melanomas', 'Disease', (157, 166))	('autoimmune leukoderma', 'Disease', 'MESH:C536955', (15, 36))	('autoimmune leukoderma', 'Disease', (15, 36))	('deplete', 'NegReg', (83, 90))	('anti-CD4', 'Var', (71, 79))	('melanomas', 'Phenotype', 'HP:0002861', (157, 166))	('melanomas', 'Disease', 'MESH:D008545', (157, 166))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('men', 'Species', '9606', (7, 10))	('mice', 'Species', '10090', (53, 57))
1407	31731645	Other biomarkers, proposed to be predictive for response to immunotherapy with check-point inhibitors, such as PD-1/PD-L1 or CTLA-4 expression, presence of an IFN-gamma signature, or augmented inflammatory cytokines, are also hallmarks of active vitiligo (Table 1).	('active vitiligo', 'Disease', (239, 254))	('CTLA-4', 'Gene', (125, 131))	('IFN-gamma signature', 'MPA', (159, 178))	('inflammatory cytokines', 'MPA', (193, 215))	('PD-L1', 'Gene', (116, 121))	('men', 'Species', '9606', (186, 189))	('vitiligo', 'Phenotype', 'HP:0001045', (246, 254))	('PD-1', 'Gene', (111, 115))	('PD-1', 'Gene', '5133', (111, 115))	('active vitiligo', 'Phenotype', 'HP:0005602', (239, 254))	('CTLA-4', 'Gene', '1493', (125, 131))	('PD-L1', 'Gene', '29126', (116, 121))	('presence', 'Var', (144, 152))
1417	31731645	Importantly, JAK1 or JAK2 mutations are also associated with acquired resistance to check-point inhibitor immunotherapy in melanoma patients.	('JAK2', 'Gene', '3717', (21, 25))	('JAK1', 'Gene', (13, 17))	('JAK', 'molecular_function', 'GO:0004713', ('13', '16'))	('associated with', 'Reg', (45, 60))	('mutations', 'Var', (26, 35))	('acquired', 'MPA', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Disease', (123, 131))	('JAK1', 'Gene', '3716', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('JAK2', 'Gene', (21, 25))	('JAK', 'molecular_function', 'GO:0004713', ('21', '24'))	('patients', 'Species', '9606', (132, 140))
1419	31731645	Variants in the gene coding for CTLA-4 associate with response to immunotherapy with check-point inhibitor in melanoma patients.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('CTLA-4', 'Gene', '1493', (32, 38))	('Variants', 'Var', (0, 8))	('melanoma', 'Disease', (110, 118))	('patients', 'Species', '9606', (119, 127))	('CTLA-4', 'Gene', (32, 38))	('associate with', 'Reg', (39, 53))
1420	31731645	Moreover, MMR deficiency predicts response to immunotherapy with check-point inhibitors in different tumor types.	('MMR', 'biological_process', 'GO:0006298', ('10', '13'))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('deficiency', 'Var', (14, 24))	('predicts', 'Reg', (25, 33))	('MMR', 'Gene', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
1422	31731645	MMR deficiency has also been linked to vitiligo development.	('men', 'Species', '9606', (55, 58))	('linked', 'Reg', (29, 35))	('deficiency', 'Var', (4, 14))	('vitiligo development', 'Disease', (39, 59))	('vitiligo', 'Phenotype', 'HP:0001045', (39, 47))	('MMR', 'Gene', (0, 3))	('MMR', 'biological_process', 'GO:0006298', ('0', '3'))
1423	31731645	A clinical report indicated that bi-allelic mutations in MMR genes associated with early onset of colorectal cancer also led to vitiligo development.	('colorectal cancer', 'Disease', (98, 115))	('vitiligo', 'Phenotype', 'HP:0001045', (128, 136))	('men', 'Species', '9606', (144, 147))	('vitiligo development', 'Disease', (128, 148))	('MMR', 'biological_process', 'GO:0006298', ('57', '60'))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('associated', 'Reg', (67, 77))	('bi-allelic mutations', 'Var', (33, 53))	('MMR', 'Gene', (57, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('led to', 'Reg', (121, 127))
1426	31731645	Several tumor-derived miRNAs were found to induce myeloid suppressor cells and predict melanoma patient resistance to immunotherapy with check-point inhibitors and poor survival (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b).	('miR', 'Gene', (245, 248))	('miR', 'Gene', (198, 201))	('let-7e', 'Var', (217, 223))	('miR', 'Gene', '220972', (235, 238))	('patient', 'Species', '9606', (96, 103))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('miR', 'Gene', (189, 192))	('miR-125a', 'Gene', '406910', (225, 233))	('miR-99b', 'Gene', (245, 252))	('miR', 'Gene', '220972', (179, 182))	('miR-146b', 'Gene', (235, 243))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('miR', 'Gene', '220972', (225, 228))	('melanoma', 'Disease', (87, 95))	('miR-125a', 'Gene', (225, 233))	('miR', 'Gene', (235, 238))	('miR', 'Gene', (179, 182))	('miR-155', 'Gene', (189, 196))	('resistance', 'CPA', (104, 114))	('miR-100', 'Gene', (208, 215))	('miR-146b', 'Gene', '574447', (235, 243))	('miR', 'Gene', '220972', (208, 211))	('miR', 'Gene', (225, 228))	('miR-155', 'Gene', '406947', (189, 196))	('miR-99b', 'Gene', '407056', (245, 252))	('tumor', 'Disease', (8, 13))	('myeloid suppressor cells', 'CPA', (50, 74))	('miR', 'Gene', (208, 211))	('miR', 'Gene', '220972', (245, 248))	('miR', 'Gene', '220972', (22, 25))	('predict', 'Reg', (79, 86))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('miR', 'Gene', '220972', (198, 201))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('miR-100', 'Gene', '406892', (208, 215))	('miR', 'Gene', '220972', (189, 192))	('induce', 'PosReg', (43, 49))	('miR', 'Gene', (22, 25))
1435	31731645	Uveal melanoma is genetically distinct from cutaneous melanoma, having activating mutations in the GNAQ or GNA11 genes in 80-90% of cases.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (44, 62))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('GNAQ', 'Gene', (99, 103))	('GNAQ', 'Gene', '2776', (99, 103))	('mutations', 'Var', (82, 91))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('cutaneous melanoma', 'Disease', (44, 62))	('melanoma', 'Disease', (6, 14))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (44, 62))	('activating', 'PosReg', (71, 81))	('GNA11', 'Gene', (107, 112))	('GNA11', 'Gene', '2767', (107, 112))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
1436	31731645	On the other hand, mutations in BRAF, NRAS, and TERT promoter that are common in cutaneous melanoma are quite absent in uveal tumors.	('NRAS', 'Gene', '4893', (38, 42))	('BRAF', 'Gene', '673', (32, 36))	('uveal tumors', 'Disease', (120, 132))	('TERT', 'Gene', '7015', (48, 52))	('uveal tumors', 'Disease', 'MESH:D014604', (120, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('BRAF', 'Gene', (32, 36))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('mutations', 'Var', (19, 28))	('TERT', 'Gene', (48, 52))	('cutaneous melanoma', 'Disease', (81, 99))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('NRAS', 'Gene', (38, 42))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (81, 99))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (81, 99))
1437	31731645	Likewise, monosomy 3 is observed in around 50% of uveal melanomas, whereas it is rarely reported in cutaneous melanoma (Table 2).	('uveal melanomas', 'Disease', (50, 65))	('uveal melanomas', 'Phenotype', 'HP:0007716', (50, 65))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('cutaneous melanoma', 'Disease', (100, 118))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (100, 118))	('uveal melanomas', 'Disease', 'MESH:C536494', (50, 65))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (100, 118))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('monosomy 3', 'Var', (10, 20))	('observed', 'Reg', (24, 32))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
1563	31545410	Our findings suggest that the calcium signaling pathway may mediate the downstream signaling of mutant GNAQ, a common uveal melanoma driver mutation.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('signaling pathway', 'biological_process', 'GO:0007165', ('38', '55'))	('GNAQ', 'Gene', '2776', (103, 107))	('mutant', 'Var', (96, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (118, 132))	('uveal melanoma', 'Disease', (118, 132))	('uveal melanoma', 'Disease', 'MESH:C536494', (118, 132))	('calcium', 'Chemical', 'MESH:D002118', (30, 37))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('calcium signaling pathway', 'Pathway', (30, 55))	('GNAQ', 'Gene', (103, 107))	('calcium signaling', 'biological_process', 'GO:0019722', ('30', '47'))
1565	31545410	For those with 'no hits' in the STR database, we performed a manual search of key melanoma mutations [e.g., BRAF(V600E), NRAS(Q61), etc.]	('V600E', 'SUBSTITUTION', 'None', (113, 118))	('NRAS', 'Gene', '4893', (121, 125))	('Q61', 'Chemical', 'MESH:C117212', (126, 129))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('V600E', 'Var', (113, 118))	('NRAS', 'Gene', (121, 125))
1567	31545410	Those that express significant M-isoform MITF are designated as 'COMPATIBLE'.	('MITF', 'Gene', '4286', (41, 45))	('MITF', 'Gene', (41, 45))	('M-isoform', 'Var', (31, 40))
1568	31545410	The following are accession numbers for cell lines from Cellosaurus (web.expasy.org/cgi-bin/cellosaurus/search): MP41 (CVCL_4D12), Mel-270 (CVCL_C302), Mel-202 (CVCL_C301), OMM2.3 (CVCL_C306), CHL-1 (CVCL_1122), MeWo (CVCL_0445), SK-MEL-2 (CVCL_0069), SK-MEL-119 (CVCL_6077), Mel JuSo (CVCL_1403), IPC-298 (CVCL_1307), UACC-903 (CVCL_4052), SK-MEL-28 (CVCL_0526) and A375 (CVCL_0132).	('CVCL_0526', 'Var', (352, 361))	('CVCL_6077', 'Var', (264, 273))	('Mel-202', 'Chemical', 'MESH:D008549', (152, 159))	('CVCL_C306', 'Var', (181, 190))	('CVCL_1403', 'Var', (286, 295))	('CVCL_4052', 'Var', (329, 338))	('CHL-1', 'Gene', '10752', (193, 198))	('CHL-1', 'Gene', (193, 198))
1609	31545410	Spheroids subjected to 48 h of treatment with 20 microM amlo-dipine displayed, on average, a significantly decreased spheroid volume growth in UMM lines compared to the DMSO control.	('DMSO', 'Chemical', 'MESH:D004121', (169, 173))	('amlo-dipine', 'Chemical', 'MESH:C007526', (56, 67))	('spheroid volume growth', 'CPA', (117, 139))	('decreased', 'NegReg', (107, 116))	('amlo-dipine', 'Var', (56, 67))	('UMM', 'Phenotype', 'HP:0007716', (143, 146))
1612	31545410	In 3 separate colonies of CMM spheroids (A375, CHL-1 and IPC-298), there was no evidence of significant growth inhibition with amlodipine treatment compared to the DMSO control, and, in fact, the treated A375 spheroids appeared to grow more rapidly than their control counterparts (Figs.	('CMM', 'Disease', 'MESH:C562393', (26, 29))	('A375', 'Var', (204, 208))	('CMM', 'Disease', (26, 29))	('CMM', 'Phenotype', 'HP:0012056', (26, 29))	('DMSO', 'Chemical', 'MESH:D004121', (164, 168))	('amlodipine', 'Chemical', 'MESH:D017311', (127, 137))	('CHL-1', 'Gene', (47, 52))	('grow', 'CPA', (231, 235))	('CHL-1', 'Gene', '10752', (47, 52))
1615	31545410	The MP41 cells exhibited a 23% Annexin V induction with 20 microM amlodipine and 6% with DMSO (P<0.0001) (Fig.	('MP41', 'Var', (4, 8))	('Annexin V', 'Gene', '308', (31, 40))	('DMSO', 'Chemical', 'MESH:D004121', (89, 93))	('Annexin V', 'Gene', (31, 40))	('induction', 'MPA', (41, 50))	('amlodipine', 'Chemical', 'MESH:D017311', (66, 76))
1626	31545410	The calcium signaling pathway, and its dysregulation, has a well-documented association with cancer survival, proliferation, migration and metastatic potential.	('dysregulation', 'Var', (39, 52))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('migration', 'CPA', (125, 134))	('calcium signaling', 'biological_process', 'GO:0019722', ('4', '21'))	('metastatic potential', 'CPA', (139, 159))	('association', 'Interaction', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('proliferation', 'CPA', (110, 123))	('calcium signaling pathway', 'Pathway', (4, 29))	('signaling pathway', 'biological_process', 'GO:0007165', ('12', '29'))	('calcium', 'Chemical', 'MESH:D002118', (4, 11))
1627	31545410	For example, calcium signaling has been reported to be involved in the proliferation of RAS-driven cancers through the interaction of calmodulin (CaM) and PI3K and the promotion of invasion and metastasis via ERK activation in both BRAF-driven and non-BRAF melanoma cells.	('interaction', 'Interaction', (119, 130))	('CaM', 'Gene', '801', (146, 149))	('calmodulin', 'Gene', (134, 144))	('BRAF', 'Gene', '673', (232, 236))	('BRAF', 'Gene', (232, 236))	('PI3K', 'Var', (155, 159))	('ERK', 'Gene', (209, 212))	('melanoma', 'Disease', 'MESH:D008545', (257, 265))	('CaM', 'Gene', (146, 149))	('promotion', 'PosReg', (168, 177))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('calcium signaling', 'MPA', (13, 30))	('involved', 'Reg', (55, 63))	('PI3K', 'molecular_function', 'GO:0016303', ('155', '159'))	('BRAF', 'Gene', '673', (252, 256))	('BRAF', 'Gene', (252, 256))	('melanoma', 'Phenotype', 'HP:0002861', (257, 265))	('melanoma', 'Disease', (257, 265))	('RAS-driven', 'Disease', (88, 98))	('calcium signaling', 'biological_process', 'GO:0019722', ('13', '30'))	('calmodulin', 'Gene', '801', (134, 144))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('ERK', 'molecular_function', 'GO:0004707', ('209', '212'))	('invasion', 'CPA', (181, 189))	('calcium', 'Chemical', 'MESH:D002118', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
1628	31545410	One such example that could explain the selectivity we observed in UMM is RasGRP3, which was identified by Chen et al (2017) as a link between MAPK activation and the GNAQ/11 mutations that characteristically drive UMM.	('MAPK activation', 'biological_process', 'GO:0000187', ('143', '158'))	('UMM', 'Disease', (215, 218))	('RasGRP3', 'Gene', (74, 81))	('UMM', 'Phenotype', 'HP:0007716', (215, 218))	('RasGRP3', 'Gene', '25780', (74, 81))	('GNAQ', 'Gene', (167, 171))	('mutations', 'Var', (175, 184))	('GNAQ', 'Gene', '2776', (167, 171))	('MAPK', 'molecular_function', 'GO:0004707', ('143', '147'))	('UMM', 'Phenotype', 'HP:0007716', (67, 70))
1629	31545410	RasGRP3, which is overex-pressed in response to GNAQ/11 mutations, reportedly drives the MAPK pathway through the activation of HRAS.	('activation', 'PosReg', (114, 124))	('HRAS', 'Gene', '3265', (128, 132))	('mutations', 'Var', (56, 65))	('GNAQ', 'Gene', '2776', (48, 52))	('RasGRP3', 'Gene', (0, 7))	('RasGRP3', 'Gene', '25780', (0, 7))	('drives', 'Reg', (78, 84))	('HRAS', 'Gene', (128, 132))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('GNAQ', 'Gene', (48, 52))	('MAPK pathway', 'Pathway', (89, 101))
1646	31545410	This study was supported in part by the US NIH (K24 CA149202 to HT) and by generous donors to Massachusetts General Hospital on behalf of melanoma research.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('K24 CA149202', 'Var', (48, 60))	('HT', 'Disease', 'MESH:D006973', (64, 66))
1663	31480356	Non-random aberrations of chromosomes 1, 3, 6 and 8 are classically found in UM and are commonly used as reliable prognostic indicators, but these are mainly associated with the progression rather than initiation of UM.	('UM', 'Disease', 'MESH:C536494', (216, 218))	('Non-random aberrations', 'Var', (0, 22))	('UM', 'Disease', 'MESH:C536494', (77, 79))	('associated', 'Reg', (158, 168))
1664	31480356	In contrast, mutations in guanine nucleotide binding proteins GNAQ and GNA11, although not prognostic, occur in approximately 80-90% of UM and are considered an early, if not initiating event in UM.	('GNAQ', 'Gene', '2776', (62, 66))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (26, 44))	('GNA11', 'Gene', (71, 76))	('GNA11', 'Gene', '2767', (71, 76))	('occur', 'Reg', (103, 108))	('GNAQ', 'Gene', (62, 66))	('UM', 'Disease', 'MESH:C536494', (136, 138))	('mutations', 'Var', (13, 22))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('34', '52'))	('UM', 'Disease', 'MESH:C536494', (195, 197))
1665	31480356	These mutations produce constitutive activation of the ERK 1/2 / MEK and Yes Associated Protein (YAP).	('YAP', 'Gene', '10413', (97, 100))	('Yes Associated Protein', 'Gene', '10413', (73, 95))	('ERK 1', 'molecular_function', 'GO:0004707', ('55', '60'))	('Yes Associated Protein', 'Gene', (73, 95))	('activation', 'PosReg', (37, 47))	('MEK', 'Gene', (65, 68))	('MEK', 'Gene', '5609', (65, 68))	('YAP', 'Gene', (97, 100))	('ERK 1/2', 'Gene', (55, 62))	('ERK 1/2', 'Gene', '5595;5594', (55, 62))	('mutations', 'Var', (6, 15))
1668	31480356	MMC prevents DNA replication by forming cross-links in DNA and is valuable as a treatment for a range of solid tumours, including conjunctival melanoma.	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('conjunctival melanoma', 'Disease', (130, 151))	('solid tumours', 'Disease', 'MESH:D009369', (105, 118))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (130, 151))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (130, 151))	('cross-links', 'MPA', (40, 51))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('solid tumours', 'Disease', (105, 118))	('DNA replication', 'MPA', (13, 28))	('MMC', 'Chemical', 'MESH:D016685', (0, 3))	('prevents', 'NegReg', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('DNA', 'MPA', (55, 58))	('DNA replication', 'biological_process', 'GO:0006260', ('13', '28'))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('MMC', 'Var', (0, 3))
1676	31480356	In this study, the spontaneous foci formation of Ser2056 DNA-PKcs was significantly higher in both UM cell lines and UM STCs when compared to the control cell lines, WM793 and MRC5VA (P < 0.01) (Figure 1).	('Ser', 'cellular_component', 'GO:0005790', ('49', '52'))	('UM', 'Disease', 'MESH:C536494', (117, 119))	('formation', 'biological_process', 'GO:0009058', ('36', '45'))	('DNA-PKcs', 'Gene', '5591', (57, 65))	('Ser', 'Chemical', 'MESH:C530429', (49, 52))	('Ser2056', 'Var', (49, 56))	('spontaneous foci formation', 'CPA', (19, 45))	('DNA-PKcs', 'Gene', (57, 65))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('UM', 'Disease', 'MESH:C536494', (99, 101))	('higher', 'PosReg', (84, 90))
1681	31480356	As previously reported, M3G8q was associated with reduced survival (P <0.0001) and DNA-PK was found to be highly expressed in the cohort of M3G8q compared to D3 (P <0.0001) (Figure S1).	('DNA-PK', 'Gene', (83, 89))	('survival', 'CPA', (58, 66))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('DNA-PK', 'Gene', '5591', (83, 89))	('M3G8q', 'Var', (140, 145))	('reduced', 'NegReg', (50, 57))	('M3G8q', 'Var', (24, 29))
1682	31480356	Of note, the survival plots for the copy number deletion of BAP1 (location 3p) and the amplification of DNA-PK/PRKDC (location 8q) matched exactly the plots for survival of M3G8q.	('PRKDC', 'Gene', '5591', (111, 116))	('DNA-PK', 'Gene', (104, 110))	('DNA-PK', 'Gene', '5591', (104, 110))	('PRKDC', 'Gene', (111, 116))	('BAP1', 'Gene', '8314', (60, 64))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('BAP1', 'Gene', (60, 64))	('copy number deletion', 'Var', (36, 56))
1686	31480356	All UM showed increased sensitivity to the DNA-PK inhibitor NU7026 when compared with the control cell lines WM793, melanocyte progenitor cell line LA1-5s and a series of sarcoma cell lines (A673, SKUT-1, SKLMS-1 and SW1353, grouped to simplify the data) (Figure 3).	('increased', 'PosReg', (14, 23))	('NU7026', 'Var', (60, 66))	('UM', 'Disease', 'MESH:C536494', (4, 6))	('sensitivity', 'MPA', (24, 35))	('sarcoma', 'Disease', 'MESH:D012509', (171, 178))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('DNA-PK', 'Gene', (43, 49))	('sarcoma', 'Disease', (171, 178))	('NU7026', 'Chemical', 'MESH:C479235', (60, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('DNA-PK', 'Gene', '5591', (43, 49))
1690	31480356	All ten UM STCs analysed were significantly more sensitive to NU7026 than the control (Figure S3) (P < 0.001 by a Student's T-test).	('UM', 'Disease', 'MESH:C536494', (8, 10))	('NU7026', 'Chemical', 'MESH:C479235', (62, 68))	('sensitive', 'MPA', (49, 58))	('NU7026', 'Var', (62, 68))
1691	31480356	The inhibition of DNA PKcs phosphorylation following the treatment with 10muM NU7026 for 24 h was confirmed using a western blot analysis (Figure 3).	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('DNA PKcs phosphorylation', 'Enzyme', (18, 42))	('inhibition', 'NegReg', (4, 14))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('NU7026', 'Chemical', 'MESH:C479235', (78, 84))	('NU7026', 'Var', (78, 84))
1692	31480356	Both UM cell lines were resistant to PARP inhibition in comparison to the HR deficient BRCA1 mutant cell line COV362 (Figure S4).	('PARP', 'Gene', (37, 41))	('BRCA1', 'Gene', '672', (87, 92))	('PARP', 'Gene', '142', (37, 41))	('BRCA1', 'Gene', (87, 92))	('mutant', 'Var', (93, 99))	('UM', 'Disease', 'MESH:C536494', (5, 7))
1694	31480356	The Annexin V positive/PI negative cells in UM and the controls 48 h following the treatment with 10 microM NU7026 (the LD50 dose for UM), were significantly higher in the UM cell lines and STCs compared to the controls (Figure 3) (P < 0.05 by a Student's T-test).	('UM', 'Disease', 'MESH:C536494', (172, 174))	('Annexin V', 'Gene', '308', (4, 13))	('Annexin V', 'Gene', (4, 13))	('NU7026', 'Chemical', 'MESH:C479235', (108, 114))	('higher', 'PosReg', (158, 164))	('NU7026', 'Var', (108, 114))	('UM', 'Disease', 'MESH:C536494', (134, 136))	('UM', 'Disease', 'MESH:C536494', (44, 46))
1696	31480356	Although NU7026 is highly selective against DNA-PK over other phosphatidyl inositol kinases (PIKs), it was necessary to determine whether the toxicity was due to specific targeting of DNA-PK or another unknown interaction.	('NU7026', 'Chemical', 'MESH:C479235', (9, 15))	('DNA', 'cellular_component', 'GO:0005574', ('184', '187'))	('DNA-PK', 'Gene', (184, 190))	('phosphatidyl inositol', 'Chemical', 'MESH:D010716', (62, 83))	('toxicity', 'Disease', 'MESH:D064420', (142, 150))	('toxicity', 'Disease', (142, 150))	('NU7026', 'Var', (9, 15))	('DNA-PK', 'Gene', '5591', (184, 190))	('DNA-PK', 'Gene', (44, 50))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('DNA-PK', 'Gene', '5591', (44, 50))
1702	31480356	The UM cell lines SOM 157D and 196B were significantly more sensitive to treatment with NU7441 compared to the MRC5VA cells and WM793 cells (Figure 4).	('sensitive', 'MPA', (60, 69))	('UM', 'Disease', 'MESH:C536494', (4, 6))	('NU7441', 'Chemical', 'MESH:C499693', (88, 94))	('NU7441', 'Var', (88, 94))
1703	31480356	Additionally, the treatment with 2.5 microM NU7441 for 48 hours selectively induces apoptosis as suggested by the increase in Annexin V positive / PI negative cells in UM (Figure 4), as opposed to no increase in apoptosis in treated control cells MRC5VA and WM793 cells (P <0.05 by a Student' T-test).	('UM', 'Disease', 'MESH:C536494', (168, 170))	('apoptosis', 'biological_process', 'GO:0006915', ('212', '221'))	('increase', 'PosReg', (114, 122))	('apoptosis', 'CPA', (84, 93))	('Annexin V', 'Gene', (126, 135))	('NU7441', 'Chemical', 'MESH:C499693', (44, 50))	('negative', 'NegReg', (150, 158))	('Annexin V', 'Gene', '308', (126, 135))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('NU7441', 'Var', (44, 50))	('apoptosis', 'biological_process', 'GO:0097194', ('212', '221'))	('induces', 'Reg', (76, 83))
1704	31480356	DNA-PK inhibitors have been shown to be effective in adjuvant therapy strategies in other tumours, and the findings of this study indicate a similar potential for UM.	('DNA-PK', 'Gene', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('adjuvant', 'CPA', (53, 61))	('DNA-PK', 'Gene', '5591', (0, 6))	('UM', 'Disease', 'MESH:C536494', (163, 165))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('inhibitors', 'Var', (7, 17))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('tumours', 'Disease', (90, 97))
1705	31480356	The DNA-PK inhibitor, NU7026 augmented the cytotoxic effects of IR in both the UM and control cell lines (Figure S5).	('DNA-PK', 'Gene', (4, 10))	('UM', 'Disease', 'MESH:C536494', (79, 81))	('DNA-PK', 'Gene', '5591', (4, 10))	('cytotoxic effects', 'CPA', (43, 60))	('augmented', 'PosReg', (29, 38))	('NU7026', 'Chemical', 'MESH:C479235', (22, 28))	('NU7026', 'Var', (22, 28))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))
1707	31480356	The potential for DNA-PK inhibitors in combined therapy also extends to previously ineffective therapies, including MMC, and in this study, the DNA-PK inhibitor NU7026 also sensitized the UM cell line SOM 196B to MMC (P = 0.02 at 20nM by a Student's T-test).	('NU7026', 'Chemical', 'MESH:C479235', (161, 167))	('DNA-PK', 'Gene', '5591', (144, 150))	('MMC', 'Chemical', 'MESH:D016685', (213, 216))	('NU7026', 'Var', (161, 167))	('MMC', 'Disease', (213, 216))	('DNA-PK', 'Gene', (18, 24))	('DNA-PK', 'Gene', '5591', (18, 24))	('MMC', 'Chemical', 'MESH:D016685', (116, 119))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('sensitized', 'Reg', (173, 183))	('UM', 'Disease', 'MESH:C536494', (188, 190))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))	('DNA-PK', 'Gene', (144, 150))
1709	31480356	In addition, most primary UM STCs were also found to be more resistant to MMC compared with the cell line WM793 (P<0.05 at 50nM), and most were sensitized to MMC with the co-administration of 10 microM NU7026 (P < 0.05 at 25 nM) (Figure S5).	('sensitized', 'Reg', (144, 154))	('NU7026', 'Var', (202, 208))	('MMC', 'Chemical', 'MESH:D016685', (74, 77))	('MMC', 'Chemical', 'MESH:D016685', (158, 161))	('resistant', 'MPA', (61, 70))	('UM', 'Disease', 'MESH:C536494', (26, 28))	('NU7026', 'Chemical', 'MESH:C479235', (202, 208))
1711	31480356	Cisplatin, another DNA cross-linking agent, is not cytotoxic in UM, but the co-administration with 10 microM NU7026 increased its cytotoxic effects in the UM cell line, SOM 196B (P = 0.04 at 2 microM) (data not shown).	('NU7026', 'Var', (109, 115))	('UM', 'Disease', 'MESH:C536494', (155, 157))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('NU7026', 'Chemical', 'MESH:C479235', (109, 115))	('cytotoxic effects', 'CPA', (130, 147))	('increased', 'PosReg', (116, 125))	('UM', 'Disease', 'MESH:C536494', (64, 66))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
1714	31480356	An increase in SCE compared to the spontaneous levels was observed following treatment with NU7026 (P < 0.05), and the relative increase in SCE levels was comparable to that for the similarly treated WM793 line (Table 1).	('SCE', 'MPA', (15, 18))	('SCE levels', 'MPA', (140, 150))	('NU7026', 'Chemical', 'MESH:C479235', (92, 98))	('NU7026', 'Var', (92, 98))	('increase', 'PosReg', (3, 11))
1729	31480356	Certainly, this study found that compound NU7026 sensitized UM cells to IR, MMC and Cisplatin.	('MMC', 'Chemical', 'MESH:D016685', (76, 79))	('NU7026', 'Chemical', 'MESH:C479235', (42, 48))	('compound NU7026', 'Var', (33, 48))	('Cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('sensitized', 'Reg', (49, 59))	('UM', 'Disease', 'MESH:C536494', (60, 62))
1738	31480356	Recent evidence has begun to suggest a consensus on how UM repair DNA damage with studies showing as the authors have, that Olaporib is not efficient alone on UM and that PRKDC is upregulated, with NU7026 being an effective regulator of UM proliferation.	('upregulated', 'PosReg', (180, 191))	('PRKDC', 'Gene', (171, 176))	('UM', 'Disease', 'MESH:C536494', (237, 239))	('UM', 'Disease', 'MESH:C536494', (56, 58))	('UM', 'Disease', 'MESH:C536494', (159, 161))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('NU7026', 'Chemical', 'MESH:C479235', (198, 204))	('PRKDC', 'Gene', '5591', (171, 176))	('NU7026', 'Var', (198, 204))
1752	31480356	The UM samples were classified into two cohorts: Monosomy 3 chromosome 8q gain (M3G8q, N = 47) and Disomy 3 (D3, N = 32).	('UM', 'Disease', 'MESH:C536494', (4, 6))	('Disomy 3', 'Var', (99, 107))	('Monosomy 3 chromosome 8q', 'Var', (49, 73))	('gain', 'PosReg', (74, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))
1755	31480356	The incremental concentrations of the DNA-PK inhibitors (NU7026 Calbiochem (MERCK) Feltham UK and NU7441 Selleckchem Houston USA, and Poly(ADP-ribose) polymerases (PARP) inhibitor (Olaparib Calbiochem) were used.	('DNA-PK', 'Gene', (38, 44))	('Poly(ADP-ribose) polymerases', 'Gene', '142', (134, 162))	('DNA-PK', 'Gene', '5591', (38, 44))	('PARP', 'Gene', (164, 168))	('NU7441', 'Chemical', 'MESH:C499693', (98, 104))	('NU7026', 'Chemical', 'MESH:C479235', (57, 63))	('Poly(ADP-ribose) polymerases', 'Gene', (134, 162))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('NU7441', 'Var', (98, 104))	('PARP', 'Gene', '142', (164, 168))	('NU7026', 'Var', (57, 63))
1769	31480356	DNA-PK inhibitors were thus found to be a universally effective treatment against all the UM tested and could sensitize UM to the effects of IR and both MMC and Cisplatin.	('sensitize', 'Reg', (110, 119))	('MMC', 'Chemical', 'MESH:D016685', (153, 156))	('DNA-PK', 'Gene', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('UM', 'Disease', 'MESH:C536494', (90, 92))	('DNA-PK', 'Gene', '5591', (0, 6))	('inhibitors', 'Var', (7, 17))	('Cisplatin', 'Chemical', 'MESH:D002945', (161, 170))	('UM', 'Disease', 'MESH:C536494', (120, 122))
1770	31480356	These findings suggest that the DNA-PK inhibitors provide a promising new line of therapy, either as a stand-alone agent, or in combination, for what has been previously a highly resistant and difficult to treat malignancy.	('inhibitors', 'Var', (39, 49))	('malignancy', 'Disease', 'MESH:D009369', (212, 222))	('malignancy', 'Disease', (212, 222))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('DNA-PK', 'Gene', (32, 38))	('DNA-PK', 'Gene', '5591', (32, 38))
1772	31480356	The following are available online at , Figure S1: Overall Survival (OS) and PRKDC (DNA-PK) gene expression difference between the cohorts of Monosomy 3 chromosome 8q gain (M3G8q, n = 47) and Disomy 3 (D3, n= 32) TCGA UM (n = 79), Figure S2: UM are insensitive to PARP inhibition, Figure S3: Sensitisation of UM to IR/MMC by inhibition of DNA-PK, Table S1: Clinico-pathological details of UM short-term cultures.	('PARP', 'Gene', '142', (264, 268))	('DNA-PK', 'Gene', '5591', (339, 345))	('DNA', 'cellular_component', 'GO:0005574', ('339', '342'))	('MMC', 'Chemical', 'MESH:D016685', (318, 321))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('DNA-PK', 'Gene', '5591', (84, 90))	('PRKDC', 'Gene', '5591', (77, 82))	('UM', 'Disease', 'MESH:C536494', (309, 311))	('chromosome', 'cellular_component', 'GO:0005694', ('153', '163'))	('Monosomy', 'Var', (142, 150))	('UM', 'Disease', 'MESH:C536494', (389, 391))	('UM', 'Disease', 'MESH:C536494', (242, 244))	('gene expression', 'biological_process', 'GO:0010467', ('92', '107'))	('DNA-PK', 'Gene', (84, 90))	('PARP', 'Gene', (264, 268))	('UM', 'Disease', 'MESH:C536494', (218, 220))	('PRKDC', 'Gene', (77, 82))	('DNA-PK', 'Gene', (339, 345))
1773	31480356	General laboratory support was provided by funding from Yorkshire Cancer Research (S294), Weston Park Cancer Charity (CA95 and CA166) and Yorkshire Eye Research.	('Cancer', 'Phenotype', 'HP:0002664', (102, 108))	('S294', 'Var', (83, 87))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Weston Park Cancer', 'Disease', 'MESH:D009369', (90, 108))	('Weston Park Cancer', 'Disease', (90, 108))
1788	31105250	Particularly in cancers such as sarcoma, glioblastoma, pancreatic cancer, breast and colon cancer, oncogenic microRNAs (e.g., microRNA-20a, microRNA-9, microRNA-21) are overexpressed and/or tumor suppressors microRNAs (e.g., microRNA-145, microRNA-204) are downregulated.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('pancreatic cancer', 'Disease', 'MESH:D010190', (55, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('downregulated', 'NegReg', (257, 270))	('microRNA-21', 'Var', (152, 163))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancers', 'Disease', (16, 23))	('pancreatic cancer', 'Disease', (55, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (41, 53))	('overexpressed', 'PosReg', (169, 182))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('microRNA-20a', 'Var', (126, 138))	('glioblastoma', 'Disease', (41, 53))	('tumor', 'Disease', (190, 195))	('glioblastoma', 'Phenotype', 'HP:0012174', (41, 53))	('microRNA-9', 'Var', (140, 150))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (55, 72))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('breast and colon cancer', 'Disease', 'MESH:D001943', (74, 97))	('sarcoma', 'Disease', 'MESH:D012509', (32, 39))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('colon cancer', 'Phenotype', 'HP:0003003', (85, 97))	('sarcoma', 'Disease', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
1789	31105250	In the present study, microRNA-34a, microRNA-182, microRNA-137 and microRNA-144 have been selected since they are downregulated in UM and other cancers.	('UM', 'Phenotype', 'HP:0007716', (131, 133))	('microRNA-34a', 'Var', (22, 34))	('microRNA-144', 'Var', (67, 79))	('microRNA-137', 'Var', (50, 62))	('microRNA-182', 'Var', (36, 48))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('downregulated', 'NegReg', (114, 127))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
1792	31105250	Moreover, overexpression of microRNA-34a can downregulate the Akt protein and cell cycle-related proteins, reducing the metastatic and proliferation potential of the cells.	('cell cycle', 'biological_process', 'GO:0007049', ('78', '88'))	('Akt', 'Gene', '207', (62, 65))	('microRNA-34a', 'Var', (28, 40))	('reducing', 'NegReg', (107, 115))	('downregulate', 'NegReg', (45, 57))	('cell', 'Protein', (78, 82))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('overexpression', 'PosReg', (10, 24))	('Akt', 'Gene', (62, 65))
1795	31105250	Furthermore, microRNA-182 controls the forkhead box protein O1 (FoxO1), which is related to osteogenesis, T-cell development and tumorigenesis.	('osteogenesis', 'biological_process', 'GO:0001503', ('92', '104'))	('controls', 'Reg', (26, 34))	('osteogenesis', 'Disease', 'MESH:D010013', (92, 104))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('osteogenesis', 'Disease', (92, 104))	('forkhead box protein O1', 'Gene', '2308', (39, 62))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('FoxO1', 'Gene', (64, 69))	('FoxO1', 'Gene', '2308', (64, 69))	('T-cell development', 'biological_process', 'GO:0030217', ('106', '124'))	('tumor', 'Disease', (129, 134))	('microRNA-182', 'Var', (13, 25))	('forkhead box protein O1', 'Gene', (39, 62))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
1799	31105250	By regulating CTBP1 through microRNA-137, it is possible to avoid E-cadherin suppression.	('microRNA-137', 'Var', (28, 40))	('CTBP1', 'Gene', '1487', (14, 19))	('CTBP1', 'Gene', (14, 19))	('regulating', 'Reg', (3, 13))	('E-cadherin', 'Gene', (66, 76))	('E-cadherin', 'Gene', '999', (66, 76))	('cadherin', 'molecular_function', 'GO:0008014', ('68', '76'))
1818	31105250	Roswell Park Memorial Institute (RPMI) medium, streptomycin-penicillin (100X), fetal bovine serum (FBS), l-glutamine (100X), trypsin (10X), phosphate-buffered saline (PBS) and cell culture plasticware were purchased from VWR.	('bovine', 'Species', '9913', (85, 91))	('streptomycin-penicillin', 'Chemical', '-', (47, 70))	('FBS', 'Disease', 'MESH:D005198', (99, 102))	('phosphate-buffered saline', 'Chemical', '-', (140, 165))	('100X', 'Var', (118, 122))	('FBS', 'Disease', (99, 102))	('l-glutamine', 'Chemical', 'MESH:D005973', (105, 116))
1879	31105250	Specifically, the bare nanoparticles were incubated with oligonucleotides (DNA mix 2 or siRNA mix) modified with a thiol moiety in the presence of NaCl for 16 h. In the case of the nanoparticle modified with SN38, the particles were previously incubated with the aptamer AS1411 for 30 min, and the modified SN38 (2) was then added to the solution (Figure 4).	('modified', 'Var', (194, 202))	('SN38', 'Chemical', 'MESH:D000077146', (307, 311))	('mix', 'Gene', '83881', (94, 97))	('oligonucleotides', 'Chemical', 'MESH:D009841', (57, 73))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('NaCl', 'Chemical', 'MESH:D012965', (147, 151))	('SN38', 'Chemical', 'MESH:D000077146', (208, 212))	('mix', 'Gene', '83881', (79, 82))	('thiol', 'Chemical', 'MESH:D013438', (115, 120))	('mix', 'Gene', (79, 82))	('AS1411', 'Chemical', 'MESH:C513936', (271, 277))	('mix', 'Gene', (94, 97))
1885	31105250	Cell viability on Mel 202 was reduced after AuNP siRNAs mix treatment, and it was further reduced when AuNP siRNAs were combined with AuNP SN38.	('mix', 'Gene', (56, 59))	('reduced', 'NegReg', (90, 97))	('SN38', 'Chemical', 'MESH:D000077146', (139, 143))	('Cell viability', 'CPA', (0, 14))	('AuNP', 'Var', (44, 48))	('reduced', 'NegReg', (30, 37))	('mix', 'Gene', '83881', (56, 59))
1886	31105250	Interestingly, the cell cycle was affected when SN38 was present, but not when siRNAs were used in the formulation (Figure 7, and Supplementary Figures S5 and S6).	('affected', 'Reg', (34, 42))	('SN38', 'Var', (48, 52))	('cell cycle', 'biological_process', 'GO:0007049', ('19', '29'))	('SN38', 'Chemical', 'MESH:D000077146', (48, 52))	('cell cycle', 'CPA', (19, 29))
1887	31105250	It requires the formation of duplexes between the oligonucleotides and the target mRNAs, which usually leads to the degradation of the RNA by ribonuclease H (RNase H).	('duplexes', 'Var', (29, 37))	('oligonucleotides', 'Chemical', 'MESH:D009841', (50, 66))	('formation', 'Reg', (16, 25))	('leads to', 'Reg', (103, 111))	('RNA', 'cellular_component', 'GO:0005562', ('135', '138'))	('degradation', 'MPA', (116, 127))	('degradation', 'biological_process', 'GO:0009056', ('116', '127'))	('formation', 'biological_process', 'GO:0009058', ('16', '25'))
1888	31105250	Herein, this reactivity has been exploited using oligonucleotides with the same sequence as four microRNAs downregulated in UM: microRNA-34a, microRNA-182, microRNA-137, and microRNA-144.	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('microRNA-182', 'Var', (142, 154))	('microRNA-144', 'Var', (174, 186))	('microRNA-137', 'Var', (156, 168))	('microRNA-34a', 'Var', (128, 140))	('downregulated', 'NegReg', (107, 120))	('oligonucleotides', 'Chemical', 'MESH:D009841', (49, 65))
1905	31105250	In contrast, SN38 promoted a reduction in the G1 phase and an increase in G2 phase (Figure 3c), as previously reported.	('SN38', 'Var', (13, 17))	('G1 phase', 'biological_process', 'GO:0051318', ('46', '54'))	('G2 phase', 'biological_process', 'GO:0051319', ('74', '82'))	('reduction', 'NegReg', (29, 38))	('SN38', 'Chemical', 'MESH:D000077146', (13, 17))	('G1 phase', 'CPA', (46, 54))	('increase', 'PosReg', (62, 70))
1915	31105250	In this regard, the addition of SN38 reduced the negative charge, as expected.	('reduced', 'NegReg', (37, 44))	('SN38', 'Var', (32, 36))	('SN38', 'Chemical', 'MESH:D000077146', (32, 36))	('negative charge', 'MPA', (49, 64))
1918	31105250	The particles prepared were tested in cell culture, individually and in combination, revealing that when the two types of nanoparticles where used (AuNP DNA mix and AuNP SN38), a higher inhibition was obtained, as observed previously with the oligonucleotides and the free drug.	('DNA', 'cellular_component', 'GO:0005574', ('153', '156'))	('SN38', 'Chemical', 'MESH:D000077146', (170, 174))	('oligonucleotides', 'Chemical', 'MESH:D009841', (243, 259))	('mix', 'Gene', '83881', (157, 160))	('AuNP SN38', 'Var', (165, 174))	('mix', 'Gene', (157, 160))
1920	31105250	In this case, the inhibition by the AuNP siRNA mix was higher than that by the AuNP DNA mix, and it was even higher when combined with SN38.	('SN38', 'Chemical', 'MESH:D000077146', (135, 139))	('mix', 'Gene', '83881', (88, 91))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('AuNP', 'Var', (36, 40))	('mix', 'Gene', '83881', (47, 50))	('mix', 'Gene', (88, 91))	('higher', 'PosReg', (109, 115))	('inhibition', 'MPA', (18, 28))	('mix', 'Gene', (47, 50))	('higher', 'PosReg', (55, 61))
1924	31105250	In other words, the selected oligonucleotides could lead the cell cycle progression as was previously reported with other microRNAs, such as the microRNA-181 family.	('cell cycle', 'biological_process', 'GO:0007049', ('61', '71'))	('oligonucleotides', 'Chemical', 'MESH:D009841', (29, 45))	('lead', 'PosReg', (52, 56))	('oligonucleotides', 'Var', (29, 45))	('cell cycle progression', 'CPA', (61, 83))
1941	30223826	Although patients with germline disease have an increased risk to develop skin melanoma, there is no established relationship between retinoblastoma and uveal melanoma.	('patients', 'Species', '9606', (9, 17))	('retinoblastoma', 'Phenotype', 'HP:0009919', (134, 148))	('develop', 'PosReg', (66, 73))	('uveal melanoma', 'Phenotype', 'HP:0007716', (153, 167))	('uveal melanoma', 'Disease', (153, 167))	('uveal melanoma', 'Disease', 'MESH:C536494', (153, 167))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('retinoblastoma', 'Disease', 'MESH:D012175', (134, 148))	('retinoblastoma', 'Disease', (134, 148))	('skin melanoma', 'Disease', 'MESH:D008545', (74, 87))	('germline disease', 'Var', (23, 39))	('skin melanoma', 'Disease', (74, 87))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
1969	28630054	Expression of SLC45A2 and CTL sensitivity could be further upregulated in BRAF(V600E)-mutant melanoma cells upon treatment with BRAF or MEK inhibitors, similarly to other MDAs.	('V600E', 'Var', (79, 84))	('melanoma cells', 'Disease', 'MESH:D008545', (93, 107))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma cells', 'Disease', (93, 107))	('further upregulated', 'PosReg', (51, 70))	('MEK', 'Gene', (136, 139))	('BRAF', 'Gene', (74, 78))	('Expression', 'MPA', (0, 10))	('MEK', 'Gene', '5609', (136, 139))	('BRAF', 'Gene', '673', (74, 78))	('V600E', 'SUBSTITUTION', 'None', (79, 84))	('BRAF', 'Gene', '673', (128, 132))	('CTL', 'MPA', (26, 29))	('BRAF', 'Gene', (128, 132))	('SLC45A2', 'Gene', (14, 21))
1977	28630054	In humans, a pathogenic mutation of SLC45A2 leads to type IV oculocutaneous albinism (OCA4; refs.).	('OCA4', 'Gene', (86, 90))	('type IV oculocutaneous albinism', 'Disease', (53, 84))	('SLC45A2', 'Gene', (36, 43))	('humans', 'Species', '9606', (3, 9))	('mutation', 'Var', (24, 32))	('pathogenic', 'Reg', (13, 23))	('leads to', 'Reg', (44, 52))	('albinism', 'Phenotype', 'HP:0001022', (76, 84))	('OCA4', 'Gene', '51151', (86, 90))
1978	28630054	SLC45A2 variants have been associated with an increased risk for melanoma.	('associated', 'Reg', (27, 37))	('variants', 'Var', (8, 16))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('SLC45A2', 'Gene', (0, 7))
2015	28630054	Primary neonatal epidermal melanocytes were transduced with lentiviral vectors that used a CMV promoter to drive expression of either wild-type (WT) BRAF or mutated BRAF(V600E), along with eGFP expression driven by a downstream IRES element, allowing for flow cytometric sorting of transduced cells followed by selection of equivalently transduced lines based on GFP expression.	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('BRAF', 'Gene', '673', (165, 169))	('V600E', 'Var', (170, 175))	('BRAF', 'Gene', (165, 169))	('V600E', 'SUBSTITUTION', 'None', (170, 175))	('mutated', 'Var', (157, 164))
2017	28630054	For induction of DCs, adherent PBMCs were cultured with GM-CSF (800 U/mL) and IL4 (500 U/mL) in AIM-V medium (Invitrogen Life Technologies) for 6 days and then matured using a 1-day incubation in IL1beta (2 ng/mL), IL6 (1,000 U/mL), TNFalpha (10 ng/mL), and PGE2(1,000 ng/mL).	('1,000', 'Var', (220, 225))	('IL6', 'molecular_function', 'GO:0005138', ('215', '218'))	('IL1beta', 'Gene', (196, 203))	('TNFalpha', 'Gene', (233, 241))	('1,000', 'Var', (263, 268))	('TNFalpha', 'Gene', '7124', (233, 241))	('PGE2', 'Chemical', 'MESH:D015232', (258, 262))	('IL1', 'molecular_function', 'GO:0005149', ('196', '199'))	('IL1beta', 'Gene', '3553', (196, 203))	('IL4', 'molecular_function', 'GO:0005136', ('78', '81'))	('GM-CSF', 'Gene', (56, 62))	('GM-CSF', 'Gene', '1437', (56, 62))	('IL4', 'Gene', '3565', (78, 81))	('IL6', 'Gene', '3569', (215, 218))	('IL6', 'Gene', (215, 218))	('IL4', 'Gene', (78, 81))
2026	28630054	Expanded T cells were also analyzed by flow cytometry for markers CD45RA, CCR7, CD62L, and CD28 to assess effector/central memory phenotype.	('CD45RA', 'Var', (66, 72))	('memory', 'biological_process', 'GO:0007613', ('123', '129'))	('CD28', 'Gene', (91, 95))	('CCR', 'molecular_function', 'GO:0043880', ('74', '77'))	('CD28', 'Gene', '940', (91, 95))	('CD62L', 'Gene', (80, 85))	('CCR7', 'Gene', '1236', (74, 78))	('CD62L', 'Gene', '6402', (80, 85))	('CCR7', 'Gene', (74, 78))
2036	28630054	Melanoma cell lines expressing mutant BRAF(V600E) (Mel526 and A375), or wild-type BRAF (MeWo) were treated with the BRAF(V600E)-specific inhibitor dabrafenib (50 nmol/L), the MEK inhibitor trametinib (50 nmol/L, GlaxoSmithKline), or both inhibitors for 48 hours.	('mutant', 'Var', (31, 37))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('MEK', 'Gene', (175, 178))	('V600E', 'Var', (121, 126))	('BRAF', 'Gene', '673', (82, 86))	('BRAF', 'Gene', '673', (116, 120))	('Melanoma', 'Disease', (0, 8))	('MEK', 'Gene', '5609', (175, 178))	('BRAF', 'Gene', (82, 86))	('BRAF', 'Gene', (116, 120))	('trametinib', 'Chemical', 'MESH:C560077', (189, 199))	('V600E', 'SUBSTITUTION', 'None', (121, 126))	('BRAF', 'Gene', '673', (38, 42))	('dabrafenib', 'Chemical', 'MESH:C561627', (147, 157))	('BRAF', 'Gene', (38, 42))	('V600E', 'Var', (43, 48))	('V600E', 'SUBSTITUTION', 'None', (43, 48))
2048	28630054	One of the two HLA-A*2402-restricted peptides (SYIGLKGLYF) was detectable on parental Mel888 cells (which naturally express HLA-A*2402), but showed an increased abundance upon A*2402 overexpression (~3-fold, Supplementary Fig.	('increased', 'PosReg', (151, 160))	('HLA-A', 'Gene', (15, 20))	('A*2402', 'Var', (176, 182))	('peptides', 'Chemical', 'MESH:D010455', (37, 45))	('HLA-A', 'Gene', '3105', (124, 129))	('abundance', 'MPA', (161, 170))	('HLA-A', 'Gene', (124, 129))	('HLA-A', 'Gene', '3105', (15, 20))	('overexpression', 'PosReg', (183, 197))
2050	28630054	Because HLA-A*0201 and A*2402 are collectively expressed by >60% of melanoma patients, the identified peptide epitopes have the potential to constitute widely shared melanoma target antigens.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('HLA-A', 'Gene', (8, 13))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('patients', 'Species', '9606', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('A*2402', 'Var', (23, 29))	('HLA-A', 'Gene', '3105', (8, 13))
2080	28630054	Therefore, we next assessed the cytotoxic activity of SLYSYFQKV-specific CD8 T cells against normal primary A*0201-expressing melanocytes compared with T cells specific for other known A*0201-restricted MDA peptides.	('peptides', 'Chemical', 'MESH:D010455', (207, 215))	('CD8', 'Gene', '925', (73, 76))	('SLYSYFQKV-specific', 'Var', (54, 72))	('CD8', 'Gene', (73, 76))
2083	28630054	When melanocyte lines were used as targets for SLC45A2-, PMEL-, or MART-1-specific CTLs, all melanocyte lines were efficiently killed by PMEL and MART-1 CTLs, but not by SLC45A2-specific T cells (Fig.	('PMEL', 'Gene', '6490', (137, 141))	('PMEL-', 'Gene', (57, 62))	('PMEL-', 'Gene', '6490', (57, 62))	('PMEL', 'Gene', (137, 141))	('PMEL', 'Gene', (57, 61))	('PMEL', 'Gene', '6490', (57, 61))	('MART-1 CTLs', 'Var', (146, 157))
2095	28630054	To investigate whether MAP kinase pathway activation through mutated BRAF(V600E) could modulate SLC45A2 expression, we transduced primary melanocytes to express GFP, wild-type (WT) BRAF, or mutant BRAF(V600E).	('modulate', 'Reg', (87, 95))	('MAP kinase pathway', 'Pathway', (23, 41))	('V600E', 'Var', (202, 207))	('BRAF', 'Gene', (197, 201))	('V600E', 'SUBSTITUTION', 'None', (202, 207))	('BRAF', 'Gene', '673', (197, 201))	('mutant', 'Var', (190, 196))	('BRAF', 'Gene', (181, 185))	('expression', 'MPA', (104, 114))	('activation', 'PosReg', (42, 52))	('V600E', 'Var', (74, 79))	('mutated', 'Var', (61, 68))	('BRAF', 'Gene', '673', (181, 185))	('BRAF', 'Gene', '673', (69, 73))	('V600E', 'SUBSTITUTION', 'None', (74, 79))	('MAP', 'molecular_function', 'GO:0004239', ('23', '26'))	('SLC45A2', 'Gene', (96, 103))	('BRAF', 'Gene', (69, 73))
2096	28630054	Gene expression microarray analysis showed that BRAF(V600E) expression led to a significant downregulation of MDAs PMEL, MART-1, TYRP1, TYR, and SLC45A2, ranging from approximately 17% to 33% of the expression in control GFP-transduced cells (Fig.	('MART-1', 'Gene', (121, 127))	('downregulation', 'NegReg', (92, 106))	('TYR', 'Enzyme', (136, 139))	('TYRP1', 'Gene', (129, 134))	('TYRP1', 'Gene', '7306', (129, 134))	('PMEL', 'Gene', (115, 119))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('TYR', 'Chemical', 'MESH:D014443', (129, 132))	('V600E', 'Var', (53, 58))	('PMEL', 'Gene', '6490', (115, 119))	('V600E', 'SUBSTITUTION', 'None', (53, 58))	('TYR', 'Chemical', 'MESH:D014443', (136, 139))	('SLC45A2', 'Enzyme', (145, 152))
2097	28630054	Thus, we next investigated whether clinically relevant BRAF and MEK inhibitors could upregulate the expression of SLC45A2 in melanoma cells, as has been demonstrated for other MDAs.	('melanoma cells', 'Disease', (125, 139))	('MEK', 'Gene', (64, 67))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('MEK', 'Gene', '5609', (64, 67))	('SLC45A2', 'Gene', (114, 121))	('upregulate', 'PosReg', (85, 95))	('inhibitors', 'Var', (68, 78))	('expression', 'MPA', (100, 110))	('BRAF', 'Gene', '673', (55, 59))	('BRAF', 'Gene', (55, 59))	('melanoma cells', 'Disease', 'MESH:D008545', (125, 139))
2098	28630054	Melanoma cells were treated with sublethal doses of the BRAF(V600E)-specific inhibitor dabrafenib, MEK inhibitor trametinib, or both inhibitors, for 48 hours, after which mRNA was isolated and expression of SLC45A2 and MART-1 analyzed by qRT-PCR.	('MEK', 'Gene', '5609', (99, 102))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('dabrafenib', 'Chemical', 'MESH:C561627', (87, 97))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('trametinib', 'Chemical', 'MESH:C560077', (113, 123))	('Melanoma', 'Disease', (0, 8))	('V600E', 'Var', (61, 66))	('V600E', 'SUBSTITUTION', 'None', (61, 66))	('MEK', 'Gene', (99, 102))
2099	28630054	A significant increase in both SLC45A2 and MART-1 gene expression was observed in BRAF(V600E)-expressing Mel526 cells after treatment with both inhibitors, alone or in combination (Fig.	('SLC45A2', 'Gene', (31, 38))	('V600E', 'Var', (87, 92))	('V600E', 'SUBSTITUTION', 'None', (87, 92))	('expression', 'MPA', (55, 65))	('gene expression', 'biological_process', 'GO:0010467', ('50', '65'))	('MART-1 gene', 'Gene', (43, 54))	('increase', 'PosReg', (14, 22))
2100	28630054	Collectively, these data indicate that MAPK pathway inhibitors can effectively upregulate the expression of SLC45A2 in BRAF(V600E)-mutated melanomas, leading to enhanced tumor cell recognition and killing by SLC45A2-specific CD8+ T cells.	('BRAF', 'Var', (119, 123))	('enhanced', 'PosReg', (161, 169))	('killing', 'CPA', (197, 204))	('melanomas', 'Disease', 'MESH:D008545', (139, 148))	('tumor', 'Disease', (170, 175))	('MAPK', 'molecular_function', 'GO:0004707', ('39', '43'))	('melanomas', 'Disease', (139, 148))	('CD8', 'Gene', (225, 228))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('SLC45A2', 'Gene', (108, 115))	('melanomas', 'Phenotype', 'HP:0002861', (139, 148))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('V600E', 'Var', (124, 129))	('cell recognition', 'biological_process', 'GO:0008037', ('176', '192'))	('expression', 'MPA', (94, 104))	('CD8', 'Gene', '925', (225, 228))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('V600E', 'SUBSTITUTION', 'None', (124, 129))	('upregulate', 'PosReg', (79, 89))
2120	28630054	These differential MDA gene expression profiles are consistent with our data showing that HLA-A*0201+primary melanocytes were readily lysed by A*0201-restricted PMEL- and MART1-specific CTLs but not by SLC45A2-specific CTLs, despite the ability of all 3 CTL lines to robustly kill melanoma tumor cells.	('gene expression', 'biological_process', 'GO:0010467', ('23', '38'))	('A*0201-restricted', 'Var', (143, 160))	('PMEL-', 'Gene', (161, 166))	('melanoma tumor', 'Disease', (281, 295))	('PMEL-', 'Gene', '6490', (161, 166))	('melanoma', 'Phenotype', 'HP:0002861', (281, 289))	('MDA', 'Gene', (19, 22))	('melanoma tumor', 'Disease', 'MESH:D008545', (281, 295))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('HLA-A', 'Gene', '3105', (90, 95))	('HLA-A', 'Gene', (90, 95))
2202	29755733	Loss-of-function mutations of the BAP1 gene are associated with the highest metastatic risk, whereas gain-of-function mutations of SF3B1 and EIF1AX often confer a better prognosis.	('Loss-of-function', 'NegReg', (0, 16))	('BAP1', 'Gene', '8314', (34, 38))	('metastatic', 'CPA', (76, 86))	('SF3B1', 'Gene', '23451', (131, 136))	('BAP1', 'Gene', (34, 38))	('mutations', 'Var', (118, 127))	('mutations', 'Var', (17, 26))	('SF3B1', 'Gene', (131, 136))	('EIF1AX', 'Gene', '1964', (141, 147))	('EIF1AX', 'Gene', (141, 147))	('gain-of-function', 'PosReg', (101, 117))
2211	29755733	A small fraction of non-heritable retinoblastoma presents with a MYCN oncogene mutation that results in a unilateral, sporadic tumor .	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('retinoblastoma', 'Gene', (34, 48))	('retinoblastoma', 'Gene', '5925', (34, 48))	('results in', 'Reg', (93, 103))	('tumor', 'Disease', (127, 132))	('MYCN', 'Gene', (65, 69))	('MYCN', 'Gene', '4613', (65, 69))	('retinoblastoma', 'Phenotype', 'HP:0009919', (34, 48))	('mutation', 'Var', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
2214	29755733	The presence of a germline RB1 mutation increases the risk for secondary cancers, especially when retinoblastoma is treated with external beam radiation (EBR) .	('RB1', 'Gene', '5925', (27, 30))	('secondary cancers', 'Disease', 'MESH:D009369', (63, 80))	('retinoblastoma', 'Gene', (98, 112))	('mutation', 'Var', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('EBR', 'Chemical', '-', (154, 157))	('secondary cancers', 'Disease', (63, 80))	('retinoblastoma', 'Phenotype', 'HP:0009919', (98, 112))	('retinoblastoma', 'Gene', '5925', (98, 112))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('RB1', 'Gene', (27, 30))
2217	29755733	Focal therapies such as laser ablation and cryotherapy can be used for retinoblastoma with ICRB classes A and B, whereas more advanced cases (ICRB class C, D, or E) are preferentially treated with systemic chemotherapy or intra-arterial chemotherapy (IAC) over EBR or plaque brachytherapy because of their adverse effects.	('EBR', 'Chemical', '-', (261, 264))	('retinoblastoma', 'Phenotype', 'HP:0009919', (71, 85))	('ICRB', 'Var', (91, 95))	('retinoblastoma', 'Gene', '5925', (71, 85))	('retinoblastoma', 'Gene', (71, 85))
2219	29755733	In 2004, a group of Japanese investigators reported a new technique of balloon-occluding the internal carotid artery distal to the ostium of the ophthalmic artery and then locally injecting melphalan to treat retinoblastoma .	('retinoblastoma', 'Gene', (209, 223))	('balloon-occluding', 'Var', (71, 88))	('retinoblastoma', 'Gene', '5925', (209, 223))	('retinoblastoma', 'Phenotype', 'HP:0009919', (209, 223))	('ostium of the ophthalmic artery', 'Phenotype', 'HP:0410006', (131, 162))	('occluding the internal carotid artery', 'Phenotype', 'HP:0005290', (79, 116))	('melphalan', 'Chemical', 'MESH:D008558', (190, 199))
2223	29755733	Bilateral retinoblastoma with a germline RB1 mutation can be treated with either systemic chemotherapy or tandem IAC, in which IAC is performed in both eyes in a single IAC session .	('RB1', 'Gene', '5925', (41, 44))	('Bilateral retinoblastoma', 'Disease', 'MESH:D012175', (0, 24))	('Bilateral retinoblastoma', 'Disease', (0, 24))	('mutation', 'Var', (45, 53))	('retinoblastoma', 'Phenotype', 'HP:0009919', (10, 24))	('RB1', 'Gene', (41, 44))
2253	29755733	Uveal melanoma is largely due to sporadic mutations in uveal melanocytes, and inherited germline mutations that contribute to the development of this tumor are extremely rare, occurring in 3% to 4% of patients .	('patients', 'Species', '9606', (201, 209))	('Uveal melanoma', 'Disease', 'MESH:C536494', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('Uveal melanoma', 'Disease', (0, 14))	('mutations', 'Var', (42, 51))
2263	29755733	Combinations of mutations of these genes lead to variations in the development and metastasis of uveal melanoma.	('metastasis of uveal melanoma', 'Disease', 'MESH:C536494', (83, 111))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('mutations', 'Var', (16, 25))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('metastasis of uveal melanoma', 'Disease', (83, 111))	('variations', 'Reg', (49, 59))	('development', 'CPA', (67, 78))
2264	29755733	Of these, GNAQ and GNA11 mutations are involved in the early stage of oncogenesis and occur in a mutually exclusive manner in approximately 91% of the patients .	('GNAQ', 'Gene', '2776', (10, 14))	('involved', 'Reg', (39, 47))	('GNA11', 'Gene', (19, 24))	('mutations', 'Var', (25, 34))	('GNA11', 'Gene', '2767', (19, 24))	('oncogenesis', 'biological_process', 'GO:0007048', ('70', '81'))	('patients', 'Species', '9606', (151, 159))	('GNAQ', 'Gene', (10, 14))
2265	29755733	Recently, a loss-of-function mutation of BAP1, a tumor suppressor gene, was discovered to be heavily associated with more malignant types of uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (141, 155))	('mutation', 'Var', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('uveal melanoma', 'Phenotype', 'HP:0007716', (141, 155))	('uveal melanoma', 'Disease', (141, 155))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('BAP1', 'Gene', (41, 45))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('49', '65'))	('tumor', 'Disease', (49, 54))	('tumor suppressor', 'biological_process', 'GO:0051726', ('49', '65'))	('loss-of-function', 'NegReg', (12, 28))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('BAP1', 'Gene', '8314', (41, 45))
2266	29755733	Loss of BAP1 induces dedifferentiation of melanoma cells and the development of stem cell-like characteristics , .	('melanoma', 'Disease', (42, 50))	('development of stem cell-like characteristics', 'CPA', (65, 110))	('induces', 'Reg', (13, 20))	('BAP1', 'Gene', '8314', (8, 12))	('dedifferentiation', 'CPA', (21, 38))	('BAP1', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))	('dedifferentiation', 'biological_process', 'GO:0043696', ('21', '38'))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
2267	29755733	On the other hand, hemizygous, gain-of-function mutations of SF3B1 and EIF1AX generally indicate a better prognosis and occur in lower-risk melanomas .	('better', 'PosReg', (99, 105))	('SF3B1', 'Gene', (61, 66))	('EIF1AX', 'Gene', '1964', (71, 77))	('EIF1AX', 'Gene', (71, 77))	('melanomas', 'Disease', (140, 149))	('SF3B1', 'Gene', '23451', (61, 66))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('gain-of-function', 'PosReg', (31, 47))	('melanomas', 'Disease', 'MESH:D008545', (140, 149))	('mutations', 'Var', (48, 57))
2268	29755733	Of note, melanomas with SF3B1 mutations are associated with late-onset metastases .	('associated', 'Reg', (44, 54))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanomas', 'Phenotype', 'HP:0002861', (9, 18))	('SF3B1', 'Gene', (24, 29))	('metastases', 'Disease', (71, 81))	('melanomas', 'Disease', 'MESH:D008545', (9, 18))	('mutations', 'Var', (30, 39))	('metastases', 'Disease', 'MESH:D009362', (71, 81))	('SF3B1', 'Gene', '23451', (24, 29))	('melanomas', 'Disease', (9, 18))
2269	29755733	BAP1, SF3B1, and EIF1AX mutations mostly occur late in tumor development and also occur in a mutually exclusive fashion .	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('BAP1', 'Gene', (0, 4))	('SF3B1', 'Gene', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('SF3B1', 'Gene', '23451', (6, 11))	('EIF1AX', 'Gene', '1964', (17, 23))	('EIF1AX', 'Gene', (17, 23))	('mutations', 'Var', (24, 33))	('BAP1', 'Gene', '8314', (0, 4))
2276	29755733	It is reported that BAP1 mutations can be observed in approximately 80% of metastatic uveal melanoma cells .	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('mutations', 'Var', (25, 34))	('uveal melanoma', 'Disease', 'MESH:C536494', (86, 100))	('BAP1', 'Gene', (20, 24))	('uveal melanoma', 'Disease', (86, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('BAP1', 'Gene', '8314', (20, 24))	('observed', 'Reg', (42, 50))
2277	29755733	In another study, 71%, 11%, and 0% of patients with primary uveal melanoma who developed metastases carried BAP1, SF3B1, and EIF1AX mutations, respectively, signifying that EIF1AX and SF3B1 mutations generally confer a good prognosis .	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('uveal melanoma', 'Disease', 'MESH:C536494', (60, 74))	('patients', 'Species', '9606', (38, 46))	('SF3B1', 'Gene', (114, 119))	('SF3B1', 'Gene', (184, 189))	('metastases', 'Disease', 'MESH:D009362', (89, 99))	('uveal melanoma', 'Disease', (60, 74))	('EIF1AX', 'Gene', (125, 131))	('EIF1AX', 'Gene', (173, 179))	('BAP1', 'Gene', '8314', (108, 112))	('mutations', 'Var', (190, 199))	('metastases', 'Disease', (89, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('EIF1AX', 'Gene', '1964', (125, 131))	('SF3B1', 'Gene', '23451', (114, 119))	('SF3B1', 'Gene', '23451', (184, 189))	('EIF1AX', 'Gene', '1964', (173, 179))	('BAP1', 'Gene', (108, 112))	('mutations', 'Var', (132, 141))
2278	29755733	In the largest single-institution case series of over 1,000 patients, 3-year Kaplan-Meier estimates for metastatic uveal melanoma were provided for the following cytogenetic abnormalities: 5% for partial monosomy of chromosome 3; 19% for complete monosomy 3; 23% for loss of 6q; 29% for loss of 8p; 21% for gain of 8q; 1% for disomy of 3, 6, and 8; 29% for complete monosomy 3, 6p gain, and 8q gain; 14% for complete monosomy of 3, disomy of 6, and gain of 8q and 8p; 27% for complete monosomy of 3, disomy of 6, and gain of 8q; and 28% for complete monosomy of 3, disomy of 6, gain of 8q, and loss of 8p .	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('chromosome', 'cellular_component', 'GO:0005694', ('216', '226'))	('gain of 8q', 'Var', (578, 588))	('uveal melanoma', 'Disease', (115, 129))	('uveal melanoma', 'Disease', 'MESH:C536494', (115, 129))	('disomy of', 'Var', (432, 441))	('uveal melanoma', 'Phenotype', 'HP:0007716', (115, 129))	('patients', 'Species', '9606', (60, 68))	('gain of 8q', 'Var', (517, 527))	('gain', 'Var', (449, 453))	('loss of 8p', 'Var', (594, 604))	('loss', 'Var', (267, 271))	('disomy of 6', 'Var', (565, 576))	('loss', 'Var', (287, 291))	('disomy of 6', 'Var', (500, 511))	('complete monosomy of 3', 'Var', (476, 498))	('complete monosomy of 3', 'Var', (541, 563))
2280	29755733	Also, class 1 tumors that are PRAME + were found to be associated with SF3B1 mutations and inversely to EIF1AX mutations .	('EIF1AX', 'Gene', (104, 110))	('SF3B1', 'Gene', (71, 76))	('associated', 'Reg', (55, 65))	('SF3B1', 'Gene', '23451', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (77, 86))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('PRAME', 'Gene', '23532', (30, 35))	('PRAME', 'Gene', (30, 35))	('EIF1AX', 'Gene', '1964', (104, 110))
2281	29755733	A combination of SF3B1 mutations and PRAME expression appears to contribute to late metastases in class 1 tumors , while PRAME + class 2 tumors exhibited accelerated progression to metastases .	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('SF3B1', 'Gene', (17, 22))	('PRAME', 'Gene', '23532', (37, 42))	('mutations', 'Var', (23, 32))	('PRAME', 'Gene', (37, 42))	('metastases', 'Disease', 'MESH:D009362', (181, 191))	('metastases', 'Disease', 'MESH:D009362', (84, 94))	('metastases', 'Disease', (181, 191))	('SF3B1', 'Gene', '23451', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('contribute', 'Reg', (65, 75))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('metastases', 'Disease', (84, 94))	('PRAME', 'Gene', '23532', (121, 126))	('PRAME', 'Gene', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
2285	29755733	Fine needle aspiration biopsy (FNAB) is performed by using small-sized needles (23-, 25-, or 27-gauge) or vitrectomy probes in either a transvitreal or a trans-scleral manner, depending on the tumor location.	('aspiration', 'Phenotype', 'HP:0002835', (12, 22))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('23-', 'Var', (80, 83))	('tumor', 'Disease', (193, 198))
2293	29755733	125I and 103Pd both emit low-energy gamma rays and thus cause less damage to surrounding healthy tissues compared with isotopes that were used in the first half of the 20th century, such as 60Co.	('rays', 'Species', '255564', (42, 46))	('low-energy gamma rays', 'MPA', (25, 46))	('125I', 'Var', (0, 4))
2301	29755733	Both plaque and proton beam therapy are known to cause ocular complications, including cataracts, radiation retinopathy, and radiation optic neuropathy.	('cataracts', 'Disease', 'MESH:D002386', (87, 96))	('ocular complications', 'Disease', 'MESH:D000783', (55, 75))	('optic neuropathy', 'Phenotype', 'HP:0001138', (135, 151))	('ocular complications', 'Disease', (55, 75))	('radiation optic neuropathy', 'Disease', 'MESH:D004194', (125, 151))	('retinopathy', 'Phenotype', 'HP:0000488', (108, 119))	('proton beam therapy', 'Var', (16, 35))	('radiation retinopathy', 'Disease', 'MESH:D004194', (98, 119))	('cataracts', 'Phenotype', 'HP:0000518', (87, 96))	('radiation retinopathy', 'Disease', (98, 119))	('radiation optic neuropathy', 'Disease', (125, 151))	('neuropathy', 'Phenotype', 'HP:0009830', (141, 151))	('cause', 'Reg', (49, 54))	('cataracts', 'Disease', (87, 96))
2303	29755733	In addition to the fact that GEP class 2 melanomas have higher mortality rates than GEP class 1 tumors, several additional factors that contribute valuable prognostic information have recently been identified.	('melanomas', 'Disease', 'MESH:D008545', (41, 50))	('mortality rates', 'MPA', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('GEP', 'Var', (29, 32))	('melanomas', 'Disease', (41, 50))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('higher', 'PosReg', (56, 62))	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))
2307	29755733	Traditionally, tumors with more malignant characteristics, such as tumors with monosomy 3 or those that metastasized, were reported to regress faster after plaque therapy , .	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('monosomy 3', 'Var', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
2312	29755733	When the BAP1 gene is mutated, proper removal of ubiquitin from H2A is inhibited, leading to a dedifferentiated state of melanoma cells .	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('ubiquitin', 'molecular_function', 'GO:0031386', ('49', '58'))	('melanoma', 'Disease', (121, 129))	('H2A', 'Gene', (64, 67))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('inhibited', 'NegReg', (71, 80))	('BAP1', 'Gene', '8314', (9, 13))	('leading to', 'Reg', (82, 92))	('mutated', 'Var', (22, 29))	('H2A', 'Gene', '8337', (64, 67))	('BAP1', 'Gene', (9, 13))	('removal of ubiquitin', 'MPA', (38, 58))
2314	29755733	Activation mutation of GNAQ or GNA11 keeps guanine nucleotide-binding proteins in an active state, which subsequently upregulates protein kinase C and mitogen-activated protein kinase pathways that are involved in the proliferation and differentiation of cells at the early stages of uveal melanoma oncogenesis .	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('upregulates', 'PosReg', (118, 129))	('guanine nucleotide-binding proteins', 'MPA', (43, 78))	('uveal melanoma oncogenesis', 'Disease', (284, 310))	('GNAQ', 'Gene', (23, 27))	('melanoma', 'Phenotype', 'HP:0002861', (290, 298))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (284, 298))	('oncogenesis', 'biological_process', 'GO:0007048', ('299', '310'))	('GNA11', 'Gene', '2767', (31, 36))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('51', '69'))	('uveal melanoma oncogenesis', 'Disease', 'MESH:C536494', (284, 310))	('mutation', 'Var', (11, 19))	('GNA11', 'Gene', (31, 36))	('GNAQ', 'Gene', '2776', (23, 27))	('protein kinase C', 'Pathway', (130, 146))	('mitogen-activated protein kinase pathways', 'Pathway', (151, 192))
2330	29651818	PBRT for intraocular tumors can induce various orbital and periorbital tissue changes.	('intraocular tumors', 'Disease', (9, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('PBRT', 'Var', (0, 4))	('induce', 'Reg', (32, 38))	('intraocular tumors', 'Disease', 'MESH:D064090', (9, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
2375	29651818	In the current study, we confirmed that PBRT can cause periorbital and orbital complications and also presented details regarding subsequent oculoplastic problems.	('periorbital', 'Disease', (55, 66))	('PBRT', 'Var', (40, 44))	('orbital complications', 'Disease', 'MESH:D009916', (71, 92))	('oculoplastic', 'Disease', 'None', (141, 153))	('orbital complications', 'Disease', (71, 92))	('cause', 'Reg', (49, 54))	('oculoplastic', 'Disease', (141, 153))
2378	29651818	It is thought that damage caused by PBRT to the conjunctiva or to the canalicular epithelium might have resulted in the chronic inflammation.	('PBRT', 'Var', (36, 40))	('inflammation', 'Disease', (128, 140))	('inflammation', 'biological_process', 'GO:0006954', ('128', '140'))	('resulted', 'Reg', (104, 112))	('inflammation', 'Disease', 'MESH:D007249', (128, 140))
2403	29651818	For instance, this study is not a prospective cohort study of intraocular tumors treated with PBRT, but a case series of intraocular tumor patients treated with PBRT and referred to the oculoplasty clinic due to periorbital or orbital complications.	('orbital complications', 'Disease', 'MESH:D009916', (227, 248))	('patients', 'Species', '9606', (139, 147))	('intraocular tumor', 'Disease', 'MESH:D064090', (62, 79))	('intraocular tumor', 'Disease', 'MESH:D064090', (121, 138))	('orbital complications', 'Disease', (227, 248))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('intraocular tumors', 'Disease', 'MESH:D064090', (62, 80))	('PBRT', 'Var', (161, 165))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('periorbital', 'Disease', (212, 223))	('intraocular tumors', 'Disease', (62, 80))	('intraocular tumor', 'Disease', (121, 138))
2407	29651818	As for the two adult patients who underwent only PBRT and did not exhibit enophthalmic features during the 2-3 years follow-up, their lesions were limited to the nasal area and it is possible that PBRT did not influence posterior orbital tissue and subsequently did not cause enophthalmos.	('enophthalmos', 'Phenotype', 'HP:0000490', (276, 288))	('cause', 'Reg', (270, 275))	('PBRT', 'Var', (197, 201))	('enophthalmos', 'Disease', 'MESH:D015841', (276, 288))	('patients', 'Species', '9606', (21, 29))	('enophthalmic features', 'Phenotype', 'HP:0000490', (74, 95))	('enophthalmic feature', 'Phenotype', 'HP:0000490', (74, 94))	('enophthalmos', 'Disease', (276, 288))
2408	29651818	In conclusion, PBRT is expected to be superior to conventional radiation therapy with respect to protecting normal surrounding tissues, yet it can still cause radiation-related orbital and periorbital complications and therefore careful orbital examination before and after treatment is mandatory.	('PBRT', 'Var', (15, 19))	('orbital complications', 'Disease', 'MESH:D009916', (193, 214))	('orbital', 'Disease', (177, 184))	('orbital complications', 'Disease', (193, 214))	('cause', 'Reg', (153, 158))
2412	23714463	For this review, we focus on three rare syndromes and their associated genetic mutations including BAP1, TP53, and SDHx (SDHA, SDHB, SDHC, SDHD, SDHAF2).	('SDHC', 'Gene', (133, 137))	('BAP1', 'Gene', (99, 103))	('SDHD', 'Gene', (139, 143))	('SDH', 'Gene', '6390', (121, 124))	('SDHAF2', 'Gene', '54949', (145, 151))	('SDHAF2', 'Gene', (145, 151))	('SDH', 'Gene', (145, 148))	('SDHB', 'Gene', (127, 131))	('SDH', 'Gene', (115, 118))	('SDH', 'Gene', '6390', (127, 130))	('mutations', 'Var', (79, 88))	('SDH', 'Gene', (139, 142))	('SDH', 'Gene', (121, 124))	('TP53', 'Gene', (105, 109))	('SDH', 'Gene', '6390', (133, 136))	('SDHx', 'Chemical', '-', (115, 119))	('SDH', 'Gene', (127, 130))	('SDHC', 'Gene', '6391', (133, 137))	('BAP1', 'Gene', '8314', (99, 103))	('SDH', 'Gene', (133, 136))	('SDH', 'Gene', '6390', (145, 148))	('SDHD', 'Gene', '6392', (139, 143))	('SDHB', 'Gene', '6390', (127, 131))	('SDH', 'Gene', '6390', (115, 118))	('SDH', 'Gene', '6390', (139, 142))	('TP53', 'Gene', '7157', (105, 109))
2413	23714463	BAP1 encodes an enzyme that catalyzes the removal of ubiquitin from protein substrates, and germline mutations of BAP1 cause a novel cancer syndrome characterized by high incidence of benign atypical melanocytic tumors, uveal melanomas, cutaneous melanomas, malignant mesotheliomas, and potentially other cancers.	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('benign atypical melanocytic tumors', 'Disease', (184, 218))	('BAP1', 'Gene', (114, 118))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (237, 256))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (237, 256))	('uveal melanoma', 'Phenotype', 'HP:0007716', (220, 234))	('ubiquitin', 'molecular_function', 'GO:0031386', ('53', '62'))	('cancers', 'Disease', 'MESH:D009369', (305, 312))	('BAP1', 'Gene', (0, 4))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (237, 255))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('cause', 'Reg', (119, 124))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (258, 281))	('uveal melanomas', 'Disease', (220, 235))	('uveal melanomas', 'Phenotype', 'HP:0007716', (220, 235))	('cancer syndrome', 'Disease', 'MESH:D009369', (133, 148))	('melanomas', 'Phenotype', 'HP:0002861', (226, 235))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (258, 280))	('mutations', 'Var', (101, 110))	('cutaneous melanomas', 'Disease', (237, 256))	('cancer syndrome', 'Disease', (133, 148))	('malignant mesotheliomas', 'Disease', (258, 281))	('benign atypical melanocytic tumors', 'Disease', 'MESH:D009508', (184, 218))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancers', 'Phenotype', 'HP:0002664', (305, 312))	('cancers', 'Disease', (305, 312))	('BAP1', 'Gene', '8314', (114, 118))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (258, 281))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('melanomas', 'Phenotype', 'HP:0002861', (247, 256))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('uveal melanomas', 'Disease', 'MESH:C536494', (220, 235))	('BAP1', 'Gene', '8314', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
2414	23714463	TP53 mutations cause Li-Fraumeni syndrome (LFS), a highly penetrant cancer syndrome associated with multiple tumors including but not limited to sarcomas, breast cancers, brain tumors, and adrenocortical carcinomas.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancers', 'Disease', 'MESH:D001943', (155, 169))	('breast cancers', 'Disease', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('brain tumors', 'Disease', (171, 183))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('cause', 'Reg', (15, 20))	('Li-Fraumeni syndrome', 'Disease', (21, 41))	('TP53', 'Gene', '7157', (0, 4))	('multiple tumors', 'Disease', 'MESH:D009369', (100, 115))	('breast cancers', 'Phenotype', 'HP:0003002', (155, 169))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (21, 41))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (189, 214))	('adrenocortical carcinomas', 'Disease', (189, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('mutations', 'Var', (5, 14))	('cancer syndrome', 'Disease', 'MESH:D009369', (68, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('TP53', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('multiple tumors', 'Disease', (100, 115))	('brain tumors', 'Disease', 'MESH:D001932', (171, 183))	('sarcomas', 'Disease', 'MESH:D012509', (145, 153))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (189, 214))	('brain tumors', 'Phenotype', 'HP:0030692', (171, 183))	('sarcomas', 'Phenotype', 'HP:0100242', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('sarcomas', 'Disease', (145, 153))	('cancer syndrome', 'Disease', (68, 83))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
2416	23714463	SDH is a mitochondrial enzyme complex involved in the tricarboxylic acid (TCA) cycle, and germline SDHx mutations lead to increased succinate with subsequent paragangliomas, pheochromocytomas, renal cell carcinomas (RCCs), gastrointestinal stromal tumors (GISTs), and other rarer cancers.	('succinate', 'MPA', (132, 141))	('cancers', 'Phenotype', 'HP:0002664', (280, 287))	('SDH', 'Gene', (99, 102))	('cancers', 'Disease', (280, 287))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (223, 254))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (223, 254))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('SDH', 'Gene', '6390', (0, 3))	('TCA', 'Chemical', 'MESH:D014233', (74, 77))	('paragangliomas', 'Disease', 'MESH:D010235', (158, 172))	('paraganglioma', 'Phenotype', 'HP:0002668', (158, 171))	('paragangliomas', 'Phenotype', 'HP:0002668', (158, 172))	('mutations', 'Var', (104, 113))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (193, 213))	('pheochromocytomas', 'Disease', 'MESH:D010673', (174, 191))	('pheochromocytomas', 'Disease', (174, 191))	('increased', 'PosReg', (122, 131))	('RCC', 'Disease', (216, 219))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))	('gastrointestinal stromal tumors', 'Disease', (223, 254))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (193, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('SDH', 'Gene', (0, 3))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (54, 72))	('cancers', 'Disease', 'MESH:D009369', (280, 287))	('SDHx', 'Chemical', '-', (99, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('increased succinate', 'Phenotype', 'HP:0020149', (122, 141))	('renal cell carcinomas', 'Disease', (193, 214))	('SDH', 'Gene', '6390', (99, 102))	('enzyme complex', 'cellular_component', 'GO:1902494', ('23', '37'))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (174, 191))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('TCA) cycle', 'biological_process', 'GO:0006099', ('74', '84'))	('paragangliomas', 'Disease', (158, 172))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (193, 214))	('succinate', 'Chemical', 'MESH:D019802', (132, 141))	('GISTs', 'Phenotype', 'HP:0100723', (256, 261))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (174, 190))	('RCCs', 'Phenotype', 'HP:0005584', (216, 220))
2424	23714463	Nearly 15 years later, Harbor and colleagues reported a high frequency of BAP1 mutations in metastasizing uveal melanoma (UM), including one that was germline in origin.	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('BAP1', 'Gene', '8314', (74, 78))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('UM', 'Phenotype', 'HP:0007716', (122, 124))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('uveal melanoma', 'Disease', (106, 120))	('BAP1', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))
2426	23714463	In one report, germline inactivating mutations of BAP1 were discovered in two families with high incidence of malignant mesothelioma (MM), UM, and other cancers.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (110, 132))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('germline inactivating mutations', 'Var', (15, 46))	('cancers', 'Disease', (153, 160))	('malignant mesothelioma', 'Disease', (110, 132))	('discovered', 'Reg', (60, 70))	('BAP1', 'Gene', '8314', (50, 54))	('UM', 'Phenotype', 'HP:0007716', (139, 141))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (110, 132))	('BAP1', 'Gene', (50, 54))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
2427	23714463	In the second report, two families were described in which germline mutations in BAP1 predisposed to multiple melanocytic tumors ranging from epithelioid nevi to atypical melanocytic tumors, with some mutation carriers developing UM or cutaneous melanoma (CM).	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('epithelioid nevi', 'Disease', (142, 158))	('multiple melanocytic tumors', 'Disease', (101, 128))	('BAP1', 'Gene', (81, 85))	('melanoma', 'Phenotype', 'HP:0002861', (246, 254))	('cutaneous melanoma', 'Disease', (236, 254))	('melanocytic tumors', 'Disease', 'MESH:D009508', (110, 128))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (236, 254))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (236, 254))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('predisposed to', 'Reg', (86, 100))	('melanocytic tumors', 'Disease', 'MESH:D009508', (171, 189))	('developing', 'PosReg', (219, 229))	('melanocytic tumors', 'Disease', (171, 189))	('nevi to atypical melanocytic tumors', 'Phenotype', 'HP:0000995', (154, 189))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('nevi', 'Phenotype', 'HP:0003764', (154, 158))	('UM', 'Phenotype', 'HP:0007716', (230, 232))	('germline mutations', 'Var', (59, 77))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('multiple melanocytic tumors', 'Disease', 'MESH:D009508', (101, 128))	('BAP1', 'Gene', '8314', (81, 85))	('CM', 'Phenotype', 'HP:0012056', (256, 258))
2428	23714463	Below, we focus on the involvement of BAP1 mutations in a new cancer predisposition disorder, now known as the BAP1 cancer syndrome.	('BAP1', 'Gene', '8314', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('BAP1', 'Gene', (38, 42))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('involvement', 'Reg', (23, 34))	('cancer syndrome', 'Disease', 'MESH:D009369', (116, 131))	('BAP1', 'Gene', (111, 115))	('mutations', 'Var', (43, 52))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('men', 'Species', '9606', (30, 33))	('cancer syndrome', 'Disease', (116, 131))	('BAP1', 'Gene', '8314', (38, 42))
2429	23714463	Notably, however, somatic BAP1 mutations have also been reported in various sporadic tumors including MM, RCC, and a rare, distinct subset of melanocytic tumors known as atypical Spitz tumors (ASTs).	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('BAP1', 'Gene', (26, 30))	('Spitz tumors', 'Disease', (179, 191))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('melanocytic tumors', 'Disease', (142, 160))	('melanocytic tumors', 'Disease', 'MESH:D009508', (142, 160))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Disease', (85, 91))	('mutations', 'Var', (31, 40))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('reported', 'Reg', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumors', 'Disease', (154, 160))	('Spitz tumors', 'Disease', 'MESH:D018332', (179, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('BAP1', 'Gene', '8314', (26, 30))
2432	23714463	Historically, the understanding of MM pathogenesis was understood in the context of somatic genetic losses within chromosome arms 3p, 9p, and 22q, the latter two specifically affecting CDKN2A and NF2, suggesting a multistep cascade involving the inactivation of multiple tumor suppressors.	('genetic', 'Var', (92, 99))	('losses', 'NegReg', (100, 106))	('CDKN2A', 'Gene', '1029', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('chromosome', 'cellular_component', 'GO:0005694', ('114', '124'))	('affecting', 'Reg', (175, 184))	('NF2', 'Gene', '4771', (196, 199))	('tumor', 'Disease', (271, 276))	('pathogenesis', 'biological_process', 'GO:0009405', ('38', '50'))	('CDKN2A', 'Gene', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('NF2', 'Gene', (196, 199))
2434	23714463	Bott and colleagues reported inactivating mutations in BAP1, a tumor suppressor gene located at 3p21.1, in 22% of sporadic MMs.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('63', '79'))	('tumor', 'Disease', (63, 68))	('BAP1', 'Gene', (55, 59))	('inactivating mutations', 'Var', (29, 51))	('MMs', 'Disease', (123, 126))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor suppressor', 'biological_process', 'GO:0051726', ('63', '79'))	('BAP1', 'Gene', '8314', (55, 59))
2436	23714463	Moreover, heterozygous germline mutations of BAP1 were identified in two high-risk cancer families in which the predominant malignancy was MM; notably, one family also had two cases of UM, a tumor type previously shown to be associated with somatic BAP1 mutations.	('UM', 'Phenotype', 'HP:0007716', (185, 187))	('BAP1', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('identified', 'Reg', (55, 65))	('BAP1', 'Gene', '8314', (45, 49))	('malignancy', 'Disease', 'MESH:D009369', (124, 134))	('BAP1', 'Gene', '8314', (249, 253))	('malignancy', 'Disease', (124, 134))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('BAP1', 'Gene', (249, 253))	('mutations', 'Var', (254, 263))	('cancer', 'Disease', (83, 89))
2442	23714463	Intriguingly, germline BAP1 mutations were also found in 2 of 26 sporadic MMs tested, and both patients with mutant BAP1 were previously diagnosed with UM.	('BAP1', 'Gene', (23, 27))	('BAP1', 'Gene', (116, 120))	('patients', 'Species', '9606', (95, 103))	('MMs', 'Disease', (74, 77))	('BAP1', 'Gene', '8314', (23, 27))	('UM', 'Phenotype', 'HP:0007716', (152, 154))	('found', 'Reg', (48, 53))	('mutant', 'Var', (109, 115))	('BAP1', 'Gene', '8314', (116, 120))	('mutations', 'Var', (28, 37))
2443	23714463	Concurrent work by Wiesner and colleagues revealed inactivating germline BAP1 mutations in two families with multiple benign melanocytic tumors; some affected individuals developed UM or CM, and one family member was subsequently diagnosed with MM.	('BAP1', 'Gene', '8314', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('BAP1', 'Gene', (73, 77))	('inactivating germline', 'Var', (51, 72))	('melanocytic tumors', 'Disease', (125, 143))	('mutations', 'Var', (78, 87))	('melanocytic tumors', 'Disease', 'MESH:D009508', (125, 143))	('CM', 'Phenotype', 'HP:0012056', (187, 189))	('developed', 'PosReg', (171, 180))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('UM', 'Phenotype', 'HP:0007716', (181, 183))	('germline', 'Var', (64, 72))
2444	23714463	The existence of a BAP1-related melanocytic disorder was confirmed by a report of germline BAP1 inactivation in families with metastatic UM or with both UM and CM; and some carriers also had atypical melanocytic tumors.	('BAP1', 'Gene', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('inactivation', 'Var', (96, 108))	('UM', 'Phenotype', 'HP:0007716', (153, 155))	('BAP1', 'Gene', '8314', (19, 23))	('melanocytic tumors', 'Disease', 'MESH:D009508', (200, 218))	('melanocytic disorder', 'Disease', 'MESH:D009508', (32, 52))	('melanocytic disorder', 'Disease', (32, 52))	('UM', 'Phenotype', 'HP:0007716', (137, 139))	('melanocytic tumors', 'Disease', (200, 218))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('BAP1', 'Gene', (19, 23))	('BAP1', 'Gene', '8314', (91, 95))	('metastatic UM', 'Disease', (126, 139))	('CM', 'Disease', (160, 162))	('CM', 'Phenotype', 'HP:0012056', (160, 162))
2445	23714463	Another group reported a germline BAP1 mutation in a family with a wide variety of cancers, including three MMs, three UMs, and three CMs.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('UM', 'Phenotype', 'HP:0007716', (119, 121))	('UMs', 'Disease', (119, 122))	('mutation', 'Var', (39, 47))	('BAP1', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('reported', 'Reg', (14, 22))	('germline', 'Var', (25, 33))	('CMs', 'Disease', (134, 137))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('BAP1', 'Gene', '8314', (34, 38))	('CM', 'Phenotype', 'HP:0012056', (134, 136))	('MMs', 'Disease', (108, 111))	('cancers', 'Disease', (83, 90))
2446	23714463	More recently, a germline BAP1 mutation was identified in a family in which MM was found in four members, none with a history of asbestos exposure; one member also had multiple melanocytic tumors.	('BAP1', 'Gene', (26, 30))	('multiple melanocytic tumors', 'Disease', 'MESH:D009508', (168, 195))	('multiple melanocytic tumors', 'Disease', (168, 195))	('mutation', 'Var', (31, 39))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('BAP1', 'Gene', '8314', (26, 30))	('asbestos', 'Chemical', 'MESH:D001194', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
2448	23714463	The full tumor spectrum associated with germline BAP1 mutations has yet to be established, as suggested by recent report of a germline BAP1 splice mutation and truncating frameshift in a family with UM, CM, suspected MM, as well as paraganglioma.	('paraganglioma', 'Phenotype', 'HP:0002668', (232, 245))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('paraganglioma', 'Disease', (232, 245))	('BAP1', 'Gene', (49, 53))	('BAP1', 'Gene', '8314', (135, 139))	('mutations', 'Var', (54, 63))	('truncating frameshift', 'Var', (160, 181))	('CM', 'Phenotype', 'HP:0012056', (203, 205))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('paraganglioma', 'Disease', 'MESH:D010235', (232, 245))	('BAP1', 'Gene', (135, 139))	('UM', 'Phenotype', 'HP:0007716', (199, 201))	('BAP1', 'Gene', '8314', (49, 53))
2454	23714463	Inactivating somatic mutations of BAP1 were identified in 26/31 (84%) metastasizing tumors, including one that was germline in origin.	('BAP1', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('identified', 'Reg', (44, 54))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('BAP1', 'Gene', '8314', (34, 38))	('Inactivating somatic mutations', 'Var', (0, 30))
2458	23714463	Biallelic inactivation of BAP1 has been documented in multiple tumors from these high-risk families, strongly suggesting that BAP1 acts as a classical tumor suppressor gene.	('tumor', 'Disease', (63, 68))	('BAP1', 'Gene', (26, 30))	('tumor suppressor', 'biological_process', 'GO:0051726', ('151', '167'))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('BAP1', 'Gene', (126, 130))	('tumor', 'Disease', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('Biallelic inactivation', 'Var', (0, 22))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('151', '167'))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('BAP1', 'Gene', '8314', (126, 130))	('BAP1', 'Gene', '8314', (26, 30))	('men', 'Species', '9606', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('multiple tumors', 'Disease', (54, 69))	('multiple tumors', 'Disease', 'MESH:D009369', (54, 69))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
2468	23714463	Mutations of BAP1 and potentially genes encoding other PR-DUB components may alter the function of the holo-complex leading to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('BAP1', 'Gene', (13, 17))	('alter', 'Reg', (77, 82))	('tumor', 'Disease', (127, 132))	('Mutations', 'Var', (0, 9))	('function', 'MPA', (87, 95))	('BAP1', 'Gene', '8314', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
2469	23714463	Germane to this, somatic ASXL1/2 alterations have been detected in human myelodysplastic disorders and solid tumors, and a conditional, systemic knockout model in which Bap1 was homozygously deleted in adult mice recapitulated features of human myelodysplastic syndrome.	('ASXL1/2', 'Gene', (25, 32))	('human', 'Species', '9606', (239, 244))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('solid tumors', 'Disease', 'MESH:D009369', (103, 115))	('myelodysplastic disorders', 'Disease', (73, 98))	('Bap1', 'Gene', '8314', (169, 173))	('Bap1', 'Gene', (169, 173))	('myelodysplastic syndrome', 'Disease', (245, 269))	('ASXL1/2', 'Gene', '171023;55252', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('alterations', 'Var', (33, 44))	('mice', 'Species', '10090', (208, 212))	('detected', 'Reg', (55, 63))	('myelodysplastic disorders', 'Phenotype', 'HP:0002863', (73, 98))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (245, 269))	('solid tumors', 'Disease', (103, 115))	('myelodysplastic disorders', 'Disease', 'MESH:D009190', (73, 98))	('human', 'Species', '9606', (67, 72))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (245, 269))
2470	23714463	While the first two reports of germline inactivating BAP1 mutations focused on different disease entities:that is, one on families with a high incidence of MM, and the other on families with multiple melanocytic tumors:both studies found recurrent UMs as well.	('mutations', 'Var', (58, 67))	('UM', 'Phenotype', 'HP:0007716', (248, 250))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('multiple melanocytic tumors', 'Disease', 'MESH:D009508', (191, 218))	('UMs', 'Disease', (248, 251))	('BAP1', 'Gene', '8314', (53, 57))	('multiple melanocytic tumors', 'Disease', (191, 218))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('focused', 'Reg', (68, 75))	('BAP1', 'Gene', (53, 57))
2471	23714463	As proposed by Goldstein, current evidence supports the notion that these initial reports of germline BAP1 mutations were describing a single syndrome consisting of a range of tumors with varying penetrance.	('BAP1', 'Gene', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('mutations', 'Var', (107, 116))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('BAP1', 'Gene', '8314', (102, 106))
2478	23714463	Moreover, why do BAP1 mutations predispose to cancer when present in the germ line, yet act as a late, somatic event in connection with UM metastasis?	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('predispose', 'Reg', (32, 42))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('UM', 'Phenotype', 'HP:0007716', (136, 138))	('BAP1', 'Gene', (17, 21))
2479	23714463	It is also unclear if variations in the number of melanocytic tumors and incidence of MM among BAP1 mutation carriers reflect differences in genetic background of affected individuals or differences in exposure to carcinogens.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('BAP1', 'Gene', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('carriers', 'Reg', (109, 117))	('mutation', 'Var', (100, 108))	('BAP1', 'Gene', '8314', (95, 99))	('melanocytic tumors', 'Disease', (50, 68))	('melanocytic tumors', 'Disease', 'MESH:D009508', (50, 68))
2481	23714463	BAP1 mutation carriers should be regularly monitored for evidence of early malignancy, and preventive measures such as avoidance of exposure to asbestos and sun should be implemented.	('asbestos', 'Chemical', 'MESH:D001194', (144, 152))	('BAP1', 'Gene', (0, 4))	('men', 'Species', '9606', (176, 179))	('malignancy', 'Disease', 'MESH:D009369', (75, 85))	('BAP1', 'Gene', '8314', (0, 4))	('malignancy', 'Disease', (75, 85))	('mutation', 'Var', (5, 13))
2484	23714463	In 1990, germline TP53 mutations were discovered to be the underlying cause of the majority of LFS cases.	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('cause', 'Reg', (70, 75))	('LFS', 'Disease', (95, 98))
2486	23714463	Approximately 1,800 different somatic and germline TP53 mutations have been reported, with most localized to the DNA binding domain (DBD) (http://p53.iarc.fr).	('DNA', 'cellular_component', 'GO:0005574', ('113', '116'))	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (51, 55))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('DNA binding', 'molecular_function', 'GO:0003677', ('113', '124'))	('TP53', 'Gene', '7157', (51, 55))
2487	23714463	Mutant p53 loss-of-function, dominant-negative and gain-of-function properties are all important for tumorigenesis in humans, with gain-of-function activities being particularly relevant.	('humans', 'Species', '9606', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('p53', 'Gene', '7157', (7, 10))	('gain-of-function', 'PosReg', (51, 67))	('loss-of-function', 'NegReg', (11, 27))	('Mutant', 'Var', (0, 6))	('p53', 'Gene', (7, 10))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
2496	23714463	Specific TP53 mutant genotype may influence age of onset and tumor spectrum.	('mutant', 'Var', (14, 20))	('age', 'MPA', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('TP53', 'Gene', '7157', (9, 13))	('influence', 'Reg', (34, 43))	('TP53', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
2497	23714463	Birch and colleagues reported a significantly higher incidence and earlier age at cancer diagnosis for breast (p = 0.006) and brain cancers (p = 0.05) in families who carry missense mutations in the DBD.	('brain cancers', 'Disease', 'MESH:D001932', (126, 139))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('brain cancers', 'Disease', (126, 139))	('higher', 'PosReg', (46, 52))	('breast', 'Disease', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('missense mutations', 'Var', (173, 191))
2499	23714463	Furthermore, nonsense, frameshift, and splice mutations are associated with particularly early tumor onset.	('nonsense', 'Var', (13, 21))	('associated', 'Reg', (60, 70))	('frameshift', 'Var', (23, 33))	('splice mutations', 'Var', (39, 55))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
2500	23714463	However, these genotype:phenotype correlations are not consistent, as numerous families carrying the same mutation express widely divergent clinical manifestations of age of onset and cancer type.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('mutation', 'Var', (106, 114))
2502	23714463	The sensitivity and specificity of the Chompret criteria are 82% and 58%, respectively, making it perhaps the most rigorous and relevant definition to justify TP53 mutation analysis.	('TP53', 'Gene', (159, 163))	('mutation', 'Var', (164, 172))	('TP53', 'Gene', '7157', (159, 163))
2508	23714463	Almost 50% of children with CPC harbor germline TP53 mutations even in the absence of a typical LFS family history.	('children', 'Species', '9606', (14, 22))	('TP53', 'Gene', '7157', (48, 52))	('CPC', 'cellular_component', 'GO:0032133', ('28', '31'))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('CPC', 'Disease', (28, 31))	('germline', 'Var', (39, 47))
2510	23714463	Approximately 20% to 30% of tumors in TP53 mutation carriers do not belong to the classical LFS tumor spectrum: Wilms tumor and phyllodes tumors of the breast are strongly associated, pancreatic cancer moderately associated, and neuroblastoma weakly associated with TP53 mutation carrier status.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TP53', 'Gene', (38, 42))	('LFS tumor', 'Disease', 'MESH:D016864', (92, 101))	('associated', 'Interaction', (172, 182))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('TP53', 'Gene', (266, 270))	('LFS tumor', 'Disease', (92, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (184, 201))	('mutation', 'Var', (43, 51))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('carrier', 'molecular_function', 'GO:0005215', ('280', '287'))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('neuroblastoma', 'Disease', (229, 242))	('neuroblastoma', 'Phenotype', 'HP:0003006', (229, 242))	('Wilms tumor', 'Disease', 'MESH:D009396', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('neuroblastoma', 'Disease', 'MESH:D009447', (229, 242))	('TP53', 'Gene', '7157', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (28, 34))	('TP53', 'Gene', '7157', (266, 270))	('Wilms tumor', 'Phenotype', 'HP:0002667', (112, 123))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic cancer', 'Disease', 'MESH:D010190', (184, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('pancreatic cancer', 'Disease', (184, 201))	('tumors', 'Disease', (138, 144))	('Wilms tumor', 'Disease', (112, 123))
2511	23714463	Carcinomas of the lung and gastrointestinal tract, lymphomas, and other neoplasms have been shown to occur in TP53 mutation carriers or first-degree relatives of carriers at much earlier ages than seen in the general population.	('carriers', 'Reg', (124, 132))	('lymphomas', 'Disease', (51, 60))	('lymphomas', 'Disease', 'MESH:D008223', (51, 60))	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))	('Carcinomas of the lung and gastrointestinal tract', 'Disease', 'MESH:D004067', (0, 49))	('neoplasms', 'Disease', 'MESH:D009369', (72, 81))	('neoplasms', 'Disease', (72, 81))	('lymphomas', 'Phenotype', 'HP:0002665', (51, 60))	('mutation', 'Var', (115, 123))	('Carcinomas', 'Phenotype', 'HP:0030731', (0, 10))	('neoplasms', 'Phenotype', 'HP:0002664', (72, 81))
2512	23714463	Approximately 1% of heritable breast cancers arise due to a germline TP53 mutation.	('mutation', 'Var', (74, 82))	('breast cancers', 'Disease', 'MESH:D001943', (30, 44))	('breast cancers', 'Disease', (30, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('arise due to', 'Reg', (45, 57))	('breast cancers', 'Phenotype', 'HP:0003002', (30, 44))	('germline', 'Var', (60, 68))
2513	23714463	However, 7% of women who develop breast cancer under 30 years of age and have no first- or second-degree relatives with cancer carry a TP53 mutation; presence of first- or second-degree relatives with cancer raises this likelihood to well over 75%.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('women', 'Species', '9606', (15, 20))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('TP53', 'Gene', '7157', (135, 139))	('cancer', 'Disease', (120, 126))	('mutation', 'Var', (140, 148))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('TP53', 'Gene', (135, 139))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
2516	23714463	In TP53 mutation carriers, the cumulative probability of a second cancer is 57% (+-10%) at 30 years.	('TP53', 'Gene', '7157', (3, 7))	('TP53', 'Gene', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutation', 'Var', (8, 16))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
2518	23714463	A unique R337H mutation exclusively found in LFS families from southeastern Brazil is a risk allele for pediatric ACC and, until recently, was thought to represent a unique example of a tissue-specific predisposing mutation.	('R337H', 'Var', (9, 14))	('R337H', 'Mutation', 'rs121912664', (9, 14))	('pediatric ACC', 'Disease', (104, 117))
2519	23714463	Nonbiased ascertainment of families with the R337H mutation shows that the cancer risk encompasses the full spectrum of tumors associated with LFS, in particular early-onset breast cancer (mean age at diagnosis below 40 years) and CPC.	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('breast cancer', 'Disease', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('CPC', 'Disease', (231, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('cancer', 'Disease', (75, 81))	('R337H', 'Mutation', 'rs121912664', (45, 50))	('R337H', 'Var', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('men', 'Species', '9606', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (181, 187))	('CPC', 'cellular_component', 'GO:0032133', ('231', '234'))
2520	23714463	Additionally, current data on overall cancer penetrance suggest that the age-related cancer risk is somewhat lower than in LFS associated with other TP53 mutations, with tumors detected in approximately 25% of carriers at the age of 30 and a lifetime risk of approximately 80%.	('cancer', 'Disease', (38, 44))	('lower', 'NegReg', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('TP53', 'Gene', '7157', (149, 153))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('TP53', 'Gene', (149, 153))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (154, 163))	('tumors', 'Disease', (170, 176))
2522	23714463	The PIN3 (16 bp duplication in intron 3) polymorphism has been associated with an increase in age of onset of tumors in TP53 mutation carriers.	('polymorphism', 'Var', (41, 53))	('PIN3', 'Gene', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('increase', 'PosReg', (82, 90))	('TP53', 'Gene', (120, 124))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('TP53', 'Gene', '7157', (120, 124))	('mutation', 'Var', (125, 133))
2523	23714463	A single nucleotide polymorphism (SNP) at codon 72 in exon 4 involves the substitution of an arginine for a proline base.	('arginine', 'MPA', (93, 101))	('proline', 'Chemical', 'MESH:D011392', (108, 115))	('arginine', 'Chemical', 'MESH:D001120', (93, 101))	('substitution', 'Var', (74, 86))
2524	23714463	The current consensus from a large number of studies is that R72 is more effective in inducing apoptosis than P72.	('P72', 'Gene', '10521', (110, 113))	('R72', 'Var', (61, 64))	('apoptosis', 'CPA', (95, 104))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('inducing', 'Reg', (86, 94))	('P72', 'Gene', (110, 113))
2525	23714463	On the other hand, the SNP309, rs2279744 T/G polymorphic substitution in the MDM2 gene appears to confer an earlier age of onset in LFS patients.	('rs2279744', 'Mutation', 'rs2279744', (31, 40))	('MDM2', 'Gene', '4193', (77, 81))	('MDM2', 'Gene', (77, 81))	('patients', 'Species', '9606', (136, 144))	('LFS', 'Disease', (132, 135))	('SNP309', 'Var', (23, 29))
2527	23714463	Interestingly, telomeres in peripheral blood leukocytes of TP53 mutation carriers are shorter than in normal individuals of corresponding age.	('mutation', 'Var', (64, 72))	('TP53', 'Gene', (59, 63))	('shorter', 'NegReg', (86, 93))	('telomeres', 'CPA', (15, 24))	('TP53', 'Gene', '7157', (59, 63))
2529	23714463	The accelerated telomere attrition in TP53 mutation carriers is postulated to lead to greater genomic instability and earlier age of cancer onset in successive generations.	('mutation', 'Var', (43, 51))	('telomere', 'MPA', (16, 24))	('greater', 'PosReg', (86, 93))	('genomic instability', 'CPA', (94, 113))	('TP53', 'Gene', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('telomere', 'cellular_component', 'GO:0000781', ('16', '24'))	('cancer', 'Disease', (133, 139))	('accelerated', 'PosReg', (4, 15))	('telomere', 'cellular_component', 'GO:0005696', ('16', '24'))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('TP53', 'Gene', '7157', (38, 42))
2530	23714463	Global copy number variation frequency and total structural variation are significantly increased in individuals with germline TP53 mutations (p = 0.01).	('mutations', 'Var', (132, 141))	('increased', 'PosReg', (88, 97))	('structural variation', 'MPA', (49, 69))	('germline', 'Var', (118, 126))	('TP53', 'Gene', '7157', (127, 131))	('Global copy number variation frequency', 'MPA', (0, 38))	('TP53', 'Gene', (127, 131))
2532	23714463	These findings, together with the accelerated telomere attrition data, support the notion that TP53 mutation carriers have inherently unstable genomes and harbor other genetic and genomic alterations that can directly modify the age phenotype.	('telomere', 'cellular_component', 'GO:0000781', ('46', '54'))	('telomere', 'cellular_component', 'GO:0005696', ('46', '54'))	('modify', 'Reg', (218, 224))	('mutation', 'Var', (100, 108))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
2533	23714463	Recent evidence suggests that the "early" germline presence of TP53 mutations in a cell may induce early critical telomere length shortening, which in turn may be involved in chromothripsis:an event of catastrophic chromosome rearrangement that is frequently seen in LFS-associated tumors.	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('telomere length shortening', 'Phenotype', 'HP:0031413', (114, 140))	('TP53', 'Gene', '7157', (63, 67))	('LFS-associated', 'Disease', (267, 281))	('TP53', 'Gene', (63, 67))	('telomere', 'cellular_component', 'GO:0000781', ('112', '120'))	('tumors', 'Disease', (282, 288))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('mutations', 'Var', (68, 77))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('telomere', 'cellular_component', 'GO:0005696', ('112', '120'))	('men', 'Species', '9606', (235, 238))	('chromosome', 'cellular_component', 'GO:0005694', ('213', '223'))	('involved', 'Reg', (163, 171))	('induce', 'Reg', (92, 98))	('chromothripsis', 'Disease', (175, 189))
2534	23714463	What the other genetic events are that modify the "driver" genotype conferred by the germline TP53 mutation are being actively explored and may ultimately lead to the development of more precise predictive algorithms of cancer phenotype and disease risk.	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('algorithms of cancer', 'Disease', 'MESH:D009369', (206, 226))	('TP53', 'Gene', '7157', (94, 98))	('lead', 'Reg', (155, 159))	('mutation', 'Var', (99, 107))	('TP53', 'Gene', (94, 98))	('algorithms of cancer', 'Disease', (206, 226))	('men', 'Species', '9606', (174, 177))
2536	23714463	For female TP53 mutation carriers, the role of prophylactic mastectomy has not been carefully evaluated.	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('mutation', 'Var', (16, 24))
2539	23714463	Although FDG-PET/CT can identify new primary cancers in TP53 mutation carriers, repeated radiation exposure may accelerate the risk of secondary malignancies.	('malignancies', 'Disease', (145, 157))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('TP53', 'Gene', '7157', (56, 60))	('mutation', 'Var', (61, 69))	('TP53', 'Gene', (56, 60))	('malignancies', 'Disease', 'MESH:D009369', (145, 157))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))	('accelerate', 'PosReg', (112, 122))
2542	23714463	Studies to improve the predictive value of genetic and genomic modifier effects on the mutant TP53-associated phenotype will inform development of more refined tumor screening protocols and lead to improved understanding of the biologic mechanisms of tumor formation in these patients.	('patients', 'Species', '9606', (276, 284))	('tumor', 'Disease', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('mutant', 'Var', (87, 93))	('men', 'Species', '9606', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('formation', 'biological_process', 'GO:0009058', ('257', '266'))	('tumor', 'Disease', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
2550	23714463	However, in the presence of an underlying germline SDHx mutation, the tumor rate may be extraordinarily high with a penetrance approaching 80%.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('germline', 'Var', (42, 50))	('SDHx', 'Gene', (51, 55))	('SDHx', 'Chemical', '-', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
2554	23714463	Over the past several years, we have learned that germline mutations in each of these SDHx genes may lead to development of paragangliomas or pheochromocytomas.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (142, 158))	('paragangliomas or pheochromocytomas', 'Disease', (124, 159))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (142, 159))	('germline mutations', 'Var', (50, 68))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('paragangliomas or pheochromocytomas', 'Disease', 'MESH:D010673', (124, 159))	('paraganglioma', 'Phenotype', 'HP:0002668', (124, 137))	('paragangliomas', 'Phenotype', 'HP:0002668', (124, 138))	('SDHx', 'Gene', (86, 90))	('men', 'Species', '9606', (116, 119))	('SDHx', 'Chemical', '-', (86, 90))	('lead to', 'Reg', (101, 108))
2557	23714463	Germline mutations in other genes such as NF1, VHL, RET, TMEM127, and MAX also have been associated with the development of paragangliomas and pheochromocytomas.	('Germline mutations', 'Var', (0, 18))	('associated with', 'Reg', (89, 104))	('VHL', 'Disease', 'MESH:D006623', (47, 50))	('paragangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (124, 160))	('VHL', 'Disease', (47, 50))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('RET', 'Gene', '5979', (52, 55))	('paraganglioma', 'Phenotype', 'HP:0002668', (124, 137))	('MAX', 'Gene', (70, 73))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (143, 160))	('TMEM127', 'Gene', (57, 64))	('paragangliomas', 'Phenotype', 'HP:0002668', (124, 138))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (143, 159))	('TMEM127', 'Gene', '55654', (57, 64))	('RET', 'Gene', (52, 55))	('NF1', 'Gene', '4763', (42, 45))	('men', 'Species', '9606', (116, 119))	('NF1', 'Gene', (42, 45))
2558	23714463	Based on gene expression and pathway analysis, these tumors can be divided into two clusters corresponding to their underlying gene mutations: Cluster 1 (Cluster 1A: SDHx, Cluster 1B: VHL), associated with pseudohypoxia and aberrant VEGF signaling, and Cluster 2 (RET/NF1/TMEM127/MAX), associated with aberrant kinase signaling pathways.	('TMEM127', 'Gene', (272, 279))	('RET', 'Gene', '5979', (264, 267))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('associated', 'Reg', (190, 200))	('pseudohypoxia', 'Disease', (206, 219))	('pseudohypoxia', 'Disease', 'None', (206, 219))	('NF1', 'Gene', '4763', (268, 271))	('gene expression', 'biological_process', 'GO:0010467', ('9', '24'))	('TMEM127', 'Gene', '55654', (272, 279))	('VEGF', 'Gene', '7422', (233, 237))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('RET', 'Gene', (264, 267))	('VEGF', 'Gene', (233, 237))	('VHL', 'Disease', (184, 187))	('tumors', 'Disease', (53, 59))	('NF1', 'Gene', (268, 271))	('VEGF signaling', 'biological_process', 'GO:0038084', ('233', '247'))	('kinase signaling pathways', 'Pathway', (311, 336))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('signaling', 'biological_process', 'GO:0023052', ('318', '327'))	('mutations', 'Var', (132, 141))	('SDHx', 'Chemical', '-', (166, 170))	('VHL', 'Disease', 'MESH:D006623', (184, 187))
2559	23714463	In the absence of SDHx mutations, paragangliomas (and sometimes pheochromocytomas) are benign and very slow growing tumors.	('SDHx', 'Chemical', '-', (18, 22))	('paragangliomas', 'Disease', (34, 48))	('very slow growing tumors', 'Disease', 'MESH:D000326', (98, 122))	('paragangliomas', 'Disease', 'MESH:D010235', (34, 48))	('paragangliomas', 'Phenotype', 'HP:0002668', (34, 48))	('paraganglioma', 'Phenotype', 'HP:0002668', (34, 47))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (64, 81))	('mutations', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (64, 80))	('SDHx', 'Gene', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('pheochromocytomas', 'Disease', (64, 81))	('very slow growing tumors', 'Disease', (98, 122))	('pheochromocytomas', 'Disease', 'MESH:D010673', (64, 81))
2561	23714463	However, when such tumors occur because of germline mutations in SDHx genes, paragangliomas and pheochromocytomas can transform to become highly aggressive and metastatic.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('paraganglioma', 'Phenotype', 'HP:0002668', (77, 90))	('germline mutations', 'Var', (43, 61))	('paragangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (77, 113))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('metastatic', 'CPA', (160, 170))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('SDHx', 'Chemical', '-', (65, 69))	('SDHx', 'Gene', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('paragangliomas', 'Phenotype', 'HP:0002668', (77, 91))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (96, 112))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (96, 113))
2563	23714463	A recent study from the National Institutes of Health demonstrated that nearly 30% of nonmetastatic paragangliomas and pheochromocytomas are due to germline SDHx mutations, and that 44% of adults and 81% of children with metastatic disease are due to germline SDHx mutations.	('mutations', 'Var', (162, 171))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('children', 'Species', '9606', (207, 215))	('SDHx', 'Chemical', '-', (260, 264))	('SDHx', 'Chemical', '-', (157, 161))	('SDHx', 'Gene', (157, 161))	('paragangliomas', 'Phenotype', 'HP:0002668', (100, 114))	('paraganglioma', 'Phenotype', 'HP:0002668', (100, 113))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (119, 135))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (119, 136))	('paragangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (100, 136))	('due', 'Reg', (141, 144))
2564	23714463	In fact, this study did not test for all of the known SDHx genes, so the actual prevalence of germline SDHx mutations in this disease may be higher.	('SDHx', 'Chemical', '-', (54, 58))	('SDHx', 'Chemical', '-', (103, 107))	('SDHx', 'Gene', (103, 107))	('mutations', 'Var', (108, 117))
2566	23714463	Each SDHx gene mutation leads to a slightly different disease phenotype and clinical presentation (see Table 2).	('mutation', 'Var', (15, 23))	('SDHx', 'Chemical', '-', (5, 9))	('SDHx', 'Gene', (5, 9))
2567	23714463	Interestingly, PGL-1 disease related to germline SDHD mutations is inherited in a maternally imprinted fashion with only the children of fathers: but not mothers: developing disease.	('children', 'Species', '9606', (125, 133))	('mutations', 'Var', (54, 63))	('PGL', 'molecular_function', 'GO:0004598', ('15', '18'))	('PGL-1 disease', 'Disease', (15, 28))	('SDHD', 'Gene', '6392', (49, 53))	('PGL-1 disease', 'Disease', 'MESH:D010235', (15, 28))	('SDHD', 'Gene', (49, 53))
2569	23714463	This is also true for germline SDHAF2 mutations (PGL-2), which are also inherited as a maternally imprinted disease.	('SDHAF2', 'Gene', '54949', (31, 37))	('SDHAF2', 'Gene', (31, 37))	('PGL-2', 'Gene', '54949', (49, 54))	('PGL', 'molecular_function', 'GO:0004598', ('49', '52'))	('mutations', 'Var', (38, 47))	('PGL-2', 'Gene', (49, 54))
2570	23714463	Disease caused by germline SDHB mutations (PGL-4) seems to be the most common and malignant of the clinical phenotypes in "Familial Paraganglioma and Pheochromocytoma Syndrome."	('PGL-4', 'Gene', '6390', (43, 48))	('Paraganglioma', 'Phenotype', 'HP:0002668', (132, 145))	('caused', 'Reg', (8, 14))	('Familial Paraganglioma', 'Disease', 'MESH:D010235', (123, 145))	('Familial Paraganglioma', 'Disease', (123, 145))	('Pheochromocytoma Syndrome', 'Disease', (150, 175))	('mutations', 'Var', (32, 41))	('PGL-4', 'Gene', (43, 48))	('Pheochromocytoma Syndrome', 'Disease', 'MESH:D010673', (150, 175))	('SDHB', 'Gene', '6390', (27, 31))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (150, 166))	('PGL', 'molecular_function', 'GO:0004598', ('43', '46'))	('SDHB', 'Gene', (27, 31))
2571	23714463	Every germline SDHx mutation (except SDHAF2) has been associated with GISTs.	('SDHx', 'Chemical', '-', (15, 19))	('SDHx', 'Gene', (15, 19))	('GISTs', 'Phenotype', 'HP:0100723', (70, 75))	('mutation', 'Var', (20, 28))	('GISTs', 'Disease', (70, 75))	('SDHAF2', 'Gene', '54949', (37, 43))	('SDHAF2', 'Gene', (37, 43))	('associated', 'Reg', (54, 64))
2573	23714463	Previously, clinical testing for the specific inherited SDHx mutations was based on disease presentation.	('SDHx', 'Gene', (56, 60))	('mutations', 'Var', (61, 70))	('SDHx', 'Chemical', '-', (56, 60))
2574	23714463	For instance, a patient with metastatic paraganglioma that secretes catecholamine would first be tested for SDHB mutations, whereas a young patient with just familial head and neck paragangliomas might first be screened for SDHD or SDHC mutations.	('tested', 'Reg', (97, 103))	('mutations', 'Var', (113, 122))	('SDHD', 'Gene', (224, 228))	('SDHB', 'Gene', '6390', (108, 112))	('patient', 'Species', '9606', (16, 23))	('paraganglioma', 'Phenotype', 'HP:0002668', (40, 53))	('paragangliomas', 'Disease', 'MESH:D010235', (181, 195))	('SDHC', 'Gene', '6391', (232, 236))	('paragangliomas', 'Phenotype', 'HP:0002668', (181, 195))	('paraganglioma', 'Phenotype', 'HP:0002668', (181, 194))	('secretes catecholamine', 'MPA', (59, 81))	('gliomas', 'Phenotype', 'HP:0009733', (188, 195))	('SDHB', 'Gene', (108, 112))	('catecholamine', 'Chemical', 'MESH:D002395', (68, 81))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (176, 195))	('just familial head', 'Phenotype', 'HP:0001357', (153, 171))	('SDHC', 'Gene', (232, 236))	('paragangliomas', 'Disease', (181, 195))	('neck', 'cellular_component', 'GO:0044326', ('176', '180'))	('paraganglioma', 'Disease', (40, 53))	('paraganglioma', 'Disease', (181, 194))	('patient', 'Species', '9606', (140, 147))	('paraganglioma', 'Disease', 'MESH:D010235', (40, 53))	('SDHD', 'Gene', '6392', (224, 228))	('paraganglioma', 'Disease', 'MESH:D010235', (181, 194))
2575	23714463	In order to identify patients at risk for underlying germline SDHx mutations, it was observed several years ago that tumor tissues could be stained by immunohistochemistry (IHC) for the SDHB protein.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('SDHB', 'Gene', (186, 190))	('protein', 'cellular_component', 'GO:0003675', ('191', '198'))	('tumor', 'Disease', (117, 122))	('mutations', 'Var', (67, 76))	('patients', 'Species', '9606', (21, 29))	('SDHx', 'Gene', (62, 66))	('SDHx', 'Chemical', '-', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('SDHB', 'Gene', '6390', (186, 190))
2582	23714463	Like LFS, we have learned that scheduled surveillance can detect early tumors in patients with underlying germline SDHx mutations.	('SDHx', 'Chemical', '-', (115, 119))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('mutations', 'Var', (120, 129))	('tumors', 'Disease', (71, 77))	('SDHx', 'Gene', (115, 119))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
2588	23714463	Fractionated metanephrines are nearly always abnormal in individuals with a hereditary syndrome characterized by secreting tumors (elevated metanephrines for RET and NF1 mutations and elevated normetanephrines for SDHx and VHL mutations).	('SDHx', 'Chemical', '-', (214, 218))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('hereditary syndrome', 'Disease', (76, 95))	('NF1', 'Gene', '4763', (166, 169))	('normetanephrines', 'Chemical', 'MESH:D009647', (193, 209))	('VHL', 'Disease', 'MESH:D006623', (223, 226))	('hereditary syndrome', 'Disease', 'MESH:D009386', (76, 95))	('RET', 'Gene', '5979', (158, 161))	('NF1', 'Gene', (166, 169))	('metanephrines', 'MPA', (140, 153))	('elevated', 'PosReg', (131, 139))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('RET', 'Gene', (158, 161))	('elevated', 'PosReg', (184, 192))	('VHL', 'Disease', (223, 226))	('normetanephrines', 'MPA', (193, 209))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('metanephrines', 'Chemical', 'MESH:D008676', (140, 153))	('tumors', 'Disease', (123, 129))	('metanephrines', 'Chemical', 'MESH:D008676', (13, 26))	('SDHx', 'Gene', (214, 218))	('mutations', 'Var', (170, 179))	('metanephrines', 'Chemical', 'MESH:D008676', (196, 209))
2593	23714463	At the University of Utah, a recent prospective observational study of whole body, rapid sequence MRI in SDHx mutation carriers demonstrated MRI sensitivity of 88% and specificity of 95% to detect new tumors compared to biochemical testing sensitivity of 38% and specificity of 95% (K. Jasperson, personal communication, submitted).	('SDHx', 'Chemical', '-', (105, 109))	('SDHx', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('mutation', 'Var', (110, 118))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Disease', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))
2594	23714463	The University of Utah now recommends whole body MRI (5-mm slices from skull base to pelvis) at least every two years for patients with underlying SDHx mutations, followed by PET scans for patients with abnormal MRI results.	('mutations', 'Var', (152, 161))	('SDHx', 'Gene', (147, 151))	('men', 'Species', '9606', (32, 35))	('SDHx', 'Chemical', '-', (147, 151))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (189, 197))
2595	23714463	As testing for SDHx mutations has become more widespread, we have learned more about the spectrum of other SDH-related tumors, including GISTs, renal tumors (RCC, oncocytoma), papillary thyroid cancer, pituitary tumors, and even neuroblastoma.	('SDHx', 'Chemical', '-', (15, 19))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('renal tumors', 'Phenotype', 'HP:0009726', (144, 156))	('GISTs', 'Phenotype', 'HP:0100723', (137, 142))	('oncocytoma', 'Disease', 'MESH:D018249', (163, 173))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('papillary thyroid cancer', 'Disease', (176, 200))	('SDH', 'Gene', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('GISTs', 'Disease', (137, 142))	('neuroblastoma', 'Disease', (229, 242))	('SDH', 'Gene', '6390', (15, 18))	('neuroblastoma', 'Phenotype', 'HP:0003006', (229, 242))	('pituitary tumors', 'Disease', 'MESH:D010911', (202, 218))	('neuroblastoma', 'Disease', 'MESH:D009447', (229, 242))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('oncocytoma', 'Disease', (163, 173))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (176, 200))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('thyroid cancer', 'Phenotype', 'HP:0002890', (186, 200))	('tumors', 'Disease', (212, 218))	('RCC', 'Disease', (158, 161))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('renal tumors', 'Disease', (144, 156))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (176, 200))	('mutations', 'Var', (20, 29))	('SDH', 'Gene', (15, 18))	('SDH', 'Gene', '6390', (107, 110))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('pituitary tumors', 'Disease', (202, 218))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('renal tumors', 'Disease', 'MESH:D007674', (144, 156))
2596	23714463	In fact, wild-type GISTs lacking somatic KIT or PDFRA mutations have been shown to be 100% SDH-deficient as measured by SDHB IHC.	('SDH-deficient', 'Disease', 'MESH:D007153', (91, 104))	('mutations', 'Var', (54, 63))	('SDHB', 'Gene', '6390', (120, 124))	('PDFRA', 'Gene', (48, 53))	('GISTs', 'Phenotype', 'HP:0100723', (19, 24))	('SDHB', 'Gene', (120, 124))	('KIT', 'molecular_function', 'GO:0005020', ('41', '44'))	('SDH-deficient', 'Disease', (91, 104))
2599	23714463	Many recent reports have demonstrated germline SDHA mutations associated with SDH-deficient (wild-type KIT/PDFRA) GISTs, which can be detected by SDHA IHC.	('mutations', 'Var', (52, 61))	('SDH-deficient', 'Disease', 'MESH:D007153', (78, 91))	('SDH', 'Gene', (78, 81))	('associated', 'Reg', (62, 72))	('SDH', 'Gene', (47, 50))	('SDH', 'Gene', '6390', (146, 149))	('GISTs', 'Phenotype', 'HP:0100723', (114, 119))	('SDH-deficient', 'Disease', (78, 91))	('SDH', 'Gene', '6390', (78, 81))	('SDH', 'Gene', (146, 149))	('KIT', 'molecular_function', 'GO:0005020', ('103', '106'))	('SDH', 'Gene', '6390', (47, 50))
2600	23714463	Germline SDHx mutations still account for less than half of SDH-deficient GISTs, and the search for underlying SDH-related genes continues for the majority of patients with SDH-deficient GISTs.	('SDH', 'Gene', (60, 63))	('mutations', 'Var', (14, 23))	('GISTs', 'Phenotype', 'HP:0100723', (187, 192))	('SDH-deficient', 'Disease', 'MESH:D007153', (173, 186))	('SDH', 'Gene', '6390', (111, 114))	('SDH', 'Gene', '6390', (9, 12))	('SDH', 'Gene', '6390', (173, 176))	('SDH-deficient', 'Disease', (173, 186))	('SDH-deficient', 'Disease', 'MESH:D007153', (60, 73))	('SDH', 'Gene', '6390', (60, 63))	('SDH-deficient', 'Disease', (60, 73))	('SDH', 'Gene', (173, 176))	('GISTs', 'Phenotype', 'HP:0100723', (74, 79))	('patients', 'Species', '9606', (159, 167))	('SDH', 'Gene', (111, 114))	('SDH', 'Gene', (9, 12))	('SDHx', 'Chemical', '-', (9, 13))
2601	23714463	It is now recommended that patients with SDH-deficient GISTs be referred for genetic evaluation for underlying SDHx mutations.	('SDH-deficient', 'Disease', (41, 54))	('men', 'Species', '9606', (15, 18))	('SDH-deficient', 'Disease', 'MESH:D007153', (41, 54))	('GISTs', 'Phenotype', 'HP:0100723', (55, 60))	('patients', 'Species', '9606', (27, 35))	('mutations', 'Var', (116, 125))	('SDHx', 'Gene', (111, 115))	('SDHx', 'Chemical', '-', (111, 115))
2602	23714463	If germline SDHx mutations are identified in patients with GISTs, they should be considered for biochemical and imaging surveillance due to risk for other tumors.	('SDHx', 'Gene', (12, 16))	('GISTs', 'Phenotype', 'HP:0100723', (59, 64))	('SDHx', 'Chemical', '-', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', (155, 161))	('patients', 'Species', '9606', (45, 53))	('mutations', 'Var', (17, 26))
2603	23714463	As familial tumors due to inherited SDHx mutations become better recognized, we will begin to learn more about the genetic, epigenetic, and metabolic alterations related to cancer risk.	('SDHx', 'Gene', (36, 40))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('mutations', 'Var', (41, 50))	('SDHx', 'Chemical', '-', (36, 40))	('cancer', 'Disease', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('familial tumors', 'Disease', 'MESH:D009386', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('familial tumors', 'Disease', (3, 18))
2611	23714463	BAP1 encodes a catalyzing enzyme that removes ubiquitin from protein substrates, and germline BAP1 mutations cause a novel cancer syndrome characterized by high incidence of benign atypical melanocytic tumors, uveal melanoma, cutaneous melanoma, malignant mesothelioma, and potentially other cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (246, 268))	('benign atypical melanocytic tumors', 'Disease', 'MESH:D009508', (174, 208))	('uveal melanoma', 'Disease', 'MESH:C536494', (210, 224))	('ubiquitin', 'molecular_function', 'GO:0031386', ('46', '55'))	('BAP1', 'Gene', (0, 4))	('uveal melanoma', 'Disease', (210, 224))	('BAP1', 'Gene', '8314', (94, 98))	('malignant mesothelioma', 'Disease', (246, 268))	('cancers', 'Phenotype', 'HP:0002664', (292, 299))	('cancers', 'Disease', (292, 299))	('cutaneous melanoma', 'Disease', (226, 244))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (226, 244))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (226, 244))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (246, 268))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('benign atypical melanocytic tumors', 'Disease', (174, 208))	('uveal melanoma', 'Phenotype', 'HP:0007716', (210, 224))	('cause', 'Reg', (109, 114))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('cancer syndrome', 'Disease', 'MESH:D009369', (123, 138))	('BAP1', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))	('mutations', 'Var', (99, 108))	('cancers', 'Disease', 'MESH:D009369', (292, 299))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('cancer syndrome', 'Disease', (123, 138))	('BAP1', 'Gene', '8314', (0, 4))
2612	23714463	BAP1 mutation carriers should have regular medical examinations in order to diagnose associated malignancies at an early, more treatable stage.	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('BAP1', 'Gene', (0, 4))	('malignancies', 'Disease', (96, 108))	('BAP1', 'Gene', '8314', (0, 4))	('mutation', 'Var', (5, 13))
2613	23714463	TP53 mutations cause Li-Fraumeni syndrome with extremely high risk for sarcomas, breast cancer, brain tumors, adrenocortical carcinomas, and other tumors.	('breast cancer', 'Disease', (81, 94))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('brain tumors', 'Disease', 'MESH:D001932', (96, 108))	('brain tumors', 'Phenotype', 'HP:0030692', (96, 108))	('sarcomas', 'Disease', 'MESH:D012509', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('cause', 'Reg', (15, 20))	('sarcomas', 'Disease', (71, 79))	('Li-Fraumeni syndrome', 'Disease', (21, 41))	('TP53', 'Gene', '7157', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('brain tumors', 'Disease', (96, 108))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (21, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (110, 135))	('mutations', 'Var', (5, 14))	('adrenocortical carcinomas', 'Disease', (110, 135))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('TP53', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (147, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (110, 135))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
2615	23714463	SDH is a mitochondrial enzyme complex involved in the tricarboxylic acid cycle, and SDHx mutations (SDHA, SDHB, SDHC, SDHD, and SDHAF2) lead to increased succinate and high risk for paragangliomas, pheochromocytomas, renal cell carcinoma (RCC), gastrointestinal stromal tumors (GISTs), and other tumors.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (217, 237))	('SDH', 'Gene', '6390', (128, 131))	('GISTs', 'Phenotype', 'HP:0100723', (278, 283))	('succinate', 'MPA', (154, 163))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (198, 214))	('tricarboxylic acid cycle', 'biological_process', 'GO:0006099', ('54', '78'))	('tumors', 'Disease', 'MESH:D009369', (296, 302))	('mutations', 'Var', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('pheochromocytomas', 'Disease', 'MESH:D010673', (198, 215))	('SDH', 'Gene', '6390', (112, 115))	('pheochromocytomas', 'Disease', (198, 215))	('SDH', 'Gene', '6390', (0, 3))	('tumors', 'Disease', (270, 276))	('SDHx', 'Chemical', '-', (84, 88))	('paragangliomas', 'Disease', 'MESH:D010235', (182, 196))	('SDH', 'Gene', (106, 109))	('SDHC', 'Gene', '6391', (112, 116))	('paraganglioma', 'Phenotype', 'HP:0002668', (182, 195))	('SDHAF2', 'Gene', (128, 134))	('SDH', 'Gene', '6390', (118, 121))	('paragangliomas', 'Phenotype', 'HP:0002668', (182, 196))	('SDHAF2', 'Gene', '54949', (128, 134))	('SDH', 'Gene', (128, 131))	('renal cell carcinoma', 'Disease', (217, 237))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (217, 237))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (245, 276))	('SDH', 'Gene', (112, 115))	('SDH', 'Gene', '6390', (100, 103))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (245, 276))	('SDHD', 'Gene', '6392', (118, 122))	('SDH', 'Gene', (0, 3))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (54, 72))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('SDHB', 'Gene', '6390', (106, 110))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (198, 215))	('RCC', 'Disease', (239, 242))	('RCC', 'Phenotype', 'HP:0005584', (239, 242))	('increased succinate', 'Phenotype', 'HP:0020149', (144, 163))	('SDH', 'Gene', '6390', (84, 87))	('enzyme complex', 'cellular_component', 'GO:1902494', ('23', '37'))	('SDH', 'Gene', (118, 121))	('SDHC', 'Gene', (112, 116))	('increased', 'PosReg', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('paragangliomas', 'Disease', (182, 196))	('SDHD', 'Gene', (118, 122))	('SDH', 'Gene', (100, 103))	('gastrointestinal stromal tumors', 'Disease', (245, 276))	('tumors', 'Disease', (296, 302))	('RCC', 'Disease', 'MESH:C538614', (239, 242))	('succinate', 'Chemical', 'MESH:D019802', (154, 163))	('SDHB', 'Gene', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('SDH', 'Gene', (84, 87))	('SDH', 'Gene', '6390', (106, 109))
2616	23714463	Regular biochemical screening and imaging in patients with germline SDHx mutations can detect early cancer to improve patient outcome.	('SDHx', 'Chemical', '-', (68, 72))	('SDHx', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('improve', 'PosReg', (110, 117))	('patient', 'Species', '9606', (45, 52))	('patients', 'Species', '9606', (45, 53))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('patient', 'Species', '9606', (118, 125))	('mutations', 'Var', (73, 82))
2623	29515971	Using data from 10,355, primary tumor resection samples and 2,787 normal samples that we extracted from The Cancer Genome Atlas and Genotype-Tissue Expression project databases, we screened the variation of CYT across 32 different cancer types and 28 different normal tissue types.	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('Cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('Cancer Genome Atlas', 'Disease', (108, 127))	('tumor', 'Disease', (32, 37))	('screened', 'Reg', (181, 189))	('variation', 'Var', (194, 203))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (108, 127))	('CYT', 'Gene', (207, 210))
2652	29515971	Using the Genomic Data Commons (GDC) Data Portal (The Cancer Genome Atlas, TCGA program3) and the GTEx web portal (Genotype-Tissue Expression project4), we extracted data from a total of 10,355 tumor resection samples and 2,935 normal samples and screened the variation of CYT across these 32 different cancer types and 28 different normal solid tissue types.	('CYT', 'Gene', (273, 276))	('Cancer Genome Atlas', 'Disease', (54, 73))	('cancer', 'Disease', (303, 309))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('variation', 'Var', (260, 269))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (54, 73))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('screened', 'Reg', (247, 255))	('tumor', 'Disease', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
2669	29515971	GZMA was stained with an anti-GZMA antibody produced in rabbit (HPA054134, 1:200 dilution, Sigma-Aldrich) and PRF1 using two different antibodies produced in rabbit (either HPA037940, 1:29 dilution, or CAB002436, 1:10 dilution, Sigma-Aldrich).	('rabbit', 'Species', '9986', (56, 62))	('antibody', 'cellular_component', 'GO:0042571', ('35', '43'))	('antibody', 'cellular_component', 'GO:0019815', ('35', '43'))	('antibody', 'cellular_component', 'GO:0019814', ('35', '43'))	('CAB002436', 'Var', (202, 211))	('rabbit', 'Species', '9986', (158, 164))	('antibody', 'molecular_function', 'GO:0003823', ('35', '43'))	('GZMA', 'Gene', (30, 34))	('GZMA', 'Gene', (0, 4))	('GZMA', 'Gene', '3001', (30, 34))	('GZMA', 'Gene', '3001', (0, 4))
2686	29515971	Importantly, we show for the first time that DLBCL and testicular cancer also rank among the top cytolytic active tumors, with DLBCL exhibiting even higher cytolytic levels compared to KIRC (>100 TPM).	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('testicular cancer', 'Phenotype', 'HP:0010788', (55, 72))	('testicular cancer', 'Disease', (55, 72))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('DLBCL', 'Disease', (45, 50))	('cytolytic levels', 'MPA', (156, 172))	('higher', 'PosReg', (149, 155))	('DLBCL', 'Var', (127, 132))	('testicular cancer', 'Disease', 'MESH:D013736', (55, 72))
2711	29515971	We next performed Kaplan-Meier survival analysis on 37 TCGA-datasets deriving from 25 different cancer types in order to estimate the risk of individual and/or simultaneous high (or low) PRF1 and GZMA expression on patient overall survival.	('high', 'Var', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('low', 'NegReg', (182, 185))	('GZMA', 'Gene', (196, 200))	('PRF1', 'Gene', (187, 191))	('GZMA', 'Gene', '3001', (196, 200))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('patient', 'Species', '9606', (215, 222))
2712	29515971	In TCGA-ACC, non-metastatic cutaneous melanoma ("m0" TCGA-SKCM), and bladder urothelial carcinoma (TCGA-BLCA but not the GSE32894 dataset), both individual and simultaneous high levels of PRF1 and GZMA were significantly associated with better prognosis.	('ACC', 'Phenotype', 'HP:0006744', (8, 11))	('non-metastatic cutaneous melanoma', 'Phenotype', 'HP:0012057', (13, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('cutaneous melanoma', 'Disease', (28, 46))	('bladder urothelial carcinoma', 'Disease', (69, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (28, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('high levels', 'Var', (173, 184))	('GZMA', 'Gene', (197, 201))	('GZMA', 'Gene', '3001', (197, 201))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (69, 97))	('PRF1', 'Gene', (188, 192))
2716	29515971	In TCGA-LIHC, only the individual high levels of PRF1 and GZMA were significantly associated with a positive effect on patient survival.	('GZMA', 'Gene', '3001', (58, 62))	('patient', 'Species', '9606', (119, 126))	('LIHC', 'Disease', (8, 12))	('PRF1', 'Gene', (49, 53))	('LIHC', 'Disease', 'None', (8, 12))	('high levels', 'Var', (34, 45))	('GZMA', 'Gene', (58, 62))
2717	29515971	A similar non-significant association of (individual or simultaneous) high GZMA and PRF1 expression with better effect on patient survival could also be observed in TCGA-MESO, ovarian cancer (GSE13876 and GSE49997), TCGA-STAD, TCGA-THCA, and TCGA-UCEC (Figure S1 in Supplementary Material).	('GZMA', 'Gene', '3001', (75, 79))	('patient', 'Species', '9606', (122, 129))	('ovarian cancer', 'Phenotype', 'HP:0100615', (176, 190))	('GSE49997', 'Var', (205, 213))	('TCGA-MESO', 'Disease', (165, 174))	('GSE13876', 'Var', (192, 200))	('TCGA-UCEC', 'Disease', (242, 251))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('GZMA', 'Gene', (75, 79))	('ovarian cancer', 'Disease', 'MESH:D010051', (176, 190))	('high', 'Var', (70, 74))	('TCGA-THCA', 'Disease', (227, 236))	('TCGA-STAD', 'Disease', (216, 225))	('ovarian cancer', 'Disease', (176, 190))	('PRF1', 'Gene', (84, 88))
2718	29515971	These data suggest that high CYT is widely associated with an improved prognosis among the above-mentioned cancer types.	('improved', 'PosReg', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('high CYT', 'Var', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
2719	29515971	On the contrary, across TCGA-LGG, BRCAs (GSE25066), and TCGA-THYM, both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both genes led to a significant shift toward positive effect (Figure 6B).	('BRCA', 'Gene', '672', (34, 38))	('GSE25066', 'Var', (41, 49))	('BRCA', 'Gene', (34, 38))	('GZMA', 'Gene', (115, 119))	('GZMA', 'Gene', '3001', (115, 119))	('PRF1', 'Gene', (124, 128))	('associated with', 'Reg', (148, 163))
2722	29515971	Analogous non-significant associations of (individual or simultaneous) high cytolytic levels with worse effect on patient survival were also observed in lung cancer (GSE30219, TCGA-LUAD, and TCGA-LUSC), TCGA-PAAD, TCGA-PRAD and GSE16560, and TCGA-READ (Figure S2 in Supplementary Material).	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('lung cancer', 'Disease', (153, 164))	('high cytolytic levels', 'MPA', (71, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('patient', 'Species', '9606', (114, 121))	('GSE30219', 'Var', (166, 174))	('PAAD', 'Phenotype', 'HP:0006725', (208, 212))
2724	29515971	Depending on the probe used, it seemed that a combination of high PRF1 and low GZMA levels yields a better patient outcome (GSE39582, TCGA-COAD, TCGA-COADREAD).	('COAD', 'Disease', (150, 154))	('low', 'NegReg', (75, 78))	('GZMA', 'Gene', '3001', (79, 83))	('PRF1', 'MPA', (66, 70))	('COAD', 'Disease', 'MESH:D029424', (139, 143))	('high', 'Var', (61, 65))	('COAD', 'Disease', 'MESH:D029424', (150, 154))	('COAD', 'Disease', (139, 143))	('patient', 'Species', '9606', (107, 114))	('GZMA', 'Gene', (79, 83))
2730	29515971	In DLBCL (GSE10846, and GSE32918), using various combinations of distinct molecular probes for the two cytolytic genes (PRF1, 214617_AT, 1553681_A_AT, or ILMN_1740633; GZMA, 205488_AT, or ILMN_1779324), we could not provide any significant association with patient survival.	('GSE32918', 'Var', (24, 32))	('GZMA', 'Gene', '3001', (168, 172))	('ILMN_1740633', 'Var', (154, 166))	('patient', 'Species', '9606', (257, 264))	('AT', 'Disease', 'None', (133, 135))	('AT', 'Disease', 'None', (147, 149))	('PRF1', 'Var', (120, 124))	('GSE10846', 'Var', (10, 18))	('AT', 'Disease', 'None', (181, 183))	('GZMA', 'Gene', (168, 172))
2731	29515971	A similar absence of significant associations was also detected in glioblastoma (GSE4271, GSE13041, and TCGA-GBM) and non-metastatic HNSCs.	('glioblastoma', 'Disease', (67, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('non-metastatic HNSCs', 'Disease', (118, 138))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('GSE13041', 'Var', (90, 98))	('GSE4271', 'Chemical', '-', (81, 88))	('GSE4271', 'Var', (81, 88))
2769	29515971	Among them, recurrent mutations in immune-related genes have been proposed, such as B2M, HLA-A, -B, and -C, and CASP8, as well as copy number aberrations in loci containing immunosuppressive factors, including the receptors PD-L1/2 and CTLA-4.	('B2M', 'Gene', (84, 87))	('CASP8', 'Gene', '841', (112, 117))	('B2M', 'Gene', '567', (84, 87))	('CTLA-4', 'Gene', '1493', (236, 242))	('copy number aberrations', 'Var', (130, 153))	('CTLA-4', 'Gene', (236, 242))	('HLA-A, -B, and -C', 'Gene', '3105;3106;3107', (89, 106))	('mutations', 'Var', (22, 31))	('PD-L1/2', 'Gene', '29126;80380', (224, 231))	('PD-L1/2', 'Gene', (224, 231))	('CASP8', 'Gene', (112, 117))
2774	29515971	Actually, recent clinical trials have demonstrated that blockage of this signaling can benefit patients with advanced melanoma, kidney, or non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (139, 165))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('patients', 'Species', '9606', (95, 103))	('blockage', 'Var', (56, 64))	('non-small cell lung cancer', 'Disease', (139, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('signaling', 'biological_process', 'GO:0023052', ('73', '82'))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (139, 165))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (143, 165))	('kidney', 'Disease', (128, 134))
2782	29515971	Importantly, CTLA-4 blockade was reported to associate with bowel inflammation in melanoma patients, signifying that its signaling is crucial for the preservation of immune homeostasis in the gut.	('associate', 'Reg', (45, 54))	('patients', 'Species', '9606', (91, 99))	('signaling', 'biological_process', 'GO:0023052', ('121', '130'))	('bowel inflammation', 'Phenotype', 'HP:0002037', (60, 78))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('CTLA-4', 'Gene', '1493', (13, 19))	('blockade', 'Var', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('bowel inflammation', 'Disease', 'MESH:D007249', (60, 78))	('inflammation', 'biological_process', 'GO:0006954', ('66', '78'))	('homeostasis', 'biological_process', 'GO:0042592', ('173', '184'))	('CTLA-4', 'Gene', (13, 19))	('bowel inflammation', 'Disease', (60, 78))
2788	29515971	Inhibition of both IDO and arginase can enhance intratumoral inflammation.	('IDO', 'Gene', '3620', (19, 22))	('inflammation', 'biological_process', 'GO:0006954', ('61', '73'))	('IDO', 'molecular_function', 'GO:0047719', ('19', '22'))	('IDO', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('arginase', 'Protein', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('tumor', 'Disease', (53, 58))	('inflammation', 'Disease', (61, 73))	('Inhibition', 'Var', (0, 10))	('IDO', 'molecular_function', 'GO:0033754', ('19', '22'))	('enhance', 'PosReg', (40, 47))
2802	29515971	A very interesting improvement in the field was further made by Riaz et al., who showed that the mutation burden in melanoma patients decreases with successful anti-PD-1 blockade therapy, suggesting that the selection against mutant neoepitopes is a critical mechanism of action of this immunotherapy.	('Riaz', 'Gene', (64, 68))	('mutant', 'Var', (226, 232))	('mutation burden', 'MPA', (97, 112))	('PD-1', 'Gene', (165, 169))	('PD-1', 'Gene', '5133', (165, 169))	('Riaz', 'Gene', '23598', (64, 68))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('decreases', 'NegReg', (134, 143))	('patients', 'Species', '9606', (125, 133))
2806	29515971	Overall, it seems that CYT is part of an inflammatory environment in a premalignant state of certain tumor types, whereas, in others, oncogenic mutations, copy number aberrations, or viral infection can induce a tumor-promoting inflammatory microenvironment, within which complex interactions between different cell types regulate cancer development and metastasis.	('copy number aberrations', 'Var', (155, 178))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('induce', 'PosReg', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('viral infection', 'Disease', 'MESH:D001102', (183, 198))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('viral infection', 'biological_process', 'GO:0016032', ('183', '198'))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('viral infection', 'Disease', (183, 198))	('tumor', 'Disease', (212, 217))	('mutations', 'Var', (144, 153))
2813	29515971	In some tumor types (ACC, SKCM, BLCA, LIHC, MESO, OV, STAD, THCA, and UCEC), high CYT was associated with an improved outcome; whereas in others (LGG, BRCA, THYM, LUAD/LUSC, PAAD, PRAD, and READ) it is correlated with a worse outcome.	('BRCA', 'Gene', '672', (151, 155))	('THYM', 'Disease', (157, 161))	('LIHC', 'Disease', 'None', (38, 42))	('BRCA', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('MESO', 'Disease', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('ACC', 'Phenotype', 'HP:0006744', (21, 24))	('PAAD', 'Phenotype', 'HP:0006725', (174, 178))	('PAAD', 'Disease', (174, 178))	('improved', 'PosReg', (109, 117))	('tumor', 'Disease', (8, 13))	('LUAD/LUSC', 'Disease', (163, 172))	('PRAD', 'Disease', (180, 184))	('LIHC', 'Disease', (38, 42))	('high CYT', 'Var', (77, 85))
2814	29515971	Among LGG, THYM, and BRCA, we showed that both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both cytolytic genes led to a significant shift toward a positive effect.	('GZMA', 'Gene', (90, 94))	('associated', 'Reg', (123, 133))	('BRCA', 'Gene', (21, 25))	('PRF1', 'Gene', (99, 103))	('high', 'Var', (75, 79))	('GZMA', 'Gene', '3001', (90, 94))	('BRCA', 'Gene', '672', (21, 25))
2845	29206102	Interestingly, EIF1AX mutations altering the human eIF1A NTT are associated with uveal melanoma (UM).	('eIF1A NTT', 'Gene', (51, 60))	('EIF1AX', 'Gene', '1964', (15, 21))	('EIF1AX', 'Gene', (15, 21))	('NTT', 'Chemical', '-', (57, 60))	('human', 'Species', '9606', (45, 50))	('associated', 'Reg', (65, 75))	('uveal melanoma', 'Disease', 'MESH:C536494', (81, 95))	('mutations', 'Var', (22, 31))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('uveal melanoma', 'Disease', (81, 95))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
2846	29206102	We found that substituting all five basic residues, and seven UM-associated substitutions, in yeast eIF1A suppresses initiation at near-cognate UUG codons and AUGs in poor context.	('initiation at near-cognate UUG codons', 'MPA', (117, 154))	('eIF1A', 'Gene', (100, 105))	('yeast', 'Species', '4932', (94, 99))	('substitutions', 'Var', (76, 89))	('AUG', 'Chemical', '-', (159, 162))	('suppresses', 'NegReg', (106, 116))	('substituting', 'Var', (14, 26))
2847	29206102	Ribosome profiling of NTT substitution R13P reveals heightened discrimination against unfavorable AUG context genome-wide.	('NTT', 'Chemical', '-', (22, 25))	('Ribosome', 'cellular_component', 'GO:0005840', ('0', '8'))	('R13P', 'SUBSTITUTION', 'None', (39, 43))	('R13P', 'Var', (39, 43))	('AUG', 'Chemical', '-', (98, 101))	('NTT', 'Gene', (22, 25))
2848	29206102	Both R13P and K16D substitutions destabilize the closed complex at UUG codons in reconstituted PICs.	('R13P', 'SUBSTITUTION', 'None', (5, 9))	('destabilize', 'NegReg', (33, 44))	('closed complex at', 'MPA', (49, 66))	('K16D', 'Mutation', 'p.K16D', (14, 18))	('PIC', 'Chemical', '-', (95, 98))	('K16D substitutions', 'Var', (14, 32))	('R13P', 'Var', (5, 9))
2850	29206102	We predict UM-associated mutations alter human gene expression by increasing discrimination against poor initiation sites.	('mutations', 'Var', (25, 34))	('human', 'Species', '9606', (41, 46))	('gene expression', 'biological_process', 'GO:0010467', ('47', '62'))	('discrimination against poor initiation sites', 'MPA', (77, 121))	('increasing', 'PosReg', (66, 76))	('alter', 'Reg', (35, 40))	('UM-associated', 'Gene', (11, 24))	('human gene expression', 'MPA', (41, 62))
2855	29206102	Start-codon recognition triggers dissociation of eIF1 from the 40S subunit, which in concert with other events allows Pi release from eIF2-GDP Pi and accommodation of Met-tRNAiMet in the PIN state of the 48S PIC (Figure 1A).	('eIF2-GDP', 'Var', (134, 142))	('PIC', 'cellular_component', 'GO:0019035', ('208', '211'))	('eIF2', 'cellular_component', 'GO:0005850', ('134', '138'))	('40S', 'Chemical', '-', (63, 66))	('PIC', 'Chemical', '-', (208, 211))	('Met-tRNAiMet', 'Var', (167, 179))	('PIC', 'cellular_component', 'GO:0097550', ('208', '211'))	('Pi release', 'MPA', (118, 128))	('GDP', 'Chemical', 'MESH:D006153', (139, 142))	('accommodation', 'MPA', (150, 163))
2856	29206102	Subsequent dissociation of eIF2-GDP and other eIFs from the 48S PIC enables eIF5B-catalyzed subunit joining and formation of an 80S initiation complex with Met-tRNAiMet base-paired to AUG in the P site (reviewed in and).	('PIC', 'cellular_component', 'GO:0019035', ('64', '67'))	('formation', 'biological_process', 'GO:0009058', ('112', '121'))	('Met-tRNAiMet', 'Var', (156, 168))	('subunit', 'Protein', (92, 99))	('PIC', 'cellular_component', 'GO:0097550', ('64', '67'))	('GDP', 'Chemical', 'MESH:D006153', (32, 35))	('AUG', 'Chemical', '-', (184, 187))	('eIF2', 'cellular_component', 'GO:0005850', ('27', '31'))	('PIC', 'Chemical', '-', (64, 67))	('eIF5B-catalyzed', 'Gene', (76, 91))
2857	29206102	eIF1 plays a dual role in the scanning mechanism, promoting rapid TC loading in the POUT conformation while blocking rearrangement to PIN at non-AUG codons by clashing with Met-tRNAi in the PIN state , thus requiring dissociation of eIF1 from the 40S subunit for start codon recognition (Figure 1A).	('rearrangement', 'MPA', (117, 130))	('blocking', 'NegReg', (108, 116))	('AUG', 'Chemical', '-', (145, 148))	('40S', 'Chemical', '-', (247, 250))	('clashing', 'Var', (159, 167))	('eIF1', 'Gene', (0, 4))	('rapid TC loading', 'MPA', (60, 76))	('TC', 'Chemical', '-', (66, 68))	('promoting', 'PosReg', (50, 59))	('requiring', 'Reg', (207, 216))
2858	29206102	Consequently, mutations that weaken eIF1 binding to the 40S subunit reduce the rate of TC loading and elevate initiation at near-cognate codons (eg.	('binding', 'molecular_function', 'GO:0005488', ('41', '48'))	('elevate', 'PosReg', (102, 109))	('initiation', 'MPA', (110, 120))	('TC loading', 'MPA', (87, 97))	('rate', 'MPA', (79, 83))	('binding', 'Interaction', (41, 48))	('reduce', 'NegReg', (68, 74))	('40S', 'Chemical', '-', (56, 59))	('TC', 'Chemical', '-', (87, 89))	('eIF1', 'Gene', (36, 40))	('mutations', 'Var', (14, 23))	('weaken', 'NegReg', (29, 35))
2862	29206102	Mutations that weaken 40S binding by eIF1 relax discrimination against the poor context of the SUI1 AUG codon and elevate eIF1 expression, overcoming autoregulation.	('eIF1', 'Gene', (37, 41))	('weaken', 'NegReg', (15, 21))	('AUG', 'Chemical', '-', (100, 103))	('eIF1', 'Gene', (122, 126))	('expression', 'MPA', (127, 137))	('binding', 'Interaction', (26, 33))	('Mutations', 'Var', (0, 9))	('SUI1', 'Gene', '855477', (95, 99))	('binding', 'molecular_function', 'GO:0005488', ('26', '33'))	('elevate', 'PosReg', (114, 121))	('discrimination', 'MPA', (48, 62))	('overcoming', 'PosReg', (139, 149))	('SUI1', 'Gene', (95, 99))	('autoregulation', 'MPA', (150, 164))	('40S', 'Chemical', '-', (22, 25))
2863	29206102	In contrast, mutations that enhance eIF1 binding to the 40S subunit impede rearrangement of the scanning PIC to the closed/PIN conformation, which increases discrimination against the poor context of the SUI1 AUG codon, to reduce eIF1 expression, and also suppresses initiation at near-cognate UUG codons.	('expression', 'MPA', (235, 245))	('initiation at near-cognate UUG codons', 'MPA', (267, 304))	('SUI1', 'Gene', (204, 208))	('AUG', 'Chemical', '-', (209, 212))	('eIF1', 'Gene', (36, 40))	('increases', 'PosReg', (147, 156))	('binding', 'molecular_function', 'GO:0005488', ('41', '48'))	('suppresses', 'NegReg', (256, 266))	('binding', 'Interaction', (41, 48))	('discrimination', 'MPA', (157, 171))	('enhance', 'PosReg', (28, 35))	('40S', 'Chemical', '-', (56, 59))	('mutations', 'Var', (13, 22))	('SUI1', 'Gene', '855477', (204, 208))	('PIC', 'cellular_component', 'GO:0019035', ('105', '108'))	('eIF1', 'Gene', (230, 234))	('PIC', 'Chemical', '-', (105, 108))	('PIC', 'cellular_component', 'GO:0097550', ('105', '108'))	('rearrangement', 'MPA', (75, 88))	('reduce', 'NegReg', (223, 229))	('impede', 'NegReg', (68, 74))
2864	29206102	Scanning enhancer (SE) elements in the eIF1A C-terminal tail (CTT) promote TC binding in the open POUT conformation and impede rearrangement to the closed PIN state, such that substitutions that impair the SE elements both impair TC recruitment and increase initiation at near-cognate start codons.	('binding', 'Interaction', (78, 85))	('initiation at near-cognate start codons', 'MPA', (258, 297))	('substitutions', 'Var', (176, 189))	('eIF1A', 'Gene', (39, 44))	('impair', 'NegReg', (223, 229))	('increase', 'PosReg', (249, 257))	('TC', 'Chemical', '-', (230, 232))	('CTT', 'Chemical', '-', (62, 65))	('impede', 'NegReg', (120, 126))	('rearrangement to the closed PIN state', 'MPA', (127, 164))	('binding', 'molecular_function', 'GO:0005488', ('78', '85'))	('TC recruitment', 'MPA', (230, 244))	('TC', 'Chemical', '-', (75, 77))	('promote', 'PosReg', (67, 74))
2865	29206102	Biochemical mapping experiments suggest that, like eIF1, the eIF1A CTT clashes with Met-tRNAi in the PIN state, and is displaced from the P site on start codon recognition to enable a functional interaction of the eIF1A CTT with the NTD of eIF5, the GTPase activating protein for eIF2, that facilitates Pi release from eIF2-GDP Pi.	('interaction', 'Interaction', (195, 206))	('eIF2', 'cellular_component', 'GO:0005850', ('280', '284'))	('protein', 'cellular_component', 'GO:0003675', ('268', '275'))	('GDP', 'Chemical', 'MESH:D006153', (324, 327))	('CTT', 'Chemical', '-', (220, 223))	('eIF1A', 'Var', (214, 219))	('Pi release', 'MPA', (303, 313))	('enable', 'PosReg', (175, 181))	('GTP', 'Chemical', 'MESH:D006160', (250, 253))	('facilitates', 'PosReg', (291, 302))	('CTT', 'Chemical', '-', (67, 70))	('eIF2', 'cellular_component', 'GO:0005850', ('319', '323'))
2867	29206102	Accordingly, substitutions that impair SI elements destabilize the closed complex and accelerate TC loading to the open complex in vitro, and promote continued scanning at UUG codons in hypoaccurate mutant cells.	('closed complex', 'MPA', (67, 81))	('TC loading', 'MPA', (97, 107))	('scanning', 'MPA', (160, 168))	('accelerate', 'PosReg', (86, 96))	('SI', 'Disease', 'None', (39, 41))	('destabilize', 'NegReg', (51, 62))	('promote', 'PosReg', (142, 149))	('substitutions', 'Var', (13, 26))	('TC', 'Chemical', '-', (97, 99))
2868	29206102	SI1 mutations also increase the probability that the scanning PIC will bypass an upstream AUG codon (leaky scanning); and one such mutation, substituting NTT residues 17-21, decreases recognition of the suboptimal AUG codon of SUI1 mRNA to reduce eIF1 expression.	('PIC', 'Chemical', '-', (62, 65))	('eIF1', 'Gene', (247, 251))	('SUI1', 'Gene', (227, 231))	('SI', 'Disease', 'None', (0, 2))	('recognition', 'MPA', (184, 195))	('AUG', 'Chemical', '-', (90, 93))	('PIC', 'cellular_component', 'GO:0097550', ('62', '65'))	('NTT', 'Chemical', '-', (154, 157))	('reduce', 'NegReg', (240, 246))	('mutations', 'Var', (4, 13))	('AUG', 'Chemical', '-', (214, 217))	('expression', 'MPA', (252, 262))	('SUI1', 'Gene', '855477', (227, 231))	('PIC', 'cellular_component', 'GO:0019035', ('62', '65'))	('decreases', 'NegReg', (174, 183))
2869	29206102	Molecular insight into the deduced function of the eIF1A-NTT of promoting AUG recognition during scanning came from the cryo-EM structure of a partial yeast 48S PIC (py48S) containing eIF1, eIF1A, TC and mRNA, with the Met-tRNAi base-paired to the AUG codon in a PIN state.	('PIC', 'cellular_component', 'GO:0019035', ('161', '164'))	('AUG recognition', 'MPA', (74, 89))	('py48S', 'Chemical', '-', (166, 171))	('AUG', 'Chemical', '-', (248, 251))	('eIF1A', 'Var', (190, 195))	('PIC', 'cellular_component', 'GO:0097550', ('161', '164'))	('eIF1', 'Var', (184, 188))	('eIF1A-NTT', 'Var', (51, 60))	('yeast', 'Species', '4932', (151, 156))	('AUG', 'Chemical', '-', (74, 77))	('TC', 'Chemical', '-', (197, 199))	('PIC', 'Chemical', '-', (161, 164))	('promoting', 'PosReg', (64, 73))
2870	29206102	All but the first four residues of the eIF1A NTT were visible in this structure, and basic NTT residues Lys7, Lys10, Arg13, and Lys16 contact either the anticodon or the +4 to +6 mRNA nucleotides adjacent to the AUG codon, while Arg14 interacts with the 18S rRNA (Figure 1B).	('Lys16', 'Var', (128, 133))	('Lys16', 'Chemical', '-', (128, 133))	('Arg13', 'Gene', (117, 122))	('AUG', 'Chemical', '-', (212, 215))	('Lys7', 'Gene', '855054', (104, 108))	('contact', 'Reg', (134, 141))	('NTT', 'Chemical', '-', (91, 94))	('eIF1A', 'Gene', (39, 44))	('Arg14', 'Chemical', '-', (229, 234))	('Lys10', 'Gene', '854714', (110, 115))	('Arg13', 'Chemical', '-', (117, 122))	('Lys7', 'Gene', (104, 108))	('NTT', 'Chemical', '-', (45, 48))	('Lys10', 'Gene', (110, 115))
2871	29206102	These findings suggest that the eIF1A NTT can directly stabilize the PIN state, and help to explain how NTT substitutions in SI1, which spans residues 1-26, increase discrimination against non-AUG codons, which form less stable codon:anticodon duplexes than do AUG codons.	('AUG', 'Chemical', '-', (261, 264))	('substitutions', 'Var', (108, 121))	('SI', 'Disease', 'None', (125, 127))	('AUG', 'Chemical', '-', (193, 196))	('NTT', 'Gene', (104, 107))	('NTT', 'Chemical', '-', (104, 107))	('increase', 'PosReg', (157, 165))	('NTT', 'Chemical', '-', (38, 41))	('discrimination', 'MPA', (166, 180))
2877	29206102	Somatic mutations in the human gene EIF1AX encoding eIF1A are frequently associated with uveal melanomas (UM) associated with disomy for chromosome 3, and all of the EIF1AX mutations sequenced thus far produce in-frame substitutions or deletions of one or more residues in the first 15 residues of the NTT.	('deletions', 'Var', (236, 245))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('associated', 'Reg', (73, 83))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('NTT', 'Chemical', '-', (302, 305))	('EIF1AX', 'Gene', (166, 172))	('mutations', 'Var', (8, 17))	('human', 'Species', '9606', (25, 30))	('associated', 'Reg', (110, 120))	('uveal melanomas', 'Disease', 'MESH:C536494', (89, 104))	('substitutions', 'Var', (219, 232))	('EIF1AX', 'Gene', '1964', (166, 172))	('EIF1AX', 'Gene', (36, 42))	('mutations', 'Var', (173, 182))	('uveal melanoma', 'Phenotype', 'HP:0007716', (89, 103))	('chromosome', 'cellular_component', 'GO:0005694', ('137', '147'))	('produce', 'Reg', (202, 209))	('uveal melanomas', 'Disease', (89, 104))	('EIF1AX', 'Gene', '1964', (36, 42))	('uveal melanomas', 'Phenotype', 'HP:0007716', (89, 104))
2878	29206102	A subset of these mutations substitute or delete two of the four basic residues that contact mRNA or the tRNAi anticodon in the yeast py48S PIC (Lys7 and Arg13), others introduce acidic residues that might electrostatically repel the phosphodiester backbone of the mRNA or tRNAi, while others affect a Gly-Gly turn that is important for correct positioning of the basic residues in the PIC (Figure 1B-C).	('Lys7', 'Gene', (145, 149))	('affect', 'Reg', (293, 299))	('Arg13', 'Chemical', '-', (154, 159))	('repel', 'NegReg', (224, 229))	('Gly', 'Chemical', 'MESH:D005998', (302, 305))	('Gly-Gly turn', 'MPA', (302, 314))	('yeast', 'Species', '4932', (128, 133))	('PIC', 'cellular_component', 'GO:0019035', ('140', '143'))	('substitute', 'Reg', (28, 38))	('Lys7', 'Gene', '855054', (145, 149))	('PIC', 'cellular_component', 'GO:0097550', ('140', '143'))	('PIC', 'cellular_component', 'GO:0019035', ('386', '389'))	('phosphodiester backbone', 'MPA', (234, 257))	('PIC', 'cellular_component', 'GO:0097550', ('386', '389'))	('PIC', 'Chemical', '-', (386, 389))	('Gly', 'Chemical', 'MESH:D005998', (306, 309))	('PIC', 'Chemical', '-', (140, 143))	('py48S', 'Chemical', '-', (134, 139))	('delete', 'NegReg', (42, 48))	('mutations', 'Var', (18, 27))
2879	29206102	Thus, all of the UM mutations might affect eIF1A function by the same mechanism, of weakening the ability of the eIF1A NTT to stabilize the PIN conformation of the tRNAi.	('ability', 'MPA', (98, 105))	('weakening', 'NegReg', (84, 93))	('function', 'MPA', (49, 57))	('NTT', 'Chemical', '-', (119, 122))	('affect', 'Reg', (36, 42))	('eIF1A', 'Gene', (113, 118))	('stabilize the PIN conformation of the tRNAi', 'MPA', (126, 169))	('mutations', 'Var', (20, 29))
2880	29206102	We set out to distinguish between these possibilities by examining the consequences of seven yeast eIF1A-NTT substitutions equivalent to those associated with UM in residues Lys3, Lys4, Thr6, Gly8, Arg13 and Gly15, and also of altering the five NTT basic residues that interact with the mRNA or anticodon in the py48S PIC (Lys7, Lys10, Arg13, Arg14 and Lys16) (Figure 1C).	('Thr6', 'Gene', '853604', (186, 190))	('Lys4', 'molecular_function', 'GO:0004409', ('180', '184'))	('Lys10', 'Gene', (329, 334))	('Arg13', 'Chemical', '-', (336, 341))	('Lys3', 'Gene', (174, 178))	('PIC', 'Chemical', '-', (318, 321))	('PIC', 'cellular_component', 'GO:0019035', ('318', '321'))	('Arg13', 'Var', (336, 341))	('Lys4', 'Gene', (180, 184))	('Gly8', 'Chemical', '-', (192, 196))	('NTT', 'Chemical', '-', (245, 248))	('PIC', 'cellular_component', 'GO:0097550', ('318', '321'))	('-NTT', 'Chemical', '-', (104, 108))	('altering', 'Reg', (227, 235))	('Thr6', 'Gene', (186, 190))	('py48S', 'Chemical', '-', (312, 317))	('yeast', 'Species', '4932', (93, 98))	('Lys7', 'Gene', (323, 327))	('Arg13', 'Chemical', '-', (198, 203))	('Lys16', 'Var', (353, 358))	('Arg14', 'Chemical', '-', (343, 348))	('Lys16', 'Chemical', '-', (353, 358))	('Lys4', 'Gene', '851820', (180, 184))	('Lys3', 'Gene', '851820', (174, 178))	('eIF1A-NTT', 'Gene', (99, 108))	('Lys7', 'Gene', '855054', (323, 327))	('NTT', 'Chemical', '-', (105, 108))	('Lys10', 'Gene', '854714', (329, 334))	('Gly15', 'Chemical', '-', (208, 213))	('Arg14', 'Var', (343, 348))
2881	29206102	Our genetic and biochemical analyses indicate that UM-associated eIF1A substitutions disrupt NTT interactions with the mRNA or tRNAi to destabilize the closed/PIN conformation of the PIC and increase discrimination against near-cognate codons or AUGs in suboptimal context, with particularly strong effects observed for substitutions of Arg13:one of five basic residues that interacts with the mRNA/tRNAi anticodon.	('NTT', 'Chemical', '-', (93, 96))	('destabilize', 'NegReg', (136, 147))	('increase', 'PosReg', (191, 199))	('PIC', 'Chemical', '-', (183, 186))	('substitutions', 'Var', (71, 84))	('AUG', 'Chemical', '-', (246, 249))	('PIC', 'cellular_component', 'GO:0097550', ('183', '186'))	('PIC', 'cellular_component', 'GO:0019035', ('183', '186'))	('NTT', 'Gene', (93, 96))	('closed/PIN conformation', 'MPA', (152, 175))	('disrupt', 'NegReg', (85, 92))	('interactions', 'Interaction', (97, 109))	('eIF1A', 'Gene', (65, 70))	('Arg13', 'Chemical', '-', (337, 342))	('discrimination', 'MPA', (200, 214))
2882	29206102	Ribosome profiling of the potent UM-associated mutant eIF1A-R13P reveals widespread increased discrimination against AUG codons in poor context, which can alter recognition of the start codon for the main coding sequences (CDS) or indirectly affect translation by modulating recognition of upstream open reading frames (uORFs) in the mRNA leader.	('recognition', 'MPA', (275, 286))	('Ribosome', 'cellular_component', 'GO:0005840', ('0', '8'))	('AUG', 'Chemical', '-', (117, 120))	('R13P', 'SUBSTITUTION', 'None', (60, 64))	('translation', 'MPA', (249, 260))	('modulating', 'Reg', (264, 274))	('affect', 'Reg', (242, 248))	('recognition', 'MPA', (161, 172))	('increased', 'PosReg', (84, 93))	('translation', 'biological_process', 'GO:0006412', ('249', '260'))	('R13P', 'Var', (60, 64))	('discrimination', 'MPA', (94, 108))	('alter', 'Reg', (155, 160))	('mutant', 'Var', (47, 53))
2883	29206102	These findings allow us to predict that eIF1A-NTT mutations alter gene expression in UM tumor cells by shifting translation initiation at main CDS and regulatory uORFs from poor to optimum initiation sites.	('translation initiation', 'MPA', (112, 134))	('eIF1A-NTT', 'Gene', (40, 49))	('translation initiation', 'biological_process', 'GO:0006413', ('112', '134'))	('alter', 'Reg', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('mutations', 'Var', (50, 59))	('shifting', 'Reg', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('gene expression', 'biological_process', 'GO:0010467', ('66', '81'))	('gene expression', 'MPA', (66, 81))	('tumor', 'Disease', (88, 93))
2884	29206102	To explore functional consequences of substitutions in human eIF1A associated with uveal melanoma, we introduced substitutions into the yeast eIF1A NTT corresponding to 7 of the 13 substitutions associated with the disease: K3D, K4D, T6R, T6D, DeltaG8, R13P, and G15D (Figure 1C).	('uveal melanoma', 'Disease', (83, 97))	('yeast', 'Species', '4932', (136, 141))	('T6D', 'Var', (239, 242))	('to 7', 'Species', '1214577', (166, 170))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('G15D', 'Var', (263, 267))	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('eIF1A', 'Gene', (142, 147))	('T6R', 'Mutation', 'p.T6R', (234, 237))	('G15D', 'Mutation', 'p.G15D', (263, 267))	('DeltaG8', 'Var', (244, 251))	('NTT', 'Chemical', '-', (148, 151))	('R13P', 'SUBSTITUTION', 'None', (253, 257))	('human', 'Species', '9606', (55, 60))	('associated', 'Reg', (67, 77))	('T6R', 'Var', (234, 237))	('R13P', 'Var', (253, 257))	('K4D', 'Var', (229, 232))	('K3D', 'Var', (224, 227))	('DeltaG8', 'DELETION', 'None', (244, 251))	('uveal melanoma', 'Disease', 'MESH:C536494', (83, 97))
2885	29206102	Asn4 and Gly6 of human eIF1A correspond to Lys4 and Thr6 in yeast, thus the yeast K4D and T6R/T6D substitutions mimic the human N4D and G6R/G6D UM-associated substitutions, respectively.	('human', 'Species', '9606', (122, 127))	('Thr6', 'Gene', (52, 56))	('K4D', 'Var', (82, 85))	('Lys4', 'Gene', (43, 47))	('human', 'Species', '9606', (17, 22))	('yeast', 'Species', '4932', (60, 65))	('eIF1A', 'Gene', (23, 28))	('T6R', 'Mutation', 'p.T6R', (90, 93))	('Lys4', 'Gene', '851820', (43, 47))	('G6D', 'Gene', (140, 143))	('Lys4', 'molecular_function', 'GO:0004409', ('43', '47'))	('Gly6', 'Chemical', '-', (9, 13))	('G6D', 'Gene', '58530', (140, 143))	('Asn4', 'Chemical', '-', (0, 4))	('T6R/T6D', 'Var', (90, 97))	('Thr6', 'Gene', '853604', (52, 56))	('yeast', 'Species', '4932', (76, 81))
2886	29206102	The deletion of Gly8 (DeltaG8) in yeast produces the same protein as the UM-associated substitution DeltaG9, leaving a single Gly residue in place of the Gly8/Gly9 pair (Figure 1C).	('Gly8', 'Chemical', '-', (16, 20))	('Gly8', 'Chemical', '-', (154, 158))	('Gly', 'Chemical', 'MESH:D005998', (154, 157))	('Gly residue', 'MPA', (126, 137))	('Gly', 'Chemical', 'MESH:D005998', (126, 129))	('Gly9', 'Chemical', '-', (159, 163))	('yeast', 'Species', '4932', (34, 39))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('DeltaG9', 'DELETION', 'None', (100, 107))	('DeltaG9', 'Var', (100, 107))	('deletion', 'Var', (4, 12))	('Gly', 'Chemical', 'MESH:D005998', (159, 162))	('Gly8', 'Gene', (16, 20))	('DeltaG8', 'DELETION', 'None', (22, 29))	('leaving', 'Reg', (109, 116))	('Gly', 'Chemical', 'MESH:D005998', (16, 19))	('DeltaG8', 'Var', (22, 29))
2887	29206102	Mutations were generated in a TIF11 allele (encoding yeast eIF1A) under the native promoter and the mutant alleles on single-copy plasmids were used to replace WT TIF11+ by plasmid-shuffling in a his4-301 yeast strain in order to examine their effects on initiation at near-cognate UUG codons.	('yeast', 'Species', '4932', (53, 58))	('yeast', 'Species', '4932', (205, 210))	('TIF11', 'Gene', (30, 35))	('his4', 'Gene', (196, 200))	('mutant', 'Var', (100, 106))	('TIF11', 'Gene', '855302', (163, 168))	('his4', 'Gene', '850327', (196, 200))	('TIF11', 'Gene', '855302', (30, 35))	('Mutations', 'Var', (0, 9))	('TIF11', 'Gene', (163, 168))
2889	29206102	None of the TIF11 mutations allows detectable growth on medium containing only 1% of the usual histidine supplement (Figure 2:figure supplement 1A, -His medium), indicating the absence of Sui- phenotypes; and none confers a slow-growth phenotype (Slg-) on complete medium (Figure 2:figure supplement 1A, +His).	('slow-growth phenotype', 'MPA', (224, 245))	('TIF11', 'Gene', '855302', (12, 17))	('histidine', 'Chemical', 'MESH:D006639', (95, 104))	('His', 'Chemical', 'MESH:D006639', (149, 152))	('slow-growth', 'Phenotype', 'HP:0001510', (224, 235))	('TIF11', 'Gene', (12, 17))	('His', 'Chemical', 'MESH:D006639', (305, 308))	('mutations', 'Var', (18, 27))
2890	29206102	We next tested the mutant alleles for the ability to suppress the elevated UUG initiation on his4-301 mRNA and the attendant His+ phenotype conferred by dominant Sui- mutations SUI5 and SUI3-2 encoding, respectively, the G31R variant of eIF5 and S264Y variant of eIF2beta.	('SUI3', 'Gene', (186, 190))	('His+', 'MPA', (125, 129))	('SUI5', 'Gene', '856154', (177, 181))	('his4', 'Gene', '850327', (93, 97))	('suppress', 'NegReg', (53, 61))	('S264Y', 'Var', (246, 251))	('his4', 'Gene', (93, 97))	('S264Y', 'SUBSTITUTION', 'None', (246, 251))	('G31R', 'Mutation', 'rs1263354783', (221, 225))	('SUI5', 'Gene', (177, 181))	('SUI3', 'Gene', '855838', (186, 190))	('His', 'Chemical', 'MESH:D006639', (125, 128))	('G31R', 'Var', (221, 225))	('eIF2', 'cellular_component', 'GO:0005850', ('263', '267'))	('UUG initiation on', 'MPA', (75, 92))	('elevated', 'PosReg', (66, 74))
2891	29206102	Remarkably, the dominant His+ phenotypes conferred by plasmid-borne SUI5 or SUI3-2 are diminished by all of the NTT mutations (Figure 2A and Figure 2:figure supplement 1B, -His); and the Slg- phenotype conferred by SUI5 in +His medium at 37 C is also suppressed by the K3E, K4D, DeltaG8, R13P, and G15D mutations (Figure 2A, +His, 37 C).	('R13P', 'SUBSTITUTION', 'None', (288, 292))	('NTT', 'Chemical', '-', (112, 115))	('R13P', 'Var', (288, 292))	('G15D mutations', 'Var', (298, 312))	('Slg- phenotype', 'MPA', (187, 201))	('SUI5', 'Gene', '856154', (215, 219))	('NTT', 'Gene', (112, 115))	('DeltaG8', 'DELETION', 'None', (279, 286))	('SUI5', 'Gene', (215, 219))	('SUI3', 'Gene', '855838', (76, 80))	('His', 'Chemical', 'MESH:D006639', (25, 28))	('His', 'Chemical', 'MESH:D006639', (224, 227))	('mutations', 'Var', (116, 125))	('K3E', 'Var', (269, 272))	('diminished', 'NegReg', (87, 97))	('His', 'Chemical', 'MESH:D006639', (326, 329))	('SUI5', 'Gene', '856154', (68, 72))	('DeltaG8', 'Var', (279, 286))	('G15D', 'Mutation', 'p.G15D', (298, 302))	('His', 'Chemical', 'MESH:D006639', (173, 176))	('SUI5', 'Gene', (68, 72))	('SUI3', 'Gene', (76, 80))	('K4D', 'Var', (274, 277))
2892	29206102	These results suggest that the UM-associated substitutions, as a group, mitigate the effects of SUI5 and SUI3-2 in elevating UUG initiation, increasing discrimination against near-cognate start codons.	('SUI5', 'Gene', (96, 100))	('SUI3', 'Gene', '855838', (105, 109))	('substitutions', 'Var', (45, 58))	('UUG initiation', 'MPA', (125, 139))	('SUI3', 'Gene', (105, 109))	('elevating', 'PosReg', (115, 124))	('mitigate', 'NegReg', (72, 80))	('SUI5', 'Gene', '856154', (96, 100))	('increasing', 'PosReg', (141, 151))	('discrimination against near-cognate start codons', 'MPA', (152, 200))
2895	29206102	With the exception of T6D, all of the UM mutations significantly reduced the HIS4-lacZ UUG:AUG initiation ratio, with R13P eliminating ~75% of the increase in the UUG/AUG initiation ratio conferred by SUI3-2 in TIF11+ cells (Figure 2B).	('TIF11', 'Gene', (211, 216))	('reduced', 'NegReg', (65, 72))	('R13P', 'SUBSTITUTION', 'None', (118, 122))	('HIS4', 'Gene', (77, 81))	('AUG', 'Chemical', '-', (91, 94))	('UUG/AUG initiation ratio', 'MPA', (163, 187))	('eliminating', 'NegReg', (123, 134))	('TIF11', 'Gene', '855302', (211, 216))	('R13P', 'Var', (118, 122))	('AUG', 'Chemical', '-', (167, 170))	('SUI3', 'Gene', '855838', (201, 205))	('SUI3', 'Gene', (201, 205))	('HIS4', 'Gene', '850327', (77, 81))
2896	29206102	Many Sui- mutations, including SUI3-2, derepress GCN4 mRNA translation in nutrient-replete cells (the Gcd- phenotype).	('Gcd', 'Chemical', '-', (102, 105))	('GCN4', 'Gene', (49, 53))	('Sui-', 'Gene', (5, 9))	('translation', 'biological_process', 'GO:0006412', ('59', '70'))	('derepress', 'Reg', (39, 48))	('mutations', 'Var', (10, 19))	('GCN4', 'Gene', '856709', (49, 53))	('SUI3', 'Gene', '855838', (31, 35))	('SUI3', 'Gene', (31, 35))	('mRNA translation', 'MPA', (54, 70))
2898	29206102	Interestingly, the Gcd- phenotype of SUI3-2, manifested as an ~3 fold derepression of a GCN4-lacZ reporter, is also significantly diminished by R13P (Figure 2:figure supplement 1C), the eIF1A NTT mutation shown above to be the strongest suppressor of the Sui- phenotype of SUI3-2 (Figure 2B).	('NTT', 'Gene', (192, 195))	('R13P', 'Var', (144, 148))	('diminished', 'NegReg', (130, 140))	('SUI3', 'Gene', '855838', (273, 277))	('GCN4', 'Gene', '856709', (88, 92))	('SUI3', 'Gene', (273, 277))	('eIF1A', 'Var', (186, 191))	('SUI3', 'Gene', (37, 41))	('SUI3', 'Gene', '855838', (37, 41))	('GCN4', 'Gene', (88, 92))	('NTT', 'Chemical', '-', (192, 195))	('R13P', 'SUBSTITUTION', 'None', (144, 148))	('derepression', 'PosReg', (70, 82))	('Gcd', 'Chemical', '-', (19, 22))
2899	29206102	Co-suppression of the Gcd- and Sui- phenotypes of SUI3-2 has been demonstrated for other Ssu- mutations in eIF1A and attributed to destabilization of the closed/PIN conformation and attendant shift to the open scanning-conducive conformation to which TC binds rapidly.	('closed/PIN conformation', 'MPA', (154, 177))	('eIF1A', 'Gene', (107, 112))	('SUI3', 'Gene', (50, 54))	('binds', 'Interaction', (254, 259))	('SUI3', 'Gene', '855838', (50, 54))	('mutations', 'Var', (94, 103))	('destabilization', 'NegReg', (131, 146))	('shift', 'Reg', (192, 197))	('TC', 'Chemical', '-', (251, 253))	('Gcd', 'Chemical', '-', (22, 25))	('Ssu-', 'Gene', (89, 93))
2900	29206102	Thus, co-suppression of the Gcd- and Sui-/hypoaccuracy phenotypes of SUI3-2 observed only for the R13P mutation suggests that it exceeds the other UM-associated mutations in destabilizing the closed/PIN conformation of the PIC.	('R13P', 'Var', (98, 102))	('closed/PIN conformation', 'MPA', (192, 215))	('PIC', 'Chemical', '-', (223, 226))	('PIC', 'cellular_component', 'GO:0019035', ('223', '226'))	('R13P', 'SUBSTITUTION', 'None', (98, 102))	('Gcd', 'Chemical', '-', (28, 31))	('PIC', 'cellular_component', 'GO:0097550', ('223', '226'))	('destabilizing', 'NegReg', (174, 187))	('SUI3', 'Gene', '855838', (69, 73))	('SUI3', 'Gene', (69, 73))
2901	29206102	In addition to reducing initiation at near-cognate UUG codons in Sui- mutants, Ssu- substitutions in eIF1 and eIF1A are known to increase discrimination against the AUG start codon of the SUI1 gene encoding eIF1, which exhibits a non-preferred Kozak context.	('AUG', 'Chemical', '-', (165, 168))	('mutants', 'Var', (70, 77))	('eIF1A', 'Gene', (110, 115))	('substitutions', 'Var', (84, 97))	('SUI1', 'Gene', '855477', (188, 192))	('increase', 'PosReg', (129, 137))	('SUI1', 'Gene', (188, 192))	('reducing', 'NegReg', (15, 23))	('eIF1', 'Gene', (101, 105))	('initiation', 'MPA', (24, 34))	('discrimination', 'MPA', (138, 152))	('Ssu-', 'Gene', (79, 83))
2903	29206102	Consistent with this, the eIF1A UM mutations reduce the steady-state level of eIF1, with the strongest reduction for R13P, lesser reductions for K3E, K4D, DeltaG8, and G15D, and the smallest effects for T6R and T6D (Figure 2C, eIF1 blot and eIF1/Gcd6 ratios).	('K3E', 'MPA', (145, 148))	('G15D', 'MPA', (168, 172))	('Gcd6', 'Gene', (246, 250))	('DeltaG8', 'DELETION', 'None', (155, 162))	('K4D', 'MPA', (150, 153))	('T6R', 'Mutation', 'p.T6R', (203, 206))	('R13P', 'Var', (117, 121))	('reductions', 'NegReg', (130, 140))	('DeltaG8', 'Var', (155, 162))	('reduce', 'NegReg', (45, 51))	('G15D', 'Mutation', 'p.G15D', (168, 172))	('eIF1A UM', 'Gene', (26, 34))	('reduction', 'NegReg', (103, 112))	('Gcd6', 'Gene', '851797', (246, 250))	('R13P', 'SUBSTITUTION', 'None', (117, 121))	('mutations', 'Var', (35, 44))
2904	29206102	This hierarchy exactly parallels that observed for suppression of the UUG:AUG initiation ratio in SUI3-2 cells for these eIF1A mutants (Figure 2B).	('eIF1A', 'Gene', (121, 126))	('SUI3', 'Gene', '855838', (98, 102))	('SUI3', 'Gene', (98, 102))	('UUG:AUG initiation ratio', 'MPA', (70, 94))	('AUG', 'Chemical', '-', (74, 77))	('mutants', 'Var', (127, 134))
2905	29206102	Results in Figure 2C also reveal that K4D, DeltaG8, T6R and T6D reduce expression of eIF1A itself (eIF1A blot).	('expression', 'MPA', (71, 81))	('DeltaG8', 'Var', (43, 50))	('DeltaG8', 'DELETION', 'None', (43, 50))	('reduce', 'NegReg', (64, 70))	('T6D', 'Var', (60, 63))	('T6R', 'Mutation', 'p.T6R', (52, 55))	('K4D', 'Var', (38, 41))	('eIF1A', 'Gene', (85, 90))	('T6R', 'Var', (52, 55))
2906	29206102	It seems unlikely that these reductions arise from altered translation of eIF1A, as the eIF1A AUG codon is in good context (A at -3) and the reductions do not correlate with decreases in eIF1 expression conferred by different eIF1A variants (Figure 2C).	('decreases', 'NegReg', (174, 183))	('AUG', 'Chemical', '-', (94, 97))	('expression', 'MPA', (192, 202))	('translation', 'biological_process', 'GO:0006412', ('59', '70'))	('eIF1', 'Gene', (187, 191))	('eIF1A', 'Gene', (226, 231))	('variants', 'Var', (232, 240))
2907	29206102	Rather, these substitutions, and those at Lys10 discussed below (Figure 4A), might impair a role of the first 10 residues of eIF1A in stabilizing the protein.	('eIF1A', 'Gene', (125, 130))	('stabilizing the protein', 'MPA', (134, 157))	('Lys10', 'Gene', (42, 47))	('Lys10', 'Gene', '854714', (42, 47))	('impair', 'NegReg', (83, 89))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('substitutions', 'Var', (14, 27))
2908	29206102	Regardless, the reduced expression of these eIF1A variants is insufficient to confer a marked reduction in eIF1 synthesis or a strong Ssu- phenotype, as both eIF1A-T6R and eIF1A-T6D are poorly expressed but have a small impact on both eIF1 expression (Figure 2C) and the enhanced UUG initiation conferred by SUI3-2 (Figure 2B).	('SUI3', 'Gene', '855838', (308, 312))	('T6R', 'Mutation', 'p.T6R', (164, 167))	('SUI3', 'Gene', (308, 312))	('enhanced', 'PosReg', (271, 279))	('reduction', 'NegReg', (94, 103))	('UUG initiation', 'MPA', (280, 294))	('insufficient', 'Disease', 'MESH:D000309', (62, 74))	('eIF1A-T6R', 'Var', (158, 167))	('expression', 'MPA', (240, 250))	('insufficient', 'Disease', (62, 74))	('variants', 'Var', (50, 58))	('synthesis', 'biological_process', 'GO:0009058', ('112', '121'))	('eIF1A-T6D', 'Var', (172, 181))	('synthesis', 'MPA', (112, 121))	('eIF1', 'Gene', (235, 239))
2909	29206102	In accordance with their effects on eIF1 expression, the R13P, K3E, K4D, DeltaG8, and G15D mutations significantly reduce expression of the WT SUI1-lacZ fusion containing the native, poor context of the eIF1 AUG codon, -3CGU-1 (Figure 2D, Native context).	('G15D', 'Mutation', 'p.G15D', (86, 90))	('expression', 'MPA', (122, 132))	('K4D', 'Var', (68, 71))	('R13P', 'SUBSTITUTION', 'None', (57, 61))	('G15D mutations', 'Var', (86, 100))	('DeltaG8', 'DELETION', 'None', (73, 80))	('SUI1', 'Gene', '855477', (143, 147))	('AUG', 'Chemical', '-', (208, 211))	('DeltaG8', 'Var', (73, 80))	('K3E', 'Var', (63, 66))	('SUI1', 'Gene', (143, 147))	('reduce', 'NegReg', (115, 121))	('R13P', 'Var', (57, 61))
2910	29206102	These eIF1A mutations also reduce expression of a second reporter in which the native AUG context is replaced with the even less favorable context of -3UUU-1, with R13P again conferring the largest reduction (Figure 2D, poor context).	('expression', 'MPA', (34, 44))	('R13P', 'Var', (164, 168))	('AUG', 'Chemical', '-', (86, 89))	('mutations', 'Var', (12, 21))	('reduce', 'NegReg', (27, 33))	('R13P', 'SUBSTITUTION', 'None', (164, 168))	('eIF1A', 'Gene', (6, 11))
2911	29206102	Thus, a subset of the UM mutations, and particularly R13P and G15D, selectively reduce recognition of the eIF1 AUG codon when it resides in its native poor context, or in another poor context, in addition to increasing discrimination against near-cognate UUG start codons.	('R13P', 'SUBSTITUTION', 'None', (53, 57))	('recognition', 'MPA', (87, 98))	('AUG', 'Chemical', '-', (111, 114))	('G15D', 'Var', (62, 66))	('eIF1 AUG', 'Gene', (106, 114))	('G15D', 'Mutation', 'p.G15D', (62, 66))	('reduce', 'NegReg', (80, 86))	('R13P', 'Var', (53, 57))	('increasing', 'PosReg', (208, 218))
2912	29206102	Among the UM mutations, R13P consistently conferred the greatest reduction in recognition of both UUG codons and AUGs in poor context (Figure 2 and Figure 2:figure supplement 1).	('R13P', 'Var', (24, 28))	('recognition', 'MPA', (78, 89))	('R13P', 'SUBSTITUTION', 'None', (24, 28))	('AUG', 'Chemical', '-', (113, 116))	('reduction', 'NegReg', (65, 74))
2913	29206102	In the structure of py48S, Arg13 contacts the +5 nucleotide in mRNA, and with Lys7, Lys10, and Lys16, is one of four basic residues in the eIF1A NTT contacting the mRNA or tRNAi anticodon (Figure 1B).	('Lys10', 'Gene', (84, 89))	('Arg13', 'Var', (27, 32))	('Lys7', 'Gene', (78, 82))	('Lys16', 'Var', (95, 100))	('Lys16', 'Chemical', '-', (95, 100))	('Arg13', 'Chemical', '-', (27, 32))	('Lys7', 'Gene', '855054', (78, 82))	('py48S', 'Chemical', '-', (20, 25))	('py48S', 'Var', (20, 25))	('Lys10', 'Gene', '854714', (84, 89))	('NTT', 'Chemical', '-', (145, 148))
2914	29206102	A fifth basic residue, Arg14 contacts A1427/G1428 of 18S rRNA located in the mRNA binding cleft.	('A1427/G1428', 'Var', (38, 49))	('mRNA binding', 'molecular_function', 'GO:0003729', ('77', '89'))	('Arg14', 'Chemical', '-', (23, 28))	('Arg14', 'Var', (23, 28))
2915	29206102	In addition, UM mutation DeltaG8 affects the tandem Gly8-Gly9 pair that mediates a turn in the NTT required for proper positioning of the four basic residues.	('NTT', 'Chemical', '-', (95, 98))	('DeltaG8', 'DELETION', 'None', (25, 32))	('affects', 'Reg', (33, 40))	('DeltaG8', 'Var', (25, 32))	('turn in the NTT required', 'MPA', (83, 107))	('Gly8-Gly9', 'Chemical', '-', (52, 61))
2916	29206102	Accordingly, we hypothesized that the hyperaccuracy phenotypes of the UM-associated substitutions R13P and DeltaG8 reflect loss of a direct contact with the mRNA (R13P) or perturbation of one or more contacts of the four basic residues with mRNA/tRNAi (DeltaG8), which destabilizes the PIN state of the 48S PIC.	('R13P', 'SUBSTITUTION', 'None', (163, 167))	('R13P', 'Var', (98, 102))	('contact', 'Interaction', (140, 147))	('PIC', 'cellular_component', 'GO:0019035', ('307', '310'))	('R13P', 'SUBSTITUTION', 'None', (98, 102))	('PIC', 'Chemical', '-', (307, 310))	('DeltaG8', 'DELETION', 'None', (107, 114))	('R13P', 'Var', (163, 167))	('PIC', 'cellular_component', 'GO:0097550', ('307', '310'))	('contacts', 'Interaction', (200, 208))	('loss', 'NegReg', (123, 127))	('DeltaG8', 'Var', (107, 114))	('DeltaG8', 'DELETION', 'None', (253, 260))	('DeltaG8', 'Var', (253, 260))	('perturbation', 'Reg', (172, 184))
2917	29206102	Moreover, insertion of an acidic side-chain between basic residues Arg14 and Lys16 by UM substitution G15D (Figure 1B), which could introduce electrostatic repulsion with the backbone of mRNA or rRNA, could likewise destabilize the 48S PIC.	('electrostatic repulsion', 'MPA', (142, 165))	('Lys16', 'Chemical', '-', (77, 82))	('introduce', 'Reg', (132, 141))	('48S PIC', 'CPA', (232, 239))	('Lys16', 'Var', (77, 82))	('G15D', 'Mutation', 'p.G15D', (102, 106))	('insertion', 'Var', (10, 19))	('PIC', 'Chemical', '-', (236, 239))	('destabilize', 'NegReg', (216, 227))	('Arg14', 'Chemical', '-', (67, 72))	('Arg14', 'Var', (67, 72))	('PIC', 'cellular_component', 'GO:0019035', ('236', '239'))	('PIC', 'cellular_component', 'GO:0097550', ('236', '239'))	('G15D', 'Var', (102, 106))
2918	29206102	Because UUG start codons form a less stable codon:anticodon helix with a U:U mismatch compared to the perfect duplex formed at AUG codons, UM substitutions that destabilize PIN should be especially deleterious to initiation at UUG codons, as we observed (Figure 2).	('mismatch', 'Var', (77, 85))	('substitutions', 'Var', (142, 155))	('destabilize', 'NegReg', (161, 172))	('PIN', 'MPA', (173, 176))	('AUG', 'Chemical', '-', (127, 130))
2919	29206102	To test this hypothesis, we introduced Ala and Asp substitutions at all five of the NTT basic residues that contact mRNA, tRNAi or rRNA in the py48S PIC, expecting to find stronger hyperaccuracy phenotypes for Asp versus Ala substitutions owing to electrostatic repulsion with the nucleic acids in the case of Asp replacements.	('Asp', 'Chemical', 'MESH:D001224', (47, 50))	('hyperaccuracy', 'MPA', (181, 194))	('NTT', 'Chemical', '-', (84, 87))	('substitutions', 'Var', (51, 64))	('PIC', 'Chemical', '-', (149, 152))	('electrostatic', 'MPA', (248, 261))	('Ala', 'Chemical', 'MESH:D000409', (221, 224))	('Asp', 'Chemical', 'MESH:D001224', (210, 213))	('PIC', 'cellular_component', 'GO:0019035', ('149', '152'))	('stronger', 'PosReg', (172, 180))	('Ala', 'Chemical', 'MESH:D000409', (39, 42))	('PIC', 'cellular_component', 'GO:0097550', ('149', '152'))	('Asp', 'Chemical', 'MESH:D001224', (310, 313))	('py48S', 'Chemical', '-', (143, 148))
2920	29206102	We also examined a double deletion of Gly8-Gly9 that we reasoned might have a stronger phenotype than the UM mutation DeltaG8.	('Gly8-Gly9', 'Var', (38, 47))	('DeltaG8', 'DELETION', 'None', (118, 125))	('DeltaG8', 'Var', (118, 125))	('Gly8-Gly9', 'Chemical', '-', (38, 47))	('double deletion', 'Var', (19, 34))
2921	29206102	We observed modest Slg- phenotypes for the R13D and R14D substitutions, but no His+ phenotypes indicative of Sui- defects for any of the targeted NTT mutations (Figure 3:figure supplement 1A).	('NTT', 'Chemical', '-', (146, 149))	('R14D', 'Var', (52, 56))	('R14D', 'Mutation', 'p.R14D', (52, 56))	('R13D', 'Mutation', 'p.R13D', (43, 47))	('His', 'Chemical', 'MESH:D006639', (79, 82))	('R13D', 'Var', (43, 47))
2922	29206102	Remarkably, both Ala and Asp substitutions of Lys10, Arg13, Arg14, and Lys16, and the Asp substitution of Lys7, all diminished the His+/Sui- phenotype of SUI3-2 (Figure 3A) and decreased the HIS4-lacZ UUG:AUG initiation ratio in SUI3-2 cells, with the greatest reductions seen for R13D, R14D, and K16D.	('SUI3', 'Gene', '855838', (229, 233))	('Lys16', 'Var', (71, 76))	('SUI3', 'Gene', (154, 158))	('decreased', 'NegReg', (177, 186))	('R14D', 'Mutation', 'p.R14D', (287, 291))	('K16D', 'Mutation', 'p.K16D', (297, 301))	('His+/Sui- phenotype', 'MPA', (131, 150))	('substitutions', 'Var', (29, 42))	('His', 'Chemical', 'MESH:D006639', (131, 134))	('Ala', 'Chemical', 'MESH:D000409', (17, 20))	('SUI3', 'Gene', (229, 233))	('K16D', 'Var', (297, 301))	('Lys10', 'Var', (46, 51))	('SUI3', 'Gene', '855838', (154, 158))	('Arg14', 'Var', (60, 65))	('Asp substitution of Lys7', 'Mutation', 'p.K7D', (86, 110))	('diminished', 'NegReg', (116, 126))	('HIS4', 'Gene', (191, 195))	('Asp substitutions of Lys10, Arg13, Arg14, and Lys16', 'Mutation', 'p.K,R,R,K10,13,14,16D', (25, 76))	('Lys7', 'Var', (106, 110))	('R14D', 'Var', (287, 291))	('Arg13', 'Var', (53, 58))	('R13D', 'Mutation', 'p.R13D', (281, 285))	('HIS4', 'Gene', '850327', (191, 195))	('AUG', 'Chemical', '-', (205, 208))
2923	29206102	In agreement with our hypothesis, the Asp versus Ala substitutions generally conferred greater suppression of the UUG:AUG ratio, but especially so at Lys10 and Lys16 (Figure 3B).	('Lys16', 'Chemical', '-', (160, 165))	('Lys10', 'Gene', '854714', (150, 155))	('Lys16', 'Var', (160, 165))	('Lys10', 'Gene', (150, 155))	('Asp', 'Chemical', 'MESH:D001224', (38, 41))	('AUG', 'Chemical', '-', (118, 121))	('suppression', 'NegReg', (95, 106))	('UUG:AUG ratio', 'MPA', (114, 127))	('Ala', 'Chemical', 'MESH:D000409', (49, 52))
2924	29206102	Using a second set of UUG and AUG reporters, expressing renilla or firefly luciferase from different transcripts under the control of the ADH1 (RLUC) or GPD (FLUC) promoter, we confirmed that the K16D and R13P substitutions reduced the elevated UUG:AUG initiation ratio conferred by SUI3-2 (Figure 3:figure supplement 1B).	('R13P', 'SUBSTITUTION', 'None', (205, 209))	('ADH', 'molecular_function', 'GO:0047636', ('138', '141'))	('ADH', 'molecular_function', 'GO:0004022', ('138', '141'))	('GPD', 'Disease', (153, 156))	('reduced', 'NegReg', (224, 231))	('GPD', 'Disease', 'MESH:D005955', (153, 156))	('SUI3', 'Gene', '855838', (283, 287))	('SUI3', 'Gene', (283, 287))	('R13P', 'Var', (205, 209))	('K16D', 'Var', (196, 200))	('ADH1', 'Gene', (138, 142))	('AUG', 'Chemical', '-', (249, 252))	('UUG:AUG initiation ratio', 'MPA', (245, 269))	('AUG', 'Chemical', '-', (30, 33))	('ADH1', 'Gene', '854068', (138, 142))	('K16D', 'Mutation', 'p.K16D', (196, 200))
2925	29206102	All of the mutations, except for K7A, also diminished the Gcd- phenotype of SUI3-2, reducing the derepression of GCN4-lacZ expression, again with generally greater reductions for Asp versus Ala replacements (Figure 3C).	('mutations', 'Var', (11, 20))	('Gcd', 'Chemical', '-', (58, 61))	('GCN4', 'Gene', '856709', (113, 117))	('Asp', 'Chemical', 'MESH:D001224', (179, 182))	('SUI3', 'Gene', (76, 80))	('Ala', 'Chemical', 'MESH:D000409', (190, 193))	('GCN4', 'Gene', (113, 117))	('derepression', 'MPA', (97, 109))	('reductions', 'NegReg', (164, 174))	('reducing', 'NegReg', (84, 92))	('SUI3', 'Gene', '855838', (76, 80))	('diminished', 'NegReg', (43, 53))
2926	29206102	The degree of suppression of the elevated UUG:AUG ratio and GCN4-lacZ expression in SUI3-2 cells was correlated, with R13D, R14D, and K16D being the strongest suppressors of both phenotypes (cf.	('R14D', 'Var', (124, 128))	('K16D', 'Mutation', 'p.K16D', (134, 138))	('GCN4', 'Gene', '856709', (60, 64))	('suppression', 'NegReg', (14, 25))	('SUI3', 'Gene', '855838', (84, 88))	('UUG:AUG ratio', 'MPA', (42, 55))	('SUI3', 'Gene', (84, 88))	('R13D', 'Mutation', 'p.R13D', (118, 122))	('R14D', 'Mutation', 'p.R14D', (124, 128))	('AUG', 'Chemical', '-', (46, 49))	('GCN4', 'Gene', (60, 64))	('expression', 'MPA', (70, 80))	('K16D', 'Var', (134, 138))	('R13D', 'Var', (118, 122))
2927	29206102	As noted above, this co-suppression of impaired TC loading (Gcd-) and increased UUG recognition (Sui-) phenotypes suggest that these eIF1A NTT substitutions specifically destabilize the closed/PIN state with attendant shift to the open/POUT scanning conformation of the PIC.	('NTT', 'Gene', (139, 142))	('shift', 'Reg', (218, 223))	('destabilize', 'NegReg', (170, 181))	('Gcd', 'Chemical', '-', (60, 63))	('open/POUT scanning conformation', 'MPA', (231, 262))	('TC', 'Chemical', '-', (48, 50))	('NTT', 'Chemical', '-', (139, 142))	('PIC', 'cellular_component', 'GO:0019035', ('270', '273'))	('PIC', 'cellular_component', 'GO:0097550', ('270', '273'))	('PIC', 'Chemical', '-', (270, 273))	('UUG recognition', 'MPA', (80, 95))	('eIF1A NTT', 'Gene', (133, 142))	('substitutions', 'Var', (143, 156))	('TC loading', 'MPA', (48, 58))	('closed/PIN state', 'MPA', (186, 202))
2928	29206102	In addition to suppressing UUG initiation, all of the targeted substitutions of the five basic residues, and the deletion of Gly8-Gly9, also increase discrimination against the non-preferred context of the eIF1 AUG codon, reducing expression of eIF1 (Figure 4A) and of the SUI1-lacZ fusions with native or poor context, without altering expression of SUI1-lacZ with optimal AUG context (Figure 4B).	('Gly8-Gly9', 'Chemical', '-', (125, 134))	('AUG', 'Chemical', '-', (374, 377))	('SUI1', 'Gene', '855477', (351, 355))	('suppressing', 'NegReg', (15, 26))	('UUG initiation', 'MPA', (27, 41))	('increase', 'PosReg', (141, 149))	('deletion', 'Var', (113, 121))	('SUI1', 'Gene', (351, 355))	('discrimination', 'MPA', (150, 164))	('SUI1', 'Gene', '855477', (273, 277))	('AUG', 'Chemical', '-', (211, 214))	('Gly8-Gly9', 'Gene', (125, 134))	('eIF1', 'Protein', (245, 249))	('SUI1', 'Gene', (273, 277))	('substitutions', 'Var', (63, 76))	('expression', 'MPA', (231, 241))	('reducing', 'NegReg', (222, 230))
2929	29206102	Again, the Asp versus Ala substitutions of the basic NTT residues generally confer stronger phenotypes (Figure 4A-B), consistent with stronger disruptions of NTT contacts with mRNA, tRNAi or rRNA on introduction of negatively charged side-chains.	('NTT', 'Protein', (158, 161))	('mRNA', 'MPA', (176, 180))	('NTT', 'Chemical', '-', (53, 56))	('Asp', 'Chemical', 'MESH:D001224', (11, 14))	('disruptions', 'NegReg', (143, 154))	('Ala', 'Chemical', 'MESH:D000409', (22, 25))	('contacts', 'Interaction', (162, 170))	('NTT', 'Chemical', '-', (158, 161))	('substitutions', 'Var', (26, 39))	('tRNAi', 'MPA', (182, 187))
2930	29206102	Several of the eIF1A variants were expressed at lower than WT levels, including K7A, K7D, K10D, and DeltaG8DeltaG9 (Figure 4A), as noted above for UM substitutions K4D, T6D, T6R, and DeltaG8 (Figure 2C).	('T6R', 'Mutation', 'p.T6R', (174, 177))	('K7D', 'Var', (85, 88))	('K7A', 'Var', (80, 83))	('K4D', 'Var', (164, 167))	('T6D', 'Var', (169, 172))	('DeltaG8', 'DELETION', 'None', (100, 107))	('K10D', 'Mutation', 'p.K10D', (90, 94))	('eIF1A', 'Gene', (15, 20))	('T6R', 'Var', (174, 177))	('DeltaG8', 'DELETION', 'None', (183, 190))	('DeltaG8', 'Var', (100, 107))	('DeltaG8', 'Var', (183, 190))	('K10D', 'Var', (90, 94))
2931	29206102	The mutant proteins K4D, DeltaG8, DeltaG8DeltaG9 and K10D were expressed from hc plasmids at levels exceeding that of WT eIF1A expressed from a single-copy plasmid (scWT); however, they all still conferred reduced levels of eIF1 expression compared to cells containing normal (scWT) or overexpressed levels of WT eIF1A (hcWT) (Figure 4:figure supplement 1A).	('K10D', 'Var', (53, 57))	('reduced', 'NegReg', (206, 213))	('DeltaG8', 'DELETION', 'None', (25, 32))	('eIF1 expression', 'MPA', (224, 239))	('DeltaG8', 'DELETION', 'None', (34, 41))	('DeltaG8', 'Var', (25, 32))	('DeltaG8', 'Var', (34, 41))	('K4D', 'Var', (20, 23))	('K10D', 'Mutation', 'p.K10D', (53, 57))
2932	29206102	The overexpressed variants also conferred reduced expression of the SUI1-lacZ fusions with native or poor context (Figure 4:figure supplement 1B); and they co-suppressed the Sui-/His+ phenotype, elevated UUG:AUG ratio and derepressed GCN4-lacZ expression conferred by SUI3-2 (Figure 4:figure supplement 2).	('GCN4', 'Gene', (234, 238))	('reduced', 'NegReg', (42, 49))	('His', 'Chemical', 'MESH:D006639', (179, 182))	('derepressed', 'NegReg', (222, 233))	('variants', 'Var', (18, 26))	('SUI1', 'Gene', '855477', (68, 72))	('UUG:AUG ratio', 'MPA', (204, 217))	('AUG', 'Chemical', '-', (208, 211))	('elevated', 'PosReg', (195, 203))	('SUI1', 'Gene', (68, 72))	('expression', 'MPA', (244, 254))	('GCN4', 'Gene', '856709', (234, 238))	('Sui-/His+ phenotype', 'MPA', (174, 193))	('SUI3', 'Gene', '855838', (268, 272))	('expression', 'MPA', (50, 60))	('SUI3', 'Gene', (268, 272))
2933	29206102	We conclude that the reduced expression of eIF1A NTT variants has little impact on their ability to increase discrimination against poor initiation sites in vivo.	('reduced', 'NegReg', (21, 28))	('NTT', 'Gene', (49, 52))	('discrimination against poor initiation sites', 'MPA', (109, 153))	('increase', 'PosReg', (100, 108))	('eIF1A NTT', 'Gene', (43, 52))	('expression', 'MPA', (29, 39))	('NTT', 'Chemical', '-', (49, 52))	('variants', 'Var', (53, 61))
2934	29206102	To obtain additional support for the conclusion that eIF1A NTT substitutions increase discrimination against AUGs in poor context, we assayed their effects on GCN4-lacZ reporters containing a modified upstream ORF1 elongated to overlap the GCN4 ORF (el.uORF1).	('GCN4', 'Gene', (240, 244))	('GCN4', 'Gene', '856709', (159, 163))	('NTT', 'Gene', (59, 62))	('GCN4', 'Gene', (159, 163))	('AUG', 'Chemical', '-', (109, 112))	('discrimination against AUGs in poor context', 'MPA', (86, 129))	('increase', 'PosReg', (77, 85))	('GCN4', 'Gene', '856709', (240, 244))	('NTT', 'Chemical', '-', (59, 62))	('eIF1A NTT', 'Gene', (53, 62))	('substitutions', 'Var', (63, 76))
2941	29206102	The UM-associated NTT mutation R13P increases leaky scanning of uAUG-1, as indicated by increased GCN4-lacZ expression for all three reporters containing el.-uORF1 but not for the uORF-less reporter (Figure 4C, cf cols.	('AUG', 'Chemical', '-', (65, 68))	('R13P', 'Var', (31, 35))	('increased', 'PosReg', (88, 97))	('GCN4', 'Gene', '856709', (98, 102))	('NTT', 'Gene', (18, 21))	('increases', 'PosReg', (36, 45))	('leaky scanning', 'MPA', (46, 60))	('NTT', 'Chemical', '-', (18, 21))	('GCN4', 'Gene', (98, 102))	('R13P', 'SUBSTITUTION', 'None', (31, 35))
2942	29206102	Calculating the percentages of ribosomes that recognize uAUG-1 revealed that R13P (i) conferred the greatest reduction in recognition of uAUG-1 when the latter resides in poor context, from ~66% to ~27%, (ii) produced a moderate reduction for the weak-context reporter, from ~89% to ~77%, and (iii) evoked only a slight reduction when uAUG-1 is in optimal context, from >99% to ~98% (Figure 4C, cf.	('R13P', 'SUBSTITUTION', 'None', (77, 81))	('reduction', 'NegReg', (229, 238))	('AUG', 'Chemical', '-', (138, 141))	('reduction', 'NegReg', (109, 118))	('AUG', 'Chemical', '-', (336, 339))	('recognition', 'MPA', (122, 133))	('AUG', 'Chemical', '-', (57, 60))	('R13P', 'Var', (77, 81))
2944	29206102	cols 7 and 9, rows 1-3); and for the targeted K16A and K16D mutations, with the Asp versus Ala replacement conferring the greater reduction in uAUG-1 recognition (Figure 4:figure supplement 3A, cf.	('K16D mutations', 'Var', (55, 69))	('AUG', 'Chemical', '-', (144, 147))	('K16D', 'Mutation', 'p.K16D', (55, 59))	('Ala', 'Chemical', 'MESH:D000409', (91, 94))	('reduction', 'NegReg', (130, 139))	('K16A', 'Mutation', 'p.K16A', (46, 50))	('Asp', 'Chemical', 'MESH:D001224', (80, 83))	('K16A', 'Var', (46, 50))	('uAUG-1 recognition', 'MPA', (143, 161))
2945	29206102	7-9); and also for the hcDeltaG8DeltaG9 and hcK10D mutations (Figure 4:figure supplement 3B, cols.	('hcDeltaG8DeltaG9', 'Var', (23, 39))	('hcK10D', 'Gene', (44, 50))	('K10D', 'Mutation', 'p.K10D', (46, 50))
2946	29206102	Thus, both targeted and UM-associated NTT mutations decrease recognition of AUG start codons by scanning PICs preferentially when they reside in poor versus optimum context.	('NTT', 'Gene', (38, 41))	('AUG', 'Chemical', '-', (76, 79))	('recognition', 'MPA', (61, 72))	('mutations', 'Var', (42, 51))	('PIC', 'Chemical', '-', (105, 108))	('decrease', 'NegReg', (52, 60))	('NTT', 'Chemical', '-', (38, 41))
2947	29206102	The multiple defects in start codon recognition conferred by the eIF1A NTT mutations suggest that they destabilize the PIN state of the 48S PIC at both UUG and AUG start codons.	('PIC', 'Chemical', '-', (140, 143))	('PIC', 'cellular_component', 'GO:0019035', ('140', '143'))	('PIN state', 'MPA', (119, 128))	('start codon recognition', 'MPA', (24, 47))	('eIF1A NTT', 'Gene', (65, 74))	('NTT', 'Chemical', '-', (71, 74))	('AUG', 'Chemical', '-', (160, 163))	('PIC', 'cellular_component', 'GO:0097550', ('140', '143'))	('mutations', 'Var', (75, 84))	('defects', 'NegReg', (13, 20))	('NTT', 'Gene', (71, 74))	('destabilize', 'NegReg', (103, 114))
2948	29206102	We tested this hypothesis by analyzing the effects of the R13P and K16D substitutions on the rate of TC dissociation from PICs reconstituted in vitro.	('TC dissociation', 'MPA', (101, 116))	('R13P', 'Var', (58, 62))	('tested', 'Reg', (3, 9))	('K16D', 'Var', (67, 71))	('R13P', 'SUBSTITUTION', 'None', (58, 62))	('TC', 'Chemical', '-', (101, 103))	('K16D', 'Mutation', 'p.K16D', (67, 71))	('PIC', 'Chemical', '-', (122, 125))
2949	29206102	Partial 43S mRNA complexes (lacking eIF3 and eIF5; henceforth p48S PICs) were formed by incubating WT TC (assembled with [35S]-Met-tRNAi and non-hydrolyzable GTP analog GDPNP) with saturating amounts of eIF1, WT or mutant eIF1A, an uncapped unstructured model mRNA containing either AUG or UUG start codon [mRNA(AUG) or mRNA(UUG)], and 40S subunits.	('GTP', 'Chemical', 'MESH:D006160', (158, 161))	('35S', 'Chemical', 'MESH:C000615320', (122, 125))	('TC', 'Chemical', '-', (102, 104))	('40S', 'Chemical', '-', (336, 339))	('eIF3', 'cellular_component', 'GO:0005852', ('36', '40'))	('PIC', 'Chemical', '-', (67, 70))	('GDPNP', 'Chemical', '-', (169, 174))	('eIF1A', 'Gene', (222, 227))	('mutant', 'Var', (215, 221))	('AUG', 'Chemical', '-', (283, 286))	('AUG', 'Chemical', '-', (312, 315))
2954	29206102	Both eIF1A substitutions R13P and K16D increased the extent and rate of TC dissociation from PICs assembled on mRNA(UUG), while having little effect on the mRNA(AUG) complexes (Figure 5A).	('K16D', 'Mutation', 'p.K16D', (34, 38))	('R13P', 'Var', (25, 29))	('PIC', 'Chemical', '-', (93, 96))	('AUG', 'Chemical', '-', (161, 164))	('eIF1A', 'Gene', (5, 10))	('TC', 'Chemical', '-', (72, 74))	('R13P', 'SUBSTITUTION', 'None', (25, 29))	('increased', 'PosReg', (39, 48))	('K16D', 'Var', (34, 38))	('TC dissociation', 'MPA', (72, 87))
2956	29206102	Thus, our results indicate that the eIF1A substitutions R13P and K16D decrease the fraction of the PICs in the hyper-stable conformation and also destabilize the PIN conformation specifically at near-cognate UUG codons.	('R13P', 'SUBSTITUTION', 'None', (56, 60))	('K16D', 'Var', (65, 69))	('PIN conformation', 'MPA', (162, 178))	('K16D', 'Mutation', 'p.K16D', (65, 69))	('R13P', 'Var', (56, 60))	('eIF1A', 'Gene', (36, 41))	('PICs', 'MPA', (99, 103))	('PIC', 'Chemical', '-', (99, 102))	('decrease', 'NegReg', (70, 78))	('destabilize', 'NegReg', (146, 157))
2957	29206102	We also examined the effects of the eIF1A R13P and K16D substitutions on PIC conformation by measuring their effects on the stability of eIF1A binding to the complex.	('binding', 'Interaction', (143, 150))	('K16D', 'Mutation', 'p.K16D', (51, 55))	('PIC', 'Chemical', '-', (73, 76))	('R13P', 'Var', (42, 46))	('complex', 'Interaction', (158, 165))	('PIC', 'cellular_component', 'GO:0019035', ('73', '76'))	('stability', 'MPA', (124, 133))	('eIF1A', 'Gene', (36, 41))	('binding', 'molecular_function', 'GO:0005488', ('143', '150'))	('effects', 'Reg', (109, 116))	('PIC', 'cellular_component', 'GO:0097550', ('73', '76'))	('R13P', 'SUBSTITUTION', 'None', (42, 46))	('K16D', 'Var', (51, 55))
2962	29206102	The anisotropy of the labeled eIF1A in the PIC (Rb) indicates rotational freedom of the eIF1A CTT, with a higher value indicating greater constraint, which characterizes the closed state.	('PIC', 'cellular_component', 'GO:0019035', ('43', '46'))	('rotational freedom', 'MPA', (62, 80))	('eIF1A', 'Var', (88, 93))	('anisotropy', 'MPA', (4, 14))	('PIC', 'cellular_component', 'GO:0097550', ('43', '46'))	('PIC', 'Chemical', '-', (43, 46))	('CTT', 'Chemical', '-', (94, 97))	('constraint', 'MPA', (138, 148))
2965	29206102	Both the R13P and K16D substitutions dramatically increase the rate of eIF1A dissociation for both mRNAs (Figure 5B-C), and evoke monophasic dissociation kinetics with rate constants (k1) much greater than the WT k2 values for both mRNA(AUG) and mRNA(UUG) (Figure 5B-D).	('AUG', 'Chemical', '-', (237, 240))	('K16D', 'Var', (18, 22))	('R13P', 'SUBSTITUTION', 'None', (9, 13))	('monophasic dissociation kinetics', 'MPA', (130, 162))	('K16D', 'Mutation', 'p.K16D', (18, 22))	('increase', 'PosReg', (50, 58))	('dissociation', 'MPA', (77, 89))	('eIF1A', 'Gene', (71, 76))	('R13P', 'Var', (9, 13))	('evoke', 'Reg', (124, 129))
2966	29206102	The Rb values also were reduced by both R13P and K16D using either mRNA.	('K16D', 'Var', (49, 53))	('R13P', 'SUBSTITUTION', 'None', (40, 44))	('reduced', 'NegReg', (24, 31))	('K16D', 'Mutation', 'p.K16D', (49, 53))	('Rb values', 'MPA', (4, 13))	('R13P', 'Var', (40, 44))
2967	29206102	These results indicate that both eIF1A NTT substitutions dramatically destabilize the closed conformation of the PIC at both AUG or UUG start codons.	('PIC', 'cellular_component', 'GO:0097550', ('113', '116'))	('closed conformation of the PIC', 'MPA', (86, 116))	('NTT', 'Gene', (39, 42))	('NTT', 'Chemical', '-', (39, 42))	('AUG', 'Chemical', '-', (125, 128))	('eIF1A NTT', 'Gene', (33, 42))	('substitutions', 'Var', (43, 56))	('destabilize', 'NegReg', (70, 81))	('PIC', 'Chemical', '-', (113, 116))	('PIC', 'cellular_component', 'GO:0019035', ('113', '116'))
2968	29206102	Finally, we examined the effects of R13P on eIF1A dissociation kinetics using eIF2 containing the eIF2ss-S264Y variant encoded by SUI3-2.	('R13P', 'SUBSTITUTION', 'None', (36, 40))	('SUI3', 'Gene', '855838', (130, 134))	('SUI3', 'Gene', (130, 134))	('R13P', 'Var', (36, 40))	('eIF2', 'cellular_component', 'GO:0005850', ('78', '82'))	('S264Y', 'Var', (105, 110))	('S264Y', 'SUBSTITUTION', 'None', (105, 110))	('eIF2', 'cellular_component', 'GO:0005850', ('98', '102'))
2969	29206102	In PICs containing mRNA(UUG) and WT eIF1A, eIF2ss-S264Y decreased k2 and increased Kamp compared to fully WT PICs, indicating greater occupancy and stability of the closed complex at UUG (Figure 5:figure supplement 1, cf.	('increased', 'PosReg', (73, 82))	('eIF2ss-S264Y', 'Var', (43, 55))	('greater', 'PosReg', (126, 133))	('eIF2', 'cellular_component', 'GO:0005850', ('43', '47'))	('mRNA', 'Var', (19, 23))	('S264Y', 'Mutation', 'p.S264Y', (50, 55))	('decreased', 'NegReg', (56, 65))	('PIC', 'Chemical', '-', (109, 112))	('Kamp', 'MPA', (83, 87))	('PIC', 'Chemical', '-', (3, 6))
2971	29206102	Remarkably, both effects of eIF2ss-S264Y on eIF1A dissociation were reversed on replacing WT eIF1A with the R13P variant, and the Rb value was also reduced (Figure 5:figure supplement 1, cf.	('Rb value', 'MPA', (130, 138))	('reduced', 'NegReg', (148, 155))	('R13P', 'Var', (108, 112))	('eIF2ss-S264Y', 'Var', (28, 40))	('eIF2', 'cellular_component', 'GO:0005850', ('28', '32'))	('R13P', 'SUBSTITUTION', 'None', (108, 112))	('S264Y', 'Mutation', 'p.S264Y', (35, 40))
2972	29206102	These findings help to account for the decreased initiation at UUG codons (Ssu- phenotype) conferred by the eIF1A R13P substitution in SUI3-2 cells (Figure 2B).	('initiation', 'MPA', (49, 59))	('R13P', 'SUBSTITUTION', 'None', (114, 118))	('SUI3', 'Gene', '855838', (135, 139))	('SUI3', 'Gene', (135, 139))	('eIF1A', 'Gene', (108, 113))	('R13P', 'Var', (114, 118))	('decreased', 'NegReg', (39, 48))
2973	29206102	The destabilization of AUG complexes produced by R13P and K16D in the presence of WT eIF2 (Figure 5B-D) also helps to explain the increased leaky scanning of AUG codons in poor context evoked by these eIF1A substitutions in otherwise WT cells (Figures 2C-D and 4A-C, and Figure 4:figure supplement 3A-B).	('destabilization', 'MPA', (4, 19))	('K16D', 'Var', (58, 62))	('substitutions', 'Var', (207, 220))	('K16D', 'Mutation', 'p.K16D', (58, 62))	('eIF1A', 'Gene', (201, 206))	('R13P', 'Var', (49, 53))	('eIF2', 'cellular_component', 'GO:0005850', ('85', '89'))	('R13P', 'SUBSTITUTION', 'None', (49, 53))	('AUG', 'Chemical', '-', (23, 26))	('increased', 'PosReg', (130, 139))	('AUG', 'Chemical', '-', (158, 161))	('leaky scanning', 'MPA', (140, 154))
2974	29206102	To examine effects of the UM-associated R13P substitution in the yeast translatome, we conducted ribosomal footprint profiling of the R13P mutant and isogenic WT strain.	('R13P', 'Var', (134, 138))	('R13P', 'SUBSTITUTION', 'None', (40, 44))	('yeast', 'Species', '4932', (65, 70))	('R13P', 'SUBSTITUTION', 'None', (134, 138))	('R13P', 'Var', (40, 44))
2976	29206102	In accordance with the reduced expression of eIF1 conferred by R13P (Figure 2C, eIF1), both RPF and mRNA reads across the SUI1 coding sequences (CDS) were diminished in R13P cells (Figure 6A).	('R13P', 'SUBSTITUTION', 'None', (169, 173))	('mRNA reads', 'MPA', (100, 110))	('R13P', 'Var', (63, 67))	('RPF', 'MPA', (92, 95))	('SUI1', 'Gene', '855477', (122, 126))	('R13P', 'SUBSTITUTION', 'None', (63, 67))	('R13P', 'Var', (169, 173))	('diminished', 'NegReg', (155, 165))	('SUI1', 'Gene', (122, 126))
2977	29206102	Consistent with these results, we showed previously that the reduced translation of SUI1 mRNA in eIF1 Ssu- mutants evoked by diminished recognition of its poor-context AUG codon is accompanied by reduced SUI1 mRNA abundance.	('translation', 'biological_process', 'GO:0006412', ('69', '80'))	('eIF1 Ssu-', 'Gene', (97, 106))	('SUI1', 'Gene', '855477', (204, 208))	('AUG', 'Chemical', '-', (168, 171))	('mutants', 'Var', (107, 114))	('SUI1', 'Gene', '855477', (84, 88))	('SUI1', 'Gene', (84, 88))	('SUI1', 'Gene', (204, 208))	('Ssu-', 'Gene', (102, 106))	('diminished', 'NegReg', (125, 135))	('recognition', 'MPA', (136, 147))	('reduced', 'NegReg', (61, 68))	('translation', 'MPA', (69, 80))	('reduced', 'NegReg', (196, 203))
2978	29206102	Examples of three other genes with poor context exhibiting reduced translation in R13P cells are shown in Figure 6:figure supplement 2A-C, which in one case (SKI2) also is accompanied by reduced mRNA levels.	('translation', 'biological_process', 'GO:0006412', ('67', '78'))	('R13P', 'SUBSTITUTION', 'None', (82, 86))	('reduced', 'NegReg', (187, 194))	('R13P', 'Var', (82, 86))	('mRNA levels', 'MPA', (195, 206))
2979	29206102	To determine whether R13P evokes widespread discrimination against AUG codons in poor context, we calculated the changes in TE in mutant versus WT cells as the ratio of TER13P to TEWT (abbreviated  TER13P) for groups of genes with different Kozak context.	('R13P', 'SUBSTITUTION', 'None', (200, 204))	('R13P', 'Var', (171, 175))	('R13P', 'Var', (21, 25))	('TER', 'cellular_component', 'GO:0097047', ('169', '172'))	('R13P', 'SUBSTITUTION', 'None', (171, 175))	('AUG', 'Chemical', '-', (67, 70))	('R13P', 'Var', (200, 204))	('R13P', 'SUBSTITUTION', 'None', (21, 25))	('mutant', 'Var', (130, 136))	('TER', 'cellular_component', 'GO:0097047', ('198', '201'))
2980	29206102	Interestingly, R13P conferred a moderate, but significant reduction in TE (log2 TER13P<0) for a group of 123 genes that contain non-preferred bases at every position surrounding the AUG codon, that is (C/U/G)-3(C/U/G)-2(C/U/G)-1(aug)(C/A)+4, that were selected from a set of 4280 genes with adequate read-depth and annotated 5'UTR lengths of >=5 nt (Figure 6B, 'Poor' context vs 'All').	('R13P', 'SUBSTITUTION', 'None', (15, 19))	('TER', 'cellular_component', 'GO:0097047', ('80', '83'))	('R13P', 'SUBSTITUTION', 'None', (82, 86))	('R13P', 'Var', (15, 19))	('reduction', 'NegReg', (58, 67))	('AUG', 'Chemical', '-', (182, 185))	('R13P', 'Var', (82, 86))	('C/U/G)-3(C/U/G)-2(C/U/G)-1', 'Var', (202, 228))
2981	29206102	A-3A-2A-1(AUG)(G/U)+4, designated 'Perfect' context, or for 3537 genes with A/G at -3, we observed a modest increase in  TER13P values, compared to all genes (Figure 6B, 'Perfect', '-3A/G' vs. 'All').	('increase', 'PosReg', (108, 116))	('AUG', 'Chemical', '-', (10, 13))	('-3A/G', 'SUBSTITUTION', 'None', (182, 187))	('TER13P values', 'MPA', (121, 134))	('TER', 'cellular_component', 'GO:0097047', ('121', '124'))	('-3A/G', 'Var', (182, 187))
2982	29206102	Knowing that changes in SUI1 mRNA translation are associated with changes in mRNA abundance in the same direction, we repeated the analysis in Figure 6B considering changes in RPFs rather than TE in the mutant cells, and obtained essentially identical results (Figure 6:figure supplement 2D).	('SUI1', 'Gene', (24, 28))	('mutant', 'Var', (203, 209))	('translation', 'biological_process', 'GO:0006412', ('34', '45'))	('mRNA abundance', 'MPA', (77, 91))	('changes', 'Var', (13, 20))	('changes', 'Reg', (66, 73))	('SUI1', 'Gene', '855477', (24, 28))
2983	29206102	These findings indicate that R13P increases discrimination against AUG start codons with non-preferred Kozak context at many genes in the manner observed for the SUI1 AUG (Figure 2C-D), while conferring an increase in TE for mRNAs with preferred context.	('SUI1', 'Gene', '855477', (162, 166))	('R13P', 'SUBSTITUTION', 'None', (29, 33))	('discrimination', 'MPA', (44, 58))	('SUI1', 'Gene', (162, 166))	('AUG', 'Chemical', '-', (67, 70))	('R13P', 'Var', (29, 33))	('AUG', 'Chemical', '-', (167, 170))	('increase', 'PosReg', (206, 214))	('increases', 'PosReg', (34, 43))
2984	29206102	Examples of genes exhibiting a relative increase in translation in R13P cells are presented in Figure 6:figure supplement 3 (panels A-C).	('R13P', 'SUBSTITUTION', 'None', (67, 71))	('increase', 'PosReg', (40, 48))	('translation', 'biological_process', 'GO:0006412', ('52', '63'))	('R13P', 'Var', (67, 71))	('translation', 'MPA', (52, 63))
2985	29206102	As an orthogonal approach to detecting increased discrimination against poor context by the R13P mutation, we sorted genes on the magnitude of  TER13P values to identify two subsets of genes exhibiting the greatest increases or decreases in TE in mutant cells.	('mutant', 'Var', (247, 253))	('R13P', 'SUBSTITUTION', 'None', (146, 150))	('TER', 'cellular_component', 'GO:0097047', ('144', '147'))	('R13P', 'SUBSTITUTION', 'None', (92, 96))	('R13P', 'Var', (146, 150))	('decreases', 'NegReg', (228, 237))	('increases', 'PosReg', (215, 224))	('R13P', 'Var', (92, 96))
2986	29206102	As shown in the heat-map of Figure 6C, there are widespread decreases or increases in TE in R13P versus WT cells involving thousands of genes, spanning an ~23 fold range of TEWT/TER13P ratios from 0.16 to 3.73.	('decreases', 'NegReg', (60, 69))	('R13P', 'SUBSTITUTION', 'None', (180, 184))	('increases', 'PosReg', (73, 82))	('R13P', 'SUBSTITUTION', 'None', (92, 96))	('R13P', 'Var', (180, 184))	('TER', 'cellular_component', 'GO:0097047', ('178', '181'))	('R13P', 'Var', (92, 96))	('TE in', 'MPA', (86, 91))
2990	29206102	The correlation between the TE changes conferred by R13P and AUG context score shown in Figure 6E-F was identified without taking into account whether the genes exhibit statistically significant differences in TE between mutant and WT cells.	('mutant', 'Var', (221, 227))	('R13P', 'Var', (52, 56))	('AUG', 'Chemical', '-', (61, 64))	('R13P', 'SUBSTITUTION', 'None', (52, 56))
2991	29206102	The 159 genes showing a decrease in ribosome occupancy in R13P cells exhibit significantly lower context scores, whereas 214 genes with elevated ribosome occupancies display higher context scores, compared to all 4307 genes examined (Figure 6:figure supplement 2E).	('lower', 'NegReg', (91, 96))	('R13P', 'Var', (58, 62))	('context scores', 'MPA', (97, 111))	('decrease', 'NegReg', (24, 32))	('R13P', 'SUBSTITUTION', 'None', (58, 62))	('ribosome', 'cellular_component', 'GO:0005840', ('145', '153'))	('ribosome occupancy', 'MPA', (36, 54))	('ribosome', 'cellular_component', 'GO:0005840', ('36', '44'))
2992	29206102	Together, the results indicate that genes with AUG codons in poor context tend to exhibit reductions in TE in R13P cells throughout the yeast translatome.	('reductions', 'NegReg', (90, 100))	('AUG codons', 'Var', (47, 57))	('R13P', 'Var', (110, 114))	('yeast', 'Species', '4932', (136, 141))	('AUG', 'Chemical', '-', (47, 50))	('R13P', 'SUBSTITUTION', 'None', (110, 114))
2993	29206102	The increases in TE observed for genes with preferred context in the mutant might result from decreased competition for limiting initiation factors or 40S subunits owing to reduced translation of mRNAs with poor context.	('increases', 'PosReg', (4, 13))	('40S', 'Chemical', '-', (151, 154))	('mutant', 'Var', (69, 75))	('competition', 'Interaction', (104, 115))	('reduced', 'NegReg', (173, 180))	('translation', 'biological_process', 'GO:0006412', ('181', '192'))	('decreased', 'NegReg', (94, 103))	('translation', 'MPA', (181, 192))	('40S subunits', 'Protein', (151, 163))
2994	29206102	We asked next whether changes in TE (or RPFs) conferred by R13P might involve other features of the initiation region, including its propensity for forming secondary structures or proximity of the AUG codon to the 5' end of the mRNA:both parameters associated with reduced initiation efficiency in WT cells.	('R13P', 'Var', (59, 63))	('reduced', 'NegReg', (265, 272))	('R13P', 'SUBSTITUTION', 'None', (59, 63))	('AUG', 'Chemical', '-', (197, 200))	('initiation efficiency', 'Disease', (273, 294))	('initiation efficiency', 'Disease', 'MESH:D007319', (273, 294))
2996	29206102	For each transcript, we tabulated the average PARS score over the entire 5'UTR (Average PARS), the sum of PARS scores for the 30nt surrounding the start codon (for genes with a 5' UTR of >=16 nt (dubbed 'Start30 PARS'), and the sum of PARS scores for the 30nt centered on the +15 (Plus15) or +30 nucleotides (Plus30) downstream of the AUG. A heat-map depiction of these PARS scores, as well as 5'UTR length, in relation to  TER13P changes for all 2355 genes with sufficient read-density tabulated in the PARS database revealed no obvious correlation between the magnitude of TE changes conferred by R13P and either 5'UTR length or PARS scores (Figure 6:figure supplement 4A).	('R13P', 'Var', (426, 430))	('R13P', 'SUBSTITUTION', 'None', (599, 603))	('R13P', 'SUBSTITUTION', 'None', (426, 430))	('R13P', 'Var', (599, 603))	('TER', 'cellular_component', 'GO:0097047', ('424', '427'))	('AUG', 'Chemical', '-', (335, 338))
2997	29206102	These results contrast with our previous findings that genes exhibiting reduced TE on inactivation of RNA helicase Ded1 tend to have unusually long and structured 5'UTRs with greater than average PARS scores.	('Ded1', 'Gene', (115, 119))	('inactivation', 'Var', (86, 98))	('Ded1', 'Gene', '854379', (115, 119))	('RNA', 'cellular_component', 'GO:0005562', ('102', '105'))
2998	29206102	We showed above that the R13P mutation decreases translation of the elongated version of GCN4 uORF1 specifically when the uORF1 AUG codon resides in poor context, increasing translation of the downstream CDS of the GCN4-lacZ reporter.	('GCN4', 'Gene', (89, 93))	('GCN4', 'Gene', '856709', (215, 219))	('AUG', 'Chemical', '-', (128, 131))	('R13P', 'Var', (25, 29))	('translation', 'biological_process', 'GO:0006412', ('49', '60'))	('translation', 'MPA', (174, 185))	('GCN4', 'Gene', (215, 219))	('R13P', 'SUBSTITUTION', 'None', (25, 29))	('translation', 'biological_process', 'GO:0006412', ('174', '185'))	('decreases', 'NegReg', (39, 48))	('GCN4', 'Gene', '856709', (89, 93))	('GCN4 uORF1', 'Gene', (89, 99))	('GCN4 uORF1', 'Gene', '856709', (89, 99))	('increasing', 'PosReg', (163, 173))	('translation', 'MPA', (49, 60))
3002	29206102	Interestingly, R13P increases ribosome occupancy in the CDS by ~60%, while decreasing ribosome occupancy in the uORF by ~10%, for a change in uORF relative to CDS ribosome occupancy (designated as relative ribosome occupancy, 'RRO') of 0.58 (Figure 7A), which suggests diminished recognition of the poor-context uORF AUG and attendant increase in CDS translation.	('CDS ribosome occupancy', 'Disease', 'MESH:C536560', (159, 181))	('CDS ribosome occupancy', 'Disease', (159, 181))	('R13P', 'SUBSTITUTION', 'None', (15, 19))	('decreasing', 'NegReg', (75, 85))	('ribosome', 'cellular_component', 'GO:0005840', ('163', '171'))	('increase', 'PosReg', (335, 343))	('AUG', 'Chemical', '-', (317, 320))	('ribosome occupancy', 'MPA', (86, 104))	('ribosome', 'cellular_component', 'GO:0005840', ('206', '214'))	('CDS translation', 'MPA', (347, 362))	('R13P', 'Var', (15, 19))	('ribosome occupancy', 'MPA', (30, 48))	('ribosome', 'cellular_component', 'GO:0005840', ('30', '38'))	('ribosome', 'cellular_component', 'GO:0005840', ('86', '94'))	('translation', 'biological_process', 'GO:0006412', ('351', '362'))	('increases', 'PosReg', (20, 29))
3004	29206102	Using bioinformatics, we identified 96 uORFs with AUG start codons that showed evidence of translation in one or more ribosome profiling datasets from WT or various mutant strains, which were obtained in our own laboratory or published by others (see Methods), and which displayed sufficient ribosome occupancies in both the WT and R13P strains analyzed here for quantitative analysis.	('R13P', 'Var', (332, 336))	('mutant', 'Var', (165, 171))	('ribosome', 'cellular_component', 'GO:0005840', ('118', '126'))	('R13P', 'SUBSTITUTION', 'None', (332, 336))	('translation', 'biological_process', 'GO:0006412', ('91', '102'))	('AUG', 'Chemical', '-', (50, 53))	('ribosome', 'cellular_component', 'GO:0005840', ('292', '300'))
3005	29206102	Interestingly, the 72 genes containing uORFs in this group that harbor non-preferred C or U bases at the -3 position mimicked CPA1 and ICY1 in showing decreased RRO values in R13P versus WT cells, compared to the 24 genes with uORFs containing the preferred bases A or G at -3 (Figure 7B).	('ICY1', 'Gene', '855235', (135, 139))	('ICY1', 'Gene', (135, 139))	('RRO values', 'MPA', (161, 171))	('decreased', 'NegReg', (151, 160))	('R13P', 'SUBSTITUTION', 'None', (175, 179))	('R13P', 'Var', (175, 179))
3007	29206102	Interestingly, the preference for non-optimal U/C at -3 is even greater, and A is the least prevalent base at -3 for the group of 30 uORFs showing the greatest reductions in RRO in R13P cells (Figure 7C, RRO_down), which is consistent with increased discrimination against uORF AUGs in poor context in the mutant.	('R13P', 'Var', (181, 185))	('AUG', 'Chemical', '-', (278, 281))	('RRO', 'MPA', (174, 177))	('reductions', 'NegReg', (160, 170))	('R13P', 'SUBSTITUTION', 'None', (181, 185))
3008	29206102	By contrast, the preference for non-optimal U/C at -3 is eliminated for the 30 uORFs that exhibit the greatest increases in RRO in R13P cells (RRO_up), indicating higher frequencies of the preferred A/G bases at this position for this group of uORFs, which is consistent with decreased discrimination in the mutant against uORF AUGs containing relatively stronger sequence contexts (Figure 7C, RRO_up).	('R13P', 'SUBSTITUTION', 'None', (131, 135))	('R13P', 'Var', (131, 135))	('A/G bases', 'Var', (199, 208))	('AUG', 'Chemical', '-', (328, 331))	('higher', 'PosReg', (163, 169))
3010	29206102	Comparing the context scores between two groups of 30 genes exhibiting the greatest increase in RRO (RRO_up) versus the largest decrease in RRO (RRO_down) in the R13P versus WT cells supports the tendency for reduced uORF translation in the mutant when the uORF AUG codon is in poor context but increased uORF translation when the uORF AUG has favorable context (Figure 7D).	('mutant', 'Var', (241, 247))	('AUG', 'Chemical', '-', (262, 265))	('R13P', 'SUBSTITUTION', 'None', (162, 166))	('translation', 'biological_process', 'GO:0006412', ('222', '233'))	('R13P', 'Var', (162, 166))	('uORF translation', 'MPA', (305, 321))	('uORF translation', 'MPA', (217, 233))	('RRO', 'MPA', (96, 99))	('reduced', 'NegReg', (209, 216))	('increased', 'PosReg', (295, 304))	('AUG', 'Chemical', '-', (336, 339))	('translation', 'biological_process', 'GO:0006412', ('310', '321'))
3011	29206102	Thus, discrimination against suboptimal context contributes to reduced uORF translation, as well as reduced main CDS translation, in R13P cells.	('reduced', 'NegReg', (63, 70))	('uORF translation', 'MPA', (71, 87))	('reduced', 'NegReg', (100, 107))	('R13P', 'SUBSTITUTION', 'None', (133, 137))	('translation', 'biological_process', 'GO:0006412', ('76', '87'))	('main CDS translation', 'MPA', (108, 128))	('translation', 'biological_process', 'GO:0006412', ('117', '128'))	('R13P', 'Var', (133, 137))
3012	29206102	The R13P mutation increases discrimination against UUG codons in SUI3-2 and SUI5 cells (Figure 2A-B).	('R13P', 'Var', (4, 8))	('increases', 'PosReg', (18, 27))	('SUI5', 'Gene', (76, 80))	('R13P', 'SUBSTITUTION', 'None', (4, 8))	('SUI3', 'Gene', '855838', (65, 69))	('SUI3', 'Gene', (65, 69))	('discrimination against UUG codons', 'MPA', (28, 61))	('SUI5', 'Gene', '856154', (76, 80))
3013	29206102	We found that in cells lacking a Sui- mutation, R13P reduced the HIS4-lacZ UUG:AUG initiation ratio by a factor of ~2 (from 0.021 +- 0.002 to 0.011 +- 0.001), smaller than the ~3 fold decrease observed in cells containing SUI3-2 (Figure 2B).	('HIS4', 'Gene', (65, 69))	('AUG', 'Chemical', '-', (79, 82))	('R13P', 'Var', (48, 52))	('HIS4', 'Gene', '850327', (65, 69))	('SUI3', 'Gene', '855838', (222, 226))	('SUI3', 'Gene', (222, 226))	('reduced', 'NegReg', (53, 60))	('R13P', 'SUBSTITUTION', 'None', (48, 52))
3014	29206102	Similarly, we found evidence that R13P decreases utilization of the near-cognate ACG start codon that initiates the longer, mitochondrial isoform of alanyl-tRNA synthetase encoded by ALA1, reducing the ratio of ribosome occupancies in the N-terminal extension relative to the CDS (DeltaNTD/CDS) in the mutant to 0.67 of the WT value (Figure 7E).	('ribosome occupancies', 'MPA', (211, 231))	('ALA1', 'Gene', '854513', (183, 187))	('ACG', 'Chemical', 'MESH:C023716', (81, 84))	('tRNA', 'molecular_function', 'GO:0030533', ('156', '160'))	('R13P', 'Var', (34, 38))	('mutant', 'Var', (302, 308))	('reducing', 'NegReg', (189, 197))	('utilization', 'MPA', (49, 60))	('ALA1', 'Gene', (183, 187))	('DeltaNTD', 'Chemical', '-', (281, 289))	('R13P', 'SUBSTITUTION', 'None', (34, 38))	('ribosome', 'cellular_component', 'GO:0005840', ('211', '219'))	('decreases', 'NegReg', (39, 48))
3016	29206102	In this report we show that all seven substitutions in the NTT of yeast eIF1A associated with uveal melanoma in humans confer hyperaccuracy phenotypes in yeast cells.	('associated', 'Reg', (78, 88))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('eIF1A', 'Gene', (72, 77))	('substitutions', 'Var', (38, 51))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('uveal melanoma', 'Disease', (94, 108))	('yeast', 'Species', '4932', (154, 159))	('humans', 'Species', '9606', (112, 118))	('yeast', 'Species', '4932', (66, 71))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('NTT', 'Chemical', '-', (59, 62))
3019	29206102	Like previously identified Ssu- substitutions in eIF1, these eIF1A NTT substitutions also suppress the toxicity of SUI5 to cell growth at elevated temperatures.	('NTT', 'Chemical', '-', (67, 70))	('suppress', 'NegReg', (90, 98))	('substitutions', 'Var', (71, 84))	('toxicity', 'Disease', 'MESH:D064420', (103, 111))	('SUI5', 'Gene', (115, 119))	('toxicity', 'Disease', (103, 111))	('cell growth', 'biological_process', 'GO:0016049', ('123', '134'))	('NTT', 'Gene', (67, 70))	('eIF1A NTT', 'Gene', (61, 70))	('SUI5', 'Gene', '856154', (115, 119))
3021	29206102	The recent structure of a yeast partial 48S PIC predicts that the UM-associated substitutions in the C-terminal portion of the NTT affect direct contacts of the NTT with mRNA nucleotides adjacent to the AUG codon, or in the anticodon of tRNAi, and both interactions are thought to stabilize the PIC in the closed conformation with Met-tRNAi accommodated in the PIN state .	('PIC', 'cellular_component', 'GO:0019035', ('295', '298'))	('affect', 'Reg', (131, 137))	('AUG', 'Chemical', '-', (203, 206))	('NTT', 'Gene', (127, 130))	('NTT', 'Gene', (161, 164))	('substitutions', 'Var', (80, 93))	('yeast', 'Species', '4932', (26, 31))	('closed', 'MPA', (306, 312))	('PIC', 'cellular_component', 'GO:0097550', ('295', '298'))	('contacts', 'Interaction', (145, 153))	('NTT', 'Chemical', '-', (127, 130))	('NTT', 'Chemical', '-', (161, 164))	('stabilize', 'Reg', (281, 290))	('PIC', 'cellular_component', 'GO:0019035', ('44', '47'))	('PIC', 'Chemical', '-', (44, 47))	('PIC', 'cellular_component', 'GO:0097550', ('44', '47'))	('PIC', 'Chemical', '-', (295, 298))
3022	29206102	Accordingly, the effects of the UM substitutions in reducing near-cognate UUG and poor-context AUG utilization can be attributed to destabilization of the PIN state with attendant increased requirement for a perfect codon-anticodon duplex and optimal context.	('substitutions', 'Var', (35, 48))	('reducing', 'NegReg', (52, 60))	('AUG', 'Chemical', '-', (95, 98))	('poor-context AUG utilization', 'MPA', (82, 110))	('near-cognate UUG', 'MPA', (61, 77))
3023	29206102	First, an identical set of phenotypes was observed for directed substitutions of conserved basic residues in the NTT that also make direct contacts with mRNA or anticodon nucleotides, namely K7, K10, K16, and R14.	('NTT', 'Gene', (113, 116))	('mRNA or', 'MPA', (153, 160))	('K16', 'Gene', (200, 203))	('K16', 'Gene', '3868', (200, 203))	('NTT', 'Chemical', '-', (113, 116))	('R14', 'Var', (209, 212))	('contacts', 'Interaction', (139, 147))	('K10', 'Gene', '3858', (195, 198))	('K10', 'Gene', (195, 198))
3024	29206102	Substitutions of these residues with Asp have stronger phenotypes than Ala substitutions, consistent with replacing electrostatic attraction (Lys/Arg) with repulsion (Asp) for the phosphodiester backbone of mRNA or tRNAi.	('Asp', 'Chemical', 'MESH:D001224', (37, 40))	('electrostatic attraction', 'MPA', (116, 140))	('Asp', 'Chemical', 'MESH:D001224', (167, 170))	('Lys', 'Chemical', 'MESH:D008239', (142, 145))	('Arg', 'Chemical', 'MESH:D001120', (146, 149))	('Ala', 'Chemical', 'MESH:D000409', (71, 74))	('replacing', 'PosReg', (106, 115))	('repulsion', 'MPA', (156, 165))	('Lys/Arg', 'Var', (142, 149))	('Substitutions', 'Var', (0, 13))
3026	29206102	Second, biochemical experiments reveal that the R13P UM substitution and the directed K16D substitution specifically destabilize the PIN state at UUG codons in vitro, increasing both the fraction of reconstituted PICs from which TC dissociates and the rate of this reaction (koff) with a UUG, but not AUG, start codon in the mRNA.	('K16D', 'Var', (86, 90))	('increasing', 'PosReg', (167, 177))	('R13P', 'Var', (48, 52))	('PIC', 'Chemical', '-', (213, 216))	('K16D', 'Mutation', 'p.K16D', (86, 90))	('AUG', 'Chemical', '-', (301, 304))	('destabilize', 'NegReg', (117, 128))	('R13P', 'SUBSTITUTION', 'None', (48, 52))	('PIN state', 'MPA', (133, 142))	('TC', 'Chemical', '-', (229, 231))
3027	29206102	These substitutions also increase the rate of eIF1A dissociation, signifying a reduced fraction of PICs in the closed conformation and decreased overall stability of these complexes, with either UUG or AUG start codons.	('substitutions', 'Var', (6, 19))	('fraction', 'MPA', (87, 95))	('AUG', 'Chemical', '-', (202, 205))	('dissociation', 'MPA', (52, 64))	('reduced', 'NegReg', (79, 86))	('eIF1A', 'Gene', (46, 51))	('complexes', 'Interaction', (172, 181))	('PICs in the closed conformation', 'MPA', (99, 130))	('stability', 'MPA', (153, 162))	('PIC', 'Chemical', '-', (99, 102))	('decreased', 'NegReg', (135, 144))	('increase', 'PosReg', (25, 33))
3028	29206102	Together, these results help to account for the decreased usage of UUGs and AUGs in poor context conferred by these mutations in vivo, and support the notion that their hyperaccuracy phenotypes result from reduced occupancy and stability of the closed/PIN state that, in turn, confers a heightened requirement for optimal initiation sites.	('reduced', 'NegReg', (206, 213))	('requirement', 'MPA', (298, 309))	('decreased', 'NegReg', (48, 57))	('AUG', 'Chemical', '-', (76, 79))	('usage', 'MPA', (58, 63))	('mutations', 'Var', (116, 125))	('stability', 'MPA', (228, 237))	('occupancy', 'MPA', (214, 223))
3029	29206102	Although reduced initiation at near-cognate UUG codons in Sui- mutants (Ssu- phenotype) was reported previously for clustered alanine substitutions of eIF1A NTT residues 7-11, 12-16, and 17-21, belonging to the scanning inhibitor element designated SI1, it was unknown which residues in these three segments are most critical for increasing UUG initiation, nor whether any residues in the 7-11 and 12-16 intervals increase initiation at AUGs in poor context.	('alanine substitutions', 'Var', (126, 147))	('alanine', 'Chemical', 'MESH:D000409', (126, 133))	('NTT', 'Gene', (157, 160))	('eIF1A NTT', 'Gene', (151, 160))	('UUG initiation', 'MPA', (341, 355))	('reduced', 'NegReg', (9, 16))	('AUG', 'Chemical', '-', (437, 440))	('NTT', 'Chemical', '-', (157, 160))	('increasing', 'PosReg', (330, 340))	('initiation', 'MPA', (17, 27))	('SI', 'Disease', 'None', (249, 251))	('Sui-', 'Var', (58, 62))
3030	29206102	Our findings establish that all five basic residues conserved between yeast and humans that contact mRNA, the anticodon, or 18S rRNA in the decoding center of the py48S PIC (K7, K10, R13, R14, and K16) are critical for efficient utilization of these suboptimal initiation sites, as is the conserved Gly8-Gly9 turn required for making these key contacts (Figure 1B-C).	('PIC', 'Chemical', '-', (169, 172))	('K16', 'Gene', (197, 200))	('K16', 'Gene', '3868', (197, 200))	('K10', 'Gene', '3858', (178, 181))	('py48S', 'Chemical', '-', (163, 168))	('PIC', 'cellular_component', 'GO:0019035', ('169', '172'))	('R13', 'Var', (183, 186))	('K10', 'Gene', (178, 181))	('yeast', 'Species', '4932', (70, 75))	('PIC', 'cellular_component', 'GO:0097550', ('169', '172'))	('Gly8-Gly9', 'Chemical', '-', (299, 308))	('humans', 'Species', '9606', (80, 86))
3032	29206102	Although the 17-21 mutation does not substitute any of the key basic residues, it might impair interactions of the C-terminal section of the eIF1A NTT with PIC components and indirectly prevent the basic residues in the N-terminal portion of the NTT from engaging with the decoding center (Figure 1B).	('interactions', 'Interaction', (95, 107))	('mutation', 'Var', (19, 27))	('NTT', 'Chemical', '-', (246, 249))	('eIF1A', 'Gene', (141, 146))	('PIC', 'cellular_component', 'GO:0097550', ('156', '159'))	('PIC', 'Chemical', '-', (156, 159))	('NTT', 'Chemical', '-', (147, 150))	('impair', 'NegReg', (88, 94))	('prevent', 'NegReg', (186, 193))	('PIC', 'cellular_component', 'GO:0019035', ('156', '159'))
3034	29206102	In addition to suppressing the elevated UUG initiation (Sui- phenotype) conferred by the eIF2ss mutation SUI3-2, the eIF1A NTT substitutions we analyzed also suppress the derepressed GCN4-lacZ expression (Gcd- phenotype) produced by SUI3-2.	('substitutions', 'Var', (127, 140))	('GCN4', 'Gene', (183, 187))	('suppressing', 'NegReg', (15, 26))	('SUI3', 'Gene', (105, 109))	('NTT', 'Gene', (123, 126))	('GCN4', 'Gene', '856709', (183, 187))	('SUI3', 'Gene', '855838', (105, 109))	('Gcd', 'Chemical', '-', (205, 208))	('NTT', 'Chemical', '-', (123, 126))	('eIF1A NTT', 'Gene', (117, 126))	('mutation', 'Var', (96, 104))	('elevated', 'PosReg', (31, 39))	('UUG initiation', 'MPA', (40, 54))	('SUI3', 'Gene', '855838', (233, 237))	('eIF2', 'cellular_component', 'GO:0005850', ('89', '93'))	('SUI3', 'Gene', (233, 237))	('suppress', 'NegReg', (158, 166))
3035	29206102	eIF1 stabilizes the open conformation of the PIC, to which TC binds most rapidly (POUT state) (Figure 1A).	('open conformation', 'MPA', (20, 37))	('eIF1', 'Var', (0, 4))	('binds', 'Interaction', (62, 67))	('PIC', 'Chemical', '-', (45, 48))	('stabilizes', 'Reg', (5, 15))	('PIC', 'cellular_component', 'GO:0019035', ('45', '48'))	('PIC', 'cellular_component', 'GO:0097550', ('45', '48'))	('TC', 'Chemical', '-', (59, 61))
3036	29206102	The Gcd- phenotypes conferred by other Sui- mutations affecting eIF1, eIF1A, and tRNAi have been attributed to destabilization of this POUT state of TC binding.	('eIF1', 'Gene', (64, 68))	('eIF1A', 'Gene', (70, 75))	('Gcd', 'Chemical', '-', (4, 7))	('binding', 'molecular_function', 'GO:0005488', ('152', '159'))	('destabilization', 'NegReg', (111, 126))	('binding', 'Interaction', (152, 159))	('mutations', 'Var', (44, 53))	('TC', 'Chemical', '-', (149, 151))	('POUT state', 'MPA', (135, 145))	('Gcd- phenotypes', 'Disease', (4, 19))
3037	29206102	This interpretation was based partly on the finding that they are suppressed by Ssu- substitutions in the SI1 and SI2 elements of eIF1A that destabilize the closed/PIN conformation and thus shift the system in the opposite direction towards the open/POUT state, which should accelerate TC binding.	('closed/PIN conformation', 'MPA', (157, 180))	('binding', 'molecular_function', 'GO:0005488', ('289', '296'))	('SI', 'Disease', 'None', (106, 108))	('accelerate', 'PosReg', (275, 285))	('binding', 'Interaction', (289, 296))	('destabilize', 'NegReg', (141, 152))	('eIF1A', 'Gene', (130, 135))	('substitutions', 'Var', (85, 98))	('TC', 'Chemical', '-', (286, 288))	('SI', 'Disease', 'None', (114, 116))	('shift', 'Reg', (190, 195))
3039	29206102	Thus, the marked co-suppression of the Sui- and Gcd- phenotypes of SUI3-2 observed here for substitutions of the key basic residues K7, K10, R13, and K16 of the NTT, particularly for the acidic Asp replacements, provides additional genetic evidence that they preferentially destabilize the closed/PIN state and shift the system towards the open conformation to which TC loads during assembly of scanning PICs.	('destabilize', 'NegReg', (274, 285))	('shift', 'Reg', (311, 316))	('SUI3', 'Gene', '855838', (67, 71))	('SUI3', 'Gene', (67, 71))	('R13', 'Var', (141, 144))	('NTT', 'Gene', (161, 164))	('TC', 'Chemical', '-', (367, 369))	('preferentially', 'PosReg', (259, 273))	('Gcd', 'Chemical', '-', (48, 51))	('NTT', 'Chemical', '-', (161, 164))	('K16', 'Gene', (150, 153))	('substitutions', 'Var', (92, 105))	('PIC', 'Chemical', '-', (404, 407))	('K10', 'Gene', (136, 139))	('K10', 'Gene', '3858', (136, 139))	('K16', 'Gene', '3868', (150, 153))	('Asp', 'Chemical', 'MESH:D001224', (194, 197))	('closed/PIN state', 'MPA', (290, 306))
3040	29206102	We used ribosome footprint profiling to demonstrate that the R13P UM substitution confers a broad decrease in utilization of AUG codons with poor Kozak context in the yeast translatome, mimicking the effect of R13P in reducing eIF1 synthesis from SUI1 mRNA.	('R13P', 'Var', (61, 65))	('synthesis', 'biological_process', 'GO:0009058', ('232', '241'))	('eIF1 synthesis', 'MPA', (227, 241))	('decrease', 'NegReg', (98, 106))	('yeast', 'Species', '4932', (167, 172))	('R13P', 'Var', (210, 214))	('AUG', 'Chemical', '-', (125, 128))	('utilization', 'MPA', (110, 121))	('R13P', 'SUBSTITUTION', 'None', (61, 65))	('SUI1', 'Gene', '855477', (247, 251))	('ribosome', 'cellular_component', 'GO:0005840', ('8', '16'))	('R13P', 'SUBSTITUTION', 'None', (210, 214))	('SUI1', 'Gene', (247, 251))
3041	29206102	R13P also reduced recognition of a subset of the ~100 uORFs whose translation we detected in both mutant and WT cells when their AUG codons reside in poor context, mimicking the effect of R13P of increasing leaky scanning through the elongated version of GCN4 uORF1 specifically when its AUG codon resides in poor context.	('R13P', 'Var', (188, 192))	('GCN4 uORF1', 'Gene', (255, 265))	('GCN4 uORF1', 'Gene', '856709', (255, 265))	('recognition', 'MPA', (18, 29))	('reduced', 'NegReg', (10, 17))	('R13P', 'Var', (0, 4))	('translation', 'biological_process', 'GO:0006412', ('66', '77'))	('R13P', 'SUBSTITUTION', 'None', (188, 192))	('R13P', 'SUBSTITUTION', 'None', (0, 4))	('increasing', 'PosReg', (196, 206))	('AUG', 'Chemical', '-', (288, 291))	('leaky scanning', 'MPA', (207, 221))	('AUG', 'Chemical', '-', (129, 132))	('mutant', 'Var', (98, 104))
3042	29206102	R13P cells also display somewhat increased discrimination against the near-cognate ACG start codon of the ALA1 mRNA that initiates an N-terminal extension of the encoded alanyl tRNA synthetase, decreasing the ratio of reads in the extension versus the CDS by ~1/3rd.	('reads', 'MPA', (218, 223))	('discrimination', 'MPA', (43, 57))	('ALA1', 'Gene', (106, 110))	('alanyl tRNA synthetase', 'Gene', (170, 192))	('R13P', 'Var', (0, 4))	('tRNA', 'molecular_function', 'GO:0030533', ('177', '181'))	('alanyl tRNA synthetase', 'Gene', '292023', (170, 192))	('R13P', 'SUBSTITUTION', 'None', (0, 4))	('increased', 'PosReg', (33, 42))	('ALA1', 'Gene', '854513', (106, 110))	('ACG', 'Chemical', 'MESH:C023716', (83, 86))	('decreasing', 'NegReg', (194, 204))
3045	29206102	On the other hand, R13P modestly decreased initiation at the UUG codon of the HIS4-lacZ reporter, even though it contains preferred A's at -4,-3, and -1.	('R13P', 'SUBSTITUTION', 'None', (19, 23))	('initiation', 'MPA', (43, 53))	('HIS4', 'Gene', (78, 82))	('decreased', 'NegReg', (33, 42))	('R13P', 'Var', (19, 23))	('HIS4', 'Gene', '850327', (78, 82))
3047	29206102	Considering that the sequence of the yeast and human eIF1A-NTT are quite similar, and that R13 is conserved between the two species (Figure 1C), our findings for the UM substitutions in yeast eIF1A lead us to propose that the corresponding substitutions in the human eIF1A NTT will favor oncogenic transformation by increasing discrimination against AUG codons with poor context or near-cognate start codons.	('substitutions', 'Var', (240, 253))	('yeast', 'Species', '4932', (186, 191))	('favor', 'PosReg', (282, 287))	('discrimination', 'MPA', (327, 341))	('NTT', 'Gene', (273, 276))	('yeast', 'Species', '4932', (37, 42))	('human', 'Species', '9606', (47, 52))	('-NTT', 'Chemical', '-', (58, 62))	('human', 'Species', '9606', (261, 266))	('NTT', 'Chemical', '-', (273, 276))	('substitutions', 'Var', (169, 182))	('increasing', 'PosReg', (316, 326))	('NTT', 'Chemical', '-', (59, 62))	('eIF1A NTT', 'Gene', (267, 276))	('oncogenic transformation', 'CPA', (288, 312))	('AUG', 'Chemical', '-', (350, 353))
3048	29206102	If one or more tumor suppressor genes contains such a poor initiation site, the UM substitutions can be expected to increase its relative translation rate and thereby impair one or more control mechanisms governing cell proliferation.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('translation', 'biological_process', 'GO:0006412', ('138', '149'))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor suppressor', 'biological_process', 'GO:0051726', ('15', '31'))	('relative translation rate', 'MPA', (129, 154))	('tumor', 'Disease', (15, 20))	('increase', 'PosReg', (116, 124))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('15', '31'))	('control mechanisms', 'MPA', (186, 204))	('cell proliferation', 'biological_process', 'GO:0008283', ('215', '233'))	('substitutions', 'Var', (83, 96))	('impair', 'NegReg', (167, 173))
3051	29206102	Given their high rates of translation during rapid cell growth, it seems likely that RPGs would exhibit favorable Kozak context, and by analogy with our findings in yeast on the eIF1A R13P substitution, the RPGs would not be expected to show decreased translation as the result of heightened discrimination against poor context.	('translation', 'biological_process', 'GO:0006412', ('252', '263'))	('cell growth', 'biological_process', 'GO:0016049', ('51', '62'))	('translation', 'biological_process', 'GO:0006412', ('26', '37'))	('yeast', 'Species', '4932', (165, 170))	('R13P', 'Var', (184, 188))	('decreased', 'NegReg', (242, 251))	('R13P', 'SUBSTITUTION', 'None', (184, 188))	('eIF1A', 'Gene', (178, 183))
3052	29206102	However, the yeast equivalent of G6D, T6D, did not significantly increase discrimination against the suboptimal eIF1 AUG codon in yeast in the manner observed for R13P.	('R13P', 'SUBSTITUTION', 'None', (163, 167))	('AUG', 'Chemical', '-', (117, 120))	('G6D', 'Gene', (33, 36))	('discrimination', 'MPA', (74, 88))	('G6D', 'Gene', '58530', (33, 36))	('yeast', 'Species', '4932', (130, 135))	('yeast', 'Species', '4932', (13, 18))	('R13P', 'Var', (163, 167))
3053	29206102	Moreover, unlike G6D in the tumor cells, we found no evidence that the UM-related substitutions in yeast eIF1A reduce bulk initiation.	('tumor', 'Disease', (28, 33))	('bulk initiation', 'MPA', (118, 133))	('yeast', 'Species', '4932', (99, 104))	('eIF1A', 'Gene', (105, 110))	('G6D', 'Gene', (17, 20))	('G6D', 'Gene', '58530', (17, 20))	('substitutions', 'Var', (82, 95))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('reduce', 'NegReg', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
3054	29206102	Thus, it is possible that the reduction in RPG expression in G6D tumor cells is a response to reduced bulk translation and cell growth; and it will be interesting to determine whether the R13P substitution in EIF1AX increases discrimination against AUGs in poor context in human cells.	('reduction', 'NegReg', (30, 39))	('increases', 'PosReg', (216, 225))	('tumor', 'Disease', (65, 70))	('bulk translation', 'MPA', (102, 118))	('translation', 'biological_process', 'GO:0006412', ('107', '118'))	('AUG', 'Chemical', '-', (249, 252))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('EIF1AX', 'Gene', '1964', (209, 215))	('reduced', 'NegReg', (94, 101))	('R13P', 'SUBSTITUTION', 'None', (188, 192))	('G6D', 'Gene', (61, 64))	('EIF1AX', 'Gene', (209, 215))	('R13P', 'Var', (188, 192))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('RPG', 'Protein', (43, 46))	('discrimination against AUGs', 'MPA', (226, 253))	('G6D', 'Gene', '58530', (61, 64))	('cell growth', 'biological_process', 'GO:0016049', ('123', '134'))	('human', 'Species', '9606', (273, 278))
3055	29206102	TIF11 mutations in plasmids p5633, p5635, p5637, p5638, p5640, p5642 and p5644 were introduced in plasmid p3990 using GeneArtSite-Directed Mutagenesis System (Invitrogen, ThermoFisher) and the appropriate set of complementary mutagenic oligonucleotide primers listed in Table S1, Supplementary file 1, following the manufacturer's instructions except for the use of Phusion High fidelity Polymerase (New England BioLabs) for the first step of amplification.	('p5638', 'Var', (49, 54))	('TIF11', 'Gene', (0, 5))	('p5644', 'Var', (73, 78))	('p5642', 'Var', (63, 68))	('Mutagenesis', 'biological_process', 'GO:0006280', ('139', '150'))	('p5633', 'Var', (28, 33))	('introduced', 'Reg', (84, 94))	('p5635', 'Var', (35, 40))	('p5637', 'Var', (42, 47))	('TIF11', 'Gene', '855302', (0, 5))	('mutations', 'Var', (6, 15))	('p5640', 'Var', (56, 61))
3056	29206102	Plasmids pPMB167 to pPMB170 were created by inserting a ~1.2 kb EcoRI-SalI fragment containing tif11-K4D, tif11-DeltaG8, tif11-DeltaG8DeltaG9 and tif11-K10D alleles from p5635, p5640, pDH481 and pDH470, respectively, into the corresponding sites of YCplac181.	('tif11', 'Gene', (95, 100))	('tif11', 'Gene', '855302', (121, 126))	('pDH', 'molecular_function', 'GO:0033718', ('195', '198'))	('pDH', 'molecular_function', 'GO:0033718', ('184', '187'))	('pDH481', 'Gene', (184, 190))	('K10D', 'Mutation', 'p.K10D', (152, 156))	('tif11', 'Gene', (146, 151))	('pDH', 'molecular_function', 'GO:0004246', ('195', '198'))	('pDH', 'molecular_function', 'GO:0004246', ('184', '187'))	('tif11', 'Gene', '855302', (95, 100))	('tif11', 'Gene', (106, 111))	('pDH470', 'Gene', (195, 201))	('tif11', 'Gene', (121, 126))	('pDH', 'molecular_function', 'GO:0004739', ('195', '198'))	('pDH', 'molecular_function', 'GO:0004739', ('184', '187'))	('p5640', 'Var', (177, 182))	('tif11', 'Gene', '855302', (146, 151))	('p5635', 'Var', (170, 175))	('tif11', 'Gene', '855302', (106, 111))
3057	29206102	Plasmids p6013 (tif11-R13P) and p6015 (tif11-K16D) for expression of eIF1A variants for biochemical analyses were made by PCR amplification of the appropriate DNA fragments from plasmids p5642 and pDH476, respectively and insertion of the resulting fragments into the NdeI-XmaI sites of pTYB2.	('R13P', 'Var', (22, 26))	('DNA', 'cellular_component', 'GO:0005574', ('159', '162'))	('K16D', 'Mutation', 'p.K16D', (45, 49))	('pDH', 'molecular_function', 'GO:0033718', ('197', '200'))	('pDH', 'molecular_function', 'GO:0004739', ('197', '200'))	('R13P', 'SUBSTITUTION', 'None', (22, 26))	('pDH', 'molecular_function', 'GO:0004246', ('197', '200'))	('tif11', 'Gene', '855302', (39, 44))	('pDH476', 'Gene', (197, 203))	('tif11', 'Gene', (39, 44))	('tif11', 'Gene', '855302', (16, 21))	('variants', 'Var', (75, 83))	('tif11', 'Gene', (16, 21))
3060	29206102	Derivatives of strain H3582 containing plasmid-borne SUI5 (p4281/YCpTIF5-G31R-W), SUI3-2 (p4280/YCpSUI3-S264Y-W) or empty vector were generated by transformation and selection on SC lacking leucine and tryptophan (SC-Leu-Trp).	('tryptophan', 'Chemical', 'MESH:D014364', (202, 212))	('p4281/YCpTIF5-G31R-W', 'Var', (59, 79))	('SUI5', 'Gene', '856154', (53, 57))	('SUI3', 'Gene', '855838', (82, 86))	('SUI3', 'Gene', (82, 86))	('G31R', 'Mutation', 'rs1263354783', (73, 77))	('S264Y', 'Var', (104, 109))	('SC-Leu-Trp', 'Chemical', '-', (214, 224))	('S264Y', 'SUBSTITUTION', 'None', (104, 109))	('SUI3', 'Gene', '855838', (99, 103))	('SUI3', 'Gene', (99, 103))	('SUI5', 'Gene', (53, 57))	('leucine', 'Chemical', 'MESH:D007930', (190, 197))
3063	29206102	WT eIF1 and eIF1A and eIF1A variants R13P and K16D were expressed in BL21(DE3) Codon Plus cells (Agilent Technologies) and purified using the IMPACT system (New England Biolabs) as described previously.	('K16D', 'Var', (46, 50))	('eIF1A', 'Gene', (12, 17))	('R13P', 'SUBSTITUTION', 'None', (37, 41))	('BL21', 'CellLine', 'CVCL:M639', (69, 73))	('eIF1', 'Gene', (3, 7))	('eIF1A', 'Gene', (22, 27))	('K16D', 'Mutation', 'p.K16D', (46, 50))	('R13P', 'Var', (37, 41))
3064	29206102	His6-tagged WT eIF2, or the variant containing eIF2beta-S264Y, were overexpressed in yeast strains GP3511 and H4560, respectively, and purified as described.	('His6', 'Gene', (0, 4))	('yeast', 'Species', '4932', (85, 90))	('His6', 'Gene', '854792', (0, 4))	('eIF2beta-S264Y', 'Var', (47, 61))	('eIF2', 'cellular_component', 'GO:0005850', ('47', '51'))	('eIF2', 'cellular_component', 'GO:0005850', ('15', '19'))	('S264Y', 'Mutation', 'p.S264Y', (56, 61))
3069	29206102	For eIF1A dissociation kinetics, the WT and mutant eIF1A proteins were labeled at their C-termini with Cys-Lys-epsilon-fluorescein dipeptide, using the Expressed Protein Ligation system as previously described.	('eIF1A', 'Gene', (51, 56))	('proteins', 'Protein', (57, 65))	('Cys-Lys-epsilon-fluorescein dipeptide', 'MPA', (103, 140))	('mutant', 'Var', (44, 50))	('Pro', 'Chemical', 'MESH:D011392', (162, 165))	('Cys-Lys-epsilon-fluorescein dipeptide', 'Chemical', '-', (103, 140))
3071	29206102	43S mRNA complexes were preassembled for 2 hr at 26 C in reactions containing 40S subunits (20 nM), eIF1 (1 microM), eIF1A (WT or mutant variants, 1 microM), mRNA (10 microM), and [35S]-TC (0.25 microM eIF2/0.1 mM GDPNP/1 nM [35S]-Met-tRNAi) in 60 microl of reaction buffer (30 mM Hepes-KOH (pH 7.4), 100 mM potassium acetate (pH 7.4), 3 mM magnesium acetate, and 2 mM dithiothreitol).	('40S', 'Chemical', '-', (78, 81))	('35S', 'Chemical', 'MESH:C000615320', (226, 229))	('GDPNP', 'Chemical', '-', (214, 219))	('eIF2', 'cellular_component', 'GO:0005850', ('202', '206'))	('35S', 'Chemical', 'MESH:C000615320', (181, 184))	('mutant variants', 'Var', (130, 145))	('TC', 'Chemical', '-', (186, 188))	('variants', 'Var', (137, 145))
3075	29206102	Ribosome profiling was conducted essentially as described previously as detailed below, on isogenic strains FZY010 and FZY011 (tif11-R13P), and PMY337 and PMY338 (WT TIF11), providing two biological replicates of each genotype, cultured in SC-Leu-Trp, except that cells were not treated with cycloheximide before harvesting, and cycloheximide was added to the lysis buffer at 5x the standard concentration.	('cycloheximide', 'Chemical', 'MESH:D003513', (292, 305))	('SC-Leu-Trp', 'Chemical', '-', (240, 250))	('PMY338', 'Var', (155, 161))	('lysis', 'biological_process', 'GO:0019835', ('360', '365'))	('Ribosome', 'cellular_component', 'GO:0005840', ('0', '8'))	('tif11', 'Gene', '855302', (127, 132))	('R13P', 'SUBSTITUTION', 'None', (133, 137))	('tif11', 'Gene', (127, 132))	('TIF11', 'Gene', '855302', (166, 171))	('TIF11', 'Gene', (166, 171))	('PMY337', 'Var', (144, 150))	('cycloheximide', 'Chemical', 'MESH:D003513', (329, 342))	('R13P', 'Var', (133, 137))
3077	29206102	tif11-R13P (FZY010, FZY011) and WT (PMY337, PMY338) yeast strains growing exponentially in SC medium at 30 C were harvested by vacuum filtration at room temperature, without prior treatment with cycloheximide, and quick-frozen in liquid nitrogen.	('tif11', 'Gene', '855302', (0, 5))	('tif11', 'Gene', (0, 5))	('R13P', 'Var', (6, 10))	('R13P', 'SUBSTITUTION', 'None', (6, 10))	('yeast', 'Species', '4932', (52, 57))	('nitrogen', 'Chemical', 'MESH:D009584', (237, 245))	('cycloheximide', 'Chemical', 'MESH:D003513', (195, 208))
3093	29206102	Thank you for submitting your article "eIF1A residues implicated in cancer stabilize translation preinitiation complexes and favor suboptimal initiation sites" for consideration by eLife.	('translation preinitiation complexes', 'MPA', (85, 120))	('residues', 'Var', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('favor', 'PosReg', (125, 130))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('stabilize', 'PosReg', (75, 84))	('suboptimal initiation sites" for consideration', 'MPA', (131, 177))
3095	29206102	Summary: The authors present a study that provides an extensive analysis of initiation codon selection in response to N-terminal mutants of yeast eIF1A.	('eIF1A', 'Gene', (146, 151))	('yeast', 'Species', '4932', (140, 145))	('N-terminal mutants', 'Var', (118, 136))	('initiation codon', 'MPA', (76, 92))
3096	29206102	The study primarily focuses on cancer-associated eIF1A-NTT mutants.	('mutants', 'Var', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('eIF1A-NTT', 'Gene', (49, 58))	('cancer', 'Disease', (31, 37))	('-NTT', 'Chemical', '-', (54, 58))
3097	29206102	Cancer-associated mutants are introduced into the yeast eIF1A protein together with some synthetic yeast mutants in the same region.	('eIF1A', 'Gene', (56, 61))	('yeast', 'Species', '4932', (50, 55))	('yeast', 'Species', '4932', (99, 104))	('mutants', 'Var', (18, 25))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
3098	29206102	Mutants confer a hyper-accuracy phenotype that is likely attributable to destabilization of a closed/Pin state of the scanning 48S PIC.	('hyper-accuracy', 'Disease', 'MESH:D053307', (17, 31))	('PIC', 'cellular_component', 'GO:0019035', ('131', '134'))	('PIC', 'cellular_component', 'GO:0097550', ('131', '134'))	('PIC', 'Chemical', '-', (131, 134))	('hyper-accuracy', 'Disease', (17, 31))	('Mutants', 'Var', (0, 7))
3099	29206102	The most potent mutant R13P confers altered start site selection genome-wide in yeast, which is consistent with the genetic experiments and in vitro kinetics.	('R13P', 'SUBSTITUTION', 'None', (23, 27))	('altered', 'Reg', (36, 43))	('mutant', 'Var', (16, 22))	('start site selection', 'MPA', (44, 64))	('yeast', 'Species', '4932', (80, 85))	('R13P', 'Var', (23, 27))
3100	29206102	Previous work from Hinnebusch and coworkers has shown that specific residues in eIF1, eIF1A and eIF2beta function in the discrimination of poor context AUG recognition and non-AUG codons (Martin-Marcos et al.	('eIF1A', 'Gene', (86, 91))	('eIF2beta', 'Gene', (96, 104))	('function', 'Reg', (105, 113))	('AUG', 'Chemical', '-', (176, 179))	('AUG', 'Chemical', '-', (152, 155))	('eIF2', 'cellular_component', 'GO:0005850', ('96', '100'))	('residues', 'Var', (68, 76))	('eIF1', 'Gene', (80, 84))
3101	29206102	Interestingly, the finding that essentially all cancer-associated mutations of eIF1A, when made in yeast eIF1A, confer a consistent hyper-accuracy phenotype, is very striking.	('mutations', 'Var', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('hyper-accuracy', 'Disease', (132, 146))	('yeast', 'Species', '4932', (99, 104))	('hyper-accuracy', 'Disease', 'MESH:D053307', (132, 146))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('eIF1A', 'Gene', (79, 84))
3103	29206102	The authors offer the reasonable prediction "If one or more tumor suppressor genes contains such a poor initiation site, the mum substitutions can be expected to increase its relative translation rate and thereby impair one or more control mechanisms governing cell proliferation" Essential revisions: 1) One concern of the study is whether the cancer-associated mutants in eIF1A are applicable to human eIF1A function and cancer.	('cancer', 'Disease', 'MESH:D009369', (423, 429))	('cancer', 'Disease', (345, 351))	('increase', 'PosReg', (162, 170))	('human', 'Species', '9606', (398, 403))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (423, 429))	('cancer', 'Disease', 'MESH:D009369', (345, 351))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('substitutions', 'Var', (129, 142))	('mutants', 'Var', (363, 370))	('eIF1A', 'Gene', (374, 379))	('tumor', 'Disease', (60, 65))	('cancer', 'Disease', (423, 429))
3107	29206102	The authors did RNAseq of polysome fractions prepared from actual mum cancer cells harboring the eIF1A-NTT mutation.	('polysome', 'cellular_component', 'GO:0005844', ('26', '34'))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('eIF1A-NTT', 'Gene', (97, 106))	('cancer', 'Disease', (70, 76))	('mutation', 'Var', (107, 115))	('-NTT', 'Chemical', '-', (102, 106))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
3108	29206102	They identified genes whose translational efficiency was affected by the knockdown of EIF1AX.	('affected', 'Reg', (57, 65))	('translational', 'MPA', (28, 41))	('EIF1AX', 'Gene', '1964', (86, 92))	('EIF1AX', 'Gene', (86, 92))	('knockdown', 'Var', (73, 82))
3109	29206102	3) Figure 5 convincingly demonstrates that the R13P and K16D mutations in eIF1A destabilize the closed/Pin conformation of the 48S PIC at UUG codons in vitro.	('K16D', 'Var', (56, 60))	('R13P', 'SUBSTITUTION', 'None', (47, 51))	('PIC', 'cellular_component', 'GO:0019035', ('131', '134'))	('eIF1A', 'Gene', (74, 79))	('PIC', 'cellular_component', 'GO:0097550', ('131', '134'))	('K16D', 'Mutation', 'p.K16D', (56, 60))	('PIC', 'Chemical', '-', (131, 134))	('closed/Pin conformation', 'MPA', (96, 119))	('R13P', 'Var', (47, 51))	('destabilize', 'NegReg', (80, 91))
3110	29206102	Could they extend these results by showing a decreased UUG/AUG start codon usage in a cell-free translation system from eIF1A-mutant cells as compared to wildtype?	('AUG', 'Chemical', '-', (59, 62))	('UUG/AUG start codon usage', 'MPA', (55, 80))	('decreased', 'NegReg', (45, 54))	('translation', 'biological_process', 'GO:0006412', ('96', '107'))	('eIF1A-mutant', 'Gene', (120, 132))	('eIF1A-mutant', 'Var', (120, 132))
3111	29206102	10.7554/eLife.31250.106 Essential revisions: 1) One concern of the study is whether the cancer-associated mutants in eIF1A are applicable to human eIF1A function and cancer.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('eIF1A', 'Gene', (117, 122))	('human', 'Species', '9606', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('mutants', 'Var', (106, 113))
3112	29206102	Ribosome profiling of human cells altered by gene editing to express the R13P tumor mutation is being planned, but is beyond the scope of this paper.	('Ribosome', 'cellular_component', 'GO:0005840', ('0', '8'))	('R13P', 'Var', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('R13P', 'SUBSTITUTION', 'None', (73, 77))	('human', 'Species', '9606', (22, 27))
3115	29206102	[...] Thus, it is possible that the reduction in RPG expression in G6D tumor cells is a response to reduced bulk translation and cell growth; and it will be interesting to determine whether the R13P substitution in EIF1X increases discrimination against AUGs in poor context in human cells."	('bulk translation', 'MPA', (108, 124))	('G6D', 'Gene', (67, 70))	('discrimination', 'MPA', (231, 245))	('G6D', 'Gene', '58530', (67, 70))	('R13P', 'SUBSTITUTION', 'None', (194, 198))	('reduced', 'NegReg', (100, 107))	('AUG', 'Chemical', '-', (254, 257))	('EIF1X', 'Gene', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('reduction', 'NegReg', (36, 45))	('increases', 'PosReg', (221, 230))	('RPG', 'Protein', (49, 52))	('human', 'Species', '9606', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('expression', 'MPA', (53, 63))	('R13P', 'Var', (194, 198))	('tumor', 'Disease', (71, 76))
3116	29206102	While we were not able to comply with this specific request, we were able to add pertinent new results that confirm the effects of both the R13P and K16D substitutions in reducing the UUG:AUG ratio in yeast cells using an independent assay based on luciferase reporters harboring UUG or AUG start codons.	('R13P', 'Var', (140, 144))	('reducing', 'NegReg', (171, 179))	('yeast', 'Species', '4932', (201, 206))	('K16D', 'Var', (149, 153))	('UUG:AUG ratio', 'MPA', (184, 197))	('R13P', 'SUBSTITUTION', 'None', (140, 144))	('K16D', 'Mutation', 'p.K16D', (149, 153))	('AUG', 'Chemical', '-', (287, 290))	('AUG', 'Chemical', '-', (188, 191))
3118	29206102	Given the complete agreement between these two orthogonal in vivo assays and the effects of these substitutions in destabilizing the closed/Pin conformation of reconstituted 48S PIC at UUG codons in vitro, we hope the reviewers will agree that the evidence is very strong that these eIF1A substitutions increase discrimination against a near-cognate start codon.	('increase', 'PosReg', (303, 311))	('PIC', 'cellular_component', 'GO:0097550', ('178', '181'))	('discrimination against a near-cognate start codon', 'MPA', (312, 361))	('substitutions', 'Var', (289, 302))	('closed/Pin conformation', 'MPA', (133, 156))	('eIF1A', 'Gene', (283, 288))	('substitutions', 'Var', (98, 111))	('PIC', 'cellular_component', 'GO:0019035', ('178', '181'))	('PIC', 'Chemical', '-', (178, 181))
3127	28791340	In the in vitro experiment, reduction of Gab2 using small interfering RNA inhibited the migration and invasion of UM cells by mediating MMPs, and fascin expression.	('inhibited', 'NegReg', (74, 83))	('fascin', 'Gene', (146, 152))	('MMPs', 'Gene', (136, 140))	('MMPs', 'Gene', '4313;4318', (136, 140))	('Gab2', 'Gene', '9846', (41, 45))	('UM', 'Phenotype', 'HP:0007716', (114, 116))	('mediating', 'Reg', (126, 135))	('small interfering', 'Var', (52, 69))	('Gab2', 'Gene', (41, 45))	('reduction', 'NegReg', (28, 37))	('RNA', 'cellular_component', 'GO:0005562', ('70', '73'))	('fascin', 'Gene', '6624', (146, 152))
3169	28791340	Western blot analyses on primary UM cell lines and tissues showed that the protein levels of Gab2 were higher in three UM cell lines 92.1, MEL270, and MEL202 compared with human normal retinal pigment epithelium cell line ARPE19 (Fig.	('Gab2', 'Gene', (93, 97))	('MEL270', 'Var', (139, 145))	('UM', 'Phenotype', 'HP:0007716', (33, 35))	('protein levels', 'MPA', (75, 89))	('human', 'Species', '9606', (172, 177))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('MEL202', 'Var', (151, 157))	('ARPE19', 'CellLine', 'CVCL:0145', (222, 228))	('Gab2', 'Gene', '9846', (93, 97))	('higher', 'PosReg', (103, 109))	('UM', 'Phenotype', 'HP:0007716', (119, 121))
3173	28791340	The proliferation assay showed that the knockdown of Gab2 did not significantly influence cell proliferation (Fig.	('knockdown', 'Var', (40, 49))	('cell proliferation', 'CPA', (90, 108))	('Gab2', 'Gene', (53, 57))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))	('Gab2', 'Gene', '9846', (53, 57))
3178	28791340	In addition, scratch assay also showed a significant difference between the migration distance of control and Gab2 knockdown cells, and Gab2 knockdown cells took a longer time to fill the gap, further supporting that Gab2 plays an important role in directional migration of UM cells (Fig.	('Gab2', 'Gene', '9846', (136, 140))	('directional migration', 'CPA', (249, 270))	('knockdown', 'Var', (115, 124))	('Gab2', 'Gene', '9846', (217, 221))	('Gab2', 'Gene', '9846', (110, 114))	('UM', 'Phenotype', 'HP:0007716', (274, 276))	('Gab2', 'Gene', (136, 140))	('Gab2', 'Gene', (110, 114))	('Gab2', 'Gene', (217, 221))	('migration distance', 'CPA', (76, 94))
3184	28791340	We have proven that Gab2 knockdown can reduce the invasive ability of UM cells.	('reduce', 'NegReg', (39, 45))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('Gab2', 'Gene', '9846', (20, 24))	('invasive ability of UM cells', 'CPA', (50, 78))	('Gab2', 'Gene', (20, 24))	('knockdown', 'Var', (25, 34))
3192	28791340	These results indicate that knockdown of Gab2 in UM cells decreased fascin expression in cells treated with EGF and strongly suggest that Gab2 was closely relevant to fascin expression in UM cells.	('Gab2', 'Gene', (138, 142))	('fascin', 'Gene', '6624', (167, 173))	('EGF', 'Gene', '1950', (108, 111))	('fascin', 'Gene', (167, 173))	('Gab2', 'Gene', '9846', (41, 45))	('UM', 'Phenotype', 'HP:0007716', (49, 51))	('decreased', 'NegReg', (58, 67))	('fascin', 'Gene', '6624', (68, 74))	('fascin', 'Gene', (68, 74))	('knockdown', 'Var', (28, 37))	('Gab2', 'Gene', (41, 45))	('Gab2', 'Gene', '9846', (138, 142))	('EGF', 'Gene', (108, 111))	('UM', 'Phenotype', 'HP:0007716', (188, 190))	('EGF', 'molecular_function', 'GO:0005154', ('108', '111'))
3195	28791340	More importantly, high Gab2 expression could be an aggressive biological feature for UM.	('Gab2', 'Gene', '9846', (23, 27))	('expression', 'MPA', (28, 38))	('Gab2', 'Gene', (23, 27))	('high', 'Var', (18, 22))	('UM', 'Phenotype', 'HP:0007716', (85, 87))
3198	28791340	Furthermore, Gab2 knockdown obviously impaired the invasiveness of UM cells.	('knockdown', 'Var', (18, 27))	('Gab2', 'Gene', '9846', (13, 17))	('UM', 'Phenotype', 'HP:0007716', (67, 69))	('invasiveness of UM cells', 'CPA', (51, 75))	('Gab2', 'Gene', (13, 17))	('impaired', 'NegReg', (38, 46))
3205	28791340	To evaluate the involvement of Gab2 in fascin expression in UM cells, fascin protein levels were tested in Gab2 knockdown and corresponding control cells.	('Gab2', 'Gene', (107, 111))	('fascin', 'Gene', '6624', (39, 45))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('fascin', 'Gene', (39, 45))	('knockdown', 'Var', (112, 121))	('Gab2', 'Gene', '9846', (31, 35))	('Gab2', 'Gene', '9846', (107, 111))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('fascin', 'Gene', '6624', (70, 76))	('fascin', 'Gene', (70, 76))	('Gab2', 'Gene', (31, 35))
3206	28791340	In accordance with previous studies, western blot analysis revealed that when treated with EGF, the Gab2 knockdown cells had obviously lower fascin expression than control cells.	('EGF', 'molecular_function', 'GO:0005154', ('91', '94'))	('EGF', 'Gene', (91, 94))	('knockdown', 'Var', (105, 114))	('EGF', 'Gene', '1950', (91, 94))	('Gab2', 'Gene', '9846', (100, 104))	('lower', 'NegReg', (135, 140))	('fascin', 'Gene', '6624', (141, 147))	('Gab2', 'Gene', (100, 104))	('fascin', 'Gene', (141, 147))
3212	28455392	Nevertheless, pathological activation of the ERK1/2 pathway is a linchpin tumorigenic mechanism associated with the majority of primary and recurrent disease.	('ERK1/2', 'Gene', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('ERK1/2', 'Gene', '5595;5594', (45, 51))	('ERK1', 'molecular_function', 'GO:0004707', ('45', '49'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('activation', 'PosReg', (27, 37))	('pathological', 'Var', (14, 26))
3213	28455392	Therefore, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathological ERK1/2 signaling.	('ERK1/2', 'Gene', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('ERK1', 'molecular_function', 'GO:0004707', ('134', '138'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('ERK1/2', 'Gene', '5595;5594', (134, 140))	('pathological', 'Var', (121, 133))
3214	28455392	By integration of multi-genome chemical and genetic screens; recurrent architectural variants in melanoma tumor genomes; and patient outcome data; we identified 2 mechanistic subtypes of BRAF(V600) melanoma that inform new cancer cell biology and offer new therapeutic opportunities.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma tumor', 'Disease', (97, 111))	('melanoma tumor', 'Disease', 'MESH:D008545', (97, 111))	('variants', 'Var', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('inform', 'Reg', (212, 218))	('BRAF(V600) melanoma', 'Disease', 'MESH:D008545', (187, 206))	('patient', 'Species', '9606', (125, 132))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Disease', (223, 229))
3217	28455392	Despite displaying the greatest mutational diversity of any neoplastic disease, fully half of all cutaneous melanomas harbor gain-of-function alleles in the BRAF proto-oncogene.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (98, 116))	('melanomas', 'Disease', 'MESH:D008545', (108, 117))	('melanomas', 'Phenotype', 'HP:0002861', (108, 117))	('BRAF proto-oncogene', 'Gene', (157, 176))	('neoplastic disease', 'Phenotype', 'HP:0002664', (60, 78))	('alleles', 'Var', (142, 149))	('neoplastic disease', 'Disease', 'MESH:D009386', (60, 78))	('cutaneous melanoma', 'Disease', (98, 116))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (98, 116))	('melanomas', 'Disease', (108, 117))	('gain-of-function', 'PosReg', (125, 141))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (98, 117))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('neoplastic disease', 'Disease', (60, 78))
3220	28455392	Identified resistance mechanisms include gain-of-function mutations in NRAS, MAP2K1 and PIK3CA; amplification of COT, upregulation of PDGFRbeta, EGFR, ERBB3 and IGFR1; and amplification or alternative splice variant expression of BRAF.	('mutations', 'Var', (58, 67))	('PIK3CA', 'Gene', '5290', (88, 94))	('ERBB3', 'Gene', '2065', (151, 156))	('NRAS', 'Gene', '4893', (71, 75))	('MAP2K', 'molecular_function', 'GO:0004708', ('77', '82'))	('BRAF', 'Gene', (230, 234))	('IGFR1', 'Gene', '100132417', (161, 166))	('upregulation', 'PosReg', (118, 130))	('MAP2K1', 'Gene', '5604', (77, 83))	('alternative splice variant', 'Var', (189, 215))	('EGFR', 'Gene', (145, 149))	('MAP2K1', 'Gene', (77, 83))	('PIK3CA', 'Gene', (88, 94))	('NRAS', 'Gene', (71, 75))	('IGFR1', 'Gene', (161, 166))	('gain-of-function', 'PosReg', (41, 57))	('PDGFRbeta', 'Gene', (134, 143))	('ERBB3', 'Gene', (151, 156))	('COT', 'Gene', (113, 116))	('EGFR', 'Gene', '1956', (145, 149))	('PDGFRbeta', 'Gene', '5159', (134, 143))	('amplification', 'PosReg', (96, 109))	('EGFR', 'molecular_function', 'GO:0005006', ('145', '149'))
3225	28455392	Remarkable advances in tolerance-breaking immune modulation may lead to effective therapy that is agnostic to BRAF mutant status and MAPK pathway activation, but this will clearly be aided by collaborating interventions that directly target tumor tissue.	('MAPK', 'molecular_function', 'GO:0004707', ('133', '137'))	('tumor', 'Disease', (241, 246))	('mutant', 'Var', (115, 121))	('MAPK pathway', 'Pathway', (133, 145))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('BRAF', 'Gene', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
3227	28455392	If detectable and actionable, targeting these liabilities would be expected to be synthetic-lethal to any and all of the myriad genomic alterations that lead to tumorigenic disregulation of the MAPK regulatory network.	('MAPK', 'molecular_function', 'GO:0004707', ('194', '198'))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('alterations', 'Var', (136, 147))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('MAPK regulatory network', 'Pathway', (194, 217))	('tumor', 'Disease', (161, 166))
3246	28455392	Indeed, we found that TGFBR2 expression is likely directly suppressed by SOX10 occupancy of TGFBR2 gene regulatory elements (Supplementary Fig.	('TGFBR2', 'Gene', '7048', (92, 98))	('TGFBR2', 'Gene', '7048', (22, 28))	('occupancy', 'Var', (79, 88))	('suppressed', 'NegReg', (59, 69))	('TGFBR2', 'Gene', (22, 28))	('TGFBR2', 'Gene', (92, 98))	('expression', 'MPA', (29, 39))
3247	28455392	Oncogenic BRAF mutations were present in both SOX10-dependent and SOX10-independent melanoma cell lines (Fig.	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('mutations', 'Var', (15, 24))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('BRAF', 'Gene', (10, 14))
3258	28455392	The samples in the tails of the score distribution (5 lowest (MNT1, SKMEL5, SKMEL28, M14 and LM38) and 5 highest (C8161, RPMI7951, LM20, A101D and LOXIMVI)) corresponded to significant differences in drug sensitivity in the directions predicted by their biomarker scores (Fig.	('SKMEL28', 'CellLine', 'CVCL:0526', (76, 83))	('RPMI7951', 'Var', (121, 129))	('drug sensitivity', 'Phenotype', 'HP:0020174', (200, 216))	('A101D', 'Var', (137, 142))	('M14', 'Var', (85, 88))	('lowest', 'NegReg', (54, 60))	('LOXIMVI', 'Chemical', '-', (147, 154))	('A101D', 'SUBSTITUTION', 'None', (137, 142))	('LM20', 'CellLine', 'CVCL:5998', (131, 135))	('drug sensitivity', 'MPA', (200, 216))	('SKMEL5', 'CellLine', 'CVCL:0527', (68, 74))	('LM38', 'Var', (93, 97))	('SKMEL5', 'Var', (68, 74))	('SKMEL28', 'Var', (76, 83))	('LM38', 'CellLine', 'CVCL:5998', (93, 97))	('differences', 'Reg', (185, 196))	('C8161', 'Var', (114, 119))	('LM20', 'Var', (131, 135))
3280	28455392	To potentially disambiguate the mode-of-action underpinning the selective toxicity of BX795, we tested a 6-aminopyrazolopyrimidine (compound II) previously developed as a selective TBK1 inhibitor with no activity against PDK1 as well as BX795 in a panel of 19 BRAF mutant melanoma cell lines (Fig.	('melanoma', 'Disease', 'MESH:D008545', (272, 280))	('toxicity', 'Disease', (74, 82))	('BX795', 'Chemical', 'MESH:C579675', (86, 91))	('TBK1', 'Gene', (181, 185))	('BX795', 'Chemical', 'MESH:C579675', (237, 242))	('6-aminopyrazolopyrimidine', 'Chemical', '-', (105, 130))	('mutant', 'Var', (265, 271))	('TBK1', 'molecular_function', 'GO:0008384', ('181', '185'))	('disambiguate', 'Chemical', '-', (15, 27))	('BRAF', 'Gene', (260, 264))	('PDK1', 'molecular_function', 'GO:0004740', ('221', '225'))	('toxicity', 'Disease', 'MESH:D064420', (74, 82))	('PDK1', 'Gene', '5163', (221, 225))	('melanoma', 'Phenotype', 'HP:0002861', (272, 280))	('PDK1', 'Gene', (221, 225))	('melanoma', 'Disease', (272, 280))
3281	28455392	Consistent with this MRT6737, a BX795 derivative that retains activity against TBK1 but not PDK1, and Momelotinib, a JAK1,2,3/TBK1/IKKepsilon inhibitor, also exhibited similar dose-dependent selective toxicity profiles (Supplementary Fig.	('MRT6737', 'Var', (21, 28))	('PDK1', 'Gene', (92, 96))	('activity', 'MPA', (62, 70))	('TBK1', 'molecular_function', 'GO:0008384', ('79', '83'))	('JAK', 'molecular_function', 'GO:0004713', ('117', '120'))	('JAK1,2,3', 'Gene', '3716;3717;3718', (117, 125))	('TBK1', 'Gene', (79, 83))	('PDK1', 'molecular_function', 'GO:0004740', ('92', '96'))	('toxicity', 'Disease', 'MESH:D064420', (201, 209))	('toxicity', 'Disease', (201, 209))	('BX795', 'Chemical', 'MESH:C579675', (32, 37))	('TBK1', 'molecular_function', 'GO:0008384', ('126', '130'))	('Momelotinib', 'Chemical', 'MESH:C546012', (102, 113))	('PDK1', 'Gene', '5163', (92, 96))
3283	28455392	S7J, S7K, S7L and S7M).	('S7M', 'Var', (18, 21))	('S7K', 'Var', (5, 8))	('S7M', 'Mutation', 'p.S7M', (18, 21))	('S7L', 'Mutation', 'p.S7L', (10, 13))	('S7L and S7M', 'Var', (10, 21))
3284	28455392	Taken together, these observations indicate selective vulnerability of vemurafenib/trametinib-resistant BRAF mutant melanoma cells to inhibition of TBK1/IKKepsilon activity.	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('vemurafenib', 'Chemical', 'MESH:D000077484', (71, 82))	('mutant', 'Var', (109, 115))	('trametinib', 'Chemical', 'MESH:C560077', (83, 93))	('TBK1', 'molecular_function', 'GO:0008384', ('148', '152'))	('BRAF', 'Gene', (104, 108))
3289	28455392	To search for an underlying discriminating feature associated with this response, we compared the whole genome transcript profiles of TBK1i-sensitive (Hs895.T, Hs934.T, Hs839.T and CHL1) and TBK1i-resistant (COLO729 and MEWO) BRAF wild-type melanoma cell lines.	('melanoma', 'Disease', 'MESH:D008545', (241, 249))	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('CHL1', 'Gene', '10752', (181, 185))	('melanoma', 'Disease', (241, 249))	('TBK1', 'molecular_function', 'GO:0008384', ('191', '195'))	('CHL1', 'Gene', (181, 185))	('Hs839.T', 'Var', (169, 176))	('TBK1', 'molecular_function', 'GO:0008384', ('134', '138'))	('Hs934.T', 'CellLine', 'CVCL:1031', (160, 167))
3297	28455392	The 2 cell lines (MEL285 and MEL290), with biomarker expression scores predicting sensitivity to TBK1/IKKepsilon inhibition, were the most responsive to both compound II and BX795 (Supplementary Fig.	('BX795', 'Chemical', 'MESH:C579675', (174, 179))	('BX795', 'Var', (174, 179))	('TBK1', 'molecular_function', 'GO:0008384', ('97', '101'))	('responsive', 'MPA', (139, 149))
3319	28455392	S9E and S9F), however unlike TBK1 inhibitors, AXL inhibitors did not show preferential toxicity against cells in the "innate immune" subtype.	('TBK1', 'molecular_function', 'GO:0008384', ('29', '33'))	('AXL', 'Gene', (46, 49))	('toxicity', 'Disease', 'MESH:D064420', (87, 95))	('S9F', 'Var', (8, 11))	('toxicity', 'Disease', (87, 95))	('AXL', 'Gene', '558', (46, 49))
3323	28455392	S10B and S10C).	('S10B', 'Var', (0, 4))	('S10B', 'SUBSTITUTION', 'None', (0, 4))	('S10C', 'Mutation', 'p.S10C', (9, 13))	('S10C', 'Var', (9, 13))
3326	28455392	However, direct chemical inhibition of AKT (MK2206), or the canonical IkappaB Kinases (IKK1/2, BMS-345541,) had limited consequences on cell viability and no selectivity among cell lines tested (Supplementary Fig.	('IKK1/2', 'Gene', '1147;3551', (87, 93))	('IKK1', 'molecular_function', 'GO:0008384', ('87', '91'))	('MK2206', 'Var', (44, 50))	('AKT', 'Gene', '207', (39, 42))	('IKK1/2', 'Gene', (87, 93))	('inhibition', 'NegReg', (25, 35))	('AKT', 'Gene', (39, 42))	('MK2206', 'Chemical', 'MESH:C548887', (44, 50))
3328	28455392	Moreover, the PI3K inhibitor LY29400 and the PI3K and mTOR dual inhibitor BEZ235 did not display selective toxicity (Supplementary Fig.	('PI3K', 'molecular_function', 'GO:0016303', ('45', '49'))	('mTOR', 'Gene', '2475', (54, 58))	('toxicity', 'Disease', 'MESH:D064420', (107, 115))	('mTOR', 'Gene', (54, 58))	('toxicity', 'Disease', (107, 115))	('LY29400', 'Var', (29, 36))	('PI3K', 'molecular_function', 'GO:0016303', ('14', '18'))	('LY29400', 'Chemical', 'MESH:C085911', (29, 36))	('BEZ235', 'Chemical', 'MESH:C531198', (74, 80))
3329	28455392	S10F and S10G) suggesting that modulation of these pathways is not sufficient to account for the selective toxicity of TBK1/IKKepsilon inhibition.	('S10G', 'Var', (9, 13))	('S10F', 'Var', (0, 4))	('TBK1', 'molecular_function', 'GO:0008384', ('119', '123'))	('S10G', 'Mutation', 'p.S10G', (9, 13))	('S10F', 'Mutation', 'p.S10F', (0, 4))	('toxicity', 'Disease', 'MESH:D064420', (107, 115))	('toxicity', 'Disease', (107, 115))
3331	28455392	S10H and S10I)) or chemical-mediated inhibition (RIP1 kinase/necrostatin1 (Supplementary Fig.	('RIP1', 'Gene', '8737', (49, 53))	('S10I', 'Var', (9, 13))	('S10I', 'Mutation', 'p.S10I', (9, 13))	('S10H', 'Mutation', 'p.S10H', (0, 4))	('RIP1', 'Gene', (49, 53))
3332	28455392	S10J)) also had no subtype-selective consequences on cell viability.	('cell viability', 'CPA', (53, 67))	('S10J', 'Var', (0, 4))	('S10J', 'SUBSTITUTION', 'None', (0, 4))
3333	28455392	Of potential mechanistic significance, YAP pathway activation has recently been identified as a BRAFi-resistance mechanism; inhibition of YAP activation has been reported upon shRNA-mediated TBK1 depletion; and a physical association of TBK1 and Hippo pathway components has been suggested by proximity-mediated ligation assays.	('YAP', 'Gene', (138, 141))	('YAP', 'Gene', '10413', (39, 42))	('TBK1', 'molecular_function', 'GO:0008384', ('191', '195'))	('depletion', 'Var', (196, 205))	('TBK1', 'molecular_function', 'GO:0008384', ('237', '241'))	('YAP', 'Gene', (39, 42))	('activation', 'PosReg', (51, 61))	('YAP', 'Gene', '10413', (138, 141))
3340	28455392	Thus the mechanism of context-specific vulnerability to TBK1/IKKepsilon inhibition is likely the combinatorial activation of the Hippo tumor suppressor pathway together with suppression of AKT cell survival signaling.	('activation', 'PosReg', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('AKT', 'Gene', (189, 192))	('signaling', 'biological_process', 'GO:0023052', ('207', '216'))	('tumor', 'Disease', (135, 140))	('inhibition', 'Var', (72, 82))	('tumor suppressor', 'biological_process', 'GO:0051726', ('135', '151'))	('TBK1/IKKepsilon', 'Gene', (56, 71))	('suppression', 'NegReg', (174, 185))	('AKT', 'Gene', '207', (189, 192))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('135', '151'))	('TBK1', 'molecular_function', 'GO:0008384', ('56', '60'))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
3351	28455392	Lactate secretion was elevated in TBK1i-sensitive relative to TBK1i-resistant cell lines-- consistent with elevated AKT activity and therefore increased glycolytic rates (Supplementary Fig.	('TBK1', 'molecular_function', 'GO:0008384', ('62', '66'))	('increased', 'PosReg', (143, 152))	('Lactate secretion', 'biological_process', 'GO:0046722', ('0', '17'))	('glycolytic rates', 'MPA', (153, 169))	('TBK1i-sensitive', 'Var', (34, 49))	('Lactate secretion', 'MPA', (0, 17))	('Lactate', 'Chemical', 'MESH:D019344', (0, 7))	('elevated', 'PosReg', (22, 30))	('AKT', 'Gene', '207', (116, 119))	('TBK1', 'molecular_function', 'GO:0008384', ('34', '38'))	('activity', 'MPA', (120, 128))	('elevated', 'PosReg', (107, 115))	('AKT', 'Gene', (116, 119))
3363	28455392	7B)-- an EZH2-dependent epigenetic mark that otherwise promotes formation of repressive chromatin.	('promotes', 'PosReg', (55, 63))	('formation of', 'MPA', (64, 76))	('epigenetic mark', 'Var', (24, 39))	('formation', 'biological_process', 'GO:0009058', ('64', '73'))	('chromatin', 'cellular_component', 'GO:0000785', ('88', '97'))	('EZH2', 'Gene', (9, 13))	('EZH2', 'Gene', '2146', (9, 13))
3365	28455392	We considered that inhibition of the H3K27 methyltransferase, EZH2, in TBK1i-resistant cells may generate a regulatory context that mimics NNMT expression and promotes addiction to TBK1/IKKepsilon activity.	('TBK1', 'molecular_function', 'GO:0008384', ('71', '75'))	('inhibition', 'Var', (19, 29))	('EZH2', 'Gene', '2146', (62, 66))	('promotes', 'PosReg', (159, 167))	('NNMT', 'Gene', (139, 143))	('EZH2', 'Gene', (62, 66))	('TBK1', 'molecular_function', 'GO:0008384', ('181', '185'))	('addiction', 'MPA', (168, 177))	('NNMT', 'Gene', '4837', (139, 143))
3366	28455392	Remarkably, we found that a 48-hour treatment with two different EZH2 inhibitors, with chemically distinct modes of action, was sufficient to sensitize 3 of the 4 TBK1i-resistant cell lines to compound II-induced programmed cell death (Fig.	('TBK1', 'molecular_function', 'GO:0008384', ('163', '167'))	('EZH2', 'Gene', (65, 69))	('EZH2', 'Gene', '2146', (65, 69))	('programmed cell death', 'biological_process', 'GO:0012501', ('213', '234'))	('inhibitors', 'Var', (70, 80))	('programmed cell death', 'CPA', (213, 234))	('sensitize', 'Reg', (142, 151))
3371	28455392	Moreover, SOX10 expression indirectly suppressed expression of both NNMT and multiple components of the polycomb repressor complex 2 (which includes EZH2) (Fig.	('NNMT', 'Gene', '4837', (68, 72))	('expression', 'Var', (16, 26))	('suppressed', 'NegReg', (38, 48))	('expression', 'MPA', (49, 59))	('EZH2', 'Gene', '2146', (149, 153))	('SOX10', 'Gene', (10, 15))	('EZH2', 'Gene', (149, 153))	('NNMT', 'Gene', (68, 72))
3372	28455392	These observations suggest that loss of SOX10 during neoplastic transformation from the neural crest lineage may account for many of the mechanistic features associated with the "innate immune" melanoma subtype we describe here.	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('account', 'Reg', (113, 120))	('melanoma', 'Disease', (194, 202))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('SOX10', 'Gene', (40, 45))	('loss', 'Var', (32, 36))
3379	28455392	S12J and S12K).	('S12K', 'Var', (9, 13))	('S12K', 'Mutation', 'p.S12K', (9, 13))	('S12J', 'SUBSTITUTION', 'None', (0, 4))	('S12J', 'Var', (0, 4))
3383	28455392	However, in stark contrast to the dearth of recurrent somatic alterations in LSCC, fully half of melanomas possess recurrent variants of the BRAF oncogene (BRAF(V600)).	('melanomas', 'Disease', 'MESH:D008545', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanomas', 'Phenotype', 'HP:0002861', (97, 106))	('BRAF(V600', 'Gene', '673', (156, 165))	('variants', 'Var', (125, 133))	('melanomas', 'Disease', (97, 106))
3402	28455392	The TBK1/IKKepsilon-sensitive cohort includes both BRAF mutant and BRAF wild-type tumors and corresponds to a gene expression phenotype reminiscent of host defense pathway activation and TGFbeta-induced mesenchymal status.	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('mutant', 'Var', (56, 62))	('TBK1', 'molecular_function', 'GO:0008384', ('4', '8'))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BRAF', 'Gene', (51, 55))	('gene expression', 'biological_process', 'GO:0010467', ('110', '125'))
3410	28455392	As mentioned above, an additional functionally relevant component of the TBK1/IKKepsilon-sensitive cell state is TBK1/IKKepsilon-dependent YAP pathway activation.	('YAP', 'Gene', '10413', (139, 142))	('TBK1', 'molecular_function', 'GO:0008384', ('73', '77'))	('TBK1/IKKepsilon-dependent', 'Var', (113, 138))	('YAP', 'Gene', (139, 142))	('activation', 'PosReg', (151, 161))	('TBK1', 'molecular_function', 'GO:0008384', ('113', '117'))
3412	28455392	However, compelling observations in drosophila, non small cell lung cancer, and aggressive glioma suggest an interplay among mitochondrial damage, TGFbeta-induced actin remodeling, and loss of PRC2 activity can all generate cell states that are permissive to YAP activation.	('small cell lung cancer', 'Disease', 'MESH:D055752', (52, 74))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (52, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('generate', 'Reg', (215, 223))	('loss', 'Var', (185, 189))	('YAP', 'Gene', '10413', (259, 262))	('aggressive glioma', 'Disease', (80, 97))	('interplay', 'Interaction', (109, 118))	('cell', 'Disease', (224, 228))	('PRC2', 'Gene', (193, 197))	('small cell lung cancer', 'Disease', (52, 74))	('activity', 'MPA', (198, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('YAP', 'Gene', (259, 262))	('TGFbeta-induced', 'Gene', (147, 162))	('aggressive glioma', 'Disease', 'MESH:D005910', (80, 97))	('drosophila', 'Species', '7227', (36, 46))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))
3414	28455392	Here, these efforts have nominated new biomarker-coupled target opportunities for mechanistic subtypes of BRAF mutant and wild-type melanomas; identified key elements within the SOX10 regulatory network required to support tumorigenicity; produced molecular predictors of best responders to BRAF(V600) targeted therapy; and delivered strategies to predict and chemically address non-responders.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('melanomas', 'Phenotype', 'HP:0002861', (132, 141))	('mutant', 'Var', (111, 117))	('melanomas', 'Disease', 'MESH:D008545', (132, 141))	('BRAF(V600', 'Gene', '673', (291, 300))	('BRAF', 'Gene', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('melanomas', 'Disease', (132, 141))
3417	28455392	LM17, LM17R, LM20 and LM38 were kind gifts from Monica Rodolfo (Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy).	('LM38', 'CellLine', 'CVCL:5998', (22, 26))	('LM20', 'Var', (13, 17))	('LM17R', 'Var', (6, 11))	('LM20', 'CellLine', 'CVCL:5998', (13, 17))	('LM38', 'Var', (22, 26))
3419	28455392	LOXIMVI, M14, UACC257, UACC62, A375, MALME3M, SKMEL2, SKMEL5 and SKMEL28 were from NCI60 (National Cancer Institute, Bethesda, MD).	('SKMEL2', 'CellLine', 'CVCL:0069', (65, 71))	('Cancer', 'Disease', 'MESH:D009369', (99, 105))	('SKMEL2', 'CellLine', 'CVCL:0069', (46, 52))	('Cancer', 'Disease', (99, 105))	('LOXIMVI', 'Chemical', '-', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('A375', 'CellLine', 'CVCL:0132', (31, 35))	('UACC257', 'Var', (14, 21))	('SKMEL28', 'CellLine', 'CVCL:0526', (65, 72))	('SKMEL5', 'CellLine', 'CVCL:0527', (54, 60))
3420	28455392	A2058, RPMI7951, A101D, SKMEL31, COLO829, MEWO, HMCB, CHL1, Hs600.T, Hs895.T, Hs934.T, Hs839.T and Hs940.T were purchased from the ATCC.	('Hs934.T', 'CellLine', 'CVCL:1031', (78, 85))	('A101D', 'Var', (17, 22))	('CHL1', 'Gene', (54, 58))	('A101D', 'SUBSTITUTION', 'None', (17, 22))	('Hs934.T', 'Var', (78, 85))	('SKMEL31', 'CellLine', 'CVCL:0600', (24, 31))	('Hs940.T', 'CellLine', 'CVCL:1038', (99, 106))	('CHL1', 'Gene', '10752', (54, 58))
3444	28455392	They are as follows: TCGA UVM: +/- .1; TCGA SKCM: +/- .05; GSE19234: +/- .05; GSE50509: +/- .05; Morrison PDX: +/- .1.	('PDX: +/- .1', 'Gene', '3651', (106, 117))	('GSE50509: +/-', 'Var', (78, 91))	('PDX: +/- .1', 'Gene', (106, 117))
3448	27282250	RNA splicing factors as oncoproteins and tumor suppressors The recent genomic characterization of cancers has revealed recurrent somatic point mutations and copy number changes affecting genes encoding RNA splicing factors.	('splicing factor', 'Gene', (4, 19))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('splicing factor', 'Gene', (206, 221))	('tumor', 'Disease', (41, 46))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('point mutations', 'Var', (137, 152))	('RNA splicing', 'biological_process', 'GO:0008380', ('202', '214'))	('splicing factor', 'Gene', '10569', (206, 221))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('splicing factor', 'Gene', '10569', (4, 19))	('copy number changes', 'Var', (157, 176))	('cancers', 'Disease', (98, 105))	('RNA', 'cellular_component', 'GO:0005562', ('202', '205'))	('RNA splicing', 'biological_process', 'GO:0008380', ('0', '12'))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
3449	27282250	Initial studies of these 'spliceosomal mutations' suggest that the proteins bearing these mutations exhibit altered splice site and/or exon recognition preferences relative to their wild-type counterparts, resulting in cancer-specific mis-splicing.	('splice site', 'MPA', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('mutations', 'Var', (90, 99))	('altered', 'Reg', (108, 115))	('resulting in', 'Reg', (206, 218))	('exon recognition', 'MPA', (135, 151))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('mis-splicing', 'MPA', (235, 247))	('splicing', 'biological_process', 'GO:0045292', ('239', '247'))	('cancer', 'Disease', (219, 225))	('proteins', 'Protein', (67, 75))
3451	27282250	Further studies to dissect the biochemical, genomic, and biological effects of spliceosomal mutations are critical for the development of cancer therapies targeted to these mutations.	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('mutations', 'Var', (92, 101))
3453	27282250	Although the functional roles of most isoforms generated by alternative splicing are unknown, specific isoforms have been identified that are selected in cancer due to their ability to promote neoplastic transformation, cancer progression, and/or therapeutic resistance (reviewed in).	('neoplastic transformation', 'Disease', (193, 218))	('neoplastic transformation', 'Disease', 'MESH:D002471', (193, 218))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('alternative splicing', 'Var', (60, 80))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('promote', 'PosReg', (185, 192))	('cancer', 'Disease', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('splicing', 'biological_process', 'GO:0045292', ('72', '80'))	('therapeutic resistance', 'CPA', (247, 269))
3458	27282250	These mutations provide a direct genetic link between dysfunction of the splicing machinery and cancer.	('splicing', 'biological_process', 'GO:0045292', ('73', '81'))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (6, 15))	('dysfunction', 'Var', (54, 65))
3459	27282250	Both the genetic spectrum of mutations and functional studies of their consequences indicate that RNA splicing factors can act as proto-oncoproteins and tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('splicing factor', 'Gene', '10569', (102, 117))	('RNA', 'cellular_component', 'GO:0005562', ('98', '101'))	('mutations', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('splicing factor', 'Gene', (102, 117))	('RNA splicing', 'biological_process', 'GO:0008380', ('98', '110'))
3460	27282250	In this Review, we outline the current genetic and functional links between dysregulated and/or mutated RNA splicing factors and cancer.	('mutated', 'Var', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('splicing factor', 'Gene', (108, 123))	('dysregulated', 'Var', (76, 88))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('RNA', 'cellular_component', 'GO:0005562', ('104', '107'))	('splicing factor', 'Gene', '10569', (108, 123))	('RNA', 'Protein', (104, 107))	('RNA splicing', 'biological_process', 'GO:0008380', ('104', '116'))
3461	27282250	We discuss how recurrent mutations affecting splicing factors might promote the development and/or maintenance of cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('mutations', 'Var', (25, 34))	('splicing factor', 'Gene', (45, 60))	('promote', 'PosReg', (68, 75))	('splicing', 'biological_process', 'GO:0045292', ('45', '53'))	('splicing factor', 'Gene', '10569', (45, 60))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
3462	27282250	We describe the challenges inherent in connecting mutations in spliceosomal proteins to specific downstream splicing changes, as well as the importance of testing whether mutated splicing factors dysregulate biological processes other than splicing itself.	('splicing', 'biological_process', 'GO:0045292', ('240', '248'))	('mutations', 'Var', (50, 59))	('splicing factor', 'Gene', '10569', (179, 194))	('splicing', 'biological_process', 'GO:0045292', ('108', '116'))	('splicing', 'biological_process', 'GO:0045292', ('179', '187'))	('mutated', 'Var', (171, 178))	('splicing factor', 'Gene', (179, 194))
3463	27282250	Finally, we discuss how determining the mechanistic consequences of mutated splicing factors may facilitate the identification of novel therapeutic opportunities to selectively target cancers with spliceosomal mutations.	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('splicing factor', 'Gene', (76, 91))	('cancers', 'Disease', (184, 191))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('splicing', 'biological_process', 'GO:0045292', ('76', '84'))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('splicing factor', 'Gene', '10569', (76, 91))	('mutated', 'Var', (68, 75))
3466	27282250	The minor spliceosome contains the U5 snRNP, along with the U11, U12, U4atac and U6atac snRNPs, which are the functional analogues of the corresponding snRNPs in the major spliceosome (reviewed in).	('spliceosome', 'cellular_component', 'GO:0005681', ('172', '183'))	('U4atac', 'Gene', '100151683', (70, 76))	('U4atac', 'Gene', (70, 76))	('snRNP', 'Gene', '57819', (152, 157))	('snRNP', 'molecular_function', 'GO:0003734', ('38', '43'))	('snRNP', 'Gene', (88, 93))	('U5 snRNP', 'cellular_component', 'GO:0005682', ('35', '43'))	('snRNP', 'Gene', '57819', (88, 93))	('spliceosome', 'cellular_component', 'GO:0005681', ('10', '21'))	('U6atac', 'Var', (81, 87))	('snRNP', 'Gene', (38, 43))	('snRNP', 'Gene', '57819', (38, 43))	('U12', 'Var', (65, 68))	('snRNP', 'Gene', (152, 157))
3484	27282250	Furthermore, alterations in the levels of core spliceosomal components such as the snRNP proteins SmB/B' (also known as snRNP-B) can regulate splicing.	('snRNP', 'cellular_component', 'GO:0030532', ('83', '88'))	('snRNP', 'molecular_function', 'GO:0003734', ('120', '125'))	('regulate', 'Reg', (133, 141))	('snRNP', 'Gene', (120, 125))	('alterations', 'Var', (13, 24))	('SmB/B', 'Gene', '6628', (98, 103))	('splicing', 'biological_process', 'GO:0045292', ('142', '150'))	('core', 'cellular_component', 'GO:0019013', ('42', '46'))	('snRNP', 'Gene', '57819', (120, 125))	('SmB/B', 'Gene', (98, 103))	('snRNP', 'Gene', (83, 88))	('snRNP', 'cellular_component', 'GO:0030532', ('120', '125'))	('snRNP', 'Gene', '57819', (83, 88))	('snRNP-B', 'Gene', (120, 127))	('snRNP', 'molecular_function', 'GO:0003734', ('83', '88'))	('splicing', 'MPA', (142, 150))	('snRNP-B', 'Gene', '6628', (120, 127))
3486	27282250	Just as regulation of alternative splicing has essential roles in cellular growth, differentiation and tissue development, dysregulated splicing can give rise to protein isoforms that contribute to tumor establishment, progression, and resistance to therapy.	('protein isoforms', 'MPA', (162, 178))	('give rise', 'Reg', (149, 158))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('splicing', 'biological_process', 'GO:0045292', ('136', '144'))	('regulation', 'biological_process', 'GO:0065007', ('8', '18'))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('progression', 'CPA', (219, 230))	('dysregulated splicing', 'Var', (123, 144))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tissue development', 'biological_process', 'GO:0009888', ('103', '121'))	('tumor', 'Disease', (198, 203))	('cellular growth', 'biological_process', 'GO:0016049', ('66', '81'))	('splicing', 'biological_process', 'GO:0045292', ('34', '42'))	('contribute to', 'Reg', (184, 197))
3496	27282250	Transgenic overexpression of SRSF6 from the collagen type Ialpha1 (Col1a1) locus in mice induced hyperplasia of skin sensitized by shaving or wounding, partially through aberrant alternative splicing of tenascin C (Tnc).	('tenascin C', 'Gene', (203, 213))	('hyperplasia of skin', 'Disease', 'MESH:D006965', (97, 116))	('Col1a1', 'Gene', '12842', (67, 73))	('Tnc', 'Gene', '21923', (215, 218))	('tenascin C', 'Gene', '21923', (203, 213))	('aberrant alternative splicing', 'Var', (170, 199))	('SRSF6', 'Var', (29, 34))	('Tnc', 'Gene', (215, 218))	('splicing', 'biological_process', 'GO:0045292', ('191', '199'))	('Col1a1', 'Gene', (67, 73))	('tenascin C', 'cellular_component', 'GO:0090733', ('203', '213'))	('collagen', 'molecular_function', 'GO:0005202', ('44', '52'))	('overexpression', 'PosReg', (11, 25))	('hyperplasia of skin', 'Disease', (97, 116))	('mice', 'Species', '10090', (84, 88))
3504	27282250	Motivated by the observation that HNRNPK (among other genes) lies within a chromosomal locus that is recurrently deleted in acute myeloid leukemia (AML), one recent mouse study found that deletion of one allele of Hnrnpk resulted in myeloid hematologic transformation.	('HNRNPK', 'Gene', (34, 40))	('myeloid hematologic transformation', 'CPA', (233, 267))	('resulted in', 'Reg', (221, 232))	('Hnrnpk', 'Gene', '15387', (214, 220))	('mouse', 'Species', '10090', (165, 170))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (124, 146))	('Hnrnpk', 'Gene', (214, 220))	('AML', 'Phenotype', 'HP:0004808', (148, 151))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (130, 146))	('AML', 'Disease', (148, 151))	('deletion', 'Var', (188, 196))	('leukemia', 'Phenotype', 'HP:0001909', (138, 146))	('HNRNPK', 'Gene', '15387', (34, 40))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (124, 146))	('AML', 'Disease', 'MESH:D015470', (148, 151))	('acute myeloid leukemia', 'Disease', (124, 146))
3510	27282250	RNA binding motif protein 5 (RBM5), RBM6 and RBM10, which encode homologous RNA-binding proteins, are commonly deleted, mutated, and/or under- or overexpressed in lung and other cancers.	('RNA binding motif protein 5', 'Gene', (0, 27))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('RBM10', 'Gene', (45, 50))	('overexpressed', 'PosReg', (146, 159))	('RBM5', 'Gene', (29, 33))	('RBM5', 'Gene', '10181', (29, 33))	('RBM10', 'Gene', '8241', (45, 50))	('RNA', 'cellular_component', 'GO:0005562', ('76', '79'))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('RNA binding motif protein 5', 'Gene', '10181', (0, 27))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('RNA-binding', 'molecular_function', 'GO:0003723', ('76', '87'))	('deleted', 'Var', (111, 118))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('RNA binding', 'molecular_function', 'GO:0003723', ('0', '11'))	('RBM6', 'Gene', (36, 40))	('under-', 'NegReg', (136, 142))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('RBM6', 'Gene', '10180', (36, 40))	('cancers', 'Disease', (178, 185))	('lung', 'Disease', (163, 167))	('mutated', 'Var', (120, 127))
3511	27282250	RBM5 or RBM6 depletion has an opposite effect to RBM10 depletion on in vitro colony formation.	('RBM5', 'Gene', '10181', (0, 4))	('RBM10', 'Gene', (49, 54))	('RBM10', 'Gene', '8241', (49, 54))	('RBM5', 'Gene', (0, 4))	('depletion', 'Var', (13, 22))	('RBM6', 'Gene', '10180', (8, 12))	('formation', 'biological_process', 'GO:0009058', ('84', '93'))	('RBM6', 'Gene', (8, 12))
3517	27282250	In a few cases, such as for hnRNP K, RBM5, RBM6 and RBM10, genetic changes such as chromosomal deletions may alter the expression of splicing factors.	('RBM10', 'Gene', '8241', (52, 57))	('splicing factor', 'Gene', '10569', (133, 148))	('RBM10', 'Gene', (52, 57))	('RBM6', 'Gene', (43, 47))	('alter', 'Reg', (109, 114))	('splicing', 'biological_process', 'GO:0045292', ('133', '141'))	('hnRNP', 'cellular_component', 'GO:0030530', ('28', '33'))	('splicing factor', 'Gene', (133, 148))	('hnRNP K', 'Gene', '3190', (28, 35))	('chromosomal deletions', 'Var', (83, 104))	('RBM6', 'Gene', '10180', (43, 47))	('RBM5', 'Gene', '10181', (37, 41))	('hnRNP', 'molecular_function', 'GO:0008436', ('28', '33'))	('RBM5', 'Gene', (37, 41))	('hnRNP K', 'Gene', (28, 35))
3519	27282250	Although these data suggest that dysregulated expression of splicing factors plays important roles in tumor development or progression, thus far there is limited functional evidence that altered levels of splicing factors alone can drive cancer initiation or that altered levels of splicing factors are required for cancer maintenance.	('splicing', 'biological_process', 'GO:0045292', ('205', '213'))	('splicing factor', 'Gene', '10569', (60, 75))	('cancer initiation', 'Disease', (238, 255))	('splicing factor', 'Gene', '10569', (282, 297))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('drive', 'PosReg', (232, 237))	('cancer', 'Disease', (238, 244))	('cancer initiation', 'Disease', 'MESH:D009369', (238, 255))	('splicing factor', 'Gene', (205, 220))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('altered', 'Var', (187, 194))	('splicing', 'biological_process', 'GO:0045292', ('282', '290'))	('cancer', 'Disease', (316, 322))	('splicing', 'biological_process', 'GO:0045292', ('60', '68'))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('splicing factor', 'Gene', (60, 75))	('tumor', 'Disease', (102, 107))	('splicing factor', 'Gene', '10569', (205, 220))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('splicing factor', 'Gene', (282, 297))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Disease', 'MESH:D009369', (316, 322))
3520	27282250	The discovery of recurrent somatic mutations in genes encoding core spliceosomal proteins throughout diverse cancer types provided the first genetic evidence directly linking RNA splicing regulation to cancer.	('regulation', 'biological_process', 'GO:0065007', ('188', '198'))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('RNA splicing', 'biological_process', 'GO:0008380', ('175', '187'))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('RNA', 'cellular_component', 'GO:0005562', ('175', '178'))	('cancer', 'Disease', (202, 208))	('core', 'cellular_component', 'GO:0019013', ('63', '67'))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (35, 44))
3522	27282250	More recently, recurrent spliceosomal mutations have also been found in several solid tumor types, including uveal melanoma (18.6%), pancreatic ductal adenocarcinoma (4%), lung adenocarcinoma (3%) and breast cancers (1.8%).	('spliceosomal mutations', 'Var', (25, 47))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (133, 165))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (172, 191))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (172, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('breast cancers', 'Disease', 'MESH:D001943', (201, 215))	('breast cancers', 'Disease', (201, 215))	('found', 'Reg', (63, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (133, 165))	('breast cancers', 'Phenotype', 'HP:0003002', (201, 215))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('tumor', 'Disease', (86, 91))	('uveal melanoma', 'Disease', 'MESH:C536494', (109, 123))	('pancreatic ductal adenocarcinoma', 'Disease', (133, 165))	('uveal melanoma', 'Disease', (109, 123))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('lung adenocarcinoma', 'Disease', (172, 191))
3523	27282250	Most reported spliceosomal mutations are concentrated in four genes: splicing factor 3B, subunit 1 (SF3B1), serine/arginine-rich splicing factor 2 (SRSF2), U2 small nuclear RNA auxiliary factor 1 (U2AF1) and zinc finger, RNA-binding motif and serine/arginine-rich 2 (ZRSR2).	('mutations', 'Var', (27, 36))	('SRSF2', 'Gene', '6427', (148, 153))	('serine/arginine-rich splicing factor 2', 'Gene', '6427', (108, 146))	('splicing', 'biological_process', 'GO:0045292', ('129', '137'))	('serine', 'Chemical', 'MESH:D012694', (108, 114))	('ZRSR2', 'Gene', (267, 272))	('SRSF2', 'Gene', (148, 153))	('small nuclear RNA', 'molecular_function', 'GO:0005570', ('159', '176'))	('splicing factor 3B, subunit 1', 'Gene', '23451', (69, 98))	('arginine', 'Chemical', 'MESH:D001120', (115, 123))	('SF3B1', 'Gene', '23451', (100, 105))	('serine/arginine-rich splicing factor 2', 'Gene', (108, 146))	('arginine', 'Chemical', 'MESH:D001120', (250, 258))	('serine', 'Chemical', 'MESH:D012694', (243, 249))	('RNA-binding', 'molecular_function', 'GO:0003723', ('221', '232'))	('splicing', 'biological_process', 'GO:0045292', ('69', '77'))	('RNA', 'cellular_component', 'GO:0005562', ('173', '176'))	('U2AF', 'cellular_component', 'GO:0089701', ('197', '201'))	('ZRSR2', 'Gene', '8233', (267, 272))	('RNA', 'cellular_component', 'GO:0005562', ('221', '224'))	('SF3B1', 'Gene', (100, 105))
3524	27282250	First, with the exception of ZRSR2 mutations, these mutations affect highly restricted amino acid residues in an exclusively heterozygous state with the wild-type allele (Fig.	('mutations', 'Var', (52, 61))	('affect', 'Reg', (62, 68))	('amino acid residues', 'MPA', (87, 106))	('ZRSR2', 'Gene', (29, 34))	('ZRSR2', 'Gene', '8233', (29, 34))
3525	27282250	These data suggest that mutations in most spliceosomal genes likely confer gain or alteration of function, except ZRSR2 mutations, which follow a pattern consistent with loss of function.	('alteration', 'Reg', (83, 93))	('ZRSR2', 'Gene', '8233', (114, 119))	('ZRSR2', 'Gene', (114, 119))	('mutations', 'Var', (120, 129))	('spliceosomal genes', 'Gene', (42, 60))	('mutations', 'Var', (24, 33))	('gain', 'PosReg', (75, 79))
3526	27282250	Second, splicing factor mutations are mutually exclusive of one another, which may be due to either functional redundancy or synthetic lethality, possibilities that have not yet been explored in published studies (Fig.	('mutations', 'Var', (24, 33))	('splicing factor', 'Gene', '10569', (8, 23))	('splicing', 'biological_process', 'GO:0045292', ('8', '16'))	('splicing factor', 'Gene', (8, 23))
3527	27282250	These genetic observations suggest that SF3B1, SRSF2 and U2AF1 may be proto-oncogenes, as they are subject to highly specific missense mutations are suggestive of gain or alteration of function.	('SF3B1', 'Gene', (40, 45))	('missense mutations', 'Var', (126, 144))	('SRSF2', 'Gene', (47, 52))	('SF3B1', 'Gene', '23451', (40, 45))	('gain', 'PosReg', (163, 167))	('alteration', 'Reg', (171, 181))	('U2AF1', 'Gene', (57, 62))	('SRSF2', 'Gene', '6427', (47, 52))	('U2AF', 'cellular_component', 'GO:0089701', ('57', '61'))
3528	27282250	In contrast, ZRSR2 may play a tumor suppressor role, as ZRSR2 mutations frequently introduce in-frame stop codons or disrupt the reading frame, likely inactivating the gene and/or protein.	('gene', 'Protein', (168, 172))	('ZRSR2', 'Gene', '8233', (56, 61))	('ZRSR2', 'Gene', (56, 61))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))	('disrupt', 'NegReg', (117, 124))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('protein', 'cellular_component', 'GO:0003675', ('180', '187'))	('protein', 'Protein', (180, 187))	('reading frame', 'MPA', (129, 142))	('inactivating', 'NegReg', (151, 163))	('stop codons', 'MPA', (102, 113))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('ZRSR2', 'Gene', '8233', (13, 18))	('tumor', 'Disease', (30, 35))	('mutations', 'Var', (62, 71))	('ZRSR2', 'Gene', (13, 18))
3532	27282250	Specific splicing factors are most frequently mutated in distinct cancer subtypes (Fig.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutated', 'Var', (46, 53))	('splicing', 'biological_process', 'GO:0045292', ('9', '17'))	('splicing factor', 'Gene', (9, 24))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('splicing factor', 'Gene', '10569', (9, 24))	('cancer', 'Disease', (66, 72))
3534	27282250	Moreover, in diseases such as MDS in which multiple splicing factors are commonly mutated, specific splicing factor mutations associate with distinct MDS subtypes.	('splicing factor', 'Gene', (100, 115))	('splicing', 'biological_process', 'GO:0045292', ('100', '108'))	('splicing factor', 'Gene', (52, 67))	('MDS', 'Phenotype', 'HP:0002863', (150, 153))	('MDS', 'Phenotype', 'HP:0002863', (30, 33))	('mutations', 'Var', (116, 125))	('splicing', 'biological_process', 'GO:0045292', ('52', '60'))	('MDS', 'Disease', (30, 33))	('MDS', 'Disease', (150, 153))	('splicing factor', 'Gene', '10569', (100, 115))	('MDS', 'Disease', 'MESH:D009190', (30, 33))	('MDS', 'Disease', 'MESH:D009190', (150, 153))	('splicing factor', 'Gene', '10569', (52, 67))	('associate', 'Reg', (126, 135))
3535	27282250	Mutations in SF3B1 are highly enriched in refractory anemia with ringed sideroblasts (RARS), a form of MDS characterized by a typically indolent course, anemia, and the accumulation of erythroid precursor cells with abnormally iron-loaded mitochondria.	('anemia', 'Disease', (153, 159))	('indole', 'Chemical', 'MESH:C030374', (136, 142))	('anemia', 'Disease', 'MESH:D000740', (53, 59))	('SF3B1', 'Gene', '23451', (13, 18))	('refractory anemia', 'Phenotype', 'HP:0005505', (42, 59))	('MDS', 'Phenotype', 'HP:0002863', (103, 106))	('refractory anemia with ringed sideroblasts', 'Phenotype', 'HP:0004828', (42, 84))	('RARS', 'Phenotype', 'HP:0004828', (86, 90))	('Mutations', 'Var', (0, 9))	('accumulation', 'PosReg', (169, 181))	('anemia', 'Phenotype', 'HP:0001903', (53, 59))	('MDS', 'Disease', 'MESH:D009190', (103, 106))	('anemia', 'Disease', 'MESH:D000740', (153, 159))	('anemia', 'Disease', (53, 59))	('iron', 'Chemical', 'MESH:D007501', (227, 231))	('mitochondria', 'cellular_component', 'GO:0005739', ('239', '251'))	('SF3B1', 'Gene', (13, 18))	('MDS', 'Disease', (103, 106))	('anemia', 'Phenotype', 'HP:0001903', (153, 159))
3538	27282250	Moreover, specific mutated residues in SF3B1 appear to be associated with distinct diseases (Fig.	('distinct diseases', 'Disease', (74, 91))	('associated', 'Reg', (58, 68))	('mutated residues', 'Var', (19, 35))	('SF3B1', 'Gene', '23451', (39, 44))	('SF3B1', 'Gene', (39, 44))
3539	27282250	For instance, SF3B1R625 mutations represent the most common SF3B1 mutation in uveal melanoma, yet are far less frequent in hematological malignancies.	('SF3B1', 'Gene', (60, 65))	('hematological malignancies', 'Disease', (123, 149))	('SF3B1', 'Gene', (14, 19))	('SF3B1', 'Gene', '23451', (60, 65))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('common', 'Reg', (53, 59))	('hematological malignancies', 'Disease', 'MESH:D019337', (123, 149))	('uveal melanoma', 'Phenotype', 'HP:0007716', (78, 92))	('uveal melanoma', 'Disease', 'MESH:C536494', (78, 92))	('SF3B1', 'Gene', '23451', (14, 19))	('mutations', 'Var', (24, 33))	('hematological malignancies', 'Phenotype', 'HP:0004377', (123, 149))	('uveal melanoma', 'Disease', (78, 92))
3540	27282250	Similarly, U2AF1 mutations affect both the S34 and Q157 residues in hematopoietic malignancies, but only mutations affecting S34 have been identified in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('U2AF1', 'Gene', (11, 16))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (68, 94))	('Q157 residues', 'Var', (51, 64))	('lung cancer', 'Disease', (153, 164))	('hematopoietic malignancies', 'Disease', (68, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('U2AF', 'cellular_component', 'GO:0089701', ('11', '15'))	('mutations', 'Var', (17, 26))	('affect', 'Reg', (27, 33))	('S34', 'Var', (43, 46))
3543	27282250	Srsf2P95H knock-in mice developed morphological dysplasia whereas the transgenic U2AF1S34F mice did not.	('mice', 'Species', '10090', (91, 95))	('Srsf2P95H', 'Var', (0, 9))	('U2AF', 'cellular_component', 'GO:0089701', ('81', '85'))	('morphological dysplasia', 'Disease', (34, 57))	('morphological dysplasia', 'Disease', 'MESH:D000013', (34, 57))	('mice', 'Species', '10090', (19, 23))
3544	27282250	However, the transcriptomes of hematopoietic stem or progenitor cells (HSPCs) from each model showed that these cells had the same genome-wide alterations in exonic splicing enhancer (Srsf2P95H) and 3' splice site (U2AF1S34F) preferences as those that were observed in patients' cells with these mutations.	('U2AF', 'cellular_component', 'GO:0089701', ('215', '219'))	('exonic splicing enhancer', 'MPA', (158, 182))	('splicing', 'biological_process', 'GO:0045292', ('165', '173'))	('alterations', 'Reg', (143, 154))	('Srsf2P95H', 'Var', (184, 193))	('patients', 'Species', '9606', (269, 277))	("3' splice site", 'MPA', (199, 213))
3545	27282250	Additionally, in both the Srsf2P95H and U2AF1S34F mouse models, there were some genes that were differentially spliced in mouse cells as well as patient cells, suggesting that the models recapitulate many molecular phenotypes of human disease.	('U2AF', 'cellular_component', 'GO:0089701', ('40', '44'))	('U2AF1S34F', 'Var', (40, 49))	('patient', 'Species', '9606', (145, 152))	('human', 'Species', '9606', (229, 234))	('mouse', 'Species', '10090', (50, 55))	('mouse', 'Species', '10090', (122, 127))	('Srsf2P95H', 'Var', (26, 35))
3546	27282250	The high frequencies with which SF3B1, SRSF2, U2AF1 and ZRSR2 are subject to specific mutations in cancer suggest that spliceosomal mutations drive tumorigenesis, at least in some cellular contexts, and are not merely passenger mutations.	('SRSF2', 'Gene', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('ZRSR2', 'Gene', '8233', (56, 61))	('U2AF', 'cellular_component', 'GO:0089701', ('46', '50'))	('U2AF1', 'Gene', (46, 51))	('ZRSR2', 'Gene', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('mutations', 'Var', (132, 141))	('tumor', 'Disease', (148, 153))	('SF3B1', 'Gene', '23451', (32, 37))	('cancer', 'Disease', (99, 105))	('SRSF2', 'Gene', '6427', (39, 44))	('drive', 'PosReg', (142, 147))	('SF3B1', 'Gene', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
3547	27282250	Spliceosomal mutations are likely to occur as both initiating and secondary genetic events, a distinction that has been best studied in liquid neoplasms.	('neoplasms', 'Phenotype', 'HP:0002664', (143, 152))	('Spliceosomal mutations', 'Var', (0, 22))	('neoplasms', 'Disease', (143, 152))	('neoplasms', 'Disease', 'MESH:D009369', (143, 152))
3548	27282250	The clonal architecture of MDS indicates that SF3B1 mutations are initiating genetic events.	('mutations', 'Var', (52, 61))	('MDS', 'Phenotype', 'HP:0002863', (27, 30))	('SF3B1', 'Gene', (46, 51))	('MDS', 'Disease', (27, 30))	('MDS', 'Disease', 'MESH:D009190', (27, 30))	('SF3B1', 'Gene', '23451', (46, 51))
3549	27282250	Similar studies of secondary AML revealed that SRSF2, U2AF1 and ZRSR2 mutations also occurred early during the leukemogenic process.	('mutations', 'Var', (70, 79))	('AML', 'Disease', 'MESH:D015470', (29, 32))	('SRSF2', 'Gene', (47, 52))	('leukemogenic', 'Disease', (111, 123))	('AML', 'Phenotype', 'HP:0004808', (29, 32))	('U2AF1', 'Gene', (54, 59))	('AML', 'Disease', (29, 32))	('U2AF', 'cellular_component', 'GO:0089701', ('54', '58'))	('SRSF2', 'Gene', '6427', (47, 52))	('occurred', 'Reg', (85, 93))	('ZRSR2', 'Gene', (64, 69))	('ZRSR2', 'Gene', '8233', (64, 69))
3550	27282250	In contrast, even though SF3B1 is the second most commonly mutated gene in CLL, SF3B1 mutations occur most frequently in advanced versus early disease, suggesting that they are secondary genetic events that facilitate progression.	('mutations', 'Var', (86, 95))	('SF3B1', 'Gene', '23451', (80, 85))	('SF3B1', 'Gene', (25, 30))	('CLL', 'Phenotype', 'HP:0005550', (75, 78))	('CLL', 'Disease', (75, 78))	('SF3B1', 'Gene', (80, 85))	('SF3B1', 'Gene', '23451', (25, 30))
3553	27282250	SF3B1 mutations are concentrated in sequence encoding its HEAT repeat domains (Fig.	('SF3B1', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('SF3B1', 'Gene', '23451', (0, 5))
3554	27282250	2b); however, the normal function of these domains is poorly characterized, rendering it difficult to predict the mechanistic consequences of SF3B1 mutations.	('SF3B1', 'Gene', (142, 147))	('mutations', 'Var', (148, 157))	('SF3B1', 'Gene', '23451', (142, 147))
3555	27282250	recently reported that SF3B1 mutations were associated with enhanced recognition of cryptic 3' splice sites between the branch point and normal 3' splice site.	('cryptic', 'Gene', '55997', (84, 91))	('cryptic', 'Gene', (84, 91))	('mutations', 'Var', (29, 38))	('SF3B1', 'Gene', '23451', (23, 28))	('SF3B1', 'Gene', (23, 28))	('enhanced', 'PosReg', (60, 68))
3557	27282250	hypothesized that SF3B1 mutations prevent this normal steric occlusion, thereby enhancing recognition of cryptic splice sites (Fig.	('cryptic', 'Gene', '55997', (105, 112))	('SF3B1', 'Gene', (18, 23))	('cryptic', 'Gene', (105, 112))	('SF3B1', 'Gene', '23451', (18, 23))	('enhancing', 'PosReg', (80, 89))	('mutations', 'Var', (24, 33))
3558	27282250	similarly reported that mutant SF3B1 enhanced recognition of intron-proximal cryptic 3' splice sites, which frequently involved normally unused upstream branch points.	('mutant', 'Var', (24, 30))	('cryptic', 'Gene', '55997', (77, 84))	('cryptic', 'Gene', (77, 84))	('recognition', 'MPA', (46, 57))	('SF3B1', 'Gene', (31, 36))	('enhanced', 'PosReg', (37, 45))	('SF3B1', 'Gene', '23451', (31, 36))
3559	27282250	However, the exact mechanism(s) by which mutations might alter SF3B1 interactions with pre-mRNA, components of the U2 snRNP or other proteins remains unknown.	('mutations', 'Var', (41, 50))	('pre', 'molecular_function', 'GO:0003904', ('87', '90'))	('alter', 'Reg', (57, 62))	('snRNP', 'Gene', '57819', (118, 123))	('SF3B1', 'Gene', (63, 68))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('115', '123'))	('interactions', 'Interaction', (69, 81))	('SF3B1', 'Gene', '23451', (63, 68))	('snRNP', 'Gene', (118, 123))	('snRNP', 'molecular_function', 'GO:0003734', ('118', '123'))
3560	27282250	A precise understanding of how mutations alter the role of SF3B1 in RNA splicing will likely require further studies of normal SF3B1 function.	('mutations', 'Var', (31, 40))	('SF3B1', 'Gene', (127, 132))	('SF3B1', 'Gene', (59, 64))	('alter', 'Reg', (41, 46))	('SF3B1', 'Gene', '23451', (59, 64))	('RNA splicing', 'MPA', (68, 80))	('SF3B1', 'Gene', '23451', (127, 132))	('RNA', 'cellular_component', 'GO:0005562', ('68', '71'))	('RNA splicing', 'biological_process', 'GO:0008380', ('68', '80'))
3561	27282250	The consequences of SF3B1 mutations may be cell type-dependent and/or allele-specific, as different SF3B1 mutations may not be phenotypically equivalent.	('SF3B1', 'Gene', (20, 25))	('SF3B1', 'Gene', (100, 105))	('mutations', 'Var', (26, 35))	('SF3B1', 'Gene', '23451', (20, 25))	('SF3B1', 'Gene', '23451', (100, 105))
3562	27282250	SF3B1 mutations in MDS versus CLL constitute initial versus secondary genetic insults and associate with favorable versus poor prognosis, respectively.	('SF3B1', 'Gene', (0, 5))	('MDS', 'Phenotype', 'HP:0002863', (19, 22))	('SF3B1', 'Gene', '23451', (0, 5))	('CLL', 'Phenotype', 'HP:0005550', (30, 33))	('MDS', 'Disease', (19, 22))	('MDS', 'Disease', 'MESH:D009190', (19, 22))	('mutations', 'Var', (6, 15))
3563	27282250	Different SF3B1 mutations are more enriched in MDS compared with CLL and other cancers (Fig.	('cancers', 'Disease', (79, 86))	('CLL', 'Phenotype', 'HP:0005550', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutations', 'Var', (16, 25))	('SF3B1', 'Gene', (10, 15))	('MDS', 'Disease', (47, 50))	('MDS', 'Disease', 'MESH:D009190', (47, 50))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('MDS', 'Phenotype', 'HP:0002863', (47, 50))	('SF3B1', 'Gene', '23451', (10, 15))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
3564	27282250	Despite the close association between SF3B1 mutations and the presence of ring sideroblasts in MDS, no studies have clearly demonstrated that SF3B1 mutations induce abnormal iron metabolism.	('mutations', 'Var', (148, 157))	('iron', 'Chemical', 'MESH:D007501', (174, 178))	('SF3B1', 'Gene', (38, 43))	('MDS', 'Disease', (95, 98))	('iron metabolism', 'MPA', (174, 189))	('SF3B1', 'Gene', (142, 147))	('SF3B1', 'Gene', '23451', (38, 43))	('mutations', 'Var', (44, 53))	('MDS', 'Disease', 'MESH:D009190', (95, 98))	('MDS', 'Phenotype', 'HP:0002863', (95, 98))	('ring sideroblasts', 'Phenotype', 'HP:0004828', (74, 91))	('metabolism', 'biological_process', 'GO:0008152', ('179', '189'))	('abnormal iron metabolism', 'Phenotype', 'HP:0011031', (165, 189))	('SF3B1', 'Gene', '23451', (142, 147))	('induce', 'Reg', (158, 164))
3566	27282250	ABCB7 encodes an iron transporter that is essential for hematopoiesis and that is mutated in X-linked sideroblastic anemia with ataxia, a genetic disease that is also characterized by the presence of ring sideroblasts.	('X-linked sideroblastic anemia', 'Disease', (93, 122))	('hematopoiesis', 'biological_process', 'GO:0030097', ('56', '69'))	('anemia', 'Phenotype', 'HP:0001903', (116, 122))	('ABCB7', 'Gene', (0, 5))	('ABCB7', 'Gene', '22', (0, 5))	('X-linked sideroblastic anemia', 'Disease', 'MESH:C536761', (93, 122))	('ring sideroblasts', 'Phenotype', 'HP:0004828', (200, 217))	('mutated', 'Var', (82, 89))	('linked sideroblastic anemia', 'Phenotype', 'HP:0004828', (95, 122))	('ataxia', 'Phenotype', 'HP:0001251', (128, 134))	('iron', 'Chemical', 'MESH:D007501', (17, 21))	('hematopoiesis', 'Disease', 'MESH:C536227', (56, 69))	('hematopoiesis', 'Disease', (56, 69))	('genetic disease', 'Disease', (138, 153))	('ataxia', 'Disease', (128, 134))	('genetic disease', 'Disease', 'MESH:D030342', (138, 153))	('encodes', 'Reg', (6, 13))	('ataxia', 'Disease', 'MESH:D001259', (128, 134))	('sideroblastic anemia', 'Phenotype', 'HP:0001924', (102, 122))
3569	27282250	In hematological cancer, such mutations have been shown to induce sequence-specific alterations in the preferred RNA motif bound by U2AF1, which normally recognizes the motif yAG r (y = pyrimidine; r = purine; lower-case nucleotides are preferred but not always required, while upper-case nucleotides are usually required; ' ' = intron-exon boundary) (Fig.	('U2AF', 'cellular_component', 'GO:0089701', ('132', '136'))	('hematological cancer', 'Phenotype', 'HP:0004377', (3, 23))	('U2AF1', 'Gene', (132, 137))	('alterations', 'Reg', (84, 95))	('hematological cancer', 'Disease', (3, 23))	('mutations', 'Var', (30, 39))	('hematological cancer', 'Disease', 'MESH:D009369', (3, 23))	('RNA', 'cellular_component', 'GO:0005562', ('113', '116'))	('purine', 'Chemical', 'MESH:C030985', (202, 208))	('pyrimidine', 'Chemical', 'MESH:C030986', (186, 196))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
3570	27282250	S34 and Q157 mutations respectively affect recognition of the -3 (pyrimidine normally preferred) and +1 (purine normally preferred) positions, where the coordinates are defined with respect to the intron-exon boundary to induce different changes in 3' splice site recognition.	('changes', 'Reg', (238, 245))	('S34', 'Gene', (0, 3))	('purine', 'Chemical', 'MESH:C030985', (105, 111))	('Q157 mutations', 'Var', (8, 22))	("3' splice site recognition", 'MPA', (249, 275))	('affect', 'Reg', (36, 42))	('pyrimidine', 'Chemical', 'MESH:C030986', (66, 76))	('recognition', 'MPA', (43, 54))
3571	27282250	Many downstream targets of mutant U2AF1 have been identified using patient transcriptomes, a transgenic mouse model of U2AF1S34F and transgenic human cells bearing each of the common U2AF1 mutations affecting the S34 and Q157 residues.	('patient', 'Species', '9606', (67, 74))	('human', 'Species', '9606', (144, 149))	('mutant', 'Var', (27, 33))	('U2AF', 'cellular_component', 'GO:0089701', ('119', '123'))	('mouse', 'Species', '10090', (104, 109))	('U2AF', 'cellular_component', 'GO:0089701', ('183', '187'))	('U2AF1', 'Gene', (183, 188))	('Q157', 'Var', (221, 225))	('mutations', 'Var', (189, 198))	('U2AF', 'cellular_component', 'GO:0089701', ('34', '38'))	('S34', 'Var', (213, 216))
3574	27282250	ZRSR2 mutations found in MDS are distributed throughout the gene, which lies on the X chromosome (Xp22.1), and frequently interrupt the coding sequence by directly or indirectly introducing in-frame stop codons (Fig.	('introducing', 'Reg', (178, 189))	('MDS', 'Disease', 'MESH:D009190', (25, 28))	('interrupt', 'NegReg', (122, 131))	('MDS', 'Phenotype', 'HP:0002863', (25, 28))	('X chromosome', 'cellular_component', 'GO:0000805', ('84', '96'))	('coding sequence', 'MPA', (136, 151))	('stop codons', 'MPA', (199, 210))	('ZRSR2', 'Gene', (0, 5))	('MDS', 'Disease', (25, 28))	('mutations', 'Var', (6, 15))	('ZRSR2', 'Gene', '8233', (0, 5))
3575	27282250	Together with the common occurrence of ZRSR2 mutations in male patients with cancer, this pattern is consistent with loss of function.	('mutations', 'Var', (45, 54))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('ZRSR2', 'Gene', '8233', (39, 44))	('ZRSR2', 'Gene', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('patients', 'Species', '9606', (63, 71))
3576	27282250	ZRSR2 mutations therefore contrast with the mutations observed in the spliceosomal genes SF3B1, SRSF2 and U2AF1, which cause missense changes at specific residues and never introduce in-frame stop codons (Fig.	('SF3B1', 'Gene', (89, 94))	('SRSF2', 'Gene', '6427', (96, 101))	('cause', 'Reg', (119, 124))	('SF3B1', 'Gene', '23451', (89, 94))	('missense changes', 'Var', (125, 141))	('SRSF2', 'Gene', (96, 101))	('ZRSR2', 'Gene', (0, 5))	('U2AF', 'cellular_component', 'GO:0089701', ('106', '110'))	('mutations', 'Var', (6, 15))	('ZRSR2', 'Gene', '8233', (0, 5))
3577	27282250	Whereas biochemical assays suggested that ZRSR2 promotes recognition of both U2- and U12-type introns, the phylogenetic observation that organisms with U12-type introns have ZRSR2 and those lacking U12-type introns also lack ZRSR2 suggested that ZRSR2 is particularly important for U12-type splicing.	('ZRSR2', 'Gene', (42, 47))	('ZRSR2', 'Gene', '8233', (174, 179))	('lack', 'NegReg', (220, 224))	('ZRSR2', 'Gene', '8233', (42, 47))	('splicing', 'biological_process', 'GO:0045292', ('291', '299'))	('ZRSR2', 'Gene', (225, 230))	('U12-type introns', 'Var', (152, 168))	('ZRSR2', 'Gene', (246, 251))	('ZRSR2', 'Gene', '8233', (225, 230))	('ZRSR2', 'Gene', '8233', (246, 251))	('ZRSR2', 'Gene', (174, 179))
3578	27282250	reported that MDS transcriptomes harboring mutations likely to inactivate ZRSR2 are characterized by frequent retention of U12-type introns, consistent with a crucial role for ZRSR2 in the minor spliceosome (Fig.	('MDS', 'Disease', (14, 17))	('MDS', 'Disease', 'MESH:D009190', (14, 17))	('ZRSR2', 'Gene', '8233', (176, 181))	('MDS', 'Phenotype', 'HP:0002863', (14, 17))	('spliceosome', 'cellular_component', 'GO:0005681', ('195', '206'))	('ZRSR2', 'Gene', (176, 181))	('ZRSR2', 'Gene', '8233', (74, 79))	('ZRSR2', 'Gene', (74, 79))	('mutations', 'Var', (43, 52))	('inactivate', 'NegReg', (63, 73))	('retention', 'biological_process', 'GO:0051235', ('110', '119'))
3579	27282250	ZRSR2 knockdown altered the in vitro differentiation potential of cord blood-derived CD34+ cells by promoting myeloid differentiation and impairing erythroid differentiation, consistent with features of human MDS.	('myeloid differentiation', 'CPA', (110, 133))	('impairing', 'NegReg', (138, 147))	('human', 'Species', '9606', (203, 208))	('promoting', 'PosReg', (100, 109))	('CD34', 'Gene', '947', (85, 89))	('altered', 'Reg', (16, 23))	('CD34', 'Gene', (85, 89))	('MDS', 'Disease', (209, 212))	('MDS', 'Disease', 'MESH:D009190', (209, 212))	('knockdown', 'Var', (6, 15))	('MDS', 'Phenotype', 'HP:0002863', (209, 212))	('ZRSR2', 'Gene', (0, 5))	('ZRSR2', 'Gene', '8233', (0, 5))	('erythroid differentiation', 'CPA', (148, 173))
3580	27282250	However, ZRSR2 knockdown also impaired the growth of K562 cells in vitro and following subcutaneous xenografting in vivo, indicating that ZRSR2 loss does not convey a proliferative advantage in the K562 genetic background.	('K562', 'CellLine', 'CVCL:0004', (198, 202))	('ZRSR2', 'Gene', '8233', (138, 143))	('ZRSR2', 'Gene', (138, 143))	('knockdown', 'Var', (15, 24))	('ZRSR2', 'Gene', '8233', (9, 14))	('ZRSR2', 'Gene', (9, 14))	('impaired', 'NegReg', (30, 38))	('growth', 'CPA', (43, 49))	('loss', 'NegReg', (144, 148))	('K562', 'CellLine', 'CVCL:0004', (53, 57))
3581	27282250	ZRSR2 mutations were associated with mis-splicing of genes relevant to the MAPK pathway and E2F transcription factor signaling, but functional experiments are needed to determine whether these or other splicing changes contribute to the hematopoietic phenotypes of ZRSR2-deficient cells.	('splicing', 'biological_process', 'GO:0045292', ('41', '49'))	('ZRSR2', 'Gene', (265, 270))	('transcription factor', 'molecular_function', 'GO:0000981', ('96', '116'))	('splicing', 'biological_process', 'GO:0045292', ('202', '210'))	('associated', 'Reg', (21, 31))	('ZRSR2', 'Gene', '8233', (265, 270))	('transcription', 'biological_process', 'GO:0006351', ('96', '109'))	('MAPK', 'molecular_function', 'GO:0004707', ('75', '79'))	('contribute', 'Reg', (219, 229))	('mis-splicing', 'MPA', (37, 49))	('ZRSR2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('ZRSR2', 'Gene', '8233', (0, 5))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))
3582	27282250	SRSF2 mutations appear most commonly (in 40-50% of patients) in chronic myelomonocytic leukemia (CMML), and are also enriched in subtypes of high-risk MDS, where they portend an increased risk of transformation to acute leukemia (Fig.	('MDS', 'Phenotype', 'HP:0002863', (151, 154))	('leukemia', 'Phenotype', 'HP:0001909', (220, 228))	('CMML', 'Phenotype', 'HP:0012325', (97, 101))	('acute leukemia', 'Phenotype', 'HP:0002488', (214, 228))	('leukemia', 'Phenotype', 'HP:0001909', (87, 95))	('SRSF2', 'Gene', (0, 5))	('chronic myelomonocytic leukemia', 'Disease', (64, 95))	('CMML', 'Disease', (97, 101))	('acute leukemia', 'Disease', 'MESH:D015470', (214, 228))	('acute leukemia', 'Disease', (214, 228))	('patients', 'Species', '9606', (51, 59))	('SRSF2', 'Gene', '6427', (0, 5))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (64, 95))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (64, 95))	('CMML', 'Disease', 'MESH:D054429', (97, 101))	('mutations', 'Var', (6, 15))	('MDS', 'Disease', (151, 154))	('MDS', 'Disease', 'MESH:D009190', (151, 154))
3585	27282250	All recurrent SRSF2 mutations affect the P95 residue, which is immediately downstream of the RRM domain (Fig.	('P95', 'Gene', (41, 44))	('P95', 'Gene', '4683', (41, 44))	('SRSF2', 'Gene', (14, 19))	('affect', 'Reg', (30, 36))	('mutations', 'Var', (20, 29))	('SRSF2', 'Gene', '6427', (14, 19))
3586	27282250	RNA-seq analyses of hematopoietic stem and progenitor cells from Srsf2P95H knock-in mice and transgenic and knock-in K562 cells expressing SRSF2P95H/L/R, and human AML and CMML patients with or without SRSF2 mutations, revealed that SRSF2 mutations alter its normal sequence-specific RNA-binding activity.	('sequence-specific', 'MPA', (266, 283))	('mutations', 'Var', (239, 248))	('mice', 'Species', '10090', (84, 88))	('RNA', 'cellular_component', 'GO:0005562', ('284', '287'))	('SRSF2', 'Gene', '6427', (139, 144))	('K562', 'CellLine', 'CVCL:0004', (117, 121))	('RNA-binding', 'molecular_function', 'GO:0003723', ('284', '295'))	('SRSF2', 'Gene', '6427', (202, 207))	('SRSF2', 'Gene', '6427', (233, 238))	('SRSF2', 'Gene', (139, 144))	('human', 'Species', '9606', (158, 163))	('AML', 'Disease', 'MESH:D015470', (164, 167))	('SRSF2', 'Gene', (202, 207))	('SRSF2', 'Gene', (233, 238))	('AML', 'Disease', (164, 167))	('AML', 'Phenotype', 'HP:0004808', (164, 167))	('CMML', 'Disease', 'MESH:D054429', (172, 176))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('patients', 'Species', '9606', (177, 185))	('CMML', 'Disease', (172, 176))	('CMML', 'Phenotype', 'HP:0012325', (172, 176))	('alter', 'Reg', (249, 254))
3587	27282250	Mutant SRSF2 preferentially recognizes a C-rich CCNG motif versus a G-rich GGNG motif, whereas wild-type SRSF2 binds both motifs with similar affinity (Fig.	('SRSF2', 'Gene', '6427', (7, 12))	('SRSF2', 'Gene', (105, 110))	('SRSF2', 'Gene', (7, 12))	('SRSF2', 'Gene', '6427', (105, 110))	('Mutant', 'Var', (0, 6))	('C-rich', 'MPA', (41, 47))	('preferentially', 'PosReg', (13, 27))
3588	27282250	These alterations in the RNA-binding activity of SRSF2 promote or repress recognition of exons containing C- or G-rich ESEs.	('RNA-binding', 'molecular_function', 'GO:0003723', ('25', '36'))	('alterations', 'Var', (6, 17))	('recognition of exons containing C- or G-rich ESEs', 'MPA', (74, 123))	('repress', 'NegReg', (66, 73))	('SRSF2', 'Gene', '6427', (49, 54))	('RNA', 'cellular_component', 'GO:0005562', ('25', '28'))	('promote', 'PosReg', (55, 62))	('SRSF2', 'Gene', (49, 54))	('RNA-binding', 'Interaction', (25, 36))
3590	27282250	SRSF2 mutations promote inclusion of a 'poison exon' of EZH2 that introduces an in-frame stop codon to induce nonsense-mediated decay (NMD) of the EZH2 transcript and consequent global downregulation of EZH2 protein and histone H3 lysine 27 trimethylation (H3K27me3) levels.	('EZH2', 'Gene', '2146', (147, 151))	('EZH2', 'Gene', (147, 151))	('EZH2', 'Gene', '2146', (203, 207))	('downregulation', 'NegReg', (185, 199))	('SRSF2', 'Gene', (0, 5))	('induce', 'PosReg', (103, 109))	('EZH2', 'Gene', (203, 207))	('nonsense-mediated decay', 'MPA', (110, 133))	('EZH2', 'Gene', '2146', (56, 60))	('lysine', 'Chemical', 'MESH:D008239', (231, 237))	('SRSF2', 'Gene', '6427', (0, 5))	('EZH2', 'Gene', (56, 60))	('protein', 'cellular_component', 'GO:0003675', ('208', '215'))	('mutations', 'Var', (6, 15))
3591	27282250	Loss-of-function mutations in EZH2 occur in MDS, and Ezh2 loss has been functionally linked to MDS development and aberrant hematopoietic stem cell self-renewal in vivo.	('Ezh2', 'Gene', (53, 57))	('Loss-of-function', 'NegReg', (0, 16))	('EZH2', 'Gene', '2146', (30, 34))	('loss', 'NegReg', (58, 62))	('Ezh2', 'Gene', '2146', (53, 57))	('EZH2', 'Gene', (30, 34))	('MDS', 'Disease', (44, 47))	('MDS', 'Disease', 'MESH:D009190', (44, 47))	('MDS', 'Disease', (95, 98))	('MDS', 'Disease', 'MESH:D009190', (95, 98))	('MDS', 'Phenotype', 'HP:0002863', (95, 98))	('MDS', 'Phenotype', 'HP:0002863', (44, 47))	('mutations', 'Var', (17, 26))
3592	27282250	Therefore, decreased EZH2 levels may partially explain how SRSF2 mutations drive MDS, and also explain the previously observed mutual exclusivity of SRSF2 and EZH2 mutations in MDS.	('drive', 'PosReg', (75, 80))	('MDS', 'Disease', (177, 180))	('EZH2', 'Gene', (21, 25))	('MDS', 'Disease', 'MESH:D009190', (177, 180))	('EZH2', 'Gene', '2146', (21, 25))	('SRSF2', 'Gene', '6427', (59, 64))	('MDS', 'Phenotype', 'HP:0002863', (177, 180))	('decreased', 'NegReg', (11, 20))	('SRSF2', 'Gene', '6427', (149, 154))	('MDS', 'Disease', (81, 84))	('SRSF2', 'Gene', (59, 64))	('EZH2', 'Gene', '2146', (159, 163))	('MDS', 'Disease', 'MESH:D009190', (81, 84))	('MDS', 'Phenotype', 'HP:0002863', (81, 84))	('EZH2', 'Gene', (159, 163))	('mutations', 'Var', (65, 74))	('SRSF2', 'Gene', (149, 154))
3594	27282250	Pre-mRNA processing factor 8 (PRPF8) is subjected to mutations or hemizygous deletions in 1-5% of patients with myeloid leukemias.	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('deletions', 'Var', (77, 86))	('myeloid leukemias', 'Disease', 'MESH:D007951', (112, 129))	('leukemia', 'Phenotype', 'HP:0001909', (120, 128))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (112, 128))	('PRPF8', 'Gene', '10594', (30, 35))	('PRPF8', 'Gene', (30, 35))	('myeloid leukemias', 'Disease', (112, 129))	('mutations', 'Var', (53, 62))	('Pre-mRNA processing factor 8', 'Gene', '10594', (0, 28))	('patients', 'Species', '9606', (98, 106))	('leukemias', 'Phenotype', 'HP:0001909', (120, 129))	('Pre-mRNA processing factor 8', 'Gene', (0, 28))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (112, 129))	('mRNA processing', 'biological_process', 'GO:0006397', ('4', '19'))
3595	27282250	Biochemical studies in yeast suggest that PRPF8 mutations may affect recognition of suboptimal 3' splice sites.	('affect', 'Reg', (62, 68))	('yeast', 'Species', '4932', (23, 28))	('PRPF8', 'Gene', '10594', (42, 47))	("recognition of suboptimal 3' splice sites", 'MPA', (69, 110))	('PRPF8', 'Gene', (42, 47))	('mutations', 'Var', (48, 57))
3596	27282250	Genes encoding splicing factors have also been identified as recurrent targets of translocations in cancer.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('splicing factor', 'Gene', (15, 30))	('translocations', 'Var', (82, 96))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('splicing', 'biological_process', 'GO:0045292', ('15', '23'))	('splicing factor', 'Gene', '10569', (15, 30))
3599	27282250	Currently, it is not known if these fusions affect the function of the splicing factors involved in the chimeric protein product.	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('splicing', 'biological_process', 'GO:0045292', ('71', '79'))	('fusions', 'Var', (36, 43))	('function', 'MPA', (55, 63))	('splicing factor', 'Gene', (71, 86))	('affect', 'Reg', (44, 50))	('splicing factor', 'Gene', '10569', (71, 86))
3600	27282250	In the case of SFPQ fusions, the sequence encoding the coiled-coil domain (which is important for protein dimerization) of SFPQ appears to be consistently included in the chimeric transcript, suggesting that SFPQ fusions may contribute to cancer by promoting aberrant dimerization of SFPQ's partner protein.	('dimerization', 'MPA', (268, 280))	('contribute', 'Reg', (225, 235))	('SFPQ', 'Gene', '6421', (208, 212))	('SFPQ', 'Gene', '6421', (284, 288))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('promoting', 'PosReg', (249, 258))	('SFPQ', 'Gene', (15, 19))	('SFPQ', 'Gene', '6421', (15, 19))	('SFPQ', 'Gene', (208, 212))	('cancer', 'Disease', (239, 245))	('SFPQ', 'Gene', (284, 288))	('SFPQ', 'Gene', (123, 127))	('SFPQ', 'Gene', '6421', (123, 127))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('fusions', 'Var', (213, 220))	('protein', 'cellular_component', 'GO:0003675', ('299', '306'))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
3602	27282250	A missense genetic variant in serine/arginine repetitive matrix 2 (SRRM2; also known as SRm300) was recently found to segregate with incidence of familial papillary thyroid carcinoma.	('familial papillary thyroid carcinoma', 'Disease', (146, 182))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (165, 182))	('serine/arginine repetitive matrix 2', 'Gene', (30, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('SRm300', 'Gene', '23524', (88, 94))	('SRm300', 'Gene', (88, 94))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (155, 182))	('serine/arginine repetitive matrix 2', 'Gene', '23524', (30, 65))	('missense genetic variant', 'Var', (2, 26))	('SRRM2', 'Gene', '23524', (67, 72))	('SRRM2', 'Gene', (67, 72))	('familial papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (146, 182))	('with', 'Reg', (128, 132))
3603	27282250	Patients carrying this SRRM2 variant exhibited mis-splicing of specific cassette exons, suggesting that the variant altered the normal function of SRRM2 in splicing.	('splicing', 'biological_process', 'GO:0045292', ('156', '164'))	('SRRM2', 'Gene', '23524', (147, 152))	('SRRM2', 'Gene', (147, 152))	('variant', 'Var', (29, 36))	('Patients', 'Species', '9606', (0, 8))	('splicing', 'biological_process', 'GO:0045292', ('51', '59'))	('SRRM2', 'Gene', '23524', (23, 28))	('SRRM2', 'Gene', (23, 28))	('splicing', 'MPA', (156, 164))	('function', 'MPA', (135, 143))	('altered', 'Reg', (116, 123))	('mis-splicing of specific cassette exons', 'MPA', (47, 86))
3605	27282250	Recent work identified both somatic mutations and genetic variants affecting DEAD-box helicase 41 (DDX41) that are associated with high-penetrance familial MDS and AML.	('variants', 'Var', (58, 66))	('MDS', 'Disease', (156, 159))	('MDS', 'Disease', 'MESH:D009190', (156, 159))	('MDS', 'Phenotype', 'HP:0002863', (156, 159))	('AML', 'Disease', 'MESH:D015470', (164, 167))	('mutations', 'Var', (36, 45))	('DEAD-box helicase 41', 'Gene', '51428', (77, 97))	('DDX41', 'Gene', '51428', (99, 104))	('AML', 'Disease', (164, 167))	('DEAD-box helicase 41', 'Gene', (77, 97))	('AML', 'Phenotype', 'HP:0004808', (164, 167))	('associated with', 'Reg', (115, 130))	('DDX41', 'Gene', (99, 104))
3606	27282250	Although the normal molecular role of DDX41 is incompletely understood, mass spectrometry data indicated that DDX41 interacts with core spliceosome components and that the likely loss-of-function DDX41 mutations perturb these interactions.	('DDX41', 'Gene', '51428', (196, 201))	('spliceosome', 'cellular_component', 'GO:0005681', ('136', '147'))	('DDX41', 'Gene', (38, 43))	('perturb', 'NegReg', (212, 219))	('interactions', 'Interaction', (226, 238))	('loss-of-function', 'NegReg', (179, 195))	('DDX41', 'Gene', '51428', (110, 115))	('DDX41', 'Gene', (196, 201))	('core spliceosome components', 'MPA', (131, 158))	('interacts', 'Interaction', (116, 125))	('DDX41', 'Gene', (110, 115))	('core', 'cellular_component', 'GO:0019013', ('131', '135'))	('DDX41', 'Gene', '51428', (38, 43))	('mutations', 'Var', (202, 211))
3607	27282250	Therefore, DDX41 may play a role in RNA splicing that is disrupted by MDS and AML - associated mutations, although that hypothesis remains to be tested.	('RNA splicing', 'biological_process', 'GO:0008380', ('36', '48'))	('MDS', 'Phenotype', 'HP:0002863', (70, 73))	('DDX41', 'Gene', (11, 16))	('AML', 'Disease', 'MESH:D015470', (78, 81))	('RNA', 'cellular_component', 'GO:0005562', ('36', '39'))	('MDS', 'Disease', (70, 73))	('MDS', 'Disease', 'MESH:D009190', (70, 73))	('RNA splicing', 'MPA', (36, 48))	('mutations', 'Var', (95, 104))	('AML', 'Phenotype', 'HP:0004808', (78, 81))	('AML', 'Disease', (78, 81))	('DDX41', 'Gene', '51428', (11, 16))
3608	27282250	Splicing factor dysregulation, including spliceosomal mutations, may directly or indirectly affect many cellular processes in addition to RNA splicing.	('spliceosomal mutations', 'Var', (41, 63))	('RNA splicing', 'biological_process', 'GO:0008380', ('138', '150'))	('Splicing', 'biological_process', 'GO:0045292', ('0', '8'))	('cellular processes', 'CPA', (104, 122))	('Splicing factor', 'Gene', (0, 15))	('affect', 'Reg', (92, 98))	('RNA', 'cellular_component', 'GO:0005562', ('138', '141'))	('Splicing factor', 'Gene', '10569', (0, 15))
3612	27282250	A recent study proposed that the spliceosome is an effector of ataxia-telangiectasia mutated (ATM) signaling, wherein DNA lesions displace spliceosomes, resulting in R loop formation and ATM activation.	('ataxia-telangiectasia mutated', 'Gene', (63, 92))	('telangiectasia', 'Phenotype', 'HP:0001009', (70, 84))	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('ataxia-telangiectasia mutated', 'Gene', '472', (63, 92))	('signaling', 'biological_process', 'GO:0023052', ('99', '108'))	('displace', 'NegReg', (130, 138))	('R loop formation', 'MPA', (166, 182))	('DNA', 'Var', (118, 121))	('activation', 'PosReg', (191, 201))	('ATM', 'Gene', '472', (187, 190))	('ATM', 'Gene', '472', (94, 97))	('ataxia', 'Phenotype', 'HP:0001251', (63, 69))	('spliceosome', 'cellular_component', 'GO:0005681', ('33', '44'))	('formation', 'biological_process', 'GO:0009058', ('173', '182'))	('ATM', 'Gene', (94, 97))	('spliceosomes', 'MPA', (139, 151))	('ATM', 'Gene', (187, 190))
3614	27282250	Histone H3 lysine 36 trimethylation (H3K36me3) is further enriched over exons, and modulation of H3K36me3 can influence splice site choice.	('modulation', 'Var', (83, 93))	('H3K36me3', 'Var', (97, 105))	('influence', 'Reg', (110, 119))	('splice site choice', 'MPA', (120, 138))	('lysine', 'Chemical', 'MESH:D008239', (11, 17))
3615	27282250	As described above, mutant SRSF2 prevents hematopoiesis in part by promoting a non-functional isoform of EZH2, resulting in global decreases in H3K27me3 levels.	('SRSF2', 'Gene', '6427', (27, 32))	('prevents', 'NegReg', (33, 41))	('hematopoiesis', 'Disease', (42, 55))	('non-functional isoform', 'MPA', (79, 101))	('H3K27me3 levels', 'MPA', (144, 159))	('decreases', 'NegReg', (131, 140))	('promoting', 'PosReg', (67, 76))	('SRSF2', 'Gene', (27, 32))	('EZH2', 'Gene', '2146', (105, 109))	('hematopoiesis', 'Disease', 'MESH:C536227', (42, 55))	('EZH2', 'Gene', (105, 109))	('mutant', 'Var', (20, 26))	('hematopoiesis', 'biological_process', 'GO:0030097', ('42', '55'))
3616	27282250	Mutant U2AF1 promotes a cancer-associated isoform of the histone variant macro-H2A.1.	('U2AF1', 'Gene', (7, 12))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('promotes', 'PosReg', (13, 21))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('U2AF', 'cellular_component', 'GO:0089701', ('7', '11'))	('Mutant', 'Var', (0, 6))
3617	27282250	Connections between SF3B1 mutations and epigenetic dysregulation have not been identified, but are plausible given the published links between splice site recognition and chromatin described above.	('SF3B1', 'Gene', '23451', (20, 25))	('mutations', 'Var', (26, 35))	('chromatin', 'cellular_component', 'GO:0000785', ('171', '180'))	('SF3B1', 'Gene', (20, 25))
3618	27282250	However, further studies are needed to determine whether potential epigenetic changes caused by U2AF1 and/or SF3B1 mutations are important for cancer initiation and progression.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('U2AF', 'cellular_component', 'GO:0089701', ('96', '100'))	('mutations', 'Var', (115, 124))	('SF3B1', 'Gene', (109, 114))	('U2AF1', 'Gene', (96, 101))	('cancer initiation', 'Disease', 'MESH:D009369', (143, 160))	('SF3B1', 'Gene', '23451', (109, 114))	('cancer initiation', 'Disease', (143, 160))
3627	27282250	NMD provides a concrete example of a cytoplasmic process that is likely affected by cancer-associated mutations affecting SF3B1, SRSF2, U2AF1 and ZRSR2, even though those proteins localize to the nucleus.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('SF3B1', 'Gene', (122, 127))	('SRSF2', 'Gene', (129, 134))	('cancer', 'Disease', (84, 90))	('ZRSR2', 'Gene', '8233', (146, 151))	('ZRSR2', 'Gene', (146, 151))	('nucleus', 'cellular_component', 'GO:0005634', ('196', '203'))	('SF3B1', 'Gene', '23451', (122, 127))	('U2AF', 'cellular_component', 'GO:0089701', ('136', '140'))	('SRSF2', 'Gene', '6427', (129, 134))	('mutations', 'Var', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('U2AF1', 'Gene', (136, 141))	('affected', 'Reg', (72, 80))
3630	27282250	Human cells express an abundance of mRNAs containing premature termination codons (one-third of all alternatively spliced isoforms by one estimate), including the EZH2 poison exon that is promoted by SRSF2 mutations.	('Human', 'Species', '9606', (0, 5))	('mutations', 'Var', (206, 215))	('promoted', 'PosReg', (188, 196))	('SRSF2', 'Gene', '6427', (200, 205))	('EZH2', 'Gene', (163, 167))	('EZH2', 'Gene', '2146', (163, 167))	('SRSF2', 'Gene', (200, 205))
3633	27282250	Interestingly, in the earliest report of splicing factor mutations, genes involved in NMD were upregulated following overexpression of mutant U2AF1, suggesting a potential link between spliceosomal mutations and overproduction of NMD substrates.	('splicing', 'biological_process', 'GO:0045292', ('41', '49'))	('splicing factor', 'Gene', (41, 56))	('upregulated', 'PosReg', (95, 106))	('U2AF1', 'Gene', (142, 147))	('NMD', 'Disease', (86, 89))	('U2AF', 'cellular_component', 'GO:0089701', ('142', '146'))	('mutant', 'Var', (135, 141))	('splicing factor', 'Gene', '10569', (41, 56))	('overexpression', 'PosReg', (117, 131))
3635	27282250	The recent discovery of recurrent mutations in UPF1, which encodes a RNA helicase that is central to NMD, in pancreatic adenosquamous carcinoma provided a genetic link between NMD and cancer.	('cancer', 'Disease', (184, 190))	('UPF1', 'Gene', (47, 51))	('pancreatic adenosquamous carcinoma', 'Disease', 'MESH:D018196', (109, 143))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('pancreatic adenosquamous carcinoma', 'Disease', (109, 143))	('UPF1', 'Gene', '5976', (47, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('RNA', 'cellular_component', 'GO:0005562', ('69', '72'))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('mutations', 'Var', (34, 43))
3636	27282250	The observed mutations induced abnormal UPF1 splicing and skipping of sequence encoding core domains, potentially resulting in partial or complete loss of UPF1 function, although further work is required to determine how these mutations affect global RNA surveillance.	('RNA surveillance', 'biological_process', 'GO:0071025', ('251', '267'))	('core', 'cellular_component', 'GO:0019013', ('88', '92'))	('skipping', 'Var', (58, 66))	('global RNA surveillance', 'MPA', (244, 267))	('UPF1', 'Gene', '5976', (40, 44))	('RNA', 'cellular_component', 'GO:0005562', ('251', '254'))	('splicing', 'biological_process', 'GO:0045292', ('45', '53'))	('UPF1', 'Gene', (155, 159))	('splicing', 'MPA', (45, 53))	('loss', 'NegReg', (147, 151))	('mutations', 'Var', (13, 22))	('function', 'MPA', (160, 168))	('UPF1', 'Gene', (40, 44))	('UPF1', 'Gene', '5976', (155, 159))
3637	27282250	Deficiencies in different NMD factors have been previously linked to disorders including intellectual disability, thrombocytopenia with absent radii syndrome and muscular dystrophy.	('Deficiencies', 'Var', (0, 12))	('linked', 'Reg', (59, 65))	('thrombocytopenia', 'Disease', 'MESH:D013921', (114, 130))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (114, 130))	('disability', 'Disease', (102, 112))	('absent radii', 'Phenotype', 'HP:0003974', (136, 148))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (162, 180))	('thrombocytopenia', 'Disease', (114, 130))	('muscular dystrophy', 'Disease', (162, 180))	('muscular dystrophy', 'Disease', 'MESH:D009136', (162, 180))	('disability', 'Disease', 'MESH:D009069', (102, 112))	('absent radii syndrome', 'Disease', 'MESH:C536940', (136, 157))	('NMD factors', 'Gene', (26, 37))	('absent radii syndrome', 'Disease', (136, 157))	('intellectual disability', 'Phenotype', 'HP:0001249', (89, 112))
3638	27282250	Given the crucial roles of specific alternatively spliced isoforms in cancer biology, as well as the potentially increased sensitivity of cancers to global perturbation of splicing efficiency relative to normal cells, pharmacological modulation of splicing may represent an important therapeutic strategy.	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('pharmacological', 'Var', (218, 233))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('splicing', 'biological_process', 'GO:0045292', ('248', '256'))	('splicing', 'biological_process', 'GO:0045292', ('172', '180'))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancers', 'Disease', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
3642	27282250	Biochemical studies identified SF3B1 as the likely target of these drugs, consistent with the observation that mutations affecting the R1074 residue of SF3B1 confer resistance to pladienolide and E7107.	('SF3B1', 'Gene', '23451', (152, 157))	('SF3B1', 'Gene', '23451', (31, 36))	('SF3B1', 'Gene', (31, 36))	('E7107', 'Chemical', 'MESH:C557411', (196, 201))	('E7107', 'Var', (196, 201))	('SF3B1', 'Gene', (152, 157))	('R1074', 'Var', (135, 140))	('pladienolide', 'Chemical', '-', (179, 191))	('mutations affecting', 'Var', (111, 130))	('resistance', 'MPA', (165, 175))
3643	27282250	Unfortunately, two separate Phase I clinical trials of E7107 revealed an unexpected and unexplained side effect of visual disturbances in 5% of subjects.	('visual disturbances', 'Phenotype', 'HP:0000505', (115, 134))	('visual disturbances', 'Disease', 'MESH:D010468', (115, 134))	('visual disturbances', 'Disease', (115, 134))	('E7107', 'Var', (55, 60))	('E7107', 'Chemical', 'MESH:C557411', (55, 60))
3647	27282250	reported that the splicing inhibitor E7107 reduced the leukemic burden and prolonged survival of mice carrying oncogene-driven myeloid leukemias if the leukemias had Srsf2 mutations, but not if the leukemias expressed only wild-type Srsf2.	('leukemias', 'Phenotype', 'HP:0001909', (135, 144))	('leukemias', 'Disease', (152, 161))	('leukemias', 'Phenotype', 'HP:0001909', (198, 207))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (127, 143))	('leukemia', 'Phenotype', 'HP:0001909', (135, 143))	('reduced', 'NegReg', (43, 50))	('leukemia', 'Phenotype', 'HP:0001909', (198, 206))	('splicing', 'biological_process', 'GO:0045292', ('18', '26'))	('leukemias', 'Disease', (198, 207))	('E7107', 'Chemical', 'MESH:C557411', (37, 42))	('leukemias', 'Disease', (135, 144))	('leukemic burden', 'Disease', (55, 70))	('Srsf2', 'Gene', (233, 238))	('myeloid leukemias', 'Disease', (127, 144))	('Srsf2', 'Gene', '20382', (233, 238))	('E7107', 'Var', (37, 42))	('myeloid leukemias', 'Disease', 'MESH:D007951', (127, 144))	('survival', 'CPA', (85, 93))	('mice', 'Species', '10090', (97, 101))	('leukemias', 'Disease', 'MESH:D007938', (152, 161))	('Srsf2', 'Gene', (166, 171))	('leukemic burden', 'Disease', 'MESH:D007938', (55, 70))	('leukemias', 'Phenotype', 'HP:0001909', (152, 161))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (127, 144))	('mutations', 'Var', (172, 181))	('Srsf2', 'Gene', '20382', (166, 171))	('prolonged', 'PosReg', (75, 84))	('leukemia', 'Phenotype', 'HP:0001909', (152, 160))	('leukemias', 'Disease', 'MESH:D007938', (135, 144))	('leukemias', 'Disease', 'MESH:D007938', (198, 207))
3648	27282250	observed similarly specific targeting of patient-derived xenograft (PDX) models of leukemias with spliceosomal mutations.	('leukemias', 'Disease', (83, 92))	('leukemia', 'Phenotype', 'HP:0001909', (83, 91))	('leukemias', 'Disease', 'MESH:D007938', (83, 92))	('patient', 'Species', '9606', (41, 48))	('leukemias', 'Phenotype', 'HP:0001909', (83, 92))	('spliceosomal mutations', 'Var', (98, 120))
3649	27282250	These data suggest that splicing inhibitors such as E7107 are synthetically lethal with genetic lesions affecting the spliceosome.	('genetic lesions', 'Disease', (88, 103))	('splicing', 'biological_process', 'GO:0045292', ('24', '32'))	('E7107', 'Var', (52, 57))	('spliceosome', 'cellular_component', 'GO:0005681', ('118', '129'))	('genetic lesions', 'Disease', 'MESH:D020022', (88, 103))	('E7107', 'Chemical', 'MESH:C557411', (52, 57))
3657	27282250	Emerging evidence supports a model in which many spliceosomal mutations induce specific changes in splice site or exon recognition, frequently via altered RNA binding, leading to genome-wide splicing changes that presumably promote cancer development.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('changes', 'Reg', (88, 95))	('RNA binding', 'Interaction', (155, 166))	('cancer', 'Disease', (232, 238))	('splicing', 'biological_process', 'GO:0045292', ('191', '199'))	('exon recognition', 'MPA', (114, 130))	('spliceosomal', 'Gene', (49, 61))	('RNA binding', 'molecular_function', 'GO:0003723', ('155', '166'))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('promote', 'PosReg', (224, 231))	('RNA', 'cellular_component', 'GO:0005562', ('155', '158'))	('splice site', 'MPA', (99, 110))	('splicing changes', 'MPA', (191, 207))	('mutations', 'Var', (62, 71))	('altered', 'Reg', (147, 154))
3658	27282250	Furthermore, it is unknown whether the pro-tumorigenic effects of mutated spliceosomal proteins are mediated by just a handful of mis-spliced isoforms, or instead are due to many splicing changes, which may even be functionally interdependent.	('mutated', 'Var', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('splicing', 'biological_process', 'GO:0045292', ('179', '187'))	('tumor', 'Disease', (43, 48))
3659	27282250	In principle, spliceosomal mutations could affect almost any biological process by inducing mis-splicing of key regulators (for example, the connection between SRSF2 and H3K27me3 deficiency via EZH2 mis-splicing).	('mutations', 'Var', (27, 36))	('spliceosomal', 'Var', (14, 26))	('splicing', 'biological_process', 'GO:0045292', ('203', '211'))	('SRSF2', 'Gene', (160, 165))	('biological process', 'biological_process', 'GO:0008150', ('61', '79'))	('deficiency', 'Var', (179, 189))	('inducing', 'Reg', (83, 91))	('affect', 'Reg', (43, 49))	('SRSF2', 'Gene', '6427', (160, 165))	('splicing', 'biological_process', 'GO:0045292', ('96', '104'))	('mis-splicing', 'MPA', (92, 104))	('H3K27me3', 'Protein', (170, 178))	('EZH2', 'Gene', (194, 198))	('EZH2', 'Gene', '2146', (194, 198))
3660	27282250	Spliceosomal mutations may also dysregulate processes including transcriptional elongation, the DNA damage response and NMD, in which splicing factors play key roles (Fig.	('DNA damage response', 'biological_process', 'GO:0006974', ('96', '115'))	('splicing factor', 'Gene', '10569', (134, 149))	('DNA damage response', 'CPA', (96, 115))	('Spliceosomal mutations', 'Var', (0, 22))	('transcriptional elongation', 'CPA', (64, 90))	('splicing', 'biological_process', 'GO:0045292', ('134', '142'))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('NMD', 'CPA', (120, 123))	('splicing factor', 'Gene', (134, 149))	('dysregulate', 'Reg', (32, 43))
3661	27282250	Although spliceosomal mutations provide the most direct link between splicing and cancer, it is also important to note that abnormal splicing is a feature of most cancers even in the absence of spliceosomal mutations.	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Disease', (163, 170))	('abnormal splicing', 'MPA', (124, 141))	('splicing', 'biological_process', 'GO:0045292', ('69', '77'))	('splicing', 'biological_process', 'GO:0045292', ('133', '141'))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancers', 'Disease', 'MESH:D009369', (163, 170))
3663	27282250	Specific perturbations may arise from dysregulation of single splicing factors that play pro- or anti-tumorigenic roles (Table 1), whereas global perturbations may arise from effects including potential transcriptional amplification driven by MYC or mutations affecting epigenetic regulators such as isocitrate dehydrogenase (IDH) or SET domain containing 2 (SETD2).	('isocitrate dehydrogenase', 'Gene', '3417', (300, 324))	('transcriptional', 'MPA', (203, 218))	('SETD2', 'Gene', '29072', (359, 364))	('tumor', 'Disease', (102, 107))	('splicing', 'biological_process', 'GO:0045292', ('62', '70'))	('splicing factor', 'Gene', '10569', (62, 77))	('MYC', 'Gene', '4609', (243, 246))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('dysregulation', 'Var', (38, 51))	('mutations', 'Var', (250, 259))	('IDH', 'Gene', (326, 329))	('MYC', 'Gene', (243, 246))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('isocitrate dehydrogenase', 'Gene', (300, 324))	('IDH', 'Gene', '3417', (326, 329))	('SETD2', 'Gene', (359, 364))	('splicing factor', 'Gene', (62, 77))
3665	27282250	For example, specific inhibition or sequestration of mutant SRSF2 and U2AF1 may be possible given their altered RNA-binding preferences.	('U2AF', 'cellular_component', 'GO:0089701', ('70', '74'))	('U2AF1', 'Gene', (70, 75))	('SRSF2', 'Gene', (60, 65))	('RNA', 'cellular_component', 'GO:0005562', ('112', '115'))	('SRSF2', 'Gene', '6427', (60, 65))	('sequestration', 'MPA', (36, 49))	('mutant', 'Var', (53, 59))	('RNA-binding', 'Interaction', (112, 123))	('RNA-binding', 'molecular_function', 'GO:0003723', ('112', '123'))
3666	27282250	However, definitive evidence that cancer cells depend on these mutated proteins, or that inhibiting the mutant allele is sufficient to restore normal splicing, is currently absent.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mutant', 'Var', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('splicing', 'biological_process', 'GO:0045292', ('150', '158'))	('normal splicing', 'MPA', (143, 158))	('cancer', 'Disease', (34, 40))
3667	27282250	(Mutant SRSF2 and U2AF1 likely act as oncoproteins to promote tumor formation, yet may not be required for subsequent tumor maintenance or growth.)	('promote', 'PosReg', (54, 61))	('U2AF1', 'Gene', (18, 23))	('SRSF2', 'Gene', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (62, 67))	('Mutant', 'Var', (1, 7))	('SRSF2', 'Gene', '6427', (8, 13))	('tumor', 'Disease', (118, 123))	('formation', 'biological_process', 'GO:0009058', ('68', '77'))	('U2AF', 'cellular_component', 'GO:0089701', ('18', '22'))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
3668	27282250	Specific mis-splicing events could potentially be corrected with antisense oligonucleotides, which have shown promise in clinical trials of disorders such as Duchenne muscular dystrophy and spinal muscular atrophy.	('antisense oligonucleotides', 'Var', (65, 91))	('spinal muscular atrophy', 'Phenotype', 'HP:0007269', (190, 213))	('Duchenne muscular dystrophy', 'Disease', 'MESH:D020388', (158, 185))	('splicing', 'biological_process', 'GO:0045292', ('13', '21'))	('spinal muscular atrophy', 'Disease', 'MESH:D009134', (190, 213))	('oligonucleotides', 'Chemical', 'MESH:D009841', (75, 91))	('spinal muscular atrophy', 'Disease', (190, 213))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (167, 185))	('Duchenne muscular dystrophy', 'Disease', (158, 185))	('muscular atrophy', 'Phenotype', 'HP:0003202', (197, 213))
3669	27282250	However, our current understanding of how spliceosomal mutations perturb cellular function is insufficient to determine which mis-splicing events to correct in cancer.	('splicing', 'biological_process', 'GO:0045292', ('130', '138'))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('mutations', 'Var', (55, 64))	('cancer', 'Disease', (160, 166))	('perturb', 'Reg', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cellular function', 'MPA', (73, 90))
3670	27282250	Furthermore, because inhibiting a mutant oncoprotein is likely more feasible than restoring the function of a disabled wild-type protein, restoring normal splicing may not be possible in the context of spliceosomal mutations that disable tumor suppressors.	('splicing', 'biological_process', 'GO:0045292', ('155', '163'))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('splicing', 'MPA', (155, 163))	('tumor', 'Disease', (238, 243))	('mutant', 'Var', (34, 40))
3671	27282250	For example, ZRSR2 mutations cause loss of ZRSR2 expression or function, and it is unclear whether restoring U12-type intron recognition in the absence of ZRSR2 is possible.	('ZRSR2', 'Gene', '8233', (155, 160))	('loss', 'NegReg', (35, 39))	('ZRSR2', 'Gene', (155, 160))	('expression', 'MPA', (49, 59))	('mutations', 'Var', (19, 28))	('function', 'MPA', (63, 71))	('ZRSR2', 'Gene', '8233', (43, 48))	('ZRSR2', 'Gene', (43, 48))	('ZRSR2', 'Gene', '8233', (13, 18))	('ZRSR2', 'Gene', (13, 18))
3672	27282250	Conversely, it may be feasible to selectively target cells expressing mutated splicing factors.	('splicing factor', 'Gene', '10569', (78, 93))	('splicing', 'biological_process', 'GO:0045292', ('78', '86'))	('mutated', 'Var', (70, 77))	('splicing factor', 'Gene', (78, 93))
3673	27282250	Just as increased somatic mutational burdens may generate neo-epitopes and render specific subsets of cancer sensitive to cancer immunotherapies, so may abnormal mRNAs generated by spliceosomal mutations result in neo-epitope production in cancers bearing these lesions.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('result in', 'Reg', (204, 213))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('neo-epitopes', 'MPA', (58, 70))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', (102, 108))	('neo-epitope production', 'MPA', (214, 236))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancers', 'Disease', (240, 247))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('mutational', 'Var', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('generate', 'Reg', (49, 57))	('cancer', 'Disease', (240, 246))	('cancers', 'Disease', 'MESH:D009369', (240, 247))
3674	27282250	Notably, these two approaches:inhibition of splicing catalysis and immunotherapy:could potentially be efficacious in the context of spliceosomal mutations that generate oncoproteins as well as those that inactivate tumor suppressors.	('oncoproteins', 'MPA', (169, 181))	('mutations', 'Var', (145, 154))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))	('splicing', 'biological_process', 'GO:0045292', ('44', '52'))
3675	27282250	Recurrent mutations in SF3B1, SRSF2, U2AF1, and ZRSR2 cause very different mechanistic alterations in splicing, yet each may render cells susceptible to further perturbation of splicing catalysis or result in the generation of neo-epitopes.	('alterations', 'Reg', (87, 98))	('SRSF2', 'Gene', '6427', (30, 35))	('splicing catalysis', 'MPA', (177, 195))	('susceptible', 'Reg', (138, 149))	('splicing', 'biological_process', 'GO:0045292', ('177', '185'))	('ZRSR2', 'Gene', '8233', (48, 53))	('SRSF2', 'Gene', (30, 35))	('render', 'Reg', (125, 131))	('SF3B1', 'Gene', (23, 28))	('perturbation', 'Reg', (161, 173))	('U2AF', 'cellular_component', 'GO:0089701', ('37', '41'))	('result in', 'Reg', (199, 208))	('splicing', 'biological_process', 'GO:0045292', ('102', '110'))	('ZRSR2', 'Gene', (48, 53))	('splicing', 'MPA', (102, 110))	('SF3B1', 'Gene', '23451', (23, 28))	('neo-epitopes', 'MPA', (227, 239))	('U2AF1', 'Gene', (37, 42))	('mutations', 'Var', (10, 19))
3690	27282250	SRSF2            This gene encodes an SR protein that binds specific exonic splicing enhancer motifs to promote recognition and inclusion of exons containing these motifs              ZRSR2            A gene encoding a component of the minor spliceosome that contacts the 3' splice site of specific U12-type introns to promote their excision Synthetic lethality The situation in which two cellular perturbations (for example, two distinct mutations, or a mutation and a particular drug) result in cell death when combined whereas each perturbation alone does not Secondary AML (sAML) Acute myeloid leukemia that develops following a previous chronic myeloid malignancy such as a myelodysplastic syndrome Cryptic 3' splice sites Potential 3' splice sites that are not normally recognized by the spliceosome.	('Cryptic', 'Gene', '55997', (704, 711))	('SR protein', 'Gene', (38, 48))	('splicing', 'biological_process', 'GO:0045292', ('76', '84'))	('ZRSR2', 'Gene', '8233', (184, 189))	('AML', 'Disease', 'MESH:D015470', (573, 576))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (679, 703))	('AML', 'Phenotype', 'HP:0004808', (573, 576))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (679, 703))	('AML', 'Disease', (573, 576))	('mutation', 'Var', (455, 463))	('chronic myeloid malignancy', 'Phenotype', 'HP:0005506', (642, 668))	('AML', 'Disease', 'MESH:D015470', (579, 582))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('spliceosome', 'cellular_component', 'GO:0005681', ('794', '805'))	('cell death', 'biological_process', 'GO:0008219', ('497', '507'))	('AML', 'Phenotype', 'HP:0004808', (579, 582))	('AML', 'Disease', (579, 582))	('Acute myeloid leukemia', 'Disease', (584, 606))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (584, 606))	('Cryptic', 'Gene', (704, 711))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (584, 606))	('spliceosome', 'cellular_component', 'GO:0005681', ('242', '253'))	('ZRSR2', 'Gene', (184, 189))	('leukemia', 'Phenotype', 'HP:0001909', (598, 606))	('SRSF2', 'Gene', '6427', (0, 5))	('myelodysplastic syndrome', 'Disease', (679, 703))	('myeloid malignancy', 'Disease', (650, 668))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (590, 606))	('SR protein', 'Gene', '10921', (38, 48))	('SRSF2', 'Gene', (0, 5))	('mutations', 'Var', (439, 448))	('myeloid malignancy', 'Disease', 'MESH:D009369', (650, 668))
3695	27282250	Splicing is closely linked to NMD, as exon-exon junctions are important components of NMD activation in human cells RNA polymerase II pause release The process by which RNA polymerase II that is paused (not actively transcribing) after the initiation of transcription is released, enabling transcriptional elongation Frameshift The disruption of an open reading frame by the insertion or deletion of nucleotide sequence whose length is not a multiple of three Expressed sequence tag (EST).	('RNA', 'cellular_component', 'GO:0005562', ('169', '172'))	('deletion of nucleotide sequence', 'Var', (388, 419))	('Splicing', 'biological_process', 'GO:0045292', ('0', '8'))	('human', 'Species', '9606', (104, 109))	('transcriptional', 'MPA', (290, 305))	('transcription', 'biological_process', 'GO:0006351', ('254', '267'))	('RNA', 'cellular_component', 'GO:0005562', ('116', '119'))	('insertion', 'Var', (375, 384))	('enabling', 'PosReg', (281, 289))
3697	27282250	Conversely, focusing on single splicing events may be beneficial when analyzing splicing mechanisms and regulation:for example, the altered motif preferences induced by U2AF1 and SRSF2 mutations:or when a particular alternatively spliced region has an important impact on gene function.	('U2AF', 'cellular_component', 'GO:0089701', ('169', '173'))	('motif preferences', 'MPA', (140, 157))	('SRSF2', 'Gene', (179, 184))	('U2AF1', 'Gene', (169, 174))	('splicing', 'biological_process', 'GO:0045292', ('31', '39'))	('regulation', 'biological_process', 'GO:0065007', ('104', '114'))	('splicing', 'biological_process', 'GO:0045292', ('80', '88'))	('mutations', 'Var', (185, 194))	('impact', 'Reg', (262, 268))	('SRSF2', 'Gene', '6427', (179, 184))
3698	27282250	Therefore, many studies instead measure absolute changes in splicing as Deltapsi, the difference in psi value between two samples, and apply thresholds on Deltapsi to identify potentially important changes in splicing (for example, using U2AF1-mutant (U2AF1 S34F, shown on the y axis) versus wild-type (U2AF WT, shown on the x axis) acute myeloid leukemia (AML) samples, with exons satisfying Deltapsi >= 10% (red) or Deltapsi <= 10% (blue) highlighted; see panel (c) of the figure).	('Deltapsi <= 10%', 'Var', (418, 433))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (333, 355))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (339, 355))	('U2AF', 'cellular_component', 'GO:0089701', ('303', '307'))	('S34F', 'Mutation', 'rs371769427', (258, 262))	('splicing', 'biological_process', 'GO:0045292', ('209', '217'))	('AML', 'Disease', 'MESH:D015470', (357, 360))	('leukemia', 'Phenotype', 'HP:0001909', (347, 355))	('U2AF', 'cellular_component', 'GO:0089701', ('238', '242'))	('acute myeloid leukemia', 'Disease', (333, 355))	('U2AF', 'cellular_component', 'GO:0089701', ('252', '256'))	('AML', 'Disease', (357, 360))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (333, 355))	('AML', 'Phenotype', 'HP:0004808', (357, 360))	('splicing', 'biological_process', 'GO:0045292', ('60', '68'))
3699	27282250	First, many studies seek to identify mechanistic changes in the splicing process itself, such as alterations caused by spliceosomal mutations or global differences between tumor and normal samples.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('splicing', 'biological_process', 'GO:0045292', ('64', '72'))	('tumor', 'Disease', (172, 177))	('spliceosomal mutations', 'Var', (119, 141))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
3704	27282250	Analyses of the hematopoietic transcriptomes of Srsf2P95H conditional knock-in (shown in figure panel a; light pink) and U2AF1S34F transgenic (shown in figure panel b; light green) murine models demonstrated that the mechanistic alterations in exon and splice site recognition induced by these mutations are conserved between human and mouse and validate these murine models for mechanistic studies of the role of splicing alterations in cancer pathogenesis.	('cancer', 'Disease', (438, 444))	('cancer', 'Disease', 'MESH:D009369', (438, 444))	('U2AF', 'cellular_component', 'GO:0089701', ('121', '125'))	('splicing', 'biological_process', 'GO:0045292', ('414', '422'))	('cancer', 'Phenotype', 'HP:0002664', (438, 444))	('murine', 'Species', '10090', (181, 187))	('Srsf2P95H', 'Gene', (48, 57))	('mutations', 'Var', (294, 303))	('human', 'Species', '9606', (326, 331))	('mouse', 'Species', '10090', (336, 341))	('murine', 'Species', '10090', (361, 367))	('pathogenesis', 'biological_process', 'GO:0009405', ('445', '457'))
3712	27282250	recently generated SRSF2P95H knock-in K562 cells to identify the changes in exon recognition and differential splicing induced by SRSF2 mutations.	('SRSF2', 'Gene', (19, 24))	('SRSF2', 'Gene', (130, 135))	('K562', 'CellLine', 'CVCL:0004', (38, 42))	('exon recognition', 'MPA', (76, 92))	('SRSF2', 'Gene', '6427', (19, 24))	('splicing', 'biological_process', 'GO:0045292', ('110', '118'))	('changes', 'Reg', (65, 72))	('mutations', 'Var', (136, 145))	('SRSF2', 'Gene', '6427', (130, 135))	('differential splicing', 'MPA', (97, 118))
3713	27282250	Combined studies of murine models, isogenic human cells, and patient cohorts will likely prove essential to identify the direct targets of mutant spliceosomal proteins with cancer relevance.	('human', 'Species', '9606', (44, 49))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('patient', 'Species', '9606', (61, 68))	('cancer', 'Disease', (173, 179))	('murine', 'Species', '10090', (20, 26))	('mutant', 'Var', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))
3715	27282250	A subset of RNA splicing factors are recurrent targets of specific point mutations in cancer.	('splicing factor', 'Gene', '10569', (16, 31))	('RNA splicing', 'biological_process', 'GO:0008380', ('12', '24'))	('RNA', 'cellular_component', 'GO:0005562', ('12', '15'))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('splicing factor', 'Gene', (16, 31))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('point mutations', 'Var', (67, 82))	('cancer', 'Disease', (86, 92))
3720	26683228	Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4 Next generation sequencing of uveal melanoma (UM) samples has identified a number of recurrent oncogenic or loss-of-function mutations in key driver genes including: GNAQ, GNA11, EIF1AX, SF3B1 and BAP1.	('mutations', 'Var', (200, 209))	('uveal melanoma', 'Disease', 'MESH:C536494', (19, 33))	('uveal melanoma', 'Disease', (19, 33))	('BAP1', 'Gene', (272, 276))	('EIF1AX', 'Gene', '1964', (254, 260))	('PLCB4', 'Gene', (69, 74))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('uveal melanoma', 'Phenotype', 'HP:0007716', (19, 33))	('loss-of-function', 'NegReg', (183, 199))	('SF3B1', 'Gene', (262, 267))	('uveal melanoma', 'Disease', (105, 119))	('GNA11', 'Gene', '2767', (247, 252))	('uveal melanoma', 'Disease', 'MESH:C536494', (105, 119))	('mutation', 'Var', (57, 65))	('GNAQ', 'Gene', '2776', (241, 245))	('uveal melanoma', 'Phenotype', 'HP:0007716', (105, 119))	('GNAQ', 'Gene', (241, 245))	('SF3B1', 'Gene', '23451', (262, 267))	('BAP1', 'Gene', '8314', (272, 276))	('EIF1AX', 'Gene', (254, 260))	('GNA11', 'Gene', (247, 252))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))
3723	26683228	In addition to mutations in the known UM driver genes, we found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM_000933), which was validated using Sanger sequencing.	('p.D630Y', 'Var', (105, 112))	('p.D630Y', 'Mutation', 'p.D630Y', (105, 112))	('PLCB4', 'Gene', (88, 93))	('c.G1888T', 'Var', (95, 103))	('c.G1888T', 'Mutation', 'c.1888G>T', (95, 103))	('PLCB4', 'Gene', '5332', (88, 93))	('NM_000933', 'Var', (114, 123))
3725	26683228	PLCB4 p.D630Y mutations are mutually exclusive with mutations in GNA11 and GNAQ, consistent with PLCB4 being the canonical downstream target of the former gene products.	('PLCB4', 'Gene', (97, 102))	('PLCB4', 'Gene', '5332', (0, 5))	('GNAQ', 'Gene', (75, 79))	('PLCB4', 'Gene', '5332', (97, 102))	('p.D630Y', 'Var', (6, 13))	('GNA11', 'Gene', '2767', (65, 70))	('PLCB4', 'Gene', (0, 5))	('GNA11', 'Gene', (65, 70))	('p.D630Y', 'Mutation', 'p.D630Y', (6, 13))	('GNAQ', 'Gene', '2776', (75, 79))
3726	26683228	Taken together these data suggest that the PLCB4 hotspot mutation is similarly a gain-of-function mutation leading to activation of the same signaling pathway, promoting UM tumorigenesis.	('mutation', 'Var', (57, 65))	('activation', 'PosReg', (118, 128))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('PLCB4', 'Gene', (43, 48))	('promoting', 'PosReg', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('signaling pathway', 'biological_process', 'GO:0007165', ('141', '158'))	('PLCB4', 'Gene', '5332', (43, 48))
3731	26683228	Hotspot GNAQ p.Q209 mutations are found in 45% of primary UM and 22% of metastases, while GNA11 p.Q209 mutations are found in 32% of primary tumors and 57% of UM metastases.	('GNA11', 'Gene', (90, 95))	('metastases', 'Disease', (72, 82))	('metastases', 'Disease', (162, 172))	('p.Q209 mutations', 'Var', (13, 29))	('metastases', 'Disease', 'MESH:D009362', (72, 82))	('metastases', 'Disease', 'MESH:D009362', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('p.Q209', 'Var', (96, 102))	('primary UM', 'Disease', (50, 60))	('mutations', 'Var', (20, 29))
3732	26683228	Overall, 83% of UM acquire mutations in either GNAQ or GNA11.	('mutations', 'Var', (27, 36))	('GNAQ', 'Gene', (47, 51))	('GNAQ', 'Gene', '2776', (47, 51))	('GNA11', 'Gene', '2767', (55, 60))	('GNA11', 'Gene', (55, 60))
3733	26683228	There are also commonly occurring loss-of-function mutations in the tumor suppressor gene BAP1 (BRCA1 associated protein-1) located on chromosome 3.	('tumor', 'Disease', (68, 73))	('BRCA1 associated protein-1', 'Gene', '8314', (96, 122))	('mutations', 'Var', (51, 60))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('68', '84'))	('BAP1', 'Gene', '8314', (90, 94))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('68', '84'))	('loss-of-function', 'NegReg', (34, 50))	('BRCA1 associated protein-1', 'Gene', (96, 122))	('chromosome', 'cellular_component', 'GO:0005694', ('135', '145'))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('BAP1', 'Gene', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
3734	26683228	Approximately 40% of UM harbor inactivating somatic mutations in BAP1, which occur along the length of the gene and generally result in protein truncations.	('mutations', 'Var', (52, 61))	('BAP1', 'Gene', '8314', (65, 69))	('BAP1', 'Gene', (65, 69))	('result in', 'Reg', (126, 135))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('inactivating', 'Reg', (31, 43))	('protein truncations', 'MPA', (136, 155))
3737	26683228	Recurrent mutations in SF3B1 occur at codon 625 in approximately 18% of tumors and are associated with better prognosis, as are mutations in EIF1AX.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('SF3B1', 'Gene', '23451', (23, 28))	('codon 625', 'Var', (38, 47))	('tumors', 'Disease', (72, 78))	('associated', 'Reg', (87, 97))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (10, 19))	('SF3B1', 'Gene', (23, 28))	('EIF1AX', 'Gene', '1964', (141, 147))	('EIF1AX', 'Gene', (141, 147))
3738	26683228	We first assessed mutations in known UM drivers and detected 11 mutations in BAP1 (7 frameshifting indels, 2 splice mutations, 1 nonsense mutation and 1 missense mutation), 14 mutations occurred at GNA11 p.Q209P, 7 mutations occurred at GNAQ p.Q209P and a single mutation at GNAQ p.G48L.	('GNAQ', 'Gene', '2776', (275, 279))	('occurred', 'Reg', (186, 194))	('GNA11', 'Gene', (198, 203))	('p.Q209P', 'Mutation', 'rs1057519742', (242, 249))	('GNAQ', 'Gene', '2776', (237, 241))	('p.Q209P', 'Var', (242, 249))	('GNA11', 'Gene', '2767', (198, 203))	('p.Q209P', 'Var', (204, 211))	('p.Q209P', 'Mutation', 'rs1057519742', (204, 211))	('GNAQ', 'Gene', (275, 279))	('BAP1', 'Gene', '8314', (77, 81))	('p.G48L', 'Mutation', 'p.G48L', (280, 286))	('GNAQ', 'Gene', (237, 241))	('BAP1', 'Gene', (77, 81))
3739	26683228	As expected the mutations in GNA11 and GNAQ were mutually exclusive.	('GNA11', 'Gene', (29, 34))	('GNAQ', 'Gene', (39, 43))	('GNA11', 'Gene', '2767', (29, 34))	('mutations', 'Var', (16, 25))	('GNAQ', 'Gene', '2776', (39, 43))
3740	26683228	We detected 4 mutations occurring in EIF1AX (p.P2L, p.G6V, p.G8R and a splice mutation) which were found to be mutually exclusive with BAP1 mutations.	('EIF1AX', 'Gene', '1964', (37, 43))	('EIF1AX', 'Gene', (37, 43))	('BAP1', 'Gene', '8314', (135, 139))	('p.P2L', 'Mutation', 'p.P2L', (45, 50))	('p.G8R', 'Var', (59, 64))	('BAP1', 'Gene', (135, 139))	('p.G8R', 'Mutation', 'p.G8R', (59, 64))	('p.G6V', 'Var', (52, 57))	('p.G6V', 'Mutation', 'p.G6V', (52, 57))	('p.P2L', 'Var', (45, 50))
3741	26683228	We also detected 3 mutations in SFB31: p.R625C, p.R625H and p.K666T (Table 1, Supplementary Table 2).	('p.R625C', 'Var', (39, 46))	('p.R625H', 'Mutation', 'rs1057519961', (48, 55))	('p.R625H', 'Var', (48, 55))	('p.K666T', 'Mutation', 'rs374250186', (60, 67))	('p.K666T', 'Var', (60, 67))	('SFB31', 'Gene', (32, 37))	('p.R625C', 'Mutation', 'rs775623976', (39, 46))
3742	26683228	PLCB4, phospholipase C, beta 4, was the only other gene that had a recurrent mutation (c.G1888T, p.D630Y, chr20:9389753, NM_000933), which occurred in 2 of 28 samples.	('p.D630Y', 'Var', (97, 104))	('p.D630Y', 'Mutation', 'p.D630Y', (97, 104))	('PLCB4', 'Gene', '5332', (0, 5))	('c.G1888T', 'Var', (87, 95))	('c.G1888T', 'Mutation', 'c.1888G>T', (87, 95))	('PLCB4', 'Gene', (0, 5))	('phospholipase C, beta 4', 'Gene', '5332', (7, 30))
3747	26683228	Interestingly, in addition to the hotspot PLCB4 mutation, 1 of 28 UM samples had a novel mutation in PLCB3, phospholipase C beta 3 (c.G2694C, p.K898N, chr11:64032834, NM_001184883).	('PLCB4', 'Gene', '5332', (42, 47))	('phospholipase C beta 3', 'Gene', '5331', (108, 130))	('phospholipase C beta 3', 'Gene', (108, 130))	('p.K898N', 'Mutation', 'p.K898N', (142, 149))	('c.G2694C', 'Mutation', 'c.2694G>C', (132, 140))	('PLCB4', 'Gene', (42, 47))	('PLCB3', 'Gene', '5331', (101, 106))	('p.K898N', 'Var', (142, 149))	('c.G2694C', 'Var', (132, 140))	('PLCB3', 'Gene', (101, 106))
3748	26683228	The location of this mutation is within the CTD linker which plays a significant role in GNAQ activation.	('GNAQ', 'Gene', (89, 93))	('GNAQ', 'Gene', '2776', (89, 93))	('mutation', 'Var', (21, 29))
3749	26683228	The two samples we identified with PLCB4 mutations did not have mutations in either GNAQ or GNA11.	('mutations', 'Var', (41, 50))	('GNA11', 'Gene', (92, 97))	('GNAQ', 'Gene', (84, 88))	('GNA11', 'Gene', '2767', (92, 97))	('PLCB4', 'Gene', '5332', (35, 40))	('GNAQ', 'Gene', '2776', (84, 88))	('PLCB4', 'Gene', (35, 40))
3750	26683228	A search of mutations in other UM WGS/WES data sets identified the same PLCB4 mutation in 1 of 56 samples, which also occurred mutually exclusive to GNAQ and GNA11 mutations.	('GNAQ', 'Gene', (149, 153))	('mutation', 'Var', (78, 86))	('PLCB4', 'Gene', '5332', (72, 77))	('GNAQ', 'Gene', '2776', (149, 153))	('GNA11', 'Gene', (158, 163))	('GNA11', 'Gene', '2767', (158, 163))	('PLCB4', 'Gene', (72, 77))
3751	26683228	Taken together these data suggest that the PLCB4 hotspot mutation is similarly a gain-of-function mutation leading to activation of the same signaling pathway.	('mutation', 'Var', (57, 65))	('PLCB4', 'Gene', (43, 48))	('gain-of-function', 'PosReg', (81, 97))	('signaling pathway', 'biological_process', 'GO:0007165', ('141', '158'))	('PLCB4', 'Gene', '5332', (43, 48))
3753	26683228	Consistent with this notion, none of the 159 reported non-synonymous PLCB4 mutations in CMM occur at the recurrent hotspot we observe in UM.	('PLCB4', 'Gene', (69, 74))	('PLCB4', 'Gene', '5332', (69, 74))	('mutations', 'Var', (75, 84))
3756	26683228	Two missense mutations were found in each of MUC3A, TCHH, TTN and LLGL1.	('MUC3A', 'Gene', '4584', (45, 50))	('LLGL1', 'Gene', '3996', (66, 71))	('TCHH', 'Gene', (52, 56))	('TTN', 'Gene', (58, 61))	('TCHH', 'Gene', '7062', (52, 56))	('missense mutations', 'Var', (4, 22))	('TTN', 'Gene', '7273', (58, 61))	('MUC3A', 'Gene', (45, 50))	('LLGL1', 'Gene', (66, 71))
3757	26683228	Only the latter has previously been associated with cancer, being a tumor suppressor in glioblastoma and oesophageal squamous cell carcinoma, aberrantly spliced in hepatocellular carcinoma and with reduced expression contributing to disease progression in CMM.	('CMM', 'Disease', (256, 259))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('68', '84'))	('oesophageal squamous cell carcinoma', 'Disease', (105, 140))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (164, 188))	('tumor', 'Disease', (68, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 140))	('tumor suppressor', 'biological_process', 'GO:0051726', ('68', '84'))	('contributing', 'Reg', (217, 229))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('hepatocellular carcinoma', 'Disease', (164, 188))	('glioblastoma', 'Disease', 'MESH:D005909', (88, 100))	('expression', 'MPA', (206, 216))	('reduced', 'NegReg', (198, 205))	('cancer', 'Disease', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('glioblastoma', 'Disease', (88, 100))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('glioblastoma', 'Phenotype', 'HP:0012174', (88, 100))	('aberrantly spliced', 'Var', (142, 160))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (164, 188))
3761	26683228	Notably, all samples with BAP1 mutation (n=6) were hemizygous for chromosome 3.	('BAP1', 'Gene', (26, 30))	('chromosome', 'cellular_component', 'GO:0005694', ('66', '76'))	('mutation', 'Var', (31, 39))	('BAP1', 'Gene', '8314', (26, 30))
3764	26683228	To assess whether this aberration occurred early or late in the tumor development, we examined the variant allele frequency (VAF) for the somatic mutations on chromosome 8q.	('tumor', 'Disease', (64, 69))	('mutations', 'Var', (146, 155))	('chromosome', 'cellular_component', 'GO:0005694', ('159', '169'))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
3770	26683228	The majority of tumors presented with a BRCA mutation signature, and as expected these sun-shielded melanomas had no ultraviolet radiation signature.	('presented', 'Reg', (23, 32))	('melanomas', 'Disease', 'MESH:D008545', (100, 109))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('BRCA', 'Gene', '672', (40, 44))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('melanomas', 'Disease', (100, 109))	('mutation', 'Var', (45, 53))	('BRCA', 'Gene', (40, 44))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('tumors', 'Disease', (16, 22))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))
3771	26683228	Analysis of SNVs identified a novel recurrent mutation in PLCB4 (p.D630Y).	('PLCB4', 'Gene', (58, 63))	('p.D630Y', 'Var', (65, 72))	('p.D630Y', 'Mutation', 'p.D630Y', (65, 72))	('PLCB4', 'Gene', '5332', (58, 63))
3774	26683228	This novel mutation is a likely driver in UM and occurs mutually exclusively with GNAQ/GNA11 mutations.	('mutations', 'Var', (93, 102))	('GNAQ', 'Gene', (82, 86))	('mutation', 'Var', (11, 19))	('GNA11', 'Gene', '2767', (87, 92))	('GNA11', 'Gene', (87, 92))	('GNAQ', 'Gene', '2776', (82, 86))
3775	26683228	Taken together these data suggest that the PLCB4 hotspot mutation is a gain-of-function mutation leading to activation of the same signaling pathway.	('mutation', 'Var', (57, 65))	('signaling pathway', 'biological_process', 'GO:0007165', ('131', '148'))	('PLCB4', 'Gene', (43, 48))	('gain-of-function', 'PosReg', (71, 87))	('same signaling pathway', 'Pathway', (126, 148))	('PLCB4', 'Gene', '5332', (43, 48))	('activation', 'PosReg', (108, 118))
3782	26683228	Non-frameshift variants that passed this set of filtering criteria were hand-curated, whereby variants in regions of trinucleotide expansions or reductions were removed from the dataset as they are likely due to poor mapping.	('trinucleotide', 'Chemical', '-', (117, 130))	('reductions', 'NegReg', (145, 155))	('trinucleotide expansions', 'Var', (117, 141))
3787	26683228	To infer the fraction of mutations on chromosome 8q that occurred before the arm was duplicated, we built a mixed model allowing for different fractions, copy numbers, cn, and tumor content, tc.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('copy', 'Var', (154, 158))	('chromosome', 'cellular_component', 'GO:0005694', ('38', '48'))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
3788	26683228	Sanger sequencing was used to confirm BAP1, SF3B1 and EIF1AX variants found by WGS/WES.	('SF3B1', 'Gene', (44, 49))	('BAP1', 'Gene', (38, 42))	('EIF1AX', 'Gene', '1964', (54, 60))	('EIF1AX', 'Gene', (54, 60))	('SF3B1', 'Gene', '23451', (44, 49))	('variants', 'Var', (61, 69))	('BAP1', 'Gene', '8314', (38, 42))
3790	26683228	While this manuscript was under review, the TCGA UM data were released (11/14/2015), which identified 2/80 samples with mutations in codon p.D630 of PLCB4.	('PLCB4', 'Gene', (149, 154))	('PLCB4', 'Gene', '5332', (149, 154))	('mutations in codon p.D630', 'Var', (120, 145))
3791	26683228	Sample TCGA-VD-A8KD carries two mutations at adjacent bases in the same codon, c.G1888T and c.A1889T, which if they are biallelic result in amino acid changes p.D630Y (the same mutation we describe here) and p.D630V, respectively, or if they occur on the same allele translate to p.D630F.	('p.D630V', 'Var', (208, 215))	('c.G1888T', 'Var', (79, 87))	('p.D630Y', 'Mutation', 'p.D630Y', (159, 166))	('p.D630V', 'Mutation', 'p.D630V', (208, 215))	('c.A1889T', 'Mutation', 'rs1135402824', (92, 100))	('c.A1889T', 'Var', (92, 100))	('c.G1888T', 'Mutation', 'c.1888G>T', (79, 87))	('p.D630F', 'SUBSTITUTION', 'None', (280, 287))	('p.D630F', 'Var', (280, 287))	('p.D630Y', 'Var', (159, 166))
3792	26683228	Sample TCGA-YZ-A985 carries a c.G1888A mutation resulting in amino acid change p.D630N.	('p.D630N', 'Var', (79, 86))	('p.D630N', 'Mutation', 'rs1318401996', (79, 86))	('c.G1888A', 'Mutation', 'rs751795238', (30, 38))	('c.G1888A', 'Var', (30, 38))
3805	26419610	The small-molecule WP1130 inhibits several DUBs and triggers apoptosis in cancer cells; the identification of novel DUB inhibitors is important for cancer therapy.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('WP1130', 'Var', (19, 25))	('apoptosis', 'CPA', (61, 70))	('inhibits', 'NegReg', (26, 34))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('P', 'Chemical', 'MESH:D010758', (20, 21))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', (74, 80))	('DUBs', 'MPA', (43, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('triggers', 'Reg', (52, 60))
3821	26419610	Protein levels of p27, a KLF5 inhibited target gene (see details below), were also upregulated by the knockdown of these DUBs (Fig.	('P', 'Chemical', 'MESH:D010758', (0, 1))	('p27', 'Gene', '10671', (18, 21))	('knockdown', 'Var', (102, 111))	('p27', 'Gene', (18, 21))	('upregulated', 'PosReg', (83, 94))	('Protein levels', 'MPA', (0, 14))
3824	26419610	In addition, BAP1 is frequently mutated in mesothelioma, uveal melanoma, melanocytic tumour, renal cell carcinoma and other cancers.	('renal cell carcinoma', 'Disease', (93, 113))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (93, 113))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('mesothelioma', 'Disease', (43, 55))	('melanocytic tumour', 'Disease', 'MESH:D009508', (73, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('mesothelioma', 'Disease', 'MESH:D008654', (43, 55))	('uveal melanoma', 'Disease', (57, 71))	('BAP1', 'Gene', (13, 17))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (93, 113))	('melanocytic tumour', 'Disease', (73, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('mutated', 'Var', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
3828	26419610	Moreover, RNA-mediated depletion of BAP1 promoted cell cycle G1-S progression.	('RNA', 'cellular_component', 'GO:0005562', ('10', '13'))	('depletion', 'Var', (23, 32))	('promoted', 'PosReg', (41, 49))	('cell cycle', 'biological_process', 'GO:0007049', ('50', '60'))	('S', 'Chemical', 'MESH:D013455', (64, 65))	('BAP1', 'Gene', (36, 40))	('cell cycle G1-S progression', 'CPA', (50, 77))
3829	26419610	In sharp contrast, RNA interference-mediated depletion of BAP1-induced cell cycle progression defects and inhibited cell proliferation in vitro, suggesting that BAP1 may have dual roles in cancer development.	('cell proliferation', 'biological_process', 'GO:0008283', ('116', '134'))	('BAP1-induced', 'Gene', (58, 70))	('RNA interference-mediated', 'MPA', (19, 44))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('inhibited', 'NegReg', (106, 115))	('RNA interference', 'biological_process', 'GO:0016246', ('19', '35'))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('RNA', 'cellular_component', 'GO:0005562', ('19', '22'))	('cell cycle progression', 'CPA', (71, 93))	('cell cycle', 'biological_process', 'GO:0007049', ('71', '81'))	('depletion', 'Var', (45, 54))	('cell proliferation in vitro', 'CPA', (116, 143))	('defects', 'NegReg', (94, 101))	('cancer', 'Disease', (189, 195))
3832	26419610	BAP1 knockdown decreased the endogenous protein levels of KLF5 and its downstream target gene FGF-BP (Fig.	('BAP1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('FGF-BP', 'Gene', '9982', (94, 100))	('decreased', 'NegReg', (15, 24))	('endogenous protein levels of KLF5', 'MPA', (29, 62))	('FGF-BP', 'Gene', (94, 100))
3839	26419610	The KLF5 mRNA levels were not decreased by BAP1 knockdown in the MCF10A and HCC1806 cells (Supplementary Fig.	('BAP1', 'Gene', (43, 47))	('KLF5 mRNA levels', 'MPA', (4, 20))	('MCF10A', 'CellLine', 'CVCL:0598', (65, 71))	('S', 'Chemical', 'MESH:D013455', (91, 92))	('HCC1806', 'CellLine', 'CVCL:1258', (76, 83))	('knockdown', 'Var', (48, 57))
3844	26419610	To further investigate whether endogenous BAP1 protects KLF5 protein from degradation, we knocked down BAP1 using two different siRNAs in MCF10A cells and measured the KLF5 protein half-lives with the cycloheximide chase assay.	('MCF10A', 'CellLine', 'CVCL:0598', (138, 144))	('cycloheximide', 'Chemical', 'MESH:D003513', (201, 214))	('BAP1', 'Gene', (103, 107))	('protein', 'cellular_component', 'GO:0003675', ('173', '180'))	('knocked', 'Var', (90, 97))	('degradation', 'biological_process', 'GO:0009056', ('74', '85'))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
3845	26419610	In addition, we measured the exogenous KLF5 protein half-lives after we overexpressed WT BAP1 and BAP1-C91S in HEK293FT cells.	('exogenous KLF5 protein half-lives', 'MPA', (29, 62))	('HEK293FT', 'CellLine', 'CVCL:6911', (111, 119))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('BAP1-C91S', 'Var', (98, 107))	('C91S', 'Mutation', 'p.C91S', (103, 107))
3846	26419610	The KLF5 protein half-life was extended from 60 to 120 min by WT BAP1, but not by BAP1-C91S (Fig.	('KLF5 protein', 'Protein', (4, 16))	('BAP1', 'Var', (65, 69))	('extended', 'PosReg', (31, 39))	('protein', 'cellular_component', 'GO:0003675', ('9', '16'))	('C91S', 'Mutation', 'p.C91S', (87, 91))
3849	26419610	BAP1, but not BAP1-C91S, markedly decreased KLF5 protein polyubiquitination (Fig.	('decreased', 'NegReg', (34, 43))	('protein polyubiquitination', 'biological_process', 'GO:0000209', ('49', '75'))	('C91S', 'Mutation', 'p.C91S', (19, 23))	('BAP1', 'Var', (0, 4))	('protein polyubiquitination', 'Disease', (49, 75))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('protein polyubiquitination', 'Disease', 'MESH:D011488', (49, 75))
3858	26419610	Finally, we demonstrated that knockdown of endogenous BAP1 increased the ubiquitination of endogenous KLF5 in HCC1806 (Fig.	('HCC1806', 'CellLine', 'CVCL:1258', (110, 117))	('knockdown', 'Var', (30, 39))	('increased', 'PosReg', (59, 68))	('BAP1', 'Gene', (54, 58))	('ubiquitination of endogenous KLF5', 'MPA', (73, 106))
3867	26419610	To identify which regions of BAP1 are responsible for the KLF5 interaction, we generated a series of GST-fused BAP1 deletion mutants and transfected them into HEK293FT cells with KLF5-3 x Flag.	('deletion mutants', 'Var', (116, 132))	('mutants', 'Var', (125, 132))	('BAP1', 'Gene', (111, 115))	('S', 'Chemical', 'MESH:D013455', (102, 103))	('HEK293FT', 'CellLine', 'CVCL:6911', (159, 167))
3880	26419610	As expected, knockdown of BAP1, HCF-1, OGT or KLF5 markedly increased p27 and decreased FGF-BP protein levels in HCC1806 cells (Fig.	('OGT', 'Gene', (39, 42))	('BAP1', 'Gene', (26, 30))	('HCC1806', 'CellLine', 'CVCL:1258', (113, 120))	('OGT', 'Gene', '8473', (39, 42))	('p27', 'Gene', '10671', (70, 73))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('decreased', 'NegReg', (78, 87))	('p27', 'Gene', (70, 73))	('FGF-BP', 'Gene', '9982', (88, 94))	('HCF-1', 'Gene', (32, 37))	('FGF-BP', 'Gene', (88, 94))	('knockdown', 'Var', (13, 22))	('increased', 'PosReg', (60, 69))	('HCF-1', 'Gene', '3054', (32, 37))
3885	26419610	Because the BAP1/KLF5/HCF-1 protein complex inhibited p27 expression, we examined the cell cycle distribution after knocking down KLF5, BAP1, HCF-1 and OGT, respectively, in HCC1806 cells.	('OGT', 'Gene', '8473', (152, 155))	('BAP1', 'Gene', (136, 140))	('HCC1806', 'CellLine', 'CVCL:1258', (174, 181))	('expression', 'MPA', (58, 68))	('inhibited', 'NegReg', (44, 53))	('protein complex', 'cellular_component', 'GO:0032991', ('28', '43'))	('HCF-1', 'Gene', '3054', (142, 147))	('HCF-1', 'Gene', (142, 147))	('p27', 'Gene', (54, 57))	('examined', 'Reg', (73, 81))	('p27', 'Gene', '10671', (54, 57))	('cell cycle', 'biological_process', 'GO:0007049', ('86', '96'))	('HCF-1', 'Gene', '3054', (22, 27))	('KLF5', 'Gene', (130, 134))	('HCF-1', 'Gene', (22, 27))	('knocking', 'Var', (116, 124))	('OGT', 'Gene', (152, 155))
3886	26419610	As expected, the number of G1-phase cells were significantly increased and the number of S-phase cells significantly decreased when KLF5, BAP1, HCF-1 or OGT were knocked down (Fig.	('OGT', 'Gene', (153, 156))	('G1-phase cells', 'CPA', (27, 41))	('OGT', 'Gene', '8473', (153, 156))	('HCF-1', 'Gene', '3054', (144, 149))	('HCF-1', 'Gene', (144, 149))	('S-phase', 'biological_process', 'GO:0051320', ('89', '96'))	('G1-phase', 'biological_process', 'GO:0051318', ('27', '35'))	('decreased', 'NegReg', (117, 126))	('KLF5', 'Gene', (132, 136))	('BAP1', 'Gene', (138, 142))	('increased', 'PosReg', (61, 70))	('knocked down', 'Var', (162, 174))	('S', 'Chemical', 'MESH:D013455', (89, 90))
3888	26419610	The G1-phase arrest induced by the knockdown of any component of the KLF5/BAP1/HCF-1 protein complex was rescued by the depletion of p27 (Fig.	('knockdown', 'Var', (35, 44))	('arrest', 'Disease', (13, 19))	('HCF-1', 'Gene', (79, 84))	('p27', 'Gene', (133, 136))	('HCF-1', 'Gene', '3054', (79, 84))	('depletion', 'Var', (120, 129))	('protein complex', 'cellular_component', 'GO:0032991', ('85', '100'))	('G1-phase', 'biological_process', 'GO:0051318', ('4', '12'))	('p27', 'Gene', '10671', (133, 136))	('arrest', 'Disease', 'MESH:D006323', (13, 19))
3892	26419610	We knocked down BAP1 in HCC1806 cells using two different siRNAs and examined DNA synthesis.	('DNA', 'MPA', (78, 81))	('HCC1806', 'CellLine', 'CVCL:1258', (24, 31))	('knocked', 'Var', (3, 10))	('examined', 'Reg', (69, 77))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))	('BAP1', 'Gene', (16, 20))	('DNA synthesis', 'biological_process', 'GO:0071897', ('78', '91'))
3902	26419610	5A,B, BAP1 overexpression elevated the KLF5 protein level, decreased the p27 protein level and significantly promoted cell growth.	('KLF5 protein level', 'MPA', (39, 57))	('cell growth', 'CPA', (118, 129))	('promoted', 'PosReg', (109, 117))	('BAP1', 'Gene', (6, 10))	('decreased', 'NegReg', (59, 68))	('overexpression', 'Var', (11, 25))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('cell growth', 'biological_process', 'GO:0016049', ('118', '129'))	('p27', 'Gene', '10671', (73, 76))	('elevated', 'PosReg', (26, 34))	('p27', 'Gene', (73, 76))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))
3905	26419610	During a 1-month period, BAP1 and KLF5 knockdown cancer cells grew significantly slower than the Lucsh control cells (Fig.	('grew', 'CPA', (62, 66))	('KLF5', 'Gene', (34, 38))	('BAP1', 'Gene', (25, 29))	('slower', 'NegReg', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('knockdown', 'Var', (39, 48))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
3906	26419610	The average tumour weights of BAP1sh#3, BAP1sh#6 and KLF5sh xenografts were significantly less than that of the Lucsh xenografts at day 28 (Fig.	('less', 'NegReg', (90, 94))	('BAP1sh#3', 'Gene', (30, 38))	('BAP1sh#3', 'Gene', '8314;10458;8938', (30, 38))	('tumour', 'Disease', (12, 18))	('BAP1sh#6', 'Var', (40, 48))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumour', 'Disease', 'MESH:D009369', (12, 18))
3907	26419610	It is clear that KLF5 knockdown inhibits tumour growth much more than BAP1 knockdown in this model (Fig.	('tumour growth', 'Disease', (41, 54))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour growth', 'Disease', 'MESH:D006130', (41, 54))	('knockdown', 'Var', (22, 31))	('inhibits', 'NegReg', (32, 40))
3909	26419610	Transient overexpression of KLF5 partially but significantly rescued the BAP1 knockdown-induced tumour growth suppression (Fig.	('tumour growth suppression', 'Disease', 'MESH:D006130', (96, 121))	('BAP1', 'Gene', (73, 77))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('knockdown-induced', 'Var', (78, 95))	('tumour growth suppression', 'Disease', (96, 121))
3913	26419610	Somatic mutation of BAP1 has been shown to associate with metastasis in uveal melanoma.	('S', 'Chemical', 'MESH:D013455', (0, 1))	('uveal melanoma', 'Disease', (72, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('BAP1', 'Gene', (20, 24))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('associate with', 'Reg', (43, 57))	('Somatic mutation', 'Var', (0, 16))	('metastasis', 'CPA', (58, 68))
3917	26419610	Consistently, silence of BAP1 or KLF5 expression significantly decreased the invasion of HCC1937 cells in transwell matrigel invasion assays (Fig.	('BAP1', 'Gene', (25, 29))	('silence', 'Var', (14, 21))	('decreased', 'NegReg', (63, 72))	('HCC1937', 'CellLine', 'CVCL:0290', (89, 96))	('KLF5', 'Gene', (33, 37))
3918	26419610	Pilot experimental results demonstrated that neither HCC1806 nor HCC1937 metastasized to distant vital organs after implanting cancer cells into the mammary fat pads of nude mice.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('nude mice', 'Species', '10090', (169, 178))	('HCC1937', 'Gene', (65, 72))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('HCC1937', 'CellLine', 'CVCL:0290', (65, 72))	('HCC1806', 'CellLine', 'CVCL:1258', (53, 60))	('cancer', 'Disease', (127, 133))	('HCC1806', 'Var', (53, 60))	('metastasized', 'CPA', (73, 85))
3924	26419610	We killed all of the mice on day 32 and found that knockdown of BAP1 or KLF5 significantly decreased lung metastasis according to ex vivo bioluminescence imaging (Fig.	('mice', 'Species', '10090', (21, 25))	('knockdown', 'Var', (51, 60))	('lung metastasis', 'CPA', (101, 116))	('KLF5', 'Gene', (72, 76))	('bioluminescence', 'biological_process', 'GO:0008218', ('138', '153'))	('decreased lung', 'Phenotype', 'HP:0002089', (91, 105))	('decreased', 'NegReg', (91, 100))	('BAP1', 'Gene', (64, 68))
3925	26419610	Transient KLF5 overexpression in 4T1 cells partially rescued BAP1 knockdown-induced metastasis inhibition (Fig.	('metastasis inhibition', 'CPA', (84, 105))	('knockdown-induced', 'Var', (66, 83))	('BAP1', 'Gene', (61, 65))	('4T1', 'CellLine', 'CVCL:0125', (33, 36))
3942	26419610	demonstrated that BAP1 knockdown in MCF10A suppressed cell growth in a DUB activity-dependent manner, while BAP1-C91S overexpression inhibited cell growth by interacting with HCF-1.	('MCF10A', 'Gene', (36, 42))	('HCF-1', 'Gene', (175, 180))	('cell growth', 'biological_process', 'GO:0016049', ('143', '154'))	('HCF-1', 'Gene', '3054', (175, 180))	('inhibited', 'NegReg', (133, 142))	('knockdown', 'Var', (23, 32))	('C91S', 'Mutation', 'p.C91S', (113, 117))	('interacting', 'Interaction', (158, 169))	('cell growth', 'CPA', (54, 65))	('BAP1', 'Gene', (18, 22))	('BAP1-C91S', 'Var', (108, 117))	('MCF10A', 'CellLine', 'CVCL:0598', (36, 42))	('cell growth', 'CPA', (143, 154))	('cell growth', 'biological_process', 'GO:0016049', ('54', '65'))	('suppressed', 'NegReg', (43, 53))
3944	26419610	showed that BAP1 overexpression in BAP1-null malignant pleural mesothelioma cell lines promoted cell proliferation and that BAP1 knockdown decreased proliferation in three malignant pleural mesothelioma cell lines.	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (172, 202))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (45, 75))	('knockdown', 'Var', (129, 138))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (182, 202))	('BAP1', 'Gene', (124, 128))	('proliferation', 'CPA', (149, 162))	('cell proliferation', 'CPA', (96, 114))	('decreased', 'NegReg', (139, 148))	('malignant pleural mesothelioma', 'Disease', (172, 202))	('malignant pleural mesothelioma', 'Disease', (45, 75))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (55, 75))	('cell proliferation', 'biological_process', 'GO:0008283', ('96', '114'))	('promoted', 'PosReg', (87, 95))	('BAP1', 'Gene', (12, 16))
3945	26419610	In this study, we showed that BAP1 knockdown decreased DNA synthesis, the number of S-phase cells and cell growth in HCC1806 cells.	('knockdown', 'Var', (35, 44))	('BAP1', 'Gene', (30, 34))	('HCC1806', 'CellLine', 'CVCL:1258', (117, 124))	('DNA synthesis', 'biological_process', 'GO:0071897', ('55', '68'))	('S', 'Chemical', 'MESH:D013455', (84, 85))	('decreased', 'NegReg', (45, 54))	('number of S-phase cells', 'CPA', (74, 97))	('S-phase', 'biological_process', 'GO:0051320', ('84', '91'))	('cell growth', 'biological_process', 'GO:0016049', ('102', '113'))	('cell growth', 'CPA', (102, 113))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('DNA synthesis', 'MPA', (55, 68))
3947	26419610	In both models, BAP1 knockdown-induced growth and metastasis inhibition was partially rescued by overexpression of KLF5 (Figs 5 and 6; Supplementary Fig.	('knockdown-induced', 'Var', (21, 38))	('BAP1', 'Gene', (16, 20))	('S', 'Chemical', 'MESH:D013455', (135, 136))
3970	26419610	Interestingly, a high level of BAP1 mRNA is associated with long relapse-free survival (Supplementary Fig.	('long relapse-free survival', 'CPA', (60, 86))	('high', 'Var', (17, 21))	('S', 'Chemical', 'MESH:D013455', (88, 89))	('BAP1', 'Gene', (31, 35))
3984	26419610	The mouse anti-p27 (#610241) monoclonal antibody was from BD Biosciences.	('mouse', 'Species', '10090', (4, 9))	('antibody', 'cellular_component', 'GO:0042571', ('40', '48'))	('antibody', 'cellular_component', 'GO:0019814', ('40', '48'))	('antibody', 'cellular_component', 'GO:0019815', ('40', '48'))	('p27', 'Gene', '10671', (15, 18))	('#610241', 'Var', (20, 27))	('antibody', 'molecular_function', 'GO:0003823', ('40', '48'))	('p27', 'Gene', (15, 18))
3985	26419610	The rabbit anti-HCF-1 (A301-399A) polyclonal antibody was from Bethyl Laboratories.	('antibody', 'cellular_component', 'GO:0019815', ('45', '53'))	('antibody', 'cellular_component', 'GO:0019814', ('45', '53'))	('antibody', 'molecular_function', 'GO:0003823', ('45', '53'))	('rabbit', 'Species', '9986', (4, 10))	('antibody', 'cellular_component', 'GO:0042571', ('45', '53'))	('HCF-1', 'Gene', '3054', (16, 21))	('HCF-1', 'Gene', (16, 21))	('A301-399A', 'Var', (23, 32))
3988	26419610	The anti-K48-polyubiquitin (#8081) and anti-K63-polyubiquitin (#5621) rabbit polyclonal were purchased from Cell Signaling.	('rabbit', 'Species', '9986', (70, 76))	('#8081', 'Var', (28, 33))	('polyubiquitin', 'biological_process', 'GO:0000209', ('48', '61'))	('polyubiquitin', 'molecular_function', 'GO:0005552', ('13', '26'))	('polyubiquitin', 'biological_process', 'GO:0000209', ('13', '26'))	('Signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('#5621', 'Var', (63, 68))	('polyubiquitin', 'molecular_function', 'GO:0005552', ('48', '61'))	('S', 'Chemical', 'MESH:D013455', (113, 114))
4019	26419610	Twenty-four NOD-SCID mice were haphazardly distributed into four groups (Lucsh, BAP1#3sh, BAP1#6sh and KLF5sh; six mice per group).	('BAP1#6sh', 'Var', (90, 98))	('NOD', 'Gene', '1822', (12, 15))	('mice', 'Species', '10090', (21, 25))	('S', 'Chemical', 'MESH:D013455', (16, 17))	('NOD', 'Gene', (12, 15))	('mice', 'Species', '10090', (115, 119))
4049	25761109	UM is genetically distinct from cutaneous melanoma, with 80% to 90% of UMs showing activating mutations in GNAQ or GNA11 and lacking activating mutations in BRAF, NRAS and TERT promoter.	('GNA11', 'Gene', '2767', (115, 120))	('NRAS', 'Gene', (163, 167))	('mutations', 'Var', (94, 103))	('NRAS', 'Gene', '4893', (163, 167))	('BRAF', 'Gene', '673', (157, 161))	('GNAQ', 'Gene', '2776', (107, 111))	('TERT', 'Gene', (172, 176))	('cutaneous melanoma', 'Disease', (32, 50))	('activating', 'PosReg', (83, 93))	('BRAF', 'Gene', (157, 161))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (32, 50))	('TERT', 'Gene', '7015', (172, 176))	('GNA11', 'Gene', (115, 120))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (32, 50))	('GNAQ', 'Gene', (107, 111))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
4051	25761109	To date, the improved understanding of the molecular biology of UM has not yet translated to successful treatment with targeted therapies, but clinical trials with protein kinase C (PKC) and MEK inhibitors (NCT01801358) as well as other agents such as the multikinase inhibitor sorafenib (NCT01377025), the c-Met/VEGFR2 inhibitor cabozantinib (NCT01835145) and the histone-deacetylase inhibitor vorinostat (NCT01587352) are in progress.	('cabozantinib', 'Chemical', 'MESH:C558660', (330, 342))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('VEGFR2', 'Gene', (313, 319))	('NCT01801358', 'Var', (207, 218))	('VEGFR2', 'Gene', '3791', (313, 319))	('c-Met', 'Gene', (307, 312))	('protein kinase C', 'Gene', '112476', (164, 180))	('PKC', 'Gene', '112476', (182, 185))	('PKC', 'molecular_function', 'GO:0004697', ('182', '185'))	('NCT01587352', 'Var', (407, 418))	('protein kinase C', 'Gene', (164, 180))	('NCT01377025', 'Var', (289, 300))	('MEK', 'Gene', '5609', (191, 194))	('PKC', 'Gene', (182, 185))	('sorafenib', 'Chemical', 'MESH:D000077157', (278, 287))	('vorinostat', 'Chemical', 'MESH:D000077337', (395, 405))	('c-Met', 'Gene', '4233', (307, 312))	('MEK', 'Gene', (191, 194))	('NCT01835145', 'Var', (344, 355))
4091	25761109	the presence of brain metastases, the number of prior therapies (0 vs. >= 1), the lactate dehydrogenase (LDH) level prior to receiving ipilimumab (<2-fold upper level norm (ULN) vs.>= 2xULN), the number of ipilimumab doses (<4 vs. 4), and the absolute lymphocyte count (ALC) (<1000/mul vs. >=1000/mul) before the first (week 1), the second (week 4) and the third dose (week 7) of ipilimumab.	('ipilimumab', 'Chemical', 'MESH:D000074324', (206, 216))	('ipilimumab', 'Chemical', 'MESH:D000074324', (380, 390))	('ipilimumab', 'Chemical', 'MESH:D000074324', (135, 145))	('brain metastases', 'Disease', 'MESH:D009362', (16, 32))	('<1000/mul', 'Var', (276, 285))	('brain metastases', 'Disease', (16, 32))	('lactate', 'MPA', (82, 89))	('ALC', 'Chemical', '-', (270, 273))
4107	25761109	The 1-year OS rate was higher in patients with a LDH level < 2xULN (33% vs. 5%, p<0.0001; Fig.	('< 2xULN', 'Var', (59, 66))	('OS', 'Chemical', '-', (11, 13))	('LDH', 'MPA', (49, 52))	('patients', 'Species', '9606', (33, 41))	('higher', 'PosReg', (23, 29))	('OS rate', 'MPA', (11, 18))
4219	32712709	Hyperplasia (localized non-neoplastic proliferation) of choroidal melanocytes focally, stimulated by local environmental conditions or by minor non-neoplastic mutations affecting a limited clone of these cells, could also account for some discrete small, flat melanocytic choroidal lesions.	('flat melanocytic choroidal lesions', 'Disease', (255, 289))	('Hyperplasia', 'Disease', (0, 11))	('mutations', 'Var', (159, 168))	('men', 'Species', '9606', (114, 117))	('neoplastic proliferation', 'Phenotype', 'HP:0002664', (27, 51))	('choroidal melanocytes', 'Phenotype', 'HP:0012054', (56, 77))	('flat melanocytic choroidal lesions', 'Disease', 'MESH:D005413', (255, 289))	('Hyperplasia', 'Disease', 'MESH:D006965', (0, 11))
4246	33067881	The panoramic picture of pepsinogen gene family with pan-cancer The panoramic picture of pepsinogen gene family with pan-cancer It is well known that pepsinogen (PGs), as an important precursor of pepsin performing digestive function, has a good correlation with the occurrence and development of gastric cancer and it is also known that ectopic PGs expression is related to the prognosis of some cancers.	('correlation', 'Reg', (246, 257))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (57, 63))	('related', 'Reg', (364, 371))	('gastric cancer', 'Phenotype', 'HP:0012126', (297, 311))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (397, 404))	('cancers', 'Disease', (397, 404))	('cancer', 'Disease', (397, 403))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('PGs', 'Chemical', 'MESH:D010715', (346, 349))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('PGs', 'Chemical', 'MESH:D010715', (162, 165))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('gastric cancer', 'Disease', (297, 311))	('ectopic', 'Var', (338, 345))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('cancers', 'Disease', 'MESH:D009369', (397, 404))	('cancer', 'Disease', (305, 311))	('gastric cancer', 'Disease', 'MESH:D013274', (297, 311))	('cancer', 'Disease', (121, 127))
4248	33067881	This study focused on elucidating the expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their potential role in human cancer.	('human', 'Species', '9606', (175, 180))	('copy number variation', 'Var', (118, 139))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('PGs', 'Chemical', 'MESH:D010715', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('PGs', 'Gene', (143, 146))	('cancer', 'Disease', (181, 187))
4249	33067881	Based on the next generation sequence data from TCGA, Oncomine, and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically by R language, including the expression, mutation, and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration, and prognostic potential in different cancers.	('cancer', 'Disease', 'MESH:D009369', (394, 400))	('cancers', 'Disease', 'MESH:D009369', (394, 401))	('PGs', 'Chemical', 'MESH:D010715', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Disease', (286, 292))	('copy number variation', 'Var', (230, 251))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('PGs', 'Gene', (255, 258))	('PGs', 'Chemical', 'MESH:D010715', (255, 258))	('cancers', 'Phenotype', 'HP:0002664', (394, 401))	('cancers', 'Disease', (394, 401))	('cancer', 'Disease', (394, 400))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('CCLE', 'Chemical', '-', (68, 72))	('tumor', 'Disease', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('Oncomine', 'Chemical', '-', (54, 62))	('signal transduction', 'biological_process', 'GO:0007165', ('301', '320'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))
4254	33067881	PGs expression was significantly related to the activation or inhibition of many signal transduction pathways, in which PGC and PGA5 are more likely to be associated with cancer-related pathways.	('signal transduction pathways', 'Pathway', (81, 109))	('PGC', 'Gene', (120, 123))	('signal transduction', 'biological_process', 'GO:0007165', ('81', '100'))	('PGA5', 'Gene', (128, 132))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('PGs', 'Chemical', 'MESH:D010715', (0, 3))	('associated', 'Reg', (155, 165))	('cancer', 'Disease', (171, 177))	('PGs', 'Var', (0, 3))	('PGA5', 'Gene', '5222', (128, 132))	('activation', 'PosReg', (48, 58))	('PGC', 'Gene', '5225', (120, 123))	('inhibition', 'NegReg', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
4260	33067881	Genetic variation analysis showed that PGC gene often mutated in uterine corpus endometrial carcinoma and stomach adenocarcinoma had extensive copy number amplification in various tumor types.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('tumor', 'Disease', (180, 185))	('PGC', 'Gene', '5225', (39, 42))	('mutated', 'Var', (54, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (80, 101))	('copy number amplification', 'MPA', (143, 168))	('endometrial carcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D016889', (80, 128))	('PGC', 'Gene', (39, 42))
4261	33067881	PGC expression was upregulated with the increase of copy number in cholangiocarcinoma, esophageal carcinoma, and kidney renal papillary cell carcinoma, while in stomach adenocarcinoma, PGC was upregulated regardless of whether the copy number was increased or decreased.	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (120, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('expression', 'MPA', (4, 14))	('esophageal carcinoma', 'Disease', (87, 107))	('cholangiocarcinoma', 'Disease', (67, 85))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))	('PGC', 'Gene', (185, 188))	('kidney renal papillary cell carcinoma', 'Disease', (113, 150))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (87, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (161, 183))	('upregulated', 'PosReg', (193, 204))	('upregulated', 'PosReg', (19, 30))	('PGC', 'Gene', (0, 3))	('PGC', 'Gene', '5225', (185, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('stomach adenocarcinoma', 'Disease', (161, 183))	('PGC', 'Gene', '5225', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('increase', 'PosReg', (40, 48))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (87, 107))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (113, 150))	('copy number', 'Var', (52, 63))
4265	33067881	The variation of copy number of PGC gene could affect the PGC expression.	('PGC', 'Gene', (58, 61))	('variation', 'Var', (4, 13))	('copy number', 'Var', (17, 28))	('expression', 'MPA', (62, 72))	('PGC', 'Gene', '5225', (32, 35))	('PGC', 'Gene', (32, 35))	('affect', 'Reg', (47, 53))	('PGC', 'Gene', '5225', (58, 61))
4267	33067881	Based on the next generation sequence data from TCGA and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically including the expression profiles, mutation and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration and prognostic potential in different cancers.	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('signal transduction', 'biological_process', 'GO:0007165', ('283', '302'))	('CCLE', 'Chemical', '-', (57, 61))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancers', 'Disease', 'MESH:D009369', (375, 382))	('correlation', 'Reg', (251, 262))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('PGs', 'Chemical', 'MESH:D010715', (113, 116))	('cancer', 'Disease', (375, 381))	('copy number variation', 'Var', (212, 233))	('PGs', 'Gene', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Disease', (268, 274))	('PGs', 'Chemical', 'MESH:D010715', (237, 240))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancers', 'Phenotype', 'HP:0002664', (375, 382))	('cancers', 'Disease', (375, 382))
4287	33067881	In this study, by using the multilevel data from TCGA based Pan-Cancer Atlas, Oncomine and Cancer Cell Line Encyclopedia (CCLE), we focused on the elucidating expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their prediction/diagnosis/prognosis potential in pan-cancer.	('Cancer', 'Disease', (91, 97))	('Cancer', 'Disease', (64, 70))	('CCLE', 'Chemical', '-', (122, 126))	('Cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('-cancer', 'Disease', 'MESH:D009369', (325, 332))	('-cancer', 'Disease', (325, 332))	('Oncomine', 'Chemical', '-', (78, 86))	('PGs', 'Chemical', 'MESH:D010715', (264, 267))	('copy number variation', 'Var', (239, 260))	('PGs', 'Gene', (264, 267))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
4288	33067881	We totally collected the information of 33 different kinds of tumors in TCGA database (http://cancergenome.nih.gov/), including the information of TPM (Transcripts Per Kilobase Million) expression, mutation, and copy number variation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('copy number variation', 'Var', (212, 233))	('TPM', 'Gene', (147, 150))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Disease', (94, 100))	('mutation', 'Var', (198, 206))
4293	33067881	CCLE database(https://portals.broadinstitute.org/ccle)was used to identify the PGs expression, mutation, and copy number variation in different cancer cell lines, including all 431 cell lines from six cancer types.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('CCLE', 'Chemical', '-', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('PGs', 'Chemical', 'MESH:D010715', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('PGs', 'Gene', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('mutation', 'Var', (95, 103))
4306	33067881	The frequency of CNV in each cancer type and cell lines was calculated as the proportion of CNV amplification and deletion.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('deletion', 'Var', (114, 122))
4318	33067881	The results showed that in stomach adenocarcinoma and lung squamous cell carcinoma, high expression of PG is a protective factor, and high expression can reduce the risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('reduce', 'NegReg', (154, 160))	('high expression', 'Var', (134, 149))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (27, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (54, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('stomach adenocarcinoma', 'Disease', (27, 49))	('lung squamous cell carcinoma', 'Disease', (54, 82))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 82))
4329	33067881	The results show that PGs expression was significantly related to the activation or inhibition of many carcinogenic pathways (Figure 7A), in which PGC and PGA5 are more likely to be associated with carcinogenic processes.	('PGC', 'Gene', (147, 150))	('carcinogenic', 'Disease', 'MESH:D063646', (198, 210))	('associated', 'Reg', (182, 192))	('carcinogenic', 'Disease', (198, 210))	('inhibition', 'NegReg', (84, 94))	('expression', 'Var', (26, 36))	('PGA5', 'Gene', (155, 159))	('PGs', 'Gene', (22, 25))	('PGA5', 'Gene', '5222', (155, 159))	('carcinogenic', 'Disease', 'MESH:D063646', (103, 115))	('carcinogenic', 'Disease', (103, 115))	('activation', 'PosReg', (70, 80))	('related', 'Reg', (55, 62))	('PGs', 'Chemical', 'MESH:D010715', (22, 25))	('PGC', 'Gene', '5225', (147, 150))
4353	33067881	The results showed that PGC gene mutations frequently occurred in uterine corpus endometrial carcinoma and stomach adenocarcinoma (Figure 10A).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('PGC', 'Gene', '5225', (24, 27))	('PGC', 'Gene', (24, 27))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (81, 102))	('endometrial carcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D016889', (81, 129))	('mutations', 'Var', (33, 42))	('occurred', 'Reg', (54, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))
4356	33067881	PGA3, PGA4, and PGA5 showed more copy number amplification in lung adenocarcinoma, esophageal carcinoma, kidney chromophobe, and copy number reduction in bladder urothelial carcinoma, lung squamous cell carcinoma, rectum adenocarcinoma, and cholangiocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('copy number', 'Var', (129, 140))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (184, 212))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('PGA4', 'Gene', '643847', (6, 10))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (241, 259))	('PGA5', 'Gene', (16, 20))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (214, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('cholangiocarcinoma', 'Disease', (241, 259))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (241, 259))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (83, 103))	('copy', 'MPA', (33, 37))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (184, 212))	('lung squamous cell carcinoma', 'Disease', (184, 212))	('PGA5', 'Gene', '5222', (16, 20))	('kidney chromophobe', 'Disease', 'MESH:D000238', (105, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('esophageal carcinoma', 'Disease', (83, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('kidney chromophobe', 'Disease', (105, 123))	('PGA3', 'Chemical', '-', (0, 4))	('rectum adenocarcinoma', 'Disease', (214, 235))	('bladder urothelial carcinoma', 'Disease', (154, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('PGA4', 'Gene', (6, 10))	('lung adenocarcinoma', 'Disease', (62, 81))	('PGA3', 'Gene', (0, 4))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (83, 103))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (154, 182))
4357	33067881	In addition, CCLE database analysis revealed the mutation status of PGs in different human cancer cell lines, which showed that there were frequent mutations of PGs in colorectal cancer and gastric cancer cell lines (Figure 11).	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))	('gastric cancer', 'Disease', 'MESH:D013274', (190, 204))	('cancer', 'Disease', (198, 204))	('PGs', 'Chemical', 'MESH:D010715', (68, 71))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('colorectal cancer', 'Disease', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('PGs', 'Gene', (161, 164))	('CCLE', 'Chemical', '-', (13, 17))	('mutations', 'Var', (148, 157))	('PGs', 'Chemical', 'MESH:D010715', (161, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (190, 204))	('rectal cancer', 'Phenotype', 'HP:0100743', (172, 185))	('human', 'Species', '9606', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (179, 185))	('gastric cancer', 'Disease', (190, 204))
4358	33067881	In order to explore whether PGC self-variation affects its expression, we analyzed the correlation between PGs mutation, CNV, and PGs expression.	('PGs', 'Gene', (107, 110))	('PGC', 'Gene', '5225', (28, 31))	('PGC', 'Gene', (28, 31))	('PGs', 'Chemical', 'MESH:D010715', (130, 133))	('expression', 'MPA', (59, 69))	('PGs', 'Chemical', 'MESH:D010715', (107, 110))	('mutation', 'Var', (111, 119))
4359	33067881	The results showed that PGs mutations did not affect the PGs expression in all cancers.	('cancers', 'Disease', (79, 86))	('PGs', 'Chemical', 'MESH:D010715', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PGs', 'Chemical', 'MESH:D010715', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('PGs', 'Gene', (24, 27))	('mutations', 'Var', (28, 37))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
4362	33067881	In this study, we used the multilevel data of TCGA, Oncomine, and CCLE to reveal the expression and activated pathways, mutation, and copy number variation, prognostic potential of PGs in all 33 types of tumors and 431 cell lines, aiming to clarify the important role of PGs in tumorigenesis and development of cancers.	('Oncomine', 'Chemical', '-', (52, 60))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('copy number variation', 'Var', (134, 155))	('tumor', 'Disease', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('CCLE', 'Chemical', '-', (66, 70))	('PGs', 'Chemical', 'MESH:D010715', (271, 274))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('cancers', 'Disease', (311, 318))	('tumor', 'Disease', (204, 209))	('PGs', 'Chemical', 'MESH:D010715', (181, 184))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
4363	33067881	The results suggest that there was differential expression of PGs between many kinds of cancer tissues and corresponding normal tissues, which is related to the prognosis of patients; PGs expression was closely associated with the activation of cancer-related pathways and immune cell infiltration; the copy number variation of PGC could affect the gene expression.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('gene expression', 'MPA', (349, 364))	('PGC', 'Gene', (328, 331))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('affect', 'Reg', (338, 344))	('gene expression', 'biological_process', 'GO:0010467', ('349', '364'))	('cancer', 'Disease', (245, 251))	('immune cell infiltration', 'CPA', (273, 297))	('PGs', 'Chemical', 'MESH:D010715', (62, 65))	('copy number variation', 'Var', (303, 324))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PGC', 'Gene', '5225', (328, 331))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('associated', 'Reg', (211, 221))	('PGs', 'Chemical', 'MESH:D010715', (184, 187))
4382	33067881	The loss of pepsinogen in advanced esophageal squamous cell carcinoma indicates that pepsin is involved in the process of protein synthesis in the esophagus and causes esophageal carcinogenesis.	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('pepsin', 'Var', (85, 91))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (168, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (35, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('causes', 'Reg', (161, 167))	('esophageal carcinogenesis', 'Disease', (168, 193))	('protein synthesis', 'biological_process', 'GO:0006412', ('122', '139'))	('esophageal squamous cell carcinoma', 'Disease', (35, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('loss', 'NegReg', (4, 8))	('pepsinogen', 'Protein', (12, 22))
4384	33067881	Both lung tissue and gastric mucosa have the same function of producing pepsinogen molecules, 11  and the injury of normal lung tissue could increase the synthesis of pepsinogen C. 22  Some studies have also suggested that the existence of pepsin in respiratory biological samples was caused by gastroesophageal reflux associated lung inhalation.	('increase', 'PosReg', (141, 149))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (295, 318))	('pepsinogen C', 'Gene', '5225', (167, 179))	('injury', 'Var', (106, 112))	('synthesis', 'biological_process', 'GO:0009058', ('154', '163'))	('pepsinogen C', 'Gene', (167, 179))	('gastroesophageal reflux', 'Disease', (295, 318))	('pepsin', 'Gene', (240, 246))	('synthesis', 'MPA', (154, 163))	('caused by', 'Reg', (285, 294))
4405	33067881	The results showed that the overall average mutation rate of PGs was 0%-5.3%, and the mutation rate of PGC was higher in stomach adenocarcinoma and endometrial carcinoma.	('higher', 'Reg', (111, 117))	('PGC', 'Gene', '5225', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('PGs', 'Chemical', 'MESH:D010715', (61, 64))	('PGC', 'Gene', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (148, 169))	('mutation', 'Var', (86, 94))	('stomach adenocarcinoma and endometrial carcinoma', 'Disease', 'MESH:D016889', (121, 169))
4406	33067881	It is worth noticed that all PGC, PGA3, and PGA5 genes had a certain degree of mutation in endometrial carcinoma, which is a tumor with high global mutation rate.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('PGA3', 'Gene', (34, 38))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (91, 112))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('PGA3', 'Chemical', '-', (34, 38))	('PGA5', 'Gene', (44, 48))	('mutation', 'Var', (79, 87))	('PGC', 'Gene', '5225', (29, 32))	('PGC', 'Gene', (29, 32))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (91, 112))	('endometrial carcinoma', 'Disease', (91, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('PGA5', 'Gene', '5222', (44, 48))
4407	33067881	31  In addition, CCLE-based analysis of human cancer cell lines showed that most of the PGs mutations were found in colorectal adenocarcinoma and stomach adenocarcinoma cell lines, suggesting PGs mutation may be the key events in tumorigenesis and development of both gastric cancer and colorectal adenocarcinoma.	('CCLE', 'Chemical', '-', (17, 21))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('gastric cancer', 'Disease', (268, 282))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (287, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (268, 282))	('colorectal adenocarcinoma', 'Disease', (116, 141))	('human', 'Species', '9606', (40, 45))	('tumor', 'Disease', (230, 235))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', (46, 52))	('PGs', 'Chemical', 'MESH:D010715', (192, 195))	('mutations', 'Var', (92, 101))	('PGs', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PGs', 'Chemical', 'MESH:D010715', (88, 91))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (116, 141))	('gastric cancer', 'Phenotype', 'HP:0012126', (268, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('colorectal adenocarcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D000230', (116, 168))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('found', 'Reg', (107, 112))	('colorectal adenocarcinoma', 'Disease', (287, 312))
4408	33067881	In this study, we also found that there was extensive copy number amplification in various tumor types, which may be related to its widespread expression in various tissues.	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('copy number amplification', 'Var', (54, 79))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
4410	33067881	The results showed that there was no correlation between PGs mutation and PGs expression in cancer cells.	('PGs', 'Chemical', 'MESH:D010715', (74, 77))	('cancer', 'Disease', (92, 98))	('PGs', 'Chemical', 'MESH:D010715', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutation', 'Var', (61, 69))	('PGs', 'Gene', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
4411	33067881	However, previous studies in our lab have found that PGC gene insertion-deletion fragment polymorphism and single nucleotide polymorphism from human germline cells can affect PGC expression.	('PGC', 'Gene', (175, 178))	('human', 'Species', '9606', (143, 148))	('expression', 'MPA', (179, 189))	('insertion-deletion fragment polymorphism', 'Var', (62, 102))	('single nucleotide polymorphism', 'Var', (107, 137))	('affect', 'Reg', (168, 174))	('PGC', 'Gene', '5225', (53, 56))	('PGC', 'Gene', (53, 56))	('PGC', 'Gene', '5225', (175, 178))
4413	33067881	In cholangiocarcinoma, esophageal cancer, and kidney renal papillary cell carcinoma, PGC expression was upregulated with the increase of copy number, but in stomach adenocarcinoma, both increase and deletion of PGC copy number could lead to the up-regulation of PGC expression.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('expression', 'MPA', (266, 276))	('PGC', 'Gene', '5225', (211, 214))	('stomach adenocarcinoma', 'Disease', (157, 179))	('deletion', 'Var', (199, 207))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('cholangiocarcinoma', 'Disease', (3, 21))	('copy number', 'Var', (215, 226))	('up-regulation', 'PosReg', (245, 258))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (46, 83))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (53, 83))	('PGC', 'Gene', (262, 265))	('upregulated', 'PosReg', (104, 115))	('PGC', 'Gene', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('PGC', 'Gene', '5225', (262, 265))	('kidney renal papillary cell carcinoma', 'Disease', (46, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('PGC', 'Gene', (211, 214))	('cancer', 'Disease', (34, 40))	('PGC', 'Gene', '5225', (85, 88))	('regulation', 'biological_process', 'GO:0065007', ('248', '258'))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (157, 179))
4442	32823698	Whereas cutaneous melanoma is characterized by a UV-mediated high mutation burden and a high incidence of activating mutations in the BRAF protein, uveal melanoma carries a low mutational burden, no UV mutation signature, and a rare occurrence of BRAF mutations.	('mutation burden', 'MPA', (66, 81))	('mutations', 'Var', (117, 126))	('activating', 'MPA', (106, 116))	('BRAF', 'Gene', '673', (247, 251))	('uveal melanoma', 'Phenotype', 'HP:0007716', (148, 162))	('mutational burden', 'MPA', (177, 194))	('BRAF', 'Gene', '673', (134, 138))	('uveal melanoma', 'Disease', 'MESH:C536494', (148, 162))	('BRAF', 'Gene', (247, 251))	('uveal melanoma', 'Disease', (148, 162))	('BRAF', 'Gene', (134, 138))	('cutaneous melanoma', 'Disease', (8, 26))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (8, 26))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (8, 26))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))
4443	32823698	Early canonical activating mutations in the MAPK pathway in GNAQ or GNA11 have not led to the successful targeting of the MAPK pathway.	('mutations', 'Var', (27, 36))	('GNAQ', 'Gene', (60, 64))	('MAPK', 'molecular_function', 'GO:0004707', ('122', '126'))	('GNA11', 'Gene', (68, 73))	('MAPK', 'molecular_function', 'GO:0004707', ('44', '48'))	('MAPK pathway', 'Pathway', (44, 56))	('GNA11', 'Gene', '2767', (68, 73))	('GNAQ', 'Gene', '2776', (60, 64))	('activating', 'PosReg', (16, 26))
4492	32823698	There were two confirmed PRs (6%) via RECIST 1.1 in patients with M1b and M1c disease in the liver, and there were no CRs.	('M1b', 'Var', (66, 69))	('patients', 'Species', '9606', (52, 60))	('M1c disease', 'Var', (74, 85))
4586	31762467	Lack of heating may cause hypothermia.	('cause', 'Reg', (20, 25))	('Lack', 'Var', (0, 4))	('hypothermia', 'Disease', (26, 37))	('hypothermia', 'Phenotype', 'HP:0002045', (26, 37))	('hypothermia', 'Disease', 'MESH:D007035', (26, 37))
4665	32131485	Among known risk factors for the development of metastatic disease is the loss of BAP1 expression and chromosome 3 monosomy in the primary tumor.	('BAP1', 'Gene', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('loss', 'NegReg', (74, 78))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('expression', 'MPA', (87, 97))	('metastatic disease', 'Disease', (48, 66))	('chromosome', 'cellular_component', 'GO:0005694', ('102', '112'))	('chromosome 3', 'CPA', (102, 114))	('BAP1', 'Gene', '8314', (82, 86))	('monosomy', 'Var', (115, 123))
4672	32131485	Moreover, differentially expressed miRNAs may be used as an interesting biomarker for the assessment of metastatic risk in uveal melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('differentially', 'Var', (10, 24))	('miRNAs', 'Protein', (35, 41))	('uveal melanoma', 'Disease', 'MESH:C536494', (123, 137))	('patients', 'Species', '9606', (138, 146))	('uveal melanoma', 'Disease', (123, 137))	('uveal melanoma', 'Phenotype', 'HP:0007716', (123, 137))
4680	32131485	The Cancer Genome Atlas (TCGA) study identified some molecular features correlated with higher risk of metastasis, including chromosome 3 monosomy, loss of BRCA-associated protein (BAP1) expression, and eukaryotic translation initiation factor 1 (EIFAX), splicing factor 3 subunit 1 (SF3B1) mutations (increasing the risk of metastases in disomy 3 tumors).	('eukaryotic translation initiation factor 1', 'Gene', '10209', (203, 245))	('splicing', 'biological_process', 'GO:0045292', ('255', '263'))	('loss', 'NegReg', (148, 152))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('eukaryotic translation initiation factor 1', 'Gene', (203, 245))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (348, 354))	('BAP1', 'Gene', '8314', (181, 185))	('chromosome', 'cellular_component', 'GO:0005694', ('125', '135'))	('metastases in disomy 3 tumors', 'Disease', 'MESH:D009362', (325, 354))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('Cancer', 'Disease', (4, 10))	('metastases in disomy 3 tumors', 'Disease', (325, 354))	('splicing factor 3 subunit 1', 'Gene', '10291', (255, 282))	('metastasis', 'Disease', (103, 113))	('BAP1', 'Gene', (181, 185))	('mutations', 'Var', (291, 300))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('splicing factor 3 subunit 1', 'Gene', (255, 282))	('SF3B1', 'Gene', (284, 289))	('translation initiation', 'biological_process', 'GO:0006413', ('214', '236'))	('SF3B1', 'Gene', '10291', (284, 289))
4723	32131485	Monosomy of chromosome 3 was detected in 23 patients (50%):14 in the primary group versus 9 in the metastatic group (Figure 3B, Table 1).	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))	('Monosomy', 'Var', (0, 8))	('patients', 'Species', '9606', (44, 52))	('detected', 'Reg', (29, 37))
4725	32131485	Besides the finding that the PFS median was lower in the patients with detected chromosome 3 monosomy or loss of BAP1 expression, there were no statistically significant differences between the observed groups (Figure 3C).	('lower', 'NegReg', (44, 49))	('PFS median', 'MPA', (29, 39))	('chromosome', 'Gene', (80, 90))	('patients', 'Species', '9606', (57, 65))	('loss', 'NegReg', (105, 109))	('BAP1', 'Gene', '8314', (113, 117))	('chromosome', 'cellular_component', 'GO:0005694', ('80', '90'))	('expression', 'MPA', (118, 128))	('BAP1', 'Gene', (113, 117))	('monosomy', 'Var', (93, 101))
4730	32131485	Similarly, the expression was also significantly higher in tumors with loss of BAP1 expression and chromosome 3 monosomy (Figure 4B).	('BAP1', 'Gene', '8314', (79, 83))	('chromosome', 'cellular_component', 'GO:0005694', ('99', '109'))	('expression', 'Protein', (84, 94))	('chromosome 3 monosomy', 'Var', (99, 120))	('BAP1', 'Gene', (79, 83))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('expression', 'MPA', (15, 25))	('loss', 'NegReg', (71, 75))	('higher', 'PosReg', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
4741	32131485	A comprehensive analysis of 80 primary tumors identified four molecular and clinical subsets, depending on chromosome 3 status, EIF1AX, SF3B1, and BAP1 gene alteration, DNA methylation, and copy number status.	('SF3B1', 'Gene', '10291', (136, 141))	('SF3B1', 'Gene', (136, 141))	('BAP1', 'Gene', (147, 151))	('EIF1AX', 'Gene', (128, 134))	('EIF1AX', 'Gene', '1964', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('DNA methylation', 'biological_process', 'GO:0006306', ('169', '184'))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('alteration', 'Var', (157, 167))	('chromosome', 'cellular_component', 'GO:0005694', ('107', '117'))	('DNA', 'cellular_component', 'GO:0005574', ('169', '172'))	('BAP1', 'Gene', '8314', (147, 151))	('tumors', 'Disease', (39, 45))
4747	32131485	determined the prognostic significance of deregulated miRNA, based on TCGA data, in a low grade vs. high-grade uveal melanoma tumor and in alive vs. deceased patient groups.	('miRNA', 'MPA', (54, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (111, 125))	('uveal melanoma', 'Disease', 'MESH:C536494', (111, 125))	('uveal melanoma', 'Disease', (111, 125))	('patient', 'Species', '9606', (158, 165))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('melanoma tumor', 'Disease', (117, 131))	('deregulated', 'Var', (42, 53))	('melanoma tumor', 'Disease', 'MESH:D008545', (117, 131))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
4780	32131485	Similar results were presented by Zhu et al., who showed, that high expression of miR-196b-5p was negatively associated with lymph node metastasis and the progression of the clinical stage in patients with breast cancer.	('associated', 'Reg', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('patients', 'Species', '9606', (192, 200))	('progression of the clinical stage', 'CPA', (155, 188))	('breast cancer', 'Disease', (206, 219))	('negatively', 'NegReg', (98, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('high', 'Var', (63, 67))	('miR-196b', 'Gene', (82, 90))	('miR-196b', 'Gene', '442920', (82, 90))	('lymph node metastasis', 'CPA', (125, 146))
4782	32131485	It is known that chromosome 3 monosomy and the loss of BAP1 expression are related to poor prognosis and an increased risk of developing metastatic disease in uveal melanoma.	('expression', 'MPA', (60, 70))	('uveal melanoma', 'Disease', 'MESH:C536494', (159, 173))	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (159, 173))	('BAP1', 'Gene', (55, 59))	('uveal melanoma', 'Disease', (159, 173))	('monosomy', 'Var', (30, 38))	('loss', 'NegReg', (47, 51))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('BAP1', 'Gene', '8314', (55, 59))
4784	32131485	We showed that average disease progression-free time was longer in patients with disomy 3 and BAP1 expression, in comparison to patients with monosomy 3 and loss of BAP1.	('disomy 3', 'Var', (81, 89))	('longer', 'PosReg', (57, 63))	('BAP1', 'Gene', '8314', (94, 98))	('patients', 'Species', '9606', (67, 75))	('BAP1', 'Gene', (165, 169))	('disease progression-free time', 'CPA', (23, 52))	('BAP1', 'Gene', (94, 98))	('patients', 'Species', '9606', (128, 136))	('BAP1', 'Gene', '8314', (165, 169))
4803	32131485	In this study, we show that miRNAs play an important role in the deregulation of several oncogenic pathways in UM primary tumors and can be responsible for the promotion of metastatic spread to distant organs.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('UM', 'Phenotype', 'HP:0007716', (111, 113))	('promotion', 'PosReg', (160, 169))	('oncogenic pathways', 'Pathway', (89, 107))	('metastatic spread to distant organs', 'CPA', (173, 208))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('deregulation', 'MPA', (65, 77))	('miRNAs', 'Var', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
4805	32131485	Inhibitors of miRNA expression (anti-miRs) and miRNA mimics have shown promising results in preclinical studies and could reverse the effects of dysregulated, metastasis-related cellular pathways, and thereby increase the likelihood of positive outcomes for uveal melanoma patients.	('uveal melanoma', 'Disease', (258, 272))	('miRNA expression', 'Protein', (14, 30))	('patients', 'Species', '9606', (273, 281))	('metastasis-related cellular pathways', 'Pathway', (159, 195))	('Inhibitors', 'Var', (0, 10))	('dysregulated', 'MPA', (145, 157))	('uveal melanoma', 'Phenotype', 'HP:0007716', (258, 272))	('uveal melanoma', 'Disease', 'MESH:C536494', (258, 272))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))	('effects', 'MPA', (134, 141))	('increase', 'PosReg', (209, 217))	('reverse', 'NegReg', (122, 129))
4806	32131485	The following are available online at , Figure S1: miRNA differentially expressed between BAP1+/- and chromosome 3 disomy/monosomy uveal melanoma tumors.	('disomy/monosomy', 'Var', (115, 130))	('uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))	('uveal melanoma', 'Disease', 'MESH:C536494', (131, 145))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('expressed', 'Reg', (72, 81))	('BAP1', 'Gene', '8314', (90, 94))	('uveal melanoma', 'Disease', (131, 145))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('BAP1', 'Gene', (90, 94))	('chromosome', 'cellular_component', 'GO:0005694', ('102', '112'))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('melanoma tumors', 'Disease', (137, 152))	('melanoma tumors', 'Disease', 'MESH:D008545', (137, 152))
4879	32194670	Aberrant genetic and epigenetic regulation of key metabolic pathways is known to contribute towards the development and progression of UVM.	('contribute', 'Reg', (81, 91))	('UVM', 'Disease', 'MESH:C536494', (135, 138))	('Aberrant genetic', 'Var', (0, 16))	('key metabolic pathways', 'Pathway', (46, 68))	('UVM', 'Disease', (135, 138))	('epigenetic regulation', 'Var', (21, 42))	('regulation', 'biological_process', 'GO:0065007', ('32', '42'))
4942	31871621	The 31-GEP test is now covered by Centers for Medicare and Medicaid Services for patients over age 65 with T1a (with adverse features), T1b and T2 tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('T1b', 'Var', (136, 139))	('patients', 'Species', '9606', (81, 89))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('T1a', 'Disease', (107, 110))
4950	31871621	This multicenter validation cohort study on 309 CM patients showed that aberrant expression of ITGB3 predicts nodal metastasis and may be used to guide decision to perform SLNB.	('predicts', 'Reg', (101, 109))	('ITGB3', 'Gene', '3690', (95, 100))	('nodal metastasis', 'CPA', (110, 126))	('ITGB3', 'Gene', (95, 100))	('CM', 'Phenotype', 'HP:0012056', (48, 50))	('aberrant expression', 'Var', (72, 91))	('patients', 'Species', '9606', (51, 59))
4961	31871621	On the other hand, there are patients with thick primary tumors or positive SLNB who do not relapse and instead demonstrate long-term survival without additional therapy.	('patients', 'Species', '9606', (29, 37))	('positive', 'Var', (67, 75))	('SLNB', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
5010	31555735	The Bap1-deficient phenotype can be rescued with human BAP1, by pharmacologic inhibition of histone deacetylase (HDAC) activity or by specific knockdown of Hdac4.	('histone deacetylase', 'Gene', (92, 111))	('BAP1', 'Gene', (55, 59))	('human', 'Species', '9606', (49, 54))	('HDAC', 'Gene', (113, 117))	('inhibition', 'NegReg', (78, 88))	('Hdac4', 'Gene', '9759', (156, 161))	('HDAC', 'Gene', '9734', (113, 117))	('Hdac4', 'Gene', (156, 161))	('knockdown', 'Var', (143, 152))	('histone deacetylase', 'Gene', '9734', (92, 111))
5013	31555735	BAP1 [breast cancer type 1 (BRCA1)-associated protein 1] is emerging as an important tumor suppressor in human cancer, as it frequently sustains inactivating mutations in uveal melanoma, renal cell carcinoma, mesothelioma, and other malignancies.	('tumor', 'Disease', (85, 90))	('renal cell carcinoma', 'Disease', (187, 207))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (187, 207))	('tumor suppressor', 'biological_process', 'GO:0051726', ('85', '101'))	('malignancies', 'Disease', 'MESH:D009369', (233, 245))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('uveal melanoma', 'Phenotype', 'HP:0007716', (171, 185))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('malignancies', 'Disease', (233, 245))	('human', 'Species', '9606', (105, 110))	('cancer', 'Disease', (111, 117))	('mesothelioma', 'Disease', (209, 221))	('BAP1', 'Gene', (0, 4))	('inactivating mutations', 'Var', (145, 167))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('mesothelioma', 'Disease', 'MESH:D008654', (209, 221))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (187, 207))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('85', '101'))	('uveal melanoma', 'Disease', (171, 185))	('breast cancer type 1 (BRCA1)-associated protein 1', 'Gene', '8314', (6, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (171, 185))
5030	31555735	The Bap1MO phenotype was rescued by coinjection of Bap1MO with either human BAP1 mRNA (fig.	('Bap1MO', 'Var', (51, 57))	('human', 'Species', '9606', (70, 75))	('Bap1MO', 'Disease', (4, 10))
5031	31555735	S4, A to C) or a morpholino-resistant Xenopus bap1 mRNA (bap1-MM) containing conservative nucleotide substitutions that abolish morpholino binding (fig.	('conservative nucleotide substitutions', 'Var', (77, 114))	('morpholino binding', 'MPA', (128, 146))	('binding', 'molecular_function', 'GO:0005488', ('139', '146'))	('abolish', 'NegReg', (120, 127))	('Xenopus', 'Species', '8364', (38, 45))
5039	31555735	Asxl1 depletion resulted in morphogenetic defects identical to those observed in Bap1-deficient embryos (fig.	('morphogenetic defects', 'CPA', (28, 49))	('depletion', 'Var', (6, 15))	('Asxl1', 'Gene', (0, 5))	('Asxl1', 'Gene', '171023', (0, 5))
5043	31555735	In contrast to wild-type Bap1 and human BAP1, Bap1DeltaABM failed to rescue the Bap1-deficient morphogenetic phenotype (fig.	('Bap1DeltaABM', 'Var', (46, 58))	('Bap1-deficient', 'Gene', (80, 94))	('human', 'Species', '9606', (34, 39))
5044	31555735	Similarly, a Bap1 mutant containing a single amino acid substitution at the conserved catalytic Cys91 residue (Bap1-C91W), corresponding to a human cancer-derived missense mutation that abrogates ubiquitin hydrolase activity, also failed to rescue the Bap1MO phenotype (fig.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('abrogates', 'NegReg', (186, 195))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('C91W', 'Var', (116, 120))	('human', 'Species', '9606', (142, 147))	('ubiquitin hydrolase activity', 'MPA', (196, 224))	('C91W', 'SUBSTITUTION', 'None', (116, 120))	('ubiquitin hydrolase activity', 'molecular_function', 'GO:0004843', ('196', '224'))	('Cys', 'Chemical', 'MESH:C046557', (96, 99))
5045	31555735	Since most BAP1 missense mutations in human tumors cluster around the ABM and catalytic domain, the functions of Bap1 in development seem to parallel those in tumor suppression.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('missense mutations', 'Var', (16, 34))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('human', 'Species', '9606', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (159, 164))	('BAP1', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', (44, 49))
5047	31555735	As expected, depletion of Bap1 resulted in a global increase in H2AK119ub and H3K27me3 around transcription start sites across the genome (Fig.	('H2A', 'Gene', (64, 67))	('transcription', 'biological_process', 'GO:0006351', ('94', '107'))	('increase', 'PosReg', (52, 60))	('H2A', 'Gene', '8337', (64, 67))	('H3K27me3', 'Var', (78, 86))	('depletion', 'MPA', (13, 22))	('Bap1', 'Gene', (26, 30))
5056	31555735	Concomitant depletion of Bap1 and Hdac4 in whole embryos using Bap1MO and Hdac4MO rescues the Bap1-deficient phenotype, as evidenced by restoration of normal morphologic development (Fig.	('Bap1-deficient', 'Gene', (94, 108))	('Hdac4MO', 'Gene', (74, 81))	('Hdac4', 'Gene', '9759', (34, 39))	('morphologic development', 'CPA', (158, 181))	('Hdac4', 'Gene', (74, 79))	('Bap1MO', 'Var', (63, 69))	('Hdac4MO', 'Gene', '9759', (74, 81))	('Hdac4', 'Gene', '9759', (74, 79))	('restoration', 'PosReg', (136, 147))	('Hdac4', 'Gene', (34, 39))	('rescues', 'PosReg', (82, 89))
5067	31555735	Hdac4 is largely restricted to the cytoplasm in BAP1 wild-type uveal melanoma cells and in normal human uveal melanocytes (UMCs), whereas it localized to the nucleus in BAP1-mutant uveal melanoma cells and in UMCs in which a BAP1 mutation was introduced using CRISPR-Cas9 (fig.	('cytoplasm', 'cellular_component', 'GO:0005737', ('35', '44'))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('uveal melanoma', 'Disease', (181, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('uveal melanoma', 'Phenotype', 'HP:0007716', (63, 77))	('uveal melanoma', 'Disease', (63, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (63, 77))	('nucleus', 'cellular_component', 'GO:0005634', ('158', '165'))	('BAP1-mutant', 'Gene', (169, 180))	('mutation', 'Var', (230, 238))	('uveal melanoma', 'Phenotype', 'HP:0007716', (181, 195))	('uveal melanoma', 'Disease', 'MESH:C536494', (181, 195))	('BAP1', 'Gene', (225, 229))	('Cas', 'cellular_component', 'GO:0005650', ('267', '270'))	('human', 'Species', '9606', (98, 103))	('Hdac4', 'Gene', (0, 5))	('BAP1-mutant', 'Var', (169, 180))	('Hdac4', 'Gene', '9759', (0, 5))
5069	31555735	Moreover, short hairpin RNA (shRNA)-mediated depletion of HDAC4 in BAP1-mutant uveal melanoma cells significantly impaired cell proliferation (fig.	('depletion', 'MPA', (45, 54))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('BAP1-mutant', 'Var', (67, 78))	('cell proliferation', 'CPA', (123, 141))	('cell proliferation', 'biological_process', 'GO:0008283', ('123', '141'))	('BAP1-mutant', 'Gene', (67, 78))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('HDAC4', 'Gene', '9759', (58, 63))	('RNA', 'cellular_component', 'GO:0005562', ('24', '27'))	('HDAC4', 'Gene', (58, 63))	('impaired', 'NegReg', (114, 122))	('uveal melanoma', 'Disease', (79, 93))
5070	31555735	Disruption of Bap1 during development results in abnormalities largely affecting ectoderm, mesoderm, and neural crest, which may help to explain the spectrum of cancers associated with BAP1 mutations, which are mostly derived from those lineages.	('ectoderm', 'CPA', (81, 89))	('affecting', 'Reg', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('BAP1', 'Gene', (185, 189))	('Bap1', 'Gene', (14, 18))	('mutations', 'Var', (190, 199))	('abnormalities', 'MPA', (49, 62))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('mesoderm', 'CPA', (91, 99))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))	('neural crest', 'CPA', (105, 117))	('Disruption', 'Var', (0, 10))
5071	31555735	At the organismal level, BAP1 primarily appears to regulate cell identity and differentiation, rather than cell cycle and proliferation, which may explain why BAP1 mutations typically are not initiating events but, rather, later events associated with cancer progression.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', (252, 258))	('cell identity', 'CPA', (60, 73))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cell cycle', 'biological_process', 'GO:0007049', ('107', '117'))	('BAP1', 'Gene', (159, 163))	('mutations', 'Var', (164, 173))
5072	31555735	Germline BAP1 mutations usually do not result in tumor formation unless accompanied by an initiating mutation, such as a Gq mutation in uveal melanoma or a BRAF mutation in cutaneous melanoma.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('BRAF', 'Gene', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('result in', 'Reg', (39, 48))	('mutation', 'Var', (161, 169))	('tumor', 'Disease', (49, 54))	('formation', 'biological_process', 'GO:0009058', ('55', '64'))	('cutaneous melanoma', 'Disease', (173, 191))	('uveal melanoma', 'Phenotype', 'HP:0007716', (136, 150))	('uveal melanoma', 'Disease', (136, 150))	('uveal melanoma', 'Disease', 'MESH:C536494', (136, 150))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (173, 191))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (173, 191))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('BRAF', 'Gene', '673', (156, 160))
5073	31555735	This phenomenon may explain why families with germline BAP1 mutations display reduced penetrance for any specific cancer type.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('BAP1', 'Gene', (55, 59))	('penetrance', 'MPA', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('reduced', 'NegReg', (78, 85))	('mutations', 'Var', (60, 69))	('germline', 'Var', (46, 54))	('cancer', 'Disease', (114, 120))
5093	31555735	The following constructs were purchased from GE Dharmacon (Lafayette, CO): asxl1 (ID446414), bap1 (ID493568), and fzd7 (ID378787).	('ID446414', 'Var', (82, 90))	('ID493568', 'Var', (99, 107))	('fzd7', 'Gene', (114, 118))	('fzd7', 'Gene', '8324', (114, 118))	('CO', 'Chemical', 'MESH:D002245', (70, 72))	('ID378787', 'Var', (120, 128))
5113	31555735	PDXs were expanded in the intrascapular fat pad of NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ JAX immunodeficient (NSG) mice for up to 3 months.	('Il2rgtm1Wjl/SzJ', 'Var', (68, 83))	('immunodeficient', 'Disease', 'MESH:D007153', (88, 103))	('immunodeficient', 'Disease', (88, 103))	('Il2', 'molecular_function', 'GO:0005134', ('68', '71'))	('mice', 'Species', '10090', (110, 114))	('PDX', 'Chemical', 'MESH:C113421', (0, 3))
5120	31555735	Immunofluorescence microscopy was performed on UM and UMC cells using Santa Cruz Biotechnology antibodies against HDAC4 (sc-46672) and BAP1 (sc-28236).	('HDAC4', 'Gene', '9759', (114, 119))	('sc-46672', 'Var', (121, 129))	('BAP1', 'Gene', (135, 139))	('HDAC4', 'Gene', (114, 119))
5181	31428573	Because a large number of studies indicate that VM+ is associated to a decrease in cancer patient survival, measured as OS or as progression-free survival (PFS).	('VM+', 'Var', (48, 51))	('decrease', 'NegReg', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('patient', 'Species', '9606', (90, 97))	('OS', 'Chemical', 'MESH:D009992', (120, 122))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
5183	31428573	Overall, 19 out of 20 reports confirm that VM+ associates with a decrease in OS; with the exception in synovial sarcoma.	('OS', 'Disease', (77, 79))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (103, 119))	('synovial sarcoma', 'Disease', 'MESH:D013584', (103, 119))	('OS', 'Chemical', 'MESH:D009992', (77, 79))	('decrease', 'NegReg', (65, 73))	('VM+', 'Var', (43, 46))	('synovial sarcoma', 'Disease', (103, 119))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))
5187	31428573	Gastric cancer patients with PAS+ structures were prone to present higher histological grade, metastasis, distant recurrence, and 12 months less cumulative OS.	('patients', 'Species', '9606', (15, 23))	('higher', 'PosReg', (67, 73))	('metastasis', 'CPA', (94, 104))	('cancer', 'Disease', (8, 14))	('PAS', 'cellular_component', 'GO:0000407', ('29', '32'))	('histological grade', 'CPA', (74, 92))	('OS', 'Chemical', 'MESH:D009992', (156, 158))	('PAS+ structures', 'Var', (29, 44))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('PAS+', 'Chemical', '-', (29, 33))	('Gastric cancer', 'Phenotype', 'HP:0012126', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('distant recurrence', 'CPA', (106, 124))
5197	31428573	reported a 65.9% of VM+ in glioblastoma patient samples, however two similar studies reported 26% and 16% also in glioblastoma.	('patient', 'Species', '9606', (40, 47))	('glioblastoma', 'Disease', (27, 39))	('glioblastoma', 'Disease', 'MESH:D005909', (27, 39))	('glioblastoma', 'Disease', (114, 126))	('glioblastoma', 'Phenotype', 'HP:0012174', (27, 39))	('glioblastoma', 'Disease', 'MESH:D005909', (114, 126))	('VM+', 'Var', (20, 23))	('glioblastoma', 'Phenotype', 'HP:0012174', (114, 126))
5202	31428573	The first report that used the PAS+/CD34- combination came in a model of B16 melanoma cells injected into C57Bl/6 mice.	('B16', 'CellLine', 'CVCL:N540', (73, 76))	('PAS+/CD34-', 'Var', (31, 41))	('PAS+', 'Chemical', '-', (31, 35))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('mice', 'Species', '10090', (114, 118))	('PAS', 'cellular_component', 'GO:0000407', ('31', '34'))
5204	31428573	Following this study, several authors reported PAS+/CD31+ (blood vessel) or PAS+/CD34- (VM) structures, however, in some cases low quality or low-resolution images failed to prove CD31- status or presence of RBCs.	('CD31', 'Gene', (180, 184))	('CD31', 'Gene', '5175', (52, 56))	('PAS', 'cellular_component', 'GO:0000407', ('47', '50'))	('CD31', 'Gene', '5175', (180, 184))	('PAS+/CD34-', 'Var', (76, 86))	('PAS+', 'Chemical', '-', (76, 80))	('PAS+', 'Chemical', '-', (47, 51))	('PAS', 'cellular_component', 'GO:0000407', ('76', '79'))	('CD31', 'Gene', (52, 56))
5207	31428573	used 3D Z-stack reconstructions to identify intratumoral structures that were both laminin+ and CD34- in metastatic uveal melanoma samples.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('CD34-', 'Var', (96, 101))	('tumor', 'Disease', (49, 54))	('uveal melanoma', 'Phenotype', 'HP:0007716', (116, 130))	('uveal melanoma', 'Disease', 'MESH:C536494', (116, 130))	('uveal melanoma', 'Disease', (116, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))
5235	31428573	Most studies used an in vivo approach, double stain PAS+/CD31- or PAS+/CD34- for VM+ and then correlated these structures with molecular markers.	('PAS+', 'Chemical', '-', (52, 56))	('PAS+', 'Chemical', '-', (66, 70))	('CD31', 'Gene', (57, 61))	('PAS+/CD34-', 'Var', (66, 76))	('PAS', 'cellular_component', 'GO:0000407', ('52', '55'))	('PAS', 'cellular_component', 'GO:0000407', ('66', '69'))	('CD31', 'Gene', '5175', (57, 61))
5236	31428573	Using our criteria for true VM structures: PAS+/CD31- or PAS+/CD34- and presence of a lumen for in vivo and in vitro studies we elaborated a list of 93 articles that fulfilled these criteria and also postulated a VM mechanism based on molecular pathways (Supplementary Table SIII).	('Supplementary Table SIII', 'Disease', 'MESH:D017034', (255, 279))	('molecular pathways', 'Pathway', (235, 253))	('CD31', 'Gene', '5175', (48, 52))	('Supplementary Table SIII', 'Disease', (255, 279))	('PAS+', 'Chemical', '-', (57, 61))	('PAS+', 'Chemical', '-', (43, 47))	('PAS', 'cellular_component', 'GO:0000407', ('43', '46'))	('PAS+/CD34-', 'Var', (57, 67))	('CD31', 'Gene', (48, 52))	('PAS', 'cellular_component', 'GO:0000407', ('57', '60'))
5245	31428573	Two related studies demonstrated VM structures were associated to AKT or correlated to MMPs, PI3K and FAK in melanoma and gallbladder cancer, respectively, adding to the possibility that the integrin-FAK and PI3K-AKT signaling pathway are also involved.	('FAK', 'Gene', '5747', (102, 105))	('PI3K', 'molecular_function', 'GO:0016303', ('208', '212'))	('signaling pathway', 'biological_process', 'GO:0007165', ('217', '234'))	('MMPs', 'Gene', (87, 91))	('gallbladder cancer', 'Disease', (122, 140))	('AKT signaling', 'biological_process', 'GO:0043491', ('213', '226'))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('FAK', 'molecular_function', 'GO:0004717', ('200', '203'))	('AKT', 'Gene', '207', (213, 216))	('FAK', 'molecular_function', 'GO:0004717', ('102', '105'))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('MMPs', 'Gene', '4313;4318;4323', (87, 91))	('FAK', 'Gene', (200, 203))	('AKT', 'Gene', (66, 69))	('correlated', 'Reg', (73, 83))	('associated', 'Reg', (52, 62))	('PI3K', 'molecular_function', 'GO:0016303', ('93', '97'))	('gallbladder cancer', 'Disease', 'MESH:D005706', (122, 140))	('FAK', 'Gene', '5747', (200, 203))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('FAK', 'Gene', (102, 105))	('PI3K', 'Var', (93, 97))	('AKT', 'Gene', '207', (66, 69))	('AKT', 'Gene', (213, 216))
5251	31428573	Antibody inhibition experiments revealed that TFPI-2 was required for VM in vitro, and that the blockade of TFPI-2 suppressed MMP2 activation.	('TFPI-2', 'Gene', '7980', (108, 114))	('MMP2', 'Gene', (126, 130))	('TFPI-2', 'Gene', '7980', (46, 52))	('MMP2', 'molecular_function', 'GO:0004228', ('126', '130'))	('TFPI-2', 'Gene', (108, 114))	('blockade', 'Var', (96, 104))	('TFPI-2', 'Gene', (46, 52))	('MMP2', 'Gene', '4313', (126, 130))	('suppressed', 'NegReg', (115, 125))
5286	31109147	Usually, loss of or deletions to chromosome 3 are accompanied by amplification of chromosome 8 long arm, leading to a higher risk of metastasis as well as a reported 10-year melanoma-related mortality rate of 71%.	('chromosome', 'cellular_component', 'GO:0005694', ('33', '43'))	('chromosome', 'cellular_component', 'GO:0005694', ('82', '92'))	('deletions', 'Var', (20, 29))	('loss of', 'NegReg', (9, 16))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Disease', (174, 182))	('metastasis', 'CPA', (133, 143))	('amplification', 'Var', (65, 78))
5287	31109147	evaluated the prognostic value of an extraocular extension of uveal melanoma related to chromosomal abnormalities, concluding that gaining 8q and extraocular extensions are related to a worsened prognosis, while the addition of chromosome 3 loss leads to a significant reduction in metastasis-free survival.	('chromosomal abnormalities', 'Disease', (88, 113))	('reduction', 'NegReg', (269, 278))	('uveal melanoma', 'Disease', (62, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('228', '238'))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('extraocular extensions', 'CPA', (146, 168))	('metastasis-free survival', 'CPA', (282, 306))	('uveal melanoma', 'Disease', 'MESH:C536494', (62, 76))	('gaining 8q', 'Var', (131, 141))	('uveal melanoma', 'Phenotype', 'HP:0007716', (62, 76))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (88, 113))
5288	31109147	Furthermore, it has been demonstrated that there is frequent association in UM between somatic mutations of the tumour suppressor gene BAP1 (3p21.1) and the single allele in chromosome 3, in cases of its monosomy.	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('tumour', 'Disease', (112, 118))	('BAP1', 'Gene', '8314', (135, 139))	('chromosome', 'cellular_component', 'GO:0005694', ('174', '184'))	('BAP1', 'Gene', (135, 139))	('mutations', 'Var', (95, 104))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('association', 'Interaction', (61, 72))
5290	31109147	A recent study showed that amplification of CNKSR 3 (member 3 of CNKSR: Connector enhancer of kinase suppressor of RAS), membrane-associated guanylate kinase interacting protein-like gene, which maps on chromosome 6q25.2, extended metastatis-free survival in a group of uveal melanomas with monosomy of chromosome 3, Figure 1.	('uveal melanomas', 'Disease', (270, 285))	('uveal melanomas', 'Phenotype', 'HP:0007716', (270, 285))	('chromosome', 'cellular_component', 'GO:0005694', ('303', '313'))	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('CNKSR 3', 'Gene', (44, 51))	('melanomas', 'Phenotype', 'HP:0002861', (276, 285))	('membrane-associated guanylate kinase', 'molecular_function', 'GO:0004384', ('121', '157'))	('extended', 'PosReg', (222, 230))	('membrane-associated guanylate kinase', 'molecular_function', 'GO:0004385', ('121', '157'))	('uveal melanomas', 'Disease', 'MESH:C536494', (270, 285))	('membrane', 'cellular_component', 'GO:0016020', ('121', '129'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (270, 284))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('amplification', 'Var', (27, 40))	('CNKSR 3', 'Gene', '154043', (44, 51))	('metastatis-free survival', 'CPA', (231, 255))	('chromosome', 'cellular_component', 'GO:0005694', ('203', '213'))
5293	31109147	Mutations in these genes are found in up to 91% of UM patients; therefore, being considered the principal driver of carcinogenesis.	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('carcinogenesis', 'Disease', 'MESH:D063646', (116, 130))	('patients', 'Species', '9606', (54, 62))	('carcinogenesis', 'Disease', (116, 130))	('Mutations', 'Var', (0, 9))
5295	31109147	These mutations occur in the alpha subunits of G protein-coupled receptor (GPCR) as single amino acid substitutions at residues Gln209 (Q209, where glutamine is mutated to either leucine or proline) or, less frequently, at Arg183 (R183).	('glutamine', 'Chemical', 'MESH:D005973', (148, 157))	('Gln209', 'Chemical', '-', (128, 134))	('Gln209', 'Var', (128, 134))	('Arg183', 'Chemical', '-', (223, 229))	('leucine', 'Chemical', 'MESH:D007930', (179, 186))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('proline', 'Chemical', 'MESH:D011392', (190, 197))	('Arg183', 'Var', (223, 229))
5296	31109147	The substitution of this critical glutamine determines constitutive GTPase activity of oncogenic Gq/11 subunits.	('GTPase', 'Enzyme', (68, 74))	('GTPase activity', 'molecular_function', 'GO:0003924', ('68', '83'))	('substitution', 'Var', (4, 16))	('activity', 'MPA', (75, 83))	('glutamine', 'Chemical', 'MESH:D005973', (34, 43))
5300	31109147	GNAQ and GNA11 mutations promote YAP activation and its nuclear localisation.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('YAP', 'Gene', '10413', (33, 36))	('promote', 'PosReg', (25, 32))	('GNAQ', 'Gene', (0, 4))	('YAP', 'Gene', (33, 36))	('localisation', 'biological_process', 'GO:0051179', ('64', '76'))	('nuclear localisation', 'MPA', (56, 76))	('GNA11', 'Gene', '2767', (9, 14))
5303	31109147	Moore and colleagues, analysing whole-genome and whole-exome sequencing data from 136 patients with uveal melanoma from multiple cohorts, found a previously undescribed mutation in CYSLTR2 encoding a p.Leu129Gln substitution.	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('p.Leu129Gln', 'Var', (200, 211))	('p.Leu129Gln', 'Mutation', 'p.L129Q', (200, 211))	('CYSLTR2', 'Gene', '57105', (181, 188))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('uveal melanoma', 'Disease', (100, 114))	('CYSLTR2', 'Gene', (181, 188))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('patients', 'Species', '9606', (86, 94))
5304	31109147	This mutation was founded only in samples lacking mutations in GNAQ, GNA11 and PLCB4 (four of nine samples), suggesting that these mutations activate the same pathway.	('mutations', 'Var', (131, 140))	('GNAQ', 'Gene', (63, 67))	('PLCB4', 'Gene', '5332', (79, 84))	('GNAQ', 'Gene', '2776', (63, 67))	('activate', 'PosReg', (141, 149))	('PLCB4', 'Gene', (79, 84))	('GNA11', 'Gene', (69, 74))	('GNA11', 'Gene', '2767', (69, 74))
5305	31109147	These findings reveal an oncogenic role for CYSLTR2 in uveal melanoma through activation of Galphaq signalling, and further suggest that Leu129Gln CysLT2R may be a potential therapeutic target in UM.	('Galphaq', 'Gene', '2776', (92, 99))	('UM', 'Phenotype', 'HP:0007716', (196, 198))	('signalling', 'biological_process', 'GO:0023052', ('100', '110'))	('CysLT2R', 'Gene', (147, 154))	('uveal melanoma', 'Phenotype', 'HP:0007716', (55, 69))	('uveal melanoma', 'Disease', (55, 69))	('uveal melanoma', 'Disease', 'MESH:C536494', (55, 69))	('Leu129Gln', 'Var', (137, 146))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('activation', 'PosReg', (78, 88))	('CysLT2R', 'Gene', '57105', (147, 154))	('CYSLTR2', 'Gene', '57105', (44, 51))	('Leu129Gln', 'SUBSTITUTION', 'None', (137, 146))	('Galphaq', 'Gene', (92, 99))	('CYSLTR2', 'Gene', (44, 51))
5307	31109147	Johansson and colleagues found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM_000933), which was validated using Sanger sequencing.	('c.G1888T', 'Var', (62, 70))	('c.G1888T', 'Mutation', 'c.1888G>T', (62, 70))	('PLCB4', 'Gene', '5332', (55, 60))	('p.D630Y', 'Var', (72, 79))	('p.D630Y', 'Mutation', 'p.D630Y', (72, 79))	('PLCB4', 'Gene', (55, 60))
3725	31109147	PLCB4 p.D630Y mutations are mutually exclusive with mutations in GNA11 and GNAQ, consistent with PLCB4 being the canonical downstream target of the former gene products.	('PLCB4', 'Gene', (97, 102))	('PLCB4', 'Gene', '5332', (0, 5))	('GNAQ', 'Gene', (75, 79))	('PLCB4', 'Gene', '5332', (97, 102))	('p.D630Y', 'Var', (6, 13))	('GNA11', 'Gene', '2767', (65, 70))	('PLCB4', 'Gene', (0, 5))	('GNA11', 'Gene', (65, 70))	('p.D630Y', 'Mutation', 'p.D630Y', (6, 13))	('GNAQ', 'Gene', '2776', (75, 79))
5309	31109147	Taken together, these data suggest that the PLCB4 hotspot mutation is similarly a gain-of-function mutation leading to activation of the same signalling pathway, promoting UM tumorigenesis.	('promoting', 'PosReg', (162, 171))	('signalling pathway', 'biological_process', 'GO:0007165', ('142', '160'))	('PLCB4', 'Gene', (44, 49))	('mutation', 'Var', (58, 66))	('UM tumorigenesis', 'CPA', (172, 188))	('activation', 'PosReg', (119, 129))	('UM', 'Phenotype', 'HP:0007716', (172, 174))	('PLCB4', 'Gene', '5332', (44, 49))
5312	31109147	BAP1 N-terminal domain mutations cause loss of protein expression and, consequently, loss of functions in this protein, which is normally involved in different cellular processes, such as cell cycle progression, DNA damage response and replication, stem cell pluripotency, histone modification and myeloid transformation.	('histone modification', 'MPA', (273, 293))	('cell cycle', 'biological_process', 'GO:0007049', ('188', '198'))	('DNA', 'cellular_component', 'GO:0005574', ('212', '215'))	('BAP1', 'Gene', (0, 4))	('myeloid transformation', 'CPA', (298, 320))	('mutations', 'Var', (23, 32))	('loss', 'NegReg', (39, 43))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('histone modification', 'biological_process', 'GO:0016570', ('273', '293'))	('protein expression', 'MPA', (47, 65))	('loss of functions', 'NegReg', (85, 102))	('BAP1', 'Gene', '8314', (0, 4))	('DNA damage response', 'biological_process', 'GO:0006974', ('212', '231'))
5316	31109147	Thus, BAP1 depletion implicates a loss of cell differentiation and a gain in stem cell characteristics.	('cell differentiation', 'CPA', (42, 62))	('BAP1', 'Gene', (6, 10))	('gain', 'PosReg', (69, 73))	('cell differentiation', 'biological_process', 'GO:0030154', ('42', '62'))	('depletion', 'Var', (11, 20))	('stem cell characteristics', 'CPA', (77, 102))	('loss', 'NegReg', (34, 38))	('BAP1', 'Gene', '8314', (6, 10))
5318	31109147	In uveal melanoma, BAP1 mutations cause cell phenotype modifications, which are associated with metastatic disease in 84% of patients and class 2 genetic features (with high metastatic potential).	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('BAP1', 'Gene', '8314', (19, 23))	('associated', 'Reg', (80, 90))	('cell', 'MPA', (40, 44))	('BAP1', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))	('metastatic disease', 'Disease', (96, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))	('patients', 'Species', '9606', (125, 133))
5319	31109147	demonstrated that BAP1 depletion increases the amount of transmigration in uveal melanoma cells, giving valuable insight into the metastasization promoting mechanism.	('BAP1', 'Gene', '8314', (18, 22))	('depletion', 'Var', (23, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (75, 89))	('BAP1', 'Gene', (18, 22))	('increases', 'PosReg', (33, 42))	('uveal melanoma', 'Disease', 'MESH:C536494', (75, 89))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('uveal melanoma', 'Disease', (75, 89))	('transmigration', 'MPA', (57, 71))
5320	31109147	Germline mutations in BAP1 have been observed in 22% of familial uveal melanoma and could be associated with early onset.	('Germline mutations', 'Var', (0, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('familial uveal melanoma', 'Disease', 'MESH:C536494', (56, 79))	('familial uveal melanoma', 'Disease', (56, 79))	('observed', 'Reg', (37, 45))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('associated', 'Reg', (93, 103))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', (22, 26))
5322	31109147	Mutation at codon 625 of the splicing factor 3b subunit 1 (SF3B1) gene (chromosome 2q) is associated with uveal melanoma development.	('SF3B1', 'Gene', '23451', (59, 64))	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('splicing factor 3b subunit 1', 'Gene', (29, 57))	('SF3B1', 'Gene', (59, 64))	('Mutation at codon', 'Var', (0, 17))	('splicing factor 3b subunit 1', 'Gene', '23451', (29, 57))	('associated with', 'Reg', (90, 105))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('uveal melanoma', 'Disease', (106, 120))	('splicing', 'biological_process', 'GO:0045292', ('29', '37'))
5323	31109147	SF3B1 is involved in mRNA splicing; therefore, its mutation causes splicing dysregulations and alters the transcription process.	('mRNA splicing', 'biological_process', 'GO:0000398', ('21', '34'))	('causes', 'Reg', (60, 66))	('SF3B1', 'Gene', (0, 5))	('mRNA splicing', 'biological_process', 'GO:0000394', ('21', '34'))	('mRNA splicing', 'biological_process', 'GO:0000372', ('21', '34'))	('alters', 'Reg', (95, 101))	('mRNA splicing', 'biological_process', 'GO:0006371', ('21', '34'))	('splicing dysregulations', 'MPA', (67, 90))	('SF3B1', 'Gene', '23451', (0, 5))	('splicing', 'biological_process', 'GO:0045292', ('67', '75'))	('transcription process', 'MPA', (106, 127))	('mutation', 'Var', (51, 59))	('mRNA splicing', 'biological_process', 'GO:0000374', ('21', '34'))	('transcription', 'biological_process', 'GO:0006351', ('106', '119'))	('mRNA splicing', 'biological_process', 'GO:0000373', ('21', '34'))
5324	31109147	SF3B1 mutation has been found in about 15% to 19% of UM cases.	('SF3B1', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('SF3B1', 'Gene', '23451', (0, 5))	('UM', 'Phenotype', 'HP:0007716', (53, 55))	('found', 'Reg', (24, 29))
5325	31109147	Interestingly, mutation in SF3B1 gene is mutually exclusive of BAP1 mutations and is usually associated with disomy of chromosome 3.	('disomy of chromosome 3', 'Disease', (109, 131))	('mutation', 'Var', (15, 23))	('chromosome', 'cellular_component', 'GO:0005694', ('119', '129'))	('BAP1', 'Gene', (63, 67))	('SF3B1', 'Gene', (27, 32))	('associated', 'Reg', (93, 103))	('SF3B1', 'Gene', '23451', (27, 32))	('BAP1', 'Gene', '8314', (63, 67))
5328	31109147	Alterations in EIF1AX gene are usually missense involving the N-terminal portion of the encoded protein.	('N-terminal portion of the', 'MPA', (62, 87))	('Alterations', 'Var', (0, 11))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('EIF1AX', 'Gene', '1964', (15, 21))	('EIF1AX', 'Gene', (15, 21))	('missense involving', 'Var', (39, 57))
5332	31109147	reported a 10-fold lower metastatic risk in patients with disomy 3 and EIF1AX mutation.	('metastatic', 'CPA', (25, 35))	('patients', 'Species', '9606', (44, 52))	('EIF1AX', 'Gene', '1964', (71, 77))	('EIF1AX', 'Gene', (71, 77))	('disomy 3', 'Var', (58, 66))	('lower', 'NegReg', (19, 24))
5334	31109147	The reported frequency of EIF1AX gene mutation is in the range of 8-18.9% of primary uveal melanoma cases.	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('EIF1AX', 'Gene', '1964', (26, 32))	('EIF1AX', 'Gene', (26, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (85, 99))	('uveal melanoma', 'Disease', 'MESH:C536494', (85, 99))	('mutation', 'Var', (38, 46))	('uveal melanoma', 'Disease', (85, 99))
5335	31109147	Telomerase reverse transcriptase (TERT) promoter mutation rarely causes uveal melanoma, representing about 1% of cases, while it is more common in conjunctival melanoma (41%) and primary-acquired melanosis (PAM) with atypia (8%).	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('uveal melanoma', 'Disease', (72, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('conjunctival melanoma', 'Disease', (147, 168))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (147, 168))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('TERT', 'Gene', (34, 38))	('transcriptase', 'molecular_function', 'GO:0003899', ('19', '32'))	('transcriptase', 'molecular_function', 'GO:0003968', ('19', '32'))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (147, 168))	('mutation', 'Var', (49, 57))	('melanosis', 'Disease', (196, 205))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanosis', 'Disease', 'MESH:D008548', (196, 205))	('TERT', 'Gene', '7015', (34, 38))	('transcriptase', 'molecular_function', 'GO:0034062', ('19', '32'))	('causes', 'Reg', (65, 71))	('common', 'Reg', (137, 143))
5336	31109147	To the best of our knowledge, two cases of uveal melanoma were reported in literature due to TERT promoter mutation with increased expression of the gene in the tumour.	('increased', 'PosReg', (121, 130))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('uveal melanoma', 'Disease', 'MESH:C536494', (43, 57))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('expression', 'MPA', (131, 141))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('uveal melanoma', 'Disease', (43, 57))	('due to', 'Reg', (86, 92))	('tumour', 'Disease', (161, 167))	('TERT', 'Gene', (93, 97))	('TERT', 'Gene', '7015', (93, 97))	('mutation', 'Var', (107, 115))
5337	31109147	Alteration in the TERT promoter gene, with an increase in its expression, leads to the immortalization of somatic cells.	('increase', 'PosReg', (46, 54))	('Alteration', 'Var', (0, 10))	('expression', 'MPA', (62, 72))	('TERT', 'Gene', (18, 22))	('immortalization of somatic cells', 'CPA', (87, 119))	('leads to', 'Reg', (74, 82))	('TERT', 'Gene', '7015', (18, 22))
5338	31109147	Tumours carrying this mutation also showed GNA11 gene alteration, Table 1.	('GNA11', 'Gene', (43, 48))	('mutation', 'Var', (22, 30))	('GNA11', 'Gene', '2767', (43, 48))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))
5346	31109147	The analysis of these two subgroups highlighted that: (i) class 1 tumour is characterised by a chromosome 6p gain; (ii) class 2 tumour is characterised by a loss of chromosome 3, associated with a gain of chromosome 8q.	('tumour', 'Disease', (128, 134))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumour', 'Disease', (66, 72))	('chromosome', 'cellular_component', 'GO:0005694', ('165', '175'))	('chromosome', 'Var', (95, 105))	('chromosome', 'cellular_component', 'GO:0005694', ('95', '105'))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('chromosome', 'cellular_component', 'GO:0005694', ('205', '215'))	('gain', 'PosReg', (197, 201))	('gain', 'PosReg', (109, 113))	('chromosome 3', 'Protein', (165, 177))	('loss', 'NegReg', (157, 161))	('tumour', 'Disease', 'MESH:D009369', (128, 134))
5355	31109147	Moreover, analysing uveal melanoma drivers of mutations, PRAME+ status was found to be directly associated with SF3B1 alterations, while it was inversely associated with EIF1AX changes in class 1 tumours.	('mutations', 'Var', (46, 55))	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('alterations', 'Var', (118, 129))	('associated', 'Reg', (96, 106))	('EIF1AX', 'Gene', (170, 176))	('SF3B1', 'Gene', '23451', (112, 117))	('EIF1AX', 'Gene', '1964', (170, 176))	('tumours', 'Phenotype', 'HP:0002664', (196, 203))	('uveal melanoma', 'Disease', 'MESH:C536494', (20, 34))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('PRAME', 'Gene', '23532', (57, 62))	('tumours', 'Disease', 'MESH:D009369', (196, 203))	('tumours', 'Disease', (196, 203))	('PRAME', 'Gene', (57, 62))	('uveal melanoma', 'Phenotype', 'HP:0007716', (20, 34))	('uveal melanoma', 'Disease', (20, 34))	('SF3B1', 'Gene', (112, 117))
5356	31109147	It has been reported that the PRAME promoter region became hypomethylated and thus activated during UM progression.	('hypomethylated', 'Var', (59, 73))	('UM', 'Phenotype', 'HP:0007716', (100, 102))	('PRAME', 'Gene', '23532', (30, 35))	('activated', 'PosReg', (83, 92))	('PRAME', 'Gene', (30, 35))
5360	31109147	In the onset/progression of different cancers, including UM, many chromosome aberrations and point mutations may occur.	('chromosome aberrations', 'Var', (66, 88))	('chromosome', 'cellular_component', 'GO:0005694', ('66', '76'))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('point mutations', 'Var', (93, 108))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancers', 'Disease', (38, 45))	('occur', 'Reg', (113, 118))
5364	31109147	These PyVs exert their transforming capabilities in human cells through the products of their viral oncogenes, the large T antigen (Tag) and small t antigen (tag).	('Tag', 'Gene', '404663', (132, 135))	('tag', 'Gene', '404663', (158, 161))	('transforming capabilities', 'CPA', (23, 48))	('PyVs', 'Species', '36362', (6, 10))	('human', 'Species', '9606', (52, 57))	('tag', 'Gene', (158, 161))	('Tag', 'Gene', (132, 135))	('small t antigen', 'Var', (141, 156))	('large', 'Protein', (115, 120))
5376	31109147	Traditionally, different types of radionuclides are used for ophthalmic brachytherapy, including ruthenium-106 (106Ru), iodine-125 (125I) and palladium-103 (103Pd).	('radionuclides', 'Chemical', 'MESH:D011868', (34, 47))	('106Ru', 'Var', (112, 117))	('103Pd', 'Var', (157, 162))	('ruthenium-106', 'Chemical', 'MESH:C000615522', (97, 110))	('iodine-125', 'Chemical', 'MESH:C000614960', (120, 130))	('palladium-103', 'Chemical', 'MESH:C000615531', (142, 155))
5411	31109147	A phase II follow-up trial confirmed a significant potential survival benefit of 14 months for patients treated with IHP compared to the longest surviving patients in Sweden during the same time period.	('survival', 'CPA', (61, 69))	('IHP', 'Var', (117, 120))	('patients', 'Species', '9606', (95, 103))	('patients', 'Species', '9606', (155, 163))
5433	31109147	Improved understanding of cutaneous and uveal melanoma mutations, particularly those involving the mitogen-activated protein kinase pathway have led to the development of targeted therapies.	('mitogen-activated protein kinase pathway', 'Pathway', (99, 139))	('involving', 'Reg', (85, 94))	('mutations', 'Var', (55, 64))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('cutaneous', 'Disease', (26, 35))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))	('uveal melanoma', 'Disease', (40, 54))	('uveal melanoma', 'Disease', 'MESH:C536494', (40, 54))
5436	31109147	Since primary uveal melanoma tumours and liver metastases, characterised by mutations in GNAQ or GNA11, have constitutive activation MAPK signalling via alternative, similar therapies targeting downstream effectors of the MEK pathway, Akt and protein kinase C (PKC) were recently investigated.	('MEK', 'Gene', '5609', (222, 225))	('MAPK', 'molecular_function', 'GO:0004707', ('133', '137'))	('activation', 'PosReg', (122, 132))	('MAPK signalling', 'biological_process', 'GO:0000165', ('133', '148'))	('GNA11', 'Gene', '2767', (97, 102))	('MEK', 'Gene', (222, 225))	('uveal melanoma', 'Phenotype', 'HP:0007716', (14, 28))	('liver metastases', 'Disease', (41, 57))	('uveal melanoma tumours', 'Disease', 'MESH:C536494', (14, 36))	('Akt', 'Gene', (235, 238))	('protein kinase C', 'Gene', '112476', (243, 259))	('protein kinase C', 'Gene', (243, 259))	('Akt', 'Gene', '207', (235, 238))	('PKC', 'Gene', '112476', (261, 264))	('protein', 'cellular_component', 'GO:0003675', ('243', '250'))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('uveal melanoma tumours', 'Disease', (14, 36))	('GNA11', 'Gene', (97, 102))	('PKC', 'molecular_function', 'GO:0004697', ('261', '264'))	('mutations', 'Var', (76, 85))	('GNAQ', 'Gene', '2776', (89, 93))	('PKC', 'Gene', (261, 264))	('liver metastases', 'Disease', 'MESH:D009362', (41, 57))	('MAPK signalling', 'MPA', (133, 148))	('GNAQ', 'Gene', (89, 93))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))
5447	31109147	Mutations in GNAQ and GNA11 activate both MEK and Akt, thus an alternative approach might be offered by a simultaneous inhibition of these two pathways.	('GNA11', 'Gene', (22, 27))	('Akt', 'Gene', '207', (50, 53))	('GNAQ', 'Gene', (13, 17))	('activate', 'PosReg', (28, 36))	('GNA11', 'Gene', '2767', (22, 27))	('Akt', 'Gene', (50, 53))	('MEK', 'Gene', (42, 45))	('MEK', 'Gene', '5609', (42, 45))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', '2776', (13, 17))
5452	31109147	Preliminary data shown during last Society of Melanoma Research (SRM) Congress suggest encouraging clinical activity of LXS196 as monotherapy in patients with metastatic UM.	('LXS196', 'Var', (120, 126))	('patients', 'Species', '9606', (145, 153))	('metastatic UM', 'Disease', (159, 172))	('LXS196', 'Chemical', '-', (120, 126))	('Melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('UM', 'Phenotype', 'HP:0007716', (170, 172))	('Melanoma', 'Disease', 'MESH:D008545', (46, 54))	('Melanoma', 'Disease', (46, 54))
5458	31109147	Furthermore, as a consequence of GNAQ/GNA11 mutation, an upregulation of MET has been implicated in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('mutation', 'Var', (44, 52))	('GNAQ', 'Gene', (33, 37))	('uveal melanoma', 'Disease', (100, 114))	('GNAQ', 'Gene', '2776', (33, 37))	('upregulation', 'PosReg', (57, 69))	('GNA11', 'Gene', '2767', (38, 43))	('GNA11', 'Gene', (38, 43))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('MET', 'MPA', (73, 76))
5464	31109147	Recently, it has been demonstrated the role of cMET in the primary resistance to MEK inhibitors in metastatic UM with GNAQ/11 mutation.	('GNAQ', 'Gene', (118, 122))	('UM', 'Phenotype', 'HP:0007716', (110, 112))	('mutation', 'Var', (126, 134))	('cMET', 'Gene', '4233', (47, 51))	('metastatic UM', 'Disease', (99, 112))	('GNAQ', 'Gene', '2776', (118, 122))	('cMET', 'Gene', (47, 51))	('MEK', 'Gene', (81, 84))	('MEK', 'Gene', '5609', (81, 84))
5483	31109147	Promising responses for metastatic UM have been observed in some retrospective or small prospective clinical trials that evaluated antibodies against two of the main molecules involved in the inhibition of the T-cell activation, CTLA-4 and PD-1.	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('PD-1', 'Gene', (240, 244))	('metastatic UM', 'CPA', (24, 37))	('PD-1', 'Gene', '5133', (240, 244))	('CTLA-4', 'Gene', (229, 235))	('T-cell activation', 'biological_process', 'GO:0042110', ('210', '227'))	('antibodies', 'Var', (131, 141))
5519	31109147	Recently, it has been reported few cases of UM with high tumour mutation burden correlated with a germline loss-of-function MBD4 mutation that were responsive to these agents.	('high tumour', 'Disease', (52, 63))	('high tumour', 'Disease', 'MESH:D009369', (52, 63))	('mutation', 'Var', (129, 137))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('loss-of-function', 'NegReg', (107, 123))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('MBD4', 'Gene', '8930', (124, 128))	('MBD4', 'Gene', (124, 128))
5523	31109147	Currently, a phase III trial (NCT01983748) is recruiting patients suffering from uveal melanoma typed positive for monosomy 3 and without evidence for metastases who will be vaccinated over a two-year period with dendritic cells loaded with autologous tumour RNA.	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('positive', 'Reg', (102, 110))	('patients', 'Species', '9606', (57, 65))	('metastases', 'Disease', 'MESH:D009362', (151, 161))	('tumour', 'Disease', (252, 258))	('uveal melanoma', 'Disease', 'MESH:C536494', (81, 95))	('monosomy 3', 'Var', (115, 125))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('uveal melanoma', 'Disease', (81, 95))	('RNA', 'cellular_component', 'GO:0005562', ('259', '262'))	('tumour', 'Phenotype', 'HP:0002664', (252, 258))	('metastases', 'Disease', (151, 161))	('tumour', 'Disease', 'MESH:D009369', (252, 258))
5553	31109147	As mentioned above, alterations in tumour suppressor genes or oncogenes can be generated by mutations or by transcriptional regulation by epigenetic mechanisms.	('epigenetic', 'Var', (138, 148))	('mutations', 'Var', (92, 101))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('regulation', 'biological_process', 'GO:0065007', ('124', '134'))	('oncogenes', 'Gene', (62, 71))	('alterations', 'Reg', (20, 31))	('tumour', 'Disease', (35, 41))
5592	29701682	Detection of ctDNA fragments relies on the identification of specific, known genetic alterations derived from mutations, chromosomal rearrangements, and copy number variations and amplifications, therefore tumor heterogeneity continues to challenge this field.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('mutations', 'Var', (110, 119))	('copy number variations', 'Var', (153, 175))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
5618	29701682	It is therefore not surprising that dysregulation of the miRNA expression profile contributes to several pathologies, including inflammation, cardiovascular diseases, neurological disorders, and many types of cancer.	('dysregulation', 'Var', (36, 49))	('contributes', 'Reg', (82, 93))	('miR', 'Gene', '220972', (57, 60))	('miR', 'Gene', (57, 60))	('inflammation', 'Disease', (128, 140))	('neurological disorders', 'Disease', 'MESH:D009422', (167, 189))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('inflammation', 'biological_process', 'GO:0006954', ('128', '140'))	('pathologies', 'Disease', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('neurological disorders', 'Disease', (167, 189))	('cardiovascular diseases', 'Disease', (142, 165))	('cancer', 'Disease', (209, 215))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (142, 165))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (142, 165))	('inflammation', 'Disease', 'MESH:D007249', (128, 140))
5620	29701682	Over the past decade, it has become increasingly clear that miRNA expression is dysregulated in human malignancies; a result of chromosomal abnormalities (i.e., insertions, deletions, and amplifications), transcriptional control changes, epigenetic changes, and defects in the miRNA biogenesis machinery, and that miRNA dysregulation directly contributes to the acquisition of the hallmarks of cancer, as defined by Hanahan and Weinberg.	('miR', 'Gene', '220972', (60, 63))	('miR', 'Gene', (277, 280))	('chromosomal abnormalities', 'Disease', (128, 153))	('cancer', 'Disease', 'MESH:D009369', (394, 400))	('transcriptional control', 'CPA', (205, 228))	('epigenetic changes', 'Var', (238, 256))	('defects', 'NegReg', (262, 269))	('miR', 'Gene', '220972', (314, 317))	('contributes', 'Reg', (343, 354))	('changes', 'Reg', (229, 236))	('miR', 'Gene', (60, 63))	('human', 'Species', '9606', (96, 101))	('miRNA biogenesis', 'biological_process', 'GO:0035196', ('277', '293'))	('miR', 'Gene', (314, 317))	('malignancies', 'Disease', 'MESH:D009369', (102, 114))	('amplifications', 'Var', (188, 202))	('transcriptional control', 'biological_process', 'GO:0006355', ('205', '228'))	('insertions', 'Var', (161, 171))	('malignancies', 'Disease', (102, 114))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (128, 153))	('cancer', 'Disease', (394, 400))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('miR', 'Gene', '220972', (277, 280))	('deletions', 'Var', (173, 182))
5719	29701682	High expression of serum miR-21 matches high miR-21 expression in metastatic melanoma tissues and an increase in miR-21 from controls through to advanced melanoma stages suggests this miRNA has possible prognostic value.	('high', 'Var', (40, 44))	('expression', 'MPA', (5, 15))	('miR', 'Gene', (45, 48))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('miR', 'Gene', '220972', (113, 116))	('miR-21', 'Gene', (45, 51))	('metastatic melanoma', 'Disease', (66, 85))	('increase', 'PosReg', (101, 109))	('miR', 'Gene', '220972', (25, 28))	('miR-21', 'Gene', '406991', (113, 119))	('metastatic melanoma', 'Disease', 'MESH:D008545', (66, 85))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('miR-21', 'Gene', '406991', (25, 31))	('miR', 'Gene', '220972', (184, 187))	('miR', 'Gene', (113, 116))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('miR', 'Gene', (25, 28))	('melanoma', 'Disease', (77, 85))	('miR', 'Gene', (184, 187))	('miR-21', 'Gene', (113, 119))	('miR-21', 'Gene', (25, 31))	('expression', 'MPA', (52, 62))	('miR', 'Gene', '220972', (45, 48))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('miR-21', 'Gene', '406991', (45, 51))
5724	29701682	Furthermore, patients with high serum miR-221 levels had a significantly lower 5-year rate and recurrence free survival (RFS) rate than those with low serum miR-221 level.	('miR-221', 'Gene', (38, 45))	('patients', 'Species', '9606', (13, 21))	('miR-221', 'Gene', '407006', (157, 164))	('high', 'Var', (27, 31))	('recurrence free survival', 'CPA', (95, 119))	('RFS', 'Disease', (121, 124))	('miR-221', 'Gene', '407006', (38, 45))	('lower', 'NegReg', (73, 78))	('RFS', 'Disease', 'MESH:D005198', (121, 124))	('5-year rate', 'CPA', (79, 90))	('miR-221', 'Gene', (157, 164))
5750	29701682	Because the measurement of miRNAs is inaccurate at very low levels due to stochastic effect, it can be advisable to use a Cq cut-off e.g., Cq > 32 (we routinely use Cq > 35).	('Cq > 32', 'Var', (139, 146))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))
5806	29701682	For example, deregulation of circulating miR-210 has been associated with renal cell carcinoma, prostate cancer, glioma, and pancreatic cancer in addition to melanoma.	('pancreatic cancer', 'Disease', 'MESH:D010190', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('deregulation', 'Var', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('prostate cancer', 'Disease', 'MESH:D011471', (96, 111))	('renal cell carcinoma', 'Disease', (74, 94))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (74, 94))	('pancreatic cancer', 'Disease', (125, 142))	('glioma', 'Disease', (113, 119))	('prostate cancer', 'Disease', (96, 111))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('miR-210', 'Gene', '406992', (41, 48))	('melanoma', 'Disease', (158, 166))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('miR-210', 'Gene', (41, 48))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (125, 142))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('associated', 'Reg', (58, 68))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (74, 94))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))
5811	29701682	As well as the advantages described above, RNA-Seq can detect miRNA isomers, including those that have been modified by the addition of U's and/or A's at the 3' end.	('U', 'Var', (136, 137))	('RNA', 'cellular_component', 'GO:0005562', ('43', '46'))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('A', 'Var', (147, 148))
5812	29701682	For example, a study on placental-specific miRNAs showed that miR-498 cluster variants had varying degrees of adenylation at the 3' end of certain miRNAs.	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (43, 46))	('miR-498', 'Gene', (62, 69))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('miR', 'Gene', '220972', (147, 150))	('miR', 'Gene', (147, 150))	('adenylation', 'MPA', (110, 121))	('variants', 'Var', (78, 86))	('miR-498', 'Gene', '574460', (62, 69))
5816	29701682	Aberrant expression of TUTases and Dis3L2 has been shown in some cancers suggesting a mechanistic link to these modified miRNAs.	('Aberrant', 'Var', (0, 8))	('Dis3L2', 'Gene', '129563', (35, 41))	('TUTases', 'Gene', (23, 30))	('Dis3L2', 'Gene', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('expression', 'MPA', (9, 19))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('miR', 'Gene', '220972', (121, 124))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('miR', 'Gene', (121, 124))	('cancers', 'Disease', (65, 72))
5876	29016654	The largest holoclones, containing between 2500-6000 cells, are described as displaying heterogeneity and as derived from cancer-initiating cells, middle sized meroclones (500-2500 cells) are probably derived from transit-amplifying cells and the smallest paraclones (<500 cells) are loosely packed cells, derived from differentiated cells.	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('500-2500 cells', 'Var', (172, 186))	('meroclones', 'Chemical', '-', (160, 170))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
5894	29016654	Despite the fact that the two melanoma lines tested were of a different origin (uveal and cutaneous), in both of them the proton beam, but not photon radiation, caused the inhibition of actively proliferating cells and long-term motility inhibition.	('proton beam', 'Var', (122, 133))	('long-term motility', 'CPA', (219, 237))	('actively proliferating cells', 'CPA', (186, 214))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Disease', (30, 38))	('inhibition', 'NegReg', (172, 182))
5904	29016654	Such increase in RBE is significant, for example, application of variable RBE resulted in an increase of RBE weighted dose in the SOBP plateau by approximately 18% for both normal and tumor human cells.	('RBE weighted dose', 'MPA', (105, 122))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('increase', 'PosReg', (93, 101))	('SOBP', 'Gene', (130, 134))	('SOBP', 'Gene', '55084', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('human', 'Species', '9606', (190, 195))	('variable', 'Var', (65, 73))
5923	29016654	Epigenetic changes may be responsible for maintaining post-radiation phenotype, and the presence of cancer stem cells may impact the post-radiation long-term response.	('post-radiation long-term response', 'CPA', (133, 166))	('impact', 'Reg', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('Epigenetic changes', 'Var', (0, 18))
5929	29016654	For 125I brachytherapy, the COMS study report 12-year mortality for older patients with large tumors also at 30%.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('patients', 'Species', '9606', (74, 82))	('125I', 'Var', (4, 8))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
5955	27119653	LCMN and GCMN are also more likely to be associated with satellite lesions and benign proliferative nodules within the lesion that can resemble melanoma.	('LCMN', 'Var', (0, 4))	('MN', 'Phenotype', 'HP:0000995', (11, 13))	('associated', 'Reg', (41, 51))	('satellite', 'Disease', (57, 66))	('MN', 'CellLine', 'CVCL:U508', (11, 13))	('benign proliferative nodules', 'CPA', (79, 107))	('MN', 'Phenotype', 'HP:0000995', (2, 4))	('MN', 'CellLine', 'CVCL:U508', (2, 4))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('GCMN', 'Var', (9, 13))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))
5957	27119653	CMN have long been recognized to be associated with an increased risk for melanoma formation within the existing CMN.	('formation', 'biological_process', 'GO:0009058', ('83', '92'))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('MN', 'CellLine', 'CVCL:U508', (114, 116))	('melanoma', 'Disease', (74, 82))	('MN', 'Phenotype', 'HP:0000995', (114, 116))	('CMN', 'Var', (0, 3))	('MN', 'CellLine', 'CVCL:U508', (1, 3))	('MN', 'Phenotype', 'HP:0000995', (1, 3))
5960	27119653	There is evidence to suggest that the risk for melanoma is higher with axial CMN and in the presence of satellite lesions.	('axial CMN', 'Var', (71, 80))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('MN', 'Phenotype', 'HP:0000995', (78, 80))	('MN', 'CellLine', 'CVCL:U508', (78, 80))
5982	27119653	LCMN and GCMN have also been associated with benign proliferative nodules that arise within the lesion and can clinically and histologically simulate melanoma.	('LCMN', 'Var', (0, 4))	('MN', 'Phenotype', 'HP:0000995', (11, 13))	('MN', 'CellLine', 'CVCL:U508', (11, 13))	('GCMN', 'Var', (9, 13))	('MN', 'Phenotype', 'HP:0000995', (2, 4))	('MN', 'CellLine', 'CVCL:U508', (2, 4))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('associated', 'Reg', (29, 39))	('melanoma', 'Disease', (150, 158))	('benign proliferative nodules', 'Disease', (45, 73))
5984	27119653	A large proportion of CMN have been found to harbor mutations in codon 61 of the NRAS gene, located on chromosome 1.	('chromosome', 'cellular_component', 'GO:0005694', ('103', '113'))	('CMN', 'Disease', (22, 25))	('NRAS', 'Gene', (81, 85))	('MN', 'Phenotype', 'HP:0000995', (23, 25))	('NRAS', 'Gene', '4893', (81, 85))	('MN', 'CellLine', 'CVCL:U508', (23, 25))	('mutations in', 'Var', (52, 64))
5988	27119653	Oncogenic BRAF and NRAS mutations have been reported in both MN and melanoma.	('NRAS', 'Gene', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('NRAS', 'Gene', '4893', (19, 23))	('melanoma', 'Disease', (68, 76))	('MN', 'Phenotype', 'HP:0000995', (61, 63))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('BRAF', 'Gene', (10, 14))	('reported', 'Reg', (44, 52))	('BRAF', 'Gene', '673', (10, 14))	('MN', 'CellLine', 'CVCL:U508', (61, 63))	('mutations', 'Var', (24, 33))
5989	27119653	Mutations in either BRAF or genes encoding other proteins in the MAPK signaling pathway play an important role in the development of both types of lesions.	('signaling pathway', 'biological_process', 'GO:0007165', ('70', '87'))	('men', 'Species', '9606', (125, 128))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', '673', (20, 24))	('MAPK', 'molecular_function', 'GO:0004707', ('65', '69'))	('BRAF', 'Gene', (20, 24))	('MAPK signaling', 'biological_process', 'GO:0000165', ('65', '79'))
5990	27119653	NRAS mutations occur with varying frequency depending on the size of the lesion.	('NRAS', 'Gene', '4893', (0, 4))	('NRAS', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
5991	27119653	An aggregate of data from multiple studies demonstrated NRAS mutations in 63% of LCMN and 45% of MCMN, while no mutations were found in SCMN.	('NRAS', 'Gene', (56, 60))	('MN', 'Phenotype', 'HP:0000995', (83, 85))	('NRAS', 'Gene', '4893', (56, 60))	('MN', 'CellLine', 'CVCL:U508', (138, 140))	('mutations', 'Var', (61, 70))	('MN', 'CellLine', 'CVCL:U508', (83, 85))	('MN', 'Phenotype', 'HP:0000995', (138, 140))	('MN', 'CellLine', 'CVCL:U508', (99, 101))	('MN', 'Phenotype', 'HP:0000995', (99, 101))
5994	27119653	CNS samples from patients with primary CNS melanoma and neuromelanosis showed the same NRAS mutation as found in their skin lesion.	('NRAS', 'Gene', '4893', (87, 91))	('mutation', 'Var', (92, 100))	('primary CNS melanoma', 'Phenotype', 'HP:0030069', (31, 51))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('patients', 'Species', '9606', (17, 25))	('primary CNS melanoma and neuromelanosis', 'Disease', 'MESH:C537387', (31, 70))	('skin lesion', 'Disease', 'MESH:D012871', (119, 130))	('NRAS', 'Gene', (87, 91))	('skin lesion', 'Disease', (119, 130))
5995	27119653	In some cases, loss of heterozygosity was associated with the progression to malignancy.	('associated', 'Reg', (42, 52))	('malignancy', 'Disease', (77, 87))	('malignancy', 'Disease', 'MESH:D009369', (77, 87))	('loss of heterozygosity', 'Var', (15, 37))
5996	27119653	NRAS codon 61 mutations have also been shown to occur with higher frequency in CMN on anatomical sites with chronic sun exposure.	('CMN', 'Disease', (79, 82))	('mutations', 'Var', (14, 23))	('MN', 'Phenotype', 'HP:0000995', (80, 82))	('MN', 'CellLine', 'CVCL:U508', (80, 82))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))
5997	27119653	NRAS and BRAF mutations seem to occur in a mutually exclusive pattern in CMN.	('BRAF', 'Gene', (9, 13))	('CMN', 'Disease', (73, 76))	('NRAS', 'Gene', '4893', (0, 4))	('NRAS', 'Gene', (0, 4))	('occur', 'Reg', (32, 37))	('MN', 'CellLine', 'CVCL:U508', (74, 76))	('MN', 'Phenotype', 'HP:0000995', (74, 76))	('mutations', 'Var', (14, 23))	('BRAF', 'Gene', '673', (9, 13))
5998	27119653	Studies have found NRAS to be the principle mutation present in LCMN; BRAF V600E mutations are found in as many as 9% of lesions.	('MN', 'Phenotype', 'HP:0000995', (66, 68))	('MN', 'CellLine', 'CVCL:U508', (66, 68))	('NRAS', 'Gene', (19, 23))	('V600E', 'Mutation', 'rs113488022', (75, 80))	('NRAS', 'Gene', '4893', (19, 23))	('V600E', 'Var', (75, 80))	('BRAF', 'Gene', '673', (70, 74))	('BRAF', 'Gene', (70, 74))
5999	27119653	Conversely, combined data from several studies showed BRAF mutations in 88% of SCMN and 25% of MCMN.	('SCMN', 'Disease', (79, 83))	('BRAF', 'Gene', '673', (54, 58))	('BRAF', 'Gene', (54, 58))	('MN', 'CellLine', 'CVCL:U508', (97, 99))	('MN', 'Phenotype', 'HP:0000995', (97, 99))	('mutations', 'Var', (59, 68))	('MN', 'Phenotype', 'HP:0000995', (81, 83))	('MN', 'CellLine', 'CVCL:U508', (81, 83))
6001	27119653	Compared to NRAS, BRAF mutant lesions show more extensive dermal and subcutaneous nodules.	('NRAS', 'Gene', (12, 16))	('NRAS', 'Gene', '4893', (12, 16))	('BRAF', 'Gene', '673', (18, 22))	('subcutaneous nodules', 'Phenotype', 'HP:0001482', (69, 89))	('BRAF', 'Gene', (18, 22))	('mutant', 'Var', (23, 29))
6002	27119653	BRAF mutant CMN also appear to have a higher association with the development of proliferative nodules.	('MN', 'CellLine', 'CVCL:U508', (13, 15))	('MN', 'Phenotype', 'HP:0000995', (13, 15))	('CMN', 'Gene', (12, 15))	('men', 'Species', '9606', (73, 76))	('proliferative nodules', 'CPA', (81, 102))	('BRAF', 'Gene', '673', (0, 4))	('mutant', 'Var', (5, 11))	('BRAF', 'Gene', (0, 4))
6004	27119653	Missense mutations in MC1R and silent mutations in TP53 have been reported in 17% and 11%, respectively, of a series of 18 SCMN and MCMN, with no CDKN2A or CDK4 mutations found.	('CDKN2A', 'Gene', (146, 152))	('CDK4', 'Gene', (156, 160))	('MC1R', 'Gene', (22, 26))	('TP53', 'Gene', (51, 55))	('CDKN2A', 'Gene', '1029', (146, 152))	('MN', 'CellLine', 'CVCL:U508', (125, 127))	('CDK4', 'Gene', '1019', (156, 160))	('MN', 'Phenotype', 'HP:0000995', (125, 127))	('CDK', 'molecular_function', 'GO:0004693', ('156', '159'))	('reported', 'Reg', (66, 74))	('MN', 'CellLine', 'CVCL:U508', (134, 136))	('silent mutations', 'Var', (31, 47))	('MN', 'Phenotype', 'HP:0000995', (134, 136))	('MC1R', 'Gene', '4157', (22, 26))	('TP53', 'Gene', '7157', (51, 55))	('Missense mutations', 'Var', (0, 18))
6005	27119653	The prevalence of HRAS, KRAS and GNAQ mutations was reported to range from 3% to 7% in a series of 43 CMN with proliferative nodules.	('MN', 'CellLine', 'CVCL:U508', (103, 105))	('KRAS', 'Gene', '3845', (24, 28))	('MN', 'Phenotype', 'HP:0000995', (103, 105))	('HRAS', 'Gene', '3265', (18, 22))	('GNAQ', 'Gene', (33, 37))	('HRAS', 'Gene', (18, 22))	('GNAQ', 'Gene', '2776', (33, 37))	('mutations', 'Var', (38, 47))	('to 7', 'Species', '1214577', (78, 82))	('KRAS', 'Gene', (24, 28))
6007	27119653	In human melanoma cells, Sox10 silencing suppresses melanoma formation by interrupting neural crest stem cell function.	('silencing', 'Var', (31, 40))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma', 'Disease', (9, 17))	('Sox10', 'Gene', (25, 30))	('human', 'Species', '9606', (3, 8))	('interrupting', 'NegReg', (74, 86))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('suppresses', 'NegReg', (41, 51))	('Sox10', 'Gene', '6663', (25, 30))	('neural crest stem cell function', 'CPA', (87, 118))	('formation', 'biological_process', 'GO:0009058', ('61', '70'))
6019	27119653	Architectural disorder refers to deviations in growth from an ordinary acquired compound nevus, including, but not limited to some asymmetry of the lesion's silhouette, variation in size and shape of nests, irregular placement of nests, and lentiginous melanocytic growth along the tips and sides of rete ridges and above dermal papillae (Figure 3C).	('nests', 'CPA', (200, 205))	('rete ridges', 'Phenotype', 'HP:0025117', (300, 311))	('variation', 'Var', (169, 178))	('lentiginous melanocytic growth along the tips', 'Disease', (241, 286))	('men', 'Species', '9606', (222, 225))	('lentiginous melanocytic growth along the tips', 'Disease', 'MESH:D007911', (241, 286))	('nevus', 'Phenotype', 'HP:0003764', (89, 94))	('Architectural disorder', 'Disease', (0, 22))
6027	27119653	Combined data from several studies have shown BRAF V600E mutations in 61% of DN.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('DN', 'Phenotype', 'HP:0001062', (77, 79))	('V600E', 'Var', (51, 56))	('V600E', 'Mutation', 'rs113488022', (51, 56))
6028	27119653	No association has been found between the grade of dysplasia and BRAF mutational status.	('mutational', 'Var', (70, 80))	('dysplasia', 'Disease', 'MESH:D004476', (51, 60))	('BRAF', 'Gene', '673', (65, 69))	('BRAF', 'Gene', (65, 69))	('dysplasia', 'Disease', (51, 60))
6029	27119653	Activation of the MAPK signaling pathway has been observed in 54% of DN harboring BRAF mutations.	('MAPK signaling', 'biological_process', 'GO:0000165', ('18', '32'))	('MAPK signaling pathway', 'Pathway', (18, 40))	('BRAF', 'Gene', '673', (82, 86))	('DN', 'Phenotype', 'HP:0001062', (69, 71))	('BRAF', 'Gene', (82, 86))	('Activation', 'PosReg', (0, 10))	('MAPK', 'molecular_function', 'GO:0004707', ('18', '22'))	('mutations', 'Var', (87, 96))	('signaling pathway', 'biological_process', 'GO:0007165', ('23', '40'))
6031	27119653	BRAF mutations appear to be more frequent in DN arising in men (70% vs. 39%).	('frequent', 'Reg', (33, 41))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('DN arising', 'Disease', (45, 55))	('DN', 'Phenotype', 'HP:0001062', (45, 47))	('men', 'Species', '9606', (59, 62))
6032	27119653	BRAF mutations are predominantly found in DN with compound histopathological architecture.	('found', 'Reg', (33, 38))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('DN', 'Phenotype', 'HP:0001062', (42, 44))
6034	27119653	DN have also been found to have mutations in the tumor suppressor proteins, p16 and p14.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('p16', 'Gene', '1029', (76, 79))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('49', '65'))	('tumor', 'Disease', (49, 54))	('mutations', 'Var', (32, 41))	('p14', 'Gene', (84, 87))	('p16', 'Gene', (76, 79))	('DN', 'Phenotype', 'HP:0001062', (0, 2))	('p14', 'Gene', '1029', (84, 87))	('tumor suppressor', 'biological_process', 'GO:0051726', ('49', '65'))
6037	27119653	Inherited germline mutations in CDKN2A and associated p16 loss have been correlated with familial atypical multiple mole melanoma syndrome (FAM).	('p16', 'Gene', (54, 57))	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('loss', 'NegReg', (58, 62))	('correlated', 'Reg', (73, 83))	('multiple mole', 'Phenotype', 'HP:0001054', (107, 120))	('CDKN2A', 'Gene', (32, 38))	('melanoma syndrome', 'Disease', (121, 138))	('CDKN2A', 'Gene', '1029', (32, 38))	('p16', 'Gene', '1029', (54, 57))	('mole', 'Phenotype', 'HP:0003764', (116, 120))	('milia', 'Phenotype', 'HP:0001056', (91, 96))	('germline mutations', 'Var', (10, 28))	('melanoma syndrome', 'Disease', 'MESH:D008545', (121, 138))	('atypical multiple mole', 'Phenotype', 'HP:0001062', (98, 120))
6063	27119653	Mitoses may also be present, however, atypical mitoses or mitoses in the deeper parts of the lesion should raise concern for melanoma.	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('atypical', 'Var', (38, 46))	('melanoma', 'Disease', (125, 133))
6066	27119653	Of these lesions, 67% also harbored mutations in the oncogene, HRAS.	('harbored', 'Reg', (27, 35))	('HRAS', 'Gene', '3265', (63, 67))	('mutations', 'Var', (36, 45))	('HRAS', 'Gene', (63, 67))
6067	27119653	Combined data from several studies showed HRAS alterations in 21% of SN.	('alterations', 'Var', (47, 58))	('HRAS', 'Gene', (42, 46))	('HRAS', 'Gene', '3265', (42, 46))
6068	27119653	HRAS mutations might be associated with a favorable clinical course since HRAS mutated Spitz lesions do not appear to metastasize and no HRAS mutations have been found in cases of fatal spitzoid melanoma.	('HRAS', 'Gene', (0, 4))	('mutated', 'Var', (79, 86))	('spitzoid melanoma', 'Disease', (186, 203))	('spitzoid melanoma', 'Disease', 'MESH:D008545', (186, 203))	('mutations', 'Var', (5, 14))	('HRAS', 'Gene', '3265', (74, 78))	('HRAS', 'Gene', '3265', (137, 141))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('HRAS', 'Gene', (74, 78))	('HRAS', 'Gene', '3265', (0, 4))	('HRAS', 'Gene', (137, 141))
6069	27119653	It has been suggested that, unlike melanoma, which have mutations in multiple oncogenes, isolated HRAS alterations might mediate oncogene-induced senescence thus preventing progression to melanoma.	('preventing', 'NegReg', (162, 172))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('alterations', 'Var', (103, 114))	('senescence', 'biological_process', 'GO:0010149', ('146', '156'))	('melanoma', 'Disease', 'MESH:D008545', (188, 196))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('melanoma', 'Disease', (188, 196))	('HRAS', 'Gene', '3265', (98, 102))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))	('HRAS', 'Gene', (98, 102))
6070	27119653	While SN appear to lack activating mutations in NRAS as seen in melanoma, BRAF mutations have been observed in 16% of lesions, some with atypical histological features.	('NRAS', 'Gene', '4893', (48, 52))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('observed', 'Reg', (99, 107))	('NRAS', 'Gene', (48, 52))	('mutations', 'Var', (79, 88))
6071	27119653	Mutually exclusive gene rearrangements in ROS1, NTRK1, ALK, BRAF, and RET, resulting in kinase fusions and constitutive activation of oncogenic signaling pathways, have also been observed (Figure 2).	('NTRK1', 'Gene', (48, 53))	('men', 'Species', '9606', (33, 36))	('rearrangements', 'Var', (24, 38))	('ALK', 'Gene', '238', (55, 58))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('RET', 'Gene', '5979', (70, 73))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('RET', 'Gene', (70, 73))	('ROS1', 'Gene', (42, 46))	('activation', 'PosReg', (120, 130))	('ROS1', 'Gene', '6098', (42, 46))	('NTRK1', 'Gene', '4914', (48, 53))	('oncogenic signaling pathways', 'Pathway', (134, 162))	('ALK', 'Gene', (55, 58))	('kinase fusions', 'MPA', (88, 102))
6072	27119653	Kinase fusions were found in 44% of SN and were not seen in lesions with HRAS mutations.	('HRAS', 'Gene', '3265', (73, 77))	('HRAS', 'Gene', (73, 77))	('found', 'Reg', (20, 25))	('Kinase fusions', 'Var', (0, 14))
6074	27119653	BDN have been associated with a familial tumour syndrome involving germline inactivating mutations in BAP1, a tumor suppressor gene located on chromosome 3p21.	('germline inactivating mutations', 'Var', (67, 98))	('familial tumour syndrome', 'Disease', 'MESH:D009386', (32, 56))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('BAP1', 'Gene', (102, 106))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('associated', 'Reg', (14, 24))	('familial tumour syndrome', 'Disease', (32, 56))	('DN', 'Phenotype', 'HP:0001062', (1, 3))	('chromosome', 'cellular_component', 'GO:0005694', ('143', '153'))	('BAP1', 'Gene', '8314', (102, 106))	('milia', 'Phenotype', 'HP:0001056', (34, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('BDN', 'Disease', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
6075	27119653	Patients harboring this mutation often present with multiple smooth papules or nodules that are either dome-shaped or pedunculated and have an average size of 5mm.	('papules', 'Phenotype', 'HP:0200034', (68, 75))	('smooth papules', 'Disease', (61, 75))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (24, 32))	('papule', 'Phenotype', 'HP:0200034', (68, 74))	('present', 'Reg', (39, 46))
6081	27119653	Loss of BAP1 disrupts this protein complex and results in aberrant histone modifications and gene expression.	('disrupts', 'NegReg', (13, 21))	('protein', 'Protein', (27, 34))	('gene expression', 'biological_process', 'GO:0010467', ('93', '108'))	('BAP1', 'Gene', '8314', (8, 12))	('results in', 'Reg', (47, 57))	('protein complex', 'cellular_component', 'GO:0032991', ('27', '42'))	('histone modifications', 'MPA', (67, 88))	('BAP1', 'Gene', (8, 12))	('gene expression', 'MPA', (93, 108))	('Loss', 'Var', (0, 4))
6082	27119653	Loss of function mutations in BAP1 occur in both uveal melanoma and BDN.	('uveal melanoma', 'Disease', 'MESH:C536494', (49, 63))	('BAP1', 'Gene', (30, 34))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('DN', 'Phenotype', 'HP:0001062', (69, 71))	('uveal melanoma', 'Disease', (49, 63))	('Loss of function', 'NegReg', (0, 16))	('BDN', 'Disease', (68, 71))	('BAP1', 'Gene', '8314', (30, 34))	('mutations', 'Var', (17, 26))	('uveal melanoma', 'Phenotype', 'HP:0007716', (49, 63))
6087	27119653	Of these lesions, 89% showed concomitant BRAF mutations.	('mutations', 'Var', (46, 55))	('BRAF', 'Gene', (41, 45))	('BRAF', 'Gene', '673', (41, 45))
6088	27119653	Unlike SN or atypical Spitz tumours, no HRAS mutations were found (Table IV).	('mutations', 'Var', (45, 54))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('Spitz tumours', 'Disease', 'MESH:D018332', (22, 35))	('HRAS', 'Gene', '3265', (40, 44))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('HRAS', 'Gene', (40, 44))	('Spitz tumours', 'Disease', (22, 35))
6109	27119653	BN have been associated with activating mutations in exon 5, codon Q209L, of GNAQ and GNA11.	('BN', 'Phenotype', 'HP:0100814', (0, 2))	('GNAQ', 'Gene', (77, 81))	('Q209L', 'Mutation', 'rs121913492', (67, 72))	('codon Q209L', 'Var', (61, 72))	('GNA11', 'Gene', (86, 91))	('activating', 'PosReg', (29, 39))	('GNAQ', 'Gene', '2776', (77, 81))	('GNA11', 'Gene', '2767', (86, 91))
6110	27119653	Mutations in GNAQ and GNA11 result in constitutive activation of the MAPK pathway, thus promoting melanocyte development.	('GNA11', 'Gene', (22, 27))	('MAPK pathway', 'Pathway', (69, 81))	('men', 'Species', '9606', (116, 119))	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (22, 27))	('GNAQ', 'Gene', '2776', (13, 17))	('activation', 'PosReg', (51, 61))	('Mutations', 'Var', (0, 9))	('MAPK', 'molecular_function', 'GO:0004707', ('69', '73'))	('promoting', 'PosReg', (88, 97))	('melanocyte development', 'CPA', (98, 120))
6111	27119653	Somatic mutations in GNAQ and GNA11 are believed to take place in the embryonic period, leading to aberrant dermal deposits of melanocytes.	('GNAQ', 'Gene', '2776', (21, 25))	('leading to', 'Reg', (88, 98))	('GNA11', 'Gene', (30, 35))	('mutations', 'Var', (8, 17))	('GNAQ', 'Gene', (21, 25))	('GNA11', 'Gene', '2767', (30, 35))
6112	27119653	The prevalence of GNAQ and GNA11 mutations varies by subgroup of BN and by anatomical site.	('GNAQ', 'Gene', '2776', (18, 22))	('BN', 'Phenotype', 'HP:0100814', (65, 67))	('mutations', 'Var', (33, 42))	('GNAQ', 'Gene', (18, 22))	('GNA11', 'Gene', (27, 32))	('GNA11', 'Gene', '2767', (27, 32))
6113	27119653	Combined data revealed GNAQ and GNA11 mutations in 63% and 6% of common BN, respectively.	('GNA11', 'Gene', '2767', (32, 37))	('GNAQ', 'Gene', (23, 27))	('GNA11', 'Gene', (32, 37))	('BN', 'Phenotype', 'HP:0100814', (72, 74))	('common BN', 'Disease', (65, 74))	('mutations', 'Var', (38, 47))	('GNAQ', 'Gene', '2776', (23, 27))
6114	27119653	GNAQ mutations were found in 13% of amelanotic BN and 44% of cellular BN.	('BN', 'Phenotype', 'HP:0100814', (47, 49))	('GNAQ', 'Gene', '2776', (0, 4))	('BN', 'Phenotype', 'HP:0100814', (70, 72))	('mutations', 'Var', (5, 14))	('GNAQ', 'Gene', (0, 4))	('found', 'Reg', (20, 25))	('amelanotic BN', 'Disease', (36, 49))
6115	27119653	Epithelioid BN have demonstrated GNAQ mutations in 20% of cases, but have not been associated with GNA11 mutations.	('GNAQ', 'Gene', (33, 37))	('GNA11', 'Gene', '2767', (99, 104))	('GNA11', 'Gene', (99, 104))	('GNAQ', 'Gene', '2776', (33, 37))	('BN', 'Phenotype', 'HP:0100814', (12, 14))	('mutations', 'Var', (38, 47))
6116	27119653	GNA11 mutated lesions occur more frequently on the upper body, while GNAQ mutations have a tendency for the lower body (buttocks and feet) and the dorsum of the hands.	('mutated lesions', 'Var', (6, 21))	('GNAQ', 'Gene', '2776', (69, 73))	('GNA11', 'Gene', (0, 5))	('mutations', 'Var', (74, 83))	('GNA11', 'Gene', '2767', (0, 5))	('GNAQ', 'Gene', (69, 73))
6117	27119653	GNAQ mutations have also been found in BN located in the oral cavity (Table V).	('GNAQ', 'Gene', '2776', (0, 4))	('found', 'Reg', (30, 35))	('mutations', 'Var', (5, 14))	('GNAQ', 'Gene', (0, 4))	('BN', 'Phenotype', 'HP:0100814', (39, 41))
6118	27119653	While BN and uveal melanoma often harbor the same mutations in GNAQ and GNA11, BN do not appear to have an associated risk for the development of melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('uveal melanoma', 'Disease', (13, 27))	('melanoma', 'Disease', (146, 154))	('GNA11', 'Gene', (72, 77))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('mutations', 'Var', (50, 59))	('GNAQ', 'Gene', '2776', (63, 67))	('men', 'Species', '9606', (138, 141))	('melanoma', 'Disease', (19, 27))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('BN', 'Phenotype', 'HP:0100814', (6, 8))	('BN', 'Phenotype', 'HP:0100814', (79, 81))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('GNAQ', 'Gene', (63, 67))	('uveal melanoma', 'Phenotype', 'HP:0007716', (13, 27))	('uveal melanoma', 'Disease', 'MESH:C536494', (13, 27))	('GNA11', 'Gene', '2767', (72, 77))
6121	27119653	GNAQ and GNA11 mutations have been demonstrated in 45% and 32% of uveal melanomas, respectively, and 22% and 57% of uveal melanoma metastases, respectively.	('GNA11', 'Gene', (9, 14))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('uveal melanomas', 'Phenotype', 'HP:0007716', (66, 81))	('uveal melanomas', 'Disease', (66, 81))	('GNAQ', 'Gene', (0, 4))	('uveal melanoma', 'Phenotype', 'HP:0007716', (116, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('GNA11', 'Gene', '2767', (9, 14))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (116, 141))	('uveal melanomas', 'Disease', 'MESH:C536494', (66, 81))	('demonstrated', 'Reg', (35, 47))	('uveal melanoma metastases', 'Disease', (116, 141))
6122	27119653	Both GNAQ and GNA11 mutations have been demonstrated in melanoma associated with blue nevi (MABN) or mimicking cellular blue nevi (MCBN).	('BN', 'Phenotype', 'HP:0100814', (133, 135))	('blue nevi', 'Phenotype', 'HP:0100814', (81, 90))	('blue nevi', 'Disease', (81, 90))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('GNAQ', 'Gene', (5, 9))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('nevi', 'Phenotype', 'HP:0003764', (86, 90))	('nevi', 'Phenotype', 'HP:0003764', (125, 129))	('BN', 'Phenotype', 'HP:0100814', (94, 96))	('demonstrated', 'Reg', (40, 52))	('associated', 'Reg', (65, 75))	('GNA11', 'Gene', (14, 19))	('GNAQ', 'Gene', '2776', (5, 9))	('GNA11', 'Gene', '2767', (14, 19))	('blue nevi', 'Phenotype', 'HP:0100814', (120, 129))	('mutations', 'Var', (20, 29))
6123	27119653	GNA11 has been shown to be mutated in 73% of MABN/MMCBN, while 9% of lesions demonstrated GNAQ mutations.	('BN', 'Phenotype', 'HP:0100814', (47, 49))	('mutated', 'Var', (27, 34))	('GNA11', 'Gene', (0, 5))	('GNAQ', 'Gene', '2776', (90, 94))	('GNA11', 'Gene', '2767', (0, 5))	('BN', 'Phenotype', 'HP:0100814', (53, 55))	('MABN/MMCBN', 'Disease', (45, 55))	('GNAQ', 'Gene', (90, 94))
6124	27119653	GNAQ mutations were also found in 50% of malignant BN.	('GNAQ', 'Gene', '2776', (0, 4))	('BN', 'Phenotype', 'HP:0100814', (51, 53))	('mutations', 'Var', (5, 14))	('GNAQ', 'Gene', (0, 4))	('found', 'Reg', (25, 30))	('malignant BN', 'Disease', (41, 53))
6143	27119653	BRAF mutations are the most common genetic alteration seen in AMN.	('AMN', 'Disease', (62, 65))	('MN', 'Phenotype', 'HP:0000995', (63, 65))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('AMN', 'Disease', 'MESH:D000326', (62, 65))	('BRAF', 'Gene', (0, 4))
6144	27119653	Aggregated data from multiple studies have shown BRAF mutations in 83% of AMN.	('AMN', 'Disease', 'MESH:D000326', (74, 77))	('mutations', 'Var', (54, 63))	('BRAF', 'Gene', '673', (49, 53))	('MN', 'Phenotype', 'HP:0000995', (75, 77))	('AMN', 'Disease', (74, 77))	('BRAF', 'Gene', (49, 53))
6145	27119653	AMN from individuals residing in geographic locations with lower UV intensity appear to have higher BRAF mutation rates.	('higher', 'PosReg', (93, 99))	('mutation', 'Var', (105, 113))	('AMN', 'Disease', (0, 3))	('BRAF', 'Gene', '673', (100, 104))	('BRAF', 'Gene', (100, 104))	('AMN', 'Disease', 'MESH:D000326', (0, 3))	('MN', 'Phenotype', 'HP:0000995', (1, 3))
6146	27119653	A greater number of BRAF mutations have also been found in AMN located on severely sun damaged skin, such as the head and neck, when compared to anatomical sites with moderate sun damage.	('mutations', 'Var', (25, 34))	('sun damage', 'Phenotype', 'HP:0000992', (176, 186))	('AMN', 'Disease', (59, 62))	('sun damage', 'Phenotype', 'HP:0000992', (83, 93))	('found', 'Reg', (50, 55))	('neck', 'cellular_component', 'GO:0044326', ('122', '126'))	('AMN', 'Disease', 'MESH:D000326', (59, 62))	('BRAF', 'Gene', '673', (20, 24))	('sun damaged skin', 'Phenotype', 'HP:0000992', (83, 99))	('BRAF', 'Gene', (20, 24))	('MN', 'Phenotype', 'HP:0000995', (60, 62))	('severely sun damaged skin', 'Phenotype', 'HP:0007537', (74, 99))
6147	27119653	However, the mutation has also been found in AMN on unexposed areas, such as genital skin.	('mutation', 'Var', (13, 21))	('AMN', 'Disease', (45, 48))	('MN', 'Phenotype', 'HP:0000995', (46, 48))	('AMN', 'Disease', 'MESH:D000326', (45, 48))	('genital skin', 'Disease', (77, 89))
6149	27119653	BRAF mutations seem to occur with varying frequency among the different histopathological subgroups of AMN.	('MN', 'Phenotype', 'HP:0000995', (104, 106))	('mutations', 'Var', (5, 14))	('AMN', 'Disease', (103, 106))	('BRAF', 'Gene', '673', (0, 4))	('occur', 'Reg', (23, 28))	('BRAF', 'Gene', (0, 4))	('AMN', 'Disease', 'MESH:D000326', (103, 106))
6151	27119653	BRAF mutations have also been associated with AMN with globular dermoscopic patterns.	('AMN', 'Disease', 'MESH:D000326', (46, 49))	('globular dermoscopic patterns', 'MPA', (55, 84))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('AMN', 'Disease', (46, 49))	('BRAF', 'Gene', (0, 4))	('MN', 'Phenotype', 'HP:0000995', (47, 49))	('associated with', 'Reg', (30, 45))
6153	27119653	BRAF mutations have been found to occur at a higher frequency in AMN that have undergone dermoscopic changes.	('MN', 'Phenotype', 'HP:0000995', (66, 68))	('AMN', 'Disease', (65, 68))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('AMN', 'Disease', 'MESH:D000326', (65, 68))
6156	27119653	A positive association was found between IRF4 rs12203952 polymorphisms and nevus counts (P<0.01).	('IRF4', 'Gene', (41, 45))	('positive', 'PosReg', (2, 10))	('rs12203952', 'Var', (46, 56))	('nevus', 'Phenotype', 'HP:0003764', (75, 80))	('rs12203952', 'Mutation', 'rs12203952', (46, 56))	('nevus counts', 'Disease', (75, 87))	('IRF4', 'Gene', '3662', (41, 45))
6157	27119653	An inverse relationship was found between nevus counts and CDK6 rs2079147 polymorphisms (P<0.05).	('rs2079147', 'Mutation', 'rs2079147', (64, 73))	('CDK', 'molecular_function', 'GO:0004693', ('59', '62'))	('nevus counts', 'CPA', (42, 54))	('inverse', 'NegReg', (3, 10))	('CDK6', 'Gene', (59, 63))	('rs2079147', 'Var', (64, 73))	('CDK6', 'Gene', '1021', (59, 63))	('nevus', 'Phenotype', 'HP:0003764', (42, 47))
6158	27119653	The IRF4 rs12203952 T allele was associated with a greater number of flat nevi and fewer raised nevi.	('IRF4', 'Gene', '3662', (4, 8))	('fewer raised nevi', 'Phenotype', 'HP:0001054', (83, 100))	('IRF4', 'Gene', (4, 8))	('rs12203952', 'Mutation', 'rs12203952', (9, 19))	('greater number of flat nevi', 'Phenotype', 'HP:0001054', (51, 78))	('nevi', 'Phenotype', 'HP:0003764', (74, 78))	('rs12203952 T', 'Var', (9, 21))	('flat', 'Disease', (69, 73))	('nevi', 'Phenotype', 'HP:0003764', (96, 100))
6160	27119653	Whereas SNP in CDKN1B, MTAP, and PARP1 were associated with reticular patterns (P=0.011, P=0.017, and P=0.050, respectively).	('associated', 'Reg', (44, 54))	('CDKN1B', 'Gene', '1027', (15, 21))	('SNP', 'Var', (8, 11))	('PARP1', 'Gene', (33, 38))	('reticular patterns', 'Disease', (60, 78))	('MTAP', 'Gene', (23, 27))	('PARP1', 'Gene', '142', (33, 38))	('CDKN1B', 'Gene', (15, 21))	('MTAP', 'Gene', '4507', (23, 27))
6164	28062663	A population-based analysis of germline BAP1 mutations in melanoma Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma.	('basal cell carcinoma', 'Disease', (217, 237))	('meningioma', 'Disease', 'MESH:D008577', (180, 190))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('BRCA1 associated protein-1', 'Gene', '8314', (92, 118))	('linked to', 'Reg', (140, 149))	('BAP1', 'Gene', (40, 44))	('BAP1', 'Gene', (120, 124))	('renal cell carcinoma', 'Disease', (192, 212))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (192, 212))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (217, 237))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('meningioma', 'Disease', (180, 190))	('mesothelioma', 'Disease', (166, 178))	('uveal melanoma', 'Disease', (150, 164))	('uveal melanoma', 'Disease', 'MESH:C536494', (150, 164))	('mesothelioma', 'Disease', 'MESH:D008654', (166, 178))	('meningioma', 'Phenotype', 'HP:0002858', (180, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('BRCA1 associated protein-1', 'Gene', (92, 118))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (217, 237))	('mutations', 'Var', (45, 54))	('BAP1', 'Gene', '8314', (40, 44))	('BAP1', 'Gene', '8314', (120, 124))	('uveal melanoma', 'Phenotype', 'HP:0007716', (150, 164))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (192, 212))	('melanoma', 'Disease', (58, 66))
6167	28062663	A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified.	('S98R', 'Mutation', 'rs371168635', (19, 23))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('66', '89'))	('S98R', 'Var', (19, 23))	('abolished', 'NegReg', (51, 60))	('BAP1 deubiquitinase', 'Enzyme', (61, 80))	('activity', 'MPA', (81, 89))	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('66', '89'))
6168	28062663	Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('uveal melanoma', 'Disease', (258, 272))	('BAP1-associated', 'Gene', (167, 182))	('uveal melanoma', 'Phenotype', 'HP:0007716', (258, 272))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Disease', (183, 190))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (199, 219))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('S98R', 'Var', (64, 68))	('meningioma', 'Disease', (238, 248))	('meningioma', 'Phenotype', 'HP:0002858', (238, 248))	('mesothelioma', 'Disease', (221, 233))	('renal cell carcinoma', 'Disease', (199, 219))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (199, 219))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('mesothelioma', 'Disease', 'MESH:D008654', (221, 233))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('S98R', 'Mutation', 'rs371168635', (64, 68))	('cancers', 'Disease', (12, 19))	('meningioma', 'Disease', 'MESH:D008577', (238, 248))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('uveal melanoma', 'Disease', 'MESH:C536494', (258, 272))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))
6169	28062663	Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation.	('melanomas', 'Disease', (77, 86))	('BAP1', 'Gene', (144, 148))	('variants', 'Var', (59, 67))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('loss-of-function', 'NegReg', (42, 58))	('BAP1', 'Gene', (37, 41))	('mutation', 'Var', (149, 157))
6170	28062663	The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants.	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('missense mutations', 'Var', (70, 88))	('germline mutations', 'Var', (25, 43))	('tumours', 'Disease', 'MESH:D009369', (138, 145))	('tumours', 'Disease', (138, 145))
6173	28062663	Additionally, studies in melanoma-prone families have found inactivating variants in CDKN2A and CDK4, and more recently, activating variants in the promoter of TERT.	('TERT', 'Gene', '7015', (160, 164))	('CDKN2A', 'Gene', (85, 91))	('CDK4', 'Gene', (96, 100))	('CDKN2A', 'Gene', '1029', (85, 91))	('variants', 'Var', (132, 140))	('CDK', 'molecular_function', 'GO:0004693', ('96', '99'))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('TERT', 'Gene', (160, 164))	('melanoma', 'Disease', (25, 33))	('CDK4', 'Gene', '1019', (96, 100))
6174	28062663	Loss-of-function variants in the protection of telomeres 1 (POT1) gene, and other members of the shelterin complex, have also been found.	('Loss-of-function', 'NegReg', (0, 16))	('variants', 'Var', (17, 25))	('POT1', 'Gene', '25913', (60, 64))	('POT1', 'Gene', (60, 64))	('shelterin complex', 'cellular_component', 'GO:0070187', ('97', '114'))
6175	28062663	Collectively, these findings indicate that strong and weakly penetrant variants influencing the same genes or biological pathways may contribute to disease development in familial and sporadic melanoma, respectively.	('variants', 'Var', (71, 79))	('familial', 'Disease', (171, 179))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('contribute', 'Reg', (134, 144))	('sporadic melanoma', 'Disease', (184, 201))	('biological pathways', 'Pathway', (110, 129))	('sporadic melanoma', 'Disease', 'MESH:D008545', (184, 201))	('weakly penetrant variants', 'Var', (54, 79))
6179	28062663	Subsequently, it was recognised that germline BAP1 mutations are associated with a risk of disparate cancers such as lung cancer, meningioma, mesothelioma, and renal cell carcinoma, with a recent pan-cancer analysis revealing that BAP1 is significantly enriched for somatic truncating mutations across a range of tumour types.	('mutations', 'Var', (51, 60))	('meningioma', 'Disease', (130, 140))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('lung cancer', 'Disease', (117, 128))	('meningioma', 'Phenotype', 'HP:0002858', (130, 140))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (160, 180))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumour', 'Phenotype', 'HP:0002664', (313, 319))	('associated with', 'Reg', (65, 80))	('BAP1', 'Gene', (46, 50))	('meningioma', 'Disease', 'MESH:D008577', (130, 140))	('tumour', 'Disease', 'MESH:D009369', (313, 319))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('tumour', 'Disease', (313, 319))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('renal cell carcinoma', 'Disease', (160, 180))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (160, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('mesothelioma', 'Disease', (142, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('mesothelioma', 'Disease', 'MESH:D008654', (142, 154))	('germline', 'Var', (37, 45))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (200, 206))
6180	28062663	Intriguingly, while germline loss of Bap1 in the mouse results in embryonic lethality, somatic loss has been associated with the development of a myelodysplastic syndrome, a disease not normally associated with loss of BAP1 in humans.	('associated', 'Reg', (109, 119))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (146, 170))	('embryonic lethality', 'Disease', 'MESH:D020964', (66, 85))	('mouse', 'Species', '10090', (49, 54))	('embryonic lethality', 'Disease', (66, 85))	('loss', 'Var', (29, 33))	('myelodysplastic syndrome', 'Disease', (146, 170))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (146, 170))	('humans', 'Species', '9606', (227, 233))	('Bap1', 'Gene', '104416', (37, 41))	('loss', 'NegReg', (95, 99))	('Bap1', 'Gene', (37, 41))
6181	28062663	Thus, mutation of BAP1, either somatically or in the germline, is associated with a range of cancers, and the biological effects of BAP1 loss are likely to manifest through a range of downstream pathways.	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('associated', 'Reg', (66, 76))	('mutation', 'Var', (6, 14))	('BAP1', 'Gene', (132, 136))	('BAP1', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('loss', 'NegReg', (137, 141))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
6182	28062663	Wiesner et al first reported a characteristic clinical and histopathological appearance of melanocytic lesions in two families with inherited BAP1 mutations, and showed somatic loss of the wildtype allele in these tumours.	('mutations', 'Var', (147, 156))	('tumours', 'Phenotype', 'HP:0002664', (214, 221))	('melanocytic lesions', 'Disease', 'MESH:D009508', (91, 110))	('melanocytic lesions', 'Disease', (91, 110))	('tumours', 'Disease', 'MESH:D009369', (214, 221))	('tumours', 'Disease', (214, 221))	('loss', 'NegReg', (177, 181))	('BAP1', 'Gene', (142, 146))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))
6183	28062663	The mutation carriers in that study developed multiple, pink melanocytic lesions from the second decade, which had an innocuous clinical appearance but were quite remarkable at a histopathological level.	('melanocytic lesions', 'Disease', 'MESH:D009508', (61, 80))	('mutation', 'Var', (4, 12))	('melanocytic lesions', 'Disease', (61, 80))
6186	28062663	One report however, described cytological findings typical of melanocytic lesions from germline BAP1 mutation carriers, including the presence of both epithelioid and naevoid-like cells except that there was no sparing of the dermo-epidermal junction.	('BAP1', 'Gene', (96, 100))	('mutation', 'Var', (101, 109))	('melanocytic lesions', 'Disease', 'MESH:D009508', (62, 81))	('melanocytic lesions', 'Disease', (62, 81))
6188	28062663	Notably, similar histological appearances have been recorded for tumours with either somatic or germline BAP1 mutations.	('mutations', 'Var', (110, 119))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('BAP1', 'Gene', (105, 109))	('tumours', 'Disease', (65, 72))
6189	28062663	Here we report germline mutations of the BAP1 gene in a sample of 1977 melanoma patients and 754 controls ascertained from the UK population as part of the Leeds Melanoma Case-Control Study.	('patients', 'Species', '9606', (80, 88))	('BAP1', 'Gene', (41, 45))	('Melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('Melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('Melanoma', 'Disease', (162, 170))	('germline mutations', 'Var', (15, 33))
6190	28062663	We also performed an evaluation of cancer incidence in BAP1 variant carriers and their families, and estimated the degree to which the histopathological features of primary tumours predict germline BAP1 variant status.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('primary tumours', 'Disease', 'MESH:D009369', (165, 180))	('BAP1', 'Gene', (55, 59))	('variant', 'Var', (60, 67))	('primary tumours', 'Disease', (165, 180))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
6193	28062663	Nine of the variants present in cases were predicted to be deleterious by either the SIFT or PolyPhen-2 algorithms (Table 1).	('SIFT', 'Disease', 'None', (85, 89))	('SIFT', 'Disease', (85, 89))	('variants', 'Var', (12, 20))
6194	28062663	To do this, we generated cDNA constructs in a pcDNA3.1 expression vector, each carrying a different BAP1 missense or frameshift variant and transfected these into BAP1-null H226 cells (Supplementary Material, Fig.	('H226', 'CellLine', 'CVCL:J621', (173, 177))	('missense', 'Var', (105, 113))	('BAP1', 'Gene', (100, 104))	('frameshift', 'Var', (117, 127))
6195	28062663	All protein-changing variants in both cases and controls were tested with the exception of R728H found in a control, the missense alleles E406A, T613M and T613A, and the splice acceptor variant Chr3: 52442623 C/T (in intron 3-4), which were found in cases and identified in a second round of sequencing (Table 1, Fig.	('R728H', 'Var', (91, 96))	('T613A', 'Mutation', 'rs749728488', (155, 160))	('T613M', 'Var', (145, 150))	('E406A', 'Mutation', 'rs535695655', (138, 143))	('T613M', 'Mutation', 'rs35448940', (145, 150))	('T613A', 'Var', (155, 160))	('E406A', 'Var', (138, 143))	('52442623 C/T', 'Mutation', 'g.52442623C>T', (200, 212))	('R728H', 'Mutation', 'rs773230722', (91, 96))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
6196	28062663	A truncating frameshift mutant that disrupts BAP1 at codon 618 (Chr3: 52437191 -/A, P618fs) produced two bands inconsistent with the expected size shift seen with the WT BAP1 cDNA construct.	('P618fs', 'Var', (84, 90))	('disrupts', 'NegReg', (36, 44))	('P618fs', 'Mutation', 'p.P618fsX', (84, 90))	('BAP1', 'Gene', (45, 49))
6199	28062663	In addition to the frameshift mutation, we also identified a missense variant (S98R) falling into the UCH domain that completely abolished deubiquitinase activity (Figs 1 and 2).	('S98R', 'Var', (79, 83))	('deubiquitinase activity', 'MPA', (139, 162))	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('139', '162'))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('139', '162'))	('S98R', 'Mutation', 'rs371168635', (79, 83))	('falling', 'Phenotype', 'HP:0002527', (85, 92))	('abolished', 'NegReg', (129, 138))
6202	28062663	Group 1 alleles were found in 3/1,977 cases (and 0/754 controls); these three definite loss-of-function variants were S98R, a frameshift and a splice acceptor variant (Fig.	('frameshift', 'Var', (126, 136))	('S98R', 'Mutation', 'rs371168635', (118, 122))	('loss-of-function', 'NegReg', (87, 103))	('S98R', 'Var', (118, 122))
6203	28062663	This study therefore suggests that complete loss-of-function germline BAP1 mutations underlie susceptibility to cutaneous melanoma in ~0.2% of the population-ascertained melanoma cases in the UK.	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('BAP1', 'Gene', (70, 74))	('cutaneous melanoma', 'Disease', (112, 130))	('mutations', 'Var', (75, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (112, 130))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('melanoma', 'Disease', (122, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('loss-of-function', 'NegReg', (44, 60))
6204	28062663	Even when variants defined by SIFT and PolyPhen-2 as possibly damaging or deleterious are also considered (n = 9, discussed below) the overall frequency of BAP1 mutations remains low (<1%) (Table 1).	('BAP1', 'Gene', (156, 160))	('SIFT', 'Disease', (30, 34))	('mutations', 'Var', (161, 170))	('SIFT', 'Disease', 'None', (30, 34))
6205	28062663	Previous reports have defined a spectrum of malignancies associated with loss-of-function germline variants of BAP1.	('malignancies', 'Disease', (44, 56))	('variants', 'Var', (99, 107))	('loss-of-function', 'NegReg', (73, 89))	('BAP1', 'Gene', (111, 115))	('malignancies', 'Disease', 'MESH:D009369', (44, 56))
6211	28062663	Thus, all three of the probands had pedigrees consistent with the described germline cancer predisposition syndrome associated with loss-of-function BAP1 alleles.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('loss-of-function', 'NegReg', (132, 148))	('BAP1', 'Gene', (149, 153))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('alleles', 'Var', (154, 161))
6212	28062663	In addition to the three families with clear loss-of-function BAP1 mutations described, there were six families with BAP1 variants that were predicted to be deleterious by SIFT/PolyPhen-2 (Group 2 [pedigrees 4-9], Table 1).	('SIFT', 'Disease', 'None', (172, 176))	('BAP1', 'Gene', (117, 121))	('variants', 'Var', (122, 130))	('SIFT', 'Disease', (172, 176))
6213	28062663	3D), carrying the R150C variant, had a history of melanoma, BCC and lymphoma and had first-degree relatives, each with a history of one of the following cancers: BCC, leukaemia and uterine cancer.	('cancer', 'Disease', (153, 159))	('cancers', 'Disease', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('lymphoma', 'Disease', (68, 76))	('R150C', 'Mutation', 'rs548946316', (18, 23))	('lymphoma', 'Disease', 'MESH:D008223', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('leukaemia', 'Disease', (167, 176))	('uterine cancer', 'Phenotype', 'HP:0010784', (181, 195))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancer', 'Disease', (189, 195))	('R150C', 'Var', (18, 23))	('BCC', 'Disease', (60, 63))	('leukaemia', 'Disease', 'MESH:D007938', (167, 176))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('melanoma', 'Disease', (50, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (68, 76))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('BCC', 'Disease', (162, 165))
6214	28062663	3E), in which the proband carried an R548H missense mutation, there was a case of stomach cancer in a first-degree relative and of uterine cancer in a second-degree relative.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('uterine cancer', 'Phenotype', 'HP:0010784', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('R548H missense', 'Var', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('R548H', 'Mutation', 'rs779877855', (37, 42))	('stomach cancer', 'Disease', 'MESH:D013274', (82, 96))	('stomach cancer', 'Phenotype', 'HP:0012126', (82, 96))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('stomach cancer', 'Disease', (82, 96))	('cancer', 'Disease', (139, 145))
6217	28062663	Of the remaining three individuals with predicted hazardous BAP1 mutations, each carrying either A130V, S292C or Y418C missense mutations, there was limited information available for family history and thus their pedigrees are not shown.	('A130V', 'Var', (97, 102))	('Y418C missense mutations', 'Var', (113, 137))	('S292C', 'Var', (104, 109))	('Y418C', 'Mutation', 'rs773947541', (113, 118))	('A130V', 'Mutation', 'rs1211721310', (97, 102))	('BAP1', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))	('S292C', 'Mutation', 'p.S292C', (104, 109))
6220	28062663	3) had features reported in the literature as being suggestive of the atypical melanocytic tumours of germline BAP1 mutation carriers (Fig.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('melanocytic tumours', 'Disease', 'MESH:D009508', (79, 98))	('mutation', 'Var', (116, 124))	('melanocytic tumours', 'Disease', (79, 98))	('germline', 'Gene', (102, 110))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
6221	28062663	Here, we discuss in detail the melanocytic lesions identified in the three probands carrying confirmed loss-of-function variants (Fig.	('melanocytic lesions', 'Disease', 'MESH:D009508', (31, 50))	('loss-of-function', 'NegReg', (103, 119))	('variants', 'Var', (120, 128))	('melanocytic lesions', 'Disease', (31, 50))
6223	28062663	This melanoma had a Breslow thickness of 1.5mm, without evidence of ulceration, and it resembled the reported features of melanocytic lesions found in BAP1 mutation carriers, being distinctly dermal in silhouette and composed of pleomorphic, epithelioid melanocytes.	('BAP1', 'Gene', (151, 155))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('melanoma', 'Disease', (5, 13))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('melanocytic lesions', 'Disease', (122, 141))	('melanocytic lesions', 'Disease', 'MESH:D009508', (122, 141))	('mutation', 'Var', (156, 164))
6227	28062663	Given that the majority of published melanoma cases in BAP1 families consist of epithelioid rather than spindled melanocytes, this histopathological appearance would be unlikely to alert a pathologist to the presence of a BAP1 mutation, not being remarkably different from melanomas seen among BAP1 wild-type individuals.	('melanomas', 'Disease', (273, 282))	('BAP1', 'Gene', (55, 59))	('melanoma', 'Phenotype', 'HP:0002861', (273, 281))	('melanoma', 'Disease', (273, 281))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('melanomas', 'Phenotype', 'HP:0002861', (273, 282))	('melanoma', 'Disease', 'MESH:D008545', (273, 281))	('melanomas', 'Disease', 'MESH:D008545', (273, 282))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('mutation', 'Var', (227, 235))	('BAP1', 'Gene', (222, 226))
6230	28062663	Such changes have previously been reported in a range of melanocytic lesions and are not known to be unique to BAP1 mutant tumours, although they have been reported to be prominent within melanocytic lesions from BAP1 syndrome families.	('BAP1 syndrome', 'Disease', 'MESH:D013577', (213, 226))	('reported', 'Reg', (34, 42))	('melanocytic lesions', 'Disease', 'MESH:D009508', (57, 76))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('melanocytic lesions', 'Disease', (57, 76))	('tumours', 'Disease', 'MESH:D009369', (123, 130))	('melanocytic lesions', 'Disease', 'MESH:D009508', (188, 207))	('melanocytic lesions', 'Disease', (188, 207))	('BAP1', 'Gene', (111, 115))	('tumours', 'Disease', (123, 130))	('mutant', 'Var', (116, 122))	('BAP1 syndrome', 'Disease', (213, 226))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
6231	28062663	In summary, two of these three probands had a melanoma that demonstrated some features of a pathogenic germline BAP1 mutation and were most prominent in the proband in family 1.	('BAP1', 'Gene', (112, 116))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('mutation', 'Var', (117, 125))
6233	28062663	The median age at diagnosis of melanoma was 57 years in cases carrying no variant or a benign variant in BAP1, compared to 49 years in cases within the 'predicted deleterious' group (Table 1).	('variant', 'Var', (94, 101))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('BAP1', 'Gene', (105, 109))
6234	28062663	There were very few cases of mesothelioma or meningioma within the cohort, so these data are based upon small numbers, but statistical analysis revealed that cases were more likely to carry a deleterious BAP1 variant compared to no variant if there was a history of meningioma or mesothelioma in the proband or their pedigree (Table 2; P = 0.02, OR = 58.3 (95% CI 1.1-670.5) and P = 3 x 10-6, OR = 233 (95% CI 26.7-1660.1), respectively).	('mesothelioma or meningioma', 'Disease', (29, 55))	('meningioma or mesothelioma', 'Disease', 'MESH:D008654', (266, 292))	('variant', 'Var', (209, 216))	('mesothelioma or meningioma', 'Disease', 'MESH:D008654', (29, 55))	('meningioma', 'Phenotype', 'HP:0002858', (266, 276))	('meningioma or mesothelioma', 'Disease', (266, 292))	('meningioma', 'Phenotype', 'HP:0002858', (45, 55))	('BAP1', 'Gene', (204, 208))
6235	28062663	It was notable that no cases with a predicted deleterious variant had a personal or family history of ocular melanoma.	('ocular melanoma', 'Phenotype', 'HP:0007716', (102, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('variant', 'Var', (58, 65))	('ocular melanoma', 'Disease', (102, 117))	('ocular melanoma', 'Disease', 'MESH:D008545', (102, 117))
6236	28062663	Interestingly, cases with the 'BAP-like phenotype (in the family)' were more likely to carry a predicted deleterious variant compared to none (Table 2; P = 0.006, OR 8.2 (95% CI 1.6-38.4)).	('variant', 'Var', (117, 124))	("'BAP-like", 'Disease', (30, 39))	('BAP', 'Chemical', '-', (31, 34))
6238	28062663	The presence of suggestive histological features ('BAP-like histology present (in the proband's melanoma)'), however, was not significantly predictive of a predicted deleterious BAP1 variant compared to no variant (Table 2; P = 0.1).	('variant', 'Var', (183, 190))	('BAP', 'Chemical', '-', (51, 54))	('BAP1', 'Gene', (178, 182))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))	('BAP', 'Chemical', '-', (178, 181))
6240	28062663	Whilst two out of three of probands with a loss-of-function BAP1 variant had BAP-like histology in the proband's melanoma, none of the remaining six cases classified as 'predicted deleterious' had such features (not shown).	('BAP-like histology', 'MPA', (77, 95))	('loss-of-function', 'NegReg', (43, 59))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('BAP', 'Chemical', '-', (60, 63))	('variant', 'Var', (65, 72))	('BAP', 'Chemical', '-', (77, 80))	('BAP1', 'Gene', (60, 64))
6241	28062663	It is possible that some variants that were not identified as loss-of-function alleles by functional testing (deubiquitinase assays), may still impair BAP1 function and predispose to cancer types associated with the BAP1 syndrome phenotype.	('variants', 'Var', (25, 33))	('cancer', 'Disease', (183, 189))	('impair', 'NegReg', (144, 150))	('BAP1 syndrome', 'Disease', 'MESH:D013577', (216, 229))	('BAP1', 'Gene', (151, 155))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('110', '124'))	('function', 'MPA', (156, 164))	('BAP1 syndrome', 'Disease', (216, 229))	('predispose to', 'Reg', (169, 182))
6242	28062663	Germline mutations in BAP1 are rare, being present in <1% of the population-ascertained melanoma cases in the UK.	('Germline mutations', 'Var', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('BAP1', 'Gene', (22, 26))
6243	28062663	It has been noted that high-penetrance variants found in melanoma-prone families can also contribute to sporadic disease, for example, germline mutations of CDKN2A have been identified in around 2% of cases in European and Australian cohorts.	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('CDKN2A', 'Gene', (157, 163))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('sporadic disease', 'Disease', 'MESH:D004421', (104, 120))	('sporadic disease', 'Disease', (104, 120))	('CDKN2A', 'Gene', '1029', (157, 163))	('contribute', 'Reg', (90, 100))	('identified', 'Reg', (174, 184))	('variants', 'Var', (39, 47))
6244	28062663	As such, we sought to determine the contribution of BAP1 variants to sporadic melanoma, and here we present the most comprehensive such analysis to-date.	('sporadic melanoma', 'Disease', (69, 86))	('BAP1', 'Gene', (52, 56))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('sporadic melanoma', 'Disease', 'MESH:D008545', (69, 86))	('variants', 'Var', (57, 65))
6245	28062663	We sequenced 1,977 melanoma cases and 754 controls, identifying a total of 30 BAP1 variants.	('variants', 'Var', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('BAP1', 'Gene', (78, 82))
6246	28062663	There was no alteration of deubiquitinase function detected with the remaining six variants that were predicted to be deleterious by SIFT/Polyphen-2.	('deubiquitinase function', 'MPA', (27, 50))	('SIFT', 'Disease', 'None', (133, 137))	('variants', 'Var', (83, 91))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('27', '41'))	('SIFT', 'Disease', (133, 137))
6247	28062663	The close relatives of the 9 probands carrying these predicted deleterious variants were an estimated 8 times more likely to report a cancer previously associated with BAP1 germline variants than among probands without a BAP1 variant allele (Table 2); however, most of this increase is due to the 3 families with loss-of-function mutations who all reported a family history of BAP1-associated cancers (mesothelioma, renal cancer).	('loss-of-function', 'NegReg', (313, 329))	('cancer', 'Disease', (422, 428))	('cancer', 'Disease', 'MESH:D009369', (393, 399))	('variants', 'Var', (75, 83))	('cancers', 'Disease', 'MESH:D009369', (393, 400))	('cancer', 'Phenotype', 'HP:0002664', (422, 428))	('renal cancer', 'Phenotype', 'HP:0009726', (416, 428))	('cancer', 'Disease', (134, 140))	('BAP1', 'Gene', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (422, 428))	('BAP1-associated', 'Gene', (377, 392))	('mesothelioma, renal cancer', 'Disease', 'MESH:D007680', (402, 428))	('cancers', 'Phenotype', 'HP:0002664', (393, 400))	('cancer', 'Disease', (393, 399))	('cancers', 'Disease', (393, 400))	('mutations', 'Var', (330, 339))	('variants', 'Var', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (393, 399))	('cancer', 'Disease', 'MESH:D009369', (134, 140))
6249	28062663	Overall, less than ~0.2% of melanoma cases had identifiable loss-of-function BAP1 variants.	('variants', 'Var', (82, 90))	('melanoma', 'Disease', (28, 36))	('BAP1', 'Gene', (77, 81))	('loss-of-function', 'NegReg', (60, 76))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
6250	28062663	3A-C), their family histories of cancer were suggestive of a deleterious BAP1 variant, although the reported cancers most strongly associated with the mutation were mesotheliomas, meningiomas and BCC rather than the uveal melanomas in which germline BAP1 mutations were first reported (Fig.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('meningiomas', 'Disease', 'MESH:D008577', (180, 191))	('BAP1', 'Gene', (73, 77))	('melanomas', 'Phenotype', 'HP:0002861', (222, 231))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('meningiomas', 'Phenotype', 'HP:0002858', (180, 191))	('meningiomas', 'Disease', (180, 191))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('uveal melanomas', 'Disease', 'MESH:C536494', (216, 231))	('mesotheliomas', 'Disease', (165, 178))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Disease', (109, 115))	('associated', 'Reg', (131, 141))	('BCC', 'Disease', (196, 199))	('cancers', 'Disease', (109, 116))	('variant', 'Var', (78, 85))	('mutation', 'Var', (151, 159))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mesotheliomas', 'Disease', 'MESH:D008654', (165, 178))	('meningioma', 'Phenotype', 'HP:0002858', (180, 190))	('uveal melanoma', 'Phenotype', 'HP:0007716', (216, 230))	('uveal melanomas', 'Disease', (216, 231))	('uveal melanomas', 'Phenotype', 'HP:0007716', (216, 231))
6251	28062663	The remaining six probands with BAP1 variants predicted to be deleterious by SIFT or PolyPhen-2 had equivocal pedigrees.	('variants', 'Var', (37, 45))	('SIFT', 'Disease', 'None', (77, 81))	('SIFT', 'Disease', (77, 81))	('BAP1', 'Gene', (32, 36))
6252	28062663	We examined the cancer history in BAP1 variant carrier cases, comparing groups with predicted deleterious variants, benign variants, and no variants.	('carrier', 'molecular_function', 'GO:0005215', ('47', '54'))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('BAP1', 'Gene', (34, 38))	('cancer', 'Disease', (16, 22))	('variant', 'Var', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
6253	28062663	The presence of a predicted deleterious variant was associated with several observations (Table 2): particularly a personal history of mesothelioma and a family history of BCC, meningioma, mesothelioma or cutaneous melanoma.	('mesothelioma', 'Disease', 'MESH:D008654', (135, 147))	('meningioma', 'Disease', (177, 187))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('meningioma', 'Phenotype', 'HP:0002858', (177, 187))	('mesothelioma', 'Disease', (189, 201))	('variant', 'Var', (40, 47))	('associated', 'Reg', (52, 62))	('cutaneous melanoma', 'Disease', (205, 223))	('meningioma', 'Disease', 'MESH:D008577', (177, 187))	('BCC', 'Disease', (172, 175))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (205, 223))	('mesothelioma', 'Disease', (135, 147))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (205, 223))	('mesothelioma', 'Disease', 'MESH:D008654', (189, 201))	('presence', 'Var', (4, 12))
6254	28062663	The presence of a 'BAP-like phenotype' in the family history highlights the importance of taking the extended pedigree into account when assessing the risk of carrying a deleterious BAP1 variant.	('variant', 'Var', (187, 194))	('BAP1', 'Gene', (182, 186))	("'BAP-like", 'Disease', (18, 27))	('BAP', 'Chemical', '-', (19, 22))	('BAP', 'Chemical', '-', (182, 185))
6255	28062663	1B) suggesting that weaker alleles, or variants that may influence BAP1 beyond its role as a deubiquitinase, may underlie some of the cancer incidence in mutation carriers.	('influence', 'Reg', (57, 66))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('underlie', 'Reg', (113, 121))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('93', '107'))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('variants', 'Var', (39, 47))	('BAP1', 'Gene', (67, 71))
6256	28062663	Also of note was the observation that none of the cases with predicted deleterious variants had a personal or family history of ocular melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('variants', 'Var', (83, 91))	('ocular melanoma', 'Disease', (128, 143))	('ocular melanoma', 'Disease', 'MESH:D008545', (128, 143))	('ocular melanoma', 'Phenotype', 'HP:0007716', (128, 143))
6257	28062663	Primary melanomas in 2/3 probands with clear loss of function mutations demonstrated some of the histopathological features described in melanocytic lesions associated with a BAP1 mutation (Fig.	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('BAP1', 'Gene', (175, 179))	('Primary melanomas', 'Disease', (0, 17))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('loss of function', 'NegReg', (45, 61))	('melanocytic lesions', 'Disease', (137, 156))	('Primary melanomas', 'Disease', 'MESH:D008545', (0, 17))	('melanocytic lesions', 'Disease', 'MESH:D009508', (137, 156))	('mutation', 'Var', (180, 188))	('mutations', 'Var', (62, 71))
6259	28062663	None of the remaining six probands with BAP1 variants, predicted to be deleterious by SIFT or PolyPhen-2, had suggestive histology and importantly, similar histological changes were seen in a significant proportion of melanoma patients without a germline BAP1 mutation.	('SIFT', 'Disease', (86, 90))	('variants', 'Var', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('SIFT', 'Disease', 'None', (86, 90))	('BAP1', 'Gene', (40, 44))	('patients', 'Species', '9606', (227, 235))
6260	28062663	Our study therefore suggests that in the absence of a family history of cancers such as mesothelioma, or meningioma, the presence of histological changes described in BAP1 mutated families is a poor predictor of a germline BAP1 mutation.	('mutation', 'Var', (228, 236))	('mesothelioma', 'Disease', 'MESH:D008654', (88, 100))	('meningioma', 'Disease', (105, 115))	('meningioma', 'Phenotype', 'HP:0002858', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('BAP1', 'Gene', (223, 227))	('meningioma', 'Disease', 'MESH:D008577', (105, 115))	('BAP1', 'Gene', (167, 171))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('mesothelioma', 'Disease', (88, 100))	('mutated', 'Var', (172, 179))	('germline', 'Var', (214, 222))
6261	28062663	The term 'BAPomas' is sometimes coined by pathologists to denote melanocytic lesions with consistent histology that occur within families with germline BAP1 mutations, which have either benign behaviour or are of uncertain malignant potential.	('BAP', 'Chemical', '-', (10, 13))	('BAP', 'Chemical', '-', (152, 155))	('mutations', 'Var', (157, 166))	('behaviour', 'biological_process', 'GO:0007610', ('193', '202'))	('BAP1', 'Gene', (152, 156))	('melanocytic lesions', 'Disease', 'MESH:D009508', (65, 84))	('melanocytic lesions', 'Disease', (65, 84))
6262	28062663	We hope that this work presents a framework for considering the management of individuals found to carry germline BAP1 mutations in the context of sporadic melanoma.	('sporadic melanoma', 'Disease', (147, 164))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('sporadic melanoma', 'Disease', 'MESH:D008545', (147, 164))	('BAP1', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))
6265	28062663	We transfected pcDNA3.1 constructs containing BAP1 variants into H226 lung cancer cells and measured deubiquitinase activity using a HA-Ub-VME activity probe, as described previously.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('101', '124'))	('deubiquitinase activity', 'MPA', (101, 124))	('variants', 'Var', (51, 59))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('101', '124'))	('BAP1', 'Gene', (46, 50))	('H226', 'CellLine', 'CVCL:J621', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
6274	28062663	We used the phenotypes of all BAP1 variant carrier cases to explore the influence of BAP1 alleles on cancer presentation.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('BAP1', 'Gene', (30, 34))	('cancer', 'Disease', (101, 107))	('carrier', 'molecular_function', 'GO:0005215', ('43', '50'))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('variant', 'Var', (35, 42))
6275	28062663	Cases carrying confirmed loss-of-function alleles were classified into group 1 (n = 3) and those carrying variants predicted to be hazardous by SIFT and/or PolyPhen-2 were classified as group 2 (n = 6).	('SIFT', 'Disease', 'None', (144, 148))	('SIFT', 'Disease', (144, 148))	('alleles', 'Var', (42, 49))	('loss-of-function', 'NegReg', (25, 41))
6276	28062663	Cases carrying variants predicted to be benign by SIFT and PolyPhen-2 (n = 14, as one case carries variants at both 3:52440269 and 3:52437206) were classified as group 3 and those carrying variants of uncertain significance (n = 86, as one case carries variants at both 3:52436441 and 3:52437424) were classified as group 4.	('3:52437206', 'Var', (131, 141))	('3:52437424', 'Var', (285, 295))	('variants', 'Var', (99, 107))	('3:52436441', 'Var', (270, 280))	('SIFT', 'Disease', (50, 54))	('3:52440269', 'Var', (116, 126))	('SIFT', 'Disease', 'None', (50, 54))
6277	28062663	The rest of the melanoma patient cohort who did not carry a variant were grouped together and defined as 'None' (n = 1,868).	('variant', 'Var', (60, 67))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanoma', 'Disease', (16, 24))	('patient', 'Species', '9606', (25, 32))
6286	28062663	The Fisher's exact test was used to assess the association between the reported history of cancer and BAP1 variant categories (Tables 1 and 2, Supplementary Material, Fig.	('BAP1', 'Gene', (102, 106))	('variant', 'Var', (107, 114))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
6351	26712692	Mutations were filtered to keep only those that had Mutation_info: exonic or splicing only; Consequence: non-synonymous or stopgain_SNV.	('splicing', 'biological_process', 'GO:0045292', ('77', '85'))	('N', 'Chemical', 'MESH:D009584', (133, 134))	('non-synonymous', 'Var', (105, 119))	('stopgain_SNV', 'Var', (123, 135))
6354	26712692	The frequency among the CM and UM tumors for specific mutations in BRAF, GNAQ, and GNA11 was determined primarily from WES analysis.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('BRAF', 'Gene', '673', (67, 71))	('GNAQ', 'Gene', '2776', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('UM', 'Phenotype', 'HP:0007716', (31, 33))	('BRAF', 'Gene', (67, 71))	('mutations', 'Var', (54, 63))	('CM', 'Phenotype', 'HP:0012056', (24, 26))	('GNAQ', 'Gene', (73, 77))	('GNA11', 'Gene', (83, 88))	('GNA11', 'Gene', '2767', (83, 88))
6454	26712692	Although normal differentiation antigens are common targets for endogenous T cells in melanoma patients, recent studies have demonstrated that unique somatic mutations expressed by tumors can also elicit autologous T cell responses.	('elicit', 'Reg', (197, 203))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('patients', 'Species', '9606', (95, 103))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('autologous T cell responses', 'CPA', (204, 231))	('mutations', 'Var', (158, 167))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
6456	26712692	Thus, we next sought to determine if the identified subset of immunogenic UM metastases also harbored a greater mutational load that might explain their enhanced T cell recognition.	('metastases', 'Disease', 'MESH:D009362', (77, 87))	('metastases', 'Disease', (77, 87))	('mutational', 'Var', (112, 122))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('enhanced', 'PosReg', (153, 161))	('enhanced T cell', 'Phenotype', 'HP:0100828', (153, 168))	('cell recognition', 'biological_process', 'GO:0008037', ('164', '180'))
6466	26712692	We found BRAF mutations in 53% of the CM metastases (n=278).	('BRAF', 'Gene', (9, 13))	('CM', 'Phenotype', 'HP:0012056', (38, 40))	('CM metastases', 'Disease', 'MESH:D009362', (38, 51))	('CM metastases', 'Disease', (38, 51))	('mutations', 'Var', (14, 23))	('BRAF', 'Gene', '673', (9, 13))
6468	26712692	In contrast, activating mutations in either of the homologous genes, GNAQ or GNA11, were identified in 91% of the UM metastases, but in only 5% of the CM metastases; (GNAQ/GNA11 mutation frequency; CM vs. UM metastases, P<0.0001).	('GNAQ', 'Gene', '2776', (69, 73))	('metastases', 'Disease', (154, 164))	('metastases', 'Disease', 'MESH:D009362', (208, 218))	('CM metastases', 'Disease', (151, 164))	('GNAQ', 'Gene', (69, 73))	('mutations', 'Var', (24, 33))	('metastases', 'Disease', (208, 218))	('GNA11', 'Gene', (77, 82))	('CM', 'Phenotype', 'HP:0012056', (151, 153))	('UM', 'Phenotype', 'HP:0007716', (114, 116))	('GNA11', 'Gene', (172, 177))	('CM', 'Phenotype', 'HP:0012056', (198, 200))	('metastases', 'Disease', 'MESH:D009362', (117, 127))	('activating', 'PosReg', (13, 23))	('CM metastases', 'Disease', 'MESH:D009362', (151, 164))	('GNAQ', 'Gene', '2776', (167, 171))	('metastases', 'Disease', (117, 127))	('GNAQ', 'Gene', (167, 171))	('GNA11', 'Gene', '2767', (77, 82))	('UM', 'Phenotype', 'HP:0007716', (205, 207))	('metastases', 'Disease', 'MESH:D009362', (154, 164))	('GNA11', 'Gene', '2767', (172, 177))
6484	26712692	Comparative whole exomic sequencing revealed CM metastases had significantly greater mutational burden compared to UM metastases with the melanoma variants also possessing quite different oncogenic driver mutations of the MAPK pathway.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('variants', 'Var', (147, 155))	('melanoma', 'Disease', (138, 146))	('metastases', 'Disease', 'MESH:D009362', (48, 58))	('MAPK', 'molecular_function', 'GO:0004707', ('222', '226'))	('metastases', 'Disease', (118, 128))	('UM', 'Phenotype', 'HP:0007716', (115, 117))	('mutational burden', 'MPA', (85, 102))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('CM', 'Phenotype', 'HP:0012056', (45, 47))	('CM metastases', 'Disease', 'MESH:D009362', (45, 58))	('greater', 'PosReg', (77, 84))	('metastases', 'Disease', (48, 58))	('CM metastases', 'Disease', (45, 58))
6485	26712692	Similar to previous reports, nearly all of the UM metastases had GNAQ and GNA11 mutations, while CM metastases commonly had BRAF mutations.	('metastases', 'Disease', (100, 110))	('GNA11', 'Gene', (74, 79))	('CM metastases', 'Disease', (97, 110))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('metastases', 'Disease', 'MESH:D009362', (100, 110))	('mutations', 'Var', (80, 89))	('GNAQ', 'Gene', '2776', (65, 69))	('GNA11', 'Gene', '2767', (74, 79))	('BRAF', 'Gene', '673', (124, 128))	('metastases', 'Disease', (50, 60))	('CM', 'Phenotype', 'HP:0012056', (97, 99))	('GNAQ', 'Gene', (65, 69))	('CM metastases', 'Disease', 'MESH:D009362', (97, 110))	('metastases', 'Disease', 'MESH:D009362', (50, 60))	('BRAF', 'Gene', (124, 128))
6496	26712692	However, beyond the targeting of these normal differentiation antigens, recent analyses have found that unique somatic mutations expressed by tumors can generate neo-epitopes that also elicit robust autologous T cell responses.	('autologous T cell responses', 'CPA', (199, 226))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('elicit', 'Reg', (185, 191))	('neo-epitopes', 'MPA', (162, 174))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('mutations', 'Var', (119, 128))
6575	23447694	A defective p53 (TP53) gene may play a significant role in the radio-resistance of some human melanoma cell lines.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('radio-resistance', 'CPA', (63, 79))	('melanoma', 'Disease', (94, 102))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('human', 'Species', '9606', (88, 93))	('defective', 'Var', (2, 11))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
6583	23447694	For the forward SILAC experiments, the control cells were cultured in Dulbecco's Modified Eagle's Medium containing 'heavy' 13C615N4-L-arginine and 13C615N2-L-lysine, while 15 h and 48 h post-irradiation group cells were maintained in normal 'light' medium containing 12C614N4-L-arginine and 12C614N2-L-lysine.	('13C615N4-L-arginine', 'Chemical', '-', (124, 143))	('13C615N2-L-lysine', 'Chemical', '-', (148, 165))	("Dulbecco's Modified Eagle's Medium", 'Chemical', '-', (70, 104))	('12C614N4-L-arginine', 'Chemical', '-', (268, 287))	('12C614N2-L-lysine', 'Chemical', '-', (292, 309))	('13C615N2-L-lysine', 'Var', (148, 165))	('13C615N4-L-arginine', 'Var', (124, 143))
6597	23447694	Xcorr >=1.8 (z = 1), 2.2 (z = 2), 3.5 (z = 3), Sp >=500, Rsp >=5, proteins with numbers of peptide >=2 and Consensus score >=10.	('proteins', 'Protein', (66, 74))	('peptide', 'Chemical', 'MESH:D010455', (91, 98))	('Sp >=500', 'Var', (47, 55))	('Rsp >=5', 'Var', (57, 64))
6618	23447694	NAP1L4 in neural stem cells can also contribute to the phenotype of higher cell proliferation observed in the Nap1L2 mutant.	('Nap1L2', 'Gene', '4674', (110, 116))	('NAP1L4', 'Gene', (0, 6))	('mutant', 'Var', (117, 123))	('Nap1L2', 'Gene', (110, 116))	('higher', 'PosReg', (68, 74))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('NAP1L4', 'Gene', '4676', (0, 6))
6626	23447694	Cells deleted for PHB1 and PHB2 showed a roughened cell surface and prolonged cell cycle after fewer divisions compared with the wild type, indicating that the normal ageing process is accelerated in cells lacking the PHB complex.	('deleted', 'Var', (6, 13))	('PHB', 'Gene', (218, 221))	('PHB', 'Gene', (27, 30))	('prolonged', 'PosReg', (68, 77))	('PHB1', 'Gene', (18, 22))	('PHB', 'Gene', '5245', (218, 221))	('PHB1', 'Gene', '5245', (18, 22))	('cell cycle', 'biological_process', 'GO:0007049', ('78', '88'))	('ageing', 'biological_process', 'GO:0007568', ('167', '173'))	('PHB', 'Gene', (18, 21))	('PHB', 'Gene', '5245', (27, 30))	('cell surface', 'cellular_component', 'GO:0009986', ('51', '63'))	('PHB2', 'Gene', (27, 31))	('PHB2', 'Gene', '11331', (27, 31))	('PHB', 'Gene', '5245', (18, 21))	('accelerated', 'PosReg', (185, 196))	('cell cycle', 'CPA', (78, 88))
6627	23447694	Similarly, lack of PHB1 in endothelial cells resulted in increased levels of reactive oxygen species (ROS), associated with a phenotype resembling senescence.	('ROS', 'Chemical', 'MESH:D017382', (102, 105))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (77, 100))	('senescence', 'Disease', (147, 157))	('senescence', 'biological_process', 'GO:0010149', ('147', '157'))	('PHB1', 'Gene', (19, 23))	('increased', 'PosReg', (57, 66))	('lack', 'Var', (11, 15))	('PHB1', 'Gene', '5245', (19, 23))
6640	23447694	show that loss of SFPQ gene function leads to increased cell death throughout the early embryo, suggesting that cell survival requires functional SFPQ protein.	('loss', 'Var', (10, 14))	('SFPQ', 'Gene', '6421', (146, 150))	('SFPQ', 'Gene', (146, 150))	('SFPQ', 'Gene', (18, 22))	('SFPQ', 'Gene', '6421', (18, 22))	('cell death', 'biological_process', 'GO:0008219', ('56', '66'))	('cell death throughout the early embryo', 'CPA', (56, 94))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))
6651	22466750	Retinal detachment and more common etiologies such as ocular trauma or disorganized growth of retinal blood vessels in premature infants (retinopathy of prematurity) can cause leukocoria, but are excluded by eliciting pertinent elements during the history and physical exam.	('retinopathy', 'Disease', 'MESH:D012164', (138, 149))	('infants', 'Species', '9606', (129, 136))	('ocular trauma', 'Disease', 'MESH:D014947', (54, 67))	('Retinal detachment', 'Disease', 'MESH:D012163', (0, 18))	('retinopathy', 'Disease', (138, 149))	('retinopathy', 'Phenotype', 'HP:0000488', (138, 149))	('Retinal detachment', 'Disease', (0, 18))	('disorganized', 'Var', (71, 83))	('leukocoria', 'Disease', 'None', (176, 186))	('retinopathy of prematurity', 'Phenotype', 'HP:0500049', (138, 164))	('leukocoria', 'Phenotype', 'HP:0000555', (176, 186))	('Retinal detachment', 'Phenotype', 'HP:0000541', (0, 18))	('ocular trauma', 'Disease', (54, 67))	('cause', 'Reg', (170, 175))	('leukocoria', 'Disease', (176, 186))
6663	22466750	While most patients present before four years of age, thirty to forty percent of patients will have a germline mutation in the RB1 gene and present at an earlier age with multifocal, bilateral disease.	('RB1', 'Gene', '5925', (127, 130))	('bilateral disease', 'Disease', (183, 200))	('germline mutation', 'Var', (102, 119))	('patients', 'Species', '9606', (81, 89))	('RB1', 'Gene', (127, 130))	('patients', 'Species', '9606', (11, 19))	('bilateral disease', 'Disease', 'MESH:D006312', (183, 200))
6664	22466750	Patients with the genetic form of retinoblastoma are at an increased risk for developing primary intracranial neuroectodermal tumors in the pineal or suprasellar region, termed "trilateral retinoblastoma"; this form of disease carries a very poor prognosis.	('retinoblastoma', 'Gene', (34, 48))	('retinoblastoma', 'Gene', '5925', (34, 48))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('retinoblastoma', 'Gene', (189, 203))	('retinoblastoma', 'Gene', '5925', (189, 203))	('retinoblastoma', 'Phenotype', 'HP:0009919', (189, 203))	('retinoblastoma', 'Phenotype', 'HP:0009919', (34, 48))	('intracranial neuroectodermal tumors', 'Disease', (97, 132))	('Patients', 'Species', '9606', (0, 8))	('intracranial neuroectodermal tumors', 'Disease', 'MESH:D017599', (97, 132))	('neuroectodermal tumors', 'Phenotype', 'HP:0030061', (110, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('genetic', 'Var', (18, 25))
6711	22466750	trisomy 13, or Walker-Warburg syndrome).	('Walker-Warburg syndrome', 'Disease', 'MESH:D058494', (15, 38))	('Walker-Warburg syndrome', 'Disease', (15, 38))	('trisomy 13', 'Var', (0, 10))
6713	22466750	Molecular testing to confirm mutations of the NDP gene (Xp11.4) is available and may be recommended with genetic counseling to ascertain carrier status for females.	('mutations', 'Var', (29, 38))	('NDP', 'Gene', '4693', (46, 49))	('carrier', 'molecular_function', 'GO:0005215', ('137', '144'))	('NDP', 'Gene', (46, 49))
6733	21555531	Using seven cell lines representing four histologically distinct solid tumors (lung adenocarcinoma, mammary carcinoma, cutaneous melanoma, and uveal melanoma), we demonstrate that transfection of human tumor cells with the gene encoding the costimulatory molecule CD80 prevents PDL1-mediated immune suppression by tumor cells and restores T cell activation.	('T cell activation', 'MPA', (339, 356))	('T cell activation', 'biological_process', 'GO:0042110', ('339', '356'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (79, 98))	('tumor', 'Disease', (314, 319))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (79, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('CD80', 'Gene', '941', (264, 268))	('prevents', 'NegReg', (269, 277))	('cutaneous melanoma', 'Disease', (119, 137))	('carcinoma', 'Disease', (89, 98))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (119, 137))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('carcinoma', 'Disease', 'MESH:D002277', (108, 117))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (119, 137))	('tumor', 'Disease', (202, 207))	('CD80', 'Gene', (264, 268))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('transfection', 'Var', (180, 192))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('solid tumors', 'Disease', (65, 77))	('carcinoma', 'Disease', 'MESH:D002277', (89, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (143, 157))	('tumor', 'Disease', (71, 76))	('uveal melanoma', 'Disease', (143, 157))	('lung adenocarcinoma', 'Disease', (79, 98))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (100, 117))	('human', 'Species', '9606', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('carcinoma', 'Disease', (108, 117))	('restores', 'PosReg', (330, 338))	('solid tumors', 'Disease', 'MESH:D009369', (65, 77))	('PDL1-mediated immune suppression', 'MPA', (278, 310))	('uveal melanoma', 'Phenotype', 'HP:0007716', (143, 157))
6741	21555531	Regardless of the mechanism by which tumor cell-expressed PDL1 promotes tumor growth, blocking PDL1-PD1 interactions with anti-PDL1 or PD1 Abs improves activation of tumor-reactive T cells and reduces tumor progression, confirming that tumor cell-expressed PDL1 is a major obstacle for cancer immunotherapies.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('reduces', 'NegReg', (193, 200))	('cancer', 'Disease', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('interactions', 'Interaction', (104, 116))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', (201, 206))	('blocking', 'Var', (86, 94))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', (166, 171))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('PDL1-PD1', 'Gene', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('improves', 'PosReg', (143, 151))	('tumor', 'Disease', (37, 42))	('activation', 'MPA', (152, 162))	('tumor', 'Disease', (236, 241))
6751	21555531	Primary uveal melanoma cell lines MEL202 and MEL270, metastatic uveal melanoma line OMM2.3, and cutaneous melanoma cell lines MEL1011, C8161, and 624MEL were obtained from the cited sources except for 624MEL and C8161, which were obtained from F. Marincola (National Cancer Institute, National Institutes of Health) and E. Seftor (Children's Memorial Research Center, Chicago, IL), respectively.	('Cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cutaneous melanoma', 'Disease', (96, 114))	('MEL1011', 'CellLine', 'CVCL:7942', (126, 133))	('uveal melanoma', 'Disease', 'MESH:C536494', (8, 22))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (96, 114))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (96, 114))	('Children', 'Species', '9606', (331, 339))	('uveal melanoma', 'Phenotype', 'HP:0007716', (8, 22))	('Primary uveal melanoma', 'Disease', 'MESH:C536494', (0, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('uveal melanoma', 'Phenotype', 'HP:0007716', (64, 78))	('uveal melanoma', 'Disease', 'MESH:C536494', (64, 78))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('Primary uveal melanoma', 'Disease', (0, 22))	('uveal melanoma', 'Disease', (64, 78))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('C8161', 'Var', (135, 140))
6762	21555531	MEL202, MEL202/DR1, MEL202/CD80, MEL202/DR1/CD80, MCF10, MCF10/DR7/CD80, H358, H358/CD80, H358/DR7, and H358/DR7/CD80 were described previously.	('H358/DR7', 'Var', (90, 98))	('CD80', 'Gene', '941', (113, 117))	('CD80', 'Gene', '941', (67, 71))	('CD80', 'Gene', (27, 31))	('MEL202/DR1', 'Gene', (33, 43))	('MCF10', 'CellLine', 'CVCL:5555', (50, 55))	('MCF10', 'CellLine', 'CVCL:5555', (57, 62))	('H358/DR7/CD80', 'Gene', (104, 117))	('CD80', 'Gene', (113, 117))	('CD80', 'Gene', (67, 71))	('MEL202/DR1', 'Gene', (8, 18))	('MEL202/DR1', 'Gene', '1810', (33, 43))	('MEL202/DR1/CD80', 'Gene', '941;1810', (33, 48))	('MEL202/DR1/CD80', 'Gene', (33, 48))	('H358', 'Var', (73, 77))	('MEL202/DR1', 'Gene', '1810', (8, 18))	('CD80', 'Gene', '941', (44, 48))	('CD80', 'Gene', '941', (84, 88))	('H358/DR7/CD80', 'Gene', '941', (104, 117))	('CD80', 'Gene', '941', (27, 31))	('CD80', 'Gene', (44, 48))	('CD80', 'Gene', (84, 88))
6813	21555531	To test functionality, we compared IFN-gamma production by PHA-activated PBMCs with and without various numbers of MEL202, MEL202/CD80, C8161, or C8161/CD80 cells (Fig.	('CD80', 'Gene', (130, 134))	('IFN-gamma', 'Gene', '3458', (35, 44))	('IFN-gamma', 'Gene', (35, 44))	('C8161', 'Var', (136, 141))	('CD80', 'Gene', '941', (130, 134))	('CD80', 'Gene', (152, 156))	('CD80', 'Gene', '941', (152, 156))
6815	21555531	To confirm that CD80 increased PBMC activation by inhibiting PDL1-mediated suppression, we compared IFN-gamma production by PHA-activated PBMCs cocultured with C8161 or C8161/CD80 in the presence of increasing quantities of recombinant human PD1-Fc (hPD1-Fc) fusion protein (Fig.	('suppression', 'MPA', (75, 86))	('human', 'Species', '9606', (236, 241))	('CD80', 'Gene', (16, 20))	('inhibiting', 'NegReg', (50, 60))	('hPD1', 'Gene', (250, 254))	('C8161', 'Var', (160, 165))	('IFN-gamma', 'Gene', '3458', (100, 109))	('IFN-gamma', 'Gene', (100, 109))	('CD80', 'Gene', (175, 179))	('CD80', 'Gene', '941', (16, 20))	('protein', 'cellular_component', 'GO:0003675', ('266', '273'))	('hPD1', 'Gene', '5133', (250, 254))	('CD80', 'Gene', '941', (175, 179))	('PDL1-mediated', 'Gene', (61, 74))
6823	21555531	To determine if CD80 inhibits translation of PDL1 mRNA, C8161, MEL202, and their CD80 transfectants were fixed, permeabilized, and stained for CD80 and PDL1 (mAb 29E.2A3) to visualize intracellular PDL1 protein (Fig.	('CD80', 'Gene', (16, 20))	('inhibits', 'NegReg', (21, 29))	('CD80', 'Gene', (81, 85))	('translation', 'biological_process', 'GO:0006412', ('30', '41'))	('CD80', 'Gene', (143, 147))	('translation', 'MPA', (30, 41))	('CD80', 'Gene', '941', (16, 20))	('CD80', 'Gene', '941', (81, 85))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('CD80', 'Gene', '941', (143, 147))	('intracellular', 'cellular_component', 'GO:0005622', ('184', '197'))	('PDL1', 'Gene', (45, 49))	('C8161', 'Var', (56, 61))
6839	21555531	In contrast, C8161 cells transiently transfected with the same vector containing a CD80 gene mutated in its N-terminal extracellular domain were not downregulated for PDL1 expression (data not shown).	('mutated', 'Var', (93, 100))	('PDL1', 'Gene', (167, 171))	('extracellular', 'cellular_component', 'GO:0005576', ('119', '132'))	('CD80', 'Gene', (83, 87))	('expression', 'MPA', (172, 182))	('downregulated', 'NegReg', (149, 162))	('CD80', 'Gene', '941', (83, 87))
6844	21555531	Gong and colleagues have shown that PDL1 protein can be regulated by microRNA-513 (miRNA-513).	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('PDL1', 'Gene', (36, 40))	('protein', 'Protein', (41, 48))	('miRNA-513', 'Chemical', '-', (83, 92))	('regulated', 'Reg', (56, 65))	('microRNA-513', 'Var', (69, 81))
6845	21555531	miRNA-513 inhibits translation of PDL1 mRNA and is downregulated by IFN-gamma, consistent with the ability of IFN-gamma to upregulate PDL1 expression.	('miRNA-513', 'Var', (0, 9))	('inhibits', 'NegReg', (10, 18))	('translation', 'biological_process', 'GO:0006412', ('19', '30'))	('translation', 'MPA', (19, 30))	('IFN-gamma', 'Gene', (110, 119))	('IFN-gamma', 'Gene', '3458', (110, 119))	('PDL1', 'Gene', (34, 38))	('downregulated', 'NegReg', (51, 64))	('miRNA-513', 'Chemical', '-', (0, 9))	('IFN-gamma', 'Gene', '3458', (68, 77))	('IFN-gamma', 'Gene', (68, 77))
6937	33250508	A BRAF mutation is not frequently seen in mucosal melanoma but was present in this patient.	('mucosal melanoma', 'Disease', (42, 58))	('BRAF', 'Gene', '673', (2, 6))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('BRAF', 'Gene', (2, 6))	('mucosal melanoma', 'Disease', 'MESH:D008545', (42, 58))	('mutation', 'Var', (7, 15))	('patient', 'Species', '9606', (83, 90))
6982	32401230	Loss of macroH2A1 decreases mitochondrial metabolism and reduces the aggressiveness of uveal melanoma cells Uveal melanoma (UM) is the most common primary intraocular tumour in adults.	('metabolism', 'biological_process', 'GO:0008152', ('42', '52'))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('macroH2A1', 'Gene', '26914', (8, 17))	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('aggressiveness of uveal melanoma', 'Disease', (69, 101))	('primary intraocular tumour', 'Disease', 'MESH:D009798', (147, 173))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('decreases mitochondrial metabolism', 'Disease', 'MESH:D028361', (18, 52))	('macroH2A1', 'Gene', (8, 17))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('primary intraocular tumour', 'Disease', (147, 173))	('decreases mitochondrial metabolism', 'Disease', (18, 52))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('reduces', 'NegReg', (57, 64))	('melanoma', 'Disease', (93, 101))	('Loss', 'Var', (0, 4))	('uveal melanoma', 'Phenotype', 'HP:0007716', (87, 101))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))	('aggressiveness of uveal melanoma', 'Disease', 'MESH:C536494', (69, 101))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('aggressiveness', 'Phenotype', 'HP:0000718', (69, 83))
6985	32401230	UM cell lines were stably knocked down (KD) for macroH2A1, and proliferation and colony formation capacity were evaluated.	('macroH2A1', 'Gene', (48, 57))	('formation', 'biological_process', 'GO:0009058', ('88', '97'))	('proliferation', 'CPA', (63, 76))	('knocked down', 'Var', (26, 38))	('colony formation capacity', 'CPA', (81, 106))	('macroH2A1', 'Gene', '26914', (48, 57))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
6994	32401230	In particular, UM lack mutations in BRAF, NRAS, or KIT, unlike cutaneous melanoma and it is characterized by activating mutations in the GPCR alpha subunits GNAQ or GNA11.	('GNAQ', 'Gene', '2776', (157, 161))	('NRAS', 'Gene', '4893', (42, 46))	('KIT', 'Gene', (51, 54))	('BRAF', 'Gene', (36, 40))	('KIT', 'molecular_function', 'GO:0005020', ('51', '54'))	('cutaneous melanoma', 'Disease', (63, 81))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (63, 81))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (63, 81))	('GNA11', 'Gene', (165, 170))	('GNAQ', 'Gene', (157, 161))	('mutations', 'Var', (23, 32))	('GNA11', 'Gene', '2767', (165, 170))	('UM', 'Phenotype', 'HP:0007716', (15, 17))	('KIT', 'Gene', '3815', (51, 54))	('NRAS', 'Gene', (42, 46))	('BRAF', 'Gene', '673', (36, 40))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
6995	32401230	Moreover, inactivating somatic mutations in the gene encoding BRCA-1 associated protein 1 (BAP1) have been observed in ~84% of metastasizing UM.	('UM', 'Phenotype', 'HP:0007716', (141, 143))	('BAP1', 'Gene', (91, 95))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('metastasizing', 'Disease', (127, 140))	('BRCA-1 associated protein 1', 'Gene', (62, 89))	('BRCA-1 associated protein 1', 'Gene', '8314', (62, 89))	('metastasizing', 'Disease', 'MESH:D009362', (127, 140))	('BAP1', 'Gene', '8314', (91, 95))	('observed', 'Reg', (107, 115))	('inactivating', 'Var', (10, 22))
6996	32401230	The frequency of BAP1 mutations in metastatic UM suggests that targeting the BAP1 pathway could be a valuable therapeutic approach.	('metastatic UM', 'Disease', (35, 48))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('BAP1', 'Gene', '8314', (77, 81))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('BAP1', 'Gene', (77, 81))	('BAP1', 'Gene', (17, 21))
6999	32401230	In UM these include DNA methylation at CpG islands in promoters leading to decrease expression of p16/INK4a tumour suppressor protein.	('tumour', 'Disease', (108, 114))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('decrease', 'NegReg', (75, 83))	('p16', 'Gene', (98, 101))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('DNA', 'cellular_component', 'GO:0005574', ('20', '23'))	('p16', 'Gene', '1029', (98, 101))	('DNA methylation', 'biological_process', 'GO:0006306', ('20', '35'))	('expression', 'MPA', (84, 94))	('DNA methylation', 'Var', (20, 35))	('tumour', 'Disease', 'MESH:D009369', (108, 114))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
7009	32401230	The role of macroH2A1 was investigated by lentiviral mediated silencing in UM 92.1 cells.	('silencing', 'Var', (62, 71))	('macroH2A1', 'Gene', '26914', (12, 21))	('macroH2A1', 'Gene', (12, 21))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('lentiviral', 'Var', (42, 52))
7012	32401230	Our group already showed that loss of macroH2A1 leads to increased stemness and decreased proliferation in liver cancer cells.	('stemness', 'CPA', (67, 75))	('proliferation', 'CPA', (90, 103))	('liver cancer', 'Phenotype', 'HP:0002896', (107, 119))	('liver cancer', 'Disease', 'MESH:D006528', (107, 119))	('decreased', 'NegReg', (80, 89))	('macroH2A1', 'Gene', '26914', (38, 47))	('increased', 'PosReg', (57, 66))	('liver cancer', 'Disease', (107, 119))	('loss', 'Var', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('macroH2A1', 'Gene', (38, 47))
7014	32401230	Interestingly, wound healing assay showed that silencing of macroH2A1 decreases wound closure ability of 92.1 UM cells (Figure 2B, Supplemental Figure 1).	('macroH2A1', 'Gene', (60, 69))	('UM', 'Phenotype', 'HP:0007716', (110, 112))	('decreases', 'NegReg', (70, 79))	('92.1 UM', 'CellLine', 'CVCL:7796', (105, 112))	('wound healing', 'biological_process', 'GO:0042060', ('15', '28'))	('silencing', 'Var', (47, 56))	('macroH2A1', 'Gene', '26914', (60, 69))	('wound closure ability of', 'CPA', (80, 104))
7015	32401230	Moreover, knockdown of macroH2A1 resulted into a decrease in migration in serum starved 92.1 UM cells (Figure 2C, Supplemental Figure 2).	('92.1 UM', 'CellLine', 'CVCL:7796', (88, 95))	('macroH2A1', 'Gene', '26914', (23, 32))	('UM', 'Phenotype', 'HP:0007716', (93, 95))	('macroH2A1', 'Gene', (23, 32))	('decrease', 'NegReg', (49, 57))	('migration', 'CPA', (61, 70))	('knockdown', 'Var', (10, 19))
7016	32401230	Upon macroH2A1 knockdown 92.1 UM cells decreased their colony formation capacity (Figure 3A).	('knockdown', 'Var', (15, 24))	('macroH2A1', 'Gene', '26914', (5, 14))	('macroH2A1', 'Gene', (5, 14))	('formation', 'biological_process', 'GO:0009058', ('62', '71'))	('92.1 UM', 'CellLine', 'CVCL:7796', (25, 32))	('UM', 'Phenotype', 'HP:0007716', (30, 32))	('decreased', 'NegReg', (39, 48))	('colony formation capacity', 'CPA', (55, 80))
7017	32401230	Therefore, macroH2A1 silencing in UM cells significantly hampers their ability to proliferate and to migrate.	('macroH2A1', 'Gene', (11, 20))	('ability to proliferate and', 'CPA', (71, 97))	('hampers', 'NegReg', (57, 64))	('UM', 'Phenotype', 'HP:0007716', (34, 36))	('macroH2A1', 'Gene', '26914', (11, 20))	('silencing', 'Var', (21, 30))
7022	32401230	Consistent with this, the NADP+/NADPH ratio is increased in UM 92.1 cells knockdown for macroH2A1 (Figure 4E), while the ratio NAD+/NADH showed a trend to be higher upon macroH2A1 silencing (Figure 4F).	('silencing', 'NegReg', (180, 189))	('NADPH', 'Gene', '1666', (32, 37))	('macroH2A1', 'Gene', '26914', (170, 179))	('NAD+', 'Chemical', 'MESH:D009243', (127, 131))	('macroH2A1', 'Gene', (170, 179))	('macroH2A1', 'Gene', '26914', (88, 97))	('knockdown', 'Var', (74, 83))	('higher', 'PosReg', (158, 164))	('NADH', 'Chemical', 'MESH:D009243', (132, 136))	('macroH2A1', 'Gene', (88, 97))	('increased', 'PosReg', (47, 56))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('NADPH', 'Gene', (32, 37))	('NADP+', 'Chemical', 'MESH:D009249', (26, 31))
7026	32401230	We thus analyzed expression of genes involved in oxidative phosphorylation: the expression of MT-ND4, MT-CO2, COX4 1, MT-CYB, ATP5F1A and TFAM mRNAs were significantly decreased in KD UM cells compared to their controls (p < 0.001) (Figure 5A).	('COX4 1', 'Gene', (110, 116))	('UM', 'Phenotype', 'HP:0007716', (184, 186))	('COX4 1', 'Gene', '1327', (110, 116))	('MT-CO2', 'Gene', (102, 108))	('decreased', 'NegReg', (168, 177))	('MT-ND4', 'Gene', (94, 100))	('KD UM', 'Var', (181, 186))	('MT-ND4', 'Gene', '4538', (94, 100))	('ATP5F1A', 'Gene', (126, 133))	('MT-CYB', 'Gene', '4519', (118, 124))	('TFAM', 'Gene', (138, 142))	('MT-CYB', 'Gene', (118, 124))	('expression', 'MPA', (80, 90))	('TFAM', 'Gene', '7019', (138, 142))	('MT-CO2', 'Gene', '4513', (102, 108))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('49', '74'))
7034	32401230	To this aim, we took into account a total of 190 samples of patients with UM and 96 retinal pigment epithelium (RPE)-choroid of healthy control subjects, pooled from 6 different publicly available Gene Expression Omnibus (GEO) repositories (GSE44295, GSE22138, GSE27831, GSE84976, GSE51880, GSE73652, GSE29801) (Table 1).	('GSE22138', 'Var', (251, 259))	('GSE84976', 'Var', (271, 279))	('GSE27831', 'Var', (261, 269))	('Gene Expression', 'biological_process', 'GO:0010467', ('197', '212'))	('GSE29801', 'Var', (301, 309))	('patients', 'Species', '9606', (60, 68))	('GSE44295', 'Var', (241, 249))	('GSE73652', 'Var', (291, 299))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('GSE51880', 'Var', (281, 289))
7046	32401230	Epigenetic changes cooperate actively with genetic alterations to drive the cancer phenotype.	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Epigenetic changes', 'Var', (0, 18))	('drive', 'Reg', (66, 71))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
7048	32401230	During carcinogenesis, the result of the interplay between oncogenes and tumor suppressor genes can sometime code for histone variants.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('variants', 'Var', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('carcinogenesis', 'Disease', 'MESH:D063646', (7, 21))	('tumor suppressor', 'biological_process', 'GO:0051726', ('73', '89'))	('tumor', 'Disease', (73, 78))	('interplay', 'Interaction', (41, 50))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('73', '89'))	('carcinogenesis', 'Disease', (7, 21))	('histone', 'Protein', (118, 125))	('code', 'Reg', (109, 113))
7050	32401230	In the present study, we report for the first time that the loss of macroH2A1 inhibits UM cells proliferation and aggressiveness, while inducing an inhibition of mitochondrial metabolism and biogenesis through a gene expression signature that is also observed in UM patients.	('UM cells proliferation', 'CPA', (87, 109))	('aggressiveness', 'Phenotype', 'HP:0000718', (114, 128))	('inhibits', 'NegReg', (78, 86))	('patients', 'Species', '9606', (266, 274))	('gene expression', 'biological_process', 'GO:0010467', ('212', '227'))	('inhibition', 'NegReg', (148, 158))	('UM', 'Phenotype', 'HP:0007716', (87, 89))	('inducing', 'NegReg', (136, 144))	('mitochondrial metabolism', 'MPA', (162, 186))	('UM', 'Phenotype', 'HP:0007716', (263, 265))	('macroH2A1', 'Gene', '26914', (68, 77))	('loss', 'Var', (60, 64))	('biogenesis', 'MPA', (191, 201))	('aggressiveness', 'Disease', 'MESH:D001523', (114, 128))	('metabolism', 'biological_process', 'GO:0008152', ('176', '186'))	('aggressiveness', 'Disease', (114, 128))	('macroH2A1', 'Gene', (68, 77))
7072	32401230	Our study identifies for the first time a correlation between the expression of COX4 1, key regulatory subunit of human cytochrome c oxidase, and UM patient survival, as observed in glioblastoma multiforme.	('COX4 1', 'Gene', '1327', (80, 86))	('cytochrome c', 'molecular_function', 'GO:0009461', ('120', '132'))	('UM', 'Phenotype', 'HP:0007716', (146, 148))	('glioblastoma multiforme', 'Disease', (182, 205))	('human', 'Species', '9606', (114, 119))	('patient', 'Species', '9606', (149, 156))	('glioblastoma', 'Phenotype', 'HP:0012174', (182, 194))	('expression', 'Var', (66, 76))	('cytochrome c', 'molecular_function', 'GO:0045155', ('120', '132'))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (182, 205))	('COX4 1', 'Gene', (80, 86))
7073	32401230	In conclusion, we suggest that strategies aiming at decreasing the expression of histone variant macroH2A1, might effectively hamper the aggressiveness of UM cells, by inhibiting their mitochondrial phosphorylation.	('aggressiveness', 'Disease', 'MESH:D001523', (137, 151))	('UM', 'Phenotype', 'HP:0007716', (155, 157))	('macroH2A1', 'Gene', (97, 106))	('mitochondrial phosphorylation', 'MPA', (185, 214))	('inhibiting', 'NegReg', (168, 178))	('aggressiveness', 'Disease', (137, 151))	('variant', 'Var', (89, 96))	('aggressiveness', 'Phenotype', 'HP:0000718', (137, 151))	('expression', 'MPA', (67, 77))	('phosphorylation', 'biological_process', 'GO:0016310', ('199', '214'))	('decreasing', 'NegReg', (52, 62))	('hamper', 'NegReg', (126, 132))	('macroH2A1', 'Gene', '26914', (97, 106))
7102	31947592	This review summarizes the current novel data on the treatment of metastatic melanoma with anti-PD-1 antibodies and combinations with other treatment modalities, including clinical trials presented at major conference meetings.	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('anti-PD-1', 'Var', (91, 100))
7105	31947592	The therapeutic use of blocking anti-PD-1 antibodies or anti-PD-L1 antibodies interferes with these immunosuppressive effects and strengthens the T-cell response to the tumor (Figure 1).	('immunosuppressive effects', 'MPA', (100, 125))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('strengthens', 'PosReg', (130, 141))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('anti-PD-L1 antibodies', 'Var', (56, 77))	('tumor', 'Disease', (169, 174))	('anti-PD-1 antibodies', 'Protein', (32, 52))	('interferes', 'NegReg', (78, 88))	('antibodies', 'Var', (67, 77))
7119	31947592	In conclusion, the anti-PD-1 antibodies nivolumab and pembrolizumab achieved an ORR of 40% to 50% and 5 year OS rates of 30 to 40% in patients with metastatic melanoma.	('melanoma', 'Disease', (159, 167))	('nivolumab', 'Chemical', 'MESH:D000077594', (40, 49))	('patients', 'Species', '9606', (134, 142))	('pembrolizumab', 'Chemical', 'MESH:C582435', (54, 67))	('OS', 'Chemical', '-', (109, 111))	('anti-PD-1', 'Var', (19, 28))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
7144	31947592	In summary, anti-PD-1 antibodies show a durable antitumor activity in patients who have completed 2 years of therapy.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('patients', 'Species', '9606', (70, 78))	('anti-PD-1 antibodies', 'Var', (12, 32))	('antibodies', 'Var', (22, 32))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
7149	31947592	For example BRAF/MEK inhibitors promote the release of cancer cell antigens, cancer antigen presentation, infiltration of T cells into tumors, recognition of cancer cells by T cells and killing of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Disease', (135, 141))	('infiltration', 'CPA', (106, 118))	('recognition', 'MPA', (143, 154))	('promote', 'PosReg', (32, 39))	('release', 'MPA', (44, 51))	('cancer', 'Disease', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', (55, 61))	('killing', 'CPA', (186, 193))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', (197, 203))	('MEK', 'Gene', '5609', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('inhibitors', 'Var', (21, 31))	('antigen presentation', 'biological_process', 'GO:0019882', ('84', '104'))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('MEK', 'Gene', (17, 20))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (55, 61))
7150	31947592	A phase III study (NCT02967692) is investigating the safety and efficacy of the anti-PD-1 antibody spartalizumab in combination with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib in untreated patients with BRAF V600-mutant metastatic melanoma.	('antibody', 'molecular_function', 'GO:0003823', ('90', '98'))	('MEK', 'Gene', (171, 174))	('dabrafenib', 'Chemical', 'MESH:C561627', (152, 162))	('spartalizumab', 'Chemical', '-', (99, 112))	('MEK', 'Gene', '5609', (171, 174))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('antibody', 'cellular_component', 'GO:0019814', ('90', '98'))	('BRAF', 'Gene', (137, 141))	('trametinib', 'Chemical', 'MESH:C560077', (185, 195))	('BRAF', 'Gene', '673', (137, 141))	('antibody', 'cellular_component', 'GO:0042571', ('90', '98'))	('V600-mutant', 'Var', (228, 239))	('BRAF', 'Gene', '673', (223, 227))	('antibody', 'cellular_component', 'GO:0019815', ('90', '98'))	('patients', 'Species', '9606', (209, 217))	('melanoma', 'Disease', 'MESH:D008545', (251, 259))	('BRAF', 'Gene', (223, 227))	('melanoma', 'Disease', (251, 259))
7158	31947592	In the KEYNOTE-022 phase-2 study (NCT02130466), 120 treatment-naive BRAF-V600E/K-mutant patients with advanced melanoma were randomized to receive the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib in combination with pembrolizumab or placebo.	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('dabrafenib', 'Chemical', 'MESH:C561627', (166, 176))	('BRAF', 'Gene', '673', (68, 72))	('patients', 'Species', '9606', (88, 96))	('MEK', 'Gene', (185, 188))	('V600E', 'Var', (73, 78))	('MEK', 'Gene', '5609', (185, 188))	('BRAF', 'Gene', (68, 72))	('BRAF', 'Gene', '673', (151, 155))	('trametinib', 'Chemical', 'MESH:C560077', (199, 209))	('BRAF', 'Gene', (151, 155))	('V600E', 'SUBSTITUTION', 'None', (73, 78))	('pembrolizumab', 'Chemical', 'MESH:C582435', (230, 243))
7163	31947592	In phase 1 of the KEYNOTE-022 trial (NCT02130466), 15 BRAF-V600E/K-mutant patients were enrolled for triplet therapy.	('BRAF', 'Gene', (54, 58))	('V600E', 'SUBSTITUTION', 'None', (59, 64))	('BRAF', 'Gene', '673', (54, 58))	('patients', 'Species', '9606', (74, 82))	('V600E', 'Var', (59, 64))
7204	31947592	In conclusion, the anti-LAG-3 antibody BMS-986016 showed efficacy in anti-PD-1/PD-L1-refractory patients, while toxicity is comparable to nivolumab monotherapy.	('BMS-986016', 'Var', (39, 49))	('antibody', 'cellular_component', 'GO:0042571', ('30', '38'))	('toxicity', 'Disease', (112, 120))	('antibody', 'cellular_component', 'GO:0019815', ('30', '38'))	('antibody', 'cellular_component', 'GO:0019814', ('30', '38'))	('patients', 'Species', '9606', (96, 104))	('nivolumab', 'Chemical', 'MESH:D000077594', (138, 147))	('antibody', 'molecular_function', 'GO:0003823', ('30', '38'))	('toxicity', 'Disease', 'MESH:D064420', (112, 120))
7219	31947592	In the phase III CheckMate 238 trial, patients who had undergone complete resection of locoregional or distant metastases were treated with anti-PD-1 nivolumab or anti-CTLA-4 ipilimumab for one year.	('metastases', 'Disease', (111, 121))	('anti-PD-1', 'Var', (140, 149))	('nivolumab', 'Chemical', 'MESH:D000077594', (150, 159))	('metastases', 'Disease', 'MESH:D009362', (111, 121))	('patients', 'Species', '9606', (38, 46))	('ipilimumab', 'Chemical', 'MESH:D000074324', (175, 185))
7224	31947592	In the phase III EORTC 1325 study, patients with completely resected locoregional metastases received anti-PD-1 pembrolizumab (514 patients) or placebo (505 patients) for 1 year.	('patients', 'Species', '9606', (131, 139))	('patients', 'Species', '9606', (157, 165))	('pembrolizumab', 'Chemical', 'MESH:C582435', (112, 125))	('patients', 'Species', '9606', (35, 43))	('metastases', 'Disease', (82, 92))	('metastases', 'Disease', 'MESH:D009362', (82, 92))	('anti-PD-1', 'Var', (102, 111))
7225	31947592	At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo with a 1 year rate of recurrence-free survival of 75.4% vs. 61.0%.	('pembrolizumab', 'Var', (36, 49))	('recurrence-free survival', 'CPA', (91, 115))	('pembrolizumab', 'Chemical', 'MESH:C582435', (36, 49))	('longer', 'PosReg', (84, 90))
7241	31947592	The approval of effective targeted and immune therapies has significantly improved the prognosis of metastatic melanoma including brain metastases with a median OS for patients with brain metastases of approximately 7 months for anti-CTLA-4 ipilimumab, 10 months for anti-PD-1 pembrolizumab or nivolumab and up to 24 months for BRAF and MEK inhibitors.	('anti-CTLA-4', 'Var', (229, 240))	('OS', 'Chemical', '-', (161, 163))	('brain metastases', 'Disease', (182, 198))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Disease', (111, 119))	('pembrolizumab', 'Chemical', 'MESH:C582435', (277, 290))	('ipilimumab', 'Chemical', 'MESH:D000074324', (241, 251))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('BRAF', 'Gene', '673', (328, 332))	('nivolumab', 'Chemical', 'MESH:D000077594', (294, 303))	('MEK', 'Gene', (337, 340))	('BRAF', 'Gene', (328, 332))	('patients', 'Species', '9606', (168, 176))	('improved', 'PosReg', (74, 82))	('brain metastases', 'Disease', 'MESH:D009362', (130, 146))	('MEK', 'Gene', '5609', (337, 340))	('brain metastases', 'Disease', (130, 146))	('brain metastases', 'Disease', 'MESH:D009362', (182, 198))
7256	31947592	Moreover, the combination of radiotherapy and immune CPIs may increase the antitumor response by promoting antigen presentation and T-cell activation.	('antigen presentation', 'biological_process', 'GO:0019882', ('107', '127'))	('tumor', 'Disease', (79, 84))	('T-cell activation', 'CPA', (132, 149))	('T-cell activation', 'biological_process', 'GO:0042110', ('132', '149'))	('promoting', 'PosReg', (97, 106))	('immune CPIs', 'Var', (46, 57))	('antigen presentation', 'MPA', (107, 127))	('CPIs', 'Chemical', '-', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('increase', 'PosReg', (62, 70))
7257	31947592	In a large real-life cohort of patients with MBM treated with CPIs or BRAF/MEK inhibitors, the risk of death was decreased by 40% for patients treated with radiotherapy, in comparison with those who did not receive radiotherapy.	('CPIs', 'Chemical', '-', (62, 66))	('MBM', 'Disease', (45, 48))	('MBM', 'Disease', 'MESH:D009362', (45, 48))	('CPIs', 'Gene', (62, 66))	('patients', 'Species', '9606', (134, 142))	('inhibitors', 'Var', (79, 89))	('patients', 'Species', '9606', (31, 39))	('BRAF', 'Gene', '673', (70, 74))	('MEK', 'Gene', (75, 78))	('decreased', 'NegReg', (113, 122))	('MEK', 'Gene', '5609', (75, 78))	('BRAF', 'Gene', (70, 74))
7259	31947592	The best survival was seen in patients treated with anti-PD-1 plus anti-CTLA-4 or anti-PD-1 alone combined with SRS with 12 month survival rates of 100% and 70%, respectively.	('patients', 'Species', '9606', (30, 38))	('anti-PD-1', 'Var', (52, 61))	('anti-CTLA-4', 'Var', (67, 78))
7266	31947592	UM is characterized by mutations in GNAQ or GNA11 resulting in activation of the mitogen-activated protein kinase (MAPK) and other signaling pathways.	('UM', 'Disease', 'MESH:C536494', (0, 2))	('GNA11', 'Gene', (44, 49))	('GNA11', 'Gene', '2767', (44, 49))	('mutations', 'Var', (23, 32))	('GNAQ', 'Gene', '2776', (36, 40))	('MAPK', 'molecular_function', 'GO:0004707', ('115', '119'))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('activation', 'PosReg', (63, 73))	('GNAQ', 'Gene', (36, 40))
7286	31947592	In a French multicenter retrospective study, 151 patients with metastatic mucosal melanoma received immunotherapy with anti-CTLA-4 (50.3%) or anti-PD-1 antibodies (49.7%).	('anti-CTLA-4', 'Var', (119, 130))	('mucosal melanoma', 'Disease', 'MESH:D008545', (74, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('anti-PD-1 antibodies', 'Protein', (142, 162))	('patients', 'Species', '9606', (49, 57))	('mucosal melanoma', 'Disease', (74, 90))
7288	31947592	The OS of mucosal melanoma patients treated with CPIs appeared to be longer than that of patients treated with chemotherapy, with a median OS of 15.97 months and 8.82 months, respectively.	('mucosal melanoma', 'Disease', (10, 26))	('OS', 'Chemical', '-', (4, 6))	('OS', 'Chemical', '-', (139, 141))	('CPIs', 'Var', (49, 53))	('patients', 'Species', '9606', (27, 35))	('mucosal melanoma', 'Disease', 'MESH:D008545', (10, 26))	('patients', 'Species', '9606', (89, 97))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('CPIs', 'Chemical', '-', (49, 53))
7304	31947592	In a retrospective study, 60 patients with advanced desmoplastic melanoma treated with anti-PD-1 or anti-PD-L1 antibodies were identified.	('desmoplastic melanoma', 'Disease', (52, 73))	('patients', 'Species', '9606', (29, 37))	('anti-PD-1', 'Var', (87, 96))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('desmoplastic melanoma', 'Disease', 'MESH:D008545', (52, 73))
7305	31947592	Patients with advanced desmoplastic melanoma appear to benefit from anti-PD-1/PD-L1 therapy.	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('desmoplastic melanoma', 'Disease', (23, 44))	('benefit', 'PosReg', (55, 62))	('desmoplastic melanoma', 'Disease', 'MESH:D008545', (23, 44))	('Patients', 'Species', '9606', (0, 8))	('anti-PD-1/PD-L1', 'Var', (68, 83))
7307	31947592	ICIs can induce immune-related adverse events (irAEs) in all organ systems, and most commonly affect the skin, gastrointestinal tract, lungs, and the endocrine, musculoskeletal, renal, nervous, hematologic, cardiovascular, and ocular systems.	('musculoskeletal', 'Disease', (161, 176))	('musculoskeletal', 'Disease', 'MESH:D009140', (161, 176))	('affect', 'Reg', (94, 100))	('immune-related adverse events', 'Disease', (16, 45))	('induce', 'Reg', (9, 15))	('gastrointestinal tract', 'Disease', 'MESH:D005770', (111, 133))	('ICIs', 'Var', (0, 4))	('gastrointestinal tract', 'Disease', (111, 133))
7326	31737436	A panel of six miRNAs (miR-16, miR-145, miR-146a, miR-204, miR-211, and miR-363-3p) showed significant differences between participants with uveal nevi compared with patients with localized and metastatic uveal melanoma.	('participants', 'Species', '9606', (123, 135))	('uveal melanoma', 'Phenotype', 'HP:0007716', (205, 219))	('miR-146a', 'Gene', '406938', (40, 48))	('miR-145', 'Gene', (31, 38))	('miR-204', 'Gene', '406987', (50, 57))	('uveal nevi', 'Disease', (141, 151))	('miR-16', 'Gene', (23, 29))	('miR-211', 'Gene', (59, 66))	('nevi', 'Phenotype', 'HP:0003764', (147, 151))	('differences', 'Reg', (103, 114))	('miR-211', 'Gene', '406993', (59, 66))	('miR-16', 'Gene', '51573', (23, 29))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('miR-204', 'Gene', (50, 57))	('uveal melanoma', 'Disease', (205, 219))	('uveal melanoma', 'Disease', 'MESH:C536494', (205, 219))	('miR-363-3p', 'Var', (72, 82))	('miR-145', 'Gene', '406937', (31, 38))	('patients', 'Species', '9606', (166, 174))	('miR-146a', 'Gene', (40, 48))
7340	31737436	Circulating GNAQ/GNA11 mutations (found in ~83% of UM) have been detected in plasma of metastatic UM patients; however, they are rarely detectable in patients with localized disease.	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('GNAQ', 'Gene', (12, 16))	('patients', 'Species', '9606', (101, 109))	('UM', 'Disease', 'MESH:C536494', (51, 53))	('localized disease', 'Disease', (164, 181))	('mutations', 'Var', (23, 32))	('GNA11', 'Gene', (17, 22))	('patients', 'Species', '9606', (150, 158))	('GNAQ', 'Gene', '2776', (12, 16))	('localized disease', 'Disease', 'MESH:D004828', (164, 181))	('GNA11', 'Gene', '2767', (17, 22))	('UM', 'Phenotype', 'HP:0007716', (98, 100))	('UM', 'Disease', 'MESH:C536494', (98, 100))
7355	31737436	Briefly, a custom reverse transcription (RT) primer pool consisting of equal amounts of miRNA-specific RT primers contained within each TaqMan Assay (Life Technologies, Carlsbad, CA); miR-16 (000391), miR-145-5p (002278), miR-146a-5p (000468), miR-204-5p (000508), miR-211-5p (000514), miR-363-3p (001271), miR-506-3p (001050), miR-508-3p (001052), miR-508-5p (002092), miR-509-3p (002236), miR-509-5p (002235), miR-513b (002757), miR-513c-5p (002756), miR-514a-3p (001147), miR-4487 (462492_mat), miR-4706 (464518_mat), and miR-4731-5p (464084_mat) along with cel-miR-39 (000200; serum spiked-in control) plus an additional pool of the corresponding TaqMan MicroRNA Assay (Pre-Amp Primer Pool) were used to preamplify the RT reaction.	('mat', 'molecular_function', 'GO:0004314', ('545', '548'))	('mat', 'molecular_function', 'GO:0004314', ('515', '518'))	('miR-211', 'Gene', (265, 272))	('miR-509-5p', 'Gene', '100616458', (391, 401))	('miR-4487', 'Gene', '100616222', (475, 483))	('miR-4731', 'Gene', (525, 533))	('miR-4706', 'Gene', (498, 506))	('miR-4706', 'Gene', '100616490', (498, 506))	('miR-513b', 'Gene', '100313822', (412, 420))	('miR-146a', 'Gene', (222, 230))	('miR-513b', 'Gene', (412, 420))	('miR-509-3p', 'Gene', '100847022', (370, 380))	('miR-146a', 'Gene', '406938', (222, 230))	('Pre', 'molecular_function', 'GO:0003904', ('674', '677'))	('miR-204', 'Gene', (244, 251))	('miR-509-5p', 'Gene', (391, 401))	('mat', 'molecular_function', 'GO:0004314', ('492', '495'))	('miR-4731', 'Gene', '100616125', (525, 533))	('miR-211', 'Gene', '406993', (265, 272))	('miR-39', 'Gene', (565, 571))	('miR-39', 'Gene', '266867', (565, 571))	('miR-145', 'Gene', '406937', (201, 208))	('miR-16', 'Gene', (184, 190))	('miR-514a-3p', 'Gene', (453, 464))	('miR-513c', 'Gene', '100302114', (431, 439))	('464084_mat', 'Var', (538, 548))	('miR-145', 'Gene', (201, 208))	('miR-204', 'Gene', '406987', (244, 251))	('reverse transcription', 'biological_process', 'GO:0001171', ('18', '39'))	('miR-513c', 'Gene', (431, 439))	('miR-509-3p', 'Gene', (370, 380))	('miR-16', 'Gene', '51573', (184, 190))	('miR-514a-3p', 'Gene', '574518', (453, 464))	('506-3p', 'Chemical', 'MESH:C012651', (311, 317))	('miR-4487', 'Gene', (475, 483))
7364	31737436	No expression was detected for miR-506-3p, miR-508-3p, miR-508-5p, miR-513b, miR-513c, or miR-514a.	('miR-513c', 'Gene', '100302114', (77, 85))	('506-3p', 'Chemical', 'MESH:C012651', (35, 41))	('miR-513b', 'Gene', '100313822', (67, 75))	('miR-506-3p', 'Var', (31, 41))	('miR-514a', 'Var', (90, 98))	('miR-508-3p', 'Var', (43, 53))	('miR-508-5p', 'Var', (55, 65))	('miR-513b', 'Gene', (67, 75))	('miR-513c', 'Gene', (77, 85))
7365	31737436	Of 11 detected miRNAs, six (miR-16, miR-145, miR-146a, miR-204, miR-211, and miR-363-3p) showed significant differences (ANOVA; P < 0.05) across the cohort.	('miR-16', 'Gene', (28, 34))	('miR-363-3p', 'Var', (77, 87))	('miR-145', 'Gene', (36, 43))	('miR-204', 'Gene', '406987', (55, 62))	('miR-16', 'Gene', '51573', (28, 34))	('differences', 'Reg', (108, 119))	('miR-145', 'Gene', '406937', (36, 43))	('miR-146a', 'Gene', (45, 53))	('miR-211', 'Gene', '406993', (64, 71))	('miR-211', 'Gene', (64, 71))	('miR-204', 'Gene', (55, 62))	('miR-146a', 'Gene', '406938', (45, 53))
7386	31737436	Interestingly, low-circulating miR-204 expression was found to be significantly (Log rank, P = 0.014) associated with poor overall survival as compared with high-circulating expression levels (Supplementary Fig.	('low-circulating', 'Var', (15, 30))	('miR-204', 'Gene', '406987', (31, 38))	('poor', 'NegReg', (118, 122))	('miR-204', 'Gene', (31, 38))	('overall survival', 'CPA', (123, 139))
7387	31737436	All other miRNA showed nonsignificant associations with OS, however high miR-211 expression did have a nonsignificant trend toward poor OS (Supplementary Fig.	('miR-211', 'Gene', '406993', (73, 80))	('miR-211', 'Gene', (73, 80))	('expression', 'MPA', (81, 91))	('high', 'Var', (68, 72))
7407	30181242	Here we show that constitutively active Galphaq in uveal melanoma (UM) cells can be targeted by the cyclic depsipeptide FR900359 (FR).	('uveal melanoma', 'Phenotype', 'HP:0007716', (51, 65))	('uveal melanoma', 'Disease', (51, 65))	('Galphaq', 'Protein', (40, 47))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('UM', 'Phenotype', 'HP:0007716', (67, 69))	('FR900359', 'Var', (120, 128))	('FR', 'Chemical', 'MESH:C000607068', (130, 132))	('FR', 'Chemical', 'MESH:C000607068', (120, 122))	('uveal melanoma', 'Disease', 'MESH:C536494', (51, 65))
7414	30181242	The cyclic depsipeptide FR900359 targets nucleotide exchange to trap constitutively active mutant Galphaq in the inactive GDP-bound state and uncover novel pathways and therapeutic opportunities in uveal melanoma and other diseases.	('GDP', 'Chemical', 'MESH:D006153', (122, 125))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('uveal melanoma', 'Phenotype', 'HP:0007716', (198, 212))	('uveal melanoma', 'Disease', 'MESH:C536494', (198, 212))	('FR', 'Chemical', 'MESH:C000607068', (24, 26))	('uveal melanoma', 'Disease', (198, 212))	('mutant', 'Var', (91, 97))	('Galphaq', 'Gene', (98, 105))
7417	30181242	In cholera, certain cancers, Sturge-Weber syndrome and other disorders, this cycle is disrupted by mutant or covalently modified Galpha subunits that, by failing to hydrolyze GTP, are constitutively active.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('GTP', 'Chemical', 'MESH:D006160', (175, 178))	('Galpha', 'Gene', '8802', (129, 135))	('cholera', 'Disease', (3, 10))	('Galpha', 'Gene', (129, 135))	('Sturge-Weber syndrome', 'Disease', (29, 50))	('Weber syndrome', 'Phenotype', 'HP:0002277', (36, 50))	('disrupted', 'Reg', (86, 95))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (29, 50))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('mutant', 'Var', (99, 105))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))
7418	30181242	Constitutively active mutant forms Galphaq or its close relative Galpha11 are the oncogenic drivers in nearly 90% of uveal melanoma (UM) patients.	('Galpha11', 'Gene', '2767', (65, 73))	('uveal melanoma', 'Disease', (117, 131))	('Galphaq', 'Gene', (35, 42))	('patients', 'Species', '9606', (137, 145))	('UM', 'Phenotype', 'HP:0007716', (133, 135))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('mutant', 'Var', (22, 28))	('uveal melanoma', 'Phenotype', 'HP:0007716', (117, 131))	('uveal melanoma', 'Disease', 'MESH:C536494', (117, 131))	('Galpha11', 'Gene', (65, 73))
7428	30181242	Here we report that constitutively active Galphaq can be targeted pharmacologically in UM cells by FR900359 (FR), a naturally occurring, cyclic depsipeptide that has been shown previously to inhibit wild type Galphaq by interfering allosterically with GDP dissociation.	('Galphaq', 'Enzyme', (209, 216))	('UM', 'Phenotype', 'HP:0007716', (87, 89))	('inhibit', 'NegReg', (191, 198))	('interfering', 'Reg', (220, 231))	('FR900359', 'Var', (99, 107))	('GDP dissociation', 'MPA', (252, 268))	('FR', 'Chemical', 'MESH:C000607068', (99, 101))	('GDP', 'Chemical', 'MESH:D006153', (252, 255))	('FR', 'Chemical', 'MESH:C000607068', (109, 111))	('allosterically', 'MPA', (232, 246))
7430	30181242	Our results suggest that targeting nucleotide exchange is a novel, general strategy for inhibiting Galpha subunits in cancer and other diseases.	('cancer', 'Disease', (118, 124))	('Galpha', 'Gene', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('inhibiting', 'NegReg', (88, 98))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('targeting nucleotide exchange', 'Var', (25, 54))	('Galpha', 'Gene', '8802', (99, 105))
7437	30181242	Conversely, FR drove constitutively active Galphaq out of the active GTP-bound state, as indicated by inhibition of split-luciferase complementation between constitutively active Galphaq and RGS2 (Fig.	('RGS2', 'Gene', (191, 195))	('complementation', 'Var', (133, 148))	('RGS2', 'Gene', '5997', (191, 195))	('RGS', 'molecular_function', 'GO:0016299', ('191', '194'))	('GTP', 'Chemical', 'MESH:D006160', (69, 72))	('FR', 'Chemical', 'MESH:C000607068', (12, 14))	('inhibition', 'NegReg', (102, 112))
7444	30181242	Crystallographic and mutagenesis studies of wild type Galphaq identified amino acid residues (Arg60, Val184, Ile190) that are important for inhibition by YM-254890 (YM), an inhibitor nearly identical to FR.	('FR', 'Chemical', 'MESH:C000607068', (203, 205))	('YM-254890', 'Var', (154, 163))	('Arg60', 'Var', (94, 99))	('Ile190', 'Var', (109, 115))	('Val184', 'Chemical', '-', (101, 107))	('Val184', 'Var', (101, 107))	('Ile190', 'Chemical', '-', (109, 115))	('YM-254890', 'Chemical', 'MESH:C475455', (154, 163))	('inhibition', 'NegReg', (140, 150))	('mutagenesis', 'biological_process', 'GO:0006280', ('21', '32'))	('Arg60', 'Chemical', '-', (94, 99))
7445	30181242	We found that single amino-acid substitutions at any of these sites (R60K, V184S, I190N) in constitutively active Galphaq were sufficient to blunt the inhibitory potency of FR (Fig.	('blunt', 'NegReg', (141, 146))	('I190N', 'Mutation', 'p.I190N', (82, 87))	('V184S', 'Mutation', 'p.V184S', (75, 80))	('R60K', 'Var', (69, 73))	('inhibitory potency', 'MPA', (151, 169))	('R60K', 'Mutation', 'p.R60K', (69, 73))	('FR', 'Chemical', 'MESH:C000607068', (173, 175))	('V184S', 'Var', (75, 80))	('I190N', 'Var', (82, 87))	('Galphaq', 'Protein', (114, 121))
7464	30181242	We found that constitutively active Galphai/q(Q204L) (equivalent to Galphaq(Q209L)) exhibited a severe defect in the catalytic rate of GTP hydrolysis that was not corrected by FR (Fig.	('Galphai/q', 'Chemical', '-', (36, 45))	('q', 'Chemical', '-', (44, 45))	('FR', 'Chemical', 'MESH:C000607068', (176, 178))	('defect', 'NegReg', (103, 109))	('Galphai/q(Q204L', 'Var', (36, 51))	('Q209L', 'Mutation', 'rs121913492', (76, 81))	('Q204L', 'Mutation', 'p.Q204L', (46, 51))	('GTP hydrolysis', 'MPA', (135, 149))	('catalytic rate', 'MPA', (117, 131))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('135', '149'))	('q', 'Chemical', '-', (55, 56))	('GTP', 'Chemical', 'MESH:D006160', (135, 138))	('q', 'Chemical', '-', (74, 75))
7468	30181242	To determine whether FR inhibits signal transduction by constitutively active Galphaq in UM cells, we analyzed two UM cell lines (Mel202 and 92.1) driven by constitutively active Galphaq(Q209L).	('FR', 'Chemical', 'MESH:C000607068', (21, 23))	('inhibits', 'NegReg', (24, 32))	('UM', 'Phenotype', 'HP:0007716', (115, 117))	('signal transduction', 'MPA', (33, 52))	('Q209L', 'Mutation', 'rs121913492', (187, 192))	('UM', 'Phenotype', 'HP:0007716', (89, 91))	('signal transduction', 'biological_process', 'GO:0007165', ('33', '52'))	('Q209L', 'Var', (187, 192))
7471	30181242	In the absence of FR, IP1 was >50-fold more abundant in Galphaq(Q209L)-driven Mel202 and 92.1 cells relative to BRAF(V600E)-driven OCM-1A cells (Fig.	('V600E', 'Var', (117, 122))	('IP1', 'Gene', '8517', (22, 25))	('FR', 'Chemical', 'MESH:C000607068', (18, 20))	('V600E', 'SUBSTITUTION', 'None', (117, 122))	('OCM-1', 'Species', '83984', (131, 136))	('IP1', 'Gene', (22, 25))	('Q209L', 'Mutation', 'rs121913492', (64, 69))
7498	30181242	In contrast, expression of PRC2-regulated genes in BRAF(V600E)-driven OCM-1A cells was unaffected by FR (fig.	('expression', 'MPA', (13, 23))	('V600E', 'Var', (56, 61))	('V600E', 'SUBSTITUTION', 'None', (56, 61))	('FR', 'Chemical', 'MESH:C000607068', (101, 103))	('OCM-1', 'Species', '83984', (70, 75))	('PRC2-regulated genes', 'Gene', (27, 47))
7512	30181242	Indeed, as predicted by this hypothesis, we found that engineering an FR binding site into an FR-insensitive Galpha subunit was sufficient to confer FR sensitivity.	('FR sensitivity', 'MPA', (149, 163))	('Galpha', 'Gene', '8802', (109, 115))	('engineering', 'Var', (55, 66))	('FR', 'Chemical', 'MESH:C000607068', (70, 72))	('confer', 'Reg', (142, 148))	('FR', 'Chemical', 'MESH:C000607068', (94, 96))	('FR', 'Chemical', 'MESH:C000607068', (149, 151))	('binding', 'molecular_function', 'GO:0005488', ('73', '80'))	('Galpha', 'Gene', (109, 115))
7513	30181242	Thus, we speculate that a collection of FR-like inhibitors, each of which selectively targets the diverged allosteric regulatory site of certain Galpha subunits, may provide a novel approach toward therapeutic development in cancers associated with other mutant constitutively active Galpha subunits, cholera, and Sturge-Weber Syndrome.	('Galpha', 'Gene', '8802', (284, 290))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('Galpha', 'Gene', (284, 290))	('mutant', 'Var', (255, 261))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('Weber Syndrome', 'Phenotype', 'HP:0002277', (321, 335))	('cancers', 'Disease', (225, 232))	('Sturge-Weber Syndrome', 'Disease', (314, 335))	('Galpha', 'Gene', (145, 151))	('Galpha', 'Gene', '8802', (145, 151))	('FR', 'Chemical', 'MESH:C000607068', (40, 42))	('cholera', 'Disease', (301, 308))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
7522	30181242	Many of these repressed genes are involved in embryonic stem cell lineage specification and differentiation, and are targets of epigenetic silencing by the polycomb repressive complex 2 (PRC2), which acts through histone H3(Lys27) trimethylation.	('involved', 'Reg', (34, 42))	('PRC2', 'Gene', (187, 191))	('Lys27', 'Chemical', '-', (224, 229))	('epigenetic silencing', 'Var', (128, 148))	('differentiation', 'CPA', (92, 107))	('embryonic', 'CPA', (46, 55))
7526	30181242	This finding, coupled with prior studies of BAP1, indicates that a temporal hierarchy of epigenetic regulation drives tumorigenesis and progression in UM.	('UM', 'Phenotype', 'HP:0007716', (151, 153))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('BAP1', 'Gene', '8314', (44, 48))	('tumor', 'Disease', (118, 123))	('epigenetic regulation', 'Var', (89, 110))	('regulation', 'biological_process', 'GO:0065007', ('100', '110'))	('BAP1', 'Gene', (44, 48))
7527	30181242	Early in tumorigenesis, mutations that constitutively activate Galphaq are acquired, which inhibits PRC2-mediated repression.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('q', 'Chemical', '-', (77, 78))	('q', 'Chemical', '-', (69, 70))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('Galphaq', 'Gene', (63, 70))	('tumor', 'Disease', (9, 14))	('PRC2-mediated repression', 'MPA', (100, 124))	('inhibits', 'NegReg', (91, 99))	('mutations', 'Var', (24, 33))	('activate', 'PosReg', (54, 62))
7528	30181242	Subsequent loss of BAP1, a histone H2A(Lys119) deubiquitinase that antagonizes repression by polycomb repressive complex 1 (PRC1), then leads to metastasis.	('q', 'Chemical', '-', (5, 6))	('leads to', 'Reg', (136, 144))	('metastasis', 'CPA', (145, 155))	('loss', 'Var', (11, 15))	('Lys119', 'Chemical', '-', (39, 45))	('BAP1', 'Gene', '8314', (19, 23))	('q', 'Chemical', '-', (52, 53))	('polycomb repressive complex 1', 'cellular_component', 'GO:0035102', ('93', '122'))	('BAP1', 'Gene', (19, 23))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('47', '61'))
7531	30181242	The N-terminal portion of click beetle green luciferase (CBGN) was inserted into the alphaB-alphaC loop within the helical domain of wild type (WT) and constitutively active (c.626A>T; Q209L) mutant forms of GNAQ (Galphaq) and GNA13 (Galpha13) (Q226L).	('Q209L', 'Mutation', 'rs121913492', (185, 190))	('GNA13', 'Gene', (227, 232))	('GNAQ', 'Gene', (208, 212))	('Galpha13', 'Gene', '10672', (234, 242))	('c.626A>T; Q209L', 'Var', (175, 190))	('Galpha13', 'Gene', (234, 242))	('GNA13', 'Gene', '10672', (227, 232))	('GNAQ', 'Gene', '2776', (208, 212))	('c.626A>T', 'Mutation', 'rs121913492', (175, 183))	('Q226L', 'Mutation', 'p.Q226L', (245, 250))
7532	30181242	Insertion of foreign proteins at this site preserves Galpha subunit function.	('Insertion', 'Var', (0, 9))	('function', 'MPA', (68, 76))	('Galpha', 'Gene', '8802', (53, 59))	('Galpha', 'Gene', (53, 59))
7538	30181242	Cells were transfected with a cAMP FRET reporter and pertussis toxin (PTX)-resistant forms of Galphai1, Galphai/q or Galphai/q(R54K).	('Galphai/q(R54K', 'Var', (117, 131))	('FR', 'Chemical', 'MESH:C000607068', (35, 37))	('Galphai', 'Chemical', '-', (94, 101))	('Galphai', 'Chemical', '-', (117, 124))	('cAMP', 'Chemical', '-', (30, 34))	('Galphai/q', 'Chemical', '-', (117, 126))	('Galphai', 'Chemical', '-', (104, 111))	('Galphai1', 'Gene', (94, 102))	('Galphai/q', 'Chemical', '-', (104, 113))	('R54K', 'Mutation', 'p.R54K', (127, 131))
7567	30181242	A pet14B-6xHIS-Galphai/q plasmid was generated by cloning a custom synthesized gBlocks gene fragment (Integrated DNA Technologies) containing mutations encoding eight amino acid substitutions (V50I, K54R, Y69F, V72L, K180P, V185I, T187Y, and H188P) in 6xHIS-Galphai1.	('K54R', 'Mutation', 'p.K54R', (199, 203))	('Galphai', 'Chemical', '-', (258, 265))	('Galphai/q', 'Chemical', '-', (15, 24))	('Y69F', 'Mutation', 'p.Y69F', (205, 209))	('V50I', 'Mutation', 'rs755077763', (193, 197))	('K180P', 'Mutation', 'p.K180P', (217, 222))	('H188P', 'Var', (242, 247))	('Y69F', 'Var', (205, 209))	('DNA', 'cellular_component', 'GO:0005574', ('113', '116'))	('H188P', 'Mutation', 'p.H188P', (242, 247))	('K180P', 'Var', (217, 222))	('V185I', 'Var', (224, 229))	('Galphai', 'Chemical', '-', (15, 22))	('K54R', 'Var', (199, 203))	('T187Y', 'Var', (231, 236))	('T187Y', 'Mutation', 'p.T187Y', (231, 236))	('V72L', 'Mutation', 'rs1445067675', (211, 215))	('V72L', 'Var', (211, 215))	('V50I', 'Var', (193, 197))	('V185I', 'Mutation', 'p.V185I', (224, 229))
7633	29028788	In the phase II KEYNOTE-002 study (ClinicalTrials.gov ID, NCT01704287; n=540), pembrolizumab demonstrated superior progression-free survival and objective response rate (ORR) and had less high-grade toxicity compared with investigator-choice chemotherapy in patients with ipilimumab-treated advanced melanoma.	('ipilimumab', 'Chemical', 'MESH:D000074324', (272, 282))	('pembrolizumab', 'Var', (79, 92))	('melanoma', 'Phenotype', 'HP:0002861', (300, 308))	('melanoma', 'Disease', (300, 308))	('melanoma', 'Disease', 'MESH:D008545', (300, 308))	('toxicity', 'Disease', 'MESH:D064420', (199, 207))	('toxicity', 'Disease', (199, 207))	('objective response', 'CPA', (145, 163))	('superior', 'PosReg', (106, 114))	('progression-free survival', 'CPA', (115, 140))	('patients', 'Species', '9606', (258, 266))	('pembrolizumab', 'Chemical', 'MESH:C582435', (79, 92))
7634	29028788	In addition, in the phase III randomized KEYNOTE-006 study (ClinicalTrials.gov, NCT01866319; n=834), pembrolizumab demonstrated superior overall survival, progression-free survival, and ORR, and less high-grade toxicity, compared with ipilimumab in patients with ipilimumab-naive advanced melanoma who received <=1 prior therapy.	('melanoma', 'Disease', 'MESH:D008545', (289, 297))	('melanoma', 'Phenotype', 'HP:0002861', (289, 297))	('melanoma', 'Disease', (289, 297))	('patients', 'Species', '9606', (249, 257))	('pembrolizumab', 'Chemical', 'MESH:C582435', (101, 114))	('pembrolizumab', 'Var', (101, 114))	('progression-free survival', 'CPA', (155, 180))	('ipilimumab', 'Chemical', 'MESH:D000074324', (263, 273))	('ORR', 'CPA', (186, 189))	('ipilimumab', 'Chemical', 'MESH:D000074324', (235, 245))	('overall survival', 'CPA', (137, 153))	('toxicity', 'Disease', 'MESH:D064420', (211, 219))	('toxicity', 'Disease', (211, 219))	('superior', 'PosReg', (128, 136))
7718	27486988	Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in Class 1 and Class 2 uveal melanomas We previously identified PRAME as a biomarker for metastatic risk in Class 1 uveal melanomas.	('PRAME', 'Gene', '23532', (168, 173))	('PRAME', 'Gene', (168, 173))	('uveal melanomas', 'Disease', (127, 142))	('uveal melanomas', 'Phenotype', 'HP:0007716', (127, 142))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('uveal melanoma', 'Phenotype', 'HP:0007716', (220, 234))	('associated', 'Reg', (62, 72))	('metastatic', 'CPA', (88, 98))	('uveal melanomas', 'Disease', (220, 235))	('uveal melanomas', 'Phenotype', 'HP:0007716', (220, 235))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanomas', 'Phenotype', 'HP:0002861', (226, 235))	('aberrant expression', 'Var', (29, 48))	('PRAME', 'Gene', '23532', (52, 57))	('PRAME', 'Gene', (52, 57))	('Epigenetic', 'Var', (0, 10))	('uveal melanomas', 'Disease', 'MESH:C536494', (127, 142))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('uveal melanomas', 'Disease', 'MESH:C536494', (220, 235))	('uveal melanoma', 'Phenotype', 'HP:0007716', (127, 141))
7719	27486988	In this study, we sought to define a threshold value for positive PRAME expression (PRAME+) in a large dataset, identify factors associated with PRAME expression, evaluate the prognostic value of PRAME in Class 2 uveal melanomas, and determine whether PRAME expression is associated with aberrant hypomethylation of the PRAME promoter.	('uveal melanomas', 'Disease', (213, 228))	('PRAME+', 'Gene', (84, 90))	('uveal melanomas', 'Phenotype', 'HP:0007716', (213, 228))	('hypomethylation', 'Var', (297, 312))	('PRAME+', 'Gene', '23532', (84, 90))	('PRAME', 'Gene', '23532', (84, 89))	('PRAME', 'Gene', (84, 89))	('PRAME', 'Gene', '23532', (252, 257))	('PRAME', 'Gene', (252, 257))	('melanomas', 'Phenotype', 'HP:0002861', (219, 228))	('PRAME', 'Gene', '23532', (196, 201))	('PRAME', 'Gene', (196, 201))	('aberrant hypomethylation', 'Var', (288, 312))	('uveal melanomas', 'Disease', 'MESH:C536494', (213, 228))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('PRAME', 'Gene', '23532', (66, 71))	('PRAME', 'Gene', '23532', (145, 150))	('PRAME', 'Gene', (66, 71))	('PRAME', 'Gene', '23532', (320, 325))	('PRAME', 'Gene', (320, 325))	('PRAME', 'Gene', (145, 150))	('uveal melanoma', 'Phenotype', 'HP:0007716', (213, 227))
7723	27486988	In Class 1 tumors, PRAME expression was directly associated with SF3B1 mutations (P < 0.0001) and inversely associated with EIF1AX mutations (P = 0.004).	('EIF1AX', 'Gene', '1964', (124, 130))	('EIF1AX', 'Gene', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('expression', 'MPA', (25, 35))	('associated', 'Reg', (49, 59))	('SF3B1', 'Gene', (65, 70))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('mutations', 'Var', (71, 80))	('PRAME', 'Gene', '23532', (19, 24))	('PRAME', 'Gene', (19, 24))	('SF3B1', 'Gene', '23451', (65, 70))
7724	27486988	PRAME expression was strongly associated with hypomethylation at 12 CpG sites near the PRAME promoter.	('associated', 'Reg', (30, 40))	('PRAME', 'Gene', '23532', (87, 92))	('PRAME', 'Gene', (87, 92))	('hypomethylation', 'Var', (46, 61))	('PRAME', 'Gene', '23532', (0, 5))	('PRAME', 'Gene', (0, 5))
7725	27486988	Analyses included PRAME mRNA expression, Class 1 versus Class 2 status, chromosomal copy number, mutation status of BAP1, EIF1AX, GNA11, GNAQ and SF3B1, and genomic DNA methylation status.	('BAP1', 'Gene', (116, 120))	('PRAME', 'Gene', '23532', (18, 23))	('PRAME', 'Gene', (18, 23))	('GNAQ', 'Gene', (137, 141))	('GNA11', 'Gene', (130, 135))	('DNA methylation', 'biological_process', 'GO:0006306', ('165', '180'))	('EIF1AX', 'Gene', '1964', (122, 128))	('EIF1AX', 'Gene', (122, 128))	('GNA11', 'Gene', '2767', (130, 135))	('SF3B1', 'Gene', (146, 151))	('mutation', 'Var', (97, 105))	('BAP1', 'Gene', '8314', (116, 120))	('GNAQ', 'Gene', '2776', (137, 141))	('DNA', 'cellular_component', 'GO:0005574', ('165', '168'))	('SF3B1', 'Gene', '23451', (146, 151))
7736	27486988	In that initial study, we found that any detectable mRNA expression of PRAME above baseline was associated with increased metastatic risk.	('PRAME', 'Gene', (71, 76))	('PRAME', 'Gene', '23532', (71, 76))	('mRNA expression', 'Var', (52, 67))	('metastatic risk', 'CPA', (122, 137))
7739	27486988	Mutations in BAP1, SF3B1 and EIF1AX are almost mutually exclusive and are associated with high, intermediate and low metastatic risk, respectively.	('BAP1', 'Gene', (13, 17))	('EIF1AX', 'Gene', '1964', (29, 35))	('EIF1AX', 'Gene', (29, 35))	('SF3B1', 'Gene', '23451', (19, 24))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (13, 17))	('SF3B1', 'Gene', (19, 24))	('associated', 'Reg', (74, 84))
7740	27486988	Also, SF3B1 mutations were found to be associated with PRAME expression.	('SF3B1', 'Gene', (6, 11))	('mutations', 'Var', (12, 21))	('PRAME', 'Gene', '23532', (55, 60))	('PRAME', 'Gene', (55, 60))	('SF3B1', 'Gene', '23451', (6, 11))	('associated', 'Reg', (39, 49))
7757	27486988	Additionally, we determined PRAME mRNA status in commonly used UM cell lines: Mel202 and MP41 are PRAME+, whereas 92.1, Mel270, Mel290, and MP46 are PRAME-.	('PRAME', 'Gene', '23532', (28, 33))	('MP41', 'Var', (89, 93))	('PRAME', 'Gene', (28, 33))	('Mel270', 'Var', (120, 126))	('MP46', 'Var', (140, 144))	('Mel202', 'Var', (78, 84))	('PRAME', 'Gene', '23532', (149, 154))	('PRAME+', 'Gene', (98, 104))	('PRAME+', 'Gene', '23532', (98, 104))	('PRAME', 'Gene', (149, 154))	('PRAME', 'Gene', '23532', (98, 103))	('PRAME', 'Gene', (98, 103))
7769	27486988	Overall, PRAME+ tumors were strongly associated with 6q loss (P < 0.0001), 8p loss (P = 0.04), 8q gain (P < 0.0001) and 16q loss (P < 0.0001) (Figure 4).	('loss', 'NegReg', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('loss', 'NegReg', (78, 82))	('PRAME+', 'Gene', '23532', (9, 15))	('gain', 'PosReg', (98, 102))	('tumors', 'Disease', (16, 22))	('16q loss', 'Var', (120, 128))	('PRAME+', 'Gene', (9, 15))
7775	27486988	To identify common driver mutations that may be associated with PRAME+ status, we analyzed 59 of our cases for which mutation data were available, as well as the 80 TCGA cases, for mutations in EIF1AX, BAP1, GNA11, GNAQ and SF3B1 (Supplementary Table S4).	('GNAQ', 'Gene', (215, 219))	('BAP1', 'Gene', (202, 206))	('GNA11', 'Gene', (208, 213))	('EIF1AX', 'Gene', '1964', (194, 200))	('EIF1AX', 'Gene', (194, 200))	('PRAME+', 'Gene', (64, 70))	('GNA11', 'Gene', '2767', (208, 213))	('PRAME+', 'Gene', '23532', (64, 70))	('GNAQ', 'Gene', '2776', (215, 219))	('SF3B1', 'Gene', (224, 229))	('mutations', 'Var', (181, 190))	('BAP1', 'Gene', '8314', (202, 206))	('SF3B1', 'Gene', '23451', (224, 229))
7776	27486988	When Class 1 and Class 2 tumors were considered together, PRAME+ status was associated with BAP1 mutations (P = 0.02).	('mutations', 'Var', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('associated', 'Reg', (76, 86))	('BAP1', 'Gene', '8314', (92, 96))	('PRAME+', 'Gene', (58, 64))	('PRAME+', 'Gene', '23532', (58, 64))	('BAP1', 'Gene', (92, 96))
7777	27486988	However, this association is likely due to BAP1 mutations occurring almost exclusively in Class 2 tumors, which we show here to be associated with PRAME+ status.	('BAP1', 'Gene', (43, 47))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('associated', 'Reg', (131, 141))	('BAP1', 'Gene', '8314', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('PRAME+', 'Gene', (147, 153))	('PRAME+', 'Gene', '23532', (147, 153))	('mutations', 'Var', (48, 57))
7778	27486988	When Class 1 tumors were analyzed separately, PRAME expression was directly associated with SF3B1 mutations (P < 0.0001) and inversely associated with EIF1AX mutations (P = 0.004).	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('SF3B1', 'Gene', '23451', (92, 97))	('PRAME', 'Gene', '23532', (46, 51))	('PRAME', 'Gene', (46, 51))	('associated', 'Reg', (76, 86))	('mutations', 'Var', (98, 107))	('EIF1AX', 'Gene', '1964', (151, 157))	('EIF1AX', 'Gene', (151, 157))	('mutations', 'Var', (158, 167))	('SF3B1', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
7781	27486988	Consequently, we hypothesized that PRAME may become aberrantly activated in uveal melanoma by hypomethylation of the promoter region.	('uveal melanoma', 'Phenotype', 'HP:0007716', (76, 90))	('uveal melanoma', 'Disease', 'MESH:C536494', (76, 90))	('PRAME', 'Gene', '23532', (35, 40))	('uveal melanoma', 'Disease', (76, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('PRAME', 'Gene', (35, 40))	('hypomethylation', 'Var', (94, 109))	('activated', 'PosReg', (63, 72))
7782	27486988	Consistent with this hypothesis, 12 CpG sites within and near the PRAME promoter were significantly hypomethylated (FDR < 0.05 for all probes) in PRAME+ tumors compared to PRAME- tumors (Figure 5B).	('hypomethylated', 'Var', (100, 114))	('PRAME', 'Gene', '23532', (66, 71))	('PRAME', 'Gene', '23532', (172, 177))	('PRAME+', 'Gene', (146, 152))	('PRAME+', 'Gene', '23532', (146, 152))	('PRAME', 'Gene', (66, 71))	('PRAME', 'Gene', (172, 177))	('tumors', 'Disease', (179, 185))	('PRAME', 'Gene', '23532', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('PRAME', 'Gene', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
7785	27486988	These data indicate that the PRAME promoter region is normally hypermethylated and silenced in virtually all normal adult tissues, but it is targeted for hypomethylation and aberrant transcriptional activation during uveal melanoma progression.	('PRAME', 'Gene', '23532', (29, 34))	('PRAME', 'Gene', (29, 34))	('uveal melanoma', 'Disease', 'MESH:C536494', (217, 231))	('uveal melanoma', 'Phenotype', 'HP:0007716', (217, 231))	('uveal melanoma', 'Disease', (217, 231))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('hypomethylation', 'Var', (154, 169))
7800	27486988	PRAME expression was associated with specific chromosomal gains and losses, some of which were specific to either Class 1 or Class 2 tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', (133, 139))	('chromosomal gains', 'Var', (46, 63))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('losses', 'NegReg', (68, 74))	('PRAME', 'Gene', '23532', (0, 5))	('PRAME', 'Gene', (0, 5))
7801	27486988	Changes that were associated with PRAME+ status in both Class 1 and Class 2 tumors included 6p gain, 6q loss, 8q gain and 16q loss.	('loss', 'NegReg', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('PRAME+', 'Gene', (34, 40))	('16q', 'Var', (122, 125))	('PRAME+', 'Gene', '23532', (34, 40))	('gain', 'PosReg', (113, 117))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('loss', 'NegReg', (126, 130))	('gain', 'PosReg', (95, 99))
7806	27486988	8p loss was associated with PRAME+ status only in Class 2 tumors, whereas 8q gain was associated with PRAME+ status in both tumor classes.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('8q gain', 'Var', (74, 81))	('tumor', 'Disease', (124, 129))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('PRAME+', 'Gene', '23532', (28, 34))	('PRAME+', 'Gene', (102, 108))	('PRAME+', 'Gene', '23532', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('8p loss', 'Var', (0, 7))	('PRAME+', 'Gene', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
7808	27486988	In Class 1 tumors, 8q gain often occurs through gain of an entire copy of chromosome 8 or by simple gain of the q arm, whereas in Class 2 tumors, 8q gain frequently occurs through formation of an isochromosome 8q, which is accompanied by loss of 8p.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('gain', 'PosReg', (100, 104))	('gain', 'PosReg', (48, 52))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('formation', 'biological_process', 'GO:0009058', ('180', '189'))	('chromosome', 'cellular_component', 'GO:0005694', ('74', '84'))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('isochromosome 8q', 'Var', (196, 212))	('gain', 'PosReg', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
7812	27486988	Hence, aberrant expression of PRAME may predispose tumor cells to isochromosome formation, as well as other forms of aneuploidy that promote tumor progression.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('promote', 'PosReg', (133, 140))	('aberrant expression', 'Var', (7, 26))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', (141, 146))	('aneuploidy', 'Disease', 'MESH:D000782', (117, 127))	('predispose', 'Reg', (40, 50))	('formation', 'biological_process', 'GO:0009058', ('80', '89'))	('isochromosome formation', 'Disease', (66, 89))	('PRAME', 'Gene', '23532', (30, 35))	('PRAME', 'Gene', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('aneuploidy', 'Disease', (117, 127))
7823	27486988	We demonstrated that specific chromosomal gains and losses, as well as specific driver mutations, are found preferentially in PRAME+ tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', (133, 139))	('PRAME+', 'Gene', (126, 132))	('PRAME+', 'Gene', '23532', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('chromosomal gains', 'Var', (30, 47))	('losses', 'NegReg', (52, 58))
7885	27391064	An additional 13 classically-secreted proteins, which are significantly elevated in the HR-UM as compared with either the LR-UM or the NCM, are presented in this study that warrant further validation in patient blood specimens.	('elevated', 'PosReg', (72, 80))	('UM', 'Phenotype', 'HP:0007716', (125, 127))	('UM', 'Phenotype', 'HP:0007716', (91, 93))	('patient', 'Species', '9606', (203, 210))	('HR-UM', 'Var', (88, 93))
7990	27069456	There are several prognostic factors for outcome of the choroidal melanoma, including age, gender, basal tumour diameter, tumour thickness, T-stage, cell morphology and various genetic changes of the tumour, especially monosomy of chromosome 3.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (56, 74))	('tumour thickness', 'Disease', (122, 138))	('basal tumour', 'Disease', (99, 111))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('basal tumour', 'Phenotype', 'HP:0002671', (99, 111))	('monosomy of chromosome 3', 'Var', (219, 243))	('tumour', 'Disease', (122, 128))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('tumour', 'Disease', 'MESH:D009369', (200, 206))	('chromosome', 'cellular_component', 'GO:0005694', ('231', '241'))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('tumour', 'Disease', (200, 206))	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('tumour', 'Disease', (105, 111))	('tumour thickness', 'Disease', 'MESH:D009369', (122, 138))	('choroidal melanoma', 'Disease', 'MESH:D008545', (56, 74))	('basal tumour', 'Disease', 'MESH:D002280', (99, 111))	('choroidal melanoma', 'Disease', (56, 74))
8029	25687848	New targeted and immunotherapeutic agents have recently been approved for the initial management of patients with stage IV melanoma, including vemurafenib, dabrafenib, and trametinib for patients with the V600 mutated BRAF gene, and immune checkpoint inhibitors such as ipilimumab and nivolumab.	('vemurafenib', 'Chemical', 'MESH:D000077484', (143, 154))	('patients', 'Species', '9606', (187, 195))	('BRAF', 'Gene', (218, 222))	('BRAF', 'Gene', '673', (218, 222))	('dabrafenib', 'Chemical', 'MESH:C561627', (156, 166))	('trametinib', 'Chemical', 'MESH:C560077', (172, 182))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('patients', 'Species', '9606', (100, 108))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('ipilimumab', 'Chemical', 'MESH:D000074324', (270, 280))	('V600 mutated', 'Var', (205, 217))	('nivolumab', 'Chemical', 'MESH:D000077594', (285, 294))
8030	25687848	In Asia, because acral or mucosal melanoma patients harboring the V600 mutated BRAF gene are rarely seen, many malignant melanoma patients are not eligible for treatment with BRAF targeting agents.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('malignant melanoma', 'Phenotype', 'HP:0002861', (111, 129))	('patients', 'Species', '9606', (43, 51))	('BRAF', 'Gene', (175, 179))	('V600 mutated', 'Var', (66, 78))	('BRAF', 'Gene', '673', (175, 179))	('patients', 'Species', '9606', (130, 138))	('BRAF', 'Gene', '673', (79, 83))	('malignant melanoma', 'Disease', (111, 129))	('malignant melanoma', 'Disease', 'MESH:D008545', (111, 129))	('mucosal melanoma', 'Disease', (26, 42))	('BRAF', 'Gene', (79, 83))	('mucosal melanoma', 'Disease', 'MESH:D008545', (26, 42))
8112	25687848	Oncogenic mutations in guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) or guanine nucleotide binding protein (G protein), alpha 11 (Gq class) (GNA11) have been reported in more than 80% of uveal melanomas; however, in our study, only one uveal melanoma patient had GNA11 Q209L mutation.	('GNAQ', 'Gene', (78, 82))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('GNA11', 'Gene', '2767', (156, 161))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('31', '49'))	('Q209L', 'Mutation', 'rs1057519742', (284, 289))	('uveal melanomas', 'Disease', 'MESH:C536494', (202, 217))	('uveal melanoma', 'Phenotype', 'HP:0007716', (251, 265))	('uveal melanoma', 'Disease', 'MESH:C536494', (202, 216))	('reported', 'Reg', (173, 181))	('uveal melanoma', 'Disease', (251, 265))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('GNA11', 'Gene', '2767', (278, 283))	('uveal melanoma', 'Phenotype', 'HP:0007716', (202, 216))	('GNA11', 'Gene', (156, 161))	('uveal melanomas', 'Disease', (202, 217))	('uveal melanomas', 'Phenotype', 'HP:0007716', (202, 217))	('Q209L mutation', 'Var', (284, 298))	('guanine nucleotide-binding protein G(q) subunit alpha', 'Gene', '2776', (23, 76))	('melanoma', 'Phenotype', 'HP:0002861', (257, 265))	('patient', 'Species', '9606', (266, 273))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('95', '113'))	('melanomas', 'Phenotype', 'HP:0002861', (208, 217))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('GNA11', 'Gene', (278, 283))	('GNAQ', 'Gene', '2776', (78, 82))	('mutations', 'Var', (10, 19))	('uveal melanoma', 'Disease', 'MESH:C536494', (251, 265))
8253	24709888	Rare SF3B1 R625 mutations in cutaneous melanoma RNA splicing is the cellular process that has only recently been found to be an important target for various cancers.	('RNA', 'cellular_component', 'GO:0005562', ('48', '51'))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cellular process', 'cellular_component', 'GO:0042995', ('68', '84'))	('RNA splicing', 'biological_process', 'GO:0008380', ('48', '60'))	('R625 mutations', 'Var', (11, 25))	('SF3B1', 'Gene', '23451', (5, 10))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('mutations', 'Var', (16, 25))	('cellular process', 'biological_process', 'GO:0009987', ('68', '84'))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (29, 47))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (157, 164))	('SF3B1', 'Gene', (5, 10))
8254	24709888	Among the spliceosome genes that are involved in cancers, SF3B1 is most frequently mutated.	('mutated', 'Var', (83, 90))	('SF3B1', 'Gene', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('spliceosome', 'cellular_component', 'GO:0005681', ('10', '21'))	('SF3B1', 'Gene', '23451', (58, 63))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))
8255	24709888	Recurrent mutation in codon 625 has been found in uveal melanoma, but this mutation has not been identified in cutaneous melanoma.	('found', 'Reg', (41, 46))	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('cutaneous melanoma', 'Disease', (111, 129))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (111, 129))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (111, 129))	('uveal melanoma', 'Disease', 'MESH:C536494', (50, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('uveal melanoma', 'Disease', (50, 64))	('mutation in codon', 'Var', (10, 27))
8257	24709888	Out of these cutaneous melanoma samples, we found 2 samples with R625 mutation in SF3B1 gene.	('SF3B1', 'Gene', (82, 87))	('SF3B1', 'Gene', '23451', (82, 87))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('R625', 'Var', (65, 69))	('cutaneous melanoma', 'Disease', (13, 31))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (13, 31))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (13, 31))
8258	24709888	We conclude that SF3B1 R625 mutation does occur in cutaneous melanoma, although with a low frequency (~1%).	('cutaneous melanoma', 'Disease', (51, 69))	('occur', 'Reg', (42, 47))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (51, 69))	('SF3B1', 'Gene', (17, 22))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (51, 69))	('R625', 'Var', (23, 27))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('SF3B1', 'Gene', '23451', (17, 22))
8259	24709888	Recent high throughput sequencing of cancer genomes has led to new discoveries of mutations in cellular processes that were not previously known to play a causal role in cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (170, 176))	('cancer', 'Disease', (37, 43))	('mutations in', 'Var', (82, 94))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cellular', 'Pathway', (95, 103))
8261	24709888	SF3B1 mutations are found with high frequency in myelodysplastic syndromes (MDS) and chronic myelogenous leukemia (CLL); it is also mutated in solid tumors such as lung adenocarcinomas, breast cancer, and pancreatic cancer.	('CLL', 'Phenotype', 'HP:0005506', (115, 118))	('MDS', 'Disease', 'MESH:D009190', (76, 79))	('pancreatic cancer', 'Disease', (205, 222))	('solid tumors', 'Disease', 'MESH:D009369', (143, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('SF3B1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('MDS', 'Disease', (76, 79))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (93, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (85, 113))	('mutations', 'Var', (6, 15))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (205, 222))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (164, 184))	('SF3B1', 'Gene', '23451', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (49, 74))	('myelodysplastic syndromes', 'Disease', (49, 74))	('breast cancer', 'Disease', (186, 199))	('leukemia', 'Phenotype', 'HP:0001909', (105, 113))	('chronic myelogenous leukemia', 'Disease', (85, 113))	('solid tumors', 'Disease', (143, 155))	('MDS', 'Phenotype', 'HP:0002863', (76, 79))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (164, 184))	('pancreatic cancer', 'Disease', 'MESH:D010190', (205, 222))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (49, 74))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (85, 113))	('lung adenocarcinomas', 'Disease', (164, 184))
8262	24709888	In uveal melanoma, recurrent mutations at codon 625 of SF3B1 have been identified .	('SF3B1', 'Gene', '23451', (55, 60))	('uveal melanoma', 'Disease', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('mutations at codon 625', 'Var', (29, 51))	('identified', 'Reg', (71, 81))	('SF3B1', 'Gene', (55, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))
8264	24709888	SF3B1 mutations usually occur within the 22 HEAT repeats in the C-terminal region.	('SF3B1', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('occur', 'Reg', (24, 29))	('SF3B1', 'Gene', '23451', (0, 5))
8265	24709888	Codon R625 has the highest mutation frequency in uveal melanoma, whereas the mutation hotspot is at K700 for MDS and CLL.	('uveal melanoma', 'Disease', 'MESH:C536494', (49, 63))	('Codon R625', 'Var', (0, 10))	('uveal melanoma', 'Disease', (49, 63))	('MDS', 'Disease', (109, 112))	('mutation', 'Var', (27, 35))	('MDS', 'Disease', 'MESH:D009190', (109, 112))	('MDS', 'Phenotype', 'HP:0002863', (109, 112))	('CLL', 'Phenotype', 'HP:0005506', (117, 120))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('uveal melanoma', 'Phenotype', 'HP:0007716', (49, 63))
8266	24709888	While multiple groups identified SF3B1 R625 mutations in uveal melanoma , none identified this mutation in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('cutaneous melanoma', 'Disease', (107, 125))	('SF3B1', 'Gene', '23451', (33, 38))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (107, 125))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (107, 125))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('uveal melanoma', 'Disease', (57, 71))	('mutations', 'Var', (44, 53))	('R625 mutations', 'Var', (39, 53))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('SF3B1', 'Gene', (33, 38))
8268	24709888	We report here that although the frequency is low, SF3B1 R625 mutation does occur in cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))	('R625', 'Var', (57, 61))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('occur', 'Reg', (76, 81))	('SF3B1', 'Gene', (51, 56))	('cutaneous melanoma', 'Disease', (85, 103))	('SF3B1', 'Gene', '23451', (51, 56))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (85, 103))
8270	24709888	The whole-exome sequencing of 295 melanoma samples identified 5 with mutations in SF3B1 R625 (Table 2).	('mutations', 'Var', (69, 78))	('SF3B1', 'Gene', (82, 87))	('R625', 'Var', (88, 92))	('SF3B1', 'Gene', '23451', (82, 87))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))
8271	24709888	Out of these five samples, two (YUBOO and G2306T) are uveal melanoma, two (YUPAO and YUGAFFE) are cutaneous melanoma, and one sample for which the location of the primary lesion is unknown (YUKAY).	('G2306T', 'Var', (42, 48))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('uveal melanoma', 'Disease', (54, 68))	('cutaneous melanoma', 'Disease', (98, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (54, 68))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (98, 116))	('G2306T', 'Mutation', 'c.2306G>T', (42, 48))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (98, 116))
8272	24709888	Three samples have p.R625H mutation, while the other two have p. R625C mutation (amino acids are numbered based on GenBank accession NM_012433.2).	('p.R625H', 'Mutation', 'rs1057519961', (19, 26))	('R625C', 'Var', (65, 70))	('R625C', 'SUBSTITUTION', 'None', (65, 70))	('p.R625H', 'Var', (19, 26))
8274	24709888	The other samples with mutations in SF3B1 R625 show similar mutation frequencies.	('mutations', 'Var', (23, 32))	('R625', 'Var', (42, 46))	('SF3B1', 'Gene', (36, 41))	('SF3B1', 'Gene', '23451', (36, 41))
8276	24709888	One melanoma sample in this cohort has BRAF V600 mutation (YUGAFFE) and none has NRAS mutation (Table 2).	('BRAF V600 mutation', 'Var', (39, 57))	('NRAS', 'Gene', (81, 85))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))	('NRAS', 'Gene', '4893', (81, 85))
8278	24709888	The report of mutations in codon 625 of SF3B1 in uveal melanoma  prompted further investigation regarding the presence of this mutation in cutaneous melanoma.	('SF3B1', 'Gene', (40, 45))	('uveal melanoma', 'Disease', 'MESH:C536494', (49, 63))	('mutations in codon 625', 'Var', (14, 36))	('uveal melanoma', 'Disease', (49, 63))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('cutaneous melanoma', 'Disease', (139, 157))	('SF3B1', 'Gene', '23451', (40, 45))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (139, 157))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (139, 157))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('uveal melanoma', 'Phenotype', 'HP:0007716', (49, 63))
8281	24709888	In our larger cohort, we found five samples with SF3B1 R625 mutations, two of which are cutaneous melanoma and one of unknown origin, showing that the mutation does occur in this type of melanoma, although at low frequency.	('SF3B1', 'Gene', '23451', (49, 54))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('R625 mutations', 'Var', (55, 69))	('cutaneous melanoma', 'Disease', (88, 106))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (88, 106))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (88, 106))	('melanoma', 'Disease', (98, 106))	('SF3B1', 'Gene', (49, 54))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('mutations', 'Var', (60, 69))
8282	24709888	We also noticed that most of our samples that have SF3B1 R625 mutations are metastatic melanoma.	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('SF3B1', 'Gene', (51, 56))	('mutations', 'Var', (62, 71))	('SF3B1', 'Gene', '23451', (51, 56))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
8283	24709888	This is in contrast to previous finding that SF3B1 R625 mutations are rare in metastatic tumors and are associated with better prognosis .	('tumors', 'Disease', (89, 95))	('mutations', 'Var', (56, 65))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('R625 mutations', 'Var', (51, 65))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('SF3B1', 'Gene', (45, 50))	('SF3B1', 'Gene', '23451', (45, 50))
8286	24709888	The other possibility is that the SF3B1 mutations might play different roles in uveal and cutaneous melanomas.	('play', 'Reg', (56, 60))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (90, 109))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (90, 109))	('roles', 'Reg', (71, 76))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (90, 108))	('SF3B1', 'Gene', (34, 39))	('uveal', 'Disease', (80, 85))	('mutations', 'Var', (40, 49))	('cutaneous melanomas', 'Disease', (90, 109))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('SF3B1', 'Gene', '23451', (34, 39))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))
8287	24709888	SF3B1 mutations have been found to be associated with different prognosis in different type of cancers.	('SF3B1', 'Gene', (0, 5))	('associated', 'Reg', (38, 48))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('type of cancers', 'Disease', 'MESH:D009369', (87, 102))	('SF3B1', 'Gene', '23451', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('type of cancers', 'Disease', (87, 102))	('mutations', 'Var', (6, 15))
8288	24709888	The SF3B1 mutations in CLL are associated with poorer prognosis, while in MDS the mutations are associated with better prognosis.	('CLL', 'Gene', (23, 26))	('SF3B1', 'Gene', (4, 9))	('CLL', 'Phenotype', 'HP:0005506', (23, 26))	('SF3B1', 'Gene', '23451', (4, 9))	('MDS', 'Disease', (74, 77))	('MDS', 'Disease', 'MESH:D009190', (74, 77))	('MDS', 'Phenotype', 'HP:0002863', (74, 77))	('mutations', 'Var', (10, 19))
8289	24709888	Different cancers also have different predominate mutations in SF3B1.	('SF3B1', 'Gene', (63, 68))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('SF3B1', 'Gene', '23451', (63, 68))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('cancers', 'Disease', (10, 17))
8290	24709888	In hematological, breast and pancreatic cancers codon K700 mutations predominate, whereas in uveal melanoma the R625 codon mutations predominate.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (29, 46))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('uveal melanoma', 'Phenotype', 'HP:0007716', (93, 107))	('uveal melanoma', 'Disease', 'MESH:C536494', (93, 107))	('breast and pancreatic cancers', 'Disease', 'MESH:D010190', (18, 47))	('uveal melanoma', 'Disease', (93, 107))	('R625', 'Var', (112, 116))	('hematological', 'Disease', (3, 16))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (29, 47))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('codon K700', 'Var', (48, 58))
8293	24709888	We detected mutations in BAP1 in both sun-exposed and uveal melanoma .	('BAP1', 'Gene', (25, 29))	('mutations', 'Var', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('uveal melanoma', 'Disease', (54, 68))	('uveal melanoma', 'Disease', 'MESH:C536494', (54, 68))	('BAP1', 'Gene', '8314', (25, 29))
8294	24709888	Another gene, EIF1AX, which encodes eukaryotic translation initiation factor 1A (eIF1A), was also recently found to be frequently mutated in uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (141, 155))	('eukaryotic translation initiation factor 1A', 'Gene', '1964', (36, 79))	('EIF1AX', 'Gene', '1964', (14, 20))	('uveal melanoma', 'Phenotype', 'HP:0007716', (141, 155))	('eukaryotic translation initiation factor 1A', 'Gene', (36, 79))	('uveal melanoma', 'Disease', (141, 155))	('eIF1A', 'Gene', (81, 86))	('mutated', 'Var', (130, 137))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('eIF1A', 'Gene', '1964', (81, 86))	('translation initiation', 'biological_process', 'GO:0006413', ('47', '69'))	('EIF1AX', 'Gene', (14, 20))
8295	24709888	Interestingly, in our cohort we also found EIF1AX mutations in both uveal and cutaneous melanomas.	('cutaneous melanomas', 'Disease', (78, 97))	('EIF1AX', 'Gene', (43, 49))	('mutations', 'Var', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (78, 96))	('EIF1AX', 'Gene', '1964', (43, 49))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (78, 97))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (78, 97))	('uveal', 'Disease', (68, 73))
8296	24709888	We found 6 mutations in 25 uveal melanomas (~24%) and 5 mutations in 231 cutaneous melanomas (~2%).	('uveal melanoma', 'Phenotype', 'HP:0007716', (27, 41))	('mutations', 'Var', (11, 20))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (73, 92))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('uveal melanomas', 'Disease', (27, 42))	('uveal melanomas', 'Phenotype', 'HP:0007716', (27, 42))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (73, 92))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('cutaneous melanomas', 'Disease', (73, 92))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('uveal melanomas', 'Disease', 'MESH:C536494', (27, 42))
8297	24709888	As discovered previously in uveal melanomas, the nonsynonymous EIF1AX mutations are clustered around the N terminus of the protein for both cutaneous and uveal melanomas in our cohort (data not shown).	('EIF1AX', 'Gene', '1964', (63, 69))	('EIF1AX', 'Gene', (63, 69))	('mutations', 'Var', (70, 79))	('uveal melanomas', 'Disease', (154, 169))	('uveal melanomas', 'Phenotype', 'HP:0007716', (154, 169))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanomas', 'Phenotype', 'HP:0002861', (160, 169))	('cutaneous', 'Disease', (140, 149))	('uveal melanomas', 'Disease', 'MESH:C536494', (154, 169))	('uveal melanomas', 'Disease', (28, 43))	('uveal melanomas', 'Phenotype', 'HP:0007716', (28, 43))	('uveal melanoma', 'Phenotype', 'HP:0007716', (154, 168))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('uveal melanoma', 'Phenotype', 'HP:0007716', (28, 42))	('uveal melanomas', 'Disease', 'MESH:C536494', (28, 43))
8299	23904987	GNAQ and BRAF mutations show differential activation of the mTOR pathway in human transformed cells Somatic mutations in GNAQ gene were described as being the main oncogenic activation in uveal melanomas, whereas mutations in BRAF gene have been described as a key genetic alteration that contributes to skin melanoma development.	('BRAF', 'Gene', (9, 13))	('mTOR', 'Gene', '2475', (60, 64))	('contributes', 'Reg', (289, 300))	('activation', 'PosReg', (42, 52))	('uveal melanoma', 'Phenotype', 'HP:0007716', (188, 202))	('melanoma', 'Phenotype', 'HP:0002861', (309, 317))	('skin melanoma', 'Disease', (304, 317))	('uveal melanomas', 'Phenotype', 'HP:0007716', (188, 203))	('uveal melanomas', 'Disease', (188, 203))	('mutations', 'Var', (14, 23))	('melanomas', 'Phenotype', 'HP:0002861', (194, 203))	('BRAF', 'Gene', '673', (226, 230))	('GNAQ', 'Gene', '2776', (121, 125))	('BRAF', 'Gene', (226, 230))	('GNAQ', 'Gene', (121, 125))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (108, 117))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('human', 'Species', '9606', (76, 81))	('GNAQ', 'Gene', (0, 4))	('skin melanoma', 'Disease', 'MESH:D008545', (304, 317))	('mTOR', 'Gene', (60, 64))	('uveal melanomas', 'Disease', 'MESH:C536494', (188, 203))	('BRAF', 'Gene', '673', (9, 13))
8300	23904987	We have previously reported differential activation of the MAPK and AKT/mTOR signalling pathways in uveal and skin melanomas harbouring, respectively, GNAQ and BRAF mutations.	('GNAQ', 'Gene', '2776', (151, 155))	('BRAF', 'Gene', (160, 164))	('BRAF', 'Gene', '673', (160, 164))	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('mTOR', 'Gene', '2475', (72, 76))	('uvea', 'Disease', 'MESH:C536494', (100, 104))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('mTOR', 'Gene', (72, 76))	('signalling', 'biological_process', 'GO:0023052', ('77', '87'))	('GNAQ', 'Gene', (151, 155))	('MAPK', 'molecular_function', 'GO:0004707', ('59', '63'))	('AKT', 'Gene', '207', (68, 71))	('skin melanomas', 'Disease', (110, 124))	('skin melanomas', 'Disease', 'MESH:D008545', (110, 124))	('mutations', 'Var', (165, 174))	('activation', 'PosReg', (41, 51))	('uvea', 'Disease', (100, 104))	('AKT', 'Gene', (68, 71))
8301	23904987	The aim of this work was to compare the functional effect of GNAQ and BRAF mutations in mTOR and MAPK pathway activation, cell proliferation and apoptosis.	('activation', 'PosReg', (110, 120))	('GNAQ', 'Gene', '2776', (61, 65))	('cell proliferation', 'biological_process', 'GO:0008283', ('122', '140'))	('GNAQ', 'Gene', (61, 65))	('MAPK pathway', 'Pathway', (97, 109))	('mTOR', 'Gene', (88, 92))	('mTOR', 'Gene', '2475', (88, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('mutations', 'Var', (75, 84))	('BRAF', 'Gene', '673', (70, 74))	('cell proliferation', 'CPA', (122, 140))	('MAPK', 'molecular_function', 'GO:0004707', ('97', '101'))	('apoptosis', 'CPA', (145, 154))	('BRAF', 'Gene', (70, 74))
8303	23904987	We treated melanoma cell lines displaying different BRAF and GNAQ mutational status with the mTOR inhibitor RAD001 and with the MEK1/2 inhibitor U0126 and evaluated the effects in the growth of the cell lines and in mTOR and MAPK pathway effectors expression.	('mTOR', 'Gene', '2475', (93, 97))	('MEK1', 'molecular_function', 'GO:0004708', ('128', '132'))	('mTOR', 'Gene', (216, 220))	('GNAQ', 'Gene', '2776', (61, 65))	('mutational', 'Var', (66, 76))	('GNAQ', 'Gene', (61, 65))	('mTOR', 'Gene', '2475', (216, 220))	('RAD', 'biological_process', 'GO:1990116', ('108', '111'))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('U0126', 'Chemical', 'MESH:C113580', (145, 150))	('MEK', 'Gene', '5609', (128, 131))	('BRAF', 'Gene', '673', (52, 56))	('BRAF', 'Gene', (52, 56))	('MAPK', 'molecular_function', 'GO:0004707', ('225', '229'))	('mTOR', 'Gene', (93, 97))	('expression', 'Species', '29278', (248, 258))	('MEK', 'Gene', (128, 131))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
8306	23904987	Cell lines harbouring a BRAF mutation were more sensitive to RAD001 treatment.	('mutation', 'Var', (29, 37))	('BRAF', 'Gene', (24, 28))	('sensitive', 'MPA', (48, 57))	('BRAF', 'Gene', '673', (24, 28))	('RAD', 'biological_process', 'GO:1990116', ('61', '64'))
8307	23904987	U0126 leads to the reduction of MAPK and mTOR pathways activation in all cell lines tested.	('reduction', 'NegReg', (19, 28))	('MAPK', 'Pathway', (32, 36))	('U0126', 'Var', (0, 5))	('MAPK', 'molecular_function', 'GO:0004707', ('32', '36'))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))	('mTOR', 'Gene', (41, 45))	('mTOR', 'Gene', '2475', (41, 45))	('activation', 'PosReg', (55, 65))
8317	23904987	In a previous work we reported BRAF mutations in 30% of skin melanomas and GNAQ gene mutations in 36% of uveal melanomas.	('uveal melanomas', 'Phenotype', 'HP:0007716', (105, 120))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('uveal melanomas', 'Disease', 'MESH:C536494', (105, 120))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('skin melanomas', 'Disease', (56, 70))	('GNAQ', 'Gene', (75, 79))	('BRAF', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('mutations', 'Var', (85, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (105, 119))	('BRAF', 'Gene', '673', (31, 35))	('skin melanomas', 'Disease', 'MESH:D008545', (56, 70))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))	('GNAQ', 'Gene', '2776', (75, 79))	('uveal melanomas', 'Disease', (105, 120))
8318	23904987	No significant association was found between BRAF or GNAQ mutations and the expression of phosphorylated ERK1/2 in tumours, as previous reported by others for BRAF mutations.	('mutations', 'Var', (58, 67))	('tumours', 'Disease', 'MESH:D009369', (115, 122))	('ERK1', 'molecular_function', 'GO:0004707', ('105', '109'))	('tumours', 'Disease', (115, 122))	('BRAF', 'Gene', (159, 163))	('GNAQ', 'Gene', (53, 57))	('expression', 'Species', '29278', (76, 86))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('BRAF', 'Gene', (45, 49))	('expression', 'MPA', (76, 86))	('BRAF', 'Gene', '673', (45, 49))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('GNAQ', 'Gene', '2776', (53, 57))	('BRAF', 'Gene', '673', (159, 163))
8319	23904987	An association between BRAF mutation and elevated mTOR pathway activation was observed in skin melanomas, whereas in a series of uveal melanomas no association was found between mTOR pathway activation and GNAQ mutation.	('melanomas', 'Phenotype', 'HP:0002861', (135, 144))	('mTOR', 'Gene', (50, 54))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('mutation', 'Var', (28, 36))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('mTOR', 'Gene', (178, 182))	('BRAF', 'Gene', '673', (23, 27))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('mTOR', 'Gene', '2475', (50, 54))	('BRAF', 'Gene', (23, 27))	('elevated', 'PosReg', (41, 49))	('uveal melanomas', 'Disease', 'MESH:C536494', (129, 144))	('mTOR', 'Gene', '2475', (178, 182))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('activation', 'PosReg', (63, 73))	('uveal melanomas', 'Disease', (129, 144))	('uveal melanomas', 'Phenotype', 'HP:0007716', (129, 144))	('GNAQ', 'Gene', '2776', (206, 210))	('skin melanomas', 'Disease', (90, 104))	('GNAQ', 'Gene', (206, 210))	('skin melanomas', 'Disease', 'MESH:D008545', (90, 104))
8320	23904987	Our group also found in papillary thyroid carcinoma (that also presents frequent mutation in BRAF gene) an increased activation of mTOR pathway in BRAF mutated PTC, and in vitro transfection of BRAFV 600E disclosed a positive association between BRAF (over)expression and mTOR pathway activation.	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (24, 51))	('mTOR', 'Gene', (131, 135))	('papillary thyroid carcinoma', 'Disease', (24, 51))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (24, 51))	('mTOR', 'Gene', (272, 276))	('BRAF', 'Gene', '673', (246, 250))	('BRAF', 'Gene', (246, 250))	('mTOR', 'Gene', '2475', (131, 135))	('BRAF', 'Gene', '673', (93, 97))	('BRAFV 600E', 'Mutation', 'rs113488022', (194, 204))	('BRAF', 'Gene', (93, 97))	('mTOR', 'Gene', '2475', (272, 276))	('expression', 'Species', '29278', (257, 267))	('mutation', 'Var', (81, 89))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('activation', 'PosReg', (117, 127))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (34, 51))	('activation', 'PosReg', (285, 295))	('BRAF', 'Gene', '673', (194, 198))	('mutated', 'Var', (152, 159))	('BRAF', 'Gene', (194, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
8321	23904987	Inactivation of LKB1 by Ser428 phosphorylation might mediate the association between BRAF expression and mTOR pathway regulation.	('regulation', 'biological_process', 'GO:0065007', ('118', '128'))	('expression', 'Species', '29278', (90, 100))	('BRAF', 'Gene', (85, 89))	('association', 'Interaction', (65, 76))	('mTOR', 'Gene', (105, 109))	('BRAF', 'Gene', '673', (85, 89))	('Ser428 phosphorylation', 'Var', (24, 46))	('Ser428', 'Chemical', '-', (24, 30))	('mTOR', 'Gene', '2475', (105, 109))	('mediate', 'Reg', (53, 60))	('LKB1', 'Gene', (16, 20))	('Ser', 'cellular_component', 'GO:0005790', ('24', '27'))	('Inactivation', 'Var', (0, 12))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))
8322	23904987	Our aim was to compare in vitro the effect of GNAQ and BRAF mutations in the activation of MAPK and mTOR pathways and in the sensitivity to the inhibition of those pathways.	('GNAQ', 'Gene', (46, 50))	('MAPK', 'molecular_function', 'GO:0004707', ('91', '95'))	('activation', 'PosReg', (77, 87))	('GNAQ', 'Gene', '2776', (46, 50))	('BRAF', 'Gene', '673', (55, 59))	('mTOR', 'Gene', (100, 104))	('mutations', 'Var', (60, 69))	('BRAF', 'Gene', (55, 59))	('mTOR', 'Gene', '2475', (100, 104))
8359	23904987	The efficiency of transfection of HEK293 cells with GNAQwt, GNAQQ209P and GNAQQ209L vectors was as high as 60% in all experiments, assessed by fluorescence microscope, and also observed by the levels of GNAQ expression and ERK1/2 activation, which was higher with the mutated vectors than with GNAQwt vector (Fig.	('expression', 'MPA', (208, 218))	('GNAQ', 'Gene', '2776', (60, 64))	('ERK1/2', 'Gene', (223, 229))	('GNAQ', 'Gene', (60, 64))	('GNAQ', 'Gene', '2776', (203, 207))	('mutated', 'Var', (268, 275))	('higher', 'PosReg', (252, 258))	('GNAQ', 'Gene', '2776', (52, 56))	('GNAQ', 'Gene', (203, 207))	('GNAQ', 'Gene', '2776', (74, 78))	('GNAQ', 'Gene', (52, 56))	('GNAQQ209P', 'Mutation', 'rs121913492', (60, 69))	('GNAQ', 'Gene', (74, 78))	('transfection', 'MPA', (18, 30))	('expression', 'Species', '29278', (208, 218))	('GNAQ', 'Gene', '2776', (294, 298))	('activation', 'PosReg', (230, 240))	('GNAQ', 'Gene', (294, 298))	('HEK293', 'CellLine', 'CVCL:0045', (34, 40))	('ERK1', 'molecular_function', 'GO:0004707', ('223', '227'))
8363	23904987	Cells transfected with BRAFV 600E disclosed higher levels of raptor than cells transfected with GNAQQ209P and GNAQQ209L mutant vectors (p = 0.03).	('levels', 'MPA', (51, 57))	('GNAQ', 'Gene', '2776', (96, 100))	('GNAQQ209P', 'Mutation', 'rs121913492', (96, 105))	('raptor', 'MPA', (61, 67))	('BRAFV 600E', 'Mutation', 'rs113488022', (23, 33))	('higher', 'PosReg', (44, 50))	('GNAQ', 'Gene', '2776', (110, 114))	('GNAQ', 'Gene', (110, 114))	('GNAQ', 'Gene', (96, 100))	('BRAFV', 'Var', (23, 28))
8364	23904987	A higher pS6 expression was found in cells transfected with BRAFV 600E than in cells transfected with GNAQQ209L vector (p = 0.05).	('higher', 'PosReg', (2, 8))	('expression', 'Species', '29278', (13, 23))	('expression', 'MPA', (13, 23))	('GNAQ', 'Gene', (102, 106))	('BRAFV 600E', 'Mutation', 'rs113488022', (60, 70))	('pS6', 'Gene', (9, 12))	('BRAFV 600E', 'Var', (60, 70))	('pS6', 'Gene', '338413', (9, 12))	('GNAQ', 'Gene', '2776', (102, 106))
8365	23904987	Although not significant, we also found a tendency for higher pmTOR, raptor and rictor expression in cells transfected with BRAFV 600E than in cells transfected with GNAQQ209L vector.	('mTOR', 'Gene', (63, 67))	('rictor', 'Gene', (80, 86))	('rictor', 'Gene', '253260', (80, 86))	('mTOR', 'Gene', '2475', (63, 67))	('BRAFV 600E', 'Var', (124, 134))	('expression', 'Species', '29278', (87, 97))	('GNAQ', 'Gene', '2776', (166, 170))	('expression', 'MPA', (87, 97))	('BRAFV 600E', 'Mutation', 'rs113488022', (124, 134))	('raptor', 'MPA', (69, 75))	('higher', 'PosReg', (55, 61))	('GNAQ', 'Gene', (166, 170))
8366	23904987	No significant alterations were found either in proliferation (BrdU assay) or in apoptosis (TUNEL assay) when comparing HEK293 cells expressing BRAF and GNAQ vectors with cells transfected with the empty vectors (Fig.	('apoptosis', 'biological_process', 'GO:0006915', ('81', '90'))	('HEK293', 'CellLine', 'CVCL:0045', (120, 126))	('vectors', 'Var', (158, 165))	('BRAF', 'Gene', '673', (144, 148))	('BrdU', 'Chemical', 'MESH:D001973', (63, 67))	('GNAQ', 'Gene', '2776', (153, 157))	('BRAF', 'Gene', (144, 148))	('apoptosis', 'biological_process', 'GO:0097194', ('81', '90'))	('GNAQ', 'Gene', (153, 157))
8370	23904987	Cell lines harbouring BRAF mutation revealed to be more sensitive to RAD001 than the other cell lines tested, with growth inhibition rates of 40% and 44% at 24 h and 47% and 50% at 48 h, with 20 nM and 50 nM of RAD001, respectively, which are significantly higher than cell lines harbouring GNAQ mutations and cell lines wild type for both genes at 24 h (p < 0.01) and also at 48 h of treatment (p <= 0.01).	('GNAQ', 'Gene', (291, 295))	('growth', 'CPA', (115, 121))	('BRAF', 'Gene', '673', (22, 26))	('mutation', 'Var', (27, 35))	('BRAF', 'Gene', (22, 26))	('higher', 'PosReg', (257, 263))	('RAD', 'biological_process', 'GO:1990116', ('69', '72'))	('RAD001', 'Gene', (211, 217))	('RAD', 'biological_process', 'GO:1990116', ('211', '214'))	('GNAQ', 'Gene', '2776', (291, 295))
8371	23904987	The efficacy of RAD001 in inhibiting the mTOR pathway was evaluated by Western blot analysis for PTEN, phosphorylated AKT at Ser473, mTOR at Ser2448, S6 at Ser235/236 and 4E-BP1 at Thr37/46AKTSer473.	('AKT', 'Gene', (118, 121))	('Ser2448', 'Chemical', '-', (141, 148))	('mTOR', 'Gene', (41, 45))	('AKT', 'Gene', (189, 192))	('Ser2448', 'Var', (141, 148))	('BP1', 'Gene', '474256', (174, 177))	('Ser473', 'Chemical', '-', (192, 198))	('Ser', 'cellular_component', 'GO:0005790', ('141', '144'))	('mTOR', 'Gene', '2475', (41, 45))	('AKT', 'Gene', '207', (118, 121))	('inhibiting', 'NegReg', (26, 36))	('PTEN', 'Gene', (97, 101))	('Ser', 'cellular_component', 'GO:0005790', ('125', '128'))	('BP1', 'Gene', (174, 177))	('mTOR', 'Gene', (133, 137))	('RAD', 'biological_process', 'GO:1990116', ('16', '19'))	('Ser473', 'Var', (125, 131))	('AKT', 'Gene', '207', (189, 192))	('Ser235', 'Chemical', '-', (156, 162))	('Ser473', 'Chemical', '-', (125, 131))	('Ser', 'cellular_component', 'GO:0005790', ('156', '159'))	('PTEN', 'Gene', '5728', (97, 101))	('mTOR', 'Gene', '2475', (133, 137))	('Thr37', 'Chemical', '-', (181, 186))
8373	23904987	Phosphorylation of AKT was enhanced after treatment with RAD001 and no alteration was found in PTEN expression.	('RAD001', 'Var', (57, 63))	('RAD', 'biological_process', 'GO:1990116', ('57', '60'))	('enhanced', 'PosReg', (27, 35))	('expression', 'Species', '29278', (100, 110))	('AKT', 'Gene', '207', (19, 22))	('Phosphorylation', 'MPA', (0, 15))	('PTEN', 'Gene', (95, 99))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('PTEN', 'Gene', '5728', (95, 99))	('AKT', 'Gene', (19, 22))
8375	23904987	U0126 effectively inhibits phosphorylation of ERK1/2 and also inhibits phosphorylation of mTOR, S6 and 4EBP1 in the evaluated cell lines.	('phosphorylation', 'MPA', (71, 86))	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('mTOR', 'Gene', (90, 94))	('inhibits', 'NegReg', (62, 70))	('mTOR', 'Gene', '2475', (90, 94))	('inhibits', 'NegReg', (18, 26))	('ERK1/2', 'Protein', (46, 52))	('phosphorylation', 'MPA', (27, 42))	('U0126', 'Var', (0, 5))	('phosphorylation', 'biological_process', 'GO:0016310', ('71', '86'))	('S6 and 4EBP1', 'Gene', '6194', (96, 108))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))	('ERK1', 'molecular_function', 'GO:0004707', ('46', '50'))
8376	23904987	Phosphorylation of AKT was generally enhanced after treatment with U0126 and PTEN expression was not altered.	('expression', 'Species', '29278', (82, 92))	('U0126', 'Var', (67, 72))	('AKT', 'Gene', '207', (19, 22))	('Phosphorylation', 'MPA', (0, 15))	('PTEN', 'Gene', (77, 81))	('U0126', 'Chemical', 'MESH:C113580', (67, 72))	('PTEN', 'Gene', '5728', (77, 81))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('AKT', 'Gene', (19, 22))	('enhanced', 'PosReg', (37, 45))
8378	23904987	In a previous report we described MAPK and AKT/mTOR pathway activations in a series of skin melanomas, where an association between BRAF mutation and high mTOR pathway activation was observed.	('BRAF', 'Gene', (132, 136))	('MAPK', 'molecular_function', 'GO:0004707', ('34', '38'))	('mTOR', 'Gene', '2475', (155, 159))	('mutation', 'Var', (137, 145))	('mTOR', 'Gene', (155, 159))	('AKT', 'Gene', '207', (43, 46))	('melanomas', 'Phenotype', 'HP:0002861', (92, 101))	('skin melanomas', 'Disease', (87, 101))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('skin melanomas', 'Disease', 'MESH:D008545', (87, 101))	('mTOR', 'Gene', '2475', (47, 51))	('activations', 'PosReg', (60, 71))	('activation', 'PosReg', (168, 178))	('mTOR', 'Gene', (47, 51))	('AKT', 'Gene', (43, 46))	('BRAF', 'Gene', '673', (132, 136))	('MAPK', 'Pathway', (34, 38))
8379	23904987	In thyroid carcinomas we also disclosed an association between BRAF mutation and mTOR pathway overactivation.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (3, 20))	('mutation', 'Var', (68, 76))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (3, 21))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (3, 21))	('thyroid carcinomas', 'Disease', (3, 21))	('BRAF', 'Gene', '673', (63, 67))	('overactivation', 'PosReg', (94, 108))	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (81, 85))	('BRAF', 'Gene', (63, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (11, 21))
8380	23904987	We have observed that BRAF over-expression lead to a significant increase in the expression level of pmTOR Ser2448 and pS6 Ser235/236 in vitro.	('increase', 'PosReg', (65, 73))	('expression', 'Species', '29278', (81, 91))	('Ser2448', 'Chemical', '-', (107, 114))	('pS6', 'Gene', '338413', (119, 122))	('Ser', 'cellular_component', 'GO:0005790', ('123', '126'))	('BRAF', 'Gene', '673', (22, 26))	('Ser235', 'Chemical', '-', (123, 129))	('BRAF', 'Gene', (22, 26))	('over-expression', 'Var', (27, 42))	('expression', 'Species', '29278', (32, 42))	('mTOR', 'Gene', (102, 106))	('Ser', 'cellular_component', 'GO:0005790', ('107', '110'))	('expression level', 'MPA', (81, 97))	('Ser2448', 'Var', (107, 114))	('pS6', 'Gene', (119, 122))	('mTOR', 'Gene', '2475', (102, 106))
8383	23904987	In the present work, GNAQ wild-type and mutant vectors lead to ERK1/2 activation, in accordance with the results reported by Raamsdonk et al., after transfection of hTERT/ CDK4R24C/ p53DD melanocytes with GNAQQ209L vector.	('ERK1', 'molecular_function', 'GO:0004707', ('63', '67'))	('GNAQ', 'Gene', '2776', (21, 25))	('hTERT', 'Gene', (165, 170))	('p53', 'Gene', '7157', (182, 185))	('GNAQ', 'Gene', '2776', (205, 209))	('GNAQ', 'Gene', (21, 25))	('CDK', 'molecular_function', 'GO:0004693', ('172', '175'))	('p53', 'Gene', (182, 185))	('mutant', 'Var', (40, 46))	('hTERT', 'Gene', '7015', (165, 170))	('activation', 'PosReg', (70, 80))	('ERK1/2', 'Pathway', (63, 69))	('GNAQ', 'Gene', (205, 209))
8384	23904987	However, neither GNAQ wild-type nor mutated forms, lead to an increase in mTOR pathway activation, which is in line with the lack of association between GNAQ mutational status and mTOR pathway activation that we have reported in human uveal melanoma samples and also with the lack of alteration in AKT phosphorylation after loss of mutant GNAQ, already reported by others in uveal melanoma cell lines.	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('mTOR', 'Gene', '2475', (180, 184))	('loss', 'NegReg', (324, 328))	('mTOR', 'Gene', (74, 78))	('phosphorylation', 'biological_process', 'GO:0016310', ('302', '317'))	('uveal melanoma', 'Disease', 'MESH:C536494', (235, 249))	('melanoma', 'Phenotype', 'HP:0002861', (381, 389))	('uveal melanoma', 'Disease', (235, 249))	('GNAQ', 'Gene', '2776', (339, 343))	('uveal melanoma', 'Disease', 'MESH:C536494', (375, 389))	('uveal melanoma', 'Disease', (375, 389))	('mTOR', 'Gene', '2475', (74, 78))	('GNAQ', 'Gene', (339, 343))	('uveal melanoma', 'Phenotype', 'HP:0007716', (235, 249))	('human', 'Species', '9606', (229, 234))	('AKT', 'Gene', (298, 301))	('GNAQ', 'Gene', '2776', (17, 21))	('uveal melanoma', 'Phenotype', 'HP:0007716', (375, 389))	('GNAQ', 'Gene', (17, 21))	('GNAQ', 'Gene', '2776', (153, 157))	('mutant', 'Var', (332, 338))	('GNAQ', 'Gene', (153, 157))	('activation', 'PosReg', (87, 97))	('mTOR', 'Gene', (180, 184))	('AKT', 'Gene', '207', (298, 301))
8385	23904987	At variance, we observed that, besides ERK1/2 activation, wild-type and mutant BRAF lead to a significant increase in the expression level of pmTOR Ser2448 and pS6 Ser235/236 in vitro.	('pS6', 'Gene', '338413', (160, 163))	('Ser2448', 'Chemical', '-', (148, 155))	('Ser', 'cellular_component', 'GO:0005790', ('148', '151'))	('mutant', 'Var', (72, 78))	('Ser', 'cellular_component', 'GO:0005790', ('164', '167'))	('Ser235', 'Chemical', '-', (164, 170))	('pS6', 'Gene', (160, 163))	('BRAF', 'Gene', '673', (79, 83))	('expression level', 'MPA', (122, 138))	('Ser2448', 'Var', (148, 155))	('mTOR', 'Gene', '2475', (143, 147))	('increase', 'PosReg', (106, 114))	('mTOR', 'Gene', (143, 147))	('BRAF', 'Gene', (79, 83))	('expression', 'Species', '29278', (122, 132))	('ERK1', 'molecular_function', 'GO:0004707', ('39', '43'))
8391	23904987	Recently, Garcia-Marcos and co-authors reported that activating mutations in GNA01 gene, which also encodes a G-protein alphaq-subunit, enhances Stat3 activation.	('Stat3', 'Gene', (145, 150))	('Stat3', 'Gene', '6774', (145, 150))	('GNA01', 'Gene', (77, 82))	('enhances', 'PosReg', (136, 144))	('Garcia-Marcos', 'Disease', (10, 23))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('mutations', 'Var', (64, 73))	('Garcia-Marcos', 'Disease', 'MESH:C536767', (10, 23))
8392	23904987	Concordantly, GNAQ wild-type and mutated forms also seem to drive higher expression of pStat3 Tyr705 (Fig.	('GNAQ', 'Gene', '2776', (14, 18))	('Tyr705', 'Var', (94, 100))	('Stat3', 'Gene', (88, 93))	('Stat3', 'Gene', '6774', (88, 93))	('expression', 'Species', '29278', (73, 83))	('mutated', 'Var', (33, 40))	('Tyr705', 'Chemical', '-', (94, 100))	('expression', 'MPA', (73, 83))	('GNAQ', 'Gene', (14, 18))	('higher', 'PosReg', (66, 72))
8394	23904987	We found higher sensitivity to RAD001 treatment in the cutaneous melanoma cell lines harbouring a BRAFV 600E mutation, in line with the higher expression of pmTOR and pS6 in cells transfected with BRAFV 600E.	('expression', 'Species', '29278', (143, 153))	('BRAFV 600E', 'Mutation', 'rs113488022', (98, 108))	('BRAFV 600E', 'Mutation', 'rs113488022', (197, 207))	('pS6', 'Gene', '338413', (167, 170))	('RAD', 'biological_process', 'GO:1990116', ('31', '34'))	('cutaneous melanoma', 'Disease', (55, 73))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (55, 73))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (55, 73))	('higher', 'PosReg', (9, 15))	('BRAFV 600E', 'Gene', (98, 108))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('sensitivity', 'MPA', (16, 27))	('pS6', 'Gene', (167, 170))	('mTOR', 'Gene', (158, 162))	('mTOR', 'Gene', '2475', (158, 162))	('mutation', 'Var', (109, 117))
8396	23904987	Similar results were reported by that observed higher sensitivity to mTOR and MEK inhibition in uveal melanoma cell lines harbouring BRAF mutations.	('MEK', 'Gene', (78, 81))	('mTOR', 'Gene', (69, 73))	('MEK', 'Gene', '5609', (78, 81))	('uveal melanoma', 'Disease', 'MESH:C536494', (96, 110))	('uveal melanoma', 'Disease', (96, 110))	('BRAF', 'Gene', '673', (133, 137))	('higher', 'PosReg', (47, 53))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('BRAF', 'Gene', (133, 137))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('sensitivity', 'MPA', (54, 65))	('mTOR', 'Gene', '2475', (69, 73))	('mutations', 'Var', (138, 147))
8397	23904987	In our work, we used cutaneous melanoma cell lines where BRAF mutations are the most common alteration and BRAF is considered an oncogene.	('BRAF', 'Gene', (107, 111))	('cutaneous melanoma', 'Disease', (21, 39))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (21, 39))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (21, 39))	('BRAF', 'Gene', '673', (57, 61))	('BRAF', 'Gene', (57, 61))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('BRAF', 'Gene', '673', (107, 111))	('mutations', 'Var', (62, 71))
8398	23904987	These data might support our previous suggestion that skin melanoma with BRAF mutation can be more sensitive to mTOR inhibition therapy.	('BRAF', 'Gene', (73, 77))	('BRAF', 'Gene', '673', (73, 77))	('mutation', 'Var', (78, 86))	('mTOR', 'Gene', '2475', (112, 116))	('skin melanoma', 'Disease', 'MESH:D008545', (54, 67))	('mTOR', 'Gene', (112, 116))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('skin melanoma', 'Disease', (54, 67))
8399	23904987	Not surprisingly, we verified that the inhibition of the mTOR pathway, by RAD001, and the MAPK pathway, by U0126, lead to AKT upregulation.	('U0126', 'Chemical', 'MESH:C113580', (107, 112))	('MAPK pathway', 'Pathway', (90, 102))	('MAPK', 'molecular_function', 'GO:0004707', ('90', '94'))	('inhibition', 'NegReg', (39, 49))	('RAD001', 'Var', (74, 80))	('RAD', 'biological_process', 'GO:1990116', ('74', '77'))	('AKT', 'Gene', '207', (122, 125))	('mTOR', 'Gene', (57, 61))	('mTOR', 'Gene', '2475', (57, 61))	('upregulation', 'PosReg', (126, 138))	('AKT', 'Gene', (122, 125))
8403	23904987	Of note, Khalili et al., proposed that PI3K inhibition enhance the effects of MEK inhibition and the combination may be an effective therapy in uveal melanoma, particularly in a GNAQ mutant background.	('MEK', 'Gene', (78, 81))	('PI3K', 'molecular_function', 'GO:0016303', ('39', '43'))	('GNAQ', 'Gene', '2776', (178, 182))	('MEK', 'Gene', '5609', (78, 81))	('enhance', 'PosReg', (55, 62))	('inhibition', 'NegReg', (44, 54))	('GNAQ', 'Gene', (178, 182))	('uveal melanoma', 'Disease', 'MESH:C536494', (144, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('PI3K', 'Var', (39, 43))	('uveal melanoma', 'Phenotype', 'HP:0007716', (144, 158))	('uveal melanoma', 'Disease', (144, 158))	('effects', 'MPA', (67, 74))
8404	23904987	We observed that the abolishment of MAPK activity by U0126 treatment leads to mTOR pathway inhibition.	('U0126', 'Var', (53, 58))	('MAPK', 'molecular_function', 'GO:0004707', ('36', '40'))	('inhibition', 'NegReg', (91, 101))	('mTOR', 'Gene', (78, 82))	('abolishment', 'NegReg', (21, 32))	('mTOR', 'Gene', '2475', (78, 82))	('U0126', 'Chemical', 'MESH:C113580', (53, 58))	('activity', 'MPA', (41, 49))	('MAPK', 'Protein', (36, 40))
8405	23904987	A synergistic reduction of melanoma cell proliferation and induction of cell death with combined mTOR and MAPK pathway inhibition was already reported, suggesting that this combined inhibitory therapy may benefit patients with BRAF mutant melanomas.	('inhibition', 'NegReg', (119, 129))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('melanoma', 'Disease', (239, 247))	('patients', 'Species', '9606', (213, 221))	('mutant', 'Var', (232, 238))	('MAPK pathway', 'Pathway', (106, 118))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('melanomas', 'Disease', 'MESH:D008545', (239, 248))	('mTOR', 'Gene', (97, 101))	('cell death', 'biological_process', 'GO:0008219', ('72', '82'))	('melanomas', 'Disease', (239, 248))	('mTOR', 'Gene', '2475', (97, 101))	('melanoma', 'Disease', 'MESH:D008545', (239, 247))	('benefit', 'PosReg', (205, 212))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('BRAF', 'Gene', (227, 231))	('BRAF', 'Gene', '673', (227, 231))	('MAPK', 'molecular_function', 'GO:0004707', ('106', '110'))	('melanomas', 'Phenotype', 'HP:0002861', (239, 248))	('cell proliferation', 'biological_process', 'GO:0008283', ('36', '54'))	('reduction', 'NegReg', (14, 23))
8409	23904987	To the best of our knowledge, this is the first study comparing the cellular effects of two major oncogenic events, BRAF and GNAQ mutations, in melanomagenesis using both cutaneous and uveal models.	('uvea', 'Disease', 'MESH:C536494', (185, 189))	('BRAF', 'Gene', '673', (116, 120))	('GNAQ', 'Gene', '2776', (125, 129))	('BRAF', 'Gene', (116, 120))	('mutations', 'Var', (130, 139))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('GNAQ', 'Gene', (125, 129))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('uvea', 'Disease', (185, 189))
8412	23904987	Thus, strategies for melanoma therapy should consider the mutational status, and BRAF mutant melanomas may be more sensitive to mTOR inhibition therapy alone or in combination with MAPK inhibitors, such as vemurafenib, the BRAFV 600E inhibitor already approved for the treatment of advanced melanoma .	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('BRAF', 'Gene', '673', (81, 85))	('BRAF', 'Gene', '673', (223, 227))	('BRAF', 'Gene', (81, 85))	('melanoma', 'Disease', 'MESH:D008545', (291, 299))	('BRAF', 'Gene', (223, 227))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('mTOR', 'Gene', (128, 132))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Disease', (21, 29))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('mTOR', 'Gene', '2475', (128, 132))	('mutant', 'Var', (86, 92))	('vemurafenib', 'Chemical', 'MESH:D000077484', (206, 217))	('melanoma', 'Phenotype', 'HP:0002861', (291, 299))	('melanoma', 'Disease', (291, 299))	('MAPK', 'molecular_function', 'GO:0004707', ('181', '185'))	('melanomas', 'Disease', 'MESH:D008545', (93, 102))	('BRAFV 600E', 'Mutation', 'rs113488022', (223, 233))	('melanomas', 'Disease', (93, 102))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))
8413	23634288	Ultradeep sequencing detects GNAQ and GNA11 mutations in cell-free DNA from plasma of patients with uveal melanoma Elevated levels of cell-free DNA (cfDNA) are frequently observed in tumor patients.	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('GNAQ', 'Gene', (29, 33))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('uveal melanoma', 'Disease', (100, 114))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('mutations', 'Var', (44, 53))	('tumor', 'Disease', (183, 188))	('GNA11', 'Gene', (38, 43))	('GNA11', 'Gene', '2767', (38, 43))	('GNAQ', 'Gene', '2776', (29, 33))	('patients', 'Species', '9606', (189, 197))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('patients', 'Species', '9606', (86, 94))
8414	23634288	Activating mutations in exon 4 (R183) and exon 5 (Q209) of GNAQ and GNA11 are almost exclusively found in uveal melanoma, thus providing a highly specific marker for the presence of circulating tumor DNA (ctDNA).	('Activating', 'PosReg', (0, 10))	('R183', 'Var', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('GNA11', 'Gene', (68, 73))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('GNAQ', 'Gene', (59, 63))	('tumor', 'Disease', (194, 199))	('GNA11', 'Gene', '2767', (68, 73))	('uveal melanoma', 'Disease', (106, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('DNA', 'cellular_component', 'GO:0005574', ('200', '203'))	('Q209', 'Var', (50, 54))	('GNAQ', 'Gene', '2776', (59, 63))
8415	23634288	To establish a reliable, noninvasive assay that might allow early detection and monitoring of metastatic disease, we determined the proportion of GNAQ or GNA11 mutant reads in cfDNA of uveal melanoma patients by ultradeep sequencing.	('patients', 'Species', '9606', (200, 208))	('GNAQ', 'Gene', '2776', (146, 150))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('GNA11', 'Gene', (154, 159))	('cfDNA', 'Disease', (176, 181))	('GNA11', 'Gene', '2767', (154, 159))	('uveal melanoma', 'Phenotype', 'HP:0007716', (185, 199))	('uveal melanoma', 'Disease', (185, 199))	('uveal melanoma', 'Disease', 'MESH:C536494', (185, 199))	('GNAQ', 'Gene', (146, 150))	('mutant reads', 'Var', (160, 172))
8418	23634288	We detected Q209 mutations (2-38% mutant reads) in either GNAQ or GNA11 in the plasma of 9 of 22 metastasized patients.	('Q209 mutations', 'Var', (12, 26))	('GNAQ', 'Gene', '2776', (58, 62))	('GNA11', 'Gene', (66, 71))	('GNAQ', 'Gene', (58, 62))	('GNA11', 'Gene', '2767', (66, 71))	('patients', 'Species', '9606', (110, 118))
8437	23634288	Genetic alterations of oncogenes or tumor-suppressor genes that occur during tumorigenesis provide highly specific markers that allow identification and quantification of circulating tumor DNA (ctDNA).	('Genetic alterations', 'Var', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('DNA', 'cellular_component', 'GO:0005574', ('189', '192'))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('36', '52'))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (36, 41))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('36', '52'))
8438	23634288	Such tumor-specific mutations have been detected in plasma of patients suffering from various solid cancers or hematopoietic malignancies (for review see).	('solid cancers', 'Disease', 'MESH:D009369', (94, 107))	('hematopoietic malignancies', 'Disease', (111, 137))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('detected', 'Reg', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (111, 137))	('tumor', 'Disease', (5, 10))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('patients', 'Species', '9606', (62, 70))	('solid cancers', 'Disease', (94, 107))	('mutations', 'Var', (20, 29))
8439	23634288	determined the number of adenomatous polyposis coli (APC) gene fragments in cfDNA of advanced colorectal cancer patients and found elevated mutant proportions in patients with advanced tumor stages .	('tumor', 'Disease', (185, 190))	('APC', 'Gene', (53, 56))	('elevated', 'PosReg', (131, 139))	('patients', 'Species', '9606', (162, 170))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (25, 46))	('APC', 'Gene', '324', (53, 56))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (25, 51))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('patients', 'Species', '9606', (112, 120))	('fragments', 'Var', (63, 72))	('adenomatous polyposis coli', 'Disease', (25, 51))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Disease', (94, 111))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('APC', 'cellular_component', 'GO:0005680', ('53', '56'))
8441	23634288	Mutations of either GNAQ or GNA11 can be detected in 83% of all (primary or metastatic) uveal melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('GNAQ', 'Gene', '2776', (20, 24))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('uveal melanomas', 'Disease', 'MESH:C536494', (88, 103))	('Mutations', 'Var', (0, 9))	('GNA11', 'Gene', (28, 33))	('GNAQ', 'Gene', (20, 24))	('GNA11', 'Gene', '2767', (28, 33))	('detected', 'Reg', (41, 49))	('uveal melanomas', 'Disease', (88, 103))	('uveal melanomas', 'Phenotype', 'HP:0007716', (88, 103))
8442	23634288	GNAQ mutations at codon Q209 were found in 45% of primary uveal melanomas, 22% of uveal melanoma metastases, and 55% of blue nevi.	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('primary uveal melanoma', 'Disease', (50, 72))	('uveal melanomas', 'Disease', 'MESH:C536494', (58, 73))	('found', 'Reg', (34, 39))	('uveal melanoma metastases', 'Disease', (82, 107))	('nevi', 'Phenotype', 'HP:0003764', (125, 129))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (82, 107))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('blue nevi', 'Disease', (120, 129))	('mutations at', 'Var', (5, 17))	('uveal melanomas', 'Disease', (58, 73))	('uveal melanomas', 'Phenotype', 'HP:0007716', (58, 73))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (50, 72))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('blue nevi', 'Phenotype', 'HP:0100814', (120, 129))	('GNAQ', 'Gene', '2776', (0, 4))	('GNAQ', 'Gene', (0, 4))
8443	23634288	Mutations in GNA11 at codon Q209 were found in 32% of primary uveal melanomas, 57% of the uveal melanoma metastases, and 7% of blue nevi.	('uveal melanomas', 'Disease', (62, 77))	('uveal melanomas', 'Phenotype', 'HP:0007716', (62, 77))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (54, 76))	('uveal melanoma', 'Phenotype', 'HP:0007716', (62, 76))	('nevi', 'Phenotype', 'HP:0003764', (132, 136))	('GNA11', 'Gene', (13, 18))	('uveal melanoma metastases', 'Disease', (90, 115))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (90, 115))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('primary uveal melanoma', 'Disease', (54, 76))	('melanomas', 'Phenotype', 'HP:0002861', (68, 77))	('found', 'Reg', (38, 43))	('uveal melanomas', 'Disease', 'MESH:C536494', (62, 77))	('blue nevi', 'Disease', (127, 136))	('GNA11', 'Gene', '2767', (13, 18))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('blue nevi', 'Phenotype', 'HP:0100814', (127, 136))
8444	23634288	Mutations at codon R183 of either GNAQ or GNA11 are rare, affecting about 6% of uveal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('uveal melanomas', 'Disease', 'MESH:C536494', (80, 95))	('Mutations at codon R183', 'Var', (0, 23))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('affecting', 'Reg', (58, 67))	('GNA11', 'Gene', (42, 47))	('uveal melanomas', 'Disease', (80, 95))	('GNAQ', 'Gene', (34, 38))	('uveal melanomas', 'Phenotype', 'HP:0007716', (80, 95))	('GNA11', 'Gene', '2767', (42, 47))	('GNAQ', 'Gene', '2776', (34, 38))
8445	23634288	Although the MAP-kinase cascade is a mutational target in several tumor entities, activation of this pathway by mutations in either GNAQ or GNA11 is specific for uveal melanomas and other nonepidermic melanocytic lesions like blue nevi.	('blue nevi', 'Disease', (226, 235))	('melanocytic lesions', 'Disease', (201, 220))	('GNAQ', 'Gene', '2776', (132, 136))	('mutations', 'Var', (112, 121))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('blue nevi', 'Phenotype', 'HP:0100814', (226, 235))	('GNAQ', 'Gene', (132, 136))	('MAP-kinase cascade', 'biological_process', 'GO:0000165', ('13', '31'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (162, 176))	('uveal melanomas', 'Disease', 'MESH:C536494', (162, 177))	('melanocytic lesions', 'Disease', 'MESH:D009508', (201, 220))	('tumor', 'Disease', (66, 71))	('GNA11', 'Gene', (140, 145))	('activation', 'PosReg', (82, 92))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('uveal melanomas', 'Disease', (162, 177))	('uveal melanomas', 'Phenotype', 'HP:0007716', (162, 177))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('nevi', 'Phenotype', 'HP:0003764', (231, 235))	('MAP', 'molecular_function', 'GO:0004239', ('13', '16'))	('GNA11', 'Gene', '2767', (140, 145))	('melanomas', 'Phenotype', 'HP:0002861', (168, 177))
8446	23634288	It has been suggested that GNAQ/GNA11 mutations are present throughout the different stages of the disease and are early events in tumorigenesis.	('GNAQ', 'Gene', '2776', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('GNA11', 'Gene', '2767', (32, 37))	('GNA11', 'Gene', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('GNAQ', 'Gene', (27, 31))	('mutations', 'Var', (38, 47))
8451	23634288	The goal of our study was to establish an assay for the detection of mutant alleles of GNAQ and GNA11 based on ultradeep amplicon sequencing.	('GNAQ', 'Gene', '2776', (87, 91))	('mutant', 'Var', (69, 75))	('GNAQ', 'Gene', (87, 91))	('GNA11', 'Gene', '2767', (96, 101))	('GNA11', 'Gene', (96, 101))
8483	23634288	Sanger sequencing of tumor DNA had previously shown GNAQ/GNA11 mutant alleles in 5 of the 22 patients.	('mutant alleles', 'Var', (63, 77))	('tumor', 'Disease', (21, 26))	('GNA11', 'Gene', (57, 62))	('GNAQ', 'Gene', '2776', (52, 56))	('GNA11', 'Gene', '2767', (57, 62))	('GNAQ', 'Gene', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('patients', 'Species', '9606', (93, 101))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
8486	23634288	Oncogenic GNAQ/GNA11 mutations were identified in cfDNA of 9 of 22 patients.	('GNA11', 'Gene', (15, 20))	('GNAQ', 'Gene', '2776', (10, 14))	('patients', 'Species', '9606', (67, 75))	('GNA11', 'Gene', '2767', (15, 20))	('GNAQ', 'Gene', (10, 14))	('cfDNA', 'Disease', (50, 55))	('mutations', 'Var', (21, 30))
8487	23634288	Mutations were restricted to codon Q209 and affected GNA11 more often than GNAQ (six and four samples, respectively).	('affected', 'Reg', (44, 52))	('GNA11', 'Gene', (53, 58))	('GNA11', 'Gene', '2767', (53, 58))	('GNAQ', 'Gene', (75, 79))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', '2776', (75, 79))
8489	23634288	A double-nucleotide substitution in GNA11 (c.626A>T [j] 627G>A) was detected in cfDNA and the primary tumor of one patient (P3).	('627G>A', 'Mutation', 'c.627G>A', (56, 62))	('GNA11', 'Gene', '2767', (36, 41))	('GNA11', 'Gene', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('detected', 'Reg', (68, 76))	('cfDNA', 'Disease', (80, 85))	('patient', 'Species', '9606', (115, 122))	('c.626A>T', 'Mutation', 'rs1057519742', (43, 51))	('tumor', 'Disease', (102, 107))	('double-nucleotide', 'Var', (2, 19))	('c.626A>T [j] 627G>A', 'Var', (43, 62))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
8490	23634288	A rare mutation (c.626A>C) that has previously reported in one uveal melanoma only was identified in the cfDNA of patient nine (P9).	('c.626A>C', 'Mutation', 'rs1057519742', (17, 25))	('uveal melanoma', 'Phenotype', 'HP:0007716', (63, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (63, 77))	('uveal melanoma', 'Disease', (63, 77))	('c.626A>C', 'Var', (17, 25))	('patient', 'Species', '9606', (114, 121))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))
8491	23634288	One patient, P4, showed mutations in both GNA11 and in GNAQ with a proportion of 38.4% and 2.6%, respectively, relative to normal sequence reads.	('GNAQ', 'Gene', '2776', (55, 59))	('patient', 'Species', '9606', (4, 11))	('GNA11', 'Gene', '2767', (42, 47))	('GNA11', 'Gene', (42, 47))	('GNAQ', 'Gene', (55, 59))	('mutations', 'Var', (24, 33))
8492	23634288	The proportion of mutant GNA11/GNAQ reads obtained from cfDNA varied between patients.	('GNAQ', 'Gene', '2776', (31, 35))	('mutant', 'Var', (18, 24))	('patients', 'Species', '9606', (77, 85))	('GNA11', 'Gene', (25, 30))	('GNAQ', 'Gene', (31, 35))	('GNA11', 'Gene', '2767', (25, 30))
8496	23634288	We compared clinical findings of patients with and without GNA11 or GNAQ mutant alleles in cfDNA as detected by deep sequencing.	('cfDNA', 'Disease', (91, 96))	('patients', 'Species', '9606', (33, 41))	('GNAQ', 'Gene', (68, 72))	('mutant', 'Var', (73, 79))	('GNA11', 'Gene', '2767', (59, 64))	('GNA11', 'Gene', (59, 64))	('GNAQ', 'Gene', '2776', (68, 72))
8500	23634288	Neither the type of treatment of the primary tumor (enucleation, brachytherapy, proton beam irradiation), nor systemic therapy of metastatic disease with multikinase inhibitor sorafenib at the time of blood collection had any discernible effect on the cfDNA mutation status.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('sorafenib', 'Chemical', 'MESH:D000077157', (176, 185))	('tumor', 'Disease', (45, 50))	('enucleation', 'biological_process', 'GO:0090601', ('52', '63'))	('cfDNA', 'Gene', (252, 257))	('mutation', 'Var', (258, 266))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
8502	23634288	Mutant alleles of the GNA11 or GNAQ genes, which are highly specific for uveal melanoma, were identified in cfDNA of 9 of 22 (41%) patients.	('patients', 'Species', '9606', (131, 139))	('GNA11', 'Gene', (22, 27))	('uveal melanoma', 'Disease', 'MESH:C536494', (73, 87))	('GNA11', 'Gene', '2767', (22, 27))	('uveal melanoma', 'Disease', (73, 87))	('identified', 'Reg', (94, 104))	('GNAQ', 'Gene', '2776', (31, 35))	('uveal melanoma', 'Phenotype', 'HP:0007716', (73, 87))	('cfDNA', 'Disease', (108, 113))	('Mutant', 'Var', (0, 6))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('GNAQ', 'Gene', (31, 35))
8503	23634288	Considering that about 80% of primary tumors or uveal melanoma metastases show mutant GNA11 or GNAQ genes, it is plausible that only a few of the remaining 13 patients had tumors without one of these mutations, and therefore, were uninformative for our study.	('primary tumors', 'Disease', 'MESH:D009369', (30, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('GNAQ', 'Gene', (95, 99))	('GNA11', 'Gene', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('uveal melanoma metastases', 'Disease', (48, 73))	('mutant', 'Var', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('patients', 'Species', '9606', (159, 167))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('GNA11', 'Gene', '2767', (86, 91))	('primary tumors', 'Disease', (30, 44))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (48, 73))	('GNAQ', 'Gene', '2776', (95, 99))
8504	23634288	In fact, we could not detect any mutant reads in cfDNA (i.e., they were ctDNA negative) in two of five patients with known GNAQ/GNA11 mutations in the primary tumors.	('GNA11', 'Gene', '2767', (128, 133))	('GNA11', 'Gene', (128, 133))	('primary tumors', 'Disease', (151, 165))	('GNAQ', 'Gene', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('primary tumors', 'Disease', 'MESH:D009369', (151, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('GNAQ', 'Gene', '2776', (123, 127))	('cfDNA', 'Disease', (49, 54))	('mutations', 'Var', (134, 143))	('patients', 'Species', '9606', (103, 111))
8506	23634288	However, applying less stringent cutoff levels to the data obtained from the two ctDNA-negative patients who had GNA11 mutations confirmed that no mutant reads were evident in their tumor cells (0% and 0.07%).	('tumor', 'Disease', (182, 187))	('GNA11', 'Gene', '2767', (113, 118))	('GNA11', 'Gene', (113, 118))	('patients', 'Species', '9606', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('mutations', 'Var', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
8507	23634288	This problem was also encountered by Madic et al., who used a very elegant and highly mutation-specific PCR method to detect ctDNA in 20 of 21 patients with metastatic uveal melanoma and known GNA11 or GNAQ mutations 2012.	('uveal melanoma', 'Disease', 'MESH:C536494', (168, 182))	('GNAQ', 'Gene', '2776', (202, 206))	('GNA11', 'Gene', (193, 198))	('GNA11', 'Gene', '2767', (193, 198))	('patients', 'Species', '9606', (143, 151))	('GNAQ', 'Gene', (202, 206))	('mutations', 'Var', (207, 216))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('uveal melanoma', 'Disease', (168, 182))
8509	23634288	(2010) that GNA11 codon Q209 mutations were more frequent than GNAQ codon Q209 mutations in metastatic uveal melanoma than in primary uveal melanoma - of the 12 mutations that we identified in either cfDNA or DNA from metastatic tissue, eight (66%) affected codon Q209 of GNA11.	('GNA11', 'Gene', '2767', (12, 17))	('codon Q209', 'Var', (258, 268))	('GNA11', 'Gene', '2767', (272, 277))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('primary uveal melanoma', 'Disease', (126, 148))	('uveal melanoma', 'Disease', 'MESH:C536494', (103, 117))	('uveal melanoma', 'Disease', (103, 117))	('GNA11', 'Gene', (12, 17))	('mutations', 'Var', (29, 38))	('uveal melanoma', 'Disease', 'MESH:C536494', (134, 148))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('GNA11', 'Gene', (272, 277))	('DNA', 'cellular_component', 'GO:0005574', ('209', '212'))	('affected', 'Reg', (249, 257))	('uveal melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('GNAQ', 'Gene', '2776', (63, 67))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (126, 148))	('GNAQ', 'Gene', (63, 67))	('uveal melanoma', 'Phenotype', 'HP:0007716', (134, 148))
8510	23634288	In the study by Raamsdonk, metastatic uveal melanoma also showed mutations affecting codon R183 of GNAQ and GNA11 (2/17, 12%).	('mutations', 'Reg', (65, 74))	('uveal melanoma', 'Disease', (38, 52))	('GNA11', 'Gene', '2767', (108, 113))	('codon R183', 'Var', (85, 95))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('GNAQ', 'Gene', (99, 103))	('uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('uveal melanoma', 'Disease', 'MESH:C536494', (38, 52))	('GNAQ', 'Gene', '2776', (99, 103))	('GNA11', 'Gene', (108, 113))
8511	23634288	Although none of our patients showed mutations at these positions, it is important to include these positions in the analysis as mutations at these sites are more frequent in metastatic than in primary uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (202, 216))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('metastatic', 'Disease', (175, 185))	('mutations', 'Var', (129, 138))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (194, 216))	('primary uveal melanoma', 'Disease', (194, 216))	('patients', 'Species', '9606', (21, 29))	('frequent', 'Reg', (163, 171))
8512	23634288	In one patient (P4), we identified mutations in GNA11 and GNAQ with mutation rates of 38.4% and 2.6%, respectively.	('patient', 'Species', '9606', (7, 14))	('GNAQ', 'Gene', '2776', (58, 62))	('GNA11', 'Gene', (48, 53))	('GNAQ', 'Gene', (58, 62))	('GNA11', 'Gene', '2767', (48, 53))	('mutations', 'Var', (35, 44))
8514	23634288	One possible explanation for this is that the GNAQ mutation occurred in a cell that already had a GNA11 mutation.	('GNAQ', 'Gene', (46, 50))	('GNA11', 'Gene', (98, 103))	('GNA11', 'Gene', '2767', (98, 103))	('GNAQ', 'Gene', '2776', (46, 50))	('occurred', 'Reg', (60, 68))	('mutation', 'Var', (104, 112))	('mutation', 'Var', (51, 59))
8515	23634288	This would result in a situation where all cells with mutant GNAQ are also mutant for GNA11, but only some cells with the GNA11 mutation also show a GNAQ mutation, leading to the higher rates of GNA11 mutation.	('higher rates', 'PosReg', (179, 191))	('GNAQ', 'Gene', (149, 153))	('mutant', 'Reg', (75, 81))	('GNA11', 'Gene', (122, 127))	('GNAQ', 'Gene', (61, 65))	('mutation', 'Var', (154, 162))	('GNAQ', 'Gene', '2776', (149, 153))	('GNA11', 'Gene', '2767', (122, 127))	('GNA11', 'Gene', '2767', (195, 200))	('GNA11', 'Gene', (195, 200))	('GNA11', 'Gene', (86, 91))	('mutation', 'Var', (128, 136))	('GNA11', 'Gene', '2767', (86, 91))	('GNAQ', 'Gene', '2776', (61, 65))
8516	23634288	However, this explanation does not support the observation that GNA11 mutations tend to be more frequent in advanced tumors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutations', 'Var', (70, 79))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('GNA11', 'Gene', '2767', (64, 69))	('frequent', 'Reg', (96, 104))	('GNA11', 'Gene', (64, 69))
8518	23634288	Under this assumption, the higher proportion of GNA11 in ctDNA from this patient indicates a greater contribution of GNA11 mutant cells to cfDNA in plasma.	('greater', 'PosReg', (93, 100))	('patient', 'Species', '9606', (73, 80))	('GNA11', 'Gene', (48, 53))	('GNA11', 'Gene', '2767', (117, 122))	('GNA11', 'Gene', (117, 122))	('GNA11', 'Gene', '2767', (48, 53))	('mutant', 'Var', (123, 129))
8525	23634288	This is relevant as exemplified by patient P3 in our series, who showed a rare oncogenic GNA11 mutation (c.626A>T [j] 627G>A) that may not have been detected using other methods.	('c.626A>T [j]', 'Var', (105, 117))	('627G>A', 'Mutation', 'c.627G>A', (118, 124))	('patient', 'Species', '9606', (35, 42))	('GNA11', 'Gene', '2767', (89, 94))	('GNA11', 'Gene', (89, 94))	('c.626A>T', 'Mutation', 'rs1057519742', (105, 113))
8545	23217102	In patients with solid tumors randomized to anti-angiogenic drug combinations, CEC were lower in patients without clinical benefit; of note, levels of VEGF did not differ in these patients.	('VEGF', 'Gene', '7422', (151, 155))	('solid tumors', 'Disease', (17, 29))	('CEC', 'Disease', (79, 82))	('CEC', 'Chemical', '-', (79, 82))	('combinations', 'Var', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('patients', 'Species', '9606', (3, 11))	('solid tumors', 'Disease', 'MESH:D009369', (17, 29))	('VEGF', 'Gene', (151, 155))	('lower', 'NegReg', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('patients', 'Species', '9606', (180, 188))	('patients', 'Species', '9606', (97, 105))
8550	23217102	miRs that can promote angiogenesis, including miR-126, 155, 199a, and miRs of the 17-92 complex, and miRs that can inhibit angiogenesis, including miR-16, 106a, 125b, and 221, have been identified.	('miR', 'Gene', (46, 49))	('angiogenesis', 'biological_process', 'GO:0001525', ('22', '34'))	('miR', 'Gene', '220972', (147, 150))	('miR', 'Gene', (70, 73))	('miR-126', 'Gene', '406913', (46, 53))	('miR', 'Gene', (101, 104))	('miR', 'Gene', (147, 150))	('miR-16', 'Gene', (147, 153))	('miR', 'Gene', '220972', (0, 3))	('promote', 'PosReg', (14, 21))	('angiogenesis', 'biological_process', 'GO:0001525', ('123', '135'))	('miR', 'Gene', '220972', (46, 49))	('miR-126', 'Gene', (46, 53))	('inhibit', 'NegReg', (115, 122))	('miR-16', 'Gene', '51573', (147, 153))	('155', 'Var', (55, 58))	('angiogenesis', 'CPA', (22, 34))	('miR', 'Gene', (0, 3))	('angiogenesis', 'CPA', (123, 135))	('miR', 'Gene', '220972', (70, 73))	('miR', 'Gene', '220972', (101, 104))
8575	23217102	Analysis was done using image cytometry, where CEC were defined as being CD146+, DAPI+, CD105+ and CD45-.	('CD45', 'Gene', '5788', (99, 103))	('CD146', 'Gene', '4162', (73, 78))	('CD146', 'Gene', (73, 78))	('CD45', 'Gene', (99, 103))	('DAPI', 'Chemical', '-', (81, 85))	('CD105+', 'Var', (88, 94))	('CEC', 'Chemical', '-', (47, 50))
8591	23217102	Significant changes in the levels of miR-20a, 125b, 146a, 155, and 221 were not observed at any time point.	('miR-20a', 'Gene', (37, 44))	('146a', 'Var', (52, 56))	('miR-20a', 'Gene', '406982', (37, 44))
8626	23217102	Significant changes in levels of miRs and also of CEC were observed after treatment with interferon-alfa-2b, but not after treatment with dacarbazine.	('miR', 'Gene', '220972', (33, 36))	('miR', 'Gene', (33, 36))	('levels', 'MPA', (23, 29))	('CEC', 'MPA', (50, 53))	('CEC', 'Chemical', '-', (50, 53))	('interferon-alfa-2b', 'Var', (89, 107))	('dacarbazine', 'Chemical', 'MESH:D003606', (138, 149))	('changes', 'Reg', (12, 19))
8632	23217102	Increases in several miRs were observed in patients with chronic hepatitis C virus infection treated with pegylated interferon-alfa-2b but did not correlate with viral load or liver function tests.	('hepatitis', 'Phenotype', 'HP:0012115', (65, 74))	('chronic hepatitis C virus infection', 'Disease', (57, 92))	('chronic hepatitis C virus infection', 'Disease', 'MESH:D019698', (57, 92))	('patients', 'Species', '9606', (43, 51))	('miR', 'Gene', '220972', (21, 24))	('pegylated', 'Var', (106, 115))	('miR', 'Gene', (21, 24))	('hepatitis C virus infection', 'Phenotype', 'HP:0410371', (65, 92))	('Increases', 'PosReg', (0, 9))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (57, 74))
8637	23217102	Measuring blood levels of specific miRs implicated in angiogenesis, including miR-16, 106a, 126, and 199a, may have clinical utility in monitoring anti-angiogenic therapy in patients with cancer.	('126', 'Var', (92, 95))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('miR-16', 'Gene', '51573', (78, 84))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', (35, 38))	('cancer', 'Disease', (188, 194))	('angiogenesis', 'biological_process', 'GO:0001525', ('54', '66'))	('miR-16', 'Gene', (78, 84))	('106a', 'Var', (86, 90))
8642	18985043	The T1799A point mutation is present in posterior uveal melanoma An activating mutation in exon 15 of the BRAF gene is present in a high proportion of cutaneous pigmented lesions.	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('activating', 'PosReg', (68, 78))	('T1799A', 'Mutation', 'rs113488022', (4, 10))	('BRAF', 'Gene', '673', (106, 110))	('cutaneous pigmented lesions', 'Disease', 'MESH:D010859', (151, 178))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('uveal melanoma', 'Disease', 'MESH:C536494', (50, 64))	('BRAF', 'Gene', (106, 110))	('T1799A', 'Var', (4, 10))	('cutaneous pigmented lesions', 'Disease', (151, 178))	('uveal melanoma', 'Disease', (50, 64))
8644	18985043	Despite this apparent lack of the BRAF mutation, inappropriate downstream activation of the Ras/Raf/MAPK pathway has been described in posterior uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (145, 159))	('uveal melanoma', 'Disease', 'MESH:C536494', (145, 159))	('mutation', 'Var', (39, 47))	('Raf', 'Gene', '22882', (96, 99))	('uveal melanoma', 'Disease', (145, 159))	('MAPK', 'molecular_function', 'GO:0004707', ('100', '104'))	('BRAF', 'Gene', '673', (34, 38))	('Raf', 'Gene', (96, 99))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('BRAF', 'Gene', (34, 38))
8645	18985043	Based on the already recognised morphological and cytogenetic heterogeneity in uveal melanoma, we hypothesised that the BRAF mutation may be present in uveal melanoma but only in some of the tumour cells.	('tumour', 'Disease', 'MESH:D009369', (191, 197))	('tumour', 'Disease', (191, 197))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('BRAF', 'Gene', '673', (120, 124))	('uveal melanoma', 'Phenotype', 'HP:0007716', (152, 166))	('uveal melanoma', 'Disease', (152, 166))	('uveal melanoma', 'Disease', 'MESH:C536494', (152, 166))	('BRAF', 'Gene', (120, 124))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('mutation', 'Var', (125, 133))	('uveal melanoma', 'Disease', (79, 93))
8649	18985043	In conclusion, the T1799A BRAF mutation is present in a proportion of posterior uveal melanomas but within these tumours the distribution of the mutation is heterogeneous.	('T1799A', 'Var', (19, 25))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('uveal melanomas', 'Disease', 'MESH:C536494', (80, 95))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('BRAF', 'Gene', '673', (26, 30))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumours', 'Disease', 'MESH:D009369', (113, 120))	('BRAF', 'Gene', (26, 30))	('uveal melanomas', 'Disease', (80, 95))	('tumours', 'Disease', (113, 120))	('uveal melanomas', 'Phenotype', 'HP:0007716', (80, 95))	('T1799A', 'Mutation', 'rs113488022', (19, 25))
8650	18985043	Mutations in the BRAF gene (a member of the Raf family that encodes a serine/threonine protein kinase) have been shown to occur in the majority of cutaneous melanomas (Brose et al, 2002; Davies et al, 2002).	('occur', 'Reg', (122, 127))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (147, 165))	('Raf', 'Gene', (44, 47))	('cutaneous melanomas', 'Disease', (147, 166))	('BRAF', 'Gene', '673', (17, 21))	('melanomas', 'Phenotype', 'HP:0002861', (157, 166))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (17, 21))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('Raf', 'Gene', '22882', (44, 47))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (147, 166))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (147, 166))
8651	18985043	In particular a single point mutation in exon 15 (T1799A), which results in constitutive kinase activity and unregulated signal transduction, is involved in up to 80% of cases (Brose et al, 2002; Davies et al, 2002).	('kinase activity', 'molecular_function', 'GO:0016301', ('89', '104'))	('single point mutation', 'Var', (16, 37))	('unregulated signal transduction', 'MPA', (109, 140))	('constitutive kinase activity', 'MPA', (76, 104))	('involved', 'Reg', (145, 153))	('T1799A', 'Mutation', 'rs113488022', (50, 56))	('results in', 'Reg', (65, 75))	('signal transduction', 'biological_process', 'GO:0007165', ('121', '140'))
8655	18985043	The reason for this discrepancy in reporting of the BRAF mutation is not clear.	('mutation', 'Var', (57, 65))	('BRAF', 'Gene', (52, 56))	('BRAF', 'Gene', '673', (52, 56))
8660	18985043	This technique was used to screen posterior uveal melanoma samples for the presence of the BRAF mutation and secondly to examine separate areas within individual tumours to confirm genetic heterogeneity.	('tumours', 'Disease', 'MESH:D009369', (162, 169))	('tumours', 'Disease', (162, 169))	('BRAF', 'Gene', '673', (91, 95))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('mutation', 'Var', (96, 104))	('BRAF', 'Gene', (91, 95))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('tumours', 'Phenotype', 'HP:0002664', (162, 169))	('uveal melanoma', 'Disease', (44, 58))
8685	18985043	For choroidal melanoma the relationship of known survival time with BRAF mutation, sex, cell type and vascular loops was tested one at a time by a Kaplan-Meier analysis and the relationship of survival time with age and tumour diameter were tested using the 'Regression with Life Data' function of Minitab 13.1 (Minitab Inc., State College, PA, USA).	('BRAF', 'Gene', '673', (68, 72))	('tumour', 'Phenotype', 'HP:0002664', (220, 226))	('choroidal melanoma', 'Disease', 'MESH:D008545', (4, 22))	('BRAF', 'Gene', (68, 72))	('tumour', 'Disease', 'MESH:D009369', (220, 226))	("'Regression with Life", 'Phenotype', 'HP:0002376', (258, 279))	('vascular loops', 'Phenotype', 'HP:0010775', (102, 116))	('choroidal melanoma', 'Disease', (4, 22))	('mutation', 'Var', (73, 81))	('tumour', 'Disease', (220, 226))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (4, 22))
8689	18985043	Positive and negative BRAF mutation controls were used to ensure the optimisation of the method.	('mutation', 'Var', (27, 35))	('BRAF', 'Gene', (22, 26))	('BRAF', 'Gene', '673', (22, 26))
8690	18985043	Two products of 200 and 100 base pairs (bp) were obtained for SK-mel28, which contains the T1799A BRAF mutation and one product of 100 bp for HFF negative control (Figure 1).	('T1799A', 'Var', (91, 97))	('BRAF', 'Gene', '673', (98, 102))	('BRAF', 'Gene', (98, 102))	('T1799A', 'Mutation', 'rs113488022', (91, 97))	('HFF', 'CellLine', 'CVCL:3285', (142, 145))
8692	18985043	The T1799A mutation was identified in 4 of the 20 ciliary body melanomas studied and in 11 of the 30 choroidal melanomas examined.	('body melanoma', 'Disease', (58, 71))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (101, 120))	('melanomas', 'Disease', 'MESH:D008545', (111, 120))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('T1799A', 'Mutation', 'rs113488022', (4, 10))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('choroidal melanomas', 'Disease', (101, 120))	('ciliary body melanomas', 'Phenotype', 'HP:0012055', (50, 72))	('body melanoma', 'Disease', 'MESH:D008545', (58, 71))	('melanomas', 'Disease', (63, 72))	('melanomas', 'Disease', (111, 120))	('T1799A', 'Var', (4, 10))	('choroidal melanomas', 'Disease', 'MESH:D008545', (101, 120))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (101, 119))	('ciliary body melanoma', 'Phenotype', 'HP:0012055', (50, 71))	('melanomas', 'Disease', 'MESH:D008545', (63, 72))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))
8693	18985043	In addition, sampling of several different areas was undertaken in the 11 positive cases of the choroidal melanoma cases to investigate potential heterogeneity of the T1799A mutation within the tumour sample.	('T1799A', 'Var', (167, 173))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('tumour', 'Disease', (194, 200))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (96, 114))	('choroidal melanoma', 'Disease', 'MESH:D008545', (96, 114))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('T1799A', 'Mutation', 'rs113488022', (167, 173))	('tumour', 'Disease', 'MESH:D009369', (194, 200))	('choroidal melanoma', 'Disease', (96, 114))
8695	18985043	Five of the 11 cases contained the BRAF mutation in all areas sampled.	('mutation', 'Var', (40, 48))	('BRAF', 'Gene', (35, 39))	('contained', 'Reg', (21, 30))	('BRAF', 'Gene', '673', (35, 39))
8719	18985043	The Kaplan-Meier survival curve for patients with tumours with and without the BRAF mutation is shown in Figure 3.	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('patients', 'Species', '9606', (36, 44))	('tumours', 'Disease', (50, 57))	('BRAF', 'Gene', '673', (79, 83))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('BRAF', 'Gene', (79, 83))	('mutation', 'Var', (84, 92))
8721	18985043	There were no statistically significant associations between any other clinical or pathological characteristics and the presence of the BRAF mutation.	('BRAF', 'Gene', (136, 140))	('BRAF', 'Gene', '673', (136, 140))	('mutation', 'Var', (141, 149))
8722	18985043	Furthermore, in tumours where several areas of the tumour were dissected there was no association between cell type in the individual areas and presence of the mutation.	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('mutation', 'Var', (160, 168))	('tumours', 'Disease', 'MESH:D009369', (16, 23))	('tumour', 'Disease', (16, 22))	('tumours', 'Disease', (16, 23))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))	('tumour', 'Disease', (51, 57))
8724	18985043	In melanoma, these BRAF mutations are found in two small regions of the kinase domain of the BRAF molecule.	('BRAF', 'Gene', (93, 97))	('BRAF', 'Gene', '673', (19, 23))	('BRAF', 'Gene', (19, 23))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('mutations', 'Var', (24, 33))	('BRAF', 'Gene', '673', (93, 97))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
8725	18985043	The predominant mutation occurs in exon 15 of the BRAF gene with a single T-to-A substitution at nucleotide 1799, although a smaller number of mutations have also been found in a region of exon 11(Brose et al, 2002; Davies et al, 2002; Goydos et al, 2005).	('T-to-A substitution at nucleotide 1799', 'Mutation', 'rs113488022', (74, 112))	('T-to-A substitution at', 'Var', (74, 96))	('BRAF', 'Gene', (50, 54))	('BRAF', 'Gene', '673', (50, 54))
8726	18985043	These mutations have been shown to be present in 66 to 80% of cutaneous melanomas and have also been detected in up to 82% of melanocytic nevi(Pollock et al, 2003).	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (62, 81))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (62, 81))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (62, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('nevi', 'Phenotype', 'HP:0003764', (138, 142))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (126, 142))	('Pollock', 'Species', '8060', (143, 150))	('cutaneous melanomas', 'Disease', (62, 81))	('melanocytic nevi', 'Disease', (126, 142))	('mutations', 'Var', (6, 15))
8729	18985043	Despite this apparent lack of the characteristic BRAF mutation, inappropriate downstream MAPK component activation has been reported by Weber et al (2003) who failed to identify the BRAF mutation in 42 primary uveal melanoma but showed immunohistochemical staining for ERK in 86% of these cases.	('mutation', 'Var', (54, 62))	('activation', 'PosReg', (104, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (210, 224))	('uveal melanoma', 'Disease', (210, 224))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('BRAF', 'Gene', '673', (182, 186))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', (182, 186))	('ERK', 'Gene', '5594', (269, 272))	('BRAF', 'Gene', (49, 53))	('ERK', 'Gene', (269, 272))	('ERK', 'molecular_function', 'GO:0004707', ('269', '272'))	('uveal melanoma', 'Disease', 'MESH:C536494', (210, 224))
8731	18985043	However, an activating BRAF mutation was found in only one cell line.	('activating', 'PosReg', (12, 22))	('mutation', 'Var', (28, 36))	('BRAF', 'Gene', (23, 27))	('BRAF', 'Gene', '673', (23, 27))
8732	18985043	Using the more sensitive nested PCR approach we have identified the T1799A BRAF mutation in 4 of 20 (20%) ciliary body melanomas and 11 of 30 (40%) choroidal melanomas.	('body melanoma', 'Disease', (114, 127))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('ciliary body melanomas', 'Phenotype', 'HP:0012055', (106, 128))	('choroidal melanomas', 'Disease', 'MESH:D008545', (148, 167))	('melanomas', 'Phenotype', 'HP:0002861', (119, 128))	('melanomas', 'Phenotype', 'HP:0002861', (158, 167))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('choroidal melanomas', 'Disease', (148, 167))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (148, 166))	('ciliary body melanoma', 'Phenotype', 'HP:0012055', (106, 127))	('melanomas', 'Disease', 'MESH:D008545', (119, 128))	('melanomas', 'Disease', 'MESH:D008545', (158, 167))	('body melanoma', 'Disease', 'MESH:D008545', (114, 127))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (148, 167))	('T1799A', 'Mutation', 'rs113488022', (68, 74))	('BRAF', 'Gene', '673', (75, 79))	('melanomas', 'Disease', (119, 128))	('melanomas', 'Disease', (158, 167))	('T1799A', 'Var', (68, 74))	('BRAF', 'Gene', (75, 79))
8733	18985043	Although more sensitive techniques including the ligase detection assay and high amplicon melting PCR have been used to identify the BRAF mutation in other tissues including cutaneous melanoma they have not been applied to uveal melanoma (Turner et al, 2005; Willmore-Payne et al, 2005).	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanoma', 'Phenotype', 'HP:0002861', (229, 237))	('BRAF', 'Gene', '673', (133, 137))	('uveal melanoma', 'Disease', 'MESH:C536494', (223, 237))	('BRAF', 'Gene', (133, 137))	('mutation', 'Var', (138, 146))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (174, 192))	('cutaneous melanoma', 'Disease', (174, 192))	('uveal melanoma', 'Phenotype', 'HP:0007716', (223, 237))	('uveal melanoma', 'Disease', (223, 237))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (174, 192))
8734	18985043	Recently, Maat et al (2008) detected the BRAF mutation in 6 of 45 uveal melanomas using the more sensitive technique of pyrophosphorolysis-activated polymerisation.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('detected', 'Reg', (28, 36))	('uveal melanomas', 'Phenotype', 'HP:0007716', (66, 81))	('BRAF', 'Gene', '673', (41, 45))	('uveal melanomas', 'Disease', (66, 81))	('BRAF', 'Gene', (41, 45))	('mutation', 'Var', (46, 54))	('uveal melanomas', 'Disease', 'MESH:C536494', (66, 81))
8740	18985043	Sandinha et al (2006) described a heterogenous distribution of cells displaying monosomy three in uveal melanoma and Maat et al (2007) described areas of unmethylated and methylated RASSF1a within individual uveal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('RASSF1a', 'Gene', '11186', (182, 189))	('uveal melanomas', 'Disease', 'MESH:C536494', (208, 223))	('methylated', 'Var', (171, 181))	('uveal melanoma', 'Disease', 'MESH:C536494', (208, 222))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('monosomy three', 'Var', (80, 94))	('RASSF1a', 'Gene', (182, 189))	('melanomas', 'Phenotype', 'HP:0002861', (214, 223))	('uveal melanoma', 'Phenotype', 'HP:0007716', (208, 222))	('uveal melanoma', 'Phenotype', 'HP:0007716', (98, 112))	('uveal melanoma', 'Disease', (98, 112))	('uveal melanoma', 'Disease', 'MESH:C536494', (98, 112))	('uveal melanomas', 'Disease', (208, 223))	('uveal melanomas', 'Phenotype', 'HP:0007716', (208, 223))
8742	18985043	To address this problem we studied several separate tumour areas in 11 choroidal melanomas positive for the T1799A mutation.	('choroidal melanomas', 'Phenotype', 'HP:0012054', (71, 90))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('T1799A', 'Mutation', 'rs113488022', (108, 114))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('choroidal melanomas', 'Disease', (71, 90))	('melanomas', 'Phenotype', 'HP:0002861', (81, 90))	('choroidal melanomas', 'Disease', 'MESH:D008545', (71, 90))	('tumour', 'Disease', (52, 58))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (71, 89))	('T1799A', 'Var', (108, 114))
8743	18985043	In six of the tumours positive for the BRAF mutation it was observed that the mutation was present in some areas of the tumour but not in others.	('tumour', 'Disease', (14, 20))	('mutation', 'Var', (44, 52))	('BRAF', 'Gene', '673', (39, 43))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('BRAF', 'Gene', (39, 43))	('tumour', 'Disease', (120, 126))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('tumour', 'Disease', 'MESH:D009369', (14, 20))	('tumours', 'Disease', 'MESH:D009369', (14, 21))	('tumours', 'Disease', (14, 21))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
8744	18985043	Although the results of this study confirm that the BRAF mutation is heterogeneously distributed in uveal melanoma the frequency of this mutation still appears considerably lower than in cutaneous melanoma.	('mutation', 'Var', (57, 65))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('uveal melanoma', 'Disease', (100, 114))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('cutaneous melanoma', 'Disease', (187, 205))	('BRAF', 'Gene', '673', (52, 56))	('lower', 'NegReg', (173, 178))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (187, 205))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (187, 205))	('BRAF', 'Gene', (52, 56))
8748	18985043	It has also been suggested that exposure to ultraviolet light may be a key factor in melanomas with the T1799A point mutation(Thomas et al, 2006).	('melanomas', 'Disease', (85, 94))	('T1799A', 'Mutation', 'rs113488022', (104, 110))	('melanomas', 'Disease', 'MESH:D008545', (85, 94))	('T1799A point mutation', 'Var', (104, 125))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))
8749	18985043	Previous research has also shown that the BRAF mutation frequency is lower in melanoma arising in sites protected from sun exposure compared with those from sun-exposed sites(Cohen et al, 2004).	('BRAF', 'Gene', '673', (42, 46))	('protected from sun exposure', 'Phenotype', 'HP:0000992', (104, 131))	('mutation', 'Var', (47, 55))	('lower', 'NegReg', (69, 74))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('BRAF', 'Gene', (42, 46))
8750	18985043	Although it is recognised that the BRAF mutation is not a UV-signature mutation, it has been suggested that it could still arise due to error-prone reduplication of UV-damaged DNA (Thomas et al, 2006).	('mutation', 'Var', (40, 48))	('BRAF', 'Gene', (35, 39))	('BRAF', 'Gene', '673', (35, 39))	('DNA', 'cellular_component', 'GO:0005574', ('176', '179'))
8752	18985043	An alternative explanation is that this BRAF mutation is an infrequent event in uveal melanoma and the observed, inappropriate downstream activation of the MAPK component is due to genetic alterations in other components of this pathway.	('BRAF', 'Gene', '673', (40, 44))	('MAPK', 'molecular_function', 'GO:0004707', ('156', '160'))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('BRAF', 'Gene', (40, 44))	('uveal melanoma', 'Disease', (80, 94))	('uveal melanoma', 'Disease', 'MESH:C536494', (80, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('mutation', 'Var', (45, 53))	('activation', 'PosReg', (138, 148))	('genetic alterations', 'Var', (181, 200))
8753	18985043	In conclusion, we have shown that the BRAF mutation is present in a proportion of posterior uveal melanomas and that within these tumours the distribution of this mutation is heterogeneous.	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('mutation', 'Var', (43, 51))	('uveal melanomas', 'Disease', (92, 107))	('uveal melanomas', 'Phenotype', 'HP:0007716', (92, 107))	('tumours', 'Disease', 'MESH:D009369', (130, 137))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('tumours', 'Disease', (130, 137))	('BRAF', 'Gene', '673', (38, 42))	('uveal melanoma', 'Phenotype', 'HP:0007716', (92, 106))	('uveal melanomas', 'Disease', 'MESH:C536494', (92, 107))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('BRAF', 'Gene', (38, 42))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))
8755	32933997	Chloroquine sensitizes GNAQ/11-mutated melanoma to MEK1/2 inhibition Mutational activation of GNAQ or GNA11 (GNAQ/11), detected in >90% of uveal melanomas, leads to constitutive activation of oncogenic pathways, including MAP kinase and YAP.	('YAP', 'Gene', (237, 240))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('GNA11', 'Gene', (102, 107))	('activation', 'PosReg', (178, 188))	('MAP', 'molecular_function', 'GO:0004239', ('222', '225'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('uveal melanomas', 'Disease', 'MESH:C536494', (139, 154))	('melanoma', 'Disease', (39, 47))	('Mutational', 'Var', (69, 79))	('YAP', 'Gene', '10413', (237, 240))	('activation', 'PosReg', (80, 90))	('MEK1/2', 'Gene', '5604;5605', (51, 57))	('MEK1', 'molecular_function', 'GO:0004708', ('51', '55'))	('MEK1/2', 'Gene', (51, 57))	('GNAQ/11', 'Chemical', '-', (109, 116))	('GNAQ/11', 'Chemical', '-', (23, 30))	('oncogenic pathways', 'Pathway', (192, 210))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('P', 'Chemical', 'MESH:D010758', (224, 225))	('MAP kinase', 'Pathway', (222, 232))	('Chloroquine', 'Chemical', 'MESH:D002738', (0, 11))	('uveal melanomas', 'Disease', (139, 154))	('uveal melanomas', 'Phenotype', 'HP:0007716', (139, 154))	('P', 'Chemical', 'MESH:D010758', (239, 240))	('melanomas', 'Phenotype', 'HP:0002861', (145, 154))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))
8764	32933997	Furthermore, T/CQ-treated cells displayed decreased YAP nuclear localization and decreased YAP transcriptional activity.	('decreased', 'NegReg', (81, 90))	('decreased', 'NegReg', (42, 51))	('localization', 'biological_process', 'GO:0051179', ('64', '76'))	('T/CQ-treated', 'Var', (13, 25))	('YAP', 'Gene', '10413', (91, 94))	('YAP', 'Gene', (52, 55))	('YAP', 'Gene', (91, 94))	('T/CQ', 'Chemical', '-', (13, 17))	('YAP', 'Gene', '10413', (52, 55))
8765	32933997	Expression of a constitutively active YAP5SA mutant conferred resistance to T/CQ-induced cell death.	('mutant', 'Var', (45, 51))	('YAP5SA', 'Gene', (38, 44))	('T/CQ', 'Chemical', '-', (76, 80))	('cell death', 'biological_process', 'GO:0008219', ('89', '99'))	('resistance', 'CPA', (62, 72))	('YAP5SA', 'Gene', '10413', (38, 44))
8768	32933997	However, GNAQ/11 mutations are uniquely enriched in more than 90% of uveal melanoma (UM), a rare subtype of melanoma that arises from melanocytes of the uveal tract of the eye.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('GNAQ/11', 'Chemical', '-', (9, 16))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('uveal melanoma', 'Disease', (69, 83))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('GNAQ/11', 'Gene', (9, 16))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('mutations', 'Var', (17, 26))	('melanoma', 'Disease', (108, 116))
8772	32933997	The most common mutations in GNAQ/11 lead to amino acid substitutions at glutamine 209 (Q209P/L) that disable the protein's ability to hydrolyze GTP.	('disable', 'NegReg', (102, 109))	('Q209P', 'Var', (88, 93))	('substitutions', 'Var', (56, 69))	('lead to', 'Reg', (37, 44))	('mutations', 'Var', (16, 25))	('protein', 'Protein', (114, 121))	('GNAQ/11', 'Chemical', '-', (29, 36))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('GNAQ/11', 'Gene', (29, 36))	('Q209P', 'SUBSTITUTION', 'None', (88, 93))	('GTP', 'Chemical', 'MESH:D006160', (145, 148))	('ability to hydrolyze GTP', 'MPA', (124, 148))	('glutamine', 'Chemical', 'MESH:D005973', (73, 82))
8773	32933997	The subsequent accumulation of active, GTP-bound GNAQ/11 results in constitutive activation of multiple downstream oncogenic signaling pathways, including the RAS-regulated PLCb>PKC>RAS>RAF>MEK1/2>ERK1/2 MAP kinase (MAPK) pathway and the TRIO>RHO/RAC-regulated Yes-associated protein (YAP) pathway.	('protein', 'cellular_component', 'GO:0003675', ('276', '283'))	('PKC', 'Gene', '112476', (178, 181))	('ERK1', 'molecular_function', 'GO:0004707', ('197', '201'))	('YAP', 'Gene', (285, 288))	('RAF', 'Gene', (186, 189))	('C', 'Chemical', 'MESH:D002738', (175, 176))	('MAPK', 'molecular_function', 'GO:0004707', ('216', '220'))	('PKC', 'Gene', (178, 181))	('GNAQ/11', 'Chemical', '-', (49, 56))	('P', 'Chemical', 'MESH:D010758', (218, 219))	('RAC', 'Gene', '5879', (247, 250))	('RAC', 'Gene', (247, 250))	('oncogenic signaling pathways', 'Pathway', (115, 143))	('P', 'Chemical', 'MESH:D010758', (178, 179))	('activation', 'PosReg', (81, 91))	('S', 'Chemical', 'MESH:D013455', (161, 162))	('MAP', 'molecular_function', 'GO:0004239', ('204', '207'))	('C', 'Chemical', 'MESH:D002738', (180, 181))	('YAP', 'Gene', '10413', (285, 288))	('PKC', 'molecular_function', 'GO:0004697', ('178', '181'))	('P', 'Chemical', 'MESH:D010758', (287, 288))	('MEK1', 'molecular_function', 'GO:0004708', ('190', '194'))	('S', 'Chemical', 'MESH:D013455', (184, 185))	('ERK1/2', 'Gene', (197, 203))	('P', 'Chemical', 'MESH:D010758', (41, 42))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('ERK1/2', 'Gene', '5595;5594', (197, 203))	('accumulation', 'PosReg', (15, 27))	('GTP', 'Chemical', 'MESH:D006160', (39, 42))	('C', 'Chemical', 'MESH:D002738', (249, 250))	('P', 'Chemical', 'MESH:D010758', (206, 207))	('RAF', 'Gene', '22882', (186, 189))	('RAS-regulated', 'Pathway', (159, 172))	('GNAQ/11', 'Var', (49, 56))	('P', 'Chemical', 'MESH:D010758', (173, 174))
8775	32933997	Recent research on RAS- or BRAF-driven cancers has demonstrated that blockade of RAF>MEK>ERK signaling results in an elevation of autophagy that protects cancer cells from the cytotoxic effects of pathway-targeted inhibition.	('MEK', 'Gene', '5609', (85, 88))	('autophagy', 'biological_process', 'GO:0016236', ('130', '139'))	('RAF', 'Gene', (28, 31))	('ERK', 'Gene', '5594', (89, 92))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('RAF', 'Gene', (81, 84))	('MEK', 'Gene', (85, 88))	('S', 'Chemical', 'MESH:D013455', (21, 22))	('cancer', 'Disease', (39, 45))	('autophagy', 'biological_process', 'GO:0006914', ('130', '139'))	('ERK', 'molecular_function', 'GO:0004707', ('89', '92'))	('signaling', 'biological_process', 'GO:0023052', ('93', '102'))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('ERK', 'Gene', (89, 92))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancers', 'Disease', (39, 46))	('BRAF', 'Gene', '673', (27, 31))	('BRAF', 'Gene', (27, 31))	('autophagy', 'CPA', (130, 139))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('RAF', 'Gene', '22882', (28, 31))	('cancer', 'Disease', (154, 160))	('RAF', 'Gene', '22882', (81, 84))	('blockade', 'Var', (69, 77))	('elevation', 'PosReg', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
8777	32933997	Here, we show that inhibition of GNAQ/11 or of RAF>MEK>ERK signaling can be combined with the antimalarial drug and lysosome inhibitor, chloroquine or it's derivative, hydroxychloroquine, to enhance cell death and inhibit tumor growth in preclinical models.	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('chloroquine', 'Chemical', 'MESH:D002738', (136, 147))	('lysosome', 'cellular_component', 'GO:0005764', ('116', '124'))	('inhibition', 'Var', (19, 29))	('cell death', 'CPA', (199, 209))	('inhibit', 'NegReg', (214, 221))	('GNAQ/11', 'Chemical', '-', (33, 40))	('MEK', 'Gene', '5609', (51, 54))	('hydroxychloroquine', 'Chemical', 'MESH:D006886', (168, 186))	('cell death', 'biological_process', 'GO:0008219', ('199', '209'))	('RAF', 'Gene', '22882', (47, 50))	('ERK', 'Gene', '5594', (55, 58))	('MEK', 'Gene', (51, 54))	('chloroquine', 'Chemical', 'MESH:D002738', (175, 186))	('ERK', 'molecular_function', 'GO:0004707', ('55', '58'))	('tumor', 'Disease', (222, 227))	('malaria', 'Disease', (98, 105))	('RAF', 'Gene', (47, 50))	('ERK', 'Gene', (55, 58))	('malaria', 'Disease', 'MESH:D008288', (98, 105))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('GNAQ/11', 'Gene', (33, 40))	('enhance', 'PosReg', (191, 198))
8809	32933997	A pool of four siRNAs against human YAP (LQ-012200-00-0005) and non-targeting control (D-001810-01-20) were purchased from HorizonTM..	('human', 'Species', '9606', (30, 35))	('LQ-012200-00-0005', 'Var', (41, 58))	('YAP', 'Gene', '10413', (36, 39))	('YAP', 'Gene', (36, 39))
8846	32933997	Inhibition of Galpha signaling with the plant (Ardisia crenata)-derived depsipetide, FR900359 (FR), has recently shown effectiveness in inhibiting growth of GNAQ/11-mutated melanoma cell lines by preventing GDP-GTP nucleotide exchange on the mutationally-activated oncoproteins.	('Inhibition', 'NegReg', (0, 10))	('FR900359', 'Var', (85, 93))	('Ardisia crenata', 'Species', '13345', (47, 62))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('Galpha', 'Gene', '8802', (14, 20))	('preventing', 'NegReg', (196, 206))	('FR', 'Chemical', 'MESH:C000607068', (85, 87))	('growth', 'MPA', (147, 153))	('depsipetide', 'Chemical', '-', (72, 83))	('GDP-GTP', 'Chemical', '-', (207, 214))	('GDP-GTP nucleotide exchange', 'MPA', (207, 234))	('inhibiting', 'NegReg', (136, 146))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('GNAQ/11', 'Chemical', '-', (157, 164))	('FR900359', 'Chemical', 'MESH:C000607068', (85, 93))	('FR', 'Chemical', 'MESH:C000607068', (95, 97))	('Galpha', 'Gene', (14, 20))	('signaling', 'biological_process', 'GO:0023052', ('21', '30'))
8852	32933997	The effects on autophagic flux assessed by flow cytometry were supported by immunoblot analysis of p62SQSTM1 expression in drug treated OMM2.5 cells where both FR and trametinib led to decreased p62SQSTM1 (Fig.	('FR', 'Chemical', 'MESH:C000607068', (160, 162))	('decreased', 'NegReg', (185, 194))	('trametinib', 'Chemical', 'MESH:C560077', (167, 177))	('S', 'Chemical', 'MESH:D013455', (200, 201))	('S', 'Chemical', 'MESH:D013455', (198, 199))	('S', 'Chemical', 'MESH:D013455', (104, 105))	('S', 'Chemical', 'MESH:D013455', (102, 103))	('p62SQSTM1', 'Var', (195, 204))	('p62SQSTM1', 'Gene', (99, 108))
8855	32933997	Genetic inhibition of autophagy in OMM2.5 cells was achieved using tetracycline-inducible expression of a dominant-negative (C74>A) form of the key autophagy cysteine protease ATG4B/Autophagin 1 (ATG4BDN).	('ATG4B', 'Gene', (196, 201))	('inhibition', 'NegReg', (8, 18))	('ATG4BDN', 'Gene', (196, 203))	('autophagy', 'biological_process', 'GO:0006914', ('148', '157'))	('ATG4B', 'Gene', (176, 181))	('autophagy', 'biological_process', 'GO:0016236', ('22', '31'))	('ATG4B', 'Gene', '23192', (176, 181))	('C74>A', 'Mutation', 'c.74C>A', (125, 130))	('Autophagin 1', 'Gene', (182, 194))	('autophagy', 'biological_process', 'GO:0016236', ('148', '157'))	('autophagy', 'biological_process', 'GO:0006914', ('22', '31'))	('ATG4BDN', 'Gene', '23192', (196, 203))	('ATG4B', 'Gene', '23192', (196, 201))	('Autophagin 1', 'Gene', '23192', (182, 194))	('tetracycline', 'Chemical', 'MESH:D013752', (67, 79))	('autophagy', 'CPA', (22, 31))	('C74>A', 'Var', (125, 130))
8856	32933997	As expected, treatment of OMM2.5/Tet-ATG4BDN cells with doxycycline (Dox) led to increased ATG4BDN expression and an accumulation of both p62SQSTM1 and LC3 expression (Fig.	('S', 'Chemical', 'MESH:D013455', (143, 144))	('expression', 'MPA', (99, 109))	('p62SQSTM1', 'Var', (138, 147))	('doxycycline', 'Chemical', 'MESH:D004318', (56, 67))	('Dox', 'Chemical', 'MESH:D004318', (69, 72))	('S', 'Chemical', 'MESH:D013455', (141, 142))	('ATG4BDN', 'Gene', '23192', (91, 98))	('accumulation', 'PosReg', (117, 129))	('ATG4BDN', 'Gene', '23192', (37, 44))	('ATG4BDN', 'Gene', (91, 98))	('LC3', 'Gene', '84557', (152, 155))	('LC3', 'Gene', (152, 155))	('ATG4BDN', 'Gene', (37, 44))	('Tet', 'Chemical', 'MESH:C010349', (33, 36))	('increased', 'PosReg', (81, 90))
8865	32933997	To evaluate pathways downstream of mutationally-activated GNAQ/11 that could be pharmacologically targeted, mouse Melan-a melanocytes, oncogenically transformed with GNAQQ209L or GNA11Q209L, were compared to non-transformed cells.	('mouse', 'Species', '10090', (108, 113))	('GNAQ/11', 'Chemical', '-', (58, 65))	('GNAQQ209L', 'Var', (166, 175))	('GNA11Q209L', 'Var', (179, 189))
8870	32933997	Furthermore, immunofluorescence imaging of trametinib-treated OMM2.5 cells revealed the presence of numerous p62SQSTM1-positive autophagic vesicles that were larger than those observed in DMSO-treated cells, demonstrating increased autophagy activity (Supp.	('p62SQSTM1-positive', 'Var', (109, 127))	('trametinib', 'Chemical', 'MESH:C560077', (43, 53))	('DMSO', 'Chemical', 'MESH:D004121', (188, 192))	('S', 'Chemical', 'MESH:D013455', (114, 115))	('S', 'Chemical', 'MESH:D013455', (190, 191))	('autophagy activity', 'CPA', (232, 250))	('S', 'Chemical', 'MESH:D013455', (112, 113))	('S', 'Chemical', 'MESH:D013455', (252, 253))	('autophagy', 'biological_process', 'GO:0016236', ('232', '241'))	('increased', 'PosReg', (222, 231))	('autophagic vesicles', 'CPA', (128, 147))	('autophagy', 'biological_process', 'GO:0006914', ('232', '241'))
8872	32933997	These findings of MAPK pathway inhibition-specific induction of autophagy are consistent with our prior study of RAS-driven cancers, thus, we next tested whether MEK1/2 inhibition plus 4-aminoquinolines such as chloroquine or hydroxychloroquine might be an effective treatment strategy, since these are FDA-approved agents that could be rapidly deployed in the clinic.	('MEK1', 'molecular_function', 'GO:0004708', ('162', '166'))	('chloroquine', 'Chemical', 'MESH:D002738', (233, 244))	('autophagy', 'biological_process', 'GO:0006914', ('64', '73'))	('hydroxychloroquine', 'Chemical', 'MESH:D006886', (226, 244))	('S', 'Chemical', 'MESH:D013455', (115, 116))	('P', 'Chemical', 'MESH:D010758', (20, 21))	('MAPK', 'Gene', (18, 22))	('inhibition-specific', 'Var', (31, 50))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tested', 'Reg', (147, 153))	('4-aminoquinolines', 'Chemical', 'MESH:C001920', (185, 202))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('autophagy', 'CPA', (64, 73))	('autophagy', 'biological_process', 'GO:0016236', ('64', '73'))	('cancers', 'Disease', (124, 131))	('chloroquine', 'Chemical', 'MESH:D002738', (211, 222))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('MAPK', 'molecular_function', 'GO:0004707', ('18', '22'))
8873	32933997	Treatment of uveal melanoma cell lines, MP41 (GNA11Q209L), MEL270 (GNAQQ209P), or OMM2.5 (GNAQQ209P) with increasing concentrations of MEK1/2 inhibitor inhibited RAF>MEK>ERK signaling in a dose-dependent manner (Supp.	('uveal melanoma', 'Disease', (13, 27))	('ERK', 'Gene', '5594', (170, 173))	('RAF', 'Gene', (162, 165))	('MEK', 'Gene', (166, 169))	('MEK', 'Gene', (135, 138))	('uveal melanoma', 'Phenotype', 'HP:0007716', (13, 27))	('S', 'Chemical', 'MESH:D013455', (212, 213))	('P', 'Chemical', 'MESH:D010758', (75, 76))	('P', 'Chemical', 'MESH:D010758', (98, 99))	('ERK', 'Gene', (170, 173))	('uveal melanoma', 'Disease', 'MESH:C536494', (13, 27))	('GNAQQ209P', 'Mutation', 'rs121913492', (67, 76))	('inhibited', 'NegReg', (152, 161))	('MEK1', 'molecular_function', 'GO:0004708', ('135', '139'))	('GNAQQ209P', 'Mutation', 'rs121913492', (90, 99))	('signaling', 'biological_process', 'GO:0023052', ('174', '183'))	('P', 'Chemical', 'MESH:D010758', (41, 42))	('GNA11Q209L', 'Var', (46, 56))	('GNAQQ209P', 'Var', (67, 76))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('ERK', 'molecular_function', 'GO:0004707', ('170', '173'))	('RAF', 'Gene', '22882', (162, 165))	('MEK', 'Gene', '5609', (166, 169))	('GNAQQ209P', 'Var', (90, 99))	('MEK', 'Gene', '5609', (135, 138))
8881	32933997	Treatment of either OMM2.5 (GNAQQ209P) or OMM1 (GNA11Q209L) UM cells with T/CQ resulted in increased cell death compared to vehicle or single agents.	('cell death', 'CPA', (101, 111))	('GNAQQ209P', 'Mutation', 'rs121913492', (28, 37))	('GNAQQ209P', 'Var', (28, 37))	('T/CQ', 'Chemical', '-', (74, 78))	('cell death', 'biological_process', 'GO:0008219', ('101', '111'))	('UM', 'Phenotype', 'HP:0007716', (60, 62))
8882	32933997	Furthermore, the anti-proliferative effects of T/CQ treatment were calculated to be synergistic in all four cell lines (Fig.	('anti-proliferative effects', 'CPA', (17, 43))	('T/CQ', 'Chemical', '-', (47, 51))	('T/CQ', 'Var', (47, 51))
8883	32933997	These results demonstrated that T/CQ is effective in eliciting synergistic cytotoxicity in GNAQ/11-mutated melanoma cell lines in vitro.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('cytotoxicity', 'Disease', (75, 87))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('GNAQ/11', 'Chemical', '-', (91, 98))	('T/CQ', 'Var', (32, 36))	('T/CQ', 'Chemical', '-', (32, 36))	('cytotoxicity', 'Disease', 'MESH:D064420', (75, 87))	('eliciting', 'Reg', (53, 62))
8890	32933997	Effective trametinib-mediated inhibition of RAF>MEK>ERK signaling and increased autophagy in tumors was inferred by immunoblotting of tumor lysates that showed decreased pERK1/2 and p62SQSTM1 expression (Supp.	('ERK', 'molecular_function', 'GO:0004707', ('52', '55'))	('ERK', 'Gene', '5594', (52, 55))	('increased', 'PosReg', (70, 79))	('autophagy', 'CPA', (80, 89))	('S', 'Chemical', 'MESH:D013455', (204, 205))	('MEK', 'Gene', (48, 51))	('ERK', 'Gene', (171, 174))	('decreased', 'NegReg', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('p62SQSTM1', 'Var', (182, 191))	('autophagy', 'biological_process', 'GO:0006914', ('80', '89'))	('ERK', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('expression', 'MPA', (192, 202))	('S', 'Chemical', 'MESH:D013455', (187, 188))	('inhibition', 'NegReg', (30, 40))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('S', 'Chemical', 'MESH:D013455', (185, 186))	('RAF', 'Gene', '22882', (44, 47))	('ERK1/2', 'Gene', (171, 177))	('tumors', 'Disease', (93, 99))	('ERK1/2', 'Gene', '5595;5594', (171, 177))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('MEK', 'Gene', '5609', (48, 51))	('ERK', 'Gene', '5594', (171, 174))	('trametinib', 'Chemical', 'MESH:C560077', (10, 20))	('autophagy', 'biological_process', 'GO:0016236', ('80', '89'))	('RAF', 'Gene', (44, 47))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
8897	32933997	Strikingly, T/HCQ treatment provided a significant survival benefit compared to all other treatments such that 100% of tumor bearing mice receiving this treatment remained alive at study conclusion (Fig.	('tumor', 'Disease', (119, 124))	('mice', 'Species', '10090', (133, 137))	('T/HCQ', 'Var', (12, 17))	('survival', 'CPA', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('T/HCQ', 'Chemical', '-', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('S', 'Chemical', 'MESH:D013455', (0, 1))
8905	32933997	Hence, using four different models of GNAQ- or GNA11-driven melanoma, we demonstrate that T/HCQ combination inhibits melanoma growth, either subcutaneous or in the liver, with or without the presence of an intact immune system, and also provides a survival advantage to T/HCQ treated tumor-bearing mice.	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('mice', 'Species', '10090', (298, 302))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('combination', 'Var', (96, 107))	('inhibits', 'NegReg', (108, 116))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('melanoma', 'Disease', (60, 68))	('survival advantage', 'CPA', (248, 266))	('T/HCQ combination', 'Var', (90, 107))	('T/HCQ', 'Chemical', '-', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('T/HCQ', 'Chemical', '-', (270, 275))	('tumor', 'Disease', (284, 289))	('melanoma', 'Disease', (117, 125))
8906	32933997	4-aminoquinolines such as chloroquine and hydroxychloroquine prevent the end-stage of the autophagy process by preventing autophagosome-lysosome fusion and the acidification of lysosomes through inhibition of the vacuolar-type H(+)-ATPase (V-ATPase).	('P', 'Chemical', 'MESH:D010758', (234, 235))	('autophagosome', 'cellular_component', 'GO:0005776', ('122', '135'))	('end-stage of', 'CPA', (73, 85))	('hydroxychloroquine', 'Chemical', 'MESH:D006886', (42, 60))	('chloroquine', 'Chemical', 'MESH:D002738', (26, 37))	('autophagy', 'biological_process', 'GO:0006914', ('90', '99'))	('acidification', 'biological_process', 'GO:0045851', ('160', '173'))	('autophagosome-lysosome fusion', 'CPA', (122, 151))	('hydroxychloroquine', 'Var', (42, 60))	('chloroquine', 'Chemical', 'MESH:D002738', (49, 60))	('inhibition', 'NegReg', (195, 205))	('lysosome', 'cellular_component', 'GO:0005764', ('136', '144'))	('autophagosome-lysosome fusion', 'biological_process', 'GO:0061909', ('122', '151'))	('acidification of lysosomes', 'MPA', (160, 186))	('prevent', 'NegReg', (61, 68))	('4-aminoquinolines', 'Chemical', 'MESH:C001920', (0, 17))	('preventing', 'NegReg', (111, 121))	('P', 'Chemical', 'MESH:D010758', (244, 245))	('V-ATPase', 'cellular_component', 'GO:0008245', ('240', '248'))	('autophagy', 'biological_process', 'GO:0016236', ('90', '99'))	('V-ATPase', 'cellular_component', 'GO:0000219', ('240', '248'))
8907	32933997	Hence, to determine if the ability of chloroquine to enhance cell death in combination with trametinib is dependent on its role as an autophagy inhibitor, we utilized genetic inhibition of autophagy using OMM2.5/Tet-ATG4BDN mutant cells (Fig.	('chloroquine', 'Chemical', 'MESH:D002738', (38, 49))	('cell death', 'CPA', (61, 71))	('mutant', 'Var', (224, 230))	('Tet', 'Chemical', 'MESH:C010349', (212, 215))	('cell death', 'biological_process', 'GO:0008219', ('61', '71'))	('autophagy', 'biological_process', 'GO:0016236', ('134', '143'))	('ATG4BDN', 'Gene', '23192', (216, 223))	('enhance', 'PosReg', (53, 60))	('autophagy', 'biological_process', 'GO:0016236', ('189', '198'))	('autophagy', 'biological_process', 'GO:0006914', ('134', '143'))	('autophagy', 'biological_process', 'GO:0006914', ('189', '198'))	('ATG4BDN', 'Gene', (216, 223))	('trametinib', 'Chemical', 'MESH:C560077', (92, 102))
8913	32933997	Because chloroquine exerts its intracellular effects on the lysosome, we next tested whether inhibition of lysosome acidification would cooperatively elicit cell death in combination with trametinib.	('elicit', 'Reg', (150, 156))	('trametinib', 'Chemical', 'MESH:C560077', (188, 198))	('tested', 'Reg', (78, 84))	('cell death', 'CPA', (157, 167))	('cell death', 'biological_process', 'GO:0008219', ('157', '167'))	('lysosome', 'cellular_component', 'GO:0005764', ('60', '68'))	('intracellular', 'cellular_component', 'GO:0005622', ('31', '44'))	('chloroquine', 'Chemical', 'MESH:D002738', (8, 19))	('lysosome', 'cellular_component', 'GO:0005764', ('107', '115'))	('acidification', 'biological_process', 'GO:0045851', ('116', '129'))	('inhibition', 'Var', (93, 103))
8922	32933997	Interestingly, as single agents, neither trametinib nor chloroquine had striking effects on total YAP expression, as measured by immunoblotting, whereas the T/CQ combination resulted in an approximately 2-fold reduction in total YAP in OMM2.5 and OMM1 cells (Figs.	('T/CQ', 'Chemical', '-', (157, 161))	('YAP', 'Gene', '10413', (229, 232))	('trametinib', 'Chemical', 'MESH:C560077', (41, 51))	('YAP', 'Gene', '10413', (98, 101))	('YAP', 'Gene', (229, 232))	('chloroquine', 'Chemical', 'MESH:D002738', (56, 67))	('T/CQ', 'Var', (157, 161))	('reduction', 'NegReg', (210, 219))	('YAP', 'Gene', (98, 101))
8925	32933997	Moreover, T/CQ treatment decreased nuclear YAP accumulation as assessed by measuring nuclear:cytoplasmic YAP.	('T/CQ', 'Var', (10, 14))	('YAP', 'Gene', '10413', (105, 108))	('YAP', 'Gene', '10413', (43, 46))	('decreased', 'NegReg', (25, 34))	('YAP', 'Gene', (105, 108))	('YAP', 'Gene', (43, 46))	('T/CQ', 'Chemical', '-', (10, 14))
8931	32933997	Consistent with the YAP expression data, T/CQ treatment led to decreased levels of YAP/TEAD-mediated luciferase activity.	('T/CQ', 'Chemical', '-', (41, 45))	('YAP', 'Gene', '10413', (83, 86))	('YAP', 'Gene', (20, 23))	('levels', 'MPA', (73, 79))	('YAP', 'Gene', (83, 86))	('C', 'Chemical', 'MESH:D002738', (43, 44))	('decreased', 'NegReg', (63, 72))	('luciferase activity', 'molecular_function', 'GO:0047077', ('101', '120'))	('C', 'Chemical', 'MESH:D002738', (0, 1))	('luciferase activity', 'molecular_function', 'GO:0045289', ('101', '120'))	('YAP', 'Gene', '10413', (20, 23))	('luciferase activity', 'molecular_function', 'GO:0047712', ('101', '120'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('101', '120'))	('T/CQ', 'Var', (41, 45))	('luciferase activity', 'molecular_function', 'GO:0050248', ('101', '120'))
8932	32933997	Indeed, T/CQ decreased YAP activity to levels comparable to the established YAP inhibitor, verteporfin (Fig.	('YAP', 'Gene', '10413', (76, 79))	('decreased', 'NegReg', (13, 22))	('YAP', 'Gene', '10413', (23, 26))	('YAP', 'Gene', (76, 79))	('T/CQ', 'Var', (8, 12))	('verteporfin', 'Chemical', 'MESH:D000077362', (91, 102))	('T/CQ', 'Chemical', '-', (8, 12))	('YAP', 'Gene', (23, 26))
8934	32933997	Correspondingly, T/CQ treatment also led to a decrease in mRNAs of known YAP target genes, CTGF and CYR61, similar to the effects of verteporfin (Fig.	('CYR61', 'Gene', (100, 105))	('CYR61', 'Gene', '3491', (100, 105))	('YAP', 'Gene', '10413', (73, 76))	('YAP', 'Gene', (73, 76))	('C', 'Chemical', 'MESH:D002738', (19, 20))	('T/CQ', 'Chemical', '-', (17, 21))	('verteporfin', 'Chemical', 'MESH:D000077362', (133, 144))	('C', 'Chemical', 'MESH:D002738', (91, 92))	('mRNAs of', 'MPA', (58, 66))	('C', 'Chemical', 'MESH:D002738', (0, 1))	('T/CQ', 'Var', (17, 21))	('CTGF', 'Gene', '1490', (91, 95))	('CTGF', 'Gene', (91, 95))	('decrease', 'NegReg', (46, 54))	('C', 'Chemical', 'MESH:D002738', (100, 101))
8949	32933997	In cells in which YAP expression was inhibited by siYAP-mediated protein knockdown (Fig.	('YAP', 'Gene', (18, 21))	('inhibited', 'NegReg', (37, 46))	('YAP', 'Gene', (52, 55))	('YAP', 'Gene', '10413', (52, 55))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('YAP', 'Gene', '10413', (18, 21))	('knockdown', 'Var', (73, 82))
8956	32933997	To further investigate the requirement of YAP inhibition in T/CQ efficacy, OMM2.5 cells were engineered to stably express a constitutively active form of YAP (YAP5SA) in which five sites of serine phosphorylation (S61A, S109A, S127A, S164A, S381A), which are required for inhibition of YAP activity by upstream LATS protein kinases, are substituted to alanine.	('phosphorylation', 'biological_process', 'GO:0016310', ('197', '212'))	('YAP', 'Gene', (286, 289))	('alanine', 'Chemical', 'MESH:D000409', (352, 359))	('S127A', 'Mutation', 'rs762471803', (227, 232))	('S109A', 'Mutation', 'p.S109A', (220, 225))	('S381A', 'Var', (241, 246))	('YAP', 'Gene', '10413', (42, 45))	('YAP', 'Gene', '10413', (159, 162))	('S', 'Chemical', 'MESH:D013455', (234, 235))	('S61A', 'Mutation', 'p.S61A', (214, 218))	('S', 'Chemical', 'MESH:D013455', (227, 228))	('S', 'Chemical', 'MESH:D013455', (220, 221))	('S', 'Chemical', 'MESH:D013455', (163, 164))	('S', 'Chemical', 'MESH:D013455', (314, 315))	('S164A', 'Var', (234, 239))	('T/CQ', 'Chemical', '-', (60, 64))	('S127A', 'Var', (227, 232))	('YAP', 'Gene', (154, 157))	('YAP', 'Gene', '10413', (286, 289))	('S381A', 'Mutation', 'p.S381A', (241, 246))	('S', 'Chemical', 'MESH:D013455', (241, 242))	('S164A', 'Mutation', 'p.S164A', (234, 239))	('YAP5SA', 'Gene', (159, 165))	('serine', 'Chemical', 'MESH:D012694', (190, 196))	('YAP5SA', 'Gene', '10413', (159, 165))	('protein', 'cellular_component', 'GO:0003675', ('316', '323'))	('S109A', 'Var', (220, 225))	('YAP', 'Gene', (159, 162))	('S61A', 'Var', (214, 218))	('YAP', 'Gene', (42, 45))	('S', 'Chemical', 'MESH:D013455', (214, 215))	('YAP', 'Gene', '10413', (154, 157))
8958	32933997	First, we noted that expression of YAP5SA sustains YAP activity in OMM2.5 cells, even in the presence of T/CQ (Fig.	('YAP', 'Gene', (51, 54))	('YAP', 'Gene', (35, 38))	('YAP5SA', 'Gene', (35, 41))	('YAP5SA', 'Gene', '10413', (35, 41))	('sustains', 'PosReg', (42, 50))	('T/CQ', 'Chemical', '-', (105, 109))	('expression', 'Var', (21, 31))	('YAP', 'Gene', '10413', (35, 38))	('YAP', 'Gene', '10413', (51, 54))
8959	32933997	Furthermore, expression of YAP5SA in OMM2.5 cells significantly diminished the cytotoxic activity of T/CQ compared to vector-expressing cells (Fig.	('YAP5SA', 'Gene', (27, 33))	('diminished', 'NegReg', (64, 74))	('T/CQ', 'Chemical', '-', (101, 105))	('YAP5SA', 'Gene', '10413', (27, 33))	('cytotoxic activity of T/CQ', 'CPA', (79, 105))	('expression', 'Var', (13, 23))
8961	32933997	T/CQ-treated cells had decreased YAP activity, and YAP5SA-transfected cells had 2-3-fold increased YAP activity that was predominantly sustained in the presence of T/CQ (Supp.	('decreased', 'NegReg', (23, 32))	('T/CQ', 'Chemical', '-', (164, 168))	('T/CQ', 'Chemical', '-', (0, 4))	('YAP', 'Gene', (51, 54))	('YAP5SA', 'Gene', (51, 57))	('S', 'Chemical', 'MESH:D013455', (55, 56))	('YAP', 'Gene', '10413', (99, 102))	('S', 'Chemical', 'MESH:D013455', (170, 171))	('YAP', 'Gene', '10413', (33, 36))	('YAP', 'Gene', (33, 36))	('YAP5SA', 'Gene', '10413', (51, 57))	('increased', 'PosReg', (89, 98))	('YAP', 'Gene', (99, 102))	('T/CQ', 'Var', (164, 168))	('YAP', 'Gene', '10413', (51, 54))
8963	32933997	Consistent with YAP5SA-expressing OMM2.5 cells, YAP5SA-expressing MP41 cells had reduced cell death in the presence of T/CQ compared to vector-expressing cells (Supp.	('YAP5SA', 'Gene', '10413', (16, 22))	('S', 'Chemical', 'MESH:D013455', (52, 53))	('P', 'Chemical', 'MESH:D010758', (67, 68))	('YAP5SA', 'Gene', (48, 54))	('cell death', 'biological_process', 'GO:0008219', ('89', '99'))	('cell death', 'CPA', (89, 99))	('MP41', 'Var', (66, 70))	('P', 'Chemical', 'MESH:D010758', (18, 19))	('YAP5SA', 'Gene', '10413', (48, 54))	('C', 'Chemical', 'MESH:D002738', (0, 1))	('T/CQ', 'Var', (119, 123))	('S', 'Chemical', 'MESH:D013455', (161, 162))	('reduced', 'NegReg', (81, 88))	('S', 'Chemical', 'MESH:D013455', (20, 21))	('YAP5SA', 'Gene', (16, 22))	('T/CQ', 'Chemical', '-', (119, 123))	('C', 'Chemical', 'MESH:D002738', (121, 122))	('P', 'Chemical', 'MESH:D010758', (50, 51))
8970	32933997	Here we show that the combination of the more potent MEK1/2 inhibitor, trametinib, plus chloroquine increases anti-proliferative activity in vitro, and suppresses tumor growth leading to prolonged survival of mice bearing melanomas driven by mutationally-activated GNAQ/11.	('trametinib', 'Chemical', 'MESH:C560077', (71, 81))	('suppresses', 'NegReg', (152, 162))	('mice', 'Species', '10090', (209, 213))	('melanomas', 'Disease', (222, 231))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('MEK1', 'molecular_function', 'GO:0004708', ('53', '57'))	('anti-proliferative activity', 'MPA', (110, 137))	('increases', 'PosReg', (100, 109))	('mutationally-activated', 'Var', (242, 264))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('melanomas', 'Disease', 'MESH:D008545', (222, 231))	('melanomas', 'Phenotype', 'HP:0002861', (222, 231))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('tumor', 'Disease', (163, 168))	('MEK1/2', 'Gene', (53, 59))	('GNAQ/11', 'Chemical', '-', (265, 272))	('prolonged', 'PosReg', (187, 196))	('chloroquine', 'Chemical', 'MESH:D002738', (88, 99))
8974	32933997	We also identified YAP signaling as a survival pathway that is inhibited by T/CQ in melanomas driven by mutationally-activated GNAQ/11.	('GNAQ/11', 'Gene', (127, 134))	('melanomas', 'Disease', (84, 93))	('mutationally-activated', 'Var', (104, 126))	('T/CQ', 'Chemical', '-', (76, 80))	('melanomas', 'Disease', 'MESH:D008545', (84, 93))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('YAP', 'Gene', '10413', (19, 22))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('T/CQ', 'Gene', (76, 80))	('GNAQ/11', 'Chemical', '-', (127, 134))	('YAP', 'Gene', (19, 22))	('inhibited', 'NegReg', (63, 72))	('signaling', 'biological_process', 'GO:0023052', ('23', '32'))
8976	32933997	MEK1/2 inhibition has also been shown to elevate YAP signaling in primary uveal melanoma cell lines at low concentrations of trametinib (10 nM).	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('YAP', 'Gene', (49, 52))	('MEK1/2', 'Gene', (0, 6))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('MEK1', 'molecular_function', 'GO:0004708', ('0', '4'))	('elevate', 'PosReg', (41, 48))	('inhibition', 'Var', (7, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('trametinib', 'Chemical', 'MESH:C560077', (125, 135))	('YAP', 'Gene', '10413', (49, 52))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('uveal melanoma', 'Disease', (74, 88))
8988	32933997	Inteerstingly, in pancreatic ductal adenocarcinoma, loss of BAP1 has been shown to activate Hippo-mediated YAP signaling through LATS2 degradation.	('degradation', 'biological_process', 'GO:0009056', ('135', '146'))	('LATS2', 'Gene', (129, 134))	('LATS2', 'Gene', '26524', (129, 134))	('loss', 'Var', (52, 56))	('activate', 'PosReg', (83, 91))	('YAP', 'Gene', (107, 110))	('signaling', 'biological_process', 'GO:0023052', ('111', '120'))	('BAP1', 'Gene', '8314', (60, 64))	('pancreatic ductal adenocarcinoma', 'Disease', (18, 50))	('BAP1', 'Gene', (60, 64))	('YAP', 'Gene', '10413', (107, 110))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (18, 50))
8996	32933997	NCT03825289, NCT03979651 and NCT04132505).	('C', 'Chemical', 'MESH:D002738', (1, 2))	('NCT03825289', 'Var', (0, 11))	('NCT04132505', 'Var', (29, 40))	('C', 'Chemical', 'MESH:D002738', (30, 31))	('NCT03979651', 'Var', (13, 24))	('C', 'Chemical', 'MESH:D002738', (14, 15))
9099	30900145	trametinib) can effectively counter BRAFV600E-mutated melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('melanomas', 'Disease', 'MESH:D008545', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('BRAFV600E-mutated', 'Var', (36, 53))	('BRAFV600E', 'Mutation', 'rs113488022', (36, 45))	('melanomas', 'Disease', (54, 63))
9126	30900145	Sequencing and BRAF inhibitor therapy changed the course of the disease for metastatic patients, as BRAF mutation is one of the key targetable genetic aberrations that occurs in melanomas (Chapman et al.).	('mutation', 'Var', (105, 113))	('melanomas', 'Phenotype', 'HP:0002861', (178, 187))	('melanomas', 'Disease', (178, 187))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanomas', 'Disease', 'MESH:D008545', (178, 187))	('BRAF', 'Gene', (100, 104))	('patients', 'Species', '9606', (87, 95))
9129	30900145	In the development of malignant melanoma, molecular alterations and protein modifications are responsible for the acquisition of a metastatic phenotype.	('malignant melanoma', 'Disease', (22, 40))	('men', 'Species', '9606', (14, 17))	('malignant melanoma', 'Disease', 'MESH:D008545', (22, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('mole', 'Phenotype', 'HP:0003764', (42, 46))	('malignant melanoma', 'Phenotype', 'HP:0002861', (22, 40))	('molecular alterations', 'Var', (42, 63))	('protein', 'Protein', (68, 75))
9154	30900145	Mutation of c-kit is a characteristic finding for ALM and also for mucosal melanomas (Curtin et al.).	('mucosal melanomas', 'Disease', 'MESH:D008545', (67, 84))	('ALM', 'Phenotype', 'HP:0012060', (50, 53))	('Mutation', 'Var', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('ALM', 'Disease', (50, 53))	('c-kit', 'Gene', '3815', (12, 17))	('c-kit', 'Gene', (12, 17))	('mucosal melanomas', 'Disease', (67, 84))
9158	30900145	Similar to ocular melanomas, these have a characteristic GNAQ mutation affecting G protein-coupled receptors (Arkenau et al.).	('affecting', 'Reg', (71, 80))	('ocular melanomas', 'Phenotype', 'HP:0025534', (11, 27))	('GNAQ', 'Gene', (57, 61))	('ocular melanomas', 'Disease', 'MESH:D008545', (11, 27))	('ocular melanomas', 'Disease', (11, 27))	('mutation', 'Var', (62, 70))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('GNAQ', 'Gene', '2776', (57, 61))	('G protein-coupled receptors', 'Protein', (81, 108))
9205	30900145	trametinib) effectively attack BRAFV600E-mutated melanomas (Falzone et al.	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('BRAFV600E', 'Mutation', 'rs113488022', (31, 40))	('melanomas', 'Disease', 'MESH:D008545', (49, 58))	('BRAFV600E-mutated', 'Var', (31, 48))	('trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('melanomas', 'Disease', (49, 58))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
9211	30900145	Targeted therapy was initiated as the melanoma was BRAFV600E positive; however, new tumours were identified on the back region during BRAF inhibition.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('BRAFV600E', 'Var', (51, 60))	('tumours', 'Disease', 'MESH:D009369', (84, 91))	('BRAFV600E', 'Mutation', 'rs113488022', (51, 60))	('tumours', 'Disease', (84, 91))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('melanoma', 'Disease', (38, 46))
9222	30900145	These widespread changes can be responsible for the clonal evolution of heterogeneous melanoma tissue and also for the clinically apparent evolution of the disease in response to the iatrogenic 'medical' environment.	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma tissue', 'Disease', (86, 101))	('melanoma tissue', 'Disease', 'MESH:D008545', (86, 101))	('changes', 'Var', (17, 24))	('men', 'Species', '9606', (211, 214))
9227	30900145	The BRAFV600E mutation, however, is identified at the genetic level but known targeted therapies act on proteins.	('BRAFV600E', 'Var', (4, 13))	('act', 'Reg', (97, 100))	('BRAFV600E', 'Mutation', 'rs113488022', (4, 13))	('proteins', 'Protein', (104, 112))
9300	30900145	In our hands, both solutions provided similar results in terms of the number of identified proteins; however, protein yield is higher with SDS/DTT.	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('SDS', 'Chemical', 'MESH:C032259', (139, 142))	('SDS/DTT', 'Var', (139, 146))	('protein yield', 'MPA', (110, 123))	('higher', 'PosReg', (127, 133))
9315	30900145	Protein reduction and alkylation were performed with 10 mM DTT and 20 mM iodoacetamide, respectively.	('alkylation', 'Var', (22, 32))	('iodoacetamide', 'Chemical', 'MESH:D007460', (73, 86))	('Protein', 'Protein', (0, 7))	('reduction', 'NegReg', (8, 17))
9387	30900145	Lysine acetylation affects the interaction of a modified protein with other molecules such as nucleic acids, or by opposing the occurrence of other PTMs targeting the same site, e.g.	('mole', 'Phenotype', 'HP:0003764', (76, 80))	('acetyl', 'Chemical', 'MESH:C011632', (7, 13))	('Lysine acetylation', 'Var', (0, 18))	('affects', 'Reg', (19, 26))	('interaction', 'Interaction', (31, 42))	('Lysine', 'Chemical', 'MESH:C114808', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('protein', 'Protein', (57, 64))
9389	30900145	There is an increasing number of studies linking dysregulation of lysine acetylation targets, interacting proteins thereof and controlling enzymes with the development and progression of cancer.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('men', 'Species', '9606', (163, 166))	('acetyl', 'Chemical', 'MESH:C011632', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('lysine', 'Chemical', 'MESH:C114808', (66, 72))	('dysregulation', 'Var', (49, 62))
9412	30900145	In several studies monitoring mutated BRAF DNA in plasma from melanoma patients, correlation has been found between levels of circulating DNA and response to treatment with BRAF inhibitors, as reviewed by Calapre et al..	('melanoma', 'Disease', (62, 70))	('men', 'Species', '9606', (163, 166))	('patients', 'Species', '9606', (71, 79))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('mutated', 'Var', (30, 37))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('BRAF', 'Gene', (38, 42))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
9421	30900145	single amino acid polymorphism, splice junction peptides and rare sequence variants.	('splice junction peptides', 'MPA', (32, 56))	('single amino acid polymorphism', 'Var', (0, 30))	('amino', 'Chemical', 'MESH:D000596', (7, 12))
9426	30900145	The inhibition of the mutated BRAF with selective inhibitors such as vemurafenib or dabrafenib has resulted in the reduction of MAPK signalling and regression of the disease.	('MAPK', 'molecular_function', 'GO:0004707', ('128', '132'))	('reduction', 'NegReg', (115, 124))	('dabrafenib', 'Chemical', 'MESH:C561627', (84, 94))	('MAPK signalling', 'biological_process', 'GO:0000165', ('128', '143'))	('BRAF', 'Gene', (30, 34))	('regression', 'CPA', (148, 158))	('mutated', 'Var', (22, 29))	('inhibition', 'NegReg', (4, 14))	('MAPK signalling', 'MPA', (128, 143))	('vemurafenib', 'Chemical', 'MESH:C551177', (69, 80))
9427	30900145	Unfortunately, most patients quickly develop resistance to drug treatment and the identification of proteins with somatic mutations that influence the development of resistance has largely remained elusive (Salemi et al.).	('develop', 'Reg', (37, 44))	('men', 'Species', '9606', (69, 72))	('mutations', 'Var', (122, 131))	('patients', 'Species', '9606', (20, 28))	('resistance', 'MPA', (45, 55))	('men', 'Species', '9606', (158, 161))
9430	30900145	Single amino acid variations were observed in a significant number of proteins.	('Single amino acid variations', 'Var', (0, 28))	('proteins', 'Protein', (70, 78))	('amino', 'Chemical', 'MESH:D000596', (7, 12))
9435	30900145	In fact, inhibitors of the PARP family of proteins are currently under preclinical and clinical evaluation as anticancer medication for melanoma and ovarian, breast and prostate cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast and prostate cancer', 'Disease', 'MESH:D001943', (158, 184))	('PARP', 'Gene', (27, 31))	('melanoma and ovarian', 'Disease', 'MESH:D010049', (136, 156))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('prostate cancer', 'Phenotype', 'HP:0012125', (169, 184))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('PARP', 'Gene', '142', (27, 31))	('inhibitors', 'Var', (9, 19))	('cancer', 'Disease', (114, 120))
9440	30900145	Compound co-expression networks based on correlation or partial correlation (Graphical Gaussian models, GGM) are also gaining momentum.	('GGM', 'Disease', 'MESH:C562602', (104, 107))	('men', 'Species', '9606', (128, 131))	('partial correlation', 'Var', (56, 75))	('GGM', 'Disease', (104, 107))
9441	30900145	differential expression, genetic mutations and differential methylation of the gene promoter region (Dimitrakopoulos et al.).	('expression', 'MPA', (13, 23))	('mutations', 'Var', (33, 42))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('methyl', 'Chemical', 'MESH:C031105', (60, 66))	('methylation', 'MPA', (60, 71))
9444	30900145	There is growing evidence demonstrating that DNA methylation may deeply alter protein expression and potentially be a causative event in cancer (Fernandez et al.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('DNA methylation', 'Var', (45, 60))	('methyl', 'Chemical', 'MESH:C031105', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('cancer', 'Disease', (137, 143))	('alter', 'Reg', (72, 77))	('methylation', 'Var', (49, 60))	('DNA methylation', 'biological_process', 'GO:0006306', ('45', '60'))	('protein expression', 'MPA', (78, 96))
9445	30900145	Hypermethylation has been associated to the silencing of genes and to decreased gene expression of tumour suppressors, whilst hypomethylation can potentially result in genomic instability and reactivation of oncogenes (Litovkin et al.	('hypomethylation', 'Var', (126, 141))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('Hypermethylation', 'Var', (0, 16))	('oncogenes', 'CPA', (208, 217))	('genes', 'Protein', (57, 62))	('tumour', 'Disease', (99, 105))	('decreased', 'NegReg', (70, 79))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('gene expression', 'biological_process', 'GO:0010467', ('80', '95'))	('methyl', 'Chemical', 'MESH:C031105', (130, 136))	('methyl', 'Chemical', 'MESH:C031105', (5, 11))	('result in', 'Reg', (158, 167))	('gene expression', 'MPA', (80, 95))	('reactivation', 'MPA', (192, 204))	('genomic instability', 'CPA', (168, 187))	('silencing of', 'MPA', (44, 56))
9446	30900145	Based on genome-wide studies, abnormal methylation patterns have been detected in melanoma patients, highlighting potential markers for disease progression and also providing an important strategy for tumour diagnosis and treatment (Fu et al.	('tumour', 'Disease', (201, 207))	('patients', 'Species', '9606', (91, 99))	('methylation', 'Var', (39, 50))	('men', 'Species', '9606', (227, 230))	('methyl', 'Chemical', 'MESH:C031105', (39, 45))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('tumour', 'Disease', 'MESH:D009369', (201, 207))
9457	30900145	The EGFR-TKIs exhibit high-affinity binding to the mutated EGFR tyrosine kinase domain and have been used as an approach to treat advanced NSCLC in Japanese populations (Dagogo-Jack et al.	('EGFR', 'Gene', '1956', (4, 8))	('EGFR', 'Gene', (59, 63))	('binding', 'molecular_function', 'GO:0005488', ('36', '43'))	('EGFR', 'Gene', (4, 8))	('tyrosine', 'Chemical', 'None', (64, 72))	('NSCLC', 'Disease', (139, 144))	('EGFR', 'molecular_function', 'GO:0005006', ('59', '63'))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('binding', 'Interaction', (36, 43))	('EGFR', 'molecular_function', 'GO:0005006', ('4', '8'))	('EGFR', 'Gene', '1956', (59, 63))	('mutated', 'Var', (51, 58))
9490	30900145	In mutant and wild-type patient tumours, a significantly different uptake of the drug in the mutated tumours was observed compared to the wild-type.	('tumours', 'Disease', 'MESH:D009369', (101, 108))	('mutant', 'Var', (3, 9))	('tumours', 'Disease', 'MESH:D009369', (32, 39))	('tumours', 'Disease', (32, 39))	('mutated', 'Var', (93, 100))	('uptake of the', 'MPA', (67, 80))	('tumours', 'Disease', (101, 108))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('patient', 'Species', '9606', (24, 31))	('uptake', 'biological_process', 'GO:0098657', ('67', '73'))	('uptake', 'biological_process', 'GO:0098739', ('67', '73'))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('different', 'Reg', (57, 66))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))
9491	30900145	Expression of the BRAF V600E was demonstrated to coincide with drug binding in areas of BRAF V600E expression (as demonstrated in Fig.	('BRAF', 'Gene', (88, 92))	('V600E', 'Mutation', 'p.V600E', (93, 98))	('BRAF', 'Var', (18, 22))	('drug binding', 'molecular_function', 'GO:0008144', ('63', '75'))	('V600E', 'Mutation', 'p.V600E', (23, 28))
9535	31336681	GNAQ Q209R Mutations Are Highly Specific for Circumscribed Choroidal Hemangioma Several tumors, including uveal melanoma, show somatic mutations of GNAQ/GNA11.	('Q209R', 'Mutation', 'rs121913492', (5, 10))	('GNAQ', 'Gene', '2776', (148, 152))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('uveal melanoma', 'Disease', (106, 120))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('GNAQ', 'Gene', (148, 152))	('GNA11', 'Gene', '2767', (153, 158))	('Choroidal Hemangioma', 'Phenotype', 'HP:0007872', (59, 79))	('Hemangioma', 'Phenotype', 'HP:0001028', (69, 79))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('Circumscribed Choroidal Hemangioma', 'Disease', (45, 79))	('Circumscribed Choroidal Hemangioma', 'Disease', 'MESH:D006391', (45, 79))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('GNA11', 'Gene', (153, 158))	('GNAQ', 'Gene', '2776', (0, 4))	('Q209R Mutations', 'Var', (5, 20))	('GNAQ', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))
9538	31336681	Here, we report the results of GNAQ/GNA11 mutation analysis in samples from circumscribed choroidal hemangioma.	('choroidal hemangioma', 'Phenotype', 'HP:0007872', (90, 110))	('choroidal hemangioma', 'Disease', (90, 110))	('GNA11', 'Gene', '2767', (36, 41))	('GNA11', 'Gene', (36, 41))	('GNAQ', 'Gene', '2776', (31, 35))	('mutation', 'Var', (42, 50))	('choroidal hemangioma', 'Disease', 'MESH:D006391', (90, 110))	('GNAQ', 'Gene', (31, 35))	('hemangioma', 'Phenotype', 'HP:0001028', (100, 110))
9539	31336681	Deep amplicon sequencing (Illumina MiSeq, San Diego, CA, USA) of positions R183 and Q209 of GNAQ and GNA11 in tissue samples from 33 patients with histologically diagnosed circumscribed choroidal hemangioma.	('GNA11', 'Gene', '2767', (101, 106))	('GNA11', 'Gene', (101, 106))	('Q209', 'Var', (84, 88))	('GNAQ', 'Gene', (92, 96))	('choroidal hemangioma', 'Disease', 'MESH:D006391', (186, 206))	('patients', 'Species', '9606', (133, 141))	('choroidal hemangioma', 'Phenotype', 'HP:0007872', (186, 206))	('choroidal hemangioma', 'Disease', (186, 206))	('Q209', 'Chemical', '-', (84, 88))	('GNAQ', 'Gene', '2776', (92, 96))	('hemangioma', 'Phenotype', 'HP:0001028', (196, 206))
9541	31336681	Samples from 28/33 patients (85%) showed a somatic missense mutation of GNAQ (c.626 A > G) predicted to result in p.Q209R.	('patients', 'Species', '9606', (19, 27))	('c.626 A > G', 'Var', (78, 89))	('GNAQ', 'Gene', '2776', (72, 76))	('p.Q209R', 'Mutation', 'rs121913492', (114, 121))	('p.Q209R', 'Var', (114, 121))	('c.626 A > G', 'Mutation', 'rs121913492', (78, 89))	('result in', 'Reg', (104, 113))	('GNAQ', 'Gene', (72, 76))
9542	31336681	Variants of GNAQ resulting in p.Q209 are characteristic for circumscribed choroidal hemangiomas.	('GNAQ', 'Gene', (12, 16))	('circumscribed choroidal hemangiomas', 'Disease', (60, 95))	('hemangioma', 'Phenotype', 'HP:0001028', (84, 94))	('circumscribed choroidal hemangiomas', 'Disease', 'MESH:D006391', (60, 95))	('p.Q209', 'Var', (30, 36))	('Q209', 'Chemical', '-', (32, 36))	('hemangiomas', 'Phenotype', 'HP:0001028', (84, 95))	('GNAQ', 'Gene', '2776', (12, 16))	('choroidal hemangioma', 'Phenotype', 'HP:0007872', (74, 94))	('choroidal hemangiomas', 'Phenotype', 'HP:0007872', (74, 95))
9543	31336681	It appears that the GNAQ mutation spectrum in this tumor is narrow, possibly restricted to p.Q209R.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('GNAQ', 'Gene', '2776', (20, 24))	('tumor', 'Disease', (51, 56))	('GNAQ', 'Gene', (20, 24))	('p.Q209R', 'Var', (91, 98))	('p.Q209R', 'Mutation', 'rs121913492', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
9544	31336681	Moreover, the spectrum is distinct from that of uveal melanoma, in which alterations resulting in p.Q209R are very rare.	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('uveal melanoma', 'Disease', (48, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('p.Q209R', 'Mutation', 'rs121913492', (98, 105))	('uveal melanoma', 'Disease', 'MESH:C536494', (48, 62))	('p.Q209R', 'Var', (98, 105))
9554	31336681	Oncogenic alterations of the GNAQ gene have been detected in endothelial cells within malformations at this location (p.R183Q, p.R183L, p.R183G in 8, 1, and 1 of 13 patients, respectively).	('p.R183G', 'Var', (136, 143))	('GNAQ', 'Gene', (29, 33))	('malformations', 'Disease', 'MESH:D000014', (86, 99))	('malformations', 'Disease', (86, 99))	('p.R183Q', 'Var', (118, 125))	('p.R183Q', 'Mutation', 'rs397514698', (118, 125))	('GNAQ', 'Gene', '2776', (29, 33))	('patients', 'Species', '9606', (165, 173))	('p.R183G', 'Mutation', 'p.R183G', (136, 143))	('p.R183L', 'Var', (127, 134))	('p.R183L', 'Mutation', 'p.R183L', (127, 134))
9555	31336681	It was postulated that GNAQ mutations in endothelial cells disturb the interaction between vascular and perivascular cells, which in turn contributes to the formation of capillary malformations with enlarged capillary lumens and ectatic venular morphology.	('capillary malformations', 'Disease', 'MESH:D000014', (170, 193))	('GNAQ', 'Gene', (23, 27))	('enlarged', 'PosReg', (199, 207))	('contributes to', 'Reg', (138, 152))	('interaction', 'Interaction', (71, 82))	('GNAQ', 'Gene', '2776', (23, 27))	('disturb', 'NegReg', (59, 66))	('capillary malformations', 'Phenotype', 'HP:0025104', (170, 193))	('capillary malformations', 'Disease', (170, 193))	('ectatic venular morphology', 'CPA', (229, 255))	('formation', 'biological_process', 'GO:0009058', ('157', '166'))	('mutations', 'Var', (28, 37))
9556	31336681	GNAQ and its paralogue GNA11 each encode an alpha subunit of a heterotrimeric G protein, a binding protein that remains in its active GTP-bound state when mutated.	('mutated', 'Var', (155, 162))	('GTP', 'Chemical', 'MESH:D006160', (134, 137))	('GNAQ', 'Gene', '2776', (0, 4))	('GNA11', 'Gene', '2767', (23, 28))	('GNA11', 'Gene', (23, 28))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('binding', 'molecular_function', 'GO:0005488', ('91', '98'))	('encode', 'Reg', (34, 40))	('GNAQ', 'Gene', (0, 4))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('63', '87'))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))
9558	31336681	Moreover, GNAQ or GNA11 mutations have been detected in several neural crest disorders such as Sturge Weber Syndrome (SWS).	('Sturge Weber Syndrome', 'Disease', (95, 116))	('GNAQ', 'Gene', '2776', (10, 14))	('Weber Syndrome', 'Phenotype', 'HP:0002277', (102, 116))	('SWS', 'Disease', 'MESH:D013341', (118, 121))	('crest disorders', 'Disease', (71, 86))	('GNAQ', 'Gene', (10, 14))	('detected', 'Reg', (44, 52))	('SWS', 'Disease', (118, 121))	('GNA11', 'Gene', (18, 23))	('mutations', 'Var', (24, 33))	('GNA11', 'Gene', '2767', (18, 23))	('crest disorders', 'Disease', 'MESH:D017675', (71, 86))
9560	31336681	In uveal melanoma, mutations are frequent (>80%) and result in alterations at position Q209 or R183 of GNAQ or GNA11.	('Q209', 'Chemical', '-', (87, 91))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('GNAQ', 'Gene', '2776', (103, 107))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('R183', 'Var', (95, 99))	('GNA11', 'Gene', (111, 116))	('GNAQ', 'Gene', (103, 107))	('GNA11', 'Gene', '2767', (111, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))	('alterations', 'Reg', (63, 74))
9561	31336681	A distinct profile is observed in affected tissues of SWS patients and of patients with non-syndromic port-wine stains where pathogenic mutations appear to be restricted to exon 4 of GNAQ.	('GNAQ', 'Gene', '2776', (183, 187))	('patients', 'Species', '9606', (74, 82))	('port-wine stains', 'Phenotype', 'HP:0001052', (102, 118))	('SWS', 'Disease', 'MESH:D013341', (54, 57))	('mutations', 'Var', (136, 145))	('SWS', 'Disease', (54, 57))	('GNAQ', 'Gene', (183, 187))	('patients', 'Species', '9606', (58, 66))
9570	31336681	We performed Sanger and deep amplicon sequencing of GNAQ and GNA11 specifically aimed at the positions coding for Q209 and R183 in DNA from all 33 tissue samples histologically diagnosed as CCH.	('Q209', 'Var', (114, 118))	('CCH', 'Disease', (190, 193))	('R183', 'Var', (123, 127))	('GNAQ', 'Gene', '2776', (52, 56))	('GNA11', 'Gene', (61, 66))	('Q209', 'Chemical', '-', (114, 118))	('GNA11', 'Gene', '2767', (61, 66))	('DNA', 'cellular_component', 'GO:0005574', ('131', '134'))	('DNA', 'Gene', (131, 134))	('GNAQ', 'Gene', (52, 56))	('CCH', 'Chemical', '-', (190, 193))
9571	31336681	In 28 of the 33 CCH biopsy samples (85%), a c.626A>G, p.Q209R variant in exon 5 of the GNAQ gene was identified.	('GNAQ', 'Gene', '2776', (87, 91))	('c.626A>G', 'Var', (44, 52))	('GNAQ', 'Gene', (87, 91))	('CCH', 'Chemical', '-', (16, 19))	('p.Q209R', 'Mutation', 'rs121913492', (54, 61))	('c.626A>G', 'Mutation', 'rs121913492', (44, 52))	('p.Q209R', 'Var', (54, 61))
9572	31336681	We confirmed the GNAQ p.Q209R mutations by Sanger sequencing using PCR primers located outside the first amplicon (GNAQ p.Q209long Table S1) in all samples with a variant allele fraction >0.2.	('GNAQ', 'Gene', (115, 119))	('Q209', 'Chemical', '-', (122, 126))	('GNAQ', 'Gene', (17, 21))	('GNAQ', 'Gene', '2776', (115, 119))	('p.Q209R', 'Mutation', 'rs121913492', (22, 29))	('p.Q209R', 'Var', (22, 29))	('GNAQ', 'Gene', '2776', (17, 21))	('Q209', 'Chemical', '-', (24, 28))	('variant', 'Var', (163, 170))
9573	31336681	We also performed Sanger sequencing of candidate regions GNA14 p.R205 and GNAQ p.G48 in all but one sample without a GNAQ p.Q209R mutation but could not detect any mutation.	('p.Q209R', 'Mutation', 'rs121913492', (122, 129))	('GNAQ', 'Gene', (74, 78))	('GNAQ', 'Gene', '2776', (117, 121))	('GNA14 p', 'Gene', (57, 64))	('GNA14 p', 'Gene', '9630', (57, 64))	('GNAQ', 'Gene', '2776', (74, 78))	('GNAQ', 'Gene', (117, 121))	('p.G48', 'Var', (79, 84))
9576	31336681	Similarly, the median tumor height in the mutation positive tumors (3.13 mm, range 1.39-5.2 mm) was smaller than in the negative tumors (4.3 mm, range 3-5.89 mm) (Figure 2b).	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('mutation', 'Var', (42, 50))	('smaller', 'NegReg', (100, 107))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (60, 65))	('tumors', 'Disease', (60, 66))
9578	31336681	Linear regression of tumor volume on variant allele fraction (VAF) showed a positive correlation (p = 0.0179, see Figure 3), whereas age at diagnosis was negatively correlated with the VAF (p = 0.000659) (Figure 4).	('variant', 'Var', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))
9593	31336681	In the remaining five samples, the signals for oncogenic alleles at GNAQ/GNA11 position Q209 or R183 were within the range of noise.	('GNA11 p', 'Gene', '2767', (73, 80))	('Q209', 'Var', (88, 92))	('GNAQ', 'Gene', (68, 72))	('Q209', 'Chemical', '-', (88, 92))	('GNA11 p', 'Gene', (73, 80))	('R183', 'Var', (96, 100))	('GNAQ', 'Gene', '2776', (68, 72))
9594	31336681	However, this does not exclude that, in some of these five samples, oncogenic activation of a G protein alpha subunit is present because of an alteration at another position of GNAQ/GNA11 or in a gene coding for another subunit, e.g., GNA14.	('GNA14', 'Gene', '9630', (235, 240))	('GNAQ', 'Gene', (177, 181))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('alteration', 'Var', (143, 153))	('GNA11', 'Gene', (182, 187))	('GNAQ', 'Gene', '2776', (177, 181))	('GNA14', 'Gene', (235, 240))	('GNA11', 'Gene', '2767', (182, 187))	('G protein', 'Protein', (94, 103))
9596	31336681	On the one hand, mutational activation in CCH appears to be restricted to one specific amino acid substitution (Q > R) at one site (p.Q209) in only one of the G protein alpha subunit genes (GNAQ), whereas other neoplasms with mutant GNAQ/GNA11 typically show some variation with respect to the kind and site of substitution and the gene.	('GNAQ', 'Gene', (190, 194))	('GNA11', 'Gene', (238, 243))	('mutant', 'Var', (226, 232))	('GNAQ', 'Gene', '2776', (233, 237))	('GNA11', 'Gene', '2767', (238, 243))	('neoplasms', 'Phenotype', 'HP:0002664', (211, 220))	('CCH', 'Chemical', '-', (42, 45))	('Q209', 'Chemical', '-', (134, 138))	('GNAQ', 'Gene', (233, 237))	('GNAQ', 'Gene', '2776', (190, 194))	('activation', 'PosReg', (28, 38))	('neoplasms', 'Disease', 'MESH:D009369', (211, 220))	('CCH', 'Disease', (42, 45))	('neoplasm', 'Phenotype', 'HP:0002664', (211, 219))	('neoplasms', 'Disease', (211, 220))	('mutational', 'Var', (17, 27))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))
9597	31336681	This result is supported by a recent report of Francis et al., who performed GNAQ/GNA11 mutation analysis in a series of neoplasms including two CCH samples.	('mutation', 'Var', (88, 96))	('GNA11', 'Gene', (82, 87))	('neoplasms', 'Disease', 'MESH:D009369', (121, 130))	('neoplasms', 'Disease', (121, 130))	('GNAQ', 'Gene', (77, 81))	('CCH', 'Chemical', '-', (145, 148))	('neoplasm', 'Phenotype', 'HP:0002664', (121, 129))	('GNA11', 'Gene', '2767', (82, 87))	('neoplasms', 'Phenotype', 'HP:0002664', (121, 130))	('GNAQ', 'Gene', '2776', (77, 81))
9598	31336681	In Table 2 of this paper, it is stated that both samples show a GNAQ p.Q209R variant.	('p.Q209R', 'Var', (69, 76))	('p.Q209R', 'Mutation', 'rs121913492', (69, 76))	('GNAQ', 'Gene', '2776', (64, 68))	('GNAQ', 'Gene', (64, 68))
9599	31336681	The second remarkable aspect is that this variant is rarely observed in other neoplasms with mutant GNAQ/GNA11.	('GNAQ', 'Gene', '2776', (100, 104))	('neoplasms', 'Phenotype', 'HP:0002664', (78, 87))	('GNA11', 'Gene', (105, 110))	('GNA11', 'Gene', '2767', (105, 110))	('mutant', 'Var', (93, 99))	('GNAQ', 'Gene', (100, 104))	('neoplasms', 'Disease', (78, 87))	('neoplasms', 'Disease', 'MESH:D009369', (78, 87))	('neoplasm', 'Phenotype', 'HP:0002664', (78, 86))
9600	31336681	For example, data available in COSMIC  show the presence of GNAQ p.Q209R in only 8/850 melanomas of the eye.	('GNAQ', 'Gene', (60, 64))	('p.Q209R', 'Var', (65, 72))	('p.Q209R', 'Mutation', 'rs121913492', (65, 72))	('GNAQ', 'Gene', '2776', (60, 64))	('melanomas of the eye', 'Disease', 'MESH:D008545', (87, 107))	('melanomas of the eye', 'Disease', (87, 107))	('melanomas', 'Phenotype', 'HP:0002861', (87, 96))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
9602	31336681	The observation that the proportion of tumor cells, defined as those cells carrying the mutation, increases with tumor volume (Figure 3) may be due to an increased proportion of normal cell that contaminate the sample in particular in biopsy of small tumors.	('tumor', 'Disease', (113, 118))	('mutation', 'Var', (88, 96))	('tumor', 'Disease', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Disease', (39, 44))	('small tumors', 'Disease', 'MESH:D058405', (245, 257))	('increases', 'PosReg', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('small tumors', 'Disease', (245, 257))
9604	31336681	Interestingly, the median age at diagnosis of CCH patients with GNAQ mutation, 50 years (range 27-77 years) was higher than that of the patients of the mutation negative cohort (35 years, range 7-58 years, Figure 2d).	('CCH', 'Disease', (46, 49))	('higher', 'PosReg', (112, 118))	('GNAQ', 'Gene', (64, 68))	('patients', 'Species', '9606', (50, 58))	('mutation', 'Var', (69, 77))	('patients', 'Species', '9606', (136, 144))	('CCH', 'Chemical', '-', (46, 49))	('GNAQ', 'Gene', '2776', (64, 68))
9605	31336681	In addition, duration of symptoms was shorter, and the tumor size was smaller in the mutation positive cases (Figure 2).	('mutation positive', 'Var', (85, 102))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('shorter', 'NegReg', (38, 45))	('smaller', 'NegReg', (70, 77))	('tumor', 'Disease', (55, 60))	('duration', 'MPA', (13, 21))
9610	31336681	Tumor entities that contribute to the cluster that is dominated by variants at GNAQ p.R183 are congenital tumors/vascular malformations such as port wine stains, portwine macrocheilia and Sturge-Weber Syndrome, non-Sturge Weber capillary malformations, and diffuse choroidal hemangioma, as well as phakomatosis pigmentvascularis.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('choroidal hemangioma', 'Phenotype', 'HP:0007872', (265, 285))	('congenital tumors/vascular malformations', 'Disease', (95, 135))	('variants', 'Var', (67, 75))	('macrocheilia', 'Disease', (171, 183))	('phakomatosis pigmentvascularis', 'Disease', 'MESH:D020752', (298, 328))	('Sturge-Weber Syndrome', 'Disease', (188, 209))	('phakomatosis pigmentvascularis', 'Disease', (298, 328))	('capillary malformations', 'Phenotype', 'HP:0025104', (228, 251))	('capillary malformations', 'Disease', 'MESH:D000014', (228, 251))	('port wine stains', 'Phenotype', 'HP:0001052', (144, 160))	('congenital tumors/vascular malformations', 'Disease', 'MESH:D000013', (95, 135))	('choroidal hemangioma', 'Disease', (265, 285))	('p.R183', 'Var', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('capillary malformations', 'Disease', (228, 251))	('hemangioma', 'Phenotype', 'HP:0001028', (275, 285))	('port wine stains', 'Disease', (144, 160))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('GNAQ', 'Gene', '2776', (79, 83))	('macrocheilia', 'Disease', 'MESH:D008556', (171, 183))	('Weber Syndrome', 'Phenotype', 'HP:0002277', (195, 209))	('GNAQ', 'Gene', (79, 83))	('choroidal hemangioma', 'Disease', 'MESH:D006391', (265, 285))
9611	31336681	These malformations/tumors are diagnosed early in life, and patients often show somatic mosaicism for the variant alleles in non-neoplastic cells.	('tumors', 'Disease', (20, 26))	('malformations', 'Disease', 'MESH:D000014', (6, 19))	('malformations', 'Disease', (6, 19))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('patients', 'Species', '9606', (60, 68))	('variant', 'Var', (106, 113))	('mosaicism', 'Var', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
9618	31336681	The fourth cluster (black bar) is characterized by mutations resulting in GNAQ p.Q209 only (exception cherry angioma with one R183G mutation).	('R183G', 'Var', (126, 131))	('angioma', 'Disease', (109, 116))	('GNAQ', 'Gene', (74, 78))	('R183G', 'Mutation', 'p.R183G', (126, 131))	('p.Q209', 'Var', (79, 85))	('GNAQ', 'Gene', '2776', (74, 78))	('Q209', 'Chemical', '-', (81, 85))	('angioma', 'Disease', 'MESH:D006391', (109, 116))
9620	31336681	In these acquired tumors, only GNAQ p.Q209H and p.Q209R mutations have been observed.	('GNAQ', 'Gene', '2776', (31, 35))	('p.Q209R', 'Var', (48, 55))	('p.Q209H', 'Mutation', 'p.Q209H', (36, 43))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('p.Q209R', 'Mutation', 'rs121913492', (48, 55))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('GNAQ', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
9621	31336681	In this group of tumors, CCHs occupy a prominent position because they exclusively exhibit Q209R mutations.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('CCH', 'Chemical', '-', (25, 28))	('exhibit', 'Reg', (83, 90))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('Q209R', 'Mutation', 'rs121913492', (91, 96))	('CCHs', 'Disease', (25, 29))	('Q209R', 'Var', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
9622	31336681	Interestingly, hepatic small vessel proliferation, which are part of the GNAQ p.Q209 cluster, can also show variants in GNA14.	('GNA14', 'Gene', (120, 125))	('GNAQ', 'Gene', '2776', (73, 77))	('small vessel proliferation', 'Phenotype', 'HP:0007850', (23, 49))	('Q209', 'Chemical', '-', (80, 84))	('GNA14', 'Gene', '9630', (120, 125))	('variants', 'Var', (108, 116))	('hepatic', 'MPA', (15, 22))	('GNAQ', 'Gene', (73, 77))
9623	31336681	Therefore, this gene is an interesting candidate for mutation analysis in variant negative CCHs.	('CCH', 'Chemical', '-', (91, 94))	('CCHs', 'Disease', (91, 95))	('variant', 'Var', (74, 81))	('negative', 'NegReg', (82, 90))
9624	31336681	For example, variants affecting p.R183 activate the p38 MAP Kinase pathway, whereas those at p.Q209 in addition activate c-Jun N-terminal kinase (JNK) and ERK.	('ERK', 'molecular_function', 'GO:0004707', ('155', '158'))	('variants', 'Var', (13, 21))	('c-Jun N-terminal', 'MPA', (121, 137))	('p38', 'Gene', (52, 55))	('p.R183', 'Var', (32, 38))	('MAP', 'molecular_function', 'GO:0004239', ('56', '59'))	('ERK', 'Pathway', (155, 158))	('p38', 'Gene', '1432', (52, 55))	('Q209', 'Chemical', '-', (95, 99))	('JNK', 'molecular_function', 'GO:0004705', ('146', '149'))	('activate', 'PosReg', (39, 47))	('activate', 'PosReg', (112, 120))
9628	31336681	However, for neoplastic cells the broader spectrum of downstream effects mediated by p.Q209 alterations is of selective advantage and this is also reflected by the predominance of p.Q209 alterations in neoplasms of the adult.	('Q209', 'Chemical', '-', (87, 91))	('Q209', 'Chemical', '-', (182, 186))	('neoplasm', 'Phenotype', 'HP:0002664', (202, 210))	('p.Q209 alterations', 'Var', (85, 103))	('neoplasms', 'Disease', (202, 211))	('neoplasms', 'Disease', 'MESH:D009369', (202, 211))	('alterations', 'Var', (92, 103))	('neoplasms', 'Phenotype', 'HP:0002664', (202, 211))	('p.Q209 alterations', 'Var', (180, 198))
9631	31336681	For validation of GNAQ p.Q209R mutation, we repeated the PCR using a second primer set located outside the first amplicon (GNAQ Q209long, Table S2).	('Q209', 'Chemical', '-', (128, 132))	('GNAQ', 'Gene', (123, 127))	('GNAQ', 'Gene', '2776', (18, 22))	('GNAQ', 'Gene', '2776', (123, 127))	('GNAQ', 'Gene', (18, 22))	('p.Q209R', 'Mutation', 'rs121913492', (23, 30))	('p.Q209R', 'Var', (23, 30))	('Q209', 'Chemical', '-', (25, 29))
9632	31336681	In brief, reads specific for GNA11 and GNAQ were separated and trimmed to a string of 20 bases including the region of interest (R183 and Q209).	('GNA11', 'Gene', (29, 34))	('Q209', 'Chemical', '-', (138, 142))	('GNAQ', 'Gene', (39, 43))	('GNA11', 'Gene', '2767', (29, 34))	('R183', 'Var', (129, 133))	('GNAQ', 'Gene', '2776', (39, 43))	('Q209', 'Var', (138, 142))
9633	31336681	To prove the quantitative nature of deep amplicon sequencing technology, we have generated a standard curve by analyzing various ratios of mutant and normal alleles adjusted by mixing tumor DNA with a heterozygous GNAQ c.626A>T mutation and normal DNA (see Supplementary Materials Figure S4).	('c.626A>T', 'Var', (219, 227))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('GNAQ', 'Gene', (214, 218))	('c.626A>T', 'Mutation', 'rs121913492', (219, 227))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('GNAQ', 'Gene', '2776', (214, 218))	('DNA', 'cellular_component', 'GO:0005574', ('248', '251'))	('DNA', 'cellular_component', 'GO:0005574', ('190', '193'))
9635	31336681	The narrow mutation spectrum of CCH, which is restricted to GNAQ p.Q209R, supports us in establishing the diagnosis of CCH.	('GNAQ', 'Gene', (60, 64))	('CCH', 'Chemical', '-', (119, 122))	('p.Q209R', 'Var', (65, 72))	('CCH', 'Disease', (119, 122))	('p.Q209R', 'Mutation', 'rs121913492', (65, 72))	('GNAQ', 'Gene', '2776', (60, 64))	('CCH', 'Chemical', '-', (32, 35))	('CCH', 'Gene', (32, 35))
9636	31336681	The following are available online at , Figure S1: Visual acuity at initial and last presentation, Figure S2: Dot plot showing relationship of age at diagnosis vs. duration of symptoms in mutation positive CCH patients, Figure S3: Distribution of the variant allele fractions over the CCH samples (n = 33), Figure S4: Standard curve, Table S1: Oligonucleotides for deep amplicon sequencing on Illumina MiSeq, Table S2: Number of samples with GNAQ/GNA11 mutations in different tumor entities.	('mutations', 'Var', (453, 462))	('GNAQ', 'Gene', (442, 446))	('tumor', 'Disease', 'MESH:D009369', (476, 481))	('CCH', 'Chemical', '-', (206, 209))	('Oligonucleotides', 'Chemical', 'MESH:D009841', (344, 360))	('CCH', 'Chemical', '-', (285, 288))	('tumor', 'Phenotype', 'HP:0002664', (476, 481))	('GNA11', 'Gene', '2767', (447, 452))	('GNA11', 'Gene', (447, 452))	('tumor', 'Disease', (476, 481))	('patients', 'Species', '9606', (210, 218))	('GNAQ', 'Gene', '2776', (442, 446))
9649	31336679	Cutaneous and conjunctival melanomas are characterised by mutations activating the MAPK (including BRAF activating mutations in around half of cutaneous cases), PI3K and receptor tyrosine kinase pathways.	('mutations', 'Var', (58, 67))	('PI3K', 'molecular_function', 'GO:0016303', ('161', '165'))	('activating', 'PosReg', (68, 78))	('receptor tyrosine kinase pathways', 'Pathway', (170, 203))	('BRAF', 'Gene', (99, 103))	('MAPK', 'Gene', (83, 87))	('conjunctival melanomas', 'Disease', (14, 36))	('BRAF', 'Gene', '673', (99, 103))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (14, 35))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (14, 36))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('MAPK', 'molecular_function', 'GO:0004707', ('83', '87'))	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))
9650	31336679	A fraction of mucosal melanomas presents with KIT mutations that are targetable with KIT inhibitors.	('KIT', 'molecular_function', 'GO:0005020', ('85', '88'))	('mutations', 'Var', (50, 59))	('KIT', 'molecular_function', 'GO:0005020', ('46', '49'))	('KIT', 'Gene', (46, 49))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('mucosal melanomas', 'Disease', (14, 31))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('mucosal melanomas', 'Disease', 'MESH:D008545', (14, 31))
9652	31336679	The first driver event is an oncogenic activating mutation in either GNAQ, GNA11, PLCB4 or CYSLTR2, which activates the Galphaq pathway.	('Galphaq', 'Gene', (120, 127))	('Galphaq', 'Gene', '2776', (120, 127))	('PLCB4', 'Gene', (82, 87))	('GNA11', 'Gene', (75, 80))	('GNAQ', 'Gene', '2776', (69, 73))	('GNA11', 'Gene', '2767', (75, 80))	('activates', 'PosReg', (106, 115))	('CYSLTR2', 'Gene', '57105', (91, 98))	('GNAQ', 'Gene', (69, 73))	('PLCB4', 'Gene', '5332', (82, 87))	('CYSLTR2', 'Gene', (91, 98))	('mutation', 'Var', (50, 58))
9653	31336679	The second genetic event consists of either: (i) the bi-allelic inactivation of BAP1 (~60% of cases), a gene located on chromosome 3p21 that is potentially involved in chromatin organisation; (ii) a change-of-function heterozygous mutation in SF3B1 (~25% of cases), a subunit of the spliceosome; or (iii) a heterozygous mutation in EIF1AX (~15% of cases), a gene involved in the initiation of mRNA translation.	('translation', 'biological_process', 'GO:0006412', ('398', '409'))	('SF3B1', 'Gene', (243, 248))	('BAP1', 'Gene', '8314', (80, 84))	('chromatin organisation', 'biological_process', 'GO:0006325', ('168', '190'))	('spliceosome', 'cellular_component', 'GO:0005681', ('283', '294'))	('chromatin', 'cellular_component', 'GO:0000785', ('168', '177'))	('SF3B1', 'Gene', '23451', (243, 248))	('EIF1AX', 'Gene', (332, 338))	('EIF1AX', 'Gene', '1964', (332, 338))	('change-of-function', 'Reg', (199, 217))	('BAP1', 'Gene', (80, 84))	('chromosome', 'cellular_component', 'GO:0005694', ('120', '130'))	('mutation', 'Var', (231, 239))
9654	31336679	In contrast to mucosal and acral melanomas, which present with a high number of structural genetic variations, UM is characterised by typical chromosomal copy number variation profiles associated with varying prognosis: Monosomy 3 and 8q gain are associated with poor survival while 6p gain predicts a favourable outcome.	('poor survival', 'CPA', (263, 276))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('UM', 'Phenotype', 'HP:0007716', (111, 113))	('acral melanomas', 'Disease', 'MESH:D008545', (27, 42))	('acral melanomas', 'Phenotype', 'HP:0012060', (27, 42))	('gain', 'PosReg', (238, 242))	('Monosomy 3', 'Var', (220, 230))	('acral melanomas', 'Disease', (27, 42))
9657	31336679	Interestingly, tumour-infiltrating lymphocytes (TILs) are infrequently observed in primary UM and are associated with chromosome 3 loss, loss of BAP1 expression and poor prognosis.	('expression', 'MPA', (150, 160))	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('chromosome', 'Gene', (118, 128))	('tumour', 'Disease', (15, 21))	('loss', 'NegReg', (131, 135))	('chromosome', 'cellular_component', 'GO:0005694', ('118', '128'))	('BAP1', 'Gene', '8314', (145, 149))	('UM', 'Phenotype', 'HP:0007716', (91, 93))	('loss', 'Var', (137, 141))	('BAP1', 'Gene', (145, 149))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))
9670	31336679	Epigenetic dysregulations are among the most encouraging targets in UM, especially in BAP1-mutated tumours, due to the role of BAP1 in chromatin remodelling.	('BAP1', 'Gene', (127, 131))	('Epigenetic dysregulations', 'Var', (0, 25))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('135', '156'))	('BAP1', 'Gene', '8314', (86, 90))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('chromatin', 'cellular_component', 'GO:0000785', ('135', '144'))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('BAP1', 'Gene', (86, 90))	('tumours', 'Disease', (99, 106))	('UM', 'Phenotype', 'HP:0007716', (68, 70))	('BAP1', 'Gene', '8314', (127, 131))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
9678	31336679	Basic research on UM, for instance, contributed to the description of the downstream Galphaq pathway and led to the discovery of recurrent splicing abnormalities, resulting in new therapeutic avenues not only in UM but also in other diseases.	('UM', 'Phenotype', 'HP:0007716', (18, 20))	('splicing', 'biological_process', 'GO:0045292', ('139', '147'))	('Galphaq', 'Gene', (85, 92))	('Galphaq', 'Gene', '2776', (85, 92))	('splicing abnormalities', 'Var', (139, 161))	('UM', 'Phenotype', 'HP:0007716', (212, 214))
9683	31336679	UM is a rare tumour but large randomised phase III trials are feasible as proven before with the SUMIT and the EORTC 18021 trials in the metastatic setting, and the FOTEADJ trial in the adjuvant setting (NCT01974752, NCT00110123, NCT02843386).	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('NCT00110123', 'Var', (217, 228))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('tumour', 'Disease', (13, 19))	('NCT01974752', 'Var', (204, 215))	('UM', 'Phenotype', 'HP:0007716', (98, 100))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
9732	31213897	miR-142-3p suppresses uveal melanoma by targeting CDC25C, TGFbetaR1, GNAQ, WASL, and RAC1 Purpose: Uveal melanoma (UM) is the most frequent metastatic ocular tumor in adults.	('GNAQ', 'Gene', '2776', (69, 73))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('uveal melanoma', 'Phenotype', 'HP:0007716', (22, 36))	('suppresses', 'NegReg', (11, 21))	('GNAQ', 'Gene', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('TGFbetaR1', 'Gene', '7046', (58, 67))	('UM', 'Phenotype', 'HP:0007716', (115, 117))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('TGFbetaR', 'molecular_function', 'GO:0005024', ('58', '66'))	('TGFbetaR1', 'Gene', (58, 67))	('WASL', 'Gene', '8976', (75, 79))	('CDC25C', 'Gene', (50, 56))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('melanoma', 'Disease', (28, 36))	('tumor', 'Disease', (158, 163))	('targeting', 'Reg', (40, 49))	('ocular tumor', 'Phenotype', 'HP:0100012', (151, 163))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('CDC25C', 'Gene', '995', (50, 56))	('uveal melanoma', 'Disease', 'MESH:C536494', (22, 36))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('uveal melanoma', 'Disease', (22, 36))	('miR-142-3p', 'Var', (0, 10))	('WASL', 'Gene', (75, 79))
9734	31213897	miR-142-3p was one of the 10 most downregulated miRNAs.	('miR-142-3p', 'Chemical', '-', (0, 10))	('miR-142-3p', 'Var', (0, 10))	('downregulated', 'NegReg', (34, 47))
9736	31213897	The results of the MTS, clone formation, scratch wound, transwell assays, and in vivo biofluorescence imaging showed that miR-142-3p overexpression significantly inhibited cell proliferation, migration, and invasiveness.	('cell proliferation', 'biological_process', 'GO:0008283', ('172', '190'))	('invasiveness', 'CPA', (207, 219))	('cell proliferation', 'CPA', (172, 190))	('formation', 'biological_process', 'GO:0009058', ('30', '39'))	('overexpression', 'PosReg', (133, 147))	('miR-142-3p', 'Var', (122, 132))	('inhibited', 'NegReg', (162, 171))	('miR-142-3p', 'Chemical', '-', (122, 132))	('migration', 'CPA', (192, 201))
9738	31213897	Cell cycle and EdU analysis showed that miR-142-3p overexpression induced G1/G2 cell cycle arrest and reduced DNA synthesis in UM cells.	('DNA synthesis', 'biological_process', 'GO:0071897', ('110', '123'))	('DNA synthesis', 'MPA', (110, 123))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (80, 97))	('arrest', 'Disease', 'MESH:D006323', (91, 97))	('EdU', 'Chemical', '-', (15, 18))	('miR-142-3p', 'Var', (40, 50))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('miR-142-3p', 'Chemical', '-', (40, 50))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('80', '97'))	('DNA', 'cellular_component', 'GO:0005574', ('110', '113'))	('reduced', 'NegReg', (102, 109))	('UM', 'Phenotype', 'HP:0007716', (127, 129))	('overexpression', 'PosReg', (51, 65))	('arrest', 'Disease', (91, 97))
9739	31213897	Microarray analysis showed that miR-142-3p mainly regulates the TGFbeta signaling pathway, and those in which MAPK and PI3K-Akt are constituents.	('Akt', 'Gene', (124, 127))	('PI3K', 'molecular_function', 'GO:0016303', ('119', '123'))	('signaling pathway', 'biological_process', 'GO:0007165', ('72', '89'))	('miR-142-3p', 'Var', (32, 42))	('miR-142-3p', 'Chemical', '-', (32, 42))	('TGFbeta signaling pathway', 'Pathway', (64, 89))	('MAPK', 'molecular_function', 'GO:0004707', ('110', '114'))	('regulates', 'Reg', (50, 59))	('Akt', 'Gene', '207', (124, 127))
9742	31213897	Conclusion: miR-143-3p is a potential therapeutic target to treat UM since overriding its declines in expression that occur in this disease reversed the pathogenesis of this disease.	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('declines', 'Disease', (90, 98))	('pathogenesis', 'biological_process', 'GO:0009405', ('153', '165'))	('miR-143-3p', 'Var', (12, 22))	('declines', 'Disease', 'MESH:D060825', (90, 98))
9749	31213897	The association between changes in miR-142-3p expression level and tumor size and metastasis has made it possible to use it as a marker of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('miR-142-3p', 'Chemical', '-', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('miR-142-3p', 'Gene', (35, 45))	('expression level', 'MPA', (46, 62))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('metastasis', 'CPA', (82, 92))	('tumor', 'Disease', (67, 72))	('changes', 'Var', (24, 31))
9750	31213897	Both in vitro and in vivo experiments have revealed that miR-142-3p upregulation can effectively inhibit the proliferation or migration of breast, cervical, and hepatocellular carcinoma cells.	('hepatocellular carcinoma', 'Disease', (161, 185))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (161, 185))	('inhibit', 'NegReg', (97, 104))	('cervical', 'Disease', (147, 155))	('miR-142-3p', 'Var', (57, 67))	('breast', 'Disease', (139, 145))	('miR-142-3p', 'Chemical', '-', (57, 67))	('upregulation', 'PosReg', (68, 80))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (161, 185))	('proliferation', 'CPA', (109, 122))	('migration', 'CPA', (126, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
9756	31213897	Our rationale for characterizing the possible role of miR-142-3p in this malignancy stemmed from miRNA microarray analysis showing that miR-142-3p was one of the most downregulated miRNAs in UM cells.	('malignancy', 'Disease', 'MESH:D009369', (73, 83))	('UM', 'Phenotype', 'HP:0007716', (191, 193))	('malignancy', 'Disease', (73, 83))	('miR-142-3p', 'Var', (136, 146))	('miR-142-3p', 'Chemical', '-', (54, 64))	('miR-142-3p', 'Chemical', '-', (136, 146))	('downregulated', 'NegReg', (167, 180))
9757	31213897	This finding coupled with the fact that UM frequently harbors mutation of GNAQ, which is a predicted target gene of miR-142-3p, prompted us to determine if it is another epigenetic modulator of UM development.	('GNAQ', 'Gene', (74, 78))	('mutation', 'Var', (62, 70))	('UM', 'Phenotype', 'HP:0007716', (40, 42))	('GNAQ', 'Gene', '2776', (74, 78))	('UM', 'Phenotype', 'HP:0007716', (194, 196))	('miR-142-3p', 'Chemical', '-', (116, 126))
9780	31213897	To obtain transfection in their suprachoroidal space, the in vivo-jetPEI delivery reagent (Polyplus-Transfection, Strasbourg, France) was injected every 7 days for 2 weeks to deliver 1 mug of either miR-142-3p or NC.	('Polyplus-Transfection', 'Disease', (91, 112))	('Polyplus-Transfection', 'Disease', 'None', (91, 112))	('mug', 'molecular_function', 'GO:0043739', ('185', '188'))	('miR-142-3p', 'Var', (199, 209))	('miR-142-3p', 'Chemical', '-', (199, 209))
9784	31213897	The remaining samples were used for extracting RNA and analyzing the expression levels of miR-142-3p in tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('miR-142-3p', 'Var', (90, 100))	('miR-142-3p', 'Chemical', '-', (90, 100))	('tumor', 'Disease', (104, 109))	('RNA', 'cellular_component', 'GO:0005562', ('47', '50'))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
9797	31213897	Combined the microarray and bioinformatic analysis, it is evident that miR-142-3p is unique for its expression pattern and the potential to regulate GNAQ.	('GNAQ', 'Gene', (149, 153))	('regulate', 'Reg', (140, 148))	('miR-142-3p', 'Var', (71, 81))	('GNAQ', 'Gene', '2776', (149, 153))	('miR-142-3p', 'Chemical', '-', (71, 81))
9798	31213897	RT-qPCR was performed to validate if there is an association between tumorigenesis and the miR-142-3p expression levels in the UM cell lines and clinical specimens.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('clinical', 'Species', '191496', (145, 153))	('miR-142-3p', 'Var', (91, 101))	('miR-142-3p', 'Chemical', '-', (91, 101))	('expression levels', 'MPA', (102, 119))	('UM', 'Phenotype', 'HP:0007716', (127, 129))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
9803	31213897	The MTS assay results showed that SP6.5 and M17 cell proliferation was suppressed by overexpression of miR-142-3p (Figure 2A).	('miR-142-3p', 'Chemical', '-', (103, 113))	('overexpression', 'PosReg', (85, 99))	('miR-142-3p', 'Var', (103, 113))	('cell proliferation', 'biological_process', 'GO:0008283', ('48', '66'))	('suppressed', 'NegReg', (71, 81))
9804	31213897	In addition, overexpression of miR-142-3p significantly reduced colony formation compared to the NC group (Figure 2B and C).	('miR-142-3p', 'Var', (31, 41))	('miR-142-3p', 'Chemical', '-', (31, 41))	('reduced', 'NegReg', (56, 63))	('colony formation', 'CPA', (64, 80))	('formation', 'biological_process', 'GO:0009058', ('71', '80'))
9805	31213897	Cell cycle analysis revealed that miR-142-3p overexpression increased cell numbers in the G1 and G2 phases accompanied with a corresponding decrease in cells in the S phase (Figure 2D).	('overexpression increased', 'PosReg', (45, 69))	('G2 phases', 'CPA', (97, 106))	('S phase', 'biological_process', 'GO:0051320', ('165', '172'))	('decrease', 'NegReg', (140, 148))	('cells in the S phase', 'CPA', (152, 172))	('miR-142-3p', 'Var', (34, 44))	('miR-142-3p', 'Chemical', '-', (34, 44))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))
9807	31213897	Similarly, DNA synthesis evaluation with the ethynyl-deoxyuridine (EdU) incorporation method showed that ectopic expression of miR-142-3p notably reduced the proportion of cells with newly replicated DNA (EdU-positive cells) compared with the NC (Figure 2E, P<0.01).	('ethynyl-deoxyuridine', 'Chemical', '-', (45, 65))	('EdU', 'Chemical', '-', (67, 70))	('DNA synthesis', 'biological_process', 'GO:0071897', ('11', '24'))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('EdU', 'Chemical', '-', (205, 208))	('reduced', 'NegReg', (146, 153))	('DNA', 'cellular_component', 'GO:0005574', ('200', '203'))	('cells with newly replicated', 'CPA', (172, 199))	('miR-142-3p', 'Var', (127, 137))	('miR-142-3p', 'Chemical', '-', (127, 137))
9808	31213897	To further assess whether or not increases in apoptosis also accounted for miR-142-3p-mediated declines in cell growth, we carried out Hoechst staining, Annexin-V/PI double-staining, and the caspase 3/7 activity assay.	('cell growth', 'CPA', (107, 118))	('cell growth', 'biological_process', 'GO:0016049', ('107', '118'))	('Annexin-V', 'Gene', '308', (153, 162))	('Annexin-V', 'Gene', (153, 162))	('Hoechst', 'Chemical', '-', (135, 142))	('caspase 3', 'Gene', (191, 200))	('miR-142-3p', 'Chemical', '-', (75, 85))	('caspase 3', 'Gene', '836', (191, 200))	('declines', 'Disease', (95, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))	('miR-142-3p-mediated', 'Var', (75, 94))	('declines', 'Disease', 'MESH:D060825', (95, 103))
9809	31213897	However, changes in apoptosis incidence were not involved because there were no significant differences in nuclear morphology, apoptotic cell ratio, caspase 3/7 activity, or sensitivity to doxorubicin between miR-142-3p transfected cells and their NC counterpart (Figure 3).	('nuclear morphology', 'biological_process', 'GO:0006997', ('107', '125'))	('miR-142-3p transfected', 'Var', (209, 231))	('caspase 3', 'Gene', (149, 158))	('caspase 3', 'Gene', '836', (149, 158))	('apoptosis', 'biological_process', 'GO:0097194', ('20', '29'))	('doxorubicin', 'Chemical', 'MESH:D004317', (189, 200))	('apoptosis', 'biological_process', 'GO:0006915', ('20', '29'))	('miR-142-3p', 'Chemical', '-', (209, 219))	('activity', 'MPA', (161, 169))
9811	31213897	The scratch wound assay results indicated that miR-142-3p transfection of UM cells slowed wound closure relative to NC group (Figure 4A).	('miR-142-3p transfection', 'Var', (47, 70))	('miR-142-3p', 'Chemical', '-', (47, 57))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('wound closure', 'CPA', (90, 103))	('slowed', 'NegReg', (83, 89))
9812	31213897	Moreover, the number of the miR-142-3p transfected cells migrating to the underside of Transwell chambers decreased in comparison to the NC treated group (Figure 4B).	('decreased', 'NegReg', (106, 115))	('miR-142-3p', 'Chemical', '-', (28, 38))	('miR-142-3p transfected', 'Var', (28, 50))
9813	31213897	Similarly, the miR-142-3p transfected cells displayed diminished invasive capacity relative to the NC cells (Figure 4C).	('diminished', 'NegReg', (54, 64))	('miR-142-3p', 'Chemical', '-', (15, 25))	('invasive capacity', 'CPA', (65, 82))	('miR-142-3p transfected', 'Var', (15, 37))
9814	31213897	Taken together, ectopic miR-142-3p expression hampers both UM cell migratory and invasive activity.	('invasive activity', 'CPA', (81, 98))	('hampers', 'NegReg', (46, 53))	('ectopic miR-142-3p expression', 'Var', (16, 45))	('UM cell migratory', 'CPA', (59, 76))	('miR-142-3p', 'Chemical', '-', (24, 34))	('UM', 'Phenotype', 'HP:0007716', (59, 61))
9816	31213897	After 3 weeks, the tumor size of miR-142-3p overexpressed xenografts was dramatically reduced compared to the NC xenografts (Figure 5).	('reduced', 'NegReg', (86, 93))	('miR-142-3p', 'Var', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('miR-142-3p', 'Chemical', '-', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('overexpressed', 'PosReg', (44, 57))
9817	31213897	The miR-142-3p expression level was markedly increased in the miR-142-3p transfected xenografts compared to the NC group (Figure S2).	('miR-142-3p', 'Chemical', '-', (62, 72))	('miR-142-3p', 'Chemical', '-', (4, 14))	('increased', 'PosReg', (45, 54))	('miR-142-3p expression level', 'MPA', (4, 31))	('miR-142-3p transfected', 'Var', (62, 84))
9818	31213897	Combined with previous in vitro results, our data demonstrated that miR-142-3p plays a suppressor role in UM growth.	('miR-142-3p', 'Var', (68, 78))	('miR-142-3p', 'Chemical', '-', (68, 78))	('UM growth', 'CPA', (106, 115))	('UM', 'Phenotype', 'HP:0007716', (106, 108))
9819	31213897	Transcriptomic microarray analysis was performed to compare gene expression profile changes in UM cells transfected with miR-142-3p with those transfected with the irrelevant NC.	('miR-142-3p', 'Chemical', '-', (121, 131))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('gene expression profile', 'MPA', (60, 83))	('gene expression', 'biological_process', 'GO:0010467', ('60', '75'))	('miR-142-3p', 'Var', (121, 131))
9820	31213897	The results of the KEGG and gene ontology (GO) enrichment analysis indicate that miR-142-3p regulates multiple signaling pathways including MAPK, TGF-beta, Rap1, cGMP-PKG, and PI3K-Akt, and several cellular functions including endocytosis, focal adhesion, actin cytoskeleton, tight junction, and adherens junction (Figure 6B).	('regulates', 'Reg', (92, 101))	('MAPK', 'Gene', (140, 144))	('cGMP-PKG', 'Gene', (162, 170))	('gene ontology', 'biological_process', 'GO:0003673', ('28', '41'))	('signaling pathways', 'Pathway', (111, 129))	('Akt', 'Gene', (181, 184))	('actin cytoskeleton', 'MPA', (256, 274))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('256', '274'))	('tight junction', 'MPA', (276, 290))	('focal adhesion', 'MPA', (240, 254))	('PI3K', 'molecular_function', 'GO:0016303', ('176', '180'))	('TGF-beta', 'Gene', (146, 154))	('tight junction', 'cellular_component', 'GO:0070160', ('276', '290'))	('Akt', 'Gene', '207', (181, 184))	('adherens junction', 'MPA', (296, 313))	('miR-142-3p', 'Chemical', '-', (81, 91))	('endocytosis', 'MPA', (227, 238))	('endocytosis', 'biological_process', 'GO:0006897', ('227', '238'))	('adherens junction', 'cellular_component', 'GO:0005912', ('296', '313'))	('Rap1', 'Gene', '5906', (156, 160))	('focal adhesion', 'cellular_component', 'GO:0005925', ('240', '254'))	('miR-142-3p', 'Var', (81, 91))	('Rap1', 'Gene', (156, 160))	('signaling', 'biological_process', 'GO:0023052', ('111', '120'))	('MAPK', 'molecular_function', 'GO:0004707', ('140', '144'))	('PKG', 'molecular_function', 'GO:0004692', ('167', '170'))
9822	31213897	Total ERK1/2 and Akt protein levels were unchanged after overexpression of miR-142-3p, but p-ERK1/2 and p-Akt expression levels decreased in both SP6.5 and M17 cells (Figure 6C).	('Akt', 'Gene', (106, 109))	('ERK1', 'molecular_function', 'GO:0004707', ('93', '97'))	('Akt', 'Gene', '207', (17, 20))	('Akt', 'Gene', '207', (106, 109))	('ERK1', 'molecular_function', 'GO:0004707', ('6', '10'))	('miR-142-3p', 'Var', (75, 85))	('ERK1/2', 'MPA', (6, 12))	('decreased', 'NegReg', (128, 137))	('miR-142-3p', 'Chemical', '-', (75, 85))	('p-ERK1/2', 'MPA', (91, 99))	('Akt', 'Gene', (17, 20))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))
9825	31213897	As shown in Figure S3A, all 3' UTRs of the target genes possess complementary binding sites for miR-142-3p, and the seed sequence is highly conserved: ACACUAC (A).	('ACACUAC', 'Gene', (151, 158))	('miR-142-3p', 'Chemical', '-', (96, 106))	('binding', 'molecular_function', 'GO:0005488', ('78', '85'))	('binding sites', 'Interaction', (78, 91))	('ACACUAC', 'Chemical', '-', (151, 158))	('miR-142-3p', 'Var', (96, 106))
9827	31213897	The results of the luciferase reporter gene assay demonstrated that transient transfection of miR-142-3p yielded a significant reduction in luciferase activity for all vectors compared with the NC (Figure 7A, P<0.01).	('miR-142-3p', 'Var', (94, 104))	('luciferase activity', 'molecular_function', 'GO:0047077', ('140', '159'))	('miR-142-3p', 'Chemical', '-', (94, 104))	('luciferase', 'Enzyme', (140, 150))	('luciferase activity', 'molecular_function', 'GO:0045289', ('140', '159'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('140', '159'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('140', '159'))	('reduction', 'NegReg', (127, 136))	('luciferase activity', 'molecular_function', 'GO:0050248', ('140', '159'))	('activity', 'MPA', (151, 159))
9828	31213897	Furthermore, mutating the seed sequences in the reporter vectors abolished the interactions between miR-142-3p and 3' UTRs of the five candidates.	('miR-142-3p', 'Chemical', '-', (100, 110))	('interactions', 'Interaction', (79, 91))	('miR-142-3p', 'Gene', (100, 110))	('abolished', 'NegReg', (65, 74))	('mutating', 'Var', (13, 21))
9830	31213897	MiR-142-3p overexpression in UM cells significantly reduced the mRNA levels of CDC25C and WASL (Figure 7C), and notably reduced the protein levels of CDC25C, TGFbetaR1, GNAQ, WASL, and RAC1 (Figure 7D).	('CDC25C', 'Gene', (150, 156))	('reduced', 'NegReg', (52, 59))	('MiR-142-3p', 'Var', (0, 10))	('WASL', 'Gene', (90, 94))	('CDC25C', 'Gene', '995', (150, 156))	('CDC25C', 'Gene', (79, 85))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('WASL', 'Gene', (175, 179))	('RAC1', 'Gene', (185, 189))	('CDC25C', 'Gene', '995', (79, 85))	('RAC1', 'Gene', '5879', (185, 189))	('TGFbetaR', 'molecular_function', 'GO:0005024', ('158', '166'))	('overexpression', 'PosReg', (11, 25))	('reduced', 'NegReg', (120, 127))	('protein levels', 'MPA', (132, 146))	('GNAQ', 'Gene', '2776', (169, 173))	('WASL', 'Gene', '8976', (90, 94))	('TGFbetaR1', 'Gene', '7046', (158, 167))	('WASL', 'Gene', '8976', (175, 179))	('GNAQ', 'Gene', (169, 173))	('UM', 'Phenotype', 'HP:0007716', (29, 31))	('TGFbetaR1', 'Gene', (158, 167))
9831	31213897	Therefore, CDC25C, TGFbetaR1, GNAQ, WASL, and RAC1 are direct gene targets of miR-142-3p in UM cells.	('TGFbetaR', 'molecular_function', 'GO:0005024', ('19', '27'))	('TGFbetaR1', 'Gene', (19, 28))	('CDC25C', 'Gene', (11, 17))	('GNAQ', 'Gene', (30, 34))	('RAC1', 'Gene', (46, 50))	('TGFbetaR1', 'Gene', '7046', (19, 28))	('WASL', 'Gene', (36, 40))	('WASL', 'Gene', '8976', (36, 40))	('miR-142-3p', 'Var', (78, 88))	('UM', 'Phenotype', 'HP:0007716', (92, 94))	('CDC25C', 'Gene', '995', (11, 17))	('miR-142-3p', 'Chemical', '-', (78, 88))	('GNAQ', 'Gene', '2776', (30, 34))	('RAC1', 'Gene', '5879', (46, 50))
9832	31213897	To confirm the identity of the aforementioned gene targets of miR-142-3p, we determined if their downregulation had the same effect as ectopic expression of this miRNA on responses controlled by these targets in UM cells.	('responses', 'MPA', (171, 180))	('miR-142-3p', 'Chemical', '-', (62, 72))	('downregulation', 'NegReg', (97, 111))	('miR-142-3p', 'Var', (62, 72))	('UM', 'Phenotype', 'HP:0007716', (212, 214))
9833	31213897	In addition, cell migration was significantly decreased following si-TGFbetaR1, si-GNAQ, si-WASL, or si-RAC1 transfection (Figure 8C).	('cell migration', 'CPA', (13, 27))	('RAC1', 'Gene', '5879', (104, 108))	('RAC1', 'Gene', (104, 108))	('transfection', 'Var', (109, 121))	('GNAQ', 'Gene', '2776', (83, 87))	('TGFbetaR1', 'Gene', '7046', (69, 78))	('WASL', 'Gene', '8976', (92, 96))	('decreased', 'NegReg', (46, 55))	('WASL', 'Gene', (92, 96))	('GNAQ', 'Gene', (83, 87))	('TGFbetaR', 'molecular_function', 'GO:0005024', ('69', '77'))	('cell migration', 'biological_process', 'GO:0016477', ('13', '27'))	('TGFbetaR1', 'Gene', (69, 78))
9834	31213897	As an important cell cycle-related protein, CDC25C is probably a key target through which miR-142-3p induces G1/G2 cell cycle arrest in UM cells.	('arrest', 'Disease', (126, 132))	('CDC25C', 'Gene', (44, 50))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (115, 132))	('miR-142-3p', 'Var', (90, 100))	('miR-142-3p', 'Chemical', '-', (90, 100))	('induces', 'PosReg', (101, 108))	('CDC25C', 'Gene', '995', (44, 50))	('arrest', 'Disease', 'MESH:D006323', (126, 132))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('UM', 'Phenotype', 'HP:0007716', (136, 138))	('cell cycle', 'biological_process', 'GO:0007049', ('16', '26'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('115', '132'))
9835	31213897	The results of cell cycle analysis confirmed this conjecture because CDC25C knockdown reduced cell cycle transitions through the G1/S checkpoint.	('reduced', 'NegReg', (86, 93))	('knockdown', 'Var', (76, 85))	('cell cycle transitions through the G1/S checkpoint', 'CPA', (94, 144))	('cell cycle', 'biological_process', 'GO:0007049', ('15', '25'))	('cell cycle', 'biological_process', 'GO:0007049', ('94', '104'))	('CDC25C', 'Gene', (69, 75))	('G1/S checkpoint', 'biological_process', 'GO:0000075', ('129', '144'))	('CDC25C', 'Gene', '995', (69, 75))
9836	31213897	As RAC1 also regulates cell cycle progression, this mode of action exists in UM cells because its knockdown led to G1 phase arrest (Figure 8D).	('RAC1', 'Gene', (3, 7))	('arrest', 'Disease', 'MESH:D006323', (124, 130))	('knockdown', 'Var', (98, 107))	('G1 phase', 'biological_process', 'GO:0051318', ('115', '123'))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('arrest', 'Disease', (124, 130))	('regulates', 'Reg', (13, 22))	('cell cycle', 'biological_process', 'GO:0007049', ('23', '33'))	('cell cycle progression', 'CPA', (23, 45))	('RAC1', 'Gene', '5879', (3, 7))
9839	31213897	Here, we discovered that miR-142-3p was dramatically decreased in both UM cell lines and clinical specimens whereas its overexpression caused G1/G2 cell cycle arrest and suppressed DNA replication in UM cells.	('miR-142-3p', 'Chemical', '-', (25, 35))	('DNA', 'cellular_component', 'GO:0005574', ('181', '184'))	('suppressed', 'NegReg', (170, 180))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (148, 165))	('arrest', 'Disease', 'MESH:D006323', (159, 165))	('overexpression', 'PosReg', (120, 134))	('DNA replication', 'CPA', (181, 196))	('UM', 'Phenotype', 'HP:0007716', (200, 202))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('148', '165'))	('arrest', 'Disease', (159, 165))	('UM', 'Phenotype', 'HP:0007716', (71, 73))	('DNA replication', 'biological_process', 'GO:0006260', ('181', '196'))	('miR-142-3p', 'Var', (25, 35))	('clinical', 'Species', '191496', (89, 97))
9848	31213897	Changes in GNAQ expression are highly susceptible to UM formation.	('GNAQ', 'Gene', '2776', (11, 15))	('UM', 'Phenotype', 'HP:0007716', (53, 55))	('Changes', 'Var', (0, 7))	('GNAQ', 'Gene', (11, 15))	('formation', 'biological_process', 'GO:0009058', ('56', '65'))
9854	31213897	Downregulating CDC25C, TGFbetaR1, GNAQ, WASL, or RAC1 mimicked the effects of miR-142-3p overexpression which inhibiting UM cell proliferation and/or migration.	('cell proliferation', 'biological_process', 'GO:0008283', ('124', '142'))	('UM cell proliferation', 'CPA', (121, 142))	('WASL', 'Gene', (40, 44))	('miR-142-3p', 'Var', (78, 88))	('migration', 'CPA', (150, 159))	('Downregulating', 'NegReg', (0, 14))	('RAC1', 'Gene', (49, 53))	('CDC25C', 'Gene', (15, 21))	('UM', 'Phenotype', 'HP:0007716', (121, 123))	('CDC25C', 'Gene', '995', (15, 21))	('RAC1', 'Gene', '5879', (49, 53))	('GNAQ', 'Gene', '2776', (34, 38))	('overexpression', 'PosReg', (89, 103))	('WASL', 'Gene', '8976', (40, 44))	('TGFbetaR1', 'Gene', '7046', (23, 32))	('GNAQ', 'Gene', (34, 38))	('TGFbetaR', 'molecular_function', 'GO:0005024', ('23', '31'))	('TGFbetaR1', 'Gene', (23, 32))	('inhibiting', 'NegReg', (110, 120))	('miR-142-3p', 'Chemical', '-', (78, 88))
9859	31213897	Our findings indicate that miR-142-3p acts as a tumor suppressor by targeting CDC25C, TGFbetaR1, GNAQ, WASL, and RAC1.	('RAC1', 'Gene', (113, 117))	('miR-142-3p', 'Chemical', '-', (27, 37))	('CDC25C', 'Gene', (78, 84))	('RAC1', 'Gene', '5879', (113, 117))	('WASL', 'Gene', (103, 107))	('targeting', 'Reg', (68, 77))	('CDC25C', 'Gene', '995', (78, 84))	('miR-142-3p', 'Var', (27, 37))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('48', '64'))	('TGFbetaR', 'molecular_function', 'GO:0005024', ('86', '94'))	('tumor', 'Disease', (48, 53))	('GNAQ', 'Gene', '2776', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor suppressor', 'biological_process', 'GO:0051726', ('48', '64'))	('GNAQ', 'Gene', (97, 101))	('WASL', 'Gene', '8976', (103, 107))	('TGFbetaR1', 'Gene', '7046', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('TGFbetaR1', 'Gene', (86, 95))
9879	28246385	As expected, C918 cells generated larger tumors than OCM1 cells in the grafted eyes and subcutaneous foci (Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('OCM1', 'Species', '83984', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('C918 cells', 'Var', (13, 23))	('larger', 'PosReg', (34, 40))	('subcutaneous foci', 'Phenotype', 'HP:0001482', (88, 105))
9880	28246385	Within 13 days after grafting, C918-derived tumors (T) completely disrupted the eye structure though the residual remnants of the lens (L), the retina (R), and the sclera (arrows) were still visible (Fig.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('eye structure', 'CPA', (80, 93))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('disrupted', 'NegReg', (66, 75))	('C918-derived', 'Var', (31, 43))
9882	28246385	These observations suggest that the rapid growing C918-derived tumors might reduce nutrient supply to the normal eye tissues and aggressively invade into the nearby normal tissues, resulting in degeneration or resolving of the eye.	('C918-derived', 'Var', (50, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('nutrient supply', 'MPA', (83, 98))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('reduce', 'NegReg', (76, 82))	('degeneration', 'Disease', (194, 206))	('degeneration', 'Disease', 'MESH:D009410', (194, 206))
9883	28246385	However, the subcutaneously grafted tumors were all capsulized and no local invasion was found though C918-grafted tumors manifested larger than OCM1-grafted ones (Fig.	('C918-grafted', 'Var', (102, 114))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('OCM1', 'Species', '83984', (145, 149))
9911	28246385	To functionally analyze how ZEB1 regulates UM progression we overexpressed ZEB1 in ZEB1low OCM1 cells (OCM1-ZEB1) and knocked it down in both ZEB1high C918 (C918-ZEB1sh) and ZEB1low OCM1 cells (OCM1-ZEB1sh) by transduction of a full-length human ZEB1 gene and a short hairpin RNA (shRNA) against human ZEB1 mRNA, respectively (see detail in Methods).	('OCM1', 'Species', '83984', (194, 198))	('transduction', 'biological_process', 'GO:0009293', ('210', '222'))	('RNA', 'cellular_component', 'GO:0005562', ('276', '279'))	('human', 'Species', '9606', (296, 301))	('human', 'Species', '9606', (240, 245))	('OCM1', 'Species', '83984', (91, 95))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('OCM1', 'Species', '83984', (103, 107))	('OCM1', 'Species', '83984', (182, 186))	('ZEB1', 'Gene', (75, 79))	('transduction', 'Reg', (210, 222))	('knocked', 'Var', (118, 125))
9914	28246385	4G-I) while TWIST1 was significantly downregulated in both OCM1 and C918 (Fig.	('downregulated', 'NegReg', (37, 50))	('OCM1', 'Species', '83984', (59, 63))	('TWIST1', 'Gene', (12, 18))	('C918', 'Var', (68, 72))
9915	28246385	We did not observe any cell morphology change in OCM1-ZEB1 and in C918-ZEB1sh as compared to their parental cells though CDH1 showed upregulation in C918-ZEB1sh and OCM1-ZEB1sh (Fig.	('C918-ZEB1sh', 'Var', (149, 160))	('CDH1', 'Gene', (121, 125))	('OCM1', 'Species', '83984', (165, 169))	('upregulation', 'PosReg', (133, 145))	('OCM1', 'Species', '83984', (49, 53))	('CDH1', 'Gene', '999', (121, 125))
9916	28246385	By contrast, knockdown of ZEB1 significantly reduced CDH2 in the both cell lines (Fig.	('reduced', 'NegReg', (45, 52))	('CDH2', 'Gene', (53, 57))	('CDH2', 'Gene', '1000', (53, 57))	('ZEB1', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))
9921	28246385	Normal melanocytes are pigmented cells, genes involving in pigment synthesis like MITF, TYR, and TYRP1 are typical differentiation makers for these cells, we therefore examined whether these pigment synthesis genes together with BAP1, another important differentiation gene whose loss-of-function mutation is frequently related to UM transformation, would be downregulated in UM and MetUM as compared to NUM.	('TYR', 'Chemical', 'MESH:D014443', (97, 100))	('UM', 'Phenotype', 'HP:0007716', (405, 407))	('mutation', 'Var', (297, 305))	('UM', 'Phenotype', 'HP:0007716', (331, 333))	('TYR', 'Chemical', 'MESH:D014443', (88, 91))	('UM', 'Phenotype', 'HP:0007716', (376, 378))	('UM transformation', 'Disease', (331, 348))	('pigment synthesis', 'biological_process', 'GO:0046148', ('191', '208'))	('UM', 'Phenotype', 'HP:0007716', (386, 388))	('pigment synthesis', 'biological_process', 'GO:0046148', ('59', '76'))	('downregulated', 'NegReg', (359, 372))	('BAP1', 'Gene', (229, 233))	('loss-of-function', 'NegReg', (280, 296))
9922	28246385	Also as expected, these genes were expressed much higher in OCM1 than in C918 (Fig.	('expressed', 'MPA', (35, 44))	('OCM1', 'Species', '83984', (60, 64))	('higher', 'PosReg', (50, 56))	('OCM1', 'Var', (60, 64))
9924	28246385	2I), and knockdown of ZEB1 significantly reduced the expression of BAP1, MITF, TYR, and TYRP1 (Fig.	('reduced', 'NegReg', (41, 48))	('TYR', 'Gene', (79, 82))	('knockdown', 'Var', (9, 18))	('TYRP1', 'Gene', (88, 93))	('TYR', 'Chemical', 'MESH:D014443', (88, 91))	('ZEB1', 'Gene', (22, 26))	('MITF', 'Gene', (73, 77))	('expression', 'MPA', (53, 63))	('TYR', 'Chemical', 'MESH:D014443', (79, 82))	('BAP1', 'Gene', (67, 71))
9926	28246385	As demonstrated early, ZEB1high C918-grafted tumors grew much larger than ZEB1low OCM1-grafted tumors (Fig.	('grew', 'CPA', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('OCM1', 'Species', '83984', (82, 86))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('ZEB1high C918-grafted', 'Var', (23, 44))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
9927	28246385	Indeed upon overexpression of ZEB1, OCM1-ZEB1-grafted tumors became visible 5 days earlier than OCM1-vector control (Fig.	('OCM1', 'Species', '83984', (36, 40))	('OCM1', 'Species', '83984', (96, 100))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('OCM1-ZEB1-grafted', 'Var', (36, 53))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
9928	28246385	5A,B), while knockdown of ZEB1 significantly reduced the growth of OCM1-ZEB1sh-grafted tumors though C918-ZEB1sh-grafted tumors only manifested a slight decrease in tumor size as compared to vector controls (Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('knockdown', 'Var', (13, 22))	('OCM1', 'Species', '83984', (67, 71))	('tumor', 'Disease', (121, 126))	('tumors', 'Disease', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('growth', 'MPA', (57, 63))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (87, 92))	('C918-ZEB1sh-grafted', 'Var', (101, 120))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('decrease', 'NegReg', (153, 161))	('tumor', 'Disease', (165, 170))	('reduced', 'NegReg', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (165, 170))
9931	28246385	As a result, the Ki67 positive cells were mostly those OCM1-ZEB1sh or C918-ZEB1sh cells with less EGFP thereby more ZEB1 in culture (Fig.	('C918-ZEB1sh', 'Var', (70, 81))	('Ki67', 'Var', (17, 21))	('OCM1', 'Species', '83984', (55, 59))
9932	28246385	To examine how ZEB1 enhances UM cell division thereby tumor growth we checked the expression levels of cell cycling-related genes and found that all detected CDKIs, except for CDKN2B (P15 INK4B), including CDKN1A (P21 CIP1), CDKN1B (P27 KIP1), CDKN2A (P16 INK4A /P14 ARF), CDKN2C (P18 INK4C), and CDKN2D (P19 INK4D) together with the nuclear phosphoprotein RB1 were underexpressed in UM and MetUM compared to NUM (Fig.	('CDKN2A', 'Gene', '1029', (244, 250))	('P18 INK4C', 'Var', (281, 290))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('UM', 'Phenotype', 'HP:0007716', (29, 31))	('cell division', 'biological_process', 'GO:0051301', ('32', '45'))	('underexpressed', 'NegReg', (366, 380))	('CDKN1A', 'Gene', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('UM', 'Phenotype', 'HP:0007716', (410, 412))	('P19 INK4D', 'Var', (305, 314))	('UM', 'Phenotype', 'HP:0007716', (384, 386))	('UM', 'Phenotype', 'HP:0007716', (394, 396))	('CDKN1A', 'Gene', '1026', (206, 212))	('P19', 'cellular_component', 'GO:0070743', ('305', '308'))	('tumor', 'Disease', (54, 59))	('CDKN2A', 'Gene', (244, 250))	('P16 INK4A /P14 ARF', 'Var', (252, 270))
9934	28246385	As speculated, knockdown of ZEB1 upregulated CDKN1A (P21 CIP1) and CDKN2A (P16 INK4A) (Fig.	('upregulated', 'PosReg', (33, 44))	('CDKN2A', 'Gene', (67, 73))	('knockdown', 'Var', (15, 24))	('CDKN2A', 'Gene', '1029', (67, 73))	('CDKN1A', 'Gene', (45, 51))	('CDKN1A', 'Gene', '1026', (45, 51))	('ZEB1', 'Gene', (28, 32))
9935	28246385	6I and J), suggesting that both P16INK4A/RB1 and TP53/P21CIP1 tumor suppression pathways are deregulated with high expression of ZEB1 in UM cells leading to rapid cell proliferation with no risk of apoptotic cell death as downregulation of the above CDKIs would phosphorylate and inactivate RB1 so as to promote cell cycling.	('leading to', 'Reg', (146, 156))	('downregulation', 'NegReg', (222, 236))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('promote', 'PosReg', (304, 311))	('rapid cell proliferation', 'CPA', (157, 181))	('tumor', 'Disease', (62, 67))	('TP53/P21CIP1', 'Gene', (49, 61))	('P16INK4A/RB1', 'Gene', (32, 44))	('cell cycling', 'CPA', (312, 324))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('198', '218'))	('cell proliferation', 'biological_process', 'GO:0008283', ('163', '181'))	('RB1', 'Gene', (291, 294))	('UM', 'Phenotype', 'HP:0007716', (137, 139))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('inactivate', 'Var', (280, 290))
9938	28246385	In addition, in melanomas of both uveal and cutaneous origins a G protein-related signaling pathway is frequently activated through a gain-of-function mutation of either large GTPase alpha subunit like GNA11 and GNAQ or their homologous:small GTPase like NRAS and its downstream effector BRAF.	('signaling pathway', 'biological_process', 'GO:0007165', ('82', '99'))	('G protein-related signaling pathway', 'Pathway', (64, 99))	('melanomas of both uveal', 'Disease', (16, 39))	('activated', 'PosReg', (114, 123))	('melanomas of both uveal', 'Disease', 'MESH:C536494', (16, 39))	('mutation', 'Var', (151, 159))	('gain-of-function', 'PosReg', (134, 150))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanomas', 'Phenotype', 'HP:0002861', (16, 25))	('GNA11', 'Gene', (202, 207))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
9939	28246385	Interestingly, we found that BRAF and GNA11 were transcriptionally upregulated in UM and MetUM while GNAQ in both OCM1 and C918 and BRAF in OCM1 were also expressed higher as compared to NUM (Fig.	('C918', 'Var', (123, 127))	('BRAF', 'Gene', (29, 33))	('UM', 'Phenotype', 'HP:0007716', (188, 190))	('OCM1', 'Species', '83984', (140, 144))	('GNA11', 'Gene', (38, 43))	('UM', 'Phenotype', 'HP:0007716', (92, 94))	('UM', 'Phenotype', 'HP:0007716', (82, 84))	('upregulated', 'PosReg', (67, 78))	('OCM1', 'Species', '83984', (114, 118))
9940	28246385	6K-M), suggesting that although or GNA11/GNAQ or NRAS/BRAF mutations are often found in uveal and cutaneous melanomas, respectively, the overall elevated transcription levels of the above genes position UM cells in a high potential readiness for extracellular signals for cell proliferation regardless of their gain-of-function mutation status.	('elevated', 'PosReg', (145, 153))	('cell proliferation', 'biological_process', 'GO:0008283', ('272', '290'))	('melanomas', 'Phenotype', 'HP:0002861', (108, 117))	('extracellular', 'cellular_component', 'GO:0005576', ('246', '259'))	('cutaneous melanomas', 'Disease', (98, 117))	('NRAS/BRAF', 'Gene', (49, 58))	('transcription levels', 'MPA', (154, 174))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (98, 116))	('mutations', 'Var', (59, 68))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (98, 117))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (98, 117))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('transcription', 'biological_process', 'GO:0006351', ('154', '167'))	('UM', 'Phenotype', 'HP:0007716', (203, 205))
9942	28246385	As shown above, ZEB1high C918-derived tumors destroyed the eye structure while ZEB1low OCM1-derived tumors did not in 13 days after cell grafting (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('ZEB1high C918-derived', 'Var', (16, 37))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('eye structure', 'CPA', (59, 72))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('C918-derived', 'Var', (25, 37))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('OCM1', 'Species', '83984', (87, 91))	('destroyed', 'NegReg', (45, 54))
9943	28246385	1C,D), suggesting that ZEB1 might increase UM cell invasiveness as with that of carcinoma cells.	('carcinoma', 'Disease', 'MESH:D002277', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('ZEB1', 'Var', (23, 27))	('UM cell invasiveness', 'CPA', (43, 63))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('carcinoma', 'Disease', (80, 89))	('increase', 'PosReg', (34, 42))
9947	28246385	More importantly, knockdown of ZEB1 reduced or completely diminished the invasive capacity of C918 and OCM1 UM cells, respectively, in the grafted eyes within 25 days after the intravitreal injection (Fig.	('knockdown', 'Var', (18, 27))	('invasive capacity', 'CPA', (73, 90))	('ZEB1', 'Gene', (31, 35))	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('diminished', 'NegReg', (58, 68))	('OCM1', 'Species', '83984', (103, 107))	('reduced', 'NegReg', (36, 43))
9948	28246385	Furthermore, high expression of ZEB1 is shown to be significantly correlated to tumor scleral invasion and metastasis (Fig.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('metastasis', 'CPA', (107, 117))	('correlated', 'Reg', (66, 76))	('ZEB1', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('high', 'Var', (13, 17))	('tumor', 'Disease', (80, 85))
9949	28246385	These proteinase genes were expressed much higher in ZEB1high C918 than ZEB1low OCM1 (Fig.	('proteinase', 'Enzyme', (6, 16))	('higher', 'PosReg', (43, 49))	('proteinase', 'molecular_function', 'GO:0004175', ('6', '16'))	('expressed', 'MPA', (28, 37))	('ZEB1high C918', 'Var', (53, 66))	('OCM1', 'Species', '83984', (80, 84))
9952	28246385	Knockdown of ZEB1 increased CDH1 and FN1 while decreased PFN1 expression in cultured UM cells (Figs 3E,L and 8C,D), suggesting that ZEB1 enhances loosening cell-cell contacts by transcriptionally repressing CDH1 and FN1 and promotes cell active locomotion by upregulating PFN1 expression.	('PFN1', 'Gene', (272, 276))	('cell active locomotion', 'CPA', (233, 255))	('enhances', 'PosReg', (137, 145))	('loosening cell-cell contacts', 'CPA', (146, 174))	('FN1', 'Gene', (216, 219))	('PFN1', 'Gene', (57, 61))	('locomotion', 'biological_process', 'GO:0040011', ('245', '255'))	('CDH1', 'Gene', '999', (28, 32))	('ZEB1', 'Var', (132, 136))	('decreased', 'NegReg', (47, 56))	('expression', 'MPA', (277, 287))	('increased', 'PosReg', (18, 27))	('CDH1', 'Gene', (28, 32))	('promotes', 'PosReg', (224, 232))	('expression', 'MPA', (62, 72))	('CDH1', 'Gene', '999', (207, 211))	('CDH1', 'Gene', (207, 211))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('upregulating', 'PosReg', (259, 271))
9955	28246385	8F) while knockdown of ZEB1 in both OCM1 and C918 significantly reduced their cell mobility accordingly (Fig.	('C918', 'Var', (45, 49))	('cell mobility accordingly', 'CPA', (78, 103))	('ZEB1', 'Gene', (23, 27))	('reduced', 'NegReg', (64, 71))	('knockdown', 'Var', (10, 19))	('OCM1', 'Species', '83984', (36, 40))
9956	28246385	And indeed, within 25 days after cell IV injection, ZEB1high C918-grafted tumors disseminated to the liver as compared to no dissemination in the ZEB1low OCM1-grafted mice though knockdown of ZEB1 in C918 seemingly had no significant effect on metastasis (Fig.	('metastasis', 'CPA', (244, 254))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('OCM1', 'Species', '83984', (154, 158))	('C918-grafted', 'Var', (61, 73))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('ZEB1high C918-grafted', 'Var', (52, 73))	('mice', 'Species', '10090', (167, 171))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
9965	28246385	In response to the critical shortening of the telomeres caused by constant cell division, another tumor suppressor TP53 would be activated to promote transcription of CDKIs particularly the P21CIP1 to activate RB1 to slow cycling down, and to prevent TP53 protein degradation and to transcript apoptosis-related genes like BAX leading to cell death.	('TP53 protein', 'Protein', (251, 263))	('tumor suppressor', 'biological_process', 'GO:0051726', ('98', '114'))	('slow cycling down', 'MPA', (217, 234))	('protein', 'cellular_component', 'GO:0003675', ('256', '263'))	('tumor', 'Disease', (98, 103))	('slow cycling', 'Phenotype', 'HP:0002067', (217, 229))	('transcription', 'MPA', (150, 163))	('apoptosis-related', 'Gene', (294, 311))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('activate', 'PosReg', (201, 209))	('promote', 'PosReg', (142, 149))	('RB1', 'Gene', (210, 213))	('transcript', 'MPA', (283, 293))	('prevent', 'NegReg', (243, 250))	('P21CIP1', 'Var', (190, 197))	('CDKIs', 'Gene', (167, 172))	('protein degradation', 'biological_process', 'GO:0030163', ('256', '275'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('BAX', 'Gene', (323, 326))	('transcription', 'biological_process', 'GO:0006351', ('150', '163'))	('cell death', 'biological_process', 'GO:0008219', ('338', '348'))	('cell division', 'biological_process', 'GO:0051301', ('75', '88'))	('apoptosis', 'biological_process', 'GO:0097194', ('294', '303'))	('protein', 'Protein', (256, 263))	('apoptosis', 'biological_process', 'GO:0006915', ('294', '303'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('98', '114'))
9972	28246385	We have noticed that both OCM1 and C918 cells may change their morphology to a small round amoeboid-like morphology at confluence particularly when the confluent culture is scratched (Fig.	('C918', 'Var', (35, 39))	('change', 'Reg', (50, 56))	('OCM1', 'Species', '83984', (26, 30))	('morphology', 'MPA', (63, 73))
10018	28246385	The tumor samples were sorted from high to low based on the expression levels of ZEB1, and divided into two groups: the top one third of tumor samples were assigned as ZEB1-high (n = 21 for GSE22138, n = 18 for GSE44299) whereas the bottom two third of tumor samples were assigned as ZEB1-low (n = 42 for GSE22138, n = 35 for GSE44299).	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('GSE22138', 'Var', (190, 198))	('tumor', 'Disease', (253, 258))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('GSE22138', 'Var', (305, 313))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
10108	25970771	Loss of the deubiquitylase BAP1 alters class I histone deacetylase expression and sensitivity of mesothelioma cells to HDAC inhibitors Histone deacetylases are important targets for cancer therapeutics, but their regulation is poorly understood.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('alters', 'Reg', (32, 38))	('deubiquitylase', 'molecular_function', 'GO:0004843', ('12', '26'))	('BAP1', 'Gene', (27, 31))	('regulation', 'biological_process', 'GO:0065007', ('213', '223'))	('mesothelioma', 'Disease', 'MESH:D008654', (97, 109))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('mesothelioma', 'Disease', (97, 109))	('cancer', 'Disease', (182, 188))	('class', 'MPA', (39, 44))	('expression', 'MPA', (67, 77))	('HDAC', 'Gene', (119, 123))	('Loss', 'Var', (0, 4))	('HDAC', 'Gene', '9734', (119, 123))	('BAP1', 'Gene', '8314', (27, 31))
10112	25970771	Endogenous HDAC2 directly correlates with BAP1 across a panel of lung cancer cell lines, and is downregulated in mesothelioma cell lines with genetic BAP1 inactivation.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('BAP1', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mesothelioma', 'Disease', 'MESH:D008654', (113, 125))	('inactivation', 'Var', (155, 167))	('BAP1', 'Gene', (42, 46))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('HDAC2', 'Gene', (11, 16))	('downregulated', 'NegReg', (96, 109))	('mesothelioma', 'Disease', (113, 125))
10127	25970771	In breast or osteoscarcoma cells HDAC1, but not HDAC2, was required for proliferation and its depletion led to cell cycle arrest and apoptosis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (111, 128))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('led to', 'Reg', (104, 110))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('111', '128'))	('apoptosis', 'CPA', (133, 142))	('breast or osteoscarcoma', 'Disease', 'MESH:D001943', (3, 26))	('breast or osteoscarcoma', 'Disease', (3, 26))	('arrest', 'Disease', 'MESH:D006323', (122, 128))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('depletion', 'Var', (94, 103))	('arrest', 'Disease', (122, 128))
10148	25970771	Whilst USP33 or USPL1 depletion increased the HDAC2/HDAC1 ratio, we identified USP27X and the tumor suppressor BAP1 as DUBs whose depletion lead to the most significant decrease in the HDAC2/HDAC1 ratio.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('94', '110'))	('USP33', 'Gene', '23032', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('decrease', 'NegReg', (169, 177))	('HDAC2/HDAC1 ratio', 'MPA', (46, 63))	('USPL1', 'Gene', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('USP', 'molecular_function', 'GO:0051748', ('7', '10'))	('depletion', 'Var', (22, 31))	('USPL1', 'Gene', '10208', (16, 21))	('tumor', 'Disease', (94, 99))	('USP27X', 'Gene', (79, 85))	('USP', 'molecular_function', 'GO:0051748', ('79', '82'))	('USP33', 'Gene', (7, 12))	('increased', 'PosReg', (32, 41))	('HDAC2/HDAC1 ratio', 'MPA', (185, 202))	('tumor suppressor', 'biological_process', 'GO:0051726', ('94', '110'))	('USP27X', 'Gene', '389856', (79, 85))
10153	25970771	BAP1 knockdown elicited this same switch in HDAC2/HDAC1 expression in two other NSCLC cell lines (Figure 2C), which endogenously express these HDACs at different levels (Figure 1B).	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('BAP1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('HDAC', 'Gene', (50, 54))	('NSCLC', 'Disease', (80, 85))	('HDAC', 'Gene', '9734', (50, 54))	('HDAC', 'Gene', (44, 48))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('HDAC', 'Gene', (143, 147))	('HDAC', 'Gene', '9734', (44, 48))	('elicited', 'Reg', (15, 23))	('HDAC', 'Gene', '9734', (143, 147))	('SCLC', 'Phenotype', 'HP:0030357', (81, 85))
10154	25970771	As loss of BAP1 function is implicated in a high proportion of mesothelioma, we next asked whether we could recapitulate this effect in MSTO-211H cells, which were derived from a grade 4 biphasic mesothelioma and retain wild-type BAP1 expression.	('loss', 'Var', (3, 7))	('rad', 'Gene', '6236', (180, 183))	('mesothelioma', 'Disease', (196, 208))	('biphasic mesothelioma', 'Disease', (187, 208))	('mesothelioma', 'Disease', (63, 75))	('MSTO-211H', 'CellLine', 'CVCL:1430', (136, 145))	('rad', 'Gene', (180, 183))	('mesothelioma', 'Disease', 'MESH:D008654', (196, 208))	('BAP1', 'Gene', (11, 15))	('mesothelioma', 'Disease', 'MESH:D008654', (63, 75))	('implicated', 'Reg', (28, 38))	('biphasic mesothelioma', 'Disease', 'MESH:D008654', (187, 208))
10156	25970771	In light of the effect of transient BAP1 depletion on HDAC expression, we hypothesized that variation in the endogenous expression of BAP1 in cancer cells may also influence HDAC levels.	('HDAC', 'Gene', '9734', (174, 178))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('BAP1', 'Gene', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('HDAC', 'Gene', (54, 58))	('influence', 'Reg', (164, 173))	('HDAC', 'Gene', '9734', (54, 58))	('HDAC', 'Gene', (174, 178))	('variation', 'Var', (92, 101))	('cancer', 'Disease', (142, 148))
10161	25970771	The MeT-5A cell line is derived from normal lung mesothelium, whilst the mesothelioma cell lines have differing BAP1 genetic status: NCI-H2052 and MSTO-211H cells retain genetically wild-type BAP1, NCI-H28 and NCI-H226 cells are BAP1 null, and NCI-H2452 cells have an inactivating mutation in the BAP1 catalytic domain.	('NCI-H2052', 'CellLine', 'CVCL:1518', (133, 142))	('mesothelioma', 'Disease', (73, 85))	('MSTO-211H', 'CellLine', 'CVCL:1430', (147, 156))	('mesothelioma', 'Disease', 'MESH:D008654', (73, 85))	('inactivating mutation in', 'Var', (268, 292))	('NCI-H226', 'CellLine', 'CVCL:1544', (210, 218))	('BAP1', 'Gene', (297, 301))	('NCI-H2452', 'CellLine', 'CVCL:1553', (244, 253))
10167	25970771	We first assessed whether inhibition of the proteasome led to accumulation of HDACs (Figure 4A).	('inhibition', 'Var', (26, 36))	('proteasome', 'molecular_function', 'GO:0004299', ('44', '54'))	('accumulation', 'PosReg', (62, 74))	('proteasome', 'cellular_component', 'GO:0000502', ('44', '54'))	('HDAC', 'Gene', (78, 82))	('HDAC', 'Gene', '9734', (78, 82))
10181	25970771	While HDAC1 depletion had little effect, depletion of HDAC2 significantly reduced cell viability, suggesting that MSTO-211H cells are dependent on HDAC2 for survival (Figure 6B, DMSO).	('cell viability', 'CPA', (82, 96))	('MSTO-211H', 'CellLine', 'CVCL:1430', (114, 123))	('depletion', 'Var', (41, 50))	('DMSO', 'Chemical', 'MESH:D004121', (178, 182))	('reduced', 'NegReg', (74, 81))
10185	25970771	Importantly, BAP1 knockdown also increased sensitivity to HDAC inhibition in a similar fashion, decreasing cell survival with both vorinostat and mocetinostat.	('knockdown', 'Var', (18, 27))	('BAP1', 'Gene', (13, 17))	('HDAC', 'Gene', (58, 62))	('mocetinostat', 'Chemical', 'MESH:C523184', (146, 158))	('HDAC', 'Gene', '9734', (58, 62))	('cell survival', 'CPA', (107, 120))	('vorinostat', 'Chemical', 'MESH:D000077337', (131, 141))	('increased', 'PosReg', (33, 42))	('decreasing', 'NegReg', (96, 106))
10187	25970771	Crucially, concomitant BAP1 and HDAC2 depletion did not additively reduce cell viability in the presence of vorinostat (Figure 6D).	('reduce', 'NegReg', (67, 73))	('vorinostat', 'Chemical', 'MESH:D000077337', (108, 118))	('cell viability', 'CPA', (74, 88))	('depletion', 'Var', (38, 47))
10191	25970771	In conclusion, loss of BAP1 in cell line models of thoracic malignancies alters expression of HDAC2.	('BAP1', 'Gene', (23, 27))	('malignancies', 'Disease', (60, 72))	('loss', 'Var', (15, 19))	('expression', 'MPA', (80, 90))	('malignancies', 'Disease', 'MESH:D009369', (60, 72))	('HDAC2', 'Gene', (94, 99))	('alters', 'Reg', (73, 79))
10195	25970771	In fact, somatic BAP1 mutation occurs in only around 1% of lung adenocarcinoma, but is far more prevalent in uveal melanoma, mesothelioma and renal clear cell carcinoma.	('prevalent', 'Reg', (96, 105))	('mutation', 'Var', (22, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (59, 78))	('mesothelioma and renal clear cell carcinoma', 'Disease', 'MESH:C538614', (125, 168))	('uveal melanoma', 'Disease', 'MESH:C536494', (109, 123))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('uveal melanoma', 'Disease', (109, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('lung adenocarcinoma', 'Disease', (59, 78))	('BAP1', 'Gene', (17, 21))
10196	25970771	Germline BAP1 mutation underpins a cancer predisposition syndrome and BAP1 protein expression is reportedly lost in around 50% of NSCLC, colon carcinoma, uveal melanoma and kidney cancers.	('colon carcinoma', 'Disease', (137, 152))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('uveal melanoma and kidney cancers', 'Disease', 'MESH:C536494', (154, 187))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('expression', 'MPA', (83, 93))	('BAP1', 'Gene', (9, 13))	('colon carcinoma', 'Disease', 'MESH:D015179', (137, 152))	('underpins', 'Reg', (23, 32))	('SCLC', 'Phenotype', 'HP:0030357', (131, 135))	('lost', 'NegReg', (108, 112))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('uveal melanoma', 'Phenotype', 'HP:0007716', (154, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('cancer', 'Disease', (180, 186))	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('BAP1', 'Gene', (70, 74))	('protein', 'Protein', (75, 82))	('NSCLC', 'Disease', (130, 135))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('mutation', 'Var', (14, 22))	('kidney cancers', 'Phenotype', 'HP:0009726', (173, 187))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (35, 41))
10203	25970771	Up to 80% of mesothelioma are directly attributable to asbestos exposure and it was recently shown that mice with heterozygous germline BAP1 knockout were predisposed to develop mesothelioma upon asbestos exposure.	('mesothelioma', 'Disease', (13, 25))	('BAP1', 'Gene', (136, 140))	('asbestos', 'Chemical', 'MESH:D001194', (55, 63))	('mesothelioma', 'Disease', 'MESH:D008654', (178, 190))	('mice', 'Species', '10090', (104, 108))	('mesothelioma', 'Disease', 'MESH:D008654', (13, 25))	('develop', 'PosReg', (170, 177))	('asbestos', 'Chemical', 'MESH:D001194', (196, 204))	('mesothelioma', 'Disease', (178, 190))	('knockout', 'Var', (141, 149))
10204	25970771	Interestingly, somatic BAP1 mutation is reported to be more common in current or ex-smokers who develop mesothelioma and could conceivably compound HDAC2 instability in response to cigarette smoke.	('BAP1', 'Gene', (23, 27))	('compound', 'Reg', (139, 147))	('develop', 'PosReg', (96, 103))	('mesothelioma', 'Disease', (104, 116))	('mutation', 'Var', (28, 36))	('mesothelioma', 'Disease', 'MESH:D008654', (104, 116))
10206	25970771	Clinically BAP1 mutation was initially linked to more aggressive, metastasizing uveal melanoma, whilst subsequent cell models suggested that BAP1 loss induces a stem cell-like phenotype.	('loss', 'NegReg', (146, 150))	('mutation', 'Var', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('uveal melanoma', 'Disease', (80, 94))	('uveal melanoma', 'Disease', 'MESH:C536494', (80, 94))	('induces', 'Reg', (151, 158))	('BAP1', 'Gene', (141, 145))	('linked', 'Reg', (39, 45))	('BAP1', 'Gene', (11, 15))	('stem cell-like', 'CPA', (161, 175))
10207	25970771	In mesothelioma, BAP1 loss is more common in a clinical sub-group that exhibit less evidence of EMT, but on asbestos exposure BAP1+/- mice develop more aggressive tumors, that invade other organs, than their wild-type littermates.	('EMT', 'Gene', (96, 99))	('mice', 'Species', '10090', (134, 138))	('BAP1+/-', 'Var', (126, 133))	('aggressive tumors', 'Disease', (152, 169))	('asbestos', 'Chemical', 'MESH:D001194', (108, 116))	('mesothelioma', 'Disease', (3, 15))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('EMT', 'Gene', '16428', (96, 99))	('loss', 'NegReg', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('develop', 'PosReg', (139, 146))	('EMT', 'biological_process', 'GO:0001837', ('96', '99'))	('mesothelioma', 'Disease', 'MESH:D008654', (3, 15))	('aggressive tumors', 'Disease', 'MESH:D001523', (152, 169))	('BAP1', 'Gene', (17, 21))
10209	25970771	Indeed uveal melanoma cells stably expressing BAP1 shRNA show no difference in their in vitro or in vivo growth kinetics and BAP1+/- mice do not spontaneously develop tumors.	('uveal melanoma', 'Disease', (7, 21))	('mice', 'Species', '10090', (133, 137))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('BAP1 shRNA', 'Var', (46, 56))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('uveal melanoma', 'Disease', 'MESH:C536494', (7, 21))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('uveal melanoma', 'Phenotype', 'HP:0007716', (7, 21))
10210	25970771	Indeed, on transient BAP1 depletion in MSTO-211H cells, we observed an approximate 50% reduction in viable cell number, comparable with previous data for this cell line.	('depletion', 'Var', (26, 35))	('BAP1', 'Gene', (21, 25))	('MSTO-211H', 'CellLine', 'CVCL:1430', (39, 48))	('viable cell number', 'CPA', (100, 118))	('reduction', 'NegReg', (87, 96))
10215	25970771	As BAP1 interacts with BRCA1, PARP inhibitors might also exhibit synthetic lethality with BAP1 mutation.	('PARP', 'Gene', '1302', (30, 34))	('BRCA1', 'Gene', (23, 28))	('PARP', 'Gene', (30, 34))	('interacts', 'Reg', (8, 17))	('BAP1', 'Gene', (90, 94))	('BRCA1', 'Gene', '672', (23, 28))	('mutation', 'Var', (95, 103))
10222	25970771	The need to stratify NSCLC patients based on EGFR mutation for EGFR inhibitor clinical trials highlights the importance of identifying biomarkers that can predict for response.	('EGFR', 'Gene', '1956', (63, 67))	('EGFR', 'Gene', (45, 49))	('NSCLC', 'Disease', (21, 26))	('EGFR', 'Gene', (63, 67))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('patients', 'Species', '9606', (27, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (21, 26))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('SCLC', 'Phenotype', 'HP:0030357', (22, 26))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))	('EGFR', 'Gene', '1956', (45, 49))	('mutation', 'Var', (50, 58))
10223	25970771	We found that despite the effect on HDAC2 expression, loss of BAP1 does not impact on total cellular HDAC activity, suggesting the compensatory increase in HDAC1 maintains cellular HDAC activity.	('HDAC', 'Gene', (101, 105))	('HDAC', 'Gene', (36, 40))	('BAP1', 'Gene', (62, 66))	('HDAC', 'Gene', (156, 160))	('HDAC', 'Gene', '9734', (101, 105))	('HDAC', 'Gene', '9734', (36, 40))	('HDAC', 'Gene', '9734', (156, 160))	('loss', 'Var', (54, 58))	('HDAC', 'Gene', (181, 185))	('HDAC', 'Gene', '9734', (181, 185))
10224	25970771	This is consistent with other reports of the HDAC relationship, for example in mice with targeted inactivation of either HDAC1 or HDAC2 in the epidermis, there is reciprocal upregulation of the opposite isoenzyme with no reduction in total HDAC activity.	('HDAC', 'Gene', (240, 244))	('inactivation', 'Var', (98, 110))	('HDAC', 'Gene', '9734', (240, 244))	('HDAC', 'Gene', (121, 125))	('mice', 'Species', '10090', (79, 83))	('HDAC', 'Gene', '9734', (121, 125))	('upregulation', 'PosReg', (174, 186))	('HDAC', 'Gene', (130, 134))	('HDAC', 'Gene', (45, 49))	('HDAC', 'Gene', '9734', (130, 134))	('HDAC', 'Gene', '9734', (45, 49))
10231	25970771	In uveal melanoma cell lines, HDAC inhibitors partially rescue the loss of melanocytic differentiation associated with BAP1 depletion.	('uveal melanoma', 'Disease', (3, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('loss of melanocytic', 'Disease', 'MESH:D009508', (67, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('HDAC', 'Gene', (30, 34))	('depletion', 'Var', (124, 133))	('HDAC', 'Gene', '9734', (30, 34))	('BAP1', 'Gene', (119, 123))	('loss of melanocytic', 'Disease', (67, 86))
10232	25970771	Furthermore, stable BAP1 depletion in a uveal melanoma cell line leads to sensitization to the HDAC inhibitor valproic acid and decreased viability.	('BAP1', 'Gene', (20, 24))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))	('uveal melanoma', 'Disease', (40, 54))	('decreased', 'NegReg', (128, 137))	('uveal melanoma', 'Disease', 'MESH:C536494', (40, 54))	('depletion', 'Var', (25, 34))	('valproic acid', 'Chemical', 'MESH:D014635', (110, 123))	('sensitization', 'biological_process', 'GO:0046960', ('74', '87'))	('HDAC', 'Gene', (95, 99))	('HDAC', 'Gene', '9734', (95, 99))	('viability', 'MPA', (138, 147))
10235	25970771	Indeed, our data suggest that cells adapt to genetic BAP1 loss, such that sensitivity to HDAC inhibitors is reduced.	('HDAC', 'Gene', (89, 93))	('loss', 'NegReg', (58, 62))	('HDAC', 'Gene', '9734', (89, 93))	('reduced', 'NegReg', (108, 115))	('genetic', 'Var', (45, 52))	('BAP1', 'Gene', (53, 57))
10236	25970771	While our findings will need to be confirmed in other models, this is potentially of clinical significance, as HDAC inhibitors are currently being investigated in clinical trials for uveal melanoma in which BAP1 mutations are common.	('HDAC', 'Gene', (111, 115))	('uveal melanoma', 'Phenotype', 'HP:0007716', (183, 197))	('uveal melanoma', 'Disease', 'MESH:C536494', (183, 197))	('HDAC', 'Gene', '9734', (111, 115))	('uveal melanoma', 'Disease', (183, 197))	('BAP1', 'Gene', (207, 211))	('mutations', 'Var', (212, 221))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))
10241	25970771	The transformed normal mesothelial cell line MeT-5A (ATCC) was cultured in Medium 199 with added 10% FBS, 2% HEPES, 0.1% Trace Elements B, 0.02% (100 mug/ml) EGF, 0.028% (1 mg/ml) Hydrocortisone, 0.05% (10 mg/ml) Insulin, and 0.01% (2 mg/ml) selenium acid.	('HEPES', 'Chemical', 'MESH:D006531', (109, 114))	('EGF', 'molecular_function', 'GO:0005154', ('158', '161'))	('Hydrocortisone', 'Chemical', 'MESH:D006854', (180, 194))	('mug', 'molecular_function', 'GO:0043739', ('150', '153'))	('FBS', 'Disease', (101, 104))	('Insulin', 'molecular_function', 'GO:0016088', ('213', '220'))	('FBS', 'Disease', 'MESH:D005198', (101, 104))	('0.02', 'Var', (139, 143))	('selenium acid', 'Chemical', '-', (242, 255))
10268	23318456	Reduced FANCD2 influences spontaneous SCE and RAD51 foci formation in uveal melanoma and Fanconi anaemia Uveal melanoma (UM) is unique among cancers in displaying reduced endogenous levels of sister chromatid exchange (SCE).	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('C', 'Chemical', 'MESH:D003596', (11, 12))	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('influences', 'Reg', (15, 25))	('endogenous levels', 'MPA', (171, 188))	('UM', 'Phenotype', 'HP:0007716', (121, 123))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('formation', 'biological_process', 'GO:0009058', ('57', '66'))	('melanoma', 'Disease', (111, 119))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('RAD51', 'Gene', (46, 51))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (105, 119))	('RAD51', 'Gene', '5888', (46, 51))	('FA', 'Phenotype', 'HP:0001994', (8, 10))	('RAD', 'biological_process', 'GO:1990116', ('46', '49'))	('C', 'Chemical', 'MESH:D003596', (39, 40))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('anaemia Uveal', 'Phenotype', 'HP:0025358', (97, 110))	('cancers', 'Disease', (141, 148))	('spontaneous', 'CPA', (26, 37))	('anaemia', 'Phenotype', 'HP:0001903', (97, 104))	('Fanconi anaemia', 'Disease', 'MESH:D005199', (89, 104))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('FANCD2', 'Gene', (8, 14))	('chromatid', 'cellular_component', 'GO:0005694', ('199', '208'))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('Fanconi anaemia', 'Phenotype', 'HP:0001994', (89, 104))	('uveal melanoma', 'Disease', (70, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('chromatid', 'cellular_component', 'GO:0005695', ('199', '208'))	('FANCD2', 'Gene', '2177', (8, 14))	('C', 'Chemical', 'MESH:D003596', (220, 221))	('Reduced', 'Var', (0, 7))	('Fanconi anaemia', 'Disease', (89, 104))
10269	23318456	Here we demonstrate that FANCD2 expression is reduced in UM and that ectopic expression of FANCD2 increased SCE.	('FANCD2', 'Gene', (25, 31))	('C', 'Chemical', 'MESH:D003596', (28, 29))	('FA', 'Phenotype', 'HP:0001994', (25, 27))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('C', 'Chemical', 'MESH:D003596', (94, 95))	('FANCD2', 'Gene', (91, 97))	('increased', 'PosReg', (98, 107))	('reduced', 'NegReg', (46, 53))	('C', 'Chemical', 'MESH:D003596', (109, 110))	('expression', 'MPA', (32, 42))	('FA', 'Phenotype', 'HP:0001994', (91, 93))	('SCE', 'Disease', (108, 111))	('ectopic expression', 'Var', (69, 87))
10271	23318456	In addition, spontaneous RAD51 foci were reduced in UM and PD20 cells compared with FANCD2-proficient cells.	('reduced', 'NegReg', (41, 48))	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('RAD', 'biological_process', 'GO:1990116', ('25', '28'))	('RAD51', 'Gene', (25, 30))	('RAD51', 'Gene', '5888', (25, 30))	('FA', 'Phenotype', 'HP:0001994', (84, 86))	('PD20 cells', 'Var', (59, 69))
10278	23318456	In addition, SCEs are induced by a variety of DNA-damaging agents such as mitomycin C (MMC) or ionising radiation; thus, alterations in DNA repair pathways have been associated with changes in SCE.	('SCEs', 'Disease', (13, 17))	('SCE', 'Disease', (193, 196))	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('alterations', 'Var', (121, 132))	('C', 'Chemical', 'MESH:D003596', (14, 15))	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('DNA repair', 'biological_process', 'GO:0006281', ('136', '146'))	('mitomycin C', 'Chemical', '-', (74, 85))	('C', 'Chemical', 'MESH:D003596', (194, 195))	('C', 'Chemical', 'MESH:D003596', (84, 85))	('MMC', 'Chemical', '-', (87, 90))	('associated', 'Reg', (166, 176))	('DNA repair pathways', 'Pathway', (136, 155))	('C', 'Chemical', 'MESH:D003596', (89, 90))
10280	23318456	All HR-defective DT40 chicken cells show reduced spontaneous and MMC-induced SCEs; however, neither Rad51D mutant CHO nor mouse fibroblast cell lines show reduced spontaneous SCEs relative to their wild-type equivalents.	('reduced', 'NegReg', (41, 48))	('Rad51D', 'Gene', (100, 106))	('mutant', 'Var', (107, 113))	('Rad', 'biological_process', 'GO:1990116', ('100', '103'))	('CHO', 'molecular_function', 'GO:0043848', ('114', '117'))	('chicken', 'Species', '9031', (22, 29))	('C', 'Chemical', 'MESH:D003596', (176, 177))	('C', 'Chemical', 'MESH:D003596', (78, 79))	('Rad51D', 'Gene', '417528', (100, 106))	('C', 'Chemical', 'MESH:D003596', (114, 115))	('spontaneous', 'CPA', (49, 60))	('CHO', 'CellLine', 'CVCL:0213', (114, 117))	('C', 'Chemical', 'MESH:D003596', (67, 68))	('MMC', 'Chemical', '-', (65, 68))	('MMC-induced SCEs', 'CPA', (65, 81))	('mouse', 'Species', '10090', (122, 127))
10281	23318456	In addition, spontaneous SCE is not affected in Rad54 knockout mice but the frequency of MMC-induced SCE is decreased, whereas CHO cells deficient in Rad51C show decreased spontaneous and induced SCEs.	('CHO', 'molecular_function', 'GO:0043848', ('127', '130'))	('spontaneous', 'CPA', (172, 183))	('C', 'Chemical', 'MESH:D003596', (26, 27))	('MMC-induced SCE', 'Disease', (89, 104))	('MMC', 'Chemical', '-', (89, 92))	('C', 'Chemical', 'MESH:D003596', (102, 103))	('C', 'Chemical', 'MESH:D003596', (127, 128))	('deficient', 'Var', (137, 146))	('Rad', 'biological_process', 'GO:1990116', ('48', '51'))	('C', 'Chemical', 'MESH:D003596', (197, 198))	('CHO', 'CellLine', 'CVCL:0213', (127, 130))	('Rad54', 'Gene', '19366', (48, 53))	('Rad51C', 'Gene', '100689078', (150, 156))	('decreased', 'NegReg', (162, 171))	('mice', 'Species', '10090', (63, 67))	('C', 'Chemical', 'MESH:D003596', (155, 156))	('Rad', 'biological_process', 'GO:1990116', ('150', '153'))	('decreased', 'NegReg', (108, 117))	('Rad51C', 'Gene', (150, 156))	('Rad54', 'Gene', (48, 53))	('C', 'Chemical', 'MESH:D003596', (91, 92))
10282	23318456	Add to this the fact that human heterozygous carriers of the BRCA2 germline mutation exhibit increased spontaneous SCEs, whereas Brca2 knockout mouse embryonic stem cells exhibit reduced spontaneous and MMC-induced SCEs, and it becomes obvious that the link between HR and SCE is complex, perhaps with different proteins controlling spontaneous and induced SCEs and interspecies differences.	('C', 'Chemical', 'MESH:D003596', (63, 64))	('mouse', 'Species', '10090', (144, 149))	('C', 'Chemical', 'MESH:D003596', (216, 217))	('C', 'Chemical', 'MESH:D003596', (274, 275))	('increased', 'PosReg', (93, 102))	('Brca2', 'Gene', (129, 134))	('BRCA2', 'Gene', (61, 66))	('Brca2', 'Gene', '675', (129, 134))	('spontaneous SCEs', 'CPA', (103, 119))	('C', 'Chemical', 'MESH:D003596', (358, 359))	('C', 'Chemical', 'MESH:D003596', (205, 206))	('MMC', 'Chemical', '-', (203, 206))	('BRCA2', 'Gene', '675', (61, 66))	('mutation', 'Var', (76, 84))	('C', 'Chemical', 'MESH:D003596', (116, 117))	('human', 'Species', '9606', (26, 31))	('reduced', 'NegReg', (179, 186))
10283	23318456	Another repair pathway associated with alterations in SCE and linked to HR is the Fanconi anaemia (FA) pathway.	('Fanconi anaemia', 'Disease', 'MESH:D005199', (82, 97))	('Fanconi anaemia', 'Phenotype', 'HP:0001994', (82, 97))	('Fanconi anaemia', 'Disease', (82, 97))	('C', 'Chemical', 'MESH:D003596', (55, 56))	('alterations', 'Var', (39, 50))	('FA', 'Phenotype', 'HP:0001994', (99, 101))	('anaemia', 'Phenotype', 'HP:0001903', (90, 97))
10291	23318456	Here we demonstrate that complementation of UM cells with FANCD2 increases SCE.	('FANCD2', 'Gene', (58, 64))	('FA', 'Phenotype', 'HP:0001994', (58, 60))	('increases', 'PosReg', (65, 74))	('SCE', 'Disease', (75, 78))	('C', 'Chemical', 'MESH:D003596', (76, 77))	('complementation', 'Var', (25, 40))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('C', 'Chemical', 'MESH:D003596', (61, 62))
10295	23318456	The expression of a panel of proteins involved in DNA repair was determined by western blotting of two established long-term UM cell lines (SOM157d and SOM196b), the cutaneous melanoma cell line WM793 and two other control cell lines routinely used in the lab (HCT116 and MRC5VA).	('WM793', 'CellLine', 'CVCL:8787', (195, 200))	('UM', 'Phenotype', 'HP:0007716', (125, 127))	('MRC5VA', 'CellLine', 'CVCL:0440', (272, 278))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('cutaneous melanoma', 'Disease', (166, 184))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (166, 184))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (166, 184))	('HCT116', 'CellLine', 'CVCL:0291', (261, 267))	('DNA repair', 'biological_process', 'GO:0006281', ('50', '60'))	('SOM196b', 'Var', (152, 159))
10298	23318456	No differences in proliferation rate or cell cycle progression were found in established UM cell lines SOM196b and SOM157d compared with WM793 or MRC5VA, excluding cell cycle differences or proliferation rates as the direct cause of reduced FANCD2 expression (Supplementary Figure 1).	('reduced', 'NegReg', (233, 240))	('WM793', 'CellLine', 'CVCL:8787', (137, 142))	('proliferation', 'CPA', (18, 31))	('FA', 'Phenotype', 'HP:0001994', (241, 243))	('expression', 'MPA', (248, 258))	('cell cycle', 'biological_process', 'GO:0007049', ('40', '50'))	('SOM196b', 'Var', (103, 110))	('MRC5VA', 'CellLine', 'CVCL:0440', (146, 152))	('UM', 'Phenotype', 'HP:0007716', (89, 91))	('cell cycle progression', 'CPA', (40, 62))	('cell cycle', 'biological_process', 'GO:0007049', ('164', '174'))	('FANCD2', 'Gene', (241, 247))
10299	23318456	In untreated UM cell lines (SOM157d and SOM196b), both FANCD2S and the monoubiquitinated form FANCD2L were seen, although at lower levels, than control WM793 cells (Figure 1a:more clearly seen in overexposed panel, right).	('WM793', 'CellLine', 'CVCL:8787', (152, 157))	('FA', 'Phenotype', 'HP:0001994', (55, 57))	('FA', 'Phenotype', 'HP:0001994', (94, 96))	('SOM157d', 'Var', (28, 35))	('UM', 'Phenotype', 'HP:0007716', (13, 15))	('SOM196b', 'Var', (40, 47))
10302	23318456	FANCD2 mRNA was reduced approximately two-fold in UM cell lines SOM157d and SOM196b compared with the cutaneous melanoma cell line WM793, and MRC5VA and HCT116 controls (Student's t-test P<0.001, for both cell lines compared with each of the controls), suggesting that in UM downregulation of FANCD2 is at the transcriptional level.	('SOM157d', 'Var', (64, 71))	('FANCD2', 'Gene', (0, 6))	('FA', 'Phenotype', 'HP:0001994', (0, 2))	('HCT116', 'CellLine', 'CVCL:0291', (153, 159))	('WM793', 'CellLine', 'CVCL:8787', (131, 136))	('reduced', 'NegReg', (16, 23))	('MRC5VA', 'CellLine', 'CVCL:0440', (142, 148))	('FA', 'Phenotype', 'HP:0001994', (293, 295))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('UM', 'Phenotype', 'HP:0007716', (272, 274))	('cutaneous melanoma', 'Disease', (102, 120))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))	('mRNA', 'MPA', (7, 11))	('SOM196b', 'Var', (76, 83))
10305	23318456	Within this region only two changes were detected; in UM cell lines SOM196b and SOM157d cytosine (C) residues 688 and 698 bp upstream of FANCD2 were unmethylated, whereas in each of the control cell lines (WM793, MRC5VA, HCT116, MCF-7, HeLa and U2OS) they were methylated.	('C', 'Chemical', 'MESH:D003596', (230, 231))	('FA', 'Phenotype', 'HP:0001994', (137, 139))	('SOM196b', 'Var', (68, 75))	('C', 'Chemical', 'MESH:D003596', (98, 99))	('MRC5VA', 'CellLine', 'CVCL:0440', (213, 219))	('WM793', 'CellLine', 'CVCL:8787', (206, 211))	('cytosine', 'Chemical', 'MESH:D003596', (88, 96))	('C', 'Chemical', 'MESH:D003596', (215, 216))	('HeLa', 'CellLine', 'CVCL:0030', (236, 240))	('U2OS', 'CellLine', 'CVCL:0042', (245, 249))	('C', 'Chemical', 'MESH:D003596', (222, 223))	('MCF-7', 'CellLine', 'CVCL:0031', (229, 234))	('UM', 'Phenotype', 'HP:0007716', (54, 56))	('SOM157d', 'Var', (80, 87))	('FANCD2', 'Gene', (137, 143))	('HCT116', 'CellLine', 'CVCL:0291', (221, 227))	('C', 'Chemical', 'MESH:D003596', (140, 141))
10307	23318456	The differentially methylated Cs are close to C698 and within C688, a putative E2F-1 binding site (Figure 2b).	('C', 'Chemical', 'MESH:D003596', (62, 63))	('Cs', 'Chemical', 'MESH:D002586', (30, 32))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('C', 'Chemical', 'MESH:D003596', (46, 47))	('C688', 'Var', (62, 66))	('C698', 'Var', (46, 50))	('C', 'Chemical', 'MESH:D003596', (30, 31))
10311	23318456	Here SCE (Figure 3d) increased when SOM196b was complemented with FANCD2 (Student's t-test P<0.001 and P<0.01 for 196bD2 compared with SOM196b and 196b-pMMP, respectively).	('SOM196b', 'Var', (36, 43))	('increased', 'PosReg', (21, 30))	('FA', 'Phenotype', 'HP:0001994', (66, 68))	('C', 'Chemical', 'MESH:D003596', (69, 70))	('C', 'Chemical', 'MESH:D003596', (6, 7))
10312	23318456	SCEs in FANCD2-complemented SOM196b were not significantly different to the level seen in cutaneous melanoma and other control cells (data not shown).	('C', 'Chemical', 'MESH:D003596', (11, 12))	('cutaneous melanoma', 'Disease', (90, 108))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (90, 108))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (90, 108))	('FANCD2-complemented SOM196b', 'Var', (8, 35))	('FA', 'Phenotype', 'HP:0001994', (8, 10))	('C', 'Chemical', 'MESH:D003596', (1, 2))	('SOM196b', 'Var', (28, 35))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))
10315	23318456	Similarly, FANCD2 is monoubiquitinated and colocalises with RAD51 during S phase, suggesting that FANCD2 may facilitate HR in the repair of endogenous damage.	('FA', 'Phenotype', 'HP:0001994', (98, 100))	('RAD51', 'Gene', '5888', (60, 65))	('FA', 'Phenotype', 'HP:0001994', (11, 13))	('S phase', 'biological_process', 'GO:0051320', ('73', '80'))	('RAD', 'biological_process', 'GO:1990116', ('60', '63'))	('FANCD2', 'Var', (98, 104))	('repair of endogenous damage', 'MPA', (130, 157))	('RAD51', 'Gene', (60, 65))	('HR in', 'CPA', (120, 125))	('facilitate', 'PosReg', (109, 119))
10316	23318456	Complementing the UM cell line SOM196b with FANCD2 significantly increased the percentage of cells containing >10 RAD51 foci/cell (Figure 4a and b; Student's t-test P<0.05 for 196b-D2 compared with either SOM196b or 196b-pMMP), whereas the addition of the empty vector control did not significantly increase RAD51 foci formation (Figure 4a and b, Student's t-test P=0.27 for 196b-pMMP compared with SOM196b).	('increased', 'PosReg', (65, 74))	('C', 'Chemical', 'MESH:D003596', (47, 48))	('RAD', 'biological_process', 'GO:1990116', ('308', '311'))	('UM', 'Phenotype', 'HP:0007716', (18, 20))	('RAD', 'biological_process', 'GO:1990116', ('114', '117'))	('SOM196b', 'Var', (31, 38))	('RAD51', 'Gene', (114, 119))	('FANCD2', 'Gene', (44, 50))	('RAD51', 'Gene', (308, 313))	('RAD51', 'Gene', '5888', (114, 119))	('formation', 'biological_process', 'GO:0009058', ('319', '328'))	('RAD51', 'Gene', '5888', (308, 313))	('C', 'Chemical', 'MESH:D003596', (0, 1))	('FA', 'Phenotype', 'HP:0001994', (44, 46))
10319	23318456	The levels of RAD51 foci were also reduced in both the primary UM short-term cultures tested (SOM569 and SOM571) compared with control cells (WM793, MRC5VA and U2OS), and a primary short-term conjunctive melanoma (Mel658) (Figure 4c; Students t-test P<0.01 for WM793 compared with either SOM157d or SOM196b and Mel658 compared with either SOM569 or SOM571), demonstrating that this function is preserved in primary tumour material.	('RAD51', 'Gene', (14, 19))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('reduced', 'NegReg', (35, 42))	('RAD51', 'Gene', '5888', (14, 19))	('UM', 'Phenotype', 'HP:0007716', (63, 65))	('WM793', 'CellLine', 'CVCL:8787', (261, 266))	('tumour', 'Phenotype', 'HP:0002664', (415, 421))	('WM793', 'CellLine', 'CVCL:8787', (142, 147))	('RAD', 'biological_process', 'GO:1990116', ('14', '17'))	('MRC5VA', 'CellLine', 'CVCL:0440', (149, 155))	('conjunctive melanoma', 'Disease', (192, 212))	('tumour', 'Disease', (415, 421))	('U2OS', 'CellLine', 'CVCL:0042', (160, 164))	('tumour', 'Disease', 'MESH:D009369', (415, 421))	('Mel658', 'Var', (311, 317))	('conjunctive melanoma', 'Disease', 'MESH:D008545', (192, 212))	('WM793', 'Var', (261, 266))
10323	23318456	Interestingly, when PD20 cells, which complemented with the monoubiquitination mutant K561R, were compared with the data above, they displayed intermediate levels of RAD51 foci formation, and individual cells had unexpectedly varied SCE rates (range 6-53 SCE/cell) when compared with PD20 (range 6-32) and PD20-D2 (range 11-41).	('K561R', 'Mutation', 'p.K561R', (86, 91))	('SCE', 'CPA', (233, 236))	('C', 'Chemical', 'MESH:D003596', (256, 257))	('RAD51', 'Gene', (166, 171))	('RAD51', 'Gene', '5888', (166, 171))	('K561R', 'Var', (86, 91))	('RAD', 'biological_process', 'GO:1990116', ('166', '169'))	('C', 'Chemical', 'MESH:D003596', (234, 235))	('formation', 'biological_process', 'GO:0009058', ('177', '186'))
10324	23318456	The average SCE/cell in PD20-K561R was 27.2 (corrected for ploidy), similar to the average of 24.62 seen in PD20-D2.	('SCE/cell', 'MPA', (12, 20))	('PD20-K561R', 'Var', (24, 34))	('C', 'Chemical', 'MESH:D003596', (13, 14))	('K561R', 'Mutation', 'p.K561R', (29, 34))
10326	23318456	Thus, there may be an additional specific function for monoubiquitinated FANCD2 at endogenous DNA lesions, and additional factors that affect SCE formation, although perhaps a note of caution should be taken in interpreting data from cells with such high levels of genetic instability.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('monoubiquitinated', 'Var', (55, 72))	('C', 'Chemical', 'MESH:D003596', (143, 144))	('SCE formation', 'CPA', (142, 155))	('affect', 'Reg', (135, 141))	('FANCD2', 'Gene', (73, 79))	('C', 'Chemical', 'MESH:D003596', (76, 77))	('FA', 'Phenotype', 'HP:0001994', (73, 75))	('formation', 'biological_process', 'GO:0009058', ('146', '155'))
10333	23318456	PD20-K561R cells were also sensitive to acetaldehyde (Student's t-test P<0.01) as compared with wild-type FANCD2-complemented cells.	('acetaldehyde', 'Chemical', 'MESH:D000079', (40, 52))	('FA', 'Phenotype', 'HP:0001994', (106, 108))	('acetaldehyde', 'MPA', (40, 52))	('K561R', 'Mutation', 'p.K561R', (5, 10))	('sensitive', 'Reg', (27, 36))	('PD20-K561R', 'Var', (0, 10))
10336	23318456	In support of this, we demonstrated that knocking down expression of FANCD2 by siRNA reduces SCE formation in MRC5VA cells.	('FANCD2', 'Gene', (69, 75))	('SCE formation in MRC5VA cells', 'CPA', (93, 122))	('C', 'Chemical', 'MESH:D003596', (72, 73))	('formation', 'biological_process', 'GO:0009058', ('97', '106'))	('FA', 'Phenotype', 'HP:0001994', (69, 71))	('expression', 'MPA', (55, 65))	('C', 'Chemical', 'MESH:D003596', (94, 95))	('MRC5VA', 'CellLine', 'CVCL:0440', (110, 116))	('C', 'Chemical', 'MESH:D003596', (112, 113))	('reduces', 'NegReg', (85, 92))	('knocking down', 'Var', (41, 54))
10341	23318456	In addition, we show that monoubiquitination mutants of FANCD2 have reduced RAD51 foci but similar SCE formation to FANCD2-proficient cells; furthermore, K561R mutation appears to have a larger effect on genomic instability than reduced expression of wild-type FANCD2.	('K561R', 'Var', (154, 159))	('FANCD2', 'Gene', (56, 62))	('C', 'Chemical', 'MESH:D003596', (264, 265))	('C', 'Chemical', 'MESH:D003596', (119, 120))	('C', 'Chemical', 'MESH:D003596', (59, 60))	('FA', 'Phenotype', 'HP:0001994', (56, 58))	('RAD', 'biological_process', 'GO:1990116', ('76', '79'))	('C', 'Chemical', 'MESH:D003596', (100, 101))	('FA', 'Phenotype', 'HP:0001994', (261, 263))	('RAD51', 'Gene', (76, 81))	('SCE', 'MPA', (99, 102))	('genomic instability', 'CPA', (204, 223))	('monoubiquitination', 'MPA', (26, 44))	('RAD51', 'Gene', '5888', (76, 81))	('formation', 'biological_process', 'GO:0009058', ('103', '112'))	('K561R', 'Mutation', 'p.K561R', (154, 159))	('reduced', 'NegReg', (68, 75))	('FA', 'Phenotype', 'HP:0001994', (116, 118))
10342	23318456	Studies in other mammalian cell lines support our findings in human cells, and CHO cells defective in several different FA proteins are reported to have reduced or unchanged levels of SCE.	('C', 'Chemical', 'MESH:D003596', (185, 186))	('C', 'Chemical', 'MESH:D003596', (79, 80))	('defective', 'Var', (89, 98))	('CHO', 'molecular_function', 'GO:0043848', ('79', '82'))	('reduced', 'NegReg', (153, 160))	('SCE', 'MPA', (184, 187))	('human', 'Species', '9606', (62, 67))	('CHO', 'CellLine', 'CVCL:0213', (79, 82))	('levels', 'MPA', (174, 180))	('FA', 'Phenotype', 'HP:0001994', (120, 122))	('mammalian', 'Species', '9606', (17, 26))
10343	23318456	However, in DT40 chicken cells, mutation of FA genes including FANCD2 result in increased spontaneous SCE, whereas similar to mammalian cells DT40 cells defective in core HR proteins do show reduced SCE.	('FANCD2', 'Gene', (63, 69))	('C', 'Chemical', 'MESH:D003596', (66, 67))	('C', 'Chemical', 'MESH:D003596', (103, 104))	('increased', 'PosReg', (80, 89))	('chicken', 'Species', '9031', (17, 24))	('FA', 'Phenotype', 'HP:0001994', (63, 65))	('C', 'Chemical', 'MESH:D003596', (200, 201))	('core', 'cellular_component', 'GO:0019013', ('166', '170'))	('mammalian', 'Species', '9606', (126, 135))	('mutation', 'Var', (32, 40))	('spontaneous SCE', 'CPA', (90, 105))	('FA', 'Phenotype', 'HP:0001994', (44, 46))
10351	23318456	Our data indicate that as in other model systems human FANCD2 is required for repair of acetaldehyde-induced DNA damage; thus, in addition to collapsed forks, FANCD2 may promote spontaneous SCE in response to endogenous lesions induced by such metabolites.	('C', 'Chemical', 'MESH:D003596', (58, 59))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('acetaldehyde', 'Chemical', 'MESH:D000079', (88, 100))	('FANCD2', 'Var', (159, 165))	('C', 'Chemical', 'MESH:D003596', (162, 163))	('human', 'Species', '9606', (49, 54))	('FA', 'Phenotype', 'HP:0001994', (55, 57))	('FA', 'Phenotype', 'HP:0001994', (159, 161))	('C', 'Chemical', 'MESH:D003596', (191, 192))	('spontaneous SCE', 'Disease', (178, 193))	('promote', 'PosReg', (170, 177))
10353	23318456	It has also been suggested that the function of FANCD2 following ICL damage is to suppress non-homologous end-joining (NHEJ), as evidenced by the fact that inhibiting NHEJ rescues the MMC-sensitive FA phenotype.	('MMC', 'Chemical', '-', (184, 187))	('FANCD2', 'Gene', (48, 54))	('NHEJ', 'biological_process', 'GO:0006303', ('167', '171'))	('rescues', 'PosReg', (172, 179))	('FA', 'Phenotype', 'HP:0001994', (48, 50))	('ICL damage', 'Disease', (65, 75))	('NHEJ', 'Protein', (167, 171))	('MMC-sensitive', 'Disease', (184, 197))	('ICL damage', 'Disease', 'MESH:D018344', (65, 75))	('inhibiting', 'Var', (156, 166))	('NHEJ', 'biological_process', 'GO:0006303', ('119', '123'))	('non-homologous end-joining', 'MPA', (91, 117))	('suppress', 'NegReg', (82, 90))	('FA', 'Phenotype', 'HP:0001994', (198, 200))
10360	23318456	Epigenetic events that alter gene expression are important in the tumourigenesis of many sporadic cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('important', 'Reg', (49, 58))	('Epigenetic events', 'Var', (0, 17))	('sporadic cancers', 'Disease', 'MESH:D009369', (89, 105))	('gene expression', 'biological_process', 'GO:0010467', ('29', '44'))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('sporadic cancers', 'Disease', (89, 105))	('tumour', 'Disease', (66, 72))
10362	23318456	Although changes in methylation have not been seen previously, lack of FANCD2 has been linked to tumourigenesis.	('tumour', 'Disease', (97, 103))	('methylation', 'MPA', (20, 31))	('linked', 'Reg', (87, 93))	('FANCD2', 'Gene', (71, 77))	('lack', 'Var', (63, 67))	('FA', 'Phenotype', 'HP:0001994', (71, 73))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('tumour', 'Disease', 'MESH:D009369', (97, 103))
10364	23318456	In addition, polymorphisms of FANCD2 have been associated with increased sporadic breast cancer.	('breast cancer', 'Disease', (82, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('polymorphisms', 'Var', (13, 26))	('FANCD2', 'Gene', (30, 36))	('FA', 'Phenotype', 'HP:0001994', (30, 32))	('associated', 'Reg', (47, 57))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
10377	23318456	All cell lines were grown in Dulbecco's modified Eagle's medium with 10% fetal bovine serum, penicillin (100 U/ml) and streptomycin sulphate (100 mug/ml) at 37  C under 5% CO2.	('C', 'Chemical', 'MESH:D003596', (172, 173))	('mug', 'molecular_function', 'GO:0043739', ('146', '149'))	('streptomycin sulphate', 'Chemical', 'MESH:D013307', (119, 140))	('100 U/ml', 'Var', (105, 113))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (29, 63))	('bovine', 'Species', '9913', (79, 85))	('CO2', 'Chemical', '-', (172, 175))	('penicillin', 'Chemical', 'MESH:D010406', (93, 103))	('C', 'Chemical', 'MESH:D003596', (161, 162))	('100', 'Var', (142, 145))
10380	23318456	PD20 K651R cells were a gift from Toshiyasu Taniguchi (Fred Hutchinson Cancer Research Center, Seattle, WA, USA).	('C', 'Chemical', 'MESH:D003596', (87, 88))	('PD20 K651R', 'Var', (0, 10))	('K651R', 'Mutation', 'p.K651R', (5, 10))	('Fred Hutchinson Cancer', 'Disease', 'MESH:D013590', (55, 77))	('Hutchinson Cancer', 'Phenotype', 'HP:0012413', (60, 77))	('C', 'Chemical', 'MESH:D003596', (71, 72))	('Fred Hutchinson Cancer', 'Disease', (55, 77))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
10434	32522791	In 80% of metastasizing UM, inactivating mutations in the gene encoding BAP-1, located on chromosome 3p21.1, have been identified.	('metastasizing UM', 'Disease', (10, 26))	('BAP-1', 'Gene', (72, 77))	('UM', 'Phenotype', 'HP:0007716', (24, 26))	('inactivating mutations', 'Var', (28, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('90', '100'))	('BAP-1', 'Gene', '8314', (72, 77))	('metastasizing UM', 'Disease', 'MESH:D009362', (10, 26))
10436	32522791	Even though BAP-1 mutations have been described to occur late in the tumour progression, it remains unclear to what extent nuclear BAP-1 expression is lost in small UM.	('tumour', 'Disease', (69, 75))	('UM', 'Phenotype', 'HP:0007716', (165, 167))	('BAP-1', 'Gene', (131, 136))	('BAP-1', 'Gene', '8314', (12, 17))	('BAP-1', 'Gene', (12, 17))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('BAP-1', 'Gene', '8314', (131, 136))	('mutations', 'Var', (18, 27))
10527	33034815	In comparison, overall survival after first diagnosis was insignificantly shorter in groupnoresection (44.7(32-56.1) months) than in grouphemihep (48.3(34.6-72.8) months; p = 0.48).	('shorter', 'NegReg', (74, 81))	('al', 'Chemical', 'MESH:D000535', (19, 21))	('groupnoresection', 'Var', (85, 101))	('al', 'Chemical', 'MESH:D000535', (29, 31))
10607	33034815	A case of death (AE grade five) occurred in grouphemihep in a patient with hepatic metastases from uveal melanoma and a high pre-interventional tumor burden (LDH 1559 U/I) (Table 1; patient seven).	('tumor', 'Disease', (144, 149))	('al', 'Chemical', 'MESH:D000535', (102, 104))	('hepatic metastases', 'Disease', (75, 93))	('LDH 1559 U/I', 'Var', (158, 170))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('death', 'Disease', 'MESH:D003643', (10, 15))	('al', 'Chemical', 'MESH:D000535', (141, 143))	('patient', 'Species', '9606', (62, 69))	('patient', 'Species', '9606', (182, 189))	('hepatic metastases', 'Disease', 'MESH:D009362', (75, 93))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('death', 'Disease', (10, 15))	('uveal melanoma', 'Disease', 'MESH:C536494', (99, 113))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('pre', 'molecular_function', 'GO:0003904', ('125', '128'))	('uveal melanoma', 'Disease', (99, 113))	('grouphemihep', 'Disease', (44, 56))
10614	33034815	The median overall survival (OS) after first CS-PHP in groupnoresection was longer (19.7 (7.5-23.8) months) than in grouphemihep with 9.3 (4.2-17) months (p = 0.53).	('overall survival', 'MPA', (11, 27))	('al', 'Chemical', 'MESH:D000535', (25, 27))	('groupnoresection', 'Var', (55, 71))	('PHP', 'Chemical', '-', (48, 51))	('longer', 'PosReg', (76, 82))	('CS', 'Gene', '1431', (45, 47))	('al', 'Chemical', 'MESH:D000535', (15, 17))
10633	33034815	Furthermore, leakages alongside the double balloon catheter (used to occlude the IVC) might increase systemic melphalan.	('al', 'Chemical', 'MESH:D000535', (44, 46))	('leakages', 'Var', (13, 21))	('increase', 'PosReg', (92, 100))	('al', 'Chemical', 'MESH:D000535', (115, 117))	('systemic melphalan', 'MPA', (101, 119))	('al', 'Chemical', 'MESH:D000535', (22, 24))	('melphalan', 'Chemical', 'MESH:D008558', (110, 119))
10646	33034815	Relapse occurred with disseminated intrahepatic metastasis and a high tumor burden (LDH 1559 U/I, norm: <= 250 U/I).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('LDH 1559 U/I', 'Var', (84, 96))	('intrahepatic metastasis', 'Disease', 'MESH:D009362', (35, 58))	('intrahepatic metastasis', 'Disease', (35, 58))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
10648	33034815	Of note, one patient in groupnoresection with high pre-interventional LDH (1064 U/I) suffered from pancytopenia and sepsis and deceased 2.8 months after the first and only CS-PHP.	('sepsis', 'Phenotype', 'HP:0100806', (116, 122))	('sepsis', 'Disease', (116, 122))	('pre', 'molecular_function', 'GO:0003904', ('51', '54'))	('1064 U/I', 'Var', (75, 83))	('PHP', 'Chemical', '-', (175, 178))	('pancytopenia', 'Disease', 'MESH:D010198', (99, 111))	('patient', 'Species', '9606', (13, 20))	('sepsis', 'Disease', 'MESH:D018805', (116, 122))	('al', 'Chemical', 'MESH:D000535', (67, 69))	('CS', 'Gene', '1431', (172, 174))	('suffered', 'Reg', (85, 93))	('pancytopenia', 'Phenotype', 'HP:0001876', (99, 111))	('pancytopenia', 'Disease', (99, 111))
10649	33034815	In both cases, the adverse outcome was most likely related to high tumor burden, which has been described to have a negative correlation to survival.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('al', 'Chemical', 'MESH:D000535', (146, 148))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('high', 'Var', (62, 66))
10668	32415113	While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('TMB', 'Chemical', '-', (47, 50))	('low tumour', 'Disease', (19, 29))	('MBD4', 'Gene', '8930', (112, 116))	('MBD4', 'Gene', (112, 116))	('low tumour', 'Disease', 'MESH:D009800', (19, 29))	('mutation', 'Var', (117, 125))	('TMB', 'Chemical', '-', (75, 78))
10672	32415113	Here, the authors report the whole genome sequence of 103 uveal melanomas and find that the tumour mutational burden is variable and that two subsets of tumours are characterised by MBD4 mutations and a UV exposure signature.	('tumours', 'Disease', 'MESH:D009369', (153, 160))	('tumour', 'Disease', (153, 159))	('tumours', 'Disease', (153, 160))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('melanomas', 'Disease', (64, 73))	('tumour', 'Disease', (92, 98))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('uveal melanomas', 'Phenotype', 'HP:0007716', (58, 73))	('mutations', 'Var', (187, 196))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('MBD4', 'Gene', '8930', (182, 186))	('MBD4', 'Gene', (182, 186))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))	('melanomas', 'Disease', 'MESH:D008545', (64, 73))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('tumour', 'Disease', 'MESH:D009369', (153, 159))
10674	32415113	Similarly we segregate our tumours into four categories based on CNAs: category 1 are chromosome 3 disomy (D3) tumours lacking chromosome 8q copy-number gain and frequently possessing EIF1AX mutations; category 2 are D3 UM with chromosome 6p and 8q gain and a high proportion of SF3B1 mutations; category 3 are chromosome 3 monosomy (M3) tumours lacking chromosome 8q gain dominated by BAP1 mutations; category 4 UMs are M3 with chromosome 8q gain and BAP1 mutations.	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('tumour', 'Phenotype', 'HP:0002664', (338, 344))	('BAP1', 'Gene', '8314', (452, 456))	('tumours', 'Disease', 'MESH:D009369', (27, 34))	('chromosome', 'cellular_component', 'GO:0005694', ('228', '238'))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('BAP1', 'Gene', '8314', (386, 390))	('mutations', 'Var', (191, 200))	('chromosome', 'cellular_component', 'GO:0005694', ('86', '96'))	('SF3B1', 'Gene', (279, 284))	('chromosome', 'cellular_component', 'GO:0005694', ('354', '364'))	('BAP1', 'Gene', (452, 456))	('mutations', 'Var', (285, 294))	('tumours', 'Disease', (111, 118))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('BAP1', 'Gene', (386, 390))	('chromosome', 'cellular_component', 'GO:0005694', ('429', '439'))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('SF3B1', 'Gene', '23451', (279, 284))	('tumours', 'Disease', (338, 345))	('EIF1AX', 'Gene', (184, 190))	('tumours', 'Disease', 'MESH:D009369', (111, 118))	('lacking', 'NegReg', (119, 126))	('mutations', 'Var', (457, 466))	('chromosome', 'cellular_component', 'GO:0005694', ('311', '321'))	('tumours', 'Phenotype', 'HP:0002664', (338, 345))	('chromosome', 'cellular_component', 'GO:0005694', ('127', '137'))	('tumours', 'Disease', (27, 34))	('tumours', 'Disease', 'MESH:D009369', (338, 345))	('EIF1AX', 'Gene', '1964', (184, 190))
10677	32415113	In line with previous studies, TMB was low in the majority of UM (median 0.50 mutations per megabase, range 248-42,669, Supplementary Data 2) and tumours generally displayed low counts of structural variations (SVs) (median: 13; range 0-213) (Fig.	('tumours', 'Disease', 'MESH:D009369', (146, 153))	('tumours', 'Disease', (146, 153))	('TMB', 'Chemical', '-', (31, 34))	('mutations', 'Var', (78, 87))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('structural variations', 'Var', (188, 209))
10678	32415113	One sample had noticeably more SVs, of which the majority (71%) were midsized (<100 kb) deletions, suggesting this was not due to chromothripsis.	('deletions', 'Var', (88, 97))	('chromothripsis', 'Disease', (130, 144))	('chromothripsis', 'Disease', 'MESH:D000072837', (130, 144))
10681	32415113	Two samples were dominated by mutation signature SBS1 (associated with spontaneous deamination) and had correspondingly high TMB (>3 mutations per Mb).	('TMB', 'MPA', (125, 128))	('associated', 'Reg', (55, 65))	('mutation signature', 'Var', (30, 48))	('TMB', 'Chemical', '-', (125, 128))	('SBS1', 'Gene', (49, 53))
10682	32415113	As previously observed, these features corresponded to the presence of germline loss-of-function (LOF) MBD4 mutations; this takes the published tally of germline MBD4 mutant UM cases to six, strengthening its role as a UM predisposition gene.	('mutations', 'Var', (108, 117))	('MBD4', 'Gene', '8930', (162, 166))	('mutant', 'Var', (167, 173))	('loss-of-function', 'NegReg', (80, 96))	('MBD4', 'Gene', (103, 107))	('MBD4', 'Gene', (162, 166))	('MBD4', 'Gene', '8930', (103, 107))
10683	32415113	The two UMs with germline LOF BAP1 mutations displayed no unique features.	('LOF', 'NegReg', (26, 29))	('BAP1', 'Gene', '8314', (30, 34))	('BAP1', 'Gene', (30, 34))	('mutations', 'Var', (35, 44))
10684	32415113	Strikingly, all iris melanomas displayed the genomic features associated with UVR damage (mutation signatures SBS7a, SBS7b and DBS1 combined with a high TMB).	('iris melanomas', 'Disease', (16, 30))	('iris melanomas', 'Disease', 'MESH:D008545', (16, 30))	('iris melanomas', 'Phenotype', 'HP:0011524', (16, 30))	('SBS7b', 'Gene', (117, 122))	('SBS7a', 'Gene', (110, 115))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('mutation', 'Var', (90, 98))	('TMB', 'Chemical', '-', (153, 156))	('DBS1', 'Gene', (127, 131))
10685	32415113	Assessment of known UM driver genes revealed an oncogenic driver mutation in 102 of 103 tumours: 51 in GNAQ (48 p.Q209P/L, two p.R183Q, one p.G48L), 46 in GNA11 (44 p.Q209L/P, two p.R183C), five in PLCB4 (three p.D630Y, two p.D630N) and two in CYSLTR2 (p.L129Q).	('GNA11', 'Gene', '2767', (155, 160))	('PLCB4', 'Gene', (198, 203))	('CYSLTR2', 'Gene', '57105', (244, 251))	('p.L129Q', 'Mutation', 'p.L129Q', (253, 260))	('p.R183Q', 'Mutation', 'rs397514698', (127, 134))	('p.D630N', 'Var', (224, 231))	('p.R183Q', 'Var', (127, 134))	('p.R183C', 'Mutation', 'p.R183C', (180, 187))	('p.D630Y', 'Mutation', 'p.D630Y', (211, 218))	('CYSLTR2', 'Gene', (244, 251))	('tumours', 'Disease', (88, 95))	('mutation', 'Var', (65, 73))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('PLCB4', 'Gene', '5332', (198, 203))	('GNA11', 'Gene', (155, 160))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('p.Q209P', 'SUBSTITUTION', 'None', (112, 119))	('p.Q209L', 'Var', (165, 172))	('p.Q209P', 'Var', (112, 119))	('p.G48L', 'Mutation', 'p.G48L', (140, 146))	('p.D630Y', 'Var', (211, 218))	('GNAQ', 'Gene', '2776', (103, 107))	('p.D630N', 'Mutation', 'p.D630N', (224, 231))	('p.Q209L', 'SUBSTITUTION', 'None', (165, 172))	('GNAQ', 'Gene', (103, 107))
10686	32415113	These mutations were generally mutually exclusive except for two PLCB4 p.D630 mutations that co-occurred with GNAQ/GNA11 p.R183H mutations.	('GNA11', 'Gene', '2767', (115, 120))	('p.R183H', 'Mutation', 'p.R183H', (121, 128))	('PLCB4', 'Gene', '5332', (65, 70))	('GNAQ', 'Gene', '2776', (110, 114))	('PLCB4', 'Gene', (65, 70))	('GNAQ', 'Gene', (110, 114))	('p.D630', 'Var', (71, 77))	('GNA11', 'Gene', (115, 120))	('p.R183H', 'Var', (121, 128))
10687	32415113	This co-occurrence between PLCB4 mutation and the minor hotspot p.R183, rather than the stronger oncogenic p.Q209 hotspot mutations, has previously been described in the UM TCGA data.	('PLCB4', 'Gene', (27, 32))	('PLCB4', 'Gene', '5332', (27, 32))	('mutation', 'Var', (33, 41))	('p.R183', 'Var', (64, 70))
10688	32415113	Though not previously highlighted, GNAQ p.G48L mutations have been reported in two UM samples from two separate studies, as well as in two hepatic small vessel neoplasms, which are driven by activating GNAQ/GNA14 mutations.	('neoplasms', 'Phenotype', 'HP:0002664', (160, 169))	('GNAQ', 'Gene', '2776', (202, 206))	('p.G48L', 'Var', (40, 46))	('hepatic small vessel neoplasms', 'Disease', 'MESH:D056486', (139, 169))	('GNA14', 'Gene', (207, 212))	('GNAQ', 'Gene', '2776', (35, 39))	('GNAQ', 'Gene', (202, 206))	('hepatic small vessel neoplasms', 'Disease', (139, 169))	('vessel neoplasms', 'Phenotype', 'HP:0100742', (153, 169))	('mutations', 'Var', (213, 222))	('activating', 'PosReg', (191, 201))	('p.G48L', 'Mutation', 'p.G48L', (40, 46))	('GNAQ', 'Gene', (35, 39))	('GNA14', 'Gene', '9630', (207, 212))
10689	32415113	This suggests that GNAQ p.G48L is another minor UM oncogenic hotspot mutation.	('GNAQ', 'Gene', '2776', (19, 23))	('GNAQ', 'Gene', (19, 23))	('p.G48L', 'Mutation', 'p.G48L', (24, 30))	('p.G48L', 'Var', (24, 30))
10690	32415113	Similar to previous observations, BAP1 was the most altered gene in M3 samples (75%), including eight splice site mutations, two germline and 32 somatic LOF mutations, and three cases with disrupted BAP1 due to SV breakpoints.	('BAP1', 'Gene', (34, 38))	('BAP1', 'Gene', (199, 203))	('altered', 'Reg', (52, 59))	('mutations', 'Var', (157, 166))	('BAP1', 'Gene', '8314', (34, 38))	('BAP1', 'Gene', '8314', (199, 203))
10691	32415113	In addition, two D3 tumours carried BAP1 mutations, indicating that although BAP1 inactivation typically occurs after M3, BAP1 aberration can also occur in D3 tumours, which may or may not later undergo loss of chromosome 3.	('mutations', 'Var', (41, 50))	('tumours', 'Disease', (159, 166))	('BAP1', 'Gene', (122, 126))	('aberration', 'Var', (127, 137))	('BAP1', 'Gene', '8314', (36, 40))	('tumours', 'Phenotype', 'HP:0002664', (20, 27))	('BAP1', 'Gene', '8314', (77, 81))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('BAP1', 'Gene', '8314', (122, 126))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('chromosome', 'cellular_component', 'GO:0005694', ('211', '221'))	('BAP1', 'Gene', (36, 40))	('inactivation', 'NegReg', (82, 94))	('tumours', 'Disease', 'MESH:D009369', (159, 166))	('tumours', 'Disease', 'MESH:D009369', (20, 27))	('BAP1', 'Gene', (77, 81))	('tumours', 'Disease', (20, 27))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
10692	32415113	Of note, one of these D3 tumours (MELA_0800) had a low BAP1 variant allele frequency (VAF = 9/80) suggesting it was only present in a subclone, and as copy number tools are not as sensitive as mutation callers, it is possible that the subclone had loss of heterozygosity (LOH) that was not detected by the algorithm.	('BAP1', 'Gene', (55, 59))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('variant', 'Var', (60, 67))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('tumours', 'Disease', (25, 32))	('loss', 'NegReg', (248, 252))	('BAP1', 'Gene', '8314', (55, 59))
10693	32415113	Five tumours had BAP1 mutations and copy-neutral LOH, suggesting that the mutations occurred before WGD in the two tetraploid UMs and before the LOH event in the three diploid UMs.	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('mutations', 'Var', (74, 83))	('tumours', 'Disease', 'MESH:D009369', (5, 12))	('tumours', 'Disease', (5, 12))	('WGD', 'Disease', (100, 103))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('BAP1', 'Gene', (17, 21))
10694	32415113	SF3B1 mutations were present in 15 tumours, the majority occurring in category 2, in line with other studies.	('tumours', 'Disease', (35, 42))	('SF3B1', 'Gene', (0, 5))	('SF3B1', 'Gene', '23451', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumours', 'Phenotype', 'HP:0002664', (35, 42))	('tumours', 'Disease', 'MESH:D009369', (35, 42))	('mutations', 'Var', (6, 15))
10695	32415113	EIF1AX hotspot mutations were observed in 19% of tumours.	('tumours', 'Disease', (49, 56))	('mutations', 'Var', (15, 24))	('hotspot', 'PosReg', (7, 14))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))
10696	32415113	EIF1AX mutations were first discovered in D3 UMs and in the TCGA cohort they were restricted to category 1 tumours (D3 and no 8q gain), while in the cohort presented by Royer-Bertrand and colleagues two of seven mutations were seen in tumours with M3 and/or 8q gain.	('tumours', 'Disease', 'MESH:D009369', (107, 114))	('tumours', 'Disease', (107, 114))	('tumours', 'Phenotype', 'HP:0002664', (235, 242))	('tumours', 'Disease', 'MESH:D009369', (235, 242))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumours', 'Disease', (235, 242))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
10697	32415113	Similarly, here six of the 20 EIF1AX mutations (30%) were seen in UM with M3 (n = 5) or 8q gain (n = 1) (Fig.	('EIF1AX', 'Gene', (30, 36))	('mutations', 'Var', (37, 46))	('gain', 'PosReg', (91, 95))	('EIF1AX', 'Gene', '1964', (30, 36))
10700	32415113	Two of the missense mutations (p.R14W and p.R251W) occurred in the kinesin motor domain (Fig.	('p.R251W', 'Var', (42, 49))	('p.R14W', 'Mutation', 'p.R14W', (31, 37))	('kinesin', 'molecular_function', 'GO:0003777', ('67', '74'))	('p.R14W', 'Var', (31, 37))	('p.R251W', 'Mutation', 'p.R251W', (42, 49))	('occurred', 'Reg', (51, 59))
10702	32415113	An additional two missense mutations were identified in the UM TCGA cohort at p.I1038T (weak ECR) and p.K1821N (reasonable ECR), both also in a coiled-coil domain.	('p.I1038T', 'Mutation', 'rs973726069', (78, 86))	('p.K1821N', 'Mutation', 'p.K1821N', (102, 110))	('p.I1038T', 'Var', (78, 86))	('p.K1821N', 'Var', (102, 110))
10704	32415113	In the UM cohort described here, one sample had a BUB1B missense substitution (p.R691H) within the region reported to directly interact with CENPE; another had a p.D303E substitution in a highly ECR of the Aurora B catalytic domain.	('p.D303E', 'Mutation', 'p.D303E', (162, 169))	('Aurora B', 'Gene', (206, 214))	('p.D303E', 'Var', (162, 169))	('Aurora B', 'Gene', '9212', (206, 214))	('p.R691H', 'Mutation', 'p.R691H', (79, 86))	('p.R691H', 'Var', (79, 86))	('BUB1B', 'Gene', '701', (50, 55))	('BUB1B', 'Gene', (50, 55))
10705	32415113	Indeed, the twelve UM with CENPE alterations had significantly higher genome percentages with CNAs (Mann-Whitney, P = 0.028, median 23% vs 15%), though this association is confounded since tumours with high CNA generally have more genome-wide regions of LOH.	('tumours', 'Disease', (189, 196))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('CNAs', 'Disease', (94, 98))	('alterations', 'Var', (33, 44))	('tumours', 'Phenotype', 'HP:0002664', (189, 196))	('tumours', 'Disease', 'MESH:D009369', (189, 196))	('higher', 'PosReg', (63, 69))
10709	32415113	A hotspot mutation p.R175H (n = 1216 in IARC TP53 database) was observed in a hypermutated metastatic UM with deficient MBD4 and another hotspot mutation p.M237I (n = 196 in IARC TP53 database) was observed in a UM in a pan-cancer study of metastatic tumours.	('TP53', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (45, 49))	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('metastatic tumours', 'Disease', 'MESH:D018223', (240, 258))	('tumours', 'Phenotype', 'HP:0002664', (251, 258))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('p.R175H', 'Var', (19, 26))	('metastatic tumours', 'Disease', (240, 258))	('p.M237I', 'Var', (154, 161))	('MBD4', 'Gene', (120, 124))	('p.M237I', 'Mutation', 'rs587782664', (154, 161))	('MBD4', 'Gene', '8930', (120, 124))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('p.R175H', 'Mutation', 'rs28934578', (19, 26))	('cancer', 'Disease', (224, 230))	('TP53', 'Gene', '7157', (179, 183))	('TP53', 'Gene', (179, 183))
10710	32415113	Here we identified TP53 as an SMG and report six somatic TP53 mutations across four tumours in addition to eight cases of LOH (Figs.	('tumours', 'Disease', 'MESH:D009369', (84, 91))	('tumours', 'Disease', (84, 91))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('mutations', 'Var', (62, 71))
10711	32415113	One LOH case overlapped with an LOF mutation (p.C277*) resulting in a double-hit in TP53.	('double-hit', 'MPA', (70, 80))	('TP53', 'Gene', '7157', (84, 88))	('p.C277*', 'Var', (46, 53))	('TP53', 'Gene', (84, 88))	('p.C277*', 'Mutation', 'p.C277fsX', (46, 53))
10712	32415113	Another double-hit was seen in a sample with two missense mutations (p.H193R and p.T155I) confirmed as occurring on different alleles by assessing read pairs spanning both mutations.	('p.T155I', 'Var', (81, 88))	('p.T155I', 'Mutation', 'rs144294099', (81, 88))	('p.H193R', 'Mutation', 'rs786201838', (69, 76))	('p.H193R', 'Var', (69, 76))
10713	32415113	To evaluate the consequence of these mutations, we applied a computational prediction tool, FATHMM, and assessed the results of two comprehensive characterisation studies of TP53 mutations (Table 1).	('TP53', 'Gene', '7157', (174, 178))	('mutations', 'Var', (37, 46))	('mutations', 'Var', (179, 188))	('TP53', 'Gene', (174, 178))
10714	32415113	p.H193R is a recurrent hotspot classified as pathogenic by PHANTM, RFS and FATHMM, while the consequence of p.T155I is more uncertain, as the variant is classified pathogenic by PHANTM but predicted to have neutral impact by RFS and FATHMM.	('p.T155I', 'Var', (108, 115))	('p.H193R', 'Var', (0, 7))	('p.T155I', 'Mutation', 'rs144294099', (108, 115))	('p.H193R', 'Mutation', 'rs786201838', (0, 7))
10715	32415113	Finally, one UM had a LOF mutation (p.R342*, COSM11073) and a missense p.R248Q mutation, both of which frequently occur in malignancies and are classified as pathogenic (Table 1).	('malignancies', 'Disease', 'MESH:D009369', (123, 135))	('p.R248Q', 'Var', (71, 78))	('malignancies', 'Disease', (123, 135))	('COSM11073', 'Chemical', '-', (45, 54))	('p.R342*', 'Var', (36, 43))	('p.R342*', 'Mutation', 'p.R342*', (36, 43))	('p.R248Q', 'Mutation', 'rs11540652', (71, 78))
10716	32415113	RNA-seq data revealed one read pair spanning both positions, which contained p.R248Q and was wildtype for p.R342; furthermore, there was a significantly lower VAF at p.R342 (4/78) than at p.R248 (25/68) (two-sided Fisher's exact test, P = 2 x 10-6).	('p.R248Q', 'Var', (77, 84))	('p.R342', 'Var', (166, 172))	('p.R248 (25/68)', 'Mutation', 'p.dupR', (188, 202))	('VAF', 'CPA', (159, 162))	('p.R342', 'Var', (106, 112))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('lower', 'NegReg', (153, 158))	('R342', 'Chemical', '-', (168, 172))	('p.R248Q', 'Mutation', 'rs11540652', (77, 84))	('R342', 'Chemical', '-', (108, 112))
10717	32415113	These data suggest the two mutations occurred on different alleles, with the majority of the transcripts from the p.R342* allele undergoing nonsense mediated decay.	('undergoing', 'Reg', (129, 139))	('nonsense mediated decay', 'MPA', (140, 163))	('p.R342*', 'Mutation', 'p.R342*', (114, 121))	('p.R342*', 'Var', (114, 121))
10719	32415113	The spectrum of a few highly recurrent missense mutations, including p.R248Q, has, however, given rise to hypotheses that these hotspot mutations translate to mutant p53 with gained oncogenic functions.	('mutant', 'Var', (159, 165))	('p53', 'Gene', (166, 169))	('p53', 'Gene', '7157', (166, 169))	('p.R248Q', 'Mutation', 'rs11540652', (69, 76))	('p.R248Q', 'Var', (69, 76))	('gained', 'PosReg', (175, 181))	('oncogenic functions', 'CPA', (182, 201))
10720	32415113	For example, the p.R248Q mutation reported here has been shown to increase the migratory potential of cells in an in vitro model.	('p.R248Q', 'Var', (17, 24))	('increase', 'PosReg', (66, 74))	('migratory potential of cells in an in vitro model', 'CPA', (79, 128))	('p.R248Q', 'Mutation', 'rs11540652', (17, 24))
10727	32415113	Given the link between RPL5 and p53, we tested for an association between aberrations in RPL5 and TP53.	('RPL5', 'Gene', '6125', (89, 93))	('tested', 'Reg', (40, 46))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('RPL5', 'Gene', (23, 27))	('RPL5', 'Gene', (89, 93))	('TP53', 'Gene', '7157', (98, 102))	('aberrations', 'Var', (74, 85))	('RPL5', 'Gene', '6125', (23, 27))	('TP53', 'Gene', (98, 102))
10733	32415113	To overcome this, it may be necessary to disrupt this pathway through mutation/loss of either RPL5, RPL11 or TP53.	('RPL11', 'Gene', '6135', (100, 105))	('RPL5', 'Gene', (94, 98))	('RPL11', 'Gene', (100, 105))	('TP53', 'Gene', '7157', (109, 113))	('RPL5', 'Gene', '6125', (94, 98))	('mutation/loss', 'NegReg', (70, 83))	('TP53', 'Gene', (109, 113))	('mutation/loss', 'Var', (70, 83))
10745	32415113	To avoid false negatives in hotspots of known UM genes, these regions (GNAQ p.48, p.183, and p.209; GNA11 p.183 and p.209; SF3B1 codons p.625, p.666 and p.700; EIF1AX codons p.1-20, PLCB4 p630; and CYSLTR2 p.129) were called with higher sensitivity.	('EIF1AX', 'Gene', (160, 166))	('p.209', 'Var', (93, 98))	('GNAQ', 'Gene', (71, 75))	('SF3B1', 'Gene', (123, 128))	('PLCB4', 'Gene', (182, 187))	('p.209', 'Var', (116, 121))	('CYSLTR2', 'Gene', (198, 205))	('EIF1AX', 'Gene', '1964', (160, 166))	('p.625', 'Var', (136, 141))	('SF3B1', 'Gene', '23451', (123, 128))	('GNA11', 'Gene', (100, 105))	('false', 'biological_process', 'GO:0071877', ('9', '14'))	('p.183', 'Var', (106, 111))	('p.666', 'Var', (143, 148))	('PLCB4', 'Gene', '5332', (182, 187))	('p.700', 'Var', (153, 158))	('false', 'biological_process', 'GO:0071878', ('9', '14'))	('CYSLTR2', 'Gene', '57105', (198, 205))	('GNAQ', 'Gene', '2776', (71, 75))	('GNA11', 'Gene', '2767', (100, 105))
10746	32415113	To evaluate the TP53 mutations, they were compared with two comprehensive characterisation studies.	('TP53', 'Gene', '7157', (16, 20))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
10747	32415113	The Phenotypic Annotation of TP53 Mutations (PHANTM) score v1.0 is a weighted sum of z-scores for which common (i.e.	('TP53', 'Gene', '7157', (29, 33))	('Mutations', 'Var', (34, 43))	('TP53', 'Gene', (29, 33))
10748	32415113	The relative fitness score (RFS) is on average -2.50 for synonymous variants, while the average score for protein truncating variants is 0.42.	('variants', 'Var', (68, 76))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('fitness', 'Disease', (13, 20))	('fitness', 'Disease', 'MESH:D012640', (13, 20))
10752	32415113	For a tetraploid tumour, two peaks in VAF are expected corresponding to mutations occurring before and after the copy number gain, with the latter having half the VAF of the former.	('copy', 'Var', (113, 117))	('mutations', 'Var', (72, 81))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tetraploid tumour', 'Disease', (6, 23))	('tetraploid tumour', 'Disease', 'MESH:D057891', (6, 23))
10794	31557816	An overlay of the Raman spectra from samples Fuc1, Fuc2, and Fuc3 showed no change in the relative intensities of the sulfate group vibrations (822.5 cm-1, 839.8 cm-1, 1065.3 cm-1, 1262.4 cm-1) and methyl group vibrations (1340.9 cm-1, 1452.5 cm-1), indicating an equal ratio between the two groups and thereby showing that no desulfation occurred during the mild acid hydrolysis.	('sulfate', 'Chemical', 'MESH:D013431', (118, 125))	('sulfate group vibrations', 'MPA', (118, 142))	('methyl', 'Chemical', 'MESH:C031105', (198, 204))	('1340.9', 'Var', (223, 229))	('methyl group', 'MPA', (198, 210))
10795	31557816	SEC-MALS (Size-exclusion chromatography-Multi-Angle Light Scattering) analysis of Fuc1 revealed a very high molecular weight average of Mw = 1548 (+- 4.1) kDa, resulting in an average degree of polymerization (DPn) of 3512, with an approximated average monosaccharide unit weight of 290 g/mol.	('monosaccharide', 'Chemical', 'MESH:D009005', (253, 267))	('polymerization', 'MPA', (194, 208))	('monosaccharide unit', 'MPA', (253, 272))	('Mw = 1548', 'Var', (136, 145))
10806	31557816	Starting with the melanoma cell line OMM-1, stress induction with 1 mM H2O2 led to decreased cell viability of between 49% and 57% (Figure 6).	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('H2O2', 'Chemical', 'MESH:D014867', (71, 75))	('decreased', 'NegReg', (83, 92))	('cell viability', 'CPA', (93, 107))	('H2O2', 'Var', (71, 75))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))
10818	31557816	Fuc3 reduced VEGF to 0.84 +- 0.05 [arb.	('VEGF', 'Gene', '7422', (13, 17))	('VEGF', 'Gene', (13, 17))	('reduced', 'NegReg', (5, 12))	('Fuc3', 'Var', (0, 4))
10822	31557816	Due to the high amount of VEGF production in RPE cells, weaker effects could be expected, but again VEGF was reduced by Fuc2 and Fuc1 (Figure 9).	('VEGF production', 'biological_process', 'GO:0010573', ('26', '41'))	('VEGF', 'Gene', '7422', (100, 104))	('VEGF', 'Gene', (26, 30))	('Fuc2', 'Var', (120, 124))	('reduced', 'NegReg', (109, 116))	('VEGF', 'Gene', (100, 104))	('Fuc1', 'Var', (129, 133))	('VEGF', 'Gene', '7422', (26, 30))
10843	31557816	Because Fuc2 and Fuc3, which were also in that range, had no effect at all, and due to the absence of polyphenols by virtue of the high purity, it could be assumed that Fuc1 had no scavenging effect but rather interacted with the antioxidant defense system of the OMM-1 cell line.	('Fuc1', 'Var', (169, 173))	('interacted', 'Reg', (210, 220))	('scavenging', 'MPA', (181, 191))	('polyphenols', 'Chemical', 'MESH:D059808', (102, 113))
10858	31557816	Even more striking is the effect in the RPE cells, in which Fuc1 and Fuc2 also decreased VEGF despite the higher secretion.	('Fuc2', 'Var', (69, 73))	('secretion', 'biological_process', 'GO:0046903', ('113', '122'))	('secretion', 'MPA', (113, 122))	('decreased', 'NegReg', (79, 88))	('VEGF', 'Gene', '7422', (89, 93))	('higher', 'PosReg', (106, 112))	('Fuc1', 'Var', (60, 64))	('VEGF', 'Gene', (89, 93))
10859	31557816	Fuc3 showed a tendency to stimulate VEGF secretion in RPE cells; however, this was not significant and its biological relevance is therefore uncertain.	('Fuc3', 'Var', (0, 4))	('secretion', 'biological_process', 'GO:0046903', ('41', '50'))	('VEGF', 'Gene', (36, 40))	('stimulate', 'PosReg', (26, 35))	('VEGF', 'Gene', '7422', (36, 40))
10907	31557816	Fuc2 and Fuc3 lowered the cell viability of the melanoma cell line OMM-1 and should therefore be tested in further tumor cell lines as to whether this is cell line specific or in general for tumor cells, which could pave the way for anticancer studies.	('melanoma', 'Disease', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Disease', (115, 120))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('Fuc3', 'Var', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('lowered', 'NegReg', (14, 21))	('cell viability', 'CPA', (26, 40))	('Fuc2', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
10909	31557816	Fuc3 reduced VEGF secretion in ARPE19 but stimulated VEGF secretion in primary RPE cells.	('ARPE19', 'CellLine', 'CVCL:0145', (31, 37))	('VEGF', 'Gene', '7422', (13, 17))	('Fuc3', 'Var', (0, 4))	('secretion', 'biological_process', 'GO:0046903', ('18', '27'))	('VEGF', 'Gene', (53, 57))	('VEGF', 'Gene', (13, 17))	('secretion', 'biological_process', 'GO:0046903', ('58', '67'))	('reduced', 'NegReg', (5, 12))	('stimulated', 'PosReg', (42, 52))	('VEGF', 'Gene', '7422', (53, 57))
10910	31557816	Conversely, Fuc2 and Fuc1 inhibited VEGF in ARPE-19 as well as in RPE, with the strongest effect seen for 50 microg/mL Fuc1.	('ARPE-19', 'CellLine', 'CVCL:0145', (44, 51))	('Fuc1', 'Var', (21, 25))	('inhibited', 'NegReg', (26, 35))	('VEGF', 'Gene', (36, 40))	('VEGF', 'Gene', '7422', (36, 40))	('Fuc1', 'Var', (119, 123))
10922	30699934	Features of the primary tumor prognostic for an increased risk of distant metastatic disease include tumor size, AJCC staging, and genomic analysis demonstrating monosomy 3 or DecisionDx-UM high-risk molecular gene signature.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('monosomy 3', 'Var', (162, 172))	('AJCC', 'Disease', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('distant metastatic disease', 'Disease', (66, 92))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
10926	30699934	In cutaneous melanoma, the use of adjuvant CTLA-4 inhibitors and PD-1 inhibitors has been proven efficacious for locally advanced disease.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('CTLA-4', 'Gene', '1493', (43, 49))	('inhibitors', 'Var', (50, 60))	('CTLA-4', 'Gene', (43, 49))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('PD-1', 'Gene', (65, 69))	('PD-1', 'Gene', '5133', (65, 69))	('inhibitors', 'Var', (70, 80))	('cutaneous melanoma', 'Disease', (3, 21))
10995	30699934	In light of this data, it is not surprising that recent studies in uveal melanoma have focused on the therapeutic effect of PD-1 inhibitors given their greater efficacy and more acceptable toxicity profile compared to CTLA-4 inhibitors in cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (239, 257))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (239, 257))	('CTLA-4', 'Gene', '1493', (218, 224))	('inhibitors', 'Var', (129, 139))	('toxicity', 'Disease', 'MESH:D064420', (189, 197))	('toxicity', 'Disease', (189, 197))	('melanoma', 'Phenotype', 'HP:0002861', (249, 257))	('uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('uveal melanoma', 'Disease', (67, 81))	('PD-1', 'Gene', (124, 128))	('uveal melanoma', 'Disease', 'MESH:C536494', (67, 81))	('CTLA-4', 'Gene', (218, 224))	('PD-1', 'Gene', '5133', (124, 128))	('cutaneous melanoma', 'Disease', (239, 257))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
11006	30269473	Loss of Nuclear BAP1 Expression Is Associated with High WHO/ISUP Grade in Clear Cell Renal Cell Carcinoma BRCA1-associated protein 1 (BAP1) mutations are frequently reported in clear cell renal cell carcinoma (ccRCC); however, very few studies have evaluated the role of these mutations in other renal cell carcinoma (RCC) subtypes.	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (74, 105))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (85, 105))	('clear cell renal cell carcinoma', 'Disease', (177, 208))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (296, 316))	('BAP1', 'Gene', '8314', (16, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (210, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('BAP1', 'Gene', '8314', (134, 138))	('BRCA1-associated protein 1', 'Gene', '8314', (106, 132))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('Loss', 'NegReg', (0, 4))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (177, 208))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (74, 105))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (188, 208))	('BAP1', 'Gene', (16, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (307, 316))	('BRCA1-associated protein 1', 'Gene', (106, 132))	('renal cell carcinoma', 'Disease', (296, 316))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (296, 316))	('BAP1', 'Gene', (134, 138))	('RCC', 'Disease', (318, 321))	('RCC', 'Phenotype', 'HP:0005584', (318, 321))	('mutations', 'Var', (140, 149))	('Clear Cell Renal Cell Carcinoma', 'Disease', (74, 105))	('reported', 'Reg', (165, 173))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (177, 208))	('RCC', 'Disease', 'MESH:C538614', (318, 321))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (188, 208))	('Carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('RCC', 'Disease', (212, 215))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))
11016	30269473	Clear cell renal cell carcinoma (ccRCC) is the most common renal tumor subtype and is closely associated with von Hippel Lindau (VHL) tumor suppressor gene mutations that lead to the stabilization of hypoxia-inducible factors in both sporadic and familial forms.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('134', '150'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('tumor suppressor', 'biological_process', 'GO:0051726', ('134', '150'))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('hypoxia', 'Disease', (200, 207))	('RCC', 'Disease', (35, 38))	('stabilization', 'MPA', (183, 196))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('hypoxia', 'Disease', 'MESH:D000860', (200, 207))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('mutations', 'Var', (156, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('renal tumor', 'Disease', 'MESH:D007674', (59, 70))	('renal tumor', 'Phenotype', 'HP:0009726', (59, 70))	('von Hippel Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (110, 139))	('renal tumor', 'Disease', (59, 70))
11018	30269473	Studies have reported BAP1 mutation in about 10%-15% of ccRCC cases.	('mutation', 'Var', (27, 35))	('BAP1', 'Gene', '8314', (22, 26))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('reported', 'Reg', (13, 21))	('BAP1', 'Gene', (22, 26))
11021	30269473	Inactivation mutations of the BAP1 gene, including insertion, deletion, frameshift, nonsense, and missense mutations, have also been reported.	('frameshift', 'Var', (72, 82))	('BAP1', 'Gene', (30, 34))	('nonsense', 'Var', (84, 92))	('missense mutations', 'Var', (98, 116))	('insertion', 'Var', (51, 60))	('BAP1', 'Gene', '8314', (30, 34))	('deletion', 'Var', (62, 70))
11022	30269473	The germline mutation in the BAP1 gene is inherited in an autosomal dominant pattern.	('BAP1', 'Gene', '8314', (29, 33))	('BAP1', 'Gene', (29, 33))	('germline mutation', 'Var', (4, 21))
11025	30269473	BAP1 germline mutations are associated with poor prognosis in uveal melanoma, cutaneous melanoma, and ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('uveal melanoma', 'Disease', (62, 76))	('BAP1', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('germline mutations', 'Var', (5, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (78, 96))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('cutaneous melanoma', 'Disease', (78, 96))	('BAP1', 'Gene', '8314', (0, 4))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (78, 96))	('uveal melanoma', 'Phenotype', 'HP:0007716', (62, 76))	('uveal melanoma', 'Disease', 'MESH:C536494', (62, 76))	('RCC', 'Disease', (104, 107))
11026	30269473	Sporadic BAP1 mutations have also been identified in several tumors, including uveal melanoma, malignant mesothelioma, and ccRCC.	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (95, 117))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('BAP1', 'Gene', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('identified', 'Reg', (39, 49))	('malignant mesothelioma', 'Disease', (95, 117))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutations', 'Var', (14, 23))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('uveal melanoma', 'Disease', (79, 93))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (95, 117))	('tumors', 'Disease', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('BAP1', 'Gene', '8314', (9, 13))
11028	30269473	Nearly half of the investigated uveal melanoma tumors harbor an inactivating BAP1 mutation, which was strongly associated with the loss of BAP1 nuclear staining and other aggressive prognostic features.	('uveal melanoma', 'Phenotype', 'HP:0007716', (32, 46))	('loss', 'NegReg', (131, 135))	('associated', 'Reg', (111, 121))	('inactivating', 'Var', (64, 76))	('BAP1', 'Gene', '8314', (139, 143))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (32, 53))	('BAP1', 'Gene', '8314', (77, 81))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('uveal melanoma tumors', 'Disease', (32, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('BAP1', 'Gene', (139, 143))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('BAP1', 'Gene', (77, 81))
11029	30269473	Furthermore, several studies have revealed the association between inactivating BAP1 mutation and high grade ccRCC, sarcomatoid transformation, and poor prognosis in patients with ccRCC, especially in those with low-grade RCC.	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('sarcomatoid transformation', 'Disease', (116, 142))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('BAP1', 'Gene', '8314', (80, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('inactivating', 'Var', (67, 79))	('mutation', 'Var', (85, 93))	('RCC', 'Phenotype', 'HP:0005584', (222, 225))	('RCC', 'Disease', 'MESH:C538614', (222, 225))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('RCC', 'Disease', (222, 225))	('BAP1', 'Gene', (80, 84))	('RCC', 'Disease', (182, 185))	('sarcomatoid transformation', 'Disease', 'MESH:C538614', (116, 142))	('patients', 'Species', '9606', (166, 174))
11030	30269473	The loss of BAP1 expression in immunohistochemical staining has been reported as a highly reliable method for the detection of BAP1 mutation.	('BAP1', 'Gene', (127, 131))	('mutation', 'Var', (132, 140))	('expression', 'MPA', (17, 27))	('BAP1', 'Gene', '8314', (12, 16))	('BAP1', 'Gene', '8314', (127, 131))	('BAP1', 'Gene', (12, 16))	('loss', 'NegReg', (4, 8))
11031	30269473	Although BAP1 mutations are frequently observed in ccRCC, limited data are available on the expression of BAP1 in other RCC types.	('BAP1', 'Gene', (106, 110))	('observed', 'Reg', (39, 47))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('BAP1', 'Gene', '8314', (9, 13))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('BAP1', 'Gene', '8314', (106, 110))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
11067	30269473	BAP1 mutation, a chromatin remodeling gene mutation, was reported in ccRCC (11.0%) and papillary RCC (5.6%) but not in chromophobe RCC.	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('BAP1', 'Gene', (0, 4))	('chromophobe RCC', 'Disease', (119, 134))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('17', '37'))	('RCC', 'Disease', (131, 134))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('chromatin', 'cellular_component', 'GO:0000785', ('17', '26'))	('ccRCC', 'Phenotype', 'HP:0006770', (69, 74))	('chromophobe RCC', 'Disease', 'MESH:C538614', (119, 134))	('BAP1', 'Gene', '8314', (0, 4))	('mutation', 'Var', (5, 13))
11068	30269473	BAP1 mutation was also shown to be correlated with decreased survival in ccRCC.	('BAP1', 'Gene', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('decreased', 'NegReg', (51, 60))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('survival', 'MPA', (61, 69))	('BAP1', 'Gene', '8314', (0, 4))	('ccRCC', 'Phenotype', 'HP:0006770', (73, 78))	('mutation', 'Var', (5, 13))
11071	30269473	BAP1 mutation was more frequent in female patients as per TCGA data.	('BAP1', 'Gene', (0, 4))	('frequent', 'Reg', (23, 31))	('BAP1', 'Gene', '8314', (0, 4))	('patients', 'Species', '9606', (42, 50))	('mutation', 'Var', (5, 13))
11073	30269473	In several studies, loss of BAP1 expression served as an independent marker of prognosis in patients with ccRCC and low-grade ccRCC.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('BAP1', 'Gene', '8314', (28, 32))	('RCC', 'Disease', (108, 111))	('RCC', 'Disease', (128, 131))	('loss', 'Var', (20, 24))	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('BAP1', 'Gene', (28, 32))	('patients', 'Species', '9606', (92, 100))	('expression', 'MPA', (33, 43))
11081	30269473	An additional analysis is needed to further elucidate the role of BAP1 and the relationship between loss of BAP1 expression in IHC and BAP1 mutation in chromophobe RCC and clear cell papillary RCC.	('expression', 'MPA', (113, 123))	('RCC', 'Disease', (193, 196))	('BAP1', 'Gene', '8314', (66, 70))	('BAP1', 'Gene', '8314', (108, 112))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('chromophobe RCC', 'Disease', 'MESH:C538614', (152, 167))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('BAP1', 'Gene', '8314', (135, 139))	('mutation', 'Var', (140, 148))	('BAP1', 'Gene', (66, 70))	('BAP1', 'Gene', (108, 112))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('BAP1', 'Gene', (135, 139))	('RCC', 'Disease', (164, 167))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('chromophobe RCC', 'Disease', (152, 167))	('loss', 'NegReg', (100, 104))
11082	30269473	In conclusion, we revealed that BAP1 expression is associated with high WHO/ISUP grade in patients with ccRCC and that BAP1 expression loss is also observed in chromophobe RCC and clear cell papillary RCC.	('expression', 'Var', (37, 47))	('chromophobe RCC', 'Disease', 'MESH:C538614', (160, 175))	('BAP1', 'Gene', (32, 36))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('BAP1', 'Gene', (119, 123))	('RCC', 'Disease', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (104, 109))	('chromophobe RCC', 'Disease', (160, 175))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('patients', 'Species', '9606', (90, 98))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('loss', 'NegReg', (135, 139))	('BAP1', 'Gene', '8314', (32, 36))	('associated', 'Reg', (51, 61))	('BAP1', 'Gene', '8314', (119, 123))	('expression', 'MPA', (124, 134))	('RCC', 'Disease', (172, 175))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))
11099	29122287	For example, tumors with a radiographic nodular growth pattern on angiography appear to be more responsive to chemoembolization or radioembolization compared to tumors classified with a radiographic infiltrative pattern.	('nodular', 'Var', (40, 47))	('growth pattern', 'biological_process', 'GO:0007150', ('48', '62'))	('growth pattern', 'biological_process', 'GO:0040007', ('48', '62'))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('responsive', 'MPA', (96, 106))
11126	29122287	IHC/IF staining confirmed the melanoma with HMB45 positivity and showed that these infiltrates contained CD31+ /CD105- endothelial cells, consistent with the endothelial lining of the sinusoidal spaces.	('CD31', 'Gene', (105, 109))	('HMB45', 'Gene', (44, 49))	('CD31', 'Gene', '5175', (105, 109))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Disease', (30, 38))	('positivity', 'Var', (50, 60))
11130	29122287	These tumors were either stage II infiltrative (Figure 6), which were composed of expanded metastases (51 - 500 um in diameter) in the sinusoidal spaces containing stellate cell lined pseudosinusoidal spaces and collagen bands that were remnants of the lobular architecture, or stage III infiltrative metastases (greater than 500 um in diameter, Figure 7), which replaced the hepatic lobule and contained only thin strands of collagen remnants of the original hepatic lobule.	('hepatic lobule', 'Phenotype', 'HP:0100752', (460, 474))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('metastases', 'Disease', (91, 101))	('metastases', 'Disease', (301, 311))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('collagen', 'molecular_function', 'GO:0005202', ('426', '434'))	('metastases', 'Disease', 'MESH:D009362', (301, 311))	('metastases', 'Disease', 'MESH:D009362', (91, 101))	('51 - 500 um', 'Var', (103, 114))	('collagen', 'molecular_function', 'GO:0005202', ('212', '220'))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('hepatic lobule', 'Phenotype', 'HP:0100752', (376, 390))
11136	29122287	As the size (diameter) of islands of tumor grows from stage I (<50microm) to stage II (50-500 microm) and stage III (>500 microm), pseudosinusoidal spaces lined by stellate cells form, thus allowing the tumor to be bathed with blood and obviate angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('angiogenesis', 'CPA', (245, 257))	('angiogenesis', 'biological_process', 'GO:0001525', ('245', '257'))	('50-500', 'Var', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('>500', 'Var', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (203, 208))
11174	30049845	There are obviously differences in the structures of subdomain P between ANGPTL3 and ANGPTL4 indicating that while loss-of-function mutations, ANGPTL3 and ANGPTL4 act by different pathways.	('ANGPTL4', 'Gene', (85, 92))	('ANGPTL3', 'Gene', '27329', (73, 80))	('ANGPTL3', 'Gene', (73, 80))	('mutations', 'Var', (132, 141))	('ANGPTL4', 'Gene', (155, 162))	('differences', 'Reg', (20, 31))	('loss-of-function', 'NegReg', (115, 131))	('ANGPTL3', 'Gene', '27329', (143, 150))	('ANGPTL3', 'Gene', (143, 150))
11176	30049845	ANGPTL4 assembles into dimers and tetramers in cells, and two cysteine residues (Cys76 and Cys80) in the N-terminal domain are crucial to the stability of intermolecular disulphide bonds in ANGPTL4 oligomers.	('N', 'Chemical', 'MESH:D009584', (191, 192))	('cysteine', 'Chemical', 'MESH:D003545', (62, 70))	('ANGPTL4', 'Gene', (0, 7))	('N', 'Chemical', 'MESH:D009584', (105, 106))	('Cys76', 'Chemical', '-', (81, 86))	('Cys76', 'Var', (81, 86))	('Cys80', 'Var', (91, 96))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('Cys80', 'Chemical', '-', (91, 96))
11177	30049845	The full-length ANGPTL4 protein is proteolytically processed in the linker region (a major cleavage site between Lys168 and Lev169, a minor cleavage site between Lys170 and Met171) by proprotein convertases.	('Lys170', 'Chemical', '-', (162, 168))	('Met171', 'Chemical', '-', (173, 179))	('ANGPTL4', 'Gene', (16, 23))	('Lys168', 'Chemical', '-', (113, 119))	('Lev169', 'Chemical', '-', (124, 130))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('Lev169', 'Var', (124, 130))	('Lys168', 'Var', (113, 119))
11181	30049845	Furthermore, chronic caloric restriction, short-term cooling, very low-calorie diet (VLCD), high-fat, high-energy diet (HFED), and free fatty acids (also called NEFA) have been shown to increase plasma concentrations of ANGPTL4.	('free fatty acids', 'Chemical', 'MESH:D005230', (131, 147))	('increase', 'PosReg', (186, 194))	('NEFA', 'Chemical', 'MESH:D005230', (161, 165))	('plasma concentrations', 'MPA', (195, 216))	('ANGPTL4', 'Protein', (220, 227))	('high-energy diet', 'Var', (102, 118))	('increase plasma concentrations', 'Phenotype', 'HP:0020170', (186, 216))	('energy', 'Chemical', '-', (107, 113))	('free fatty acids', 'Var', (131, 147))	('high-fat', 'Var', (92, 100))
11196	30049845	Furthermore, E40K nucleotide polymorphisms of the ANGPTL4 gene decreased oligomer formation, which is correlated with decreased LPL inhibition activity and significantly lower triglyceride levels.	('triglyceride', 'Chemical', 'MESH:D014280', (176, 188))	('LPL', 'Gene', (128, 131))	('LPL', 'Gene', '4023', (128, 131))	('decreased', 'NegReg', (63, 72))	('E40K', 'Mutation', 'rs116843064', (13, 17))	('E40K nucleotide polymorphisms', 'Var', (13, 42))	('decreased', 'NegReg', (118, 127))	('lower', 'NegReg', (170, 175))	('formation', 'biological_process', 'GO:0009058', ('82', '91'))	('ANGPTL4', 'Gene', (50, 57))	('oligomer formation', 'MPA', (73, 91))	('triglyceride levels', 'MPA', (176, 195))	('lower triglyceride levels', 'Phenotype', 'HP:0012153', (170, 195))
11202	30049845	demonstrated that plasma ANGPTL4 was higher in patients with metabolic syndrome, and the number of single nucleotide polymorphisms in ANGPTL4 could predict future cardiovascular events.	('ANGPTL4', 'Gene', (134, 141))	('plasma ANGPTL4', 'MPA', (18, 32))	('higher', 'PosReg', (37, 43))	('cardiovascular events', 'Phenotype', 'HP:0001626', (163, 184))	('predict', 'Reg', (148, 155))	('patients', 'Species', '9606', (47, 55))	('metabolic syndrome', 'Disease', 'MESH:D008659', (61, 79))	('cardiovascular events', 'Disease', (163, 184))	('single nucleotide polymorphisms', 'Var', (99, 130))	('metabolic syndrome', 'Disease', (61, 79))
11203	30049845	Further study showed that carriers of inactivating genetic variants of ANGPTL4 had lower triglyceride levels and CAD risk, suggesting that ANGPTL4 might be a possible therapeutic target for the treatment of ischemic heart disease.	('ischemic heart disease', 'Disease', (207, 229))	('CAD risk', 'CPA', (113, 121))	('lower', 'NegReg', (83, 88))	('lower triglyceride levels', 'Phenotype', 'HP:0012153', (83, 108))	('ischemic heart disease', 'Disease', 'MESH:D003324', (207, 229))	('triglyceride', 'Chemical', 'MESH:D014280', (89, 101))	('triglyceride levels', 'MPA', (89, 108))	('ANGPTL4', 'Gene', (71, 78))	('inactivating', 'Var', (38, 50))
11220	30049845	High levels of ANGPTL4 are associated with a poor prognosis in solid tumors, such as prostate cancer, melanoma, hepatocellular carcinoma, bladder cancer, scirrhous gastric cancer, giant cell tumor, oral tongue cancer, and tongue squamous cell carcinoma.	('bladder cancer', 'Disease', 'MESH:D001749', (138, 152))	('bladder cancer', 'Disease', (138, 152))	('gastric cancer', 'Phenotype', 'HP:0012126', (164, 178))	('giant cell tumor', 'Disease', (180, 196))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('High levels', 'Var', (0, 11))	('bladder cancer', 'Phenotype', 'HP:0009725', (138, 152))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tongue squamous cell carcinoma', 'Disease', (222, 252))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('giant cell tumor', 'Phenotype', 'HP:0011847', (180, 196))	('solid tumors', 'Disease', 'MESH:D009369', (63, 75))	('hepatocellular carcinoma', 'Disease', (112, 136))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (229, 252))	('melanoma', 'Disease', (102, 110))	('oral tongue cancer', 'Disease', (198, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (222, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('giant cell tumor', 'Disease', 'MESH:D005870', (180, 196))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (112, 136))	('prostate cancer', 'Disease', 'MESH:D011471', (85, 100))	('ANGPTL4', 'Gene', (15, 22))	('prostate cancer', 'Phenotype', 'HP:0012125', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('scirrhous gastric cancer', 'Disease', 'MESH:D013274', (154, 178))	('scirrhous gastric cancer', 'Disease', (154, 178))	('solid tumors', 'Disease', (63, 75))	('associated', 'Reg', (27, 37))	('oral tongue cancer', 'Disease', 'MESH:D014062', (198, 216))	('prostate cancer', 'Disease', (85, 100))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (222, 252))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (112, 136))
11221	30049845	found that T266M cANGPTL4 bound to integrin alpha5beta1 contributed to the weaker activation of downstream signaling molecules, leading to reduced proliferation, anoikis resistance, migratory capability, and impaired adenylate energy charge.	('activation', 'MPA', (82, 92))	('cANGPTL4', 'Chemical', '-', (17, 25))	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('impaired', 'NegReg', (208, 216))	('anoikis', 'biological_process', 'GO:0043276', ('162', '169'))	('T266M', 'Mutation', 'rs1044250', (11, 16))	('adenylate energy charge', 'MPA', (217, 240))	('cANGPTL4', 'Gene', (17, 25))	('anoikis resistance', 'CPA', (162, 180))	('downstream signaling molecules', 'MPA', (96, 126))	('reduced', 'NegReg', (139, 146))	('migratory capability', 'CPA', (182, 202))	('energy', 'Chemical', '-', (227, 233))	('bound', 'Interaction', (26, 31))	('T266M', 'Var', (11, 16))
11223	30049845	In breast cancer, knockdown of ANGPTL4 had no effect on tumor metastasis in local lymph nodes and bone, but could inhibit metastasis in the lung.	('knockdown', 'Var', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('inhibit', 'NegReg', (114, 121))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('metastasis in the lung', 'CPA', (122, 144))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('ANGPTL4', 'Gene', (31, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('tumor metastasis', 'Disease', 'MESH:D009362', (56, 72))	('tumor metastasis', 'Disease', (56, 72))
11260	30049845	Here, we review the aberrant expression of ANGPTL4 in eye diseases and summarize specific its pathogenic functions and possible mechanisms (Table 1).	('eye diseases', 'Phenotype', 'HP:0000478', (54, 66))	('ANGPTL4', 'Gene', (43, 50))	('aberrant', 'Var', (20, 28))	('eye diseases', 'Disease', 'MESH:D005128', (54, 66))	('eye diseases', 'Disease', (54, 66))	('eye disease', 'Phenotype', 'HP:0000478', (54, 65))
11282	30049845	assessed the role of ANGPTL4 in the changes in VEGF expression levels under high glucose conditions in HRMECs, with the knockdown of ANGPTL4, VEGF mRNA and secretion declined indicating the upstream role for ANGPTL4 with respect to VEGF.	('VEGF', 'Gene', (142, 146))	('VEGF', 'Gene', '7422', (47, 51))	('ANGPTL4', 'Gene', (133, 140))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('expression levels', 'MPA', (52, 69))	('secretion', 'biological_process', 'GO:0046903', ('156', '165'))	('N', 'Chemical', 'MESH:D009584', (209, 210))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('VEGF', 'Gene', '7422', (142, 146))	('high glucose', 'Phenotype', 'HP:0003074', (76, 88))	('knockdown', 'Var', (120, 129))	('VEGF', 'Gene', (232, 236))	('glucose', 'Chemical', 'MESH:D005947', (81, 88))	('VEGF', 'Gene', (47, 51))	('ME', 'Phenotype', 'HP:0040049', (105, 107))	('N', 'Chemical', 'MESH:D009584', (149, 150))	('VEGF', 'Gene', '7422', (232, 236))	('declined', 'NegReg', (166, 174))
11297	30049845	reported that HIF-1a accumulation in primary rabbit conjunctival epithelial cells promotes ANGPTL4 expression, and inhibition of ANGPTL4 expression is sufficient to inhibit the angiogenic phenotype of these cells.	('ANGPTL4', 'Gene', (129, 136))	('expression', 'MPA', (99, 109))	('promotes', 'PosReg', (82, 90))	('angiogenic phenotype of these cells', 'CPA', (177, 212))	('HIF-1a', 'Gene', (14, 20))	('HIF-1a', 'Gene', '100009579', (14, 20))	('inhibition', 'Var', (115, 125))	('inhibit', 'NegReg', (165, 172))	('rabbit', 'Species', '9986', (45, 51))	('ANGPTL4', 'Gene', (91, 98))
11304	30049845	These findings sustain the potential role for ANGPTL4 in the promotion of metastasis in UM and provide a basis for future investigations to determine more effective therapies like combining inhibition of both ANGPTL4 and VEGF to simultaneously target tumor-induced angiogenesis and metastasis.	('metastasis', 'CPA', (282, 292))	('VEGF', 'Gene', (221, 225))	('tumor', 'Disease', (251, 256))	('inhibition', 'Var', (190, 200))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('metastasis', 'CPA', (74, 84))	('VEGF', 'Gene', '7422', (221, 225))	('UM', 'Phenotype', 'HP:0007716', (88, 90))	('promotion', 'PosReg', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('angiogenesis', 'biological_process', 'GO:0001525', ('265', '277'))	('ANGPTL4', 'Gene', (46, 53))	('ANGPTL4', 'Gene', (209, 216))
11307	30049845	first discovered that ANGPTL4 knockout mice presented with substantially increased leakage of retinal capillaries with a reduction in pericytes, perturbation of caveolae, VE-cadherin, and ZO-1.	('retinal capillaries', 'Disease', (94, 113))	('perturbation', 'NegReg', (145, 157))	('increased', 'PosReg', (73, 82))	('caveolae', 'cellular_component', 'GO:0005901', ('161', '169'))	('retinal capillaries', 'Disease', 'MESH:D012173', (94, 113))	('mice', 'Species', '10090', (39, 43))	('knockout', 'Var', (30, 38))	('cadherin', 'molecular_function', 'GO:0008014', ('174', '182'))	('pericytes', 'MPA', (134, 143))	('caveolae', 'Protein', (161, 169))	('reduction', 'NegReg', (121, 130))	('VE-cadherin', 'Protein', (171, 182))	('ANGPTL4', 'Gene', (22, 29))
11312	30049845	doubt the safety and application value of developing anti-ANGPTL4 therapy because 93% perinatal mortality was found in newborn ANGPTL4 knockout mice, suggesting that ANGPTL4 may be indispensable for normal embryonic development.	('mice', 'Species', '10090', (144, 148))	('ANGPTL4', 'Gene', (127, 134))	('knockout', 'Var', (135, 143))
11322	28404968	DNA sequence analysis of BAP1 from 12 OMM patient samples revealed missense mutations in the tissues from four patients.	('missense mutations in', 'Var', (67, 88))	('BAP1', 'Gene', (25, 29))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('patient', 'Species', '9606', (42, 49))	('patient', 'Species', '9606', (111, 118))	('BAP1', 'Gene', '8314', (25, 29))	('patients', 'Species', '9606', (111, 119))
11325	28404968	It thus appears that loss of nuclear BAP1 expression is an independent prognostic factor of poor overall survival and associated with distant metastasis in OMM.	('loss', 'Var', (21, 25))	('overall survival', 'CPA', (97, 113))	('nuclear', 'Protein', (29, 36))	('poor', 'NegReg', (92, 96))	('BAP1', 'Gene', '8314', (37, 41))	('distant metastasis', 'CPA', (134, 152))	('associated', 'Reg', (118, 128))	('BAP1', 'Gene', (37, 41))	('OMM', 'Disease', (156, 159))
11329	28404968	The BAP1 gene locus is located on chromosome 3 (3p21.1) and frequent deletions of the 3p21 region has been commonly observed in lung and breast cancer cell lines.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('BAP1', 'Gene', (4, 8))	('lung', 'Disease', (128, 132))	('chromosome', 'cellular_component', 'GO:0005694', ('34', '44'))	('observed', 'Reg', (116, 124))	('deletions', 'Var', (69, 78))	('BAP1', 'Gene', '8314', (4, 8))
11330	28404968	In addition, germline and/or somatic mutations in BAP1 are reported in uveal melanoma, atypical epithelioid Spitz tumors, cutaneous melanoma, mesothelioma, renal cell carcinoma, lung adenocarcinoma, meningioma and many other cancers.	('reported', 'Reg', (59, 67))	('renal cell carcinoma', 'Disease', (156, 176))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (156, 176))	('cancers', 'Disease', (225, 232))	('epithelioid Spitz tumors', 'Disease', 'MESH:D018332', (96, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('lung adenocarcinoma', 'Disease', (178, 197))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('meningioma', 'Disease', (199, 209))	('meningioma', 'Phenotype', 'HP:0002858', (199, 209))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (178, 197))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('germline', 'Var', (13, 21))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('epithelioid Spitz tumors', 'Disease', (96, 120))	('uveal melanoma', 'Disease', 'MESH:C536494', (71, 85))	('BAP1', 'Gene', '8314', (50, 54))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (178, 197))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('mesothelioma', 'Disease', (142, 154))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (156, 176))	('uveal melanoma', 'Disease', (71, 85))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('cutaneous melanoma', 'Disease', (122, 140))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (122, 140))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (122, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('meningioma', 'Disease', 'MESH:D008577', (199, 209))	('mesothelioma', 'Disease', 'MESH:D008654', (142, 154))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('uveal melanoma', 'Phenotype', 'HP:0007716', (71, 85))	('BAP1', 'Gene', (50, 54))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
11333	28404968	Inactivation mutations in BAP1 have been associated with the pre-disposition and outcomes of many malignant tumors.	('BAP1', 'Gene', (26, 30))	('associated', 'Reg', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('malignant tumors', 'Disease', (98, 114))	('Inactivation mutations', 'Var', (0, 22))	('pre', 'molecular_function', 'GO:0003904', ('61', '64'))	('malignant tumors', 'Disease', 'MESH:D018198', (98, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('BAP1', 'Gene', '8314', (26, 30))
11334	28404968	Harbour and co-workers showed inactivating BAP1 mutations in majority of metastasizing uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (87, 102))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('BAP1', 'Gene', (43, 47))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (87, 101))	('BAP1', 'Gene', '8314', (43, 47))	('inactivating', 'Var', (30, 42))	('uveal melanomas', 'Disease', (87, 102))	('uveal melanomas', 'Phenotype', 'HP:0007716', (87, 102))	('mutations', 'Var', (48, 57))
11337	28404968	Loss of BAP1 was also associated with poor disease-free survival (DFS) and melanoma-specific survival (MSS) after adjusting for clinical and pathological factors in cutaneous melanoma.	('disease-free', 'Disease', (43, 55))	('cutaneous melanoma', 'Disease', (165, 183))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (165, 183))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (165, 183))	('poor', 'NegReg', (38, 42))	('BAP1', 'Gene', '8314', (8, 12))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('BAP1', 'Gene', (8, 12))	('melanoma', 'Disease', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('Loss', 'Var', (0, 4))
11338	28404968	Recently, loss of BAP1 expression has been used as a biomarker for therapeutic strategies.	('loss', 'Var', (10, 14))	('BAP1', 'Gene', '8314', (18, 22))	('expression', 'MPA', (23, 33))	('BAP1', 'Gene', (18, 22))
11341	28404968	The sequence analysis of the BAP1 gene from 12 OMM patients revealed missense mutations in four patients (Chr3: 52407995 C>G, p.S113T; Chr3: 52409864 C>A, p.W5C; Chr3: 52408565 T>A, p.E55V; Chr3: 52402325 C>T, p.R718Q) and this included identifying mutations in both the tumor and the blood samples of one of the patients (Table 1 and Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('p.E55V', 'Var', (182, 188))	('p.R718Q', 'Mutation', 'rs1440748203', (210, 217))	('p.S113T', 'Mutation', 'p.S113T', (126, 133))	('52409864 C>A', 'Mutation', 'rs916069743', (141, 153))	('p.W5C', 'Var', (155, 160))	('BAP1', 'Gene', '8314', (29, 33))	('patients', 'Species', '9606', (51, 59))	('p.R718Q', 'Var', (210, 217))	('patients', 'Species', '9606', (313, 321))	('Chr3: 52409864 C>A', 'Var', (135, 153))	('p.W5C', 'SUBSTITUTION', 'None', (155, 160))	('tumor', 'Disease', (271, 276))	('patients', 'Species', '9606', (96, 104))	('52407995 C>G', 'Mutation', 'g.52407995C>G', (112, 124))	('p.E55V', 'Mutation', 'p.E55V', (182, 188))	('BAP1', 'Gene', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('mutations', 'Var', (249, 258))	('52408565 T>A', 'Mutation', 'g.52408565T>A', (168, 180))	('52402325 C>T', 'Mutation', 'rs1440748203', (196, 208))
11342	28404968	Of the four mutations, three mutations (Chr3: 52407995 C>G, p.S113T; Chr3: 52409864 C>A, p.W5C; Chr3: 52408565 T>A, p.E55V) were located in the UCH (ubiquitin COOH-terminal hydrolase) domain (amino acids 1-240), whereas the fourth mutation (Chr3: 52402325 C>T, p.R718Q.)	('p.W5C', 'Var', (89, 94))	('52402325 C>T', 'Mutation', 'rs1440748203', (247, 259))	('p.R718Q', 'Mutation', 'rs1440748203', (261, 268))	('52408565 T>A', 'Mutation', 'g.52408565T>A', (102, 114))	('UCH', 'Gene', '7345', (144, 147))	('52407995 C>G', 'Mutation', 'g.52407995C>G', (46, 58))	('p.E55V', 'Mutation', 'p.E55V', (116, 122))	('UCH', 'Gene', (144, 147))	('ubiquitin', 'molecular_function', 'GO:0031386', ('149', '158'))	('p.W5C', 'SUBSTITUTION', 'None', (89, 94))	('Chr3: 52408565 T>A', 'Var', (96, 114))	('52409864 C>A', 'Mutation', 'rs916069743', (75, 87))	('p.S113T', 'Mutation', 'p.S113T', (60, 67))
11358	28404968	In our previous studies, we showed that only 7% tumors harbored KIT mutations and 3.5% harbored BRAF mutations, whereas, the classic BRAF V600E mutation was not detected in OMM and no mutation was found in NRAS and GNAQ/GNA11.	('NRAS', 'Gene', '4893', (206, 210))	('tumors', 'Disease', (48, 54))	('V600E', 'Mutation', 'rs113488022', (138, 143))	('BRAF', 'Gene', '673', (133, 137))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('BRAF', 'Gene', (133, 137))	('NRAS', 'Gene', (206, 210))	('GNA11', 'Gene', (220, 225))	('mutations', 'Var', (101, 110))	('V600E', 'Var', (138, 143))	('KIT', 'molecular_function', 'GO:0005020', ('64', '67'))	('GNAQ', 'Gene', '2776', (215, 219))	('KIT mutations', 'Var', (64, 77))	('GNAQ', 'Gene', (215, 219))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('GNA11', 'Gene', '2767', (220, 225))	('mutations', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
11360	28404968	Recent studies revealed that BAP1 mutations are closely associated with the onset and prognosis of melanoma and other malignancies.	('associated', 'Reg', (56, 66))	('BAP1', 'Gene', '8314', (29, 33))	('malignancies', 'Disease', 'MESH:D009369', (118, 130))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('BAP1', 'Gene', (29, 33))	('malignancies', 'Disease', (118, 130))	('mutations', 'Var', (34, 43))
11361	28404968	BAP1 mutations were detected in 32.5% of uveal melanoma and 2.4% of cutaneous melanoma according to the TCGA database.	('detected', 'Reg', (20, 28))	('uveal melanoma', 'Disease', (41, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (41, 55))	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('BAP1', 'Gene', (0, 4))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (68, 86))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('BAP1', 'Gene', '8314', (0, 4))	('cutaneous melanoma', 'Disease', (68, 86))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (68, 86))
11362	28404968	In this study, we detected BAP1 mutations in 4 out of 12 patients and the rate of mutation was higher than other classic mutations in OMM.	('detected', 'Reg', (18, 26))	('patients', 'Species', '9606', (57, 65))	('BAP1', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('BAP1', 'Gene', '8314', (27, 31))
11372	28404968	BAP1 mutation and its correlation with the outcome of malignancies have been widely reported.	('malignancies', 'Disease', (54, 66))	('BAP1', 'Gene', (0, 4))	('malignancies', 'Disease', 'MESH:D009369', (54, 66))	('BAP1', 'Gene', '8314', (0, 4))	('mutation', 'Var', (5, 13))
11375	28404968	Also, the cutaneous melanomas showed functional inactivation (by mutation or epigenetic mechanisms) of BAP1.	('BAP1', 'Gene', '8314', (103, 107))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (10, 29))	('BAP1', 'Gene', (103, 107))	('inactivation', 'NegReg', (48, 60))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (10, 29))	('epigenetic', 'Var', (77, 87))	('cutaneous melanomas', 'Disease', (10, 29))	('mutation', 'Var', (65, 73))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanomas', 'Phenotype', 'HP:0002861', (20, 29))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (10, 28))
11376	28404968	In the present study, loss of nuclear BAP1 was associated with mutations in the BAP1 exons in four of the twelve patient samples analyzed and was an independent prognostic factor that predicted poor OS.	('mutations', 'Var', (63, 72))	('patient', 'Species', '9606', (113, 120))	('BAP1', 'Gene', (38, 42))	('BAP1', 'Gene', '8314', (80, 84))	('loss', 'NegReg', (22, 26))	('BAP1', 'Gene', (80, 84))	('poor OS', 'Disease', (194, 201))	('BAP1', 'Gene', '8314', (38, 42))
11377	28404968	Therefore, results of our study concur with previous findings in uveal melanoma and cutaneous melanoma that, suggested that loss of nuclear BAP1 protein expression correlated with an aggressive subtype with poor survival in OMM patients.	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('uveal melanoma', 'Disease', (65, 79))	('loss', 'Var', (124, 128))	('BAP1', 'Gene', (140, 144))	('protein', 'Protein', (145, 152))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('cutaneous melanoma', 'Disease', (84, 102))	('patients', 'Species', '9606', (228, 236))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('OMM', 'Disease', (224, 227))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (84, 102))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (84, 102))	('BAP1', 'Gene', '8314', (140, 144))	('uveal melanoma', 'Disease', 'MESH:C536494', (65, 79))
11379	28404968	Mutation in BAP1 has been correlated with the cell type of melanoma in many studies.	('Mutation', 'Var', (0, 8))	('BAP1', 'Gene', (12, 16))	('BAP1', 'Gene', '8314', (12, 16))	('correlated', 'Reg', (26, 36))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
11380	28404968	Loss of BAP1 was also associated with the epithelioid histological type of melanocytic neoplasms including uveal melanoma and epithelioid atypical Spitz tumor and the presence of epithelioid cells in uveal melanoma.	('uveal melanoma', 'Disease', (107, 121))	('melanocytic neoplasms', 'Disease', (75, 96))	('BAP1', 'Gene', '8314', (8, 12))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('uveal melanoma', 'Disease', (200, 214))	('uveal melanoma', 'Disease', 'MESH:C536494', (200, 214))	('tumor', 'Disease', (153, 158))	('BAP1', 'Gene', (8, 12))	('associated', 'Reg', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('uveal melanoma', 'Disease', 'MESH:C536494', (107, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (200, 214))	('neoplasms', 'Phenotype', 'HP:0002664', (87, 96))	('Loss', 'Var', (0, 4))	('neoplasm', 'Phenotype', 'HP:0002664', (87, 95))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (75, 96))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (75, 96))
11383	28404968	Therefore, BAP1 appears to function in the uveal melanocyte lineage primarily as a regulator of differentiation, with cells deficient for BAP1 exhibiting stem-like features.	('BAP1', 'Gene', '8314', (138, 142))	('BAP1', 'Gene', '8314', (11, 15))	('BAP1', 'Gene', (138, 142))	('BAP1', 'Gene', (11, 15))	('deficient', 'Var', (124, 133))
11385	28404968	Also, the loss of BAP1 could regulate class I HDAC expression and affect the sensitivity of tumor cells to HDAC inhibitors.	('loss', 'Var', (10, 14))	('affect', 'Reg', (66, 72))	('BAP1', 'Gene', '8314', (18, 22))	('HDAC', 'Gene', (46, 50))	('HDAC', 'Gene', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('HDAC', 'Gene', '9734', (46, 50))	('HDAC', 'Gene', '9734', (107, 111))	('BAP1', 'Gene', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('expression', 'MPA', (51, 61))	('tumor', 'Disease', (92, 97))	('regulate', 'Reg', (29, 37))	('sensitivity', 'MPA', (77, 88))
11391	28404968	In conclusion, we detected four mis-sense BAP1 mutations in the twelve OMM patient samples that were sequenced.	('BAP1', 'Gene', '8314', (42, 46))	('BAP1', 'Gene', (42, 46))	('patient', 'Species', '9606', (75, 82))	('mutations', 'Var', (47, 56))
11441	15560844	However, another study using human tumour xenografts found that gefitinib caused growth inhibition of tumours and enhancement of the activity of a number of cytotoxic drugs, but neither was dependent on high levels of EGFR expression.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('EGFR', 'molecular_function', 'GO:0005006', ('218', '222'))	('tumour', 'Disease', (102, 108))	('raf', 'Gene', '22882', (47, 50))	('EGFR', 'Gene', (218, 222))	('gefitinib', 'Chemical', 'MESH:D000077156', (64, 73))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('gefitinib', 'Var', (64, 73))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('activity', 'MPA', (133, 141))	('tumour', 'Disease', (35, 41))	('EGFR', 'Gene', '1956', (218, 222))	('human', 'Species', '9606', (29, 34))	('tumours', 'Disease', (102, 109))	('raf', 'Gene', (47, 50))	('enhancement', 'PosReg', (114, 125))	('growth inhibition', 'CPA', (81, 98))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('tumours', 'Disease', 'MESH:D009369', (102, 109))
11444	15560844	epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha); heterodimerization with HER2 and cross talk with heterologous receptors; and EGFR mutations yielding a constitutively active receptor that is not down-regulated by endocytosis.	('EGFR', 'Gene', (157, 161))	('TGF-alpha', 'Gene', '7039', (68, 77))	('heterodimerization', 'MPA', (80, 98))	('mutations', 'Var', (162, 171))	('transforming growth factor-alpha', 'molecular_function', 'GO:0005154', ('34', '66'))	('TGF-alpha', 'Gene', (68, 77))	('endocytosis', 'biological_process', 'GO:0006897', ('244', '255'))	('EGFR', 'molecular_function', 'GO:0005006', ('157', '161'))	('EGF', 'molecular_function', 'GO:0005154', ('25', '28'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('0', '23'))	('HER2', 'Gene', (104, 108))	('EGFR', 'Gene', '1956', (157, 161))	('HER2', 'Gene', '2064', (104, 108))
11445	15560844	There is evidence that the ras/raf pathway mediates proliferation, whereas the PI3/Akt pathway is essential for cell survival and may be constitutively activated in many tumours by loss of PTEN.	('PTEN', 'Gene', (189, 193))	('PTEN', 'Gene', '5728', (189, 193))	('Akt', 'Gene', (83, 86))	('raf', 'Gene', (31, 34))	('tumours', 'Disease', (170, 177))	('tumours', 'Disease', 'MESH:D009369', (170, 177))	('tumours', 'Phenotype', 'HP:0002664', (170, 177))	('Akt', 'Gene', '207', (83, 86))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('loss', 'Var', (181, 185))	('activated', 'PosReg', (152, 161))	('raf', 'Gene', '22882', (31, 34))
11454	15560844	Of the remaining samples, 10/86 had been treated with a variety of chemotherapy regimens and some patients had more than one treatment; epirubicin + cisplatin + 5-Fluorouracil (5-FU) (n = 3), epirubicin + cyclophosphamide (4-HC) (n = 1), 4-HC+methotrexate+5-FU (CMF) (n = 2), cisplatin + vinorelbine (n = 1), mitomycin C + 5-FU (n = 1), mitoxantrone + paclitaxel (n = 1), chlorambucil (n = 1), 4-HC (n = 1) and irinotecan (n = 1).	('mitoxantrone', 'Var', (337, 349))	('cisplatin', 'Chemical', 'MESH:D002945', (276, 285))	('patients', 'Species', '9606', (98, 106))	('paclitaxel', 'Chemical', 'MESH:D017239', (352, 362))	('cisplatin', 'Chemical', 'MESH:D002945', (149, 158))	('mitomycin', 'Var', (309, 318))
11497	15560844	In 38% of tumours (29/76), the combination of gefitinib + cytotoxic caused the IndexSUM to increase thereby increasing resistance.	('tumours', 'Disease', (10, 17))	('gefitinib', 'Var', (46, 55))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('increase', 'PosReg', (91, 99))	('tumours', 'Disease', 'MESH:D009369', (10, 17))	('gefitinib', 'Chemical', 'MESH:D000077156', (46, 55))	('resistance', 'MPA', (119, 129))	('tumours', 'Phenotype', 'HP:0002664', (10, 17))	('increasing', 'PosReg', (108, 118))
11538	26683624	Germline BAP1 mutations cause a cancer syndrome characterized by high incidence of mesothelioma (MM), uveal melanoma and other cancers, and by very high penetrance, as all individuals carrying BAP1 mutations developed at least one, and usually several, malignancies throughout their lives.	('cancer syndrome', 'Disease', 'MESH:D009369', (32, 47))	('cause', 'Reg', (24, 29))	('mesothelioma', 'Disease', (83, 95))	('mesothelioma', 'Disease', 'MESH:D008654', (83, 95))	('BAP1', 'Gene', (9, 13))	('cancer syndrome', 'Disease', (32, 47))	('mutations', 'Var', (198, 207))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancers', 'Disease', (127, 134))	('malignancies', 'Disease', 'MESH:D009369', (253, 265))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('mutations', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('malignancies', 'Disease', (253, 265))	('uveal melanoma', 'Disease', (102, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (102, 116))	('developed', 'Reg', (208, 217))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('BAP1', 'Gene', (193, 197))
11539	26683624	Through screening MM patients with histories of multiple cancers, we found four supposedly unrelated patients that shared an identical germline BAP1 mutation.	('multiple cancers', 'Disease', (48, 64))	('patients', 'Species', '9606', (101, 109))	('BAP1', 'Gene', (144, 148))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('multiple cancers', 'Disease', 'MESH:D009369', (48, 64))	('patients', 'Species', '9606', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutation', 'Var', (149, 157))
11540	26683624	We investigated whether this BAP1 mutation occurred in a 'hot-spot' for "de novo" mutations or whether these four MM patients shared a common ancestor.	('patients', 'Species', '9606', (117, 125))	('BAP1', 'Gene', (29, 33))	('mutation', 'Var', (34, 42))
11541	26683624	Our study shows that the application of modern genomic analyses, coupled with "classical" family histories collected by the treating physician, and with genealogical searches, offer a powerful strategy to identify high-risk germline BAP1 mutation carriers that will benefit from genetic counseling and early detection cancer screening.	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('cancer', 'Disease', (318, 324))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('germline', 'Gene', (224, 232))	('mutation', 'Var', (238, 246))
11543	26683624	In subsequent studies in US families with high incidence of MM and of uveal melanoma (UM) and no apparent exposure to mineral fibers, we identified germline mutations in the BAP1 gene, as the major risk factor for MM and UM development.	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('uveal melanoma', 'Disease', (70, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('UM development', 'CPA', (221, 235))	('BAP1', 'Gene', (174, 178))	('risk factor', 'Reg', (198, 209))	('germline', 'Var', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
11544	26683624	Thereafter, we and others confirmed that germline BAP1 mutations are a common heritable factor that predispose to MM, UM, cutaneous melanoma (CM), cholangiocarcinoma, renal cell carcinoma (RCC), and basal cell carcinoma (BCC), and to benign atypical melanocytic lesions known as MBAITs, and likely to several other malignancies including brain, breast, lung cancer, and sarcomas,:recently grouped together into the "BAP1 cancer syndrome".	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (199, 219))	('predispose', 'Reg', (100, 110))	('cancer syndrome', 'Disease', 'MESH:D009369', (421, 436))	('lung cancer', 'Phenotype', 'HP:0100526', (353, 364))	('melanocytic lesions', 'Disease', 'MESH:D009508', (250, 269))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (147, 165))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (167, 187))	('basal cell carcinoma', 'Disease', (199, 219))	('cancer syndrome', 'Disease', (421, 436))	('cholangiocarcinoma', 'Disease', (147, 165))	('cancer', 'Phenotype', 'HP:0002664', (358, 364))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (147, 165))	('cancer', 'Phenotype', 'HP:0002664', (421, 427))	('sarcomas', 'Disease', 'MESH:D012509', (370, 378))	('sarcomas', 'Phenotype', 'HP:0100242', (370, 378))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('mutations', 'Var', (55, 64))	('sarcomas', 'Disease', (370, 378))	('renal cell carcinoma', 'Disease', (167, 187))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (167, 187))	('cutaneous melanoma', 'Disease', (122, 140))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (122, 140))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (122, 140))	('brain', 'Disease', (338, 343))	('malignancies', 'Disease', 'MESH:D009369', (315, 327))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (199, 219))	('melanocytic lesions', 'Disease', (250, 269))	('malignancies', 'Disease', (315, 327))	('CM', 'Disease', 'MESH:D009202', (142, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('BAP1', 'Gene', (50, 54))	('RCC', 'Disease', (189, 192))	('breast, lung cancer', 'Disease', 'MESH:D001943', (345, 364))
11545	26683624	Thus, similarly to germline TP53 mutations that cause the Li-Fraumeni syndrome, germline BAP1 mutations are associated with a variety of cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (58, 78))	('TP53', 'Gene', '7157', (28, 32))	('BAP1', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('Li-Fraumeni syndrome', 'Disease', (58, 78))	('TP53', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('associated', 'Reg', (108, 118))	('cancers', 'Disease', (137, 144))
11547	26683624	BAP1 tumor suppressor functions have been attributed to its ability to regulate gene transcription via (i) interaction to host cell factor-1 (HCF1), Ying Yang 1 (YY1), and E2F1, (ii) modulation of histone H2A ubiquitylation, (iii) maintaining DNA integrity and modulating DNA repair by homologous recombination.	('YY1', 'Gene', (162, 165))	('regulate', 'Reg', (71, 79))	('ubiquitylation', 'MPA', (209, 223))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('transcription', 'biological_process', 'GO:0006351', ('85', '98'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('5', '21'))	('BAP1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('HCF1', 'Gene', (142, 146))	('host cell factor-1', 'Gene', '3054', (122, 140))	('tumor suppressor', 'biological_process', 'GO:0051726', ('5', '21'))	('DNA repair', 'biological_process', 'GO:0006281', ('272', '282'))	('host cell factor-1', 'Gene', (122, 140))	('DNA', 'cellular_component', 'GO:0005574', ('272', '275'))	('modulating', 'Reg', (261, 271))	('HCF1', 'Gene', '3054', (142, 146))	('modulation', 'Var', (183, 193))	('interaction', 'Interaction', (107, 118))	('host cell', 'cellular_component', 'GO:0043657', ('122', '131'))	('DNA', 'cellular_component', 'GO:0005574', ('243', '246'))	('E2F1', 'Gene', (172, 176))	('histone H2A', 'Protein', (197, 208))	('DNA', 'MPA', (243, 246))	('homologous recombination', 'biological_process', 'GO:0035825', ('286', '310'))	('maintaining', 'PosReg', (231, 242))	('gene transcription', 'MPA', (80, 98))	('tumor', 'Disease', (5, 10))	('YY1', 'Gene', '7528', (162, 165))	('E2F1', 'Gene', '1869', (172, 176))
11549	26683624	All carriers of germline BAP1 mutations studied so far have developed at least one malignancy by age 55 and many developed multiple cancers.	('developed', 'Reg', (113, 122))	('multiple cancers', 'Disease', 'MESH:D009369', (123, 139))	('BAP1', 'Gene', (25, 29))	('malignancy', 'Disease', 'MESH:D009369', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (30, 39))	('malignancy', 'Disease', (83, 93))	('multiple cancers', 'Disease', (123, 139))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
11551	26683624	Thus, MM patients carrying germline BAP1 mutations benefit from this information, and their relatives may benefit from screening programs for early cancer detection, when these malignancies can be cured by resection (melanomas) or are more susceptible to therapy (MM and other cancers).	('cancer', 'Disease', (148, 154))	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('patients', 'Species', '9606', (9, 17))	('cancer', 'Disease', (277, 283))	('malignancies', 'Disease', (177, 189))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('melanomas', 'Disease', (217, 226))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancers', 'Disease', (277, 284))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('melanomas', 'Phenotype', 'HP:0002861', (217, 226))	('BAP1', 'Gene', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('melanomas', 'Disease', 'MESH:D008545', (217, 226))	('malignancies', 'Disease', 'MESH:D009369', (177, 189))
11554	26683624	Sequence analysis of DNA isolated from peripheral blood mononuclear cells of these patients revealed that 4/22 of these familial MM cases, carried germline BAP1 mutations.	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('familial MM', 'Disease', (120, 131))	('mutations', 'Var', (161, 170))	('patients', 'Species', '9606', (83, 91))	('BAP1', 'Gene', (156, 160))
11555	26683624	One patient with peritoneal MM carried a heterozygous BAP1 variant (c.1938T>A, p.Tyr646*) in exon 15, leading to a stop codon and a truncated BAP1 protein, predicted to be 646 amino acids long and lacking the nuclear localization signal.	('protein', 'Protein', (147, 154))	('localization', 'biological_process', 'GO:0051179', ('217', '229'))	('c.1938T>A', 'Var', (68, 77))	('p.Tyr646*', 'Mutation', 'p.Y646*', (79, 88))	('patient', 'Species', '9606', (4, 11))	('BAP1', 'Gene', (142, 146))	('p.Tyr646*', 'Var', (79, 88))	('truncated', 'MPA', (132, 141))	('BAP1', 'Gene', (54, 58))	('c.1938T>A', 'Mutation', 'c.1938T>A', (68, 77))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))
11556	26683624	The other three MM patients with germline BAP1 mutations (MARF11-III-1, MARF18-III-1, MARF40-III-1) carried an identical mutation (c.1717_1717delC, p.Leu573fs*3, Fig 1A) in exon 13.	('patients', 'Species', '9606', (19, 27))	('p.Leu573fs*3', 'Var', (148, 160))	('p.Leu573fs*3', 'FRAMESHIFT', 'None', (148, 160))	('MARF', 'Gene', '9927', (58, 62))	('MARF', 'Gene', (86, 90))	('BAP1', 'Gene', (42, 46))	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (131, 146))	('MARF', 'Gene', '9927', (72, 76))	('MARF', 'Gene', '9927', (86, 90))	('MARF', 'Gene', (58, 62))	('MARF', 'Gene', (72, 76))	('c.1717_1717delC', 'Var', (131, 146))
11558	26683624	We previously found the same BAP1 germline deletion in another apparently unrelated patient from Texas, MARF2-IV-2 (referred to as SP-002 in our previous study).	('SP', 'Chemical', 'MESH:C000604007', (131, 133))	('MARF', 'Gene', '9927', (104, 108))	('germline', 'Var', (34, 42))	('MARF', 'Gene', (104, 108))	('BAP1', 'Gene', (29, 33))	('patient', 'Species', '9606', (84, 91))
11559	26683624	Based on these results, we concluded that either c.1717_1717delC was a hotspot for "de novo" BAP1 mutations or these four families had a common ancestor and BAP1 mutation was transmitted across multiple generations.	('mutations', 'Var', (98, 107))	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (49, 64))	('c.1717_1717delC', 'Var', (49, 64))	('BAP1', 'Gene', (93, 97))
11560	26683624	Sanger sequencing revealed that the four probands sharing the c.1717_1717delC BAP1 mutation also shared a rare allele of a synonymous SNP (rs71651686, minor allele frequency = 0.0016, according to NCBI dbSNP database) in exon 11, which is located 1770 bp upstream of the c.1717_1717delC variant in exon 13.	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (62, 77))	('rs71651686', 'Var', (139, 149))	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (271, 286))	('mutation', 'Var', (83, 91))	('c.1717_1717delC', 'Var', (62, 77))	('c.1717_1717delC', 'Var', (271, 286))	('rs71651686', 'Mutation', 'rs71651686', (139, 149))	('BAP1', 'Gene', (78, 82))
11563	26683624	Moreover, the BAP1 c.1717_1717delC mutation is not present in any of the three genome-wide/exome-sequencing variant databases (1000G+UK10K+ESP: which include a total of 8286 genomes surveyed).	('SP', 'Chemical', 'MESH:C000604007', (140, 142))	('c.1717_1717delC', 'Var', (19, 34))	('BAP1', 'Gene', (14, 18))	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (19, 34))
11565	26683624	We genotyped these four MM patients sharing the c.1717_1717delC BAP1 mutation and four unrelated healthy controls for 657,893 SNPs using the Illumina OmniExpress (OE) platform.	('c.1717_1717delC', 'Var', (48, 63))	('patients', 'Species', '9606', (27, 35))	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (48, 63))	('BAP1', 'Gene', (64, 68))
11568	26683624	The heterozygous BAP1 mutation found in the four probands (MARF2-IV-2, MARF11-III-1, MARF18-III-1, MARF40-III-1) causes a frame shift deletion (c.1717_1717delC) where Leu Trp, leading to a premature stop codon, which occurs two amino acids downstream.	('MARF', 'Gene', '9927', (85, 89))	('MARF', 'Gene', '9927', (99, 103))	('MARF', 'Gene', (71, 75))	('mutation', 'Var', (22, 30))	('MARF', 'Gene', '9927', (59, 63))	('causes', 'Reg', (113, 119))	('MARF', 'Gene', (99, 103))	('MARF', 'Gene', (85, 89))	('MARF', 'Gene', (59, 63))	('c.1717_1717delC', 'Var', (144, 159))	('Trp', 'Chemical', 'MESH:D014364', (171, 174))	('premature stop codon', 'MPA', (189, 209))	('MARF', 'Gene', '9927', (71, 75))	('Leu', 'Chemical', 'MESH:D007930', (167, 170))	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (144, 159))	('BAP1', 'Gene', (17, 21))
11572	26683624	These data confirmed that the malignancies observed in the four probands are associated with BAP1 alterations.	('malignancies', 'Disease', (30, 42))	('BAP1', 'Gene', (93, 97))	('associated', 'Reg', (77, 87))	('alterations', 'Var', (98, 109))	('malignancies', 'Disease', 'MESH:D009369', (30, 42))
11573	26683624	The extent of the shared haplotypes surrounding the BAP1 gene, between the four MARF probands carrying the c.1717_1717delC BAP1 mutation, indicated that these, presumably unrelated individuals, had a common ancestor.	('BAP1', 'Gene', (123, 127))	('c.1717_1717delC', 'Var', (107, 122))	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (107, 122))	('BAP1', 'Gene', (52, 56))	('MARF', 'Gene', '9927', (80, 84))	('MARF', 'Gene', (80, 84))
11575	26683624	This pedigree connected the lineage of the four probands carrying the c.1717_1717delC BAP1 mutation and the rare allele rs71651686 to a couple born in Germany in 1710 (male):whose ancestors were traced back to 1588 in Switzerland and immigrated to Germany in the 17th century:and in 1712 (female).	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (70, 85))	('rs71651686', 'Var', (120, 130))	('rs71651686', 'Mutation', 'rs71651686', (120, 130))	('BAP1', 'Gene', (86, 90))	('c.1717_1717delC', 'Var', (70, 85))
11578	26683624	This pedigree confirmed the relationship among the four c.1717_1717delC BAP1 mutant probands, as indicated by the molecular studies.	('BAP1', 'Gene', (72, 76))	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (56, 71))	('c.1717_1717delC', 'Var', (56, 71))
11580	26683624	Using our screening criteria, we found germline BAP1 mutations in 18% (4/22) MM patients.	('patients', 'Species', '9606', (80, 88))	('BAP1', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))
11581	26683624	The much higher rate of germline BAP1 mutations that we found in our selected cohort, compared to the percentage (1-2%) found in previous studies among "unselected" MM patients, indicates that the selection criteria we used, based on patient's and family history, are efficient to identify patients with the BAP1 cancer syndrome.	('cancer syndrome', 'Disease', 'MESH:D009369', (313, 328))	('cancer syndrome', 'Disease', (313, 328))	('patient', 'Species', '9606', (290, 297))	('patients', 'Species', '9606', (290, 298))	('patient', 'Species', '9606', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('patient', 'Species', '9606', (234, 241))	('patients', 'Species', '9606', (168, 176))	('BAP1', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))
11582	26683624	We have identified a heterozygous germline BAP1 c.1717_1717delC mutation that is responsible for a high incidence of MM, UM, and other cancers among four families (Fig 3 and S2 Table).	('c.1717_1717delC', 'Var', (48, 63))	('BAP1', 'Gene', (43, 47))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('responsible', 'Reg', (81, 92))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (48, 63))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))
11583	26683624	The absence of a history of asbestos exposure in all four probands suggests that the high penetrance of MM in the BAP1 mutant families may not require exposure to asbestos (e.g., at least professional exposure or identifiable environmental exposure, for a critical analysis of human carcinogen see ref.).	('asbestos', 'Chemical', 'MESH:D001194', (28, 36))	('asbestos', 'Chemical', 'MESH:D001194', (163, 171))	('BAP1', 'Gene', (114, 118))	('mutant', 'Var', (119, 125))	('human', 'Species', '9606', (277, 282))
11584	26683624	At the same time, only some BAP1 mutant families experience a high prevalence of MM, suggesting that in some families a low level of asbestos exposure may be a co-factor, while other families have higher prevalence of different tumor types, such as melanomas, etc.	('melanomas', 'Phenotype', 'HP:0002861', (249, 258))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('BAP1', 'Gene', (28, 32))	('melanomas', 'Disease', 'MESH:D008545', (249, 258))	('melanoma', 'Phenotype', 'HP:0002861', (249, 257))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('asbestos', 'Chemical', 'MESH:D001194', (133, 141))	('mutant', 'Var', (33, 39))	('tumor', 'Disease', (228, 233))	('melanomas', 'Disease', (249, 258))
11586	26683624	Thus, it is possible that exposure to low levels of asbestos may have triggered MM also in some of these individuals carrying germline BAP1 mutations.	('triggered', 'Reg', (70, 79))	('asbestos', 'Chemical', 'MESH:D001194', (52, 60))	('BAP1', 'Gene', (135, 139))	('mutations', 'Var', (140, 149))
11588	26683624	Through combined molecular and genealogical approaches we determined that these four probands, carrying the BAP1 c.1717_1717delC mutation, are related to a common ancestor, traced through nine generations.	('BAP1', 'Gene', (108, 112))	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (113, 128))	('c.1717_1717delC mutation', 'Var', (113, 137))
11591	26683624	We found that the c.1717_1717delC BAP1 mutation identified in our K4 was recently reported by Cebulla et al.	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (18, 33))	('c.1717_1717delC', 'Var', (18, 33))	('BAP1', 'Gene', (34, 38))
11592	26683624	Likewise, recurrent mutations in other parts of the BAP1 gene -i.e., not the c.1717_1717delC reported in this manuscript- have been found in several different families, see S4 Fig and S3 Table, suggesting the possibility that also those families are related.	('BAP1', 'Gene', (52, 56))	('found', 'Reg', (132, 137))	('mutations', 'Var', (20, 29))	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (77, 92))
11593	26683624	BAP1 mutations usually cause cancer after the peak of the reproductive age is passed.	('cancer', 'Disease', (29, 35))	('BAP1', 'Gene', (0, 4))	('cause', 'Reg', (23, 28))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
11594	26683624	Since these mutations do not appear to have deleterious effects, other than causing cancer in individuals after the reproductive age, they are not negatively selected for, and instead they are transmitted across generations, as we discovered and reported here.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('mutations', 'Var', (12, 21))	('causing', 'Reg', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
11595	26683624	Here we demonstrate and propose that a combination of a carefully taken patient and family history, together with modern molecular genetics and genealogical studies can be used to identify potential carriers of germline BAP1 mutations and to build large family trees.	('patient', 'Species', '9606', (72, 79))	('BAP1', 'Gene', (220, 224))	('mutations', 'Var', (225, 234))
11600	26683624	Her relatives and descendants are now been closely monitored for early cancer detection and are being tested for germline BAP1 mutations.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('BAP1', 'Gene', (122, 126))	('cancer', 'Disease', (71, 77))	('tested', 'Reg', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mutations', 'Var', (127, 136))
11602	26683624	Once new branches of the family carrying germline BAP1 mutations are identified, these family members, affected by MM, can be informed that their malignancy is usually associated with significantly longer survival than those occurring sporadically.	('mutations', 'Var', (55, 64))	('malignancy', 'Disease', 'MESH:D009369', (146, 156))	('BAP1', 'Gene', (50, 54))	('malignancy', 'Disease', (146, 156))	('longer', 'PosReg', (198, 204))
11604	26683624	Those who do not have disease and who did not inherit the mutation can be reassured they and their descendants are not at higher risk of malignancy than the general population.	('mutation', 'Var', (58, 66))	('malignancy', 'Disease', (137, 147))	('malignancy', 'Disease', 'MESH:D009369', (137, 147))
11607	26683624	In summary, it is clinically relevant to identify carriers of BAP1 mutations and patients who developed cancer in a background of germline BAP1 mutations.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('BAP1', 'Gene', (62, 66))	('patients', 'Species', '9606', (81, 89))	('mutations', 'Var', (67, 76))	('BAP1', 'Gene', (139, 143))	('mutations', 'Var', (144, 153))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
11624	26683624	The BAP1 mutation c.1717_1717delC is detected with the following forward primer: CCTCACCCACCCCCAGCA, and reverse primer TGGGAAGAGAGGTCACAA GAAAA.	('BAP1', 'Gene', (4, 8))	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (18, 33))	('c.1717_1717delC', 'Var', (18, 33))
11631	26683624	investigated the common ancestors of the four MM patients carrying germline BAP1 deletion c.1717_1717delC.	('deletion c.1717_1717delC', 'Var', (81, 105))	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (90, 105))	('BAP1', 'Gene', (76, 80))	('patients', 'Species', '9606', (49, 57))	('c.1717_1717delC', 'Var', (90, 105))
11759	25678394	Although the present study was small and selection bias toward patients without extrahepatic metastases was present, the results appear promising, especially considering the fact that this intervention adds essentially no further toxicity to BE and that development of extrahepatic metastases was delayed with immunoembolization compared with BE.	('extrahepatic metastases', 'Disease', (269, 292))	('extrahepatic metastases', 'Disease', (80, 103))	('BE', 'Chemical', '-', (343, 345))	('toxicity', 'Disease', 'MESH:D064420', (230, 238))	('toxicity', 'Disease', (230, 238))	('extrahepatic metastases', 'Disease', 'MESH:D009362', (269, 292))	('extrahepatic metastases', 'Disease', 'MESH:D009362', (80, 103))	('patients', 'Species', '9606', (63, 71))	('immunoembolization', 'Var', (310, 328))	('BE', 'Chemical', '-', (242, 244))
11771	24128712	Brief Report: Clinical characteristics of patients with malignant pleural mesothelioma harboring somatic BAP1 mutations Genomic studies of malignant pleural mesothelioma (MPM) have recently identified frequent mutations in the BAP1 gene.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (149, 169))	('BAP1', 'Gene', '8314', (227, 231))	('mutations', 'Var', (210, 219))	('mutations', 'Var', (110, 119))	('BAP1', 'Gene', '8314', (105, 109))	('BAP1', 'Gene', (227, 231))	('malignant pleural mesothelioma', 'Disease', (56, 86))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (56, 86))	('malignant pleural mesothelioma', 'Disease', (139, 169))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (139, 169))	('patients', 'Species', '9606', (42, 50))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (66, 86))	('BAP1', 'Gene', (105, 109))
11772	24128712	In uveal melanoma and clear cell renal cell carcinoma, BAP1 mutations are associated with poor outcomes but their clinical significance in MPM is unknown.	('uveal melanoma', 'Disease', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (22, 53))	('BAP1', 'Gene', (55, 59))	('clear cell renal cell carcinoma', 'Disease', (22, 53))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (33, 53))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (22, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('mutations', 'Var', (60, 69))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('BAP1', 'Gene', '8314', (55, 59))
11773	24128712	We therefore undertook this study to define the characteristics of patients whose MPM tumors harbor somatic BAP1 mutation and to examine the relationship between BAP1 mutation and survival.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutation', 'Var', (113, 121))	('MPM tumors', 'Disease', (82, 92))	('BAP1', 'Gene', '8314', (108, 112))	('harbor', 'Reg', (93, 99))	('BAP1', 'Gene', '8314', (162, 166))	('patients', 'Species', '9606', (67, 75))	('MPM tumors', 'Disease', 'MESH:D009369', (82, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('BAP1', 'Gene', (108, 112))	('BAP1', 'Gene', (162, 166))
11774	24128712	We reviewed the charts of 121 patients with MPM tumors diagnosed between 1990 and 2009 tested for BAP1 mutation and extracted the following information: age at diagnosis, sex, histology, stage, smoking status, asbestos exposure, family or personal history of malignancy, and treatment including surgery, chemotherapy, and radiation as well as survival status.	('MPM tumors', 'Disease', (44, 54))	('BAP1', 'Gene', (98, 102))	('MPM tumors', 'Disease', 'MESH:D009369', (44, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('malignancy', 'Disease', 'MESH:D009369', (259, 269))	('patients', 'Species', '9606', (30, 38))	('BAP1', 'Gene', '8314', (98, 102))	('malignancy', 'Disease', (259, 269))	('men', 'Species', '9606', (280, 283))	('mutation', 'Var', (103, 111))	('tested', 'Reg', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('asbestos', 'Chemical', 'MESH:D001194', (210, 218))
11775	24128712	Twenty-four (20%) of the 121 tumors harbored somatic BAP1 mutations.	('mutations', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('BAP1', 'Gene', '8314', (53, 57))	('tumors', 'Disease', (29, 35))	('BAP1', 'Gene', (53, 57))
11776	24128712	The percent of current or former smokers among cases with BAP1 mutations was significantly higher than in BAP1 wild-type cases, (75% vs 42%; p=0.006).	('mutations', 'Var', (63, 72))	('BAP1', 'Gene', (106, 110))	('higher', 'PosReg', (91, 97))	('BAP1', 'Gene', (58, 62))	('BAP1', 'Gene', '8314', (106, 110))	('BAP1', 'Gene', '8314', (58, 62))
11777	24128712	However, the types of nucleotide substitutions in BAP1 did not suggest that this association was due to a causative role of smoking in BAP1 mutations.	('BAP1', 'Gene', '8314', (135, 139))	('BAP1', 'Gene', '8314', (50, 54))	('BAP1', 'Gene', (135, 139))	('mutations', 'Var', (140, 149))	('BAP1', 'Gene', (50, 54))
11778	24128712	No other clinical feature was significantly different among those with and without BAP1 mutations in their MPM.	('BAP1', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('BAP1', 'Gene', '8314', (83, 87))
11779	24128712	There was also no difference in survival according to somatic BAP1 mutation status.	('BAP1', 'Gene', (62, 66))	('BAP1', 'Gene', '8314', (62, 66))	('mutation', 'Var', (67, 75))
11780	24128712	There is no apparent distinct clinical phenotype for MPM with somatic BAP1 mutation.	('BAP1', 'Gene', '8314', (70, 74))	('mutation', 'Var', (75, 83))	('MPM', 'Disease', (53, 56))	('BAP1', 'Gene', (70, 74))
11786	24128712	While it has been known for many years that inactivating mutations in neurofibromatosis 2 (NF2) and deletions of p16 are common in MPM, another commonly mutated gene, BRCA-associated protein 1 (BAP1), was only recently identified.	('p16', 'Gene', (113, 116))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('BRCA-associated protein 1', 'Gene', (167, 192))	('neurofibromatosis 2', 'Gene', (70, 89))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (70, 87))	('MPM', 'Gene', (131, 134))	('p16', 'Gene', '1029', (113, 116))	('BAP1', 'Gene', '8314', (194, 198))	('NF2', 'Gene', (91, 94))	('neurofibromatosis 2', 'Gene', '4771', (70, 89))	('deletions', 'Var', (100, 109))	('BRCA-associated protein 1', 'Gene', '8314', (167, 192))	('inactivating mutations', 'Var', (44, 66))	('BAP1', 'Gene', (194, 198))	('NF2', 'Gene', '4771', (91, 94))
11787	24128712	In the initial report, BAP1 mutations were identified in 23% of the MPM specimens.	('BAP1', 'Gene', (23, 27))	('men', 'Species', '9606', (77, 80))	('MPM', 'Disease', (68, 71))	('BAP1', 'Gene', '8314', (23, 27))	('mutations', 'Var', (28, 37))
11788	24128712	Loss of nuclear BAP1 protein expression was confirmed by immunohistochemistry in MPM with BAP1 mutation.	('MPM', 'Disease', (81, 84))	('BAP1', 'Gene', '8314', (90, 94))	('Loss', 'NegReg', (0, 4))	('BAP1', 'Gene', '8314', (16, 20))	('BAP1', 'Gene', (90, 94))	('BAP1', 'Gene', (16, 20))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('mutation', 'Var', (95, 103))
11789	24128712	No association was identified between BAP1 mutation and other commonly identified genetic alterations including p16 loss and NF2 mutation and/or loss.	('p16', 'Gene', (112, 115))	('mutation', 'Var', (129, 137))	('mutation', 'Var', (43, 51))	('BAP1', 'Gene', (38, 42))	('loss', 'NegReg', (145, 149))	('NF2', 'Gene', (125, 128))	('p16', 'Gene', '1029', (112, 115))	('loss', 'NegReg', (116, 120))	('NF2', 'Gene', '4771', (125, 128))	('BAP1', 'Gene', '8314', (38, 42))
11793	24128712	Mutations in BAP1 have also been described in other cancers.	('BAP1', 'Gene', (13, 17))	('cancers', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('described', 'Reg', (33, 42))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('BAP1', 'Gene', '8314', (13, 17))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
11794	24128712	In particular, BAP1 mutation is common in uveal melanoma (UM), the most frequent ocular tumor in Caucasian adults, where it is strongly associated with poor outcomes.	('associated', 'Reg', (136, 146))	('UM', 'Phenotype', 'HP:0007716', (58, 60))	('mutation', 'Var', (20, 28))	('BAP1', 'Gene', '8314', (15, 19))	('common', 'Reg', (32, 38))	('ocular tumor', 'Disease', 'MESH:D009369', (81, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('ocular tumor', 'Disease', (81, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('BAP1', 'Gene', (15, 19))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('uveal melanoma', 'Disease', (42, 56))	('ocular tumor', 'Phenotype', 'HP:0100012', (81, 93))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
11796	24128712	A multi-gene expression profiling assay divides UMs into low and high metastatic risk with 84% of metastatic UM harboring BAP1 mutation compared to only 4% of low risk cases.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('BAP1', 'Gene', (122, 126))	('gene expression', 'biological_process', 'GO:0010467', ('8', '23'))	('mutation', 'Var', (127, 135))	('UM', 'Phenotype', 'HP:0007716', (109, 111))	('BAP1', 'Gene', '8314', (122, 126))
11797	24128712	Likewise, in clear cell renal cell carcinoma, somatic BAP1 mutations associated with higher grade tumors shorter cancer-specific survival.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (13, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('higher grade', 'Disease', (85, 97))	('associated', 'Reg', (69, 79))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (113, 119))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (13, 44))	('clear cell renal cell carcinoma', 'Disease', (13, 44))	('BAP1', 'Gene', '8314', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutations', 'Var', (59, 68))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (24, 44))	('shorter', 'NegReg', (105, 112))	('BAP1', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
11798	24128712	Furthermore, recent reports have described germline BAP1 mutations in families predisposed to MPM and UM as well as atypical melanocytic tumors and renal cell carcinoma.	('renal cell carcinoma', 'Disease', (148, 168))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('BAP1', 'Gene', '8314', (52, 56))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (148, 168))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (148, 168))	('melanocytic tumors', 'Disease', (125, 143))	('melanocytic tumors', 'Disease', 'MESH:D009508', (125, 143))	('BAP1', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))	('UM', 'Phenotype', 'HP:0007716', (102, 104))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('MPM', 'Disease', (94, 97))
11799	24128712	These findings clearly suggest the existence of a new hereditary cancer predisposition syndrome but the phenotype and penetrance of germline BAP1 mutations remains unclear as does the role of gene-environment interactions in the development of these tumors.	('BAP1', 'Gene', '8314', (141, 145))	('mutations', 'Var', (146, 155))	('tumors', 'Disease', (250, 256))	('hereditary cancer', 'Disease', 'MESH:D009369', (54, 71))	('BAP1', 'Gene', (141, 145))	('men', 'Species', '9606', (236, 239))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('men', 'Species', '9606', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('hereditary cancer', 'Disease', (54, 71))	('tumors', 'Disease', 'MESH:D009369', (250, 256))
11800	24128712	While BAP1 mutation is considered a crucial event in the progression of UM, the clinical impact of BAP1 mutation in MPM remains unknown.	('BAP1', 'Gene', (99, 103))	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('BAP1', 'Gene', (6, 10))	('mutation', 'Var', (104, 112))	('BAP1', 'Gene', '8314', (99, 103))	('BAP1', 'Gene', '8314', (6, 10))
11801	24128712	Therefore, the purpose of this study was to characterize the clinical features of MPM patients whose tumors harbor BAP1 mutations.	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('BAP1', 'Gene', '8314', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('MPM', 'Disease', (82, 85))	('BAP1', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('patients', 'Species', '9606', (86, 94))
11802	24128712	Additionally, we examined the relationship between BAP1 mutation and survival.	('mutation', 'Var', (56, 64))	('BAP1', 'Gene', '8314', (51, 55))	('examined', 'Reg', (17, 25))	('BAP1', 'Gene', (51, 55))
11803	24128712	With the approval of the Memorial Sloan-Kettering Cancer Center Institutional Review Board, the clinical records of 121 patients whose MPM tumors had been tested for BAP1 mutation by conventional Sanger sequencing were reviewed.	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('Cancer', 'Disease', (50, 56))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutation', 'Var', (171, 179))	('BAP1', 'Gene', '8314', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('MPM tumors', 'Disease', (135, 145))	('patients', 'Species', '9606', (120, 128))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('BAP1', 'Gene', (166, 170))	('MPM tumors', 'Disease', 'MESH:D009369', (135, 145))	('tested', 'Reg', (155, 161))
11806	24128712	The relationship between BAP1 mutation status and age, sex, histology, stage, smoking status, asbestos exposure, and family or personal history of malignancy was assessed using Fisher's exact tests.	('malignancy', 'Disease', 'MESH:D009369', (147, 157))	('BAP1', 'Gene', (25, 29))	('malignancy', 'Disease', (147, 157))	('mutation', 'Var', (30, 38))	('asbestos', 'Chemical', 'MESH:D001194', (94, 102))	('BAP1', 'Gene', '8314', (25, 29))
11810	24128712	The BAP1 mutant and BAP1 wild-type groups were compared with respect to OS using the log-rank test.	('BAP1', 'Gene', (20, 24))	('BAP1', 'Gene', (4, 8))	('mutant', 'Var', (9, 15))	('BAP1', 'Gene', '8314', (20, 24))	('BAP1', 'Gene', '8314', (4, 8))
11811	24128712	Twenty-four of 121 MPM tumors harbored a somatic BAP1 mutation, giving a frequency of 20% (95% CI: 13-27%).	('MPM tumors', 'Disease', (19, 29))	('mutation', 'Var', (54, 62))	('BAP1', 'Gene', (49, 53))	('harbored', 'Reg', (30, 38))	('MPM tumors', 'Disease', 'MESH:D009369', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('BAP1', 'Gene', '8314', (49, 53))
11820	24128712	As shown in Table 2, there was no significant difference in age, sex, asbestos exposure, surgery, chemotherapy, radiation, family history of mesothelioma, family history of cancer, and personal history of cancer among patients with BAP1 mutant and BAP1 wild-type MPM.	('BAP1', 'Gene', (232, 236))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('mutant', 'Var', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('BAP1', 'Gene', '8314', (248, 252))	('cancer', 'Disease', (173, 179))	('patients', 'Species', '9606', (218, 226))	('cancer', 'Disease', (205, 211))	('asbestos', 'Chemical', 'MESH:D001194', (70, 78))	('BAP1', 'Gene', (248, 252))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('mesothelioma', 'Disease', (141, 153))	('BAP1', 'Gene', '8314', (232, 236))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))
11821	24128712	However, a smoking history, either former or current, was more common among those with BAP1 mutant tumors, 75% versus 42% (p=0.006).	('BAP1', 'Gene', '8314', (87, 91))	('common', 'Reg', (63, 69))	('BAP1', 'Gene', (87, 91))	('mutant', 'Var', (92, 98))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
11822	24128712	Based on this association, we reviewed the spectrum of nucleotide substitutions in BAP1-mutated cases for evidence of a causal link to smoking.	('nucleotide substitutions', 'Var', (55, 79))	('BAP1', 'Gene', (83, 87))	('BAP1', 'Gene', '8314', (83, 87))
11823	24128712	Fourteen of the 24 mutations identified in BAP1 were point mutations.	('BAP1', 'Gene', '8314', (43, 47))	('BAP1', 'Gene', (43, 47))	('point mutations', 'Var', (53, 68))	('mutations', 'Var', (19, 28))
11825	24128712	There was no significant difference (p=0.43) in the stage at presentation for BAP1 mutant versus wild-type disease (Figure 1).	('mutant', 'Var', (83, 89))	('BAP1', 'Gene', '8314', (78, 82))	('BAP1', 'Gene', (78, 82))
11826	24128712	Similarly, there was no difference (p=0.28) in the distribution of histologies among BAP1 mutant versus wild-type disease (Figure 2).	('BAP1', 'Gene', (85, 89))	('mutant', 'Var', (90, 96))	('BAP1', 'Gene', '8314', (85, 89))
11827	24128712	No difference in overall survival was associated with BAP1 mutation status (Figure 3).	('BAP1', 'Gene', '8314', (54, 58))	('BAP1', 'Gene', (54, 58))	('mutation status', 'Var', (59, 74))
11828	24128712	Those with BAP1 mutant tumors had a median overall survival of 14.3 months (95% CI: 12.4-19.4) while those with BAP1 wild-type tumors had a median overall survival of 14.8 months (95% CI: 10.6-37.3), p=0.81.	('BAP1', 'Gene', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (127, 133))	('BAP1', 'Gene', '8314', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('BAP1', 'Gene', (11, 15))	('mutant', 'Var', (16, 22))	('BAP1', 'Gene', '8314', (112, 116))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
11829	24128712	Twenty percent of MPM tumors harbor mutations in BAP1.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('BAP1', 'Gene', (49, 53))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('MPM tumors', 'Disease', (18, 28))	('MPM tumors', 'Disease', 'MESH:D009369', (18, 28))	('BAP1', 'Gene', '8314', (49, 53))
11830	24128712	We find that a smoking history is significantly more common in MPM patients whose tumors harbor a BAP1 mutation.	('BAP1', 'Gene', (98, 102))	('tumors', 'Disease', (82, 88))	('patients', 'Species', '9606', (67, 75))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('common', 'Reg', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BAP1', 'Gene', '8314', (98, 102))	('MPM', 'Disease', (63, 66))	('mutation', 'Var', (103, 111))
11831	24128712	Perhaps, BAP1 mutation is a sequela of toxic exposure to smoking but the wide variety of mutations is not typical of tobacco smoke mutagenesis (only 2 of 24 mutations were G to T transversions consistent with classic smoking associated changes).	('BAP1', 'Gene', '8314', (9, 13))	('mutations', 'Var', (157, 166))	('tobacco', 'Species', '4097', (117, 124))	('BAP1', 'Gene', (9, 13))	('mutagenesis', 'biological_process', 'GO:0006280', ('131', '142'))	('G to T transversions', 'Var', (172, 192))
11833	24128712	Other clinical characteristics were similar among those with mutant and wild-type BAP1 MPM.	('BAP1', 'Gene', (82, 86))	('mutant', 'Var', (61, 67))	('BAP1', 'Gene', '8314', (82, 86))
11834	24128712	While another group reported that BAP1 mutated cases were more likely to be partly or entirely epithelioid, this difference was not statistically significant in our larger cohort.	('mutated', 'Var', (39, 46))	('BAP1', 'Gene', '8314', (34, 38))	('BAP1', 'Gene', (34, 38))
11835	24128712	Similarly, while the initial report of BAP1 mutations in MPM found an association between older age and BAP1 mutation, this is not confirmed in this larger series.	('BAP1', 'Gene', '8314', (104, 108))	('mutation', 'Var', (109, 117))	('BAP1', 'Gene', (104, 108))	('mutations', 'Var', (44, 53))	('MPM', 'Gene', (57, 60))	('BAP1', 'Gene', '8314', (39, 43))	('BAP1', 'Gene', (39, 43))
11837	24128712	Finally, as these specimens were obtained over an 18 year period, changes in therapy could have obscured differences in survival by BAP1 mutation status.	('mutation status', 'Var', (137, 152))	('men', 'Species', '9606', (23, 26))	('BAP1', 'Gene', '8314', (132, 136))	('BAP1', 'Gene', (132, 136))
11838	24128712	Since the initial reports of germline BAP1 mutations, numerous other neoplasms including meningiomas, renal cell carcinoma, lung cancer, breast cancer, ovarian cancer, pancreas cancer, and leukemia have been associated with BAP1 mutation.	('BAP1', 'Gene', (224, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('pancreas cancer', 'Disease', 'MESH:D010190', (168, 183))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('BAP1', 'Gene', '8314', (38, 42))	('pancreas cancer', 'Phenotype', 'HP:0002894', (168, 183))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('neoplasms', 'Disease', 'MESH:D009369', (69, 78))	('leukemia', 'Phenotype', 'HP:0001909', (189, 197))	('pancreas cancer', 'Disease', (168, 183))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('lung cancer', 'Disease', (124, 135))	('meningiomas', 'Disease', 'MESH:D008577', (89, 100))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (102, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (152, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('meningiomas', 'Phenotype', 'HP:0002858', (89, 100))	('neoplasms', 'Disease', (69, 78))	('BAP1', 'Gene', (38, 42))	('leukemia', 'Disease', (189, 197))	('leukemia', 'Disease', 'MESH:D007938', (189, 197))	('meningiomas', 'Disease', (89, 100))	('BAP1', 'Gene', '8314', (224, 228))	('mutation', 'Var', (229, 237))	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('ovarian cancer', 'Disease', (152, 166))	('breast cancer', 'Disease', (137, 150))	('renal cell carcinoma', 'Disease', (102, 122))	('mutations', 'Var', (43, 52))	('associated', 'Reg', (208, 218))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (152, 166))	('neoplasms', 'Phenotype', 'HP:0002664', (69, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))
11839	24128712	While there is no apparent distinct phenotype for MPM with somatic BAP1 mutation, further study is needed to identify and characterize patients with germline BAP1 mutations.	('patients', 'Species', '9606', (135, 143))	('BAP1', 'Gene', (158, 162))	('BAP1', 'Gene', '8314', (67, 71))	('mutation', 'Var', (72, 80))	('BAP1', 'Gene', '8314', (158, 162))	('BAP1', 'Gene', (67, 71))
11840	24128712	To help describe the spectrum of disease associated with germline BAP1 mutation, we have initiated a prospective clinical protocol for patients with MPM, UM, and choroidal nevus (a premalignant eye tumor).	('premalignant eye tumor', 'Disease', 'MESH:D005134', (181, 203))	('patients', 'Species', '9606', (135, 143))	('BAP1', 'Gene', '8314', (66, 70))	('mutation', 'Var', (71, 79))	('premalignant eye tumor', 'Disease', (181, 203))	('BAP1', 'Gene', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('eye tumor', 'Phenotype', 'HP:0100012', (194, 203))	('UM', 'Phenotype', 'HP:0007716', (154, 156))	('choroidal nevus', 'Disease', (162, 177))	('nevus', 'Phenotype', 'HP:0003764', (172, 177))	('MPM', 'Disease', (149, 152))	('choroidal nevus', 'Phenotype', 'HP:0025314', (162, 177))
11841	24128712	First, patients will provide samples to participate in an anonymous estimate of the prevalence of germline BAP1 mutations.	('mutations', 'Var', (112, 121))	('BAP1', 'Gene', '8314', (107, 111))	('patients', 'Species', '9606', (7, 15))	('BAP1', 'Gene', (107, 111))
11842	24128712	Additionally, patients whose tumors harbor BAP1 mutation or meet pre-specified criteria will be offered identified germline BAP1 testing.	('BAP1', 'Gene', (43, 47))	('BAP1', 'Gene', '8314', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('BAP1', 'Gene', (124, 128))	('BAP1', 'Gene', '8314', (43, 47))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('pre', 'molecular_function', 'GO:0003904', ('65', '68'))	('mutation', 'Var', (48, 56))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('patients', 'Species', '9606', (14, 22))
11843	24128712	Those patients identified as carrying germline BAP1 mutations will be asked to invite both potentially affected and unaffected family members for testing through our Clinical Genetics Service.	('mutations', 'Var', (52, 61))	('BAP1', 'Gene', '8314', (47, 51))	('patients', 'Species', '9606', (6, 14))	('BAP1', 'Gene', (47, 51))
11844	24128712	We will also continue to explore the interaction of BAP1 mutation with other somatic mutations, environmental exposures, and single nucleotide polymorphisms.	('BAP1', 'Gene', (52, 56))	('mutation', 'Var', (57, 65))	('men', 'Species', '9606', (103, 106))	('BAP1', 'Gene', '8314', (52, 56))
11897	25624683	reported that uveal melanomas with chromosome 3 monosomy showed faster and greater tumor regression at 12 and 15 months following plaque radiotherapy and thermotherapy than melanomas with diosomy 3.	('melanomas', 'Disease', (173, 182))	('uveal melanoma', 'Phenotype', 'HP:0007716', (14, 28))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('tumor', 'Disease', (83, 88))	('melanomas', 'Disease', 'MESH:D008545', (173, 182))	('melanomas', 'Phenotype', 'HP:0002861', (173, 182))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanomas', 'Disease', (20, 29))	('melanomas', 'Phenotype', 'HP:0002861', (20, 29))	('chromosome', 'cellular_component', 'GO:0005694', ('35', '45'))	('monosomy', 'Var', (48, 56))	('greater', 'PosReg', (75, 82))	('uveal melanomas', 'Disease', (14, 29))	('melanomas', 'Disease', 'MESH:D008545', (20, 29))	('uveal melanomas', 'Phenotype', 'HP:0007716', (14, 29))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('uveal melanomas', 'Disease', 'MESH:C536494', (14, 29))
11931	24880939	Those with deeper localized AJCC stage IIB-C have an increased risk of relapse and death, while microscopic regional stage IIIA disease detectable with sentinel lymph node mapping and biopsy have intermediate risk.	('AJCC', 'Disease', (28, 32))	('relapse', 'CPA', (71, 78))	('death', 'Disease', 'MESH:D003643', (83, 88))	('regional stage IIIA', 'Phenotype', 'HP:0032055', (108, 127))	('death', 'Disease', (83, 88))	('stage IIB-C', 'Var', (33, 44))
11952	24880939	Approximately 40% of familial melanomas were attributed to heritable germline mutation in cyclin dependent kinase (CDK) gene CDKN2A.	('CDK', 'Gene', (115, 118))	('familial melanomas', 'Disease', (21, 39))	('cyclin', 'molecular_function', 'GO:0016538', ('90', '96'))	('CDK', 'molecular_function', 'GO:0004693', ('115', '118'))	('melanomas', 'Phenotype', 'HP:0002861', (30, 39))	('germline mutation', 'Var', (69, 86))	('CDKN2A', 'Gene', (125, 131))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('attributed', 'Reg', (45, 55))	('CDKN2A', 'Gene', '1029', (125, 131))	('familial melanomas', 'Disease', 'OMIM:155600', (21, 39))
11953	24880939	Defects in CDK4, xeroderma pigmentosum and MC1R genes have been implicated in familial melanomas.	('MC1R', 'Gene', (43, 47))	('CDK4', 'Gene', '1019', (11, 15))	('melanomas', 'Phenotype', 'HP:0002861', (87, 96))	('Defects', 'Var', (0, 7))	('CDK', 'molecular_function', 'GO:0004693', ('11', '14'))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (17, 38))	('implicated', 'Reg', (64, 74))	('familial melanomas', 'Disease', 'OMIM:155600', (78, 96))	('MC1R', 'Gene', '4157', (43, 47))	('familial melanomas', 'Disease', (78, 96))	('CDK4', 'Gene', (11, 15))	('xeroderma pigmentosum', 'Disease', (17, 38))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
11958	24880939	Systematic genetic typing identified the V600E variant to be frequent in cutaneous melanoma in 2002.	('cutaneous melanoma', 'Disease', (73, 91))	('V600E', 'Var', (41, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (73, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('V600E', 'Mutation', 'rs113488022', (41, 46))
11959	24880939	This mutation and its constitutive activation of the MAPK pathway have become the target of multiple pharmaceutical trials of small molecule inhibitors resulting in several new FDA-approved therapies.	('MAPK', 'molecular_function', 'GO:0004707', ('53', '57'))	('MAPK', 'Gene', '5594', (53, 57))	('mole', 'Phenotype', 'HP:0003764', (132, 136))	('MAPK', 'Gene', (53, 57))	('mutation', 'Var', (5, 13))
11961	24880939	Uveal melanomas exhibit driver mutations in GNAQ, GNA11 and BAP1 with low incidence of BRAF.	('mutations', 'Var', (31, 40))	('GNAQ', 'Gene', (44, 48))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('GNA11', 'Gene', '2767', (50, 55))	('GNA11', 'Gene', (50, 55))	('melanomas', 'Disease', (6, 15))	('BAP1', 'Gene', '8314', (60, 64))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))	('GNAQ', 'Gene', '2776', (44, 48))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('BRAF', 'Gene', (87, 91))	('BAP1', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (87, 91))
11962	24880939	The differing pattern of driver mutations in different histologic subtypes of melanoma, and the numeric burden of mutations in different melanoma cell lines from single tumors and in tumor samples ex vivo  reflect the genetic heterogeneity of melanoma and are likely to have profound implications for the molecular as well as immunological therapy of melanoma.	('mutations', 'Var', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('mole', 'Phenotype', 'HP:0003764', (305, 309))	('melanoma', 'Disease', 'MESH:D008545', (243, 251))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('mutations', 'Var', (32, 41))	('melanoma', 'Disease', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('tumor', 'Disease', (169, 174))	('melanoma', 'Disease', 'MESH:D008545', (351, 359))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('melanoma', 'Phenotype', 'HP:0002861', (243, 251))	('melanoma', 'Disease', (243, 251))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('tumors', 'Disease', (169, 175))	('melanoma', 'Phenotype', 'HP:0002861', (351, 359))	('melanoma', 'Disease', (351, 359))
11976	24880939	BRCA2 mutation carriers are noted to have a 2.58 times greater risk than non-carriers of developing melanoma.	('BRCA2', 'Gene', '675', (0, 5))	('mutation', 'Var', (6, 14))	('BRCA2', 'Gene', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))
12003	24880939	In thin melanomas, mitotic rate >= 1 serves as an indication of higher risk, and therefore warrant sentinel lymph node evaluation.	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('melanomas', 'Disease', 'MESH:D008545', (8, 17))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('mitotic rate >= 1', 'Var', (19, 36))	('melanomas', 'Disease', (8, 17))
12004	24880939	NRAS and BRAF mutations are also associated with differing patterns of disease aggressiveness.	('aggressiveness', 'Disease', 'MESH:D001523', (79, 93))	('BRAF', 'Gene', (9, 13))	('NRAS', 'Gene', '4893', (0, 4))	('aggressiveness', 'Disease', (79, 93))	('NRAS', 'Gene', (0, 4))	('aggressiveness', 'Phenotype', 'HP:0000718', (79, 93))	('mutations', 'Var', (14, 23))	('BRAF', 'Gene', '673', (9, 13))
12104	24880939	For the 40% of patients with mutated BRAF V600E who have responded and then relapsed (or less often failed altogether to respond) with molecularly targeted therapies including the BRAF and MEK inhibitors, disease progression is often rapid and options remain palliative in nature.	('mole', 'Phenotype', 'HP:0003764', (135, 139))	('BRAF', 'Gene', (180, 184))	('patients', 'Species', '9606', (15, 23))	('V600E', 'Var', (42, 47))	('BRAF', 'Gene', '673', (37, 41))	('MEK', 'Gene', (189, 192))	('BRAF', 'Gene', (37, 41))	('MEK', 'Gene', '5609', (189, 192))	('mutated', 'Var', (29, 36))	('V600E', 'Mutation', 'rs113488022', (42, 47))	('BRAF', 'Gene', '673', (180, 184))
12123	24880939	Progression-free survival, the primary endpoint, was significantly improved, with nab-paclitaxel (median 4.8 versus 2.5 months, HR 0.79, 95% CI 0.63-0.99).	('improved', 'PosReg', (67, 75))	('paclitaxel', 'Chemical', 'MESH:D017239', (86, 96))	('nab-paclitaxel', 'Var', (82, 96))	('Progression-free survival', 'CPA', (0, 25))
12159	24880939	Nivolumab (BMS936558) is an anti PD-1 antibody that was evaluated in a phase1/2 study in patients with advanced cancers including 94 patients with melanoma.	('antibody', 'cellular_component', 'GO:0019815', ('38', '46'))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('antibody', 'cellular_component', 'GO:0019814', ('38', '46'))	('Nivolumab', 'Chemical', 'MESH:D000077594', (0, 9))	('patients', 'Species', '9606', (133, 141))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('BMS936558', 'Var', (11, 20))	('antibody', 'molecular_function', 'GO:0003823', ('38', '46'))	('patients', 'Species', '9606', (89, 97))	('cancers', 'Disease', (112, 119))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('PD-1', 'Gene', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('PD-1', 'Gene', '5133', (33, 37))	('BMS936558', 'Chemical', 'MESH:D000077594', (11, 20))	('antibody', 'cellular_component', 'GO:0042571', ('38', '46'))
12161	24880939	BMS936559, an anti PDL-1 antibody showed 20% ORR (9 out of 52 evaluable melanoma patients) in phase 1 trial.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('PDL-1', 'Gene', (19, 24))	('melanoma', 'Disease', (72, 80))	('antibody', 'cellular_component', 'GO:0019815', ('25', '33'))	('patients', 'Species', '9606', (81, 89))	('antibody', 'cellular_component', 'GO:0019814', ('25', '33'))	('antibody', 'molecular_function', 'GO:0003823', ('25', '33'))	('BMS936559', 'Var', (0, 9))	('PDL-1', 'Gene', '29126', (19, 24))	('antibody', 'cellular_component', 'GO:0042571', ('25', '33'))
12166	24880939	Discovery of activating mutations in BRAF V600E/K in 40-50% of cutaneous melanomas, and NRAS mutations in another 20% of cutaneous melanomas, coupled with highly active and specific agents that are capable of inhibiting these pathways has translated into a therapeutic revolution with significant palliative effect for many patients with metastatic melanoma, and improved survival for patients with metastatic melanoma.	('melanoma', 'Disease', (73, 81))	('V600E', 'SUBSTITUTION', 'None', (42, 47))	('man', 'Species', '9606', (319, 322))	('melanoma', 'Disease', 'MESH:D008545', (410, 418))	('melanoma', 'Phenotype', 'HP:0002861', (349, 357))	('cutaneous melanomas', 'Disease', (121, 140))	('melanoma', 'Disease', (349, 357))	('patients', 'Species', '9606', (324, 332))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (63, 82))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (63, 82))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (63, 81))	('NRAS', 'Gene', (88, 92))	('patients', 'Species', '9606', (385, 393))	('improved', 'PosReg', (363, 371))	('melanomas', 'Phenotype', 'HP:0002861', (131, 140))	('survival', 'MPA', (372, 380))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('BRAF', 'Gene', '673', (37, 41))	('activating', 'PosReg', (13, 23))	('melanoma', 'Phenotype', 'HP:0002861', (410, 418))	('BRAF', 'Gene', (37, 41))	('melanoma', 'Disease', (410, 418))	('cutaneous melanomas', 'Disease', (63, 82))	('melanoma', 'Disease', 'MESH:D008545', (349, 357))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('V600E', 'Var', (42, 47))	('melanoma', 'Disease', (131, 139))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (121, 140))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (121, 140))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (121, 139))	('NRAS', 'Gene', '4893', (88, 92))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
12167	24880939	FDA approved BRAF inhibitors (BRAFi)- Vemurafenib and Dabrafenib (Braf V600E or E and K mutation positive), and the MEK inhibitor (MEKi) Trametinib.	('MEK', 'Gene', '5609', (131, 134))	('Braf', 'Gene', '673', (66, 70))	('MEK', 'Gene', (116, 119))	('MEK', 'Gene', '5609', (116, 119))	('BRAF', 'Gene', '673', (13, 17))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('Dabrafenib', 'Chemical', 'MESH:C561627', (54, 64))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (38, 49))	('BRAF', 'Gene', (13, 17))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('V600E', 'Var', (71, 76))	('MEK', 'Gene', (131, 134))	('Dabrafenib', 'Gene', (54, 64))	('BRAFi', 'Chemical', '-', (30, 35))	('Trametinib', 'Chemical', 'MESH:C560077', (137, 147))	('Braf', 'Gene', (66, 70))
12172	24880939	Trametinib was compared to dacarbazine or taxol in BRAF V600E/K mutant patients.	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('patients', 'Species', '9606', (71, 79))	('V600E', 'Var', (56, 61))	('V600E', 'SUBSTITUTION', 'None', (56, 61))	('dacarbazine', 'Chemical', 'MESH:D003606', (27, 38))	('BRAF', 'Gene', '673', (51, 55))	('BRAF', 'Gene', (51, 55))	('taxol', 'Chemical', 'MESH:D017239', (42, 47))
12174	24880939	MEKi play a role in patients with BRAF mutant as well as those with the non-overlapping NRAS mutations found in cutaneous and also in uveal melanomas.	('uveal melanomas', 'Disease', (134, 149))	('uveal melanomas', 'Phenotype', 'HP:0007716', (134, 149))	('mutations', 'Var', (93, 102))	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('NRAS', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (34, 38))	('uveal melanomas', 'Disease', 'MESH:C536494', (134, 149))	('patients', 'Species', '9606', (20, 28))	('NRAS', 'Gene', '4893', (88, 92))	('mutant', 'Var', (39, 45))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('BRAF', 'Gene', (34, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (134, 148))
12177	24880939	Eventual development of resistance to these agents with NRAS or MEK mutations, BRAF truncations and amplification, and increased expression of receptor tyrosine kinases is a problem.	('MEK', 'Gene', (64, 67))	('NRAS', 'Gene', (56, 60))	('MEK', 'Gene', '5609', (64, 67))	('expression', 'MPA', (129, 139))	('NRAS', 'Gene', '4893', (56, 60))	('truncations', 'Var', (84, 95))	('men', 'Species', '9606', (16, 19))	('BRAF', 'Gene', '673', (79, 83))	('mutations', 'Var', (68, 77))	('BRAF', 'Gene', (79, 83))	('increased', 'PosReg', (119, 128))
12182	24880939	Although it showed limited efficacy in phase II trials, it was shown to have impressive response in patients with activating cKit mutation.	('mutation', 'Var', (130, 138))	('patients', 'Species', '9606', (100, 108))	('cKit', 'Gene', (125, 129))	('activating', 'PosReg', (114, 124))
12222	24872713	In GIST, sunitinib against wild-type and exon 9-mutant Kit was superior to that of imatinib in vitro, whereas both drugs exhibited similar potency against Kit exon-11 mutant kinases.	('sunitinib', 'Chemical', 'MESH:D000077210', (9, 18))	('GIST', 'Phenotype', 'HP:0100723', (3, 7))	('exon 9-mutant', 'Var', (41, 54))	('Kit', 'Gene', (55, 58))	('imatinib', 'Chemical', 'MESH:D000068877', (83, 91))
12226	24872713	FLT3 is another TKI that when mutated may lead to the development of a specific type of leukemia, known as acute myeloid leukemia.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (107, 129))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (113, 129))	('FLT3', 'Gene', '2322', (0, 4))	('leukemia', 'Disease', (121, 129))	('mutated', 'Var', (30, 37))	('leukemia', 'Disease', 'MESH:D007938', (121, 129))	('leukemia', 'Phenotype', 'HP:0001909', (121, 129))	('leukemia', 'Phenotype', 'HP:0001909', (88, 96))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (107, 129))	('acute myeloid leukemia', 'Disease', (107, 129))	('lead to', 'Reg', (42, 49))	('FLT3', 'Gene', (0, 4))	('leukemia', 'Disease', (88, 96))	('leukemia', 'Disease', 'MESH:D007938', (88, 96))
12227	24872713	Furthermore, sunitinib targets mutant RET, which is involved in the multiple endocrine neoplasia types 2A and 2B autosomal-dominant syndromes, familial medullary thyroid carcinoma, and perhaps sporadic NETs.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (162, 179))	('mutant', 'Var', (31, 37))	('sunitinib', 'Chemical', 'MESH:D000077210', (13, 22))	('RET', 'Gene', '5979', (38, 41))	('neoplasia', 'Disease', 'MESH:D009369', (87, 96))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (152, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('neoplasia', 'Phenotype', 'HP:0002664', (87, 96))	('thyroid carcinoma', 'Disease', (162, 179))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (162, 179))	('multiple', 'Disease', (68, 76))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (77, 96))	('RET', 'Gene', (38, 41))	('involved', 'Reg', (52, 60))	('neoplasia', 'Disease', (87, 96))
12282	24872713	Moreover, a number of more selective VEGFR inhibitors were also found to induce PUMA and apoptosis in colon cancer cells, supporting the non-angiogenic role of anti-VEGFR therapies.	('inhibitors', 'Var', (43, 53))	('VEGFR', 'Gene', '3791', (165, 170))	('VEGFR', 'Gene', (37, 42))	('apoptosis', 'CPA', (89, 98))	('colon cancer', 'Phenotype', 'HP:0003003', (102, 114))	('PUMA', 'CPA', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colon cancer', 'Disease', 'MESH:D015179', (102, 114))	('VEGFR', 'Gene', (165, 170))	('colon cancer', 'Disease', (102, 114))	('VEGFR', 'Gene', '3791', (37, 42))	('induce', 'PosReg', (73, 79))	('apoptosis', 'biological_process', 'GO:0097194', ('89', '98'))	('apoptosis', 'biological_process', 'GO:0006915', ('89', '98'))
12294	24872713	Further studies are required to confirm that targeting EMMPRIN in RCC inhibits tumor angiogenesis, progression, and resistance to TKIs and mammalian target-of-rapamycin inhibitors.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('resistance', 'CPA', (116, 126))	('progression', 'CPA', (99, 110))	('tumor', 'Disease', (79, 84))	('mammalian target-of-rapamycin', 'Gene', '2475', (139, 168))	('inhibits', 'NegReg', (70, 78))	('angiogenesis', 'biological_process', 'GO:0001525', ('85', '97'))	('EMMPRIN', 'Gene', '682', (55, 62))	('EMMPRIN', 'Gene', (55, 62))	('targeting', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('RCC', 'Disease', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('mammalian target-of-rapamycin', 'Gene', (139, 168))
12307	24872713	In vitro, sunitinib inhibited VEGF-dependent proliferation and migration of human umbilical endothelial cells and disrupted capillary tube formation, and in in vivo models of cancer angiogenesis, sunitinib decreased tumor-microvessel density, blocked vascularization in the vascular window tumor model, and decreased the metastatic potential of several cancers, such as Lewis lung cancer.	('sunitinib', 'Var', (196, 205))	('VEGF', 'Gene', '7422', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))	('cancer', 'Disease', (175, 181))	('metastatic potential', 'CPA', (321, 341))	('angiogenesis', 'biological_process', 'GO:0001525', ('182', '194'))	('inhibited', 'NegReg', (20, 29))	('VEGF', 'Gene', (30, 34))	('Lewis lung cancer', 'Disease', (370, 387))	('Lewis lung cancer', 'Disease', 'MESH:D018827', (370, 387))	('lung cancer', 'Phenotype', 'HP:0100526', (376, 387))	('tumor', 'Disease', (290, 295))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Disease', (216, 221))	('cancer', 'Disease', 'MESH:D009369', (353, 359))	('blocked', 'NegReg', (243, 250))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('cancers', 'Disease', 'MESH:D009369', (353, 360))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('cancer', 'Disease', (381, 387))	('sunitinib', 'Chemical', 'MESH:D000077210', (196, 205))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('tube formation', 'biological_process', 'GO:0035148', ('134', '148'))	('decreased', 'NegReg', (206, 215))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('decreased', 'NegReg', (307, 316))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('vascularization', 'CPA', (251, 266))	('sunitinib', 'Chemical', 'MESH:D000077210', (10, 19))	('cancers', 'Phenotype', 'HP:0002664', (353, 360))	('human', 'Species', '9606', (76, 81))	('cancers', 'Disease', (353, 360))	('cancer', 'Disease', (353, 359))	('cancer', 'Disease', 'MESH:D009369', (381, 387))	('migration', 'CPA', (63, 72))
12334	24653814	More accurate prognosticators are under development; these include chromosomal profile, expression profile and nowadays BAP1 mutation status.	('mutation status', 'Var', (125, 140))	('BAP1', 'Gene', '8314', (120, 124))	('BAP1', 'Gene', (120, 124))
12366	23441115	MiRNAs have been identified in many ocular tissues and have been shown to play a role in lens and retina development, ocular physiology, and several ocular diseases.	('ocular diseases', 'Disease', (149, 164))	('ocular diseases', 'Phenotype', 'HP:0000478', (149, 164))	('MiRNAs', 'Var', (0, 6))	('play', 'Reg', (74, 78))	('role', 'Reg', (81, 85))	('ocular diseases', 'Disease', 'MESH:D005128', (149, 164))	('ocular physiology', 'CPA', (118, 135))
12477	22353812	Prognostic significance of chromosome 3 alterations determined by microsatellite analysis in uveal melanoma: a long-term follow-up study In uveal melanoma (UM), the most frequent primary intraocular tumour in adults, loss of one entire chromosome 3 (monosomy 3 (M3)) is observed in ~50% of tumours and is significantly associated with metastatic disease.	('tumours', 'Phenotype', 'HP:0002664', (290, 297))	('uveal melanoma', 'Disease', 'MESH:C536494', (93, 107))	('uveal melanoma', 'Disease', (93, 107))	('tumours', 'Disease', 'MESH:D009369', (290, 297))	('UM', 'Phenotype', 'HP:0007716', (156, 158))	('uveal melanoma', 'Phenotype', 'HP:0007716', (140, 154))	('tumour', 'Phenotype', 'HP:0002664', (290, 296))	('associated with', 'Reg', (319, 334))	('uveal melanoma', 'Phenotype', 'HP:0007716', (93, 107))	('chromosome', 'cellular_component', 'GO:0005694', ('27', '37'))	('intraocular tumour', 'Disease', (187, 205))	('chromosome', 'cellular_component', 'GO:0005694', ('236', '246'))	('metastatic disease', 'Disease', (335, 353))	('intraocular tumour', 'Disease', 'MESH:D064090', (187, 205))	('uveal melanoma', 'Disease', 'MESH:C536494', (140, 154))	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('loss', 'Var', (217, 221))	('tumours', 'Disease', (290, 297))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('uveal melanoma', 'Disease', (140, 154))
12484	22353812	Mortality rate of tumours showing partial M3 (8.3%) was as low as that for tumours with D3.	('tumours', 'Disease', 'MESH:D009369', (75, 82))	('tumours', 'Disease', (18, 25))	('tumours', 'Disease', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('partial M3', 'Var', (34, 44))	('tumours', 'Phenotype', 'HP:0002664', (18, 25))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('tumours', 'Disease', 'MESH:D009369', (18, 25))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
12485	22353812	This shows that large tumours with disomy 3 have an increased risk to develop metastases.	('metastases', 'Disease', 'MESH:D009362', (78, 88))	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('disomy 3', 'Var', (35, 43))	('tumours', 'Disease', (22, 29))	('metastases', 'Disease', (78, 88))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))
12488	22353812	In 1996, discovered the strong association between the loss of an entire chromosome 3 (monosomy 3 (M3)) in the tumour and metastatic death of patients.	('death', 'Disease', (133, 138))	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('loss', 'Var', (55, 59))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('patients', 'Species', '9606', (142, 150))	('tumour', 'Disease', (111, 117))	('death', 'Disease', 'MESH:D003643', (133, 138))
12516	22353812	The following chromosome 3 and chromosome 8 polymorphic microsatellite loci were analysed: D3S3050-HEX, D3S1263-FAM, D3S1481-FAM, D3S2406-TET, D3S3045-FAM, D3S1744-TET, D3S2421-FAM, D3S1311-HEX, D8S1119-TET, D8S1132-FAM, D8S1128-TET, and D8S265-HEX.	('D3S1481-FAM', 'Var', (117, 128))	('HEX', 'Gene', '3087', (99, 102))	('chromosome', 'cellular_component', 'GO:0005694', ('31', '41'))	('D3S2406-TET', 'Var', (130, 141))	('D3S1744-TET', 'Var', (156, 167))	('D3S1263-FAM', 'Var', (104, 115))	('D8S1119-TET', 'Var', (195, 206))	('D3S3045-FAM', 'Var', (143, 154))	('D8S1132-FAM', 'Var', (208, 219))	('chromosome', 'cellular_component', 'GO:0005694', ('14', '24'))	('HEX', 'Gene', (245, 248))	('HEX', 'Gene', (190, 193))	('HEX', 'Gene', (99, 102))	('D3S2421-FAM', 'Var', (169, 180))	('D8S1128-TET', 'Var', (221, 232))	('HEX', 'Gene', '3087', (245, 248))	('HEX', 'Gene', '3087', (190, 193))
12518	22353812	PCR was performed as follows: ~40 ng template DNA were added to a 20-mul reaction mixture containing 2 mul 10 x Mastermix II (Applied Biosystems, Foster City, CA, USA), 1.25 m each of deoxynucleotide triphosphate, 0.2 U Taq polymerase (Applied Biosystems), 8 pmol each primer pair, and T4gp32 (Q-BIOgene, Inc., Carlsbad, CA, USA) at a final concentration of 5 ng mul-1.	('mul-1', 'Gene', '79594', (363, 368))	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('mul-1', 'Gene', (363, 368))	('T4gp32', 'Var', (286, 292))	('deoxynucleotide triphosphate', 'Chemical', '-', (184, 212))
12532	22353812	On the basis of the chromosome 3 MSA results, we classified the tumours into four groups: 128 tumours with disomy 3, 211 tumours with M3, 16 tumours with partial M3, and 19 tumours with AI (see Materials and Methods for description of AI).	('19 tumours', 'Disease', (170, 180))	('tumours', 'Disease', (121, 128))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('disomy 3', 'Var', (107, 115))	('tumours', 'Disease', (64, 71))	('19 tumours', 'Disease', 'MESH:D009369', (170, 180))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('chromosome', 'cellular_component', 'GO:0005694', ('20', '30'))	('tumours', 'Disease', (141, 148))	('tumours', 'Disease', (94, 101))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('tumours', 'Disease', (173, 180))	('tumours', 'Disease', 'MESH:D009369', (121, 128))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('tumours', 'Disease', 'MESH:D009369', (141, 148))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('tumours', 'Disease', 'MESH:D009369', (94, 101))	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))
12542	22353812	For this outcome, death by UM metastases, disease-specific survival curves for each of the four classes of chromosome 3 alteration (D3, M3, AI, and partial M3) are shown in Figure 1.	('UM', 'Phenotype', 'HP:0007716', (27, 29))	('partial M3', 'Var', (148, 158))	('D3', 'Var', (132, 134))	('death', 'Disease', 'MESH:D003643', (18, 23))	('chromosome', 'cellular_component', 'GO:0005694', ('107', '117'))	('death', 'Disease', (18, 23))	('metastases', 'Disease', (30, 40))	('metastases', 'Disease', 'MESH:D009362', (30, 40))
12543	22353812	In our patient cohort, loss of one chromosome 3 in the tumour was strongly associated with metastatic death of patients, and survival in the M3 group was even worse when additional chromosome 8 alterations were present as observed in previous studies.	('tumour', 'Disease', (55, 61))	('associated with', 'Reg', (75, 90))	('death', 'Disease', 'MESH:D003643', (102, 107))	('death', 'Disease', (102, 107))	('patient', 'Species', '9606', (7, 14))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('chromosome', 'cellular_component', 'GO:0005694', ('181', '191'))	('chromosome', 'cellular_component', 'GO:0005694', ('35', '45'))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('patient', 'Species', '9606', (111, 118))	('loss', 'Var', (23, 27))	('patients', 'Species', '9606', (111, 119))
12545	22353812	Retention of both chromosomes 3 in a tumour is associated with a good overall prognosis, whereas a total of 12 of the 128 patients with disomy 3 in their tumour died of metastasis.	('disomy', 'Var', (136, 142))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('tumour', 'Disease', (37, 43))	('tumour', 'Disease', (154, 160))	('patients', 'Species', '9606', (122, 130))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
12550	22353812	Interestingly, a low mortality rate (8.3%) was found for tumours showing partial M3 (Figure 1) irrespective of which of the eight chromosome 3 markers showed loss of heterozygosity (data not shown).	('partial M3', 'Var', (73, 83))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('tumours', 'Disease', (57, 64))	('chromosome', 'cellular_component', 'GO:0005694', ('130', '140'))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))
12559	22353812	They found that patients with 'borderline' or 'equivocal abnormality,' of chromosome 3 are also more likely to die from metastases and suggested that these MLPA results are due to a heterogeneous mixture of melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (207, 215))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanoma', 'Disease', (207, 215))	('patients', 'Species', '9606', (16, 24))	('chromosome', 'cellular_component', 'GO:0005694', ('74', '84'))	('metastases', 'Disease', (120, 130))	("'borderline'", 'Var', (30, 42))	('metastases', 'Disease', 'MESH:D009362', (120, 130))
12561	22353812	In our cohort, partial M3 was found in tumours of only 16 patients (4%), which is at the lower end of partial M3 frequencies reported in other studies (0-48%).	('tumours', 'Phenotype', 'HP:0002664', (39, 46))	('partial M3', 'Var', (15, 25))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumours', 'Disease', 'MESH:D009369', (39, 46))	('tumours', 'Disease', (39, 46))	('patients', 'Species', '9606', (58, 66))
12563	22353812	In other studies, mortality rates of patients with partial M3 are much higher.	('higher', 'PosReg', (71, 77))	('mortality rates', 'MPA', (18, 33))	('partial M3', 'Var', (51, 61))	('patients', 'Species', '9606', (37, 45))
12566	22353812	In the past, partial chromosome 3 deletions in UMs have been mapped to obtain positional information on putative tumour-suppressor genes.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('deletions', 'Var', (34, 43))	('UMs', 'Gene', (47, 50))	('tumour', 'Disease', (113, 119))	('chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))	('UM', 'Phenotype', 'HP:0007716', (47, 49))
12568	22353812	Our observation that partial M3 tumours rarely metastasise does not therefore support a major role for genes affected by the partial deletions in metastatic progression of UM.	('partial deletions', 'Var', (125, 142))	('M3 tumours', 'Disease', 'MESH:D015473', (29, 39))	('M3 tumours', 'Disease', (29, 39))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('UM', 'Phenotype', 'HP:0007716', (172, 174))
12569	22353812	In spite of the overall good prognosis for disomy 3, 9% of all patients (12 patients) with disomy 3 in their tumour (D3met tumours) died from metastasis, a percentage similar to that found in other studies using chromosome 3 testing.	('patients', 'Species', '9606', (76, 84))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))	('tumour', 'Disease', 'MESH:D009369', (123, 129))	('tumours', 'Disease', (123, 130))	('metastasis', 'CPA', (142, 152))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('tumours', 'Disease', 'MESH:D009369', (123, 130))	('tumour', 'Disease', (109, 115))	('tumour', 'Disease', (123, 129))	('patients', 'Species', '9606', (63, 71))	('disomy 3', 'Var', (91, 99))	('died', 'Reg', (132, 136))	('chromosome', 'cellular_component', 'GO:0005694', ('212', '222'))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
12570	22353812	It has been proposed that this could be explained by mis-sampling of cells with a normal chromosome 3 status from tumours otherwise composed of tumour cells with M3, or by misclassification of UM that have a partial deletion of chromosome 3.	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('tumour', 'Disease', (114, 120))	('tumours', 'Disease', (114, 121))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('UM', 'Phenotype', 'HP:0007716', (193, 195))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('chromosome', 'cellular_component', 'GO:0005694', ('89', '99'))	('tumour', 'Disease', (144, 150))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('chromosome', 'cellular_component', 'GO:0005694', ('228', '238'))	('partial deletion', 'Var', (208, 224))	('tumour', 'Disease', 'MESH:D009369', (114, 120))
12583	19936769	Activating mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system Primary melanocytic neoplasms of the central nervous system (CNS) are uncommon neoplasms derived from melanocytes that normally can be found in the leptomeninges.	('mutations', 'Var', (11, 20))	('melanocytic neoplasms', 'Disease', (67, 88))	('neoplasms', 'Disease', 'MESH:D009369', (79, 88))	('neoplasms of the central nervous', 'Phenotype', 'HP:0100006', (139, 171))	('neoplasms', 'Disease', 'MESH:D009369', (198, 207))	('melanocytic neoplasms of the central nervous system', 'Phenotype', 'HP:0100836', (127, 178))	('neoplasms', 'Disease', (79, 88))	('neoplasms', 'Phenotype', 'HP:0002664', (139, 148))	('GNAQ', 'Gene', '2776', (28, 32))	('neoplasms', 'Disease', (198, 207))	('Primary melanocytic neoplasms of the central nervous system', 'Disease', 'MESH:D016543', (119, 178))	('GNAQ', 'Gene', (28, 32))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (127, 148))	('neoplasms of the central nervous', 'Phenotype', 'HP:0100006', (79, 111))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (127, 148))	('melanocytic neoplasms of the central nervous system', 'Phenotype', 'HP:0100836', (67, 118))	('melanocytic neoplasms', 'Disease', (127, 148))	('neoplasms', 'Disease', 'MESH:D009369', (139, 148))	('neoplasms', 'Phenotype', 'HP:0002664', (79, 88))	('neoplasms', 'Phenotype', 'HP:0002664', (198, 207))	('neoplasms', 'Disease', (139, 148))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (67, 88))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (67, 88))
12586	19936769	Using direct sequencing, we investigated 19 primary melanocytic lesions of the CNS (12 melanocytomas, 3 intermediate-grade melanocytomas, and 4 melanomas) for hotspot oncogenic mutations commonly found in melanocytic tumors of the skin (BRAF, NRAS, and HRAS genes) and uvea (GNAQ gene).	('melanocytomas', 'Disease', 'None', (87, 100))	('lesions of the CNS', 'Phenotype', 'HP:0100006', (64, 82))	('tumors of the skin', 'Phenotype', 'HP:0008069', (217, 235))	('melanocytic tumors of the skin', 'Phenotype', 'HP:0002861', (205, 235))	('mutations', 'Var', (177, 186))	('uvea', 'Disease', 'MESH:C536494', (269, 273))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanocytic tumors of the skin', 'Disease', 'MESH:D012878', (205, 235))	('BRAF', 'Gene', '673', (237, 241))	('NRAS', 'Gene', '4893', (243, 247))	('melanomas', 'Disease', 'MESH:D008545', (144, 153))	('BRAF', 'Gene', (237, 241))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('melanomas', 'Disease', (144, 153))	('melanocytomas', 'Disease', (123, 136))	('melanocytic tumors of the skin', 'Disease', (205, 235))	('melanocytic lesions', 'Disease', (52, 71))	('melanocytomas', 'Disease', 'None', (123, 136))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('uvea', 'Disease', (269, 273))	('NRAS', 'Gene', (243, 247))	('HRAS', 'Gene', '3265', (253, 257))	('melanomas', 'Phenotype', 'HP:0002861', (144, 153))	('melanocytic lesions', 'Disease', 'MESH:D009508', (52, 71))	('melanocytomas', 'Disease', (87, 100))	('HRAS', 'Gene', (253, 257))
12587	19936769	Somatic mutations in the GNAQ gene at codon 209, resulting in constitutive activation of GNAQ, were detected in 7/19 (37%) tumors, including 6/12 melanocytomas, 0/3 intermediate-grade melanocytomas, and 1/4 melanomas.	('melanocytomas', 'Disease', 'None', (146, 159))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('melanocytomas', 'Disease', 'None', (184, 197))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanomas', 'Disease', 'MESH:D008545', (207, 216))	('constitutive', 'MPA', (62, 74))	('activation', 'PosReg', (75, 85))	('mutations', 'Var', (8, 17))	('melanomas', 'Phenotype', 'HP:0002861', (207, 216))	('GNAQ', 'Gene', (25, 29))	('GNAQ', 'Gene', (89, 93))	('melanocytomas', 'Disease', (184, 197))	('melanocytomas', 'Disease', (146, 159))	('melanomas', 'Disease', (207, 216))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('detected', 'Reg', (100, 108))
12589	19936769	One melanoma carried a BRAF point mutation that is frequently found in cutaneous melanomas (c.1799 T>A, p.V600E), raising the question whether this is a metastatic rather than a primary tumor.	('tumor', 'Disease', (186, 191))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (71, 90))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (71, 90))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (71, 89))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('BRAF', 'Gene', '673', (23, 27))	('BRAF', 'Gene', (23, 27))	('cutaneous melanomas', 'Disease', (71, 90))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('p.V600E', 'Mutation', 'rs113488022', (104, 111))	('c.1799 T>A', 'Mutation', 'rs113488022', (92, 102))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('p.V600E', 'Var', (104, 111))	('melanoma', 'Disease', (4, 12))	('melanomas', 'Phenotype', 'HP:0002861', (81, 90))	('c.1799 T>A', 'Var', (92, 102))
12593	19936769	The prognostic and predictive value of GNAQ mutations in primary melanocytic lesions of the CNS needs to be determined in future studies.	('lesions of the CNS', 'Phenotype', 'HP:0100006', (77, 95))	('GNAQ', 'Gene', (39, 43))	('mutations', 'Var', (44, 53))	('melanocytic lesions', 'Disease', 'MESH:D009508', (65, 84))	('melanocytic lesions', 'Disease', (65, 84))
12607	19936769	In melanocytic lesions of the skin:benign nevi as well as melanomas:oncogenic mutations in signaling components of the MAP kinase pathway are frequent.	('nevi', 'Phenotype', 'HP:0003764', (42, 46))	('melanocytic lesions of the skin', 'Disease', 'MESH:D012871', (3, 34))	('melanocytic lesions of the skin', 'Phenotype', 'HP:0002861', (3, 34))	('mutations', 'Var', (78, 87))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('melanomas', 'Disease', (58, 67))	('MAP', 'molecular_function', 'GO:0004239', ('119', '122'))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('benign nevi', 'Disease', (35, 46))	('melanocytic lesions of the skin', 'Disease', (3, 34))	('melanomas', 'Disease', 'MESH:D008545', (58, 67))	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))
12608	19936769	These mutations mostly involve exon 15 of the BRAF gene and exon 3 (codon 61) of the proto-oncogene NRAS.	('BRAF', 'Gene', (46, 50))	('NRAS', 'Gene', '4893', (100, 104))	('BRAF', 'Gene', '673', (46, 50))	('involve', 'Reg', (23, 30))	('NRAS', 'Gene', (100, 104))	('mutations', 'Var', (6, 15))
12609	19936769	Mutations in HRAS are less frequent.	('HRAS', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('HRAS', 'Gene', '3265', (13, 17))
12612	19936769	In the present study, we investigated the mutation status of the GNAQ, BRAF, NRAS, and HRAS genes in a group of 19 primary melanocytic lesions of the CNS and found that somatic mutations in the GNAQ gene at codon 209 are relatively frequently present in these tumors.	('HRAS', 'Gene', '3265', (87, 91))	('GNAQ', 'Gene', (194, 198))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('BRAF', 'Gene', '673', (71, 75))	('HRAS', 'Gene', (87, 91))	('mutations', 'Var', (177, 186))	('NRAS', 'Gene', (77, 81))	('BRAF', 'Gene', (71, 75))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('lesions of the CNS', 'Phenotype', 'HP:0100006', (135, 153))	('NRAS', 'Gene', '4893', (77, 81))	('melanocytic lesions', 'Disease', 'MESH:D009508', (123, 142))	('GNAQ', 'Gene', (65, 69))	('melanocytic lesions', 'Disease', (123, 142))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('tumors', 'Disease', (260, 266))
12613	19936769	While the exact diagnostic, prognostic, and predictive value of GNAQ mutations in primary melanocytic lesions of the CNS is not yet clear, it is to be expected that a better knowledge of the genetic background of these lesions may not only facilitate adequate diagnosis but also identification of (novel) therapeutic targets, and thereby ultimately may have predictive value as well.	('lesions of the CNS', 'Phenotype', 'HP:0100006', (102, 120))	('mutations', 'Var', (69, 78))	('melanocytic lesions', 'Disease', 'MESH:D009508', (90, 109))	('GNAQ', 'Gene', (64, 68))	('facilitate', 'PosReg', (240, 250))	('melanocytic lesions', 'Disease', (90, 109))
12615	19936769	The diagnosis of 'melanocytoma', 'intermediate-grade melanocytoma' or 'melanoma' was based on histomorphological criteria, as described by Brat et al., and immunohistochemical stains (S100 positivity and at least one additional melanocytic marker (HMB45 or MelanA) positive in combination with lack of EMA staining).	("melanocytoma' or 'melanoma'", 'Disease', (53, 80))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('positivity', 'Var', (189, 199))	('HMB45', 'Gene', (248, 253))	("melanocytoma' or 'melanoma'", 'Disease', 'MESH:D008545', (53, 80))	("'melanocytoma'", 'Disease', 'None', (17, 31))	("'melanocytoma'", 'Disease', (17, 31))
12634	19936769	In this group of 19 primary melanocytic neoplasms of the CNS, we detected 7 mutations in the GNAQ gene (37%) (Table 3).	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (28, 49))	('mutations', 'Var', (76, 85))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (28, 49))	('neoplasms of the CNS', 'Phenotype', 'HP:0100006', (40, 60))	('neoplasms', 'Phenotype', 'HP:0002664', (40, 49))	('melanocytic neoplasms', 'Disease', (28, 49))	('GNAQ', 'Gene', (93, 97))	('melanocytic neoplasms of the CNS', 'Phenotype', 'HP:0100836', (28, 60))
12635	19936769	All mutations were present in codon 209 (p.Gln209Pro and p.Gln209Leu) and were somatic mutations (Fig.	('p.Gln209Leu', 'Mutation', 'rs121913492', (57, 68))	('p.Gln209Leu', 'Var', (57, 68))	('p.Gln209Pro', 'Var', (41, 52))	('p.Gln209Pro', 'Mutation', 'rs121913492', (41, 52))
12636	19936769	Of these seven GNAQ mutant lesions, six were melanocytomas (50%) and one was a melanoma (1/4, 25%).	('melanocytomas', 'Disease', 'None', (45, 58))	('GNAQ', 'Gene', (15, 19))	('melanocytomas', 'Disease', (45, 58))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('mutant', 'Var', (20, 26))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
12640	19936769	The one melanoma containing a GNAQ mutation was located in the spinal cord (sacral) and was mildly pigmented.	('melanoma', 'Disease', 'MESH:D008545', (8, 16))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('melanoma', 'Disease', (8, 16))	('GNAQ', 'Gene', (30, 34))	('mutation', 'Var', (35, 43))
12641	19936769	Mutation analysis of the BRAF gene revealed one BRAF mutation (c.1799 T>A, p.V600E), in a melanoma.	('melanoma', 'Disease', (90, 98))	('c.1799 T>A', 'Mutation', 'rs113488022', (63, 73))	('p.V600E', 'Mutation', 'rs113488022', (75, 82))	('c.1799 T>A', 'Var', (63, 73))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('p.V600E', 'Var', (75, 82))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (25, 29))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
12646	19936769	Most melanocytic nevi and melanomas of the skin show oncogenic mutations in signaling components of the MAP kinase pathway, in particular BRAF and NRAS, although in uveal melanoma, Spitz nevi and blue nevi, these mutations are infrequent.	('uveal melanoma', 'Disease', (165, 179))	('melanocytic nevi', 'Disease', (5, 21))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (165, 179))	('mutations', 'Var', (63, 72))	('blue nevi', 'Phenotype', 'HP:0100814', (196, 205))	('nevi', 'Phenotype', 'HP:0003764', (187, 191))	('NRAS', 'Gene', '4893', (147, 151))	('melanomas of the skin', 'Disease', 'MESH:D008545', (26, 47))	('nevi', 'Phenotype', 'HP:0003764', (201, 205))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (5, 21))	('melanomas of the skin', 'Disease', (26, 47))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('nevi', 'Phenotype', 'HP:0003764', (17, 21))	('BRAF', 'Gene', '673', (138, 142))	('BRAF', 'Gene', (138, 142))	('MAP', 'molecular_function', 'GO:0004239', ('104', '107'))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('MAP', 'Pathway', (104, 107))	('melanomas', 'Phenotype', 'HP:0002861', (26, 35))	('NRAS', 'Gene', (147, 151))	('uveal melanoma', 'Disease', 'MESH:C536494', (165, 179))
12647	19936769	Very recently, mutations in the GNAQ gene at codon 209 were described as an alternative route to MAP kinase activation in a particular subgroup of melanocytic neoplasms, namely uveal melanomas and specific intradermal melanocytic lesions such as blue nevi and nevi of Ota.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanomas', 'Phenotype', 'HP:0002861', (183, 192))	('nevi', 'Phenotype', 'HP:0003764', (251, 255))	('uveal melanomas', 'Disease', 'MESH:C536494', (177, 192))	('mutations', 'Var', (15, 24))	('nevi', 'Phenotype', 'HP:0003764', (260, 264))	('nevi of Ota', 'Phenotype', 'HP:0009920', (260, 271))	('nevi of Ota', 'Disease', (260, 271))	('uveal melanoma', 'Phenotype', 'HP:0007716', (177, 191))	('intradermal melanocytic lesions', 'Disease', 'MESH:D018330', (206, 237))	('uveal melanomas', 'Disease', (177, 192))	('uveal melanomas', 'Phenotype', 'HP:0007716', (177, 192))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (147, 168))	('blue nevi', 'Disease', (246, 255))	('neoplasms', 'Phenotype', 'HP:0002664', (159, 168))	('GNAQ', 'Gene', (32, 36))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (147, 168))	('melanocytic neoplasms', 'Disease', (147, 168))	('MAP', 'molecular_function', 'GO:0004239', ('97', '100'))	('blue nevi', 'Phenotype', 'HP:0100814', (246, 255))	('intradermal melanocytic lesions', 'Disease', (206, 237))	('activation', 'PosReg', (108, 118))
12648	19936769	We analyzed a group of 19 primary melanocytic lesions of the CNS for hotspot oncogenic mutations as described in melanocytic tumors of the skin (exon 15 of BRAF gene, exon 3 of NRAS, and exon 3 of HRAS) and uvea (exon 5 of GNAQ).	('melanocytic tumors of the skin', 'Disease', (113, 143))	('BRAF', 'Gene', (156, 160))	('tumors of the skin', 'Phenotype', 'HP:0008069', (125, 143))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('uvea', 'Disease', (207, 211))	('NRAS', 'Gene', (177, 181))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('melanocytic lesions', 'Disease', (34, 53))	('uvea', 'Disease', 'MESH:C536494', (207, 211))	('HRAS', 'Gene', '3265', (197, 201))	('melanocytic lesions', 'Disease', 'MESH:D009508', (34, 53))	('NRAS', 'Gene', '4893', (177, 181))	('melanocytic tumors of the skin', 'Disease', 'MESH:D012878', (113, 143))	('melanocytic tumors of the skin', 'Phenotype', 'HP:0002861', (113, 143))	('HRAS', 'Gene', (197, 201))	('mutations', 'Var', (87, 96))	('BRAF', 'Gene', '673', (156, 160))	('lesions of the CNS', 'Phenotype', 'HP:0100006', (46, 64))
12651	19936769	Mutations in this catalytic domain prevent hydrolysis of GTP and turns GNAQ into its active, GTP-bound state.	('GTP', 'Chemical', 'MESH:D006160', (57, 60))	('GTP', 'MPA', (57, 60))	('turns', 'Reg', (65, 70))	('Mutations', 'Var', (0, 9))	('GTP', 'Chemical', 'MESH:D006160', (93, 96))	('prevent', 'NegReg', (35, 42))	('hydrolysis', 'MPA', (43, 53))
12653	19936769	The presence of GNAQ mutations in primary melanocytic neoplasms of the CNS as well as in uveal melanomas and intradermal melanocytic proliferations such as nevi of Ota and blue nevi is interesting as these lesions share some other features.	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (42, 63))	('GNAQ', 'Gene', (16, 20))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('blue nevi', 'Disease', (172, 181))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (42, 63))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('melanocytic neoplasms', 'Disease', (42, 63))	('blue nevi', 'Phenotype', 'HP:0100814', (172, 181))	('intradermal melanocytic proliferations', 'Disease', 'MESH:D059545', (109, 147))	('neoplasms of the CNS', 'Phenotype', 'HP:0100006', (54, 74))	('nevi', 'Phenotype', 'HP:0003764', (156, 160))	('uveal melanomas', 'Disease', 'MESH:C536494', (89, 104))	('intradermal melanocytic proliferations', 'Disease', (109, 147))	('uveal melanoma', 'Phenotype', 'HP:0007716', (89, 103))	('nevi of Ota', 'Disease', (156, 167))	('melanocytic neoplasms of the CNS', 'Phenotype', 'HP:0100836', (42, 74))	('nevi of Ota', 'Phenotype', 'HP:0009920', (156, 167))	('mutations', 'Var', (21, 30))	('neoplasms', 'Phenotype', 'HP:0002664', (54, 63))	('uveal melanomas', 'Disease', (89, 104))	('uveal melanomas', 'Phenotype', 'HP:0007716', (89, 104))	('nevi', 'Phenotype', 'HP:0003764', (177, 181))
12659	19936769	Thus, it appears that GNAQ mutations are preferentially present in a group of non-epithelium-related melanocytic lesions, sharing histological features and occurring in an anatomical distribution indicating a possible role of GNAQ in migration of melanocytes early during embryonic development.	('mutations', 'Var', (27, 36))	('melanocytic lesions', 'Disease', (101, 120))	('melanocytic lesions', 'Disease', 'MESH:D009508', (101, 120))	('GNAQ', 'Gene', (22, 26))	('non-epithelium-related', 'Disease', (78, 100))
12660	19936769	Interestingly, tumorigenicity studies in nude mice with injection of human GNAQQ209L resulted in heavily pigmented melanocytic tumors at the injection site.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', (127, 132))	('pigmented melanocytic tumors', 'Disease', (105, 133))	('resulted in', 'Reg', (85, 96))	('GNAQQ209L', 'Var', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('human', 'Species', '9606', (69, 74))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('pigmented melanocytic tumors', 'Disease', 'MESH:D010859', (105, 133))	('nude mice', 'Species', '10090', (41, 50))
12661	19936769	Furthermore, dominant dark skin (Dsk) mutations that are found in mutant mice with increased dermal melanin, are mutations of the mouse GNAQ gene, and the hyperpigmentation in these mutant mice is due to an increase of intradermal, but not epidermal melanocytes.	('increase', 'PosReg', (207, 215))	('mouse', 'Species', '10090', (130, 135))	('mice', 'Species', '10090', (189, 193))	('GNAQ', 'Gene', (136, 140))	('mice', 'Species', '10090', (73, 77))	('dark skin', 'Phenotype', 'HP:0000953', (22, 31))	('Dsk', 'Gene', (33, 36))	('mutations', 'Var', (38, 47))	('hyperpigmentation', 'Disease', 'MESH:D017495', (155, 172))	('Dsk', 'Phenotype', 'HP:0000953', (33, 36))	('hyperpigmentation', 'Disease', (155, 172))	('melanin', 'Chemical', 'MESH:D008543', (100, 107))
12663	19936769	Other studies in mice have shown that activating mutations in GNAQ or Galpha11, another gene encoding G-protein subunits, result in an aberrant accumulation of melanin-producing melanocytes in the dermal layer of the skin.	('Galpha11', 'Gene', (70, 78))	('mice', 'Species', '10090', (17, 21))	('mutations', 'Var', (49, 58))	('melanin', 'Chemical', 'MESH:D008543', (160, 167))	('activating', 'PosReg', (38, 48))	('accumulation', 'PosReg', (144, 156))	('Galpha11', 'Gene', '14672', (70, 78))	('GNAQ', 'Gene', (62, 66))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))
12665	19936769	For instance, in our series, one melanoma contained a GNAQ mutation, which, in the differential diagnosis with a metastasis of a primary cutaneous melanoma:often harboring BRAF or NRAS mutations:might favor a primary location in the CNS.	('GNAQ', 'Gene', (54, 58))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (137, 155))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('NRAS', 'Gene', (180, 184))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('favor', 'Reg', (201, 206))	('harboring', 'Reg', (162, 171))	('melanoma', 'Disease', (33, 41))	('NRAS', 'Gene', '4893', (180, 184))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('mutations', 'Var', (185, 194))	('mutation', 'Var', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('BRAF', 'Gene', '673', (172, 176))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('cutaneous melanoma', 'Disease', (137, 155))	('BRAF', 'Gene', (172, 176))
12666	19936769	So, the presence of GNAQ mutations and lack of BRAF or NRAS mutations in melanocytic neoplasms of the CNS seems to strongly indicate a primary CNS tumor, a diagnosis that has obvious prognostic implications.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('mutations', 'Var', (25, 34))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (73, 94))	('melanocytic neoplasms of the CNS', 'Phenotype', 'HP:0100836', (73, 105))	('NRAS', 'Gene', '4893', (55, 59))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('CNS tumor', 'Phenotype', 'HP:0100006', (143, 152))	('neoplasms', 'Phenotype', 'HP:0002664', (85, 94))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (73, 94))	('CNS tumor', 'Disease', 'MESH:D009369', (143, 152))	('GNAQ', 'Gene', (20, 24))	('melanocytic neoplasms', 'Disease', (73, 94))	('CNS tumor', 'Disease', (143, 152))	('neoplasms of the CNS', 'Phenotype', 'HP:0100006', (85, 105))	('NRAS', 'Gene', (55, 59))	('indicate', 'Reg', (124, 132))	('lack', 'NegReg', (39, 43))
12667	19936769	Vice versa, as BRAF point mutations are a frequent event in cutaneous melanomas, the one melanoma in our series with a BRAF point mutation (case 15; c.1799 T>A, p.V600E) might be a metastasis rather than a primary tumor.	('cutaneous melanomas', 'Disease', (60, 79))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('BRAF', 'Gene', '673', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('BRAF', 'Gene', (119, 123))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))	('BRAF', 'Gene', '673', (15, 19))	('BRAF', 'Gene', (15, 19))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanoma', 'Disease', (70, 78))	('c.1799 T>A', 'Mutation', 'rs113488022', (149, 159))	('p.V600E', 'Mutation', 'rs113488022', (161, 168))	('tumor', 'Disease', (214, 219))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (60, 79))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (60, 79))	('p.V600E', 'Var', (161, 168))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (60, 78))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('c.1799 T>A', 'Var', (149, 159))
12670	19936769	In our study, GNAQ mutations were preferentially present in the melanocytomas, while the intermediate melanocytomas and melanomas were only infrequently mutated.	('melanocytomas', 'Disease', (64, 77))	('melanocytomas', 'Disease', (102, 115))	('present', 'Reg', (49, 56))	('melanocytomas', 'Disease', 'None', (64, 77))	('mutations', 'Var', (19, 28))	('melanocytomas', 'Disease', 'None', (102, 115))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanomas', 'Phenotype', 'HP:0002861', (120, 129))	('GNAQ', 'Gene', (14, 18))	('melanocytomas and melanomas', 'Disease', 'MESH:D008545', (102, 129))
12671	19936769	On the other hand, activating GNAQ mutations are also reported in uveal melanomas, and, in addition, are shown to have no effect on disease-free survival in these neoplasms.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('neoplasms', 'Phenotype', 'HP:0002664', (163, 172))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('activating', 'PosReg', (19, 29))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('GNAQ', 'Gene', (30, 34))	('uveal melanomas', 'Phenotype', 'HP:0007716', (66, 81))	('neoplasms', 'Disease', 'MESH:D009369', (163, 172))	('neoplasms', 'Disease', (163, 172))	('uveal melanomas', 'Disease', (66, 81))	('uveal melanomas', 'Disease', 'MESH:C536494', (66, 81))	('mutations', 'Var', (35, 44))
12672	19936769	In conclusion, mutations in the GNAQ gene are a frequent event in primary melanocytic neoplasms of the CNS.	('GNAQ', 'Gene', (32, 36))	('melanocytic neoplasms', 'Disease', (74, 95))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (74, 95))	('mutations', 'Var', (15, 24))	('melanocytic neoplasms of the CNS', 'Phenotype', 'HP:0100836', (74, 106))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (74, 95))	('frequent', 'Reg', (48, 56))	('neoplasms of the CNS', 'Phenotype', 'HP:0100006', (86, 106))	('neoplasms', 'Phenotype', 'HP:0002664', (86, 95))
12676	33179075	In addition, whether high PARP1 expression was associated with poor overall survival in melanoma, and whether a combination effect existed between PARPis and other anti-tumour compounds (e.g., sunitinib) was analysed.	('PARP', 'Gene', (26, 30))	('tumour', 'Disease', (169, 175))	('PARP', 'Gene', (147, 151))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('high', 'Var', (21, 25))	('PARP', 'Gene', '142', (26, 30))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('overall survival', 'MPA', (68, 84))	('sunitinib', 'Chemical', 'MESH:D000077210', (193, 202))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('poor', 'NegReg', (63, 67))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('expression', 'MPA', (32, 42))	('PARP', 'Gene', '142', (147, 151))
12688	33179075	Besides breast cancer gene (BRCA) mutation-associated cancer, the benefits of PARPis in earlier treatment settings, including neoadjuvant, adjuvant and promising combination therapeutic strategies, such as those with other DNA damage response inhibitors and immune checkpoint inhibitors, are of increasing interest.	('breast cancer', 'Disease', 'MESH:D001943', (8, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (8, 21))	('PARP', 'Gene', (78, 82))	('BRCA', 'Gene', '672', (28, 32))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('BRCA', 'Gene', (28, 32))	('DNA damage response', 'biological_process', 'GO:0006974', ('223', '242'))	('cancer', 'Disease', (54, 60))	('PARP', 'Gene', '142', (78, 82))	('DNA', 'cellular_component', 'GO:0005574', ('223', '226'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutation-associated', 'Var', (34, 53))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('breast cancer', 'Disease', (8, 21))
12691	33179075	Melanoma is associated with numerous genetic mutations or alterations in signalling pathways (e.g.	('alterations', 'Reg', (58, 69))	('mutations', 'Var', (45, 54))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('signalling', 'biological_process', 'GO:0023052', ('73', '83'))	('Melanoma', 'Disease', (0, 8))	('associated', 'Reg', (12, 22))	('signalling pathways', 'Pathway', (73, 92))
12696	33179075	Besides, while olaparib increased response to dacarbazine (an alkylating agent) in uveal melanoma, both veliparib and olaparib combined increased the sensitivity of various histological subtypes of single-nucleotide polymorphism (SNP)-carrier cancer cells to alkylating agents, without an effect on wild-type cells.	('sensitivity', 'MPA', (150, 161))	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('uveal melanoma', 'Disease', (83, 97))	('dacarbazine', 'Chemical', 'MESH:D003606', (46, 57))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('olaparib', 'Chemical', 'MESH:C531550', (118, 126))	('single-nucleotide polymorphism', 'Var', (198, 228))	('veliparib', 'Chemical', 'MESH:C521013', (104, 113))	('carrier', 'molecular_function', 'GO:0005215', ('235', '242'))	('response', 'MPA', (34, 42))	('olaparib', 'Chemical', 'MESH:C531550', (15, 23))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('increased', 'PosReg', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('uveal melanoma', 'Disease', 'MESH:C536494', (83, 97))	('increased', 'PosReg', (24, 33))
12704	33179075	Our previous study in prostate cancer demonstrated that inhibition of PARP1 expression significantly reduced prostate cancer cell proliferation and migration irrespective of BRCA1/2 mutations.	('BRCA1/2', 'Gene', '672;675', (174, 181))	('prostate cancer', 'Disease', 'MESH:D011471', (109, 124))	('prostate cancer', 'Disease', (22, 37))	('prostate cancer', 'Disease', (109, 124))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('migration', 'CPA', (148, 157))	('cell proliferation', 'biological_process', 'GO:0008283', ('125', '143'))	('PARP1', 'Gene', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('prostate cancer', 'Disease', 'MESH:D011471', (22, 37))	('reduced', 'NegReg', (101, 108))	('reduced prostate', 'Phenotype', 'HP:0008687', (101, 117))	('prostate cancer', 'Phenotype', 'HP:0012125', (22, 37))	('inhibition', 'Var', (56, 66))	('BRCA1/2', 'Gene', (174, 181))	('prostate cancer', 'Phenotype', 'HP:0012125', (109, 124))
12705	33179075	However, in vascular smooth muscle cells and endothelial cells, PARP1 inhibition may be protective against apoptosis and/or necrosis in response to H2O2 or tumour necrosis factor.	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('H2O2', 'Chemical', 'MESH:D006861', (148, 152))	('necrosis', 'biological_process', 'GO:0070265', ('124', '132'))	('necrosis', 'biological_process', 'GO:0019835', ('124', '132'))	('necrosis', 'biological_process', 'GO:0001906', ('124', '132'))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('necrosis', 'biological_process', 'GO:0008219', ('163', '171'))	('tumour necrosis', 'Disease', 'MESH:D009336', (156, 171))	('necrosis', 'Disease', 'MESH:D009336', (124, 132))	('apoptosis', 'CPA', (107, 116))	('tumour necrosis', 'Disease', (156, 171))	('necrosis', 'biological_process', 'GO:0008220', ('163', '171'))	('necrosis', 'Disease', (124, 132))	('necrosis', 'biological_process', 'GO:0008219', ('124', '132'))	('inhibition', 'Var', (70, 80))	('necrosis', 'Disease', 'MESH:D009336', (163, 171))	('necrosis', 'biological_process', 'GO:0070265', ('163', '171'))	('PARP1', 'Gene', (64, 69))	('necrosis', 'biological_process', 'GO:0019835', ('163', '171'))	('necrosis', 'biological_process', 'GO:0001906', ('163', '171'))	('necrosis', 'Disease', (163, 171))	('necrosis', 'biological_process', 'GO:0008220', ('124', '132'))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))
12707	33179075	The present study explored the role of PARPis and PARP1 in tumour progression, and screened for compounds that significantly promoted melanoma efficacy and modulated PARP1 expression to provide a potential basis for assessing related drugs for targeting PARP1 in melanoma.	('PARP', 'Gene', (39, 43))	('melanoma', 'Phenotype', 'HP:0002861', (263, 271))	('melanoma', 'Disease', (263, 271))	('PARP', 'Gene', '142', (50, 54))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('PARP', 'Gene', (50, 54))	('tumour', 'Disease', (59, 65))	('promoted', 'PosReg', (125, 133))	('modulated', 'Var', (156, 165))	('melanoma', 'Disease', 'MESH:D008545', (263, 271))	('PARP', 'Gene', '142', (254, 258))	('PARP', 'Gene', '142', (166, 170))	('PARP', 'Gene', (254, 258))	('PARP', 'Gene', '142', (39, 43))	('expression', 'MPA', (172, 182))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('PARP', 'Gene', (166, 170))
12728	33179075	The membranes were cut and blocked with 5% skimmed milk for 1-2 h in the room temperature and incubated overnight at 4 C with the primary antibodies of the PARP-1 (1:200), FoxO3a (1:1,000), p-FoxO3a (1:1,000), tubulin (1:1,000) and anti-Bcl-2 (1:1,000).	('Bcl-2', 'Gene', (237, 242))	('Bcl-2', 'Gene', '596', (237, 242))	('FoxO3a', 'Gene', (172, 178))	('1:1,000', 'Var', (219, 226))	('PARP-1', 'Gene', (156, 162))	('PARP-1', 'Gene', '142', (156, 162))	('1:200', 'Var', (164, 169))	('1:1,000', 'Var', (180, 187))	('1:1,000', 'Var', (200, 207))	('FoxO3a', 'Gene', '2309', (192, 198))	('Bcl-2', 'molecular_function', 'GO:0015283', ('237', '242'))	('FoxO3a', 'Gene', '2309', (172, 178))	('tubulin', 'Protein', (210, 217))	('FoxO3a', 'Gene', (192, 198))
12746	33179075	Our previous study demonstrated that PARP1 small interfering RNA inhibited prostate cancer cell proliferation.	('small interfering RNA', 'Var', (43, 64))	('prostate cancer', 'Disease', (75, 90))	('PARP1', 'Gene', (37, 42))	('cell proliferation', 'biological_process', 'GO:0008283', ('91', '109'))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('inhibited', 'NegReg', (65, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (75, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (75, 90))	('RNA', 'cellular_component', 'GO:0005562', ('61', '64'))
12748	33179075	Data from the GEPIA database demonstrated that high PARP expression was correlated with poor OS in melanoma (Fig.	('PARP', 'Gene', '142', (52, 56))	('high', 'Var', (47, 51))	('PARP', 'Gene', (52, 56))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('I', 'Chemical', 'MESH:D007455', (17, 18))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('poor OS', 'Disease', (88, 95))
12754	33179075	Data from the GEPIA database demonstrated that high PARP expression was associated with poor OS in melanoma (Fig.	('PARP', 'Gene', '142', (52, 56))	('high', 'Var', (47, 51))	('PARP', 'Gene', (52, 56))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('I', 'Chemical', 'MESH:D007455', (17, 18))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('poor OS', 'Disease', (88, 95))
12755	33179075	Additionally, high PARP2 expression was associated with a poor OS in UVM (Fig.	('PARP2', 'Gene', (19, 24))	('expression', 'MPA', (25, 35))	('UVM', 'Disease', (69, 72))	('high', 'Var', (14, 18))	('PARP2', 'Gene', '10038', (19, 24))
12760	33179075	As an antiangiogenic drug, sunitinib may have activity in patients with melanoma and KIT mutations.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('KIT', 'molecular_function', 'GO:0005020', ('85', '88'))	('melanoma', 'Disease', (72, 80))	('KIT', 'Gene', '3815', (85, 88))	('sunitinib', 'Chemical', 'MESH:D000077210', (27, 36))	('activity', 'MPA', (46, 54))	('KIT', 'Gene', (85, 88))	('mutations', 'Var', (89, 98))	('patients', 'Species', '9606', (58, 66))
12779	33179075	4F and G. Based on the molecular characteristics and medicinal properties of tanshinone I and simvastatin, the combination of simvastatin and tanshinone I may exert an inhibitory effect on tumour progression.	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('tanshinone I', 'Chemical', 'MESH:C021751', (142, 154))	('inhibitory effect', 'NegReg', (168, 185))	('simvastatin', 'Chemical', 'MESH:D019821', (126, 137))	('tanshinone', 'Gene', (142, 152))	('simvastatin', 'Chemical', 'MESH:D019821', (94, 105))	('combination', 'Var', (111, 122))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('tumour', 'Disease', (189, 195))	('tanshinone I', 'Chemical', 'MESH:C021751', (77, 89))
12787	33179075	The present study identified tanshinone I and simvastatin as compounds that exerted inhibitory effects on PARP1 expression, and demonstrated that tanshinone I improved tumour sensitivity to simvastatin.	('improved', 'PosReg', (159, 167))	('tanshinone', 'Var', (146, 156))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('PARP1', 'Gene', (106, 111))	('tanshinone I', 'Chemical', 'MESH:C021751', (146, 158))	('tanshinone I', 'Chemical', 'MESH:C021751', (29, 41))	('tumour', 'Disease', (168, 174))	('simvastatin', 'Chemical', 'MESH:D019821', (190, 201))	('simvastatin', 'Chemical', 'MESH:D019821', (46, 57))
12791	33179075	KIT mutations may serve as an adverse prognostic factor in metastatic melanoma and sunitinib may have activity in patients with melanoma and KIT mutations.	('melanoma', 'Disease', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('sunitinib', 'Chemical', 'MESH:D000077210', (83, 92))	('patients', 'Species', '9606', (114, 122))	('KIT', 'molecular_function', 'GO:0005020', ('141', '144'))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('mutations', 'Var', (145, 154))	('KIT', 'Gene', '3815', (0, 3))	('activity', 'MPA', (102, 110))	('KIT', 'Gene', (141, 144))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', '3815', (141, 144))	('KIT', 'Gene', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanoma', 'Disease', (128, 136))
12795	33179075	Cells overexpressing Bcl-2 have been reported to exhibit a significantly improved response to salvage radiotherapy compared with that of cells with low Bcl-2 expression.	('Bcl-2', 'Gene', (21, 26))	('Bcl-2', 'molecular_function', 'GO:0015283', ('152', '157'))	('Bcl-2', 'Gene', '596', (152, 157))	('Bcl-2', 'Gene', (152, 157))	('improved', 'PosReg', (73, 81))	('response to salvage radiotherapy', 'CPA', (82, 114))	('Bcl-2', 'molecular_function', 'GO:0015283', ('21', '26'))	('overexpressing', 'Var', (6, 20))	('Bcl-2', 'Gene', '596', (21, 26))
12818	33179075	These findings suggested that inhibiting PARP1 expression may be a potential method for treatment of melanoma and renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (114, 134))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('PARP1', 'Gene', (41, 46))	('melanoma and renal cell carcinoma', 'Disease', 'MESH:C538614', (101, 134))	('expression', 'MPA', (47, 57))	('inhibiting', 'Var', (30, 40))
12827	30511391	Site of origin seems to correlate best with tumoural somatic profile, with melanomas arising from chronically sun damaged (CSD) sites having a higher mutational burden than tumours arising from non-CSD sites 1 - a direct consequence of the UV-induced C>T transitions at dipyrimidines that dominate the majority of CM genomes 2, 3, 4.	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('tumours', 'Disease', (173, 180))	('melanomas', 'Disease', (75, 84))	('mutational burden', 'MPA', (150, 167))	('tumoural', 'Disease', 'MESH:D009369', (44, 52))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('CM', 'Phenotype', 'HP:0012056', (314, 316))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('melanomas', 'Disease', 'MESH:D008545', (75, 84))	('tumoural', 'Disease', (44, 52))	('sun damaged', 'Phenotype', 'HP:0000992', (110, 121))	('C>T transitions', 'Var', (251, 266))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('dipyrimidines', 'Chemical', '-', (270, 283))
12829	30511391	The BRAF, NRAS and NF1 driver alterations all activate the mitogen-activated protein kinase (MAPK) pathway and generally occur at the earlier stages of tumour evolution 5.	('NRAS', 'Gene', '4893', (10, 14))	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('tumour', 'Disease', (152, 158))	('NF1', 'Gene', (19, 22))	('NF1', 'Gene', '4763', (19, 22))	('alterations', 'Var', (30, 41))	('BRAF', 'Gene', (4, 8))	('activate', 'PosReg', (46, 54))	('BRAF', 'Gene', '673', (4, 8))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('NRAS', 'Gene', (10, 14))	('MAPK', 'molecular_function', 'GO:0004707', ('93', '97'))
12830	30511391	In CM, it has been proposed that subsequent mutations occur in the TERT promoter and in regulators of the cell cycle such as CDKN2A, which precede mutations in chromatin remodelers such as members of the SWI/SNF complex and TP53, the latter being associated with more advanced stages of primary tumour progression 5.	('TERT', 'Gene', (67, 71))	('tumour', 'Disease', 'MESH:D009369', (295, 301))	('TERT', 'Gene', '7015', (67, 71))	('associated', 'Reg', (247, 257))	('chromatin', 'cellular_component', 'GO:0000785', ('160', '169'))	('TP53', 'Gene', (224, 228))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('204', '219'))	('CM', 'Phenotype', 'HP:0012056', (3, 5))	('tumour', 'Disease', (295, 301))	('cell cycle', 'biological_process', 'GO:0007049', ('106', '116'))	('mutations', 'Var', (44, 53))	('CDKN2A', 'Gene', (125, 131))	('tumour', 'Phenotype', 'HP:0002664', (295, 301))	('CDKN2A', 'Gene', '1029', (125, 131))	('TP53', 'Gene', '7157', (224, 228))
12833	30511391	CM has the highest burden of somatic mutations across the major cancer subtypes, with a mutational landscape that is dominated by the UV mutational signature, primarily C>T transitions as described earlier 2, 3, 4.	('C>T transitions', 'Var', (169, 184))	('CM', 'Phenotype', 'HP:0012056', (0, 2))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
12834	30511391	About 45-50% of CM are BRAF-mutant (principally through mutations at the V600 codon), ~30% are RAS-mutant (either NRAS, principally at codon Q61, KRAS or HRAS), 10-15% are NF1-mutant and about 5-10% are TWT 3, 4 (Table 1).	('mutations at', 'Var', (56, 68))	('KRAS', 'Gene', (146, 150))	('HRAS', 'Gene', (154, 158))	('RAS-mutant', 'Disease', (95, 105))	('BRAF', 'Gene', '673', (23, 27))	('NRAS', 'Gene', (114, 118))	('KRAS', 'Gene', '3845', (146, 150))	('BRAF', 'Gene', (23, 27))	('NRAS', 'Gene', '4893', (114, 118))	('NF1', 'Gene', (172, 175))	('NF1', 'Gene', '4763', (172, 175))	('CM', 'Phenotype', 'HP:0012056', (16, 18))	('HRAS', 'Gene', '3265', (154, 158))	('V600', 'Var', (73, 77))
12835	30511391	Melanomas that arise on skin with intermittent sun exposure are generally more likely to have a BRAF mutation compared with melanomas occurring on chronically sun-exposed skin 8.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanomas', 'Phenotype', 'HP:0002861', (124, 133))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('melanomas', 'Disease', 'MESH:D008545', (124, 133))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('Melanomas', 'Disease', (0, 9))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('melanomas', 'Disease', (124, 133))	('mutation', 'Var', (101, 109))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))
12836	30511391	Melanomas with BRAF mutations are also more common in younger patients, in the superficial spreading histopathologic subtype and on the trunk 9, 10.	('BRAF', 'Gene', '673', (15, 19))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('BRAF', 'Gene', (15, 19))	('superficial spreading', 'Disease', (79, 100))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('Melanomas', 'Disease', (0, 9))	('trunk', 'cellular_component', 'GO:0043198', ('136', '141'))	('common', 'Reg', (44, 50))	('patients', 'Species', '9606', (62, 70))	('mutations', 'Var', (20, 29))
12837	30511391	NRAS mutations appear more frequently in older patients, in the nodular histopathologic subtype and on skin with chronic UV-damaged skin 11, 12.	('patients', 'Species', '9606', (47, 55))	('NRAS', 'Gene', '4893', (0, 4))	('NRAS', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
12838	30511391	Additional recurrent mutations identified in large-scale sequencing studies include disruptive variants in CDKN2A, TP53, ARID2 and PTEN, and 5' UTR hotspot mutations in RPS27 and MRPS31, both ribosomal proteins 3, 4.	('CDKN2A', 'Gene', '1029', (107, 113))	('PTEN', 'Gene', (131, 135))	('mutations', 'Var', (156, 165))	('ARID2', 'Gene', (121, 126))	('TP53', 'Gene', '7157', (115, 119))	('RPS27', 'Gene', (169, 174))	('MRPS31', 'Gene', '10240', (179, 185))	('RPS27', 'Gene', '6232', (169, 174))	('PTEN', 'Gene', '5728', (131, 135))	('TP53', 'Gene', (115, 119))	('variants', 'Var', (95, 103))	('CDKN2A', 'Gene', (107, 113))	('MRPS31', 'Gene', (179, 185))	('ARID2', 'Gene', '196528', (121, 126))
12839	30511391	Driver alterations and mutational burden are also related; tumours driven by BRAF V600E mutations tend to have fewer somatic mutations than tumours bearing other, possibly less potent, alterations such as loss of NF1 and activation of NRAS, KIT and BRAF non-V600E 1.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('mutations', 'Var', (88, 97))	('NF1', 'Gene', (213, 216))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('tumours', 'Disease', 'MESH:D009369', (140, 147))	('V600E', 'Mutation', 'rs113488022', (258, 263))	('KIT', 'molecular_function', 'GO:0005020', ('241', '244'))	('V600E', 'Mutation', 'rs113488022', (82, 87))	('V600E mutations', 'Var', (82, 97))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('NRAS', 'Gene', '4893', (235, 239))	('somatic mutations', 'MPA', (117, 134))	('KIT', 'CPA', (241, 244))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (77, 81))	('BRAF', 'Gene', '673', (249, 253))	('fewer', 'NegReg', (111, 116))	('BRAF', 'Gene', (249, 253))	('activation', 'PosReg', (221, 231))	('loss', 'NegReg', (205, 209))	('NRAS', 'Gene', (235, 239))	('NF1', 'Gene', '4763', (213, 216))	('tumours', 'Disease', (140, 147))	('tumours', 'Disease', (59, 66))
12840	30511391	This may be due to these cancers being promoted by additional mutations spread through different biological pathways, and accordingly, tend to present in later life 1.	('promoted', 'PosReg', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('mutations', 'Var', (62, 71))
12842	30511391	More than 50% of advanced CMs have mutations in the TERT (telomerase reverse transcriptase) promoter that create binding sites for the E26 transformation-specific (ETS) family of transcription factors 14.	('CM', 'Phenotype', 'HP:0012056', (26, 28))	('transcriptase', 'molecular_function', 'GO:0003899', ('77', '90'))	('transcription', 'biological_process', 'GO:0006351', ('179', '192'))	('binding', 'molecular_function', 'GO:0005488', ('113', '120'))	('telomerase reverse transcriptase', 'Gene', '7015', (58, 90))	('transcriptase', 'molecular_function', 'GO:0034062', ('77', '90'))	('advanced CMs', 'Disease', (17, 29))	('TERT', 'Gene', (52, 56))	('TERT', 'Gene', '7015', (52, 56))	('transcriptase', 'molecular_function', 'GO:0003968', ('77', '90'))	('binding', 'Interaction', (113, 120))	('telomerase reverse transcriptase', 'Gene', (58, 90))	('mutations', 'Var', (35, 44))
12844	30511391	MITF amplification is present in about 10% of primary melanomas, with a higher incidence reported among metastatic melanomas 18.	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('melanomas', 'Disease', 'MESH:D008545', (115, 124))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('amplification', 'Var', (5, 18))	('melanomas', 'Disease', 'MESH:D008545', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('MITF', 'Gene', '4286', (0, 4))	('melanomas', 'Disease', (115, 124))	('MITF', 'Gene', (0, 4))	('melanomas', 'Disease', (54, 63))
12850	30511391	While the majority of studies investigating the relationship between BRAF mutations and clinical outcomes are focused on patients with metastatic disease, recent studies have demonstrated that BRAF-mutant melanomas are also associated with a shorter disease-free and melanoma-specific survival in patients with early-stage disease 24, 25.	('BRAF', 'Gene', (193, 197))	('BRAF', 'Gene', '673', (193, 197))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('melanoma', 'Disease', (205, 213))	('melanoma', 'Disease', (267, 275))	('BRAF', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('melanomas', 'Disease', 'MESH:D008545', (205, 214))	('patients', 'Species', '9606', (297, 305))	('melanoma', 'Disease', 'MESH:D008545', (267, 275))	('melanomas', 'Phenotype', 'HP:0002861', (205, 214))	('shorter', 'NegReg', (242, 249))	('BRAF', 'Gene', '673', (69, 73))	('patients', 'Species', '9606', (121, 129))	('melanomas', 'Disease', (205, 214))
12852	30511391	In particular, no impact on survival was seen when NRAS mutations were measured in primary disease 26, 27, however when measured from metastases, NRAS mutations were associated with improved survival compared to tumours with BRAF mutations or TWT tumours 28, 29.	('TWT tumours', 'Disease', (243, 254))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('tumours', 'Disease', (247, 254))	('survival', 'MPA', (191, 199))	('tumours', 'Phenotype', 'HP:0002664', (247, 254))	('tumours', 'Disease', 'MESH:D009369', (247, 254))	('metastases', 'Disease', 'MESH:D009362', (134, 144))	('mutations', 'Var', (151, 160))	('NRAS', 'Gene', '4893', (51, 55))	('tumour', 'Phenotype', 'HP:0002664', (247, 253))	('NRAS', 'Gene', '4893', (146, 150))	('improved', 'PosReg', (182, 190))	('metastases', 'Disease', (134, 144))	('tumours', 'Disease', (212, 219))	('BRAF', 'Gene', (225, 229))	('BRAF', 'Gene', '673', (225, 229))	('TWT tumours', 'Disease', 'MESH:D009369', (243, 254))	('tumours', 'Phenotype', 'HP:0002664', (212, 219))	('tumours', 'Disease', 'MESH:D009369', (212, 219))	('NRAS', 'Gene', (51, 55))	('NRAS', 'Gene', (146, 150))
12853	30511391	Despite the undoubted prognostic relevance of American Joint Committee on Cancer (AJCC) classification and certain driver mutations, our ability to predict those early-stage patients at highest metastatic risk remains conspicuously limited.	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Cancer', 'Disease', (74, 80))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))	('patients', 'Species', '9606', (174, 182))	('mutations', 'Var', (122, 131))
12859	30511391	Importantly, the MITF-low/proliferative subtype, characterised by an absence of the expression of immune-response genes, had only BRAF/NRAS-mutated samples and more tumours with CDKN2A deletions, and was significantly associated with a poorer prognosis.	('NRAS', 'Gene', (135, 139))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('BRAF', 'Gene', '673', (130, 134))	('NRAS', 'Gene', '4893', (135, 139))	('deletions', 'Var', (185, 194))	('BRAF', 'Gene', (130, 134))	('CDKN2A', 'Gene', (178, 184))	('MITF', 'Gene', (17, 21))	('MITF', 'Gene', '4286', (17, 21))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('immune-response', 'biological_process', 'GO:0006955', ('98', '113'))	('tumours', 'Disease', 'MESH:D009369', (165, 172))	('CDKN2A', 'Gene', '1029', (178, 184))	('tumours', 'Disease', (165, 172))
12864	30511391	Combined treatment with BRAF and MEK inhibitors achieves radiological responses in ~70% of patients with BRAF V600 mutations 68.	('BRAF', 'Gene', '673', (105, 109))	('V600 mutations', 'Var', (110, 124))	('patients', 'Species', '9606', (91, 99))	('BRAF', 'Gene', (105, 109))	('radiological responses', 'CPA', (57, 79))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('MEK', 'Gene', (33, 36))	('MEK', 'Gene', '5609', (33, 36))
12870	30511391	The most common mechanism of acquired resistance is via reactivation of the MAPK/ERK pathway 72.	('ERK', 'Gene', '5594', (81, 84))	('ERK', 'Gene', (81, 84))	('MAPK', 'molecular_function', 'GO:0004707', ('76', '80'))	('reactivation', 'Var', (56, 68))	('acquired resistance', 'Disease', (29, 48))	('ERK', 'molecular_function', 'GO:0004707', ('81', '84'))
12872	30511391	It is hypothesised that the mutational status of a cancer influences anti-tumour immune and ICI responses, presumably by virtue of enhanced neoantigen formation due to increased number of non-synonymous single-nucleotide variants 75, 76.	('ICI responses', 'CPA', (92, 105))	('neoantigen formation', 'MPA', (140, 160))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('influences', 'Reg', (58, 68))	('tumour', 'Disease', (74, 80))	('formation', 'biological_process', 'GO:0009058', ('151', '160'))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('enhanced', 'PosReg', (131, 139))	('mutational', 'Var', (28, 38))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
12873	30511391	Consistent with this notion, tumours with microsatellite instability resulting from acquired deficiency of DNA mismatch repair are also associated with enhanced response to PD-1 blockade 77, 78.	('deficiency', 'NegReg', (93, 103))	('PD-1', 'Gene', '9825', (173, 177))	('tumours', 'Disease', 'MESH:D009369', (29, 36))	('mismatch repair', 'biological_process', 'GO:0006298', ('111', '126'))	('tumours', 'Disease', (29, 36))	('DNA', 'Gene', (107, 110))	('response', 'MPA', (161, 169))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('enhanced', 'PosReg', (152, 160))	('PD-1', 'Gene', (173, 177))	('microsatellite instability', 'Var', (42, 68))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))
12884	30511391	DMs also tend to have lower DNA copy number alterations than other melanoma subtypes; the few focal deletions that have been observed target CDKN2A and NF1, whereas amplifications affect EGFR, CDK4, MDM2, TERT, MAP3K1, MET, YAP1 and NFKBIE 13.	('NF1', 'Gene', (152, 155))	('melanoma subtypes', 'Disease', 'MESH:D008545', (67, 84))	('CDKN2A', 'Gene', '1029', (141, 147))	('YAP1', 'Gene', (224, 228))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('deletions', 'Var', (100, 109))	('CDK4', 'Gene', (193, 197))	('EGFR', 'Gene', '1956', (187, 191))	('DM', 'Disease', 'MESH:D009223', (0, 2))	('MAP3K', 'molecular_function', 'GO:0004709', ('211', '216'))	('melanoma subtypes', 'Disease', (67, 84))	('CDK', 'molecular_function', 'GO:0004693', ('193', '196'))	('NFKBIE', 'Gene', '4794', (233, 239))	('CDK4', 'Gene', '1019', (193, 197))	('NFKBIE', 'Gene', (233, 239))	('MDM2', 'Gene', (199, 203))	('CDKN2A', 'Gene', (141, 147))	('MAP3K1', 'Gene', (211, 217))	('NF1', 'Gene', '4763', (152, 155))	('YAP1', 'Gene', '10413', (224, 228))	('MAP3K1', 'Gene', '4214', (211, 217))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('MDM2', 'Gene', '4193', (199, 203))	('DM', 'Disease', 'MESH:D009223', (200, 202))	('EGFR', 'Gene', (187, 191))	('TERT', 'Gene', (205, 209))	('TERT', 'Gene', '7015', (205, 209))	('EGFR', 'molecular_function', 'GO:0005006', ('187', '191'))
12888	30511391	No melanoma hotspot mutations in BRAF or NRAS have been identified in studies focusing on DM 13, 90, 91; the MAPK pathway seems instead to be activated by other mutations 13 (Table 1).	('NRAS', 'Gene', '4893', (41, 45))	('BRAF', 'Gene', '673', (33, 37))	('BRAF', 'Gene', (33, 37))	('NRAS', 'Gene', (41, 45))	('MAPK pathway', 'Pathway', (109, 121))	('mutations', 'Var', (161, 170))	('DM', 'Disease', 'MESH:D009223', (90, 92))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('MAPK', 'molecular_function', 'GO:0004707', ('109', '113'))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
12889	30511391	Indeed, possible oncogenic MAPK mutations in this subtype of melanoma include alterations detected in NF1, CBL, ERBB2, MAP2K1 and MAP3K1, as well as mutations that are hotspot in other types of cancers such as BRAF G469E, G466E and D594N and NRAS Q61H 13.	('D594N', 'Var', (232, 237))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('ERBB2', 'Gene', (112, 117))	('MAPK', 'Gene', (27, 31))	('NRAS', 'Gene', (242, 246))	('MAP2K1', 'Gene', '5604', (119, 125))	('cancers', 'Disease', (194, 201))	('NF1', 'Gene', '4763', (102, 105))	('CBL', 'Gene', '867', (107, 110))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('G466E', 'Var', (222, 227))	('MAP2K1', 'Gene', (119, 125))	('ERBB2', 'Gene', '2064', (112, 117))	('NF1', 'Gene', (102, 105))	('mutations', 'Var', (32, 41))	('G466E', 'Mutation', 'rs121913351', (222, 227))	('G469E', 'Mutation', 'rs121913355', (215, 220))	('MAP2K', 'molecular_function', 'GO:0004708', ('119', '124'))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('BRAF', 'Gene', (210, 214))	('BRAF', 'Gene', '673', (210, 214))	('NRAS', 'Gene', '4893', (242, 246))	('D594N', 'Mutation', 'rs397516896', (232, 237))	('MAP3K1', 'Gene', (130, 136))	('MAP3K1', 'Gene', '4214', (130, 136))	('Q61H', 'Mutation', 'rs121913255', (247, 251))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('MAPK', 'molecular_function', 'GO:0004707', ('27', '31'))	('CBL', 'Gene', (107, 110))	('MAP3K', 'molecular_function', 'GO:0004709', ('130', '135'))
12890	30511391	Following the recognition that somatic non-synonymous mutational load might be associated with improved immune checkpoint responses, Eroglu and colleagues hypothesised that patients with DM may respond well to ICI therapies 92.	('immune', 'CPA', (104, 110))	('patients', 'Species', '9606', (173, 181))	('improved', 'PosReg', (95, 103))	('non-synonymous mutational load', 'Var', (39, 69))	('DM', 'Disease', 'MESH:D009223', (187, 189))
12892	30511391	Whole-exome sequencing data from 17 patients revealed driver NF1 mutations in 14/17 samples (82.4%) and enrichment of loss-of-function mutations in TP53 and ARID2.	('patients', 'Species', '9606', (36, 44))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('NF1', 'Gene', (61, 64))	('ARID2', 'Gene', '196528', (157, 162))	('NF1', 'Gene', '4763', (61, 64))	('loss-of-function', 'NegReg', (118, 134))	('ARID2', 'Gene', (157, 162))	('mutations', 'Var', (65, 74))
12898	30511391	A large proportion of AMs fall into the TWT subtype, with only 42-55% of tumours having mutations in BRAF, NRAS or NF1 3, 44 (Table 1).	('BRAF', 'Gene', (101, 105))	('tumours', 'Disease', (73, 80))	('NF1', 'Gene', (115, 118))	('AM', 'Phenotype', 'HP:0012060', (22, 24))	('fall', 'Phenotype', 'HP:0002527', (26, 30))	('NF1', 'Gene', '4763', (115, 118))	('mutations', 'Var', (88, 97))	('NRAS', 'Gene', '4893', (107, 111))	('AMs', 'Disease', (22, 25))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('BRAF', 'Gene', '673', (101, 105))	('tumours', 'Disease', 'MESH:D009369', (73, 80))	('NRAS', 'Gene', (107, 111))
12899	30511391	KIT mutation and amplifications are also AM drivers, with between 3 and 36% of tumours bearing these alterations 44, 52.	('alterations 44', 'Var', (101, 115))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('AM', 'Phenotype', 'HP:0012060', (41, 43))	('amplifications', 'Var', (17, 31))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('tumours', 'Disease', 'MESH:D009369', (79, 86))	('tumours', 'Disease', (79, 86))
12904	30511391	Genes frequently targeted by amplifications are KIT, TERT, PAK1, CDK4 and CCND1, and genes recurrently deleted include CDKN2A, PTEN and NF1 44, 104 (Table 1).	('TERT', 'Gene', (53, 57))	('KIT', 'Gene', (48, 51))	('TERT', 'Gene', '7015', (53, 57))	('CCND1', 'Gene', (74, 79))	('KIT', 'molecular_function', 'GO:0005020', ('48', '51'))	('CDKN2A', 'Gene', (119, 125))	('PAK1', 'Gene', '5058', (59, 63))	('PAK1', 'Gene', (59, 63))	('CDK', 'molecular_function', 'GO:0004693', ('65', '68'))	('NF1', 'Gene', (136, 139))	('CDKN2A', 'Gene', '1029', (119, 125))	('CDK4', 'Gene', (65, 69))	('PTEN', 'Gene', (127, 131))	('amplifications', 'Var', (29, 43))	('NF1', 'Gene', '4763', (136, 139))	('PTEN', 'Gene', '5728', (127, 131))	('CCND1', 'Gene', '595', (74, 79))	('CDK4', 'Gene', '1019', (65, 69))
12906	30511391	In this study, AM cell lines and patient-derived xenografts containing cyclin dependent kinase 4 (CDK4) pathway aberrations were sensitive to CDK4/6 inhibitors 105 and clinical studies are anticipated (NCT03454919).	('CDK4/6', 'Gene', (142, 148))	('CDK4', 'Gene', '1019', (142, 146))	('patient', 'Species', '9606', (33, 40))	('CDK', 'molecular_function', 'GO:0004693', ('142', '145'))	('cyclin dependent kinase 4', 'Gene', (71, 96))	('CDK4', 'Gene', (98, 102))	('cyclin', 'molecular_function', 'GO:0016538', ('71', '77'))	('cyclin dependent kinase 4', 'Gene', '1019', (71, 96))	('CDK4/6', 'Gene', '1019;1021', (142, 148))	('CDK4', 'Gene', '1019', (98, 102))	('CDK', 'molecular_function', 'GO:0004693', ('98', '101'))	('AM', 'Phenotype', 'HP:0012060', (15, 17))	('CDK4', 'Gene', (142, 146))	('aberrations', 'Var', (112, 123))
12907	30511391	There are other, infrequently altered genes identified by AM sequencing studies; for example, mutations of MAP2K2 and loss of ARID2 44.	('AM', 'Phenotype', 'HP:0012060', (58, 60))	('MAP2K2', 'Gene', (107, 113))	('mutations', 'Var', (94, 103))	('loss', 'NegReg', (118, 122))	('ARID2', 'Gene', '196528', (126, 131))	('MAP2K', 'molecular_function', 'GO:0004708', ('107', '112'))	('ARID2', 'Gene', (126, 131))	('MAP2K2', 'Gene', '5605', (107, 113))
12910	30511391	Although AMs harbouring BRAF or KIT mutations may respond to the appropriate inhibitors, the majority of patients do not currently have any genotype-specific treatment options.	('patients', 'Species', '9606', (105, 113))	('KIT', 'Gene', (32, 35))	('KIT', 'molecular_function', 'GO:0005020', ('32', '35'))	('mutations', 'Var', (36, 45))	('respond', 'MPA', (50, 57))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('AM', 'Phenotype', 'HP:0012060', (9, 11))
12913	30511391	Activating mutations in the guanine-nucleotide proteins GNAQ and GNA11 occur in the great majority of tumours (a combined frequency of ~85-92.5%), and in CYSLTR2 (4%) and PLCB4 (2.5%), all in a mutually exclusive manner 4, 56, as these may all activate the MAPK pathway 56, 109 (Figure 2, Table 1).	('CYSLTR2', 'Gene', (154, 161))	('mutations', 'Var', (11, 20))	('Activating', 'PosReg', (0, 10))	('PLCB4', 'Gene', '5332', (171, 176))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('MAPK', 'molecular_function', 'GO:0004707', ('257', '261'))	('GNAQ', 'Gene', '2776', (56, 60))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('activate', 'PosReg', (244, 252))	('PLCB4', 'Gene', (171, 176))	('tumours', 'Disease', 'MESH:D009369', (102, 109))	('MAPK pathway 56', 'Pathway', (257, 272))	('GNA11', 'Gene', (65, 70))	('GNA11', 'Gene', '2767', (65, 70))	('guanine-nucleotide', 'Chemical', 'MESH:D006150', (28, 46))	('CYSLTR2', 'Gene', '57105', (154, 161))	('tumours', 'Disease', (102, 109))	('GNAQ', 'Gene', (56, 60))
12914	30511391	Other significantly mutated genes in UM are BAP1, EIF1AX and SF3B1, which also form a second mutually-exclusive subgroup 56 (Table 2).	('SF3B1', 'Gene', (61, 66))	('EIF1AX', 'Gene', '1964', (50, 56))	('EIF1AX', 'Gene', (50, 56))	('BAP1', 'Gene', (44, 48))	('UM', 'Phenotype', 'HP:0007716', (37, 39))	('SF3B1', 'Gene', '23451', (61, 66))	('BAP1', 'Gene', '8314', (44, 48))	('mutated', 'Var', (20, 27))
12915	30511391	Different studies have found a number of mutational signatures in these tumours, most notably one associated with ageing and explained by spontaneous deamination of 5-methylcytosine, and others related to defects in nucleotide excision and in DNA mismatch repair 4, 48.	('ageing', 'biological_process', 'GO:0007568', ('114', '120'))	('related', 'Reg', (194, 201))	('defects', 'NegReg', (205, 212))	('deamination of 5-methylcytosine', 'MPA', (150, 181))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('mismatch repair', 'biological_process', 'GO:0006298', ('247', '262'))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (165, 181))	('DNA', 'cellular_component', 'GO:0005574', ('243', '246'))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('tumours', 'Disease', (72, 79))	('associated', 'Reg', (98, 108))	('nucleotide excision', 'MPA', (216, 235))	('mutational', 'Var', (41, 51))
12919	30511391	The M3 cluster is characterised by aberrations in BAP1, as well as 8q gain, but the extent and type of this chromosomal gain varies between the two sub-clusters.	('BAP1', 'Gene', (50, 54))	('BAP1', 'Gene', '8314', (50, 54))	('gain', 'PosReg', (70, 74))	('aberrations', 'Var', (35, 46))
12921	30511391	The D3 cluster further subdivides into two subsets, one characterised by little aneuploidy, gains of chromosome 6p (short-arm) and somatic mutations in EIF1AX, and the second with gains of chromosomes 6p and 8q (long-arm) and somatic mutations in SF3B1.	('gains', 'PosReg', (180, 185))	('short-arm', 'Phenotype', 'HP:0009824', (116, 125))	('chromosome', 'cellular_component', 'GO:0005694', ('101', '111'))	('EIF1AX', 'Gene', '1964', (152, 158))	('mutations', 'Var', (139, 148))	('EIF1AX', 'Gene', (152, 158))	('SF3B1', 'Gene', (247, 252))	('gains', 'PosReg', (92, 97))	('SF3B1', 'Gene', '23451', (247, 252))	('mutations', 'Var', (234, 243))
12922	30511391	Given the prevalence of observed alterations, it has been proposed that mutations in GNAQ, GNA11, CYSLTR2 or PLCB4 represent an early event, followed by loss of chromosome 3 and mutation of BAP1 in the case of M3, and by mutation of EIF1AX or SF3B1 in the case of D3 48.	('SF3B1', 'Gene', (243, 248))	('BAP1', 'Gene', '8314', (190, 194))	('mutation', 'Var', (178, 186))	('GNA11', 'Gene', '2767', (91, 96))	('chromosome', 'cellular_component', 'GO:0005694', ('161', '171'))	('GNAQ', 'Gene', '2776', (85, 89))	('mutations', 'Var', (72, 81))	('PLCB4', 'Gene', (109, 114))	('GNAQ', 'Gene', (85, 89))	('SF3B1', 'Gene', '23451', (243, 248))	('BAP1', 'Gene', (190, 194))	('CYSLTR2', 'Gene', '57105', (98, 105))	('GNA11', 'Gene', (91, 96))	('loss', 'NegReg', (153, 157))	('EIF1AX', 'Gene', (233, 239))	('PLCB4', 'Gene', '5332', (109, 114))	('CYSLTR2', 'Gene', (98, 105))	('mutation', 'Var', (221, 229))	('EIF1AX', 'Gene', '1964', (233, 239))	('chromosome 3', 'Protein', (161, 173))
12925	30511391	Class 1A tumours are also associated with D3 and EIF1AX mutations.	('tumours', 'Disease', 'MESH:D009369', (9, 16))	('EIF1AX', 'Gene', (49, 55))	('mutations', 'Var', (56, 65))	('EIF1AX', 'Gene', '1964', (49, 55))	('tumours', 'Disease', (9, 16))	('tumours', 'Phenotype', 'HP:0002664', (9, 16))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('associated', 'Reg', (26, 36))
12926	30511391	Class 2 UM tumours exhibit a dedifferentiated stem-cell-like and epithelioid phenotype that is associated with M3 and BAP1 mutations and confers a high metastatic risk 118, 125.	('BAP1', 'Gene', (118, 122))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('UM', 'Phenotype', 'HP:0007716', (8, 10))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('BAP1', 'Gene', '8314', (118, 122))	('tumours', 'Disease', 'MESH:D009369', (11, 18))	('associated', 'Reg', (95, 105))	('tumours', 'Disease', (11, 18))	('mutations', 'Var', (123, 132))
12930	30511391	Mutations in BRAF, NRAS or NF1 in MM are less prevalent than in CM, with loss of PTEN (4-25% of samples 3, 54) mutation or amplification of KIT (7-25% of MM samples 3, 54, 132) and CCND1 or CDK4 104 being more common (Table 1).	('MM', 'Phenotype', 'HP:0002861', (34, 36))	('NRAS', 'Gene', (19, 23))	('amplification', 'MPA', (123, 136))	('CDK4', 'Gene', '1019', (190, 194))	('KIT', 'molecular_function', 'GO:0005020', ('140', '143'))	('KIT', 'Gene', (140, 143))	('CM', 'Phenotype', 'HP:0012056', (64, 66))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('NF1', 'Gene', '4763', (27, 30))	('CCND1', 'Gene', '595', (181, 186))	('NRAS', 'Gene', '4893', (19, 23))	('NF1', 'Gene', (27, 30))	('CCND1', 'Gene', (181, 186))	('PTEN', 'Gene', (81, 85))	('CDK', 'molecular_function', 'GO:0004693', ('190', '193'))	('CDK4', 'Gene', (190, 194))	('PTEN', 'Gene', '5728', (81, 85))	('MM', 'Phenotype', 'HP:0002861', (154, 156))
12931	30511391	In fact, Hayward and colleagues identified a previously unappreciated set of driver genes shared between UM and MM, with two-thirds of TWT MM showing activating mutations in GNAQ and SF3B1.	('GNAQ', 'Gene', '2776', (174, 178))	('activating', 'PosReg', (150, 160))	('SF3B1', 'Gene', '23451', (183, 188))	('GNAQ', 'Gene', (174, 178))	('mutations', 'Var', (161, 170))	('MM', 'Phenotype', 'HP:0002861', (139, 141))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('SF3B1', 'Gene', (183, 188))	('MM', 'Phenotype', 'HP:0002861', (112, 114))
12941	30511391	Therefore, the question remains, if the CM driver mutations arose in melanocytes from glabrous skin, and vice versa, would melanocytes transform and form tumours?	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('mutations', 'Var', (50, 59))	('tumours', 'Disease', 'MESH:D009369', (154, 161))	('tumours', 'Disease', (154, 161))	('CM', 'Phenotype', 'HP:0012056', (40, 42))
12947	30511391	RR described the prognostic and therapeutic implications of molecular aberrations across the melanoma subtypes, and drafted sections of the introduction and conclusion.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma subtypes', 'Disease', 'MESH:D008545', (93, 110))	('melanoma subtypes', 'Disease', (93, 110))	('molecular aberrations', 'Var', (60, 81))
12962	29530782	Suppression of the nuclear localization of BAP1 (biallelic suppression) occurs in monosomy 3 because it is combined with assorted mutations on the remaining allele that may truncate the BAP1 protein, or affect nuclear localizer regions.	('BAP1', 'Gene', (43, 47))	('monosomy 3', 'Disease', (82, 92))	('protein', 'cellular_component', 'GO:0003675', ('191', '198'))	('BAP1', 'Gene', '8314', (186, 190))	('localization', 'biological_process', 'GO:0051179', ('27', '39'))	('BAP1', 'Gene', (186, 190))	('BAP1', 'Gene', '8314', (43, 47))	('protein', 'Protein', (191, 198))	('mutations', 'Var', (130, 139))	('nuclear localization', 'MPA', (19, 39))	('Suppression', 'NegReg', (0, 11))	('affect', 'Reg', (203, 209))	('truncate', 'NegReg', (173, 181))	('nuclear localizer regions', 'MPA', (210, 235))
12996	29530782	A partial list includes the unrecognized source material (false negative in gene expression profile and chromosomal analysis), the presence of point mutations that affect function but not nuclear translocation (false negative BAP1), the presence of isodisomy (false negative for chromosomal analysis), and the presence of germ line mutations (false negative chromosomal analysis).	('false', 'biological_process', 'GO:0071878', ('260', '265'))	('BAP1', 'Gene', (226, 230))	('function', 'MPA', (171, 179))	('false', 'biological_process', 'GO:0071877', ('58', '63'))	('gene expression', 'biological_process', 'GO:0010467', ('76', '91'))	('point mutations', 'Var', (143, 158))	('false', 'biological_process', 'GO:0071878', ('343', '348'))	('false', 'biological_process', 'GO:0071877', ('211', '216'))	('disomy', 'Disease', (252, 258))	('disomy', 'Disease', 'MESH:D024182', (252, 258))	('false', 'biological_process', 'GO:0071878', ('58', '63'))	('false', 'biological_process', 'GO:0071877', ('260', '265'))	('false', 'biological_process', 'GO:0071877', ('343', '348'))	('BAP1', 'Gene', '8314', (226, 230))	('false', 'biological_process', 'GO:0071878', ('211', '216'))	('affect', 'Reg', (164, 170))
12999	29530782	Bialleic suppression can also result from mutations that affect both alleles such as in isodisomy of chromosome 3p.	('chromosome', 'cellular_component', 'GO:0005694', ('101', '111'))	('Bialleic', 'MPA', (0, 8))	('result', 'Reg', (30, 36))	('suppression', 'NegReg', (9, 20))	('disomy', 'Disease', (91, 97))	('disomy', 'Disease', 'MESH:D024182', (91, 97))	('mutations', 'Var', (42, 51))
13001	29530782	Point mutations may negate the function of the BAP1 as a tumor suppressor gene without hampering its nuclear localization.	('negate', 'NegReg', (20, 26))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('57', '73'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('57', '73'))	('function', 'MPA', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('localization', 'biological_process', 'GO:0051179', ('109', '121'))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('BAP1', 'Gene', '8314', (47, 51))	('Point mutations', 'Var', (0, 15))	('tumor', 'Disease', (57, 62))	('BAP1', 'Gene', (47, 51))
13016	29269732	Moreover, large-scale genomic and transcriptomic analyses have identified a broad spectrum of mutations, copy number variations and mRNA expression changes in multiple RBPs across a variety of tumor types, ranging from glioblastoma to breast, colon, kidney, lung, prostate or thyroid carcinomas.	('mRNA expression', 'MPA', (132, 147))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (276, 293))	('RBP', 'Gene', '57794', (168, 171))	('glioblastoma', 'Disease', 'MESH:D005909', (219, 231))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (276, 294))	('thyroid carcinomas', 'Disease', (276, 294))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('colon', 'Disease', (243, 248))	('glioblastoma', 'Disease', (219, 231))	('breast', 'Disease', (235, 241))	('tumor', 'Disease', (193, 198))	('glioblastoma', 'Phenotype', 'HP:0012174', (219, 231))	('changes', 'Reg', (148, 155))	('mutations', 'Var', (94, 103))	('RBP', 'Gene', (168, 171))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (276, 294))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('copy number variations', 'Var', (105, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (284, 294))	('kidney', 'Disease', (250, 256))	('lung', 'Disease', (258, 262))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('prostate', 'Disease', (264, 272))
13026	29269732	Expression studies in clinical biopsies, and comprehensive transcriptomic and proteomic analyses of RBP-dependent functions become more important in the light of a broad spectrum of synonymous mutations in melanoma cells, not only at intergenic sites, but at untranslated (UTR) regions of mRNAs.	('RBP', 'Gene', (100, 103))	('RBP', 'Gene', '57794', (100, 103))	('mutations', 'Var', (193, 202))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('melanoma', 'Disease', (206, 214))	('melanoma', 'Disease', 'MESH:D008545', (206, 214))
13029	29269732	Here, we mined clinical data sets for an unbiased characterization of the genomic status (mutations, amplifications, deletions, translocations) of all known mRBPs in human melanomas.	('RBP', 'Gene', (158, 161))	('RBP', 'Gene', '57794', (158, 161))	('translocations', 'Var', (128, 142))	('human', 'Species', '9606', (166, 171))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanomas', 'Disease', (172, 181))	('deletions', 'Var', (117, 126))	('melanomas', 'Disease', 'MESH:D008545', (172, 181))	('melanomas', 'Phenotype', 'HP:0002861', (172, 181))
13034	29269732	We have recently reported a broad spectrum of mutations and copy number variations (CNVs) of RBPs in a series of non-melanoma solid tumors.	('mutations', 'Var', (46, 55))	('non-melanoma solid tumors', 'Disease', (113, 138))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('non-melanoma solid tumors', 'Disease', 'MESH:D008545', (113, 138))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('copy number variations', 'Var', (60, 82))	('RBP', 'Gene', (93, 96))	('RBP', 'Gene', '57794', (93, 96))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
13036	29269732	Intriguingly, even if pooling mutations, genomic amplifications and deletions, the frequency of genomic alterations per mRBP was rather low, with an average of 2.4% affected patients per gene (Fig.	('RBP', 'Gene', '57794', (121, 124))	('patients', 'Species', '9606', (174, 182))	('RBP', 'Gene', (121, 124))	('deletions', 'Var', (68, 77))
13037	29269732	This is contrast, for example, to over 50% of CNVs in splicing factors for example in lung or colon carcinomas (Fig.	('lung or colon carcinomas', 'Disease', (86, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('lung or colon carcinomas', 'Disease', 'MESH:D008175', (86, 110))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('CNVs', 'Var', (46, 50))	('splicing', 'biological_process', 'GO:0045292', ('54', '62'))	('splicing factors', 'Gene', (54, 70))
13038	29269732	RNA sequencing (RNA-Seq) was then set to assess gene expression differences in normal skin melanocytes and the well-characterized UACC-62, SK-Mel-147, and SK-Mel-28 cell lines, representative of metastatic melanomas with prototypical mutations in BRAF, NRAS, and p53 respectively (Supplementary Table 1).	('RNA', 'cellular_component', 'GO:0005562', ('16', '19'))	('gene expression', 'biological_process', 'GO:0010467', ('48', '63'))	('melanomas', 'Disease', 'MESH:D008545', (206, 215))	('BRAF', 'Gene', '673', (247, 251))	('NRAS', 'Gene', (253, 257))	('p53', 'Gene', (263, 266))	('BRAF', 'Gene', (247, 251))	('melanomas', 'Disease', (206, 215))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('NRAS', 'Gene', '4893', (253, 257))	('p53', 'Gene', '7157', (263, 266))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('mutations', 'Var', (234, 243))	('melanomas', 'Phenotype', 'HP:0002861', (206, 215))
13054	29269732	However, only high CELF1 mRNA expression significantly correlated with poor prognosis of primary melanoma patients in this set (Fig.	('correlated', 'Reg', (55, 65))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('mRNA expression', 'MPA', (25, 40))	('high', 'Var', (14, 18))	('CELF1', 'Gene', (19, 24))	('patients', 'Species', '9606', (106, 114))	('CELF1', 'Gene', '10658', (19, 24))
13072	29269732	No significant cell death was observed even at late times after CELF1 depletion, in contrast to HeLa or cells from laryngeal or oral squamous cell carcinoma, where CELF1 was found to control pro-apoptotic genes.	('CELF1', 'Gene', (164, 169))	('CELF1', 'Gene', (64, 69))	('CELF1', 'Gene', '10658', (164, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (128, 156))	('depletion', 'Var', (70, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('cell death', 'biological_process', 'GO:0008219', ('15', '25'))	('HeLa', 'CellLine', 'CVCL:0030', (96, 100))	('CELF1', 'Gene', '10658', (64, 69))	('oral squamous cell carcinoma', 'Disease', (128, 156))
13074	29269732	6a-c no obvious changes in the splicing expression was found in melanoma cells following CELF1 depletion.	('CELF1', 'Gene', (89, 94))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('depletion', 'Var', (95, 104))	('melanoma', 'Disease', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('splicing', 'biological_process', 'GO:0045292', ('31', '39'))	('CELF1', 'Gene', '10658', (89, 94))
13103	29269732	With this approach, 233 CELF1 RIP-Seq targets were found to undergo significant changes in mRNA expression after transduction of CELF1 shRNA (Fisher's test p-value<0.05; see Supplementary Data 5).	('CELF1', 'Gene', '10658', (24, 29))	('changes', 'Reg', (80, 87))	('transduction', 'biological_process', 'GO:0009293', ('113', '125'))	('CELF1', 'Gene', (24, 29))	('mRNA expression', 'MPA', (91, 106))	('CELF1', 'Gene', '10658', (129, 134))	('CELF1', 'Gene', (129, 134))	('transduction', 'Var', (113, 125))
13104	29269732	Consistent with previous roles of CELF1 in mRNA decay, 37% of transcripts indeed accumulated in melanoma cells expressing shRNA (Fig.	('CELF1', 'Gene', (34, 39))	('transcripts', 'MPA', (62, 73))	('mRNA decay', 'biological_process', 'GO:0006402', ('43', '53'))	('accumulated', 'PosReg', (81, 92))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))	('shRNA', 'Var', (122, 127))	('CELF1', 'Gene', '10658', (34, 39))
13106	29269732	Moreover, over two thirds of CELF1 RIP-Seq targets were downregulated upon CELF1 depletion (Fig.	('depletion', 'Var', (81, 90))	('downregulated', 'NegReg', (56, 69))	('CELF1', 'Gene', '10658', (29, 34))	('CELF1', 'Gene', '10658', (75, 80))	('CELF1', 'Gene', (29, 34))	('CELF1', 'Gene', (75, 80))
13109	29269732	These data provide a mechanistic explanation as to why CELF1 depletion in melanoma cells results in an inhibited cell proliferation, instead of exiting from quiescence as reported in activated T cells, or instead of apoptosis as described for laryngeal, hepatocellular or oral squamous cell carcinoma.	('quiescence', 'biological_process', 'GO:0044838', ('157', '167'))	('hepatocellular', 'Disease', (254, 268))	('depletion', 'Var', (61, 70))	('cell proliferation', 'CPA', (113, 131))	('CELF1', 'Gene', '10658', (55, 60))	('CELF1', 'Gene', (55, 60))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (272, 300))	('melanoma', 'Disease', (74, 82))	('inhibited', 'NegReg', (103, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('laryngeal', 'Disease', (243, 252))	('apoptosis', 'biological_process', 'GO:0097194', ('216', '225'))	('apoptosis', 'biological_process', 'GO:0006915', ('216', '225'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (277, 300))	('oral squamous cell carcinoma', 'Disease', (272, 300))	('cell proliferation', 'biological_process', 'GO:0008283', ('113', '131'))
13112	29269732	HJAY identified 1361 and 698 altered genes upon CELF1 depletion in SK-Mel-103 and UACC-62, respectively (Fig.	('depletion', 'Var', (54, 63))	('CELF1', 'Gene', (48, 53))	('CELF1', 'Gene', '10658', (48, 53))
13114	29269732	To determine whether these changes in mRNA expression are also selective for melanoma cells, we performed comparative analyses to data in leukemia and hepatocellular cancer cell lines available in ENCODE (ENCSR605MFS and ENCSR695XOD, respectively).	('ENCSR695XOD', 'Var', (221, 232))	('leukemia and hepatocellular cancer', 'Disease', 'MESH:D006528', (138, 172))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('leukemia', 'Phenotype', 'HP:0001909', (138, 146))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (151, 172))	('ENCSR605MFS', 'Var', (205, 216))
13117	29269732	With respect to iTRAQ, LC-MS/MS (liquid chromatography-mass spectrometry) revealed 1020 and 532 proteins deregulated by CELF1 depletion in SK-Mel-103 and UACC-62 cell lines, respectively (Student's t test p < 0.05; see Volcano plots in Fig.	('proteins', 'Protein', (96, 104))	('depletion', 'Var', (126, 135))	('deregulated', 'NegReg', (105, 116))	('CELF1', 'Gene', (120, 125))	('CELF1', 'Gene', '10658', (120, 125))
13142	29269732	CELF1 depletion (by shRNA) reduced DEK expression in 5 out of 6 cell lines (Fig.	('CELF1', 'Gene', (0, 5))	('DEK', 'Gene', (35, 38))	('reduced', 'NegReg', (27, 34))	('depletion', 'Var', (6, 15))	('DEK', 'Gene', '7913', (35, 38))	('CELF1', 'Gene', '10658', (0, 5))
13148	29269732	To further address this rescue activity, melanoma cells were transduced with DEK mutants lacking DNA binding activity (Fig.	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('lacking', 'NegReg', (89, 96))	('DEK', 'Gene', '7913', (77, 80))	('DNA binding', 'molecular_function', 'GO:0003677', ('97', '108'))	('melanoma', 'Disease', (41, 49))	('DNA binding', 'Interaction', (97, 108))	('activity', 'MPA', (109, 117))	('DEK', 'Gene', (77, 80))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('mutants', 'Var', (81, 88))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))
13149	29269732	Specifically, we tested (i) DEK constructs deleted for amino acids 87-186, which encompass a distinct pseudo-SAF/SAF-box (scaffold attachment factor domain) with potent DNA binding and supercoiling effects and (ii) mutants devoid also of amino acids 260-350, a domain that binds DNA, but displays weak supercoiling activity (see schematic in Fig.	('DEK', 'Gene', '7913', (28, 31))	('-186', 'Gene', (69, 73))	('deleted', 'Var', (43, 50))	('-186', 'Gene', '7913', (69, 73))	('DEK', 'Gene', (28, 31))	('SAF', 'Gene', '100302740', (113, 116))	('DNA binding', 'molecular_function', 'GO:0003677', ('169', '180'))	('supercoiling', 'MPA', (185, 197))	('DNA', 'cellular_component', 'GO:0005574', ('279', '282'))	('binding', 'Interaction', (173, 180))	('binds', 'Interaction', (273, 278))	('SAF', 'Gene', (109, 112))	('DNA', 'cellular_component', 'GO:0005574', ('169', '172'))	('SAF', 'Gene', (113, 116))	('DNA', 'MPA', (169, 172))	('SAF', 'Gene', '100302740', (109, 112))
13150	29269732	Cells expressing full length or either of these mutants were then transduced with CELF1 shRNA (Fig.	('mutants', 'Var', (48, 55))	('CELF1', 'Gene', '10658', (82, 87))	('CELF1', 'Gene', (82, 87))
13160	29269732	6m, CELF1 depletion significantly shortened DEK mRNA half-life.	('CELF1', 'Gene', '10658', (4, 9))	('shortened', 'NegReg', (34, 43))	('DEK', 'Gene', '7913', (44, 47))	('depletion', 'Var', (10, 19))	('DEK', 'Gene', (44, 47))	('CELF1', 'Gene', (4, 9))
13211	29269732	Full-length DEK and the Delta-SAF and the double SAF-C end deletion mutants (see schematic of constructs in Fig.	('SAF', 'Gene', (49, 52))	('DEK', 'Gene', (12, 15))	('SAF', 'Gene', '100302740', (49, 52))	('deletion mutants', 'Var', (59, 75))	('SAF', 'Gene', (30, 33))	('SAF', 'Gene', '100302740', (30, 33))	('DEK', 'Gene', '7913', (12, 15))
13220	29269732	Low confluency colony formation assays were performed by seeding 1 x 103 (SK-Mel-103 and SK-Mel-147) or 5 x 103 (SK-Mel-5, SK-Mel-19, SK-Mel-28, SK-Mel-29, UACC-62, and LU-1205) cells per well onto six-well plates.	('SK-Mel-147', 'Var', (89, 99))	('Low confluency colony formation assays', 'CPA', (0, 38))	('formation', 'biological_process', 'GO:0009058', ('22', '31'))	('SK-Mel-5', 'Var', (113, 121))	('SK-Mel-29', 'Var', (145, 154))	('SK-Mel-19', 'Var', (123, 132))	('LU-1205', 'CellLine', 'CVCL:5239', (169, 176))	('SK-Mel-28', 'Var', (134, 143))
13286	29269732	Briefly, MMLV-RT retrotranscription of samples from a T7 promoter primer was followed by a T7 RNA pol catalyzed in vitro transcription reaction in the presence of either Cy3-CTP or Cy5-CTP fluorophores.	('Cy3-CTP', 'Chemical', '-', (170, 177))	('Cy5-CTP', 'Chemical', '-', (181, 188))	('transcription', 'biological_process', 'GO:0006351', ('121', '134'))	('Cy5-CTP', 'Var', (181, 188))	('RNA', 'cellular_component', 'GO:0005562', ('94', '97'))	('Cy3-CTP', 'Var', (170, 177))	('MMLV', 'Species', '11801', (9, 13))
13292	29269732	BAM files containing the read alignments of the samples belonging to two CELF1 RNA-seq experiments were downloaded from ENCODE database repertoire: K562 shCELF1 RNA-seq (ENCSR605MFS) and shCELF1 HepG2 RNA-seq (ENCSR695XOD).	('CELF1', 'Gene', (189, 194))	('K562', 'Var', (148, 152))	('CELF1', 'Gene', '10658', (189, 194))	('RNA', 'cellular_component', 'GO:0005562', ('161', '164'))	('CELF1', 'Gene', '10658', (155, 160))	('CELF1', 'Gene', (155, 160))	('CELF1', 'Gene', '10658', (73, 78))	('CELF1', 'Gene', (73, 78))	('RNA', 'cellular_component', 'GO:0005562', ('79', '82'))	('K562', 'CellLine', 'CVCL:0004', (148, 152))	('RNA', 'cellular_component', 'GO:0005562', ('201', '204'))	('HepG2', 'CellLine', 'CVCL:0027', (195, 200))
13303	29269732	Data sets generated for CELF in melanoma cells are as follows: RNA-Seq (GSE88741), RIP-seq (GSE83231), HJAY (GSE83590), iTRAQ (PXD003112), splicing-arrays (GSE83678), and DEK cDNA arrays (GSE83614).	('GSE83678', 'Var', (156, 164))	('GSE83614', 'Var', (188, 196))	('GSE88741', 'Var', (72, 80))	('CELF', 'Gene', '1052', (24, 28))	('melanoma', 'Disease', (32, 40))	('GSE83231', 'Var', (92, 100))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('PXD003112', 'Var', (127, 136))	('DEK', 'Gene', '7913', (171, 174))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))	('splicing', 'biological_process', 'GO:0045292', ('139', '147'))	('DEK', 'Gene', (171, 174))	('CELF', 'Gene', (24, 28))	('GSE83590', 'Var', (109, 117))
13304	29269732	For expression analyses of CELF1 function in other tumor types, RIP+Microarray data with identifiers ENCSR000AYU (K562) and ENCSR000AYA (GM12878), and transcriptomic data with identifiers ENCSR605MFS (K562) and ENCSR695XOD (HepG2) were extracted from the ENCODE database.	('ENCSR605MFS', 'Var', (188, 199))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('CELF1', 'Gene', (27, 32))	('CELF1', 'Gene', '10658', (27, 32))	('tumor', 'Disease', (51, 56))	('K562', 'CellLine', 'CVCL:0004', (201, 205))	('K562', 'CellLine', 'CVCL:0004', (114, 118))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('HepG2', 'CellLine', 'CVCL:0027', (224, 229))
13305	29269732	Mutant DEK plasmid generation: H.G.	('Mutant', 'Var', (0, 6))	('DEK', 'Gene', (7, 10))	('DEK', 'Gene', '7913', (7, 10))
13308	28594900	Known recurrent mutations were identified in GNAQ, GNA11, BAP1, EIF1AX, and SF3B1.	('GNA11', 'Gene', '2767', (51, 56))	('GNAQ', 'Gene', '2776', (45, 49))	('BAP1', 'Gene', (58, 62))	('mutations', 'Var', (16, 25))	('EIF1AX', 'Gene', '1964', (64, 70))	('EIF1AX', 'Gene', (64, 70))	('SF3B1', 'Gene', (76, 81))	('GNAQ', 'Gene', (45, 49))	('GNA11', 'Gene', (51, 56))	('SF3B1', 'Gene', '23451', (76, 81))	('BAP1', 'Gene', '8314', (58, 62))
13309	28594900	The role of mutated EIF1AX was tested using loss of function approaches including viability and translational efficiency assays.	('EIF1AX', 'Gene', '1964', (20, 26))	('EIF1AX', 'Gene', (20, 26))	('mutated', 'Var', (12, 19))
13310	28594900	Knockdown of both wild type and mutant EIF1AX was lethal to uveal melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('EIF1AX', 'Gene', '1964', (39, 45))	('EIF1AX', 'Gene', (39, 45))	('mutant', 'Var', (32, 38))	('uveal melanoma', 'Disease', 'MESH:C536494', (60, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('uveal melanoma', 'Disease', (60, 74))
13311	28594900	We probed the function of N-terminal tail EIF1AX mutations by performing RNA sequencing of polysome-associated transcripts in cells expressing endogenous wild type or mutant EIF1AX.	('mutations', 'Var', (49, 58))	('RNA', 'cellular_component', 'GO:0005562', ('73', '76'))	('EIF1AX', 'Gene', '1964', (174, 180))	('EIF1AX', 'Gene', (174, 180))	('mutant', 'Var', (167, 173))	('polysome', 'cellular_component', 'GO:0005844', ('91', '99'))	('EIF1AX', 'Gene', '1964', (42, 48))	('EIF1AX', 'Gene', (42, 48))
13312	28594900	Ribosome occupancy of the global translational apparatus was sensitive to suppression of wild type but not mutant EIF1AX.	('EIF1AX', 'Gene', '1964', (114, 120))	('EIF1AX', 'Gene', (114, 120))	('mutant', 'Var', (107, 113))	('Ribosome', 'cellular_component', 'GO:0005840', ('0', '8'))	('suppression', 'NegReg', (74, 85))	('Ribosome occupancy of', 'MPA', (0, 21))
13313	28594900	Together, these studies suggest that cells expressing mutant EIF1AX may exhibit aberrant translational regulation, which may provide clonal selective advantage in the subset of uveal melanoma that harbors this mutation.	('exhibit', 'Reg', (72, 79))	('translational regulation', 'MPA', (89, 113))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('uveal melanoma', 'Phenotype', 'HP:0007716', (177, 191))	('uveal melanoma', 'Disease', 'MESH:C536494', (177, 191))	('EIF1AX', 'Gene', '1964', (61, 67))	('EIF1AX', 'Gene', (61, 67))	('uveal melanoma', 'Disease', (177, 191))	('mutant', 'Var', (54, 60))	('regulation', 'biological_process', 'GO:0065007', ('103', '113'))
13316	28594900	Over 80% of UM tumors harbor activating hotspot mutations in GNAQ or GNA11, which encode alpha subunits of guanine nucleotide binding (G) proteins.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('GNAQ', 'Gene', '2776', (61, 65))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('115', '133'))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('GNAQ', 'Gene', (61, 65))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('GNA11', 'Gene', '2767', (69, 74))	('activating hotspot', 'PosReg', (29, 47))	('GNA11', 'Gene', (69, 74))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (107, 125))	('mutations', 'Var', (48, 57))	('tumors', 'Disease', (15, 21))
13317	28594900	Mutations at residues 183 and 209 of these proteins result in constitutive downstream signaling to the protein kinase C, mitogen-activated protein kinase (MAPK), and YAP1 pathways.	('protein kinase C', 'Pathway', (103, 119))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('Mutations at', 'Var', (0, 12))	('MAPK', 'molecular_function', 'GO:0004707', ('155', '159'))	('YAP1', 'Gene', (166, 170))	('YAP1', 'Gene', '10413', (166, 170))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('constitutive downstream signaling', 'MPA', (62, 95))	('result in', 'Reg', (52, 61))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))
13318	28594900	Frequently observed copy number alterations in UM tumors include loss of a single copy of chromosome 3 (monosomy 3), amplification of 8q or 6p, and less frequently 8p gain or 1p, 6q, 16q loss.	('loss', 'NegReg', (65, 69))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('loss', 'NegReg', (187, 191))	('chromosome', 'cellular_component', 'GO:0005694', ('90', '100'))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('amplification', 'Var', (117, 130))	('gain', 'PosReg', (167, 171))
13319	28594900	Monosomy 3 is predictive of worse prognosis and often co-occurs with loss of function mutations in the tumor suppressor BAP1, which is located on chromosome 3.	('mutations', 'Var', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('chromosome', 'cellular_component', 'GO:0005694', ('146', '156'))	('tumor', 'Disease', (103, 108))	('loss of function', 'NegReg', (69, 85))	('BAP1', 'Gene', '8314', (120, 124))	('tumor suppressor', 'biological_process', 'GO:0051726', ('103', '119'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('103', '119'))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('Monosomy 3', 'Var', (0, 10))	('BAP1', 'Gene', (120, 124))
13320	28594900	In addition to GNAQ, GNA11, and BAP1, recurrent mutations in the splicing factor, SF3B1, as well as the translation initiation factor, EIF1AX, have been recently characterized in primary UM tumors.	('EIF1AX', 'Gene', (135, 141))	('GNAQ', 'Gene', (15, 19))	('SF3B1', 'Gene', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('UM', 'Phenotype', 'HP:0007716', (187, 189))	('BAP1', 'Gene', (32, 36))	('tumors', 'Disease', (190, 196))	('splicing', 'biological_process', 'GO:0045292', ('65', '73'))	('characterized', 'Reg', (162, 175))	('mutations', 'Var', (48, 57))	('EIF1AX', 'Gene', '1964', (135, 141))	('SF3B1', 'Gene', '23451', (82, 87))	('GNA11', 'Gene', (21, 26))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('translation initiation', 'biological_process', 'GO:0006413', ('104', '126'))	('BAP1', 'Gene', '8314', (32, 36))	('GNAQ', 'Gene', '2776', (15, 19))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('GNA11', 'Gene', '2767', (21, 26))
13330	28594900	Consistent with prior studies, the majority of patients who had or went on to develop metastatic disease (11/13) harbored monosomy 3 (S2 Table).	('metastatic disease', 'CPA', (86, 104))	('monosomy 3', 'Var', (122, 132))	('patients', 'Species', '9606', (47, 55))
13332	28594900	Consistent with prior analyses, presence of BAP1 mutation, versus either a SF3B1 or EIF1AX mutation portends a poorer survival (S2C and S2D Fig).	('survival', 'MPA', (118, 126))	('EIF1AX', 'Gene', '1964', (84, 90))	('EIF1AX', 'Gene', (84, 90))	('mutation', 'Var', (49, 57))	('poorer', 'NegReg', (111, 117))	('SF3B1', 'Gene', '23451', (75, 80))	('BAP1', 'Gene', '8314', (44, 48))	('SF3B1', 'Gene', (75, 80))	('BAP1', 'Gene', (44, 48))
13334	28594900	Four genes (GNAQ, GNA11, BAP1, and EIF1AX) were mutated more frequently than expected by chance (Fig 1B).	('GNAQ', 'Gene', (12, 16))	('EIF1AX', 'Gene', (35, 41))	('EIF1AX', 'Gene', '1964', (35, 41))	('mutated', 'Var', (48, 55))	('BAP1', 'Gene', (25, 29))	('GNAQ', 'Gene', '2776', (12, 16))	('GNA11', 'Gene', (18, 23))	('BAP1', 'Gene', '8314', (25, 29))	('GNA11', 'Gene', '2767', (18, 23))
13338	28594900	Re-sequencing also identified several additional hotspot mutations in GNAQ (Q209), EIF1AX (G15), and SF3B1 (R625) (Fig 1B).	('EIF1AX', 'Gene', '1964', (83, 89))	('GNAQ', 'Gene', '2776', (70, 74))	('mutations', 'Var', (57, 66))	('SF3B1', 'Gene', (101, 106))	('GNAQ', 'Gene', (70, 74))	('EIF1AX', 'Gene', (83, 89))	('SF3B1', 'Gene', '23451', (101, 106))
13340	28594900	One sample (OM-01-110) contained a novel GNAQ mutation, which harbored two mutations at the same codon (GGA>CTA) resulting in a G48L substitution.	('G48L', 'Mutation', 'p.G48L', (128, 132))	('GNAQ', 'Gene', (41, 45))	('GNAQ', 'Gene', '2776', (41, 45))	('G48L substitution', 'Var', (128, 145))
13342	28594900	Mutations in BAP1, EIF1AX, and SF3B1 were almost entirely mutually exclusive of each other (although most often co-occurring with GNAQ and GNA11 mutations), with only 2 out of 29 mutant samples harboring alterations in more than one gene.	('BAP1', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (139, 144))	('GNA11', 'Gene', (139, 144))	('GNAQ', 'Gene', (130, 134))	('EIF1AX', 'Gene', '1964', (19, 25))	('EIF1AX', 'Gene', (19, 25))	('SF3B1', 'Gene', (31, 36))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (13, 17))	('GNAQ', 'Gene', '2776', (130, 134))	('SF3B1', 'Gene', '23451', (31, 36))
13343	28594900	This observation suggests three predominant genetic classes of UM, defined by these three recurring mutations, and is supported by data indicating that mutant BAP1 is associated with a worse prognosis, while EIF1AX and SF3B1 mutations indicate a better prognosis.	('EIF1AX', 'Gene', (208, 214))	('BAP1', 'Gene', '8314', (159, 163))	('EIF1AX', 'Gene', '1964', (208, 214))	('UM', 'Phenotype', 'HP:0007716', (63, 65))	('SF3B1', 'Gene', (219, 224))	('mutant', 'Var', (152, 158))	('SF3B1', 'Gene', '23451', (219, 224))	('BAP1', 'Gene', (159, 163))	('associated', 'Reg', (167, 177))
13344	28594900	Indeed, mutations in EIF1AX occurred more frequently in Disomy 3 patients (S1 Fig), consistent with prior findings.	('Disomy 3 patients', 'Disease', (56, 73))	('mutations', 'Var', (8, 17))	('patients', 'Species', '9606', (65, 73))	('EIF1AX', 'Gene', '1964', (21, 27))	('EIF1AX', 'Gene', (21, 27))
13345	28594900	No patients with EIF1AX or SF3B1 mutations in this cohort are known to have developed metastatic disease with the exception of 2 patients that had co-occurring BAP1 mutations (S2 Table).	('metastatic', 'CPA', (86, 96))	('patients', 'Species', '9606', (129, 137))	('BAP1', 'Gene', '8314', (160, 164))	('mutations', 'Var', (33, 42))	('SF3B1', 'Gene', (27, 32))	('patients', 'Species', '9606', (3, 11))	('BAP1', 'Gene', (160, 164))	('EIF1AX', 'Gene', '1964', (17, 23))	('EIF1AX', 'Gene', (17, 23))	('SF3B1', 'Gene', '23451', (27, 32))
13346	28594900	Patient OM-091 harbored missense mutations in both EIF1AX (R13C) and BAP1 (N102K); however, mutant EIF1AX was present at a low allelic fraction (0.051), suggesting a subclonal event.	('EIF1AX', 'Gene', (51, 57))	('BAP1', 'Gene', '8314', (69, 73))	('missense mutations', 'Var', (24, 42))	('BAP1', 'Gene', (69, 73))	('EIF1AX', 'Gene', '1964', (99, 105))	('EIF1AX', 'Gene', (99, 105))	('R13C', 'Mutation', 'p.R13C', (59, 63))	('N102K', 'Mutation', 'p.N102K', (75, 80))	('N102K);', 'Var', (75, 82))	('Patient', 'Species', '9606', (0, 7))	('EIF1AX', 'Gene', '1964', (51, 57))
13347	28594900	Sample UM36 contained missense mutations in both BAP1 (G185R; with an allelic fraction of 0.83) and SF3B1 (K666T; with an allelic fraction of 0.48).	('missense mutations', 'Var', (22, 40))	('BAP1', 'Gene', (49, 53))	('G185R', 'Mutation', 'p.G185R', (55, 60))	('G185R;', 'Var', (55, 61))	('SF3B1', 'Gene', (100, 105))	('K666T;', 'Var', (107, 113))	('UM', 'Phenotype', 'HP:0007716', (7, 9))	('K666T', 'Mutation', 'rs374250186', (107, 112))	('SF3B1', 'Gene', '23451', (100, 105))	('BAP1', 'Gene', '8314', (49, 53))
13348	28594900	The majority of SF3B1 mutations in UM occur at residue 625, however, lysine 666 is recurrently mutated in CLL.	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('lysine', 'Chemical', 'MESH:D008239', (69, 75))	('SF3B1', 'Gene', '23451', (16, 21))	('mutations', 'Var', (22, 31))	('SF3B1', 'Gene', (16, 21))
13349	28594900	Both OM-091 and UM36 patients died of metastatic UM (S2 Table), consistent with previous studies linking BAP1 mutations in primary UM with a high likelihood of developing metastatic disease.	('mutations', 'Var', (110, 119))	('UM', 'Phenotype', 'HP:0007716', (131, 133))	('UM', 'Phenotype', 'HP:0007716', (49, 51))	('BAP1', 'Gene', '8314', (105, 109))	('patients', 'Species', '9606', (21, 29))	('UM', 'Phenotype', 'HP:0007716', (16, 18))	('metastatic UM', 'Disease', (38, 51))	('BAP1', 'Gene', (105, 109))
13351	28594900	We utilized the ABSOLUTE algorithm to assign each somatic mutation a cancer cell fraction (CCF), which corresponds to the percentage of tumor cells harboring the genetic event.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('mutation', 'Var', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Disease', (136, 141))	('cancer', 'Disease', (69, 75))	('cell fraction', 'cellular_component', 'GO:0000267', ('76', '89'))
13354	28594900	Only 4 clonal missense mutations were present in both samples (MAN2A1, UHRF1BP1L, HCFC2, CYSLTR2), including the recently described L129Q alteration in CYSLTR2 (Fig 1D, top right).	('MAN2A1', 'Gene', '4124', (63, 69))	('HCFC2', 'Gene', '29915', (82, 87))	('CYSLTR2', 'Gene', '57105', (152, 159))	('UHRF1BP1L', 'Gene', (71, 80))	('UHRF1BP1L', 'Gene', '23074', (71, 80))	('L129Q', 'Var', (132, 137))	('CYSLTR2', 'Gene', (152, 159))	('CYSLTR2', 'Gene', '57105', (89, 96))	('L129Q', 'Mutation', 'p.L129Q', (132, 137))	('HCFC2', 'Gene', (82, 87))	('MAN2A1', 'Gene', (63, 69))	('CYSLTR2', 'Gene', (89, 96))
13358	28594900	Although the functional consequence of this mutation within the cellular context of uveal melanoma awaits further study, codon 1192 resides within the conserved C-terminal helicase domain and is recurrently mutated across multiple cancer types (http://www.cbioportal.org).	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('uveal melanoma', 'Disease', (84, 98))	('cancer', 'Disease', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('codon 1192', 'Var', (121, 131))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
13361	28594900	Here, the pre-treatment tumor harbored only 4 missense mutations that were not observed in the post-treatment sample (1 clonal and 3 subclonal), while the post-treatment sample harbored 25 mutations that were not observed in the pre-treatment sample (1 clonal and 24 subclonal).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('missense mutations', 'Var', (46, 64))	('tumor', 'Disease', (24, 29))	('pre', 'molecular_function', 'GO:0003904', ('10', '13'))	('pre', 'molecular_function', 'GO:0003904', ('229', '232'))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
13367	28594900	Consistent with prior studies, we observed recurrent mutations within the N-terminal 15 amino acids of EIF1AX that co-occur with GNAQ or GNA11 mutations (Fig 2A).	('GNAQ', 'Gene', (129, 133))	('mutations', 'Var', (53, 62))	('GNA11', 'Gene', (137, 142))	('GNAQ', 'Gene', '2776', (129, 133))	('GNA11', 'Gene', '2767', (137, 142))	('co-occur', 'Reg', (115, 123))	('EIF1AX', 'Gene', '1964', (103, 109))	('EIF1AX', 'Gene', (103, 109))
13369	28594900	All EIF1AX mutations in our UM cohort were non-synonymous and localized within the unstructured N-terminal tail (NTT).	('EIF1AX', 'Gene', (4, 10))	('mutations', 'Var', (11, 20))	('EIF1AX', 'Gene', '1964', (4, 10))	('UM', 'Phenotype', 'HP:0007716', (28, 30))
13370	28594900	Transcriptome analysis (RNAseq) of 92.1 cells demonstrated faithful transcription of the G6D missense mutation, without evidence for altered mRNA splicing or wild type allele expression (S6A Fig).	('mRNA splicing', 'biological_process', 'GO:0000394', ('141', '154'))	('mRNA splicing', 'biological_process', 'GO:0000373', ('141', '154'))	('transcription', 'biological_process', 'GO:0006351', ('68', '81'))	('mRNA splicing', 'biological_process', 'GO:0000398', ('141', '154'))	('missense mutation', 'Var', (93, 110))	('mRNA splicing', 'biological_process', 'GO:0000372', ('141', '154'))	('G6D', 'Gene', (89, 92))	('G6D', 'Gene', '58530', (89, 92))	('mRNA splicing', 'biological_process', 'GO:0000374', ('141', '154'))	('mRNA splicing', 'biological_process', 'GO:0006371', ('141', '154'))
13371	28594900	This finding is consistent with prior studies demonstrating exclusive expression of mutant EIF1AX mRNA in tumor samples from both male and female individuals.	('EIF1AX', 'Gene', '1964', (91, 97))	('EIF1AX', 'Gene', (91, 97))	('mutant', 'Var', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
13374	28594900	However, the 92.1 cell line containing a homozygous mutation was from a female patient, suggesting poor sequencing of the inactivated X chromosome or genetic loss of the EIF1AX region.	('genetic', 'Var', (150, 157))	('EIF1AX', 'Gene', '1964', (170, 176))	('EIF1AX', 'Gene', (170, 176))	('X chromosome', 'cellular_component', 'GO:0000805', ('134', '146'))	('patient', 'Species', '9606', (79, 86))	('mutation', 'Var', (52, 60))	('loss', 'NegReg', (158, 162))
13375	28594900	Examination of even larger cohorts may provide further insight into association of EIF1AX mutations and sex chromosome inactivation.	('association', 'Interaction', (68, 79))	('sex chromosome inactivation', 'Disease', (104, 131))	('mutations', 'Var', (90, 99))	('EIF1AX', 'Gene', '1964', (83, 89))	('chromosome inactivation', 'biological_process', 'GO:0009048', ('108', '131'))	('sex chromosome', 'cellular_component', 'GO:0000803', ('104', '118'))	('EIF1AX', 'Gene', (83, 89))
13379	28594900	Therefore, somatic mutations in the EIF1AX-NTT may result in changes in translational regulation:either global or specific mRNA effects.	('changes', 'Reg', (61, 68))	('EIF1AX', 'Gene', (36, 42))	('EIF1AX', 'Gene', '1964', (36, 42))	('translational regulation', 'MPA', (72, 96))	('mutations', 'Var', (19, 28))	('regulation', 'biological_process', 'GO:0065007', ('86', '96'))	('result', 'Reg', (51, 57))
13380	28594900	To gain preliminary insights into the function of mutant EIF1AX in UM cells, we used lentiviral shRNA knockdown to suppress EIF1AX expression in a panel of UM cell lines, including the 92.1 line, which contains an EIF1AXG6D mutation.	('EIF1AX', 'Gene', '1964', (124, 130))	('EIF1AX', 'Gene', (124, 130))	('EIF1AX', 'Gene', (214, 220))	('EIF1AX', 'Gene', '1964', (57, 63))	('EIF1AX', 'Gene', (57, 63))	('suppress', 'NegReg', (115, 123))	('EIF1AX', 'Gene', '1964', (214, 220))	('expression', 'MPA', (131, 141))	('UM', 'Phenotype', 'HP:0007716', (156, 158))	('UM', 'Phenotype', 'HP:0007716', (67, 69))	('mutant', 'Var', (50, 56))
13383	28594900	Based on these knock down results, EIF1AX-NTT mutations in UM likely do not solely confer loss of wild type protein function.	('EIF1AX', 'Gene', '1964', (35, 41))	('EIF1AX', 'Gene', (35, 41))	('mutations', 'Var', (46, 55))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('UM', 'Phenotype', 'HP:0007716', (59, 61))
13390	28594900	We next sought to test the hypothesis that EIF1AX-NTT mutations might regulate translation of a distinct set of transcripts compared to wild type EIF1AX.	('EIF1AX', 'Gene', '1964', (146, 152))	('EIF1AX', 'Gene', (43, 49))	('EIF1AX', 'Gene', (146, 152))	('mutations', 'Var', (54, 63))	('EIF1AX', 'Gene', '1964', (43, 49))	('translation of a distinct set of transcripts', 'MPA', (79, 123))	('translation', 'biological_process', 'GO:0006412', ('79', '90'))	('regulate', 'Reg', (70, 78))
13391	28594900	To investigate this possibility, we performed polysome profiling of EIF1AX mutant and wild type UM cell lines expressing shRNAs targeting EIF1AX or Luciferase (shLuc; control).	('EIF1AX', 'Gene', '1964', (138, 144))	('EIF1AX', 'Gene', (138, 144))	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('polysome', 'cellular_component', 'GO:0005844', ('46', '54'))	('EIF1AX', 'Gene', '1964', (68, 74))	('EIF1AX', 'Gene', (68, 74))	('mutant', 'Var', (75, 81))
13392	28594900	Interestingly, the 80S peak in the EIF1AX mutant cell line (92.1) showed greater amplitude than that seen in EIF1AX wild type cells (Omm2.3 and Omm1), raising the possibility that mutant EIF1AX might be associated with altered protein translation (Fig 2D).	('EIF1AX', 'Gene', '1964', (35, 41))	('EIF1AX', 'Gene', (35, 41))	('mutant', 'Var', (42, 48))	('EIF1AX', 'Gene', '1964', (187, 193))	('EIF1AX', 'Gene', (187, 193))	('protein', 'cellular_component', 'GO:0003675', ('227', '234'))	('associated', 'Reg', (203, 213))	('protein translation', 'biological_process', 'GO:0006412', ('227', '246'))	('EIF1AX', 'Gene', '1964', (109, 115))	('EIF1AX', 'Gene', (109, 115))	('mutant', 'Var', (180, 186))	('protein translation', 'MPA', (227, 246))	('altered', 'Reg', (219, 226))
13395	28594900	RNAseq was used to confirm extent of EIF1AX knockdown in shRNA expressing cells (S6B and S6C Fig).	('knockdown', 'Var', (44, 53))	('EIF1AX', 'Gene', '1964', (37, 43))	('EIF1AX', 'Gene', (37, 43))
13396	28594900	To identify transcripts regulated by EIF1AX, we tested which polysomal/total RNA ratios were significantly altered upon EIF1AX knockdown.	('EIF1AX', 'Gene', '1964', (37, 43))	('EIF1AX', 'Gene', (37, 43))	('polysomal/total RNA ratios', 'MPA', (61, 87))	('altered', 'Reg', (107, 114))	('EIF1AX', 'Gene', '1964', (120, 126))	('EIF1AX', 'Gene', (120, 126))	('RNA', 'cellular_component', 'GO:0005562', ('77', '80'))	('knockdown', 'Var', (127, 136))
13397	28594900	Next, we identified genes whose translational efficiency was affected by the knockdown of EIF1AX.	('EIF1AX', 'Gene', (90, 96))	('translational', 'MPA', (32, 45))	('affected', 'Reg', (61, 69))	('knockdown', 'Var', (77, 86))	('EIF1AX', 'Gene', '1964', (90, 96))
13398	28594900	Of these, nearly all showed reduced translational efficiency:only 7 genes showed increased translational efficiency following EIF1AX knockdown.	('knockdown', 'Var', (133, 142))	('EIF1AX', 'Gene', '1964', (126, 132))	('EIF1AX', 'Gene', (126, 132))	('translational efficiency', 'MPA', (91, 115))	('increased', 'PosReg', (81, 90))
13400	28594900	Overall, the genes within a cluster display a common change in translational efficiency following EIF1AX knockdown (Fig 3B).	('translational efficiency', 'MPA', (63, 87))	('knockdown', 'Var', (105, 114))	('EIF1AX', 'Gene', '1964', (98, 104))	('EIF1AX', 'Gene', (98, 104))	('change', 'Reg', (53, 59))
13402	28594900	These genes represent those commonly regulated by wild type and mutant EIF1AX.	('mutant', 'Var', (64, 70))	('EIF1AX', 'Gene', '1964', (71, 77))	('EIF1AX', 'Gene', (71, 77))
13406	28594900	We found that the median translational efficiency of all ribosomal protein genes was reduced following EIF1AX knockdown in wild type, but not mutant cells (Fig 3C).	('ribosomal protein genes', 'Gene', (57, 80))	('knockdown', 'Var', (110, 119))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('57', '74'))	('translational efficiency', 'MPA', (25, 49))	('mutant', 'Var', (142, 148))	('reduced', 'NegReg', (85, 92))	('EIF1AX', 'Gene', '1964', (103, 109))	('EIF1AX', 'Gene', (103, 109))
13407	28594900	This was the only gene family that exhibited extensive coordinated regulation in the context of EIF1AX knockdown.	('EIF1AX', 'Gene', '1964', (96, 102))	('regulation', 'biological_process', 'GO:0065007', ('67', '77'))	('EIF1AX', 'Gene', (96, 102))	('knockdown', 'Var', (103, 112))
13408	28594900	In addition, these genes demonstrated already reduced translational efficiency in the mutant cell line (92.1), and were not additionally affected by EIF1AX knockdown in this setting (Fig 3C).	('EIF1AX', 'Gene', '1964', (149, 155))	('EIF1AX', 'Gene', (149, 155))	('mutant', 'Var', (86, 92))	('reduced', 'NegReg', (46, 53))	('translational efficiency', 'MPA', (54, 78))
13411	28594900	Consistent with prior studies, recurrent mutations were observed in GNAQ, GNA11, BAP1, EIF1AX, and SF3B1; no additional genes met the threshold for significance.	('mutations', 'Var', (41, 50))	('GNA11', 'Gene', (74, 79))	('EIF1AX', 'Gene', '1964', (87, 93))	('EIF1AX', 'Gene', (87, 93))	('BAP1', 'Gene', (81, 85))	('SF3B1', 'Gene', (99, 104))	('GNAQ', 'Gene', (68, 72))	('GNA11', 'Gene', '2767', (74, 79))	('GNAQ', 'Gene', '2776', (68, 72))	('SF3B1', 'Gene', '23451', (99, 104))	('BAP1', 'Gene', '8314', (81, 85))
13413	28594900	This study confirms the relative mutually exclusive nature of BAP1, SF3B1, and EIF1AX gene mutations.	('EIF1AX', 'Gene', (79, 85))	('BAP1', 'Gene', '8314', (62, 66))	('SF3B1', 'Gene', (68, 73))	('BAP1', 'Gene', (62, 66))	('SF3B1', 'Gene', '23451', (68, 73))	('mutations', 'Var', (91, 100))	('EIF1AX', 'Gene', '1964', (79, 85))
13415	28594900	Recent data suggest that clinical benefit to immune checkpoint blockade therapy (e.g., anti-CTLA4) in cutaneous melanoma is associated with higher mutational burden.	('CTLA4', 'Gene', (92, 97))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('cutaneous melanoma', 'Disease', (102, 120))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))	('CTLA4', 'Gene', '1493', (92, 97))	('mutational', 'Var', (147, 157))
13418	28594900	To date, monosomy 3 and mutated BAP1 have been associated with UM metastasis, but limited analyses of metastatic tumor genomes have been reported.	('tumor', 'Disease', (113, 118))	('mutated', 'Var', (24, 31))	('UM', 'Phenotype', 'HP:0007716', (63, 65))	('BAP1', 'Gene', '8314', (32, 36))	('UM metastasis', 'CPA', (63, 76))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('BAP1', 'Gene', (32, 36))	('monosomy 3', 'Var', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('associated', 'Reg', (47, 57))
13420	28594900	SMARCA4 mutations were recently reported in metastatic UM tumors, although matched primary tumor DNA was not sequenced for comparison.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('SMARCA4', 'Gene', (0, 7))	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('SMARCA4', 'Gene', '6597', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('mutations', 'Var', (8, 17))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('reported', 'Reg', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', (91, 96))
13423	28594900	We identified EIF1AX N-terminal tail mutations in approximately 20% of primary UM tumors, consistent with prior studies.	('EIF1AX', 'Gene', '1964', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('EIF1AX', 'Gene', (14, 20))
13424	28594900	Putative driver mutations in this translation factor are of interest given that increased protein synthesis is frequently observed in rapidly proliferating cancer cells.	('protein synthesis', 'MPA', (90, 107))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('translation', 'biological_process', 'GO:0006412', ('34', '45'))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('increased', 'PosReg', (80, 89))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('rapidly proliferating', 'Disease', (134, 155))	('protein synthesis', 'biological_process', 'GO:0006412', ('90', '107'))
13426	28594900	Consistent with these general observations, our RNAi knockdown experiments suggest an essential role for EIF1AX in both wild type and mutant settings.	('RNAi', 'biological_process', 'GO:0016246', ('48', '52'))	('mutant', 'Var', (134, 140))	('EIF1AX', 'Gene', '1964', (105, 111))	('EIF1AX', 'Gene', (105, 111))
13429	28594900	We performed RNA sequencing of polysome-associated mRNAs and observed similar suppression of the translational efficiency of ribosomal proteins following EIF1AX knockdown in wild type EIF1AX cells.	('polysome', 'cellular_component', 'GO:0005844', ('31', '39'))	('EIF1AX', 'Gene', '1964', (154, 160))	('EIF1AX', 'Gene', (154, 160))	('translational efficiency of ribosomal proteins', 'MPA', (97, 143))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('knockdown', 'Var', (161, 170))	('suppression', 'NegReg', (78, 89))	('EIF1AX', 'Gene', '1964', (184, 190))	('EIF1AX', 'Gene', (184, 190))
13430	28594900	In contrast, mutant EIF1AX cells did not display this phenotype.	('mutant', 'Var', (13, 19))	('EIF1AX', 'Gene', '1964', (20, 26))	('EIF1AX', 'Gene', (20, 26))
13431	28594900	First, the level of knockdown achieved may not be sufficient to impair mutant EIF1AX function (thus, ribosomal proteins continue to be translated sufficiently by this mechanism).	('function', 'MPA', (85, 93))	('EIF1AX', 'Gene', '1964', (78, 84))	('EIF1AX', 'Gene', (78, 84))	('mutant', 'Var', (71, 77))	('impair', 'NegReg', (64, 70))
13432	28594900	This model could be operant if mutated EIF1AX has enhanced function over wild type.	('EIF1AX', 'Gene', '1964', (39, 45))	('EIF1AX', 'Gene', (39, 45))	('function', 'MPA', (59, 67))	('enhanced', 'PosReg', (50, 58))	('mutated', 'Var', (31, 38))
13433	28594900	However, the observed 80S accumulation following shRNA expression is consistent with the notion that the magnitude of EIF1AX knockdown achieved here is functionally consequential.	('knockdown', 'Var', (125, 134))	('80S', 'MPA', (22, 25))	('EIF1AX', 'Gene', '1964', (118, 124))	('EIF1AX', 'Gene', (118, 124))
13434	28594900	Second, translation in the setting of mutant EIF1AX may be less efficient overall, such that knockdown does not further impair ribosomal functions.	('EIF1AX', 'Gene', (45, 51))	('translation', 'biological_process', 'GO:0006412', ('8', '19'))	('EIF1AX', 'Gene', '1964', (45, 51))	('mutant', 'Var', (38, 44))
13435	28594900	This model is supported by the higher 80S peak observed in mutant EIF1AX cells in comparison to wildtype (Fig 2D).	('80S peak', 'MPA', (38, 46))	('mutant', 'Var', (59, 65))	('higher', 'PosReg', (31, 37))	('EIF1AX', 'Gene', '1964', (66, 72))	('EIF1AX', 'Gene', (66, 72))
13436	28594900	This model may also imply that mutant EIF1AX harbors previously unrecognized yet essential functions that may or may not be related to translation.	('mutant', 'Var', (31, 37))	('EIF1AX', 'Gene', '1964', (38, 44))	('EIF1AX', 'Gene', (38, 44))	('translation', 'biological_process', 'GO:0006412', ('135', '146'))
13438	28594900	As EIF1AX mutations are associated with a low risk of developing metastatic disease, additional functional studies are required to determine the specific mechanisms by which EIF1AX mutations provide a selective advantage to UM cells in which they are present.	('UM', 'Phenotype', 'HP:0007716', (224, 226))	('advantage', 'PosReg', (211, 220))	('metastatic', 'CPA', (65, 75))	('EIF1AX', 'Gene', '1964', (174, 180))	('EIF1AX', 'Gene', (174, 180))	('mutations', 'Var', (181, 190))	('EIF1AX', 'Gene', '1964', (3, 9))	('EIF1AX', 'Gene', (3, 9))	('mutations', 'Var', (10, 19))
13439	28594900	In summary, this study utilized systematic genomic approaches to probe the somatic genetics of primary and metastatic UM, as well as the function of mutated EIF1AX.	('mutated', 'Var', (149, 156))	('primary', 'Disease', (95, 102))	('UM', 'Phenotype', 'HP:0007716', (118, 120))	('EIF1AX', 'Gene', '1964', (157, 163))	('EIF1AX', 'Gene', (157, 163))
13440	28594900	This is the first study of deregulated translation by a mutated initiation factor in cancer.	('deregulated translation', 'MPA', (27, 50))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('mutated', 'Var', (56, 63))	('translation', 'biological_process', 'GO:0006412', ('39', '50'))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
13459	28594900	Genes whose translation efficiency was affected by the knockdown of EIF1AX were then identified using the edgeR package.	('translation', 'MPA', (12, 23))	('knockdown', 'Var', (55, 64))	('translation', 'biological_process', 'GO:0006412', ('12', '23'))	('affected', 'Reg', (39, 47))	('EIF1AX', 'Gene', '1964', (68, 74))	('EIF1AX', 'Gene', (68, 74))
13462	25521456	BAP1 PLAYS A SURVIVAL ROLE IN CUTANEOUS MELANOMA Although the pattern of BAP1 inactivation in ocular melanoma specimens and in the BAP1 cutaneous/ocular melanoma (CM/OM) predisposition syndrome suggests a tumor suppressor function, the specific role of this gene in the pathogenesis of cutaneous melanoma is not fully understood.	('inactivation', 'Var', (78, 90))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cutaneous melanoma', 'Disease', (286, 304))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('ocular melanoma', 'Disease', (146, 161))	('BAP1', 'Gene', (73, 77))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (286, 304))	('CM', 'Disease', 'MESH:D009202', (163, 165))	('ocular melanoma', 'Disease', 'MESH:D008545', (94, 109))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (286, 304))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('205', '221'))	('BAP1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor suppressor', 'biological_process', 'GO:0051726', ('205', '221'))	('CUTANEOUS MELANOMA', 'Phenotype', 'HP:0012056', (30, 48))	('ocular melanoma', 'Phenotype', 'HP:0007716', (146, 161))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('ocular melanoma', 'Disease', (94, 109))	('BAP1', 'Gene', '8314', (131, 135))	('ocular melanoma', 'Disease', 'MESH:D008545', (146, 161))	('MELANOMA', 'Phenotype', 'HP:0002861', (40, 48))	('pathogenesis', 'biological_process', 'GO:0009405', ('270', '282'))	('BAP1', 'Gene', '8314', (73, 77))	('tumor', 'Disease', (205, 210))	('ocular melanoma', 'Phenotype', 'HP:0007716', (94, 109))	('BAP1', 'Gene', (131, 135))	('BAP1', 'Gene', '8314', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (296, 304))
13465	25521456	Genetic depletion of BAP1 in melanoma cells reduced proliferation and colony forming capability, induced apoptosis and inhibited melanoma tumor growth in vivo.	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('melanoma tumor', 'Disease', 'MESH:D008545', (129, 143))	('induced', 'Reg', (97, 104))	('apoptosis', 'biological_process', 'GO:0097194', ('105', '114'))	('apoptosis', 'biological_process', 'GO:0006915', ('105', '114'))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('colony forming capability', 'CPA', (70, 95))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('proliferation', 'CPA', (52, 65))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('BAP1', 'Gene', (21, 25))	('melanoma tumor', 'Disease', (129, 143))	('depletion', 'Var', (8, 17))	('apoptosis', 'CPA', (105, 114))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('inhibited', 'NegReg', (119, 128))	('reduced', 'NegReg', (44, 51))
13471	25521456	Many groups have described germline BAP1 alterations in families predisposed to cutaneous and ocular melanoma among other malignancies.	('malignancies', 'Disease', 'MESH:D009369', (122, 134))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('ocular melanoma', 'Disease', (94, 109))	('malignancies', 'Disease', (122, 134))	('ocular melanoma', 'Disease', 'MESH:D008545', (94, 109))	('ocular melanoma', 'Phenotype', 'HP:0007716', (94, 109))	('BAP1', 'Gene', (36, 40))	('alterations', 'Var', (41, 52))
13472	25521456	To date, both heritable and acquired mutations in BAP1 have been deleterious with loss-of-heterozygosity described in melanoma tumor specimens.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma tumor', 'Disease', (118, 132))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('melanoma tumor', 'Disease', 'MESH:D008545', (118, 132))	('mutations', 'Var', (37, 46))	('BAP1', 'Gene', (50, 54))	('loss-of-heterozygosity', 'NegReg', (82, 104))
13474	25521456	However, unlike ocular melanomas, cutaneous melanomas do not commonly harbor BAP1 mutations outside of the familial context.	('cutaneous melanomas', 'Disease', 'MESH:C562393', (34, 53))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (34, 52))	('cutaneous melanomas', 'Disease', (34, 53))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('ocular melanomas', 'Phenotype', 'HP:0025534', (16, 32))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('ocular melanomas', 'Disease', 'MESH:D008545', (16, 32))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('mutations', 'Var', (82, 91))	('ocular melanomas', 'Disease', (16, 32))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (34, 53))	('BAP1', 'Gene', (77, 81))	('ocular melanoma', 'Phenotype', 'HP:0007716', (16, 31))	('harbor', 'Reg', (70, 76))
13479	25521456	Even among uveal melanomas, where the prevalence of deleterious mutations remains the highest, recent studies suggest that BAP1 is not functionally suppressive and that the biology of this deubiquitinase is highly complex.	('BAP1', 'Gene', (123, 127))	('uveal melanoma', 'Phenotype', 'HP:0007716', (11, 25))	('melanomas', 'Phenotype', 'HP:0002861', (17, 26))	('uveal melanomas', 'Disease', (11, 26))	('uveal melanomas', 'Phenotype', 'HP:0007716', (11, 26))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('mutations', 'Var', (64, 73))	('uveal melanomas', 'Disease', 'MESH:C536494', (11, 26))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('189', '203'))
13495	25521456	As shown in Figure 2, depletion of BAP1 in two BRAF(V600E)-mutant lines (A375 and SKmel-28, Fig 2a) and two NRAS(Q61R)-mutant lines (SKmel-119 and SKmel-63, Fig 2b) led to dramatic reductions in melanoma proliferation.	('NRAS', 'Gene', (108, 112))	('melanoma proliferation', 'Disease', (195, 217))	('melanoma proliferation', 'Disease', 'MESH:D008545', (195, 217))	('NRAS', 'Gene', '4893', (108, 112))	('V600E', 'Var', (52, 57))	('BRAF', 'Gene', (47, 51))	('V600E', 'SUBSTITUTION', 'None', (52, 57))	('A375', 'CellLine', 'CVCL:0132', (73, 77))	('Q61R', 'Mutation', 'rs11554290', (113, 117))	('reductions', 'NegReg', (181, 191))	('depletion', 'MPA', (22, 31))	('BAP1', 'Gene', (35, 39))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))
13497	25521456	As shown in Figure 2d, BAP1 depletion diminished the tumorigenicity of melanoma xenografts in immunocompromised mice.	('BAP1', 'Gene', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('diminished', 'NegReg', (38, 48))	('melanoma xenografts', 'Disease', 'MESH:D008545', (71, 90))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma xenografts', 'Disease', (71, 90))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('depletion', 'Var', (28, 37))	('tumor', 'Disease', (53, 58))	('mice', 'Species', '10090', (112, 116))
13499	25521456	For the cell cycle and apoptosis assays (Fig 3), A375 [BRAF(V600E)], SKmel-119 [NRAS(Q61R)] and C918 (uveal melanoma) cells were used.	('NRAS', 'Gene', (80, 84))	('A375', 'CellLine', 'CVCL:0132', (49, 53))	('apoptosis assays', 'CPA', (23, 39))	('cell cycle', 'biological_process', 'GO:0007049', ('8', '18'))	('apoptosis', 'biological_process', 'GO:0097194', ('23', '32'))	('NRAS', 'Gene', '4893', (80, 84))	('Q61R', 'Mutation', 'rs11554290', (85, 89))	('cell cycle', 'CPA', (8, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('uveal melanoma', 'Disease', (102, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (102, 116))	('apoptosis', 'biological_process', 'GO:0006915', ('23', '32'))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('V600E', 'Var', (60, 65))	('V600E', 'SUBSTITUTION', 'None', (60, 65))
13501	25521456	Since one of the IAP family members- BIRC5, or survivin- has been implicated both as a viability factor in melanoma and a target of BAP1 regulation in U2OS cells, we hypothesized that BAP1 depletion may have an effect on survivin levels.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('U2OS', 'CellLine', 'CVCL:0042', (151, 155))	('BIRC5', 'Gene', '332', (37, 42))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('BIRC5', 'Gene', (37, 42))	('regulation', 'biological_process', 'GO:0065007', ('137', '147'))	('depletion', 'Var', (189, 198))	('survivin levels', 'MPA', (221, 236))	('effect', 'Reg', (211, 217))
13511	25521456	As shown in Figure S4, total protein ubiquitination was dramatically increased by the MG132 treatment.	('protein ubiquitination', 'biological_process', 'GO:0016567', ('29', '51'))	('increased', 'PosReg', (69, 78))	('MG132', 'Var', (86, 91))	('MG132', 'Chemical', 'MESH:C072553', (86, 91))	('total protein ubiquitination', 'MPA', (23, 51))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))
13514	25521456	In untreated A375 and C918 cells, the loss of BAP1 was associated with a dramatic reduction in survivin levels (Fig 4d, control "C" lanes), consistent with the prior analysis.	('loss', 'Var', (38, 42))	('reduction', 'NegReg', (82, 91))	('BAP1', 'Gene', (46, 50))	('survivin levels', 'MPA', (95, 110))	('A375', 'CellLine', 'CVCL:0132', (13, 17))
13516	25521456	Both A375(shBAP1) and C918(shBAP1) lines exhibited appropriate survivin decay upon release of MG132 and inhibition of new protein synthesis by CHX despite having attenuated survivin protein levels at baseline.	('inhibition', 'NegReg', (104, 114))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('new protein synthesis', 'MPA', (118, 139))	('attenuated', 'NegReg', (162, 172))	('MG132', 'Chemical', 'MESH:C072553', (94, 99))	('CHX', 'Chemical', 'MESH:D003513', (143, 146))	('survivin protein levels', 'MPA', (173, 196))	('protein synthesis', 'biological_process', 'GO:0006412', ('122', '139'))	('A375', 'CellLine', 'CVCL:0132', (5, 9))	('protein', 'cellular_component', 'GO:0003675', ('182', '189'))	('C918', 'Var', (22, 26))	('survivin decay', 'MPA', (63, 77))	('release', 'MPA', (83, 90))
13517	25521456	Since BAP1 depletion led to diminished resting levels of survivin but did not abrogate survivin decay upon MG132/CHX treatment, BAP1 likely participates in the homeostatic maintenance of survivin levels through other mechanisms beyond simple deubiquitination.	('BAP1', 'Gene', (6, 10))	('deubiquitination', 'biological_process', 'GO:0016579', ('242', '258'))	('CHX', 'Chemical', 'MESH:D003513', (113, 116))	('MG132', 'Chemical', 'MESH:C072553', (107, 112))	('diminished', 'NegReg', (28, 38))	('resting levels of survivin', 'MPA', (39, 65))	('depletion', 'Var', (11, 20))
13523	25521456	On the other hand, ectopic expression of BAP1 in three distinct melanoma cell lines led to a modest increase in survivin and proliferation (Fig 5b).	('ectopic expression', 'Var', (19, 37))	('BAP1', 'Gene', (41, 45))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('proliferation', 'CPA', (125, 138))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('survivin', 'Protein', (112, 120))	('increase', 'PosReg', (100, 108))
13524	25521456	Although inactivating germline mutations of BAP1 have been described in families prone to cutaneous and ocular melanoma, the role of BAP1 in the pathogenesis of cutaneous melanoma outside of the familial context is not fully known.	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('cutaneous melanoma', 'Disease', (161, 179))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (161, 179))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (161, 179))	('ocular melanoma', 'Disease', 'MESH:D008545', (104, 119))	('ocular melanoma', 'Disease', (104, 119))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('ocular melanoma', 'Phenotype', 'HP:0007716', (104, 119))	('inactivating germline mutations', 'Var', (9, 40))	('pathogenesis', 'biological_process', 'GO:0009405', ('145', '157'))	('BAP1', 'Gene', (44, 48))
13534	25521456	BAP1 depletion diminished proliferation, and enhanced apoptosis, both in vitro and in vivo, and phenotypically inhibited tumor growth in mice xenografts.	('apoptosis', 'CPA', (54, 63))	('depletion', 'Var', (5, 14))	('BAP1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('enhanced', 'PosReg', (45, 53))	('tumor', 'Disease', (121, 126))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))	('inhibited', 'NegReg', (111, 120))	('mice', 'Species', '10090', (137, 141))	('diminished', 'NegReg', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
13536	25521456	Others have also observed growth arrest in non-melanoma cancer cells with loss of BAP1.	('BAP1', 'Gene', (82, 86))	('growth arrest', 'Disease', 'MESH:D006323', (26, 39))	('growth arrest', 'Disease', (26, 39))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('non-melanoma cancer', 'Disease', (43, 62))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('loss', 'Var', (74, 78))	('growth arrest', 'Phenotype', 'HP:0001510', (26, 39))	('non-melanoma cancer', 'Disease', 'MESH:D008545', (43, 62))
13539	25521456	Germline Bap1 deletion in mice is lethal during embryogenesis indicating that fetal growth and development requires this gene.	('embryogenesis', 'biological_process', 'GO:0009790', ('48', '61'))	('embryogenesis', 'biological_process', 'GO:0009793', ('48', '61'))	('Bap1', 'Gene', '104416', (9, 13))	('Bap1', 'Gene', (9, 13))	('deletion', 'Var', (14, 22))	('embryogenesis', 'biological_process', 'GO:0009792', ('48', '61'))	('mice', 'Species', '10090', (26, 30))
13687	22784677	Thus, anti-CAII autoantibodies can decrease retinal cell survival.	('retinal cell survival', 'CPA', (44, 65))	('CAII', 'Gene', '760', (11, 15))	('decrease', 'NegReg', (35, 43))	('autoantibodies', 'Var', (16, 30))	('CAII', 'Gene', (11, 15))	('decrease retinal cell', 'Phenotype', 'HP:0007770', (35, 56))
13706	20525172	Since the vast majority of clinically detected cancers present self-peptides the model assumes that tumour cells are, paradoxically, under homeostatic T cell control.	('self-peptides', 'Var', (63, 76))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumour', 'Disease', (100, 106))
13707	20525172	The novelty of our hypothesis therefore is that resection of the primary tumour mass is perceived as loss of 'normal' tissue cells.	('resection', 'Var', (48, 57))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (73, 79))
13781	20525172	Note added in proof: Since submission of the revised manuscript supporting ideas were expressed in Science and J Med Screen respectively: "Understanding the extent to which tumor-induced lymphoid tissue-like structures are plastic will go a long way toward determining if blocking CCL21 and/or LTi cell function can disrupt immune tolerance of the tumor-induced structures, thereby releasing host immunity to aid in eliminating the malignant cells."	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('immune tolerance', 'CPA', (324, 340))	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('disrupt', 'NegReg', (316, 323))	('lymphoid', 'Disease', 'MESH:D008223', (187, 195))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('blocking', 'Var', (272, 280))	('tumor', 'Disease', (173, 178))	('lymphoid', 'Disease', (187, 195))	('releasing', 'PosReg', (382, 391))	('CCL21', 'Gene', '6366', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (348, 353))	('CCL21', 'Gene', (281, 286))
13792	19661223	Four human uveal melanoma and three mouse melanoma cell lines were found to express PEDF mRNA.	('melanoma', 'Disease', (42, 50))	('uveal melanoma', 'Phenotype', 'HP:0007716', (11, 25))	('uveal melanoma', 'Disease', (11, 25))	('PEDF mRNA', 'Var', (84, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (11, 25))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('melanoma', 'Disease', (17, 25))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('human', 'Species', '9606', (5, 10))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('mouse', 'Species', '10090', (36, 41))
13807	19661223	In this study, we hypothesize that PEDF will inhibit uveal melanoma migration in vitro and angiogenesis in a mouse model of uveal melanoma, thus exhibiting direct and indirect anti-tumor activity.	('angiogenesis', 'biological_process', 'GO:0001525', ('91', '103'))	('tumor', 'Disease', (181, 186))	('uveal melanoma migration', 'Disease', (53, 77))	('PEDF', 'Var', (35, 39))	('uveal melanoma', 'Disease', (124, 138))	('angiogenesis', 'CPA', (91, 103))	('uveal melanoma', 'Disease', 'MESH:C536494', (124, 138))	('uveal melanoma migration', 'Disease', 'MESH:C536494', (53, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (124, 138))	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (53, 67))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('inhibit', 'NegReg', (45, 52))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('mouse', 'Species', '10090', (109, 114))
13809	19661223	Low levels or loss of expression of PEDF has been correlated with an increased incidence of metastasis and poor prognosis in cutaneous melanoma, prostate carcinoma, pancreatic cancinoma, neuroblastoma, and glioma.	('neuroblastoma', 'Disease', 'MESH:D009447', (187, 200))	('glioma', 'Phenotype', 'HP:0009733', (206, 212))	('expression', 'Species', '29278', (22, 32))	('pancreatic cancinoma', 'Disease', (165, 185))	('cutaneous melanoma', 'Disease', (125, 143))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (125, 143))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (125, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('metastasis', 'CPA', (92, 102))	('prostate carcinoma', 'Disease', 'MESH:D011472', (145, 163))	('PEDF', 'Gene', (36, 40))	('Low levels', 'Var', (0, 10))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (145, 163))	('glioma', 'Disease', (206, 212))	('pancreatic cancinoma', 'Disease', 'MESH:D010195', (165, 185))	('loss of expression', 'NegReg', (14, 32))	('neuroblastoma', 'Disease', (187, 200))	('glioma', 'Disease', 'MESH:D005910', (206, 212))	('prostate carcinoma', 'Disease', (145, 163))	('neuroblastoma', 'Phenotype', 'HP:0003006', (187, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))
13814	19661223	We also demonstrate that constitutive overexpression of PEDF induced by a lentiviral vector-mediated PEDF gene inhibits tumor growth and hepatic micrometastasis.	('expression', 'Species', '29278', (42, 52))	('hepatic micrometastasis', 'CPA', (137, 160))	('inhibits', 'NegReg', (111, 119))	('PEDF', 'Gene', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('overexpression', 'PosReg', (38, 52))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('gene', 'Var', (106, 110))	('tumor', 'Disease', (120, 125))
13852	19661223	After B16LS9-PEDF, B16LS9-LacZ and B16LS9 cells were marked with CytoTracker , they were plated onto the endothelial cell monolayer in the upper inserts via bottom inserts containing RPMI with or without 10%FBS.	('B16LS9', 'CellLine', 'CVCL:2105', (6, 12))	('B16LS9-LacZ', 'Var', (19, 30))	('B16LS9', 'CellLine', 'CVCL:2105', (35, 41))	('B16LS9-LacZ', 'CellLine', 'CVCL:L291', (19, 30))	('B16LS9-PEDF', 'Var', (6, 17))	('B16LS9', 'Var', (35, 41))	('B16LS9', 'CellLine', 'CVCL:2105', (19, 25))	('RPMI', 'Chemical', '-', (183, 187))
13855	19661223	5x105 of stably PEDF overexpressing B16LS9 (B16LS9-mPEDF), or vehicle control B16LS9 (B16LS9-LacZ) or control B16LS9 cells were inoculated into the posterior compartment of the right eye in C57BL/6 mice, the eye was enucleated at 7 days after inoculation, fixed in 10% formalin and routinely processed for light microscopic examination.	('formalin', 'Chemical', 'MESH:D005557', (269, 277))	('B16LS9', 'CellLine', 'CVCL:2105', (86, 92))	('B16LS9', 'CellLine', 'CVCL:2105', (110, 116))	('B16LS9', 'CellLine', 'CVCL:2105', (44, 50))	('B16LS9', 'CellLine', 'CVCL:2105', (36, 42))	('B16LS9', 'CellLine', 'CVCL:2105', (78, 84))	('mice', 'Species', '10090', (198, 202))	('B16LS9', 'Var', (36, 42))	('overexpressing', 'PosReg', (21, 35))	('B16LS9-LacZ', 'CellLine', 'CVCL:L291', (86, 97))
13860	19661223	B16LS9 orthografts were used rather than human uveal melanoma xenografts because B16LS9 cells have a similar biologic behavior to human uveal melanoma cells that metastasize to the liver without immune suppression that is needed in a xenograft model.	('B16LS9', 'CellLine', 'CVCL:2105', (0, 6))	('B16LS9', 'Var', (81, 87))	('metastasize', 'CPA', (162, 173))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('human', 'Species', '9606', (41, 46))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (136, 150))	('uveal melanoma', 'Disease', (136, 150))	('uveal melanoma', 'Disease', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (136, 150))	('B16LS9', 'CellLine', 'CVCL:2105', (81, 87))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('human', 'Species', '9606', (130, 135))
13878	19661223	Western blot analysis showed that compared with B16LS9-LacZ and B16LS9, the PEDF protein was over-expressed in B16LS9-mPEDF cells (Fig.	('B16LS9', 'CellLine', 'CVCL:2105', (111, 117))	('B16LS9-LacZ', 'CellLine', 'CVCL:L291', (48, 59))	('over-expressed', 'PosReg', (93, 107))	('B16LS9', 'CellLine', 'CVCL:2105', (64, 70))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('B16LS9', 'CellLine', 'CVCL:2105', (48, 54))	('B16LS9-mPEDF', 'Var', (111, 123))
13879	19661223	The clones with V5 tag expression and PEDF over-expression, in which the levels of PEDF mRNA were up-regulated more than 2.5-fold, were used for further in vitro and in vivo experiments.	('expression', 'Species', '29278', (48, 58))	('levels', 'MPA', (73, 79))	('V5 tag expression', 'Var', (16, 33))	('up-regulated', 'PosReg', (98, 110))	('expression', 'Species', '29278', (23, 33))	('over-expression', 'PosReg', (43, 58))
13880	19661223	There was a significant difference in the value of relative fluorescence units (RFU) from B16LS9 transduced by lentivirus-mediated PEDF compared to vehicle control B16LS9 transduced by lentivirus-mediated LacZ (p<0.01) and control B16LS9 cells, and no significant difference in the RFU between the vehicle LacZ and control cells (P>0.05, Fig 3).	('transduced', 'Var', (97, 107))	('B16LS9', 'CellLine', 'CVCL:2105', (90, 96))	('B16LS9', 'Gene', (90, 96))	('B16LS9', 'CellLine', 'CVCL:2105', (231, 237))	('relative fluorescence units', 'MPA', (51, 78))	('B16LS9', 'CellLine', 'CVCL:2105', (164, 170))
13881	19661223	The total length of all the tubes produced by B16LS9-mPEDF, B16LS9-LacZ and B16LS9 were 76+-14 pixels, 890+-91 pixels and 830+-61 pixels, respectively.	('B16LS9-LacZ', 'Var', (60, 71))	('B16LS9', 'CellLine', 'CVCL:2105', (76, 82))	('B16LS9-LacZ', 'CellLine', 'CVCL:L291', (60, 71))	('B16LS9', 'Var', (76, 82))	('B16LS9', 'CellLine', 'CVCL:2105', (46, 52))	('B16LS9', 'CellLine', 'CVCL:2105', (60, 66))	('B16LS9-mPEDF', 'Var', (46, 58))
13882	19661223	The ability of tube formation in B16LS9-mPEDF was significantly reduced, compared with B16LS9-LacZ and B16LS9 cells (P<0.01) The values of the patterns were separately recognized as 1, 4, 4 in B16LS9-mPEDF, B16LS9-LacZ and B16LS9 cells, respectively (Fig 4).	('B16LS9', 'CellLine', 'CVCL:2105', (103, 109))	('B16LS9', 'CellLine', 'CVCL:2105', (223, 229))	('B16LS9-mPEDF', 'Var', (33, 45))	('B16LS9-LacZ', 'CellLine', 'CVCL:L291', (207, 218))	('B16LS9-LacZ', 'CellLine', 'CVCL:L291', (87, 98))	('B16LS9', 'CellLine', 'CVCL:2105', (87, 93))	('B16LS9', 'CellLine', 'CVCL:2105', (33, 39))	('tube formation', 'CPA', (15, 29))	('B16LS9', 'CellLine', 'CVCL:2105', (193, 199))	('B16LS9', 'CellLine', 'CVCL:2105', (207, 213))	('tube formation', 'biological_process', 'GO:0035148', ('15', '29'))	('reduced', 'NegReg', (64, 71))
13885	19661223	The average areas of ocular tumor were 133404+-19430 pixel2, 303738+-40536 pixel2 and 497782+-129479 pixel2 in the eye inoculated with B16LS9-mPEDF, B16LS9-LacZ and B16LS9 cells, respectively (Fig 5 A, B, C).	('ocular tumor', 'Phenotype', 'HP:0100012', (21, 33))	('B16LS9-LacZ', 'CellLine', 'CVCL:L291', (149, 160))	('133404+-19430 pixel2', 'Var', (39, 59))	('B16LS9', 'Var', (165, 171))	('497782+-129479 pixel2', 'Var', (86, 107))	('B16LS9', 'CellLine', 'CVCL:2105', (149, 155))	('B16LS9', 'CellLine', 'CVCL:2105', (135, 141))	('303738+-40536 pixel2', 'Var', (61, 81))	('B16LS9-LacZ', 'Var', (149, 160))	('ocular tumor', 'Disease', 'MESH:D009369', (21, 33))	('ocular tumor', 'Disease', (21, 33))	('B16LS9-mPEDF', 'Var', (135, 147))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('B16LS9', 'CellLine', 'CVCL:2105', (165, 171))
13886	19661223	The size of the ocular tumor in mice inoculated with B16LS9-mPEDF cells was significantly lower than those inoculated with B16LS9-LacZ or B16LS9 cells (P<0.01).	('ocular tumor', 'Disease', 'MESH:D009369', (16, 28))	('B16LS9-mPEDF', 'Var', (53, 65))	('ocular tumor', 'Disease', (16, 28))	('B16LS9', 'CellLine', 'CVCL:2105', (138, 144))	('B16LS9', 'CellLine', 'CVCL:2105', (53, 59))	('ocular tumor', 'Phenotype', 'HP:0100012', (16, 28))	('lower', 'NegReg', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mice', 'Species', '10090', (32, 36))	('B16LS9-LacZ', 'CellLine', 'CVCL:L291', (123, 134))	('B16LS9', 'CellLine', 'CVCL:2105', (123, 129))
13887	19661223	The number of capillaries of the ocular tumors inoculated with B16LS9-mPEDF cells (81.67 +- 22.50) was less than those inoculated with B16LS9-LacZ cells (215.67 +-54.79, P=0.0086) (Figure 5 E, F).	('B16LS9', 'CellLine', 'CVCL:2105', (63, 69))	('capillaries of the ocular tumors inoculated', 'Disease', (14, 57))	('B16LS9-LacZ', 'CellLine', 'CVCL:L291', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('B16LS9', 'CellLine', 'CVCL:2105', (135, 141))	('capillaries of the ocular tumors inoculated', 'Disease', 'MESH:D002372', (14, 57))	('ocular tumor', 'Phenotype', 'HP:0100012', (33, 45))	('ocular tumors', 'Phenotype', 'HP:0100012', (33, 46))	('less', 'NegReg', (103, 107))	('B16LS9-mPEDF cells', 'Var', (63, 81))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
13888	19661223	The sum of capillary length in the ocular tumors inoculated with B16LS9-mPEDF cells (492.71 +- 93.11 mum) was significantly less than those inoculated with B16LS9-LacZ cells (1205.16 +-26.34, P=0.00024).	('ocular tumors inoculated', 'Disease', (35, 59))	('B16LS9', 'CellLine', 'CVCL:2105', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('ocular tumor', 'Phenotype', 'HP:0100012', (35, 47))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('B16LS9-LacZ', 'CellLine', 'CVCL:L291', (156, 167))	('B16LS9', 'CellLine', 'CVCL:2105', (156, 162))	('ocular tumors inoculated', 'Disease', 'MESH:D002372', (35, 59))	('ocular tumors', 'Phenotype', 'HP:0100012', (35, 48))	('B16LS9-mPEDF cells', 'Var', (65, 83))	('less', 'NegReg', (124, 128))
13889	19661223	After establishing the mouse ocular melanoma model with B16LS9-mPEDF, B16LS9-LacZ and B16LS9 cells, histologic examination showed that the number of hepatic micrometastasis in group 1 inoculated with B16LS9-mPEDF cells (42+-21) was significantly lower than the number of hepatic micrometastasis in group 2 inoculated with B16LS9-LacZ cells (116+-75) and group 3 inoculated with B16LS9 (81+-36).	('B16LS9-LacZ', 'CellLine', 'CVCL:L291', (70, 81))	('B16LS9', 'CellLine', 'CVCL:2105', (56, 62))	('B16LS9', 'CellLine', 'CVCL:2105', (70, 76))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('hepatic', 'MPA', (149, 156))	('B16LS9', 'CellLine', 'CVCL:2105', (86, 92))	('B16LS9', 'CellLine', 'CVCL:2105', (200, 206))	('ocular melanoma', 'Phenotype', 'HP:0007716', (29, 44))	('B16LS9-LacZ', 'CellLine', 'CVCL:L291', (322, 333))	('ocular melanoma', 'Disease', (29, 44))	('B16LS9', 'CellLine', 'CVCL:2105', (322, 328))	('mouse', 'Species', '10090', (23, 28))	('ocular melanoma', 'Disease', 'MESH:D008545', (29, 44))	('B16LS9', 'CellLine', 'CVCL:2105', (378, 384))	('B16LS9-mPEDF', 'Var', (200, 212))	('lower', 'NegReg', (246, 251))
13908	19661223	Transfection of an oncogene into tumor cells may increase angiogenic activity by increasing tumor expression of vascular endothelial growth factor (VEGF) and by decreasing expression of antiangiogenic proteins, such as PEDF, which has been identified as the most potent endogenous inhibitor of angiogenesis in the mammalian eye.	('angiogenesis', 'biological_process', 'GO:0001525', ('294', '306'))	('VEGF', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('VEGF', 'Gene', '22339', (148, 152))	('expression', 'Species', '29278', (172, 182))	('Transfection', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (33, 38))	('expression', 'Species', '29278', (98, 108))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('mammalian', 'Species', '9606', (314, 323))	('oncogene', 'Gene', (19, 27))	('angiogenic activity', 'CPA', (58, 77))	('decreasing', 'NegReg', (161, 171))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('112', '146'))	('increase', 'PosReg', (49, 57))	('increasing', 'PosReg', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('expression', 'MPA', (172, 182))	('tumor', 'Disease', (92, 97))
13916	19661223	Our results show that the melanoma cells overexpressing PEDF exhibit decreased transendothelial migration, lose their ability to form tubes in vitro and microvessel density is decreased in the ocular tumor created by inoculation of PEDF overexpressing melanoma cells.	('lose', 'NegReg', (107, 111))	('PEDF', 'Var', (56, 60))	('transendothelial migration', 'CPA', (79, 105))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('ocular tumor', 'Disease', 'MESH:D009369', (193, 205))	('ocular tumor', 'Disease', (193, 205))	('decreased', 'NegReg', (69, 78))	('decreased', 'NegReg', (176, 185))	('melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('melanoma', 'Disease', (252, 260))	('microvessel density', 'CPA', (153, 172))	('melanoma', 'Disease', 'MESH:D008545', (252, 260))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (26, 34))	('ocular tumor', 'Phenotype', 'HP:0100012', (193, 205))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))
13952	33649778	A further relevant risk factor for the development of UM is the mutation of the onco-suppressor gene, BRCA1 associated protein 1 (BAP1).	('BAP1', 'Gene', (130, 134))	('BRCA1 associated protein 1', 'Gene', '8314', (102, 128))	('mutation', 'Var', (64, 72))	('BRCA1 associated protein 1', 'Gene', (102, 128))	('UM', 'Phenotype', 'HP:0007716', (54, 56))	('BAP1', 'Gene', '8314', (130, 134))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))
13954	33649778	The mutation of this gene has been associated with a hereditary cancer syndrome.	('associated', 'Reg', (35, 45))	('mutation', 'Var', (4, 12))	('hereditary cancer syndrome', 'Disease', 'MESH:D061325', (53, 79))	('hereditary cancer syndrome', 'Disease', (53, 79))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
13955	33649778	Tumors, such as malignant mesothelioma, basal cell carcinoma, cutaneous melanomas, UMs and renal cell carcinoma, can be developed following either the somatic or germline mutation of BAP1.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (16, 38))	('renal cell carcinoma', 'Disease', (91, 111))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (91, 111))	('BAP1', 'Gene', (183, 187))	('basal cell carcinoma', 'Disease', (40, 60))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (62, 81))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (62, 81))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (62, 80))	('UM', 'Phenotype', 'HP:0007716', (83, 85))	('malignant mesothelioma', 'Disease', (16, 38))	('Tumors', 'Disease', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (16, 38))	('cutaneous melanomas', 'Disease', (62, 81))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (91, 111))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (40, 60))	('germline mutation', 'Var', (162, 179))	('BAP1', 'Gene', '8314', (183, 187))	('UMs', 'Disease', (83, 86))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (40, 60))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
13956	33649778	In the case of germline mutation, the tumors seem to be less aggressive than those without this mutation.	('less', 'NegReg', (56, 60))	('germline mutation', 'Var', (15, 32))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))
13958	33649778	Of note, patients affected by UM present a higher risk compared to the general population (approximately >=11%) of a developing a secondary cancer, including renal cell carcinoma and cutaneous melanoma, which could be related to germline BAP1 mutations.	('patients', 'Species', '9606', (9, 17))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cutaneous melanoma', 'Disease', (183, 201))	('mutations', 'Var', (243, 252))	('renal cell carcinoma', 'Disease', (158, 178))	('BAP1', 'Gene', '8314', (238, 242))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (183, 201))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (158, 178))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (183, 201))	('UM', 'Phenotype', 'HP:0007716', (30, 32))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('BAP1', 'Gene', (238, 242))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (158, 178))
13962	33649778	Iris melanomas are relatively uncommon (3-5% of UMs) and diagnosis is mostly secondary to heterochromia, i.e., changes in iris color, and corectopia, i.e., abnormality in pupil shape, which is present in approximately 45% of cases.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('abnormality in pupil shape', 'Phenotype', 'HP:0025309', (156, 182))	('abnormality', 'Var', (156, 167))	('Iris melanomas', 'Disease', 'MESH:D008545', (0, 14))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('abnormality in pupil', 'Phenotype', 'HP:0000615', (156, 176))	('corectopia', 'Disease', (138, 148))	('melanomas', 'Phenotype', 'HP:0002861', (5, 14))	('corectopia', 'Phenotype', 'HP:0009918', (138, 148))	('heterochromia', 'Disease', 'MESH:C538115', (90, 103))	('corectopia', 'Disease', 'MESH:C563581', (138, 148))	('changes in iris color', 'Phenotype', 'HP:0007730', (111, 132))	('Iris melanoma', 'Phenotype', 'HP:0011524', (0, 13))	('heterochromia', 'Disease', (90, 103))	('changes', 'Reg', (111, 118))	('Iris melanomas', 'Disease', (0, 14))	('Iris melanomas', 'Phenotype', 'HP:0011524', (0, 14))
14012	33649778	The presence of one or more TFSOM UHHD factors indicates a 'high-risk' nevus.	('UHHD', 'Disease', (34, 38))	('nevus', 'Phenotype', 'HP:0003764', (71, 76))	('nevus', 'Disease', (71, 76))	('UHHD', 'Disease', 'None', (34, 38))	('presence', 'Var', (4, 12))	("'high-risk' nevus", 'Disease', (59, 76))
14045	33649778	It seems that a younger age may exert a protective effect against metastatic disease as the immune response is more robust, lesions tend to be smaller and genetic mutations are less common compared to older aged patients.	('immune response', 'biological_process', 'GO:0006955', ('92', '107'))	('genetic mutations', 'Var', (155, 172))	('metastatic disease', 'Disease', (66, 84))	('patients', 'Species', '9606', (212, 220))
14053	33649778	A previous meta-analysis on choroidal melanomas treated with enucleation reported a 5-year mortality rate of 16% in the case of tumors with a thickness of <2 or 3 mm and a basal diameter <10 or 11 mm, 32% in case of tumors with a thickness of 3-8 mm and a basal diameter <15 or 16 mm, and 53% in case of tumors with a thickness of >8 mm and a >16 mm basal diameter.	('tumors', 'Disease', (304, 310))	('enucleation', 'biological_process', 'GO:0090601', ('61', '72'))	('tumors', 'Disease', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('tumors', 'Disease', 'MESH:D009369', (304, 310))	('choroidal melanomas', 'Disease', 'MESH:D008545', (28, 47))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('mortality', 'Disease', (91, 100))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('<10 or 11', 'Var', (187, 196))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (28, 46))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumors', 'Phenotype', 'HP:0002664', (304, 310))	('mortality', 'Disease', 'MESH:D003643', (91, 100))	('choroidal melanomas', 'Disease', (28, 47))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (28, 47))
14066	33649778	Those with monosomy 3 presented a 3-year mortality rate of 50 vs. 0% of those without monosomy 3.	('mortality', 'Disease', (41, 50))	('monosomy 3', 'Var', (11, 21))	('mortality', 'Disease', 'MESH:D003643', (41, 50))
14067	33649778	Furthermore, BAP1 has been located on the short arm of this chromosome (3p21.1) and BAP1 mutation has been found to be a prognostic factor for metastatic disease.	('BAP1', 'Gene', (13, 17))	('mutation', 'Var', (89, 97))	('metastatic disease', 'Disease', (143, 161))	('p21', 'Gene', (73, 76))	('BAP1', 'Gene', '8314', (84, 88))	('p21', 'Gene', '644914', (73, 76))	('short arm', 'Phenotype', 'HP:0009824', (42, 51))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))	('BAP1', 'Gene', '8314', (13, 17))	('BAP1', 'Gene', (84, 88))
14069	33649778	On the contrary, chromosome 6 loss is a predictor of an unfavorable prognosis: The loss of 6q has been found in 40% of tumors with metastatic disease vs. 7% of metastasis-free melanomas.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('melanomas', 'Phenotype', 'HP:0002861', (176, 185))	('metastasis-free melanomas', 'Disease', (160, 185))	('loss', 'NegReg', (30, 34))	('metastatic disease', 'CPA', (131, 149))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('found', 'Reg', (103, 108))	('metastasis-free melanomas', 'Disease', 'MESH:D008569', (160, 185))	('loss of', 'Var', (83, 90))
14116	33649778	The local recurrence rate has been reported as 3% for palladium-103, 7-10% for iodine-125 and 14.7% for ruthenium-106.	('ruthenium-106', 'Chemical', 'MESH:C000615522', (104, 117))	('local recurrence', 'CPA', (4, 20))	('palladium-103', 'Chemical', 'MESH:C000615531', (54, 67))	('iodine-125', 'Chemical', 'MESH:C000614960', (79, 89))	('palladium-103', 'Var', (54, 67))
14148	33649778	Endoresection has been proposed to treat posterior UMs with a juxta-papillary location, as radiotherapy is likely to cause radiation-induced optic neuropathy.	('optic neuropathy', 'Phenotype', 'HP:0001138', (141, 157))	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('radiotherapy', 'Var', (91, 103))	('optic neuropathy', 'Disease', (141, 157))	('neuropathy', 'Phenotype', 'HP:0009830', (147, 157))	('optic neuropathy', 'Disease', 'MESH:D009901', (141, 157))	('papillary location', 'Phenotype', 'HP:0007482', (68, 86))
14198	33649778	While BRAF inhibitors, such as dabrafenib and vemurafenib, have been used in cutaneous melanoma, which typically harbors BRAF and NRAS mutations, there is no rationale for the use of these agents in UM due to the different molecular profile compared to cutaneous ones.	('BRAF', 'Gene', (121, 125))	('BRAF', 'Gene', '673', (121, 125))	('mutations', 'Var', (135, 144))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (77, 95))	('BRAF', 'Gene', '673', (6, 10))	('NRAS', 'Gene', (130, 134))	('vemurafenib', 'Chemical', 'MESH:D000077484', (46, 57))	('cutaneous melanoma', 'Disease', (77, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (77, 95))	('BRAF', 'Gene', (6, 10))	('NRAS', 'Gene', '4893', (130, 134))	('UM', 'Phenotype', 'HP:0007716', (199, 201))	('dabrafenib', 'Chemical', 'MESH:C561627', (31, 41))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
14199	33649778	Given the commonly harbored GNAQ/GNA11 mutations in UM, agents targeting downstream effectors of biological pathways GNAQ/GNA11-related, such as MEK and protein kinase C (PKC), have been investigated.	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('GNA11', 'Gene', (33, 38))	('GNAQ', 'Gene', '2776', (28, 32))	('PKC', 'molecular_function', 'GO:0004697', ('171', '174'))	('GNA11', 'Gene', (122, 127))	('GNAQ', 'Gene', '2776', (117, 121))	('GNA11', 'Gene', '2767', (33, 38))	('protein', 'cellular_component', 'GO:0003675', ('153', '160'))	('MEK', 'Gene', (145, 148))	('mutations', 'Var', (39, 48))	('MEK', 'Gene', '5609', (145, 148))	('GNA11', 'Gene', '2767', (122, 127))	('GNAQ', 'Gene', (117, 121))	('GNAQ', 'Gene', (28, 32))
14219	33649778	Genetic and epigenetic characteristics of tumors have been given ever-increasing attention over the past years, not only due to their relevant role in the carcinogenesis process, but also as they can provide new insight into tumor behavior.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('past', 'Gene', (100, 104))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('epigenetic', 'Var', (12, 22))	('tumor', 'Disease', (225, 230))	('past', 'Gene', '10938', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
14220	33649778	Conversely, epigenetic alterations modulate gene activity and expression without involving any changes in the DNA sequence; these include the alteration of microRNA (miRNA/miR) expression levels, DNA methylation and histone modifications.	('methylation', 'Var', (200, 211))	('gene activity', 'MPA', (44, 57))	('alteration', 'Reg', (142, 152))	('epigenetic alterations', 'Var', (12, 34))	('expression', 'MPA', (62, 72))	('DNA', 'MPA', (196, 199))	('miR', 'Gene', '220972', (172, 175))	('miR', 'Gene', (172, 175))	('DNA', 'cellular_component', 'GO:0005574', ('196', '199'))	('DNA', 'cellular_component', 'GO:0005574', ('110', '113'))	('histone modifications', 'MPA', (216, 237))	('miR', 'Gene', '220972', (166, 169))	('miR', 'Gene', (166, 169))	('DNA methylation', 'biological_process', 'GO:0006306', ('196', '211'))	('modulate', 'Reg', (35, 43))
14223	33649778	As regards somatic mutations, the most commonly mutated genes that have been identified in UM patients are GNAQ, GNA11 mainly affected by specific point mutations (p.Q209P and p.Q209L, respectively) and BAP1 that is subjected to several mutations occurring in the whole gene sequence.	('BAP1', 'Gene', '8314', (203, 207))	('patients', 'Species', '9606', (94, 102))	('BAP1', 'Gene', (203, 207))	('affected', 'Reg', (126, 134))	('p.Q209L', 'Mutation', 'rs1057519742', (176, 183))	('GNA11', 'Gene', (113, 118))	('GNAQ', 'Gene', '2776', (107, 111))	('GNA11', 'Gene', '2767', (113, 118))	('UM', 'Phenotype', 'HP:0007716', (91, 93))	('p.Q209P', 'Mutation', 'rs1057519742', (164, 171))	('p.Q209P', 'Var', (164, 171))	('GNAQ', 'Gene', (107, 111))	('p.Q209L', 'Var', (176, 183))
14228	33649778	Oncogenic mutations of GNAQ and GNA11 genes are usually mutually exclusive and were found in up to 83% of Ums.	('GNA11', 'Gene', '2767', (32, 37))	('GNAQ', 'Gene', (23, 27))	('found', 'Reg', (84, 89))	('GNA11', 'Gene', (32, 37))	('mutations', 'Var', (10, 19))	('GNAQ', 'Gene', '2776', (23, 27))
14232	33649778	Inactivating somatic mutations of BAP1 have been associated with metastatic disease: Up to 84% of metastasizing UMs harbor inactivating mutations of this onco-suppressor gene.	('metastasizing UMs harbor', 'Disease', (98, 122))	('BAP1', 'Gene', (34, 38))	('metastasizing UMs harbor', 'Disease', 'MESH:D009362', (98, 122))	('UM', 'Phenotype', 'HP:0007716', (112, 114))	('BAP1', 'Gene', '8314', (34, 38))	('inactivating mutations', 'Var', (123, 145))
14234	33649778	In particular, BAP1 regulates genes involved in melanocyte function and differentiation: Inactivating mutations can lead to melanocytic de-differentiation, promoting a pro-metastatic behavior.	('melanocytic de-differentiation', 'CPA', (124, 154))	('promoting', 'PosReg', (156, 165))	('Inactivating mutations', 'Var', (89, 111))	('lead to', 'Reg', (116, 123))	('pro-metastatic behavior', 'CPA', (168, 191))	('BAP1', 'Gene', '8314', (15, 19))	('BAP1', 'Gene', (15, 19))
14236	33649778	Of note, BAP1 mutations can also occur in germline featuring the BAP1 familial cancer syndrome, which predisposes to several cancers, including UM.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('BAP1', 'Gene', '8314', (65, 69))	('cancers', 'Disease', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('familial cancer syndrome', 'Disease', 'MESH:D009369', (70, 94))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('BAP1', 'Gene', (65, 69))	('BAP1', 'Gene', '8314', (9, 13))	('familial cancer syndrome', 'Disease', (70, 94))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('UM', 'Phenotype', 'HP:0007716', (144, 146))
14239	33649778	It has been shown that BAP1 depletion determines a loss of differentiation in cancer cells through the hyperubiquitination of histone H2A.	('BAP1', 'Gene', (23, 27))	('differentiation', 'CPA', (59, 74))	('hyperubiquitination', 'Disease', (103, 122))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('BAP1', 'Gene', '8314', (23, 27))	('histone H2A', 'Protein', (126, 137))	('depletion', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('loss', 'NegReg', (51, 55))	('hyperubiquitination', 'Disease', 'None', (103, 122))
14243	33649778	The functional alteration of this enzyme, together with that of other methyltransferases (DNMT3A and DNMT3B) that catalyze the de novo DNA methylation, is responsible for the global hypomethylation and hypermethylation of widespread regions of the tumor cell genome.	('de novo DNA methylation', 'biological_process', 'GO:0043045', ('127', '150'))	('tumor', 'Disease', (248, 253))	('de novo DNA methylation', 'biological_process', 'GO:0043046', ('127', '150'))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('DNMT3B', 'Gene', (101, 107))	('DNMT3B', 'Gene', '1789', (101, 107))	('hypermethylation', 'MPA', (202, 218))	('DNMT3A', 'Gene', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('DNMT3A', 'Gene', '1788', (90, 96))	('responsible', 'Reg', (155, 166))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('alteration', 'Var', (15, 25))
14244	33649778	As regards UM, the hypomethylation of sites close to the preferentially expressed antigen in melanoma (PRAME) promoter has been shown to promote PRAME activation with subsequent increase in metastatic risk.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('activation', 'PosReg', (151, 161))	('UM', 'Phenotype', 'HP:0007716', (11, 13))	('PRAME', 'Gene', '23532', (103, 108))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('PRAME', 'Gene', '23532', (145, 150))	('PRAME', 'Gene', (103, 108))	('promote', 'PosReg', (137, 144))	('metastatic risk', 'CPA', (190, 205))	('PRAME', 'Gene', (145, 150))	('increase', 'PosReg', (178, 186))	('hypomethylation', 'Var', (19, 34))
14245	33649778	The hypomethylation of the deleted in split hand/split foot 1 (DSS1) promoter has been found to be a frequent event in UM.	('deleted in split hand/split foot 1', 'Gene', (27, 61))	('hypomethylation', 'Var', (4, 19))	('deleted in split hand/split foot 1', 'Gene', '7979', (27, 61))	('split foot', 'Phenotype', 'HP:0001839', (49, 59))	('DSS1', 'Gene', (63, 67))	('split hand', 'Phenotype', 'HP:0001171', (38, 48))	('UM', 'Phenotype', 'HP:0007716', (119, 121))	('DSS1', 'Gene', '7979', (63, 67))
14246	33649778	Hypermethylation of the following oncosuppressor gene promoters has been demonstrated in UM: p16, RASSF1A, RASEF, TIMP3 and EFS.	('TIMP3', 'Gene', '7078', (114, 119))	('TIMP3', 'Gene', (114, 119))	('p16', 'Gene', '1029', (93, 96))	('Hypermethylation', 'Var', (0, 16))	('RASSF1A', 'Gene', '11186', (98, 105))	('RASEF', 'Gene', (107, 112))	('RASEF', 'Gene', '158158', (107, 112))	('p16', 'Gene', (93, 96))	('UM', 'Phenotype', 'HP:0007716', (89, 91))	('RASSF1A', 'Gene', (98, 105))
14249	33649778	TRAIL receptors DcR1 and DcR2 were found hypermethylated in both UMs and cutaneous melanomas.	('UM', 'Phenotype', 'HP:0007716', (65, 67))	('DcR2', 'Gene', (25, 29))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (73, 92))	('UMs', 'Disease', (65, 68))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (73, 92))	('DcR1', 'Gene', '8794', (16, 20))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('hypermethylated', 'Var', (41, 56))	('cutaneous melanomas', 'Disease', (73, 92))	('DcR1', 'Gene', (16, 20))	('DcR2', 'Gene', '8793', (25, 29))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))
14250	33649778	Of note, the hypermethylation of a site on chromosome 3 at BAP1 locus determines BAP1 downregulation, showing the epigenetic regulation of this gene.	('BAP1', 'Gene', (81, 85))	('BAP1', 'Gene', (59, 63))	('BAP1', 'Gene', '8314', (59, 63))	('regulation', 'biological_process', 'GO:0065007', ('125', '135'))	('chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('downregulation', 'NegReg', (86, 100))	('hypermethylation', 'Var', (13, 29))	('BAP1', 'Gene', '8314', (81, 85))
14254	33649778	The dysregulation of specific miRNAs has been associated with the onset and progression of a number of types of cancer, including UM.	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('dysregulation', 'Var', (4, 17))	('UM', 'Phenotype', 'HP:0007716', (130, 132))	('associated', 'Reg', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
14258	33649778	Worley et al demonstrated that the expression of 6 miRNAs (let-7b, miR-199a*, miR-199a, miR-193b, miR-143 and miR-652) could be used to distinguish class1 UM (low metastatic risk) from class 2 ones (high metastatic risk) with maximum sensitivity and specificity.	('class1', 'Var', (148, 154))	('UM', 'Phenotype', 'HP:0007716', (155, 157))	('miR', 'Gene', (78, 81))	('miR', 'Gene', '220972', (51, 54))	('let-7b', 'Gene', '406884', (59, 65))	('miR-652', 'Gene', (110, 117))	('miR', 'Gene', (67, 70))	('miR-143', 'Gene', '406935', (98, 105))	('miR', 'Gene', '220972', (98, 101))	('miR-143', 'Gene', (98, 105))	('miR-193b', 'Gene', '574455', (88, 96))	('miR-652', 'Gene', '724022', (110, 117))	('miR', 'Gene', (51, 54))	('let-7b', 'Gene', (59, 65))	('miR', 'Gene', '220972', (88, 91))	('miR', 'Gene', (98, 101))	('miR', 'Gene', '220972', (110, 113))	('miR', 'Gene', (88, 91))	('miR', 'Gene', '220972', (78, 81))	('miR-193b', 'Gene', (88, 96))	('miR', 'Gene', (110, 113))	('miR', 'Gene', '220972', (67, 70))
14271	33649778	In particular, a previous study demonstrated how the analysis of liquid biopsy samples and circulating DNA may be useful for the early detection of genetic aberrations and epigenetic markers of precancerous and cancerous lesions.	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('genetic aberrations', 'Var', (148, 167))	('cancerous lesions', 'Disease', 'MESH:D009369', (211, 228))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (197, 203))	('cancer', 'Disease', (211, 217))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('epigenetic markers', 'Var', (172, 190))	('cancerous lesions', 'Disease', (211, 228))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
14272	33649778	In this context, novel high-sensitive techniques, such as next generation sequencing and droplet digital PCR (ddPCR), have been used for the analysis of liquid biopsy samples to detect low amounts of miRNAs, circulating mutations, microbial nucleic acids, etc..	('miR', 'Gene', '220972', (200, 203))	('miR', 'Gene', (200, 203))	('circulating mutations', 'Var', (208, 229))
14282	32704424	VEGFR1 was highly expressed, and knockdown of VEGFR1 significantly decreased VM protein expression and disrupted VM formation in MUM-2B melanoma.	('VEGFR1', 'Gene', '2321', (0, 6))	('formation', 'biological_process', 'GO:0009058', ('116', '125'))	('VM protein', 'Protein', (77, 87))	('VEGFR1', 'Gene', (0, 6))	('knockdown', 'Var', (33, 42))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('VM formation', 'CPA', (113, 125))	('MUM-2', 'Gene', (129, 134))	('VEGFR1', 'Gene', (46, 52))	('VEGFR1', 'Gene', '2321', (46, 52))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('MUM-2', 'Gene', '245828', (129, 134))	('disrupted', 'NegReg', (103, 112))	('melanoma', 'Disease', (136, 144))	('decreased', 'NegReg', (67, 76))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))
14284	32704424	CEUS with VEGFR1-targeted MBs showed significant imaging enhancement throughout the entire perfusion phase compared with CEUS with IgG MBs.	('VEGFR1', 'Gene', '2321', (10, 16))	('VEGFR1', 'Gene', (10, 16))	('enhancement', 'PosReg', (57, 68))	('imaging', 'MPA', (49, 56))	('MBs', 'Var', (26, 29))
14285	32704424	VEGFR1-targeted imaging was able to detect a decrease in maximum intensity and mean transit time in VEGFR1 knockdown melanoma compared with control melanoma.	('knockdown', 'Var', (107, 116))	('maximum intensity', 'MPA', (57, 74))	('VEGFR1', 'Gene', '2321', (0, 6))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('VEGFR1', 'Gene', (0, 6))	('VEGFR1', 'Gene', '2321', (100, 106))	('mean transit time', 'MPA', (79, 96))	('VEGFR1', 'Gene', (100, 106))	('decrease', 'NegReg', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
14367	32704424	Many VEGFR1 MBs attached to the MUM-2B melanoma cells in vitro and showed strong, round fluorescence on the cell surface, whereas cells incubated with IgG MBs with few non-specific MBs bound to the cells showed weak, dotted green fluorescence (Fig.	('cell surface', 'cellular_component', 'GO:0009986', ('108', '120'))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('MUM-2', 'Gene', (32, 37))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('VEGFR1', 'Gene', '2321', (5, 11))	('MBs', 'Var', (12, 15))	('attached', 'Reg', (16, 24))	('MUM-2', 'Gene', '245828', (32, 37))	('VEGFR1', 'Gene', (5, 11))
14410	32704424	Furthermore, our results showed that VEGFR1 knockdown inhibited tube formation by MUM-2B cells and tumor growth (Figs.	('tumor', 'Disease', (99, 104))	('inhibited', 'NegReg', (54, 63))	('MUM-2B cell', 'Chemical', '-', (82, 93))	('VEGFR1', 'Gene', '2321', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tube formation by', 'CPA', (64, 81))	('knockdown', 'Var', (44, 53))	('VEGFR1', 'Gene', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tube formation', 'biological_process', 'GO:0035148', ('64', '78'))
14428	32704424	Targeted CEUS imaging with VEGFR1 MBs and IgG MBs was subsequently performed in an ocular melanoma animal model.	('ocular melanoma', 'Disease', 'MESH:D008545', (83, 98))	('VEGFR1', 'Gene', '2321', (27, 33))	('MBs', 'Var', (34, 37))	('ocular melanoma', 'Disease', (83, 98))	('VEGFR1', 'Gene', (27, 33))	('ocular melanoma', 'Phenotype', 'HP:0007716', (83, 98))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
14430	32704424	CEUS with VEGFR1 MBs quantitatively showed higher IMAX and mTT values than IgG MBs.	('VEGFR1', 'Gene', '2321', (10, 16))	('higher', 'PosReg', (43, 49))	('MBs', 'Var', (17, 20))	('VEGFR1', 'Gene', (10, 16))	('IMAX', 'MPA', (50, 54))	('mTT values', 'MPA', (59, 69))	('mTT', 'Chemical', '-', (59, 62))
14433	32704424	CEUS with VEGFR1 MBs quantitatively showed lower IMAX and mTT values in VEGFR1 knockdown melanoma than in control melanoma (Fig.	('knockdown', 'Var', (79, 88))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('melanoma', 'Disease', (114, 122))	('VEGFR1', 'Gene', '2321', (10, 16))	('VEGFR1', 'Gene', '2321', (72, 78))	('VEGFR1', 'Gene', (10, 16))	('VEGFR1', 'Gene', (72, 78))	('IMAX', 'MPA', (49, 53))	('mTT values', 'MPA', (58, 68))	('mTT', 'Chemical', '-', (58, 61))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('lower', 'NegReg', (43, 48))
14572	32352002	Since then, genetic knockout mice havebecome the primary tool to study the disease, based on the fact that BCC patients suffer from a mutation in the Patched 1 (PTCH1) gene, dysregulating the Sonic Hedgehog (SHH) pathway.	('PTCH1', 'Gene', (161, 166))	('suffer from', 'Reg', (120, 131))	('dysregulating', 'Reg', (174, 187))	('Sonic Hedgehog', 'Gene', '6469', (192, 206))	('mutation', 'Var', (134, 142))	('mice', 'Species', '10090', (29, 33))	('BCC', 'Phenotype', 'HP:0002671', (107, 110))	('Patched 1', 'Gene', (150, 159))	('PTCH1', 'Gene', '5727', (161, 166))	('Patched 1', 'Gene', '5727', (150, 159))	('BCC', 'Disease', (107, 110))	('Sonic Hedgehog', 'Gene', (192, 206))	('patients', 'Species', '9606', (111, 119))
14573	32352002	The first transgenic mice were developed to overexpress the SHH protein, or a mutant variant of the downstream protein SMO.	('SHH protein', 'Protein', (60, 71))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('mutant variant', 'Var', (78, 92))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('SMO', 'Gene', (119, 122))	('transgenic mice', 'Species', '10090', (10, 25))	('overexpress', 'PosReg', (44, 55))
14579	32352002	Over the past few years, discoveries in cancer research have pointed out several factors implicated in the BCC pathophysiology, including mutations in the tumor-suppressing gene p53, activation of the Wnt/beta-catenin pathway, and signaling through the epidermal growth factor receptor.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('p53', 'Gene', '7157', (178, 181))	('activation', 'PosReg', (183, 193))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('253', '276'))	('epidermal growth factor receptor', 'Gene', '1956', (253, 285))	('beta-catenin', 'Gene', (205, 217))	('tumor', 'Disease', (155, 160))	('cancer', 'Disease', (40, 46))	('BCC', 'Phenotype', 'HP:0002671', (107, 110))	('signaling', 'biological_process', 'GO:0023052', ('231', '240'))	('beta-catenin', 'Gene', '1499', (205, 217))	('p53', 'Gene', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('BCC', 'Disease', (107, 110))	('epidermal growth factor receptor', 'Gene', (253, 285))	('mutations', 'Var', (138, 147))
14600	32352002	The biallelic NF1 inactivation in Schwann cells is suggested to be the first step of cNF formation, but the exact biological mechanism remains poorly understood.	('NF1', 'Gene', '4763', (14, 17))	('inactivation', 'Var', (18, 30))	('biallelic', 'Var', (4, 13))	('NF1', 'Gene', (14, 17))	('formation', 'biological_process', 'GO:0009058', ('89', '98'))
14601	32352002	Complete loss of NF1 function alone cannot explain tumor development, and several experimental studies suggest that other factors such as the NF1 haploinsufficient cellular type or the stromal microenvironment may also be involved.	('NF1', 'Gene', '4763', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('men', 'Species', '9606', (205, 208))	('NF1', 'Gene', (17, 20))	('NF1', 'Gene', '4763', (17, 20))	('men', 'Species', '9606', (88, 91))	('men', 'Species', '9606', (64, 67))	('haploinsufficient', 'Var', (146, 163))	('NF1', 'Gene', (142, 145))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
14624	32352002	Crosstalk between melanoma cells and the TME, including immune cells, further influence metastatic progression, which ultimately results in the invasion of capillaries and dissemination to distant sites.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('influence', 'Reg', (78, 87))	('dissemination to distant sites', 'CPA', (172, 202))	('results in', 'Reg', (129, 139))	('Crosstalk', 'Var', (0, 9))	('metastatic progression', 'CPA', (88, 110))	('invasion of capillaries', 'CPA', (144, 167))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))
14766	24461645	In theory, excess ingestion of l-lysine will lead to decreased replication of FHV-1 through reduction in viral protein synthesis.	('viral protein synthesis', 'biological_process', 'GO:0019081', ('105', '128'))	('l-lysine', 'Var', (31, 39))	('l-lysine', 'Chemical', 'MESH:D008239', (31, 39))	('reduction', 'NegReg', (92, 101))	('replication', 'MPA', (63, 74))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('decreased', 'NegReg', (53, 62))	('FHV-1', 'Gene', (78, 83))	('viral protein synthesis', 'MPA', (105, 128))
14767	24461645	In a placebo controlled experimental study, cats receiving 500 mg l-lysine every 12 h had less severe conjunctivitis than control cats.	('conjunctivitis', 'Disease', 'MESH:D003231', (102, 116))	('cats', 'Species', '9685', (44, 48))	('cats', 'Species', '9685', (130, 134))	('l-lysine every', 'Var', (66, 80))	('conjunctivitis', 'Phenotype', 'HP:0000509', (102, 116))	('l-lysine', 'Chemical', 'MESH:D008239', (66, 74))	('conjunctivitis', 'Disease', (102, 116))
14826	24461645	However, in one histopathologic study of 50 cases of lymphosarcoma, a high percentage of tumors still contained FeLV proviral DNA, suggesting that regressively infected cats (those that are infected but have become aviremic) might have proviral DNA that can cause generalized lymphosarcoma.	('infected', 'Disease', (190, 198))	('tumors', 'Disease', (89, 95))	('lymphosarcoma', 'Disease', 'MESH:D008228', (53, 66))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('lymphosarcoma', 'Disease', (53, 66))	('DNA', 'cellular_component', 'GO:0005574', ('245', '248'))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('proviral DNA', 'Var', (236, 248))	('cause', 'Reg', (258, 263))	('FeLV', 'Species', '11768', (112, 116))	('infected', 'Disease', 'MESH:D007239', (160, 168))	('lymphosarcoma', 'Disease', 'MESH:D008228', (276, 289))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('infected', 'Disease', (160, 168))	('cats', 'Species', '9685', (169, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('lymphosarcoma', 'Disease', (276, 289))	('sarcoma', 'Phenotype', 'HP:0100242', (282, 289))	('infected', 'Disease', 'MESH:D007239', (190, 198))
14843	24461645	Hypotheses to explain viral pathogenesis include de novo FCoV mutation giving rise to virulence and distinct circulating avirulent and virulent strains.	('virulence', 'MPA', (86, 95))	('FCoV', 'Gene', (57, 61))	('virulence', 'biological_process', 'GO:0009406', ('86', '95'))	('virulence', 'biological_process', 'GO:0016032', ('86', '95'))	('giving rise to', 'Reg', (71, 85))	('virulence', 'biological_process', 'GO:0009405', ('86', '95'))	('mutation', 'Var', (62, 70))	('pathogenesis', 'biological_process', 'GO:0009405', ('28', '40'))	('FCoV', 'Species', '12663', (57, 61))
14894	31394807	Inflammation, characterized by high numbers of infiltrating leukocytes and a high HLA Class I expression, is associated with a bad prognosis in uveal melanoma (UM).	('high', 'Var', (77, 81))	('Inflammation', 'biological_process', 'GO:0006954', ('0', '12'))	('uveal melanoma', 'Disease', 'MESH:C536494', (144, 158))	('HLA Class I', 'Protein', (82, 93))	('expression', 'MPA', (94, 104))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('uveal melanoma', 'Phenotype', 'HP:0007716', (144, 158))	('uveal melanoma', 'Disease', (144, 158))
14895	31394807	We wondered whether mutations in GNA11 or GNAQ differentially affect inflammation and HLA expression, and thereby progression of the disease.	('affect', 'Reg', (62, 68))	('HLA', 'Protein', (86, 89))	('GNA11', 'Gene', (33, 38))	('inflammation', 'Disease', (69, 81))	('GNAQ', 'Gene', '2776', (42, 46))	('GNA11', 'Gene', '2767', (33, 38))	('GNAQ', 'Gene', (42, 46))	('inflammation', 'biological_process', 'GO:0006954', ('69', '81'))	('mutations', 'Var', (20, 29))	('inflammation', 'Disease', 'MESH:D007249', (69, 81))
14896	31394807	The type of GNAQ/11 mutation was analyzed using dPCR; chromosome aberrations were determined by Fluorescence in Situ Hybridization (FISH), karyotyping, and single nucleotide polymorphism (SNP) analysis, and mRNA expression by Illumina PCR.	('GNAQ', 'Gene', (12, 16))	('GNAQ', 'Gene', '2776', (12, 16))	('chromosome', 'cellular_component', 'GO:0005694', ('54', '64'))	('single nucleotide polymorphism', 'Var', (156, 186))
14897	31394807	Comparing tumors with a GNAQ mutation with those with a GNA11 mutation yielded no significant differences in histopathological characteristics, infiltrate, or HLA expression.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mutation', 'Var', (29, 37))	('GNAQ', 'Gene', '2776', (24, 28))	('HLA expression', 'MPA', (159, 173))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('GNAQ', 'Gene', (24, 28))	('GNA11', 'Gene', (56, 61))	('GNA11', 'Gene', '2767', (56, 61))
14898	31394807	When comparing the Q209L mutations with Q209P mutations in tumors with monosomy of chromosome 3, a higher mitotic count was found in the Q209P/M3 tumors (p = 0.007).	('Q209L', 'Var', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('M3 tumors', 'Disease', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('higher', 'PosReg', (99, 105))	('Q209P', 'Var', (40, 45))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('Q209P', 'Mutation', 'rs1057519742', (40, 45))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('chromosome', 'cellular_component', 'GO:0005694', ('83', '93'))	('Q209P', 'Mutation', 'rs1057519742', (137, 142))	('Q209L', 'Mutation', 'rs1057519742', (19, 24))	('tumors', 'Disease', (146, 152))	('mitotic count', 'CPA', (106, 119))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('M3 tumors', 'Disease', 'MESH:D015473', (143, 152))
14900	31394807	We conclude that the type (Q209P/Q209L) or location of the mutation (GNA11/GNAQ) do not have a significant effect on the immunological characteristics of the tumors, such as infiltrate and HLA Class I expression.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('GNAQ', 'Gene', (75, 79))	('Q209P', 'SUBSTITUTION', 'None', (27, 32))	('Q209P', 'Var', (27, 32))	('Q209L', 'Mutation', 'rs1057519742', (33, 38))	('GNA11', 'Gene', (69, 74))	('expression', 'MPA', (201, 211))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('GNA11', 'Gene', '2767', (69, 74))	('GNAQ', 'Gene', '2776', (75, 79))	('HLA Class I', 'Protein', (189, 200))
14904	31394807	The primary GNAQ/GNA11 mutation in UM occurs in the melanocyte and is already present in choroidal nevi.	('GNAQ', 'Gene', (12, 16))	('choroidal nevi', 'Phenotype', 'HP:0025314', (89, 103))	('mutation', 'Var', (23, 31))	('GNA11', 'Gene', (17, 22))	('GNAQ', 'Gene', '2776', (12, 16))	('nevi', 'Phenotype', 'HP:0003764', (99, 103))	('GNA11', 'Gene', '2767', (17, 22))
14905	31394807	During malignant progression, this genetic modification is usually followed by gain of chromosome 6q or gain of 8q, as well as a mutation in the BAP1, EIF1AX, or SF3B1 gene, and/or a complete loss of one chromosome 3 (monosomy 3 (M3)).	('chromosome', 'cellular_component', 'GO:0005694', ('87', '97'))	('EIF1AX', 'Gene', '1964', (151, 157))	('mutation', 'Var', (129, 137))	('gain', 'PosReg', (104, 108))	('gain', 'PosReg', (79, 83))	('BAP1', 'Gene', '8314', (145, 149))	('chromosome', 'cellular_component', 'GO:0005694', ('204', '214'))	('SF3B1', 'Gene', (162, 167))	('loss', 'NegReg', (192, 196))	('EIF1AX', 'Gene', (151, 157))	('SF3B1', 'Gene', '23451', (162, 167))	('BAP1', 'Gene', (145, 149))
14906	31394807	M3 loss and mutations in BAP1 often co-occur and are associated with a bad prognosis.	('BAP1', 'Gene', '8314', (25, 29))	('mutations', 'Var', (12, 21))	('BAP1', 'Gene', (25, 29))	('loss', 'NegReg', (3, 7))
14907	31394807	Gain of 8q is associated with metastases but often occurs together with monosomy 3.	('metastases', 'Disease', 'MESH:D009362', (30, 40))	('metastases', 'Disease', (30, 40))	('Gain', 'Var', (0, 4))
14912	31394807	From previous research it is known that HLA-A and HLA-B expression is higher in patients with an M3 status.	('HLA-A', 'Gene', '3105', (40, 45))	('patients', 'Species', '9606', (80, 88))	('HLA-A', 'Gene', (40, 45))	('HLA-B', 'Protein', (50, 55))	('M3 status', 'Var', (97, 106))	('higher', 'PosReg', (70, 76))
14916	31394807	However, research from our lab has shown a low expression of HLA-G. From previous research it is known that HLA-A and HLA-B expression is higher in patients with an M3 status.	('patients', 'Species', '9606', (148, 156))	('M3 status', 'Var', (165, 174))	('HLA-B', 'Gene', (118, 123))	('HLA-A', 'Gene', '3105', (108, 113))	('expression', 'MPA', (124, 134))	('HLA-A', 'Gene', (108, 113))	('higher', 'PosReg', (138, 144))	('HLA-G', 'Gene', (61, 66))	('HLA-G', 'Gene', '3135', (61, 66))
14918	31394807	We wondered whether the expression of different types of HLA molecules in UM is similarly related to loss of chromosome 3 or might be related to the type of basic mutation (GNAQ or GNA11 mutation or the type of mutation (Q209P/Q209L)).	('Q209L', 'Mutation', 'rs1057519742', (227, 232))	('GNAQ', 'Gene', (173, 177))	('GNAQ', 'Gene', '2776', (173, 177))	('Q209P', 'SUBSTITUTION', 'None', (221, 226))	('loss', 'Var', (101, 105))	('GNA11', 'Gene', '2767', (181, 186))	('GNA11', 'Gene', (181, 186))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('related', 'Reg', (90, 97))	('Q209P', 'Var', (221, 226))
14922	31394807	Q209 is a hotspot for missense mutations where the proteins translated from GNAQ/GNA11 often have glutamine replaced by proline (Q209P mutation) or by leucine (Q209L mutation).	('proline', 'Chemical', 'MESH:D011392', (120, 127))	('leucine (Q209L mutation', 'Var', (151, 174))	('Q209P mutation', 'Var', (129, 143))	('leucine', 'Chemical', 'MESH:D007930', (151, 158))	('GNA11', 'Gene', '2767', (81, 86))	('GNA11', 'Gene', (81, 86))	('GNAQ', 'Gene', '2776', (76, 80))	('Q209P', 'Mutation', 'rs1057519742', (129, 134))	('glutamine', 'Chemical', 'MESH:D005973', (98, 107))	('Q209L', 'Mutation', 'rs1057519742', (160, 165))	('GNAQ', 'Gene', (76, 80))	('glutamine', 'MPA', (98, 107))
14923	31394807	We set out to determine whether the difference between a GNAQ or GNA11 mutation or the type of mutation in these genes (Q209L versus Q209P) influenced the level of HLA expression and infiltrate in UM.	('Q209P', 'Var', (133, 138))	('GNAQ', 'Gene', (57, 61))	('Q209L', 'Var', (120, 125))	('Q209P', 'Mutation', 'rs1057519742', (133, 138))	('level', 'MPA', (155, 160))	('influenced', 'Reg', (140, 150))	('GNA11', 'Gene', '2767', (65, 70))	('GNA11', 'Gene', (65, 70))	('HLA', 'Protein', (164, 167))	('GNAQ', 'Gene', '2776', (57, 61))	('Q209L', 'Mutation', 'rs1057519742', (120, 125))
14927	31394807	We set out to determine if mutations in GNAQ and GNA11 are responsible for different degrees of inflammation within the D3 or M3 groups.	('mutations', 'Var', (27, 36))	('GNAQ', 'Gene', (40, 44))	('inflammation', 'biological_process', 'GO:0006954', ('96', '108'))	('GNAQ', 'Gene', '2776', (40, 44))	('inflammation', 'Disease', 'MESH:D007249', (96, 108))	('responsible', 'Reg', (59, 70))	('GNA11', 'Gene', '2767', (49, 54))	('GNA11', 'Gene', (49, 54))	('inflammation', 'Disease', (96, 108))
14928	31394807	The comparisons of clinical and histopathological information can be seen in Table 1 and Table 2: Table 1 contains the tumors with GNAQ or GNA11 mutations, while Table 2 contains the data of tumors identified by Q209L and Q209P mutations.	('GNAQ', 'Gene', (131, 135))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('GNA11', 'Gene', '2767', (139, 144))	('GNA11', 'Gene', (139, 144))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('mutations', 'Var', (145, 154))	('Q209L', 'Var', (212, 217))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('Q209P', 'Mutation', 'rs1057519742', (222, 227))	('GNAQ', 'Gene', '2776', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Q209L', 'Mutation', 'rs1057519742', (212, 217))	('Q209P mutations', 'Var', (222, 237))
14929	31394807	We subsequently set out to investigate whether the differences in levels of infiltrating leukocytes or in HLA expression were related to the presence of GNAQ/GNA11 mutations (Table 3), or the type of mutation Q209L/Q209P (Table 4).	('Q209P', 'Mutation', 'rs1057519742', (215, 220))	('Q209L', 'Var', (209, 214))	('Q209L', 'SUBSTITUTION', 'None', (209, 214))	('GNA11', 'Gene', (158, 163))	('GNAQ', 'Gene', '2776', (153, 157))	('GNA11', 'Gene', '2767', (158, 163))	('mutations', 'Var', (164, 173))	('HLA', 'Protein', (106, 109))	('GNAQ', 'Gene', (153, 157))
14933	31394807	In Figure 2a,b there is no significant difference between the GNA11/GNAQ or Q209L/Q209P mutations.	('GNAQ', 'Gene', (68, 72))	('Q209P', 'Mutation', 'rs1057519742', (82, 87))	('Q209L', 'SUBSTITUTION', 'None', (76, 81))	('Q209L', 'Var', (76, 81))	('GNA11', 'Gene', '2767', (62, 67))	('GNA11', 'Gene', (62, 67))	('GNAQ', 'Gene', '2776', (68, 72))
14935	31394807	While almost all M3 tumors also have additional copies of 8q, there is variety between D3 tumors.	('M3 tumors', 'Disease', (17, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Disease', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('copies', 'Var', (48, 54))	('M3 tumors', 'Disease', 'MESH:D015473', (17, 26))
14937	31394807	Despite the small group sizes for GNA11 and GNAQ tumors it is quite clear that there is no significant difference in the expression patterns of HLA Class I and the presence of T cells or macrophages between tumors with either a GNAQ or GNA11 mutation or a Q209P or Q209P mutation.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Disease', (49, 55))	('GNAQ', 'Gene', '2776', (44, 48))	('tumors', 'Disease', (207, 213))	('GNAQ', 'Gene', '2776', (228, 232))	('GNA11', 'Gene', '2767', (34, 39))	('Q209P', 'Var', (265, 270))	('GNAQ', 'Gene', (228, 232))	('GNAQ', 'Gene', (44, 48))	('GNA11', 'Gene', (236, 241))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('presence of T cells', 'Phenotype', 'HP:0100828', (164, 183))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('GNA11', 'Gene', (34, 39))	('Q209P', 'Mutation', 'rs1057519742', (265, 270))	('Q209P', 'Mutation', 'rs1057519742', (256, 261))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('GNA11', 'Gene', '2767', (236, 241))	('HLA Class I', 'Protein', (144, 155))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('Q209P or', 'Var', (256, 264))	('mutation', 'Var', (242, 250))
14938	31394807	Therefore, there is no evidence that the differences in inflammation found in groups with the same chromosome 3 status are caused by the different mutations on GNAQ or GNA11 or the type of mutation Q209L or Q209P.	('inflammation', 'Disease', 'MESH:D007249', (56, 68))	('Q209P', 'Var', (207, 212))	('GNAQ', 'Gene', (160, 164))	('Q209L', 'Var', (198, 203))	('chromosome', 'cellular_component', 'GO:0005694', ('99', '109'))	('inflammation', 'Disease', (56, 68))	('Q209P', 'Mutation', 'rs1057519742', (207, 212))	('GNAQ', 'Gene', '2776', (160, 164))	('GNA11', 'Gene', '2767', (168, 173))	('GNA11', 'Gene', (168, 173))	('inflammation', 'biological_process', 'GO:0006954', ('56', '68'))	('Q209L', 'Mutation', 'rs1057519742', (198, 203))	('caused', 'Reg', (123, 129))
14939	31394807	The literature also suggests mutations on GNAQ do not affect the survival, and this was confirmed in this study, as no difference between GNAQ/GNA11 was observed.	('GNAQ', 'Gene', '2776', (42, 46))	('GNAQ', 'Gene', '2776', (138, 142))	('mutations', 'Var', (29, 38))	('GNAQ', 'Gene', (42, 46))	('GNA11', 'Gene', (143, 148))	('GNAQ', 'Gene', (138, 142))	('GNA11', 'Gene', '2767', (143, 148))
14940	31394807	Due to Q209 being crucial for GTPase activity, GTP hydrolysis is abolished in both types of mutation in both genes.	('GTP', 'Chemical', 'MESH:D006160', (47, 50))	('abolished', 'NegReg', (65, 74))	('GTP', 'Chemical', 'MESH:D006160', (30, 33))	('GTPase', 'Protein', (30, 36))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('47', '61'))	('Q209', 'Var', (7, 11))	('GTPase activity', 'molecular_function', 'GO:0003924', ('30', '45'))	('GTP hydrolysis', 'MPA', (47, 61))
14941	31394807	As we did not find any difference, there is probably no difference in any pathway activation between the different mutations, or any different secondary effect of the sub-units formed from GNA11 and GNAQ.	('GNAQ', 'Gene', '2776', (199, 203))	('mutations', 'Var', (115, 124))	('GNA11', 'Gene', (189, 194))	('GNAQ', 'Gene', (199, 203))	('GNA11', 'Gene', '2767', (189, 194))
14942	31394807	If a specific mutation would have changed the protein into one that remained functional but with less affinity, the different mutations could have explained the difference in inflammation.	('inflammation', 'biological_process', 'GO:0006954', ('175', '187'))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('mutation', 'Var', (14, 22))	('explained', 'Reg', (147, 156))	('inflammation', 'Disease', 'MESH:D007249', (175, 187))	('inflammation', 'Disease', (175, 187))	('changed', 'Reg', (34, 41))
14948	31394807	If the heatmap from Figure 1 is rearranged according to the GNAQ/GNA11 mutation status, no obvious difference is seen between the GNA11-mutated tumors on the left and the GNAQ-mutated tumors on the right.	('tumors', 'Disease', (144, 150))	('GNAQ', 'Gene', '2776', (171, 175))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('GNAQ', 'Gene', (60, 64))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('mutation', 'Var', (71, 79))	('GNA11', 'Gene', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Disease', (184, 190))	('GNAQ', 'Gene', (171, 175))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('GNA11', 'Gene', '2767', (130, 135))	('GNA11', 'Gene', '2767', (65, 70))	('GNA11', 'Gene', (65, 70))	('GNAQ', 'Gene', '2776', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
14952	31394807	The heatmap in Figure 4 clearly shows that several groups with different levels of inflammation and HLA expression exist in the different GNAQ or GNA11 mutated tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('GNA11', 'Gene', '2767', (146, 151))	('inflammation', 'Disease', (83, 95))	('mutated', 'Var', (152, 159))	('GNAQ', 'Gene', '2776', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('GNAQ', 'Gene', (138, 142))	('tumors', 'Disease', (160, 166))	('inflammation', 'biological_process', 'GO:0006954', ('83', '95'))	('GNA11', 'Gene', (146, 151))	('inflammation', 'Disease', 'MESH:D007249', (83, 95))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
14956	31394807	We do not find a difference in survival between the tumors with different GNAQ/GNA11 mutations, while a clear difference can be observed between patients with a different chromosome 3 status.	('patients', 'Species', '9606', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('chromosome', 'cellular_component', 'GO:0005694', ('171', '181'))	('GNAQ', 'Gene', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('mutations', 'Var', (85, 94))	('GNA11', 'Gene', '2767', (79, 84))	('GNA11', 'Gene', (79, 84))	('GNAQ', 'Gene', '2776', (74, 78))
14957	31394807	How the loss of chromosome 3/BAP1 leads to an inflammatory phenotype will be the subject of further studies.	('leads to', 'Reg', (34, 42))	('BAP1', 'Gene', '8314', (29, 33))	('inflammatory phenotype', 'MPA', (46, 68))	('loss', 'Var', (8, 12))	('chromosome', 'cellular_component', 'GO:0005694', ('16', '26'))	('BAP1', 'Gene', (29, 33))
14969	31394807	The presence of a mutation in either GNAQ/GNA11 was analyzed using hydrolysis probes in a duplex dPCR.	('GNAQ', 'Gene', (37, 41))	('GNA11', 'Gene', (42, 47))	('mutation', 'Var', (18, 26))	('GNA11', 'Gene', '2767', (42, 47))	('GNAQ', 'Gene', '2776', (37, 41))
14978	31394807	When separated on chromosome 3 status and GNAQ/11 mutations the following group sizes were created: D3 + GNA11 n = 9, D3 + GNAQ n = 12, M3 + GNA11 n = 23, M3 + GNAQ n = 15, D3 + Q209L n = 15, D3 + Q209P n = 6, M3 + Q209L n = 27, and M3 + Q209P n = 11.	('Q209P', 'Mutation', 'rs1057519742', (238, 243))	('chromosome', 'cellular_component', 'GO:0005694', ('18', '28'))	('D3 + Q209P', 'Var', (192, 202))	('GNAQ', 'Gene', '2776', (123, 127))	('GNA11', 'Gene', (141, 146))	('M3 + Q209L', 'Var', (210, 220))	('GNAQ', 'Gene', (123, 127))	('Q209P', 'Mutation', 'rs1057519742', (197, 202))	('GNA11', 'Gene', '2767', (105, 110))	('M3 + Q209P', 'Var', (233, 243))	('Q209L', 'Mutation', 'rs1057519742', (178, 183))	('GNAQ', 'Gene', '2776', (42, 46))	('GNAQ', 'Gene', '2776', (160, 164))	('GNAQ', 'Gene', (42, 46))	('GNA11', 'Gene', '2767', (141, 146))	('GNAQ', 'Gene', (160, 164))	('GNA11', 'Gene', (105, 110))	('D3 + Q209L', 'Var', (173, 183))	('Q209L', 'Mutation', 'rs1057519742', (215, 220))
14979	31394807	The type and location of mutations on GNAQ/GNA11 do not seem to affect the progression of UM.	('mutations', 'Var', (25, 34))	('GNAQ', 'Gene', '2776', (38, 42))	('GNA11', 'Gene', (43, 48))	('GNA11', 'Gene', '2767', (43, 48))	('GNAQ', 'Gene', (38, 42))	('affect', 'Reg', (64, 70))
14980	31394807	The main difference between inflamed and non-inflamed tumors is the chromosome 3 status.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('chromosome', 'Var', (68, 78))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
14982	31464824	Evaluation of the contribution of germline variants in BRCA1 and BRCA2 to uveal and cutaneous melanoma Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate.	('cancers', 'Disease', 'MESH:D009369', (236, 243))	('mutations', 'Var', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('variants', 'Var', (43, 51))	('BRCA2', 'Gene', '675', (65, 70))	('BRCA2', 'Gene', (135, 140))	('cutaneous melanoma', 'Disease', (84, 102))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (84, 102))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (84, 102))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('cancers', 'Disease', (236, 243))	('BRCA2', 'Gene', '675', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('ovarian cancer', 'Phenotype', 'HP:0100615', (193, 207))	('predispose', 'Reg', (141, 151))	('BRCA1', 'Gene', '672', (55, 60))	('BRCA1', 'Gene', '672', (125, 130))	('BRCA1', 'Gene', (55, 60))	('BRCA1', 'Gene', (125, 130))	('BRCA2', 'Gene', (65, 70))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (182, 207))
14983	31464824	BRCA2 mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1 mutation carriers have been mixed.	('BRCA1', 'Gene', '672', (139, 144))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('BRCA2', 'Gene', (0, 5))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('BRCA1', 'Gene', (139, 144))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('BRCA2', 'Gene', '675', (0, 5))	('uveal melanoma', 'Phenotype', 'HP:0007716', (51, 65))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('cutaneous melanoma', 'Disease', (75, 93))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (75, 93))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (75, 93))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('mutation', 'Var', (6, 14))
14986	31464824	A nonsense and a frameshift mutation were identified in BRCA1, both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of 7 amino acids due to a frameshift deletion).	('p.Q516', 'Var', (131, 137))	('BRCA1', 'Gene', '672', (56, 61))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('BRCA1', 'Gene', (56, 61))	('frameshift', 'Var', (17, 27))	('Q516', 'Chemical', '-', (133, 137))	('protein', 'Protein', (109, 116))	('resulting in', 'Reg', (68, 80))	('premature truncation', 'MPA', (81, 101))
14987	31464824	These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('variants', 'Var', (6, 14))	('pancreatic', 'Disease', (115, 125))	('breast cancer', 'Disease', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('prostate', 'Disease', (127, 135))	('pancreatic', 'Disease', 'MESH:D010195', (115, 125))
14988	31464824	Seeking further evidence of an association between BRCA1 variants and melanoma, we examined two whole genome/exome sequenced collections of sporadic CM patients (total N = 763).	('melanoma', 'Disease', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('BRCA1', 'Gene', '672', (51, 56))	('association', 'Interaction', (31, 42))	('BRCA1', 'Gene', (51, 56))	('variants', 'Var', (57, 65))	('patients', 'Species', '9606', (152, 160))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
14989	31464824	We identified one individual with a deleterious BRCA1 variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1 was not a driver of tumorigenesis in this instance.	('BRCA1', 'Gene', '672', (48, 53))	('BRCA1', 'Gene', '672', (182, 187))	('variant', 'Var', (54, 61))	('BRCA1', 'Gene', (48, 53))	('BRCA1', 'Gene', (182, 187))
14990	31464824	While this is the first time deleterious BRCA1 mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is due to these variants.	('BRCA1', 'Gene', '672', (41, 46))	('variants', 'Var', (244, 252))	('familial CM', 'Disease', (195, 206))	('BRCA1', 'Gene', (41, 46))	('mutations', 'Var', (47, 56))
14991	31464824	Additionally, in conjunction with other studies, we conclude that the previously described association between BRCA2 mutations and UM susceptibility represents a rare source of increased risk.	('UM susceptibility', 'Disease', (131, 148))	('BRCA2', 'Gene', (111, 116))	('mutations', 'Var', (117, 126))	('BRCA2', 'Gene', '675', (111, 116))
14993	31464824	Several somatic mutations have been associated with uveal melanoma (UM) development and progression, including GNAQ, GNA11, BAP1, SF3B1, PLCB4, CYSTLR2, and EIF1AX.	('uveal melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('SF3B1', 'Gene', (130, 135))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('BAP1', 'Gene', '8314', (124, 128))	('PLCB4', 'Gene', '5332', (137, 142))	('GNAQ', 'Gene', '2776', (111, 115))	('GNAQ', 'Gene', (111, 115))	('mutations', 'Var', (16, 25))	('associated', 'Reg', (36, 46))	('BAP1', 'Gene', (124, 128))	('SF3B1', 'Gene', '23451', (130, 135))	('PLCB4', 'Gene', (137, 142))	('GNA11', 'Gene', '2767', (117, 122))	('GNA11', 'Gene', (117, 122))	('EIF1AX', 'Gene', '1964', (157, 163))	('EIF1AX', 'Gene', (157, 163))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
14994	31464824	UM also has a heritable component, with germline variants in BAP1, and rarely CDKN2A, being associated with predisposition.	('BAP1', 'Gene', (61, 65))	('CDKN2A', 'Gene', (78, 84))	('CDKN2A', 'Gene', '1029', (78, 84))	('germline variants', 'Var', (40, 57))	('BAP1', 'Gene', '8314', (61, 65))	('associated', 'Reg', (92, 102))
14996	31464824	As with UM, susceptibility to CM is sometimes heritable due to single-gene defects, with germline mutations in CDKN2A, CDK4, BAP1, MITF, TERT, POT1, ACD and TERF2IP contributing to CM development in high-density melanoma families.	('MITF', 'Gene', (131, 135))	('ACD', 'Gene', (149, 152))	('POT1', 'Gene', (143, 147))	('CDK', 'molecular_function', 'GO:0004693', ('119', '122'))	('BAP1', 'Gene', '8314', (125, 129))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Disease', (212, 220))	('CDKN2A', 'Gene', (111, 117))	('TERF2IP', 'Gene', (157, 164))	('TERT', 'Gene', (137, 141))	('TERF2IP', 'Gene', '54386', (157, 164))	('TERT', 'Gene', '7015', (137, 141))	('CDK4', 'Gene', (119, 123))	('BAP1', 'Gene', (125, 129))	('ACD', 'Gene', '65057', (149, 152))	('CDKN2A', 'Gene', '1029', (111, 117))	('MITF', 'Gene', '4286', (131, 135))	('contributing', 'Reg', (165, 177))	('POT1', 'Gene', '25913', (143, 147))	('mutations', 'Var', (98, 107))	('CDK4', 'Gene', '1019', (119, 123))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))
14997	31464824	Indeed, the coexistence of UM and CM in some patients suggests a similar predisposition to both melanoma subtypes, exemplified by predisposition to CM and UM conferred by germline BAP1 and CDKN2A mutations.	('germline', 'Var', (171, 179))	('BAP1', 'Gene', '8314', (180, 184))	('CDKN2A', 'Gene', '1029', (189, 195))	('patients', 'Species', '9606', (45, 53))	('BAP1', 'Gene', (180, 184))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))	('CDKN2A', 'Gene', (189, 195))	('mutations', 'Var', (196, 205))
15000	31464824	Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer.	('Germline mutations', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('BRCA2', 'Gene', (32, 37))	('BRCA1', 'Gene', (22, 27))	('ovarian cancer', 'Phenotype', 'HP:0100615', (90, 104))	('BRCA1', 'Gene', '672', (22, 27))	('BRCA2', 'Gene', '675', (32, 37))	('predispose', 'Reg', (38, 48))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (79, 104))
15001	31464824	Both BRCA1 and BRCA2 are crucial for the process of homologous recombination repair, largely involving the repair of DNA lesions that stall DNA replication forks and/or cause DNA double-strand breaks.	('stall', 'NegReg', (134, 139))	('BRCA2', 'Gene', (15, 20))	('DNA replication', 'biological_process', 'GO:0006260', ('140', '155'))	('DNA', 'cellular_component', 'GO:0005574', ('117', '120'))	('DNA replication', 'MPA', (140, 155))	('homologous recombination', 'biological_process', 'GO:0035825', ('52', '76'))	('BRCA1', 'Gene', '672', (5, 10))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('BRCA2', 'Gene', '675', (15, 20))	('lesions', 'Var', (121, 128))	('DNA', 'cellular_component', 'GO:0005574', ('175', '178'))	('BRCA1', 'Gene', (5, 10))	('DNA double-strand breaks', 'MPA', (175, 199))	('cause', 'Reg', (169, 174))
15002	31464824	In cohorts of BRCA1 or BRCA2 mutation carriers, increased risks of other cancers have been observed, including those of the pancreas and prostate.	('BRCA1', 'Gene', '672', (14, 19))	('mutation', 'Var', (29, 37))	('cancers', 'Disease', (73, 80))	('BRCA2', 'Gene', (23, 28))	('prostate', 'Disease', (137, 145))	('BRCA1', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('pancreas', 'Disease', (124, 132))	('BRCA2', 'Gene', '675', (23, 28))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
15003	31464824	Both UM and CM were found at significantly increased frequency in BRCA2 mutation carriers, but only a trend towards increased risk of CM in BRCA1 mutation carriers was found.	('BRCA2', 'Gene', (66, 71))	('BRCA1', 'Gene', (140, 145))	('BRCA2', 'Gene', '675', (66, 71))	('increased', 'PosReg', (43, 52))	('mutation', 'Var', (72, 80))	('BRCA1', 'Gene', '672', (140, 145))
15004	31464824	One screen for germline variants in BRCA1 or BRCA2 in 82 individuals with both a breast cancer and CM diagnosis revealed 2 pathogenic BRCA1 and 2 pathogenic BRCA2 mutations.	('BRCA1', 'Gene', (36, 41))	('BRCA1', 'Gene', (134, 139))	('breast cancer', 'Disease', (81, 94))	('mutations', 'Var', (163, 172))	('BRCA2', 'Gene', (45, 50))	('BRCA2', 'Gene', '675', (45, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('BRCA2', 'Gene', (157, 162))	('BRCA1 and 2', 'Gene', '672;675', (134, 145))	('pathogenic', 'Reg', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('BRCA1', 'Gene', '672', (36, 41))	('BRCA1', 'Gene', '672', (134, 139))	('BRCA2', 'Gene', '675', (157, 162))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
15005	31464824	Some screens of UM patients have revealed a small number of deleterious truncating mutations in BRCA2, but this was not seen in all cohorts.	('truncating mutations', 'Var', (72, 92))	('BRCA2', 'Gene', '675', (96, 101))	('patients', 'Species', '9606', (19, 27))	('BRCA2', 'Gene', (96, 101))
15006	31464824	We sought to assess the role that novel or rare (VAF<0.01) germline BRCA1 and BRCA2 mutations play in melanoma susceptibility in a large, well characterised, cohort of families and individuals with CM and/or UM.	('BRCA1', 'Gene', (68, 73))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('BRCA2', 'Gene', (78, 83))	('melanoma', 'Disease', (102, 110))	('mutations', 'Var', (84, 93))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('BRCA2', 'Gene', '675', (78, 83))	('BRCA1', 'Gene', '672', (68, 73))
15007	31464824	Potential pathogenicity of the mutations was analysed with respect to co-segregation with melanoma, bioinformatic prediction of protein effect and evidence from functional studies.	('melanoma', 'Disease', (90, 98))	('mutations', 'Var', (31, 40))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
15008	31464824	All participants gave written informed consent for participation and were wild-type for germline CDKN2A, CDK4 and BAP1 mutations.	('CDKN2A', 'Gene', (97, 103))	('CDK4', 'Gene', (105, 109))	('CDKN2A', 'Gene', '1029', (97, 103))	('CDK4', 'Gene', '1019', (105, 109))	('BAP1', 'Gene', '8314', (114, 118))	('CDK', 'molecular_function', 'GO:0004693', ('105', '108'))	('participants', 'Species', '9606', (4, 16))	('BAP1', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))
15018	31464824	WGS or WES was performed on 298 individuals from 160 high density CM, CM/UM families, or UM cases from Australia, Denmark, and Sweden, to examine if germline variants in BRCA1 or BRCA2 predispose to CM or UM (Supplementary Table 1).	('BRCA2', 'Gene', '675', (179, 184))	('BRCA2', 'Gene', (179, 184))	('variants', 'Var', (158, 166))	('CM or UM', 'Disease', (199, 207))	('BRCA1', 'Gene', '672', (170, 175))	('predispose to', 'Reg', (185, 198))	('BRCA1', 'Gene', (170, 175))
15020	31464824	With a population frequency cut-off of <0.01, 10 variants in BRCA1 were identified in 13 families (Table 1) and 24 variants in BRCA2 were identified in 30 families (Table 2).	('BRCA1', 'Gene', (61, 66))	('BRCA2', 'Gene', '675', (127, 132))	('BRCA1', 'Gene', '672', (61, 66))	('variants', 'Var', (49, 57))	('BRCA2', 'Gene', (127, 132))
15022	31464824	not present in the ExAC aggregated population, no dbSNP ID and not present in the LOVD BRCA1 database) was identified: a c.2450-2451 TT deletion resulting in a frameshift and introduction of seven amino acids (894: T-K-S-K-S-H-F :900) before a stop at codon 901 (Figure 1A).	('introduction', 'PosReg', (175, 187))	('c.2450-2451 TT', 'Var', (121, 135))	('BRCA1', 'Gene', '672', (87, 92))	('894: T-K-S-K-S-H-F', 'Var', (210, 228))	('BRCA1', 'Gene', (87, 92))	('frameshift', 'Var', (160, 170))
15029	31464824	A second deleterious variant was identified in BRCA1, a c.C1546T mutation (rs80356898), leading to a premature stop at p.Q516X; this is classified as pathogenic by ClinVar (Supplementary Table 3).	('rs80356898', 'Mutation', 'rs80356898', (75, 85))	('rs80356898', 'Var', (75, 85))	('BRCA1', 'Gene', (47, 52))	('p.Q516X', 'Mutation', 'rs80356898', (119, 126))	('c.C1546T', 'Mutation', 'rs80356898', (56, 64))	('BRCA1', 'Gene', '672', (47, 52))	('c.C1546T', 'Var', (56, 64))	('p.Q516X', 'Var', (119, 126))
15031	31464824	The protein truncates 1347 amino acids prematurely, resulting in significant loss of many functional domains, including RAD50, RAD51, MSH2, ATM, PALB2 and BACH1 binding domains, as well as serine residues that are important phosphorylation targets of proteins involved in the control of DNA damage response and cell cycle control.	('PALB2', 'Gene', '79728', (145, 150))	('DNA', 'cellular_component', 'GO:0005574', ('287', '290'))	('serine', 'Chemical', 'MESH:D012694', (189, 195))	('RAD', 'biological_process', 'GO:1990116', ('127', '130'))	('functional domains', 'MPA', (90, 108))	('loss', 'NegReg', (77, 81))	('RAD50', 'Gene', (120, 125))	('truncates', 'Var', (12, 21))	('MSH2', 'Gene', (134, 138))	('BACH1', 'Gene', (155, 160))	('ATM', 'Gene', '472', (140, 143))	('RAD51', 'Gene', (127, 132))	('RAD50', 'Gene', '10111', (120, 125))	('binding', 'Interaction', (161, 168))	('RAD51', 'Gene', '5888', (127, 132))	('MSH2', 'Gene', '4436', (134, 138))	('phosphorylation', 'biological_process', 'GO:0016310', ('224', '239'))	('binding', 'molecular_function', 'GO:0005488', ('161', '168'))	('PALB2', 'Gene', (145, 150))	('DNA damage response', 'biological_process', 'GO:0006974', ('287', '306'))	('RAD', 'biological_process', 'GO:1990116', ('120', '123'))	('cell cycle control', 'biological_process', 'GO:1901987', ('311', '329'))	('ATM', 'Gene', (140, 143))	('BACH1', 'Gene', '571', (155, 160))	('serine residues', 'MPA', (189, 204))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
15032	31464824	The p.Q516X mutation was present in both available Swedish individuals who had CM; no further information was available regarding other cancers in this family (Figure 2).	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('p.Q516X', 'Var', (4, 11))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('p.Q516X', 'Mutation', 'rs80356898', (4, 11))	('CM', 'Disease', (79, 81))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
15033	31464824	This is the first time BRCA1 mutations have been described in families that were specifically ascertained due to a history of CM.	('mutations', 'Var', (29, 38))	('BRCA1', 'Gene', '672', (23, 28))	('BRCA1', 'Gene', (23, 28))
15040	31464824	In the AMGP cohort, one deleterious germline BRCA1 mutation was identified (c.69_79delGTGTCCCATCT, rs80357696; ClinVar ID: 55676); however, in the tumour sample this allele was lost (with the remaining allele being the wild-type), suggesting that this tumour was not driven by BRCA1 loss.	('BRCA1', 'Gene', (277, 282))	('lost', 'NegReg', (177, 181))	('rs80357696', 'Mutation', 'rs80357696', (99, 109))	('c.69_79delGTGTCCCATCT', 'Var', (76, 97))	('BRCA1', 'Gene', '672', (45, 50))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour', 'Disease', (252, 258))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('rs80357696', 'Var', (99, 109))	('BRCA1', 'Gene', (45, 50))	('c.69_79delGTGTCCCATCT', 'Mutation', 'c.69_79del', (76, 97))	('BRCA1', 'Gene', '672', (277, 282))	('tumour', 'Disease', (147, 153))	('tumour', 'Phenotype', 'HP:0002664', (252, 258))	('tumour', 'Disease', 'MESH:D009369', (252, 258))
15041	31464824	Despite more robust association having been described between UM and deleterious BRCA1 or BRCA2 mutations in breast and/or ovarian family cohorts, we did not observe any deleterious BRCA2 variants in the germline of 47 UM cases from 42 families assessed by WES/WGS.	('variants', 'Var', (188, 196))	('ovarian', 'Disease', (123, 130))	('BRCA1', 'Gene', (81, 86))	('BRCA2', 'Gene', (90, 95))	('BRCA2', 'Gene', '675', (182, 187))	('BRCA2', 'Gene', '675', (90, 95))	('BRCA1', 'Gene', '672', (81, 86))	('mutations', 'Var', (96, 105))	('BRCA2', 'Gene', (182, 187))	('ovarian', 'Disease', 'MESH:D010049', (123, 130))
15042	31464824	These observations are in agreement with a previous screen of 385 UM patients, but not with two other studies, assessing 62 and 143 UM cases for deleterious BRCA2 mutations, respectively.	('patients', 'Species', '9606', (69, 77))	('BRCA2', 'Gene', (157, 162))	('BRCA2', 'Gene', '675', (157, 162))	('mutations', 'Var', (163, 172))
15043	31464824	These latter two studies identified 3 deleterious BRCA2 mutations, and 4 carriers of the Ashkenazi population-specific BRCA2 c.6174delT variant in an Israeli Jewish cohort, respectively.	('c.6174delT', 'Var', (125, 135))	('mutations', 'Var', (56, 65))	('c.6174delT', 'Mutation', 'rs786204278', (125, 135))	('BRCA2', 'Gene', (50, 55))	('BRCA2', 'Gene', (119, 124))	('BRCA2', 'Gene', '675', (50, 55))	('BRCA2', 'Gene', '675', (119, 124))
15044	31464824	Together, these data suggest that BRCA1 or BRCA2 mutations are not a common cause of UM susceptibility, but are associated with increased risk in some carriers.	('BRCA1', 'Gene', '672', (34, 39))	('mutations', 'Var', (49, 58))	('BRCA1', 'Gene', (34, 39))	('BRCA2', 'Gene', (43, 48))	('BRCA2', 'Gene', '675', (43, 48))	('associated', 'Reg', (112, 122))
15045	31464824	A large number of missense variants with an aggregated ExAC population frequency of <0.01, were identified in the CM/UM patients examined in this study (Figure 1A and 1B; Table 1 and Table 2.	('missense variants', 'Var', (18, 35))	('patients', 'Species', '9606', (120, 128))	('CM/UM', 'Disease', (114, 119))
15046	31464824	While 6 of the 33 variants, across nine families, were present in all family members affected with melanoma, all 33 variants were classified as either benign, or of unknown clinical significance, by ClinVar (Supplementary Table 3), which is corroborated by functional analyses compiled by LOVD, when the mutation is present in the database (n=22/33; Supplementary Table 4).	('variants', 'Var', (116, 124))	('variants', 'Var', (18, 26))	('affected', 'Reg', (85, 93))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))
15047	31464824	The recent investigation of BRCA1 missense variants in the RING (exons 2 - 5) and BRCT (exons 15 - 23) domains by saturation genome editing only contained a single of our variants (p.T1726S), which was classified as benign in this study; it is classified as unknown clinical significance in ClinVar (Supplementary Table 3).	('BRCA1', 'Gene', '672', (28, 33))	('p.T1726S', 'Mutation', 'rs80357324', (181, 189))	('BRCA1', 'Gene', (28, 33))	('p.T1726S', 'Var', (181, 189))	('missense variants', 'Var', (34, 51))
15048	31464824	Of potential note, however, is the BRCA1 p.S1465I variant, which has an ExAC population frequency of 0.002 and we observed it in 3 families: 1) in 4/5 CM individuals; 2) in 3/3 CM individuals and 3) in 1/2 CM individuals.	('BRCA1', 'Gene', '672', (35, 40))	('p.S1465I', 'Var', (41, 49))	('BRCA1', 'Gene', (35, 40))	('p.S1465I', 'Mutation', 'rs1800744', (41, 49))
15049	31464824	In the latter family, one member (who has not developed melanoma by >80 years) was homozygous for this variant and had developed bilateral breast cancer in their 50s.	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('bilateral breast cancer', 'Disease', 'MESH:D001943', (129, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('variant', 'Var', (103, 110))	('bilateral breast cancer', 'Disease', (129, 152))
15050	31464824	The BRCA1 p.S1465l variant was predicted as damaging by 2 of the 4 in silico prediction algorithms employed (Supplementary Table 5).	('BRCA1', 'Gene', '672', (4, 9))	('p.S1465l', 'Var', (10, 18))	('BRCA1', 'Gene', (4, 9))
15051	31464824	A number of functional experiments have been performed by different research groups to assess the potential deleterious effects of this variant, as summarised in LOVD (Supplementary Table 4) and reviewed by an expert panel in ClinVar, concluding that this variant is benign, with a neutral effect on BRCA1 function (Supplementary Table 3).	('BRCA1', 'Gene', '672', (300, 305))	('variant', 'Var', (256, 263))	('BRCA1', 'Gene', (300, 305))	('variant', 'Var', (136, 143))	('function', 'MPA', (306, 314))
15052	31464824	Finally, while several individuals carried multiple variants (in BRCA1: p.D167G and an intronic A/G putative splicing variant (rs80358033); and in BRCA2: (i) p.A75P and p.K3326X; (ii) p.V2728I and p.K3326X; (iii) p.S384F and p.A2951T; Table 1 and Table 2), not all melanoma-affected individuals within a family carry both variants.	('p.A2951T', 'Var', (225, 233))	('p.A75P', 'Var', (158, 164))	('p.S384F', 'Mutation', 'rs41293475', (213, 220))	('p.D167G', 'Mutation', 'rs55680408', (72, 79))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('BRCA1', 'Gene', '672', (65, 70))	('BRCA2', 'Gene', '675', (147, 152))	('BRCA1', 'Gene', (65, 70))	('p.V2728I', 'Var', (184, 192))	('p.K3326X', 'Var', (169, 177))	('p.A2951T', 'Mutation', 'rs11571769', (225, 233))	('p.A75P', 'Mutation', 'rs28897701', (158, 164))	('rs80358033);', 'Var', (127, 139))	('splicing', 'biological_process', 'GO:0045292', ('109', '117'))	('p.V2728I', 'Mutation', 'rs28897749', (184, 192))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('melanoma', 'Disease', (265, 273))	('p.S384F', 'Var', (213, 220))	('p.K3326X', 'Mutation', 'rs11571833', (169, 177))	('p.K3326X', 'Var', (197, 205))	('p.D167G', 'Var', (72, 79))	('rs80358033', 'Mutation', 'rs80358033', (127, 137))	('p.K3326X', 'Mutation', 'rs11571833', (197, 205))	('BRCA2', 'Gene', (147, 152))
15053	31464824	The contribution of a combination of variants to melanoma susceptibility is therefore likely minimal.	('variants', 'Var', (37, 45))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
15056	31464824	While we did observe deleterious truncating mutations in BRCA1 in two CM families, we are unable to corroborate a role for these variants in melanoma development, as no tumour samples from carriers were available.	('BRCA1', 'Gene', (57, 62))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('tumour', 'Disease', (169, 175))	('truncating mutations', 'Var', (33, 53))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('BRCA1', 'Gene', '672', (57, 62))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (169, 175))
15057	31464824	Therefore, we sought to examine if deleterious truncating variants in BRCA1 or BRCA2 were present in CM cohorts of the AMGP or TCGA, and if they were associated with a subsequent somatic second hit in the melanoma.	('truncating variants', 'Var', (47, 66))	('BRCA2', 'Gene', '675', (79, 84))	('BRCA1', 'Gene', '672', (70, 75))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('melanoma', 'Disease', (205, 213))	('BRCA1', 'Gene', (70, 75))	('BRCA2', 'Gene', (79, 84))	('associated with', 'Reg', (150, 165))
15058	31464824	In the one instance where a BRCA1 germline frameshift variant was found, no second hit was present in the tumour.	('BRCA1', 'Gene', '672', (28, 33))	('germline frameshift variant', 'Var', (34, 61))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('BRCA1', 'Gene', (28, 33))	('tumour', 'Disease', (106, 112))
15059	31464824	Taken together with previous studies, we conclude that BRCA1 and BRCA2 loss of function mutations are not a common risk factor for CM or UM.	('loss of function', 'NegReg', (71, 87))	('BRCA2', 'Gene', '675', (65, 70))	('BRCA1', 'Gene', '672', (55, 60))	('mutations', 'Var', (88, 97))	('BRCA1', 'Gene', (55, 60))	('BRCA2', 'Gene', (65, 70))
15060	30883995	Germline large deletion of BAP1 and decreased expression in non-tumor choroid in uveal melanoma patients with high risk for inherited cancer Uveal melanoma (UM) is the most common phenotype in patients with germline BAP1 mutation.	('BAP1', 'Gene', (216, 220))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('melanoma', 'Disease', (87, 95))	('large deletion', 'Var', (9, 23))	('cancer', 'Disease', (134, 140))	('tumor choroid in uveal melanoma', 'Disease', 'MESH:C536494', (64, 95))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('BAP1', 'Gene', '8314', (27, 31))	('patients', 'Species', '9606', (193, 201))	('patients', 'Species', '9606', (96, 104))	('BAP1', 'Gene', '8314', (216, 220))	('melanoma', 'Disease', (147, 155))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (141, 155))	('expression', 'MPA', (46, 56))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('BAP1', 'Gene', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('tumor choroid in uveal melanoma', 'Disease', (64, 95))	('decreased', 'NegReg', (36, 45))
15061	30883995	This study aimed to identify selection criteria for BAP1 germline testing and assessed the role of large deletion/duplication and epigenetic inactivation.	('BAP1', 'Gene', (52, 56))	('BAP1', 'Gene', '8314', (52, 56))	('epigenetic inactivation', 'Var', (130, 153))	('large deletion/duplication', 'Var', (99, 125))
15063	30883995	Germline variants in BAP1 were assessed by direct sequencing and large deletion/duplication by multiplex ligation-dependent probe amplification.	('BAP1', 'Gene', (21, 25))	('large deletion/duplication', 'Var', (65, 91))	('BAP1', 'Gene', '8314', (21, 25))
15066	30883995	140 patients were assessed for large deletion/duplication and in one BAP1 whole gene deletion was detected.	('large deletion/duplication', 'Var', (31, 57))	('BAP1', 'Gene', (69, 73))	('patients', 'Species', '9606', (4, 12))	('BAP1', 'Gene', '8314', (69, 73))
15067	30883995	In total, eight patients (4.7%) had pathogenic alterations in BAP1 with the highest frequencies of in patients with a personal/family history of >= 2 BAP1-related cancers 6/16 (38%), age of onset < 35 years 4/21 (19%) and familial UM 6/34 (18%).	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('BAP1', 'Gene', '8314', (150, 154))	('cancers', 'Disease', (163, 170))	('BAP1', 'Gene', (150, 154))	('BAP1', 'Gene', '8314', (62, 66))	('patients', 'Species', '9606', (102, 110))	('familial UM', 'Disease', (222, 233))	('patients', 'Species', '9606', (16, 24))	('BAP1', 'Gene', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('pathogenic', 'Reg', (36, 46))	('alterations', 'Var', (47, 58))	('cancers', 'Disease', 'MESH:D009369', (163, 170))
15069	30883995	UM patients with a strong personal or family history of cancers associated with BAP1, early age of onset and familial UM should be assessed for germline variants in BAP1, including large deletions.	('cancers', 'Disease', (56, 63))	('associated', 'Reg', (64, 74))	('large deletions', 'Var', (181, 196))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('BAP1', 'Gene', (165, 169))	('BAP1', 'Gene', '8314', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('patients', 'Species', '9606', (3, 11))	('BAP1', 'Gene', (80, 84))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('BAP1', 'Gene', '8314', (165, 169))
15073	30883995	Germline mutation in BRCA1 associated protein 1 (BAP1) is associated with a Tumor Predisposition Syndrome (BAP1-TPDS, OMIM #614327) with at least four main cancers: UM, cutaneous melanoma (CM), mesothelioma (MMe), and renal cell carcinoma (RCC).	('BAP1', 'Gene', (49, 53))	('mesothelioma', 'Disease', (194, 206))	('mesothelioma', 'Disease', 'MESH:D008654', (194, 206))	('Tumor Predisposition Syndrome', 'Disease', 'OMIM:614327', (76, 105))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('BRCA1 associated protein 1', 'Gene', '8314', (21, 47))	('MMe', 'Gene', '4311', (208, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('renal cell carcinoma', 'Disease', (218, 238))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (218, 238))	('RCC', 'Disease', (240, 243))	('BAP1', 'Gene', '8314', (107, 111))	('Tumor', 'Phenotype', 'HP:0002664', (76, 81))	('MMe', 'Gene', (208, 211))	('Tumor Predisposition Syndrome', 'Disease', (76, 105))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('Germline mutation', 'Var', (0, 17))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('RCC', 'Disease', 'MESH:C538614', (240, 243))	('BAP1', 'Gene', '8314', (49, 53))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('associated', 'Reg', (58, 68))	('cancers', 'Disease', (156, 163))	('cutaneous melanoma', 'Disease', (169, 187))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (169, 187))	('BAP1', 'Gene', (107, 111))	('BRCA1 associated protein 1', 'Gene', (21, 47))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (169, 187))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (218, 238))
15076	30883995	The vast majority of germline alterations reported in BAP1 have been single base pair changes and small insertions and deletions (INDELs) that could be readily identified by direct sequencing.	('BAP1', 'Gene', '8314', (54, 58))	('alterations', 'Var', (30, 41))	('BAP1', 'Gene', (54, 58))	('insertions', 'Var', (104, 114))
15077	30883995	Large deletions make up a significant percentage of the somatic alterations in BAP1 in UM and other cancers such as MMe, but these have not been investigated as a mechanism of germline inactivation of BAP1 in UM.	('BAP1', 'Gene', '8314', (79, 83))	('MMe', 'Gene', (116, 119))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('BAP1', 'Gene', '8314', (201, 205))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('BAP1', 'Gene', (79, 83))	('BAP1', 'Gene', (201, 205))	('alterations', 'Var', (64, 75))	('MMe', 'Gene', '4311', (116, 119))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('Large deletions', 'Var', (0, 15))	('cancers', 'Disease', (100, 107))
15079	30883995	In addition, germline epigenetic inactivation has been observed in few genes such as PTEN but has also not been investigated as a mechanism for BAP1 inactivation in UM.	('epigenetic inactivation', 'Var', (22, 45))	('BAP1', 'Gene', (144, 148))	('PTEN', 'Gene', (85, 89))	('PTEN', 'Gene', '5728', (85, 89))	('BAP1', 'Gene', '8314', (144, 148))
15080	30883995	The aim of this study was to assess the frequency of germline alterations in BAP1 in UM patients at high-risk for hereditary cancer and determine selection criteria for UM patients for germline testing.	('hereditary cancer', 'Disease', 'MESH:D009369', (114, 131))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('hereditary cancer', 'Disease', (114, 131))	('BAP1', 'Gene', '8314', (77, 81))	('patients', 'Species', '9606', (172, 180))	('germline alterations', 'Var', (53, 73))	('BAP1', 'Gene', (77, 81))
15087	30883995	All patients with no detected germline BAP1 sequence mutations were assessed for deletions and duplications utilizing multiplex ligation-dependent probe amplification (MLPA) analysis.	('deletions', 'Var', (81, 90))	('mutations', 'Var', (53, 62))	('BAP1', 'Gene', '8314', (39, 43))	('patients', 'Species', '9606', (4, 12))	('BAP1', 'Gene', (39, 43))
15091	30883995	The variant c.2057-4G>T within 4 base pairs from exon/intron boundary was further assessed by RT-PCR of RNA extracted from peripheral blood leukocytes and/or tumor using primers spanning the predicted spliced exons (5'-ACCCAAGGAGCTGCTGGC-3' and 5'-CGTTTCCGCCGGTCAGGCTT -3').	('tumor', 'Disease', (158, 163))	('c.2057-4G>T', 'Mutation', 'rs149499021', (12, 23))	('c.2057-4G>T', 'Var', (12, 23))	('RNA', 'cellular_component', 'GO:0005562', ('104', '107'))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
15100	30883995	No tumor tissue was available for further study of the functional impact of the variant in the 3'UTR region on gene expression of the gene.	('gene expression', 'biological_process', 'GO:0010467', ('111', '126'))	('tumor', 'Disease', (3, 8))	('variant', 'Var', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
15101	30883995	Five variants (rs139414598, rs372474338, rs141917607, rs28997577, and rs146661777) were detected in a family with a truncating BAP1 mutation p. Gly267*.	('rs146661777', 'Var', (70, 81))	('BAP1', 'Gene', (127, 131))	('BAP1', 'Gene', '8314', (127, 131))	('rs372474338', 'Mutation', 'rs372474338', (28, 39))	('p. Gly267*', 'Var', (141, 151))	('rs28997577', 'Mutation', 'rs28997577', (54, 64))	('rs141917607', 'Mutation', 'rs141917607', (41, 52))	('rs372474338', 'Var', (28, 39))	('rs146661777', 'Mutation', 'rs146661777', (70, 81))	('rs28997577', 'Var', (54, 64))	('rs139414598', 'Var', (15, 26))	('rs141917607', 'Var', (41, 52))	('rs139414598', 'Mutation', 'rs139414598', (15, 26))
15102	30883995	Four of these (rs28997577, rs139414598, rs141917607, and rs372474338) were also identified in a patient with familial UM but were not detected in the patient's father who also has UM indicating that they are benign.	('patient', 'Species', '9606', (150, 157))	('rs139414598', 'Mutation', 'rs139414598', (27, 38))	('rs141917607', 'Mutation', 'rs141917607', (40, 51))	('rs139414598', 'Var', (27, 38))	('rs28997577', 'Mutation', 'rs28997577', (15, 25))	('rs28997577', 'Var', (15, 25))	('rs141917607', 'Var', (40, 51))	('patient', 'Species', '9606', (96, 103))	('rs372474338', 'Mutation', 'rs372474338', (57, 68))	('rs372474338', 'Var', (57, 68))
15103	30883995	Out of the 161 patients assessed for large deletion/duplication in BAP1 140 passed the quality control measures.	('patients', 'Species', '9606', (15, 23))	('BAP1', 'Gene', '8314', (67, 71))	('large deletion/duplication', 'Var', (37, 63))	('BAP1', 'Gene', (67, 71))
15104	30883995	Of those, one patient showed a large deletion affecting all BAP1 probes (Figure 1).	('patient', 'Species', '9606', (14, 21))	('BAP1', 'Gene', '8314', (60, 64))	('BAP1', 'Gene', (60, 64))	('deletion', 'Var', (37, 45))
15110	30883995	Of the remaining two patients one was a male with a nonsense mutation, c.15G>A, cDNA.487G>A, p.W5*.	('p.W5*', 'Var', (93, 98))	('p.W5*', 'SUBSTITUTION', 'None', (93, 98))	('patients', 'Species', '9606', (21, 29))	('cDNA.487G>A', 'Mutation', 'c..487G>A', (80, 91))	('c.15G>A', 'Var', (71, 78))	('c.15G>A', 'Mutation', 'rs778325523', (71, 78))
15117	30883995	Of the 8 patients with pathogenic BAP1 alterations, only one patient had a confirmed metastasis.	('patients', 'Species', '9606', (9, 17))	('patient', 'Species', '9606', (61, 68))	('BAP1', 'Gene', (34, 38))	('alterations', 'Var', (39, 50))	('pathogenic', 'Reg', (23, 33))	('patient', 'Species', '9606', (9, 16))	('BAP1', 'Gene', '8314', (34, 38))
15129	30883995	We investigated BAP1 promotor methylation as a potential mechanism for epigenetic inactivation in 19 subjects with sufficient tumor and non-tumor tissues including the proband 7002 with downregulation of BAP1 in non-tumor choroid.	('tumor', 'Disease', (216, 221))	('tumor choroid', 'Disease', 'MESH:D002830', (216, 229))	('tumor', 'Disease', (140, 145))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('BAP1', 'Gene', '8314', (204, 208))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('BAP1', 'Gene', '8314', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('BAP1', 'Gene', (204, 208))	('BAP1', 'Gene', (16, 20))	('epigenetic inactivation', 'Var', (71, 94))	('downregulation', 'NegReg', (186, 200))	('tumor choroid', 'Disease', (216, 229))	('tumor', 'Disease', (126, 131))
15131	30883995	The reported frequencies of germline pathogenic and likely pathogenic variants in BAP1 vary between 1.6-3% in the unselected UM patient population.	('variants', 'Var', (70, 78))	('BAP1', 'Gene', (82, 86))	('BAP1', 'Gene', '8314', (82, 86))	('patient', 'Species', '9606', (128, 135))
15132	30883995	Our study was designed to identify patients who should be prioritized for germline BAP1 mutation testing.	('BAP1', 'Gene', '8314', (83, 87))	('mutation', 'Var', (88, 96))	('BAP1', 'Gene', (83, 87))	('patients', 'Species', '9606', (35, 43))
15133	30883995	This study focused on patients at high-risk for germline BAP1 mutations, including those with early onset of UM (<35 yrs) and those with strong personal and/or family history of cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('patients', 'Species', '9606', (22, 30))	('BAP1', 'Gene', '8314', (57, 61))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('germline', 'Var', (48, 56))	('BAP1', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
15134	30883995	To our surprise, even for these high-risk patients only 4.7% (8/172) had detectable pathogenic alterations in BAP1.	('patients', 'Species', '9606', (42, 50))	('alterations', 'Var', (95, 106))	('BAP1', 'Gene', '8314', (110, 114))	('BAP1', 'Gene', (110, 114))
15135	30883995	The highest frequency of germline BAP1 pathogenic alterations was identified in UM patients with >=2 personal or family history of cancers associated with BAP1-TPDS (36%, 6/16) followed by those with young age of onset of their tumors (19%, 4/21) and those with familial UM (18%, 6/34).	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('BAP1', 'Gene', '8314', (34, 38))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('BAP1', 'Gene', '8314', (155, 159))	('cancers', 'Disease', (131, 138))	('BAP1', 'Gene', (34, 38))	('alterations', 'Var', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('BAP1', 'Gene', (155, 159))	('tumors', 'Disease', (228, 234))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('patients', 'Species', '9606', (83, 91))	('tumors', 'Disease', 'MESH:D009369', (228, 234))
15136	30883995	None of the 53 UM patients with personal or family history of CM without personal or family history RCC and MMe had pathogenic variants in BAP1.	('variants', 'Var', (127, 135))	('MMe', 'Gene', (108, 111))	('BAP1', 'Gene', '8314', (139, 143))	('pathogenic', 'Reg', (116, 126))	('patients', 'Species', '9606', (18, 26))	('BAP1', 'Gene', (139, 143))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('MMe', 'Gene', '4311', (108, 111))
15138	30883995	Of note, we have previously tested germline mutations in CDK4 and CDKN2A two genes associated with familial melanoma and did not identify any pathogenic variants in a cohort of 53 high-risk UM patients.	('patients', 'Species', '9606', (193, 201))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('CDK4', 'Gene', (57, 61))	('CDKN2A', 'Gene', '1029', (66, 72))	('CDK4', 'Gene', '1019', (57, 61))	('associated', 'Reg', (83, 93))	('tested', 'Reg', (28, 34))	('CDK', 'molecular_function', 'GO:0004693', ('57', '60'))	('germline mutations', 'Var', (35, 53))	('familial melanoma', 'Disease', (99, 116))	('CDKN2A', 'Gene', (66, 72))	('familial melanoma', 'Disease', 'MESH:C562393', (99, 116))
15139	30883995	Also, none of the 66 patients with personal or family histories of cancers other than the four main cancers associated with BAP1 had pathogenic mutations in BAP1, which again suggests the possibility of additional candidate genes/phenotypes.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('BAP1', 'Gene', '8314', (124, 128))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancers', 'Disease', (67, 74))	('BAP1', 'Gene', (157, 161))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('BAP1', 'Gene', (124, 128))	('patients', 'Species', '9606', (21, 29))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('BAP1', 'Gene', '8314', (157, 161))	('mutations', 'Var', (144, 153))	('cancers', 'Disease', (100, 107))
15140	30883995	One of the important findings in our study is that 1/8 (13%) of the germline pathogenic variants detected in BAP1 was due to a whole gene deletion.	('BAP1', 'Gene', (109, 113))	('variants', 'Var', (88, 96))	('BAP1', 'Gene', '8314', (109, 113))	('due to', 'Reg', (118, 124))
15141	30883995	Although large deletions have been reported as a common somatic alterations in BAP1 in UM and other cancers, to our knowledge this is only the second report of germline whole-gene deletion of BAP1 in a UM patient.	('deletion', 'Var', (180, 188))	('BAP1', 'Gene', '8314', (79, 83))	('BAP1', 'Gene', (192, 196))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('BAP1', 'Gene', '8314', (192, 196))	('BAP1', 'Gene', (79, 83))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('deletions', 'Var', (15, 24))	('patient', 'Species', '9606', (205, 212))	('cancers', 'Disease', (100, 107))
15143	30883995	It is worth noting that in this study direct sequencing had only 87.5% sensitivity for detection of germline alterations in BAP1 in patients with UM.	('alterations', 'Var', (109, 120))	('patients', 'Species', '9606', (132, 140))	('BAP1', 'Gene', '8314', (124, 128))	('BAP1', 'Gene', (124, 128))
15145	30883995	Proper counseling of patients and physicians for the sensitivity of the assay used for detection of alterations in BAP1 highlighting the limitation of direct sequencing will be crucial.	('patients', 'Species', '9606', (21, 29))	('BAP1', 'Gene', '8314', (115, 119))	('BAP1', 'Gene', (115, 119))	('alterations', 'Var', (100, 111))
15146	30883995	The deletion in the patient included two genes in the vicinity of BAP1, DNAH1 and PHF7.	('DNAH1', 'Gene', (72, 77))	('BAP1', 'Gene', '8314', (66, 70))	('DNAH1', 'Gene', '25981', (72, 77))	('PHF7', 'Gene', (82, 86))	('BAP1', 'Gene', (66, 70))	('patient', 'Species', '9606', (20, 27))	('deletion', 'Var', (4, 12))	('included', 'Reg', (28, 36))	('PHF7', 'Gene', '51533', (82, 86))
15147	30883995	PHF7 and DNAH1 are both important in spermatogenesis with no association with cancer so the phenotype is caused mostly by deletion of BAP1.	('BAP1', 'Gene', (134, 138))	('DNAH1', 'Gene', '25981', (9, 14))	('PHF7', 'Gene', '51533', (0, 4))	('DNAH1', 'Gene', (9, 14))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('spermatogenesis', 'biological_process', 'GO:0007283', ('37', '52'))	('PHF7', 'Gene', (0, 4))	('deletion', 'Var', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('caused', 'Reg', (105, 111))	('BAP1', 'Gene', '8314', (134, 138))
15148	30883995	The patient with whole gene deletion was diagnosed at age 16 years which has been reported as the youngest age of onset of UM in patients with pathogenic mutations in BAP1.	('patients', 'Species', '9606', (129, 137))	('patient', 'Species', '9606', (4, 11))	('BAP1', 'Gene', '8314', (167, 171))	('mutations', 'Var', (154, 163))	('BAP1', 'Gene', (167, 171))	('patient', 'Species', '9606', (129, 136))
15150	30883995	A potential explanation is germline epigenetic inactivation of BAP1 in these subjects.	('BAP1', 'Gene', (63, 67))	('BAP1', 'Gene', '8314', (63, 67))	('epigenetic inactivation', 'Var', (36, 59))
15152	30883995	This suggests other potential mechanisms for germline epigenetic regulation of BAP1 such as alterations in miRNA and/or an enhancer element.	('BAP1', 'Gene', '8314', (79, 83))	('epigenetic regulation', 'Var', (54, 75))	('miRNA', 'MPA', (107, 112))	('BAP1', 'Gene', (79, 83))	('alterations', 'Reg', (92, 103))	('regulation', 'biological_process', 'GO:0065007', ('65', '75'))	('enhancer', 'PosReg', (123, 131))
15155	30883995	A recent study showed that variants in the G-quadruplexes in the BAP1 promoter region strongly regulate its expression.	('variants', 'Var', (27, 35))	('BAP1', 'Gene', '8314', (65, 69))	('regulate', 'Reg', (95, 103))	('BAP1', 'Gene', (65, 69))	('expression', 'MPA', (108, 118))
15157	30883995	Further investigation using next generation sequencing strategies could identify variants in the 5'UTR of BAP1.	('BAP1', 'Gene', '8314', (106, 110))	('variants', 'Var', (81, 89))	('BAP1', 'Gene', (106, 110))
15158	30883995	Identification of high frequency of benign germline variants and VUS in BAP1 in UM patients highlights the importance of carrying out germline genetic testing through clinical geneticists/genetic counselors, as these professionals are more capable of counseling patients and families with benign variants and VUS.	('BAP1', 'Gene', '8314', (72, 76))	('variants', 'Var', (52, 60))	('BAP1', 'Gene', (72, 76))	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (262, 270))
15159	30883995	It has been suggested that germline BAP1 mutations are preferentially associated with metastatic UM.	('mutations', 'Var', (41, 50))	('metastatic UM', 'Disease', (86, 99))	('BAP1', 'Gene', '8314', (36, 40))	('associated', 'Reg', (70, 80))	('BAP1', 'Gene', (36, 40))
15160	30883995	In a larger follow up study the same group did not confirm such association but suggested that tumors from germline BAP1 mutations carriers present with relatively larger tumors, average largest tumor diameter of 15.9 mm, and a high frequency, 75%, of ciliary body involvement, two criteria that have been linked to aggressive diseases.	('tumor', 'Disease', (195, 200))	('mutations', 'Var', (121, 130))	('aggressive diseases', 'Disease', (316, 335))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('ciliary body involvement', 'CPA', (252, 276))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('BAP1', 'Gene', '8314', (116, 120))	('larger', 'PosReg', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumors', 'Disease', (171, 177))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Disease', (95, 100))	('BAP1', 'Gene', (116, 120))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('aggressive diseases', 'Disease', 'MESH:D001523', (316, 335))
15161	30883995	Our results do not support or dispute the association of germline BAP1 mutations with aggressive disease and further larger studies will be needed.	('germline', 'Var', (57, 65))	('BAP1', 'Gene', '8314', (66, 70))	('association', 'Interaction', (42, 53))	('BAP1', 'Gene', (66, 70))	('mutations', 'Var', (71, 80))	('aggressive disease', 'Disease', 'MESH:D001523', (86, 104))	('aggressive disease', 'Disease', (86, 104))
15162	30883995	However, the strong evidence of association of somatic biallelic inactivation of BAP1 with aggressive UM warrants managing these patients as high-risk for metastasis.	('aggressive UM', 'Disease', (91, 104))	('BAP1', 'Gene', (81, 85))	('patients', 'Species', '9606', (129, 137))	('biallelic inactivation', 'Var', (55, 77))	('BAP1', 'Gene', '8314', (81, 85))	('association', 'Interaction', (32, 43))
15163	30883995	In conclusion, our results suggest that in UM patients, germline BAP1 mutation testing should be prioritized to 1) those with familial UM; 2) those with early age of onset of their tumors (< 35 years old); and 3) those with personal or family history of at least one cancer associated with BAP1-TPDS such as MMe or RCC.	('BAP1', 'Gene', (290, 294))	('patients', 'Species', '9606', (46, 54))	('BAP1', 'Gene', '8314', (65, 69))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('BAP1', 'Gene', (65, 69))	('MMe', 'Gene', '4311', (308, 311))	('RCC', 'Disease', 'MESH:C538614', (315, 318))	('RCC', 'Disease', (315, 318))	('BAP1', 'Gene', '8314', (290, 294))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('mutation', 'Var', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('MMe', 'Gene', (308, 311))
15164	30883995	Assessment for large deletions should be included in testing for germline alterations in BAP1.	('BAP1', 'Gene', '8314', (89, 93))	('BAP1', 'Gene', (89, 93))	('deletions', 'Var', (21, 30))
15165	30883995	Finally, epigenetic germline inactivation of BAP1 and alterations in additional candidate genes could explain the hereditary predisposition of a subset of UM patients to cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('explain', 'Reg', (102, 109))	('BAP1', 'Gene', (45, 49))	('epigenetic germline inactivation', 'Var', (9, 41))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('alterations', 'Var', (54, 65))	('patients', 'Species', '9606', (158, 166))	('BAP1', 'Gene', '8314', (45, 49))
15170	30783010	Biochemical and biophysical assays revealed that disruption of the autoinhibited conformation destabilized and activated the TrioC module in vitro.	('TrioC module', 'Protein', (125, 137))	('destabilized', 'NegReg', (94, 106))	('TrioC', 'Chemical', '-', (125, 130))	('disruption', 'Var', (49, 59))	('activated', 'PosReg', (111, 120))
15171	30783010	Finally, mutations in the DH-PH interface found in cancer patients activated TrioC and, in the context of full-length Trio, led to increased abundance of guanosine triphosphate-bound RhoA (RhoA GTP) in human cells.	('abundance', 'MPA', (141, 150))	('RhoA', 'Gene', '387', (183, 187))	('mutations', 'Var', (9, 18))	('human', 'Species', '9606', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('RhoA', 'Gene', (189, 193))	('GTP', 'Chemical', 'MESH:D006160', (194, 197))	('activated', 'PosReg', (67, 76))	('increased', 'PosReg', (131, 140))	('DH-PH interface', 'Gene', (26, 41))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('RhoA', 'Gene', '387', (189, 193))	('TrioC', 'MPA', (77, 82))	('patients', 'Species', '9606', (58, 66))	('TrioC', 'Chemical', '-', (77, 82))	('RhoA', 'Gene', (183, 187))	('cancer', 'Disease', (51, 57))	('guanosine triphosphate', 'Chemical', 'MESH:D006160', (154, 176))	('DH', 'Chemical', '-', (26, 28))
15172	30783010	These mutations increase mitogenic signaling through the RhoA axis and, therefore, may represent cancer drivers operating in a Galphaq/11-independent manner.	('mitogenic signaling', 'MPA', (25, 44))	('cancer', 'Disease', (97, 103))	('signaling', 'biological_process', 'GO:0023052', ('35', '44'))	('increase', 'PosReg', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('RhoA', 'Gene', (57, 61))	('RhoA', 'Gene', '387', (57, 61))	('mutations', 'Var', (6, 15))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
15177	30783010	In >80% of cases, a constitutively active mutation in Galphaq/11 drives the progression of uveal melanoma (UM) in a Trio dependent fashion.	('UM', 'Phenotype', 'HP:0007716', (107, 109))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('uveal melanoma', 'Disease', 'MESH:C536494', (91, 105))	('mutation', 'Var', (42, 50))	('uveal melanoma', 'Phenotype', 'HP:0007716', (91, 105))	('uveal melanoma', 'Disease', (91, 105))	('Galphaq/11', 'Gene', (54, 64))
15187	30783010	Furthermore, we demonstrated that mutations found in the TrioC alphaN region in cancer patients not only activate the TrioC fragment in GEF assays, but also full-length Trio in human cells, allowing for sustained signaling through RhoA.	('allowing', 'Reg', (190, 198))	('RhoA', 'Gene', '387', (231, 235))	('TrioC fragment', 'MPA', (118, 132))	('human', 'Species', '9606', (177, 182))	('TrioC', 'Chemical', '-', (57, 62))	('cancer', 'Disease', (80, 86))	('sustained signaling', 'MPA', (203, 222))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('TrioC', 'Gene', (57, 62))	('GEF', 'Gene', (136, 139))	('activate', 'PosReg', (105, 113))	('signaling', 'biological_process', 'GO:0023052', ('213', '222'))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('TrioC', 'Chemical', '-', (118, 123))	('RhoA', 'Gene', (231, 235))	('GEF', 'Gene', '6654', (136, 139))	('alphaN', 'Chemical', '-', (63, 69))	('GEF', 'molecular_function', 'GO:0005085', ('136', '139'))	('patients', 'Species', '9606', (87, 95))	('mutations', 'Var', (34, 43))
15199	30783010	1C, inset) packs against the side chain of Pro2066 in alpha3 of the DH domain, enabling closer proximity of the TrioC DH and PH domains (Fig.	('TrioC', 'Chemical', '-', (112, 117))	('DH', 'Chemical', '-', (68, 70))	('proximity', 'Interaction', (95, 104))	('DH', 'Chemical', '-', (118, 120))	('Pro2066', 'Var', (43, 50))
15200	30783010	Meanwhile, TrioC-Arg2150 forms an interdomain salt bridge with Glu2069 in alpha3, which is substituted by Ala817 in Dbs.	('Glu2069', 'Var', (63, 70))	('Dbs', 'Gene', (116, 119))	('TrioC-Arg2150', 'Var', (11, 24))	('Glu2069', 'Chemical', '-', (63, 70))	('Ala817', 'Chemical', '-', (106, 112))	('Dbs', 'Gene', '23263', (116, 119))	('TrioC-Arg2150', 'Chemical', '-', (11, 24))
15201	30783010	The side chain of Met2146 also bridges the DH and PH domains by forming a hydrogen bond with the side chain of Arg2150 and hydrophobic contacts with the DH domain.	('forming', 'Reg', (64, 71))	('DH', 'Chemical', '-', (43, 45))	('hydrogen', 'Chemical', 'MESH:D006859', (74, 82))	('hydrophobic contacts', 'CPA', (123, 143))	('Met2146', 'Var', (18, 25))	('hydrogen bond', 'MPA', (74, 87))	('DH', 'Chemical', '-', (153, 155))	('Arg2150', 'Chemical', '-', (111, 118))	('Met2146', 'Chemical', '-', (18, 25))	('Arg2150', 'Var', (111, 118))
15202	30783010	These interactions are broken upon the binding of Galphaq GDP AlF4-, as seen in the active p63RhoGEF structure (Fig.	('Galphaq GDP', 'Var', (50, 61))	('binding', 'molecular_function', 'GO:0005488', ('39', '46'))	('GDP', 'Chemical', 'MESH:D006153', (58, 61))	('interactions', 'Interaction', (6, 18))	('RhoGEF', 'molecular_function', 'GO:0005089', ('94', '100'))	('binding', 'Interaction', (39, 46))	('AlF4', 'Chemical', 'MESH:C050992', (62, 66))
15203	30783010	Glu2069, Gly2149, and Arg2150 are invariant in the TrioC subfamily, but not conserved in Dbs or the closely related N-terminal DH/PH modules of Trio and Kalirin (fig.	('Gly2149', 'Var', (9, 16))	('Arg2150', 'Var', (22, 29))	('DH', 'Chemical', '-', (127, 129))	('Kalirin', 'Gene', (153, 160))	('Glu2069', 'Chemical', '-', (0, 7))	('TrioC', 'Chemical', '-', (51, 56))	('Kalirin', 'Gene', '8997', (153, 160))	('Dbs', 'Gene', '23263', (89, 92))	('Dbs', 'Gene', (89, 92))	('Glu2069', 'Var', (0, 7))	('Gly2149', 'Chemical', '-', (9, 16))	('Arg2150', 'Chemical', '-', (22, 29))
15204	30783010	Met2146, however, is conserved as a hydrophobic residue in most RhoGEFs that forms direct contacts with Switch II of bound GTPases.	('Met2146', 'Var', (0, 7))	('GEF', 'Gene', (67, 70))	('Met2146', 'Chemical', '-', (0, 7))	('contacts', 'Interaction', (90, 98))	('GEF', 'Gene', '6654', (67, 70))	('GTPases', 'Protein', (123, 130))	('GTP', 'Chemical', 'MESH:D006160', (123, 126))
15205	30783010	Although not as highly conserved among TrioC subfamily members, residues 2204-2212 in the beta3-beta4 of the PH domain loop bury the Arg2150-Glu2069 salt bridge and form additional interactions with alpha3 in the DH domain, including a hydrogen bond between the hydroxyl of Ser2208 and side chain of Glu2069.	('hydrogen bond', 'Reg', (236, 249))	('interactions', 'Interaction', (181, 193))	('residues 2204-2212', 'Var', (64, 82))	('hydrogen', 'Chemical', 'MESH:D006859', (236, 244))	('DH', 'Chemical', '-', (213, 215))	('Ser', 'cellular_component', 'GO:0005790', ('274', '277'))	('Arg2150', 'Chemical', '-', (133, 140))	('Ser2208', 'Chemical', '-', (274, 281))	('Arg2150-Glu2069', 'Var', (133, 148))	('Glu2069', 'Chemical', '-', (141, 148))	('Glu2069', 'Chemical', '-', (300, 307))	('TrioC', 'Chemical', '-', (39, 44))	('alpha3', 'Protein', (199, 205))
15206	30783010	In the active p63RhoGEF structure, beta3-beta4 is disordered (Fig.	('disordered', 'Disease', 'MESH:D030342', (50, 60))	('p63RhoGEF', 'Var', (14, 23))	('RhoGEF', 'molecular_function', 'GO:0005089', ('17', '23'))	('disordered', 'Disease', (50, 60))	('beta3-beta4', 'Protein', (35, 46))
15211	30783010	This allows Glu2069 and Met2146, which interact directly with RhoA in the activated p63RhoGEF structure, to instead directly engage Arg2150.	('Glu2069', 'Chemical', '-', (12, 19))	('RhoA', 'Gene', '387', (62, 66))	('RhoGEF', 'molecular_function', 'GO:0005089', ('87', '93'))	('Glu2069', 'Var', (12, 19))	('Met2146', 'Var', (24, 31))	('Met2146', 'Chemical', '-', (24, 31))	('engage', 'Reg', (125, 131))	('Arg2150', 'Var', (132, 139))	('RhoA', 'Gene', (62, 66))	('Arg2150', 'Chemical', '-', (132, 139))
15214	30783010	We hypothesized that variants which disrupted important contacts in the DH-PH interface would be more sensitive to thermal denaturation [meaning a lower melting temperature (Tm) relative to wild type (WT)], as measured by differential scanning fluorimetry (DSF), and display increased GEF activity.	('variants', 'Var', (21, 29))	('increased', 'PosReg', (275, 284))	('GEF', 'Gene', (285, 288))	('lower', 'NegReg', (147, 152))	('sensitive', 'MPA', (102, 111))	('activity', 'MPA', (289, 297))	('GEF', 'Gene', '6654', (285, 288))	('GEF', 'molecular_function', 'GO:0005085', ('285', '288'))	('DH', 'Chemical', '-', (72, 74))	('melting temperature', 'MPA', (153, 172))
15215	30783010	Thus, we introduced site-directed mutations into the alpha6-alphaN hinge, the beta3-beta4 loop, and alpha3.	('alpha6-alphaN', 'Protein', (53, 66))	('alphaN', 'Chemical', '-', (60, 66))	('mutations', 'Var', (34, 43))
15216	30783010	E2069A, M2146A, and S2208A variant proteins exhibited lower melting points by 3 to 7  C, whereas R2150A and F2207A (beta3-beta4 loop) variants were 1  C more thermostable than was WT TrioC (Table 2).	('proteins', 'Protein', (35, 43))	('M2146A', 'Mutation', 'p.M2146A', (8, 14))	('S2208A', 'Var', (20, 26))	('F2207A', 'Var', (108, 114))	('M2146A', 'Var', (8, 14))	('F2207A', 'Mutation', 'p.F2207A', (108, 114))	('thermostable', 'MPA', (158, 170))	('lower', 'NegReg', (54, 59))	('E2069A', 'Var', (0, 6))	('to 7', 'Species', '1214577', (80, 84))	('S2208A', 'Mutation', 'p.S2208A', (20, 26))	('R2150A', 'Mutation', 'p.R2150A', (97, 103))	('TrioC', 'Chemical', '-', (183, 188))	('melting points', 'MPA', (60, 74))	('R2150A', 'Var', (97, 103))	('more', 'PosReg', (153, 157))	('E2069A', 'Mutation', 'p.E2069A', (0, 6))
15218	30783010	The G2149I variant, replacing the position with the cognate residue in Dbs, reduced the Tm over 6  C and displayed 2-fold higher exchange relative to WT.	('G2149I', 'Mutation', 'p.G2149I', (4, 10))	('Tm over 6  C', 'MPA', (88, 100))	('G2149I', 'Var', (4, 10))	('higher', 'PosReg', (122, 128))	('Dbs', 'Gene', (71, 74))	('reduced', 'NegReg', (76, 83))	('Dbs', 'Gene', '23263', (71, 74))	('exchange', 'MPA', (129, 137))
15219	30783010	The E2069R/R2150E double mutant, designed to test the importance of the salt bridge, destabilized protein 8  C and activated 3-fold.	('R2150E', 'Mutation', 'p.R2150E', (11, 17))	('E2069R', 'SUBSTITUTION', 'None', (4, 10))	('activated', 'MPA', (115, 124))	('E2069R', 'Var', (4, 10))	('destabilized', 'NegReg', (85, 97))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('protein', 'Protein', (98, 105))
15220	30783010	The single R2150E mutant was not significantly different from WT in terms of its nucleotide exchange activity or thermostability, whereas E2069R yielded insoluble protein and could not be assayed.	('R2150E', 'Var', (11, 17))	('E2069R', 'Mutation', 'p.E2069R', (138, 144))	('R2150E', 'Mutation', 'p.R2150E', (11, 17))	('insoluble protein', 'MPA', (153, 170))	('nucleotide exchange activity', 'MPA', (81, 109))	('protein', 'cellular_component', 'GO:0003675', ('163', '170'))	('E2069R', 'Var', (138, 144))
15221	30783010	Thus, the E2069R substitution is most likely responsible for the activation exhibited by the E2069R/R2150E double mutant, but it is only stable in the context of a salt bridge swap.	('R2150E', 'Mutation', 'p.R2150E', (100, 106))	('E2069R', 'SUBSTITUTION', 'None', (10, 16))	('E2069R', 'Mutation', 'p.E2069R', (93, 99))	('E2069R', 'SUBSTITUTION', 'None', (93, 99))	('E2069R', 'Var', (10, 16))	('E2069R', 'Var', (93, 99))	('E2069R', 'Mutation', 'p.E2069R', (10, 16))	('activation', 'PosReg', (65, 75))
15222	30783010	We conclude from these results that mutations that introduced bulk or collisions in the closed interface (such as G2149I and E2069R/R2150E) had a greater ability to destabilize and activate the DH/PH module compared to mutations that simply remove contacts (such as R2150A).	('DH', 'Chemical', '-', (194, 196))	('E2069R', 'SUBSTITUTION', 'None', (125, 131))	('R2150E', 'Mutation', 'p.R2150E', (132, 138))	('activate', 'PosReg', (181, 189))	('G2149I', 'Mutation', 'p.G2149I', (114, 120))	('destabilize', 'NegReg', (165, 176))	('G2149I', 'Var', (114, 120))	('DH/PH module', 'Enzyme', (194, 206))	('E2069R', 'Var', (125, 131))	('R2150A', 'Mutation', 'p.R2150A', (266, 272))
15223	30783010	Analysis of the cBioPortal database revealed that truncations 2152Delta (stop codon after residue 2152) and 2153Delta occur in human cancer patients.	('human', 'Species', '9606', (127, 132))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('patients', 'Species', '9606', (140, 148))	('2153Delta', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
15224	30783010	2153Delta removes the bulk of the PH domain yet leaves alphaN intact.	('2153Delta', 'Var', (0, 9))	('removes', 'NegReg', (10, 17))	('bulk', 'MPA', (22, 26))	('alphaN', 'MPA', (55, 61))	('alphaN', 'Chemical', '-', (55, 61))	('PH domain', 'MPA', (34, 43))
15225	30783010	This variant activated the DH/PH module 3-fold relative to wild type TrioC (Table 2).	('TrioC', 'Chemical', '-', (69, 74))	('DH', 'Chemical', '-', (27, 29))	('variant', 'Var', (5, 12))	('activated', 'PosReg', (13, 22))	('DH/PH module', 'Enzyme', (27, 39))
15226	30783010	To assess the consequences of further truncation, we assayed 2147Delta, which removes all of alphaN and found that it was 14-fold activated.	('alphaN', 'Protein', (93, 99))	('alphaN', 'Chemical', '-', (93, 99))	('2147Delta', 'Var', (61, 70))
15227	30783010	A final truncation, 2143Delta, which in addition removes a portion of alpha6, had ~5-fold lower GEF activity than WT, likely due to loss of RhoA binding residues.	('GEF', 'Gene', (96, 99))	('alpha6', 'Protein', (70, 76))	('loss', 'NegReg', (132, 136))	('binding', 'molecular_function', 'GO:0005488', ('145', '152'))	('GEF', 'Gene', '6654', (96, 99))	('removes', 'NegReg', (49, 56))	('GEF', 'molecular_function', 'GO:0005085', ('96', '99'))	('lower', 'NegReg', (90, 95))	('2143Delta', 'Var', (20, 29))	('RhoA', 'Gene', (140, 144))	('RhoA', 'Gene', '387', (140, 144))
15228	30783010	The cBioPortal database also contains the G2149W, R2150Q, and R2150W variants, which we hypothesized would be activating due to steric or electrostatic disruption of the autoinhibited DH-PH interface.	('G2149W', 'Mutation', 'p.G2149W', (42, 48))	('R2150Q', 'Var', (50, 56))	('R2150Q', 'Mutation', 'rs182423419', (50, 56))	('DH', 'Chemical', '-', (184, 186))	('activating', 'PosReg', (110, 120))	('R2150W', 'Mutation', 'rs1264087949', (62, 68))	('G2149W', 'Var', (42, 48))	('R2150W', 'Var', (62, 68))
15230	30783010	We also found that G2149W and R2150Q could be activated by Galphaq in an AlF4--dependent manner in the same assay format, although these two variants were activated to a lesser extent (~2 fold) than TrioC WT (~3-fold).	('TrioC', 'Chemical', '-', (199, 204))	('G2149W', 'Var', (19, 25))	('R2150Q', 'Var', (30, 36))	('R2150Q', 'Mutation', 'rs182423419', (30, 36))	('AlF4', 'Chemical', 'MESH:C050992', (73, 77))	('G2149W', 'Mutation', 'p.G2149W', (19, 25))
15236	30783010	S3C), the regions in close proximity to the R2150W mutation exchanged backbone hydrogens more than in WT, and residues in alpha3 also display a marked increase in exchange, supporting the notion that these two regions directly interact in the autoinhibited, basal state.	('exchanged', 'Reg', (60, 69))	('backbone hydrogens', 'MPA', (70, 88))	('R2150W', 'Mutation', 'rs1264087949', (44, 50))	('R2150W', 'Var', (44, 50))	('hydrogens', 'Chemical', 'MESH:D006859', (79, 88))
15237	30783010	Thus we compared the activity of the cancer-associated variants, G2149W, R2150Q, and R2150W, to WT in the context of human Trio (residues 61-3097) under serum starved conditions to detect inherent Trio activity.	('R2150Q', 'Mutation', 'rs182423419', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('G2149W', 'Var', (65, 71))	('human', 'Species', '9606', (117, 122))	('cancer', 'Disease', (37, 43))	('G2149W', 'Mutation', 'p.G2149W', (65, 71))	('R2150W', 'Var', (85, 91))	('R2150W', 'Mutation', 'rs1264087949', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('activity', 'MPA', (21, 29))	('R2150Q', 'Var', (73, 79))
15239	30783010	A pulldown assay using the Rho-binding domain of the RhoA effector Rhotekin (Cytoskeleton, Inc.) was employed to determine the relative ratio of active RhoA (RhoA GTP) to total RhoA content in response to expression of WT and mutant Trio.	('RhoA', 'Gene', '387', (158, 162))	('mutant', 'Var', (226, 232))	('RhoA', 'Gene', (152, 156))	('RhoA', 'Gene', (177, 181))	('RhoA', 'Gene', '387', (152, 156))	('RhoA', 'Gene', (53, 57))	('RhoA', 'Gene', '387', (177, 181))	('GTP', 'Chemical', 'MESH:D006160', (163, 166))	('binding', 'molecular_function', 'GO:0005488', ('31', '38'))	('RhoA', 'Gene', '387', (53, 57))	('Cytoskeleton', 'cellular_component', 'GO:0005856', ('77', '89'))	('RhoA', 'Gene', (158, 162))
15240	30783010	Expression of R2150W, R2150Q, G2149W, and 2152Delta Trio mutants all led to a >2-fold increase in the abundance of RhoA GTP as compared to expression of WT Trio (Fig.	('increase', 'PosReg', (86, 94))	('GTP', 'Chemical', 'MESH:D006160', (120, 123))	('R2150W', 'Mutation', 'rs1264087949', (14, 20))	('2152Delta', 'Var', (42, 51))	('R2150Q', 'Var', (22, 28))	('RhoA', 'Gene', (115, 119))	('R2150W', 'Var', (14, 20))	('R2150Q', 'Mutation', 'rs182423419', (22, 28))	('RhoA', 'Gene', '387', (115, 119))	('G2149W', 'Var', (30, 36))	('abundance', 'MPA', (102, 111))	('G2149W', 'Mutation', 'p.G2149W', (30, 36))
15247	30783010	It showed that Gly2149 and Arg2150 both make extensive contacts with the DH domain, with Gly2149 enabling closer proximity of alphaN to the DH domain than in other DH/PH modules, and Arg2150 sequestering DH domain residues Glu2069 and Met2146, which both make contact with RhoA in the bound state.	('contacts', 'Interaction', (55, 63))	('DH', 'Chemical', '-', (73, 75))	('Gly2149', 'Chemical', '-', (15, 22))	('sequestering', 'biological_process', 'GO:0051235', ('191', '203'))	('Gly2149', 'Var', (15, 22))	('Arg2150', 'Var', (27, 34))	('DH', 'Chemical', '-', (204, 206))	('Glu2069', 'Chemical', '-', (223, 230))	('Met2146', 'Var', (235, 242))	('sequestering', 'NegReg', (191, 203))	('DH', 'Chemical', '-', (140, 142))	('DH', 'Chemical', '-', (164, 166))	('enabling', 'PosReg', (97, 105))	('RhoA', 'Gene', (273, 277))	('Arg2150', 'Chemical', '-', (27, 34))	('Arg2150', 'Var', (183, 190))	('Gly2149', 'Chemical', '-', (89, 96))	('Met2146', 'Chemical', '-', (235, 242))	('alphaN', 'Chemical', '-', (126, 132))	('Gly2149', 'Var', (89, 96))	('proximity', 'Interaction', (113, 122))	('Arg2150', 'Chemical', '-', (183, 190))	('RhoA', 'Gene', '387', (273, 277))	('Glu2069', 'Var', (223, 230))
15249	30783010	The presence of Gly2149 and Arg2150 is likely a prerequisite for alphaN to follow a standard helical track at the end of alpha6 in order to block the switch II binding site of RhoA on the DH domain.	('RhoA', 'Gene', (176, 180))	('Gly2149', 'Var', (16, 23))	('DH', 'Chemical', '-', (188, 190))	('binding', 'molecular_function', 'GO:0005488', ('160', '167'))	('RhoA', 'Gene', '387', (176, 180))	('Arg2150', 'Var', (28, 35))	('alphaN', 'Chemical', '-', (65, 71))	('Arg2150', 'Chemical', '-', (28, 35))	('Gly2149', 'Chemical', '-', (16, 23))	('switch', 'MPA', (150, 156))	('block', 'NegReg', (140, 145))
15250	30783010	Accordingly, mutations of Gly2149 and Arg2150 were generally activating.	('Gly2149', 'Chemical', '-', (26, 33))	('Gly2149', 'Var', (26, 33))	('Arg2150', 'Chemical', '-', (38, 45))	('Arg2150', 'Var', (38, 45))	('activating', 'PosReg', (61, 71))
15251	30783010	Mutation of the analogous residues in p63RhoGEF (Gly340 and Arg341) were also activating, and we predict this trend would hold true for the KalirinC module.	('Kalirin', 'Gene', '8997', (140, 147))	('activating', 'MPA', (78, 88))	('Arg341', 'Chemical', '-', (60, 66))	('RhoGEF', 'molecular_function', 'GO:0005089', ('41', '47'))	('Arg341', 'Var', (60, 66))	('Gly340', 'Chemical', '-', (49, 55))	('Gly340', 'Var', (49, 55))	('Kalirin', 'Gene', (140, 147))
15256	30783010	The TrioC 2153Delta, 2152Delta, and 2147Delta truncations were all activated relative to WT TrioC (Table 2).	('TrioC', 'Chemical', '-', (92, 97))	('TrioC', 'Chemical', '-', (4, 9))	('activated', 'PosReg', (67, 76))	('2152Delta', 'Var', (21, 30))	('truncations', 'Var', (46, 57))	('2153Delta', 'Var', (10, 19))	('2147Delta truncations', 'Var', (36, 57))
15260	30783010	Although the WT alpha6-alphaN region in Tgat is entirely present, the lack of the core PH domain fold in this variant could mean that the alphaN helix is disordered and thus cannot confer full autoinhibition as we see in the 2153Delta and 2152Delta variants.	('2153Delta', 'Var', (225, 234))	('alphaN', 'Chemical', '-', (23, 29))	('disordered', 'Disease', 'MESH:D030342', (154, 164))	('Tgat', 'Gene', (40, 44))	('core', 'cellular_component', 'GO:0019013', ('82', '86'))	('Tgat', 'Gene', '7204', (40, 44))	('2152Delta', 'Var', (239, 248))	('disordered', 'Disease', (154, 164))	('alphaN', 'Chemical', '-', (138, 144))
15262	30783010	Alanine scanning mutations throughout the DH-PH interface did not affect TrioC activity.	('Alanine', 'Chemical', 'MESH:D000409', (0, 7))	('Alanine scanning mutations', 'Var', (0, 26))	('DH', 'Chemical', '-', (42, 44))	('TrioC', 'Chemical', '-', (73, 78))	('TrioC', 'MPA', (73, 78))
15263	30783010	In contrast, substitutions that introduced bulk into the interface such as G2149I/W, E2069R/R2150E, and R2150W were able to activate TrioC >2-fold.	('TrioC', 'Chemical', '-', (133, 138))	('R2150W', 'Var', (104, 110))	('E2069R', 'Var', (85, 91))	('TrioC', 'MPA', (133, 138))	('activate', 'PosReg', (124, 132))	('R2150E', 'Mutation', 'p.R2150E', (92, 98))	('G2149I', 'SUBSTITUTION', 'None', (75, 81))	('E2069R', 'SUBSTITUTION', 'None', (85, 91))	('G2149I', 'Var', (75, 81))	('R2150W', 'Mutation', 'rs1264087949', (104, 110))
15264	30783010	These data suggest that in the absence of the interactions formed by one side chain, as in the R2150A variant, the remaining residues in the DH-PH interface can still contact each other and stabilize the autoinhibited conformation.	('stabilize', 'Reg', (190, 199))	('R2150A', 'Var', (95, 101))	('contact', 'Interaction', (167, 174))	('autoinhibited conformation', 'MPA', (204, 230))	('DH', 'Chemical', '-', (141, 143))	('R2150A', 'Mutation', 'p.R2150A', (95, 101))
15265	30783010	In contrast, variants which insert steric bulk into the interface will disrupt the majority of DH-PH interfacial contacts from forming.	('variants', 'Var', (13, 21))	('DH-PH interfacial contacts', 'CPA', (95, 121))	('DH', 'Chemical', '-', (95, 97))	('disrupt', 'NegReg', (71, 78))
15269	30783010	Truncation of the analogous loop in p63RhoGEF (Delta397-402) has no effect on activity.	('activity', 'MPA', (78, 86))	('Delta397', 'Mutation', 'c.del397', (47, 55))	('RhoGEF', 'molecular_function', 'GO:0005089', ('39', '45'))	('Delta397-402', 'Var', (47, 59))
15270	30783010	The beta3-beta4 loops in TrioN and Dbs make contacts with the bound GTPase, but mutation of the loop has no effect in vitro.	('Dbs', 'Gene', (35, 38))	('GTP', 'Chemical', 'MESH:D006160', (68, 71))	('Dbs', 'Gene', '23263', (35, 38))	('GTPase', 'Protein', (68, 74))	('contacts', 'Interaction', (44, 52))	('mutation', 'Var', (80, 88))
15273	30783010	TrioC can sample a conformation which is active in the absence of Galphaq GTP, and the cancer point variants we profiled are able to shift the equilibrium towards this state (Fig.	('cancer', 'Disease', (87, 93))	('shift', 'Reg', (133, 138))	('TrioC', 'Chemical', '-', (0, 5))	('variants', 'Var', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('equilibrium', 'MPA', (143, 154))	('GTP', 'Chemical', 'MESH:D006160', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
15277	30783010	Our results suggest that because the cancer-associated point variants favor a conformation similar to that produced by Galphaq GTP binding, they synergistically enhanced Galphaq GTP binding and a maximum activation rate.	('favor', 'PosReg', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('GTP', 'Chemical', 'MESH:D006160', (178, 181))	('enhanced', 'PosReg', (161, 169))	('Galphaq', 'Protein', (170, 177))	('cancer', 'Disease', (37, 43))	('GTP', 'Chemical', 'MESH:D006160', (127, 130))	('GTP binding', 'molecular_function', 'GO:0005525', ('178', '189'))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('activation', 'MPA', (204, 214))	('GTP binding', 'molecular_function', 'GO:0005525', ('127', '138'))	('conformation', 'MPA', (78, 90))	('variants', 'Var', (61, 69))
15280	30783010	We posit that activation of TrioC by Galphaq GTP, by point mutation, and by truncation all depend on the same biophysical mechanism: displacement of alphaN from the contacts made with alpha3 seen in our crystal structure.	('activation', 'PosReg', (14, 24))	('Galphaq GTP', 'Var', (37, 48))	('GTP', 'Chemical', 'MESH:D006160', (45, 48))	('alphaN', 'Chemical', '-', (149, 155))	('TrioC', 'Chemical', '-', (28, 33))	('alphaN', 'Protein', (149, 155))	('point mutation', 'Var', (53, 67))	('displacement', 'MPA', (133, 145))
15282	30783010	Thus, in human cancer, Trio has the potential to bypass regulation by Galphaq/11 by truncation or point variation, which would lead to the activation of RhoA and downstream proliferative signaling through the AP-1 and YAP-TEAD axes.	('Galphaq/11', 'Gene', (70, 80))	('truncation', 'Var', (84, 94))	('cancer', 'Disease', (15, 21))	('activation', 'PosReg', (139, 149))	('RhoA', 'Gene', (153, 157))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('AP-1', 'cellular_component', 'GO:0005907', ('209', '213'))	('signaling', 'biological_process', 'GO:0023052', ('187', '196'))	('regulation', 'biological_process', 'GO:0065007', ('56', '66'))	('RhoA', 'Gene', '387', (153, 157))	('point variation', 'Var', (98, 113))	('human', 'Species', '9606', (9, 14))	('YAP', 'Gene', '10413', (218, 221))	('YAP', 'Gene', (218, 221))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
15288	30783010	TrioC C was designed based on the prediction that the conserved C-terminal extension of the PH domain (residues 2275-2290) is likely disordered in the absence of Galphaq.	('residues 2275-2290', 'Var', (103, 121))	('disordered', 'Disease', 'MESH:D030342', (133, 143))	('disordered', 'Disease', (133, 143))	('TrioC C', 'Chemical', '-', (0, 7))
15293	30783010	To generate variants in TrioFL-pEGFP (containing Trio residues 61-3097), a 1000 base pair fragment containing the mutations was PCR amplified from TrioC mutants in pMalC2H10T.	('mutants', 'Var', (153, 160))	('variants', 'Var', (12, 20))	('pMalC2H10T', 'Gene', (164, 174))	('TrioC', 'Chemical', '-', (147, 152))
15294	30783010	Plasmids encoding TrioC variants and RhoA were transformed into Rosetta (DE3) pLysS E. coli cells (Novagen) and grown in Terrific Broth (EMD Millipore Sigma) with 100 mug/mL carbenicillin at 37  C with 200 rpm shaking.	('mug', 'molecular_function', 'GO:0043739', ('167', '170'))	('variants', 'Var', (24, 32))	('TrioC', 'Chemical', '-', (18, 23))	('TrioC', 'Gene', (18, 23))	('E. coli', 'Species', '562', (84, 91))	('RhoA', 'Gene', (37, 41))	('RhoA', 'Gene', '387', (37, 41))	('EMD', 'Disease', (137, 140))	('carbenicillin', 'Chemical', 'MESH:D002228', (174, 187))	('EMD', 'Disease', 'None', (137, 140))
15302	30783010	The elution fractions were then incubated with 5% (w/w) tobacco etch virus protease in order to cleave the N-terminal MBP expression tag and the mixture was dialyzed against a buffer containing 20 mM HEPES pH 8.0, 200 mM NaCl, and 2 mM DTT.	('DTT', 'Chemical', 'MESH:D004229', (236, 239))	('cleave', 'Var', (96, 102))	('MBP', 'Gene', '4155', (118, 121))	('MBP', 'Gene', (118, 121))	('NaCl', 'Chemical', 'MESH:D012965', (221, 225))	('HEPES', 'Chemical', 'MESH:D006531', (200, 205))
15317	30783010	Although the absolute Tm for WT TrioC was different for each dye, we tested TrioC WT and R2150E and found DeltaTm for R2150E (Tm R2150E - Tm WT) was similar: +0.9  C on the ThermoFluor instrument, and +0.6  C on the PCR instruments (N=3 independent experiments performed in at least duplicate).	('R2150E', 'Var', (118, 124))	('R2150E', 'Mutation', 'p.R2150E', (118, 124))	('R2150E', 'Var', (89, 95))	('R2150E', 'Mutation', 'p.R2150E', (129, 135))	('TrioC', 'Chemical', '-', (76, 81))	('R2150E', 'Mutation', 'p.R2150E', (89, 95))	('TrioC', 'Chemical', '-', (32, 37))
15339	30783010	For FRET activity assays comparing TrioC variants to WT, kobs values for each variant were normalized to matched WT kobs for each experimental N to generate fold GEF activation values for each variant.	('variants', 'Var', (41, 49))	('GEF', 'molecular_function', 'GO:0005085', ('162', '165'))	('kobs', 'Species', '59530', (57, 61))	('GEF', 'Gene', (162, 165))	('TrioC', 'Chemical', '-', (35, 40))	('kobs', 'Species', '59530', (116, 120))	('GEF', 'Gene', '6654', (162, 165))
15341	30783010	Statistical significance was assessed using a one-way ANOVA test with a post-hoc Dunnett's test for multiple comparisons to compare N=3 fold GEF activation values of each variant with N=51 WT fold GEF activation values.	('GEF', 'Gene', (141, 144))	('activation', 'PosReg', (145, 155))	('GEF', 'molecular_function', 'GO:0005085', ('197', '200'))	('GEF', 'Gene', '6654', (141, 144))	('GEF', 'Gene', (197, 200))	('variant', 'Var', (171, 178))	('GEF', 'Gene', '6654', (197, 200))	('GEF', 'molecular_function', 'GO:0005085', ('141', '144'))
15344	26774355	A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer Germline mutations in the tumor suppressor gene, BRCA-1 associated protein (BAP1), underlie a tumor predisposition syndrome characterized by increased risk for numerous cancers including uveal melanoma, melanocytic tumors and mesothelioma, among others.	('BRCA-1 associated protein', 'Gene', (131, 156))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (41, 62))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (41, 62))	('uveal melanoma', 'Phenotype', 'HP:0007716', (269, 283))	('associated', 'Reg', (25, 35))	('BRCA-1 associated protein', 'Gene', '8315', (131, 156))	('thyroid cancer', 'Disease', (67, 81))	('neoplasms', 'Phenotype', 'HP:0002664', (53, 62))	('melanocytic neoplasms', 'Disease', (41, 62))	('BAP1', 'Gene', '8314', (8, 12))	('tumor', 'Disease', (108, 113))	('BAP1', 'Gene', '8314', (158, 162))	('tumor', 'Disease', (297, 302))	('numerous cancers', 'Disease', 'MESH:D009369', (242, 258))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('melanocytic tumors', 'Disease', (285, 303))	('melanocytic tumors', 'Disease', 'MESH:D009508', (285, 303))	('thyroid cancer', 'Disease', 'MESH:D013964', (67, 81))	('BAP1', 'Gene', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('melanoma', 'Phenotype', 'HP:0002861', (275, 283))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('numerous cancers', 'Disease', (242, 258))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('BAP1', 'Gene', (158, 162))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('108', '124'))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('thyroid cancer', 'Phenotype', 'HP:0002890', (67, 81))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('mesothelioma', 'Disease', (308, 320))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('uveal melanoma', 'Disease', (269, 283))	('uveal melanoma', 'Disease', 'MESH:C536494', (269, 283))	('mutation', 'Var', (13, 21))	('mesothelioma', 'Disease', 'MESH:D008654', (308, 320))	('tumor suppressor', 'biological_process', 'GO:0051726', ('108', '124'))	('mutations', 'Var', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
15345	26774355	In the present study we report the identification of a novel germline BAP1 mutation, c.1777C>T, which produces a truncated BAP1 protein product and segregates with cancer.	('BAP1', 'Gene', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('truncated', 'MPA', (113, 122))	('BAP1', 'Gene', '8314', (70, 74))	('c.1777C>T', 'Mutation', 'rs1064795638', (85, 94))	('cancer', 'Disease', (164, 170))	('BAP1', 'Gene', (70, 74))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('BAP1', 'Gene', '8314', (123, 127))	('c.1777C>T', 'Var', (85, 94))
15346	26774355	Family members with this mutation demonstrated a primary clinical phenotype of autosomal dominant, early-onset melanocytic neoplasms with immunohistochemistry (IHC) of these tumors demonstrating lack of BAP1 protein expression.	('BAP1', 'Gene', '8314', (203, 207))	('protein', 'cellular_component', 'GO:0003675', ('208', '215'))	('lack', 'NegReg', (195, 199))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (111, 132))	('BAP1', 'Gene', (203, 207))	('mutation', 'Var', (25, 33))	('neoplasms', 'Phenotype', 'HP:0002664', (123, 132))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (111, 132))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('protein', 'Protein', (208, 215))	('melanocytic neoplasms', 'Disease', (111, 132))	('autosomal dominant', 'Disease', (79, 97))
15347	26774355	In addition, family members harboring the BAP1 c.1777C>T germline mutation developed other neoplastic disease including thyroid cancer.	('BAP1', 'Gene', '8314', (42, 46))	('developed', 'Reg', (75, 84))	('BAP1', 'Gene', (42, 46))	('neoplastic disease', 'Phenotype', 'HP:0002664', (91, 109))	('thyroid cancer', 'Phenotype', 'HP:0002890', (120, 134))	('thyroid cancer', 'Disease', (120, 134))	('neoplastic disease', 'Disease', 'MESH:D009386', (91, 109))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('c.1777C>T', 'Var', (47, 56))	('c.1777C>T', 'Mutation', 'rs1064795638', (47, 56))	('thyroid cancer', 'Disease', 'MESH:D013964', (120, 134))	('neoplastic disease', 'Disease', (91, 109))
15349	26774355	Our investigation identifies a new BAP1 mutation, further highlights the relevance of BAP1 as a clinically important tumor suppressor gene, and broadens the range of cancers associated with BAP1 inactivation.	('mutation', 'Var', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('cancers', 'Disease', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('BAP1', 'Gene', '8314', (86, 90))	('BAP1', 'Gene', '8314', (190, 194))	('tumor', 'Disease', (117, 122))	('BAP1', 'Gene', '8314', (35, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('117', '133'))	('BAP1', 'Gene', (86, 90))	('BAP1', 'Gene', (190, 194))	('BAP1', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('117', '133'))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
15352	26774355	Germline mutations in BAP1 have been implicated in causing an autosomal dominant tumor predisposition syndrome (OMIM #6143237) that is associated with predisposition to uveal melanomas, melanocytic tumors and mesotheliomas.	('Germline mutations', 'Var', (0, 18))	('mesotheliomas', 'Disease', (209, 222))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('associated', 'Reg', (135, 145))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('mesotheliomas', 'Disease', 'MESH:D008654', (209, 222))	('uveal melanomas', 'Disease', 'MESH:C536494', (169, 184))	('BAP1', 'Gene', '8314', (22, 26))	('causing', 'Reg', (51, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (169, 183))	('autosomal dominant tumor', 'Disease', (62, 86))	('melanocytic tumors', 'Disease', 'MESH:D009508', (186, 204))	('melanocytic tumors', 'Disease', (186, 204))	('uveal melanomas', 'Disease', (169, 184))	('uveal melanomas', 'Phenotype', 'HP:0007716', (169, 184))	('BAP1', 'Gene', (22, 26))	('implicated', 'Reg', (37, 47))	('autosomal dominant tumor', 'Disease', 'MESH:D030342', (62, 86))	('melanomas', 'Phenotype', 'HP:0002861', (175, 184))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
15353	26774355	Since the original description of the BAP1 predisposition syndrome additional cancers such as renal cell carcinoma, cutaneous melanoma and basal cell carcinoma, have been linked with germline mutations of BAP1.	('germline mutations', 'Var', (183, 201))	('BAP1', 'Gene', '8314', (205, 209))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('BAP1', 'Gene', '8314', (38, 42))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (94, 114))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (139, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('cutaneous melanoma', 'Disease', (116, 134))	('BAP1', 'Gene', (205, 209))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (116, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (116, 134))	('BAP1', 'Gene', (38, 42))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (139, 159))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('linked', 'Reg', (171, 177))	('renal cell carcinoma', 'Disease', (94, 114))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (94, 114))	('basal cell carcinoma', 'Disease', (139, 159))
15354	26774355	In the present study we report a novel germline BAP1 mutation, c.1777C>T, identified in a patient with multiple cancers and a family history remarkable for autosomal dominant, early age melanocytic tumors and cutaneous melanomas.	('BAP1', 'Gene', '8314', (48, 52))	('cutaneous melanomas', 'Disease', (209, 228))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('multiple cancers', 'Disease', 'MESH:D009369', (103, 119))	('BAP1', 'Gene', (48, 52))	('melanomas', 'Phenotype', 'HP:0002861', (219, 228))	('melanocytic tumors', 'Disease', 'MESH:D009508', (186, 204))	('melanocytic tumors', 'Disease', (186, 204))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (209, 228))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (209, 228))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('multiple cancers', 'Disease', (103, 119))	('c.1777C>T', 'Var', (63, 72))	('c.1777C>T', 'Mutation', 'rs1064795638', (63, 72))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (209, 227))	('patient', 'Species', '9606', (90, 97))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
15355	26774355	The c.1777C>T mutation introduces a premature stop codon into the BAP1 open reading frame with resultant expression of a truncated protein.	('BAP1', 'Gene', '8314', (66, 70))	('c.1777C>T', 'Var', (4, 13))	('BAP1', 'Gene', (66, 70))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('expression', 'MPA', (105, 115))	('c.1777C>T', 'Mutation', 'rs1064795638', (4, 13))
15357	26774355	Additionally, IHC analysis of a thyroid papillary carcinoma and a thyroid adenoma arising in the proband carrying the c.1777C>T mutation germline mutation demonstrated loss of BAP1 protein expression in these tumors.	('loss', 'NegReg', (168, 172))	('tumors', 'Disease', (209, 215))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('thyroid adenoma', 'Disease', (66, 81))	('thyroid papillary carcinoma', 'Disease', (32, 59))	('BAP1', 'Gene', '8314', (176, 180))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('c.1777C>T', 'Var', (118, 127))	('c.1777C>T', 'Mutation', 'rs1064795638', (118, 127))	('thyroid adenoma', 'Phenotype', 'HP:0000854', (66, 81))	('thyroid papillary carcinoma', 'Disease', 'MESH:D000077273', (32, 59))	('BAP1', 'Gene', (176, 180))	('thyroid adenoma', 'Disease', 'MESH:D013964', (66, 81))	('thyroid papillary carcinoma', 'Phenotype', 'HP:0002895', (32, 59))	('protein', 'cellular_component', 'GO:0003675', ('181', '188'))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
15380	26774355	A novel point mutation was identified in exon 14, c.1777C>T (p.Q593X), of the BAP1 gene (Figure 1B, C) resulting in the introduction of a truncating, premature stop codon.	('truncating', 'MPA', (138, 148))	('c.1777C>T', 'Var', (50, 59))	('c.1777C>T', 'Mutation', 'rs1064795638', (50, 59))	('BAP1', 'Gene', '8314', (78, 82))	('p.Q593X', 'Mutation', 'rs1064795638', (61, 68))	('BAP1', 'Gene', (78, 82))
15383	26774355	DNA from the proband's mother was not available; however, the familial patterning of the BAP1 mutation is consistent with obligate transmission via the maternal lineage.	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('mutation', 'Var', (94, 102))	('BAP1', 'Gene', '8314', (89, 93))	('BAP1', 'Gene', (89, 93))
15386	26774355	Although thyroid cancers have been identified in families of known BAP1 mutation carrier, to date, loss of BAP1 protein expression or bi-allelic BAP1 gene deletion has yet to be documented for these specific tumors.	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('thyroid cancers', 'Disease', (9, 24))	('BAP1', 'Gene', (145, 149))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('carrier', 'molecular_function', 'GO:0005215', ('81', '88'))	('deletion', 'Var', (155, 163))	('BAP1', 'Gene', '8314', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('BAP1', 'Gene', '8314', (67, 71))	('mutation', 'Var', (72, 80))	('thyroid cancers', 'Disease', 'MESH:D013964', (9, 24))	('thyroid cancer', 'Phenotype', 'HP:0002890', (9, 23))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('BAP1', 'Gene', (107, 111))	('BAP1', 'Gene', '8314', (145, 149))	('tumors', 'Disease', (208, 214))	('BAP1', 'Gene', (67, 71))
15391	26774355	In the current study we identify a novel germline BAP1 mutation, c.1777C>T, resulting in a truncated protein, in a family with multiple cancers.	('multiple cancers', 'Disease', 'MESH:D009369', (127, 143))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('c.1777C>T', 'Mutation', 'rs1064795638', (65, 74))	('BAP1', 'Gene', '8314', (50, 54))	('BAP1', 'Gene', (50, 54))	('truncated protein', 'MPA', (91, 108))	('multiple cancers', 'Disease', (127, 143))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('c.1777C>T', 'Var', (65, 74))
15396	26774355	Previously identified germline BAP1 mutations are mostly nonsense or frameshift mutations; the c.1777C>T mutation described in the current study is a nonsense mutation.	('frameshift', 'Var', (69, 79))	('BAP1', 'Gene', '8314', (31, 35))	('BAP1', 'Gene', (31, 35))	('c.1777C>T', 'Mutation', 'rs1064795638', (95, 104))	('c.1777C>T', 'Var', (95, 104))
15397	26774355	The germline BAP1 mutations described to date are evenly distributed across the open reading frame of the BAP1 gene, although a disproportionate number of mutations are situated on exon 13 as it represents the largest exon.	('BAP1', 'Gene', (13, 17))	('BAP1', 'Gene', (106, 110))	('BAP1', 'Gene', '8314', (106, 110))	('BAP1', 'Gene', '8314', (13, 17))	('mutations', 'Var', (18, 27))
15398	26774355	Approximately one half of reported germline BAP1 mutations occur within a functional domain; and these mutations exhibit proportional prevalence across these domains.	('BAP1', 'Gene', '8314', (44, 48))	('occur', 'Reg', (59, 64))	('mutations', 'Var', (49, 58))	('BAP1', 'Gene', (44, 48))
15400	26774355	The tumors originally associated with mutated germline BAP1 include melanocytic tumors, uveal melanomas and mesotheliomas.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (80, 86))	('mutated', 'Var', (38, 45))	('germline', 'Gene', (46, 54))	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('BAP1', 'Gene', '8314', (55, 59))	('BAP1', 'Gene', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('uveal melanomas and mesotheliomas', 'Disease', 'MESH:C536494', (88, 121))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('melanocytic tumors', 'Disease', (68, 86))	('melanocytic tumors', 'Disease', 'MESH:D009508', (68, 86))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('uveal melanomas', 'Phenotype', 'HP:0007716', (88, 103))
15401	26774355	At that same time, it was postulated that germline BAP1 mutations likely additionally promote cutaneous melanoma, and might predispose to a constellation of additional cancers.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (56, 65))	('predispose', 'Reg', (124, 134))	('BAP1', 'Gene', (51, 55))	('cutaneous melanoma', 'Disease', (94, 112))	('germline', 'Var', (42, 50))	('constellation of additional cancers', 'Disease', 'MESH:D009369', (140, 175))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (94, 112))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (94, 112))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('promote', 'PosReg', (86, 93))	('constellation of additional cancers', 'Disease', (140, 175))	('BAP1', 'Gene', '8314', (51, 55))
15402	26774355	And since the initial reports of these cancers linked with germline mutated BAP1, the scope of associated cancers has, indeed, significantly expanded.	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('BAP1', 'Gene', '8314', (76, 80))	('cancers', 'Disease', (39, 46))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancers', 'Disease', (106, 113))	('BAP1', 'Gene', (76, 80))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('linked', 'Reg', (47, 53))	('germline mutated', 'Var', (59, 75))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
15403	26774355	The strongest causative association between loss of BAP1 expression and a specific cancer are those cancers for which bi-allelic mutations/deletions and/or disruption of BAP1 protein expression have been demonstrated in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('loss', 'NegReg', (44, 48))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('protein', 'Protein', (175, 182))	('expression', 'MPA', (57, 67))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('protein', 'cellular_component', 'GO:0003675', ('175', '182'))	('disruption', 'Var', (156, 166))	('BAP1', 'Gene', '8314', (52, 56))	('BAP1', 'Gene', '8314', (170, 174))	('tumor', 'Disease', (224, 229))	('cancer', 'Disease', (100, 106))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('cancers', 'Disease', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('BAP1', 'Gene', (52, 56))	('BAP1', 'Gene', (170, 174))	('cancer', 'Disease', (83, 89))
15409	26774355	Both RAS gene mutations and PAX8/PPARgamma gene fusions have previously been implicated as initiating events of this molecular sequence; the current study raises speculation that loss of BAP1 expression may represent an alternate early event in this progression pathway.	('PPARgamma', 'Gene', (33, 42))	('mole', 'Phenotype', 'HP:0003764', (117, 121))	('PAX8', 'Gene', '7849', (28, 32))	('BAP1', 'Gene', '8314', (187, 191))	('PPARgamma', 'Gene', '5468', (33, 42))	('BAP1', 'Gene', (187, 191))	('PAX8', 'Gene', (28, 32))	('loss', 'Var', (179, 183))
15410	26774355	The question arises whether loss of BAP1 expression may also drive similar early adenoma-initiating events in other tissues.	('loss', 'Var', (28, 32))	('adenoma', 'Disease', (81, 88))	('BAP1', 'Gene', '8314', (36, 40))	('BAP1', 'Gene', (36, 40))	('adenoma', 'Disease', 'MESH:D000236', (81, 88))
15412	26774355	This circumstance may belie singular molecular pathways which are fostered by the underlying germline BAP1 mutation; further elucidation of other somatic mutations in these thyroid tumors may provide further insight into such pathways.	('BAP1', 'Gene', (102, 106))	('mole', 'Phenotype', 'HP:0003764', (37, 41))	('fostered', 'PosReg', (66, 74))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('BAP1', 'Gene', '8314', (102, 106))	('thyroid tumors', 'Disease', (173, 187))	('thyroid tumors', 'Disease', 'MESH:D013959', (173, 187))	('mutation', 'Var', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
15414	26774355	Relative to solid tumors, there exist few reports of hematopoietic cancers associated with germline mutations of BAP1.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('solid tumors', 'Disease', 'MESH:D009369', (12, 24))	('germline mutations', 'Var', (91, 109))	('hematopoietic cancers', 'Disease', (53, 74))	('BAP1', 'Gene', '8314', (113, 117))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('solid tumors', 'Disease', (12, 24))	('hematopoietic cancers', 'Disease', 'MESH:D019337', (53, 74))	('associated', 'Reg', (75, 85))	('BAP1', 'Gene', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
15415	26774355	Previous associations are limited to histories of family members of patients carrying germline BAP1 mutations having leukemia and one unspecified hematologic cancer.	('mutations', 'Var', (100, 109))	('hematologic cancer', 'Disease', 'MESH:D009369', (146, 164))	('BAP1', 'Gene', (95, 99))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('leukemia', 'Disease', 'MESH:D007938', (117, 125))	('patients', 'Species', '9606', (68, 76))	('leukemia', 'Disease', (117, 125))	('hematologic cancer', 'Disease', (146, 164))	('BAP1', 'Gene', '8314', (95, 99))	('hematologic cancer', 'Phenotype', 'HP:0004377', (146, 164))	('germline', 'Var', (86, 94))	('unspecified', 'Species', '32644', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
15416	26774355	Laboratory investigations, however, unambiguously document that loss of BAP1 expression can disrupt normal bone marrow function, cause myeloid transformation and give rise to myeloid dysplasia.	('cause', 'Reg', (129, 134))	('BAP1', 'Gene', '8314', (72, 76))	('myeloid dysplasia', 'Disease', 'MESH:D007951', (175, 192))	('myeloid transformation', 'CPA', (135, 157))	('BAP1', 'Gene', (72, 76))	('myeloid dysplasia', 'Disease', (175, 192))	('loss', 'Var', (64, 68))	('give rise to', 'Reg', (162, 174))	('disrupt', 'NegReg', (92, 99))
15417	26774355	The present study broadens the list of hematopoietic cancers associated with individuals carrying germline BAP1 mutations; our investigation suggests that loss of BAP1 expression may disrupt not merely ontogeny of the myeloid cell lineage but may extend to lymphoid cell lineage causing B cell lymphoma, as well.	('ontogeny of the myeloid cell lineage', 'CPA', (202, 238))	('disrupt', 'Reg', (183, 190))	('BAP1', 'Gene', '8314', (107, 111))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (287, 302))	('hematopoietic cancers', 'Disease', (39, 60))	('lymphoma', 'Disease', 'MESH:D008223', (294, 302))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('lymphoma', 'Phenotype', 'HP:0002665', (294, 302))	('BAP1', 'Gene', '8314', (163, 167))	('loss', 'Var', (155, 159))	('BAP1', 'Gene', (107, 111))	('mutations', 'Var', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('BAP1', 'Gene', (163, 167))	('hematopoietic cancers', 'Disease', 'MESH:D019337', (39, 60))	('lymphoma', 'Disease', (294, 302))	('extend', 'Reg', (247, 253))
15418	26774355	Pancreatic cancer has been reported previously in family members of patient's having deleterious BAP1 mutations.	('Pancreatic cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('BAP1', 'Gene', '8314', (97, 101))	('patient', 'Species', '9606', (68, 75))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))
15420	26774355	In the current study we document the occurrence of a BAP1 mutation in a patient (patient III.6, Figure 1) with pancreatic cancer which further strengthens this association.	('patient', 'Species', '9606', (81, 88))	('pancreatic cancer', 'Disease', 'MESH:D010190', (111, 128))	('pancreatic cancer', 'Disease', (111, 128))	('patient', 'Species', '9606', (72, 79))	('mutation', 'Var', (58, 66))	('BAP1', 'Gene', '8314', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (111, 128))	('BAP1', 'Gene', (53, 57))
15423	26774355	The father of the proband (Figure 1, patient II.3) did not carry a BAP1 mutation, suggesting a high probability that this mutation originated in the mother unless the BAP1 mutation was de novo (Figure 1, patient II.4).	('patient', 'Species', '9606', (37, 44))	('BAP1', 'Gene', (67, 71))	('BAP1', 'Gene', '8314', (67, 71))	('BAP1', 'Gene', '8314', (167, 171))	('mutation', 'Var', (72, 80))	('BAP1', 'Gene', (167, 171))	('patient', 'Species', '9606', (204, 211))
15427	26774355	That there manifests some diversity with regard to what tumors develop within and among families with germline mutations of BAP1 may also imply that the gene exhibits variable penetrance and/or exerts a modifier effect within the context of a landscape of additional familial genetic variation.	('mutations', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('BAP1', 'Gene', '8314', (124, 128))	('BAP1', 'Gene', (124, 128))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('modifier', 'Reg', (203, 211))
15428	26774355	Therefore, it is reasonable to consider germline BAP1 mutations as a possible causative mechanism in families exhibiting a familial cancer syndrome but whose genetic workup identifies no typical genetic abnormality.	('familial cancer syndrome', 'Disease', (123, 147))	('genetic abnormality', 'Disease', (195, 214))	('BAP1', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('genetic abnormality', 'Disease', 'MESH:D030342', (195, 214))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('familial cancer syndrome', 'Disease', 'MESH:D009386', (123, 147))	('BAP1', 'Gene', '8314', (49, 53))
15429	26774355	It may be anticipated that as whole exome sequencing becomes more widely adopted as a part of medical genetic and, more specifically, cancer genetic workups, the identification of additional germline BAP1 mutations and clarification of the molecular mechanisms contributing to the development of familial cancer syndrome will be forthcoming.	('familial cancer syndrome', 'Disease', 'MESH:D009386', (296, 320))	('cancer', 'Disease', (305, 311))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('familial cancer syndrome', 'Disease', (296, 320))	('mutations', 'Var', (205, 214))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('BAP1', 'Gene', '8314', (200, 204))	('mole', 'Phenotype', 'HP:0003764', (240, 244))	('BAP1', 'Gene', (200, 204))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
15432	28810145	We report change-of-function SRSF2 mutations.	('change-of-function', 'Reg', (10, 28))	('SRSF2', 'Gene', '6427', (29, 34))	('SRSF2', 'Gene', (29, 34))	('mutations', 'Var', (35, 44))
15433	28810145	Within D3-UM, EIF1AX- and SRSF2/SF3B1 -mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low-versus intermediate-risk clinical mutation subtypes.	('EIF1AX', 'Gene', '1964', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('DNA methylation', 'biological_process', 'GO:0006306', ('103', '118'))	('SRSF2', 'Gene', (26, 31))	('SF3B1', 'Gene', '23451', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('-mutant', 'Var', (38, 45))	('tumors', 'Disease', (46, 52))	('SRSF2', 'Gene', '6427', (26, 31))	('SF3B1', 'Gene', (32, 37))	('EIF1AX', 'Gene', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
15438	28810145	Loss-of-function mutations in BAP1, which is located on 3p21, have been identified in M3-UM, and decreased BAP1 mRNA and protein expression, indicating BAP1 aberrancy, are highly correlated with the development of UM metastases.	('metastases', 'Disease', 'MESH:D009362', (217, 227))	('Loss-of-function', 'NegReg', (0, 16))	('M3-UM', 'Disease', (86, 91))	('BAP1', 'Gene', '8314', (107, 111))	('BAP1', 'Gene', (30, 34))	('BAP1', 'Gene', '8314', (152, 156))	('BAP1', 'Gene', (107, 111))	('decreased', 'NegReg', (97, 106))	('BAP1', 'Gene', (152, 156))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('BAP1', 'Gene', '8314', (30, 34))	('metastases', 'Disease', (217, 227))	('mutations', 'Var', (17, 26))
15440	28810145	Recent analysis of a large D3-UM cohort showed SF3B1 mutation to be associated with an intermediate risk of developing later-onset metastatic UM.	('later-onset metastatic UM', 'Disease', (119, 144))	('SF3B1', 'Gene', (47, 52))	('mutation', 'Var', (53, 61))	('SF3B1', 'Gene', '23451', (47, 52))
15441	28810145	Despite prognosis being clearly correlated with the expression of a small panel of marker genes, with M3, and with BAP1 aberrancy or SF3B1 mutation, the molecular pathways involved in the development of metastatic disease have not been elucidated.	('mutation', 'Var', (139, 147))	('SF3B1', 'Gene', '23451', (133, 138))	('BAP1', 'Gene', '8314', (115, 119))	('correlated', 'Reg', (32, 42))	('BAP1', 'Gene', (115, 119))	('SF3B1', 'Gene', (133, 138))
15447	28810145	In D3-UM, cluster 1 showed the least aneuploidy and was enriched for partial or total 6p gain, with no other significant chromosome aberrations; cluster 2 showed 6p gain and partial 8q arm gains.	('gain', 'PosReg', (165, 169))	('gain', 'PosReg', (89, 93))	('partial 8q arm gains', 'Var', (174, 194))	('8q', 'Chemical', '-', (182, 184))	('chromosome', 'cellular_component', 'GO:0005694', ('121', '131'))	('aneuploidy', 'Disease', (37, 47))	('aneuploidy', 'Disease', 'MESH:D000782', (37, 47))
15455	28810145	We found mutually exclusive somatic mutations in the G-protein pathway-associated GNAQ and/or GNA11 (92.5%), CYSLTR2 (4%), and PLCB4 (2.5%) genes, consistent with previous findings (Figure S1C).	('CYSLTR2', 'Gene', (109, 116))	('GNA11', 'Gene', '2767', (94, 99))	('G-protein pathway-associated', 'Pathway', (53, 81))	('GNAQ', 'Gene', (82, 86))	('PLCB4', 'Gene', '5332', (127, 132))	('CYSLTR2', 'Gene', '57105', (109, 116))	('mutations', 'Var', (36, 45))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('PLCB4', 'Gene', (127, 132))	('GNAQ', 'Gene', '2776', (82, 86))	('GNA11', 'Gene', (94, 99))
15456	28810145	EIF1AX and SF3B1 mutations in 27 of the 80 UM (34%) were nearly mutually exclusive, consistent with.	('SF3B1', 'Gene', (11, 16))	('mutations', 'Var', (17, 26))	('SF3B1', 'Gene', '23451', (11, 16))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))
15457	28810145	Nine of ten EIF1AX-mutant cases had their mutations in the protein N-terminal region (G6-G15), as in papillary thyroid carcinomas.	('EIF1AX', 'Gene', (12, 18))	('papillary thyroid carcinomas', 'Disease', (101, 129))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (101, 129))	('EIF1AX', 'Gene', '1964', (12, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('G6-G15', 'Gene', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (101, 129))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (111, 129))	('mutations', 'Var', (42, 51))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
15458	28810145	EIF1AX mutations were present only in UM with neither M3 nor 8q gain, and were exclusively in SCNA cluster 1 (Figure 1A).	('8q', 'Chemical', '-', (61, 63))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
15459	28810145	SF3B1 mutations resulted in R625C/H amino acid alterations in 14 of 18 samples, while in four UM, mutations resulted in H662R (n = 2), K666T, or T663P, which are frequently altered sites in other malignancies.	('R625C', 'Var', (28, 33))	('K666T', 'Mutation', 'rs374250186', (135, 140))	('T663P', 'Var', (145, 150))	('SF3B1', 'Gene', (0, 5))	('resulted in', 'Reg', (16, 27))	('H662R', 'Mutation', 'p.H662R', (120, 125))	('malignancies', 'Disease', 'MESH:D009369', (196, 208))	('T663P', 'Mutation', 'p.T663P', (145, 150))	('H662R', 'Var', (120, 125))	('malignancies', 'Disease', (196, 208))	('R625C', 'SUBSTITUTION', 'None', (28, 33))	('SF3B1', 'Gene', '23451', (0, 5))	('resulted in', 'Reg', (108, 119))	('mutations', 'Var', (6, 15))	('K666T', 'Var', (135, 140))
15460	28810145	Only one UM harbored both an EIF1AX and a SF3B1 mutation; the latter was an atypical T663P.	('EIF1AX', 'Gene', '1964', (29, 35))	('EIF1AX', 'Gene', (29, 35))	('SF3B1', 'Gene', (42, 47))	('T663P', 'Var', (85, 90))	('SF3B1', 'Gene', '23451', (42, 47))	('T663P', 'Mutation', 'p.T663P', (85, 90))
15461	28810145	As was the case for EIF1AX mutations, the majority (78%) of UM with SF3B1 mutations were present in D3-UM, consistent with.	('SF3B1', 'Gene', (68, 73))	('mutations', 'Var', (74, 83))	('EIF1AX', 'Gene', '1964', (20, 26))	('SF3B1', 'Gene', '23451', (68, 73))	('EIF1AX', 'Gene', (20, 26))
15462	28810145	However, unlike EIF1AX mutations, SF3B1 mutations in D3-UM were associated with SCNA cluster 2, most with partial 8q gains.	('associated', 'Reg', (64, 74))	('SCNA cluster 2', 'Disease', (80, 94))	('EIF1AX', 'Gene', '1964', (16, 22))	('EIF1AX', 'Gene', (16, 22))	('SF3B1', 'Gene', (34, 39))	('mutations', 'Var', (40, 49))	('partial 8q gains', 'Var', (106, 122))	('8q', 'Chemical', '-', (114, 116))	('SF3B1', 'Gene', '23451', (34, 39))	('D3-UM', 'Gene', (53, 58))
15464	28810145	We identified SRSF2 as an SMG that harbored in-frame Y92 deletions (Y92del) in two UM and an S174del in a third.	('deletions', 'Var', (57, 66))	('S174del', 'Var', (93, 100))	('Y92del', 'Mutation', 'p.92delY', (68, 74))	('SMG', 'Gene', (26, 29))	('SMG', 'Gene', '23034', (26, 29))	('SRSF2', 'Gene', (14, 19))	('Y92', 'Gene', (53, 56))	('S174del', 'Mutation', 'p.174delS', (93, 100))	('SRSF2', 'Gene', '6427', (14, 19))
15465	28810145	Tumors with SRSF2 mutations had neither SF3B1 nor EIF1AX mutations, and were found in both D3-UM and M3-UM with 8q gains, suggesting functional similarities between SRSF2- and SF3B1-mutant UM.	('SF3B1', 'Gene', (40, 45))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SRSF2', 'Gene', (12, 17))	('EIF1AX', 'Gene', '1964', (50, 56))	('EIF1AX', 'Gene', (50, 56))	('SF3B1', 'Gene', '23451', (40, 45))	('Tumors', 'Disease', (0, 6))	('SF3B1', 'Gene', (176, 181))	('SRSF2', 'Gene', (165, 170))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('SRSF2', 'Gene', '6427', (12, 17))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('SRSF2', 'Gene', '6427', (165, 170))	('8q', 'Chemical', '-', (112, 114))	('SF3B1', 'Gene', '23451', (176, 181))	('mutations', 'Var', (18, 27))
15466	28810145	Missense mutations at K666 and R625 in splicing factor SF3B1 are associated with alternative branchpoint usage, and missense mutations at P95 in splicing factor SRSF2 are associated with exon exclusion in myelodysplastic syndrome/acute myeloid leukemia.	('SF3B1', 'Gene', '23451', (55, 60))	('Missense mutations at K666', 'Var', (0, 26))	('P95', 'Gene', (138, 141))	('associated', 'Reg', (65, 75))	('splicing factor', 'Gene', '10569', (145, 160))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (230, 252))	('R625', 'Var', (31, 35))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (230, 252))	('P95', 'Gene', '4683', (138, 141))	('splicing', 'biological_process', 'GO:0045292', ('39', '47'))	('leukemia', 'Phenotype', 'HP:0001909', (244, 252))	('splicing', 'biological_process', 'GO:0045292', ('145', '153'))	('myelodysplastic syndrome', 'Disease', (205, 229))	('SRSF2', 'Gene', '6427', (161, 166))	('splicing factor', 'Gene', (39, 54))	('associated', 'Reg', (171, 181))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (236, 252))	('SRSF2', 'Gene', (161, 166))	('SF3B1', 'Gene', (55, 60))	('splicing factor', 'Gene', (145, 160))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (205, 229))	('splicing factor', 'Gene', '10569', (39, 54))	('alternative branchpoint usage', 'MPA', (81, 110))	('acute myeloid leukemia', 'Disease', (230, 252))	('exon', 'MPA', (187, 191))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (205, 229))
15467	28810145	Using rMATS to compare RNA sequencing (RNA-seq) data for UM with mutations in either gene versus UM with wild-type SF3B1 and SRSF2 suggested that such mutations may alter translation initiation in a large subset of UM.	('translation initiation', 'MPA', (171, 193))	('SRSF2', 'Gene', '6427', (125, 130))	('alter', 'Reg', (165, 170))	('translation initiation', 'biological_process', 'GO:0006413', ('171', '193'))	('SF3B1', 'Gene', (115, 120))	('RNA', 'cellular_component', 'GO:0005562', ('23', '26'))	('SF3B1', 'Gene', '23451', (115, 120))	('RNA', 'cellular_component', 'GO:0005562', ('39', '42'))	('SRSF2', 'Gene', (125, 130))	('mutations', 'Var', (65, 74))
15468	28810145	For example, when SF3B1 has a K666/R625 mutation, EIF4A2 used a neo-acceptor that resulted in a frameshift in the open reading frame (Figure S1D), and when SRSF2 had a Y92del, EIF4A2 had a skipped exon.	('EIF4A2', 'Gene', (50, 56))	('Y92del', 'Mutation', 'p.92delY', (168, 174))	('EIF4', 'cellular_component', 'GO:0008304', ('176', '180'))	('EIF4', 'cellular_component', 'GO:0008304', ('50', '54'))	('SRSF2', 'Gene', (156, 161))	('EIF4A2', 'Gene', '1974', (50, 56))	('K666/R625', 'Var', (30, 39))	('SF3B1', 'Gene', (18, 23))	('Y92del', 'Var', (168, 174))	('SRSF2', 'Gene', '6427', (156, 161))	('SF3B1', 'Gene', '23451', (18, 23))	('EIF4A2', 'Gene', '1974', (176, 182))	('EIF4A2', 'Gene', (176, 182))	('frameshift', 'Var', (96, 106))
15469	28810145	In SRSF2 Y92del UM, Src kinase FYN had a skipped exon and a larger ratio of FYN-T versus FYN-B isoforms (Figures S1E and S1F).	('FYN', 'Gene', (76, 79))	('FYN', 'Gene', '2534', (76, 79))	('FYN', 'Gene', (89, 92))	('SRSF2', 'Gene', (3, 8))	('Y92del', 'Mutation', 'p.92delY', (9, 15))	('larger', 'PosReg', (60, 66))	('FYN', 'Gene', '2534', (89, 92))	('FYN', 'Gene', (31, 34))	('ratio', 'MPA', (67, 72))	('SRSF2', 'Gene', '6427', (3, 8))	('FYN', 'Gene', '2534', (31, 34))	('Y92del UM', 'Var', (9, 18))
15471	28810145	Both germline and somatic BAP1 alterations have been described in UM.	('BAP1', 'Gene', (26, 30))	('alterations', 'Var', (31, 42))	('BAP1', 'Gene', '8314', (26, 30))
15472	28810145	While Sanger sequencing initially identified truncating and non-trun-cating BAP1 mutations in 81.5% of M3-UM, in our cohort standard SNP/indel analysis of WES data identified only 40.5% (17/42) of M3-UM as having BAP1 mutations.	('truncating', 'MPA', (45, 55))	('BAP1', 'Gene', (213, 217))	('BAP1', 'Gene', '8314', (76, 80))	('BAP1', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('BAP1', 'Gene', '8314', (213, 217))
15474	28810145	Combining results from both methods and data types identified an additional 18 UM with BAP1 alterations, often long or complex, raising the percentage of samples with BAP1 alterations to 83.3% (Figure S1G).	('BAP1', 'Gene', '8314', (87, 91))	('BAP1', 'Gene', (87, 91))	('alterations', 'Var', (92, 103))	('BAP1', 'Gene', '8314', (167, 171))	('raising', 'PosReg', (128, 135))	('BAP1', 'Gene', (167, 171))
15478	28810145	We used ABSOLUTE to determine the relative timing of chromosome 3 loss and of BAP1 alterations (Figure 1C).	('loss', 'NegReg', (66, 70))	('alterations', 'Var', (83, 94))	('BAP1', 'Gene', '8314', (78, 82))	('chromosome', 'cellular_component', 'GO:0005694', ('53', '63'))	('BAP1', 'Gene', (78, 82))
15479	28810145	Most BAP1 alterations were predicted to be either subclonal or clonally homozygous.	('BAP1', 'Gene', '8314', (5, 9))	('alterations', 'Var', (10, 21))	('BAP1', 'Gene', (5, 9))
15482	28810145	Cancer cell fractions of BAP1 alterations were lower (mean = 0.88) and fractions of other putative passenger mutations on chromosome 3 were even lower (mean = 0.60).	('lower', 'NegReg', (47, 52))	('BAP1', 'Gene', (25, 29))	('chromosome', 'cellular_component', 'GO:0005694', ('122', '132'))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('alterations', 'Var', (30, 41))	('lower', 'NegReg', (145, 150))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('BAP1', 'Gene', '8314', (25, 29))
15483	28810145	From these results, we infer that M3 occurs prior to BAP1 alterations, and that both events occur prior to other mutations on the remaining chromosome 3, followed by WGD in some cases (Figure 1D).	('alterations', 'Var', (58, 69))	('chromosome', 'cellular_component', 'GO:0005694', ('140', '150'))	('BAP1', 'Gene', '8314', (53, 57))	('BAP1', 'Gene', (53, 57))
15484	28810145	EIF1AX mutant tumors were only present in DNA methylation cluster 1, while UM in DNA methylation clusters 2 and 3 were highly enriched (12 of 16 tumors) in SF3B1/SRFR2 mutations.	('DNA methylation', 'biological_process', 'GO:0006306', ('42', '57'))	('mutant', 'Var', (7, 13))	('SF3B1', 'Gene', '23451', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('DNA methylation', 'biological_process', 'GO:0006306', ('81', '96'))	('tumors', 'Disease', (14, 20))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('EIF1AX', 'Gene', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('mutations', 'Var', (168, 177))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('EIF1AX', 'Gene', '1964', (0, 6))	('SF3B1', 'Gene', (156, 161))
15485	28810145	Thus, D3-UM with EIF1AX versus SF3B1/SRFR2 mutations possessed distinct DNA methylation patterns.	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('SF3B1', 'Gene', (31, 36))	('mutations', 'Var', (43, 52))	('DNA methylation', 'biological_process', 'GO:0006306', ('72', '87'))	('DNA methylation', 'MPA', (72, 87))	('EIF1AX', 'Gene', '1964', (17, 23))	('EIF1AX', 'Gene', (17, 23))	('SF3B1', 'Gene', '23451', (31, 36))
15496	28810145	MicroRNA sequencing (miRNA-seq) data identified four consensus clusters, with a two-sample outlier group in which cancer-associated miRNAs were differentially abundant (e.g., miR-9, -21, -182/3, -375; Figure S3A).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('S3A', 'Gene', (208, 211))	('miR-9', 'Var', (175, 180))	('S3A', 'Gene', '6189', (208, 211))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
15497	28810145	Consistent with, miR-199a-3p/5p, miR-199b-3p, and let-7b-5p were more highly expressed in the M3-enriched miRNA cluster 3 (Figure S3D).	('miR-199a-3p', 'Gene', '406977', (17, 28))	('miR-199a-3p', 'Gene', (17, 28))	('let-7b-5p', 'Var', (50, 59))	('miR-199b-3p', 'Var', (33, 44))
15498	28810145	In addition, miR-486-5p and miR-451a were abundant in miRNA cluster 3, while cluster-4 tumors showed higher expression of miR-142, -150, -21, -29b, -146b, and -155.	('miR-142', 'Gene', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('higher', 'PosReg', (101, 107))	('miR-451a', 'Gene', '574411', (28, 36))	('miR-451a', 'Gene', (28, 36))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('miR-486-5p', 'Var', (13, 23))	('expression', 'MPA', (108, 118))	('tumors', 'Disease', (87, 93))	('miR-142', 'Gene', '406934', (122, 129))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
15501	28810145	Expression of certain miRNAs was influenced by SCNA; miR-30d and miR-151a expression was correlated with 8q SCNA (Figures S3E-S3G), and M3-UM had lower expression of a number of chromosome 3 miRNAs, including let-7g, miR-28, and miR-191.	('let-7g', 'Gene', (209, 215))	('miR-30d', 'Gene', '407033', (53, 60))	('miR-28', 'Gene', (217, 223))	('M3-UM', 'Var', (136, 141))	('miR-28', 'Gene', '407020', (217, 223))	('miR-30d', 'Gene', (53, 60))	('lower', 'NegReg', (146, 151))	('let-7g', 'Gene', '406890', (209, 215))	('miR-191', 'Gene', '406966', (229, 236))	('miR-151a', 'Gene', (65, 73))	('miR-151a', 'Gene', '442893', (65, 73))	('miR-191', 'Gene', (229, 236))	('expression', 'MPA', (152, 162))	('chromosome', 'cellular_component', 'GO:0005694', ('178', '188'))	('8q', 'Chemical', '-', (105, 107))
15517	28810145	Thus, activities for MYC/MAX/MIZ, but not MYC/MAX, corresponded with M3/8q-gain status.	('activities', 'MPA', (6, 16))	('M3/8q-gain', 'Var', (69, 79))	('MYC', 'Gene', (42, 45))	('8q', 'Chemical', '-', (72, 74))	('MYC', 'Gene', '4609', (21, 24))	('MYC', 'Gene', '4609', (42, 45))	('MYC', 'Gene', (21, 24))
15520	28810145	M3/BAP1-aberrant UM had a higher (p = 0.017) DDR pathway score than D3/SF3B1 R625-mutant UM (Figure 5B and Table S3).	('SF3B1', 'Gene', (71, 76))	('BAP1', 'Gene', '8314', (3, 7))	('higher', 'PosReg', (26, 32))	('DDR', 'Chemical', '-', (45, 48))	('BAP1', 'Gene', (3, 7))	('R625-mutant', 'Var', (77, 88))	('SF3B1', 'Gene', '23451', (71, 76))	('DDR pathway score', 'Pathway', (45, 62))
15521	28810145	This is consistent with PARADIGM pathway results; with in vitro data indicating a role for BAP1 in homologous recombination DDR; and with each of the M3/BAP1-aberrant UM evaluated in the RPPA analysis having evidence of isochromosome 8q gain, which can be mediated through inefficient repair of homologous recombination.	('isochromosome', 'Var', (220, 233))	('BAP1', 'Gene', (91, 95))	('DDR', 'Chemical', '-', (124, 127))	('gain', 'PosReg', (237, 241))	('BAP1', 'Gene', '8314', (153, 157))	('8q', 'Chemical', '-', (234, 236))	('BAP1', 'Gene', '8314', (91, 95))	('homologous recombination', 'biological_process', 'GO:0035825', ('99', '123'))	('BAP1', 'Gene', (153, 157))	('homologous recombination', 'biological_process', 'GO:0035825', ('295', '319'))
15522	28810145	All of the samples tested by RPPA harbored an activating GNAQ/11 mutation, and protein kinase C (PKC) isoforms are downstream effectors of activated mutant GNAQ/11.	('GNAQ', 'Gene', (156, 160))	('protein kinase C', 'Gene', '112476', (79, 95))	('GNAQ', 'Gene', (57, 61))	('PKC', 'Gene', (97, 100))	('PKC', 'Gene', '112476', (97, 100))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('protein kinase C', 'Gene', (79, 95))	('GNAQ', 'Gene', '2776', (156, 160))	('mutation', 'Var', (65, 73))	('PKC', 'molecular_function', 'GO:0004697', ('97', '100'))	('activating', 'PosReg', (46, 56))	('GNAQ', 'Gene', '2776', (57, 61))
15533	28810145	We show that poor-prognosis M3-UM is associated with a distinct global DNA methylation pattern that differs from the pattern observed in D3-UM, suggesting that BAP1 aberrancy may result in metastasis-prone DNA methylation state.	('DNA methylation', 'biological_process', 'GO:0006306', ('71', '86'))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('aberrancy', 'Var', (165, 174))	('DNA', 'cellular_component', 'GO:0005574', ('206', '209'))	('BAP1', 'Gene', '8314', (160, 164))	('result in', 'Reg', (179, 188))	('DNA methylation', 'biological_process', 'GO:0006306', ('206', '221'))	('BAP1', 'Gene', (160, 164))	('metastasis-prone DNA methylation state', 'MPA', (189, 227))	('M3-UM', 'Disease', (28, 33))
15535	28810145	Given the proposed role of BAP1 in DDR, and the upregulated DDR pathway activity by both transcription- and protein-based pathway analyses, these data suggest that loss of BAP1 function may result in inefficient DDR, and may play a role in isochromosome 8q formation observed in all SCNA cluster 4 and one-fourth of SCNA cluster 3 M3-UM samples; however, studies to confirm this hypothesis are beyond the scope of TCGA.	('loss', 'Var', (164, 168))	('DDR', 'MPA', (212, 215))	('DDR', 'Chemical', '-', (212, 215))	('BAP1', 'Gene', (27, 31))	('BAP1', 'Gene', (172, 176))	('DDR', 'Chemical', '-', (35, 38))	('inefficient', 'NegReg', (200, 211))	('8q', 'Chemical', '-', (254, 256))	('BAP1', 'Gene', '8314', (172, 176))	('isochromosome 8q formation', 'MPA', (240, 266))	('transcription', 'biological_process', 'GO:0006351', ('89', '102'))	('upregulated', 'PosReg', (48, 59))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('formation', 'biological_process', 'GO:0009058', ('257', '266'))	('DDR', 'Chemical', '-', (60, 63))	('BAP1', 'Gene', '8314', (27, 31))
15537	28810145	In contrast, the MYC/MAX/MIZ1 complex targets were most prominently activated only in samples with 8q gain, suggesting that other processes, in addition to copy number gain, e.g., post-transcriptional alterations, may also be relevant to MYC signaling in these UM subtypes.	('MYC', 'Gene', (17, 20))	('MIZ1', 'Gene', (25, 29))	('MIZ1', 'Gene', '9063', (25, 29))	('signaling', 'biological_process', 'GO:0023052', ('242', '251'))	('MYC', 'Gene', (238, 241))	('8q gain', 'Var', (99, 106))	('activated', 'PosReg', (68, 77))	('MYC', 'Gene', '4609', (17, 20))	('8q', 'Chemical', '-', (99, 101))	('MYC', 'Gene', '4609', (238, 241))
15543	28810145	We ultimately identified BAP1 alterations in ~85% of M3-UM, consistent with the initial report using Sanger sequencing.While next-generation sequencing (NGS) has become the standard for detecting germline and somatic BAP1 alterations in both research and clinical settings, more than half of the BAP1 alterations were initially missed by NGS mutation detection algorithms used in our study, and the identification of additional BAP1 alterations required assembly-based methods.	('BAP1', 'Gene', '8314', (217, 221))	('BAP1', 'Gene', '8314', (296, 300))	('BAP1', 'Gene', (25, 29))	('BAP1', 'Gene', (217, 221))	('BAP1', 'Gene', (296, 300))	('alterations', 'Var', (301, 312))	('BAP1', 'Gene', '8314', (428, 432))	('alterations', 'Var', (222, 233))	('BAP1', 'Gene', '8314', (25, 29))	('BAP1', 'Gene', (428, 432))
15545	28810145	Almost all of our UM harbored mutually exclusive hotspot mutations in GNAQ, GNA11, CYSLTR2, or PLCB4, suggesting that constitutively activated G-protein signaling plays a central role in early UM development.	('GNA11', 'Gene', '2767', (76, 81))	('GNA11', 'Gene', (76, 81))	('signaling', 'biological_process', 'GO:0023052', ('153', '162'))	('CYSLTR2', 'Gene', '57105', (83, 90))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('GNAQ', 'Gene', '2776', (70, 74))	('PLCB4', 'Gene', (95, 100))	('CYSLTR2', 'Gene', (83, 90))	('mutations', 'Var', (57, 66))	('GNAQ', 'Gene', (70, 74))	('PLCB4', 'Gene', '5332', (95, 100))
15546	28810145	Furthermore, neither CYSLTR2 nor PLCB4 mutations preferentially localized to a specific subset of UM, consistent with mutations in these genes functioning like GNAQ/11 mutations to drive tumorigenesis without initiating metastasis.	('CYSLTR2', 'Gene', '57105', (21, 28))	('GNAQ', 'Gene', (160, 164))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('PLCB4', 'Gene', (33, 38))	('CYSLTR2', 'Gene', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('mutations', 'Var', (118, 127))	('drive', 'PosReg', (181, 186))	('GNAQ', 'Gene', '2776', (160, 164))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', (187, 192))	('PLCB4', 'Gene', '5332', (33, 38))
15547	28810145	Mutant-activated GNAQ/11 signal through PKC-alpha, and we show that M3/BAP1-aberrant tumors had elevated total and activated PKC-alpha (and -delta) protein levels.	('PKC-alpha', 'Gene', (40, 49))	('PKC-alpha', 'Gene', '5578', (40, 49))	('PKC', 'molecular_function', 'GO:0004697', ('40', '43'))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('BAP1', 'Gene', (71, 75))	('Mutant-activated', 'Var', (0, 16))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('PKC', 'molecular_function', 'GO:0004697', ('125', '128'))	('GNAQ', 'Gene', (17, 21))	('PKC-alpha', 'Gene', (125, 134))	('BAP1', 'Gene', '8314', (71, 75))	('GNAQ', 'Gene', '2776', (17, 21))	('elevated', 'PosReg', (96, 104))	('PKC-alpha', 'Gene', '5578', (125, 134))	('activated', 'PosReg', (115, 124))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
15548	28810145	Thus, BAP1 aberrancy may enhance the effector function of PKC downstream of mutant-activated GNAQ/11.	('PKC', 'Gene', (58, 61))	('effector function', 'MPA', (37, 54))	('mutant-activated', 'Var', (76, 92))	('PKC', 'Gene', '112476', (58, 61))	('PKC', 'molecular_function', 'GO:0004697', ('58', '61'))	('BAP1', 'Gene', (6, 10))	('enhance', 'PosReg', (25, 32))	('GNAQ', 'Gene', '2776', (93, 97))	('aberrancy', 'Var', (11, 20))	('BAP1', 'Gene', '8314', (6, 10))	('GNAQ', 'Gene', (93, 97))
15551	28810145	We showed that UM with SRSF2 or SF3B1 mutations have mutation-specific mis-splicing that affects elongation initiation factors and signaling gene transcripts that are known to play a role in tumorigenesis.	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('mis-splicing', 'Var', (71, 83))	('SRSF2', 'Gene', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('affects', 'Reg', (89, 96))	('SF3B1', 'Gene', '23451', (32, 37))	('signaling gene transcripts', 'MPA', (131, 157))	('SRSF2', 'Gene', '6427', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('splicing', 'biological_process', 'GO:0045292', ('75', '83'))	('elongation initiation factors', 'MPA', (97, 126))	('mutations', 'Var', (38, 47))	('SF3B1', 'Gene', (32, 37))
15552	28810145	Previous genetic studies had identified nearly mutually exclusive mutations in SF3B1 and EIF1AX in UM.	('mutations', 'Var', (66, 75))	('SF3B1', 'Gene', (79, 84))	('EIF1AX', 'Gene', '1964', (89, 95))	('EIF1AX', 'Gene', (89, 95))	('SF3B1', 'Gene', '23451', (79, 84))
15553	28810145	In our cohort, UM with SF3B1 mutations were enriched in SCNA clusters 2 and 3, while virtually absent in UM with the lowest and highest levels of aneuploidy (clusters 1 and 4 respectively).	('SF3B1', 'Gene', '23451', (23, 28))	('mutations', 'Var', (29, 38))	('aneuploidy', 'Disease', (146, 156))	('aneuploidy', 'Disease', 'MESH:D000782', (146, 156))	('SF3B1', 'Gene', (23, 28))	('SCNA clusters 2', 'Disease', (56, 71))
15554	28810145	UM with SRSF2 mutations harbored neither EIF1AX nor SF3B1 mutations, and, like all but one SF3B1-mutated case, were observed only in SCNA clusters 2 and 3.	('SRSF2', 'Gene', (8, 13))	('SF3B1', 'Gene', (91, 96))	('EIF1AX', 'Gene', (41, 47))	('SF3B1', 'Gene', '23451', (91, 96))	('SF3B1', 'Gene', (52, 57))	('SRSF2', 'Gene', '6427', (8, 13))	('SF3B1', 'Gene', '23451', (52, 57))	('EIF1AX', 'Gene', '1964', (41, 47))	('mutations', 'Var', (14, 23))
15574	28810145	We say "and/or" because, while BAP1 alterations in the setting of M3 typically result in decreased BAP1 mRNA expression, we detected no BAP1 alterations in 7 of 42 M3 tumors in our cohort.	('BAP1', 'Gene', (99, 103))	('BAP1', 'Gene', (136, 140))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('BAP1', 'Gene', '8314', (31, 35))	('alterations', 'Var', (36, 47))	('BAP1', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('BAP1', 'Gene', '8314', (99, 103))	('BAP1', 'Gene', '8314', (136, 140))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('decreased', 'NegReg', (89, 98))
15575	28810145	It is possible that BAP1 alterations were present in these cases, but our approaches failed to detect them; alternatively, BAP1 with unaltered sequence may be epigenetically modulated in these cases.	('BAP1', 'Gene', (123, 127))	('BAP1', 'Gene', (20, 24))	('epigenetically modulated', 'Var', (159, 183))	('BAP1', 'Gene', '8314', (123, 127))	('BAP1', 'Gene', '8314', (20, 24))
15577	28810145	Eleven of these 12 cases had BAP1, SF3B1 or EIF1AX mutations; V4-A9EH did not, and was removed from further analysis (Table S1).	('SF3B1', 'Gene', '23451', (35, 40))	('mutations', 'Var', (51, 60))	('EIF1AX', 'Gene', '1964', (44, 50))	('EIF1AX', 'Gene', (44, 50))	('BAP1', 'Gene', '8314', (29, 33))	('SF3B1', 'Gene', (35, 40))	('BAP1', 'Gene', (29, 33))
15594	28810145	Somatic insertions or deletions (sINDELs) were identified using Indelocator, which similarly uses pileups to identify tumor-specific variants.	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('deletions', 'Var', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (118, 123))
15610	28810145	As part of this process of copy number assessment and segmentation, regions corresponding to germline copy number alterations were removed by applying filters generated from either the 80 UM blood normals, or the larger cohort of blood normals in the TCGA ovarian cancer analysis.	('alterations', 'Var', (114, 125))	('ovarian cancer', 'Disease', 'MESH:D010051', (256, 270))	('segmentation', 'biological_process', 'GO:0035282', ('54', '66'))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('ovarian cancer', 'Disease', (256, 270))	('ovarian cancer', 'Phenotype', 'HP:0100615', (256, 270))
15619	28810145	In VD-AA8O, when a homozygous deletion within BAP1 was reported from DNA data but not by our analysis of RNA-seq data, we used deFuse on the RNA-seq data to confirm the deletion.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('RNA', 'cellular_component', 'GO:0005562', ('105', '108'))	('BAP1', 'Gene', '8314', (46, 50))	('deletion', 'Var', (30, 38))	('BAP1', 'Gene', (46, 50))	('RNA', 'cellular_component', 'GO:0005562', ('141', '144'))
15624	28810145	Splicing defects associated with mutations in splicing factors SRSF2 or SF3B1 were identified with rMATS 3.0.9.	('Splicing', 'biological_process', 'GO:0045292', ('0', '8'))	('splicing factor', 'Gene', (46, 61))	('mutations', 'Var', (33, 42))	('SF3B1', 'Gene', (72, 77))	('Splicing defects', 'MPA', (0, 16))	('splicing', 'biological_process', 'GO:0045292', ('46', '54'))	('SRSF2', 'Gene', (63, 68))	('SRSF2', 'Gene', '6427', (63, 68))	('SF3B1', 'Gene', '23451', (72, 77))	('splicing factor', 'Gene', '10569', (46, 61))
15625	28810145	Two samples with in-frame deletions in the SRSF2 linker sequence between the functional RRM and RS domains were compared with five randomly chosen control samples that had no somatic mutations in spliceosomal genes.	('SRSF2', 'Gene', '6427', (43, 48))	('SRSF2', 'Gene', (43, 48))	('deletions', 'Var', (26, 35))
15626	28810145	Eighteen samples with SF3B1 missense mutations in HEAT domains were compared to 20 control samples.	('SF3B1', 'Gene', '23451', (22, 27))	('missense mutations', 'Var', (28, 46))	('SF3B1', 'Gene', (22, 27))
15627	28810145	To increase sensitivity to novel splice junctions in the SF3B1 comparison, a custom annotation was created from mutant and control samples with Cufflinks 2.2.1 using default parameters.	('SF3B1', 'Gene', (57, 62))	('SF3B1', 'Gene', '23451', (57, 62))	('mutant', 'Var', (112, 118))
15639	28810145	After passing quality control, bisulfite-converted DNA samples were whole-genome amplified followed by enzymatic fragmentation and hybridized overnight to BeadChips followed by a locus-specific base extension with labeled nucleotides (cy3 and cy5).	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('cy5', 'Chemical', 'MESH:C085321', (243, 246))	('cy3', 'Var', (235, 238))	('cy5', 'Var', (243, 246))	('cy3', 'Chemical', '-', (235, 238))	('bisulfite', 'Chemical', 'MESH:C042345', (31, 40))
15648	28810145	Variants from tumor genomes were filtered by those in normal genomes, and germline events were removed.	('Variants', 'Var', (0, 8))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
15661	28810145	Of the 12 samples that had RPPA data available, 6 were D3/SF3B1 mutants and 5 were M3/BAP1-aberrant in a mutually exclusive manner.	('BAP1', 'Gene', '8314', (86, 90))	('SF3B1', 'Gene', (58, 63))	('BAP1', 'Gene', (86, 90))	('SF3B1', 'Gene', '23451', (58, 63))	('mutants', 'Var', (64, 71))
15675	28810145	An initial minimum variation filter (at least 1 sample with absolute activity > 0.05) was applied, resulting in 15,502 concepts (5,898 proteins, 7,307 complexes, 1,916 families, 12 mRNAs, 15 miRNAs and 354 abstract processes) with relative activities showing distinguishable variation across tumors (syn4556729) for use in our differential pathway regulator analysis.	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('tumors', 'Disease', (292, 298))	('tumors', 'Disease', 'MESH:D009369', (292, 298))	('syn4556729', 'Var', (300, 310))
15683	28810145	for CD44, given 13 probes we used 229221_at; for MALAT1, given 12 probes we used 224559_at).	('229221_at', 'Var', (34, 43))	('MALAT1', 'Gene', '378938', (49, 55))	('CD44', 'Gene', '960', (4, 8))	('MALAT1', 'Gene', (49, 55))	('CD44', 'Gene', (4, 8))
15686	28810145	Both D3 and M3-UM divide into molecularly distinct subsets with different outcomes Poor-prognosis M3-UM are characterized by a global DNA methylation pattern Poor-prognosis M3-UM subsets have distinct genomic, signaling, and immune profiles EIF1AX and SRSF2/SF3B1 mutant D3-UM have different genomic/DNA methylation profiles Using sequence assembly approaches, we identified complex alterations in BAP1 in multiple UM that were not revealed by applying standard SNP/indel algorithms to next-generation sequencing data, suggesting that many BAP1 alterations are undetected using current techniques.	('BAP1', 'Gene', '8314', (398, 402))	('DNA methylation', 'biological_process', 'GO:0006306', ('300', '315'))	('SRSF2', 'Gene', (252, 257))	('BAP1', 'Gene', '8314', (540, 544))	('signaling', 'biological_process', 'GO:0023052', ('210', '219'))	('DNA methylation', 'biological_process', 'GO:0006306', ('134', '149'))	('DNA', 'cellular_component', 'GO:0005574', ('300', '303'))	('BAP1', 'Gene', (398, 402))	('mutant', 'Var', (264, 270))	('SF3B1', 'Gene', (258, 263))	('BAP1', 'Gene', (540, 544))	('SRSF2', 'Gene', '6427', (252, 257))	('EIF1AX', 'Gene', '1964', (241, 247))	('SF3B1', 'Gene', '23451', (258, 263))	('EIF1AX', 'Gene', (241, 247))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))
15687	28810145	We show that poor-prognosis UM initially develop monosomy 3 (M3), followed by BAP1 alterations that are associated with a unique global DNA methylation profile.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('alterations', 'Var', (83, 94))	('monosomy 3', 'Disease', (49, 59))	('DNA methylation', 'biological_process', 'GO:0006306', ('136', '151'))	('BAP1', 'Gene', '8314', (78, 82))	('BAP1', 'Gene', (78, 82))
15699	28303962	The most frequent chromosomal abnormalities in uveal melanoma are loss of chromosome 3 and gains of 8q and 6p.	('gains', 'Var', (91, 96))	('loss', 'NegReg', (66, 70))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('chromosomal abnormalities', 'Disease', (18, 43))	('chromosome', 'cellular_component', 'GO:0005694', ('74', '84'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (18, 43))	('uveal melanoma', 'Disease', (47, 61))
15701	28303962	Mutations in G-protein-alpha subunits GNAQ or GNA11 are observed in >=80% of primary uveal melanomas and inactivating BAP1 mutations are found in approximately 50% of all cases, most frequently in metastatic disease.	('GNAQ', 'Gene', '2776', (38, 42))	('inactivating', 'Var', (105, 117))	('GNAQ', 'Gene', (38, 42))	('uveal melanoma', 'Phenotype', 'HP:0007716', (85, 99))	('observed', 'Reg', (56, 64))	('uveal melanomas', 'Disease', (85, 100))	('G-protein-alpha', 'Protein', (13, 28))	('uveal melanomas', 'Phenotype', 'HP:0007716', (85, 100))	('BAP1', 'Gene', '8314', (118, 122))	('Mutations', 'Var', (0, 9))	('GNA11', 'Gene', '2767', (46, 51))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('BAP1', 'Gene', (118, 122))	('metastatic disease', 'Disease', (197, 215))	('uveal melanomas', 'Disease', 'MESH:C536494', (85, 100))	('GNA11', 'Gene', (46, 51))	('mutations', 'Var', (123, 132))
15702	28303962	Mutations that are associated with a less aggressive behavior are those in splicing factor 3B subunit 1 (SF3B1) and eukaryotic translation initiation factor 1A, X-linked (EIF1AX).	('aggressive behavior', 'biological_process', 'GO:0002118', ('42', '61'))	('SF3B1', 'Gene', (105, 110))	('eukaryotic translation initiation factor 1A, X-linked', 'Gene', '1964', (116, 169))	('splicing factor 3B subunit 1', 'Gene', '23451', (75, 103))	('EIF1AX', 'Gene', '1964', (171, 177))	('EIF1AX', 'Gene', (171, 177))	('SF3B1', 'Gene', '23451', (105, 110))	('splicing factor 3B subunit 1', 'Gene', (75, 103))	('Mutations', 'Var', (0, 9))	('splicing', 'biological_process', 'GO:0045292', ('75', '83'))	('aggressive behavior', 'Phenotype', 'HP:0000718', (42, 61))	('translation initiation', 'biological_process', 'GO:0006413', ('127', '149'))
15727	28303962	The top identified drugs were the following: BRD-K07220430 (Cinnarizine), an anti-histaminic drug used for motion sickness, was predicted for its ability to downregulate CHAC1 and to upregulate MBNL1, LPAR6, PLSCR4, NDN, ABHD6, ZSCAN18 and ZBTB20; Digitoxigenin, for its ability to downregulate CDC25B, IDE, INTS8 and MTDH, while upregulating F11R, ID2, and RAB11FIP1; clofazimine, a fat-soluble iminophenazine used in leprosy, which is able to downregulate CDC25B, CHAC1, and SHC1, and to upregulate ABHD6, PLOD2, PLSCR4, ZBTB20, ZSCAN18.	('ZBTB20', 'Gene', '26137', (240, 246))	('ZSCAN18', 'Gene', '65982', (228, 235))	('Cinnarizine', 'Chemical', 'MESH:D002936', (60, 71))	('soluble', 'cellular_component', 'GO:0005625', ('388', '395'))	('PLSCR4', 'Gene', '57088', (515, 521))	('ZSCAN18', 'Gene', (531, 538))	('RAB11FIP1', 'Gene', '80223', (358, 367))	('IDE', 'Gene', (303, 306))	('NDN', 'Gene', '4692', (216, 219))	('CDC25B', 'Gene', '994', (295, 301))	('CDC25B', 'Gene', (295, 301))	('ABHD6', 'Gene', '57406', (501, 506))	('clofazimine', 'Chemical', 'MESH:D002991', (369, 380))	('ABHD6', 'Gene', '57406', (221, 226))	('ZBTB20', 'Gene', '26137', (523, 529))	('upregulate', 'PosReg', (490, 500))	('IDE', 'Gene', '3416', (303, 306))	('ZSCAN18', 'Gene', (228, 235))	('CHAC1', 'Gene', '79094', (466, 471))	('PLOD2', 'Gene', '5352', (508, 513))	('PLSCR4', 'Gene', (208, 214))	('INTS8', 'Gene', '55656', (308, 313))	('LPAR6', 'Gene', '10161', (201, 206))	('MTDH', 'Gene', (318, 322))	('PLSCR4', 'Gene', '57088', (208, 214))	('CHAC1', 'Gene', '79094', (170, 175))	('LPAR6', 'Gene', (201, 206))	('ID2', 'Gene', '3398', (349, 352))	('MBNL1', 'Gene', (194, 199))	('SHC1', 'Gene', (477, 481))	('MTDH', 'Gene', '92140', (318, 322))	('ZBTB20', 'Gene', (240, 246))	('F11R', 'Var', (343, 347))	('ID2', 'Gene', (349, 352))	('CDC25B', 'Gene', '994', (458, 464))	('iminophenazine', 'Chemical', '-', (396, 410))	('BRD-K07220430', 'Chemical', '-', (45, 58))	('Digitoxigenin', 'Chemical', 'MESH:D004073', (248, 261))	('CDC25B', 'Gene', (458, 464))	('downregulate', 'NegReg', (445, 457))	('CHAC1', 'Gene', (466, 471))	('SHC1', 'Gene', '6464', (477, 481))	('ZSCAN18', 'Gene', '65982', (531, 538))	('RAB11FIP1', 'Gene', (358, 367))	('ABHD6', 'Gene', (501, 506))	('leprosy', 'Disease', (419, 426))	('ABHD6', 'Gene', (221, 226))	('NDN', 'Gene', (216, 219))	('PLSCR4', 'Gene', (515, 521))	('INTS8', 'Gene', (308, 313))	('MBNL1', 'Gene', '4154', (194, 199))	('leprosy', 'Disease', 'MESH:D007918', (419, 426))	('ZBTB20', 'Gene', (523, 529))	('F11R', 'SUBSTITUTION', 'None', (343, 347))	('CHAC1', 'Gene', (170, 175))	('PLOD2', 'Gene', (508, 513))	('IDE', 'molecular_function', 'GO:0004231', ('303', '306'))
15728	28303962	Accordingly, the top three most promising drug combination found were: BRD-K07220430 and Digitoxigenin; Digitoxigenin and OSSK_645683; BRD-K07220430 and HDAC6 inhibitor ISOX (for the complete list, see Table 5).	('ISOX', 'Chemical', '-', (169, 173))	('BRD-K07220430', 'Chemical', '-', (71, 84))	('BRD-K07220430', 'Chemical', '-', (135, 148))	('Digitoxigenin', 'Chemical', 'MESH:D004073', (89, 102))	('HDAC6', 'Gene', '10013', (153, 158))	('BRD-K07220430', 'Var', (135, 148))	('HDAC6', 'Gene', (153, 158))	('BRD-K07220430', 'Var', (71, 84))	('OSSK_645683', 'Chemical', '-', (122, 133))	('Digitoxigenin', 'Chemical', 'MESH:D004073', (104, 117))
15747	28303962	Klisovic and collaborators have shown that the histone deacetylase inhibitor, Depsipeptide (FR901228), inhibits proliferation and induces apoptosis in primary and metastatic human uveal melanoma cell lines, as well as it is able to inhibit in vitro uveal melanoma cell lines migration via downregulation of Matrix MetalloProteinases 2, 9 and Membrane Type-1/MMP (MMP-2, MMP-9 and MT-1/MMP) and the upregulation of Tissue Inhibitors of Matrix MetalloProteinases 1 and 2 (TIMP-1 and TIMP-2).	('TIMP-1', 'Gene', '7076', (470, 476))	('uveal melanoma', 'Phenotype', 'HP:0007716', (180, 194))	('inhibits', 'NegReg', (103, 111))	('uveal melanoma', 'Disease', (249, 263))	('uveal melanoma', 'Disease', 'MESH:C536494', (249, 263))	('MT-1/MMP', 'Gene', '4323;644314', (380, 388))	('MMP-9', 'Gene', '4318', (370, 375))	('MMP-2', 'Gene', (363, 368))	('MMP-9', 'molecular_function', 'GO:0004229', ('370', '375'))	('upregulation', 'PosReg', (398, 410))	('MMP-9', 'Gene', (370, 375))	('FR901228', 'Var', (92, 100))	('uveal melanoma', 'Phenotype', 'HP:0007716', (249, 263))	('apoptosis', 'CPA', (138, 147))	('MMP', 'molecular_function', 'GO:0004235', ('385', '388'))	('induces', 'Reg', (130, 137))	('Matrix MetalloProteinases 2, 9 and Membrane Type-1/MMP', 'Gene', '4313;4318', (307, 361))	('TIMP-2', 'Gene', '7077', (481, 487))	('human', 'Species', '9606', (174, 179))	('MT-1', 'molecular_function', 'GO:0043791', ('380', '384'))	('MMP-2', 'molecular_function', 'GO:0004228', ('363', '368'))	('TIMP-2', 'Gene', (481, 487))	('Tissue', 'MPA', (414, 420))	('downregulation', 'NegReg', (289, 303))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('inhibit', 'NegReg', (232, 239))	('uveal melanoma', 'Disease', (180, 194))	('uveal melanoma', 'Disease', 'MESH:C536494', (180, 194))	('MMP-2', 'Gene', '4313', (363, 368))	('apoptosis', 'biological_process', 'GO:0097194', ('138', '147'))	('MT-1/MMP', 'Gene', (380, 388))	('MT-1', 'molecular_function', 'GO:0047152', ('380', '384'))	('melanoma', 'Phenotype', 'HP:0002861', (255, 263))	('apoptosis', 'biological_process', 'GO:0006915', ('138', '147'))	('MT-1', 'molecular_function', 'GO:0043834', ('380', '384'))	('MMP', 'molecular_function', 'GO:0004235', ('358', '361'))	('proliferation', 'CPA', (112, 125))	('TIMP-1', 'Gene', (470, 476))
15748	28303962	Chen and collaborators have shown that microRNA-137 and microRNA-124a act as a tumor suppressors in uveal melanoma and could be successfully silenced by using the histone deacetylase inhibitor, trichostatin A. Landreville and collegues have shown that in three uveal melanoma cell lines (92.1, OCM1A, and Mel202), Trichostatin A was able to reduce the fraction of viable cells and increase the proportion of cells undergoing apoptosis.	('uveal melanoma', 'Phenotype', 'HP:0007716', (261, 275))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('uveal melanoma', 'Disease', (100, 114))	('fraction of viable cells', 'CPA', (352, 376))	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('trichostatin A', 'Chemical', 'MESH:C012589', (194, 208))	('OCM1', 'Species', '83984', (294, 298))	('tumor', 'Disease', (79, 84))	('apoptosis', 'biological_process', 'GO:0097194', ('425', '434'))	('apoptosis', 'biological_process', 'GO:0006915', ('425', '434'))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('Trichostatin A', 'Chemical', 'MESH:C012589', (314, 328))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (261, 275))	('uveal melanoma', 'Disease', (261, 275))	('Trichostatin', 'Var', (314, 326))	('increase', 'PosReg', (381, 389))	('reduce', 'NegReg', (341, 347))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
15827	27453764	Association of tumor and plasma microRNA expression with tumor monosomy-3 in patients with uveal melanoma Epigenetic events mediated by methylation and histone modifications have been associated with the development of metastasis in patients with uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('uveal melanoma', 'Disease', 'MESH:C536494', (91, 105))	('uveal melanoma', 'Disease', (91, 105))	('melanoma', 'Phenotype', 'HP:0002861', (253, 261))	('Epigenetic events', 'MPA', (106, 123))	('patients', 'Species', '9606', (77, 85))	('histone modifications', 'Var', (152, 173))	('uveal melanoma', 'Phenotype', 'HP:0007716', (91, 105))	('metastasis', 'CPA', (219, 229))	('associated with', 'Reg', (184, 199))	('tumor', 'Disease', (57, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (247, 261))	('uveal melanoma', 'Disease', (247, 261))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (15, 20))	('patients', 'Species', '9606', (233, 241))	('uveal melanoma', 'Phenotype', 'HP:0007716', (247, 261))	('methylation', 'Var', (136, 147))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('methylation', 'biological_process', 'GO:0032259', ('136', '147'))
15829	27453764	miR profiling of tumors by microarray found six miRs over-expressed and 19 under-expressed in 33 tumors with monosomy-3 compared to 22 without.	('under-expressed', 'NegReg', (75, 90))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', (17, 23))	('miRs', 'Gene', (48, 52))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('monosomy-3', 'Var', (109, 119))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('over-expressed', 'PosReg', (53, 67))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
15830	27453764	None of the miRs differentially expressed in tumors with and without monosomy-3 was differentially expressed in tumors with and without tumor infiltrating lymphocytes.	('monosomy-3', 'Var', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Disease', (136, 141))	('tumors', 'Disease', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
15831	27453764	Tumors manifesting monosomy-3 were also characterized by higher levels of TARBP2 and DDX17 and by lower levels of XPO5 and HIWI, miR biogenesis factors.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('XPO5', 'Gene', (114, 118))	('XPO5', 'Gene', '57510', (114, 118))	('higher', 'PosReg', (57, 63))	('DDX17', 'Gene', (85, 90))	('monosomy-3', 'Var', (19, 29))	('Tumors', 'Disease', (0, 6))	('levels', 'MPA', (64, 70))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('TARBP2', 'Gene', '6895', (74, 80))	('DDX17', 'Gene', '10521', (85, 90))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('HIWI', 'Gene', (123, 127))	('TARBP2', 'Gene', (74, 80))	('HIWI', 'Gene', '9271', (123, 127))	('lower', 'NegReg', (98, 103))
15835	27453764	Elevated plasma levels in patients with tumor monosomy-3 of miR-92b, identified in the tumor array, and of miR-199-5p and miR-223, identified in the plasma array, were confirmed by quantitative real-time polymerase chain reaction.	('miR-223', 'Gene', (122, 129))	('miR-92b', 'Gene', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('plasma levels', 'MPA', (9, 22))	('tumor array', 'Disease', 'MESH:D009369', (87, 98))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (87, 92))	('patients', 'Species', '9606', (26, 34))	('tumor array', 'Disease', (87, 98))	('Elevated', 'PosReg', (0, 8))	('miR-92b', 'Gene', '693235', (60, 67))	('miR-223', 'Gene', '407008', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('miR-199-5p', 'Var', (107, 117))
15837	27453764	These results support a role for epigenetic mechanisms in the development of metastasis in patients with uveal melanoma and the analysis of miRs as biomarkers of metastatic risk.	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('patients', 'Species', '9606', (91, 99))	('epigenetic', 'Var', (33, 43))	('metastasis', 'CPA', (77, 87))	('uveal melanoma', 'Phenotype', 'HP:0007716', (105, 119))	('uveal melanoma', 'Disease', 'MESH:C536494', (105, 119))	('uveal melanoma', 'Disease', (105, 119))
15840	27453764	That loss of chromosome 3 in tumors is associated with the development of metastasis is well established, and a variety of techniques are being used to test tumors for monosomy-3.	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('associated', 'Reg', (39, 49))	('loss', 'Var', (5, 9))	('tumors', 'Disease', (29, 35))	('chromosome', 'cellular_component', 'GO:0005694', ('13', '23'))
15842	27453764	Epigenetic events have also been implicated in uveal melanoma metastasis.	('implicated', 'Reg', (33, 43))	('uveal melanoma metastasis', 'Disease', 'MESH:C536494', (47, 72))	('uveal melanoma metastasis', 'Disease', (47, 72))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('Epigenetic events', 'Var', (0, 17))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))
15844	27453764	Expression levels of a number of histone-modifying genes and polycomb family members are significantly lower in uveal melanoma with monosomy-3/class-2 GEP.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('Expression levels', 'MPA', (0, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (112, 126))	('lower', 'NegReg', (103, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (112, 126))	('uveal melanoma', 'Disease', (112, 126))	('monosomy-3/class-2 GEP', 'Var', (132, 154))
15845	27453764	Although epigenetic events mediated by microRNA (miR) have been implicated in uveal melanoma development, a role for miRs in the metastatic process has not been established.	('epigenetic events', 'Var', (9, 26))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('implicated', 'Reg', (64, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (78, 92))	('uveal melanoma', 'Disease', 'MESH:C536494', (78, 92))	('microRNA', 'Protein', (39, 47))	('uveal melanoma', 'Disease', (78, 92))
15846	27453764	found six miRs to be upregulated in 12 tumors expressing high-risk, class-2 GEP and 68 to be upregulated in 12 tumors expressing low-risk, class-1 GEP.	('class-2 GEP', 'Var', (68, 79))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('GEP', 'Var', (76, 79))	('upregulated', 'PosReg', (21, 32))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('upregulated', 'PosReg', (93, 104))	('tumors', 'Disease', (39, 45))
15853	27453764	miR and gene expression profiles of 33 enucleated uveal tumors with monosomy-3 and 22 without were obtained.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('gene expression', 'biological_process', 'GO:0010467', ('8', '23'))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('monosomy-3', 'Var', (68, 78))	('uveal tumors', 'Disease', (50, 62))	('uveal tumors', 'Disease', 'MESH:D014604', (50, 62))
15858	27453764	None of the miRs differentially expressed in tumors with and without monosomy-3 was differentially expressed in tumors with and without TILs.	('monosomy-3', 'Var', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', (112, 118))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
15860	27453764	Tumors manifesting monosomy-3 were characterized by higher levels of TARB2 and DDX17 and lower levels of XPO5 and HIWI (Fig.	('levels', 'MPA', (59, 65))	('lower', 'NegReg', (89, 94))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('XPO5', 'Gene', (105, 109))	('TARB2', 'MPA', (69, 74))	('XPO5', 'Gene', '57510', (105, 109))	('monosomy-3', 'Var', (19, 29))	('Tumors', 'Disease', (0, 6))	('DDX17', 'Gene', (79, 84))	('HIWI', 'Gene', (114, 118))	('HIWI', 'Gene', '9271', (114, 118))	('higher', 'PosReg', (52, 58))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('DDX17', 'Gene', '10521', (79, 84))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
15869	27453764	The focus was on the two miRs that were over-expressed in the tumor array that were measurable in plasma, miR-92b and miR-142-5p, and three miRs elevated in the plasma array, miR-191, miR-199a-5p, and miR-223.	('miR-223', 'Gene', '407008', (201, 208))	('tumor array', 'Disease', (62, 73))	('miR-191', 'Gene', '406966', (175, 182))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('miR-142', 'Gene', '406934', (118, 125))	('miR-191', 'Gene', (175, 182))	('miR-223', 'Gene', (201, 208))	('miR-92b', 'Gene', (106, 113))	('miR-199a-5p', 'Var', (184, 195))	('miR-142', 'Gene', (118, 125))	('over-expressed', 'PosReg', (40, 54))	('tumor array', 'Disease', 'MESH:D009369', (62, 73))	('miR-92b', 'Gene', '693235', (106, 113))
15871	27453764	miR-92b, miR-199a-5p, and miR-223 were significant higher in both the qNPA and the qRT-PCR analysis.	('miR-223', 'Gene', '407008', (26, 33))	('qNPA', 'Disease', (70, 74))	('miR-223', 'Gene', (26, 33))	('miR-92b', 'Gene', (0, 7))	('miR-199a-5p', 'Var', (9, 20))	('higher', 'PosReg', (51, 57))	('miR-92b', 'Gene', '693235', (0, 7))
15876	27453764	Plasma levels of miR-92b, 199a-5p, and 223 were significantly higher in patients with monosomy-3 when compared to patients with disomy; levels of all three were also higher when compared to levels of normal controls (Fig.	('higher', 'PosReg', (166, 172))	('miR-92b', 'Gene', (17, 24))	('higher', 'PosReg', (62, 68))	('patients', 'Species', '9606', (114, 122))	('Plasma levels', 'MPA', (0, 13))	('miR-92b', 'Gene', '693235', (17, 24))	('monosomy-3', 'Var', (86, 96))	('patients', 'Species', '9606', (72, 80))
15878	27453764	Of 858 miRs assessed in tumors manifesting monosomy-3, an accurate predictor of the development of metastasis, 6 were found to be over-expressed and 20, under-expressed.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('monosomy-3', 'Var', (43, 53))	('under-expressed', 'NegReg', (153, 168))	('over-expressed', 'PosReg', (130, 144))
15880	27453764	None of the miRs we found to be differentially expressed in tumors with monosomy-3 was differentially expressed in tumors studied by Worley et al., who used the class-2 GEP as a surrogate for metastasis.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('monosomy-3', 'Var', (72, 82))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
15881	27453764	The most significant discriminators in our study were under-expression of miRs of the 506-514 cluster, which has been implicated in initiating melanocyte transformation and promoting melanoma growth and invasiveness.	('melanocyte transformation', 'CPA', (143, 168))	('invasiveness', 'CPA', (203, 215))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('promoting', 'PosReg', (173, 182))	('miRs of the 506-514', 'Gene', (74, 93))	('under-expression', 'Var', (54, 70))	('melanoma growth', 'Disease', (183, 198))	('melanoma growth', 'Disease', 'MESH:D008545', (183, 198))
15882	27453764	Tumors manifesting monosomy-3 were characterized by alterations in miR processing factors, which have been associated with the development of metastasis in several types of cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('alterations', 'Reg', (52, 63))	('cancer', 'Disease', (173, 179))	('associated', 'Reg', (107, 117))	('miR processing', 'Protein', (67, 81))	('monosomy-3', 'Var', (19, 29))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
15889	27453764	Most of the miRs identified that were discriminatory in tumors with monosomy-3 were down-regulated.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('miRs', 'Protein', (12, 16))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('monosomy-3', 'Var', (68, 78))	('down-regulated', 'NegReg', (84, 98))
15893	27453764	These included one miR over-expressed in the tumor array, miR-92b, and two increased in the plasma array, miR-199a-5p and miR-223.	('miR-223', 'Gene', (122, 129))	('tumor array', 'Disease', (45, 56))	('tumor array', 'Disease', 'MESH:D009369', (45, 56))	('miR-199a-5p', 'Var', (106, 117))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('miR-92b', 'Gene', (58, 65))	('miR-223', 'Gene', '407008', (122, 129))	('over-expressed', 'PosReg', (23, 37))	('increased', 'PosReg', (75, 84))	('miR-92b', 'Gene', '693235', (58, 65))
15894	27453764	Of note, miR-92b belongs to a cluster of miRs that regulate T cells, including regulatory T cells, miR-199a-5p promotes regulatory T cells, and miR-223 regulates myeloid suppressor cells.	('miR-92b', 'Gene', (9, 16))	('miR-223', 'Gene', (144, 151))	('miR-92b', 'Gene', '693235', (9, 16))	('myeloid suppressor cells', 'CPA', (162, 186))	('miR-223', 'Gene', '407008', (144, 151))	('promotes', 'PosReg', (111, 119))	('regulates', 'Reg', (152, 161))	('regulatory T cells', 'CPA', (120, 138))	('miR-199a-5p', 'Var', (99, 110))
15902	27453764	At least 100 different miRs have been shown to circulate in the blood of healthy donors, including most of the miRs we found to be differentially increased, miR-19b, miR-191, miR-199a-5p, miR-25, miR-23a, miR-223, and miR-93.	('miR-199a-5p', 'Var', (175, 186))	('miR-223', 'Gene', '407008', (205, 212))	('miR-19b', 'Gene', '406980', (157, 164))	('increased', 'PosReg', (146, 155))	('miR-23a', 'Gene', '407010', (196, 203))	('miR-25', 'Gene', '407014', (188, 194))	('miR-191', 'Gene', '406966', (166, 173))	('donor', 'Species', '9606', (81, 86))	('miR-25', 'Gene', (188, 194))	('miR-223', 'Gene', (205, 212))	('miR-191', 'Gene', (166, 173))	('miR-23a', 'Gene', (196, 203))	('miR-93', 'Gene', '407051', (218, 224))	('miR-19b', 'Gene', (157, 164))	('miR-93', 'Gene', (218, 224))
15903	27453764	Several of the differentially expressed miRs identified have been previously reported to be elevated in the plasma or serum of patients with cancer, including miR-92b in prostate; miR-223 in lung, esophageal, and hepatocellular; and miRs-199a-5p, miRs-19b, miRs-15b, and miRs-25 in lung.	('miR-92b', 'Gene', '693235', (159, 166))	('miR-223', 'Gene', '407008', (180, 187))	('miRs-15b', 'Var', (257, 265))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('miRs-25', 'Var', (271, 278))	('elevated', 'PosReg', (92, 100))	('patients', 'Species', '9606', (127, 135))	('miR-223', 'Gene', (180, 187))	('miRs-199a-5p', 'Var', (233, 245))	('miRs-19b', 'Var', (247, 255))	('miR-92b', 'Gene', (159, 166))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
15904	27453764	In addition to chromosome 3, abnormalities in chromosomes 1, 6, and 8 have also been associated with metastasis in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('associated with', 'Reg', (85, 100))	('uveal melanoma', 'Disease', 'MESH:C536494', (115, 129))	('uveal melanoma', 'Disease', (115, 129))	('uveal melanoma', 'Phenotype', 'HP:0007716', (115, 129))	('abnormalities', 'Var', (29, 42))	('chromosome', 'cellular_component', 'GO:0005694', ('15', '25'))	('metastasis', 'CPA', (101, 111))
15914	27453764	These results, which derive from the largest number of uveal melanoma samples reported to date, support a role for epigenetic events mediated by miRs in uveal melanoma metastasis and further analysis of miRs as biomarkers of metastatic risk.	('epigenetic', 'Var', (115, 125))	('uveal melanoma metastasis', 'Disease', 'MESH:C536494', (153, 178))	('uveal melanoma', 'Phenotype', 'HP:0007716', (55, 69))	('uveal melanoma', 'Disease', (55, 69))	('uveal melanoma', 'Disease', 'MESH:C536494', (55, 69))	('uveal melanoma', 'Disease', 'MESH:C536494', (153, 167))	('uveal melanoma metastasis', 'Disease', (153, 178))	('uveal melanoma', 'Phenotype', 'HP:0007716', (153, 167))	('miRs', 'Gene', (145, 149))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
15938	26911405	Secondary objectives were progression-free survival (PFS), overall survival (OS), and safety; liver perfusion computed tomography (CT) for response imaging; and impact of VEGF-A gene polymorphisms on bevacizumab pharmacodynamics.	('VEGF-A', 'Gene', (171, 177))	('polymorphisms', 'Var', (183, 196))	('VEGF-A', 'Gene', '7422', (171, 177))	('bevacizumab', 'Chemical', 'MESH:D000068258', (200, 211))
15992	26911405	Our prospective analysis of an association of VEGF-A gene polymorphisms and toxicity and patient outcome with bevacizumab-based therapy in MUM did not find an association with any of the five functional analyzed VEGF-A polymorphisms in this small cohort (supplemental online Table 1), as previously reported in a larger study with BEV in metastatic breast cancer.	('bevacizumab', 'Chemical', 'MESH:D000068258', (110, 121))	('VEGF-A', 'Gene', '7422', (212, 218))	('patient', 'Species', '9606', (89, 96))	('breast cancer', 'Disease', 'MESH:D001943', (349, 362))	('breast cancer', 'Phenotype', 'HP:0003002', (349, 362))	('VEGF-A', 'Gene', (212, 218))	('breast cancer', 'Disease', (349, 362))	('polymorphisms', 'Var', (219, 232))	('toxicity', 'Disease', 'MESH:D064420', (76, 84))	('UM', 'Phenotype', 'HP:0007716', (140, 142))	('toxicity', 'Disease', (76, 84))	('BEV', 'Chemical', 'MESH:D000068258', (331, 334))	('VEGF-A', 'Gene', '7422', (46, 52))	('VEGF-A', 'Gene', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))
16007	25278770	The discovery of activating mutations in the MAPK pathway has led to the development of MAPK pathway inhibitors.	('MAPK', 'Gene', '5595;5594;5595', (88, 92))	('MAPK', 'molecular_function', 'GO:0004707', ('88', '92'))	('MAPK', 'Gene', '5595;5594;5595', (45, 49))	('MAPK', 'Gene', (45, 49))	('activating', 'PosReg', (17, 27))	('MAPK', 'Gene', (88, 92))	('MAPK', 'molecular_function', 'GO:0004707', ('45', '49'))	('mutations', 'Var', (28, 37))
16019	25278770	Recently, mitogen-activated protein kinase (MAPK) pathway inhibitors, including selective BRAF inhibitors (dabrafenib and vemurafenib) and a selective MEK inhibitor (trametinib), have shown significant improvement of PFS and OS over chemotherapy in patients with BRAF mutant melanoma, which led to the approval of these drugs.	('BRAF', 'Gene', (90, 94))	('vemurafenib', 'Chemical', 'MESH:D000077484', (122, 133))	('BRAF', 'Gene', (263, 267))	('patients', 'Species', '9606', (249, 257))	('mutant', 'Var', (268, 274))	('MAPK', 'molecular_function', 'GO:0004707', ('44', '48'))	('PFS', 'MPA', (217, 220))	('melanoma', 'Disease', 'MESH:D008545', (275, 283))	('dabrafenib', 'Chemical', 'MESH:C561627', (107, 117))	('improvement', 'PosReg', (202, 213))	('trametinib', 'Chemical', 'MESH:C560077', (166, 176))	('MAPK', 'Gene', (44, 48))	('melanoma', 'Phenotype', 'HP:0002861', (275, 283))	('MAPK', 'Gene', '5595;5594;5595', (44, 48))	('melanoma', 'Disease', (275, 283))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
16022	25278770	One of the biggest milestones in melanoma research is the identification of BRAF gene mutations in melanoma.	('mutations', 'Var', (86, 95))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('BRAF gene', 'Gene', (76, 85))
16025	25278770	Up to 75% of melanomas have dysregulated MAPK signaling pathway via BRAF (50%) or NRAS mutations (15%-25%), which results in unregulated cell proliferation and growth.	('cell proliferation', 'CPA', (137, 155))	('MAPK', 'Gene', (41, 45))	('melanomas', 'Disease', (13, 22))	('MAPK', 'Gene', '5595;5594;5595', (41, 45))	('BRAF', 'Gene', (68, 72))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('growth', 'CPA', (160, 166))	('results', 'Reg', (114, 121))	('NRAS', 'Gene', (82, 86))	('dysregulated', 'Reg', (28, 40))	('MAPK', 'molecular_function', 'GO:0004707', ('41', '45'))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('cell proliferation', 'biological_process', 'GO:0008283', ('137', '155'))	('signaling pathway', 'biological_process', 'GO:0007165', ('46', '63'))	('melanomas', 'Disease', 'MESH:D008545', (13, 22))	('mutations', 'Var', (87, 96))	('MAPK signaling', 'biological_process', 'GO:0000165', ('41', '55'))
16026	25278770	Dysregulation of MAPK pathway in the majority of melanoma and other malignancies, including colon, pancreatic, and non-small-cell lung cancer, makes MEK an attractive therapeutic target as one of the main downstream molecules of MAPK pathway.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('colon', 'Disease', (92, 97))	('MAPK', 'Gene', '5595;5594;5595', (17, 21))	('Dysregulation', 'Var', (0, 13))	('pancreatic', 'Disease', 'MESH:D010195', (99, 109))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (119, 141))	('MAPK', 'Gene', (17, 21))	('MAPK', 'molecular_function', 'GO:0004707', ('229', '233'))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('pancreatic', 'Disease', (99, 109))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (115, 141))	('MAPK', 'Gene', '5595;5594;5595', (229, 233))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('MAPK', 'Gene', (229, 233))	('malignancies', 'Disease', 'MESH:D009369', (68, 80))	('MAPK', 'molecular_function', 'GO:0004707', ('17', '21'))	('malignancies', 'Disease', (68, 80))	('non-small-cell lung cancer', 'Disease', (115, 141))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (115, 141))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
16027	25278770	Initial preclinical studies of selective MEK inhibitors have been shown to have promising antitumor activities in BRAF and NRAS mutant tumor cell lines.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('MEK', 'Gene', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('mutant', 'Var', (128, 134))	('NRAS', 'Gene', (123, 127))	('tumor', 'Disease', (94, 99))	('BRAF', 'Disease', (114, 118))
16028	25278770	Solit et al showed complete abrogation of BRAF mutant melanoma growth and partial inhibition of NRAS mutant melanoma growth in murine xenografts with selective MEK inhibitors such as CI-1040 and PD0325901.	('BRAF', 'Gene', (42, 46))	('melanoma growth', 'Disease', (54, 69))	('melanoma growth', 'Disease', 'MESH:D008545', (54, 69))	('murine', 'Species', '10090', (127, 133))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma growth', 'Disease', (108, 123))	('mutant', 'Var', (101, 107))	('PD0325901', 'Chemical', 'MESH:C506614', (195, 204))	('inhibition', 'NegReg', (82, 92))	('CI-1040', 'Chemical', '-', (183, 190))	('NRAS', 'Gene', (96, 100))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('mutant', 'Var', (47, 53))	('abrogation', 'NegReg', (28, 38))	('melanoma growth', 'Disease', 'MESH:D008545', (108, 123))
16029	25278770	However, clinical development of these MEK inhibitors, including CI-1040 and PD0325901, was discontinued because of a lack of clinical activity of CI-1040 and severe and frequent neurologic, musculoskeletal, and ocular toxicities of PD0325901.	('ocular toxicities', 'Disease', 'MESH:D005128', (212, 229))	('CI-1040', 'Chemical', '-', (147, 154))	('PD0325901', 'Chemical', 'MESH:C506614', (77, 86))	('CI-1040', 'Chemical', '-', (65, 72))	('PD0325901', 'Var', (233, 242))	('CI-1040', 'Var', (147, 154))	('PD0325901', 'Chemical', 'MESH:C506614', (233, 242))	('lack', 'NegReg', (118, 122))	('ocular toxicities', 'Disease', (212, 229))
16031	25278770	Selumetinib (AZD6244, ARRY-142886; AstraZeneca, PLC, London, United Kingdom) is a highly selective, ATP-uncompetitive allosteric inhibitor of both MEK1 and MEK2 and has the empirical formula of C17H15BrCLFN4O3 (Figure 2).	('MEK2', 'molecular_function', 'GO:0004708', ('156', '160'))	('C17H15BrCLFN4O3', 'Var', (194, 209))	('MEK1', 'Gene', '5604', (147, 151))	('AZD6244', 'Chemical', 'MESH:C517975', (13, 20))	('PLC', 'Gene', '3339', (48, 51))	('PLC', 'Gene', (48, 51))	('ARRY-142886', 'Chemical', 'MESH:C517975', (22, 33))	('ATP', 'Chemical', 'MESH:D000255', (100, 103))	('C17H15BrCLFN4O3', 'Chemical', '-', (194, 209))	('PLC', 'cellular_component', 'GO:0042824', ('48', '51'))	('MEK1', 'Gene', (147, 151))	('MEK2', 'Gene', (156, 160))	('MEK2', 'Gene', '5605', (156, 160))	('Selumetinib', 'Chemical', 'MESH:C517975', (0, 11))	('MEK1', 'molecular_function', 'GO:0004708', ('147', '151'))
16033	25278770	Although a majority of melanomas have dysregulated MAPK pathway via BRAF and NRAS mutations, 90% of pancreatic cancers, 50% of colorectal cancers, and 25% of non-small-cell lung cancers also have constitutively activated MAPK pathway via KRAS mutations.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('lung cancers', 'Phenotype', 'HP:0100526', (173, 185))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (158, 184))	('MAPK', 'Gene', (51, 55))	('colorectal cancers', 'Disease', (127, 145))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (100, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('MAPK', 'Gene', '5595;5594;5595', (221, 225))	('dysregulated', 'Reg', (38, 50))	('pancreatic cancers', 'Disease', (100, 118))	('non-small-cell lung cancer', 'Disease', (158, 184))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (158, 184))	('colorectal cancers', 'Disease', 'MESH:D015179', (127, 145))	('BRAF', 'Gene', (68, 72))	('MAPK', 'Gene', (221, 225))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (162, 184))	('melanomas', 'Disease', 'MESH:D008545', (23, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))	('lung cancers', 'Disease', 'MESH:D008175', (173, 185))	('pancreatic cancers', 'Disease', 'MESH:D010190', (100, 118))	('melanomas', 'Disease', (23, 32))	('MAPK', 'Gene', '5595;5594;5595', (51, 55))	('NRAS', 'Gene', (77, 81))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('MAPK', 'molecular_function', 'GO:0004707', ('221', '225'))	('MAPK', 'molecular_function', 'GO:0004707', ('51', '55'))	('KRAS', 'Gene', (238, 242))	('mutations', 'Var', (82, 91))	('lung cancers', 'Disease', (173, 185))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (100, 117))
16035	25278770	Phosphorylation of ERK1/2, downstream molecules of MEK, was effectively inhibited with selumetinib in melanoma, colorectal cancer, pancreatic cancer, non-small-cell lung cancer, and hepatocellular cancer cell lines harboring BRAF, NRAS, or KRAS mutations.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (150, 176))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('ERK1', 'molecular_function', 'GO:0004707', ('19', '23'))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('ERK1/2', 'Gene', '5595;5594', (19, 25))	('ERK1/2', 'Gene', (19, 25))	('colorectal cancer', 'Disease', (112, 129))	('mutations', 'Var', (245, 254))	('NRAS', 'Gene', (231, 235))	('pancreatic cancer', 'Disease', 'MESH:D010190', (131, 148))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('hepatocellular cancer', 'Disease', (182, 203))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (150, 176))	('KRAS', 'Gene', (240, 244))	('BRAF', 'Disease', (225, 229))	('non-small-cell lung cancer', 'Disease', (150, 176))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (182, 203))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (182, 203))	('pancreatic cancer', 'Disease', (131, 148))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('inhibited', 'NegReg', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (154, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('selumetinib', 'Chemical', 'MESH:C517975', (87, 98))	('Phosphorylation', 'MPA', (0, 15))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))
16038	25278770	The combined treatment with selumetinib and cytotoxic chemotherapy such as irinotecan, docetaxel, temozolomide, and doxorubicin resulted in significant enhanced antitumor efficacy by both cell cycle arrest and apoptosis in mice xenografts of BRAF mutant melanoma, as well as KRAS mutant colon cancer, non-small-cell lung cancer, pancreatic cancer, and hepatocellular carcinoma.	('temozolomide', 'Chemical', 'MESH:D000077204', (98, 110))	('irinotecan', 'Chemical', 'MESH:D000077146', (75, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (329, 346))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('enhanced', 'PosReg', (152, 160))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('melanoma', 'Phenotype', 'HP:0002861', (254, 262))	('apoptosis', 'biological_process', 'GO:0097194', ('210', '219'))	('melanoma', 'Disease', (254, 262))	('arrest', 'Disease', 'MESH:D006323', (199, 205))	('apoptosis', 'biological_process', 'GO:0006915', ('210', '219'))	('mutant', 'Var', (247, 253))	('selumetinib', 'Chemical', 'MESH:C517975', (28, 39))	('docetaxel', 'Chemical', 'MESH:D000077143', (87, 96))	('colon cancer', 'Phenotype', 'HP:0003003', (287, 299))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (352, 376))	('non-small-cell lung cancer', 'Disease', (301, 327))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (301, 327))	('pancreatic cancer', 'Disease', 'MESH:D010190', (329, 346))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (352, 376))	('colon cancer', 'Disease', 'MESH:D015179', (287, 299))	('lung cancer', 'Phenotype', 'HP:0100526', (316, 327))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (188, 205))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('188', '205'))	('apoptosis', 'CPA', (210, 219))	('melanoma', 'Disease', 'MESH:D008545', (254, 262))	('pancreatic cancer', 'Disease', (329, 346))	('tumor', 'Disease', (165, 170))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (305, 327))	('arrest', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (340, 346))	('BRAF', 'Gene', (242, 246))	('mice', 'Species', '10090', (223, 227))	('doxorubicin', 'Chemical', 'MESH:D004317', (116, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (367, 376))	('hepatocellular carcinoma', 'Disease', (352, 376))	('colon cancer', 'Disease', (287, 299))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('KRAS', 'Var', (275, 279))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (301, 327))
16039	25278770	Gopal et al have reported that the PI3K/AKT pathway plays a critical role in the antitumor efficacy of selumetinib in BRAF mutant melanoma, and inhibition of PI3K/AKT pathway results in synergistic antitumor activity with selumetinib.	('tumor', 'Disease', (85, 90))	('PI3K', 'molecular_function', 'GO:0016303', ('158', '162'))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('synergistic', 'MPA', (186, 197))	('tumor', 'Disease', (202, 207))	('AKT', 'Gene', (163, 166))	('AKT', 'Gene', '207', (40, 43))	('inhibition', 'Var', (144, 154))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))	('BRAF', 'Gene', (118, 122))	('AKT', 'Gene', '207', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('selumetinib', 'Chemical', 'MESH:C517975', (103, 114))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('AKT', 'Gene', (40, 43))	('melanoma', 'Disease', (130, 138))	('selumetinib', 'Chemical', 'MESH:C517975', (222, 233))	('mutant', 'Var', (123, 129))
16041	25278770	The combination of selumetinib and WNT3A, a ligand of Wnt/beta-catenin pathway, induced apoptosis of melanoma cell lines harboring BRAF or NRAS mutations by degradation of AXIN1, a negative regulator of Wnt/beta-catenin signaling.	('AXIN1', 'Gene', '8312', (172, 177))	('apoptosis', 'CPA', (88, 97))	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('WNT3A', 'Gene', (35, 40))	('BRAF', 'Gene', (131, 135))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('NRAS', 'Gene', (139, 143))	('degradation', 'biological_process', 'GO:0009056', ('157', '168'))	('AXIN1', 'Gene', (172, 177))	('melanoma cell', 'Disease', (101, 114))	('degradation', 'NegReg', (157, 168))	('selumetinib', 'Chemical', 'MESH:C517975', (19, 30))	('WNT3A', 'Gene', '89780', (35, 40))	('signaling', 'biological_process', 'GO:0023052', ('220', '229'))	('ligand', 'molecular_function', 'GO:0005488', ('44', '50'))	('melanoma cell', 'Disease', 'MESH:D008545', (101, 114))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))	('mutations', 'Var', (144, 153))
16042	25278770	Apoptosis-resistant BRAF and NRAS mutant melanoma cell lines were able to sensitize to selumetinib by knock-down of AXIN1 expression with siRNA in the study.	('sensitize', 'MPA', (74, 83))	('knock-down', 'Var', (102, 112))	('melanoma cell', 'Disease', 'MESH:D008545', (41, 54))	('selumetinib', 'Chemical', 'MESH:C517975', (87, 98))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('AXIN1', 'Gene', '8312', (116, 121))	('AXIN1', 'Gene', (116, 121))	('mutant', 'Var', (34, 40))	('melanoma cell', 'Disease', (41, 54))
16043	25278770	Recently, histone deacetylases have been reported to be up-regulated in cancer cells and lead to suppression of tumor suppressor gene expression such as p53 by a post-translational modification.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('112', '128'))	('up-regulated', 'PosReg', (56, 68))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('suppression', 'NegReg', (97, 108))	('post-translational modification', 'biological_process', 'GO:0043687', ('162', '193'))	('post-translational modification', 'Var', (162, 193))	('gene expression', 'biological_process', 'GO:0010467', ('129', '144'))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('p53', 'Gene', (153, 156))	('p53', 'Gene', '7157', (153, 156))	('histone', 'Protein', (10, 17))	('tumor', 'Disease', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('tumor suppressor', 'biological_process', 'GO:0051726', ('112', '128'))	('cancer', 'Disease', (72, 78))
16044	25278770	The combination of selumetinib and vorinostat, a histone deacetylase inhibitor, was evaluated in KRAS mutant colorectal cancer.	('colorectal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('vorinostat', 'Chemical', 'MESH:D000077337', (35, 45))	('selumetinib', 'Chemical', 'MESH:C517975', (19, 30))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('KRAS mutant', 'Var', (97, 108))
16045	25278770	The treatment with selumetinib plus vorinostat induced a synergistic antiproliferative activity against KRAS mutant colorectal cancer cell lines by the mechanism of apoptosis, cell-cycle arrest, and reduced cellular migration and VEGF-A secretion in vitro and in vivo.	('apoptosis', 'biological_process', 'GO:0097194', ('165', '174'))	('apoptosis', 'biological_process', 'GO:0006915', ('165', '174'))	('VEGF-A', 'Gene', '7422', (230, 236))	('apoptosis', 'CPA', (165, 174))	('secretion', 'biological_process', 'GO:0046903', ('237', '246'))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('176', '193'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (116, 133))	('selumetinib', 'Chemical', 'MESH:C517975', (19, 30))	('cellular migration', 'CPA', (207, 225))	('arrest', 'Disease', (187, 193))	('KRAS', 'Gene', (104, 108))	('reduced', 'NegReg', (199, 206))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('VEGF-A', 'Gene', (230, 236))	('colorectal cancer', 'Disease', 'MESH:D015179', (116, 133))	('mutant', 'Var', (109, 115))	('antiproliferative activity', 'CPA', (69, 95))	('colorectal cancer', 'Disease', (116, 133))	('arrest', 'Disease', 'MESH:D006323', (187, 193))	('vorinostat', 'Chemical', 'MESH:D000077337', (36, 46))
16046	25278770	Although uveal melanomas rarely have BRAF and NRAS mutations, the MAPK pathway is constitutively activated by GNAQ or GNA11 mutations that occur in approximately 80% of primary uveal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanomas', 'Phenotype', 'HP:0002861', (183, 192))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('MAPK', 'Gene', '5595;5594;5595', (66, 70))	('GNA11', 'Gene', (118, 123))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('uveal melanomas', 'Disease', 'MESH:C536494', (177, 192))	('MAPK', 'Gene', (66, 70))	('activated', 'PosReg', (97, 106))	('uveal melanoma', 'Phenotype', 'HP:0007716', (9, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (177, 191))	('uveal melanomas', 'Disease', 'MESH:C536494', (9, 24))	('uveal melanomas', 'Disease', (177, 192))	('uveal melanomas', 'Phenotype', 'HP:0007716', (177, 192))	('mutations', 'Var', (124, 133))	('GNA11', 'Gene', '2767', (118, 123))	('GNAQ', 'Gene', '2776', (110, 114))	('MAPK', 'molecular_function', 'GO:0004707', ('66', '70'))	('GNAQ', 'Gene', (110, 114))	('uveal melanomas', 'Disease', (9, 24))	('uveal melanomas', 'Phenotype', 'HP:0007716', (9, 24))
16047	25278770	Because direct pharmacologic targeting of GNAQ/GNA11 mutations is not feasible, inhibition of the key downstream effectors of MAPK pathway has been studied.	('GNAQ', 'Gene', '2776', (42, 46))	('MAPK', 'molecular_function', 'GO:0004707', ('126', '130'))	('MAPK', 'Gene', '5595;5594;5595', (126, 130))	('GNA11', 'Gene', '2767', (47, 52))	('GNA11', 'Gene', (47, 52))	('MAPK', 'Gene', (126, 130))	('mutations', 'Var', (53, 62))	('GNAQ', 'Gene', (42, 46))
16050	25278770	Another preclinical study demonstrated that the combination of selumetinib and a mammalian target of rapamycin (mTOR) inhibitor (AZD8055) which is downstream of PI3K/AKT pathway, induces tumor regression in BRAF mutant uveal melanoma cell lines but not GNAQ mutant cell lines.	('BRAF', 'Gene', (207, 211))	('uveal melanoma', 'Disease', (219, 233))	('GNAQ', 'Gene', (253, 257))	('mammalian target of rapamycin', 'Gene', (81, 110))	('tumor', 'Disease', (187, 192))	('AKT', 'Gene', (166, 169))	('uveal melanoma', 'Phenotype', 'HP:0007716', (219, 233))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('melanoma cell', 'Disease', 'MESH:D008545', (225, 238))	('mTOR', 'Gene', (112, 116))	('AZD8055', 'Chemical', 'MESH:C546624', (129, 136))	('AKT', 'Gene', '207', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('melanoma cell', 'Disease', (225, 238))	('mTOR', 'Gene', '2475', (112, 116))	('selumetinib', 'Chemical', 'MESH:C517975', (63, 74))	('induces', 'PosReg', (179, 186))	('mutant', 'Var', (212, 218))	('PI3K', 'molecular_function', 'GO:0016303', ('161', '165'))	('mammalian target of rapamycin', 'Gene', '2475', (81, 110))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('GNAQ', 'Gene', '2776', (253, 257))	('uveal melanoma', 'Disease', 'MESH:C536494', (219, 233))
16051	25278770	Unfortunately, these cell lines are likely contaminants of cutaneous melanoma cell lines because BRAF mutations are not present in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))	('melanoma cell', 'Disease', (69, 82))	('uveal melanoma', 'Disease', 'MESH:C536494', (131, 145))	('cutaneous melanoma', 'Disease', (59, 77))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (59, 77))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (59, 77))	('uveal melanoma', 'Disease', (131, 145))	('melanoma cell', 'Disease', 'MESH:D008545', (69, 82))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('mutations', 'Var', (102, 111))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('BRAF', 'Gene', (97, 101))
16052	25278770	The resistance to selumetinib plus AZD8055 in GNAQ mutant uveal melanoma cell lines is associated with expression of the prosurvival protein MCL1.	('melanoma cell', 'Disease', 'MESH:D008545', (64, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('GNAQ', 'Gene', (46, 50))	('selumetinib', 'Chemical', 'MESH:C517975', (18, 29))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('mutant', 'Var', (51, 57))	('AZD8055', 'Var', (35, 42))	('GNAQ', 'Gene', '2776', (46, 50))	('associated', 'Reg', (87, 97))	('AZD8055', 'Chemical', 'MESH:C546624', (35, 42))	('melanoma cell', 'Disease', (64, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (58, 72))	('MCL1', 'Gene', '4170', (141, 145))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('MCL1', 'Gene', (141, 145))	('uveal melanoma', 'Disease', (58, 72))
16054	25278770	One study has shown that the combination of a MEK inhibitor (trametinib) with a PI3K inhibitor (GSK2126468) induced significant antitumor activity with a GNAQ mutant melanoma cell line, whereas the other study demonstrated that concurrent treatment of a MEK inhibitor (selumetinib) and mTOR inhibitor (AZD8055) does not result in any significant apoptosis or tumor growth suppression with the same GNAQ mutant cell line.	('melanoma cell', 'Disease', (166, 179))	('tumor', 'Disease', (132, 137))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('trametinib', 'Chemical', 'MESH:C560077', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('apoptosis', 'biological_process', 'GO:0097194', ('346', '355'))	('apoptosis', 'biological_process', 'GO:0006915', ('346', '355'))	('mutant', 'Var', (159, 165))	('GSK2126468', 'Chemical', '-', (96, 106))	('tumor', 'Disease', (359, 364))	('PI3K', 'molecular_function', 'GO:0016303', ('80', '84'))	('GNAQ', 'Gene', '2776', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (359, 364))	('mTOR', 'Gene', (286, 290))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('AZD8055', 'Chemical', 'MESH:C546624', (302, 309))	('GNAQ', 'Gene', (154, 158))	('GNAQ', 'Gene', '2776', (398, 402))	('mTOR', 'Gene', '2475', (286, 290))	('selumetinib', 'Chemical', 'MESH:C517975', (269, 280))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('GSK', 'molecular_function', 'GO:0050321', ('96', '99'))	('GNAQ', 'Gene', (398, 402))	('melanoma cell', 'Disease', 'MESH:D008545', (166, 179))
16075	25278770	In the study, a median time to progression of patients with BRAF mutant melanoma was 51 weeks, and for wild BRAF it was 12 weeks (hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.06-0.82; P=0.02).	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('patients', 'Species', '9606', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('BRAF', 'Gene', (60, 64))	('mutant', 'Var', (65, 71))
16083	25278770	Because MEK inhibition has better antitumor activity in melanoma harboring BRAF mutations than wild BRAF, clinical efficacy of Hyd-Sulfate selumetinib was evaluated in selected patients with BRAF mutant melanoma in another phase 2 study.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mutations', 'Var', (80, 89))	('melanoma', 'Disease', (56, 64))	('inhibition', 'NegReg', (12, 22))	('patients', 'Species', '9606', (177, 185))	('Hyd-Sulfate selumetinib', 'Chemical', '-', (127, 150))	('better', 'PosReg', (27, 33))	('BRAF', 'Gene', (75, 79))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('MEK', 'Gene', (8, 11))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))
16084	25278770	In addition, all patients were stratified by activation of PI3K/AKT pathway based on phosphorylated-AKT (pAKT) expression (high versus low) in the study, as PI3K/AKT pathway is one of the critical regulators of selumetinib efficacy in BRAF mutant melanoma.	('AKT', 'Gene', (106, 109))	('AKT', 'Gene', '207', (162, 165))	('PI3K', 'molecular_function', 'GO:0016303', ('157', '161'))	('AKT', 'Gene', (100, 103))	('BRAF', 'Gene', (235, 239))	('mutant', 'Var', (240, 246))	('AKT', 'Gene', (162, 165))	('AKT', 'Gene', '207', (64, 67))	('selumetinib', 'Chemical', 'MESH:C517975', (211, 222))	('AKT', 'Gene', '207', (100, 103))	('patients', 'Species', '9606', (17, 25))	('AKT', 'Gene', '207', (106, 109))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('melanoma', 'Disease', (247, 255))	('AKT', 'Gene', (64, 67))	('melanoma', 'Disease', 'MESH:D008545', (247, 255))	('PI3K', 'molecular_function', 'GO:0016303', ('59', '63'))
16088	25278770	In a double-blind randomized phase 2 study, the combination of Hyd-Sulfate selumetinib and dacarbazine was evaluated as a first-line treatment for BRAF mutant metastatic melanoma.	('dacarbazine', 'Chemical', 'MESH:D003606', (91, 102))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('Hyd-Sulfate selumetinib', 'Chemical', '-', (63, 86))	('BRAF', 'Gene', (147, 151))	('mutant', 'Var', (152, 158))
16089	25278770	Patients with metastatic melanoma harboring BRAF mutations were randomly assigned to either selumetinib combined with dacarbazine or to dacarbazine alone, and the primary objective was to compare overall survival analyzed by intention to treat between the two groups.	('dacarbazine', 'Chemical', 'MESH:D003606', (136, 147))	('mutations', 'Var', (49, 58))	('Patients', 'Species', '9606', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('selumetinib', 'Chemical', 'MESH:C517975', (92, 103))	('melanoma', 'Disease', (25, 33))	('dacarbazine', 'Chemical', 'MESH:D003606', (118, 129))
16095	25278770	In the study, patients were randomized to receive either selumetinib or temozolomide, and all patients were stratified by GNAQ and GNA11 mutations.	('patients', 'Species', '9606', (94, 102))	('GNAQ', 'Gene', (122, 126))	('selumetinib', 'Chemical', 'MESH:C517975', (57, 68))	('mutations', 'Var', (137, 146))	('temozolomide', 'Chemical', 'MESH:D000077204', (72, 84))	('patients', 'Species', '9606', (14, 22))	('GNAQ', 'Gene', '2776', (122, 126))	('GNA11', 'Gene', '2767', (131, 136))	('GNA11', 'Gene', (131, 136))
16103	25278770	Two BRAF inhibitors such as vemurafenib and dabrafenib have been approved by the FDA after demonstrating a survival benefit for patients with BRAF V600E/K mutant melanoma.	('V600E', 'Var', (147, 152))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('vemurafenib', 'Chemical', 'MESH:D000077484', (28, 39))	('V600E', 'SUBSTITUTION', 'None', (147, 152))	('dabrafenib', 'Chemical', 'MESH:C561627', (44, 54))	('patients', 'Species', '9606', (128, 136))	('BRAF', 'Gene', (142, 146))
16104	25278770	The combination of a BRAF inhibitor with a MEK inhibitor has shown better toxicity profiles and clinical benefit than monotherapy in patients with a BRAF V600E/K mutation.	('BRAF', 'Gene', (149, 153))	('toxicity', 'Disease', (74, 82))	('V600E', 'SUBSTITUTION', 'None', (154, 159))	('patients', 'Species', '9606', (133, 141))	('toxicity', 'Disease', 'MESH:D064420', (74, 82))	('V600E', 'Var', (154, 159))	('combination', 'Interaction', (4, 15))
16107	25278770	NRAS is upstream of MAPK pathway, and point mutation of the NRAS gene both is the second most common mutation in melanoma (15%-25%) and is associated with progression of melanoma.	('associated with', 'Reg', (139, 154))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('point mutation', 'Var', (38, 52))	('MAPK', 'Gene', '5595;5594;5595', (20, 24))	('MAPK', 'molecular_function', 'GO:0004707', ('20', '24'))	('MAPK', 'Gene', (20, 24))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('NRAS', 'Gene', (60, 64))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))
16108	25278770	In a phase 2 study of MEK162, 6 (20%) of 30 patients with metastatic melanoma harboring NRAS mutations had an objective clinical response.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('MEK1', 'Gene', '5604', (22, 26))	('mutations', 'Var', (93, 102))	('patients', 'Species', '9606', (44, 52))	('NRAS', 'Gene', (88, 92))	('MEK1', 'Gene', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
16109	25278770	However, other clinical studies of MEK inhibitors using trametinib or selumetinib in patients with NRAS mutant melanoma failed to show clinical activity.	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('selumetinib', 'Chemical', 'MESH:C517975', (70, 81))	('mutant', 'Var', (104, 110))	('patients', 'Species', '9606', (85, 93))	('trametinib', 'Chemical', 'MESH:C560077', (56, 66))	('NRAS', 'Gene', (99, 103))
16110	25278770	One of the possible explanations for the failed anticancer activity is that NRAS mutations activate multiple pathways including CDK4 driven cell-cycle progression and PI3K/AKT signaling in addition to MAPK pathway.	('CDK4', 'Gene', '1019', (128, 132))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('NRAS', 'Gene', (76, 80))	('MAPK', 'molecular_function', 'GO:0004707', ('201', '205'))	('AKT', 'Gene', (172, 175))	('CDK', 'molecular_function', 'GO:0004693', ('128', '131'))	('cell-cycle', 'biological_process', 'GO:0007049', ('140', '150'))	('AKT signaling', 'biological_process', 'GO:0043491', ('172', '185'))	('cell-cycle progression', 'CPA', (140, 162))	('PI3K', 'molecular_function', 'GO:0016303', ('167', '171'))	('MAPK', 'Gene', '5595;5594;5595', (201, 205))	('AKT', 'Gene', '207', (172, 175))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', (52, 58))	('MAPK', 'Gene', (201, 205))	('CDK4', 'Gene', (128, 132))	('activate', 'PosReg', (91, 99))
16111	25278770	Therefore, selumetinib plus other signaling pathway blockade such as CDK4 inhibitors and PI3K/AKT inhibitors may be a reasonable strategy for NRAS mutant melanoma.	('CDK4', 'Gene', '1019', (69, 73))	('mutant', 'Var', (147, 153))	('NRAS', 'Gene', (142, 146))	('AKT', 'Gene', '207', (94, 97))	('signaling pathway', 'biological_process', 'GO:0007165', ('34', '51'))	('PI3K', 'molecular_function', 'GO:0016303', ('89', '93'))	('CDK', 'molecular_function', 'GO:0004693', ('69', '72'))	('AKT', 'Gene', (94, 97))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('CDK4', 'Gene', (69, 73))	('selumetinib', 'Chemical', 'MESH:C517975', (11, 22))
16112	25278770	In contrast to cutaneous melanoma, uveal melanomas do not harbor BRAF or NRAS mutations.	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))	('cutaneous melanoma', 'Disease', (15, 33))	('mutations', 'Var', (78, 87))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (15, 33))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (15, 33))	('uveal melanomas', 'Disease', (35, 50))	('uveal melanomas', 'Phenotype', 'HP:0007716', (35, 50))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('BRAF', 'Gene', (65, 69))	('uveal melanomas', 'Disease', 'MESH:C536494', (35, 50))	('NRAS', 'Gene', (73, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))
16113	25278770	Instead, point mutations of GNAQ or GNA11 have been reported in more than 80% of uveal melanomas, and the mutations are associated with activation of MAPK pathway and progression of uveal melanoma.	('associated', 'Reg', (120, 130))	('GNA11', 'Gene', '2767', (36, 41))	('reported', 'Reg', (52, 60))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('GNAQ', 'Gene', '2776', (28, 32))	('uveal melanomas', 'Disease', 'MESH:C536494', (81, 96))	('activation', 'PosReg', (136, 146))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('uveal melanoma', 'Disease', 'MESH:C536494', (81, 95))	('GNAQ', 'Gene', (28, 32))	('MAPK', 'Gene', '5595;5594;5595', (150, 154))	('MAPK', 'molecular_function', 'GO:0004707', ('150', '154'))	('GNA11', 'Gene', (36, 41))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('point mutations', 'Var', (9, 24))	('uveal melanoma', 'Disease', 'MESH:C536494', (182, 196))	('uveal melanoma', 'Disease', (182, 196))	('uveal melanomas', 'Disease', (81, 96))	('uveal melanomas', 'Phenotype', 'HP:0007716', (81, 96))	('MAPK', 'Gene', (150, 154))	('mutations', 'Var', (106, 115))	('melanomas', 'Phenotype', 'HP:0002861', (87, 96))	('uveal melanoma', 'Phenotype', 'HP:0007716', (182, 196))
16115	25278770	Despite the promising result of the study showing improvement in PFS with no improvement in OS in selumetinib-treated patients, combination therapy may be more effective than selumetinib single-agent therapy in GNAQ/GNA11 mutant uveal melanoma.	('selumetinib', 'Chemical', 'MESH:C517975', (175, 186))	('GNAQ', 'Gene', (211, 215))	('selumetinib', 'Chemical', 'MESH:C517975', (98, 109))	('PFS', 'MPA', (65, 68))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('GNA11', 'Gene', (216, 221))	('GNAQ', 'Gene', '2776', (211, 215))	('uveal melanoma', 'Disease', 'MESH:C536494', (229, 243))	('uveal melanoma', 'Phenotype', 'HP:0007716', (229, 243))	('mutant', 'Var', (222, 228))	('GNA11', 'Gene', '2767', (216, 221))	('uveal melanoma', 'Disease', (229, 243))	('patients', 'Species', '9606', (118, 126))
16117	25278770	Although MAPK pathway inhibitors such as BRAF inhibitors and MEK inhibitors have demonstrated significant improvement of the clinical response rate, PFS, and OS in comparison with chemotherapy in patients with advanced melanoma harboring BRAF mutations, most responders develop a resistance to the therapy within a year.	('clinical response', 'CPA', (125, 142))	('MAPK', 'molecular_function', 'GO:0004707', ('9', '13'))	('melanoma', 'Disease', (219, 227))	('patients', 'Species', '9606', (196, 204))	('mutations', 'Var', (243, 252))	('MAPK', 'Gene', '5595;5594;5595', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('MAPK', 'Gene', (9, 13))	('resistance', 'CPA', (280, 290))	('melanoma', 'Disease', 'MESH:D008545', (219, 227))	('improvement', 'PosReg', (106, 117))
16119	25278770	MEK-dependent resistance has been explained by the acquisition of new NRAS or MEK mutation, overexpression of COT-1 (serine/threonine kinase protein), elevated CRAF kinase protein expression, and alternate splicing of the BRAF gene.	('MEK', 'Gene', (78, 81))	('NRAS', 'Gene', (70, 74))	('overexpression', 'PosReg', (92, 106))	('mutation', 'Var', (82, 90))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('splicing', 'biological_process', 'GO:0045292', ('206', '214'))	('alternate splicing', 'Var', (196, 214))	('CRAF', 'Gene', (160, 164))	('BRAF', 'Gene', (222, 226))	('CRAF', 'Gene', '5894', (160, 164))	('elevated', 'PosReg', (151, 159))	('CRAF', 'molecular_function', 'GO:0004709', ('160', '164'))	('COT-1', 'Gene', (110, 115))
16120	25278770	In particular, a MEK1 mutation was identified as acquired resistance to selumetinib therapy in melanoma cell lines and tumor samples of patients treated with selumetinib.	('melanoma cell', 'Disease', 'MESH:D008545', (95, 108))	('MEK1', 'molecular_function', 'GO:0004708', ('17', '21'))	('tumor', 'Disease', (119, 124))	('selumetinib', 'Chemical', 'MESH:C517975', (72, 83))	('mutation', 'Var', (22, 30))	('MEK1', 'Gene', '5604', (17, 21))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('MEK1', 'Gene', (17, 21))	('patients', 'Species', '9606', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('selumetinib', 'Chemical', 'MESH:C517975', (158, 169))	('melanoma cell', 'Disease', (95, 108))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
16121	25278770	The MEK-dependent resistance can be overcome by more potent inhibition of the MAPK pathway, such as the combination of BRAF inhibitors and MEK inhibitors and ERK inhibitors.	('ERK', 'molecular_function', 'GO:0004707', ('158', '161'))	('MAPK', 'molecular_function', 'GO:0004707', ('78', '82'))	('inhibition', 'NegReg', (60, 70))	('BRAF', 'Gene', (119, 123))	('ERK', 'Gene', '5594', (158, 161))	('ERK', 'Gene', (158, 161))	('MEK', 'Gene', (139, 142))	('MAPK', 'Gene', (78, 82))	('inhibitors', 'Var', (124, 134))	('MAPK', 'Gene', '5595;5594;5595', (78, 82))
16139	25278770	Preclinical data have demonstrated that MEK inhibition by selumetinib is one of the effective strategies for targeting dysregulated MAPK pathway that leads to unregulated cell proliferation and development and progression of melanoma.	('leads to', 'Reg', (150, 158))	('development', 'CPA', (194, 205))	('cell proliferation', 'CPA', (171, 189))	('MEK', 'Enzyme', (40, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('171', '189'))	('melanoma', 'Disease', 'MESH:D008545', (225, 233))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('melanoma', 'Disease', (225, 233))	('unregulated', 'MPA', (159, 170))	('MAPK', 'Gene', '5595;5594;5595', (132, 136))	('progression', 'CPA', (210, 221))	('inhibition', 'NegReg', (44, 54))	('MAPK', 'Gene', (132, 136))	('MAPK', 'molecular_function', 'GO:0004707', ('132', '136'))	('dysregulated', 'Var', (119, 131))	('selumetinib', 'Chemical', 'MESH:C517975', (58, 69))
16140	25278770	Clinical studies have proven the potential antitumor activity of selumetinib in a subset of melanoma patients such as BRAF mutant melanoma and uveal melanoma harboring GNAQ/GNA11 mutations.	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('BRAF', 'Disease', (118, 122))	('GNA11', 'Gene', (173, 178))	('patients', 'Species', '9606', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('selumetinib', 'Chemical', 'MESH:C517975', (65, 76))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('mutations', 'Var', (179, 188))	('uveal melanoma', 'Disease', 'MESH:C536494', (143, 157))	('tumor', 'Disease', (47, 52))	('uveal melanoma', 'Disease', (143, 157))	('GNA11', 'Gene', '2767', (173, 178))	('GNAQ', 'Gene', '2776', (168, 172))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('GNAQ', 'Gene', (168, 172))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Disease', (130, 138))	('mutant', 'Var', (123, 129))	('uveal melanoma', 'Phenotype', 'HP:0007716', (143, 157))
16158	22805292	Most approved treatments, such as dacarbazine, high-dose interleukin-2, and ipilimumab have response rates (RR) of 6-20% and are associated with severe toxicities including capillary leak syndrome and immune-mediated issues.	('ipilimumab', 'Chemical', 'MESH:D000074324', (76, 86))	('capillary leak syndrome', 'Disease', 'MESH:D019559', (173, 196))	('capillary leak syndrome', 'Disease', (173, 196))	('dacarbazine', 'Chemical', 'MESH:D003606', (34, 45))	('toxicities', 'Disease', (152, 162))	('interleukin-2', 'Gene', '3558', (57, 70))	('interleukin-2', 'Gene', (57, 70))	('capillary leak', 'Phenotype', 'HP:0030005', (173, 187))	('toxicities', 'Disease', 'MESH:D064420', (152, 162))	('high-dose', 'Var', (47, 56))
16160	22805292	Constitutive activation of MEK through genetic mutations results in oncogenic transformation of normal cells.	('MEK', 'Gene', (27, 30))	('MEK', 'Gene', '5609', (27, 30))	('genetic mutations', 'Var', (39, 56))	('results in', 'Reg', (57, 67))	('oncogenic transformation of normal cells', 'CPA', (68, 108))	('activation', 'PosReg', (13, 23))
16161	22805292	Activating mutations within the MAPK pathway are common in melanoma.	('common', 'Reg', (49, 55))	('Activating mutations', 'Var', (0, 20))	('MAPK pathway', 'Pathway', (32, 44))	('MAPK', 'molecular_function', 'GO:0004707', ('32', '36'))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
16162	22805292	Mutations in neuroblastoma RAS viral oncogene homolog (NRAS) are observed in 10-20% of cutaneous melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanomas', 'Phenotype', 'HP:0002861', (97, 106))	('neuroblastoma', 'Phenotype', 'HP:0003006', (13, 26))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (87, 106))	('NRAS', 'Gene', '4893', (55, 59))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (87, 105))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (87, 106))	('neuroblastoma RAS viral', 'Disease', (13, 36))	('Mutations', 'Var', (0, 9))	('cutaneous melanomas', 'Disease', (87, 106))	('observed', 'Reg', (65, 73))	('NRAS', 'Gene', (55, 59))	('neuroblastoma RAS viral', 'Disease', 'MESH:D009447', (13, 36))
16163	22805292	Serine/threonine-protein kinase B-Raf (BRAF) mutations are more common, occurring in 40-60% of cutaneous melanomas.	('mutations', 'Var', (45, 54))	('BRAF', 'Gene', '673', (39, 43))	('cutaneous melanomas', 'Disease', (95, 114))	('B-Raf', 'Gene', '673', (32, 37))	('B-Raf', 'Gene', (32, 37))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('BRAF', 'Gene', (39, 43))	('melanomas', 'Phenotype', 'HP:0002861', (105, 114))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (95, 113))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (95, 114))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (95, 114))
16164	22805292	Over 80% of BRAF mutations have substitution of valine with glutamic acid at amino acid residue 600 (V600E), while substitution with lysine (V600K) occurs in 3-20% of cases.	('V600E', 'Mutation', 'rs113488022', (101, 106))	('valine', 'Protein', (48, 54))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('valine with glutamic acid at amino acid residue 600', 'Mutation', 'rs113488022', (48, 99))	('V600K', 'Mutation', 'rs121913227', (141, 146))	('lysine', 'Chemical', 'MESH:D008239', (133, 139))	('mutations', 'Var', (17, 26))
16165	22805292	In uveal melanoma, BRAF mutations are rare, but MAPK activating mutations in guanine nucleotide-1 binding protein q polypeptide (GNAQ) or guanine nucleotide-binding protein alpha 11 (GNA11) are common, detected in approximately 80% of cases.	('GNA11', 'Gene', (183, 188))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('uveal melanoma', 'Disease', (3, 17))	('MAPK', 'molecular_function', 'GO:0004707', ('48', '52'))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('guanine nucleotide-binding protein alpha 11', 'Gene', (138, 181))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('binding', 'molecular_function', 'GO:0005488', ('98', '105'))	('GNAQ', 'Gene', '2776', (129, 133))	('mutations', 'Var', (64, 73))	('guanine nucleotide-binding protein alpha 11', 'Gene', '2767', (138, 181))	('activating', 'PosReg', (53, 63))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('GNA11', 'Gene', '2767', (183, 188))	('GNAQ', 'Gene', (129, 133))	('MAPK', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (19, 23))	('BRAF', 'Gene', (19, 23))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('146', '164'))
16184	22805292	Eligibility criteria included age >=18 years, histologically or cytologically confirmed diagnosis of solid tumour or lymphoma, Eastern Cooperative Oncology Group (ECOG) performance status <=1, and adequate haematological, hepatic, renal, and cardiac function.	('solid tumour', 'Disease', 'MESH:D009369', (101, 113))	('<=1', 'Var', (188, 191))	('Oncology', 'Phenotype', 'HP:0002664', (147, 155))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('lymphoma', 'Disease', (117, 125))	('solid tumour', 'Disease', (101, 113))	('lymphoma', 'Disease', 'MESH:D008223', (117, 125))	('lymphoma', 'Phenotype', 'HP:0002665', (117, 125))
16193	22805292	Submitted tumour samples were analysed at Response Genetics, Inc. (RGI; Los Angeles, CA, USA) using allele-specific PCR to identify BRAFV600E and BRAFV600K mutations.	('BRAFV600K', 'Var', (146, 155))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('BRAFV600E', 'Var', (132, 141))	('BRAFV600E', 'Mutation', 'rs113488022', (132, 141))	('tumour', 'Disease', 'MESH:D009369', (10, 16))	('tumour', 'Disease', (10, 16))	('BRAFV600K', 'Mutation', 'rs121913227', (146, 155))
16194	22805292	BRAF mutation-negative results are referred to as BRAF wild-type.	('BRAF', 'Gene', (50, 54))	('BRAF', 'Gene', '673', (0, 4))	('mutation-negative', 'Var', (5, 22))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (50, 54))
16195	22805292	Patients with at least one positive BRAF mutation test were considered to be BRAF-mutant.	('BRAF', 'Gene', (36, 40))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (77, 81))	('mutation', 'Var', (41, 49))	('Patients', 'Species', '9606', (0, 8))	('BRAF', 'Gene', '673', (36, 40))
16233	22805292	The best response observed in seven patients with an NRAS mutation was SD (n=2), one of whom received treatment for 48 weeks.	('mutation', 'Var', (58, 66))	('patients', 'Species', '9606', (36, 44))	('NRAS', 'Gene', '4893', (53, 57))	('NRAS', 'Gene', (53, 57))
16234	22805292	Of the six patients with unknown BRAF mutational status, three achieved SD, one of whom received study treatment for 22 weeks.	('BRAF', 'Gene', '673', (33, 37))	('BRAF', 'Gene', (33, 37))	('achieved', 'PosReg', (63, 71))	('patients', 'Species', '9606', (11, 19))	('mutational', 'Var', (38, 48))
16237	22805292	The Illumina platform evaluated mutational status and copy number status of 78 different genes commonly implicated in tumourogenesis.	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', (118, 124))	('copy number status', 'Var', (54, 72))
16239	22805292	Overall, 33 genes were found to have mutations, and BRAF mutation results were generally concordant (18 of 19; 95% agreement) between Illumina genotyping and RGI.	('mutation', 'Var', (57, 65))	('mutations', 'Var', (37, 46))	('BRAF', 'Gene', (52, 56))	('BRAF', 'Gene', '673', (52, 56))
16241	22805292	Of these three samples, Illumina genotyping identified mutations in NRAS (n=2) and KRAS (n=1).	('KRAS', 'Gene', (83, 87))	('KRAS', 'Gene', '3845', (83, 87))	('mutations', 'Var', (55, 64))	('NRAS', 'Gene', (68, 72))	('NRAS', 'Gene', '4893', (68, 72))
16243	22805292	Two non-BRAFV600 mutations (L597V, intermediate activity; G469A, low activity) were identified by Illumina genotyping in the 23 BRAF wild-type melanoma samples.	('BRAF', 'Gene', '673', (128, 132))	('BRAF', 'Gene', '673', (8, 12))	('BRAF', 'Gene', (8, 12))	('L597V', 'Mutation', 'rs121913369', (28, 33))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('L597V', 'Var', (28, 33))	('melanoma', 'Disease', (143, 151))	('G469A', 'Var', (58, 63))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('G469A', 'Mutation', 'rs121913355', (58, 63))	('BRAF', 'Gene', (128, 132))
16245	22805292	The patient with L597V had a confirmed PR with 60% tumour reduction and received study treatment for >2 years.	('patient', 'Species', '9606', (4, 11))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('L597V', 'Mutation', 'rs121913369', (17, 22))	('tumour reduction', 'Disease', (51, 67))	('L597V', 'Var', (17, 22))	('tumour reduction', 'Disease', 'MESH:D009369', (51, 67))
16249	22805292	Combined exploratory and clinical genetics for patients with uveal melanoma identified GNAQ and GNA11 mutations in six patients, in which three SD and three PD were the best responses.	('GNAQ', 'Gene', '2776', (87, 91))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('patients', 'Species', '9606', (119, 127))	('patients', 'Species', '9606', (47, 55))	('uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('uveal melanoma', 'Disease', 'MESH:C536494', (61, 75))	('mutations', 'Var', (102, 111))	('GNAQ', 'Gene', (87, 91))	('uveal melanoma', 'Disease', (61, 75))	('GNA11', 'Gene', '2767', (96, 101))	('GNA11', 'Gene', (96, 101))
16250	22805292	One patient with a GNA11 mutation identified by Illumina genotyping stayed on study treatment for >40 weeks.	('GNA11', 'Gene', '2767', (19, 24))	('mutation', 'Var', (25, 33))	('GNA11', 'Gene', (19, 24))	('patient', 'Species', '9606', (4, 11))
16255	22805292	Notably absent was the occurrence of proliferative skin lesions, including squamous cell carcinoma, which have been associated with selective BRAF inhibitors, presumably by the paradoxical activation of the MAPK pathway resulting in increased pERK in normal cells.	('BRAF', 'Gene', '673', (142, 146))	('pERK', 'Gene', '9451', (243, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('MAPK', 'molecular_function', 'GO:0004707', ('207', '211'))	('MAPK pathway', 'Pathway', (207, 219))	('skin lesions', 'Disease', (51, 63))	('inhibitors', 'Var', (147, 157))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('BRAF', 'Gene', (142, 146))	('squamous cell carcinoma', 'Disease', (75, 98))	('activation', 'PosReg', (189, 199))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 98))	('skin lesions', 'Disease', 'MESH:D012871', (51, 63))	('increased', 'PosReg', (233, 242))	('pERK', 'Gene', (243, 247))
16263	22805292	Durable responses to trametinib were observed in patients with both BRAFV600E and BRAFV600K mutations.	('BRAFV600K', 'Mutation', 'rs121913227', (82, 91))	('trametinib', 'Chemical', 'MESH:C560077', (21, 31))	('BRAFV600K', 'Var', (82, 91))	('patients', 'Species', '9606', (49, 57))	('BRAFV600E', 'Var', (68, 77))	('BRAFV600E', 'Mutation', 'rs113488022', (68, 77))
16264	22805292	Exploratory genetic data revealed one patient with a non-V600 BRAF mutation (L597V) who achieved a confirmed PR with 60% tumour reduction and received study treatment for >2 years, which could suggest that other less common non-V600 BRAF mutant tumours may be sensitive to MEK inhibition.	('BRAF', 'Gene', '673', (62, 66))	('tumour reduction', 'Disease', 'MESH:D009369', (121, 137))	('tumours', 'Phenotype', 'HP:0002664', (245, 252))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('MEK', 'Gene', '5609', (273, 276))	('non-V600', 'Var', (224, 232))	('tumours', 'Disease', 'MESH:D009369', (245, 252))	('L597V', 'Mutation', 'rs121913369', (77, 82))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('patient', 'Species', '9606', (38, 45))	('tumours', 'Disease', (245, 252))	('BRAF', 'Gene', (233, 237))	('BRAF', 'Gene', '673', (233, 237))	('BRAF', 'Gene', (62, 66))	('tumour reduction', 'Disease', (121, 137))	('MEK', 'Gene', (273, 276))
16271	22805292	Uveal melanoma accounts for approximately 5% of all melanomas and frequently has MAPK pathway activation, most commonly via mutation in GNAQ and GNA11.	('melanomas', 'Disease', 'MESH:D008545', (52, 61))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('MAPK pathway', 'Pathway', (81, 93))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('GNAQ', 'Gene', (136, 140))	('GNA11', 'Gene', '2767', (145, 150))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('melanomas', 'Disease', (52, 61))	('activation', 'PosReg', (94, 104))	('MAPK', 'molecular_function', 'GO:0004707', ('81', '85'))	('mutation', 'Var', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))	('GNAQ', 'Gene', '2776', (136, 140))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))	('GNA11', 'Gene', (145, 150))
16278	22805292	The discovery of BRAFV600-activating mutations and the development of selective, small-molecule inhibitors have revolutionised melanoma treatment.	('BRAF', 'Gene', '673', (17, 21))	('mutations', 'Var', (37, 46))	('BRAF', 'Gene', (17, 21))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))
16285	22805292	Acquired mutations in MEK to both MEK and BRAF inhibitor therapy have now been described.	('BRAF', 'Gene', '673', (42, 46))	('MEK', 'Gene', (34, 37))	('mutations', 'Var', (9, 18))	('MEK', 'Gene', '5609', (34, 37))	('BRAF', 'Gene', (42, 46))	('MEK', 'Gene', (22, 25))	('MEK', 'Gene', '5609', (22, 25))
16300	24423917	Mutation frequencies of GNAQ, GNA11, BAP1, SF3B1, EIF1AX and TERT in uveal melanoma: detection of an activating mutation in the TERT gene promoter in a single case of uveal melanoma Uveal melanoma is the most frequent primary tumour of the eye.	('SF3B1', 'Gene', (43, 48))	('uveal melanoma', 'Disease', (69, 83))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('EIF1AX', 'Gene', '1964', (50, 56))	('tumour of the eye', 'Disease', 'MESH:D005134', (226, 243))	('Uveal melanoma', 'Disease', (182, 196))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('TERT', 'Gene', (61, 65))	('GNA11', 'Gene', (30, 35))	('TERT', 'Gene', '7015', (61, 65))	('SF3B1', 'Gene', '23451', (43, 48))	('BAP1', 'Gene', '8314', (37, 41))	('uveal melanoma', 'Disease', 'MESH:C536494', (167, 181))	('Uveal melanoma', 'Disease', 'MESH:C536494', (182, 196))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('uveal melanoma', 'Disease', (167, 181))	('mutation', 'Var', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('uveal melanoma', 'Phenotype', 'HP:0007716', (167, 181))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (182, 196))	('TERT', 'Gene', (128, 132))	('TERT', 'Gene', '7015', (128, 132))	('activating', 'PosReg', (101, 111))	('BAP1', 'Gene', (37, 41))	('tumour of the eye', 'Phenotype', 'HP:0100012', (226, 243))	('GNAQ', 'Gene', '2776', (24, 28))	('EIF1AX', 'Gene', (50, 56))	('GNAQ', 'Gene', (24, 28))	('GNA11', 'Gene', '2767', (30, 35))	('tumour of the eye', 'Disease', (226, 243))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))
16303	24423917	The recent identification of driver mutations in the promoter of the telomerase reverse transcriptase (TERT) gene with UV-induced cytidine-to-thymidine transitions in cutaneous melanoma prompted us to investigate whether these mutations also occur in uveal melanoma.	('cytidine', 'Chemical', 'MESH:D003562', (130, 138))	('telomerase reverse transcriptase', 'Gene', '7015', (69, 101))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('uveal melanoma', 'Phenotype', 'HP:0007716', (251, 265))	('transcriptase', 'molecular_function', 'GO:0003968', ('88', '101'))	('thymidine', 'Chemical', 'MESH:D013936', (142, 151))	('uveal melanoma', 'Disease', (251, 265))	('transcriptase', 'molecular_function', 'GO:0034062', ('88', '101'))	('melanoma', 'Phenotype', 'HP:0002861', (257, 265))	('UV-induced cytidine-to-thymidine transitions', 'MPA', (119, 163))	('telomerase reverse transcriptase', 'Gene', (69, 101))	('transcriptase', 'molecular_function', 'GO:0003899', ('88', '101'))	('mutations', 'Var', (36, 45))	('cutaneous melanoma', 'Disease', (167, 185))	('TERT', 'Gene', (103, 107))	('TERT', 'Gene', '7015', (103, 107))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (167, 185))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (167, 185))	('uveal melanoma', 'Disease', 'MESH:C536494', (251, 265))
16304	24423917	We analysed 50 cases of uveal melanoma obtained from enucleation surgery for mutations in the genes GNAQ, GNA11, BAP1, SF3B1, EIFAX1 and TERT, measured gene expression using microarrays and analysed gene copy numbers by SNP arrays.	('uveal melanoma', 'Disease', (24, 38))	('TERT', 'Gene', (137, 141))	('GNAQ', 'Gene', '2776', (100, 104))	('SF3B1', 'Gene', (119, 124))	('enucleation', 'biological_process', 'GO:0090601', ('53', '64'))	('GNA11', 'Gene', (106, 111))	('EIFAX1', 'Gene', (126, 132))	('TERT', 'Gene', '7015', (137, 141))	('BAP1', 'Gene', '8314', (113, 117))	('GNAQ', 'Gene', (100, 104))	('mutations', 'Var', (77, 86))	('SF3B1', 'Gene', '23451', (119, 124))	('GNA11', 'Gene', '2767', (106, 111))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (24, 38))	('uveal melanoma', 'Disease', 'MESH:C536494', (24, 38))	('BAP1', 'Gene', (113, 117))	('gene expression', 'biological_process', 'GO:0010467', ('152', '167'))
16306	24423917	The tumour showed mutations in GNA11 and EIF1AX that are typical for uveal melanoma and absent from cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('cutaneous melanoma', 'Disease', (100, 118))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (100, 118))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('uveal melanoma', 'Disease', (69, 83))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (100, 118))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('GNA11', 'Gene', '2767', (31, 36))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('GNA11', 'Gene', (31, 36))	('EIF1AX', 'Gene', '1964', (41, 47))	('EIF1AX', 'Gene', (41, 47))	('mutations', 'Var', (18, 27))
16308	24423917	Several tumours among which the one carrying the TERT promoter mutation showed elevated TERT expression.	('tumours', 'Disease', (8, 15))	('TERT', 'Gene', '7015', (88, 92))	('mutation', 'Var', (63, 71))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('TERT', 'Gene', (49, 53))	('TERT', 'Gene', '7015', (49, 53))	('elevated', 'PosReg', (79, 87))	('tumours', 'Disease', 'MESH:D009369', (8, 15))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('TERT', 'Gene', (88, 92))
16309	24423917	Consistent with previous reports, GNAQ is inversely associated with chromosome 3 monosomy and metastasis.	('metastasis', 'CPA', (94, 104))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('GNAQ', 'Gene', (34, 38))	('chromosome', 'Var', (68, 78))	('inversely', 'NegReg', (42, 51))	('GNAQ', 'Gene', '2776', (34, 38))
16310	24423917	BAP1 mutations are significantly associated with chromosome 3 monosomy but not with relapse.	('chromosome 3 monosomy', 'Disease', (49, 70))	('BAP1', 'Gene', (0, 4))	('chromosome', 'cellular_component', 'GO:0005694', ('49', '59'))	('mutations', 'Var', (5, 14))	('associated', 'Reg', (33, 43))	('BAP1', 'Gene', '8314', (0, 4))
16315	24423917	The mutations typically encountered in cutaneous and conjunctival melanomas, BRAF and NRAS, are rare in uveal melanomas that are characterised by mutations of the G-proteins GNAQ and GNA11 occurring in mutual exclusive manner in ~85% of the cases.	('conjunctival melanomas', 'Disease', 'MESH:D003229', (53, 75))	('GNAQ', 'Gene', '2776', (174, 178))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('GNA11', 'Gene', (183, 188))	('GNAQ', 'Gene', (174, 178))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('conjunctival melanomas', 'Disease', (53, 75))	('NRAS', 'Gene', '4893', (86, 90))	('uveal melanomas', 'Disease', 'MESH:C536494', (104, 119))	('GNA11', 'Gene', '2767', (183, 188))	('BRAF', 'Gene', '673', (77, 81))	('cutaneous', 'Disease', (39, 48))	('BRAF', 'Gene', (77, 81))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('NRAS', 'Gene', (86, 90))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('mutations', 'Var', (146, 155))	('uveal melanomas', 'Disease', (104, 119))	('uveal melanomas', 'Phenotype', 'HP:0007716', (104, 119))
16317	24423917	Cytidine-to-thymidine transition frequency has not been addressed by the two exome sequencing studies of uveal melanoma but the complete lack of overlap among the driver mutations in the two pathologies is consistent with a different aetiology.	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('Cytidine', 'Chemical', 'MESH:D003562', (0, 8))	('mutations', 'Var', (170, 179))	('thymidine', 'Chemical', 'MESH:D013936', (12, 21))	('uveal melanoma', 'Phenotype', 'HP:0007716', (105, 119))	('uveal melanoma', 'Disease', 'MESH:C536494', (105, 119))	('uveal melanoma', 'Disease', (105, 119))
16318	24423917	Recently, three mutations in the promoter of the telomerase reverse transcriptase (TERT) needed for telomere maintenance in cancer cells, close to the transcriptional start site, have been described for sporadic and familiar forms of cutaneous melanoma.	('telomere maintenance', 'biological_process', 'GO:0000723', ('100', '120'))	('described', 'Reg', (189, 198))	('telomere', 'cellular_component', 'GO:0000781', ('100', '108'))	('telomere', 'cellular_component', 'GO:0005696', ('100', '108'))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('telomerase reverse transcriptase', 'Gene', (49, 81))	('mutations', 'Var', (16, 25))	('transcriptase', 'molecular_function', 'GO:0003968', ('68', '81'))	('TERT', 'Gene', (83, 87))	('TERT', 'Gene', '7015', (83, 87))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('transcriptase', 'molecular_function', 'GO:0034062', ('68', '81'))	('cutaneous melanoma', 'Disease', (234, 252))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (234, 252))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (234, 252))	('telomerase reverse transcriptase', 'Gene', '7015', (49, 81))	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('transcriptase', 'molecular_function', 'GO:0003899', ('68', '81'))
16321	24423917	The mutations consisted in cytidine-to-thymidine transitions at a dipyrimidine motif consistent with ultraviolet (UV) light-induced damage.	('cytidine', 'Chemical', 'MESH:D003562', (27, 35))	('dipyrimidine', 'Chemical', '-', (66, 78))	('thymidine', 'Chemical', 'MESH:D013936', (39, 48))	('mutations', 'Var', (4, 13))	('consisted in', 'Reg', (14, 26))	('cytidine-to-thymidine transitions', 'MPA', (27, 60))
16322	24423917	All three mutations created novel binding sites for the transcription factor E-twenty-six (ETS) in the TERT promoter within 100 bp upstream of the transcription start site (TSS) in sporadic cases and closer to the TTS (-57 bp) in the familiar cases.	('binding', 'molecular_function', 'GO:0005488', ('34', '41'))	('transcription', 'biological_process', 'GO:0006351', ('56', '69'))	('binding', 'Interaction', (34, 41))	('transcription', 'biological_process', 'GO:0006351', ('147', '160'))	('TERT', 'Gene', (103, 107))	('TERT', 'Gene', '7015', (103, 107))	('mutations', 'Var', (10, 19))	('transcription factor', 'molecular_function', 'GO:0000981', ('56', '76'))
16324	24423917	It is therefore probable that the mutation strongly contributes to the development of aggressively growing cutaneous melanoma. )	('cutaneous melanoma', 'Disease', (107, 125))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (107, 125))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (107, 125))	('mutation', 'Var', (34, 42))	('contributes', 'Reg', (52, 63))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
16326	24423917	In the present study, we describe the analysis of TERT promoter mutations in a series of 50 uveal melanomas.	('TERT', 'Gene', '7015', (50, 54))	('uveal melanomas', 'Disease', (92, 107))	('uveal melanomas', 'Phenotype', 'HP:0007716', (92, 107))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('uveal melanoma', 'Phenotype', 'HP:0007716', (92, 106))	('uveal melanomas', 'Disease', 'MESH:C536494', (92, 107))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('mutations', 'Var', (64, 73))	('TERT', 'Gene', (50, 54))
16327	24423917	A mutation was detected in a single case that also carried mutations in GNA11 and EIF1AX, typical for this disease and absent from conjunctival and cutaneous melanomas.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (148, 167))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (148, 167))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (148, 166))	('EIF1AX', 'Gene', '1964', (82, 88))	('EIF1AX', 'Gene', (82, 88))	('mutations', 'Var', (59, 68))	('GNA11', 'Gene', (72, 77))	('melanomas', 'Phenotype', 'HP:0002861', (158, 167))	('cutaneous melanomas', 'Disease', (148, 167))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('GNA11', 'Gene', '2767', (72, 77))
16338	24423917	Telomerase reverse transcriptase promoter region oligonucleotide primers were synthesised according to the Eukaryotic Promoter Database genomic reference sequence of TERT and designed to amplify a portion of the TERT core promoter (-144 to +43).	('-144', 'Var', (232, 236))	('transcriptase', 'molecular_function', 'GO:0003968', ('19', '32'))	('transcriptase', 'molecular_function', 'GO:0003899', ('19', '32'))	('TERT', 'Gene', (212, 216))	('TERT', 'Gene', '7015', (212, 216))	('core', 'cellular_component', 'GO:0019013', ('217', '221'))	('Telomerase reverse transcriptase', 'Gene', (0, 32))	('Telomerase reverse transcriptase', 'Gene', '7015', (0, 32))	('transcriptase', 'molecular_function', 'GO:0034062', ('19', '32'))	('TERT', 'Gene', (166, 170))	('TERT', 'Gene', '7015', (166, 170))
16342	24423917	One (MU076) of these 50 cases showed a heterozygous mutation in the promoter of TERT, a C to T transition on chromosome 5 in position 1 295 228 (Figure 1A) that increases the likelihood of the sequence to bind ETS transcription factors from 78.4 (wild type) to 86.3 (mutation) as analysed by TFSEARCH and has been shown to drive TERT promoter activity.	('bind', 'Interaction', (205, 209))	('TERT', 'Gene', (329, 333))	('TERT', 'Gene', '7015', (329, 333))	('drive', 'Reg', (323, 328))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('transcription', 'biological_process', 'GO:0006351', ('214', '227'))	('mutation', 'Var', (52, 60))	('TERT', 'Gene', (80, 84))	('TERT', 'Gene', '7015', (80, 84))	('increases', 'PosReg', (161, 170))
16343	24423917	The same tumour showed a heterozygous GNA11 mutation in exon 5 (Figure 1B) and wild-type sequences for BAP1 and SF3B1 (data not shown).	('BAP1', 'Gene', '8314', (103, 107))	('tumour', 'Disease', (9, 15))	('mutation', 'Var', (44, 52))	('SF3B1', 'Gene', '23451', (112, 117))	('BAP1', 'Gene', (103, 107))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('GNA11', 'Gene', '2767', (38, 43))	('GNA11', 'Gene', (38, 43))	('tumour', 'Disease', 'MESH:D009369', (9, 15))	('SF3B1', 'Gene', (112, 117))
16344	24423917	EIF1AX exon 2 showed a mutated sequence in addition to the wild-type allele (Figure 1C).	('mutated', 'Var', (23, 30))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))
16346	24423917	EIF1AX mutations exclusively occurred in disomic, non-metastatic cases.	('occurred', 'Reg', (29, 37))	('disomic', 'Disease', (41, 48))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
16347	24423917	One of the three SF3B1 mutations detected occurred in a metastatic case with uniparental disomy of chromosome 3.	('occurred', 'Reg', (42, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('99', '109'))	('uniparental disomy', 'Disease', 'MESH:D024182', (77, 95))	('SF3B1', 'Gene', (17, 22))	('mutations', 'Var', (23, 32))	('SF3B1', 'Gene', '23451', (17, 22))	('uniparental disomy', 'Disease', (77, 95))
16348	24423917	GNAQ and GNA11 mutations accounted for ~84% of the cases.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('GNAQ', 'Gene', (0, 4))	('GNA11', 'Gene', '2767', (9, 14))
16352	24423917	Cytogenetic analyses divide uveal melanomas into two distinct patterns: the first, detected in ~50% of uveal melanomas, characterised by loss of chromosome 3, often associated with chromosome 8 gain and strongly linked to metastatic disease.	('uveal melanomas', 'Disease', (103, 118))	('uveal melanomas', 'Phenotype', 'HP:0007716', (103, 118))	('gain', 'PosReg', (194, 198))	('uveal melanoma', 'Phenotype', 'HP:0007716', (28, 42))	('uveal melanomas', 'Disease', 'MESH:C536494', (28, 43))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('chromosome', 'cellular_component', 'GO:0005694', ('181', '191'))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('associated', 'Reg', (165, 175))	('metastatic disease', 'Disease', (222, 240))	('uveal melanomas', 'Disease', (28, 43))	('uveal melanomas', 'Phenotype', 'HP:0007716', (28, 43))	('loss', 'Var', (137, 141))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('chromosome', 'cellular_component', 'GO:0005694', ('145', '155'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('uveal melanomas', 'Disease', 'MESH:C536494', (103, 118))	('linked to', 'Reg', (212, 221))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))
16353	24423917	The second pattern accounts for 25% of uveal melanomas and is characterised by chromosome 6p gain, often associated with 6p loss but rarely with chromosome 3 loss.	('uveal melanomas', 'Disease', (39, 54))	('loss', 'NegReg', (124, 128))	('uveal melanomas', 'Phenotype', 'HP:0007716', (39, 54))	('gain', 'PosReg', (93, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (39, 53))	('chromosome', 'cellular_component', 'GO:0005694', ('79', '89'))	('uveal melanomas', 'Disease', 'MESH:C536494', (39, 54))	('chromosome', 'Var', (79, 89))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('chromosome', 'cellular_component', 'GO:0005694', ('145', '155'))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))
16354	24423917	Copy number alteration analysis of the uveal melanoma carrying the TERT promoter mutation using Affymetrix 250K SNP arrays revealed disomy of chromosome 3 and copy number gain of the short arm of chromosome 6.	('short arm', 'Phenotype', 'HP:0009824', (183, 192))	('TERT', 'Gene', (67, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('196', '206'))	('TERT', 'Gene', '7015', (67, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('142', '152'))	('uveal melanoma', 'Disease', 'MESH:C536494', (39, 53))	('disomy', 'Disease', (132, 138))	('disomy', 'Disease', 'MESH:D024182', (132, 138))	('mutation', 'Var', (81, 89))	('uveal melanoma', 'Phenotype', 'HP:0007716', (39, 53))	('uveal melanoma', 'Disease', (39, 53))	('copy number', 'Var', (159, 170))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))
16360	24423917	The expression of TERT as revealed by microarray gene expression data shows that the tumour carrying the mutation, as well as several other tumours with wild-type TERT promoters, has elevated levels of TERT expression as compared with the mean of TERT expression in the whole cohort (Figure 4).	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('tumour', 'Disease', (85, 91))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('tumour', 'Disease', (140, 146))	('tumours', 'Disease', 'MESH:D009369', (140, 147))	('mutation', 'Var', (105, 113))	('TERT', 'Gene', (202, 206))	('TERT', 'Gene', '7015', (202, 206))	('gene expression', 'biological_process', 'GO:0010467', ('49', '64'))	('TERT', 'Gene', (163, 167))	('elevated', 'PosReg', (183, 191))	('TERT', 'Gene', '7015', (163, 167))	('TERT', 'Gene', (247, 251))	('TERT', 'Gene', '7015', (247, 251))	('TERT', 'Gene', (18, 22))	('TERT', 'Gene', '7015', (18, 22))	('tumours', 'Disease', (140, 147))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
16363	24423917	However, despite this trend, high TERT expression levels are not significantly associated with disease-free survival (P=0.338) or other clinical, pathological or molecular features of the tumours (Figure 4; supplementary table 1).	('high', 'Var', (29, 33))	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('disease-free survival', 'CPA', (95, 116))	('tumours', 'Phenotype', 'HP:0002664', (188, 195))	('TERT', 'Gene', (34, 38))	('tumours', 'Disease', 'MESH:D009369', (188, 195))	('tumours', 'Disease', (188, 195))	('TERT', 'Gene', '7015', (34, 38))
16364	24423917	The analysis of the recently identified uveal melanoma driver mutations in the genes GNAQ, GNA11, BAP1, SF3B1 and EIF1AX generally confirms the observed mutation frequencies and the prevalence of SF3B1 and EIF1AX mutations in disomic, non-metastatic cases.	('BAP1', 'Gene', (98, 102))	('EIF1AX', 'Gene', '1964', (114, 120))	('GNA11', 'Gene', '2767', (91, 96))	('SF3B1', 'Gene', '23451', (196, 201))	('GNAQ', 'Gene', '2776', (85, 89))	('EIF1AX', 'Gene', (206, 212))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('GNAQ', 'Gene', (85, 89))	('SF3B1', 'Gene', (104, 109))	('mutations', 'Var', (62, 71))	('EIF1AX', 'Gene', '1964', (206, 212))	('GNA11', 'Gene', (91, 96))	('uveal melanoma', 'Disease', (40, 54))	('uveal melanoma', 'Disease', 'MESH:C536494', (40, 54))	('BAP1', 'Gene', '8314', (98, 102))	('SF3B1', 'Gene', '23451', (104, 109))	('EIF1AX', 'Gene', (114, 120))	('SF3B1', 'Gene', (196, 201))	('disomic', 'Disease', (226, 233))	('uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))
16365	24423917	Also the mutual exclusive mutations of GNAQ and GNA11 and the association of the latter with a more aggressive tumour phenotype could be confirmed.	('aggressive tumour', 'Disease', (100, 117))	('GNAQ', 'Gene', (39, 43))	('association', 'Interaction', (62, 73))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (26, 35))	('GNA11', 'Gene', (48, 53))	('GNAQ', 'Gene', '2776', (39, 43))	('GNA11', 'Gene', '2767', (48, 53))	('aggressive tumour', 'Disease', 'MESH:D001523', (100, 117))
16366	24423917	Mutations of the tumour suppressor gene BAP1 are associated with monosomy of chromosome 3 yet in our cohort, there are several cases without metastases despite monosomy of chromosome 3 and BAP1 mutation.	('BAP1', 'Gene', '8314', (189, 193))	('mutation', 'Var', (194, 202))	('monosomy of chromosome 3', 'Disease', (65, 89))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('chromosome', 'cellular_component', 'GO:0005694', ('77', '87'))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('BAP1', 'Gene', (189, 193))	('associated', 'Reg', (49, 59))	('metastases', 'Disease', 'MESH:D009362', (141, 151))	('BAP1', 'Gene', '8314', (40, 44))	('Mutations', 'Var', (0, 9))	('chromosome', 'cellular_component', 'GO:0005694', ('172', '182'))	('tumour', 'Disease', (17, 23))	('BAP1', 'Gene', (40, 44))	('metastases', 'Disease', (141, 151))
16367	24423917	In addition, we show here a case of uveal melanoma that carries one of the two mutations in the promoter region of TERT that have been described for sporadic cutaneous melanoma that closely resembles cutaneous melanoma with which it shares BRAF and NRAS mutations (and references therein).	('NRAS', 'Gene', (249, 253))	('uveal melanoma', 'Disease', 'MESH:C536494', (36, 50))	('uveal melanoma', 'Disease', (36, 50))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('cutaneous melanoma', 'Disease', (158, 176))	('mutations', 'Var', (79, 88))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (158, 176))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (158, 176))	('uveal melanoma', 'Phenotype', 'HP:0007716', (36, 50))	('TERT', 'Gene', (115, 119))	('TERT', 'Gene', '7015', (115, 119))	('NRAS', 'Gene', '4893', (249, 253))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('cutaneous melanoma', 'Disease', (200, 218))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (200, 218))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (200, 218))	('BRAF', 'Gene', '673', (240, 244))	('BRAF', 'Gene', (240, 244))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
16368	24423917	In fact, TERT mutations in conjunctival melanomas also occurred in concomitance with BRAF and NRAS mutations.	('NRAS', 'Gene', (94, 98))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('TERT', 'Gene', '7015', (9, 13))	('NRAS', 'Gene', '4893', (94, 98))	('mutations', 'Var', (99, 108))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('conjunctival melanomas', 'Disease', (27, 49))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (27, 49))	('TERT', 'Gene', (9, 13))	('occurred', 'Reg', (55, 63))
16371	24423917	The tumour carrying this mutation can clearly be identified as a uveal melanoma as it was located in the posterior chamber of the eye, showed the typical epitheloid morphology and carries a mutation in the GNA11 gene.	('mutation', 'Var', (190, 198))	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('uveal melanoma', 'Disease', (65, 79))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('mutation', 'Var', (25, 33))	('GNA11', 'Gene', '2767', (206, 211))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('GNA11', 'Gene', (206, 211))	('uveal melanoma', 'Disease', 'MESH:C536494', (65, 79))
16372	24423917	GNA11 mutations occur in 33.2% of uveal melanomas and in 6.5% of blue nevi but are absent from other nevi (n=105) and extraocular melanomas (n=273) (; see Supplementary Table 2 for mutation frequencies of GNAQ, GNA11, BAP1, SF3B1 and EIF1AX as obtained from the Catologue of somatic mutations in Cancer (COSMIC) database; http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/).	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('GNA11', 'Gene', '2767', (211, 216))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('Cancer', 'Phenotype', 'HP:0002664', (296, 302))	('uveal melanomas', 'Disease', 'MESH:C536494', (34, 49))	('nevi', 'Phenotype', 'HP:0003764', (70, 74))	('nevi', 'Phenotype', 'HP:0003764', (101, 105))	('cancer', 'Disease', (349, 355))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('GNA11', 'Gene', '2767', (0, 5))	('Cancer', 'Disease', (296, 302))	('ocular melanomas', 'Phenotype', 'HP:0025534', (123, 139))	('SF3B1', 'Gene', (224, 229))	('uveal melanoma', 'Phenotype', 'HP:0007716', (34, 48))	('ocular melanomas', 'Disease', 'MESH:D008545', (123, 139))	('mutations', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('blue nevi', 'Phenotype', 'HP:0100814', (65, 74))	('uveal melanomas', 'Phenotype', 'HP:0007716', (34, 49))	('uveal melanomas', 'Disease', (34, 49))	('GNA11', 'Gene', (211, 216))	('BAP1', 'Gene', '8314', (218, 222))	('melanomas', 'Phenotype', 'HP:0002861', (130, 139))	('Cancer', 'Disease', 'MESH:D009369', (296, 302))	('EIF1AX', 'Gene', '1964', (234, 240))	('EIF1AX', 'Gene', (234, 240))	('SF3B1', 'Gene', '23451', (224, 229))	('ocular melanomas', 'Disease', (123, 139))	('GNA11', 'Gene', (0, 5))	('cancer', 'Disease', (329, 335))	('GNAQ', 'Gene', '2776', (205, 209))	('cancer', 'Disease', 'MESH:D009369', (349, 355))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('BAP1', 'Gene', (218, 222))	('GNAQ', 'Gene', (205, 209))
16374	24423917	The mutation in EIF1AX has also been shown to be frequent in uveal melanoma.	('EIF1AX', 'Gene', '1964', (16, 22))	('EIF1AX', 'Gene', (16, 22))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('mutation', 'Var', (4, 12))	('uveal melanoma', 'Disease', 'MESH:C536494', (61, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('uveal melanoma', 'Disease', (61, 75))	('frequent', 'Reg', (49, 57))
16378	24423917	The occurrence of an EIF1AX mutation in a disomic case with a GNA11 mutation but without BAP1 and SF3B1 mutations is consistent with the original report of this mutation. )	('BAP1', 'Gene', (89, 93))	('mutation', 'Var', (68, 76))	('EIF1AX', 'Gene', '1964', (21, 27))	('SF3B1', 'Gene', '23451', (98, 103))	('mutation', 'Var', (28, 36))	('GNA11', 'Gene', '2767', (62, 67))	('GNA11', 'Gene', (62, 67))	('EIF1AX', 'Gene', (21, 27))	('BAP1', 'Gene', '8314', (89, 93))	('SF3B1', 'Gene', (98, 103))
16379	24423917	have shown that the TERT promoter mutation determines increased promoter activity in a luciferase reporter system.	('mutation', 'Var', (34, 42))	('increased', 'PosReg', (54, 63))	('TERT', 'Gene', (20, 24))	('promoter activity', 'MPA', (64, 81))	('TERT', 'Gene', '7015', (20, 24))	('luciferase reporter', 'Enzyme', (87, 106))
16380	24423917	We show here for the first time that the mutation in the promoter is actually associated with increased expression of the gene in the tumour.	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('increased', 'PosReg', (94, 103))	('tumour', 'Disease', (134, 140))	('expression', 'MPA', (104, 114))	('mutation in', 'Var', (41, 52))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
16384	24423917	Telomerase reverse transcriptase promoter mutations have been observed in a variety of tumours and it has been speculated that these mutations could be more frequent in tumours derived from tissues with low self-renewal where tumour development might be hindered by the inherently lower telomerase activity.	('tumour', 'Disease', (87, 93))	('telomerase activity', 'molecular_function', 'GO:0003720', ('287', '306'))	('tumours', 'Disease', (169, 176))	('Telomerase reverse transcriptase', 'Gene', '7015', (0, 32))	('tumours', 'Phenotype', 'HP:0002664', (169, 176))	('tumours', 'Disease', 'MESH:D009369', (169, 176))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('transcriptase', 'molecular_function', 'GO:0003899', ('19', '32'))	('tumour', 'Disease', 'MESH:D009369', (226, 232))	('Telomerase reverse transcriptase', 'Gene', (0, 32))	('mutations', 'Var', (133, 142))	('tumour', 'Disease', (226, 232))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('tumours', 'Disease', (87, 94))	('tumour', 'Disease', (169, 175))	('frequent', 'Reg', (157, 165))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('tumours', 'Disease', 'MESH:D009369', (87, 94))	('transcriptase', 'molecular_function', 'GO:0003968', ('19', '32'))	('transcriptase', 'molecular_function', 'GO:0034062', ('19', '32'))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('mutations', 'Var', (42, 51))
16385	24423917	Telomere shrinkage can also be overcome in cancer cells by mutations in the genes alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain-associated protein (DAXX) leading to recombination-mediated telomere maintenance.	('mental retardation', 'Phenotype', 'HP:0001249', (100, 118))	('recombination-mediated telomere maintenance', 'MPA', (197, 240))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('telomere', 'cellular_component', 'GO:0005696', ('220', '228'))	('cancer', 'Disease', (43, 49))	('DAXX', 'Gene', '1616', (180, 184))	('alpha thalassemia/mental retardation syndrome X-linked', 'Gene', '546', (82, 136))	('Telomere', 'cellular_component', 'GO:0000781', ('0', '8'))	('ATRX', 'Gene', (138, 142))	('telomere', 'cellular_component', 'GO:0000781', ('220', '228'))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('mutations', 'Var', (59, 68))	('telomere maintenance', 'biological_process', 'GO:0000723', ('220', '240'))	('DAXX', 'Gene', (180, 184))	('Telomere', 'cellular_component', 'GO:0005696', ('0', '8'))	('ATRX', 'Gene', '546', (138, 142))
16387	24423917	The case carrying this mutation shows disomy of chromosome 3 and wild-type status of the tumour suppressor gene BAP1 that is frequently mutated in tumours that undergo metastasis and that show a chromosome 3 monosomy-associated gene expression profile.	('BAP1', 'Gene', (112, 116))	('gene expression', 'biological_process', 'GO:0010467', ('228', '243'))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('mutation', 'Var', (23, 31))	('disomy', 'Disease', 'MESH:D024182', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumours', 'Phenotype', 'HP:0002664', (147, 154))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour', 'Disease', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('tumours', 'Disease', 'MESH:D009369', (147, 154))	('tumours', 'Disease', (147, 154))	('BAP1', 'Gene', '8314', (112, 116))	('chromosome', 'cellular_component', 'GO:0005694', ('195', '205'))	('chromosome', 'cellular_component', 'GO:0005694', ('48', '58'))	('tumour', 'Disease', (147, 153))	('disomy', 'Disease', (38, 44))
16389	24423917	Given the strong prognostic effect of chromosome 3 monosomy, this tumour would be considered as at low risk of metastasis despite epitheloid morphology and tumour dimensions.	('tumour', 'Disease', (156, 162))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('chromosome', 'cellular_component', 'GO:0005694', ('38', '48'))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('monosomy', 'Var', (51, 59))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumour', 'Disease', (66, 72))	('tumour', 'Disease', 'MESH:D009369', (156, 162))
16390	24423917	The patient whose uveal melanoma carried the TERT mutation is free of disease at 31 months after diagnosis but an effect of the mutation in the TERT promoter on the metastasis risk cannot be definitely excluded.	('uveal melanoma', 'Phenotype', 'HP:0007716', (18, 32))	('uveal melanoma', 'Disease', 'MESH:C536494', (18, 32))	('TERT', 'Gene', (45, 49))	('uveal melanoma', 'Disease', (18, 32))	('TERT', 'Gene', (144, 148))	('TERT', 'Gene', '7015', (144, 148))	('patient', 'Species', '9606', (4, 11))	('TERT', 'Gene', '7015', (45, 49))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('mutation', 'Var', (50, 58))
16392	24423917	The mutation detected in the melanoma family showed high penetrance and occurred in aggressive melanomas with early onset and short survival after diagnosis even in some cases of the last generation where present day management of the disease can be assumed.	('aggressive melanomas', 'Disease', (84, 104))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('melanoma', 'Disease', (95, 103))	('mutation', 'Var', (4, 12))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('aggressive melanomas', 'Disease', 'MESH:D008545', (84, 104))	('occurred in', 'Reg', (72, 83))
16395	24423917	If so, this mutation could be associated with the rare cases of uveal melanoma with disomy and BAP1 wild type that develop metastases and that, though rare, determine pitfalls in prognostic testing.	('associated', 'Reg', (30, 40))	('BAP1', 'Gene', (95, 99))	('disomy', 'Disease', (84, 90))	('disomy', 'Disease', 'MESH:D024182', (84, 90))	('BAP1', 'Gene', '8314', (95, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (64, 78))	('metastases', 'Disease', (123, 133))	('uveal melanoma', 'Disease', 'MESH:C536494', (64, 78))	('mutation', 'Var', (12, 20))	('metastases', 'Disease', 'MESH:D009362', (123, 133))	('uveal melanoma', 'Disease', (64, 78))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
16396	24423917	GNAQ and GNA11 mutations are not sufficient for the generation of a metastatic phenotype of uveal melanoma.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('uveal melanoma', 'Phenotype', 'HP:0007716', (92, 106))	('uveal melanoma', 'Disease', (92, 106))	('uveal melanoma', 'Disease', 'MESH:C536494', (92, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('GNAQ', 'Gene', (0, 4))	('GNA11', 'Gene', '2767', (9, 14))
16397	24423917	In most cases, the metastatic phenotype is acquired only after loss of one copy of chromosome 3 and BAP1 mutation.	('BAP1', 'Gene', '8314', (100, 104))	('mutation', 'Var', (105, 113))	('BAP1', 'Gene', (100, 104))	('chromosome', 'cellular_component', 'GO:0005694', ('83', '93'))
16398	24423917	The association of the GNA11 mutation with another driver mutation in TERT might drive a more aggressive phenotype independently of chromosome 3 monosomy and BAP1 mutation.	('mutation', 'Var', (29, 37))	('drive', 'Reg', (81, 86))	('GNA11', 'Gene', '2767', (23, 28))	('GNA11', 'Gene', (23, 28))	('association', 'Interaction', (4, 15))	('BAP1', 'Gene', (158, 162))	('TERT', 'Gene', (70, 74))	('BAP1', 'Gene', '8314', (158, 162))	('chromosome', 'cellular_component', 'GO:0005694', ('132', '142'))	('TERT', 'Gene', '7015', (70, 74))
16425	21523560	More recently, epigenetic events associated with tumor development and progression have been found to underlie changes in HLA antigen, antigen processing machinery, co-stimulatory molecule, and tumor antigen (TA) expression in malignant cells.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('expression', 'MPA', (213, 223))	('epigenetic', 'Var', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor antigen', 'molecular_function', 'GO:0008222', ('194', '207'))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (49, 54))	('TA', 'Gene', '404663', (209, 211))	('antigen processing', 'biological_process', 'GO:0019882', ('135', '153'))	('HLA antigen', 'Protein', (122, 133))	('tumor antigen', 'Gene', (194, 207))	('tumor', 'Disease', (194, 199))	('tumor antigen', 'Gene', '404663', (194, 207))	('antigen processing', 'MPA', (135, 153))	('changes', 'Reg', (111, 118))
16458	21523560	Specifically, HLA class I antigen defects are rarely observed in tumors derived from hepatocytes, uveal melanocytes, testicular germ cells as well as hematologic malignancies.	('defects', 'Var', (34, 41))	('HLA class I antigen', 'Gene', '100507436', (14, 33))	('hematologic malignancies', 'Disease', 'MESH:D019337', (150, 174))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('hematologic malignancies', 'Disease', (150, 174))	('HLA class I antigen', 'Gene', (14, 33))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
16459	21523560	Moreover, colon cancer cells which demonstrate microsatellite instability (MSI) as well as primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma cell lines lose HLA class II antigen expression due to somatic mutations affecting HLA class II antigen-regulatory genes.	('lymphoma', 'Phenotype', 'HP:0002665', (149, 157))	('expression', 'MPA', (195, 205))	('mutations', 'Var', (221, 230))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))	('lose', 'NegReg', (169, 173))	('HLA class II antigen-regulatory genes', 'Gene', (241, 278))	('B-cell lymphoma', 'Disease', (111, 126))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (111, 126))	('classical Hodgkin lymphoma', 'Disease', 'MESH:D006689', (131, 157))	('colon cancer', 'Phenotype', 'HP:0003003', (10, 22))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (111, 126))	('microsatellite instability', 'MPA', (47, 73))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('colon cancer', 'Disease', 'MESH:D015179', (10, 22))	('HLA class II antigen', 'Protein', (174, 194))	('colon cancer', 'Disease', (10, 22))	('classical Hodgkin lymphoma', 'Disease', (131, 157))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (141, 157))
16465	21523560	In the last decade, the cancer immune surveillance theory has been revived by countless studies in mice supporting the notion that both CD8(+) and CD4(+) T cells and NK cells are engaged in the control of tumor cell growth.	('mice', 'Species', '10090', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('CD8', 'Gene', (136, 139))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('CD8', 'Gene', '925', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('cell growth', 'biological_process', 'GO:0016049', ('211', '222'))	('CD4', 'Var', (147, 150))
16474	21523560	In this regard, it is assumed that tumors arise from a single normal cell by a series of cumulative genetic and epigenetic changes through a sequential evolutionary process of mutation and selection.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('changes', 'Var', (123, 130))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
16475	21523560	Malignant cells within a tumor may harbor different mutations in a number of critical genes at various stages during the evolution of the tumor, providing some malignant cells with a selective advantage.	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (25, 30))	('providing', 'Reg', (145, 154))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
16477	21523560	Therefore, this complex interplay between tumor cell heterogeneity and tumor microenvironment not only determines but also shapes the phenotype of malignant cells towards generation of mutant resistant variants.	('tumor', 'Disease', (42, 47))	('mutant', 'Var', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('shapes', 'Reg', (123, 129))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
16481	21523560	Moreover, metastatic tumor variants derived from transplants into normal mice regularly lose MHC class I antigen expression, while cells from similar transplants into immunocompromised (athymic nude) mice do not.	('variants', 'Var', (27, 35))	('tumor', 'Disease', (21, 26))	('lose', 'NegReg', (88, 92))	('mice', 'Species', '10090', (73, 77))	('MHC class I antigen', 'Protein', (93, 112))	('mice', 'Species', '10090', (200, 204))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
16486	21523560	In other words, the tumor's MHC phenotype has been "immunoedited" in the course of the disease, resulting in the survival of tumor variants with defective presentation of antigen-derived peptides by MHC class I antigens.	('presentation of antigen-derived peptides', 'MPA', (155, 195))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('MHC', 'Gene', (28, 31))	('MHC', 'Gene', '3107', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('MHC', 'Gene', '3107', (28, 31))	('MHC', 'Gene', (199, 202))	('variants', 'Var', (131, 139))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))	('defective', 'NegReg', (145, 154))
16487	21523560	Along similar lines, both we [Ferrone unpublished] and others have observed that adoptive transfer of antigen-specific CTL to SCID mice implanted with autologous melanoma cells leads to immunoselection of HLA class I antigen and TA loss variants.	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('HLA class I antigen', 'Gene', (205, 224))	('melanoma', 'Disease', (162, 170))	('TA', 'Gene', '404663', (229, 231))	('immunoselection', 'MPA', (186, 201))	('variants', 'Var', (237, 245))	('SCID', 'Disease', (126, 130))	('HLA class I antigen', 'Gene', '100507436', (205, 224))	('Ferrone', 'Chemical', 'MESH:C031621', (30, 37))	('SCID', 'Disease', 'MESH:D053632', (126, 130))	('mice', 'Species', '10090', (131, 135))
16499	21523560	Among them is loss of HLA class I antigen expression by tumor cells due to mutations in one copy of the beta-2-microglobulin (beta2m) gene associated with loss of the other copy.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('HLA class I antigen', 'Gene', (22, 41))	('expression', 'MPA', (42, 52))	('tumor', 'Disease', (56, 61))	('mutations in', 'Var', (75, 87))	('beta2m', 'Gene', '567', (126, 132))	('beta2m', 'Gene', (126, 132))	('HLA class I antigen', 'Gene', '100507436', (22, 41))	('beta-2-microglobulin', 'Gene', '567', (104, 124))	('beta-2-microglobulin', 'Gene', (104, 124))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('loss', 'NegReg', (14, 18))
16501	21523560	Additional studies have revealed a mutational hotspot in the beta2m gene that may be associated with immune selective pressure introduced by T-cell-based immunotherapy.	('beta2m', 'Gene', '567', (61, 67))	('mutational', 'Var', (35, 45))	('associated', 'Reg', (85, 95))	('beta2m', 'Gene', (61, 67))
16503	21523560	The latter relationship is further supported by an elevated frequency of beta2m gene CT dinucleotide deletion mutations identified in MSI (+) colon carcinoma lesions.	('beta2m', 'Gene', (73, 79))	('colon carcinoma lesions', 'Disease', 'MESH:D003108', (142, 165))	('dinucleotide deletion mutations', 'Var', (88, 119))	('MSI', 'Gene', (134, 137))	('colon carcinoma lesions', 'Disease', (142, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('beta2m', 'Gene', '567', (73, 79))
16504	21523560	The beta2m gene mutations may be preferentially selected by T cell selective pressure.	('beta2m', 'Gene', '567', (4, 10))	('mutations', 'Var', (16, 25))	('beta2m', 'Gene', (4, 10))
16505	21523560	In this regard, the impairment of HLA class I antigen expression is a frequent even in MSI (+) colon carcinoma and predominantly mediated by frameshift mutations of the beta2m gene likely reflecting immunoselective pressure.	('expression', 'MPA', (54, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('frameshift mutations', 'Var', (141, 161))	('HLA class I antigen', 'Gene', (34, 53))	('mediated by', 'Reg', (129, 140))	('beta2m', 'Gene', '567', (169, 175))	('MSI', 'Disease', (87, 90))	('HLA class I antigen', 'Gene', '100507436', (34, 53))	('colon carcinoma', 'Disease', 'MESH:D015179', (95, 110))	('colon carcinoma', 'Disease', (95, 110))	('beta2m', 'Gene', (169, 175))
16519	21523560	Since HLA class I antigens play a crucial role in the control of tumor growth by CTLs in the tumor microenvironment, HLA antigen abnormalities in tumor cells may be envisioned as the result of immune selection advantageous to tumor cell survival in situations where T cells play a major role in controlling tumor growth.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('abnormalities', 'Var', (129, 142))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Disease', (307, 312))	('HLA class I antigen', 'Gene', (6, 25))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('HLA class I antigen', 'Gene', '100507436', (6, 25))	('tumor', 'Disease', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
16527	21523560	Changes in HLA antigen expression have been attributed to defects in beta2m synthesis, loss of the gene(s) encoding HLA antigen heavy chain(s), mutations which inhibit HLA antigen heavy chain transcription or translation, defects in the regulatory mechanisms which control HLA antigen expression, and/or abnormalities in one or more of the antigen processing machinery components.	('loss', 'NegReg', (87, 91))	('translation', 'biological_process', 'GO:0006412', ('209', '220'))	('transcription', 'biological_process', 'GO:0006351', ('192', '205'))	('inhibit', 'NegReg', (160, 167))	('transcription', 'MPA', (192, 205))	('mutations', 'Var', (144, 153))	('antigen processing', 'biological_process', 'GO:0019882', ('340', '358'))	('synthesis', 'biological_process', 'GO:0009058', ('76', '85'))	('abnormalities', 'Var', (304, 317))	('HLA antigen', 'Gene', (11, 22))	('translation', 'MPA', (209, 220))	('beta2m', 'Gene', '567', (69, 75))	('defects', 'NegReg', (58, 65))	('beta2m', 'Gene', (69, 75))	('defects', 'Var', (222, 229))	('Changes', 'Reg', (0, 7))	('expression', 'MPA', (23, 33))
16528	21523560	More recently, epigenetic events associated with tumor development and progression have been found to underlie changes in HLA antigen, antigen processing machinery, co-stimulatory molecule, and TA expression in malignant cells.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('epigenetic events', 'Var', (15, 32))	('TA', 'Gene', '404663', (194, 196))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('antigen processing', 'biological_process', 'GO:0019882', ('135', '153'))	('HLA antigen', 'Protein', (122, 133))	('changes', 'Reg', (111, 118))
16529	21523560	In this regard, the ability of epigenetic drugs to restore the defective HLA antigen, APM component and co-stimulatory molecule expression, and the consequent increase in immune recognition of malignant cells provides us with new therapeutic tools that may improve the clinical efficacy of active-specific immuno-therapy for the treatment of malignant disease.	('malignant disease', 'Disease', 'MESH:D009369', (342, 359))	('malignant disease', 'Disease', (342, 359))	('immune', 'MPA', (171, 177))	('restore', 'PosReg', (51, 58))	('expression', 'MPA', (128, 138))	('HLA antigen', 'Protein', (73, 84))	('increase', 'PosReg', (159, 167))	('epigenetic', 'Var', (31, 41))
16543	20795869	Class 2 gene expression profile signature, loss of chromosome 3 and increased aneuploidy were significantly associated with Ki-67 positivity (P=0.04, P=0.004 and P=0.03, respectively).	('Ki-67', 'Gene', '17345', (124, 129))	('gene expression', 'biological_process', 'GO:0010467', ('8', '23'))	('aneuploidy', 'Disease', 'MESH:D000782', (78, 88))	('aneuploidy', 'Disease', (78, 88))	('chromosome', 'cellular_component', 'GO:0005694', ('51', '61'))	('Ki-67', 'Gene', (124, 129))	('loss', 'Var', (43, 47))
16544	20795869	Tumor thickness and epithelioid cell type showed a borderline significant association with Ki-67 positivity (P=0.06 and P=0.07, respectively).	('Ki-67', 'Gene', (91, 96))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('positivity', 'Var', (97, 107))	('Ki-67', 'Gene', '17345', (91, 96))
16546	20795869	Using this dichotomous classification, Ki-67 positivity exhibited a significant association with metastasis (log rank test, P=0.01).	('Ki-67', 'Gene', '17345', (39, 44))	('positivity', 'Var', (45, 55))	('metastasis', 'CPA', (97, 107))	('Ki-67', 'Gene', (39, 44))
16557	20795869	Among class 2 tumors, loss of chromosome 3 is a frequent finding.	('chromosome', 'cellular_component', 'GO:0005694', ('30', '40'))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('loss', 'Var', (22, 26))
16562	20795869	In an earlier study, we showed that deletion of a metastasis modifier locus on chromosome 8p was associated with increased migration and invasion of uveal melanoma cells, but this deletion occurred in only a quarter of class 2 tumors, which would leave unexplained the high metastatic rate of the other three quarters of class 2 tumors.	('tumors', 'Disease', (329, 335))	('tumors', 'Disease', 'MESH:D009369', (329, 335))	('deletion', 'Var', (36, 44))	('uveal melanoma', 'Disease', 'MESH:C536494', (149, 163))	('uveal melanoma', 'Phenotype', 'HP:0007716', (149, 163))	('tumors', 'Phenotype', 'HP:0002664', (329, 335))	('invasion', 'CPA', (137, 145))	('tumors', 'Disease', (227, 233))	('uveal melanoma', 'Disease', (149, 163))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('chromosome', 'cellular_component', 'GO:0005694', ('79', '89'))	('increased', 'PosReg', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('migration', 'CPA', (123, 132))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
16564	20795869	Another possibility is that class 2 tumors proliferate more rapidly, which can promote metastasis by accelerating the accumulation of new mutations that convey a selective advantage to the evolving tumor.	('metastasis', 'CPA', (87, 97))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('promote', 'PosReg', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Disease', (198, 203))	('tumors', 'Disease', (36, 42))	('tumor', 'Disease', (36, 41))	('mutations', 'Var', (138, 147))
16567	20795869	Factors that have been associated Ki-67 positivity include p53 expression, larger tumor size, epithelioid cells, microcirculation patterns and shorter survival.	('p53', 'Gene', (59, 62))	('Ki-67', 'Gene', (34, 39))	('p53', 'Gene', '7157', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Ki-67', 'Gene', '17345', (34, 39))	('tumor', 'Disease', (82, 87))	('positivity', 'Var', (40, 50))
16570	20795869	We found a significant association between increased Ki-67 positivity and class 2 signature, loss of chromosomes 3, increased aneuploidy and metastasis.	('metastasis', 'CPA', (141, 151))	('aneuploidy', 'Disease', 'MESH:D000782', (126, 136))	('positivity', 'Var', (59, 69))	('Ki-67', 'Gene', '17345', (53, 58))	('loss', 'Var', (93, 97))	('aneuploidy', 'Disease', (126, 136))	('Ki-67', 'Gene', (53, 58))	('increased', 'PosReg', (43, 52))	('increased', 'PosReg', (116, 125))
16591	20795869	Class 2 gene expression profile and loss of heterozygosity of chromosome 3 (Mann-Whitney test, P=0.04 and P=0.004, respectively), and increased aneuploidy (Spearman correlation, P=0.03) were significantly associated with increased Ki-67 positivity (Figure 2).	('Ki-67', 'Gene', '17345', (231, 236))	('chromosome', 'cellular_component', 'GO:0005694', ('62', '72'))	('aneuploidy', 'Disease', 'MESH:D000782', (144, 154))	('increased', 'PosReg', (221, 230))	('gene expression', 'biological_process', 'GO:0010467', ('8', '23'))	('Ki-67', 'Gene', (231, 236))	('loss', 'Var', (36, 40))	('aneuploidy', 'Disease', (144, 154))
16595	20795869	Using this dichotomous classification, Ki-67 positivity exhibited a significant association with metastasis (log rank test, P=0.002)(Figure 3).	('Ki-67', 'Gene', '17345', (39, 44))	('positivity', 'Var', (45, 55))	('metastasis', 'CPA', (97, 107))	('Ki-67', 'Gene', (39, 44))
16599	20795869	One possibility is that more rapidly proliferating tumors are more likely to acquire the mutation(s) that are responsible for the class 2 tumor type.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (138, 143))	('mutation', 'Var', (89, 97))	('tumor', 'Disease', (51, 56))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('rapidly proliferating', 'CPA', (29, 50))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
16600	20795869	In support of this possibility was the observed association between Ki-67 positivity and increased aneuploidy.	('positivity', 'Var', (74, 84))	('aneuploidy', 'Disease', 'MESH:D000782', (99, 109))	('Ki-67', 'Gene', '17345', (68, 73))	('aneuploidy', 'Disease', (99, 109))	('Ki-67', 'Gene', (68, 73))
16602	20795869	Conversely, it may be that the mutation(s) that bring about the class 2 tumor type concomitantly (but independently) increase proliferation.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('proliferation', 'CPA', (126, 139))	('increase', 'PosReg', (117, 125))	('tumor', 'Disease', (72, 77))	('mutation', 'Var', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
16608	20795869	In more recent studies, Ki-67 positivity was associated with p53 expression, larger tumor size, epithelioid cells, microcirculation patterns and shorter survival.	('positivity', 'Var', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('epithelioid', 'Disease', (96, 107))	('Ki-67', 'Gene', (24, 29))	('shorter', 'NegReg', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('associated', 'Reg', (45, 55))	('tumor', 'Disease', (84, 89))	('expression', 'MPA', (65, 75))	('Ki-67', 'Gene', '17345', (24, 29))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))
16609	20795869	This allowed us to identify an optimal value of Ki-67 positivity for dichotomous classification into low and high groups.	('Ki-67', 'Gene', '17345', (48, 53))	('Ki-67', 'Gene', (48, 53))	('positivity', 'Var', (54, 64))
16610	20795869	This technique allowed us to confirm thatKi-67 positivity is strongly associated with metastatic risk.	('Ki-67', 'Gene', (41, 46))	('metastatic risk', 'Disease', (86, 101))	('associated', 'Reg', (70, 80))	('Ki-67', 'Gene', '17345', (41, 46))	('positivity', 'Var', (47, 57))
16687	32085617	LUMPO was developed to estimate survival probability in patients treated for UM, combining (a) anatomical predictors, such as largest basal diameter of the tumor, tumor thickness, ciliary body involvement and extra-ocular extension; (b) histological predictors, including epithelioid cell type, presence of closed loops and tumor mitotic count; and (c) genetic predictors, including chromosome-3 deletion and polysomy 8q.	('chromosome-3 deletion', 'Var', (383, 404))	('patients', 'Species', '9606', (56, 64))	('chromosome', 'cellular_component', 'GO:0005694', ('383', '393'))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumor', 'Disease', (324, 329))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('tumor', 'Disease', (163, 168))	('UM', 'Phenotype', 'HP:0007716', (1, 3))	('polysomy 8q', 'Var', (409, 420))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
16704	32085617	Of the cohorts with available genetic data, patients from Genoa had a higher percentage of alterations in both chromosome 3 and chromosome 8q than was seen in Liverpool (Binomial Test: z = 2.718 (p < 0.001) and z = 3.45 (p = 0.001) respectively).	('chromosome 3', 'Gene', (111, 123))	('patients', 'Species', '9606', (44, 52))	('chromosome', 'cellular_component', 'GO:0005694', ('128', '138'))	('alterations', 'Var', (91, 102))	('Genoa', 'Var', (58, 63))	('chromosome', 'cellular_component', 'GO:0005694', ('111', '121'))
16742	32002039	In addition, genetic mutations and epigenetic modifications are regarded as potential causes of tumorigenesis in BC.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('BC', 'Disease', 'MESH:D001943', (113, 115))	('tumor', 'Disease', (96, 101))	('epigenetic modifications', 'Var', (35, 59))	('causes', 'Reg', (86, 92))	('genetic mutations', 'Var', (13, 30))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
16750	32002039	In addition, circHIPK3 may function as a miR-124 sponge and inhibit its antineoplastic function, thus inducing the proliferation of BC cells.	('BC', 'Disease', 'MESH:D001943', (132, 134))	('inhibit', 'NegReg', (60, 67))	('proliferation', 'CPA', (115, 128))	('circHIPK3', 'Var', (13, 22))	('antineoplastic function', 'CPA', (72, 95))	('inducing', 'NegReg', (102, 110))
16785	32002039	The circRNAs that ranked in the top four according to the  logFC  were hsa_circ_0000520, hsa_circ_0006220, hsa_circ_0000977 and hsa_circ_0043278.	('hsa', 'Species', '9606', (107, 110))	('hsa', 'Species', '9606', (128, 131))	('hsa', 'Species', '9606', (71, 74))	('hsa_circ_0043278', 'Var', (128, 144))	('hsa', 'Species', '9606', (89, 92))	('hsa_circ_0000977', 'Var', (107, 123))
16795	32002039	For hsa_circ_0000520, the main enriched pathways for target genes were 'endocytosis' and the 'cell cycle' (Fig.	("'endocytosis'", 'MPA', (71, 84))	('hsa_circ_0000520', 'Var', (4, 20))	('cell cycle', 'biological_process', 'GO:0007049', ('94', '104'))	('endocytosis', 'biological_process', 'GO:0006897', ('72', '83'))	('hsa', 'Species', '9606', (4, 7))
16804	32002039	The relative expression levels of hsa_circ_0006220, hsa_circ_0000977 and hsa_circ_0043278 were significantly lower in BC than in the adjacent normal tissues and MCF-10A cells (Fig.	('expression levels', 'MPA', (13, 30))	('hsa', 'Species', '9606', (52, 55))	('lower', 'NegReg', (109, 114))	('BC', 'Disease', 'MESH:D001943', (118, 120))	('MCF-10A', 'CellLine', 'CVCL:0598', (161, 168))	('hsa_circ_0043278', 'Var', (73, 89))	('hsa_circ_0006220', 'Var', (34, 50))	('hsa', 'Species', '9606', (34, 37))	('hsa', 'Species', '9606', (73, 76))
16809	32002039	The mechanisms of tumorigenesis remain unclear due to the complex genetic mutations and epigenetic alterations involved in this process.	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('epigenetic alterations', 'Var', (88, 110))	('tumor', 'Disease', (18, 23))
16814	32002039	For example, circCEP128 promotes bladder cancer progression by sponging miR-145-5p, which inhibits the function of SRY-box transcription factor 11.	('circCEP128', 'Var', (13, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('bladder cancer', 'Disease', (33, 47))	('transcription factor', 'molecular_function', 'GO:0000981', ('123', '143'))	('function', 'MPA', (103, 111))	('promotes', 'PosReg', (24, 32))	('bladder cancer', 'Phenotype', 'HP:0009725', (33, 47))	('miR-145-5p', 'Var', (72, 82))	('transcription', 'biological_process', 'GO:0006351', ('123', '136'))
16836	32002039	circTADA2A, also known as hsa_circ_0043278, has been demonstrated to serve a role in promoting osteosarcoma progression and metastasis by sponging miR-203a-3p.	('TADA2A', 'Gene', '6871', (4, 10))	('TADA2A', 'Gene', (4, 10))	('metastasis', 'CPA', (124, 134))	('sponging', 'Var', (138, 146))	('promoting', 'PosReg', (85, 94))	('hsa', 'Species', '9606', (26, 29))	('osteosarcoma', 'Phenotype', 'HP:0002669', (95, 107))	('osteosarcoma', 'Disease', (95, 107))	('osteosarcoma', 'Disease', 'MESH:D012516', (95, 107))	('miR-203a-3p', 'MPA', (147, 158))
16850	32002039	For hsa_circ_0000520, the main enriched pathways were 'endocytosis' and the 'cell cycle'.	("'endocytosis'", 'MPA', (54, 67))	('endocytosis', 'biological_process', 'GO:0006897', ('55', '66'))	('hsa_circ_0000520', 'Var', (4, 20))	('cell cycle', 'biological_process', 'GO:0007049', ('77', '87'))	('hsa', 'Species', '9606', (4, 7))
16852	32002039	For hsa_circ_0006220, the most enriched pathway was the 'PI3K-AKT signaling pathway'.	('AKT', 'Gene', (62, 65))	('signaling pathway', 'biological_process', 'GO:0007165', ('66', '83'))	('AKT signaling', 'biological_process', 'GO:0043491', ('62', '75'))	('hsa_circ_0006220', 'Var', (4, 20))	('AKT', 'Gene', '207', (62, 65))	('PI3K', 'molecular_function', 'GO:0016303', ('57', '61'))	('hsa', 'Species', '9606', (4, 7))
16854	32002039	Imbalance in the components of this pathway may cause cells to proliferate abnormally, which may facilitate tumor formation and progression.	('Imbalance', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Imbalance', 'Phenotype', 'HP:0002172', (0, 9))	('cause', 'Reg', (48, 53))	('tumor', 'Disease', (108, 113))	('facilitate', 'PosReg', (97, 107))	('progression', 'CPA', (128, 139))	('formation', 'biological_process', 'GO:0009058', ('114', '123'))
16858	32002039	KEGG pathway analysis demonstrated that hsa_circ_0043278 was mainly associated with the 'PI3K-AKT signaling pathway' and 'signaling pathways regulating pluripotency of stem cells'.	('AKT', 'Gene', '207', (94, 97))	('AKT signaling', 'biological_process', 'GO:0043491', ('94', '107'))	('PI3K', 'molecular_function', 'GO:0016303', ('89', '93'))	('associated', 'Reg', (68, 78))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('AKT', 'Gene', (94, 97))	('hsa', 'Species', '9606', (40, 43))	('hsa_circ_0043278', 'Var', (40, 56))	('signaling pathway', 'biological_process', 'GO:0007165', ('98', '115'))
16885	31748560	Monosomy of chromosome 3 often co-occurs with mutation of the BAP1 gene in 3p21.1, results in bi-allelic inactivation and is a hallmark of uveal melanoma with unfavorable prognosis.	('results in', 'Reg', (83, 93))	('hallmark of uveal melanoma', 'Disease', (127, 153))	('Monosomy', 'Disease', (0, 8))	('BAP1', 'Gene', '8314', (62, 66))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('BAP1', 'Gene', (62, 66))	('mutation', 'Var', (46, 54))	('bi-allelic inactivation', 'MPA', (94, 117))	('hallmark of uveal melanoma', 'Disease', 'MESH:C536494', (127, 153))
16886	31748560	However, the BAP1 mutation is rare in other cancer types (less than 5%), with the exception of kidney cancer, mesothelioma and cholangiocarcinoma.	('exception of kidney cancer', 'Disease', 'MESH:D007680', (82, 108))	('BAP1', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mesothelioma and cholangiocarcinoma', 'Disease', 'MESH:D018281', (110, 145))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (127, 145))	('mutation', 'Var', (18, 26))	('BAP1', 'Gene', '8314', (13, 17))	('kidney cancer', 'Phenotype', 'HP:0009726', (95, 108))	('exception of kidney cancer', 'Disease', (82, 108))
16890	31748560	A recent integrative study of uveal melanoma has further characterized four distinct classes, primarily based on chromosome 3 and chromosome 8 copy number alterations and secondarily based on gene alterations (EIF1AX, SF3B1), gene expression and methylation patterns.	('SF3B1', 'Gene', (218, 223))	('chromosome', 'cellular_component', 'GO:0005694', ('130', '140'))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('alterations', 'Var', (155, 166))	('SF3B1', 'Gene', '23451', (218, 223))	('gene expression', 'biological_process', 'GO:0010467', ('226', '241'))	('uveal melanoma', 'Disease', 'MESH:C536494', (30, 44))	('methylation', 'biological_process', 'GO:0032259', ('246', '257'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('uveal melanoma', 'Disease', (30, 44))	('chromosome', 'cellular_component', 'GO:0005694', ('113', '123'))	('EIF1AX', 'Gene', '1964', (210, 216))	('EIF1AX', 'Gene', (210, 216))
16897	31748560	High expression of BAP1, suggestive of chromosome 3 disomy, was associated with a low risk of relapse (HR = 0.64, 95% 0.54-0.78, FDR < 0.001).	('High expression', 'Var', (0, 15))	('disomy', 'Disease', 'MESH:D024182', (52, 58))	('BAP1', 'Gene', '8314', (19, 23))	('BAP1', 'Gene', (19, 23))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))	('disomy', 'Disease', (52, 58))
16904	31748560	We further reasoned that it would be necessary to adjust for chromosome 3 loss, which is known to be associated with BAP1 biallelic inactivation and metastatic risk in uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (168, 182))	('chromosome', 'cellular_component', 'GO:0005694', ('61', '71'))	('BAP1', 'Gene', '8314', (117, 121))	('loss', 'NegReg', (74, 78))	('BAP1', 'Gene', (117, 121))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('associated', 'Reg', (101, 111))	('biallelic inactivation', 'Var', (122, 144))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('uveal melanoma', 'Disease', (168, 182))
16905	31748560	BAP1 inactivation (mutation or loss) is a rare event in most cancer types and would be unlikely to be a universal predictor of liver metastasis.	('mutation', 'Var', (19, 27))	('BAP1', 'Gene', (0, 4))	('loss', 'NegReg', (31, 35))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('inactivation', 'NegReg', (5, 17))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('BAP1', 'Gene', '8314', (0, 4))
16942	31748560	Interestingly, copy number gains of PTP4A3 at 8q are more frequent in colorectal tumors with liver metastases although this observation also includes broader alterations such as loss of 8p and gain of centromeric 8q.	('loss', 'Var', (178, 182))	('colorectal tumors', 'Disease', 'MESH:D015179', (70, 87))	('PTP4A3', 'Gene', '11156', (36, 42))	('colorectal tumors', 'Disease', (70, 87))	('PTP4A3', 'Gene', (36, 42))	('gain', 'PosReg', (193, 197))	('liver metastases', 'Disease', (93, 109))	('copy number gains', 'Var', (15, 32))	('centromeric', 'MPA', (201, 212))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('liver metastases', 'Disease', 'MESH:D009362', (93, 109))	('frequent', 'Reg', (58, 66))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
16945	31748560	Even in the absence of a direct causal relation, JPH1 upregulation may reflect other upstream events, such as driver mutations in other genes or copy number gains in 8q21 involving nearby regulatory regions.	('mutations', 'Var', (117, 126))	('JPH1', 'Gene', (49, 53))	('upregulation', 'PosReg', (54, 66))	('copy number gains', 'Var', (145, 162))	('JPH1', 'Gene', '56704', (49, 53))
16954	31748560	For example, previous studies have shown that the expression of Claudin-2 is associated with early liver relapse in triple negative and hormone receptor positive breast cancer.	('expression', 'Var', (50, 60))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('Claudin-2', 'Gene', (64, 73))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('Claudin-2', 'Gene', '9075', (64, 73))	('breast cancer', 'Disease', (162, 175))	('early liver relapse', 'Disease', (93, 112))	('associated with', 'Reg', (77, 92))
16957	31748560	CMS was also predictive of liver relapse in colorectal cancer, with CMS1 having a significantly lower proportion of liver relapses than CMS2-4.	('colorectal cancer', 'Disease', (44, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lower', 'NegReg', (96, 101))	('colorectal cancer', 'Disease', 'MESH:D015179', (44, 61))	('colorectal cancer', 'Phenotype', 'HP:0003003', (44, 61))	('CMS1', 'Var', (68, 72))	('liver relapse', 'Disease', (27, 40))
16976	31748560	Inactivation of BAP1 is common in uveal melanoma but can also occur in kidney cancer, mesothelioma and cholangiocarcinoma.	('mesothelioma and cholangiocarcinoma', 'Disease', 'MESH:D018281', (86, 121))	('kidney cancer', 'Disease', (71, 84))	('occur', 'Reg', (62, 67))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('BAP1', 'Gene', '8314', (16, 20))	('kidney cancer', 'Disease', 'MESH:D007680', (71, 84))	('uveal melanoma', 'Phenotype', 'HP:0007716', (34, 48))	('uveal melanoma', 'Disease', 'MESH:C536494', (34, 48))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('kidney cancer', 'Phenotype', 'HP:0009726', (71, 84))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (103, 121))	('Inactivation', 'Var', (0, 12))	('BAP1', 'Gene', (16, 20))	('uveal melanoma', 'Disease', (34, 48))
17005	31433788	It has been reported that miRNAs, such as microRNA-182, miR-9, MicroRNA-34a, microRNA-137, and MiR-140, can inhibit UVMs via the process of proliferation, migration, invasiveness and cell cycle.	('migration', 'CPA', (155, 164))	('MiR-140', 'Gene', '406932', (95, 102))	('microRNA-182', 'Var', (42, 54))	('invasiveness', 'CPA', (166, 178))	('MicroRNA-34a', 'Var', (63, 75))	('cell cycle', 'CPA', (183, 193))	('microRNA-137', 'Var', (77, 89))	('miR-9', 'Var', (56, 61))	('MiR-140', 'Gene', (95, 102))	('inhibit', 'NegReg', (108, 115))	('cell cycle', 'biological_process', 'GO:0007049', ('183', '193'))	('UVMs', 'CPA', (116, 120))
17007	31433788	Aberrant hypermethylation of promoter CpG islands and subsequent inactivation of key tumor suppressor genes are a frequent step in tumorigenesis of most human cancers.	('cancers', 'Disease', (159, 166))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor suppressor', 'biological_process', 'GO:0051726', ('85', '101'))	('Aberrant hypermethylation', 'Var', (0, 25))	('inactivation', 'NegReg', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', (131, 136))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('85', '101'))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('human', 'Species', '9606', (153, 158))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
17008	31433788	The associations between aberrant DNA methylation events and the silencing of individual miRNAs and lncRNAs have been demonstrated in many cancer types.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('aberrant', 'Var', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('DNA methylation', 'biological_process', 'GO:0006306', ('34', '49'))	('silencing', 'NegReg', (65, 74))	('associations', 'Interaction', (4, 16))	('cancer', 'Disease', (139, 145))
17025	31433788	In many cancer types, aberrant DNA methylation was associated with the silencing of individual miRNAs and lncRNAs.	('aberrant', 'Var', (22, 30))	('DNA', 'Protein', (31, 34))	('cancer', 'Disease', (8, 14))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('associated', 'Reg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('DNA methylation', 'biological_process', 'GO:0006306', ('31', '46'))	('silencing', 'MPA', (71, 80))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
17026	31433788	The results of function annotation showed that the aberrant methylation of sites targeted miRNAs can influence malignancy related pathways, including the regulation of cell development, transcription, protein kinase activity, DNA binding, cellular component (dendrite, cell body, synapse, and axon) and PI3K-Akt signaling pathway, MAPK signaling pathway, Ras signaling pathway.	('protein kinase activity', 'molecular_function', 'GO:0004672', ('201', '224'))	('signaling pathway', 'biological_process', 'GO:0007165', ('312', '329'))	('MAPK signaling pathway', 'Pathway', (331, 353))	('transcription', 'biological_process', 'GO:0006351', ('186', '199'))	('malignancy', 'Disease', (111, 121))	('Akt', 'Gene', (308, 311))	('cell body', 'cellular_component', 'GO:0044297', ('269', '278'))	('axon', 'cellular_component', 'GO:0030424', ('293', '297'))	('regulation', 'MPA', (154, 164))	('DNA binding', 'Interaction', (226, 237))	('Ras signaling pathway', 'Pathway', (355, 376))	('regulation of cell development', 'biological_process', 'GO:0060284', ('154', '184'))	('MAPK', 'molecular_function', 'GO:0004707', ('331', '335'))	('Akt', 'Gene', '207', (308, 311))	('MAPK signaling', 'biological_process', 'GO:0000165', ('331', '345'))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('signaling pathway', 'biological_process', 'GO:0007165', ('336', '353'))	('dendrite', 'cellular_component', 'GO:0030425', ('259', '267'))	('influence', 'Reg', (101, 110))	('PI3K', 'molecular_function', 'GO:0016303', ('303', '307'))	('signaling pathway', 'biological_process', 'GO:0007165', ('359', '376'))	('cellular component', 'cellular_component', 'GO:0005575', ('239', '257'))	('methylation', 'Var', (60, 71))	('DNA binding', 'molecular_function', 'GO:0003677', ('226', '237'))	('DNA', 'cellular_component', 'GO:0005574', ('226', '229'))	('transcription', 'MPA', (186, 199))	('Akt signaling', 'biological_process', 'GO:0043491', ('308', '321'))	('synapse', 'cellular_component', 'GO:0045202', ('280', '287'))	('protein', 'cellular_component', 'GO:0003675', ('201', '208'))	('malignancy', 'Disease', 'MESH:D009369', (111, 121))	('protein', 'Protein', (201, 208))	('cell development', 'CPA', (168, 184))	('aberrant methylation', 'Var', (51, 71))
17028	31433788	Then through the activation of the phospholipids produced by PI3Ks, Akt modulates can activate the function of numerous substrates involved in the regulation of cell survival, cycle progression, and cellular growth.	('PI3Ks', 'Var', (61, 66))	('Akt', 'Gene', '207', (68, 71))	('phospholipids', 'Chemical', 'MESH:D010743', (35, 48))	('phospholipids', 'MPA', (35, 48))	('activate', 'PosReg', (86, 94))	('function of numerous substrates', 'MPA', (99, 130))	('activation', 'PosReg', (17, 27))	('Akt', 'Gene', (68, 71))	('regulation', 'biological_process', 'GO:0065007', ('147', '157'))	('cellular growth', 'biological_process', 'GO:0016049', ('199', '214'))
17030	31433788	Furthermore, compared to any other pathway in cancer patients, the components of PI3K/Akt pathway are targeted by amplification, mutation, and translocation more frequently, exploiting this pathway a promising candidate for cancer drug discovery.	('PI3K', 'molecular_function', 'GO:0016303', ('81', '85'))	('Akt', 'Gene', (86, 89))	('amplification', 'Var', (114, 127))	('translocation', 'Var', (143, 156))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('patients', 'Species', '9606', (53, 61))	('mutation', 'Var', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', (46, 52))	('Akt', 'Gene', '207', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', (224, 230))	('targeted', 'Reg', (102, 110))
17031	31433788	The dysregulation of the MAPK signaling pathway is common in many human cancers via constitutive activation, including melanoma.	('MAPK signaling pathway', 'Pathway', (25, 47))	('activation', 'PosReg', (97, 107))	('dysregulation', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('MAPK signaling', 'biological_process', 'GO:0000165', ('25', '39'))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('MAPK', 'molecular_function', 'GO:0004707', ('25', '29'))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('signaling pathway', 'biological_process', 'GO:0007165', ('30', '47'))
17033	31433788	The results of functional annotation of lncRNAs showed that the aberrant methylation of sites that co-expressed with lncRNAs can influence the functions related to sequence-specific DNA binding, regulation of ion transmembrane transport, cAMP signaling pathway, and calcium signaling pathway.	('calcium', 'Chemical', 'MESH:D002118', (266, 273))	('ion transmembrane transport', 'MPA', (209, 236))	('calcium signaling', 'biological_process', 'GO:0019722', ('266', '283'))	('sequence-specific DNA binding', 'Interaction', (164, 193))	('methylation', 'biological_process', 'GO:0032259', ('73', '84'))	('calcium signaling pathway', 'Pathway', (266, 291))	('transmembrane', 'cellular_component', 'GO:0016021', ('213', '226'))	('aberrant methylation', 'Var', (64, 84))	('regulation of ion transmembrane transport', 'biological_process', 'GO:0034765', ('195', '236'))	('signaling pathway', 'biological_process', 'GO:0007165', ('274', '291'))	('signaling pathway', 'biological_process', 'GO:0007165', ('243', '260'))	('cAMP', 'Chemical', 'MESH:D000242', (238, 242))	('transmembrane', 'cellular_component', 'GO:0044214', ('213', '226'))	('sequence-specific DNA binding', 'molecular_function', 'GO:0043565', ('164', '193'))	('cAMP signaling pathway', 'Pathway', (238, 260))	('cAMP signaling', 'biological_process', 'GO:0019933', ('238', '252'))	('functions', 'MPA', (143, 152))	('influence', 'Reg', (129, 138))	('methylation', 'Var', (73, 84))	('DNA', 'cellular_component', 'GO:0005574', ('182', '185'))
17034	31433788	Mis-regulation of local cyclic AMP (cAMP) signaling proved to have pathophysiological consequences, including cancer and can act as a promising cellular target for antitumor treatments.	('regulation', 'biological_process', 'GO:0065007', ('4', '14'))	('cyclic AMP', 'Chemical', 'MESH:D000242', (24, 34))	('cancer', 'Disease', (110, 116))	('cAMP', 'Chemical', 'MESH:D000242', (36, 40))	('tumor', 'Disease', (168, 173))	('cAMP) signaling', 'biological_process', 'GO:0019933', ('36', '51'))	('Mis-regulation', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
17036	31433788	The deregulation of Ca 2+ homeostasis results in tumorigenesis, including proliferation, angiogenesis, apoptosis, and gene transcription and several cancers are closely connected with Ca 2+ channels and pumps.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Ca 2+', 'Chemical', 'MESH:D000069285', (20, 25))	('homeostasis', 'biological_process', 'GO:0042592', ('26', '37'))	('angiogenesis', 'biological_process', 'GO:0001525', ('89', '101'))	('angiogenesis', 'CPA', (89, 101))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('Ca 2+', 'Chemical', 'MESH:D000069285', (184, 189))	('deregulation', 'Var', (4, 16))	('cancers', 'Disease', (149, 156))	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('tumor', 'Disease', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('gene transcription', 'CPA', (118, 136))	('results in', 'Reg', (38, 48))	('transcription', 'biological_process', 'GO:0006351', ('123', '136'))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('Ca 2+ homeostasis', 'MPA', (20, 37))	('apoptosis', 'CPA', (103, 112))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
17041	31433788	Aberrant DNA methylation of some genes has been proved to be associated with the repression in many cancers.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('Aberrant DNA methylation', 'Var', (0, 24))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('associated', 'Reg', (61, 71))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
17043	31433788	The gene symbol of miRNA CpG sites cg07815521 is miR-641, and Tingting Y et al.	('miR-641', 'Gene', (49, 56))	('miR-641', 'Gene', '693226', (49, 56))	('cg07815521', 'Var', (35, 45))
17044	31433788	found the relationship between hypermethylation of miR-641 and HPV infection in cervical cell lines.	('miR-641', 'Gene', (51, 58))	('hypermethylation', 'Var', (31, 47))	('HPV infection', 'Disease', (63, 76))	('miR-641', 'Gene', '693226', (51, 58))	('infection in cervical cell', 'Phenotype', 'HP:0030159', (67, 93))	('HPV infection', 'Disease', 'MESH:D030361', (63, 76))
17046	31433788	MiR-154 (cg21492137) proved to inhibit migration and invasion of human non-small cell lung cancer.	('human', 'Species', '9606', (65, 70))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (71, 97))	('cg21492137', 'Var', (9, 19))	('invasion', 'CPA', (53, 61))	('non-small cell lung cancer', 'Disease', (71, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (75, 97))	('migration', 'CPA', (39, 48))	('MiR-154', 'Gene', '406946', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('inhibit', 'NegReg', (31, 38))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (71, 97))	('MiR-154', 'Gene', (0, 7))
17047	31433788	As for lncRNAs, the overexpression of TUNAR (cg14011368) significantly inhibited glioma malignancy.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('TUNAR', 'Gene', '100507043', (38, 43))	('TUNAR', 'Gene', (38, 43))	('inhibited', 'NegReg', (71, 80))	('glioma malignancy', 'Disease', 'MESH:D005910', (81, 98))	('overexpression', 'PosReg', (20, 34))	('glioma malignancy', 'Disease', (81, 98))	('cg14011368', 'Var', (45, 55))
17058	29610291	In this issue of Clinical Cancer Research, Jin and colleagues demonstrate that neddylation blockade inhibits uveal melanoma (UM) tumor growth and hepatic metastases via repression of cancer stem-like cells (CSC) and angiogenesis.	('hepatic metastases via repression of cancer', 'Disease', 'MESH:D009362', (146, 189))	('blockade', 'Var', (91, 99))	('neddylation', 'Gene', (79, 90))	('inhibits', 'NegReg', (100, 108))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))	('UM', 'Phenotype', 'HP:0007716', (125, 127))	('uveal melanoma', 'Disease', 'MESH:C536494', (109, 123))	('tumor growth', 'Disease', (129, 141))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('angiogenesis', 'CPA', (216, 228))	('tumor growth', 'Disease', 'MESH:D006130', (129, 141))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('hepatic metastases via repression of cancer', 'Disease', (146, 189))	('uveal melanoma', 'Disease', (109, 123))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('angiogenesis', 'biological_process', 'GO:0001525', ('216', '228'))
17070	29610291	Inhibition of NEDD8-activating enzyme (NAE) or other components of the neddylation pathway disrupts CRL-mediated ubiquitination of key players involved in tumor growth and survival.	('tumor growth', 'Disease', (155, 167))	('tumor growth', 'Disease', 'MESH:D006130', (155, 167))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('NAE', 'Chemical', '-', (39, 42))	('NEDD8', 'Gene', '4738', (14, 19))	('NEDD8', 'Gene', (14, 19))	('CRL-mediated ubiquitination', 'MPA', (100, 127))	('Inhibition', 'Var', (0, 10))	('disrupts', 'NegReg', (91, 99))
17071	29610291	MLN4924 (pevonedistat) is a first-in-class, potent small-molecule NAE inhibitor with preclinical antitumor activity against a number of solid and hematologic malignancies.	('MLN4924', 'Var', (0, 7))	('hematologic malignancies', 'Disease', 'MESH:D019337', (146, 170))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('hematologic malignancies', 'Disease', (146, 170))	('tumor', 'Disease', (101, 106))	('NAE', 'Chemical', '-', (66, 69))	('NAE', 'Protein', (66, 69))	('MLN4924', 'Chemical', 'MESH:C539933', (0, 7))	('pevonedistat', 'Chemical', 'MESH:C539933', (9, 21))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
17075	29610291	The authors proceed to show that MLN4924 inhibits UM cell growth via activation of apoptosis and the DNA damage response, triggered predominantly by formation of double-stranded DNA breaks.	('inhibits', 'NegReg', (41, 49))	('activation of apoptosis', 'biological_process', 'GO:0006915', ('69', '92'))	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('MLN4924', 'Chemical', 'MESH:C539933', (33, 40))	('DNA damage response', 'biological_process', 'GO:0006974', ('101', '120'))	('activation of apoptosis', 'biological_process', 'GO:0043065', ('69', '92'))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('UM cell growth', 'CPA', (50, 64))	('MLN4924', 'Var', (33, 40))	('DNA damage response', 'CPA', (101, 120))	('DNA', 'cellular_component', 'GO:0005574', ('101', '104'))	('apoptosis', 'CPA', (83, 92))	('formation', 'biological_process', 'GO:0009058', ('149', '158'))	('cell growth', 'biological_process', 'GO:0016049', ('53', '64'))	('activation', 'PosReg', (69, 79))
17076	29610291	In vivo efficacy of MLN4924 was confirmed using a NOD-SCID mouse xenograft model, and tumor analysis showed inhibition of the neddylation pathway with increased levels of the CRL substrates p21 and p27.	('increased', 'PosReg', (151, 160))	('p27', 'Gene', (198, 201))	('MLN4924', 'Var', (20, 27))	('inhibition', 'NegReg', (108, 118))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('MLN4924', 'Chemical', 'MESH:C539933', (20, 27))	('mouse', 'Species', '10090', (59, 64))	('tumor', 'Disease', (86, 91))	('p27', 'Gene', '12576', (198, 201))	('CRL', 'MPA', (175, 178))	('neddylation pathway', 'Pathway', (126, 145))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('p21', 'MPA', (190, 193))	('levels', 'MPA', (161, 167))
17079	29610291	In the present study, the authors show that MLN4924 blocks angiogenesis by impairing VEGF-C secretion, resulting in reduced microvascular density of UM hepatic metastases.	('secretion', 'biological_process', 'GO:0046903', ('92', '101'))	('VEGF-C', 'Gene', '7424', (85, 91))	('MLN4924', 'Chemical', 'MESH:C539933', (44, 51))	('UM', 'Phenotype', 'HP:0007716', (149, 151))	('metastases', 'Disease', (160, 170))	('blocks', 'NegReg', (52, 58))	('VEGF-C', 'Gene', (85, 91))	('angiogenesis', 'biological_process', 'GO:0001525', ('59', '71'))	('MLN4924', 'Var', (44, 51))	('impairing', 'NegReg', (75, 84))	('angiogenesis', 'CPA', (59, 71))	('reduced', 'NegReg', (116, 123))	('metastases', 'Disease', 'MESH:D009362', (160, 170))
17080	29610291	Preclinical studies demonstrate that MLN4924 triggers an irreversible, p21-dependent senescence associated with sustained activation of the DNA damage response.	('DNA damage response', 'MPA', (140, 159))	('MLN4924', 'Chemical', 'MESH:C539933', (37, 44))	('DNA damage response', 'biological_process', 'GO:0006974', ('140', '159'))	('senescence', 'biological_process', 'GO:0010149', ('85', '95'))	('activation', 'PosReg', (122, 132))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('MLN4924', 'Var', (37, 44))	('p21-dependent senescence', 'MPA', (71, 95))
17081	29610291	In fact, notably increased levels of p21 are observed in UM tumors harvested from MLN4924-treated mice.	('increased', 'PosReg', (17, 26))	('p21', 'MPA', (37, 40))	('MLN4924', 'Chemical', 'MESH:C539933', (82, 89))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('MLN4924-treated', 'Var', (82, 97))	('levels', 'MPA', (27, 33))	('mice', 'Species', '10090', (98, 102))	('tumors', 'Disease', (60, 66))
17082	29610291	Thus, NAE inhibition may not only contribute to sustained tumor dormancy via impaired angiogenesis but also eradicate dormant tumor cells, which are generally not susceptible to conventional cytotoxic agents, by actuating cellular senescence.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cellular senescence', 'MPA', (222, 241))	('dormancy', 'biological_process', 'GO:0030431', ('64', '72'))	('angiogenesis', 'biological_process', 'GO:0001525', ('86', '98'))	('cellular senescence', 'biological_process', 'GO:0090398', ('222', '241'))	('actuating', 'Reg', (212, 221))	('NAE', 'Gene', (6, 9))	('impaired', 'NegReg', (77, 85))	('NAE', 'Chemical', '-', (6, 9))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('inhibition', 'Var', (10, 20))	('angiogenesis', 'CPA', (86, 98))	('eradicate', 'NegReg', (108, 117))	('tumor', 'Disease', (126, 131))
17084	29610291	Further corroborating the role of CSCs in UM pathogenesis is the prognostic significance of BAP1 (BRCA1-associated protein 1) mutations, found in approximately 47% of primary UM and 84% of metastatic UM cases, which are strongly associated with increased metastatic risk.	('UM', 'Phenotype', 'HP:0007716', (200, 202))	('primary UM', 'Disease', (167, 177))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('BAP1', 'Gene', '8314', (92, 96))	('BRCA1-associated protein 1', 'Gene', '8314', (98, 124))	('mutations', 'Var', (126, 135))	('UM', 'Phenotype', 'HP:0007716', (42, 44))	('pathogenesis', 'biological_process', 'GO:0009405', ('45', '57'))	('BRCA1-associated protein 1', 'Gene', (98, 124))	('UM', 'Phenotype', 'HP:0007716', (175, 177))	('BAP1', 'Gene', (92, 96))
17085	29610291	Loss of BAP1 abrogates melanocytic differentiation and leads to acquisition of a class 2 gene expression profile, which confers multipotent, stem cell-like properties.	('gene expression', 'biological_process', 'GO:0010467', ('89', '104'))	('acquisition', 'PosReg', (64, 75))	('class 2 gene expression profile', 'MPA', (81, 112))	('BAP1', 'Gene', '8314', (8, 12))	('melanocytic differentiation', 'CPA', (23, 50))	('BAP1', 'Gene', (8, 12))	('abrogates', 'NegReg', (13, 22))	('Loss', 'Var', (0, 4))
17086	29610291	Thus, we can surmise that BAP1 mutations mechanistically drive metastasis by promoting the formation of CSCs.	('BAP1', 'Gene', (26, 30))	('metastasis', 'CPA', (63, 73))	('mutations', 'Var', (31, 40))	('formation of', 'CPA', (91, 103))	('formation', 'biological_process', 'GO:0009058', ('91', '100'))	('promoting', 'PosReg', (77, 86))	('BAP1', 'Gene', '8314', (26, 30))	('drive', 'Reg', (57, 62))
17087	29610291	Jin and colleagues show that MLN4924 inhibits the self-renewal and maintenance of CSCs in UM cell lines via increased degradation of the zinc-finger transcription factor Slug, a known regulator of epithelial-to-mesenchymal transition.	('transcription', 'biological_process', 'GO:0006351', ('149', '162'))	('UM', 'Phenotype', 'HP:0007716', (90, 92))	('degradation', 'MPA', (118, 129))	('increased', 'PosReg', (108, 117))	('self-renewal', 'CPA', (50, 62))	('MLN4924', 'Chemical', 'MESH:C539933', (29, 36))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('197', '233'))	('Slug', 'Gene', '6591', (170, 174))	('degradation', 'biological_process', 'GO:0009056', ('118', '129'))	('transcription factor', 'molecular_function', 'GO:0000981', ('149', '169'))	('maintenance of CSCs', 'CPA', (67, 86))	('MLN4924', 'Var', (29, 36))	('Slug', 'Gene', (170, 174))	('inhibits', 'NegReg', (37, 45))
17088	29610291	By eliminating CSCs, MLN4924 may prevent UM cells from exiting dormancy and establishing overt metastases.	('dormancy', 'biological_process', 'GO:0030431', ('63', '71'))	('exiting dormancy', 'CPA', (55, 71))	('prevent', 'NegReg', (33, 40))	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('metastases', 'Disease', (95, 105))	('MLN4924', 'Chemical', 'MESH:C539933', (21, 28))	('establishing', 'Reg', (76, 88))	('metastases', 'Disease', 'MESH:D009362', (95, 105))	('MLN4924', 'Var', (21, 28))
17089	29610291	Although MLN4924 monotherapy appears to have limited to modest activity in the completed phase I trials, ongoing studies are investigating MLN4924 in combination with various cytotoxic and epigenetic modifying agents.	('MLN4924', 'Chemical', 'MESH:C539933', (139, 146))	('MLN4924', 'Var', (139, 146))	('MLN4924', 'Chemical', 'MESH:C539933', (9, 16))	('MLN4924', 'Var', (9, 16))
17090	29610291	In a phase Ib study in elderly, treatment-naive AML patients unfit for standard induction chemotherapy, MLN4924 plus azacitidine achieved a promising 50% response rate and an 8.3-month median duration of remission.	('MLN4924', 'Chemical', 'MESH:C539933', (104, 111))	('azacitidine', 'Chemical', 'MESH:D001374', (117, 128))	('AML', 'Disease', (48, 51))	('AML', 'Disease', 'MESH:D015470', (48, 51))	('MLN4924 plus', 'Var', (104, 116))	('patients', 'Species', '9606', (52, 60))
17091	29610291	In the present study, MLN4924 induces apoptosis in UM cells by decreasing levels of the antiapoptotic proteins survivin and Bcl-xL.	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('MLN4924', 'Chemical', 'MESH:C539933', (22, 29))	('apoptosis', 'biological_process', 'GO:0097194', ('38', '47'))	('Bcl-xL', 'Gene', '598', (124, 130))	('apoptosis', 'CPA', (38, 47))	('apoptosis', 'biological_process', 'GO:0006915', ('38', '47'))	('levels of the antiapoptotic proteins survivin', 'MPA', (74, 119))	('MLN4924', 'Var', (22, 29))	('Bcl-xL', 'Gene', (124, 130))	('decreasing', 'NegReg', (63, 73))
17093	29610291	In fact, the combination of JQ1, a first-generation bromodomain inhibitor, and MLN4294 showed highly potent antitumor activity in pancreatic adenocarcinoma and may prove synergistic in UM as well.	('MLN4294', 'Chemical', '-', (79, 86))	('UM', 'Phenotype', 'HP:0007716', (185, 187))	('MLN4294', 'Var', (79, 86))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (130, 155))	('JQ1', 'Gene', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (130, 155))	('pancreatic adenocarcinoma', 'Disease', (130, 155))
17094	29610291	Inhibition of the cell-cycle checkpoint proteins Chk1 and Wee1 enhanced the antitumor effects of MLN4924 in UM cells and warrants further preclinical investigation.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('MLN4924', 'Chemical', 'MESH:C539933', (97, 104))	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('Wee1', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('enhanced', 'PosReg', (63, 71))	('cell-cycle checkpoint', 'biological_process', 'GO:0000075', ('18', '39'))	('Wee1', 'Gene', '7465', (58, 62))	('MLN4924', 'Var', (97, 104))	('tumor', 'Disease', (80, 85))	('Chk1', 'Gene', (49, 53))	('Chk1', 'Gene', '1111', (49, 53))
17098	29610291	NAE inhibition targets several of these key processes by prolonging tumor dormancy, eradicating dormant UM cells by actuating senescence, and preventing the establishment of clinically significant metastases via elimination of CSCs.	('CSCs', 'MPA', (227, 231))	('dormancy', 'biological_process', 'GO:0030431', ('74', '82'))	('UM', 'Phenotype', 'HP:0007716', (104, 106))	('actuating', 'Reg', (116, 125))	('preventing', 'NegReg', (142, 152))	('NAE', 'Gene', (0, 3))	('prolonging tumor', 'Disease', (57, 73))	('eradicating', 'NegReg', (84, 95))	('inhibition', 'Var', (4, 14))	('metastases', 'Disease', (197, 207))	('NAE', 'Chemical', '-', (0, 3))	('prolonging tumor', 'Disease', 'MESH:D011273', (57, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('metastases', 'Disease', 'MESH:D009362', (197, 207))	('senescence', 'biological_process', 'GO:0010149', ('126', '136'))	('senescence', 'MPA', (126, 136))
17138	29928440	There is a well-known association of monosomy 3 and the development of aggressive uveal melanoma.	('men', 'Species', '9606', (63, 66))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('aggressive uveal melanoma', 'Disease', (71, 96))	('aggressive uveal melanoma', 'Disease', 'MESH:C536494', (71, 96))	('monosomy 3', 'Var', (37, 47))	('association', 'Interaction', (22, 33))
17140	29928440	Genetics studies have emphasized the role of specific mutations of GNAQ and GNA11 (members of large G proteins) as well as CDKN2A, BRCA2, p14/ARF and BAP1 genes in the development of choroidal melanoma.	('GNA11', 'Gene', '2767', (76, 81))	('choroidal melanoma', 'Disease', (183, 201))	('BRCA2', 'Gene', '675', (131, 136))	('CDKN2A', 'Gene', (123, 129))	('p14', 'Gene', '1029', (138, 141))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (183, 201))	('BAP1', 'Gene', '8314', (150, 154))	('ARF', 'Disease', (142, 145))	('mutations', 'Var', (54, 63))	('p14', 'Gene', (138, 141))	('GNAQ', 'Gene', '2776', (67, 71))	('CDKN2A', 'Gene', '1029', (123, 129))	('men', 'Species', '9606', (175, 178))	('GNA11', 'Gene', (76, 81))	('BAP1', 'Gene', (150, 154))	('GNAQ', 'Gene', (67, 71))	('ARF', 'Disease', 'MESH:D058186', (142, 145))	('choroidal melanoma', 'Disease', 'MESH:D008545', (183, 201))	('BRCA2', 'Gene', (131, 136))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))
17141	29928440	A previous study, which focused on genetic factors associated with pigmentation traits, demonstrated the importance of rs12913832, rs1129038 and rs916977 polymorphisms of HERC2/OCA2 genomic region as susceptibility factors of uveal melanoma.	('rs12913832', 'Var', (119, 129))	('rs1129038', 'Mutation', 'rs1129038', (131, 140))	('rs916977', 'Var', (145, 153))	('susceptibility factors', 'Reg', (200, 222))	('OCA2', 'Gene', (177, 181))	('rs1129038', 'Var', (131, 140))	('men', 'Species', '9606', (70, 73))	('HERC2', 'Gene', (171, 176))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('pigmentation', 'biological_process', 'GO:0043473', ('67', '79'))	('rs12913832', 'Mutation', 'rs12913832', (119, 129))	('HERC2', 'Gene', '8924', (171, 176))	('uveal melanoma', 'Disease', 'MESH:C536494', (226, 240))	('rs916977', 'Mutation', 'rs916977', (145, 153))	('OCA2', 'Gene', '4948', (177, 181))	('uveal melanoma', 'Disease', (226, 240))	('uveal melanoma', 'Phenotype', 'HP:0007716', (226, 240))
17142	29928440	Next generation sequence performed by using uveal melanoma tumors indicated the significance of mutations of EIF1AX and SF3B1 genes as predisposition factors.	('SF3B1', 'Gene', (120, 125))	('EIF1AX', 'Gene', '1964', (109, 115))	('EIF1AX', 'Gene', (109, 115))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('SF3B1', 'Gene', '23451', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (44, 65))	('uveal melanoma tumors', 'Disease', (44, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mutations', 'Var', (96, 105))
17144	29928440	Of note, comparative genomic hybridization failed to detect any defects or deletions when DNA from tumors was analyzed.	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('deletions', 'Var', (75, 84))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
17218	29414877	Plaque brachytherapy with I125 and Ru106 is currently the most common treatment modality for ocular melanoma.	('ocular melanoma', 'Disease', (93, 108))	('I125', 'Var', (26, 30))	('ocular melanoma', 'Disease', 'MESH:D008545', (93, 108))	('ocular melanoma', 'Phenotype', 'HP:0007716', (93, 108))	('Ru106', 'Var', (35, 40))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('Ru106', 'Chemical', 'MESH:C000615522', (35, 40))
17221	29414877	In a previous review, Rundle evaluated the local tumor control rate after PDT for choroidal melanoma, highlighting a local control rate ranging from 80% to 89% among series, compared with 95-97% local control rates reported for proton beam radiotherapy and stereotactic radiosurgery.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('choroidal melanoma', 'Disease', 'MESH:D008545', (82, 100))	('tumor', 'Disease', (49, 54))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (82, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('choroidal melanoma', 'Disease', (82, 100))	('PDT', 'Var', (74, 77))
17227	29414877	In consideration of the strict relation between tumor thickness and total radiation dose to the macula and optic nerve, PDT has also been proposed as neo-adjuvant treatment for amelanotic choroidal melanoma, in order to reduce tumor thickness and minimize overall radiation-related toxicity.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', (227, 232))	('PDT', 'Var', (120, 123))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('amelanotic choroidal melanoma', 'Disease', 'MESH:D018328', (177, 206))	('toxicity', 'Disease', 'MESH:D064420', (282, 290))	('reduce', 'NegReg', (220, 226))	('toxicity', 'Disease', (282, 290))	('amelanotic choroidal melanoma', 'Disease', (177, 206))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (188, 206))
17229	29414877	In our study, PDT allowed for a reduction in tumor thickness in 73.4% of patients, with a minor decrease in visual acuity in pre-treated patients following radiation treatment and no local recurrence.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('patients', 'Species', '9606', (137, 145))	('PDT', 'Var', (14, 17))	('decrease', 'NegReg', (96, 104))	('reduction', 'NegReg', (32, 41))	('decrease in visual acuity', 'Phenotype', 'HP:0007663', (96, 121))	('pre', 'molecular_function', 'GO:0003904', ('125', '128'))	('patients', 'Species', '9606', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('minor decrease in visual acuity', 'Phenotype', 'HP:0032037', (90, 121))	('visual acuity', 'MPA', (108, 121))
17304	28917578	There is a well-known repertoire of common driver mutations in melanoma, with the most prevalent being mutations in BRAF (50% of melanomas), NRAS (10-25%), and NF1 (14%).	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('prevalent', 'Reg', (87, 96))	('mutations', 'Var', (103, 112))	('NF1', 'Gene', (160, 163))	('NRAS', 'Gene', '4893', (141, 145))	('BRAF', 'Gene', '673', (116, 120))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('NF1', 'Gene', '4763', (160, 163))	('melanomas', 'Disease', 'MESH:D008545', (129, 138))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('BRAF', 'Gene', (116, 120))	('melanomas', 'Phenotype', 'HP:0002861', (129, 138))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('melanomas', 'Disease', (129, 138))	('melanoma', 'Disease', (63, 71))	('NRAS', 'Gene', (141, 145))
17307	28917578	Several studies have shown that BRAF mutational status does not appear to be associated with response to ipilimumab or combination ipilimumab plus nivolumab therapy.	('BRAF', 'Gene', (32, 36))	('BRAF', 'Gene', '673', (32, 36))	('mutational status', 'Var', (37, 54))
17308	28917578	NRAS mutations have historically been associated with inferior survival compared to other common melanoma subtypes.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('mutations', 'Var', (5, 14))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))
17309	28917578	In a retrospective study, NRAS mutated patients had superior response rates to first-line immune therapy with IL-2, ipilimumab or anti-PD-1/PD-L1 therapy compared to NRAS wild type patients (28% vs. 16%, P=0.04).	('NRAS', 'Gene', (166, 170))	('patients', 'Species', '9606', (39, 47))	('IL-2', 'Gene', '3558', (110, 114))	('IL-2', 'molecular_function', 'GO:0005134', ('110', '114'))	('NRAS', 'Gene', '4893', (166, 170))	('IL-2', 'Gene', (110, 114))	('NRAS', 'Gene', (26, 30))	('patients', 'Species', '9606', (181, 189))	('PD-1', 'Gene', (135, 139))	('NRAS', 'Gene', '4893', (26, 30))	('PD-1', 'Gene', '5133', (135, 139))	('mutated', 'Var', (31, 38))
17310	28917578	The NRAS mutated group had a striking 64% response rate to anti-PD-1 therapy, and these tumors demonstrated a non-significant trend toward increased PD-L1 expression.	('PD-1', 'Gene', (64, 68))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('PD-1', 'Gene', '5133', (64, 68))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('PD-L1', 'Protein', (149, 154))	('mutated', 'Var', (9, 16))	('increased', 'PosReg', (139, 148))	('expression', 'MPA', (155, 165))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('NRAS', 'Gene', (4, 8))	('tumors', 'Disease', (88, 94))	('increased PD', 'Phenotype', 'HP:0008151', (139, 151))	('NRAS', 'Gene', '4893', (4, 8))
17311	28917578	NF1 mutated melanomas are associated with ultraviolet light damage, a high mutational load and have been associated with high response rates to anti-PD-1 therapy.	('mutated', 'Var', (4, 11))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanomas', 'Phenotype', 'HP:0002861', (12, 21))	('NF1', 'Gene', '4763', (0, 3))	('melanomas', 'Disease', 'MESH:D008545', (12, 21))	('NF1', 'Gene', (0, 3))	('mutational load', 'Var', (75, 90))	('PD-1', 'Gene', '5133', (149, 153))	('melanomas', 'Disease', (12, 21))	('associated', 'Reg', (26, 36))	('PD-1', 'Gene', (149, 153))
17313	28917578	prior BRAF inhibitors), or associations with other biomarkers of response to immunotherapies such as mutational load or PD-L1 expression.	('associations', 'Interaction', (27, 39))	('BRAF', 'Gene', (6, 10))	('PD-L1', 'Gene', (120, 125))	('BRAF', 'Gene', '673', (6, 10))	('mutational load', 'Var', (101, 116))
17335	28917578	As mentioned above, high expression of CTLA-4 and PD-1 on CTLs was associated with better PFS after treatment with anti-PD-1 therapy.	('PD-1', 'Gene', (120, 124))	('PD-1', 'Gene', '5133', (120, 124))	('PFS', 'Disease', (90, 93))	('CTLA-4', 'Gene', '1493', (39, 45))	('high expression', 'Var', (20, 35))	('CTLA-4', 'Gene', (39, 45))	('better', 'PosReg', (83, 89))	('PD-1', 'Gene', (50, 54))	('PD-1', 'Gene', '5133', (50, 54))
17351	28917578	Multiple pathways and aberrations in cell signaling such as the Ras/MAPK pathway, WNT/beta-catenin and PTEN/PI3K pathways have been associated with absence of a T cell infiltrate.	('PTEN', 'Gene', (103, 107))	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('PTEN', 'Gene', '5728', (103, 107))	('cell signaling', 'Pathway', (37, 51))	('beta-catenin', 'Gene', (86, 98))	('PI3K', 'molecular_function', 'GO:0016303', ('108', '112'))	('beta-catenin', 'Gene', '1499', (86, 98))	('aberrations', 'Var', (22, 33))	('Ras/MAPK pathway', 'Pathway', (64, 80))	('MAPK', 'molecular_function', 'GO:0004707', ('68', '72'))
17352	28917578	Activation of the Ras/MAPK pathway in tumor cells suppresses antigen presentation in multiple tumor types, and combinations of MEK inhibitors with ICIs have shown synergy in animal models as well as clinically in immune-refractory tumor types.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('antigen presentation', 'biological_process', 'GO:0019882', ('61', '81'))	('Ras/MAPK pathway', 'Pathway', (18, 34))	('MEK', 'Gene', (127, 130))	('multiple tumor', 'Disease', 'MESH:D009369', (85, 99))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('suppresses', 'NegReg', (50, 60))	('multiple tumor', 'Disease', (85, 99))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('inhibitors', 'Var', (131, 141))	('tumor', 'Disease', (38, 43))	('MAPK', 'molecular_function', 'GO:0004707', ('22', '26'))	('antigen presentation', 'MPA', (61, 81))	('MEK', 'Gene', '5609', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', (94, 99))	('combinations', 'Interaction', (111, 123))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
17358	28917578	Ultimately, these mutational and transcriptional alterations have more value as a roadmap to tumor-immune interactions rather than as true predictive biomarkers.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('alterations', 'Var', (49, 60))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
17362	28917578	One reason melanoma is thought to be immunologically active is the high rate of mutations associated with ultraviolet sun damage.	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('mutations', 'Var', (80, 89))	('sun damage', 'Phenotype', 'HP:0000992', (118, 128))	('associated', 'Reg', (90, 100))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
17363	28917578	In melanoma patients treated with anti-CTLA-4 antibodies, mutational load as detected by whole exome sequencing (WES) was significantly associated with clinical benefit, but there were still tumors with high mutational loads that did not benefit, suggesting that mutational load alone is not a sufficient predictor of response.	('antibodies', 'Var', (46, 56))	('mutational load', 'Var', (58, 73))	('patients', 'Species', '9606', (12, 20))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('CTLA-4', 'Gene', '1493', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('CTLA-4', 'Gene', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('tumors', 'Disease', (191, 197))
17364	28917578	However, the sequence of resulting mutated peptides predicted binding to MHC class-I molecules, models of T cell receptor (TCR) binding, patient-specific human leukocyte antigen (HLA) type, and epitope-homology analysis showed a greater association with clinical benefit to anti-CTLA-4.	('mutated', 'Var', (35, 42))	('TCR', 'Gene', '6962', (123, 126))	('human', 'Species', '9606', (154, 159))	('patient', 'Species', '9606', (137, 144))	('CTLA-4', 'Gene', (279, 285))	('TCR) binding', 'molecular_function', 'GO:0042608', ('123', '135'))	('binding', 'Interaction', (62, 69))	('T cell receptor', 'Gene', (106, 121))	('T cell receptor', 'Gene', '6962', (106, 121))	('TCR', 'cellular_component', 'GO:0042101', ('123', '126'))	('clinical benefit', 'MPA', (254, 270))	('TCR', 'Gene', (123, 126))	('CTLA-4', 'Gene', '1493', (279, 285))	('binding', 'molecular_function', 'GO:0005488', ('62', '69'))	('TCR', 'biological_process', 'GO:0006283', ('123', '126'))
17368	28917578	Along these lines, another intriguing mutational event associated with response to anti-CTLA-4 therapies in melanoma are mutations in SERPINB3 and SERPINB4.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('CTLA-4', 'Gene', '1493', (88, 94))	('SERPINB3', 'Gene', (134, 142))	('mutations', 'Var', (121, 130))	('SERPINB4', 'Gene', '6318', (147, 155))	('CTLA-4', 'Gene', (88, 94))	('SERPINB4', 'Gene', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('SERPINB3', 'Gene', '6317', (134, 142))	('melanoma', 'Disease', (108, 116))
17373	28917578	In melanoma patients treated with anti-CTLA-4 antibodies, a low degree of neoantigen intra-tumor heterogeneity and a high number of clonal neoantigens were significantly associated with improved overall survival.	('antibodies', 'Var', (46, 56))	('patients', 'Species', '9606', (12, 20))	('CTLA-4', 'Gene', '1493', (39, 45))	('intra-tumor', 'Disease', 'MESH:D009369', (85, 96))	('improved', 'PosReg', (186, 194))	('CTLA-4', 'Gene', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('overall survival', 'MPA', (195, 211))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('intra-tumor', 'Disease', (85, 96))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
17376	28917578	Patients who responded had higher mutational loads than non-responders (median 45.6 versus 3.9 mutations/MB in the initial cohort with P=0.003 and median 37.1 versus 12.8 mutations/MB in the validation cohort with P=0.002).	('Patients', 'Species', '9606', (0, 8))	('mutational loads', 'MPA', (34, 50))	('mutations/MB', 'Var', (95, 107))
17377	28917578	In this analysis, the authors noted frequent mutations in the gene LRP1B among responders.	('LRP1B', 'Gene', (67, 72))	('mutations', 'Var', (45, 54))	('LRP1B', 'Gene', '53353', (67, 72))
17378	28917578	In TCGA samples melanomas with a mutation in LRP1B harbored significantly more mutations than those with wild type LRP1B (median 542 vs. 219 mutations, P<0.001), suggesting that LRP1B mutations may serve as a single gene surrogate of mutational load.	('LRP1B', 'Gene', '53353', (45, 50))	('mutation', 'Var', (33, 41))	('LRP1B', 'Gene', '53353', (115, 120))	('mutations', 'Var', (79, 88))	('LRP1B', 'Gene', (178, 183))	('melanomas', 'Disease', 'MESH:D008545', (16, 25))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanomas', 'Phenotype', 'HP:0002861', (16, 25))	('LRP1B', 'Gene', (45, 50))	('LRP1B', 'Gene', (115, 120))	('LRP1B', 'Gene', '53353', (178, 183))	('melanomas', 'Disease', (16, 25))
17379	28917578	In another NGS panel of 170 genes, predicted mutational load was correlated with response to ipilimumab and adoptive T cell therapy in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('cutaneous melanoma', 'Disease', (135, 153))	('mutational load', 'Var', (45, 60))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (135, 153))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (135, 153))	('correlated', 'Reg', (65, 75))
17380	28917578	Finally, this concept was validated further in urothelial bladder cancer, as high mutation load in 315 genes associated with response to atezolizumab.	('urothelial bladder cancer', 'Disease', (47, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (47, 72))	('high mutation load', 'Var', (77, 95))	('associated with', 'Reg', (109, 124))	('response', 'MPA', (125, 133))
17382	28917578	Uveal melanoma is a relatively uncommon subtype driven by GNAQ and GNA11 mutations and has a very low mutation burden.	('GNA11', 'Gene', (67, 72))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('GNAQ', 'Gene', '2776', (58, 62))	('GNA11', 'Gene', '2767', (67, 72))	('Uveal melanoma', 'Disease', 'MESH:C536494', (0, 14))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('GNAQ', 'Gene', (58, 62))	('Uveal melanoma', 'Disease', (0, 14))	('driven', 'Reg', (48, 54))	('mutations', 'Var', (73, 82))
17383	28917578	Interestingly, some non-uveal melanomas also harbor GNAQ and GNA11 mutations and these tumors are also associated with a low mutational load compared to all other melanomas.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('melanomas', 'Disease', (30, 39))	('melanomas', 'Disease', 'MESH:D008545', (163, 172))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('uveal melanomas', 'Phenotype', 'HP:0007716', (24, 39))	('melanomas', 'Disease', (163, 172))	('GNAQ', 'Gene', '2776', (52, 56))	('GNA11', 'Gene', (61, 66))	('melanomas', 'Phenotype', 'HP:0002861', (30, 39))	('tumors', 'Disease', (87, 93))	('GNAQ', 'Gene', (52, 56))	('harbor', 'Reg', (45, 51))	('uveal melanoma', 'Disease', 'MESH:C536494', (24, 38))	('uveal melanoma', 'Disease', (24, 38))	('melanomas', 'Phenotype', 'HP:0002861', (163, 172))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('uveal melanoma', 'Phenotype', 'HP:0007716', (24, 38))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('GNA11', 'Gene', '2767', (61, 66))	('mutations', 'Var', (67, 76))	('melanomas', 'Disease', 'MESH:D008545', (30, 39))
17384	28917578	Of 11 patients with GNAQ/GNA11 mutations treated with immunotherapy, only one responded to treatment, suggesting that GNAQ/GNA11 mutations may be a surrogate marker for low mutational load and poor response to immunotherapy in non-uveal as well as uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (254, 262))	('GNAQ', 'Gene', (118, 122))	('mutations', 'Var', (31, 40))	('uveal melanoma', 'Disease', 'MESH:C536494', (248, 262))	('poor response to immunotherapy', 'Phenotype', 'HP:0002721', (193, 223))	('GNAQ', 'Gene', '2776', (20, 24))	('uveal melanoma', 'Phenotype', 'HP:0007716', (248, 262))	('uveal melanoma', 'Disease', (248, 262))	('mutations', 'Var', (129, 138))	('non-uveal', 'Disease', (227, 236))	('GNAQ', 'Gene', (20, 24))	('GNA11', 'Gene', (123, 128))	('patients', 'Species', '9606', (6, 14))	('GNAQ', 'Gene', '2776', (118, 122))	('GNA11', 'Gene', (25, 30))	('GNA11', 'Gene', '2767', (123, 128))	('GNA11', 'Gene', '2767', (25, 30))
17385	28917578	Conversely, BRCA2 and NF1 has been reported to be mutated more frequently in responders to anti-PD-1 therapy and mutations are associated with a higher mutational load.	('NF1', 'Gene', (22, 25))	('associated', 'Reg', (127, 137))	('NF1', 'Gene', '4763', (22, 25))	('BRCA2', 'Gene', (12, 17))	('PD-1', 'Gene', (96, 100))	('PD-1', 'Gene', '5133', (96, 100))	('mutations', 'Var', (113, 122))	('BRCA2', 'Gene', '675', (12, 17))	('mutational load', 'MPA', (152, 167))
17388	28917578	Notably the Food and Drug Administration (FDA) recently granted its first tissue/site-agnostic approval to pembrolizumab (anti-PD-1) for unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed on prior treatment and who have no satisfactory alternate treatment options.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('mismatch repair deficient (dMMR) solid tumors', 'Disease', 'MESH:C536928', (208, 253))	('PD-1', 'Gene', (127, 131))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('PD-1', 'Gene', '5133', (127, 131))	('microsatellite instability-high', 'Var', (165, 196))	('mismatch repair', 'biological_process', 'GO:0006298', ('208', '223'))	('MSI', 'Gene', '5928', (198, 201))	('MSI', 'Gene', (198, 201))
17400	28917578	In melanoma patients treated with anti-PD-1 antibodies, expression of MHC-II was associated with improved response and improved overall survival.	('PD-1', 'Gene', (39, 43))	('patients', 'Species', '9606', (12, 20))	('PD-1', 'Gene', '5133', (39, 43))	('improved', 'PosReg', (97, 105))	('overall', 'MPA', (128, 135))	('MHC-II', 'Gene', (70, 76))	('response', 'MPA', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('improved', 'PosReg', (119, 127))	('melanoma', 'Disease', (3, 11))	('expression', 'Var', (56, 66))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
17406	28917578	In two elegant studies, pre-existing or acquired mutations in JAK1 or JAK2 resulted in loss of JAK-STAT mediated IFN-gamma signaling, leading to antigen-presentation defects, loss of PD-L1 expression, and therapeutic resistance.	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('antigen-presentation', 'biological_process', 'GO:0019882', ('145', '165'))	('antigen-presentation defects', 'MPA', (145, 173))	('mutations', 'Var', (49, 58))	('JAK', 'molecular_function', 'GO:0004713', ('70', '73'))	('JAK1', 'Gene', (62, 66))	('JAK2', 'Gene', '3717', (70, 74))	('therapeutic resistance', 'CPA', (205, 227))	('JAK', 'molecular_function', 'GO:0004713', ('62', '65'))	('loss', 'NegReg', (175, 179))	('loss', 'NegReg', (87, 91))	('JAK2', 'Gene', (70, 74))	('pre', 'molecular_function', 'GO:0003904', ('24', '27'))	('PD-L1', 'Protein', (183, 188))	('expression', 'MPA', (189, 199))	('IFN-gamma', 'Gene', '3458', (113, 122))	('IFN-gamma', 'Gene', (113, 122))	('JAK', 'molecular_function', 'GO:0004713', ('95', '98'))	('JAK1', 'Gene', '3716', (62, 66))
17418	28917578	Similarly, other studies have looked at the consequences of aberrations in downstream IFN-gamma signaling, such as JAK-STAT.	('JAK-STAT', 'Disease', (115, 123))	('signaling', 'biological_process', 'GO:0023052', ('96', '105'))	('IFN-gamma', 'Gene', '3458', (86, 95))	('IFN-gamma', 'Gene', (86, 95))	('aberrations', 'Var', (60, 71))	('JAK', 'molecular_function', 'GO:0004713', ('115', '118'))
17419	28917578	Loss-of-function mutations in JAK1/2 genes have been associated with both primary and acquired resistance to anti-PD-1 therapy, suggesting a functional connection between IFN-gamma release, tumor cell response, and ICI therapy outcomes .	('primary', 'CPA', (74, 81))	('JAK1/2', 'Gene', (30, 36))	('Loss-of-function', 'NegReg', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('acquired resistance', 'CPA', (86, 105))	('JAK', 'molecular_function', 'GO:0004713', ('30', '33'))	('tumor', 'Disease', (190, 195))	('IFN-gamma', 'Gene', '3458', (171, 180))	('IFN-gamma', 'Gene', (171, 180))	('PD-1', 'Gene', (114, 118))	('JAK1/2', 'Gene', '3716;3717', (30, 36))	('mutations', 'Var', (17, 26))	('PD-1', 'Gene', '5133', (114, 118))
17426	28917578	In this analysis a low frequency of myeloid-derived suppressor cells (MDSCs), defined by flow cytometry as Lin-CD14+HLA-DR-/low, was associated with the highest probability of long term survival; 2-year OS was 34.5% for patients with baseline MDSCs <5.1% compared to 0% of 65 patients with >5.1% MDSCs (P=6.73x10-11).	('patients', 'Species', '9606', (276, 284))	('<5.1%', 'Var', (249, 254))	('patients', 'Species', '9606', (220, 228))	('CD14', 'Gene', (111, 115))	('CD14', 'Gene', '929', (111, 115))
17427	28917578	Other markers associated with a favorable outcome included absolute monocyte count <650/microliter, CD14+ monocytes <28%, low absolute eosinophil count, low relative eosinophil count and CD4+CD25+Foxp3+ T-regulatory cells >1.5% (P=1.35x10-8, P=6.58x10-7, P=5.06x10-5, P=2.14x10-4, and P=8.7x10-5, respectively).	('CD25', 'Gene', '3559', (191, 195))	('CD4', 'Gene', (187, 190))	('CD14', 'Gene', (100, 104))	('low', 'NegReg', (122, 125))	('low relative eosinophil count', 'Phenotype', 'HP:0031891', (153, 182))	('low absolute eosinophil count', 'Phenotype', 'HP:0031891', (122, 151))	('<650/microliter', 'Var', (83, 98))	('CD4', 'Gene', '920', (187, 190))	('CD14', 'Gene', '929', (100, 104))	('CD25', 'Gene', (191, 195))	('absolute monocyte count', 'Phenotype', 'HP:0012311', (59, 82))
17431	28917578	High baseline angiopoietin-2 is associated with worse OS in patients treated with ipilimumab alone or ipilimumab plus the anti-VEGF agent bevacizumab (10.9 vs. 19.3 months, P=0.0125).	('VEGF', 'Gene', '7422', (127, 131))	('High', 'Var', (0, 4))	('worse OS', 'Disease', (48, 56))	('patients', 'Species', '9606', (60, 68))	('angiopoietin-2', 'Gene', '285', (14, 28))	('angiopoietin-2', 'Gene', (14, 28))	('VEGF', 'Gene', (127, 131))
17435	28917578	It is unclear whether levels of sPD-L1 may be associated with an anti-tumor immune response, a pro-tumor inflammatory response or both, depending on the tumor context and levels of sPD-L1.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('sPD-L1', 'Var', (32, 38))	('immune response', 'biological_process', 'GO:0006955', ('76', '91'))	('tumor', 'Disease', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('associated', 'Reg', (46, 56))	('inflammatory response', 'biological_process', 'GO:0006954', ('105', '126'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
17475	28917578	Others, such as mutational burden, neoantigen load, ctDNA, and immune signaling have been less completely characterized and are more likely to provide insights into the biology of tumor immunity.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('mutational', 'Var', (16, 26))	('tumor', 'Disease', (180, 185))	('signaling', 'biological_process', 'GO:0023052', ('70', '79'))	('ctDNA', 'Disease', (52, 57))
17483	19369244	The percentage of CD11b+ cells in PBMCs of patients with uveal melanoma increased 1.8-fold in comparison to healthy donors and comprised three subsets: CD68 negative CD15+ granulocytes, which increased 4.1-fold; CD68- CD15- cells, which increased threefold; and CD68+ CD15low cells, which were unchanged.	('CD15', 'Gene', (218, 222))	('CD68', 'Gene', '968', (262, 266))	('CD68', 'Gene', (152, 156))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('CD68', 'Gene', '968', (212, 216))	('CD68', 'Gene', (262, 266))	('CD15', 'Gene', '2526', (218, 222))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('uveal melanoma', 'Disease', (57, 71))	('CD68', 'Gene', (212, 216))	('CD15', 'Gene', (166, 170))	('patients', 'Species', '9606', (43, 51))	('CD11b+ cells', 'Var', (18, 30))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('CD15', 'Gene', (268, 272))	('CD15', 'Gene', '2526', (166, 170))	('increased', 'PosReg', (72, 81))	('CD68', 'Gene', '968', (152, 156))	('donor', 'Species', '9606', (116, 121))	('CD15', 'Gene', '2526', (268, 272))
17486	19369244	Activated CD11b+ CD15+ granulocytes expand in the blood of patients with uveal melanoma and may contribute to immune evasion by ocular tumors by inhibiting T-cell function via decreasing CD3zeta chain expression.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('CD15', 'Gene', (17, 21))	('CD11b+', 'Var', (10, 16))	('immune evasion', 'biological_process', 'GO:0051842', ('110', '124'))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('inhibiting T-cell function', 'Phenotype', 'HP:0005435', (145, 171))	('T-cell', 'MPA', (156, 162))	('CD3zeta chain', 'Gene', '919', (187, 200))	('CD15', 'Gene', '2526', (17, 21))	('patients', 'Species', '9606', (59, 67))	('inhibiting', 'NegReg', (145, 155))	('ocular tumors', 'Disease', (128, 141))	('decreasing', 'NegReg', (176, 186))	('uveal melanoma', 'Disease', 'MESH:C536494', (73, 87))	('ocular tumors', 'Disease', 'MESH:D009369', (128, 141))	('ocular tumor', 'Phenotype', 'HP:0100012', (128, 140))	('uveal melanoma', 'Disease', (73, 87))	('ocular tumors', 'Phenotype', 'HP:0100012', (128, 141))	('contribute', 'Reg', (96, 106))	('immune evasion', 'MPA', (110, 124))	('uveal melanoma', 'Phenotype', 'HP:0007716', (73, 87))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('CD3zeta chain', 'Gene', (187, 200))	('immune evasion', 'biological_process', 'GO:0042783', ('110', '124'))
17491	19369244	The poor prognosis associated with these measures has been explained by an abrogation of tumoricidal NK cell responses due to inhibitory class I expression.	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('inhibitory', 'Var', (126, 136))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))
17492	19369244	However, as CD8+ T cells infiltrate progressively growing primary tumors expressing HLA class I, these data also clearly indicate that the tumoricidal activity of CD8+ CTLs is somehow inhibited.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('CD8', 'Gene', (163, 166))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('CD8', 'Gene', '925', (12, 15))	('primary tumors', 'Disease', (58, 72))	('tumor', 'Disease', (66, 71))	('primary tumors', 'Disease', 'MESH:D009369', (58, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('HLA', 'Var', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('CD8', 'Gene', '925', (163, 166))	('CD8', 'Gene', (12, 15))	('inhibited', 'NegReg', (184, 193))
17494	19369244	An unfavorable prognosis is also associated with uveal melanomas with an inflammatory infiltrate of CD11b+ CD68+ macrophages, which correlates with high HLA expression, and CD3+ T-cell infiltration, as well as other poor prognostic indicators including: large tumor size, epithelioid cell type, and monosomy of chromosome 3.	('tumor', 'Disease', (260, 265))	('high HLA', 'Protein', (148, 156))	('melanomas', 'Phenotype', 'HP:0002861', (55, 64))	('CD68', 'Gene', (107, 111))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('chromosome', 'cellular_component', 'GO:0005694', ('311', '321'))	('CD11b+', 'Var', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('CD68', 'Gene', '968', (107, 111))	('HLA', 'Protein', (153, 156))	('uveal melanomas', 'Disease', (49, 64))	('uveal melanomas', 'Phenotype', 'HP:0007716', (49, 64))	('monosomy', 'Var', (299, 307))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('uveal melanomas', 'Disease', 'MESH:C536494', (49, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (49, 63))
17538	19369244	CD11b+ CD15+ granulocytes are normally excluded from PBMC isolates of healthy donor blood after density gradient centrifugation because granulocytes pellet with red blood cells.	('CD15', 'Gene', (7, 11))	('donor', 'Species', '9606', (78, 83))	('CD11b+', 'Var', (0, 6))	('CD15', 'Gene', '2526', (7, 11))
17553	19369244	A generalized additive model was used to fit a cubic spline (green line) that demonstrated a statistically significant relationship (P = 0.00025) in which CD3zeta chain expression was relatively constant for total CD11b+ cell percentages less than 30% but decreased when CD11b+ cell percentages were greater than 30% (Fig.	('CD3zeta chain', 'Gene', '919', (155, 168))	('CD11b+', 'Var', (214, 220))	('expression', 'MPA', (169, 179))	('CD3zeta chain', 'Gene', (155, 168))	('less', 'Var', (238, 242))	('decreased', 'NegReg', (256, 265))
17555	19369244	The relationship between CD3zeta chain expression and CD11b+, CD15-, CD68- cells was significant (P = 0.006) when modeled as a spline function (Fig.	('CD68', 'Gene', (69, 73))	('CD68', 'Gene', '968', (69, 73))	('CD3zeta chain', 'Gene', (25, 38))	('CD15', 'Gene', '2526', (62, 66))	('CD15', 'Gene', (62, 66))	('CD3zeta chain', 'Gene', '919', (25, 38))	('CD11b+', 'Var', (54, 60))
17556	19369244	These data indicate that reduced CD3zeta chain expression, a marker of T-cell dysfunction, is associated with: percentages of total CD11b+ myeloid cells above 33.8%, which occurred in 9 (90%) of 10 patients with uveal melanoma but in only 4 (17%) of 24 healthy control donors and percentages of CD11b+ CD15+ CD68- cells above 3.7% which occurred in 5 (50%) of 10 patients with uveal melanoma but only 4 (17%) of 24 healthy control donors.	('patients', 'Species', '9606', (198, 206))	('patients', 'Species', '9606', (363, 371))	('melanoma', 'Phenotype', 'HP:0002861', (383, 391))	('T-cell dysfunction', 'Phenotype', 'HP:0005435', (71, 89))	('CD68', 'Gene', '968', (308, 312))	('uveal melanoma', 'Phenotype', 'HP:0007716', (212, 226))	('CD3zeta chain', 'Gene', (33, 46))	('uveal melanoma', 'Disease', 'MESH:C536494', (377, 391))	('uveal melanoma', 'Disease', (377, 391))	('reduced', 'NegReg', (25, 32))	('uveal melanoma', 'Disease', (212, 226))	('donor', 'Species', '9606', (431, 436))	('CD68', 'Gene', (308, 312))	('CD15', 'Gene', (302, 306))	('uveal melanoma', 'Phenotype', 'HP:0007716', (377, 391))	('CD3zeta chain', 'Gene', '919', (33, 46))	('CD11b+', 'Var', (132, 138))	('CD15', 'Gene', '2526', (302, 306))	('T-cell dysfunction', 'Disease', 'MESH:C536780', (71, 89))	('donor', 'Species', '9606', (269, 274))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('T-cell dysfunction', 'Disease', (71, 89))	('uveal melanoma', 'Disease', 'MESH:C536494', (212, 226))
17561	19369244	Both CD11b+ and CD3epsilon+ leukocytes infiltrated primary uveal melanomas in four of six tumors.	('infiltrated', 'Reg', (39, 50))	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('CD3epsilon', 'Gene', '916', (16, 26))	('primary uveal melanomas', 'Disease', 'MESH:C536494', (51, 74))	('primary uveal melanomas', 'Disease', (51, 74))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('uveal melanomas', 'Phenotype', 'HP:0007716', (59, 74))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('CD11b+', 'Var', (5, 11))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanomas', 'Phenotype', 'HP:0002861', (65, 74))	('CD3epsilon', 'Gene', (16, 26))
17564	19369244	CD11b+ cells within the tumor microenvironment primarily expressed CD68, a marker of macrophages, but not CD15, which is markedly different from the myeloid cell populations that expanded in the blood of these same patients and expressed CD15 but not CD68 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('patients', 'Species', '9606', (215, 223))	('CD15', 'Gene', '2526', (238, 242))	('CD15', 'Gene', (238, 242))	('CD11b+', 'Var', (0, 6))	('men', 'Species', '9606', (42, 45))	('tumor', 'Disease', (24, 29))	('CD15', 'Gene', '2526', (106, 110))	('CD15', 'Gene', (106, 110))	('CD68', 'Gene', (67, 71))	('CD68', 'Gene', '968', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('CD68', 'Gene', (251, 255))	('CD68', 'Gene', '968', (251, 255))
17570	19369244	The percentage of CD11b+ cells was lower than CD3epsilon+ T cells in all uveal melanomas that were digested in collagenase IV.	('uveal melanomas', 'Disease', 'MESH:C536494', (73, 88))	('CD3epsilon', 'Gene', '916', (46, 56))	('collagenase IV', 'molecular_function', 'GO:0004228', ('111', '125'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (73, 87))	('CD11b+ cells', 'Var', (18, 30))	('lower', 'NegReg', (35, 40))	('uveal melanomas', 'Disease', (73, 88))	('uveal melanomas', 'Phenotype', 'HP:0007716', (73, 88))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))	('CD3epsilon', 'Gene', (46, 56))	('collagenase IV', 'molecular_function', 'GO:0004229', ('111', '125'))
17579	19369244	In other malignancies:for example, renal cell carcinoma and pancreatic cancer:the expansion of CD11b+ CD15+ granulocytes has been associated with inhibited T-cell function.	('malignancies', 'Disease', (9, 21))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (35, 55))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('CD11b+', 'Gene', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (35, 55))	('CD15', 'Gene', '2526', (102, 106))	('expansion', 'Var', (82, 91))	('CD15', 'Gene', (102, 106))	('inhibited', 'NegReg', (146, 155))	('pancreatic cancer', 'Disease', (60, 77))	('malignancies', 'Disease', 'MESH:D009369', (9, 21))	('T-cell function', 'CPA', (156, 171))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('renal cell carcinoma', 'Disease', (35, 55))
17587	19369244	Two mechanisms of CD3zeta chain downmodulation by CD11b+ MDSCs have been described.	('CD3zeta chain', 'Gene', '919', (18, 31))	('CD11b+ MDSCs', 'Var', (50, 62))	('downmodulation', 'NegReg', (32, 46))	('CD3zeta chain', 'Gene', (18, 31))
17588	19369244	In patients with renal cell carcinoma, arginase activity of CD11b+ CD15+ cells significantly correlated with reduced CD3zeta chain expression, and depletion of CD11b+ cells within the PBMCs of these patients restored CD3zeta chain expression and T-cell function to levels observed in healthy control subjects.	('CD15', 'Gene', (67, 71))	('CD3zeta chain', 'Gene', (217, 230))	('CD11b+', 'Var', (160, 166))	('restored', 'PosReg', (208, 216))	('arginase', 'Enzyme', (39, 47))	('CD15', 'Gene', '2526', (67, 71))	('activity', 'MPA', (48, 56))	('renal cell carcinoma', 'Disease', (17, 37))	('CD3zeta chain', 'Gene', '919', (217, 230))	('depletion', 'Var', (147, 156))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (17, 37))	('CD11b+', 'Gene', (60, 66))	('CD3zeta chain', 'Gene', (117, 130))	('patients', 'Species', '9606', (3, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('reduced', 'NegReg', (109, 116))	('arginase activity', 'molecular_function', 'GO:0004053', ('39', '56'))	('patients', 'Species', '9606', (199, 207))	('T-cell function', 'MPA', (246, 261))	('CD3zeta chain', 'Gene', '919', (117, 130))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (17, 37))
17596	19369244	The addition of H2O2 or granulocytes to PBMC cultures of healthy donors inhibited T-cell function in this study.	('T-cell function', 'CPA', (82, 97))	('H2O2', 'Chemical', 'MESH:D006861', (16, 20))	('H2O2', 'Var', (16, 20))	('inhibited', 'NegReg', (72, 81))	('donor', 'Species', '9606', (65, 70))
17604	19369244	We have recently demonstrated that the failure to control tumors developing in the anterior chamber of the eye of mice is associated with an accumulation of CD11b+ GR-1+ cells within the ocular tumor microenvironment that suppressed CD8+ CTL responses in vitro.	('CD11b+', 'Var', (157, 163))	('suppressed', 'NegReg', (222, 232))	('ocular tumor', 'Disease', 'MESH:D009369', (187, 199))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('ocular tumor', 'Disease', (187, 199))	('ocular tumor', 'Phenotype', 'HP:0100012', (187, 199))	('CD8', 'Gene', (233, 236))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('CD8', 'Gene', '925', (233, 236))	('mice', 'Species', '10090', (114, 118))	('men', 'Species', '9606', (212, 215))
17614	19369244	CD11b+, GR-1+, CD115+ MDSCs have also been shown to induce the development of CD4+ FoxP3+ Tregs.	('FoxP3', 'Gene', '50943', (83, 88))	('CD4', 'Gene', '920', (78, 81))	('CD11b+', 'Var', (0, 6))	('FoxP3', 'Gene', (83, 88))	('men', 'Species', '9606', (70, 73))	('CD115+ MDSCs', 'Var', (15, 27))	('induce', 'PosReg', (52, 58))	('development', 'CPA', (63, 74))	('CD4', 'Gene', (78, 81))
17616	19369244	Therefore, MDSC may suppress tumoricidal T-cell activity by both direct (CD3zeta chain downmodulation) and indirect (Treg induction) mechanisms.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('MDSC', 'Var', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('CD3zeta chain', 'Gene', (73, 86))	('downmodulation', 'NegReg', (87, 101))	('CD3zeta chain', 'Gene', '919', (73, 86))	('suppress', 'NegReg', (20, 28))
17625	19369244	Hence, an alternative explanation is that ocular tumor-associated CD68+ macrophages and CD11b+ CD15+ granulocytes in peripheral blood reduce CD3zeta expression by increased arginase activity and/or increased reactive oxygen production, as has been reported by others.	('CD68', 'Gene', (66, 70))	('ocular tumor', 'Disease', (42, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('reduce', 'NegReg', (134, 140))	('CD3zeta', 'Gene', (141, 148))	('reactive oxygen production', 'MPA', (208, 234))	('CD3zeta', 'Gene', '919', (141, 148))	('arginase activity', 'molecular_function', 'GO:0004053', ('173', '190'))	('increased', 'PosReg', (163, 172))	('ocular tumor', 'Disease', 'MESH:D009369', (42, 54))	('arginase', 'Enzyme', (173, 181))	('activity', 'MPA', (182, 190))	('ocular tumor', 'Phenotype', 'HP:0100012', (42, 54))	('oxygen', 'Chemical', 'MESH:D010100', (217, 223))	('increased arginase', 'Phenotype', 'HP:0500153', (163, 181))	('CD15', 'Gene', (95, 99))	('expression', 'MPA', (149, 159))	('CD68', 'Gene', '968', (66, 70))	('CD15', 'Gene', '2526', (95, 99))	('increased', 'PosReg', (198, 207))	('CD11b+', 'Var', (88, 94))
17627	19369244	We have demonstrated in a murine model of ocular tumor development that intratumoral accumulation of CD11b+ GR-1+ cells correlates with tumor burden, suggesting a causal relationship.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('men', 'Species', '9606', (62, 65))	('ocular tumor', 'Disease', (42, 54))	('ocular tumor', 'Phenotype', 'HP:0100012', (42, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('murine', 'Species', '10090', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('CD11b+', 'Var', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('ocular tumor', 'Disease', 'MESH:D009369', (42, 54))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (136, 141))
17630	19369244	Along those lines, two independent laboratories have recently shown that S100 A8/A9 proteins regulate the accumulation of CD11b+ GR-1+ cells in mice.	('CD11b+ GR-1+ cells', 'MPA', (122, 140))	('mice', 'Species', '10090', (144, 148))	('accumulation', 'MPA', (106, 118))	('proteins', 'Protein', (84, 92))	('S100 A8/A9', 'Var', (73, 83))	('regulate', 'Reg', (93, 101))
17631	19369244	S100 A8/A9 proteins are upregulated during inflammation and in some circumstances may be expressed by tumors.	('S100 A8/A9', 'Var', (0, 10))	('proteins', 'Protein', (11, 19))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('inflammation', 'Disease', 'MESH:D007249', (43, 55))	('upregulated', 'PosReg', (24, 35))	('inflammation', 'Disease', (43, 55))	('inflammation', 'biological_process', 'GO:0006954', ('43', '55'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
17632	19369244	Tumor cell-conditioned medium has been shown to upregulate the S100 A9 gene in hematopoietic progenitor cells, preventing their differentiation into CD11c+ dendritic cells and promoting their differentiation into CD11b+ GR-1+ MDSCs, which also express S100 A8/A9 proteins.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('preventing', 'NegReg', (111, 121))	('promoting', 'PosReg', (176, 185))	('differentiation', 'CPA', (128, 143))	('S100 A9', 'Gene', (63, 70))	('upregulate', 'PosReg', (48, 58))	('proteins', 'Protein', (263, 271))	('S100', 'Var', (252, 256))	('differentiation', 'CPA', (192, 207))	('CD11c', 'Gene', '3687', (149, 154))	('S100 A9', 'Gene', '6280', (63, 70))	('CD11c', 'Gene', (149, 154))
17633	19369244	Hence, tumor-induced expression of S100 A8/A9 increases CD11b+ GR-1+ cells systemically by preventing the normal differentiation of myeloid progenitors and promotes their migration into the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('S100 A8/A9', 'Var', (35, 45))	('increases', 'PosReg', (46, 55))	('preventing', 'NegReg', (91, 101))	('men', 'Species', '9606', (208, 211))	('tumor', 'Disease', (190, 195))	('normal differentiation of myeloid progenitors', 'CPA', (106, 151))	('CD11b+', 'Gene', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('promotes', 'PosReg', (156, 164))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
17635	19369244	In summary, our data demonstrate that expansion of activated CD11b+ myeloid cells in the blood correlates with reduced CD3zeta chain expression by T cells in the blood and within primary uveal melanomas.	('primary uveal melanomas', 'Disease', (179, 202))	('CD11b+', 'Gene', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('CD3zeta chain', 'Gene', (119, 132))	('melanomas', 'Phenotype', 'HP:0002861', (193, 202))	('reduced', 'NegReg', (111, 118))	('uveal melanoma', 'Phenotype', 'HP:0007716', (187, 201))	('expansion', 'Var', (38, 47))	('CD3zeta chain', 'Gene', '919', (119, 132))	('uveal melanomas', 'Phenotype', 'HP:0007716', (187, 202))	('primary uveal melanomas', 'Disease', 'MESH:C536494', (179, 202))
17650	28103611	In addition, the uveal melanoma subtype usually lacks BRAF mutations, and with the exception of selumetinib, few data exist supporting the use of BRAF or MEK inhibitors in uveal melanoma.	('uveal melanoma', 'Disease', (172, 186))	('lacks', 'NegReg', (48, 53))	('melanoma subtype', 'Disease', (23, 39))	('MEK', 'Gene', '5609', (154, 157))	('uveal melanoma', 'Phenotype', 'HP:0007716', (172, 186))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('uveal melanoma', 'Disease', 'MESH:C536494', (17, 31))	('uveal melanoma', 'Disease', (17, 31))	('MEK', 'Gene', (154, 157))	('selumetinib', 'Chemical', 'MESH:C517975', (96, 107))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('mutations', 'Var', (59, 68))	('BRAF', 'Gene', '673', (146, 150))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))	('BRAF', 'Gene', (146, 150))	('melanoma subtype', 'Disease', 'MESH:D008545', (23, 39))	('uveal melanoma', 'Disease', 'MESH:C536494', (172, 186))
17653	28103611	MET pathway activation and dysregulation have been implicated in multiple cancers, including melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('multiple cancers', 'Disease', (65, 81))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('activation', 'PosReg', (12, 22))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('multiple cancers', 'Disease', 'MESH:D009369', (65, 81))	('dysregulation', 'Var', (27, 40))	('MET pathway', 'Pathway', (0, 11))	('implicated', 'Reg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
17657	28103611	Moreover, amplification of the gene encoding MET has been implicated in acquired resistance to the BRAF inhibitor vemurafenib in cultured melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('acquired resistance to the', 'MPA', (72, 98))	('MET', 'Gene', (45, 48))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('vemurafenib', 'Chemical', 'MESH:D000077484', (114, 125))	('amplification', 'Var', (10, 23))	('implicated in', 'Reg', (58, 71))
17659	28103611	Mutations in the GNAQ and GNA11 genes, which encode guanine nucleotide-binding protein alpha subunits, are found in up to 83% of uveal melanomas.	('uveal melanomas', 'Disease', (129, 144))	('uveal melanomas', 'Phenotype', 'HP:0007716', (129, 144))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanomas', 'Phenotype', 'HP:0002861', (135, 144))	('GNAQ', 'Gene', (17, 21))	('GNA11', 'Gene', (26, 31))	('GNA11', 'Gene', '2767', (26, 31))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('Mutations', 'Var', (0, 9))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('60', '78'))	('uveal melanomas', 'Disease', 'MESH:C536494', (129, 144))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('found', 'Reg', (107, 112))	('GNAQ', 'Gene', '2776', (17, 21))
17660	28103611	These mutations can lead to upregulation of MET, which is implicated in proliferation and migration of uveal melanoma cells.	('uveal melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('uveal melanoma', 'Disease', (103, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('MET', 'Gene', (44, 47))	('uveal melanoma', 'Disease', 'MESH:C536494', (103, 117))	('mutations', 'Var', (6, 15))	('upregulation', 'PosReg', (28, 40))
17693	28103611	Other exploratory endpoints included analysis of changes in the circulating bone biomarker C-terminal cross-linked telopeptide of type I collagen (CTx), assessment of bone scan resolution (when applicable), and analysis of BRAF and/or GNAQ/GNA11 mutational status of tumour samples.	('GNAQ', 'Gene', (235, 239))	('tumour', 'Disease', (267, 273))	('mutational', 'Var', (246, 256))	('BRAF', 'Gene', '673', (223, 227))	('CTx', 'Gene', (147, 150))	('GNA11', 'Gene', (240, 245))	('GNAQ', 'Gene', '2776', (235, 239))	('CTx', 'Gene', '1593', (147, 150))	('tumour', 'Phenotype', 'HP:0002664', (267, 273))	('BRAF', 'Gene', (223, 227))	('GNA11', 'Gene', '2767', (240, 245))	('tumour', 'Disease', 'MESH:D009369', (267, 273))	('collagen', 'molecular_function', 'GO:0005202', ('137', '145'))
17702	28103611	Among the 54 patients with available mutation data, BRAF mutations were detected in 31%.	('mutations', 'Var', (57, 66))	('patients', 'Species', '9606', (13, 21))	('BRAF', 'Gene', (52, 56))	('BRAF', 'Gene', '673', (52, 56))
17714	28103611	Reduction in measurable disease appeared to be independent of BRAF mutation status.	('mutation', 'Var', (67, 75))	('Reduction', 'NegReg', (0, 9))	('BRAF', 'Gene', '673', (62, 66))	('measurable disease', 'MPA', (13, 31))	('BRAF', 'Gene', (62, 66))
17724	28103611	The majority (9/10) of patient samples analysed for GNAQ/GNA11 mutation status harboured either a GNAQ (n=5) or GNA11 mutation (n=4) (Table 2).	('GNA11', 'Gene', (112, 117))	('GNA11', 'Gene', (57, 62))	('GNAQ', 'Gene', '2776', (52, 56))	('GNA11', 'Gene', '2767', (112, 117))	('GNAQ', 'Gene', (98, 102))	('mutation', 'Var', (63, 71))	('GNA11', 'Gene', '2767', (57, 62))	('harboured', 'Reg', (79, 88))	('GNAQ', 'Gene', (52, 56))	('GNAQ', 'Gene', '2776', (98, 102))	('patient', 'Species', '9606', (23, 30))
17751	28103611	Also, it should be noted that only ~50% of melanomas carry the BRAF mutation, and that BRAF mutations are very rare in uveal melanoma.	('melanomas', 'Disease', (43, 52))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('mutation', 'Var', (68, 76))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanomas', 'Phenotype', 'HP:0002861', (43, 52))	('uveal melanoma', 'Phenotype', 'HP:0007716', (119, 133))	('melanomas', 'Disease', 'MESH:D008545', (43, 52))	('uveal melanoma', 'Disease', 'MESH:C536494', (119, 133))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', (87, 91))	('uveal melanoma', 'Disease', (119, 133))	('BRAF', 'Gene', (63, 67))	('BRAF', 'Gene', '673', (87, 91))
17767	28103611	There was no apparent association between BRAF mutation status and clinical outcome, and tumour reduction was observed in patients both with and without detectable BRAF mutations in their tumours.	('BRAF', 'Gene', '673', (42, 46))	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('tumours', 'Phenotype', 'HP:0002664', (188, 195))	('mutations', 'Var', (169, 178))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour reduction', 'Disease', (89, 105))	('mutation', 'Var', (47, 55))	('tumour reduction', 'Disease', 'MESH:D009369', (89, 105))	('BRAF', 'Gene', '673', (164, 168))	('tumours', 'Disease', 'MESH:D009369', (188, 195))	('tumours', 'Disease', (188, 195))	('patients', 'Species', '9606', (122, 130))	('BRAF', 'Gene', (164, 168))	('BRAF', 'Gene', (42, 46))
17769	28103611	Therefore, it is reasonable to surmise that combining a BRAF inhibitor and cabozantinib may be a useful approach in patients with BRAF mutation-positive tumours and may delay or prevent the development of resistance.	('tumours', 'Disease', 'MESH:D009369', (153, 160))	('mutation-positive', 'Var', (135, 152))	('tumours', 'Disease', (153, 160))	('BRAF', 'Gene', '673', (130, 134))	('BRAF', 'Gene', '673', (56, 60))	('patients', 'Species', '9606', (116, 124))	('resistance', 'MPA', (205, 215))	('BRAF', 'Gene', (130, 134))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))	('cabozantinib', 'Chemical', 'MESH:C558660', (75, 87))	('BRAF', 'Gene', (56, 60))
17971	22980115	But CT might miss out brain metastasis from orbital melanoma < 2cm in diameter and the role of CT has been limited by poor tissue definition (, pp143-161,, pp27-34).	('miss', 'Reg', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('orbital melanoma', 'Disease', (44, 60))	('pp143-161', 'Gene', (144, 153))	('pp27-34', 'Var', (156, 163))	('pp143-161', 'Gene', '8471', (144, 153))	('brain metastasis', 'CPA', (22, 38))	('orbital melanoma', 'Disease', 'MESH:D008545', (44, 60))
17977	22980115	This melanin shortens T1 and T2 relaxation times leading to T1W hyperintense orbital melanoma which is a hypointense on T2W with respect to the hyperintense vitreous (, pp 76-9, pp143-161, pp 773-9; Mafee et al,1989, pp 773-80) (, pp 773-9) Peyster et al reported these characteristic pattern in 93% of melanoma in their evaluations of intra-ocular tumours (, pp 340-8).	('tumour', 'Phenotype', 'HP:0002664', (349, 355))	('melanoma', 'Disease', 'MESH:D008545', (303, 311))	('tumours', 'Phenotype', 'HP:0002664', (349, 356))	('pp143-161', 'Gene', '8471', (178, 187))	('melanin', 'Chemical', 'MESH:D008543', (5, 12))	('orbital melanoma', 'Disease', (77, 93))	('pp143-161', 'Gene', (178, 187))	('orbital melanoma', 'Disease', 'MESH:D008545', (77, 93))	('intra-ocular tumours', 'Disease', (336, 356))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('intra-ocular tumours', 'Disease', 'MESH:D005134', (336, 356))	('melanoma', 'Disease', (85, 93))	('T1W', 'Var', (60, 63))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('shortens', 'NegReg', (13, 21))	('melanoma', 'Phenotype', 'HP:0002861', (303, 311))	('melanoma', 'Disease', (303, 311))
17981	22980115	Amelanotic melanoma exists, behaving just like any other tumour with hypointense or isointense T1W and hyperintense/isointense T2W (Ogwa, 2003, pp548-551,, pp 625-639).	('Amelanotic melanoma', 'Disease', (0, 19))	('tumour', 'Disease', (57, 63))	('isointense T1W', 'Var', (84, 98))	('Amelanotic melanoma', 'Disease', 'MESH:D018328', (0, 19))	('hypointense', 'Var', (69, 80))	('hyperintense/isointense T2W', 'Var', (103, 130))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
17988	22980115	Post-contrast T1W with fat suppression may help to differentiate these masses from MM as retinal detachment do not enhance and Choroidal haemangioma with high vascular flow and enhancement exhibit isointensity to slight hyperintensity on T1W and hyperintense T2 weighting which is isointense to vitreous.	('Choroidal haemangioma', 'Disease', 'MESH:D002833', (127, 148))	('retinal detachment', 'Phenotype', 'HP:0000541', (89, 107))	('Choroidal haemangioma', 'Phenotype', 'HP:0007872', (127, 148))	('enhancement', 'PosReg', (177, 188))	('retinal detachment', 'Disease', (89, 107))	('Choroidal haemangioma', 'Disease', (127, 148))	('men', 'Species', '9606', (103, 106))	('men', 'Species', '9606', (184, 187))	('retinal detachment', 'Disease', 'MESH:D012163', (89, 107))	('isointensity', 'Var', (197, 209))
18091	26645696	In a study of 232 enucleated eyes from patients with uveal melanoma, the 10-year survival was 82% in patients with less than 0.5 epitheloid cells/ HPF, 55% for 0.5 to 4.9 epitheloid cells/HPF, and 33% in patients with >5 epitheloid cells/HPF.	('patients', 'Species', '9606', (204, 212))	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (39, 47))	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('uveal melanoma', 'Disease', (53, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (53, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('less', 'Var', (115, 119))
18099	26409435	Germline BAP1 mutation in a family with high incidence of multiple primary cancers and a potential gene-environment interaction We report a high-risk cancer family with multiple mesotheliomas, cutaneous melanomas, basal cell carcinomas, and meningiomas segregating with a germline nonsense mutation in BAP1 (c.1938T>A; p.Y646X).	('p.Y646X', 'Mutation', 'p.Y646X', (319, 326))	('BAP1', 'Gene', '8314', (302, 306))	('multiple primary cancers', 'Disease', (58, 82))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (214, 234))	('c.1938T>A; p.Y646X', 'Var', (308, 326))	('carcinomas', 'Phenotype', 'HP:0030731', (225, 235))	('meningioma', 'Phenotype', 'HP:0002858', (241, 251))	('multiple mesotheliomas', 'Disease', 'MESH:D008654', (169, 191))	('BAP1', 'Gene', (9, 13))	('meningiomas', 'Disease', 'MESH:D008577', (241, 252))	('cutaneous melanomas', 'Disease', (193, 212))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('meningiomas', 'Phenotype', 'HP:0002858', (241, 252))	('cancer', 'Disease', (150, 156))	('BAP1', 'Gene', (302, 306))	('melanomas', 'Phenotype', 'HP:0002861', (203, 212))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('meningiomas', 'Disease', (241, 252))	('multiple primary cancers', 'Disease', 'MESH:D009369', (58, 82))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (214, 235))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('basal cell carcinomas', 'Disease', (214, 235))	('BAP1', 'Gene', '8314', (9, 13))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (193, 212))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (193, 212))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (193, 211))	('c.1938T>A', 'Mutation', 'c.1938T>A', (308, 317))	('multiple mesotheliomas', 'Disease', (169, 191))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (214, 235))
18108	26409435	Notably, inactivating somatic mutations of the tumor suppressor gene encoding the BRCA1-associated protein 1 (BAP1) have been reported in nearly 85% of metastasizing UMs.	('tumor suppressor', 'biological_process', 'GO:0051726', ('47', '63'))	('inactivating somatic mutations', 'Var', (9, 39))	('BAP1', 'Gene', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('UM', 'Phenotype', 'HP:0007716', (166, 168))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('BRCA1-associated protein 1', 'Gene', '8314', (82, 108))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('47', '63'))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('metastasizing UMs', 'Disease', (152, 169))	('tumor', 'Disease', (47, 52))	('BRCA1-associated protein 1', 'Gene', (82, 108))	('reported', 'Reg', (126, 134))
18112	26409435	The cloning and identification of somatic mutations of the BAP1 tumor suppressor gene in lung and breast cancer cells were first reported by the Rauscher laboratory.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('tumor', 'Disease', (64, 69))	('tumor suppressor', 'biological_process', 'GO:0051726', ('64', '80'))	('breast cancer', 'Disease', (98, 111))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('64', '80'))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mutations', 'Var', (42, 51))
18113	26409435	Simultaneously, germline BAP1 mutations were reported in two families with atypical melanocytic tumors, CM, and UM.	('reported', 'Reg', (45, 53))	('BAP1', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('CM', 'Disease', 'MESH:D009202', (104, 106))	('CM', 'Phenotype', 'HP:0012056', (104, 106))	('UM', 'Phenotype', 'HP:0007716', (112, 114))	('mutations', 'Var', (30, 39))	('melanocytic tumors', 'Disease', 'MESH:D009508', (84, 102))	('melanocytic tumors', 'Disease', (84, 102))
18118	26409435	The Human Genome Variation Society (HGVS, http://www.hgvs.org/mutnomen) standardized mutation nomenclature was used to describe the BAP1 mutation using cDNA accession # NM_004656 and protein accession # NP_004647 as references.	('BAP1', 'Gene', (132, 136))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('Human', 'Species', '9606', (4, 9))	('mutation', 'Var', (137, 145))
18123	26409435	Genomic DNA was isolated from blood of all 10 participants for mutation screening of BAP1.	('BAP1', 'Gene', (85, 89))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('participants', 'Species', '9606', (46, 58))	('mutation', 'Var', (63, 71))
18124	26409435	We identified a nonsense mutation in exon 15 (c.1938T>A), which is predicted to result in nonsense-mediated decay of the BAP1 mRNA or truncation of the translated BAP1 protein (p.Tyr646X), with loss of the C-terminal nuclear localization signal (Fig.	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('truncation', 'MPA', (134, 144))	('C-terminal nuclear localization signal', 'MPA', (206, 244))	('p.Tyr646X', 'Var', (177, 186))	('BAP1', 'Gene', (121, 125))	('loss', 'NegReg', (194, 198))	('decay', 'NegReg', (108, 113))	('c.1938T>A', 'Mutation', 'c.1938T>A', (46, 55))	('c.1938T>A', 'Var', (46, 55))	('localization', 'biological_process', 'GO:0051179', ('225', '237'))	('p.Tyr646X', 'Mutation', 'p.Y646X', (177, 186))
18125	26409435	Individuals who tested positive for this mutation and the types of cancers are shown in the family pedigree (Fig.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('mutation', 'Var', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
18132	26409435	Sequencing of the BAP1 gene in the same tumor DNA showed that the vast majority of the remaining BAP1 allele was the mutant copy (Fig.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('mutant', 'Var', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('BAP1', 'Gene', (18, 22))	('BAP1', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
18134	26409435	Notably, monosomy 3 appears to be the primary (driver) somatic genetic change in this tumor, given that this copy number loss was observed in nearly 100% of tumor cells, with the most clear evidence for loss of heterozygosity (LOH) among all the chromosomal losses observed.	('tumor', 'Disease', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('monosomy', 'Var', (9, 17))	('loss', 'NegReg', (121, 125))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('loss', 'NegReg', (203, 207))
18144	26409435	Additionally, although UV light does not have a clear role in the cause of UM in the general population, BAP1 mutation carriers may be more prone to the carcinogenic effects of sunlight, similar to the way that asbestos-exposed mice carrying a Bap1 mutation show an increased incidence of MM compared to that observed in asbestos-exposed wild type littermates.	('mutation', 'Var', (249, 257))	('Bap1', 'Gene', (244, 248))	('asbestos', 'Chemical', 'MESH:D001194', (211, 219))	('asbestos', 'Chemical', 'MESH:D001194', (321, 329))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('mutation', 'Var', (110, 118))	('prone', 'Reg', (140, 145))	('carcinogenic', 'Disease', 'MESH:D063646', (153, 165))	('mice', 'Species', '10090', (228, 232))	('BAP1', 'Gene', (105, 109))	('carcinogenic', 'Disease', (153, 165))	('Bap1', 'Gene', '104416', (244, 248))
18146	26409435	Two sisters (III-09 and III-10) were diagnosed with meningioma as well as MM, and both were found to carry a BAP1 mutation.	('meningioma', 'Disease', 'MESH:D008577', (52, 62))	('meningioma', 'Disease', (52, 62))	('mutation', 'Var', (114, 122))	('BAP1', 'Gene', (109, 113))	('meningioma', 'Phenotype', 'HP:0002858', (52, 62))
18149	26409435	It is also noteworthy that family member IV-03, another BAP1 mutation carrier, had an atypical Spitz nevus, and well-documented studies have shown that such benign melanocytic tumors can be the predominant type of tumor in some families with germline mutation of BAP1.	('carrier', 'molecular_function', 'GO:0005215', ('70', '77'))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('nevus', 'Phenotype', 'HP:0003764', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('Spitz nevus', 'Disease', (95, 106))	('germline mutation', 'Var', (242, 259))	('benign melanocytic tumors', 'Disease', (157, 182))	('mutation', 'Var', (61, 69))	('tumor', 'Disease', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('BAP1', 'Gene', (56, 60))	('tumor', 'Disease', (214, 219))	('benign melanocytic tumors', 'Disease', 'MESH:D009508', (157, 182))	('BAP1', 'Gene', (263, 267))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('atypical Spitz nevus', 'Phenotype', 'HP:0001062', (86, 106))
18153	26409435	We previously reported in a mouse model that germline mutation of Bap1 predisposes to the tumorigenic effects of asbestos and that high penetrance of MM requires such environmental exposure.	('mouse', 'Species', '10090', (28, 33))	('Bap1', 'Gene', '104416', (66, 70))	('predisposes', 'Reg', (71, 82))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('Bap1', 'Gene', (66, 70))	('germline mutation', 'Var', (45, 62))	('asbestos', 'Chemical', 'MESH:D001194', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
18156	26409435	The findings in this highly unusual family provide strong evidence for a BAP1 cancer syndrome characterized by susceptibility to a growing list of tumor types, including MM, CM, UM, basal cell carcinoma, atypical Spitz nevi, RCC, meningioma, and potentially other neoplasms in association with germline mutation of BAP1.	('meningioma', 'Disease', 'MESH:D008577', (230, 240))	('neoplasms', 'Disease', (264, 273))	('germline mutation', 'Var', (294, 311))	('atypical Spitz nevi', 'Disease', (204, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('BAP1', 'Gene', (73, 77))	('atypical Spitz nevi', 'Phenotype', 'HP:0001062', (204, 223))	('UM', 'Phenotype', 'HP:0007716', (178, 180))	('basal cell carcinoma', 'Disease', (182, 202))	('tumor', 'Disease', (147, 152))	('CM', 'Phenotype', 'HP:0012056', (174, 176))	('RCC', 'Disease', (225, 228))	('cancer syndrome', 'Disease', 'MESH:D009369', (78, 93))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('neoplasms', 'Phenotype', 'HP:0002664', (264, 273))	('nevi', 'Phenotype', 'HP:0003764', (219, 223))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('meningioma', 'Disease', (230, 240))	('cancer syndrome', 'Disease', (78, 93))	('meningioma', 'Phenotype', 'HP:0002858', (230, 240))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (182, 202))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('CM', 'Disease', 'MESH:D009202', (174, 176))	('BAP1', 'Gene', (315, 319))	('neoplasms', 'Disease', 'MESH:D009369', (264, 273))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (182, 202))
18157	26409435	MM and UM are the two cancer types most frequently reported in BAP1 mutation carriers, with a recent review uncovering 39 of 174 (22%) reported BAP1 mutation carriers having MM and 54 of 174 (31%) having UM.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('UM', 'Phenotype', 'HP:0007716', (204, 206))	('BAP1', 'Gene', (144, 148))	('cancer', 'Disease', (22, 28))	('UM', 'Phenotype', 'HP:0007716', (7, 9))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('mutation', 'Var', (149, 157))
18158	26409435	Moreover, somatic mutations and deletions of BAP1 have been reported in 60-65% of sporadic MMs and in ~85% of metastasizing UMs, lending further support for a strong connection between BAP1 inactivation and these two malignancies.	('deletions', 'Var', (32, 41))	('BAP1', 'Gene', (45, 49))	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('MMs', 'Disease', (91, 94))	('malignancies', 'Disease', 'MESH:D009369', (217, 229))	('malignancies', 'Disease', (217, 229))	('reported', 'Reg', (60, 68))
18171	23714557	Mutations in the Gq alpha subunits GNAQ and GNA11 are mutually exclusive and represent early or initiating events that constitutively activate the MAPK pathway.	('MAPK', 'molecular_function', 'GO:0004707', ('147', '151'))	('activate', 'PosReg', (134, 142))	('GNA11', 'Gene', (44, 49))	('GNAQ', 'Gene', '2776', (35, 39))	('GNA11', 'Gene', '2767', (44, 49))	('Mutations', 'Var', (0, 9))	('MAPK pathway', 'Pathway', (147, 159))	('GNAQ', 'Gene', (35, 39))
18172	23714557	Mutations in BRCA1-associated protein-1 (BAP1) and splicing factor 3B subunit 1 (SF3B1) also appear to be largely mutually exclusive, and they occur later in tumor progression.	('splicing factor 3B subunit 1', 'Gene', (51, 79))	('BRCA1-associated protein-1', 'Gene', '8314', (13, 39))	('tumor', 'Disease', (158, 163))	('SF3B1', 'Gene', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('BAP1', 'Gene', (41, 45))	('occur', 'Reg', (143, 148))	('SF3B1', 'Gene', '23451', (81, 86))	('Mutations', 'Var', (0, 9))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('BRCA1-associated protein-1', 'Gene', (13, 39))	('splicing', 'biological_process', 'GO:0045292', ('51', '59'))	('splicing factor 3B subunit 1', 'Gene', '23451', (51, 79))	('BAP1', 'Gene', '8314', (41, 45))
18173	23714557	BAP1 mutations are strongly associated with metastasis, whereas SF3B1 mutations are associated with a more favorable outcome.	('mutations', 'Var', (70, 79))	('SF3B1', 'Gene', (64, 69))	('BAP1', 'Gene', (0, 4))	('associated', 'Reg', (28, 38))	('mutations', 'Var', (5, 14))	('metastasis', 'CPA', (44, 54))	('SF3B1', 'Gene', '23451', (64, 69))	('BAP1', 'Gene', '8314', (0, 4))
18174	23714557	BAP1 mutations can arise in the germ line, leading to a newly described BAP1 familial cancer syndrome.	('BAP1', 'Gene', (0, 4))	('BAP1', 'Gene', '8314', (72, 76))	('leading to', 'Reg', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (5, 14))	('BAP1', 'Gene', (72, 76))	('familial cancer syndrome', 'Disease', 'MESH:D009386', (77, 101))	('familial cancer syndrome', 'Disease', (77, 101))	('BAP1', 'Gene', '8314', (0, 4))
18180	23714557	Further, chromosome-based tests suffer from a susceptibility to sampling error resulting from intratumoral genetic heterogeneity, limited clinical validation, lack of standardized testing platforms, and high technical failure rates.	('tumor', 'Disease', (99, 104))	('chromosome', 'cellular_component', 'GO:0005694', ('9', '19'))	('chromosome-based', 'Var', (9, 25))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
18188	23714557	The PI3K/AKT pathway is constitutively activated in a majority of UMs, and phosphorylated AKT correlates with poor prognosis.	('phosphorylated', 'Var', (75, 89))	('AKT', 'Gene', '207', (9, 12))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('activated', 'PosReg', (39, 48))	('UMs', 'Disease', (66, 69))	('AKT', 'Gene', (90, 93))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('AKT', 'Gene', (9, 12))	('AKT', 'Gene', '207', (90, 93))
18190	23714557	In one study, loss of heterozygosity at the PTEN locus was found in 76% of UMs, and mutations within the PTEN coding region were found in 11% of tumors.	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('found', 'Reg', (129, 134))	('PTEN', 'Gene', (105, 109))	('PTEN', 'Gene', '5728', (105, 109))	('tumors', 'Disease', (145, 151))	('mutations', 'Var', (84, 93))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('PTEN', 'Gene', (44, 48))	('PTEN', 'Gene', '5728', (44, 48))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('UMs', 'Disease', (75, 78))	('loss', 'NegReg', (14, 18))
18191	23714557	PTEN inactivation was also found to be associated with increased aneuploidy and decreased survival in UM.	('aneuploidy', 'Disease', (65, 75))	('increased', 'PosReg', (55, 64))	('decreased', 'NegReg', (80, 89))	('aneuploidy', 'Disease', 'MESH:D000782', (65, 75))	('survival in UM', 'CPA', (90, 104))	('inactivation', 'Var', (5, 17))	('PTEN', 'Gene', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (102, 104))	('PTEN', 'Gene', '5728', (0, 4))
18192	23714557	However, mutations in known upstream activators such as KIT and the RAS and RAF family members are extremely rare in UM.	('KIT', 'Gene', (56, 59))	('mutations', 'Var', (9, 18))	('KIT', 'molecular_function', 'GO:0005020', ('56', '59'))	('RAF', 'Gene', (76, 79))	('RAF', 'Gene', '673', (76, 79))	('UM', 'Phenotype', 'HP:0007716', (117, 119))
18193	23714557	GNAQ/11 mutations are found in benign uveal nevi and in the vast majority of UMs regardless of cytogenetic status or GEP class, suggesting that these mutations are early or perhaps initiating events and are not sufficient for full malignant transformation.	('GNAQ', 'Gene', '2776', (0, 4))	('benign uveal', 'Disease', 'MESH:D014603', (31, 43))	('mutations', 'Var', (8, 17))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('nevi', 'Phenotype', 'HP:0003764', (44, 48))	('GNAQ', 'Gene', (0, 4))	('benign uveal', 'Disease', (31, 43))
18194	23714557	It has been known for many years that loss of one copy of chromosome 3 in UM is associated with metastasis and poor prognosis, which led to speculation that one or more tumor suppressor genes may reside on this chromosome that are mutated in UM.	('loss', 'Var', (38, 42))	('metastasis', 'CPA', (96, 106))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('169', '185'))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('UM', 'Phenotype', 'HP:0007716', (242, 244))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('associated', 'Reg', (80, 90))	('tumor', 'Disease', (169, 174))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('211', '221'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('169', '185'))
18195	23714557	We found that BRCA1-associated protein 1 (BAP1), located at chromosome 3p21.1, was mutated in approximately 85% of class 2 UMs, but such mutations were rare in low-grade class 1 UMs, suggesting that BAP1 may function as a metastasis suppressor in this cancer.	('BAP1', 'Gene', '8314', (42, 46))	('mutated', 'Var', (83, 90))	('BRCA1-associated protein 1', 'Gene', '8314', (14, 40))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('BAP1', 'Gene', (199, 203))	('cancer', 'Disease', (252, 258))	('BRCA1-associated protein 1', 'Gene', (14, 40))	('BAP1', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))	('UM', 'Phenotype', 'HP:0007716', (178, 180))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('UM', 'Phenotype', 'HP:0007716', (123, 125))	('BAP1', 'Gene', '8314', (199, 203))
18197	23714557	The precise molecular explanation for why loss of BAP1 leads to metastasis in UM remains unclear.	('loss', 'Var', (42, 46))	('UM', 'Phenotype', 'HP:0007716', (78, 80))	('leads to', 'Reg', (55, 63))	('BAP1', 'Gene', '8314', (50, 54))	('BAP1', 'Gene', (50, 54))	('metastasis', 'CPA', (64, 74))
18198	23714557	Familial UM is generally regarded as rare, so we were surprised to find that one patient with UM in our original study carried a germ-line BAP1 mutation that was reduced to homozygosity in tumor cells by loss of the other chromosome 3.	('chromosome', 'cellular_component', 'GO:0005694', ('222', '232'))	('tumor', 'Disease', (189, 194))	('UM', 'Phenotype', 'HP:0007716', (94, 96))	('patient', 'Species', '9606', (81, 88))	('BAP1', 'Gene', '8314', (139, 143))	('loss', 'NegReg', (204, 208))	('mutation', 'Var', (144, 152))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('BAP1', 'Gene', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
18199	23714557	Subsequently, there have been many groups reporting families with germ-line BAP1 mutations in association with UM and many other cancers, including mesothelioma, cutaneous melanoma, renal cell carcinoma, and others.	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('cancers', 'Disease', (129, 136))	('mutations', 'Var', (81, 90))	('association', 'Reg', (94, 105))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (182, 202))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cutaneous melanoma', 'Disease', (162, 180))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (162, 180))	('BAP1', 'Gene', '8314', (76, 80))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (162, 180))	('renal cell carcinoma', 'Disease', (182, 202))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (182, 202))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('UM', 'Phenotype', 'HP:0007716', (111, 113))	('mesothelioma', 'Disease', (148, 160))	('BAP1', 'Gene', (76, 80))	('mesothelioma', 'Disease', 'MESH:D008654', (148, 160))
18201	23714557	We searched for additional mutations in UM by exome sequencing and identified novel mutations in splicing factor 3B subunit 1 (SF3B1).	('splicing factor 3B subunit 1', 'Gene', '23451', (97, 125))	('splicing', 'biological_process', 'GO:0045292', ('97', '105'))	('SF3B1', 'Gene', (127, 132))	('splicing factor 3B subunit 1', 'Gene', (97, 125))	('mutations', 'Var', (84, 93))	('UM', 'Phenotype', 'HP:0007716', (40, 42))	('SF3B1', 'Gene', '23451', (127, 132))
18202	23714557	Among 102 primary tumors, 19 (18.6%) contained mutations in SF3B1, similar to the frequency in myelodysplastic syndrome and chronic lymphocytic leukemia, and higher than that in breast cancer.	('SF3B1', 'Gene', (60, 65))	('leukemia', 'Phenotype', 'HP:0001909', (144, 152))	('tumors', 'Disease', (18, 24))	('myelodysplastic syndrome', 'Disease', (95, 119))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('SF3B1', 'Gene', '23451', (60, 65))	('mutations', 'Var', (47, 56))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (124, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (95, 119))	('chronic lymphocytic leukemia', 'Disease', (124, 152))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (95, 119))	('contained', 'Reg', (37, 46))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (124, 152))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('breast cancer', 'Disease', (178, 191))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))
18203	23714557	Interestingly, the mutations always involved an amino acid substitution at arginine-625, and all were somatic in origin.	('arginine', 'Chemical', 'MESH:D001120', (75, 83))	('amino acid substitution at arginine-625', 'Var', (48, 87))	('involved', 'Reg', (36, 44))
18204	23714557	The molecular effect of the mutations appeared to be dominant-negative, gain-of-function or haploinsufficiency, but this remains to be firmly established.	('gain-of-function', 'PosReg', (72, 88))	('haploinsufficiency', 'Disease', 'MESH:D058495', (92, 110))	('haploinsufficiency', 'Disease', (92, 110))	('mutations', 'Var', (28, 37))
18205	23714557	SF3B1 mutations were largely mutually exclusive with BAP1 mutations and were associated with favorable prognosis.	('SF3B1', 'Gene', (0, 5))	('SF3B1', 'Gene', '23451', (0, 5))	('BAP1', 'Gene', '8314', (53, 57))	('BAP1', 'Gene', (53, 57))	('mutations', 'Var', (6, 15))	('associated', 'Reg', (77, 87))
18209	23714557	GNAQ/11 mutations have stimulated interest in MEK and protein kinase C inhibitors in UM.	('GNAQ', 'Gene', '2776', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('mutations', 'Var', (8, 17))	('GNAQ', 'Gene', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('MEK', 'Gene', (46, 49))	('MEK', 'Gene', '5609', (46, 49))
18210	23714557	BAP1 mutations have suggested a utility for histone deacetylase (HDAC) inhibitors to reverse the biochemical effects of BAP1 loss by reversing histone H2A hyperubiquitination.	('reversing', 'NegReg', (133, 142))	('histone', 'MPA', (143, 150))	('HDAC', 'Gene', (65, 69))	('loss', 'NegReg', (125, 129))	('BAP1', 'Gene', (0, 4))	('HDAC', 'Gene', '9734', (65, 69))	('hyperubiquitination', 'Disease', (155, 174))	('histone deacetylase', 'Gene', (44, 63))	('mutations', 'Var', (5, 14))	('BAP1', 'Gene', '8314', (0, 4))	('BAP1', 'Gene', '8314', (120, 124))	('hyperubiquitination', 'Disease', 'None', (155, 174))	('histone deacetylase', 'Gene', '9734', (44, 63))	('BAP1', 'Gene', (120, 124))
18211	23714557	With attention now focused on these mutations, not only in UM but in other cancers as well, it is anticipated that new classes of therapeutic compounds that target these pathways will soon emerge.	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Disease', (75, 82))	('mutations', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('UM', 'Phenotype', 'HP:0007716', (59, 61))
18213	23714557	Mutually exclusive mutations in GNAQ and GNA11 represent early or initiating events in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('GNAQ', 'Gene', (32, 36))	('uveal melanoma', 'Disease', (87, 101))	('mutations', 'Var', (19, 28))	('GNAQ', 'Gene', '2776', (32, 36))	('GNA11', 'Gene', (41, 46))	('GNA11', 'Gene', '2767', (41, 46))	('uveal melanoma', 'Phenotype', 'HP:0007716', (87, 101))	('uveal melanoma', 'Disease', 'MESH:C536494', (87, 101))
18214	23714557	Mutations in BAP1 and SF3B1 represent later events associated with poor and good outcome, respectively.	('BAP1', 'Gene', (13, 17))	('SF3B1', 'Gene', '23451', (22, 27))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (13, 17))	('SF3B1', 'Gene', (22, 27))
18217	21945171	Mutational screening for alterations in GNAQ and GNA11 genes was carried out by restriction fragment length polymorphism.	('alterations', 'Var', (25, 36))	('GNAQ', 'Gene', (40, 44))	('GNAQ', 'Gene', '2776', (40, 44))	('GNA11', 'Gene', '2767', (49, 54))	('GNA11', 'Gene', (49, 54))
18220	21945171	The DNA obtained is of sufficient quality to carry out genotyping for markers on chromosome 3, 6 and 8, as well as screening for somatic mutations in GNAQ and GNA11 genes.	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('mutations', 'Var', (137, 146))	('GNAQ', 'Gene', (150, 154))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('GNAQ', 'Gene', '2776', (150, 154))	('GNA11', 'Gene', '2767', (159, 164))	('GNA11', 'Gene', (159, 164))
18222	21945171	While genetic alterations in chromosomal arm 6p has been associated with less aggressive tumors.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('associated', 'Reg', (57, 67))	('aggressive tumors', 'Disease', 'MESH:D001523', (78, 95))	('genetic alterations', 'Var', (6, 25))	('aggressive tumors', 'Disease', (78, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('chromosomal arm 6p', 'Gene', (29, 47))
18247	21945171	We tested for the most common, somatic mutations in both GNAQ and GNA11 genes located at codon 209 of both genes.	('GNAQ', 'Gene', (57, 61))	('tested', 'Reg', (3, 9))	('mutations', 'Var', (39, 48))	('GNA11', 'Gene', (66, 71))	('GNAQ', 'Gene', '2776', (57, 61))	('GNA11', 'Gene', '2767', (66, 71))
18249	21945171	Primers for codon 209 mutational screening of GNA11 were F: 5'GGTGGGAGCCGTCCTGGGAT and R: 5'GGCAGAGGGAATCAGAGGGGC.	('GNA11', 'Gene', '2767', (46, 51))	('GNA11', 'Gene', (46, 51))	("F: 5'GGTGGGAGCCGTCCTGGGAT", 'Var', (57, 82))	("R: 5'GGCAGAGGGAATCAGAGGGGC", 'Var', (87, 113))
18266	21945171	For detection of GNAQ/GNA11 mutation status lower amount of DNA 150 pg (25 cells) are needed.	('GNA11', 'Gene', (22, 27))	('GNA11', 'Gene', '2767', (22, 27))	('GNAQ', 'Gene', (17, 21))	('mutation', 'Var', (28, 36))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('GNAQ', 'Gene', '2776', (17, 21))
18288	24003303	Recently, Daniels et al demonstrated that the vast majority (91%) of large UM harbor mutually exclusive mutations in GNAQ (47%) or GNA11 (44%), but very rarely have the oncogenic mutations that are reported commonly in other cancers.	('cancers', 'Phenotype', 'HP:0002664', (225, 232))	('mutations', 'Var', (104, 113))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('cancers', 'Disease', (225, 232))	('GNAQ', 'Gene', '2776', (117, 121))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('GNAQ', 'Gene', (117, 121))	('GNA11', 'Gene', '2767', (131, 136))	('GNA11', 'Gene', (131, 136))
18289	24003303	The GNAQ and GNA11 mutations lead to activation of the mitogen-activated protein kinase pathway that consequently can be a potential target for therapy of UM that have these mutations.	('GNAQ', 'Gene', '2776', (4, 8))	('mitogen-activated protein kinase', 'Gene', (55, 87))	('UM', 'Phenotype', 'HP:0007716', (155, 157))	('activation', 'PosReg', (37, 47))	('mitogen-activated protein kinase', 'Gene', '5609', (55, 87))	('mutations', 'Var', (19, 28))	('GNAQ', 'Gene', (4, 8))	('GNA11', 'Gene', (13, 18))	('GNA11', 'Gene', '2767', (13, 18))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))
18321	24003303	Most recently, the largest retrospective comparative study to date of 133 patients treated either with BT + TTT (n = 63) or with BT alone (n = 70) revealed there to be significant benefits from simultaneous TTT + BT.	('TTT', 'Chemical', '-', (207, 210))	('benefits', 'PosReg', (180, 188))	('BT + TTT', 'Var', (103, 111))	('patients', 'Species', '9606', (74, 82))	('TTT', 'Chemical', '-', (108, 111))
18343	24003303	Between the two treatments, CPT and 125I BT, there was no significant reduction in mortality (OR 0.13, 95% CI 0.01-1.63), or significant difference in risk of subsequent enucleation (OR 0.53, 95% CI 0.23-1.18).	('enucleation', 'biological_process', 'GO:0090601', ('170', '181'))	('reduction', 'NegReg', (70, 79))	('125I BT', 'Var', (36, 43))	('CPT', 'molecular_function', 'GO:0004142', ('28', '31'))	('CPT', 'molecular_function', 'GO:0004095', ('28', '31'))	('mortality', 'CPA', (83, 92))	('CPT', 'Chemical', '-', (28, 31))	('CPT', 'Var', (28, 31))
18453	24003303	Jampol et al demonstrated that NFkappaB is expressed by primary UM and its liver metastases, NFkappaB inhibitors reducing metastatic cell proliferation.	('liver metastases', 'Disease', (75, 91))	('cell proliferation', 'biological_process', 'GO:0008283', ('133', '151'))	('liver metastases', 'Disease', 'MESH:D009362', (75, 91))	('NFkappaB', 'Gene', (31, 39))	('metastatic cell proliferation', 'CPA', (122, 151))	('inhibitors', 'Var', (102, 112))	('NFkappaB', 'Gene', '4790', (31, 39))	('NFkappaB', 'Gene', (93, 101))	('UM', 'Phenotype', 'HP:0007716', (64, 66))	('NFkappaB', 'Gene', '4790', (93, 101))	('reducing', 'NegReg', (113, 121))
18460	24003303	As mentioned, about 80% to 91% of large UMs have mutations in the GNAQ or GNA11 genes, and these mutations are associated to activation of the mitogen-activated protein kinase pathway.	('activation', 'PosReg', (125, 135))	('mitogen-activated protein kinase', 'Gene', '5609', (143, 175))	('GNA11', 'Gene', (74, 79))	('mutations', 'Var', (49, 58))	('GNA11', 'Gene', '2767', (74, 79))	('GNAQ', 'Gene', '2776', (66, 70))	('UM', 'Phenotype', 'HP:0007716', (40, 42))	('GNAQ', 'Gene', (66, 70))	('mitogen-activated protein kinase', 'Gene', (143, 175))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))
18466	24003303	Somatic activating mutations in the RAS/RAF/MEK/ERK signaling pathway are frequent in cutaneous melanomas, with 50%-70% of them harboring BRAF mutations.	('signaling pathway', 'biological_process', 'GO:0007165', ('52', '69'))	('activating', 'PosReg', (8, 18))	('RAF', 'Gene', '22882', (40, 43))	('RAF', 'Gene', (139, 142))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('MEK', 'Gene', '5609', (44, 47))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (86, 105))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (86, 105))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (86, 104))	('RAF', 'Gene', (40, 43))	('ERK', 'Gene', '5594', (48, 51))	('MEK', 'Gene', (44, 47))	('mutations', 'Var', (143, 152))	('cutaneous melanomas', 'Disease', (86, 105))	('ERK', 'molecular_function', 'GO:0004707', ('48', '51'))	('BRAF', 'Gene', '673', (138, 142))	('BRAF', 'Gene', (138, 142))	('ERK', 'Gene', (48, 51))	('RAF', 'Gene', '22882', (139, 142))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))
18468	24003303	However, in UM, BRAF mutations are rare.	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('mutations', 'Var', (21, 30))
18473	24003303	Nonetheless, there is a Phase III study (NCT01245062) assessing the efficacy of an MEK inhibitor (trametinib) in progression-free survival and overall survival compared with chemotherapy in patients with BRAFV600E/K mutant advanced or metastatic cutaneous melanoma.	('advanced', 'Disease', (223, 231))	('BRAFV600E/K mutant', 'Var', (204, 222))	('patients', 'Species', '9606', (190, 198))	('MEK', 'Gene', (83, 86))	('BRAFV600E', 'Mutation', 'rs113488022', (204, 213))	('MEK', 'Gene', '5609', (83, 86))	('melanoma', 'Phenotype', 'HP:0002861', (256, 264))	('cutaneous melanoma', 'Disease', (246, 264))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (246, 264))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (246, 264))	('trametinib', 'Chemical', 'MESH:C560077', (98, 108))
18509	24003303	Their blockage enhances immune function and serves as antitumor activity.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('immune function', 'CPA', (24, 39))	('enhances', 'PosReg', (15, 23))	('enhances immune function', 'Phenotype', 'HP:0002721', (15, 39))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('blockage', 'Var', (6, 14))
18547	21215251	UV radiation can also cause oxidative stress in skin cells, which is thought to be another contributor to skin disease and skin carcinogenesis.	('oxidative stress', 'MPA', (28, 44))	('cause', 'Reg', (22, 27))	('skin disease', 'Phenotype', 'HP:0000951', (106, 118))	('skin disease', 'Disease', (106, 118))	('skin carcinogenesis', 'Disease', (123, 142))	('skin disease', 'Disease', 'MESH:D012871', (106, 118))	('oxidative stress', 'Phenotype', 'HP:0025464', (28, 44))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (123, 142))	('UV radiation', 'Var', (0, 12))
18601	21215251	This study, for the first time, suggested that i) resveratrol imparts strong chemopreventive effects against UVB exposure-mediated skin carcinogenesis, and ii) the chemopreventive effects of resveratrol may, at least in part, be mediated via modulations in Survivin and other associated events.	('skin carcinogenesis', 'Disease', 'MESH:D063646', (131, 150))	('Survivin', 'Gene', (257, 265))	('Survivin', 'Gene', '11799', (257, 265))	('skin carcinogenesis', 'Disease', (131, 150))	('resveratrol', 'Chemical', 'MESH:D000077185', (191, 202))	('modulations', 'Var', (242, 253))	('resveratrol', 'Chemical', 'MESH:D000077185', (50, 61))	('chemopreventive effects', 'CPA', (77, 100))
18622	21215251	Similarly, Moran and colleagues showed that fluorinated analogues of resveratrol had better growth inhibitory potential against melanoma cells.	('better', 'PosReg', (85, 91))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('fluorinated analogues', 'Var', (44, 65))	('resveratrol', 'Chemical', 'MESH:D000077185', (69, 80))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
18648	21215251	The nano-formulations can possibly improve resveratrol transport across the membrane as well as increase solubility.	('solubility', 'MPA', (105, 115))	('membrane', 'cellular_component', 'GO:0016020', ('76', '84'))	('nano-formulations', 'Var', (4, 21))	('improve', 'PosReg', (35, 42))	('increase', 'PosReg', (96, 104))	('resveratrol transport across the membrane', 'MPA', (43, 84))	('resveratrol', 'Chemical', 'MESH:D000077185', (43, 54))	('transport', 'biological_process', 'GO:0006810', ('55', '64'))
18695	19668492	However, monosomy in chromosome 3 is a marker of poor prognosis in posterior uveal melanoma, and may imply a similarly poor prognosis in iris melanoma.	('monosomy', 'Var', (9, 17))	('iris melanoma', 'Phenotype', 'HP:0011524', (137, 150))	('uveal melanoma', 'Disease', 'MESH:C536494', (77, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (77, 91))	('uveal melanoma', 'Disease', (77, 91))	('iris melanoma', 'Disease', 'MESH:D007499', (137, 150))	('chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('iris melanoma', 'Disease', (137, 150))
18854	33627107	When analyzed by genetic class, we observed an increase in c-Myc levels in GEP Class-2 vitreous compared to GEP Class-1A (p = 0.009; Figs.	('c-Myc', 'Gene', (59, 64))	('c-Myc', 'Gene', '4609', (59, 64))	('GEP Class-2', 'Var', (75, 86))	('increase', 'PosReg', (47, 55))
18885	33627107	VBM is supported by NIH grants [R01EY026682, R01EY024665, R01EY025225, R01EY024698, R01EY03195201, and P30EY026877] and Research to Prevent Blindness (RPB), New York, NY.	('R01EY024665', 'Var', (45, 56))	('Blindness', 'Phenotype', 'HP:0000618', (140, 149))	('VBM', 'Chemical', 'MESH:C035913', (0, 3))	('R01EY024698', 'Var', (71, 82))	('Blindness', 'Disease', 'MESH:D001766', (140, 149))	('R01EY025225', 'Var', (58, 69))	('R01EY03195201', 'Var', (84, 97))	('Blindness', 'Disease', (140, 149))	('[R01EY026682', 'Var', (31, 43))	('P30EY026877]', 'Var', (103, 115))
18903	32992823	Most relevant predisposing factors for the development of UM are the presence of dysplastic nevus syndrome, choroidal nevi, ocular or oculodermal melanocytosis, familial syndromes including germline BAP1 (BRCA1-associated protein 1) mutations, and neurofibromatosis.	('dysplastic nevus syndrome', 'Disease', (81, 106))	('neurofibromatosis', 'Disease', 'MESH:C537392', (248, 265))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (81, 97))	('dysplastic nevus syndrome', 'Disease', 'MESH:D004416', (81, 106))	('neurofibromatosis', 'Disease', (248, 265))	('BRCA1-associated protein 1', 'Gene', (205, 231))	('BAP1', 'Gene', (199, 203))	('melanocytosis', 'Disease', 'MESH:C535835', (146, 159))	('choroidal nevi', 'Phenotype', 'HP:0025314', (108, 122))	('nevi', 'Phenotype', 'HP:0003764', (118, 122))	('protein', 'cellular_component', 'GO:0003675', ('222', '229'))	('choroidal nevi', 'Disease', (108, 122))	('nevus', 'Phenotype', 'HP:0003764', (92, 97))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (248, 265))	('melanocytosis', 'Disease', (146, 159))	('oculodermal melanocytosis', 'Phenotype', 'HP:0009920', (134, 159))	('BRCA1-associated protein 1', 'Gene', '8314', (205, 231))	('mutations', 'Var', (233, 242))	('BAP1', 'Gene', '8314', (199, 203))
18916	32992823	Interestingly, BRCA1-associated protein-1 (BAP1) is a tumor-suppressor gene placed on chromosome 3, and it is mutated in 47% of primary UM and up to 91% of metastatic UM.	('BRCA1-associated protein-1', 'Gene', (15, 41))	('BAP1', 'Gene', (43, 47))	('mutated', 'Var', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('54', '70'))	('BAP1', 'Gene', '8314', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('primary UM', 'Disease', (128, 138))	('BRCA1-associated protein-1', 'Gene', '8314', (15, 41))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('54', '70'))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('chromosome', 'cellular_component', 'GO:0005694', ('86', '96'))	('metastatic UM', 'CPA', (156, 169))	('tumor', 'Disease', (54, 59))
18918	32992823	Eukaryotic translation initiation factor 1A, X-linked (EIF1AX) gene mutations are also described along with SF3B1 in UM with disomy 3, but metastatic tendency is less frequent.	('SF3B1', 'Gene', '23451', (108, 113))	('EIF1AX', 'Gene', '1964', (55, 61))	('EIF1AX', 'Gene', (55, 61))	('disomy 3', 'Disease', (125, 133))	('translation initiation', 'biological_process', 'GO:0006413', ('11', '33'))	('SF3B1', 'Gene', (108, 113))	('mutations', 'Var', (68, 77))	('Eukaryotic translation initiation factor 1A, X-linked', 'Gene', '1964', (0, 53))
18932	32992823	PRAME expression positively correlated with larger tumor diameter and SF3B1 mutations as well as gain of 1q, 6p, 8q, and 9q and loss of 6q and 11q.	('mutations', 'Var', (76, 85))	('loss', 'NegReg', (128, 132))	('SF3B1', 'Gene', '23451', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('gain', 'PosReg', (97, 101))	('SF3B1', 'Gene', (70, 75))	('larger', 'PosReg', (44, 50))	('PRAME', 'Gene', '23532', (0, 5))	('PRAME', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
18970	32992823	The dormancy of disseminated tumor cells is supposed to be the result of a balance between anti- and protumorigenic immune and inflammatory responses, failure in activating the angiogenic switch, genetic modulation by metastasis suppressor genes (MSGs), and associated signaling pathways.	('failure', 'NegReg', (151, 158))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('signaling', 'biological_process', 'GO:0023052', ('269', '278'))	('angiogenic', 'CPA', (177, 187))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('activating', 'MPA', (162, 172))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (29, 34))	('signaling pathways', 'Pathway', (269, 287))	('dormancy', 'biological_process', 'GO:0030431', ('4', '12'))	('genetic modulation', 'Var', (196, 214))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
18994	32992823	Specifically, the MSGs KISS1, RhoG-DI2, and Nm23-H1 showed to be able to suppress the development of distant metastases without significantly affecting tumor growth at the primary site.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('suppress', 'NegReg', (73, 81))	('Nm23-H1', 'Gene', '4830', (44, 51))	('RhoG-DI2', 'Gene', '397', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('RhoG-DI2', 'Gene', (30, 38))	('KISS1', 'Gene', (23, 28))	('Nm23-H1', 'Gene', (44, 51))	('tumor', 'Disease', (152, 157))	('metastases', 'Disease', (109, 119))	('KISS1', 'Gene', '3814', (23, 28))	('MSGs', 'Var', (18, 22))	('metastases', 'Disease', 'MESH:D009362', (109, 119))
18995	32992823	Interestingly, MSGs rarely mutate, and their downregulation in highly metastatic tumors would rather be associated with epigenetic modifications.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('epigenetic modifications', 'Var', (120, 144))	('downregulation', 'NegReg', (45, 59))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
19018	32992823	The SCANDIUM study:a randomized multicenter phase III clinical trial:is currently ongoing in patients with UM and isolated liver metastases to evaluate the efficacy of IHP melphalan compared with the best alternative care in OS.	('IHP', 'Var', (168, 171))	('liver metastases', 'Disease', 'MESH:D009362', (123, 139))	('melphalan', 'Chemical', 'MESH:D008558', (172, 181))	('IHP', 'Chemical', '-', (168, 171))	('liver metastases', 'Disease', (123, 139))	('patients', 'Species', '9606', (93, 101))
19019	32992823	Results from a randomized phase III trial including 93 patients with melanoma metastatic to the liver (88% ocular, 12% cutaneous) treated with either PHP with melphalan or best available care:showed that PHP was effective in significantly improving median PFS (245 days vs. 49 days, P < 0.001) and overall response rate (34.1 vs. 2% P < 0.001).	('melphalan', 'Chemical', 'MESH:D008558', (159, 168))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('improving', 'PosReg', (239, 248))	('PHP', 'Var', (204, 207))	('patients', 'Species', '9606', (55, 63))	('PFS', 'MPA', (256, 259))	('melanoma', 'Disease', (69, 77))	('response', 'MPA', (306, 314))
19055	32992823	Specifically, mutations of the GNAQ and GNA11 genes encoding for Galpha subunits of G-proteins drive oncogenesis in most of primary and mUM, whereas mutations in the phospholipase C4 (PLCB4) or in the Cysteinyl Leukotriene Receptor 2 (CYSLTR2) genes occur less frequently.	('oncogenesis', 'biological_process', 'GO:0007048', ('101', '112'))	('PLCB4', 'Gene', (184, 189))	('drive', 'Reg', (95, 100))	('mutations', 'Var', (14, 23))	('Cysteinyl Leukotriene Receptor 2', 'Gene', '57105', (201, 233))	('Cysteinyl Leukotriene Receptor 2', 'Gene', (201, 233))	('GNA11', 'Gene', (40, 45))	('GNA11', 'Gene', '2767', (40, 45))	('Galpha', 'Gene', '8802', (65, 71))	('PLCB4', 'Gene', '5332', (184, 189))	('CYSLTR2', 'Gene', '57105', (235, 242))	('Galpha', 'Gene', (65, 71))	('GNAQ', 'Gene', (31, 35))	('CYSLTR2', 'Gene', (235, 242))	('oncogenesis', 'CPA', (101, 112))
19061	32992823	GNAQ/GNA11 mutations drive the constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, and therapies targeting downstream effectors of Galpha at the level of MEK, PKC, and AKT have been investigated.	('PKC', 'molecular_function', 'GO:0004697', ('187', '190'))	('mutations', 'Var', (11, 20))	('GNA11', 'Gene', (5, 10))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('GNA11', 'Gene', '2767', (5, 10))	('activation', 'PosReg', (44, 54))	('MAPK', 'molecular_function', 'GO:0004707', ('96', '100'))	('Galpha', 'Gene', (159, 165))	('Galpha', 'Gene', '8802', (159, 165))
19063	32992823	The combination of selumetinib with the AKT inhibitor MK2206 resulted in synergistic suppression of GNAQ mutant cell viability in vitro and in xenograft mouse models of UM.	('mutant', 'Var', (105, 111))	('selumetinib', 'Chemical', 'MESH:C517975', (19, 30))	('mouse', 'Species', '10090', (153, 158))	('GNAQ', 'Gene', (100, 104))	('suppression', 'NegReg', (85, 96))	('combination', 'Interaction', (4, 15))	('MK2206', 'Chemical', 'MESH:C548887', (54, 60))
19068	32992823	Currently active phase I/II trials in mUM, targeting molecules other than MEK, AKT, and PKC, are based on BVD-523 (ERK1/ERK2 inhibitor), BPX-701 (a genetically modified autologous T cell product incorporating an HLA-A2-restricted PRAME-directed TCR), and cabozantinib (multikinase inhibitor) versus temozolomide or dacarbazine.	('ERK1', 'Gene', (115, 119))	('PRAME', 'Gene', (230, 235))	('cabozantinib', 'Chemical', 'MESH:C558660', (255, 267))	('dacarbazine', 'Chemical', 'MESH:D003606', (315, 326))	('ERK2', 'Gene', (120, 124))	('BPX-701', 'Chemical', '-', (137, 144))	('TCR', 'Gene', (245, 248))	('ERK2', 'molecular_function', 'GO:0004707', ('120', '124'))	('temozolomide', 'Chemical', 'MESH:D000077204', (299, 311))	('TCR', 'cellular_component', 'GO:0042101', ('245', '248'))	('ERK1', 'molecular_function', 'GO:0004707', ('115', '119'))	('ERK2', 'Gene', '5594', (120, 124))	('TCR', 'biological_process', 'GO:0006283', ('245', '248'))	('ERK1', 'Gene', '5595', (115, 119))	('TCR', 'Gene', '6962', (245, 248))	('BPX-701', 'Var', (137, 144))	('PRAME', 'Gene', '23532', (230, 235))	('PKC', 'molecular_function', 'GO:0004697', ('88', '91'))
19082	32785074	Our panel can also be expanded to include new targetable and treatment resistance mutations to improve the tracking of treatment response and resistance in melanoma patients treated with systemic drug therapies.	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('mutations', 'Var', (82, 91))	('patients', 'Species', '9606', (165, 173))
19086	32785074	Melanoma ctDNA is often detected using single gene assays that monitor a driver mutation that has been previously identified in patient-matched cancer tissue.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('Melanoma', 'Disease', (0, 8))	('cancer', 'Disease', (144, 150))	('patient', 'Species', '9606', (128, 135))	('mutation', 'Var', (80, 88))
19087	32785074	Furthermore, with increased genomic coverage and sequencing error rates in the order of 0.1-1%, whole-exome NGS of ctDNA does not provide the limit of detection (LOD) required to accurately identify low frequency mutations (<1%), which may occur in pre-existing or emerging treatment resistant subclones.	('LOD', 'molecular_function', 'GO:0033736', ('162', '165'))	('age', 'Gene', (41, 44))	('mutations', 'Var', (213, 222))	('age', 'Gene', '5973', (41, 44))	('pre', 'molecular_function', 'GO:0003904', ('249', '252'))
19088	32785074	The use of customized gene mutation panels in NGS of ctDNA can produce significantly lower levels of mutation detection, and these panels typically monitor common melanoma driver mutations in BRAF, NRAS and KIT, along with mutations in tumor suppressor genes, such as TP53.	('KIT', 'Gene', '3815', (207, 210))	('TP53', 'Gene', '7157', (268, 272))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('236', '252'))	('NRAS', 'Gene', (198, 202))	('melanoma', 'Disease', (163, 171))	('KIT', 'Gene', (207, 210))	('TP53', 'Gene', (268, 272))	('BRAF', 'Gene', '673', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('NRAS', 'Gene', '4893', (198, 202))	('BRAF', 'Gene', (192, 196))	('KIT', 'molecular_function', 'GO:0005020', ('207', '210'))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('mutations', 'Var', (179, 188))	('tumor suppressor', 'biological_process', 'GO:0051726', ('236', '252'))	('tumor', 'Disease', (236, 241))
19089	32785074	A commercially-available targeted melanoma panel (UltraSEEK) for ctDNA, which covers 61 mutations in 13 genes with a LOD of 0.1%, has been developed for the study of melanoma disease progression and resistance to systemic treatments.	('melanoma panel', 'Disease', 'MESH:D008545', (34, 48))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma disease', 'Disease', (166, 182))	('mutations', 'Var', (88, 97))	('melanoma panel', 'Disease', (34, 48))	('LOD', 'molecular_function', 'GO:0033736', ('117', '120'))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma disease', 'Disease', 'MESH:D008545', (166, 182))
19103	32785074	Of the patients with stage IV disease, 5 patients had M1a, 7 had M1b, 16 had M1c and 10 had M1d disease (with concurrent extracranial metastases in 9/10 patients).	('patients', 'Species', '9606', (153, 161))	('M1b', 'Var', (65, 68))	('M1a', 'Var', (54, 57))	('stage IV disease', 'Disease', (21, 37))	('metastases', 'Disease', (134, 144))	('patients', 'Species', '9606', (41, 49))	('stage IV disease', 'Disease', 'MESH:D058625', (21, 37))	('metastases', 'Disease', 'MESH:D009362', (134, 144))	('patients', 'Species', '9606', (7, 15))
19112	32785074	As a result, no EF1AX or TERT promoter mutations were detected in our patient cohort.	('TERT', 'Gene', (25, 29))	('EF1AX', 'Var', (16, 21))	('patient', 'Species', '9606', (70, 77))	('TERT', 'Gene', '7015', (25, 29))
19114	32785074	The LOD in our panel was analyzed by spiking patient samples with NRAS A59T and Q61K mutations at the MAFs of 1.3%, 0.26% and 0.13% (Horizon standards).	('Q61K', 'Var', (80, 84))	('NRAS', 'Gene', (66, 70))	('NRAS', 'Gene', '4893', (66, 70))	('patient', 'Species', '9606', (45, 52))	('A59T', 'Mutation', 'rs730880965', (71, 75))	('LOD', 'molecular_function', 'GO:0033736', ('4', '7'))	('Q61K', 'Mutation', 'rs121913254', (80, 84))
19115	32785074	The melanoma panel consistently detected both NRAS mutations at 1.3% and 0.26% frequency but did not accurately detect the NRAS mutations at 0.13% MAF (Table S4).	('mutations', 'Var', (51, 60))	('NRAS', 'Gene', (46, 50))	('melanoma panel', 'Disease', 'MESH:D008545', (4, 18))	('NRAS', 'Gene', '4893', (46, 50))	('detected', 'Reg', (32, 40))	('NRAS', 'Gene', (123, 127))	('NRAS', 'Gene', '4893', (123, 127))	('melanoma panel', 'Disease', (4, 18))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))
19118	32785074	ctDNA melanoma mutation detectability was also stratified according to disease distribution and stage.	('mutation', 'Var', (15, 23))	('age', 'Gene', (98, 101))	('age', 'Gene', '5973', (98, 101))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
19120	32785074	For stage IV patients, detectability was 3/5 (60%) for M1a, 6/7 (86%) for M1b, 12/16 (75%) for M1c and 7/10 (70%) for M1d melanoma (Figure 4A).	('age', 'Gene', '5973', (6, 9))	('detectability', 'MPA', (23, 36))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('patients', 'Species', '9606', (13, 21))	('age', 'Gene', (6, 9))	('M1b', 'Var', (74, 77))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('M1a', 'Var', (55, 58))	('melanoma', 'Disease', (122, 130))	('M1c', 'Var', (95, 98))
19122	32785074	In particular, whereas only 12/19 (63%) stage IV patients had detectable mutations with input cfDNA <20 ng, this increased to 16/19 (84%) mutations detected with input cfDNA >=20 ng (maximum of 30 ng) (Figure 4B).	('age', 'Gene', '5973', (42, 45))	('mutations', 'Var', (73, 82))	('patients', 'Species', '9606', (49, 57))	('age', 'Gene', (42, 45))
19126	32785074	Both patients with M1c and M1d disease had very low volume disease: the M1c patient had 6-mm lung and 23-mm peritoneal metastases and the M1d patient had a brain metastasis and a subcentimeter solitary lung metastasis.	('very low volume disease', 'Disease', (43, 66))	('patient', 'Species', '9606', (5, 12))	('patients', 'Species', '9606', (5, 13))	('metastases', 'Disease', (119, 129))	('M1c', 'Var', (72, 75))	('brain metastasis', 'CPA', (156, 172))	('patient', 'Species', '9606', (142, 149))	('patient', 'Species', '9606', (76, 83))	('very low volume disease', 'Disease', 'MESH:D009800', (43, 66))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
19127	32785074	We identified BRAF mutations in 21/74 (28%) patients, NRAS mutations in 4/74 (5.4%) patients, NF1 mutations in 1/74 (1.4%) patients and GNAQ mutations in 1/74 (uveal melanoma) (1.4%) patients, as well as BRAF/NRAS (1/74; 1.4%) and GNAQ/NF1 (1/74; 1.4%) double mutations (Figure 4C).	('NF1', 'Gene', '4763', (94, 97))	('NF1', 'Gene', '4763', (236, 239))	('NRAS', 'Gene', '4893', (54, 58))	('NRAS', 'Gene', (209, 213))	('NF1', 'Gene', (94, 97))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('patients', 'Species', '9606', (44, 52))	('patients', 'Species', '9606', (84, 92))	('NF1', 'Gene', (236, 239))	('patients', 'Species', '9606', (123, 131))	('BRAF', 'Gene', '673', (14, 18))	('BRAF', 'Gene', (14, 18))	('BRAF', 'Gene', '673', (204, 208))	('BRAF', 'Gene', (204, 208))	('NRAS', 'Gene', (54, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (160, 174))	('GNAQ', 'Gene', '2776', (231, 235))	('uveal melanoma', 'Disease', (160, 174))	('mutations', 'Var', (59, 68))	('NRAS', 'Gene', '4893', (209, 213))	('GNAQ', 'Gene', '2776', (136, 140))	('patients', 'Species', '9606', (183, 191))	('GNAQ', 'Gene', (231, 235))	('GNAQ', 'Gene', (136, 140))	('mutations', 'Var', (19, 28))	('mutations', 'Var', (98, 107))	('uveal melanoma', 'Phenotype', 'HP:0007716', (160, 174))
19130	32785074	Only 4/20 patients had other ctDNA-associated mutations detected at a MAF of >0.2% (GRIN2A P1171L, RAC1 A27P, STK19 T80N and TP53 V173M).	('ctDNA-associated', 'Disease', (29, 45))	('T80N', 'Mutation', 'rs1057519999', (116, 120))	('STK19', 'Gene', (110, 115))	('TP53', 'Gene', '7157', (125, 129))	('GRIN2A', 'Gene', (84, 90))	('P1171L', 'Var', (91, 97))	('GRIN2A', 'Gene', '2903', (84, 90))	('TP53', 'Gene', (125, 129))	('RAC1', 'Gene', (99, 103))	('STK19', 'molecular_function', 'GO:0004686', ('110', '115'))	('V173M', 'Mutation', 'rs876660754', (130, 135))	('STK19', 'Gene', '8859', (110, 115))	('A27P', 'Mutation', 'rs730882000', (104, 108))	('A27P', 'Var', (104, 108))	('P1171L', 'Mutation', 'p.P1171L', (91, 97))	('patients', 'Species', '9606', (10, 18))
19132	32785074	In 18/36 patients, a melanoma driver mutation was detected in the tissue specimen and a matching ctDNA mutation was detected in 12 of these patients (66.7%) (Figure 5).	('patients', 'Species', '9606', (9, 17))	('mutation', 'Var', (37, 45))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('patients', 'Species', '9606', (140, 148))	('melanoma', 'Disease', (21, 29))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))
19133	32785074	In Patients 13 and 33, an additional rare BRAF driver mutation was identified in the ctDNA sample (Table S7).	('BRAF', 'Gene', (42, 46))	('mutation', 'Var', (54, 62))	('BRAF', 'Gene', '673', (42, 46))	('Patients', 'Species', '9606', (3, 11))
19134	32785074	In the 18 patients with no driver mutation detected in the melanoma tissue biopsy, six patients had a driver mutation identified in the ctDNA (Figure 5), including three patients with rare BRAF kinase domain mutations (BRAF G466A, BRAF G469A and BRAF T599dup) and one patient with a predominant NF1 R1241* nonsense mutation (MAF 27.65%) and a low frequency GNAQ R183Q mutation (MAF 0.71%) (Table S7).	('BRAF', 'Gene', (231, 235))	('BRAF', 'Gene', '673', (231, 235))	('patient', 'Species', '9606', (10, 17))	('NF1', 'Gene', (295, 298))	('G466A', 'Mutation', 'rs121913351', (224, 229))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('BRAF', 'Gene', '673', (246, 250))	('R1241*', 'Var', (299, 305))	('R1241*', 'SUBSTITUTION', 'None', (299, 305))	('BRAF', 'Gene', (246, 250))	('patient', 'Species', '9606', (87, 94))	('BRAF', 'Gene', (189, 193))	('BRAF', 'Gene', '673', (189, 193))	('patients', 'Species', '9606', (170, 178))	('BRAF', 'Gene', (219, 223))	('G469A', 'Mutation', 'rs121913355', (236, 241))	('patients', 'Species', '9606', (10, 18))	('BRAF', 'Gene', '673', (219, 223))	('patient', 'Species', '9606', (268, 275))	('GNAQ', 'Gene', '2776', (357, 361))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('GNAQ', 'Gene', (357, 361))	('T599dup', 'Mutation', 'c.599dupT', (251, 258))	('R183Q', 'Mutation', 'rs397514698', (362, 367))	('NF1', 'Gene', '4763', (295, 298))	('patients', 'Species', '9606', (87, 95))	('patient', 'Species', '9606', (170, 177))
19135	32785074	Cancer-associated mutations were also identified in the ctDNA of 9/36 patients (Table S7), and, although these were not validated in this study, it is worth noting that six of these nine patients (67%) had no driver mutation identified in the tissue biopsy.	('patients', 'Species', '9606', (187, 195))	('patients', 'Species', '9606', (70, 78))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (18, 27))
19136	32785074	We initially analyzed the performance of our custom melanoma panel by validating driver mutations identified in the ctDNA of 13 selected patients.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma panel', 'Disease', 'MESH:D008545', (52, 66))	('mutations', 'Var', (88, 97))	('patients', 'Species', '9606', (137, 145))	('melanoma panel', 'Disease', (52, 66))
19150	32785074	To the best of our knowledge, there is only one cutaneous melanoma specific panel for liquid biopsy on the market which includes only 61 variants across 16 genes.	('cutaneous melanoma', 'Disease', (48, 66))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (48, 66))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 66))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('variants', 'Var', (137, 145))
19155	32785074	Both DDX3X and EIF1AX mutations account for 10% of melanomas and they generally co-occur with NRAS mutations.	('NRAS', 'Gene', (94, 98))	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('DDX3X', 'Gene', (5, 10))	('melanomas', 'Disease', 'MESH:D008545', (51, 60))	('EIF1AX', 'Gene', '1964', (15, 21))	('EIF1AX', 'Gene', (15, 21))	('NRAS', 'Gene', '4893', (94, 98))	('mutations', 'Var', (22, 31))	('melanomas', 'Disease', (51, 60))	('DDX3X', 'Gene', '1654', (5, 10))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('co-occur', 'Reg', (80, 88))
19157	32785074	Based on ctDNA, just 3% of this cohort had NF1 mutations, which is significantly lower than the TCGA value of 10% for cutaneous melanoma.	('NF1', 'Gene', (43, 46))	('cutaneous melanoma', 'Disease', (118, 136))	('mutations', 'Var', (47, 56))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (118, 136))	('NF1', 'Gene', '4763', (43, 46))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (118, 136))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))
19158	32785074	Given NF1 exons span 8520 bp and sequencing amplicons are typically less than 100 bp, it would not be feasible to cover the complete NF1 gene, but the select inclusion of 10 additional amplicons would cover the majority of NF1 mutations identified in BRAF/NRAS wild-type melanoma patients and should increase our coverage to ~90%.	('NF1', 'Gene', '4763', (223, 226))	('age', 'Gene', (318, 321))	('patients', 'Species', '9606', (280, 288))	('NRAS', 'Gene', (256, 260))	('NF1', 'Gene', (133, 136))	('age', 'Gene', '5973', (318, 321))	('BRAF', 'Gene', (251, 255))	('BRAF', 'Gene', '673', (251, 255))	('melanoma', 'Disease', (271, 279))	('NF1', 'Gene', '4763', (133, 136))	('NRAS', 'Gene', '4893', (256, 260))	('NF1', 'Gene', (6, 9))	('melanoma', 'Disease', 'MESH:D008545', (271, 279))	('melanoma', 'Phenotype', 'HP:0002861', (271, 279))	('NF1', 'Gene', '4763', (6, 9))	('NF1', 'Gene', (223, 226))	('mutations', 'Var', (227, 236))
19166	32785074	We found that 28% (21/74) of our patient cohort had TP53 mutations.	('mutations', 'Var', (57, 66))	('patient', 'Species', '9606', (33, 40))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))
19167	32785074	Some of these p53 mutations have been shown to be a result of clonal hematopoiesis.	('hematopoiesis', 'Disease', (69, 82))	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', (14, 17))	('hematopoiesis', 'Disease', 'MESH:C536227', (69, 82))	('hematopoiesis', 'biological_process', 'GO:0030097', ('69', '82'))	('mutations', 'Var', (18, 27))
19174	32785074	Importantly, TERT promoter mutations are detectable by ddPCR and the assay sensitivity can be enhanced by incorporation of 7-deaza-dGTP.	('mutations', 'Var', (27, 36))	('TERT', 'Gene', (13, 17))	('TERT', 'Gene', '7015', (13, 17))	('7-deaza-dGTP', 'Chemical', '-', (123, 135))	('enhanced', 'PosReg', (94, 102))
19176	32785074	The MAF of these TERT promoter mutations were low (in the range 0.15-0.8%) compared to values of 2-20% previously reported for a cohort of stage IV melanoma patients.	('age', 'Gene', '5973', (141, 144))	('mutations', 'Var', (31, 40))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('TERT', 'Gene', (17, 21))	('TERT', 'Gene', '7015', (17, 21))	('patients', 'Species', '9606', (157, 165))	('age', 'Gene', (141, 144))
19177	32785074	Ideally, detection of TERT promoter mutations needs to be included in any future workflow to maximize detection of melanoma based on ctDNA.	('TERT', 'Gene', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('TERT', 'Gene', '7015', (22, 26))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('mutations', 'Var', (36, 45))
19179	32785074	This panel could include multiplex screening with primer/probes for detection of BRAF V600E/K/R, NRAS G12A/C/D/S/V, NRAS G13D/R/V, NRAS Q61H/K/L/R along with pooled primer/probes for TERT promoter mutations -124 C > T and -146 C > T. This concept of following BRAF, NRAS and TERT in the context of melanoma in a multiplex assay has been explored in a recent study.	('Q61H', 'SUBSTITUTION', 'None', (136, 140))	('NRAS', 'Gene', (131, 135))	('BRAF', 'Gene', '673', (81, 85))	('TERT', 'Gene', (275, 279))	('TERT', 'Gene', '7015', (275, 279))	('BRAF', 'Gene', (81, 85))	('melanoma', 'Disease', 'MESH:D008545', (298, 306))	('G13D', 'Var', (121, 125))	('-146 C > T', 'Mutation', 'rs1251469075', (222, 232))	('NRAS', 'Gene', (97, 101))	('V600E', 'Var', (86, 91))	('NRAS', 'Gene', '4893', (266, 270))	('NRAS', 'Gene', '4893', (116, 120))	('V600E', 'SUBSTITUTION', 'None', (86, 91))	('BRAF', 'Gene', '673', (260, 264))	('NRAS', 'Gene', '4893', (131, 135))	('melanoma', 'Phenotype', 'HP:0002861', (298, 306))	('TERT', 'Gene', (183, 187))	('BRAF', 'Gene', (260, 264))	('melanoma', 'Disease', (298, 306))	('TERT', 'Gene', '7015', (183, 187))	('Q61H', 'Var', (136, 140))	('G13D', 'SUBSTITUTION', 'None', (121, 125))	('NRAS', 'Gene', (266, 270))	('NRAS', 'Gene', '4893', (97, 101))	('G12A', 'Var', (102, 106))	('-124 C > T', 'Mutation', 'rs1242535815', (207, 217))	('NRAS', 'Gene', (116, 120))	('G12A', 'SUBSTITUTION', 'None', (102, 106))
19181	32785074	Analysis of NRAS and BRAF mutations in stage IV melanoma patients by single reaction ddPCR has shown an overall detection rate of 73%.	('melanoma', 'Disease', (48, 56))	('patients', 'Species', '9606', (57, 65))	('NRAS', 'Gene', (12, 16))	('age', 'Gene', (41, 44))	('BRAF', 'Gene', '673', (21, 25))	('mutations', 'Var', (26, 35))	('NRAS', 'Gene', '4893', (12, 16))	('BRAF', 'Gene', (21, 25))	('age', 'Gene', '5973', (41, 44))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
19183	32785074	Such a ddPCR panel, with lower cost, turnaround time of 1 day and requirement for less cfDNA (<10 ng) than the NGS assay (>20 ng), could be used as a first pass for detection of melanoma mutations using ctDNA.	('mutations', 'Var', (187, 196))	('melanoma', 'Disease', (178, 186))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))
19186	32785074	The Oncofocus panel (Agena Bioscience, San Diego, CA, USA) was used for detection of melanoma-associated BRAF, NRAS, KRAS and KIT variants in paired tissue samples.	('KRAS', 'Gene', (117, 121))	('variants', 'Var', (130, 138))	('NRAS', 'Gene', (111, 115))	('BRAF', 'Gene', '673', (105, 109))	('NRAS', 'Gene', '4893', (111, 115))	('BRAF', 'Gene', (105, 109))	('KRAS', 'Gene', '3845', (117, 121))	('KIT', 'molecular_function', 'GO:0005020', ('126', '129'))	('KIT', 'Gene', '3815', (126, 129))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('KIT', 'Gene', (126, 129))
19193	32785074	The panel covers nucleotide variants which give rise to melanoma-associated amino acid changes across 29 gene targets, as well as 6 melanoma-associated nucleotide variants in the promoter region of the TERT gene.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('melanoma', 'Disease', (56, 64))	('variants', 'Var', (28, 36))	('TERT', 'Gene', (202, 206))	('TERT', 'Gene', '7015', (202, 206))	('amino acid changes', 'MPA', (76, 94))
19196	32785074	The copy number of ctDNA per mL of plasma was determined using the QX200 droplet digital PCR (ddPCR) (Bio-Rad, Hercules, CA, USA) system to detect tumor-associated BRAF E586K, V600E/K, K601E, GNAQ R183C, Q209P or NRAS Q61K mutations, as previously described.	('V600E', 'SUBSTITUTION', 'None', (176, 181))	('Rad', 'Gene', '6236', (106, 109))	('NRAS', 'Gene', '4893', (213, 217))	('Rad', 'Gene', (106, 109))	('tumor', 'Disease', (147, 152))	('Q209P', 'Mutation', 'rs121913492', (204, 209))	('E586K', 'Var', (169, 174))	('Q61K', 'Mutation', 'rs121913254', (218, 222))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('K601E', 'Mutation', 'rs121913364', (185, 190))	('GNAQ', 'Gene', '2776', (192, 196))	('GNAQ', 'Gene', (192, 196))	('BRAF', 'Gene', '673', (164, 168))	('BRAF', 'Gene', (164, 168))	('NRAS', 'Gene', (213, 217))	('Q209P', 'Var', (204, 209))	('K601E', 'Var', (185, 190))	('R183C', 'Mutation', 'p.R183C', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('V600E', 'Var', (176, 181))	('E586K', 'Mutation', 'rs121913340', (169, 174))	('Rad', 'biological_process', 'GO:1990116', ('106', '109'))
19197	32785074	ddPCR mutation assays for BRAF E586K, K601E and GNAQ R183C were kindly provided by Elin Gray (Edith Cowan University) while the remainder were obtained from Bio-Rad (Hercules, CA, USA).	('K601E', 'Var', (38, 43))	('R183C', 'Mutation', 'p.R183C', (53, 58))	('BRAF', 'Gene', '673', (26, 30))	('GNAQ', 'Gene', '2776', (48, 52))	('Rad', 'biological_process', 'GO:1990116', ('161', '164'))	('BRAF', 'Gene', (26, 30))	('GNAQ', 'Gene', (48, 52))	('E586K', 'Mutation', 'rs121913340', (31, 36))	('K601E', 'Mutation', 'rs121913364', (38, 43))	('R183C', 'Var', (53, 58))	('Rad', 'Gene', '6236', (161, 164))	('E586K', 'Var', (31, 36))	('Rad', 'Gene', (161, 164))
19198	32785074	TERT promoter mutations -124 C > T and -146 C > T were identified using ddPCR expert design assays dHsaEXD20945488 (TERT C228T_88) and dHsaEXD85215261 (TERT C250T_88) (Bio-Rad, Hercules, CA, USA), according to the manufacturer's instructions.	('TERT', 'Gene', '7015', (152, 156))	('TERT', 'Gene', (116, 120))	('C250T', 'Mutation', 'c.250C>T', (157, 162))	('TERT', 'Gene', '7015', (116, 120))	('Rad', 'biological_process', 'GO:1990116', ('172', '175'))	('TERT', 'Gene', (0, 4))	('dHsaEXD20945488', 'Var', (99, 114))	('TERT', 'Gene', '7015', (0, 4))	('Rad', 'Gene', '6236', (172, 175))	('TERT', 'Gene', (152, 156))	('C228T', 'Mutation', 'c.228C>T', (121, 126))	('-146 C > T', 'Mutation', 'rs1251469075', (39, 49))	('Rad', 'Gene', (172, 175))	('-124 C > T', 'Mutation', 'rs1242535815', (24, 34))
19200	32785074	The DNA copy number/mL of plasma for mutant and wild-type circulating DNA species was determined with Quantasoft software version 1.7.4 (Bio-Rad, Hercules, CA, USA) using a manual threshold setting.	('Rad', 'biological_process', 'GO:1990116', ('141', '144'))	('Rad', 'Gene', (141, 144))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('mutant', 'Var', (37, 43))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('Rad', 'Gene', '6236', (141, 144))
19204	32785074	With refinement, our panel will prove particularly useful in detecting tumor heterogeneity, potentially new targetable mutations and tracking treatment response and resistance in melanoma patients treated with systemic drug therapies.	('detecting', 'Reg', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('patients', 'Species', '9606', (188, 196))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mutations', 'Var', (119, 128))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('tumor', 'Disease', (71, 76))	('melanoma', 'Disease', (179, 187))
19226	32363001	In contrast to cutaneous melanoma, UM has a lower mutational burden and lacks characteristic BRAF and NRAS mutations.	('BRAF', 'Gene', (93, 97))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('mutations', 'Var', (107, 116))	('BRAF', 'Gene', '673', (93, 97))	('cutaneous melanoma', 'Disease', (15, 33))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (15, 33))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (15, 33))	('NRAS', 'Gene', (102, 106))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('NRAS', 'Gene', '4893', (102, 106))	('mutational burden', 'MPA', (50, 67))
19227	32363001	Rather, most UM tumors contain GNAQ or GNA11 mutations, MAPK pathway activations, and cytogenetic abnormalities (monosomy 3 and trisomy 8q).	('mutations', 'Var', (45, 54))	('activations', 'PosReg', (69, 80))	('GNAQ', 'Gene', (31, 35))	('GNA11', 'Gene', (39, 44))	('MAPK pathway', 'Pathway', (56, 68))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('GNA11', 'Gene', '2767', (39, 44))	('GNAQ', 'Gene', '2776', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('MAPK', 'molecular_function', 'GO:0004707', ('56', '60'))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('trisomy 8q', 'Disease', (128, 138))	('tumors', 'Disease', (16, 22))	('UM', 'Phenotype', 'HP:0007716', (13, 15))
19228	32363001	Several genetic mutations and gene expression alterations have been associated with the molecular mechanisms responsible for the progression of UM.	('associated', 'Reg', (68, 78))	('expression', 'Species', '29278', (35, 45))	('alterations', 'Var', (46, 57))	('UM', 'Phenotype', 'HP:0007716', (144, 146))	('gene expression', 'biological_process', 'GO:0010467', ('30', '45'))
19229	32363001	It has also been shown that epigenetic modifications including microRNAs (miRNAs) are associated with the pathology and progression of UM.	('miR', 'Gene', (74, 77))	('miR', 'Gene', '220972', (74, 77))	('UM', 'Phenotype', 'HP:0007716', (135, 137))	('microRNAs', 'MPA', (63, 72))	('associated', 'Reg', (86, 96))	('epigenetic modifications', 'Var', (28, 52))
19265	32363001	The top canonical pathways associated with these genes include p53 signaling, regulation of epithelial-mesenchymal transition pathway, cell cycle G1/S checkpoint regulation, ILK signaling, and PTEN signaling (Table 4).	('regulation', 'biological_process', 'GO:0065007', ('78', '88'))	('signaling', 'biological_process', 'GO:0023052', ('198', '207'))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('PTEN', 'Gene', (193, 197))	('PTEN', 'Gene', '5728', (193, 197))	('signaling', 'biological_process', 'GO:0023052', ('178', '187'))	('cell cycle', 'biological_process', 'GO:0007049', ('135', '145'))	('ILK', 'Gene', (174, 177))	('ILK', 'Gene', '3611', (174, 177))	('G1/S checkpoint', 'biological_process', 'GO:0000075', ('146', '161'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('92', '125'))	('genes', 'Var', (49, 54))	('regulation', 'biological_process', 'GO:0065007', ('162', '172'))	('epithelial-mesenchymal transition pathway', 'Pathway', (92, 133))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))
19273	32363001	It has been established that aberrant expression of miRNAs leads to progression and metastasis of several cancers.	('expression', 'Species', '29278', (38, 48))	('leads to', 'Reg', (59, 67))	('progression', 'CPA', (68, 79))	('metastasis', 'CPA', (84, 94))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('aberrant expression', 'Var', (29, 48))	('miR', 'Gene', '220972', (52, 55))	('miR', 'Gene', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
19282	32363001	For miR-508-3p, a recent study showed that decreased expression was significantly associated with metastasis, while overexpression suppressed the epithelial-mesenchymal transition process, in patients with triple-negative breast cancer.	('breast cancer', 'Disease', (222, 235))	('associated', 'Reg', (82, 92))	('miR-508-3p', 'Var', (4, 14))	('miR-508-3p', 'Chemical', '-', (4, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('146', '179'))	('patients', 'Species', '9606', (192, 200))	('metastasis', 'CPA', (98, 108))	('expression', 'Species', '29278', (53, 63))	('epithelial-mesenchymal transition process', 'CPA', (146, 187))	('suppressed', 'NegReg', (131, 141))	('expression', 'MPA', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('decreased', 'NegReg', (43, 52))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))	('expression', 'Species', '29278', (120, 130))
19292	32363001	Overexpression of miR-125b-5p inhibited cell proliferation, migration, and invasion in esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (87, 121))	('expression', 'Species', '29278', (4, 14))	('invasion', 'CPA', (75, 83))	('inhibited', 'NegReg', (30, 39))	('miR-125b-5p', 'Var', (18, 29))	('esophageal squamous cell carcinoma', 'Disease', (87, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('migration', 'CPA', (60, 69))	('cell proliferation', 'biological_process', 'GO:0008283', ('40', '58'))	('cell proliferation', 'CPA', (40, 58))	('miR-125b-5p', 'Chemical', '-', (18, 29))
19338	32337074	Defective apoptosis, which contributes to sustained cell survival, is a major causative factor in the development and progression of cancer.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('apoptosis', 'CPA', (10, 19))	('cancer', 'Disease', (133, 139))	('apoptosis', 'biological_process', 'GO:0097194', ('10', '19'))	('Defective', 'Var', (0, 9))	('apoptosis', 'biological_process', 'GO:0006915', ('10', '19'))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
19342	32337074	Overexpression of the pro-survival BCL-2 family members is commonly associated with cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('associated', 'Reg', (68, 78))	('cancer', 'Disease', (84, 90))	('BCL-2', 'molecular_function', 'GO:0015283', ('35', '40'))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('pro-survival', 'biological_process', 'GO:0043066', ('22', '34'))	('Overexpression', 'Var', (0, 14))
19357	32337074	Accordingly, cell death was higher in OMM1 and OMM2.5 cells compared to Mel270 and 92.1 cells (Fig.	('cell death', 'CPA', (13, 23))	('Mel270', 'Chemical', '-', (72, 78))	('OMM2.5', 'Var', (47, 53))	('cell death', 'biological_process', 'GO:0008219', ('13', '23'))	('higher', 'PosReg', (28, 34))
19365	32337074	Additionally, ABT-263 induced a time-dependent decrease of the full-length PARP protein, and caspase 3 zymogen (Fig.	('ABT-263', 'Var', (14, 21))	('caspase 3', 'Gene', (93, 102))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('PARP', 'Gene', (75, 79))	('decrease', 'NegReg', (47, 55))	('caspase 3', 'Gene', '836', (93, 102))	('full-length', 'MPA', (63, 74))	('PARP', 'Gene', '142', (75, 79))	('ABT-263', 'Chemical', 'MESH:C528561', (14, 21))
19393	32337074	We also did not detect PERK and IRE1alpha phosphorylation (Thy980 and Ser724 respectively) in OMM1 and OMM2.5 cell lines treated with ABT-263 (data not shown).	('Ser', 'cellular_component', 'GO:0005790', ('70', '73'))	('IRE1alpha', 'Gene', (32, 41))	('Ser724', 'Chemical', '-', (70, 76))	('ABT-263', 'Chemical', 'MESH:C528561', (134, 141))	('PERK', 'Gene', '9451', (23, 27))	('Ser724', 'Var', (70, 76))	('Thy980', 'Chemical', '-', (59, 65))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('PERK', 'Gene', (23, 27))	('Thy980', 'Var', (59, 65))	('IRE1alpha', 'Gene', '2081', (32, 41))
19397	32337074	PERK and EIF2alpha were phosphorylated (Thy980 and Ser51, respectively) and ATF4 increased.	('PERK', 'Gene', (0, 4))	('Ser51', 'Chemical', '-', (51, 56))	('Thy980', 'Chemical', '-', (40, 46))	('PERK', 'Gene', '9451', (0, 4))	('Thy980', 'Var', (40, 46))	('ATF4', 'Gene', '468', (76, 80))	('EIF2alpha', 'Gene', '83939', (9, 18))	('EIF2', 'cellular_component', 'GO:0005850', ('9', '13'))	('Ser', 'cellular_component', 'GO:0005790', ('51', '54'))	('EIF2alpha', 'Gene', (9, 18))	('Ser51', 'Var', (51, 56))	('ATF4', 'Gene', (76, 80))
19402	32337074	Altogether, our data indicate that ABT-263 elicits activation of the ER stress pathway in Mel270 and 92.1 uveal melanoma cells, while there are signs of defective activation of this pathway in OMM1 and OMM2.5 cells.	('ER stress pathway', 'Pathway', (69, 86))	('Mel270', 'Chemical', '-', (90, 96))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('uveal melanoma', 'Disease', (106, 120))	('ABT-263', 'Chemical', 'MESH:C528561', (35, 42))	('activation', 'PosReg', (51, 61))	('ABT-263', 'Var', (35, 42))
19412	32337074	PERK inhibition also impaired EIF2alpha activation as revealed by the loss of EIF2alpha phosphorylation in both basal and ABT-263-treated 92.1 cells (Fig.	('phosphorylation', 'MPA', (88, 103))	('phosphorylation', 'biological_process', 'GO:0016310', ('88', '103'))	('PERK', 'Gene', (0, 4))	('EIF2', 'cellular_component', 'GO:0005850', ('78', '82'))	('loss', 'NegReg', (70, 74))	('inhibition', 'Var', (5, 15))	('PERK', 'Gene', '9451', (0, 4))	('EIF2alpha', 'Gene', '83939', (78, 87))	('impaired', 'NegReg', (21, 29))	('ABT-263', 'Chemical', 'MESH:C528561', (122, 129))	('EIF2', 'cellular_component', 'GO:0005850', ('30', '34'))	('EIF2alpha', 'Gene', '83939', (30, 39))	('EIF2alpha', 'Gene', (78, 87))	('activation', 'MPA', (40, 50))	('EIF2alpha', 'Gene', (30, 39))
19416	32337074	We also tested the effect of GSK2606414, a cell-permeable PERK inhibitor.	('tested', 'Reg', (8, 14))	('GSK', 'molecular_function', 'GO:0050321', ('29', '32'))	('PERK', 'Gene', (58, 62))	('PERK', 'Gene', '9451', (58, 62))	('GSK2606414', 'Chemical', 'MESH:C576403', (29, 39))	('GSK2606414', 'Var', (29, 39))
19418	32337074	Whereas GSK2606414 alone displayed no effect on cell viability, the effect of ABT-263 was improved when combined with GSK2606414 (Fig.	('GSK', 'molecular_function', 'GO:0050321', ('8', '11'))	('combined', 'Interaction', (104, 112))	('improved', 'PosReg', (90, 98))	('ABT-263', 'Chemical', 'MESH:C528561', (78, 85))	('ABT-263', 'Gene', (78, 85))	('effect', 'MPA', (68, 74))	('GSK2606414', 'Chemical', 'MESH:C576403', (8, 18))	('GSK', 'molecular_function', 'GO:0050321', ('118', '121'))	('GSK2606414', 'Chemical', 'MESH:C576403', (118, 128))	('GSK2606414', 'Var', (118, 128))
19425	32337074	In line with that, BCL-2 transgenic mice exclusively develop hematopoietic malignancies.	('malignancies', 'Disease', 'MESH:D009369', (75, 87))	('BCL-2', 'Gene', (19, 24))	('malignancies', 'Disease', (75, 87))	('develop', 'PosReg', (53, 60))	('transgenic mice', 'Species', '10090', (25, 40))	('BCL-2', 'molecular_function', 'GO:0015283', ('19', '24'))	('transgenic', 'Var', (25, 35))
19427	32337074	Previous studies showed that inhibition of BCL-2 alone by antisense oligonucleotides caused cell death of uveal melanoma cells and that reduction in BCL-2 through the use of miR-182 suppressed the in vitro and in vivo growth of uveal melanoma cells.	('antisense oligonucleotides', 'Var', (58, 84))	('BCL-2', 'Gene', (43, 48))	('oligonucleotides', 'Chemical', 'MESH:D009841', (68, 84))	('miR-182', 'Gene', (174, 181))	('uveal melanoma', 'Phenotype', 'HP:0007716', (228, 242))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('miR-182', 'Gene', '406958', (174, 181))	('uveal melanoma', 'Disease', (106, 120))	('inhibition', 'NegReg', (29, 39))	('suppressed', 'NegReg', (182, 192))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('BCL-2', 'MPA', (149, 154))	('reduction', 'NegReg', (136, 145))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('cell death', 'biological_process', 'GO:0008219', ('92', '102'))	('cell death', 'CPA', (92, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (228, 242))	('BCL-2', 'molecular_function', 'GO:0015283', ('149', '154'))	('uveal melanoma', 'Disease', (228, 242))	('BCL-2', 'molecular_function', 'GO:0015283', ('43', '48'))
19433	32337074	Noteworthy, in another study, monotherapy with S44563-2, another BCL-2/BCL-xL inhibitor, exhibited a limited effect on uveal melanoma cells; however, the killing efficacy of S44563-2 was improved when combined with fotemustine.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('BCL-xL', 'Gene', '598', (71, 77))	('improved', 'PosReg', (187, 195))	('BCL-2', 'molecular_function', 'GO:0015283', ('65', '70'))	('fotemustine', 'Chemical', 'MESH:C054368', (215, 226))	('uveal melanoma', 'Disease', 'MESH:C536494', (119, 133))	('uveal melanoma', 'Phenotype', 'HP:0007716', (119, 133))	('S44563-2', 'Var', (174, 182))	('BCL-xL', 'Gene', (71, 77))	('uveal melanoma', 'Disease', (119, 133))	('killing efficacy', 'CPA', (154, 170))
19435	32337074	Another explanation might be that the level of BCL-2 and BCL-xL expression varied in the cells selected in these two different studies and thereby influenced their response to ABT-263 and S44563-2.	('response to ABT-263', 'MPA', (164, 183))	('BCL-2', 'molecular_function', 'GO:0015283', ('47', '52'))	('S44563-2', 'Var', (188, 196))	('influenced', 'Reg', (147, 157))	('BCL-xL', 'Gene', '598', (57, 63))	('BCL-xL', 'Gene', (57, 63))	('ABT-263', 'Chemical', 'MESH:C528561', (176, 183))
19441	32337074	However, tunicamycin (a known ER stress inducer), enhanced CHOP levels (Supplementary Fig.	('enhanced CHOP', 'Phenotype', 'HP:0007906', (50, 63))	('tunicamycin', 'Chemical', 'MESH:D014415', (9, 20))	('CHOP', 'Gene', '1649', (59, 63))	('tunicamycin', 'Var', (9, 20))	('CHOP', 'Gene', (59, 63))	('enhanced', 'PosReg', (50, 58))
19451	32337074	Indeed, in contrast to IRE1alpha inhibition that did not change the effect of ABT-263, the combination of ABT-263 with PERK inhibition synergistically reduced the survival rate of primary uveal melanoma cells.	('IRE1alpha', 'Gene', (23, 32))	('IRE1alpha', 'Gene', '2081', (23, 32))	('reduced', 'NegReg', (151, 158))	('combination', 'Interaction', (91, 102))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('uveal melanoma', 'Disease', 'MESH:C536494', (188, 202))	('ABT-263', 'Chemical', 'MESH:C528561', (78, 85))	('survival rate', 'CPA', (163, 176))	('ABT-263', 'Chemical', 'MESH:C528561', (106, 113))	('uveal melanoma', 'Phenotype', 'HP:0007716', (188, 202))	('uveal melanoma', 'Disease', (188, 202))	('PERK', 'Gene', (119, 123))	('ABT-263', 'Var', (106, 113))	('PERK', 'Gene', '9451', (119, 123))
19464	32337074	Antibodies to BCL-2 (ms-123-P0) was from neomarker, to caspase 3 (#610323) was from BD, to BAX (#8429) was from sigma, to PARP (#9542), BCL-XL (#2762), CASPASE 9 (#9502), PUMA (#4976), CHOP (#2895), PERK (#5683), Phospho-PERK (#3179), IRE1alpha (#3294), BIP (#3177), were from Cell Signaling Technology Inc, to phospho-IRE1alpha (#NB100-2323) was from Novus, to MCL1 (#sc-819), to NOXA (#sc-56169), and HSP90 (#sc-13119) were from Santa Cruz biotechnology.	('BCL-XL', 'Gene', (136, 142))	('PERK', 'Gene', '9451', (199, 203))	('CASPASE 9', 'Gene', (152, 161))	('PERK', 'Gene', '9451', (221, 225))	('MCL1', 'Gene', '4170', (362, 366))	('CHOP', 'Gene', (185, 189))	('IRE1alpha', 'Gene', '2081', (235, 244))	('IRE1alpha', 'Gene', (319, 328))	('BCL-XL', 'Gene', '598', (136, 142))	('PARP', 'Gene', '142', (122, 126))	('HSP90', 'Gene', (403, 408))	('BIP', 'Gene', '3309', (254, 257))	('#NB100-2323', 'Var', (330, 341))	('NOXA', 'Gene', '5366', (381, 385))	('PUMA', 'Gene', '27113', (171, 175))	('PARP', 'Gene', (122, 126))	('caspase 3', 'Gene', (55, 64))	('caspase 3', 'Gene', '836', (55, 64))	('BAX', 'Gene', (91, 94))	('IRE1alpha', 'Gene', (235, 244))	('BAX', 'Gene', '581', (91, 94))	('PERK', 'Gene', (199, 203))	('HSP90', 'Gene', '3320', (403, 408))	('NOXA', 'Gene', (381, 385))	('Signaling', 'biological_process', 'GO:0023052', ('282', '291'))	('BIP', 'Gene', (254, 257))	('PERK', 'Gene', (221, 225))	('IRE1alpha', 'Gene', '2081', (319, 328))	('CHOP', 'Gene', '1649', (185, 189))	('MCL1', 'Gene', (362, 366))	('PUMA', 'Gene', (171, 175))	('CASPASE 9', 'Gene', '842', (152, 161))	('BCL-2', 'molecular_function', 'GO:0015283', ('14', '19'))
19483	32042336	In cutaneous melanoma (CM), genetic alterations have been implicated in drug resistance, yet the main cause of this resistance seems to be non-genetic in nature with a change in transcription programs within cell subpopulations.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('genetic alterations', 'Var', (28, 47))	('CM', 'Phenotype', 'HP:0012056', (23, 25))	('transcription programs', 'MPA', (178, 200))	('drug resistance', 'biological_process', 'GO:0042493', ('72', '87'))	('change', 'Reg', (168, 174))	('drug resistance', 'Phenotype', 'HP:0020174', (72, 87))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('transcription', 'biological_process', 'GO:0006351', ('178', '191'))	('CM', 'Disease', 'MESH:C562393', (23, 25))	('implicated', 'Reg', (58, 68))	('drug resistance', 'MPA', (72, 87))	('drug resistance', 'biological_process', 'GO:0009315', ('72', '87'))	('cutaneous melanoma', 'Disease', (3, 21))
19484	32042336	Because they are reversible in nature, epigenetic changes are a growing focus in cancer research aiming to prevent or revert the drug resistance with current therapies.	('epigenetic changes', 'Var', (39, 57))	('drug resistance', 'Phenotype', 'HP:0020174', (129, 144))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('drug resistance', 'biological_process', 'GO:0009315', ('129', '144'))	('drug resistance', 'biological_process', 'GO:0042493', ('129', '144'))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
19485	32042336	Here, we review the multiplicity of epigenetic alterations, mainly histone alterations and chromatin remodeling in both cutaneous and uveal melanomas, opening opportunities for further research in the field and providing clues to specifically control these modifications.	('histone', 'Protein', (67, 74))	('uveal melanomas', 'Disease', (134, 149))	('uveal melanomas', 'Phenotype', 'HP:0007716', (134, 149))	('chromatin', 'cellular_component', 'GO:0000785', ('91', '100'))	('opening opportunities', 'Disease', 'MESH:D005597', (151, 172))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('91', '111'))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('alterations', 'Var', (75, 86))	('uveal melanomas', 'Disease', 'MESH:C536494', (134, 149))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('uveal melanoma', 'Phenotype', 'HP:0007716', (134, 148))	('opening opportunities', 'Disease', (151, 172))
19493	32042336	Epigenetic reprogramming rewires metabolic and signaling networks, thereby driving the emergence of tumor cell subpopulations with distinct behavior and altered antigenic landscape.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('rewires', 'Reg', (25, 32))	('tumor', 'Disease', (100, 105))	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))	('Epigenetic reprogramming', 'Var', (0, 24))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
19498	32042336	We also discuss epigenetic changes, which are now receiving attention in metastatic uveal melanoma (UM), for which therapeutic intervention remains extremely limited.	('UM', 'Phenotype', 'HP:0007716', (100, 102))	('epigenetic changes', 'Var', (16, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma', 'Disease', (84, 98))	('UM', 'Disease', 'MESH:C536494', (100, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
19499	32042336	Additional important epigenetic events such as DNA methylation and non-coding RNAs are beyond the aim of this review.	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('DNA methylation', 'biological_process', 'GO:0006306', ('47', '62'))	('non-coding RNAs', 'Var', (67, 82))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('DNA methylation', 'Var', (47, 62))
19503	32042336	Changes include post-translational modifications (affecting histones N-terminal tails, such as acetylation (ac), methylation (me), ubiquitylation, phosphorylation, sumoylation or glycosylation), ATP-dependent chromatin remodeling, and the incorporation of specialized histone variants into chromatin.	('acetylation', 'MPA', (95, 106))	('histones', 'Protein', (60, 68))	('post-translational modifications', 'MPA', (16, 48))	('acetyl', 'Chemical', 'MESH:C011632', (95, 101))	('N', 'Chemical', 'MESH:D009584', (69, 70))	('sumoylation', 'biological_process', 'GO:0016925', ('164', '175'))	('ATP-dependent chromatin', 'CPA', (195, 218))	('ATP', 'Chemical', 'MESH:D000255', (195, 198))	('glycosylation', 'biological_process', 'GO:0070085', ('179', '192'))	('chromatin', 'cellular_component', 'GO:0000785', ('209', '218'))	('methylation', 'MPA', (113, 124))	('chromatin', 'cellular_component', 'GO:0000785', ('290', '299'))	('histone', 'Protein', (268, 275))	('sumoylation', 'MPA', (164, 175))	('variants', 'Var', (276, 284))	('ATP-dependent chromatin remodeling', 'biological_process', 'GO:0043044', ('195', '229'))	('incorporation', 'Reg', (239, 252))	('methylation', 'biological_process', 'GO:0032259', ('113', '124'))	('phosphorylation', 'MPA', (147, 162))	('glycosylation', 'MPA', (179, 192))	('ubiquitylation', 'MPA', (131, 145))	('phosphorylation', 'biological_process', 'GO:0016310', ('147', '162'))
19506	32042336	The balance of these histone modifications orchestrates the above mentioned states by modifying the charges of the nucleosomal structure by respectively decreasing or increasing the histone-DNA interactions and therefore modulation of transcriptional activation and repression.	('histone-DNA interactions', 'MPA', (182, 206))	('N', 'Chemical', 'MESH:D009584', (191, 192))	('modulation', 'Reg', (221, 231))	('modifying', 'Reg', (86, 95))	('increasing', 'PosReg', (167, 177))	('charges of the nucleosomal structure', 'MPA', (100, 136))	('modifications', 'Var', (29, 42))	('transcriptional activation', 'MPA', (235, 261))	('repression', 'MPA', (266, 276))	('DNA', 'cellular_component', 'GO:0005574', ('190', '193'))
19508	32042336	For example, H3K4me1 was the first histone modification connected with distal regulatory regions, called enhancers, whereas H3K4me3 is enriched at active promoters.	('H3K4me3', 'Chemical', 'MESH:C024755', (124, 131))	('H3K4me1', 'Chemical', 'MESH:C024755', (13, 20))	('histone modification', 'biological_process', 'GO:0016570', ('35', '55'))	('H3K4me3', 'Var', (124, 131))	('H3K4me1', 'Var', (13, 20))
19509	32042336	In addition to its status, the methylation site on the histone tail is also critical for diverse functions; H3K79me2 or H3K36me3 are mainly found where active transcription takes place whereas H3K9me3 or H3K27me3 are linked to transcriptional repression.	('H3K36me3', 'Var', (120, 128))	('H3K9me3', 'Chemical', 'MESH:C033990', (193, 200))	('transcription', 'biological_process', 'GO:0006351', ('159', '172'))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('active', 'MPA', (152, 158))	('H3K79me2', 'Chemical', 'MESH:C024755', (108, 116))	('H3K79me2', 'Var', (108, 116))
19514	32042336	Histone variants can have temporal and tissue-specific expression and affect a variety of DNA-templated processes.	('affect', 'Reg', (70, 76))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('Histone', 'Protein', (0, 7))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('DNA-templated processes', 'CPA', (90, 113))	('variants', 'Var', (8, 16))
19515	32042336	Strikingly, it has become evident in the last decade that the epigenetic landscape contains a unique ability to regulate key cellular and developmental processes, and that its deregulation may contribute to melanoma initiation, progression and drug resistance that will be discussed hereafter.	('epigenetic', 'Var', (62, 72))	('drug resistance', 'biological_process', 'GO:0009315', ('244', '259'))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('contribute', 'Reg', (193, 203))	('drug resistance', 'CPA', (244, 259))	('melanoma initiation', 'Disease', 'MESH:D008545', (207, 226))	('regulate', 'Reg', (112, 120))	('melanoma initiation', 'Disease', (207, 226))	('drug resistance', 'biological_process', 'GO:0042493', ('244', '259'))	('drug resistance', 'Phenotype', 'HP:0020174', (244, 259))	('deregulation', 'PosReg', (176, 188))	('progression', 'CPA', (228, 239))
19516	32042336	Despite the unquestionable importance of oncogene activation and/or tumor suppressor inactivation in melanoma tumor burden, a growing body of evidence suggests that modifications in the epigenetic landscape drives the alteration of transcriptional programs that are tightly associated with the development of melanoma pathogenesis.	('tumor', 'Disease', (68, 73))	('pathogenesis', 'biological_process', 'GO:0009405', ('318', '330'))	('transcriptional programs', 'MPA', (232, 256))	('melanoma tumor', 'Disease', (101, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('melanoma tumor', 'Disease', 'MESH:D008545', (101, 115))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('tumor suppressor', 'biological_process', 'GO:0051726', ('68', '84'))	('alteration', 'Reg', (218, 228))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('68', '84'))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('melanoma pathogenesis', 'Disease', 'MESH:D008545', (309, 330))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('modifications', 'Var', (165, 178))	('melanoma', 'Phenotype', 'HP:0002861', (309, 317))	('melanoma pathogenesis', 'Disease', (309, 330))
19517	32042336	Epigenetic regulations in melanoma, especially through these histone modifications, are gaining more and more attention.	('Epigenetic', 'Var', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (26, 34))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))	('histone modifications', 'Var', (61, 82))
19518	32042336	To begin with, insight into the importance of histone modifications in melanoma development emerged due to the fact that nevi, which are benign melanocytic lesions, mostly carry the oncogenic BRAFV600E mutated form but rarely become malignant melanoma.	('BRAFV600E', 'Mutation', 'rs113488022', (192, 201))	('malignant melanoma', 'Disease', 'MESH:D008545', (233, 251))	('nevi', 'Phenotype', 'HP:0003764', (121, 125))	('melanoma', 'Phenotype', 'HP:0002861', (243, 251))	('malignant melanoma', 'Disease', (233, 251))	('melanoma', 'Disease', (243, 251))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('BRAFV600E mutated', 'Var', (192, 209))	('melanoma', 'Disease', 'MESH:D008545', (243, 251))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('benign melanocytic lesions', 'Phenotype', 'HP:0000995', (137, 163))	('nevi', 'Disease', (121, 125))	('malignant melanoma', 'Phenotype', 'HP:0002861', (233, 251))
19520	32042336	Patton et al., developed the first animal model of a BRAFV600E driven melanoma using a transgenic zebrafish model expressing the human BRAFV600E under the control of the mitfa promoter.	('melanoma', 'Disease', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('BRAFV600E', 'Var', (135, 144))	('BRAFV600E', 'Mutation', 'rs113488022', (135, 144))	('BRAFV600E', 'Var', (53, 62))	('BRAFV600E', 'Mutation', 'rs113488022', (53, 62))	('human', 'Species', '9606', (129, 134))	('zebrafish', 'Species', '7955', (98, 107))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
19525	32042336	Relevant in the scope of this review, they found H3K27ac super-enhancer marks (enhancer cluster regions) at the sox10 locus, which plays a key role in neural crest formation and melanomagenesis, suggesting an epigenetic mechanism to increase SOX10 expression leading to the reemergence of the neural crest progenitor state to initiate melanoma.	('increase', 'PosReg', (233, 241))	('SOX10', 'Gene', (242, 247))	('SOX10', 'Gene', '6663', (242, 247))	('sox10', 'Gene', '6663', (112, 117))	('neural crest formation', 'biological_process', 'GO:0014029', ('151', '173'))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('expression', 'MPA', (248, 258))	('melanoma', 'Disease', (178, 186))	('melanoma', 'Disease', 'MESH:D008545', (335, 343))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('epigenetic', 'Var', (209, 219))	('melanoma', 'Phenotype', 'HP:0002861', (335, 343))	('melanoma', 'Disease', (335, 343))	('sox10', 'Gene', (112, 117))
19533	32042336	Of note, the most proximal genes to these enhancers were KMT2D target genes suggesting that KMT2D deregulates enhancer activity to promote tumorigenesis.	('enhancer', 'Protein', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('KMT2D', 'Gene', '8085', (92, 97))	('KMT2D', 'Gene', (57, 62))	('KMT2D', 'Gene', '8085', (57, 62))	('KMT2D', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('deregulates', 'Var', (98, 109))	('promote', 'PosReg', (131, 138))
19536	32042336	Another "chromatin writers" implicated in melanoma is the SET domain bifurcated 1 (SETDB1), a member of the SUV39 family of histone lysine methyltransferases, catalyzing methylation of lysine 9 on the histone 3 which leads to epigenetically mediated gene expression silencing.	('melanoma', 'Disease', (42, 50))	('chromatin', 'cellular_component', 'GO:0000785', ('8', '17'))	('lysine', 'Chemical', 'MESH:C114808', (132, 138))	('epigenetically mediated gene expression', 'MPA', (226, 265))	('SETDB1', 'Gene', (83, 89))	('SET domain bifurcated 1', 'Gene', '9869', (58, 81))	('SET domain bifurcated 1', 'Gene', (58, 81))	('lysine', 'Chemical', 'MESH:C114808', (185, 191))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('methylation', 'Var', (170, 181))
19540	32042336	Recently, the study from Orouji et al., unraveled a SETDB1-mediated epigenetic mechanism in melanoma progression.	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('epigenetic', 'Var', (68, 78))	('SETDB1-mediated', 'Gene', (52, 67))
19543	32042336	Indeed, they identified enrichment for H3K4me1 upstream of the THBS1 gene which was reversely influenced by SETDB1 expression suggesting that SETDB1 may act not only on regulating H3K9me3 distribution but also on additional epigenetic marks to impact gene activation or repression.	('H3K9me3 distribution', 'MPA', (180, 200))	('THBS1', 'Gene', (63, 68))	('H3K9me3', 'Chemical', 'MESH:C033990', (180, 187))	('activation', 'PosReg', (256, 266))	('H3K4me1', 'Var', (39, 46))	('impact', 'PosReg', (244, 250))	('repression', 'MPA', (270, 280))	('H3K4me1', 'Chemical', 'MESH:C024755', (39, 46))
19549	32042336	Its conditional ablation inhibits tumor growth and metastases in a NRASQ61K melanoma mouse model.	('melanoma', 'Disease', (76, 84))	('mouse', 'Species', '10090', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('inhibits', 'NegReg', (25, 33))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('metastases', 'Disease', 'MESH:D009362', (51, 61))	('NRAS', 'Gene', (67, 71))	('ablation', 'Var', (16, 24))	('NRAS', 'Gene', '4893', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('metastases', 'Disease', (51, 61))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
19550	32042336	Conversely, the most common human EZH2Y646N gain of function somatic mutation (Y641F in mouse) through H3K27me3 accumulation and gene repression, favors melanoma progression.	('accumulation', 'PosReg', (112, 124))	('gain of function', 'PosReg', (44, 60))	('human', 'Species', '9606', (28, 33))	('favors', 'PosReg', (146, 152))	('Y641F', 'Var', (79, 84))	('melanoma', 'Disease', (153, 161))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('H3K27me3', 'Protein', (103, 111))	('N', 'Chemical', 'MESH:D009584', (42, 43))	('mouse', 'Species', '10090', (88, 93))	('Y641F', 'Mutation', 'rs267601394', (79, 84))	('EZH2Y646N', 'Var', (34, 43))	('gene', 'CPA', (129, 133))
19551	32042336	EZH2 has been shown to exert its effect through stimulation of the noncanonical NF-kB pathway leading to senescence bypass and epigenetic silencing of primary cilium genes that results in activation of the pro-tumorigenic WNT/beta-catenin signaling.	('primary cilium genes', 'Gene', (151, 171))	('epigenetic silencing', 'Var', (127, 147))	('beta-catenin', 'Gene', '1499', (226, 238))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('primary cilium', 'cellular_component', 'GO:0005929', ('151', '165'))	('EZH2', 'Gene', (0, 4))	('tumor', 'Disease', (210, 215))	('beta-catenin', 'Gene', (226, 238))	('stimulation', 'PosReg', (48, 59))	('N', 'Chemical', 'MESH:D009584', (80, 81))	('senescence', 'biological_process', 'GO:0010149', ('105', '115'))	('N', 'Chemical', 'MESH:D009584', (223, 224))	('signaling', 'biological_process', 'GO:0023052', ('239', '248'))	('activation', 'PosReg', (188, 198))	('primary cilium', 'cellular_component', 'GO:0097731', ('151', '165'))	('noncanonical NF-kB pathway', 'Pathway', (67, 93))	('senescence bypass', 'MPA', (105, 122))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
19552	32042336	A specific cooperation between Ezh2Y641F and B-RafV600E but not N-RasQ61R in inducing melanoma in mice was also reported.	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('B-RafV600E', 'Var', (45, 55))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('Ezh2Y641F', 'Var', (31, 40))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('mice', 'Species', '10090', (98, 102))
19558	32042336	This regulation mediated by c-Myc is essential for BRAFV600E-induced H3K27me3 deposition and gene silencing in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('gene silencing', 'biological_process', 'GO:0016458', ('93', '107'))	('c-Myc', 'Gene', (28, 33))	('BRAFV600E', 'Mutation', 'rs113488022', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('H3K27me3', 'Protein', (69, 77))	('regulation', 'biological_process', 'GO:0065007', ('5', '15'))	('c-Myc', 'Gene', '4609', (28, 33))	('BRAFV600E-induced', 'Var', (51, 68))	('gene silencing', 'Var', (93, 107))
19565	32042336	The same group has also shown that I-BET151 inhibits melanoma growth in vivo and induces apoptosis which is caspase-dependent and associated with G1 cell cycle arrest in melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (149, 166))	('melanoma', 'Disease', (170, 178))	('I-BET151', 'Var', (35, 43))	('apoptosis', 'CPA', (89, 98))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('melanoma', 'Disease', (53, 61))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('arrest', 'Disease', 'MESH:D006323', (160, 166))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('arrest', 'Disease', (160, 166))	('inhibits', 'NegReg', (44, 52))	('apoptosis', 'biological_process', 'GO:0097194', ('89', '98'))	('apoptosis', 'biological_process', 'GO:0006915', ('89', '98'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('149', '166'))	('induces', 'Reg', (81, 88))
19566	32042336	Interestingly, by using the BrDi MS436 or MS417, another BrDi previously reported to have higher binding affinity and specificity for BET family members, similar observations (cytostatic effect along with G1 arrest) were reported.	('binding', 'molecular_function', 'GO:0005488', ('97', '104'))	('MS436', 'Var', (33, 38))	('arrest', 'Disease', 'MESH:D006323', (208, 214))	('BrDi', 'Chemical', 'MESH:C068746', (28, 32))	('arrest', 'Disease', (208, 214))	('binding', 'Interaction', (97, 104))	('BrDi', 'Chemical', 'MESH:C068746', (57, 61))	('MS417', 'Var', (42, 47))
19576	32042336	Underlying the clinical aspect of these studies, the co-targeting of BET and MEK has been proposed in NRAS mutant melanoma cell lines or for melanomas with no other therapeutic options to offset resistance to targeted and/or immunotherapies.	('melanomas', 'Disease', 'MESH:D008545', (141, 150))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('mutant', 'Var', (107, 113))	('melanomas', 'Phenotype', 'HP:0002861', (141, 150))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('NRAS', 'Gene', (102, 106))	('melanomas', 'Disease', (141, 150))	('MEK', 'Gene', (77, 80))	('NRAS', 'Gene', '4893', (102, 106))	('MEK', 'Gene', '5609', (77, 80))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
19581	32042336	Studies of epigenomic alterations using non-tumorigenic melanocytes from nevi and tumorigenic melanocytes from melanomas revealed a loss of histone acetylation and H3K4me2/3 on regulatory regions proximal to specific cancer-regulatory genes involved in important signaling pathway-driving melanoma.	('H3K4me2/3', 'Protein', (164, 173))	('loss', 'NegReg', (132, 136))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (44, 49))	('melanoma', 'Disease', 'MESH:D008545', (289, 297))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('histone acetylation', 'biological_process', 'GO:0016573', ('140', '159'))	('signaling pathway', 'biological_process', 'GO:0007165', ('263', '280'))	('H3K4me2', 'Chemical', 'MESH:C024755', (164, 171))	('melanomas', 'Disease', 'MESH:D008545', (111, 120))	('histone', 'Protein', (140, 147))	('acetyl', 'Chemical', 'MESH:C011632', (148, 154))	('melanomas', 'Disease', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('nevi', 'Phenotype', 'HP:0003764', (73, 77))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (289, 297))	('melanoma', 'Disease', (289, 297))	('cancer', 'Disease', (217, 223))	('alterations', 'Var', (22, 33))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
19597	32042336	Wilmott et al., have shown that increased percentage of nuclear HDAC3 and cytoplasmic HDAC8 is associated with better prognosis from the time of diagnosis of primary melanoma.	('HDAC8', 'Gene', (86, 91))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('HDAC3', 'Gene', (64, 69))	('HDAC3', 'Gene', '8841', (64, 69))	('cytoplasmic', 'Var', (74, 85))	('better', 'PosReg', (111, 117))	('HDAC8', 'Gene', '55869', (86, 91))	('primary melanoma', 'Disease', (158, 174))	('primary melanoma', 'Disease', 'MESH:D008545', (158, 174))
19615	32042336	Of note, deregulation of histone demethylases resulting in aberrant histone methylation patterns have been linked to melanoma pathogenesis (Figure 3).	('linked', 'Reg', (107, 113))	('deregulation', 'Var', (9, 21))	('histone', 'Protein', (25, 32))	('histone methylation', 'biological_process', 'GO:0016571', ('68', '87'))	('pathogenesis', 'biological_process', 'GO:0009405', ('126', '138'))	('melanoma pathogenesis', 'Disease', 'MESH:D008545', (117, 138))	('aberrant histone methylation patterns', 'MPA', (59, 96))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma pathogenesis', 'Disease', (117, 138))
19617	32042336	The slow-cycling JARID1B-positive subpopulation shows increased in vitro self-renewal and knockdown of JARID1B caused exhaustion of melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('knockdown', 'Var', (90, 99))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('JARID1B', 'Gene', '10765', (17, 24))	('JARID1B', 'Gene', (17, 24))	('increased', 'PosReg', (54, 63))	('JARID1B', 'Gene', '10765', (103, 110))	('JARID1B', 'Gene', (103, 110))
19622	32042336	Moreover, it has been shown that two different types of histone H3 lysine 9 demethylases, Lysine-Specific Histone Demethylase 1A (LSD1 i.e KDM1A) and Jumonji Domain-Containing Protein 2D (JMJD2C i.e KDM4C), promote the bypass of oncogenic HRasG12V- or BrafV600E-induced senescence by preventing H3K9 Trimethylation at E2F target gene promoters, thereby favoring melanomagenesis.	('melanoma', 'Disease', 'MESH:D008545', (362, 370))	('preventing', 'NegReg', (284, 294))	('promote', 'PosReg', (207, 214))	('BrafV600E', 'Mutation', 'rs113488022', (252, 261))	('Lysine-Specific Histone Demethylase 1A', 'Gene', '23028', (90, 128))	('Jumonji Domain-Containing Protein 2D', 'Gene', '55693', (150, 186))	('melanoma', 'Phenotype', 'HP:0002861', (362, 370))	('melanoma', 'Disease', (362, 370))	('KDM1A', 'Gene', (139, 144))	('HRasG12V-', 'Var', (239, 248))	('Jumonji Domain-Containing Protein 2D', 'Gene', (150, 186))	('favoring', 'PosReg', (353, 361))	('BrafV600E-induced', 'Var', (252, 269))	('KDM1A', 'Gene', '23028', (139, 144))	('senescence', 'biological_process', 'GO:0010149', ('270', '280'))	('H3K9', 'Protein', (295, 299))	('lysine', 'Chemical', 'MESH:C114808', (67, 73))	('KDM4C', 'Gene', (199, 204))	('KDM4C', 'Gene', '23081', (199, 204))	('Trimethylation', 'MPA', (300, 314))	('Lysine-Specific Histone Demethylase 1A', 'Gene', (90, 128))
19623	32042336	Inhibition of these H3K9 demethylases restored senescence and growth arrest.	('growth arrest', 'Phenotype', 'HP:0001510', (62, 75))	('senescence', 'CPA', (47, 57))	('restored', 'PosReg', (38, 46))	('H3K9', 'Protein', (20, 24))	('growth arrest', 'Disease', 'MESH:D006323', (62, 75))	('Inhibition', 'Var', (0, 10))	('growth arrest', 'Disease', (62, 75))	('senescence', 'biological_process', 'GO:0010149', ('47', '57'))
19625	32042336	However, the regulation of methylation is complex since histone hypermethylation induced by low glutamine in tumor core regions or in patient-derived BRAFV600E melanoma cells resulted in cancer cell de-differentiation or resistance to targeted therapy which will be discussed later.	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('low', 'Var', (92, 95))	('low glutamine', 'Phenotype', 'HP:0500147', (92, 105))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('regulation', 'biological_process', 'GO:0065007', ('13', '23'))	('BRAFV600E', 'Mutation', 'rs113488022', (150, 159))	('patient', 'Species', '9606', (134, 141))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('methylation', 'biological_process', 'GO:0032259', ('27', '38'))	('histone', 'MPA', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('hypermethylation', 'PosReg', (64, 80))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('resistance', 'CPA', (221, 231))	('cancer', 'Disease', (187, 193))	('resulted in', 'Reg', (175, 186))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('core', 'cellular_component', 'GO:0019013', ('115', '119'))	('glutamine', 'Chemical', 'MESH:C578860', (96, 105))	('glutamine', 'Protein', (96, 105))	('tumor', 'Disease', (109, 114))
19626	32042336	Importantly, knockdown of the H3K27-specific demethylase KDM6B (i.e jumonji domain-containing 3, JMJD3) reproduced the low-glutamine effects in vitro and in vivo, whereas EZH2 knockdown (described in the "writers") attenuates them.	('low-glutamine effects', 'MPA', (119, 140))	('KDM6B', 'Gene', (57, 62))	('JMJD3', 'Gene', '23135', (97, 102))	('KDM6B', 'Gene', '23135', (57, 62))	('glutamine', 'Chemical', 'MESH:C578860', (123, 132))	('knockdown', 'Var', (13, 22))	('JMJD3', 'Gene', (97, 102))
19630	32042336	Importantly, SWI/SNF member's alterations have been linked to melanoma.	('melanoma', 'Disease', (62, 70))	('linked', 'Reg', (52, 58))	('alterations', 'Var', (30, 41))	('N', 'Chemical', 'MESH:D009584', (18, 19))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
19631	32042336	Especially, loss-of-function mutation in components of this complex such as ARID2, ARID1A, ARID1B or SMARCA4 are found in 13% of melanomas, suggesting a tumor suppressor role and highlighting the importance of chromatin remodeling in melanomagenesis.	('mutation', 'Var', (29, 37))	('ARID2', 'Gene', (76, 81))	('melanomas', 'Disease', 'MESH:D008545', (129, 138))	('ARID1A', 'Gene', (83, 89))	('SMARCA4', 'Gene', '6597', (101, 108))	('melanomas', 'Disease', (129, 138))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))	('ARID1A', 'Gene', '8289', (83, 89))	('tumor', 'Disease', (153, 158))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('melanomas', 'Phenotype', 'HP:0002861', (129, 138))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('153', '169'))	('SMARCA4', 'Gene', (101, 108))	('ARID1B', 'Gene', (91, 97))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('melanoma', 'Disease', (234, 242))	('ARID1B', 'Gene', '57492', (91, 97))	('ARID2', 'Gene', '196528', (76, 81))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('210', '230'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('153', '169'))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('loss-of-function', 'NegReg', (12, 28))	('chromatin', 'cellular_component', 'GO:0000785', ('210', '219'))
19636	32042336	In line with this study, using a mouse melanoma model conditionally expressing BRAFV600E along with Pten inactivation that rapidly develop melanoma, it has been shown that somatic inactivation of Brg1 and Bptf (the defining subunit of the NURF complex) delay tumor formation and deregulate a substantial and common gene expression programs critical for normal tumor cell growth.	('BRAFV600E', 'Mutation', 'rs113488022', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('deregulate', 'Reg', (279, 289))	('inactivation', 'Var', (180, 192))	('Brg1', 'Gene', '20586', (196, 200))	('tumor', 'Disease', (259, 264))	('tumor', 'Disease', (360, 365))	('Bptf', 'Gene', (205, 209))	('Bptf', 'Gene', '207165', (205, 209))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('NURF complex', 'cellular_component', 'GO:0016589', ('239', '251'))	('cell growth', 'biological_process', 'GO:0016049', ('366', '377'))	('tumor', 'Disease', 'MESH:D009369', (360, 365))	('BRAFV600E', 'Var', (79, 88))	('delay tumor', 'Disease', (253, 264))	('Brg1', 'Gene', (196, 200))	('delay tumor', 'Disease', 'MESH:D009369', (253, 264))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('N', 'Chemical', 'MESH:D009584', (239, 240))	('gene expression', 'biological_process', 'GO:0010467', ('315', '330'))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('common gene expression', 'MPA', (308, 330))	('Pten', 'Gene', (100, 104))	('mouse', 'Species', '10090', (33, 38))	('Pten', 'Gene', '19211', (100, 104))	('formation', 'biological_process', 'GO:0009058', ('265', '274'))
19643	32042336	We will discuss here few of the first discoveries including variants of H2A and H3 in melanoma pathogenesis.	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma pathogenesis', 'Disease', (86, 107))	('H2A', 'Gene', '8337', (72, 75))	('pathogenesis', 'biological_process', 'GO:0009405', ('95', '107'))	('H2A', 'Gene', (72, 75))	('variants', 'Var', (60, 68))	('melanoma pathogenesis', 'Disease', 'MESH:D008545', (86, 107))
19647	32042336	Overexpression of H3.3, a variant of H3, represses E2F target genes and triggers senescence.	('H3.3', 'Gene', (18, 22))	('represses', 'NegReg', (41, 50))	('H3.3', 'Gene', '109836', (18, 22))	('variant', 'Var', (26, 33))	('senescence', 'biological_process', 'GO:0010149', ('81', '91'))	('E2F target genes', 'Gene', (51, 67))	('senescence', 'MPA', (81, 91))	('triggers', 'Reg', (72, 80))
19652	32042336	The essential role of these variants in melanoma or the chaperones upstream depositing them into defined region of the genome, should be taken in consideration to explore potential therapeutic strategies to alter sensitivity of melanoma cells to current therapies.	('variants', 'Var', (28, 36))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Disease', 'MESH:D008545', (228, 236))	('melanoma', 'Disease', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('melanoma', 'Disease', (228, 236))
19653	32042336	Hyperactivation of the MAPK signaling pathway via mutations in BRAF, NRAS, or NF1, drives CM progression, underlining the fundamental role of controlled MAPK signaling for melanocyte homeostasis.	('NRAS', 'Gene', '4893', (69, 73))	('CM', 'Disease', 'MESH:C562393', (90, 92))	('MAPK signaling', 'biological_process', 'GO:0000165', ('153', '167'))	('signaling pathway', 'biological_process', 'GO:0007165', ('28', '45'))	('mutations', 'Var', (50, 59))	('MAPK', 'molecular_function', 'GO:0004707', ('23', '27'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('23', '37'))	('NF1', 'Gene', (78, 81))	('MAPK signaling pathway', 'Pathway', (23, 45))	('CM', 'Phenotype', 'HP:0012056', (90, 92))	('homeostasis', 'biological_process', 'GO:0042592', ('183', '194'))	('Hyperactivation', 'PosReg', (0, 15))	('NF1', 'Gene', '4763', (78, 81))	('MAPK', 'molecular_function', 'GO:0004707', ('153', '157'))	('NRAS', 'Gene', (69, 73))	('BRAF', 'Gene', (63, 67))
19655	32042336	BRAFV600E is the most common mutation in CM (>50%), which leads to constitutive activation of MEK/ERK signaling independently of upstream Receptor Tyrosine Kinases (RTK) or RAS activation, resulting in recurrent positive regulation of genes involved in cell proliferation and survival, that is, uncontrolled cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('253', '271'))	('genes', 'Gene', (235, 240))	('positive regulation', 'PosReg', (212, 231))	('cell', 'CPA', (253, 257))	('ERK', 'molecular_function', 'GO:0004707', ('98', '101'))	('ERK', 'Gene', '5594', (98, 101))	('MEK', 'Gene', (94, 97))	('CM', 'Phenotype', 'HP:0012056', (41, 43))	('signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('CM', 'Disease', 'MESH:C562393', (41, 43))	('regulation', 'biological_process', 'GO:0065007', ('221', '231'))	('cell proliferation', 'biological_process', 'GO:0008283', ('308', '326'))	('ERK', 'Gene', (98, 101))	('BRAFV600E', 'Var', (0, 9))	('activation', 'PosReg', (80, 90))	('Kinases', 'Disease', (156, 163))	('MEK', 'Gene', '5609', (94, 97))	('Tyrosine', 'Chemical', 'None', (147, 155))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('Kinases', 'Disease', 'MESH:D058495', (156, 163))
19656	32042336	BRAF inhibitors (BRAFi: vemurafenib, dabrafenib, encorazfenib) and more recently, the combination of a BRAFi and MEKi (cobimetinib, trametinib, binimetinib) have shown remarkable clinical activity in advanced metastatic CM in patients with mutant BRAFV600E/K .	('MEK', 'Gene', '5609', (113, 116))	('CM', 'Disease', 'MESH:C562393', (220, 222))	('BRAFV600E', 'Mutation', 'rs113488022', (247, 256))	('encorazfenib', 'Chemical', 'None', (49, 61))	('dabrafenib', 'Chemical', 'MESH:C561627', (37, 47))	('mutant', 'Var', (240, 246))	('CM', 'Phenotype', 'HP:0012056', (220, 222))	('BRAFV600E/K', 'Gene', (247, 258))	('binimetinib', 'Chemical', 'MESH:C581313', (144, 155))	('patients', 'Species', '9606', (226, 234))	('cobimetinib', 'Chemical', 'MESH:C574276', (119, 130))	('trametinib', 'Chemical', 'MESH:C560077', (132, 142))	('vemurafenib', 'Chemical', 'MESH:C551177', (24, 35))	('MEK', 'Gene', (113, 116))
19659	32042336	Mechanisms underlying acquired resistance to ERK signaling inhibitors include alterations of BRAFV600E (overexpression, amplification and aberrant splicing), upregulation of kinases (e.g.	('ERK', 'Gene', (45, 48))	('splicing', 'biological_process', 'GO:0045292', ('147', '155'))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('ERK', 'molecular_function', 'GO:0004707', ('45', '48'))	('BRAFV600E', 'Mutation', 'rs113488022', (93, 102))	('kinases', 'MPA', (174, 181))	('alterations', 'Var', (78, 89))	('BRAFV600E', 'Gene', (93, 102))	('ERK', 'Gene', '5594', (45, 48))	('upregulation', 'PosReg', (158, 170))
19660	32042336	Tpl2/Cot) and RTK or RAS mutations, amongst others - all of which reactivate ERK signaling.	('RTK', 'Gene', (14, 17))	('mutations', 'Var', (25, 34))	('RAS', 'Gene', (21, 24))	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('ERK', 'Gene', '5594', (77, 80))	('ERK', 'Gene', (77, 80))	('Cot', 'Gene', '1326', (5, 8))	('ERK', 'molecular_function', 'GO:0004707', ('77', '80'))	('Tpl2', 'Gene', (0, 4))	('Tpl2', 'Gene', '1326', (0, 4))	('reactivate', 'Reg', (66, 76))	('Cot', 'Gene', (5, 8))
19662	32042336	Not only epigenetic alterations were proved to be involved in melanoma development but also in mechanisms underlying acquired resistance to targeted- and immunotherapies that we will discuss here after (Table 2).	('melanoma', 'Disease', (62, 70))	('epigenetic alterations', 'Var', (9, 31))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('involved', 'Reg', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
19664	32042336	Recent reports have implicated DNA methylation, transcriptional changes, microRNA alterations, as well as microenvironmental stressors in promoting melanoma drug resistance to MAPKi in BRAFV600-mutant melanoma.	('melanoma', 'Disease', (201, 209))	('BRAFV600-mutant', 'Var', (185, 200))	('drug resistance', 'Phenotype', 'HP:0020174', (157, 172))	('N', 'Chemical', 'MESH:D009584', (32, 33))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('drug resistance', 'biological_process', 'GO:0009315', ('157', '172'))	('promoting', 'PosReg', (138, 147))	('drug resistance', 'biological_process', 'GO:0042493', ('157', '172'))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('DNA methylation', 'biological_process', 'GO:0006306', ('31', '46'))	('MAPKi', 'Gene', (176, 181))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))
19666	32042336	Importantly, it suggests that epigenetic alterations may play a key role in rewiring the chromatin landscape of melanoma cells to allow adaptation to current therapies.	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('epigenetic alterations', 'Var', (30, 52))	('melanoma', 'Disease', (112, 120))	('chromatin', 'cellular_component', 'GO:0000785', ('89', '98'))
19675	32042336	Importantly, inhibition of mitochondrial respiration blocks the emergence of the KDM5B(high) subpopulation and sensitized melanoma cells to therapy.	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('respiration', 'biological_process', 'GO:0007585', ('41', '52'))	('KDM5B', 'Gene', '10765', (81, 86))	('inhibition', 'Var', (13, 23))	('KDM5B', 'Gene', (81, 86))	('respiration', 'biological_process', 'GO:0045333', ('41', '52'))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('mitochondrial', 'MPA', (27, 40))	('blocks', 'NegReg', (53, 59))
19678	32042336	A concomitant chromatin modification state was observed with a decrease of the histone marks targeted by these enzymes, respectively H3K4me3 and H3K27me3, highlighting epigenetic remodeling.	('chromatin modification', 'biological_process', 'GO:0006325', ('14', '36'))	('H3K27me3', 'Var', (145, 153))	('chromatin modification', 'biological_process', 'GO:0016569', ('14', '36'))	('H3K4me3', 'Var', (133, 140))	('decrease', 'NegReg', (63, 71))	('chromatin', 'cellular_component', 'GO:0000785', ('14', '23'))	('chromatin modification', 'MPA', (14, 36))	('H3K4me3', 'Chemical', 'MESH:C024755', (133, 140))
19691	32042336	Especially, this transition is mediated first by a dedifferentiation state followed by activation of new signaling pathways mediated respectively by loss of SOX10 (regulates neural crest development in melanocytes) and activation of TEAD (regulates invasion in melanoma) among others.	('activation', 'PosReg', (87, 97))	('signaling pathways', 'Pathway', (105, 123))	('SOX10', 'Gene', '6663', (157, 162))	('loss', 'Var', (149, 153))	('SOX10', 'Gene', (157, 162))	('activation', 'PosReg', (219, 229))	('dedifferentiation', 'biological_process', 'GO:0043696', ('51', '68'))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('melanoma', 'Disease', 'MESH:D008545', (261, 269))	('TEAD', 'Gene', (233, 237))	('melanoma', 'Phenotype', 'HP:0002861', (261, 269))	('melanoma', 'Disease', (261, 269))
19694	32042336	Taking all this in consideration, there is no doubt today that shedding light onto the transcriptomic and epigenetic alterations underlying acquired MAPKi resistance in melanoma is of critical importance to improve patients' clinical outcome.	('MAPKi resistance', 'Gene', (149, 165))	('patients', 'Species', '9606', (215, 223))	('acquired', 'Var', (140, 148))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanoma', 'Disease', (169, 177))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))
19697	32042336	Previous report on sirtuins in melanoma showed that SIRT1 inhibition decreases melanoma cell growth and rescues the sensitivity to PLX4032 of PLX4032-resistant BRAFV600E-mutated melanoma cells.	('sensitivity to PLX4032', 'MPA', (116, 138))	('BRAFV600E-mutated', 'Var', (160, 177))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (31, 39))	('melanoma', 'Disease', (79, 87))	('SIRT1', 'Gene', (52, 57))	('PLX4032', 'Chemical', 'MESH:C551177', (142, 149))	('decreases melanoma', 'Disease', (69, 87))	('cell growth', 'biological_process', 'GO:0016049', ('88', '99'))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('decreases melanoma', 'Disease', 'MESH:D008545', (69, 87))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))	('PLX4032', 'Chemical', 'MESH:C551177', (131, 138))	('BRAFV600E', 'Mutation', 'rs113488022', (160, 169))	('rescues', 'PosReg', (104, 111))	('SIRT1', 'Gene', '23411', (52, 57))
19698	32042336	On the other hand, an shRNA screen identified that SIRT2 depletion conferred resistance to MAPKi in BRAFV600E melanoma cells through ERK reactivation.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('depletion', 'Var', (57, 66))	('MAPKi', 'Gene', (91, 96))	('BRAFV600E', 'Mutation', 'rs113488022', (100, 109))	('resistance', 'MPA', (77, 87))	('SIRT2', 'Gene', '22933', (51, 56))	('ERK', 'Gene', '5594', (133, 136))	('ERK', 'molecular_function', 'GO:0004707', ('133', '136'))	('ERK', 'Gene', (133, 136))	('N', 'Chemical', 'MESH:D009584', (25, 26))	('SIRT2', 'Gene', (51, 56))
19702	32042336	We favored the hypothesis that epigenetic mechanisms altering gene expression programs contribute to ERK signaling inhibitor resistance.	('contribute', 'Reg', (87, 97))	('gene expression', 'biological_process', 'GO:0010467', ('62', '77'))	('epigenetic mechanisms', 'Var', (31, 52))	('ERK', 'Gene', '5594', (101, 104))	('ERK', 'Gene', (101, 104))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('ERK', 'molecular_function', 'GO:0004707', ('101', '104'))
19707	32042336	Using, a combination of transcriptomic, epigenomic and proteomic analyses we demonstrated that haploinsufficiency of SIRT6 in BRAF-mutant melanoma cells decreases sensitivity to MAPKi independently of the ERK signaling pathway.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('ERK', 'Gene', '5594', (205, 208))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('haploinsufficiency', 'Disease', 'MESH:D058495', (95, 113))	('sensitivity to MAPKi', 'MPA', (163, 183))	('ERK', 'Gene', (205, 208))	('BRAF-mutant', 'Gene', (126, 137))	('signaling pathway', 'biological_process', 'GO:0007165', ('209', '226'))	('decreases', 'NegReg', (153, 162))	('SIRT6', 'Gene', '51548', (117, 122))	('ERK', 'molecular_function', 'GO:0004707', ('205', '208'))	('haploinsufficiency', 'Disease', (95, 113))	('SIRT6', 'Gene', (117, 122))	('BRAF-mutant', 'Var', (126, 137))
19712	32042336	Strikingly, we observed that IGFBP2 protein levels correlated with resistance to MAPKi in several BRAF-mutant melanoma cell lines and are associated with poor prognosis in primary melanomas.	('BRAF-mutant', 'Gene', (98, 109))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('BRAF-mutant', 'Var', (98, 109))	('resistance to MAPKi', 'MPA', (67, 86))	('correlated', 'Reg', (51, 61))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (180, 189))	('melanoma', 'Disease', (110, 118))	('IGFBP2', 'Gene', '3485', (29, 35))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('IGFBP2', 'Gene', (29, 35))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('protein', 'Protein', (36, 43))	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanomas', 'Disease', 'MESH:D008545', (180, 189))	('associated', 'Reg', (138, 148))	('melanomas', 'Disease', (180, 189))	('primary melanoma', 'Disease', 'MESH:D008545', (172, 188))	('primary melanoma', 'Disease', (172, 188))
19713	32042336	Importantly, we showed that co-targeting the MAPK and IGF-1R pathways can prevent/delay resistance to targeted MAPKi therapies, particularly for patients with high levels of IGFBP2, highlighting the importance of early detection as previously mentioned.	('patients', 'Species', '9606', (145, 153))	('IGF-1R', 'Gene', '3480', (54, 60))	('co-targeting', 'Var', (28, 40))	('prevent/delay', 'NegReg', (74, 87))	('IGF-1R', 'Gene', (54, 60))	('IGFBP2', 'Gene', '3485', (174, 180))	('resistance to targeted', 'MPA', (88, 110))	('MAPK', 'molecular_function', 'GO:0004707', ('45', '49'))	('IGFBP2', 'Gene', (174, 180))	('MAPK', 'Pathway', (45, 49))
19718	32042336	While we can refer to these cells as "IDTCs; drug tolerant persisters or slow cycling drug tolerant cells", we now know that the burden of acquired melanoma resistance not only arise from genetic alterations but also from the emergence of these subpopulations.	('slow cycling', 'Phenotype', 'HP:0002067', (73, 85))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('genetic alterations', 'Var', (188, 207))
19738	32042336	Epigenetic remodeling is a common feature of human melanoma and other tumor types and plays a key role in the immune escape of neoplastic cells from antigen specific T cell recognition.	('cell recognition', 'biological_process', 'GO:0008037', ('168', '184'))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('human', 'Species', '9606', (45, 50))	('Epigenetic remodeling', 'Var', (0, 21))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
19741	32042336	Despite recent studies pointing out epigenetic regulations contributing to tumor immune escape, antigen expression or presentation, regulating tumor cell killing or T-cell response (and we refer the reader this review for more details) our knowledge in epigenetic mechanisms involved in resistance to immunotherapies is still in its infancy.	('tumor', 'Disease', (143, 148))	('epigenetic regulations', 'Var', (36, 58))	('contributing', 'Reg', (59, 71))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('cell killing', 'biological_process', 'GO:0001906', ('149', '161'))
19742	32042336	Indeed, to the best of our knowledge, only a few studies to date reported epigenetic players in melanoma immunotherapy resistance (Table 2).	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('epigenetic players', 'Var', (74, 92))	('melanoma', 'Disease', (96, 104))
19744	32042336	In particular, they showed that EZH2 is upregulated upon anti-CTLA-4 or IL-2 immunotherapies in cancer cells, leading to a loss of tumor control.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('IL-2', 'Gene', '3558', (72, 76))	('IL-2', 'Gene', (72, 76))	('tumor', 'Disease', (131, 136))	('IL-2', 'molecular_function', 'GO:0005134', ('72', '76'))	('loss', 'NegReg', (123, 127))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('EZH2', 'Gene', (32, 36))	('anti-CTLA-4', 'Var', (57, 68))	('cancer', 'Disease', (96, 102))	('upregulated', 'PosReg', (40, 51))
19745	32042336	Importantly, GSK503 an inhibitor of the methyltransferase activity of EZH2, restored tumor immunogenicity and T-cell infiltration and suppressed melanoma growth upon immunotherapy.	('tumor', 'Disease', (85, 90))	('suppressed', 'NegReg', (134, 144))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('GSK503', 'Var', (13, 19))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('restored', 'PosReg', (76, 84))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('T-cell infiltration', 'CPA', (110, 129))	('methyltransferase activity', 'molecular_function', 'GO:0008168', ('40', '66'))	('GSK', 'molecular_function', 'GO:0050321', ('13', '16'))	('EZH2', 'Gene', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
19748	32042336	Briefly, inactivation of either ARID2, PBRM1 and BRD7 of the PBAF complex sensitized melanoma cells to cytotoxic T-cells via an enhanced response to IFN-gamma.	('PBRM1', 'Gene', '55193', (39, 44))	('BAF', 'Gene', (62, 65))	('IFN-gamma', 'Gene', '3458', (149, 158))	('IFN-gamma', 'Gene', (149, 158))	('ARID2', 'Gene', '196528', (32, 37))	('BRD7', 'Gene', '29117', (49, 53))	('ARID2', 'Gene', (32, 37))	('BAF', 'Gene', '8815', (62, 65))	('enhanced', 'PosReg', (128, 136))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('inactivation', 'Var', (9, 21))	('melanoma', 'Disease', (85, 93))	('PBAF complex', 'cellular_component', 'GO:0016586', ('61', '73'))	('sensitized', 'Reg', (74, 84))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('BRD7', 'Gene', (49, 53))	('PBRM1', 'Gene', (39, 44))
19752	32042336	Importantly, LSD1 depletion renders refractory mouse tumors responsive to anti-PD-1 therapy.	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PD-1', 'Gene', (79, 83))	('PD-1', 'Gene', '5133', (79, 83))	('depletion', 'Var', (18, 27))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('LSD1', 'Gene', (13, 17))	('tumors', 'Disease', (53, 59))	('mouse', 'Species', '10090', (47, 52))
19754	32042336	Moreover, this provides a strong rationale for implementing epigenetically-based immunotherapies in cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('epigenetically-based', 'Var', (60, 80))	('patients', 'Species', '9606', (107, 115))
19757	32042336	The efficacy of combining epigenetic modulators such as the DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-AZA-CdR) and immunotherapy caused a 77-81% reduction in tumor volume and was much more effective than the effect mediated by single agents.	('tumor', 'Disease', (168, 173))	('N', 'Chemical', 'MESH:D009584', (61, 62))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('epigenetic modulators', 'Var', (26, 47))	('reduction', 'NegReg', (155, 164))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:C014347', (86, 108))
19769	32042336	Genetic alterations most often observed in UM are somatic activating mutations in the G-protein coupled receptor GNAQ signaling cascade associated with mutations prognostically significant of the metastatic risk in BAP1, SF3B1, and EIF1AX (BSE mutations).	('associated', 'Reg', (136, 146))	('mutations', 'Var', (69, 78))	('GNAQ', 'Gene', (113, 117))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('mutations', 'Var', (152, 161))	('signaling cascade', 'biological_process', 'GO:0007165', ('118', '135'))	('activating', 'PosReg', (58, 68))	('EIF1AX', 'Gene', '1964', (232, 238))	('EIF1AX', 'Gene', (232, 238))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('SF3B1', 'Gene', (221, 226))	('UM', 'Disease', 'MESH:C536494', (43, 45))	('GNAQ', 'Gene', '2776', (113, 117))	('BAP1', 'Gene', (215, 219))	('SF3B1', 'Gene', '23451', (221, 226))
19775	32042336	Given the reversible nature of some epigenetic regulations, inhibition of the epigenetic enzymes in cancer cells might switch these modifications back to a "normal-like" chromatin landscape.	('inhibition', 'Var', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('chromatin', 'cellular_component', 'GO:0000785', ('168', '177'))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
19779	32042336	Consistently, knockdown of BAP1 in UM cells induced a marked increase in H2A ubiquitination.	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('UM', 'Disease', 'MESH:C536494', (35, 37))	('BAP1', 'Gene', (27, 31))	('H2A', 'Gene', '8337', (73, 76))	('H2A', 'Gene', (73, 76))	('knockdown', 'Var', (14, 23))	('increase', 'PosReg', (61, 69))
19781	32042336	In the nucleosomes, ubiquitinated H2A is situated close to linker histone H1.	('histone H1', 'Gene', '3005', (66, 76))	('H2A', 'Gene', (34, 37))	('histone H1', 'Gene', (66, 76))	('ubiquitinated', 'Var', (20, 33))	('H2A', 'Gene', '8337', (34, 37))
19783	32042336	Depletion of BAP1 in cultured cells induces a switch in transcriptional programs from differentiated poorly aggressive Class 1 to dedifferentiated highly aggressive Class 2 gene expression profile and re-programmation of UM cells towards a stem-like phenotype.	('BAP1', 'Gene', (13, 17))	('gene expression', 'biological_process', 'GO:0010467', ('173', '188'))	('re-programmation', 'CPA', (201, 217))	('UM', 'Phenotype', 'HP:0007716', (221, 223))	('Depletion', 'Var', (0, 9))	('UM', 'Disease', 'MESH:C536494', (221, 223))	('switch', 'Reg', (46, 52))	('transcriptional programs', 'MPA', (56, 80))
19789	32042336	By inducibly knocking down BAP1 expression, a methylomic repatterning was observed and enriched for genes similar to UM tumors.	('tumors', 'Disease', (120, 126))	('UM', 'Disease', 'MESH:C536494', (117, 119))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('BAP1', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('expression', 'MPA', (32, 42))	('knocking', 'Var', (13, 21))	('UM', 'Phenotype', 'HP:0007716', (117, 119))
19790	32042336	This study supports previous work and suggests a chronological order for UM divergence from Class 1 to Class 2 with loss of one chromosome 3 copy, a BAP1 mutation on the other copy leading to a methylomic redistribution characteristic of Class 2 UMs, thereby a more aggressive state.	('methylomic redistribution', 'MPA', (194, 219))	('aggressive', 'MPA', (266, 276))	('aggressive state', 'Phenotype', 'HP:0000718', (266, 282))	('UM', 'Phenotype', 'HP:0007716', (73, 75))	('chromosome', 'cellular_component', 'GO:0005694', ('128', '138'))	('UM', 'Disease', 'MESH:C536494', (73, 75))	('mutation', 'Var', (154, 162))	('UM', 'Disease', 'MESH:C536494', (246, 248))	('leading to', 'Reg', (181, 191))	('BAP1', 'Gene', (149, 153))	('UM', 'Phenotype', 'HP:0007716', (246, 248))
19804	32042336	Thus, combining epigenetic drugs and chemotherapy, immunotherapy or targeted therapy may prove to have clinical value especially in the case of UM where loss of BAP1 and epigenetic alterations are critically involved in the pathogenesis.	('epigenetic alterations', 'Var', (170, 192))	('loss', 'Var', (153, 157))	('pathogenesis', 'biological_process', 'GO:0009405', ('224', '236'))	('involved', 'Reg', (208, 216))	('UM', 'Disease', 'MESH:C536494', (144, 146))	('UM', 'Phenotype', 'HP:0007716', (144, 146))	('BAP1', 'Protein', (161, 165))
19813	32042336	MS-275 increases in a variable manner expression of the TRAIL receptors DR4, DR5, and procaspase 8 as well as recurrently inhibits expression of the anti-apoptotic effector cFLIP expression.	('increases', 'PosReg', (7, 16))	('inhibits', 'NegReg', (122, 130))	('TRAIL', 'Gene', '8743', (56, 61))	('MS-275', 'Var', (0, 6))	('expression', 'MPA', (38, 48))	('DR5', 'Gene', (77, 80))	('procaspase 8', 'Protein', (86, 98))	('expression', 'MPA', (131, 141))	('DR4', 'Gene', '3126', (72, 75))	('DR4', 'Gene', (72, 75))	('TRAIL', 'Gene', (56, 61))	('DR5', 'Gene', '8795', (77, 80))	('anti-apoptotic effector cFLIP expression', 'MPA', (149, 189))
19815	32042336	In a model of hematopoietic transformation in mice, Bap1 loss is associated with decreased H4K20me1 at the EZH2 locus, allowing its expression and in turn catalyzes H3K27me3.	('decreased', 'NegReg', (81, 90))	('catalyzes', 'MPA', (155, 164))	('H4K20me1', 'Protein', (91, 99))	('Bap1', 'Gene', (52, 56))	('H4K20me1', 'Chemical', 'MESH:C024755', (91, 99))	('mice', 'Species', '10090', (46, 50))	('loss', 'NegReg', (57, 61))	('H3K27me3', 'Var', (165, 173))	('allowing', 'PosReg', (119, 127))	('expression', 'MPA', (132, 142))
19816	32042336	Regulation of H4K20me1 is mediated through SETD8 the only known methyltransferase that places H4K20me1 on chromatin.	('H4K20me1', 'Chemical', 'MESH:C024755', (14, 22))	('SETD8', 'Gene', '387893', (43, 48))	('H4K20me1', 'Chemical', 'MESH:C024755', (94, 102))	('SETD8', 'Gene', (43, 48))	('chromatin', 'cellular_component', 'GO:0000785', ('106', '115'))	('H4K20me1', 'Var', (94, 102))
19817	32042336	Further, the myeloproliferation syndrome associated with Bap1-KO mice is reduced by treatment with the small-molecule EZH2 inhibitor EPZ011989, suggesting that EZH2 might represent a therapeutic target in BAP1-deficient malignancies, including UM cells.	('UM', 'Phenotype', 'HP:0007716', (244, 246))	('UM', 'Disease', 'MESH:C536494', (244, 246))	('myeloproliferation syndrome', 'Disease', 'MESH:D061325', (13, 40))	('reduced', 'NegReg', (73, 80))	('mice', 'Species', '10090', (65, 69))	('myeloproliferation syndrome', 'Phenotype', 'HP:0005547', (13, 40))	('myeloproliferation syndrome', 'Disease', (13, 40))	('Bap1-KO', 'Var', (57, 64))	('EPZ011989', 'Chemical', 'MESH:C000593333', (133, 142))
19822	32042336	The significant role that is taking epigenetic dysregulation in melanoma inspires scientists to orientate their studies into compounds that target epigenetic regulators.	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('epigenetic dysregulation', 'Var', (36, 60))	('melanoma', 'Disease', (64, 72))
19823	32042336	Few drugs inhibiting epigenetic writers and erasers have been FDA-approved for the treatment of cancer.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('epigenetic', 'Var', (21, 31))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
19836	32042336	Several lines of evidence demonstrate that epigenetic modifications play an important role in melanoma initiation, progression, and metastasis.	('melanoma initiation', 'Disease', 'MESH:D008545', (94, 113))	('epigenetic modifications', 'Var', (43, 67))	('metastasis', 'CPA', (132, 142))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma initiation', 'Disease', (94, 113))
19838	32042336	Targeting epigenetic modifications is of intense interest in the treatment against cancer and epigenetic drug discovery is a rapidly advancing field.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('epigenetic modifications', 'Var', (10, 34))	('cancer', 'Disease', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))
19843	32042336	We focused in this review on histone modifications among various other mechanisms, but we have to keep in mind that they are working in concert with other epigenetic aberrations such as DNA methylation or miRNA dysregulations and genetic alterations.	('N', 'Chemical', 'MESH:D009584', (187, 188))	('DNA methylation', 'biological_process', 'GO:0006306', ('186', '201'))	('DNA', 'Var', (186, 189))	('miRNA', 'Var', (205, 210))	('DNA', 'cellular_component', 'GO:0005574', ('186', '189'))	('N', 'Chemical', 'MESH:D009584', (208, 209))
19844	32042336	In particular, aberrant DNA methylation associated with transcriptional repression is a major phenomenon observed in cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('transcriptional', 'MPA', (56, 71))	('DNA methylation', 'biological_process', 'GO:0006306', ('24', '39'))	('N', 'Chemical', 'MESH:D009584', (25, 26))	('DNA', 'MPA', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('aberrant', 'Var', (15, 23))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
19847	32042336	In that case, aberrant DNA methylation potentiate the transcriptional silencing already existing such as a lock-off mechanism.	('transcriptional silencing', 'MPA', (54, 79))	('aberrant', 'Var', (14, 22))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('DNA', 'Protein', (23, 26))	('DNA methylation', 'biological_process', 'GO:0006306', ('23', '38'))	('potentiate', 'PosReg', (39, 49))
19848	32042336	Another view is that aberrant DNA methylation has a key role in the reversion of the epigenetic state at specific genomic loci and activates silent genes.	('activates', 'PosReg', (131, 140))	('aberrant', 'Var', (21, 29))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('DNA', 'Protein', (30, 33))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('DNA methylation', 'biological_process', 'GO:0006306', ('30', '45'))	('silent genes', 'Gene', (141, 153))	('reversion of the epigenetic state', 'MPA', (68, 101))
19850	32042336	Combinations of epigenetic drugs with other anti-cancer agents such as targeted therapy or immunomodulatory drugs is a promising avenue for improving the effectiveness of treatments in both cutaneous and uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (204, 218))	('cutaneous', 'Disease', (190, 199))	('epigenetic drugs', 'Var', (16, 32))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('uveal melanoma', 'Disease', (204, 218))	('Combinations', 'Interaction', (0, 12))	('uveal melanoma', 'Phenotype', 'HP:0007716', (204, 218))	('improving', 'PosReg', (140, 149))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('cancer', 'Disease', (49, 55))
19853	31024753	Main outcomes were copy number changes in chromosomes 1, 3, 6, and 8 and mutations in GNAQ, GNA11, SF3B1, EIF1AX, BAP1, SRSF2, U2AF1, and PLCB4.	('SF3B1', 'Gene', (99, 104))	('copy number changes', 'Var', (19, 38))	('GNAQ', 'Gene', '2776', (86, 90))	('EIF1AX', 'Gene', '1964', (106, 112))	('BAP1', 'Gene', (114, 118))	('GNAQ', 'Gene', (86, 90))	('GNA11', 'Gene', (92, 97))	('U2AF', 'cellular_component', 'GO:0089701', ('127', '131'))	('SF3B1', 'Gene', '23451', (99, 104))	('PLCB4', 'Gene', (138, 143))	('SRSF2', 'Gene', '6427', (120, 125))	('U2AF1', 'Gene', (127, 132))	('PLCB4', 'Gene', '5332', (138, 143))	('SRSF2', 'Gene', (120, 125))	('GNA11', 'Gene', '2767', (92, 97))	('BAP1', 'Gene', '8314', (114, 118))	('EIF1AX', 'Gene', (106, 112))	('U2AF1', 'Gene', '7307', (127, 132))	('mutations', 'Var', (73, 82))
19856	31024753	Chromosome 3 loss was detected in 30 patients and was associated with larger basal tumor diameter (Wilcoxon rank sum test, P = 0.015), greater thickness (Wilcoxon rank sum test, P = 0.016) and tumor, node, metastasis stage (Fisher test, P = 0.006), epithelioid cytology (Fisher test, P < 0.001), BAP1 mutation (Fisher test, P < 0.001), and chromosome 8q gain (Fisher test, P < 0.001).	('chromosome 8q', 'Gene', (340, 353))	('greater thickness', 'CPA', (135, 152))	('tumor', 'Disease', (83, 88))	('BAP1', 'Gene', (296, 300))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('basal tumor', 'Disease', 'MESH:D002280', (77, 88))	('basal tumor', 'Disease', (77, 88))	('larger', 'PosReg', (70, 76))	('patients', 'Species', '9606', (37, 45))	('Chromosome 3', 'Gene', (0, 12))	('tumor', 'Disease', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('epithelioid cytology', 'CPA', (249, 269))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('basal tumor', 'Phenotype', 'HP:0002671', (77, 88))	('BAP1', 'Gene', '8314', (296, 300))	('chromosome', 'cellular_component', 'GO:0005694', ('340', '350'))	('mutation', 'Var', (301, 309))	('gain', 'PosReg', (354, 358))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('loss', 'NegReg', (13, 17))
19859	31024753	All metastatic cases had chromosome 3 loss, 8 gain, BAP1 mutation, and class 2 GEP.	('mutation', 'Var', (57, 65))	('BAP1', 'Gene', '8314', (52, 56))	('chromosome', 'cellular_component', 'GO:0005694', ('25', '35'))	('BAP1', 'Gene', (52, 56))	('gain', 'PosReg', (46, 50))	('chromosome', 'Gene', (25, 35))	('loss', 'NegReg', (38, 42))
19860	31024753	Five class 1 tumors had chromosome 3 loss.	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', (13, 19))	('chromosome', 'cellular_component', 'GO:0005694', ('24', '34'))	('loss', 'NegReg', (37, 41))	('chromosome', 'Var', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
19863	31024753	Of all predictive factors, tumor genetic information remains the most informative, with chromosome 3 loss and BAP1 mutation, as well as class 2 gene expression profile (GEP) correlating most strongly with metastatic death.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('BAP1', 'Gene', '8314', (110, 114))	('gene expression', 'biological_process', 'GO:0010467', ('144', '159'))	('loss', 'NegReg', (101, 105))	('tumor', 'Disease', (27, 32))	('metastatic death', 'CPA', (205, 221))	('BAP1', 'Gene', (110, 114))	('chromosome', 'cellular_component', 'GO:0005694', ('88', '98'))	('mutation', 'Var', (115, 123))
19864	31024753	Chromosome 6p gain is associated with a relatively good prognosis and is rare in tumors with chromosome 3 loss.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('gain', 'PosReg', (14, 18))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('Chromosome', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
19865	31024753	More than 85% of UMs show GNAQ or GNA11 mutation, which are mutually exclusive, initiating oncogenic events, and are, therefore, useful in differentiating UM from other lesions such as choroidal metastases.	('mutation', 'Var', (40, 48))	('UM', 'Phenotype', 'HP:0007716', (155, 157))	('UMs', 'Disease', (17, 20))	('GNAQ', 'Gene', (26, 30))	('choroidal metastases', 'Disease', (185, 205))	('GNA11', 'Gene', (34, 39))	('choroidal metastases', 'Disease', 'MESH:D009362', (185, 205))	('GNA11', 'Gene', '2767', (34, 39))	('GNAQ', 'Gene', '2776', (26, 30))	('UM', 'Phenotype', 'HP:0007716', (17, 19))
19866	31024753	Loss-of-function mutations in the BAP1 tumor suppressor gene on chromosome 3 are found in 49% of UM and are strongly correlated with metastasis.	('Loss-of-function', 'NegReg', (0, 16))	('BAP1', 'Gene', (34, 38))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('39', '55'))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('UM', 'Phenotype', 'HP:0007716', (97, 99))	('chromosome', 'cellular_component', 'GO:0005694', ('64', '74'))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor suppressor', 'biological_process', 'GO:0051726', ('39', '55'))	('tumor', 'Disease', (39, 44))	('metastasis', 'CPA', (133, 143))	('BAP1', 'Gene', '8314', (34, 38))	('mutations', 'Var', (17, 26))
19867	31024753	Mutations in EIF1AX and SF3B1, which also tend to occur in a mutually exclusive pattern, are associated with low and intermediate risk, respectively.	('SF3B1', 'Gene', (24, 29))	('Mutations', 'Var', (0, 9))	('EIF1AX', 'Gene', '1964', (13, 19))	('EIF1AX', 'Gene', (13, 19))	('SF3B1', 'Gene', '23451', (24, 29))
19868	31024753	Other less common UM mutations include SRSF2, U2AF1, PLCB4, and CYSLTR2.	('SRSF2', 'Gene', (39, 44))	('U2AF', 'cellular_component', 'GO:0089701', ('46', '50'))	('U2AF1', 'Gene', (46, 51))	('PLCB4', 'Gene', (53, 58))	('U2AF1', 'Gene', '7307', (46, 51))	('UM', 'Phenotype', 'HP:0007716', (18, 20))	('CYSLTR2', 'Gene', '57105', (64, 71))	('SRSF2', 'Gene', '6427', (39, 44))	('CYSLTR2', 'Gene', (64, 71))	('PLCB4', 'Gene', '5332', (53, 58))	('mutations', 'Var', (21, 30))
19874	31024753	Chromosome 3 loss (a metastasis predictor) was correlated with known genetic aberrations in UM, such as GNAQ, GNA11, SF3B1, EIF1AX, and BAP1 mutations, GEP class, and with established clinical and histopathologic parameters associated with metastatic risk.	('EIF1AX', 'Gene', '1964', (124, 130))	('EIF1AX', 'Gene', (124, 130))	('GNA11', 'Gene', '2767', (110, 115))	('BAP1', 'Gene', (136, 140))	('mutations', 'Var', (141, 150))	('GNAQ', 'Gene', '2776', (104, 108))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('SF3B1', 'Gene', (117, 122))	('GNAQ', 'Gene', (104, 108))	('loss', 'NegReg', (13, 17))	('UM', 'Phenotype', 'HP:0007716', (92, 94))	('BAP1', 'Gene', '8314', (136, 140))	('GNA11', 'Gene', (110, 115))	('SF3B1', 'Gene', '23451', (117, 122))
19890	31024753	The log-rank test was performed to demonstrate associations between metastasis-free survival and chromosome 3 loss, chromosome 8q gain, BAP1 mutation, and GEP class.	('loss', 'NegReg', (110, 114))	('chromosome', 'Gene', (97, 107))	('BAP1', 'Gene', (136, 140))	('chromosome', 'cellular_component', 'GO:0005694', ('97', '107'))	('chromosome', 'Gene', (116, 126))	('chromosome', 'cellular_component', 'GO:0005694', ('116', '126'))	('gain', 'PosReg', (130, 134))	('BAP1', 'Gene', '8314', (136, 140))	('associations', 'Interaction', (47, 59))	('mutation', 'Var', (141, 149))	('metastasis-free survival', 'CPA', (68, 92))
19900	31024753	Chromosome 8q gain and 6p gain were seen in 32 (52%) and 21 (34%) tumors, respectively.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('gain', 'PosReg', (14, 18))	('tumors', 'Disease', (66, 72))	('Chromosome 8q', 'Var', (0, 13))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('gain', 'PosReg', (26, 30))
19901	31024753	GNAQ and GNA11 mutations were present in 36 (58%) and 26 (42%) tumors, respectively, and were mutually exclusive.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('GNAQ', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('GNA11', 'Gene', '2767', (9, 14))
19902	31024753	BAP1 inactivating mutations were present in 23 (37%) patients.	('BAP1', 'Gene', '8314', (0, 4))	('inactivating mutations', 'Var', (5, 27))	('BAP1', 'Gene', (0, 4))	('patients', 'Species', '9606', (53, 61))
19903	31024753	SF3B1 mutations and EIF1AX mutations were detected in 19 (31%) and 8 (13%) tumors, respectively.	('mutations', 'Var', (27, 36))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('SF3B1', 'Gene', (0, 5))	('SF3B1', 'Gene', '23451', (0, 5))	('EIF1AX', 'Gene', '1964', (20, 26))	('EIF1AX', 'Gene', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('mutations', 'Var', (6, 15))	('detected', 'Reg', (42, 50))
19904	31024753	No tumors had SRSF2, U2AF1, or PLCB4 mutations.	('U2AF1', 'Gene', (21, 26))	('U2AF1', 'Gene', '7307', (21, 26))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('PLCB4', 'Gene', '5332', (31, 36))	('U2AF', 'cellular_component', 'GO:0089701', ('21', '25'))	('SRSF2', 'Gene', (14, 19))	('mutations', 'Var', (37, 46))	('PLCB4', 'Gene', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('SRSF2', 'Gene', '6427', (14, 19))
19909	31024753	Chromosome 3 loss was more frequent in tumors with larger basal diameter (Wilcoxon rank sum test, P = 0.015), greater thickness (P = 0.016), more advanced TNM stage (P = 0.006), presence of any epithelioid cells (P < 0.001), BAP1 mutation (P < 0.001), and chromosome 8q gain (P < 0.001).	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('greater thickness', 'CPA', (110, 127))	('BAP1', 'Gene', '8314', (225, 229))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('mutation', 'Var', (230, 238))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('gain', 'PosReg', (270, 274))	('chromosome', 'cellular_component', 'GO:0005694', ('256', '266'))	('Chromosome 3', 'Gene', (0, 12))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('loss', 'NegReg', (13, 17))	('BAP1', 'Gene', (225, 229))	('chromosome 8q', 'Gene', (256, 269))	('tumors', 'Disease', (39, 45))	('TNM stage', 'CPA', (155, 164))
19910	31024753	There was no statistically significant association found between chromosome 3 loss and the mutational status of GNAQ (P = 0.200), GNA11 (P = 0.200), or SF3B1 (P = 0.280).	('SF3B1', 'Gene', '23451', (152, 157))	('GNAQ', 'Gene', (112, 116))	('GNA11', 'Gene', (130, 135))	('GNA11', 'Gene', '2767', (130, 135))	('loss', 'NegReg', (78, 82))	('mutational status', 'Var', (91, 108))	('SF3B1', 'Gene', (152, 157))	('GNAQ', 'Gene', '2776', (112, 116))	('chromosome', 'cellular_component', 'GO:0005694', ('65', '75'))
19913	31024753	All patients with metastases had chromosome 3 loss, chromosome 8q gain, BAP1 mutation, and class 2 GEP.	('chromosome', 'cellular_component', 'GO:0005694', ('52', '62'))	('chromosome', 'cellular_component', 'GO:0005694', ('33', '43'))	('class 2 GEP', 'CPA', (91, 102))	('chromosome', 'Var', (33, 43))	('metastases', 'Disease', (18, 28))	('BAP1', 'Gene', '8314', (72, 76))	('loss', 'NegReg', (46, 50))	('gain', 'PosReg', (66, 70))	('mutation', 'Var', (77, 85))	('metastases', 'Disease', 'MESH:D009362', (18, 28))	('BAP1', 'Gene', (72, 76))	('patients', 'Species', '9606', (4, 12))	('chromosome', 'Var', (52, 62))
19914	31024753	Chromosome 3 loss (P = 6.54 x 10-5) alone and combined chromosome 3 loss, chromosome 8q gain, and BAP1 mutation (P = 5 x 10-7) were associated with metastatic disease.	('BAP1', 'Gene', (98, 102))	('associated', 'Reg', (132, 142))	('chromosome', 'cellular_component', 'GO:0005694', ('74', '84'))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('chromosome 8q', 'Gene', (74, 87))	('loss', 'NegReg', (68, 72))	('gain', 'PosReg', (88, 92))	('loss', 'NegReg', (13, 17))	('mutation', 'Var', (103, 111))	('BAP1', 'Gene', '8314', (98, 102))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))	('chromosome', 'Gene', (55, 65))	('metastatic disease', 'Disease', (148, 166))
19915	31024753	Kaplan-Meier curves (Figure 3) show that the median survival was 37 months in patients whose tumors showed chromosome 3 loss and 35 months in patients whose tumor showed combined chromosome 3 loss, chromosome 8q gain and BAP1 mutation (log rank test, P < 0.001).	('BAP1', 'Gene', '8314', (221, 225))	('chromosome', 'cellular_component', 'GO:0005694', ('179', '189'))	('mutation', 'Var', (226, 234))	('patients', 'Species', '9606', (78, 86))	('chromosome', 'cellular_component', 'GO:0005694', ('198', '208'))	('chromosome', 'Var', (179, 189))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('BAP1', 'Gene', (221, 225))	('loss', 'NegReg', (192, 196))	('chromosome', 'cellular_component', 'GO:0005694', ('107', '117'))	('tumors', 'Disease', (93, 99))	('loss', 'NegReg', (120, 124))	('gain', 'PosReg', (212, 216))	('tumor', 'Disease', (157, 162))	('chromosome', 'Var', (198, 208))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('patients', 'Species', '9606', (142, 150))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
19917	31024753	The method is quantitative and sensitive enough to detect melanoma mutations, even in the presence of a considerable fraction of stromal cells.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))	('mutations', 'Var', (67, 76))
19918	31024753	The low complexity of the genetic landscape of UMs with highly recurrent mutations at hotspots of a few genes allows for accurate quantitation of tumor fractions, providing a potential advantage over gene expression analyses.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('gene expression', 'biological_process', 'GO:0010467', ('200', '215'))	('tumor', 'Disease', (146, 151))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('mutations', 'Var', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
19919	31024753	An additional advantage of UCSF500 is its ability to confirm that the biopsy specimen is of uveal melanocytic origin, by detecting GNAQ and GNA11 mutations.	('GNAQ', 'Gene', (131, 135))	('uveal melanocytic', 'Disease', (92, 109))	('mutations', 'Var', (146, 155))	('uveal melanocytic', 'Disease', 'MESH:D014603', (92, 109))	('GNA11', 'Gene', (140, 145))	('GNAQ', 'Gene', '2776', (131, 135))	('GNA11', 'Gene', '2767', (140, 145))	('detecting', 'Reg', (121, 130))
19922	31024753	An advantage of this pancancer assay is also that genetic mutations of relevance to a variety of cancers can also be added to the assay as new discoveries are made.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('genetic mutations', 'Var', (50, 67))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))
19923	31024753	The version of the assay in this study investigated mutations in GNAQ, GNA11, SF3B1, EIF1AX, BAP1, and PCLB4.	('mutations', 'Var', (52, 61))	('BAP1', 'Gene', '8314', (93, 97))	('PCLB4', 'Gene', (103, 108))	('GNAQ', 'Gene', '2776', (65, 69))	('GNA11', 'Gene', (71, 76))	('SF3B1', 'Gene', '23451', (78, 83))	('EIF1AX', 'Gene', '1964', (85, 91))	('EIF1AX', 'Gene', (85, 91))	('GNA11', 'Gene', '2767', (71, 76))	('BAP1', 'Gene', (93, 97))	('GNAQ', 'Gene', (65, 69))	('SF3B1', 'Gene', (78, 83))
19926	31024753	Chromosome 3 loss was associated with BAP1 mutation, chromosome 8q gain, largest basal tumor diameter, tumor thickness, TNM stage, and presence of epithelioid cells.	('basal tumor', 'Disease', 'MESH:D002280', (81, 92))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('chromosome', 'Var', (53, 63))	('mutation', 'Var', (43, 51))	('BAP1', 'Gene', (38, 42))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (87, 92))	('TNM stage', 'CPA', (120, 129))	('BAP1', 'Gene', '8314', (38, 42))	('basal tumor', 'Phenotype', 'HP:0002671', (81, 92))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('loss', 'NegReg', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('gain', 'PosReg', (67, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('53', '63'))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('basal tumor', 'Disease', (81, 92))
19928	31024753	Although CYSLTR2 was not included in the UCSF500 at the time of the study, all tumors sequenced had GNAQ and GNA11 mutations.	('mutations', 'Var', (115, 124))	('GNAQ', 'Gene', '2776', (100, 104))	('GNA11', 'Gene', (109, 114))	('tumors', 'Disease', (79, 85))	('GNAQ', 'Gene', (100, 104))	('CYSLTR2', 'Gene', '57105', (9, 16))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('GNA11', 'Gene', '2767', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('CYSLTR2', 'Gene', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
19929	31024753	Because CYSLTR2 is mutually exclusive of these mutations, it is unlikely the lack of the gene in the assay affected study results.	('CYSLTR2', 'Gene', (8, 15))	('CYSLTR2', 'Gene', '57105', (8, 15))	('mutations', 'Var', (47, 56))
19930	31024753	As expected, all 11 tumors that metastasized during the study period had chromosome 3 loss, chromosome 8q gain, BAP1 mutation, and class 2 GEP.	('BAP1', 'Gene', (112, 116))	('chromosome', 'Var', (73, 83))	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('tumors', 'Disease', (20, 26))	('loss', 'NegReg', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('chromosome', 'Var', (92, 102))	('chromosome', 'cellular_component', 'GO:0005694', ('92', '102'))	('BAP1', 'Gene', '8314', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mutation', 'Var', (117, 125))	('gain', 'PosReg', (106, 110))
19932	31024753	No significant association between SF3B1 mutation and chromosome 3 loss was seen.	('SF3B1', 'Gene', '23451', (35, 40))	('chromosome', 'cellular_component', 'GO:0005694', ('54', '64'))	('chromosome', 'Gene', (54, 64))	('mutation', 'Var', (41, 49))	('loss', 'NegReg', (67, 71))	('SF3B1', 'Gene', (35, 40))
19934	31024753	Longer-term follow up will be needed to determine the prognostic relevance of SF3B1 mutations.	('mutations', 'Var', (84, 93))	('SF3B1', 'Gene', '23451', (78, 83))	('SF3B1', 'Gene', (78, 83))
19937	31024753	Although the histopathology was interpreted as inconclusive due to paucicellular sample in three of these cases, NGS identified GNAQ or GNA11 mutations in all of these, providing evidence that the neoplasms were of melanocytic lineage.	('mutations', 'Var', (142, 151))	('neoplasms', 'Phenotype', 'HP:0002664', (197, 206))	('GNA11', 'Gene', (136, 141))	('GNAQ', 'Gene', '2776', (128, 132))	('GNA11', 'Gene', '2767', (136, 141))	('neoplasms', 'Disease', 'MESH:D009369', (197, 206))	('GNAQ', 'Gene', (128, 132))	('neoplasms', 'Disease', (197, 206))
19938	31024753	In two of these tumors with inconclusive histology, NGS also confirmed malignancy by identifying chromosome 6p gain in one tumor and SF3B1 mutation, loss of chromosome 1p, partial chromosome 3 deletion, and chromosome 8q gain in the other tumor.	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('malignancy', 'Disease', (71, 81))	('tumors', 'Disease', (16, 22))	('mutation', 'Var', (139, 147))	('tumor', 'Disease', (123, 128))	('partial chromosome 3 deletion', 'Var', (172, 201))	('loss', 'Var', (149, 153))	('chromosome', 'cellular_component', 'GO:0005694', ('180', '190'))	('tumor', 'Disease', (239, 244))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('SF3B1', 'Gene', (133, 138))	('chromosome 1p', 'Protein', (157, 170))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('gain', 'PosReg', (111, 115))	('gain', 'PosReg', (221, 225))	('chromosome', 'cellular_component', 'GO:0005694', ('97', '107'))	('chromosome 8q', 'Var', (207, 220))	('tumor', 'Disease', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('SF3B1', 'Gene', '23451', (133, 138))	('chromosome', 'Var', (97, 107))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('malignancy', 'Disease', 'MESH:D009369', (71, 81))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('chromosome', 'cellular_component', 'GO:0005694', ('207', '217'))	('chromosome', 'cellular_component', 'GO:0005694', ('157', '167'))
19940	31024753	In any case, NGS provided a diagnosis of melanoma by demonstrating GNA11 and SF3B1 mutations as well as chromosome 6p gain.	('mutations', 'Var', (83, 92))	('SF3B1', 'Gene', (77, 82))	('GNA11', 'Gene', (67, 72))	('chromosome 6p gain', 'Var', (104, 122))	('GNA11', 'Gene', '2767', (67, 72))	('SF3B1', 'Gene', '23451', (77, 82))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('chromosome', 'cellular_component', 'GO:0005694', ('104', '114'))
19942	31024753	Surprisingly, 4 of 20 (20%) class 1A tumors and 1 of 13 (8%) class 1B tumors showed chromosome 3 loss.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('loss', 'NegReg', (97, 101))	('chromosome', 'Var', (84, 94))	('1B tumors', 'Disease', 'MESH:C565748', (67, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('1B tumors', 'Disease', (67, 76))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
19944	31024753	Long-term follow up is needed to determine if partial chromosome 3 loss will lead to increased metastatic risk in these patients.	('chromosome', 'cellular_component', 'GO:0005694', ('54', '64'))	('partial chromosome', 'Var', (46, 64))	('loss', 'NegReg', (67, 71))	('patients', 'Species', '9606', (120, 128))	('metastatic', 'CPA', (95, 105))
19948	31024753	Although the preferred input for UCSF500 extracted from formalin-fixed paraffin-embedded tissue is 100 ng to yield a median coverage of 200 or more unique sequence reads, it can reliably detect UM typical alterations in unfixed samples with 10 ng of input material or less.	('alterations', 'Var', (205, 216))	('UCSF500', 'Gene', (33, 40))	('detect', 'Reg', (187, 193))	('UM', 'Phenotype', 'HP:0007716', (194, 196))	('paraffin', 'Chemical', 'MESH:D010232', (71, 79))	('formalin', 'Chemical', 'MESH:D005557', (56, 64))
19951	27089234	Comparative analysis of the GNAQ, GNA11, SF3B1, and EIF1AX driver mutations in melanoma and across the cancer spectrum Uveal melanoma is characterized by recurrent mutations in GNAQ, GNA11, SF3B1, and EIF1AX, as well as a low total mutational burden.	('mutations', 'Var', (66, 75))	('GNA11', 'Gene', (183, 188))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('Uveal melanoma', 'Disease', (119, 133))	('cancer', 'Disease', (103, 109))	('GNA11', 'Gene', '2767', (34, 39))	('melanoma', 'Disease', (79, 87))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('GNAQ', 'Gene', '2776', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('SF3B1', 'Gene', (41, 46))	('Uveal melanoma', 'Disease', 'MESH:C536494', (119, 133))	('SF3B1', 'Gene', (190, 195))	('GNAQ', 'Gene', (28, 32))	('EIF1AX', 'Gene', (52, 58))	('GNA11', 'Gene', '2767', (183, 188))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (119, 133))	('GNA11', 'Gene', (34, 39))	('GNAQ', 'Gene', '2776', (177, 181))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('mutations', 'Var', (164, 173))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))	('GNAQ', 'Gene', (177, 181))	('EIF1AX', 'Gene', (201, 207))
19952	27089234	The frequency and clinical significance of these mutations in non-uveal melanoma and other cancers is not well described.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('mutations', 'Var', (49, 58))	('clinical', 'Species', '191496', (18, 26))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('non-uveal melanoma', 'Disease', (62, 80))	('cancers', 'Disease', (91, 98))	('non-uveal melanoma', 'Disease', 'MESH:C536494', (62, 80))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
19953	27089234	We identified that GNAQ/GNA11 mutations occur in 0.5-1% of non-uveal melanomas and are essentially melanoma-specific.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('GNAQ', 'Gene', (19, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (63, 77))	('non-uveal melanomas', 'Disease', (59, 78))	('GNAQ', 'Gene', '2776', (19, 23))	('uveal melanomas', 'Phenotype', 'HP:0007716', (63, 78))	('mutations', 'Var', (30, 39))	('GNA11', 'Gene', '2767', (24, 29))	('melanoma', 'Disease', (99, 107))	('GNA11', 'Gene', (24, 29))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('non-uveal melanomas', 'Disease', 'MESH:C536494', (59, 78))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanomas', 'Phenotype', 'HP:0002861', (69, 78))	('melanoma', 'Disease', (69, 77))
19954	27089234	Further, these mutations are associated with a lack of other typical melanoma mutations (BRAF, NRAS, KIT, NF1), a low mutational burden, and, in a small subset, lack of response to immunotherapy.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('KIT', 'Gene', (101, 104))	('mutations', 'Var', (15, 24))	('NF1', 'Gene', (106, 109))	('KIT', 'molecular_function', 'GO:0005020', ('101', '104'))	('NRAS', 'Disease', (95, 99))	('melanoma', 'Disease', (69, 77))
19955	27089234	We suggest that GNAQ/GNA11 mutations characterize an uncommon but distinct subtype of non-uveal melanomas.	('mutations', 'Var', (27, 36))	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('non-uveal melanomas', 'Disease', (86, 105))	('GNAQ', 'Gene', (16, 20))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('uveal melanomas', 'Phenotype', 'HP:0007716', (90, 105))	('GNA11', 'Gene', (21, 26))	('GNAQ', 'Gene', '2776', (16, 20))	('non-uveal melanomas', 'Disease', 'MESH:C536494', (86, 105))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('GNA11', 'Gene', '2767', (21, 26))
19958	27089234	Instead, recurrent mutations in GNAQ, GNA11, SF3B1, and EIF1AX predominate in UMs.	('GNAQ', 'Gene', (32, 36))	('UMs', 'Disease', (78, 81))	('mutations', 'Var', (19, 28))	('GNAQ', 'Gene', '2776', (32, 36))	('SF3B1', 'Gene', (45, 50))	('GNA11', 'Gene', '2767', (38, 43))	('GNA11', 'Gene', (38, 43))	('UM', 'Phenotype', 'HP:0007716', (78, 80))	('EIF1AX', 'Gene', (56, 62))
19959	27089234	GNAQ/GNA11 codon 209 mutations induce mitogen-activated protein kinase (MAPK) signaling and occur in ~80% of UMs (and in rare melanocytic neoplasms: blue nevi, central nervous system melanocytomas).	('central nervous system melanocytomas', 'Disease', 'MESH:D002493', (160, 196))	('mitogen-activated protein kinase', 'MPA', (38, 70))	('blue nevi', 'Phenotype', 'HP:0100814', (149, 158))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('neoplasms', 'Phenotype', 'HP:0002664', (138, 147))	('GNA11', 'Gene', (5, 10))	('MAPK) signaling', 'biological_process', 'GO:0000165', ('72', '87'))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (126, 147))	('UMs', 'Disease', (109, 112))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (126, 147))	('MAPK', 'molecular_function', 'GO:0004707', ('72', '76'))	('melanocytic neoplasms', 'Disease', (126, 147))	('induce', 'PosReg', (31, 37))	('nevi', 'Phenotype', 'HP:0003764', (154, 158))	('mutations', 'Var', (21, 30))	('GNAQ', 'Gene', '2776', (0, 4))	('GNA11', 'Gene', '2767', (5, 10))	('central nervous system melanocytomas', 'Disease', (160, 196))	('UM', 'Phenotype', 'HP:0007716', (109, 111))	('GNAQ', 'Gene', (0, 4))	('blue nevi', 'Disease', (149, 158))
19960	27089234	The frequency, genetic profile (including co-occurring mutations), and clinical implications of these stereotypical UM mutations in NUM and other cancers have not been thoroughly characterized.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('UM', 'Phenotype', 'HP:0007716', (133, 135))	('clinical', 'Species', '191496', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('UM', 'Phenotype', 'HP:0007716', (116, 118))	('mutations', 'Var', (119, 128))	('NUM', 'Disease', (132, 135))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
19962	27089234	We then reviewed the sequencing data from >2000 patients from four large melanoma centers (Vanderbilt, MD Anderson, Memorial Sloan Kettering, Moffitt Cancer Centers), to characterize the clinical and pathologic features of melanomas harboring these mutations.	('melanoma', 'Disease', (223, 231))	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('Cancer', 'Phenotype', 'HP:0002664', (150, 156))	('mutations', 'Var', (249, 258))	('clinical', 'Species', '191496', (187, 195))	('melanomas', 'Disease', (223, 232))	('Moffitt Cancer', 'Disease', (142, 156))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('melanomas', 'Phenotype', 'HP:0002861', (223, 232))	('patients', 'Species', '9606', (48, 56))	('Moffitt Cancer', 'Disease', 'MESH:D009369', (142, 156))	('melanomas', 'Disease', 'MESH:D008545', (223, 232))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
19963	27089234	Across the cancer spectrum in the TCGA (17 malignancies, 4972 individual samples) and two other publically-available melanoma databases, we did not identify any GNAQ/GNA11Q209 mutations outside of cutaneous melanomas (non-cutaneous melanomas were excluded from the TCGA).	('mutations', 'Var', (176, 185))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanoma', 'Disease', (207, 215))	('malignancies', 'Disease', (43, 55))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('melanomas', 'Phenotype', 'HP:0002861', (207, 216))	('melanoma', 'Disease', (232, 240))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (222, 241))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (222, 241))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (197, 216))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (197, 216))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('GNAQ', 'Gene', '2776', (161, 165))	('cutaneous melanomas', 'Disease', (222, 241))	('melanoma', 'Disease', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('GNA11', 'Gene', '2767', (166, 171))	('melanoma', 'Disease', 'MESH:D008545', (207, 215))	('GNAQ', 'Gene', (161, 165))	('melanoma', 'Disease', 'MESH:D008545', (232, 240))	('cutaneous melanomas', 'Disease', (197, 216))	('melanomas', 'Phenotype', 'HP:0002861', (232, 241))	('cancer', 'Disease', (11, 17))	('GNA11', 'Gene', (166, 171))	('malignancies', 'Disease', 'MESH:D009369', (43, 55))
19964	27089234	Sporadic cases of non-Q209 GNAQ/GNA11 mutations were identified in various malignancies (<1% incidence); all were distinct and non-recurrent (Table S1).	('malignancies', 'Disease', 'MESH:D009369', (75, 87))	('GNAQ', 'Gene', '2776', (27, 31))	('GNA11', 'Gene', '2767', (32, 37))	('GNA11', 'Gene', (32, 37))	('malignancies', 'Disease', (75, 87))	('GNAQ', 'Gene', (27, 31))	('mutations', 'Var', (38, 47))	('non-Q209', 'Var', (18, 26))
19966	27089234	By contrast SF3B1K700E mutations predominated in breast carcinoma (8/11 samples, 73%), similar to myelodysplastic syndrome and chronic lymphocytic leukemia.	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (127, 155))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('chronic lymphocytic leukemia', 'Disease', (127, 155))	('SF3B1K700E mutations', 'Var', (12, 32))	('breast carcinoma', 'Disease', (49, 65))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (98, 122))	('breast carcinoma', 'Disease', 'MESH:D001943', (49, 65))	('breast carcinoma', 'Phenotype', 'HP:0003002', (49, 65))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (127, 155))	('myelodysplastic syndrome', 'Disease', (98, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (98, 122))
19967	27089234	EIF1AX alterations occurred infrequently in low-grade gliomas (1.4%), uterus endometrial carcinoma (1.25%), thyroid carcinoma (1%), and lung adenocarcinoma (0.4%) (Table S1).	('uterus endometrial carcinoma', 'Disease', (70, 98))	('uterus endometrial carcinoma', 'Disease', 'MESH:D016889', (70, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (77, 98))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (108, 125))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (136, 155))	('gliomas', 'Disease', 'MESH:D005910', (54, 61))	('gliomas', 'Phenotype', 'HP:0009733', (54, 61))	('gliomas', 'Disease', (54, 61))	('thyroid carcinoma', 'Disease', (108, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('lung adenocarcinoma', 'Disease', (136, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (136, 155))	('alterations', 'Var', (7, 18))	('EIF1AX', 'Gene', (0, 6))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (108, 125))
19968	27089234	We then assessed the frequency of GNAQ, GNA11, SF3B1, and EIF1AX mutations in NUMs using three large publically-available melanoma sequencing databases.	('SF3B1', 'Gene', (47, 52))	('GNA11', 'Gene', (40, 45))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('GNA11', 'Gene', '2767', (40, 45))	('GNAQ', 'Gene', (34, 38))	('EIF1AX', 'Gene', (58, 64))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('mutations', 'Var', (65, 74))	('GNAQ', 'Gene', '2776', (34, 38))
19969	27089234	We identified two GNAQQ209P and two GNA11Q209 mutant samples, comprising 0.83% of the total NUMs (4 of 483).	('GNAQQ209P', 'Mutation', 'rs121913492', (18, 27))	('GNA11', 'Gene', '2767', (36, 41))	('GNA11', 'Gene', (36, 41))	('UM', 'Phenotype', 'HP:0007716', (93, 95))	('GNAQQ209P', 'Var', (18, 27))
19970	27089234	SF3B1 "hotspot" mutations were present in 8 NUMs (1.66%), including three with concurrent GNAQ/GNA11Q209 mutations.	('GNA11', 'Gene', (95, 100))	('GNAQ', 'Gene', '2776', (90, 94))	('mutations', 'Var', (16, 25))	('GNA11', 'Gene', '2767', (95, 100))	('GNAQ', 'Gene', (90, 94))	('UM', 'Phenotype', 'HP:0007716', (45, 47))
19971	27089234	Three NUMs harbored EIF1AX mutations (0.62%) and overlapped with a GNA11Q209 mutation in one case.	('mutations', 'Var', (27, 36))	('GNA11', 'Gene', (67, 72))	('GNA11', 'Gene', '2767', (67, 72))	('EIF1AX', 'Gene', (20, 26))	('UM', 'Phenotype', 'HP:0007716', (7, 9))
19972	27089234	Notably, activating GNAQ/GNA11 mutations did not co-occur with other common melanoma "driver" mutations affecting MAPK signaling (e.g., BRAF, NRAS, KIT) in NUM, supporting the notion that activated GNAQ/GNA11 is sufficient to activate the MAPK pathway (Figure 1).	('MAPK signaling', 'MPA', (114, 128))	('GNAQ', 'Gene', (198, 202))	('KIT', 'molecular_function', 'GO:0005020', ('146', '149'))	('activate', 'PosReg', (226, 234))	('GNAQ', 'Gene', '2776', (20, 24))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('MAPK pathway', 'Pathway', (239, 251))	('GNAQ', 'Gene', (20, 24))	('GNA11', 'Gene', (203, 208))	('MAPK signaling', 'biological_process', 'GO:0000165', ('112', '126'))	('GNA11', 'Gene', '2767', (25, 30))	('mutations', 'Var', (31, 40))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('melanoma', 'Disease', (76, 84))	('MAPK', 'molecular_function', 'GO:0004707', ('237', '241'))	('activating', 'PosReg', (9, 19))	('GNAQ', 'Gene', '2776', (198, 202))	('GNA11', 'Gene', '2767', (203, 208))	('GNA11', 'Gene', (25, 30))	('UM', 'Phenotype', 'HP:0007716', (157, 159))	('MAPK', 'molecular_function', 'GO:0004707', ('112', '116'))
19973	27089234	By contrast, the 8 samples with SF3B1 or EIF1AX mutations without GNAQ/GNA11 mutations, frequently overlapped with BRAFV600 mutations (n=4) or NRASQ61 mutations (n=3).	('GNA11', 'Gene', (71, 76))	('GNAQ', 'Gene', '2776', (66, 70))	('BRAFV600', 'Gene', (115, 123))	('GNA11', 'Gene', '2767', (71, 76))	('GNAQ', 'Gene', (66, 70))	('SF3B1', 'Gene', (32, 37))	('EIF1AX', 'Gene', (41, 47))	('mutations', 'Var', (48, 57))
19976	27089234	Among clinical samples, targeted NGS (sequencing 236 genes) for 3 GNAQ/GNA11-mutated melanomas was performed; these samples had fewer mutations compared to 48 other unselected melanoma samples (median 8 vs. 17 mutations; p=0.03; Figure S1B).	('clinical samples', 'Species', '191496', (6, 22))	('melanomas', 'Disease', (85, 94))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))	('GNA11', 'Gene', (71, 76))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('GNAQ', 'Gene', '2776', (66, 70))	('GNA11', 'Gene', '2767', (71, 76))	('melanomas', 'Disease', 'MESH:D008545', (85, 94))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('mutations', 'Var', (134, 143))	('melanoma', 'Disease', (85, 93))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('GNAQ', 'Gene', (66, 70))
19983	27089234	Among these 17 tumors with GNAQ/GNA11Q209 mutations, concurrent BRAF, NRAS, KIT, NF1 or other MAPK-activating alterations were not identified, with one exception (vulvar melanoma with GNA11Q209H, KITV559D, and BRAFG469V mutations).	('MAPK', 'molecular_function', 'GO:0004707', ('94', '98'))	('GNAQ', 'Gene', '2776', (27, 31))	('vulvar melanoma', 'Disease', 'MESH:D008545', (163, 178))	('GNA11', 'Gene', '2767', (184, 189))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('GNA11', 'Gene', '2767', (32, 37))	('GNA11', 'Gene', (32, 37))	('vulvar melanoma', 'Disease', (163, 178))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('KITV559D', 'Var', (196, 204))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('BRAFG469V mutations', 'Var', (210, 229))	('GNAQ', 'Gene', (27, 31))	('KIT', 'molecular_function', 'GO:0005020', ('76', '79'))	('vulvar melanoma', 'Phenotype', 'HP:0030418', (163, 178))	('tumors', 'Disease', (15, 21))	('GNA11', 'Gene', (184, 189))
19984	27089234	We then assessed treatment outcomes; of 11 patients with GNAQ/GNA11 mutations who received immunotherapy, only one responded to treatment.	('GNAQ', 'Gene', (57, 61))	('patients', 'Species', '9606', (43, 51))	('mutations', 'Var', (68, 77))	('GNA11', 'Gene', '2767', (62, 67))	('GNA11', 'Gene', (62, 67))	('GNAQ', 'Gene', '2776', (57, 61))
19986	27089234	The single patient with an immunotherapy response had the only highly-mutated tumor in this group (49 mutations on targeted NGS as mentioned above).	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('patient', 'Species', '9606', (11, 18))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', (78, 83))
19987	27089234	In conclusion, we identified that GNAQ/GNA11Q209 mutations characterized a distinct, albeit uncommon subtype of NUM (0.5-1%).	('GNA11', 'Gene', (39, 44))	('mutations', 'Var', (49, 58))	('NUM', 'Disease', (112, 115))	('GNA11', 'Gene', '2767', (39, 44))	('GNAQ', 'Gene', (34, 38))	('UM', 'Phenotype', 'HP:0007716', (113, 115))	('GNAQ', 'Gene', '2776', (34, 38))
19988	27089234	These mutations were essentially melanoma-specific, occurred in all subtypes of this disease (including cutaneous, mucosal, uveal, and unknown primary), and were mutually exclusive with other common melanoma mutations.	('cutaneous', 'Disease', (104, 113))	('occurred', 'Reg', (52, 60))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('uveal', 'Disease', (124, 129))	('mucosal', 'Disease', (115, 122))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('melanoma', 'Disease', (199, 207))	('mutations', 'Var', (6, 15))
20011	28559841	Histopathological examination of the biopsy specimen showed malignant melanoma of the epitheloid type G2-3 with necrotic spaces, S100+, HMB45+, MelanA+, cyclin D1 -, p53-, Bcl2+ 20%, Ki67+ 30%, with poor prognosis (Fig.	('MelanA+', 'Var', (144, 151))	('malignant melanoma', 'Disease', 'MESH:D008545', (60, 78))	('Ki67+', 'Var', (183, 188))	('cyclin D1', 'Gene', '595', (153, 162))	('malignant melanoma', 'Disease', (60, 78))	('Bcl2', 'Gene', (172, 176))	('necrotic', 'Disease', 'MESH:D009336', (112, 120))	('p53', 'Gene', (166, 169))	('cyclin D1', 'Gene', (153, 162))	('p53', 'Gene', '7157', (166, 169))	('Bcl2', 'Gene', '596', (172, 176))	('cyclin', 'molecular_function', 'GO:0016538', ('153', '159'))	('HMB45+', 'Var', (136, 142))	('S100+', 'Var', (129, 134))	('necrotic', 'Disease', (112, 120))	('Bcl2', 'molecular_function', 'GO:0015283', ('172', '176'))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('malignant melanoma', 'Phenotype', 'HP:0002861', (60, 78))
20029	27830163	The mean number of liver metastases detected was significant higher on 80-kVp images than on virtual 120-kVp/DSA images (5.6 +- 2.1 vs. 4.1 +- 1.8/4.3 +- 1.6); (p < 0.001).	('liver metastases', 'Disease', (19, 35))	('higher', 'PosReg', (61, 67))	('80-kVp', 'Var', (71, 77))	('liver metastases', 'Disease', 'MESH:D009362', (19, 35))
20036	27830163	Higher detection rates were explained by higher attenuation of iodine in the low-kVp images in comparison to 140-kVp and virtual 120-kVp images.	('attenuation', 'MPA', (48, 59))	('low-kVp', 'Var', (77, 84))	('detection', 'MPA', (7, 16))	('iodine', 'Chemical', 'MESH:D007455', (63, 69))	('Higher', 'PosReg', (0, 6))	('iodine', 'Protein', (63, 69))
20058	27830163	We could show that significant more and smaller metastases can be detected with the help of low kVp images compared to the virtual 120 kVp and DSA images.	('low kVp', 'Var', (92, 99))	('metastases', 'Disease', 'MESH:D009362', (48, 58))	('smaller', 'NegReg', (40, 47))	('metastases', 'Disease', (48, 58))
20061	27830163	The poorer image quality of low kVp images caused by the increased image noise had no negative influence on the recognizability of metastases because sensitivity was increased by the higher SNR and CNR.	('sensitivity', 'MPA', (150, 161))	('CNR', 'Var', (198, 201))	('metastases', 'Disease', (131, 141))	('increased', 'PosReg', (166, 175))	('SNR', 'Var', (190, 193))	('metastases', 'Disease', 'MESH:D009362', (131, 141))
20073	27499155	The three most significantly associated variants rs12913832 (OR = 0.529, 95% CI 0.415-0.673; p = 8.47E-08), rs1129038 (OR = 0.533, 95% CI 0.419-0.678; p = 1.19E-07) and rs916977 (OR = 0.465, 95% CI 0.339-0.637; p = 3.04E-07) are correlated (r2 > 0.5) and map at 15q12 in the region of HERC2/OCA2, which determines eye-color in the human population.	('HERC2', 'Gene', '8924', (285, 290))	('rs1129038', 'Mutation', 'rs1129038', (108, 117))	('rs1129038', 'Var', (108, 117))	('human', 'Species', '9606', (331, 336))	('OCA2', 'Gene', (291, 295))	('rs12913832', 'Var', (49, 59))	('rs916977', 'Var', (169, 177))	('rs916977', 'Mutation', 'rs916977', (169, 177))	('HERC2', 'Gene', (285, 290))	('OCA2', 'Gene', '4948', (291, 295))	('rs12913832', 'Mutation', 'rs12913832', (49, 59))
20077	27499155	Despite this, currently known highly penetrant germline mutations in BAP1, CDKN2A, or BRCA2 explain only about 3% of UM population-specific risk.	('BRCA2', 'Gene', (86, 91))	('germline mutations', 'Var', (47, 65))	('CDKN2A', 'Gene', (75, 81))	('BAP1', 'Gene', (69, 73))	('BRCA2', 'Gene', '675', (86, 91))	('CDKN2A', 'Gene', '1029', (75, 81))	('UM', 'Phenotype', 'HP:0007716', (117, 119))	('BAP1', 'Gene', '8314', (69, 73))
20080	27499155	Recently, a number of genetic variants have been reproducibly associated in GWASs with the risk of CM and skin/eye pigmentation traits (Supplementary Table 1).	('variants', 'Var', (30, 38))	('eye pigmentation', 'biological_process', 'GO:0048069', ('111', '127'))	('associated', 'Reg', (62, 72))	('skin/eye pigmentation traits', 'Disease', (106, 134))	('skin/eye pigmentation traits', 'Disease', 'MESH:D010859', (106, 134))	('CM', 'Disease', 'MESH:D009202', (99, 101))	('CM', 'Phenotype', 'HP:0012056', (99, 101))
20081	27499155	The shared etiological risk factors between CM and UM (including pigmentation) suggest that a subset of CM risk variants would associate with genetic susceptibility to UM.	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('pigmentation', 'Disease', 'MESH:D010859', (65, 77))	('CM', 'Phenotype', 'HP:0012056', (44, 46))	('UM', 'Phenotype', 'HP:0007716', (168, 170))	('CM', 'Disease', 'MESH:D009202', (44, 46))	('pigmentation', 'biological_process', 'GO:0043473', ('65', '77'))	('pigmentation', 'Disease', (65, 77))	('CM', 'Disease', 'MESH:D009202', (104, 106))	('CM', 'Phenotype', 'HP:0012056', (104, 106))	('associate', 'Reg', (127, 136))	('variants', 'Var', (112, 120))
20083	27499155	Logistic regression analysis adjusted by age and gender revealed a novel association with reduced UM risk in the locus of HERC2/OCA2 at 15q13 for 3 correlated SNPs (r2 > 0.5), which were still significant following adjustment for multiple testing (Table 1, full results in Supplementary Table 3): rs12913832 (OR = 0.529, 95% CI 0.415-0.673; p = 8.47E-08), rs1129038 (OR = 0.533, 95% CI 0.419-0.678; p = 1.19E-07) and rs916977 (OR = 0.465, 95% CI 0.339-0.637; p = 3.04E-07).	('rs916977', 'Var', (417, 425))	('reduced', 'NegReg', (90, 97))	('rs12913832', 'Mutation', 'rs12913832', (297, 307))	('OCA2', 'Gene', '4948', (128, 132))	('HERC2', 'Gene', (122, 127))	('rs916977', 'Mutation', 'rs916977', (417, 425))	('HERC2', 'Gene', '8924', (122, 127))	('rs12913832', 'Var', (297, 307))	('rs1129038', 'Mutation', 'rs1129038', (356, 365))	('UM', 'Phenotype', 'HP:0007716', (98, 100))	('OCA2', 'Gene', (128, 132))
20086	27499155	The directionality and magnitude of odds ratios for all three SNPs reported for CM and UM risk are similar (for rs12913832 OR = 0.69 versus 0.53, respectively), further suggesting that pigmentation is a shared etiological risk factor between both diseases.	('pigmentation', 'Disease', 'MESH:D010859', (185, 197))	('pigmentation', 'Disease', (185, 197))	('UM', 'Phenotype', 'HP:0007716', (87, 89))	('pigmentation', 'biological_process', 'GO:0043473', ('185', '197'))	('rs12913832', 'Mutation', 'rs12913832', (112, 122))	('CM', 'Disease', 'MESH:D009202', (80, 82))	('CM', 'Phenotype', 'HP:0012056', (80, 82))	('rs12913832', 'Var', (112, 122))
20087	27499155	The associations with UM risk remained comparably significant after adjustment for family history of other cancers (including family history of CM), personal history of CM or major UM subtypes (for rs12913832: p = 7.08E-06, p = 1.23E-06 and p = 3.06E-06, respectively).	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('CM', 'Disease', 'MESH:D009202', (144, 146))	('rs12913832', 'Mutation', 'rs12913832', (198, 208))	('CM', 'Phenotype', 'HP:0012056', (144, 146))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('CM', 'Disease', 'MESH:D009202', (169, 171))	('UM', 'Phenotype', 'HP:0007716', (22, 24))	('CM', 'Phenotype', 'HP:0012056', (169, 171))	('rs12913832', 'Var', (198, 208))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('UM', 'Phenotype', 'HP:0007716', (181, 183))
20089	27499155	Prior functional data show that our most significant variant rs12913832 in the intronic region of HERC2, is a key pigmentation "regulator allele" that impacts the expression of OCA2 via a long range enhancer mechanism.	('pigmentation', 'biological_process', 'GO:0043473', ('114', '126'))	('enhancer', 'PosReg', (199, 207))	('OCA2', 'Gene', (177, 181))	('rs12913832', 'Mutation', 'rs12913832', (61, 71))	('HERC2', 'Gene', (98, 103))	('pigmentation', 'Disease', 'MESH:D010859', (114, 126))	('pigmentation', 'Disease', (114, 126))	('HERC2', 'Gene', '8924', (98, 103))	('impacts', 'Reg', (151, 158))	('expression', 'MPA', (163, 173))	('OCA2', 'Gene', '4948', (177, 181))	('rs12913832', 'Var', (61, 71))
20090	27499155	The less common T-allele (darker eye color) of rs12913832, associated with UM-protective effect in our data, enhances OCA2 expression resulting in darkly pigmented melanocytes.	('enhances', 'PosReg', (109, 117))	('expression', 'MPA', (123, 133))	('OCA2', 'Gene', (118, 122))	('rs12913832', 'Mutation', 'rs12913832', (47, 57))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('darkly pigmented melanocytes', 'CPA', (147, 175))	('OCA2', 'Gene', '4948', (118, 122))	('darker eye color', 'Phenotype', 'HP:0007730', (26, 42))	('rs12913832', 'Var', (47, 57))
20095	27499155	1, Table 1 and Supplementary Table 3), interestingly, imputed data showed an association signal, albeit with reduced significance, for another correlated variant, rs1667394 (r2 = 0.48) (Supplementary Table 5), that was also previously identified in a GWAS for association with eye color.	('rs1667394', 'Mutation', 'rs1667394', (163, 172))	('rs1667394', 'Var', (163, 172))	('association', 'Interaction', (77, 88))	('eye color', 'Disease', (277, 286))
20096	27499155	While the data with imputed variants confine the association locus to a narrow ~250 kb region at HERC2/OCA2, none of the associations remained statistically significant after conditioning the analysis for rs12913832 (data not shown).	('HERC2', 'Gene', '8924', (97, 102))	('rs12913832', 'Mutation', 'rs12913832', (205, 215))	('variants', 'Var', (28, 36))	('OCA2', 'Gene', '4948', (103, 107))	('OCA2', 'Gene', (103, 107))	('HERC2', 'Gene', (97, 102))
20097	27499155	This suggests that all observed associations at HERC2/OCA2 stem from a signal driven by rs12913832.	('rs12913832', 'Mutation', 'rs12913832', (88, 98))	('OCA2', 'Gene', (54, 58))	('associations', 'Interaction', (32, 44))	('HERC2', 'Gene', (48, 53))	('OCA2', 'Gene', '4948', (54, 58))	('rs12913832', 'Var', (88, 98))	('HERC2', 'Gene', '8924', (48, 53))
20098	27499155	These findings together with prior established functional data on rs12913832 and eye pigmentation indicate that this is the strongest candidate to be biologically relevant in UM development.	('eye pigmentation', 'Disease', (81, 97))	('rs12913832', 'Mutation', 'rs12913832', (66, 76))	('rs12913832', 'Var', (66, 76))	('eye pigmentation', 'Disease', 'MESH:D010859', (81, 97))	('eye pigmentation', 'biological_process', 'GO:0048069', ('81', '97'))	('UM', 'Phenotype', 'HP:0007716', (175, 177))
20101	27499155	The most significant associations at HERC2/OCA2 locus (Table 1), as well as rs12203592 in IRF4, all show odds ratios <0.6 or >1.4, respectively (Table 1).	('HERC2', 'Gene', (37, 42))	('OCA2', 'Gene', (43, 47))	('IRF4', 'Gene', '3662', (90, 94))	('IRF4', 'Gene', (90, 94))	('HERC2', 'Gene', '8924', (37, 42))	('rs12203592', 'Var', (76, 86))	('OCA2', 'Gene', '4948', (43, 47))	('rs12203592', 'Mutation', 'rs12203592', (76, 86))
20104	27499155	The molecular effect of pigmentation on different UM subtypes has recently been suggested, as different GNAQ mutation signatures were observed in posterior (choroid) versus anterior UM tumors (ciliary body, iris), likely reflecting divergent UM pathways related to toxic pheomelanin synthesis.	('pigmentation', 'biological_process', 'GO:0043473', ('24', '36'))	('UM', 'Phenotype', 'HP:0007716', (182, 184))	('pigmentation', 'Disease', 'MESH:D010859', (24, 36))	('pheomelanin', 'Chemical', 'MESH:C018362', (271, 282))	('pigmentation', 'Disease', (24, 36))	('GNAQ', 'Gene', '2776', (104, 108))	('UM', 'Phenotype', 'HP:0007716', (242, 244))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('synthesis', 'biological_process', 'GO:0009058', ('283', '292'))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('GNAQ', 'Gene', (104, 108))	('mutation', 'Var', (109, 117))
20105	27499155	This molecular support for a role of melanin in UM histologies and the association of germline variants of eye color with UM risk found in this study suggest interplay between both somatic and inherited factors of pigmentation pathways in UM development.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('UM', 'Phenotype', 'HP:0007716', (239, 241))	('pigmentation', 'biological_process', 'GO:0043473', ('214', '226'))	('melanin', 'Chemical', 'MESH:D008543', (37, 44))	('variants', 'Var', (95, 103))	('pigmentation', 'Disease', 'MESH:D010859', (214, 226))	('pigmentation', 'Disease', (214, 226))	('UM', 'Phenotype', 'HP:0007716', (122, 124))
20107	27499155	Both control sets show comparable allele frequencies of HERC2/OCA2 variants, indicating similarities in distribution of pigmentation in both control sets.	('pigmentation', 'Disease', 'MESH:D010859', (120, 132))	('pigmentation', 'Disease', (120, 132))	('HERC2', 'Gene', '8924', (56, 61))	('OCA2', 'Gene', '4948', (62, 66))	('pigmentation', 'biological_process', 'GO:0043473', ('120', '132'))	('HERC2', 'Gene', (56, 61))	('OCA2', 'Gene', (62, 66))	('variants', 'Var', (67, 75))
20108	27499155	Also, it has been previously demonstrated that the distribution of pigmentation variants, including rs12913832, in European populations along a north-south axis often manifests with significant Hardy Weinberg equilibrium (HWE) departures, likely as reult of underlying selection pressure for these alleles.	('Hardy Weinberg equilibrium', 'MPA', (194, 220))	('pigmentation', 'biological_process', 'GO:0043473', ('67', '79'))	('departures', 'Var', (227, 237))	('rs12913832', 'Var', (100, 110))	('pigmentation', 'Disease', 'MESH:D010859', (67, 79))	('pigmentation', 'Disease', (67, 79))	('rs12913832', 'Mutation', 'rs12913832', (100, 110))
20129	27499155	To test the association of common genetic variants (MAF > 0.05) with the risk of UM, a total of 29 SNPs were selected through the comprehensive search of published GWAS data on melanoma risk, nevi-driven phenotypes, pigmentation, hair color, skin color and other melanoma risk etiologies.	('pigmentation', 'biological_process', 'GO:0043473', ('216', '228'))	('pigmentation', 'Disease', 'MESH:D010859', (216, 228))	('pigmentation', 'Disease', (216, 228))	('variants', 'Var', (42, 50))	('UM', 'Phenotype', 'HP:0007716', (81, 83))	('melanoma', 'Disease', 'MESH:D008545', (263, 271))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('melanoma', 'Phenotype', 'HP:0002861', (263, 271))	('melanoma', 'Disease', (263, 271))	('melanoma', 'Disease', (177, 185))	('hair color', 'Disease', (230, 240))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('nevi', 'Phenotype', 'HP:0003764', (192, 196))	('hair color', 'Disease', 'MESH:D003117', (230, 240))
20131	27499155	This left all 8 genotyped variants in HERC2/OCA2 locus to be used for inference.	('OCA2', 'Gene', (44, 48))	('HERC2', 'Gene', (38, 43))	('OCA2', 'Gene', '4948', (44, 48))	('HERC2', 'Gene', '8924', (38, 43))	('variants', 'Var', (26, 34))
20133	27499155	To assess if these were independent signals, SNPTEST was used to perform conditional logistic regression based on rs12913832 for all genotyped and imputed HERC2/OCA2 variants again with an additive model and using genotype dosages to account for genotype uncertainty.	('rs12913832', 'Mutation', 'rs12913832', (114, 124))	('OCA2', 'Gene', (161, 165))	('rs12913832', 'Var', (114, 124))	('variants', 'Var', (166, 174))	('HERC2', 'Gene', (155, 160))	('OCA2', 'Gene', '4948', (161, 165))	('HERC2', 'Gene', '8924', (155, 160))
20134	27499155	Genetic markers of pigmentation are novel risk loci for uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('uveal melanoma', 'Disease', (56, 70))	('Genetic', 'Var', (0, 7))	('pigmentation', 'biological_process', 'GO:0043473', ('19', '31'))	('pigmentation', 'Disease', 'MESH:D010859', (19, 31))	('pigmentation', 'Disease', (19, 31))	('uveal melanoma', 'Disease', 'MESH:C536494', (56, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
20151	24811334	Other biomarkers such as circulating tumor DNA (ctDNA) and mutant mitochondrial DNA (mtDNA) are being investigated for potential insights into genomic stability, heterogeneity, cancer progression, and tailoring patient specific treatment options (personalized medicine).	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('66', '83'))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mitochondrial DNA', 'Gene', (66, 83))	('mutant', 'Var', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('mtDNA', 'cellular_component', 'GO:0000262', ('85', '90'))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('patient', 'Species', '9606', (211, 218))
20204	24811334	An exploratory analysis within the patients with cutaneous melanoma, positive for BRAF V600E mutation, (N = 7) identified a stronger trend between lower CMCs (<= 100/mL of blood) and increased survival (p = 0.06).	('CMC', 'Chemical', '-', (153, 156))	('V600E', 'Var', (87, 92))	('lower', 'NegReg', (147, 152))	('BRAF', 'Gene', '673', (82, 86))	('cutaneous melanoma', 'Disease', (49, 67))	('survival', 'MPA', (193, 201))	('increased', 'PosReg', (183, 192))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (49, 67))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (49, 67))	('BRAF', 'Gene', (82, 86))	('patients', 'Species', '9606', (35, 43))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('V600E', 'Mutation', 'rs113488022', (87, 92))
20223	24811334	Nevertheless, preliminary analysis of the overall survival based on the CMC counts within our tested cohort of patients indicated a negative trend between survival and CMC counts in all patients (p = 0.12) and particularly for BRAFV600E cutaneous melanoma patients (p = 0.06).	('BRAFV600E', 'Var', (227, 236))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (237, 255))	('BRAFV600E', 'Mutation', 'rs113488022', (227, 236))	('CMC', 'Chemical', '-', (168, 171))	('patients', 'Species', '9606', (256, 264))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (237, 255))	('patients', 'Species', '9606', (111, 119))	('negative', 'NegReg', (132, 140))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('CMC', 'Chemical', '-', (72, 75))	('patients', 'Species', '9606', (186, 194))	('cutaneous melanoma', 'Disease', (237, 255))
20230	24811334	Alternate biomarkers such as ctDNA and mutant mtDNA are also being studied to gain insights into mechanisms of tumor progression and dynamics.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('ctDNA', 'Disease', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mtDNA', 'Gene', (46, 51))	('tumor', 'Disease', (111, 116))	('mtDNA', 'cellular_component', 'GO:0000262', ('46', '51'))	('mutant', 'Var', (39, 45))
20348	23645822	Coleman and co-workeres used 20-MHz ultrasound to visualize the retina, choroid and sclera, and showed that 20-MHz ultrasound provided a 2-fold improvement in resolution compared to the conventional 10-MHz instruments.	('20-MHz', 'Var', (108, 114))	('resolution', 'MPA', (159, 169))	('choroid', 'Disease', (72, 79))	('choroid', 'Disease', 'MESH:D002833', (72, 79))	('improvement', 'PosReg', (144, 155))
20382	23762736	There are certain genomic abnormalities associated with poor prognosis in uveal melanoma, such as inactivation of BAP1 and loss of an entire copy of chromosome 3 (monosomy 3).	('inactivation', 'Var', (98, 110))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('BAP1', 'Gene', '8314', (114, 118))	('loss', 'Var', (123, 127))	('BAP1', 'Gene', (114, 118))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('uveal melanoma', 'Disease', (74, 88))	('chromosome', 'cellular_component', 'GO:0005694', ('149', '159'))
20436	33012143	A positive family history of UM, increased frequency of oculodermal melanocytosis, BAP1 mutations and dysplastic nevi have also been linked to a higher incidence of UM.	('UM', 'Phenotype', 'HP:0007716', (165, 167))	('dysplastic', 'Disease', 'MESH:D004416', (102, 112))	('dysplastic', 'Disease', (102, 112))	('BAP1', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('UM', 'Phenotype', 'HP:0007716', (29, 31))	('nevi', 'Phenotype', 'HP:0003764', (113, 117))	('melanocytosis', 'Disease', (68, 81))	('oculodermal melanocytosis', 'Phenotype', 'HP:0009920', (56, 81))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (102, 117))	('melanocytosis', 'Disease', 'MESH:C535835', (68, 81))	('BAP1', 'Gene', '8314', (83, 87))
20463	33012143	However, in spite of a precise homogenous dose delivery to the tumor, CPRT can also cause damage to the surrounding normal ocular structures leading to toxicities such as maculopathy, retinal detachment, glaucoma, cataract, vitreous hemorrhage and papillopathy.	('glaucoma', 'Phenotype', 'HP:0000501', (204, 212))	('glaucoma', 'Disease', (204, 212))	('retinal detachment', 'Phenotype', 'HP:0000541', (184, 202))	('maculopathy', 'Disease', 'MESH:D008268', (171, 182))	('vitreous hemorrhage and papillopathy', 'Disease', 'MESH:D014823', (224, 260))	('glaucoma', 'Disease', 'MESH:D005901', (204, 212))	('cause', 'Reg', (84, 89))	('toxicities', 'Disease', 'MESH:D064420', (152, 162))	('tumor', 'Disease', (63, 68))	('cataract', 'Phenotype', 'HP:0000518', (214, 222))	('toxicities', 'Disease', (152, 162))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('retinal detachment', 'Disease', (184, 202))	('CPRT', 'Var', (70, 74))	('retinal detachment', 'Disease', 'MESH:D012163', (184, 202))	('maculopathy', 'Disease', (171, 182))	('cataract', 'Disease', (214, 222))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('vitreous hemorrhage', 'Phenotype', 'HP:0007902', (224, 243))	('cataract', 'Disease', 'MESH:D002386', (214, 222))
20478	33012143	They concluded that 103Pd provided a superior option compared to alternative forms of radiation and demonstrated a local control of 96.7%; only 14 patients in the study required enucleation at a later date.	('103Pd', 'Var', (20, 25))	('local control', 'CPA', (115, 128))	('patients', 'Species', '9606', (147, 155))	('enucleation', 'biological_process', 'GO:0090601', ('178', '189'))
20551	32352005	Using various manipulations of the actin cytoskeleton, a Rho kinase inhibitor, Y27632, increased the number of vesicles transferred, while inhibition of the Arp2/3 complex with CK-666 reduced vesicle transfer.	('increased', 'PosReg', (87, 96))	('inhibition', 'NegReg', (139, 149))	('number of vesicles transferred', 'MPA', (101, 131))	('Y27632', 'Var', (79, 85))	('Y27632', 'Chemical', 'MESH:C108830', (79, 85))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('61', '77'))	('vesicle', 'MPA', (192, 199))	('Arp2/3', 'Protein', (157, 163))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('35', '53'))	('vesicle', 'cellular_component', 'GO:0031982', ('192', '199'))
20572	32352005	Mutations in OPA1 and MFN2 genes cause autosomal dominant optic atrophy (DOA); mutations in WFS1 and CISD2 can cause Wolfram syndrome, while Leber's hereditary optic neuropathy (LHON) is associated with mutations in mitochondrial ND1, ND4, and ND6 genes.	('cause', 'Reg', (33, 38))	('Wolfram syndrome', 'Disease', 'MESH:D014929', (117, 133))	('hereditary optic neuropathy', 'Disease', 'MESH:D009901', (149, 176))	('WFS1', 'Gene', '22393', (92, 96))	('MFN2', 'Gene', (22, 26))	('optic atrophy', 'Disease', (58, 71))	('CISD2', 'Gene', '67006', (101, 106))	('cause', 'Reg', (111, 116))	('mutations', 'Var', (79, 88))	('optic atrophy', 'Phenotype', 'HP:0000648', (58, 71))	('WFS1', 'Gene', (92, 96))	('hereditary optic neuropathy', 'Disease', (149, 176))	('ND4', 'Gene', (235, 238))	('Mutations', 'Var', (0, 9))	('ND1', 'Gene', '17716', (230, 233))	('neuropathy', 'Phenotype', 'HP:0009830', (166, 176))	('MFN2', 'Gene', '170731', (22, 26))	('ND1', 'Gene', (230, 233))	('ND4', 'Gene', '17719', (235, 238))	('optic neuropathy', 'Phenotype', 'HP:0001138', (160, 176))	('CISD2', 'Gene', (101, 106))	('Wolfram syndrome', 'Disease', (117, 133))	('ND6', 'Gene', '17722', (244, 247))	('associated', 'Reg', (187, 197))	('optic atrophy', 'Disease', 'MESH:D009896', (58, 71))	('mutations', 'Var', (203, 212))	('OPA1', 'Gene', '74143', (13, 17))	('OPA1', 'Gene', (13, 17))	('ND6', 'Gene', (244, 247))
20578	32352005	Other groups have suggested that TNT-mediated transfer could induce differentiation of mesenchymal stem cells into renal tubule cells, while mitochondrial transfer in cocultures of endothelial cells and cancer cells conveyed chemoresistance to the cancer cells receiving the mitochondria.	('cancer', 'Disease', (248, 254))	('transfer', 'Var', (46, 54))	('mitochondrial transfer', 'Var', (141, 163))	('chemoresistance', 'CPA', (225, 240))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('mitochondria', 'cellular_component', 'GO:0005739', ('275', '287'))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('conveyed', 'Reg', (216, 224))	('induce', 'Reg', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('differentiation', 'CPA', (68, 83))
20599	32352005	The neck domain of Myo10, which contains IQ motifs, may regulate the motor activity of the head domain or increase flexibility of the molecule as it walks hand-over-hand along actin filaments.	('neck', 'cellular_component', 'GO:0044326', ('4', '8'))	('Myo10', 'Gene', '17909', (19, 24))	('motifs', 'Var', (44, 50))	('regulate', 'Reg', (56, 64))	('increase', 'PosReg', (106, 114))	('motor activity', 'molecular_function', 'GO:0003774', ('69', '83'))	('Myo10', 'Gene', (19, 24))	('flexibility', 'MPA', (115, 126))	('motor activity', 'MPA', (69, 83))
20603	32352005	Overexpression of Myo10 in a variety of cell types increases the number of filopodia emanating from the cell surface, while Myo10 knockdown reduces filopodia number.	('reduces', 'NegReg', (140, 147))	('Myo10', 'Gene', (18, 23))	('increases', 'PosReg', (51, 60))	('knockdown', 'Var', (130, 139))	('Myo10', 'Gene', '17909', (18, 23))	('cell surface', 'cellular_component', 'GO:0009986', ('104', '116'))	('Myo10', 'Gene', (124, 129))	('Myo10', 'Gene', '17909', (124, 129))	('filopodia number', 'CPA', (148, 164))
20615	32352005	In an anterior eye study, RNAi silencing lentivirus was generated to selectively knock down Myo10 in TM tissue and cells.	('knock', 'Var', (81, 86))	('Myo10', 'Gene', (92, 97))	('RNAi', 'biological_process', 'GO:0016246', ('26', '30'))	('Myo10', 'Gene', '17909', (92, 97))
20616	32352005	First, Myo10 silencing lentivirus was applied to an ex vivo organ culture perfusion model to examine the effects on outflow and IOP regulation.	('Myo10', 'Gene', (7, 12))	('Myo10', 'Gene', '17909', (7, 12))	('silencing', 'Var', (13, 22))	('regulation', 'biological_process', 'GO:0065007', ('132', '142'))
20621	32352005	The first knockout model ablated both full-length and headless forms of Myo10.	('Myo10', 'Gene', (72, 77))	('ablated', 'Var', (25, 32))	('Myo10', 'Gene', '17909', (72, 77))
20622	32352005	Between embryonic days E12.5 and E17.5, approximately 60% of Myo10 knockout mice exhibited exencephaly, a lethal neural tube closure defect.	('Myo10', 'Gene', (61, 66))	('Myo10', 'Gene', '17909', (61, 66))	('exencephaly', 'Phenotype', 'HP:0030769', (91, 102))	('neural tube closure', 'biological_process', 'GO:0001843', ('113', '132'))	('knockout', 'Var', (67, 75))	('neural tube closure defect', 'Phenotype', 'HP:0045005', (113, 139))	('exencephaly', 'Disease', 'MESH:D009436', (91, 102))	('mice', 'Species', '10090', (76, 80))	('exhibited', 'Reg', (81, 90))	('exencephaly', 'Disease', (91, 102))
20631	32352005	A second Myo10 knockout mouse was developed, which selectively knocked out the full-length Myo10 molecule, the actin-binding form, but "headless" Myo10 expression was unaffected.	('mouse', 'Species', '10090', (24, 29))	('Myo10', 'Gene', '17909', (146, 151))	('actin-binding', 'molecular_function', 'GO:0003779', ('111', '124'))	('Myo10', 'Gene', '17909', (91, 96))	('Myo10', 'Gene', (146, 151))	('Myo10', 'Gene', (9, 14))	('Myo10', 'Gene', '17909', (9, 14))	('knocked', 'Var', (63, 70))	('Myo10', 'Gene', (91, 96))
20632	32352005	Similar to the complete Myo10 knockout, persistent hyaloid vasculature, white belly spots, and syndactyly were common, but there was a reduced rate of exencephaly (24%) (Figure 5(c)).	('persistent hyaloid vasculature', 'Phenotype', 'HP:0007968', (40, 70))	('syndactyly', 'Disease', 'MESH:D013576', (95, 105))	('exencephaly', 'Disease', (151, 162))	('syndactyly', 'Phenotype', 'HP:0001159', (95, 105))	('Myo10', 'Gene', (24, 29))	('knockout', 'Var', (30, 38))	('Myo10', 'Gene', '17909', (24, 29))	('exencephaly', 'Phenotype', 'HP:0030769', (151, 162))	('syndactyly', 'Disease', (95, 105))	('reduced', 'NegReg', (135, 142))	('exencephaly', 'Disease', 'MESH:D009436', (151, 162))
20656	32352005	Thus, control of TNTs may provide a novel mechanism to transport normal proteins to diseased cells in lysosomal storage diseases.	('TNTs', 'Gene', (17, 21))	('lysosomal storage disease', 'Disease', (102, 127))	('lysosomal storage disease', 'Disease', 'MESH:D016464', (102, 127))	('TNTs', 'Chemical', '-', (17, 21))	('transport normal proteins', 'MPA', (55, 80))	('control', 'Var', (6, 13))	('transport', 'biological_process', 'GO:0006810', ('55', '64'))	('storage', 'biological_process', 'GO:0051235', ('112', '119'))
20665	32352005	This modified, inactive AAV2 virus is delivered by subretinal injection to replace defective RPE65 in children with Leber's congenital amaurosis.	('congenital amaurosis', 'Disease', (124, 144))	('defective', 'Var', (83, 92))	('congenital amaurosis', 'Phenotype', 'HP:0007875', (124, 144))	('congenital amaurosis', 'Disease', 'MESH:D001766', (124, 144))	('RPE65', 'Gene', '6121', (93, 98))	('RPE65', 'Gene', (93, 98))	('children', 'Species', '9606', (102, 110))	('AAV2', 'Species', '10804', (24, 28))
20686	31740654	Silencing of HOXA9 attenuated the miR-652 inhibitor decreased cell growth rate and decreased migration ability in uveal melanoma cells.	('cell growth rate', 'CPA', (62, 78))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('HOXA9', 'Gene', (13, 18))	('decreased', 'NegReg', (52, 61))	('decreased', 'NegReg', (83, 92))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('miR-652', 'Gene', '724022', (34, 41))	('uveal melanoma', 'Disease', (114, 128))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('migration ability', 'CPA', (93, 110))	('miR-652', 'Gene', (34, 41))	('Silencing', 'Var', (0, 9))	('attenuated', 'NegReg', (19, 29))	('HOXA9', 'Gene', '3205', (13, 18))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))
20691	31740654	Certain mutations, such as monosomy 3, has been identified as drivers of metastasis of patients with UM, and were proved to be prognostic predictors for patients.	('patients', 'Species', '9606', (153, 161))	('metastasis', 'CPA', (73, 83))	('UM', 'Phenotype', 'HP:0007716', (101, 103))	('monosomy', 'Var', (27, 35))	('UM', 'Disease', 'MESH:C536494', (101, 103))	('patients', 'Species', '9606', (87, 95))
20695	31740654	As the target genes can be oncogenes or tumor suppressors, dysregulation of miRNAs is critical for cancer progression and is observed in many cancer types.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('dysregulation', 'Var', (59, 72))	('cancer', 'Disease', (99, 105))	('miR', 'Gene', '220972', (76, 79))	('miR', 'Gene', (76, 79))	('tumor', 'Disease', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Disease', (142, 148))
20700	31740654	A later study indicated that monosomy 3 can promote miR-199-5p expression to facilitate metastasis in UM.	('UM', 'Disease', 'MESH:C536494', (102, 104))	('promote', 'PosReg', (44, 51))	('metastasis', 'CPA', (88, 98))	('facilitate', 'PosReg', (77, 87))	('monosomy 3', 'Var', (29, 39))	('miR', 'Gene', '220972', (52, 55))	('miR', 'Gene', (52, 55))	('UM', 'Phenotype', 'HP:0007716', (102, 104))
20711	31740654	Moreover, silencing of HOXA9 attenuated miR-652 inhibitor-induced inhibition of cell proliferation and migration in UM cells.	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('66', '98'))	('HOXA9', 'Gene', (23, 28))	('miR-652', 'Gene', (40, 47))	('attenuated', 'NegReg', (29, 39))	('UM', 'Disease', 'MESH:C536494', (116, 118))	('HOXA9', 'Gene', '3205', (23, 28))	('UM', 'Phenotype', 'HP:0007716', (116, 118))	('miR-652', 'Gene', '724022', (40, 47))	('inhibition', 'NegReg', (66, 76))	('silencing', 'Var', (10, 19))
20721	31740654	On the next day, cells were transfected with 100 nM miR-NC inhibitor or miR-652 inhibitor using Lipofectamine RNAiMAX reagent (Invitrogen) following the manufacturer's instructions.	('miR-652', 'Gene', '724022', (72, 79))	('inhibitor', 'Var', (80, 89))	('miR-652', 'Gene', (72, 79))	('miR', 'Gene', '220972', (52, 55))	('miR', 'Gene', '220972', (72, 75))	('miR', 'Gene', (52, 55))	('miR', 'Gene', (72, 75))
20724	31740654	Secondary HRP-conjugated antibodies against rabbit (#7074, 1: 100000) and mouse (#7076, 1: 100000) were products of Cell Signaling Technology (Beverly, MA).	('Signaling', 'biological_process', 'GO:0023052', ('121', '130'))	('rabbit', 'Species', '9986', (44, 50))	('mouse', 'Species', '10090', (74, 79))	('#7074', 'Var', (52, 57))	('#7076', 'Var', (81, 86))	('Secondary HRP-conjugated', 'Protein', (0, 24))
20732	31740654	Site mutations were introduced into pGL3-HOXA9 3'UTR-WT to construct pGL3-HOXA9 3'UTR-Mut using the QuickChange Site-Directed Mutagenesis Kit (Agilent, Santa Clara, CA).	('pGL3', 'Gene', (36, 40))	('HOXA9', 'Gene', '3205', (41, 46))	('mutations', 'Var', (5, 14))	('pGL3', 'Gene', '6391', (69, 73))	('Mutagenesis', 'biological_process', 'GO:0006280', ('126', '137'))	('HOXA9', 'Gene', '3205', (74, 79))	('pGL', 'molecular_function', 'GO:0004598', ('69', '72'))	('pGL3', 'Gene', '6391', (36, 40))	('HOXA9', 'Gene', (41, 46))	('HOXA9', 'Gene', (74, 79))	('pGL', 'molecular_function', 'GO:0004598', ('36', '39'))	('pGL3', 'Gene', (69, 73))
20743	31740654	In the cell migration assay, downregulation of miR-652-inhibited cells migrated towards the wound area in MUM-2B and MEL270, suggesting the cell migration ability was inhibited (Figure 2D, 2E).	('downregulation', 'NegReg', (29, 43))	('UM', 'Phenotype', 'HP:0007716', (107, 109))	('inhibited', 'NegReg', (167, 176))	('MUM-2', 'Gene', '58485', (106, 111))	('miR-652', 'Gene', '724022', (47, 54))	('cell migration', 'CPA', (7, 21))	('miR-652', 'Gene', (47, 54))	('cell migration ability', 'CPA', (140, 162))	('cells migrated towards the wound area', 'CPA', (65, 102))	('MUM-2', 'Gene', (106, 111))	('cell migration', 'biological_process', 'GO:0016477', ('7', '21'))	('cell migration', 'biological_process', 'GO:0016477', ('140', '154'))	('MEL270', 'CellLine', 'CVCL:C302', (117, 123))	('MEL270', 'Var', (117, 123))
20751	31740654	Similarly, miR-652 mimic also decreased relative luciferase activity in MEL270 cells transfected with HOXA9 3'UTR (Figure 4C).	('luciferase activity', 'molecular_function', 'GO:0045289', ('49', '68'))	('mimic', 'Var', (19, 24))	('luciferase activity', 'molecular_function', 'GO:0047712', ('49', '68'))	('MEL270', 'CellLine', 'CVCL:C302', (72, 78))	('luciferase activity', 'molecular_function', 'GO:0050397', ('49', '68'))	('HOXA9', 'Gene', (102, 107))	('luciferase activity', 'molecular_function', 'GO:0050248', ('49', '68'))	('miR-652', 'Gene', '724022', (11, 18))	('luciferase activity', 'molecular_function', 'GO:0047077', ('49', '68'))	('activity', 'MPA', (60, 68))	('miR-652', 'Gene', (11, 18))	('luciferase', 'Enzyme', (49, 59))	('decreased', 'NegReg', (30, 39))	('HOXA9', 'Gene', '3205', (102, 107))
20754	31740654	The Western blotting results showed that miR-652 downregulation increased HOXA9 and decreased HIF-1alpha and HK2 protein expression, and silencing of HOXA9 reversed downregulation of HIF-1alpha and HK2 in MUM-2B cells (Figure 5C, 5D).	('miR-652', 'Gene', '724022', (41, 48))	('HIF-1alpha', 'Gene', (94, 104))	('MUM-2', 'Gene', (205, 210))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('HOXA9', 'Gene', (150, 155))	('HIF-1alpha', 'Gene', '3091', (183, 193))	('HOXA9', 'Gene', '3205', (150, 155))	('MUM-2', 'Gene', '58485', (205, 210))	('HK2', 'Gene', (198, 201))	('HK2', 'Gene', (109, 112))	('HK2', 'Gene', '3099', (109, 112))	('HK2', 'Gene', '3099', (198, 201))	('HK2', 'molecular_function', 'GO:0008256', ('109', '112'))	('silencing', 'Var', (137, 146))	('HK2', 'molecular_function', 'GO:0008256', ('198', '201'))	('decreased', 'NegReg', (84, 93))	('HIF-1alpha', 'Gene', '3091', (94, 104))	('HOXA9', 'Gene', (74, 79))	('UM', 'Phenotype', 'HP:0007716', (206, 208))	('HIF-1alpha', 'Gene', (183, 193))	('HOXA9', 'Gene', '3205', (74, 79))	('miR-652', 'Gene', (41, 48))	('downregulation', 'NegReg', (49, 63))	('increased', 'PosReg', (64, 73))
20757	31740654	We observed decreased c-Myc after miR-652 downregulation, and silencing of HOXA9 reversed downregulation of c-Myc (Figure 5E, 5F).	('silencing', 'Var', (62, 71))	('c-Myc', 'Gene', '4609', (108, 113))	('miR-652', 'Gene', (34, 41))	('HOXA9', 'Gene', (75, 80))	('miR-652', 'Gene', '724022', (34, 41))	('c-Myc', 'Gene', (108, 113))	('downregulation', 'NegReg', (42, 56))	('c-Myc', 'Gene', '4609', (22, 27))	('decreased', 'NegReg', (12, 21))	('c-Myc', 'Gene', (22, 27))	('HOXA9', 'Gene', '3205', (75, 80))
20761	31740654	Additionally, the decreased MUM-2B cell growth rate induced by miR-652 inhibitor was also reversed after HOXA9 silencing (Figure 6B).	('HOXA9', 'Gene', (105, 110))	('decreased', 'NegReg', (18, 27))	('MUM-2', 'Gene', '58485', (28, 33))	('UM', 'Phenotype', 'HP:0007716', (29, 31))	('miR-652', 'Gene', '724022', (63, 70))	('cell growth', 'biological_process', 'GO:0016049', ('35', '46'))	('HOXA9', 'Gene', '3205', (105, 110))	('MUM-2', 'Gene', (28, 33))	('miR-652', 'Gene', (63, 70))	('inhibitor', 'Var', (71, 80))
20779	31740654	The expression of HOXA9 was regulated by methylation and miRNAs in different backgrounds.	('miR', 'Gene', '220972', (57, 60))	('HOXA9', 'Gene', '3205', (18, 23))	('miR', 'Gene', (57, 60))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('expression', 'MPA', (4, 14))	('HOXA9', 'Gene', (18, 23))	('methylation', 'Var', (41, 52))	('regulated', 'Reg', (28, 37))
20786	31740654	Moreover, the downregulation of HIF-1alpha and HK2 was recovered after HOXA9 silencing, indicating miR-652 controls HIF-1 signaling via HOXA9.	('HOXA9', 'Gene', '3205', (136, 141))	('HOXA9', 'Gene', (71, 76))	('HOXA9', 'Gene', (136, 141))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('HIF-1', 'Gene', '3091', (32, 37))	('miR-652', 'Gene', (99, 106))	('HIF-1alpha', 'Gene', (32, 42))	('HIF-1', 'Gene', '3091', (116, 121))	('silencing', 'Var', (77, 86))	('HK2', 'Gene', (47, 50))	('HK2', 'Gene', '3099', (47, 50))	('HK2', 'molecular_function', 'GO:0008256', ('47', '50'))	('HOXA9', 'Gene', '3205', (71, 76))	('HIF-1', 'Gene', (32, 37))	('HIF-1', 'Gene', (116, 121))	('miR-652', 'Gene', '724022', (99, 106))	('HIF-1alpha', 'Gene', '3091', (32, 42))
20788	31740654	Finally, the decreased cell growth rate and migration inhibition caused by miR-652 inhibitor was also partially reversed by HOXA9 silencing.	('decreased', 'NegReg', (13, 22))	('miR-652', 'Gene', (75, 82))	('migration inhibition', 'CPA', (44, 64))	('miR-652', 'Gene', '724022', (75, 82))	('cell growth', 'biological_process', 'GO:0016049', ('23', '34'))	('inhibitor', 'Var', (83, 92))	('HOXA9', 'Gene', '3205', (124, 129))	('cell growth rate', 'CPA', (23, 39))	('silencing', 'Var', (130, 139))	('HOXA9', 'Gene', (124, 129))
20811	31046743	In the remaining 10%, recurrent mutations can be seen in CYSLTR2 and PLCB4.	('CYSLTR2', 'Gene', (57, 64))	('PLCB4', 'Gene', '5332', (69, 74))	('mutations', 'Var', (32, 41))	('PLCB4', 'Gene', (69, 74))	('CYSLTR2', 'Gene', '57105', (57, 64))
20812	31046743	GNAQ/11 mutations result in activation of the Hippo and MAP-kinase pathways.	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (8, 17))	('MAP-kinase pathways', 'Pathway', (56, 75))	('GNAQ', 'Gene', (0, 4))	('activation', 'PosReg', (28, 38))	('MAP', 'molecular_function', 'GO:0004239', ('56', '59'))
20815	31046743	Another common genetic alteration in UM is inactivation or loss of the BAP1 tumor suppressor gene, which results in metastatic progression.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('results in', 'Reg', (105, 115))	('BAP1', 'Gene', '8314', (71, 75))	('tumor suppressor', 'biological_process', 'GO:0051726', ('76', '92'))	('metastatic progression', 'CPA', (116, 138))	('loss', 'NegReg', (59, 63))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('76', '92'))	('BAP1', 'Gene', (71, 75))	('inactivation', 'Var', (43, 55))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
20820	31046743	Unfortunately, there are no accurate animal models of GNAQ/11 mutated uveal melanoma which develop liver metastases, and biopsies from metastases, e.g.	('liver metastases', 'Disease', 'MESH:D009362', (99, 115))	('GNAQ', 'Gene', (54, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('uveal melanoma', 'Disease', (70, 84))	('metastases', 'Disease', (135, 145))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('metastases', 'Disease', 'MESH:D009362', (135, 145))	('metastases', 'Disease', (105, 115))	('develop', 'PosReg', (91, 98))	('GNAQ', 'Gene', '2776', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('liver metastases', 'Disease', (99, 115))	('metastases', 'Disease', 'MESH:D009362', (105, 115))	('mutated', 'Var', (62, 69))
20878	29992790	These findings lead us to conclude that HOXA11-AS participate in the complex network of cancers and plays an important role in the tumorigenesis and progression.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('tumor', 'Disease', (131, 136))	('role', 'Reg', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('HOXA11-AS', 'Var', (40, 49))
20898	29992790	Growing researches demonstrate that aberrantly expressed HOXA11-AS play key roles in the development and progression of cancers.	('HOXA11-AS', 'Gene', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('aberrantly expressed', 'Var', (36, 56))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('roles', 'Reg', (76, 81))
20904	29992790	HOXA11-AS was notably highly expressed in squamous cell carcinoma and lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('highly expressed', 'PosReg', (22, 38))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (70, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('HOXA11-AS', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('squamous cell carcinoma and lung adenocarcinoma', 'Disease', 'MESH:D002294', (42, 89))
20905	29992790	HOXA11-AS may play an important role in development as well as the progression of NSCLCs through regulation of numerous pathways and genes.	('regulation', 'biological_process', 'GO:0065007', ('97', '107'))	('NSCLCs', 'Disease', 'MESH:D002289', (82, 88))	('NSCLCs', 'Disease', (82, 88))	('regulation', 'Reg', (97, 107))	('HOXA11-AS', 'Var', (0, 9))
20906	29992790	Zhang et al revealed that HOXA11-AS was markedly overexpressed in NSCLC tissues as well as cells both in vivo and vitro.	('HOXA11-AS', 'Var', (26, 35))	('overexpressed', 'PosReg', (49, 62))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('NSCLC', 'Disease', (66, 71))
20907	29992790	Moreover, knockdown of HOXA11-AS inhibited the proliferation, migration, invasion, tumorigenic as well as the angiogenic capability of NSCLC cells and induced apoptosis.	('migration', 'CPA', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('apoptosis', 'biological_process', 'GO:0097194', ('159', '168'))	('tumor', 'Disease', (83, 88))	('NSCLC', 'Disease', (135, 140))	('apoptosis', 'biological_process', 'GO:0006915', ('159', '168'))	('induced', 'Reg', (151, 158))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('invasion', 'CPA', (73, 81))	('angiogenic capability', 'CPA', (110, 131))	('knockdown', 'Var', (10, 19))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('inhibited', 'NegReg', (33, 42))	('apoptosis', 'CPA', (159, 168))	('HOXA11-AS', 'Gene', (23, 32))
20908	29992790	HOXA11-AS also leads to cell cycle arrest at G0/G1 or G2/M phase.10 In another study, Chen et al concluded that HOXA11-AS was considerably upregulated in NSCLC tissues, compared with that of normal tissues.	('upregulated', 'PosReg', (139, 150))	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('24', '41'))	('M phase', 'biological_process', 'GO:0000279', ('57', '64'))	('HOXA11-AS', 'Var', (112, 121))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (24, 41))	('NSCLC', 'Disease', (154, 159))
20909	29992790	They further stated that HOXA11-AS was also engaged in the NSCLC cell invasion along with epithelial-mesenchymal transition (EMT) process and knockdown of HOXA11-AS in NSCCL cells inhibited cell invasive ability combined with decreased the expression of EMT-related transcription factors by means of repressing miR-200b through interacting with zeste homolog 2 (EZH2) and DNMT1 in NSCLC.11 Additionally, HOXA11-AS might play an important role in NSCLC development as well as progression through regulating the expression of numerous pathways and genes, especially DOCK8 and TGF-beta (TGF-beta) pathway.12 As a conclusion, these results indicate that HOXA11-AS plays a key role in NSCLC and it can be a novel therapeutic target for the treatment of NSCLC.	('TGF-beta', 'Gene', '7040', (574, 582))	('EMT', 'biological_process', 'GO:0001837', ('125', '128'))	('transcription', 'biological_process', 'GO:0006351', ('266', '279'))	('HOXA11-AS', 'Var', (650, 659))	('DOCK8', 'Gene', '81704', (564, 569))	('NSCLC', 'Disease', 'MESH:D002289', (381, 386))	('miR-200b', 'Gene', (311, 319))	('TGF-beta', 'Gene', (584, 592))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('TGF-beta', 'Gene', (574, 582))	('NSCLC', 'Disease', (381, 386))	('NSCLC', 'Disease', 'MESH:D002289', (680, 685))	('NSCLC', 'Disease', (59, 64))	('NSCLC', 'Disease', 'MESH:D002289', (446, 451))	('EMT', 'biological_process', 'GO:0001837', ('254', '257'))	('miR-200b', 'Gene', '406984', (311, 319))	('DNMT1', 'Gene', '1786', (372, 377))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('90', '123'))	('NSCLC', 'Disease', (680, 685))	('EZH2', 'Gene', (362, 366))	('EZH2', 'Gene', '2146', (362, 366))	('DOCK8', 'Gene', (564, 569))	('NSCLC', 'Disease', (446, 451))	('NSCLC', 'Disease', 'MESH:D002289', (748, 753))	('TGF-beta', 'Gene', '7040', (584, 592))	('NSCLC', 'Disease', (748, 753))	('DNMT1', 'Gene', (372, 377))
20910	29992790	However, further functional experiments are needed to verify the exact molecular mechanism involved in the role of HOXA11-AS in NSCLC carcinogenesis as well as its progression.	('NSCLC carcinogenesis', 'Disease', 'MESH:D063646', (128, 148))	('HOXA11-AS', 'Var', (115, 124))	('NSCLC carcinogenesis', 'Disease', (128, 148))
20914	29992790	Cui et al stated that the overexpression of HOXA11-AS was noted to be upregulated both in OS tissues and cell lines (KHOS MG-63 and U2OS).	('KHOS MG-63', 'CellLine', 'CVCL:0426', (117, 127))	('overexpression', 'PosReg', (26, 40))	('U2OS', 'CellLine', 'CVCL:0042', (132, 136))	('upregulated', 'PosReg', (70, 81))	('HOXA11-AS', 'Var', (44, 53))
20918	29992790	These findings indicate that HOXA11-AS may serve as a tumor accelerator via promoting cell growth and invasion in OS progression.	('cell growth', 'CPA', (86, 97))	('invasion in OS progression', 'CPA', (102, 128))	('cell growth', 'biological_process', 'GO:0016049', ('86', '97'))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('HOXA11-AS', 'Var', (29, 38))	('promoting', 'PosReg', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
20923	29992790	Knockdown of HOXA11-AS increased cell cycle regulation gene p21 (target of EZH2) expression, and knockdown of EZH2 upregulated p21 expression levels in UM cells.	('p21', 'Gene', (127, 130))	('EZH2', 'Gene', (75, 79))	('knockdown', 'Var', (97, 106))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('33', '54'))	('p21', 'Gene', '644914', (127, 130))	('EZH2', 'Gene', (110, 114))	('EZH2', 'Gene', '2146', (110, 114))	('expression levels', 'MPA', (131, 148))	('increased', 'PosReg', (23, 32))	('p21', 'Gene', (60, 63))	('upregulated', 'PosReg', (115, 126))	('EZH2', 'Gene', '2146', (75, 79))	('expression', 'MPA', (81, 91))	('p21', 'Gene', '644914', (60, 63))
20927	29992790	HOXA11-AS was also found to function as a competing endogenous RNA and sponged miR-124 in UM cells.	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', (79, 82))	('HOXA11-AS', 'Var', (0, 9))	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))
20933	29992790	Thus, these results indicate that HOXA11-AS may serve as a prognostic evaluation biomarker for glioma patients, and HOXA11-AS sponging miR-140-5p might play a vital role in the pathogenesis of glioma.	('miR', 'Gene', (135, 138))	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('glioma', 'Disease', (193, 199))	('patients', 'Species', '9606', (102, 110))	('glioma', 'Disease', (95, 101))	('pathogenesis', 'biological_process', 'GO:0009405', ('177', '189'))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('HOXA11-AS', 'Var', (116, 125))	('miR', 'Gene', '220972', (135, 138))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
20935	29992790	LATS1 genes were also detected as the downstream target genes for HOXA11-AS, which could be inhibited by HOXA11-AS via linking EZH2 proteins enhancers.19  In conclusion, HOXA11-AS may act as an oncogene in HCC development.	('EZH2', 'Gene', (127, 131))	('EZH2', 'Gene', '2146', (127, 131))	('HOXA11-AS', 'Var', (170, 179))	('LATS1', 'Gene', (0, 5))	('HCC', 'Disease', (206, 209))	('LATS1', 'Gene', '9113', (0, 5))
20938	29992790	GC has high mortality and is the second most common cause of cancer-related death worldwide.20 The epidemiology study demonstrated that the environmental factors and lifestyles are vital etiology factors of GC.21 Numerous genetic modifications contribute to the onset of GC, including oncogenes, tumor suppressor genes, as well as growth factors.22  Overexpressed HOXA11-AS was detected in human GC tissues when compared to matched normal tissues.23 Liu et al found that knockdown of HOXA11-AS hindered GC cell proliferation along with the cell cycle progression from G1 to G0 phase, and suppressed GC cells migration as well as invasion in vivo.	('hindered', 'NegReg', (494, 502))	('cell cycle progression from', 'CPA', (540, 567))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('GC cell proliferation', 'CPA', (503, 524))	('death', 'Disease', 'MESH:D003643', (76, 81))	('suppressed', 'NegReg', (588, 598))	('invasion in vivo', 'CPA', (629, 645))	('tumor', 'Disease', (296, 301))	('cell cycle', 'biological_process', 'GO:0007049', ('540', '550'))	('human', 'Species', '9606', (390, 395))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('knockdown', 'Var', (471, 480))	('cell proliferation', 'biological_process', 'GO:0008283', ('506', '524'))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('296', '312'))	('death', 'Disease', (76, 81))	('GC cells migration', 'CPA', (599, 617))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('HOXA11-AS', 'Gene', (484, 493))	('tumor suppressor', 'biological_process', 'GO:0051726', ('296', '312'))	('G0 phase', 'biological_process', 'GO:0044838', ('574', '582'))
20939	29992790	Besides, the mechanistic investigation revealed that HOXA11-AS could have an interaction with WDR5 and stimulate the transcription of beta-catenin as well as binds with EZH2 and inhibits the transcription of P21.	('binds', 'Interaction', (158, 163))	('inhibits', 'NegReg', (178, 186))	('beta-catenin', 'Gene', '1499', (134, 146))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('EZH2', 'Gene', (169, 173))	('P21', 'Gene', (208, 211))	('transcription', 'MPA', (117, 130))	('stimulate', 'PosReg', (103, 112))	('EZH2', 'Gene', '2146', (169, 173))	('WDR5', 'Gene', '11091', (94, 98))	('HOXA11-AS', 'Var', (53, 62))	('transcription', 'biological_process', 'GO:0006351', ('191', '204'))	('interaction', 'Interaction', (77, 88))	('transcription', 'MPA', (191, 204))	('beta-catenin', 'Gene', (134, 146))	('P21', 'Gene', '644914', (208, 211))	('WDR5', 'Gene', (94, 98))
20940	29992790	Additionally, HOXA11-AS induces the degradation of KLF2 mRNA through interacting with STAU1.23  Sun et al reported that patients with high HOXA11-AS expression had a shorter survival and poorer prognosis.24 HOXA11-AS alterations showed a complexly integrated phenotype affecting cell growth, migration, invasion, and apoptosis both in vitro as well as in vivo.	('invasion', 'CPA', (303, 311))	('cell growth', 'CPA', (279, 290))	('KLF2', 'Gene', (51, 55))	('apoptosis', 'biological_process', 'GO:0006915', ('317', '326'))	('cell growth', 'biological_process', 'GO:0016049', ('279', '290'))	('apoptosis', 'biological_process', 'GO:0097194', ('317', '326'))	('degradation', 'biological_process', 'GO:0009056', ('36', '47'))	('patients', 'Species', '9606', (120, 128))	('apoptosis', 'CPA', (317, 326))	('alterations', 'Var', (217, 228))	('STAU1', 'Gene', (86, 91))	('affecting', 'Reg', (269, 278))	('KLF2', 'Gene', '10365', (51, 55))	('STAU1', 'Gene', '6780', (86, 91))	('migration', 'CPA', (292, 301))	('HOXA11-AS', 'Gene', (207, 216))
20942	29992790	This finding may signify novel therapeutic directions in GC.24  In conclusion, HOXA11-AS has found to be linked with tumor suppressor or oncogenic pathways of GC, whereas altered expression of HOXA11-AS was linked with the incidence as well as the development of GC.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('tumor suppressor', 'biological_process', 'GO:0051726', ('117', '133'))	('linked', 'Reg', (207, 213))	('linked', 'Reg', (105, 111))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('117', '133'))	('oncogenic', 'CPA', (137, 146))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('HOXA11-AS', 'Var', (79, 88))
20944	29992790	HOXA11-AS may be a promising tumor biomarker for early detection, and a potential therapeutic target for breast cancer patients.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('HOXA11-AS', 'Var', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
20949	29992790	HOXA11-AS was proved to be an independent prognosticator of cervical cancer patients, and higher expression of HOXA11-AS correlates with poor survival.	('patients', 'Species', '9606', (76, 84))	('cervical cancer', 'Disease', (60, 75))	('cervical cancer', 'Disease', 'MESH:D002583', (60, 75))	('HOXA11-AS', 'Var', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('higher', 'PosReg', (90, 96))	('expression', 'MPA', (97, 107))
20960	29992790	The aberrant expression of HOXA11 has been related to the prognosis of numerous cancers, comprising GBM.	('HOXA11', 'Gene', (27, 33))	('GBM', 'Disease', (100, 103))	('numerous cancers', 'Disease', 'MESH:D009369', (71, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('related', 'Reg', (43, 50))	('aberrant expression', 'Var', (4, 23))	('numerous cancers', 'Disease', (71, 87))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
20962	29992790	The methylation of HOXA11 was related to the older patient as well as poor survival in GBM.	('related', 'Reg', (30, 37))	('methylation', 'Var', (4, 15))	('HOXA11', 'Gene', (19, 25))	('patient', 'Species', '9606', (51, 58))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))
20963	29992790	Furthermore, this study discovered candidate mediators (TGFBR2, CRIM1, TXNIP, DPYSL2, and CRMP1) that may impart treatment resistance following HOXA11 suppression.33 As a conclusion, these results indicate that HOXA11-AS plays a key role in GBM and it can be a novel therapeutic target for the treatment of GBM.	('CRIM1', 'Gene', (64, 69))	('CRMP1', 'Gene', '1400', (90, 95))	('GBM', 'Disease', (241, 244))	('TGFBR2', 'Gene', (56, 62))	('DPYSL2', 'Gene', '1808', (78, 84))	('CRMP1', 'Gene', (90, 95))	('TXNIP', 'Gene', '10628', (71, 76))	('DPYSL2', 'Gene', (78, 84))	('TXNIP', 'Gene', (71, 76))	('HOXA11-AS', 'Var', (211, 220))	('TGFBR2', 'Gene', '7048', (56, 62))	('CRIM1', 'Gene', '51232', (64, 69))
20970	29992790	Dysregulation of ncRNAs is involved in malignant cells, leading to cancer progressive, indicating that ncRNAs may be a new answer for cancers.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('Dysregulation', 'Var', (0, 13))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('leading to', 'Reg', (56, 66))
20982	29121185	Mutations were detected in known oncogenes, including BRAF, NRAS, NF1, EGFR, ALK, TERT, and APC.	('ALK', 'Gene', (77, 80))	('APC', 'Disease', 'MESH:D011125', (92, 95))	('TERT', 'Gene', (82, 86))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('APC', 'cellular_component', 'GO:0005680', ('92', '95'))	('NRAS', 'Gene', (60, 64))	('APC', 'Disease', (92, 95))	('detected', 'Reg', (15, 23))	('TERT', 'Gene', '7015', (82, 86))	('ALK', 'Gene', '238', (77, 80))	('Mutations', 'Var', (0, 9))	('EGFR', 'Gene', '1956', (71, 75))	('NF1', 'Gene', (66, 69))	('NRAS', 'Gene', '4893', (60, 64))	('EGFR', 'molecular_function', 'GO:0005006', ('71', '75'))	('NF1', 'Gene', '4763', (66, 69))	('EGFR', 'Gene', (71, 75))
20983	29121185	None of the mutations associated with uveal melanoma were found.	('uveal melanoma', 'Disease', (38, 52))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('mutations', 'Var', (12, 21))	('uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('uveal melanoma', 'Disease', 'MESH:C536494', (38, 52))	('associated', 'Reg', (22, 32))
20990	29121185	One study reported mutations in BRAF and NRAS in 29% and 18% of CMs, respectively, but the technology used in this study did not allow for a comprehensive assessment of driver mutations, chromosome copy number aberrations (CNAs), and mutational signatures.	('NRAS', 'Gene', '4893', (41, 45))	('BRAF', 'Gene', '673', (32, 36))	('BRAF', 'Gene', (32, 36))	('CM', 'Phenotype', 'HP:0007716', (64, 66))	('mutations', 'Var', (19, 28))	('chromosome', 'cellular_component', 'GO:0005694', ('187', '197'))	('NRAS', 'Gene', (41, 45))
20994	29121185	Since matched blood samples were not available, we used a panel of normal tissue samples (n = 117), a high-coverage blood sample, and somatic single-nucleotide and insertion and deletion (indel) variant-caller MuTect2 to call out tumor variants and filter out likely silent germline polymorphisms.	('tumor', 'Disease', (230, 235))	('variant-caller', 'Var', (195, 209))	('insertion', 'Var', (164, 173))	('deletion', 'Var', (178, 186))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('MuTect2', 'Gene', (210, 217))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
21002	29121185	One sample (patient 2) harbored a mutation in the tumor suppressor NF1 (without systemic manifestations), which previously has been reported in CM only in association with neurofibromatosis.	('neurofibromatosis', 'Disease', 'MESH:C537392', (172, 189))	('NF1', 'Gene', (67, 70))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (172, 189))	('NF1', 'Gene', '4763', (67, 70))	('mutation', 'Var', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor suppressor', 'biological_process', 'GO:0051726', ('50', '66'))	('neurofibromatosis', 'Disease', (172, 189))	('CM', 'Phenotype', 'HP:0007716', (144, 146))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('50', '66'))	('patient', 'Species', '9606', (12, 19))	('tumor', 'Disease', (50, 55))
21003	29121185	Mutations previously unreported in CM occurred in other cancer-associated genes, including APC (n = 2), EGFR (n = 1), CBL (n = 1), and ALK (n = 1).	('ALK', 'Gene', (135, 138))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('APC', 'Disease', (91, 94))	('EGFR', 'Gene', (104, 108))	('APC', 'cellular_component', 'GO:0005680', ('91', '94'))	('CBL', 'Gene', '867', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ALK', 'Gene', '238', (135, 138))	('Mutations', 'Var', (0, 9))	('CBL', 'Gene', (118, 121))	('CM', 'Phenotype', 'HP:0007716', (35, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('104', '108'))	('cancer', 'Disease', (56, 62))	('APC', 'Disease', 'MESH:D011125', (91, 94))	('EGFR', 'Gene', '1956', (104, 108))
21004	29121185	In cutaneous melanoma as well as CM, TERT mutations have been found to occur in the promoter sequence, there by altering messenger RNA expression, whereas the TERT mutation in the present case was a missense alteration within the coding sequence and was there fore predicted to alter protein function.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('TERT', 'Gene', (37, 41))	('CM', 'Phenotype', 'HP:0007716', (33, 35))	('TERT', 'Gene', '7015', (37, 41))	('RNA', 'cellular_component', 'GO:0005562', ('131', '134'))	('protein', 'cellular_component', 'GO:0003675', ('284', '291'))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('messenger RNA expression', 'MPA', (121, 145))	('mutations', 'Var', (42, 51))	('alter', 'Reg', (278, 283))	('TERT', 'Gene', (159, 163))	('altering', 'Reg', (112, 120))	('TERT', 'Gene', '7015', (159, 163))	('cutaneous melanoma', 'Disease', (3, 21))
21005	29121185	Mutations were also found in epigenetic regulators, including TET2 (n = 1), ATRX (n = 1), and ASXL1 (n = 1).	('TET2', 'Gene', (62, 66))	('ATRX', 'Gene', '546', (76, 80))	('ASXL1', 'Gene', (94, 99))	('Mutations', 'Var', (0, 9))	('ATRX', 'Gene', (76, 80))	('TET2', 'Gene', '54790', (62, 66))	('ASXL1', 'Gene', '171023', (94, 99))	('epigenetic', 'MPA', (29, 39))
21007	29121185	The mutations in BRAF, NRAS, and NF1 activate the mitogen-activated protein kinase (MAPK) pathway, which can be pharmacologically inhibited with mitogen-activated protein kinase kinase (MEK) inhibitors.	('activate', 'PosReg', (37, 45))	('MAPK', 'molecular_function', 'GO:0004707', ('84', '88'))	('NF1', 'Gene', (33, 36))	('protein', 'cellular_component', 'GO:0003675', ('163', '170'))	('NRAS', 'Gene', (23, 27))	('BRAF', 'Gene', '673', (17, 21))	('NF1', 'Gene', '4763', (33, 36))	('NRAS', 'Gene', '4893', (23, 27))	('BRAF', 'Gene', (17, 21))	('mitogen-activated protein kinase kinase', 'Gene', '5609', (145, 184))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('mitogen-activated protein kinase kinase', 'Gene', (145, 184))	('mutations', 'Var', (4, 13))	('MEK', 'Gene', (186, 189))	('MEK', 'Gene', '5609', (186, 189))
21009	29121185	Notably, non-UV-exposed conjunctival melanomas with KIT mutations have also been described, particularly in Chinese populations.	('mutations', 'Var', (56, 65))	('KIT', 'Gene', (52, 55))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanomas', 'Phenotype', 'HP:0002861', (37, 46))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (24, 46))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (24, 45))	('KIT', 'molecular_function', 'GO:0005020', ('52', '55'))	('conjunctival melanomas', 'Disease', (24, 46))
21010	29121185	The only CNA identified in all 5 samples was a chromosome 6p gain, which is also common in cutaneous melanoma and uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('uveal melanoma', 'Disease', (114, 128))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('cutaneous melanoma', 'Disease', (91, 109))	('chromosome 6p gain', 'Var', (47, 65))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (91, 109))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (91, 109))
21012	29121185	Interestingly, the 2 samples from individuals who experienced rapid recurrences within a year (patient 2 and patient 4) had the greatest number of mutations (Figure) and the largest amount of CNAs (Figure), suggesting that WES data may be valuable in predicting clinical outcome.	('patient', 'Species', '9606', (109, 116))	('mutations', 'Var', (147, 156))	('CNAs', 'MPA', (192, 196))	('patient', 'Species', '9606', (95, 102))
21018	29121185	With WES, CM was found to harbor mutations in BRAF, NRAS, and NF1; previously unreported mutations in EGFR, APC, TERT and other cancer-associated genes; and the C T mutation signature consistent with UV-induced DNA damage.	('NRAS', 'Gene', (52, 56))	('mutations', 'Var', (33, 42))	('NF1', 'Gene', (62, 65))	('mutations', 'Var', (89, 98))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('EGFR', 'Gene', '1956', (102, 106))	('cancer', 'Disease', (128, 134))	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('DNA', 'cellular_component', 'GO:0005574', ('211', '214'))	('APC', 'Disease', 'MESH:D011125', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('CM', 'Phenotype', 'HP:0007716', (10, 12))	('APC', 'Disease', (108, 111))	('TERT', 'Gene', (113, 117))	('NRAS', 'Gene', '4893', (52, 56))	('TERT', 'Gene', '7015', (113, 117))	('EGFR', 'Gene', (102, 106))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('APC', 'cellular_component', 'GO:0005680', ('108', '111'))	('NF1', 'Gene', '4763', (62, 65))
21019	29121185	Whole-exome sequencing might enable the detection of molecular mutations targetable by cancer therapies and provide insight into the pathogenesis of CM.	('mutations', 'Var', (63, 72))	('cancer', 'Disease', (87, 93))	('pathogenesis', 'biological_process', 'GO:0009405', ('133', '145'))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('molecular mutations', 'Var', (53, 72))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('CM', 'Phenotype', 'HP:0007716', (149, 151))
21023	28129639	Our data showed that LDX-mediated inhibition of CXCR1/2 abrogated motility and induced apoptosis in cultured cutaneous and uveal melanoma cells and xenografts independently of the molecular defects associated with the malignant phenotype.	('abrogated', 'NegReg', (56, 65))	('inhibition', 'Var', (34, 44))	('motility', 'CPA', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('LDX', 'Chemical', 'MESH:C511776', (21, 24))	('apoptosis', 'CPA', (87, 96))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('uveal melanoma', 'Disease', 'MESH:C536494', (123, 137))	('induced', 'Reg', (79, 86))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (123, 137))	('uveal melanoma', 'Disease', (123, 137))
21025	28129639	Moreover, systemic treatment of melanoma-bearing mice with LDX also polarized intratumoral macrophages to M1 phenotype, abrogated intratumoral de novo angiogenesis and inhibited melanoma self-renewal.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('LDX', 'Var', (59, 62))	('tumor', 'Disease', (83, 88))	('melanoma', 'Disease', (32, 40))	('tumor', 'Disease', (135, 140))	('mice', 'Species', '10090', (49, 53))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('LDX', 'Chemical', 'MESH:C511776', (59, 62))	('inhibited', 'NegReg', (168, 177))	('abrogated', 'NegReg', (120, 129))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('angiogenesis', 'biological_process', 'GO:0001525', ('151', '163'))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
21043	28129639	In this study, we demonstrated that LDX attenuates progression of different melanoma types in vivo via inhibition of cell cycle progression and motility, blocking of the pro-survival intracellular signals and induction of apoptosis, alteration of the intratumoral recruitment of the endothelial cells and de novo angiogenesis, and hindering of the melanoma self-renewal mechanisms.	('induction', 'Reg', (209, 218))	('de novo angiogenesis', 'CPA', (305, 325))	('cell cycle progression', 'CPA', (117, 139))	('apoptosis', 'CPA', (222, 231))	('pro-survival', 'Protein', (170, 182))	('motility', 'CPA', (144, 152))	('blocking', 'NegReg', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (348, 356))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('melanoma', 'Disease', (348, 356))	('cell cycle', 'biological_process', 'GO:0007049', ('117', '127'))	('angiogenesis', 'biological_process', 'GO:0001525', ('313', '325'))	('alteration', 'Reg', (233, 243))	('tumor', 'Disease', (256, 261))	('intracellular', 'cellular_component', 'GO:0005622', ('183', '196'))	('hindering', 'NegReg', (331, 340))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('209', '231'))	('LDX', 'Var', (36, 39))	('attenuates', 'NegReg', (40, 50))	('LDX', 'Chemical', 'MESH:C511776', (36, 39))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('pro-survival', 'biological_process', 'GO:0043066', ('170', '182'))	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (348, 356))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('inhibition', 'NegReg', (103, 113))
21045	28129639	Cutaneous melanoma cells expressing mutant BRAFV600E(WM164, WM115, WM873), cells with non-defined molecular defect expressing BRAFG464E and KRASG12D (C8161) and uveal melanoma cells harboring an activating mutation in GNAQQ209P (UM001) were used for this assessment.	('BRAFV600E', 'Gene', (43, 52))	('uveal melanoma', 'Disease', (161, 175))	('uveal melanoma', 'Phenotype', 'HP:0007716', (161, 175))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('BRAFG464E', 'Var', (126, 135))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('mutant', 'Var', (36, 42))	('BRAFV600E', 'Mutation', 'rs113488022', (43, 52))	('GNAQQ209P', 'Mutation', 'rs121913492', (218, 227))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('uveal melanoma', 'Disease', 'MESH:C536494', (161, 175))	('GNAQQ209P', 'Gene', (218, 227))	('Cutaneous melanoma', 'Disease', (0, 18))
21046	28129639	RT-PCR analysis showed that CXCL1 and CXCL8 were differently expressed in the analyzed cells with the overall lowest expression in WM164 and WM115 and the highest in WM873-1and in C8161 melanoma cells (Figure 1A).	('CXCL8', 'Gene', '3576', (38, 43))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanoma', 'Disease', (186, 194))	('WM873-1and', 'Var', (166, 176))	('melanoma', 'Disease', 'MESH:D008545', (186, 194))	('CXCL8', 'Gene', (38, 43))	('expression', 'MPA', (117, 127))	('CXCL1', 'Gene', '2919', (28, 33))	('WM115', 'Var', (141, 146))	('CXCL1', 'Gene', (28, 33))	('lowest', 'NegReg', (110, 116))
21065	28129639	Based on the in situ cell death detection (TUNEL) assay, on average, about 3% of all control cells were identified as apoptotic whereas LDX treatment increased apoptosis up to 10% for C8161 and WM873 cells, 25 % for WM 164 and WM115 cells, and up to 40% for UM001 (Figure 2D, 2E).	('apoptosis', 'CPA', (160, 169))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('cell death', 'biological_process', 'GO:0008219', ('21', '31'))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('LDX', 'Chemical', 'MESH:C511776', (136, 139))	('increased', 'PosReg', (150, 159))	('C8161', 'Var', (184, 189))
21071	28129639	It was most prominent in WM35, WM164, WM115, and UM001, and less pronounced in C8161 cells (Figure 2C).	('WM35', 'CellLine', 'CVCL:0580', (25, 29))	('WM164', 'Var', (31, 36))	('WM115', 'Var', (38, 43))	('WM35', 'Var', (25, 29))
21075	28129639	CXCL8 (IL-8) signaling has been implicated in STAT3 activation and nuclear translocation, suggesting that inhibition of CXCR1/2 may also lead to the inhibition of STAT3 in melanoma cells.	('STAT3', 'Gene', '6774', (46, 51))	('inhibition', 'NegReg', (149, 159))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('STAT3', 'Gene', '6774', (163, 168))	('CXCL8', 'Gene', (0, 5))	('STAT3', 'Gene', (46, 51))	('STAT3', 'Gene', (163, 168))	('signaling', 'biological_process', 'GO:0023052', ('13', '22'))	('inhibition', 'Var', (106, 116))	('IL-8', 'molecular_function', 'GO:0005153', ('7', '11'))	('CXCR1/2', 'MPA', (120, 127))	('IL-8', 'Gene', '3576', (7, 11))	('IL-8', 'Gene', (7, 11))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('CXCL8', 'Gene', '3576', (0, 5))	('melanoma', 'Disease', (172, 180))
21079	28129639	To evaluate the extent of LDX-mediated melanoma inhibition in vivo and better define the underlying molecular mechanisms, 4 different human melanoma cell lines characterized by various levels of cell surface CXCR1/2, ligands secretion and distinct molecular defects (WM164V600E,C8161, UM001Q209P and UM004Q209L) were inoculated into nude athymic mice.	('human', 'Species', '9606', (134, 139))	('UM004Q209L', 'Var', (300, 310))	('secretion', 'biological_process', 'GO:0046903', ('225', '234'))	('LDX', 'Chemical', 'MESH:C511776', (26, 29))	('WM164V600E', 'Var', (267, 277))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('cell surface', 'cellular_component', 'GO:0009986', ('195', '207'))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('UM001Q209P', 'Var', (285, 295))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('C8161', 'Var', (278, 283))	('melanoma', 'Disease', (140, 148))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('mice', 'Species', '10090', (346, 350))
21092	28129639	Inverse correlation between Ki-67+ proliferating and M30+ apoptotic cell was most distinct in WM164 treated melanomas (Figure 3C, 3D).	('melanomas', 'Disease', 'MESH:D008545', (108, 117))	('melanomas', 'Phenotype', 'HP:0002861', (108, 117))	('melanomas', 'Disease', (108, 117))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('M30+', 'Var', (53, 57))
21098	28129639	Indirect immunofluorescent detection of the CD31+ intratumoral blood vasculature demonstrated a drastic reduction of endothelial cell recruitment and formation of the intratumoral blood vessels in all examined LDX-treated lesions.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CD31+', 'Var', (44, 49))	('reduction', 'NegReg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', (55, 60))	('endothelial cell recruitment', 'CPA', (117, 145))	('LDX', 'Chemical', 'MESH:C511776', (210, 213))	('formation', 'biological_process', 'GO:0009058', ('150', '159'))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
21105	28129639	Concurrently, a higher percentage of the ALDH+ cells was detected in non-proliferating, apoptotic, M30+ regions of LDX treated lesions (Figure 5B, 5C).	('apoptotic', 'CPA', (88, 97))	('LDX', 'Chemical', 'MESH:C511776', (115, 118))	('ALDH', 'Gene', '11670', (41, 45))	('ALDH', 'molecular_function', 'GO:0004030', ('41', '45'))	('non-proliferating', 'CPA', (69, 86))	('ALDH', 'Gene', (41, 45))	('M30+', 'Var', (99, 103))
21109	28129639	For example, G31P, an IL-8 analog, was shown to block neutrophil infiltration, pyrexia, and pulmonary vascular pathology in endotoxemic animals.	('G31P', 'Var', (13, 17))	('block', 'NegReg', (48, 53))	('pyrexia', 'Disease', (79, 86))	('G31P', 'SUBSTITUTION', 'None', (13, 17))	('pyrexia', 'Disease', 'MESH:D005334', (79, 86))	('pyrexia', 'Phenotype', 'HP:0001945', (79, 86))	('IL-8', 'Gene', '3576', (22, 26))	('IL-8', 'molecular_function', 'GO:0005153', ('22', '26'))	('IL-8', 'Gene', (22, 26))	('pulmonary vascular pathology', 'CPA', (92, 120))	('pyrexia', 'biological_process', 'GO:0001660', ('79', '86'))	('neutrophil infiltration', 'CPA', (54, 77))
21110	28129639	SCH-527123 and SCH-479833, dual CXCR1/2 and CXCR2 antagonists, were shown to inhibit migration and proliferation of A375SM melanoma cells.	('CXCR2', 'Gene', (44, 49))	('CXCR2', 'Gene', '3579', (44, 49))	('inhibit', 'NegReg', (77, 84))	('SCH-479833', 'Var', (15, 25))	('A375SM', 'CellLine', 'CVCL:5649', (116, 122))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('migration', 'CPA', (85, 94))	('SCH-527123', 'Var', (0, 10))	('SCH-527123', 'Chemical', 'MESH:C516686', (0, 10))	('proliferation', 'CPA', (99, 112))
21111	28129639	SCH-527123 was described as a potent inhibitor of CXCR1- (IC50 = 41 nM) and CXCR2 (IC50 = 3 nM) mediated chemotaxis with high affinity.	('CXCR1', 'Gene', '3577', (50, 55))	('SCH-527123', 'Chemical', 'MESH:C516686', (0, 10))	('CXCR2', 'Gene', '3579', (76, 81))	('SCH-527123', 'Var', (0, 10))	('chemotaxis', 'biological_process', 'GO:0006935', ('105', '115'))	('CXCR1', 'Gene', (50, 55))	('CXCR2', 'Gene', (76, 81))
21128	28129639	Importantly, treatment of different melanoma cells in vitro with 1microM LDX was more effective than treatment of A37SM with 250 microM SCH-527123 (29).	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('SCH-527123', 'Chemical', 'MESH:C516686', (136, 146))	('1microM', 'Var', (65, 72))	('LDX', 'Gene', (73, 76))	('LDX', 'Chemical', 'MESH:C511776', (73, 76))
21130	28129639	Thus, statistically significant inhibition of BRAFV600E WM164, GNA11Q209L UM001 and GNAQQ209P UM004 melanomas was observed (Figure 3).	('melanomas', 'Disease', 'MESH:D008545', (100, 109))	('inhibition', 'NegReg', (32, 42))	('BRAFV600E', 'Mutation', 'rs113488022', (46, 55))	('melanomas', 'Disease', (100, 109))	('BRAFV600E WM164', 'Var', (46, 61))	('GNAQQ209P UM004', 'Var', (84, 99))	('GNAQQ209P', 'Mutation', 'rs121913492', (84, 93))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))
21132	28129639	Although, treatment of C8161 melanoma-bearing mice with LDX did not alter outgrowth of the intradermal tumors, normalized rate of apoptosis and inhibition of proliferation were similar in all LDX-treated lesions (Figure 3D) and C8161 lesions contained large apoptotic regions approaching 2/3 of the entire tumor volume.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('intradermal tumors', 'Disease', (91, 109))	('LDX', 'Chemical', 'MESH:C511776', (192, 195))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('tumor', 'Disease', (306, 311))	('proliferation', 'CPA', (158, 171))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('LDX', 'Chemical', 'MESH:C511776', (56, 59))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('C8161', 'Var', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('mice', 'Species', '10090', (46, 50))	('intradermal tumors', 'Disease', 'MESH:D018330', (91, 109))
21134	28129639	Together with the inhibition of AKT and NF-KB activation/phosphorylation in vitro (Figure 2) and in vivo (Figure 4A), our data indicate that LDX-mediated induction of apoptosis in malignant cells is associated with down-modulation of the AKT/NF-kB-mediated pro-survival signals.	('AKT', 'Gene', '207', (32, 35))	('AKT', 'Gene', '207', (238, 241))	('AKT', 'Gene', (238, 241))	('apoptosis', 'CPA', (167, 176))	('down-modulation', 'NegReg', (215, 230))	('AKT', 'Gene', (32, 35))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('LDX', 'Chemical', 'MESH:C511776', (141, 144))	('pro-survival', 'biological_process', 'GO:0043066', ('257', '269'))	('LDX-mediated', 'Var', (141, 153))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('154', '176'))
21140	28129639	These findings also indicate that LDX-mediated alteration of the melanoma-supporting microenvironment additionally attenuates tumor progression and may further contribute to the induction of apoptosis of the malignant cells (eg.	('induction', 'Reg', (178, 187))	('apoptosis', 'CPA', (191, 200))	('alteration', 'Var', (47, 57))	('contribute', 'Reg', (160, 170))	('attenuates', 'NegReg', (115, 125))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('178', '200'))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('LDX', 'Chemical', 'MESH:C511776', (34, 37))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('tumor', 'Disease', (126, 131))
21142	28129639	Several recent studies demonstrated that a distinct population of human melanoma cells with high ALDH activity is responsible for tumorigenesis and tumor self-renewal and that silencing of ALDH by shRNA leads to melanoma cell cycle arrest, apoptosis, decreased cell viability in vitro and reduced tumorigenesis in vivo.	('ALDH', 'molecular_function', 'GO:0004030', ('189', '193'))	('reduced', 'NegReg', (289, 296))	('melanoma cell cycle arrest', 'Disease', (212, 238))	('human', 'Species', '9606', (66, 71))	('ALDH', 'Gene', '11670', (189, 193))	('shRNA', 'Gene', (197, 202))	('tumor', 'Disease', (130, 135))	('ALDH', 'Gene', (97, 101))	('tumor', 'Disease', (297, 302))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('221', '238'))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('melanoma', 'Disease', (72, 80))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Disease', (212, 220))	('apoptosis', 'biological_process', 'GO:0097194', ('240', '249'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (221, 238))	('apoptosis', 'biological_process', 'GO:0006915', ('240', '249'))	('cell viability', 'CPA', (261, 275))	('apoptosis', 'CPA', (240, 249))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('ALDH', 'Gene', '11670', (97, 101))	('ALDH', 'Gene', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('silencing', 'Var', (176, 185))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('tumor', 'Disease', (148, 153))	('decreased', 'NegReg', (251, 260))	('ALDH', 'molecular_function', 'GO:0004030', ('97', '101'))	('melanoma cell cycle arrest', 'Disease', 'MESH:D006323', (212, 238))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
21152	28129639	Uveal melanoma lines UM001 and UM004 characterized by the activating mutations in GNAQQ209P and GNA11Q209L were provided by Dr. T. Sato (Thomas Jefferson University, Philadelphia PA) and cultured in RPMI1640 media supplemented with 10% FBS, beta-mercaptoethanol, penicillin and streptomycin.	('mutations', 'Var', (69, 78))	('penicillin', 'Chemical', 'MESH:D010406', (263, 273))	('streptomycin', 'Chemical', 'MESH:D013307', (278, 290))	('Philadelphia PA', 'Disease', (166, 181))	('melanoma lines UM001', 'Disease', 'MESH:D008545', (6, 26))	('activating', 'PosReg', (58, 68))	('Philadelphia PA', 'Disease', 'MESH:D010677', (166, 181))	('GNA11Q209L', 'Var', (96, 106))	('FBS', 'Disease', (236, 239))	('beta-mercaptoethanol', 'Chemical', 'MESH:D008623', (241, 261))	('GNAQQ209P', 'Gene', (82, 91))	('GNAQQ209P', 'Mutation', 'rs121913492', (82, 91))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('RPMI1640 media', 'Chemical', '-', (199, 213))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma lines UM001', 'Disease', (6, 26))	('FBS', 'Disease', 'MESH:D005198', (236, 239))
21165	28129639	The dose was abopted from prior experiments on the 1st generation of CXCR1 inhibitor, Reparixin  Eight cohorts of NCrNU-M nude spontaneous mutant standard athymic mice (Taconic, Hudson, NY) (n = 10 per cohort) were intradermally injected with 1x106 melanoma cells (WM164, C8161, UM001, UM004) into right flanks in 30microl of saline.	('saline', 'Chemical', 'MESH:D012965', (326, 332))	('CXCR1', 'Gene', (69, 74))	('Reparixin', 'Chemical', 'MESH:C490707', (86, 95))	('melanoma', 'Disease', 'MESH:D008545', (249, 257))	('melanoma', 'Phenotype', 'HP:0002861', (249, 257))	('melanoma', 'Disease', (249, 257))	('mice', 'Species', '10090', (163, 167))	('C8161', 'Var', (272, 277))	('CXCR1', 'Gene', '3577', (69, 74))
21170	28129639	Species-specific AlexaFluor488- or AlexaFluor594 - labeled secondary antibodies were from Thermo-Fisher (Thermo/Fisher, Grand Island, NY).	('AlexaFluor488-', 'Var', (17, 31))	('AlexaFluor594', 'Chemical', '-', (35, 48))	('AlexaFluor488', 'Chemical', '-', (17, 30))	('AlexaFluor594 -', 'Var', (35, 50))
21186	26217306	Previous studies of UM cancers identified key mutations in three genes: GNAQ, GNA11, and BRAF.	('GNA11', 'Gene', (78, 83))	('mutations', 'Var', (46, 55))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('GNAQ', 'Gene', '2776', (72, 76))	('GNA11', 'Gene', '2767', (78, 83))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('BRAF', 'Gene', '673', (89, 93))	('BRAF', 'Gene', (89, 93))	('UM', 'Phenotype', 'HP:0007716', (20, 22))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('GNAQ', 'Gene', (72, 76))
21193	26217306	Recent mutational profiling studies of UM have identified mutually exclusive, activating mutations in two G protein coupled receptor alpha subunits, GNAQ and GNA11, in more than 80% of profiled UM tumors.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('GNAQ', 'Gene', (149, 153))	('activating', 'PosReg', (78, 88))	('UM', 'Phenotype', 'HP:0007716', (39, 41))	('GNAQ', 'Gene', '2776', (149, 153))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('GNA11', 'Gene', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('mutations', 'Var', (89, 98))	('GNA11', 'Gene', '2767', (158, 163))	('UM', 'Phenotype', 'HP:0007716', (194, 196))	('tumors', 'Disease', (197, 203))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
21194	26217306	These mutations appear to be relatively UM specific and are only found in about 5% of cases in other tumor types.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('UM', 'Phenotype', 'HP:0007716', (40, 42))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
21195	26217306	The nearly ubiquitous presence of the GNAQ and GNA11 mutations in UM suggests that they would make an effective therapeutic target, but functional studies of these mutations have noted them to be relatively weak oncoproteins that require other genetic alterations (including p53 and p16/CDK4/RB1 pathway inactivation) to transform immortalized melanocytes.	('RB1', 'Gene', (292, 295))	('p16', 'Gene', (283, 286))	('GNAQ', 'Gene', '2776', (38, 42))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('CDK', 'molecular_function', 'GO:0004693', ('287', '290'))	('p53', 'Gene', '7157', (275, 278))	('GNA11', 'Gene', '2767', (47, 52))	('GNA11', 'Gene', (47, 52))	('RB1', 'Gene', '5925', (292, 295))	('CDK4', 'Gene', '1019', (287, 291))	('CDK4', 'Gene', (287, 291))	('GNAQ', 'Gene', (38, 42))	('mutations', 'Var', (53, 62))	('p16', 'Gene', '1029', (283, 286))	('mutations', 'Var', (164, 173))	('p53', 'Gene', (275, 278))
21221	26217306	When the UM samples were clustered together with the previously published NCI-60 NR expression data, it was found that RXRg expression defined a "melanoma cluster," which contained both UM and CM samples (Figure S2 in Supplementary Material).	('melanoma cluster', 'Disease', (146, 162))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('RXRg expression', 'Var', (119, 134))	('melanoma cluster', 'Disease', 'MESH:D008545', (146, 162))	('UM', 'Phenotype', 'HP:0007716', (186, 188))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('CM', 'Phenotype', 'HP:0012056', (193, 195))
21238	26217306	Comparisons between the BRAF mutant UM lines OCM1 and OCM3 and the rest of the panel found that the BRAF mutants retained expression levels of AR comparable to the melanocyte while the other cell lines had lost AR expression.	('AR', 'Gene', '367', (143, 145))	('AR', 'Gene', '367', (211, 213))	('OCM1', 'Species', '83984', (45, 49))	('BRAF', 'Gene', '673', (100, 104))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('mutants', 'Var', (105, 112))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (100, 104))	('CM', 'Phenotype', 'HP:0012056', (55, 57))	('expression levels', 'MPA', (122, 139))	('CM', 'Phenotype', 'HP:0012056', (46, 48))
21239	26217306	Finally, it was found that both OMM2.3 and MEL270 (GNAQ mutants) had almost completely lost RORa expression while the other cell lines maintained RORa expression at levels comparable to the primary melanocyte line.	('GNAQ', 'Gene', '2776', (51, 55))	('RORa', 'Gene', '6095', (92, 96))	('RORa', 'Gene', (146, 150))	('mutants', 'Var', (56, 63))	('lost', 'NegReg', (87, 91))	('RORa', 'Gene', (92, 96))	('RORa', 'Gene', '6095', (146, 150))	('GNAQ', 'Gene', (51, 55))
21251	26217306	We also examined whether there are NRs preferentially expressed in the different mutational subtypes of UM (GNA11Q209L, BRAFV600E, and GNAQQ209P) and identified receptors (NOR1, AR, and RORa, respectively) exhibiting mutation-specific expression patterns.	('GNA11', 'Gene', '2767', (108, 113))	('BRAFV600E', 'Gene', (120, 129))	('UM', 'Phenotype', 'HP:0007716', (104, 106))	('NOR1', 'Gene', '8013', (172, 176))	('RORa', 'Gene', (186, 190))	('RORa', 'Gene', '6095', (186, 190))	('NOR1', 'Gene', (172, 176))	('GNAQQ209P', 'Mutation', 'rs121913492', (135, 144))	('AR', 'Gene', '367', (178, 180))	('NOR', 'cellular_component', 'GO:0005731', ('172', '175'))	('GNAQQ209P', 'Var', (135, 144))	('BRAFV600E', 'Gene', '673', (120, 129))	('GNA11', 'Gene', (108, 113))
21270	26217306	Mutational profiling of UM has identified mutually exclusive, UM specific, activating mutations in two paralogs (GNAQ and GNA11) in more than 80% of UM cases.	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('mutations', 'Var', (86, 95))	('UM', 'Phenotype', 'HP:0007716', (24, 26))	('GNAQ', 'Gene', (113, 117))	('UM', 'Phenotype', 'HP:0007716', (149, 151))	('GNA11', 'Gene', (122, 127))	('GNA11', 'Gene', '2767', (122, 127))	('GNAQ', 'Gene', '2776', (113, 117))	('activating', 'PosReg', (75, 85))
21271	26217306	Although these mutations would seem obvious targets for therapeutic intervention, GNAQ/11 mutations have not been amenable to therapeutic development in UM and recent work has instead focused on inhibiting downstream events and gene networks driven by these mutations.	('mutations', 'Var', (90, 99))	('GNAQ', 'Gene', (82, 86))	('inhibiting', 'NegReg', (195, 205))	('UM', 'Phenotype', 'HP:0007716', (153, 155))	('gene networks', 'Pathway', (228, 241))	('GNAQ', 'Gene', '2776', (82, 86))
21272	26217306	As an example, combination therapy with inhibitors of GNAQ/11 downstream target protein kinase C (PKC) and MEK has been shown to inhibit the in vitro growth of GNAQ/11 UM mutant cell lines.	('UM', 'Phenotype', 'HP:0007716', (168, 170))	('GNAQ', 'Gene', (54, 58))	('GNAQ', 'Gene', (160, 164))	('combination', 'Interaction', (15, 26))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('inhibitors', 'Var', (40, 50))	('PKC', 'molecular_function', 'GO:0004697', ('98', '101'))	('inhibit', 'NegReg', (129, 136))	('GNAQ', 'Gene', '2776', (160, 164))	('MEK', 'Gene', (107, 110))	('MEK', 'Gene', '5609', (107, 110))	('GNAQ', 'Gene', '2776', (54, 58))
21273	26217306	Another recently identified downstream target of GNAQ/11 mutants is YAP1 and a YAP1 inhibitor, verteporfin, has also been shown to be effective inhibiting UM growth in xenograft models.	('UM', 'Phenotype', 'HP:0007716', (155, 157))	('inhibiting', 'NegReg', (144, 154))	('YAP1', 'Gene', (79, 83))	('verteporfin', 'Chemical', 'MESH:D000077362', (95, 106))	('YAP1', 'Gene', '10413', (79, 83))	('GNAQ', 'Gene', '2776', (49, 53))	('YAP1', 'Gene', '10413', (68, 72))	('GNAQ', 'Gene', (49, 53))	('mutants', 'Var', (57, 64))	('YAP1', 'Gene', (68, 72))	('UM growth', 'CPA', (155, 164))
21274	26217306	However, as was pointed out in a recent preview opinion from Field and Barbour, it is important to note that these inhibitors alone will likely be insufficient for treating UM metastases as GNAQ/11 mutations are only weakly oncogenic being unable to transform immortalized melanocytes without additional, cooperating mutations.	('GNAQ', 'Gene', (190, 194))	('metastases', 'Disease', 'MESH:D009362', (176, 186))	('UM', 'Phenotype', 'HP:0007716', (173, 175))	('mutations', 'Var', (198, 207))	('GNAQ', 'Gene', '2776', (190, 194))	('metastases', 'Disease', (176, 186))
21278	26217306	Other ligand/receptor combinations known to elicit broad-scale expression changes include mifepristone/progesterone receptor in endometrial tissue and T0901317/liver X receptors in the human monocytic cell line THP-1.	('T0901317/liver', 'Var', (151, 165))	('human', 'Species', '9606', (185, 190))	('progesterone receptor', 'Gene', (103, 124))	('progesterone receptor', 'Gene', '5241', (103, 124))	('THP-1', 'Gene', '2736', (211, 216))	('THP-1', 'Gene', (211, 216))	('ligand', 'molecular_function', 'GO:0005488', ('6', '12'))
21280	24413085	Combined PKC and MEK inhibition for treating metastatic uveal melanoma Uveal melanoma (UM) is the most common primary intraocular malignancy and the second most common form of melanoma.	('PKC', 'molecular_function', 'GO:0004697', ('9', '12'))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('intraocular malignancy', 'Disease', 'MESH:C563596', (118, 140))	('PKC', 'Gene', '112476', (9, 12))	('uveal melanoma', 'Disease', 'MESH:C536494', (56, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('melanoma', 'Disease', (62, 70))	('uveal melanoma', 'Disease', (56, 70))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (71, 85))	('MEK', 'Gene', '5609', (17, 20))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('PKC', 'Gene', (9, 12))	('melanoma', 'Disease', (77, 85))	('MEK', 'Gene', (17, 20))	('intraocular malignancy', 'Disease', (118, 140))	('uveal melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('UM', 'Phenotype', 'HP:0007716', (87, 89))	('inhibition', 'Var', (21, 31))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))
21281	24413085	Activating oncogenic mutations are commonly found in GNAQ and GNA11 in UM, and inhibiting key downstream effectors of the GNAQ/11 signaling pathway represents a rational therapeutic approach for treating metastatic UM.	('Activating', 'PosReg', (0, 10))	('GNAQ', 'Gene', (53, 57))	('GNAQ', 'Gene', (122, 126))	('inhibiting', 'NegReg', (79, 89))	('signaling pathway', 'biological_process', 'GO:0007165', ('130', '147'))	('UM', 'Phenotype', 'HP:0007716', (71, 73))	('UM', 'Phenotype', 'HP:0007716', (215, 217))	('GNAQ', 'Gene', '2776', (53, 57))	('GNA11', 'Gene', '2767', (62, 67))	('GNA11', 'Gene', (62, 67))	('GNAQ', 'Gene', '2776', (122, 126))	('mutations', 'Var', (21, 30))
21282	24413085	Chen et al., doi:10.1038/onc.2013.418, now confirm activation of the MAPK and PKC pathways as a result of GNAQ and GNA11 activating mutations in melanocytes, and they demonstrate that MAPK activation occurs downstream of PKC activation.	('GNA11', 'Gene', '2767', (115, 120))	('MAPK activation', 'biological_process', 'GO:0000187', ('184', '199'))	('mutations', 'Var', (132, 141))	('PKC', 'molecular_function', 'GO:0004697', ('221', '224'))	('activating', 'PosReg', (121, 131))	('GNAQ', 'Gene', (106, 110))	('PKC', 'Gene', '112476', (78, 81))	('PKC', 'Gene', (221, 224))	('PKC', 'Gene', '112476', (221, 224))	('PKC activation', 'biological_process', 'GO:1990051', ('221', '235'))	('PKC', 'molecular_function', 'GO:0004697', ('78', '81'))	('MAPK', 'molecular_function', 'GO:0004707', ('69', '73'))	('GNA11', 'Gene', (115, 120))	('PKC', 'Gene', (78, 81))	('activation', 'PosReg', (51, 61))	('MAPK', 'molecular_function', 'GO:0004707', ('184', '188'))	('GNAQ', 'Gene', '2776', (106, 110))
21283	24413085	PKC inhibitors disrupt MAPK signaling and block proliferation of GNAQ/11 mutant UM cell lines and slow the in vivo growth of xenografted UM tumors without inducing their shrinkage.	('proliferation', 'CPA', (48, 61))	('MAPK signaling', 'Pathway', (23, 37))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('slow', 'NegReg', (98, 102))	('MAPK signaling', 'biological_process', 'GO:0000165', ('23', '37'))	('mutant', 'Var', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('UM', 'Phenotype', 'HP:0007716', (137, 139))	('in vivo growth', 'CPA', (107, 121))	('block', 'NegReg', (42, 47))	('PKC', 'Gene', '112476', (0, 3))	('tumors', 'Disease', (140, 146))	('GNAQ', 'Gene', '2776', (65, 69))	('UM', 'Phenotype', 'HP:0007716', (80, 82))	('MAPK', 'molecular_function', 'GO:0004707', ('23', '27'))	('disrupt', 'Reg', (15, 22))	('GNAQ', 'Gene', (65, 69))	('PKC', 'molecular_function', 'GO:0004697', ('0', '3'))	('PKC', 'Gene', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (140, 146))
21285	24413085	Hence, the authors concluded that MEK and PKC inhibition is synergistic, with superior efficacy to treatment of GNAQ/GNA11 mutant UMs with either drug alone.	('GNAQ', 'Gene', (112, 116))	('PKC', 'Gene', (42, 45))	('PKC', 'Gene', '112476', (42, 45))	('PKC', 'molecular_function', 'GO:0004697', ('42', '45'))	('UM', 'Phenotype', 'HP:0007716', (130, 132))	('GNA11', 'Gene', '2767', (117, 122))	('GNA11', 'Gene', (117, 122))	('GNAQ', 'Gene', '2776', (112, 116))	('mutant', 'Var', (123, 129))
21289	24413085	As early as 2005, the RAS-RAF-MEK-ERK (extracellular signal-regulated kinase) or mitogen-activated protein kinase (MAPK) pathway was shown to be constitutively activated in UM despite an absence of BRAF or RAS mutations.	('RAF', 'Gene', (199, 202))	('RAS', 'Gene', (206, 209))	('mutations', 'Var', (210, 219))	('RAF', 'Gene', '22882', (199, 202))	('BRAF', 'Gene', '673', (198, 202))	('ERK', 'molecular_function', 'GO:0004707', ('34', '37'))	('extracellular', 'cellular_component', 'GO:0005576', ('39', '52'))	('BRAF', 'Gene', (198, 202))	('UM', 'Phenotype', 'HP:0007716', (173, 175))	('MAPK', 'molecular_function', 'GO:0004707', ('115', '119'))	('RAF', 'Gene', (26, 29))	('RAF', 'Gene', '22882', (26, 29))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))
21291	24413085	Activating mutations at either codon 209 or 183 in the Gq alpha subunits GNAQ and GNA11 are now known to represent early, mutually exclusive events that constitutively activate the MAPK pathway in the development of UM.	('MAPK pathway', 'Pathway', (181, 193))	('GNAQ', 'Gene', '2776', (73, 77))	('GNA11', 'Gene', (82, 87))	('activate', 'PosReg', (168, 176))	('GNA11', 'Gene', '2767', (82, 87))	('GNAQ', 'Gene', (73, 77))	('mutations at', 'Var', (11, 23))	('UM', 'Phenotype', 'HP:0007716', (216, 218))	('MAPK', 'molecular_function', 'GO:0004707', ('181', '185'))
21292	24413085	Other genetic drivers of UM include mutations in the BRCA1-associated protein-1 (BAP1), which are found in ~84% of metastasizing class 2 UMs, and in splicing factor 3B subunit 1 (SF3B1), which are found in ~15% of UMs and are associated with a more favorable outcome.	('BRCA1-associated protein-1', 'Gene', (53, 79))	('BAP1', 'Gene', (81, 85))	('SF3B1', 'Gene', (179, 184))	('associated', 'Reg', (226, 236))	('splicing factor 3B subunit 1', 'Gene', (149, 177))	('splicing', 'biological_process', 'GO:0045292', ('149', '157'))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('mutations', 'Var', (36, 45))	('SF3B1', 'Gene', '23451', (179, 184))	('UM', 'Phenotype', 'HP:0007716', (214, 216))	('BRCA1-associated protein-1', 'Gene', '8314', (53, 79))	('UM', 'Phenotype', 'HP:0007716', (137, 139))	('splicing factor 3B subunit 1', 'Gene', '23451', (149, 177))	('BAP1', 'Gene', '8314', (81, 85))	('UM', 'Phenotype', 'HP:0007716', (25, 27))
21293	24413085	Alterations in Eukaryotic translation initiation factor 1 A, X linked (EIF1AX) are present in ~8% of tumors with favorable outcome that lack SF3B1 mutations.	('SF3B1', 'Gene', '23451', (141, 146))	('mutations', 'Var', (147, 156))	('translation initiation', 'biological_process', 'GO:0006413', ('26', '48'))	('EIF1AX', 'Gene', '1964', (71, 77))	('EIF1AX', 'Gene', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('Alterations', 'Var', (0, 11))	('Eukaryotic translation initiation factor 1 A, X linked', 'Gene', '1964', (15, 69))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('SF3B1', 'Gene', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))
21302	24413085	Inhibitors of ERK1/2 and NF-kB pathways were also shown to reduce viability of UM cells.	('NF-kB', 'Gene', (25, 30))	('NF-kB', 'Gene', '4790', (25, 30))	('ERK1/2', 'Gene', (14, 20))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('Inhibitors', 'Var', (0, 10))	('ERK1/2', 'Gene', '5595;5594', (14, 20))	('reduce', 'NegReg', (59, 65))	('ERK1', 'molecular_function', 'GO:0004707', ('14', '18'))	('viability of UM cells', 'CPA', (66, 87))
21304	24413085	to evaluate a combination of small molecules inhibiting both MEK and PI3K in UM cells with different GNAQ/11 mutation backgrounds.	('PI3K', 'molecular_function', 'GO:0016303', ('69', '73'))	('GNAQ', 'Gene', '2776', (101, 105))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('inhibiting', 'NegReg', (45, 55))	('MEK', 'Pathway', (61, 64))	('PI3K', 'Pathway', (69, 73))	('GNAQ', 'Gene', (101, 105))	('mutation', 'Var', (109, 117))
21309	24413085	Synergistic reductions in cell viability were observed with AZD8055/selumetinib in both BRAF and GNAQ mutant cell lines, although apoptosis was preferentially induced in BRAF mutant cells and in a BRAF mutant xenograft model but not GNAQ mutant model.	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('induced', 'PosReg', (159, 166))	('AZD8055', 'Chemical', 'MESH:C546624', (60, 67))	('selumetinib', 'Chemical', 'MESH:C517975', (68, 79))	('cell viability', 'CPA', (26, 40))	('mutant', 'Var', (175, 181))	('reductions', 'NegReg', (12, 22))	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('GNAQ', 'Gene', '2776', (233, 237))	('apoptosis', 'CPA', (130, 139))	('BRAF', 'Gene', (197, 201))	('GNAQ', 'Gene', '2776', (97, 101))	('AZD8055/selumetinib', 'Gene', (60, 79))	('AZD8055/selumetinib', 'Var', (60, 79))	('BRAF', 'Gene', '673', (197, 201))	('GNAQ', 'Gene', (233, 237))	('BRAF', 'Gene', '673', (170, 174))	('GNAQ', 'Gene', (97, 101))	('mutant', 'Var', (102, 108))	('BRAF', 'Gene', (170, 174))	('preferentially', 'PosReg', (144, 158))	('mutant', 'Var', (202, 208))
21310	24413085	confirm activation of the MAPK and PKC pathways as a result of GNAQ and GNA11 activating mutations in melanocytes and demonstrate (not unexpectedly) that MAPK activation occurs downstream of PKC activation.	('PKC', 'molecular_function', 'GO:0004697', ('35', '38'))	('activating', 'PosReg', (78, 88))	('PKC', 'Gene', (35, 38))	('activation', 'PosReg', (8, 18))	('GNAQ', 'Gene', (63, 67))	('PKC', 'Gene', '112476', (35, 38))	('GNAQ', 'Gene', '2776', (63, 67))	('MAPK activation', 'biological_process', 'GO:0000187', ('154', '169'))	('PKC', 'molecular_function', 'GO:0004697', ('191', '194'))	('PKC activation', 'biological_process', 'GO:1990051', ('191', '205'))	('PKC', 'Gene', (191, 194))	('PKC', 'Gene', '112476', (191, 194))	('mutations', 'Var', (89, 98))	('GNA11', 'Gene', (72, 77))	('MAPK', 'molecular_function', 'GO:0004707', ('26', '30'))	('MAPK', 'molecular_function', 'GO:0004707', ('154', '158'))	('GNA11', 'Gene', '2767', (72, 77))
21312	24413085	Activation of PKC in GNAQ/11 mutant tumors was determined on the basis of increased phosphorylation of the PKC substrate MARCKS, whereas activation of the MAPK pathway was determined on the basis of the presence of p-ERK and pp90RSK.	('GNAQ', 'Gene', '2776', (21, 25))	('PKC', 'Gene', (14, 17))	('PKC', 'Gene', '112476', (107, 110))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('PKC', 'molecular_function', 'GO:0004697', ('14', '17'))	('GNAQ', 'Gene', (21, 25))	('PKC', 'Gene', (107, 110))	('increased', 'PosReg', (74, 83))	('p-ERK', 'Gene', '9451', (215, 220))	('ERK', 'molecular_function', 'GO:0004707', ('217', '220'))	('p-ERK', 'Gene', (215, 220))	('PKC', 'molecular_function', 'GO:0004697', ('107', '110'))	('MAPK', 'molecular_function', 'GO:0004707', ('155', '159'))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('MARCKS', 'Gene', (121, 127))	('mutant', 'Var', (29, 35))	('Activation', 'PosReg', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('phosphorylation', 'MPA', (84, 99))	('MAPK pathway', 'Pathway', (155, 167))	('pp90RSK', 'Var', (225, 232))	('PKC', 'Gene', '112476', (14, 17))	('MARCKS', 'Gene', '4082', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (36, 42))
21314	24413085	These molecules inhibited pMARCKS and MAPK signaling and proliferation of melanoma cell lines in GNAQ/11 mutant cells, whereas the MEK inhibitor PD0325901 did not inhibit proliferation of these lines.	('PD0325901', 'Chemical', 'MESH:C506614', (145, 154))	('inhibited', 'NegReg', (16, 25))	('MARCKS', 'Gene', '4082', (27, 33))	('GNAQ', 'Gene', '2776', (97, 101))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('proliferation', 'CPA', (57, 70))	('MAPK', 'molecular_function', 'GO:0004707', ('38', '42'))	('MARCKS', 'Gene', (27, 33))	('mutant', 'Var', (105, 111))	('MAPK signaling', 'biological_process', 'GO:0000165', ('38', '52'))	('GNAQ', 'Gene', (97, 101))
21315	24413085	Treatment with two different MEK inhibitors, PD0325901 and MEK162, inhibited the proliferation of melanoma cell lines irrespective of their mutation status (Figure 1).	('inhibited', 'NegReg', (67, 76))	('PD0325901', 'Var', (45, 54))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('MEK162', 'Gene', (59, 65))	('proliferation', 'CPA', (81, 94))	('PD0325901', 'Chemical', 'MESH:C506614', (45, 54))	('MEK', 'Gene', (29, 32))
21316	24413085	The authors interpreted this to be that in the context of GNAQ or GNA11 mutation, MAPK activation can be attributed to activated PKC.	('activation', 'PosReg', (87, 97))	('PKC', 'molecular_function', 'GO:0004697', ('129', '132'))	('MAPK activation', 'biological_process', 'GO:0000187', ('82', '97'))	('PKC', 'Gene', '112476', (129, 132))	('GNAQ', 'Gene', '2776', (58, 62))	('GNA11', 'Gene', (66, 71))	('PKC', 'Gene', (129, 132))	('GNAQ', 'Gene', (58, 62))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))	('GNA11', 'Gene', '2767', (66, 71))	('mutation', 'Var', (72, 80))	('MAPK', 'Gene', (82, 86))
21321	24413085	The authors conclude that PKC is a rational therapeutic target for melanoma patients with GNAQ or GNA11 mutations, and that combined MEK and PKC inhibition provides a synergistic effect with superior efficacy compared with treatment with either approach alone.	('patients', 'Species', '9606', (76, 84))	('mutations', 'Var', (104, 113))	('PKC', 'Gene', (141, 144))	('GNA11', 'Gene', (98, 103))	('MEK', 'Enzyme', (133, 136))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('GNAQ', 'Gene', '2776', (90, 94))	('PKC', 'Gene', '112476', (141, 144))	('GNA11', 'Gene', '2767', (98, 103))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('PKC', 'Gene', (26, 29))	('PKC', 'Gene', '112476', (26, 29))	('PKC', 'molecular_function', 'GO:0004697', ('141', '144'))	('GNAQ', 'Gene', (90, 94))	('PKC', 'molecular_function', 'GO:0004697', ('26', '29'))	('inhibition', 'NegReg', (145, 155))
21322	24413085	This therefore leads one to ask whether the PKC and RAS/RAF/MEK pathways leading to MAPK activation are independent in the context of mutant GNAQ/GNA11.	('GNA11', 'Gene', '2767', (146, 151))	('MAPK', 'molecular_function', 'GO:0004707', ('84', '88'))	('PKC', 'Gene', '112476', (44, 47))	('RAF', 'Gene', '22882', (56, 59))	('GNAQ', 'Gene', (141, 145))	('RAF', 'Gene', (56, 59))	('GNAQ', 'Gene', '2776', (141, 145))	('PKC', 'molecular_function', 'GO:0004697', ('44', '47'))	('MAPK activation', 'biological_process', 'GO:0000187', ('84', '99'))	('mutant', 'Var', (134, 140))	('activation', 'PosReg', (89, 99))	('PKC', 'Gene', (44, 47))	('GNA11', 'Gene', (146, 151))	('MAPK', 'Gene', (84, 88))
21324	24413085	Will inhibition of the GNAQ/11 pathway alone be sufficient for sustained efficacy in human subjects with metastatic UM, when the vast majority of them will have BAP1 mutations that may also require pharmacologic modulation?	('BAP1', 'Gene', (161, 165))	('mutations', 'Var', (166, 175))	('GNAQ', 'Gene', (23, 27))	('metastatic UM', 'Disease', (105, 118))	('UM', 'Phenotype', 'HP:0007716', (116, 118))	('BAP1', 'Gene', '8314', (161, 165))	('GNAQ', 'Gene', '2776', (23, 27))	('human', 'Species', '9606', (85, 90))
21349	24705312	Ambiguous Melanocytic Tumors with loss of 3p21 Germline loss of function mutations in BAP1 are associated with the development of cutaneous melanocytic tumors with some histopathologic characteristics seen in Spitz nevi.	('Ambiguous Melanocytic Tumors', 'Disease', 'MESH:D012734', (0, 28))	('BAP1', 'Gene', '8314', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('Ambiguous Melanocytic Tumors', 'Disease', (0, 28))	('Tumors', 'Phenotype', 'HP:0002664', (22, 28))	('nevi', 'Phenotype', 'HP:0003764', (215, 219))	('BAP1', 'Gene', (86, 90))	('loss of function', 'NegReg', (56, 72))	('cutaneous melanocytic tumors', 'Disease', (130, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('mutations', 'Var', (73, 82))	('Spitz nevi', 'Disease', (209, 219))	('cutaneous melanocytic tumors', 'Disease', 'MESH:D009508', (130, 158))
21351	24705312	In some of these sporadic tumors, loss of BAP1 occurs through mutation of one allele and genomic loss of the other.	('BAP1', 'Gene', '8314', (42, 46))	('BAP1', 'Gene', (42, 46))	('sporadic tumors', 'Disease', 'MESH:D009369', (17, 32))	('mutation', 'Var', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('loss', 'NegReg', (34, 38))	('genomic loss', 'CPA', (89, 101))	('sporadic tumors', 'Disease', (17, 32))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
21352	24705312	We screened our database of comparative genomic hybridization profiles of ambiguous melanocytic tumors to identify cases with a single genomic event involving loss of the BAP1 locus.	('BAP1', 'Gene', (171, 175))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('loss', 'Var', (159, 163))	('ambiguous melanocytic tumors', 'Disease', 'MESH:D012734', (74, 102))	('ambiguous melanocytic tumors', 'Disease', (74, 102))	('BAP1', 'Gene', '8314', (171, 175))
21353	24705312	The prevalence of tumors with a single genomic event involving loss of BAP1 was 6.7% in our study population.	('loss', 'Var', (63, 67))	('BAP1', 'Gene', '8314', (71, 75))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('BAP1', 'Gene', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
21356	24705312	Germline loss of function mutations in BAP1 have recently been identified in families with increased incidence of uveal melanoma, mesothelioma, renal cell carcinoma, and other malignancies.	('malignancies', 'Disease', (176, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('mesothelioma', 'Disease', (130, 142))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (144, 164))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('mesothelioma', 'Disease', 'MESH:D008654', (130, 142))	('malignancies', 'Disease', 'MESH:D009369', (176, 188))	('uveal melanoma', 'Disease', (114, 128))	('mutations', 'Var', (26, 35))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('BAP1', 'Gene', '8314', (39, 43))	('renal cell carcinoma', 'Disease', (144, 164))	('loss of function', 'NegReg', (9, 25))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (144, 164))	('BAP1', 'Gene', (39, 43))
21357	24705312	While BAP1 mutations have been known to occur in rare cases of non-small cell lung cancer and breast cancer, more recently BAP1 mutations have been identified in uveal melanoma, clear cell renal cell carcinoma, and myelodysplasia expanding the spectrum of neoplasia associated with loss of BAP1.	('identified in', 'Reg', (148, 161))	('mutations', 'Var', (11, 20))	('uveal melanoma', 'Disease', (162, 176))	('uveal melanoma', 'Disease', 'MESH:C536494', (162, 176))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (67, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('neoplasia', 'Disease', (256, 265))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (63, 89))	('myelodysplasia', 'Phenotype', 'HP:0002863', (215, 229))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('BAP1', 'Gene', '8314', (6, 10))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (178, 209))	('uveal melanoma', 'Phenotype', 'HP:0007716', (162, 176))	('myelodysplasia', 'Disease', 'MESH:D009190', (215, 229))	('mutations', 'Var', (128, 137))	('BAP1', 'Gene', '8314', (290, 294))	('BAP1', 'Gene', '8314', (123, 127))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('non-small cell lung cancer', 'Disease', (63, 89))	('neoplasia', 'Phenotype', 'HP:0002664', (256, 265))	('breast cancer', 'Disease', (94, 107))	('BAP1', 'Gene', (6, 10))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (178, 209))	('BAP1', 'Gene', (123, 127))	('BAP1', 'Gene', (290, 294))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (63, 89))	('myelodysplasia', 'Disease', (215, 229))	('clear cell renal cell carcinoma', 'Disease', (178, 209))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (189, 209))	('neoplasia', 'Disease', 'MESH:D009369', (256, 265))
21361	24705312	Loss of BAP1 sensitizes cells to ionizing radiation due to its role in homologous recombination.	('BAP1', 'Gene', '8314', (8, 12))	('BAP1', 'Gene', (8, 12))	('homologous recombination', 'biological_process', 'GO:0035825', ('71', '95'))	('sensitizes', 'Reg', (13, 23))	('Loss', 'Var', (0, 4))
21362	24705312	BAP1 biallelic loss in uveal melanoma and clear cell renal cell carcinoma is associated with poor prognosis and typically occurs as the result of somatic mutation of one allele and chromosomal loss of the other.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (42, 73))	('chromosomal loss', 'Var', (181, 197))	('BAP1', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('uveal melanoma', 'Phenotype', 'HP:0007716', (23, 37))	('biallelic loss', 'Var', (5, 19))	('uveal melanoma', 'Disease', 'MESH:C536494', (23, 37))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (53, 73))	('uveal melanoma', 'Disease', (23, 37))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (42, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('BAP1', 'Gene', '8314', (0, 4))	('clear cell renal cell carcinoma', 'Disease', (42, 73))
21363	24705312	An increase in cutaneous melanocytic tumors has been observed in several families with germline BAP1 loss of function mutations.	('cutaneous melanocytic tumors', 'Disease', 'MESH:D009508', (15, 43))	('BAP1', 'Gene', (96, 100))	('mutations', 'Var', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cutaneous melanocytic tumors', 'Disease', (15, 43))	('loss of function', 'NegReg', (101, 117))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('BAP1', 'Gene', '8314', (96, 100))
21366	24705312	A majority of these melanocytic neoplasms were considered to be benign by histopathologic criteria in the original report and often demonstrated a loss of function mutation of one BAP1 allele and loss of the genetic material containing the other BAP1 allele, loss of BAP1 expression, and activating BRAF mutations.	('activating', 'PosReg', (288, 298))	('expression', 'MPA', (272, 282))	('loss of function', 'NegReg', (147, 163))	('loss', 'NegReg', (259, 263))	('mutation', 'Var', (164, 172))	('BAP1', 'Gene', '8314', (246, 250))	('BAP1', 'Gene', '8314', (180, 184))	('BRAF', 'Gene', '673', (299, 303))	('BAP1', 'Gene', '8314', (267, 271))	('BRAF', 'Gene', (299, 303))	('BAP1', 'Gene', (246, 250))	('neoplasm', 'Phenotype', 'HP:0002664', (32, 40))	('BAP1', 'Gene', (180, 184))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (20, 41))	('BAP1', 'Gene', (267, 271))	('neoplasms', 'Phenotype', 'HP:0002664', (32, 41))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (20, 41))	('melanocytic neoplasms', 'Disease', (20, 41))	('mutations', 'Var', (304, 313))	('loss', 'NegReg', (196, 200))
21367	24705312	Njauw and colleagues also identified families with germline BAP1 mutations, but characterized their cutaneous melanocytic tumors as "severely atypical" and "reminiscent of nevoid melanoma," in many cases falling "short of frank malignancy though these lesions clearly lie within the spectrum of nevoid melanomas."	('melanomas', 'Phenotype', 'HP:0002861', (302, 311))	('frank malignancy', 'Disease', (222, 238))	('frank malignancy', 'Disease', 'MESH:D009369', (222, 238))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (302, 310))	('cutaneous melanocytic tumors', 'Disease', (100, 128))	('melanoma', 'Disease', (302, 310))	('BAP1', 'Gene', '8314', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('melanomas', 'Disease', 'MESH:D008545', (302, 311))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('falling', 'Phenotype', 'HP:0002527', (204, 211))	('melanomas', 'Disease', (302, 311))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanoma', 'Disease', (179, 187))	('BAP1', 'Gene', (60, 64))	('melanoma', 'Disease', 'MESH:D008545', (302, 310))	('cutaneous melanocytic tumors', 'Disease', 'MESH:D009508', (100, 128))	('mutations', 'Var', (65, 74))
21371	24705312	As the distinct cutaneous tumors seen in patients with germline BAP1 mutations fell within the spectrum of what Wiesner and colleagues term "atypical Spitz tumors with epithelioid morphology" they screened a subset of these tumors encountered in two dermatopathology practices for loss of BAP1.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (224, 230))	('Spitz tumors', 'Disease', (150, 162))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('cutaneous tumors', 'Phenotype', 'HP:0008069', (16, 32))	('BAP1', 'Gene', (64, 68))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('germline', 'Var', (55, 63))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('BAP1', 'Gene', '8314', (289, 293))	('mutations', 'Var', (69, 78))	('Spitz tumors', 'Disease', 'MESH:D018332', (150, 162))	('cutaneous tumors', 'Disease', 'MESH:D009369', (16, 32))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cutaneous tumors', 'Disease', (16, 32))	('patients', 'Species', '9606', (41, 49))	('tumors', 'Disease', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('BAP1', 'Gene', (289, 293))	('BAP1', 'Gene', '8314', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Disease', (26, 32))
21373	24705312	Not surprisingly, these tumors with BAP1 loss demonstrated similar features to those melanocytic tumors identified in patients with germline BAP1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('melanocytic tumors', 'Disease', 'MESH:D009508', (85, 103))	('BAP1', 'Gene', '8314', (141, 145))	('mutations', 'Var', (146, 155))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('BAP1', 'Gene', '8314', (36, 40))	('BAP1', 'Gene', (141, 145))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('BAP1', 'Gene', (36, 40))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('patients', 'Species', '9606', (118, 126))	('loss', 'NegReg', (41, 45))	('melanocytic tumors', 'Disease', (85, 103))
21375	24705312	recently reported a series of 6 combined "atypical spitz tumors" occurring in a sporadic setting in which the spitzoid component lacked BAP1 expression by immunohistochemistry while the conventional component retained BAP1 expression, and both components harbored BRAFV600E mutation.	('spitzoid', 'Chemical', '-', (110, 118))	('lacked', 'NegReg', (129, 135))	('BAP1', 'Gene', (136, 140))	('BRAFV600E mutation', 'Var', (264, 282))	('BRAFV600E', 'Mutation', 'rs113488022', (264, 273))	('harbored', 'Reg', (255, 263))	('spitz tumors', 'Disease', 'MESH:D018332', (51, 63))	('BAP1', 'Gene', '8314', (218, 222))	('BAP1', 'Gene', '8314', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('expression', 'MPA', (141, 151))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('spitz tumors', 'Disease', (51, 63))	('BAP1', 'Gene', (218, 222))
21383	24705312	All cases were further evaluated when possible for mutations within the coding region of the remaining BAP1 allele or loss of BAP1 staining.	('BAP1', 'Gene', '8314', (103, 107))	('mutations', 'Var', (51, 60))	('BAP1', 'Gene', (126, 130))	('BAP1', 'Gene', (103, 107))	('BAP1', 'Gene', '8314', (126, 130))
21391	24705312	We identified a loss of function mutation in BAP1 in 10 of 11 cases sequenced across BAP1 coding regions.	('BAP1', 'Gene', (85, 89))	('mutation', 'Var', (33, 41))	('BAP1', 'Gene', (45, 49))	('loss of function', 'NegReg', (16, 32))	('BAP1', 'Gene', '8314', (85, 89))	('BAP1', 'Gene', '8314', (45, 49))
21393	24705312	Additionally, loss of function of BAP1 was confirmed in 17 of these cases either by identification of a BAP1 loss of function mutation or loss of BAP1 immunohistochemical staining (Table 2).	('loss of function', 'NegReg', (109, 125))	('loss', 'NegReg', (138, 142))	('BAP1', 'Gene', '8314', (104, 108))	('BAP1', 'Gene', '8314', (146, 150))	('BAP1', 'Gene', (34, 38))	('loss of function', 'NegReg', (14, 30))	('mutation', 'Var', (126, 134))	('BAP1', 'Gene', (146, 150))	('BAP1', 'Gene', (104, 108))	('BAP1', 'Gene', '8314', (34, 38))
21413	24705312	The finding that in some families a germline mutation of BAP1 predisposes to distinctive spitzoid melanocytic lesions established multiple such lesions as a marker for increased risk of cutaneous and uveal melanoma and mesothelioma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (200, 214))	('germline mutation', 'Var', (36, 53))	('spitzoid melanocytic lesions', 'Disease', (89, 117))	('BAP1', 'Gene', '8314', (57, 61))	('spitzoid melanocytic lesions', 'Disease', 'MESH:D009508', (89, 117))	('predisposes', 'Reg', (62, 73))	('uveal melanoma and mesothelioma', 'Disease', 'MESH:C536494', (200, 231))	('BAP1', 'Gene', (57, 61))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))
21417	24705312	We use CGH to assess copy number changes, with no aberrations favoring a benign or indeterminate interpretation (depending on the morphologic features), certain distinctive findings such as isolated gain of 7q or 11p favoring a Spitz nevus, and multiple aberrations involving chromosomes often involved in melanoma favoring that diagnosis.	('Spitz nevus', 'Disease', (228, 239))	('melanoma', 'Phenotype', 'HP:0002861', (306, 314))	('melanoma', 'Disease', (306, 314))	('gain', 'PosReg', (199, 203))	('melanoma', 'Disease', 'MESH:D008545', (306, 314))	('copy', 'Var', (21, 25))	('nevus', 'Phenotype', 'HP:0003764', (234, 239))	('favoring', 'Reg', (217, 225))
21419	24705312	The correlation between losses involving chromosome 3p21 and BAP1 mutation was strong.	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))	('BAP1', 'Gene', (61, 65))	('mutation', 'Var', (66, 74))	('losses', 'NegReg', (24, 30))	('BAP1', 'Gene', '8314', (61, 65))
21421	24705312	We also found that with the exception of a blue nevus-like melanoma with monosomy of chromosome 3, 3p21 loss was limited to spitzoid neoplasms.	('loss', 'NegReg', (104, 108))	('neoplasms', 'Phenotype', 'HP:0002664', (133, 142))	('chromosome', 'cellular_component', 'GO:0005694', ('85', '95'))	('3p21', 'Gene', (99, 103))	('spitzoid neoplasms', 'Disease', 'MESH:D009369', (124, 142))	('blue nevus', 'Phenotype', 'HP:0100814', (43, 53))	('neoplasm', 'Phenotype', 'HP:0002664', (133, 141))	('spitzoid neoplasms', 'Disease', (124, 142))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (48, 67))	('monosomy', 'Var', (73, 81))	('nevus', 'Phenotype', 'HP:0003764', (48, 53))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
21427	24705312	Of these cases, 4 had features similar to those observed with BAP1 biallelic loss, and 3 did not.	('BAP1', 'Gene', '8314', (62, 66))	('BAP1', 'Gene', (62, 66))	('biallelic', 'Var', (67, 76))
21428	24705312	It is notable that a clinical halo was not noted in the many lesions that occur in each patient with BAP1 mutations in a familial setting, and that the reported cases of sporadic lesions have not mentioned a halo, either.	('patient', 'Species', '9606', (88, 95))	('halo', 'cellular_component', 'GO:1990038', ('208', '212'))	('BAP1', 'Gene', '8314', (101, 105))	('BAP1', 'Gene', (101, 105))	('mutations', 'Var', (106, 115))	('halo', 'cellular_component', 'GO:1990038', ('30', '34'))
21431	24705312	Two cases in patients with germline mutations in BAP1 have been reported which sheets of anaplastic melanocytes were present adjacent to a lesion that otherwise resembled one of the multiple spitzoid neoplasms.	('BAP1', 'Gene', (49, 53))	('patients', 'Species', '9606', (13, 21))	('spitzoid neoplasms', 'Disease', 'MESH:D009369', (191, 209))	('neoplasm', 'Phenotype', 'HP:0002664', (200, 208))	('germline mutations', 'Var', (27, 45))	('neoplasms', 'Phenotype', 'HP:0002664', (200, 209))	('spitzoid neoplasms', 'Disease', (191, 209))	('BAP1', 'Gene', '8314', (49, 53))	('anaplastic melanocytes', 'Phenotype', 'HP:0002861', (89, 111))
21432	24705312	Clearly, given these two cases, and the role of BAP-1 mutation in cancer progression in other lineages, there may be an increased risk for melanoma to develop in a spitzoid lesion with BAP1 mutation compared to a banal nevus, or even a dysplastic nevus.	('BAP1', 'Gene', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('develop', 'Reg', (151, 158))	('nevus', 'Phenotype', 'HP:0003764', (247, 252))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (236, 252))	('dysplastic nevus', 'Disease', (236, 252))	('dysplastic nevus', 'Disease', 'MESH:D004416', (236, 252))	('BAP-1', 'Gene', '8314', (48, 53))	('nevus', 'Phenotype', 'HP:0003764', (219, 224))	('BAP1', 'Gene', '8314', (185, 189))	('BAP-1', 'Gene', (48, 53))	('mutation', 'Var', (190, 198))	('mutation', 'Var', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('cancer', 'Disease', (66, 72))	('spitzoid', 'Chemical', '-', (164, 172))
21435	24705312	We would not be surprised if like other spitzoid neoplasms, cases with bialleleic BAP1 loss but no features of melanoma will be shown to involve local lymph nodes (as evidenced by their positivity in sentinel lymph node biopsies).	('loss', 'NegReg', (87, 91))	('spitzoid neoplasms', 'Disease', (40, 58))	('BAP1', 'Gene', (82, 86))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Disease', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('neoplasm', 'Phenotype', 'HP:0002664', (49, 57))	('involve', 'Reg', (137, 144))	('spitzoid neoplasms', 'Disease', 'MESH:D009369', (40, 58))	('bialleleic', 'Var', (71, 81))	('BAP1', 'Gene', '8314', (82, 86))	('neoplasms', 'Phenotype', 'HP:0002664', (49, 58))
21441	24705312	The presence of additional chromosomal gains or losses would be worrisome for melanoma, depending on the specific genomic regions that are involved.	('chromosomal gains', 'Var', (27, 44))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('losses', 'NegReg', (48, 54))
21442	24705312	While previous studies of Spitz nevi with BAP1 loss only identified BRAFV600E mutations in such tumors, we have identified one case with an activating NRAS mutation.	('BAP1', 'Gene', '8314', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Spitz nevi', 'Disease', (26, 36))	('tumors', 'Disease', (96, 102))	('BAP1', 'Gene', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('nevi', 'Phenotype', 'HP:0003764', (32, 36))	('loss', 'NegReg', (47, 51))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('NRAS', 'Gene', (151, 155))	('BRAFV600E', 'Var', (68, 77))	('BRAFV600E', 'Mutation', 'rs113488022', (68, 77))	('NRAS', 'Gene', '4893', (151, 155))
21443	24705312	This lesion demonstrated similar histopathologic features to the BRAF mutant tumors, although it was one of the more pigmented tumors in the series.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('mutant', 'Var', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('BRAF', 'Gene', '673', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('pigmented tumors', 'Disease', 'MESH:D010859', (117, 133))	('BRAF', 'Gene', (65, 69))	('pigmented tumors', 'Disease', (117, 133))
21444	24705312	Thus, this morphology is not isolated to BRAF mutant tumors, and the relative frequency of BRAF to NRAS mutations may be similar to the relative frequency of mutations in these genes in conventional nevi.	('mutations', 'Var', (104, 113))	('BRAF', 'Gene', '673', (91, 95))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('BRAF', 'Gene', (91, 95))	('BRAF', 'Gene', '673', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('NRAS', 'Gene', (99, 103))	('nevi', 'Phenotype', 'HP:0003764', (199, 203))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('BRAF', 'Gene', (41, 45))	('NRAS', 'Gene', '4893', (99, 103))	('tumors', 'Disease', (53, 59))
21446	24705312	Blue nevi and melanomas arising in them mostly have initiating mutations involving GNAQ or GNA11(p11), while Spitz nevi with BAP1 loss lack such mutations, and instead have BRAFV600E mutations.	('GNA11', 'Gene', '2767', (91, 96))	('melanomas', 'Phenotype', 'HP:0002861', (14, 23))	('mutations', 'Var', (63, 72))	('GNAQ', 'Gene', '2776', (83, 87))	('BAP1', 'Gene', '8314', (125, 129))	('nevi', 'Phenotype', 'HP:0003764', (5, 9))	('BRAFV600E', 'Mutation', 'rs113488022', (173, 182))	('loss', 'NegReg', (130, 134))	('GNAQ', 'Gene', (83, 87))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('p11', 'Gene', '6281', (97, 100))	('GNA11', 'Gene', (91, 96))	('nevi', 'Phenotype', 'HP:0003764', (115, 119))	('BAP1', 'Gene', (125, 129))	('Blue nevi', 'Phenotype', 'HP:0100814', (0, 9))	('p11', 'Gene', (97, 100))	('melanomas', 'Disease', 'MESH:D008545', (14, 23))	('melanomas', 'Disease', (14, 23))	('Blue nevi', 'Disease', (0, 9))	('BRAFV600E', 'Var', (173, 182))
21447	24705312	In a previous study, including colleagues from our dermatopathology section, multiple genomic aberrations were the most common correlate by CGH in blue nevus-like melanoma, with only one or two copy number changes in so-called atypical blue nevi.	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (152, 171))	('nevi', 'Phenotype', 'HP:0003764', (241, 245))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('common', 'Reg', (120, 126))	('CGH', 'Var', (140, 143))	('blue nevi', 'Phenotype', 'HP:0100814', (236, 245))	('blue nevus', 'Phenotype', 'HP:0100814', (147, 157))	('nevus', 'Phenotype', 'HP:0003764', (152, 157))
21451	24705312	As both blue nevi and uveal melanoma are driven by GNAQ or GNA11 mutations, we hypothesize that BAP1 mutations in blue nevus-like lesions are a marker for the acquisition of metastatic capacity.	('blue nevus-like', 'Disease', (114, 129))	('BAP1', 'Gene', (96, 100))	('uveal melanoma', 'Phenotype', 'HP:0007716', (22, 36))	('nevi', 'Phenotype', 'HP:0003764', (13, 17))	('GNAQ', 'Gene', '2776', (51, 55))	('GNA11', 'Gene', (59, 64))	('nevus', 'Phenotype', 'HP:0003764', (119, 124))	('GNAQ', 'Gene', (51, 55))	('mutations', 'Var', (101, 110))	('blue nevi', 'Disease', (8, 17))	('BAP1', 'Gene', '8314', (96, 100))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('driven', 'Reg', (41, 47))	('blue nevus', 'Phenotype', 'HP:0100814', (114, 124))	('uveal melanoma', 'Disease', 'MESH:C536494', (22, 36))	('GNA11', 'Gene', '2767', (59, 64))	('blue nevi', 'Phenotype', 'HP:0100814', (8, 17))	('uveal melanoma', 'Disease', (22, 36))	('mutations', 'Var', (65, 74))
21467	23913718	Whereas cutaneous melanoma often harbors activating mutations in BRAF and NRAS, mutations in the heterotrimeric G protein alpha-subunits, GNAQ and GNA11, have been reported in approximately 80% of uveal melanomas.	('activating', 'PosReg', (41, 51))	('reported', 'Reg', (164, 172))	('NRAS', 'Gene', (74, 78))	('uveal melanoma', 'Phenotype', 'HP:0007716', (197, 211))	('cutaneous melanoma', 'Disease', (8, 26))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (8, 26))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (8, 26))	('GNA11', 'Gene', '2767', (147, 152))	('uveal melanomas', 'Disease', (197, 212))	('uveal melanomas', 'Phenotype', 'HP:0007716', (197, 212))	('mutations', 'Var', (80, 89))	('GNAQ', 'Gene', '2776', (138, 142))	('GNAQ', 'Gene', (138, 142))	('melanomas', 'Phenotype', 'HP:0002861', (203, 212))	('BRAF', 'Gene', (65, 69))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('97', '121'))	('NRAS', 'Gene', '4893', (74, 78))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('GNA11', 'Gene', (147, 152))	('mutations', 'Var', (52, 61))	('uveal melanomas', 'Disease', 'MESH:C536494', (197, 212))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('BRAF', 'Gene', '673', (65, 69))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))
21468	23913718	GNAQ and GNA11 mutations are not, however, correlated with disease free survival or the development of metastasis.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('GNAQ', 'Gene', (0, 4))	('GNA11', 'Gene', '2767', (9, 14))
21536	23913718	Based on a multivariable Cox proportional hazard model of overall survival with ECOG status and LDH class as covariates, ECOG status of 0 demonstrated an 87% reduction in the hazard of death compared with ECOG 1-2 (hazard ratio (HR): 0.13, 95% CI (0.04 to 0.44), p=0.001) and LDH within institutional normal limits showed an 82% reduction in the hazard of death (HR: 0.18, 95% CI (0.05 to 0.73), p=0.02).	('death', 'Disease', 'MESH:D003643', (356, 361))	('death', 'Disease', (356, 361))	('ECOG', 'Var', (121, 125))	('death', 'Disease', 'MESH:D003643', (185, 190))	('death', 'Disease', (185, 190))	('reduction', 'NegReg', (158, 167))	('reduction', 'NegReg', (329, 338))
21550	23913718	Our retrospective study evaluating the activity of ipilimumab in 39 patients from four academic centers in the United States and Europe is the largest report to date of the activity of ipilimumab in uveal melanoma and provides the first evidence that ipilimumab can generate mWHO and irRC responses, as well as stable disease, in patients with metastatic uveal melanoma.	('ipilimumab', 'Chemical', 'MESH:D000074324', (251, 261))	('uveal melanoma', 'Phenotype', 'HP:0007716', (355, 369))	('uveal melanoma', 'Disease', (355, 369))	('uveal melanoma', 'Phenotype', 'HP:0007716', (199, 213))	('melanoma', 'Phenotype', 'HP:0002861', (361, 369))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('mWHO', 'MPA', (275, 279))	('ipilimumab', 'Chemical', 'MESH:D000074324', (51, 61))	('ipilimumab', 'Chemical', 'MESH:D000074324', (185, 195))	('patients', 'Species', '9606', (68, 76))	('ipilimumab', 'Var', (251, 261))	('patients', 'Species', '9606', (330, 338))	('uveal melanoma', 'Disease', 'MESH:C536494', (199, 213))	('irRC responses', 'MPA', (284, 298))	('uveal melanoma', 'Disease', (199, 213))	('uveal melanoma', 'Disease', 'MESH:C536494', (355, 369))
21593	22453016	The recent discovery of mutations that underlie uveal melanoma metastasis, growth and survival provide a key to the molecular understanding of this disease.	('uveal melanoma metastasis', 'Disease', (48, 73))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('mutations', 'Var', (24, 33))	('uveal melanoma metastasis', 'Disease', 'MESH:C536494', (48, 73))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))
21598	22453016	Multiple anatomical, histological and molecular poor prognostic features within primary tumors have been identified: 1) ciliary body (poorer) > choroid >> iris (rarely metastasize), 2) greater tumor size, 3) extrascleral invasion, 4) epithelioid > spindle cell histology, 5) greater mitotic number, 6) presence of monosomy 3, 7) presence of chr 8q gain, and 8) a class 2 gene expression profile.	('epithelioid > spindle cell', 'CPA', (234, 260))	('greater', 'PosReg', (275, 282))	('class', 'Reg', (363, 368))	('primary tumors', 'Disease', (80, 94))	('gene expression', 'biological_process', 'GO:0010467', ('371', '386'))	('spindle', 'cellular_component', 'GO:0005819', ('248', '255'))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('primary tumors', 'Disease', 'MESH:D009369', (80, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('mitotic number', 'CPA', (283, 297))	('monosomy', 'Var', (314, 322))	('chr', 'Gene', (341, 344))	('extrascleral invasion', 'CPA', (208, 229))	('gain', 'PosReg', (348, 352))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
21599	22453016	However, the strongest indicators of whether a primary uveal melanoma tumor will metastasize are copy number profile (e.g.	('uveal melanoma tumor', 'Disease', (55, 75))	('uveal melanoma tumor', 'Disease', 'MESH:C536494', (55, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (55, 69))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('metastasize', 'CPA', (81, 92))	('copy number profile', 'Var', (97, 116))
21610	22453016	A large-scale chemical mutagenesis screen to elucidate genes involved in the hyperpigmentation of mice showed mutations in the alpha subunits of the heterotrimeric g-proteins GNAQ and GNA11 to be involved.	('mutations', 'Var', (110, 119))	('mutagenesis', 'biological_process', 'GO:0006280', ('23', '34'))	('pigmentation', 'Disease', (82, 94))	('GNAQ', 'Gene', (175, 179))	('pigmentation', 'Disease', 'MESH:D010859', (82, 94))	('heterotrimeric g-proteins', 'Protein', (149, 174))	('mice', 'Species', '10090', (98, 102))	('GNA11', 'Gene', (184, 189))
21611	22453016	Mutations in these genes resulted in dermal melanocytosis (uveal tract melanocytes were not investigated in this study).	('dermal melanocytosis', 'Phenotype', 'HP:0100814', (37, 57))	('Mutations', 'Var', (0, 9))	('resulted in', 'Reg', (25, 36))	('dermal melanocytosis', 'Disease', (37, 57))	('dermal melanocytosis', 'Disease', 'MESH:C535835', (37, 57))
21613	22453016	Uveal melanoma tumors appear to have aberrations in these same pathways that are crucial to uveal melanocyte development.	('melanoma tumors', 'Disease', 'MESH:D008545', (6, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('aberrations', 'Var', (37, 48))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('melanoma tumors', 'Disease', (6, 21))
21615	22453016	Uveal melanoma tumors often contain alterations in chromosome 1, 3, 6 and 8.	('melanoma tumors', 'Disease', 'MESH:D008545', (6, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('alterations', 'Var', (36, 47))	('chromosome', 'cellular_component', 'GO:0005694', ('51', '61'))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('melanoma tumors', 'Disease', (6, 21))
21616	22453016	By far the most salient chromosomal aberration associated with metastatic uveal melanoma is loss of chromosome 3.	('chromosomal aberration', 'Phenotype', 'HP:0040012', (24, 46))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('loss', 'Var', (92, 96))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('uveal melanoma', 'Disease', (74, 88))	('chromosome', 'cellular_component', 'GO:0005694', ('100', '110'))
21617	22453016	The finding of monosomy 3 in a primary tumor strongly correlates with risk of metastatic disease.	('metastatic disease', 'CPA', (78, 96))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('monosomy 3', 'Var', (15, 25))
21618	22453016	For example, a few groups have shown that loss of 1p in addition to monosomy 3 is an independent prognostic factor for reduced disease free survival.	('loss of 1p', 'Var', (42, 52))	('reduced disease', 'Disease', 'MESH:D015354', (119, 134))	('reduced disease', 'Disease', (119, 134))
21619	22453016	Likewise, chromosome 8q copy gains, which often occur in the same tumors that have chromosome 3 loss, appear to portend a worse prognosis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('chromosome', 'Gene', (83, 93))	('chromosome 8q copy gains', 'Var', (10, 34))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('chromosome', 'cellular_component', 'GO:0005694', ('10', '20'))	('chromosome', 'cellular_component', 'GO:0005694', ('83', '93'))	('loss', 'NegReg', (96, 100))
21620	22453016	Given the observation that activating mutations in GNAQ or GNA11 result in dermal melanocytosis in mice, van raamsdonk and Bastian investigated the GNAQ and GNA11 mutation status of tissues from intradermal melanocytic proliferative conditions, such as blue nevi.	('mice', 'Species', '10090', (99, 103))	('nevi', 'Phenotype', 'HP:0003764', (258, 262))	('dermal melanocytosis', 'Disease', 'MESH:C535835', (75, 95))	('activating', 'PosReg', (27, 37))	('dermal melanocytosis', 'Phenotype', 'HP:0100814', (75, 95))	('van raamsdonk', 'Disease', (105, 118))	('dermal melanocytosis', 'Disease', (75, 95))	('GNA11', 'Gene', (59, 64))	('blue nevi', 'Phenotype', 'HP:0100814', (253, 262))	('GNAQ', 'Gene', (51, 55))	('van raamsdonk', 'Disease', 'MESH:C536530', (105, 118))	('mutations', 'Var', (38, 47))	('blue nevi', 'Disease', (253, 262))
21622	22453016	They discovered mutually exclusive recurrent mutations in exon 4 (R183) or exon 5 (Q209) in both GNAQ and GNA11 in both blue nevi and uveal melanoma (Table 1).	('blue nevi', 'Disease', (120, 129))	('nevi', 'Phenotype', 'HP:0003764', (125, 129))	('GNA11', 'Gene', (106, 111))	('uveal melanoma', 'Disease', 'MESH:C536494', (134, 148))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('Q209', 'Var', (83, 87))	('uveal melanoma', 'Disease', (134, 148))	('uveal melanoma', 'Phenotype', 'HP:0007716', (134, 148))	('R183', 'Var', (66, 70))	('blue nevi', 'Phenotype', 'HP:0100814', (120, 129))
21623	22453016	GNAQ (Q209) mutations were more frequent in blue nevi and primary uveal melanomas, compared to GNA11 (Q209), GNAQ (R183) or GNA11 (R183) mutations.	('blue nevi', 'Disease', (44, 53))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('nevi', 'Phenotype', 'HP:0003764', (49, 53))	('mutations', 'Var', (12, 21))	('blue nevi', 'Phenotype', 'HP:0100814', (44, 53))	('uveal melanomas', 'Phenotype', 'HP:0007716', (66, 81))	('uveal melanomas', 'Disease', (66, 81))	('GNAQ (Q209', 'Gene', (0, 10))	('uveal melanomas', 'Disease', 'MESH:C536494', (66, 81))	('frequent', 'Reg', (32, 40))
21625	22453016	No statistically significant correlation have been observed between GNAQ or GNA11 mutations in the primary uveal melanoma tumors when compared to sex, age, overall survival, metastasis-free survival, tumor thickness, diameter, pigmentation, extracellular matrix patterns, cytogenetics (e.g., chromosome 3 status, 8q gain, 6p gain, 8p loss), or molecular (beta-catenin, e-cadherin, cytokeratin-18) variables.	('cadherin', 'molecular_function', 'GO:0008014', ('371', '379'))	('pigmentation', 'Disease', (227, 239))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('241', '261'))	('tumor', 'Disease', (122, 127))	('cytokeratin-18', 'Gene', (381, 395))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('pigmentation', 'biological_process', 'GO:0043473', ('227', '239'))	('GNAQ', 'Gene', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('loss', 'NegReg', (334, 338))	('GNA11', 'Gene', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('pigmentation', 'Disease', 'MESH:D010859', (227, 239))	('beta-catenin', 'Gene', (355, 367))	('beta-catenin', 'Gene', '1499', (355, 367))	('chromosome', 'cellular_component', 'GO:0005694', ('292', '302'))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('e-cadherin', 'Gene', '999', (369, 379))	('cytokeratin-18', 'Gene', '3875', (381, 395))	('metastasis', 'Disease', (174, 184))	('gain', 'PosReg', (325, 329))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (107, 128))	('uveal melanoma tumors', 'Disease', (107, 128))	('gain', 'PosReg', (316, 320))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('e-cadherin', 'Gene', (369, 379))	('mutations', 'Var', (82, 91))	('metastasis', 'Disease', 'MESH:D009362', (174, 184))
21626	22453016	GNA11 mutations were, however, observed to be more prevalent in ciliochoroid tumors (i.e., tumors that involve both the ciliary body and choroid).	('ciliochoroid tumors', 'Disease', (64, 83))	('tumors', 'Disease', (91, 97))	('prevalent', 'Reg', (51, 60))	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('GNA11', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ciliochoroid tumors', 'Disease', 'MESH:D000080324', (64, 83))	('mutations', 'Var', (6, 15))
21627	22453016	Non-truncating (missense, in-frame deletions and termination read-through) and truncating (nonsense, splice, and insertion/deletion) mutations in the nuclear ubiquitin carboxy-terminal hydrolase BAP1 have also recently been identified in primary uveal melanoma tumors.	('Non-truncating', 'MPA', (0, 14))	('ubiquitin', 'molecular_function', 'GO:0031386', ('158', '167'))	('BAP1', 'Gene', (195, 199))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('identified', 'Reg', (224, 234))	('insertion/deletion', 'Var', (113, 131))	('melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('in-frame deletions', 'Var', (26, 44))	('uveal melanoma', 'Phenotype', 'HP:0007716', (246, 260))	('uveal melanoma tumors', 'Disease', (246, 267))	('mutations', 'Var', (133, 142))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (246, 267))	('truncating', 'MPA', (79, 89))
21628	22453016	Given the localization of BAP1 on chr 3p21.1, the identification of BAP1 mutations primarily in tumors with monosomy 3 provides strong evidence that loss of heterozygosity of BAP1 may be a very important mediator of metastatic disease.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('localization', 'biological_process', 'GO:0051179', ('10', '22'))	('loss of heterozygosity', 'Var', (149, 171))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('metastatic', 'Disease', (216, 226))	('BAP1', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))
21629	22453016	Within tumors that showed monosomy 3, and for which BAP1 mutant status could be determined, BAP1 mutations were present in 81% (21/26) of cases.	('mutations', 'Var', (97, 106))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('BAP1', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('monosomy 3', 'Var', (26, 36))	('BAP1', 'Gene', (92, 96))
21630	22453016	BAP1 mutations were highly correlated with class 2 tumor status (a gene expression profiling test for high metastatic risk), chromosome 3 loss in primary tumors, and the ultimate emergence of metastatic disease in the patients (Table 2).	('chromosome', 'cellular_component', 'GO:0005694', ('125', '135'))	('loss', 'NegReg', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('BAP1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('patients', 'Species', '9606', (218, 226))	('gene expression', 'biological_process', 'GO:0010467', ('67', '82'))	('tumor', 'Disease', (51, 56))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('primary tumors', 'Disease', (146, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('primary tumors', 'Disease', 'MESH:D009369', (146, 160))	('chromosome', 'Gene', (125, 135))	('tumor', 'Disease', (154, 159))
21634	22453016	The exact mechanism(s) by which loss of BAP1 mediates primary uveal melanoma metastasis is currently being investigated.	('mediates', 'Reg', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('loss', 'Var', (32, 36))	('uveal melanoma metastasis', 'Disease', 'MESH:C536494', (62, 87))	('uveal melanoma metastasis', 'Disease', (62, 87))	('BAP1', 'Gene', (40, 44))	('uveal melanoma', 'Phenotype', 'HP:0007716', (62, 76))
21635	22453016	However, a recent study indicates that loss of BAP1 results in the accumulation of mono-ubiquitinated histone H2A and a more de-differentiated cellular phenotype.	('more', 'PosReg', (120, 124))	('mono-ubiquitin', 'Chemical', '-', (83, 97))	('mono-ubiquitinated', 'MPA', (83, 101))	('histone H2A', 'Gene', (102, 113))	('loss', 'Var', (39, 43))	('histone H2A', 'Gene', '3772346', (102, 113))	('BAP1', 'Gene', (47, 51))	('accumulation', 'PosReg', (67, 79))
21638	22453016	However, unlike their cutaneous counterparts, uveal melanoma tissues lack the typical oncogenic upstream mediators of this pathway (e.g., mutant BRAF, NRAS, KIT).	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('BRAF', 'Gene', (145, 149))	('lack', 'NegReg', (69, 73))	('mutant', 'Var', (138, 144))	('uveal melanoma', 'Disease', 'MESH:C536494', (46, 60))	('KIT', 'molecular_function', 'GO:0005020', ('157', '160'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (46, 60))	('uveal melanoma', 'Disease', (46, 60))	('NRAS', 'Gene', '4893', (151, 155))	('KIT', 'Gene', (157, 160))	('NRAS', 'Gene', (151, 155))	('BRAF', 'Gene', '673', (145, 149))
21639	22453016	In uveal melanoma, mutant GNAQ and GNA11 appear to be major upstream mediators of the MEK/MAPK pathway.	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('MEK', 'Gene', (86, 89))	('GNAQ', 'Gene', (26, 30))	('MAPK', 'molecular_function', 'GO:0004707', ('90', '94'))	('MEK', 'Gene', '5609', (86, 89))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('mutant', 'Var', (19, 25))	('GNA11', 'Gene', (35, 40))	('uveal melanoma', 'Disease', (3, 17))
21640	22453016	Exogenous expression of mutant GNAQ increased MAPK phosphorylation, whereas knockdown of GNAQ in uveal melanoma cell lines with mutant GNAQ diminished MAPK phosphorylation and increases the number of cells in the sub-G0/G1 fraction.	('mutant', 'Var', (24, 30))	('GNAQ', 'Gene', (135, 139))	('MAPK phosphorylation', 'MPA', (151, 171))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('diminished', 'NegReg', (140, 150))	('phosphorylation', 'biological_process', 'GO:0016310', ('156', '171'))	('increases', 'PosReg', (176, 185))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('uveal melanoma', 'Disease', (97, 111))	('mutant', 'Var', (128, 134))	('MAPK', 'molecular_function', 'GO:0004707', ('46', '50'))	('increased', 'PosReg', (36, 45))	('MAPK', 'molecular_function', 'GO:0004707', ('151', '155'))	('MAPK phosphorylation', 'MPA', (46, 66))	('GNAQ', 'Gene', (31, 35))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
21642	22453016	There is some evidence to suggest that activation of AKT is associated with a higher risk of metastatic disease, however, these observations were seen in enucleated-only (versus radiotherapy and enucleated eyes), and in another study only associated with phospho-AKT (Thr308), not phosphor-AKT (Ser473).	('Thr308', 'Var', (268, 274))	('Ser', 'cellular_component', 'GO:0005790', ('295', '298'))	('activation', 'PosReg', (39, 49))	('AKT', 'Gene', '207', (290, 293))	('AKT', 'Gene', '207', (263, 266))	('metastatic disease', 'Disease', (93, 111))	('AKT', 'Gene', '207', (53, 56))	('Ser473', 'Chemical', '-', (295, 301))	('Thr308', 'Chemical', '-', (268, 274))	('AKT', 'Gene', (290, 293))	('AKT', 'Gene', (263, 266))	('AKT', 'Gene', (53, 56))
21644	22453016	We have determined that typical activating mutations in AKT (1,2,3) or PI3K found in other cancers are not present in uveal melanoma cell lines and loss of GNAQ had little effect on the activation of AKT, although inhibition of MEK results in a compensatory upregulation of phospho-AKT in these cell lines (submitted for publication).	('uveal melanoma', 'Phenotype', 'HP:0007716', (118, 132))	('AKT', 'Gene', (56, 59))	('MEK', 'Gene', (228, 231))	('GNAQ', 'Gene', (156, 160))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('AKT', 'Gene', '207', (200, 203))	('loss', 'Var', (148, 152))	('activation', 'MPA', (186, 196))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('AKT', 'Gene', '207', (56, 59))	('AKT', 'Gene', (282, 285))	('upregulation', 'PosReg', (258, 270))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('uveal melanoma', 'Disease', (118, 132))	('uveal melanoma', 'Disease', 'MESH:C536494', (118, 132))	('mutations', 'Var', (43, 52))	('AKT', 'Gene', (200, 203))	('MEK', 'Gene', '5609', (228, 231))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('AKT', 'Gene', '207', (282, 285))
21646	22453016	One report has shown that approximately three-fourths of primary uveal melanoma tumors show a loss of PTEN heterozygosity and about roughly one-tenth of these exhibit mutations in PTEN.	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (65, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('exhibit', 'Reg', (159, 166))	('loss', 'NegReg', (94, 98))	('heterozygosity', 'MPA', (107, 121))	('PTEN', 'Gene', (180, 184))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('mutations', 'Var', (167, 176))	('PTEN', 'Gene', '5728', (180, 184))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('PTEN', 'Gene', (102, 106))	('PTEN', 'Gene', '5728', (102, 106))	('uveal melanoma tumors', 'Disease', (65, 86))
21663	22453016	of three distinct trials in which 20 metastatic uveal melanoma patients were treated either upfront with the MEK inhibitor AZD6244 or following progression on temozolomide.	('uveal melanoma', 'Disease', (48, 62))	('temozolomide', 'Chemical', 'MESH:D000077204', (159, 171))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('AZD6244', 'Var', (123, 130))	('MEK', 'Gene', '5609', (109, 112))	('patients', 'Species', '9606', (63, 71))	('AZD6244', 'Chemical', 'MESH:C517975', (123, 130))	('MEK', 'Gene', (109, 112))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (48, 62))
21666	22453016	Finally, a more definitive prospective phase II trial treating metastatic uveal melanoma patients with AZD6244 and assessing progression-free survival is currently accruing (NCT01143402).	('AZD6244', 'Chemical', 'MESH:C517975', (103, 110))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('patients', 'Species', '9606', (89, 97))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('uveal melanoma', 'Disease', (74, 88))	('AZD6244', 'Var', (103, 110))
21667	22453016	This trial will randomize temozolomide/dacarbazine naive patients to either AZD6244 or temozolomide, with a GNAQ or GNA11 mutant cohort versus a cohort accrued regardless of GNAQ or GNA11 mutation status.	('temozolomide', 'Chemical', 'MESH:D000077204', (26, 38))	('GNA11', 'Gene', (116, 121))	('patients', 'Species', '9606', (57, 65))	('dacarbazine', 'Chemical', 'MESH:D003606', (39, 50))	('temozolomide', 'Chemical', 'MESH:D000077204', (87, 99))	('AZD6244', 'Chemical', 'MESH:C517975', (76, 83))	('GNAQ', 'Gene', (108, 112))	('mutant', 'Var', (122, 128))
21668	22453016	A third cohort of temozolomide/dacarbazine exposed, GNAQ or GNA11 mutant patients will also be assessed following AZD6244 treatment.	('AZD6244', 'Chemical', 'MESH:C517975', (114, 121))	('mutant', 'Var', (66, 72))	('GNA11', 'Gene', (60, 65))	('temozolomide', 'Chemical', 'MESH:D000077204', (18, 30))	('dacarbazine', 'Chemical', 'MESH:D003606', (31, 42))	('patients', 'Species', '9606', (73, 81))
21673	22453016	The rationale for this trial is that among its many potentially anti-cancer effects, pasireotide has been shown to diminish IGF-1 levels.	('IGF-1 levels', 'MPA', (124, 136))	('diminish', 'NegReg', (115, 123))	('diminish IGF', 'Phenotype', 'HP:0002850', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('pasireotide', 'Var', (85, 96))
21677	22453016	Although there are as of yet no MET inhibitor trials dedicated exclusively to uveal melanoma patients, there are multiple MET inhibitors in early phase clinical trials for solid tumors: GSK1363089, ARQ197, XL-184, EMD1204831, PF-02341066, and PRO143966.	('MET', 'Gene', '4233', (122, 125))	('ARQ197', 'Var', (198, 204))	('MET', 'Gene', (122, 125))	('uveal melanoma', 'Phenotype', 'HP:0007716', (78, 92))	('MET', 'Gene', '4233', (32, 35))	('patients', 'Species', '9606', (93, 101))	('MET', 'Gene', (32, 35))	('solid tumors', 'Disease', (172, 184))	('GSK1363089', 'Chemical', 'MESH:C544831', (186, 196))	('GSK', 'molecular_function', 'GO:0050321', ('186', '189'))	('XL-184', 'Var', (206, 212))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('GSK1363089', 'Var', (186, 196))	('EMD1204831', 'Var', (214, 224))	('PF-02341066', 'Var', (226, 237))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('solid tumors', 'Disease', 'MESH:D009369', (172, 184))	('uveal melanoma', 'Disease', 'MESH:C536494', (78, 92))	('PRO143966', 'Var', (243, 252))	('uveal melanoma', 'Disease', (78, 92))
21683	22453016	Loss of BAP1 poses a difficult therapeutic challenge, as it is appears to represent a classic loss of a tumor suppressor, and direct therapies would require the re-initiation of function.	('tumor suppressor', 'biological_process', 'GO:0051726', ('104', '120'))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('104', '120'))	('tumor', 'Disease', (104, 109))	('BAP1', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
21684	22453016	A recent publication demonstrated that loss of BAP1 results in an accumulation of mono-ubiquitin on histone H2A, thus altering the transcriptional profile within these cells.	('histone H2A', 'Gene', '3772346', (100, 111))	('transcriptional profile', 'MPA', (131, 154))	('mono-ubiquitin', 'Chemical', '-', (82, 96))	('mono-ubiquitin', 'MPA', (82, 96))	('accumulation', 'PosReg', (66, 78))	('altering', 'Reg', (118, 126))	('loss', 'Var', (39, 43))	('ubiquitin', 'molecular_function', 'GO:0031386', ('87', '96'))	('histone H2A', 'Gene', (100, 111))	('BAP1', 'Gene', (47, 51))
21701	22453016	Although direct targeting of mutant GNAQ or GNA11, or BAP1 loss is presently not possible, interventions that target downstream effectors of these genetic aberrations may be possible, in addition to targeting other important non-mutated molecular drivers It is clear that mutations that activate GNAQ and GNA11, in part, signal through the MEK/MAPK pathway, and inhibition of this pathway with MEK inhibitors may affect cell growth.	('mutations', 'Var', (272, 281))	('cell growth', 'biological_process', 'GO:0016049', ('420', '431'))	('MEK', 'Gene', (394, 397))	('MEK', 'Gene', '5609', (394, 397))	('GNA11', 'Gene', (305, 310))	('MEK', 'Gene', (340, 343))	('mutant', 'Var', (29, 35))	('cell growth', 'CPA', (420, 431))	('MEK', 'Gene', '5609', (340, 343))	('affect', 'Reg', (413, 419))	('signal', 'Reg', (321, 327))	('GNAQ', 'Gene', (296, 300))	('MAPK', 'molecular_function', 'GO:0004707', ('344', '348'))	('activate', 'PosReg', (287, 295))
21702	22453016	However, it is also likely that multiple other cellular processes are affected by mutated GNAQ and GNA11, BAP1 loss, and other molecular aberrations in uveal melanoma tumors.	('loss', 'NegReg', (111, 115))	('BAP1', 'Gene', (106, 110))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (152, 173))	('uveal melanoma', 'Phenotype', 'HP:0007716', (152, 166))	('uveal melanoma tumors', 'Disease', (152, 173))	('GNA11', 'Gene', (99, 104))	('mutated', 'Var', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('affected', 'Reg', (70, 78))	('GNAQ', 'Gene', (90, 94))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
21760	23032880	The Down's syndrome cataract has been shown to be associated with trisomy of chromosome 21; the human beta amyloid gene is located on chromosome 21 and its triplication accelerates the accumulation of the beta amyloid protein.	('s syndrome cataract', 'Disease', (9, 28))	("'s syndrome", 'Disease', (8, 19))	('chromosome', 'cellular_component', 'GO:0005694', ('77', '87'))	('human', 'Species', '9606', (96, 101))	('accelerates', 'PosReg', (169, 180))	('accumulation', 'MPA', (185, 197))	('s syndrome cataract', 'Disease', 'MESH:D002386', (9, 28))	('cataract', 'Phenotype', 'HP:0000518', (20, 28))	('amyloid protein', 'molecular_function', 'GO:0005208', ('210', '225'))	('protein', 'cellular_component', 'GO:0003675', ('218', '225'))	('rat', 'Species', '10116', (175, 178))	('chromosome', 'cellular_component', 'GO:0005694', ('134', '144'))	("'s syndrome", 'Disease', 'MESH:D010300', (8, 19))	('triplication', 'Var', (156, 168))
21816	23032880	LBNL postulated that dysfunctional regulation of FGF-2 expression might cause down regulation of the apoptotic mechanism, resulting in the migration and differentiation of damaged lens cells leading to aberrant lens crystallin expression and lens opacification.	('dysfunctional regulation', 'Var', (21, 45))	('FGF-2', 'Gene', '2247', (49, 54))	('regulation', 'biological_process', 'GO:0065007', ('83', '93'))	('regulation', 'biological_process', 'GO:0065007', ('35', '45'))	('migration', 'CPA', (139, 148))	('down regulation', 'NegReg', (78, 93))	('differentiation', 'CPA', (153, 168))	('lens opacification', 'Phenotype', 'HP:0000518', (242, 260))	('aberrant lens', 'Phenotype', 'HP:0000517', (202, 215))	('lens', 'MPA', (211, 215))	('apoptotic mechanism', 'CPA', (101, 120))	('FGF-2', 'Gene', (49, 54))	('rat', 'Species', '10116', (142, 145))	('lens opacification', 'CPA', (242, 260))
21858	23032880	The importance of understanding the functional relevance of gene alterations in human cancers has become clear.	('alterations', 'Var', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('rat', 'Species', '10116', (69, 72))
21865	23032880	Similar studies comparing carbon ions and x rays have been completed investigating different mechanisms of cell death in radiosensitive and radioresistant p53 mutated head and neck squamous cell carcinoma (HNSCC) cell lines.	('neck', 'cellular_component', 'GO:0044326', ('176', '180'))	('p53', 'Gene', (155, 158))	('mutated', 'Var', (159, 166))	('p53', 'Gene', '7157', (155, 158))	('cell death', 'biological_process', 'GO:0008219', ('107', '117'))	('neck squamous cell carcinoma', 'Disease', (176, 204))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (176, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (181, 204))	('rays', 'Species', '255564', (44, 48))	('carbon', 'Chemical', 'MESH:D002244', (26, 32))	('HNSCC', 'CellLine', 'CVCL:5985', (206, 211))
21873	23032880	Sublethal photon irradiation was recently suspected to increase tumor cell motility and invasiveness of human malignant glioma cells.	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('increase', 'PosReg', (55, 63))	('tumor', 'Disease', (64, 69))	('cell motility', 'biological_process', 'GO:0048870', ('70', '83'))	('human', 'Species', '9606', (104, 109))	('invasiveness', 'CPA', (88, 100))	('glioma', 'Disease', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('Sublethal', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
21875	23032880	BCL-2 gene transfer and irradiation cooperate to enhance migration and invasiveness in a synergistic manner.	('gene transfer', 'Var', (6, 19))	('BCL-2', 'Gene', (0, 5))	('enhance', 'PosReg', (49, 56))	('rat', 'Species', '10116', (60, 63))	('migration', 'CPA', (57, 66))	('invasiveness', 'CPA', (71, 83))	('rat', 'Species', '10116', (41, 44))	('BCL-2', 'molecular_function', 'GO:0015283', ('0', '5'))	('BCL-2', 'Gene', '596', (0, 5))
21919	23032880	Proinflammatory cytokines and nitric oxide were induced in macrophages by LPS but not by irradiation alone.	('Proinflammatory cytokines', 'MPA', (0, 25))	('nitric oxide', 'MPA', (30, 42))	('nitric oxide', 'Chemical', 'MESH:D009569', (30, 42))	('LPS', 'Chemical', 'MESH:D008070', (74, 77))	('LPS', 'Var', (74, 77))	('induced', 'Reg', (48, 55))
21928	23032880	All of these genes appear to impact the normal differentiation of lens epithelial cells into fiber cells that leads to the orchestration of a uniform set of morphological formations (such as evidenced by the incomplete denucleation that occurs at terminal differentiation), and may also impact potential modes of cell senescence or death.	('senescence', 'biological_process', 'GO:0010149', ('318', '328'))	('terminal differentiation', 'biological_process', 'GO:0048468', ('247', '271'))	('impact', 'Reg', (287, 293))	('leads to', 'Reg', (110, 118))	('orchestration of', 'MPA', (123, 139))	('genes', 'Var', (13, 18))	('rat', 'Species', '10116', (130, 133))	('uniform set of morphological formations', 'MPA', (142, 181))	('impact', 'Reg', (29, 35))
21943	22515704	Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines TAK733 is a novel allosteric, non-ATP-binding, inhibitor of the BRAF substrates MEK-1/2.	('MEK-1', 'molecular_function', 'GO:0004708', ('200', '205'))	('BRAF', 'Gene', (184, 188))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('MEK-1/2', 'Gene', '5604;5605', (200, 207))	('MEK-1/2', 'Gene', (200, 207))	('ATP', 'Chemical', 'MESH:D000255', (154, 157))	('MEK', 'Gene', '5609', (51, 54))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('MEK', 'Gene', (51, 54))	('TAK733', 'Var', (120, 126))	('TAK733', 'Chemical', 'MESH:C558666', (120, 126))	('MEK', 'Gene', '5609', (200, 203))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('TAK733', 'Chemical', 'MESH:C558666', (65, 71))	('ATP-binding', 'molecular_function', 'GO:0005524', ('154', '165'))	('uveal melanoma', 'Disease', (94, 108))	('Antitumor effects', 'CPA', (0, 17))	('MEK', 'Gene', (200, 203))	('BRAF', 'Gene', '673', (184, 188))
21946	22515704	Fourteen cutaneous melanoma cell lines with different driver mutations were sensitive to the antiproliferative effects of TAK733, with a higher proportion of BRAFV600E mutant cell lines being highly sensitive with IC50s below 1 nM.	('mutant', 'Var', (168, 174))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('cutaneous melanoma', 'Disease', (9, 27))	('mutations', 'Var', (61, 70))	('antiproliferative effects', 'MPA', (93, 118))	('TAK733', 'Gene', (122, 128))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (9, 27))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (9, 27))	('TAK733', 'Chemical', 'MESH:C558666', (122, 128))	('BRAFV600E mutant', 'Var', (158, 174))	('BRAFV600E', 'Mutation', 'rs113488022', (158, 167))	('50s', 'Species', '1214577', (216, 219))
21947	22515704	The five uveal melanoma cell lines had GNAQ or GNA11 mutations and were either moderately or highly sensitive to TAK733.	('GNAQ', 'Gene', (39, 43))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('GNA11', 'Gene', '2767', (47, 52))	('GNA11', 'Gene', (47, 52))	('uveal melanoma', 'Disease', (9, 23))	('uveal melanoma', 'Disease', 'MESH:C536494', (9, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (9, 23))	('mutations', 'Var', (53, 62))	('TAK733', 'Chemical', 'MESH:C558666', (113, 119))	('GNAQ', 'Gene', '2776', (39, 43))
21948	22515704	The tested cell lines wild type for NRAS, BRAF, GNAQ and GNA11 driver mutations were moderately to highly resistant to TAK733.	('BRAF', 'Gene', '673', (42, 46))	('mutations', 'Var', (70, 79))	('GNAQ', 'Gene', '2776', (48, 52))	('GNA11', 'Gene', (57, 62))	('NRAS', 'Gene', (36, 40))	('GNA11', 'Gene', '2767', (57, 62))	('NRAS', 'Gene', '4893', (36, 40))	('GNAQ', 'Gene', (48, 52))	('BRAF', 'Gene', (42, 46))	('TAK733', 'Chemical', 'MESH:C558666', (119, 125))
21949	22515704	TAK733 led to a decrease in pERK and G1 arrest in most of these melanoma cell lines regardless of their origin, driver oncogenic mutations and in vitro sensitivity to TAK733.	('TAK733', 'Var', (0, 6))	('TAK733', 'Chemical', 'MESH:C558666', (0, 6))	('G1 arrest', 'MPA', (37, 46))	('decrease', 'NegReg', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('TAK733', 'Chemical', 'MESH:C558666', (167, 173))	('pERK', 'Gene', '9451', (28, 32))	('pERK', 'Gene', (28, 32))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))
21950	22515704	MEK inhibition resulted in increase in pMEK more prominently in NRASQ61L mutant and GNAQ mutant cell lines than in BRAFV600E mutant cell lines.	('MEK', 'Gene', '5609', (40, 43))	('GNAQ', 'Gene', (84, 88))	('MEK', 'Gene', (0, 3))	('BRAFV600E', 'Mutation', 'rs113488022', (115, 124))	('MEK', 'Gene', '5609', (0, 3))	('NRAS', 'Gene', (64, 68))	('GNAQ', 'Gene', '2776', (84, 88))	('mutant', 'Var', (89, 95))	('NRAS', 'Gene', '4893', (64, 68))	('inhibition', 'NegReg', (4, 14))	('increase', 'PosReg', (27, 35))	('MEK', 'Gene', (40, 43))
21951	22515704	Uptake of the metabolic tracers FDG and FLT was inhibited by TAK733 in a manner that closely paralleled the in vitro sensitivity assays.	('Uptake', 'MPA', (0, 6))	('Uptake', 'biological_process', 'GO:0098739', ('0', '6'))	('FLT', 'Gene', '2321', (40, 43))	('FLT', 'Gene', (40, 43))	('TAK733', 'Var', (61, 67))	('TAK733', 'Chemical', 'MESH:C558666', (61, 67))	('inhibited', 'NegReg', (48, 57))	('Uptake', 'biological_process', 'GO:0098657', ('0', '6'))
21954	22515704	These mutations render melanoma cells independent of the normal receptor tyrosine kinase (RTK)-mediated pathway regulation, and constitutively drive melanoma cells to oncogenic proliferation and survival.	('RTK', 'Gene', (90, 93))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('drive', 'Reg', (143, 148))	('survival', 'CPA', (195, 203))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('oncogenic proliferation', 'CPA', (167, 190))	('melanoma', 'Disease', (23, 31))	('RTK', 'Gene', '5979', (90, 93))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('receptor tyrosine kinase', 'Gene', (64, 88))	('receptor tyrosine kinase', 'Gene', '5979', (64, 88))	('mutations', 'Var', (6, 15))	('regulation', 'biological_process', 'GO:0065007', ('112', '122'))
21958	22515704	Tumor responses were dependent on the presence of the BRAFV600E oncogene and efficient inhibition of the MAPK pathway as detected by decreased phosphorylation of ERK.	('inhibition', 'NegReg', (87, 97))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ERK', 'Gene', (162, 165))	('MAPK', 'molecular_function', 'GO:0004707', ('105', '109'))	('phosphorylation', 'MPA', (143, 158))	('BRAFV600E', 'Var', (54, 63))	('BRAFV600E', 'Mutation', 'rs113488022', (54, 63))	('MAPK pathway', 'Pathway', (105, 117))	('phosphorylation', 'biological_process', 'GO:0016310', ('143', '158'))	('ERK', 'Gene', '5594', (162, 165))	('Tumor responses', 'CPA', (0, 15))	('decreased', 'NegReg', (133, 142))	('ERK', 'molecular_function', 'GO:0004707', ('162', '165'))
21959	22515704	Inhibition of the immediately downstream MEK1/2 kinases in BRAFV600E mutant cutaneous melanoma was shown to lead to marked inhibition of cell proliferation in cell lines.	('BRAFV600E', 'Mutation', 'rs113488022', (59, 68))	('MEK1/2', 'Gene', '5604;5605', (41, 47))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('MEK1/2', 'Gene', (41, 47))	('cutaneous melanoma', 'Disease', (76, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (76, 94))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (76, 94))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('123', '155'))	('MEK1', 'molecular_function', 'GO:0004708', ('41', '45'))	('inhibition', 'NegReg', (123, 133))	('cell proliferation in cell lines', 'CPA', (137, 169))	('BRAFV600E', 'Var', (59, 68))
21963	22515704	Gene expression profiling studies mapping the gene signatures downstream of a constitutively activated MAPK pathway suggested that cutaneous melanoma cell lines with NRAS mutations are less dependent in signaling through this pathway compared to BRAFV600E mutant cutaneous melanoma cell lines, explaining in part the differential sensitivity of NRAS and BRAF mutant cells to MEK inhibitors.	('NRAS', 'Gene', (345, 349))	('NRAS', 'Gene', '4893', (166, 170))	('BRAFV600E', 'Mutation', 'rs113488022', (246, 255))	('less', 'NegReg', (185, 189))	('BRAF', 'Gene', '673', (246, 250))	('BRAF', 'Gene', (246, 250))	('MEK', 'Gene', '5609', (375, 378))	('BRAF', 'Gene', '673', (354, 358))	('BRAF', 'Gene', (354, 358))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('NRAS', 'Gene', (166, 170))	('cutaneous melanoma', 'Disease', (131, 149))	('MEK', 'Gene', (375, 378))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (131, 149))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (131, 149))	('dependent', 'MPA', (190, 199))	('NRAS', 'Gene', '4893', (345, 349))	('signaling', 'biological_process', 'GO:0023052', ('203', '212'))	('mutations', 'Var', (171, 180))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('melanoma', 'Phenotype', 'HP:0002861', (273, 281))	('MAPK', 'molecular_function', 'GO:0004707', ('103', '107'))	('cutaneous melanoma', 'Disease', (263, 281))	('signaling', 'MPA', (203, 212))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (263, 281))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (263, 281))
21964	22515704	BRAF and NRAS mutations are absent in melanomas arising in the uveal layer of the eye, but mutually exclusive somatic mutations in the heterotrimeric G protein alpha-subunit, GNAQ, or in GNA11, are present in the great majority of uveal melanomas.	('uveal melanomas', 'Disease', (231, 246))	('uveal melanomas', 'Phenotype', 'HP:0007716', (231, 246))	('GNA11', 'Gene', '2767', (187, 192))	('BRAF', 'Gene', '673', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('melanomas', 'Phenotype', 'HP:0002861', (237, 246))	('BRAF', 'Gene', (0, 4))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('135', '159'))	('NRAS', 'Gene', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('GNA11', 'Gene', (187, 192))	('mutations', 'Var', (118, 127))	('uveal melanomas', 'Disease', 'MESH:C536494', (231, 246))	('melanomas', 'Disease', 'MESH:D008545', (38, 47))	('GNAQ', 'Gene', '2776', (175, 179))	('melanomas', 'Disease', 'MESH:D008545', (237, 246))	('melanomas', 'Disease', (38, 47))	('GNAQ', 'Gene', (175, 179))	('melanomas', 'Disease', (237, 246))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('NRAS', 'Gene', '4893', (9, 13))	('uveal melanoma', 'Phenotype', 'HP:0007716', (231, 245))
21965	22515704	It had long been noted that uveal melanomas have constitutive MAPK signaling, and it is now understood that it is because of the presence of GNAQ or GNA11 mutations.	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('GNA11', 'Gene', '2767', (149, 154))	('GNA11', 'Gene', (149, 154))	('mutations', 'Var', (155, 164))	('constitutive', 'MPA', (49, 61))	('GNAQ', 'Gene', '2776', (141, 145))	('MAPK', 'molecular_function', 'GO:0004707', ('62', '66'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('62', '76'))	('uveal melanomas', 'Disease', (28, 43))	('uveal melanomas', 'Phenotype', 'HP:0007716', (28, 43))	('uveal melanomas', 'Disease', 'MESH:C536494', (28, 43))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('uveal melanoma', 'Phenotype', 'HP:0007716', (28, 42))	('GNAQ', 'Gene', (141, 145))	('MAPK signaling', 'Pathway', (62, 76))
21966	22515704	GNAQ knockdown, as well as treatment with the U0126 MEK inhibitor, resulted in inhibition of MAPK signaling and loss of viability.	('MAPK signaling', 'biological_process', 'GO:0000165', ('93', '107'))	('GNAQ', 'Gene', '2776', (0, 4))	('knockdown', 'Var', (5, 14))	('U0126', 'Chemical', 'MESH:C113580', (46, 51))	('MAPK signaling', 'Pathway', (93, 107))	('loss', 'NegReg', (112, 116))	('GNAQ', 'Gene', (0, 4))	('inhibition', 'NegReg', (79, 89))	('MEK', 'Gene', (52, 55))	('MEK', 'Gene', '5609', (52, 55))	('MAPK', 'molecular_function', 'GO:0004707', ('93', '97'))	('viability', 'CPA', (120, 129))
21967	22515704	Therefore, MEK inhibition may be a way to treat metastatic melanoma of uveal origin, a disease that has been highly refractory to most therapies tested to date.	('MEK', 'Gene', (11, 14))	('MEK', 'Gene', '5609', (11, 14))	('metastatic melanoma of uveal origin', 'Phenotype', 'HP:0007716', (48, 83))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma of uveal', 'Disease', 'MESH:C536494', (59, 76))	('inhibition', 'Var', (15, 25))	('melanoma of uveal', 'Disease', (59, 76))
21968	22515704	TAK733 represents a novel and distinct inhibitor of MEK that is capable of allosteric inhibition of the RAF substrates MEK-1 and MEK-2.	('TAK733', 'Var', (0, 6))	('MEK', 'Gene', (119, 122))	('TAK733', 'Chemical', 'MESH:C558666', (0, 6))	('MEK-1', 'Gene', (119, 124))	('MEK', 'Gene', '5609', (119, 122))	('allosteric inhibition', 'MPA', (75, 96))	('RAF', 'Gene', (104, 107))	('MEK-2', 'molecular_function', 'GO:0004708', ('129', '134'))	('RAF', 'Gene', '22882', (104, 107))	('MEK-1', 'molecular_function', 'GO:0004708', ('119', '124'))	('MEK-2', 'Gene', (129, 134))	('MEK', 'Gene', (52, 55))	('MEK', 'Gene', '5609', (52, 55))	('MEK-1', 'Gene', '5604', (119, 124))	('MEK-2', 'Gene', '5605', (129, 134))	('MEK', 'Gene', (129, 132))	('MEK', 'Gene', '5609', (129, 132))
21971	22515704	Among 12 BRAFV600E mutated cutaneous cell lines tested, seven were highly sensitive to TAK-733 with IC50s less than 1 nM (Figure 1 and Additional file 1: Figure S1).	('sensitive', 'MPA', (74, 83))	('BRAFV600E', 'Var', (9, 18))	('BRAFV600E', 'Mutation', 'rs113488022', (9, 18))	('TAK-733', 'Chemical', 'MESH:C558666', (87, 94))	('50s', 'Species', '1214577', (102, 105))
21972	22515704	Five BRAFV600E mutant cutaneous cell lines had an IC50 higher than 100 nM and were considered highly resistant to this agent..	('BRAFV600E', 'Var', (5, 14))	('BRAFV600E', 'Mutation', 'rs113488022', (5, 14))	('IC50', 'MPA', (50, 54))
21973	22515704	Among ten NRASQ61 mutant cutaneous melanoma cell lines, four were sensitive with IC50s below 10 nM, but none was highly sensitive.	('NRAS', 'Gene', '4893', (10, 14))	('cutaneous melanoma', 'Disease', (25, 43))	('50s', 'Species', '1214577', (83, 86))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (25, 43))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (25, 43))	('mutant', 'Var', (18, 24))	('NRAS', 'Gene', (10, 14))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))
21974	22515704	Our panel also included five cutaneous melanoma cell lines wild type for mutations in NRAS, BRAF, GNAQ and GNA11 and only one was highly sensitive to TAK733 with IC50s below 1 nM, while two were considered sensitive with IC50 less than 10 nM.	('NRAS', 'Gene', (86, 90))	('BRAF', 'Gene', '673', (92, 96))	('NRAS', 'Gene', '4893', (86, 90))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('BRAF', 'Gene', (92, 96))	('GNAQ', 'Gene', (98, 102))	('cutaneous melanoma', 'Disease', (29, 47))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (29, 47))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (29, 47))	('TAK733', 'Chemical', 'MESH:C558666', (150, 156))	('GNAQ', 'Gene', '2776', (98, 102))	('GNA11', 'Gene', '2767', (107, 112))	('GNA11', 'Gene', (107, 112))	('mutations', 'Var', (73, 82))	('50s', 'Species', '1214577', (164, 167))
21975	22515704	All five uveal melanoma cell lines were sensitive to TAK733 with IC50 values below 10 nM, with three of them being highly sensitive.	('sensitive', 'Reg', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('IC50', 'MPA', (65, 69))	('uveal melanoma', 'Phenotype', 'HP:0007716', (9, 23))	('uveal melanoma', 'Disease', (9, 23))	('uveal melanoma', 'Disease', 'MESH:C536494', (9, 23))	('TAK733', 'Var', (53, 59))	('TAK733', 'Chemical', 'MESH:C558666', (53, 59))
21976	22515704	All these cell lines carried GNAQ or GNA11 driver mutations (Figure 1 and Table 1).	('GNAQ', 'Gene', (29, 33))	('GNA11', 'Gene', '2767', (37, 42))	('GNA11', 'Gene', (37, 42))	('mutations', 'Var', (50, 59))	('GNAQ', 'Gene', '2776', (29, 33))	('carried', 'Reg', (21, 28))
21977	22515704	Overall, there was a clear trend of higher sensitivity in BRAF mutant cell lines, but all subgroups included cell lines with variable sensitivity and also high resistance to exposure to the MEK inhibitor.	('higher', 'PosReg', (36, 42))	('mutant', 'Var', (63, 69))	('sensitivity', 'MPA', (43, 54))	('MEK', 'Gene', (190, 193))	('BRAF', 'Gene', '673', (58, 62))	('BRAF', 'Gene', (58, 62))	('MEK', 'Gene', '5609', (190, 193))
21979	22515704	For these studies we chose two NRAS mutants and four BRAF mutants that represented the spectrum of sensitivities of these cell lines.	('BRAF', 'Gene', '673', (53, 57))	('NRAS', 'Gene', '4893', (31, 35))	('BRAF', 'Gene', (53, 57))	('mutants', 'Var', (36, 43))	('mutants', 'Var', (58, 65))	('NRAS', 'Gene', (31, 35))
21980	22515704	The NRAS mutants M207 (sensitive) and M244 (highly resistant) both had a dose-dependent G1 arrest with increasing concentrations of TAK733 (Figure 2c).	('M244', 'Var', (38, 42))	('G1 arrest', 'CPA', (88, 97))	('TAK733', 'Chemical', 'MESH:C558666', (132, 138))	('NRAS', 'Gene', (4, 8))	('M207', 'Var', (17, 21))	('NRAS', 'Gene', '4893', (4, 8))
21981	22515704	The same was evident with the four BRAF mutants, including the two with high sensitivity (M229 and M249) and the highly resistant (M233 and M263).	('BRAF', 'Gene', (35, 39))	('M249', 'Var', (99, 103))	('M263', 'Var', (140, 144))	('M233', 'Var', (131, 135))	('BRAF', 'Gene', '673', (35, 39))	('M229', 'Var', (90, 94))
21985	22515704	Among the BRAFV600E mutant cutaneous group we chose M229 and M249 as representatives of highly sensitive cutaneous cell lines, and M233 and M263 as resistant cutaneous cell lines.	('BRAFV600E', 'Var', (10, 19))	('M229', 'Var', (52, 56))	('M249', 'Var', (61, 65))	('BRAFV600E', 'Mutation', 'rs113488022', (10, 19))
21986	22515704	In our panel, all the uveal melanoma cell lines were sensitive to TAK733 and we picked three as representative samples with GNAQ mutations.	('GNAQ', 'Gene', '2776', (124, 128))	('mutations', 'Var', (129, 138))	('uveal melanoma', 'Phenotype', 'HP:0007716', (22, 36))	('uveal melanoma', 'Disease', 'MESH:C536494', (22, 36))	('GNAQ', 'Gene', (124, 128))	('uveal melanoma', 'Disease', (22, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('TAK733', 'Chemical', 'MESH:C558666', (66, 72))
21987	22515704	As expected based on prior data, MEK inhibition resulted in increase of pMEK in non-BRAFV600E mutant cell lines (Figure 3).	('non-BRAFV600E mutant', 'Var', (80, 100))	('inhibition', 'NegReg', (37, 47))	('mutant', 'Var', (94, 100))	('increase', 'PosReg', (60, 68))	('MEK', 'Gene', (73, 76))	('MEK', 'Gene', '5609', (73, 76))	('BRAFV600E', 'Mutation', 'rs113488022', (84, 93))	('MEK', 'Gene', (33, 36))	('MEK', 'Gene', '5609', (33, 36))
21989	22515704	In all cases, TAK733 induced a marked dose-dependent decrease of pERK, regardless of the driver oncogenic mutation or the sensitivity or resistance to this agent in cell viability assays.	('TAK733', 'Chemical', 'MESH:C558666', (14, 20))	('decrease', 'NegReg', (53, 61))	('TAK733', 'Var', (14, 20))	('pERK', 'Gene', (65, 69))	('pERK', 'Gene', '9451', (65, 69))
21991	22515704	BRAFV600E mutant cell lines resistant to TAK733 showed no inhibition of pAKT or pS6K, while there was a general trend towards inhibition of these two phosphorylated molecules in sensitive cell lines.	('pS6K', 'Gene', '6198', (80, 84))	('AKT', 'Gene', (73, 76))	('pS6K', 'Gene', (80, 84))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('AKT', 'Gene', '207', (73, 76))	('BRAFV600E', 'Var', (0, 9))	('TAK733', 'Chemical', 'MESH:C558666', (41, 47))
21994	22515704	In a time-course analysis of signaling events upon exposure to TAK733, both the sensitive M229 and the resistant M233 cell lines with BRAFV600E mutations showed initial inhibition of pERK, but the resistant cell line recovered pERK signaling with time (Additional file 2: Figure S2).	('signaling', 'biological_process', 'GO:0023052', ('29', '38'))	('inhibition', 'NegReg', (169, 179))	('BRAFV600E', 'Gene', (134, 143))	('TAK733', 'Chemical', 'MESH:C558666', (63, 69))	('pERK', 'Gene', (227, 231))	('pERK', 'Gene', (183, 187))	('pERK', 'Gene', '9451', (227, 231))	('pERK', 'Gene', '9451', (183, 187))	('BRAFV600E', 'Mutation', 'rs113488022', (134, 143))	('mutations', 'Var', (144, 153))	('signaling', 'biological_process', 'GO:0023052', ('232', '241'))
21998	22515704	Consistent with the cell cycle analysis data, all the tested cell lines had some degree of inhibition of tritium-labeled thymidine (3H-thymidine) uptake upon exposure to TAK733 regardless of their sensitivity in vitro.	('3H-thymidine', 'Chemical', '-', (132, 144))	('cell cycle', 'biological_process', 'GO:0007049', ('20', '30'))	('uptake', 'biological_process', 'GO:0098739', ('146', '152'))	('thymidine', 'Chemical', 'MESH:D013936', (121, 130))	('TAK733', 'Var', (170, 176))	('TAK733', 'Chemical', 'MESH:C558666', (170, 176))	('tritium', 'Chemical', 'MESH:D014316', (105, 112))	('inhibition', 'NegReg', (91, 101))	('uptake', 'biological_process', 'GO:0098657', ('146', '152'))	('thymidine', 'Chemical', 'MESH:D013936', (135, 144))
22001	22515704	The lowest degree of inhibition was in the two most resistant cell lines, the BRAFV600E mutant M233 and the NRASQ61K mutant M244 (Figure 4b).	('NRAS', 'Gene', '4893', (108, 112))	('BRAFV600E', 'Var', (78, 87))	('BRAFV600E', 'Mutation', 'rs113488022', (78, 87))	('NRAS', 'Gene', (108, 112))
22003	22515704	Initial data testing MEK inhibitors in melanoma cell lines suggested a high level and selective sensitivity in BRAFV600E mutant melanoma cell lines, with low sensitivity in melanoma cell lines with other driver oncogenes.	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('mutant', 'Var', (121, 127))	('MEK', 'Gene', (21, 24))	('MEK', 'Gene', '5609', (21, 24))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('BRAFV600E', 'Mutation', 'rs113488022', (111, 120))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Disease', (173, 181))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('BRAFV600E', 'Gene', (111, 120))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
22004	22515704	Further testing with expanded panels of cell lines has confirmed a trend towards higher sensitivity in BRAFV600E mutant melanoma, but has also provided evidence that some melanoma cell lines with NRAS activating mutations are sensitive to MEK inhibitors.	('MEK', 'Gene', (239, 242))	('MEK', 'Gene', '5609', (239, 242))	('BRAFV600E', 'Var', (103, 112))	('BRAFV600E', 'Mutation', 'rs113488022', (103, 112))	('higher', 'PosReg', (81, 87))	('NRAS', 'Gene', (196, 200))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', (171, 179))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('NRAS', 'Gene', '4893', (196, 200))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('sensitivity', 'MPA', (88, 99))
22005	22515704	The higher sensitivity of BRAF mutant cell lines compared to NRAS mutant cell lines is generally represented in our series, but some BRAF mutants have high resistance to the MEK inhibitor while some NRAS mutants are sensitive.	('MEK', 'Gene', (174, 177))	('mutants', 'Var', (138, 145))	('BRAF', 'Gene', '673', (26, 30))	('resistance', 'MPA', (156, 166))	('BRAF', 'Gene', '673', (133, 137))	('MEK', 'Gene', '5609', (174, 177))	('BRAF', 'Gene', (26, 30))	('BRAF', 'Gene', (133, 137))	('NRAS', 'Gene', (61, 65))	('NRAS', 'Gene', (199, 203))	('NRAS', 'Gene', '4893', (61, 65))	('NRAS', 'Gene', '4893', (199, 203))
22007	22515704	The molecular basis for this relative high frequency of natural resistance of BRAFV600E mutant cutaneous melanoma cell lines in our series is currently not well understood.	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('BRAFV600E', 'Var', (78, 87))	('BRAFV600E', 'Mutation', 'rs113488022', (78, 87))	('cutaneous melanoma', 'Disease', (95, 113))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (95, 113))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (95, 113))
22008	22515704	Initial exploration of secondary oncogenic events in the PI3K/AKT pathway (such as PTEN deletions) did not clearly differentiate naturally sensitive and resistant BRAFV600E mutant cutaneous melanomas to the BRAF inhibitor vemurafenib, but downstream signaling studies did suggest that the PI3K/AKT pathway may be involved.	('BRAF', 'Gene', (207, 211))	('BRAF', 'Gene', '673', (207, 211))	('AKT', 'Gene', (62, 65))	('melanomas', 'Phenotype', 'HP:0002861', (190, 199))	('PTEN', 'Gene', (83, 87))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('signaling', 'biological_process', 'GO:0023052', ('250', '259'))	('AKT', 'Gene', '207', (294, 297))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (180, 198))	('AKT', 'Gene', '207', (62, 65))	('deletions', 'Var', (88, 97))	('PTEN', 'Gene', '5728', (83, 87))	('PI3K', 'molecular_function', 'GO:0016303', ('289', '293'))	('BRAFV600E', 'Mutation', 'rs113488022', (163, 172))	('mutant', 'Var', (173, 179))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (180, 199))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (180, 199))	('PI3K', 'molecular_function', 'GO:0016303', ('57', '61'))	('vemurafenib', 'Chemical', 'MESH:D000077484', (222, 233))	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('cutaneous melanomas', 'Disease', (180, 199))	('AKT', 'Gene', (294, 297))
22011	22515704	This observation may provide means to explore combinations of MEK inhibitors with PI3K or AKT inhibitors that may be useful in NRAS or BRAF mutant melanomas, which could be due to hyperactive receptor tyrosine kinase signaling leading to resistance.	('BRAF', 'Gene', '673', (135, 139))	('receptor tyrosine kinase', 'Gene', '5979', (192, 216))	('MEK', 'Gene', (62, 65))	('signaling', 'biological_process', 'GO:0023052', ('217', '226'))	('MEK', 'Gene', '5609', (62, 65))	('BRAF', 'Gene', (135, 139))	('AKT', 'Gene', (90, 93))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('melanomas', 'Phenotype', 'HP:0002861', (147, 156))	('melanomas', 'Disease', (147, 156))	('NRAS', 'Gene', (127, 131))	('hyperactive', 'PosReg', (180, 191))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('NRAS', 'Gene', '4893', (127, 131))	('melanomas', 'Disease', 'MESH:D008545', (147, 156))	('AKT', 'Gene', '207', (90, 93))	('mutant', 'Var', (140, 146))	('receptor tyrosine kinase', 'Gene', (192, 216))
22015	22515704	This could be explained by the paradoxical activation of the MAPK pathway in BRAF wild type cutaneous cells, where type I BRAF inhibitors increase (or do not change) MAPK signaling in normal cells, while they efficiently block the MAPK pathway downstream of oncogenic BRAFV600.	('BRAF', 'Gene', (268, 272))	('MAPK signaling', 'MPA', (166, 180))	('increase', 'PosReg', (138, 146))	('MAPK signaling', 'biological_process', 'GO:0000165', ('166', '180'))	('BRAF', 'Gene', '673', (268, 272))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', '673', (122, 126))	('activation', 'PosReg', (43, 53))	('MAPK pathway', 'Pathway', (231, 243))	('MAPK', 'molecular_function', 'GO:0004707', ('231', '235'))	('BRAF', 'Gene', (77, 81))	('BRAF', 'Gene', (122, 126))	('block', 'NegReg', (221, 226))	('inhibitors', 'Var', (127, 137))	('MAPK', 'molecular_function', 'GO:0004707', ('61', '65'))	('MAPK', 'molecular_function', 'GO:0004707', ('166', '170'))	('MAPK pathway', 'Pathway', (61, 73))
22017	22515704	This lack of differentiation most likely causes the dose limiting toxicities (DLT) at exposures in vivo that do not adequately block the MAPK pathway in BRAFV600 mutant melanoma.	('toxicities', 'Disease', (66, 76))	('BRAF', 'Gene', (153, 157))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanoma', 'Disease', (169, 177))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('mutant', 'Var', (162, 168))	('toxicities', 'Disease', 'MESH:D064420', (66, 76))	('MAPK', 'molecular_function', 'GO:0004707', ('137', '141'))	('MAPK pathway', 'Pathway', (137, 149))	('BRAF', 'Gene', '673', (153, 157))
22018	22515704	Despite this, MEK inhibitors are likely to have a role in the treatment of cancers with constitutive MAPK signaling from oncogenic mutations upstream of MEK.	('mutations', 'Var', (131, 140))	('MAPK', 'molecular_function', 'GO:0004707', ('101', '105'))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('constitutive MAPK signaling', 'MPA', (88, 115))	('MAPK signaling', 'biological_process', 'GO:0000165', ('101', '115'))	('MEK', 'Gene', (14, 17))	('MEK', 'Gene', '5609', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('MEK', 'Gene', (153, 156))	('MEK', 'Gene', '5609', (153, 156))
22019	22515704	In particular the combination of MEK and RAF inhibitors may be beneficial by inducing higher MAPK inhibition in mutant cells and therefore lowering the cancer escape mechanisms and also decreasing toxicities from paradoxical MAPK activation, such as the development of cutaneous squamous cell carcinomas.	('cutaneous squamous cell carcinomas', 'Disease', 'MESH:D002294', (269, 303))	('MAPK activation', 'biological_process', 'GO:0000187', ('225', '240'))	('mutant', 'Var', (112, 118))	('decreasing', 'NegReg', (186, 196))	('cancer', 'Disease', (152, 158))	('RAF', 'Gene', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('MAPK', 'Protein', (93, 97))	('cutaneous squamous cell carcinomas', 'Phenotype', 'HP:0006739', (269, 303))	('carcinomas', 'Phenotype', 'HP:0030731', (293, 303))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (279, 303))	('inhibition', 'MPA', (98, 108))	('MAPK', 'molecular_function', 'GO:0004707', ('93', '97'))	('MEK', 'Gene', '5609', (33, 36))	('MAPK', 'molecular_function', 'GO:0004707', ('225', '229'))	('toxicities', 'Disease', 'MESH:D064420', (197, 207))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('lowering', 'NegReg', (139, 147))	('toxicities', 'Disease', (197, 207))	('MEK', 'Gene', (33, 36))	('cutaneous squamous cell carcinomas', 'Disease', (269, 303))	('RAF', 'Gene', '22882', (41, 44))
22020	22515704	The majority of uveal melanomas bear a mutually exclusive activating mutation in either GNAQ or GNA11, resulting in overlapping functions in melanoma cells with the constitutive upregulation of the MAPK pathway.	('uveal melanomas', 'Disease', (16, 31))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('MAPK', 'molecular_function', 'GO:0004707', ('198', '202'))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('GNA11', 'Gene', '2767', (96, 101))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('uveal melanomas', 'Disease', 'MESH:C536494', (16, 31))	('functions', 'MPA', (128, 137))	('upregulation', 'PosReg', (178, 190))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma', 'Disease', (22, 30))	('MAPK pathway', 'Pathway', (198, 210))	('GNAQ', 'Gene', '2776', (88, 92))	('GNAQ', 'Gene', (88, 92))	('activating', 'PosReg', (58, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('mutation', 'Var', (69, 77))	('uveal melanomas', 'Phenotype', 'HP:0007716', (16, 31))	('GNA11', 'Gene', (96, 101))
22022	22515704	Our data demonstrating the sensitivity of uveal melanoma cell lines to TAK733 provides further evidence that it may be a clinical strategy to use MEK inhibitors to treat metastatic uveal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('TAK733', 'Chemical', 'MESH:C558666', (71, 77))	('melanomas', 'Phenotype', 'HP:0002861', (187, 196))	('uveal melanomas', 'Disease', (181, 196))	('uveal melanomas', 'Phenotype', 'HP:0007716', (181, 196))	('TAK733', 'Var', (71, 77))	('MEK', 'Gene', (146, 149))	('MEK', 'Gene', '5609', (146, 149))	('uveal melanoma', 'Phenotype', 'HP:0007716', (181, 195))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('uveal melanoma', 'Disease', 'MESH:C536494', (181, 195))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('uveal melanoma', 'Disease', (42, 56))	('uveal melanomas', 'Disease', 'MESH:C536494', (181, 196))
22028	22515704	We confirmed the previously reported cytotoxic effect of a MEK inhibitor against cell lines with BRAFV600E mutations, but in addition the cytotoxic activity was evident in a high proportion of melanoma cell lines with NRAS, GNAQ or GNA11 driver mutations.	('GNAQ', 'Gene', '2776', (224, 228))	('mutations', 'Var', (107, 116))	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('GNA11', 'Gene', (232, 237))	('melanoma', 'Disease', (193, 201))	('MEK', 'Gene', (59, 62))	('NRAS', 'Gene', (218, 222))	('MEK', 'Gene', '5609', (59, 62))	('BRAFV600E', 'Mutation', 'rs113488022', (97, 106))	('GNA11', 'Gene', '2767', (232, 237))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('GNAQ', 'Gene', (224, 228))	('NRAS', 'Gene', '4893', (218, 222))	('BRAFV600E', 'Gene', (97, 106))	('cytotoxic', 'MPA', (37, 46))
22040	22515704	Primary antibodies included pAkt (Ser473), pAkt (Thr308), Akt, pS6K (Thr389), S6K, pS6 (Ser235/236), S6, pMEK (Ser217/221), MEK, pERK1/2 (Thr204/205), and ERK (all from Cell Signaling Technology, Danvers, MA), and alpha-actin (Sigma-Aldrich).	('ERK', 'Gene', (155, 158))	('S6K', 'Gene', '6198', (78, 81))	('pS6', 'Gene', (63, 66))	('Ser', 'cellular_component', 'GO:0005790', ('88', '91'))	('Ser', 'cellular_component', 'GO:0005790', ('34', '37'))	('Ser473', 'Var', (34, 40))	('ERK', 'Gene', '5594', (130, 133))	('MEK', 'Gene', '5609', (124, 127))	('Ser473', 'Chemical', '-', (34, 40))	('Ser235/236', 'Var', (88, 98))	('pERK', 'Gene', '9451', (129, 133))	('Thr204', 'Chemical', '-', (138, 144))	('pERK', 'Gene', (129, 133))	('S6K', 'Gene', (64, 67))	('Thr389', 'Var', (69, 75))	('Akt', 'Gene', (29, 32))	('MEK', 'Gene', (124, 127))	('pS6', 'Gene', '338413', (63, 66))	('Akt', 'Gene', (44, 47))	('ERK', 'Gene', (130, 133))	('Akt', 'Gene', (58, 61))	('Thr389', 'Chemical', '-', (69, 75))	('pS6K', 'Gene', '6198', (63, 67))	('S6K', 'Gene', (78, 81))	('Ser217/221', 'Var', (111, 121))	('Akt', 'Gene', '207', (44, 47))	('Ser', 'cellular_component', 'GO:0005790', ('111', '114'))	('pS6', 'Gene', (83, 86))	('pS6K', 'Gene', (63, 67))	('Akt', 'Gene', '207', (29, 32))	('MEK', 'Gene', '5609', (106, 109))	('Ser217', 'Chemical', '-', (111, 117))	('Akt', 'Gene', '207', (58, 61))	('Thr308', 'Chemical', '-', (49, 55))	('ERK', 'molecular_function', 'GO:0004707', ('155', '158'))	('ERK', 'Gene', '5594', (155, 158))	('S6K', 'Gene', '6198', (64, 67))	('MEK', 'Gene', (106, 109))	('pS6', 'Gene', '338413', (83, 86))	('Ser235', 'Chemical', '-', (88, 94))	('Signaling', 'biological_process', 'GO:0023052', ('174', '183'))
22060	22848417	The expression of oncogene c-Met and its downstream Akt and ERK1/2 pathways was also downregulated by miR-182.	('miR-182', 'Var', (102, 109))	('c-Met', 'Gene', (27, 32))	('downregulated', 'NegReg', (85, 98))	('c-Met', 'Gene', '4233', (27, 32))	('Akt', 'Gene', (52, 55))	('ERK1', 'molecular_function', 'GO:0004707', ('60', '64'))	('Akt', 'Gene', '207', (52, 55))	('expression', 'MPA', (4, 14))	('ERK1/2', 'Gene', (60, 66))	('oncogene', 'Gene', (18, 26))	('ERK1/2', 'Gene', '5595;5594', (60, 66))
22066	22848417	Consequently, iris melanomas frequently harbor BRAF gene mutations associated with ultraviolet damage, and are less likely to metastasize than other uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (149, 164))	('melanomas', 'Phenotype', 'HP:0002861', (155, 164))	('iris melanomas', 'Phenotype', 'HP:0011524', (14, 28))	('uveal melanoma', 'Phenotype', 'HP:0007716', (149, 163))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('BRAF', 'Gene', (47, 51))	('iris melanomas', 'Disease', 'MESH:D007499', (14, 28))	('BRAF', 'Gene', '673', (47, 51))	('harbor', 'Reg', (40, 46))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('uveal melanomas', 'Disease', (149, 164))	('mutations', 'Var', (57, 66))	('uveal melanomas', 'Phenotype', 'HP:0007716', (149, 164))	('associated', 'Reg', (67, 77))	('iris melanoma', 'Phenotype', 'HP:0011524', (14, 27))	('metastasize', 'CPA', (126, 137))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('iris melanomas', 'Disease', (14, 28))
22068	22848417	Posterior uveal melanomas frequently harbor GNAQ mutations, but rarely BRAF mutations.	('GNAQ', 'Gene', (44, 48))	('harbor', 'Reg', (37, 43))	('mutations', 'Var', (49, 58))	('BRAF', 'Gene', '673', (71, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (10, 24))	('BRAF', 'Gene', (71, 75))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanomas', 'Phenotype', 'HP:0002861', (16, 25))	('uveal melanomas', 'Disease', (10, 25))	('uveal melanomas', 'Phenotype', 'HP:0007716', (10, 25))	('GNAQ', 'Gene', '2776', (44, 48))	('uveal melanomas', 'Disease', 'MESH:C536494', (10, 25))
22072	22848417	While MITF expression in melanoma is variable across specimens, studies have suggested that alterations to the repertoire of signals that determine MITF activity dictate the proliferative and invasive potential of melanoma cells.	('dictate', 'Reg', (162, 169))	('invasive potential', 'CPA', (192, 210))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('melanoma', 'Disease', (214, 222))	('melanoma', 'Disease', 'MESH:D008545', (214, 222))	('alterations', 'Var', (92, 103))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))
22073	22848417	Disruptions in the MITF cascade, such as levels of the MITF regulator, BRAF, and the MITF target, c-Met, can lead to melanoma progression.	('Disruptions', 'Var', (0, 11))	('lead to', 'Reg', (109, 116))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('BRAF', 'Gene', '673', (71, 75))	('BRAF', 'Gene', (71, 75))	('c-Met', 'Gene', (98, 103))	('c-Met', 'Gene', '4233', (98, 103))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
22097	22848417	The decrease in cell number was significant between cells transfected with miR-182 and cells transfected with a negative control at day 5 (42.81+-3.61% decrease in M23 cells and 47.02+-1.10% decrease in SP6.5 cells, p<0.01, n = 3).	('SP6', 'Gene', '80320', (203, 206))	('M23 cells', 'CPA', (164, 173))	('decrease', 'NegReg', (4, 12))	('miR-182', 'Var', (75, 82))	('decrease', 'NegReg', (152, 160))	('SP6', 'Gene', (203, 206))	('cell number', 'CPA', (16, 27))
22098	22848417	Complementary to the finding that miR-182 inhibited cell proliferation, miR-182 was found to cause increased G1 cell cycle arrest in these cells.	('arrest', 'Disease', (123, 129))	('miR-182', 'Var', (72, 79))	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (112, 129))	('increased', 'PosReg', (99, 108))	('arrest', 'Disease', 'MESH:D006323', (123, 129))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('112', '129'))
22099	22848417	M23 cells transfected with miR-182 showed 82.48% G1 arrest in comparison to 62.76% for negative control.	('arrest', 'Disease', (52, 58))	('arrest', 'Disease', 'MESH:D006323', (52, 58))	('miR-182', 'Var', (27, 34))
22100	22848417	SP6.5 cells transfected with miR-182 showed 81.85% G1 arrest in comparison to 51.07% with negative control (Fig.	('arrest', 'Disease', (54, 60))	('arrest', 'Disease', 'MESH:D006323', (54, 60))	('SP6', 'Gene', (0, 3))	('miR-182', 'Var', (29, 36))	('SP6', 'Gene', '80320', (0, 3))
22103	22848417	3A, the HGF-induced migration was significantly decreased when comparing miR-182 transfected cells to negative control transfected cells (174+-15 vs. 398+-32 in M23 cells, and 124+-12 vs. 236+-20 in SP6.5, p<0.01, n = 3).	('decreased', 'NegReg', (48, 57))	('HGF', 'Gene', (8, 11))	('miR-182', 'Gene', (73, 80))	('transfected', 'Var', (81, 92))	('SP6', 'Gene', (199, 202))	('HGF', 'Gene', '3082', (8, 11))	('SP6', 'Gene', '80320', (199, 202))
22104	22848417	3B showed that HGF-induced invasiveness was also significantly hampered following miR-182 transfection (65+-6 vs. 170+-13 in M23 cells, and 42+-5 vs. 95+-6 in SP6.5, p<0.01, n = 3).	('SP6', 'Gene', '80320', (159, 162))	('invasiveness', 'Disease', 'MESH:D009362', (27, 39))	('miR-182', 'Gene', (82, 89))	('hampered', 'NegReg', (63, 71))	('HGF', 'Gene', '3082', (15, 18))	('invasiveness', 'Disease', (27, 39))	('HGF', 'Gene', (15, 18))	('transfection', 'Var', (90, 102))	('SP6', 'Gene', (159, 162))
22105	22848417	After 48 hours, caspase 3/7 activity was significantly increased in miR-182 transfected cells in comparison to negative control after doxorubicin treatment.	('miR-182 transfected', 'Var', (68, 87))	('activity', 'MPA', (28, 36))	('doxorubicin', 'Chemical', 'MESH:D004317', (134, 145))	('increased', 'PosReg', (55, 64))	('transfected', 'Var', (76, 87))	('caspase 3', 'Gene', (16, 25))	('caspase 3', 'Gene', '836', (16, 25))
22109	22848417	SP6.5 cells transfected with miR-182 had 11.65+-1.44% apoptotic cells versus 3.82+-0.89% apoptotic cells in negative control transfected cells (p<0.01, n = 3).	('miR-182', 'Var', (29, 36))	('apoptotic cells', 'CPA', (54, 69))	('SP6', 'Gene', '80320', (0, 3))	('SP6', 'Gene', (0, 3))
22112	22848417	BCL2 contains three target sequences at positions 205-211, 310-316, and 2540-2546.	('310-316', 'Var', (59, 66))	('BCL2', 'molecular_function', 'GO:0015283', ('0', '4'))	('2540-2546', 'Var', (72, 81))	('BCL2', 'Gene', (0, 4))	('BCL2', 'Gene', '596', (0, 4))
22113	22848417	Cyclin D2 contains two target sequences at positions 3554-3560 and 3613-3619 (Fig.	('Cyclin D2', 'Gene', (0, 9))	('3613-3619', 'Var', (67, 76))	('Cyclin', 'molecular_function', 'GO:0016538', ('0', '6'))	('3554-3560', 'Var', (53, 62))	('Cyclin D2', 'Gene', '894', (0, 9))
22117	22848417	To demonstrate the specificity of miR-182 against the MITF, BCL2 and cyclin D2 genes, we generated mutation reporter constructs of each of the three genes and examined if these mutations would eliminate the suppression of the luciferase reporter activity.	('MITF', 'Gene', (54, 58))	('mutations', 'Var', (177, 186))	('eliminate', 'NegReg', (193, 202))	('BCL2', 'molecular_function', 'GO:0015283', ('60', '64'))	('BCL2', 'Gene', (60, 64))	('cyclin D2', 'Gene', '894', (69, 78))	('BCL2', 'Gene', '596', (60, 64))	('cyclin', 'molecular_function', 'GO:0016538', ('69', '75'))	('luciferase', 'Enzyme', (226, 236))	('suppression', 'MPA', (207, 218))	('cyclin D2', 'Gene', (69, 78))
22119	22848417	c-Met, which is a target of MITF, was decreased in M23 and SP6.5 cells transfected with miR-182 in comparison to either mock or a negative control transfected cells (Fig.	('c-Met', 'Gene', '4233', (0, 5))	('decreased', 'NegReg', (38, 47))	('miR-182', 'Var', (88, 95))	('SP6', 'Gene', '80320', (59, 62))	('c-Met', 'Gene', (0, 5))	('SP6', 'Gene', (59, 62))
22121	22848417	6C, downregulation of c-Met by miR-182 led to a significant reduction of phosphorylated-Akt and phosphorylated-ERK1/2 in both M23 and SP6.5 cells.	('Akt', 'Gene', '207', (88, 91))	('ERK1/2', 'Gene', (111, 117))	('ERK1', 'molecular_function', 'GO:0004707', ('111', '115'))	('miR-182', 'Var', (31, 38))	('ERK1/2', 'Gene', '5595;5594', (111, 117))	('reduction', 'NegReg', (60, 69))	('Akt', 'Gene', (88, 91))	('downregulation', 'NegReg', (4, 18))	('c-Met', 'Gene', (22, 27))	('SP6', 'Gene', (134, 137))	('c-Met', 'Gene', '4233', (22, 27))	('SP6', 'Gene', '80320', (134, 137))
22122	22848417	Both total Akt and total ERK1/2 were not affected when comparing miR-182 transfection to negative control transfection (Fig.	('ERK1', 'molecular_function', 'GO:0004707', ('25', '29'))	('ERK1/2', 'Gene', '5595;5594', (25, 31))	('miR-182', 'Gene', (65, 72))	('Akt', 'Gene', '207', (11, 14))	('transfection', 'Var', (73, 85))	('Akt', 'Gene', (11, 14))	('ERK1/2', 'Gene', (25, 31))
22125	22848417	MTS assays showed that transfection of c-Met siRNA caused a dramatic inhibition of M23 and SP6.5 cell growth at 72 hours (21.58+-3.28% decrease in M23 cells and 23.47+-3.46% decrease in SP6.5 cells, p<0.01, n = 3; Fig.	('transfection', 'Var', (23, 35))	('decrease', 'NegReg', (174, 182))	('M23 cells', 'CPA', (147, 156))	('SP6', 'Gene', (186, 189))	('cell growth', 'biological_process', 'GO:0016049', ('97', '108'))	('SP6', 'Gene', '80320', (91, 94))	('SP6', 'Gene', '80320', (186, 189))	('SP6', 'Gene', (91, 94))	('c-Met', 'Gene', (39, 44))	('c-Met', 'Gene', '4233', (39, 44))	('decrease', 'NegReg', (135, 143))	('inhibition', 'NegReg', (69, 79))
22129	22848417	Primary targets of miR-182 including BCL2 and cyclin D2 were suppressed by miR-182, as expected (Fig.	('cyclin D2', 'Gene', '894', (46, 55))	('miR-182', 'Gene', (19, 26))	('suppressed', 'NegReg', (61, 71))	('BCL2', 'Gene', (37, 41))	('cyclin D2', 'Gene', (46, 55))	('BCL2', 'Gene', '596', (37, 41))	('miR-182', 'Var', (75, 82))	('BCL2', 'molecular_function', 'GO:0015283', ('37', '41'))	('cyclin', 'molecular_function', 'GO:0016538', ('46', '52'))
22135	22848417	After 4 weeks, the averaged tumor volumes were significantly lower in cells infected with lentivirus expressing miR-182, as compared with control (Fig.	('lower', 'NegReg', (61, 66))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('miR-182', 'Var', (112, 119))
22137	22848417	Aberrant regulation of miRNAs has been implicated in human uveal melanoma development.	('regulation', 'biological_process', 'GO:0065007', ('9', '19'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('uveal melanoma', 'Disease', (59, 73))	('miR', 'Gene', (23, 26))	('implicated', 'Reg', (39, 49))	('miR', 'Gene', '22877', (23, 26))	('human', 'Species', '9606', (53, 58))	('Aberrant regulation', 'Var', (0, 19))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('uveal melanoma', 'Disease', 'MESH:C536494', (59, 73))
22142	22848417	Recently, studies of aberrant miR-182 expression demonstrated that miR-182 promotes cutaneous melanoma metastasis by suppressing the transcription factors FOXO3 and MITF.	('miR-182', 'Gene', (30, 37))	('FOXO3', 'Gene', '2309', (155, 160))	('transcription', 'biological_process', 'GO:0006351', ('133', '146'))	('aberrant', 'Var', (21, 29))	('promotes', 'PosReg', (75, 83))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma metastasis', 'Disease', (94, 113))	('cutaneous melanoma', 'Disease', (84, 102))	('suppressing', 'NegReg', (117, 128))	('MITF', 'Gene', (165, 169))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (84, 102))	('melanoma metastasis', 'Disease', 'MESH:D009362', (94, 113))	('FOXO3', 'Gene', (155, 160))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (84, 102))	('miR-182', 'Gene', (67, 74))
22146	22848417	Furthermore, MITF amplification is associated with BRAF mutation and p16 inactivation.	('inactivation', 'NegReg', (73, 85))	('associated', 'Reg', (35, 45))	('MITF', 'Gene', (13, 17))	('p16', 'Gene', (69, 72))	('BRAF', 'Gene', '673', (51, 55))	('amplification', 'Var', (18, 31))	('mutation', 'Var', (56, 64))	('BRAF', 'Gene', (51, 55))	('p16', 'Gene', '1029', (69, 72))
22153	22848417	Concordant with these findings, MITF in choroidal melanoma behaves as an oncogenic factor that is suppressed by miR-182 as demonstrated in this study, as well as by miR-137 in our previous report.	('suppressed', 'NegReg', (98, 108))	('miR-137', 'Gene', (165, 172))	('choroidal melanoma', 'Disease', 'MESH:D008545', (40, 58))	('choroidal melanoma', 'Disease', (40, 58))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('miR-137', 'Gene', '406928', (165, 172))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (40, 58))	('miR-182', 'Var', (112, 119))	('MITF', 'Gene', (32, 36))
22155	22848417	Taken together, we surmise that MITF causes cellular proliferation and oncogenesis in most posterior uveal melanomas and some cutaneous melanomas with MITF amplification.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (126, 145))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (126, 145))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('amplification', 'Var', (156, 169))	('uveal melanomas', 'Phenotype', 'HP:0007716', (101, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (101, 115))	('cellular proliferation', 'CPA', (44, 66))	('cutaneous melanomas', 'Disease', (126, 145))	('melanomas', 'Phenotype', 'HP:0002861', (136, 145))	('oncogenesis', 'biological_process', 'GO:0007048', ('71', '82'))	('posterior uveal melanomas', 'Disease', (91, 116))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('posterior uveal melanomas', 'Disease', 'MESH:C536494', (91, 116))	('causes', 'Reg', (37, 43))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (126, 144))	('oncogenesis', 'CPA', (71, 82))	('MITF', 'Gene', (32, 36))
22156	22848417	In this study, miR-182 was shown to inhibit cell proliferation and migration by regulating the expression of MITF, which in turn downregulated c-Met expression (Fig.	('c-Met', 'Gene', (143, 148))	('downregulated', 'NegReg', (129, 142))	('MITF', 'Gene', (109, 113))	('c-Met', 'Gene', '4233', (143, 148))	('cell proliferation', 'CPA', (44, 62))	('inhibit', 'NegReg', (36, 43))	('miR-182', 'Var', (15, 22))	('regulating', 'Reg', (80, 90))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))	('expression', 'MPA', (95, 105))
22164	22848417	Consistent with those observations, our results showed that CDK2 and CDK4 were downregulated in cells with suppression of MITF after introduction of miR-182 (Fig.	('CDK4', 'Gene', '1019', (69, 73))	('CDK', 'molecular_function', 'GO:0004693', ('69', '72'))	('suppression', 'NegReg', (107, 118))	('CDK2', 'Gene', '1017', (60, 64))	('miR-182', 'Var', (149, 156))	('MITF', 'Gene', (122, 126))	('downregulated', 'NegReg', (79, 92))	('CDK', 'molecular_function', 'GO:0004693', ('60', '63'))	('CDK2', 'Gene', (60, 64))	('CDK4', 'Gene', (69, 73))
22167	22848417	This study also found that miR-182 can inhibit BCL2 and cyclin D2 directly (Fig.	('cyclin D2', 'Gene', (56, 65))	('BCL2', 'molecular_function', 'GO:0015283', ('47', '51'))	('BCL2', 'Gene', (47, 51))	('cyclin', 'molecular_function', 'GO:0016538', ('56', '62'))	('miR-182', 'Var', (27, 34))	('inhibit', 'NegReg', (39, 46))	('cyclin D2', 'Gene', '894', (56, 65))	('BCL2', 'Gene', '596', (47, 51))
22168	22848417	BCL2, which is an anti-apoptotic gene, is also influenced by the presence of MITF.	('BCL2', 'molecular_function', 'GO:0015283', ('0', '4'))	('presence', 'Var', (65, 73))	('MITF', 'Gene', (77, 81))	('BCL2', 'Gene', (0, 4))	('influenced', 'Reg', (47, 57))	('BCL2', 'Gene', '596', (0, 4))
22169	22848417	Cyclin D2, as a positive regulator of G1 phase cell cycle progression, is shown to be a direct target of miR-182 in this study (Fig.	('G1 phase', 'biological_process', 'GO:0051318', ('38', '46'))	('Cyclin D2', 'Gene', (0, 9))	('cell cycle', 'biological_process', 'GO:0007049', ('47', '57'))	('Cyclin', 'molecular_function', 'GO:0016538', ('0', '6'))	('miR-182', 'Var', (105, 112))	('Cyclin D2', 'Gene', '894', (0, 9))
22198	22848417	M23 cells (5x106) or SP6.5 cells (5x106) expressing miR-182 or the negative control were inoculated subcutaneously into the flanks of nude mice.	('nude mice', 'Species', '10090', (134, 143))	('SP6', 'Gene', '80320', (21, 24))	('SP6', 'Gene', (21, 24))	('miR-182', 'Var', (52, 59))
22294	22566838	As an example, IFNgamma-induced MHC-II expression results in an increase in active histone marks, i.e., acetylation of histone H3 and H4, and 3meK4-H3 at the MHC-II promoter, while at the same time a decrease in the repressive 3meK9-H3 histone mark is noted (Chou and Tomasi,).	('IFNgamma', 'Gene', '3458', (15, 23))	('active', 'MPA', (76, 82))	('IFNgamma', 'Gene', (15, 23))	('histone H3', 'Protein', (119, 129))	('3meK9-H3', 'MPA', (227, 235))	('increase', 'PosReg', (64, 72))	('MHC-II', 'Gene', (32, 38))	('acetylation', 'MPA', (104, 115))	('3meK4-H3', 'Var', (142, 150))	('decrease', 'NegReg', (200, 208))
22373	22566838	Notably, the transcriptional silencing of MHC2TA by histone methylation in the absence of CpG dinucleotide methylation is in line with the observation that the 3meK27-H3 modification pre-marks genes for de novo methylation in cancer (Schlesinger et al.,).	('methylation', 'biological_process', 'GO:0032259', ('211', '222'))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (90, 106))	('silencing', 'NegReg', (29, 38))	('3meK27-H3', 'Var', (160, 169))	('methylation', 'biological_process', 'GO:0032259', ('107', '118'))	('cancer', 'Disease', (226, 232))	('transcriptional', 'MPA', (13, 28))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('pre', 'molecular_function', 'GO:0003904', ('183', '186'))	('MHC2TA', 'Gene', (42, 48))	('MHC2TA', 'Gene', '4261', (42, 48))	('histone methylation', 'biological_process', 'GO:0016571', ('52', '71'))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
22374	22566838	It could therefore be argued that the epigenetic make-up of the CIITA-PIV region in uveal melanoma reflects pre-marking for de novo methylation of DNA, and that this reflects an intermediate epigenetic state of MHC2TA in the complete shut down of MHC-II mediated antigen presentation functions.	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma', 'Disease', (84, 98))	('MHC2TA', 'Gene', (211, 217))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('antigen presentation', 'biological_process', 'GO:0019882', ('263', '283'))	('methylation', 'biological_process', 'GO:0032259', ('132', '143'))	('MHC2TA', 'Gene', '4261', (211, 217))	('methylation', 'Var', (132, 143))	('pre', 'molecular_function', 'GO:0003904', ('108', '111'))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
22411	21479172	Molecular tests associated with subtypes 1.1-1.4 include: BRAF targeted sequencing for the presence of V600E mutation, Immuno-Histo-Chemical (IHC) tests for reduced PTEN protein levels, tests examining increased copy number of AKT, and IHC indicating increased CCND1/Cyclin D protein levels.	('increased', 'PosReg', (251, 260))	('protein', 'cellular_component', 'GO:0003675', ('276', '283'))	('increased', 'PosReg', (202, 211))	('V600E', 'Var', (103, 108))	('Cyclin', 'Gene', (267, 273))	('AKT', 'Gene', (227, 230))	('PTEN protein levels', 'MPA', (165, 184))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('Cyclin', 'molecular_function', 'GO:0016538', ('267', '273'))	('Cyclin', 'Gene', '5111', (267, 273))	('V600E', 'Mutation', 'rs113488022', (103, 108))	('AKT', 'Gene', '207', (227, 230))	('reduced', 'NegReg', (157, 164))
22416	21479172	In some melanomas, BRAF mutations occur along with other mutations in genes such as PTEN and CDK4.	('CDK', 'molecular_function', 'GO:0004693', ('93', '96'))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('CDK4', 'Gene', '1019', (93, 97))	('melanomas', 'Disease', 'MESH:D008545', (8, 17))	('BRAF', 'Gene', (19, 23))	('occur', 'Reg', (34, 39))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('PTEN', 'Gene', (84, 88))	('mutations', 'Var', (24, 33))	('CDK4', 'Gene', (93, 97))	('melanomas', 'Disease', (8, 17))
22422	21479172	Sorafenib suppresses BRAF as well as CRAF with similar efficiency by stabilizing the inactive conformations, though it is less efficacious on the BRAF V600E form than on wildtype.	('stabilizing', 'MPA', (69, 80))	('V600E', 'Var', (151, 156))	('BRAF', 'Disease', (21, 25))	('CRAF', 'molecular_function', 'GO:0004709', ('37', '41'))	('CRAF', 'Gene', (37, 41))	('inactive conformations', 'MPA', (85, 107))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('suppresses', 'NegReg', (10, 20))	('CRAF', 'Gene', '5894', (37, 41))	('V600E', 'Mutation', 'rs113488022', (151, 156))
22427	21479172	Further testing is ongoing in patients with the BRAF V600E mutation.	('BRAF', 'Gene', (48, 52))	('patients', 'Species', '9606', (30, 38))	('V600E', 'Var', (53, 58))	('V600E', 'Mutation', 'rs113488022', (53, 58))
22428	21479172	Another exciting inhibitor of BRAF V600E is GSK2118436 which is a highly potent and selective ATP competitive BRAF inhibitor with >100-fold selectivity for mutant (mut) BRAF over wild type (wt) in cell lines.	('BRAF', 'Gene', (169, 173))	('V600E', 'Var', (35, 40))	('GSK2118436', 'Chemical', 'MESH:C561627', (44, 54))	('mutant', 'Var', (156, 162))	('ATP', 'Chemical', 'MESH:D000255', (94, 97))	('GSK', 'molecular_function', 'GO:0050321', ('44', '47'))	('V600E', 'Mutation', 'rs113488022', (35, 40))
22429	21479172	In a Phase I/II, clinical activity with minimal toxicity was observed at multiple dose levels in mutant BRAF tumors.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('toxicity', 'Disease', 'MESH:D064420', (48, 56))	('mutant', 'Var', (97, 103))	('toxicity', 'Disease', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('BRAF', 'Gene', (104, 108))	('tumors', 'Disease', (109, 115))
22432	21479172	Other selective BRAF inhibitors in clinical testing include RAF265 (an inhibitor of ARAF, CRAF and mutant & wildtype BRAF) and XL281 (an inhibitor of CRAF and both wildtype and V600E BRAF).	('CRAF', 'Gene', (150, 154))	('CRAF', 'Gene', '5894', (150, 154))	('and', 'Gene', (123, 126))	('RAF265', 'Gene', (60, 66))	('ARAF', 'Gene', '369', (84, 88))	('V600E', 'Mutation', 'rs113488022', (177, 182))	('ARAF', 'Gene', (84, 88))	('CRAF', 'Gene', (90, 94))	('CRAF', 'Gene', '5894', (90, 94))	('RAF265', 'Chemical', 'MESH:C559019', (60, 66))	('and', 'Var', (173, 176))	('mutant', 'Var', (99, 105))	('CRAF', 'molecular_function', 'GO:0004709', ('90', '94'))	('CRAF', 'molecular_function', 'GO:0004709', ('150', '154'))
22434	21479172	RAF265 is currently being evaluated in the Phase I setting for melanoma.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('RAF265', 'Var', (0, 6))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('RAF265', 'Chemical', 'MESH:C559019', (0, 6))
22435	21479172	While there is great hope that these drugs will successfully halt progress in patients with BRAF mutant melanomas, emerging data suggests that they might be counterproductive for patients with wildtype BRAF.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanomas', 'Phenotype', 'HP:0002861', (104, 113))	('melanomas', 'Disease', 'MESH:D008545', (104, 113))	('BRAF', 'Gene', (92, 96))	('patients', 'Species', '9606', (78, 86))	('mutant', 'Var', (97, 103))	('patients', 'Species', '9606', (179, 187))	('melanomas', 'Disease', (104, 113))
22437	21479172	The MEK inhibitor, AZD6244/ARRY-142886, is an ATP non-competitive, allosteric inhibitor of MEK1/MEK2.	('MEK1', 'molecular_function', 'GO:0004708', ('91', '95'))	('MEK2', 'molecular_function', 'GO:0004708', ('96', '100'))	('MEK1', 'Gene', '5604', (91, 95))	('MEK', 'Gene', (4, 7))	('MEK', 'Gene', (96, 99))	('MEK2', 'Gene', (96, 100))	('MEK1', 'Gene', (91, 95))	('MEK', 'Gene', '5609', (4, 7))	('MEK', 'Gene', '5609', (96, 99))	('MEK2', 'Gene', '5605', (96, 100))	('AZD6244/ARRY-142886', 'Var', (19, 38))	('ATP', 'Chemical', 'MESH:D000255', (46, 49))	('AZD6244', 'Chemical', 'MESH:C517975', (19, 26))	('MEK', 'Gene', (91, 94))	('ARRY-142886', 'Chemical', 'MESH:C517975', (27, 38))	('MEK', 'Gene', '5609', (91, 94))
22438	21479172	In a Phase II trial in melanoma, AZD6244 did not appear superior as compared to temozolomide.	('AZD6244', 'Var', (33, 40))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('AZD6244', 'Chemical', 'MESH:C517975', (33, 40))	('temozolomide', 'Chemical', 'MESH:D000077204', (80, 92))
22441	21479172	Another MEK1/2 inhibitor, GSK1120212, is in Phase II for BRAF-mutant melanoma as well as for melanomas with GNAQ and GNA11 mutations.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('GSK', 'molecular_function', 'GO:0050321', ('26', '29'))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('melanomas', 'Disease', 'MESH:D008545', (93, 102))	('MEK1/2', 'Gene', '5604;5605', (8, 14))	('GSK1120212', 'Chemical', 'MESH:C560077', (26, 36))	('MEK1/2', 'Gene', (8, 14))	('melanomas', 'Disease', (93, 102))	('MEK1', 'molecular_function', 'GO:0004708', ('8', '12'))	('BRAF-mutant', 'Gene', (57, 68))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('mutations', 'Var', (123, 132))	('melanoma', 'Disease', (69, 77))
22450	21479172	BRAF mutations are often accompanied by loss of PTEN or activation of AKT, 2.	('BRAF', 'Disease', (0, 4))	('mutations', 'Var', (5, 14))	('loss', 'NegReg', (40, 44))	('activation', 'PosReg', (56, 66))	('PTEN', 'Protein', (48, 52))	('AKT, 2', 'Gene', '208', (70, 76))
22451	21479172	PTEN silencing is required for malignant transformation of BRAF-mutant melanoctyes in a mouse model, and 3. pharmacological inhibition of both, but not individual, pathways is highly effective in suppressing melanoma disease in pre-clinical models.	('pre', 'molecular_function', 'GO:0003904', ('228', '231'))	('melanoma disease', 'Disease', 'MESH:D008545', (208, 224))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma disease', 'Disease', (208, 224))	('suppressing', 'NegReg', (196, 207))	('mouse', 'Species', '10090', (88, 93))	('inhibition', 'Var', (124, 134))
22452	21479172	There are several potential targets for therapeutic intervention for both pathways (i.e., BRAF and MEK for the MAPK pathway, and PI3K, AKT, and mTOR for the AKT/PI3K pathway).	('AKT', 'Gene', (157, 160))	('MEK', 'Gene', '5609', (99, 102))	('AKT', 'Gene', '207', (135, 138))	('PI3K', 'molecular_function', 'GO:0016303', ('161', '165'))	('MAPK pathway', 'Pathway', (111, 123))	('AKT', 'Gene', (135, 138))	('AKT', 'Gene', '207', (157, 160))	('PI3K', 'molecular_function', 'GO:0016303', ('129', '133'))	('PI3K', 'Var', (129, 133))	('MAPK', 'molecular_function', 'GO:0004707', ('111', '115'))	('mTOR', 'Gene', (144, 148))	('mTOR', 'Gene', '2475', (144, 148))	('MEK', 'Gene', (99, 102))
22454	21479172	Subtype 1.4 is associated with aberrations in both the MAPK and CDK pathways, specifically activation of BRAF and over-expression of CCND1/Cyclin D. The CDK pathway has been suggested to contribute to metastasis of melanoma with BRAF mutations.	('contribute', 'Reg', (187, 197))	('MAPK', 'molecular_function', 'GO:0004707', ('55', '59'))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('BRAF', 'Gene', (229, 233))	('Cyclin', 'Gene', (139, 145))	('Cyclin', 'molecular_function', 'GO:0016538', ('139', '145'))	('metastasis of melanoma', 'Disease', 'MESH:D009362', (201, 223))	('CDK', 'molecular_function', 'GO:0004693', ('64', '67'))	('metastasis of melanoma', 'Disease', (201, 223))	('Cyclin', 'Gene', '5111', (139, 145))	('CDK', 'molecular_function', 'GO:0004693', ('153', '156'))	('mutations', 'Var', (234, 243))
22456	21479172	Unlike primary melanomas, >15% of metastatic melanoma samples with BRAF mutations exhibit amplification of CCND1.	('mutations', 'Var', (72, 81))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('melanoma', 'Disease', (15, 23))	('BRAF', 'Gene', (67, 71))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('melanomas', 'Disease', 'MESH:D008545', (15, 24))	('amplification', 'MPA', (90, 103))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('melanomas', 'Disease', (15, 24))	('CCND1', 'Gene', (107, 112))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
22459	21479172	This subtype is characterized by mutations in the c-KIT pathway/complex, a receptor tyrosine kinase (RTK) that regulates intracellular processes such as cell growth, division, and migration in response to Stem Cell Factor (SCF) activity.	('cell growth', 'CPA', (153, 164))	('SCF', 'Gene', '4254', (223, 226))	('response to Stem Cell Factor', 'biological_process', 'GO:0036215', ('193', '221'))	('mutations', 'Var', (33, 42))	('division', 'CPA', (166, 174))	('receptor tyrosine kinase', 'Gene', (75, 99))	('cell growth', 'biological_process', 'GO:0016049', ('153', '164'))	('KIT', 'molecular_function', 'GO:0005020', ('52', '55'))	('intracellular', 'cellular_component', 'GO:0005622', ('121', '134'))	('Stem Cell Factor', 'Gene', '4254', (205, 221))	('SCF', 'Gene', (223, 226))	('SCF', 'molecular_function', 'GO:0005173', ('223', '226'))	('migration', 'CPA', (180, 189))	('Stem Cell Factor', 'Gene', (205, 221))	('Stem Cell Factor', 'molecular_function', 'GO:0005173', ('205', '221'))	('c-KIT', 'Gene', (50, 55))	('regulates', 'Reg', (111, 120))	('c-KIT', 'Gene', '3815', (50, 55))	('RTK', 'Gene', (101, 104))	('receptor tyrosine kinase', 'Gene', '5979', (75, 99))	('RTK', 'Gene', '5979', (101, 104))
22461	21479172	Activating c-KIT mutations have been implicated in a variety of cancers starting with GIST (Gastrointestinal stromal tumors) and CML (Chronic Myelogenous Leukemia).	('Activating', 'PosReg', (0, 10))	('Gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (92, 123))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('CML', 'Disease', (129, 132))	('GIST', 'Disease', (86, 90))	('Chronic Myelogenous Leukemia', 'Disease', (134, 162))	('Leukemia', 'Phenotype', 'HP:0001909', (154, 162))	('mutations', 'Var', (17, 26))	('Myelogenous Leukemia', 'Phenotype', 'HP:0012324', (142, 162))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('GIST', 'Disease', 'MESH:D046152', (86, 90))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('Gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (92, 123))	('Chronic Myelogenous Leukemia', 'Phenotype', 'HP:0005506', (134, 162))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('KIT', 'molecular_function', 'GO:0005020', ('13', '16'))	('c-KIT', 'Gene', (11, 16))	('c-KIT', 'Gene', '3815', (11, 16))	('Chronic Myelogenous Leukemia', 'Disease', 'MESH:D015464', (134, 162))	('implicated', 'Reg', (37, 47))	('Gastrointestinal stromal tumors', 'Disease', (92, 123))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('CML', 'Disease', 'MESH:D015464', (129, 132))
22463	21479172	Mutations in c-KIT exon 11 (L576P) and exon 13 can be detected by targeted sequencing.	('c-KIT', 'Gene', (13, 18))	('L576P', 'Mutation', 'rs121913513', (28, 33))	('c-KIT', 'Gene', '3815', (13, 18))	('L576P', 'Var', (28, 33))	('KIT', 'molecular_function', 'GO:0005020', ('15', '18'))
22465	21479172	In 2006, Bastian and colleagues conducted a systematic study evaluating the frequency of c-KIT aberrations in melanoma finding mutations and/or copy number increases in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in melanomas on skin without chronic sun damage.	('mucosal', 'Disease', (176, 183))	('copy number', 'Var', (144, 155))	('aberrations', 'Var', (95, 106))	('melanoma', 'Disease', 'MESH:D008545', (210, 218))	('melanomas', 'Disease', 'MESH:D008545', (210, 219))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('melanomas', 'Disease', 'MESH:D008545', (264, 273))	('KIT', 'molecular_function', 'GO:0005020', ('91', '94'))	('melanomas', 'Disease', (264, 273))	('melanomas', 'Disease', (210, 219))	('sun damage', 'Phenotype', 'HP:0000992', (298, 308))	('mutations', 'Var', (127, 136))	('melanoma', 'Disease', 'MESH:D008545', (264, 272))	('sun-damaged', 'Phenotype', 'HP:0000992', (235, 246))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('melanoma', 'Disease', (210, 218))	('melanomas', 'Phenotype', 'HP:0002861', (264, 273))	('c-KIT', 'Gene', (89, 94))	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (210, 219))	('c-KIT', 'Gene', '3815', (89, 94))	('increases', 'PosReg', (156, 165))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))	('melanoma', 'Disease', (264, 272))
22474	21479172	A patient with KIT V560D mutant anal melanoma with isolated lung metastases had a complete response to a combination of Nexavar and Temozolomide.	('isolated lung metastases', 'Disease', 'MESH:D009362', (51, 75))	('anal melanoma', 'Phenotype', 'HP:0030444', (32, 45))	('Temozolomide', 'Chemical', 'MESH:D000077204', (132, 144))	('KIT', 'Gene', (15, 18))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('V560D mutant', 'Var', (19, 31))	('melanoma', 'Disease', (37, 45))	('isolated lung metastases', 'Disease', (51, 75))	('Nexavar', 'Chemical', 'MESH:D000077157', (120, 127))	('V560D', 'Mutation', 'rs121913521', (19, 24))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('KIT', 'molecular_function', 'GO:0005020', ('15', '18'))	('patient', 'Species', '9606', (2, 9))
22475	21479172	A patient with with a KIT PYDHKWE duplication rectal melanoma demonstrated a significant clinical response after 4 weeks of Gleevec treatment.	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('duplication', 'Var', (34, 45))	('melanoma', 'Disease', (53, 61))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('Gleevec', 'Chemical', 'MESH:D000068877', (124, 131))	('KIT', 'molecular_function', 'GO:0005020', ('22', '25'))	('patient', 'Species', '9606', (2, 9))
22476	21479172	A patient with a KIT L576P vaginal mucosal melanoma and extensive metastases to lymph nodes demonstrated a dramatic reduction in metabolic activity with Sprycel.	('metastases', 'Disease', (66, 76))	('L576P', 'Mutation', 'rs121913513', (21, 26))	('metastases', 'Disease', 'MESH:D009362', (66, 76))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('reduction', 'NegReg', (116, 125))	('KIT', 'molecular_function', 'GO:0005020', ('17', '20'))	('vaginal mucosal melanoma', 'Disease', 'MESH:D008545', (27, 51))	('KIT L576P', 'Var', (17, 26))	('patient', 'Species', '9606', (2, 9))	('vaginal mucosal melanoma', 'Disease', (27, 51))	('metabolic activity', 'MPA', (129, 147))
22479	21479172	All patients in this trial had specific mutations in c-KIT and/or amplification of c-KIT as well as acral, mucosal, or chronic sun damaged melanoma (which often demonstrate c-KIT aberrations).	('amplification', 'MPA', (66, 79))	('c-KIT', 'Gene', (53, 58))	('c-KIT', 'Gene', (173, 178))	('sun damaged', 'Phenotype', 'HP:0000992', (127, 138))	('c-KIT', 'Gene', '3815', (173, 178))	('c-KIT', 'Gene', '3815', (53, 58))	('c-KIT', 'Gene', (83, 88))	('acral', 'Disease', (100, 105))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('mutations', 'Var', (40, 49))	('c-KIT', 'Gene', '3815', (83, 88))	('patients', 'Species', '9606', (4, 12))	('KIT', 'molecular_function', 'GO:0005020', ('85', '88'))	('KIT', 'molecular_function', 'GO:0005020', ('55', '58'))	('KIT', 'molecular_function', 'GO:0005020', ('175', '178'))	('mucosal', 'Disease', (107, 114))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('sun damage', 'Phenotype', 'HP:0000992', (127, 137))
22484	21479172	Five of 10 patients with KIT mutations demonstrated a partial response to imatinib treatment, three of whom also had amplified KIT.	('KIT', 'molecular_function', 'GO:0005020', ('127', '130'))	('mutations', 'Var', (29, 38))	('imatinib', 'Chemical', 'MESH:D000068877', (74, 82))	('KIT', 'molecular_function', 'GO:0005020', ('25', '28'))	('patients', 'Species', '9606', (11, 19))	('KIT', 'Gene', (25, 28))
22486	21479172	Mutations in GNAQ have been found in >85 of blue naevi, >50% of malignant blue naevi and ~50% of ocular melanoma of the uvea.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('malignant blue naevi', 'Disease', (64, 84))	('naevi', 'Phenotype', 'HP:0003764', (79, 84))	('ocular melanoma of the uvea', 'Disease', 'MESH:C536494', (97, 124))	('GNAQ', 'Gene', (13, 17))	('naevi', 'Phenotype', 'HP:0003764', (49, 54))	('Mutations', 'Var', (0, 9))	('blue naevi', 'Phenotype', 'HP:0100814', (74, 84))	('blue naevi', 'Phenotype', 'HP:0100814', (44, 54))	('found', 'Reg', (28, 33))	('ocular melanoma of the uvea', 'Phenotype', 'HP:0007716', (97, 124))	('ocular melanoma of the uvea', 'Disease', (97, 124))	('blue naevi', 'Disease', (44, 54))
22487	21479172	While GNAQ is primarily viewed as relevant to uveal melanoma, anecdotal reports have found mutations in this gene in non-uveal melanoma patients as well.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (121, 135))	('uveal melanoma', 'Disease', 'MESH:C536494', (46, 60))	('non-uveal melanoma', 'Disease', (117, 135))	('non-uveal melanoma', 'Disease', 'MESH:C536494', (117, 135))	('patients', 'Species', '9606', (136, 144))	('uveal melanoma', 'Disease', (46, 60))	('mutations', 'Var', (91, 100))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('uveal melanoma', 'Phenotype', 'HP:0007716', (46, 60))	('uveal melanoma', 'Disease', 'MESH:C536494', (121, 135))
22490	21479172	Also like GNAQ, although GNA11 is primarily viewed as relevant to uveal melanoma, anecdotal reports have found mutations in this gene in non-uveal melanoma patients.	('patients', 'Species', '9606', (156, 164))	('uveal melanoma', 'Disease', (66, 80))	('mutations', 'Var', (111, 120))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (141, 155))	('non-uveal melanoma', 'Disease', 'MESH:C536494', (137, 155))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (141, 155))	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('non-uveal melanoma', 'Disease', (137, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))
22498	21479172	The Q61R and Q61L NRAS mutations can be detected by targeted sequencing.	('NRAS', 'Gene', '4893', (18, 22))	('Q61R', 'Var', (4, 8))	('Q61L', 'Mutation', 'rs11554290', (13, 17))	('Q61R', 'Mutation', 'rs11554290', (4, 8))	('Q61L', 'Var', (13, 17))	('NRAS', 'Gene', (18, 22))
22499	21479172	Subtype 4.1 is characterized by mutations in NRAS, which are observed in approximately 20% of melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('melanomas', 'Disease', 'MESH:D008545', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('observed', 'Reg', (61, 69))	('mutations', 'Var', (32, 41))	('NRAS', 'Gene', (45, 49))	('melanomas', 'Disease', (94, 103))	('NRAS', 'Gene', '4893', (45, 49))
22507	21479172	This subtype is characterized by aberrations in MITF.	('aberrations', 'Var', (33, 44))	('MITF', 'Gene', '4286', (48, 52))	('MITF', 'Gene', (48, 52))
22509	21479172	Furthermore, MITF amplification correlated with decreased overall patient survival.	('MITF', 'Gene', '4286', (13, 17))	('MITF', 'Gene', (13, 17))	('decreased', 'NegReg', (48, 57))	('patient', 'Species', '9606', (66, 73))	('amplification', 'Var', (18, 31))
22510	21479172	In addition, MITF amplification was associated with increased resistance to chemotherapy suggesting that it may serve as a good target for therapeutic intervention.	('increased', 'PosReg', (52, 61))	('MITF', 'Gene', '4286', (13, 17))	('MITF', 'Gene', (13, 17))	('resistance to chemotherapy', 'MPA', (62, 88))	('amplification', 'Var', (18, 31))
22514	21479172	This subtype is associated with abnormalities in the AKT/PI3K signaling pathway which plays a pivotal role in modulating cellular functions such as proliferation, growth, survival, and metabolism in response to extracellular cues mediated by cell surface receptors and G-proteins.	('survival', 'CPA', (171, 179))	('extracellular', 'cellular_component', 'GO:0005576', ('211', '224'))	('cell surface', 'cellular_component', 'GO:0009986', ('242', '254'))	('growth', 'CPA', (163, 169))	('signaling pathway', 'biological_process', 'GO:0007165', ('62', '79'))	('AKT', 'Gene', '207', (53, 56))	('metabolism', 'biological_process', 'GO:0008152', ('185', '195'))	('abnormalities', 'Var', (32, 45))	('PI3K', 'molecular_function', 'GO:0016303', ('57', '61'))	('AKT', 'Gene', (53, 56))	('PI3K signaling', 'biological_process', 'GO:0014065', ('57', '71'))
22517	21479172	The balance between PIP2 and PIP3 is maintained by PTEN (Phosphatase and TENsin homolog) and PI3K, a kinase that converts PIP2 into PIP3.	('PIP3', 'Chemical', '-', (29, 33))	('Phosphatase', 'molecular_function', 'GO:0016791', ('57', '68'))	('Phosphatase and TENsin homolog', 'cellular_component', 'GO:1990455', ('57', '87'))	('PI3K', 'molecular_function', 'GO:0016303', ('93', '97'))	('PIP2', 'Chemical', 'MESH:D019269', (122, 126))	('PI3K', 'Var', (93, 97))	('PTEN', 'Var', (51, 55))	('PIP3', 'Chemical', '-', (132, 136))	('PIP2', 'Chemical', 'MESH:D019269', (20, 24))
22521	21479172	Aberrations in AKT levels can be detected by copy number analysis.	('Aberrations', 'Var', (0, 11))	('AKT', 'Gene', '207', (15, 18))	('AKT', 'Gene', (15, 18))
22525	21479172	Inactivation of PTEN is associated with a variety of cancers including glioblastoma, melanoma, and carcinomas of prostate, breast, and endometrial origins.	('associated', 'Reg', (24, 34))	('glioblastoma', 'Disease', (71, 83))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('carcinomas of prostate', 'Disease', 'MESH:D011472', (99, 121))	('carcinomas of prostate', 'Phenotype', 'HP:0012125', (99, 121))	('Inactivation', 'Var', (0, 12))	('breast', 'Disease', (123, 129))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('endometrial origins', 'Disease', (135, 154))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('carcinomas of prostate', 'Disease', (99, 121))	('glioblastoma', 'Disease', 'MESH:D005909', (71, 83))	('PTEN', 'Gene', (16, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))
22529	21479172	Subtype 6.1 specifically deals with dysregulation of PTEN in the absence of BRAF mutations which leads us to consider AKT/PI3K inhibitors as potential therapies for this subtype.	('BRAF', 'Gene', (76, 80))	('AKT', 'Gene', '207', (118, 121))	('dysregulation', 'MPA', (36, 49))	('AKT', 'Gene', (118, 121))	('mutations', 'Var', (81, 90))	('PI3K', 'molecular_function', 'GO:0016303', ('122', '126'))
22530	21479172	Subtype 6.2 consists of aberrations in Akt, a protein kinase of the Protein Kinase B (PKB) family that plays a central role in coordinating cellular behavior with signals from a variety of extracellular pathways.	('Protein Kinase B', 'Gene', '2185', (68, 84))	('Akt', 'Gene', '207', (39, 42))	('aberrations', 'Var', (24, 35))	('PKB', 'Gene', '2185', (86, 89))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('PKB', 'Gene', (86, 89))	('extracellular', 'cellular_component', 'GO:0005576', ('189', '202'))	('Akt', 'Gene', (39, 42))	('Protein Kinase B', 'Gene', (68, 84))
22537	21479172	AKT dysregulation has been observed to occur in conjunction with mutations in BRAF, and this combination has been classified as subtype 1.3.	('AKT', 'Gene', (0, 3))	('BRAF', 'Gene', (78, 82))	('AKT', 'Gene', '207', (0, 3))	('mutations', 'Var', (65, 74))
22539	21479172	Subtype 6.2 specifically deals with dysregulation of Akt in the absence of BRAF mutations, which leads us to consider AKT/PI3K inhibitors as potential therapies for this subtype.	('AKT', 'Gene', '207', (118, 121))	('Akt', 'Gene', '207', (53, 56))	('mutations', 'Var', (80, 89))	('dysregulation', 'MPA', (36, 49))	('AKT', 'Gene', (118, 121))	('BRAF', 'Gene', (75, 79))	('Akt', 'Gene', (53, 56))	('PI3K', 'molecular_function', 'GO:0016303', ('122', '126'))
22540	21479172	Subtype 6.3 is characterized by aberrations in PI3K, a lipid kinases that regulates growth through the AKT/PI3K pathway.	('AKT', 'Gene', '207', (103, 106))	('PI3K', 'Gene', (47, 51))	('PI3K', 'molecular_function', 'GO:0016303', ('107', '111'))	('AKT', 'Gene', (103, 106))	('aberrations', 'Var', (32, 43))	('lipid', 'Chemical', 'MESH:D008055', (55, 60))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))
22541	21479172	As described above, PI3K acts antagonistically with the lipid phosphatase, PTEN, to tip the balance between two signaling molecules, PIP2 and PIP3.	('phosphatase', 'molecular_function', 'GO:0016791', ('62', '73'))	('PI3K', 'Var', (20, 24))	('lipid', 'Chemical', 'MESH:D008055', (56, 61))	('tip', 'PosReg', (84, 87))	('signaling', 'biological_process', 'GO:0023052', ('112', '121'))	('PIP2', 'Chemical', 'MESH:D019269', (133, 137))	('PI3K', 'molecular_function', 'GO:0016303', ('20', '24'))	('PIP3', 'Chemical', '-', (142, 146))	('balance between two signaling molecules', 'MPA', (92, 131))
22546	21479172	PI3K expression is higher in malignant melanomas (as compared to blue nevi) and is correlated with a worse prognosis.	('blue nevi', 'Phenotype', 'HP:0100814', (65, 74))	('PI3K', 'Var', (0, 4))	('expression', 'MPA', (5, 15))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('nevi', 'Phenotype', 'HP:0003764', (70, 74))	('malignant melanomas', 'Disease', 'MESH:D008545', (29, 48))	('higher', 'PosReg', (19, 25))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanomas', 'Phenotype', 'HP:0002861', (39, 48))	('malignant melanomas', 'Phenotype', 'HP:0002861', (29, 48))	('malignant melanomas', 'Disease', (29, 48))
22550	21479172	Results of these trials are anxiously awaited though they may be mixed because none of them are focused exclusively on patients with PTEN aberrations (or aberrations in the AKT/PI3K pathway).	('AKT', 'Gene', '207', (173, 176))	('patients', 'Species', '9606', (119, 127))	('aberrations', 'Var', (138, 149))	('AKT', 'Gene', (173, 176))	('PTEN', 'Gene', (133, 137))	('PI3K', 'molecular_function', 'GO:0016303', ('177', '181'))
22556	21479172	This subtype is characterized by aberrations in the G1/S Cyclin/CDK pathways.	('Cyclin', 'Gene', (57, 63))	('CDK', 'molecular_function', 'GO:0004693', ('64', '67'))	('aberrations', 'Var', (33, 44))	('Cyclin', 'molecular_function', 'GO:0016538', ('57', '63'))	('Cyclin', 'Gene', '5111', (57, 63))
22562	21479172	Targeted sequencing and Comparative Genomic Hybridization (CGH) assays are available for ARF/INK4A, copy number analysis for CDK4, and IHC for CCND1/Cyclin D. This subtype is associated with aberrations in ARF/INK4A, which encodes for p16INK4, a cell cycle regulator, and p14ARF, a regulator of the p53 pathway (http://www.ncbi.nlm.nih.gov/gene/1029).	('associated', 'Reg', (175, 185))	('CDK4', 'Gene', (125, 129))	('Cyclin', 'Gene', (149, 155))	('CDK4', 'Gene', '1019', (125, 129))	('ARF/INK4A', 'Gene', '1029', (89, 98))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('246', '266'))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('246', '266'))	('aberrations', 'Var', (191, 202))	('p16INK4', 'Gene', '1029', (235, 242))	('Cyclin', 'molecular_function', 'GO:0016538', ('149', '155'))	('p14ARF', 'Gene', (272, 278))	('ARF/INK4A', 'Gene', (89, 98))	('Cyclin', 'Gene', '5111', (149, 155))	('ARF/INK4A', 'Gene', '1029', (206, 215))	('CDK', 'molecular_function', 'GO:0004693', ('125', '128'))	('p14ARF', 'Gene', '1029', (272, 278))	('p16INK4', 'Gene', (235, 242))	('ARF/INK4A', 'Gene', (206, 215))
22566	21479172	ARF/INK4A mutations in melanoma typically occur in the p16INK4 gene either alone or in combination with p14ARF, suggesting that p16INK4 is the relevant tumor suppressor.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('p14ARF', 'Gene', '1029', (104, 110))	('ARF/INK4A', 'Gene', '1029', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('occur', 'Reg', (42, 47))	('p16INK4', 'Gene', '1029', (55, 62))	('p16INK4', 'Gene', '1029', (128, 135))	('p16INK4', 'Gene', (55, 62))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('tumor', 'Disease', (152, 157))	('melanoma', 'Disease', (23, 31))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('152', '168'))	('ARF/INK4A', 'Gene', (0, 9))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('tumor suppressor', 'biological_process', 'GO:0051726', ('152', '168'))	('p16INK4', 'Gene', (128, 135))	('p14ARF', 'Gene', (104, 110))	('mutations', 'Var', (10, 19))
22567	21479172	p16INK4 is deleted in approximately 50% of melanomas and inactivated by point mutations in about 10%.	('melanomas', 'Disease', (43, 52))	('p16INK4', 'Gene', '1029', (0, 7))	('p16INK4', 'Gene', (0, 7))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanomas', 'Phenotype', 'HP:0002861', (43, 52))	('melanomas', 'Disease', 'MESH:D008545', (43, 52))	('point mutations', 'Var', (72, 87))	('inactivated', 'NegReg', (57, 68))
22569	21479172	However, some families harbor mutations only in p14ARF suggesting a role in melanoma progression.	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('p14ARF', 'Gene', (48, 54))	('mutations', 'Var', (30, 39))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('p14ARF', 'Gene', '1029', (48, 54))
22571	21479172	This subtype is characterized by aberrations in CDK4, which drives passage from G1 to S phase in complex with Cyclin D by phosphorylating and inactivating the retinoblastoma protein (RB) inhibitor.	('S phase', 'biological_process', 'GO:0051320', ('86', '93'))	('Cyclin', 'Gene', (110, 116))	('CDK4', 'Gene', '1019', (48, 52))	('inactivating', 'NegReg', (142, 154))	('retinoblastoma', 'Disease', 'MESH:D012175', (159, 173))	('retinoblastoma', 'Disease', (159, 173))	('CDK', 'molecular_function', 'GO:0004693', ('48', '51'))	('Cyclin', 'molecular_function', 'GO:0016538', ('110', '116'))	('aberrations', 'Var', (33, 44))	('Cyclin', 'Gene', '5111', (110, 116))	('retinoblastoma', 'Phenotype', 'HP:0009919', (159, 173))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('CDK4', 'Gene', (48, 52))
22572	21479172	CDK4 amplification is relatively common in acral and mucosal melanomas.	('mucosal melanomas', 'Disease', 'MESH:D008545', (53, 70))	('amplification', 'Var', (5, 18))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('CDK', 'molecular_function', 'GO:0004693', ('0', '3'))	('common', 'Reg', (33, 39))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('CDK4', 'Gene', (0, 4))	('CDK4', 'Gene', '1019', (0, 4))	('mucosal melanomas', 'Disease', (53, 70))
22573	21479172	Additionally, a substitution of Cysteine for Arginine at the 24th codon of CDK4 is observed in a small percentage of melanoma-prone families.	('Cysteine', 'Chemical', 'MESH:D003545', (32, 40))	('substitution', 'Var', (16, 28))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('Arginine', 'MPA', (45, 53))	('CDK', 'molecular_function', 'GO:0004693', ('75', '78'))	('Arginine', 'Chemical', 'MESH:D001120', (45, 53))	('CDK4', 'Gene', (75, 79))	('CDK4', 'Gene', '1019', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
22575	21479172	Subtype 7.3 is characterized by aberrations in Cyclin D, which drives passage from G1 to S in complex with CDK4 and CDK6.	('drives', 'Reg', (63, 69))	('CDK4', 'Gene', '1019', (107, 111))	('CDK', 'molecular_function', 'GO:0004693', ('116', '119'))	('CDK6', 'Gene', (116, 120))	('Cyclin', 'Gene', (47, 53))	('CDK6', 'Gene', '1021', (116, 120))	('aberrations', 'Var', (32, 43))	('CDK', 'molecular_function', 'GO:0004693', ('107', '110'))	('Cyclin', 'molecular_function', 'GO:0016538', ('47', '53'))	('Cyclin', 'Gene', '5111', (47, 53))	('CDK4', 'Gene', (107, 111))
22576	21479172	Cyclin D is commonly found to be aberrant in cancer in terms of mutation, amplification, and/or overexpression.	('mutation', 'Var', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Cyclin', 'Gene', '5111', (0, 6))	('Cyclin', 'molecular_function', 'GO:0016538', ('0', '6'))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('overexpression', 'PosReg', (96, 110))	('Cyclin', 'Gene', (0, 6))	('cancer', 'Disease', (45, 51))	('amplification', 'MPA', (74, 87))
22578	21479172	Amplification of the Cyclin D gene has been observed in tumors such as head and neck carcinomas, pituitary tumors, esophageal squamous cell carcinoma, and breast cancer.	('neck carcinomas', 'Disease', (80, 95))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('pituitary tumors', 'Disease', (97, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (115, 149))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('Cyclin', 'Gene', (21, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('observed', 'Reg', (44, 52))	('tumors', 'Disease', (107, 113))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('breast cancer', 'Disease', (155, 168))	('Cyclin', 'molecular_function', 'GO:0016538', ('21', '27'))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('Amplification', 'Var', (0, 13))	('Cyclin', 'Gene', '5111', (21, 27))	('head and neck carcinomas', 'Phenotype', 'HP:0012288', (71, 95))	('pituitary tumors', 'Disease', 'MESH:D010911', (97, 113))	('neck carcinomas', 'Disease', 'MESH:D006258', (80, 95))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('esophageal squamous cell carcinoma', 'Disease', (115, 149))	('neck', 'cellular_component', 'GO:0044326', ('80', '84'))
22579	21479172	In melanoma, genomic amplifications of Cyclin D are primarily found in acral lentiginous melanoma (~44%), and to a lesser degree in other types (11% for lentigo maligna and 6% for superficial spreading melanoma).	('Cyclin', 'Gene', (39, 45))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('lentigo maligna', 'Phenotype', 'HP:0012059', (153, 168))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('acral lentiginous melanoma', 'Disease', (71, 97))	('Cyclin', 'molecular_function', 'GO:0016538', ('39', '45'))	('Cyclin', 'Gene', '5111', (39, 45))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('lentigo maligna', 'Disease', (153, 168))	('acral lentiginous melanoma', 'Phenotype', 'HP:0012060', (71, 97))	('genomic amplifications', 'Var', (13, 35))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', (202, 210))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('lentigo maligna', 'Disease', 'MESH:D018327', (153, 168))	('found', 'Reg', (62, 67))	('superficial spreading melanoma', 'Phenotype', 'HP:0012057', (180, 210))	('acral lentiginous melanoma', 'Disease', 'MESH:D007911', (71, 97))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))
22580	21479172	Antisense-mediated knockdown of CCND1 triggers apoptosis in vitro and shrinkage of xenografts in mice, suggesting that Cyclin D plays a role in melanoma tumorigenesis and so may be a good target for therapeutic intervention.	('Cyclin', 'Gene', '5111', (119, 125))	('apoptosis', 'biological_process', 'GO:0097194', ('47', '56'))	('Antisense-mediated knockdown', 'Var', (0, 28))	('apoptosis', 'biological_process', 'GO:0006915', ('47', '56'))	('knockdown', 'Var', (19, 28))	('apoptosis', 'CPA', (47, 56))	('CCND1', 'Gene', (32, 37))	('Cyclin', 'molecular_function', 'GO:0016538', ('119', '125'))	('mice', 'Species', '10090', (97, 101))	('melanoma tumor', 'Disease', (144, 158))	('Cyclin', 'Gene', (119, 125))	('melanoma tumor', 'Disease', 'MESH:D008545', (144, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('shrinkage', 'CPA', (70, 79))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('role', 'Reg', (136, 140))
22582	21479172	Tumors with mutations that only affect p16INK4 could potentially be addressed with inhibitors of CDK4/6.	('CDK', 'molecular_function', 'GO:0004693', ('97', '100'))	('CDK4/6', 'Gene', (97, 103))	('CDK4/6', 'Gene', '1019;1021', (97, 103))	('mutations', 'Var', (12, 21))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('p16INK4', 'Gene', '1029', (39, 46))	('p16INK4', 'Gene', (39, 46))
22588	21479172	IHC can detect aberrations in the level of BCL-2, and targeted sequencing can detect P53 mutations.	('BCL-2', 'Gene', (43, 48))	('P53', 'Gene', (85, 88))	('P53', 'Gene', '7157', (85, 88))	('mutations', 'Var', (89, 98))	('BCL-2', 'molecular_function', 'GO:0015283', ('43', '48'))	('BCL-2', 'Gene', '596', (43, 48))	('detect', 'Reg', (78, 84))
22589	21479172	Subtype 8.1 is characterized by aberrations in Bcl-2, a key inhibitor of cell apoptosis.	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('aberrations', 'Var', (32, 43))	('Bcl-2', 'Gene', (47, 52))	('Bcl-2', 'Gene', '596', (47, 52))	('Bcl-2', 'molecular_function', 'GO:0015283', ('47', '52'))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))
22596	21479172	Subtype 8.2 is characterized by mutations in the tumor suppressor, p53.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('49', '65'))	('p53', 'Gene', (67, 70))	('tumor', 'Disease', (49, 54))	('mutations', 'Var', (32, 41))	('tumor suppressor', 'biological_process', 'GO:0051726', ('49', '65'))
22597	21479172	p53 is mutated in greater than half of all human cancers but in only about 10% of melanomas.	('p53', 'Gene', (0, 3))	('melanomas', 'Disease', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('melanomas', 'Disease', 'MESH:D008545', (82, 91))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('mutated', 'Var', (7, 14))	('cancers', 'Disease', (49, 56))	('human', 'Species', '9606', (43, 48))
22600	21479172	Consistent with this, there are sporadic examples of human melanoma cases with mutated p19ARF.	('mutated', 'Var', (79, 86))	('p19ARF', 'Gene', '1029', (87, 93))	('p19ARF', 'Gene', (87, 93))	('p19', 'cellular_component', 'GO:0070743', ('87', '90'))	('human', 'Species', '9606', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
22602	21479172	Mutant p53 cell lines appear to be refractory to drugs like cisplatin, vincristine and camptothecin.	('camptothecin', 'Chemical', 'MESH:D002166', (87, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))	('Mutant', 'Var', (0, 6))	('vincristine', 'Chemical', 'MESH:D014750', (71, 82))	('p53', 'Gene', (7, 10))
22676	33726696	Some studies indicate monosomy 3 and gene expression profiling are reliable prognostic indicator for metastatic potential in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (125, 139))	('uveal melanoma', 'Disease', 'MESH:C536494', (125, 139))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('monosomy', 'Var', (22, 30))	('metastatic potential', 'CPA', (101, 121))	('uveal melanoma', 'Disease', (125, 139))	('gene expression', 'biological_process', 'GO:0010467', ('37', '52'))
22699	33726696	Some studies retorted that uveal melanomas with chromosome 3 monosomy showed faster and greater tumor regression after plaque radiotherapy and thermotherapy than melanomas with disomy 3, the authors believed tumor regression is an adverse prognostic factor as chromosome 3 monosomy, which is highly lethal.	('melanomas', 'Disease', 'MESH:D008545', (162, 171))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanomas', 'Disease', (162, 171))	('chromosome', 'cellular_component', 'GO:0005694', ('48', '58'))	('uveal melanomas', 'Disease', 'MESH:C536494', (27, 42))	('melanomas', 'Disease', 'MESH:D008545', (33, 42))	('tumor', 'Disease', (208, 213))	('mos', 'Gene', '4342', (52, 55))	('melanomas', 'Disease', (33, 42))	('mos', 'Gene', (52, 55))	('uveal melanoma', 'Phenotype', 'HP:0007716', (27, 41))	('melanomas', 'Phenotype', 'HP:0002861', (162, 171))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('uveal melanomas', 'Disease', (27, 42))	('monosomy', 'Var', (61, 69))	('tumor', 'Disease', (96, 101))	('uveal melanomas', 'Phenotype', 'HP:0007716', (27, 42))	('mos', 'Gene', '4342', (264, 267))	('chromosome', 'cellular_component', 'GO:0005694', ('260', '270'))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('mos', 'Gene', (264, 267))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))
22701	33726696	What is interesting is that some academics demonstrated that GEP class1 UM tumors tend to regress more rapidly than class2 tumors after plaque radiotherapy.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('GEP class1 UM', 'Var', (61, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('regress', 'CPA', (90, 97))	('tumors', 'Disease', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
22730	33138120	Moreover, narrowing or closure of the capillary lumen causes retinal ischemia.	('retinal ischemia', 'Phenotype', 'HP:0002637', (61, 77))	('retinal ischemia', 'Disease', (61, 77))	('narrowing', 'Var', (10, 19))	('retinal ischemia', 'Disease', 'MESH:D007511', (61, 77))
22792	33138120	on 93 patients demonstrated OCTA structural and microvascular changes to have significant impact on visual acuity, with worse visual acuity associated with the enlargement of the FAZ and reduced vessel density at the superficial and deep plexuses.	('vascular changes', 'Phenotype', 'HP:0002597', (53, 69))	('changes', 'Var', (62, 69))	('reduced', 'NegReg', (187, 194))	('enlargement', 'PosReg', (160, 171))	('patients', 'Species', '9606', (6, 14))	('visual', 'MPA', (100, 106))	('OCTA', 'Chemical', '-', (28, 32))	('FAZ', 'cellular_component', 'GO:0120119', ('179', '182'))	('impact', 'Reg', (90, 96))
22823	32864546	Aberrant RNA Splicing in Cancer RNA splicing, the enzymatic process of removing segments of premature RNA to produce mature RNA, is a key mediator of proteome diversity and regulator of gene expression.	('RNA Splicing', 'biological_process', 'GO:0008380', ('9', '21'))	('RNA', 'cellular_component', 'GO:0005562', ('9', '12'))	('Aberrant', 'Var', (0, 8))	('RNA splicing', 'biological_process', 'GO:0008380', ('32', '44'))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Cancer', 'Disease', (25, 31))	('gene expression', 'biological_process', 'GO:0010467', ('186', '201'))	('RNA', 'cellular_component', 'GO:0005562', ('102', '105'))	('Cancer', 'Disease', 'MESH:D009369', (25, 31))	('RNA', 'cellular_component', 'GO:0005562', ('32', '35'))	('RNA', 'cellular_component', 'GO:0005562', ('124', '127'))
22825	32864546	These findings, in combination with the discovery of recurrent change-of-function mutations in splicing factors in a variety of cancers, suggest that alterations in splicing are drivers of tumorigenesis.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('tumor', 'Disease', (189, 194))	('splicing factor', 'Gene', '10569', (95, 110))	('cancers', 'Disease', (128, 135))	('splicing', 'biological_process', 'GO:0045292', ('165', '173'))	('splicing', 'MPA', (165, 173))	('splicing factor', 'Gene', (95, 110))	('mutations', 'Var', (82, 91))	('alterations', 'Var', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('splicing', 'biological_process', 'GO:0045292', ('95', '103'))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
22829	32864546	These include mutations in DNA that abolish or generate splicing regulatory sequences in cis, mutations in genes encoding RNA splicing regulators, changes in the expression of splicing factors by oncogenic processes, and alterations in chromatin state that modify splicing patterns (Figure 1).	('DNA', 'Gene', (27, 30))	('splicing regulatory', 'MPA', (56, 75))	('mutations', 'Var', (94, 103))	('alterations', 'Reg', (221, 232))	('RNA', 'cellular_component', 'GO:0005562', ('122', '125'))	('splicing factor', 'Gene', (176, 191))	('splicing', 'biological_process', 'GO:0045292', ('56', '64'))	('chromatin', 'cellular_component', 'GO:0000785', ('236', '245'))	('changes', 'Reg', (147, 154))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))	('expression', 'MPA', (162, 172))	('splicing', 'biological_process', 'GO:0045292', ('264', '272'))	('splicing patterns', 'MPA', (264, 281))	('abolish', 'NegReg', (36, 43))	('splicing', 'biological_process', 'GO:0045292', ('176', '184'))	('RNA splicing', 'biological_process', 'GO:0008380', ('122', '134'))	('mutations', 'Var', (14, 23))	('splicing factor', 'Gene', '10569', (176, 191))
22845	32864546	Efforts to analyze the transcriptomes of tumor versus normal tissue, such as The Cancer Genome Atlas, have revealed that many cancers exhibit aberrant splicing, including changes in usage of annotated transcript isoforms and increased use of aberrant unannotated splicing events.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('Cancer', 'Phenotype', 'HP:0002664', (81, 87))	('aberrant', 'Var', (142, 150))	('as', 'Gene', '112935892', (98, 100))	('as', 'Gene', '112935892', (74, 76))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Cancer', 'Disease', (81, 87))	('tumor', 'Disease', (41, 46))	('changes', 'Reg', (171, 178))	('usage', 'MPA', (182, 187))	('splicing', 'MPA', (151, 159))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('as', 'Gene', '112935892', (230, 232))	('splicing', 'biological_process', 'GO:0045292', ('263', '271'))	('Cancer', 'Disease', 'MESH:D009369', (81, 87))	('splicing', 'biological_process', 'GO:0045292', ('151', '159'))
22847	32864546	Moreover, the number of AS changes in a tumor was inversely correlated with the number of driver mutations, and AS switches displayed some mutual exclusion with driver mutations, suggesting that AS may serve as independent tumorigenic processes.	('mutations', 'Var', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('as', 'Gene', '112935892', (208, 210))	('AS', 'Gene', '112935892', (24, 26))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('AS', 'Gene', '112935892', (112, 114))	('tumor', 'Disease', (40, 45))	('as', 'Gene', '112935892', (47, 49))	('AS', 'Gene', '112935892', (195, 197))
22849	32864546	Aberrant splicing in cancer has also been linked to DNA mutations that abolish ss or generate novel ss.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('mutations', 'Var', (56, 65))	('as', 'Gene', '112935892', (29, 31))	('splicing', 'biological_process', 'GO:0045292', ('9', '17'))	('Aberrant splicing', 'Var', (0, 17))	('abolish', 'NegReg', (71, 78))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('linked', 'Reg', (42, 48))
22850	32864546	The largest effort yet to characterize mutations altering ss in cis utilized whole-exome sequencing of more than 8,000 tumors across 33 cancer types and identified that many mutations that alter ss were previously misannotated as missense or silent mutations.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('mutations', 'Var', (39, 48))	('cancer', 'Disease', (136, 142))	('mutations', 'Var', (174, 183))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('as', 'Gene', '112935892', (227, 229))
22851	32864546	Given that critical regulatory splice sequences are far from the consensus 5' or 3' ss, it is important to further integrate data from whole-genome sequencing with RNA-seq for a more comprehensive model of how cancer-associated mutations impact splicing in cis.	('splicing', 'MPA', (245, 253))	('RNA', 'cellular_component', 'GO:0005562', ('164', '167'))	('impact', 'Reg', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('mutations', 'Var', (228, 237))	('splicing', 'biological_process', 'GO:0045292', ('245', '253'))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('as', 'Gene', '112935892', (217, 219))	('cancer', 'Disease', (210, 216))
22852	32864546	Recurrent heterozygous change-of-function mutations affecting specific residues (or hot spots) in splicing factors have been described in cancer (Figure 2).	('cancer', 'Disease', (138, 144))	('change-of-function', 'PosReg', (23, 41))	('splicing factor', 'Gene', '10569', (98, 113))	('splicing', 'biological_process', 'GO:0045292', ('98', '106'))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('splicing factor', 'Gene', (98, 113))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
22854	32864546	Several SF3B1-mutant residues are enriched in specific disease subtypes.	('as', 'Gene', '112935892', (59, 61))	('SF3B1-mutant', 'Gene', (8, 20))	('residues', 'Var', (21, 29))
22855	32864546	For example, mutations at R625 and E902 appear specific to uveal melanoma (UM) and bladder cancer, respectively.	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('E902', 'Var', (35, 39))	('bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('bladder cancer', 'Disease', 'MESH:D001749', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('bladder cancer', 'Disease', (83, 97))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
22856	32864546	SF3B1 mutational hot spots occur within the HEAT domains [a repeated motif consisting of two alpha helices linked by a short loop found in Huntingtin, elongation factor 3 (EF3), PP2A, and yeast TOR1] and possibly affect protein-protein interactions.	('mutational', 'Var', (6, 16))	('interactions', 'Interaction', (236, 248))	('SF3B1', 'Gene', (0, 5))	('protein-protein', 'Protein', (220, 235))	('protein', 'cellular_component', 'GO:0003675', ('228', '235'))	('TOR1', 'Gene', '853529', (194, 198))	('protein', 'cellular_component', 'GO:0003675', ('220', '227'))	('yeast', 'Species', '4932', (188, 193))	('TOR1', 'Gene', (194, 198))	('affect', 'Reg', (213, 219))
22857	32864546	Global changes in splicing have been observed in cells harboring SF3B1 mutations and are also seen in mouse cells upon introduction of the Sf3b1K700E mutation.	('splicing', 'biological_process', 'GO:0045292', ('18', '26'))	('changes', 'Reg', (7, 14))	('SF3B1', 'Gene', (65, 70))	('mutations', 'Var', (71, 80))	('splicing', 'MPA', (18, 26))	('mouse', 'Species', '10090', (102, 107))
22858	32864546	Cancer-associated SF3B1 mutations have repeatedly been found to alter 3' ss via preference of intron-proximal cryptic 3' ss over normal sites.	('SF3B1', 'Gene', (18, 23))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('alter', 'Reg', (64, 69))	('mutations', 'Var', (24, 33))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('preference', 'PosReg', (80, 90))	("3' ss", 'MPA', (70, 75))	('as', 'Gene', '112935892', (7, 9))
22860	32864546	To this end, it has been demonstrated that the introduction of SF3B1 mutations in yeast (homolog Hsh155p) alters the physical interaction with Prp5p (DDX46 in humans), an ATP-dependent RNA helicase important in stabilizing the U2 snRNP/pre-mRNA interaction.	('humans', 'Species', '9606', (159, 165))	('DDX46', 'Gene', (150, 155))	('Prp5p', 'Gene', (143, 148))	('ATP', 'Chemical', 'MESH:D000255', (171, 174))	('SF3B1', 'Gene', (63, 68))	('as', 'Gene', '112935892', (194, 196))	('as', 'Gene', '112935892', (17, 19))	('physical interaction', 'MPA', (117, 137))	('mutations', 'Var', (69, 78))	('DDX46', 'Gene', '9879', (150, 155))	('snRNP', 'Gene', (230, 235))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('227', '235'))	('alters', 'Reg', (106, 112))	('snRNP', 'Gene', '57819', (230, 235))	('Prp5p', 'Gene', '852539', (143, 148))	('RNA', 'cellular_component', 'GO:0005562', ('185', '188'))	('Hsh155p', 'Gene', '855332', (97, 104))	('yeast', 'Species', '4932', (82, 87))	('snRNP', 'molecular_function', 'GO:0003734', ('230', '235'))	('Hsh155p', 'Gene', (97, 104))	('as', 'Gene', '112935892', (84, 86))	('pre', 'molecular_function', 'GO:0003904', ('236', '239'))
22861	32864546	Confirmation of physical interactions between mutant SF3B1 and DDX46 in mammalian homologs will be critical.	('mammalian', 'Species', '9606', (72, 81))	('DDX46', 'Gene', '9879', (63, 68))	('DDX46', 'Gene', (63, 68))	('mutant', 'Var', (46, 52))	('SF3B1', 'Gene', (53, 58))
22862	32864546	Of note, the change in 3' ss preference associated with mutant SF3B1 is distinct from splicing changes observed with genetic loss or pharmacologic inhibition of SF3B1.	('SF3B1', 'Gene', (63, 68))	('mutant', 'Var', (56, 62))	('genetic loss', 'Disease', (117, 129))	('as', 'Gene', '112935892', (40, 42))	('genetic loss', 'Disease', 'MESH:D030342', (117, 129))	('splicing', 'biological_process', 'GO:0045292', ('86', '94'))	("3' ss preference", 'MPA', (23, 39))
22863	32864546	In MDS, SF3B1 mutations are highly enriched within a low-risk subtype known as MDS with ring sideroblasts (MDS-RS).	('as', 'Gene', '112935892', (76, 78))	('MDS', 'Disease', (107, 110))	('MDS', 'Disease', 'MESH:D009190', (107, 110))	('MDS-RS', 'Disease', 'MESH:D009190', (107, 113))	('MDS', 'Phenotype', 'HP:0002863', (107, 110))	('MDS-RS', 'Disease', (107, 113))	('as', 'Gene', '112935892', (101, 103))	('MDS', 'Phenotype', 'HP:0002863', (79, 82))	('MDS', 'Phenotype', 'HP:0002863', (3, 6))	('MDS', 'Disease', (3, 6))	('ring sideroblasts', 'Phenotype', 'HP:0004828', (88, 105))	('MDS', 'Disease', 'MESH:D009190', (3, 6))	('mutations', 'Var', (14, 23))	('SF3B1', 'Gene', (8, 13))	('MDS', 'Disease', (79, 82))	('MDS', 'Disease', 'MESH:D009190', (79, 82))
22864	32864546	Although the exact link between SF3B1 mutations and MDS-RS is unknown, clinical diagnostic criteria for MDS-RS incorporate mutation status.	('MDS-RS', 'Disease', 'MESH:D009190', (52, 58))	('MDS-RS', 'Disease', (52, 58))	('MDS-RS', 'Disease', 'MESH:D009190', (104, 110))	('MDS', 'Phenotype', 'HP:0002863', (104, 107))	('MDS', 'Phenotype', 'HP:0002863', (52, 55))	('MDS-RS', 'Disease', (104, 110))	('mutations', 'Var', (38, 47))	('SF3B1', 'Gene', (32, 37))
22865	32864546	In contrast to the favorable outcome of SF3B1 mutations in MDS, SF3B1 mutations in CLL are associated with adverse outcome and chemoresistance.	('mutations', 'Var', (70, 79))	('SF3B1', 'Gene', (64, 69))	('CLL', 'Phenotype', 'HP:0005550', (83, 86))	('as', 'Gene', '112935892', (8, 10))	('as', 'Gene', '112935892', (91, 93))	('CLL', 'Gene', (83, 86))	('chemoresistance', 'CPA', (127, 142))	('MDS', 'Phenotype', 'HP:0002863', (59, 62))	('MDS', 'Disease', (59, 62))	('MDS', 'Disease', 'MESH:D009190', (59, 62))
22866	32864546	Finally, in the context of UM, SF3B1 mutations are associated with disomy 3 and intermediate risk.	('UM', 'Phenotype', 'HP:0007716', (27, 29))	('as', 'Gene', '112935892', (51, 53))	('disomy 3', 'Disease', (67, 75))	('mutations', 'Var', (37, 46))	('SF3B1', 'Gene', (31, 36))	('intermediate risk', 'Disease', (80, 97))
22867	32864546	SRSF2, which promotes exon splicing, is found to be mutated in chronic myelomonocytic leukemia (CMML), AML, high-risk MDS, myeloproliferative neoplasms, and a small percentage of patients with disomy 3 UM.	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (63, 94))	('CMML', 'Disease', (96, 100))	('CMML', 'Phenotype', 'HP:0012325', (96, 100))	('myeloproliferative neoplasms', 'Disease', (123, 151))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (123, 151))	('UM', 'Phenotype', 'HP:0007716', (202, 204))	('MDS', 'Phenotype', 'HP:0002863', (118, 121))	('leukemia', 'Phenotype', 'HP:0001909', (86, 94))	('patients', 'Species', '9606', (179, 187))	('AML', 'Disease', 'MESH:D015470', (103, 106))	('chronic myelomonocytic leukemia', 'Disease', (63, 94))	('AML', 'Disease', (103, 106))	('mutated', 'Var', (52, 59))	('AML', 'Phenotype', 'HP:0004808', (103, 106))	('MDS', 'Disease', 'MESH:D009190', (118, 121))	('SRSF2', 'Gene', '6427', (0, 5))	('neoplasms', 'Phenotype', 'HP:0002664', (142, 151))	('splicing', 'biological_process', 'GO:0045292', ('27', '35'))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (63, 94))	('MDS', 'Disease', (118, 121))	('SRSF2', 'Gene', (0, 5))	('exon splicing', 'MPA', (22, 35))	('CMML', 'Disease', 'MESH:D054429', (96, 100))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (123, 151))
22869	32864546	SRSF2 mutations concentrate on residue P95 (Figure 2) and confer altered RNA-binding preference that favors recognition of C-rich CCNG over G-rich ESEs and leads to altered splicing of hundreds of mRNAs.	('As', 'Gene', '112935892', (200, 202))	('altered', 'Reg', (165, 172))	('splicing', 'biological_process', 'GO:0045292', ('173', '181'))	('RNA-binding', 'Interaction', (73, 84))	('favors', 'PosReg', (101, 107))	('recognition', 'MPA', (108, 119))	('RNA', 'cellular_component', 'GO:0005562', ('73', '76'))	('SRSF2', 'Gene', (0, 5))	('CCNG', 'Gene', '900', (130, 134))	('RNA-binding', 'molecular_function', 'GO:0003723', ('73', '84'))	('P95', 'Gene', '4683', (39, 42))	('SRSF2', 'Gene', '6427', (0, 5))	('CCNG', 'Gene', (130, 134))	('P95', 'Gene', (39, 42))	('mutations', 'Var', (6, 15))
22870	32864546	One key alteration in SRSF2-mutant cells is altered splicing of EZH2 mRNA, encoding a protein that regulates histone methylation that is also affected by loss-of-function mutations in myeloid neoplasms.	('SRSF2', 'Gene', (22, 27))	('histone methylation', 'biological_process', 'GO:0016571', ('109', '128'))	('histone methylation', 'MPA', (109, 128))	('loss-of-function', 'NegReg', (154, 170))	('regulates', 'Reg', (99, 108))	('myeloid neoplasms', 'Disease', (184, 201))	('SRSF2', 'Gene', '6427', (22, 27))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (184, 201))	('altered', 'Reg', (44, 51))	('mutations', 'Var', (171, 180))	('splicing', 'biological_process', 'GO:0045292', ('52', '60'))	('neoplasms', 'Phenotype', 'HP:0002664', (192, 201))	('splicing', 'MPA', (52, 60))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('EZH2', 'Gene', (64, 68))	('EZH2', 'Gene', '2146', (64, 68))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (184, 201))
22871	32864546	The aberrant EZH2 mRNA produced by mutant SRSF2 is targeted for nonsense-mediated decay, and mutations in EZH2 and SRSF2 are significantly mutually exclusive in MDS.	('EZH2', 'Gene', (13, 17))	('EZH2', 'Gene', '2146', (13, 17))	('EZH2', 'Gene', (106, 110))	('SRSF2', 'Gene', '6427', (115, 120))	('EZH2', 'Gene', '2146', (106, 110))	('MDS', 'Phenotype', 'HP:0002863', (161, 164))	('mutant', 'Var', (35, 41))	('SRSF2', 'Gene', (42, 47))	('MDS', 'Disease', (161, 164))	('MDS', 'Disease', 'MESH:D009190', (161, 164))	('SRSF2', 'Gene', '6427', (42, 47))	('SRSF2', 'Gene', (115, 120))
22872	32864546	Hot spot mutations in RNA splicing factors occur with mutual exclusivity across the myeloid neoplasms.	('RNA', 'cellular_component', 'GO:0005562', ('22', '25'))	('exclusivity across the myeloid neoplasms', 'Disease', 'MESH:C580202', (61, 101))	('splicing factor', 'Gene', '10569', (26, 41))	('exclusivity across the myeloid neoplasms', 'Disease', (61, 101))	('neoplasms', 'Phenotype', 'HP:0002664', (92, 101))	('mutations', 'Var', (9, 18))	('splicing factor', 'Gene', (26, 41))	('RNA splicing', 'biological_process', 'GO:0008380', ('22', '34'))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (84, 101))
22874	32864546	Mutations across SF3B1 and SRSF2 confer distinct effects on RNA splicing.	('SRSF2', 'Gene', '6427', (27, 32))	('effects', 'Reg', (49, 56))	('RNA', 'cellular_component', 'GO:0005562', ('60', '63'))	('SF3B1', 'Gene', (17, 22))	('RNA splicing', 'MPA', (60, 72))	('SRSF2', 'Gene', (27, 32))	('Mutations', 'Var', (0, 9))	('RNA splicing', 'biological_process', 'GO:0008380', ('60', '72'))
22875	32864546	Likewise, mutations in U2AF1, required for recognition of the AG-dependent 3' ss recognized by the major spliceosome, are exclusive to SF3B1 and SRSF2 mutations in myeloid neoplasms.	('myeloid neoplasms', 'Disease', (164, 181))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (164, 181))	('SRSF2', 'Gene', '6427', (145, 150))	('U2AF1', 'Gene', '7307', (23, 28))	('spliceosome', 'cellular_component', 'GO:0005681', ('105', '116'))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (164, 181))	('U2AF1', 'Gene', (23, 28))	('SF3B1', 'Gene', (135, 140))	('neoplasms', 'Phenotype', 'HP:0002664', (172, 181))	('mutations', 'Var', (10, 19))	('SRSF2', 'Gene', (145, 150))	('mutations', 'Var', (151, 160))	('U2AF', 'cellular_component', 'GO:0089701', ('23', '27'))
22876	32864546	U2AF1 mutations predominantly affect S34 and U157 in the zinc fingers (Figure 2).	('S34', 'Var', (37, 40))	('U2AF', 'cellular_component', 'GO:0089701', ('0', '4'))	('U157', 'Var', (45, 49))	('U2AF1', 'Gene', '7307', (0, 5))	('affect', 'Reg', (30, 36))	('mutations', 'Var', (6, 15))	('U2AF1', 'Gene', (0, 5))
22877	32864546	These mutations alter recognition of the 3' ss, but mutations at each site are associated with differences in splicing events based on the nucleotide surrounding the 3' AG dinucleotide.	('mutations', 'Var', (52, 61))	('alter', 'Reg', (16, 21))	('as', 'Gene', '112935892', (79, 81))	('differences', 'Reg', (95, 106))	('recognition', 'MPA', (22, 33))	('splicing', 'biological_process', 'GO:0045292', ('110', '118'))	('splicing events', 'MPA', (110, 125))	('as', 'Gene', '112935892', (127, 129))	('mutations', 'Var', (6, 15))
22878	32864546	The seemingly disparate effects of mutations in SF3B1, SRSF2, and U2AF1 on splicing led to a search for convergent effects of these mutations in processes unrelated to splicing.	('U2AF1', 'Gene', (66, 71))	('U2AF1', 'Gene', '7307', (66, 71))	('splicing', 'biological_process', 'GO:0045292', ('168', '176'))	('splicing', 'MPA', (75, 83))	('SRSF2', 'Gene', '6427', (55, 60))	('SF3B1', 'Gene', (48, 53))	('U2AF', 'cellular_component', 'GO:0089701', ('66', '70'))	('splicing', 'biological_process', 'GO:0045292', ('75', '83'))	('SRSF2', 'Gene', (55, 60))	('mutations', 'Var', (35, 44))
22879	32864546	To this end, cells bearing mutations in U2AF1 as well as SRSF2 have been reported to have augmented the formation of R-loops, three-stranded nucleic acid structures composed of DNA-RNA hybrids.	('mutations', 'Var', (27, 36))	('U2AF', 'cellular_component', 'GO:0089701', ('40', '44'))	('R-loops', 'MPA', (117, 124))	('SRSF2', 'Gene', (57, 62))	('augmented', 'PosReg', (90, 99))	('RNA', 'cellular_component', 'GO:0005562', ('181', '184'))	('DNA', 'cellular_component', 'GO:0005574', ('177', '180'))	('nucleic acid', 'cellular_component', 'GO:0005561', ('141', '153'))	('as', 'Gene', '112935892', (54, 56))	('as', 'Gene', '112935892', (46, 48))	('SRSF2', 'Gene', '6427', (57, 62))	('formation', 'MPA', (104, 113))	('three-stranded nucleic acid structures', 'MPA', (126, 164))	('U2AF1', 'Gene', '7307', (40, 45))	('U2AF1', 'Gene', (40, 45))	('formation', 'biological_process', 'GO:0009058', ('104', '113'))
22881	32864546	Although it is not clear how mutant U2AF1 augments R-loops, mutant SRSF2-induced increased transcriptional pausing appears to increase R-loop generation.	('R-loop generation', 'MPA', (135, 152))	('R-loops', 'MPA', (51, 58))	('SRSF2', 'Gene', (67, 72))	('U2AF1', 'Gene', (36, 41))	('as', 'Gene', '112935892', (86, 88))	('as', 'Gene', '112935892', (131, 133))	('mutant', 'Var', (29, 35))	('transcriptional pausing', 'MPA', (91, 114))	('SRSF2', 'Gene', '6427', (67, 72))	('U2AF1', 'Gene', '7307', (36, 41))	('augments', 'PosReg', (42, 50))	('mutant', 'Var', (60, 66))	('U2AF', 'cellular_component', 'GO:0089701', ('36', '40'))
22882	32864546	These data provide a potential unifying effect of mutant U2AF1 and SRSF2 with important therapeutic implications.	('SRSF2', 'Gene', (67, 72))	('SRSF2', 'Gene', '6427', (67, 72))	('U2AF1', 'Gene', (57, 62))	('mutant', 'Var', (50, 56))	('U2AF1', 'Gene', '7307', (57, 62))	('U2AF', 'cellular_component', 'GO:0089701', ('57', '61'))
22883	32864546	In addition to an effect on R-loops, one recent report suggested that the U2AF1 S34F mutation may alter interactions with the cleavage and polyadenylation (CP) machinery, resulting in increased use of a distal CP site and longer 3' untranslated regions (UTRs).	('distal CP site', 'MPA', (203, 217))	("3' untranslated regions", 'MPA', (229, 252))	('alter', 'Reg', (98, 103))	('use', 'MPA', (194, 197))	('S34F', 'Var', (80, 84))	('S34F', 'Mutation', 'rs371769427', (80, 84))	('as', 'Gene', '112935892', (189, 191))	('interactions', 'Interaction', (104, 116))	('U2AF1', 'Gene', (74, 79))	('U2AF1', 'Gene', '7307', (74, 79))	('U2AF', 'cellular_component', 'GO:0089701', ('74', '78'))
22884	32864546	In particular, altered CP of the mRNA encoding the autophagy protein ATG7 was found to result in decreased ATG7, impaired autophagy, and accumulation of secondary mutations.	('accumulation', 'PosReg', (137, 149))	('autophagy', 'biological_process', 'GO:0006914', ('51', '60'))	('ATG7', 'Gene', (107, 111))	('as', 'Gene', '112935892', (75, 77))	('impaired', 'NegReg', (113, 121))	('ATG7', 'Gene', '10533', (69, 73))	('autophagy', 'biological_process', 'GO:0016236', ('122', '131'))	('autophagy', 'biological_process', 'GO:0016236', ('51', '60'))	('altered', 'Var', (15, 22))	('secondary mutations', 'CPA', (153, 172))	('ATG7', 'Gene', '10533', (107, 111))	('autophagy', 'biological_process', 'GO:0006914', ('122', '131'))	('autophagy', 'CPA', (122, 131))	('as', 'Gene', '112935892', (102, 104))	('ATG7', 'Gene', (69, 73))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
22885	32864546	Future efforts will need to confirm if other mutations in U2AF1 or other splicing factors similarly alter CP usage, 3' UTR length, or autophagy.	('mutations', 'Var', (45, 54))	('U2AF1', 'Gene', (58, 63))	('U2AF', 'cellular_component', 'GO:0089701', ('58', '62'))	('splicing', 'biological_process', 'GO:0045292', ('73', '81'))	('U2AF1', 'Gene', '7307', (58, 63))	('splicing factor', 'Gene', (73, 88))	('autophagy', 'biological_process', 'GO:0016236', ('134', '143'))	('alter', 'Reg', (100, 105))	('splicing factor', 'Gene', '10569', (73, 88))	('autophagy', 'biological_process', 'GO:0006914', ('134', '143'))	('autophagy', 'CPA', (134, 143))	("3' UTR length", 'CPA', (116, 129))
22886	32864546	Until recently, recurrent mutations in SF3B1, U2AF1, and SRSF2 were the only splicing factors known to harbor hot spot mutations.	('splicing factor', 'Gene', '10569', (77, 92))	('SRSF2', 'Gene', (57, 62))	('U2AF', 'cellular_component', 'GO:0089701', ('46', '50'))	('U2AF1', 'Gene', (46, 51))	('U2AF1', 'Gene', '7307', (46, 51))	('mutations', 'Var', (26, 35))	('SRSF2', 'Gene', '6427', (57, 62))	('splicing factor', 'Gene', (77, 92))	('SF3B1', 'Gene', (39, 44))	('splicing', 'biological_process', 'GO:0045292', ('77', '85'))
22887	32864546	However, a recent reanalysis of whole-exome sequencing data from 119 patients with 33 solid tumor types has identified recurrent hot spot mutations in PHF5A (a key U2 snRNP component that interacts with SF3B1) and the hnRNP proteins hn-RNPCL1 and PCBP1 (Figure 2).	('PCBP1', 'Gene', '5093', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('patients', 'Species', '9606', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('hnRNP', 'Gene', '3183', (218, 223))	('as', 'Gene', '112935892', (105, 107))	('PCBP1', 'Gene', (247, 252))	('snRNP', 'Gene', (167, 172))	('hnRNP', 'cellular_component', 'GO:0030530', ('218', '223'))	('snRNP', 'Gene', '57819', (167, 172))	('PHF5A', 'Gene', (151, 156))	('hnRNP', 'Gene', (218, 223))	('mutations', 'Var', (138, 147))	('PHF5A', 'Gene', '84844', (151, 156))	('hnRNP', 'molecular_function', 'GO:0008436', ('218', '223'))	('interacts', 'Interaction', (188, 197))	('tumor', 'Disease', (92, 97))	('snRNP', 'molecular_function', 'GO:0003734', ('167', '172'))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('164', '172'))
22889	32864546	In addition to the mutually exclusive mutations in SF3B1, SRSF2, and U2AF1 in myeloid malignancies, loss-of-function mutations in ZRSR2, essential for 3' ss recognition in U12-type splicing, were also identified in early reports (Figure 2).	('mutations', 'Var', (117, 126))	('U2AF1', 'Gene', (69, 74))	('U2AF1', 'Gene', '7307', (69, 74))	('SRSF2', 'Gene', '6427', (58, 63))	('U2AF', 'cellular_component', 'GO:0089701', ('69', '73'))	('loss-of-function', 'NegReg', (100, 116))	('splicing', 'biological_process', 'GO:0045292', ('181', '189'))	('myeloid malignancies', 'Disease', 'MESH:D009369', (78, 98))	('SRSF2', 'Gene', (58, 63))	('ZRSR2', 'Gene', (130, 135))	('myeloid malignancies', 'Disease', (78, 98))	('ZRSR2', 'Gene', '8233', (130, 135))
22890	32864546	ZRSR2 mutations are enriched in MDS, a form of AML known as blastic plasmacytoid dendritic cell neoplasms, in a small percentage of T cell acute lymphoblastic leukemias, and in thyroid cancers.	('lymphoblastic leukemias', 'Disease', 'MESH:D054198', (145, 168))	('leukemias', 'Phenotype', 'HP:0001909', (159, 168))	('MDS', 'Phenotype', 'HP:0002863', (32, 35))	('as', 'Gene', '112935892', (101, 103))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('blastic plasmacytoid dendritic cell neoplasms', 'Disease', 'MESH:D008258', (60, 105))	('ZRSR2', 'Gene', '8233', (0, 5))	('as', 'Gene', '112935892', (153, 155))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('MDS', 'Disease', 'MESH:D009190', (32, 35))	('as', 'Gene', '112935892', (57, 59))	('thyroid cancers', 'Disease', 'MESH:D013964', (177, 192))	('mutations', 'Var', (6, 15))	('lymphoblastic leukemias', 'Phenotype', 'HP:0005526', (145, 168))	('MDS', 'Disease', (32, 35))	('AML', 'Disease', 'MESH:D015470', (47, 50))	('small percentage of T cell', 'Phenotype', 'HP:0005403', (112, 138))	('AML', 'Disease', (47, 50))	('lymphoblastic leukemias', 'Disease', (145, 168))	('ZRSR2', 'Gene', (0, 5))	('neoplasms', 'Phenotype', 'HP:0002664', (96, 105))	('AML', 'Phenotype', 'HP:0004808', (47, 50))	('as', 'Gene', '112935892', (62, 64))	('T cell acute lymphoblastic leukemias', 'Phenotype', 'HP:0006727', (132, 168))	('as', 'Gene', '112935892', (70, 72))	('as', 'Gene', '112935892', (166, 168))	('leukemia', 'Phenotype', 'HP:0001909', (159, 167))	('blastic plasmacytoid dendritic cell neoplasms', 'Disease', (60, 105))	('thyroid cancers', 'Disease', (177, 192))	('acute lymphoblastic leukemias', 'Phenotype', 'HP:0006721', (139, 168))
22891	32864546	ZRSR2 is affected by nonsense or frameshift mutations, which presumably result in loss of ZRSR2.	('affected', 'Reg', (9, 17))	('ZRSR2', 'Gene', (90, 95))	('ZRSR2', 'Gene', '8233', (90, 95))	('frameshift mutations', 'Var', (33, 53))	('loss', 'NegReg', (82, 86))	('nonsense', 'Var', (21, 29))	('ZRSR2', 'Gene', (0, 5))	('ZRSR2', 'Gene', '8233', (0, 5))
22892	32864546	Coincident with the role of ZRSR2 in the minor spliceosome, mutation or suppression of ZRSR2 appears to result in retention of U12-type introns.	('ZRSR2', 'Gene', (28, 33))	('mutation', 'Var', (60, 68))	('ZRSR2', 'Gene', (87, 92))	('retention', 'biological_process', 'GO:0051235', ('114', '123'))	('ZRSR2', 'Gene', '8233', (28, 33))	('suppression', 'NegReg', (72, 83))	('ZRSR2', 'Gene', '8233', (87, 92))	('U12-type', 'Protein', (127, 135))	('spliceosome', 'cellular_component', 'GO:0005681', ('47', '58'))
22893	32864546	Splicing events altered by ZRSR2 mutations appear to impact expression of MAPK pathway members and E2F transcription factors.	('impact', 'Reg', (53, 59))	('expression', 'MPA', (60, 70))	('ZRSR2', 'Gene', '8233', (27, 32))	('E2F', 'Protein', (99, 102))	('transcription', 'biological_process', 'GO:0006351', ('103', '116'))	('ZRSR2', 'Gene', (27, 32))	('MAPK', 'molecular_function', 'GO:0004707', ('74', '78'))	('Splicing', 'biological_process', 'GO:0045292', ('0', '8'))	('mutations', 'Var', (33, 42))	('MAPK pathway', 'Pathway', (74, 86))	('Splicing events', 'MPA', (0, 15))
22894	32864546	Further work defining how ZRSR2 mutations relate to the mutually exclusive mutations in other splicing factors in MDS may provide novel clues to a shared disease mechanism.	('MDS', 'Disease', (114, 117))	('MDS', 'Disease', 'MESH:D009190', (114, 117))	('MDS', 'Phenotype', 'HP:0002863', (114, 117))	('splicing factor', 'Gene', (94, 109))	('splicing', 'biological_process', 'GO:0045292', ('94', '102'))	('mutations', 'Var', (32, 41))	('splicing factor', 'Gene', '10569', (94, 109))	('ZRSR2', 'Gene', (26, 31))	('ZRSR2', 'Gene', '8233', (26, 31))	('as', 'Gene', '112935892', (158, 160))
22895	32864546	Loss-of-function mutations also prominently affect the splicing factor RBM10, an RNA-binding protein that generally represses splicing (Figure 2).	('Loss-of-function', 'NegReg', (0, 16))	('splicing factor', 'Gene', (55, 70))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('RNA-binding', 'molecular_function', 'GO:0003723', ('81', '92'))	('RNA-binding protein', 'Gene', '5725', (81, 100))	('splicing', 'MPA', (126, 134))	('RNA-binding protein', 'Gene', (81, 100))	('splicing factor', 'Gene', '10569', (55, 70))	('splicing', 'biological_process', 'GO:0045292', ('126', '134'))	('splicing', 'biological_process', 'GO:0045292', ('55', '63'))	('mutations', 'Var', (17, 26))	('RNA', 'cellular_component', 'GO:0005562', ('81', '84'))
22896	32864546	RBM10 mutations are present in lung and bladder adenocarcinomas as well as fatal nonanaplastic thyroid carcinomas.	('as', 'Gene', '112935892', (72, 74))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (95, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (95, 113))	('present', 'Reg', (20, 27))	('bladder adenocarcinomas', 'Disease', (40, 63))	('thyroid carcinomas', 'Disease', (95, 113))	('bladder adenocarcinomas', 'Disease', 'MESH:D001749', (40, 63))	('as', 'Gene', '112935892', (111, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('as', 'Gene', '112935892', (89, 91))	('as', 'Gene', '112935892', (64, 66))	('as', 'Gene', '112935892', (61, 63))	('RBM10', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
22897	32864546	RBM10 mutations are associated with exon inclusion while RBM10 loss has been shown to promote the proliferation of mouse and human immortalized cells.	('as', 'Gene', '112935892', (69, 71))	('as', 'Gene', '112935892', (20, 22))	('exon inclusion', 'Var', (36, 50))	('RBM10', 'Gene', (0, 5))	('mouse', 'Species', '10090', (115, 120))	('human', 'Species', '9606', (125, 130))	('promote', 'PosReg', (86, 93))	('RBM10', 'Gene', (57, 62))	('proliferation', 'CPA', (98, 111))	('loss', 'NegReg', (63, 67))	('mutations', 'Var', (6, 15))
22900	32864546	In lung and thyroid cancers, RBM10 is frequently mutated with commonly mutated kinases (KRAS, BRAF, EGFR, and PI3K), although the biological significance of these concurrent mutations remains unknown.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutated', 'Var', (49, 56))	('EGFR', 'Gene', '1956', (100, 104))	('lung', 'Disease', (3, 7))	('BRAF', 'Gene', (94, 98))	('PI3K', 'molecular_function', 'GO:0016303', ('110', '114'))	('as', 'Gene', '112935892', (82, 84))	('EGFR', 'Gene', (100, 104))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))	('KRAS', 'Gene', (88, 92))	('RBM10', 'Gene', (29, 34))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('KRAS', 'Gene', '3845', (88, 92))	('thyroid cancers', 'Disease', (12, 27))	('BRAF', 'Gene', '673', (94, 98))	('thyroid cancers', 'Disease', 'MESH:D013964', (12, 27))
22901	32864546	Other splicing factors recurrently affected by loss-of-function mutations are shown in Figure 2.	('loss-of-function', 'NegReg', (47, 63))	('splicing factor', 'Gene', '10569', (6, 21))	('mutations', 'Var', (64, 73))	('splicing factor', 'Gene', (6, 21))	('splicing', 'biological_process', 'GO:0045292', ('6', '14'))
22902	32864546	The spectrum and frequency of these mutations across cancer types are best described by.	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Disease', (53, 59))	('mutations', 'Var', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (53, 59))
22903	32864546	Although hot spot mutations have called attention to the concept of splicing factors as potential oncogenes, the expression of splicing factors in tumors changes frequently and may be driven by oncogenic signaling.	('expression', 'MPA', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('signaling', 'biological_process', 'GO:0023052', ('204', '213'))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('called attention', 'Phenotype', 'HP:0000736', (33, 49))	('changes', 'Reg', (154, 161))	('splicing factor', 'Gene', '10569', (127, 142))	('splicing factor', 'Gene', '10569', (68, 83))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('splicing', 'biological_process', 'GO:0045292', ('127', '135'))	('as', 'Gene', '112935892', (85, 87))	('splicing factor', 'Gene', (68, 83))	('splicing factor', 'Gene', (127, 142))	('splicing', 'biological_process', 'GO:0045292', ('68', '76'))	('mutations', 'Var', (18, 27))
22912	32864546	BUD31 knockdown led to intron retention and cell death in MYC cells, but not in HER2- or EGFR-transformed cells.	('HER2', 'Gene', '2064', (80, 84))	('EGFR', 'Gene', (89, 93))	('HER2', 'Gene', (80, 84))	('intron', 'MPA', (23, 29))	('BUD31', 'Gene', '8896', (0, 5))	('retention', 'biological_process', 'GO:0051235', ('30', '39'))	('cell death', 'biological_process', 'GO:0008219', ('44', '54'))	('knockdown', 'Var', (6, 15))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('death', 'Disease', 'MESH:D003643', (49, 54))	('BUD31', 'Gene', (0, 5))	('death', 'Disease', (49, 54))	('EGFR', 'Gene', '1956', (89, 93))
22917	32864546	Alternative and aberrant splicing of numerous members of cancer-associated cell growth and death pathways (MAPK, PI3K-AKT, HIPPO, and apoptosis) have been described.	('aberrant splicing', 'Var', (16, 33))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('AKT', 'Gene', '207', (118, 121))	('cell growth', 'Pathway', (75, 86))	('death', 'Disease', (91, 96))	('death', 'Disease', 'MESH:D003643', (91, 96))	('apoptosis', 'biological_process', 'GO:0006915', ('134', '143'))	('cancer', 'Disease', (57, 63))	('apoptosis', 'CPA', (134, 143))	('HIPPO', 'Disease', (123, 128))	('AKT', 'Gene', (118, 121))	('as', 'Gene', '112935892', (64, 66))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cell growth', 'biological_process', 'GO:0016049', ('75', '86'))	('splicing', 'biological_process', 'GO:0045292', ('25', '33'))	('MAPK', 'molecular_function', 'GO:0004707', ('107', '111'))	('PI3K', 'molecular_function', 'GO:0016303', ('113', '117'))	('apoptosis', 'biological_process', 'GO:0097194', ('134', '143'))
22921	32864546	The variant that includes exon 10 enhances kinase activity and affinity for downstream kinases MEK1/2, while inclusion of exon 8b has the opposite effect.	('as', 'Gene', '112935892', (90, 92))	('as', 'Gene', '112935892', (131, 133))	('MEK1', 'molecular_function', 'GO:0004708', ('95', '99'))	('kinase activity', 'molecular_function', 'GO:0016301', ('43', '58'))	('enhances', 'PosReg', (34, 42))	('MEK1/2', 'Gene', '5604;5605', (95, 101))	('as', 'Gene', '112935892', (46, 48))	('variant', 'Var', (4, 11))	('affinity', 'MPA', (63, 71))	('MEK1/2', 'Gene', (95, 101))
22922	32864546	Aside from these annotated isoforms, several pathological aberrant forms of wild-type and mutant BRAF have been described.	('BRAF', 'Gene', '673', (97, 101))	('mutant', 'Var', (90, 96))	('As', 'Gene', '112935892', (0, 2))	('BRAF', 'Gene', (97, 101))
22925	32864546	This variant results in the production of a stable truncated BRAFV600E protein lacking the RAS-binding domain (RBD).	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('lacking', 'NegReg', (79, 86))	('BRAFV600E', 'Var', (61, 70))	('BRAFV600E', 'Mutation', 'rs113488022', (61, 70))	('AS', 'Gene', '112935892', (92, 94))
22935	32864546	For example, the variant of EGFR known as variant EGFRvIII contains an in-frame deletion of exons 2-7 and can be generated by rearrangement or altered pre-mRNA processing.	('EGFR', 'Gene', '1956', (28, 32))	('deletion', 'Var', (80, 88))	('EGFR', 'Gene', (28, 32))	('as', 'Gene', '112935892', (39, 41))	('EGFR', 'Gene', '1956', (50, 54))	('EGFR', 'Gene', (50, 54))	('EGFR', 'molecular_function', 'GO:0005006', ('28', '32'))	('mRNA processing', 'biological_process', 'GO:0006397', ('155', '170'))	('pre', 'molecular_function', 'GO:0003904', ('151', '154'))
22937	32864546	Another EGFR isoform produced by skipping exon 4, de4 EGFR, is also constitutively active and promotes metastases (Figure 3).	('EGFR', 'molecular_function', 'GO:0005006', ('54', '58'))	('EGFR', 'molecular_function', 'GO:0005006', ('8', '12'))	('promotes', 'PosReg', (94, 102))	('skipping exon', 'Var', (33, 46))	('metastases', 'Disease', 'MESH:D009362', (103, 113))	('EGFR', 'Gene', '1956', (8, 12))	('EGFR', 'Gene', '1956', (54, 58))	('metastases', 'Disease', (103, 113))	('EGFR', 'Gene', (8, 12))	('EGFR', 'Gene', (54, 58))
22940	32864546	MET exon 14 alterations have been detected in a variety of cancers and confer sensitivity to MET inhibitors.	('detected', 'Reg', (34, 42))	('sensitivity', 'MPA', (78, 89))	('MET', 'Gene', '79811', (0, 3))	('alterations', 'Var', (12, 23))	('MET', 'Gene', '79811', (93, 96))	('MET', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('MET', 'Gene', (93, 96))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))
22944	32864546	Lastly, splice variants resulting from increased hnRNPA2 expression induce a positive-feedback loop that promotes MAPK signaling to maintain tumor cells.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('promotes', 'PosReg', (105, 113))	('induce', 'Reg', (68, 74))	('MAPK signaling', 'MPA', (114, 128))	('hnRNPA2', 'Gene', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('splice variants', 'Var', (8, 23))	('positive-feedback loop', 'MPA', (77, 99))	('as', 'Gene', '112935892', (1, 3))	('as', 'Gene', '112935892', (44, 46))	('MAPK', 'molecular_function', 'GO:0004707', ('114', '118'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('114', '128'))	('hnRNPA2', 'Gene', '3181', (49, 56))
22946	32864546	The rationale for these approaches is supported by the observation that cancer cells bearing heterozygous change-of-function mutations in SF3B1, SRSF2, and U2AF1 require the wild-type allele for survival and are expressed in a mutually exclusive manner, in part, due to a synthetic lethal interaction between these mutations.	('mutations', 'Var', (125, 134))	('SRSF2', 'Gene', '6427', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('SF3B1', 'Gene', (138, 143))	('change-of-function', 'PosReg', (106, 124))	('U2AF1', 'Gene', (156, 161))	('U2AF1', 'Gene', '7307', (156, 161))	('U2AF', 'cellular_component', 'GO:0089701', ('156', '160'))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('SRSF2', 'Gene', (145, 150))	('cancer', 'Disease', (72, 78))
22947	32864546	Furthermore, given that SF3B1 is an essential protein, cancer cells with partial copy number loss of SF3B1 are preferentially sensitive to inhibition of residual SF3B1.	('preferentially', 'PosReg', (111, 125))	('sensitive', 'Reg', (126, 135))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('partial copy number loss', 'Var', (73, 97))	('SF3B1', 'Gene', (101, 106))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
22950	32864546	These agents informed the development of synthetic analogs E7107 and H3B-8800.	('H3B', 'Gene', '8351', (69, 72))	('E7107', 'Var', (59, 64))	('E7107', 'Chemical', 'MESH:C557411', (59, 64))	('H3B', 'Gene', (69, 72))
22951	32864546	Structures of the SF3B complex bound to pladienolide B or E7107 have shown that these molecules bind in the branch point binding pocket of the SF3B complex and thereby block splicing (Figure 4a).	('block', 'NegReg', (168, 173))	('splicing', 'MPA', (174, 182))	('pladienolide B', 'Chemical', 'MESH:C522342', (40, 54))	('E7107', 'Var', (58, 63))	('splicing', 'biological_process', 'GO:0045292', ('174', '182'))	('binding', 'molecular_function', 'GO:0005488', ('121', '128'))	('E7107', 'Chemical', 'MESH:C557411', (58, 63))
22952	32864546	Moreover, studies of cancer cells with acquired resistance to SF3B inhibitor compounds have identified mutations in SF3B1 as well as PHF5A that confer resistance to these compounds.	('PHF5A', 'Gene', (133, 138))	('mutations', 'Var', (103, 112))	('SF3B1', 'Gene', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('as', 'Gene', '112935892', (130, 132))	('as', 'Gene', '112935892', (122, 124))	('PHF5A', 'Gene', '84844', (133, 138))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('resistance', 'MPA', (151, 161))
22954	32864546	The SF3B modulator E7107 was previously studied in two phase I clinical trials in patients with advanced carcinomas.	('E7107', 'Var', (19, 24))	('E7107', 'Chemical', 'MESH:C557411', (19, 24))	('patients', 'Species', '9606', (82, 90))	('as', 'Gene', '112935892', (113, 115))	('carcinomas', 'Disease', 'MESH:D009369', (105, 115))	('as', 'Gene', '112935892', (26, 28))	('as', 'Gene', '112935892', (57, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('carcinomas', 'Disease', (105, 115))
22955	32864546	However, development of ocular complications via an undefined mechanism halted further development of E7107.	('E7107', 'Var', (102, 107))	('E7107', 'Chemical', 'MESH:C557411', (102, 107))	('ocular', 'Disease', (24, 30))
22963	32864546	Degradation of RBM39, an RNA-binding protein known to associate with the U2AF complex, causes intron retention and exon skipping.	('intron retention', 'MPA', (94, 110))	('RNA-binding protein', 'Gene', (25, 44))	('RBM39', 'Gene', (15, 20))	('RNA-binding', 'molecular_function', 'GO:0003723', ('25', '36'))	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('Degradation', 'Var', (0, 11))	('retention', 'biological_process', 'GO:0051235', ('101', '110'))	('U2AF', 'cellular_component', 'GO:0089701', ('73', '77'))	('RBM39', 'Gene', '9584', (15, 20))	('RNA', 'cellular_component', 'GO:0005562', ('25', '28'))	('as', 'Gene', '112935892', (54, 56))	('exon', 'MPA', (115, 119))	('causes', 'Reg', (87, 93))	('RNA-binding protein', 'Gene', '5725', (25, 44))
22964	32864546	Supporting evidence for on-target effects of sulfonamides for RBM39 includes the fact that mutations within RBM39 confer resistance to these compounds.	('sulfonamides', 'Chemical', 'MESH:D013449', (45, 57))	('RBM39', 'Gene', '9584', (62, 67))	('RBM39', 'Gene', '9584', (108, 113))	('mutations', 'Var', (91, 100))	('RBM39', 'Gene', (62, 67))	('RBM39', 'Gene', (108, 113))	('resistance', 'MPA', (121, 131))
22967	32864546	In future studies, RBM39 mutational status and DCAF15 expression levels may therefore predict response or resistance to these agents.	('expression', 'MPA', (54, 64))	('predict', 'Reg', (86, 93))	('mutational', 'Var', (25, 35))	('DCAF15', 'Gene', (47, 53))	('resistance', 'CPA', (106, 116))	('RBM39', 'Gene', '9584', (19, 24))	('DCAF15', 'Gene', '90379', (47, 53))	('RBM39', 'Gene', (19, 24))
22970	32864546	Rationale for the use of PRMT5 inhibitors in cancers sensitive to alterations in splicing comes from work by, which identified several components of splicing machinery as key effectors of MYC in the Emu-myc mouse model of lymphoma, exposing therapeutic vulnerabilities in MYC-driven cancers where existing therapeutic strategies are limited.	('cancers', 'Disease', 'MESH:D009369', (283, 290))	('lymphoma', 'Disease', 'MESH:D008223', (222, 230))	('myc', 'Gene', '17869', (203, 206))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('mouse', 'Species', '10090', (207, 212))	('alterations', 'Var', (66, 77))	('myc', 'Gene', (203, 206))	('MYC', 'Disease', (188, 191))	('as', 'Gene', '112935892', (168, 170))	('cancers', 'Phenotype', 'HP:0002664', (283, 290))	('cancers', 'Disease', (283, 290))	('lymphoma', 'Phenotype', 'HP:0002665', (222, 230))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('cancers', 'Disease', (45, 52))	('PRMT5', 'Gene', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('splicing', 'biological_process', 'GO:0045292', ('149', '157'))	('splicing', 'biological_process', 'GO:0045292', ('81', '89'))	('lymphoma', 'Disease', (222, 230))
22971	32864546	Outside of spliceosomal proteins, a genome-wide CRISPR-based screen recently identified that inhibition of DCPS, an mRNA-decapping enzyme, also perturbs splicing and alters RNA degradation.	('splicing', 'MPA', (153, 161))	('splicing', 'biological_process', 'GO:0045292', ('153', '161'))	('perturbs', 'NegReg', (144, 152))	('as', 'Gene', '112935892', (56, 58))	('DCPS', 'Gene', '28960', (107, 111))	('DCPS', 'Gene', (107, 111))	('RNA', 'cellular_component', 'GO:0005562', ('173', '176'))	('RNA degradation', 'biological_process', 'GO:0006401', ('173', '188'))	('RNA degradation', 'MPA', (173, 188))	('inhibition', 'Var', (93, 103))	('alters', 'Reg', (166, 172))
22972	32864546	DCPS deletion or inhibition using RG3039, a DCPS inhibitor, decreased proliferation and induced differentiation of AML cells (Figure 4d).	('DCPS', 'Gene', (0, 4))	('AML', 'Disease', 'MESH:D015470', (115, 118))	('differentiation', 'CPA', (96, 111))	('deletion', 'Var', (5, 13))	('induced', 'Reg', (88, 95))	('RG3039', 'Chemical', 'MESH:C587914', (34, 40))	('as', 'Gene', '112935892', (65, 67))	('AML', 'Phenotype', 'HP:0004808', (115, 118))	('RG3039', 'Gene', (34, 40))	('AML', 'Disease', (115, 118))	('proliferation', 'CPA', (70, 83))	('DCPS', 'Gene', (44, 48))	('DCPS', 'Gene', '28960', (44, 48))	('inhibition', 'NegReg', (17, 27))	('DCPS', 'Gene', '28960', (0, 4))
22974	32864546	Nonetheless, prior use of RG3039 in clinical trials in spinal muscular atrophy patients will hopefully facilitate use of this compound in cancer patients soon.	('patients', 'Species', '9606', (145, 153))	('spinal muscular atrophy', 'Disease', 'MESH:D009134', (55, 78))	('cancer', 'Disease', (138, 144))	('spinal muscular atrophy', 'Disease', (55, 78))	('muscular atrophy', 'Phenotype', 'HP:0003202', (62, 78))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('patients', 'Species', '9606', (79, 87))	('RG3039', 'Chemical', 'MESH:C587914', (26, 32))	('spinal muscular atrophy', 'Phenotype', 'HP:0007269', (55, 78))	('RG3039', 'Var', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
22978	32864546	Moreover, refined use of RNA-seq and proteomic profiling will help address these outstanding questions and inform the development of a unified theme describing the effects of altered RNA splicing in cancer.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('RNA splicing', 'biological_process', 'GO:0008380', ('183', '195'))	('altered RNA splicing', 'Var', (175, 195))	('RNA', 'cellular_component', 'GO:0005562', ('183', '186'))	('RNA', 'cellular_component', 'GO:0005562', ('25', '28'))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))
22985	31052228	Oxidative stress was induced by H2O2 or tert-Butyl hydroperoxide (TBHP).	('H2O2', 'Chemical', 'MESH:D006861', (32, 36))	('H2O2', 'Var', (32, 36))	('TBHP', 'Chemical', 'MESH:D020122', (66, 70))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('tert-Butyl hydroperoxide', 'Chemical', 'MESH:D020122', (40, 64))	('Oxidative stress', 'MPA', (0, 16))
23012	31052228	We have previously shown that commercial fucoidan from Fucus vesiculosus protected several uveal melanoma cells, including OMM-1, from oxidative stress induced by H2O2.	('fucoidan', 'Chemical', 'MESH:C007789', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('oxidative stress', 'MPA', (135, 151))	('H2O2', 'Chemical', 'MESH:D006861', (163, 167))	('H2O2', 'Var', (163, 167))	('uveal melanoma', 'Phenotype', 'HP:0007716', (91, 105))	('Fucus vesiculosus', 'Species', '49266', (55, 72))	('uveal melanoma cells', 'Disease', (91, 111))	('uveal melanoma cells', 'Disease', 'MESH:C536494', (91, 111))	('oxidative stress', 'Phenotype', 'HP:0025464', (135, 151))
23017	31052228	Incubation with 1 mM H2O2 resulted in a reduction of cell viability to 68.75% (+-5.07).	('reduction', 'NegReg', (40, 49))	('H2O2', 'Var', (21, 25))	('H2O2', 'Chemical', 'MESH:D006861', (21, 25))	('cell viability', 'CPA', (53, 67))
23018	31052228	In the experiments testing fucoidan from Laminaria digitata, incubation with 1 mM H2O2 reduced cell viability to 57.50% (+-2.29).	('fucoidan', 'Chemical', 'MESH:C007789', (27, 35))	('reduced', 'NegReg', (87, 94))	('H2O2', 'Chemical', 'MESH:D006861', (82, 86))	('H2O2', 'Var', (82, 86))	('Laminaria digitata', 'Species', '80365', (41, 59))	('cell viability', 'CPA', (95, 109))
23021	31052228	Testing fucoidan from Fucus serratus, incubation with 1 mM H2O2 resulted in a reduction of cell viability to 39.00% (+-3.67).	('Fucus serratus', 'Species', '87148', (22, 36))	('Fucus serratus', 'Phenotype', 'HP:0000767', (22, 36))	('fucoidan', 'Chemical', 'MESH:C007789', (8, 16))	('reduction', 'NegReg', (78, 87))	('H2O2', 'Chemical', 'MESH:D006861', (59, 63))	('cell viability', 'CPA', (91, 105))	('H2O2', 'Var', (59, 63))
23023	31052228	When testing the fucoidan from Fucus vesiculosus, incubation with 1 mM H2O2 resulted in a reduction of cell viability to 63.50% (+-2.60).	('reduction', 'NegReg', (90, 99))	('cell viability', 'CPA', (103, 117))	('H2O2', 'Chemical', 'MESH:D006861', (71, 75))	('H2O2', 'Var', (71, 75))	('Fucus vesiculosus', 'Species', '49266', (31, 48))	('fucoidan', 'Chemical', 'MESH:C007789', (17, 25))
23026	31052228	evanescens, incubation with 1 mM H2O2 resulted in a reduction of cell viability to 36.50% (+-8.44).	('H2O2', 'Chemical', 'MESH:D006861', (33, 37))	('cell viability', 'CPA', (65, 79))	('H2O2', 'Var', (33, 37))	('reduction', 'NegReg', (52, 61))
23037	31052228	Treatment with H2O2 induced a significant reduction in cell viability, detected in ANOVA.	('cell viability', 'CPA', (55, 69))	('reduction', 'NegReg', (42, 51))	('H2O2', 'Chemical', 'MESH:D006861', (15, 19))	('H2O2', 'Var', (15, 19))
23038	31052228	While incubation with 100 and 200 microM H2O2 did not induce any significant reduction in cell viability compared to the control (100 microM 11.45 +- 9.65%; 200 microM 96.07 +- 14.75%), 400 and 1000 microM H2O2 significantly reduced cell survival (400 microM 86.75 +- 18.62%, p < 0.01; 1000 microM 76.2 +- 22.74%, p < 0.001).	('cell survival', 'CPA', (233, 246))	('reduced', 'NegReg', (225, 232))	('H2O2', 'Chemical', 'MESH:D006861', (41, 45))	('H2O2', 'Var', (41, 45))	('H2O2', 'Chemical', 'MESH:D006861', (206, 210))	('H2O2', 'Var', (206, 210))
23098	31052228	As has been known for a long time that heparin and other sulfated polysaccharides have a high affinity for VEGF, fucoidans may not only reduce the secretion of VEGF but also directly antagonize its actions.	('VEGF', 'Gene', '7422', (160, 164))	('fucoidans', 'Var', (113, 122))	('VEGF', 'Gene', (107, 111))	('antagonize', 'NegReg', (183, 193))	('heparin', 'Chemical', 'MESH:D006493', (39, 46))	('VEGF', 'Gene', (160, 164))	('reduce', 'NegReg', (136, 142))	('secretion', 'MPA', (147, 156))	('VEGF', 'Gene', '7422', (107, 111))	('fucoidan', 'Chemical', 'MESH:C007789', (113, 121))	('secretion', 'biological_process', 'GO:0046903', ('147', '156'))	('actions', 'MPA', (198, 205))	('polysaccharides', 'Chemical', 'MESH:D011134', (66, 81))
23130	31052228	Indeed, knock-out of Nrf2 renders RPE cells highly susceptible to oxidative stress insults and Nrf2 knock-out mice develop AMD-like features at an older age.	('knock-out', 'Var', (8, 17))	('Nrf2', 'Gene', (95, 99))	('AMD', 'Disease', 'MESH:D006009', (123, 126))	('Nrf2', 'Gene', (21, 25))	('mice', 'Species', '10090', (110, 114))	('susceptible', 'MPA', (51, 62))	('AMD', 'Disease', (123, 126))	('develop', 'PosReg', (115, 122))	('oxidative stress', 'Phenotype', 'HP:0025464', (66, 82))
23167	31052228	Therefore, fucoidans may also be of great interest for diabetic patients, especially considering that fucoidan may also reduce blood glucose levels and ameliorate hypertension.	('ameliorate', 'PosReg', (152, 162))	('blood glucose', 'Chemical', 'MESH:D001786', (127, 140))	('reduce blood glucose levels', 'Phenotype', 'HP:0001943', (120, 147))	('patients', 'Species', '9606', (64, 72))	('reduce', 'NegReg', (120, 126))	('fucoidan', 'Chemical', 'MESH:C007789', (11, 19))	('diabetic', 'Disease', 'MESH:D003920', (55, 63))	('fucoidan', 'Var', (102, 110))	('hypertension', 'Disease', 'MESH:D006973', (163, 175))	('blood glucose levels', 'MPA', (127, 147))	('diabetic', 'Disease', (55, 63))	('hypertension', 'Phenotype', 'HP:0000822', (163, 175))	('fucoidan', 'Chemical', 'MESH:C007789', (102, 110))	('hypertension', 'Disease', (163, 175))
23264	30122992	Maspin has a positive correlation with VM; deregulated maspin facilitates tumor cell invasion and metastasis in non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (112, 138))	('facilitates', 'PosReg', (62, 73))	('Maspin', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('deregulated', 'Var', (43, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (116, 138))	('metastasis', 'CPA', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('non-small cell lung cancer', 'Disease', (112, 138))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('maspin', 'Gene', (55, 61))	('tumor', 'Disease', (74, 79))	('maspin', 'Gene', '5268', (55, 61))	('Maspin', 'Gene', '5268', (0, 6))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (112, 138))
23299	30122992	Massi et al indicated that, in patients with pT3 and pT4 cutaneous melanoma, there is no evidence of VM as a prognostic factor.	('pT4', 'Var', (53, 56))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('pT3', 'Gene', '7694', (45, 48))	('pT3', 'Gene', (45, 48))	('patients', 'Species', '9606', (31, 39))	('cutaneous melanoma', 'Disease', (57, 75))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (57, 75))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (57, 75))
23308	30122992	VM channels decrease cancer latency and increase intratumoral cisplatin delivery but may also reduce drug efficacy.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumoral', 'Disease', (54, 61))	('tumoral', 'Disease', 'MESH:D009369', (54, 61))	('reduce', 'NegReg', (94, 100))	('increase', 'PosReg', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('drug efficacy', 'MPA', (101, 114))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('decrease', 'NegReg', (12, 20))	('reduce drug efficacy', 'Phenotype', 'HP:0020173', (94, 114))	('VM channels', 'Var', (0, 11))
23341	30122992	A study by Wan et al revealed miRNA-124 inhibits VM formation of cervical cancer cells by targeting AmotL1 and suppressing the EMT process.	('formation', 'biological_process', 'GO:0009058', ('52', '61'))	('miRNA-124', 'Chemical', '-', (30, 39))	('EMT', 'biological_process', 'GO:0001837', ('127', '130'))	('AmotL1', 'Gene', '154810', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('EMT process', 'CPA', (127, 138))	('AmotL1', 'Gene', (100, 106))	('VM formation of cervical', 'CPA', (49, 73))	('cancer', 'Disease', (74, 80))	('miRNA-124', 'Var', (30, 39))	('inhibits', 'NegReg', (40, 48))	('targeting', 'Reg', (90, 99))	('suppressing', 'NegReg', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
23357	29166932	BAP1: case report and insight into a novel tumor suppressor BRCA1-Associated-Protein 1 (BAP1) is a dynamic tumor suppressor which, when mutated, has been associated with an increased risk of uveal melanoma, cutaneous melanoma, mesothelioma, and several other cancers.	('associated with', 'Reg', (154, 169))	('tumor', 'Disease', (107, 112))	('cutaneous melanoma', 'Disease', (207, 225))	('mesothelioma', 'Disease', (227, 239))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (207, 225))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (207, 225))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor suppressor', 'biological_process', 'GO:0051726', ('107', '123'))	('mesothelioma', 'Disease', 'MESH:D008654', (227, 239))	('tumor', 'Disease', (43, 48))	('BAP1', 'Gene', (88, 92))	('BAP1', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('BRCA1-Associated-Protein 1', 'Gene', '8314', (60, 86))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('107', '123'))	('BRCA1-Associated-Protein 1', 'Gene', (60, 86))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('uveal melanoma', 'Disease', 'MESH:C536494', (191, 205))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('uveal melanoma', 'Disease', (191, 205))	('mutated', 'Var', (136, 143))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('43', '59'))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('cancers', 'Disease', (259, 266))	('uveal melanoma', 'Phenotype', 'HP:0007716', (191, 205))	('BAP1', 'Gene', '8314', (88, 92))	('tumor suppressor', 'biological_process', 'GO:0051726', ('43', '59'))	('BAP1', 'Gene', '8314', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))
23358	29166932	Germline BAP1 mutations have been extensively studied, where they have been found to cause hereditary cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cause', 'Reg', (85, 90))	('BAP1', 'Gene', '8314', (9, 13))	('hereditary cancer', 'Disease', 'MESH:D009369', (91, 108))	('BAP1', 'Gene', (9, 13))	('hereditary cancer', 'Disease', (91, 108))	('mutations', 'Var', (14, 23))
23359	29166932	However, their sporadic counterparts, tumors that display a loss of BAP1 expression due to somatically arising mutations in the BAP1 gene, remain a poorly described entity.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('mutations', 'Var', (111, 120))	('tumors', 'Disease', (38, 44))	('BAP1', 'Gene', '8314', (128, 132))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('loss', 'NegReg', (60, 64))	('BAP1', 'Gene', '8314', (68, 72))	('expression', 'MPA', (73, 83))	('BAP1', 'Gene', (128, 132))	('BAP1', 'Gene', (68, 72))
23365	29166932	Within the last decade, the BRCA1-Associated-Protein 1 (BAP1) has been increasingly appreciated for its tumor suppressor activities, given that a loss of BAP1 can drive carcinogenesis in diverse tissue types.	('tumor suppressor', 'biological_process', 'GO:0051726', ('104', '120'))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('carcinogenesis', 'Disease', (169, 183))	('BRCA1-Associated-Protein 1', 'Gene', (28, 54))	('BAP1', 'Gene', (154, 158))	('BAP1', 'Gene', '8314', (56, 60))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('104', '120'))	('loss', 'Var', (146, 150))	('tumor', 'Disease', (104, 109))	('BRCA1-Associated-Protein 1', 'Gene', '8314', (28, 54))	('BAP1', 'Gene', (56, 60))	('carcinogenesis', 'Disease', 'MESH:D063646', (169, 183))	('drive', 'Reg', (163, 168))	('BAP1', 'Gene', '8314', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
23366	29166932	Germline mutations in BAP1 have been described in families with a hereditary increase in the risk of uveal melanoma, cutaneous melanoma, mesothelioma, Merkel cell carcinoma, and several other cancers.	('Germline mutations', 'Var', (0, 18))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (151, 172))	('uveal melanoma', 'Disease', 'MESH:C536494', (101, 115))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('uveal melanoma', 'Disease', (101, 115))	('described', 'Reg', (37, 46))	('cancers', 'Disease', (192, 199))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('mesothelioma', 'Disease', (137, 149))	('cutaneous melanoma', 'Disease', (117, 135))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (117, 135))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (117, 135))	('uveal melanoma', 'Phenotype', 'HP:0007716', (101, 115))	('mesothelioma', 'Disease', 'MESH:D008654', (137, 149))	('Merkel cell carcinoma', 'Disease', (151, 172))	('BAP1', 'Gene', '8314', (22, 26))	('increase', 'Reg', (77, 85))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('BAP1', 'Gene', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))
23367	29166932	Strikingly, a large-scale systematic review found that patients with BAP1 mutations face increased mortality, both general and cancer-specific, as well as increased likelihood of cancer relapse.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('BAP1', 'Gene', (69, 73))	('increased', 'PosReg', (155, 164))	('mutations', 'Var', (74, 83))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (127, 133))	('patients', 'Species', '9606', (55, 63))	('increased', 'PosReg', (89, 98))	('cancer', 'Disease', (179, 185))	('BAP1', 'Gene', '8314', (69, 73))
23368	29166932	Thus, mutations in BAP1, along with family history, can be used as an assessment for a patient's risk of certain cancers, and confers importance to the knowledge of a patient's BAP1 mutation status.	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('patient', 'Species', '9606', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('BAP1', 'Gene', '8314', (19, 23))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('BAP1', 'Gene', '8314', (177, 181))	('patient', 'Species', '9606', (87, 94))	('BAP1', 'Gene', (19, 23))	('BAP1', 'Gene', (177, 181))	('mutations', 'Var', (6, 15))
23369	29166932	More recently, sporadic somatic BAP1 mutations have been shown to occur in the setting of both mesothelioma and uveal melanoma.	('mesothelioma and uveal melanoma', 'Disease', 'MESH:C536494', (95, 126))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('BAP1', 'Gene', '8314', (32, 36))	('occur', 'Reg', (66, 71))	('uveal melanoma', 'Phenotype', 'HP:0007716', (112, 126))	('mutations', 'Var', (37, 46))	('BAP1', 'Gene', (32, 36))
23371	29166932	These BAP1 negative tumors, or "BAPomas", can be screened for using immunohistological staining, following which genetic testing can confirm the presence or absence of a BAP1 mutation in the germline.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('BAP1', 'Gene', (6, 10))	('BAP1', 'Gene', '8314', (170, 174))	('mutation', 'Var', (175, 183))	('BAP1', 'Gene', (170, 174))	('BAPomas', 'Disease', 'None', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('BAP1', 'Gene', '8314', (6, 10))	('BAPomas', 'Disease', (32, 39))
23380	29166932	Although her personal and family history was not suggestive of a BAP1-associated cancer syndrome, the patient underwent genetic testing for a germline mutation in the BAP1 gene.	('BAP1', 'Gene', '8314', (65, 69))	('patient', 'Species', '9606', (102, 109))	('cancer syndrome', 'Disease', 'MESH:D009369', (81, 96))	('cancer syndrome', 'Disease', (81, 96))	('BAP1', 'Gene', (65, 69))	('BAP1', 'Gene', '8314', (167, 171))	('germline mutation in', 'Var', (142, 162))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('BAP1', 'Gene', (167, 171))
23381	29166932	Sequencing and deletion/duplication analysis of the BAP1 gene was negative, evidence supporting a sporadic BAP1 mutation in the lesion where the BAPoma formed.	('BAP1', 'Gene', '8314', (107, 111))	('BAP1', 'Gene', '8314', (52, 56))	('mutation', 'Var', (112, 120))	('BAP1', 'Gene', (107, 111))	('BAP1', 'Gene', (52, 56))
23385	29166932	In addition, BAP1 has been implicated in the DNA damage response through its involvement in the ataxia telangiectasia-mutated (ATM) signaling pathway, as well as in epigenetic transcriptional regulation associated with preventing cancerous proliferation.	('epigenetic', 'Var', (165, 175))	('telangiectasia', 'Phenotype', 'HP:0001009', (103, 117))	('BAP1', 'Gene', (13, 17))	('DNA damage response', 'biological_process', 'GO:0006974', ('45', '64'))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('involvement', 'Reg', (77, 88))	('ataxia', 'Phenotype', 'HP:0001251', (96, 102))	('ATM', 'Gene', (127, 130))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('ataxia telangiectasia-mutated', 'Gene', '472', (96, 125))	('signaling pathway', 'biological_process', 'GO:0007165', ('132', '149'))	('cancerous', 'Disease', (230, 239))	('regulation', 'biological_process', 'GO:0065007', ('192', '202'))	('implicated', 'Reg', (27, 37))	('BAP1', 'Gene', '8314', (13, 17))	('ataxia telangiectasia-mutated', 'Gene', (96, 125))	('ATM', 'Gene', '472', (127, 130))	('cancerous', 'Disease', 'MESH:D009369', (230, 239))
23389	29166932	Consistent with this, lung cancer cells with mutant BAP1 typically possess truncations or other mutations that negatively impact its deubiquitinase and nuclear localization ability.	('lung cancer', 'Disease', (22, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('deubiquitinase', 'MPA', (133, 147))	('mutant', 'Var', (45, 51))	('truncations', 'MPA', (75, 86))	('BAP1', 'Gene', '8314', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('lung cancer', 'Disease', 'MESH:D008175', (22, 33))	('nuclear localization', 'MPA', (152, 172))	('BAP1', 'Gene', (52, 56))	('localization', 'biological_process', 'GO:0051179', ('160', '172'))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('133', '147'))
23394	29166932	However, positive BRAFV600E expression in many BAP1 negative lesions, as well as a lack of epidermal hyperplasia, clefting between melanocytes, and Kamino bodies, sets this population apart from traditional Spitz nevi.	('BRAFV600E', 'Var', (18, 27))	('hyperplasia', 'Disease', (101, 112))	('BRAFV600E', 'Mutation', 'rs113488022', (18, 27))	('BAP1', 'Gene', '8314', (47, 51))	('negative', 'NegReg', (52, 60))	('hyperplasia', 'Disease', 'MESH:D006965', (101, 112))	('nevi', 'Phenotype', 'HP:0003764', (213, 217))	('BAP1', 'Gene', (47, 51))
23413	23392528	Uveal melanoma that spreads to the liver can be categorized as stage 1 (<=50 mum in diameter), stage 2 (51-500 mum in diameter), or stage 3 (>500 mum in diameter) metastases.	('mum', 'Gene', '56925', (77, 80))	('metastases', 'Disease', (163, 173))	('mum', 'Gene', (146, 149))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('mum', 'Gene', (111, 114))	('mum', 'Gene', (77, 80))	('<=50', 'Var', (72, 76))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('metastases', 'Disease', 'MESH:D009362', (163, 173))	('Uveal', 'Disease', (0, 5))	('>500', 'Var', (141, 145))	('melanoma', 'Disease', (6, 14))	('mum', 'Gene', '56925', (146, 149))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))	('mum', 'Gene', '56925', (111, 114))
23479	23392528	The hypothesis based on the histologic findings is that the stage 2 metastases identified in the present study appear to have arisen from expansions of clusters of stage 1 metastases.	('stage 2', 'Disease', (60, 67))	('metastases', 'Disease', 'MESH:D009362', (172, 182))	('expansions', 'Var', (138, 148))	('metastases', 'Disease', (68, 78))	('metastases', 'Disease', (172, 182))	('metastases', 'Disease', 'MESH:D009362', (68, 78))	('arisen from', 'Reg', (126, 137))
23509	24882515	Hippo-Independent Activation of YAP by the GNAQ Uveal Melanoma Oncogene through a Trio-regulated Rho GTPase Signaling Circuitry Mutually exclusive activating mutations in the GNAQ and GNA11 oncogenes, encoding heterotrimeric Galphaq family members, have been identified in ~83% and ~6% of uveal and skin melanomas, respectively.	('Trio', 'Gene', '7204', (82, 86))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('Melanoma', 'Disease', 'MESH:D008545', (54, 62))	('YAP', 'Gene', '10413', (32, 35))	('GNA11', 'Gene', '2767', (184, 189))	('mutations', 'Var', (158, 167))	('GNAQ', 'Gene', '2776', (43, 47))	('Activation', 'PosReg', (18, 28))	('Melanoma', 'Disease', (54, 62))	('Signaling', 'biological_process', 'GO:0023052', ('108', '117'))	('GNAQ', 'Gene', (43, 47))	('melanomas', 'Phenotype', 'HP:0002861', (304, 313))	('Trio', 'Gene', (82, 86))	('skin melanomas', 'Disease', (299, 313))	('Melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('skin melanomas', 'Disease', 'MESH:D008545', (299, 313))	('GNAQ', 'Gene', '2776', (175, 179))	('GNA11', 'Gene', (184, 189))	('Galphaq', 'Chemical', '-', (225, 232))	('activating', 'PosReg', (147, 157))	('GNAQ', 'Gene', (175, 179))	('melanoma', 'Phenotype', 'HP:0002861', (304, 312))	('YAP', 'Gene', (32, 35))
23511	24882515	We found that Galphaq stimulates YAP through a Trio-Rho/Rac signaling circuitry promoting actin polymerization, independently of PLCbeta and the canonical Hippo pathway.	('stimulates', 'PosReg', (22, 32))	('Rac', 'Gene', '5879', (56, 59))	('actin polymerization', 'MPA', (90, 110))	('promoting', 'PosReg', (80, 89))	('Rac', 'Gene', (56, 59))	('YAP', 'MPA', (33, 36))	('actin polymerization', 'biological_process', 'GO:0030041', ('90', '110'))	('Galphaq', 'Chemical', '-', (14, 21))	('Galphaq', 'Var', (14, 21))	('signaling', 'biological_process', 'GO:0023052', ('60', '69'))
23513	24882515	Mutations in GNAQ and GNA11, encoding two members of the Galphaq family of heterotrimeric G protein alpha subunits, Galphaq and Galpha11, respectively, occur in roughly 5% of all tumors sequenced to date.	('Galpha11', 'Gene', (128, 136))	('GNA11', 'Gene', (22, 27))	('Galpha11', 'Gene', '2767', (128, 136))	('GNAQ', 'Gene', (13, 17))	('tumors', 'Disease', (179, 185))	('GNA11', 'Gene', '2767', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('Mutations', 'Var', (0, 9))	('occur', 'Reg', (152, 157))	('Galphaq', 'Chemical', '-', (57, 64))	('Galphaq', 'Chemical', '-', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('75', '99'))
23514	24882515	The majority of these mutations affect residues Q209 and R183, which are required for Galphaq GTPase activity.	('Galphaq', 'Chemical', '-', (86, 93))	('R183', 'Var', (57, 61))	('GTPase activity', 'molecular_function', 'GO:0003924', ('94', '109'))	('affect', 'Reg', (32, 38))
23515	24882515	Thus, the most frequent mutations observed in GNAQ and GNA11 render them GTPase defective and constitutively active, leading to prolonged signaling.	('GTPase', 'Protein', (73, 79))	('GNAQ', 'Gene', (46, 50))	('signaling', 'biological_process', 'GO:0023052', ('138', '147'))	('prolonged signaling', 'MPA', (128, 147))	('defective', 'NegReg', (80, 89))	('mutations', 'Var', (24, 33))	('leading to', 'Reg', (117, 127))	('GNA11', 'Gene', '2767', (55, 60))	('GNA11', 'Gene', (55, 60))
23516	24882515	Of interest, ~83% of ocular melanomas harbor mutations in GNAQ or GNA11, where they are now considered to represent the driver oncogenes.	('ocular melanomas', 'Disease', 'MESH:D008545', (21, 37))	('mutations', 'Var', (45, 54))	('ocular melanomas', 'Disease', (21, 37))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('GNA11', 'Gene', (66, 71))	('GNAQ', 'Gene', (58, 62))	('ocular melanomas', 'Phenotype', 'HP:0025534', (21, 37))	('GNA11', 'Gene', '2767', (66, 71))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
23517	24882515	This provides a clear example of a human malignancy that is initiated by gain of function mutations in Galphaq and Galpha11 proteins.	('Galphaq', 'Chemical', '-', (103, 110))	('Galpha11', 'Gene', (115, 123))	('mutations', 'Var', (90, 99))	('malignancy', 'Disease', 'MESH:D009369', (41, 51))	('malignancy', 'Disease', (41, 51))	('proteins', 'Protein', (124, 132))	('Galphaq', 'Gene', (103, 110))	('human', 'Species', '9606', (35, 40))	('Galpha11', 'Gene', '2767', (115, 123))	('gain of function', 'PosReg', (73, 89))
23518	24882515	Although less studied, GNAQ and GNA11 mutations are also frequently found in leptomeningeal melanocytomas (50%) and melanomas (25%) arising from the meninges, in most blue nevi of the skin (83%), and in a subset (6%) of cutaneous melanomas.	('melanomas', 'Disease', (116, 125))	('GNAQ', 'Gene', (23, 27))	('GNA11', 'Gene', (32, 37))	('found', 'Reg', (68, 73))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('melanomas', 'Disease', 'MESH:D008545', (230, 239))	('mutations', 'Var', (38, 47))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (220, 239))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (220, 239))	('blue nevi', 'Disease', (167, 176))	('melanomas', 'Disease', (230, 239))	('nevi', 'Phenotype', 'HP:0003764', (172, 176))	('GNA11', 'Gene', '2767', (32, 37))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (220, 238))	('leptomeningeal melanocytomas', 'Disease', (77, 105))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('blue nevi', 'Phenotype', 'HP:0100814', (167, 176))	('cutaneous melanomas', 'Disease', (220, 239))	('melanomas', 'Disease', 'MESH:D008545', (116, 125))	('melanomas', 'Phenotype', 'HP:0002861', (230, 239))	('leptomeningeal melanocytomas', 'Disease', 'MESH:D008577', (77, 105))
23519	24882515	The best-known downstream signaling event initiated by Galphaq involves its ability is to activate phospholipase C (PLC) beta and the consequent increased hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to produce two second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).	('Galphaq', 'Chemical', '-', (55, 62))	('phosphatidylinositol 4,5-bisphosphate', 'Chemical', 'MESH:D019269', (169, 206))	('Galphaq', 'Var', (55, 62))	('IP3', 'Chemical', 'MESH:D015544', (278, 281))	('phospholipase C', 'Enzyme', (99, 114))	('diacylglycerol', 'Chemical', 'MESH:D004075', (287, 301))	('PLC', 'cellular_component', 'GO:0042824', ('116', '119'))	('increased', 'PosReg', (145, 154))	('PIP2', 'Chemical', 'MESH:D019269', (208, 212))	('hydrolysis', 'MPA', (155, 165))	('diacylglycerol', 'MPA', (287, 301))	('activate', 'PosReg', (90, 98))	('increased hydrolysis of phosphatidylinositol 4,5-bisphosphate', 'Phenotype', 'HP:0003240', (145, 206))	('inositol 1,4,5-trisphosphate', 'Chemical', 'MESH:D015544', (248, 276))	('DAG', 'Chemical', 'MESH:D004075', (303, 306))	('signaling', 'biological_process', 'GO:0023052', ('26', '35'))
23520	24882515	IP3 raises cytoplasmic Ca2+ levels, which stimulates multiple calcium-regulated pathways and, together with DAG, activates classic protein kinase C (PKC) isoforms.	('cytoplasmic Ca2+ levels', 'MPA', (11, 34))	('PKC', 'molecular_function', 'GO:0004697', ('149', '152'))	('stimulates', 'PosReg', (42, 52))	('calcium-regulated pathways', 'Pathway', (62, 88))	('activates', 'PosReg', (113, 122))	('DAG', 'Chemical', 'MESH:D004075', (108, 111))	('IP3', 'Chemical', 'MESH:D015544', (0, 3))	('Ca2+', 'Chemical', 'MESH:D000069285', (23, 27))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('raises', 'PosReg', (4, 10))	('calcium', 'Chemical', 'MESH:D002118', (62, 69))	('IP3', 'Var', (0, 3))
23524	24882515	In this study, we show that activating mutation of Galphaq can trigger YAP translocation into the nucleus and stimulates YAP-dependent transcription, and that this process is independent from PLCbeta stimulation but requires the activation of a Galphaq-regulated guanine nucleotide exchange factor, Trio, and the subsequent activation of the small GTPases RhoA and Rac1 and their associated signaling networks.	('Rac1', 'Gene', (365, 369))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (263, 281))	('RhoA', 'Gene', '387', (356, 360))	('transcription', 'biological_process', 'GO:0006351', ('135', '148'))	('mutation', 'Var', (39, 47))	('YAP-dependent transcription', 'MPA', (121, 148))	('Galphaq', 'Gene', (51, 58))	('Galphaq', 'Chemical', '-', (245, 252))	('YAP translocation into the nucleus', 'MPA', (71, 105))	('activating', 'PosReg', (28, 38))	('signaling', 'biological_process', 'GO:0023052', ('391', '400'))	('trigger', 'Reg', (63, 70))	('nucleus', 'cellular_component', 'GO:0005634', ('98', '105'))	('stimulates', 'PosReg', (110, 120))	('Rac1', 'Gene', '5879', (365, 369))	('RhoA', 'Gene', (356, 360))	('Galphaq', 'Chemical', '-', (51, 58))
23526	24882515	To assess the expression and localization of the transcriptional co-activator, YAP, in response to activating mutations in GNAQ, we transfected HEK-293 cells with HA-tagged GalphaqQL (Q209L), one of the most frequent GNAQ mutants in uveal melanoma, using empty vector and wild type Galphaq as controls.	('uveal melanoma', 'Disease', (233, 247))	('Galphaq', 'Chemical', '-', (173, 180))	('Galphaq', 'Chemical', '-', (282, 289))	('mutations', 'Var', (110, 119))	('Q209L', 'Mutation', 'rs121913492', (184, 189))	('expression', 'Species', '29278', (14, 24))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('GalphaqQL', 'Var', (173, 182))	('localization', 'biological_process', 'GO:0051179', ('29', '41'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (233, 247))	('uveal melanoma', 'Disease', 'MESH:C536494', (233, 247))	('GalphaqQL', 'Chemical', '-', (173, 182))	('Q209L', 'Var', (184, 189))	('HEK-293', 'CellLine', 'CVCL:0045', (144, 151))
23528	24882515	GalphaqQL also caused a remarkable increase in the luciferase activity of a YAP reporter system driven by a TEAD4-Gal4 chimera, which included the TEAD4 transactivation and YAP-binding domain, and promoted the expression of endogenous YAP-regulated genes, including CTGF and CYR61 (Figure 1E, and Figure S1A).	('GalphaqQL', 'Chemical', '-', (0, 9))	('Gal4', 'Gene', (114, 118))	('luciferase activity', 'molecular_function', 'GO:0045289', ('51', '70'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('51', '70'))	('TEAD4', 'Gene', (108, 113))	('expression', 'MPA', (210, 220))	('CTGF', 'Gene', (266, 270))	('YAP-regulated genes', 'Gene', (235, 254))	('TEAD4', 'Gene', (147, 152))	('promoted', 'PosReg', (197, 205))	('luciferase activity', 'molecular_function', 'GO:0050397', ('51', '70'))	('binding', 'molecular_function', 'GO:0005488', ('177', '184'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('51', '70'))	('TEAD4', 'Gene', '7004', (108, 113))	('increase', 'PosReg', (35, 43))	('activity', 'MPA', (62, 70))	('expression', 'Species', '29278', (210, 220))	('transactivation', 'biological_process', 'GO:2000144', ('153', '168'))	('luciferase', 'Enzyme', (51, 61))	('TEAD4', 'Gene', '7004', (147, 152))	('CYR61', 'Gene', (275, 280))	('Gal4', 'Gene', '3960', (114, 118))	('GalphaqQL', 'Var', (0, 9))	('luciferase activity', 'molecular_function', 'GO:0047077', ('51', '70'))
23534	24882515	Knock down of Trio did not affect the expression levels of GalphaqQL, but abolished its ability to promote the accumulation of activated RhoA and Rac1 (Figure 1G).	('expression', 'Species', '29278', (38, 48))	('ability', 'MPA', (88, 95))	('GalphaqQL', 'Chemical', '-', (59, 68))	('promote', 'PosReg', (99, 106))	('RhoA', 'Gene', (137, 141))	('abolished', 'NegReg', (74, 83))	('accumulation', 'MPA', (111, 123))	('RhoA', 'Gene', '387', (137, 141))	('Rac1', 'Gene', '5879', (146, 150))	('Knock down', 'Var', (0, 10))	('Rac1', 'Gene', (146, 150))
23535	24882515	Knock down of Trio also prevented the activation of the YAP transcriptional activity caused by GalphaqQL (Figure 1H and Figure S1C).	('GalphaqQL', 'Chemical', '-', (95, 104))	('YAP transcriptional activity', 'MPA', (56, 84))	('prevented', 'NegReg', (24, 33))	('activation', 'PosReg', (38, 48))	('Knock down', 'Var', (0, 10))
23537	24882515	Interestingly, knockdown of either of these two Rho-GTPases prevented the transcriptional activation of YAP induced by GalphaqQL (Figure 1N and Figure S1D-E).	('prevented', 'NegReg', (60, 69))	('GalphaqQL', 'Chemical', '-', (119, 128))	('knockdown', 'Var', (15, 24))	('YAP', 'Gene', (104, 107))	('transcriptional activation', 'MPA', (74, 100))
23538	24882515	Thus, while the activated mutants of either RhoA or Rac1 can activate YAP, the concomitant activation of both endogenous GTPases appears to be required for the full stimulation of endogenous YAP when activated by oncogenic forms of Galphaq.	('activate', 'PosReg', (61, 69))	('Galphaq', 'Chemical', '-', (232, 239))	('activation', 'PosReg', (91, 101))	('RhoA', 'Gene', (44, 48))	('YAP', 'CPA', (70, 73))	('mutants', 'Var', (26, 33))	('RhoA', 'Gene', '387', (44, 48))	('Rac1', 'Gene', (52, 56))	('Rac1', 'Gene', '5879', (52, 56))
23539	24882515	To investigate whether activated GNAQ can drive melanocyte transformation in vivo, we generated a mouse model expressing HA-GalphaqQL under the control of the tet-responsive elements (tet-HA-GalphaqQL) and bred them with mice expressing the reverse tetracycline-activated transactivator rtTA2, regulated by the melanocyte-specific dopachrome tautomerase (Dct) gene promoter (Dct-rtTA).	('Dct', 'Gene', '13190', (375, 378))	('HA-GalphaqQL', 'Chemical', '-', (188, 200))	('tet', 'Chemical', 'MESH:C010349', (249, 252))	('Dct', 'Gene', '13190', (355, 358))	('mouse', 'Species', '10090', (98, 103))	('Dct', 'Gene', (375, 378))	('mice', 'Species', '10090', (221, 225))	('tetracycline', 'Chemical', 'MESH:D013752', (249, 261))	('Dct', 'Gene', (355, 358))	('tet', 'Chemical', 'MESH:C010349', (159, 162))	('HA-GalphaqQL', 'Chemical', '-', (121, 133))	('HA-GalphaqQL', 'Var', (121, 133))	('tet', 'Chemical', 'MESH:C010349', (184, 187))
23541	24882515	The tet-HA-GalphaqQL and Dct-rtTA transgenic mice were also bred with mice defective in p16Ink4a and p19Ink4b (p16p19KO) (Figure 2C), as genetic and epigenetic inactivation of this tumor suppressive pathway is a frequent event in uveal and cutaneous melanoma.	('Dct', 'Gene', '13190', (25, 28))	('Ink4', 'Gene', (91, 95))	('mice', 'Species', '10090', (45, 49))	('p16Ink4a', 'Gene', (88, 96))	('Ink4', 'Gene', (104, 108))	('mice', 'Species', '10090', (70, 74))	('Ink4', 'Gene', '1029', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('p16Ink4a', 'Gene', '12578', (88, 96))	('Ink4', 'Gene', '1029', (104, 108))	('p19', 'cellular_component', 'GO:0070743', ('114', '117'))	('tet', 'Chemical', 'MESH:C010349', (4, 7))	('transgenic mice', 'Species', '10090', (34, 49))	('cutaneous melanoma', 'Disease', (240, 258))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (240, 258))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (240, 258))	('tumor', 'Disease', (181, 186))	('Dct', 'Gene', (25, 28))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('HA-GalphaqQL', 'Chemical', '-', (8, 20))	('p19', 'cellular_component', 'GO:0070743', ('101', '104'))	('epigenetic inactivation', 'Var', (149, 172))	('tumor', 'Disease', 'MESH:D009369', (181, 186))
23543	24882515	Using this animal model system, we observed that when HA-GalphaqQL was expressed in response to doxycycline treatment in the p16p19KO background, more than 50% of the mice develop cutaneous lesions of melanocytic origin expressing Dct (Figure 2D and E and data not shown).	('Dct', 'Gene', (231, 234))	('develop', 'PosReg', (172, 179))	('mice', 'Species', '10090', (167, 171))	('doxycycline', 'Chemical', 'MESH:D004318', (96, 107))	('p16p19KO', 'Var', (125, 133))	('cutaneous lesions of melanocytic', 'Disease', 'MESH:D009508', (180, 212))	('Dct', 'Gene', '13190', (231, 234))	('p19', 'cellular_component', 'GO:0070743', ('128', '131'))	('cutaneous lesions of melanocytic', 'Disease', (180, 212))	('HA-GalphaqQL', 'Chemical', '-', (54, 66))	('HA-GalphaqQL', 'Var', (54, 66))
23544	24882515	This is aligned with the finding that hot spot mutations in GNAQ and its related GNA11 are mutated in 5% of all cutaneous melanomas, which based on our observations may represent a tumor-initiating genetic event.	('cutaneous melanomas', 'Disease', (112, 131))	('GNAQ', 'Gene', (60, 64))	('tumor', 'Disease', (181, 186))	('GNA11', 'Gene', '2767', (81, 86))	('GNA11', 'Gene', (81, 86))	('mutated', 'Var', (91, 98))	('mutations', 'Var', (47, 56))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (112, 131))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (112, 131))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
23545	24882515	In these lesions, most HA-GalphaqQL expressing cells exhibit nuclear YAP, in contrast to normal tissues in which control GFP expressing melanocytes exhibit cytoplasmic YAP (Figure 2F and G).	('HA-GalphaqQL', 'Chemical', '-', (23, 35))	('nuclear YAP', 'CPA', (61, 72))	('HA-GalphaqQL', 'Var', (23, 35))
23546	24882515	Thus, mutated GNAQ can initiate melanocyte transformation and tumor formation in mice when expressed in a progenitor cell compartment, and results in YAP nuclear localization in vivo.	('results in', 'Reg', (139, 149))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('mice', 'Species', '10090', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('initiate', 'PosReg', (23, 31))	('YAP nuclear localization', 'MPA', (150, 174))	('GNAQ', 'Gene', (14, 18))	('melanocyte transformation', 'CPA', (32, 57))	('localization', 'biological_process', 'GO:0051179', ('162', '174'))	('formation', 'biological_process', 'GO:0009058', ('68', '77'))	('mutated', 'Var', (6, 13))
23552	24882515	This suggests that YAP may contribute to the oncogenic pathway initiated by GNAQ and GNA11 activating mutations in human uveal melanomas.	('uveal melanoma', 'Phenotype', 'HP:0007716', (121, 135))	('initiated', 'Reg', (63, 72))	('GNA11', 'Gene', '2767', (85, 90))	('GNA11', 'Gene', (85, 90))	('human', 'Species', '9606', (115, 120))	('uveal melanomas', 'Disease', (121, 136))	('uveal melanomas', 'Phenotype', 'HP:0007716', (121, 136))	('mutations', 'Var', (102, 111))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('uveal melanomas', 'Disease', 'MESH:C536494', (121, 136))	('oncogenic pathway', 'Pathway', (45, 62))
23555	24882515	The nuclear localization of YAP was abolished after GNAQ knock down in uveal melanoma cell lines (Figure 3E and F).	('GNAQ', 'Protein', (52, 56))	('nuclear localization', 'MPA', (4, 24))	('localization', 'biological_process', 'GO:0051179', ('12', '24'))	('YAP', 'Gene', (28, 31))	('uveal melanoma', 'Disease', 'MESH:C536494', (71, 85))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('knock down', 'Var', (57, 67))	('uveal melanoma', 'Phenotype', 'HP:0007716', (71, 85))	('uveal melanoma', 'Disease', (71, 85))	('abolished', 'NegReg', (36, 45))
23556	24882515	Similarly, knock down of Trio, RhoA and Rac1 prevented the nuclear accumulation of YAP in these cells, and diminished the expression of endogenous YAP-regulated genes, CTGF and CYR61 (Figure 3E-G).	('nuclear accumulation', 'MPA', (59, 79))	('knock down', 'Var', (11, 21))	('Rac1', 'Gene', (40, 44))	('expression', 'MPA', (122, 132))	('RhoA', 'Gene', (31, 35))	('CTGF', 'Gene', (168, 172))	('RhoA', 'Gene', '387', (31, 35))	('CYR61', 'Gene', (177, 182))	('prevented', 'NegReg', (45, 54))	('diminished', 'NegReg', (107, 117))	('Rac1', 'Gene', '5879', (40, 44))	('expression', 'Species', '29278', (122, 132))
23557	24882515	These findings support that in uveal melanoma cells harboring GNAQ mutations, Galphaq primarily signals through Trio to RhoA and Rac1 to promote the nuclear localization and activation of YAP, independent of PLC activation and its downstream regulated events.	('YAP', 'Protein', (188, 191))	('activation', 'MPA', (174, 184))	('uveal melanoma', 'Disease', (31, 45))	('Rac1', 'Gene', '5879', (129, 133))	('uveal melanoma', 'Phenotype', 'HP:0007716', (31, 45))	('Rac1', 'Gene', (129, 133))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('nuclear localization', 'MPA', (149, 169))	('promote', 'PosReg', (137, 144))	('mutations', 'Var', (67, 76))	('Galphaq', 'Chemical', '-', (78, 85))	('uveal melanoma', 'Disease', 'MESH:C536494', (31, 45))	('PLC', 'cellular_component', 'GO:0042824', ('208', '211'))	('localization', 'biological_process', 'GO:0051179', ('157', '169'))	('GNAQ', 'Gene', (62, 66))	('RhoA', 'Gene', (120, 124))	('RhoA', 'Gene', '387', (120, 124))	('Galphaq', 'Gene', (78, 85))
23564	24882515	To explore this possibility, we knocked down LATS1/2 in HEK293 cells, which alone induced only a slight increase in YAP transcriptional activity in confluent cells.	('YAP transcriptional activity', 'MPA', (116, 144))	('LATS1/2', 'Gene', (45, 52))	('knocked down', 'Var', (32, 44))	('HEK293', 'CellLine', 'CVCL:0045', (56, 62))
23565	24882515	Interestingly, the GNAQ oncogene induced the transcriptional activation of YAP even when the repressing signals converging on LATS1/2 were suppressed by knock down of both human LATS isoforms (Figure 4D-F), supporting that activation of YAP by GalphaqQL is not solely dependent on the inhibition of the Hippo pathway.	('LATS', 'Gene', '43651', (178, 182))	('LATS', 'Gene', (178, 182))	('GalphaqQL', 'Chemical', '-', (244, 253))	('knock down', 'Var', (153, 163))	('human', 'Species', '9606', (172, 177))	('YAP', 'Gene', (75, 78))	('LATS', 'Gene', '43651', (126, 130))	('LATS', 'Gene', (126, 130))	('transcriptional', 'MPA', (45, 60))
23569	24882515	Knock down of LATS1/2 resulted in a remarkable increase in the expression of YAP regulated genes in uveal melanoma cells, further supporting that the Hippo pathway still remains active in these cells, restraining maximal YAP activation (Figure 5A and B).	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('restraining', 'NegReg', (201, 212))	('Knock down', 'Var', (0, 10))	('expression', 'Species', '29278', (63, 73))	('uveal melanoma', 'Disease', (100, 114))	('expression', 'MPA', (63, 73))	('maximal YAP activation', 'MPA', (213, 235))	('increase', 'PosReg', (47, 55))	('LATS1/2', 'Gene', (14, 21))	('YAP regulated genes', 'Gene', (77, 96))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
23570	24882515	Even when LATS1/2 was knocked down, inhibition of actin polymerization decreased YAP activity, both in uveal melanoma and GalphaqQL transfected cells (Figure 5B-D), suggesting that F-actin accumulation and LATS inhibition may act in a coordinated fashion.	('LATS', 'Gene', '43651', (10, 14))	('uveal melanoma', 'Disease', 'MESH:C536494', (103, 117))	('uveal melanoma', 'Disease', (103, 117))	('uveal melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('inhibition', 'Var', (36, 46))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('actin polymerization', 'biological_process', 'GO:0030041', ('50', '70'))	('GalphaqQL', 'Chemical', '-', (122, 131))	('decreased', 'NegReg', (71, 80))	('LATS', 'Gene', '43651', (206, 210))	('F-actin', 'cellular_component', 'GO:0031941', ('181', '188'))	('YAP activity', 'MPA', (81, 93))	('LATS', 'Gene', (10, 14))	('LATS', 'Gene', (206, 210))
23576	24882515	Consistently, AMOT knock down had limited impact on YAP-dependent gene expression in uveal melanoma cells, as it is expected to bind YAP poorly in the presence of cytosolic F-actin, but AMOT knock down rescued YAP function inhibition caused by actin depolymerization (Figure 5G and H).	('actin depolymerization', 'biological_process', 'GO:0030042', ('244', '266'))	('YAP', 'Gene', (210, 213))	('expression', 'Species', '29278', (71, 81))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('AMOT', 'Gene', '154796', (186, 190))	('F-actin', 'cellular_component', 'GO:0031941', ('173', '180'))	('AMOT', 'Gene', '154796', (14, 18))	('knock down', 'Var', (191, 201))	('uveal melanoma', 'Phenotype', 'HP:0007716', (85, 99))	('uveal melanoma', 'Disease', 'MESH:C536494', (85, 99))	('AMOT', 'Gene', (14, 18))	('gene expression', 'biological_process', 'GO:0010467', ('66', '81'))	('uveal melanoma', 'Disease', (85, 99))	('actin depolymerization', 'MPA', (244, 266))	('function', 'MPA', (214, 222))	('AMOT', 'Gene', (186, 190))
23579	24882515	For these studies, we established lentiviral delivered shRNAs knocking down YAP and control shRNA in uveal melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('knocking down', 'Var', (62, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (101, 115))	('uveal melanoma', 'Disease', 'MESH:C536494', (101, 115))	('YAP', 'Gene', (76, 79))	('uveal melanoma', 'Disease', (101, 115))
23580	24882515	This approach revealed that YAP knock down resulted in reduced YAP-dependent expression of typical YAP-regulated genes and decreased proliferation of uveal melanoma cells (Figure 6A-C).	('expression', 'MPA', (77, 87))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('decreased', 'NegReg', (123, 132))	('reduced', 'NegReg', (55, 62))	('YAP', 'Gene', (28, 31))	('knock down', 'Var', (32, 42))	('uveal melanoma', 'Phenotype', 'HP:0007716', (150, 164))	('uveal melanoma', 'Disease', (150, 164))	('uveal melanoma', 'Disease', 'MESH:C536494', (150, 164))	('proliferation', 'CPA', (133, 146))	('YAP-regulated', 'Gene', (99, 112))	('expression', 'Species', '29278', (77, 87))
23581	24882515	Furthermore, knock down of YAP led to reduced number of colonies in uveal melanoma cells cultured in 3D matrix, as well as a reduced colony size (Figure 6D).	('YAP', 'Gene', (27, 30))	('reduced', 'NegReg', (38, 45))	('colony size', 'CPA', (133, 144))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('reduced', 'NegReg', (125, 132))	('uveal melanoma', 'Disease', 'MESH:C536494', (68, 82))	('knock down', 'Var', (13, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('uveal melanoma', 'Disease', (68, 82))
23582	24882515	Taking advantage of the ability to establish uveal melanoma xenografts in immune compromised mice, we observed that YAP knockdown reduced tumor size in vivo (Figure 6E).	('YAP', 'Gene', (116, 119))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('uveal melanoma', 'Disease', (45, 59))	('tumor', 'Disease', (138, 143))	('knockdown', 'Var', (120, 129))	('mice', 'Species', '10090', (93, 97))	('reduced', 'NegReg', (130, 137))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('uveal melanoma', 'Disease', 'MESH:C536494', (45, 59))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
23588	24882515	Recent large cancer sequencing efforts have revealed an unexpected high frequency of gain of function mutations in heterotrimeric G protein alpha-subunits.	('heterotrimeric G protein alpha-subunits', 'Protein', (115, 154))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('115', '139'))	('cancer', 'Disease', (13, 19))	('gain of function', 'PosReg', (85, 101))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('mutations', 'Var', (102, 111))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))
23589	24882515	Among them, mutations in the GNAQ oncogenes, GNAQ and GNA11, are now believed to represent the genetic initiating event in uveal melanomas, and in a subset of melanomas arising in the skin among other tumors.	('melanomas', 'Phenotype', 'HP:0002861', (159, 168))	('melanomas', 'Disease', 'MESH:D008545', (129, 138))	('uveal melanomas', 'Disease', 'MESH:C536494', (123, 138))	('GNAQ', 'Gene', (45, 49))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('melanomas', 'Disease', (129, 138))	('GNA11', 'Gene', (54, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (123, 137))	('melanomas', 'Disease', 'MESH:D008545', (159, 168))	('event', 'Reg', (114, 119))	('uveal melanomas', 'Disease', (123, 138))	('uveal melanomas', 'Phenotype', 'HP:0007716', (123, 138))	('melanomas', 'Phenotype', 'HP:0002861', (129, 138))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('melanomas', 'Disease', (159, 168))	('mutations', 'Var', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('GNA11', 'Gene', '2767', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', (201, 207))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
23590	24882515	In this study, we show that YAP activation represents a key molecular event contributing to GNAQ-induced tumorigenesis, which is dependent on the activation of Trio and its regulated Rho GTPases, RhoA and Rac1, in uveal melanoma cells harboring activating GNAQ mutations.	('mutations', 'Var', (261, 270))	('GNAQ-induced', 'Gene', (92, 104))	('activation', 'PosReg', (146, 156))	('uveal melanoma', 'Disease', 'MESH:C536494', (214, 228))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('uveal melanoma', 'Phenotype', 'HP:0007716', (214, 228))	('uveal melanoma', 'Disease', (214, 228))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Rac1', 'Gene', '5879', (205, 209))	('RhoA', 'Gene', (196, 200))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('tumor', 'Disease', (105, 110))	('Rac1', 'Gene', (205, 209))	('RhoA', 'Gene', '387', (196, 200))
23591	24882515	These findings suggest that inhibition of YAP function may represent a suitable pharmacological intervention strategy in uveal melanoma and other hyperproliferative lesions that result from gain of function GNAQ mutations.	('gain of function', 'PosReg', (190, 206))	('uveal melanoma', 'Phenotype', 'HP:0007716', (121, 135))	('hyperproliferative lesions', 'Disease', (146, 172))	('uveal melanoma', 'Disease', (121, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('mutations', 'Var', (212, 221))	('GNAQ', 'Gene', (207, 211))	('uveal melanoma', 'Disease', 'MESH:C536494', (121, 135))
23596	24882515	Despite this, somatic or germline mutations in Hippo pathway genes are uncommon, prompting the exploration of other mechanism(s) underlying YAP activation in each tumor type.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('germline', 'Var', (25, 33))	('tumor', 'Disease', (163, 168))	('Hippo pathway', 'Gene', (47, 60))
23598	24882515	Whether GNAQ-activating mutations and the large family of receptors regulating cell growth through Galphaq affect the Hippo pathway, however, is much less understood.	('Hippo pathway', 'Pathway', (118, 131))	('affect', 'Reg', (107, 113))	('Galphaq', 'Chemical', '-', (99, 106))	('cell growth', 'biological_process', 'GO:0016049', ('79', '90'))	('mutations', 'Var', (24, 33))
23599	24882515	In our study, we found that YAP is a key pro-tumorigenic gene in uveal melanoma cells harboring GNAQ activating mutations, which is critical for uveal melanoma growth and tumor formation as judged by knock down experiments and by the use of small molecule inhibitors.	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('mutations', 'Var', (112, 121))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('uveal melanoma', 'Disease', 'MESH:C536494', (145, 159))	('uveal melanoma', 'Disease', (145, 159))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('uveal melanoma', 'Disease', 'MESH:C536494', (65, 79))	('uveal melanoma', 'Phenotype', 'HP:0007716', (145, 159))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('uveal melanoma', 'Disease', (65, 79))	('YAP', 'Gene', (28, 31))	('GNAQ', 'Gene', (96, 100))	('activating', 'PosReg', (101, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('tumor', 'Disease', (171, 176))	('formation', 'biological_process', 'GO:0009058', ('177', '186'))
23602	24882515	Instead, our results suggest that Galphaq stimulates YAP by a process involving changes in actin dynamics rather than solely on Hippo kinase cascade regulation, resembling recent findings in the context of mechanosensing transduction signals.	('changes', 'Reg', (80, 87))	('YAP', 'Disease', (53, 56))	('transduction', 'biological_process', 'GO:0009293', ('221', '233'))	('stimulates', 'PosReg', (42, 52))	('regulation', 'biological_process', 'GO:0065007', ('149', '159'))	('Galphaq', 'Chemical', '-', (34, 41))	('actin dynamics', 'MPA', (91, 105))	('Galphaq', 'Var', (34, 41))
23608	24882515	In line with this possibility, in uveal melanoma cells LATS1 is phosphorylated in its activation loop, while LATS1/2 knockdown results in a remarkable increase in the transcriptional activity of YAP, indicating that these core Hippo kinases retain a restraining activity on YAP function.	('LATS1', 'Gene', '9113', (55, 60))	('transcriptional activity', 'MPA', (167, 191))	('YAP', 'Gene', (195, 198))	('core', 'cellular_component', 'GO:0019013', ('222', '226'))	('LATS1', 'Gene', (109, 114))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('LATS1', 'Gene', '9113', (109, 114))	('knockdown', 'Var', (117, 126))	('uveal melanoma', 'Phenotype', 'HP:0007716', (34, 48))	('uveal melanoma', 'Disease', 'MESH:C536494', (34, 48))	('increase', 'PosReg', (151, 159))	('LATS1', 'Gene', (55, 60))	('uveal melanoma', 'Disease', (34, 48))
23609	24882515	Instead, disruption of the actin cytoskeleton diminishes both the basal activity of YAP and YAP hyperactivation caused by LATS1/2 reduced expression.	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('27', '45'))	('basal', 'CPA', (66, 71))	('expression', 'Species', '29278', (138, 148))	('LATS1/2', 'Gene', (122, 129))	('hyperactivation', 'Disease', 'MESH:D011504', (96, 111))	('hyperactivation', 'Disease', (96, 111))	('expression', 'MPA', (138, 148))	('reduced', 'NegReg', (130, 137))	('diminishes', 'NegReg', (46, 56))	('disruption', 'Var', (9, 19))
23619	24882515	A high rate of mutations in GPCRs and G proteins has been recently identified in melanoma.	('G proteins', 'Protein', (38, 48))	('GPCRs', 'Protein', (28, 33))	('mutations', 'Var', (15, 24))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('identified', 'Reg', (67, 77))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))
23620	24882515	Strikingly, mutations in GNAQ and GNA11 have been observed in the majority of uveal melanomas, 83% of blue naevi, 6% of cutaneous melanomas, and 59% of tumors arising in the meninges.	('uveal melanoma', 'Phenotype', 'HP:0007716', (78, 92))	('GNA11', 'Gene', '2767', (34, 39))	('tumors', 'Disease', (152, 158))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (120, 139))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (120, 139))	('uveal melanomas', 'Disease', (78, 93))	('uveal melanomas', 'Phenotype', 'HP:0007716', (78, 93))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('blue naevi', 'Disease', (102, 112))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('cutaneous melanomas', 'Disease', (120, 139))	('melanomas', 'Phenotype', 'HP:0002861', (130, 139))	('GNAQ', 'Gene', (25, 29))	('GNA11', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('observed', 'Reg', (50, 58))	('mutations', 'Var', (12, 21))	('naevi', 'Phenotype', 'HP:0003764', (107, 112))	('uveal melanomas', 'Disease', 'MESH:C536494', (78, 93))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('blue naevi', 'Phenotype', 'HP:0100814', (102, 112))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (120, 138))
23621	24882515	Somatic mosaic mutations in GNAQ have been also recently identified in port-wine stains in infants and as the genetic alteration underlying Sturge-Weber syndrome, while GNA11 gain of function mutations causes autosomal dominant hypocalcemia.	('hypocalcemia', 'Phenotype', 'HP:0002901', (228, 240))	('GNA11', 'Gene', '2767', (169, 174))	('GNA11', 'Gene', (169, 174))	('port-wine stains', 'Phenotype', 'HP:0001052', (71, 87))	('gain of function', 'PosReg', (175, 191))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (140, 161))	('port-wine stains', 'Disease', (71, 87))	('hypocalcemia', 'Disease', 'MESH:D006996', (228, 240))	('mosaic mutations', 'Var', (8, 24))	('Sturge-Weber syndrome', 'Disease', (140, 161))	('Weber syndrome', 'Phenotype', 'HP:0002277', (147, 161))	('hypocalcemia', 'Disease', (228, 240))	('GNAQ', 'Gene', (28, 32))	('mutations', 'Var', (192, 201))	('infants', 'Species', '9606', (91, 98))
23622	24882515	The growth promoting potential of GNAQ mutants requires the activation of a complex signaling network stimulating the expression of AP-1 regulated genes.	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('expression', 'Species', '29278', (118, 128))	('growth', 'MPA', (4, 10))	('mutants', 'Var', (39, 46))	('GNAQ', 'Gene', (34, 38))	('AP-1', 'cellular_component', 'GO:0005907', ('132', '136'))	('expression', 'MPA', (118, 128))
23626	24882515	Both YAP knock down and verteporfin treatment reduce uveal melanoma cell growth in vitro and tumor formation in vivo.	('reduce', 'NegReg', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cell growth', 'biological_process', 'GO:0016049', ('68', '79'))	('knock down', 'Var', (9, 19))	('tumor', 'Disease', (93, 98))	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('uveal melanoma', 'Disease', (53, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (53, 67))	('YAP', 'Gene', (5, 8))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('verteporfin', 'Chemical', 'MESH:D000077362', (24, 35))	('formation', 'biological_process', 'GO:0009058', ('99', '108'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
23629	24882515	Indeed, although it is unclear whether VP may be also active in cancers driven by other tumor promoting genes, we can postulate that the transcriptional co-activator YAP may represent a suitable therapeutic target for the treatment of uveal melanoma and other human diseases that result from gain of function mutations in the GNAQ and GNA11 oncogenes.	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('mutations', 'Var', (309, 318))	('VP', 'Chemical', 'MESH:D000077362', (39, 41))	('GNA11', 'Gene', (335, 340))	('uveal melanoma', 'Disease', (235, 249))	('GNAQ', 'Gene', (326, 330))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('uveal melanoma', 'Disease', 'MESH:C536494', (235, 249))	('cancers', 'Disease', (64, 71))	('GNA11', 'Gene', '2767', (335, 340))	('uveal melanoma', 'Phenotype', 'HP:0007716', (235, 249))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('gain of function', 'PosReg', (292, 308))	('tumor', 'Disease', (88, 93))	('human', 'Species', '9606', (260, 265))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
23647	24882515	Recent findings revealed that activating mutations in GNAQ and GNA11, encoding members of the Galphaq family of G protein alpha subunits, drive uveal melanoma oncogenesis.	('Galphaq', 'Chemical', '-', (94, 101))	('GNAQ', 'Gene', (54, 58))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('GNA11', 'Gene', (63, 68))	('activating mutations', 'Var', (30, 50))	('oncogenesis', 'biological_process', 'GO:0007048', ('159', '170'))	('uveal melanoma oncogenesis', 'Disease', (144, 170))	('drive', 'PosReg', (138, 143))	('GNA11', 'Gene', '2767', (63, 68))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('uveal melanoma', 'Phenotype', 'HP:0007716', (144, 158))	('uveal melanoma oncogenesis', 'Disease', 'MESH:C536494', (144, 170))
23655	24886631	Our report indicates a significant higher prevalence of antibodies against SV-40 capsid protein antigens in serum samples from UM patients compared to controls.	('SV-40', 'Species', '1891767', (75, 80))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('patients', 'Species', '9606', (130, 138))	('antibodies', 'Var', (56, 66))	('SV-40', 'Gene', (75, 80))	('higher', 'PosReg', (35, 41))	('UM', 'Phenotype', 'HP:0007716', (127, 129))
23658	24886631	BAP1, a gene encoding a deubiquitinant enzyme, is mutated in several UM cases and in the malignant pleural mesothelioma (MPM), a human tumour found be associated with the Simian Virus 40 (SV-40) infection.	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (89, 119))	('infection', 'Disease', (195, 204))	('BAP1', 'Gene', (0, 4))	('infection', 'Disease', 'MESH:D007239', (195, 204))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (99, 119))	('malignant pleural mesothelioma', 'Disease', (89, 119))	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('SV-40', 'Species', '1891767', (188, 193))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('mutated', 'Var', (50, 57))	('human', 'Species', '9606', (129, 134))	('Simian Virus 40', 'Species', '1891767', (171, 186))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('BAP1', 'Gene', '8314', (0, 4))	('tumour', 'Disease', (135, 141))
23667	24886631	The overall prevalence, by combining SV-40-positive sera for both VP1 B and VP2/3 C peptides, in UM patients was 33%, higher than that detected in HSON or HS, 17% and 15% respectively.	('VP1 B', 'Var', (66, 71))	('UM', 'Phenotype', 'HP:0007716', (97, 99))	('patients', 'Species', '9606', (100, 108))	('VP2', 'Gene', (76, 79))	('VP2', 'Gene', '29031016', (76, 79))	('SV-40', 'Species', '1891767', (37, 42))	('sera', 'molecular_function', 'GO:0004617', ('52', '56'))
23680	23335975	MicroRNA-193b Enhances Tumor Progression via Down Regulation of Neurofibromin 1 Despite improvements in therapeutic approaches for head and neck squamous cell carcinomas (HNSCC), clinical outcome has remained disappointing, with 5-year overall survival rates hovering around 40-50%, underscoring an urgent need to better understand the biological bases of this disease.	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('Enhances', 'PosReg', (14, 22))	('Neurofibromin', 'Gene', '4763', (64, 77))	('Neurofibromin', 'Gene', (64, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (145, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (159, 169))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (131, 169))	('Down Regulation', 'NegReg', (45, 60))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (140, 169))	('Tumor Progression', 'CPA', (23, 40))	('MicroRNA-193b', 'Var', (0, 13))	('HNSCC', 'Phenotype', 'HP:0012288', (171, 176))	('Tumor', 'Phenotype', 'HP:0002664', (23, 28))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (145, 169))	('neck squamous cell carcinomas', 'Disease', (140, 169))	('neck', 'cellular_component', 'GO:0044326', ('140', '144'))
23684	23335975	Concordantly, miR-193b knockdown decreased NF1 transcript and protein levels significantly.	('miR-193b', 'Gene', (14, 22))	('knockdown', 'Var', (23, 32))	('decreased', 'NegReg', (33, 42))	('miR-193b', 'Gene', '574455', (14, 22))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
23686	23335975	Moreover, p-ERK, a downstream target of NF1 was also suppressed after miR-193b knockdown.	('miR-193b', 'Gene', '574455', (70, 78))	('p-ERK', 'Gene', (10, 15))	('miR-193b', 'Gene', (70, 78))	('ERK', 'molecular_function', 'GO:0004707', ('12', '15'))	('suppressed', 'NegReg', (53, 63))	('knockdown', 'Var', (79, 88))	('p-ERK', 'Gene', '9451', (10, 15))
23687	23335975	FaDu cells treated with a p-ERK inhibitor (U0126) phenocopied the reduced cell proliferation, migration and invasion observed with miR-193b knockdown.	('reduced', 'NegReg', (66, 73))	('cell proliferation', 'CPA', (74, 92))	('miR-193b', 'Gene', '574455', (131, 139))	('migration', 'CPA', (94, 103))	('miR-193b', 'Gene', (131, 139))	('ERK', 'molecular_function', 'GO:0004707', ('28', '31'))	('p-ERK', 'Gene', '9451', (26, 31))	('U0126', 'Chemical', 'MESH:C113580', (43, 48))	('knockdown', 'Var', (140, 149))	('invasion', 'CPA', (108, 116))	('cell proliferation', 'biological_process', 'GO:0008283', ('74', '92'))	('p-ERK', 'Gene', (26, 31))
23693	23335975	In recent years, aberrant miRNA expression has been recognized to enhance cancer progression via their mRNA targets.	('aberrant', 'Var', (17, 25))	('enhance', 'PosReg', (66, 73))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('miRNA expression', 'Protein', (26, 42))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
23706	23335975	Briefly, 72 hours after transfection with LNA-scrambled or LNA-193b, FaDu cells were re-seeded in 6-well plates, and incubated at 37 C under 5% CO2 for 8-12 days.	('CO2', 'Chemical', '-', (144, 147))	('LNA-193b', 'Var', (59, 67))	('LNA-scrambled', 'Var', (42, 55))
23714	23335975	Another vector was constructed which carried a mutation of the NF1 3'UTR in the seed region of the miR-193b binding site using the indicated primers (Table S1B).	('miR-193b', 'Gene', (99, 107))	('mutation', 'Var', (47, 55))	('miR-193b', 'Gene', '574455', (99, 107))	('NF1', 'Gene', (63, 66))	('binding', 'molecular_function', 'GO:0005488', ('108', '115'))
23715	23335975	Cells were then transfected with 40 nM of LNA-scrambled or LNA-193b, and 4-6 hours later, cells were co-transfected with 100 ng of pMIR-REPORT or pMIR-REPORT NF1-UTR, along with 50 ng of pRL-SV40 vector (Promega Biosciences) carrying the Renilla luciferase gene.	('Renilla luciferase', 'Disease', (238, 256))	('LNA-193b', 'Var', (59, 67))	('Renilla luciferase', 'Disease', 'None', (238, 256))
23721	23335975	When blotting for p-ERK at the 72-hour time point, the media was changed 24 hours after transfection with LNA-193b and LNA-scrambled since no protein otherwise would be detected.	('p-ERK', 'Gene', '9451', (18, 23))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('p-ERK', 'Gene', (18, 23))	('LNA-193b', 'Var', (106, 114))	('ERK', 'molecular_function', 'GO:0004707', ('20', '23'))
23734	23335975	Corroboration of sustained reduction in miR-193b expression after LNA-193b was observed for up to 72 hours for all three HNSCC cell lines (Fig.	('HNSCC', 'Phenotype', 'HP:0012288', (121, 126))	('miR-193b', 'Gene', '574455', (40, 48))	('expression', 'MPA', (49, 59))	('miR-193b', 'Gene', (40, 48))	('LNA-193b', 'Var', (66, 74))	('reduction', 'NegReg', (27, 36))
23735	23335975	Cell cycle analysis was employed to examine the mode of cytotoxicity inflicted by miR-193b knock-down.	('cytotoxicity', 'Disease', 'MESH:D064420', (56, 68))	('miR-193b', 'Gene', '574455', (82, 90))	('miR-193b', 'Gene', (82, 90))	('cytotoxicity', 'Disease', (56, 68))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('knock-down', 'Var', (91, 101))
23737	23335975	Tumorigenicity was measured in vivo using SCID mice injected intra-muscularly with FaDu cells transfected with LNA-193b or LNA-scrambled.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumorigenicity', 'MPA', (0, 14))	('SCID', 'Disease', 'MESH:D053632', (42, 46))	('LNA-193b', 'Var', (111, 119))	('SCID', 'Disease', (42, 46))	('mice', 'Species', '10090', (47, 51))
23743	23335975	To validate these candidate targets, mRNA transcript levels were measured by qRT-PCR at 72 hours post-miR-193b knockdown.	('miR-193b', 'Gene', (102, 110))	('knockdown', 'Var', (111, 120))	('mRNA transcript levels', 'MPA', (37, 59))	('miR-193b', 'Gene', '574455', (102, 110))
23744	23335975	The results demonstrated that the level of 3 candidate targets (PER2, DUSP1 and NF1) increased significantly by >1.5-fold after miR-193b knockdown, compared to the negative control (Fig.	('DUSP1', 'Gene', (70, 75))	('miR-193b', 'Gene', '574455', (128, 136))	('miR-193b', 'Gene', (128, 136))	('NF1', 'Gene', (80, 83))	('DUSP1', 'Gene', '1843', (70, 75))	('PER2', 'Gene', (64, 68))	('knockdown', 'Var', (137, 146))	('increased', 'PosReg', (85, 94))	('PER2', 'Gene', '8864', (64, 68))
23746	23335975	After miR-193b knockdown, both NF1 and PER2 transcript (Fig.	('knockdown', 'Var', (15, 24))	('PER2', 'Gene', (39, 43))	('miR-193b', 'Gene', '574455', (6, 14))	('NF1', 'Gene', (31, 34))	('PER2', 'Gene', '8864', (39, 43))	('miR-193b', 'Gene', (6, 14))
23749	23335975	This effect was completely abrogated after mutating the NF1 3'UTR of miR-193b, thereby validating NF1 as a bona fide miR-193b target (Fig.	('abrogated', 'NegReg', (27, 36))	('miR-193b', 'Gene', '574455', (117, 125))	('miR-193b', 'Gene', (69, 77))	('miR-193b', 'Gene', (117, 125))	('mutating', 'Var', (43, 51))	('miR-193b', 'Gene', '574455', (69, 77))	('NF1', 'Gene', (56, 59))
23758	23335975	FaDu cells treated with U0126 demonstrated a reduction in cell viability compared to the negative control (DMSO) (Fig.	('cell viability', 'CPA', (58, 72))	('U0126', 'Chemical', 'MESH:C113580', (24, 29))	('U0126', 'Var', (24, 29))	('DMSO', 'Chemical', 'MESH:D004121', (107, 111))	('reduction', 'NegReg', (45, 54))
23759	23335975	Furthermore, FaDu cells treated with U0126 illustrated a significant reduction in migration (50%) and invasion (45%) compared to cells treated with DMSO (Figs.	('U0126', 'Var', (37, 42))	('invasion', 'CPA', (102, 110))	('migration', 'CPA', (82, 91))	('U0126', 'Chemical', 'MESH:C113580', (37, 42))	('reduction', 'NegReg', (69, 78))	('DMSO', 'Chemical', 'MESH:D004121', (148, 152))
23766	23335975	Finally, when the expression of miR-193b from the 51 HNSCC patients previous profiled by our lab was dichotomized between high miR-193b (> median) vs. low (<= median) expression, the former group experienced a worse disease-free survival compared to the latter (HR = 1.41; p = 0.18); although statistical significance was not attained due to the small cohort size (Fig.	('miR-193b', 'Gene', '574455', (32, 40))	('disease-free survival', 'CPA', (216, 237))	('high', 'Var', (122, 126))	('HNSCC', 'Phenotype', 'HP:0012288', (53, 58))	('miR-193b', 'Gene', (32, 40))	('miR-193b', 'Gene', '574455', (127, 135))	('patients', 'Species', '9606', (59, 67))	('miR-193b', 'Gene', (127, 135))
23770	23335975	Furthermore, HNSCCs with higher miR-193b expression levels fared worse than lower miR-193b tumours, which all collectively demonstrate that dysregulation of the miR-193b~NF1~ERK axis is yet another mechanism which can drive HNSCC progression.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('tumours', 'Disease', 'MESH:D009369', (91, 98))	('miR-193b', 'Gene', '574455', (32, 40))	('HNSCC', 'Disease', (224, 229))	('dysregulation', 'Var', (140, 153))	('HNSCC', 'Phenotype', 'HP:0012288', (224, 229))	('ERK', 'molecular_function', 'GO:0004707', ('174', '177'))	('tumours', 'Disease', (91, 98))	('miR-193b', 'Gene', (32, 40))	('ERK', 'Gene', '5594', (174, 177))	('miR-193b', 'Gene', '574455', (82, 90))	('miR-193b', 'Gene', (82, 90))	('miR-193b', 'Gene', '574455', (161, 169))	('ERK', 'Gene', (174, 177))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('miR-193b', 'Gene', (161, 169))	('HNSCC', 'Phenotype', 'HP:0012288', (13, 18))
23773	23335975	Alterations in key players of the miRNA processing machinery, such as Dicer, Drosha, DGCR8, AGO2 or XPO5, have been reported to contribute to aberrant miRNA expression.	('Dicer', 'Gene', '23405', (70, 75))	('DGCR8', 'Gene', '54487', (85, 90))	('Dicer', 'Gene', (70, 75))	('XPO5', 'Gene', '57510', (100, 104))	('miRNA processing', 'biological_process', 'GO:0035196', ('34', '50'))	('AGO2', 'Gene', (92, 96))	('Alterations', 'Var', (0, 11))	('Drosha', 'Gene', (77, 83))	('AGO2', 'Gene', '27161', (92, 96))	('DGCR8', 'Gene', (85, 90))	('miRNA expression', 'MPA', (151, 167))	('Drosha', 'Gene', '29102', (77, 83))	('XPO5', 'Gene', (100, 104))	('contribute', 'Reg', (128, 138))
23778	23335975	In our study, miR-193b appears to be mediating oncogenic signals; other reports in breast, prostate and leukemia however, have identified miR-193b to be a tumour suppressor, wherein low miR-193b expression promoted tumour progression.	('miR-193b', 'Gene', (138, 146))	('tumour', 'Disease', 'MESH:D009369', (215, 221))	('miR-193b', 'Gene', (14, 22))	('miR-193b', 'Gene', '574455', (186, 194))	('miR-193b', 'Gene', (186, 194))	('tumour', 'Disease', (215, 221))	('leukemia', 'Disease', (104, 112))	('low', 'Var', (182, 185))	('promoted', 'PosReg', (206, 214))	('leukemia', 'Disease', 'MESH:D007938', (104, 112))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('miR-193b', 'Gene', '574455', (138, 146))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Phenotype', 'HP:0002664', (215, 221))	('miR-193b', 'Gene', '574455', (14, 22))	('tumour', 'Disease', (155, 161))
23788	23335975	Furthermore, mutations and genomic alterations of NF1 have been reported in a number of other cancer cells and tumor tissues.	('genomic alterations', 'Var', (27, 46))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('NF1', 'Gene', (50, 53))	('tumor', 'Disease', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('reported', 'Reg', (64, 72))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
23796	23335975	The relevance of the ERK pathway in HNSCC has also been reported by others, wherein treatment of HNSCC cells (UM-SCC-9 and UM-SCC-11B) with U0126 decreased cell viability, confirming the observations made in this current study.	('ERK', 'molecular_function', 'GO:0004707', ('21', '24'))	('HNSCC cells', 'CellLine', 'CVCL:5985', (97, 108))	('HNSCC', 'Phenotype', 'HP:0012288', (97, 102))	('U0126', 'Var', (140, 145))	('decreased', 'NegReg', (146, 155))	('HNSCC', 'Phenotype', 'HP:0012288', (36, 41))	('ERK', 'Gene', '5594', (21, 24))	('UM-SCC-9', 'CellLine', 'CVCL:7793', (110, 118))	('cell viability', 'CPA', (156, 170))	('U0126', 'Chemical', 'MESH:C113580', (140, 145))	('ERK', 'Gene', (21, 24))
23798	23335975	Colorectal cancer patients with activating RAS mutations are resistant to EGFR inhibitors such as Cetuximab.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('EGFR', 'molecular_function', 'GO:0005006', ('74', '78'))	('RAS', 'Gene', (43, 46))	('mutations', 'Var', (47, 56))	('Cetuximab', 'Chemical', 'MESH:D000068818', (98, 107))	('resistant', 'MPA', (61, 70))	('EGFR', 'Gene', '1956', (74, 78))	('patients', 'Species', '9606', (18, 26))	('Colorectal cancer', 'Disease', (0, 17))	('activating', 'PosReg', (32, 42))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('EGFR', 'Gene', (74, 78))
23803	23335975	In this current study, we established an interaction between miR-193b and PER2, whereby miR-193b knockdown increased PER2 transcript and protein expression (Fig.	('protein expression', 'MPA', (137, 155))	('PER2', 'Gene', (117, 121))	('knockdown', 'Var', (97, 106))	('increased', 'PosReg', (107, 116))	('PER2', 'Gene', '8864', (117, 121))	('transcript', 'MPA', (122, 132))	('miR-193b', 'Gene', '574455', (88, 96))	('miR-193b', 'Gene', (88, 96))	('PER2', 'Gene', (74, 78))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('miR-193b', 'Gene', '574455', (61, 69))	('miR-193b', 'Gene', (61, 69))	('PER2', 'Gene', '8864', (74, 78))
23806	23335975	Hence, in this current report, we propose a miRNA-mediated mechanism for PER2 under-expression, which in turn, promotes HNSCC progression.	('PER2', 'Gene', (73, 77))	('PER2', 'Gene', '8864', (73, 77))	('HNSCC', 'Disease', (120, 125))	('promotes', 'PosReg', (111, 119))	('under-expression', 'Var', (78, 94))	('HNSCC', 'Phenotype', 'HP:0012288', (120, 125))
23810	23335975	Pre-clinical studies have certainly demonstrated the growth inhibitory effects of p-ERK inactivation in HNSCC cells, along with reduced migration and invasion.	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('HNSCC', 'Disease', (104, 109))	('reduced', 'NegReg', (128, 135))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('growth inhibitory', 'MPA', (53, 70))	('invasion', 'CPA', (150, 158))	('p-ERK', 'Gene', '9451', (82, 87))	('p-ERK', 'Gene', (82, 87))	('migration', 'CPA', (136, 145))	('ERK', 'molecular_function', 'GO:0004707', ('84', '87'))	('HNSCC cells', 'CellLine', 'CVCL:5985', (104, 115))	('inactivation', 'Var', (88, 100))
23831	22798969	Somatic chromosomal abnormalities including monosomy of chromosome 3 and chromosome 8 gains have been found to be predictive of metastatic development.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (8, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('gains', 'PosReg', (86, 91))	('monosomy', 'Var', (44, 52))	('chromosome', 'cellular_component', 'GO:0005694', ('56', '66'))	('metastatic development', 'CPA', (128, 150))	('chromosomal abnormalities', 'Disease', (8, 33))	('chromosome 8', 'Gene', (73, 85))
23832	22798969	Importantly, monosomy of chromosome 3 in metastatic UM has now been associated with a poor response to metastatic treatment, whereas disomy and partial change of chromosome 3 is associated with a better response.	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('disomy', 'Disease', 'MESH:D024182', (133, 139))	('monosomy', 'Var', (13, 21))	('chromosome', 'cellular_component', 'GO:0005694', ('25', '35'))	('disomy', 'Disease', (133, 139))	('chromosome', 'cellular_component', 'GO:0005694', ('162', '172'))
23845	18586737	When these checkpoints are bypassed the genome may evolve and undergo alterations to a point where the cell can become premalignant and further genome alterations lead to invasive cancers.	('invasive cancers', 'Disease', 'MESH:D009362', (171, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('invasive cancers', 'Disease', (171, 187))	('lead to', 'Reg', (163, 170))	('alterations', 'Var', (151, 162))
23847	18586737	A CNV can be a deletion or a gain of small or large DNA regions, an amplification or an aneuploidy (change in chromosome number).	('CNV', 'Var', (2, 5))	('aneuploidy', 'Disease', (88, 98))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('gain', 'PosReg', (29, 33))	('aneuploidy', 'Disease', 'MESH:D000782', (88, 98))
23848	18586737	Many cancers present recurrent CNVs of the genome, like, for example, monoploidy of chromosome 3 in uveal melanoma (Speicher et al.,), loss of chromosome 9 and amplification of the region of cyclin D1 (11q13) in bladder carcinomas (Blaveri et al.,), loss of 1p and gain of 17q in neuroblastoma (Bown et al.,; Van Roy et al.,), EGFR amplification and deletion in 1p and 19q in gliomas (Idbaih et al.,) or amplifications of 1q, 8q24, 11q13, 17q21-q23 and 20q13 in breast cancer (Yao et al.,).	('neuroblastoma', 'Disease', 'MESH:D009447', (280, 293))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('bladder carcinomas', 'Disease', 'MESH:D001749', (212, 230))	('breast cancer', 'Disease', (462, 475))	('uveal melanoma', 'Disease', (100, 114))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('deletion', 'Var', (350, 358))	('chromosome', 'cellular_component', 'GO:0005694', ('143', '153'))	('loss', 'Var', (135, 139))	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('bladder carcinomas', 'Disease', (212, 230))	('gliomas', 'Disease', (376, 383))	('gain', 'PosReg', (265, 269))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('EGFR', 'Gene', (327, 331))	('cyclin D1', 'Gene', (191, 200))	('EGFR', 'molecular_function', 'GO:0005006', ('327', '331'))	('cancer', 'Phenotype', 'HP:0002664', (469, 475))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('amplifications', 'Var', (404, 418))	('gliomas', 'Disease', 'MESH:D005910', (376, 383))	('cyclin D1', 'Gene', '595', (191, 200))	('cyclin', 'molecular_function', 'GO:0016538', ('191', '197'))	('loss', 'Var', (250, 254))	('breast cancer', 'Phenotype', 'HP:0003002', (462, 475))	('gliomas', 'Phenotype', 'HP:0009733', (376, 383))	('carcinomas', 'Phenotype', 'HP:0030731', (220, 230))	('neuroblastoma', 'Disease', (280, 293))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('cancers', 'Disease', (5, 12))	('EGFR', 'Gene', '1956', (327, 331))	('neuroblastoma', 'Phenotype', 'HP:0003006', (280, 293))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (212, 230))	('breast cancer', 'Disease', 'MESH:D001943', (462, 475))
23898	18586737	Interestingly, we retrieve the regions whose alteration was already reported as recurrent events of uveal melanoma: chromosomes 3, 1p, 6q, 8p, 8q, 16q.	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('uveal melanoma', 'Disease', (100, 114))	('chromosomes 3', 'Var', (116, 129))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
23946	17125516	EpCAM overexpression is correlated with poor disease free suvival in breast cancer, and loss of EpCAM expression in gastric adenocarcinoma has been reported to be associated with poor TNM staging prognosis, although inconsistent.	('poor', 'NegReg', (40, 44))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (116, 138))	('TNM', 'Gene', (184, 187))	('EpCAM', 'Gene', (96, 101))	('gastric adenocarcinoma', 'Disease', (116, 138))	('disease free suvival', 'CPA', (45, 65))	('expression', 'MPA', (102, 112))	('EpCAM', 'Gene', '4072', (0, 5))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('EpCAM', 'Gene', '4072', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Disease', (69, 82))	('loss', 'Var', (88, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('overexpression', 'PosReg', (6, 20))	('TNM', 'Gene', '10178', (184, 187))	('EpCAM', 'Gene', (0, 5))
23966	34031440	Bisbee exhibits improved sensitivity and specificity over existing approaches and can be used to identify tissue-specific splice variants whose protein-level expression can be confirmed by mass spectrometry.	('splice variants', 'Var', (122, 137))	('Bisbee', 'Chemical', '-', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('sensitivity', 'MPA', (25, 36))
23967	34031440	We also applied Bisbee to assess evidence for a pathogenic splicing variant contributing to a rare disease and to identify tumor-specific splice isoforms associated with an oncogenic mutation.	('tumor', 'Disease', (123, 128))	('splicing variant', 'Var', (59, 75))	('contributing', 'Reg', (76, 88))	('splicing', 'biological_process', 'GO:0045292', ('59', '67'))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('pathogenic', 'Reg', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('Bisbee', 'Chemical', '-', (16, 22))
23969	34031440	For example, global dysregulation of splicing, as well as mutations in genes regulating splicing, such as SF3B1, have been observed in a variety of tumors.	('mutations', 'Var', (58, 67))	('splicing', 'MPA', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('SF3B1', 'Gene', (106, 111))	('SF3B1', 'Gene', '23451', (106, 111))	('observed', 'Reg', (123, 131))	('splicing', 'biological_process', 'GO:0045292', ('88', '96'))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('splicing', 'biological_process', 'GO:0045292', ('37', '45'))
23976	34031440	The analysis of splicing outliers may also be used to identify splice variant-induced antigens in a target individual's tumor that do not exist in normal tissues.	('splice variant-induced', 'Var', (63, 85))	('splicing', 'biological_process', 'GO:0045292', ('16', '24'))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
23977	34031440	In addition, some rare Mendelian disorders are caused by variants that disrupt splicing.	('Mendelian disorders', 'Disease', 'MESH:D030342', (23, 42))	('caused by', 'Reg', (47, 56))	('splicing', 'MPA', (79, 87))	('Mendelian disorders', 'Disease', (23, 42))	('variants', 'Var', (57, 65))	('splicing', 'biological_process', 'GO:0045292', ('79', '87'))
23980	34031440	Alternative splicing may also give rise to novel protein sequences in a cancer cell that could be recognized by the immune system.	('protein', 'Protein', (49, 56))	('give rise to', 'Reg', (30, 42))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Alternative splicing', 'Var', (0, 20))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('splicing', 'biological_process', 'GO:0045292', ('12', '20'))	('cancer', 'Disease', (72, 78))
23990	34031440	In order to examine the utility of the Bisbee package for research and clinical applications, we analyzed disease-causing splice mutation in the nuclear-encoded mitochondrial methionyl-tRNA formyltransferase (MTFMT).	('Bisbee', 'Chemical', '-', (39, 45))	('disease-causing', 'Reg', (106, 121))	('MTFMT', 'Gene', '123263', (209, 214))	('tRNA', 'molecular_function', 'GO:0030533', ('185', '189'))	('splice mutation', 'Var', (122, 137))	('MTFMT', 'Gene', (209, 214))	('methionyl-tRNA formyltransferase', 'Gene', (175, 207))	('methionyl-tRNA formyltransferase', 'Gene', '123263', (175, 207))
23991	34031440	We previously identified homozygous mutation (c. 626 C > T) in the MTFMT gene in three children from two unrelated families (Clinvar Accession#VCV000039827.4) with Leigh syndrome and combined oxidative phosphorylation (OXPHOS) deficiency.	('children', 'Species', '9606', (87, 95))	('deficiency', 'Disease', (227, 237))	('626 C > T', 'SUBSTITUTION', 'None', (49, 58))	('deficiency', 'Disease', 'MESH:D007153', (227, 237))	('626 C > T', 'Var', (49, 58))	('Leigh syndrome', 'Disease', 'MESH:D007888', (164, 178))	('MTFMT', 'Gene', '123263', (67, 72))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('192', '217'))	('OXPHOS', 'biological_process', 'GO:0002082', ('219', '225'))	('MTFMT', 'Gene', (67, 72))	('Leigh syndrome', 'Disease', (164, 178))
23992	34031440	The MTFMT mutation c. 626 C > T in the coding region resulted in a Ser209Leu (S209L) amino acid substitution, which is likely a non-pathogenic event.	('resulted in', 'Reg', (53, 64))	('S209L', 'Mutation', 'rs201431517', (78, 83))	('Ser', 'cellular_component', 'GO:0005790', ('67', '70'))	('Ser209Leu', 'Var', (67, 76))	('626 C > T', 'SUBSTITUTION', 'None', (22, 31))	('626 C > T', 'Var', (22, 31))	('Ser209Leu', 'SUBSTITUTION', 'None', (67, 76))	('MTFMT', 'Gene', '123263', (4, 9))	('MTFMT', 'Gene', (4, 9))
23993	34031440	However, c.626 C > T is predicted to generate a splicing suppressor that results in skipping of exon 4, leading to frame shift and truncation of the protein (p. R181SfsX5).	('p. R181SfsX5', 'Mutation', 'p.R181SfsX5', (158, 170))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('leading to', 'Reg', (104, 114))	('truncation', 'MPA', (131, 141))	('splicing', 'biological_process', 'GO:0045292', ('48', '56'))	('frame shift', 'MPA', (115, 126))	('protein', 'Protein', (149, 156))	('c.626 C > T', 'Mutation', 'rs201431517', (9, 20))	('skipping', 'MPA', (84, 92))	('c.626 C > T', 'Var', (9, 20))
24003	34031440	We selected the TCGA uveal melanoma dataset as an example application as there is a recurrent mutation in the splicing factor 3B1 gene (SF3B1) that has been previously shown to cause aberrant 3' splice site usage.	('SF3B1', 'Gene', (136, 141))	("3' splice site usage", 'MPA', (192, 212))	('SF3B1', 'Gene', '23451', (136, 141))	('splicing', 'biological_process', 'GO:0045292', ('110', '118'))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('mutation', 'Var', (94, 102))	('cause', 'Reg', (177, 182))	('uveal melanoma', 'Phenotype', 'HP:0007716', (21, 35))
24005	34031440	In examining the total number of splice outliers per patient, we observed a large increase in alternative 3' splice site outliers with SF3B1 mutation as well as significantly increased exon skipping, intron retention, and mutually exclusive exon outlier burden (Fig.	('intron retention', 'MPA', (200, 216))	('exon skipping', 'MPA', (185, 198))	('retention', 'biological_process', 'GO:0051235', ('207', '216'))	('SF3B1', 'Gene', (135, 140))	('increase', 'PosReg', (82, 90))	('increased', 'PosReg', (175, 184))	('mutation', 'Var', (141, 149))	('patient', 'Species', '9606', (53, 60))	('SF3B1', 'Gene', '23451', (135, 140))
24006	34031440	We also ran Bisbee Diff to identify differentially spliced events between SF3B1 mutant and wild-type tumors.	('Bisbee', 'Chemical', '-', (12, 18))	('SF3B1', 'Gene', '23451', (74, 79))	('mutant', 'Var', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('SF3B1', 'Gene', (74, 79))	('tumors', 'Disease', (101, 107))
24008	34031440	previously identified differentially spliced events between SF3B1 mutant and wild-type tumors in an independent dataset, and selected seven of these events to validate in isogenic cell lines using a mini-gene splice assay.	('SF3B1', 'Gene', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mutant', 'Var', (66, 72))	('SF3B1', 'Gene', '23451', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
24010	34031440	In order to identify protein isoforms that may be specific to SF3B1 mutant tumors, we selected splice events that were common between the differential splicing and outlier analysis (494) and then identified those predicted to result in altered protein sequence (321).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('protein', 'cellular_component', 'GO:0003675', ('244', '251'))	('altered', 'Reg', (236, 243))	('SF3B1', 'Gene', (62, 67))	('protein sequence', 'MPA', (244, 260))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('splicing', 'biological_process', 'GO:0045292', ('151', '159'))	('tumors', 'Disease', (75, 81))	('SF3B1', 'Gene', '23451', (62, 67))	('mutant', 'Var', (68, 74))
24011	34031440	These events are primarily alternative 3' events causing insertions or frame disruptions resulting in novel protein isoforms in the uveal melanoma tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (132, 153))	('uveal melanoma', 'Phenotype', 'HP:0007716', (132, 146))	('uveal melanoma tumors', 'Disease', (132, 153))	('frame disruptions', 'Var', (71, 88))	('resulting', 'Reg', (89, 98))	('insertions', 'Var', (57, 67))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('protein isoforms', 'MPA', (108, 124))
24012	34031440	In addition to observing splice events associated with SF3B1 mutation, we also observed splice events common across the TCGA uveal melanoma cohort, irrespective of SF3B1 mutation status.	('SF3B1', 'Gene', '23451', (55, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (125, 139))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('splice', 'MPA', (25, 31))	('SF3B1', 'Gene', (164, 169))	('mutation', 'Var', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('splice events', 'MPA', (88, 101))	('SF3B1', 'Gene', '23451', (164, 169))	('SF3B1', 'Gene', (55, 60))
24042	34031440	Previous work has suggested that splicing dysregulation in cancer may be a greater source of tumor specific antigens than somatic point mutations.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('splicing', 'biological_process', 'GO:0045292', ('33', '41'))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('splicing dysregulation', 'Var', (33, 55))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
24044	34031440	Splice events that are both outliers compared to normal tissues and differentially spliced between SF3B1 mutant and wild-type tumors are promising candidates as tumor-specific neoantigens, as many of these are predicted to generate novel sequences through frame disruptions and insertions in the tumor-specific isoforms (Fig.	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('SF3B1', 'Gene', (99, 104))	('insertions', 'Var', (278, 288))	('tumor', 'Disease', (296, 301))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('SF3B1', 'Gene', '23451', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutant', 'Var', (105, 111))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('tumor', 'Disease', (126, 131))
24045	34031440	SF3B1 mutant uveal melanomas have better prognosis than SF3B1 wild-type.	('mutant', 'Var', (6, 12))	('SF3B1', 'Gene', (0, 5))	('uveal melanomas', 'Phenotype', 'HP:0007716', (13, 28))	('melanomas', 'Disease', 'MESH:D008545', (19, 28))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('SF3B1', 'Gene', '23451', (0, 5))	('SF3B1', 'Gene', (56, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (13, 27))	('SF3B1', 'Gene', '23451', (56, 61))	('melanomas', 'Disease', (19, 28))
24046	34031440	We hypothesize that the tumor-specific splice isoforms associated with SF3B1 mutations may act as antigens enabling better immune control of the tumors.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('SF3B1', 'Gene', (71, 76))	('immune control', 'CPA', (123, 137))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('SF3B1', 'Gene', '23451', (71, 76))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', (145, 150))	('mutations', 'Var', (77, 86))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
24048	34031440	We also detected splice outliers common to uveal melanoma regardless of SF3B1 mutation status, and these results showed strong concordance in an independent melanoma cohort.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('mutation', 'Var', (78, 86))	('splice outliers', 'Var', (17, 32))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('common', 'Reg', (33, 39))	('SF3B1', 'Gene', (72, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('SF3B1', 'Gene', '23451', (72, 77))	('melanoma', 'Disease', (49, 57))
24076	34031440	NJS is funded in part by NIH grants UH2 AG064706, U19 AG023122, U24 AG051129, U24 AG051129-04S1; NSF grant (FAIN number) 2031819; and the Ivy and Ottesen Foundations.	('U24 AG051129', 'Var', (64, 76))	('UH2 AG064706', 'Var', (36, 48))	('NSF', 'Gene', '4905', (97, 100))	('U24 AG051129-04S1', 'Var', (78, 95))	('AG023122', 'Var', (54, 62))	('NSF', 'Gene', (97, 100))
24113	33467722	HIF-1alpha reaches the maximum level in a cell after 6 h of chronic hypoxia, whereas HIF-2alpha reaches this after 48 h. The expressions of PHD2 and PHD3 are increased by HIF-1 and HIF-2, which makes HIF-alpha degrade more intensely during reoxygenation.	('chronic hypoxia', 'Disease', (60, 75))	('PHD3', 'Gene', (149, 153))	('HIF-1', 'Gene', '3091', (0, 5))	('HIF-1', 'Gene', (0, 5))	('HIF-2', 'Var', (181, 186))	('PHD2', 'Gene', (140, 144))	('expressions', 'MPA', (125, 136))	('chronic hypoxia', 'Disease', 'MESH:D000860', (60, 75))	('oxygen', 'Chemical', 'MESH:D010100', (242, 248))	('HIF-1', 'Gene', '3091', (171, 176))	('HIF-1alpha', 'Gene', '3091', (0, 10))	('PHD', 'molecular_function', 'GO:0050175', ('140', '143'))	('PHD2', 'Gene', '54583', (140, 144))	('HIF-1', 'Gene', (171, 176))	('degrade', 'MPA', (210, 217))	('PHD3', 'Gene', '112399', (149, 153))	('PHD', 'molecular_function', 'GO:0050175', ('149', '152'))	('increased', 'PosReg', (158, 167))	('HIF-1alpha', 'Gene', (0, 10))
24154	33467722	This is related to, among other things, mutations in the VHL gene which encodes pVHL, resulting in the loss of biological function of pVHL, thereby reducing the degradation of HIF-1alpha.	('biological function', 'MPA', (111, 130))	('pVHL', 'Gene', (134, 138))	('VHL', 'Gene', (135, 138))	('VHL', 'Gene', (81, 84))	('HIF-1alpha', 'Gene', (176, 186))	('VHL', 'Gene', '7428', (135, 138))	('pVHL', 'Gene', '7428', (80, 84))	('VHL', 'Gene', '7428', (81, 84))	('degradation', 'biological_process', 'GO:0009056', ('161', '172'))	('VHL', 'Gene', (57, 60))	('pVHL', 'Gene', (80, 84))	('mutations', 'Var', (40, 49))	('reducing', 'NegReg', (148, 156))	('VHL', 'Gene', '7428', (57, 60))	('HIF-1alpha', 'Gene', '3091', (176, 186))	('pVHL', 'Gene', '7428', (134, 138))	('loss', 'NegReg', (103, 107))	('degradation', 'MPA', (161, 172))
24155	33467722	Tumors also exhibit deletions of parts of the chromosome where the HIF1AN gene locus are located.	('HIF1AN', 'Gene', (67, 73))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('deletions', 'Var', (20, 29))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('HIF1AN', 'Gene', '55662', (67, 73))
24170	33467722	VEGF activity also induces an increase in the expression of CXCL1 and CXCL8 in endothelial cells which enhances angiogenesis.	('CXCL1', 'Gene', '2919', (60, 65))	('CXCL1', 'Gene', (60, 65))	('angiogenesis', 'CPA', (112, 124))	('activity', 'Var', (5, 13))	('VEGF', 'Gene', '7422', (0, 4))	('CXCL8', 'Gene', (70, 75))	('CXCL8', 'Gene', '3576', (70, 75))	('angiogenesis', 'biological_process', 'GO:0001525', ('112', '124'))	('increase', 'PosReg', (30, 38))	('expression', 'MPA', (46, 56))	('VEGF', 'Gene', (0, 4))	('enhances', 'PosReg', (103, 111))
24176	33467722	Of the remaining CXC chemokines, CXCL13 interferes with the action of basic fibroblast growth factor (bFGF) which inhibits angiogenesis, CXCL14 also has angiostatic properties and CXCL16 is an angiogenic chemokine, similar to CXCL17, a chemoattractant for monocytes and macrophages in which it increases the expression of VEGF-A.	('basic fibroblast growth factor', 'Gene', '2247', (70, 100))	('bFGF', 'Gene', (102, 106))	('CXCL13', 'Gene', '10563', (33, 39))	('VEGF-A', 'Gene', '7422', (322, 328))	('basic fibroblast growth factor', 'Gene', (70, 100))	('CXCL13', 'Gene', (33, 39))	('angiostatic properties', 'CPA', (153, 175))	('inhibits', 'NegReg', (114, 122))	('CXCL16', 'Gene', '58191', (180, 186))	('angiogenesis', 'biological_process', 'GO:0001525', ('123', '135'))	('VEGF-A', 'Gene', (322, 328))	('bFGF', 'Gene', '2247', (102, 106))	('action', 'MPA', (60, 66))	('expression', 'MPA', (308, 318))	('CXCL17', 'Gene', (226, 232))	('CXCL17', 'Gene', '284340', (226, 232))	('CXCL16', 'Gene', (180, 186))	('angiogenesis', 'CPA', (123, 135))	('CXCL14', 'Var', (137, 143))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('76', '100'))	('interferes', 'NegReg', (40, 50))
24182	33467722	CXCL14 stimulates the autocrine growth of cancer-associated fibroblasts (CAFs).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('stimulates', 'PosReg', (7, 17))	('autocrine growth', 'CPA', (22, 38))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', (42, 48))	('CXCL14', 'Var', (0, 6))
24183	33467722	On the other hand, the ligands of CXCR3, and CXCL14 and CXCL16, cause tumor infiltration by anticancer tumor-infiltrating lymphocytes (TILs) and thus show anticancer properties.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cause', 'Reg', (64, 69))	('CXCR3', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('CXCL14', 'Var', (45, 51))	('CXCL16', 'Gene', '58191', (56, 62))	('CXCR3', 'Gene', '2833', (34, 39))	('tumor', 'Disease', (103, 108))	('CXCL16', 'Gene', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('rat', 'Species', '10116', (115, 118))	('tumor', 'Disease', (70, 75))	('rat', 'Species', '10116', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
24194	33467722	This effect on the hypoxia-induced production of CXCL1 and CXCL2 in TAMs and MDSCs may be associated with the presence of HRE in the promoters of the CXCL1 and CXCL2 genes.	('presence', 'Var', (110, 118))	('TAMs', 'Chemical', '-', (68, 72))	('hypoxia', 'Disease', (19, 26))	('hypoxia', 'Disease', 'MESH:D000860', (19, 26))	('CXCL1', 'Gene', '2919', (150, 155))	('CXCL2', 'Gene', (59, 64))	('CXCL1', 'Gene', (150, 155))	('CXCL2', 'Gene', '2920', (160, 165))	('associated', 'Reg', (90, 100))	('CXCL1', 'Gene', '2919', (49, 54))	('CXCL2', 'Gene', '2920', (59, 64))	('HRE', 'Protein', (122, 125))	('CXCL1', 'Gene', (49, 54))	('CXCL2', 'Gene', (160, 165))
24272	33467722	Screening studies did not show any influence on three cell lines: PC-3 (prostate cancer cells), SK-OV-3 (ovarian adenocarcinoma cells) and WM793B (melanoma cells).	('SK-OV-3', 'CellLine', 'CVCL:0532', (96, 103))	('prostate cancer', 'Disease', 'MESH:D011471', (72, 87))	('WM793B', 'CellLine', 'CVCL:8787', (139, 145))	('prostate cancer', 'Phenotype', 'HP:0012125', (72, 87))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (105, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('prostate cancer', 'Disease', (72, 87))	('melanoma', 'Disease', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('WM793B', 'Var', (139, 145))	('PC-3', 'CellLine', 'CVCL:0035', (66, 70))	('ovarian adenocarcinoma', 'Disease', 'MESH:D000230', (105, 127))	('ovarian adenocarcinoma', 'Disease', (105, 127))
24305	33467722	miRNA-302d reduces the expression of CXCL12:i.e., hypoxia increases the expression of this chemokine via NF-kappaB.	('hypoxia increases', 'Disease', 'MESH:D000860', (50, 67))	('NF-kappaB', 'Gene', '4790', (105, 114))	('NF-kappaB', 'Gene', (105, 114))	('hypoxia increases', 'Disease', (50, 67))	('expression', 'MPA', (72, 82))	('CXCL12', 'Gene', (37, 43))	('miRNA-302d', 'Var', (0, 10))	('CXCL12', 'Gene', '6387', (37, 43))
24320	33467722	As such, miRNA-181a increases the expression of CXCR4.	('CXCR4', 'molecular_function', 'GO:0038147', ('48', '53'))	('CXCR4', 'Gene', '7852', (48, 53))	('increases', 'PosReg', (20, 29))	('CXCR4', 'Gene', (48, 53))	('miRNA-181a', 'Var', (9, 19))
24322	33467722	This miRNA regulates the expression of CXCR4:therefore, reducing the level of miRNA-302a increases the expression of CXCR4.	('CXCR4', 'Gene', (117, 122))	('CXCR4', 'Gene', (39, 44))	('CXCR4', 'Gene', '7852', (117, 122))	('reducing', 'Var', (56, 64))	('CXCR4', 'molecular_function', 'GO:0038147', ('39', '44'))	('CXCR4', 'molecular_function', 'GO:0038147', ('117', '122'))	('CXCR4', 'Gene', '7852', (39, 44))	('increases', 'PosReg', (89, 98))
24326	33467722	Activation of this receptor reduces the action of CXCL12 on multiple myeloma cells.	('reduces', 'NegReg', (28, 35))	('CXCL12', 'Gene', (50, 56))	('multiple myeloma', 'Disease', 'MESH:D009101', (60, 76))	('Activation', 'Var', (0, 10))	('multiple myeloma', 'Phenotype', 'HP:0006775', (60, 76))	('CXCL12', 'Gene', '6387', (50, 56))	('multiple myeloma', 'Disease', (60, 76))
24393	33467722	Inactivation of PD-L1 is also being studied as a way to increase the effectiveness of anticancer immunotherapy.	('increase', 'PosReg', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('PD-L1', 'Gene', (16, 21))	('PD-L1', 'Gene', '29126', (16, 21))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('Inactivation', 'Var', (0, 12))
24407	33467722	Another direction of research is the use of gene therapy to increase the expression of chemokines that induce the infiltration of a tumor by anticancer TILs:for example, CXCR3 ligands such as CXCL10 and CXCL11.	('cancer', 'Disease', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('CXCR3', 'Gene', '2833', (170, 175))	('CXCL10', 'Var', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('increase', 'PosReg', (60, 68))	('CXCL11', 'Gene', (203, 209))	('expression', 'MPA', (73, 83))	('tumor', 'Disease', (132, 137))	('CXCL11', 'Gene', '6373', (203, 209))	('rat', 'Species', '10116', (120, 123))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('CXCR3', 'Gene', (170, 175))
24408	33467722	However, CXCL10 induces tamoxifen resistance in breast cancer and therefore any interference with the expression of the aforementioned chemokine during therapy should be performed after careful examination of its interaction with other anticancer drugs.	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('tamoxifen', 'Chemical', 'MESH:D013629', (24, 33))	('breast cancer', 'Disease', (48, 61))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('induces', 'Reg', (16, 23))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('CXCL10', 'Var', (9, 15))	('cancer', 'Disease', (240, 246))	('tamoxifen resistance', 'MPA', (24, 44))	('cancer', 'Disease', (55, 61))
24639	33333869	This remarkable process occurs throughout the organism's lifespan, and alterations in the lens structure and, consequently, in its transparency can lead to blinding pathologies such as cataracts.	('cataracts', 'Phenotype', 'HP:0000518', (185, 194))	('rat', 'Species', '10116', (75, 78))	('alterations', 'Var', (71, 82))	('cataract', 'Phenotype', 'HP:0000518', (185, 193))	('cataracts', 'Disease', 'MESH:D002386', (185, 194))	('cataracts', 'Disease', (185, 194))	('lead to', 'Reg', (148, 155))
24679	33333869	They found that LBs were damaged by UV exposure and could not be used for further experiments; however, H2O2 accelerated opacification and increased the crystallin protein aggregation in LBs, which suggests that this 3D system can be used to investigate human cataract formation.	('protein aggregation', 'Disease', (164, 183))	('rat', 'Species', '10116', (115, 118))	('human', 'Species', '9606', (254, 259))	('cataract', 'Disease', (260, 268))	('cataract', 'Disease', 'MESH:D002386', (260, 268))	('accelerated', 'PosReg', (109, 120))	('increased', 'PosReg', (139, 148))	('protein aggregation', 'Disease', 'MESH:D001796', (164, 183))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('cataract', 'Phenotype', 'HP:0000518', (260, 268))	('LB', 'Chemical', '-', (187, 189))	('LB', 'Chemical', '-', (16, 18))	('opacification', 'MPA', (121, 134))	('formation', 'biological_process', 'GO:0009058', ('269', '278'))	('H2O2', 'Chemical', 'MESH:D006861', (104, 108))	('H2O2', 'Var', (104, 108))
24695	32718045	Most relevant for current practice is the absence of BRAF mutations in posterior uveal melanoma, although present in some iris melanomas and conjunctival melanomas.	('mutations', 'Var', (58, 67))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('melanoma', 'Disease', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('iris melanoma', 'Phenotype', 'HP:0011524', (122, 135))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('melanomas', 'Phenotype', 'HP:0002861', (154, 163))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('iris melanomas', 'Phenotype', 'HP:0011524', (122, 136))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('iris melanomas and conjunctival melanomas', 'Disease', 'MESH:D008545', (122, 163))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (141, 162))
24697	32718045	The discovery of drugs targeting the mitogen-activated protein kinase (MAPK) pathway constitutes a major advancement in the treatment of patients with metastatic cutaneous melanoma harboring a somatic mutation in the BRAF gene on chromosome 7.	('cutaneous melanoma', 'Disease', (162, 180))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (162, 180))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (162, 180))	('patients', 'Species', '9606', (137, 145))	('MAPK', 'molecular_function', 'GO:0004707', ('71', '75'))	('BRAF', 'Gene', '673', (217, 221))	('chromosome', 'cellular_component', 'GO:0005694', ('230', '240'))	('BRAF', 'Gene', (217, 221))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('mutation', 'Var', (201, 209))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))
24698	32718045	Combined BRAF/MEK inhibition induces objective responses in approximately 65% of patients with a BRAF V600 mutation and improves the progression-free and overall survival.	('inhibition', 'NegReg', (18, 28))	('BRAF', 'Gene', (9, 13))	('progression-free', 'CPA', (133, 149))	('patients', 'Species', '9606', (81, 89))	('MEK', 'Gene', (14, 17))	('improves', 'PosReg', (120, 128))	('MEK', 'Gene', '5609', (14, 17))	('V600 mutation', 'Var', (102, 115))	('BRAF', 'Gene', '673', (97, 101))	('BRAF', 'Gene', (97, 101))	('BRAF', 'Gene', '673', (9, 13))
24720	32718045	Most posterior UM harbor a driver mutation in GNAQ (~55%) or GNA11 (~40%) (Table 1).	('GNAQ', 'Gene', (46, 50))	('GNA11', 'Gene', '2767', (61, 66))	('GNA11', 'Gene', (61, 66))	('mutation', 'Var', (34, 42))	('GNAQ', 'Gene', '2776', (46, 50))	('UM', 'Phenotype', 'HP:0007716', (15, 17))
24721	32718045	Mutations in GNAQ and GNA11 are mutually exclusive and can lead to the activation of multiple downstream pathways involved in proliferation and cell growth.	('GNA11', 'Gene', (22, 27))	('cell growth', 'biological_process', 'GO:0016049', ('144', '155'))	('GNAQ', 'Gene', (13, 17))	('activation', 'PosReg', (71, 81))	('GNA11', 'Gene', '2767', (22, 27))	('lead to', 'Reg', (59, 66))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', '2776', (13, 17))
24723	32718045	Of the chromosomal aberrations, loss of chromosome 3 with or without gains of chromosome 8q is associated with a high risk of metastatic disease (>50%) and occurs in approximately half of the patients.	('metastatic disease', 'CPA', (126, 144))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (7, 30))	('chromosome', 'cellular_component', 'GO:0005694', ('40', '50'))	('chromosome', 'cellular_component', 'GO:0005694', ('78', '88'))	('patients', 'Species', '9606', (192, 200))	('loss', 'Var', (32, 36))
24725	32718045	The most important secondary driver mutations occur in BAP1, SF3B1, or EIF1AX and are generally mutually exclusive.	('SF3B1', 'Gene', (61, 66))	('EIF1AX', 'Gene', '1964', (71, 77))	('EIF1AX', 'Gene', (71, 77))	('BAP1', 'Gene', (55, 59))	('mutations', 'Var', (36, 45))	('SF3B1', 'Gene', '23451', (61, 66))	('BAP1', 'Gene', '8314', (55, 59))
24726	32718045	BRAF and NRAS mutations, frequently occurring in cutaneous melanoma, do not occur in posterior UM.	('cutaneous melanoma', 'Disease', (49, 67))	('NRAS', 'Gene', (9, 13))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (49, 67))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (49, 67))	('NRAS', 'Gene', '4893', (9, 13))	('BRAF', 'Gene', '673', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('mutations', 'Var', (14, 23))
24727	32718045	KIT mutations are rare.	('mutations', 'Var', (4, 13))	('KIT', 'Gene', '3815', (0, 3))	('KIT', 'Gene', (0, 3))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))
24728	32718045	Inactivation of the tumor-suppressor gene BAP1, located on chromosome 3, usually occurs by a BAP1 mutation combined with monosomy 3.	('BAP1', 'Gene', '8314', (42, 46))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('20', '36'))	('BAP1', 'Gene', '8314', (93, 97))	('chromosome', 'cellular_component', 'GO:0005694', ('59', '69'))	('mutation', 'Var', (98, 106))	('occurs by', 'Reg', (81, 90))	('BAP1', 'Gene', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('BAP1', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('20', '36'))	('Inactivation', 'Var', (0, 12))	('tumor', 'Disease', (20, 25))
24730	32718045	BAP1 inactivation gives a high risk of metastatic disease.	('inactivation', 'Var', (5, 17))	('BAP1', 'Gene', '8314', (0, 4))	('BAP1', 'Gene', (0, 4))	('metastatic disease', 'CPA', (39, 57))
24731	32718045	Mutations in the splicing gene SF3B1, located on chromosome 2, occur mainly in disomy 3 tumors and give an intermediate risk to developing metastasis, occurring late compared to BAP1-mutated tumors.	('BAP1', 'Gene', '8314', (178, 182))	('disomy 3 tumors', 'Disease', 'MESH:D024182', (79, 94))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('splicing', 'biological_process', 'GO:0045292', ('17', '25'))	('occur', 'Reg', (63, 68))	('chromosome', 'cellular_component', 'GO:0005694', ('49', '59'))	('BAP1', 'Gene', (178, 182))	('disomy 3 tumors', 'Disease', (79, 94))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('SF3B1', 'Gene', (31, 36))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('SF3B1', 'Gene', '23451', (31, 36))	('tumors', 'Disease', (191, 197))
24732	32718045	UM with mutations in EIF1AX, located on the X chromosome, are usually also only present in disomy 3 tumors and seldomly metastasize.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('X chromosome', 'cellular_component', 'GO:0000805', ('44', '56'))	('disomy 3 tumors', 'Disease', (91, 106))	('mutations', 'Var', (8, 17))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('disomy 3 tumors', 'Disease', 'MESH:D024182', (91, 106))	('EIF1AX', 'Gene', '1964', (21, 27))	('EIF1AX', 'Gene', (21, 27))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
24733	32718045	Although exceptional, BAP1 mutations can occur in combination with disomy 3 and SF3B1 or EIF1AX mutations in combination with monosomy 3.	('mutations', 'Var', (27, 36))	('SF3B1', 'Gene', '23451', (80, 85))	('occur', 'Reg', (41, 46))	('EIF1AX', 'Gene', '1964', (89, 95))	('EIF1AX', 'Gene', (89, 95))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', (22, 26))	('SF3B1', 'Gene', (80, 85))	('mutations', 'Var', (96, 105))
24734	32718045	In addition, albeit often described as mutually exclusive mutations, SF3B1 mutations are described in combination with EIF1AX or BAP1 mutations.	('BAP1', 'Gene', '8314', (129, 133))	('SF3B1', 'Gene', (69, 74))	('EIF1AX', 'Gene', '1964', (119, 125))	('mutations', 'Var', (75, 84))	('EIF1AX', 'Gene', (119, 125))	('BAP1', 'Gene', (129, 133))	('SF3B1', 'Gene', '23451', (69, 74))
24736	32718045	GEP class 1 tumors mainly contain tumors with disomy 3 and EIF1AX or SF3B1 mutations, where monosomy 3 tumors with BAP1 mutations are mainly classified as GEP class 2 tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('GEP class 1', 'Gene', (0, 11))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('BAP1', 'Gene', '8314', (115, 119))	('SF3B1', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('EIF1AX', 'Gene', (59, 65))	('tumors', 'Disease', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('disomy 3', 'Var', (46, 54))	('BAP1', 'Gene', (115, 119))	('mutations', 'Var', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('SF3B1', 'Gene', '23451', (69, 74))	('EIF1AX', 'Gene', '1964', (59, 65))
24739	32718045	The mutational load is among the lowest of all cancer types, comparable to that of pediatric cancers.	('cancers', 'Disease', (93, 100))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('mutational load', 'Var', (4, 19))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
24741	32718045	Preferably, fresh tumor material is used for genetic or transcriptomic analyses or formalin-fixed paraffin-embedded material for BAP1 inactivation testing, which can be determined by protein expression immunohistochemistry.	('inactivation', 'Var', (134, 146))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('tumor', 'Disease', (18, 23))	('BAP1', 'Gene', '8314', (129, 133))	('formalin', 'Chemical', 'MESH:D005557', (83, 91))	('paraffin', 'Chemical', 'MESH:D010232', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('BAP1', 'Gene', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
24756	32718045	In contrast to posterior UM, mutations in BRAF (0-47%) and NRAS have been described in iris melanoma, although the frequency of their presence is unclear, and they might not represent driver mutations (Table 1).	('BRAF', 'Gene', '673', (42, 46))	('iris melanoma', 'Disease', (87, 100))	('mutations', 'Var', (29, 38))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('iris melanoma', 'Phenotype', 'HP:0011524', (87, 100))	('described', 'Reg', (74, 83))	('NRAS', 'Gene', (59, 63))	('BRAF', 'Gene', (42, 46))	('iris melanoma', 'Disease', 'MESH:D008545', (87, 100))	('NRAS', 'Gene', '4893', (59, 63))	('UM', 'Phenotype', 'HP:0007716', (25, 27))
24757	32718045	As the iris is not protected from UV damage, UV-induced mutational signatures have recently been detected in iris melanoma.	('mutational', 'Var', (56, 66))	('iris melanoma', 'Phenotype', 'HP:0011524', (109, 122))	('iris melanoma', 'Disease', 'MESH:D008545', (109, 122))	('iris melanoma', 'Disease', (109, 122))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
24768	32718045	In contrast to posterior UM and other mucosal melanoma subtypes, conjunctival melanoma quite frequently expresses BRAF mutations (~20-55% of patients; Table 1).	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('mucosal melanoma', 'Disease', (38, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('conjunctival melanoma', 'Disease', (65, 86))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (65, 86))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (65, 86))	('mucosal melanoma', 'Disease', 'MESH:D008545', (38, 54))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('mutations', 'Var', (119, 128))	('patients', 'Species', '9606', (141, 149))	('UM', 'Phenotype', 'HP:0007716', (25, 27))
24769	32718045	NRAS is mutated in ~20% of conjunctival melanomas, and KIT mutations are reported in 0-7%.	('KIT', 'Gene', (55, 58))	('KIT', 'molecular_function', 'GO:0005020', ('55', '58'))	('mutated', 'Var', (8, 15))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('conjunctival melanomas', 'Disease', (27, 49))	('NRAS', 'Gene', (0, 4))	('KIT', 'Gene', '3815', (55, 58))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (27, 49))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (27, 48))	('NRAS', 'Gene', '4893', (0, 4))
24770	32718045	In-line with cutaneous melanoma, UV radiation plays a role in the development of conjunctival melanoma; UV-induced mutation signatures are demonstrated, as well as a high mutational load.	('mutational load', 'Var', (171, 186))	('conjunctival melanoma', 'Disease', (81, 102))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (81, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (81, 102))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('mutation', 'Var', (115, 123))	('cutaneous melanoma', 'Disease', (13, 31))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (13, 31))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (13, 31))
24777	32718045	The M category of the AJCC staging system is different from cutaneous melanoma and solely based on the diameter of the largest metastasis (M1a <= 3 m, M1b 3.1-8.0 cm, and M1c >= 8.1 cm), which strongly correlates with survival.	('M1b', 'Var', (151, 154))	('M1c >=', 'Var', (171, 177))	('M1a', 'Var', (139, 142))	('correlates', 'Reg', (202, 212))	('cutaneous melanoma', 'Disease', (60, 78))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (60, 78))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (60, 78))
24779	32718045	The genetic high-risk features, such as monosomy 3 and BAP1 mutations, are more frequently seen in patients with metastatic disease.	('BAP1', 'Gene', (55, 59))	('metastatic disease', 'Disease', (113, 131))	('patients', 'Species', '9606', (99, 107))	('mutations', 'Var', (60, 69))	('monosomy 3', 'Var', (40, 50))	('BAP1', 'Gene', '8314', (55, 59))
24780	32718045	Whether any of the genetic alterations are also of prognostic value once metastases are present is unknown and, thus, abates the reason for genetic testing if not determined at first presentation.	('metastases', 'Disease', 'MESH:D009362', (73, 83))	('metastases', 'Disease', (73, 83))	('alterations', 'Var', (27, 38))	('genetic alterations', 'Var', (19, 38))
24781	32718045	This includes the analyses of mutations in GNAQ and GNA11, which were hoped to be predictive of MEK inhibition, as the mutations constitutively activate the MAPK pathway.	('MAPK', 'molecular_function', 'GO:0004707', ('157', '161'))	('activate', 'PosReg', (144, 152))	('GNAQ', 'Gene', (43, 47))	('MEK', 'Gene', (96, 99))	('GNA11', 'Gene', '2767', (52, 57))	('MEK', 'Gene', '5609', (96, 99))	('mutations', 'Var', (30, 39))	('GNA11', 'Gene', (52, 57))	('mutations', 'Var', (119, 128))	('GNAQ', 'Gene', '2776', (43, 47))	('MAPK pathway', 'Pathway', (157, 169))
24784	32718045	KIT mutations rarely occur in posterior UM, and UM patients were not included in the phase II clinical trials studying the effect of the tyrosine kinase inhibitor imatinib in KIT-mutated melanoma.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('imatinib', 'Chemical', 'MESH:D000068877', (163, 171))	('KIT', 'Gene', '3815', (175, 178))	('KIT', 'Gene', '3815', (0, 3))	('UM', 'Phenotype', 'HP:0007716', (40, 42))	('patients', 'Species', '9606', (51, 59))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('146', '162'))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (175, 178))	('KIT', 'Gene', (0, 3))	('KIT', 'molecular_function', 'GO:0005020', ('175', '178'))
24785	32718045	The response rates in these trials were moderate and may be limited to patients with KIT mutations in certain hotspots of clinical relevance.	('KIT', 'molecular_function', 'GO:0005020', ('85', '88'))	('patients', 'Species', '9606', (71, 79))	('KIT', 'Gene', '3815', (85, 88))	('KIT', 'Gene', (85, 88))	('mutations', 'Var', (89, 98))
24801	32718045	As BRAF mutations do occur in iris melanoma, genetic testing to detect BRAF mutations can be considered.	('iris melanoma', 'Disease', (30, 43))	('BRAF', 'Gene', '673', (71, 75))	('iris melanoma', 'Phenotype', 'HP:0011524', (30, 43))	('occur', 'Reg', (21, 26))	('mutations', 'Var', (8, 17))	('BRAF', 'Gene', (71, 75))	('BRAF', 'Gene', '673', (3, 7))	('iris melanoma', 'Disease', 'MESH:D008545', (30, 43))	('BRAF', 'Gene', (3, 7))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))
24809	32718045	BRAF/MEK inhibition showed the stable disease in one metastatic patient and (near) complete responses in two patients with local recurrent disease.	('MEK', 'Gene', '5609', (5, 8))	('patient', 'Species', '9606', (64, 71))	('patient', 'Species', '9606', (109, 116))	('patients', 'Species', '9606', (109, 117))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('MEK', 'Gene', (5, 8))	('inhibition', 'Var', (9, 19))
24819	32718045	Additionally, neo-adjuvant BRAF/MEK inhibition is worth consideration in irresectable primary or local recurrent tumors with a BRAF mutation.	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('BRAF', 'Gene', '673', (127, 131))	('local recurrent', 'CPA', (97, 112))	('BRAF', 'Gene', (127, 131))	('BRAF', 'Gene', '673', (27, 31))	('irresectable primary', 'Disease', (73, 93))	('BRAF', 'Gene', (27, 31))	('MEK', 'Gene', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('MEK', 'Gene', '5609', (32, 35))	('mutation', 'Var', (132, 140))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
24825	32718045	The mutation profile of melanoma of unknown primary is similar to cutaneous melanoma, with frequent BRAF (~50%) and NRAS (~20%) mutations.	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('cutaneous melanoma', 'Disease', (66, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (66, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('mutations', 'Var', (128, 137))	('BRAF', 'Gene', '673', (100, 104))	('NRAS', 'Gene', (116, 120))	('BRAF', 'Gene', (100, 104))	('NRAS', 'Gene', '4893', (116, 120))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
24826	32718045	The detection of KIT, GNA11, or GNAQ mutations might warrant further screening for a primary mucosal or primary UM, as GNAQ/GNA11 mutations are generally mutually exclusive with BRAF/NRAS mutations.	('NRAS', 'Gene', (183, 187))	('GNA11', 'Gene', '2767', (124, 129))	('GNAQ', 'Gene', (32, 36))	('GNA11', 'Gene', (22, 27))	('NRAS', 'Gene', '4893', (183, 187))	('GNA11', 'Gene', '2767', (22, 27))	('GNAQ', 'Gene', (119, 123))	('GNAQ', 'Gene', '2776', (32, 36))	('mutations', 'Var', (37, 46))	('mutations', 'Var', (130, 139))	('KIT', 'Gene', '3815', (17, 20))	('UM', 'Phenotype', 'HP:0007716', (112, 114))	('KIT', 'molecular_function', 'GO:0005020', ('17', '20'))	('BRAF', 'Gene', (178, 182))	('BRAF', 'Gene', '673', (178, 182))	('GNA11', 'Gene', (124, 129))	('KIT', 'Gene', (17, 20))	('GNAQ', 'Gene', '2776', (119, 123))
24827	32718045	For example, one of our patients with widespread metastases of melanoma showed both a GNA11 Q209L and a BRAF V600K mutation.	('V600K', 'Mutation', 'rs121913227', (109, 114))	('metastases of melanoma', 'Disease', (49, 71))	('Q209L', 'Var', (92, 97))	('patients', 'Species', '9606', (24, 32))	('BRAF', 'Gene', '673', (104, 108))	('Q209L', 'Mutation', 'rs1057519742', (92, 97))	('GNA11', 'Gene', (86, 91))	('metastases of melanoma', 'Disease', 'MESH:D009362', (49, 71))	('BRAF', 'Gene', (104, 108))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('GNA11', 'Gene', '2767', (86, 91))
24833	32718045	In addition, BRAF mutations are absent in posterior UM, and testing for the BRAF status in this patient group is ineffectual.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('BRAF', 'Gene', '673', (13, 17))	('patient', 'Species', '9606', (96, 103))	('BRAF', 'Gene', (13, 17))	('absent', 'NegReg', (32, 38))	('mutations', 'Var', (18, 27))
24838	32718045	However, in the metastatic setting, BRAF(/MEK) inhibition can induce clinical responses, and, thus, the BRAF status is a valuable predictive genetic biomarker.	('BRAF', 'Gene', (36, 40))	('inhibition', 'Var', (47, 57))	('induce', 'Reg', (62, 68))	('MEK', 'Gene', (42, 45))	('MEK', 'Gene', '5609', (42, 45))	('clinical responses', 'CPA', (69, 87))	('BRAF', 'Gene', '673', (104, 108))	('BRAF', 'Gene', (104, 108))	('BRAF', 'Gene', '673', (36, 40))
24840	32718045	Successful targeting of other mutations might be possible in the future, both in uveal and conjunctival melanoma, but the rarity of the diseases causes research to move forward slowly.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('uveal and conjunctival melanoma', 'Phenotype', 'HP:0007716', (81, 112))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (91, 112))	('mutations', 'Var', (30, 39))	('conjunctival melanoma', 'Disease', (91, 112))	('uveal', 'Disease', (81, 86))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (91, 112))
24841	32718045	AJCC American Joint Committee on Cancer  GEP Gene expression profiling  LDH Lactate dehydrogenase  MAPK Mitogen-activated protein kinase  OcM Ocular melanoma  UM Uveal melanoma	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('Cancer', 'Disease', 'MESH:D009369', (33, 39))	('Cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Mitogen-activated', 'Var', (104, 121))	('OcM', 'Phenotype', 'HP:0025534', (138, 141))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('UM', 'Phenotype', 'HP:0007716', (159, 161))	('OcM Ocular melanoma  UM Uveal melanoma', 'Disease', (138, 176))	('Gene expression', 'biological_process', 'GO:0010467', ('45', '60'))	('Ocular melanoma', 'Phenotype', 'HP:0007716', (142, 157))	('MAPK', 'molecular_function', 'GO:0004707', ('99', '103'))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (162, 176))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('OcM Ocular melanoma  UM Uveal melanoma', 'Disease', 'MESH:C536494', (138, 176))	('Cancer', 'Disease', (33, 39))
24935	32727533	As a one-shot gentle treatment, 106Ru plaque brachytherapy provides good local control of the tumor and protects the visual acuity.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('local control', 'CPA', (73, 86))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('protects', 'NegReg', (104, 112))	('tumor', 'Disease', (94, 99))	('visual acuity', 'CPA', (117, 130))	('106Ru', 'Var', (32, 37))
24937	32727533	The major findings in our study were the high local control rate with 106Ru brachytherapy even in tumors with a depth of more than 5 mm and the overall low acute and long-term toxicities.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('toxicities', 'Disease', (176, 186))	('local control', 'CPA', (46, 59))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('toxicities', 'Disease', 'MESH:D064420', (176, 186))	('106Ru', 'Var', (70, 75))
24938	32727533	Despite the limited number of patients, these results prove 106Ru brachytherapy to be an excellent treatment option in clinical practice for uveal melanoma and should be promoted in well-selected patients.	('106Ru', 'Var', (60, 65))	('uveal melanoma', 'Phenotype', 'HP:0007716', (141, 155))	('patients', 'Species', '9606', (196, 204))	('patients', 'Species', '9606', (30, 38))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))
24954	32010430	In order to investigate the mechanism of the induction of MASPIN by AEZS-108, OCM3 cells were treated with free DOX, D-Lys6 LHRH analog, or AEZS-108.	('AEZS-108', 'Var', (68, 76))	('MASPIN', 'Gene', '5268', (58, 64))	('MASPIN', 'Gene', (58, 64))	('D-Lys6', 'Var', (117, 123))	('DOX', 'Chemical', 'MESH:D004317', (112, 115))
24955	32010430	qRT- PCR analysis revealed in OCM3 cells that AEZS-108 is a more potent inducer of MASPIN than free DOX.	('inducer', 'PosReg', (72, 79))	('DOX', 'Chemical', 'MESH:D004317', (100, 103))	('MASPIN', 'Gene', '5268', (83, 89))	('MASPIN', 'Gene', (83, 89))	('AEZS-108', 'Var', (46, 54))
24968	32010430	Moreover, AEZS-108 was found to be able to inhibit the growth of doxorubicin resistant cells.	('doxorubicin', 'Chemical', 'MESH:D004317', (65, 76))	('AEZS-108', 'Var', (10, 18))	('growth of doxorubicin resistant cells', 'MPA', (55, 92))	('inhibit', 'NegReg', (43, 50))
24972	32010430	Our results shows that AEZS-108, as well as doxorubicin significantly inhibited the proliferation of OCM3 human uveal melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('AEZS-108', 'Var', (23, 31))	('human', 'Species', '9606', (106, 111))	('doxorubicin', 'Chemical', 'MESH:D004317', (44, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (112, 126))	('uveal melanoma', 'Phenotype', 'HP:0007716', (112, 126))	('uveal melanoma', 'Disease', (112, 126))	('proliferation', 'CPA', (84, 97))	('inhibited', 'NegReg', (70, 79))
24975	32010430	The qRT-PCR array results showed that AEZS-108 altered the expression of MASPIN, HIF1A and its target genes.	('HIF1A', 'Gene', (81, 86))	('HIF1A', 'Gene', '3091', (81, 86))	('AEZS-108', 'Var', (38, 46))	('expression', 'MPA', (59, 69))	('altered', 'Reg', (47, 54))	('MASPIN', 'Gene', '5268', (73, 79))	('MASPIN', 'Gene', (73, 79))
24976	32010430	Furthermore, qRT-PCR analysis revealed that AEZS-108 is a more potent inducer of MASPIN tumor suppressor than free DOX in OCM3 cells.	('inducer', 'PosReg', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('MASPIN', 'Gene', '5268', (81, 87))	('MASPIN', 'Gene', (81, 87))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('88', '104'))	('DOX', 'Chemical', 'MESH:D004317', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor suppressor', 'biological_process', 'GO:0051726', ('88', '104'))	('tumor', 'Disease', (88, 93))	('AEZS-108', 'Var', (44, 52))
24980	32010430	In order to investigate whether AEZS-108 inhibits cell proliferation and its extent, OCM3 cells were treated either with 5 microM AEZS-108 or equal amount of doxorubicin.	('inhibits', 'NegReg', (41, 49))	('doxorubicin', 'Chemical', 'MESH:D004317', (158, 169))	('AEZS-108', 'Var', (130, 138))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('AEZS-108', 'Var', (32, 40))	('cell proliferation', 'CPA', (50, 68))
24982	32010430	AEZS-108 and doxorubicin have been shown to reduce cell proliferation by 36.3% (p < 0.001) and 62.9% (p < 0.001) respectively after 24 hours, and by 84.7% (p < 0.001) and 89.7% (p < 0.001) respectively after 48 hours, (Figure 2).	('cell proliferation', 'biological_process', 'GO:0008283', ('51', '69'))	('reduce', 'NegReg', (44, 50))	('doxorubicin', 'Chemical', 'MESH:D004317', (13, 24))	('AEZS-108', 'Var', (0, 8))	('cell proliferation', 'CPA', (51, 69))	('doxorubicin', 'Var', (13, 24))
24986	32010430	OCM3 cells were treated with AEZS-108, D-Lys6 LHRH analog or free DOX.	('DOX', 'Chemical', 'MESH:D004317', (66, 69))	('D-Lys6', 'Var', (39, 45))	('AEZS-108', 'Var', (29, 37))
24987	32010430	Our results clearly showed that D-Lys6 LHRH-treated cells do not express MASPIN, while free DOX and AEZS-108 induces MASPIN expression.	('MASPIN', 'Gene', '5268', (73, 79))	('AEZS-108', 'Var', (100, 108))	('expression', 'MPA', (124, 134))	('MASPIN', 'Gene', '5268', (117, 123))	('MASPIN', 'Gene', (117, 123))	('induces', 'PosReg', (109, 116))	('DOX', 'Chemical', 'MESH:D004317', (92, 95))	('MASPIN', 'Gene', (73, 79))
24988	32010430	However, equal dose of AEZS-108 and DOX show significantly different effect on MASPIN expression, namely, that AEZS-108 treatment results in significantly higher MASPIN expression than free DOX treatment (Figure 3).	('MASPIN', 'Gene', '5268', (162, 168))	('MASPIN', 'Gene', (162, 168))	('DOX', 'Chemical', 'MESH:D004317', (190, 193))	('DOX', 'Chemical', 'MESH:D004317', (36, 39))	('MASPIN', 'Gene', '5268', (79, 85))	('MASPIN', 'Gene', (79, 85))	('AEZS-108', 'Var', (111, 119))	('higher', 'PosReg', (155, 161))
24992	32010430	SDS PAGE Western blot analysis confirmed the qRT-PCR results, namely, that MASPIN production in untreated OCM3 cells is very low, however, treatment with AEZS-108 or free DOX slightly increases the expression of MASPIN tumor suppressor (Figure 4).	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('SDS', 'Chemical', 'MESH:C032259', (0, 3))	('AEZS-108', 'Var', (154, 162))	('MASPIN', 'Gene', (75, 81))	('tumor', 'Disease', (219, 224))	('increases', 'PosReg', (184, 193))	('MASPIN', 'Gene', '5268', (75, 81))	('tumor suppressor', 'biological_process', 'GO:0051726', ('219', '235'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('219', '235'))	('MASPIN', 'Gene', '5268', (212, 218))	('MASPIN', 'Gene', (212, 218))	('expression', 'MPA', (198, 208))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('low', 'NegReg', (125, 128))	('DOX', 'Chemical', 'MESH:D004317', (171, 174))
24993	32010430	As seen at mRNA and protein levels, AEZS-108 is a more potent inducer of MASPIN than free DOX.	('inducer', 'PosReg', (62, 69))	('DOX', 'Chemical', 'MESH:D004317', (90, 93))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('AEZS-108', 'Var', (36, 44))	('MASPIN', 'Gene', '5268', (73, 79))	('MASPIN', 'Gene', (73, 79))
24994	32010430	Furthermore, in order to unravel whether AEZS-108 or free DOX has an effect on angiogenesis, HIF1A and its target proteins, VEGFA and VEGFB angiogenesis related proteins were also investigated.	('VEGFB', 'Gene', '7423', (134, 139))	('DOX', 'Chemical', 'MESH:D004317', (58, 61))	('effect', 'Reg', (69, 75))	('VEGFB', 'Gene', (134, 139))	('AEZS-108', 'Var', (41, 49))	('angiogenesis', 'biological_process', 'GO:0001525', ('79', '91'))	('HIF1A', 'Gene', (93, 98))	('VEGFA', 'Gene', (124, 129))	('HIF1A', 'Gene', '3091', (93, 98))	('angiogenesis', 'biological_process', 'GO:0001525', ('140', '152'))	('angiogenesis', 'CPA', (79, 91))	('VEGFA', 'Gene', '7422', (124, 129))
24995	32010430	Our data showed that treatment with AEZS-108 and DOX significantly decreased HIF1A, VEGFA and VEGFB expression (Figure 4).	('VEGFB', 'Gene', (94, 99))	('HIF1A', 'Gene', (77, 82))	('VEGFA', 'Gene', '7422', (84, 89))	('HIF1A', 'Gene', '3091', (77, 82))	('decreased', 'NegReg', (67, 76))	('DOX', 'Chemical', 'MESH:D004317', (49, 52))	('expression', 'MPA', (100, 110))	('VEGFA', 'Gene', (84, 89))	('VEGFB', 'Gene', '7423', (94, 99))	('AEZS-108', 'Var', (36, 44))
25000	32010430	Previous studies have demonstrated that AEZS-108 strongly inhibits the growth of experimental human prostatic, mammary, ovarian and urinary bladder cancers as well as melanomas expressing LHRH receptors.	('ovarian', 'Disease', (120, 127))	('growth', 'MPA', (71, 77))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('AEZS-108', 'Var', (40, 48))	('ovarian', 'Disease', 'MESH:D010049', (120, 127))	('inhibits', 'NegReg', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('urinary bladder cancers', 'Disease', 'MESH:D001749', (132, 155))	('melanomas', 'Disease', 'MESH:D008545', (167, 176))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanomas', 'Phenotype', 'HP:0002861', (167, 176))	('human', 'Species', '9606', (94, 99))	('mammary', 'Disease', (111, 118))	('urinary bladder cancers', 'Disease', (132, 155))	('bladder cancers', 'Phenotype', 'HP:0009725', (140, 155))	('LHRH receptors', 'Protein', (188, 202))	('melanomas', 'Disease', (167, 176))
25001	32010430	Previous in vivo investigations have demonstrated that AEZS-108 has a prominent antitumor activity and less toxicity than unconjugated DOX in various cancer types.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('toxicity', 'Disease', 'MESH:D064420', (108, 116))	('toxicity', 'Disease', (108, 116))	('tumor', 'Disease', (84, 89))	('cancer', 'Disease', (150, 156))	('AEZS-108', 'Var', (55, 63))	('DOX', 'Chemical', 'MESH:D004317', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
25004	32010430	As a relevant in vitro model of UM, OCM3 cell line was selected in order to investigate the antitumor-effect of AEZS-108 compared to its unconjugated cytotoxic consituent, doxorubicin.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('AEZS-108', 'Var', (112, 120))	('tumor', 'Disease', (96, 101))	('doxorubicin', 'Chemical', 'MESH:D004317', (172, 183))	('UM', 'Disease', 'MESH:C536494', (32, 34))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
25005	32010430	To demonstrate if AEZS-108 induces cytotoxicity, OCM3 cells were treated with 5 microM AEZS-108 or equal amount of doxorubicin and then MTS-assay was performed.	('MTS', 'Chemical', 'MESH:C070380', (136, 139))	('cytotoxicity', 'Disease', (35, 47))	('AEZS-108', 'Var', (87, 95))	('cytotoxicity', 'Disease', 'MESH:D064420', (35, 47))	('doxorubicin', 'Chemical', 'MESH:D004317', (115, 126))
25020	32010430	In order to investigate the mechanism of the induction of MASPIN, OCM3 cells were treated with free DOX, D-Lys6 LHRH analog, or AEZS-108.	('DOX', 'Chemical', 'MESH:D004317', (100, 103))	('MASPIN', 'Gene', '5268', (58, 64))	('MASPIN', 'Gene', (58, 64))	('D-Lys6 LHRH', 'Var', (105, 116))
25021	32010430	AEZS-108 induced greater MASPIN expression compared to free DOX.	('greater', 'PosReg', (17, 24))	('AEZS-108', 'Var', (0, 8))	('MASPIN', 'Gene', '5268', (25, 31))	('MASPIN', 'Gene', (25, 31))	('DOX', 'Chemical', 'MESH:D004317', (60, 63))
25024	32010430	The upregulation of MASPIN expression might be explained by a probable decrease in transporter activity in the presence of AEZS-108.	('transporter activity', 'MPA', (83, 103))	('AEZS-108', 'Var', (123, 131))	('decrease', 'NegReg', (71, 79))	('expression', 'MPA', (27, 37))	('MASPIN', 'Gene', '5268', (20, 26))	('MASPIN', 'Gene', (20, 26))	('transporter activity', 'molecular_function', 'GO:0005215', ('83', '103'))	('upregulation', 'PosReg', (4, 16))
25056	32010430	Based on the results of the array, particularly, the expression of MASPIN tumor suppressor gene has been further investigated after treatment with AEZS-108, DOX or D-Lys6 LHRH using SYBR Green Supermix (Bio-Rad Laboratories, USA) in a 20 microl total volume according to the manufacturer's instructions.	('MASPIN', 'Gene', '5268', (67, 73))	('MASPIN', 'Gene', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('Rad', 'biological_process', 'GO:1990116', ('207', '210'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('AEZS-108', 'Var', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('tumor', 'Disease', (74, 79))	('D-Lys6 LHRH', 'Var', (164, 175))	('DOX', 'Chemical', 'MESH:D004317', (157, 160))
25184	29044496	Similarly, therapy targeted at the common activating V600 mutations in BRAF have proven effective, with high response rates, although responses are generally not as durable as with immunotherapy.	('V600', 'Var', (53, 57))	('activating', 'PosReg', (42, 52))	('BRAF', 'Gene', (71, 75))	('BRAF', 'Gene', '673', (71, 75))
25196	29044496	Multiple studies have demonstrated the adverse effects of vascular endothelial growth factor (VEGF) expression in melanoma including its association with worsened prognosis, chemotherapy resistance, and immunosuppression.	('chemotherapy resistance', 'CPA', (174, 197))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('VEGF', 'Gene', (94, 98))	('vascular endothelial growth factor', 'Gene', (58, 92))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('58', '92'))	('vascular endothelial growth factor', 'Gene', '7422', (58, 92))	('expression', 'Var', (100, 110))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
25198	29044496	mTOR, the target of everolimus, can induce expression of VEGF-C, and inhibition of mTOR with rapamycin has been shown to potently reduce VEGF-C expression in a murine skin flap model and murine tumor xenografts.	('VEGF-C', 'Gene', '22341', (57, 63))	('murine', 'Species', '10090', (187, 193))	('mTOR', 'Gene', (83, 87))	('reduce', 'NegReg', (130, 136))	('murine', 'Species', '10090', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('expression', 'MPA', (144, 154))	('VEGF-C', 'Gene', '22341', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('VEGF-C', 'Gene', (57, 63))	('tumor', 'Disease', (194, 199))	('everolimus', 'Chemical', 'MESH:D000068338', (20, 30))	('inhibition', 'Var', (69, 79))	('expression', 'MPA', (43, 53))	('VEGF-C', 'Gene', (137, 143))	('rapamycin', 'Chemical', 'MESH:D020123', (93, 102))
25242	29044496	In addition, 19.5% of patients had proven BRAF mutations.	('BRAF', 'Gene', (42, 46))	('patients', 'Species', '9606', (22, 30))	('BRAF', 'Gene', '673', (42, 46))	('mutations', 'Var', (47, 56))
25246	29044496	Patient characteristics further delineated by uveal, non-uveal, and BRAF mutation status are show in Supplementary Tables 1-3.	('mutation', 'Var', (73, 81))	('Patient', 'Species', '9606', (0, 7))	('BRAF', 'Gene', (68, 72))	('BRAF', 'Gene', '673', (68, 72))
25265	29044496	Additionally, toxicity was higher for CPBE post addendum versus CPB for Grade 3+ for all adverse events regardless of attribution.	('CPB', 'Chemical', '-', (38, 41))	('toxicity', 'Disease', 'MESH:D064420', (14, 22))	('CPB', 'Chemical', '-', (64, 67))	('toxicity', 'Disease', (14, 22))	('CPBE', 'Chemical', '-', (38, 42))	('higher', 'PosReg', (27, 33))	('CPBE', 'Var', (38, 42))
25275	29044496	We compared outcomes in each arm for patients with known BRAF mutant tumors vs known wildtype.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mutant', 'Var', (62, 68))	('BRAF', 'Gene', '673', (57, 61))	('patients', 'Species', '9606', (37, 45))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('BRAF', 'Gene', (57, 61))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
25277	29044496	(Supplementary Figure 2) However, for the CPBE arm, BRAF mutant patients had a superior PFS to wildtype patients (median 6.0 vs 3.9 months, p-value=0.039).	('PFS', 'CPA', (88, 91))	('patients', 'Species', '9606', (64, 72))	('patients', 'Species', '9606', (104, 112))	('mutant', 'Var', (57, 63))	('BRAF', 'Gene', '673', (52, 56))	('CPBE', 'Chemical', '-', (42, 46))	('BRAF', 'Gene', (52, 56))
25301	29044496	There were a relatively large number enrolled, likely due to other trial options and intercurrent approvals (Supplementary Figure 3) for cutaneous melanoma including BRAF inihibitors and immunotherapy, which likely also impacted the frequency of BRAF mutant patients enrolled.	('BRAF', 'Gene', (166, 170))	('mutant', 'Var', (251, 257))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (137, 155))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('BRAF', 'Gene', '673', (246, 250))	('BRAF', 'Gene', (246, 250))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('patients', 'Species', '9606', (258, 266))	('cutaneous melanoma', 'Disease', (137, 155))	('BRAF', 'Gene', '673', (166, 170))
25307	29044496	In our study, patients with BRAF mutations had improved PFS in the CPBE arm compared to CPB arm (6.0 vs 3.9 months respectively).	('improved', 'PosReg', (47, 55))	('CPBE', 'Chemical', '-', (67, 71))	('BRAF', 'Gene', '673', (28, 32))	('CPB', 'Chemical', '-', (67, 70))	('CPB', 'Chemical', '-', (88, 91))	('mutations', 'Var', (33, 42))	('PFS', 'MPA', (56, 59))	('BRAF', 'Gene', (28, 32))	('patients', 'Species', '9606', (14, 22))
25308	29044496	There is some rationale as to BRAF mutant melanomas having an activated mTOR pathway, with the latter representing a resistance mechanism to targeted therapy.	('mutant', 'Var', (35, 41))	('melanomas', 'Disease', (42, 51))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('mTOR pathway', 'Pathway', (72, 84))	('melanomas', 'Phenotype', 'HP:0002861', (42, 51))	('activated', 'PosReg', (62, 71))	('melanomas', 'Disease', 'MESH:D008545', (42, 51))
25309	29044496	For instance, in an in vitro study, the combination of BRAF inhibitors plus mTOR inhibition in vitro enhanced cell growth inhibition while decreasing expression of proteins involved in mTOR activation, thus overcoming the resistance of mutated cells to BRAF inhibition.	('decreasing', 'NegReg', (139, 149))	('BRAF', 'Gene', '673', (253, 257))	('BRAF', 'Gene', (253, 257))	('mTOR', 'MPA', (185, 189))	('expression of proteins involved', 'MPA', (150, 181))	('inhibitors', 'Var', (60, 70))	('cell growth inhibition', 'CPA', (110, 132))	('enhanced', 'PosReg', (101, 109))	('cell growth', 'biological_process', 'GO:0016049', ('110', '121'))	('BRAF', 'Gene', '673', (55, 59))	('overcoming', 'PosReg', (207, 217))	('BRAF', 'Gene', (55, 59))
25310	29044496	In brain tumors, mTOR activation has been shown to be increased in BRAF mutant tumors, as measured through expression of pS6.	('BRAF', 'Gene', '673', (67, 71))	('mutant', 'Var', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('BRAF', 'Gene', (67, 71))	('pS6', 'Gene', (121, 124))	('increased', 'PosReg', (54, 63))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('mTOR activation', 'MPA', (17, 32))	('brain tumors', 'Disease', 'MESH:D001932', (3, 15))	('tumors', 'Disease', (9, 15))	('pS6', 'Gene', '338413', (121, 124))	('brain tumors', 'Phenotype', 'HP:0030692', (3, 15))	('brain tumors', 'Disease', (3, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
25311	29044496	In a phase I clinical trial of vemurafenib and everolimus, 65% of patients with BRAF mutant advanced cancers responded to this combination chemotherapy, while also being safe and well-tolerated, although this is comparable to response rates of vemurafenib alone.	('BRAF', 'Gene', (80, 84))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('vemurafenib', 'Chemical', 'MESH:D000077484', (31, 42))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('vemurafenib', 'Chemical', 'MESH:D000077484', (244, 255))	('everolimus', 'Chemical', 'MESH:D000068338', (47, 57))	('mutant', 'Var', (85, 91))	('BRAF', 'Gene', '673', (80, 84))	('patients', 'Species', '9606', (66, 74))
25312	29044496	Therefore, our results suggesting an improved PFS with the addition of everolimus in the BRAF mutant patients are of interest, and merit further study, although the benefit appears mostly due to underperfomance of CPBE in the wildtype patients.	('CPBE', 'Chemical', '-', (214, 218))	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (235, 243))	('everolimus', 'Chemical', 'MESH:D000068338', (71, 81))	('mutant', 'Var', (94, 100))	('BRAF', 'Gene', '673', (89, 93))	('improved', 'PosReg', (37, 45))	('BRAF', 'Gene', (89, 93))	('PFS', 'MPA', (46, 49))
25362	28645290	This new SOI with liver pocket method was successfully performed on all 20 recipient mice, with ten receiving UM001 tumor pieces and ten receiving UM004 tumor pieces (Additional file 1: Table S1).	('mice', 'Species', '10090', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('UM001', 'Var', (110, 115))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
25395	28645290	Among the three freezing methods tested, Cryomedium D (DMEM containing medium) resulted in the highest growth rates following thawing and re-implantation of the frozen tumor samples.	('DMEM', 'Chemical', '-', (55, 59))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('growth', 'MPA', (103, 109))	('Cryomedium', 'Var', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
25404	28645290	We identified five representative mutations in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('uveal melanoma', 'Disease', (47, 61))	('mutations', 'Var', (34, 43))
25405	28645290	In 10 out of 12 samples available for mutation analysis, the xenograft tumors contained the exact same mutations as their corresponding original patient tumors.	('mutations', 'Var', (103, 112))	('contained', 'Reg', (78, 87))	('xenograft tumors', 'Disease', (61, 77))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('patient', 'Species', '9606', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', (71, 77))	('xenograft tumors', 'Disease', 'MESH:D009369', (61, 77))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
25408	28645290	Mutations in GNAQ and GNA11 were mutually exclusive, as were mutations in BAP1, SF3B1, and EIF1AX with each other.	('GNA11', 'Gene', (22, 27))	('EIF1AX', 'Gene', '66235', (91, 97))	('GNA11', 'Gene', '14672', (22, 27))	('GNAQ', 'Gene', (13, 17))	('SF3B1', 'Gene', '81898', (80, 85))	('BAP1', 'Gene', '104416', (74, 78))	('GNAQ', 'Gene', '14682', (13, 17))	('mutations', 'Var', (61, 70))	('EIF1AX', 'Gene', (91, 97))	('Mutations', 'Var', (0, 9))	('SF3B1', 'Gene', (80, 85))	('BAP1', 'Gene', (74, 78))
25410	28645290	The patterns of copy number variations (CNVs) in the original patient tumors are mostly maintained in the corresponding first-, second-, and third-generation xenograft tumors, as well as in tumors generated by re-implantation of cryopreserved samples (Fig.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumors', 'Disease', (168, 174))	('patient', 'Species', '9606', (62, 69))	('copy number variations', 'Var', (16, 38))	('xenograft tumors', 'Disease', (158, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('xenograft tumors', 'Disease', 'MESH:D009369', (158, 174))
25411	28645290	CNVs in tumors displayed representative characteristics of uveal melanoma cells, including monosomy 3 accompanied by chromosome 1p loss, 8q gain, and 8p loss.	('gain', 'PosReg', (140, 144))	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('uveal melanoma', 'Disease', (59, 73))	('chromosome', 'cellular_component', 'GO:0005694', ('117', '127'))	('loss', 'NegReg', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('monosomy 3', 'Disease', (91, 101))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('chromosome', 'Var', (117, 127))	('uveal melanoma', 'Disease', 'MESH:C536494', (59, 73))
25442	28645290	In 10 successful cases, both the original tumors and the corresponding xenograft tumors show the same tissue histologic features in H&E staining and immunohistochemistry, mutations and CNV in genomic analyses, and RPPA in proteomic analyses.	('original tumors', 'Disease', (33, 48))	('xenograft tumors', 'Disease', (71, 87))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('and', 'Var', (181, 184))	('H&E', 'Chemical', '-', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('xenograft tumors', 'Disease', 'MESH:D009369', (71, 87))	('original tumors', 'Disease', 'MESH:D009369', (33, 48))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
25448	28645290	Cytogenetic investigations have revealed that most uveal melanomas have abnormal chromosomes 1, 3, 6 and 8.	('uveal melanomas', 'Disease', 'MESH:C536494', (51, 66))	('uveal melanoma', 'Phenotype', 'HP:0007716', (51, 65))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('abnormal', 'Var', (72, 80))	('uveal melanomas', 'Disease', (51, 66))	('uveal melanomas', 'Phenotype', 'HP:0007716', (51, 66))	('abnormal chromosomes', 'Phenotype', 'HP:0031411', (72, 92))
25449	28645290	Monosomy 3 is observed in 50% of uveal melanoma, and 70% of patients with monosomy 3 die of metastases within four years after the initial diagnosis, whereas patients with disomy 3 (normal chromosome 3) rarely develop metastatic uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (33, 47))	('patients', 'Species', '9606', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('uveal melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('uveal melanoma', 'Disease', (33, 47))	('metastases', 'Disease', (92, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (229, 243))	('uveal melanoma', 'Phenotype', 'HP:0007716', (229, 243))	('metastases', 'Disease', 'MESH:D009362', (92, 102))	('uveal melanoma', 'Disease', (229, 243))	('patients', 'Species', '9606', (158, 166))	('chromosome', 'cellular_component', 'GO:0005694', ('189', '199'))	('monosomy 3', 'Var', (74, 84))
25450	28645290	Recently, researchers have identified mutations in BAP1 gene, located on chromosome 3, and this gene seems to play a major role in tumor progression in uveal melanoma.	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('BAP1', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('uveal melanoma', 'Phenotype', 'HP:0007716', (152, 166))	('uveal melanoma', 'Disease', (152, 166))	('uveal melanoma', 'Disease', 'MESH:C536494', (152, 166))	('tumor', 'Disease', (131, 136))	('play', 'Reg', (110, 114))	('mutations', 'Var', (38, 47))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('BAP1', 'Gene', '104416', (51, 55))
25452	28645290	A previous PDX study reported that tumors from patients having monosomy 3 or class 2 in GEP were relatively easy to engraft into mice.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('patients', 'Species', '9606', (47, 55))	('class 2', 'Var', (77, 84))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('monosomy 3', 'Var', (63, 73))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('mice', 'Species', '10090', (129, 133))	('GEP', 'Gene', (88, 91))
25455	28645290	Ki67 positivity is reported to be strongly associated with class 2 in GEP and monosomy 3.	('positivity', 'Var', (5, 15))	('Ki67', 'Gene', '17345', (0, 4))	('class 2', 'Disease', (59, 66))	('monosomy 3', 'Disease', (78, 88))	('Ki67', 'Gene', (0, 4))	('associated', 'Reg', (43, 53))	('GEP', 'Disease', (70, 73))
25522	25683463	NKT cell-deficient CD1d-/- mice and WT C57BL/6 mice treated with anti-CD1d antibody developed significantly fewer liver metastases than WT mice following either intraocular or intrasplenic injection of B16LS9 melanoma cells.	('intraocular', 'Disease', (161, 172))	('antibody', 'cellular_component', 'GO:0019815', ('75', '83'))	('antibody', 'cellular_component', 'GO:0042571', ('75', '83'))	('antibody', 'cellular_component', 'GO:0019814', ('75', '83'))	('mice', 'Species', '10090', (27, 31))	('intraocular', 'Disease', 'MESH:D064090', (161, 172))	('fewer', 'NegReg', (108, 113))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('liver metastases', 'Disease', (114, 130))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('antibody', 'molecular_function', 'GO:0003823', ('75', '83'))	('mice', 'Species', '10090', (139, 143))	('liver metastases', 'Disease', 'MESH:D009362', (114, 130))	('melanoma', 'Disease', (209, 217))	('mice', 'Species', '10090', (47, 51))	('anti-CD1d', 'Var', (65, 74))	('B16LS9', 'CellLine', 'CVCL:2105', (202, 208))
25538	25683463	Studies in nude mice, which cannot mount a T cell-dependent adaptive immune response, but have an intact NK cell repertoire, have shown that the depletion of NK cells in vivo results in a significant increase in the number of liver metastases arising from human uveal melanoma cells transplanted into the eye.	('liver metastases', 'Disease', (226, 242))	('human', 'Species', '9606', (256, 261))	('uveal melanoma', 'Disease', (262, 276))	('increase', 'PosReg', (200, 208))	('liver metastases', 'Disease', 'MESH:D009362', (226, 242))	('adaptive immune response', 'biological_process', 'GO:0002250', ('60', '84'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (262, 276))	('nude mice', 'Species', '10090', (11, 20))	('uveal melanoma', 'Disease', 'MESH:C536494', (262, 276))	('depletion', 'Var', (145, 154))	('melanoma', 'Phenotype', 'HP:0002861', (268, 276))
25563	25683463	NK cell-enriched suspensions were examined by flow cytometry for purity using anti-NK1.1 antibody (BD Biosciences, San Jose, CA) and anti-CD8 monoclonal antibody (BD Biosciences) and were found to be 74% NK1.1+ and <4% CD8+.	('NK1.1', 'Gene', (204, 209))	('antibody', 'cellular_component', 'GO:0019815', ('89', '97'))	('antibody', 'cellular_component', 'GO:0042571', ('153', '161'))	('NK1.1', 'Gene', '17059', (83, 88))	('antibody', 'cellular_component', 'GO:0019814', ('89', '97'))	('antibody', 'molecular_function', 'GO:0003823', ('89', '97'))	('NK1.1', 'Gene', '17059', (204, 209))	('antibody', 'cellular_component', 'GO:0019815', ('153', '161'))	('NK1.1', 'Gene', (83, 88))	('antibody', 'cellular_component', 'GO:0019814', ('153', '161'))	('antibody', 'cellular_component', 'GO:0042571', ('89', '97'))	('antibody', 'molecular_function', 'GO:0003823', ('153', '161'))	('anti-CD8', 'Var', (133, 141))
25592	25683463	We next sought to confirm our previous findings indicating that in vivo blockade of IL-10 through the administration of anti-IL-10 antibody reversed the depressed liver NK cell cytolytic activity, which ostensibly played a crucial role in the formation of liver metastases in B16LS9 melanoma-bearing mice.	('melanoma', 'Disease', 'MESH:D008545', (283, 291))	('IL-10', 'molecular_function', 'GO:0005141', ('125', '130'))	('liver metastases', 'Disease', (256, 272))	('mice', 'Species', '10090', (300, 304))	('depressed liver', 'Phenotype', 'HP:0001410', (153, 168))	('rat', 'Species', '10116', (110, 113))	('antibody', 'cellular_component', 'GO:0019814', ('131', '139'))	('B16LS9', 'CellLine', 'CVCL:2105', (276, 282))	('depressed liver NK', 'Disease', 'MESH:D000275', (153, 171))	('IL-10', 'Gene', (84, 89))	('antibody', 'molecular_function', 'GO:0003823', ('131', '139'))	('formation', 'biological_process', 'GO:0009058', ('243', '252'))	('IL-10', 'molecular_function', 'GO:0005141', ('84', '89'))	('melanoma', 'Phenotype', 'HP:0002861', (283, 291))	('melanoma', 'Disease', (283, 291))	('antibody', 'cellular_component', 'GO:0042571', ('131', '139'))	('blockade', 'Var', (72, 80))	('liver metastases', 'Disease', 'MESH:D009362', (256, 272))	('anti-IL-10', 'Var', (120, 130))	('depressed liver NK', 'Disease', (153, 171))	('antibody', 'cellular_component', 'GO:0019815', ('131', '139'))
25597	25683463	There was a four-fold reduction in the number of liver metastases in IL-10-/- mice in comparison with WT mice indicating the important role of IL-10 in exacerbating liver metastases in melanoma-bearing mice (Fig.	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('liver metastases', 'Disease', (165, 181))	('IL-10-/-', 'Gene', (69, 77))	('IL-10', 'molecular_function', 'GO:0005141', ('69', '74'))	('mice', 'Species', '10090', (202, 206))	('IL-10', 'Var', (143, 148))	('liver metastases', 'Disease', (49, 65))	('liver metastases', 'Disease', 'MESH:D009362', (165, 181))	('exacerbating', 'PosReg', (152, 164))	('reduction', 'NegReg', (22, 31))	('IL-10', 'molecular_function', 'GO:0005141', ('143', '148'))	('liver metastases', 'Disease', 'MESH:D009362', (49, 65))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('mice', 'Species', '10090', (105, 109))	('melanoma', 'Disease', (185, 193))	('mice', 'Species', '10090', (78, 82))
25627	25683463	NKG2D expression was the same in WT mice, CD1d-/- mice, and WT mice treated with anti-CD1d antibody on days 0 and 14 post tumor injection, but was significantly increased in CD1d-/- and WT anti-CD1d antibody-treated mice on day 9 post tumor injection (Figs.	('NKG2D', 'Gene', '27007', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('NKG2D', 'Gene', (0, 5))	('antibody', 'cellular_component', 'GO:0019815', ('91', '99'))	('mice', 'Species', '10090', (36, 40))	('tumor', 'Disease', (122, 127))	('antibody', 'cellular_component', 'GO:0019815', ('199', '207'))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mice', 'Species', '10090', (50, 54))	('increased', 'PosReg', (161, 170))	('antibody', 'cellular_component', 'GO:0019814', ('91', '99'))	('CD1d-/-', 'Var', (174, 181))	('antibody', 'cellular_component', 'GO:0019814', ('199', '207'))	('mice', 'Species', '10090', (216, 220))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('antibody', 'molecular_function', 'GO:0003823', ('91', '99'))	('antibody', 'molecular_function', 'GO:0003823', ('199', '207'))	('antibody', 'cellular_component', 'GO:0042571', ('91', '99'))	('expression', 'MPA', (6, 16))	('mice', 'Species', '10090', (63, 67))	('tumor', 'Disease', (235, 240))	('antibody', 'cellular_component', 'GO:0042571', ('199', '207'))
25658	25683463	Although the NK cell activation receptor NKG2D was upregulated on NK cells in CD1d-/- mice on day 9 post tumor injection, we do not believe that this contributed to the enhanced NK cell mediated cytolysis in CD1d-/- mice as we did not detect the expression of the two major ligands for the NKG2D receptor, Rae1 and Mult1, on B16LS9 melanoma cells by flow cytometry.	('Mult1', 'Gene', '77777', (315, 320))	('NKG2D', 'Gene', '27007', (41, 46))	('mice', 'Species', '10090', (86, 90))	('NKG2D', 'Gene', (41, 46))	('B16LS9', 'CellLine', 'CVCL:2105', (325, 331))	('enhanced', 'PosReg', (169, 177))	('melanoma', 'Phenotype', 'HP:0002861', (332, 340))	('melanoma', 'Disease', (332, 340))	('upregulated', 'PosReg', (51, 62))	('tumor', 'Disease', (105, 110))	('Rae1', 'Gene', (306, 310))	('mice', 'Species', '10090', (216, 220))	('Rae1', 'Gene', '66679', (306, 310))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('CD1d-/-', 'Var', (78, 85))	('NKG2D', 'Gene', (290, 295))	('NKG2D', 'Gene', '27007', (290, 295))	('NK cell mediated cytolysis', 'biological_process', 'GO:0042267', ('178', '204'))	('NK cell mediated cytolysis', 'CPA', (178, 204))	('NK cell activation', 'biological_process', 'GO:0030101', ('13', '31'))	('melanoma', 'Disease', 'MESH:D008545', (332, 340))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Mult1', 'Gene', (315, 320))
25663	26119091	Most studies of CAS proteins to date have been focused on the first two members, BCAR1 and NEDD9, with altered expression of these proteins now appreciated as influencing disease development and prognosis for cancer and other serious pathological conditions.	('BCAR1', 'Gene', (81, 86))	('altered', 'Var', (103, 110))	('disease development', 'CPA', (171, 190))	('influencing', 'Reg', (159, 170))	('NEDD9', 'Gene', '4739', (91, 96))	('NEDD9', 'Gene', (91, 96))	('BCAR1', 'Gene', '9564', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', (209, 215))	('CAS', 'cellular_component', 'GO:0005650', ('16', '19'))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
25671	26119091	As one example, clinical effectiveness of RAF inhibitors in the context of V600E mutant (constitutively active) versus wild type BRAF is influenced strongly by the functionality of the paralogous CRAF protein, based on heterodimerization and transactivation processes specific to each of the two proteins.	('transactivation', 'biological_process', 'GO:2000144', ('242', '257'))	('RAF', 'Gene', (42, 45))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('RAF', 'Gene', '22882', (42, 45))	('CRAF', 'Gene', '5894', (196, 200))	('protein', 'cellular_component', 'GO:0003675', ('201', '208'))	('V600E', 'Mutation', 'rs113488022', (75, 80))	('RAF', 'Gene', (197, 200))	('RAF', 'Gene', '22882', (197, 200))	('CRAF', 'molecular_function', 'GO:0004709', ('196', '200'))	('V600E', 'Var', (75, 80))	('influenced', 'Reg', (137, 147))	('RAF', 'Gene', (130, 133))	('CRAF', 'Gene', (196, 200))	('RAF', 'Gene', '22882', (130, 133))
25676	26119091	Based on these non-canonical roles, NEDD9 function has recently been shown to modulate pathogenesis of the ciliopathy autosomal dominant polycystic kidney disease (ADPKD).	('function', 'Var', (42, 50))	('polycystic kidney', 'Phenotype', 'HP:0000113', (137, 154))	('ADPKD', 'Disease', (164, 169))	('ciliopathy autosomal dominant polycystic kidney disease', 'Disease', 'MESH:D007690', (107, 162))	('modulate', 'Reg', (78, 86))	('NEDD9', 'Gene', '4739', (36, 41))	('NEDD9', 'Gene', (36, 41))	('ADPKD', 'Disease', 'MESH:D007690', (164, 169))	('pathogenesis', 'biological_process', 'GO:0009405', ('87', '99'))	('kidney disease', 'Phenotype', 'HP:0000112', (148, 162))
25700	26119091	The PTP-PEST proline-rich sequence 332PPKPPR337 has been shown to interact directly with the SH3 domain of members of EFS.	('332PPKPPR337', 'Var', (35, 47))	('proline', 'Chemical', 'MESH:D011392', (13, 20))	('interact', 'Interaction', (66, 74))
25714	26119091	Alexandropoulos and colleagues showed that SRC directly phosphorylates residues Y576 and Y577 tyrosine sites on the EFS, thus enhancing FAK targeting, and eventually the solubility and/or stability of the complex.	('complex', 'Interaction', (205, 212))	('stability', 'MPA', (188, 197))	('enhancing', 'PosReg', (126, 135))	('tyrosine', 'Chemical', 'MESH:D014443', (94, 102))	('Y576', 'Var', (80, 84))	('FAK targeting', 'MPA', (136, 149))	('Y577', 'Var', (89, 93))	('FAK', 'molecular_function', 'GO:0004717', ('136', '139'))	('solubility', 'MPA', (170, 180))
25715	26119091	Reciprocally, EFS activates SRC signaling through c-CRK and RAP1, a process associated with cell migration for multiple family members .	('RAP1', 'Gene', '5906', (60, 64))	('cell migration', 'biological_process', 'GO:0016477', ('92', '106'))	('RAP1', 'Gene', (60, 64))	('c-CRK', 'Gene', '23552', (50, 55))	('SRC signaling', 'MPA', (28, 41))	('signaling', 'biological_process', 'GO:0023052', ('32', '41'))	('c-CRK', 'Gene', (50, 55))	('EFS', 'Var', (14, 17))	('activates', 'PosReg', (18, 27))
25724	26119091	In direct comparison to NEDD9, overexpression of CASS4 was shown to act similarly in activating FAK phosphorylation and promoting cell spreading, but to a lesser degree than for NEDD9, and only in a subset of cells overexpressing the protein.	('protein', 'cellular_component', 'GO:0003675', ('234', '241'))	('NEDD9', 'Gene', '4739', (24, 29))	('phosphorylation', 'biological_process', 'GO:0016310', ('100', '115'))	('overexpression', 'Var', (31, 45))	('CASS4', 'Gene', (49, 54))	('activating FAK phosphorylation', 'MPA', (85, 115))	('cell spreading', 'CPA', (130, 144))	('FAK', 'molecular_function', 'GO:0004717', ('96', '99'))	('NEDD9', 'Gene', '4739', (178, 183))	('NEDD9', 'Gene', (24, 29))	('NEDD9', 'Gene', (178, 183))	('promoting', 'PosReg', (120, 129))
25729	26119091	In these studies, mice with genetic reduction of EFS levels developed normally during embryogenesis but after 7-14 months of life developed massive inflammatory lesions with T-cells infiltration in multiple tissues including the small intestine, liver, kidneys and lungs that bore a striking histological resemblance to inflammatory bowel disorders resembling Crohn's disease.	('embryogenesis', 'biological_process', 'GO:0009790', ('86', '99'))	("Crohn's disease", 'Disease', 'MESH:D003424', (360, 375))	("Crohn's disease", 'Disease', (360, 375))	('embryogenesis', 'biological_process', 'GO:0009793', ('86', '99'))	('mice', 'Species', '10090', (18, 22))	('genetic', 'Var', (28, 35))	('reduction', 'NegReg', (36, 45))	('inflammatory bowel disorders', 'Disease', (320, 348))	('inflammatory bowel disorders', 'Disease', 'MESH:D015212', (320, 348))	('inflammatory bowel disorders', 'Phenotype', 'HP:0002037', (320, 348))	('embryogenesis', 'biological_process', 'GO:0009792', ('86', '99'))	("Crohn's disease", 'Phenotype', 'HP:0100280', (360, 375))
25730	26119091	linked EFS single nucleotide polymorphisms (SNPs) to Crohn's disease using a novel Sherlock algorithm on a study of 3,230 cases versus 4,829 controls despite the fact that initial genome-wide association studies (GWAS) of Crohn's disease did not identify EFS.	('single nucleotide polymorphisms', 'Var', (11, 42))	("Crohn's disease", 'Phenotype', 'HP:0100280', (53, 68))	("Crohn's disease", 'Disease', (53, 68))	("Crohn's disease", 'Phenotype', 'HP:0100280', (222, 237))	("Crohn's disease", 'Disease', 'MESH:D003424', (53, 68))	('EFS', 'Gene', (7, 10))	("Crohn's disease", 'Disease', 'MESH:D003424', (222, 237))	("Crohn's disease", 'Disease', (222, 237))
25747	26119091	However, changes in CASS4 expression have been linked to atopic asthma in a study performed by Esnault et al..	('expression', 'MPA', (26, 36))	('changes', 'Var', (9, 16))	('CASS4', 'Gene', (20, 25))	('asthma', 'Phenotype', 'HP:0002099', (64, 70))	('atopic asthma', 'Disease', 'MESH:C565292', (57, 70))	('atopic asthma', 'Disease', (57, 70))	('linked', 'Reg', (47, 53))
25750	26119091	found a locus associated with lower susceptibility to AD on chromosome 20 at the location of the CASS4 gene, and identified a corresponding SNP - rs7274581 T/C (OR = 0.87) - which reached genome-wide significance in both the first stage (p-value 1.6*10-6 in the analysis of 4 combined samples totaling 17,008 cases versus 37,154 controls) and the second stage (p-value 4.1*10-3 in the replication study by genotyping SNPs showed moderate significance in stage 1 in an independent sample of 8,572 cases versus 11,312 controls) analysis.	('SNP', 'Var', (140, 143))	('lower', 'NegReg', (30, 35))	('AD', 'Disease', 'MESH:D000544', (54, 56))	('AD', 'Disease', (54, 56))	('CASS4', 'Gene', (97, 102))	('susceptibility', 'MPA', (36, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))	('rs7274581', 'Mutation', 'rs7274581', (146, 155))
25753	26119091	Two additional CASS4 SNPs were reported to be associated with AD susceptibility: rs6024870 (RegulomeDB score 2b) by Rosenthal et al.	('AD', 'Disease', (62, 64))	('rs6024870', 'Var', (81, 90))	('rs6024870', 'Mutation', 'rs6024870', (81, 90))	('AD', 'Disease', 'MESH:D000544', (62, 64))
25757	26119091	The Gene Modifier Study (GMS) included unrelated affected individuals homozygous for CTFR allele p.Phe508del, common in cystic fibrosis; the Canadian Consortium for Genetic Studies (CGS) was a population-based study of patients with cystic fibrosis; and the Twins & Sibs Study (TSS) assessed families with two or more surviving children with cystic fibrosis.	('cystic fibrosis', 'Disease', 'MESH:D003550', (233, 248))	('p.Phe508del', 'Mutation', 'p.508delF', (97, 108))	('cystic fibrosis', 'Disease', 'MESH:D003550', (120, 135))	('cystic fibrosis', 'Disease', (342, 357))	('CTFR', 'Gene', (85, 89))	('cystic fibrosis', 'Disease', (120, 135))	('cystic fibrosis', 'Disease', (233, 248))	('GMS', 'Chemical', '-', (25, 28))	('children', 'Species', '9606', (328, 336))	('patients', 'Species', '9606', (219, 227))	('p.Phe508del', 'Var', (97, 108))	('cystic fibrosis', 'Disease', 'MESH:D003550', (342, 357))
25764	26119091	Based on information in the genomic databases available through the cBioportal site (The Cancer Genome Atlas (TCGA) and others), the CASS4 and EFS genes show copy number, gene expression changes, or mutation in a subset of tumors for most tumor types for which information is available (Figure 4).	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('gene expression', 'biological_process', 'GO:0010467', ('171', '186'))	('Cancer Genome Atlas', 'Disease', (89, 108))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('copy number', 'Var', (158, 169))	('tumors', 'Disease', (223, 229))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (89, 108))	('gene expression', 'MPA', (171, 186))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('mutation', 'Var', (199, 207))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('Cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', (239, 244))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('EFS', 'Gene', (143, 146))	('CASS4', 'Gene', (133, 138))
25769	26119091	In one study, the local and systemic recurrence of prostate cancer was associated with CpG site hypermethylation of number of genes, including EFS, FLNC, ECRG4, PITX2, PDLIM4, and KCNMA1.	('PITX2', 'Gene', (161, 166))	('FLNC', 'Gene', (148, 152))	('ECRG4', 'Gene', (154, 159))	('prostate cancer', 'Disease', 'MESH:D011471', (51, 66))	('prostate cancer', 'Disease', (51, 66))	('prostate cancer', 'Phenotype', 'HP:0012125', (51, 66))	('PDLIM4', 'Gene', '8572', (168, 174))	('ECRG4', 'Gene', '84417', (154, 159))	('FLNC', 'Gene', '2318', (148, 152))	('KCNMA1', 'Gene', '3778', (180, 186))	('PITX2', 'Gene', '5308', (161, 166))	('EFS', 'Gene', (143, 146))	('KCNMA1', 'Gene', (180, 186))	('associated', 'Reg', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('PDLIM4', 'Gene', (168, 174))	('hypermethylation', 'Var', (96, 112))
25775	26119091	Methylation of the EFS CpG island was observed in 69% of cases of uveal melanoma (UM), with methylation only observed in cases of metastatic disease.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('uveal melanoma', 'Disease', (66, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('Methylation', 'Var', (0, 11))	('methylation', 'biological_process', 'GO:0032259', ('92', '103'))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('observed', 'Reg', (38, 46))
25777	26119091	Importantly, EFS knockdown with siRNA restored trastuzumab sensitivity.	('trastuzumab', 'Chemical', 'MESH:D000068878', (47, 58))	('restored', 'PosReg', (38, 46))	('knockdown', 'Var', (17, 26))	('EFS', 'Gene', (13, 16))	('trastuzumab sensitivity', 'MPA', (47, 70))
25778	26119091	Reflecting the importance of post-translational modification of CAS proteins, in a study of cell lines and tumor tissue in malignant melanoma, EFS phosphorylation and activity significantly decreased (p<0.05) in response to vemurafenib treatment in BRAF wild-type melanoma tumors compared to tumors with a BRAF V600E mutation with additional resistance to vemurfenib.	('malignant melanoma', 'Phenotype', 'HP:0002861', (123, 141))	('tumor', 'Disease', (107, 112))	('malignant melanoma', 'Disease', 'MESH:D008545', (123, 141))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))	('melanoma tumors', 'Disease', 'MESH:D008545', (264, 279))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('post-translational modification', 'biological_process', 'GO:0043687', ('29', '60'))	('tumor', 'Disease', (273, 278))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('activity', 'MPA', (167, 175))	('CAS', 'cellular_component', 'GO:0005650', ('64', '67'))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('melanoma tumors', 'Disease', (264, 279))	('tumors', 'Disease', (292, 298))	('vemurafenib', 'Chemical', 'MESH:D000077484', (224, 235))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('decreased', 'NegReg', (190, 199))	('V600E', 'Var', (311, 316))	('tumors', 'Phenotype', 'HP:0002664', (273, 279))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('EFS phosphorylation', 'MPA', (143, 162))	('malignant melanoma', 'Disease', (123, 141))	('V600E', 'Mutation', 'rs113488022', (311, 316))	('tumors', 'Disease', 'MESH:D009369', (292, 298))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumors', 'Disease', (273, 279))	('BRAF', 'Gene', '673', (306, 310))	('BRAF', 'Gene', '673', (249, 253))	('BRAF', 'Gene', (306, 310))	('BRAF', 'Gene', (249, 253))	('tumor', 'Disease', (292, 297))	('vemurfenib', 'Chemical', '-', (356, 366))	('phosphorylation', 'biological_process', 'GO:0016310', ('147', '162'))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('tumors', 'Disease', 'MESH:D009369', (273, 279))
25786	26119091	MSS mutations confer a poor patient prognosis, whereas MSI mutant colorectal cancers have an excellent prognosis.	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('colorectal cancers', 'Disease', 'MESH:D015179', (66, 84))	('patient', 'Species', '9606', (28, 35))	('colorectal cancers', 'Disease', (66, 84))	('MSS', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutations', 'Var', (4, 13))	('MSS', 'Chemical', '-', (0, 3))
25795	25594048	The majority (~80%) of UM cases are driven by mutually exclusive mutations in GNAQ or GNA11, the genes encoding two homologous alpha subunits (Galphaq or Galpha11, hereafter referred to as Gq/11) of the heterotrimeric G-protein.	('Galphaq', 'Gene', (143, 150))	('driven by', 'Reg', (36, 45))	('Galphaq', 'Gene', '2776', (143, 150))	('GNAQ', 'Gene', (78, 82))	('Gq/11', 'Chemical', '-', (189, 194))	('heterotrimeric G-protein', 'molecular_function', 'GO:0005065', ('203', '227'))	('protein', 'cellular_component', 'GO:0003675', ('220', '227'))	('Galpha11', 'Gene', (154, 162))	('GNA11', 'Gene', (86, 91))	('GNAQ', 'Gene', '2776', (78, 82))	('Galpha11', 'Gene', '2767', (154, 162))	('GNA11', 'Gene', '2767', (86, 91))	('mutations', 'Var', (65, 74))
25798	25594048	However, mutant Gq/11 may activate downstream signaling events to promote UM, therefore defining the key molecular mechanisms involved in mutant Gq/11-induced carcinogenesis may provide novel drug targets for UM intervention.	('carcinogenesis', 'Disease', (159, 173))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('carcinogenesis', 'Disease', 'MESH:D063646', (159, 173))	('activate', 'PosReg', (26, 34))	('mutant', 'Var', (9, 15))	('Gq/11', 'Chemical', '-', (145, 150))	('mutant', 'Var', (138, 144))	('Gq/11', 'Chemical', '-', (16, 21))	('promote', 'PosReg', (66, 73))	('Gq/11-induced', 'Gene', (145, 158))	('Gq/11', 'Gene', (16, 21))
25799	25594048	The Hippo pathway plays a critical role in regulating tissue growth and organ size, and its dysregulation leads to neoplastic growth and cancer.	('neoplastic growth', 'Disease', (115, 132))	('dysregulation', 'Var', (92, 105))	('leads to', 'Reg', (106, 114))	('neoplastic growth', 'Disease', 'MESH:D006130', (115, 132))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('Hippo pathway', 'Pathway', (4, 17))
25803	25594048	We have previously demonstrated that the Hippo pathway is modulated by G-protein-coupled receptor (GPCR) signaling, and active Gq/11 can activate YAP by inhibiting Lats1/2 kinase activity.	('Gq/11', 'Chemical', '-', (127, 132))	('YAP', 'Gene', '10413', (146, 149))	('Gq/11', 'Gene', (127, 132))	('active', 'Var', (120, 126))	('YAP', 'Gene', (146, 149))	('Lats1/2', 'Gene', '8140;7462', (164, 171))	('Hippo pathway', 'Pathway', (41, 54))	('kinase activity', 'molecular_function', 'GO:0016301', ('172', '187'))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('Lats1/2', 'Gene', (164, 171))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('inhibiting', 'NegReg', (153, 163))	('activate', 'PosReg', (137, 145))
25804	25594048	These findings suggest that the Hippo pathway may contributes to development of tumors containing mutant Gq/11, such as UM.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Hippo pathway', 'Pathway', (32, 45))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('contributes', 'Reg', (50, 61))	('tumors', 'Disease', (80, 86))	('Gq/11', 'Chemical', '-', (105, 110))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('Gq/11', 'Gene', (105, 110))	('mutant', 'Var', (98, 104))
25805	25594048	In two recent reports in Cancer Cell, we and Gutkind's team have independently shown that YAP mediates the oncogenic activity of mutant Gq/11 in UM.	('Gq/11', 'Gene', (136, 141))	('oncogenic activity', 'CPA', (107, 125))	('YAP', 'Gene', (90, 93))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('YAP', 'Gene', '10413', (90, 93))	('Gq/11', 'Chemical', '-', (136, 141))	('mutant', 'Var', (129, 135))
25806	25594048	Accumulation of dephosphorylated (active) Yap in the nucleus is observed in multiple cell lines derived from UMs with Gq/11 mutations, and Yap nuclear localization correlates with Gq/11 mutations in UM patient samples.	('localization', 'biological_process', 'GO:0051179', ('151', '163'))	('mutations', 'Var', (124, 133))	('Accumulation', 'PosReg', (0, 12))	('Gq/11', 'Chemical', '-', (180, 185))	('Gq/11', 'Chemical', '-', (118, 123))	('patient', 'Species', '9606', (202, 209))	('nucleus', 'cellular_component', 'GO:0005634', ('53', '60'))	('Gq/11', 'Gene', (118, 123))
25807	25594048	In a transgenic mouse model, expression of mutant Gq, driven by lineage-specific promoters, results in cutaneous melanoma or skin carcinoma, and Yap is also nuclear in these tumors.	('tumors', 'Disease', (174, 180))	('cutaneous melanoma', 'Disease', (103, 121))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (103, 121))	('results in', 'Reg', (92, 102))	('skin carcinoma', 'Disease', 'MESH:D012878', (125, 139))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (103, 121))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('skin carcinoma', 'Disease', (125, 139))	('mutant', 'Var', (43, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('mouse', 'Species', '10090', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
25808	25594048	These results indicate that Yap activity is elevated in mutant Gq/11-induced primary human UMs and mouse tumors.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('Gq/11', 'Chemical', '-', (63, 68))	('mouse', 'Species', '10090', (99, 104))	('elevated', 'PosReg', (44, 52))	('Yap activity', 'MPA', (28, 40))	('mutant', 'Var', (56, 62))	('Gq/11-induced', 'Gene', (63, 76))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('human', 'Species', '9606', (85, 90))	('Gq/11-induced', 'Reg', (63, 76))
25809	25594048	Moreover, when Yap is knocked down, tumor growth of Gq mutated UM cells in nude mice is significantly blocked, indicating an essential role of Yap in mediating the oncogenic effect of mutant Gq/11 in UM.	('mutant', 'Var', (184, 190))	('mutated', 'Var', (55, 62))	('nude mice', 'Species', '10090', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('blocked', 'NegReg', (102, 109))	('Gq/11', 'Chemical', '-', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Gq/11', 'Gene', (191, 196))	('tumor', 'Disease', (36, 41))
25811	25594048	When Verteporfin is given to mice after UM cells have been grafted subcutaneously or orthotopically into the eye, tumor growth of UM cells harboring the Gq mutation is significantly blocked.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mice', 'Species', '10090', (29, 33))	('tumor', 'Disease', (114, 119))	('blocked', 'NegReg', (182, 189))	('Verteporfin', 'Chemical', 'MESH:D000077362', (5, 16))	('mutation', 'Var', (156, 164))
25818	25594048	Activating Gq/11 mutations and dysregulated GPCR signaling are also present in other types of cancer.	('Activating', 'PosReg', (0, 10))	('Gq/11', 'Chemical', '-', (11, 16))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('Gq/11', 'Gene', (11, 16))	('GPCR signaling', 'MPA', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
25819	25594048	Especially, mutations in RhoA, a strong upstream activator of YAP, have been recently found in human cancers.	('found', 'Reg', (86, 91))	('human', 'Species', '9606', (95, 100))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('RhoA', 'Gene', '387', (25, 29))	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('YAP', 'Gene', '10413', (62, 65))	('RhoA', 'Gene', (25, 29))	('YAP', 'Gene', (62, 65))
25820	25594048	Moreover, mutations in Hippo pathway components, such as Nf2, are also observed in schwannoma, meningioma, and mesothelioma, in which YAP activation may play a major role.	('schwannoma', 'Phenotype', 'HP:0100008', (83, 93))	('meningioma', 'Disease', (95, 105))	('Nf2', 'Gene', (57, 60))	('meningioma', 'Phenotype', 'HP:0002858', (95, 105))	('observed', 'Reg', (71, 79))	('mesothelioma', 'Disease', (111, 123))	('schwannoma', 'Disease', (83, 93))	('meningioma', 'Disease', 'MESH:D008577', (95, 105))	('YAP', 'Gene', '10413', (134, 137))	('schwannoma', 'Disease', 'MESH:D009442', (83, 93))	('mutations', 'Var', (10, 19))	('mesothelioma', 'Disease', 'MESH:D008654', (111, 123))	('YAP', 'Gene', (134, 137))
25856	25448994	The principal reason for this analysis was to determine whether patients with discordant GEP class at the two sites had a survival experience more like that of concordant Class 2 patients, concordant Class 1 patients, or intermediate between the two concordant Class patients.	('GEP', 'Gene', (89, 92))	('patients', 'Species', '9606', (208, 216))	('patients', 'Species', '9606', (267, 275))	('patients', 'Species', '9606', (64, 72))	('discordant', 'Var', (78, 88))	('patients', 'Species', '9606', (179, 187))
25964	25254213	CXCR4 is upregulated in metastatic breast cancer cell lines and lymph node metastasis, and cells expressing CXCR4 predominantly migrate to tissues that express the ligand CXCL12.	('upregulated', 'PosReg', (9, 20))	('CXCL12', 'Gene', '6387', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('CXCR4', 'MPA', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('CXCR4', 'molecular_function', 'GO:0038147', ('108', '113'))	('CXCR4', 'Var', (108, 113))	('ligand', 'molecular_function', 'GO:0005488', ('164', '170'))	('CXCR4', 'molecular_function', 'GO:0038147', ('0', '5'))	('breast cancer', 'Disease', (35, 48))	('CXCL12', 'Gene', (171, 177))
25966	25254213	Interestingly, in vivo inhibition of the CXCR4/CXCL12 axis reduced lymph node and lung metastasis.	('CXCL12', 'Gene', '6387', (47, 53))	('reduced', 'NegReg', (59, 66))	('CXCR4', 'molecular_function', 'GO:0038147', ('41', '46'))	('inhibition', 'Var', (23, 33))	('reduced lymph node', 'Phenotype', 'HP:0002732', (59, 77))	('CXCL12', 'Gene', (47, 53))
25969	25254213	In prostate cancer, CXCR4 expression has been shown to increase tumor invasion and metastasis.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('increase', 'PosReg', (55, 63))	('tumor', 'Disease', (64, 69))	('metastasis', 'CPA', (83, 93))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('CXCR4', 'molecular_function', 'GO:0038147', ('20', '25'))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('CXCR4 expression', 'Var', (20, 36))
25976	25254213	Senescence can be prematurely induced by stress factors and DNA damage, for example, upon oncogene expression or UV irradiation, and is mediated by activation of the Arf/p53/p21 and/or p16/pRb pathways.	('pRb', 'Gene', '5925', (189, 192))	('p21', 'Gene', (174, 177))	('p21', 'Gene', '644914', (174, 177))	('activation', 'PosReg', (148, 158))	('oncogene expression', 'Var', (90, 109))	('p53', 'Gene', (170, 173))	('p16', 'Gene', (185, 188))	('expression', 'Var', (99, 109))	('p16', 'Gene', '1029', (185, 188))	('p53', 'Gene', '7157', (170, 173))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('Senescence', 'biological_process', 'GO:0010149', ('0', '10'))	('pRb', 'Gene', (189, 192))	('Senescence', 'CPA', (0, 10))
25978	25254213	Human nevi, for instance, are frequently positive for activating BRafV600E mutations; however, these cells bear a senescent phenotype.	('activating', 'PosReg', (54, 64))	('Human', 'Species', '9606', (0, 5))	('nevi', 'Phenotype', 'HP:0003764', (6, 10))	('BRafV600E', 'Var', (65, 74))	('BRafV600E', 'Mutation', 'rs113488022', (65, 74))
25979	25254213	Abrogation of such oncogene-induced senescence by PI3K activation allows for melanoma formation.	('senescence', 'biological_process', 'GO:0010149', ('36', '46'))	('PI3K', 'molecular_function', 'GO:0016303', ('50', '54'))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('Abrogation', 'NegReg', (0, 10))	('melanoma', 'Disease', (77, 85))	('formation', 'biological_process', 'GO:0009058', ('86', '95'))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('PI3K', 'Var', (50, 54))
25981	25254213	Recently, however, it became apparent that senescence in surrounding tissue cells might have both tumor-suppressive as well as promoting consequences.	('senescence', 'Var', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('senescence', 'biological_process', 'GO:0010149', ('43', '53'))	('tumor', 'Disease', (98, 103))
25986	25254213	Importantly, induction of senescence in NK cells has recently been reported to promote vascular remodeling and angiogenesis, opening the possibility that senescence and SASP may also contribute to tumor-associated lymphangiogenesis, although this remains to be demonstrated experimentally.	('angiogenesis', 'CPA', (111, 123))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('214', '231'))	('induction', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('senescence', 'biological_process', 'GO:0010149', ('154', '164'))	('SASP', 'Gene', (169, 173))	('SASP', 'Gene', '7295', (169, 173))	('senescence', 'biological_process', 'GO:0010149', ('26', '36'))	('angiogenesis', 'biological_process', 'GO:0001525', ('111', '123'))	('promote', 'PosReg', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('vascular remodeling', 'CPA', (87, 106))	('tumor', 'Disease', (197, 202))	('contribute', 'Reg', (183, 193))
26003	25254213	However, it was demonstrated recently that low molecular weight hyaluronan promoted lymphatic endothelial cell (LEC) proliferation, migration, and tube formation, mediated via binding to LYVE-1.	('binding', 'molecular_function', 'GO:0005488', ('176', '183'))	('hyaluronan', 'Chemical', 'MESH:D006820', (64, 74))	('tube formation', 'CPA', (147, 161))	('tube formation', 'biological_process', 'GO:0035148', ('147', '161'))	('promoted', 'PosReg', (75, 83))	('migration', 'CPA', (132, 141))	('low molecular weight', 'Var', (43, 63))	('binding', 'Interaction', (176, 183))	('LYVE-1', 'Gene', '10894', (187, 193))	('LYVE-1', 'Gene', (187, 193))
26016	25254213	The modulation of the tumor microenvironment induces angiogenesis and lymphangiogenesis.	('lymphangiogenesis', 'CPA', (70, 87))	('modulation', 'Var', (4, 14))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('70', '87'))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('angiogenesis', 'CPA', (53, 65))	('angiogenesis', 'biological_process', 'GO:0001525', ('53', '65'))	('induces', 'Reg', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))
26052	25254213	pDCs seem to have immunoregulatory properties in the tumor microenvironment and induce Tregs in the human ovarian carcinoma.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('human', 'Species', '9606', (100, 105))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (106, 123))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Tregs', 'CPA', (87, 92))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (106, 123))	('induce', 'PosReg', (80, 86))	('ovarian carcinoma', 'Disease', (106, 123))	('tumor', 'Disease', (53, 58))	('pDCs', 'Var', (0, 4))
26076	25254213	TAMs have also been shown to express LYVE-1 and F4/80+ LYVE-1 + macrophages integrated into peritumoral lymphatic vessels.	('LYVE-1', 'Gene', (37, 43))	('TAMs', 'Chemical', '-', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('LYVE-1', 'Gene', '10894', (55, 61))	('F4/80+', 'Var', (48, 54))	('LYVE-1', 'Gene', '10894', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('LYVE-1', 'Gene', (55, 61))
26101	25254213	Moreover, VEGF increased IL-10 secretion of these cells and might therefore direct chemotaxis and immune modulation of T-cells in tumor tissues.	('tumor', 'Disease', (130, 135))	('VEGF', 'Var', (10, 14))	('IL-10', 'Gene', '3586', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('IL-10', 'molecular_function', 'GO:0005141', ('25', '30'))	('increased', 'PosReg', (15, 24))	('secretion', 'MPA', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('IL-10 secretion', 'biological_process', 'GO:0072608', ('25', '40'))	('IL-10', 'Gene', (25, 30))	('chemotaxis', 'biological_process', 'GO:0006935', ('83', '93'))
26113	25254213	In a mice lung cancer model celecoxib, a selective COX2 inhibitor reduced lymphangiogenesis and lymph node metastasis indicating that VEGF expression and thereby lymphangiogenesis might be associated with prostaglandins.	('reduced', 'NegReg', (66, 73))	('mice', 'Species', '10090', (5, 9))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('74', '91'))	('celecoxib', 'Chemical', 'MESH:D000068579', (28, 37))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('162', '179'))	('inhibitor', 'Var', (56, 65))	('lung cancer', 'Disease', (10, 21))	('COX2', 'Gene', '5743', (51, 55))	('COX2', 'Gene', (51, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (10, 21))	('lymph node metastasis', 'CPA', (96, 117))	('prostaglandins', 'Chemical', 'MESH:D011453', (205, 219))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('lung cancer', 'Disease', 'MESH:D008175', (10, 21))	('VEGF', 'Protein', (134, 138))
26116	25254213	Therefore, blocking this ligand on the tumor cells and on antigen presenting cells improves tumor defense and T-cells with anticancer properties restore their effector function.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ligand', 'molecular_function', 'GO:0005488', ('25', '31'))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('cancer', 'Disease', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('blocking', 'Var', (11, 19))	('improves', 'PosReg', (83, 91))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (92, 97))	('effector function', 'MPA', (159, 176))
26126	25254213	Anti-CTLA4 antibodies such as ipilimumab are immune modulatory biologics and are regarded as a milestone in the treatment of metastatic melanoma.	('Anti-CTLA4', 'Var', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))	('ipilimumab', 'Chemical', 'MESH:D000074324', (30, 40))
26129	25254213	CTLA4 deficient mice die early as a result of an uncontrolled lymphocyte proliferation that leads to multiorgan destruction.	('lymphocyte proliferation', 'biological_process', 'GO:0046651', ('62', '86'))	('multiorgan destruction', 'CPA', (101, 123))	('CTLA4', 'Gene', (0, 5))	('mice', 'Species', '10090', (16, 20))	('deficient', 'Var', (6, 15))	('leads to', 'Reg', (92, 100))
26133	25254213	Antagonists of CCL21 seem to prevent the development of chronic graft versus host disease or reduced allergic conjunctivitis by blocking CCR7 in mice.	('CCR7', 'Gene', (137, 141))	('Antagonists', 'Var', (0, 11))	('blocking', 'NegReg', (128, 136))	('conjunctivitis', 'Phenotype', 'HP:0000509', (110, 124))	('CCL21', 'Gene', '6366', (15, 20))	('CCR', 'molecular_function', 'GO:0043880', ('137', '140'))	('CCL', 'molecular_function', 'GO:0044101', ('15', '18'))	('chronic graft versus host disease', 'Disease', 'MESH:D006086', (56, 89))	('CCL21', 'Gene', (15, 20))	('reduced allergic conjunctivitis', 'Disease', (93, 124))	('mice', 'Species', '10090', (145, 149))	('reduced allergic conjunctivitis', 'Disease', 'MESH:D004342', (93, 124))	('allergic conjunctivitis', 'Phenotype', 'HP:0007879', (101, 124))	('chronic graft versus host disease', 'Disease', (56, 89))	('prevent', 'NegReg', (29, 36))
26141	23977234	A BAP1 Mutation in a Danish Family Predisposes to Uveal Melanoma and Other Cancers Truncating germline mutations in the tumor suppressor gene BRCA-1 associated protein-1 (BAP1) have been reported in families predisposed to developing a wide range of different cancer types including uveal melanoma and cutaneous melanoma.	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('tumor suppressor', 'biological_process', 'GO:0051726', ('120', '136'))	('cutaneous melanoma', 'Disease', (302, 320))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (302, 320))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (302, 320))	('uveal melanoma', 'Phenotype', 'HP:0007716', (283, 297))	('BRCA-1 associated protein-1', 'Gene', '8314', (142, 169))	('Mutation', 'Var', (7, 15))	('BAP1', 'Gene', (2, 6))	('BRCA-1 associated protein-1', 'Gene', (142, 169))	('Truncating', 'Var', (83, 93))	('BAP1', 'Gene', '8314', (171, 175))	('Cancers', 'Phenotype', 'HP:0002664', (75, 82))	('tumor', 'Disease', (120, 125))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('Melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('cancer', 'Disease', (260, 266))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('BAP1', 'Gene', (171, 175))	('melanoma', 'Phenotype', 'HP:0002861', (289, 297))	('uveal melanoma', 'Disease', 'MESH:C536494', (283, 297))	('Predisposes', 'Reg', (35, 46))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('120', '136'))	('melanoma', 'Phenotype', 'HP:0002861', (312, 320))	('reported', 'Reg', (187, 195))	('BAP1', 'Gene', '8314', (2, 6))	('uveal melanoma', 'Disease', (283, 297))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Melanoma and Other Cancers', 'Disease', 'MESH:C563985', (56, 82))
26142	23977234	There has also been an association between amelanotic tumor development and germline BAP1 mutation suggesting a possible phenotypic characteristic of BAP1 mutation carriers.	('BAP1', 'Gene', (85, 89))	('BAP1', 'Gene', (150, 154))	('amelanotic tumor', 'Disease', (43, 59))	('amelanotic tumor', 'Disease', 'MESH:D018328', (43, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('germline', 'Var', (76, 84))	('BAP1', 'Gene', '8314', (85, 89))	('BAP1', 'Gene', '8314', (150, 154))	('mutation', 'Var', (90, 98))
26143	23977234	Though there have been many types of cancer associated with germline BAP1 mutation, the full spectrum of disease association is yet to be ascertained.	('associated', 'Reg', (44, 54))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('BAP1', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('germline', 'Var', (60, 68))	('BAP1', 'Gene', '8314', (69, 73))
26150	23977234	BAP1 was found to be the only gene that was mutated on chromosome 3 in each of these samples and both mutations led to truncation of the protein.	('BAP1', 'Gene', (0, 4))	('truncation', 'MPA', (119, 129))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))	('led to', 'Reg', (112, 118))	('mutations', 'Var', (102, 111))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('BAP1', 'Gene', '8314', (0, 4))	('protein', 'Protein', (137, 144))
26151	23977234	They next interrogated 57 UMM tumors using Sanger sequencing and found that BAP1 mutations occurred predominantly in tumors that had metastasized.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('BAP1', 'Gene', '8314', (76, 80))	('UMM', 'Phenotype', 'HP:0007716', (26, 29))	('occurred', 'Reg', (91, 99))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('BAP1', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutations', 'Var', (81, 90))
26152	23977234	Overall, 26/31 of the metastasizing (high risk) tumors had inactivating BAP1 somatic mutations compared to only 1/26 of the low risk (non-metastatic) group.	('BAP1', 'Gene', '8314', (72, 76))	('tumors', 'Disease', (48, 54))	('metastasizing', 'CPA', (22, 35))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('BAP1', 'Gene', (72, 76))	('inactivating', 'Var', (59, 71))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
26153	23977234	For the 20 samples with a matched normal DNA sample, almost all BAP1 mutations were found to be acquired somatically, the exception being a single case with a matching germline frameshift mutation.	('mutations', 'Var', (69, 78))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('BAP1', 'Gene', '8314', (64, 68))	('BAP1', 'Gene', (64, 68))
26154	23977234	This mutation introduced the possibility that BAP1 defects could predispose to UMM.	('defects', 'Var', (51, 58))	('predispose', 'Reg', (65, 75))	('BAP1', 'Gene', '8314', (46, 50))	('BAP1', 'Gene', (46, 50))	('UMM', 'Disease', (79, 82))	('UMM', 'Phenotype', 'HP:0007716', (79, 82))
26155	23977234	al., several groups have looked at the risk of disease conferred by germline BAP1 mutation.	('BAP1', 'Gene', '8314', (77, 81))	('germline', 'Var', (68, 76))	('BAP1', 'Gene', (77, 81))
26156	23977234	Testa and colleagues investigated BAP1 mutations in two American families presenting with mesothelioma and who had no contact with any of the known environmental risk factors for this disease.	('BAP1', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))	('mesothelioma', 'Disease', (90, 102))	('BAP1', 'Gene', '8314', (34, 38))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))
26157	23977234	They found two different frameshift mutations in BAP1 responsible for the elevated risk of mesothelioma in these individuals.	('frameshift mutations', 'Var', (25, 45))	('mesothelioma', 'Disease', 'MESH:D008654', (91, 103))	('BAP1', 'Gene', (49, 53))	('responsible', 'Reg', (54, 65))	('mesothelioma', 'Disease', (91, 103))	('BAP1', 'Gene', '8314', (49, 53))
26161	23977234	A report by Wiesner showed BAP1 mutations in two families that had an autosomal dominant syndrome characterized by UMM, CMM and atypical benign melanocytic nevi.	('melanocytic nevi', 'Phenotype', 'HP:0000995', (144, 160))	('UMM', 'Phenotype', 'HP:0007716', (115, 118))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (70, 97))	('CMM', 'Gene', (120, 123))	('UMM', 'Disease', (115, 118))	('BAP1', 'Gene', (27, 31))	('nevi', 'Phenotype', 'HP:0003764', (156, 160))	('mutations', 'Var', (32, 41))	('CMM', 'Gene', '1243', (120, 123))	('CMM', 'Phenotype', 'HP:0012056', (120, 123))	('BAP1', 'Gene', '8314', (27, 31))	('atypical benign melanocytic nevi', 'Disease', (128, 160))	('autosomal dominant syndrome', 'Disease', (70, 97))
26162	23977234	In a follow up report, Wiesner and colleagues identified a third family with a BAP1 mutation that co-segregated with mesothelioma and also showed evidence of a melanocytic lesion in a mutation carrier.	('mutation', 'Var', (84, 92))	('BAP1', 'Gene', '8314', (79, 83))	('mesothelioma', 'Disease', (117, 129))	('BAP1', 'Gene', (79, 83))	('melanocytic lesion', 'Disease', 'MESH:D009508', (160, 178))	('mesothelioma', 'Disease', 'MESH:D008654', (117, 129))	('carrier', 'molecular_function', 'GO:0005215', ('193', '200'))	('melanocytic lesion', 'Disease', (160, 178))
26163	23977234	Other groups have also described BAP1 mutations in individuals presenting with atypical intradermal tumors, proposing that these lesions may be a phenotypic characteristic of BAP1 mutation carriers.	('intradermal tumors', 'Disease', (88, 106))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('BAP1', 'Gene', (175, 179))	('BAP1', 'Gene', '8314', (175, 179))	('BAP1', 'Gene', '8314', (33, 37))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('BAP1', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))	('intradermal tumors', 'Disease', 'MESH:D018330', (88, 106))
26164	23977234	A recent study of Portuguese siblings with a rare subtype of epithelioid mesothelioma uncovered a germline BAP1 mutation as the possible cause of the only known familial clustering of well-differentiated papillary mesothelioma.	('BAP1', 'Gene', '8314', (107, 111))	('epithelioid mesothelioma', 'Disease', 'MESH:D008654', (61, 85))	('mutation', 'Var', (112, 120))	('papillary mesothelioma', 'Disease', (204, 226))	('BAP1', 'Gene', (107, 111))	('cause', 'Reg', (137, 142))	('papillary mesothelioma', 'Disease', 'MESH:D008654', (204, 226))	('epithelioid mesothelioma', 'Disease', (61, 85))
26166	23977234	BAP1 mutation has also been implicated in the development of renal cell carcinoma and some of the relatives of these cases have had UMM or CMM also.	('UMM', 'Phenotype', 'HP:0007716', (132, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('BAP1', 'Gene', (0, 4))	('CMM', 'Gene', '1243', (139, 142))	('CMM', 'Phenotype', 'HP:0012056', (139, 142))	('BAP1', 'Gene', '8314', (0, 4))	('renal cell carcinoma', 'Disease', (61, 81))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (61, 81))	('CMM', 'Gene', (139, 142))	('implicated', 'Reg', (28, 38))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (61, 81))	('mutation', 'Var', (5, 13))	('UMM', 'Disease', (132, 135))
26167	23977234	As evidenced by the literature, there is a large tumor spectrum that appears to accompany BAP1 germline mutation.	('germline', 'Var', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('BAP1', 'Gene', '8314', (90, 94))	('tumor', 'Disease', (49, 54))	('BAP1', 'Gene', (90, 94))
26174	23977234	Aside from the striking incidence of cancer, this family presents with other clinical features that have become indications of BAP1 mutation.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('BAP1', 'Gene', (127, 131))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('BAP1', 'Gene', '8314', (127, 131))	('mutation', 'Var', (132, 140))
26180	23977234	In order to find disease-associated variants, whole-exome sequencing was carried out on key individuals representative of the tumor burden in this family.	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('variants', 'Var', (36, 44))	('tumor', 'Disease', (126, 131))
26181	23977234	SAMTOOLS was then used to detect the SNPs and indels.	('indels', 'Var', (46, 52))	('SAMTOOLS', 'Chemical', '-', (0, 8))	('SNPs', 'Var', (37, 41))
26182	23977234	Exome-sequencing uncovered a BAP1 splice mutation, which results in the premature truncation of the protein, in one (III:17) of the two individuals and was seen as a likely candidate responsible for UMM susceptibility due to the supporting literature.	('premature truncation of the protein', 'MPA', (72, 107))	('results in', 'Reg', (57, 67))	('BAP1', 'Gene', '8314', (29, 33))	('splice mutation', 'Var', (34, 49))	('UMM', 'Phenotype', 'HP:0007716', (199, 202))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('UMM', 'Disease', (199, 202))	('BAP1', 'Gene', (29, 33))
26183	23977234	Following this, co-segregation analysis was carried out to determine how well the variant segregated with disease in the family and whether it was present in individuals with different cancer types.	('segregated', 'Reg', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('variant', 'Var', (82, 89))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
26185	23977234	Additionally, a new blood sample was obtained from individual III:14 since the initial sample did not show presence of a germline BAP1 mutation.	('BAP1', 'Gene', (130, 134))	('mutation', 'Var', (135, 143))	('BAP1', 'Gene', '8314', (130, 134))
26187	23977234	RT-PCR was performed on cDNA from one carrier (III:6) to verify that the BAP1 mutation was indeed a splicing variant.	('BAP1', 'Gene', '8314', (73, 77))	('splicing', 'biological_process', 'GO:0045292', ('100', '108'))	('mutation', 'Var', (78, 86))	('carrier', 'molecular_function', 'GO:0005215', ('38', '45'))	('BAP1', 'Gene', (73, 77))
26194	23977234	Whole-exome-sequencing identified a BAP1 splice mutation (c.581-2A>G) in an individual with UMM from a Danish family predisposed to developing UMM as well as a host of other cancers.	('c.581-2A>G', 'Var', (58, 68))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('UMM', 'Phenotype', 'HP:0007716', (92, 95))	('BAP1', 'Gene', '8314', (36, 40))	('cancers', 'Disease', (174, 181))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('UMM', 'Disease', (143, 146))	('UMM', 'Phenotype', 'HP:0007716', (143, 146))	('BAP1', 'Gene', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('c.581-2A>G', 'Mutation', 'rs1430317959', (58, 68))
26196	23977234	Additionally, there were four other individuals with different cancer types that also carried the mutation.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (63, 69))	('mutation', 'Var', (98, 106))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
26198	23977234	To confirm that individual III:14 was wildtype for the BAP1 mutation a newly obtained blood sample was screened.	('BAP1', 'Gene', (55, 59))	('mutation', 'Var', (60, 68))	('BAP1', 'Gene', '8314', (55, 59))
26199	23977234	Indeed, the analysis confirmed the absence of BAP1 mutation suggesting that this case is a phenocopy.	('BAP1', 'Gene', '8314', (46, 50))	('mutation', 'Var', (51, 59))	('BAP1', 'Gene', (46, 50))
26200	23977234	Loss of heterozygosity (LOH) of the BAP1 mutation was also observed in DNA from tumor tissue from II:11.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('BAP1', 'Gene', '8314', (36, 40))	('tumor', 'Disease', (80, 85))	('mutation', 'Var', (41, 49))	('Loss', 'NegReg', (0, 4))	('BAP1', 'Gene', (36, 40))
26201	23977234	Consistent with data from the 1000 Genomes Project, genotyping results showed that this variant was only present in the current family, that is only 1/1655 melanoma probands carried the variant and 0/1596 controls.	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('variant', 'Var', (186, 193))
26202	23977234	Exome data from 200 healthy Danish controls was also examined for BAP1 mutation and no protein altering variant was seen.	('mutation', 'Var', (71, 79))	('BAP1', 'Gene', '8314', (66, 70))	('BAP1', 'Gene', (66, 70))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
26203	23977234	There have been several cancer types associated with BAP1 germline mutations but the full spectrum of tumor susceptibility is still to be ascertained.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('BAP1', 'Gene', '8314', (53, 57))	('germline mutations', 'Var', (58, 76))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('BAP1', 'Gene', (53, 57))
26205	23977234	Whole-exome sequencing of a UMM case identified a BAP1 splice mutation (c.581-2A>G), which leads to premature truncation of BAP1.	('c.581-2A>G', 'Mutation', 'rs1430317959', (72, 82))	('premature truncation', 'MPA', (100, 120))	('BAP1', 'Gene', '8314', (124, 128))	('BAP1', 'Gene', '8314', (50, 54))	('BAP1', 'Gene', (124, 128))	('BAP1', 'Gene', (50, 54))	('UMM', 'Phenotype', 'HP:0007716', (28, 31))	('c.581-2A>G', 'Var', (72, 82))	('leads to', 'Reg', (91, 99))
26211	23977234	The family described here also had a variety of other cancer types, some of which have been implicated with BAP1 mutation (lung) and some that have not (stomach, neuroendocrine).	('mutation', 'Var', (113, 121))	('BAP1', 'Gene', '8314', (108, 112))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('BAP1', 'Gene', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
26213	23778528	Patient survival in uveal melanoma is not affected by oncogenic mutations in GNAQ and GNA11 Mutations in GNAQ and GNA11, encoding the oncogenic G-protein alpha subunit q and 11, respectively, occur frequently in the majority of uveal melanomas.	('uveal melanoma', 'Phenotype', 'HP:0007716', (228, 242))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('GNA11', 'Gene', (86, 91))	('uveal melanomas', 'Disease', (228, 243))	('uveal melanomas', 'Phenotype', 'HP:0007716', (228, 243))	('GNAQ', 'Gene', '2776', (77, 81))	('uveal melanoma', 'Phenotype', 'HP:0007716', (20, 34))	('GNA11', 'Gene', '2767', (114, 119))	('GNAQ', 'Gene', (77, 81))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('GNAQ', 'Gene', '2776', (105, 109))	('melanomas', 'Phenotype', 'HP:0002861', (234, 243))	('GNAQ', 'Gene', (105, 109))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('GNA11', 'Gene', '2767', (86, 91))	('GNA11', 'Gene', (114, 119))	('Mutations', 'Var', (92, 101))	('uveal melanoma', 'Disease', 'MESH:C536494', (228, 242))	('uveal melanomas', 'Disease', 'MESH:C536494', (228, 243))	('uveal melanoma', 'Disease', 'MESH:C536494', (20, 34))	('Patient', 'Species', '9606', (0, 7))	('uveal melanoma', 'Disease', (20, 34))
26217	23778528	Only 1 out of 92 (1.1%) melanomas showed a mutation in GNA11 exon 4 codon 183, whereas 39 out of 92 (42.4%) harboured a mutation in exon 5 of GNA11 codon 209.	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('mutation', 'Var', (43, 51))	('melanomas', 'Disease', (24, 33))	('melanomas', 'Phenotype', 'HP:0002861', (24, 33))	('GNA11', 'Gene', (142, 147))	('melanomas', 'Disease', 'MESH:D008545', (24, 33))	('GNA11', 'Gene', '2767', (55, 60))	('GNA11', 'Gene', (55, 60))	('GNA11', 'Gene', '2767', (142, 147))
26219	23778528	GNAQ and GNA11 mutations are, in equal matter, not associated with patient outcome.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('GNAQ', 'Gene', (0, 4))	('patient', 'Species', '9606', (67, 74))	('GNA11', 'Gene', '2767', (9, 14))
26222	23778528	Mutations in GNAQ, or its paralog GNA11 (together referred to as Galpha genes), occur mutually exclusively in codon 183 (exon 4) or 209 (exon 5), leading to a constitutive activation of the MAP kinase (MAPK) pathway.	('MAPK', 'molecular_function', 'GO:0004707', ('202', '206'))	('MAP', 'molecular_function', 'GO:0004239', ('190', '193'))	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (34, 39))	('Galpha', 'Gene', '8802', (65, 71))	('Mutations', 'Var', (0, 9))	('GNA11', 'Gene', (34, 39))	('Galpha', 'Gene', (65, 71))	('activation', 'PosReg', (172, 182))	('GNAQ', 'Gene', '2776', (13, 17))
26223	23778528	We examined to what extent oncogenic GNAQ and GNA11 mutations are correlated with the patient survival.	('mutations', 'Var', (52, 61))	('GNA11', 'Gene', '2767', (46, 51))	('GNAQ', 'Gene', (37, 41))	('patient', 'Species', '9606', (86, 93))	('GNAQ', 'Gene', '2776', (37, 41))	('GNA11', 'Gene', (46, 51))
26235	23778528	In a previous study, our group performed mutation analysis of GNAQ exon 5 in 75 samples.	('mutation', 'Var', (41, 49))	('GNAQ', 'Gene', (62, 66))	('GNAQ', 'Gene', '2776', (62, 66))
26247	23778528	All uveal melanomas were analysed for GNAQ and GNA11 mutations and for chromosomal aberrations in chromosome 1, 3, 6, and 8.	('GNAQ', 'Gene', '2776', (38, 42))	('uveal melanoma', 'Phenotype', 'HP:0007716', (4, 18))	('chromosome', 'cellular_component', 'GO:0005694', ('98', '108'))	('chromosomal aberrations', 'Disease', 'MESH:D002869', (71, 94))	('GNA11', 'Gene', '2767', (47, 52))	('GNA11', 'Gene', (47, 52))	('uveal melanomas', 'Phenotype', 'HP:0007716', (4, 19))	('mutations', 'Var', (53, 62))	('GNAQ', 'Gene', (38, 42))	('uveal melanomas', 'Disease', (4, 19))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('uveal melanomas', 'Disease', 'MESH:C536494', (4, 19))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (71, 94))	('chromosomal aberrations', 'Disease', (71, 94))
26249	23778528	Forty-six tumours (50.0%) harboured a mutation in GNAQ exon 5 codon 209; details are shown in Table 1.	('tumours', 'Disease', (10, 17))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('GNAQ', 'Gene', '2776', (50, 54))	('tumours', 'Phenotype', 'HP:0002664', (10, 17))	('mutation', 'Var', (38, 46))	('tumours', 'Disease', 'MESH:D009369', (10, 17))	('GNAQ', 'Gene', (50, 54))
26250	23778528	Although only one mutated case was found in GNA11 exon 4, 39 tumours (42.4%) harboured a mutation in GNA11 exon 5.	('GNA11', 'Gene', '2767', (101, 106))	('GNA11', 'Gene', (101, 106))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('GNA11', 'Gene', (44, 49))	('mutation', 'Var', (89, 97))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('GNA11', 'Gene', '2767', (44, 49))	('tumours', 'Disease', (61, 68))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
26252	23778528	One tumour (EOM-0179) showed two mutations in GNA11 exon 5 (resulting in p.Q209L and p.R214M).	('GNA11', 'Gene', '2767', (46, 51))	('p.Q209L', 'Mutation', 'rs1057519742', (73, 80))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('p.R214M', 'Var', (85, 92))	('p.R214M', 'Mutation', 'p.R214M', (85, 92))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('p.Q209L', 'Var', (73, 80))	('GNA11', 'Gene', (46, 51))
26255	23778528	Univariate analyses showed that the DFS was significantly shorter in patients with tumours with loss of chromosome 3, loss of chromosome 8p and gain of chromosome 8q.	('tumours', 'Disease', (83, 90))	('shorter', 'NegReg', (58, 65))	('gain', 'PosReg', (144, 148))	('chromosome', 'cellular_component', 'GO:0005694', ('152', '162'))	('loss', 'Var', (96, 100))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('loss', 'Var', (118, 122))	('tumours', 'Disease', 'MESH:D009369', (83, 90))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('chromosome', 'cellular_component', 'GO:0005694', ('126', '136'))	('patients', 'Species', '9606', (69, 77))	('chromosome', 'cellular_component', 'GO:0005694', ('104', '114'))	('DFS', 'MPA', (36, 39))
26256	23778528	The DFS in patients with tumours harbouring GNAQ or GNA11 mutations was not significantly less than that in the wild-type tumours (Figure 1).	('mutations', 'Var', (58, 67))	('less', 'NegReg', (90, 94))	('GNAQ', 'Gene', (44, 48))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('GNA11', 'Gene', '2767', (52, 57))	('DFS', 'MPA', (4, 7))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('type tumours', 'Disease', 'MESH:D009369', (117, 129))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('GNA11', 'Gene', (52, 57))	('GNAQ', 'Gene', '2776', (44, 48))	('patients', 'Species', '9606', (11, 19))	('tumours', 'Disease', (122, 129))	('tumours', 'Disease', (25, 32))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('type tumours', 'Disease', (117, 129))
26257	23778528	Correlations between the clinical and histopathological parameters, chromosomal parameters, and GNAQ and GNA11 mutations using the Fisher's exact test and the Mann-Whitney test showed a weak association between age and both GNAQ and GNA11 mutation status (P=0.017 and 0.004, respectively; Table 2).	('mutations', 'Var', (111, 120))	('GNAQ', 'Gene', '2776', (224, 228))	('GNAQ', 'Gene', '2776', (96, 100))	('GNA11', 'Gene', (105, 110))	('GNAQ', 'Gene', (224, 228))	('GNA11', 'Gene', '2767', (105, 110))	('GNA11', 'Gene', '2767', (233, 238))	('GNAQ', 'Gene', (96, 100))	('GNA11', 'Gene', (233, 238))
26258	23778528	GNA11 mutation status was also correlated with loss of chromosome 6q (P=0.045).	('GNA11', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('loss', 'NegReg', (47, 51))	('GNA11', 'Gene', '2767', (0, 5))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))
26259	23778528	We examined the possibility that GNAQ and GNA11 mutations may affect the prognosis of patients with monosomy 3 by constructing Kaplan-Meier curves for changes in chromosome 3, stratified for GNAQ and GNA11 mutations.	('monosomy 3', 'Disease', (100, 110))	('affect', 'Reg', (62, 68))	('GNA11', 'Gene', '2767', (200, 205))	('GNAQ', 'Gene', (33, 37))	('mutations', 'Var', (48, 57))	('GNAQ', 'Gene', (191, 195))	('GNAQ', 'Gene', '2776', (191, 195))	('GNAQ', 'Gene', '2776', (33, 37))	('GNA11', 'Gene', (42, 47))	('GNA11', 'Gene', '2767', (42, 47))	('chromosome', 'cellular_component', 'GO:0005694', ('162', '172'))	('GNA11', 'Gene', (200, 205))	('patients', 'Species', '9606', (86, 94))
26260	23778528	Log-rank tests showed that there was no significant effect on the DFS in tumours with loss of chromosome 3 and the presence of GNAQ or GNA11 mutation (P=0.745).	('GNA11', 'Gene', '2767', (135, 140))	('tumours', 'Disease', (73, 80))	('loss', 'Var', (86, 90))	('GNAQ', 'Gene', (127, 131))	('presence', 'Var', (115, 123))	('tumours', 'Disease', 'MESH:D009369', (73, 80))	('chromosome', 'cellular_component', 'GO:0005694', ('94', '104'))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('GNA11', 'Gene', (135, 140))	('mutation', 'Var', (141, 149))	('GNAQ', 'Gene', '2776', (127, 131))
26262	23778528	The presence of epithelioid cells, largest tumour diameter, involvement of the ciliary body, chromosome 3 loss, chromosome 8p loss, and mutations in GNAQ (P=0.587) or GNA11 (P=0.796) were rejected.	('GNAQ', 'Gene', (149, 153))	('GNA11', 'Gene', '2767', (167, 172))	('tumour', 'Disease', (43, 49))	('GNA11', 'Gene', (167, 172))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('GNAQ', 'Gene', '2776', (149, 153))	('mutations', 'Var', (136, 145))	('loss', 'NegReg', (106, 110))	('loss', 'NegReg', (126, 130))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('chromosome', 'cellular_component', 'GO:0005694', ('112', '122'))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
26263	23778528	Only the variable chromosome 8q gain (HR 6.562, P=0.000 for both GNAQ and GNA11 mutation status) and chromosome 6p gain (HR 0.419, P=0.014 for both GNAQ and GNA11 mutation status) were independent predictors of DFS.	('DFS', 'Disease', (211, 214))	('chromosome', 'cellular_component', 'GO:0005694', ('101', '111'))	('GNA11', 'Gene', (74, 79))	('chromosome', 'Var', (18, 28))	('GNAQ', 'Gene', '2776', (65, 69))	('GNA11', 'Gene', '2767', (74, 79))	('chromosome', 'cellular_component', 'GO:0005694', ('18', '28'))	('GNAQ', 'Gene', '2776', (148, 152))	('GNA11', 'Gene', '2767', (157, 162))	('GNA11', 'Gene', (157, 162))	('gain', 'PosReg', (115, 119))	('GNAQ', 'Gene', (65, 69))	('gain', 'PosReg', (32, 36))	('HR 6.562', 'CellLine', 'CVCL:X233', (38, 46))	('GNAQ', 'Gene', (148, 152))
26265	23778528	We found that these mutations occur mutually exclusive in the majority of uveal melanomas, up to 93.4%, which is in the same range as reported previously.	('melanomas', 'Phenotype', 'HP:0002861', (80, 89))	('uveal melanomas', 'Disease', (74, 89))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('uveal melanomas', 'Disease', 'MESH:C536494', (74, 89))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('mutations', 'Var', (20, 29))	('uveal melanomas', 'Phenotype', 'HP:0007716', (74, 89))
26266	23778528	suggested that GNA11 mutations might have more potent effect on melanocytes than mutations in GNAQ.	('GNA11', 'Gene', (15, 20))	('GNA11', 'Gene', '2767', (15, 20))	('GNAQ', 'Gene', '2776', (94, 98))	('melanocytes', 'CPA', (64, 75))	('GNAQ', 'Gene', (94, 98))	('mutations', 'Var', (21, 30))
26267	23778528	Because the mutations occur in 93.4% of the tumours, it seems to be an early event in the development of a melanoma, and our study demonstrates that mutations in GNAQ and GNA11 do not contribute to the patients' prognosis.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('melanoma', 'Disease', (107, 115))	('mutations', 'Var', (149, 158))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('tumours', 'Disease', 'MESH:D009369', (44, 51))	('mutations', 'Var', (12, 21))	('GNAQ', 'Gene', '2776', (162, 166))	('GNA11', 'Gene', '2767', (171, 176))	('GNA11', 'Gene', (171, 176))	('tumours', 'Disease', (44, 51))	('patients', 'Species', '9606', (202, 210))	('GNAQ', 'Gene', (162, 166))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
26268	23778528	Moreover, we conclude that GNA11 mutations are not more harmful than GNAQ mutations in uveal melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('uveal melanoma', 'Disease', (87, 101))	('patients', 'Species', '9606', (102, 110))	('GNAQ', 'Gene', '2776', (69, 73))	('mutations', 'Var', (33, 42))	('GNA11', 'Gene', (27, 32))	('GNAQ', 'Gene', (69, 73))	('GNA11', 'Gene', '2767', (27, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (87, 101))	('uveal melanoma', 'Disease', 'MESH:C536494', (87, 101))
26270	23778528	Surprisingly, one tumour harboured a double mutation in GNA11 codons 209 and 214.	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('GNA11', 'Gene', (56, 61))	('double mutation', 'Var', (37, 52))	('tumour', 'Disease', (18, 24))	('GNA11', 'Gene', '2767', (56, 61))
26271	23778528	The reported heterozygous non-synonymous variant in codon 214 results in arginine to methionine transition.	('arginine to methionine transition', 'MPA', (73, 106))	('methionine', 'Chemical', 'MESH:D008715', (85, 95))	('results in', 'Reg', (62, 72))	('codon 214', 'Gene', (52, 61))	('arginine', 'Chemical', 'MESH:D001120', (73, 81))	('variant', 'Var', (41, 48))	('non-synonymous variant', 'Var', (26, 48))
26272	23778528	The tumour with the double mutation had no chromosomal alterations, and this patient has not developed any metastases at a follow-up time of 154.1 months.	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('double mutation', 'Var', (20, 35))	('metastases', 'Disease', 'MESH:D009362', (107, 117))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('patient', 'Species', '9606', (77, 84))	('metastases', 'Disease', (107, 117))
26273	23778528	To our knowledge, this is the first reported double mutation in GNA11 exon 5 in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('uveal melanoma', 'Disease', (80, 94))	('double mutation', 'Var', (45, 60))	('uveal melanoma', 'Disease', 'MESH:C536494', (80, 94))	('GNA11', 'Gene', '2767', (64, 69))	('GNA11', 'Gene', (64, 69))
26275	23778528	This is in line with our findings that patient outcome is not influenced by the presence of mutations in GNAQ or GNA11.	('GNAQ', 'Gene', (105, 109))	('patient', 'Species', '9606', (39, 46))	('GNA11', 'Gene', '2767', (113, 118))	('mutations', 'Var', (92, 101))	('GNA11', 'Gene', (113, 118))	('GNAQ', 'Gene', '2776', (105, 109))
26276	23778528	GNAQ and GNA11 are involved in the MAPK pathway, and mutations in these genes lead to downstream oncogenic signalling.	('GNA11', 'Gene', (9, 14))	('MAPK pathway', 'Pathway', (35, 47))	('GNAQ', 'Gene', '2776', (0, 4))	('oncogenic signalling', 'CPA', (97, 117))	('lead to', 'Reg', (78, 85))	('MAPK', 'molecular_function', 'GO:0004707', ('35', '39'))	('mutations', 'Var', (53, 62))	('GNAQ', 'Gene', (0, 4))	('signalling', 'biological_process', 'GO:0023052', ('107', '117'))	('GNA11', 'Gene', '2767', (9, 14))
26277	23778528	MEK is a potential target in the MAPK pathway, and the effects of several MEK inhibitors on uveal melanoma cell lines with Galpha mutations have been described.	('MEK', 'Gene', '5609', (74, 77))	('Galpha', 'Gene', (123, 129))	('MEK', 'Gene', (0, 3))	('Galpha', 'Gene', '8802', (123, 129))	('MEK', 'Gene', '5609', (0, 3))	('MAPK', 'molecular_function', 'GO:0004707', ('33', '37'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (92, 106))	('uveal melanoma', 'Disease', (92, 106))	('uveal melanoma', 'Disease', 'MESH:C536494', (92, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('mutations', 'Var', (130, 139))	('MEK', 'Gene', (74, 77))
26279	23778528	Dual-pathway inhibition of the MAPK and the PI3K/AKT pathway with MEK inhibitor GSK1120212 and PI3K inhibitor GSK2126458 resulted in induction of apoptosis in Galpha-mutant uveal melanoma cells.	('uveal melanoma', 'Phenotype', 'HP:0007716', (173, 187))	('GSK', 'molecular_function', 'GO:0050321', ('110', '113'))	('AKT', 'Gene', '207', (49, 52))	('GSK1120212', 'Chemical', 'MESH:C560077', (80, 90))	('MEK', 'Gene', '5609', (66, 69))	('Galpha', 'Gene', (159, 165))	('inhibition', 'NegReg', (13, 23))	('apoptosis', 'CPA', (146, 155))	('induction', 'Reg', (133, 142))	('PI3K', 'molecular_function', 'GO:0016303', ('95', '99'))	('MAPK', 'Pathway', (31, 35))	('GSK', 'molecular_function', 'GO:0050321', ('80', '83'))	('GSK2126458', 'Chemical', 'MESH:C561454', (110, 120))	('MAPK', 'molecular_function', 'GO:0004707', ('31', '35'))	('MEK', 'Gene', (66, 69))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('133', '155'))	('GSK2126458', 'Var', (110, 120))	('Galpha', 'Gene', '8802', (159, 165))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('AKT', 'Gene', (49, 52))	('uveal melanoma', 'Disease', (173, 187))	('uveal melanoma', 'Disease', 'MESH:C536494', (173, 187))	('GSK1120212', 'Var', (80, 90))	('PI3K', 'molecular_function', 'GO:0016303', ('44', '48'))
26280	23778528	In conclusion, we confirm that mutations in GNAQ and GNA11 are, in equal matter, not associated with patient outcome.	('mutations', 'Var', (31, 40))	('GNAQ', 'Gene', (44, 48))	('GNA11', 'Gene', (53, 58))	('GNA11', 'Gene', '2767', (53, 58))	('GNAQ', 'Gene', '2776', (44, 48))	('patient', 'Species', '9606', (101, 108))
26282	23778528	Because the mutations occur in the majority of the tumours, and slowly growing as well as fast growing metastases, targeting of the downstream pathway seems promising.	('metastases', 'Disease', 'MESH:D009362', (103, 113))	('mutations', 'Var', (12, 21))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('metastases', 'Disease', (103, 113))	('tumours', 'Disease', 'MESH:D009369', (51, 58))	('occur', 'Reg', (22, 27))	('tumours', 'Disease', (51, 58))
26314	23862155	While patients with mutated EGFR might benefit from Erlotinib (an EGFR inhibitor), the side effects limit the efficacy of the drug.	('Erlotinib', 'Chemical', 'MESH:D000069347', (52, 61))	('EGFR', 'Gene', (28, 32))	('EGFR', 'molecular_function', 'GO:0005006', ('28', '32'))	('benefit', 'PosReg', (39, 46))	('mutated', 'Var', (20, 27))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
26418	21386926	Most strongly correlated with increased risk of metastasis are cytogenetic aberrations and gene expression abnormalities in melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('correlated', 'Reg', (14, 24))	('gene expression', 'biological_process', 'GO:0010467', ('91', '106'))	('metastasis', 'CPA', (48, 58))	('gene expression abnormalities', 'Var', (91, 120))
26419	21386926	Melanoma cytogenetic abnormalities provide information regarding the fundamental molecular biology of choroidal melanoma and may uncover potential genes for targeted therapy.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('choroidal melanoma', 'Disease', 'MESH:D008545', (102, 120))	('choroidal melanoma', 'Disease', (102, 120))	('Melanoma', 'Disease', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (102, 120))	('abnormalities', 'Var', (21, 34))
26429	21386926	Each of the three cell lines were derived from two pooled fine needle aspirates containing approximately 110, 500, or 350 viable cells for MEL20-06-039, MEL20-06-045, or MEL20-07-070, respectively, as determined by counts of adherent cells obtained 24 h after initial seeding in a 12.5 cm2 flask.	('MEL20-06-039', 'Var', (139, 151))	('MEL20-07-070', 'Var', (170, 182))	('MEL20-06-045', 'Var', (153, 165))	('MEL20-06-045', 'CellLine', 'CVCL:8474', (153, 165))
26432	21386926	Cytogenetically, two of the three cell lines (MEL20-06-039 and MEL20-07-070) demonstrated the chromosomal aberration pattern present in the respective primary melanoma, including monosomy 3, 6q loss, 8p loss, multiple 8q gain and 16q loss (Figure 2).	('melanoma', 'Disease', (159, 167))	('monosomy 3', 'Var', (179, 189))	('multiple 8q gain', 'Phenotype', 'HP:0003689', (209, 225))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (94, 116))	('gain', 'PosReg', (221, 225))	('loss', 'NegReg', (194, 198))	('16q', 'Disease', (230, 233))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
26434	21386926	Additionally, the MEL20-06-045 cell line and both the MEL 20-07-070 cell line and primary tumor exhibited chromosome 6p gain.	('MEL20-06-045', 'CellLine', 'CVCL:8474', (18, 30))	('gain', 'PosReg', (120, 124))	('chromosome', 'cellular_component', 'GO:0005694', ('106', '116'))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('primary tumor', 'Disease', (82, 95))	('chromosome', 'Var', (106, 116))	('primary tumor', 'Disease', 'MESH:D009369', (82, 95))
26435	21386926	Moreover, two of the cell lines (MEL20-06-039 and MEL20-07-070) had RNA expression array characteristics similar to the respective primary tumor for the 25 most overexpressed and the 20 most under-expressed genes from a comparative gene list composed of genes most overexpressed and under-expressed in an integrated analysis of choroidal melanoma with chromosome 3 loss versus 6p gain in the absence of chromosome 3 loss (Figure 3A,B).	('melanoma', 'Phenotype', 'HP:0002861', (338, 346))	('gain', 'PosReg', (380, 384))	('choroidal melanoma', 'Disease', 'MESH:D008545', (328, 346))	('MEL20-07-070', 'Var', (50, 62))	('chromosome', 'Var', (352, 362))	('choroidal melanoma', 'Disease', (328, 346))	('loss', 'NegReg', (365, 369))	('overexpressed', 'PosReg', (265, 278))	('primary tumor', 'Disease', (131, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('chromosome', 'cellular_component', 'GO:0005694', ('403', '413'))	('primary tumor', 'Disease', 'MESH:D009369', (131, 144))	('RNA', 'cellular_component', 'GO:0005562', ('68', '71'))	('chromosome', 'cellular_component', 'GO:0005694', ('352', '362'))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (328, 346))
26437	21386926	Sequence analysis of exon 5 of GNAQ demonstrated heterozygous mutations in codon 209 in two of the three cultures (resulting in either Q209L or Q209P) and wild-type sequence in the third culture (Figure 4).	('Q209P', 'Var', (144, 149))	('GNAQ', 'Gene', '2776', (31, 35))	('Q209L', 'Mutation', 'rs121913492', (135, 140))	('Q209P', 'Mutation', 'rs121913492', (144, 149))	('Q209L', 'Var', (135, 140))	('GNAQ', 'Gene', (31, 35))	('codon 209', 'Gene', (75, 84))
26441	21386926	Cell line characterization at passage 3 with 250K Mapping Arrays showed that each of the three cell lines and the two respective primary melanomas had common cytogenetic characteristics for monosomy 3, 6q loss, 8p loss, multiple 8q gain, and 16q loss.	('melanomas', 'Disease', (137, 146))	('multiple 8q gain', 'Phenotype', 'HP:0003689', (220, 236))	('16q loss', 'Var', (242, 250))	('monosomy 3', 'Disease', (190, 200))	('melanomas', 'Phenotype', 'HP:0002861', (137, 146))	('melanomas', 'Disease', 'MESH:D008545', (137, 146))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('gain', 'PosReg', (232, 236))
26446	21386926	GNAQ codon 209 mutations in choroidal melanoma have been shown to be important in primary melanoma tumor development.	('important', 'Reg', (69, 78))	('melanoma tumor', 'Disease', 'MESH:D008545', (90, 104))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (28, 46))	('GNAQ', 'Gene', '2776', (0, 4))	('codon', 'Var', (5, 10))	('choroidal melanoma', 'Disease', (28, 46))	('choroidal melanoma', 'Disease', 'MESH:D008545', (28, 46))	('GNAQ', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('melanoma tumor', 'Disease', (90, 104))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
26450	21386926	Second, cancer evolves through a process of step-wise accumulation of genetic alterations that result in uncontrolled cell proliferation and a lack of response to normal apoptotic stimuli.	('cancer', 'Disease', (8, 14))	('response to normal apoptotic', 'MPA', (151, 179))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('genetic alterations', 'Var', (70, 89))	('cell proliferation', 'biological_process', 'GO:0008283', ('118', '136'))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('lack', 'NegReg', (143, 147))
26457	21386926	Choroidal melanoma cell lines with genetic alterations that reflect their primary tumor provide malleable in vitro models.	('genetic alterations', 'Var', (35, 54))	('Choroidal melanoma', 'Phenotype', 'HP:0012054', (0, 18))	('Choroidal melanoma', 'Disease', (0, 18))	('primary tumor', 'Disease', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('primary tumor', 'Disease', 'MESH:D009369', (74, 87))	('Choroidal melanoma', 'Disease', 'MESH:D008545', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))
26462	21386926	In summary, FNAB of primary choroidal melanomas that developed clinical metastases resulted in the development of three low-passage, highly characterized cell lines that exhibited the chromosomal aberrations and gene expression profiles present in the primary choroidal melanomas.	('metastases', 'Disease', (72, 82))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (28, 46))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (28, 47))	('gene expression', 'biological_process', 'GO:0010467', ('212', '227'))	('metastases', 'Disease', 'MESH:D009362', (72, 82))	('primary choroidal melanomas', 'Disease', 'MESH:D008545', (252, 279))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (260, 279))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (184, 206))	('primary choroidal melanomas', 'Disease', 'MESH:D008545', (20, 47))	('melanoma', 'Phenotype', 'HP:0002861', (270, 278))	('primary choroidal melanomas', 'Disease', (252, 279))	('melanomas', 'Phenotype', 'HP:0002861', (270, 279))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (184, 207))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('FNAB', 'Var', (12, 16))	('primary choroidal melanomas', 'Disease', (20, 47))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (260, 278))
26467	7599046	Also, it has been suggested that surgical manipulation of the eye, such as occurs during enucleation, can provoke uveal melanoma dissemination.	('surgical manipulation', 'Var', (33, 54))	('enucleation', 'biological_process', 'GO:0090601', ('89', '100'))	('uveal melanoma dissemination', 'Disease', 'MESH:C536494', (114, 142))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('provoke', 'Reg', (106, 113))	('uveal melanoma dissemination', 'Disease', (114, 142))
26491	33634026	The haplotype of chromosome 3 and amplification of chromosome 8 are significantly associated with tumor metastasis, consistent with the American Joint Committee on Cancer (AJCC) staging of the tumor.	('tumor metastasis', 'Disease', 'MESH:D009362', (98, 114))	('associated with', 'Reg', (82, 97))	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('Cancer', 'Disease', (164, 170))	('amplification', 'Var', (34, 47))	('tumor metastasis', 'Disease', (98, 114))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('Cancer', 'Disease', 'MESH:D009369', (164, 170))	('haplotype', 'Var', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('Cancer', 'Phenotype', 'HP:0002664', (164, 170))	('chromosome', 'cellular_component', 'GO:0005694', ('51', '61'))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (193, 198))
26493	33634026	At the genetic level, mutations in BAP1, EIF1AX, SF3B1 and other genes have been shown to affect patient prognosis; specifically, patients with EIF1AX mutations have relatively more positive prognoses, while patients with SF3B1 mutations are more prone to have advanced metastasis.	('EIF1AX', 'Gene', '1964', (144, 150))	('BAP1', 'Gene', (35, 39))	('patient', 'Species', '9606', (97, 104))	('EIF1AX', 'Gene', '1964', (41, 47))	('patient', 'Species', '9606', (208, 215))	('SF3B1', 'Gene', (49, 54))	('SF3B1', 'Gene', (222, 227))	('mutations', 'Var', (151, 160))	('affect', 'Reg', (90, 96))	('patients', 'Species', '9606', (130, 138))	('mutations', 'Var', (22, 31))	('advanced metastasis', 'CPA', (261, 280))	('SF3B1', 'Gene', '23451', (49, 54))	('patient', 'Species', '9606', (130, 137))	('patients', 'Species', '9606', (208, 216))	('SF3B1', 'Gene', '23451', (222, 227))	('BAP1', 'Gene', '8314', (35, 39))	('EIF1AX', 'Gene', (144, 150))	('positive', 'PosReg', (182, 190))	('EIF1AX', 'Gene', (41, 47))
26571	33634026	Chromosome 3 monosomy and chromosome 8 amplification are strongly correlated with choroidal melanoma metastasis.	('correlated', 'Reg', (66, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('amplification', 'Var', (39, 52))	('monosomy', 'Var', (13, 21))	('chromosome 8', 'Gene', (26, 38))	('choroidal melanoma metastasis', 'Disease', 'MESH:D009362', (82, 111))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('choroidal melanoma metastasis', 'Disease', (82, 111))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (82, 100))
26575	33634026	Therefore, SUVmax > 4 may be an indirect indicator of chromosome 3 monosomy in choroidal melanomas.	('chromosome', 'cellular_component', 'GO:0005694', ('54', '64'))	('choroidal melanomas', 'Disease', (79, 98))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (79, 97))	('choroidal melanomas', 'Disease', 'MESH:D008545', (79, 98))	('monosomy', 'Var', (67, 75))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (79, 98))
26652	33466278	Moreover, stem cell self-renewal regulation, involve multiple signaling pathways associated with oncogenesis, including the Notch, Sonic hedgehog and Wnt signaling and their impairment has been shown to impact on the poorer prognosis and higher recurrence rate after CCA surgical resection and treatment.	('Sonic hedgehog', 'Gene', (131, 145))	('stem cell self-renewal regulation', 'CPA', (10, 43))	('impairment', 'Var', (174, 184))	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('CCA', 'Phenotype', 'HP:0030153', (267, 270))	('signaling', 'biological_process', 'GO:0023052', ('62', '71'))	('CCA', 'Disease', (267, 270))	('impact', 'Reg', (203, 209))	('oncogenesis', 'biological_process', 'GO:0007048', ('97', '108'))	('regulation', 'biological_process', 'GO:0065007', ('33', '43'))	('recurrence', 'CPA', (245, 255))	('Sonic hedgehog', 'Gene', '6469', (131, 145))
26653	33466278	At a genomic level, primary liver cancer heterogeneity is linked to a complex mutational landscape with molecular and biological variations that also contribute to disease development, drug resistance and tumor relapse following therapy, thus influencing significantly patient's outcomes.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('linked', 'Reg', (58, 64))	('variations', 'Var', (129, 139))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('drug resistance', 'Phenotype', 'HP:0020174', (185, 200))	('liver cancer', 'Disease', 'MESH:D006528', (28, 40))	('liver cancer', 'Phenotype', 'HP:0002896', (28, 40))	('contribute', 'Reg', (150, 160))	('drug resistance', 'biological_process', 'GO:0009315', ('185', '200'))	('drug resistance', 'biological_process', 'GO:0042493', ('185', '200'))	('liver cancer', 'Disease', (28, 40))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('patient', 'Species', '9606', (269, 276))	('influencing', 'Reg', (243, 254))
26658	33466278	Different non-genomic events, including histone modifications, DNA hypo- or hyper- methylation, non-coding RNAs, and transcriptional regulators, by disrupting the epigenome, are able to contribute to intratumor heterogeneity, through their impact on regulating the spatial chromatin organization and altering the transcriptome.	('modifications', 'Var', (48, 61))	('histone', 'Var', (40, 47))	('spatial chromatin organization', 'MPA', (265, 295))	('regulating', 'Reg', (250, 260))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('chromatin organization', 'biological_process', 'GO:0006325', ('273', '295'))	('altering', 'Reg', (300, 308))	('transcriptome', 'MPA', (313, 326))	('chromatin', 'cellular_component', 'GO:0000785', ('273', '282'))	('epigenome', 'MPA', (163, 172))	('methylation', 'biological_process', 'GO:0032259', ('83', '94'))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('impact', 'Reg', (240, 246))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('hyper- methylation', 'Var', (76, 94))	('contribute', 'Reg', (186, 196))	('disrupting', 'NegReg', (148, 158))
26663	33466278	For example, when interpreting the importance of intratumor genomic heterogeneity, a step forward is the development of a genome-axis evolution model, which sustain that multiple gene modifications could increase the adaptive function of a cell and influence its survival.	('adaptive function', 'CPA', (217, 234))	('modifications', 'Var', (184, 197))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('increase', 'PosReg', (204, 212))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('influence', 'Reg', (249, 258))	('survival', 'CPA', (263, 271))
26665	33466278	However, finding specific CCA treatments is challenging, again, because of the marked heterogeneity of this disease, being only small percentages of patients responsive to inhibitors targeting genes mutations or aberrations.	('mutations', 'Var', (199, 208))	('CCA', 'Phenotype', 'HP:0030153', (26, 29))	('patients', 'Species', '9606', (149, 157))	('CCA', 'Disease', (26, 29))
26673	33466278	Results showed a significant advantage in median overall survival (OS) for patients receiving adjuvant capecitabine in respect to those undergoing observation (51.1 versus 36.4 months),.	('advantage', 'PosReg', (29, 38))	('overall survival', 'MPA', (49, 65))	('patients', 'Species', '9606', (75, 83))	('capecitabine', 'Chemical', 'MESH:D000069287', (103, 115))	('adjuvant', 'Var', (94, 102))
26685	33466278	Numerous potentially targetable genetic driver alterations, including high microsatellite instability (MSI-H), isocitrate dehydrogenase (IDH)-1 and -2 mutations, and fibroblast growth factor receptor (FGFR) alterations, have recently been discovered and resumed for iCCA in Table 1 with ongoing related clinical trials.	('high microsatellite instability', 'MPA', (70, 101))	('alterations', 'Var', (207, 218))	('isocitrate dehydrogenase (IDH)-1 and -2', 'Gene', '3417;3418', (111, 150))	('FGFR', 'Gene', (201, 205))	('FGFR', 'molecular_function', 'GO:0005007', ('201', '205'))	('mutations', 'Var', (151, 160))	('CCA', 'Phenotype', 'HP:0030153', (267, 270))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('166', '190'))
26694	33466278	HAI has been shown to produce better response rates than systemic chemotherapy despite little impact on survival, mainly due to the development of extra-hepatic metastases.	('hepatic metastases', 'Disease', (153, 171))	('hepatic metastases', 'Disease', 'MESH:D009362', (153, 171))	('HAI', 'Var', (0, 3))
26707	33466278	Firstly, there is in vitro evidence to suggest that L-PAM is effective in killing HCC cell lines.	('L-PAM', 'Var', (52, 57))	('HCC cell lines', 'CPA', (82, 96))	('L-PAM', 'Chemical', 'MESH:D008558', (52, 57))
27055	32279660	However, unlike tRFs, the partial copies of the longer rRNAs such as 12S, 16S, 18S, and 28S that can be found on the genome are themselves long.	('tRF', 'Gene', (16, 19))	('18S', 'Var', (79, 82))	('tRF', 'Gene', '7013', (16, 19))
27112	32279660	293T cell samples are as follows: SRR5628228, SRR5628229, and SRR5628230.	('SRR5628229', 'Var', (46, 56))	('293T', 'CellLine', 'CVCL:0063', (0, 4))	('SRR5628230', 'Var', (62, 72))	('SRR5628228', 'Chemical', '-', (34, 44))	('SRR5628228', 'Var', (34, 44))	('SRR5628229', 'Chemical', '-', (46, 56))	('SRR5628230', 'Chemical', '-', (62, 72))
27113	32279660	The EV samples are as follows: SRR5628231, SRR5628232, and SRR5628233.	('SRR5628233', 'Chemical', '-', (59, 69))	('SRR5628232', 'Var', (43, 53))	('SRR5628233', 'Var', (59, 69))	('SRR5628231', 'Chemical', '-', (31, 41))	('SRR5628232', 'Chemical', '-', (43, 53))	('SRR5628231', 'Var', (31, 41))
27136	32279660	The cell lines are the following: CEU females (GM12769, GM12807, GM12837) CEU males (GM12884, GM12905, GM12919), YRI females (GM18487, GM18523, GM18870), YRI males (GM18907, GM19203, GM19239), GBR females (HG00122, HG00134, HG00137), and GBR males (HG00243, HG00264, HG01789).	('GM19203', 'Var', (174, 181))	('HG00122', 'Var', (206, 213))	('HG00243', 'Var', (249, 256))	('GM12919', 'Var', (103, 110))	('GM12807', 'Var', (56, 63))	('HG00137', 'Var', (224, 231))	('GM12769', 'Var', (47, 54))	('GM18870', 'Var', (144, 151))	('GM18523', 'Var', (135, 142))	('GM18907', 'Var', (165, 172))	('GM12905', 'Var', (94, 101))	('CEU', 'Chemical', '-', (74, 77))	('GBR', 'Chemical', 'MESH:C013003', (193, 196))	('CEU', 'Chemical', '-', (34, 37))	('GM12837', 'Var', (65, 72))	('GM19239', 'Var', (183, 190))	('GM18487', 'Var', (126, 133))	('GM12884', 'Var', (85, 92))	('GBR', 'Chemical', 'MESH:C013003', (238, 241))
27201	31807277	Toxicity was greater with the addition of TNF-alpha, including two toxicity-related amputations among 68 patients.	('Toxicity', 'Disease', (0, 8))	('Toxicity', 'Disease', 'MESH:D064420', (0, 8))	('TNF-alpha', 'Protein', (42, 51))	('toxicity', 'Disease', 'MESH:D064420', (67, 75))	('addition', 'Var', (30, 38))	('toxicity', 'Disease', (67, 75))
27230	31807277	Fenestrations in the double balloon catheter provide hepatic venous outflow to the extracorporeal circuit, which comprises a centrifugal pump and two activated charcoal filters.	('hepatic venous', 'Disease', 'MESH:D056486', (53, 67))	('Fenestrations', 'Var', (0, 13))	('hepatic venous', 'Disease', (53, 67))
27271	31357599	Mutations in alpha G-protein subunits, GNAQ and GNA11, were found in 92.5% of the samples, in a mutually exclusive pattern consistent with prior observations.	('GNAQ', 'Gene', (39, 43))	('Mutations', 'Var', (0, 9))	('GNA11', 'Gene', (48, 53))	('found', 'Reg', (60, 65))	('GNA11', 'Gene', '2767', (48, 53))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))
27272	31357599	Tumors that did not harbor these mutations were found to have mutations in CYSLTR2, a G-protein-coupled receptor, in 4% of samples and in PLCB4, a downstream effector of GNAQ signaling in 2.5% of samples, highlighting the involvement of G-protein signaling in the biology of uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (275, 289))	('uveal melanoma', 'Disease', (275, 289))	('uveal melanoma', 'Disease', 'MESH:C536494', (275, 289))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('PLCB4', 'Gene', '5332', (138, 143))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('CYSLTR2', 'Gene', '57105', (75, 82))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('melanoma', 'Phenotype', 'HP:0002861', (281, 289))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('signaling', 'biological_process', 'GO:0023052', ('247', '256'))	('PLCB4', 'Gene', (138, 143))	('CYSLTR2', 'Gene', (75, 82))	('protein', 'cellular_component', 'GO:0003675', ('239', '246'))	('mutations', 'Var', (62, 71))
27274	31357599	Ectopic expression of the activating mutation GNAQ/11.Q209L in zebrafish along with inactivation of the tumor suppressor TP53 led to tumor formation, while expression of GNAQ/11.Q209L alone led to profound pigmentation defects without oncogenic transformation, supporting the hypothesis that the activating GNAQ/11 mutations are precursor events requiring a 'second hit' in order to lead to malignant transformation, as shown in Figure 1.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Q209L', 'Mutation', 'rs121913492', (54, 59))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('104', '120'))	('GNAQ/11', 'Gene', (307, 314))	('zebrafish', 'Species', '7955', (63, 72))	('formation', 'biological_process', 'GO:0009058', ('139', '148'))	('Q209L', 'Mutation', 'rs121913492', (178, 183))	('pigmentation defects', 'Disease', 'MESH:D010859', (206, 226))	('tumor suppressor', 'biological_process', 'GO:0051726', ('104', '120'))	('TP53', 'Gene', '30590', (121, 125))	('tumor', 'Disease', (104, 109))	('TP53', 'Gene', (121, 125))	('pigmentation', 'biological_process', 'GO:0043473', ('206', '218'))	('tumor', 'Disease', (133, 138))	('mutations', 'Var', (315, 324))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('activating', 'PosReg', (296, 306))	('pigmentation defects', 'Disease', (206, 226))	('pigmentation defects', 'Phenotype', 'HP:0001000', (206, 226))
27275	31357599	A second layer of mutations consist of mutations in SF3B1, EIF1AX, BAP1, and were found in a nearly mutually exclusive manner.	('EIF1AX', 'Gene', (59, 65))	('mutations', 'Var', (39, 48))	('SF3B1', 'Gene', (52, 57))	('SF3B1', 'Gene', '23451', (52, 57))	('EIF1AX', 'Gene', '1964', (59, 65))	('BAP1', 'Gene', (67, 71))
27276	31357599	All tumors with BAP1 mutations had genomic copy loss in chromosome 3, while none of those with EIF1AX and only 22% of UM with SF3B1 mutations had monosomy 3.	('SF3B1', 'Gene', (126, 131))	('EIF1AX', 'Gene', (95, 101))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('UM', 'Phenotype', 'HP:0007716', (118, 120))	('SF3B1', 'Gene', '23451', (126, 131))	('EIF1AX', 'Gene', '1964', (95, 101))	('chromosome', 'cellular_component', 'GO:0005694', ('56', '66'))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('BAP1', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
27280	31357599	Interestingly, in the TCGA report, genes involved in DNA damage repair/response (DDR) were upregulated in monosomy 3 tumors harboring BAP1 mutations compared to disomy 3 tumors with SF3B1 mutations.	('upregulated', 'PosReg', (91, 102))	('disomy 3 tumors', 'Disease', (161, 176))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('BAP1', 'Gene', (134, 138))	('mutations', 'Var', (139, 148))	('DNA damage repair/response', 'MPA', (53, 79))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('SF3B1', 'Gene', (182, 187))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('SF3B1', 'Gene', '23451', (182, 187))	('monosomy 3', 'Disease', (106, 116))	('tumors', 'Disease', (170, 176))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('disomy 3 tumors', 'Disease', 'MESH:D024182', (161, 176))
27281	31357599	Mutations in SRSF2 were found in three samples which had wildtype EIF1AX and SF3B1.	('SF3B1', 'Gene', (77, 82))	('SRSF2', 'Gene', (13, 18))	('SF3B1', 'Gene', '23451', (77, 82))	('Mutations', 'Var', (0, 9))	('found', 'Reg', (24, 29))	('SRSF2', 'Gene', '6427', (13, 18))	('EIF1AX', 'Gene', '1964', (66, 72))	('EIF1AX', 'Gene', (66, 72))
27282	31357599	Samples with SRSF2 mutations had an SCNA profile similar to that of SF3B1, suggesting a common molecular basis for both genes in the UM development.	('SF3B1', 'Gene', (68, 73))	('SRSF2', 'Gene', (13, 18))	('mutations', 'Var', (19, 28))	('SF3B1', 'Gene', '23451', (68, 73))	('SRSF2', 'Gene', '6427', (13, 18))	('UM', 'Phenotype', 'HP:0007716', (133, 135))
27284	31357599	In fact, UM with mutations in either of those genes had alternatively spliced transcripts in a subset of genes compared to UM with wildtype SF3B1/SRSF2.	('SRSF2', 'Gene', '6427', (146, 151))	('SF3B1', 'Gene', (140, 145))	('SF3B1', 'Gene', '23451', (140, 145))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('SRSF2', 'Gene', (146, 151))	('UM', 'Phenotype', 'HP:0007716', (123, 125))	('mutations', 'Var', (17, 26))
27288	31357599	EIF1AX mutations were only present in cluster 1, and mutations in SF3B1/SRSF2 were mainly present in cluster 2 and, to a lesser extent, in cluster 3.	('SRSF2', 'Gene', '6427', (72, 77))	('mutations', 'Var', (53, 62))	('SF3B1', 'Gene', (66, 71))	('SF3B1', 'Gene', '23451', (66, 71))	('SRSF2', 'Gene', (72, 77))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))
27289	31357599	Moreover, isodisomy 8 was seen in a subset of UM with monosomy 3:these had the worst prognosis.	('isodisomy 8', 'Chemical', '-', (10, 21))	('monosomy 3', 'Var', (54, 64))	('isodisomy', 'Disease', (10, 19))	('UM', 'Phenotype', 'HP:0007716', (46, 48))
27290	31357599	Whole genome doubling was also noted in tumors with monosomy 3.	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('monosomy 3', 'Var', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
27294	31357599	Cancer cell fractions of monosomy 3 were close to 1 (mean 0.97), whereas those of BAP1 alterations were lower (mean 0.88), and other passenger mutations on chromosome 3 occurred with much less frequency (mean 0.60).	('chromosome', 'cellular_component', 'GO:0005694', ('156', '166'))	('BAP1', 'Gene', (82, 86))	('monosomy 3', 'Var', (25, 35))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
27295	31357599	Another means by which cancer cells may up- or downregulate gene expression is through DNA methylation.	('methylation', 'Var', (91, 102))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('gene expression', 'MPA', (60, 75))	('downregulate', 'NegReg', (47, 59))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('gene expression', 'biological_process', 'GO:0010467', ('60', '75'))	('DNA methylation', 'biological_process', 'GO:0006306', ('87', '102'))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('up-', 'PosReg', (40, 43))
27299	31357599	Within disomy 3 UM, tumors with EIF1AX mutations had a different methylation profile than those with SF3B1 mutations.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('EIF1AX', 'Gene', (32, 38))	('methylation profile', 'MPA', (65, 84))	('EIF1AX', 'Gene', '1964', (32, 38))	('mutations', 'Var', (39, 48))	('different', 'Reg', (55, 64))	('UM', 'Phenotype', 'HP:0007716', (16, 18))	('SF3B1', 'Gene', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))	('SF3B1', 'Gene', '23451', (101, 106))
27300	31357599	Expectedly, monosomy 3/BAP1-aberrant tumors had a distinct transcriptomic profiles than tumors with disomy 3 and high BAP1 levels.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('transcriptomic profiles', 'MPA', (59, 82))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('distinct', 'Reg', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (37, 43))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('monosomy 3/BAP1-aberrant', 'Var', (12, 36))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
27323	31357599	In the United States, ocular oncologists utilize either a DNA-based test which relies on karyotypic analysis of the tumor (mainly monosomy 3, 8q, and 6p gain) or a RNA-based test, commercially offered by Castle Biosciences, wherein a 12-gene panel is used to estimate prognosis (Class 1A, 1B, or 2, with low, intermediate, and high risk of metastasis, respectively).	('RNA', 'cellular_component', 'GO:0005562', ('164', '167'))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('monosomy 3', 'Var', (130, 140))
27324	31357599	The multi-dimensional TCGA-UM analysis indicated that segregating tumors into two major prognostic groups can be equally achieved by analyzing chromosome 3 status (disomy 3 vs. monosomy 3) or analyzing the transcriptome (Castle Biosciences GEP class 1 vs. 2/TCGA clusters 1 and 2 vs. 3 and 4).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('UM', 'Phenotype', 'HP:0007716', (27, 29))	('disomy', 'Var', (164, 170))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('chromosome', 'cellular_component', 'GO:0005694', ('143', '153'))	('transcriptome', 'MPA', (206, 219))	('analyzing', 'Reg', (133, 142))
27334	31357599	In the TCGA cohort, mutations in GNAQ/11, CYSLTR2, and PLCB4 (2.5%) were found in 92.5%, 4%, and 2.5% of the samples, respectively, highlighting the involvement of G-protein signaling in the biology of uveal melanoma.	('uveal melanoma', 'Disease', (202, 216))	('uveal melanoma', 'Disease', 'MESH:C536494', (202, 216))	('involvement', 'Reg', (149, 160))	('found', 'Reg', (73, 78))	('CYSLTR2', 'Gene', '57105', (42, 49))	('uveal melanoma', 'Phenotype', 'HP:0007716', (202, 216))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('CYSLTR2', 'Gene', (42, 49))	('signaling', 'biological_process', 'GO:0023052', ('174', '183'))	('PLCB4', 'Gene', '5332', (55, 60))	('GNAQ/11', 'Gene', (33, 40))	('mutations', 'Var', (20, 29))	('PLCB4', 'Gene', (55, 60))
27337	31357599	Interestingly, even though GNAQ/11 mutations were present in 93% of the samples, protein analysis showed that levels of PKC, a downstream effector of GNAQ/11, were markedly higher in monosomy 3/BAP1-aberrant UM, indicating that GNAQ/11 signaling may be further enhanced in M3 tumors.	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('PKC', 'Disease', (120, 123))	('levels', 'MPA', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('tumors', 'Disease', 'MESH:D009369', (276, 282))	('UM', 'Phenotype', 'HP:0007716', (208, 210))	('PKC', 'molecular_function', 'GO:0004697', ('120', '123'))	('signaling', 'biological_process', 'GO:0023052', ('236', '245'))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('monosomy 3/BAP1-aberrant', 'Var', (183, 207))	('PKC', 'Disease', 'MESH:C537180', (120, 123))	('tumors', 'Disease', (276, 282))	('higher', 'PosReg', (173, 179))
27346	28012237	Sporadic melanotic schwannoma overlapping with features of melanocytoma bearing a GNA11 mutation in an adolescent girl Melanotic schwannoma (MS) is a rare soft tissue neoplasm that shares histological features with both melanocytic tumors and schwannomas.	('Melanotic schwannoma', 'Disease', 'MESH:D009442', (119, 139))	('melanocytoma', 'Disease', (59, 71))	('schwannomas', 'Phenotype', 'HP:0100008', (243, 254))	('schwannoma', 'Phenotype', 'HP:0100008', (243, 253))	('GNA11', 'Gene', '2767', (82, 87))	('Sporadic melanotic schwannoma', 'Disease', (0, 29))	('Sporadic melanotic schwannoma', 'Disease', 'MESH:D009442', (0, 29))	('neoplasm', 'Disease', 'MESH:D009369', (167, 175))	('soft tissue neoplasm', 'Phenotype', 'HP:0031459', (155, 175))	('schwannoma', 'Phenotype', 'HP:0100008', (19, 29))	('melanocytic tumors and schwannomas', 'Disease', 'MESH:D009464', (220, 254))	('schwannoma', 'Phenotype', 'HP:0100008', (129, 139))	('melanocytoma', 'Disease', 'None', (59, 71))	('neoplasm', 'Disease', (167, 175))	('mutation', 'Var', (88, 96))	('GNA11', 'Gene', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('neoplasm', 'Phenotype', 'HP:0002664', (167, 175))	('Melanotic schwannoma', 'Disease', (119, 139))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))
27348	28012237	CNC is caused by mutations in the PRKAR1A gene.	('CNC', 'Disease', (0, 3))	('PRKAR1A', 'Gene', (34, 41))	('caused by', 'Reg', (7, 16))	('mutations', 'Var', (17, 26))	('PRKAR1A', 'Gene', '5573', (34, 41))
27351	28012237	This lesion carried a mutation of the GNA11 gene, which is considered highly specific for UM or MC.	('mutation', 'Var', (22, 30))	('UM', 'Phenotype', 'HP:0007716', (90, 92))	('carried', 'Reg', (12, 19))	('MC', 'Chemical', '-', (96, 98))	('GNA11', 'Gene', '2767', (38, 43))	('GNA11', 'Gene', (38, 43))
27352	28012237	We conclude that sporadic MS may occur rarely in adolescents without CNC; MS may also be associated with somatic GNA11 mutations.	('associated', 'Reg', (89, 99))	('mutations', 'Var', (119, 128))	('GNA11', 'Gene', '2767', (113, 118))	('GNA11', 'Gene', (113, 118))
27362	28012237	We report a case of an adolescent presenting with a large sporadic abdominal mesenteric MS with overlapping features with melanocytoma, bearing a mutation of the GNA11 gene, which is considered highly specific for uveal melanomas (UM) or MC.	('uveal melanomas', 'Disease', 'MESH:C536494', (214, 229))	('uveal melanomas', 'Phenotype', 'HP:0007716', (214, 229))	('melanocytoma', 'Disease', 'None', (122, 134))	('UM', 'Phenotype', 'HP:0007716', (231, 233))	('MC', 'Chemical', '-', (238, 240))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('melanomas', 'Phenotype', 'HP:0002861', (220, 229))	('GNA11', 'Gene', (162, 167))	('uveal melanomas', 'Disease', (214, 229))	('mutation', 'Var', (146, 154))	('melanocytoma', 'Disease', (122, 134))	('GNA11', 'Gene', '2767', (162, 167))
27383	28012237	Molecular analysis of the tumor was positive for the mutation c.626A>T, p.Q209L on exon 5 of the GNA11 gene, while the same mutation was not identified in the germline.	('p.Q209L', 'Mutation', 'rs1057519742', (72, 79))	('c.626A>T', 'Var', (62, 70))	('c.626A>T', 'Mutation', 'rs1057519742', (62, 70))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('p.Q209L', 'Var', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('GNA11', 'Gene', '2767', (97, 102))	('GNA11', 'Gene', (97, 102))
27384	28012237	Gene analysis of the tumor for the common mutations of the BRAF and GNAQ genes was negative, while both peripheral and tumor DNA were also negative for PRKAR1A gene mutations.	('tumor', 'Disease', (119, 124))	('PRKAR1A', 'Gene', '5573', (152, 159))	('tumor', 'Disease', (21, 26))	('GNAQ', 'Gene', (68, 72))	('DNA', 'cellular_component', 'GO:0005574', ('125', '128'))	('negative', 'NegReg', (83, 91))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('GNAQ', 'Gene', '2776', (68, 72))	('mutations', 'Var', (42, 51))	('PRKAR1A', 'Gene', (152, 159))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
27385	28012237	The germline DNA was further tested for Copy Number Variants (CNVs) with array Comparative Genomic Hybridization (CGH), while whole exome sequencing was also performed with no identification of any further genetic abnormalities, including no mutations of the NF2 gene, responsible for neurofibromatosis type 2 (NF2), or any other tumor genes.	('neurofibromatosis type 2', 'Gene', '4771', (285, 309))	('NF2', 'Gene', '4771', (259, 262))	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (285, 302))	('neurofibromatosis type 2', 'Gene', (285, 309))	('tumor', 'Disease', (330, 335))	('mutations', 'Var', (242, 251))	('genetic abnormalities', 'Disease', 'MESH:D030342', (206, 227))	('NF2', 'Gene', '4771', (311, 314))	('NF2', 'Gene', (311, 314))	('genetic abnormalities', 'Disease', (206, 227))	('NF2', 'Gene', (259, 262))	('tumor', 'Disease', 'MESH:D009369', (330, 335))
27391	28012237	Our patient did not have CNC, her tumor was not PMS, and did not carry PRKAR1A mutations.	('PMS', 'Chemical', '-', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('PRKAR1A', 'Gene', '5573', (71, 78))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('PRKAR1A', 'Gene', (71, 78))	('mutations', 'Var', (79, 88))
27392	28012237	Instead, our patient's tumor harbored a GNA11 gene mutation.	('GNA11', 'Gene', (40, 45))	('patient', 'Species', '9606', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('GNA11', 'Gene', '2767', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutation', 'Var', (51, 59))	('tumor', 'Disease', (23, 28))	('harbored', 'Reg', (29, 37))
27395	28012237	Mutations of either gene result in persistent linking of the alpha subunit to GTP, which causes the constitutive activation of the pathway.	('GTP', 'Gene', (78, 81))	('constitutive', 'MPA', (100, 112))	('causes', 'Reg', (89, 95))	('GTP', 'Chemical', 'MESH:D006160', (78, 81))	('linking', 'Interaction', (46, 53))	('alpha subunit', 'Protein', (61, 74))	('Mutations', 'Var', (0, 9))
27396	28012237	GNA11 mutations have been reported as a potential molecular marker to differentiate melanocytic tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('GNA11', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('GNA11', 'Gene', '2767', (0, 5))	('melanocytic tumors', 'Disease', 'MESH:D009508', (84, 102))	('melanocytic tumors', 'Disease', (84, 102))	('mutations', 'Var', (6, 15))
27397	28012237	In UMs and MCs, the gene mutations are common with a reported frequency of 32-57%, whereas in MS, GNA11 gene defects have not been described.	('mutations', 'Var', (25, 34))	('UMs', 'Disease', (3, 6))	('GNA11', 'Gene', (98, 103))	('GNA11', 'Gene', '2767', (98, 103))	('MC', 'Chemical', '-', (11, 13))	('MCs', 'cellular_component', 'GO:0044232', ('11', '14'))	('MCs', 'Disease', (11, 14))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
27398	28012237	The finding of a GNA11 gene mutation in the described tumor, which was characterized as MS with some characteristics of MC, suggests that this gene defect may not be as exclusive as previously thought.	('MC', 'Chemical', '-', (120, 122))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('GNA11', 'Gene', (17, 22))	('mutation', 'Var', (28, 36))	('GNA11', 'Gene', '2767', (17, 22))	('tumor', 'Disease', (54, 59))
27402	28012237	MS may also be associated with somatic GNA11 mutations, especially when histologic features of MC are also present, a finding that has implications for both prognosis and possibly the cellular origin of these tumors.	('tumors', 'Disease', (209, 215))	('mutations', 'Var', (45, 54))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('GNA11', 'Gene', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('MC', 'Chemical', '-', (95, 97))	('GNA11', 'Gene', '2767', (39, 44))	('associated', 'Reg', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
27420	28709702	By carefully evaluating over 300 fluid foci in eyes of cancer patients on MEK inhibition, this study analyzed the clinical and morphologic characteristics and the associated retinal, RPE and choroidal changes.	('MEK', 'Gene', '5609', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('inhibition', 'Var', (78, 88))	('eyes of cancer', 'Disease', (47, 61))	('choroidal changes', 'Phenotype', 'HP:0000610', (191, 208))	('patients', 'Species', '9606', (62, 70))	('eyes of cancer', 'Disease', 'MESH:D005134', (47, 61))	('MEK', 'Gene', (74, 77))
27461	28709702	Dysregulation of this pathway in human cancers makes them susceptible to treatment with targeted drugs that block this pathway, such as MEK-inhibitors.	('MEK', 'Gene', (136, 139))	('Dysregulation', 'Var', (0, 13))	('MEK', 'Gene', '5609', (136, 139))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancers', 'Disease', (39, 46))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('human', 'Species', '9606', (33, 38))
27462	28709702	For instance, aberrations in the MAPK pathway occurs in uveal melanoma and are the premise behind treatment with the MEK inhibitor, selumetinib; and MEK inhibition has proven successful in prolonging overall survival of patients with cutaneous melanoma.	('selumetinib', 'Chemical', 'MESH:C517975', (132, 143))	('MEK', 'Gene', (149, 152))	('MAPK', 'molecular_function', 'GO:0004707', ('33', '37'))	('MEK', 'Gene', '5609', (117, 120))	('patients', 'Species', '9606', (220, 228))	('inhibition', 'Var', (153, 163))	('prolonging', 'PosReg', (189, 199))	('MEK', 'Gene', (117, 120))	('MAPK pathway', 'Pathway', (33, 45))	('overall', 'MPA', (200, 207))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('uveal melanoma', 'Disease', 'MESH:C536494', (56, 70))	('occurs', 'Reg', (46, 52))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('cutaneous melanoma', 'Disease', (234, 252))	('aberrations', 'Var', (14, 25))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (234, 252))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (234, 252))	('uveal melanoma', 'Disease', (56, 70))	('uveal melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('MEK', 'Gene', '5609', (149, 152))
27482	28709702	In this series of patients with MEK inhibition, just over a third of the fluid foci exhibited elongation of the IZ.	('elongation of the IZ', 'CPA', (94, 114))	('inhibition', 'Var', (36, 46))	('patients', 'Species', '9606', (18, 26))	('MEK', 'Gene', (32, 35))	('MEK', 'Gene', '5609', (32, 35))
27592	27647839	The central role of the CaSR in Ca2+o homeostasis has been highlighted by the identification of mutations affecting the CASR gene on chromosome 3q21.1.	('Ca2', 'Gene', '760', (32, 35))	('CASR', 'Gene', (120, 124))	('homeostasis', 'biological_process', 'GO:0042592', ('38', '49'))	('Ca2', 'Gene', (32, 35))	('chromosome', 'cellular_component', 'GO:0005694', ('133', '143'))	('CASR', 'Gene', '846', (120, 124))	('mutations', 'Var', (96, 105))
27593	27647839	Loss-of-function CASR mutations cause familial hypocalciuric hypercalcaemia (FHH), whereas gain-of-function mutations lead to autosomal dominant hypocalcaemia (ADH).	('ADH', 'Gene', (160, 163))	('Loss-of-function', 'NegReg', (0, 16))	('autosomal dominant hypocalcaemia', 'Disease', (126, 158))	('autosomal dominant hypocalcaemia', 'Disease', 'MESH:D017827', (126, 158))	('gain-of-function', 'PosReg', (91, 107))	('ADH', 'molecular_function', 'GO:0047636', ('160', '163'))	('familial hypocalciuric hypercalcaemia', 'Disease', 'MESH:C537145', (38, 75))	('CASR', 'Gene', (17, 21))	('FHH', 'Gene', (77, 80))	('hypocalcaemia', 'Phenotype', 'HP:0002901', (145, 158))	('ADH', 'molecular_function', 'GO:0004022', ('160', '163'))	('familial hypocalciuric hypercalcaemia', 'Disease', (38, 75))	('mutations', 'Var', (22, 31))	('ADH', 'Gene', '127', (160, 163))	('hypercalcaemia', 'Phenotype', 'HP:0003072', (61, 75))	('CASR', 'Gene', '846', (17, 21))	('FHH', 'Gene', '846', (77, 80))
27595	27647839	Thus, loss- and gain-of-function mutations of the GNA11 gene on chromosome 19p13.3, which encodes the G-protein alpha-11 (Galpha11) subunit, lead to FHH type 2 and ADH type 2, respectively; whilst loss-of-function mutations of AP2S1 on chromosome 19q13.3, which encodes the adaptor-related protein complex 2 sigma (AP2sigma) subunit, cause FHH type 3.	('FHH type 2', 'Disease', 'MESH:C537145', (149, 159))	('AP2', 'Gene', (227, 230))	('AP2', 'Gene', '7020', (227, 230))	('AP2', 'cellular_component', 'GO:0005908', ('227', '230'))	('mutations', 'Var', (33, 42))	('AP2S1', 'Gene', '1175', (227, 232))	('ADH', 'molecular_function', 'GO:0004022', ('164', '167'))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('FHH', 'Gene', (149, 152))	('AP2S1', 'Gene', (227, 232))	('chromosome', 'cellular_component', 'GO:0005694', ('236', '246'))	('GNA11', 'Gene', '2767', (50, 55))	('mutations', 'Var', (214, 223))	('FHH', 'Gene', '846', (149, 152))	('FHH', 'Gene', (340, 343))	('AP2', 'cellular_component', 'GO:0005908', ('315', '318'))	('FHH', 'Gene', '846', (340, 343))	('ADH', 'Gene', '127', (164, 167))	('ADH', 'molecular_function', 'GO:0047636', ('164', '167'))	('chromosome', 'cellular_component', 'GO:0005694', ('64', '74'))	('ADH', 'Gene', (164, 167))	('adaptor-related protein complex 2', 'Gene', (274, 307))	('loss-of-function', 'NegReg', (197, 213))	('AP2', 'Gene', (315, 318))	('AP2', 'Gene', '7020', (315, 318))	('G-protein alpha-11', 'Gene', '2767', (102, 120))	('gain-of-function', 'PosReg', (16, 32))	('G-protein alpha-11', 'Gene', (102, 120))	('GNA11', 'Gene', (50, 55))	('loss-', 'NegReg', (6, 11))	('FHH type 2', 'Disease', (149, 159))	('protein complex', 'cellular_component', 'GO:0032991', ('290', '305'))	('adaptor-related protein complex 2', 'Gene', '7020', (274, 307))
27608	27647839	This article will provide an overview of the role of the CaSR, Galpha11 and AP2sigma proteins, review the disorders caused by mutations of these proteins, outline potential targeted therapies, and describe insights gained into the molecular basis of Ca2+o homeostasis by studies of the CaSR and its partner proteins.	('Ca2', 'Gene', '760', (250, 253))	('AP2', 'Gene', (76, 79))	('homeostasis', 'biological_process', 'GO:0042592', ('256', '267'))	('AP2', 'Gene', '7020', (76, 79))	('mutations', 'Var', (126, 135))	('Ca2', 'Gene', (250, 253))	('AP2', 'cellular_component', 'GO:0005908', ('76', '79'))
27613	27647839	IP3 in turn stimulates the rapid release of calcium from intracellular stores, whereas DAG activates the mitogen-activated protein kinase (MAPK) cascade.	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('MAPK', 'molecular_function', 'GO:0004707', ('139', '143'))	('IP3', 'Var', (0, 3))	('MAPK) cascade', 'biological_process', 'GO:0000165', ('139', '152'))	('calcium', 'Chemical', 'MESH:D002118', (44, 51))	('DAG', 'Chemical', 'MESH:D004075', (87, 90))	('intracellular', 'cellular_component', 'GO:0005622', ('57', '70'))	('rapid release of calcium from intracellular stores', 'MPA', (27, 77))	('IP3', 'Chemical', 'MESH:D015544', (0, 3))
27619	27647839	These mutations may cause a loss of CaSR function and give rise to hypercalcaemic disorders such as FHH type 1 (FHH1), neonatal severe hyperparathyroidism (NSHPT) and adult-onset primary hyperparathyroidism (PHPT); or lead to a gain of function that is associated with hypocalcaemic disorders such as ADH type 1 (ADH1) and Bartter syndrome type V (Table 1).	('NSHPT', 'Gene', (156, 161))	('FHH type 1 (FHH1), neonatal severe hyperparathyroidism', 'Disease', 'MESH:C537145', (100, 154))	('ADH', 'molecular_function', 'GO:0004022', ('313', '316'))	('gain of function', 'PosReg', (228, 244))	('primary hyperparathyroidism', 'Disease', 'MESH:D049950', (179, 206))	('NSHPT', 'Gene', '846', (156, 161))	('ADH', 'Gene', '127', (301, 304))	('CaSR function', 'MPA', (36, 49))	('loss', 'NegReg', (28, 32))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (187, 206))	('hypercalcaemic disorders', 'Disease', (67, 91))	('ADH', 'molecular_function', 'GO:0004022', ('301', '304'))	('ADH', 'Gene', (301, 304))	('hypocalcaemic disorders', 'Disease', (269, 292))	('primary hyperparathyroidism', 'Phenotype', 'HP:0008200', (179, 206))	('mutations', 'Var', (6, 15))	('hypocalcaemic disorders', 'Phenotype', 'HP:0002901', (269, 292))	('ADH', 'molecular_function', 'GO:0047636', ('313', '316'))	('hypocalcaemic disorders', 'Disease', 'MESH:D030342', (269, 292))	('hypercalcaemic disorders', 'Disease', 'MESH:D030342', (67, 91))	('Bartter syndrome type V', 'Disease', 'MESH:C537653', (323, 346))	('ADH', 'molecular_function', 'GO:0047636', ('301', '304'))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (135, 154))	('PHPT', 'Phenotype', 'HP:0008200', (208, 212))	('Bartter syndrome type V', 'Disease', (323, 346))	('ADH', 'Gene', '127', (313, 316))	('ADH', 'Gene', (313, 316))	('primary hyperparathyroidism', 'Disease', (179, 206))
27620	27647839	FHH comprises three genetically distinct conditions, designated as FHH types 1-3 (Table 1), which are due to loss-of-function mutations affecting the CaSR, Galpha11 and AP2sigma proteins, respectively.	('FHH', 'Gene', '846', (0, 3))	('AP2', 'Gene', '7020', (169, 172))	('AP2', 'Gene', (169, 172))	('FHH', 'Gene', (0, 3))	('mutations', 'Var', (126, 135))	('CaSR', 'Protein', (150, 154))	('FHH', 'Gene', '846', (67, 70))	('Galpha11', 'Protein', (156, 164))	('AP2', 'cellular_component', 'GO:0005908', ('169', '172'))	('FHH', 'Gene', (67, 70))
27626	27647839	Mutational analysis may be required to distinguish FHH from PHPT, and to date, FHH1 has been associated with >130 different mutations of the CASR gene (Fig.	('mutations', 'Var', (124, 133))	('CASR', 'Gene', '846', (141, 145))	('FHH', 'Gene', '846', (51, 54))	('FHH', 'Gene', '846', (79, 82))	('associated', 'Reg', (93, 103))	('PHPT', 'Phenotype', 'HP:0008200', (60, 64))	('FHH', 'Gene', (51, 54))	('CASR', 'Gene', (141, 145))	('FHH', 'Gene', (79, 82))
27627	27647839	Studies of FHH1-associated CaSR mutations have identified critical receptor structure-function relationships and demonstrated a mutational hotspot within the ECD.	('FHH', 'Gene', '846', (11, 14))	('mutations', 'Var', (32, 41))	('FHH', 'Gene', (11, 14))	('CaSR', 'Gene', (27, 31))
27628	27647839	Indeed, an analysis of the locations of recurrent FHH1-causing CaSR mutations or residues affected by multiple different loss-of-function CaSR mutations has revealed a clustering of mutations at the major predicted Ca2+o binding site located within the cleft region of the bilobed extracellular VFT domain of the CaSR (Fig.	('binding', 'molecular_function', 'GO:0005488', ('221', '228'))	('FHH', 'Gene', (50, 53))	('Ca2', 'Gene', '760', (215, 218))	('extracellular', 'cellular_component', 'GO:0005576', ('281', '294'))	('FHH', 'Gene', '846', (50, 53))	('Ca2', 'Gene', (215, 218))	('mutations', 'Var', (68, 77))	('mutations', 'Var', (143, 152))	('mutations', 'Var', (182, 191))
27629	27647839	These mutated residues may be directly involved in the binding of Ca2+o or indirectly influence alterations in receptor conformational states that occur upon Ca2+o binding.	('involved', 'Reg', (39, 47))	('Ca2', 'Gene', (66, 69))	('Ca2', 'Gene', (158, 161))	('Ca2', 'Gene', '760', (158, 161))	('binding', 'molecular_function', 'GO:0005488', ('164', '171'))	('binding', 'Interaction', (55, 62))	('receptor conformational states', 'MPA', (111, 141))	('Ca2', 'Gene', '760', (66, 69))	('influence alterations', 'Reg', (86, 107))	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))	('mutated', 'Var', (6, 13))	('binding', 'Interaction', (164, 171))
27631	27647839	FHH-causing mutations also cluster in the CaSR transmembrane domain (TMD) and may inhibit the transmission of activation signals to the intracellular environment, by impairing interactions with heterotrimeric G proteins and other components of the CaSR signal transduction pathway.	('signal transduction', 'biological_process', 'GO:0007165', ('253', '272'))	('intracellular', 'cellular_component', 'GO:0005622', ('136', '149'))	('TMD', 'Disease', 'MESH:D049310', (69, 72))	('FHH', 'Gene', '846', (0, 3))	('transmembrane', 'cellular_component', 'GO:0016021', ('47', '60'))	('mutations', 'Var', (12, 21))	('impairing', 'NegReg', (166, 175))	('inhibit', 'NegReg', (82, 89))	('heterotrimeric G proteins', 'Protein', (194, 219))	('FHH', 'Gene', (0, 3))	('interactions', 'Interaction', (176, 188))	('TMD', 'Disease', (69, 72))	('CaSR signal transduction pathway', 'Pathway', (248, 280))	('transmembrane', 'cellular_component', 'GO:0044214', ('47', '60'))
27632	27647839	Some loss-of-function CaSR mutations have been shown to cause signalling bias by switching the wild-type CaSR from preferentially coupling with intracellular Ca2+ (Ca2+i) to a mutant receptor that signals equally via the Ca2+i and MAPK pathways, or which predominantly acts via MAPK.	('mutations', 'Var', (27, 36))	('MAPK', 'molecular_function', 'GO:0004707', ('278', '282'))	('preferentially', 'PosReg', (115, 129))	('Ca2', 'Gene', (158, 161))	('Ca2', 'Gene', '760', (221, 224))	('CaSR', 'Gene', (22, 26))	('signalling', 'biological_process', 'GO:0023052', ('62', '72'))	('MAPK', 'molecular_function', 'GO:0004707', ('231', '235'))	('Ca2', 'Gene', (221, 224))	('Ca2', 'Gene', '760', (158, 161))	('Ca2', 'Gene', '760', (164, 167))	('intracellular', 'cellular_component', 'GO:0005622', ('144', '157'))	('signalling bias', 'MPA', (62, 77))	('MAPK pathways', 'Pathway', (231, 244))	('loss-of-function', 'NegReg', (5, 21))	('Ca2', 'Gene', (164, 167))
27633	27647839	Loss-of-function CaSR mutations causing signalling bias are located within the ECD and TMD; however, the structural motifs within these regions that determine whether the CaSR preferentially couples to Ca2+i or MAPK pathways remain to be established.	('Loss-of-function', 'NegReg', (0, 16))	('Ca2', 'Gene', (202, 205))	('TMD', 'Disease', 'MESH:D049310', (87, 90))	('MAPK', 'molecular_function', 'GO:0004707', ('211', '215'))	('signalling bias', 'MPA', (40, 55))	('mutations', 'Var', (22, 31))	('Ca2', 'Gene', '760', (202, 205))	('signalling', 'biological_process', 'GO:0023052', ('40', '50'))	('CaSR', 'Gene', (17, 21))	('TMD', 'Disease', (87, 90))
27634	27647839	Around 50% of CaSR mutations that lead to FHH1 have been shown to result in reduced cell-surface receptor expression as a consequence of defective trafficking to the plasma membrane, with mutant CaSRs being retained intracellularly and unable to exit either the endoplasmic reticulum or Golgi apparatus.	('cell-surface', 'cellular_component', 'GO:0009986', ('84', '96'))	('defective', 'NegReg', (137, 146))	('cell-surface receptor', 'Protein', (84, 105))	('Golgi apparatus', 'cellular_component', 'GO:0005794', ('287', '302'))	('expression', 'MPA', (106, 116))	('FHH', 'Gene', '846', (42, 45))	('mutations', 'Var', (19, 28))	('trafficking to the plasma membrane', 'MPA', (147, 181))	('reduced', 'NegReg', (76, 83))	('FHH', 'Gene', (42, 45))	('plasma membrane', 'cellular_component', 'GO:0005886', ('166', '181'))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('262', '283'))	('CaSR', 'Gene', (14, 18))
27635	27647839	Such cellular studies also provide an explanation for the benign phenotype of FHH1, which is a heterozygous condition, by demonstrating that co-expression of wild-type and mutant FHH1-causing CaSRs ameliorates the loss of function, with the co-expressed wild-type CaSRs increasing trafficking of mutant receptors to the plasma membrane via the ADIS mechanism.	('mutant', 'Var', (172, 178))	('mutant', 'Var', (296, 302))	('increasing', 'PosReg', (270, 280))	('FHH', 'Gene', '846', (179, 182))	('plasma membrane', 'cellular_component', 'GO:0005886', ('320', '335'))	('FHH', 'Gene', (78, 81))	('FHH', 'Gene', (179, 182))	('trafficking', 'MPA', (281, 292))	('FHH', 'Gene', '846', (78, 81))
27636	27647839	NSHPT (OMIM #239200) is a potentially life-threatening disorder most often caused by homozygous or compound heterozygous loss-of-function CaSR mutations (Table 1).	('CaSR', 'Gene', (138, 142))	('NSHPT', 'Gene', '846', (0, 5))	('NSHPT', 'Gene', (0, 5))	('loss-of-function', 'NegReg', (121, 137))	('mutations', 'Var', (143, 152))
27639	27647839	Severe neonatal hypercalcaemia is also reported to be associated with heterozygous loss-of-function CaSR mutations, and these findings indicate that NSHPT may be due to factors other than mutant gene dosage.	('neonatal hypercalcaemia', 'Phenotype', 'HP:0008250', (7, 30))	('neonatal hypercalcaemia', 'Disease', (7, 30))	('loss-of-function', 'NegReg', (83, 99))	('hypercalcaemia', 'Phenotype', 'HP:0003072', (16, 30))	('mutations', 'Var', (105, 114))	('NSHPT', 'Gene', '846', (149, 154))	('NSHPT', 'Gene', (149, 154))	('neonatal hypercalcaemia', 'Disease', 'OMIM:202370', (7, 30))	('CaSR', 'Gene', (100, 104))
27640	27647839	For example, the degree of severity of a dominant-negative mutation or maternal serum calcium concentration may play a role in the phenotypic expression of a CaSR mutation in the neonate.	('calcium', 'Chemical', 'MESH:D002118', (86, 93))	('mutation', 'Var', (163, 171))	('CaSR', 'Gene', (158, 162))	('play', 'Reg', (112, 116))
27641	27647839	More than 25 different CaSR mutations have been described in association with NSHPT, of which >40% are either nonsense or frameshift mutations that are predicted to lead to a truncated CaSR.	('NSHPT', 'Gene', (78, 83))	('truncated', 'MPA', (175, 184))	('association', 'Reg', (61, 72))	('lead to', 'Reg', (165, 172))	('CaSR', 'Gene', (23, 27))	('frameshift', 'Var', (122, 132))	('NSHPT', 'Gene', '846', (78, 83))	('mutations', 'Var', (28, 37))
27642	27647839	Loss-of-function CaSR mutations may occasionally present after the neonatal period with marked hypercalcaemia.	('Loss-of-function', 'NegReg', (0, 16))	('hypercalcaemia', 'Disease', 'MESH:D006934', (95, 109))	('hypercalcaemia', 'Disease', (95, 109))	('mutations', 'Var', (22, 31))	('CaSR', 'Gene', (17, 21))	('hypercalcaemia', 'Phenotype', 'HP:0003072', (95, 109))
27643	27647839	Indeed, homozygous loss-of function mutations, which are located at the N-terminal region of the CaSR, have been reported to lead to symptomatic hypercalcaemia in childhood or early adulthood, which required treatment with parathyroidectomy.	('hypercalcaemia', 'Phenotype', 'HP:0003072', (145, 159))	('mutations', 'Var', (36, 45))	('loss-of function', 'NegReg', (19, 35))	('hypercalcaemia', 'Disease', 'MESH:D006934', (145, 159))	('hypercalcaemia', 'Disease', (145, 159))
27644	27647839	Occasionally, heterozygous and homozygous loss-of function CaSR mutations have been detected in adult patients with PHPT caused by parathyroid adenomas or hyperplasia (Table 1).	('CaSR', 'Gene', (59, 63))	('loss-of function', 'NegReg', (42, 58))	('patients', 'Species', '9606', (102, 110))	('PHPT', 'Phenotype', 'HP:0008200', (116, 120))	('PHPT', 'Disease', (116, 120))	('parathyroid adenomas or hyperplasia', 'Disease', (131, 166))	('mutations', 'Var', (64, 73))	('parathyroid adenomas or hyperplasia', 'Disease', 'MESH:D010282', (131, 166))	('parathyroid adenomas', 'Phenotype', 'HP:0002897', (131, 151))
27645	27647839	The occurrence of PHPT or severe FHH after infancy may be due to the degree of loss of function associated with the underlying CaSR mutations.	('PHPT', 'Phenotype', 'HP:0008200', (18, 22))	('mutations', 'Var', (132, 141))	('FHH', 'Gene', (33, 36))	('loss of function', 'NegReg', (79, 95))	('CaSR', 'Gene', (127, 131))	('PHPT', 'Disease', (18, 22))	('FHH', 'Gene', '846', (33, 36))
27646	27647839	Indeed, the homozygous CaSR mutations, present in these patients, have been associated with milder alterations in Ca2+i signalling than homozygous mutations leading to NSHPT.	('patients', 'Species', '9606', (56, 64))	('signalling', 'biological_process', 'GO:0023052', ('120', '130'))	('NSHPT', 'Gene', '846', (168, 173))	('NSHPT', 'Gene', (168, 173))	('Ca2', 'Gene', (114, 117))	('CaSR', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))	('Ca2', 'Gene', '760', (114, 117))
27647	27647839	An analysis of CaSR mutations identified in patients with PHPT or severe FHH that presented after infancy has indicated that CaSR mutations located in the receptor ECD are associated with more severe hypercalcaemia.	('hypercalcaemia', 'Disease', (200, 214))	('FHH', 'Gene', (73, 76))	('severe hypercalcaemia', 'Phenotype', 'HP:0005897', (193, 214))	('CaSR', 'Gene', (125, 129))	('patients', 'Species', '9606', (44, 52))	('associated with', 'Reg', (172, 187))	('hypercalcaemia', 'Phenotype', 'HP:0003072', (200, 214))	('mutations', 'Var', (130, 139))	('FHH', 'Gene', '846', (73, 76))	('hypercalcaemia', 'Disease', 'MESH:D006934', (200, 214))	('PHPT', 'Phenotype', 'HP:0008200', (58, 62))
27651	27647839	ADH comprises two genetically distinct disorders, designated as ADH types 1 and 2 (Table 1), which are caused by germline gain-of-function mutations of the CaSR and Galpha11 proteins, respectively.	('ADH', 'Gene', '127', (64, 67))	('ADH', 'molecular_function', 'GO:0047636', ('64', '67'))	('ADH', 'Gene', '127', (0, 3))	('mutations', 'Var', (139, 148))	('ADH', 'Gene', (64, 67))	('ADH', 'molecular_function', 'GO:0004022', ('64', '67'))	('CaSR', 'Gene', (156, 160))	('gain-of-function', 'PosReg', (122, 138))	('ADH', 'molecular_function', 'GO:0004022', ('0', '3'))	('ADH', 'Gene', (0, 3))	('Galpha11', 'Gene', (165, 173))	('proteins', 'Protein', (174, 182))	('ADH', 'molecular_function', 'GO:0047636', ('0', '3'))
27657	27647839	Patients with severe gain-of-function CaSR mutations may also have Bartter syndrome type 5, which is characterised by hypokalaemic alkalosis, renal salt wasting and hyperreninaemic hyperaldosteronism.	('hypokalaemic alkalosis', 'Disease', 'MESH:D000471', (118, 140))	('alkalosis', 'Phenotype', 'HP:0001948', (131, 140))	('hyperreninaemic hyperaldosteronism', 'Disease', (165, 199))	('renal salt wasting', 'Phenotype', 'HP:0000127', (142, 160))	('gain-of-function', 'PosReg', (21, 37))	('mutations', 'Var', (43, 52))	('Bartter syndrome', 'Disease', 'MESH:D001477', (67, 83))	('Patients', 'Species', '9606', (0, 8))	('Bartter syndrome', 'Disease', (67, 83))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (181, 199))	('hyperreninaemic hyperaldosteronism', 'Phenotype', 'HP:0011741', (165, 199))	('hypokalaemic alkalosis', 'Phenotype', 'HP:0001949', (118, 140))	('hypokalaemic alkalosis', 'Disease', (118, 140))	('CaSR', 'Gene', (38, 42))	('hyperreninaemic hyperaldosteronism', 'Disease', 'MESH:D003480', (165, 199))
27658	27647839	Mutational analysis is commonly required for the diagnosis of ADH, and >70 different CaSR mutations have been identified to date in individuals affected with ADH1.	('ADH', 'molecular_function', 'GO:0047636', ('158', '161'))	('mutations', 'Var', (90, 99))	('ADH', 'molecular_function', 'GO:0004022', ('62', '65'))	('ADH', 'Gene', (158, 161))	('identified', 'Reg', (110, 120))	('ADH', 'Gene', '127', (62, 65))	('ADH', 'molecular_function', 'GO:0047636', ('62', '65'))	('ADH', 'molecular_function', 'GO:0004022', ('158', '161'))	('ADH', 'Gene', (62, 65))	('CaSR', 'Gene', (85, 89))	('ADH', 'Gene', '127', (158, 161))
27659	27647839	Mutations affecting this extracellular peptide loop may lead to a gain of function by promoting conformational changes such as dimer rotation that facilitates receptor activation.	('dimer rotation', 'Disease', (127, 141))	('facilitates', 'PosReg', (147, 158))	('extracellular', 'cellular_component', 'GO:0005576', ('25', '38'))	('promoting', 'PosReg', (86, 95))	('receptor', 'MPA', (159, 167))	('Mutations', 'Var', (0, 9))	('conformational changes', 'MPA', (96, 118))	('activation', 'PosReg', (168, 178))	('dimer rotation', 'Disease', 'MESH:D009069', (127, 141))
27660	27647839	A second hotspot for ADH1-associated mutations is located in a region that encompasses transmembrane domains 6 and 7, and the intervening third extracellular loop of the CaSR (residues 819-837) (Fig.	('transmembrane', 'cellular_component', 'GO:0044214', ('87', '100'))	('ADH', 'Gene', '127', (21, 24))	('transmembrane', 'cellular_component', 'GO:0016021', ('87', '100'))	('ADH', 'molecular_function', 'GO:0047636', ('21', '24'))	('extracellular', 'cellular_component', 'GO:0005576', ('144', '157'))	('ADH', 'Gene', (21, 24))	('ADH', 'molecular_function', 'GO:0004022', ('21', '24'))	('mutations', 'Var', (37, 46))
27662	27647839	Cellular studies have demonstrated that most ADH1-causing CaSR mutations cause a signalling bias by coupling more strongly to Ca2+i mobilisation than to the MAPK pathway, which contrasts with FHH1-causing CaSR mutations, which are biased towards MAPK signalling.	('mutations', 'Var', (63, 72))	('Ca2', 'Gene', (126, 129))	('ADH', 'molecular_function', 'GO:0047636', ('45', '48'))	('CaSR', 'Gene', (58, 62))	('FHH', 'Gene', '846', (192, 195))	('MAPK', 'molecular_function', 'GO:0004707', ('157', '161'))	('ADH', 'Gene', '127', (45, 48))	('MAPK signalling', 'biological_process', 'GO:0000165', ('246', '261'))	('MAPK', 'molecular_function', 'GO:0004707', ('246', '250'))	('ADH', 'Gene', (45, 48))	('FHH', 'Gene', (192, 195))	('signalling bias', 'MPA', (81, 96))	('Ca2', 'Gene', '760', (126, 129))	('signalling', 'biological_process', 'GO:0023052', ('81', '91'))	('ADH', 'molecular_function', 'GO:0004022', ('45', '48'))	('MAPK pathway', 'Pathway', (157, 169))	('coupling', 'MPA', (100, 108))
27667	27647839	Cinacalcet has also been successfully used to manage life-threatening hypercalcaemia in NSHPT probands harbouring a heterozygous CaSR mutation, Arg185Gln.	('Arg185Gln', 'SUBSTITUTION', 'None', (144, 153))	('Arg185Gln', 'Var', (144, 153))	('hypercalcaemia', 'Phenotype', 'HP:0003072', (70, 84))	('Cinacalcet', 'Chemical', 'MESH:D000069449', (0, 10))	('NSHPT', 'Gene', '846', (88, 93))	('hypercalcaemia', 'Disease', 'MESH:D006934', (70, 84))	('hypercalcaemia', 'Disease', (70, 84))	('NSHPT', 'Gene', (88, 93))
27668	27647839	However, it is ineffective for NSHPT caused by biallelic deletional CaSR mutations.	('biallelic deletional', 'Var', (47, 67))	('NSHPT', 'Gene', '846', (31, 36))	('CaSR', 'Gene', (68, 72))	('NSHPT', 'Gene', (31, 36))
27675	27647839	In vitro studies have shown that NPS-2143, a long-acting calcilytic, corrects the gain of function associated with ADH-causing CaSR mutations.	('ADH', 'molecular_function', 'GO:0047636', ('115', '118'))	('NPS-2143', 'Var', (33, 41))	('gain of function', 'PosReg', (82, 98))	('mutations', 'Var', (132, 141))	('ADH', 'molecular_function', 'GO:0004022', ('115', '118'))	('CaSR', 'Disease', (127, 131))	('ADH', 'Gene', '127', (115, 118))	('ADH', 'Gene', (115, 118))
27676	27647839	However, the in vitro efficacy of NPS-2143 was reduced by mutations affecting NPS-2143-binding residues within the TMD.	('TMD', 'Disease', (115, 118))	('mutations', 'Var', (58, 67))	('binding', 'molecular_function', 'GO:0005488', ('87', '94'))	('NPS-2143-binding', 'Interaction', (78, 94))	('TMD', 'Disease', 'MESH:D049310', (115, 118))	('NPS-2143-binding', 'Gene', (78, 94))	('reduced', 'NegReg', (47, 54))
27677	27647839	In contrast, the quinazolinone calcilytic drugs (ATF936 and AXT914) have been demonstrated to rectify the excessive signalling responses of all ADH mutants evaluated to date, including those mutations leading to constitutive activation and/or Bartter syndrome type 5.	('leading to', 'Reg', (201, 211))	('constitutive activation', 'Disease', (212, 235))	('mutants', 'Var', (148, 155))	('ADH', 'Gene', '127', (144, 147))	('mutations', 'Var', (191, 200))	('signalling', 'biological_process', 'GO:0023052', ('116', '126'))	('ADH', 'molecular_function', 'GO:0047636', ('144', '147'))	('excessive signalling responses', 'MPA', (106, 136))	('ADH', 'Gene', (144, 147))	('quinazolinone', 'Chemical', 'MESH:D052999', (17, 30))	('ADH', 'molecular_function', 'GO:0004022', ('144', '147'))	('Bartter syndrome', 'Disease', 'MESH:D001477', (243, 259))	('Bartter syndrome', 'Disease', (243, 259))
27678	27647839	To assess whether calcilytics may ameliorate the hypocalcaemia associated with ADH1, these drugs have been administered to mouse models harbouring germline gain-of-function CaSR mutations.	('ADH', 'molecular_function', 'GO:0004022', ('79', '82'))	('gain-of-function', 'PosReg', (156, 172))	('hypocalcaemia', 'Disease', (49, 62))	('mouse', 'Species', '10090', (123, 128))	('ADH', 'Gene', '127', (79, 82))	('ADH', 'Gene', (79, 82))	('CaSR', 'Gene', (173, 177))	('ADH', 'molecular_function', 'GO:0047636', ('79', '82'))	('mutations', 'Var', (178, 187))	('hypocalcaemia', 'Disease', 'None', (49, 62))	('hypocalcaemia', 'Phenotype', 'HP:0002901', (49, 62))
27679	27647839	In a single-dose in vivo study, NPS-2143 was administered to Nuf mice, which have hypocalcaemia, reduced plasma PTH concentrations and ectopic calcification in association with a germline gain of function Casr mutation, Leu723Gln.	('Leu723Gln', 'Var', (220, 229))	('calcification', 'Disease', (143, 156))	('plasma PTH concentrations', 'MPA', (105, 130))	('gain of function', 'PosReg', (188, 204))	('Casr', 'Gene', '12374', (205, 209))	('mice', 'Species', '10090', (65, 69))	('Leu723Gln', 'SUBSTITUTION', 'None', (220, 229))	('hypocalcaemia', 'Disease', (82, 95))	('reduced', 'NegReg', (97, 104))	('Casr', 'Gene', (205, 209))	('calcification', 'Disease', 'MESH:D002114', (143, 156))	('hypocalcaemia', 'Disease', 'None', (82, 95))	('reduced plasma PTH', 'Phenotype', 'HP:0031817', (97, 115))	('hypocalcaemia', 'Phenotype', 'HP:0002901', (82, 95))	('ectopic calcification', 'Phenotype', 'HP:0010766', (135, 156))
27680	27647839	Intraperitoneal injection of NPS-2143 significantly increased plasma calcium and PTH concentrations in heterozygous- and homozygous-affected Nuf mice at 1 h after administration, with values returning to baseline after 4 h. The elevations in plasma calcium induced by NPS-2143 were not associated with any increase in urinary calcium excretion.	('increased plasma calcium', 'Phenotype', 'HP:0003072', (52, 76))	('excretion', 'biological_process', 'GO:0007588', ('334', '343'))	('calcium', 'Chemical', 'MESH:D002118', (249, 256))	('plasma calcium', 'MPA', (242, 256))	('calcium', 'Chemical', 'MESH:D002118', (326, 333))	('NPS-2143', 'Var', (268, 276))	('mice', 'Species', '10090', (145, 149))	('calcium', 'Chemical', 'MESH:D002118', (69, 76))
27681	27647839	Longer-term in vivo studies involving the JTT-305/MK-5442 calcilytic compound have been undertaken in two ADH1 mouse models, which harbour germline Cys129Ser and Ala843Glu gain-of-function CaSR mutations, respectively.	('ADH', 'molecular_function', 'GO:0004022', ('106', '109'))	('CaSR', 'Gene', (189, 193))	('ADH', 'Gene', '127', (106, 109))	('mouse', 'Species', '10090', (111, 116))	('Ser', 'cellular_component', 'GO:0005790', ('154', '157'))	('ADH', 'Gene', (106, 109))	('Ala843Glu', 'SUBSTITUTION', 'None', (162, 171))	('Cys129Ser', 'Var', (148, 157))	('gain-of-function', 'PosReg', (172, 188))	('Cys129Ser', 'SUBSTITUTION', 'None', (148, 157))	('ADH', 'molecular_function', 'GO:0047636', ('106', '109'))	('Ala843Glu', 'Var', (162, 171))
27682	27647839	Administration of JTT-305/MK-5442 by daily oral gavage over a 12-week period led to sustained increases in serum calcium concentrations and a significant reduction in urinary calcium excretion in both ADH1 mouse mutants.	('ADH', 'molecular_function', 'GO:0004022', ('201', '204'))	('JTT-305/MK-5442', 'Var', (18, 33))	('mouse', 'Species', '10090', (206, 211))	('excretion', 'biological_process', 'GO:0007588', ('183', '192'))	('urinary calcium excretion', 'MPA', (167, 192))	('increases', 'PosReg', (94, 103))	('calcium', 'Chemical', 'MESH:D002118', (113, 120))	('ADH', 'Gene', '127', (201, 204))	('reduction', 'NegReg', (154, 163))	('calcium', 'Chemical', 'MESH:D002118', (175, 182))	('ADH', 'molecular_function', 'GO:0047636', ('201', '204'))	('serum calcium concentrations', 'MPA', (107, 135))	('ADH', 'Gene', (201, 204))
27684	27647839	The intravenous administration of NPSP795 significantly increased plasma PTH concentrations and reduced urinary calcium excretion.	('reduced urinary calcium', 'Phenotype', 'HP:0003127', (96, 119))	('increased', 'PosReg', (56, 65))	('excretion', 'biological_process', 'GO:0007588', ('120', '129'))	('calcium', 'Chemical', 'MESH:D002118', (112, 119))	('increased plasma PTH', 'Phenotype', 'HP:0003165', (56, 76))	('urinary calcium excretion', 'MPA', (104, 129))	('plasma PTH concentrations', 'MPA', (66, 91))	('NPSP795', 'Var', (34, 41))	('reduced', 'NegReg', (96, 103))
27686	27647839	The optimal dosing regimen for NPSP795, which is a short-acting calcilytic compound intended to elicit a rapid and transient increase in plasma levels of PTH, remains to be established in ADH1 patients.	('patients', 'Species', '9606', (193, 201))	('ADH', 'Gene', '127', (188, 191))	('ADH', 'molecular_function', 'GO:0004022', ('188', '191'))	('increase', 'PosReg', (125, 133))	('ADH', 'Gene', (188, 191))	('plasma levels', 'MPA', (137, 150))	('ADH', 'molecular_function', 'GO:0047636', ('188', '191'))	('NPSP795', 'Var', (31, 38))
27690	27647839	Loss-of-function Galpha11 mutations give rise to FHH2, whereas germline gain-of-function Galpha11 mutations are associated with ADH2 (Fig.	('ADH2', 'Gene', (128, 132))	('gain-of-function', 'PosReg', (72, 88))	('Loss-of-function', 'NegReg', (0, 16))	('ADH', 'molecular_function', 'GO:0047636', ('128', '131'))	('ADH', 'molecular_function', 'GO:0004022', ('128', '131'))	('FHH', 'Gene', '846', (49, 52))	('ADH2', 'Gene', '127', (128, 132))	('mutations', 'Var', (98, 107))	('mutations', 'Var', (26, 35))	('Galpha11', 'Gene', (89, 97))	('Galpha11', 'Gene', (17, 25))	('FHH', 'Gene', (49, 52))
27691	27647839	4 and Table 1) and somatic gain-of-function Galpha11 mutations cause uveal melanomas.	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('Galpha11', 'Gene', (44, 52))	('mutations', 'Var', (53, 62))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('gain-of-function', 'PosReg', (27, 43))	('uveal melanomas', 'Disease', (69, 84))	('uveal melanomas', 'Phenotype', 'HP:0007716', (69, 84))	('uveal melanomas', 'Disease', 'MESH:C536494', (69, 84))
27695	27647839	Moreover, mouse model studies have demonstrated parathyroid specific ablation of Galpha11, and the related Galphaq protein, to result in marked hypercalcaemia, hyperparathyroidism and parathyroid gland enlargement.	('Galphaq', 'Gene', '14682', (107, 114))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (160, 179))	('mouse', 'Species', '10090', (10, 15))	('parathyroid gland enlargement', 'Phenotype', 'HP:0008208', (184, 213))	('Galpha11', 'Gene', (81, 89))	('Galphaq', 'Gene', (107, 114))	('hypercalcaemia, hyperparathyroidism and parathyroid gland enlargement', 'Disease', 'MESH:D006961', (144, 213))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('ablation', 'Var', (69, 77))	('hypercalcaemia', 'Phenotype', 'HP:0003072', (144, 158))
27696	27647839	DNA sequence analysis of the reported FHH2 kindred revealed a germline heterozygous GNA11 mutation that resulted in an in-frame isoleucine deletion at codon 199 or 200 (Ile199/200del) of the Galpha11 protein.	('resulted in an', 'Reg', (104, 118))	('Galpha11', 'Gene', (191, 199))	('GNA11', 'Gene', '2767', (84, 89))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('isoleucine', 'MPA', (128, 138))	('FHH', 'Gene', '846', (38, 41))	('Ile199/200del', 'Mutation', 'p.199/200del', (169, 182))	('protein', 'cellular_component', 'GO:0003675', ('200', '207'))	('FHH', 'Gene', (38, 41))	('mutation', 'Var', (90, 98))	('GNA11', 'Gene', (84, 89))
27697	27647839	Mutational analysis of the GNA11 gene in additional FHH probands, who did not harbour CASR mutations, has identified heterozygous Leu135Gln and Thr54Met missense mutations in two unrelated probands.	('Leu135Gln', 'SUBSTITUTION', 'None', (130, 139))	('Thr54Met', 'SUBSTITUTION', 'None', (144, 152))	('CASR', 'Gene', '846', (86, 90))	('FHH', 'Gene', '846', (52, 55))	('Leu135Gln', 'Var', (130, 139))	('CASR', 'Gene', (86, 90))	('GNA11', 'Gene', (27, 32))	('GNA11', 'Gene', '2767', (27, 32))	('FHH', 'Gene', (52, 55))	('Thr54Met', 'Var', (144, 152))
27698	27647839	The Thr54Met, Leu135Gln and Ile199/200del Galpha11 mutations are associated with a mild FHH phenotype characterised by serum adjusted calcium concentrations <2.80 mmol/L.	('Ile199/200del', 'Var', (28, 41))	('Thr54Met', 'Var', (4, 12))	('Thr54Met', 'SUBSTITUTION', 'None', (4, 12))	('FHH', 'Gene', (88, 91))	('Ile199/200del', 'Mutation', 'p.199/200del', (28, 41))	('Leu135Gln', 'SUBSTITUTION', 'None', (14, 23))	('calcium', 'Chemical', 'MESH:D002118', (134, 141))	('serum adjusted calcium concentrations', 'MPA', (119, 156))	('associated', 'Reg', (65, 75))	('Galpha11', 'Gene', (42, 50))	('Leu135Gln', 'Var', (14, 23))	('FHH', 'Gene', '846', (88, 91))
27699	27647839	In keeping with these clinical findings, in vitro studies have shown that these FHH2-associated Galpha11 mutations lead to a mild impairment of CaSR signal transduction.	('FHH', 'Gene', (80, 83))	('signal transduction', 'biological_process', 'GO:0007165', ('149', '168'))	('CaSR signal transduction', 'MPA', (144, 168))	('mutations', 'Var', (105, 114))	('Galpha11', 'Gene', (96, 104))	('FHH', 'Gene', '846', (80, 83))	('impairment', 'NegReg', (130, 140))
27700	27647839	Indeed, the Thr54Met, Leu135Gln and Ile199/200del FHH2 mutants were associated with around a 30% increase in the half-maximal effective concentration (EC50) of CaSR-expressing cells, whereas CaSR mutations leading to FHH1 generally cause a >50% increase in the EC50 value.	('increase', 'PosReg', (97, 105))	('FHH', 'Gene', (217, 220))	('FHH', 'Gene', (50, 53))	('FHH', 'Gene', '846', (217, 220))	('Thr54Met', 'Var', (12, 20))	('Thr54Met', 'SUBSTITUTION', 'None', (12, 20))	('Ile199/200del', 'Var', (36, 49))	('Leu135Gln', 'Var', (22, 31))	('half-maximal effective concentration', 'MPA', (113, 149))	('Ile199/200del', 'Mutation', 'p.199/200del', (36, 49))	('FHH', 'Gene', '846', (50, 53))	('Leu135Gln', 'SUBSTITUTION', 'None', (22, 31))
27701	27647839	Homology modelling revealed that FHH2-causing mutations are located within key regions of the Galpha11-subunit, which consists of a GTPase domain that binds GDP and GTP and a smaller helical domain that acts as a clasp to secure these bound guanine nucleotides (Fig.	('GDP', 'MPA', (157, 160))	('mutations', 'Var', (46, 55))	('GDP', 'Chemical', 'MESH:D006153', (157, 160))	('binds', 'Interaction', (151, 156))	('FHH', 'Gene', (33, 36))	('GTP', 'Chemical', 'MESH:D006160', (165, 168))	('guanine nucleotides', 'Chemical', 'MESH:D006150', (241, 260))	('GTP', 'Chemical', 'MESH:D006160', (132, 135))	('GTP', 'MPA', (165, 168))	('FHH', 'Gene', '846', (33, 36))
27702	27647839	Thus, the Ile199/200del mutation is located within the GTPase domain and predicted to disrupt a hairpin loop, which comprises part of the Galpha-GPCR interface and is also situated between flexible 'switch' regions (Fig.	('Ile199/200del', 'Mutation', 'p.199/200del', (10, 23))	('hairpin loop', 'MPA', (96, 108))	('GPCR', 'Gene', '151', (145, 149))	('GTP', 'Chemical', 'MESH:D006160', (55, 58))	('Galpha', 'Gene', '8802', (138, 144))	('Galpha', 'Gene', (138, 144))	('disrupt', 'Reg', (86, 93))	('Ile199/200del', 'Var', (10, 23))	('GPCR', 'Gene', (145, 149))
27707	27647839	Thus, the identification of these FHH2-causing Galpha11 mutations has revealed residues critical for Galpha11-subunit function.	('mutations', 'Var', (56, 65))	('Galpha11', 'Gene', (47, 55))	('FHH', 'Gene', '846', (34, 37))	('FHH', 'Gene', (34, 37))
27708	27647839	After the identification of loss-of-function Galpha11 mutations leading to FHH2, it was hypothesised that gain-of-function germline Galpha11 mutations may have opposite effects on Ca2+o homeostasis and give rise to a disorder with an ADH-like phenotype.	('Ca2', 'Gene', '760', (180, 183))	('Galpha11', 'Gene', (132, 140))	('FHH', 'Gene', (75, 78))	('mutations', 'Var', (141, 150))	('ADH', 'Gene', '127', (234, 237))	('ADH', 'molecular_function', 'GO:0047636', ('234', '237'))	('give rise to', 'Reg', (202, 214))	('mutations', 'Var', (54, 63))	('loss-of-function', 'NegReg', (28, 44))	('gain-of-function', 'PosReg', (106, 122))	('ADH', 'Gene', (234, 237))	('Ca2', 'Gene', (180, 183))	('ADH', 'molecular_function', 'GO:0004022', ('234', '237'))	('disorder', 'Disease', (217, 225))	('FHH', 'Gene', '846', (75, 78))	('Galpha11', 'Gene', (45, 53))	('homeostasis', 'biological_process', 'GO:0042592', ('186', '197'))
27709	27647839	DNA sequence analysis of eight ADH probands, who did not harbour CaSR mutations, identified germline heterozygous Galpha11 mutations in two individuals.	('Galpha11', 'Gene', (114, 122))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('ADH', 'molecular_function', 'GO:0047636', ('31', '34'))	('ADH', 'Gene', '127', (31, 34))	('ADH', 'Gene', (31, 34))	('ADH', 'molecular_function', 'GO:0004022', ('31', '34'))	('mutations', 'Var', (123, 132))
27710	27647839	In vitro functional studies of these mutations, which comprised Arg181Gln and Phe341Leu Galpha11 missense substitutions, demonstrated cells expressing the mutant Galpha11 proteins to have enhanced sensitivity to Ca2+o, consistent with a gain of function.	('Ca2', 'Gene', (212, 215))	('enhanced', 'PosReg', (188, 196))	('Galpha11', 'Gene', (162, 170))	('Arg181Gln', 'SUBSTITUTION', 'None', (64, 73))	('Galpha11', 'Gene', (88, 96))	('mutant', 'Var', (155, 161))	('missense', 'Var', (97, 105))	('Phe341Leu', 'Var', (78, 87))	('Phe341Leu', 'SUBSTITUTION', 'None', (78, 87))	('Ca2', 'Gene', '760', (212, 215))	('Arg181Gln', 'Var', (64, 73))	('proteins', 'Protein', (171, 179))
27712	27647839	DNA sequence analysis revealed the occurrence of germline heterozygous Galpha11 mutations, Arg60Cys and Ser211Trp.	('Arg60Cys', 'Var', (91, 99))	('mutations', 'Var', (80, 89))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('Arg60Cys', 'SUBSTITUTION', 'None', (91, 99))	('Galpha11', 'Gene', (71, 79))	('Ser', 'cellular_component', 'GO:0005790', ('104', '107'))	('Ser211Trp', 'SUBSTITUTION', 'None', (104, 113))	('Ser211Trp', 'Var', (104, 113))
27713	27647839	Moreover, heterozygous Arg60Leu and Val340Met Galpha11 mutations have been identified by whole-exome sequencing in additional ADH kindreds, and these mutations were demonstrated to lead to enhanced CaSR-mediated signal transduction.	('Val340Met', 'SUBSTITUTION', 'None', (36, 45))	('ADH', 'molecular_function', 'GO:0047636', ('126', '129'))	('Galpha11', 'Gene', (46, 54))	('Arg60Leu', 'SUBSTITUTION', 'None', (23, 31))	('ADH', 'Gene', '127', (126, 129))	('ADH', 'molecular_function', 'GO:0004022', ('126', '129'))	('enhanced', 'PosReg', (189, 197))	('signal transduction', 'biological_process', 'GO:0007165', ('212', '231'))	('CaSR-mediated signal transduction', 'MPA', (198, 231))	('Val340Met', 'Var', (36, 45))	('ADH', 'Gene', (126, 129))	('Arg60Leu', 'Var', (23, 31))
27714	27647839	These individuals and families with gain-of-function Galpha11 mutations, who were designated as having ADH2 (OMIM #615361) (Table 1), generally had serum-adjusted calcium concentrations ranging 1.75-2.15 mmol/L.	('gain-of-function', 'PosReg', (36, 52))	('calcium', 'Chemical', 'MESH:D002118', (163, 170))	('ADH2', 'Gene', '127', (103, 107))	('ADH', 'molecular_function', 'GO:0047636', ('103', '106'))	('Galpha11', 'Gene', (53, 61))	('serum-adjusted calcium concentrations', 'MPA', (148, 185))	('ADH', 'molecular_function', 'GO:0004022', ('103', '106'))	('ADH2', 'Gene', (103, 107))	('mutations', 'Var', (62, 71))
27717	27647839	Furthermore, patients with germline gain-of-function Galpha11 mutations, in contrast to patients with gain-of-function CaSR mutations, harbour non-calcitropic phenotypes.	('gain-of-function', 'PosReg', (36, 52))	('patients', 'Species', '9606', (88, 96))	('patients', 'Species', '9606', (13, 21))	('Galpha11', 'Gene', (53, 61))	('mutations', 'Var', (62, 71))
27718	27647839	For example, studies of the kindred with the Arg60Leu Galpha11 mutation showed this to be associated with impaired post-natal growth, and the affected adults were significantly shorter than unaffected adult family members (height >2SD below mean of unaffected individuals).	('Arg60Leu', 'Var', (45, 53))	('Galpha11', 'Gene', (54, 62))	('impaired', 'NegReg', (106, 114))	('shorter', 'NegReg', (177, 184))	('post-natal growth', 'CPA', (115, 132))	('Arg60Leu', 'SUBSTITUTION', 'None', (45, 53))
27719	27647839	In addition, some affected members of the kindred with the Val340Met Galpha11 mutation were found to have keratoconus, a corneal disorder.	('corneal disorder', 'Phenotype', 'HP:0000481', (121, 137))	('Val340Met', 'SUBSTITUTION', 'None', (59, 68))	('keratoconus', 'Disease', (106, 117))	('keratoconus', 'Phenotype', 'HP:0000563', (106, 117))	('Val340Met', 'Var', (59, 68))	('Galpha11', 'Gene', (69, 77))	('corneal disorder', 'Disease', (121, 137))	('corneal disorder', 'Disease', 'MESH:D003316', (121, 137))
27720	27647839	In contrast to germline gain-of-function Galpha11 mutations, which affect Ca2+o homeostasis, somatic gain-of-function Galpha11 mutations are reported to cause uveal melanoma, a primary intraocular tumour, by inducing constitutive upregulation of proliferative signalling involving extracellular signal-regulated kinases 1 and 2 (ERK1/2), which are components of the MAPK signalling pathway.	('ERK1/2', 'Gene', '5595;5594', (329, 335))	('homeostasis', 'biological_process', 'GO:0042592', ('80', '91'))	('Ca2', 'Gene', '760', (74, 77))	('upregulation', 'PosReg', (230, 242))	('MAPK signalling', 'biological_process', 'GO:0000165', ('366', '381'))	('gain-of-function', 'PosReg', (101, 117))	('extracellular signal-regulated kinases 1 and 2', 'Gene', '5594', (281, 327))	('MAPK', 'molecular_function', 'GO:0004707', ('366', '370'))	('inducing', 'PosReg', (208, 216))	('proliferative signalling', 'MPA', (246, 270))	('intraocular tumour', 'Disease', (185, 203))	('Ca2', 'Gene', (74, 77))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('mutations', 'Var', (127, 136))	('Galpha11', 'Gene', (118, 126))	('uveal melanoma', 'Disease', 'MESH:C536494', (159, 173))	('intraocular tumour', 'Disease', 'MESH:D064090', (185, 203))	('uveal melanoma', 'Disease', (159, 173))	('cause', 'Reg', (153, 158))	('ERK1', 'molecular_function', 'GO:0004707', ('329', '333'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (159, 173))	('extracellular', 'cellular_component', 'GO:0005576', ('281', '294'))	('signalling pathway', 'biological_process', 'GO:0007165', ('371', '389'))	('signalling', 'biological_process', 'GO:0023052', ('260', '270'))	('ERK1/2', 'Gene', (329, 335))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))
27721	27647839	However, in vitro studies have shown that the ADH-causing Galpha11 mutations do not have such oncogenic potential, and that these ADH-causing germline mutants phosphorylated ERK1/2 only in the presence of Ca2+o, and were thus not constitutively activating.	('ADH', 'Gene', (46, 49))	('Ca2', 'Gene', '760', (205, 208))	('ADH', 'molecular_function', 'GO:0004022', ('46', '49'))	('ADH', 'Gene', '127', (130, 133))	('ADH', 'molecular_function', 'GO:0004022', ('130', '133'))	('ADH', 'Gene', (130, 133))	('mutations', 'Var', (67, 76))	('Ca2', 'Gene', (205, 208))	('ERK1/2', 'Gene', '5595;5594', (174, 180))	('ERK1', 'molecular_function', 'GO:0004707', ('174', '178'))	('ADH', 'molecular_function', 'GO:0047636', ('46', '49'))	('ADH', 'Gene', '127', (46, 49))	('Galpha11', 'Gene', (58, 66))	('ADH', 'molecular_function', 'GO:0047636', ('130', '133'))	('ERK1/2', 'Gene', (174, 180))
27722	27647839	Thus, the milder disturbance of signalling associated with the ADH2 mutants may provide an explanation for their occurrence as a post-natal phenotype that can be transmitted as an autosomal dominant disorder, in contrast to the uveal melanoma-associated constitutively activating G-protein mutation, Gln209Leu, which has been shown to be cytotoxic when expressed at high levels and is likely to be embryonically lethal if present within the germline.	('embryonic', 'Disease', (398, 407))	('protein', 'cellular_component', 'GO:0003675', ('282', '289'))	('ADH2', 'Gene', '127', (63, 67))	('signalling', 'biological_process', 'GO:0023052', ('32', '42'))	('Gln209Leu', 'Mutation', 'p.Q209L', (300, 309))	('uveal melanoma', 'Disease', 'MESH:C536494', (228, 242))	('autosomal dominant disorder', 'Disease', (180, 207))	('uveal melanoma', 'Phenotype', 'HP:0007716', (228, 242))	('uveal melanoma', 'Disease', (228, 242))	('embryonic', 'Disease', 'MESH:D009373', (398, 407))	('ADH', 'molecular_function', 'GO:0047636', ('63', '66'))	('ADH', 'molecular_function', 'GO:0004022', ('63', '66'))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('ADH2', 'Gene', (63, 67))	('mutants', 'Var', (68, 75))	('Gln209Leu', 'Var', (300, 309))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (180, 207))
27723	27647839	An analysis of the location of ADH2-causing mutations revealed that mutated Arg60 and Arg181 residues are situated adjacent to the linker 1 and linker 2 peptides, respectively.	('Arg181', 'Chemical', '-', (86, 92))	('Arg60', 'Chemical', '-', (76, 81))	('Arg60', 'Var', (76, 81))	('ADH2', 'Gene', '127', (31, 35))	('ADH', 'molecular_function', 'GO:0047636', ('31', '34'))	('Arg181 residues', 'Var', (86, 101))	('ADH2', 'Gene', (31, 35))	('ADH', 'molecular_function', 'GO:0004022', ('31', '34'))	('mutated Arg60', 'Var', (68, 81))
27725	27647839	Thus, mutations affecting the Arg60 and Arg181 residues may lead to the opening of the Galpha11 clamshell and induce G protein activation by promoting the exchange of GDP for GTP.	('GTP', 'Chemical', 'MESH:D006160', (175, 178))	('GDP', 'Chemical', 'MESH:D006153', (167, 170))	('Galpha11 clamshell', 'Protein', (87, 105))	('lead to', 'Reg', (60, 67))	('promoting', 'PosReg', (141, 150))	('Arg181', 'Var', (40, 46))	('exchange', 'MPA', (155, 163))	('Arg60', 'Chemical', '-', (30, 35))	('GDP for GTP', 'MPA', (167, 178))	('Arg181', 'Chemical', '-', (40, 46))	('induce', 'PosReg', (110, 116))	('Arg60', 'Var', (30, 35))	('opening', 'MPA', (72, 79))	('activation', 'PosReg', (127, 137))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('mutations', 'Var', (6, 15))	('G protein', 'Protein', (117, 126))
27726	27647839	The ADH2-causing Ser211Trp mutation is located within the region of Galpha11, which binds to the Gbetagamma heterodimer, and this mutation may promote the dissociation of the Galpha11 subunit, thus enhancing CaSR-mediated signal transduction.	('ADH2', 'Gene', '127', (4, 8))	('CaSR-mediated signal transduction', 'MPA', (208, 241))	('Ser', 'cellular_component', 'GO:0005790', ('17', '20'))	('promote', 'PosReg', (143, 150))	('ADH', 'molecular_function', 'GO:0047636', ('4', '7'))	('signal transduction', 'biological_process', 'GO:0007165', ('222', '241'))	('Ser211Trp', 'SUBSTITUTION', 'None', (17, 26))	('Galpha11 subunit', 'Protein', (175, 191))	('ADH2', 'Gene', (4, 8))	('Ser211Trp', 'Var', (17, 26))	('enhancing', 'PosReg', (198, 207))	('ADH', 'molecular_function', 'GO:0004022', ('4', '7'))	('dissociation', 'MPA', (155, 167))
27727	27647839	The mutated Phe341 residue is located at the C-terminus of the Galpha-subunit (Fig.	('Phe341', 'Chemical', '-', (12, 18))	('Phe341', 'Var', (12, 18))	('mutated Phe341', 'Var', (4, 18))
27728	27647839	4) and forms a part of the cluster of phenylalanine residues, which likely stabilises GTP in a conformation required for its hydrolysis, and the ADH2-causing Phe341Leu mutation is thus predicted to activate Galpha11 by impairing the hydrolysis of GTP to GDP.	('impairing', 'NegReg', (219, 228))	('ADH2', 'Gene', (145, 149))	('phenylalanine', 'Chemical', 'MESH:D010649', (38, 51))	('Galpha11', 'Gene', (207, 215))	('hydrolysis of GTP to GDP', 'MPA', (233, 257))	('Phe341Leu', 'SUBSTITUTION', 'None', (158, 167))	('GTP', 'Chemical', 'MESH:D006160', (247, 250))	('GTP', 'Chemical', 'MESH:D006160', (86, 89))	('ADH', 'molecular_function', 'GO:0004022', ('145', '148'))	('GDP', 'Chemical', 'MESH:D006153', (254, 257))	('ADH2', 'Gene', '127', (145, 149))	('activate', 'PosReg', (198, 206))	('ADH', 'molecular_function', 'GO:0047636', ('145', '148'))	('Phe341Leu', 'Var', (158, 167))
27729	27647839	In contrast to these predicted effects of the Phe341Leu mutation, the neighbouring Val340 residue is not involved in GDP/GTP exchange, but instead may influence the stability of Galpha-GPCR interactions.	('stability', 'MPA', (165, 174))	('Val340', 'Chemical', '-', (83, 89))	('Galpha', 'Gene', '8802', (178, 184))	('Galpha', 'Gene', (178, 184))	('Phe341Leu', 'Var', (46, 55))	('Phe341Leu', 'SUBSTITUTION', 'None', (46, 55))	('Val340', 'Var', (83, 89))	('GDP', 'Chemical', 'MESH:D006153', (117, 120))	('GTP', 'Chemical', 'MESH:D006160', (121, 124))	('GPCR', 'Gene', (185, 189))	('influence', 'Reg', (151, 160))	('GPCR', 'Gene', '151', (185, 189))
27730	27647839	Although calcimimetic and calcilytic compounds represented targeted therapies for patients with CaSR mutations resulting in symptomatic forms of FHH1 and ADH1, it was unclear if these CaSR allosteric modulators may rectify abnormalities of the downstream Galpha11 protein, and thus, have potential benefit for FHH2 and ADH2 patients.	('ADH2', 'Gene', '127', (319, 323))	('ADH', 'Gene', (319, 322))	('rectify', 'Reg', (215, 222))	('CaSR', 'Gene', (96, 100))	('patients', 'Species', '9606', (324, 332))	('ADH', 'molecular_function', 'GO:0047636', ('319', '322'))	('FHH', 'Gene', (310, 313))	('resulting in', 'Reg', (111, 123))	('ADH2', 'Gene', (319, 323))	('FHH', 'Gene', '846', (310, 313))	('ADH', 'molecular_function', 'GO:0004022', ('154', '157'))	('mutations', 'Var', (101, 110))	('patients', 'Species', '9606', (82, 90))	('abnormalities', 'MPA', (223, 236))	('FHH', 'Gene', (145, 148))	('ADH', 'Gene', '127', (154, 157))	('ADH', 'Gene', (154, 157))	('protein', 'cellular_component', 'GO:0003675', ('264', '271'))	('ADH', 'molecular_function', 'GO:0004022', ('319', '322'))	('FHH', 'Gene', '846', (145, 148))	('Galpha11 protein', 'Protein', (255, 271))	('ADH', 'molecular_function', 'GO:0047636', ('154', '157'))	('ADH', 'Gene', '127', (319, 322))
27731	27647839	Recent in vitro studies have revealed cinacalcet and NPS-2143 to correct the loss and gain of function associated with Galpha11 mutations leading to FHH2 and ADH2, respectively.	('ADH', 'molecular_function', 'GO:0047636', ('158', '161'))	('ADH2', 'Gene', '127', (158, 162))	('mutations', 'Var', (128, 137))	('ADH', 'molecular_function', 'GO:0004022', ('158', '161'))	('Galpha11', 'Gene', (119, 127))	('FHH', 'Gene', '846', (149, 152))	('ADH2', 'Gene', (158, 162))	('gain of function', 'PosReg', (86, 102))	('FHH', 'Gene', (149, 152))	('cinacalcet', 'Chemical', 'MESH:D000069449', (38, 48))
27732	27647839	Indeed, siRNA knockdown studies showed that these CaSR allosteric modulators directly influence signalling mediated by the FHH2 and ADH2 mutant Galpha11 proteins rather than by exerting indirect effects on endogenously expressed wild-type Galpha11 proteins.	('FHH', 'Gene', '846', (123, 126))	('signalling', 'MPA', (96, 106))	('influence', 'Reg', (86, 95))	('ADH2', 'Gene', '127', (132, 136))	('FHH', 'Gene', (123, 126))	('ADH', 'molecular_function', 'GO:0004022', ('132', '135'))	('proteins', 'Protein', (153, 161))	('Galpha11', 'Gene', (144, 152))	('ADH2', 'Gene', (132, 136))	('mutant', 'Var', (137, 143))	('signalling', 'biological_process', 'GO:0023052', ('96', '106'))	('ADH', 'molecular_function', 'GO:0047636', ('132', '135'))
27733	27647839	However, some Galpha11 mutations (Ile199/200del and Phe341Leu) showed diminished sensitivity to cinacalcet and NPS-2143 and these differences in the sensitivities of the mutants to CaSR-targeted drugs may be explained by an analysis of the crystal structure of the G protein alpha-s (Galphas) complexed with the beta2-adrenergic receptor.	('Phe341Leu', 'Var', (52, 61))	('Phe341Leu', 'SUBSTITUTION', 'None', (52, 61))	('Ile199/200del', 'Mutation', 'p.199/200del', (34, 47))	('cinacalcet', 'Chemical', 'MESH:D000069449', (96, 106))	('Galphas', 'Chemical', '-', (284, 291))	('Ile199/200del', 'Var', (34, 47))	('beta2-adrenergic receptor', 'Gene', (312, 337))	('beta2-adrenergic receptor', 'Gene', '154', (312, 337))	('diminished', 'NegReg', (70, 80))	('protein', 'cellular_component', 'GO:0003675', ('267', '274'))	('sensitivity', 'MPA', (81, 92))	('Galpha11', 'Gene', (14, 22))
27734	27647839	The analysis showed that residues homologous to Ile199 and Phe341, in the related Galphas protein, are located within a hydrophobic pocket at the interface between GPCR and Galpha-subunit (Fig.	('Phe341', 'Chemical', '-', (59, 65))	('Galpha', 'Gene', '8802', (82, 88))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('Galpha', 'Gene', (82, 88))	('Ile199', 'Chemical', '-', (48, 54))	('Galphas', 'Chemical', '-', (82, 89))	('GPCR', 'Gene', (164, 168))	('Phe341', 'Var', (59, 65))	('Ile199', 'Var', (48, 54))	('Galpha', 'Gene', (173, 179))	('Galpha', 'Gene', '8802', (173, 179))	('GPCR', 'Gene', '151', (164, 168))
27735	27647839	Thus, Galpha11 mutations located at the GPCR-Galpha interface may potentially influence the efficacy of CaSR allosteric modulators.	('GPCR', 'Gene', (40, 44))	('Galpha11', 'Gene', '2767', (6, 14))	('influence', 'Reg', (78, 87))	('mutations', 'Var', (15, 24))	('Galpha', 'Gene', (45, 51))	('efficacy', 'MPA', (92, 100))	('GPCR', 'Gene', '151', (40, 44))	('Galpha', 'Gene', '8802', (6, 12))	('Galpha', 'Gene', '8802', (45, 51))	('Galpha', 'Gene', (6, 12))	('Galpha11', 'Gene', (6, 14))
27736	27647839	The NPS-2143 calcilytic compound was also shown to rectify the constitutive activation caused by a uveal melanoma-associated Galpha11 mutation, and these findings suggest a potential therapeutic role for calcilytics in the management of this intraocular tumour.	('Galpha11', 'Gene', (125, 133))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('mutation', 'Var', (134, 142))	('intraocular tumour', 'Disease', (242, 260))	('constitutive activation', 'MPA', (63, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('uveal melanoma', 'Disease', 'MESH:C536494', (99, 113))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))	('uveal melanoma', 'Disease', (99, 113))	('intraocular tumour', 'Disease', 'MESH:D064090', (242, 260))
27739	27647839	Whole-exome capture and high-throughput sequence analysis revealed that affected individuals from the unrelated FHHOK and FHHNI kindreds harbour the same heterozygous germline Arg15Cys mutation of the adaptor-related protein complex 2 sigma subunit 1 (AP2S1) gene, which encodes the sigma-subunit of the ubiquitously expressed heterotetrameric AP2 complex.	('FHH', 'Gene', '846', (112, 115))	('AP2S1', 'Gene', '1175', (252, 257))	('FHH', 'Gene', '846', (122, 125))	('adaptor-related protein complex 2', 'Gene', (201, 234))	('Arg15Cys', 'SUBSTITUTION', 'None', (176, 184))	('AP2', 'Gene', '7020', (344, 347))	('AP2', 'Gene', (344, 347))	('mutation', 'Var', (185, 193))	('FHH', 'Gene', (112, 115))	('FHH', 'Gene', (122, 125))	('AP2', 'Gene', '7020', (252, 255))	('AP2', 'Gene', (252, 255))	('protein complex', 'cellular_component', 'GO:0032991', ('217', '232'))	('AP2', 'cellular_component', 'GO:0005908', ('252', '255'))	('adaptor-related protein complex 2', 'Gene', '7020', (201, 234))	('AP2', 'cellular_component', 'GO:0005908', ('344', '347'))	('AP2S1', 'Gene', (252, 257))	('Arg15Cys', 'Var', (176, 184))
27741	27647839	To date, AP2S1 mutations have been reported in >60 FHH3 patients and families.	('patients', 'Species', '9606', (56, 64))	('reported', 'Reg', (35, 43))	('mutations', 'Var', (15, 24))	('AP2S1', 'Gene', '1175', (9, 14))	('FHH', 'Gene', '846', (51, 54))	('AP2S1', 'Gene', (9, 14))	('AP2', 'cellular_component', 'GO:0005908', ('9', '12'))	('FHH', 'Gene', (51, 54))
27742	27647839	All affected individuals harbour a heterozygous missense mutation affecting the Arg15 residue of the encoded AP2sigma-subunit (Fig.	('missense mutation', 'Var', (48, 65))	('AP2', 'cellular_component', 'GO:0005908', ('109', '112'))	('Arg15', 'Chemical', '-', (80, 85))	('AP2', 'Gene', (109, 112))	('AP2', 'Gene', '7020', (109, 112))	('Arg15', 'Var', (80, 85))
27743	27647839	6) and resulting in Arg15Cys, Arg15His or Arg15Leu.	('Arg15Cys', 'SUBSTITUTION', 'None', (20, 28))	('Arg15Leu', 'Var', (42, 50))	('resulting in', 'Reg', (7, 19))	('Arg15Cys', 'Var', (20, 28))	('Arg15Leu', 'SUBSTITUTION', 'None', (42, 50))	('Arg15His', 'SUBSTITUTION', 'None', (30, 38))	('Arg15His', 'Var', (30, 38))
27744	27647839	Crystallography studies have revealed that the Arg15 residue plays a key role in binding to membrane cargo proteins (Fig.	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('Arg15', 'Chemical', '-', (47, 52))	('Arg15 residue', 'Var', (47, 60))	('membrane', 'cellular_component', 'GO:0016020', ('92', '100'))	('binding', 'Interaction', (81, 88))	('cargo', 'molecular_function', 'GO:0140355', ('101', '106'))
27745	27647839	It is predicted that these FHH3-causing Arg15 mutations disrupt an interaction between the AP2 complex and the intracellular carboxyl terminus of the CaSR, thereby impairing endocytosis of this GPCR.	('GPCR', 'Gene', (194, 198))	('mutations', 'Var', (46, 55))	('intracellular', 'cellular_component', 'GO:0005622', ('111', '124'))	('FHH', 'Gene', '846', (27, 30))	('disrupt', 'NegReg', (56, 63))	('Arg15', 'Gene', (40, 45))	('GPCR', 'Gene', '151', (194, 198))	('AP2', 'Gene', '7020', (91, 94))	('AP2', 'Gene', (91, 94))	('interaction', 'Interaction', (67, 78))	('AP2', 'cellular_component', 'GO:0005908', ('91', '94'))	('FHH', 'Gene', (27, 30))	('impairing', 'NegReg', (164, 173))	('endocytosis', 'biological_process', 'GO:0006897', ('174', '185'))	('Arg15', 'Chemical', '-', (40, 45))
27746	27647839	This hypothesis is supported by in vitro expression studies, which have demonstrated that these FHH3-causing AP2sigma mutations alter CaSR cell-surface expression and impair signal transduction in a dominant-negative manner.	('alter', 'Reg', (128, 133))	('cell-surface', 'cellular_component', 'GO:0009986', ('139', '151'))	('signal transduction', 'biological_process', 'GO:0007165', ('174', '193'))	('FHH', 'Gene', '846', (96, 99))	('mutations', 'Var', (118, 127))	('AP2', 'Gene', '7020', (109, 112))	('AP2', 'cellular_component', 'GO:0005908', ('109', '112'))	('FHH', 'Gene', (96, 99))	('AP2', 'Gene', (109, 112))	('CaSR cell-surface expression', 'MPA', (134, 162))	('signal transduction', 'MPA', (174, 193))	('impair', 'NegReg', (167, 173))
27748	27647839	Nucleotide substitutions affecting codon 15 of the AP2S1 gene are predicted to result in the replacement of the wild-type Arg residue with a mutant Cys, Gly, His, Leu, Pro or Ser residue.	('Arg', 'Chemical', 'MESH:D001120', (122, 125))	('Leu', 'Var', (163, 166))	('Ser', 'Chemical', 'MESH:D012694', (175, 178))	('Cys', 'Chemical', 'MESH:D003545', (148, 151))	('mutant Cys', 'Var', (141, 151))	('His', 'Chemical', 'MESH:D006639', (158, 161))	('Cys', 'Var', (148, 151))	('Gly', 'Var', (153, 156))	('Pro', 'MPA', (168, 171))	('Ser', 'MPA', (175, 178))	('AP2S1', 'Gene', (51, 56))	('Leu', 'Chemical', 'MESH:D007930', (163, 166))	('AP2', 'cellular_component', 'GO:0005908', ('51', '54'))	('Pro', 'Chemical', 'MESH:D011392', (168, 171))	('Ser', 'cellular_component', 'GO:0005790', ('175', '178'))	('AP2S1', 'Gene', '1175', (51, 56))	('Nucleotide substitutions', 'Var', (0, 24))	('Gly', 'Chemical', 'MESH:D005998', (153, 156))
27749	27647839	All of these potential missense AP2sigma substitutions have been demonstrated to diminish CaSR signal transduction in vitro.	('signal transduction', 'biological_process', 'GO:0007165', ('95', '114'))	('AP2', 'cellular_component', 'GO:0005908', ('32', '35'))	('AP2', 'Gene', '7020', (32, 35))	('AP2', 'Gene', (32, 35))	('diminish', 'NegReg', (81, 89))	('CaSR signal transduction', 'MPA', (90, 114))	('substitutions', 'Var', (41, 54))	('missense', 'Var', (23, 31))
27750	27647839	However, to date, only Arg15Cys, Arg15His and Arg15Leu AP2sigma mutations have been observed in FHH3 patients (Fig.	('patients', 'Species', '9606', (101, 109))	('Arg15Leu', 'SUBSTITUTION', 'None', (46, 54))	('AP2', 'Gene', '7020', (55, 58))	('AP2', 'Gene', (55, 58))	('FHH', 'Gene', '846', (96, 99))	('Arg15Cys', 'Var', (23, 31))	('AP2', 'cellular_component', 'GO:0005908', ('55', '58'))	('Arg15His', 'Var', (33, 41))	('Arg15Leu', 'Var', (46, 54))	('Arg15His', 'SUBSTITUTION', 'None', (33, 41))	('FHH', 'Gene', (96, 99))	('Arg15Cys', 'SUBSTITUTION', 'None', (23, 31))
27751	27647839	These studies have shown that the non-observed Arg15Gly, Arg15Pro and Arg15Ser AP2sigma mutants impair cell growth in vitro.	('AP2', 'Gene', '7020', (79, 82))	('Arg15Ser', 'SUBSTITUTION', 'None', (70, 78))	('AP2', 'Gene', (79, 82))	('Ser', 'cellular_component', 'GO:0005790', ('75', '78'))	('AP2', 'cellular_component', 'GO:0005908', ('79', '82'))	('impair', 'NegReg', (96, 102))	('cell growth', 'biological_process', 'GO:0016049', ('103', '114'))	('cell growth in vitro', 'CPA', (103, 123))	('Arg15Gly', 'SUBSTITUTION', 'None', (47, 55))	('Arg15Gly', 'Var', (47, 55))	('Arg15Ser', 'Var', (70, 78))	('Arg15Pro', 'SUBSTITUTION', 'None', (57, 65))	('Arg15Pro', 'Var', (57, 65))
27752	27647839	Thus, a possible explanation for the absence of the Arg15Gly, Arg15Pro and Arg15Ser AP2sigma mutations in patients is that these deleterious mutations are embryonically lethal, whereas the FHH3-causing AP2sigma mutations (Arg15Cys, Arg15His and Arg15Leu) are tolerated and compatible with embryonic and post-natal survival.	('AP2', 'Gene', (202, 205))	('AP2', 'Gene', '7020', (202, 205))	('AP2', 'cellular_component', 'GO:0005908', ('202', '205'))	('Arg15Ser', 'SUBSTITUTION', 'None', (75, 83))	('AP2', 'cellular_component', 'GO:0005908', ('84', '87'))	('Arg15Leu', 'Var', (245, 253))	('Arg15Pro', 'Var', (62, 70))	('Arg15Gly', 'Var', (52, 60))	('Arg15Ser', 'Var', (75, 83))	('Arg15His', 'Var', (232, 240))	('FHH', 'Gene', (189, 192))	('embryonic', 'Disease', 'MESH:D009373', (155, 164))	('Arg15Cys', 'SUBSTITUTION', 'None', (222, 230))	('Ser', 'cellular_component', 'GO:0005790', ('80', '83'))	('embryonic', 'Disease', (155, 164))	('mutations', 'Var', (93, 102))	('FHH', 'Gene', '846', (189, 192))	('Arg15Pro', 'SUBSTITUTION', 'None', (62, 70))	('patients', 'Species', '9606', (106, 114))	('embryonic', 'Disease', 'MESH:D009373', (289, 298))	('Arg15Leu', 'SUBSTITUTION', 'None', (245, 253))	('Arg15Cys', 'Var', (222, 230))	('Arg15Gly', 'SUBSTITUTION', 'None', (52, 60))	('embryonic', 'Disease', (289, 298))	('AP2', 'Gene', '7020', (84, 87))	('Arg15His', 'SUBSTITUTION', 'None', (232, 240))	('AP2', 'Gene', (84, 87))
27753	27647839	FHH3 may be associated with symptomatic hypercalcaemia and reduced bone mineral density, and with cognitive deficits and/or behavioural disturbances in children harbouring the Arg15Cys or Arg15Leu AP2sigma mutations.	('reduced', 'NegReg', (59, 66))	('Arg15Cys', 'SUBSTITUTION', 'None', (176, 184))	('FHH', 'Gene', (0, 3))	('AP2', 'cellular_component', 'GO:0005908', ('197', '200'))	('Arg15Leu', 'Var', (188, 196))	('cognitive deficits', 'Phenotype', 'HP:0100543', (98, 116))	('FHH', 'Gene', '846', (0, 3))	('hypercalcaemia', 'Disease', (40, 54))	('children', 'Species', '9606', (152, 160))	('cognitive deficits', 'Disease', 'MESH:D003072', (98, 116))	('Arg15Cys', 'Var', (176, 184))	('hypercalcaemia', 'Phenotype', 'HP:0003072', (40, 54))	('reduced bone mineral density', 'Phenotype', 'HP:0004349', (59, 87))	('cognitive deficits', 'Disease', (98, 116))	('AP2', 'Gene', '7020', (197, 200))	('AP2', 'Gene', (197, 200))	('associated', 'Reg', (12, 22))	('Arg15Leu', 'SUBSTITUTION', 'None', (188, 196))	('hypercalcaemia', 'Disease', 'MESH:D006934', (40, 54))	('behavioural disturbances', 'Phenotype', 'HP:0000708', (124, 148))	('bone mineral density', 'CPA', (67, 87))
27755	27647839	Furthermore, an analysis of adults and children with AP2sigma mutations, by one study, has revealed a genotype-phenotype correlation with Arg15Leu probands having significantly higher serum calcium concentrations and presenting at a younger age, typically in childhood, compared with probands with Arg15Cys or Arg15His mutations.	('serum calcium concentrations', 'MPA', (184, 212))	('higher', 'PosReg', (177, 183))	('AP2', 'cellular_component', 'GO:0005908', ('53', '56'))	('Arg15Cys', 'Var', (298, 306))	('calcium', 'Chemical', 'MESH:D002118', (190, 197))	('Arg15His', 'SUBSTITUTION', 'None', (310, 318))	('Arg15His', 'Var', (310, 318))	('Arg15Leu', 'Var', (138, 146))	('children', 'Species', '9606', (39, 47))	('AP2', 'Gene', (53, 56))	('Arg15Leu', 'SUBSTITUTION', 'None', (138, 146))	('AP2', 'Gene', '7020', (53, 56))	('Arg15Cys', 'SUBSTITUTION', 'None', (298, 306))
27756	27647839	The absence of such a genotype-phenotype correlation in another study, which consisted of mainly adult FHH3 patients, suggests that the more severe hypercalcaemia associated with the Arg15Leu mutation might be age dependent.	('severe hypercalcaemia', 'Phenotype', 'HP:0005897', (141, 162))	('hypercalcaemia', 'Disease', 'MESH:D006934', (148, 162))	('hypercalcaemia', 'Disease', (148, 162))	('FHH', 'Gene', (103, 106))	('Arg15Leu', 'Var', (183, 191))	('FHH', 'Gene', '846', (103, 106))	('hypercalcaemia', 'Phenotype', 'HP:0003072', (148, 162))	('patients', 'Species', '9606', (108, 116))	('Arg15Leu', 'SUBSTITUTION', 'None', (183, 191))
27758	27647839	In vitro studies revealed that this calcimimetic drug rectifies the significantly impaired intracellular calcium and MAPK responses associated with all three FHH3-causing AP2sigma mutations.	('MAPK', 'molecular_function', 'GO:0004707', ('117', '121'))	('FHH', 'Gene', '846', (158, 161))	('mutations', 'Var', (180, 189))	('calcium', 'Chemical', 'MESH:D002118', (105, 112))	('impaired', 'NegReg', (82, 90))	('FHH', 'Gene', (158, 161))	('intracellular', 'cellular_component', 'GO:0005622', ('91', '104'))	('MAPK responses', 'MPA', (117, 131))	('AP2', 'cellular_component', 'GO:0005908', ('171', '174'))	('intracellular calcium', 'MPA', (91, 112))	('AP2', 'Gene', '7020', (171, 174))	('AP2', 'Gene', (171, 174))
27759	27647839	The administration of cinacalcet at a dose of 30-60 mg daily to three symptomatic FHH3 probands, each harbouring an Arg15Cys, Arg15His or Arg15Leu AP2sigma mutation, led to >20% reductions in serum calcium concentrations and improved symptoms in all three FHH probands.	('AP2', 'Gene', '7020', (147, 150))	('AP2', 'Gene', (147, 150))	('FHH', 'Gene', '846', (82, 85))	('Arg15Cys', 'Var', (116, 124))	('Arg15Leu', 'SUBSTITUTION', 'None', (138, 146))	('Arg15His', 'SUBSTITUTION', 'None', (126, 134))	('symptoms', 'MPA', (234, 242))	('reductions', 'NegReg', (178, 188))	('Arg15Leu', 'Var', (138, 146))	('serum calcium concentrations', 'MPA', (192, 220))	('cinacalcet', 'Chemical', 'MESH:D000069449', (22, 32))	('Arg15Cys', 'SUBSTITUTION', 'None', (116, 124))	('Arg15His', 'Var', (126, 134))	('FHH', 'Gene', (256, 259))	('calcium', 'Chemical', 'MESH:D002118', (198, 205))	('FHH', 'Gene', (82, 85))	('AP2', 'cellular_component', 'GO:0005908', ('147', '150'))	('improved', 'PosReg', (225, 233))	('FHH', 'Gene', '846', (256, 259))
27760	27647839	These studies show that cinacalcet-mediated allosteric modulation of the CaSR can rectify the loss-of-function and symptomatic hypercalcaemia that are associated with the three types of FHH3-causing Arg15 AP2sigma mutations.	('FHH', 'Gene', (186, 189))	('hypercalcaemia', 'Phenotype', 'HP:0003072', (127, 141))	('Arg15', 'Chemical', '-', (199, 204))	('AP2', 'cellular_component', 'GO:0005908', ('205', '208'))	('mutations', 'Var', (214, 223))	('AP2', 'Gene', '7020', (205, 208))	('hypercalcaemia', 'Disease', (127, 141))	('AP2', 'Gene', (205, 208))	('hypercalcaemia', 'Disease', 'MESH:D006934', (127, 141))	('FHH', 'Gene', '846', (186, 189))	('loss-of-function', 'NegReg', (94, 110))	('cinacalcet', 'Chemical', 'MESH:D000069449', (24, 34))
27761	27647839	Cinacalcet has also been shown to correct the hypercalcaemia in a patient with chromosome 22q11.2 deletion syndrome who also had an Arg15Leu AP2sigma mutation.	('hypercalcaemia', 'Disease', 'MESH:D006934', (46, 60))	('AP2', 'Gene', '7020', (141, 144))	('AP2', 'Gene', (141, 144))	('Arg15Leu', 'Var', (132, 140))	('hypercalcaemia', 'Disease', (46, 60))	('patient', 'Species', '9606', (66, 73))	('deletion syndrome', 'Var', (98, 115))	('AP2', 'cellular_component', 'GO:0005908', ('141', '144'))	('Cinacalcet', 'Chemical', 'MESH:D000069449', (0, 10))	('hypercalcaemia', 'Phenotype', 'HP:0003072', (46, 60))	('Arg15Leu', 'SUBSTITUTION', 'None', (132, 140))	('chromosome', 'cellular_component', 'GO:0005694', ('79', '89'))
27762	27647839	Germline coding-region mutations of the CASR and GNA11 genes, which enhance CaSR-mediated signal transduction, have been identified in around 70% of ADH cases.	('identified', 'Reg', (121, 131))	('CaSR-mediated signal transduction', 'MPA', (76, 109))	('signal transduction', 'biological_process', 'GO:0007165', ('90', '109'))	('ADH', 'molecular_function', 'GO:0047636', ('149', '152'))	('ADH', 'Gene', '127', (149, 152))	('mutations', 'Var', (23, 32))	('CASR', 'Gene', '846', (40, 44))	('ADH', 'molecular_function', 'GO:0004022', ('149', '152'))	('CASR', 'Gene', (40, 44))	('ADH', 'Gene', (149, 152))	('GNA11', 'Gene', '2767', (49, 54))	('GNA11', 'Gene', (49, 54))	('enhance', 'PosReg', (68, 75))
27763	27647839	This raises the possibility that ADH patients who do not harbour such mutations may instead have abnormalities of the untranslated or non-coding regulatory regions of CASR and GNA11 or have mutations involving other mediators of Ca2+o homeostasis.	('mutations', 'Var', (70, 79))	('ADH', 'molecular_function', 'GO:0004022', ('33', '36'))	('Ca2', 'Gene', '760', (229, 232))	('CASR', 'Gene', (167, 171))	('ADH', 'Gene', (33, 36))	('mutations', 'Var', (190, 199))	('patients', 'Species', '9606', (37, 45))	('ADH', 'Gene', '127', (33, 36))	('abnormalities', 'MPA', (97, 110))	('homeostasis', 'biological_process', 'GO:0042592', ('235', '246'))	('involving', 'Reg', (200, 209))	('Ca2', 'Gene', (229, 232))	('GNA11', 'Gene', (176, 181))	('CASR', 'Gene', '846', (167, 171))	('untranslated', 'MPA', (118, 130))	('ADH', 'molecular_function', 'GO:0047636', ('33', '36'))	('GNA11', 'Gene', '2767', (176, 181))
27764	27647839	It had been postulated that some patients with ADH might harbour AP2sigma mutations, which enhance the sensitivity of CaSR-expressing cells to Ca2+o, and this putative form of ADH was designated ADH type 3 (ADH3).	('ADH', 'Gene', '127', (176, 179))	('ADH', 'Gene', '127', (207, 210))	('ADH', 'molecular_function', 'GO:0004022', ('176', '179'))	('ADH', 'Gene', (176, 179))	('ADH', 'Gene', (207, 210))	('AP2', 'Gene', (65, 68))	('AP2', 'Gene', '7020', (65, 68))	('ADH', 'molecular_function', 'GO:0047636', ('195', '198'))	('Ca2', 'Gene', '760', (143, 146))	('enhance', 'PosReg', (91, 98))	('AP2', 'cellular_component', 'GO:0005908', ('65', '68'))	('ADH', 'Gene', '127', (47, 50))	('ADH', 'molecular_function', 'GO:0004022', ('47', '50'))	('ADH', 'Gene', (47, 50))	('ADH', 'molecular_function', 'GO:0004022', ('207', '210'))	('ADH', 'molecular_function', 'GO:0047636', ('176', '179'))	('Ca2', 'Gene', (143, 146))	('patients', 'Species', '9606', (33, 41))	('ADH', 'Gene', '127', (195, 198))	('mutations', 'Var', (74, 83))	('ADH', 'Gene', (195, 198))	('ADH', 'molecular_function', 'GO:0047636', ('47', '50'))	('ADH', 'molecular_function', 'GO:0047636', ('207', '210'))	('ADH', 'molecular_function', 'GO:0004022', ('195', '198'))
27767	27647839	Thus, these studies indicated that AP2sigma mutations are unlikely to cause hypocalcaemic disorders such as ADH.	('AP2', 'Gene', '7020', (35, 38))	('ADH', 'molecular_function', 'GO:0004022', ('108', '111'))	('AP2', 'Gene', (35, 38))	('ADH', 'molecular_function', 'GO:0047636', ('108', '111'))	('ADH', 'Gene', '127', (108, 111))	('hypocalcaemic disorders', 'Disease', (76, 99))	('mutations', 'Var', (44, 53))	('cause', 'Reg', (70, 75))	('ADH', 'Gene', (108, 111))	('AP2', 'cellular_component', 'GO:0005908', ('35', '38'))	('hypocalcaemic disorders', 'Phenotype', 'HP:0002901', (76, 99))	('hypocalcaemic disorders', 'Disease', 'MESH:D030342', (76, 99))
27768	27647839	The identification and characterisation of gene abnormalities underlying FHH and ADH have led to the delineation of a parathyroid and renal G protein-coupled Ca2+o-sensing mechanism, which involves the CaSR, Galpha11 and AP2sigma proteins.	('FHH', 'Gene', (73, 76))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('abnormalities', 'Var', (48, 61))	('ADH', 'Gene', (81, 84))	('ADH', 'molecular_function', 'GO:0047636', ('81', '84'))	('AP2', 'cellular_component', 'GO:0005908', ('221', '224'))	('ADH', 'molecular_function', 'GO:0004022', ('81', '84'))	('AP2', 'Gene', '7020', (221, 224))	('Ca2', 'Gene', '760', (158, 161))	('AP2', 'Gene', (221, 224))	('FHH', 'Gene', '846', (73, 76))	('CaSR', 'Protein', (202, 206))	('ADH', 'Gene', '127', (81, 84))	('Ca2', 'Gene', (158, 161))	('Galpha11', 'Protein', (208, 216))
27774	26994139	Allosteric Modulation of the Calcium-sensing Receptor Rectifies Signaling Abnormalities Associated with G-protein alpha-11 Mutations Causing Hypercalcemic and Hypocalcemic Disorders* Germline loss- and gain-of-function mutations of G-protein alpha-11 (Galpha11), which couples the calcium-sensing receptor (CaSR) to intracellular calcium (Ca2+i) signaling, lead to familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2), respectively, whereas somatic Galpha11 mutations mediate uveal melanoma development by constitutively up-regulating MAPK signaling.	('ADH2', 'Gene', '127', (460, 464))	('Signaling Abnormalities', 'Disease', (64, 87))	('ADH', 'molecular_function', 'GO:0047636', ('460', '463'))	('autosomal dominant hypocalcemia type 2', 'Gene', (420, 458))	('Signaling Abnormalities', 'Disease', 'MESH:C566796', (64, 87))	('intracellular', 'cellular_component', 'GO:0005622', ('316', '329'))	('calcium-sensing receptor', 'Gene', (281, 305))	('familial hypocalciuric hypercalcemia type 2', 'Disease', 'MESH:C537146', (365, 408))	('mediate', 'Reg', (516, 523))	('protein', 'cellular_component', 'GO:0003675', ('234', '241'))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('Signaling', 'biological_process', 'GO:0023052', ('64', '73'))	('signaling', 'biological_process', 'GO:0023052', ('346', '355'))	('Calcium-sensing Receptor', 'Gene', (29, 53))	('gain-of-function', 'PosReg', (202, 218))	('calcium', 'Chemical', 'MESH:D002118', (281, 288))	('ADH2', 'Gene', (460, 464))	('autosomal dominant hypocalcemia type 2', 'Gene', '127', (420, 458))	('Galpha11', 'Gene', '2767', (252, 260))	('Galpha11', 'Gene', '2767', (497, 505))	('melanoma', 'Phenotype', 'HP:0002861', (530, 538))	('Hypocalcemic Disorders', 'Disease', 'MESH:C562794', (159, 181))	('MAPK', 'molecular_function', 'GO:0004707', ('583', '587'))	('hypocalcemia', 'Phenotype', 'HP:0002901', (439, 451))	('mutations', 'Var', (506, 515))	('FHH', 'Gene', (410, 413))	('ADH', 'molecular_function', 'GO:0004022', ('460', '463'))	('Ca2', 'Gene', '760', (339, 342))	('Calcium-sensing Receptor', 'Gene', '846', (29, 53))	('Hypocalcemic Disorders', 'Phenotype', 'HP:0002901', (159, 181))	('loss-', 'NegReg', (192, 197))	('uveal melanoma', 'Disease', (524, 538))	('uveal melanoma', 'Disease', 'MESH:C536494', (524, 538))	('MAPK signaling', 'Pathway', (583, 597))	('mutations', 'Var', (219, 228))	('FHH', 'Gene', '846', (410, 413))	('hypercalcemia', 'Phenotype', 'HP:0003072', (388, 401))	('Galpha11', 'Gene', (497, 505))	('Galpha11', 'Gene', (252, 260))	('Hypocalcemic Disorders', 'Disease', (159, 181))	('MAPK signaling', 'biological_process', 'GO:0000165', ('583', '597'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (524, 538))	('up-regulating', 'PosReg', (569, 582))	('familial hypocalciuric hypercalcemia type 2', 'Disease', (365, 408))	('calcium', 'Chemical', 'MESH:D002118', (330, 337))	('Ca2', 'Gene', (339, 342))	('calcium-sensing receptor', 'Gene', '846', (281, 305))
27775	26994139	Cinacalcet and NPS-2143 are allosteric CaSR activators and inactivators, respectively, that ameliorate signaling disturbances associated with CaSR mutations, but their potential to modulate abnormalities of the downstream Galpha11 protein is unknown.	('mutations', 'Var', (147, 156))	('NPS-2143', 'Gene', (15, 23))	('ameliorate', 'PosReg', (92, 102))	('signaling disturbances', 'MPA', (103, 125))	('CaSR', 'Gene', (142, 146))	('Galpha11', 'Gene', (222, 230))	('signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('Cinacalcet', 'Chemical', 'MESH:D000069449', (0, 10))	('protein', 'cellular_component', 'GO:0003675', ('231', '238'))	('Galpha11', 'Gene', '2767', (222, 230))
27776	26994139	This study investigated whether cinacalcet and NPS-2143 may rectify Ca2+i alterations associated with FHH2- and ADH2-causing Galpha11 mutations, and evaluated the influence of germline gain-of-function Galpha11 mutations on MAPK signaling by measuring ERK phosphorylation, and assessed the effect of NPS-2143 on a uveal melanoma Galpha11 mutant.	('melanoma', 'Phenotype', 'HP:0002861', (320, 328))	('uveal melanoma', 'Disease', 'MESH:C536494', (314, 328))	('MAPK', 'molecular_function', 'GO:0004707', ('224', '228'))	('uveal melanoma', 'Disease', (314, 328))	('Galpha11', 'Gene', (329, 337))	('MAPK signaling', 'biological_process', 'GO:0000165', ('224', '238'))	('Ca2', 'Gene', (68, 71))	('ADH', 'molecular_function', 'GO:0004022', ('112', '115'))	('ERK', 'molecular_function', 'GO:0004707', ('252', '255'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (314, 328))	('Galpha11', 'Gene', '2767', (125, 133))	('ADH2', 'Gene', (112, 116))	('FHH', 'Gene', (102, 105))	('cinacalcet', 'Chemical', 'MESH:D000069449', (32, 42))	('mutations', 'Var', (134, 143))	('Galpha11', 'Gene', '2767', (202, 210))	('FHH', 'Gene', '846', (102, 105))	('ERK', 'Gene', '5594', (252, 255))	('ADH', 'molecular_function', 'GO:0047636', ('112', '115'))	('gain-of-function', 'PosReg', (185, 201))	('Galpha11', 'Gene', (125, 133))	('Galpha11', 'Gene', '2767', (329, 337))	('ERK', 'Gene', (252, 255))	('mutations', 'Var', (211, 220))	('Ca2', 'Gene', '760', (68, 71))	('phosphorylation', 'biological_process', 'GO:0016310', ('256', '271'))	('Galpha11', 'Gene', (202, 210))	('ADH2', 'Gene', '127', (112, 116))
27777	26994139	WT and mutant Galpha11 proteins causing FHH2, ADH2 or uveal melanoma were transfected in CaSR-expressing HEK293 cells, and Ca2+i and ERK phosphorylation responses measured by flow-cytometry and Alphascreen immunoassay following exposure to extracellular Ca2+ (Ca2+o) and allosteric modulators.	('HEK293', 'CellLine', 'CVCL:0045', (105, 111))	('ADH', 'molecular_function', 'GO:0004022', ('46', '49'))	('FHH', 'Gene', (40, 43))	('extracellular', 'cellular_component', 'GO:0005576', ('240', '253'))	('ADH2', 'Gene', '127', (46, 50))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('Ca2', 'Gene', (123, 126))	('FHH', 'Gene', '846', (40, 43))	('Galpha11', 'Gene', '2767', (14, 22))	('ADH', 'molecular_function', 'GO:0047636', ('46', '49'))	('Ca2', 'Gene', '760', (254, 257))	('ADH2', 'Gene', (46, 50))	('mutant', 'Var', (7, 13))	('Ca2', 'Gene', '760', (260, 263))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('ERK', 'Gene', '5594', (133, 136))	('Galpha11', 'Gene', (14, 22))	('Ca2', 'Gene', (254, 257))	('Ca2', 'Gene', '760', (123, 126))	('ERK', 'molecular_function', 'GO:0004707', ('133', '136'))	('ERK', 'Gene', (133, 136))	('uveal melanoma', 'Disease', (54, 68))	('causing', 'Reg', (32, 39))	('uveal melanoma', 'Disease', 'MESH:C536494', (54, 68))	('Ca2', 'Gene', (260, 263))	('phosphorylation', 'biological_process', 'GO:0016310', ('137', '152'))
27778	26994139	Cinacalcet and NPS-2143 rectified the Ca2+i responses of FHH2- and ADH2-associated Galpha11 loss- and gain-of-function mutations, respectively.	('FHH', 'Gene', '846', (57, 60))	('Ca2', 'Gene', (38, 41))	('Galpha11', 'Gene', '2767', (83, 91))	('loss-', 'NegReg', (92, 97))	('gain-of-function', 'PosReg', (102, 118))	('ADH', 'molecular_function', 'GO:0047636', ('67', '70'))	('ADH2', 'Gene', (67, 71))	('FHH', 'Gene', (57, 60))	('ADH', 'molecular_function', 'GO:0004022', ('67', '70'))	('Cinacalcet', 'Chemical', 'MESH:D000069449', (0, 10))	('ADH2', 'Gene', '127', (67, 71))	('Galpha11', 'Gene', (83, 91))	('mutations', 'Var', (119, 128))	('Ca2', 'Gene', '760', (38, 41))
27779	26994139	ADH2-causing Galpha11 mutations were demonstrated not to be constitutively activating and induced ERK phosphorylation following Ca2+o stimulation only.	('ERK', 'molecular_function', 'GO:0004707', ('98', '101'))	('ADH', 'molecular_function', 'GO:0004022', ('0', '3'))	('ERK', 'Gene', '5594', (98, 101))	('Ca2', 'Gene', (128, 131))	('phosphorylation', 'biological_process', 'GO:0016310', ('102', '117'))	('Galpha11', 'Gene', (13, 21))	('ADH2', 'Gene', (0, 4))	('ERK', 'Gene', (98, 101))	('mutations', 'Var', (22, 31))	('Galpha11', 'Gene', '2767', (13, 21))	('induced', 'Reg', (90, 97))	('ADH', 'molecular_function', 'GO:0047636', ('0', '3'))	('Ca2', 'Gene', '760', (128, 131))	('ADH2', 'Gene', '127', (0, 4))
27780	26994139	The increased ERK phosphorylation associated with ADH2 and uveal melanoma mutants was rectified by NPS-2143.	('ERK', 'Gene', (14, 17))	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('uveal melanoma', 'Disease', (59, 73))	('ADH2', 'Gene', (50, 54))	('ADH', 'molecular_function', 'GO:0004022', ('50', '53'))	('ADH', 'molecular_function', 'GO:0047636', ('50', '53'))	('ERK', 'molecular_function', 'GO:0004707', ('14', '17'))	('ADH2', 'Gene', '127', (50, 54))	('phosphorylation', 'MPA', (18, 33))	('ERK', 'Gene', '5594', (14, 17))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('mutants', 'Var', (74, 81))	('increased', 'PosReg', (4, 13))	('uveal melanoma', 'Disease', 'MESH:C536494', (59, 73))	('phosphorylation', 'biological_process', 'GO:0016310', ('18', '33'))
27781	26994139	These findings demonstrate that CaSR-targeted compounds can rectify signaling disturbances caused by germline and somatic Galpha11 mutations, which respectively lead to calcium disorders and tumorigenesis; and that ADH2-causing Galpha11 mutations induce non-constitutive alterations in MAPK signaling.	('Galpha11', 'Gene', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('ADH', 'molecular_function', 'GO:0047636', ('215', '218'))	('MAPK signaling', 'MPA', (286, 300))	('MAPK', 'molecular_function', 'GO:0004707', ('286', '290'))	('calcium disorders', 'MPA', (169, 186))	('calcium', 'Chemical', 'MESH:D002118', (169, 176))	('ADH2', 'Gene', (215, 219))	('Galpha11', 'Gene', '2767', (228, 236))	('mutations', 'Var', (237, 246))	('signaling', 'biological_process', 'GO:0023052', ('68', '77'))	('lead to', 'Reg', (161, 168))	('tumor', 'Disease', (191, 196))	('ADH', 'molecular_function', 'GO:0004022', ('215', '218'))	('Galpha11', 'Gene', '2767', (122, 130))	('mutations', 'Var', (131, 140))	('signaling disturbances', 'MPA', (68, 90))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('Galpha11', 'Gene', (228, 236))	('MAPK signaling', 'biological_process', 'GO:0000165', ('286', '300'))	('ADH2', 'Gene', '127', (215, 219))
27785	26994139	The identification of germline heterozygous loss- and gain-of-function mutations of Galpha11, which is encoded by the GNA11 gene on chromosome 19p13.3, that lead to forms of familial hypocalciuric hypercalcemia (FHH) or autosomal dominant hypocalcemia (ADH), respectively, has demonstrated the importance of this G-protein subunit in Ca2+o homeostasis.	('ADH', 'molecular_function', 'GO:0047636', ('253', '256'))	('gain-of-function', 'PosReg', (54, 70))	('protein', 'cellular_component', 'GO:0003675', ('315', '322'))	('Ca2', 'Gene', '760', (334, 337))	('GNA11', 'Gene', (118, 123))	('autosomal dominant hypocalcemia', 'Disease', (220, 251))	('loss-', 'NegReg', (44, 49))	('mutations', 'Var', (71, 80))	('FHH', 'Gene', (212, 215))	('Galpha11', 'Gene', '2767', (84, 92))	('familial hypocalciuric hypercalcemia', 'Gene', '846', (174, 210))	('homeostasis', 'biological_process', 'GO:0042592', ('340', '351'))	('chromosome', 'cellular_component', 'GO:0005694', ('132', '142'))	('Ca2', 'Gene', (334, 337))	('FHH', 'Gene', '846', (212, 215))	('ADH', 'molecular_function', 'GO:0004022', ('253', '256'))	('autosomal dominant hypocalcemia', 'Disease', 'MESH:D006996', (220, 251))	('hypocalcemia', 'Phenotype', 'HP:0002901', (239, 251))	('GNA11', 'Gene', '2767', (118, 123))	('Galpha11', 'Gene', (84, 92))	('familial hypocalciuric hypercalcemia', 'Gene', (174, 210))	('hypercalcemia', 'Phenotype', 'HP:0003072', (197, 210))
27788	26994139	FHH type 1 (FHH1, OMIM #145980) is caused by loss-of-function mutations of the CASR gene, and FHH type 2 (FHH2, OMIM #145981) is caused by loss-of-function Galpha11 mutations, which comprise a L135Q missense substitution and in-frame isoleucine deletion at codon 199 or 200 (I199/200del) that impair CaSR signal transduction and were identified in two unrelated probands and families.	('FHH type 2', 'Disease', 'MESH:C537145', (94, 104))	('FHH', 'Gene', '846', (106, 109))	('FHH', 'Gene', (0, 3))	('L135Q', 'Var', (193, 198))	('impair', 'NegReg', (293, 299))	('loss-of-function', 'NegReg', (139, 155))	('FHH', 'Gene', (94, 97))	('FHH', 'Gene', '846', (0, 3))	('Galpha11', 'Gene', '2767', (156, 164))	('FHH', 'Gene', '846', (94, 97))	('mutations', 'Var', (165, 174))	('mutations', 'Var', (62, 71))	('CaSR signal transduction', 'MPA', (300, 324))	('FHH', 'Gene', (12, 15))	('L135Q', 'Mutation', 'rs587777019', (193, 198))	('FHH', 'Gene', '846', (12, 15))	('Galpha11', 'Gene', (156, 164))	('CASR', 'Gene', '846', (79, 83))	('loss-of-function', 'NegReg', (45, 61))	('CASR', 'Gene', (79, 83))	('FHH', 'Gene', (106, 109))	('I199/200del', 'Mutation', 'c.199,200delI,/', (275, 286))	('signal transduction', 'biological_process', 'GO:0007165', ('305', '324'))	('FHH type 2', 'Disease', (94, 104))
27789	26994139	ADH is also genetically heterogeneous and caused by germline gain-of-function mutations of the CASR and GNA11 genes, which lead to ADH types 1 (ADH1, OMIM #601198) and 2 (ADH2, OMIM #615361), respectively.	('GNA11', 'Gene', '2767', (104, 109))	('ADH2', 'Gene', '127', (171, 175))	('gain-of-function', 'PosReg', (61, 77))	('ADH', 'molecular_function', 'GO:0047636', ('171', '174'))	('CASR', 'Gene', (95, 99))	('ADH', 'molecular_function', 'GO:0047636', ('0', '3'))	('ADH', 'molecular_function', 'GO:0047636', ('131', '134'))	('ADH', 'molecular_function', 'GO:0004022', ('0', '3'))	('ADH types 1', 'Disease', (131, 142))	('mutations', 'Var', (78, 87))	('ADH2', 'Gene', (171, 175))	('ADH', 'molecular_function', 'GO:0004022', ('171', '174'))	('ADH', 'molecular_function', 'GO:0004022', ('131', '134'))	('ADH', 'molecular_function', 'GO:0047636', ('144', '147'))	('ADH', 'molecular_function', 'GO:0004022', ('144', '147'))	('GNA11', 'Gene', (104, 109))	('CASR', 'Gene', '846', (95, 99))	('ADH', 'Disease', (0, 3))
27791	26994139	In contrast to germline gain-of-function Galpha11 mutations, which affect Ca2+o homeostasis, somatic gain-of-function Galpha11 mutations have been reported to lead to uveal melanoma, which is a primary intraocular tumor, by inducing constitutive up-regulation of proliferative signaling involving ERK, which is a component of the MAPK signaling pathway.	('intraocular tumor', 'Disease', 'MESH:D064090', (202, 219))	('homeostasis', 'biological_process', 'GO:0042592', ('80', '91'))	('Ca2', 'Gene', '760', (74, 77))	('Galpha11', 'Gene', '2767', (118, 126))	('ERK', 'Gene', (297, 300))	('signaling', 'biological_process', 'GO:0023052', ('277', '286'))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('Galpha11', 'Gene', (41, 49))	('proliferative signaling', 'MPA', (263, 286))	('inducing', 'PosReg', (224, 232))	('gain-of-function', 'PosReg', (101, 117))	('intraocular tumor', 'Disease', (202, 219))	('uveal melanoma', 'Disease', 'MESH:C536494', (167, 181))	('up-regulation', 'PosReg', (246, 259))	('signaling pathway', 'biological_process', 'GO:0007165', ('335', '352'))	('Ca2', 'Gene', (74, 77))	('uveal melanoma', 'Disease', (167, 181))	('mutations', 'Var', (127, 136))	('Galpha11', 'Gene', (118, 126))	('MAPK signaling', 'biological_process', 'GO:0000165', ('330', '344'))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('regulation', 'biological_process', 'GO:0065007', ('249', '259'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (167, 181))	('lead to', 'Reg', (159, 166))	('Galpha11', 'Gene', '2767', (41, 49))	('ERK', 'Gene', '5594', (297, 300))	('MAPK', 'molecular_function', 'GO:0004707', ('330', '334'))	('ERK', 'molecular_function', 'GO:0004707', ('297', '300'))
27795	26994139	The objective of this study was to undertake in vitro studies to determine whether allosteric modulators targeted to the CaSR may also rectify the loss- and gain-of-function associated with FHH2- and ADH2-causing germline Galpha11 mutations, respectively, and the up-regulation of ERK phosphorylation caused by a uveal melanoma-associated somatic Galpha11 mutation.	('up-regulation', 'PosReg', (264, 277))	('mutations', 'Var', (231, 240))	('gain-of-function', 'PosReg', (157, 173))	('ERK', 'Gene', '5594', (281, 284))	('melanoma', 'Phenotype', 'HP:0002861', (319, 327))	('ADH', 'molecular_function', 'GO:0004022', ('200', '203'))	('Galpha11', 'Gene', '2767', (222, 230))	('uveal melanoma', 'Phenotype', 'HP:0007716', (313, 327))	('ADH2', 'Gene', (200, 204))	('FHH', 'Gene', (190, 193))	('Galpha11', 'Gene', '2767', (347, 355))	('loss-', 'NegReg', (147, 152))	('ERK', 'Gene', (281, 284))	('FHH', 'Gene', '846', (190, 193))	('uveal melanoma', 'Disease', (313, 327))	('Galpha11', 'Gene', (222, 230))	('ADH', 'molecular_function', 'GO:0047636', ('200', '203'))	('regulation', 'biological_process', 'GO:0065007', ('267', '277'))	('ERK', 'molecular_function', 'GO:0004707', ('281', '284'))	('Galpha11', 'Gene', (347, 355))	('mutation', 'Var', (356, 364))	('ADH2', 'Gene', '127', (200, 204))	('phosphorylation', 'biological_process', 'GO:0016310', ('285', '300'))	('uveal melanoma', 'Disease', 'MESH:C536494', (313, 327))
27796	26994139	In addition, this study evaluated whether germline ADH2-causing gain-of-function Galpha11 mutations may constitutively activate MAPK signaling and thus pose a risk for the development of uveal melanomas.	('MAPK', 'molecular_function', 'GO:0004707', ('128', '132'))	('ADH2', 'Gene', '127', (51, 55))	('uveal melanomas', 'Disease', (187, 202))	('ADH', 'molecular_function', 'GO:0004022', ('51', '54'))	('mutations', 'Var', (90, 99))	('uveal melanomas', 'Disease', 'MESH:C536494', (187, 202))	('gain-of-function', 'PosReg', (64, 80))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('MAPK signaling', 'Pathway', (128, 142))	('melanomas', 'Phenotype', 'HP:0002861', (193, 202))	('Galpha11', 'Gene', (81, 89))	('uveal melanoma', 'Phenotype', 'HP:0007716', (187, 201))	('MAPK signaling', 'biological_process', 'GO:0000165', ('128', '142'))	('ADH2', 'Gene', (51, 55))	('ADH', 'molecular_function', 'GO:0047636', ('51', '54'))	('Galpha11', 'Gene', '2767', (81, 89))	('activate', 'PosReg', (119, 127))	('uveal melanomas', 'Phenotype', 'HP:0007716', (187, 202))
27797	26994139	Functional studies of mutant Galpha11 proteins were performed in HEK293 cells that stably expressed the CaSR (HEK-CaSR).	('Galpha11', 'Gene', (29, 37))	('Galpha11', 'Gene', '2767', (29, 37))	('HEK293', 'CellLine', 'CVCL:0045', (65, 71))	('HEK-CaSR', 'CellLine', 'CVCL:E339', (110, 118))	('mutant', 'Var', (22, 28))
27798	26994139	HEK293 cells endogenously express Galpha11, and co-expression of mutant Galpha11 proteins approximately represented the heterozygous state in FHH2 and ADH2 patients.	('Galpha11', 'Gene', (72, 80))	('ADH2', 'Gene', '127', (151, 155))	('Galpha11', 'Gene', '2767', (34, 42))	('patients', 'Species', '9606', (156, 164))	('mutant', 'Var', (65, 71))	('Galpha11', 'Gene', '2767', (72, 80))	('ADH', 'molecular_function', 'GO:0004022', ('151', '154'))	('ADH', 'molecular_function', 'GO:0047636', ('151', '154'))	('FHH', 'Gene', '846', (142, 145))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('Galpha11', 'Gene', (34, 42))	('ADH2', 'Gene', (151, 155))	('proteins', 'Protein', (81, 89))	('FHH', 'Gene', (142, 145))
27801	26994139	WT and mutant GNA11-pBI-CMV2 constructs were transiently transfected into HEK-CaSR cells using Lipofectamine 2000.	('HEK-CaSR', 'CellLine', 'CVCL:E339', (74, 82))	('mutant', 'Var', (7, 13))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (95, 113))	('GNA11', 'Gene', (14, 19))	('GNA11', 'Gene', '2767', (14, 19))
27803	26994139	Expression of WT and mutant Galpha11 proteins were determined by Western blot analysis using a mouse monoclonal anti-Galpha11 antibody (SantaCruz Biotechnology, sc-390382, 1:750), and the membrane was re-probed with a polyclonal rabbit anti-alpha-tubulin antibody (Abcam, ab15246, 1:1000) as a loading control.	('antibody', 'cellular_component', 'GO:0019814', ('255', '263'))	('Galpha11', 'Gene', (117, 125))	('antibody', 'molecular_function', 'GO:0003823', ('255', '263'))	('antibody', 'cellular_component', 'GO:0019815', ('126', '134'))	('mutant', 'Var', (21, 27))	('Galpha11', 'Gene', '2767', (117, 125))	('Galpha11', 'Gene', '2767', (28, 36))	('antibody', 'cellular_component', 'GO:0019814', ('126', '134'))	('rabbit', 'Species', '9986', (229, 235))	('antibody', 'cellular_component', 'GO:0042571', ('255', '263'))	('antibody', 'molecular_function', 'GO:0003823', ('126', '134'))	('antibody', 'cellular_component', 'GO:0042571', ('126', '134'))	('antibody', 'cellular_component', 'GO:0019815', ('255', '263'))	('Galpha11', 'Gene', (28, 36))	('membrane', 'cellular_component', 'GO:0016020', ('188', '196'))	('mouse', 'Species', '10090', (95, 100))
27805	26994139	Studies involving siRNA knockdown of endogenous Galpha11 were undertaken in HEK293 cells that stably expressed WT or mutant Galpha11 proteins (HEK-Galpha11).	('Galpha11', 'Gene', '2767', (48, 56))	('mutant', 'Var', (117, 123))	('Galpha11', 'Gene', '2767', (124, 132))	('HEK-Galpha11', 'CellLine', 'CVCL:H515', (143, 155))	('Galpha11', 'Gene', (147, 155))	('HEK293', 'CellLine', 'CVCL:0045', (76, 82))	('proteins', 'Protein', (133, 141))	('Galpha11', 'Gene', (48, 56))	('Galpha11', 'Gene', (124, 132))	('Galpha11', 'Gene', '2767', (147, 155))
27807	26994139	WT and mutant GNA11 constructs were cloned into the pcDNA5/FLP recombination target (FRT) expression vector (Life Technologies), and silent mutations introduced to render the constructs resistant to GNA11-targeted siRNA, thereby allowing investigation of the mutant Galpha11 protein in the absence of endogenous WT Galpha11.	('Galpha11', 'Gene', '2767', (315, 323))	('Galpha11', 'Gene', (266, 274))	('protein', 'Protein', (275, 282))	('resistant', 'MPA', (186, 195))	('GNA11', 'Gene', (199, 204))	('mutant', 'Var', (259, 265))	('Galpha11', 'Gene', '2767', (266, 274))	('protein', 'cellular_component', 'GO:0003675', ('275', '282'))	('GNA11', 'Gene', (14, 19))	('GNA11', 'Gene', '2767', (199, 204))	('Galpha11', 'Gene', (315, 323))	('GNA11', 'Gene', '2767', (14, 19))
27811	26994139	The effect of allosteric CaSR modulators on cells expressing WT or mutant Galpha11 proteins was assessed by a flow cytometry-based Ca2+i assay, as reported.	('proteins', 'Protein', (83, 91))	('Ca2', 'Gene', '760', (131, 134))	('Galpha11', 'Gene', (74, 82))	('Ca2', 'Gene', (131, 134))	('mutant', 'Var', (67, 73))	('Galpha11', 'Gene', '2767', (74, 82))
27816	26994139	HEK-CaSR cells, transfected with WT or mutant Galpha11 proteins for 24 h, were seeded in 48-well plates and cultured overnight in high glucose DMEM containing 10% FBS, prior to being incubated for 4 h with serum-free DMEM containing 0.5 mm Ca2+, 25 mm HEPES buffer with or without cinacalcet or NPS-2143 at 10-500 nm concentrations.	('HEPES', 'Chemical', 'MESH:D006531', (252, 257))	('proteins', 'Protein', (55, 63))	('Galpha11', 'Gene', (46, 54))	('FBS', 'Disease', (163, 166))	('Ca2', 'Gene', (240, 243))	('DMEM', 'Chemical', '-', (217, 221))	('glucose', 'Chemical', 'MESH:D005947', (135, 142))	('Galpha11', 'Gene', '2767', (46, 54))	('HEK-CaSR', 'CellLine', 'CVCL:E339', (0, 8))	('mutant', 'Var', (39, 45))	('FBS', 'Disease', 'MESH:D005198', (163, 166))	('Ca2', 'Gene', '760', (240, 243))	('cinacalcet', 'Chemical', 'MESH:D000069449', (281, 291))	('DMEM', 'Chemical', '-', (143, 147))	('high glucose', 'Phenotype', 'HP:0003074', (130, 142))
27820	26994139	The Ca2+i and ERK phosphorylation responses of cells expressing WT or mutant Galpha11 proteins were compared from a minimum of four experiments using the F-test and Mann-Whitney U test, respectively.	('ERK', 'Gene', (14, 17))	('Ca2', 'Gene', (4, 7))	('mutant', 'Var', (70, 76))	('proteins', 'Protein', (86, 94))	('ERK', 'molecular_function', 'GO:0004707', ('14', '17'))	('Galpha11', 'Gene', (77, 85))	('Ca2', 'Gene', '760', (4, 7))	('ERK', 'Gene', '5594', (14, 17))	('Galpha11', 'Gene', '2767', (77, 85))	('phosphorylation', 'biological_process', 'GO:0016310', ('18', '33'))
27821	26994139	The FHH2-associated L135Q and I199/200del Galpha11 mutations have been reported to impair the sensitivity of CaSR-expressing cells to Ca2+o, and we hypothesized that cinacalcet-mediated allosteric activation of the CaSR would ameliorate the loss-of-function associated with germline mutations of Galpha11, thereby rectifying the signal transduction abnormalities in cells expressing these FHH2-associated mutant Galpha11 proteins.	('Ca2', 'Gene', (134, 137))	('mutations', 'Var', (51, 60))	('L135Q', 'Mutation', 'rs587777019', (20, 25))	('FHH', 'Gene', '846', (389, 392))	('Galpha11', 'Gene', (42, 50))	('Galpha11', 'Gene', (296, 304))	('I199/200del', 'Var', (30, 41))	('Galpha11', 'Gene', '2767', (412, 420))	('signal transduction', 'biological_process', 'GO:0007165', ('329', '348'))	('loss-of-function', 'NegReg', (241, 257))	('impair', 'NegReg', (83, 89))	('cinacalcet', 'Chemical', 'MESH:D000069449', (166, 176))	('Ca2', 'Gene', '760', (134, 137))	('FHH', 'Gene', (4, 7))	('Galpha11', 'Gene', (412, 420))	('L135Q', 'Var', (20, 25))	('Galpha11', 'Gene', '2767', (42, 50))	('FHH', 'Gene', '846', (4, 7))	('I199/200del', 'Mutation', 'c.199,200delI,/', (30, 41))	('Galpha11', 'Gene', '2767', (296, 304))	('FHH', 'Gene', (389, 392))
27822	26994139	To investigate this hypothesis, WT or mutant GNA11-pBI-CMV2 constructs were transiently transfected in HEK-CaSR cells and the effect of cinacalcet on the responses of Ca2+i concentrations ([Ca2+]i) to alterations in [Ca2+]o was assessed.	('mutant', 'Var', (38, 44))	('Ca2', 'Gene', (217, 220))	('Ca2', 'Gene', '760', (190, 193))	('GNA11', 'Gene', '2767', (45, 50))	('Ca2', 'Gene', '760', (167, 170))	('Ca2', 'Gene', (190, 193))	('HEK-CaSR', 'CellLine', 'CVCL:E339', (103, 111))	('GNA11', 'Gene', (45, 50))	('cinacalcet', 'Chemical', 'MESH:D000069449', (136, 146))	('Ca2', 'Gene', '760', (217, 220))	('Ca2', 'Gene', (167, 170))
27824	26994139	CaSR expression, which was normalized by comparison to alpha-tubulin expression, did not differ between cells transfected with WT or FHH2-associated mutant GNA11-pBI-CMV2 vectors when compared with cells transfected with empty vector, whereas the expression of Galpha11 was greater in cells transfected with WT or mutant constructs (Fig.	('GNA11', 'Gene', (156, 161))	('Galpha11', 'Gene', '2767', (261, 269))	('FHH', 'Gene', (133, 136))	('GNA11', 'Gene', '2767', (156, 161))	('mutant', 'Var', (149, 155))	('Galpha11', 'Gene', (261, 269))	('FHH', 'Gene', '846', (133, 136))
27825	26994139	HEK-CaSR cells transiently transfected with WT or mutant Galpha11 proteins were exposed to varying [Ca2+]o, and measurement of [Ca2+]i responses by flow cytometry revealed the FHH2-associated Gln-135 and del199/200 Galpha11 mutants to result in a rightward shift of the concentration-response curves (Fig.	('FHH', 'Gene', (176, 179))	('Ca2', 'Gene', (100, 103))	('Galpha11', 'Gene', (215, 223))	('Galpha11', 'Gene', (57, 65))	('rightward', 'CPA', (247, 256))	('del199/200', 'Var', (204, 214))	('Ca2', 'Gene', (128, 131))	('Galpha11', 'Gene', '2767', (215, 223))	('Ca2', 'Gene', '760', (100, 103))	('HEK-CaSR', 'CellLine', 'CVCL:E339', (0, 8))	('FHH', 'Gene', '846', (176, 179))	('Gln-135', 'Var', (192, 199))	('Gln', 'Chemical', 'MESH:D005973', (192, 195))	('Galpha11', 'Gene', '2767', (57, 65))	('Ca2', 'Gene', '760', (128, 131))
27826	26994139	1C) with a significant reduction in AUC values and increases in EC50 values (Gln-135 = 3.54 +- 0.07 mm, del199/200 = 3.49 +- 0.04 mm) compared with WT Galpha11 (2.67 +- 0.03 mm; p < 0.0001) (Fig.	('del199/200', 'Var', (104, 114))	('Gln-135', 'Var', (77, 84))	('increases', 'PosReg', (51, 60))	('Gln', 'Chemical', 'MESH:D005973', (77, 80))	('reduction', 'NegReg', (23, 32))	('Galpha11', 'Gene', (151, 159))	('EC50 values', 'MPA', (64, 75))	('Galpha11', 'Gene', '2767', (151, 159))	('AUC values', 'MPA', (36, 46))
27827	26994139	A dose-titration of cinacalcet in cells expressing the Gln-135 Galpha11 mutant revealed this calcimimetic to act in a dose-dependent manner, with 10 and 20 nm drug concentrations significantly (p < 0.0001) reducing the Gln-135 mutant EC50 values to 2.75 +- 0.03 and 2.61 +- 0.09 mm, respectively (Fig.	('Gln', 'Chemical', 'MESH:D005973', (219, 222))	('Gln', 'Chemical', 'MESH:D005973', (55, 58))	('Galpha11', 'Gene', '2767', (63, 71))	('reducing', 'NegReg', (206, 214))	('mutant', 'Var', (72, 78))	('Gln-135', 'Var', (55, 62))	('EC50', 'MPA', (234, 238))	('Galpha11', 'Gene', (63, 71))	('Gln-135', 'Var', (219, 226))	('cinacalcet', 'Chemical', 'MESH:D000069449', (20, 30))
27828	26994139	Indeed, 10 nm of cinacalcet induced a leftward shift of the mutant concentration-response curve, so that this was indistinguishable from that of WT-expressing cells (Fig.	('mutant', 'Var', (60, 66))	('cinacalcet', 'Chemical', 'MESH:D000069449', (17, 27))	('leftward', 'MPA', (38, 46))
27829	26994139	The addition of 10 and 20 nm cinacalcet lowered the EC50 values of cells expressing the del199/200 Galpha11 mutant (Fig.	('lowered', 'NegReg', (40, 47))	('EC50 values', 'MPA', (52, 63))	('del199/200', 'Var', (88, 98))	('cinacalcet', 'Chemical', 'MESH:D000069449', (29, 39))	('Galpha11', 'Gene', (99, 107))	('Galpha11', 'Gene', '2767', (99, 107))
27830	26994139	However, despite the del199/200 mutant having an almost identical EC50 value to the Gln-135 Galpha11 mutant protein, these cinacalcet doses were insufficient to rectify the loss-of-function associated with the del199/200 Galpha11 mutant (Fig.	('del199/200', 'Var', (210, 220))	('del199/200', 'Var', (21, 31))	('Galpha11', 'Gene', (221, 229))	('Galpha11', 'Gene', (92, 100))	('Galpha11', 'Gene', '2767', (221, 229))	('Gln', 'Chemical', 'MESH:D005973', (84, 87))	('insufficient', 'Disease', 'MESH:D000309', (145, 157))	('insufficient', 'Disease', (145, 157))	('Galpha11', 'Gene', '2767', (92, 100))	('cinacalcet', 'Chemical', 'MESH:D000069449', (123, 133))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
27831	26994139	Subsequently, when cinacalcet was added at a 40 nm concentration to cells expressing the del199/200 Galpha11 mutant, this lowered the EC50 value to 2.68 +- 0.04 mm (Fig.	('cinacalcet', 'Chemical', 'MESH:D000069449', (19, 29))	('lowered', 'NegReg', (122, 129))	('del199/200', 'Var', (89, 99))	('Galpha11', 'Gene', (100, 108))	('EC50 value', 'MPA', (134, 144))	('Galpha11', 'Gene', '2767', (100, 108))
27832	26994139	1E), so that the del199/200 mutant concentration-response curve overlapped with that of the WT Galpha11 protein (Fig.	('Galpha11', 'Gene', (95, 103))	('Galpha11', 'Gene', '2767', (95, 103))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('del199/200', 'Var', (17, 27))
27833	26994139	We previously reported the germline R181Q and F341L Galpha11 mutations to enhance the sensitivity of CaSR-expressing cells to Ca2+o, thereby giving rise to the hypocalcemic disorder of ADH2.	('Ca2', 'Gene', (126, 129))	('ADH2', 'Gene', '127', (185, 189))	('rise to the hypocalcemic disorder', 'Disease', (148, 181))	('R181Q', 'Mutation', 'rs587777020', (36, 41))	('F341L', 'Var', (46, 51))	('Galpha11', 'Gene', '2767', (52, 60))	('sensitivity', 'MPA', (86, 97))	('ADH', 'molecular_function', 'GO:0004022', ('185', '188'))	('rise to the hypocalcemic disorder', 'Disease', 'MESH:C562794', (148, 181))	('Galpha11', 'Gene', (52, 60))	('Ca2', 'Gene', '760', (126, 129))	('ADH2', 'Gene', (185, 189))	('F341L', 'Mutation', 'rs140749796', (46, 51))	('ADH', 'molecular_function', 'GO:0047636', ('185', '188'))	('hypocalcemic disorder', 'Phenotype', 'HP:0002901', (160, 181))	('R181Q', 'Var', (36, 41))	('enhance', 'PosReg', (74, 81))
27834	26994139	To determine whether allosteric inhibition of the CaSR can rectify the gain-of-function associated with ADH2-causing Galpha11 mutations, WT or ADH2-associated mutant GNA11-pBI-CMV2 vectors were transiently transfected into HEK-CaSR cells, and the responses of [Ca2+]i to alterations in [Ca2+]o assayed.	('ADH', 'molecular_function', 'GO:0004022', ('143', '146'))	('gain-of-function', 'PosReg', (71, 87))	('ADH2', 'Gene', (104, 108))	('ADH', 'molecular_function', 'GO:0004022', ('104', '107'))	('Galpha11', 'Gene', '2767', (117, 125))	('ADH2', 'Gene', (143, 147))	('Ca2', 'Gene', '760', (287, 290))	('ADH', 'molecular_function', 'GO:0047636', ('143', '146'))	('Ca2', 'Gene', '760', (261, 264))	('mutations', 'Var', (126, 135))	('HEK-CaSR', 'CellLine', 'CVCL:E339', (223, 231))	('GNA11', 'Gene', '2767', (166, 171))	('ADH', 'molecular_function', 'GO:0047636', ('104', '107'))	('Ca2', 'Gene', (287, 290))	('Galpha11', 'Gene', (117, 125))	('Ca2', 'Gene', (261, 264))	('ADH2', 'Gene', '127', (104, 108))	('ADH2', 'Gene', '127', (143, 147))	('GNA11', 'Gene', (166, 171))
27836	26994139	Western blot analysis confirmed an increase in the expression of Galpha11 in cells transfected with WT or ADH2-associated mutant proteins, when compared with cells transfected with empty vector alone (Fig.	('ADH2', 'Gene', '127', (106, 110))	('increase', 'PosReg', (35, 43))	('Galpha11', 'Gene', '2767', (65, 73))	('ADH', 'molecular_function', 'GO:0004022', ('106', '109'))	('ADH2', 'Gene', (106, 110))	('expression', 'MPA', (51, 61))	('ADH', 'molecular_function', 'GO:0047636', ('106', '109'))	('proteins', 'Protein', (129, 137))	('mutant', 'Var', (122, 128))	('Galpha11', 'Gene', (65, 73))
27837	26994139	An assessment of the Ca2+i responses of HEK-CaSR cells transiently transfected with WT or ADH2-associated mutant Galpha11 proteins following stimulation with [Ca2+]o, demonstrated cells expressing the Gln-181 or Leu-341 mutants to induce a leftward shift of the concentration-response curves (Fig.	('HEK-CaSR', 'CellLine', 'CVCL:E339', (40, 48))	('ADH2', 'Gene', (90, 94))	('Ca2', 'Gene', (21, 24))	('mutant', 'Var', (106, 112))	('Ca2', 'Gene', (159, 162))	('Gln-181', 'Var', (201, 208))	('ADH', 'molecular_function', 'GO:0047636', ('90', '93'))	('Galpha11', 'Gene', (113, 121))	('Gln', 'Chemical', 'MESH:D005973', (201, 204))	('ADH2', 'Gene', '127', (90, 94))	('leftward shift', 'CPA', (240, 254))	('Leu-341', 'Var', (212, 219))	('Ca2', 'Gene', '760', (21, 24))	('Galpha11', 'Gene', '2767', (113, 121))	('Ca2', 'Gene', '760', (159, 162))	('induce', 'Reg', (231, 237))	('Leu', 'Chemical', 'MESH:D007930', (212, 215))	('ADH', 'molecular_function', 'GO:0004022', ('90', '93'))
27838	26994139	The addition of NPS-2143 to cells expressing the Gln-181 Galpha11 mutant revealed a 10 nm concentration of this calcilytic compound to normalize the mutant EC50 value to 2.57 +- 0.07 mm (Fig.	('Gln', 'Chemical', 'MESH:D005973', (49, 52))	('Galpha11', 'Gene', (57, 65))	('Galpha11', 'Gene', '2767', (57, 65))	('EC50 value', 'MPA', (156, 166))	('Gln-181', 'Var', (49, 56))
27840	26994139	In contrast to these studies involving the Gln-181 Galpha11 mutant protein, the addition of 20 nm NPS 2143 to cells expressing the Leu-341 Galpha11 mutant did not significantly alter the EC50.	('Leu-341', 'Var', (131, 138))	('Galpha11', 'Gene', '2767', (51, 59))	('Galpha11', 'Gene', (139, 147))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('Leu', 'Chemical', 'MESH:D007930', (131, 134))	('Gln', 'Chemical', 'MESH:D005973', (43, 46))	('Galpha11', 'Gene', '2767', (139, 147))	('EC50', 'MPA', (187, 191))	('Galpha11', 'Gene', (51, 59))
27841	26994139	Indeed, NPS-2143 at a concentration of 30 nm was required to increase the Leu-341 mutant EC50 value to 2.66 +- 0.09 mm and rectify the shift in the mutant concentration-response curve (Fig.	('Leu-341', 'Var', (74, 81))	('EC50', 'MPA', (89, 93))	('Leu', 'Chemical', 'MESH:D007930', (74, 77))	('mutant concentration-response curve', 'MPA', (148, 183))	('increase', 'PosReg', (61, 69))
27842	26994139	To determine whether CaSR-targeted drugs rectify the Ca2+i responses of FHH2- and ADH2-mutant expressing cells by directly influencing mutant Galpha11-signaling or by indirect effects on WT Galpha11 protein that is endogenously expressed in HEK293 cells, siRNA knockdown of endogenous WT Galpha11 was undertaken in HEK-Galpha11 cells stably expressing WT, FHH2-associated Gln-135, or ADH2-associated Gln-181 mutant Galpha11 proteins.	('Galpha11', 'Gene', '2767', (142, 150))	('Galpha11', 'Gene', (288, 296))	('Gln-181', 'Var', (400, 407))	('Galpha11', 'Gene', '2767', (190, 198))	('ADH2', 'Gene', (82, 86))	('ADH2', 'Gene', (384, 388))	('HEK-Galpha11', 'CellLine', 'CVCL:H515', (315, 327))	('signaling', 'biological_process', 'GO:0023052', ('151', '160'))	('Ca2', 'Gene', (53, 56))	('Galpha11', 'Gene', (415, 423))	('FHH', 'Gene', (72, 75))	('influencing', 'Reg', (123, 134))	('Gln', 'Chemical', 'MESH:D005973', (372, 375))	('ADH', 'molecular_function', 'GO:0004022', ('384', '387'))	('ADH', 'molecular_function', 'GO:0004022', ('82', '85'))	('FHH', 'Gene', (356, 359))	('FHH', 'Gene', '846', (72, 75))	('proteins', 'Protein', (424, 432))	('Galpha11', 'Gene', (319, 327))	('Galpha11', 'Gene', (142, 150))	('protein', 'cellular_component', 'GO:0003675', ('199', '206'))	('FHH', 'Gene', '846', (356, 359))	('Galpha11', 'Gene', (190, 198))	('Galpha11', 'Gene', '2767', (288, 296))	('ADH2', 'Gene', '127', (82, 86))	('ADH', 'molecular_function', 'GO:0047636', ('384', '387'))	('ADH2', 'Gene', '127', (384, 388))	('Galpha11', 'Gene', '2767', (415, 423))	('ADH', 'molecular_function', 'GO:0047636', ('82', '85'))	('Ca2', 'Gene', '760', (53, 56))	('Gln', 'Chemical', 'MESH:D005973', (400, 403))	('HEK293', 'CellLine', 'CVCL:0045', (241, 247))	('Galpha11', 'Gene', '2767', (319, 327))
27846	26994139	3B), but did not affect the levels of stably expressed WT or mutant Galpha11 proteins in HEK-Galpha11 cells (Fig.	('Galpha11', 'Gene', '2767', (93, 101))	('Galpha11', 'Gene', (68, 76))	('HEK-Galpha11', 'CellLine', 'CVCL:H515', (89, 101))	('mutant', 'Var', (61, 67))	('Galpha11', 'Gene', '2767', (68, 76))	('proteins', 'Protein', (77, 85))	('Galpha11', 'Gene', (93, 101))
27847	26994139	3B), which contained constructs with silent mutations that had rendered them resistant to GNA11-targeted siRNA.	('GNA11', 'Gene', '2767', (90, 95))	('GNA11', 'Gene', (90, 95))	('silent mutations', 'Var', (37, 53))
27849	26994139	The effects of cinacalcet or NPS-2143 on the Ca2+i responses of the FHH2- and ADH2-associated Galpha11 mutants were assessed following knockdown of endogenous WT Galpha11 using GNA11-targeted siRNAs (Fig.	('Ca2', 'Gene', '760', (45, 48))	('Galpha11', 'Gene', (162, 170))	('FHH', 'Gene', '846', (68, 71))	('Galpha11', 'Gene', (94, 102))	('Ca2', 'Gene', (45, 48))	('GNA11', 'Gene', '2767', (177, 182))	('mutants', 'Var', (103, 110))	('GNA11', 'Gene', (177, 182))	('cinacalcet', 'Chemical', 'MESH:D000069449', (15, 25))	('ADH2', 'Gene', (78, 82))	('Galpha11', 'Gene', '2767', (162, 170))	('FHH', 'Gene', (68, 71))	('ADH', 'molecular_function', 'GO:0047636', ('78', '81'))	('Galpha11', 'Gene', '2767', (94, 102))	('ADH', 'molecular_function', 'GO:0004022', ('78', '81'))	('ADH2', 'Gene', '127', (78, 82))
27850	26994139	These studies revealed that: 10 nm of cinacalcet could rectify the rightward shift in the concentration-response curve and lower the significantly raised EC50 of the FHH2-associated Gln-135 Galpha11 mutant from a value of 3.85 +- 0.12 mm to values of 3.23 +- 0.1 mm and 3.17 +- 0.08 mm, respectively, in the presence of GNA11-targeted or scrambled siRNA (Fig.	('FHH', 'Gene', (166, 169))	('GNA11', 'Gene', '2767', (320, 325))	('EC50', 'MPA', (154, 158))	('Galpha11', 'Gene', (190, 198))	('lower', 'NegReg', (123, 128))	('Galpha11', 'Gene', '2767', (190, 198))	('GNA11', 'Gene', (320, 325))	('FHH', 'Gene', '846', (166, 169))	('raised', 'PosReg', (147, 153))	('Gln', 'Chemical', 'MESH:D005973', (182, 185))	('Gln-135', 'Var', (182, 189))	('cinacalcet', 'Chemical', 'MESH:D000069449', (38, 48))
27851	26994139	3, D and E), so that these values were not significantly different from HEK-Galpha11 cells stably expressing WT Galpha11 (EC50 = 3.33 +- 0.06 mm); and that 10 nm of NPS-2143 could normalize the leftward shift of the concentration-response curve and increased the EC50 of the ADH2-associated Gln-181 Galpha11 mutant from a value of 2.70 +- 0.07 mm to values of 3.26 +- 0.06 mm and 3.11 +- 0.08 mm, respectively, in the presence of GNA11-targeted or scrambled siRNA (Fig.	('leftward shift of the concentration-response curve', 'MPA', (194, 244))	('Galpha11', 'Gene', '2767', (299, 307))	('EC50', 'MPA', (263, 267))	('Galpha11', 'Gene', (76, 84))	('ADH2', 'Gene', '127', (275, 279))	('Galpha11', 'Gene', '2767', (76, 84))	('Gln', 'Chemical', 'MESH:D005973', (291, 294))	('ADH', 'molecular_function', 'GO:0047636', ('275', '278'))	('Galpha11', 'Gene', (112, 120))	('increased', 'PosReg', (249, 258))	('Gln-181', 'Var', (291, 298))	('ADH2', 'Gene', (275, 279))	('GNA11', 'Gene', (430, 435))	('ADH', 'molecular_function', 'GO:0004022', ('275', '278'))	('GNA11', 'Gene', '2767', (430, 435))	('Galpha11', 'Gene', '2767', (112, 120))	('Galpha11', 'Gene', (299, 307))	('HEK-Galpha11', 'CellLine', 'CVCL:H515', (72, 84))
27853	26994139	Thus, these results show that CaSR-targeted drugs can influence the signaling responses of downstream mutant Galpha11 proteins.	('mutant', 'Var', (102, 108))	('signaling responses', 'MPA', (68, 87))	('proteins', 'Protein', (118, 126))	('Galpha11', 'Gene', (109, 117))	('signaling', 'biological_process', 'GO:0023052', ('68', '77'))	('Galpha11', 'Gene', '2767', (109, 117))	('influence', 'Reg', (54, 63))
27854	26994139	To investigate whether the germline R181Q and F341L ADH2-associated mutant Galpha11 proteins may lead to constitutive up-regulation of MAPK signaling, WT and mutant GNA11-pBI-CMV2 vectors were transiently transfected into HEK-CaSR cells and fold-change ERK phosphorylation (phospho-ERK) responses assessed following exposure to varying [Ca2+]o.	('Galpha11', 'Gene', (75, 83))	('GNA11', 'Gene', (165, 170))	('proteins', 'Protein', (84, 92))	('R181Q', 'Mutation', 'rs587777020', (36, 41))	('ADH', 'molecular_function', 'GO:0047636', ('52', '55'))	('MAPK signaling', 'MPA', (135, 149))	('ERK', 'Gene', (282, 285))	('Ca2', 'Gene', (337, 340))	('phosphorylation', 'biological_process', 'GO:0016310', ('257', '272'))	('ADH2', 'Gene', (52, 56))	('MAPK signaling', 'biological_process', 'GO:0000165', ('135', '149'))	('F341L', 'Mutation', 'rs140749796', (46, 51))	('mutant', 'Var', (158, 164))	('mutant', 'Var', (68, 74))	('R181Q', 'Var', (36, 41))	('ERK', 'Gene', '5594', (253, 256))	('ADH2', 'Gene', '127', (52, 56))	('HEK-CaSR', 'CellLine', 'CVCL:E339', (222, 230))	('up-regulation', 'PosReg', (118, 131))	('GNA11', 'Gene', '2767', (165, 170))	('Galpha11', 'Gene', '2767', (75, 83))	('ERK', 'molecular_function', 'GO:0004707', ('253', '256'))	('regulation', 'biological_process', 'GO:0065007', ('121', '131'))	('MAPK', 'molecular_function', 'GO:0004707', ('135', '139'))	('F341L', 'Var', (46, 51))	('ADH', 'molecular_function', 'GO:0004022', ('52', '55'))	('ERK', 'Gene', (253, 256))	('ERK', 'molecular_function', 'GO:0004707', ('282', '285'))	('Ca2', 'Gene', '760', (337, 340))	('ERK', 'Gene', '5594', (282, 285))
27855	26994139	The effects of the ADH2-associated mutants on phospho-ERK responses were compared with the uveal melanoma-associated Q209L Galpha11 mutation.	('ADH', 'molecular_function', 'GO:0004022', ('19', '22'))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('ADH2', 'Gene', (19, 23))	('ERK', 'Gene', '5594', (54, 57))	('mutants', 'Var', (35, 42))	('Q209L', 'Mutation', 'rs1057519742', (117, 122))	('ERK', 'molecular_function', 'GO:0004707', ('54', '57'))	('uveal melanoma', 'Disease', 'MESH:C536494', (91, 105))	('Q209L', 'Var', (117, 122))	('ERK', 'Gene', (54, 57))	('Galpha11', 'Gene', (123, 131))	('ADH2', 'Gene', '127', (19, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (91, 105))	('uveal melanoma', 'Disease', (91, 105))	('ADH', 'molecular_function', 'GO:0047636', ('19', '22'))	('Galpha11', 'Gene', '2767', (123, 131))
27856	26994139	Following stimulation with Ca2+o, the germline Gln-181 and Leu-341 mutants were revealed to have significantly (p < 0.001) increased maximal phospho-ERK fold-change responses (Gln-181 = 18.1 +- 1.1, Leu-341 = 18.3 +- 0.9) compared with WT Galpha11 (14.7 +- 0.3), consistent with a gain-of-function (Fig.	('increased', 'PosReg', (123, 132))	('Gln-181', 'Var', (176, 183))	('ERK', 'Gene', (149, 152))	('Ca2', 'Gene', (27, 30))	('Leu', 'Chemical', 'MESH:D007930', (59, 62))	('ERK', 'molecular_function', 'GO:0004707', ('149', '152'))	('Gln', 'Chemical', 'MESH:D005973', (176, 179))	('Galpha11', 'Gene', (239, 247))	('Leu-341', 'Var', (59, 66))	('Gln-181', 'Var', (47, 54))	('Leu-341', 'Var', (199, 206))	('Gln', 'Chemical', 'MESH:D005973', (47, 50))	('Ca2', 'Gene', '760', (27, 30))	('Galpha11', 'Gene', '2767', (239, 247))	('ERK', 'Gene', '5594', (149, 152))	('Leu', 'Chemical', 'MESH:D007930', (199, 202))
27857	26994139	However, in the absence of Ca2+o stimulation, the basal phospho-ERK responses of the ADH2 mutants were demonstrated to not differ from WT Galpha11 (Fig.	('Ca2', 'Gene', (27, 30))	('mutants', 'Var', (90, 97))	('Galpha11', 'Gene', '2767', (138, 146))	('ERK', 'Gene', '5594', (64, 67))	('ADH2', 'Gene', (85, 89))	('ERK', 'Gene', (64, 67))	('Ca2', 'Gene', '760', (27, 30))	('ADH', 'molecular_function', 'GO:0047636', ('85', '88'))	('ADH2', 'Gene', '127', (85, 89))	('ERK', 'molecular_function', 'GO:0004707', ('64', '67'))	('Galpha11', 'Gene', (138, 146))	('ADH', 'molecular_function', 'GO:0004022', ('85', '88'))
27858	26994139	In contrast, the tumor-associated somatic Q209L Galpha11 mutation led to both significantly (p < 0.0001) increased basal and maximal phospho-ERK fold-change responses when compared with the ADH2 mutants or WT Galpha11, consistent with a constitutive up-regulation of MAPK signaling (Fig.	('Galpha11', 'Gene', '2767', (48, 56))	('MAPK signaling', 'biological_process', 'GO:0000165', ('267', '281'))	('ADH', 'molecular_function', 'GO:0047636', ('190', '193'))	('Galpha11', 'Gene', (209, 217))	('ADH2', 'Gene', '127', (190, 194))	('MAPK', 'molecular_function', 'GO:0004707', ('267', '271'))	('ERK', 'molecular_function', 'GO:0004707', ('141', '144'))	('ERK', 'Gene', '5594', (141, 144))	('Galpha11', 'Gene', (48, 56))	('ADH2', 'Gene', (190, 194))	('Q209L', 'Mutation', 'rs1057519742', (42, 47))	('tumor', 'Disease', (17, 22))	('regulation', 'biological_process', 'GO:0065007', ('253', '263'))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('increased', 'PosReg', (105, 114))	('ADH', 'molecular_function', 'GO:0004022', ('190', '193'))	('Galpha11', 'Gene', '2767', (209, 217))	('ERK', 'Gene', (141, 144))	('Q209L', 'Var', (42, 47))	('up-regulation', 'PosReg', (250, 263))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
27859	26994139	The effect of NPS-2143 on the phospho-ERK responses of HEK-CaSR cells expressing the ADH2-associated Gln-181 or Leu-341 mutants, or the uveal melanoma-associated Leu-209 mutant, was also assessed.	('ADH', 'molecular_function', 'GO:0047636', ('85', '88'))	('Leu', 'Chemical', 'MESH:D007930', (162, 165))	('Gln-181', 'Var', (101, 108))	('ERK', 'molecular_function', 'GO:0004707', ('38', '41'))	('Gln', 'Chemical', 'MESH:D005973', (101, 104))	('Leu-341', 'Var', (112, 119))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('ADH2', 'Gene', (85, 89))	('uveal melanoma', 'Phenotype', 'HP:0007716', (136, 150))	('uveal melanoma', 'Disease', (136, 150))	('HEK-CaSR', 'CellLine', 'CVCL:E339', (55, 63))	('uveal melanoma', 'Disease', 'MESH:C536494', (136, 150))	('Leu', 'Chemical', 'MESH:D007930', (112, 115))	('ERK', 'Gene', '5594', (38, 41))	('ADH2', 'Gene', '127', (85, 89))	('ERK', 'Gene', (38, 41))	('ADH', 'molecular_function', 'GO:0004022', ('85', '88'))
27860	26994139	NPS-2143 was added at 10 and 30 nm concentrations to cells expressing the Gln-181 and Leu-341 mutants, respectively, as these doses had rectified the Ca2+i responses of the Galpha11 mutants (Fig.	('Leu', 'Chemical', 'MESH:D007930', (86, 89))	('Galpha11', 'Gene', (173, 181))	('Ca2', 'Gene', '760', (150, 153))	('Gln-181', 'Var', (74, 81))	('rectified', 'NegReg', (136, 145))	('Gln', 'Chemical', 'MESH:D005973', (74, 77))	('Galpha11', 'Gene', '2767', (173, 181))	('Ca2', 'Gene', (150, 153))	('Leu-341', 'Var', (86, 93))
27861	26994139	The addition of 10 and 30 nm NPS-2143 significantly lowered the maximal fold-change responses of the Gln-181 and Leu-341 mutants to 14.0 +- 0.5 and 14.9 +- 0.4, respectively, so that these values did not differ from the phospho-ERK responses of cells expressing WT Galpha11 (Fig.	('Galpha11', 'Gene', '2767', (265, 273))	('ERK', 'Gene', '5594', (228, 231))	('NPS-2143', 'Var', (29, 37))	('Gln-181', 'Var', (101, 108))	('Leu-341', 'Var', (113, 120))	('ERK', 'Gene', (228, 231))	('Gln', 'Chemical', 'MESH:D005973', (101, 104))	('Leu', 'Chemical', 'MESH:D007930', (113, 116))	('lowered', 'NegReg', (52, 59))	('ERK', 'molecular_function', 'GO:0004707', ('228', '231'))	('Galpha11', 'Gene', (265, 273))
27862	26994139	However, cells expressing the uveal melanoma-associated Leu-209 mutant required NPS-2143 at a higher dose of 500 nm to successfully rectify increases in phospho-ERK responses (Fig.	('increases', 'PosReg', (140, 149))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('Leu', 'Chemical', 'MESH:D007930', (56, 59))	('uveal melanoma', 'Disease', 'MESH:C536494', (30, 44))	('ERK', 'Gene', '5594', (161, 164))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('uveal melanoma', 'Disease', (30, 44))	('ERK', 'Gene', (161, 164))	('Leu-209', 'Var', (56, 63))	('ERK', 'molecular_function', 'GO:0004707', ('161', '164'))
27863	26994139	Our studies demonstrate that cinacalcet and NPS-2143, which are allosteric CaSR activators and inactivators, respectively, can successfully rectify the loss-of-function associated with FHH2-causing Galpha11 mutations and the gain-of-function associated with Galpha11 mutations that lead to ADH2 or uveal melanomas.	('FHH', 'Gene', '846', (185, 188))	('uveal melanomas', 'Disease', 'MESH:C536494', (298, 313))	('Galpha11', 'Gene', '2767', (198, 206))	('ADH', 'molecular_function', 'GO:0004022', ('290', '293'))	('mutations', 'Var', (207, 216))	('uveal melanoma', 'Phenotype', 'HP:0007716', (298, 312))	('loss-of-function', 'NegReg', (152, 168))	('ADH2', 'Gene', '127', (290, 294))	('gain-of-function', 'PosReg', (225, 241))	('Galpha11', 'Gene', '2767', (258, 266))	('uveal melanomas', 'Disease', (298, 313))	('Galpha11', 'Gene', (198, 206))	('uveal melanomas', 'Phenotype', 'HP:0007716', (298, 313))	('melanomas', 'Phenotype', 'HP:0002861', (304, 313))	('mutations', 'Var', (267, 276))	('ADH', 'molecular_function', 'GO:0047636', ('290', '293'))	('cinacalcet', 'Chemical', 'MESH:D000069449', (29, 39))	('ADH2', 'Gene', (290, 294))	('melanoma', 'Phenotype', 'HP:0002861', (304, 312))	('FHH', 'Gene', (185, 188))	('Galpha11', 'Gene', (258, 266))
27865	26994139	These compounds have been reported to rectify the activity of FHH1- and ADH1-associated mutant CaSR proteins in vitro.	('ADH', 'molecular_function', 'GO:0004022', ('72', '75'))	('proteins', 'Protein', (100, 108))	('FHH', 'Gene', '846', (62, 65))	('rectify', 'Reg', (38, 45))	('activity', 'MPA', (50, 58))	('mutant', 'Var', (88, 94))	('FHH', 'Gene', (62, 65))	('ADH1-associated', 'Gene', (72, 87))	('CaSR', 'Gene', (95, 99))	('ADH', 'molecular_function', 'GO:0047636', ('72', '75'))
27866	26994139	The in vitro findings of our study indicate allosteric modulation at the level of the receptor can rectify such loss- and gain-of-function associated with mutations of the intracellular Galpha11 protein.	('mutations', 'Var', (155, 164))	('Galpha11', 'Gene', (186, 194))	('allosteric modulation', 'MPA', (44, 65))	('loss-', 'NegReg', (112, 117))	('gain-of-function', 'PosReg', (122, 138))	('Galpha11', 'Gene', '2767', (186, 194))	('intracellular', 'cellular_component', 'GO:0005622', ('172', '185'))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))
27867	26994139	Indeed, these studies demonstrate that pharmacological GPCR modulation may directly overcome abnormalities affecting the downstream effector G-protein rather than by indirect effects on endogenously expressed WT G-proteins.	('GPCR', 'Gene', '151', (55, 59))	('pharmacological', 'Var', (39, 54))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('abnormalities', 'MPA', (93, 106))	('GPCR', 'Gene', (55, 59))	('G-protein', 'Protein', (141, 150))
27868	26994139	However, the Galpha11 mutations showed differences in their responsiveness to allosteric CaSR modulators.	('Galpha11', 'Gene', (13, 21))	('mutations', 'Var', (22, 31))	('responsiveness to allosteric CaSR modulators', 'MPA', (60, 104))	('Galpha11', 'Gene', '2767', (13, 21))
27869	26994139	For example, our study of the FHH2 mutants revealed that a 4-fold increase in the cinacalcet dose was required to normalize the loss-of-function associated with I199/200del compared withthe L135Q mutation, despite both mutations having similar EC50 values.	('I199/200del', 'Var', (161, 172))	('FHH', 'Gene', (30, 33))	('I199/200del', 'Mutation', 'c.199,200delI,/', (161, 172))	('loss-of-function', 'NegReg', (128, 144))	('L135Q', 'Mutation', 'rs587777019', (190, 195))	('FHH', 'Gene', '846', (30, 33))	('cinacalcet', 'Chemical', 'MESH:D000069449', (82, 92))
27870	26994139	Similarly, a 3-fold increase in the NPS-2143 dosage was required to rectify the gain-of-function due to the ADH2-associated F341L mutation when compared with the gain-of-function R181Q mutation, despite both mutations having similar EC50 values.	('ADH', 'molecular_function', 'GO:0004022', ('108', '111'))	('R181Q', 'Mutation', 'rs587777020', (179, 184))	('ADH2', 'Gene', (108, 112))	('F341L', 'Var', (124, 129))	('ADH2', 'Gene', '127', (108, 112))	('F341L', 'Mutation', 'rs140749796', (124, 129))	('ADH', 'molecular_function', 'GO:0047636', ('108', '111'))	('gain-of-function', 'PosReg', (80, 96))
27871	26994139	Thus, the I199/200del and F341L mutations showed diminished sensitivity to cinacalcet and NPS-2143, respectively, and these differences in the sensitivities of the mutants to CaSR-targeted drugs may be explained by a reported crystallography study, which showed residues homologous to Ile-199 and Phe-341, in the related Galphas protein to be located at the interface between GPCR and Galpha-subunit.	('Galpha', 'Gene', (321, 327))	('protein', 'cellular_component', 'GO:0003675', ('329', '336'))	('F341L', 'Mutation', 'rs140749796', (26, 31))	('F341L mutations', 'Var', (26, 41))	('GPCR', 'Gene', '151', (376, 380))	('I199/200del', 'Var', (10, 21))	('Ile', 'Chemical', 'MESH:D007532', (285, 288))	('Galpha', 'Gene', '8802', (385, 391))	('mutations', 'Var', (32, 41))	('Galpha', 'Gene', (385, 391))	('cinacalcet', 'Chemical', 'MESH:D000069449', (75, 85))	('Phe', 'Chemical', 'MESH:D010649', (297, 300))	('I199/200del', 'Mutation', 'c.199,200delI,/', (10, 21))	('diminished', 'NegReg', (49, 59))	('Galpha', 'Gene', '8802', (321, 327))	('sensitivity', 'MPA', (60, 71))	('GPCR', 'Gene', (376, 380))
27735	26994139	Thus, Galpha11 mutations located at the GPCR-Galpha interface may potentially influence the efficacy of CaSR allosteric modulators.	('GPCR', 'Gene', (40, 44))	('Galpha11', 'Gene', '2767', (6, 14))	('influence', 'Reg', (78, 87))	('mutations', 'Var', (15, 24))	('Galpha', 'Gene', (45, 51))	('efficacy', 'MPA', (92, 100))	('GPCR', 'Gene', '151', (40, 44))	('Galpha', 'Gene', '8802', (6, 12))	('Galpha', 'Gene', '8802', (45, 51))	('Galpha', 'Gene', (6, 12))	('Galpha11', 'Gene', (6, 14))
27872	26994139	Cells expressing loss- and gain-of-function Galpha11 mutants responded to nanomolar concentrations of cinacalcet (10-40 nm, which is equivalent to 3.6-14.3 ng/ml) and NPS-2143 (10-30 nm, which is equivalent to 4.4-13.3 ng/ml), respectively.	('Galpha11', 'Gene', (44, 52))	('mutants', 'Var', (53, 60))	('gain-of-function', 'PosReg', (27, 43))	('Galpha11', 'Gene', '2767', (44, 52))	('loss-', 'NegReg', (17, 22))	('cinacalcet', 'Chemical', 'MESH:D000069449', (102, 112))
27873	26994139	However, previous in vitro studies of CaSR mutations leading to FHH and ADH have indicated that micromolar concentrations of these drugs may be required to rectify associated signal transduction abnormalities, and in vivo studies in WT rats have reported that the plasma drug concentrations of cinacalcet and NPS-2143 required to alter PTH secretion are >=20 ng/ml and >100 ng/ml, respectively.	('ADH', 'molecular_function', 'GO:0004022', ('72', '75'))	('CaSR', 'Gene', (38, 42))	('signal transduction', 'biological_process', 'GO:0007165', ('175', '194'))	('cinacalcet', 'Chemical', 'MESH:D000069449', (294, 304))	('PTH secretion', 'MPA', (336, 349))	('leading', 'Reg', (53, 60))	('FHH', 'Gene', (64, 67))	('mutations', 'Var', (43, 52))	('NPS-2143', 'Gene', (309, 317))	('PTH', 'Chemical', 'MESH:D010281', (336, 339))	('ADH', 'molecular_function', 'GO:0047636', ('72', '75'))	('ADH', 'Gene', (72, 75))	('PTH secretion', 'biological_process', 'GO:0035898', ('336', '349'))	('rats', 'Species', '10116', (236, 240))	('FHH', 'Gene', '846', (64, 67))
27874	26994139	The responsiveness of Galpha11 mutants to low doses of CaSR-targeted drugs may be explained by the finding that these mutants induced only minor disturbances of CaSR signal transduction.	('mutants', 'Var', (31, 38))	('signal transduction', 'biological_process', 'GO:0007165', ('166', '185'))	('Galpha11', 'Gene', (22, 30))	('CaSR signal transduction', 'MPA', (161, 185))	('Galpha11', 'Gene', '2767', (22, 30))
27875	26994139	Indeed, the FHH2 and ADH2 mutants were associated with up to a 30% shift in the EC50 values of HEK-CaSR cells used in this study, whereas CaSR mutations leading to FHH1 and ADH1 generally cause a >50% shift in the EC50 value.	('ADH1', 'Gene', (173, 177))	('FHH', 'Gene', (12, 15))	('EC50 values', 'MPA', (80, 91))	('ADH2', 'Gene', '127', (21, 25))	('ADH', 'molecular_function', 'GO:0047636', ('21', '24'))	('FHH', 'Gene', '846', (164, 167))	('shift', 'Reg', (67, 72))	('ADH', 'molecular_function', 'GO:0047636', ('173', '176'))	('ADH2', 'Gene', (21, 25))	('ADH', 'molecular_function', 'GO:0004022', ('21', '24'))	('mutants', 'Var', (26, 33))	('FHH', 'Gene', (164, 167))	('FHH', 'Gene', '846', (12, 15))	('ADH', 'molecular_function', 'GO:0004022', ('173', '176'))	('HEK-CaSR', 'CellLine', 'CVCL:E339', (95, 103))	('mutations', 'Var', (143, 152))
27877	26994139	Somatic gain-of-function Galpha11 mutations that induce constitutive MAPK activation have been reported in uveal melanoma and are associated with an increased likelihood of metastases.	('Galpha11', 'Gene', '2767', (25, 33))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('uveal melanoma', 'Disease', (107, 121))	('metastases', 'Disease', (173, 183))	('MAPK activation', 'biological_process', 'GO:0000187', ('69', '84'))	('MAPK', 'Gene', (69, 73))	('metastases', 'Disease', 'MESH:D009362', (173, 183))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('activation', 'PosReg', (74, 84))	('MAPK', 'molecular_function', 'GO:0004707', ('69', '73'))	('Galpha11', 'Gene', (25, 33))	('gain-of-function', 'PosReg', (8, 24))	('mutations', 'Var', (34, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (107, 121))
27878	26994139	We therefore assessed the effects of germline ADH2-associated R181Q and F341L gain-of-function Galpha11 mutations on MAPK signaling by measuring phospho-ERK responses.	('MAPK', 'molecular_function', 'GO:0004707', ('117', '121'))	('ADH2', 'Gene', (46, 50))	('ADH', 'molecular_function', 'GO:0004022', ('46', '49'))	('F341L', 'Var', (72, 77))	('gain-of-function', 'PosReg', (78, 94))	('Galpha11', 'Gene', (95, 103))	('ERK', 'Gene', '5594', (153, 156))	('ERK', 'Gene', (153, 156))	('R181Q', 'Var', (62, 67))	('R181Q', 'Mutation', 'rs587777020', (62, 67))	('ADH2', 'Gene', '127', (46, 50))	('ERK', 'molecular_function', 'GO:0004707', ('153', '156'))	('F341L', 'Mutation', 'rs140749796', (72, 77))	('Galpha11', 'Gene', '2767', (95, 103))	('ADH', 'molecular_function', 'GO:0047636', ('46', '49'))	('MAPK signaling', 'MPA', (117, 131))	('MAPK signaling', 'biological_process', 'GO:0000165', ('117', '131'))
27879	26994139	Our studies demonstrated that the ADH2 Galpha11 mutants induced a milder increase in ERK phosphorylation when compared with the uveal melanoma Q209L Galpha11 mutant.	('Q209L', 'Mutation', 'rs1057519742', (143, 148))	('Galpha11', 'Gene', '2767', (39, 47))	('ADH2', 'Gene', (34, 38))	('ADH', 'molecular_function', 'GO:0047636', ('34', '37'))	('Galpha11', 'Gene', '2767', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('ERK', 'molecular_function', 'GO:0004707', ('85', '88'))	('uveal melanoma', 'Disease', 'MESH:C536494', (128, 142))	('Galpha11', 'Gene', (39, 47))	('ERK', 'Gene', '5594', (85, 88))	('uveal melanoma', 'Disease', (128, 142))	('phosphorylation', 'biological_process', 'GO:0016310', ('89', '104'))	('ADH2', 'Gene', '127', (34, 38))	('Galpha11', 'Gene', (149, 157))	('increase', 'PosReg', (73, 81))	('uveal melanoma', 'Phenotype', 'HP:0007716', (128, 142))	('mutants', 'Var', (48, 55))	('ERK', 'Gene', (85, 88))	('ADH', 'molecular_function', 'GO:0004022', ('34', '37'))
27880	26994139	Moreover, up-regulation of ERK phosphorylation by the ADH2-associated Galpha11 mutants only occurred in the presence of Ca2+o stimulation, and therefore these R181Q and F341L Galpha11 mutants do not harbor constitutive activity.	('regulation', 'biological_process', 'GO:0065007', ('13', '23'))	('ADH2', 'Gene', '127', (54, 58))	('F341L', 'Mutation', 'rs140749796', (169, 174))	('ERK', 'Gene', (27, 30))	('Galpha11', 'Gene', '2767', (70, 78))	('ADH', 'molecular_function', 'GO:0047636', ('54', '57'))	('Ca2', 'Gene', '760', (120, 123))	('Galpha11', 'Gene', (175, 183))	('ADH2', 'Gene', (54, 58))	('ERK', 'molecular_function', 'GO:0004707', ('27', '30'))	('R181Q', 'Mutation', 'rs587777020', (159, 164))	('F341L', 'Var', (169, 174))	('up-regulation', 'PosReg', (10, 23))	('Ca2', 'Gene', (120, 123))	('Galpha11', 'Gene', (70, 78))	('mutants', 'Var', (79, 86))	('R181Q', 'Var', (159, 164))	('ERK', 'Gene', '5594', (27, 30))	('ADH', 'molecular_function', 'GO:0004022', ('54', '57'))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))	('Galpha11', 'Gene', '2767', (175, 183))
27881	26994139	These findings are consistent with a recent report of an ADH2-associated R60L Galpha11 mutation, which also enhanced MAPK activation in a non-constitutive manner.	('MAPK', 'molecular_function', 'GO:0004707', ('117', '121'))	('R60L', 'Var', (73, 77))	('ADH2', 'Gene', (57, 61))	('R60L', 'Mutation', 'rs587777707', (73, 77))	('Galpha11', 'Gene', (78, 86))	('ADH', 'molecular_function', 'GO:0047636', ('57', '60'))	('enhanced', 'PosReg', (108, 116))	('MAPK activation', 'biological_process', 'GO:0000187', ('117', '132'))	('ADH', 'molecular_function', 'GO:0004022', ('57', '60'))	('MAPK', 'Protein', (117, 121))	('Galpha11', 'Gene', '2767', (78, 86))	('ADH2', 'Gene', '127', (57, 61))	('activation', 'MPA', (122, 132))
27882	26994139	The finding that ADH2-associated mutations are not constitutively activating can be explained by their locations within the GTPase domain of the Galpha subunit.	('ADH2', 'Gene', '127', (17, 21))	('ADH', 'molecular_function', 'GO:0047636', ('17', '20'))	('GTP', 'Chemical', 'MESH:D006160', (124, 127))	('ADH2', 'Gene', (17, 21))	('mutations', 'Var', (33, 42))	('Galpha', 'Gene', (145, 151))	('Galpha', 'Gene', '8802', (145, 151))	('ADH', 'molecular_function', 'GO:0004022', ('17', '20'))
27883	26994139	Thus, the Gln-209 residue, which is mutated in uveal melanomas, is required to spatially orientate the terminal phosphate group of Galpha-bound GTP, thereby facilitating its hydrolysis and the conversion of GTP to GDP.	('Gln', 'Chemical', 'MESH:D005973', (10, 13))	('phosphate', 'Chemical', 'MESH:D010710', (112, 121))	('Galpha', 'Gene', '8802', (131, 137))	('uveal melanomas', 'Disease', (47, 62))	('uveal melanomas', 'Phenotype', 'HP:0007716', (47, 62))	('Gln-209', 'Var', (10, 17))	('conversion', 'MPA', (193, 203))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('GTP', 'Chemical', 'MESH:D006160', (207, 210))	('GDP', 'Chemical', 'MESH:D006153', (214, 217))	('GDP', 'MPA', (214, 217))	('GTP', 'MPA', (207, 210))	('hydrolysis', 'MPA', (174, 184))	('GTP', 'Chemical', 'MESH:D006160', (144, 147))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('facilitating', 'PosReg', (157, 169))	('uveal melanomas', 'Disease', 'MESH:C536494', (47, 62))	('Galpha', 'Gene', (131, 137))
27884	26994139	Mutations affecting the Gln-209 residue have been shown to abolish GTP hydrolysis, thereby leaving the Galpha subunit in a permanent GTP-bound state of activation.	('Gln', 'Chemical', 'MESH:D005973', (24, 27))	('GTP', 'Chemical', 'MESH:D006160', (133, 136))	('abolish', 'NegReg', (59, 66))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('67', '81'))	('Gln-209', 'Var', (24, 31))	('Galpha', 'Gene', '8802', (103, 109))	('leaving', 'Reg', (91, 98))	('Galpha', 'Gene', (103, 109))	('Mutations', 'Var', (0, 9))	('GTP', 'Chemical', 'MESH:D006160', (67, 70))	('GTP hydrolysis', 'MPA', (67, 81))
27885	26994139	In contrast, the Arg-181 and Phe-341 Galpha11 residues, which are mutated in ADH2, are not located near to the terminal phosphate of GTP, and likely induce more indirect and subtle effects on GTP hydrolysis.	('effects', 'Reg', (181, 188))	('GTP', 'Chemical', 'MESH:D006160', (133, 136))	('GTP', 'Chemical', 'MESH:D006160', (192, 195))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('192', '206'))	('GTP hydrolysis', 'MPA', (192, 206))	('ADH2', 'Gene', (77, 81))	('Galpha11', 'Gene', (37, 45))	('induce', 'Reg', (149, 155))	('phosphate', 'Chemical', 'MESH:D010710', (120, 129))	('Galpha11', 'Gene', '2767', (37, 45))	('ADH', 'molecular_function', 'GO:0047636', ('77', '80'))	('Arg-181', 'Var', (17, 24))	('Phe', 'Chemical', 'MESH:D010649', (29, 32))	('Arg', 'Chemical', 'MESH:D001120', (17, 20))	('ADH2', 'Gene', '127', (77, 81))	('ADH', 'molecular_function', 'GO:0004022', ('77', '80'))
27886	26994139	The ADH2-associated Galpha11 mutations represent the first reports of non-constitutively activating G-protein mutations, and the milder nature of these mutations is consistent with post-natal survival, in contrast to the constitutively activating Q209L mutation, which has been shown to be cytotoxic when expressed at high levels, and is likely to be embryonically lethal.	('Q209L', 'Mutation', 'rs1057519742', (247, 252))	('Galpha11', 'Gene', '2767', (20, 28))	('ADH2', 'Gene', '127', (4, 8))	('mutations', 'Var', (110, 119))	('mutations', 'Var', (29, 38))	('Q209L', 'Var', (247, 252))	('ADH', 'molecular_function', 'GO:0047636', ('4', '7'))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('Galpha11', 'Gene', (20, 28))	('ADH2', 'Gene', (4, 8))	('G-protein', 'Protein', (100, 109))	('ADH', 'molecular_function', 'GO:0004022', ('4', '7'))
27887	26994139	The occurrence of non-constitutively activating Galpha11 mutations that are tolerated in humans and heritable, highlights the potential for such germline mutations to affect other G-proteins and be associated with disease-related phenotypes, and this possibility remains to be explored.	('Galpha11', 'Gene', '2767', (48, 56))	('affect', 'Reg', (167, 173))	('mutations', 'Var', (57, 66))	('humans', 'Species', '9606', (89, 95))	('associated', 'Reg', (198, 208))	('G-proteins', 'Protein', (180, 190))	('activating', 'PosReg', (37, 47))	('Galpha11', 'Gene', (48, 56))
27888	26994139	In summary, our studies have revealed that germline gain-of-function Galpha11 mutations induce non-constitutive alterations in MAPK signaling, and that CaSR-targeted compounds may rectify signaling disturbances caused by germline and somatic Galpha11 mutations, which are associated with calcium disorders and tumorigenesis, respectively.	('signaling disturbances', 'MPA', (188, 210))	('mutations', 'Var', (251, 260))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('Galpha11', 'Gene', '2767', (69, 77))	('Galpha11', 'Gene', (242, 250))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('Galpha11', 'Gene', (69, 77))	('Galpha11', 'Gene', '2767', (242, 250))	('mutations', 'Var', (78, 87))	('calcium', 'Chemical', 'MESH:D002118', (288, 295))	('MAPK signaling', 'biological_process', 'GO:0000165', ('127', '141'))	('calcium disorders', 'Disease', (288, 305))	('tumor', 'Disease', (310, 315))	('MAPK signaling', 'MPA', (127, 141))	('signaling', 'biological_process', 'GO:0023052', ('188', '197'))	('gain-of-function', 'PosReg', (52, 68))	('rectify', 'NegReg', (180, 187))	('MAPK', 'molecular_function', 'GO:0004707', ('127', '131'))
27915	25219541	Phosphorylation at tyrosine sites was shown to prevent interaction with receptor type protein tyrosine phosphates (rPTPnu) CD148, and recent work pointed to an interesting interaction with ubiquitin (Ub), regulated by the N-terminal.	('CD148', 'Gene', '5795', (123, 128))	('tyrosine phosphates', 'Chemical', 'MESH:D019000', (94, 113))	('interaction', 'Interaction', (172, 183))	('ubiquitin', 'Protein', (189, 198))	('Phosphorylation', 'Var', (0, 15))	('prevent', 'NegReg', (47, 54))	('tyrosine', 'Chemical', 'MESH:D014443', (94, 102))	('interaction', 'Interaction', (55, 66))	('tyrosine', 'Chemical', 'MESH:D014443', (19, 27))	('CD148', 'Gene', (123, 128))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('189', '198'))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))
27917	25219541	A conserved LYPSL sequence in the N terminus of MDA-9/Syntenin binds a unique site on the C terminus of Ub, interacting equally well with Lys48- or Lys63-linked poly-Ub chains.	('interacting', 'Interaction', (108, 119))	('MDA-9/Syntenin', 'Gene', (48, 62))	('Lys63-linked', 'Var', (148, 160))	('Lys48', 'Chemical', '-', (138, 143))	('Lys48-', 'Var', (138, 144))	('Lys63', 'Chemical', '-', (148, 153))
27922	25219541	When MDA-9/Syntenin mutants were expressed that lose the ability to bind Ub, they demonstrated reduced co-localization with CD63, a marker for late endosomes and lysosomes.	('lose', 'NegReg', (48, 52))	('mutants', 'Var', (20, 27))	('ability', 'MPA', (57, 64))	('CD63', 'Gene', (124, 128))	('localization', 'biological_process', 'GO:0051179', ('106', '118'))	('co-localization', 'MPA', (103, 118))	('rat', 'Species', '10116', (89, 92))	('bind', 'Interaction', (68, 72))	('MDA-9/Syntenin', 'Gene', (5, 19))	('reduced', 'NegReg', (95, 102))	('CD63', 'Gene', '967', (124, 128))
27925	25219541	Additionally, a mutant mimicking phosphorylation at Tyr56 (Y56E) was strongly enriched at the plasma membrane, indicating that N-terminal phosphorylation negates autoinhibition and leads to enhanced plasma membrane association.	('plasma membrane association', 'MPA', (199, 226))	('Y56E', 'Mutation', 'p.Y56E', (59, 63))	('Tyr56', 'Chemical', '-', (52, 57))	('autoinhibition', 'MPA', (162, 176))	('enhanced', 'PosReg', (190, 198))	('N-terminal', 'Var', (127, 137))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('199', '214'))	('phosphorylation', 'biological_process', 'GO:0016310', ('138', '153'))	('negates', 'NegReg', (154, 161))	('plasma membrane', 'cellular_component', 'GO:0005886', ('94', '109'))
27935	25219541	This is similar to an earlier finding in Xenopus that found knockdown of syntenin homologues resulted in a shorter body axis.	('shorter', 'NegReg', (107, 114))	('Xenopus', 'Species', '8355', (41, 48))	('knockdown', 'Var', (60, 69))
27940	25219541	Synaptic function is tightly regulated, and dysfunction can be associated with a variety of neurological pathology, including neurodegenerative states such as Alzheimer's, and psychiatric disorders such as schizophrenia.	('psychiatric disorders', 'Disease', 'MESH:D001523', (176, 197))	('schizophrenia', 'Phenotype', 'HP:0100753', (206, 219))	('associated', 'Reg', (63, 73))	("Alzheimer's", 'Disease', 'MESH:D000544', (159, 170))	('rat', 'Species', '10116', (137, 140))	('psychiatric disorders', 'Phenotype', 'HP:0000708', (176, 197))	('Alzheimer', 'Disease', (159, 168))	('psychiatric disorders', 'Disease', (176, 197))	('dysfunction', 'Var', (44, 55))	('schizophrenia', 'Disease', 'MESH:D012559', (206, 219))	('schizophrenia', 'Disease', (206, 219))
27943	25219541	In PC12 cells, a model for neuron-like cells, Akt inhibition, either through dominant negative (DN) expression or through pharmacological inhibition, led to an increase in MDA-9/Syntenin expression and improvement in neurite outgrowth.	('neurite', 'cellular_component', 'GO:0043005', ('217', '224'))	('neurite outgrowth', 'biological_process', 'GO:0031175', ('217', '234'))	('inhibition', 'NegReg', (50, 60))	('MDA-9/Syntenin', 'Protein', (172, 186))	('increase', 'PosReg', (160, 168))	('Akt', 'Pathway', (46, 49))	('dominant negative', 'Var', (77, 94))	('neurite outgrowth', 'CPA', (217, 234))	('PC12', 'CellLine', 'CVCL:0481', (3, 7))	('expression', 'MPA', (187, 197))	('improvement', 'PosReg', (202, 213))
27945	25219541	Among the receptors that interact with MDA-9/Syntenin at the synaptic cleft are glutamate receptors, involved in the transport of the main excitatory neurotransmitter in the CNS.	('transport', 'biological_process', 'GO:0006810', ('117', '126'))	('MDA-9/Syntenin', 'Var', (39, 53))	('synaptic cleft', 'cellular_component', 'GO:0043083', ('61', '75'))	('glutamate', 'Chemical', 'MESH:D018698', (80, 89))	('glutamate receptors', 'Protein', (80, 99))
27959	25219541	Furthermore, genetic manipulation of cancers forcing elevated expression in cells with lower baseline levels of MDA-9/Syntenin consistently leads to increased migration and invasion.	('invasion', 'CPA', (173, 181))	('rat', 'Species', '10116', (162, 165))	('elevated', 'PosReg', (53, 61))	('increased', 'PosReg', (149, 158))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('expression', 'MPA', (62, 72))	('genetic manipulation', 'Var', (13, 33))	('cancers', 'Disease', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('MDA-9/Syntenin', 'Gene', (112, 126))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
27965	25219541	Furthermore, silencing MDA-9/Syntenin led to an accumulation of cells in G1 along with enhance p21 and p27 expression.	('accumulation', 'PosReg', (48, 60))	('enhance', 'PosReg', (87, 94))	('cells in G1', 'CPA', (64, 75))	('p27', 'Gene', (103, 106))	('MDA-9/Syntenin', 'Gene', (23, 37))	('p27', 'Gene', '3429', (103, 106))	('p21', 'Gene', (95, 98))	('p21', 'Gene', '644914', (95, 98))	('silencing', 'Var', (13, 22))
27967	25219541	Furthermore, overall survival and disease-free survival were shorter in patients with high MDA-9/Syntenin tumor expression.	('shorter', 'NegReg', (61, 68))	('patients', 'Species', '9606', (72, 80))	('disease-free survival', 'CPA', (34, 55))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('MDA-9/Syntenin', 'Gene', (91, 105))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('overall survival', 'CPA', (13, 29))	('high', 'Var', (86, 90))	('tumor', 'Disease', (106, 111))	('expression', 'MPA', (112, 122))
27972	25219541	Uveal melanoma metastasizes to the liver in nearly 50% of patients, and patients with higher expression of MDA-9/-Syntenin showed significantly shorter disease-free survival.	('metastasizes', 'CPA', (15, 27))	('MDA-9/-Syntenin', 'Var', (107, 122))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('shorter', 'NegReg', (144, 151))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('disease-free survival', 'CPA', (152, 173))	('patients', 'Species', '9606', (58, 66))	('melanoma', 'Disease', (6, 14))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))	('patients', 'Species', '9606', (72, 80))
27973	25219541	Additionally, knockdown of MDA-9/Syntenin in vitro inhibited HGF-induced invasion in matrigel.	('HGF', 'Gene', (61, 64))	('MDA-9/Syntenin', 'Gene', (27, 41))	('HGF', 'Gene', '3082', (61, 64))	('knockdown', 'Var', (14, 23))	('inhibited', 'NegReg', (51, 60))
27986	25219541	c-Src interaction is mediated through the PDZ domains of MDA-9/Syntenin, as deletion mutants lacking PDZ1 or PDZ2 dramatically reduce c-Src binding.	('deletion mutants', 'Var', (76, 92))	('PDZ2', 'Gene', (109, 113))	('binding', 'molecular_function', 'GO:0005488', ('140', '147'))	('binding', 'Interaction', (140, 147))	('interaction', 'Interaction', (6, 17))	('PDZ1', 'Gene', (101, 105))	('reduce', 'NegReg', (127, 133))	('c-Src', 'Gene', (0, 5))	('MDA-9/Syntenin', 'Gene', (57, 71))	('c-Src', 'Gene', (134, 139))	('lacking', 'NegReg', (93, 100))	('c-Src', 'Gene', '6714', (0, 5))	('c-Src', 'Gene', '6714', (134, 139))
27990	25219541	Integrin stimulation leads to the autophosphorylation of FAK at Tyr397, which creates a binding site for SFKs.	('binding', 'molecular_function', 'GO:0005488', ('88', '95'))	('FAK', 'Gene', (57, 60))	('FAK', 'Gene', '5747', (57, 60))	('autophosphorylation', 'MPA', (34, 53))	('FAK', 'molecular_function', 'GO:0004717', ('57', '60'))	('Tyr397', 'Var', (64, 70))	('Tyr397', 'Chemical', '-', (64, 70))	('binding', 'Interaction', (88, 95))
27997	25219541	Inhibiting PKC-alpha in this scenario suppresses focal adhesion formation and cell migration, critical steps in cancer cell invasion.	('focal adhesion', 'cellular_component', 'GO:0005925', ('49', '63'))	('PKC', 'molecular_function', 'GO:0004697', ('11', '14'))	('Inhibiting', 'Var', (0, 10))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('PKC-alpha', 'Gene', (11, 20))	('cell migration', 'biological_process', 'GO:0016477', ('78', '92'))	('focal adhesion formation', 'CPA', (49, 73))	('PKC-alpha', 'Gene', '5578', (11, 20))	('focal adhesion formation', 'biological_process', 'GO:0048041', ('49', '73'))	('suppresses', 'NegReg', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('rat', 'Species', '10116', (86, 89))	('cell migration', 'CPA', (78, 92))
28006	25219541	The p38MAPK pathway is a known activator of NF-kappaB, and MDA-9/Syntenin inhibition can reduce the levels of phosphorylated p38MAPK in melanoma and glioma.	('MAPK', 'molecular_function', 'GO:0004707', ('128', '132'))	('melanoma and glioma', 'Disease', 'MESH:D005910', (136, 155))	('inhibition', 'Var', (74, 84))	('NF-kappaB', 'Gene', '4790', (44, 53))	('MAPK', 'molecular_function', 'GO:0004707', ('7', '11'))	('levels of phosphorylated', 'MPA', (100, 124))	('reduce', 'NegReg', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('NF-kappaB', 'Gene', (44, 53))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('p38MAPK pathway', 'Pathway', (4, 19))
28013	25219541	In SCLC, MDA-9/Syntenin led to the activation of p38MAPK and Akt and production of MT1-MMP and MMP2.	('SCLC', 'Gene', '7864', (3, 7))	('SCLC', 'Phenotype', 'HP:0030357', (3, 7))	('SCLC', 'Gene', (3, 7))	('MMP2', 'Gene', (95, 99))	('activation', 'PosReg', (35, 45))	('MDA-9/Syntenin', 'Var', (9, 23))	('p38MAPK', 'Pathway', (49, 56))	('MT1', 'molecular_function', 'GO:0043834', ('83', '86'))	('MT1-MMP', 'Gene', '4323', (83, 90))	('MMP2', 'Gene', '4313', (95, 99))	('MT1', 'molecular_function', 'GO:0043791', ('83', '86'))	('MT1-MMP', 'Gene', (83, 90))	('MAPK', 'molecular_function', 'GO:0004707', ('52', '56'))	('MMP2', 'molecular_function', 'GO:0004228', ('95', '99'))	('MT1', 'molecular_function', 'GO:0047152', ('83', '86'))	('production', 'MPA', (69, 79))	('MMP', 'molecular_function', 'GO:0004235', ('87', '90'))	('Akt', 'Pathway', (61, 64))
28014	25219541	Additionally, the transcription factor SP1, which can promote MT1-MMP and MMP2 production, was activated by MDA-9/Syntenin, adding to the growing number of pathways that MDA-9/Syntenin influences.	('promote', 'PosReg', (54, 61))	('MDA-9/Syntenin', 'Var', (108, 122))	('MT1', 'molecular_function', 'GO:0043791', ('62', '65'))	('MMP2', 'molecular_function', 'GO:0004228', ('74', '78'))	('MT1-MMP', 'Gene', '4323', (62, 69))	('MMP2', 'Gene', '4313', (74, 78))	('MT1-MMP', 'Gene', (62, 69))	('MT1', 'molecular_function', 'GO:0047152', ('62', '65'))	('transcription factor', 'molecular_function', 'GO:0000981', ('18', '38'))	('transcription', 'biological_process', 'GO:0006351', ('18', '31'))	('MMP2', 'Gene', (74, 78))	('MT1', 'molecular_function', 'GO:0043834', ('62', '65'))	('MMP', 'molecular_function', 'GO:0004235', ('66', '69'))
28022	25219541	The MDA-9/Syntenin-syndecan interaction was the first characterized functional interaction of this protein and was further defined when studies demonstrated MDA-9/ Syntenin altered PIP2 binding led to trapping of syndecans in the perinuclear recycling endosomes.	('syndecan', 'Gene', '6382', (213, 221))	('syndecan', 'Gene', (19, 27))	('syndecan', 'Gene', '6382', (19, 27))	('syndecan', 'molecular_function', 'GO:0015023', ('19', '27'))	('MDA-9/', 'Var', (157, 163))	('rat', 'Species', '10116', (151, 154))	('syndecan', 'Gene', (213, 221))	('binding', 'Interaction', (186, 193))	('PIP2 binding', 'molecular_function', 'GO:0005546', ('181', '193'))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('PIP2', 'Chemical', 'MESH:D019269', (181, 185))	('trapping', 'MPA', (201, 209))
28032	25219541	Its processing and activation is dependent on MDA-9/Syntenin's interaction with syndecan-1, and knockdown of MDA-9/Syntenin can inhibit heparanase processing by > 50%.	('knockdown', 'Var', (96, 105))	('heparanase', 'Gene', '10855', (136, 146))	('inhibit', 'NegReg', (128, 135))	('syndecan-1', 'Gene', '6382', (80, 90))	('heparanase', 'Gene', (136, 146))	('MDA-9/Syntenin', 'Gene', (109, 123))	('syndecan-1', 'Gene', (80, 90))	('syndecan', 'molecular_function', 'GO:0015023', ('80', '88'))
28034	25219541	MDA-9/Syntenin knockdown led to both reduced numbers and average size of exosomes detected, while overexpression of MDA-9/Syntenin could increase the number of exosomes approximately twofold in breast cancer cells.	('breast cancer', 'Disease', (194, 207))	('knockdown', 'Var', (15, 24))	('average size of exosomes detected', 'MPA', (57, 90))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('reduced', 'NegReg', (37, 44))	('numbers', 'MPA', (45, 52))	('MDA-9/Syntenin', 'Gene', (0, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
28038	25219541	Tetraspannins are found in the plasma membrane and can associate with numerous receptors and cell-surface molecules, including RTKs and integrins, and regulate their maturation, activity and processing.	('processing', 'MPA', (191, 201))	('maturation', 'MPA', (166, 176))	('rat', 'Species', '10116', (170, 173))	('regulate', 'Reg', (151, 159))	('Tetraspannins', 'Var', (0, 13))	('plasma membrane', 'cellular_component', 'GO:0005886', ('31', '46'))	('cell-surface', 'cellular_component', 'GO:0009986', ('93', '105'))	('activity', 'MPA', (178, 186))	('associate', 'Interaction', (55, 64))
28040	25219541	When MDA-9/Syntenin is overexpressed, the constitutive rapid internalization of CD63 is slowed, and an N-terminal-lacking deletion mutant of MDA-9/Syntenin blocked the internalization of CD63.	('CD63', 'Gene', '967', (80, 84))	('CD63', 'Gene', '967', (187, 191))	('blocked', 'NegReg', (156, 163))	('internalization', 'MPA', (168, 183))	('MDA-9/Syntenin', 'Gene', (141, 155))	('CD63', 'Gene', (187, 191))	('deletion mutant', 'Var', (122, 137))	('CD63', 'Gene', (80, 84))	('slowed', 'NegReg', (88, 94))
28045	25219541	Analysis of human epidermal stem cells revealed that a more proliferative and adhesive population of stem cells marked by high delta-like 1, a binding partner of MDA-9/Syntenin, had over 13-fold higher MDA-9/Syntenin expression.	('MDA-9/Syntenin', 'Gene', (202, 216))	('rat', 'Species', '10116', (67, 70))	('high', 'Var', (122, 126))	('higher', 'PosReg', (195, 201))	('expression', 'MPA', (217, 227))	('binding', 'molecular_function', 'GO:0005488', ('143', '150'))	('human', 'Species', '9606', (12, 17))	('more', 'PosReg', (55, 59))
28049	25219541	When the C-terminal of Delta1 is mutated in the region of its PDZ-binding motif, or if MDA-9/Syntenin expression is downregulated, Notch-driven transcriptional activation was dramatically increased.	('binding', 'molecular_function', 'GO:0005488', ('66', '73'))	('downregulated', 'NegReg', (116, 129))	('activation', 'PosReg', (160, 170))	('Notch', 'Gene', '4851', (131, 136))	('mutated', 'Var', (33, 40))	('Notch', 'Gene', (131, 136))	('Delta1', 'Gene', (23, 29))	('Delta1', 'Gene', '8788', (23, 29))	('increased', 'PosReg', (188, 197))
28058	25219541	Other reports support this role for MDA-9/Syntenin as EphB1 and EphB2 have been shown to bind the PDZ domains of MDA-9/Syntenin to enable synaptic development and inhibition of this partnership prevents presynaptic development.	('EphB1', 'Gene', (54, 59))	('prevents', 'NegReg', (194, 202))	('EphB1', 'Gene', '2047', (54, 59))	('enable', 'PosReg', (131, 137))	('EphB2', 'Gene', '2048', (64, 69))	('presynaptic development', 'CPA', (203, 226))	('synaptic development', 'CPA', (138, 158))	('EphB2', 'Gene', (64, 69))	('MDA-9/Syntenin', 'Gene', (113, 127))	('bind', 'Interaction', (89, 93))	('inhibition', 'Var', (163, 173))
28065	25219541	An in vitro proxy of FDC cells derived from tonsil tissue (the HK cell line) showed that knockdown of MDA-9/Syntenin reduced FAK activation, similar to observations in cancer-derived cell lines.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('reduced', 'NegReg', (117, 124))	('FAK', 'Gene', '5747', (125, 128))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('FAK', 'molecular_function', 'GO:0004717', ('125', '128'))	('cancer', 'Disease', (168, 174))	('knockdown', 'Var', (89, 98))	('MDA-9/Syntenin', 'Gene', (102, 116))	('FAK', 'Gene', (125, 128))
28071	25219541	When MDA-9/Syntenin is knocked down in T cells, actin polymerization is decreased, while PIP2 production is increased along with HIV-1 entry.	('knocked down', 'Var', (23, 35))	('decreased', 'NegReg', (72, 81))	('increased', 'PosReg', (108, 117))	('HIV-1', 'Species', '11676', (129, 134))	('PIP2 production', 'MPA', (89, 104))	('actin polymerization', 'MPA', (48, 68))	('MDA-9/Syntenin', 'Gene', (5, 19))	('PIP2', 'Chemical', 'MESH:D019269', (89, 93))	('actin polymerization', 'biological_process', 'GO:0030041', ('48', '68'))
28075	25219541	In both melanoma and glioma, MDA-9/Syntenin was shown to increase angiogenic potential in tumor cells.	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('MDA-9/Syntenin', 'Var', (29, 43))	('glioma', 'Phenotype', 'HP:0009733', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('increase', 'PosReg', (57, 65))	('melanoma and glioma', 'Disease', 'MESH:D005910', (8, 27))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
28076	25219541	In melanoma, MDA-9/Syntenin was found to induce angiogenesis by activating Akt, leading to hypoxia inducible factor-1alpha induction and transcription of IGF binding protein - 2 (IGFBP-2).	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('induction', 'PosReg', (123, 132))	('Akt', 'Pathway', (75, 78))	('IGF binding protein - 2', 'Gene', (154, 177))	('IGFBP-2', 'Gene', (179, 186))	('hypoxia inducible factor-1alpha', 'Gene', '3091', (91, 122))	('induce', 'PosReg', (41, 47))	('transcription', 'biological_process', 'GO:0006351', ('137', '150'))	('hypoxia inducible factor-1alpha', 'Gene', (91, 122))	('MDA-9/Syntenin', 'Var', (13, 27))	('angiogenesis', 'biological_process', 'GO:0001525', ('48', '60'))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('angiogenesis', 'CPA', (48, 60))	('activating', 'MPA', (64, 74))	('IGF binding protein - 2', 'Gene', '3485', (154, 177))	('IGFBP-2', 'Gene', '3485', (179, 186))	('transcription', 'MPA', (137, 150))	('IGF binding', 'molecular_function', 'GO:0005520', ('154', '165'))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))
28078	25219541	In glioma, MDA-9/Syntenin induced NF-kappaB activation and the production of the prominent angiogenic chemokine IL-8 at both the transcript and protein expression levels.	('IL-8', 'Gene', '3576', (112, 116))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('NF-kappaB', 'Gene', '4790', (34, 43))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('production of', 'MPA', (63, 76))	('IL-8', 'molecular_function', 'GO:0005153', ('112', '116'))	('activation', 'PosReg', (44, 54))	('IL-8', 'Gene', (112, 116))	('NF-kappaB', 'Gene', (34, 43))	('glioma', 'Disease', (3, 9))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('34', '54'))	('MDA-9/Syntenin', 'Var', (11, 25))
28079	25219541	Furthermore, knockdown of MDA-9/Syntenin reduced microvessel branching in in vivo assays, and reduced tumor vascularity in an orthotopic xenograft mouse model.	('reduced', 'NegReg', (41, 48))	('mouse', 'Species', '10090', (147, 152))	('reduced', 'NegReg', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('knockdown', 'Var', (13, 22))	('microvessel branching', 'CPA', (49, 70))	('MDA-9/Syntenin', 'Gene', (26, 40))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
28080	25219541	MDA-9/Syntenin was also shown to help maintain the blood-brain barrier (BBB) integrity, as miR-155 targeting of MDA-9/Syntenin can lead to downregulation and higher measures of BBB permeability.	('targeting', 'Var', (99, 108))	('BBB permeability', 'MPA', (177, 193))	('higher', 'PosReg', (158, 164))	('MDA-9/Syntenin', 'Gene', (112, 126))	('miR-155', 'Gene', '406947', (91, 98))	('miR-155', 'Gene', (91, 98))	('downregulation', 'NegReg', (139, 153))
28082	25219541	A recent study demonstrated that excessive Ang2 secretion could be rescued by syndecan-4 knockout or syntenin inhibition.	('secretion', 'biological_process', 'GO:0046903', ('48', '57'))	('rat', 'Species', '10116', (22, 25))	('syndecan-4', 'Gene', (78, 88))	('syndecan', 'molecular_function', 'GO:0015023', ('78', '86'))	('Ang2', 'Gene', (43, 47))	('Ang2', 'Gene', '285', (43, 47))	('knockout', 'Var', (89, 97))	('syndecan-4', 'Gene', '6385', (78, 88))
28083	25219541	Notably, knockdown of MDA-9/Syntenin, which can bind all syndecans, had a larger reductive effect in Ang2 secretion than single syndecan knockdown.	('syndecan', 'Gene', '6382', (128, 136))	('knockdown', 'Var', (9, 18))	('Ang2', 'Gene', (101, 105))	('syndecan', 'Gene', (57, 65))	('Ang2', 'Gene', '285', (101, 105))	('syndecan', 'Gene', '6382', (57, 65))	('secretion', 'biological_process', 'GO:0046903', ('106', '115'))	('MDA-9/Syntenin', 'Gene', (22, 36))	('syndecan', 'Gene', (128, 136))	('syndecan', 'molecular_function', 'GO:0015023', ('128', '136'))	('reductive effect', 'MPA', (81, 97))
28096	25219541	Published results in numerous tumors utilizing genetic inhibition of MDA-9/Syntenin have thus far supported this view.	('genetic inhibition', 'Var', (47, 65))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('MDA-9/Syntenin', 'Gene', (69, 83))	('numerous tumors', 'Disease', (21, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('numerous tumors', 'Disease', 'MESH:D009369', (21, 36))
28105	25219541	While inhibiting MDA-9/Syntenin can reduce the proliferation rate of some cancer types, the level to which it slows growth is not nearly as dramatic as true cytotoxic therapies.	('inhibiting', 'Var', (6, 16))	('reduce', 'NegReg', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('rat', 'Species', '10116', (54, 57))	('rat', 'Species', '10116', (61, 64))	('cancer', 'Disease', (74, 80))	('slows growth', 'Phenotype', 'HP:0001510', (110, 122))	('proliferation rate', 'CPA', (47, 65))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('MDA-9/Syntenin', 'Gene', (17, 31))
28115	25219541	In these contexts, inhibitors of MDA-9/Syntenin, both direct and those that block its interaction with partner proteins, or its critical downstream pathways may usher in new approaches for successfully treating and potentially preventing tumor spread and metastasis.	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('interaction', 'Interaction', (86, 97))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('inhibitors', 'Var', (19, 29))	('MDA-9/Syntenin', 'Gene', (33, 47))	('tumor', 'Disease', (238, 243))	('preventing', 'NegReg', (227, 237))
28119	25219541	Numerous binding partners and downstream effectors have been identified, many known to be involved in cancer progression including: c-Src, focal adhesion kinase, Akt, p38MAPK, NF-kappaB and MMPs.	('p38MAPK', 'Var', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('c-Src', 'Gene', (132, 137))	('c-Src', 'Gene', '6714', (132, 137))	('Akt', 'Pathway', (162, 165))	('MMPs', 'Gene', '4313;4323', (190, 194))	('NF-kappaB', 'Gene', '4790', (176, 185))	('focal adhesion kinase', 'Gene', '5747', (139, 160))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('MAPK', 'molecular_function', 'GO:0004707', ('170', '174'))	('binding', 'molecular_function', 'GO:0005488', ('9', '16'))	('binding', 'Interaction', (9, 16))	('focal adhesion', 'cellular_component', 'GO:0005925', ('139', '153'))	('focal adhesion kinase', 'Gene', (139, 160))	('NF-kappaB', 'Gene', (176, 185))	('MMPs', 'Gene', (190, 194))
28123	25682876	The development of uveal melanoma is a multistep process involving genetic and epigenetic alteration of proto-oncogenes and tumor-suppressor genes.	('proto-oncogenes', 'Protein', (104, 119))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('uveal melanoma', 'Disease', 'MESH:C536494', (19, 33))	('tumor', 'Disease', (124, 129))	('uveal melanoma', 'Phenotype', 'HP:0007716', (19, 33))	('uveal melanoma', 'Disease', (19, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('epigenetic alteration', 'Var', (79, 100))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('124', '140'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('124', '140'))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
28148	25682876	The most significant discriminators were let-7b and miR-199a, and the expression of these miRNAs was further validated by quantitative PCR.	('let-7b', 'Gene', '406884', (41, 47))	('let-7b', 'Gene', (41, 47))	('miR-199a', 'Var', (52, 60))
28153	25682876	demonstrated that miRNA-20a, miRNA-106a, miRNA-17, miRNA-21, and miRNA-34a were up-regulated, while miRNA-145 and miRNA-204 expression were down-regulated in four uveal melanoma tissues.	('uveal melanoma', 'Disease', 'MESH:C536494', (163, 177))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('up-regulated', 'PosReg', (80, 92))	('uveal melanoma', 'Disease', (163, 177))	('miRNA-204', 'Gene', (114, 123))	('uveal melanoma', 'Phenotype', 'HP:0007716', (163, 177))	('miRNA-34a', 'Gene', '407040', (65, 74))	('miRNA-20a', 'Gene', (18, 27))	('miRNA-17', 'Gene', '406952', (41, 49))	('miRNA-145', 'Gene', (100, 109))	('miRNA-204', 'Gene', '406987', (114, 123))	('down-regulated', 'NegReg', (140, 154))	('miRNA-17', 'Gene', (41, 49))	('miRNA-20a', 'Gene', '406982', (18, 27))	('miRNA-145', 'Gene', '406937', (100, 109))	('miRNA-34a', 'Gene', (65, 74))	('miRNA-21', 'Gene', '406991', (51, 59))	('miRNA-106a', 'Var', (29, 39))	('miRNA-21', 'Gene', (51, 59))
28161	25682876	found that plasma levels of miR-20a, 125b, 146a, 155, 181a, and 223 were higher in the study patients at diagnosis as uveal melanoma compared to controls.	('plasma levels', 'MPA', (11, 24))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('uveal melanoma', 'Phenotype', 'HP:0007716', (118, 132))	('uveal melanoma', 'Disease', (118, 132))	('uveal melanoma', 'Disease', 'MESH:C536494', (118, 132))	('146a', 'Var', (43, 47))	('miR-20a', 'Gene', (28, 35))	('miR-20a', 'Gene', '406982', (28, 35))	('patients', 'Species', '9606', (93, 101))	('higher', 'PosReg', (73, 79))
28162	25682876	Plasma levels of miR-20a, 125b, 146a, 155, and 223 increased, and miR-181a decreased when metastasis manifested.	('miR-20a', 'Gene', (17, 24))	('increased', 'PosReg', (51, 60))	('155', 'Var', (38, 41))	('146a', 'Var', (32, 36))	('miR', 'Gene', (17, 20))	('miR-20a', 'Gene', '406982', (17, 24))	('miR', 'Gene', (66, 69))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', '220972', (66, 69))	('Plasma levels', 'MPA', (0, 13))
28169	25682876	The transfection of miR-34b/c into uveal melanoma cells also leads to a significant reduction in cell growth and migration.	('uveal melanoma', 'Disease', 'MESH:C536494', (35, 49))	('uveal melanoma', 'Disease', (35, 49))	('reduction', 'NegReg', (84, 93))	('cell growth', 'biological_process', 'GO:0016049', ('97', '108'))	('transfection', 'Var', (4, 16))	('miR-34b', 'Gene', (20, 27))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('miR-34b', 'Gene', '407041', (20, 27))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))
28198	25682876	To date, despite overwhelming reports of dysregulated miRNAs in uveal melanoma tissues, no circulating miRNA has been identified for non-invasive diagnosis of uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (159, 173))	('dysregulated', 'Var', (41, 53))	('uveal melanoma', 'Phenotype', 'HP:0007716', (159, 173))	('uveal melanoma', 'Disease', (159, 173))	('uveal melanoma', 'Phenotype', 'HP:0007716', (64, 78))	('uveal melanoma', 'Disease', 'MESH:C536494', (64, 78))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('uveal melanoma', 'Disease', (64, 78))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
28200	25682876	Recent works have provided new insights to explain miRNA deregulation in uveal melanoma, including epigenetic alteration and deregulated transcription.	('uveal melanoma', 'Disease', 'MESH:C536494', (73, 87))	('miRNA', 'Var', (51, 56))	('uveal melanoma', 'Disease', (73, 87))	('uveal melanoma', 'Phenotype', 'HP:0007716', (73, 87))	('transcription', 'biological_process', 'GO:0006351', ('137', '150'))	('epigenetic alteration', 'Var', (99, 120))	('deregulated transcription', 'MPA', (125, 150))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))
28277	24729954	These tumor-derived endothelial cells carried glioblastoma-specific chromosomal aberrations, were not sensitive to VEGF inhibition, and they contributed substantially to the tumor vasculature (range of 20-90%).	('tumor', 'Disease', (174, 179))	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (68, 91))	('carried', 'Reg', (38, 45))	('VEGF', 'Gene', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('VEGF', 'Gene', '7422', (115, 119))	('glioblastoma', 'Disease', (46, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (46, 58))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('chromosomal aberrations', 'Var', (68, 91))
28283	24729954	Inhibition of tumor-associated blood vessels would also eliminate the principal routes of metastasis.	('principal routes of metastasis', 'CPA', (70, 100))	('tumor', 'Disease', (14, 19))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('eliminate', 'NegReg', (56, 65))
28294	24729954	In further support of this theory, AG28262 (a selective inhibitor of VEGFR-1, R-2 and R-3) had no effect on in vitro tube formation or percentage of glioblastoma tumor-derived vessels in vivo.	('VEGFR-1', 'Gene', '2321', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (149, 167))	('R-2 and R-3', 'Gene', '913;912', (78, 89))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('glioblastoma tumor', 'Disease', (149, 167))	('AG28262', 'Var', (35, 42))	('tube formation', 'biological_process', 'GO:0035148', ('117', '131'))	('VEGFR-1', 'Gene', (69, 76))	('AG28262', 'Chemical', '-', (35, 42))
28341	20661247	The most important factors predicting metastatic disease are: (1) basal tumour diameter; (2) ciliary body involvement; (3) transscleral extension; (4) epithelioid melanoma cytomorphology; (5) high mitotic rate; (6) extravascular matrix patterns such as closed loops; (7) microvascular density; (8) chromosome 3 deletion, chromosome 8q gain and lack of chromosome 6p gain and (9) a class 2 gene expression.	('chromosome', 'cellular_component', 'GO:0005694', ('321', '331'))	('deletion', 'Var', (311, 319))	('basal tumour', 'Disease', 'MESH:D002280', (66, 78))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('gene expression', 'biological_process', 'GO:0010467', ('389', '404'))	('chromosome', 'Var', (321, 331))	('expression', 'Reg', (394, 404))	('chromosome', 'Gene', (298, 308))	('lack', 'NegReg', (344, 348))	('gain', 'PosReg', (366, 370))	('gain', 'PosReg', (335, 339))	('chromosome', 'cellular_component', 'GO:0005694', ('298', '308'))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('metastatic disease', 'Disease', (38, 56))	('basal tumour', 'Disease', (66, 78))	('basal tumour', 'Phenotype', 'HP:0002671', (66, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('352', '362'))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))
28366	20661247	In 1996, Prescher et al found that metastatic death occurred exclusively in patients with a monosomy-3 melanoma.	('metastatic death', 'CPA', (35, 51))	('patients', 'Species', '9606', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('monosomy-3', 'Var', (92, 102))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
28369	20661247	The correlation between tumour size and increased mortality (Figure 3) was attributed to the higher prevalence of monosomy-3 in large tumours rather than to any beneficial therapeutic effect.	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('tumours', 'Phenotype', 'HP:0002664', (134, 141))	('monosomy-3', 'Var', (114, 124))	('tumours', 'Disease', 'MESH:D009369', (134, 141))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('tumour', 'Disease', (134, 140))	('tumours', 'Disease', (134, 141))	('tumour', 'Disease', (24, 30))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
28370	20661247	According to this view, uveal melanomas become large after developing monosomy-3 and not before so that correlations between size and mortality reflect rate of tumour growth.	('melanomas', 'Phenotype', 'HP:0002861', (30, 39))	('uveal melanomas', 'Disease', (24, 39))	('uveal melanomas', 'Phenotype', 'HP:0007716', (24, 39))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('tumour growth', 'Disease', (160, 173))	('uveal melanoma', 'Phenotype', 'HP:0007716', (24, 38))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('uveal melanomas', 'Disease', 'MESH:C536494', (24, 39))	('tumour growth', 'Disease', 'MESH:D006130', (160, 173))	('monosomy-3', 'Var', (70, 80))
28373	20661247	It was therefore assumed by some that monosomy-3 was the lethal abnormality and that chromosome 8q gain merely accelerated metastatic death, possibly because of increased expression of the C-MYC gene.	('expression', 'MPA', (171, 181))	('accelerated', 'PosReg', (111, 122))	('chromosome', 'cellular_component', 'GO:0005694', ('85', '95'))	('C-MYC', 'Gene', (189, 194))	('chromosome', 'Var', (85, 95))	('C-MYC', 'Gene', '4609', (189, 194))	('monosomy-3', 'Var', (38, 48))	('metastatic death', 'CPA', (123, 139))	('increased', 'PosReg', (161, 170))	('gain', 'PosReg', (99, 103))
28377	20661247	Histology and genetic studies showed the base of the tumour to consist of low-grade, spindle-cell melanoma with only partial chromosome 3 loss whereas the apical region showed high-grade, epithelioid cells with monosomy-3 and gains in chromosome 8q.	('chromosome', 'cellular_component', 'GO:0005694', ('125', '135'))	('loss', 'NegReg', (138, 142))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', (53, 59))	('monosomy-3', 'Var', (211, 221))	('spindle', 'cellular_component', 'GO:0005819', ('85', '92'))	('chromosome', 'cellular_component', 'GO:0005694', ('235', '245'))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('gains', 'PosReg', (226, 231))	('tumour', 'Disease', 'MESH:D009369', (53, 59))
28425	17971774	Criteria for entry into the study were: systemically pretreated relapsed AJCC stage IV cutaneous malignant melanoma; white blood cell count >3500 mul-1; platelet count >100 000 mul-1; haematocrit >30%; serum creatinin and bilirubin <1.5 of the upper normal limit; age between 18 and 80 years, and a life expectancy of >3 months.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('mul-1', 'Gene', '79594', (177, 182))	('bilirubin', 'Chemical', 'MESH:D001663', (222, 231))	('>100 000', 'Var', (168, 176))	('mul-1', 'Gene', (177, 182))	('>3500', 'Var', (140, 145))	('malignant melanoma', 'Disease', 'MESH:D008545', (97, 115))	('mul-1', 'Gene', '79594', (146, 151))	('malignant melanoma', 'Phenotype', 'HP:0002861', (97, 115))	('malignant melanoma', 'Disease', (97, 115))	('mul-1', 'Gene', (146, 151))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (87, 115))
28469	9484806	Changes in integrin expression have been shown to be important for the growth and metastatic capacity of melanoma cells.	('expression', 'MPA', (20, 30))	('metastatic capacity', 'CPA', (82, 101))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('integrin', 'Protein', (11, 19))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('Changes', 'Var', (0, 7))
28489	33194647	During the past few decades, genetic or epigenetic alterations have been confirmed to be associated with the tumorigenesis and progression of UM.	('associated', 'Reg', (89, 99))	('UM', 'Phenotype', 'HP:0007716', (142, 144))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('epigenetic alterations', 'Var', (40, 62))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('genetic', 'Var', (29, 36))	('tumor', 'Disease', (109, 114))
28490	33194647	According to reports, GNAQ and GNA11 mutations can promote cell proliferation and metastasis.	('GNAQ', 'Gene', (22, 26))	('cell proliferation', 'CPA', (59, 77))	('mutations', 'Var', (37, 46))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('promote', 'PosReg', (51, 58))	('GNAQ', 'Gene', '2776', (22, 26))	('GNA11', 'Gene', (31, 36))	('GNA11', 'Gene', '2767', (31, 36))
28491	33194647	In addition, other chromosomal abnormalities have been shown to correlate with poor prognosis and these include 6q loss, lack of 6p gain, 1p loss, and 16q loss.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (19, 44))	('16q', 'CPA', (151, 154))	('loss', 'NegReg', (115, 119))	('gain', 'PosReg', (132, 136))	('lack', 'Var', (121, 125))	('chromosomal abnormalities', 'Disease', (19, 44))
28535	33194647	Combining the results of correlation analysis (Figure 10A, Supplementary Table 7) and difference analysis (Figure 10B), a total of three TICs were associated with ten-gene signature risk score (Figure 10C).	('TICs', 'Phenotype', 'HP:0100033', (137, 141))	('TICs', 'Disease', (137, 141))	('associated', 'Reg', (147, 157))	('TICs', 'Disease', 'MESH:D020323', (137, 141))	('ten-gene signature', 'Var', (163, 181))
28560	33194647	Deregulated APOBEC activity is the source of a variety of cancer mutagenesis.	('APOBEC', 'Protein', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Deregulated', 'Var', (0, 11))	('mutagenesis', 'biological_process', 'GO:0006280', ('65', '76'))	('activity', 'MPA', (19, 27))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('APOBEC', 'cellular_component', 'GO:0030895', ('12', '18'))	('cancer', 'Disease', (58, 64))
28561	33194647	HMCES can respond to APOBEC-induced abasic sites, maintain genome stability, and promote replication extension; otherwise, replication will be slowed down by the participation of TLS polymerase.	('maintain', 'PosReg', (50, 58))	('APOBEC', 'cellular_component', 'GO:0030895', ('21', '27'))	('promote', 'PosReg', (81, 88))	('HMCES', 'Gene', '56941', (0, 5))	('APOBEC-induced', 'Gene', (21, 35))	('replication extension', 'CPA', (89, 110))	('HMCES', 'Gene', (0, 5))	('abasic sites', 'Var', (36, 48))	('TLS', 'Gene', (179, 182))	('genome stability', 'CPA', (59, 75))	('TLS', 'Gene', '2521', (179, 182))
28573	33194647	These findings demonstrated that ten-gene signature might potentially participate in the immune-dominant tumor microenvironment.	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('ten-gene signature', 'Var', (33, 51))	('participate', 'Reg', (70, 81))
28601	32340176	Targeted Next-Generation Sequencing of 117 Routine Clinical Samples Provides Further Insights into the Molecular Landscape of Uveal Melanoma Uveal melanoma (UM) has well-characterised somatic copy number alterations (SCNA) in chromosomes 1, 3, 6 and 8, in addition to mutations in GNAQ, GNA11, CYSLTR2, PLCB4, BAP1, SF3B1 and EIF1AX, most being linked to metastatic-risk.	('CYSLTR2', 'Gene', (294, 301))	('PLCB4', 'Gene', (303, 308))	('BAP1', 'Gene', '8314', (310, 314))	('EIF1AX', 'Gene', (326, 332))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('copy number alterations', 'Var', (192, 215))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (126, 140))	('GNA11', 'Gene', '2767', (287, 292))	('EIF1AX', 'Gene', '1964', (326, 332))	('PLCB4', 'Gene', '5332', (303, 308))	('Melanoma', 'Disease', 'MESH:D008545', (132, 140))	('BAP1', 'Gene', (310, 314))	('GNAQ', 'Gene', '2776', (281, 285))	('mutations', 'Var', (268, 277))	('GNAQ', 'Gene', (281, 285))	('SF3B1', 'Gene', (316, 321))	('Melanoma', 'Disease', (132, 140))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (141, 155))	('CYSLTR2', 'Gene', '57105', (294, 301))	('GNA11', 'Gene', (287, 292))	('linked', 'Reg', (345, 351))	('Melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('UM', 'Phenotype', 'HP:0007716', (157, 159))	('SF3B1', 'Gene', '23451', (316, 321))
28602	32340176	UM clinical samples processed either as fresh-frozen, formalin-fixed paraffin embedded (FFPE), small intraocular biopsies or following irradiation were successfully profiled using NGS, with hybrid capture outperforming the PCR-based enrichment methodology.	('formalin', 'Chemical', 'MESH:D005557', (54, 62))	('paraffin', 'Chemical', 'MESH:D010232', (69, 77))	('intraocular', 'Disease', 'MESH:D009798', (101, 112))	('intraocular', 'Disease', (101, 112))	('hybrid', 'Var', (190, 196))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
28603	32340176	We identified monosomy 3 (M3)-UM that were wild-type for BAP1 but harbored SF3B1 mutations, novel frameshift deletions in SF3B1 and EIF1AX, as well as a PLCB4 mutation outside of the hotspot on exon 20 coinciding with a GNAQ mutation in some UM.	('SF3B1', 'Gene', (122, 127))	('GNAQ', 'Gene', '2776', (220, 224))	('EIF1AX', 'Gene', '1964', (132, 138))	('PLCB4', 'Gene', (153, 158))	('EIF1AX', 'Gene', (132, 138))	('UM', 'Phenotype', 'HP:0007716', (242, 244))	('SF3B1', 'Gene', '23451', (122, 127))	('SF3B1', 'Gene', '23451', (75, 80))	('BAP1', 'Gene', '8314', (57, 61))	('mutation', 'Var', (159, 167))	('GNAQ', 'Gene', (220, 224))	('mutations', 'Var', (81, 90))	('frameshift deletions', 'Var', (98, 118))	('PLCB4', 'Gene', '5332', (153, 158))	('BAP1', 'Gene', (57, 61))	('SF3B1', 'Gene', (75, 80))	('UM', 'Phenotype', 'HP:0007716', (30, 32))
28604	32340176	We observed samples that harboured mutations in both BAP1 and SF3B1, and SF3B1 and EIF1AX, respectively.	('EIF1AX', 'Gene', '1964', (83, 89))	('SF3B1', 'Gene', '23451', (73, 78))	('SF3B1', 'Gene', (62, 67))	('BAP1', 'Gene', '8314', (53, 57))	('BAP1', 'Gene', (53, 57))	('SF3B1', 'Gene', (73, 78))	('EIF1AX', 'Gene', (83, 89))	('SF3B1', 'Gene', '23451', (62, 67))	('mutations', 'Var', (35, 44))
28605	32340176	Novel mutations were also identified in TTC28, KTN1, CSMD1 and TP53BP1.	('KTN1', 'Gene', '3895', (47, 51))	('CSMD1', 'Gene', (53, 58))	('CSMD1', 'Gene', '64478', (53, 58))	('KTN1', 'Gene', (47, 51))	('TP53BP1', 'Gene', '7158', (63, 70))	('TTC28', 'Gene', '23331', (40, 45))	('TTC28', 'Gene', (40, 45))	('mutations', 'Var', (6, 15))	('TP53BP1', 'Gene', (63, 70))
28612	32340176	Liver resection has been shown to prolong the median survival of UM patients by 19 months compared with patients treated palliatively.	('UM', 'Phenotype', 'HP:0007716', (65, 67))	('prolong', 'PosReg', (34, 41))	('Liver resection', 'Var', (0, 15))	('patients', 'Species', '9606', (68, 76))	('patients', 'Species', '9606', (104, 112))
28614	32340176	In addition to these well-characterised SCNA, UM has two sets of driver mutations: one which initiates tumorigenesis in the form of mutually exclusive gain-of-function mutations in GNAQ, GNA11, CYSLTR2 or PLCB4, major players in the Gq signalling pathway; and the other consists of mutations in BAP1, SF3B1/SRSF2 and EIF1AX, which have been correlated with high-, intermediate- and low-metastatic risk groups, respectively.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('GNA11', 'Gene', '2767', (187, 192))	('GNAQ', 'Gene', (181, 185))	('mutations', 'Var', (168, 177))	('EIF1AX', 'Gene', (317, 323))	('BAP1', 'Gene', (295, 299))	('PLCB4', 'Gene', (205, 210))	('SRSF2', 'Gene', '6427', (307, 312))	('CYSLTR2', 'Gene', '57105', (194, 201))	('SRSF2', 'Gene', (307, 312))	('SF3B1', 'Gene', (301, 306))	('GNA11', 'Gene', (187, 192))	('EIF1AX', 'Gene', '1964', (317, 323))	('tumor', 'Disease', (103, 108))	('PLCB4', 'Gene', '5332', (205, 210))	('mutations', 'Var', (282, 291))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('CYSLTR2', 'Gene', (194, 201))	('signalling pathway', 'biological_process', 'GO:0007165', ('236', '254'))	('SF3B1', 'Gene', '23451', (301, 306))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('gain-of-function', 'PosReg', (151, 167))	('BAP1', 'Gene', '8314', (295, 299))	('GNAQ', 'Gene', '2776', (181, 185))
28615	32340176	Inactivating mutations in BAP1 are closely associated with HR-M3 UM, with recent data suggesting that the bi-allelic inactivation of BAP1 is required to influence prognosis.	('UM', 'Phenotype', 'HP:0007716', (65, 67))	('BAP1', 'Gene', (26, 30))	('Inactivating mutations', 'Var', (0, 22))	('HR-M3 UM', 'Disease', (59, 67))	('BAP1', 'Gene', '8314', (133, 137))	('BAP1', 'Gene', '8314', (26, 30))	('associated', 'Reg', (43, 53))	('BAP1', 'Gene', (133, 137))
28616	32340176	Missense mutations in splicing factor SF3B1 are often observed in disomy 3 (D3) UM and have been shown to predispose patients to late-onset metastatic disease.	('disomy 3', 'Disease', (66, 74))	('SF3B1', 'Gene', (38, 43))	('UM', 'Phenotype', 'HP:0007716', (80, 82))	('observed', 'Reg', (54, 62))	('late-onset metastatic disease', 'Disease', (129, 158))	('SF3B1', 'Gene', '23451', (38, 43))	('patients', 'Species', '9606', (117, 125))	('splicing', 'biological_process', 'GO:0045292', ('22', '30'))	('predispose', 'Reg', (106, 116))	('Missense mutations', 'Var', (0, 18))
28617	32340176	Similarly, mutations in SRSF2, another member of the spliceosome, are observed in D3-UM, suggesting there are some functional similarities between SRSF2- and SF3B1-mutant UM.	('SRSF2', 'Gene', '6427', (24, 29))	('mutations', 'Var', (11, 20))	('SRSF2', 'Gene', '6427', (147, 152))	('spliceosome', 'cellular_component', 'GO:0005681', ('53', '64'))	('SF3B1', 'Gene', (158, 163))	('SRSF2', 'Gene', (24, 29))	('SF3B1', 'Gene', '23451', (158, 163))	('SRSF2', 'Gene', (147, 152))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('UM', 'Phenotype', 'HP:0007716', (171, 173))
28618	32340176	Mutations in EIF1AX are mainly observed in D3-UM and are associated with LR-UM.	('LR-UM', 'Disease', (73, 78))	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('D3-UM', 'Disease', (43, 48))	('Mutations', 'Var', (0, 9))	('EIF1AX', 'Gene', '1964', (13, 19))	('EIF1AX', 'Gene', (13, 19))	('observed', 'Reg', (31, 39))	('associated', 'Reg', (57, 67))
28620	32340176	In 2017, a bespoke NGS panel was designed to examine mutations in skin melanoma and UM simultaneously; however, this only examined mutations in GNAQ and GNA11, which are not associated with patient prognosis.	('bespoke NGS', 'Disease', 'None', (11, 22))	('bespoke NGS', 'Disease', (11, 22))	('mutations', 'Var', (131, 140))	('GNAQ', 'Gene', '2776', (144, 148))	('GNA11', 'Gene', '2767', (153, 158))	('GNA11', 'Gene', (153, 158))	('skin melanoma', 'Disease', 'MESH:D008545', (66, 79))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('mutations', 'Var', (53, 62))	('GNAQ', 'Gene', (144, 148))	('skin melanoma', 'Disease', (66, 79))	('patient', 'Species', '9606', (190, 197))
28621	32340176	Another panel combined SCNA analysis of chromosomes 1, 3 and 8 and mutation analysis of GNAQ, GNA11, BAP1, SF3B1 and EIF1AX using the Ion Torrent (Thermofisher Scientific) sequencing platform.	('GNAQ', 'Gene', (88, 92))	('GNA11', 'Gene', '2767', (94, 99))	('mutation', 'Var', (67, 75))	('BAP1', 'Gene', '8314', (101, 105))	('SF3B1', 'Gene', (107, 112))	('EIF1AX', 'Gene', '1964', (117, 123))	('BAP1', 'Gene', (101, 105))	('GNAQ', 'Gene', '2776', (88, 92))	('SF3B1', 'Gene', '23451', (107, 112))	('GNA11', 'Gene', (94, 99))	('EIF1AX', 'Gene', (117, 123))
28625	32340176	We examined the ability of NGS to detect both SCNA in chr 1, 3, 6 and 8, and mutations in GNAQ, GNA11, CYSLTR2, PLCB4, BAP1, SF3B1, SRSF2, EIF1AX, FBXW7, DLK2, CSMD1, KTN1, TP53BP1 and TTC28, in irradiated UM, as well as in FFPE tumor samples.	('SF3B1', 'Gene', '23451', (125, 130))	('TTC28', 'Gene', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('KTN1', 'Gene', (167, 171))	('CYSLTR2', 'Gene', (103, 110))	('PLCB4', 'Gene', '5332', (112, 117))	('DLK2', 'Gene', '65989', (154, 158))	('DLK2', 'Gene', (154, 158))	('BAP1', 'Gene', (119, 123))	('TP53BP1', 'Gene', '7158', (173, 180))	('FBXW7', 'Gene', '55294', (147, 152))	('SRSF2', 'Gene', '6427', (132, 137))	('GNA11', 'Gene', '2767', (96, 101))	('SRSF2', 'Gene', (132, 137))	('TP53BP1', 'Gene', (173, 180))	('EIF1AX', 'Gene', (139, 145))	('KTN1', 'Gene', '3895', (167, 171))	('CSMD1', 'Gene', '64478', (160, 165))	('GNAQ', 'Gene', '2776', (90, 94))	('CSMD1', 'Gene', (160, 165))	('tumor', 'Disease', (229, 234))	('mutations', 'Var', (77, 86))	('SF3B1', 'Gene', (125, 130))	('GNAQ', 'Gene', (90, 94))	('UM', 'Phenotype', 'HP:0007716', (206, 208))	('TTC28', 'Gene', '23331', (185, 190))	('EIF1AX', 'Gene', '1964', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('PLCB4', 'Gene', (112, 117))	('CYSLTR2', 'Gene', '57105', (103, 110))	('BAP1', 'Gene', '8314', (119, 123))	('FBXW7', 'Gene', (147, 152))	('GNA11', 'Gene', (96, 101))
28635	32340176	There was 100% concordance for GNAQ, GNA11, BAP1, SF3B1 and EIF1AX mutations between both testing platforms.	('SF3B1', 'Gene', (50, 55))	('GNA11', 'Gene', '2767', (37, 42))	('GNA11', 'Gene', (37, 42))	('GNAQ', 'Gene', '2776', (31, 35))	('EIF1AX', 'Gene', '1964', (60, 66))	('EIF1AX', 'Gene', (60, 66))	('mutations', 'Var', (67, 76))	('SF3B1', 'Gene', '23451', (50, 55))	('BAP1', 'Gene', '8314', (44, 48))	('GNAQ', 'Gene', (31, 35))	('BAP1', 'Gene', (44, 48))
28637	32340176	Driver mutations occurred in 50/117 (43%) for BAP1 (1/50 (2%) occurring in a D3-UM); 25/117 (21%) for SF3B1 (3/25 (12%) coincided with a BAP1 mutation 2/25 (8%) coincided with an EIF1AX mutation, 5/25 (20%) had partial loss or M3); 22/117 (19%) for EIF1AX (2/22 (9%) occurring in a M3-UM).	('BAP1', 'Gene', (137, 141))	('SF3B1', 'Gene', (102, 107))	('UM', 'Phenotype', 'HP:0007716', (285, 287))	('BAP1', 'Gene', '8314', (46, 50))	('EIF1AX', 'Gene', '1964', (179, 185))	('UM', 'Phenotype', 'HP:0007716', (80, 82))	('EIF1AX', 'Gene', (249, 255))	('SF3B1', 'Gene', '23451', (102, 107))	('EIF1AX', 'Gene', '1964', (249, 255))	('BAP1', 'Gene', (46, 50))	('BAP1', 'Gene', '8314', (137, 141))	('EIF1AX', 'Gene', (179, 185))	('mutation', 'Var', (186, 194))	('mutations', 'Var', (7, 16))
28638	32340176	Interestingly, two D3-UM were found to have concurrent EIF1AX and SF3B1 mutations.	('mutations', 'Var', (72, 81))	('EIF1AX', 'Gene', '1964', (55, 61))	('EIF1AX', 'Gene', (55, 61))	('SF3B1', 'Gene', (66, 71))	('UM', 'Phenotype', 'HP:0007716', (22, 24))	('SF3B1', 'Gene', '23451', (66, 71))
28639	32340176	Novel mutations were observed in: PLCB4: 1/117 p.Met549_Gly556delinsIle; KTN1: 2/117 p.Pro195Thr p.Gln86dup; TTC28: 4/117p.	('TTC28', 'Gene', (109, 114))	('TTC28', 'Gene', '23331', (109, 114))	('PLCB4', 'Gene', '5332', (34, 39))	('p.Pro195Thr p.Gln86dup', 'Var', (85, 107))	('p.Met549_Gly556delinsIle', 'DELETION_INSERTION', 'None', (47, 71))	('p.Gln86dup', 'DUPLICATION', 'None', (97, 107))	('KTN1', 'Gene', '3895', (73, 77))	('p.Pro195Thr', 'Mutation', 'p.P195T', (85, 96))	('PLCB4', 'Gene', (34, 39))	('p.Gln86dup', 'Var', (97, 107))	('p.Met549_Gly556delinsIle', 'Var', (47, 71))	('KTN1', 'Gene', (73, 77))
28640	32340176	Arg21*, p.Pro1216His, p.Ala18Gly and p.lleI1296Val; CCMD1: 2/117 p.Pro1097His, p.Pro108Leu; TP53BP1: 2/117 p.Ile455_Pro456del and p.Glu1529*.	('p.Ala18Gly', 'Mutation', 'rs1234275172', (22, 32))	('p.Pro1216His', 'Mutation', 'p.P1216H', (8, 20))	('p.Glu1529*', 'Var', (130, 140))	('p.Glu1529*', 'Mutation', 'p.E1529*', (130, 140))	('TP53BP1', 'Gene', '7158', (92, 99))	('TP53BP1', 'Gene', (92, 99))	('p.Pro1097His', 'Mutation', 'p.P1097H', (65, 77))	('p.Ile455_Pro456del', 'Mutation', 'p.455_,456delP', (107, 125))	('Arg21*', 'Var', (0, 6))	('p.Pro108Leu', 'Mutation', 'p.P108L', (79, 90))	('p.Ile455_Pro456del', 'Var', (107, 125))	('lleI1296Val', 'Chemical', '-', (39, 50))	('Arg21', 'Chemical', '-', (0, 5))	('p.Pro108Leu', 'Var', (79, 90))	('p.Pro1097His', 'Var', (65, 77))	('p.Pro1216His', 'Var', (8, 20))
28643	32340176	Kaplan-Meier survival curves and tables were examined for all primary UM stratified according to: chr3 status, extra copies of chr8q, and mutations in BAP1 and SF3B1.	('SF3B1', 'Gene', (160, 165))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('BAP1', 'Gene', (151, 155))	('chr8q', 'Gene', (127, 132))	('SF3B1', 'Gene', '23451', (160, 165))	('BAP1', 'Gene', '8314', (151, 155))	('extra copies', 'Var', (111, 123))	('mutations', 'Var', (138, 147))
28644	32340176	The following were significantly associated with a reduced survival time: loss of chr3 (Log Rank p  <  0.001), BAP1 mutations (Log Rank p  <  0.001), M3-UM with more than two copies of 8q (Log Rank p  =  0.014) and D3-UM with SF3B1 mutations (Log Rank p  =  0.027) (Figure 2).	('reduced', 'NegReg', (51, 58))	('SF3B1', 'Gene', (226, 231))	('BAP1', 'Gene', '8314', (111, 115))	('survival time', 'CPA', (59, 72))	('chr3', 'Gene', (82, 86))	('UM', 'Phenotype', 'HP:0007716', (153, 155))	('UM', 'Phenotype', 'HP:0007716', (218, 220))	('loss', 'NegReg', (74, 78))	('SF3B1', 'Gene', '23451', (226, 231))	('mutations', 'Var', (232, 241))	('BAP1', 'Gene', (111, 115))	('mutations', 'Var', (116, 125))
28646	32340176	nBAP1 protein was absent in 38/70 cases (54%) of which 31 (82%) UM also had mutations in the BAP1 gene.	('protein', 'Protein', (6, 13))	('BAP1', 'Gene', '8314', (93, 97))	('mutations', 'Var', (76, 85))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('absent', 'NegReg', (18, 24))	('BAP1', 'Gene', '8314', (1, 5))	('BAP1', 'Gene', (93, 97))	('UM', 'Phenotype', 'HP:0007716', (64, 66))	('BAP1', 'Gene', (1, 5))
28647	32340176	Of the 7/38 (18%) UM with no BAP1 mutations, four patients had M3-UM and three had died from metastatic disease.	('died', 'Disease', 'MESH:D003643', (83, 87))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('patients', 'Species', '9606', (50, 58))	('UM', 'Phenotype', 'HP:0007716', (18, 20))	('BAP1', 'Gene', '8314', (29, 33))	('M3-UM', 'Disease', (63, 68))	('BAP1', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))	('died', 'Disease', (83, 87))
28648	32340176	Furthermore, 3/32 (9%) UM positively expressed nBAP1 protein but had clear mutations in BAP1, all of which were missense alterations (q.Glu31Lys, q.Cys91Gly and q.Ala142Pro).	('BAP1', 'Gene', '8314', (48, 52))	('q.Ala142Pro', 'Var', (161, 172))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('BAP1', 'Gene', (48, 52))	('positively', 'PosReg', (26, 36))	('q.Cys91Gly', 'Var', (146, 156))	('BAP1', 'Gene', '8314', (88, 92))	('q.Glu31Lys', 'Var', (134, 144))	('protein', 'Protein', (53, 60))	('UM', 'Phenotype', 'HP:0007716', (23, 25))	('BAP1', 'Gene', (88, 92))
28649	32340176	SF3B1 mutations have previously been associated with D3-UM with late onset metastasis.	('SF3B1', 'Gene', (0, 5))	('D3-UM', 'Disease', (53, 58))	('SF3B1', 'Gene', '23451', (0, 5))	('associated', 'Reg', (37, 47))	('mutations', 'Var', (6, 15))	('UM', 'Phenotype', 'HP:0007716', (56, 58))
28650	32340176	In our cohort, 5/25 cases (20%) with SF3B1 mutations died of metastatic UM at the time of study closure.	('metastatic UM', 'CPA', (61, 74))	('SF3B1', 'Gene', '23451', (37, 42))	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('mutations', 'Var', (43, 52))	('died', 'Disease', (53, 57))	('died', 'Disease', 'MESH:D003643', (53, 57))	('SF3B1', 'Gene', (37, 42))
28651	32340176	Of these five cases, four tumors were D3-UM and one was a M3-UM with a BAP1 mutation.	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('BAP1', 'Gene', '8314', (71, 75))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('mutation', 'Var', (76, 84))	('BAP1', 'Gene', (71, 75))	('D3-UM', 'Disease', (38, 43))	('tumors', 'Disease', (26, 32))
28652	32340176	To investigate the prevalence of SF3B1 mutations in M3-UM that lacked mutations in BAP1, we identified 20 additional cases of M3-UM where DNA was available and previous IHC analysis had demonstrated strong nBAP1 positivity, correlating with wild-type BAP1.	('positivity', 'MPA', (212, 222))	('BAP1', 'Gene', (251, 255))	('SF3B1', 'Gene', '23451', (33, 38))	('BAP1', 'Gene', '8314', (207, 211))	('BAP1', 'Gene', (83, 87))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('mutations', 'Var', (39, 48))	('UM', 'Phenotype', 'HP:0007716', (129, 131))	('BAP1', 'Gene', (207, 211))	('BAP1', 'Gene', '8314', (251, 255))	('SF3B1', 'Gene', (33, 38))	('BAP1', 'Gene', '8314', (83, 87))
28653	32340176	Of these additional 20 UM, 5 (25%) had mutations in SF3B1; 3/5 (60%) q.Arg625Cys and 2/5 (40%) q.Arg625His.	('mutations', 'Var', (39, 48))	('SF3B1', 'Gene', (52, 57))	('UM', 'Phenotype', 'HP:0007716', (23, 25))	('SF3B1', 'Gene', '23451', (52, 57))	('q.Arg625Cys', 'Var', (69, 80))	('q.Arg625His', 'Var', (95, 106))
28656	32340176	We identified a subset of M3-UM-patients without nBAP1 loss that demonstrated mutations in SF3B1 and also describe concurrent disruptive frameshift deletions in SF3B1 and EIF1AX.	('SF3B1', 'Gene', (91, 96))	('SF3B1', 'Gene', (161, 166))	('patients', 'Species', '9606', (32, 40))	('EIF1AX', 'Gene', '1964', (171, 177))	('EIF1AX', 'Gene', (171, 177))	('SF3B1', 'Gene', '23451', (91, 96))	('mutations', 'Var', (78, 87))	('frameshift deletions', 'Var', (137, 157))	('BAP1', 'Gene', '8314', (50, 54))	('SF3B1', 'Gene', '23451', (161, 166))	('UM', 'Phenotype', 'HP:0007716', (29, 31))	('BAP1', 'Gene', (50, 54))
28657	32340176	This is consistent with the observation in one case sequenced in TCGA that harboured both an EIF1AX and an atypical SF3B1 (T663P) mutation.	('SF3B1', 'Gene', (116, 121))	('EIF1AX', 'Gene', '1964', (93, 99))	('EIF1AX', 'Gene', (93, 99))	('SF3B1', 'Gene', '23451', (116, 121))	('T663P', 'Var', (123, 128))	('T663P', 'Mutation', 'p.T663P', (123, 128))
28658	32340176	We also observed co-occurring mutations in BAP1 and SF3B1 and EIF1AX and SF3B1.	('BAP1', 'Gene', (43, 47))	('SF3B1', 'Gene', '23451', (73, 78))	('SF3B1', 'Gene', (52, 57))	('BAP1', 'Gene', '8314', (43, 47))	('mutations', 'Var', (30, 39))	('EIF1AX', 'Gene', '1964', (62, 68))	('SF3B1', 'Gene', (73, 78))	('SF3B1', 'Gene', '23451', (52, 57))	('EIF1AX', 'Gene', (62, 68))
28659	32340176	Of interest, we identified a mutation in PLCB4 that does not fall within the hotspot on exon 20 and coincides with a GNAQ mutation.	('mutation', 'Var', (29, 37))	('fall', 'Phenotype', 'HP:0002527', (61, 65))	('GNAQ', 'Gene', '2776', (117, 121))	('PLCB4', 'Gene', '5332', (41, 46))	('PLCB4', 'Gene', (41, 46))	('GNAQ', 'Gene', (117, 121))
28661	32340176	Similar comparison investigations in other cancer types found limited sensitivity of PCR-based sequencing, with several variants being missed due to regions of high guanine-cytosine content and suboptimal PCR conditions, yielding a minimal coverage not found when using hybrid capture.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('guanine-cytosine content', 'MPA', (165, 189))	('variants', 'Var', (120, 128))	('guanine', 'Chemical', 'MESH:D006147', (165, 172))	('cytosine', 'Chemical', 'MESH:D003596', (173, 181))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
28662	32340176	Of the remaining six discordant samples, four had been classified as M3 by MLPA but as D3 by NGS; two of these cases had SF3B1 mutations but all patients were alive at the study closure.	('patients', 'Species', '9606', (145, 153))	('mutations', 'Var', (127, 136))	('SF3B1', 'Gene', (121, 126))	('SF3B1', 'Gene', '23451', (121, 126))
28663	32340176	Two had been classified as D3 by MLPA but M3 by NGS; one had a BAP1 mutation and both patients had died from metastatic disease.	('mutation', 'Var', (68, 76))	('BAP1', 'Gene', (63, 67))	('died', 'Disease', (99, 103))	('died', 'Disease', 'MESH:D003643', (99, 103))	('BAP1', 'Gene', '8314', (63, 67))	('patients', 'Species', '9606', (86, 94))
28665	32340176	The frequency of BAP1 mutations in the present study was 43% in total, occurring in 82% of M3-UM; these data are consistent with the findings of others.	('UM', 'Phenotype', 'HP:0007716', (94, 96))	('occurring', 'Reg', (71, 80))	('M3-UM', 'Disease', (91, 96))	('mutations', 'Var', (22, 31))	('BAP1', 'Gene', '8314', (17, 21))	('BAP1', 'Gene', (17, 21))
28666	32340176	The presence of a BAP1 mutation in UM was associated with a worse survival.	('BAP1', 'Gene', '8314', (18, 22))	('BAP1', 'Gene', (18, 22))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('mutation', 'Var', (23, 31))
28667	32340176	We have previously reported that nBAP1+ M3-UM have a better prognosis as compared with nBAP1- M3-UM; however, interestingly in this current study, M3-UM that were wild-type for BAP1 (10/57; 18%) did not correlate with an increased survival time as compared with M3-UM with BAP1 mutations.	('BAP1', 'Gene', (34, 38))	('UM', 'Phenotype', 'HP:0007716', (265, 267))	('UM', 'Phenotype', 'HP:0007716', (97, 99))	('BAP1', 'Gene', (88, 92))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('BAP1', 'Gene', '8314', (177, 181))	('BAP1', 'Gene', '8314', (88, 92))	('BAP1', 'Gene', '8314', (273, 277))	('UM', 'Phenotype', 'HP:0007716', (150, 152))	('M3-UM', 'Var', (147, 152))	('BAP1', 'Gene', '8314', (34, 38))	('BAP1', 'Gene', (177, 181))	('BAP1', 'Gene', (273, 277))
28668	32340176	This may be due to either the observation that BAP1 mutations do not always correlate with loss of nBAP1 protein expression, or to the smaller cohort of patients in the present study.	('mutations', 'Var', (52, 61))	('expression', 'MPA', (113, 123))	('BAP1', 'Gene', '8314', (100, 104))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('patients', 'Species', '9606', (153, 161))	('BAP1', 'Gene', (100, 104))	('BAP1', 'Gene', '8314', (47, 51))	('loss', 'NegReg', (91, 95))	('protein', 'Protein', (105, 112))	('BAP1', 'Gene', (47, 51))
28669	32340176	The frequency of SF3B1 mutations in UM ranges in the literature from 11-34%, and in this study SF3B1 mutations occurred in 21% of cases.	('SF3B1', 'Gene', (95, 100))	('SF3B1', 'Gene', (17, 22))	('SF3B1', 'Gene', '23451', (95, 100))	('mutations', 'Var', (23, 32))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('SF3B1', 'Gene', '23451', (17, 22))
28670	32340176	SF3B1 mutations are reported to occur mainly in D3-UM associated with late onset metastasis and decreased survival (22).	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('SF3B1', 'Gene', (0, 5))	('decreased', 'NegReg', (96, 105))	('survival', 'CPA', (106, 114))	('SF3B1', 'Gene', '23451', (0, 5))	('associated', 'Reg', (54, 64))	('mutations', 'Var', (6, 15))
28671	32340176	This is consistent with our study in which 20/25 (80%) SF3B1 mutations occurred in D3-UM with a significantly reduced survival time as compared with D3/SF3B1wt UM (p = 0.027).	('SF3B1', 'Gene', '23451', (152, 157))	('SF3B1', 'Gene', '23451', (55, 60))	('UM', 'Phenotype', 'HP:0007716', (86, 88))	('reduced', 'NegReg', (110, 117))	('mutations', 'Var', (61, 70))	('UM', 'Phenotype', 'HP:0007716', (160, 162))	('SF3B1', 'Gene', (152, 157))	('SF3B1', 'Gene', (55, 60))	('survival time', 'CPA', (118, 131))
28672	32340176	A novel disruptive frameshift deletion in SF3B1 of 15 nucleotides was observed in p.Lys653_Ser657del on heat domain 4, outside the hotspot region of codon 625; the significance of this is unclear.	('p.Lys653_Ser657del', 'Mutation', 'p.653_,657delS', (82, 100))	('SF3B1', 'Gene', (42, 47))	('SF3B1', 'Gene', '23451', (42, 47))	('p.Lys653_Ser657del', 'Var', (82, 100))	('Ser', 'cellular_component', 'GO:0005790', ('91', '94'))
28673	32340176	Of particular interest in our study are five M3-UM or UM with PL of chromosome 3 with SF3B1 mutations.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('mutations', 'Var', (92, 101))	('SF3B1', 'Gene', (86, 91))	('UM', 'Phenotype', 'HP:0007716', (54, 56))	('SF3B1', 'Gene', '23451', (86, 91))
28674	32340176	Two of these UM harboured BAP1 mutations, previously described in one other study (11); one patient succumbed to metastatic disease 12 months after primary management, and the second patient died of other causes 99 months (8.25 years) later.	('BAP1', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('patient', 'Species', '9606', (92, 99))	('died', 'Disease', 'MESH:D003643', (191, 195))	('died', 'Disease', (191, 195))	('patient', 'Species', '9606', (183, 190))	('BAP1', 'Gene', '8314', (26, 30))	('UM', 'Phenotype', 'HP:0007716', (13, 15))
28675	32340176	Three SF3B1 mutations were recorded in M3-BAP1wt UM, a phenomenon only observed in one other study to date.	('BAP1', 'Gene', '8314', (42, 46))	('SF3B1', 'Gene', (6, 11))	('UM', 'Phenotype', 'HP:0007716', (49, 51))	('mutations', 'Var', (12, 21))	('BAP1', 'Gene', (42, 46))	('SF3B1', 'Gene', '23451', (6, 11))	('recorded', 'Reg', (27, 35))
28676	32340176	To examine this further, we tested an additional 20 cases of M3-UM with nBAP1 positivity and identified five cases with SF3B1 mutations; at the time of study closure, all five patients were alive.	('patients', 'Species', '9606', (176, 184))	('BAP1', 'Gene', '8314', (73, 77))	('positivity', 'Var', (78, 88))	('SF3B1', 'Gene', (120, 125))	('BAP1', 'Gene', (73, 77))	('SF3B1', 'Gene', '23451', (120, 125))	('tested', 'Reg', (28, 34))	('mutations', 'Var', (126, 135))	('UM', 'Phenotype', 'HP:0007716', (64, 66))
28677	32340176	Additional cases and longer follow-up are required to fully understand the clinical relevance of SF3B1 mutations in M3-UM.	('mutations', 'Var', (103, 112))	('SF3B1', 'Gene', '23451', (97, 102))	('M3-UM', 'Gene', (116, 121))	('SF3B1', 'Gene', (97, 102))	('UM', 'Phenotype', 'HP:0007716', (119, 121))
28678	32340176	EIF1AX mutations were detected in the present study in 19% of UM, which is consistent with that reported by other groups.	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('detected', 'Reg', (22, 30))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
28679	32340176	Interestingly, two UM demonstrated mutations in both EIF1AX and SF3B1 despite previous reports describing that these occur in a mutually exclusive manner.	('SF3B1', 'Gene', (64, 69))	('EIF1AX', 'Gene', '1964', (53, 59))	('EIF1AX', 'Gene', (53, 59))	('SF3B1', 'Gene', '23451', (64, 69))	('UM', 'Phenotype', 'HP:0007716', (19, 21))	('mutations', 'Var', (35, 44))
28681	32340176	EIF1AX mutations are typically associated with D3-UM; however, we identified two M3-UM that displayed mutations in this gene.	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('associated', 'Reg', (31, 41))	('M3-UM', 'Disease', (81, 86))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('D3-UM', 'Disease', (47, 52))	('mutations', 'Var', (102, 111))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
28682	32340176	A novel disruptive frameshift deletion of 6 nucleotides from the coding sequence was also identified in p.Arg14_Gly15del of EIF1AX.	('EIF1AX', 'Gene', '1964', (124, 130))	('EIF1AX', 'Gene', (124, 130))	('p.Arg14_Gly15del', 'Mutation', 'p.14,15del', (104, 120))	('p.Arg14_Gly15del', 'Var', (104, 120))
28683	32340176	Mutations in GNAQ and GNA11 occurred in 89% of UM in a mutually exclusive manner (53% and 39%, respectively), consistent with the literature.	('occurred', 'Reg', (28, 36))	('GNA11', 'Gene', (22, 27))	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (22, 27))	('Mutations', 'Var', (0, 9))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('GNAQ', 'Gene', '2776', (13, 17))
28684	32340176	Mutations predominantly occurred in exon 5 for GNAQ and GNA11, and two UM had mutations in exon 4.	('GNAQ', 'Gene', (47, 51))	('UM', 'Phenotype', 'HP:0007716', (71, 73))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', '2776', (47, 51))	('GNA11', 'Gene', (56, 61))	('occurred', 'Reg', (24, 32))	('GNA11', 'Gene', '2767', (56, 61))
28685	32340176	One sample contained two unusual mutations in exon 4 of GNA11 p.R214K and p.R214S.	('p.R214K', 'Mutation', 'p.R214K', (62, 69))	('p.R214K', 'Var', (62, 69))	('p.R214S', 'Mutation', 'p.R214S', (74, 81))	('GNA11', 'Gene', (56, 61))	('p.R214S', 'Var', (74, 81))	('GNA11', 'Gene', '2767', (56, 61))
28687	32340176	Mutations in CYSLTR2 were found in two UM in the hot spot region p.L129Q in exon 1 and occurred in a mutually exclusive manner to mutations in GNAQ and GNA11, as previously reported.	('GNA11', 'Gene', '2767', (152, 157))	('CYSLTR2', 'Gene', (13, 20))	('GNAQ', 'Gene', (143, 147))	('p.L129Q', 'Mutation', 'p.L129Q', (65, 72))	('UM', 'Phenotype', 'HP:0007716', (39, 41))	('p.L129Q', 'Var', (65, 72))	('GNAQ', 'Gene', '2776', (143, 147))	('CYSLTR2', 'Gene', '57105', (13, 20))	('GNA11', 'Gene', (152, 157))
28689	32340176	Disruptive frameshift deletions in p.M549_G556delinsI and M561_G568delinsI mutations were observed in PLCB4 in a single UM sample.	('p.M549_G556delinsI', 'Mutation', 'p.549,556delinsG,I', (35, 53))	('p.M549_G556delinsI', 'Var', (35, 53))	('PLCB4', 'Gene', '5332', (102, 107))	('M561_G568delinsI', 'Var', (58, 74))	('PLCB4', 'Gene', (102, 107))	('UM', 'Phenotype', 'HP:0007716', (120, 122))	('frameshift deletions', 'Var', (11, 31))
28690	32340176	These cases also showed a p.R183Q mutation in GNAQ.	('p.R183Q', 'Var', (26, 33))	('GNAQ', 'Gene', (46, 50))	('p.R183Q', 'Mutation', 'rs397514698', (26, 33))	('GNAQ', 'Gene', '2776', (46, 50))
28691	32340176	Previous studies identified recurrent mutations in PLCB4 in a hot-spot region p.D630Y and p.D630N on exon 20.	('p.D630N', 'Var', (90, 97))	('p.D630Y', 'Var', (78, 85))	('PLCB4', 'Gene', '5332', (51, 56))	('p.D630Y', 'Mutation', 'p.D630Y', (78, 85))	('p.D630N', 'Mutation', 'p.D630N', (90, 97))	('PLCB4', 'Gene', (51, 56))
28692	32340176	Though it was initially thought that PLCB4 mutations occurred in a mutually exclusive manner to GNAQ, GNA11 and CYSLTR2, our study and that of Robertson et al.	('CYSLTR2', 'Gene', (112, 119))	('GNAQ', 'Gene', '2776', (96, 100))	('GNA11', 'Gene', (102, 107))	('PLCB4', 'Gene', (37, 42))	('GNA11', 'Gene', '2767', (102, 107))	('mutations', 'Var', (43, 52))	('GNAQ', 'Gene', (96, 100))	('CYSLTR2', 'Gene', '57105', (112, 119))	('PLCB4', 'Gene', '5332', (37, 42))
28693	32340176	demonstrate PLCB4 mutations concurrent to GNAQ and GNA11 mutations.	('GNA11', 'Gene', '2767', (51, 56))	('GNAQ', 'Gene', '2776', (42, 46))	('PLCB4', 'Gene', '5332', (12, 17))	('PLCB4', 'Gene', (12, 17))	('GNAQ', 'Gene', (42, 46))	('GNA11', 'Gene', (51, 56))	('mutations', 'Var', (18, 27))
28696	32340176	Due to their low frequency in this study, no association could be made between the mutations in TTC28, CSMD1, KTN1 or TP53BP1 and UM with particular clinical or morphological features.	('mutations', 'Var', (83, 92))	('TP53BP1', 'Gene', '7158', (118, 125))	('TP53BP1', 'Gene', (118, 125))	('TTC28', 'Gene', '23331', (96, 101))	('TTC28', 'Gene', (96, 101))	('KTN1', 'Gene', '3895', (110, 114))	('UM', 'Phenotype', 'HP:0007716', (130, 132))	('KTN1', 'Gene', (110, 114))	('CSMD1', 'Gene', (103, 108))	('CSMD1', 'Gene', '64478', (103, 108))
28709	32340176	Both panels were designed to cover mutations in GNAQ (exons 4 & 5), GNA11 (exons 4 & 5), SF3B1 (exons 12 & 14), EIF1AX (exons 1 and 2), and all exons of BAP1, FBXW7, DLK2, CSMD1, CYSLTR2, KTN1, TP53BP1, SRSF2, PLCB4, TTC28 and BRAF (negative control).	('CSMD1', 'Gene', (172, 177))	('TTC28', 'Gene', (217, 222))	('TP53BP1', 'Gene', (194, 201))	('EIF1AX', 'Gene', '1964', (112, 118))	('PLCB4', 'Gene', '5332', (210, 215))	('GNA11', 'Gene', '2767', (68, 73))	('BAP1', 'Gene', (153, 157))	('FBXW7', 'Gene', (159, 164))	('CYSLTR2', 'Gene', '57105', (179, 186))	('SRSF2', 'Gene', '6427', (203, 208))	('SF3B1', 'Gene', (89, 94))	('KTN1', 'Gene', (188, 192))	('SRSF2', 'Gene', (203, 208))	('CYSLTR2', 'Gene', (179, 186))	('DLK2', 'Gene', '65989', (166, 170))	('DLK2', 'Gene', (166, 170))	('all', 'Gene', (140, 143))	('GNA11', 'Gene', (68, 73))	('FBXW7', 'Gene', '55294', (159, 164))	('SF3B1', 'Gene', '23451', (89, 94))	('BRAF', 'Gene', (227, 231))	('BRAF', 'Gene', '673', (227, 231))	('PLCB4', 'Gene', (210, 215))	('KTN1', 'Gene', '3895', (188, 192))	('TTC28', 'Gene', '23331', (217, 222))	('GNAQ', 'Gene', '2776', (48, 52))	('TP53BP1', 'Gene', '7158', (194, 201))	('EIF1AX', 'Gene', (112, 118))	('BAP1', 'Gene', '8314', (153, 157))	('GNAQ', 'Gene', (48, 52))	('CSMD1', 'Gene', '64478', (172, 177))	('mutations', 'Var', (35, 44))
28717	32340176	Subsequently, the Genome Analysis Toolkit (GATK) (version 3.7) Indel Re-Aligner module was used to locally realign reads around the putative insertion and deletion sites.	('kit', 'Gene', (38, 41))	('kit', 'Gene', '3815', (38, 41))	('insertion', 'Var', (141, 150))	('deletion', 'Var', (155, 163))
28720	32340176	Moreover, consistent with other reports, BAP1 and SF3B1 mutations in addition to 8q copy number are of added importance when determining patient outcome and moves UM stratification away from a binary genetic classification based on chr3 copy number only.	('mutations', 'Var', (56, 65))	('SF3B1', 'Gene', (50, 55))	('patient', 'Species', '9606', (137, 144))	('UM', 'Phenotype', 'HP:0007716', (163, 165))	('BAP1', 'Gene', (41, 45))	('SF3B1', 'Gene', '23451', (50, 55))	('BAP1', 'Gene', '8314', (41, 45))
28729	31558480	Rates of PFS4 in arm 1 and arm 2 were 32.3% and 26.7% (p=0.35), respectively, with median PFS time of 60 and 59 days (p=0.964; HR=0.99).	('arm 1', 'Gene', (17, 22))	('arm 1', 'Gene', '11047', (17, 22))	('PFS4', 'Chemical', '-', (9, 13))	('arm 2', 'Gene', (27, 32))	('arm 2', 'Gene', '51155', (27, 32))	('PFS4', 'Var', (9, 13))
28735	31558480	As opposed to cutaneous melanoma, UMs lack mutations of B-RAF, N-RAS, and c-KIT; however, the majority carry a mutation in either the G-protein alpha-subunit q (GNAQ) or 11 (GNA11).	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('N-RAS', 'Gene', '4893', (63, 68))	('GNAQ', 'Gene', '2776', (161, 165))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (14, 32))	('c-KIT', 'Gene', '3815', (74, 79))	('KIT', 'molecular_function', 'GO:0005020', ('76', '79'))	('GNA11', 'Gene', (174, 179))	('B-RAF', 'Gene', '673', (56, 61))	('c-KIT', 'Gene', (74, 79))	('GNAQ', 'Gene', (161, 165))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('GNA11', 'Gene', '2767', (174, 179))	('N-RAS', 'Gene', (63, 68))	('mutation', 'Var', (111, 119))	('UM', 'Phenotype', 'HP:0007716', (34, 36))	('B-RAF', 'Gene', (56, 61))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))
28738	31558480	These include the tumor suppressor BAP1, RNA splicing factor SF3B1, the transcription initiation factor EIF1AX, and the phospholipase C regulator PCLB4 in the rare non-GNAQ/GNA11 mutated UM.	('EIF1AX', 'Gene', (104, 110))	('RNA', 'cellular_component', 'GO:0005562', ('41', '44'))	('UM', 'Phenotype', 'HP:0007716', (187, 189))	('SF3B1', 'Gene', '23451', (61, 66))	('BAP1', 'Gene', (35, 39))	('RNA splicing', 'biological_process', 'GO:0008380', ('41', '53'))	('GNA11', 'Gene', (173, 178))	('EIF1AX', 'Gene', '1964', (104, 110))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('mutated', 'Var', (179, 186))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('18', '34'))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('SF3B1', 'Gene', (61, 66))	('GNA11', 'Gene', '2767', (173, 178))	('GNAQ', 'Gene', '2776', (168, 172))	('BAP1', 'Gene', '8314', (35, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('18', '34'))	('transcription', 'biological_process', 'GO:0006351', ('72', '85'))	('GNAQ', 'Gene', (168, 172))
28740	31558480	MET expression has been associated with a significantly higher risk of death from metastatic disease and MET expression influences melanoma-specific mortality.	('MET expression', 'Var', (0, 14))	('death', 'Disease', 'MESH:D003643', (71, 76))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('death', 'Disease', (71, 76))	('melanoma', 'Disease', (131, 139))	('mortality', 'Disease', (149, 158))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('metastatic disease', 'CPA', (82, 100))	('MET', 'Var', (105, 108))	('mortality', 'Disease', 'MESH:D003643', (149, 158))	('influences', 'Reg', (120, 130))
28752	31558480	All patients had to meet eligibility criteria including, but not limited to: histologically confirmed metastatic UM, Eastern Cooperative Oncology Group (ECOG) performance status (0-1), response evaluation criteria in solid tumors (RECIST) version 1.0 measurable disease, any number of prior therapies except MET/VEGFR2 inhibitors or alkylating chemotherapy and no increased risk of thrombosis, hemorrhage or pancreatitis as well as standard biochemical parameters including hepatic liver enzymes up to 5 times the upper limit of normal.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('hemorrhage', 'Disease', 'MESH:D006470', (394, 404))	('inhibitors', 'Var', (319, 329))	('thrombosis', 'Disease', 'MESH:D013927', (382, 392))	('VEGFR2', 'Gene', (312, 318))	('thrombosis', 'Disease', (382, 392))	('pancreatitis', 'Phenotype', 'HP:0001733', (408, 420))	('UM', 'Phenotype', 'HP:0007716', (113, 115))	('patients', 'Species', '9606', (4, 12))	('hepatic liver enzymes', 'MPA', (474, 495))	('VEGFR2', 'Gene', '3791', (312, 318))	('hemorrhage', 'Disease', (394, 404))	('solid tumors', 'Disease', (217, 229))	('metastatic', 'Disease', (102, 112))	('pancreatitis', 'Disease', 'MESH:D010195', (408, 420))	('pancreatitis', 'Disease', (408, 420))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('Oncology', 'Phenotype', 'HP:0002664', (137, 145))	('solid tumors', 'Disease', 'MESH:D009369', (217, 229))
28769	31558480	The tumor mutational mutation burden was calculated by the number of mutations that were predicted to cause protein sequencing change, including non-synonymous/stopgain/stoploss SNVs, frameshift/non-frameshift indels, and variants that modify splicing sites.	('tumor', 'Disease', (4, 9))	('mutations', 'Var', (69, 78))	('protein sequencing', 'MPA', (108, 126))	('non-synonymous/stopgain/stoploss', 'Var', (145, 177))	('variants', 'Var', (222, 230))	('splicing', 'MPA', (243, 251))	('splicing', 'biological_process', 'GO:0045292', ('243', '251'))	('change', 'Reg', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('frameshift/non-frameshift indels', 'Var', (184, 216))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
28778	31558480	Prior treatment included ipilimumab in 26% of patients, anti-PD1 antibodies in 17% (no patients received ipilimumab plus nivolumab) and hepatic arterial embolization in 13%.	('arterial embolization', 'Phenotype', 'HP:0004420', (144, 165))	('ipilimumab', 'Chemical', 'MESH:D000074324', (25, 35))	('patients', 'Species', '9606', (46, 54))	('hepatic arterial embolization', 'Disease', 'MESH:D056486', (136, 165))	('hepatic arterial embolization', 'Disease', (136, 165))	('antibodies', 'Var', (65, 75))	('ipilimumab', 'Chemical', 'MESH:D000074324', (105, 115))	('nivolumab', 'Chemical', 'MESH:D000077594', (121, 130))	('hepatic arterial embolization', 'Phenotype', 'HP:0030243', (136, 165))	('PD1', 'Gene', (61, 64))	('PD1', 'Gene', '5133', (61, 64))	('patients', 'Species', '9606', (87, 95))
28779	31558480	Outcomes for response, median PFS, PFS2, PFS4 and OS are described in Table 2.	('PFS2', 'Gene', (35, 39))	('PFS2', 'Gene', '51659', (35, 39))	('PFS4', 'Var', (41, 45))	('PFS4', 'Chemical', '-', (41, 45))
28781	31558480	Of the 31 patients randomized to arm 1, 10 met the primary endpoint of PFS4 (32.3%) compared to 4 of 15 randomized to arm 2 (26.7%; p=0.350).	('arm 1', 'Gene', (33, 38))	('PFS4', 'Chemical', '-', (71, 75))	('PFS4', 'Var', (71, 75))	('patients', 'Species', '9606', (10, 18))	('arm 1', 'Gene', '11047', (33, 38))	('arm 2', 'Gene', (118, 123))	('arm 2', 'Gene', '51155', (118, 123))
28796	31558480	Within the G protein-coupled receptor (GPCR) signaling pathway, mutations in GNA11/Q were enriched.	('GNA11', 'Gene', (77, 82))	('GPCR) signaling pathway', 'biological_process', 'GO:0007186', ('39', '62'))	('GNA11', 'Gene', '2767', (77, 82))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('mutations', 'Var', (64, 73))
28798	31558480	This includes mutations in GOLGA6L10 (32%, n=6), PKD1L3 (26%, n=5), and FAM228B (16%, n=3).	('PKD1L3', 'Gene', (49, 55))	('FAM228B', 'Gene', '375190', (72, 79))	('GOLGA6L10', 'Gene', (27, 36))	('PKD1L3', 'Gene', '342372', (49, 55))	('FAM228B', 'Gene', (72, 79))	('GOLGA6L10', 'Gene', '647042', (27, 36))	('mutations', 'Var', (14, 23))
28806	31558480	The baseline patient characteristics in A091201 suggested a poor risk group with nearly all patients having liver metastases and high levels of LDH.	('metastases', 'Disease', (114, 124))	('LDH', 'MPA', (144, 147))	('patient', 'Species', '9606', (92, 99))	('A091201', 'Var', (40, 47))	('patient', 'Species', '9606', (13, 20))	('patients', 'Species', '9606', (92, 100))	('metastases', 'Disease', 'MESH:D009362', (114, 124))	('A091201', 'Chemical', '-', (40, 47))
28817	31558480	Therefore, a reasonable historical comparison from randomized clinical trials of metastatic UM could be considered to be a weighted median of 2.4 months (175 patients A091201 and SUMIT) or 1.9 months (78 patients A091201 plus patients treated with DTIC plus placebo in SUMIT).	('DTIC', 'Chemical', 'MESH:D003606', (248, 252))	('patients', 'Species', '9606', (204, 212))	('A091201', 'Chemical', '-', (213, 220))	('UM', 'Phenotype', 'HP:0007716', (92, 94))	('UM', 'Phenotype', 'HP:0007716', (180, 182))	('A091201', 'Var', (167, 174))	('A091201', 'Var', (213, 220))	('UM', 'Phenotype', 'HP:0007716', (270, 272))	('patients', 'Species', '9606', (226, 234))	('patients', 'Species', '9606', (158, 166))	('A091201', 'Chemical', '-', (167, 174))
28830	31558480	For example, mutations in the GPCR signaling pathway were most common: GNA11 occurred more frequently than GNAQ, and in a mutually exclusive pattern.	('GPCR signaling pathway', 'Pathway', (30, 52))	('GNA11', 'Gene', (71, 76))	('GNA11', 'Gene', '2767', (71, 76))	('GNAQ', 'Gene', '2776', (107, 111))	('occurred', 'Reg', (77, 85))	('GPCR signaling pathway', 'biological_process', 'GO:0007186', ('30', '52'))	('mutations', 'Var', (13, 22))	('GNAQ', 'Gene', (107, 111))
28831	31558480	Mutations in SF3B1 and BAP1 were also common; BAP1 mutations occurred exclusively in the presence of SF3B1 wild-type tumors as has previously been reported in the analyses of primary UM samples.	('BAP1', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutations', 'Var', (51, 60))	('SF3B1', 'Gene', (13, 18))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('BAP1', 'Gene', '8314', (46, 50))	('UM', 'Phenotype', 'HP:0007716', (183, 185))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('BAP1', 'Gene', '8314', (23, 27))	('SF3B1', 'Gene', (101, 106))	('occurred', 'Reg', (61, 69))	('BAP1', 'Gene', (46, 50))	('SF3B1', 'Gene', '23451', (13, 18))	('SF3B1', 'Gene', '23451', (101, 106))
28833	31558480	As a biomarker, TMB has also been explored in cutaneous melanoma where, when combined with interferon-gamma gene expression signatures, a high mutational burden increased the prognostic power to predict a prolonged relapse-free survival in stage III melanoma.	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('relapse-free survival', 'CPA', (215, 236))	('interferon-gamma', 'Gene', '3458', (91, 107))	('melanoma', 'Disease', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mutational burden', 'Var', (143, 160))	('melanoma', 'Disease', 'MESH:D008545', (250, 258))	('interferon-gamma', 'Gene', (91, 107))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('melanoma', 'Disease', (250, 258))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('91', '107'))	('TMB', 'Chemical', '-', (16, 19))	('gene expression', 'biological_process', 'GO:0010467', ('108', '123'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('increased', 'PosReg', (161, 170))
28841	31558480	There is no clear standard of care therapy for metastatic disease as these melanomas lack BRAF mutations and only rarely respond to immune checkpoint blockade.	('lack', 'NegReg', (85, 89))	('BRAF', 'Gene', (90, 94))	('melanomas', 'Disease', (75, 84))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('mutations', 'Var', (95, 104))	('melanomas', 'Disease', 'MESH:D008545', (75, 84))	('BRAF', 'Gene', '673', (90, 94))
28915	31487962	The Cancer Genome Atlas (TCGA) data mining indicates that high levels of FGF and/or FGF receptor (FGFR) expression are associated with reduced overall survival, chromosome 3 monosomy and BAP1 mutation in human uveal melanoma (UM), pointing to the FGF/FGFR system as a target for UM treatment.	('monosomy', 'Var', (174, 182))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('chromosome', 'cellular_component', 'GO:0005694', ('161', '171'))	('UM', 'Phenotype', 'HP:0007716', (226, 228))	('uveal melanoma', 'Disease', 'MESH:C536494', (210, 224))	('uveal melanoma', 'Disease', (210, 224))	('BAP1', 'Gene', '8314', (187, 191))	('mutation', 'Var', (192, 200))	('UM', 'Disease', 'MESH:C536494', (226, 228))	('uveal melanoma', 'Phenotype', 'HP:0007716', (210, 224))	('UM', 'Phenotype', 'HP:0007716', (279, 281))	('BAP1', 'Gene', (187, 191))	('reduced', 'NegReg', (135, 142))	('human', 'Species', '9606', (204, 209))	('FGFR', 'molecular_function', 'GO:0005007', ('251', '255'))	('UM', 'Disease', 'MESH:C536494', (279, 281))	('FGFR', 'molecular_function', 'GO:0005007', ('98', '102'))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('overall survival', 'CPA', (143, 159))
28921	31487962	In addition, NSC12 caused caspase-3 activation and PARP cleavage followed by apoptotic cell death as well as beta-catenin degradation and inhibition of UM cell migration.	('cell migration', 'biological_process', 'GO:0016477', ('155', '169'))	('inhibition', 'NegReg', (138, 148))	('PARP', 'Gene', '1302', (51, 55))	('cleavage', 'NegReg', (56, 64))	('NSC12', 'Var', (13, 18))	('PARP', 'Gene', (51, 55))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('77', '97'))	('activation', 'PosReg', (36, 46))	('UM', 'Disease', 'MESH:C536494', (152, 154))	('apoptotic cell death', 'CPA', (77, 97))	('beta-catenin', 'Gene', (109, 121))	('UM', 'Phenotype', 'HP:0007716', (152, 154))	('caspase-3', 'Gene', (26, 35))	('beta-catenin', 'Gene', '1499', (109, 121))	('caspase-3', 'Gene', '836', (26, 35))	('degradation', 'biological_process', 'GO:0009056', ('122', '133'))
28930	31487962	Accordingly, transgenic PTX3 overexpression impairs efficaciously the activation and signaling of the FGF/FGFR system in FGF-driven tumors, thus affecting tumor growth and metastasis.	('overexpression', 'PosReg', (29, 43))	('activation', 'MPA', (70, 80))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('efficaciously', 'MPA', (52, 65))	('impairs', 'NegReg', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('FGFR', 'molecular_function', 'GO:0005007', ('106', '110'))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('PTX3', 'Gene', (24, 28))	('transgenic', 'Var', (13, 23))	('affecting', 'Reg', (145, 154))	('tumors', 'Disease', (132, 138))	('signaling', 'MPA', (85, 94))	('transgenic', 'Species', '10090', (13, 23))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('FGF/FGFR', 'Gene', (102, 110))
28937	31487962	Again, FGF overexpression appears to be associated to a reduced survival in UM patients, even though the difference between the two groups did not reach the statistical significance (Figure 1D).	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('overexpression', 'Var', (11, 25))	('reduced', 'NegReg', (56, 63))	('survival', 'MPA', (64, 72))	('FGF', 'Gene', (7, 10))	('UM', 'Disease', 'MESH:C536494', (76, 78))	('patients', 'Species', '9606', (79, 87))
28939	31487962	Among them, UMs with loss of chromosome 3 are characterized by a poor prognosis when compared to chromosome 3 disomic lesions.	('loss', 'Var', (21, 25))	('disomic lesions', 'Disease', (110, 125))	('chromosome', 'Gene', (29, 39))	('chromosome', 'cellular_component', 'GO:0005694', ('29', '39'))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('chromosome', 'cellular_component', 'GO:0005694', ('97', '107'))	('UM', 'Disease', 'MESH:C536494', (12, 14))	('disomic lesions', 'Disease', 'MESH:D051437', (110, 125))
28942	31487962	The tumor suppressor BAP1 plays a key role in UM progression and monosomy of chromosome 3 is highly associated with the loss of nuclear expression of BAP1, frequently related to loss-of-function BAP1 mutations (see and references therein).	('tumor', 'Disease', (4, 9))	('loss-of-function', 'NegReg', (178, 194))	('mutations', 'Var', (200, 209))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('UM', 'Disease', 'MESH:C536494', (46, 48))	('BAP1', 'Gene', '8314', (150, 154))	('nuclear expression', 'MPA', (128, 146))	('BAP1', 'Gene', '8314', (21, 25))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('4', '20'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('4', '20'))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('BAP1', 'Gene', '8314', (195, 199))	('BAP1', 'Gene', (150, 154))	('monosomy', 'Disease', (65, 73))	('BAP1', 'Gene', (21, 25))	('loss', 'NegReg', (120, 124))	('BAP1', 'Gene', (195, 199))	('chromosome', 'cellular_component', 'GO:0005694', ('77', '87'))	('UM', 'Phenotype', 'HP:0007716', (46, 48))
28943	31487962	Accordingly, 13 out of the 40 chromosome 3 monosomic tumors present in the UM TCGA dataset carried a BAP1 mutation, absent in the 40 disomic specimens.	('chromosome', 'cellular_component', 'GO:0005694', ('30', '40'))	('BAP1', 'Gene', '8314', (101, 105))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('mutation', 'Var', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('BAP1', 'Gene', (101, 105))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('UM', 'Disease', 'MESH:C536494', (75, 77))	('tumors', 'Disease', (53, 59))
28944	31487962	Notably, various members of the FGF/FGFR families appear to be upregulated in this subset of BAP1 mutated tumors when compared to BAP1 wild-type UMs (Figure 2).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('BAP1', 'Gene', (130, 134))	('BAP1', 'Gene', '8314', (93, 97))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('UM', 'Disease', 'MESH:C536494', (145, 147))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('FGF/FGFR', 'Gene', (32, 40))	('upregulated', 'PosReg', (63, 74))	('BAP1', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('BAP1', 'Gene', '8314', (130, 134))	('mutated', 'Var', (98, 105))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
28950	31487962	Addition of exogenous FGF2 to B16-LS9 cells causes no or only a very modest further increase in FGFR phosphorylation and of the downstream signaling mediators phospho-AKT and phospho-ERK1,2, thus confirming the presence of a constitutive autocrine FGF/FGFR loop of activation in these cells under basal cell culture conditions.	('AKT', 'Gene', (167, 170))	('FGF2', 'Gene', (22, 26))	('ERK1', 'molecular_function', 'GO:0004707', ('183', '187'))	('exogenous', 'Var', (12, 21))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))	('FGFR', 'Protein', (96, 100))	('AKT', 'Gene', '207', (167, 170))	('phosphorylation', 'biological_process', 'GO:0016310', ('101', '116'))	('FGFR', 'molecular_function', 'GO:0005007', ('252', '256'))	('phosphorylation', 'MPA', (101, 116))
28992	31487962	Notably, NSC12 was able to suppress the growth of these cells also when orthotopically implanted in the eye of zebrafish embryos or when injected into the liver of syngeneic mice.	('mice', 'Species', '10090', (174, 178))	('zebrafish', 'Species', '7955', (111, 120))	('NSC12', 'Var', (9, 14))	('growth', 'CPA', (40, 46))	('suppress', 'NegReg', (27, 35))
28999	31487962	Notably, our data demonstrate that NSC12 induces a decrease of beta-catenin levels in UM cells that was paralleled by a significant inhibition of UM cell migration in a Boyden chamber assay or following the mechanical wound of the cell monolayer.	('beta-catenin', 'Gene', (63, 75))	('UM', 'Phenotype', 'HP:0007716', (86, 88))	('UM', 'Phenotype', 'HP:0007716', (146, 148))	('inhibition', 'NegReg', (132, 142))	('UM', 'Disease', 'MESH:C536494', (86, 88))	('beta-catenin', 'Gene', '1499', (63, 75))	('UM', 'Disease', 'MESH:C536494', (146, 148))	('NSC12', 'Var', (35, 40))	('cell migration', 'biological_process', 'GO:0016477', ('149', '163'))	('decrease', 'NegReg', (51, 59))
29000	31487962	Further studies will be required to dissect the impact of beta-catenin downregulation induced by FGF inhibitors on the tumorigenic and metastatic behavior of UM cells.	('downregulation', 'NegReg', (71, 85))	('tumor', 'Disease', (119, 124))	('inhibitors', 'Var', (101, 111))	('beta-catenin', 'Gene', (58, 70))	('beta-catenin', 'Gene', '1499', (58, 70))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('UM', 'Phenotype', 'HP:0007716', (158, 160))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('UM', 'Disease', 'MESH:C536494', (158, 160))	('FGF', 'Gene', (97, 100))
29001	31487962	In keeping with our preclinical observations, the analysis of the publicly available mRNA profiling dataset of 80 primary human UM specimens present in TCGA indicates that the upregulation of different members of the FGF or FGFR families are associated with poorer prognosis, chromosome 3 monosomy, and BAP1 mutation.	('chromosome', 'Disease', (276, 286))	('human', 'Species', '9606', (122, 127))	('FGFR', 'molecular_function', 'GO:0005007', ('224', '228'))	('upregulation', 'PosReg', (176, 188))	('chromosome', 'cellular_component', 'GO:0005694', ('276', '286'))	('poorer prognosis', 'CPA', (258, 274))	('mutation', 'Var', (308, 316))	('BAP1', 'Gene', (303, 307))	('FGFR', 'Gene', (224, 228))	('UM', 'Phenotype', 'HP:0007716', (128, 130))	('UM', 'Disease', 'MESH:C536494', (128, 130))	('FGF', 'Gene', (217, 220))	('BAP1', 'Gene', '8314', (303, 307))
29003	31487962	Similar to NSC12, neutralizing antibodies and an antisense oligonucleotide directed against FGF2 have been shown to reduce cell proliferation and survival in various human UM cell lines.	('antisense', 'Var', (49, 58))	('UM', 'Disease', 'MESH:C536494', (172, 174))	('reduce', 'NegReg', (116, 122))	('cell proliferation', 'CPA', (123, 141))	('cell proliferation', 'biological_process', 'GO:0008283', ('123', '141'))	('human', 'Species', '9606', (166, 171))	('neutralizing', 'Var', (18, 30))	('survival', 'CPA', (146, 154))	('FGF2', 'Gene', (92, 96))	('UM', 'Phenotype', 'HP:0007716', (172, 174))
29020	31487962	Anti-phospho-FGFR1 (Tyr766), anti-phospho-FRS2 (Tyr196), anti-FGFR3, and anti-GAPDH were from Santa Cruz (Santa Cruz, CA, USA).	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('FRS2', 'Gene', (42, 46))	('Tyr196', 'Var', (48, 54))	('FGFR3', 'Gene', '2261', (62, 67))	('FGFR', 'molecular_function', 'GO:0005007', ('62', '66'))	('FGFR1', 'Gene', (13, 18))	('FGFR1', 'Gene', '2260', (13, 18))	('FGFR3', 'Gene', (62, 67))	('FRS2', 'Gene', '10818', (42, 46))	('GAPDH', 'Gene', '2597', (78, 83))	('Tyr766', 'Var', (20, 26))	('GAPDH', 'Gene', (78, 83))
29021	31487962	Anti-phospho-FGFR3 (Tyr724) was from ABCAM (Cambridge, UK).	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('FGFR3', 'Gene', (13, 18))	('Tyr724', 'Var', (20, 26))	('Tyr724', 'Chemical', 'MESH:C487766', (20, 26))	('FGFR3', 'Gene', '2261', (13, 18))
29058	31514412	In vitro and in vivo ECT caused a significant reduction in tumor size and viability compared to electroporation or chemotherapy in both sections of our study.	('reduction', 'NegReg', (46, 55))	('tumor', 'Disease', (59, 64))	('ECT', 'Var', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('viability', 'CPA', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
29069	31514412	Furthermore, UM is characterized in ~80% of cases by mutually exclusive initiating mutations in guanine nucleotide binding protein G(q) subunit alpha (GNAQ) and quinine nucleotide binding protein subunit alpha 11 (GNA11).	('mutations', 'Var', (83, 92))	('UM', 'Disease', 'MESH:C536494', (13, 15))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('GNA11', 'Gene', (214, 219))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('GNAQ', 'Gene', (151, 155))	('quinine', 'Species', '50278', (161, 168))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('104', '122'))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (96, 114))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('169', '187'))
29111	31514412	In peripheral regions of the Matrigel grafts, tumor cells were Ki67+ and showed almost no cytotoxic effects.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Disease', (46, 51))	('Ki67+', 'Var', (63, 68))
29152	31514412	These cell lines are characterized by monosomy 3 or BAP1 mutation.	('BAP1', 'Gene', (52, 56))	('mutation', 'Var', (57, 65))	('BAP1', 'Gene', '8314', (52, 56))	('monosomy 3', 'Disease', (38, 48))
29181	31320995	We tested the novel agent Tris DBA palladium and found that it was markedly more effective against GNAQ mutant melanomas than wild type uveal melanomas.	('uveal melanomas', 'Phenotype', 'HP:0007716', (136, 151))	('melanomas', 'Disease', 'MESH:D008545', (111, 120))	('melanomas', 'Disease', 'MESH:D008545', (142, 151))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('uveal melanomas', 'Disease', (136, 151))	('mutant', 'Var', (104, 110))	('GNAQ', 'Gene', (99, 103))	('uveal melanomas', 'Disease', 'MESH:C536494', (136, 151))	('melanomas', 'Disease', (111, 120))	('melanomas', 'Disease', (142, 151))	('effective', 'MPA', (81, 90))	('uveal melanoma', 'Phenotype', 'HP:0007716', (136, 150))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))	('more', 'PosReg', (76, 80))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanomas', 'Phenotype', 'HP:0002861', (142, 151))
29182	31320995	Given that ARF6 has recently been discovered as a node in GNAQ mutations, we evaluated the efficacy of Tris DBA palladium on ARF6 signaling and found that it was effective in inhibiting ARF6 activation.	('mutations', 'Var', (63, 72))	('inhibiting', 'NegReg', (175, 185))	('ARF6', 'Gene', (186, 190))	('ARF6', 'Gene', '382', (125, 129))	('ARF6', 'Gene', '382', (186, 190))	('ARF6', 'Gene', (11, 15))	('GNAQ', 'Gene', (58, 62))	('signaling', 'biological_process', 'GO:0023052', ('130', '139'))	('ARF6', 'Gene', '382', (11, 15))	('ARF6', 'Gene', (125, 129))	('activation', 'MPA', (191, 201))
29183	31320995	Tris DBA Palladium deserves further evaluation as a systemic agent for uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('DBA Palladium', 'Chemical', '-', (5, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (71, 85))	('uveal melanoma', 'Disease', (71, 85))	('Tris DBA', 'Var', (0, 8))
29184	31320995	Second, it appears to be genetically distinct from cutaneous melanoma, with driver mutations in GNAQ and GNA11 being most common in uveal melanoma, while Braf and Nras are the most common driver mutations in cutaneous melanoma.	('mutations', 'Var', (83, 92))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('GNA11', 'Gene', (105, 110))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (51, 69))	('uveal melanoma', 'Phenotype', 'HP:0007716', (132, 146))	('uveal melanoma', 'Disease', (132, 146))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('GNA11', 'Gene', '2767', (105, 110))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (208, 226))	('common', 'Reg', (122, 128))	('GNAQ', 'Gene', (96, 100))
29188	31320995	In cutaneous melanoma, we found that Tris DBA palladium inhibits N-myristoyltransferase 1 (NMT1) and blocks tumor growth in vivo.	('N-myristoyltransferase 1', 'Gene', (65, 89))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('NMT', 'Gene', '4836', (91, 94))	('NMT1', 'Gene', '4836', (91, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('N-myristoyltransferase 1', 'Gene', '4836', (65, 89))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('blocks tumor', 'Disease', (101, 113))	('Tris DBA', 'Var', (37, 45))	('inhibits', 'NegReg', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('tumor', 'Disease', (108, 113))	('blocks tumor', 'Disease', 'MESH:D006327', (101, 113))	('NMT', 'Gene', (91, 94))	('NMT1', 'Gene', (91, 95))
29189	31320995	In pancreatic carcinoma, we demonstrated that Tris DBA palladium inhibits motility and metastases of orthotopic pancreatic carcinoma to the liver.	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (112, 132))	('Tris DBA', 'Var', (46, 54))	('inhibits', 'NegReg', (65, 73))	('metastases of orthotopic pancreatic carcinoma to the liver', 'Disease', 'MESH:D009362', (87, 145))	('pancreatic carcinoma', 'Disease', (3, 23))	('pancreatic carcinoma', 'Disease', (112, 132))	('motility', 'CPA', (74, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (3, 23))
29190	31320995	In this report, we demonstrate that Tris DBA palladium is effective in vitro against a panel of human uveal melanoma cell lines with mutations in GNAQ and GNA11.	('human', 'Species', '9606', (96, 101))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('mutations', 'Var', (133, 142))	('GNA11', 'Gene', (155, 160))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('GNAQ', 'Gene', (146, 150))
29191	31320995	The GI50 value was 1.1 muM for the GNAQ and GNA11 mutant cell lines and 2.7 muM for the wild type cell line (Figure 1).	('GNA11', 'Gene', (44, 49))	('muM', 'Gene', '56925', (76, 79))	('mutant', 'Var', (50, 56))	('muM', 'Gene', (76, 79))	('muM', 'Gene', '56925', (23, 26))	('muM', 'Gene', (23, 26))
29192	31320995	In view of Tris DBA effects observed in vitro, we elected to determine whether this therapy is effective in a GNAQ mutant xenograft mouse model.	('mutant', 'Var', (115, 121))	('mouse', 'Species', '10090', (132, 137))	('GNAQ', 'Gene', (110, 114))
29199	31320995	For both cell lines, we observed a concentration-dependent reduction in ARF6 activation (ARG6-GTP) without a change in total ARF6 expression that reached statistical significance at 3 muM for Mel92.1 and 5 muM for Mel202.	('Mel202', 'Var', (214, 220))	('activation', 'PosReg', (77, 87))	('Mel92.1', 'Var', (192, 199))	('ARG6-GTP', 'Chemical', '-', (89, 97))	('reduction', 'NegReg', (59, 68))	('ARF6', 'Gene', (72, 76))
29203	31320995	Genes reported upregulated by Tris DBA palladium in vivo include GSTM2, which has been associated with improved prognosis in solid tumors and often demonstrates promoter hypermethylation in advanced cancer.	('solid tumors', 'Disease', 'MESH:D009369', (125, 137))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('upregulated', 'PosReg', (15, 26))	('GSTM2', 'Gene', (65, 70))	('promoter hypermethylation', 'MPA', (161, 186))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('improved', 'PosReg', (103, 111))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('Tris DBA', 'Var', (30, 38))	('GSTM2', 'Gene', '2946', (65, 70))	('solid tumors', 'Disease', (125, 137))
29211	31320995	These include discovery of the major driver mutations in uveal melanoma, and prognostic factors for metastatic spread, including monosomy 3 and BAP1 mutation.	('monosomy 3', 'Var', (129, 139))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('BAP1', 'Gene', (144, 148))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('uveal melanoma', 'Disease', (57, 71))	('mutations', 'Var', (44, 53))	('mutation', 'Var', (149, 157))	('BAP1', 'Gene', '8314', (144, 148))
29214	31320995	Of interest, Tris DBA was able to significantly prevent liver metastases of pancreatic cancer, and similar signaling processes might underlie hepatic metastases from uveal melanoma.	('metastases of pancreatic cancer', 'Disease', 'MESH:D009362', (62, 93))	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (166, 180))	('uveal melanoma', 'Disease', (166, 180))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('Tris DBA', 'Var', (13, 21))	('metastases of pancreatic cancer', 'Disease', (62, 93))	('prevent', 'NegReg', (48, 55))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (76, 93))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('hepatic', 'Disease', (142, 149))
29218	31320995	Tris DBA Palladium caused membrane localization of beta catenin and downregulated Cyr61, both of which are observed upon ARF6 inhibition.	('localization', 'biological_process', 'GO:0051179', ('35', '47'))	('downregulated', 'NegReg', (68, 81))	('Cyr61', 'Gene', (82, 87))	('membrane', 'cellular_component', 'GO:0016020', ('26', '34'))	('beta catenin', 'Gene', '1499', (51, 63))	('Tris DBA', 'Var', (0, 8))	('beta catenin', 'Gene', (51, 63))	('membrane localization', 'MPA', (26, 47))
29227	31320995	Antibodies used to probe were NMT1 and GNAQ (Santa Cruz Biotechnology), phospho-p44/42 MAPK (ERK1/2), Total p44/42 MAPK (ERK1/2), phospho-Akt (Ser473), phospho-FAK (Tyr576/577), Na,K-ATPase, GAPDH, Caspase-3, and Cleaved PARP (Cell Signaling).	('p44', 'Gene', '10561', (108, 111))	('MAPK', 'molecular_function', 'GO:0004707', ('87', '91'))	('Signaling', 'biological_process', 'GO:0023052', ('232', '241'))	('Ser', 'cellular_component', 'GO:0005790', ('143', '146'))	('ERK1', 'molecular_function', 'GO:0004707', ('121', '125'))	('ERK1', 'molecular_function', 'GO:0004707', ('93', '97'))	('p44', 'Gene', (108, 111))	('GAPDH', 'Gene', '2597', (191, 196))	('Caspase-3', 'Gene', (198, 207))	('Tyr576', 'Chemical', '-', (165, 171))	('MAPK', 'molecular_function', 'GO:0004707', ('115', '119'))	('GAPDH', 'Gene', (191, 196))	('Ser473', 'Var', (143, 149))	('Ser473', 'Chemical', '-', (143, 149))	('p44', 'Gene', (80, 83))	('FAK', 'molecular_function', 'GO:0004717', ('160', '163'))	('p44', 'Gene', '10561', (80, 83))	('K-ATPase', 'Protein', (181, 189))	('PARP', 'Gene', (221, 225))	('Caspase-3', 'Gene', '836', (198, 207))
29264	31117965	The complete culture medium included RPMI1640 with HEPES, L-glutamine, 10% FBS, 1% nonessential amino acids, 1% sodium pyruvate solution, 1% MEM vitamin solution, and a 1% antibiotic-antimycotic solution and incubated at 37  C/5%CO2.	('L-glutamine', 'Var', (58, 69))	('L-glutamine', 'Chemical', 'MESH:D005973', (58, 69))	('FBS', 'Gene', '14123', (75, 78))	('CO2', 'Chemical', '-', (229, 232))	('HEPES', 'Chemical', 'MESH:D006531', (51, 56))	('RPMI1640', 'Chemical', '-', (37, 45))	('sodium pyruvate', 'Chemical', '-', (112, 127))	('FBS', 'Gene', (75, 78))
29272	31117965	Eight-week old female C57BL/6 J, C57BL/6 PEDF-/-, and C57BL/6 J anti-asialo GM1-treated mice were inoculated in the posterior compartment of the right eye with 5 x 105 B16-LS9 melanoma cells in a 2.5 muL final volume using a transcorneal technique with a 30-gauge needle under guidance of a dissection microscope.	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))	('B16-LS9', 'CellLine', 'CVCL:2105', (168, 175))	('GM1', 'Gene', (76, 79))	('GM1', 'Gene', '210582', (76, 79))	('C57BL/6', 'Var', (33, 40))	('C57BL/6 J', 'Var', (54, 63))	('mice', 'Species', '10090', (88, 92))
29281	31117965	Metastases were separated by size into stage 1 (< 50 mum in diameter), stage 2 (50-200 mum), and stage 3 macrometastases (> 200 mum).	('metastases', 'Disease', (110, 120))	('50-200', 'Var', (80, 86))	('metastases', 'Disease', 'MESH:D009362', (110, 120))	('Metastases', 'Disease', (0, 10))	('Metastases', 'Disease', 'MESH:D009362', (0, 10))
29283	31117965	C57BL/6 J, n = 9; C57BL/6 PEDF-/-, n = 9; and C57BL/6 J anti-asialo GM1-treated mice, n = 8.	('GM1', 'Gene', (68, 71))	('GM1', 'Gene', '210582', (68, 71))	('C57BL/6', 'Var', (0, 7))	('C57BL/6', 'Var', (18, 25))	('mice', 'Species', '10090', (80, 84))	('C57BL/6 J', 'Var', (46, 55))
29286	31117965	Cell suspension was labeled with the following antibodies: anti-CD11b (clone M1-70) PE, anti-Ly-6C (clone HK1.4) FITC, anti-Ly-6G (clone 18A) APC, anti-Gr-1 (clone RB6-8C5) FITC, and anti-F4/80 (clone BM8) PE.	('F4/80', 'Gene', '13733', (188, 193))	('APC', 'cellular_component', 'GO:0005680', ('142', '145'))	('FITC', 'Chemical', 'MESH:D016650', (173, 177))	('FITC', 'Chemical', 'MESH:D016650', (113, 117))	('APC', 'Disease', 'MESH:D011125', (142, 145))	('Ly-6C', 'Gene', (93, 98))	('Ly-6G', 'Gene', '546644', (124, 129))	('Ly-6G', 'Gene', (124, 129))	('HK1', 'molecular_function', 'GO:0004673', ('106', '109'))	('APC', 'Disease', (142, 145))	('anti-Gr-1', 'Var', (147, 156))	('anti-CD11b', 'Var', (59, 69))	('F4/80', 'Gene', (188, 193))	('Ly-6C', 'Gene', '17067', (93, 98))
29290	31117965	We used the following assays (Thermo Fisher Scientific): Tnfa: Mm00443258_m1; Socs3: Mm00545913_s1; Arg1: Mm00475988_m1; Tgfb1: Mm01178820_m1; Gapdh: Mm99999915_g1; Casp3: Mm01195085_m1; Trp53: Mm01731290_g1; Cd68:Mm03047340_m1.	('Mm01195085_m1', 'Var', (172, 185))	('Gapdh', 'Gene', (143, 148))	('Tnfa', 'Gene', '21926', (57, 61))	('Mm00545913_s1', 'Var', (85, 98))	('Cd68', 'Gene', (209, 213))	('Mm00475988_m1', 'Var', (106, 119))	('Mm01731290_g1', 'Var', (194, 207))	('Arg1', 'Gene', '11846', (100, 104))	('Mm99999915_g1', 'Var', (150, 163))	('Cd68', 'Gene', '12514', (209, 213))	('Socs3', 'Gene', '12702', (78, 83))	('Trp53', 'Gene', '22059', (187, 192))	('Tgfb1', 'Gene', (121, 126))	('Gapdh', 'Gene', '14433', (143, 148))	('Arg1', 'Gene', (100, 104))	('Socs3', 'Gene', (78, 83))	('Trp53', 'Gene', (187, 192))	('Mm03047340_m1', 'Var', (214, 227))	('Tnfa', 'Gene', (57, 61))	('Casp3', 'Gene', (165, 170))	('Tgfb1', 'Gene', '21803', (121, 126))	('Casp3', 'Gene', '12367', (165, 170))	('Mm01178820_m1', 'Var', (128, 141))
29294	31117965	We measured a significant increase in the average number of metastases in the NK-depleted (***p < 0.001) and PEDF-/- (***p < 0.001) groups compared to WT controls (Fig.	('metastases', 'Disease', 'MESH:D009362', (60, 70))	('increase', 'PosReg', (26, 34))	('metastases', 'Disease', (60, 70))	('PEDF-/-', 'Var', (109, 116))
29301	31117965	The PEDF-/- group showed a significant increase in the average number of metastases following the infiltrative patter in stage 2 (**p < 0.005) compared to WT.	('increase', 'PosReg', (39, 47))	('metastases', 'Disease', (73, 83))	('metastases', 'Disease', 'MESH:D009362', (73, 83))	('PEDF-/-', 'Var', (4, 11))
29306	31117965	Measurement of Socs3 mRNA revealed higher expression in WT and NK depleted groups compared to the PEDF-/- group.	('expression', 'MPA', (42, 52))	('Socs3', 'Gene', (15, 20))	('Socs3', 'Gene', '12702', (15, 20))	('NK depleted', 'Var', (63, 74))	('higher', 'PosReg', (35, 41))
29314	31117965	Myeloid derived suppressor cells (MDSCs) have distinct phenotypes based on Ly6C or Ly6G expression.	('Ly6C', 'Gene', (75, 79))	('Ly6G', 'Chemical', '-', (83, 87))	('Ly6G expression', 'Var', (83, 98))	('Ly6C', 'Gene', '17067', (75, 79))
29316	31117965	However, there was a significant reduction in the percentage of live CD11b+Ly6G+ cells, which are considered neutrophils, in the NK-depleted (*p < 0.05) and PEDF-/- (*p < 0.05) groups compared to WT (Fig.	('PEDF-/-', 'Var', (157, 164))	('Ly6G', 'Chemical', '-', (75, 79))	('reduction', 'NegReg', (33, 42))
29317	31117965	Quantitation of cells with the immature myeloid phenotype CD11b+Gr-1+ (a composite epitope between the Ly6C and Ly6G antigens) revealed a significant reduction in the percentage of live CD11b+Gr-1+ cells in the NK depleted (*p < 0.05) and PEDF-/- (**p < 0.005) groups compared to WT (Fig.	('Ly6C', 'Gene', (103, 107))	('Ly6C', 'Gene', '17067', (103, 107))	('PEDF-/-', 'Var', (239, 246))	('reduction', 'NegReg', (150, 159))	('CD11b+Gr-1+', 'Var', (186, 197))	('Ly6G', 'Chemical', '-', (112, 116))
29343	31117965	Based on the work performed in the human livers from metastatic UM patients we hypothesized that the nodular pattern is controlled by PEDF in the periportal area, thus, absence of PEDF will increase the ratio of nodular to infiltrative growth.	('absence', 'Var', (169, 176))	('nodular', 'CPA', (212, 219))	('patients', 'Species', '9606', (67, 75))	('ratio', 'MPA', (203, 208))	('human', 'Species', '9606', (35, 40))	('increase', 'PosReg', (190, 198))	('UM', 'Phenotype', 'HP:0007716', (64, 66))
29348	31117965	Our results showed a reduction in CD11b+Ly6C+, CD11b+Ly6G+, and CD11b+Gr-1+ cells in the NK-depleted and PEDF-/- groups.	('CD11b+Ly6G+', 'Var', (47, 58))	('Ly6C', 'Gene', (40, 44))	('Ly6C', 'Gene', '17067', (40, 44))	('reduction', 'NegReg', (21, 30))	('Ly6G', 'Chemical', '-', (53, 57))	('CD11b+Gr-1+', 'Var', (64, 75))
29376	30483120	VEGF (10 ng/ml) elicited Ca2+ transients and augmented whole-cell currents, which were blocked by capsazepine (CPZ; 20 muM) but not by a highly selective TRPM8 blocker, AMTB (20 muM).	('muM', 'Gene', (119, 122))	('capsazepine', 'Chemical', 'MESH:C071423', (98, 109))	('Ca2+', 'Chemical', 'MESH:D000069285', (25, 29))	('Ca2+ transients', 'MPA', (25, 40))	('muM', 'Gene', (178, 181))	('CPZ', 'Chemical', 'MESH:C071423', (111, 114))	('augmented', 'PosReg', (45, 54))	('muM', 'Gene', '56925', (178, 181))	('muM', 'Gene', '56925', (119, 122))	('elicited', 'Reg', (16, 24))	('10 ng/ml', 'Var', (6, 14))	('AMTB', 'Chemical', 'MESH:C080838', (169, 173))	('whole-cell currents', 'MPA', (55, 74))
29379	30483120	3-T1AM exposure suppressed both VEGF-induced Ca2+ transients and increases in underlying whole-cell currents.	('suppressed', 'NegReg', (16, 26))	('Ca2+', 'Chemical', 'MESH:D000069285', (45, 49))	('3-T1AM', 'Chemical', '-', (0, 6))	('increases', 'PosReg', (65, 74))	('whole-cell currents', 'MPA', (89, 108))	('3-T1AM', 'Var', (0, 6))	('VEGF-induced Ca2+ transients', 'MPA', (32, 60))
29391	30483120	Dysfunctional TRPs are implicated in cancer formation (reviewed in Bodding,; Prevarskaya et al.,).	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('formation', 'biological_process', 'GO:0009058', ('44', '53'))	('cancer', 'Disease', (37, 43))	('TRPs', 'Protein', (14, 18))	('implicated', 'Reg', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Dysfunctional', 'Var', (0, 13))
29401	30483120	Likewise, 3-T1AM is a multi-target ligand modulating beta-adrenergic receptor 2 signaling in ocular epithelial cells (Dinter et al.,).	('modulating', 'Reg', (42, 52))	('3-T1AM', 'Chemical', '-', (10, 16))	('ligand', 'molecular_function', 'GO:0005488', ('35', '41'))	('beta-adrenergic receptor 2 signaling', 'MPA', (53, 89))	('3-T1AM', 'Var', (10, 16))	('signaling', 'biological_process', 'GO:0023052', ('80', '89'))
29402	30483120	In corneal epithelial and endothelial cells as well as thyroid cells, 3-T1AM acts as a selective TRPM8 agonist (Khajavi et al.,; Lucius et al.,; Schanze et al.,).	('TRPM8', 'Gene', (97, 102))	('3-T1AM', 'Var', (70, 76))	('3-T1AM', 'Chemical', '-', (70, 76))	('agonist', 'PosReg', (103, 110))
29405	30483120	We show here that crosstalk between members of this receptor triad affects Ca2+ signaling responses induced by VEGFR transactivation of TRPV1 in UM 92.1 melanoma cells.	('Ca2+', 'Chemical', 'MESH:D000069285', (75, 79))	('affects', 'Reg', (67, 74))	('transactivation', 'biological_process', 'GO:2000144', ('117', '132'))	('transactivation', 'Var', (117, 132))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', (153, 161))	('TRPV1', 'Gene', (136, 141))	('Ca2+ signaling responses', 'MPA', (75, 99))	('crosstalk', 'Reg', (18, 27))	('VEGFR', 'Gene', '3791', (111, 116))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('triad', 'cellular_component', 'GO:0030315', ('61', '66'))	('signaling', 'biological_process', 'GO:0023052', ('80', '89'))	('VEGFR', 'Gene', (111, 116))
29406	30483120	Therefore, selective targeting of TRPM8 control of TRPV1 responsiveness to transactivation by VEGF may ultimately provide an alternative approach to reduce tumor growth in a clinical setting.	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('responsiveness to transactivation', 'MPA', (57, 90))	('selective targeting', 'Var', (11, 30))	('TRPV1', 'Gene', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('transactivation', 'biological_process', 'GO:2000144', ('75', '90'))	('tumor', 'Disease', (156, 161))	('TRPM8', 'Gene', (34, 39))	('reduce', 'NegReg', (149, 155))
29447	30483120	Irrespective of 3-T1AM ranging from 200 nM to 10 muM, its effects were essentially the same as those obtained with menthol (Figures 6A,B).	('muM', 'Gene', '56925', (49, 52))	('3-T1AM', 'Var', (16, 22))	('muM', 'Gene', (49, 52))	('menthol', 'Chemical', 'MESH:D008610', (115, 122))	('3-T1AM', 'Chemical', '-', (16, 22))
29450	30483120	Similarly, 3-T1AM also increased the outward currents from 80 +- 24 pA/pF (control) to 142 +- 40 pA/pF, which AMTB suppressed to 112 +- 45 pA/pF (n = 7-9; p < 0.05) (Figure 6C).	('3-T1AM', 'Chemical', '-', (11, 17))	('AMTB', 'Chemical', 'MESH:C080838', (110, 114))	('3-T1AM', 'Var', (11, 17))	('increased', 'PosReg', (23, 32))	('outward currents', 'MPA', (37, 53))
29451	30483120	In TRPM8 transfected cells, 3-T1AM and BCTC increased and inhibited Ca2+transients, respectively (Lucius et al.,).	('BCTC', 'Chemical', '-', (39, 43))	('Ca2+transients', 'MPA', (68, 82))	('3-T1AM', 'Chemical', '-', (28, 34))	('increased', 'PosReg', (44, 53))	('TRPM8', 'Gene', (3, 8))	('inhibited', 'NegReg', (58, 67))	('transfected', 'Var', (9, 20))	('Ca2+', 'Chemical', 'MESH:D000069285', (68, 72))	('BCTC', 'MPA', (39, 43))
29453	30483120	3-T1AM (5 muM) induced a [Ca2+]i transient (p < 0.01; n = 9; Figures 7A,C) whereas 20 muM BCTC inhibited this response (p < 0.05; n = 4; Figures 7B,C).	('muM', 'Gene', '56925', (10, 13))	('muM', 'Gene', '56925', (86, 89))	('3-T1AM', 'Chemical', '-', (0, 6))	('[Ca2+]i transient', 'MPA', (25, 42))	('muM', 'Gene', (10, 13))	('muM', 'Gene', (86, 89))	('3-T1AM', 'Var', (0, 6))	('BCTC', 'Chemical', '-', (90, 94))	('Ca2+', 'Chemical', 'MESH:D000069285', (26, 30))
29455	30483120	3-T1AM suppressed the 10 ng/ml VEGF-induced Ca2+ transient (Figures 7E,F).	('3-T1AM', 'Chemical', '-', (0, 6))	('VEGF-induced Ca2+ transient', 'MPA', (31, 58))	('suppressed', 'NegReg', (7, 17))	('3-T1AM', 'Var', (0, 6))	('Ca2+', 'Chemical', 'MESH:D000069285', (44, 48))
29458	30483120	As shown in Figure 9A, a reduced CAP concentration (10 muM) led to an increase of f340nm/f380nm from 0.2021 +- 0.0004 (100 s) to 0.2094 +- 0.0013 (300 s) (n = 19; p < 0.005) whereas a washout did not reduce the Ca2+ level.	('0.2094 +-', 'Var', (129, 138))	('muM', 'Gene', '56925', (55, 58))	('f340nm/f380nm', 'Var', (82, 95))	('muM', 'Gene', (55, 58))	('Ca2+', 'Chemical', 'MESH:D000069285', (211, 215))	('CAP', 'Chemical', 'MESH:D002211', (33, 36))
29460	30483120	However, preincubation of the cells with icilin suppressed the VEGF-induced increase to 0.2058 +- 0.0023 at 300 s (p < 0.005) and to 0.2187 +- 0.0034 at 600 s (both n = 65; p < 0.01) (Figures 9C,D).	('0.2058 +- 0.0023', 'Var', (88, 104))	('icilin', 'Chemical', 'MESH:C490483', (41, 47))	('0.2187 +- 0.0034', 'Var', (133, 149))
29463	30483120	Furthermore, as with icilin, preincubation of the cells with menthol suppressed the VEGF-induced Ca2+ transient even at a higher VEGF concentration since 20 ng/ml VEGF increased the f340nm/f380nm ratio from 0.1991 +- 0.011 (100 s) to 0.2212 +- 0.0021 (250 s) (n = 25; p < 0.005) (Figure 10D).	('menthol', 'Chemical', 'MESH:D008610', (61, 68))	('Ca2+', 'Chemical', 'MESH:D000069285', (97, 101))	('f340nm/f380nm', 'Var', (182, 195))	('suppressed', 'NegReg', (69, 79))	('VEGF-induced Ca2+ transient', 'MPA', (84, 111))	('0.2212 +- 0.0021', 'Var', (234, 250))	('icilin', 'Chemical', 'MESH:C490483', (21, 27))
29464	30483120	In contrast, 200 muM menthol completely blocked this effect (e.g., f340nm/f380nm = 0.2009 +- 0.0007 at 250 s; n = 32; p < 0.005) (Figures 10E,F).	('f340nm/f380nm =', 'Var', (67, 82))	('muM', 'Gene', '56925', (17, 20))	('muM', 'Gene', (17, 20))	('menthol', 'Chemical', 'MESH:D008610', (21, 28))
29465	30483120	In summary, the near equivalence between the transients induced by either icilin, menthol, or 3-T1AM and their inhibitory effects on VEGF-induced TRPV1 transactivation confirms that this thyroid hormone metabolite is a selective TRPM8 agonist.	('menthol', 'Chemical', 'MESH:D008610', (82, 89))	('3-T1AM', 'Chemical', '-', (94, 100))	('transactivation', 'MPA', (152, 167))	('icilin', 'Chemical', 'MESH:C490483', (74, 80))	('transactivation', 'biological_process', 'GO:2000144', ('152', '167'))	('TRPV1', 'Protein', (146, 151))	('3-T1AM', 'Var', (94, 100))
29468	30483120	WIN 55,212-2 induced a Ca2+ transient at a different cell passage compared to our previous studies (n = 27; p < 0.005).	('Ca2+ transient', 'MPA', (23, 37))	('Ca2+', 'Chemical', 'MESH:D000069285', (23, 27))	('induced', 'Reg', (13, 20))	('WIN', 'Var', (0, 3))
29472	30483120	On the other hand, preincubation of the cells with the CB1 blocker AM251 (10 muM) augmented this rise induced by 3-T1AM.	('muM', 'Gene', (77, 80))	('CB1', 'Gene', '1268', (55, 58))	('CB1', 'Gene', (55, 58))	('3-T1AM', 'Var', (113, 119))	('muM', 'Gene', '56925', (77, 80))	('AM251', 'Chemical', 'MESH:C103505', (67, 72))	('3-T1AM', 'Chemical', '-', (113, 119))
29473	30483120	The transient reached with 3-T1AM by itself was 0.2155 +- 0.0014 (n = 13) at 400 s only whereas with AM251 (10 muM) it rose to 0.2446 +- 0.0037 at the same time (n = 46; p < 0.005) (Figures 11D,E,G).	('3-T1AM', 'Chemical', '-', (27, 33))	('AM251', 'Chemical', 'MESH:C103505', (101, 106))	('muM', 'Gene', '56925', (111, 114))	('3-T1AM', 'Var', (27, 33))	('muM', 'Gene', (111, 114))
29475	30483120	In summary, changes in CB1 activity and/or coupled G-protein activity modulate interactions between TRPV1 and TRPM8.	('modulate', 'Reg', (70, 78))	('coupled G-protein', 'Protein', (43, 60))	('interactions', 'Interaction', (79, 91))	('TRPM8', 'Gene', (110, 115))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('activity', 'MPA', (27, 35))	('TRPV1', 'Protein', (100, 105))	('CB1', 'Gene', '1268', (23, 26))	('activity', 'MPA', (61, 69))	('G-protein', 'Protein', (51, 60))	('changes', 'Var', (12, 19))	('CB1', 'Gene', (23, 26))
29509	30483120	The 3-T1AM mediated Ca2+ transients as well as increases in their underlying currents occurred at lower concentrations in UM 92.1 melanoma cells than those in healthy cells or thyroid cells (Khajavi et al.,; Schanze et al.,).	('3-T1AM', 'Chemical', '-', (4, 10))	('Ca2+', 'Chemical', 'MESH:D000069285', (20, 24))	('Ca2+ transients', 'MPA', (20, 35))	('underlying currents', 'MPA', (66, 85))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('3-T1AM', 'Var', (4, 10))	('increases', 'PosReg', (47, 56))	('melanoma', 'Disease', (130, 138))	('UM', 'Phenotype', 'HP:0007716', (122, 124))
29510	30483120	Specifically, 3-T1AM was used over a concentration range from 0.2 to 10 muM with 1-5 muM having maximal stimulatory effects on whole-cell currents, which agrees with previous studies using corneal epithelial cells (Lucius et al.,).	('muM', 'Gene', (85, 88))	('muM', 'Gene', '56925', (72, 75))	('3-T1AM', 'Chemical', '-', (14, 20))	('whole-cell currents', 'MPA', (127, 146))	('muM', 'Gene', (72, 75))	('3-T1AM', 'Var', (14, 20))	('muM', 'Gene', '56925', (85, 88))
29511	30483120	3-T1AM had a concentration dependent inhibitory effect on Ca2+ transients that may be attributable to different modes of action.	('3-T1AM', 'Chemical', '-', (0, 6))	('Ca2+ transients', 'MPA', (58, 73))	('Ca2+', 'Chemical', 'MESH:D000069285', (58, 62))	('inhibitory effect', 'MPA', (37, 54))	('3-T1AM', 'Var', (0, 6))
29512	30483120	With 0.5 muM 3-T1AM, only whole-cell currents increased without any inhibitory effect on VEGF-induced rises in Ca2+ influx (data not shown).	('Ca2+ influx', 'MPA', (111, 122))	('Ca2+', 'Chemical', 'MESH:D000069285', (111, 115))	('3-T1AM', 'Var', (13, 19))	('muM', 'Gene', '56925', (9, 12))	('3-T1AM', 'Chemical', '-', (13, 19))	('muM', 'Gene', (9, 12))
29514	30483120	It is conceivable that the effect of 0.5 muM 3-T1AM is membrane delimited rather than causing release of Ca2+ from intracellular stores.	('muM', 'Gene', '56925', (41, 44))	('3-T1AM', 'Chemical', '-', (45, 51))	('muM', 'Gene', (41, 44))	('intracellular', 'cellular_component', 'GO:0005622', ('115', '128'))	('3-T1AM', 'Var', (45, 51))	('Ca2+', 'Chemical', 'MESH:D000069285', (105, 109))	('membrane', 'cellular_component', 'GO:0016020', ('55', '63'))
29516	30483120	If this supposition is proven to be correct, 3-T1AM may have dual effects that include activating TRPM8 and at higher concentrations also suppressing TRPV1 activation induced by VEGF.	('3-T1AM', 'Chemical', '-', (45, 51))	('TRPV1', 'Protein', (150, 155))	('TRPM8', 'Protein', (98, 103))	('activating', 'PosReg', (87, 97))	('3-T1AM', 'Var', (45, 51))	('suppressing', 'NegReg', (138, 149))	('activation', 'MPA', (156, 166))
29520	30483120	On the other hand, the possible Ca2+ signal transduction pathways activated by 3-T1AM as a specific activator of TRPM8 may be more complex as suggested in Figure 12 (Khajavi et al.,).	('signal transduction', 'biological_process', 'GO:0007165', ('37', '56'))	('3-T1AM', 'Chemical', '-', (79, 85))	('TRPM8', 'Gene', (113, 118))	('Ca2+', 'Chemical', 'MESH:D000069285', (32, 36))	('activator', 'PosReg', (100, 109))	('3-T1AM', 'Var', (79, 85))
29522	30483120	3-T1AM has also been described as an antagonist of muscarinic type 3 receptor (Laurino et al.,).	('muscarinic', 'Protein', (51, 61))	('3-T1AM', 'Var', (0, 6))	('3-T1AM', 'Chemical', '-', (0, 6))
29524	30483120	In addition, changes in K+ channel activity have been implicated in modulating progression of melanoma (Oppitz et al.,; Luo et al.,).	('channel activity', 'molecular_function', 'GO:0015267', ('27', '43'))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('K+ channel activity', 'MPA', (24, 43))	('changes', 'Var', (13, 20))
29535	30483120	Since TRPM8 activation has an opposing effect on TRPV1 activity, targeting TRPM8 may provide an effective alternative to suppress metastatic melanoma progression without side effects.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('suppress', 'NegReg', (121, 129))	('melanoma', 'Disease', (141, 149))	('activity', 'MPA', (55, 63))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('TRPM8', 'Gene', (75, 80))	('targeting', 'Var', (65, 74))	('TRPM8', 'Gene', (6, 11))	('TRPV1', 'Protein', (49, 54))
29545	24937456	GNAQ/11 Mutations in Uveal Melanoma: Is YAP the Key to Targeted Therapy?	('Melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('Mutations', 'Var', (8, 17))	('GNAQ', 'Gene', '2776', (0, 4))	('Melanoma', 'Disease', 'MESH:D008545', (27, 35))	('Melanoma', 'Disease', (27, 35))	('YAP', 'Gene', '10413', (40, 43))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (21, 35))	('GNAQ', 'Gene', (0, 4))	('YAP', 'Gene', (40, 43))
29547	24937456	In this issue of Cancer Cell, Feng and colleagues and Yu and colleagues demonstrate that the oncogenic activity of mutant GNAQ/11 is mediated at least in part through YAP, potentially uncovering a new therapeutic strategy.	('YAP', 'CPA', (167, 170))	('oncogenic activity', 'CPA', (93, 111))	('mediated', 'Reg', (133, 141))	('Cancer', 'Disease', (17, 23))	('GNAQ', 'Gene', (122, 126))	('mutant', 'Var', (115, 121))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('GNAQ', 'Gene', '2776', (122, 126))
29551	24937456	Mutually exclusive mutations in the G protein-coupled receptor (GPCR) alpha subunits GNAQ and GNA11 (encoding Gq and G11 proteins, respectively) are present in ~85% of uveal melanocytic tumors, including benign nevi, primary melanomas of all stages, and metastatic lesions.	('melanomas', 'Disease', 'MESH:D008545', (225, 234))	('uveal melanocytic tumors', 'Disease', 'MESH:D014604', (168, 192))	('melanomas', 'Disease', (225, 234))	('GNAQ', 'Gene', '2776', (85, 89))	('GNA11', 'Gene', (94, 99))	('nevi', 'Phenotype', 'HP:0003764', (211, 215))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('GNAQ', 'Gene', (85, 89))	('present', 'Reg', (149, 156))	('G11', 'Gene', '8859', (117, 120))	('benign nevi', 'Disease', (204, 215))	('melanomas', 'Phenotype', 'HP:0002861', (225, 234))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('uveal melanocytic tumors', 'Disease', (168, 192))	('uveal melanocytic tumors', 'Phenotype', 'HP:0007716', (168, 192))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('GNA11', 'Gene', '2767', (94, 99))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('GPCR', 'Gene', (64, 68))	('G11', 'Gene', (117, 120))	('mutations', 'Var', (19, 28))
29552	24937456	This spectrum suggests that GNAQ/11 mutations occur early and may even represent initiating events in tumorigenesis .	('GNAQ', 'Gene', '2776', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('mutations', 'Var', (36, 45))	('GNAQ', 'Gene', (28, 32))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
29553	24937456	As such, these inactivating mutations result in constitutive activation of oncogenic Gq/11 subunits.	('Gq/11', 'Chemical', '-', (85, 90))	('inactivating mutations', 'Var', (15, 37))	('activation', 'PosReg', (61, 71))	('oncogenic Gq/11 subunits', 'Protein', (75, 99))
29557	24937456	MEK and PKC inhibitors inhibit the proliferation of Gq/11 mutant uveal melanoma cell lines in vitro.	('mutant', 'Var', (58, 64))	('uveal melanoma cell lines', 'Disease', (65, 90))	('PKC', 'molecular_function', 'GO:0004697', ('8', '11'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('uveal melanoma cell lines', 'Disease', 'MESH:C536494', (65, 90))	('MEK', 'Gene', (0, 3))	('Gq/11', 'Chemical', '-', (52, 57))	('proliferation', 'CPA', (35, 48))	('MEK', 'Gene', '5609', (0, 3))	('inhibit', 'NegReg', (23, 30))	('Gq/11', 'Gene', (52, 57))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))
29562	24937456	In this issue of Cancer Cell, and show that Gq/11 mutants found in uveal melanoma promote tumorigenesis by activating YAP.	('Gq/11', 'Gene', (44, 49))	('YAP', 'MPA', (118, 121))	('promote', 'PosReg', (82, 89))	('Cancer', 'Disease', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('activating', 'PosReg', (107, 117))	('uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('uveal melanoma', 'Disease', (67, 81))	('uveal melanoma', 'Disease', 'MESH:C536494', (67, 81))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('mutants', 'Var', (50, 57))	('Gq/11', 'Chemical', '-', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
29563	24937456	Mutant Gq/11, but not wild-type Gq/11, was found to trigger dephosphorylation and nuclear localization of YAP, associated with YAP-dependent transcription.	('Gq/11', 'Chemical', '-', (7, 12))	('YAP', 'Gene', (106, 109))	('Gq/11', 'Gene', (7, 12))	('localization', 'biological_process', 'GO:0051179', ('90', '102'))	('trigger', 'PosReg', (52, 59))	('transcription', 'biological_process', 'GO:0006351', ('141', '154'))	('Gq/11', 'Chemical', '-', (32, 37))	('dephosphorylation', 'MPA', (60, 77))	('Mutant', 'Var', (0, 6))	('nuclear localization', 'MPA', (82, 102))	('dephosphorylation', 'biological_process', 'GO:0016311', ('60', '77'))
29564	24937456	Importantly, this activity of mutant Gq/11 is independent of PLCbeta .	('mutant', 'Var', (30, 36))	('Gq/11', 'Chemical', '-', (37, 42))	('Gq/11', 'Gene', (37, 42))
29565	24937456	In uveal melanoma cell lines and human tumor samples, there was a strong correlation between the presence of Gq/11 mutations and activated YAP, as indicated by its nuclear localization and increased levels of unphosphorylated YAP.	('uveal melanoma cell lines', 'Disease', (3, 28))	('nuclear localization', 'MPA', (164, 184))	('mutations', 'Var', (115, 124))	('Gq/11', 'Gene', (109, 114))	('uveal melanoma cell lines', 'Disease', 'MESH:C536494', (3, 28))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('activated', 'PosReg', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('localization', 'biological_process', 'GO:0051179', ('172', '184'))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('human', 'Species', '9606', (33, 38))	('YAP', 'Gene', (139, 142))	('tumor', 'Disease', (39, 44))	('Gq/11', 'Chemical', '-', (109, 114))	('levels', 'MPA', (199, 205))	('increased', 'PosReg', (189, 198))
29566	24937456	The question then arises as to whether this YAP activation by mutant Gq/11 is mediated solely through inhibition of LATS1/2.	('LATS1/2', 'Gene', '9113;26524', (116, 123))	('Gq/11', 'Chemical', '-', (69, 74))	('mutant', 'Var', (62, 68))	('Gq/11', 'Gene', (69, 74))	('YAP', 'MPA', (44, 47))	('LATS1/2', 'Gene', (116, 123))	('activation', 'PosReg', (48, 58))
29567	24937456	In their current article and in a recent publication by the same group, show that activation of YAP by mutant Gq requires the guanine nucleotide exchange factor, Trio, and downstream small GTPases RhoA and Rac1.	('guanine nucleotide exchange factor', 'MPA', (126, 160))	('YAP', 'Gene', (96, 99))	('mutant', 'Var', (103, 109))	('RhoA', 'Gene', (197, 201))	('Rac1', 'Gene', '5879', (206, 210))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (126, 144))	('activation', 'PosReg', (82, 92))	('Rac1', 'Gene', (206, 210))	('RhoA', 'Gene', '387', (197, 201))	('Trio', 'Gene', '7204', (162, 166))	('Trio', 'Gene', (162, 166))
29569	24937456	Thus, mutant Gq/11 may activate YAP not only by inhibiting LATS1/2, but also by promoting actin polymerization independently of the canonical Hippo pathway.	('activate', 'PosReg', (23, 31))	('mutant', 'Var', (6, 12))	('LATS1/2', 'Gene', '9113;26524', (59, 66))	('Gq/11', 'Gene', (13, 18))	('actin polymerization', 'MPA', (90, 110))	('promoting', 'PosReg', (80, 89))	('inhibiting', 'NegReg', (48, 58))	('LATS1/2', 'Gene', (59, 66))	('actin polymerization', 'biological_process', 'GO:0030041', ('90', '110'))	('YAP', 'Disease', (32, 35))	('Gq/11', 'Chemical', '-', (13, 18))
29570	24937456	A major implication of these findings is that traditional GPCR signaling through PLCb may not be the only, or even the most important, mechanism for propagating mutant Gq/11 activity.	('Gq/11', 'Chemical', '-', (168, 173))	('mutant', 'Var', (161, 167))	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('Gq/11', 'Gene', (168, 173))	('PLCb', 'Gene', (81, 85))	('activity', 'MPA', (174, 182))
29571	24937456	Pharmacologic targeting of this novel YAP-dependent pathway may be critical for effective therapy against Gq/11 mutant cancers.	('Gq/11', 'Gene', (106, 111))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('mutant', 'Var', (112, 118))	('Gq/11', 'Chemical', '-', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
29572	24937456	Prompted by the recent identification of verteporfin as an inhibitor of YAP activity, both groups show that verteporfin inhibits the growth of uveal melanomas in xenograft mouse models.	('inhibits', 'NegReg', (120, 128))	('verteporfin', 'Chemical', 'MESH:D000077362', (108, 119))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanomas', 'Phenotype', 'HP:0002861', (149, 158))	('uveal melanomas', 'Disease', (143, 158))	('mouse', 'Species', '10090', (172, 177))	('uveal melanomas', 'Phenotype', 'HP:0007716', (143, 158))	('uveal melanomas', 'Disease', 'MESH:C536494', (143, 158))	('uveal melanoma', 'Phenotype', 'HP:0007716', (143, 157))	('verteporfin', 'Chemical', 'MESH:D000077362', (41, 52))	('verteporfin', 'Var', (108, 119))
29574	24937456	Although these findings are promising, it is unlikely that inhibition of mutant Gq/11 signaling alone will be sufficient for treating metastatic uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (145, 159))	('uveal melanoma', 'Disease', 'MESH:C536494', (145, 159))	('Gq/11', 'Chemical', '-', (80, 85))	('uveal melanoma', 'Disease', (145, 159))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('mutant', 'Var', (73, 79))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('Gq/11', 'Gene', (80, 85))
29575	24937456	Mutant Gq and G11 are relatively weak oncoproteins that are only able to transform immortalized melanocytes that have been genetically altered to be deficient in the p53 and p16/CDK4/RB pathways.	('p16', 'Gene', (174, 177))	('G11', 'Gene', (14, 17))	('CDK', 'molecular_function', 'GO:0004693', ('178', '181'))	('p53', 'Gene', (166, 169))	('p53', 'Gene', '7157', (166, 169))	('G11', 'Gene', '8859', (14, 17))	('p16', 'Gene', '1029', (174, 177))	('Mutant', 'Var', (0, 6))	('deficient', 'NegReg', (149, 158))	('CDK4', 'Gene', '1019', (178, 182))	('CDK4', 'Gene', (178, 182))
29576	24937456	Further, the vast majority of uveal melanocytic tumors with Gq/11 mutations are benign and do not metastasize, indicating that they require additional mutations to acquire metastatic potential.	('mutations', 'Var', (66, 75))	('uveal melanocytic tumors', 'Disease', (30, 54))	('uveal melanocytic tumors', 'Phenotype', 'HP:0007716', (30, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('uveal melanocytic tumors', 'Disease', 'MESH:D014604', (30, 54))	('Gq/11', 'Chemical', '-', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('Gq/11', 'Gene', (60, 65))
29578	24937456	Because inactivating mutations in the tumor suppressor BRCA1-associated protein 1 (BAP1) are present in the vast majority of metastasizing uveal melanomas, BAP1 is a leading candidate for such therapeutic targeting.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('BRCA1-associated protein 1', 'Gene', (55, 81))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('BAP1', 'Gene', '8314', (156, 160))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('uveal melanomas', 'Disease', 'MESH:C536494', (139, 154))	('tumor suppressor', 'biological_process', 'GO:0051726', ('38', '54'))	('BAP1', 'Gene', '8314', (83, 87))	('inactivating mutations', 'Var', (8, 30))	('BAP1', 'Gene', (156, 160))	('tumor', 'Disease', (38, 43))	('uveal melanomas', 'Disease', (139, 154))	('uveal melanomas', 'Phenotype', 'HP:0007716', (139, 154))	('melanomas', 'Phenotype', 'HP:0002861', (145, 154))	('BAP1', 'Gene', (83, 87))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('BRCA1-associated protein 1', 'Gene', '8314', (55, 81))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
29585	26655090	Antibody-mediated depletion of NK cells from mice abrogated entolimod's antimetastatic activity in the liver and eliminated the entolimod-elicited in vitro cytotoxic activity of hepatic lymphocytes against B16LS9 cells.	('B16LS9', 'CellLine', 'CVCL:2105', (206, 212))	('mice', 'Species', '10090', (45, 49))	('abrogated', 'NegReg', (50, 59))	('eliminated', 'NegReg', (113, 123))	('depletion', 'Var', (18, 27))	('antimetastatic activity', 'CPA', (72, 95))
29631	26655090	Using naive non-tumor-bearing mice, we sought to determine whether entolimod treatment stimulates a similar pattern of hepatic NK cell maturation and differentiation by following the acquisition of specific markers of NK cell maturation [CD49b (DX5)] and differentiation (CD11b and CD43) by cells in the hepatic NK lineage (NK1.1+CD3epsilon-) using FACS as described previously.	('CD3epsilon-', 'Gene', (330, 341))	('mice', 'Species', '10090', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('CD11b', 'Var', (272, 277))	('cell maturation', 'biological_process', 'GO:0048469', ('130', '145'))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('NK1.1', 'Gene', '17059', (324, 329))	('cell maturation', 'biological_process', 'GO:0048469', ('221', '236'))	('DX5', 'Gene', '16398', (245, 248))	('CD3epsilon-)', 'Gene', '916', (330, 342))	('tumor', 'Disease', (16, 21))	('FACS', 'Gene', '14081', (349, 353))	('CD43', 'Gene', '6693', (282, 286))	('FACS', 'Gene', (349, 353))	('NK1.1', 'Gene', (324, 329))	('DX5', 'Gene', (245, 248))	('CD43', 'Gene', (282, 286))
29653	26655090	FACS analysis of liver cell populations 21 day after B16LS9 tumor cell inoculation confirmed reduction of NK cell levels in the liver by > 80% following anti-asialo GM1 treatment (data not shown).	('reduction of NK cell levels', 'Phenotype', 'HP:0040218', (93, 120))	('reduction', 'NegReg', (93, 102))	('FACS', 'Gene', '14081', (0, 4))	('anti-asialo', 'Var', (153, 164))	('NK cell levels', 'MPA', (106, 120))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('B16LS9', 'CellLine', 'CVCL:2105', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('GM1', 'Chemical', 'MESH:D005677', (165, 168))	('tumor', 'Disease', (60, 65))	('FACS', 'Gene', (0, 4))
29657	26655090	Pathological examination of lungs collected from these mice 14 days after removal of the tumor-bearing eye (i.e., on Day 21 post-inoculation) showed that, with or without entolimod treatment, the mean number of metastases in the lungs was significantly higher in anti-asialo GM1 antibody-treated groups compared to control IgG-treated groups.	('antibody', 'cellular_component', 'GO:0042571', ('279', '287'))	('higher', 'PosReg', (253, 259))	('metastases', 'Disease', (211, 221))	('antibody', 'cellular_component', 'GO:0019815', ('279', '287'))	('mice', 'Species', '10090', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('antibody', 'cellular_component', 'GO:0019814', ('279', '287'))	('GM1', 'Chemical', 'MESH:D005677', (275, 278))	('antibody', 'molecular_function', 'GO:0003823', ('279', '287'))	('anti-asialo', 'Var', (263, 274))	('metastases', 'Disease', 'MESH:D009362', (211, 221))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
29664	26655090	As a direct assay of the antitumor activity stimulated by entolimod in vivo, we isolated the total lymphocyte population from livers of naive mice or mice inoculated with B16LS9 tumor cells and treated with anti-asialo GM1 antibodies (or control IgG) and entolimod (or vehicle), as described above, and tested their cytotoxicity towards B16LS9 target cells in vitro.	('tested', 'Reg', (303, 309))	('mice', 'Species', '10090', (150, 154))	('tumor', 'Disease', (178, 183))	('B16LS9', 'CellLine', 'CVCL:2105', (337, 343))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('cytotoxicity', 'Disease', 'MESH:D064420', (316, 328))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mice', 'Species', '10090', (142, 146))	('anti-asialo', 'Var', (207, 218))	('tumor', 'Disease', (29, 34))	('cytotoxicity', 'Disease', (316, 328))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('B16LS9', 'CellLine', 'CVCL:2105', (171, 177))	('GM1', 'Chemical', 'MESH:D005677', (219, 222))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
29738	26655090	Single cell suspensions were stained for 20 minutes at 4 C with the following cocktails of monoclonal antibodies (mAbs): (1) Pacific Blue CD45 (clone 30-F11), Brilliant Violet (BV) 711 CD3epsilon (clone 145-2C11), PE-Cy5 NK1.1 (clone 29A1.4); (2) Pacific Blue CD45 (clone 30-F11), BV711 CD3epsilon (clone 145-2C11), PE-Cy5 NK1.1 (clone 29A1.4), PE-Cy7 CD49b (clone DX5), Ax700 CD11b (clone M1/70), PE CD43 (clone 1B11); (3) Pacific Blue CD45 (clone 30-F11), BV711 CD3epsilon (clone 145-2C11), PE-Cy5 NK1.1 (clone 29A1.4), PE-Cy7 CD49b (clone DX5), PE FasL (clone MFL3), BV605 CD69 (clone H1.2F3).	('PE-Cy7 CD49b', 'Var', (522, 534))	('DX5', 'Gene', (542, 545))	('NK1.1', 'Gene', '17059', (500, 505))	('NK1.1', 'Gene', (500, 505))	('CD69', 'Gene', (576, 580))	('CD43', 'Gene', '6693', (401, 405))	('NK1.1', 'Gene', '17059', (323, 328))	('NK1.1', 'Gene', '17059', (221, 226))	('DX5', 'Gene', '16398', (365, 368))	('CD69', 'Gene', '12515', (576, 580))	('CD43', 'Gene', (401, 405))	('NK1.1', 'Gene', (323, 328))	('NK1.1', 'Gene', (221, 226))	('DX5', 'Gene', (365, 368))	('DX5', 'Gene', '16398', (542, 545))
29747	26655090	Livers were harvested 5, 24, and 120 h after treatment by in vivo perfusion followed by in vitro digestion to assess presence of adoptively transferred NK cells (CD45+ GFP+ CD3epsilon- NK1.1+) similarly as above by FACS analysis.	('NK1.1', 'Gene', '17059', (185, 190))	('digestion', 'biological_process', 'GO:0007586', ('97', '106'))	('NK1.1', 'Gene', (185, 190))	('FACS', 'Gene', (215, 219))	('FACS', 'Gene', '14081', (215, 219))	('CD45+ GFP+', 'Var', (162, 172))
29833	25109840	NCCs can give rise to a number of differentiated cell and tissue types including sensory neurons and glial cells, melanocytes, craniofacial cartilage and bone, and smooth muscle.	('NCCs', 'Var', (0, 4))	('craniofacial cartilage', 'Disease', 'MESH:D019465', (127, 149))	('melanocytes', 'CPA', (114, 125))	('give rise to', 'Reg', (9, 21))	('craniofacial cartilage', 'Disease', (127, 149))	('smooth muscle', 'CPA', (164, 177))
29844	25109840	Constitutively activating BRAF and NRAS mutations are found in nearly 50% and 20% of melanomas, respectively.	('melanomas', 'Disease', (85, 94))	('NRAS', 'Gene', (35, 39))	('BRAF', 'Gene', (26, 30))	('mutations', 'Var', (40, 49))	('activating', 'PosReg', (15, 25))	('melanomas', 'Disease', 'MESH:D008545', (85, 94))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))
29846	25109840	The most common T1799A point mutation in BRAF gene causes the V600E amino acid substitution, resulting in a 500-fold increase in inherent BRAF kinase activity that enhances cell division and survival.	('kinase activity', 'molecular_function', 'GO:0016301', ('143', '158'))	('T1799A', 'Var', (16, 22))	('increase', 'PosReg', (117, 125))	('V600E', 'Var', (62, 67))	('cell division', 'CPA', (173, 186))	('BRAF', 'Enzyme', (138, 142))	('cell division', 'biological_process', 'GO:0051301', ('173', '186'))	('V600E', 'Mutation', 'rs113488022', (62, 67))	('enhances', 'PosReg', (164, 172))	('T1799A', 'Mutation', 'rs113488022', (16, 22))	('survival', 'CPA', (191, 199))	('BRAF gene', 'Gene', (41, 50))
29847	25109840	Notably, many human nevi harbor BRAFV600E or NRAS mutations, which suggests that BRAF and NRAS mutations are critical but not sufficient for melanoma formation.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('nevi', 'Phenotype', 'HP:0003764', (20, 24))	('melanoma', 'Disease', (141, 149))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('human', 'Species', '9606', (14, 19))	('BRAFV600E', 'Var', (32, 41))	('BRAFV600E', 'Mutation', 'rs113488022', (32, 41))	('NRAS', 'Gene', (45, 49))	('formation', 'biological_process', 'GO:0009058', ('150', '159'))
29848	25109840	Another common genetic mutation in melanoma is the deletion of the CDKN2A locus, which encodes two tumor suppressor proteins, p16INK4a and p14ARF.	('CDKN2A', 'Gene', '12578', (67, 73))	('tumor', 'Disease', (99, 104))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('CDKN2A', 'Gene', (67, 73))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('99', '115'))	('p14ARF', 'Var', (139, 145))	('p16INK4a', 'Gene', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('p16INK4a', 'Gene', '12578', (126, 134))	('deletion', 'Var', (51, 59))	('melanoma', 'Disease', (35, 43))	('tumor suppressor', 'biological_process', 'GO:0051726', ('99', '115'))
29849	25109840	While p16INK4a is an inhibitor of the cyclin-dependent kinases CDK4 and CDK6 and prevents cell cycle progression, p14ARF functions as a positive regulator of p53.	('CDK4', 'Gene', (63, 67))	('p16INK4a', 'Gene', '12578', (6, 14))	('CDK', 'molecular_function', 'GO:0004693', ('72', '75'))	('CDK6', 'Gene', '12571', (72, 76))	('p53', 'Gene', '22060', (158, 161))	('cell cycle progression', 'CPA', (90, 112))	('p14ARF', 'Var', (114, 120))	('prevents', 'NegReg', (81, 89))	('cyclin', 'molecular_function', 'GO:0016538', ('38', '44'))	('p16INK4a', 'Gene', (6, 14))	('CDK', 'molecular_function', 'GO:0004693', ('63', '66'))	('p53', 'Gene', (158, 161))	('CDK6', 'Gene', (72, 76))	('cell cycle', 'biological_process', 'GO:0007049', ('90', '100'))	('CDK4', 'Gene', '12567', (63, 67))
29850	25109840	Deletions of the CDKN2A locus have been found in up to 50% of melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('CDKN2A', 'Gene', '12578', (17, 23))	('melanomas', 'Disease', (62, 71))	('found', 'Reg', (40, 45))	('CDKN2A', 'Gene', (17, 23))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('Deletions', 'Var', (0, 9))	('melanomas', 'Disease', 'MESH:D008545', (62, 71))
29853	25109840	On the other hand, deletion of CDKN2A and the associated signaling alterations also contributes to melanoma progression.	('signaling', 'MPA', (57, 66))	('contributes', 'Reg', (84, 95))	('deletion', 'Var', (19, 27))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('CDKN2A', 'Gene', '12578', (31, 37))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('CDKN2A', 'Gene', (31, 37))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))
29868	25109840	Dispersed gray hair was detectable when two Notch alleles are floxed in Tyr:Cre/ ; Notch1flox/+; Notch2flox/+, Tyr:Cre/ ; Notch1+/+; Notch2flox/flox and Tyr:Cre/ ; Notch1flox/flox; Notch2+/+ mice, and pigmentation of hair was almost completely lost in the absence of both Notch1 and Notch2 (Tyr:Cre/ ; Notch1flox/flox; Notch2flox/flox mice).	('Notch2', 'Gene', '18129', (97, 103))	('Notch2', 'Gene', (319, 325))	('Tyr', 'Chemical', 'MESH:D014443', (291, 294))	('Notch2', 'Gene', (97, 103))	('pigmentation of hair', 'Disease', 'MESH:D010859', (201, 221))	('Notch2', 'Gene', '18129', (283, 289))	('lost', 'NegReg', (244, 248))	('Notch2', 'Gene', '18129', (133, 139))	('pigmentation', 'biological_process', 'GO:0043473', ('201', '213'))	('Notch2', 'Gene', '18129', (181, 187))	('pigmentation of hair', 'Disease', (201, 221))	('Notch2', 'Gene', (283, 289))	('Notch2', 'Gene', (133, 139))	('Notch2', 'Gene', (181, 187))	('mice', 'Species', '10090', (191, 195))	('Tyr', 'Chemical', 'MESH:D014443', (153, 156))	('mice', 'Species', '10090', (335, 339))	('Tyr', 'Chemical', 'MESH:D014443', (72, 75))	('Tyr', 'Chemical', 'MESH:D014443', (111, 114))	('Notch1flox/+', 'Var', (83, 95))	('Notch2', 'Gene', '18129', (319, 325))	('Notch1+/+', 'Var', (122, 131))
29869	25109840	Interestingly, while epidermal melanocytes are eliminated in the melanocyte-specific Notch1 and Notch2 double-deficient mice, dermal and choroidal melanocytes are left unaffected.	('choroidal melanocytes', 'Phenotype', 'HP:0012054', (137, 158))	('mice', 'Species', '10090', (120, 124))	('eliminated', 'NegReg', (47, 57))	('double-deficient', 'Var', (103, 119))	('Notch2', 'Gene', (96, 102))	('Notch1', 'Gene', (85, 91))	('Notch2', 'Gene', '18129', (96, 102))
29871	25109840	A gradual increase in gray spots was observed in YO01027-treated mice, which remained stable for at least 20 weeks after discontinuing the GSI.	('YO01027', 'Chemical', '-', (49, 56))	('GSI', 'Chemical', '-', (139, 142))	('mice', 'Species', '10090', (65, 69))	('increase', 'PosReg', (10, 18))	('gray', 'MPA', (22, 26))	('YO01027-treated', 'Var', (49, 64))
29881	25109840	Constitutive activation of Notch1 signaling by ectopic expression of the Notch1 intracellular domain enabled primary melanoma cells to present higher survival capacities when cultured as three-dimensional spheroids and gain metastatic potential in vivo.	('intracellular', 'cellular_component', 'GO:0005622', ('80', '93'))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('Notch1', 'Gene', (27, 33))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('gain', 'PosReg', (219, 223))	('ectopic expression', 'Var', (47, 65))	('Notch1', 'Gene', (73, 79))	('activation', 'PosReg', (13, 23))	('higher', 'PosReg', (143, 149))	('metastatic potential', 'CPA', (224, 244))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
29882	25109840	Such oncogenic effect is associated with beta-catenin signaling, as its expression was up-regulated following Notch1 activation and suppression of beta-catenin expression reversed Notch1-induced tumor growth and metastasis.	('signaling', 'biological_process', 'GO:0023052', ('54', '63'))	('up-regulated', 'PosReg', (87, 99))	('tumor', 'Disease', (195, 200))	('suppression', 'NegReg', (132, 143))	('Notch1', 'Gene', (110, 116))	('Notch1-induced', 'Var', (180, 194))	('expression', 'MPA', (72, 82))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('activation', 'PosReg', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
29887	25109840	Lack of Notch1 function sensitizes melanoma cells to hypoxia-induced cell death through apoptosis and inhibits cell proliferation partially through down-regulating cyclin D1, which collectively results in reduction in melanoma growth.	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('down-regulating', 'NegReg', (148, 163))	('cell proliferation', 'biological_process', 'GO:0008283', ('111', '129'))	('reduction', 'NegReg', (205, 214))	('melanoma growth', 'Disease', 'MESH:D008545', (218, 233))	('sensitizes', 'Reg', (24, 34))	('inhibits', 'NegReg', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('Lack', 'Var', (0, 4))	('cyclin', 'molecular_function', 'GO:0016538', ('164', '170'))	('Notch1', 'Gene', (8, 14))	('cell proliferation', 'CPA', (111, 129))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('melanoma growth', 'Disease', (218, 233))	('cell death', 'biological_process', 'GO:0008219', ('69', '79'))	('hypoxia', 'Disease', (53, 60))	('cyclin D1', 'Gene', '12443', (164, 173))	('cyclin D1', 'Gene', (164, 173))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))	('apoptosis', 'CPA', (88, 97))	('hypoxia', 'Disease', 'MESH:D000860', (53, 60))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))
29896	25109840	Activated Notch3 signaling is associated with enhanced melanoma cell migration without affecting tumor cell growth.	('melanoma cell migration', 'Disease', (55, 78))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Notch3 signaling', 'Gene', (10, 26))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cell growth', 'biological_process', 'GO:0016049', ('103', '114'))	('tumor', 'Disease', (97, 102))	('Activated', 'Var', (0, 9))	('cell migration', 'biological_process', 'GO:0016477', ('64', '78'))	('enhanced', 'PosReg', (46, 54))	('signaling', 'biological_process', 'GO:0023052', ('17', '26'))	('melanoma cell migration', 'Disease', 'MESH:D008545', (55, 78))
29900	25109840	A significant reduction of Notch3 expression was observed in melanoma samples compared with normal tissues, and restoration of Notch3 expression led to activation of senescence and inhibition of cell proliferation.	('activation', 'PosReg', (152, 162))	('expression', 'MPA', (34, 44))	('cell proliferation', 'CPA', (195, 213))	('expression', 'MPA', (134, 144))	('senescence', 'CPA', (166, 176))	('Notch3', 'Gene', (127, 133))	('Notch3', 'Gene', (27, 33))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('inhibition', 'NegReg', (181, 191))	('melanoma', 'Disease', (61, 69))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('181', '213'))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('senescence', 'biological_process', 'GO:0010149', ('166', '176'))	('reduction', 'NegReg', (14, 23))	('restoration', 'Var', (112, 123))
29921	25109840	You et al found that Wnt2 expression level was high in melanoma cell lines, and antibodies against Wnt2 inhibited beta-catenin signaling and suppressed tumor growth in an in vivo xenograft model by inducing apoptosis.	('apoptosis', 'CPA', (207, 216))	('Wnt2', 'Gene', (99, 103))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))	('Wnt2', 'Gene', '22413', (21, 25))	('tumor', 'Disease', (152, 157))	('suppressed', 'NegReg', (141, 151))	('inducing', 'Reg', (198, 206))	('antibodies', 'Var', (80, 90))	('beta-catenin signaling', 'MPA', (114, 136))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('apoptosis', 'biological_process', 'GO:0006915', ('207', '216'))	('apoptosis', 'biological_process', 'GO:0097194', ('207', '216'))	('signaling', 'biological_process', 'GO:0023052', ('127', '136'))	('Wnt2', 'Gene', (21, 25))	('inhibited', 'NegReg', (104, 113))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('Wnt2', 'Gene', '22413', (99, 103))
29941	25109840	Recently, Biechele et al have shown that suppression of endogenous beta-catenin may be achieved through constitutive activation of BRAF by the V600E mutation.	('V600E', 'Var', (143, 148))	('endogenous beta-catenin', 'MPA', (56, 79))	('BRAF', 'Gene', (131, 135))	('V600E', 'Mutation', 'rs113488022', (143, 148))	('activation', 'PosReg', (117, 127))	('suppression', 'NegReg', (41, 52))
29951	25109840	As indicated by immunohistochemical analysis, detection of high Wnt5a in tumors was subsequently correlated with poor patient survival.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Wnt5a', 'Gene', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('high', 'Var', (59, 63))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('patient', 'Species', '9606', (118, 125))
29962	25109840	Deletions or mutations of Ednrb or Edn3 in mice resulted in an almost complete loss of melanocytes (Table 1B).	('mice', 'Species', '10090', (43, 47))	('loss', 'NegReg', (79, 83))	('Ednrb', 'Gene', (26, 31))	('Ednrb', 'Gene', '13618', (26, 31))	('Edn3', 'Gene', (35, 39))	('mutations', 'Var', (13, 22))	('Deletions', 'Var', (0, 9))
29964	25109840	Genetic disruption of the Ednrb gene caused a drastic reduction in the number of Mbs by embryonic day 12.5 (E12.5), which suggests that Ednrb signaling affects melanocyte development prior to or at E12.5.	('Ednrb', 'Gene', (136, 141))	('affects', 'Reg', (152, 159))	('Ednrb', 'Gene', '13618', (136, 141))	('Ednrb', 'Gene', (26, 31))	('signaling', 'biological_process', 'GO:0023052', ('142', '151'))	('Ednrb', 'Gene', '13618', (26, 31))	('reduction', 'NegReg', (54, 63))	('Genetic disruption', 'Var', (0, 18))	('Mbs', 'CPA', (81, 84))	('melanocyte development', 'CPA', (160, 182))
29985	25109840	Edn1 partially rescued the defect in colony formation and cell proliferation in melanoma cells with the knockdown of oncogenic BRAFV600E.	('BRAFV600E', 'Mutation', 'rs113488022', (127, 136))	('formation', 'biological_process', 'GO:0009058', ('44', '53'))	('BRAFV600E', 'Gene', (127, 136))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('colony formation', 'CPA', (37, 53))	('Edn1', 'Gene', (0, 4))	('cell proliferation', 'biological_process', 'GO:0008283', ('58', '76'))	('knockdown', 'Var', (104, 113))
29987	25109840	BQ788 was found to inhibit the growth of human melanoma cell lines, enhance pigmentation of the cell and alter cell morphology to dendritic shape that resembles mature melanocytes.	('alter', 'Reg', (105, 110))	('inhibit', 'NegReg', (19, 26))	('BQ788', 'Chemical', 'MESH:C086539', (0, 5))	('pigmentation', 'biological_process', 'GO:0043473', ('76', '88'))	('human', 'Species', '9606', (41, 46))	('pigmentation', 'Disease', 'MESH:D010859', (76, 88))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('pigmentation', 'Disease', (76, 88))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('BQ788', 'Var', (0, 5))	('enhance pigmentation', 'Phenotype', 'HP:0000953', (68, 88))	('cell morphology', 'CPA', (111, 126))	('enhance', 'PosReg', (68, 75))
29995	25109840	As loss of SOX9 or SOX10 is associated with an almost complete lack of NCCs and even causes early embryonic lethality in mice, their functions throughout Mb development have not been fully determined.	('NCCs', 'Protein', (71, 75))	('causes', 'Reg', (85, 91))	('loss', 'Var', (3, 7))	('embryonic lethality', 'Disease', 'MESH:D020964', (98, 117))	('lack', 'NegReg', (63, 67))	('embryonic lethality', 'Disease', (98, 117))	('SOX10', 'Gene', (19, 24))	('SOX9', 'Gene', (11, 15))	('mice', 'Species', '10090', (121, 125))
29996	25109840	However, through loss-of-function studies using animals carrying SOX10 mutations, a critical role for Sox10 in the establishment of the melanocyte lineage has been indicated by the exhibited pigmentary defects of these animals.	('Sox10', 'Gene', '20665', (102, 107))	('loss-of-function', 'NegReg', (17, 33))	('pigmentary defects', 'Disease', 'MESH:D005902', (191, 209))	('pigmentary defects', 'Phenotype', 'HP:0001000', (191, 209))	('pigmentary defects', 'Disease', (191, 209))	('mutations', 'Var', (71, 80))	('SOX10', 'Gene', (65, 70))	('Sox10', 'Gene', (102, 107))
30007	25109840	Stable SOX10 knockdown in human melanoma cells resulted in arrested cell growth, altered cellular morphology and induction of cellular senescence.	('cell growth', 'biological_process', 'GO:0016049', ('68', '79'))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('human', 'Species', '9606', (26, 31))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('cellular senescence', 'CPA', (126, 145))	('cellular senescence', 'biological_process', 'GO:0090398', ('126', '145'))	('arrested', 'NegReg', (59, 67))	('cell growth', 'CPA', (68, 79))	('knockdown', 'Var', (13, 22))	('SOX10', 'Gene', (7, 12))	('altered', 'Reg', (81, 88))	('cellular morphology', 'CPA', (89, 108))	('induction', 'Reg', (113, 122))
30008	25109840	Inhibition of SOX10 was also found to cause a significant reduction in invasive capacity both in human melanoma cell lines and the chick embryo model.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('chick', 'Species', '9031', (131, 136))	('human', 'Species', '9606', (97, 102))	('Inhibition', 'Var', (0, 10))	('SOX10', 'Gene', (14, 19))	('invasive capacity', 'CPA', (71, 88))	('reduction', 'NegReg', (58, 67))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
30009	25109840	Interestingly, SOX10 appears to play a role in reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('inhibition', 'NegReg', (97, 107))	('V600E', 'Var', (90, 95))	('V600E', 'SUBSTITUTION', 'None', (90, 95))
30036	24049435	Larger tumors were associated with a higher percentage of cells positive for monosomy 3.	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Disease', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('monosomy 3', 'Var', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
30038	24049435	Patients whose tumors had 1%-33% of cells positive for monosomy 3 had a significantly lower risk of metastasis-related death compared to patients whose tumors harbored a higher percentage of monosomy 3 (p=0.04).	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('death', 'Disease', 'MESH:D003643', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('death', 'Disease', (119, 124))	('lower', 'NegReg', (86, 91))	('patients', 'Species', '9606', (137, 145))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('Patients', 'Species', '9606', (0, 8))	('monosomy 3', 'Var', (55, 65))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('tumors', 'Disease', (15, 21))
30039	24049435	Larger tumors were more likely to have a higher percentage of monosomy 3 positive cells in the sample.	('monosomy 3 positive', 'Var', (62, 81))	('tumors', 'Disease', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
30040	24049435	Furthermore, patients whose tumors had more than 33% of cells positive for monosomy 3 had a poorer prognosis than patients whose tumors had lower percentages of monosomy 3.	('monosomy 3', 'Var', (75, 85))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Disease', (28, 34))	('patients', 'Species', '9606', (13, 21))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('patients', 'Species', '9606', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
30044	24049435	Previous studies have established that, among uveal melanomas positive for monosomy 3, this cytogenetic alteration may not be present in every tumor cell.	('monosomy 3', 'Var', (75, 85))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('uveal melanomas', 'Disease', 'MESH:C536494', (46, 61))	('positive', 'Reg', (62, 70))	('uveal melanoma', 'Phenotype', 'HP:0007716', (46, 60))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))	('uveal melanomas', 'Disease', (46, 61))	('uveal melanomas', 'Phenotype', 'HP:0007716', (46, 61))
30046	24049435	recently reported that a monosomy 3 cutoff value of 30% was the most robust predictor of metastasis-related death, although cutoff values of 5% and 50% also predicted poor prognosis.	('death', 'Disease', 'MESH:D003643', (108, 113))	('death', 'Disease', (108, 113))	('monosomy', 'Var', (25, 33))
30047	24049435	Tumors were stratified into three groups based on the percentage of monosomy 3, and prognosis was incrementally worse with higher percentages of monosomy 3.	('monosomy 3', 'Var', (68, 78))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('worse', 'Reg', (112, 117))	('monosomy 3', 'Var', (145, 155))
30048	24049435	Although larger tumor size correlates with the presence of monosomy 3, the relationship between tumor size and percentage of monosomy 3 in the tumor has not been established.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('monosomy 3', 'Var', (59, 69))	('tumor', 'Disease', (16, 21))	('presence', 'Var', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
30049	24049435	We hypothesized that larger tumors may have a higher percentage of cells with monosomy 3, because they are more advanced and the cells may therefore have had more opportunity to lose a copy of chromosome 3.	('monosomy 3', 'Var', (78, 88))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('chromosome', 'cellular_component', 'GO:0005694', ('193', '203'))	('lose', 'NegReg', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
30050	24049435	Most previous studies on the prognostic value of monosomy 3 in uveal melanoma used tumor samples obtained during enucleation.	('enucleation', 'biological_process', 'GO:0090601', ('113', '124'))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (63, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (63, 77))	('uveal melanoma', 'Disease', (63, 77))	('tumor', 'Disease', (83, 88))	('monosomy 3', 'Var', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))
30054	24049435	Based on these data, we evaluated whether there was an association between 1) percentage of monosomy 3 and metastatic disease and 2) tumor height and percentage of monosomy 3.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('metastatic disease', 'Disease', (107, 125))	('monosomy 3', 'Var', (92, 102))
30065	24049435	For FISH analysis, a directly labeled centromeric probe specific for chromosome 3, CEP-3 Spectrum Orange (Vysis, Downers Grove, IL), was used to assess monosomy or disomy.	('CEP', 'molecular_function', 'GO:0047849', ('83', '86'))	('disomy', 'Disease', (164, 170))	('chromosome', 'cellular_component', 'GO:0005694', ('69', '79'))	('monosomy', 'Var', (152, 160))	('disomy', 'Disease', 'MESH:D024182', (164, 170))	('CEP-3', 'Gene', (83, 88))
30076	24049435	Between January 2005 and September 2011, 93 patients with uveal melanoma who had undergone tumor treatment with iodine-125 plaque brachytherapy were identified whose FISH result from FNAB was positive for monosomy 3.	('patients', 'Species', '9606', (44, 52))	('tumor', 'Disease', (91, 96))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('uveal melanoma', 'Disease', 'MESH:C536494', (58, 72))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('monosomy 3', 'Var', (205, 215))	('iodine', 'Chemical', 'MESH:D007455', (112, 118))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('uveal melanoma', 'Disease', (58, 72))
30084	24049435	There was a significant positive correlation between tumor height and percentage of monosomy 3 (p=0.02).	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('monosomy 3', 'Var', (84, 94))	('tumor', 'Disease', (53, 58))
30087	24049435	However, there was no significant difference in the metastasis-free survival rate between patients who had 33%-66% cells positive for monosomy 3 and patients who had 66%-100% cells positive for monosomy 3.	('monosomy 3', 'Var', (134, 144))	('patients', 'Species', '9606', (90, 98))	('metastasis-free survival', 'CPA', (52, 76))	('patients', 'Species', '9606', (149, 157))
30089	24049435	Percentage of monosomy 3 ranged between 4.7% and 100%, with a mean of 62.9%, which is consistent with previous reports of variation in chromosome 3 copy number in uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (163, 178))	('uveal melanoma', 'Phenotype', 'HP:0007716', (163, 177))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanomas', 'Phenotype', 'HP:0002861', (169, 178))	('monosomy 3', 'Var', (14, 24))	('chromosome', 'cellular_component', 'GO:0005694', ('135', '145'))	('uveal melanomas', 'Disease', (163, 178))	('uveal melanomas', 'Phenotype', 'HP:0007716', (163, 178))
30091	24049435	Moreover, we found a significant association between the percentage of monosomy 3 in a biopsy sample and the development of metastatic disease in the patient.	('patient', 'Species', '9606', (150, 157))	('metastatic disease', 'CPA', (124, 142))	('monosomy 3', 'Var', (71, 81))
30093	24049435	In addition, there was a significant positive correlation between tumor height and percentage of monosomy 3.	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('monosomy 3', 'Var', (97, 107))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
30099	24049435	Our finding that a percentage of monosomy 3 above 33% is associated with significantly decreased metastasis-free survival is similar to the findings of Bronkhorst et al., who performed karyotyping and FISH on cultured cells and FISH on isolated nuclei of enucleated specimens of primary uveal melanoma.	('decreased', 'NegReg', (87, 96))	('uveal melanoma', 'Phenotype', 'HP:0007716', (287, 301))	('uveal melanoma', 'Disease', (287, 301))	('uveal melanoma', 'Disease', 'MESH:C536494', (287, 301))	('metastasis-free survival', 'CPA', (97, 121))	('monosomy 3', 'Var', (33, 43))	('melanoma', 'Phenotype', 'HP:0002861', (293, 301))
30100	24049435	The authors found a range of percentages for monosomy 3 in the samples, and evaluated the predictive value of monosomy 3 at various percentages for death by metastatic disease.	('death', 'Disease', 'MESH:D003643', (148, 153))	('death', 'Disease', (148, 153))	('monosomy 3', 'Var', (45, 55))
30101	24049435	Monosomy 3 positivity with a cutoff value of 30% was the most robust predictor of death due to metastasis.	('positivity', 'Var', (11, 21))	('death', 'Disease', 'MESH:D003643', (82, 87))	('death', 'Disease', (82, 87))	('Monosomy', 'Var', (0, 8))
30102	24049435	The authors also found that threshold monosomy 3 percentages of 5% and 50%, in addition to 30%, were associated with significantly increased risk of metastasis-related death.	('death', 'Disease', (168, 173))	('monosomy 3', 'Var', (38, 48))	('death', 'Disease', 'MESH:D003643', (168, 173))
30104	24049435	In that study, risk of death from metastatic disease was analyzed with FISH among patients with tumor specimens harboring 0%-33%, 33%-66%, and 66%-100% cells positive for monosomy 3.	('death', 'Disease', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('death', 'Disease', 'MESH:D003643', (23, 28))	('monosomy 3', 'Var', (171, 181))
30106	24049435	In our study, we found, similar to Van Den Bosch et al., that patients with 1%-33% cells positive for monosomy 3 had a significantly better metastasis-free survival rate.	('better', 'PosReg', (133, 139))	('metastasis-free survival rate', 'CPA', (140, 169))	('patients', 'Species', '9606', (62, 70))	('monosomy 3', 'Var', (102, 112))
30110	24049435	Several studies have reported that larger tumors are more likely to be positive for monosomy 3.	('positive', 'Reg', (71, 79))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('monosomy 3', 'Var', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
30111	24049435	We evaluated the relationship between tumor height and percentage of cells positive for monosomy 3, and we found that larger tumors contained a significantly higher percentage of monosomy 3 cells (Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('monosomy 3 cells', 'Var', (179, 195))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('higher', 'PosReg', (158, 164))	('tumor', 'Disease', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
30115	24049435	In many cases, the monosomy 3 tumor cells may be physically clustered within a tumor such that when a positive sample is obtained, most of the cells are positive for monosomy 3.	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('monosomy 3', 'Var', (166, 176))	('positive', 'Reg', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
30116	24049435	The loss of one copy of chromosome 3 is associated with several factors known to portend poor prognosis in uveal melanoma, including ciliary body involvement, extraocular spread, larger basal tumor diameter, epithelioid cells, closed vascular loops, and high mitotic rate.	('vascular loops', 'Phenotype', 'HP:0010775', (234, 248))	('tumor', 'Disease', (192, 197))	('uveal melanoma', 'Disease', 'MESH:C536494', (107, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('uveal melanoma', 'Disease', (107, 121))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('extraocular spread', 'CPA', (159, 177))	('chromosome', 'cellular_component', 'GO:0005694', ('24', '34'))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('basal tumor', 'Phenotype', 'HP:0002671', (186, 197))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('epithelioid cells', 'CPA', (208, 225))	('closed vascular loops', 'CPA', (227, 248))	('ciliary body involvement', 'Disease', (133, 157))	('loss', 'Var', (4, 8))
30117	24049435	In addition, monosomy 3 is associated with all other cytogenetic alterations in uveal melanomas, particularly abnormalities in chromosomes 1, 6, and 8, and the loss of chromosome 3 is thought to represent the initial cytogenetic aberration necessary for the development of metastatic potential.	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('uveal melanomas', 'Disease', 'MESH:C536494', (80, 95))	('monosomy 3', 'Var', (13, 23))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('chromosome', 'cellular_component', 'GO:0005694', ('168', '178'))	('abnormalities', 'Var', (110, 123))	('loss', 'Var', (160, 164))	('associated', 'Reg', (27, 37))	('uveal melanomas', 'Disease', (80, 95))	('uveal melanomas', 'Phenotype', 'HP:0007716', (80, 95))
30118	24049435	Mutations in the BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) (BAP1) gene on chromosome 3p21 may be the reason melanoma cells lose one copy of chromosome 3.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('chromosome', 'cellular_component', 'GO:0005694', ('98', '108'))	('BRCA1 associated protein-1', 'Gene', (17, 43))	('BAP1', 'Gene', '8314', (84, 88))	('Mutations', 'Var', (0, 9))	('chromosome', 'cellular_component', 'GO:0005694', ('164', '174'))	('lose', 'NegReg', (147, 151))	('BAP1', 'Gene', (84, 88))	('BRCA1 associated protein-1', 'Gene', '8314', (17, 43))	('ubiquitin', 'molecular_function', 'GO:0031386', ('45', '54'))
30121	24049435	Identifying the specific pathway by which monosomy 3 leads to uveal melanoma metastasis will guide future efforts to develop targeted therapies for this disease.	('monosomy 3', 'Var', (42, 52))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('uveal melanoma metastasis', 'Disease', 'MESH:C536494', (62, 87))	('uveal melanoma metastasis', 'Disease', (62, 87))	('leads to', 'Reg', (53, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (62, 76))
30127	24049435	Moreover, our results indicate that tumors with more than 33% of cells positive for monosomy 3 in an FNAB specimen have a poor prognosis compared to tumors with lower percentages of monosomy 3.	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Disease', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('monosomy 3', 'Var', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
30129	31801083	YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression Uveal melanoma (UM), the most common ocular malignancy, is characterized by GNAQ/11 mutations.	('GNAQ/11', 'Gene', (144, 151))	('YAP', 'Gene', (0, 3))	('ocular malignancy', 'Disease', 'MESH:D009369', (105, 122))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (26, 40))	('mutations', 'Var', (152, 161))	('ocular malignancy', 'Phenotype', 'HP:0100012', (105, 122))	('YAP', 'Gene', '22601', (0, 3))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('Melanoma Initiation', 'Disease', 'MESH:D008545', (32, 51))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('TAZ', 'Gene', '66826', (4, 7))	('melanoma', 'Disease', (74, 82))	('TAZ', 'Gene', (4, 7))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('Melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('Melanoma Initiation', 'Disease', (32, 51))	('ocular malignancy', 'Disease', (105, 122))
30132	31801083	We find that genetic activation of YAP, but not Kras, is sufficient to initiate UM.	('Kras', 'Gene', '16653', (48, 52))	('Kras', 'Gene', (48, 52))	('genetic activation', 'Var', (13, 31))	('YAP', 'Gene', (35, 38))
30133	31801083	We show that YAP/TAZ activation induced by Lats1/2 deletion cooperates with Kras to promote UM progression via downstream transcriptional reinforcement.	('YAP/TAZ', 'Gene', '22601;66826', (13, 20))	('UM progression', 'CPA', (92, 106))	('promote', 'PosReg', (84, 91))	('Kras', 'Gene', '16653', (76, 80))	('YAP/TAZ', 'Gene', (13, 20))	('Lats1/2', 'Gene', (43, 50))	('activation', 'PosReg', (21, 31))	('Kras', 'Gene', (76, 80))	('deletion', 'Var', (51, 59))
30137	31801083	Unlike cutaneous melanoma, UM is genetically characterized by distinct mutations in GANQ and GNA11.	('cutaneous melanoma', 'Disease', (7, 25))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (7, 25))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (7, 25))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('mutations', 'Var', (71, 80))	('GANQ', 'Gene', (84, 88))	('GNA11', 'Gene', (93, 98))
30138	31801083	More than 80% of human UMs harbor activating mutations in GNAQ or GNA11, which encode the heterotrimeric G protein alpha subunits of the Q class (Galphaq/11).	('Galphaq', 'Gene', '14682', (146, 153))	('activating', 'Reg', (34, 44))	('mutations', 'Var', (45, 54))	('human', 'Species', '9606', (17, 22))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('90', '114'))	('Galphaq', 'Gene', (146, 153))	('GNA11', 'Gene', (66, 71))	('GNAQ', 'Gene', (58, 62))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
30139	31801083	The highly conserved glutamine 209 (Q209) or arginine 183 (R183) mutations of GNAQ and GNA11 render the guanosine triphosphatase (GTPase) of these proteins defective and lead to constitutive activation of downstream pathways in UM cells.	('Q209', 'Var', (36, 40))	('GNAQ', 'Gene', (78, 82))	('activation', 'PosReg', (191, 201))	('arginine', 'Chemical', 'MESH:D001120', (45, 53))	('glutamine', 'Chemical', 'MESH:D005973', (21, 30))	('downstream pathways', 'Pathway', (205, 224))	('GNA11', 'Gene', (87, 92))	('mutations', 'Var', (65, 74))	('defective', 'NegReg', (156, 165))
30146	31801083	Upon Hippo pathway inactivation, YAP and TAZ translocate into the nucleus and interact with the Tead family of transcription factors, thereby inducing downstream gene transcription.	('inducing', 'PosReg', (142, 150))	('Hippo', 'Gene', '37247', (5, 10))	('Tead', 'Gene', (96, 100))	('interact', 'Reg', (78, 86))	('Tead', 'Gene', '32536', (96, 100))	('nucleus', 'cellular_component', 'GO:0005634', ('66', '73'))	('transcription', 'biological_process', 'GO:0006351', ('167', '180'))	('transcription', 'biological_process', 'GO:0006351', ('111', '124'))	('downstream gene transcription', 'MPA', (151, 180))	('inactivation', 'Var', (19, 31))	('Hippo', 'Gene', (5, 10))
30147	31801083	Mis-regulation of the Hippo pathway has been implicated in a variety of human cancers, including UM.	('regulation', 'biological_process', 'GO:0065007', ('4', '14'))	('Hippo', 'Gene', '37247', (22, 27))	('Mis-regulation', 'Var', (0, 14))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('human', 'Species', '9606', (72, 77))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('implicated', 'Reg', (45, 55))	('Hippo', 'Gene', (22, 27))
30149	31801083	Two recent studies generated mouse models of UM by crossing the conditional mice carrying the mutated GNAQ or GNA11 alleles in the Rosa26 locus to two different mouse melanocyte Cre lines.	('mutated', 'Var', (94, 101))	('GNAQ', 'Gene', (102, 106))	('Rosa26', 'Gene', (131, 137))	('mice', 'Species', '10090', (76, 80))	('mouse', 'Species', '10090', (29, 34))	('GNA11', 'Gene', (110, 115))	('mouse', 'Species', '10090', (161, 166))	('Rosa26', 'Gene', '14910', (131, 137))
30154	31801083	We found that deletion of the core Hippo kinases Lats1/2 through AAV-CMV-Cre injection efficiently induced tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('induced', 'Reg', (99, 106))	('tumor', 'Disease', (107, 112))	('core', 'cellular_component', 'GO:0019013', ('30', '34'))	('formation', 'biological_process', 'GO:0009058', ('113', '122'))	('Hippo', 'Gene', (35, 40))	('AAV', 'Chemical', '-', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('deletion', 'Var', (14, 22))	('Lats1/2', 'Gene', (49, 56))	('Hippo', 'Gene', '37247', (35, 40))
30156	31801083	Tumors developed in the mice carrying the R26mT/mG reporter allele were GFP-positive (Figure 1H), suggesting that they originated from the cells that underwent Cre recombination.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('originated', 'Reg', (119, 129))	('mice', 'Species', '10090', (24, 28))	('R26mT/mG', 'Var', (42, 50))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
30159	31801083	These data suggest that Hippo pathway inactivation by Lats1/2 deletion drives UM formation, and that the AAV-based eye local injection is an effective method to induce Cre recombination in the mouse uveal tract that can be used for UM tumor modeling.	('UM formation', 'CPA', (78, 90))	('formation', 'biological_process', 'GO:0009058', ('81', '90'))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('AAV', 'Chemical', '-', (105, 108))	('inactivation', 'NegReg', (38, 50))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('Lats1/2', 'Gene', (54, 61))	('Hippo', 'Gene', (24, 29))	('mouse', 'Species', '10090', (193, 198))	('tumor', 'Disease', (235, 240))	('Hippo', 'Gene', '37247', (24, 29))	('deletion', 'Var', (62, 70))
30160	31801083	To achieve specific deletion of Lats1/2 kinases in uveal melanocytes, we generated an AAV expression vector that drives the expression of the nuclear GFP-Cre fusion protein under the control of a 1.7-kb mouse tyrosinase-related protein 2 (Trp2) promoter (Figure 2A).	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('Trp2', 'Gene', (239, 243))	('mouse', 'Species', '10090', (203, 208))	('protein', 'cellular_component', 'GO:0003675', ('228', '235'))	('Lats1/2', 'Gene', (32, 39))	('Trp2', 'molecular_function', 'GO:0004167', ('239', '243'))	('tyrosinase-related protein 2', 'Gene', '13190', (209, 237))	('tyrosinase-related protein 2', 'Gene', (209, 237))	('deletion', 'Var', (20, 28))	('Trp2', 'Gene', '13190', (239, 243))	('AAV', 'Chemical', '-', (86, 89))
30164	31801083	We showed that the GFP-positive tumor cells carrying the R26mT/mG reporter allele were stained negatively for RPE65 (Figures 2E and 2F), a specific marker for the retinal pigmented epithelium (RPE).	('retinal pigmented epithelium', 'Disease', (163, 191))	('retinal pigmented epithelium', 'Disease', 'MESH:C536309', (163, 191))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('R26mT/mG', 'Var', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('RPE65', 'Gene', '19892', (110, 115))	('negatively', 'NegReg', (95, 105))	('tumor', 'Disease', (32, 37))	('RPE65', 'Gene', (110, 115))
30166	31801083	Interestingly, our data also revealed that the cells in the RPE layer showed much higher nuclear YAP/TAZ levels than the cells in the adjacent choroid region of control animals (Figure 2G), suggesting that Hippo signaling and Lats1/2 kinases normally function to suppress YAP/TAZ activity in wild-type uveal melanocytes, and Lats1/2 removal in the melanocytes leads to YAP/TAZ activation, thereby inducing oncogenic transformation and subsequent UM formation.	('removal', 'Var', (333, 340))	('YAP/TAZ', 'Gene', (97, 104))	('Hippo signaling', 'biological_process', 'GO:0035329', ('206', '221'))	('YAP/TAZ', 'Gene', (369, 376))	('UM formation', 'CPA', (446, 458))	('suppress', 'NegReg', (263, 271))	('inducing', 'PosReg', (397, 405))	('Hippo', 'Gene', (206, 211))	('Lats1/2', 'Gene', (325, 332))	('YAP/TAZ', 'Gene', '22601;66826', (272, 279))	('YAP/TAZ', 'Gene', '22601;66826', (97, 104))	('YAP/TAZ', 'Gene', '22601;66826', (369, 376))	('activation', 'PosReg', (377, 387))	('formation', 'biological_process', 'GO:0009058', ('449', '458'))	('oncogenic transformation', 'CPA', (406, 430))	('Hippo', 'Gene', '37247', (206, 211))	('YAP/TAZ', 'Gene', (272, 279))
30167	31801083	Next, we set out to test whether YAP/TAZ is genetically required for UM formation induced by Lats1/2 deletion.	('deletion', 'Var', (101, 109))	('Lats1/2', 'Gene', (93, 100))	('YAP/TAZ', 'Gene', (33, 40))	('YAP/TAZ', 'Gene', '22601;66826', (33, 40))	('formation', 'biological_process', 'GO:0009058', ('72', '81'))
30168	31801083	We crossed the YAP and TAZ conditional alleles, YAPfl and TAZfl, into the mice carrying Lats1/2 conditional alleles in order to delete all four proteins simultaneously.	('mice', 'Species', '10090', (74, 78))	('proteins', 'Protein', (144, 152))	('delete', 'Var', (128, 134))
30170	31801083	Consistent with the reported role of YAP/TAZ in mediating Lats1/2 function, YAP/TAZ deletion abolished upregulation of downstream target gene transcription induced by Lats1/2 deletion (Figure S1), and the uveal tract appeared phenotypically normal in the mice carrying Lats1/2 and YAP/TAZ conditional alleles after Cre injection (Figure S1).	('YAP/TAZ', 'Gene', '22601;66826', (281, 288))	('transcription', 'biological_process', 'GO:0006351', ('142', '155'))	('deletion', 'Var', (84, 92))	('YAP/TAZ', 'Gene', (76, 83))	('upregulation', 'MPA', (103, 115))	('mice', 'Species', '10090', (255, 259))	('YAP/TAZ', 'Gene', (37, 44))	('abolished', 'NegReg', (93, 102))	('deletion', 'Var', (175, 183))	('Lats1/2', 'Gene', (167, 174))	('YAP/TAZ', 'Gene', '22601;66826', (76, 83))	('YAP/TAZ', 'Gene', (281, 288))	('YAP/TAZ', 'Gene', '22601;66826', (37, 44))
30171	31801083	These data suggest that YAP/TAZ function is critical for UM development following Lats1/2 inactivation in uveal melanocytes.	('YAP/TAZ', 'Gene', (24, 31))	('Lats1/2', 'Gene', (82, 89))	('inactivation', 'Var', (90, 102))	('YAP/TAZ', 'Gene', '22601;66826', (24, 31))
30172	31801083	To examine whether YAP activation alone is able to drive UM formation, we utilized a Rosa26 conditional allele we recently generated, R26YAP5SA, which allows Cre-mediated expression of a constitutively active form of YAP, YAP5SA.	('formation', 'biological_process', 'GO:0009058', ('60', '69'))	('R26YAP5SA', 'Var', (134, 143))	('Rosa26', 'Gene', (85, 91))	('Rosa26', 'Gene', '14910', (85, 91))
30173	31801083	YAP5SA has five canonical LATS phosphorylation sites mutated from serine to alanine to prevent Hippo/Lats-mediated inhibition and degradation.	('Hippo', 'Gene', (95, 100))	('degradation', 'biological_process', 'GO:0009056', ('130', '141'))	('serine', 'Chemical', 'MESH:D012694', (66, 72))	('alanine', 'Chemical', 'MESH:D000409', (76, 83))	('mutated', 'Var', (53, 60))	('degradation', 'MPA', (130, 141))	('Hippo', 'Gene', '37247', (95, 100))	('prevent', 'NegReg', (87, 94))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))
30174	31801083	Consistent with the results in Cre-injected Lats1/2 conditional mice, most of the R26YAP5SA mice developed Ums following Cre injection (Figures 3A and 3C).	('Ums', 'CPA', (107, 110))	('mice', 'Species', '10090', (92, 96))	('mice', 'Species', '10090', (64, 68))	('R26YAP5SA', 'Var', (82, 91))
30186	31801083	Thus, we performed Tead4 ChIP-qPCR in mouse UM cells with Lats1/2 deletion and found that, in addition to the known YAP/Tead direct targets CTGF, Cyr61, and Ankrd1, Tead4 also occupied the promoter regions of Rras2 and Nras in mouse UM cells (Figure 4E).	('Cyr61', 'Gene', (146, 151))	('Rras2', 'Gene', '66922', (209, 214))	('mouse', 'Species', '10090', (38, 43))	('Tead', 'Gene', (120, 124))	('Tead', 'Gene', (165, 169))	('Rras2', 'Gene', (209, 214))	('Tead', 'Gene', '32536', (19, 23))	('Cyr61', 'Gene', '16007', (146, 151))	('mouse', 'Species', '10090', (227, 232))	('Tead', 'Gene', '32536', (165, 169))	('Ankrd1', 'Gene', '107765', (157, 163))	('Nras', 'Gene', (219, 223))	('Ankrd1', 'Gene', (157, 163))	('Tead', 'Gene', (19, 23))	('Tead', 'Gene', '32536', (120, 124))	('Lats1/2', 'Gene', (58, 65))	('Nras', 'Gene', '18176', (219, 223))	('deletion', 'Var', (66, 74))
30191	31801083	We demonstrated that DN-TEAD4 could effectively inhibit both YAP- and TAZ-induced downstream gene transcription, measured by the activity of a Tead binding site-driven luciferase reporter (8XGIITC-Luc) (Figure S3B).	('Tead', 'Gene', (143, 147))	('S3B', 'Gene', '11778', (210, 213))	('binding', 'molecular_function', 'GO:0005488', ('148', '155'))	('Tead', 'Gene', '32536', (143, 147))	('S3B', 'Gene', (210, 213))	('DN-TEAD4', 'Var', (21, 29))	('TAZ-induced', 'Gene', (70, 81))	('transcription', 'biological_process', 'GO:0006351', ('98', '111'))	('inhibit', 'NegReg', (48, 55))
30192	31801083	More importantly, DN-TEAD4 expression by lentiviral infection was able to block endogenous transcription of the YAP/TAZ target genes, CTGF, CYR61, and ANKRD1, in human 92-1 UM cells (Figure 4G).	('transcription', 'biological_process', 'GO:0006351', ('91', '104'))	('DN-TEAD4 expression', 'Var', (18, 37))	('92-1 UM', 'CellLine', 'CVCL:7796', (168, 175))	('CYR61', 'Gene', (140, 145))	('infection', 'Disease', (52, 61))	('human', 'Species', '9606', (162, 167))	('block', 'NegReg', (74, 79))	('YAP/TAZ', 'Gene', (112, 119))	('endogenous transcription', 'MPA', (80, 104))	('infection', 'Disease', 'MESH:D007239', (52, 61))	('ANKRD1', 'Gene', (151, 157))	('YAP/TAZ', 'Gene', '22601;66826', (112, 119))	('CTGF', 'Gene', (134, 138))
30193	31801083	92-1 cells are a human UM cell line that carries the characteristic GalphaqQL mutation and was previously shown to be sensitive to YAP inhibition.	('human', 'Species', '9606', (17, 22))	('Galphaq', 'Gene', (68, 75))	('mutation', 'Var', (78, 86))	('Galphaq', 'Gene', '14682', (68, 75))
30194	31801083	In agreement with our data from mouse UMs with Lats1/2 deletion or YAP activation, we found that Tead inhibition by DN-TEAD4 in human 92-1 cells also decreased RRAS2, NRAS, and PRKCD gene transcription (Figure 4G).	('RRAS2', 'Gene', (160, 165))	('Tead', 'Gene', '32536', (97, 101))	('RRAS2', 'Gene', '22800', (160, 165))	('PRKCD', 'Gene', (177, 182))	('PRKCD', 'Gene', '5580', (177, 182))	('NRAS', 'Gene', (167, 171))	('DN-TEAD4', 'Gene', (116, 124))	('Tead', 'Gene', (97, 101))	('transcription', 'biological_process', 'GO:0006351', ('188', '201'))	('mouse', 'Species', '10090', (32, 37))	('human', 'Species', '9606', (128, 133))	('inhibition', 'NegReg', (102, 112))	('deletion', 'Var', (55, 63))	('NRAS', 'Gene', '4893', (167, 171))	('decreased', 'NegReg', (150, 159))
30195	31801083	Western blot analysis showed downregulation of Ras/MAPK activity in 92-1 cells by DN-TEAD4, as evidenced by decreased phosphorylation of both MEK1/2 and ERK1/2 kinases (Figure 4H).	('ERK1', 'molecular_function', 'GO:0004707', ('153', '157'))	('downregulation', 'NegReg', (29, 43))	('ERK1/2', 'Gene', '26417;26413', (153, 159))	('activity', 'MPA', (56, 64))	('MEK1/2', 'Gene', '26395;26396', (142, 148))	('ERK1/2', 'Gene', (153, 159))	('Ras/MAPK', 'Enzyme', (47, 55))	('MEK1/2', 'Gene', (142, 148))	('MEK1', 'molecular_function', 'GO:0004708', ('142', '146'))	('DN-TEAD4', 'Var', (82, 90))	('decreased', 'NegReg', (108, 117))	('MAPK', 'molecular_function', 'GO:0004707', ('51', '55'))	('phosphorylation', 'biological_process', 'GO:0016310', ('118', '133'))	('phosphorylation', 'MPA', (118, 133))
30199	31801083	However, the combination of Lats1/2 deletion and Kras activation significantly accelerated tumor progression, measured by tumor sizes and overall survival time of Cre-injected mice (Figures 5B-5E).	('deletion', 'Var', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('activation', 'PosReg', (54, 64))	('mice', 'Species', '10090', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('Kras', 'Gene', (49, 53))	('Kras', 'Gene', '16653', (49, 53))	('survival time', 'CPA', (146, 159))	('accelerated', 'PosReg', (79, 90))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (122, 127))	('Lats1/2', 'Gene', (28, 35))
30205	31801083	To test this hypothesis, we first looked at YAP, TAZ, and Tead expression in mouse UM tumors with Lats1/2 deletion or Kras activation and did not detect significant change in their mRNA or protein levels, measured by qPCR or western blot analysis (Figures 5G, 5H, and S4B).	('Kras', 'Gene', (118, 122))	('Kras', 'Gene', '16653', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('Tead', 'Gene', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('Lats1/2', 'Gene', (98, 105))	('deletion', 'Var', (106, 114))	('activation', 'PosReg', (123, 133))	('Tead', 'Gene', '32536', (58, 62))	('mouse', 'Species', '10090', (77, 82))
30213	31801083	PD0325901 inhibited ERK phosphorylation in a dose-dependent manner in 92-1 cells (Figure 6D).	('ERK', 'Protein', (20, 23))	('PD0325901', 'Var', (0, 9))	('ERK', 'molecular_function', 'GO:0004707', ('20', '23'))	('inhibited', 'NegReg', (10, 19))	('PD0325901', 'Chemical', 'MESH:C506614', (0, 9))	('phosphorylation', 'biological_process', 'GO:0016310', ('24', '39'))
30214	31801083	The expression of several AP1 genes, including c-Jun, Fos, FosL1, and FosL2, was downregulated after PD0325901 treatment, and their transcription was synergistically suppressed when both MEK and TEAD activation was inhibited (Figure 6E).	('PD0325901', 'Chemical', 'MESH:C506614', (101, 110))	('Fos', 'Gene', '14281', (54, 57))	('TEAD', 'Gene', '32536', (195, 199))	('expression', 'MPA', (4, 14))	('Fos', 'Gene', (70, 73))	('TEAD', 'Gene', (195, 199))	('Fos', 'Gene', '14281', (70, 73))	('downregulated', 'NegReg', (81, 94))	('Fos', 'Gene', (59, 62))	('c-Jun', 'Gene', (47, 52))	('AP1', 'Gene', '16476', (26, 29))	('suppressed', 'NegReg', (166, 176))	('Fos', 'Gene', '14281', (59, 62))	('transcription', 'MPA', (132, 145))	('AP1', 'cellular_component', 'GO:0005907', ('26', '29'))	('PD0325901', 'Var', (101, 110))	('FosL2', 'Gene', (70, 75))	('AP1', 'Gene', (26, 29))	('c-Jun', 'Gene', '16476', (47, 52))	('transcription', 'biological_process', 'GO:0006351', ('132', '145'))	('FosL1', 'Gene', '14283', (59, 64))	('FosL2', 'Gene', '14284', (70, 75))	('FosL1', 'Gene', (59, 64))	('Fos', 'Gene', (54, 57))
30216	31801083	Consistent with the notion of transcriptional cooperation between the two pathways, we found that ectopic expression of DN-TEAD4 and treatment of PD0325901 synergized to inhibit the transcription of CTGF, CYR61, and ANKRD1 (Figure 6G), as well as the YAP/TAZ target genes involved in regulation of cell proliferation and apoptosis, Myc, Cyclin D1, and BirC5 (Figures 6G and 7A).	('BirC5', 'Gene', (352, 357))	('YAP/TAZ', 'Gene', (251, 258))	('ANKRD1', 'Gene', (216, 222))	('PD0325901', 'Chemical', 'MESH:C506614', (146, 155))	('BirC5', 'Gene', '11799', (352, 357))	('Myc', 'Gene', (332, 335))	('transcription', 'MPA', (182, 195))	('ectopic expression', 'Var', (98, 116))	('Cyclin D1', 'Gene', '12443', (337, 346))	('DN-TEAD4', 'Var', (120, 128))	('regulation of cell proliferation', 'biological_process', 'GO:0042127', ('284', '316'))	('YAP/TAZ', 'Gene', '22601;66826', (251, 258))	('Myc', 'Gene', '17869', (332, 335))	('Cyclin', 'molecular_function', 'GO:0016538', ('337', '343'))	('CYR61', 'Gene', (205, 210))	('apoptosis', 'biological_process', 'GO:0097194', ('321', '330'))	('apoptosis', 'biological_process', 'GO:0006915', ('321', '330'))	('CTGF', 'Gene', (199, 203))	('inhibit', 'NegReg', (170, 177))	('Cyclin D1', 'Gene', (337, 346))	('PD0325901', 'Var', (146, 155))	('transcription', 'biological_process', 'GO:0006351', ('182', '195'))
30217	31801083	Further analysis showed PD0325901 treatment at 10 nM, a concentration that effectively blocked ERK phosphorylation in 92-1 UM cells (Figure 6D), had largely no effect on cell viability, measured by the MTT assay (Figure 7B).	('phosphorylation', 'biological_process', 'GO:0016310', ('99', '114'))	('92-1 UM', 'CellLine', 'CVCL:7796', (118, 125))	('ERK phosphorylation', 'Protein', (95, 114))	('PD0325901', 'Var', (24, 33))	('MTT', 'Chemical', 'MESH:C070243', (202, 205))	('PD0325901', 'Chemical', 'MESH:C506614', (24, 33))	('ERK', 'molecular_function', 'GO:0004707', ('95', '98'))	('blocked', 'NegReg', (87, 94))
30218	31801083	MEK inhibition by PD0325901 also did not significantly induce apoptosis in 92-1 UM cells, detected by western blot analysis of cleaved poly(ADP-ribose) polymerase (PARP) (Figure 7A).	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('PARP', 'Gene', (164, 168))	('MEK', 'Enzyme', (0, 3))	('92-1 UM', 'CellLine', 'CVCL:7796', (75, 82))	('PARP', 'Gene', '11545', (164, 168))	('PD0325901', 'Var', (18, 27))	('poly(ADP-ribose) polymerase', 'Gene', (135, 162))	('poly(ADP-ribose) polymerase', 'Gene', '11545', (135, 162))	('PD0325901', 'Chemical', 'MESH:C506614', (18, 27))
30224	31801083	Using this robust platform, we demonstrated the ability of Lats1/2 deletion or YAP activation to initiate UM and uncovered its cooperation with Kras to promote UM progression.	('YAP', 'Gene', (79, 82))	('deletion', 'Var', (67, 75))	('Kras', 'Gene', (144, 148))	('Kras', 'Gene', '16653', (144, 148))	('Lats1/2', 'Gene', (59, 66))	('promote', 'PosReg', (152, 159))
30228	31801083	Our data focus on the role of dysregulated Hippo signaling via Lats1/2 inactivation or YAP activation in UM genesis; however, additional studies are needed to explore the possible interactions between Hippo/Yap and other oncogenic pathways downstream of GNAQ/11, such as PLCbeta and PKC.	('Hippo', 'Gene', (43, 48))	('Lats1/2', 'Gene', (63, 70))	('Hippo', 'Gene', '37247', (201, 206))	('Hippo signaling', 'biological_process', 'GO:0035329', ('43', '58'))	('PKC', 'molecular_function', 'GO:0004697', ('283', '286'))	('PLCbeta', 'Gene', '14827', (271, 278))	('Hippo', 'Gene', '37247', (43, 48))	('PLCbeta', 'Gene', (271, 278))	('interactions', 'Interaction', (180, 192))	('PKC', 'Gene', (283, 286))	('PKC', 'Gene', '112476', (283, 286))	('Yap', 'Gene', (207, 210))	('Yap', 'Gene', '22601', (207, 210))	('inactivation', 'Var', (71, 83))	('Hippo', 'Gene', (201, 206))
30246	31801083	LSL-KrasG12D and R26mT/mG mice were obtained from the Jackson laboratory.	('mice', 'Species', '10090', (26, 30))	('R26mT/mG', 'Var', (17, 25))	('Kras', 'Gene', (4, 8))	('Kras', 'Gene', '16653', (4, 8))
30288	31801083	Modeling uveal melanoma (UM) via AAV-based Cre delivery into uveal tract Lats1/2 kinases suppress UM formation in uveal melanocytes Lats1/2 deletion cooperates with Kras activation to promote UM progression Dual inhibition of YAP/TAZ and Ras/MAPK synergizes to suppress UM cell growth	('Modeling uveal melanoma', 'Disease', 'MESH:C536494', (0, 23))	('Modeling uveal melanoma', 'Disease', (0, 23))	('YAP/TAZ', 'Gene', '22601;66826', (226, 233))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (9, 23))	('Kras', 'Gene', (165, 169))	('AAV', 'Chemical', '-', (33, 36))	('Kras', 'Gene', '16653', (165, 169))	('UM progression', 'CPA', (192, 206))	('cell growth', 'biological_process', 'GO:0016049', ('273', '284'))	('UM formation', 'MPA', (98, 110))	('deletion', 'Var', (140, 148))	('MAPK', 'molecular_function', 'GO:0004707', ('242', '246'))	('YAP/TAZ', 'Gene', (226, 233))	('suppress', 'NegReg', (89, 97))	('formation', 'biological_process', 'GO:0009058', ('101', '110'))	('promote', 'PosReg', (184, 191))
30316	30719144	Using the HaloPlex Target Enrichment System (Agilent Technologies), NGS was performed to investigate mutations in a 35-gene panel composed of cancer-related genes.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mutations', 'Var', (101, 110))	('cancer', 'Disease', (142, 148))
30318	30719144	FOXO1, PIK3R1 and HIF1A were also found to harbour somatic mutations in more than 20% of patients, a result that may indicate previously undescribed associations between these genes and UM pathogenesis.	('PIK3R1', 'Gene', '5295', (7, 13))	('pathogenesis', 'biological_process', 'GO:0009405', ('189', '201'))	('FOXO1', 'Gene', (0, 5))	('FOXO1', 'Gene', '2308', (0, 5))	('PIK3R1', 'Gene', (7, 13))	('UM', 'Phenotype', 'HP:0007716', (186, 188))	('HIF1A', 'Gene', (18, 23))	('HIF1A', 'Gene', '3091', (18, 23))	('associations', 'Interaction', (149, 161))	('patients', 'Species', '9606', (89, 97))	('mutations', 'Var', (59, 68))
30319	30719144	Patients with HIF1A and FOXO1 mutations exhibited worse overall survival (OS).	('overall survival', 'MPA', (56, 72))	('HIF1A', 'Gene', (14, 19))	('HIF1A', 'Gene', '3091', (14, 19))	('FOXO1', 'Gene', '2308', (24, 29))	('Patients', 'Species', '9606', (0, 8))	('FOXO1', 'Gene', (24, 29))	('mutations', 'Var', (30, 39))	('OS', 'Chemical', '-', (74, 76))
30320	30719144	In multivariate analysis, FOXO1 mutation was an independent prognostic factor for OS (P<0.05) that was associated with an increase in the risk ratio by a factor of 1.35.	('mutation', 'Var', (32, 40))	('FOXO1', 'Gene', (26, 31))	('FOXO1', 'Gene', '2308', (26, 31))	('OS', 'Chemical', '-', (82, 84))
30321	30719144	Notably, we found that HIF1A and FOXO1 mutations were associated with metastatic transformation of UM (P<0.05 and P<0.001, respectively).	('FOXO1', 'Gene', (33, 38))	('HIF1A', 'Gene', '3091', (23, 28))	('HIF1A', 'Gene', (23, 28))	('mutations', 'Var', (39, 48))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('metastatic transformation of UM', 'CPA', (70, 101))	('FOXO1', 'Gene', '2308', (33, 38))	('associated with', 'Reg', (54, 69))
30326	30719144	Targeted therapy such as the use of BRAF and MEK mutation inhibitors can improve overall survival (OS) for CM patients who harbour specific mutations.	('BRAF', 'Gene', (36, 40))	('CM', 'Disease', 'MESH:D009202', (107, 109))	('MEK', 'Gene', (45, 48))	('MEK', 'Gene', '5609', (45, 48))	('improve', 'PosReg', (73, 80))	('mutations', 'Var', (140, 149))	('CM', 'Phenotype', 'HP:0012056', (107, 109))	('overall survival', 'MPA', (81, 97))	('OS', 'Chemical', '-', (99, 101))	('BRAF', 'Gene', '673', (36, 40))	('patients', 'Species', '9606', (110, 118))
30328	30719144	Driver mutations related to the pathogenesis of UM, such as mutations in GNAQ, GNA11, and BAP1, have also been revealed; these mutations are distinct from those related to CM.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('CM', 'Disease', 'MESH:D009202', (172, 174))	('GNAQ', 'Gene', '2776', (73, 77))	('BAP1', 'Gene', '8314', (90, 94))	('CM', 'Phenotype', 'HP:0012056', (172, 174))	('GNA11', 'Gene', '2767', (79, 84))	('GNA11', 'Gene', (79, 84))	('BAP1', 'Gene', (90, 94))	('GNAQ', 'Gene', (73, 77))	('pathogenesis', 'biological_process', 'GO:0009405', ('32', '44'))	('mutations', 'Var', (60, 69))
30329	30719144	GNAQ or GNA11 mutations lead to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and represent early events in tumourigenesis in UM.	('GNA11', 'Gene', (8, 13))	('GNAQ', 'Gene', '2776', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (159, 161))	('MAPK', 'molecular_function', 'GO:0004707', ('97', '101'))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('GNA11', 'Gene', '2767', (8, 13))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('GNAQ', 'Gene', (0, 4))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('tumour', 'Disease', (141, 147))	('activation', 'PosReg', (45, 55))	('mutations', 'Var', (14, 23))
30330	30719144	[8]BAP1 mutations are strongly associated with the progression and metastasis of UM.	('BAP1', 'Gene', '8314', (3, 7))	('metastasis', 'CPA', (67, 77))	('BAP1', 'Gene', (3, 7))	('mutations', 'Var', (8, 17))	('associated with', 'Reg', (31, 46))	('progression', 'CPA', (51, 62))	('UM', 'Phenotype', 'HP:0007716', (81, 83))
30339	30719144	Using the HaloPlex Target Enrichment System (Agilent Technologies), NGS was performed to investigate mutations in a panel of 35 cancer-related genes.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (101, 110))	('cancer', 'Disease', (128, 134))
30349	30719144	Associations between mutations in MAPK pathway genes and patients' clinicopathological features were analysed.	('MAPK pathway', 'Gene', (34, 46))	('patients', 'Species', '9606', (57, 65))	('MAPK', 'molecular_function', 'GO:0004707', ('34', '38'))	('mutations', 'Var', (21, 30))
30350	30719144	We found that HIF1A mutation was significantly correlated with tumour metastasis (Table 2, P<0.05).	('tumour metastasis', 'Disease', (63, 80))	('HIF1A', 'Gene', (14, 19))	('mutation', 'Var', (20, 28))	('HIF1A', 'Gene', '3091', (14, 19))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('correlated', 'Reg', (47, 57))	('tumour metastasis', 'Disease', 'MESH:D009362', (63, 80))
30351	30719144	We further analysed the types of gene mutations detected in BRAF, NRAS, GNA11, GNAQ, HIF1A and PTEN in training cohort, as shown in Figure 1.	('NRAS', 'Gene', (66, 70))	('GNAQ', 'Gene', '2776', (79, 83))	('HIF1A', 'Gene', (85, 90))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('PTEN', 'Gene', '5728', (95, 99))	('HIF1A', 'Gene', '3091', (85, 90))	('NRAS', 'Gene', '4893', (66, 70))	('PTEN', 'Gene', (95, 99))	('GNAQ', 'Gene', (79, 83))	('GNA11', 'Gene', (72, 77))	('mutations', 'Var', (38, 47))	('GNA11', 'Gene', '2767', (72, 77))
30352	30719144	For the 4 patients harbouring BRAF mutations, the mutation, V600E, involved the well-known V600 amino acid residue.	('BRAF', 'Gene', (30, 34))	('V600E', 'Mutation', 'rs113488022', (60, 65))	('BRAF', 'Gene', '673', (30, 34))	('patients', 'Species', '9606', (10, 18))	('V600E', 'Var', (60, 65))
30353	30719144	All 4 patients with NRAS mutations had hot-spot mutations, including mutations at Q61 (n=3, 75%) and G12 (n=1, 25%).	('mutations', 'Var', (25, 34))	('G12', 'Var', (101, 104))	('patients', 'Species', '9606', (6, 14))	('NRAS', 'Gene', (20, 24))	('NRAS', 'Gene', '4893', (20, 24))	('mutations at Q61', 'Var', (69, 85))
30354	30719144	The 8 patients carrying GNA11 mutations shared a Q209 mutation.	('patients', 'Species', '9606', (6, 14))	('mutations', 'Var', (30, 39))	('Q209', 'Var', (49, 53))	('GNA11', 'Gene', (24, 29))	('GNA11', 'Gene', '2767', (24, 29))
30355	30719144	Among the 18 patients carrying GNAQ mutations, 11 (61%) patients shared the Q209P mutation, 5 (28%) patients shared the Q209L mutation, and 2 (11%) patients shared the R183Q mutation.	('patients', 'Species', '9606', (56, 64))	('patients', 'Species', '9606', (148, 156))	('Q209L', 'Var', (120, 125))	('patients', 'Species', '9606', (13, 21))	('GNAQ', 'Gene', '2776', (31, 35))	('Q209P', 'Mutation', 'rs121913492', (76, 81))	('patients', 'Species', '9606', (100, 108))	('R183Q', 'Mutation', 'rs397514698', (168, 173))	('Q209L', 'Mutation', 'rs121913492', (120, 125))	('GNAQ', 'Gene', (31, 35))	('Q209P', 'Var', (76, 81))
30356	30719144	Among the 12 patients with HIF1A mutations, 5 (42%) patients had the P606S mutation, 3 (25%) patients had the I136T mutation, and 4 (33%) patients had both the D373N and P606S mutations.	('patients', 'Species', '9606', (138, 146))	('I136T', 'Var', (110, 115))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (33, 42))	('HIF1A', 'Gene', (27, 32))	('P606S', 'Mutation', 'rs11549465', (69, 74))	('HIF1A', 'Gene', '3091', (27, 32))	('D373N', 'Var', (160, 165))	('P606S', 'Var', (69, 74))	('P606S', 'Mutation', 'rs11549465', (170, 175))	('D373N', 'Mutation', 'rs142179458', (160, 165))	('I136T', 'Mutation', 'rs1157339420', (110, 115))	('patients', 'Species', '9606', (93, 101))	('P606S', 'Var', (170, 175))	('patients', 'Species', '9606', (52, 60))
30357	30719144	All 4 patients harbouring PTEN mutations shared the M270I mutation.	('M270I', 'Var', (52, 57))	('patients', 'Species', '9606', (6, 14))	('PTEN', 'Gene', (26, 30))	('PTEN', 'Gene', '5728', (26, 30))	('M270I', 'Mutation', 'rs1195369834', (52, 57))
30358	30719144	We also investigated associations between MAPK pathway gene mutations and prognosis for UM patients and demonstrated that HIF1A mutation was associated with a worse prognosis in training cohort (P<0.05), as shown in Figure 2A.	('HIF1A', 'Gene', (122, 127))	('patients', 'Species', '9606', (91, 99))	('HIF1A', 'Gene', '3091', (122, 127))	('MAPK', 'molecular_function', 'GO:0004707', ('42', '46'))	('UM', 'Phenotype', 'HP:0007716', (88, 90))	('mutation', 'Var', (128, 136))
30359	30719144	In univariate analyses, HIF1A mutation status was significantly associated with OS for UM patients (P<0.05), as shown in Table 2.	('associated with', 'Reg', (64, 79))	('UM', 'Phenotype', 'HP:0007716', (87, 89))	('HIF1A', 'Gene', (24, 29))	('HIF1A', 'Gene', '3091', (24, 29))	('OS', 'Chemical', '-', (80, 82))	('mutation status', 'Var', (30, 45))	('patients', 'Species', '9606', (90, 98))
30361	30719144	We evaluated associations between mutations in PI3K/AKT pathway genes and patients' clinicopathological features and found that FOXO1 mutation was associated with metastatic transformation (P<0.001).	('FOXO1', 'Gene', (128, 133))	('associated', 'Reg', (147, 157))	('patients', 'Species', '9606', (74, 82))	('AKT', 'Gene', (52, 55))	('mutation', 'Var', (134, 142))	('metastatic transformation', 'CPA', (163, 188))	('FOXO1', 'Gene', '2308', (128, 133))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))	('AKT', 'Gene', '207', (52, 55))
30362	30719144	Details regarding the types of gene mutations detected in FOXO1, PIK3R1, TSC1, TSC2 and AKT1 in training cohort are shown in Figure 1.	('TSC2', 'Gene', '7249', (79, 83))	('TSC2', 'Gene', (79, 83))	('PIK3R1', 'Gene', '5295', (65, 71))	('FOXO1', 'Gene', '2308', (58, 63))	('mutations', 'Var', (36, 45))	('PIK3R1', 'Gene', (65, 71))	('FOXO1', 'Gene', (58, 63))	('TSC1', 'Gene', '7248', (73, 77))	('AKT1', 'Gene', '207', (88, 92))	('AKT1', 'Gene', (88, 92))	('TSC1', 'Gene', (73, 77))
30363	30719144	Among the 16 patients carrying FOXO1 mutations, 10 (63%) patients had the D82N mutation, and 6 (37%) patients had the A511V mutation.	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (13, 21))	('A511V', 'Var', (118, 123))	('mutations', 'Var', (37, 46))	('FOXO1', 'Gene', (31, 36))	('FOXO1', 'Gene', '2308', (31, 36))	('D82N', 'Mutation', 'rs34733279', (74, 78))	('D82N', 'Var', (74, 78))	('A511V', 'Mutation', 'rs70961707', (118, 123))
30364	30719144	The 20 patients harbouring PIK3R1 mutations had the M56I mutation.	('M56I', 'Mutation', 'rs3730089', (52, 56))	('PIK3R1', 'Gene', '5295', (27, 33))	('PIK3R1', 'Gene', (27, 33))	('M56I', 'Var', (52, 56))	('patients', 'Species', '9606', (7, 15))
30365	30719144	The 4 patients with NRAS mutations had hot-spot mutations, including mutations at Q61 (n=3, 75%) and G12 (n=1, 25%).	('mutations', 'Var', (25, 34))	('G12', 'Var', (101, 104))	('patients', 'Species', '9606', (6, 14))	('NRAS', 'Gene', (20, 24))	('NRAS', 'Gene', '4893', (20, 24))	('mutations at Q61', 'Var', (69, 85))
30366	30719144	Among the 7 patients with TSC1 mutations, 2 (29%) patients had the E894Q mutation, 2 (29%) patients had the M271T mutation, 2 (29%) patients had the Q603E mutation, and 1 (13%) patient had the M374V mutation.	('E894Q', 'Mutation', 'p.E894Q', (67, 72))	('E894Q', 'Var', (67, 72))	('patients', 'Species', '9606', (132, 140))	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (91, 99))	('M271T', 'Mutation', 'rs1073123', (108, 113))	('mutations', 'Var', (31, 40))	('patients', 'Species', '9606', (50, 58))	('TSC1', 'Gene', (26, 30))	('patient', 'Species', '9606', (12, 19))	('patient', 'Species', '9606', (132, 139))	('patient', 'Species', '9606', (91, 98))	('M271T', 'Var', (108, 113))	('Q603E', 'Mutation', 'rs75820036', (149, 154))	('Q603E', 'Var', (149, 154))	('TSC1', 'Gene', '7248', (26, 30))	('patient', 'Species', '9606', (177, 184))	('patient', 'Species', '9606', (50, 57))	('M374V', 'Mutation', 'rs753199284', (193, 198))
30367	30719144	Six patients harboured TSC2 mutations, including 3 (50%) patients with the R1115W mutation and 3 (50%) patients with the V591I mutation.	('patients', 'Species', '9606', (57, 65))	('harboured', 'Reg', (13, 22))	('R1115W', 'Var', (75, 81))	('V591I', 'Var', (121, 126))	('TSC2', 'Gene', '7249', (23, 27))	('patients', 'Species', '9606', (4, 12))	('R1115W', 'Mutation', 'rs45517295', (75, 81))	('patients', 'Species', '9606', (103, 111))	('TSC2', 'Gene', (23, 27))	('V591I', 'Mutation', 'rs984275273', (121, 126))
30368	30719144	The 4 patients carrying AKT mutations shared the V416A mutation.	('AKT', 'Gene', (24, 27))	('V416A', 'Var', (49, 54))	('patients', 'Species', '9606', (6, 14))	('AKT', 'Gene', '207', (24, 27))	('V416A', 'Mutation', 'p.V416A', (49, 54))
30369	30719144	We evaluated the effects of individual gene mutations in the PI3K/AKT pathway on UM patient survival and showed that FOXO1 mutation was correlated with a worse prognosis in training cohort (P<0.05), as shown in Figure 2B.	('PI3K', 'molecular_function', 'GO:0016303', ('61', '65'))	('AKT', 'Gene', (66, 69))	('mutation', 'Var', (123, 131))	('UM', 'Phenotype', 'HP:0007716', (81, 83))	('FOXO1', 'Gene', '2308', (117, 122))	('FOXO1', 'Gene', (117, 122))	('AKT', 'Gene', '207', (66, 69))	('patient', 'Species', '9606', (84, 91))
30371	30719144	In univariate analyses, FOXO1 mutation status was significantly correlated with worse OS for UM patients (P<0.05), as shown in Table 2.	('correlated with', 'Reg', (64, 79))	('OS', 'Chemical', '-', (86, 88))	('FOXO1', 'Gene', '2308', (24, 29))	('UM', 'Phenotype', 'HP:0007716', (93, 95))	('worse OS', 'Disease', (80, 88))	('FOXO1', 'Gene', (24, 29))	('mutation status', 'Var', (30, 45))	('patients', 'Species', '9606', (96, 104))
30373	30719144	In this multivariate analysis, FOXO1 mutation was an independent prognostic factor for OS (P<0.05) that was associated with an increase in the risk ratio by a factor of 1.35, as shown in Table 3.	('FOXO1', 'Gene', '2308', (31, 36))	('OS', 'Chemical', '-', (87, 89))	('FOXO1', 'Gene', (31, 36))	('mutation', 'Var', (37, 45))
30375	30719144	Instead, 83% of UM patients harbour mutations in GNAQ or GNA11.	('patients', 'Species', '9606', (19, 27))	('GNA11', 'Gene', (57, 62))	('GNAQ', 'Gene', '2776', (49, 53))	('GNA11', 'Gene', '2767', (57, 62))	('mutations', 'Var', (36, 45))	('UM', 'Phenotype', 'HP:0007716', (16, 18))	('GNAQ', 'Gene', (49, 53))
30376	30719144	The reported frequencies of GNAQ mutation range from 42-49% in Caucasian populations.	('GNAQ', 'Gene', (28, 32))	('mutation', 'Var', (33, 41))	('GNAQ', 'Gene', '2776', (28, 32))
30377	30719144	[5 8 13] In the cohort examined in this investigation, the gene mutation rate for GNAQ was 46.7%, which was similar to previously reported rates in Caucasian populations.	('GNAQ', 'Gene', (82, 86))	('gene mutation', 'Var', (59, 72))	('GNAQ', 'Gene', '2776', (82, 86))
30378	30719144	Although the GNA11 mutation rate was reported to be 32.6% in a Caucasian population, this rate was only 21.5% in the current study, a much lower frequency than that observed in the Caucasian cohort.	('mutation', 'Var', (19, 27))	('GNA11', 'Gene', '2767', (13, 18))	('GNA11', 'Gene', (13, 18))
30381	30719144	In our cohort, we found that HIF1A and FOXO1 mutations were associated with metastatic transformation of UM (P<0.05 and P<0.001, respectively).	('FOXO1', 'Gene', (39, 44))	('mutations', 'Var', (45, 54))	('metastatic transformation of', 'CPA', (76, 104))	('HIF1A', 'Gene', '3091', (29, 34))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('HIF1A', 'Gene', (29, 34))	('FOXO1', 'Gene', '2308', (39, 44))	('associated with', 'Reg', (60, 75))
30386	30719144	Hanna found that inactivation of HIF1A led to decreased melanoma metastasis.	('inactivation', 'Var', (17, 29))	('HIF1A', 'Gene', '3091', (33, 38))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('decreased melanoma metastasis', 'Disease', 'MESH:D009362', (46, 75))	('decreased melanoma metastasis', 'Disease', (46, 75))	('HIF1A', 'Gene', (33, 38))
30388	30719144	Consistent with these previous results, we found that HIF1A mutation was significantly associated with tumour metastasis in UM.	('HIF1A', 'Gene', (54, 59))	('HIF1A', 'Gene', '3091', (54, 59))	('mutation', 'Var', (60, 68))	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('tumour metastasis', 'Disease', (103, 120))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('associated with', 'Reg', (87, 102))	('tumour metastasis', 'Disease', 'MESH:D009362', (103, 120))
30389	30719144	Cox univariate analyses also indicated that HIF1A mutation was significantly associated with outcome for UM.	('HIF1A', 'Gene', (44, 49))	('HIF1A', 'Gene', '3091', (44, 49))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('mutation', 'Var', (50, 58))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('associated with', 'Reg', (77, 92))
30393	30719144	Zhang showed that in prostate cancer, inactivation of FOXO1 could drive the promiscuous expression of Runx2 target genes involved in cell migration and invasion and promote tumour progression.	('prostate cancer', 'Disease', 'MESH:D011471', (21, 36))	('tumour', 'Disease', (173, 179))	('FOXO1', 'Gene', (54, 59))	('FOXO1', 'Gene', '2308', (54, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (21, 36))	('inactivation', 'Var', (38, 50))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('promote', 'PosReg', (165, 172))	('prostate cancer', 'Disease', (21, 36))	('drive', 'PosReg', (66, 71))	('promiscuous expression', 'MPA', (76, 98))	('Runx2', 'Gene', '860', (102, 107))	('Runx2', 'Gene', (102, 107))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cell migration', 'biological_process', 'GO:0016477', ('133', '147'))
30395	30719144	In our cohort, the FOXO1 mutation was significantly associated with metastatic transformation of UM.	('FOXO1', 'Gene', (19, 24))	('FOXO1', 'Gene', '2308', (19, 24))	('metastatic transformation', 'CPA', (68, 93))	('UM', 'Phenotype', 'HP:0007716', (97, 99))	('mutation', 'Var', (25, 33))	('associated with', 'Reg', (52, 67))
30396	30719144	The FOXO1 mutation was also found to be an independent prognostic factor for UM in both univariate and multivariate analyses.	('FOXO1', 'Gene', (4, 9))	('FOXO1', 'Gene', '2308', (4, 9))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('mutation', 'Var', (10, 18))
30398	30719144	Overall, 80% of UM patients have mutations in the GNAQ and GNA11 genes, which constitutively activate the MAPK and PI3K/AKT pathways; therapies targeting downstream effectors of these pathways, such as MEK, AKT, and protein kinase C (PKC), are currently being investigated.	('AKT', 'Gene', (120, 123))	('PKC', 'Gene', '112476', (234, 237))	('mutations', 'Var', (33, 42))	('activate', 'PosReg', (93, 101))	('PKC', 'Gene', (234, 237))	('AKT', 'Gene', '207', (207, 210))	('PKC', 'molecular_function', 'GO:0004697', ('234', '237'))	('MEK', 'Gene', '5609', (202, 205))	('GNAQ', 'Gene', '2776', (50, 54))	('GNA11', 'Gene', (59, 64))	('AKT', 'Gene', '207', (120, 123))	('protein', 'cellular_component', 'GO:0003675', ('216', '223'))	('GNAQ', 'Gene', (50, 54))	('PI3K', 'molecular_function', 'GO:0016303', ('115', '119'))	('MEK', 'Gene', (202, 205))	('patients', 'Species', '9606', (19, 27))	('UM', 'Phenotype', 'HP:0007716', (16, 18))	('protein kinase C', 'Gene', '112476', (216, 232))	('MAPK', 'molecular_function', 'GO:0004707', ('106', '110'))	('protein kinase C', 'Gene', (216, 232))	('AKT', 'Gene', (207, 210))	('GNA11', 'Gene', '2767', (59, 64))
30400	30719144	In conclusion, in this study, we showed for the mutation patterns of UM in a non-Caucasian cohort, with a focus on gene mutations that affect key molecules in the MAPK and PI3K/AKT pathways.	('AKT', 'Gene', '207', (177, 180))	('affect', 'Reg', (135, 141))	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('AKT', 'Gene', (177, 180))	('MAPK', 'molecular_function', 'GO:0004707', ('163', '167'))	('PI3K', 'molecular_function', 'GO:0016303', ('172', '176'))	('mutations', 'Var', (120, 129))
30409	29284076	M-PHP results in durable intrahepatic disease control and can form the basis for an integrated multimodality treatment approach in appropriately selected UM patients.	('hepatic disease', 'Phenotype', 'HP:0001392', (30, 45))	('patients', 'Species', '9606', (157, 165))	('intrahepatic disease', 'Disease', (25, 45))	('M-PHP', 'Var', (0, 5))	('UM', 'Phenotype', 'HP:0007716', (154, 156))	('intrahepatic disease', 'Disease', 'MESH:D002780', (25, 45))
30454	29284076	On univariate analysis only high baseline LDH, high disease burden (50% liver parenchymal replacement and/or >10 deposits) and presence of extrahepatic disease at treatment onset predicted for worse OS (Figure 3C-E) while age, gender, previous liver directed, or systemic treatment, prolonged lead time from diagnosis of stage IV disease, ECOG Performance status, and deranged baseline liver function, did not.	('OS', 'Chemical', '-', (199, 201))	('hepatic disease', 'Phenotype', 'HP:0001392', (144, 159))	('stage IV disease', 'Disease', (321, 337))	('LDH', 'MPA', (42, 45))	('extrahepatic disease', 'Disease', 'MESH:D001651', (139, 159))	('high', 'Var', (28, 32))	('stage IV disease', 'Disease', 'MESH:D058625', (321, 337))	('liver parenchyma', 'Disease', 'MESH:D010195', (72, 88))	('extrahepatic disease', 'Disease', (139, 159))	('liver parenchyma', 'Disease', (72, 88))
30488	29284076	In a recently published case series of UM patients treated with second line pembrolizumab, outcomes were much better for patients without progressive liver-only disease.11 It is possible that in our group of patients, the degree of intrahepatic disease control provided by M-PHP was sufficient to augment the systemic effect of immunotherapy, and at least partially overcome UM's innate resistance to this treatment modality.	('patients', 'Species', '9606', (208, 216))	('pembrolizumab', 'Chemical', 'MESH:C582435', (76, 89))	('intrahepatic disease', 'Disease', 'MESH:D002780', (232, 252))	('intrahepatic disease', 'Disease', (232, 252))	('hepatic disease', 'Phenotype', 'HP:0001392', (237, 252))	('UM', 'Phenotype', 'HP:0007716', (39, 41))	('UM', 'Phenotype', 'HP:0007716', (375, 377))	('M-PHP', 'Var', (273, 278))	('liver-only disease', 'Disease', (150, 168))	('systemic', 'MPA', (309, 317))	('augment', 'PosReg', (297, 304))	('liver-only disease', 'Disease', 'MESH:D008107', (150, 168))	('patients', 'Species', '9606', (42, 50))	('patients', 'Species', '9606', (121, 129))
30490	29284076	Release of tumor antigens and modification of an immunosuppressive liver microenvironment are additional ways through which PHP might augment an anti-tumor immune response.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('immune response', 'biological_process', 'GO:0006955', ('156', '171'))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('PHP', 'Var', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('augment', 'PosReg', (134, 141))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
30495	29284076	Our results clearly demonstrate that M-PHP appears to be an effective means of obtaining rapid intrahepatic disease control, is a sensible option in patients with liver predominant disease in the absence of established effective systemic treatments and support the role of M-PHP as part of an integrated multi-disciplinary approach to the management of UM.	('intrahepatic disease', 'Disease', (95, 115))	('patients', 'Species', '9606', (149, 157))	('liver predominant disease', 'Disease', (163, 188))	('M-PHP', 'Var', (37, 42))	('intrahepatic disease', 'Disease', 'MESH:D002780', (95, 115))	('hepatic disease', 'Phenotype', 'HP:0001392', (100, 115))	('UM', 'Phenotype', 'HP:0007716', (353, 355))
30498	29490280	GNA11 Q209L Mouse Model Reveals RasGRP3 as an Essential Signaling Node in Uveal Melanoma Uveal melanoma (UM) is characterized by mutually exclusive activating mutations in GNAQ, GNA11, CYSLTR2, and PLCB4, four genes in a linear pathway to activation of PLCbeta in almost all tumors and loss of BAP1 in the aggressive subset.	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('PLCB4', 'Gene', (198, 203))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('Melanoma', 'Disease', 'MESH:D008545', (80, 88))	('GNA11', 'Gene', '14672', (0, 5))	('BAP1', 'Gene', (294, 298))	('PLCbeta', 'Gene', (253, 260))	('mutations', 'Var', (159, 168))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('CYSLTR2', 'Gene', '70086', (185, 192))	('Signaling', 'biological_process', 'GO:0023052', ('56', '65'))	('GNAQ', 'Gene', (172, 176))	('RasGRP3', 'Gene', (32, 39))	('Melanoma', 'Disease', (80, 88))	('RasGRP3', 'Gene', '240168', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('Mouse', 'Species', '10090', (12, 17))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('tumors', 'Disease', (275, 281))	('Melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('GNA11', 'Gene', (178, 183))	('activation', 'PosReg', (239, 249))	('GNAQ', 'Gene', '14682', (172, 176))	('CYSLTR2', 'Gene', (185, 192))	('GNA11', 'Gene', (0, 5))	('PLCB4', 'Gene', '18798', (198, 203))	('tumors', 'Disease', 'MESH:D009369', (275, 281))	('GNA11', 'Gene', '14672', (178, 183))	('PLCbeta', 'Gene', '18795', (253, 260))	('Q209L', 'Mutation', 'rs1057519742', (6, 11))
30500	29490280	The GNA11Q209L mice recapitulated human Gq-associated melanomas, and they developed pigmented neoplastic lesions from melanocytes of the skin and non-cutaneous organs, including the eye and leptomeninges, as well as at atypical sites, including the lymph nodes and lungs.	('human', 'Species', '9606', (34, 39))	('pigmented neoplastic lesions', 'Disease', 'MESH:D010859', (84, 112))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (94, 112))	('GNA11Q209L', 'Var', (4, 14))	('melanomas', 'Disease', 'MESH:D008545', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('pigmented neoplastic lesions from melanocytes of the skin', 'Phenotype', 'HP:0002861', (84, 141))	('pigmented neoplastic lesions', 'Disease', (84, 112))	('developed', 'PosReg', (74, 83))	('mice', 'Species', '10090', (15, 19))	('melanomas', 'Disease', (54, 63))
30512	29490280	Molecularly, CM is driven by recurrent somatic mutations that activate the mitogen-activated protein kinase (MAPK) pathway, including BRAF, NRAS, NF1, and KIT.	('KIT', 'molecular_function', 'GO:0005020', ('155', '158'))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('KIT', 'Disease', (155, 158))	('activate', 'PosReg', (62, 70))	('BRAF', 'Disease', (134, 138))	('mutations', 'Var', (47, 56))	('NF1', 'Gene', '18015', (146, 149))	('NRAS', 'Gene', '18176', (140, 144))	('NRAS', 'Gene', (140, 144))	('MAPK', 'molecular_function', 'GO:0004707', ('109', '113'))	('NF1', 'Gene', (146, 149))
30513	29490280	Approximately 90% of UMs harbor activating mutations in two homologous G-protein alpha (Galpha) subunits, GNA11 (Galpha11) and GNAQ (Galphaq), at codons Gln209 or Arg183 (, 2010).	('Galphaq', 'Gene', (133, 140))	('Gln209', 'Var', (153, 159))	('GNAQ', 'Gene', (127, 131))	('Arg183', 'Chemical', '-', (163, 169))	('GNA11', 'Gene', (106, 111))	('GNAQ', 'Gene', '14682', (127, 131))	('Galphaq', 'Gene', '14682', (133, 140))	('GNA11', 'Gene', '14672', (106, 111))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('activating', 'PosReg', (32, 42))	('Arg183', 'Var', (163, 169))
30514	29490280	Among the remaining 10% of UMs, most harbor activating mutations in a G-protein-coupled receptor (CYSLTR2 at the Leu129 codon activates Galpha11/q) or in phospholipase C beta4 (PLCB4) (at the Asp630 codon, a direct downstream effector of Galpha11/q cleaves phosphatidylinositol 4,5-bisphosphate [PIP2] to produce the second messengers diacylglycerol [DAG] and inositol triphosphate [IP3].	('CYSLTR2', 'Gene', (98, 105))	('mutations', 'Var', (55, 64))	('Galpha11/q', 'MPA', (136, 146))	('phospholipase C beta4', 'Gene', '18798', (154, 175))	('PLCB4', 'Gene', (177, 182))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('phospholipase C beta4', 'Gene', (154, 175))	('DAG', 'Chemical', 'MESH:D004075', (351, 354))	('p63', 'Gene', '22061', (194, 197))	('activates', 'PosReg', (126, 135))	('PLCB4', 'Gene', '18798', (177, 182))	('p63', 'Gene', (194, 197))	('diacylglycerol [', 'MPA', (335, 351))	('inositol triphosphate', 'MPA', (360, 381))	('CYSLTR2', 'Gene', '70086', (98, 105))
30516	29490280	While essentially all UMs harbor mutations in the CYSLTR2-Galpha11/q-PLCbeta pathway, the prognosis is largely determined by the presence of cooperative mutations.	('PLCbeta', 'Gene', '18795', (69, 76))	('mutations', 'Var', (33, 42))	('PLCbeta', 'Gene', (69, 76))	('CYSLTR2', 'Gene', '70086', (50, 57))	('CYSLTR2', 'Gene', (50, 57))
30518	29490280	Most of these tumors harbor inactivating mutations in BAP1, located at 3q21, and essentially all of these tumors lose expression of the BAP1 protein, implicating BAP1 loss as a critical cooperating lesion driving poor prognosis in UM.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('inactivating mutations', 'Var', (28, 50))	('BAP1 protein', 'Protein', (136, 148))	('protein', 'Protein', (141, 148))	('lose', 'NegReg', (113, 117))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('expression', 'Species', '29278', (118, 128))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('expression', 'MPA', (118, 128))	('BAP1', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
30519	29490280	Among tumors with disomy 3, there are mutually exclusive mutations in SF3B1, associated with intermediate prognosis, and in EIF1AX, associated with favorable prognosis.	('EIF1AX', 'Gene', (124, 130))	('disomy', 'Disease', 'MESH:D024182', (18, 24))	('SF3B1', 'Gene', '81898', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('disomy', 'Disease', (18, 24))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('mutations', 'Var', (57, 66))	('SF3B1', 'Gene', (70, 75))	('associated', 'Reg', (132, 142))	('EIF1AX', 'Gene', '66235', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('associated', 'Reg', (77, 87))
30520	29490280	In addition to UM, CYSLTR2-Galpha11/q-PLCbeta pathway mutations are found in most leptomeningeal melanocytic neoplasms (LMNs) and blue nevi.	('blue nevi', 'Disease', (130, 139))	('leptomeningeal melanocytic neoplasms', 'Disease', 'MESH:D008577', (82, 118))	('PLCbeta', 'Gene', '18795', (38, 45))	('mutations', 'Var', (54, 63))	('neoplasms', 'Phenotype', 'HP:0002664', (109, 118))	('nevi', 'Phenotype', 'HP:0003764', (135, 139))	('found', 'Reg', (68, 73))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (97, 118))	('PLCbeta', 'Gene', (38, 45))	('blue nevi', 'Phenotype', 'HP:0100814', (130, 139))	('CYSLTR2', 'Gene', '70086', (19, 26))	('CYSLTR2', 'Gene', (19, 26))	('leptomeningeal melanocytic neoplasms', 'Disease', (82, 118))
30525	29490280	Recent genetic characterization of a large cohort of blue nevi showed both benign and malignant blue nevi harbored CYSLTR2-Galpha11/q-PLCbeta pathway mutations.	('blue nevi', 'Phenotype', 'HP:0100814', (96, 105))	('PLCbeta', 'Gene', (134, 141))	('PLCbeta', 'Gene', '18795', (134, 141))	('nevi', 'Phenotype', 'HP:0003764', (58, 62))	('nevi', 'Phenotype', 'HP:0003764', (101, 105))	('blue nevi', 'Disease', (96, 105))	('blue nevi', 'Phenotype', 'HP:0100814', (53, 62))	('CYSLTR2', 'Gene', (115, 122))	('mutations', 'Var', (150, 159))	('CYSLTR2', 'Gene', '70086', (115, 122))
30526	29490280	EIF1AX mutations are found only in benign blue nevi, while SF3B1 and BAP1 mutations are found only in malignant blue nevi.	('benign', 'Disease', (35, 41))	('nevi', 'Phenotype', 'HP:0003764', (117, 121))	('blue nevi', 'Phenotype', 'HP:0100814', (42, 51))	('BAP1', 'Gene', (69, 73))	('SF3B1', 'Gene', (59, 64))	('nevi', 'Phenotype', 'HP:0003764', (47, 51))	('EIF1AX', 'Gene', '66235', (0, 6))	('SF3B1', 'Gene', '81898', (59, 64))	('blue nevi', 'Phenotype', 'HP:0100814', (112, 121))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
30527	29490280	Therefore, UM, LMN, and blue nevi represent a molecularly similar spectrum of diseases that commonly harbor CYSLTR2-Galpha11/q-PLCbeta mutations and whose disease aggressiveness is defined by co-mutations, especially BAP1.	('aggressiveness', 'Phenotype', 'HP:0000718', (163, 177))	('blue nevi', 'Disease', (24, 33))	('mutations', 'Var', (135, 144))	('PLCbeta', 'Gene', (127, 134))	('aggressiveness', 'Disease', 'MESH:D001523', (163, 177))	('CYSLTR2', 'Gene', (108, 115))	('CYSLTR2', 'Gene', '70086', (108, 115))	('LMN', 'Disease', (15, 18))	('nevi', 'Phenotype', 'HP:0003764', (29, 33))	('blue nevi', 'Phenotype', 'HP:0100814', (24, 33))	('aggressiveness', 'Disease', (163, 177))	('PLCbeta', 'Gene', '18795', (127, 134))	('BAP1', 'Disease', (217, 221))
30534	29490280	Deletion of Bap1 accelerated skin tumor growth and mouse mortality.	('mouse mortality', 'CPA', (51, 66))	('skin tumor', 'Disease', (29, 39))	('skin tumor', 'Disease', 'MESH:D012878', (29, 39))	('mouse', 'Species', '10090', (51, 56))	('skin tumor', 'Phenotype', 'HP:0008069', (29, 39))	('accelerated', 'PosReg', (17, 28))	('Bap1', 'Gene', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('Deletion', 'Var', (0, 8))
30535	29490280	The GNA11Q209L, Bap1 loss tumors were resistant to the MEK inhibitor trametinib.	('MEK', 'Gene', '17242', (55, 58))	('loss tumors', 'Disease', 'MESH:D009369', (21, 32))	('loss tumors', 'Disease', (21, 32))	('GNA11Q209L', 'Var', (4, 14))	('MEK', 'Gene', (55, 58))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('trametinib', 'Chemical', 'MESH:C560077', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('resistant', 'MPA', (38, 47))
30536	29490280	To identify alternative therapeutic targets, we performed integrative analysis comparing BRAF mutant and Galpha11/q mutant human and murine cancers, and we identified a critical requirement of a Ras guanine exchange factor (GEF), RasGRP3, for Galpha11/q-mediated tumorigenesis.	('GEF', 'Gene', (224, 227))	('Ras guanine exchange factor', 'Gene', '20662', (195, 222))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('GEF', 'molecular_function', 'GO:0005085', ('224', '227'))	('human', 'Species', '9606', (123, 128))	('GEF', 'Gene', '16800', (224, 227))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('Galpha11/q', 'Gene', (105, 115))	('mutant', 'Var', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('Ras guanine exchange factor', 'Gene', (195, 222))	('tumor', 'Disease', (263, 268))	('cancers', 'Disease', (140, 147))	('murine', 'Species', '10090', (133, 139))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('BRAF', 'Gene', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutant', 'Var', (116, 122))
30537	29490280	To express GNA11Q209L in the melanocyte lineage, we generated a genetically engineered mouse model (GEMM) with a conditional GNA11Q209L allele (R26-LSL-GNA11Q209L) under the control of the endogenous Rosa26 promoter (Figures S1A and S1B).	('Rosa26', 'Gene', (200, 206))	('Rosa26', 'Gene', '14910', (200, 206))	('R26-LSL-GNA11Q209L', 'Var', (144, 162))	('mouse', 'Species', '10090', (87, 92))
30544	29490280	In Tyr-CreERT2;GNA11Q209L mice, pathological analysis of the skin 3 months post-induction showed extensive follicular and dermal melanocytic proliferation (Figure 1C), which progressed to melanomas encompassing the dermis and subcutaneous tissues in 50% of mice by 6 months after injection (Figure 1D).	('dermal melanocytic proliferation', 'Disease', 'MESH:D059545', (122, 154))	('mice', 'Species', '10090', (257, 261))	('melanomas encompassing the dermis', 'Phenotype', 'HP:0002861', (188, 221))	('Tyr-CreERT2;GNA11Q209L', 'Var', (3, 25))	('melanomas', 'Disease', (188, 197))	('progressed', 'PosReg', (174, 184))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('melanomas', 'Phenotype', 'HP:0002861', (188, 197))	('melanomas', 'Disease', 'MESH:D008545', (188, 197))	('dermal melanocytic proliferation', 'Disease', (122, 154))	('mice', 'Species', '10090', (26, 30))
30547	29490280	We next examined the oncogenic role of GNA11Q209L and BRafV600E expression in uveal melanocytes.	('BRafV600E', 'Mutation', 'rs113488022', (54, 63))	('GNA11Q209L', 'Var', (39, 49))	('expression', 'Species', '29278', (64, 74))	('BRafV600E', 'Gene', (54, 63))
30548	29490280	Within the uveal tract, tamoxifen-injected Tyr-CreERT2;GNA11Q209L mice displayed diffuse hyperplasia, thickening of the choroid and ciliary body that progressed over time to overt UM with intraocular infiltration that distorted the normal architecture of the globe (Figures 1E and 1F).	('hyperplasia', 'Disease', 'MESH:D006965', (89, 100))	('distorted', 'Reg', (218, 227))	('mice', 'Species', '10090', (66, 70))	('tamoxifen', 'Chemical', 'MESH:D013629', (24, 33))	('hyperplasia', 'Disease', (89, 100))	('Tyr-CreERT2;GNA11Q209L', 'Var', (43, 65))	('thickening', 'CPA', (102, 112))
30555	29490280	Pathological evaluation of the CNS of the Tyr-CreERT2;GNA11Q209L mice showed melanocytic proliferation in the leptomeninges at the base of the brain, around cranial nerve roots, and within the longitudinal fissure (Figure 2A, ii-iv).	('melanocytic proliferation', 'Disease', (77, 102))	('melanocytic proliferation', 'Disease', 'MESH:D059545', (77, 102))	('Tyr-CreERT2;GNA11Q209L', 'Var', (42, 64))	('mice', 'Species', '10090', (65, 69))	('cranial nerve', 'Phenotype', 'HP:0001291', (157, 170))	('longitudinal fissure', 'Phenotype', 'HP:0100953', (193, 213))
30559	29490280	Examining the melanocytes of the heart in GNA11Q209L mice, we observed invasive neoplasms that infiltrated and thickened the tricuspid valve and infiltrated the myocardium of the right atrium and interventricular septum (Figures 2B and 2C).	('mice', 'Species', '10090', (53, 57))	('GNA11Q209L', 'Var', (42, 52))	('interventricular septum', 'Phenotype', 'HP:0005144', (196, 219))	('septum', 'cellular_component', 'GO:0030428', ('213', '219'))	('invasive neoplasms', 'Disease', (71, 89))	('neoplasms', 'Phenotype', 'HP:0002664', (80, 89))	('thickened', 'PosReg', (111, 120))	('invasive neoplasms', 'Disease', 'MESH:D009361', (71, 89))	('tricuspid valve', 'CPA', (125, 140))	('atrium and interventricular septum', 'Phenotype', 'HP:0001631', (185, 219))
30562	29490280	In GNA11Q209L mice, we observed multi-focal lesions in the lungs that may represent metastases, although we cannot rule out transformation of rare resident lung melanocytes (Figures 2B, 2D, and 2E).	('metastases', 'Disease', (84, 94))	('GNA11Q209L', 'Var', (3, 13))	('mice', 'Species', '10090', (14, 18))	('metastases', 'Disease', 'MESH:D009362', (84, 94))
30567	29490280	Our data are consistent with the clinical absence of BRAF mutations in UMs and LMNs and the sporadic occurrence of GNAQ/11 mutations in CMs.	('mutations', 'Var', (58, 67))	('GNAQ', 'Gene', (115, 119))	('BRAF', 'Gene', (53, 57))	('GNAQ', 'Gene', '14682', (115, 119))
30570	29490280	When activated in 8-week-old adult mice using Tyr-CreERT2, GNAQQ209L drove melanocyte overgrowth without progression to melanoma.	('GNAQQ209L', 'Var', (59, 68))	('overgrowth', 'Phenotype', 'HP:0001548', (86, 96))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('Tyr-CreERT2', 'Var', (46, 57))	('mice', 'Species', '10090', (35, 39))	('melanocyte overgrowth', 'CPA', (75, 96))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))
30571	29490280	The phenotype of our Tyr-CreERT2; GNA11Q209L mouse model, activated at 4 weeks, appears to be an intermediate between Mitf-Cre activated before birth and Tyr-CreERT2 activated at 8 weeks.	('Tyr-CreERT2', 'Var', (21, 32))	('Mitf', 'Gene', '17342', (118, 122))	('mouse', 'Species', '10090', (45, 50))	('Mitf', 'Gene', (118, 122))
30573	29490280	We sought to examine the combinatorial effect of GNA11Q209L and the loss of the tumor suppressor Bap1 in the development of UM.	('loss of the tumor', 'Disease', (68, 85))	('loss of the tumor', 'Disease', 'MESH:D009369', (68, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('GNA11Q209L', 'Var', (49, 59))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))
30574	29490280	To achieve Bap1 deletion, we crossed Bap1lox/lox mice to the Tyr-CreERT2;GNA11Q209L line.	('deletion', 'Var', (16, 24))	('lox', 'Gene', (41, 44))	('lox', 'Gene', (45, 48))	('lox', 'Gene', '16948', (41, 44))	('Bap1', 'Gene', (11, 15))	('mice', 'Species', '10090', (49, 53))	('lox', 'Gene', '16948', (45, 48))
30575	29490280	Tamoxifen-treated Tyr-CreERT2;Bap1KO mice had no discernible phenotype and were histologically normal over ~20 months, indicating Bap1 loss alone was insufficient to initiate melanoma (n = 35; Figures S4A and S4B).	('Bap1', 'Gene', (130, 134))	('loss', 'NegReg', (135, 139))	('Tyr-CreERT2', 'Var', (18, 29))	('insufficient to initiate melanoma', 'Disease', (150, 183))	('Tamoxifen', 'Chemical', 'MESH:D013629', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('insufficient to initiate melanoma', 'Disease', 'MESH:D000309', (150, 183))	('mice', 'Species', '10090', (37, 41))
30577	29490280	We observed a stronger ocular phenotype in GNA11Q209L than GNA11Q209L Bap1KO mice (Figures 3A-3C).	('ocular', 'CPA', (23, 29))	('mice', 'Species', '10090', (77, 81))	('GNA11Q209L', 'Var', (43, 53))	('stronger', 'PosReg', (14, 22))
30578	29490280	However, the GNA11Q209L Bap1KO mice succumbed to disease at an accelerated rate compared to GNA11Q209L or GNA11Q209L Bap1lox/+ mice (Figure 3D; p < 0.05), due to increased skin melanoma burden (Figures 3E and 3F).	('mice', 'Species', '10090', (127, 131))	('increased', 'PosReg', (162, 171))	('skin melanoma burden', 'Disease', (172, 192))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('mice', 'Species', '10090', (31, 35))	('GNA11Q209L Bap1KO', 'Var', (13, 30))	('lox', 'Gene', (121, 124))	('Bap1KO', 'Var', (24, 30))	('lox', 'Gene', '16948', (121, 124))	('skin melanoma burden', 'Disease', 'MESH:D008545', (172, 192))
30579	29490280	The loss of Bap1 in these mice did not appreciably alter the size or incidence of uveal lesions, but it contributed to an increased progression to skin melanomas originating from the tail and ears (Figures 3E-3G).	('uveal lesions', 'Disease', (82, 95))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanomas', 'Phenotype', 'HP:0002861', (152, 161))	('uveal lesions', 'Disease', 'MESH:D014603', (82, 95))	('skin melanomas', 'Disease', (147, 161))	('skin melanomas', 'Disease', 'MESH:D008545', (147, 161))	('mice', 'Species', '10090', (26, 30))	('Bap1', 'Gene', (12, 16))	('increased progression', 'PosReg', (122, 143))	('loss', 'Var', (4, 8))
30581	29490280	We observed no significant increase in the size or incidence of lung lesions in the absence of Bap1 (Figures S3E and S4F-S4H).	('lung lesions', 'Disease', (64, 76))	('S4F-S4H', 'Var', (117, 124))	('Bap1', 'Gene', (95, 99))	('lung lesions', 'Disease', 'MESH:D008171', (64, 76))	('absence', 'Var', (84, 91))
30582	29490280	Histologically, GNA11Q209L skin melanomas exhibited slender oval nuclei while GNA11Q209L;Bap1KO had larger euchromatic nuclei (Figure 3H).	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanomas', 'Phenotype', 'HP:0002861', (32, 41))	('skin melanomas', 'Disease', (27, 41))	('skin melanomas', 'Disease', 'MESH:D008545', (27, 41))	('GNA11Q209L', 'Var', (16, 26))
30583	29490280	GNA11Q209L;Bap1KO skin melanomas exhibited a higher proliferation index (Figures 3H and 3I; p < 0.0001).	('proliferation index', 'CPA', (52, 71))	('GNA11Q209L;Bap1KO', 'Var', (0, 17))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('skin melanomas', 'Disease', (18, 32))	('higher', 'PosReg', (45, 51))	('skin melanomas', 'Disease', 'MESH:D008545', (18, 32))
30586	29490280	Analysis of RNA-seq of GNA11Q209L and GNA11Q209L;Bap1KO skin melanomas confirmed deletion of Bap1 (Figure S5B).	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('skin melanomas', 'Disease', (56, 70))	('deletion', 'Var', (81, 89))	('RNA', 'cellular_component', 'GO:0005562', ('12', '15'))	('S5B', 'Gene', (106, 109))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('S5B', 'Gene', '66998', (106, 109))	('Bap1', 'Gene', (93, 97))	('skin melanomas', 'Disease', 'MESH:D008545', (56, 70))
30587	29490280	Using a gene set comprised of genes upregulated in GNA11Q209L;Bap1KO versus GNA11Q209L skin melanomas (Mouse_Bap1KO_UP), we performed gene set enrichment analysis (GSEA) using The Cancer Genome Atlas (TCGA) UM dataset.	('upregulated', 'PosReg', (36, 47))	('melanomas', 'Phenotype', 'HP:0002861', (92, 101))	('skin melanomas', 'Disease', (87, 101))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('GNA11Q209L', 'Var', (76, 86))	('skin melanomas', 'Disease', 'MESH:D008545', (87, 101))	('Cancer', 'Phenotype', 'HP:0002664', (180, 186))	('GNA11Q209L;Bap1KO', 'Var', (51, 68))	('GSEA', 'Chemical', '-', (164, 168))
30588	29490280	This showed Mouse_Bap1KO_UP genes are significantly enriched among genes negatively correlated with BAP1 expression in UM, suggesting BAP1 deletion in skin melanomas of mice results in the upregulation of similar genes to human UM (Figure 3J; Table S1).	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('deletion', 'Var', (139, 147))	('BAP1', 'Gene', (134, 138))	('melanomas', 'Phenotype', 'HP:0002861', (156, 165))	('skin melanomas', 'Disease', (151, 165))	('skin melanomas', 'Disease', 'MESH:D008545', (151, 165))	('mice', 'Species', '10090', (169, 173))	('expression', 'Species', '29278', (105, 115))	('human', 'Species', '9606', (222, 227))	('upregulation', 'PosReg', (189, 201))
30591	29490280	In a complementary approach, we identified a UM primary tumor line, UPMM3, contained a frameshift deletion of BAP1 (Figure S5C).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('BAP1', 'Gene', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('frameshift deletion', 'Var', (87, 106))
30593	29490280	As controls, we expressed BAP1 with mutations in the deubiquitinase domain (p.Cys91Trp, p.Ala95Pro) found in cancer as well as EGFP.	('BAP1', 'Gene', (26, 30))	('p.Cys91Trp', 'Var', (76, 86))	('p.Ala95Pro', 'Var', (88, 98))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('p.Ala95Pro', 'Mutation', 'p.A95P', (88, 98))	('cancer', 'Disease', (109, 115))	('p.Cys91Trp', 'SUBSTITUTION', 'None', (76, 86))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('53', '67'))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
30597	29490280	Therefore, in UM, the loss of Bap1 can promote aggressive disease with a propensity to proliferate and metastasize, consistent with clinical data implicating BAP1 loss as a poor prognostic biomarker.	('Bap1', 'Gene', (30, 34))	('aggressive disease', 'Disease', 'MESH:D001523', (47, 65))	('promote', 'PosReg', (39, 46))	('BAP1', 'Gene', (158, 162))	('proliferate', 'CPA', (87, 98))	('aggressive disease', 'Disease', (47, 65))	('loss', 'Var', (22, 26))
30599	29490280	While preclinical data using UM cell lines suggest MEK inhibition may be a therapeutic strategy, a recent phase 3 study comparing selumetinib and chemotherapy failed to show significant improvement in progression-free or overall survival.	('inhibition', 'Var', (55, 65))	('MEK', 'Gene', (51, 54))	('selumetinib', 'Chemical', 'MESH:C517975', (130, 141))	('MEK', 'Gene', '17242', (51, 54))
30600	29490280	Prolonged selumetinib treatment induces RAF-MEK dimer formation, leading to reactivation of MAPK signaling, particularly in non-BRAFV600E-driven tumors.	('MAPK', 'molecular_function', 'GO:0004707', ('92', '96'))	('selumetinib', 'Chemical', 'MESH:C517975', (10, 21))	('reactivation', 'MPA', (76, 88))	('non-BRAFV600E-driven', 'Var', (124, 144))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('MAPK signaling', 'biological_process', 'GO:0000165', ('92', '106'))	('tumors', 'Disease', (145, 151))	('MEK', 'Gene', '17242', (44, 47))	('MAPK signaling', 'Pathway', (92, 106))	('BRAFV600E', 'Mutation', 'rs113488022', (128, 137))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('formation', 'biological_process', 'GO:0009058', ('54', '63'))	('MEK', 'Gene', (44, 47))
30604	29490280	We observed Bap1KO also accelerated BRafV600E-driven tumors to form nodules amenable for treatment (unpublished data).	('BRafV600E-driven', 'MPA', (36, 52))	('BRafV600E', 'Mutation', 'rs113488022', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Bap1KO', 'Var', (12, 18))	('accelerated', 'PosReg', (24, 35))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
30605	29490280	We subcutaneously grafted skin melanomas, isolated from BRafV600E;Bap1KO and GNA11Q209L;Bap1KO mice, into severe combined immunodeficiency (SCID) mice.	('immunodeficiency', 'Disease', (122, 138))	('GNA11Q209L', 'Var', (77, 87))	('skin melanomas', 'Disease', (26, 40))	('mice', 'Species', '10090', (95, 99))	('skin melanomas', 'Disease', 'MESH:D008545', (26, 40))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (113, 138))	('SCID', 'Disease', (140, 144))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))	('SCID', 'Disease', 'MESH:D053632', (140, 144))	('mice', 'Species', '10090', (146, 150))	('immunodeficiency', 'Phenotype', 'HP:0002721', (122, 138))	('immunodeficiency', 'Disease', 'MESH:D007153', (122, 138))	('BRafV600E;Bap1KO', 'Var', (56, 72))	('BRafV600E', 'Mutation', 'rs113488022', (56, 65))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (106, 138))
30606	29490280	The grafts retained features of the in situ tumors, where GNA11Q209L;Bap1KO tumors retained hyper-pigmentation whereas BRafV600E;Bap1KO tumors were hypopigmented and exhibited elevated MAPK output (Figures 4A and 4B).	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('BRafV600E;Bap1KO', 'Var', (119, 135))	('hypopigmented', 'Disease', 'MESH:D017496', (148, 161))	('MAPK output', 'MPA', (185, 196))	('BRafV600E', 'Mutation', 'rs113488022', (119, 128))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('hypopigmented', 'Disease', (148, 161))	('tumors retained hyper-pigmentation', 'Disease', (76, 110))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('elevated', 'PosReg', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('MAPK', 'molecular_function', 'GO:0004707', ('185', '189'))	('situ tumors', 'Disease', (39, 50))	('situ tumors', 'Disease', 'MESH:D002278', (39, 50))	('tumors', 'Disease', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumors retained hyper-pigmentation', 'Disease', 'MESH:D010859', (76, 110))	('GNA11Q209L;Bap1KO', 'Var', (58, 75))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('hyper-pigmentation', 'Phenotype', 'HP:0000953', (92, 110))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('pigmentation', 'biological_process', 'GO:0043473', ('98', '110'))
30607	29490280	In BRafV600E Bap1KO tumors, short-term trametinib treatment decreased proliferation and MAPK output, whereas in GNA11Q209L Bap1KO tumors, the effects were modest (Figures 4A-4C).	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('decreased', 'NegReg', (60, 69))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('Bap1KO', 'Gene', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('MAPK output', 'MPA', (88, 99))	('BRafV600E', 'Var', (3, 12))	('MAPK', 'molecular_function', 'GO:0004707', ('88', '92'))	('proliferation', 'CPA', (70, 83))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('BRafV600E', 'Mutation', 'rs113488022', (3, 12))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('trametinib', 'Chemical', 'MESH:C560077', (39, 49))
30608	29490280	Long-term treatment resulted in initial tumor shrinkage followed by stabilization in BRafV600E Bap1KO tumors (Figure 4D).	('tumors', 'Disease', (102, 108))	('BRafV600E', 'Var', (85, 94))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('Bap1KO', 'Disease', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('BRafV600E', 'Mutation', 'rs113488022', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('shrinkage', 'NegReg', (46, 55))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
30609	29490280	However, GNA11Q209L Bap1KO tumors were resistant to trametinib treatment (Figure 4D).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('Bap1KO', 'Gene', (20, 26))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('GNA11Q209L', 'Var', (9, 19))	('trametinib', 'Chemical', 'MESH:C560077', (52, 62))
30610	29490280	To determine if relative resistance to trametinib treatment was more generalized, we treated human BRAFV600E CM and Galphaq/11 mutant UM cell lines with a clinically achievable concentration of trametinib (10 nM).	('human', 'Species', '9606', (93, 98))	('BRAFV600E CM', 'Var', (99, 111))	('Galphaq/11', 'Gene', (116, 126))	('trametinib', 'Chemical', 'MESH:C560077', (194, 204))	('trametinib', 'Chemical', 'MESH:C560077', (39, 49))
30613	29490280	This is consistent with known hypersensitivity of BRAFV600E melanoma to MEK inhibition.	('hypersensitivity of', 'Disease', (30, 49))	('MEK', 'Gene', '17242', (72, 75))	('hypersensitivity', 'biological_process', 'GO:0002524', ('30', '46'))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('BRAFV600E', 'Var', (50, 59))	('BRAFV600E', 'Mutation', 'rs113488022', (50, 59))	('MEK', 'Gene', (72, 75))	('hypersensitivity of', 'Disease', 'MESH:D004342', (30, 49))
30614	29490280	Together, activating mutations in the Galpha11/q pathway exhibit in vivo and in vitro resistance to MEK inhibition.	('MEK', 'Gene', (100, 103))	('activating', 'PosReg', (10, 20))	('Galpha11/q', 'Gene', (38, 48))	('MEK', 'Gene', '17242', (100, 103))	('mutations', 'Var', (21, 30))
30617	29490280	We generated GEMM Galpha11 and BRaf signatures with differentially expressed genes between GNA11Q209L Bap1KO and BRafV600E Bap1KO melanomas (>3-fold, false discovery rate [FDR] < 0.01).	('GNA11Q209L', 'Var', (91, 101))	('BRaf', 'Gene', '109880', (113, 117))	('melanomas', 'Disease', (130, 139))	('BRaf', 'Gene', (113, 117))	('false', 'biological_process', 'GO:0071878', ('150', '155'))	('differentially', 'Reg', (52, 66))	('melanomas', 'Phenotype', 'HP:0002861', (130, 139))	('BRafV600E', 'Mutation', 'rs113488022', (113, 122))	('BRaf', 'Gene', (31, 35))	('melanomas', 'Disease', 'MESH:D008545', (130, 139))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('false', 'biological_process', 'GO:0071877', ('150', '155'))	('BRaf', 'Gene', '109880', (31, 35))
30618	29490280	In human melanoma, we combined and curated TCGA skin CM (SKCM) and UM datasets, and we compared tumors with hotspot mutations in Galpha11/q (74/80 UM and 5/333 SKCM) with BRAFV600E (0/80 UM and 121/333 SKCM).	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('melanoma', 'Disease', (9, 17))	('human', 'Species', '9606', (3, 8))	('tumors', 'Disease', (96, 102))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('Galpha11/q', 'Gene', (129, 139))	('mutations', 'Var', (116, 125))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('BRAFV600E', 'Mutation', 'rs113488022', (171, 180))
30619	29490280	GSEA using the GEMM signatures on the TCGA transcriptomes showed significant enrichment of the Galpha11 and Braf signatures in human Galpha11/q-mutated and BRAFV600E tumors, respectively (Figure 5A).	('Galpha11/q-mutated', 'Var', (133, 151))	('Braf', 'Gene', '673', (108, 112))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('human', 'Species', '9606', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('Galpha11', 'Gene', (95, 103))	('BRAFV600E', 'Var', (156, 165))	('BRAFV600E', 'Mutation', 'rs113488022', (156, 165))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('GSEA', 'Chemical', '-', (0, 4))	('Braf', 'Gene', (108, 112))
30621	29490280	Functional annotation of the leading edge Galpha11/q signature genes showed upregulation of pigmentation and melanocyte differentiation pathways (Figures 5B-5D), consistent with the observation of highly pigmented melanomas in the GNA11Q209L GEMM (Figures 1, 2, and 4).	('pigmentation', 'biological_process', 'GO:0043473', ('92', '104'))	('Galpha11/q signature', 'Gene', (42, 62))	('upregulation', 'PosReg', (76, 88))	('pigmented melanomas', 'Disease', (204, 223))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('melanomas', 'Phenotype', 'HP:0002861', (214, 223))	('pigmentation', 'CPA', (92, 104))	('pigmented melanomas', 'Disease', 'MESH:D008545', (204, 223))	('melanocyte differentiation', 'biological_process', 'GO:0030318', ('109', '135'))	('GNA11Q209L', 'Var', (231, 241))	('melanocyte differentiation pathways', 'Pathway', (109, 144))
30625	29490280	Notably, all TCGA UMs expressed high RASGRP3, and the five TCGA SKCMs with the highest RASGRP3 expression harbored either GNAQ or GNA11 mutations and either BAP1 loss (mutation or monosomy 3) or SF3B1 mutations, suggesting they may be malignant blue nevi (Figure 5E, circled).	('mutations', 'Var', (201, 210))	('malignant blue nevi', 'Disease', (235, 254))	('loss', 'NegReg', (162, 166))	('BAP1', 'Gene', (157, 161))	('GNA11', 'Gene', (130, 135))	('GNAQ', 'Gene', (122, 126))	('SF3B1', 'Gene', (195, 200))	('GNA11', 'Gene', '14672', (130, 135))	('GNAQ', 'Gene', '14682', (122, 126))	('SF3B1', 'Gene', '81898', (195, 200))	('blue nevi', 'Phenotype', 'HP:0100814', (245, 254))	('mutations', 'Var', (136, 145))	('nevi', 'Phenotype', 'HP:0003764', (250, 254))	('expression', 'Species', '29278', (95, 105))
30630	29490280	Depletion of RasGRP3 significantly reduced cell proliferation in GNA11 or GNAQ mutant cells (Figures 6A and S7A).	('GNAQ', 'Gene', (74, 78))	('GNAQ', 'Gene', '14682', (74, 78))	('reduced', 'NegReg', (35, 42))	('RasGRP3', 'Gene', (13, 20))	('cell proliferation', 'biological_process', 'GO:0008283', ('43', '61'))	('mutant', 'Var', (79, 85))	('GNA11', 'Gene', '14672', (65, 70))	('GNA11', 'Gene', (65, 70))	('Depletion', 'MPA', (0, 9))	('cell proliferation', 'CPA', (43, 61))
30637	29490280	In contrast, the percentage of KRASG12V-expressing GFP-positive cells increased after RasGRP3 depletion compared to shSCR in all three UM lines (Figure 6D), indicating KRASG12V conveys a growth advantage specifically after RasGRP3 depletion.	('KRAS', 'Gene', (31, 35))	('KRAS', 'Gene', '16653', (31, 35))	('growth advantage', 'CPA', (187, 203))	('increased', 'PosReg', (70, 79))	('depletion', 'Var', (94, 103))	('KRAS', 'Gene', (168, 172))	('KRAS', 'Gene', '16653', (168, 172))
30641	29490280	Human UM cells harboring Galpha11/q mutations selectively require RasGRP3 for growth and MAPK activation, suggesting Galpha11/q-mediated oncogenesis might require RasGRP3.	('Human', 'Species', '9606', (0, 5))	('MAPK activation', 'biological_process', 'GO:0000187', ('89', '104'))	('oncogenesis', 'biological_process', 'GO:0007048', ('137', '148'))	('mutations', 'Var', (36, 45))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('Galpha11/q', 'Gene', (25, 35))
30644	29490280	We transduced melan-a cells with GNAQQ209L, BRAFV600E, and KRASG12V, and we cultured the cells in the absence of TPA to establish oncogene-dependent growth.	('TPA', 'molecular_function', 'GO:0031299', ('113', '116'))	('TPA', 'Chemical', 'MESH:D013755', (113, 116))	('BRAFV600E', 'Var', (44, 53))	('KRAS', 'Gene', '16653', (59, 63))	('KRAS', 'Gene', (59, 63))	('GNAQQ209L', 'Var', (33, 42))	('BRAFV600E', 'Mutation', 'rs113488022', (44, 53))
30647	29490280	BRAFV600E- and KRASG12V-dependent cells lost pigmentation and expression of melanocyte lineage proteins, while GNAQQ209L-dependent cells retained pigmentation and melanocyte lineage proteins (Figure S7C).	('pigmentation', 'biological_process', 'GO:0043473', ('45', '57'))	('expression', 'Species', '29278', (62, 72))	('BRAFV600E-', 'Var', (0, 10))	('pigmentation', 'MPA', (45, 57))	('KRAS', 'Gene', (15, 19))	('melanocyte lineage', 'Gene', (76, 94))	('expression', 'MPA', (62, 72))	('KRAS', 'Gene', '16653', (15, 19))	('pigmentation', 'MPA', (146, 158))	('pigmentation', 'biological_process', 'GO:0043473', ('146', '158'))	('lost', 'NegReg', (40, 44))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))
30648	29490280	Re-introduction of TPA to the media of BRAFV600E- and KRASG12V-dependent cells failed to re-establish Rasgrp3 expression (Figure S7D).	('TPA', 'molecular_function', 'GO:0031299', ('19', '22'))	('Rasgrp3', 'Gene', '240168', (102, 109))	('KRAS', 'Gene', '16653', (54, 58))	('expression', 'Species', '29278', (110, 120))	('KRAS', 'Gene', (54, 58))	('BRAFV600E', 'Mutation', 'rs113488022', (39, 48))	('Rasgrp3', 'Gene', (102, 109))	('BRAFV600E-', 'Var', (39, 49))	('TPA', 'Chemical', 'MESH:D013755', (19, 22))
30649	29490280	The difference in melanocyte lineage commitment between Galpha11/q and RAS/RAF-driven transformed melanocytes is consistent with observations in our GEMMs and patient tumors.	('melanocyte lineage commitment', 'CPA', (18, 47))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('patient', 'Species', '9606', (159, 166))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('Galpha11/q', 'Var', (56, 66))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
30651	29490280	Knockdown of Rasgrp3 significantly reduced cell growth in GNAQQ209L-dependent, but not in BRAFV600E- or KRASG12V-dependent, melan-a cells (Figures 7A and S7E).	('reduced', 'NegReg', (35, 42))	('GNAQQ209L-dependent', 'Var', (58, 77))	('Rasgrp3', 'Gene', '240168', (13, 20))	('BRAFV600E', 'Mutation', 'rs113488022', (90, 99))	('cell growth', 'CPA', (43, 54))	('Rasgrp3', 'Gene', (13, 20))	('cell growth', 'biological_process', 'GO:0016049', ('43', '54'))	('KRAS', 'Gene', (104, 108))	('KRAS', 'Gene', '16653', (104, 108))
30653	29490280	UMs, LMNs, and blue nevi harbor activating mutations along the CYSLTR2-Galpha11/q-PLCbeta pathway, and they can have mutually exclusive cooperating mutations in BAP1, SF3B1, and EIF1AX that convey poor, intermediate, and favorable risk, respectively.	('nevi', 'Phenotype', 'HP:0003764', (20, 24))	('mutations', 'Var', (148, 157))	('BAP1', 'Gene', (161, 165))	('SF3B1', 'Gene', (167, 172))	('PLCbeta', 'Gene', (82, 89))	('EIF1AX', 'Gene', '66235', (178, 184))	('CYSLTR2', 'Gene', '70086', (63, 70))	('CYSLTR2', 'Gene', (63, 70))	('blue nevi', 'Phenotype', 'HP:0100814', (15, 24))	('mutations', 'Var', (43, 52))	('EIF1AX', 'Gene', (178, 184))	('SF3B1', 'Gene', '81898', (167, 172))	('activating', 'PosReg', (32, 42))	('PLCbeta', 'Gene', '18795', (82, 89))
30664	29490280	We found GNA11Q209L drove neoplastic growth in cutaneous and many non-cutaneous sites whereas BRafV600E only promotes CM.	('GNA11Q209L', 'Var', (9, 19))	('BRafV600E', 'Mutation', 'rs113488022', (94, 103))	('neoplastic growth', 'CPA', (26, 43))
30666	29490280	GNA11Q209L-driven tumors were highly pigmented compared to BRafV600E, consistent with clinical observation that Galpha11/q-driven primary blue nevi, UM, and UM metastases retain pigmentation.	('primary blue nevi', 'Disease', (130, 147))	('pigmentation', 'biological_process', 'GO:0043473', ('178', '190'))	('blue nevi', 'Phenotype', 'HP:0100814', (138, 147))	('metastases retain pigmentation', 'Disease', (160, 190))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('nevi', 'Phenotype', 'HP:0003764', (143, 147))	('BRafV600E', 'Mutation', 'rs113488022', (59, 68))	('GNA11Q209L-driven', 'Var', (0, 17))	('metastases retain pigmentation', 'Disease', 'MESH:D009362', (160, 190))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
30668	29490280	Bap1 loss in our GEMM accelerated skin melanoma growth, consistent with the clinical observation that BAP1 loss is found in transformed, but not benign, blue nevi.	('accelerated', 'PosReg', (22, 33))	('skin melanoma growth', 'Disease', (34, 54))	('skin melanoma growth', 'Disease', 'MESH:D008545', (34, 54))	('Bap1', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('blue nevi', 'Phenotype', 'HP:0100814', (153, 162))	('loss', 'Var', (5, 9))	('nevi', 'Phenotype', 'HP:0003764', (158, 162))
30671	29490280	We additionally showed engineered cells driven by mutant Galpha11/q specifically require RasGRP3 for Ras activation and growth.	('RasGRP3', 'Protein', (89, 96))	('Galpha11/q', 'Gene', (57, 67))	('mutant', 'Var', (50, 56))	('Ras', 'Chemical', 'MESH:D011883', (101, 104))	('Ras', 'Chemical', 'MESH:D011883', (89, 92))	('require', 'Reg', (81, 88))
30672	29490280	RASGPR3 expression is tissue specific and, among cancers, constrained to Galpha11/q-driven melanomas, leukemias, and lymphomas, suggesting RasGRP3 is a specific vulnerability in Galpha11/q-driven tumors and potentially a therapeutic target.	('lymphomas', 'Disease', 'MESH:D008223', (117, 126))	('RasGRP3', 'Var', (139, 146))	('leukemias', 'Phenotype', 'HP:0001909', (102, 111))	('lymphomas', 'Phenotype', 'HP:0002665', (117, 126))	('melanomas', 'Disease', 'MESH:D008545', (91, 100))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))	('melanomas', 'Disease', (91, 100))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('leukemias', 'Disease', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('lymphomas', 'Disease', (117, 126))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('tumors', 'Disease', (196, 202))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('expression', 'Species', '29278', (8, 18))	('leukemias', 'Disease', 'MESH:D007938', (102, 111))
30674	29490280	For GEMM studies, three cohorts of mice, Tyr-CreERT2;GNA11Q209L, Tyr-CreERT2;GNA11Q209L;Bap1lox/lox, and Tyr-CreERT2;BRafCA/+;Bap1lox/lox, were administered with intraperitoneal tamoxifen at 4 weeks of age with no regard to the sex of the animals, and histology was similar between males and females.	('lox', 'Gene', (92, 95))	('GNA11Q209L', 'Var', (77, 87))	('lox', 'Gene', (130, 133))	('lox', 'Gene', (134, 137))	('lox', 'Gene', (96, 99))	('lox', 'Gene', '16948', (92, 95))	('tamoxifen', 'Chemical', 'MESH:D013629', (178, 187))	('Tyr-CreERT2', 'Var', (65, 76))	('lox', 'Gene', '16948', (130, 133))	('lox', 'Gene', '16948', (134, 137))	('lox', 'Gene', '16948', (96, 99))	('mice', 'Species', '10090', (35, 39))	('BRaf', 'Gene', '109880', (117, 121))	('BRaf', 'Gene', (117, 121))	('GNA11Q209L', 'Var', (53, 63))
30680	29490280	Melan-a cells were provided by D. Bennett; MEL202, MEL270, OMM1.3, COLO800, UPMM3, A375, and A2058 cells were submitted for short tandem repeat (STR) profiling and MSK-IMPACT (integration mutation profiling of actionable cancer targets) for mutational status at MSKCC to confirm their authenticity.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', (221, 227))	('A375', 'CellLine', 'CVCL:0132', (83, 87))	('MSKCC', 'Gene', (262, 267))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('A2058', 'CellLine', 'CVCL:1059', (93, 98))	('mutational', 'Var', (241, 251))
30681	29490280	GNA11 Q209L mouse model induces uveal, cutaneous, and leptomeningeal melanoma Loss of Bap1 promotes aggressive melanomas RasGRP3 links GNA11/GNAQ activation to RAS activation RasGRP3 is required for GNA11/GNAQ-driven tumorigenesis	('GNA11', 'Gene', '14672', (199, 204))	('leptomeningeal melanoma', 'Disease', (54, 77))	('GNA11', 'Gene', '14672', (0, 5))	('GNAQ', 'Gene', (141, 145))	('GNAQ', 'Gene', '14682', (205, 209))	('tumor', 'Disease', (217, 222))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('GNA11', 'Gene', '14672', (135, 140))	('Q209L', 'Var', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('GNAQ', 'Gene', '14682', (141, 145))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanomas', 'Disease', 'MESH:D008545', (111, 120))	('melanomas', 'Disease', (111, 120))	('mouse', 'Species', '10090', (12, 17))	('leptomeningeal melanoma', 'Disease', 'MESH:D008545', (54, 77))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('Q209L', 'Mutation', 'rs1057519742', (6, 11))	('GNA11', 'Gene', (0, 5))	('Loss', 'Var', (78, 82))	('GNA11', 'Gene', (199, 204))	('Bap1', 'Gene', (86, 90))	('GNA11', 'Gene', (135, 140))	('GNAQ', 'Gene', (205, 209))
30691	29204166	Enucleation was associated with inferior DSS and OS compared to GPT in multivariate analysis (MVA) (p < 0.01).	('Enucleation', 'biological_process', 'GO:0090601', ('0', '11'))	('OS', 'Chemical', '-', (49, 51))	('GPT', 'molecular_function', 'GO:0004021', ('64', '67'))	('DSS', 'Gene', (41, 44))	('DSS', 'Gene', '5376', (41, 44))	('Enucleation', 'Var', (0, 11))	('GPT', 'Chemical', '-', (64, 67))
30692	29204166	Limited surgical resection or ablation and radiation had similar DSS and OS.	('DSS', 'Gene', '5376', (65, 68))	('OS', 'Chemical', '-', (73, 75))	('DSS', 'Gene', (65, 68))	('ablation', 'Var', (30, 38))
30713	29204166	Allowed International Classification of Diseases for Oncology (ICD-O-3) histology codes were 8720, 8730, and 8770-8774 corresponding to melanoma histology.	('8730', 'Var', (99, 103))	('Oncology', 'Phenotype', 'HP:0002664', (53, 61))	('8770-8774', 'Var', (109, 118))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))
30766	29204166	Local surgical resection or ablation was associated with superior DSS and OS on univariate analysis compared to RT (univariate RT vs. LSRA DSS HR 3.71, 95% CI: 1.18-11.59, p = 0.02).	('DSS', 'Gene', (139, 142))	('DSS', 'Gene', '5376', (139, 142))	('ablation', 'Var', (28, 36))	('DSS', 'Gene', (66, 69))	('OS', 'Chemical', '-', (74, 76))	('DSS', 'Gene', '5376', (66, 69))
30768	29204166	In subgroup analysis, LSRA may be associated with improved DSS compared to RT in patients with ciliary body tumors as seen in Table 5.	('ciliary body tumors', 'Disease', (95, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('patients', 'Species', '9606', (81, 89))	('LSRA', 'Var', (22, 26))	('improved', 'PosReg', (50, 58))	('DSS', 'Gene', (59, 62))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('ciliary body tumors', 'Disease', 'MESH:D013035', (95, 114))	('DSS', 'Gene', '5376', (59, 62))
30780	29204166	The Collaborative Ocular Melanoma Study concluded that there was no difference in the 5-year and 12-year melanoma-related mortality with medium sized choroidal melanomas treated with 125I brachytherapy or enucleation.	('Ocular Melanoma', 'Disease', 'MESH:D008545', (18, 33))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (160, 168))	('melanoma', 'Disease', (105, 113))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (150, 169))	('melanomas', 'Phenotype', 'HP:0002861', (160, 169))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('enucleation', 'biological_process', 'GO:0090601', ('205', '216'))	('Ocular Melanoma', 'Phenotype', 'HP:0007716', (18, 33))	('Ocular Melanoma', 'Disease', (18, 33))	('choroidal melanomas', 'Disease', (150, 169))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (150, 168))	('choroidal melanomas', 'Disease', 'MESH:D008545', (150, 169))	('125I', 'Chemical', 'MESH:C000614960', (183, 187))	('medium sized', 'Var', (137, 149))	('Melanoma', 'Phenotype', 'HP:0002861', (25, 33))
30808	29204166	When compared with charged particle radiotherapy complications, plaque radiotherapy results in more severe radiation retinopathy and optic neuropathy, because plaque irradiation is deposited over the area of the posterior tumor.	('radiation retinopathy', 'Disease', 'MESH:D004194', (107, 128))	('retinopathy', 'Phenotype', 'HP:0000488', (117, 128))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('optic neuropathy', 'Disease', 'MESH:D009901', (133, 149))	('radiation retinopathy', 'Disease', (107, 128))	('optic neuropathy', 'Phenotype', 'HP:0001138', (133, 149))	('plaque radiotherapy', 'Var', (64, 83))	('optic neuropathy', 'Disease', (133, 149))	('tumor', 'Disease', (222, 227))	('neuropathy', 'Phenotype', 'HP:0009830', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))
30826	29204166	The SEER data identified an association of RT+SLT with improved survival from uveal melanoma compared to radiation alone on the univariate analysis with a remarkable absolute difference of 87% vs. 95% at 5-years.	('improved', 'PosReg', (55, 63))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('uveal melanoma', 'Phenotype', 'HP:0007716', (78, 92))	('uveal melanoma', 'Disease', 'MESH:C536494', (78, 92))	('uveal melanoma', 'Disease', (78, 92))	('RT+SLT', 'Var', (43, 49))
30913	25485307	Theoretically, expression of these molecules would evoke the anti-tumor immunity through activation of NK cells and co-stimulation of CD8 T cells, NKT, and subsets of gamma-delta T cells.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('NK cells', 'CPA', (103, 111))	('expression', 'Var', (15, 25))	('CD8 T cells', 'CPA', (134, 145))	('tumor', 'Disease', (66, 71))	('evoke', 'PosReg', (51, 56))	('activation', 'PosReg', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('NKT', 'CPA', (147, 150))
30925	25485307	The loss of membrane-bound NKG2D ligand and concurrent increase in sNKG2D-L pose profound negative imprints in anti-tumor immune responses through mechanism of: 1) reduction of susceptibility of tumor cells to the cytotoxicity of NKG2D-positive lymphocytes due to reduced density of cell surface NKG2D-L; 2) down regulation of NKG2D expression on NK, NKT, gammadelta and CD8 T cells by sNKG2D-L; and 3) impairs NK cell homeostatic maintenance.	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('reduction', 'NegReg', (164, 173))	('loss', 'NegReg', (4, 8))	('reduced', 'NegReg', (264, 271))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('membrane', 'cellular_component', 'GO:0016020', ('12', '20'))	('expression', 'MPA', (333, 343))	('cytotoxicity', 'Disease', (214, 226))	('cell surface', 'cellular_component', 'GO:0009986', ('283', '295'))	('ligand', 'molecular_function', 'GO:0005488', ('33', '39'))	('sNKG2D-L', 'Var', (386, 394))	('cytotoxicity', 'Disease', 'MESH:D064420', (214, 226))	('regulation', 'biological_process', 'GO:0065007', ('313', '323'))	('NKG2D', 'Gene', (327, 332))	('down regulation', 'NegReg', (308, 323))	('sNKG2D-L', 'Gene', (67, 75))	('tumor', 'Disease', (116, 121))	('impairs', 'NegReg', (403, 410))
30927	25485307	As an evitable consequence of tumor shedding NKG2D-L, serum levels of soluble NKG2D ligand hence elevated.	('elevated', 'PosReg', (97, 105))	('ligand', 'molecular_function', 'GO:0005488', ('84', '90'))	('soluble', 'cellular_component', 'GO:0005625', ('70', '77'))	('NKG2D-L', 'Var', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('serum levels of soluble', 'MPA', (54, 77))	('tumor', 'Disease', (30, 35))
30929	25485307	Indeed, large patient cohort studies from various types of cancers, including lung, colorectal, breast, ovarian, prostate, and other gastrointestinal cancers, by Salih's group have shown a significant correlation of high serum sMICA or sMICB with metastatic diseases.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('colorectal, breast, ovarian, prostate', 'Disease', 'MESH:D061325', (84, 121))	('sMIC', 'Chemical', '-', (236, 240))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('MICB', 'Gene', '4277', (237, 241))	('cancers', 'Disease', (150, 157))	('MICA', 'Gene', (228, 232))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('lung', 'Disease', (78, 82))	('sMIC', 'Chemical', '-', (227, 231))	('MICB', 'Gene', (237, 241))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (133, 157))	('high serum', 'Var', (216, 226))	('patient', 'Species', '9606', (14, 21))	('metastatic diseases', 'Disease', (247, 266))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('gastrointestinal cancers', 'Disease', (133, 157))	('MICA', 'Gene', '100507436', (228, 232))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))
30936	25485307	With these lines of mouse models, Liu et al demonstrated that retaining of membrane-bound NKG2D ligand on tumor cells evoked anti-tumor immune response and prevented tumor development, whereas shedding of NKG2D ligand by tumor cells resulted in elevation of serum sMIC and expedited disease progression to metastasis.	('men', 'Species', '9606', (179, 182))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (130, 135))	('shedding', 'Var', (193, 201))	('tumor', 'Disease', (106, 111))	('expedited', 'PosReg', (273, 282))	('evoked', 'PosReg', (118, 124))	('serum sMIC', 'MPA', (258, 268))	('ligand', 'molecular_function', 'GO:0005488', ('96', '102'))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('immune response', 'biological_process', 'GO:0006955', ('136', '151'))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('prevented', 'NegReg', (156, 165))	('membrane', 'cellular_component', 'GO:0016020', ('75', '83'))	('ligand', 'molecular_function', 'GO:0005488', ('211', '217'))	('mouse', 'Species', '10090', (20, 25))	('tumor', 'Disease', (221, 226))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('sMIC', 'Chemical', '-', (264, 268))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('elevation', 'PosReg', (245, 254))	('disease progression to metastasis', 'CPA', (283, 316))	('NKG2D', 'Gene', (90, 95))
30974	20370332	In addition, epigenetic gene regulation by factors within the ocular tumor environment favors the generation of tumor variants that are resistant to CD8+ CTL.	('ocular tumor', 'Disease', 'MESH:D009369', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('regulation', 'biological_process', 'GO:0065007', ('29', '39'))	('ocular tumor', 'Disease', (62, 74))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('ocular tumor', 'Phenotype', 'HP:0100012', (62, 74))	('epigenetic gene regulation', 'Var', (13, 39))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('CD8', 'Gene', (149, 152))	('CD8', 'Gene', '925', (149, 152))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
30983	20370332	In this review, we highlight how ocular immune privilege creates an environment, which is permissive for tumor growth and persistence by directly inhibiting immune responses within the eye and by promoting the generation of tumor escape variants, which are no longer recognized by the immune response.	('promoting', 'PosReg', (196, 205))	('immune responses', 'CPA', (157, 173))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('variants', 'Var', (237, 245))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('immune response', 'biological_process', 'GO:0006955', ('285', '300'))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('inhibiting', 'NegReg', (146, 156))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
30999	20370332	The significance of these death-inducing molecules in maintaining immune privilege is well established in corneal transplantation as mice that are deficient in either of these molecules reject corneal allografts at a higher frequency than their wild-type counterparts.	('reject', 'NegReg', (186, 192))	('deficient', 'Var', (147, 156))	('mice', 'Species', '10090', (133, 137))	('corneal allografts', 'CPA', (193, 211))
31000	20370332	Mice harboring progressively growing ocular tumors expressing minor MHC antigen differences with their host display prolonged acceptance of skin grafts sharing the same haplotype as ocular tumors, whereas major and minor MHC antigen-disparate skin grafts are rejected with normal kinetics.	('ocular tumor', 'Phenotype', 'HP:0100012', (182, 194))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('ocular tumors', 'Disease', (37, 50))	('ocular tumors', 'Phenotype', 'HP:0100012', (182, 195))	('ocular tumors', 'Disease', 'MESH:D009369', (37, 50))	('differences', 'Var', (80, 91))	('ocular tumors', 'Disease', (182, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('acceptance', 'CPA', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('ocular tumors', 'Phenotype', 'HP:0100012', (37, 50))	('Mice', 'Species', '10090', (0, 4))	('ocular tumor', 'Phenotype', 'HP:0100012', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('ocular tumors', 'Disease', 'MESH:D009369', (182, 195))
31016	20370332	Tumors in the equilibrium phase are subjected to constant selection pressure provided by the immune system, which promotes random genetic mutations and epigenetic changes.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('promotes', 'PosReg', (114, 122))	('epigenetic changes', 'Var', (152, 170))
31020	20370332	Therefore, the plasticity of tumor cells allows for the generation of tumor variants, some of which may express the phenotype of an immune-privileged tissue.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('express', 'Reg', (104, 111))	('variants', 'Var', (76, 84))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
31025	20370332	Genomic modifications induce either initiation or silencing of gene expression through (i) point mutations, (ii) frameshift mutations, (iii) genomic translocations, (iv) insertions, and (v) deletions.	('point mutations', 'Var', (91, 106))	('genomic translocations', 'CPA', (141, 163))	('initiation', 'Disease', (36, 46))	('gene expression', 'biological_process', 'GO:0010467', ('63', '78'))	('silencing', 'NegReg', (50, 59))	('modifications', 'Var', (8, 21))	('initiation', 'Disease', 'MESH:D007319', (36, 46))	('frameshift mutations', 'Var', (113, 133))	('deletions', 'Var', (190, 199))	('insertions', 'Var', (170, 180))
31026	20370332	Examples of genes that undergo genetic mutation include the BRCA-1 gene in breast cancer, the epidermal growth factor receptor gene in non-small cell lung cancer and recently, GNAQ, a stimulatory alphaq subunit of heterodimeric G-protein in UM.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (139, 161))	('epidermal growth factor receptor', 'Gene', (94, 126))	('BRCA-1', 'Gene', (60, 66))	('BRCA-1', 'Gene', '12189', (60, 66))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (135, 161))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('non-small cell lung cancer', 'Disease', (135, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('94', '117'))	('epidermal growth factor receptor', 'Gene', '13649', (94, 126))	('GNAQ', 'Gene', (176, 180))	('GNAQ', 'Gene', '14682', (176, 180))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('breast cancer', 'Disease', (75, 88))	('mutation', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (135, 161))	('protein', 'cellular_component', 'GO:0003675', ('230', '237'))
31029	20370332	Hypermethylation and/or acetylation of genomic DNA are catalysts that initiate the modulation of gene expression and are associated with certain malignancies.	('acetylation', 'Var', (24, 35))	('malignancies', 'Disease', (145, 157))	('modulation of gene expression', 'MPA', (83, 112))	('gene expression', 'biological_process', 'GO:0010467', ('97', '112'))	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('Hypermethylation', 'Var', (0, 16))	('associated', 'Reg', (121, 131))	('malignancies', 'Disease', 'MESH:D009369', (145, 157))
31030	20370332	Specifically, CpG islands, regions of DNA composed of clusters of cytosine and guanine nucleotides are hypermethylated in a number of tumors resulting in the downregulation of tumor suppressor genes including the retinoblastoma suppressor gene (rb), p16ink4a, and p53.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('176', '192'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (213, 227))	('rb', 'Gene', (245, 247))	('downregulation', 'NegReg', (158, 172))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cytosine', 'Chemical', 'MESH:D003596', (66, 74))	('retinoblastoma', 'Disease', (213, 227))	('tumors', 'Disease', (134, 140))	('p53', 'Gene', (264, 267))	('tumor suppressor', 'biological_process', 'GO:0051726', ('176', '192'))	('tumor', 'Disease', (176, 181))	('p16ink4a', 'Gene', (250, 258))	('p53', 'Gene', '22060', (264, 267))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('p16ink4a', 'Gene', '12578', (250, 258))	('guanine nucleotides', 'Chemical', 'MESH:D006150', (79, 98))	('retinoblastoma', 'Disease', 'MESH:D012175', (213, 227))	('tumor', 'Disease', (134, 139))	('hypermethylated', 'Var', (103, 118))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (134, 139))
31040	20370332	However, it is interesting to note that the DNMT3b isoforms are overexpressed in a number of tumors suggesting that epigenetic gene regulation by de novo methylation plays a role in tumor progression.	('DNMT3b', 'Gene', (44, 50))	('tumor', 'Disease', (182, 187))	('methylation', 'Var', (154, 165))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', (93, 98))	('DNMT3b', 'Gene', '13436', (44, 50))	('epigenetic', 'Var', (116, 126))	('methylation', 'biological_process', 'GO:0032259', ('154', '165'))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('regulation', 'biological_process', 'GO:0065007', ('132', '142'))	('tumors', 'Disease', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
31041	20370332	Recent studies have investigated whether epigenetic gene regulation plays a role in the tumorigenesis of UM.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('regulation', 'biological_process', 'GO:0065007', ('57', '67'))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('epigenetic gene regulation', 'Var', (41, 67))	('tumor', 'Disease', (88, 93))
31043	20370332	In addition, UM are resistant to IFN-gamma-induced upregulation of MHC class II molecules due to the epigenetic suppression of the MHC class II transactivator Class II Transactivator (CIITA).	('upregulation', 'PosReg', (51, 63))	('class II transactivator', 'Gene', (135, 158))	('Class II Transactivator', 'Gene', (159, 182))	('epigenetic', 'Var', (101, 111))	('Class II Transactivator', 'Gene', '12265', (159, 182))	('CIITA', 'Gene', '12265', (184, 189))	('CIITA', 'Gene', (184, 189))	('suppression', 'NegReg', (112, 123))	('class II transactivator', 'Gene', '12265', (135, 158))
31045	20370332	demonstrated that mice immunized against P815 tumor cells were protected against a subsequent P815 tumor challenge in the flank but were not protected against an identical tumor challenge in the immune-privileged a.c. of the eye.	('tumor', 'Disease', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('P815', 'Var', (41, 45))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', (46, 51))	('mice', 'Species', '10090', (18, 22))	('P815', 'Gene', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
31052	20370332	Moreover, purified histone preparations from eye-derived P815 cells demonstrate increases in dimethylated and trimethylated H3 histones on lysine 27 (K27) residues, an epigenetic mark compared to wild-type P815 cells, suggesting that factors in the immune-privileged ocular environment induced epigenetic gene regulation locally by gene-specific methylation as well as globally by affecting chromatin structure conformation.	('lysine', 'Chemical', 'MESH:D008239', (139, 145))	('methylation', 'Var', (346, 357))	('methylation', 'biological_process', 'GO:0032259', ('346', '357'))	('affecting', 'Reg', (381, 390))	('increases', 'PosReg', (80, 89))	('H3 histones', 'Protein', (124, 135))	('chromatin structure conformation', 'MPA', (391, 423))	('regulation', 'biological_process', 'GO:0065007', ('310', '320'))	('induced', 'Reg', (286, 293))	('epigenetic gene regulation', 'MPA', (294, 320))	('chromatin', 'cellular_component', 'GO:0000785', ('391', '400'))
31094	20370332	However, this evolutionary compromise comes at the price of impaired intraocular tumoricidal immune responses because factors within the ocular microenvironment inhibit critical effector functions of infiltrating immune cells and promote the generation of tumor escape variants that escape detection by the host immune response.	('impaired intraocular tumoricidal', 'Disease', 'MESH:D009422', (60, 92))	('impaired intraocular tumoricidal', 'Disease', (60, 92))	('promote', 'PosReg', (230, 237))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('immune response', 'biological_process', 'GO:0006955', ('312', '327'))	('variants', 'Var', (269, 277))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('inhibit', 'NegReg', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ocular tumor', 'Phenotype', 'HP:0100012', (74, 86))	('tumor', 'Disease', (256, 261))	('tumor', 'Disease', (81, 86))
31097	20370332	Intratumoral macrophages may also be essential for eliminating tumor variants that are no longer recognized by CTL because their tumoricidal activity is nonspecific.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('variants', 'Var', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', (129, 134))
31111	32850409	Approximately 80% of the mutations in sunlight-induced melanoma are UV signature and cytosine to thymine transitions generated from cytosine-containing cyclobutane pyrimidine dimers (CPDs).	('cytosine', 'Chemical', 'MESH:D003596', (132, 140))	('mutations', 'Var', (25, 34))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('cytosine to thymine', 'MPA', (85, 104))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('cyclobutane pyrimidine', 'Chemical', '-', (152, 174))	('cytosine', 'Chemical', 'MESH:D003596', (85, 93))	('CPDs', 'Disease', (183, 187))	('thymine', 'Chemical', 'MESH:D013941', (97, 104))	('CPDs', 'Disease', 'MESH:C565866', (183, 187))	('melanoma', 'Disease', (55, 63))	('rat', 'Species', '10116', (121, 124))
31114	32850409	Exogenous factors like UV and chemical pollutants and endogenous factors like spontaneous mutations further elevate the oxidative stress, which then strongly drives melanocytic transformation into melanoma.	('melanocytic', 'Disease', (165, 176))	('mutations', 'Var', (90, 99))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('oxidative stress', 'Phenotype', 'HP:0025464', (120, 136))	('melanoma', 'Disease', (197, 205))	('elevate', 'PosReg', (108, 115))	('oxidative stress', 'MPA', (120, 136))	('drives', 'Reg', (158, 164))
31123	32850409	Sunlight-induced melanoma exhibits UV signature mutations which arise from CPDs, adducts that are created spontaneously in response to UV exposure.	('CPDs', 'Disease', (75, 79))	('response to UV', 'biological_process', 'GO:0009411', ('123', '137'))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('CPDs', 'Disease', 'MESH:C565866', (75, 79))	('melanoma', 'Disease', (17, 25))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('mutations', 'Var', (48, 57))
31138	32850409	Similarly, spontaneous melanoma initiation was observed in MC1R-truncated, BRAFV600E-mutated mouse models.	('MC1R-truncated', 'Gene', (59, 73))	('mouse', 'Species', '10090', (93, 98))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma initiation', 'Disease', 'MESH:D008545', (23, 42))	('melanoma initiation', 'Disease', (23, 42))	('BRAFV600E-mutated', 'Var', (75, 92))	('BRAFV600E', 'Mutation', 'rs113488022', (75, 84))
31139	32850409	The MC1R truncation leads to higher pheomelanin/eumelanin ratio and golden coat color.	('higher', 'PosReg', (29, 35))	('truncation', 'Var', (9, 19))	('MC1R', 'Gene', (4, 8))	('eumelanin', 'Chemical', 'MESH:C041877', (48, 57))	('rat', 'Species', '10116', (58, 61))	('pheomelanin', 'Gene', (36, 47))	('golden coat color', 'CPA', (68, 85))	('pheomelanin', 'Gene', '114618', (36, 47))
31141	32850409	However, we suggest a prominent contribution of protein modifications by RNS and RCS, and DNA mutations from chemiexcitation.	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('RNS', 'Gene', (73, 76))	('RCS', 'Gene', (81, 84))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('mutations', 'Var', (94, 103))	('DNA', 'Gene', (90, 93))	('protein modifications', 'MPA', (48, 69))	('RNS', 'Chemical', 'MESH:D026361', (73, 76))
31143	32850409	In addition to skin melanoma, melanin chemiexcitation might be responsible for UV signature and somatic mutations in other subtypes like acral and uveal melanoma; however, very few investigations have been done to reveal this.	('uveal melanoma', 'Disease', (147, 161))	('mutations', 'Var', (104, 113))	('melanin', 'Chemical', 'MESH:D008543', (30, 37))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('acral', 'Disease', (137, 142))	('skin melanoma', 'Disease', 'MESH:D008545', (15, 28))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('skin melanoma', 'Disease', (15, 28))	('uveal melanoma', 'Phenotype', 'HP:0007716', (147, 161))	('uveal melanoma', 'Disease', 'MESH:C536494', (147, 161))
31148	32850409	Accordingly, we predict that the somatic and passenger mutations in the uveal melanoma are a result of melanin chemiexcitation.	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('uveal melanoma', 'Disease', (72, 86))	('mutations', 'Var', (55, 64))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanin', 'Chemical', 'MESH:D008543', (103, 110))
31155	32850409	This revealed CPD hyperspots (ultra-sensitive sites) in pigmented melanocytes that had a precise alignment with the recurrent UV-signature mutations in individual gene promoters of melanomas.	('pigmented', 'Disease', (56, 65))	('pigmented', 'Disease', 'MESH:D010859', (56, 65))	('melanomas', 'Disease', (181, 190))	('mutations', 'Var', (139, 148))	('CPD hyperspots', 'Disease', (14, 28))	('CPD hyperspots', 'Disease', 'MESH:C565865', (14, 28))	('melanomas', 'Phenotype', 'HP:0002861', (181, 190))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('melanomas', 'Disease', 'MESH:D008545', (181, 190))
31162	32850409	Such hypersensitivity can alter melanocytic physiology through transcriptional blockade or epigenetic behavior in addition to the mutations.	('transcriptional blockade', 'Var', (63, 87))	('epigenetic behavior', 'Var', (91, 110))	('alter', 'Reg', (26, 31))	('hypersensitivity', 'Disease', 'MESH:D004342', (5, 21))	('hypersensitivity', 'biological_process', 'GO:0002524', ('5', '21'))	('melanocytic physiology', 'MPA', (32, 54))	('hypersensitivity', 'Disease', (5, 21))
31178	32850409	We believe that NOS- and NOX-mediated promotion of pheomelanogenesis is a pre-requisite for melanoma initiation from dysplastic nevi with BRAF/NRAS mutational background.	('nevi', 'Phenotype', 'HP:0003764', (128, 132))	('NRAS', 'Gene', '4893', (143, 147))	('BRAF', 'Gene', '673', (138, 142))	('mutational', 'Var', (148, 158))	('melanoma initiation', 'Disease', 'MESH:D008545', (92, 111))	('NRAS', 'Gene', (143, 147))	('dysplastic nevi', 'Disease', (117, 132))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma initiation', 'Disease', (92, 111))	('BRAF', 'Gene', (138, 142))	('pre', 'molecular_function', 'GO:0003904', ('74', '77'))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (117, 132))	('dysplastic nevi', 'Disease', 'MESH:D004416', (117, 132))
31190	32850409	The misdiagnosis due to lack of color is another clinical factor responsible for poor prognosis in addition to the enhanced DNA damage and passenger mutations from melanin chemiexcitation.	('DNA damage', 'MPA', (124, 134))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('melanin', 'Chemical', 'MESH:D008543', (164, 171))	('enhanced', 'PosReg', (115, 123))	('passenger mutations', 'Var', (139, 158))
31197	32850409	RCS cause tissue disintegration and promote proliferative cell-signaling in several human malignancies including melanoma.	('malignancies', 'Disease', (90, 102))	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('tissue disintegration', 'CPA', (10, 31))	('promote', 'PosReg', (36, 43))	('cause', 'Reg', (4, 9))	('RCS', 'Var', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('human', 'Species', '9606', (84, 89))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('rat', 'Species', '10116', (25, 28))	('proliferative cell-signaling', 'MPA', (44, 72))	('rat', 'Species', '10116', (51, 54))
31223	32850409	Adducts of formaldehyde carbonyls and proteins are known to bias the immune system toward a hypersensitive Th2 response.	('proteins', 'Protein', (38, 46))	('Th2', 'Chemical', '-', (107, 110))	('formaldehyde', 'Chemical', 'MESH:D005557', (11, 23))	('bias', 'Reg', (60, 64))	('hypersensitive', 'Disease', (92, 106))	('hypersensitive', 'Disease', 'MESH:D004342', (92, 106))	('Adducts', 'Var', (0, 7))
31230	32850409	Just like the chalcones and zerumbone, peroxynitrite is known to induce apoptosis in human thymocytes.	('peroxynitrite', 'Var', (39, 52))	('chalcones', 'Chemical', 'MESH:D047188', (14, 23))	('peroxynitrite', 'Chemical', 'MESH:D030421', (39, 52))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('human', 'Species', '9606', (85, 90))	('apoptosis', 'CPA', (72, 81))	('zerumbone', 'Chemical', 'MESH:C403304', (28, 37))
31231	32850409	Nitration/nitrosylation reduces the immunogenicity of peptides, antigen presentation by MHC, or TCR functions.	('TCR', 'cellular_component', 'GO:0042101', ('96', '99'))	('TCR functions', 'CPA', (96, 109))	('reduces', 'NegReg', (24, 31))	('immunogenicity of peptides', 'MPA', (36, 62))	('nitrosyl', 'Chemical', 'MESH:D009569', (10, 18))	('TCR', 'biological_process', 'GO:0006283', ('96', '99'))	('antigen presentation', 'biological_process', 'GO:0019882', ('64', '84'))	('rat', 'Species', '10116', (3, 6))	('Nitration/nitrosylation', 'Var', (0, 23))	('antigen presentation', 'MPA', (64, 84))
31233	32850409	Nitration is known to block cytotoxic T cells from infiltrating non-melanoma tumors through sparsely known mechanisms.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('melanoma tumors', 'Disease', 'MESH:D008545', (68, 83))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('rat', 'Species', '10116', (57, 60))	('block', 'NegReg', (22, 27))	('Nitration', 'Var', (0, 9))	('melanoma tumors', 'Disease', (68, 83))	('rat', 'Species', '10116', (3, 6))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))
31235	32850409	Matched detection of chemotaxis and activation markers such as CCL2, CCL5, CXCL12, CD3, CD4, CD8, CTLA-4, PD-1, and CXCR4 and nitration in melanoma tissue will establish the role of NOS and NOX in inhibiting the T cell infiltration/activation in melanoma.	('inhibiting', 'NegReg', (197, 207))	('nitration', 'Var', (126, 135))	('CCL5', 'Gene', (69, 73))	('CCL', 'molecular_function', 'GO:0044101', ('63', '66'))	('CCL2', 'Gene', '6347', (63, 67))	('T cell infiltration/activation', 'CPA', (212, 242))	('CXCL12', 'Gene', '6387', (75, 81))	('PD-1', 'Gene', '5133', (106, 110))	('chemotaxis', 'biological_process', 'GO:0006935', ('21', '31'))	('PD-1', 'Gene', (106, 110))	('CXCR4', 'Gene', '7852', (116, 121))	('melanoma', 'Phenotype', 'HP:0002861', (246, 254))	('CTLA-4', 'Gene', '1493', (98, 104))	('melanoma', 'Disease', (246, 254))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('CXCL12', 'Gene', (75, 81))	('CXCR4', 'Gene', (116, 121))	('CXCR4', 'molecular_function', 'GO:0038147', ('116', '121'))	('CTLA-4', 'Gene', (98, 104))	('CD8', 'Gene', '925', (93, 96))	('CCL5', 'Gene', '6352', (69, 73))	('CD4', 'Gene', '920', (88, 91))	('CCL2', 'Gene', (63, 67))	('rat', 'Species', '10116', (225, 228))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('rat', 'Species', '10116', (129, 132))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Disease', 'MESH:D008545', (246, 254))	('CCL', 'molecular_function', 'GO:0044101', ('69', '72'))	('CD4', 'Gene', (88, 91))	('CD8', 'Gene', (93, 96))
31239	32850409	The well-known BRAF and NRAS mutations in melanoma lead to the constitutive activation of the p44/p42 MAPK pathway, which upregulates iNOS expression).	('melanoma', 'Disease', (42, 50))	('NRAS', 'Gene', '4893', (24, 28))	('BRAF', 'Gene', '673', (15, 19))	('iNOS', 'Gene', (134, 138))	('p44', 'Gene', '10561', (94, 97))	('BRAF', 'Gene', (15, 19))	('mutations', 'Var', (29, 38))	('MAPK', 'molecular_function', 'GO:0004707', ('102', '106'))	('p42 MAPK', 'Gene', (98, 106))	('p42 MAPK', 'Gene', '5594', (98, 106))	('upregulates', 'PosReg', (122, 133))	('NRAS', 'Gene', (24, 28))	('p44', 'Gene', (94, 97))	('iNOS', 'Gene', '4843', (134, 138))	('activation', 'PosReg', (76, 86))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
31242	32850409	Additionally, NOS inhibition upregulates apoptotic proteins like Bax, Caspase-1, Caspase-3, Caspase-6, and Mdm2.	('Caspase-3', 'Gene', '836', (81, 90))	('Caspase-1', 'Gene', '834', (70, 79))	('NOS', 'Gene', (14, 17))	('Caspase-6', 'Gene', '839', (92, 101))	('Mdm2', 'Gene', '4193', (107, 111))	('upregulates', 'PosReg', (29, 40))	('Bax', 'Gene', '581', (65, 68))	('Caspase-6', 'Gene', (92, 101))	('Bax', 'Gene', (65, 68))	('Caspase-1', 'Gene', (70, 79))	('inhibition', 'Var', (18, 28))	('apoptotic proteins', 'Protein', (41, 59))	('Mdm2', 'Gene', (107, 111))	('Caspase-3', 'Gene', (81, 90))
31244	32850409	Conversely, NOS inhibition downregulates Bcl-2, decreases intratumoral microvessel density, and increases intratumoral apoptosis in vivo.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('Bcl-2', 'Gene', (41, 46))	('Bcl-2', 'Gene', '596', (41, 46))	('increases', 'PosReg', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('NOS', 'Gene', (12, 15))	('decreases', 'NegReg', (48, 57))	('apoptosis', 'biological_process', 'GO:0097194', ('119', '128'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('41', '46'))	('rat', 'Species', '10116', (61, 64))	('tumor', 'Disease', (111, 116))	('rat', 'Species', '10116', (109, 112))	('downregulates', 'NegReg', (27, 40))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('apoptosis', 'biological_process', 'GO:0006915', ('119', '128'))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('inhibition', 'Var', (16, 26))
31247	32850409	Similarly, NOX4 knockdown arrests the cell cycle at G2-M stage, thus abolishing melanoma proliferation and tumor formation.	('cell cycle', 'CPA', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('NOX4', 'Gene', (11, 15))	('knockdown', 'Var', (16, 25))	('formation', 'biological_process', 'GO:0009058', ('113', '122'))	('abolishing', 'NegReg', (69, 79))	('cell cycle', 'biological_process', 'GO:0007049', ('38', '48'))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('rat', 'Species', '10116', (96, 99))	('NOX4', 'Gene', '50507', (11, 15))
31252	32850409	NOS- and NOX-mediated RNS induces posttranslational modifications (PTMs) like nitrosylation and nitration.	('RNS', 'Chemical', 'MESH:D026361', (22, 25))	('nitration', 'MPA', (96, 105))	('rat', 'Species', '10116', (99, 102))	('nitrosylation', 'MPA', (78, 91))	('posttranslational modifications', 'MPA', (34, 65))	('RNS', 'Var', (22, 25))	('nitrosyl', 'Chemical', 'MESH:D009569', (78, 86))
31253	32850409	Accordingly, inhibiting NOS-NOX will reactivate the intrinsic apoptotic pathway proteins like SMACS, Bcl-2 family, caspases, and cytochrome c. Caspases and cytochrome c are of special interest because PTMs like nitration/nitrosylation are known to inhibit their apoptotic function.	('inhibit', 'NegReg', (248, 255))	('Bcl-2', 'Gene', (101, 106))	('cytochrome c', 'Gene', (156, 168))	('nitrosyl', 'Chemical', 'MESH:D009569', (221, 229))	('Bcl-2', 'Gene', '596', (101, 106))	('cytochrome c', 'molecular_function', 'GO:0009461', ('129', '141'))	('cytochrome c', 'Gene', (129, 141))	('rat', 'Species', '10116', (214, 217))	('Caspases', 'Gene', (143, 151))	('intrinsic apoptotic pathway', 'biological_process', 'GO:0097193', ('52', '79'))	('caspases', 'Gene', (115, 123))	('cytochrome c', 'molecular_function', 'GO:0045155', ('156', '168'))	('Caspases', 'Gene', '834;839;842', (143, 151))	('Bcl-2', 'molecular_function', 'GO:0015283', ('101', '106'))	('cytochrome c', 'Gene', '54205', (156, 168))	('cytochrome c', 'molecular_function', 'GO:0009461', ('156', '168'))	('apoptotic function', 'CPA', (262, 280))	('caspases', 'Gene', '834;839;842', (115, 123))	('cytochrome c', 'Gene', '54205', (129, 141))	('nitration/nitrosylation', 'Var', (211, 234))	('cytochrome c', 'molecular_function', 'GO:0045155', ('129', '141'))
31254	32850409	The MAPK pathway, which is constitutively activated by BRAF and NRAS mutations in melanoma, is positively associated with iNOS expression.	('MAPK', 'molecular_function', 'GO:0004707', ('4', '8'))	('mutations', 'Var', (69, 78))	('expression', 'MPA', (127, 137))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('NRAS', 'Gene', (64, 68))	('associated', 'Interaction', (106, 116))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('BRAF', 'Gene', '673', (55, 59))	('NRAS', 'Gene', '4893', (64, 68))	('iNOS', 'Gene', '4843', (122, 126))	('activated', 'PosReg', (42, 51))	('iNOS', 'Gene', (122, 126))	('MAPK pathway', 'Pathway', (4, 16))	('BRAF', 'Gene', (55, 59))
31256	32850409	This suggests a direct interaction and functional correlation between NOS and NOX, BRAF/NRAS mutations, melanoma progression, and drug-resistance.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('drug-resistance', 'biological_process', 'GO:0009315', ('130', '145'))	('mutations', 'Var', (93, 102))	('NRAS', 'Gene', (88, 92))	('interaction', 'Interaction', (23, 34))	('NRAS', 'Gene', '4893', (88, 92))	('BRAF', 'Gene', '673', (83, 87))	('drug-resistance', 'Phenotype', 'HP:0020174', (130, 145))	('BRAF', 'Gene', (83, 87))	('drug-resistance', 'biological_process', 'GO:0042493', ('130', '145'))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
31259	32850409	However, this will promote clonal growth p53 mutated melanoma cells, which is not yet known.	('p53', 'Gene', '7157', (41, 44))	('promote', 'PosReg', (19, 26))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('p53', 'Gene', (41, 44))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('mutated', 'Var', (45, 52))	('clonal growth', 'CPA', (27, 40))
31266	32850409	NF-kappaB nitrosylation inhibits its DNA binding).	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('NF-kappaB', 'Gene', '4790', (0, 9))	('nitrosyl', 'Chemical', 'MESH:D009569', (10, 18))	('inhibits', 'NegReg', (24, 32))	('NF-kappaB', 'Gene', (0, 9))	('nitrosylation', 'Var', (10, 23))	('DNA binding', 'Interaction', (37, 48))	('DNA binding', 'molecular_function', 'GO:0003677', ('37', '48'))
31273	32850409	NO -nitrosated GAPDH aids in degrading lysine methylases, thus making lysine available for acetylation.	('NO -nitrosated', 'Var', (0, 14))	('making', 'Reg', (63, 69))	('degrading', 'NegReg', (29, 38))	('lysine', 'Chemical', 'MESH:D008239', (39, 45))	('GAPDH', 'Gene', '2597', (15, 20))	('GAPDH', 'Gene', (15, 20))	('lysine available for acetylation', 'MPA', (70, 102))	('lysine methylases', 'Enzyme', (39, 56))	('lysine', 'Chemical', 'MESH:D008239', (70, 76))
31274	32850409	On the contrary, NO  is also known to nitrosylate cysteine residues on HDACs that blocks their binding to chromatin.	('nitrosyl', 'Chemical', 'MESH:D009569', (38, 46))	('blocks', 'NegReg', (82, 88))	('cysteine', 'Chemical', 'MESH:D003545', (50, 58))	('chromatin', 'cellular_component', 'GO:0000785', ('106', '115'))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('nitrosylate', 'Var', (38, 49))	('chromatin', 'Protein', (106, 115))	('binding', 'Interaction', (95, 102))
31282	32850409	In melanoma, the MAPK mutations like BRAFV600E are known to further upregulate NOS and NOX activity and expression.	('MAPK', 'Gene', (17, 21))	('MAPK', 'molecular_function', 'GO:0004707', ('17', '21'))	('upregulate', 'PosReg', (68, 78))	('BRAFV600E', 'Var', (37, 46))	('expression', 'MPA', (104, 114))	('BRAFV600E', 'Mutation', 'rs113488022', (37, 46))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
31297	32682400	The most prevalent RNA methylation is N6-methyladenosine (m6A), which exists in about 25% of transcripts at the genome-wide level and was firstly discovered in the 1970s.	('m6A', 'Gene', '56339', (58, 61))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (38, 56))	('N6-methyladenosine', 'Var', (38, 56))	('RNA', 'cellular_component', 'GO:0005562', ('19', '22'))	('RNA methylation', 'biological_process', 'GO:0001510', ('19', '34'))	('m6A', 'Gene', (58, 61))
31301	32682400	m6A modification not only plays a vital role in the pathogenesis of a variety of human disease including obesity, neuronal disorders and immunological disease, but also has been shown to contribute to tumor initiation and promote progression of cancer and recurrence.	('m6A', 'Gene', '56339', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('immunological disease', 'Disease', (137, 158))	('modification', 'Var', (4, 16))	('human', 'Species', '9606', (81, 86))	('m6A', 'Gene', (0, 3))	('contribute', 'Reg', (187, 197))	('neuronal disorders', 'Disease', 'MESH:D009410', (114, 132))	('obesity', 'Disease', (105, 112))	('progression', 'CPA', (230, 241))	('tumor', 'Disease', (201, 206))	('immunological disease', 'Disease', 'MESH:D007154', (137, 158))	('immunological disease', 'Phenotype', 'HP:0002715', (137, 158))	('obesity', 'Disease', 'MESH:D009765', (105, 112))	('pathogenesis', 'biological_process', 'GO:0009405', ('52', '64'))	('promote', 'PosReg', (222, 229))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('cancer', 'Disease', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('neuronal disorders', 'Disease', (114, 132))	('obesity', 'Phenotype', 'HP:0001513', (105, 112))
31321	32682400	Differences in the expression of m6A regulators between mutant and wildtype of top 5 mutated genes were performed by multiple testing and the corrected p-value was calculated with the Benjamini-Hockberg method.	('Differences', 'Reg', (0, 11))	('expression', 'MPA', (19, 29))	('mutant', 'Var', (56, 62))	('m6A', 'Gene', (33, 36))	('m6A', 'Gene', '56339', (33, 36))
31330	32682400	The heatmap of differences in the expression of m6A regulators between mutant and wildtype of top 5 mutated genes indicated that SF3B1 was the most significantly regulated the expression of m6A regulators (Fig.	('SF3B1', 'Gene', (129, 134))	('regulated', 'Reg', (162, 171))	('m6A', 'Gene', (190, 193))	('SF3B1', 'Gene', '23451', (129, 134))	('m6A', 'Gene', '56339', (48, 51))	('expression', 'MPA', (176, 186))	('mutant', 'Var', (71, 77))	('m6A', 'Gene', '56339', (190, 193))	('m6A', 'Gene', (48, 51))
31352	32682400	The associations between risk score of m6A regulators and clinical variables such as chromosome 3 status, mutated SF3B1, mutated BAP1 and subtype were explored.	('SF3B1', 'Gene', '23451', (114, 119))	('chromosome', 'cellular_component', 'GO:0005694', ('85', '95'))	('m6A', 'Gene', '56339', (39, 42))	('mutated', 'Var', (121, 128))	('m6A', 'Gene', (39, 42))	('BAP1', 'Gene', '8314', (129, 133))	('SF3B1', 'Gene', (114, 119))	('BAP1', 'Gene', (129, 133))	('mutated', 'Var', (106, 113))
31353	32682400	5a), wildtype of SF3B1 own higher risk scores than mutant (Fig.	('risk scores', 'MPA', (34, 45))	('SF3B1', 'Gene', (17, 22))	('higher', 'PosReg', (27, 33))	('SF3B1', 'Gene', '23451', (17, 22))	('wildtype', 'Var', (5, 13))
31354	32682400	While, subgroup of mutated BAP1 manifested that there is on significant difference between mutant and wildtype (Fig.	('BAP1', 'Gene', (27, 31))	('mutant', 'Var', (91, 97))	('BAP1', 'Gene', '8314', (27, 31))	('mutated', 'Var', (19, 26))
31370	32682400	SF3B1 (splicing factor 3subunit B1) mutations can be generally found in 10 to 21% of cases of UM.	('UM', 'Phenotype', 'HP:0007716', (94, 96))	('SF3B1', 'Gene', (0, 5))	('splicing', 'biological_process', 'GO:0045292', ('7', '15'))	('mutations', 'Var', (36, 45))	('SF3B1', 'Gene', '23451', (0, 5))	('splicing factor 3subunit B1', 'Gene', '23451', (7, 34))	('found', 'Reg', (63, 68))	('splicing factor 3subunit B1', 'Gene', (7, 34))
31371	32682400	Previous researches have shown that SF3B1 mutations in UM patients are associated with favorable prognosis.	('SF3B1', 'Gene', (36, 41))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('SF3B1', 'Gene', '23451', (36, 41))	('patients', 'Species', '9606', (58, 66))	('mutations', 'Var', (42, 51))
31373	32682400	In our research, the results showed that the mutation of SF3B1 will generally significantly down-regulated the expression of m6A regulators, including "eraser" such as ALKBH5 and FTO; "writer" such as WTAP and KIAA1429; "reader" such as YTHDF1, YTHDF2 and YTHDC2 (Fig.	('FTO', 'Gene', '79068', (179, 182))	('YTHDF2', 'Gene', (245, 251))	('WTAP', 'Gene', '9589', (201, 205))	('KIAA1429', 'Gene', (210, 218))	('FTO', 'Gene', (179, 182))	('KIAA1429', 'Gene', '25962', (210, 218))	('ALKBH5', 'Gene', (168, 174))	('YTHDC2', 'Gene', '64848', (256, 262))	('SF3B1', 'Gene', (57, 62))	('expression', 'MPA', (111, 121))	('m6A', 'Gene', '56339', (125, 128))	('WTAP', 'Gene', (201, 205))	('ALKBH5', 'Gene', '54890', (168, 174))	('down-regulated', 'NegReg', (92, 106))	('YTHDF2', 'Gene', '51441', (245, 251))	('YTHDC2', 'Gene', (256, 262))	('m6A', 'Gene', (125, 128))	('SF3B1', 'Gene', '23451', (57, 62))	('YTHDF1', 'Gene', (237, 243))	('mutation', 'Var', (45, 53))	('YTHDF1', 'Gene', '54915', (237, 243))
31374	32682400	Therefore, it easily envisaged that the mutant of SF3B1 may lead to down-regulate the expression of "eraser" such as ALKBH5 and FTO and finally result in a better survival in UM.	('ALKBH5', 'Gene', (117, 123))	('SF3B1', 'Gene', (50, 55))	('UM', 'Phenotype', 'HP:0007716', (175, 177))	('down-regulate', 'NegReg', (68, 81))	('FTO', 'Gene', '79068', (128, 131))	('SF3B1', 'Gene', '23451', (50, 55))	('expression', 'MPA', (86, 96))	('result in', 'Reg', (144, 153))	('mutant', 'Var', (40, 46))	('FTO', 'Gene', (128, 131))	('ALKBH5', 'Gene', '54890', (117, 123))	('better', 'PosReg', (156, 162))
31376	32682400	Stratified analysis of clinical characteristics between low- and high- risk groups also revealed that lots of risk factors like mortality rate, subtype 4 and monosomy 3 are take higher percentage in high-risk group (Table 2).	('monosomy 3', 'Disease', (158, 168))	('subtype', 'Var', (144, 151))	('mortality', 'Disease', (128, 137))	('mortality', 'Disease', 'MESH:D003643', (128, 137))
31378	32682400	The risk sores of monosomy 3, SF3B1-wildtype, and subtype 4 were respectively higher than disomy 3, SF3B1-mutated and subtype 1 in UM, which was consistent with previous researches.	('SF3B1', 'Gene', (30, 35))	('UM', 'Phenotype', 'HP:0007716', (131, 133))	('higher', 'PosReg', (78, 84))	('SF3B1', 'Gene', '23451', (30, 35))	('SF3B1', 'Gene', (100, 105))	('monosomy 3', 'Var', (18, 28))	('SF3B1', 'Gene', '23451', (100, 105))
31379	32682400	For example, in human breast cancer cells, knockdown ALKBH5 contributed to significantly decrease the number of cancer stem cells and the opportunity of tumorigenesis.	('cancer', 'Disease', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('breast cancer', 'Disease', (22, 35))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('ALKBH5', 'Gene', '54890', (53, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('decrease', 'NegReg', (89, 97))	('knockdown', 'Var', (43, 52))	('ALKBH5', 'Gene', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('human', 'Species', '9606', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
31380	32682400	In addition, the high expression of ALKBH5 in glioblastoma can lead to stem-like cell proliferation and tumorigenesis.	('glioblastoma', 'Phenotype', 'HP:0012174', (46, 58))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('ALKBH5', 'Gene', '54890', (36, 42))	('stem-like cell proliferation', 'CPA', (71, 99))	('high', 'Var', (17, 21))	('tumor', 'Disease', (104, 109))	('ALKBH5', 'Gene', (36, 42))	('cell proliferation', 'biological_process', 'GO:0008283', ('81', '99'))	('lead to', 'Reg', (63, 70))	('glioblastoma', 'Disease', (46, 58))	('glioblastoma', 'Disease', 'MESH:D005909', (46, 58))	('expression', 'MPA', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
31403	29570931	Uveal melanoma driver mutations in GNAQ/11 yield numerous changes in melanocyte biology.	('GNAQ', 'Gene', '570108', (35, 39))	('Uveal melanoma', 'Disease', 'MESH:C536494', (0, 14))	('melanocyte', 'CPA', (69, 79))	('changes', 'Reg', (58, 65))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('mutations', 'Var', (22, 31))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('Uveal melanoma', 'Disease', (0, 14))	('GNAQ', 'Gene', (35, 39))
31405	29570931	Here we present zebrafish models of UM, which are driven by melanocyte-specific expression of activating GNAQ or GNA11 alleles, GNAQ/11Q209L, the predominant initiating mutations for human UM.	('GNA11', 'Gene', (113, 118))	('human', 'Species', '9606', (183, 188))	('activating', 'PosReg', (94, 104))	('zebrafish', 'Species', '7955', (16, 25))	('GNAQ/11Q209L', 'Var', (128, 140))	('GNA11', 'Gene', '563953', (113, 118))
31406	29570931	When combined with mutant tp53, GNAQ/11Q209L transgenics develop various melanocytic tumors, including UM, with near complete penetrance.	('melanocytic tumors', 'Disease', (73, 91))	('tp53', 'Gene', '30590', (26, 30))	('melanocytic tumors', 'Disease', 'MESH:D009508', (73, 91))	('mutant', 'Var', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('GNAQ/11Q209L', 'Var', (32, 44))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tp53', 'Gene', (26, 30))	('develop', 'PosReg', (57, 64))
31408	29570931	We show that GNAQ/11Q209L expression induces profound melanocyte defects independent of tp53 mutation, which are apparent within 3 days of development.	('induces', 'Reg', (37, 44))	('tp53', 'Gene', (88, 92))	('tp53', 'Gene', '30590', (88, 92))	('GNAQ/11Q209L expression', 'Var', (13, 36))
31410	29570931	Collectively, these data show that GNAQ/11Q209L is sufficient to induce numerous pro-tumorigenic changes within melanocytes.	('tumor', 'Disease', (85, 90))	('GNAQ/11Q209L', 'Var', (35, 47))	('induce', 'Reg', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
31414	29570931	Using a zebrafish model of GNAQ/11Q209L-driven UM, we demonstrate that oncogenic GNAQ/11 causes rapid and profound changes in melanocyte biology, including alterations in proliferation, migration, and survival, which occur well before acquisition of the transformed state.	('oncogenic', 'Var', (71, 80))	('migration', 'CPA', (186, 195))	('alterations', 'Reg', (156, 167))	('melanocyte biology', 'CPA', (126, 144))	('GNAQ/11', 'Gene', (81, 88))	('survival', 'CPA', (201, 209))	('zebrafish', 'Species', '7955', (8, 17))	('proliferation', 'CPA', (171, 184))	('changes', 'Reg', (115, 122))
31419	29570931	Most cutaneous melanomas carry oncogenic mutations in B-RAF or N-RAS, but these are rarely observed in UM.	('mutations', 'Var', (41, 50))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (5, 23))	('N-RAS', 'Gene', '30380', (63, 68))	('cutaneous melanomas', 'Disease', (5, 24))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('B-RAF', 'Gene', (54, 59))	('B-RAF', 'Gene', '403065', (54, 59))	('N-RAS', 'Gene', (63, 68))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (5, 24))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (5, 24))
31420	29570931	Instead, more than 80% of UM cases have gain-of-function mutations in GNAQ or GNA11.	('gain-of-function', 'PosReg', (40, 56))	('GNA11', 'Gene', (78, 83))	('GNA11', 'Gene', '563953', (78, 83))	('mutations', 'Var', (57, 66))	('GNAQ', 'Gene', (70, 74))
31421	29570931	They activate the MAPK/MEK/ERK cascade and phospholipase C (PLCbeta), which can transduce signals to protein kinase C. More recently, oncogenic GNAQ/11Q209L was shown to activate YAP signaling via a HIPPO-independent pathway and also the ARF6-beta-catenin pathway.	('ARF6', 'Gene', (238, 242))	('ERK cascade', 'biological_process', 'GO:0070371', ('27', '38'))	('MAPK/MEK/ERK cascade', 'Pathway', (18, 38))	('signaling', 'biological_process', 'GO:0023052', ('183', '192'))	('ERK', 'molecular_function', 'GO:0004707', ('27', '30'))	('GNAQ/11Q209L', 'Var', (144, 156))	('HIPPO-independent pathway', 'Pathway', (199, 224))	('YAP signaling', 'Pathway', (179, 192))	('beta-catenin', 'Gene', (243, 255))	('beta-catenin', 'Gene', '30265', (243, 255))	('ARF6', 'Gene', '336063', (238, 242))	('activate', 'PosReg', (170, 178))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('oncogenic GNAQ/11Q209L', 'Var', (134, 156))	('MAPK', 'molecular_function', 'GO:0004707', ('18', '22'))
31426	29570931	This second class includes zebrafish mutants defective in background adaptation, a process by which the melanin granules disperse or contract within the melanocyte in response to adrenergic or hormonal cues to camouflage the fish in different surroundings.	('melanin', 'Chemical', 'MESH:D008543', (104, 111))	('zebrafish', 'Species', '7955', (27, 36))	('contract', 'MPA', (133, 141))	('mutants', 'Var', (37, 44))	('background', 'MPA', (58, 68))
31428	29570931	Mutation of numerous oncogenes and tumor suppressor genes yields the appropriate tissue tumor type in zebrafish.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Mutation', 'Var', (0, 8))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('tumor', 'Disease', (88, 93))	('zebrafish', 'Species', '7955', (102, 111))
31429	29570931	A recent study showed that melanocyte-specific expression of GNAQQ209P, in combination with inactivation of the tp53 tumor suppressor, results in development of UM.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('GNAQQ209P', 'Var', (61, 70))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('117', '133'))	('tumor', 'Disease', (117, 122))	('tumor suppressor', 'biological_process', 'GO:0051726', ('117', '133'))	('tp53', 'Gene', '30590', (112, 116))	('GNAQQ209P', 'Mutation', 'rs121913492', (61, 70))	('tp53', 'Gene', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('results in', 'Reg', (135, 145))
31430	29570931	We have generated a similar zebrafish model of UM that is driven by the expression of GNAQQ209L or GNA11Q209L, and have used this to determine how GNAQ/11Q209L modulates melanocyte biology.	('zebrafish', 'Species', '7955', (28, 37))	('melanocyte biology', 'CPA', (170, 188))	('GNAQ/11Q209L', 'Var', (147, 159))	('GNA11', 'Gene', (99, 104))	('modulates', 'Reg', (160, 169))	('GNAQQ209L', 'Var', (86, 95))	('GNA11', 'Gene', '563953', (99, 104))
31431	29570931	Our data reveal that GNAQ/11Q209L causes profound pigmentation defects that result from changes in numerous pro-tumorigenic processes, including proliferation, survival, signaling and migration.	('survival', 'CPA', (160, 168))	('pigmentation defects', 'Disease', (50, 70))	('migration', 'CPA', (184, 193))	('changes', 'Reg', (88, 95))	('GNAQ/11Q209L', 'Var', (21, 33))	('pigmentation defects', 'Phenotype', 'HP:0001000', (50, 70))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('pigmentation defects', 'Disease', 'MESH:D010859', (50, 70))	('signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('proliferation', 'CPA', (145, 158))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('signaling', 'CPA', (170, 179))	('tumor', 'Disease', (112, 117))	('pigmentation', 'biological_process', 'GO:0043473', ('50', '62'))
31433	29570931	The resulting chimeric zebrafish displayed patches of hyperpigmentation providing early evidence that expression of GNAQ/11Q209L alters melanocyte biology (Figure S1).	('hyperpigmentation', 'Disease', (54, 71))	('hyperpigmentation', 'Disease', 'MESH:D017495', (54, 71))	('GNAQ/11Q209L', 'Gene', (116, 128))	('alters', 'Reg', (129, 135))	('expression', 'Var', (102, 112))	('melanocyte biology', 'CPA', (136, 154))	('patches of hyperpigmentation', 'Phenotype', 'HP:0005585', (43, 71))	('zebrafish', 'Species', '7955', (23, 32))
31434	29570931	We observed germline transmission from numerous GNAQQ209L and GNA11Q209L chimeras, and further breeding and analyses yielded three Tg(mitfa:GNAQQ209L) and four Tg(mitfa:GNA11Q209L) stable independent transgenic lines (generically referred to as Tg+) with single copy insertions (data not shown).	('Tg', 'Chemical', '-', (131, 133))	('GNA11', 'Gene', (169, 174))	('GNA11', 'Gene', '563953', (62, 67))	('Tg', 'Chemical', '-', (160, 162))	('Tg', 'Chemical', '-', (245, 247))	('GNA11', 'Gene', '563953', (169, 174))	('GNAQQ209L', 'Var', (48, 57))	('GNA11', 'Gene', (62, 67))
31437	29570931	Additionally, histological analyses revealed internal pigment defects in Tg+ animals (Figure 1C).	('internal pigment defects', 'Disease', (45, 69))	('Tg', 'Chemical', '-', (73, 75))	('internal pigment defects', 'Disease', 'MESH:D010859', (45, 69))	('Tg+', 'Var', (73, 76))
31445	29570931	The addition of Tg+ alleles to both tp53M214K/M214K and tp53M214K/+ backgrounds resulted in reduced lifespans (Figures 2A, 2B, S3) and altered tumor spectrum (discussed below).	('tp53M214K/+', 'Var', (56, 67))	('lifespans', 'CPA', (100, 109))	('Tg', 'Chemical', '-', (16, 18))	('M214K', 'Mutation', 'p.M214K', (46, 51))	('M214K', 'Mutation', 'p.M214K', (40, 45))	('altered tumor', 'Disease', (135, 148))	('reduced', 'NegReg', (92, 99))	('tp53M214K/M214K', 'Var', (36, 51))	('altered tumor', 'Disease', 'MESH:D009369', (135, 148))	('M214K', 'Mutation', 'p.M214K', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
31446	29570931	The reduction in lifespan varied for individual Tg+ alleles, but was statistically significant for six of the seven Tg(mitfa:GNAQ/11Q209L);tp53M214K/M214K lines relative to their tp53M214K/M214K clutchmate controls (Figure 2B; p<0.0001).	('M214K', 'Mutation', 'p.M214K', (189, 194))	('M214K', 'Mutation', 'p.M214K', (143, 148))	('M214K', 'Mutation', 'p.M214K', (183, 188))	('Tg', 'Chemical', '-', (116, 118))	('lifespan', 'CPA', (17, 25))	('M214K', 'Mutation', 'p.M214K', (149, 154))	('reduction', 'NegReg', (4, 13))	('tp53M214K/M214K', 'Var', (139, 154))	('Tg', 'Chemical', '-', (48, 50))
31447	29570931	The variation in Tg+ effects was highly consistent from one generation to the next (Figure S3A,B) and covered a similar range for both GNAQ and GNA11 mutant lines (compare red/orange versus blue curves in Figure 2B).	('GNA11', 'Gene', (144, 149))	('Tg', 'Chemical', '-', (17, 19))	('mutant', 'Var', (150, 156))	('GNA11', 'Gene', '563953', (144, 149))
31448	29570931	This finding, together with the other shared phenotypes of our Tg+ lines (see below), fits with the synonymous roles of GNAQQ209L and GNA11Q209L in human UM.	('GNAQQ209L', 'Var', (120, 129))	('fits', 'Disease', 'MESH:D012640', (86, 90))	('GNA11', 'Gene', (134, 139))	('human', 'Species', '9606', (148, 153))	('GNA11', 'Gene', '563953', (134, 139))	('fits', 'Disease', (86, 90))	('Tg', 'Chemical', '-', (63, 65))
31449	29570931	Importantly, the lifespan shortening effect of the Tg+ alleles accompanied a profound switch in tumor phenotype; the Tg-;tp53 mutant clutchmate controls developed predominantly MPNST and never melanoma, while the Tg+;tp53 mutants developed melanotic tumors with near complete penetrance.	('melanotic tumors', 'Disease', (240, 256))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Tg', 'Chemical', '-', (213, 215))	('Tg', 'Chemical', '-', (117, 119))	('tumor', 'Disease', (250, 255))	('MPNST', 'CPA', (177, 182))	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('tp53', 'Gene', (217, 221))	('melanotic tumors', 'Disease', 'MESH:D017600', (240, 256))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tp53', 'Gene', (121, 125))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('mutant', 'Var', (126, 132))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tp53', 'Gene', '30590', (217, 221))	('Tg', 'Chemical', '-', (51, 53))	('tp53', 'Gene', '30590', (121, 125))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('melanoma', 'Disease', (193, 201))
31457	29570931	Tumors arising in the Tg+;tp53M214K/+ zebrafish displayed loss of heterozygosity for tp53 (as judged by analysis of tumor versus fin DNA, data not shown), confirming the need for cooperating mutations in Tg+ driven tumors.	('heterozygosity', 'MPA', (66, 80))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Disease', (215, 221))	('Tg', 'Chemical', '-', (204, 206))	('Tg', 'Chemical', '-', (22, 24))	('Tumors', 'Disease', (0, 6))	('tp53', 'Gene', '30590', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('tp53', 'Gene', (26, 30))	('zebrafish', 'Species', '7955', (38, 47))	('loss', 'NegReg', (58, 62))	('Tg+', 'Var', (22, 25))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (215, 220))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tp53', 'Gene', '30590', (26, 30))	('tumor', 'Disease', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tp53', 'Gene', (85, 89))
31458	29570931	To validate whether the GNAQ/11Q209L-driven tumors recapitulate aspects of human UM, we screened sections from both ocular (n=4) and internally-arising (n=14) melanotic tumors, for UM-relevant events.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('melanotic tumors', 'Disease', (159, 175))	('human', 'Species', '9606', (75, 80))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('GNAQ/11Q209L-driven', 'Var', (24, 43))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('melanotic tumors', 'Disease', 'MESH:D017600', (159, 175))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumors', 'Disease', (169, 175))
31460	29570931	We then screened for nuclear YAP, a downstream effector that is a distinguishing hallmark of human UM driven by GNAQ/11 mutations, but not the much rarer BRAF or NRAS mutations, and observed positive nuclear YAP staining within uveal, cutaneous and internal melanotic tumors, but not surrounding healthy zebrafish tissue (Figure 2H and S5).	('melanotic tumors', 'Disease', (258, 274))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('human', 'Species', '9606', (93, 98))	('NRAS', 'Gene', '4893', (162, 166))	('BRAF', 'Gene', '673', (154, 158))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('melanotic tumors', 'Disease', 'MESH:D017600', (258, 274))	('BRAF', 'Gene', (154, 158))	('GNAQ/11', 'Gene', (112, 119))	('mutations', 'Var', (120, 129))	('nuclear', 'MPA', (200, 207))	('zebrafish', 'Species', '7955', (304, 313))	('NRAS', 'Gene', (162, 166))
31462	29570931	We then used this model to establish how oncogenic GNAQ/11Q209L expression alters the melanocyte biology prior to the development of tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('alters', 'Reg', (75, 81))	('tumors', 'Disease', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('GNAQ/11Q209L', 'Var', (51, 63))	('melanocyte biology', 'CPA', (86, 104))
31466	29570931	We generated cohorts of Wt and Tg+ clutchmates from representative GNAQ and GNA11 mutant lines (Q-1 and 11-4) and followed them through development.	('GNA11', 'Gene', (76, 81))	('GNAQ', 'Gene', (67, 71))	('GNA11', 'Gene', '563953', (76, 81))	('Tg', 'Chemical', '-', (31, 33))	('mutant', 'Var', (82, 88))
31472	29570931	Importantly, we observed a similar spectrum and time of onset for pigment defects in both the GNAQ (Q-1) and GNA11 (11-4) mutant lines (Figure S6A), indicating that they are consistent and robust consequences of oncogenic GNAQ/11Q209L expression.	('pigment defects', 'Disease', 'MESH:D010859', (66, 81))	('GNA11', 'Gene', (109, 114))	('pigment defects', 'Disease', (66, 81))	('GNA11', 'Gene', '563953', (109, 114))	('mutant', 'Var', (122, 128))	('GNAQ', 'Gene', (94, 98))
31475	29570931	We examined the degree of hyperpigmentation in 5 dpf embryonic fish that had been either dark or light adapted, and showed that the Tg+ zebrafish had a higher percentage of total area covered in melanin than their Tg+ clutchmate controls under both conditions (Figure 3B,C; p<0.0001).	('higher', 'PosReg', (152, 158))	('Tg', 'Chemical', '-', (214, 216))	('Tg+', 'Var', (132, 135))	('Tg', 'Chemical', '-', (132, 134))	('hyperpigmentation', 'Disease', 'MESH:D017495', (26, 43))	('hyperpigmentation', 'Disease', (26, 43))	('melanin', 'Chemical', 'MESH:D008543', (195, 202))	('zebrafish', 'Species', '7955', (136, 145))
31476	29570931	First, the area of melanin coverage per melanocyte was substantially increased in Tg+ fish as quantitated under dark adaption conditions to measure melanocytes in the melanin-expanded state (Figure 3D; p<0.0001).	('increased', 'PosReg', (69, 78))	('melanin', 'Chemical', 'MESH:D008543', (19, 26))	('Tg', 'Chemical', '-', (82, 84))	('melanin', 'Chemical', 'MESH:D008543', (167, 174))	('Tg+', 'Var', (82, 85))
31477	29570931	Second, the Tg+ fish had significantly more melanocytes, as judged by quantification of their melanin puncta (resulting from clustered melanosomes) in light-adapted fish (Figure 3E; p>0.0001).	('more', 'PosReg', (39, 43))	('clustered melanosomes', 'Phenotype', 'HP:0005592', (125, 146))	('Tg', 'Chemical', '-', (12, 14))	('melanin puncta', 'MPA', (94, 108))	('Tg+', 'Var', (12, 15))	('melanocytes', 'CPA', (44, 55))	('melanin', 'Chemical', 'MESH:D008543', (94, 101))
31479	29570931	Having shown that transgene expression expands the per-cell melanin coverage, we wished to determine whether this results from altered intracellular distribution of melanin and/or an increase in cell size.	('transgene expression', 'Var', (18, 38))	('melanin', 'Chemical', 'MESH:D008543', (60, 67))	('increase', 'PosReg', (183, 191))	('cell size', 'CPA', (195, 204))	('expands', 'PosReg', (39, 46))	('expression', 'Var', (28, 38))	('intracellular', 'cellular_component', 'GO:0005622', ('135', '148'))	('melanin', 'Chemical', 'MESH:D008543', (165, 172))	('per-cell melanin coverage', 'CPA', (51, 76))	('altered', 'Reg', (127, 134))
31483	29570931	By isolating Wt and Tg+ melanocytes from 5 dpf fish, and measuring absorbance at 475nm of the lysed cells, we determined Tg+ melanocytes had a significantly higher melanin concentration (Figure 3H; p=0.0121).	('Tg+ melanocytes', 'Var', (121, 136))	('melanin concentration', 'MPA', (164, 185))	('melanin', 'Chemical', 'MESH:D008543', (164, 171))	('higher', 'PosReg', (157, 163))	('Tg', 'Chemical', '-', (20, 22))	('Tg', 'Chemical', '-', (121, 123))
31484	29570931	Therefore, oncogenic GNAQ expands the per cell melanin coverage by increasing the melanin content of the cells without increasing cell size.	('per cell melanin coverage', 'CPA', (38, 63))	('expands', 'PosReg', (26, 33))	('melanin', 'Chemical', 'MESH:D008543', (82, 89))	('melanin', 'Chemical', 'MESH:D008543', (47, 54))	('oncogenic', 'Var', (11, 20))	('melanin content', 'MPA', (82, 97))	('increasing', 'PosReg', (67, 77))
31493	29570931	Melanocyte survival declines drastically in both genotypes from Day 1 to Day 2, but after this initial phase the Tg+ melanocytes displayed improved in vitro survival compared to the Wt controls [Figure 4D; p-value close to zero using the Generalized Estimation Equation (GEE) with link function of Poisson distribution].	('Tg', 'Chemical', '-', (113, 115))	('improved', 'PosReg', (139, 147))	('Melanocyte survival', 'CPA', (0, 19))	('Tg+', 'Var', (113, 116))
31496	29570931	Consistent with the in vivo phenotype (Figure 5A), seeded Tg+ melanocytes appeared more dendritic than the Wt controls.	('Tg', 'Chemical', '-', (58, 60))	('dendritic', 'CPA', (88, 97))	('Tg+', 'Var', (58, 61))	('more', 'PosReg', (83, 87))
31497	29570931	This established that the two genotypes had a highly significant difference in mean convexity (p<0.0001), with both the mean and minimal convexity being considerably lower in Tg+ melanocytes (Figure 5B).	('Tg', 'Chemical', '-', (175, 177))	('convexity', 'MPA', (84, 93))	('lower', 'NegReg', (166, 171))	('Tg+', 'Var', (175, 178))
31503	29570931	First, quantitation of the total path length (total distance traveled) established that Tg+ melanocytes had traveled significantly greater distances than their Wt control counterparts over the 24 hr period (Figure 5D,E; p<0.0001).	('Tg', 'Chemical', '-', (88, 90))	('greater', 'PosReg', (131, 138))	('Tg+', 'Var', (88, 91))
31505	29570931	Thus, collectively, these in vitro analyses establish that oncogenic GNAQ causes striking changes in the survival, morphology and migratory persistence that are highly consistent with the in vivo phenotypes of the Tg+ melanocytes.	('morphology', 'CPA', (115, 125))	('Tg', 'Chemical', '-', (214, 216))	('migratory persistence', 'CPA', (130, 151))	('oncogenic', 'Var', (59, 68))	('GNAQ', 'Gene', (69, 73))	('changes', 'Reg', (90, 97))	('survival', 'CPA', (105, 113))
31506	29570931	We have generated a zebrafish model of UM through the melanocytic expression of human UM driver mutations, GNAQQ209L and GNA11Q209L.	('zebrafish', 'Species', '7955', (20, 29))	('GNA11', 'Gene', '563953', (121, 126))	('human', 'Species', '9606', (80, 85))	('GNA11', 'Gene', (121, 126))	('GNAQQ209L', 'Var', (107, 116))
31508	29570931	When combined with tp53M214K/M214K mutations, oncogenic GNAQ/11Q209L yields uveal melanomas, with similar morphology to human UM, and other aggressive, melanotic tumors originating from cutaneous or internal melanocytes.	('uveal melanomas', 'Disease', 'MESH:C536494', (76, 91))	('human', 'Species', '9606', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('melanotic tumors', 'Disease', (152, 168))	('uveal melanomas', 'Disease', (76, 91))	('uveal melanomas', 'Phenotype', 'HP:0007716', (76, 91))	('M214K', 'Mutation', 'p.M214K', (23, 28))	('M214K', 'Mutation', 'p.M214K', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('yields', 'Reg', (69, 75))	('GNAQ/11Q209L', 'Var', (56, 68))	('melanotic tumors', 'Disease', 'MESH:D017600', (152, 168))	('tp53M214K/M214K', 'Var', (19, 34))
31510	29570931	Our analysis of the transgenic zebrafish has provided key insight into the effects of GNAQ/11Q209L on melanocyte biology, revealing profound pigment defects, including hyperpigmentation and aberrant morphology and localization, which are apparent by 3 dpf and become more exaggerated over time.	('localization', 'biological_process', 'GO:0051179', ('214', '226'))	('pigment defects', 'Disease', (141, 156))	('zebrafish', 'Species', '7955', (31, 40))	('pigment defects', 'Disease', 'MESH:D010859', (141, 156))	('hyperpigmentation', 'Disease', 'MESH:D017495', (168, 185))	('hyperpigmentation', 'Disease', (168, 185))	('GNAQ/11Q209L', 'Var', (86, 98))	('aberrant morphology', 'CPA', (190, 209))	('localization', 'MPA', (214, 226))
31513	29570931	Furthermore, the GNAQ/11Q209L transgenics clearly belong in both of the general subclasses of pigmentation mutants; they disrupt melanocyte development and also their response to environmental cues, which establish the adult stripe pattern (as reviewed in).	('establish', 'Reg', (205, 214))	('response to environmental cues', 'MPA', (167, 197))	('GNAQ/11Q209L', 'Var', (17, 29))	('pigmentation', 'biological_process', 'GO:0043473', ('94', '106'))	('disrupt', 'NegReg', (121, 128))	('pigmentation', 'Disease', 'MESH:D010859', (94, 106))	('pigmentation', 'Disease', (94, 106))	('melanocyte development', 'CPA', (129, 151))
31514	29570931	One of the most striking phenotypes of the Tg+ zebrafish is hyperpigmentation.	('hyperpigmentation', 'Disease', (60, 77))	('hyperpigmentation', 'Disease', 'MESH:D017495', (60, 77))	('Tg', 'Chemical', '-', (43, 45))	('Tg+', 'Var', (43, 46))	('zebrafish', 'Species', '7955', (47, 56))
31519	29570931	Second, the purified Tg+ melanocytes display increased survival in vitro.	('Tg', 'Chemical', '-', (21, 23))	('Tg+', 'Var', (21, 24))	('survival', 'CPA', (55, 63))	('increased', 'PosReg', (45, 54))
31520	29570931	Specifically, GNAQ expression enhances the survival of human UM cell lines but promotes apoptosis of human T-cells and murine melanocytes in the interfollicular epidermis.	('apoptosis', 'CPA', (88, 97))	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('expression', 'Var', (19, 29))	('human', 'Species', '9606', (55, 60))	('enhances', 'PosReg', (30, 38))	('human', 'Species', '9606', (101, 106))	('promotes', 'PosReg', (79, 87))	('GNAQ', 'Gene', (14, 18))	('murine', 'Species', '10090', (119, 125))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))	('survival', 'CPA', (43, 51))
31523	29570931	Moreover, they occur independent of, and are not enhanced by, tp53 mutation.	('tp53', 'Gene', (62, 66))	('tp53', 'Gene', '30590', (62, 66))	('mutation', 'Var', (67, 75))
31536	28781888	A GWAS in uveal melanoma identifies risk polymorphisms in the CLPTM1L locus Uveal melanoma, a rare malignant tumor of the eye, is predominantly observed in populations of European ancestry.	('uveal melanoma', 'Disease', 'MESH:C536494', (10, 24))	('malignant tumor', 'Disease', 'MESH:D018198', (99, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (10, 24))	('uveal melanoma', 'Disease', (10, 24))	('Uveal melanoma', 'Disease', (76, 90))	('polymorphisms', 'Var', (41, 54))	('CLPTM1L', 'Gene', '81037', (62, 69))	('tumor of the eye', 'Phenotype', 'HP:0100012', (109, 125))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('CLPTM1L', 'Gene', (62, 69))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('malignant tumor', 'Disease', (99, 114))	('Uveal melanoma', 'Disease', 'MESH:C536494', (76, 90))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (76, 90))
31538	28781888	In addition, risk variants from this region were positively associated with higher expression of CLPTM1L.	('variants', 'Var', (18, 26))	('higher', 'PosReg', (76, 82))	('CLPTM1L', 'Gene', '81037', (97, 104))	('expression', 'MPA', (83, 93))	('CLPTM1L', 'Gene', (97, 104))
31540	28781888	Researchers have discovered an important genetic risk variant linked to uveal melanoma, a rare malignant tumor of the eye.	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('uveal melanoma', 'Disease', (72, 86))	('malignant tumor', 'Disease', 'MESH:D018198', (95, 110))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('tumor of the eye', 'Phenotype', 'HP:0100012', (105, 121))	('variant', 'Var', (54, 61))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('malignant tumor', 'Disease', (95, 110))	('linked', 'Reg', (62, 68))
31541	28781888	Marc-Henri Stern from Institut Curie in Paris, France, and colleagues compared more than 860,000 single DNA variants covering the entire genome, from the genomes of 259 people with uveal melanoma and 401 healthy controls, all of whom were of European ancestry.	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('people', 'Species', '9606', (169, 175))	('variants', 'Var', (108, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (181, 195))	('uveal melanoma', 'Disease', 'MESH:C536494', (181, 195))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('uveal melanoma', 'Disease', (181, 195))
31542	28781888	The researchers found that a series of closely linked gene variants on the short arm of chromosome 5 were significantly more common in the melanoma patients.	('common', 'Reg', (125, 131))	('patients', 'Species', '9606', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('variants', 'Var', (59, 67))	('melanoma', 'Disease', (139, 147))	('short arm', 'Phenotype', 'HP:0009824', (75, 84))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('chromosome', 'cellular_component', 'GO:0005694', ('88', '98'))
31544	28781888	Expression analyses showed that the CLPTM1L gene contained in this region was more expressed in people with the risk variants, pointing to CLPTM1L playing a role in tumor development.	('CLPTM1L', 'Gene', (36, 43))	('CLPTM1L', 'Gene', (139, 146))	('CLPTM1L', 'Gene', '81037', (36, 43))	('people', 'Species', '9606', (96, 102))	('more', 'PosReg', (78, 82))	('CLPTM1L', 'Gene', '81037', (139, 146))	('variants', 'Var', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('expressed', 'MPA', (83, 92))	('tumor', 'Disease', (165, 170))
31549	28781888	The first event includes mutually exclusive activating mutations leading to the constitutive activation of the Galphaq pathway targeting most often GNA11 or GNAQ genes, encoding G-alpha proteins, or more rarely of CYSLTR2, a GPCR coupled with Galphaq, or of PLCB4, downstream of Galphaq.	('Galphaq', 'Gene', (243, 250))	('GNAQ', 'Gene', '2776', (157, 161))	('Galphaq', 'Gene', '2776', (243, 250))	('activation', 'PosReg', (93, 103))	('Galphaq', 'Gene', (279, 286))	('mutations', 'Var', (55, 64))	('Galphaq', 'Gene', '2776', (279, 286))	('PLCB4', 'Gene', '5332', (258, 263))	('GNAQ', 'Gene', (157, 161))	('Galphaq', 'Gene', (111, 118))	('Galphaq', 'Gene', '2776', (111, 118))	('CYSLTR2', 'Gene', '57105', (214, 221))	('PLCB4', 'Gene', (258, 263))	('GNA11', 'Gene', (148, 153))	('CYSLTR2', 'Gene', (214, 221))	('GNA11', 'Gene', '2767', (148, 153))
31550	28781888	The second genetic event includes recurrent mutations targeting the BAP1, SF3B1 and EIF1AX genes in an almost mutually exclusive manner, with BAP1 inactivation associated with a high risk of metastasis.	('EIF1AX', 'Gene', '1964', (84, 90))	('EIF1AX', 'Gene', (84, 90))	('inactivation', 'Var', (147, 159))	('BAP1', 'Gene', '8314', (142, 146))	('SF3B1', 'Gene', '23451', (74, 79))	('metastasis', 'CPA', (191, 201))	('BAP1', 'Gene', '8314', (68, 72))	('BAP1', 'Gene', (142, 146))	('mutations', 'Var', (44, 53))	('BAP1', 'Gene', (68, 72))	('SF3B1', 'Gene', (74, 79))	('associated', 'Reg', (160, 170))
31556	28781888	In one region on chromosome 5p15.33, 2 SNPs in high linkage disequilibrium (LD; r 2 > 0.9), rs421284 and rs452932, showed evidence of association with P-values lower than 3.3 x 10-7 using logistic regression (Odds ratio [OR] = 1.95, 95% CI 1.11-3.44, P = 7.5 x 10-8 and OR = 1.91, P = 1.1 x 10-7, 95% CI 1.10-3.30, respectively), while multiple surrounding SNPs showed association consistent with degradation of LD around this association peak (Figs 1 and 2, Supplementary Fig.	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('rs421284', 'Var', (92, 100))	('rs421284', 'Mutation', 'rs421284', (92, 100))	('rs452932', 'Var', (105, 113))	('degradation', 'biological_process', 'GO:0009056', ('397', '408'))	('rs452932', 'Mutation', 'rs452932', (105, 113))
31557	28781888	A second locus showed many SNPs in LD on chromosome 15 (OCA2/HERC2 locus) but did not reached significant threshold of 3.3 x 10-7.	('OCA2', 'Gene', (56, 60))	('HERC2', 'Gene', (61, 66))	('OCA2', 'Gene', '4948', (56, 60))	('HERC2', 'Gene', '8924', (61, 66))	('SNPs', 'Var', (27, 31))	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))
31559	28781888	These samples were genotyped by TaqMan assays for the two most significant SNPs identified on the discovery series: rs421284 and rs452932 (5p15.33).	('rs421284', 'Var', (116, 124))	('rs452932', 'Mutation', 'rs452932', (129, 137))	('rs452932', 'Var', (129, 137))	('rs421284', 'Mutation', 'rs421284', (116, 124))
31560	28781888	These analyses confirmed the association observed in the discovery set (rs421284: OR = 1.46, 95% CI 1.11-1.91, P = 6 x 10-3 and rs452932: OR = 1.49, 95% CI 1.14-1.97, P = 8 x 10-3) for 5p15.33.	('rs421284', 'Mutation', 'rs421284', (72, 80))	('rs452932', 'Var', (128, 136))	('rs452932', 'Mutation', 'rs452932', (128, 136))	('rs421284:', 'Var', (72, 81))
31561	28781888	Meta-analyses performed on both discovery and validation series for rs421284 and rs452932 reinforced the association observed for 5p15.33 (OR = 1.71, 95% CI 1.43-2.05, P = 5 x 10-9 and OR = 1.72, 95% CI 1.44-2.06, P = 2 x 10-9, respectively) (Table 1).	('rs421284', 'Mutation', 'rs421284', (68, 76))	('rs452932', 'Mutation', 'rs452932', (81, 89))	('rs452932', 'Var', (81, 89))	('rs421284', 'Var', (68, 76))
31562	28781888	All 5p15.33 risk variant SNPs were found within the TERT/CLPTM1L locus.	('CLPTM1L', 'Gene', (57, 64))	('5p15.33', 'Gene', (4, 11))	('TERT', 'Gene', (52, 56))	('TERT', 'Gene', '7015', (52, 56))	('variant', 'Var', (17, 24))	('CLPTM1L', 'Gene', '81037', (57, 64))
31563	28781888	To evaluate the impact of SNPs on gene regulation, an eQTL analysis was performed for the 5p15.33 region using expression data from tumors of two in-house series of 73 and 55 UM patients, respectively, which were genotyped for rs421284.	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('patients', 'Species', '9606', (178, 186))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('rs421284', 'Var', (227, 235))	('regulation', 'biological_process', 'GO:0065007', ('39', '49'))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('UM', 'Phenotype', 'HP:0007716', (175, 177))	('rs421284', 'Mutation', 'rs421284', (227, 235))
31565	28781888	The expression of a single gene with the 500 kb region surrounding rs421284 was found correlated with the risk allele in the 2 series: CLPTM1L (Cleft lip and palate transmembrane protein 1-like), for which a positive correlation with the risk allele was found (Fig.	('correlated', 'Reg', (86, 96))	('rs421284', 'Var', (67, 75))	('transmembrane', 'cellular_component', 'GO:0016021', ('165', '178'))	('expression', 'MPA', (4, 14))	('rs421284', 'Mutation', 'rs421284', (67, 75))	('transmembrane', 'cellular_component', 'GO:0044214', ('165', '178'))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('CLPTM1L', 'Gene', '81037', (135, 142))	('Cleft lip', 'Phenotype', 'HP:0410030', (144, 153))	('CLPTM1L', 'Gene', (135, 142))	('Cleft lip and palate transmembrane protein 1-like', 'Gene', '81037', (144, 193))
31566	28781888	In addition, the influence of rs465498 on CLPTM1L expression was confirmed on normal airway epithelium from 95 individuals, with a higher expression associated with the risk allele of rs465498 (OR = 1.82, 95% CI 1.08-3.06, P = 5 x 10-7), in high LD with rs421284 (r 2 > 0.9) (Fig.	('rs465498', 'Var', (184, 192))	('rs465498', 'Mutation', 'rs465498', (30, 38))	('CLPTM1L', 'Gene', '81037', (42, 49))	('rs421284', 'Var', (254, 262))	('expression', 'MPA', (138, 148))	('CLPTM1L', 'Gene', (42, 49))	('rs465498', 'Mutation', 'rs465498', (184, 192))	('rs421284', 'Mutation', 'rs421284', (254, 262))	('higher', 'PosReg', (131, 137))
31567	28781888	Finally, we conducted an eQTL analysis on 333 cutaneous melanomas from The Cancer Genome Atlas and also showed a higher expression of CLPTM1L with the risk allele of rs465498 (Supplementary Fig.	('Cancer Genome Atlas', 'Disease', (75, 94))	('rs465498', 'Var', (166, 174))	('CLPTM1L', 'Gene', (134, 141))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (75, 94))	('expression', 'MPA', (120, 130))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('higher', 'PosReg', (113, 119))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (46, 65))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (46, 65))	('rs465498', 'Mutation', 'rs465498', (166, 174))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('cutaneous melanomas', 'Disease', (46, 65))	('CLPTM1L', 'Gene', '81037', (134, 141))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
31569	28781888	To evaluate whether the variants we identified in CLPTM1L could explain the prevalence of UM in the different human populations, we conducted a haplotype analysis on the 5p15.33 region using HapMap populations.	('CLPTM1L', 'Gene', (50, 57))	('UM', 'Phenotype', 'HP:0007716', (90, 92))	('variants', 'Var', (24, 32))	('human', 'Species', '9606', (110, 115))	('CLPTM1L', 'Gene', '81037', (50, 57))
31571	28781888	Association analyses identified a susceptibility locus at 5p15.33 in a region showing the strongest association and including multiple SNPs in LD with rs421284 and rs452932.	('rs452932', 'Var', (164, 172))	('rs452932', 'Mutation', 'rs452932', (164, 172))	('rs421284', 'Var', (151, 159))	('rs421284', 'Mutation', 'rs421284', (151, 159))
31574	28781888	In human cutaneous melanoma, recurrent mutations in the TERT promoter have previously been identified.	('human', 'Species', '9606', (3, 8))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('cutaneous melanoma', 'Disease', (9, 27))	('mutations', 'Var', (39, 48))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (9, 27))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (9, 27))	('TERT', 'Gene', (56, 60))	('TERT', 'Gene', '7015', (56, 60))
31575	28781888	A single UM tumor has been reported as carrying a mutation in the TERT promoter (chr5:1,295,226G > A) leading to elevated TERT expression.	('TERT', 'Gene', (122, 126))	('TERT', 'Gene', '7015', (122, 126))	('elevated', 'PosReg', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('226G > A', 'Mutation', 'rs764351570', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('TERT', 'Gene', (66, 70))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('TERT', 'Gene', '7015', (66, 70))	('tumor', 'Disease', (12, 17))	('mutation', 'Var', (50, 58))
31577	28781888	Some variants of CLPTM1L have previously been negatively or positively associated with different cancers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('CLPTM1L', 'Gene', '81037', (17, 24))	('cancers', 'Disease', (97, 104))	('negatively', 'NegReg', (46, 56))	('CLPTM1L', 'Gene', (17, 24))	('positively', 'PosReg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('variants', 'Var', (5, 13))	('associated', 'Reg', (71, 81))
31579	28781888	Conversely, rs31489, rs401681, and rs402710 (CLPTM1L introns 2, 13, and 16, respectively) have been associated by multiple GWAS with several cancer types such as cutaneous melanoma, bladder, pancreatic, and lung carcinomas.	('rs402710', 'Var', (35, 43))	('lung carcinomas', 'Disease', 'MESH:D008175', (207, 222))	('rs402710', 'Mutation', 'rs402710', (35, 43))	('CLPTM1L', 'Gene', '81037', (45, 52))	('rs31489', 'Var', (12, 19))	('lung carcinomas', 'Disease', (207, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('cancer', 'Disease', (141, 147))	('rs401681', 'Var', (21, 29))	('pancreatic', 'Disease', 'MESH:D010195', (191, 201))	('cutaneous melanoma', 'Disease', (162, 180))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (162, 180))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (162, 180))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('associated', 'Reg', (100, 110))	('CLPTM1L', 'Gene', (45, 52))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('carcinomas', 'Phenotype', 'HP:0030731', (212, 222))	('rs31489', 'Mutation', 'rs31489', (12, 19))	('pancreatic', 'Disease', (191, 201))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('bladder', 'Disease', (182, 189))	('rs401681', 'Mutation', 'rs401681', (21, 29))
31580	28781888	In particular, rs401681 shows an inverse association with cutaneous melanoma and may change its risk via the variation of nevus counts.	('cutaneous melanoma', 'Disease', (58, 76))	('inverse', 'NegReg', (33, 40))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (58, 76))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (58, 76))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('rs401681', 'Mutation', 'rs401681', (15, 23))	('rs401681', 'Var', (15, 23))	('nevus', 'Phenotype', 'HP:0003764', (122, 127))	('change', 'Reg', (85, 91))
31581	28781888	This SNP is part of the CLPTM1L peak detected in our GWAS (Supplementary Table 1) and is in high LD with rs421284 (r 2 = 0.93).	('CLPTM1L', 'Gene', (24, 31))	('rs421284', 'Var', (105, 113))	('CLPTM1L', 'Gene', '81037', (24, 31))	('rs421284', 'Mutation', 'rs421284', (105, 113))
31582	28781888	Our eQTL analyses revealed a positive correlation between risk allele of rs421284 and CLPTM1L expression in UM tumors.	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('rs421284', 'Mutation', 'rs421284', (73, 81))	('CLPTM1L', 'Gene', '81037', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('CLPTM1L', 'Gene', (86, 93))	('expression', 'MPA', (94, 104))	('rs421284', 'Var', (73, 81))
31583	28781888	In normal tissue, the risk allele of rs465498, another SNP of the region, was also found to be positively correlated with CLPTM1L expression.	('expression', 'MPA', (130, 140))	('rs465498', 'Var', (37, 45))	('CLPTM1L', 'Gene', '81037', (122, 129))	('CLPTM1L', 'Gene', (122, 129))	('rs465498', 'Mutation', 'rs465498', (37, 45))	('correlated', 'Reg', (106, 116))
31584	28781888	In accordance with our results, James and colleagues have previously reported a correlation between CLPTM1L expression and rs31489 alleles in normal lung tissue.	('CLPTM1L', 'Gene', '81037', (100, 107))	('correlation', 'Interaction', (80, 91))	('CLPTM1L', 'Gene', (100, 107))	('expression', 'MPA', (108, 118))	('rs31489', 'Mutation', 'rs31489', (123, 130))	('rs31489', 'Var', (123, 130))
31585	28781888	rs31489 was part of the peak at 5p15.33 and is in high LD (r 2 = 0.8) with rs421284.	('rs421284', 'Var', (75, 83))	('rs421284', 'Mutation', 'rs421284', (75, 83))	('rs31489', 'Mutation', 'rs31489', (0, 7))	('rs31489', 'Var', (0, 7))
31586	28781888	In addition, we showed a positive correlation between the rs465498 risk allele and CLPTM1L expression in cutaneous melanoma.	('expression', 'MPA', (91, 101))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (105, 123))	('rs465498', 'Mutation', 'rs465498', (58, 66))	('CLPTM1L', 'Gene', '81037', (83, 90))	('rs465498', 'Var', (58, 66))	('cutaneous melanoma', 'Disease', (105, 123))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (105, 123))	('CLPTM1L', 'Gene', (83, 90))	('positive correlation', 'Reg', (25, 45))
31587	28781888	Interestingly, the SNPs we discovered with the highest OR at 5p15.33 are located close to or within a region highly marked for H3K27ac (ENCODE) and associated with DNase I hypersensitivity clusters in CLPTM1L intron 8, both of which are indicative of an active enhancer region (Supplementary Fig.	('hypersensitivity', 'biological_process', 'GO:0002524', ('172', '188'))	('hypersensitivity', 'Disease', 'MESH:D004342', (172, 188))	('DNase I', 'molecular_function', 'GO:0004530', ('164', '171'))	('hypersensitivity', 'Disease', (172, 188))	('5p15.33', 'Var', (61, 68))	('CLPTM1L', 'Gene', '81037', (201, 208))	('CLPTM1L', 'Gene', (201, 208))	('H3K27ac', 'Var', (127, 134))
31599	28781888	Nevertheless, rs4911442 in the NCAO6/ASIP region and associated with cutaneous melanoma, exhibited a high OR (OR = 1.77, 95% CI 0.90-3.50, P = 5.6 x 10-3) in our study, but did not achieve the significance threshold.	('rs4911442', 'Var', (14, 23))	('ASIP', 'Gene', '434', (37, 41))	('cutaneous melanoma', 'Disease', (69, 87))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (69, 87))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (69, 87))	('ASIP', 'Gene', (37, 41))	('associated', 'Reg', (53, 63))	('rs4911442', 'Mutation', 'rs4911442', (14, 23))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))
31601	28781888	Authors described rs12913832 at the HERC2/OCA2 locus as the most significantly associated with UM risk.	('rs12913832', 'Mutation', 'rs12913832', (18, 28))	('associated', 'Reg', (79, 89))	('OCA2', 'Gene', '4948', (42, 46))	('HERC2', 'Gene', (36, 41))	('UM risk', 'Disease', (95, 102))	('HERC2', 'Gene', '8924', (36, 41))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('rs12913832', 'Var', (18, 28))	('OCA2', 'Gene', (42, 46))
31602	28781888	Interestingly, three SNPs at the HERC2/OCA2 locus, rs12913832, rs11074306, and rs3930739 displayed a clear peak in the Manhattan plot in our study, although not reaching our empirical significance threshold (Supplementary Table 1).	('rs11074306', 'Var', (63, 73))	('HERC2', 'Gene', (33, 38))	('HERC2', 'Gene', '8924', (33, 38))	('rs3930739', 'Mutation', 'rs3930739', (79, 88))	('rs3930739', 'Var', (79, 88))	('OCA2', 'Gene', (39, 43))	('rs12913832', 'Var', (51, 61))	('rs12913832', 'Mutation', 'rs12913832', (51, 61))	('OCA2', 'Gene', '4948', (39, 43))	('rs11074306', 'Mutation', 'rs11074306', (63, 73))
31603	28781888	A combined risk analyses was performed between OCA2 alleles and rs421284.	('OCA2', 'Gene', '4948', (47, 51))	('OCA2', 'Gene', (47, 51))	('rs421284', 'Var', (64, 72))	('rs421284', 'Mutation', 'rs421284', (64, 72))
31604	28781888	Ferguson and colleagues also showed that rs12203592 at the IRF4 locus was associated with UM risk.	('IRF4', 'Gene', '3662', (59, 63))	('IRF4', 'Gene', (59, 63))	('UM', 'Phenotype', 'HP:0007716', (90, 92))	('rs12203592', 'Var', (41, 51))	('rs12203592', 'Mutation', 'rs12203592', (41, 51))	('associated', 'Reg', (74, 84))
31605	28781888	To be noticed, Ferguson and colleagues also evaluated rs401681 located in the CLPTM1L locus, which did not reach significance in their study.	('rs401681', 'Var', (54, 62))	('CLPTM1L', 'Gene', '81037', (78, 85))	('rs401681', 'Mutation', 'rs401681', (54, 62))	('CLPTM1L', 'Gene', (78, 85))
31609	28781888	One possibility is that these pigmentation variants reflect a population bias in UM patients, which escaped the PCA stratification.	('pigmentation', 'Disease', (30, 42))	('patients', 'Species', '9606', (84, 92))	('UM', 'Phenotype', 'HP:0007716', (81, 83))	('pigmentation', 'biological_process', 'GO:0043473', ('30', '42'))	('variants', 'Var', (43, 51))	('pigmentation', 'Disease', 'MESH:D010859', (30, 42))
31611	28781888	By which mechanisms pigmentation gene polymorphisms contribute to UM epidemiology remain to be unraveled.	('pigmentation', 'Disease', 'MESH:D010859', (20, 32))	('pigmentation', 'Disease', (20, 32))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('polymorphisms', 'Var', (38, 51))	('contribute', 'Reg', (52, 62))	('pigmentation', 'biological_process', 'GO:0043473', ('20', '32'))
31642	27285292	Previous work has shown that both uveal melanoma and primary leptomeningeal melanocytic neoplasms frequently harbor activating mutations in the G-protein coding genes, GNAQ and GNA11, which behave in a manner similar to activating RAS mutations.	('activating', 'PosReg', (116, 126))	('leptomeningeal melanocytic neoplasms', 'Disease', 'MESH:D008577', (61, 97))	('GNAQ', 'Gene', '2776', (168, 172))	('GNA11', 'Gene', '2767', (177, 182))	('GNA11', 'Gene', (177, 182))	('neoplasms', 'Phenotype', 'HP:0002664', (88, 97))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('GNAQ', 'Gene', (168, 172))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (76, 97))	('uveal melanoma', 'Disease', 'MESH:C536494', (34, 48))	('uveal melanoma', 'Phenotype', 'HP:0007716', (34, 48))	('mutations', 'Var', (127, 136))	('leptomeningeal melanocytic neoplasms', 'Disease', (61, 97))	('uveal melanoma', 'Disease', (34, 48))
31643	27285292	More recently, a study has shown that uveal melanomas and leptomeningeal melanocytic neoplasms also share mutations in SF3B1, a mediator of mRNA splicing, and EIF1A, a component of the translation machinery.	('leptomeningeal melanocytic neoplasms', 'Disease', (58, 94))	('leptomeningeal melanocytic neoplasms', 'Disease', 'MESH:D008577', (58, 94))	('uveal melanomas', 'Disease', (38, 53))	('uveal melanomas', 'Phenotype', 'HP:0007716', (38, 53))	('neoplasms', 'Phenotype', 'HP:0002664', (85, 94))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (73, 94))	('mRNA splicing', 'biological_process', 'GO:0006371', ('140', '153'))	('mRNA splicing', 'biological_process', 'GO:0000398', ('140', '153'))	('mRNA splicing', 'biological_process', 'GO:0000394', ('140', '153'))	('translation', 'biological_process', 'GO:0006412', ('185', '196'))	('EIF1A', 'Gene', '1964', (159, 164))	('mRNA splicing', 'biological_process', 'GO:0000374', ('140', '153'))	('SF3B1', 'Gene', (119, 124))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('EIF1A', 'Gene', (159, 164))	('uveal melanomas', 'Disease', 'MESH:C536494', (38, 53))	('mRNA splicing', 'biological_process', 'GO:0000373', ('140', '153'))	('mRNA splicing', 'biological_process', 'GO:0000372', ('140', '153'))	('SF3B1', 'Gene', '23451', (119, 124))	('mutations', 'Var', (106, 115))	('uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))
31689	27285292	Rather than perform another meningeal biopsy or brain biopsy, we next sought to determine whether the CSF CTCs had a GNAQ or GNA11 mutations, both commonly found in uveal melanomas.	('mutations', 'Var', (131, 140))	('uveal melanoma', 'Phenotype', 'HP:0007716', (165, 179))	('GNAQ', 'Gene', '2776', (117, 121))	('uveal melanomas', 'Disease', (165, 180))	('uveal melanomas', 'Phenotype', 'HP:0007716', (165, 180))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanomas', 'Phenotype', 'HP:0002861', (171, 180))	('GNAQ', 'Gene', (117, 121))	('uveal melanomas', 'Disease', 'MESH:C536494', (165, 180))	('GNA11', 'Gene', '2767', (125, 130))	('GNA11', 'Gene', (125, 130))
31691	27285292	The sequencing indicated a Q209P mutation in GNAQ at an allelic frequency of 4%.	('indicated', 'Reg', (15, 24))	('Q209P', 'Var', (27, 32))	('GNAQ', 'Gene', (45, 49))	('Q209P', 'Mutation', 'rs121913492', (27, 32))	('GNAQ', 'Gene', '2776', (45, 49))
31692	27285292	The analysis also found two additional nonsynonymous mutations: MET N373S and TP53 P72R; however, these were polymorphic and in all likelihood are germline alterations without a well-defined clinical significance.	('N373S', 'Mutation', 'p.N373S', (68, 73))	('MET N373S', 'Var', (64, 73))	('TP53', 'Gene', '7157', (78, 82))	('P72R', 'Mutation', 'rs1042522', (83, 87))	('TP53', 'Gene', (78, 82))	('P72R', 'Var', (83, 87))
31712	27285292	Although mutations in BRAF, NRAS, or NF1 account for the majority of driver mutations in cutaneous melanomas, these are rarely detected in uveal tumors.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (89, 107))	('NRAS', 'Gene', '4893', (28, 32))	('mutations', 'Var', (76, 85))	('cutaneous melanomas', 'Disease', (89, 108))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mutations', 'Var', (9, 18))	('NF1', 'Gene', (37, 40))	('BRAF', 'Gene', '673', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('NF1', 'Gene', '4763', (37, 40))	('BRAF', 'Gene', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanomas', 'Phenotype', 'HP:0002861', (99, 108))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (89, 108))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (89, 108))	('uveal tumors', 'Disease', (139, 151))	('NRAS', 'Gene', (28, 32))	('uveal tumors', 'Disease', 'MESH:D014604', (139, 151))
31713	27285292	Instead, ~ 80% of uveal melanomas harbor activating mutations in GNA11 or GNAQ, leading to constitutive signaling to the MAPK and phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway.	('Akt', 'Gene', '207', (160, 163))	('activating', 'PosReg', (41, 51))	('GNA11', 'Gene', '2767', (65, 70))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('PI3K', 'molecular_function', 'GO:0016303', ('165', '169'))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('MAPK', 'Gene', (121, 125))	('GNAQ', 'Gene', '2776', (74, 78))	('uveal melanomas', 'Disease', 'MESH:C536494', (18, 33))	('GNAQ', 'Gene', (74, 78))	('MAPK', 'Gene', '5594', (121, 125))	('MAPK', 'molecular_function', 'GO:0004707', ('121', '125'))	('Akt', 'Gene', (170, 173))	('GNA11', 'Gene', (65, 70))	('PI3K/Akt', 'Gene', (165, 173))	('Akt', 'Gene', '207', (170, 173))	('mutations', 'Var', (52, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (18, 32))	('PI3K/Akt', 'Gene', '5290;207', (165, 173))	('uveal melanomas', 'Disease', (18, 33))	('Akt', 'Gene', (160, 163))	('uveal melanomas', 'Phenotype', 'HP:0007716', (18, 33))	('melanomas', 'Phenotype', 'HP:0002861', (24, 33))	('constitutive signaling', 'MPA', (91, 113))
31714	27285292	Only recently has it been discovered that both uveal melanomas and primary melanocytic leptomeningeal neoplasms share driving mutations in GNAQ, GNA11, SF3B1, and EIF1A.	('SF3B1', 'Gene', '23451', (152, 157))	('melanocytic leptomeningeal neoplasms', 'Disease', 'MESH:D008577', (75, 111))	('melanocytic leptomeningeal neoplasms', 'Disease', (75, 111))	('uveal melanomas', 'Disease', (47, 62))	('uveal melanomas', 'Phenotype', 'HP:0007716', (47, 62))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('EIF1A', 'Gene', '1964', (163, 168))	('neoplasms', 'Phenotype', 'HP:0002664', (102, 111))	('GNAQ', 'Gene', (139, 143))	('GNAQ', 'Gene', '2776', (139, 143))	('SF3B1', 'Gene', (152, 157))	('mutations', 'Var', (126, 135))	('uveal melanomas', 'Disease', 'MESH:C536494', (47, 62))	('EIF1A', 'Gene', (163, 168))	('GNA11', 'Gene', '2767', (145, 150))	('GNA11', 'Gene', (145, 150))
31734	28429726	In particular, non-light activated VP was shown to inhibit the transcriptional output of the HIPPO growth regulatory pathway (the name comes from one of its key signaling components the protein kinase Hippo (HPO) - mutations in this gene results in tissue overgrowth or a "hippopotamus" like phenotype) by binding to Yes-associated protein (YAP; encoded by YAP1) and disrupting the YAP1-TEAD/TEF complex inhibiting the growth of hepatocellular carcinoma, retinoblastoma and uveal melanoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (429, 453))	('uveal melanoma', 'Disease', (474, 488))	('uveal melanoma', 'Disease', 'MESH:C536494', (474, 488))	('disrupting', 'NegReg', (367, 377))	('Yes-associated protein', 'Gene', (317, 339))	('signaling', 'biological_process', 'GO:0023052', ('161', '170'))	('YAP', 'Gene', (341, 344))	('growth', 'MPA', (419, 425))	('VP', 'Chemical', 'MESH:D000077362', (35, 37))	('hepatocellular carcinoma', 'Disease', (429, 453))	('transcriptional', 'MPA', (63, 78))	('YAP', 'Gene', '10413', (382, 385))	('uveal melanoma', 'Phenotype', 'HP:0007716', (474, 488))	('carcinoma', 'Phenotype', 'HP:0030731', (444, 453))	('retinoblastoma', 'Disease', 'MESH:D012175', (455, 469))	('mutations', 'Var', (215, 224))	('hippopotamus', 'Species', '9833', (273, 285))	('binding', 'Interaction', (306, 313))	('protein', 'cellular_component', 'GO:0003675', ('186', '193'))	('YAP', 'Gene', '10413', (357, 360))	('YAP', 'Gene', '10413', (341, 344))	('binding', 'molecular_function', 'GO:0005488', ('304', '311'))	('Yes-associated protein', 'Gene', '10413', (317, 339))	('protein', 'cellular_component', 'GO:0003675', ('330', '337'))	('inhibit', 'NegReg', (51, 58))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (429, 453))	('retinoblastoma', 'Phenotype', 'HP:0009919', (455, 469))	('overgrowth', 'Phenotype', 'HP:0001548', (256, 266))	('retinoblastoma', 'Disease', (455, 469))	('YAP', 'Gene', (382, 385))	('melanoma', 'Phenotype', 'HP:0002861', (480, 488))	('inhibiting', 'NegReg', (404, 414))	('YAP', 'Gene', (357, 360))
31735	28429726	It has been suggested that non light activated VP inhibits autophagy by inducing the formation of high molecular weight protein complexes (HMWC) involved in autophagy machinery such as p62 and that non-light activated VP can inhibit colon cancer cell growth via HMWC proteotoxicity.	('autophagy', 'biological_process', 'GO:0016236', ('157', '166'))	('VP', 'Chemical', 'MESH:D000077362', (218, 220))	('colon cancer', 'Phenotype', 'HP:0003003', (233, 245))	('formation', 'biological_process', 'GO:0009058', ('85', '94'))	('non-light activated', 'Var', (198, 217))	('autophagy', 'biological_process', 'GO:0006914', ('157', '166'))	('colon cancer', 'Disease', 'MESH:D015179', (233, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('autophagy', 'CPA', (59, 68))	('inducing', 'PosReg', (72, 80))	('autophagy', 'biological_process', 'GO:0016236', ('59', '68'))	('inhibits', 'NegReg', (50, 58))	('toxicity', 'Disease', 'MESH:D064420', (273, 281))	('inhibit', 'NegReg', (225, 232))	('colon cancer', 'Disease', (233, 245))	('formation', 'MPA', (85, 94))	('p62', 'Gene', '23636', (185, 188))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('p62', 'Gene', (185, 188))	('cell growth', 'biological_process', 'GO:0016049', ('246', '257'))	('autophagy', 'biological_process', 'GO:0006914', ('59', '68'))	('VP', 'Chemical', 'MESH:D000077362', (47, 49))	('toxicity', 'Disease', (273, 281))
31746	28429726	Singlet oxygen can lead to direct protein oxidation that can result in the presence of oxidized methionine on the protein.	('lead to', 'Reg', (19, 26))	('protein oxidation', 'MPA', (34, 51))	('Singlet oxygen', 'Chemical', 'MESH:D026082', (0, 14))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('protein oxidation', 'biological_process', 'GO:0018158', ('34', '51'))	('presence of oxidized methionine', 'MPA', (75, 106))	('Singlet oxygen', 'Var', (0, 14))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('result in', 'Reg', (61, 70))	('methionine', 'Chemical', 'MESH:D008715', (96, 106))
31802	28429726	Heat-inactivated fetal bovine serum (HI-FBS) (10438-026) and Penicillin-Streptomycin (15140122) were purchased from Life Technologies (Grand Island, NY).	('Penicillin', 'Chemical', 'MESH:D010406', (61, 71))	('HI-FBS', 'Disease', 'MESH:D005198', (37, 43))	('HI-FBS', 'Disease', (37, 43))	('Streptomycin', 'Chemical', 'MESH:D013307', (72, 84))	('10438-026', 'Var', (46, 55))	('bovine', 'Species', '9913', (23, 29))	('15140122', 'Var', (86, 94))
31879	27239566	IOP and high diurnal IOP variation in all eyes with PEX are considered a risk factor for the development of glaucoma.	('glaucoma', 'Phenotype', 'HP:0000501', (108, 116))	('glaucoma', 'Disease', (108, 116))	('high diurnal IOP', 'Phenotype', 'HP:0007906', (8, 24))	('IOP', 'MPA', (0, 3))	('high diurnal IOP variation', 'Phenotype', 'HP:0008499', (8, 34))	('variation', 'Var', (25, 34))	('glaucoma', 'Disease', 'MESH:D005901', (108, 116))
31903	27239566	The low rate of monosomy C3 and low mortality rate may be an indication of a better prognosis of uveal melanoma in Iran.	('monosomy C3', 'Var', (16, 27))	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('uveal melanoma', 'Disease', (97, 111))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
31921	27239566	12.2% of the deaf children were amblyopic compared to 1.2% of the control group (p < 0.001).	('deaf children', 'Phenotype', 'HP:0000365', (13, 26))	('children', 'Species', '9606', (18, 26))	('deaf', 'Var', (13, 17))	('amblyopic', 'Disease', (32, 41))
31925	25431638	103Pd versus 125I ophthalmic plaque brachytherapy: preoperative comparative radiation dosimetry for 319 uveal melanomas This study was conducted to compare the relative, clinical intraocular dose distribution for palladium-103 (103Pd) versus iodine-125 (125I) ophthalmic plaque radiation therapy.	('103Pd', 'Var', (228, 233))	('uveal melanomas', 'Disease', 'MESH:C536494', (104, 119))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('uveal melanomas', 'Phenotype', 'HP:0007716', (104, 119))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('iodine-125', 'Chemical', 'MESH:C000614960', (242, 252))	('uveal melanomas', 'Disease', (104, 119))	('103Pd', 'Chemical', 'MESH:C000615531', (228, 233))	('palladium-103', 'Chemical', 'MESH:C000615531', (213, 226))	('103Pd', 'Chemical', 'MESH:C000615531', (0, 5))
31929	25431638	When compared to 125I, 103Pd was associated with a mean 41.9 % lower radiation dose to the opposite eye wall (p < 0.001), 12.7 % to the lens center (p < 0.001), 7.5 % to the optic disc (p = 0.008), and a 3.8 % decrease to the fovea (p = 0.034).	('lower', 'NegReg', (63, 68))	('radiation dose', 'MPA', (69, 83))	('decrease', 'NegReg', (210, 218))	('103Pd', 'Chemical', 'MESH:C000615531', (23, 28))	('103Pd', 'Var', (23, 28))
31936	25431638	For an equivalent tumor target dose, the less energetic (21 keV) 103Pd-photons were more quickly absorbed than those from the (28 keV) 125I plaques within the eye and vitreous before it reached the episcleral dosimeters.	('103Pd', 'Chemical', 'MESH:C000615531', (65, 70))	('vitreous before it', 'Phenotype', 'HP:0100832', (167, 185))	('tumor', 'Disease', (18, 23))	('103Pd-photons', 'Var', (65, 78))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
31939	25431638	In 2011, the American Association of Physicists in Medicine (AAPM) Task Group-129 (TG-129) examined the relative ocular dose distributions of 125I versus 103Pd plaque treatment for a single moderately sized T1 tumor and found relative dose advantages with the use of 103Pd.	('103Pd', 'Chemical', 'MESH:C000615531', (154, 159))	('TG', 'Chemical', '-', (83, 85))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (210, 215))	('dose', 'MPA', (235, 239))	('103Pd', 'Chemical', 'MESH:C000615531', (267, 272))	('advantages', 'PosReg', (240, 250))	('125I', 'Var', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
31942	25431638	Since 2006, at The New York Eye Cancer Center and affiliated hospitals, we have routinely compared 125I to 103Pd prior to ophthalmic plaque brachytherapy.	('Cancer', 'Disease', (32, 38))	('Eye Cancer', 'Phenotype', 'HP:0100012', (28, 38))	('Cancer', 'Disease', 'MESH:D009369', (32, 38))	('103Pd', 'Chemical', 'MESH:C000615531', (107, 112))	('125I', 'Var', (99, 103))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))
31960	25431638	Therefore, the use of 103Pd was found to steepen the dose gradient within the tumor.	('103Pd', 'Var', (22, 27))	('use', 'Var', (15, 18))	('103Pd', 'Chemical', 'MESH:C000615531', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('dose gradient within', 'MPA', (53, 73))	('tumor', 'Disease', (78, 83))	('steepen', 'PosReg', (41, 48))
31961	25431638	Specifically, for an equivalent tumor-apex dose, the use of 103Pd increased the mean radiation dose within the tumor by mean 7.6 % (157.9 versus 146.7 Gy) compared to 125I.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('103Pd', 'Var', (60, 65))	('increased', 'PosReg', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('apex', 'cellular_component', 'GO:0097683', ('38', '42'))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('103Pd', 'Chemical', 'MESH:C000615531', (60, 65))
31963	25431638	At that data point, the use of 103Pd resulted in a 41.9 % reduction of radiation dose (p < 0.001).	('reduction', 'NegReg', (58, 67))	('radiation dose', 'MPA', (71, 85))	('103Pd', 'Chemical', 'MESH:C000615531', (31, 36))	('103Pd', 'Var', (31, 36))
31970	25431638	Similarly, the use of 103Pd reduced the radiation dose to the opposite retina by 41.5 % (p < 0.001) and 43.1 % (p < 0.001) for anterior and posterior melanomas, respectively.	('103Pd', 'Var', (22, 27))	('reduced', 'NegReg', (28, 35))	('melanomas', 'Disease', (150, 159))	('melanomas', 'Phenotype', 'HP:0002861', (150, 159))	('radiation dose', 'MPA', (40, 54))	('melanomas', 'Disease', 'MESH:D008545', (150, 159))	('103Pd', 'Chemical', 'MESH:C000615531', (22, 27))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))
31974	25431638	These differences were found to affect the relative dose distributions for 103Pd versus 125I plaques.	('103Pd', 'Var', (75, 80))	('103Pd', 'Chemical', 'MESH:C000615531', (75, 80))	('affect', 'Reg', (32, 38))
31975	25431638	Specifically, in treatment of anterior tumors, 103Pd offered relative dose reductions of a mean 4.7 % (p = 0.285) to the relatively close lens.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('103Pd', 'Var', (47, 52))	('dose', 'MPA', (70, 74))	('reductions', 'NegReg', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('anterior tumors', 'Disease', (30, 45))	('103Pd', 'Chemical', 'MESH:C000615531', (47, 52))	('anterior tumors', 'Disease', 'MESH:C537775', (30, 45))
31976	25431638	However, in treatment of posteriorly located melanomas, the use of 103Pd reduced the lens dose by 23.0 % (p < 0.001).	('103Pd', 'Var', (67, 72))	('reduced', 'NegReg', (73, 80))	('melanomas', 'Disease', (45, 54))	('lens dose', 'MPA', (85, 94))	('103Pd', 'Chemical', 'MESH:C000615531', (67, 72))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanomas', 'Disease', 'MESH:D008545', (45, 54))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))
31979	25431638	This analysis revealed that 103Pd typically reduced the mean dose to the lens, fovea, and optic disc.	('103Pd', 'Chemical', 'MESH:C000615531', (28, 33))	('reduced', 'NegReg', (44, 51))	('103Pd', 'Var', (28, 33))
31982	25431638	For example, axial dosimetry for T1-staged tumors (n = 146) and T4-staged tumors (n = 7) revealed that 103Pd was associated with a mean increase in dose to the inner sclera of 4.5 % (p = 0.066) versus 32.2 % (p = 0.208), respectively.	('103Pd', 'Chemical', 'MESH:C000615531', (103, 108))	('dose', 'MPA', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('103Pd', 'Var', (103, 108))	('increase', 'PosReg', (136, 144))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
31983	25431638	This shows that while all tumors received a higher mean scleral dose using 103Pd, the dose difference increased with tumor size.	('103Pd', 'Var', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('higher', 'PosReg', (44, 50))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('scleral dose', 'MPA', (56, 68))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('103Pd', 'Chemical', 'MESH:C000615531', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumors', 'Disease', (26, 32))
31984	25431638	Similarly, the radiation dose to a 5-mm axial depth demonstrated a decrease of 6.6 % with 103Pd for the relatively short T1 tumors and an increase of 24.2 % for T4 tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('decrease', 'NegReg', (67, 75))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Disease', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('103Pd', 'Chemical', 'MESH:C000615531', (90, 95))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('103Pd', 'Var', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
31989	25431638	However, all the important anatomical ocular structures (lens center, optic disc, and fovea) demonstrated mean dose reduction with 103Pd versus 125I for T1 to T3 tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('103Pd', 'Chemical', 'MESH:C000615531', (131, 136))	('125I', 'Var', (144, 148))	('reduction', 'NegReg', (116, 125))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('T1 to T3', 'Disease', (153, 161))	('103Pd', 'Var', (131, 136))
31990	25431638	Here, comparative dosimetry revealed that the use of 103Pd decreased the mean dose to the opposite eye wall, while 103Pd increased the mean dose to the lens, optic disc, and fovea in T4-staged uveal melanomas (Fig.	('103Pd', 'Var', (53, 58))	('decreased', 'NegReg', (59, 68))	('uveal melanomas', 'Disease', 'MESH:C536494', (193, 208))	('increased', 'PosReg', (121, 130))	('103Pd', 'Chemical', 'MESH:C000615531', (115, 120))	('103Pd', 'Chemical', 'MESH:C000615531', (53, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (193, 207))	('dose', 'MPA', (78, 82))	('103Pd', 'Var', (115, 120))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('melanomas', 'Phenotype', 'HP:0002861', (199, 208))	('uveal melanomas', 'Disease', (193, 208))	('uveal melanomas', 'Phenotype', 'HP:0007716', (193, 208))
31991	25431638	Detailed subset analysis demonstrated that the use of 103Pd would increase the dose (for T4-staged tumors) to the lens and fovea in three eyes (n = 3/7, 43 %) and to the optic disc in two eyes (n = 2/7, 29 %).	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('increase', 'PosReg', (66, 74))	('dose', 'MPA', (79, 83))	('103Pd', 'Var', (54, 59))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('use', 'Var', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('103Pd', 'Chemical', 'MESH:C000615531', (54, 59))	('tumors', 'Disease', (99, 105))
31992	25431638	No eye with a tumor in the T4 subset exhibited a relative increase to all three ocular structures (optic disc, fovea, and lens) using 103Pd.	('increase', 'PosReg', (58, 66))	('tumor', 'Disease', (14, 19))	('103Pd', 'Var', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('103Pd', 'Chemical', 'MESH:C000615531', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
31998	25431638	Overall, three patients received lower optic disc dose due to the use of 125I and all four patients received lower fovea dose with 125I.	('patients', 'Species', '9606', (15, 23))	('lower', 'NegReg', (109, 114))	('patients', 'Species', '9606', (91, 99))	('lower fovea', 'Phenotype', 'HP:0007750', (109, 120))	('125I', 'Var', (73, 77))	('optic disc dose', 'MPA', (39, 54))	('lower', 'NegReg', (33, 38))
32001	25431638	Evaluations along the central axis of the plaque revealed that the scleral dose was higher utilizing 103Pd.	('scleral dose', 'MPA', (67, 79))	('103Pd', 'Chemical', 'MESH:C000615531', (101, 106))	('103Pd', 'Var', (101, 106))	('higher', 'PosReg', (84, 90))
32002	25431638	Therefore, with an equivalent planned apex prescription, the use of 103Pd increased the mean tumor dose.	('103Pd', 'Chemical', 'MESH:C000615531', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('103Pd', 'Var', (68, 73))	('apex', 'cellular_component', 'GO:0097683', ('38', '42'))	('tumor', 'Disease', (93, 98))	('increased', 'PosReg', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
32003	25431638	Here, the use of 103Pd was associated with an overall reduction of 41.9 % (p < 0.001).	('reduction', 'NegReg', (54, 63))	('103Pd', 'Chemical', 'MESH:C000615531', (17, 22))	('103Pd', 'Var', (17, 22))
32007	25431638	Conversely, the mean percent decrease in dose to the opposite retina provided by 103Pd relative to 125I trended to diminish as the tumors get larger, T1 45.92 % (p < 0.001), T2 47.1 % (p < 0.001), T3 30.0 % (p < 0.001), and T4 29.9 % (p = 0.208).	('103Pd', 'Var', (81, 86))	('diminish', 'NegReg', (115, 123))	('125I', 'Var', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('103Pd', 'Chemical', 'MESH:C000615531', (81, 86))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('dose', 'MPA', (41, 45))	('decrease', 'NegReg', (29, 37))
32017	25431638	Our study revealed that when comparing 125I versus 103Pd plaque therapy for uveal melanoma, both tumor size and location affected the relative dose to critical normal intraocular structures.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (76, 90))	('uveal melanoma', 'Disease', 'MESH:C536494', (76, 90))	('125I', 'Var', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('uveal melanoma', 'Disease', (76, 90))	('103Pd', 'Chemical', 'MESH:C000615531', (51, 56))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('tumor', 'Disease', (97, 102))	('affected', 'Reg', (121, 129))	('relative dose', 'MPA', (134, 147))
32018	25431638	In 319 patients, the use of 103Pd resulted in a trend toward increased dose within the tumor target volume and decreased dose to most normal ocular structures.	('dose', 'MPA', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('103Pd', 'Chemical', 'MESH:C000615531', (28, 33))	('decreased', 'NegReg', (111, 120))	('tumor', 'Disease', (87, 92))	('103Pd', 'Var', (28, 33))	('dose', 'MPA', (71, 75))	('increased', 'PosReg', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('patients', 'Species', '9606', (7, 15))
32049	24737949	Importantly, ipilimumab has improved survival by 10% at 2 and 3 years when compared with other therapies.	('ipilimumab', 'Chemical', 'MESH:D000074324', (13, 23))	('survival', 'MPA', (37, 45))	('ipilimumab', 'Var', (13, 23))	('improved', 'PosReg', (28, 36))
32056	24737949	The discovery of v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations by the Sanger Institute has been the defining moment in melanoma molecular biology to date.	('mutations', 'Var', (70, 79))	('BRAF', 'Gene', (64, 68))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', '673', (17, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', (17, 62))
32058	24737949	BRAF is highly expressed in testis, hematopoietic stems cells, neuronal tissue and melanocytes with mutations identified most frequently in papillary thyroid cancer, colorectal cancer and melanoma (BRAF mutations have also been discovered in a multitude of other cancers, but at a much lower rates).	('mutations', 'Var', (100, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (166, 183))	('cancers', 'Disease', 'MESH:D009369', (263, 270))	('cancers', 'Phenotype', 'HP:0002664', (263, 270))	('papillary thyroid cancer', 'Disease', (140, 164))	('colorectal cancer', 'Phenotype', 'HP:0003003', (166, 183))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (140, 164))	('cancers', 'Disease', (263, 270))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (140, 164))	('melanoma', 'Disease', 'MESH:D008545', (188, 196))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('melanoma', 'Disease', (188, 196))	('colorectal cancer', 'Disease', (166, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('thyroid cancer', 'Phenotype', 'HP:0002890', (150, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
32059	24737949	Approximately, 50% of cutaneous melanomas harbor a BRAF mutation, 97% of which are a result of a substitution of valine for glutamate at the 600 position of the amino acid sequence, the so-called V600E mutation.	('valine', 'Protein', (113, 119))	('substitution', 'Var', (97, 109))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (22, 40))	('V600E', 'Var', (196, 201))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanomas', 'Phenotype', 'HP:0002861', (32, 41))	('glutamate', 'Protein', (124, 133))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (22, 41))	('V600E', 'Mutation', 'rs113488022', (196, 201))	('result of', 'Reg', (85, 94))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (22, 41))	('mutation', 'Var', (56, 64))	('BRAF', 'Gene', (51, 55))	('valine for glutamate at the 600', 'Mutation', 'rs113488022', (113, 144))	('cutaneous melanomas', 'Disease', (22, 41))
32061	24737949	Development of specific and highly potent BRAF mutant inhibitors such as vemurafenib resulted in responses of approximately 80% in a Phase I/II trial.	('BRAF', 'Gene', (42, 46))	('mutant', 'Var', (47, 53))	('vemurafenib', 'Chemical', 'MESH:D000077484', (73, 84))
32064	24737949	Dabrafenib is another orally administered potent inhibitor of mutant BRAF and showed promising results in the early Phase I/II trials, with a RR of 69% and a dose of 150 mg twice daily was established.	('mutant', 'Var', (62, 68))	('abl', 'Gene', (192, 195))	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('BRAF', 'Gene', (69, 73))	('abl', 'Gene', '25', (192, 195))
32069	24737949	Resistance has been documented to occur via a number of MAPK dependent pathways (e.g., mitogen-activated/extracellular signal - regulated protein kinase, MEK mutations; NRAS up-regulation) and non-MAPK dependent pathways (e.g.	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('NRAS', 'Gene', (169, 173))	('MAPK', 'molecular_function', 'GO:0004707', ('56', '60'))	('NRAS', 'Gene', '4893', (169, 173))	('extracellular', 'cellular_component', 'GO:0005576', ('105', '118'))	('non-MAPK dependent pathways', 'Pathway', (193, 220))	('MAPK', 'molecular_function', 'GO:0004707', ('197', '201'))	('regulation', 'biological_process', 'GO:0065007', ('177', '187'))	('mutations', 'Var', (158, 167))	('MEK', 'Gene', (154, 157))	('MEK', 'Gene', '5609', (154, 157))
32079	24737949	Although this was a population unselected for mutations in BRAF/NRAS, five of the six partial responders to selumetinib were BRAF mutant suggesting its utility as a biomarker for further study.	('mutations', 'Var', (46, 55))	('selumetinib', 'Chemical', 'MESH:C517975', (108, 119))	('NRAS', 'Gene', (64, 68))	('NRAS', 'Gene', '4893', (64, 68))	('mutant', 'Var', (130, 136))
32081	24737949	Phase I and II trial data demonstrated its activity in BRAF inhibitor-naive BRAF mutant melanoma.	('BRAF', 'Gene', (76, 80))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('activity', 'MPA', (43, 51))	('mutant', 'Var', (81, 87))
32085	24737949	METRIC was a Phase III randomized, controlled clinical trial of trametinib 2 mg once daily as compared to chemotherapy (dacarbazine or paclitaxel, investigator preference) in treatment-naive advanced melanoma patients who were BRAF V600E or K mutant.	('BRAF V600E', 'Var', (227, 237))	('paclitaxel', 'Chemical', 'MESH:D017239', (135, 145))	('V600E', 'Mutation', 'rs113488022', (232, 237))	('melanoma', 'Disease', 'MESH:D008545', (200, 208))	('trametinib', 'Chemical', 'MESH:C560077', (64, 74))	('melanoma', 'Disease', (200, 208))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('dacarbazine', 'Chemical', 'MESH:D003606', (120, 131))	('K mutant', 'Var', (241, 249))	('patients', 'Species', '9606', (209, 217))
32097	24737949	In addition, another benefit of MEK and BRAF combination therapy is the potential for reduced rates of SCC development, which has been associated with MAPK activation.	('reduced', 'NegReg', (86, 93))	('MAPK activation', 'biological_process', 'GO:0000187', ('151', '166'))	('combination', 'Var', (45, 56))	('SCC', 'Gene', (103, 106))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('SCC', 'Gene', '6317', (103, 106))	('MAPK', 'molecular_function', 'GO:0004707', ('151', '155'))	('MEK', 'Gene', (32, 35))	('MEK', 'Gene', '5609', (32, 35))
32098	24737949	To explore these hypotheses, a Phase I/II open label trial of dabrafenib and trametinib in advanced melanoma patients with BRAFV600E/K mutations was conducted in three parts.	('BRAFV600E', 'Mutation', 'rs113488022', (123, 132))	('trametinib', 'Chemical', 'MESH:C560077', (77, 87))	('patients', 'Species', '9606', (109, 117))	('BRAFV600E/K mutations', 'Var', (123, 144))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('dabrafenib', 'Chemical', 'MESH:C561627', (62, 72))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))
32105	24737949	Deregulation of AKT3 has been shown to promote melanomagenesis and may occur in up to 60% of melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('melanomagenesis', 'Disease', (47, 62))	('promote', 'PosReg', (39, 46))	('Deregulation', 'Var', (0, 12))	('melanomas', 'Disease', 'MESH:D008545', (93, 102))	('melanomagenesis', 'Disease', 'None', (47, 62))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanomas', 'Disease', (93, 102))	('AKT3', 'Gene', (16, 20))	('AKT3', 'Gene', '10000', (16, 20))
32110	24737949	Recently, combined inhibition of MEK and the PI3K-AKT-mTOR pathways was shown to be required for complete inhibition of NRAS mutant melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('AKT', 'Gene', '207', (50, 53))	('mutant', 'Var', (125, 131))	('melanomas', 'Phenotype', 'HP:0002861', (132, 141))	('PI3K', 'molecular_function', 'GO:0016303', ('45', '49'))	('melanomas', 'Disease', 'MESH:D008545', (132, 141))	('NRAS', 'Gene', (120, 124))	('mTOR', 'Gene', '2475', (54, 58))	('AKT', 'Gene', (50, 53))	('mTOR', 'Gene', (54, 58))	('NRAS', 'Gene', '4893', (120, 124))	('MEK', 'Gene', (33, 36))	('melanomas', 'Disease', (132, 141))	('MEK', 'Gene', '5609', (33, 36))
32114	24737949	Combining BRAF/MEK inhibitors with the PI3K/mTOR inhibitor, GSK2126458, decreased cell growth in vitro among cell lines resistant to BRAF inhibition.	('PI3K', 'molecular_function', 'GO:0016303', ('39', '43'))	('cell growth in vitro', 'CPA', (82, 102))	('decreased', 'NegReg', (72, 81))	('inhibitors', 'Var', (19, 29))	('cell growth', 'biological_process', 'GO:0016049', ('82', '93'))	('mTOR', 'Gene', (44, 48))	('mTOR', 'Gene', '2475', (44, 48))	('GSK', 'molecular_function', 'GO:0050321', ('60', '63'))	('GSK2126458', 'Chemical', 'MESH:C561454', (60, 70))	('MEK', 'Gene', (15, 18))	('MEK', 'Gene', '5609', (15, 18))
32119	24737949	Perifosine, an alkylphosphocholine analog, has been shown to decrease levels of AKT.	('Perifosine', 'Chemical', 'MESH:C105905', (0, 10))	('decrease', 'NegReg', (61, 69))	('AKT', 'Gene', '207', (80, 83))	('AKT', 'Gene', (80, 83))	('Perifosine', 'Var', (0, 10))	('alkylphosphocholine', 'Chemical', '-', (15, 34))
32158	24737949	Mutations in c-kit, resulting in constitutive activation of the pathway, are common in gastrointestinal stromal tumors (GIST).	('c-kit', 'Gene', '3815', (13, 18))	('c-kit', 'Gene', (13, 18))	('gastrointestinal stromal tumors', 'Disease', (87, 118))	('GIST', 'Phenotype', 'HP:0100723', (120, 124))	('activation', 'PosReg', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('common', 'Reg', (77, 83))	('Mutations', 'Var', (0, 9))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (87, 118))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (87, 118))	('GIST', 'Disease', 'MESH:D046152', (120, 124))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('GIST', 'Disease', (120, 124))
32159	24737949	In the unselected melanoma population, c-kit mutations occur at a low rate.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('mutations', 'Var', (45, 54))	('c-kit', 'Gene', '3815', (39, 44))	('c-kit', 'Gene', (39, 44))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))
32160	24737949	However, in selected melanoma patients with chronic sun damaged skin, acral lentiginous or mucosal melanoma sub-types, mutations or amplification of c-kit have been described in up 25% of cases.	('melanoma', 'Disease', 'MESH:D008545', (21, 29))	('sun damaged', 'Phenotype', 'HP:0000992', (52, 63))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('acral lentiginous or mucosal melanoma', 'Disease', 'MESH:D007911', (70, 107))	('amplification', 'Var', (132, 145))	('acral lentiginous or mucosal melanoma', 'Disease', (70, 107))	('patients', 'Species', '9606', (30, 38))	('sun damaged skin', 'Phenotype', 'HP:0000992', (52, 68))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('c-kit', 'Gene', '3815', (149, 154))	('melanoma', 'Disease', (21, 29))	('c-kit', 'Gene', (149, 154))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('mutations', 'Var', (119, 128))	('described', 'Reg', (165, 174))
32164	24737949	Subsequent case reports noted major responses in melanoma patients with KIT mutated melanoma.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('KIT', 'molecular_function', 'GO:0005020', ('72', '75'))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('KIT mutated', 'Var', (72, 83))	('melanoma', 'Disease', (84, 92))	('patients', 'Species', '9606', (58, 66))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
32165	24737949	Two Phase II trials utilizing imatinib in melanoma patients with c-kit aberrations have been completed.	('melanoma', 'Disease', (42, 50))	('c-kit', 'Gene', '3815', (65, 70))	('c-kit', 'Gene', (65, 70))	('aberrations', 'Var', (71, 82))	('patients', 'Species', '9606', (51, 59))	('imatinib', 'Chemical', 'MESH:D000068877', (30, 38))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
32166	24737949	conducted a single group, open-label, Phase II trial in patients with metastatic melanoma arising from mucosal, acral or chronic sun damaged and c-kit mutations or amplification.	('patients', 'Species', '9606', (56, 64))	('sun damaged', 'Phenotype', 'HP:0000992', (129, 140))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('c-kit', 'Gene', '3815', (145, 150))	('c-kit', 'Gene', (145, 150))	('melanoma', 'Disease', (81, 89))	('amplification', 'Var', (164, 177))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('mutations', 'Var', (151, 160))
32168	24737949	also conducted a Phase II open label single arm trial of imatinib in metastatic melanoma patients with c-kit mutations or amplification.	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('c-kit', 'Gene', (103, 108))	('c-kit', 'Gene', '3815', (103, 108))	('amplification', 'Var', (122, 135))	('imatinib', 'Chemical', 'MESH:D000068877', (57, 65))	('patients', 'Species', '9606', (89, 97))	('mutations', 'Var', (109, 118))
32170	24737949	9 of the 10 responses had c-kit mutations in exons 11 or 13.	('c-kit', 'Gene', '3815', (26, 31))	('c-kit', 'Gene', (26, 31))	('mutations in', 'Var', (32, 44))
32171	24737949	Other oral TKI's with KIT inhibitor activity-dasatinib, nilotinib, sorafenib and sunitinib, have also been reported to induce responses in melanoma patient with KIT mutations.	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('dasatinib', 'Chemical', 'MESH:D000069439', (45, 54))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('KIT', 'molecular_function', 'GO:0005020', ('161', '164'))	('nilotinib', 'Chemical', 'MESH:C498826', (56, 65))	('sorafenib', 'Chemical', 'MESH:D000077157', (67, 76))	('KIT', 'molecular_function', 'GO:0005020', ('22', '25'))	('mutations', 'Var', (165, 174))	('patient', 'Species', '9606', (148, 155))	('sunitinib', 'Chemical', 'MESH:D000077210', (81, 90))	('KIT', 'Gene', (161, 164))	('responses', 'MPA', (126, 135))
32172	24737949	Ongoing clinical trials utilizing drugs targeting c-kit mutations in melanoma will continue to define their role in this disease.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('mutations', 'Var', (56, 65))	('melanoma', 'Disease', (69, 77))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('c-kit', 'Gene', '3815', (50, 55))	('c-kit', 'Gene', (50, 55))
32179	24737949	Due to this, blockade of the PD-1 pathway has been postulated to cause fewer side effects when compared to CTLA-4 blockade.	('blockade', 'Var', (13, 21))	('PD-1', 'Gene', '5133', (29, 33))	('PD-1', 'Gene', (29, 33))
32195	24737949	Mutations in NRAS, which modulates survival and proliferation of melanoma, are present in 15-20% of cutaneous melanomas and are virtually mutually exclusive with BRAF (<1%).	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('melanoma', 'Disease', (110, 118))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (100, 119))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (100, 119))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (100, 118))	('cutaneous melanomas', 'Disease', (100, 119))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('NRAS', 'Gene', '4893', (13, 17))	('melanoma', 'Disease', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
32196	24737949	To date, no drugs have been developed which inhibit mutant NRAS.	('NRAS', 'Gene', '4893', (59, 63))	('NRAS', 'Gene', (59, 63))	('mutant', 'Var', (52, 58))
32197	24737949	MEK inhibition alone was shown to be effective in NRAS mutant melanoma cells lines.	('melanoma', 'Disease', (62, 70))	('MEK', 'Gene', (0, 3))	('NRAS', 'Gene', (50, 54))	('MEK', 'Gene', '5609', (0, 3))	('mutant', 'Var', (55, 61))	('NRAS', 'Gene', '4893', (50, 54))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
32198	24737949	The MEK inhibitors selumetinib and trametinib failed to show activity in NRAS mutant melanoma.	('NRAS', 'Gene', '4893', (73, 77))	('MEK', 'Gene', (4, 7))	('MEK', 'Gene', '5609', (4, 7))	('selumetinib', 'Chemical', 'MESH:C517975', (19, 30))	('trametinib', 'Chemical', 'MESH:C560077', (35, 45))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('mutant', 'Var', (78, 84))	('NRAS', 'Gene', (73, 77))
32201	24737949	Pre-clinically, in vitro and in vivo, combined inhibition of MEK and PI3K/mTOR has been shown to more effectively inhibit NRAS mutant melanoma.	('mutant', 'Var', (127, 133))	('MEK', 'Gene', (61, 64))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('MEK', 'Gene', '5609', (61, 64))	('inhibit', 'NegReg', (114, 121))	('PI3K', 'molecular_function', 'GO:0016303', ('69', '73'))	('inhibition', 'NegReg', (47, 57))	('mTOR', 'Gene', (74, 78))	('mTOR', 'Gene', '2475', (74, 78))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('NRAS', 'Gene', (122, 126))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('NRAS', 'Gene', '4893', (122, 126))
32202	24737949	Immunotherapy also appears to be promising in this patient cohort as mutant NRAS was shown to be predictive of response to HD IL-2 in one retrospective review combining data from 2 high-volume treatment centers.	('IL-2', 'Gene', '3558', (126, 130))	('NRAS', 'Gene', (76, 80))	('IL-2', 'Gene', (126, 130))	('mutant', 'Var', (69, 75))	('NRAS', 'Gene', '4893', (76, 80))	('patient', 'Species', '9606', (51, 58))	('HD', 'Disease', 'MESH:D006816', (123, 125))	('IL-2', 'molecular_function', 'GO:0005134', ('126', '130'))
32203	24737949	GNAQ or GNA11 mutations, present in 83% of uveal melanomas cause activation of the MAPK pathway.	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('uveal melanomas', 'Disease', (43, 58))	('MAPK pathway', 'Pathway', (83, 95))	('GNA11', 'Gene', (8, 13))	('GNAQ', 'Gene', '2776', (0, 4))	('uveal melanomas', 'Phenotype', 'HP:0007716', (43, 58))	('activation', 'PosReg', (65, 75))	('GNA11', 'Gene', '2767', (8, 13))	('uveal melanomas', 'Disease', 'MESH:C536494', (43, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('GNAQ', 'Gene', (0, 4))	('MAPK', 'molecular_function', 'GO:0004707', ('83', '87'))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('mutations', 'Var', (14, 23))
32207	24737949	Ongoing work is aiming to improve treatment options for patients with metastatic uveal melanoma and GNAQ/GNA11 mutations as chemotherapy and immunotherapy trials have largely been unsuccessful in this disease.	('mutations', 'Var', (111, 120))	('patients', 'Species', '9606', (56, 64))	('GNAQ', 'Gene', '2776', (100, 104))	('GNA11', 'Gene', (105, 110))	('uveal melanoma', 'Disease', 'MESH:C536494', (81, 95))	('GNA11', 'Gene', '2767', (105, 110))	('GNAQ', 'Gene', (100, 104))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('uveal melanoma', 'Disease', (81, 95))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
32213	24737949	All patients with unresectable or advanced melanoma must routinely have their tumor tissue tested for BRAFV600 mutations as initial stratification.	('mutations', 'Var', (111, 120))	('abl', 'Gene', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', (78, 83))	('abl', 'Gene', '25', (26, 29))	('BRAFV600', 'Gene', (102, 110))
32230	23935884	High expression of HMGA1 was also independently associated with an increased risk of distant metastases as determined using the Cox proportional hazards regression model (multivariate hazard ratio: 3.44; 95% confidence interval: 1.56-7.60; log rank P = 0.0022).	('High expression', 'Var', (0, 15))	('metastases', 'Disease', (93, 103))	('associated', 'Reg', (48, 58))	('Cox', 'Gene', '1351', (128, 131))	('metastases', 'Disease', 'MESH:D009362', (93, 103))	('Cox', 'Gene', (128, 131))	('HMGA1', 'Gene', (19, 24))
32231	23935884	These findings suggest that high levels of HMGA1 are associated with adverse clinical outcomes in UM patients and that further evaluation of HMGA1 as a potential therapeutic target in UM is warranted.	('patients', 'Species', '9606', (101, 109))	('UM', 'Phenotype', 'HP:0007716', (184, 186))	('HMGA1', 'Protein', (43, 48))	('high levels', 'Var', (28, 39))	('associated', 'Reg', (53, 63))	('UM', 'Phenotype', 'HP:0007716', (98, 100))
32240	23935884	Regarding genetic evaluation, chromosome 3 monosomy, mutations of GNAQ or GNA11 and breast cancer 1-associated protein (BAP1) have all been found to impart poor prognosis.	('GNA11', 'Gene', (74, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('chromosome', 'cellular_component', 'GO:0005694', ('30', '40'))	('GNA11', 'Gene', '2767', (74, 79))	('GNAQ', 'Gene', '2776', (66, 70))	('mutations', 'Var', (53, 62))	('chromosome', 'Var', (30, 40))	('BAP1', 'Gene', '8314', (120, 124))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('GNAQ', 'Gene', (66, 70))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('breast cancer', 'Disease', (84, 97))	('BAP1', 'Gene', (120, 124))
32266	23935884	The Ki67 labeling index (LI) was determined by counting the number of positive cells in a total of 800-1000 tumor cells observed in regions of highest staining (hot spot) at several HPF (x400).	('x400', 'Var', (187, 191))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))
32280	23935884	During the clinically disease-free survival period, high expression of HMGA1 was significantly correlated with increased risk of distant metastases using the log-rank test analysis (log rank P = 0.0012; Figure 3A).	('HMGA1', 'Gene', (71, 76))	('high expression', 'Var', (52, 67))	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('metastases', 'Disease', (137, 147))
32281	23935884	By univariate Cox regression, presence of epithelioid cell pattern (hazard ratio (HR), 3.02; 95% CI, 1.26-7.29; P = 0.013), high level of mitoses count (HR, 5.02; 95% CI, 2.31-9.31; P = 0.0012), high Ki67 LI (HR, 3.35; 95% CI, 1.51-6.48; P = 0.0034), and high level of HMGA1 expression (HR, 3.41; 95% CI, 1.55-7.50; P = 0.0023), were significantly associated with an increased risk of distant metastases (Table 2).	('metastases', 'Disease', (393, 403))	('high level', 'Var', (255, 265))	('metastases', 'Disease', 'MESH:D009362', (393, 403))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('associated', 'Reg', (348, 358))	('HMGA1', 'Gene', (269, 274))
32282	23935884	By multivariate Cox regression (Table 2), both high mitoses count and high level of HMGA1 expression were significant prognostic predictors of distant metastases (multivariate HR, 4.17; 95% CI, 1.86-8.28; P = 0.005; multivariate HR, 3.44; 95% CI, 1.56-7.60; P = 0.0022; respectively).	('metastases', 'Disease', 'MESH:D009362', (151, 161))	('high', 'Var', (47, 51))	('expression', 'MPA', (90, 100))	('Cox', 'Gene', '1351', (16, 19))	('Cox', 'Gene', (16, 19))	('metastases', 'Disease', (151, 161))	('HMGA1', 'Gene', (84, 89))
32283	23935884	By univariate Cox regression, presence of epithelioid cell pattern (HR, 3.26; 95% CI, 1.27-7.32; P = 0.014), high level of mitoses count (HR, 5.12; 95% CI, 3.39-10.02; P = 0.0014), high Ki67 LI (HR, 3.52; 95% CI, 1.56-7.81; P = 0.0025), and high level of HMGA1 expression (HR, 3.46; 95% CI, 1.67-8.16; P = 0.0013), were significantly associated with an increased risk of disease-specific mortality (Table 2).	('associated', 'Reg', (334, 344))	('expression', 'MPA', (261, 271))	('Cox', 'Gene', (14, 17))	('Cox', 'Gene', '1351', (14, 17))	('disease-specific', 'Disease', (371, 387))	('HMGA1', 'Gene', (255, 260))	('high level', 'Var', (241, 251))
32284	23935884	By multivariate Cox regression (Table 2), both high mitoses count and high level of HMGA1 expression were significant prognostic predictors of worse outcome (multivariate HR, 4.15; 95% CI, 2.91-8.37; P = 0.006; multivariate HR, 2.41; 95% CI, 1.10-5.53; P = 0.041; respectively).	('high', 'Var', (47, 51))	('expression', 'MPA', (90, 100))	('Cox', 'Gene', '1351', (16, 19))	('Cox', 'Gene', (16, 19))	('HMGA1', 'Gene', (84, 89))
32286	23935884	Genomic changes, including monosomy 3, BAP1 and somatic mutations in GNA11, are associated with metastic UM.	('monosomy 3', 'Var', (27, 37))	('associated', 'Reg', (80, 90))	('BAP1', 'Gene', '8314', (39, 43))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('GNA11', 'Gene', (69, 74))	('metastic UM', 'Disease', (96, 107))	('GNA11', 'Gene', '2767', (69, 74))	('BAP1', 'Gene', (39, 43))
32295	23935884	Adjusted for the largest basal tumor diameter, tumor thickness and epithelioid cell pattern, high level expression of HMGA1 was found to be associated independently with an increased risk of distant metastasis, and with shorter UM specific survival.	('HMGA1', 'Gene', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('associated', 'Reg', (140, 150))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('basal tumor', 'Phenotype', 'HP:0002671', (25, 36))	('high level', 'Var', (93, 103))	('shorter', 'NegReg', (220, 227))	('basal tumor', 'Disease', (25, 36))	('distant metastasis', 'CPA', (191, 209))	('tumor', 'Disease', (31, 36))	('basal tumor', 'Disease', 'MESH:D002280', (25, 36))	('UM', 'Phenotype', 'HP:0007716', (228, 230))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('UM specific survival', 'CPA', (228, 248))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
32302	23935884	In fact, in pancreatic adenocarcinoma, blocking HMGA protein synthesis reduced tumor cell proliferation and metastatic potential, brought about a reduction in the Ki67 LI and caused an increase in the level of apoptosis.	('metastatic potential', 'CPA', (108, 128))	('cell proliferation', 'biological_process', 'GO:0008283', ('85', '103'))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('apoptosis', 'biological_process', 'GO:0097194', ('210', '219'))	('apoptosis', 'biological_process', 'GO:0006915', ('210', '219'))	('apoptosis', 'MPA', (210, 219))	('reduction', 'NegReg', (146, 155))	('blocking', 'Var', (39, 47))	('reduced', 'NegReg', (71, 78))	('tumor', 'Disease', (79, 84))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (12, 37))	('protein synthesis', 'biological_process', 'GO:0006412', ('53', '70'))	('Ki67 LI', 'CPA', (163, 170))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('HMGA protein synthesis', 'Protein', (48, 70))	('increase', 'PosReg', (185, 193))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (12, 37))	('pancreatic adenocarcinoma', 'Disease', (12, 37))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
32304	23935884	In our previous study, we identified miRNAs that were dysregulated by HMGA1 in retinoblastoma, further supporting the notion that HMGA1 is not only a marker for aggressive UM but also actively involved in gene regulation in this tumor.	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('retinoblastoma', 'Phenotype', 'HP:0009919', (79, 93))	('dysregulated', 'Var', (54, 66))	('regulation', 'biological_process', 'GO:0065007', ('210', '220'))	('HMGA1', 'Gene', (70, 75))	('tumor', 'Disease', (229, 234))	('UM', 'Phenotype', 'HP:0007716', (172, 174))	('retinoblastoma', 'Disease', 'MESH:D012175', (79, 93))	('retinoblastoma', 'Disease', (79, 93))
32374	21707960	Genome-wide studies have also identified some of the same genes as being associated with nevi (MTAP) and pigmentation traits (MC1R, TYR), confirming the epidemiological inference that these constitutional factors are likely heritable contributors to melanoma risk.	('nevi', 'Phenotype', 'HP:0003764', (89, 93))	('MC1R', 'Gene', '4157', (126, 130))	('TYR', 'Chemical', 'MESH:D014443', (132, 135))	('MC1R', 'Gene', (126, 130))	('melanoma', 'Disease', 'MESH:D008545', (250, 258))	('associated', 'Reg', (73, 83))	('pigmentation', 'Disease', 'MESH:D010859', (105, 117))	('nevi', 'Disease', (89, 93))	('genes', 'Var', (58, 63))	('pigmentation', 'Disease', (105, 117))	('melanoma', 'Disease', (250, 258))	('MTAP', 'Gene', (95, 99))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('pigmentation', 'biological_process', 'GO:0043473', ('105', '117'))	('MTAP', 'Gene', '4507', (95, 99))
32402	21707960	The frequency of NRAS mutations is approximately 15% in most melanoma types, while HRAS or KRAS are infrequently mutated.	('HRAS', 'Gene', '3265', (83, 87))	('HRAS', 'Gene', (83, 87))	('NRAS', 'Gene', (17, 21))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('mutations', 'Var', (22, 31))	('NRAS', 'Gene', '4893', (17, 21))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('KRAS', 'Gene', (91, 95))	('KRAS', 'Gene', '3845', (91, 95))
32404	21707960	found that one of 68 melanomas analyzed had an HRAS mutation and none had any KRAS mutation, and found one HRAS mutation and no KRAS mutations in 126 primary melanomas of different types.	('KRAS', 'Gene', (128, 132))	('HRAS', 'Gene', '3265', (107, 111))	('melanomas', 'Disease', (158, 167))	('melanomas', 'Disease', 'MESH:D008545', (158, 167))	('KRAS', 'Gene', '3845', (128, 132))	('KRAS', 'Gene', (78, 82))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanomas', 'Disease', (21, 30))	('HRAS', 'Gene', (107, 111))	('HRAS', 'Gene', '3265', (47, 51))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('mutation', 'Var', (52, 60))	('melanomas', 'Phenotype', 'HP:0002861', (158, 167))	('KRAS', 'Gene', '3845', (78, 82))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('HRAS', 'Gene', (47, 51))
32406	21707960	Earlier studies by and found a higher frequency of NRAS mutations in melanomas on sun-exposed sites.	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('mutations', 'Var', (56, 65))	('melanomas', 'Disease', (69, 78))	('NRAS', 'Gene', (51, 55))	('melanomas', 'Disease', 'MESH:D008545', (69, 78))	('melanomas', 'Phenotype', 'HP:0002861', (69, 78))	('NRAS', 'Gene', '4893', (51, 55))
32407	21707960	In a subsequent larger study of 175 primary tumor samples, 63 metastases, and 32 cell lines, also found the highest incidence of mutant NRAS in tumors arising on body sites such as the face or head (22%), compared with the limbs (15%) or the trunk (11%).	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Disease', (144, 149))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('metastases', 'Disease', 'MESH:D009362', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('NRAS', 'Gene', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('trunk', 'cellular_component', 'GO:0043198', ('242', '247'))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('NRAS', 'Gene', '4893', (136, 140))	('tumor', 'Disease', (44, 49))	('metastases', 'Disease', (62, 72))	('mutant', 'Var', (129, 135))
32408	21707960	By contrast, other studies did not find a significant association of NRAS mutations with anatomical site of origin or degree of sun exposure of the primary as assessed by the degree of solar elastosis in the adjacent skin.	('NRAS', 'Gene', '4893', (69, 73))	('mutations', 'Var', (74, 83))	('solar elastosis', 'Disease', 'MESH:D005148', (185, 200))	('NRAS', 'Gene', (69, 73))	('solar elastosis', 'Disease', (185, 200))
32409	21707960	Similarly, some studies reported NRAS mutations associated with certain histopathological subtypes, while others found no such associations.	('mutations', 'Var', (38, 47))	('associated', 'Reg', (48, 58))	('NRAS', 'Gene', '4893', (33, 37))	('NRAS', 'Gene', (33, 37))
32413	21707960	Finally, NRAS mutations were initially reported to be associated with tumor thickness and level of invasion, but such associations have not been consistently observed throughout studies.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('NRAS', 'Gene', (9, 13))	('tumor', 'Disease', (70, 75))	('NRAS', 'Gene', '4893', (9, 13))	('mutations', 'Var', (14, 23))	('associated', 'Reg', (54, 64))
32414	21707960	Contrasting with the findings for NRAS, BRAF mutations, originally discovered in melanoma cell lines, have been reproducibly associated with specific clinical and histopathological characteristics of melanoma.	('BRAF', 'Gene', '673', (40, 44))	('mutations', 'Var', (45, 54))	('BRAF', 'Gene', (40, 44))	('melanoma', 'Disease', 'MESH:D008545', (200, 208))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('melanoma', 'Disease', (200, 208))	('associated', 'Reg', (125, 135))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('NRAS', 'Gene', (34, 38))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('NRAS', 'Gene', '4893', (34, 38))
32418	21707960	BRAF mutations are also commonly found in acquired melanocytic nevi, and as these nevi tend to arise in the first two decades of life, it is likely that BRAF-mutant melanomas and nevi may be part of the same spectrum of melanocytic neoplasia.	('melanocytic neoplasia', 'Disease', (220, 241))	('BRAF', 'Gene', (153, 157))	('nevi', 'Phenotype', 'HP:0003764', (63, 67))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (51, 67))	('melanomas', 'Disease', (165, 174))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('mutations', 'Var', (5, 14))	('melanocytic neoplasia', 'Disease', 'MESH:D009369', (220, 241))	('BRAF', 'Gene', '673', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (165, 174))	('acquired melanocytic nevi', 'Disease', (42, 67))	('nevi', 'Phenotype', 'HP:0003764', (82, 86))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Disease', 'MESH:D008545', (165, 174))	('neoplasia', 'Phenotype', 'HP:0002664', (232, 241))	('nevi', 'Phenotype', 'HP:0003764', (179, 183))	('BRAF', 'Gene', '673', (153, 157))
32420	21707960	This suggests that BRAF mutation is an early event that by itself is insufficient to cause melanoma.	('BRAF', 'Gene', '673', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('BRAF', 'Gene', (19, 23))	('melanoma', 'Disease', (91, 99))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('mutation', 'Var', (24, 32))
32422	21707960	The observation that the BRAF mutation frequency decreases in older individuals indicates a window of vulnerability to develop these mutations early in life, consistent with epidemiological findings discussed above.	('BRAF', 'Gene', (25, 29))	('BRAF', 'Gene', '673', (25, 29))	('mutation', 'Var', (30, 38))	('decreases', 'NegReg', (49, 58))
32423	21707960	A detailed morphologic analysis of primary melanomas revealed that a combination of phenotypic features of the RGP of a primary tumor had a higher predictive value for the presence of a BRAF mutation than the histologic subtype of melanoma or any of the other features listed above.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('BRAF', 'Gene', (186, 190))	('melanomas', 'Disease', (43, 52))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('melanoma', 'Disease', (231, 239))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanomas', 'Phenotype', 'HP:0002861', (43, 52))	('melanoma', 'Disease', (43, 51))	('BRAF', 'Gene', '673', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('melanomas', 'Disease', 'MESH:D008545', (43, 52))	('tumor', 'Disease', (128, 133))	('mutation', 'Var', (191, 199))
32425	21707960	In aggregate, the reproducible association with younger age, clinical and histopathological features, and pattern of metastasis strongly suggest that melanomas with BRAF mutation are part of a biological subtype of melanoma.	('melanomas', 'Disease', (150, 159))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('melanoma', 'Disease', (215, 223))	('melanoma', 'Disease', 'MESH:D008545', (215, 223))	('BRAF', 'Gene', '673', (165, 169))	('melanomas', 'Phenotype', 'HP:0002861', (150, 159))	('BRAF', 'Gene', (165, 169))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanomas', 'Disease', 'MESH:D008545', (150, 159))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('mutation', 'Var', (170, 178))
32427	21707960	The oncogenic alterations equivalent to BRAF or NRAS are not known in a substantial proportion of melanomas, and it is to be expected that there are other mutations or combinations thereof that are functionally equivalent to BRAF mutation and therefore result in (or are associated with) similar phenotypic alterations.	('BRAF', 'Gene', '673', (40, 44))	('melanomas', 'Disease', (98, 107))	('BRAF', 'Gene', (225, 229))	('NRAS', 'Gene', '4893', (48, 52))	('BRAF', 'Gene', '673', (225, 229))	('mutations', 'Var', (155, 164))	('BRAF', 'Gene', (40, 44))	('result in', 'Reg', (253, 262))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('mutation', 'Var', (230, 238))	('melanomas', 'Disease', 'MESH:D008545', (98, 107))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('NRAS', 'Gene', (48, 52))
32428	21707960	This was suggested in a recent study in which melanomas that were predicted to be BRAF mutant based on the three features listed above, but that did not have BRAF or NRAS mutations, and were also more similar in other features associated with BRAF mutations.	('NRAS', 'Gene', (166, 170))	('BRAF', 'Gene', '673', (243, 247))	('BRAF', 'Gene', '673', (82, 86))	('melanomas', 'Disease', 'MESH:D008545', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('BRAF', 'Gene', (243, 247))	('BRAF', 'Gene', (82, 86))	('BRAF', 'Gene', '673', (158, 162))	('NRAS', 'Gene', '4893', (166, 170))	('mutant', 'Var', (87, 93))	('melanomas', 'Disease', (46, 55))	('BRAF', 'Gene', (158, 162))
32429	21707960	It remains to be demonstrated whether these 'BRAF-like' melanomas have other genetic or biological similarities to melanomas with BRAF mutations.	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanomas', 'Disease', 'MESH:D008545', (115, 124))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('BRAF', 'Gene', '673', (130, 134))	('mutations', 'Var', (135, 144))	('BRAF', 'Gene', (130, 134))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('melanomas', 'Disease', (56, 65))	('melanomas', 'Disease', (115, 124))	('melanomas', 'Disease', 'MESH:D008545', (56, 65))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
32430	21707960	Mutations in KIT are found in melanomas arising on glabrous skin or the nail apparatus, the mucosa, or skin with cumulative sun-induced damage (CSD melanomas) and are relatively absent in melanomas on skin without chronic sun-induced damage.	('KIT', 'molecular_function', 'GO:0005020', ('13', '16'))	('melanomas', 'Disease', (30, 39))	('melanomas', 'Disease', 'MESH:D008545', (148, 157))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanomas', 'Disease', (188, 197))	('CSD melanomas', 'Disease', 'MESH:C562576', (144, 157))	('melanomas', 'Phenotype', 'HP:0002861', (30, 39))	('Mutations', 'Var', (0, 9))	('melanomas', 'Disease', (148, 157))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('melanomas', 'Disease', 'MESH:D008545', (30, 39))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanomas', 'Phenotype', 'HP:0002861', (148, 157))	('KIT', 'Gene', (13, 16))	('melanomas', 'Disease', 'MESH:D008545', (188, 197))	('melanomas', 'Phenotype', 'HP:0002861', (188, 197))	('CSD melanomas', 'Disease', (144, 157))
32431	21707960	In the melanoma types in which KIT mutations are found, BRAF mutations are relatively uncommon, and therefore, the two mutation spectra represent somewhat of a mirror image of each other.	('melanoma', 'Disease', 'MESH:D008545', (7, 15))	('KIT', 'Gene', (31, 34))	('BRAF', 'Gene', (56, 60))	('BRAF', 'Gene', '673', (56, 60))	('mutations', 'Var', (61, 70))	('KIT', 'molecular_function', 'GO:0005020', ('31', '34'))	('melanoma', 'Phenotype', 'HP:0002861', (7, 15))	('melanoma', 'Disease', (7, 15))	('mutations', 'Var', (35, 44))
32440	21707960	Acral and mucosal melanomas both have a distinctive type of genomic instability that results in numerous focused gene amplifications and deletions scattered throughout the genome.	('focused gene amplifications', 'MPA', (105, 132))	('deletions', 'Var', (137, 146))	('mucosal melanomas', 'Disease', (10, 27))	('results in', 'Reg', (85, 95))	('mucosal melanomas', 'Disease', 'MESH:D008545', (10, 27))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))
32445	21707960	Amplification of the genomic region harboring the catalytic subunit of telomerase has been observed in acral melanoma and has been shown to coincide with the development of the vertical growth phase in some cases.	('men', 'Species', '9606', (165, 168))	('Amplification', 'Var', (0, 13))	('observed', 'Reg', (91, 99))	('acral melanoma', 'Disease', 'MESH:D008545', (103, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('acral melanoma', 'Phenotype', 'HP:0012060', (103, 117))	('coincide', 'Reg', (140, 148))	('acral melanoma', 'Disease', (103, 117))
32447	21707960	Despite the relative paucity of BRAF mutations and the presence of KIT mutations that are shared between acral, mucosal, and CSD melanomas, the latter category is set apart by the absence of the numerous high-level amplifications that are found consistently in acral and mucosal melanomas.	('BRAF', 'Gene', '673', (32, 36))	('mucosal melanomas', 'Disease', 'MESH:D008545', (271, 288))	('KIT', 'molecular_function', 'GO:0005020', ('67', '70'))	('BRAF', 'Gene', (32, 36))	('KIT', 'Gene', (67, 70))	('mucosal melanomas', 'Disease', (271, 288))	('CSD melanomas', 'Disease', (125, 138))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanomas', 'Phenotype', 'HP:0002861', (129, 138))	('mutations', 'Var', (37, 46))	('mutations', 'Var', (71, 80))	('CSD melanomas', 'Disease', 'MESH:C562576', (125, 138))	('melanoma', 'Phenotype', 'HP:0002861', (279, 287))	('melanomas', 'Phenotype', 'HP:0002861', (279, 288))
32449	21707960	For example, amplifications in acral melanomas most frequently involved chromosome 11q13, centering on the cyclin D1 locus, as well as hTERT on chromosome 5p.	('acral melanomas', 'Phenotype', 'HP:0012060', (31, 46))	('cyclin D1', 'Gene', (107, 116))	('acral melanomas', 'Disease', (31, 46))	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('amplifications', 'Var', (13, 27))	('cyclin', 'molecular_function', 'GO:0016538', ('107', '113'))	('chromosome', 'cellular_component', 'GO:0005694', ('144', '154'))	('involved', 'Reg', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanomas', 'Phenotype', 'HP:0002861', (37, 46))	('acral melanomas', 'Disease', 'MESH:D008545', (31, 46))	('acral melanoma', 'Phenotype', 'HP:0012060', (31, 45))	('cyclin D1', 'Gene', '595', (107, 116))
32451	21707960	Recently, mutations in G-proteins of the Galphaq family of GTPases have been described in certain subsets of melanocytic neoplasia.	('melanocytic neoplasia', 'Disease', 'MESH:D009369', (109, 130))	('G-proteins', 'Protein', (23, 33))	('neoplasia', 'Phenotype', 'HP:0002664', (121, 130))	('GTP', 'Chemical', 'MESH:D006160', (59, 62))	('GTPases', 'Gene', (59, 66))	('melanocytic neoplasia', 'Disease', (109, 130))	('described', 'Reg', (77, 86))	('Galphaq', 'Protein', (41, 48))	('mutations', 'Var', (10, 19))
32452	21707960	A role for the two closely related Galphaq family members Gq and G11 (encoded by the genes GNAQ and GNA11, respectively) in melanocyte biology was suggested because hypermorphic mutations in both genes were found to result in skin darkening in a mutagenesis screen in mice.	('skin darkening', 'Phenotype', 'HP:0000953', (226, 240))	('mutagenesis', 'biological_process', 'GO:0006280', ('246', '257'))	('G11', 'Gene', (65, 68))	('mice', 'Species', '10090', (268, 272))	('result in', 'Reg', (216, 225))	('hypermorphic mutations', 'Var', (165, 187))	('skin darkening', 'CPA', (226, 240))	('G11', 'Gene', '14672', (65, 68))
32453	21707960	A subsequent study in benign and malignant melanocytic neoplasms identified recurrent mutations of GNAQ in blue nevi and uveal melanomas.	('mutations', 'Var', (86, 95))	('uveal melanoma', 'Phenotype', 'HP:0007716', (121, 135))	('malignant melanocytic neoplasms', 'Phenotype', 'HP:0002861', (33, 64))	('blue nevi', 'Phenotype', 'HP:0100814', (107, 116))	('neoplasm', 'Phenotype', 'HP:0002664', (55, 63))	('GNAQ', 'Gene', (99, 103))	('blue nevi', 'Disease', (107, 116))	('uveal melanomas', 'Disease', (121, 136))	('malignant melanocytic neoplasms', 'Disease', (33, 64))	('malignant melanocytic neoplasms', 'Disease', 'MESH:D009369', (33, 64))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('neoplasms', 'Phenotype', 'HP:0002664', (55, 64))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('nevi', 'Phenotype', 'HP:0003764', (112, 116))	('uveal melanomas', 'Phenotype', 'HP:0007716', (121, 136))	('uveal melanomas', 'Disease', 'MESH:C536494', (121, 136))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (43, 64))
32454	21707960	The mutations were different from the mutations initially found in the germline of mice, in that they exclusively affected codon 209 and by consequence effectively crippled the GTPase activity of GNAQ, leading to a GTP-bound, constitutively activated state.	('leading to', 'Reg', (202, 212))	('GTPase activity', 'molecular_function', 'GO:0003924', ('177', '192'))	('mice', 'Species', '10090', (83, 87))	('constitutively activated state', 'MPA', (226, 256))	('GTP', 'Chemical', 'MESH:D006160', (177, 180))	('codon 209', 'Var', (123, 132))	('GTPase', 'Enzyme', (177, 183))	('affected', 'Reg', (114, 122))	('GTP-bound', 'MPA', (215, 224))	('GTP', 'Chemical', 'MESH:D006160', (215, 218))	('mutations', 'Var', (4, 13))	('crippled', 'NegReg', (164, 172))
32455	21707960	Subsequent studies have confirmed that the mutations are likely to occur early in the progression of melanocytic neoplasia, as suggested by their presence in benign nevi and the fact that they are not associated with outcome.	('nevi', 'Phenotype', 'HP:0003764', (165, 169))	('melanocytic neoplasia', 'Disease', (101, 122))	('mutations', 'Var', (43, 52))	('melanocytic neoplasia', 'Disease', 'MESH:D009369', (101, 122))	('neoplasia', 'Phenotype', 'HP:0002664', (113, 122))
32456	21707960	GNAQ mutations have also been identified in melanocytomas of the central nervous system, benign melanocytic neoplasms closely resembling blue nevi.	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (96, 117))	('nevi', 'Phenotype', 'HP:0003764', (142, 146))	('neoplasm', 'Phenotype', 'HP:0002664', (108, 116))	('benign melanocytic neoplasms', 'Disease', 'MESH:D009369', (89, 117))	('benign melanocytic neoplasms', 'Disease', (89, 117))	('mutations', 'Var', (5, 14))	('GNAQ', 'Gene', (0, 4))	('blue nevi', 'Phenotype', 'HP:0100814', (137, 146))	('neoplasms', 'Phenotype', 'HP:0002664', (108, 117))	('identified', 'Reg', (30, 40))	('melanocytomas of the central nervous system', 'Disease', (44, 87))	('blue nevi', 'Disease', (137, 146))	('melanocytomas of the central nervous system', 'Disease', 'MESH:D002493', (44, 87))
32457	21707960	A more recent study has identified recurrent mutations of GNA11 in the same spectrum of melanocytic neoplasms in which GNAQ mutations are observed, albeit with different mutation frequencies.	('mutations', 'Var', (45, 54))	('neoplasm', 'Phenotype', 'HP:0002664', (100, 108))	('melanocytic neoplasms', 'Disease', (88, 109))	('neoplasms', 'Phenotype', 'HP:0002664', (100, 109))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (88, 109))	('GNA11', 'Gene', (58, 63))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (88, 109))
32458	21707960	While GNAQ mutations are common (approximately 80%) in blue nevi and less common in malignant tumors, GNA11 mutations are most common in uveal melanoma metastases, with a substantially lower mutation frequency in blue nevi (<10%), suggesting that it may have more powerful oncogenic effects than GNAQ.	('mutations', 'Var', (11, 20))	('malignant tumors', 'Disease', (84, 100))	('blue nevi', 'Phenotype', 'HP:0100814', (213, 222))	('mutations', 'Var', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('GNA11', 'Gene', (102, 107))	('malignant tumors', 'Disease', 'MESH:D018198', (84, 100))	('blue nevi', 'Phenotype', 'HP:0100814', (55, 64))	('nevi', 'Phenotype', 'HP:0003764', (218, 222))	('nevi', 'Phenotype', 'HP:0003764', (60, 64))	('blue nevi', 'Disease', (55, 64))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('uveal melanoma', 'Phenotype', 'HP:0007716', (137, 151))	('uveal melanoma metastases', 'Disease', (137, 162))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (137, 162))	('common', 'Reg', (127, 133))
32459	21707960	Strikingly, the mutations in GNAQ and GNA11 are restricted to blue nevi and uveal melanomas, with virtually no mutations in other benign or malignant melanocytic neoplasms harboring these mutations.	('uveal melanomas', 'Disease', 'MESH:C536494', (76, 91))	('GNAQ', 'Gene', (29, 33))	('uveal melanoma', 'Phenotype', 'HP:0007716', (76, 90))	('blue nevi', 'Phenotype', 'HP:0100814', (62, 71))	('mutations', 'Var', (16, 25))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('malignant melanocytic neoplasms', 'Phenotype', 'HP:0002861', (140, 171))	('blue nevi', 'Disease', (62, 71))	('uveal melanomas', 'Disease', (76, 91))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('nevi', 'Phenotype', 'HP:0003764', (67, 71))	('uveal melanomas', 'Phenotype', 'HP:0007716', (76, 91))	('neoplasm', 'Phenotype', 'HP:0002664', (162, 170))	('GNA11', 'Gene', (38, 43))	('neoplasms', 'Phenotype', 'HP:0002664', (162, 171))	('malignant melanocytic neoplasms', 'Disease', (140, 171))	('malignant melanocytic neoplasms', 'Disease', 'MESH:D009369', (140, 171))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (150, 171))
32460	21707960	To date, additional searches for GNAQ and GNA11 mutations have yet to yield other human neoplasms with recurrent mutations of these two Galphaq family members.	('GNAQ', 'Gene', (33, 37))	('neoplasms', 'Phenotype', 'HP:0002664', (88, 97))	('GNA11', 'Gene', (42, 47))	('mutations', 'Var', (113, 122))	('neoplasms', 'Disease', 'MESH:D009369', (88, 97))	('neoplasms', 'Disease', (88, 97))	('neoplasm', 'Phenotype', 'HP:0002664', (88, 96))	('mutations', 'Var', (48, 57))	('human', 'Species', '9606', (82, 87))
32494	21707960	Misexpression of the metabotropic glutamate receptor GRM1 in melanocyte lineage also results in an increased dermal melanocyte expansion, pigmentation, and nevus formation.	('nevus formation', 'CPA', (156, 171))	('pigmentation', 'Disease', 'MESH:D010859', (138, 150))	('pigmentation', 'Disease', (138, 150))	('Misexpression', 'Var', (0, 13))	('nevus', 'Phenotype', 'HP:0003764', (156, 161))	('increased', 'PosReg', (99, 108))	('GRM1', 'Gene', (53, 57))	('formation', 'biological_process', 'GO:0009058', ('162', '171'))	('dermal melanocyte expansion', 'CPA', (109, 136))	('pigmentation', 'biological_process', 'GO:0043473', ('138', '150'))
32495	21707960	Interestingly, both ENDRB, the receptor for endothelin 3, and GRM1 are G-protein-coupled receptors that signal through Ga subunits of the Gq family of which two members, GNAQ and GNA11, are frequently mutated in intradermal proliferations and uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (243, 257))	('mutated', 'Var', (201, 208))	('melanoma', 'Phenotype', 'HP:0002861', (249, 257))	('intradermal', 'Disease', (212, 223))	('uveal melanoma', 'Phenotype', 'HP:0007716', (243, 257))	('uveal melanoma', 'Disease', (243, 257))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))
32501	21707960	Culturing neural crest cells isolated from the recessive white mutant chick embryos results in both albino (presumed epidermal) and pigmented (presumed uveal) melanocytes, supporting an intrinsic difference between the two populations that is not overcome by culture conditions.	('uvea', 'Disease', (152, 156))	('mutant', 'Var', (63, 69))	('chick', 'Species', '9031', (70, 75))	('men', 'Species', '9606', (135, 138))	('uvea', 'Disease', 'MESH:C536494', (152, 156))	('results', 'Reg', (84, 91))	('pigmented', 'CPA', (132, 141))	('albino', 'CPA', (100, 106))
32504	21707960	As described previously, genetic analyses have found that mutations in specific pathways are more prevalent in some melanoma subtypes than others.	('mutations', 'Var', (58, 67))	('prevalent', 'Reg', (98, 107))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))
32505	21707960	For example, mutations in uveal melanoma, blue nevi and central nervous system harbor mutations in GNAQ and GNA11, but typically lack mutations in the BRAF, NRAS, or KIT pathways.	('mutations', 'Var', (86, 95))	('KIT', 'molecular_function', 'GO:0005020', ('166', '169'))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('blue nevi', 'Phenotype', 'HP:0100814', (42, 51))	('BRAF', 'Gene', '673', (151, 155))	('blue nevi', 'Disease', (42, 51))	('GNAQ', 'Gene', (99, 103))	('NRAS', 'Gene', (157, 161))	('uveal melanoma', 'Disease', (26, 40))	('BRAF', 'Gene', (151, 155))	('KIT pathways', 'Pathway', (166, 178))	('uveal melanoma', 'Disease', 'MESH:C536494', (26, 40))	('nevi', 'Phenotype', 'HP:0003764', (47, 51))	('uveal melanoma', 'Phenotype', 'HP:0007716', (26, 40))	('lack', 'NegReg', (129, 133))	('mutations', 'Var', (13, 22))	('GNA11', 'Gene', (108, 113))	('NRAS', 'Gene', '4893', (157, 161))
32506	21707960	Is it that the GTPase pathway genes are particularly prone to mutate in uveal, dermal, and CNS melanoma precursors, or rather that certain pathways are constitutively activated only in certain sublineages of melanocytes?	('GTPase pathway genes', 'Gene', (15, 35))	('uvea', 'Disease', (72, 76))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('uvea', 'Disease', 'MESH:C536494', (72, 76))	('melanoma', 'Disease', (95, 103))	('prone', 'Reg', (53, 58))	('mutate', 'Var', (62, 68))	('GTP', 'Chemical', 'MESH:D006160', (15, 18))
32508	21707960	In animal models, many mutations exist that affect melanocyte development and function.	('men', 'Species', '9606', (69, 72))	('melanocyte development', 'CPA', (51, 73))	('mutations', 'Var', (23, 32))	('affect', 'Reg', (44, 50))	('function', 'CPA', (78, 86))
32509	21707960	If specific pathway mutations act only within some subsets of melanocytes (as proposed above), then one would expect to see distinct patterns of melanocyte defects and melanoma.	('melanocyte defects', 'Disease', (145, 163))	('melanocyte defects', 'Disease', 'MESH:D009508', (145, 163))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', (168, 176))	('mutations', 'Var', (20, 29))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
32510	21707960	From genetic screens for darker skin and hair in mice, mutations have been identified that result in elevations of melanocyte numbers in dermal versus epidermal compartments.	('skin and hair', 'Disease', 'MESH:D012871', (32, 45))	('melanocyte numbers', 'CPA', (115, 133))	('elevations', 'PosReg', (101, 111))	('mutations', 'Var', (55, 64))	('mice', 'Species', '10090', (49, 53))	('darker skin', 'Phenotype', 'HP:0000953', (25, 36))	('men', 'Species', '9606', (168, 171))
32511	21707960	For example, mutations of the GTPases, Galphaq, and Galpha11, which act downstream of EDNRB, cause dermal hyper-pigmentation owing to expansion of dermal melanocytes.	('GTPases', 'Gene', (30, 37))	('EDNRB', 'Gene', '1910', (86, 91))	('dermal hyper-pigmentation', 'Disease', 'MESH:D010859', (99, 124))	('Galpha11', 'Gene', '2767', (52, 60))	('cause', 'Reg', (93, 98))	('EDNRB', 'Gene', (86, 91))	('expansion', 'PosReg', (134, 143))	('pigmentation', 'biological_process', 'GO:0043473', ('112', '124'))	('mutations', 'Var', (13, 22))	('hyper-pigmentation', 'Phenotype', 'HP:0000953', (106, 124))	('GTP', 'Chemical', 'MESH:D006160', (30, 33))	('dermal hyper-pigmentation', 'Disease', (99, 124))	('Galphaq', 'Gene', (39, 46))	('Galpha11', 'Gene', (52, 60))
32513	21707960	In contrast, overexpression of KITL either through transgene expression or by mutations in ribosomal proteins RPS19 and RPS20 leads to increases in the number of epidermal melanocytes.	('RPS20', 'Gene', (120, 125))	('KITL', 'Gene', (31, 35))	('increases', 'PosReg', (135, 144))	('mutations', 'Var', (78, 87))	('RPS20', 'Gene', '6224', (120, 125))	('overexpression', 'PosReg', (13, 27))	('transgene', 'Var', (51, 60))	('RPS19', 'Gene', '6223', (110, 115))	('RPS19', 'Gene', (110, 115))
32515	21707960	This does not appear to be the case for all genetic mutations however, as overexpression of mutant BRAFV600E in mouse melanocytes affects both dermal and epidermal melanocytes.	('BRAFV600E', 'Gene', (99, 108))	('affects', 'Reg', (130, 137))	('overexpression', 'PosReg', (74, 88))	('mutant', 'Var', (92, 98))	('mouse', 'Species', '10090', (112, 117))	('BRAFV600E', 'Mutation', 'rs113488022', (99, 108))
32522	21707960	The notion of at least two different types of melanoma on the sun-exposed skin was independently confirmed by the molecular studies associating BRAF and KIT mutations with distinct clinical and histopathological features.	('KIT', 'molecular_function', 'GO:0005020', ('153', '156'))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('KIT', 'Gene', (153, 156))	('BRAF', 'Gene', '673', (144, 148))	('mutations', 'Var', (157, 166))	('BRAF', 'Gene', (144, 148))
32529	21707960	Molecularly, CSD melanomas have a lower prevalence of mutant BRAF than non-CSD melanomas, with 30-40% showing mutations in KIT or NRAS, and a considerable proportion likely to have mutations in as yet undiscovered oncogenes.	('non-CSD melanomas', 'Disease', (71, 88))	('CSD melanomas', 'Disease', 'MESH:C562576', (75, 88))	('mutations', 'Var', (110, 119))	('CSD melanomas', 'Disease', (13, 26))	('non-CSD melanomas', 'Disease', 'MESH:C562576', (71, 88))	('melanomas', 'Phenotype', 'HP:0002861', (17, 26))	('BRAF', 'Gene', '673', (61, 65))	('KIT', 'molecular_function', 'GO:0005020', ('123', '126'))	('CSD melanomas', 'Disease', 'MESH:C562576', (13, 26))	('BRAF', 'Gene', (61, 65))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('NRAS', 'Gene', (130, 134))	('KIT', 'Gene', (123, 126))	('mutant', 'Var', (54, 60))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('NRAS', 'Gene', '4893', (130, 134))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))
32535	21707960	On a molecular level, these melanomas, as well as the melanocytic nevi associated with this phenotype, are characterized by a high frequency of BRAF mutations (about 70%).	('nevi', 'Phenotype', 'HP:0003764', (66, 70))	('mutations', 'Var', (149, 158))	('melanocytic nevi', 'Disease', (54, 70))	('melanomas', 'Disease', (28, 37))	('BRAF', 'Gene', '673', (144, 148))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (54, 70))	('BRAF', 'Gene', (144, 148))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('melanomas', 'Disease', 'MESH:D008545', (28, 37))
32537	21707960	A recent study showed evidence that a low level of solar elastosis is independently associated with BRAF mutation status, but it remains unclear what the underlying mechanisms are.	('solar elastosis', 'Disease', (51, 66))	('mutation status', 'Var', (105, 120))	('BRAF', 'Gene', '673', (100, 104))	('associated', 'Reg', (84, 94))	('BRAF', 'Gene', (100, 104))	('solar elastosis', 'Disease', 'MESH:D005148', (51, 66))
32542	21707960	Thus, the finding of multiple, mutant BRAF-driven melanocytic neoplasms:nevi and melanomas:developing relatively early in life and on areas of the skin with comparatively little cumulative sun exposure implies a constitutional susceptibility to this class of lesions.	('melanocytic neoplasms', 'Disease', (50, 71))	('mutant', 'Var', (31, 37))	('melanomas', 'Disease', (81, 90))	('nevi', 'Phenotype', 'HP:0003764', (72, 76))	('neoplasm', 'Phenotype', 'HP:0002664', (62, 70))	('BRAF', 'Gene', '673', (38, 42))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (50, 71))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanomas', 'Phenotype', 'HP:0002861', (81, 90))	('neoplasms', 'Phenotype', 'HP:0002664', (62, 71))	('BRAF', 'Gene', (38, 42))	('melanomas', 'Disease', 'MESH:D008545', (81, 90))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (50, 71))	('nevi', 'Disease', (72, 76))
32543	21707960	One aspect of this heritability has been linked to constitutional variation of the melanocortin 1 receptor MC1R.	('linked', 'Reg', (41, 47))	('MC1R', 'Gene', (107, 111))	('MC1R', 'Gene', '4157', (107, 111))	('constitutional variation', 'Var', (51, 75))
32544	21707960	Within the category of non-CSD melanomas, germline polymorphisms in MC1R have been associated with BRAF mutations in several studies, raising the possibility that altered signaling downstream of the melanocortin receptor may be one of several possible factors contributing to this susceptibility.	('MC1R', 'Gene', (68, 72))	('non-CSD melanomas', 'Disease', (23, 40))	('mutations', 'Var', (104, 113))	('non-CSD melanomas', 'Disease', 'MESH:C562576', (23, 40))	('signaling', 'biological_process', 'GO:0023052', ('171', '180'))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('associated', 'Reg', (83, 93))	('MC1R', 'Gene', '4157', (68, 72))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))
32545	21707960	Of note, the association of BRAF mutations with MC1R variants appears strictly confined to the setting of non-CSD melanomas.	('association', 'Interaction', (13, 24))	('BRAF', 'Gene', '673', (28, 32))	('melanomas', 'Phenotype', 'HP:0002861', (114, 123))	('non-CSD melanomas', 'Disease', (106, 123))	('MC1R', 'Gene', '4157', (48, 52))	('MC1R', 'Gene', (48, 52))	('non-CSD melanomas', 'Disease', 'MESH:C562576', (106, 123))	('mutations', 'Var', (33, 42))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('BRAF', 'Gene', (28, 32))	('variants', 'Var', (53, 61))
32546	21707960	As MC1R variants are even more common in people with CSD melanomas and because CSD melanomas are driven by mutations other than BRAF, analyses of data sets that include CSD melanomas may miss the association with BRAF mutation or even detect an inverse association.	('common', 'Reg', (31, 37))	('inverse', 'NegReg', (245, 252))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('CSD melanomas', 'Disease', (53, 66))	('people', 'Species', '9606', (41, 47))	('mutation', 'Var', (218, 226))	('association', 'Interaction', (196, 207))	('melanomas', 'Phenotype', 'HP:0002861', (173, 182))	('variants', 'Var', (8, 16))	('miss', 'NegReg', (187, 191))	('BRAF', 'Gene', (213, 217))	('BRAF', 'Gene', '673', (213, 217))	('CSD melanomas', 'Disease', 'MESH:C562576', (169, 182))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('CSD melanomas', 'Disease', 'MESH:C562576', (79, 92))	('CSD melanomas', 'Disease', (169, 182))	('BRAF', 'Gene', (128, 132))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('CSD melanomas', 'Disease', (79, 92))	('MC1R', 'Gene', '4157', (3, 7))	('MC1R', 'Gene', (3, 7))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('BRAF', 'Gene', '673', (128, 132))	('CSD melanomas', 'Disease', 'MESH:C562576', (53, 66))
32547	21707960	This suggests further, unexplored heterogeneity within the category of non-CSD melanoma, one in which BRAF is associated with variation of MC1R, and another in which wild-type MC1R is associated with NRAS and other, yet to be discovered, oncogenic alterations.	('variation', 'Var', (126, 135))	('NRAS', 'Gene', (200, 204))	('BRAF', 'Gene', '673', (102, 106))	('NRAS', 'Gene', '4893', (200, 204))	('BRAF', 'Gene', (102, 106))	('MC1R', 'Gene', '4157', (176, 180))	('associated', 'Reg', (110, 120))	('MC1R', 'Gene', (176, 180))	('MC1R', 'Gene', '4157', (139, 143))	('associated', 'Reg', (184, 194))	('MC1R', 'Gene', (139, 143))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
32550	21707960	It is attractive to speculate that this prolonged period of homeostatic proliferation may set up a state of vulnerability for the effects of mutant BRAF.	('BRAF', 'Gene', '673', (148, 152))	('mutant', 'Var', (141, 147))	('BRAF', 'Gene', (148, 152))
32552	21707960	Molecularly, BRAF mutations are observed at lower frequency than for non-CSD melanomas, with about 20% having mutations in KIT and about 50% likely to have mutations in yet to be discovered oncogenes.	('mutations', 'Var', (110, 119))	('BRAF', 'Gene', '673', (13, 17))	('KIT', 'molecular_function', 'GO:0005020', ('123', '126'))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('BRAF', 'Gene', (13, 17))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('non-CSD melanomas', 'Disease', (69, 86))	('KIT', 'Gene', (123, 126))	('non-CSD melanomas', 'Disease', 'MESH:C562576', (69, 86))	('mutations', 'Var', (18, 27))
32561	21707960	However, the genomic regions recurrently affected by these amplifications differ from those found in acral melanomas.	('acral melanomas', 'Disease', 'MESH:D008545', (101, 116))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('acral melanoma', 'Phenotype', 'HP:0012060', (101, 115))	('acral melanomas', 'Disease', (101, 116))	('acral melanomas', 'Phenotype', 'HP:0012060', (101, 116))	('amplifications', 'Var', (59, 73))
32562	21707960	Cyclin D1 amplifications are less common than in acral melanoma and, instead, amplification of the CDK4 locus on chromosome 12q are frequently found.	('acral melanoma', 'Disease', (49, 63))	('chromosome', 'cellular_component', 'GO:0005694', ('113', '123'))	('amplification', 'Var', (78, 91))	('Cyclin D1', 'Gene', '595', (0, 9))	('acral melanoma', 'Disease', 'MESH:D008545', (49, 63))	('CDK4', 'Gene', (99, 103))	('acral melanoma', 'Phenotype', 'HP:0012060', (49, 63))	('amplifications', 'Var', (10, 24))	('CDK', 'molecular_function', 'GO:0004693', ('99', '102'))	('Cyclin', 'molecular_function', 'GO:0016538', ('0', '6'))	('found', 'Reg', (143, 148))	('CDK4', 'Gene', '1019', (99, 103))	('Cyclin D1', 'Gene', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))
32565	21707960	In all types, mutations of G-protein alpha subunits of the Gq family, GNAQ, and GNA11, are found in the majority of cases, and these mutations are virtually absent in melanocytic neoplasms arising from epithelia-associated melanocytes.	('neoplasm', 'Phenotype', 'HP:0002664', (179, 187))	('melanocytic neoplasms', 'Disease', (167, 188))	('found', 'Reg', (91, 96))	('neoplasms', 'Phenotype', 'HP:0002664', (179, 188))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (167, 188))	('G-protein', 'Protein', (27, 36))	('GNAQ', 'Gene', (70, 74))	('mutations', 'Var', (14, 23))	('GNA11', 'Gene', (80, 85))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (167, 188))
32569	21707960	This pattern may be due to the acquisition of Galphaq mutations during different time points of melanocyte development and migration, where mutations arising early in this migration result in localized tumors of the central nervous system, mutations arising during migrating melanoblasts result in segmentally distributed lesions, whereas blue nevi and related neoplasms arise from mutations of distal progeny of these melanocytes.	('blue nevi', 'Disease', (339, 348))	('men', 'Species', '9606', (114, 117))	('neoplasms', 'Phenotype', 'HP:0002664', (361, 370))	('blue nevi', 'Phenotype', 'HP:0100814', (339, 348))	('localized tumors of the central nervous system', 'Disease', 'MESH:D016543', (192, 238))	('men', 'Species', '9606', (301, 304))	('localized tumors of the central nervous system', 'Disease', (192, 238))	('neoplasm', 'Phenotype', 'HP:0002664', (361, 369))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (202, 238))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('neoplasms', 'Disease', 'MESH:D009369', (361, 370))	('result in', 'Reg', (288, 297))	('mutations', 'Var', (140, 149))	('lesions', 'MPA', (322, 329))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('neoplasms', 'Disease', (361, 370))	('nevi', 'Phenotype', 'HP:0003764', (344, 348))	('result in', 'Reg', (182, 191))	('mutations', 'Var', (240, 249))
32570	21707960	Future studies will have to determine whether peripheral nerves harbor an active pool of melanocyte stem cells that provides melanocytes for the skin and can give rise to specific neoplasms, if transformed by mutations in Galphaq family members.	('neoplasms', 'Phenotype', 'HP:0002664', (180, 189))	('Galphaq', 'Gene', (222, 229))	('give rise to', 'Reg', (158, 170))	('neoplasm', 'Phenotype', 'HP:0002664', (180, 188))	('neoplasms', 'Disease', 'MESH:D009369', (180, 189))	('neoplasms', 'Disease', (180, 189))	('mutations', 'Var', (209, 218))
32573	21707960	On a molecular level, they are characterized by mutations in GNAQ or GNA11 with no mutations in BRAF, NRAS, or KIT.	('GNAQ', 'Gene', (61, 65))	('KIT', 'molecular_function', 'GO:0005020', ('111', '114'))	('NRAS', 'Gene', (102, 106))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('GNA11', 'Gene', (69, 74))	('NRAS', 'Gene', '4893', (102, 106))	('mutations', 'Var', (48, 57))
32574	21707960	Additional mutations in the histone de-ubiquitinase BAP1 arise later during progression followed by loss of chromosome 3, eliminating the remaining wild-type BAP1 allele.	('mutations', 'Var', (11, 20))	('BAP1', 'Gene', '8314', (52, 56))	('BAP1', 'Gene', (158, 162))	('BAP1', 'Gene', (52, 56))	('chromosome', 'cellular_component', 'GO:0005694', ('108', '118'))	('eliminating', 'NegReg', (122, 133))	('BAP1', 'Gene', '8314', (158, 162))
32577	21707960	These melanocytic neoplasms of the central nervous system closely resemble blue nevi and also show frequent mutations in GNAQ and probably GNA11.	('blue nevi', 'Disease', (75, 84))	('GNA11', 'Gene', (139, 144))	('neoplasms of the central nervous', 'Phenotype', 'HP:0100006', (18, 50))	('mutations', 'Var', (108, 117))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (6, 27))	('neoplasm', 'Phenotype', 'HP:0002664', (18, 26))	('nevi', 'Phenotype', 'HP:0003764', (80, 84))	('melanocytic neoplasms of the central nervous system', 'Phenotype', 'HP:0100836', (6, 57))	('melanocytic neoplasms of the central nervous system', 'Disease', 'MESH:D016543', (6, 57))	('blue nevi', 'Phenotype', 'HP:0100814', (75, 84))	('neoplasms', 'Phenotype', 'HP:0002664', (18, 27))	('GNAQ', 'Gene', (121, 125))
32578	21707960	They can pose differential diagnostic problems to melanoma metastases, and the detection of Galphaq mutations may help to establish the diagnosis.	('mutations', 'Var', (100, 109))	('melanoma metastases', 'Disease', 'MESH:D009362', (50, 69))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma metastases', 'Disease', (50, 69))	('Galphaq', 'Gene', (92, 99))
32739	20969762	Among the 180 ophthalmologic controls, 47 controls suffered exclusively from diseases of the anterior eye segment (ICD10: H25-H26: cataract, H00-H06: diseases of the eyelid, lacrimal system and orbit, H10-H13: diseases of the conjunctiva, and others), 70 controls exclusively from diseases of the posterior eye segment (H30-H36: disorders of the choroid and retina, H40-H42: glaucoma, H49-H52: diseases of ocular muscles, binocular movement, accommodation and refraction, and others), and 34 controls from diseases of both segments.	('cataract', 'Phenotype', 'HP:0000518', (131, 139))	('men', 'Species', '9606', (526, 529))	('men', 'Species', '9606', (314, 317))	('H49-H52', 'Var', (385, 392))	('diseases of the anterior eye segment', 'Disease', (77, 113))	('choroid', 'Disease', (346, 353))	('cataract', 'Disease', (131, 139))	('H40-H42', 'Var', (366, 373))	('diseases of the eyelid', 'Phenotype', 'HP:0010604', (150, 172))	('cataract', 'Disease', 'MESH:D002386', (131, 139))	('refraction', 'Disease', (460, 470))	('binocular movement', 'Disease', (422, 440))	('men', 'Species', '9606', (436, 439))	('choroid', 'Disease', 'MESH:D002833', (346, 353))	('glaucoma', 'Phenotype', 'HP:0000501', (375, 383))	('glaucoma', 'Disease', (375, 383))	('men', 'Species', '9606', (109, 112))	('glaucoma', 'Disease', 'MESH:D005901', (375, 383))	('diseases of the anterior eye segment', 'Disease', 'MESH:C537775', (77, 113))	('accommodation', 'Disease', (442, 455))
32780	17699951	Due to transection of the melanoma, the eye was enucleated two weeks later.	('melanoma', 'Disease', 'MESH:D008545', (26, 34))	('transection', 'Var', (7, 18))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (26, 34))
32785	17699951	In a matched, case-control study comparing transscleral resection and I 125  brachytherapy for uveal melanoma, patients who underwent transcleral resection were found to have a significantly smaller risk of developing cataract, vitreous hemorrhage and maculopathy compared to those treated with brachytherapy.	('cataract', 'Disease', 'MESH:D002386', (218, 226))	('vitreous hemorrhage', 'Phenotype', 'HP:0007902', (228, 247))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('cataract', 'Disease', (218, 226))	('cataract', 'Phenotype', 'HP:0000518', (218, 226))	('transcleral resection', 'Var', (134, 155))	('maculopathy', 'Disease', 'MESH:D008268', (252, 263))	('uveal melanoma', 'Disease', 'MESH:C536494', (95, 109))	('vitreous hemorrhage', 'Disease', (228, 247))	('uveal melanoma', 'Phenotype', 'HP:0007716', (95, 109))	('uveal melanoma', 'Disease', (95, 109))	('maculopathy', 'Disease', (252, 263))	('vitreous hemorrhage', 'Disease', 'MESH:D014823', (228, 247))	('patients', 'Species', '9606', (111, 119))
32788	17699951	There was greater local tumor control in the I 125  treated group compared with the locally resected group.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('greater', 'PosReg', (10, 17))	('I 125', 'Var', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
32807	18001467	A proliferation assay was also used to test effects TN14003 would have on cellular proliferation.	('TN14003', 'Chemical', 'MESH:C488289', (52, 59))	('cellular proliferation', 'CPA', (74, 96))	('TN14003', 'Var', (52, 59))
32814	18001467	All 5 cell lines pre-incubated with TN14003 prevented cellular migration towards chemokine CXCL12 (p < 0.01).	('CXCL12', 'Gene', '6387', (91, 97))	('TN14003', 'Chemical', 'MESH:C488289', (36, 43))	('prevented', 'NegReg', (44, 53))	('pre', 'molecular_function', 'GO:0003904', ('17', '20'))	('CXCL12', 'Gene', (91, 97))	('cellular migration', 'CPA', (54, 72))	('TN14003', 'Var', (36, 43))
32833	18001467	This is important because epigenetic silencing of CXCL12 in human colorectal carcinoma cell lines has shown to promote and even enhance tumor metastasis in vitro and in vivo.	('colorectal carcinoma', 'Disease', (66, 86))	('CXCL12', 'Gene', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (66, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('enhance', 'PosReg', (128, 135))	('epigenetic silencing', 'Var', (26, 46))	('human', 'Species', '9606', (60, 65))	('CXCL12', 'Gene', '6387', (50, 56))	('tumor', 'Disease', (136, 141))	('promote', 'PosReg', (111, 118))
32834	18001467	These results suggest that when autocrine signaling in the CXCR4/CXCL12 axis is disrupted, tumor cells become more "malignant" due to the fact that they can more readily sense CXCL12 secreted from distant sites.	('disrupted', 'Var', (80, 89))	('CXCL12', 'Gene', (176, 182))	('CXCL12', 'Gene', (65, 71))	('CXCR4', 'Gene', '7852', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('more', 'PosReg', (157, 161))	('CXCL12', 'Gene', '6387', (176, 182))	('CXCL12', 'Gene', '6387', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('autocrine signaling', 'biological_process', 'GO:0035425', ('32', '51'))	('CXCR4', 'Gene', (59, 64))	('CXCR4', 'molecular_function', 'GO:0038147', ('59', '64'))	('tumor', 'Disease', (91, 96))
32864	18001467	Results from the migration assay for each cell line (cells incubated with TN14003) were directly compared to a matched group of cells incubated solely with CXCL12 using a Student's t-test.	('migration assay', 'CPA', (17, 32))	('TN14003', 'Chemical', 'MESH:C488289', (74, 81))	('TN14003', 'Var', (74, 81))	('CXCL12', 'Gene', (156, 162))	('CXCL12', 'Gene', '6387', (156, 162))
32870	18001467	The proliferation rate of the 5 UM cell lines when pre-incubated with TN14003 did decrease slightly in all 5 cell lines, but was not statistically significant (p > 0.05) when compared back to the lines that were not pre-incubated with the peptide inhibitor (Figure 2).	('pre', 'molecular_function', 'GO:0003904', ('51', '54'))	('pre', 'molecular_function', 'GO:0003904', ('216', '219'))	('decrease', 'NegReg', (82, 90))	('UM', 'Phenotype', 'HP:0007716', (32, 34))	('TN14003', 'Chemical', 'MESH:C488289', (70, 77))	('TN14003', 'Var', (70, 77))	('proliferation rate', 'CPA', (4, 22))
32872	18001467	All 5 cell lines pre-incubated with TN14003 (4 ng/ml) did not migrate towards the chemokine CXCL12 (p < 0.01 in all cases).	('not', 'NegReg', (58, 61))	('TN14003', 'Chemical', 'MESH:C488289', (36, 43))	('CXCL12', 'Gene', (92, 98))	('pre', 'molecular_function', 'GO:0003904', ('17', '20'))	('CXCL12', 'Gene', '6387', (92, 98))	('TN14003', 'Var', (36, 43))
32876	18001467	We also analyzed if TN14003 (4 ng/ml) would bind to cell surface CXCR4 receptors and shift the binding of the biotinylated SDF-1alpha cytokine, in turn causing a shift in the level of florecesence when being read by the flow cytometer.	('SDF-1', 'Gene', '6387', (123, 128))	('SDF-1', 'Gene', (123, 128))	('CXCR4', 'Gene', '7852', (65, 70))	('causing', 'Reg', (152, 159))	('bind', 'Interaction', (44, 48))	('level of florecesence', 'MPA', (175, 196))	('CXCR4', 'molecular_function', 'GO:0038147', ('65', '70'))	('TN14003', 'Chemical', 'MESH:C488289', (20, 27))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('TN14003', 'Var', (20, 27))	('cell surface', 'cellular_component', 'GO:0009986', ('52', '64'))	('CXCR4', 'Gene', (65, 70))	('binding', 'Interaction', (95, 102))	('shift', 'Reg', (162, 167))
32887	18001467	This point is particularly interesting to note due to the fact that it has previously been shown in colorectal carcinoma that when endogenous sources of CXCL12 are epigenetically silenced, these cells more readily metastasize compared to those that engage in CXCR4/CXCL12 autocrine signaling.	('more readily', 'PosReg', (201, 213))	('CXCL12', 'Gene', (265, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (100, 120))	('CXCR4', 'Gene', (259, 264))	('CXCL12', 'Gene', (153, 159))	('epigenetically silenced', 'Var', (164, 187))	('CXCL12', 'Gene', '6387', (265, 271))	('autocrine signaling', 'biological_process', 'GO:0035425', ('272', '291'))	('CXCL12', 'Gene', '6387', (153, 159))	('colorectal carcinoma', 'Disease', (100, 120))	('CXCR4', 'Gene', '7852', (259, 264))	('CXCR4', 'molecular_function', 'GO:0038147', ('259', '264'))
32890	18001467	Both studies concluded that TN14003 was a very effective inhibitor of the CXCR4/CXCL12 chemokine axis, and may be a possible future therapy for breast and pancreatic cancer.	('CXCR4', 'Gene', '7852', (74, 79))	('CXCR4', 'Gene', (74, 79))	('CXCL12', 'Gene', (80, 86))	('CXCR4', 'molecular_function', 'GO:0038147', ('74', '79'))	('TN14003', 'Chemical', 'MESH:C488289', (28, 35))	('TN14003', 'Var', (28, 35))	('CXCL12', 'Gene', '6387', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast and pancreatic cancer', 'Disease', 'MESH:D010190', (144, 172))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (155, 172))
32891	18001467	We showed that TN14003 at concentrations of 4 ng/ml is extremely effective at inhibiting the migratory ability of human uveal melanoma cell lines.	('TN14003', 'Chemical', 'MESH:C488289', (15, 22))	('TN14003', 'Var', (15, 22))	('inhibiting', 'NegReg', (78, 88))	('uveal melanoma', 'Disease', 'MESH:C536494', (120, 134))	('human', 'Species', '9606', (114, 119))	('uveal melanoma', 'Phenotype', 'HP:0007716', (120, 134))	('uveal melanoma', 'Disease', (120, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))
32892	18001467	TN14003 did not significantly reduce the proliferative ability of the cells due to the fact that CXCL12 is not produced by these cell lines.	('TN14003', 'Chemical', 'MESH:C488289', (0, 7))	('CXCL12', 'Gene', '6387', (97, 103))	('TN14003', 'Var', (0, 7))	('CXCL12', 'Gene', (97, 103))
32900	18001467	Cellular proliferation of the UM cell lines tested were not significantly inhibited by TN14003.	('TN14003', 'Chemical', 'MESH:C488289', (87, 94))	('TN14003', 'Var', (87, 94))	('Cellular proliferation', 'CPA', (0, 22))	('UM', 'Phenotype', 'HP:0007716', (30, 32))
32902	33302435	Monosomy-3 Alters the Expression Profile of the Glucose Transporters GLUT1-3 in Uveal Melanoma Monosomy-3 in uveal melanoma (UM) cells increases the risk of fatal metastases.	('Monosomy-3', 'Var', (95, 105))	('UM', 'Phenotype', 'HP:0007716', (125, 127))	('metastases', 'Disease', (163, 173))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('Melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('Expression Profile', 'MPA', (22, 40))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('increases', 'PosReg', (135, 144))	('Melanoma', 'Disease', 'MESH:D008545', (86, 94))	('metastases', 'Disease', 'MESH:D009362', (163, 173))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('Glucose', 'Chemical', 'MESH:D005947', (48, 55))	('Melanoma', 'Disease', (86, 94))
32906	33302435	GLUT3 expression was stronger in the irradiated samples with disomy-3 versus monosomy-3, but the ratio of the GLUT3 isoform to total GLUT1-3 did not differ with regard to the monosomy-3 status in the irradiated or non-irradiated subgroups.	('GLUT3', 'Gene', '6515', (0, 5))	('GLUT3', 'Gene', (0, 5))	('expression', 'MPA', (6, 16))	('stronger', 'PosReg', (21, 29))	('disomy-3', 'Var', (61, 69))	('GLUT3', 'Gene', '6515', (110, 115))	('GLUT3', 'Gene', (110, 115))
32907	33302435	Systemic metastases were associated with the presence of monosomy-3 in the primary and circulating tumor cells as well as a higher GLUT1 ratio.	('tumor', 'Disease', (99, 104))	('metastases', 'Disease', (9, 19))	('GLUT1 ratio', 'MPA', (131, 142))	('monosomy-3', 'Var', (57, 67))	('metastases', 'Disease', 'MESH:D009362', (9, 19))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('higher', 'PosReg', (124, 130))
32912	33302435	The most important prognostic factor for UM is the loss of one copy of chromosome 3 (monosomy-3) in the primary tumor cells, which significantly increases the likelihood of systemic metastases in patients having this aberration.	('metastases', 'Disease', 'MESH:D009362', (182, 192))	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('loss', 'Var', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('patients', 'Species', '9606', (196, 204))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('increases', 'PosReg', (145, 154))	('chromosome', 'cellular_component', 'GO:0005694', ('71', '81'))	('metastases', 'Disease', (182, 192))	('tumor', 'Disease', (112, 117))
32913	33302435	Likewise, an earlier study, which included n = 11 UM patients with pathologically confirmed metastatic disease reported that the metastases of UMs with monosomy-3 (n = 4 patients, 36.4%) exhibited a more rapid disease progression compared to the tumors with disomy-3 or partial chromosome 3 anomalies (n = 7 patients, 63.6%).	('patients', 'Species', '9606', (170, 178))	('disease progression', 'CPA', (210, 229))	('metastatic disease', 'Disease', (92, 110))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('patients', 'Species', '9606', (53, 61))	('monosomy-3', 'Var', (152, 162))	('chromosome', 'cellular_component', 'GO:0005694', ('278', '288'))	('patients', 'Species', '9606', (308, 316))	('metastatic disease', 'Disease', 'MESH:C538445', (92, 110))	('metastases', 'Disease', (129, 139))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('UM', 'Phenotype', 'HP:0007716', (143, 145))	('metastases', 'Disease', 'MESH:D009362', (129, 139))	('tumors', 'Disease', (246, 252))
32918	33302435	Remarkably, the metabolic activity of primary UMs in FDG-PET scans was positively correlated with the presence of monosomy-3 in these tumors.	('tumors', 'Disease', (134, 140))	('monosomy-3', 'Var', (114, 124))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('correlated', 'Reg', (82, 92))	('FDG', 'Chemical', 'MESH:D019788', (53, 56))	('metabolic activity', 'MPA', (16, 34))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
32919	33302435	These findings, therefore, suggest that the UM cells with monosomy-3 execute a higher rate of glucose influx.	('higher', 'PosReg', (79, 85))	('glucose', 'Chemical', 'MESH:D005947', (94, 101))	('monosomy-3', 'Var', (58, 68))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('glucose influx', 'MPA', (94, 108))
32938	33302435	In addition, the GLUT1 protein can become upregulated in the UM cells under hypoxia and the knockdown of the hypoxia-response genes in a mouse xenograft model of UM could suppress the expression of GLUT1.	('hypoxia', 'Disease', (76, 83))	('mouse', 'Species', '10090', (137, 142))	('hypoxia', 'Disease', (109, 116))	('hypoxia', 'Disease', 'MESH:D000860', (109, 116))	('GLUT1', 'Gene', (17, 22))	('knockdown', 'Var', (92, 101))	('UM', 'Phenotype', 'HP:0007716', (162, 164))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('suppress', 'NegReg', (171, 179))	('protein', 'Protein', (23, 30))	('upregulated', 'PosReg', (42, 53))	('expression', 'MPA', (184, 194))	('hypoxia', 'Disease', 'MESH:D000860', (76, 83))	('GLUT1', 'Gene', (198, 203))
32939	33302435	However, it is not known yet, which glucose transporters predominate in the primary UM samples and whether the presence of monosomy-3 is correlated with the expression of another GLUT isoform with a higher affinity as a possible compensation for GLUT2.	('glucose transporter', 'Gene', '6513', (36, 55))	('glucose transporter', 'Gene', (36, 55))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('monosomy-3', 'Var', (123, 133))	('GLUT', 'Gene', (246, 250))	('GLUT', 'Gene', '6513', (246, 250))	('GLUT', 'Gene', (179, 183))	('GLUT', 'Gene', '6513', (179, 183))
32943	33302435	Our findings provide the first sign for a more favorable constellation of hexose transporters in the primary UMs with monosomy-3 that may be increasing the risk of systemic metastases by enhancing the rate of glucose influx.	('monosomy-3', 'Var', (118, 128))	('hexose transporters', 'MPA', (74, 93))	('metastases', 'Disease', (173, 183))	('glucose influx', 'MPA', (209, 223))	('metastases', 'Disease', 'MESH:D009362', (173, 183))	('glucose', 'Chemical', 'MESH:D005947', (209, 216))	('UM', 'Phenotype', 'HP:0007716', (109, 111))	('increasing', 'PosReg', (141, 151))	('rate', 'MPA', (201, 205))	('enhancing', 'PosReg', (187, 196))
32952	33302435	The intensity of GLUT2 was approximately 57% lower in the tumors with monosomy-3 vs. disomy-3 (p = 0.0006, Mann-Whitney U test, n = 14 and 20 samples, respectively).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('intensity', 'MPA', (4, 13))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('lower', 'NegReg', (45, 50))	('GLUT2', 'Protein', (17, 22))	('monosomy-3', 'Var', (70, 80))
32956	33302435	Among the non-irradiated samples (n = 15), the total intensity score for GLUT1-3 was reduced in the tumors with monosomy-3 (median: 2.76, range: 0.82-5.95) compared to disomy-3 (median intensity: 3.28, range: 0.89-5.23), but this effect did not reach a significance (p = 0.892, two-sided t-test, n = 8 and 7 tumors, respectively, Figure 2A-F).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', 'MESH:D009369', (308, 314))	('monosomy-3', 'Var', (112, 122))	('GLUT1-3', 'Protein', (73, 80))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('intensity score', 'MPA', (53, 68))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('reduced', 'NegReg', (85, 92))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))	('tumors', 'Disease', (308, 314))
32957	33302435	The non-irradiated tumors with monosomy-3 exhibited a mainly epithelioid morphology with an approximately 1.8-fold increase in the ratio of GLUT1 to the total levels of GLUT1-3 (p = 0.014, two-sided t-test, Figure 2A-C,F).	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('increase', 'PosReg', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('ratio', 'MPA', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('epithelioid morphology', 'CPA', (61, 83))	('GLUT1', 'MPA', (140, 145))	('monosomy-3', 'Var', (31, 41))
32959	33302435	In contrast, the ratio of GLUT2 to total GLUT1-3 was 41% less in the monosomy-3 vs. disomy-3 tumors (p = 0.010, two-sided t-test, Figure 2A,D).	('disomy-3 tumors', 'Disease', (84, 99))	('monosomy-3', 'Var', (69, 79))	('GLUT1-3', 'Protein', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('GLUT2', 'Protein', (26, 31))	('less', 'NegReg', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('disomy-3 tumors', 'Disease', 'MESH:D024182', (84, 99))
32964	33302435	The total levels of these transporters were significantly less in the monosomy-3 tumors (median: 2.46, range: 1.68-4.61, n = 6) compared to the disomy-3 samples (median: 4.29, range: 2.94-5.33, n = 13, p = 0.002, two-sided t-test, Figure 3F).	('levels of these transporters', 'MPA', (10, 38))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('less', 'NegReg', (58, 62))	('monosomy-3', 'Var', (70, 80))
32975	33302435	Likewise, the prevalence of monosomy-3 was higher in both the primary tumors and the circulating melanoma cells (CMC) of the patients who developed metastases (p < 0.02, Table 2).	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('melanoma', 'Disease', (97, 105))	('higher', 'PosReg', (43, 49))	('metastases', 'Disease', (148, 158))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('metastases', 'Disease', 'MESH:D009362', (148, 158))	('monosomy-3', 'Var', (28, 38))	('patients', 'Species', '9606', (125, 133))
32978	33302435	Despite the well-established association of monosomy-3 with a higher risk of developing lethal UM metastases, the cellular mechanisms underlying this event have not been sufficiently elucidated for the development of efficient and preventive therapies.	('metastases', 'Disease', (98, 108))	('monosomy-3', 'Var', (44, 54))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('metastases', 'Disease', 'MESH:D009362', (98, 108))
32979	33302435	The extent of monosomy-3 in the primary UMs was positively correlated with the metabolic activity of these tumors in FDG-PET scans.	('monosomy-3', 'Var', (14, 24))	('metabolic activity', 'MPA', (79, 97))	('FDG', 'Chemical', 'MESH:D019788', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('UM', 'Phenotype', 'HP:0007716', (40, 42))
32980	33302435	This suggests that the malignant UM cells with monosomy-3 exhibit a higher rate of glucose uptake, but the regulation of glucose influx in UM has surprisingly received very little attention so far.	('glucose', 'Chemical', 'MESH:D005947', (83, 90))	('glucose', 'Chemical', 'MESH:D005947', (121, 128))	('UM', 'Phenotype', 'HP:0007716', (33, 35))	('UM', 'Phenotype', 'HP:0007716', (139, 141))	('higher', 'PosReg', (68, 74))	('regulation', 'biological_process', 'GO:0065007', ('107', '117'))	('monosomy-3', 'Var', (47, 57))	('glucose uptake', 'MPA', (83, 97))	('glucose uptake', 'biological_process', 'GO:0046323', ('83', '97'))
32988	33302435	Our findings, therefore, suggest that GLUT1 rather than GLUT3 is the preferentially upregulated isoform in the UMs with monosomy-3 possibly as a compensation for GLUT2.	('upregulated', 'PosReg', (84, 95))	('preferentially', 'PosReg', (69, 83))	('UM', 'Phenotype', 'HP:0007716', (111, 113))	('GLUT3', 'Gene', '6515', (56, 61))	('GLUT3', 'Gene', (56, 61))	('monosomy-3', 'Var', (120, 130))
32995	33302435	A possible reason accounting for this observation might be the downregulation of genes encoding ribosomal components in the UM cells with monosomy-3, which may be hindering the protein translation in the metabolically challenged, irradiated tumors.	('monosomy-3', 'Var', (138, 148))	('genes', 'Gene', (81, 86))	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('tumors', 'Disease', (241, 247))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('hindering', 'NegReg', (163, 172))	('protein translation', 'biological_process', 'GO:0006412', ('177', '196'))	('downregulation', 'NegReg', (63, 77))	('protein translation', 'MPA', (177, 196))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
32996	33302435	Accordingly, the intensity of the GLUT3 immunoreactivity was weaker in the irradiated tumors with monosomy-3, but the ratio of the GLUT3 isoform to total GLUT1-3 did not differ in the non-irradiated or the irradiated groups with regard to the monosomy-3 status.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('weaker', 'NegReg', (61, 67))	('GLUT3', 'Gene', '6515', (34, 39))	('GLUT3', 'Gene', (34, 39))	('monosomy-3', 'Var', (98, 108))	('intensity', 'MPA', (17, 26))	('tumors', 'Disease', (86, 92))	('GLUT3', 'Gene', '6515', (131, 136))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('GLUT3', 'Gene', (131, 136))
32997	33302435	The lower immunoreactivity for GLUT3 in the irradiated tumors with monosomy-3 may initially appear as a very contradictory finding due to the stronger affinity of GLUT3 for glucose compared to GLUT1.	('glucose', 'Chemical', 'MESH:D005947', (173, 180))	('lower', 'NegReg', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('monosomy-3', 'Var', (67, 77))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('GLUT3', 'Gene', '6515', (31, 36))	('GLUT3', 'Gene', '6515', (163, 168))	('tumors', 'Disease', (55, 61))	('stronger', 'PosReg', (142, 150))	('affinity', 'Interaction', (151, 159))	('GLUT3', 'Gene', (31, 36))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('GLUT3', 'Gene', (163, 168))	('glucose', 'MPA', (173, 180))	('immunoreactivity', 'MPA', (10, 26))
33002	33302435	Likewise, mannose could impair the tumor glycolysis and enhance chemosensitivity in a cell culture and animal studies.	('impair', 'NegReg', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor glycolysis', 'Disease', 'MESH:C564972', (35, 51))	('glycolysis', 'biological_process', 'GO:0006096', ('41', '51'))	('enhance', 'PosReg', (56, 63))	('mannose', 'Chemical', 'MESH:D008358', (10, 17))	('tumor glycolysis', 'Disease', (35, 51))	('mannose', 'Var', (10, 17))	('chemosensitivity in a', 'CPA', (64, 85))
33006	33302435	Since an aberrant YAP1 activity is also implicated in the pathogenesis of UM, it would be very informative to conduct further studies on the involvement of YAP1 in the regulation of GLUT isoforms in UM.	('GLUT', 'Gene', (182, 186))	('GLUT', 'Gene', '6513', (182, 186))	('pathogenesis', 'biological_process', 'GO:0009405', ('58', '70'))	('YAP1', 'Gene', (18, 22))	('YAP1', 'Gene', '10413', (18, 22))	('implicated', 'Reg', (40, 50))	('YAP1', 'Gene', (156, 160))	('activity', 'MPA', (23, 31))	('YAP1', 'Gene', '10413', (156, 160))	('aberrant', 'Var', (9, 17))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('UM', 'Phenotype', 'HP:0007716', (199, 201))	('regulation', 'biological_process', 'GO:0065007', ('168', '178'))
33008	33302435	Several "hot-spot" mutations of p53 that are frequently observed in various tumors have resulted in the upregulation of GLUT1.	('upregulation', 'PosReg', (104, 116))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('GLUT1', 'Protein', (120, 125))	('mutations', 'Var', (19, 28))	('p53', 'Gene', (32, 35))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('p53', 'Gene', '7157', (32, 35))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
33009	33302435	However, such mutations have led to a significant increase in the levels of the p53 protein.	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('p53', 'Gene', (80, 83))	('increase', 'PosReg', (50, 58))	('p53', 'Gene', '7157', (80, 83))	('levels of', 'MPA', (66, 75))	('mutations', 'Var', (14, 23))
33012	33302435	The dysregulation of GLUT1 dynamics in response to the p53-overexpression in UM cells may, therefore, be a novel aspect involved in the aggressive course of this disease, which deserves further investigation.	('p53', 'Gene', '7157', (55, 58))	('p53', 'Gene', (55, 58))	('involved', 'Reg', (120, 128))	('dysregulation', 'Var', (4, 17))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('GLUT1', 'Protein', (21, 26))
33020	33302435	We have also recently reported a more insulin-resistant gene expression profile in the UMs with monosomy-3, which might interfere with the storage of excessive glucose as normal glycogen in such tumors.	('insulin', 'Gene', '3630', (38, 45))	('monosomy-3', 'Var', (96, 106))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('UM', 'Phenotype', 'HP:0007716', (87, 89))	('storage', 'biological_process', 'GO:0051235', ('139', '146'))	('age', 'Gene', (143, 146))	('insulin', 'molecular_function', 'GO:0016088', ('38', '45'))	('glucose', 'Chemical', 'MESH:D005947', (160, 167))	('interfere', 'NegReg', (120, 129))	('gene expression', 'biological_process', 'GO:0010467', ('56', '71'))	('insulin', 'Gene', (38, 45))	('excessive glucose', 'Phenotype', 'HP:0003074', (150, 167))	('age', 'Gene', '5973', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('more', 'PosReg', (33, 37))	('glycogen', 'Chemical', 'MESH:D006003', (178, 186))
33031	33302435	Since the uptake of glucose, which is available at an extracellular concentration of 9.2 mM, can be efficiently mediated by GLUT1 (Km: 3-7 mM) but not GLUT2 (Km: 17 mM), the disseminated UM cells with monosomy-3 and a higher GLUT1:GLUT2 ratio might have profited more from such a hyperglycemic environment.	('mediated', 'Reg', (112, 120))	('uptake of glucose', 'MPA', (10, 27))	('UM', 'Phenotype', 'HP:0007716', (187, 189))	('uptake', 'biological_process', 'GO:0098657', ('10', '16'))	('hyperglycemic environment', 'Phenotype', 'HP:0003074', (280, 305))	('GLUT1', 'Var', (124, 129))	('extracellular', 'cellular_component', 'GO:0005576', ('54', '67'))	('uptake', 'biological_process', 'GO:0098739', ('10', '16'))	('glucose', 'Chemical', 'MESH:D005947', (20, 27))
33035	33302435	The small molecules WZB117 and STF-31, which act as the inhibitors of GLUT1, could also suppress the tumor growth in cell lines and animal experiments while exerting a synergism with the chemotherapeutics such as Cisplatin or Paclitaxel.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('WZB117', 'Chemical', 'MESH:C576807', (20, 26))	('Paclitaxel', 'Chemical', 'MESH:D017239', (226, 236))	('suppress', 'NegReg', (88, 96))	('WZB117', 'Var', (20, 26))	('STF-31', 'Gene', (31, 37))	('Cisplatin', 'Chemical', 'MESH:D002945', (213, 222))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
33063	33302435	Signal quantification was performed by determining both the percentage of the cells with monosomy-3 within an area and the chromosomal index as described.	('monosomy-3', 'Var', (89, 99))	('age', 'Gene', '5973', (67, 70))	('age', 'Gene', (67, 70))
33064	33302435	For the former method, the percentage of cells with or without monosomy-3 within a given area was calculated in a minimum of n = 203 non-overlapping nuclei except for one patient with a very small sample (n = 88 quantified nuclei).	('age', 'Gene', (34, 37))	('monosomy-3', 'Var', (63, 73))	('patient', 'Species', '9606', (171, 178))	('age', 'Gene', '5973', (34, 37))
33065	33302435	Tumors with a percentage of monosomy-3-positive cells equal to or above the median were scored as "1".	('monosomy-3-positive cells', 'Var', (28, 53))	('age', 'Gene', (21, 24))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('age', 'Gene', '5973', (21, 24))
33067	33302435	The tumors that received the score "1" for both parameters were classified as monosomy-3 tumors whereas the samples that received the score "0" with both methods were classified as disomy-3.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('score "1', 'Var', (29, 37))	('monosomy-3', 'Disease', (78, 88))
33074	33302435	In conclusion, our findings provide the first insight into the monosomy-3-dependent alterations in the glucose transporter profile of UM cells.	('alterations', 'Reg', (84, 95))	('UM', 'Phenotype', 'HP:0007716', (134, 136))	('monosomy-3-dependent', 'Var', (63, 83))	('glucose transporter', 'Gene', (103, 122))	('glucose transporter', 'Gene', '6513', (103, 122))
33075	33302435	Upregulation of the high-affinity transporter GLUT1 possibly as a compensation for the low-affinity isoform GLUT2 may be a novel mechanism that increases the metastatic potential of the UM cells with monosomy-3 by enhancing the basal level of glucose uptake.	('Upregulation', 'PosReg', (0, 12))	('increases', 'PosReg', (144, 153))	('monosomy-3', 'Var', (200, 210))	('basal level of glucose uptake', 'MPA', (228, 257))	('UM', 'Phenotype', 'HP:0007716', (186, 188))	('glucose', 'Chemical', 'MESH:D005947', (243, 250))	('glucose uptake', 'biological_process', 'GO:0046323', ('243', '257'))	('metastatic potential', 'CPA', (158, 178))	('enhancing', 'PosReg', (214, 223))
33221	33302412	Quantitative reverse transcription real time PCR (qRT-PCR) was performed using TaqMan primer probes (Applied Biosystems, Foster City, CA, USA) as described before: glycerinaldehyde-3-phosphate-dehydrogenase (GAPDH) (Hs99999905_m1), VEGF-A (Hs_00173626_m1), FLT-1/VEGFR1 (Hs00176573_m1), KDR/VEGFR2 (Hs_00176676_m1).	('VEGFR2', 'Gene', (291, 297))	('reverse transcription', 'biological_process', 'GO:0001171', ('13', '34'))	('Hs99999905_m1', 'Var', (216, 229))	('VEGFR1', 'Gene', '2321', (263, 269))	('Hs00176573_m1', 'Var', (271, 284))	('Hs_00173626_m1', 'Var', (240, 254))	('VEGFR2', 'Gene', '3791', (291, 297))	('Hs_00176676_m1', 'Var', (299, 313))	('VEGFR1', 'Gene', (263, 269))	('VEGF-A', 'Gene', '7422', (232, 238))	('VEGF-A', 'Gene', (232, 238))
33303	25812921	Trametinib in the treatment of melanoma Aberrant Mitogen Activated Protein Kinase (MAPK) pathway signaling is a hallmark of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('hallmark of melanoma', 'Disease', (112, 132))	('hallmark of melanoma', 'Disease', 'MESH:D008545', (112, 132))	('signaling', 'biological_process', 'GO:0023052', ('97', '106'))	('MAPK', 'molecular_function', 'GO:0004707', ('83', '87'))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('Aberrant', 'Var', (40, 48))
33306	25812921	Trametinib was the first MEK inhibitor approved for use in treatment of advanced BRAFV600 mutant melanoma as a single agent and in combination with BRAF inhibitor, dabrafenib.	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('MEK', 'Gene', (25, 28))	('MEK', 'Gene', '5609', (25, 28))	('mutant', 'Var', (90, 96))	('BRAF', 'Gene', '673', (81, 85))	('BRAF', 'Gene', (81, 85))	('dabrafenib', 'Chemical', 'MESH:C561627', (164, 174))	('BRAF', 'Gene', '673', (148, 152))	('BRAF', 'Gene', (148, 152))
33308	25812921	Furthermore, we briefly comment on trametinib for NRAS mutant and other non-BRAF mutant subsets of melanoma.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('NRAS', 'Gene', (50, 54))	('mutant', 'Var', (55, 61))	('trametinib', 'Chemical', 'MESH:C560077', (35, 45))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))
33309	25812921	Trametinib is a novel oral MEK inhibitor with clinical activity in BRAFV600 mutant metastatic melanoma alone and in combination with dabrafenib.	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('BRAF', 'Gene', '673', (67, 71))	('MEK', 'Gene', (27, 30))	('MEK', 'Gene', '5609', (27, 30))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('mutant', 'Var', (76, 82))	('BRAF', 'Gene', (67, 71))	('dabrafenib', 'Chemical', 'MESH:C561627', (133, 143))
33310	25812921	Trametinib is currently being explored in other genetic subsets as well, particularly those with NRAS mutations or atypical BRAF alterations.	('NRAS', 'Gene', (97, 101))	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('BRAF', 'Gene', '673', (124, 128))	('mutations', 'Var', (102, 111))	('alterations', 'Var', (129, 140))	('BRAF', 'Gene', (124, 128))
33316	25812921	BRAFV600 mutations are seen in 40-50% of all melanomas.	('mutations', 'Var', (9, 18))	('BRAF', 'Gene', '673', (0, 4))	('melanomas', 'Disease', (45, 54))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanomas', 'Disease', 'MESH:D008545', (45, 54))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))
33317	25812921	A substitution of valine for glutamine at this codon (V600E) occurs in nearly 90% of all BRAF mutant melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (101, 110))	('valine', 'Chemical', 'MESH:D014633', (18, 24))	('melanomas', 'Disease', 'MESH:D008545', (101, 110))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('glutamine', 'Chemical', 'MESH:D005973', (29, 38))	('mutant', 'Var', (94, 100))	('V600E', 'Mutation', 'rs113488022', (54, 59))	('BRAF', 'Gene', '673', (89, 93))	('melanomas', 'Disease', (101, 110))	('BRAF', 'Gene', (89, 93))	('V600E', 'Var', (54, 59))
33318	25812921	Following BRAF, NRAS mutations are frequently noted in 15-25% of all melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('noted', 'Reg', (46, 51))	('NRAS', 'Gene', (16, 20))	('melanomas', 'Disease', (69, 78))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('melanomas', 'Disease', 'MESH:D008545', (69, 78))	('melanomas', 'Phenotype', 'HP:0002861', (69, 78))	('mutations', 'Var', (21, 30))
33319	25812921	Other less common alterations include KIT mutations (1-2%), and mutations in GNAQ and GNA11 (80-90% of ocular melanomas).	('GNA11', 'Gene', '2767', (86, 91))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('KIT', 'molecular_function', 'GO:0005020', ('38', '41'))	('ocular melanomas', 'Disease', 'MESH:D008545', (103, 119))	('GNAQ', 'Gene', (77, 81))	('ocular melanomas', 'Phenotype', 'HP:0025534', (103, 119))	('ocular melanomas', 'Disease', (103, 119))	('mutations', 'Var', (64, 73))	('GNA11', 'Gene', (86, 91))	('mutations', 'Var', (42, 51))	('GNAQ', 'Gene', '2776', (77, 81))	('KIT', 'Gene', (38, 41))
33321	25812921	However, recently the NF1 mutated or deleted (a potential driver mutation) subset overall appears to represent up to 12% melanomas and is found within the BRAF-,NRAS-,CKIT- melanomas.	('melanomas', 'Disease', 'MESH:D008545', (121, 130))	('melanomas', 'Disease', (173, 182))	('BRAF', 'Gene', (155, 159))	('NF1', 'Gene', (22, 25))	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanomas', 'Phenotype', 'HP:0002861', (121, 130))	('NF1', 'Gene', '4763', (22, 25))	('melanomas', 'Disease', 'MESH:D008545', (173, 182))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanomas', 'Phenotype', 'HP:0002861', (173, 182))	('mutated', 'Var', (26, 33))	('melanomas', 'Disease', (121, 130))	('BRAF', 'Gene', '673', (155, 159))
33322	25812921	Of note, certain mutations are notably associated with specific subtypes of melanomas such as KIT mutations seen in 15-20% of acral and mucosal melanoma.	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('mucosal melanoma', 'Disease', (136, 152))	('KIT', 'molecular_function', 'GO:0005020', ('94', '97'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (136, 152))	('melanomas', 'Disease', 'MESH:D008545', (76, 85))	('KIT', 'Gene', (94, 97))	('mutations', 'Var', (98, 107))	('associated', 'Reg', (39, 49))	('melanomas', 'Disease', (76, 85))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('mutations', 'Var', (17, 26))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
33323	25812921	Likewise, GNAQ and GNA11 mutations are seen in the large majority of uveal melanomas.	('mutations', 'Var', (25, 34))	('GNAQ', 'Gene', '2776', (10, 14))	('GNA11', 'Gene', (19, 24))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('GNA11', 'Gene', '2767', (19, 24))	('GNAQ', 'Gene', (10, 14))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('uveal melanomas', 'Disease', (69, 84))	('uveal melanomas', 'Phenotype', 'HP:0007716', (69, 84))	('seen', 'Reg', (39, 43))	('uveal melanomas', 'Disease', 'MESH:C536494', (69, 84))
33324	25812921	Among several MEK inhibitors in clinical development, Trametinib (GSK1120212, Mekinist , GlaxoSmithKline, London) is the only MEK 1/2 inhibitor approved by FDA either as monotherapy or in combination with dabrafenib for the treatment of unresectable or metastatic BRAFV600E or BRAFV600K mutant melanoma.	('MEK', 'Gene', '5609', (126, 129))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('melanoma', 'Disease', (294, 302))	('MEK', 'Gene', '5609', (14, 17))	('metastatic', 'CPA', (253, 263))	('BRAFV600E', 'Var', (264, 273))	('MEK', 'Gene', (126, 129))	('MEK', 'Gene', (14, 17))	('BRAFV600K', 'Var', (277, 286))	('MEK 1/2', 'Gene', '5604;5605', (126, 133))	('dabrafenib', 'Chemical', 'MESH:C561627', (205, 215))	('BRAFV600K', 'Mutation', 'rs121913227', (277, 286))	('melanoma', 'Disease', 'MESH:D008545', (294, 302))	('MEK 1/2', 'Gene', (126, 133))	('BRAFV600E', 'Mutation', 'rs113488022', (264, 273))	('GSK', 'molecular_function', 'GO:0050321', ('66', '69'))	('MEK 1', 'molecular_function', 'GO:0004708', ('126', '131'))	('Trametinib', 'Chemical', 'MESH:C560077', (54, 64))	('GSK1120212', 'Chemical', 'MESH:C560077', (66, 76))
33327	25812921	In particular, there has been remarkable progress for the BRAF mutant subset of melanoma with the development of the selective BRAF and MEK inhibitors.	('mutant', 'Var', (63, 69))	('MEK', 'Gene', (136, 139))	('BRAF', 'Gene', '673', (127, 131))	('MEK', 'Gene', '5609', (136, 139))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Disease', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('BRAF', 'Gene', (127, 131))	('BRAF', 'Gene', '673', (58, 62))	('BRAF', 'Gene', (58, 62))
33330	25812921	These resistance mechanisms include aberrant BRAF splicing, increase in BRAF copy number gains, mutations in NRAS or MEK1/2, COT overexpression, growth factor up regulation, and alterations in the PI3K/AKT pathway.	('MEK1/2', 'Gene', '5604;5605', (117, 123))	('MEK1/2', 'Gene', (117, 123))	('splicing', 'biological_process', 'GO:0045292', ('50', '58'))	('regulation', 'biological_process', 'GO:0065007', ('162', '172'))	('BRAF', 'Gene', '673', (72, 76))	('mutations', 'Var', (96, 105))	('BRAF', 'Gene', (72, 76))	('up regulation', 'PosReg', (159, 172))	('PI3K', 'molecular_function', 'GO:0016303', ('197', '201'))	('COT', 'Gene', (125, 128))	('increase', 'PosReg', (60, 68))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('COT', 'Gene', '1326', (125, 128))	('BRAF copy number gains', 'Disease', 'MESH:D015430', (72, 94))	('alterations', 'Reg', (178, 189))	('AKT', 'Gene', (202, 205))	('NRAS', 'Gene', (109, 113))	('BRAF copy number gains', 'Disease', (72, 94))	('growth factor', 'CPA', (145, 158))	('AKT', 'Gene', '207', (202, 205))	('MEK1', 'molecular_function', 'GO:0004708', ('117', '121'))
33335	25812921	Although the initial responses are more prolonged with the combination of BRAF and MEK inhibition (approximately 9-11 months), acquired resistance still occurs and usually involves MAPK reactivation.	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('MAPK reactivation', 'MPA', (181, 198))	('MEK', 'Gene', (83, 86))	('MEK', 'Gene', '5609', (83, 86))	('acquired resistance', 'MPA', (127, 146))	('inhibition', 'Var', (87, 97))	('MAPK', 'molecular_function', 'GO:0004707', ('181', '185'))
33336	25812921	In addition, there is encouraging early clinical activity of other MEK inhibitors (binimetinib, RO4987655) alone and in combination with CDK4/6 inhibitors (palbociclib, LEE011) and also emerging evidence of synergistic activity of trametinib in combination with metformin in NRAS mutant melanoma.	('LEE011', 'Chemical', 'MESH:C000589651', (169, 175))	('CDK4/6', 'Gene', '1019;1021', (137, 143))	('trametinib', 'Chemical', 'MESH:C560077', (231, 241))	('RO4987655', 'Chemical', 'MESH:C559138', (96, 105))	('CDK', 'molecular_function', 'GO:0004693', ('137', '140'))	('melanoma', 'Phenotype', 'HP:0002861', (287, 295))	('mutant', 'Var', (280, 286))	('melanoma', 'Disease', (287, 295))	('palbociclib', 'Chemical', 'MESH:C500026', (156, 167))	('CDK4/6', 'Gene', (137, 143))	('MEK', 'Gene', (67, 70))	('MEK', 'Gene', '5609', (67, 70))	('metformin', 'Chemical', 'MESH:D008687', (262, 271))	('melanoma', 'Disease', 'MESH:D008545', (287, 295))	('NRAS', 'Gene', (275, 279))	('binimetinib', 'Chemical', 'MESH:C581313', (83, 94))
33362	25812921	Likewise, trametinib has also shown differential high sensitivity against BRAF (IC50 = 0.3-0.85 nM) and NRAS mutant cell lines (IC50 = 0.36-0.63 nM), as compared with wild type (IC50 = 0.31-10 nM) melanoma cell lines.	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('melanoma', 'Disease', (197, 205))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('trametinib', 'Chemical', 'MESH:C560077', (10, 20))	('mutant', 'Var', (109, 115))	('NRAS', 'Gene', (104, 108))	('sensitivity', 'MPA', (54, 65))
33363	25812921	In cell lines and xenograft models of RAS mutated tumors, MEK was identified as potential therapeutic target based on the complete suppression of tumor growth in BRAF mutant xenografts and partial inhibition in RAS mutant tumors with use of selective MEK inhibitors.	('MEK', 'Gene', '5609', (251, 254))	('tumor', 'Disease', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('mutant', 'Var', (167, 173))	('tumors', 'Disease', (222, 228))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('MEK', 'Gene', (251, 254))	('MEK', 'Gene', '5609', (58, 61))	('RAS', 'Gene', (211, 214))	('tumor', 'Disease', (50, 55))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('MEK', 'Gene', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', (222, 227))	('BRAF', 'Gene', '673', (162, 166))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('BRAF', 'Gene', (162, 166))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('suppression', 'NegReg', (131, 142))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', (50, 56))
33367	25812921	In vitro, trametinib suppressed the tumor growth and had a favorable pharmacokinetic profile with a long circulating half-life and sustained suppression of p-ERK1/2 for more than 24 hours with greater antitumor effect among mutant BRAF or RAS tumors.	('BRAF', 'Gene', (231, 235))	('BRAF', 'Gene', '673', (231, 235))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', (243, 248))	('suppression', 'NegReg', (141, 152))	('mutant', 'Var', (224, 230))	('ERK', 'Gene', '5594', (158, 161))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('RAS tumors', 'Disease', (239, 249))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('suppressed', 'NegReg', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('greater', 'PosReg', (193, 200))	('ERK', 'Gene', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('RAS tumors', 'Disease', 'MESH:D009369', (239, 249))	('ERK1', 'molecular_function', 'GO:0004707', ('158', '162'))	('tumor', 'Disease', (205, 210))	('trametinib', 'Chemical', 'MESH:C560077', (10, 20))
33373	25812921	Among all patients, objective tumor responses were noted in 10% with majority of responses in BRAF mutant melanomas.	('BRAF', 'Gene', (94, 98))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanomas', 'Disease', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('BRAF', 'Gene', '673', (94, 98))	('melanomas', 'Phenotype', 'HP:0002861', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('patients', 'Species', '9606', (10, 18))	('melanomas', 'Disease', 'MESH:D008545', (106, 115))	('mutant', 'Var', (99, 105))	('tumor', 'Disease', (30, 35))
33374	25812921	Among melanoma patients, the response rates were significantly better in BRAF mutant melanoma (33%) compared to BRAF wild type tumors (10%).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('BRAF', 'Gene', '673', (73, 77))	('patients', 'Species', '9606', (15, 23))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('response', 'MPA', (29, 37))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('better', 'PosReg', (63, 69))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('BRAF', 'Gene', (73, 77))	('melanoma', 'Disease', (6, 14))	('type tumors', 'Disease', 'MESH:D009369', (122, 133))	('mutant', 'Var', (78, 84))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))	('type tumors', 'Disease', (122, 133))
33375	25812921	Although no objective responses were noted in NRAS mutant or uveal melanoma patients, approximately 27% (2 of 7) and 12% (2 of 16) had stable disease respectively.	('patients', 'Species', '9606', (76, 84))	('NRAS', 'Gene', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('mutant', 'Var', (51, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('uveal melanoma', 'Disease', 'MESH:C536494', (61, 75))	('uveal melanoma', 'Disease', (61, 75))
33382	25812921	Additionally, preclinical studies in human leukemic cells and primary mouse leukemia with NRAS mutations showed that trametinib reduced cell proliferation and prolonged survival.	('survival', 'CPA', (169, 177))	('NRAS', 'Gene', (90, 94))	('leukemic', 'Disease', (43, 51))	('reduced', 'NegReg', (128, 135))	('mouse', 'Species', '10090', (70, 75))	('trametinib', 'Chemical', 'MESH:C560077', (117, 127))	('prolonged', 'PosReg', (159, 168))	('leukemia', 'Disease', (76, 84))	('mutations', 'Var', (95, 104))	('leukemia', 'Disease', 'MESH:D007938', (76, 84))	('leukemic', 'Disease', 'MESH:D007938', (43, 51))	('human', 'Species', '9606', (37, 42))	('leukemia', 'Phenotype', 'HP:0001909', (76, 84))	('cell proliferation', 'biological_process', 'GO:0008283', ('136', '154'))	('cell proliferation', 'CPA', (136, 154))
33383	25812921	An early phase I trial showed promising clinical activity of trametinib in NRAS or KRAS mutant acute myeloid leukemia (AML).	('KRAS', 'Gene', (83, 87))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (95, 117))	('trametinib', 'Chemical', 'MESH:C560077', (61, 71))	('KRAS', 'Gene', '3845', (83, 87))	('acute myeloid leukemia', 'Disease', (95, 117))	('AML', 'Disease', 'MESH:D015470', (119, 122))	('NRAS', 'Gene', (75, 79))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (95, 117))	('mutant', 'Var', (88, 94))	('AML', 'Disease', (119, 122))	('leukemia', 'Phenotype', 'HP:0001909', (109, 117))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (101, 117))
33385	25812921	In a phase 1b dose escalation study of 113 patients with RAS or BRAF mutant advanced solid tumors, the combination of trametinib with pan PIK3 inhibitor, buparlisib (BKM120) is well tolerated and showed favorable activity especially in KRAS mutant ovarian cancer patients.	('RAS', 'Gene', (57, 60))	('BRAF', 'Gene', '673', (64, 68))	('BRAF', 'Gene', (64, 68))	('KRAS', 'Gene', (236, 240))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('trametinib', 'Chemical', 'MESH:C560077', (118, 128))	('solid tumors', 'Disease', (85, 97))	('PIK3', 'Gene', (138, 142))	('PIK3', 'Gene', '5294', (138, 142))	('BKM120', 'Chemical', 'MESH:C571178', (166, 172))	('ovarian cancer', 'Disease', 'MESH:D010051', (248, 262))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('activity', 'MPA', (213, 221))	('patients', 'Species', '9606', (43, 51))	('solid tumors', 'Disease', 'MESH:D009369', (85, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('buparlisib', 'Chemical', 'MESH:C571178', (154, 164))	('ovarian cancer', 'Disease', (248, 262))	('mutant', 'Var', (69, 75))	('patients', 'Species', '9606', (263, 271))	('ovarian cancer', 'Phenotype', 'HP:0100615', (248, 262))	('KRAS', 'Gene', '3845', (236, 240))
33388	25812921	In a phase II open label study of metastatic BRAFV600 mutant melanoma treated with trametinib, the response rates and progression free survival were significantly better for BRAF inhibitor naive patients.	('response rates', 'CPA', (99, 113))	('BRAF', 'Gene', '673', (174, 178))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('BRAF', 'Gene', (45, 49))	('better', 'PosReg', (163, 169))	('BRAF', 'Gene', (174, 178))	('melanoma', 'Disease', (61, 69))	('BRAF', 'Gene', '673', (45, 49))	('patients', 'Species', '9606', (195, 203))	('mutant', 'Var', (54, 60))	('trametinib', 'Chemical', 'MESH:C560077', (83, 93))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('progression free survival', 'CPA', (118, 143))
33398	25812921	In the open label phase III METRIC study, a total of 322 patients with metastatic BRAFV600E or BRAFV600K mutated melanoma were randomized to receive either trametinib 2mg once daily or chemotherapy (dacarbazine or paclitaxel).	('BRAFV600K mutated', 'Var', (95, 112))	('patients', 'Species', '9606', (57, 65))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('BRAFV600K', 'Mutation', 'rs121913227', (95, 104))	('melanoma', 'Disease', (113, 121))	('paclitaxel', 'Chemical', 'MESH:D017239', (214, 224))	('BRAFV600E', 'Var', (82, 91))	('BRAFV600E', 'Mutation', 'rs113488022', (82, 91))	('dacarbazine', 'Chemical', 'MESH:D003606', (199, 210))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('trametinib', 'Chemical', 'MESH:C560077', (156, 166))
33401	25812921	In the phase III COMBI-d trial, 423 patients with newly diagnosed advanced BRAFV600E or BRAFV600K mutated melanoma were treated with either dabrafenib plus trametinib or to dabrafenib plus placebo.	('BRAFV600E', 'Var', (75, 84))	('BRAFV600K mutated', 'Var', (88, 105))	('dabrafenib', 'Chemical', 'MESH:C561627', (173, 183))	('patients', 'Species', '9606', (36, 44))	('BRAFV600K', 'Mutation', 'rs121913227', (88, 97))	('dabrafenib', 'Chemical', 'MESH:C561627', (140, 150))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('BRAFV600E', 'Mutation', 'rs113488022', (75, 84))	('melanoma', 'Disease', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('trametinib', 'Chemical', 'MESH:C560077', (156, 166))
33406	25812921	NRAS mutant melanomas are the second most common molecular cohort representing nearly 15-25% of all melanomas.	('melanomas', 'Disease', 'MESH:D008545', (100, 109))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanomas', 'Phenotype', 'HP:0002861', (12, 21))	('melanomas', 'Disease', 'MESH:D008545', (12, 21))	('melanomas', 'Disease', (100, 109))	('mutant', 'Var', (5, 11))	('NRAS', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanomas', 'Disease', (12, 21))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))
33407	25812921	Unlike mutant BRAF, mutant NRAS activates downstream CRAF, MEK, and ERK in the MAP kinase pathway bypassing BRAF.	('ERK', 'molecular_function', 'GO:0004707', ('68', '71'))	('CRAF', 'molecular_function', 'GO:0004709', ('53', '57'))	('BRAF', 'Gene', (108, 112))	('MAP kinase pathway', 'Pathway', (79, 97))	('MEK', 'Gene', (59, 62))	('MEK', 'Gene', '5609', (59, 62))	('ERK', 'Gene', '5594', (68, 71))	('MAP', 'molecular_function', 'GO:0004239', ('79', '82'))	('activates', 'PosReg', (32, 41))	('BRAF', 'Gene', '673', (14, 18))	('ERK', 'Gene', (68, 71))	('BRAF', 'Gene', '673', (108, 112))	('BRAF', 'Gene', (14, 18))	('NRAS', 'Gene', (27, 31))	('CRAF', 'Gene', (53, 57))	('CRAF', 'Gene', '5894', (53, 57))	('mutant', 'Var', (20, 26))
33409	25812921	MEK inhibition, by contrast, may have a role in treating NRAS mutant melanoma.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('mutant', 'Var', (62, 68))	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('NRAS', 'Gene', (57, 61))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
33415	25812921	In a phase 1b/2 study of the combination of binimetinib with selective CDK4/6 inhibitor LEE011 in NRAS mutant melanoma, 7 of 21 patients had partial responses (33%) and >80% of patients had some degree of tumor regression.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('mutant', 'Var', (103, 109))	('CDK4/6', 'Gene', (71, 77))	('patients', 'Species', '9606', (177, 185))	('binimetinib', 'Chemical', 'MESH:C581313', (44, 55))	('LEE011', 'Var', (88, 94))	('NRAS', 'Gene', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('CDK', 'molecular_function', 'GO:0004693', ('71', '74'))	('CDK4/6', 'Gene', '1019;1021', (71, 77))	('patients', 'Species', '9606', (128, 136))	('LEE011', 'Chemical', 'MESH:C000589651', (88, 94))
33417	25812921	Furthermore, strong preclinical evidence suggests dual inhibition of PI3K/AKT/mTOR pathway along with MAPK pathway is important in NRAS mutant melanoma.	('PI3K', 'molecular_function', 'GO:0016303', ('69', '73'))	('NRAS', 'Gene', (131, 135))	('AKT', 'Gene', '207', (74, 77))	('MAPK', 'molecular_function', 'GO:0004707', ('102', '106'))	('mTOR', 'Gene', (78, 82))	('MAPK pathway', 'Pathway', (102, 114))	('mTOR', 'Gene', '2475', (78, 82))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('AKT', 'Gene', (74, 77))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('mutant', 'Var', (136, 142))	('inhibition', 'NegReg', (55, 65))
33418	25812921	Recently, the combination of trametinib with metformin (which indirectly inhibits the PI3K/AKT/mTOR pathway) showed synergistic activity in NRAS mutant cell lines as well as in xenograft tumor models.	('AKT', 'Gene', '207', (91, 94))	('xenograft tumor', 'Disease', 'MESH:D009369', (177, 192))	('combination', 'Interaction', (14, 25))	('mutant', 'Var', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('inhibits', 'NegReg', (73, 81))	('AKT', 'Gene', (91, 94))	('metformin', 'Chemical', 'MESH:D008687', (45, 54))	('NRAS', 'Gene', (140, 144))	('mTOR', 'Gene', (95, 99))	('trametinib', 'Chemical', 'MESH:C560077', (29, 39))	('mTOR', 'Gene', '2475', (95, 99))	('PI3K', 'molecular_function', 'GO:0016303', ('86', '90'))	('xenograft tumor', 'Disease', (177, 192))
33419	25812921	Combined inhibition of MEK and ERK also appears to be a promising strategy in NRAS-mutant pre-clinical models.	('inhibition', 'NegReg', (9, 19))	('ERK', 'Gene', (31, 34))	('NRAS-mutant', 'Gene', (78, 89))	('NRAS-mutant', 'Var', (78, 89))	('ERK', 'molecular_function', 'GO:0004707', ('31', '34'))	('pre', 'molecular_function', 'GO:0003904', ('90', '93'))	('ERK', 'Gene', '5594', (31, 34))	('MEK', 'Gene', (23, 26))	('MEK', 'Gene', '5609', (23, 26))
33420	25812921	Rationally designed targeted therapies combinations including trametinib may play a major role in the therapy of NRAS mutant melanoma in the future.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('NRAS', 'Gene', (113, 117))	('mutant', 'Var', (118, 124))	('trametinib', 'Chemical', 'MESH:C560077', (62, 72))
33421	25812921	Despite rapid developments in BRAF mutant melanoma, no targeted therapy options exist for patients with BRAF/NRAS wild type melanoma.	('melanoma', 'Disease', (42, 50))	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('type melanoma', 'Disease', 'MESH:D008545', (119, 132))	('melanoma', 'Disease', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('mutant', 'Var', (35, 41))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('BRAF', 'Gene', '673', (104, 108))	('type melanoma', 'Disease', (119, 132))	('BRAF', 'Gene', (104, 108))	('patients', 'Species', '9606', (90, 98))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
33422	25812921	Preclinical evidence suggests activity of trametinib in BRAF/NRAS wild type melanoma cell lines with or without loss of NF1 (~12% of melanomas).	('melanomas', 'Disease', (133, 142))	('BRAF', 'Gene', '673', (56, 60))	('type melanoma', 'Disease', 'MESH:D008545', (71, 84))	('trametinib', 'Chemical', 'MESH:C560077', (42, 52))	('melanomas', 'Disease', 'MESH:D008545', (133, 142))	('type melanoma', 'Disease', (71, 84))	('NF1', 'Gene', (120, 123))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('NF1', 'Gene', '4763', (120, 123))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('loss', 'Var', (112, 116))	('activity', 'MPA', (30, 38))	('BRAF', 'Gene', (56, 60))
33424	25812921	Intriguingly several responses in patients with atypical BRAF mutations have been noted.	('patients', 'Species', '9606', (34, 42))	('mutations', 'Var', (62, 71))	('BRAF', 'Gene', (57, 61))	('BRAF', 'Gene', '673', (57, 61))
33425	25812921	Specifically, pre-clinical data, early trametinib studies, and a retrospective series the uncommon BRAF K601E and L597 mutations are sensitive to trametinib.	('K601E', 'Mutation', 'rs121913364', (104, 109))	('sensitive to trametinib', 'MPA', (133, 156))	('K601E', 'Var', (104, 109))	('BRAF', 'Gene', '673', (99, 103))	('BRAF', 'Gene', (99, 103))	('L597', 'Var', (114, 118))	('trametinib', 'Chemical', 'MESH:C560077', (146, 156))	('pre', 'molecular_function', 'GO:0003904', ('14', '17'))	('trametinib', 'Chemical', 'MESH:C560077', (39, 49))
33426	25812921	A phase II study of trametinib in patients with atypical BRAF mutations and fusions is now ongoing.	('BRAF', 'Gene', '673', (57, 61))	('trametinib', 'Chemical', 'MESH:C560077', (20, 30))	('BRAF', 'Gene', (57, 61))	('patients', 'Species', '9606', (34, 42))	('mutations', 'Var', (62, 71))
33428	25812921	atypical BRAF mutations), combinatorial strategies will likely be needed to prevent compensatory upregulation of the MAPK and other signaling pathways in BRAF/NRAS WT melanoma.	('MAPK', 'Pathway', (117, 121))	('NRAS WT melanoma', 'Disease', 'MESH:D008545', (159, 175))	('upregulation', 'PosReg', (97, 109))	('MAPK', 'molecular_function', 'GO:0004707', ('117', '121'))	('NRAS WT melanoma', 'Disease', (159, 175))	('BRAF', 'Gene', (9, 13))	('BRAF', 'Gene', '673', (154, 158))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('signaling', 'biological_process', 'GO:0023052', ('132', '141'))	('BRAF', 'Gene', (154, 158))	('mutations', 'Var', (14, 23))	('BRAF', 'Gene', '673', (9, 13))
33432	25812921	Other selective MEK inhibitors with preferential affinity for either BRAF or RAS mutant malignancies are also being developed.	('malignancies', 'Disease', (88, 100))	('MEK', 'Gene', (16, 19))	('RAS', 'Gene', (77, 80))	('mutant', 'Var', (81, 87))	('BRAF', 'Gene', '673', (69, 73))	('MEK', 'Gene', '5609', (16, 19))	('BRAF', 'Gene', (69, 73))	('malignancies', 'Disease', 'MESH:D009369', (88, 100))
33461	25812921	Recent randomized phase III studies have established this combination as the standard first-line targeted therapy options for patients with BRAFV600 mutant melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('mutant', 'Var', (149, 155))	('BRAF', 'Gene', '673', (140, 144))	('BRAF', 'Gene', (140, 144))	('patients', 'Species', '9606', (126, 134))
33465	25812921	Trametinib is the first FDA approved MEK inhibitor for the treatment of BRAFV600 mutant metastatic melanoma as single agent and in combination with dabrafenib.	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('dabrafenib', 'Chemical', 'MESH:C561627', (148, 158))	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (72, 76))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('mutant', 'Var', (81, 87))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('MEK', 'Gene', (37, 40))	('MEK', 'Gene', '5609', (37, 40))
33471	25812921	While trametinib and cobimetinib seem to have more activity in BRAF mutant melanomas, binimetinib has shown more promising activity in NRAS mutant melanoma.	('binimetinib', 'Chemical', 'MESH:C581313', (86, 97))	('activity', 'MPA', (51, 59))	('NRAS', 'Gene', (135, 139))	('melanomas', 'Disease', (75, 84))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('trametinib', 'Chemical', 'MESH:C560077', (6, 16))	('melanoma', 'Disease', (75, 83))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('BRAF', 'Gene', '673', (63, 67))	('melanomas', 'Disease', 'MESH:D008545', (75, 84))	('melanoma', 'Disease', (147, 155))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('BRAF', 'Gene', (63, 67))	('cobimetinib', 'Chemical', 'MESH:C574276', (21, 32))	('mutant', 'Var', (140, 146))	('mutant', 'Var', (68, 74))
33472	25812921	Other MEK inhibitors such as GDC-0623 and CH4987655 may have better efficacy in RAS mutant tumors by blocking feedback activation of MEK by BRAF wild type tumors.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('MEK', 'Gene', '5609', (133, 136))	('CH4987655', 'Chemical', 'MESH:C559138', (42, 51))	('MEK', 'Gene', '5609', (6, 9))	('MEK', 'Gene', (133, 136))	('MEK', 'Gene', (6, 9))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('type tumors', 'Disease', 'MESH:D009369', (150, 161))	('CH4987655', 'Var', (42, 51))	('feedback activation', 'MPA', (110, 129))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('GDC-0623', 'Chemical', 'MESH:C000622437', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('BRAF', 'Gene', '673', (140, 144))	('BRAF', 'Gene', (140, 144))	('tumors', 'Disease', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Disease', (91, 97))	('blocking', 'NegReg', (101, 109))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('type tumors', 'Disease', (150, 161))
33474	25812921	Unlike BRAFV600 mutant melanoma, targeted treatment options for non-BRAF mutant melanoma including those with NRAS mutations, atypical BRAF alterations, and deletions of NF1 are limited.	('BRAF', 'Gene', '673', (135, 139))	('NF1', 'Gene', (170, 173))	('mutations', 'Var', (115, 124))	('deletions', 'Var', (157, 166))	('BRAF', 'Gene', (135, 139))	('BRAF', 'Gene', '673', (68, 72))	('NF1', 'Gene', '4763', (170, 173))	('melanoma', 'Disease', (80, 88))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('BRAF', 'Gene', (68, 72))	('melanoma', 'Disease', (23, 31))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('mutant', 'Var', (73, 79))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('BRAF', 'Gene', '673', (7, 11))	('NRAS', 'Gene', (110, 114))	('BRAF', 'Gene', (7, 11))
33475	25812921	Preclinical and early clinical trials suggest sensitivity of trametinib to atypical BRAF mutations (non-V600) and NRAS mutant melanoma.	('trametinib', 'Chemical', 'MESH:C560077', (61, 71))	('BRAF', 'Gene', '673', (84, 88))	('NRAS', 'Gene', (114, 118))	('non-V600', 'Var', (100, 108))	('mutations (non-V600', 'Var', (89, 108))	('BRAF', 'Gene', (84, 88))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('mutant', 'Var', (119, 125))	('melanoma', 'Disease', (126, 134))
33481	25812921	While combined BRAF/MEK regimens have induced higher response rates, their use is limited to BRAF mutant melanoma.	('BRAF', 'Gene', '673', (15, 19))	('BRAF', 'Gene', (93, 97))	('BRAF', 'Gene', (15, 19))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('MEK', 'Gene', (20, 23))	('melanoma', 'Disease', (105, 113))	('MEK', 'Gene', '5609', (20, 23))	('response', 'MPA', (53, 61))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('BRAF', 'Gene', '673', (93, 97))	('mutant', 'Var', (98, 104))
33485	25812921	In addition, in a phase I study of 53 patients, the combination of ipilimumab with nivolumab resulted in rapid durable tumor regressions (80% or more) irrespective of BRAF mutations status in around 40% of patients but severe grade 3 or 4 adverse events were noted in 62% of patients.	('mutations', 'Var', (172, 181))	('tumor', 'Disease', (119, 124))	('regressions', 'NegReg', (125, 136))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('ipilimumab', 'Chemical', 'MESH:D000074324', (67, 77))	('nivolumab', 'Chemical', 'MESH:D000077594', (83, 92))	('patients', 'Species', '9606', (206, 214))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('patients', 'Species', '9606', (38, 46))	('patients', 'Species', '9606', (275, 283))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('combination', 'Interaction', (52, 63))
33488	25812921	Appropriate sequencing or combination of these targeted and immune agents in the treatment of BRAF mutant melanoma remains elusive.	('BRAF', 'Gene', (94, 98))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('mutant', 'Var', (99, 105))	('melanoma', 'Disease', (106, 114))	('BRAF', 'Gene', '673', (94, 98))
33492	25812921	In summary, trametinib in combination with dabrafenib has been a remarkable advancement in the treatment of BRAF mutant melanoma and has future potential in other non-BRAF mutant melanomas as well.	('melanomas', 'Disease', 'MESH:D008545', (179, 188))	('dabrafenib', 'Chemical', 'MESH:C561627', (43, 53))	('melanomas', 'Disease', (179, 188))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('advancement', 'PosReg', (76, 87))	('melanomas', 'Phenotype', 'HP:0002861', (179, 188))	('BRAF', 'Gene', '673', (108, 112))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('mutant', 'Var', (113, 119))	('melanoma', 'Disease', (179, 187))	('BRAF', 'Gene', (108, 112))	('trametinib', 'Chemical', 'MESH:C560077', (12, 22))
33525	31262050	The discovery of genetic alterations has led to the development of targeted therapies, such as tyrosine kinase inhibitors or BRAF inhibitors, new therapeutic options, and stratification of patients.	('alterations', 'Var', (25, 36))	('patients', 'Species', '9606', (189, 197))	('tyrosine kinase inhibitors', 'MPA', (95, 121))	('genetic alterations', 'Var', (17, 36))
33577	31262050	First analysed through candidate gene approaches, mutations were reported on NRAS, at the same hotspots as in human cancers (NRASQ61), and on PTEN, but not on BRAFV600 and KIT.	('mutations', 'Var', (50, 59))	('human', 'Species', '9606', (110, 115))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('KIT', 'molecular_function', 'GO:0005020', ('172', '175'))	('NRAS', 'Disease', (77, 81))
33578	31262050	Then, using array-comparative genomic hybridization (aCGH), recurrent deletions including CDKN2A and PTEN tumor suppressor genes were described.	('PTEN', 'Gene', (101, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('106', '122'))	('CDKN2A', 'Gene', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor suppressor', 'biological_process', 'GO:0051726', ('106', '122'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('deletions', 'Var', (70, 79))	('tumor', 'Disease', (106, 111))
33579	31262050	Substantial recurrent gains of chromosomes, notably, CFA13 (Canis familiaris) and CFA17 (involving at least KIT and MYC oncogenes) were identified, the most recurrent aberrations being a complex copy number profile on CFA30 with alternate losses and gains and CFA 10 rearrangements encompassing the oncogenes MDM2 and CDK4.	('CDK4', 'Gene', '481131', (318, 322))	('CFA30', 'Gene', (218, 223))	('CFA 10', 'Gene', (260, 266))	('MYC', 'Gene', '403924', (116, 119))	('CDK4', 'Gene', (318, 322))	('CDK', 'molecular_function', 'GO:0004693', ('318', '321'))	('KIT', 'molecular_function', 'GO:0005020', ('108', '111'))	('gains', 'PosReg', (250, 255))	('gains', 'PosReg', (22, 27))	('CFA17', 'Gene', (82, 87))	('MDM2', 'Gene', (309, 313))	('losses', 'NegReg', (239, 245))	('Canis familiaris', 'Species', '9615', (60, 76))	('CFA13', 'Gene', (53, 58))	('rearrangements', 'Var', (267, 281))	('MDM2', 'Gene', '403693', (309, 313))	('MYC', 'Gene', (116, 119))
33580	31262050	Most recent findings from NGS methods on canine oral melanoma of several breeds, through whole genome sequencing of five cases and targeted sequencing of 26 cases, exome sequencing of 65 FFPE (formalin fixed and paraffin embedded) cases, and exome sequencing of 69 cases showed concordant results: mutations on NRAS, KRAS, occurred in 10-20% of cases, PTEN and TP53 in 10 % and 8-28% of cases, respectively.	('oral melanoma', 'Disease', (48, 61))	('KRAS', 'Gene', (317, 321))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('oral melanoma', 'Disease', 'MESH:D008545', (48, 61))	('NRAS', 'Gene', (311, 315))	('mutations', 'Var', (298, 307))	('KRAS', 'Gene', '403871', (317, 321))	('paraffin', 'Chemical', 'MESH:D010232', (212, 220))	('canine', 'Species', '9615', (41, 47))	('formalin', 'Chemical', 'MESH:D005557', (193, 201))
33581	31262050	Importantly, canine oral melanoma presents numerous copy number alterations (CNA) and a relatively low single nucleotide variation (SNV) rate with general non-UV mutation signatures, as first shown in human mucosal melanomas.	('mucosal melanomas', 'Disease', 'MESH:D008545', (207, 224))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('single nucleotide variation', 'MPA', (103, 130))	('copy number alterations', 'Var', (52, 75))	('oral melanoma', 'Disease', 'MESH:D008545', (20, 33))	('melanomas', 'Phenotype', 'HP:0002861', (215, 224))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('human', 'Species', '9606', (201, 206))	('canine', 'Species', '9615', (13, 19))	('mucosal melanomas', 'Disease', (207, 224))	('oral melanoma', 'Disease', (20, 33))
33583	31262050	SNV detected in canine oral melanomas are also present in human mucosal melanoma, with exceptions for SF3B1, ATRX, and SPRED1 mutations, that were not identified in dogs.	('mucosal melanoma', 'Disease', 'MESH:D008545', (64, 80))	('SF3B1', 'Gene', (102, 107))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('human', 'Species', '9606', (58, 63))	('ATRX', 'Gene', '546', (109, 113))	('dogs', 'Species', '9615', (165, 169))	('SPRED1', 'Gene', (119, 125))	('SPRED1', 'Gene', '161742', (119, 125))	('oral melanomas', 'Disease', 'MESH:D008545', (23, 37))	('canine', 'Species', '9615', (16, 22))	('SF3B1', 'Gene', '23451', (102, 107))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('mutations', 'Var', (126, 135))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('ATRX', 'Gene', (109, 113))	('oral melanomas', 'Disease', (23, 37))	('mucosal melanoma', 'Disease', (64, 80))
33586	31262050	Further studies in canine oral melanomas should shed some light on these aspects, revealing recurrent mutations with strong effect in specific locations and specific breeds, reflecting different genetic backgrounds that are easiest to investigate in dog breeds.	('oral melanomas', 'Disease', (26, 40))	('oral melanomas', 'Disease', 'MESH:D008545', (26, 40))	('dog', 'Species', '9615', (250, 253))	('canine', 'Species', '9615', (19, 25))	('mutations', 'Var', (102, 111))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))
33608	31262050	Hendricks et al., (2018) provided genetic results of two cutaneous melanoma cases: an NRAS mutation and a translocation in chromosome 10 (region 10-12 Mbases) for one case (Whole Genome Sequencing) and KRAS, TP53, and KIT mutations with amplification of chromosome 30 (region 16,164778 -16,525074 Mbases) for the other case (targeted sequencing).	('NRAS', 'Gene', (86, 90))	('mutation', 'Var', (91, 99))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (57, 75))	('KIT', 'molecular_function', 'GO:0005020', ('218', '221'))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('KRAS', 'Gene', '403871', (202, 206))	('chromosome', 'cellular_component', 'GO:0005694', ('254', '264'))	('cutaneous melanoma', 'Disease', (57, 75))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (57, 75))	('KRAS', 'Gene', (202, 206))	('translocation', 'Var', (106, 119))	('chromosome', 'cellular_component', 'GO:0005694', ('123', '133'))
33613	31262050	While several dog breeds are predisposed to cutaneous melanoma, germline variants are worth exploring to inform the genetics of the rare non-UV-induced subtypes of human melanomas.	('melanomas', 'Disease', 'MESH:D008545', (170, 179))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanomas', 'Phenotype', 'HP:0002861', (170, 179))	('human', 'Species', '9606', (164, 169))	('variants', 'Var', (73, 81))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanomas', 'Disease', (170, 179))	('cutaneous melanoma', 'Disease', (44, 62))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (44, 62))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (44, 62))	('dog', 'Species', '9615', (14, 17))
33622	31262050	A few studies have reported that chemotherapy does not lead to a survival benefit; xenogeneic DNA vaccine is safe and resulted in an MST of 476 days, but still 50% of dogs treated developed metastases during the course of treatment.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('metastases', 'Disease', (190, 200))	('xenogeneic', 'Var', (83, 93))	('metastases', 'Disease', 'MESH:D009362', (190, 200))	('developed', 'Reg', (180, 189))	('dogs', 'Species', '9615', (167, 171))
33623	31262050	To date, only 3 canine acral tumors have been studied and all harboured RAS mutations (2 KRAS and 1 NRAS), and CNA involving CFA30 was found in one case.	('acral tumors', 'Disease', 'MESH:D009369', (23, 35))	('mutations', 'Var', (76, 85))	('canine', 'Species', '9615', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('RAS', 'Gene', (72, 75))	('harboured', 'Reg', (62, 71))	('KRAS', 'Gene', '403871', (89, 93))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('acral tumors', 'Disease', (23, 35))	('KRAS', 'Gene', (89, 93))
33646	31262050	However, in humans, frequent somatic activating mutations in GNAQ or GNA11 have been found, leading to the stimulation of both MAPK and PIK3/AKT pathways.	('PIK3', 'Gene', (136, 140))	('humans', 'Species', '9606', (12, 18))	('mutations', 'Var', (48, 57))	('AKT', 'Gene', (141, 144))	('GNAQ', 'Gene', (61, 65))	('PIK3', 'Gene', '5294', (136, 140))	('GNA11', 'Gene', '2767', (69, 74))	('MAPK', 'Pathway', (127, 131))	('GNA11', 'Gene', (69, 74))	('AKT', 'Gene', '207', (141, 144))	('activating', 'PosReg', (37, 47))	('MAPK', 'molecular_function', 'GO:0004707', ('127', '131'))	('stimulation', 'PosReg', (107, 118))
33649	31262050	(2017) performed an integrated study of 80 uveal melanoma patients, and genetic alterations, such as chromosome 3 monosomy/disomy, alterations in EIF1AX, SF3B1, and BAP-1, together with CNA and the global DNA methylation status, have been demonstrated to carry a prognostic value.	('chromosome', 'cellular_component', 'GO:0005694', ('101', '111'))	('patients', 'Species', '9606', (58, 66))	('SF3B1', 'Gene', (154, 159))	('EIF1AX', 'Gene', (146, 152))	('chromosome', 'Var', (101, 111))	('EIF1AX', 'Gene', '1964', (146, 152))	('BAP-1', 'Gene', '8314', (165, 170))	('alterations', 'Var', (131, 142))	('uveal melanoma', 'Disease', 'MESH:C536494', (43, 57))	('SF3B1', 'Gene', '23451', (154, 159))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('uveal melanoma', 'Disease', (43, 57))	('disomy', 'Disease', 'MESH:D024182', (123, 129))	('DNA methylation', 'biological_process', 'GO:0006306', ('205', '220'))	('DNA', 'cellular_component', 'GO:0005574', ('205', '208'))	('BAP-1', 'Gene', (165, 170))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('disomy', 'Disease', (123, 129))
33661	31262050	However, it has been recently shown that PD-1 and CTLA-4 are significantly overexpressed by peripheral blood T lymphocytes in cancer-bearing dogs compared with in healthy controls and that PD-1 blockade enhances T-cell activation.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('blockade', 'Var', (194, 202))	('PD-1', 'Gene', '486213', (189, 193))	('PD-1', 'Gene', (41, 45))	('PD-1', 'Gene', (189, 193))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('dogs', 'Species', '9615', (141, 145))	('CTLA-4', 'Gene', (50, 56))	('T-cell activation', 'biological_process', 'GO:0042110', ('212', '229'))	('enhances', 'PosReg', (203, 211))	('T-cell activation', 'CPA', (212, 229))	('overexpressed', 'PosReg', (75, 88))	('PD-1', 'Gene', '486213', (41, 45))
33667	31262050	Those therapies are used according to the molecular profile of the tumors, and cutaneous melanomas with BRAF V600 mutations are likely to benefit from the combination of BRAF (vemurafenib, dabrafenib) and MEK inhibitors (trametinib).	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (79, 98))	('benefit', 'PosReg', (138, 145))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (79, 98))	('cutaneous melanomas', 'Disease', (79, 98))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('vemurafenib', 'Chemical', 'MESH:D000077484', (176, 187))	('V600 mutations', 'Var', (109, 123))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('BRAF', 'Gene', (104, 108))	('dabrafenib', 'Chemical', 'MESH:C561627', (189, 199))	('tumors', 'Disease', (67, 73))	('trametinib', 'Chemical', 'MESH:C560077', (221, 231))
33668	31262050	Although typically of short duration, antitumor activity with KIT inhibitors like imatinib has been observed in mucosal melanoma harboring KIT mutations.	('tumor', 'Disease', (42, 47))	('mucosal melanoma', 'Disease', 'MESH:D008545', (112, 128))	('KIT', 'molecular_function', 'GO:0005020', ('62', '65'))	('KIT', 'Gene', (139, 142))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('imatinib', 'Chemical', 'MESH:D000068877', (82, 90))	('KIT', 'molecular_function', 'GO:0005020', ('139', '142'))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('mucosal melanoma', 'Disease', (112, 128))	('mutations', 'Var', (143, 152))
33702	31213847	SKP2 targeted inhibition suppresses human uveal melanoma progression by blocking ubiquitylation of p27 Background: SKP2 is considered an oncogene involved in various malignancies.	('uveal melanoma', 'Disease', (42, 56))	('ubiquitylation', 'MPA', (81, 95))	('SKP2', 'Gene', (115, 119))	('blocking', 'NegReg', (72, 80))	('SKP2', 'Gene', '6502', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('malignancies', 'Disease', 'MESH:D009369', (166, 178))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('suppresses', 'NegReg', (25, 35))	('human', 'Species', '9606', (36, 41))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('SKP2', 'Gene', (0, 4))	('inhibition', 'Var', (14, 24))	('SKP2', 'Gene', '6502', (115, 119))	('malignancies', 'Disease', (166, 178))	('p27', 'Protein', (99, 102))
33706	31213847	We then knocked down SKP2 in OM431 and MUM2B cells and confirmed its roles in cell proliferation via CCK8 assay.	('cell proliferation', 'biological_process', 'GO:0008283', ('78', '96'))	('knocked', 'Var', (8, 15))	('UM', 'Phenotype', 'HP:0007716', (40, 42))	('OM431', 'CellLine', 'CVCL:J308', (29, 34))	('SKP2', 'Gene', (21, 25))	('cell proliferation', 'CPA', (78, 96))
33708	31213847	Western blot and Immunoprecipitation assay were performed to detect the change of p27 and its ubiquitylation level in UM cells treated with SKPin C1, respectively.	('p27', 'Gene', '3429', (82, 85))	('p27', 'Gene', (82, 85))	('UM', 'Phenotype', 'HP:0007716', (118, 120))	('SKPin', 'Var', (140, 145))	('ubiquitylation level', 'MPA', (94, 114))	('SKPin C1', 'Chemical', '-', (140, 148))
33714	31213847	On the other hand, previous studies have found that UM is characterized by mutations in GNAQ or GNA11 that constitutively activate the MAPK and PI3K/Akt pathways.	('activate', 'PosReg', (122, 130))	('GNAQ', 'Gene', (88, 92))	('Akt', 'Gene', (149, 152))	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('MAPK', 'molecular_function', 'GO:0004707', ('135', '139'))	('PI3K', 'molecular_function', 'GO:0016303', ('144', '148'))	('Akt', 'Gene', '207', (149, 152))	('mutations', 'Var', (75, 84))	('GNAQ', 'Gene', '2776', (88, 92))	('GNA11', 'Gene', '2767', (96, 101))	('GNA11', 'Gene', (96, 101))
33716	31213847	Dysregulation of the UPS has been implicated in the development of various cancers.	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('Dysregulation', 'Var', (0, 13))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Disease', (75, 82))	('implicated', 'Reg', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
33723	31213847	SKP2 inactivation restricts cancer development by targeting cellular senescence in a p27-dependent manner.	('cellular senescence', 'biological_process', 'GO:0090398', ('60', '79'))	('p27', 'Gene', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cellular senescence', 'MPA', (60, 79))	('restricts', 'NegReg', (18, 27))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('inactivation', 'Var', (5, 17))	('SKP2', 'Gene', (0, 4))	('p27', 'Gene', '3429', (85, 88))
33725	31213847	In addition, the excessive degradation of p27 also has been seen in human cancers and loss of p27 plays a critical role in the aggressiveness of cancers such as gastroenteropancreatic neuroendocrine tumors.	('cancers', 'Disease', (145, 152))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', (161, 205))	('degradation', 'biological_process', 'GO:0009056', ('27', '38'))	('human', 'Species', '9606', (68, 73))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancers', 'Disease', (74, 81))	('p27', 'Gene', '3429', (94, 97))	('p27', 'Gene', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('loss', 'Var', (86, 90))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('degradation', 'MPA', (27, 38))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('aggressiveness of cancers', 'Disease', 'MESH:D009369', (127, 152))	('aggressiveness', 'Phenotype', 'HP:0000718', (127, 141))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (184, 205))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', 'MESH:C535650', (161, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('aggressiveness of cancers', 'Disease', (127, 152))	('p27', 'Gene', '3429', (42, 45))	('p27', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))
33766	31213847	Based on the expression level of SKP2 and the characteristics of UM cells, we chose OM431 and MUM2B cells for this experiment, and SKP2 was successfully knocked down via the classical siRNA method (Figure 2A and B), of which the siRNA sequence was referenced to the literature published by Hu R. et al.	('UM', 'Phenotype', 'HP:0007716', (65, 67))	('SKP2', 'Gene', (131, 135))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('OM431', 'CellLine', 'CVCL:J308', (84, 89))	('knocked down', 'Var', (153, 165))
33767	31213847	Taken together, these data indicated that knockdown of SKP2 inhibited UM proliferation in vitro, suggesting that SKP2 might play a tumorigenic regulatory role in UM.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('UM proliferation in vitro', 'CPA', (70, 95))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('UM', 'Phenotype', 'HP:0007716', (162, 164))	('inhibited', 'NegReg', (60, 69))	('tumor', 'Disease', (131, 136))	('knockdown', 'Var', (42, 51))	('SKP2', 'Gene', (55, 59))
33784	31213847	Our results suggest that SKP2 targeted inhibition interferes with ubiquitylation and degradation of p27, resulting in accumulation of p27, and induces G1 phase arrest in UM cells.	('inhibition', 'Var', (39, 49))	('G1 phase arrest', 'CPA', (151, 166))	('induces', 'Reg', (143, 150))	('p27', 'Gene', (134, 137))	('p27', 'Gene', '3429', (134, 137))	('degradation', 'biological_process', 'GO:0009056', ('85', '96'))	('p27', 'Gene', '3429', (100, 103))	('p27', 'Gene', (100, 103))	('G1 phase', 'biological_process', 'GO:0051318', ('151', '159'))	('degradation', 'MPA', (85, 96))	('ubiquitylation', 'MPA', (66, 80))	('UM', 'Phenotype', 'HP:0007716', (170, 172))	('interferes', 'NegReg', (50, 60))	('accumulation', 'PosReg', (118, 130))	('SKP2', 'Gene', (25, 29))
33785	31213847	Subsequent functional and mechanistic experiments showed that knockdown or inhibition of SKP2 caused UM cell cycle arrest, primarily through the SKP2-p27 axis, thereby significantly inhibiting the proliferation of UM cells.	('p27', 'Gene', (150, 153))	('UM cell cycle arrest', 'CPA', (101, 121))	('p27', 'Gene', '3429', (150, 153))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (104, 121))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('104', '121'))	('inhibition', 'NegReg', (75, 85))	('inhibiting', 'NegReg', (182, 192))	('UM', 'Phenotype', 'HP:0007716', (101, 103))	('UM', 'Phenotype', 'HP:0007716', (214, 216))	('proliferation', 'CPA', (197, 210))	('SKP2', 'Gene', (89, 93))	('knockdown', 'Var', (62, 71))
33787	31213847	The dysfunction or dysregulation of the UPS is closely related to the development and progression of various cancers.	('dysregulation', 'Var', (19, 32))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('dysfunction', 'Disease', 'MESH:D006331', (4, 15))	('related', 'Reg', (55, 62))	('dysfunction', 'Disease', (4, 15))
33807	31213847	Furthermore, the inhibition of SKP2 not only directly inhibits tumors, but also enhances the sensitivity of tumors to some existing treatments.	('enhances', 'PosReg', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('SKP2', 'Gene', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('inhibition', 'Var', (17, 27))	('sensitivity', 'MPA', (93, 104))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', (108, 114))	('inhibits', 'NegReg', (54, 62))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
33833	28503286	Initial laboratory workup showed lymphopenia (586 cells/muL) and prolonged coagulation times (INR 1.62, aPTT 84.8 s).	('586 cells/muL', 'Var', (46, 59))	('coagulation times', 'MPA', (75, 92))	('coagulation', 'biological_process', 'GO:0050817', ('75', '86'))	('lymphopenia', 'Disease', (33, 44))	('prolonged', 'PosReg', (65, 74))	('prolonged coagulation times', 'Phenotype', 'HP:0005542', (65, 92))	('lymphopenia', 'Phenotype', 'HP:0001888', (33, 44))	('lymphopenia', 'Disease', 'MESH:D008231', (33, 44))
33880	27764126	Gain of 6p is only rarely observed in the same tumor as monosomy 3, and is associated with a favorable prognosis, while gain of 8q is often associated with monosomy of chromosome 3 and associated with a bad prognosis.	('monosomy', 'Var', (156, 164))	('chromosome', 'cellular_component', 'GO:0005694', ('168', '178'))	('gain of 8q', 'Var', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
33885	27764126	As especially UM with a high HLA expression give rise to metastases in patients, this possible escape mechanism may also be present in humans.	('humans', 'Species', '9606', (135, 141))	('UM', 'Phenotype', 'HP:0007716', (14, 16))	('patients', 'Species', '9606', (71, 79))	('metastases', 'Disease', (57, 67))	('HLA', 'Gene', (29, 32))	('high', 'Var', (24, 28))	('HLA', 'Gene', '3128', (29, 32))	('metastases', 'Disease', 'MESH:D009362', (57, 67))
33887	27764126	This faces us with an intriguing paradox because in general, chromosomal gain tends to lead to an increased gene expression in tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('chromosomal gain', 'Var', (61, 77))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('gene expression', 'biological_process', 'GO:0010467', ('108', '123'))	('increased', 'PosReg', (98, 107))	('gene expression', 'MPA', (108, 123))
33891	27764126	Therefore we looked in a previous study at the association between HLA expression and LOH (Loss of Heterozygosity) of chromosome 6.	('HLA', 'Gene', (67, 70))	('chromosome', 'cellular_component', 'GO:0005694', ('118', '128'))	('LOH', 'Var', (86, 89))	('HLA', 'Gene', '3128', (67, 70))
33897	27764126	Furthermore, Holling et al., using UM cell lines, reported that HLA class II could be induced in half of theirUM cell lines, and showed that the lack of HLA class II expression in one particular cell line was caused by epigenetic silencing of the gene encoding CIITA.	('HLA class I', 'Gene', '3105', (64, 75))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('epigenetic silencing', 'Var', (219, 239))	('UM', 'Phenotype', 'HP:0007716', (110, 112))	('HLA class I', 'Gene', (64, 75))	('lack', 'NegReg', (145, 149))	('CIITA', 'Gene', (261, 266))	('HLA class I', 'Gene', '3105', (153, 164))	('HLA class I', 'Gene', (153, 164))	('expression', 'MPA', (166, 176))
33898	27764126	Silencing of CIITA was mediated through EZH2 (Enhancer of Zeste Homologue 2, a Polycomb Repressive Complex 2 subunit; chr7q), which triple methylates lysine 27 in histone H3.	('CIITA', 'Gene', (13, 18))	('Silencing', 'NegReg', (0, 9))	('lysine 27', 'Var', (150, 159))	('lysine', 'Chemical', 'MESH:D008239', (150, 156))	('EZH2', 'Gene', (40, 44))	('methylates', 'Var', (139, 149))
33923	27764126	Primers for ACTB (beta-actin; OMIM 102630), GAPDH (OMIM 138400), RPL13 (OMIM 113703), and RSP11 (OMIM 180471) were included for selecting suitable reference genes.	('OMIM', 'Var', (51, 55))	('beta-actin', 'Gene', (18, 28))	('RPL13', 'Gene', '6137', (65, 70))	('RPL13', 'Gene', (65, 70))	('ACTB', 'Gene', '60', (12, 16))	('ACTB', 'Gene', (12, 16))	('GAPDH', 'Gene', '2597', (44, 49))	('beta-actin', 'Gene', '728378', (18, 28))	('GAPDH', 'Gene', (44, 49))
33947	27764126	Additionally, we examined the gene-dose effect of chromosome 3, as a previous study from our laboratory had indicated an association between loss of chromosome 3 and increased HLA expression levels on primary UM(8).	('chromosome', 'Gene', (149, 159))	('HLA', 'Gene', (176, 179))	('increased', 'PosReg', (166, 175))	('loss', 'Var', (141, 145))	('HLA', 'Gene', '3128', (176, 179))	('chromosome', 'cellular_component', 'GO:0005694', ('50', '60'))	('UM', 'Phenotype', 'HP:0007716', (209, 211))	('chromosome', 'cellular_component', 'GO:0005694', ('149', '159'))
33948	27764126	Monosomy 3 was present in fourteen (50%) cases and associated with death due to metastases (Kaplan-Meier, p < 0.001).	('death', 'Disease', 'MESH:D003643', (67, 72))	('death', 'Disease', (67, 72))	('metastases', 'Disease', (80, 90))	('metastases', 'Disease', 'MESH:D009362', (80, 90))	('associated with', 'Reg', (51, 66))	('Monosomy 3', 'Var', (0, 10))
33951	27764126	Monosomy of chromosome 3 was associated with an increased gene expression of HLA class I and B2M but not of HLA class II.	('Monosomy', 'Var', (0, 8))	('increased', 'PosReg', (48, 57))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))	('HLA class I', 'Gene', (77, 88))	('gene expression', 'MPA', (58, 73))	('HLA class I', 'Gene', '3105', (108, 119))	('B2M', 'Gene', (93, 96))	('B2M', 'Gene', '567', (93, 96))	('gene expression', 'biological_process', 'GO:0010467', ('58', '73'))	('HLA class I', 'Gene', (108, 119))	('HLA class I', 'Gene', '3105', (77, 88))
33952	27764126	Gain of 6p occurred almost exclusively in tumors without monosomy 3, and when looking at all tumors, an association was observed between 6p gain and less HLA-B expression (p = 0.049).	('gain', 'PosReg', (140, 144))	('less', 'NegReg', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('HLA-B', 'Gene', '3106', (154, 159))	('HLA-B', 'Gene', (154, 159))	('monosomy 3', 'Var', (57, 67))
33955	27764126	As the group with monosomy 3 with gain of 6p consisted of only one tumor, we did not use this case for analysis.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('monosomy', 'Var', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
33980	27764126	Expression of several HLA class 1 and 2 molecules, regulators of the antigen-presenting machinery, as well as several of the transcriptional regulators, are thus co-regulated in human UM samples, and the presence of most of these, showed an association with loss of one chromosome 3.	('UM', 'Phenotype', 'HP:0007716', (184, 186))	('human', 'Species', '9606', (178, 183))	('HLA', 'Gene', (22, 25))	('presence', 'Var', (204, 212))	('loss', 'CPA', (258, 262))	('HLA', 'Gene', '3128', (22, 25))	('association', 'Reg', (241, 252))	('chromosome', 'cellular_component', 'GO:0005694', ('270', '280'))
34001	27764126	In our earlier work on the same tumors, we had used karyograms and FISH analysis on isolated nuclei for determining the presence of monosomy 3, while in the current study we used the more precise SNP array.	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('monosomy 3', 'Var', (132, 142))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
34002	27764126	We here show that loss of one chromosome 3 is associated with an increased leukocytic infiltrate, and increased expression of not only the HLA class I and II molecules, but also of molecules related to the peptide-loading machinery and transcriptional regulators.	('increased', 'PosReg', (65, 74))	('HLA class I', 'Gene', (139, 150))	('loss', 'Var', (18, 22))	('chromosome', 'cellular_component', 'GO:0005694', ('30', '40'))	('leukocytic infiltrate', 'CPA', (75, 96))	('increased', 'PosReg', (102, 111))	('HLA class I', 'Gene', '3105', (139, 150))	('expression', 'MPA', (112, 122))
34009	27764126	Monosomy 3 in uveal melanoma is associated with loss of BAP1 (BRCA1 associated protein-1; chr3p),, which is connected to PRC2 (of which EZH2 is a member) through ASXL1(additional sex combs-like transcriptional regulator 1).	('loss', 'NegReg', (48, 52))	('uveal melanoma', 'Phenotype', 'HP:0007716', (14, 28))	('ASXL1', 'Gene', (162, 167))	('uveal melanoma', 'Disease', 'MESH:C536494', (14, 28))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('uveal melanoma', 'Disease', (14, 28))	('BRCA1 associated protein-1', 'Gene', (62, 88))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('BAP1', 'Gene', (56, 60))	('ASXL1', 'Gene', '171023', (162, 167))	('Monosomy 3', 'Var', (0, 10))	('BRCA1 associated protein-1', 'Gene', '8314', (62, 88))
34010	27764126	This could represent a possible connection between BAP1 and expression of HLA in uveal melanoma, as study in mice showed that loss of BAP1 leads to increased levels of EZH2 (and PRC2) with repressed expression of its targets, including thus CIITA, leading ultimately to less HLA class II expression.	('expression', 'MPA', (288, 298))	('HLA', 'Gene', '3128', (74, 77))	('EZH2', 'MPA', (168, 172))	('BAP1', 'Gene', (134, 138))	('less', 'NegReg', (270, 274))	('increased', 'PosReg', (148, 157))	('HLA', 'Gene', '3128', (275, 278))	('HLA class I', 'Gene', '3105', (275, 286))	('HLA', 'Gene', (74, 77))	('uveal melanoma', 'Disease', (81, 95))	('uveal melanoma', 'Disease', 'MESH:C536494', (81, 95))	('HLA class I', 'Gene', (275, 286))	('mice', 'Species', '10090', (109, 113))	('levels', 'MPA', (158, 164))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('HLA', 'Gene', (275, 278))	('loss', 'Var', (126, 130))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
34029	27764126	As T cells may produce factors that bring in macrophages, T-cell depletion may also reduce macrophages density, and this may subsequently influence the development of the primary tumor or metastases, as the presence of macrophages is related to angiogenesis and most of the macrophages in UM are of the pro-angiogenic M2 type.	('development', 'CPA', (152, 163))	('reduce', 'NegReg', (84, 90))	('angiogenesis', 'biological_process', 'GO:0001525', ('245', '257'))	('UM', 'Phenotype', 'HP:0007716', (289, 291))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('macrophages', 'MPA', (45, 56))	('depletion', 'Var', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('metastases', 'Disease', (188, 198))	('influence', 'Reg', (138, 147))	('macrophages density', 'CPA', (91, 110))	('metastases', 'Disease', 'MESH:D009362', (188, 198))	('tumor', 'Disease', (179, 184))
34036	25901283	In particular, targeting of the inhibitory receptors CTLA-4 and PD-1 or its ligand PD-L1 have been shown to be beneficial for patients with melanoma, renal cell cancer, non-small cell lung cancer and a growing list of other cancers with impressive response rates.	('patients', 'Species', '9606', (126, 134))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('cancers', 'Disease', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('non-small cell lung cancer', 'Disease', (169, 195))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('beneficial', 'PosReg', (111, 121))	('renal cell cancer', 'Disease', 'MESH:C538614', (150, 167))	('renal cell cancer', 'Disease', (150, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('targeting', 'Var', (15, 24))	('PD-1', 'Gene', (64, 68))	('renal cell cancer', 'Phenotype', 'HP:0005584', (150, 167))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('PD-L1', 'Gene', (83, 88))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (169, 195))	('PD-L1', 'Gene', '29126', (83, 88))	('ligand', 'molecular_function', 'GO:0005488', ('76', '82'))	('CTLA-4', 'Gene', '1493', (53, 59))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (173, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('CTLA-4', 'Gene', (53, 59))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (169, 195))
34086	25901283	Similarly, pneumonitis, a potentially life-threatening complication, was noted less frequently with pembrolizumab than in studies using nivolumab alone, although the tumor type likely plays a role in the toxicity profile.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('pneumonitis', 'Disease', (11, 22))	('pembrolizumab', 'Var', (100, 113))	('pembrolizumab', 'Chemical', 'MESH:C582435', (100, 113))	('pneumonitis', 'Disease', 'MESH:D011014', (11, 22))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('nivolumab', 'Chemical', 'MESH:D000077594', (136, 145))	('tumor', 'Disease', (166, 171))	('toxicity', 'Disease', 'MESH:D064420', (204, 212))	('toxicity', 'Disease', (204, 212))
34090	25901283	While a similar spectrum of toxicities was observed with anti-PD-1 antibody nivolumab and anti-PD-L1 antibody, only one case of myocarditis was reported in a phase one trial testing anti-PD-L1 antibody.	('myocarditis', 'Disease', 'MESH:D009205', (128, 139))	('antibody', 'cellular_component', 'GO:0019815', ('193', '201'))	('antibody', 'cellular_component', 'GO:0019815', ('101', '109'))	('antibody', 'cellular_component', 'GO:0019815', ('67', '75'))	('PD-L1', 'Gene', (95, 100))	('myocarditis', 'Phenotype', 'HP:0012819', (128, 139))	('antibody', 'cellular_component', 'GO:0019814', ('193', '201'))	('PD-L1', 'Gene', '29126', (95, 100))	('antibody', 'cellular_component', 'GO:0019814', ('101', '109'))	('anti-PD-1', 'Var', (57, 66))	('antibody', 'cellular_component', 'GO:0019814', ('67', '75'))	('myocarditis', 'Disease', (128, 139))	('nivolumab', 'Chemical', 'MESH:D000077594', (76, 85))	('antibody', 'molecular_function', 'GO:0003823', ('193', '201'))	('PD-L1', 'Gene', (187, 192))	('antibody', 'molecular_function', 'GO:0003823', ('101', '109'))	('antibody', 'molecular_function', 'GO:0003823', ('67', '75'))	('toxicities', 'Disease', 'MESH:D064420', (28, 38))	('PD-L1', 'Gene', '29126', (187, 192))	('antibody', 'cellular_component', 'GO:0042571', ('193', '201'))	('antibody', 'cellular_component', 'GO:0042571', ('101', '109'))	('antibody', 'cellular_component', 'GO:0042571', ('67', '75'))	('toxicities', 'Disease', (28, 38))
34095	25901283	There is almost no inflammation in the heart of these mice and subsequent analyses revealed that auto-antibodies against cardiac troponin I are responsible for the disease.	('auto-antibodies', 'Var', (97, 112))	('inflammation', 'Disease', 'MESH:D007249', (19, 31))	('cardiac troponin I', 'Gene', (121, 139))	('responsible', 'Reg', (144, 155))	('inflammation', 'biological_process', 'GO:0006954', ('19', '31'))	('inflammation', 'Disease', (19, 31))	('mice', 'Species', '10090', (54, 58))	('cardiac troponin I', 'Gene', '21954', (121, 139))	('inflammation in the heart', 'Phenotype', 'HP:0012819', (19, 44))
34106	25901283	We report here an autoimmune myocarditis as a side effect of an anti-PD-1-antibody, completely resolving after a therapy with high-dose corticosteroids.	('autoimmune myocarditis', 'Disease', (18, 40))	('autoimmune myocarditis', 'Disease', 'MESH:D009205', (18, 40))	('antibody', 'cellular_component', 'GO:0042571', ('74', '82'))	('antibody', 'cellular_component', 'GO:0019814', ('74', '82'))	('antibody', 'cellular_component', 'GO:0019815', ('74', '82'))	('anti-PD-1-antibody', 'Var', (64, 82))	('myocarditis', 'Phenotype', 'HP:0012819', (29, 40))	('antibody', 'molecular_function', 'GO:0003823', ('74', '82'))
34114	25803691	We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations.	('CDKN2A', 'Gene', (33, 39))	('CM', 'Phenotype', 'HP:0012056', (158, 160))	('CDKN2A', 'Gene', '1029', (33, 39))	('CDKN2A', 'Gene', (120, 126))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Disease', (95, 103))	('p.E318K', 'Mutation', 'rs149617956', (67, 74))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('CDKN2A', 'Gene', '1029', (120, 126))	('CDK4', 'Gene', (41, 45))	('MC1R', 'Gene', (53, 57))	('BAP1', 'Gene', '8314', (47, 51))	('MITFp.E318K', 'Var', (63, 74))	('CDK', 'molecular_function', 'GO:0004693', ('41', '44'))	('CDK4', 'Gene', '1019', (41, 45))	('MC1R', 'Gene', '4157', (53, 57))	('BAP1', 'Gene', (47, 51))
34116	25803691	The MITF p.E318K variant similarly occurred at an approximately three-fold higher frequency in melanoma cases than controls.	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('p.E318K', 'Mutation', 'rs149617956', (9, 16))	('MITF', 'Gene', '4286', (4, 8))	('MITF', 'Gene', (4, 8))	('p.E318K', 'Var', (9, 16))
34123	25803691	Mutations are most frequently seen in CDKN2A, where pathogenic mutations are detected in 20-40% of families with three or more cases of CM.	('CM', 'Phenotype', 'HP:0012056', (136, 138))	('Mutations', 'Var', (0, 9))	('CDKN2A', 'Gene', (38, 44))	('CDKN2A', 'Gene', '1029', (38, 44))	('seen', 'Reg', (30, 34))
34128	25803691	However, mutations in these other high-risk genes are rare and each account for a minority of melanoma-dense families.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('mutations', 'Var', (9, 18))	('melanoma', 'Disease', (94, 102))
34129	25803691	In CDK4 only two mutations (p.R24H, p.R24C), affecting binding to p16, have been identified.	('p.R24C', 'Var', (36, 42))	('p.R24C', 'Mutation', 'rs11547328', (36, 42))	('p16', 'Gene', (66, 69))	('p.R24H', 'Mutation', 'rs104894340', (28, 34))	('affecting', 'Reg', (45, 54))	('binding', 'Interaction', (55, 62))	('p.R24H', 'Var', (28, 34))	('CDK4', 'Gene', (3, 7))	('CDK', 'molecular_function', 'GO:0004693', ('3', '6'))	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))	('CDK4', 'Gene', '1019', (3, 7))	('p16', 'Gene', '1029', (66, 69))
34130	25803691	Families with CDK4 and CDKN2A mutations have similar phenotypes regarding CM, with cases frequently having multiple primary melanoma (MPM), early onset CM, and high numbers of clinically atypical nevi.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('CDKN2A', 'Gene', (23, 29))	('atypical nevi', 'Phenotype', 'HP:0001062', (187, 200))	('CDKN2A', 'Gene', '1029', (23, 29))	('mutations', 'Var', (30, 39))	('CDK4', 'Gene', (14, 18))	('CM', 'Phenotype', 'HP:0012056', (152, 154))	('CDK', 'molecular_function', 'GO:0004693', ('14', '17'))	('CDK4', 'Gene', '1019', (14, 18))	('nevi', 'Phenotype', 'HP:0003764', (196, 200))	('CM', 'Phenotype', 'HP:0012056', (74, 76))
34131	25803691	In a subset of families with CDKN2A mutations, an increased risk of pancreatic cancer has been reported.	('CDKN2A', 'Gene', (29, 35))	('CDKN2A', 'Gene', '1029', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('mutations', 'Var', (36, 45))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (50, 85))	('pancreatic cancer', 'Disease', (68, 85))	('pancreatic cancer', 'Disease', 'MESH:D010190', (68, 85))
34132	25803691	The precise relationship between mutations in CDKN2A and pancreatic cancer is unknown, but pancreatic cancer has predominantly been reported in Swedish, Italian, Dutch and North American CM families, and mainly with mutations affecting ankyrin repeats 3 and 4.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('CDKN2A', 'Gene', (46, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (57, 74))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('reported', 'Reg', (132, 140))	('mutations', 'Var', (33, 42))	('CDKN2A', 'Gene', '1029', (46, 52))	('CM', 'Phenotype', 'HP:0012056', (187, 189))	('ankyrin', 'Protein', (236, 243))	('mutations', 'Var', (216, 225))	('pancreatic cancer', 'Disease', (57, 74))	('pancreatic cancer', 'Disease', (91, 108))	('pancreatic cancer', 'Disease', 'MESH:D010190', (57, 74))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))
34134	25803691	MC1R is highly polymorphic in the Caucasian population and the variants most strongly associated with red hair color (designated R alleles) confer a per-allele risk of ~2-fold for CM.	('MC1R', 'Gene', '4157', (0, 4))	('variants', 'Var', (63, 71))	('MC1R', 'Gene', (0, 4))	('associated', 'Reg', (86, 96))	('red hair color', 'Disease', (102, 116))	('red hair color', 'Disease', 'MESH:D003117', (102, 116))	('CM', 'Phenotype', 'HP:0012056', (180, 182))	('red hair', 'Phenotype', 'HP:0002297', (102, 110))
34138	25803691	One mutation in MITF (p.E318K) is linked to moderate (~2-fold) increased risk of CM and renal cell carcinoma (RCC).	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('CM', 'Phenotype', 'HP:0012056', (81, 83))	('p.E318K', 'Var', (22, 29))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('MITF', 'Gene', (16, 20))	('renal cell carcinoma', 'Disease', (88, 108))	('MITF', 'Gene', '4286', (16, 20))	('p.E318K', 'Mutation', 'rs149617956', (22, 29))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (88, 108))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (88, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))
34140	25803691	The p.E318K mutation is associated with non-blue eye color and increased nevus count.	('blue eye', 'Phenotype', 'HP:0000635', (44, 52))	('nevus count', 'CPA', (73, 84))	('nevus', 'Phenotype', 'HP:0003764', (73, 78))	('p.E318K', 'Mutation', 'rs149617956', (4, 11))	('increased', 'PosReg', (63, 72))	('non-blue eye color', 'Disease', (40, 58))	('p.E318K', 'Var', (4, 11))
34147	25803691	There have been isolated reports of UM in CDKN2A mutation carriers, and BRCA2 mutation carriers, but in light of the many families published with mutations in these two genes, and only single reports of UM, the risk of UM in carriers of CDKN2A or BRCA2 mutations is probably low.	('BRCA2', 'Gene', (72, 77))	('BRCA2', 'Gene', '675', (247, 252))	('mutation', 'Var', (78, 86))	('BRCA2', 'Gene', '675', (72, 77))	('mutations', 'Var', (253, 262))	('mutation', 'Var', (49, 57))	('CDKN2A', 'Gene', (42, 48))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('CDKN2A', 'Gene', '1029', (42, 48))	('CDKN2A', 'Gene', (237, 243))	('BRCA2', 'Gene', (247, 252))	('UM', 'Phenotype', 'HP:0007716', (219, 221))	('UM', 'Phenotype', 'HP:0007716', (203, 205))	('CDKN2A', 'Gene', '1029', (237, 243))
34148	25803691	To date there has been no large study of genetic alterations in Danish high-risk melanoma cases, and we were intrigued by a clinical observation of an apparently low frequency of CDKN2A mutations when testing was conducted in a clinical genetic setting.	('CDKN2A', 'Gene', '1029', (179, 185))	('mutations', 'Var', (186, 195))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('CDKN2A', 'Gene', (179, 185))
34149	25803691	A low frequency of CDKN2A mutations has previously been reported in German and Latvian studies.	('CDKN2A', 'Gene', '1029', (19, 25))	('mutations', 'Var', (26, 35))	('CDKN2A', 'Gene', (19, 25))
34150	25803691	Here, we examined the frequency of CDKN2A, CDK4, BAP1, MC1R and MITF (p.E318K) mutations in a large sample of Danish high-risk CM and UM cases.	('p.E318K', 'Mutation', 'rs149617956', (70, 77))	('p.E318K) mutations', 'Var', (70, 88))	('CDKN2A', 'Gene', '1029', (35, 41))	('MC1R', 'Gene', '4157', (55, 59))	('MITF', 'Gene', '4286', (64, 68))	('MITF', 'Gene', (64, 68))	('BAP1', 'Gene', (49, 53))	('CM', 'Phenotype', 'HP:0012056', (127, 129))	('CDK4', 'Gene', (43, 47))	('BAP1', 'Gene', '8314', (49, 53))	('MC1R', 'Gene', (55, 59))	('CDK4', 'Gene', '1019', (43, 47))	('UM', 'Phenotype', 'HP:0007716', (134, 136))	('CDK', 'molecular_function', 'GO:0004693', ('43', '46'))	('CDKN2A', 'Gene', (35, 41))	('mutations', 'Var', (79, 88))
34156	25803691	We did not contact all of the isolated MPM cases, because many of these patients were fair skinned and frequent users of indoor tanning facilities, and were judged less likely for finding mutations in high-risk melanoma genes, than patients with a family report of melanoma.	('patients', 'Species', '9606', (232, 240))	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Disease', (211, 219))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('fair skin', 'Phenotype', 'HP:0007513', (86, 95))	('fair skinned', 'Phenotype', 'HP:0007513', (86, 98))	('mutations', 'Var', (188, 197))	('melanoma', 'Disease', (265, 273))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('patients', 'Species', '9606', (72, 80))
34165	25803691	In families with a CDKN2A mutation, MC1R was examined in all mutation carriers.	('mutation', 'Var', (26, 34))	('CDKN2A', 'Gene', (19, 25))	('CDKN2A', 'Gene', '1029', (19, 25))	('MC1R', 'Gene', '4157', (36, 40))	('MC1R', 'Gene', (36, 40))
34167	25803691	Information of cancer occurrence in these families was included in the analysis of CDKN2A and CDK4 alterations.	('CDK4', 'Gene', (94, 98))	('CDKN2A', 'Gene', '1029', (83, 89))	('CDK', 'molecular_function', 'GO:0004693', ('94', '97'))	('CDK4', 'Gene', '1019', (94, 98))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('alterations', 'Var', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('CDKN2A', 'Gene', (83, 89))
34171	25803691	In families with a CDKN2A mutation, blood samples were also collected from healthy mutation carriers.	('CDKN2A', 'Gene', '1029', (19, 25))	('CDKN2A', 'Gene', (19, 25))	('mutation', 'Var', (26, 34))
34172	25803691	164 families were screened for variants in BAP1 and CDKN2A in a targeted sequencing approach using Ion AmpliSeq library kits (Life Technologies, CA, USA).	('BAP1', 'Gene', (43, 47))	('variants', 'Var', (31, 39))	('BAP1', 'Gene', '8314', (43, 47))	('CDKN2A', 'Gene', (52, 58))	('CDKN2A', 'Gene', '1029', (52, 58))
34174	25803691	Variants occurring in the NHLBI Exome Sequencing Project (ESP6500) with minor allele frequency (MAF) >0.01, and synonymous variants were excluded.	('Variants', 'Var', (0, 8))	('ESP', 'Gene', (58, 61))	('ESP', 'Gene', '148713', (58, 61))
34175	25803691	130 blood samples were screened with high-resolution melting analysis for CDK4 mutations p.R24C or p.R24H.	('p.R24H', 'Var', (99, 105))	('p.R24C', 'Var', (89, 95))	('CDK4', 'Gene', (74, 78))	('CDK4', 'Gene', '1019', (74, 78))	('p.R24C', 'Mutation', 'rs11547328', (89, 95))	('p.R24H', 'Mutation', 'rs104894340', (99, 105))	('CDK', 'molecular_function', 'GO:0004693', ('74', '77'))
34176	25803691	Standard methods for Sanger sequencing were used to screen an additional 196 samples for mutations in CDKN2A and CDK4; 29 samples for mutations in BAP1; 280 samples for variants in MC1R, in which the following five variants: p.D84E, p.R151C, p.R160W, p.D294H, p.R142H; and null mutations, were classified as R variants and others were classified as r variants, except synonymous changes, which were counted as wild-type.	('p.R151C', 'Mutation', 'rs1805007', (233, 240))	('p.D84E', 'Mutation', 'rs1805006', (225, 231))	('mutations', 'Var', (89, 98))	('CDKN2A', 'Gene', '1029', (102, 108))	('MC1R', 'Gene', '4157', (181, 185))	('MC1R', 'Gene', (181, 185))	('p.R160W', 'Mutation', 'rs1805008', (242, 249))	('CDK4', 'Gene', (113, 117))	('p.D294H', 'Var', (251, 258))	('p.R160W', 'Var', (242, 249))	('BAP1', 'Gene', '8314', (147, 151))	('CDK', 'molecular_function', 'GO:0004693', ('113', '116'))	('CDK4', 'Gene', '1019', (113, 117))	('p.D294H', 'Mutation', 'rs1805009', (251, 258))	('p.R142H', 'Var', (260, 267))	('p.R142H', 'Mutation', 'rs11547464', (260, 267))	('BAP1', 'Gene', (147, 151))	('p.D84E', 'Var', (225, 231))	('CDKN2A', 'Gene', (102, 108))	('p.R151C', 'Var', (233, 240))
34177	25803691	296 samples were assessed for MITF p.E318K by a standard TaqMan assay.	('p.E318K', 'Var', (35, 42))	('MITF', 'Gene', '4286', (30, 34))	('MITF', 'Gene', (30, 34))	('p.E318K', 'Mutation', 'rs149617956', (35, 42))
34178	25803691	Hazard ratios for CDKN2A mutation carriers were calculated using Cox regression.	('CDKN2A', 'Gene', '1029', (18, 24))	('Cox', 'Gene', '1351', (65, 68))	('mutation', 'Var', (25, 33))	('Cox', 'Gene', (65, 68))	('CDKN2A', 'Gene', (18, 24))
34179	25803691	A Cox proportional-hazards model was used to generate the survival curve showing age-specific probability of melanoma development for CDKN2A mutations carriers.	('mutations', 'Var', (141, 150))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('CDKN2A', 'Gene', (134, 140))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('CDKN2A', 'Gene', '1029', (134, 140))	('carriers', 'Reg', (151, 159))	('Cox', 'Gene', '1351', (2, 5))	('Cox', 'Gene', (2, 5))
34181	25803691	13 of 327 cases with early onset CM or MPM carried mutations in CDKN2A (Table 1).	('early onset CM', 'Disease', (21, 35))	('mutations', 'Var', (51, 60))	('CDKN2A', 'Gene', (64, 70))	('MPM', 'Disease', (39, 42))	('CDKN2A', 'Gene', '1029', (64, 70))	('CM', 'Phenotype', 'HP:0012056', (33, 35))	('carried', 'Reg', (43, 50))
34182	25803691	Three mutations: c.47_50del p.(L16Pfs*9), c.62G>A p.(R21K), and c.94_99dup p.(L32_E33dup) mutations have not previously been described.	('c.62G>A', 'Var', (42, 49))	('c.47_50del', 'Mutation', 'c.47_50del', (17, 27))	('p.(L32_E33dup)', 'DUPLICATION', 'None', (75, 89))	('c.62G>A', 'Mutation', 'rs1057517601', (42, 49))	('p.(L16Pfs*9)', 'Mutation', 'rs587782206', (28, 40))	('c.47_50del', 'Var', (17, 27))	('p.(R21K)', 'Mutation', 'rs1057517601', (50, 58))	('p.(L32_E33dup', 'Var', (75, 88))	('c.94_99dup', 'DUPLICATION', 'None', (64, 74))	('c.94_99dup p.(L32_E33dup', 'Var', (64, 88))
34183	25803691	The novel frameshift mutation c.47_50del, p.(L16Pfs*9) is likely to be highly deleterious to the p16 protein function since it causes premature truncation of the protein.	('c.47_50del', 'Var', (30, 40))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('p16', 'Gene', '1029', (97, 100))	('p.(L16Pfs*9)', 'Mutation', 'rs587782206', (42, 54))	('causes', 'Reg', (127, 133))	('protein', 'Protein', (162, 169))	('p16', 'Gene', (97, 100))	('c.47_50del', 'Mutation', 'c.47_50del', (30, 40))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('premature truncation', 'MPA', (134, 154))
34185	25803691	In one family we found a duplication of 6 bp (c.94_99dup, p.(L32_E33dup)) causing a 2 amino acid duplication in the first ankyrin-repeat of p16.	('c.94_99dup', 'Mutation', 'c.94_99dup', (46, 56))	('c.94_99dup', 'Var', (46, 56))	('p16', 'Gene', (140, 143))	('p.(L32_E33dup)', 'DUPLICATION', 'None', (58, 72))	('causing', 'Reg', (74, 81))	('p16', 'Gene', '1029', (140, 143))
34186	25803691	A missense mutation in p14 (c.62G>A, p.(R21K), exon 1beta) was identified in an individual affected with CM aged 54 years and no family history of CM.	('CM', 'Phenotype', 'HP:0012056', (105, 107))	('c.62G>A', 'Var', (28, 35))	('c.62G>A', 'Mutation', 'rs1057517601', (28, 35))	('p.(R21K)', 'Mutation', 'rs1057517601', (37, 45))	('CM', 'Phenotype', 'HP:0012056', (147, 149))	('p14', 'Gene', (23, 26))	('p14', 'Gene', '1029', (23, 26))
34187	25803691	To-date, no melanoma families have been identified that carry missense mutations in exon 1beta, however, very recent studies have shown that p14-specific alterations in CDKN2A exon 2 impair the ability of p14 to control superoxide levels and suppress growth of melanoma cells in vivo.	('CDKN2A', 'Gene', (169, 175))	('suppress', 'NegReg', (242, 250))	('ability', 'MPA', (194, 201))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', (12, 20))	('CDKN2A', 'Gene', '1029', (169, 175))	('control superoxide levels', 'MPA', (212, 237))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('p14', 'Gene', (141, 144))	('p14', 'Gene', (205, 208))	('alterations', 'Var', (154, 165))	('impair', 'NegReg', (183, 189))	('p14', 'Gene', '1029', (141, 144))	('p14', 'Gene', '1029', (205, 208))	('superoxide', 'Chemical', 'MESH:D013481', (220, 230))	('melanoma', 'Disease', 'MESH:D008545', (261, 269))	('melanoma', 'Phenotype', 'HP:0002861', (261, 269))	('melanoma', 'Disease', (261, 269))
34188	25803691	Previously, only whole gene deletions, insertions or splice-site mutations in p14, have been determined as pathogenetic.	('insertions', 'Var', (39, 49))	('splice-site mutations', 'Var', (53, 74))	('p14', 'Gene', '1029', (78, 81))	('p14', 'Gene', (78, 81))
34190	25803691	One family has previously been described with 9 persons affected with CM, many with MPM, and segregation of the mutation with melanoma resulting in a LOD-score of 3.6.	('mutation', 'Var', (112, 120))	('LOD', 'molecular_function', 'GO:0033736', ('150', '153'))	('CM', 'Phenotype', 'HP:0012056', (70, 72))	('persons', 'Species', '9606', (48, 55))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))
34193	25803691	The missense mutation p.(G35R) in p16 has previously been found in melanoma cases (unpublished data) as well as in tumor tissue.	('p.(G35R)', 'Mutation', 'rs757066045', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('p16', 'Gene', (34, 37))	('melanoma', 'Disease', (67, 75))	('tumor', 'Disease', (115, 120))	('p16', 'Gene', '1029', (34, 37))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('found', 'Reg', (58, 63))	('p.(G35R', 'Var', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
34195	25803691	The other individual heterozygous for p.(G35R) mutation had MPM in young age, and no maternal history of cancer.	('MPM', 'Disease', (60, 63))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('p.(G35R)', 'Mutation', 'rs757066045', (38, 46))	('p.(G35R', 'Var', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
34197	25803691	Several known mutations were also found in CDKN2A.	('CDKN2A', 'Gene', '1029', (43, 49))	('mutations', 'Var', (14, 23))	('found', 'Reg', (34, 39))	('CDKN2A', 'Gene', (43, 49))
34199	25803691	Additionally, we observed the p.(A4_P11dup), p.(A4_P11del), and p.G101W mutations.	('p.(A4_P11del', 'Var', (45, 57))	('p.(A4_P11dup', 'Var', (30, 42))	('p.G101W', 'Var', (64, 71))	('p.G101W', 'Mutation', 'rs104894094', (64, 71))	('p.(A4_P11del)', 'DELETION', 'None', (45, 58))	('p.(A4_P11dup)', 'DUPLICATION', 'None', (30, 43))
34200	25803691	In 18 cases we found the well-described CDKN2A p.A148T variant.	('p.A148T', 'Mutation', 'rs3731249', (47, 54))	('CDKN2A', 'Gene', '1029', (40, 46))	('CDKN2A', 'Gene', (40, 46))	('p.A148T', 'Var', (47, 54))
34202	25803691	The average age of first melanoma was 42.8 years in CDKN2A mutation carriers (excluding those carrying the missense variant in p14), which is significantly younger (48.3 years, p = 0.035) than non-CDKN2A mutation carriers (Table 2).	('p14', 'Gene', (127, 130))	('p14', 'Gene', '1029', (127, 130))	('CDKN2A', 'Gene', (197, 203))	('CDKN2A', 'Gene', '1029', (197, 203))	('mutation', 'Var', (59, 67))	('CDKN2A', 'Gene', (52, 58))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))	('CDKN2A', 'Gene', '1029', (52, 58))
34203	25803691	Overall, we analysed CDKN2A in 304 unrelated melanoma cases suspected of a hereditary predisposition to CM and found a pathogenetic mutation in 3.9% (Table 3).	('pathogenetic', 'Reg', (119, 131))	('CM', 'Phenotype', 'HP:0012056', (104, 106))	('CDKN2A', 'Gene', (21, 27))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('mutation', 'Var', (132, 140))	('CDKN2A', 'Gene', '1029', (21, 27))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
34204	25803691	In 107 individuals with MPM or melanoma before 40 years, we found 3 CDKN2A mutations, all in individuals with MPM, first diagnosed with CM aged 28, 33, and 40 years, respectively.	('CM', 'Phenotype', 'HP:0012056', (136, 138))	('CDKN2A', 'Gene', (68, 74))	('CDKN2A', 'Gene', '1029', (68, 74))	('mutations', 'Var', (75, 84))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))
34207	25803691	Similarly, no CDKN2A mutations were seen in 3 individuals with isolated pancreatic cancer, and 6 individuals with pancreatic cancer and a first-degree relative with pancreatic cancer.	('mutations', 'Var', (21, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (165, 182))	('CDKN2A', 'Gene', '1029', (14, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (72, 89))	('isolated pancreatic cancer', 'Disease', (63, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('pancreatic cancer', 'Disease', 'MESH:D010190', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('pancreatic cancer', 'Disease', (114, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 131))	('pancreatic cancer', 'Disease', 'MESH:D010190', (114, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('isolated pancreatic cancer', 'Disease', 'MESH:D010190', (63, 89))	('CDKN2A', 'Gene', (14, 20))	('pancreatic cancer', 'Disease', (165, 182))
34208	25803691	Among 15 families with pancreatic cancer and CM, we found 1 family with a CDKN2A mutation.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (23, 40))	('mutation', 'Var', (81, 89))	('CDKN2A', 'Gene', '1029', (74, 80))	('CDKN2A', 'Gene', (74, 80))	('CM', 'Phenotype', 'HP:0012056', (45, 47))	('pancreatic cancer', 'Disease', (23, 40))	('pancreatic cancer', 'Disease', 'MESH:D010190', (23, 40))
34209	25803691	In the 13 families with CDKN2A mutations, only 1 had a case of pancreatic cancer, in a person with unknown carrier status (the same family as above) (Table 1).	('pancreatic cancer', 'Disease', (63, 80))	('mutations', 'Var', (31, 40))	('pancreatic cancer', 'Disease', 'MESH:D010190', (63, 80))	('person', 'Species', '9606', (87, 93))	('CDKN2A', 'Gene', (24, 30))	('carrier', 'molecular_function', 'GO:0005215', ('107', '114'))	('CDKN2A', 'Gene', '1029', (24, 30))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
34210	25803691	The calculated age-specific penetrances for CM in CDKN2A mutation carriers are shown in Fig.	('mutation', 'Var', (57, 65))	('CDKN2A', 'Gene', '1029', (50, 56))	('CDKN2A', 'Gene', (50, 56))	('CM', 'Phenotype', 'HP:0012056', (44, 46))
34211	25803691	In the 12 CDKN2A mutation positive families we identified 34 cases with CM, of which 27 (79%) were known gene carriers.	('CDKN2A', 'Gene', '1029', (10, 16))	('CDKN2A', 'Gene', (10, 16))	('mutation', 'Var', (17, 25))	('CM', 'Phenotype', 'HP:0012056', (72, 74))
34213	25803691	Of the 327 families examined, a CDK4 mutation (p.R24H) was only found in one.	('CDK4', 'Gene', (32, 36))	('CDK', 'molecular_function', 'GO:0004693', ('32', '35'))	('CDK4', 'Gene', '1019', (32, 36))	('p.R24H', 'Var', (47, 53))	('p.R24H', 'Mutation', 'rs104894340', (47, 53))
34214	25803691	This illustrates that CDK4 mutations are very rare in Denmark, which is in accordance with reports from other countries.	('mutations', 'Var', (27, 36))	('CDK4', 'Gene', (22, 26))	('CDK', 'molecular_function', 'GO:0004693', ('22', '25'))	('CDK4', 'Gene', '1019', (22, 26))	('Denmark', 'Disease', (54, 61))
34217	25803691	In 12 individuals with UM and unknown family history of cancer, we found no BAP1 mutations.	('BAP1', 'Gene', '8314', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('BAP1', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('UM', 'Phenotype', 'HP:0007716', (23, 25))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
34219	25803691	We analysed BAP1 in 6 families with 2 or more cases of UM and found truncating BAP1 mutations in 4 families (66.7%), all of which have been published.	('BAP1', 'Gene', '8314', (79, 83))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('BAP1', 'Gene', (79, 83))	('BAP1', 'Gene', '8314', (12, 16))	('mutations', 'Var', (84, 93))	('BAP1', 'Gene', (12, 16))
34220	25803691	We analysed 5 families with CM and mesothelioma, and found truncating BAP1 mutations in 2 of the families.	('mesothelioma', 'Disease', (35, 47))	('BAP1', 'Gene', '8314', (70, 74))	('CM', 'Phenotype', 'HP:0012056', (28, 30))	('BAP1', 'Gene', (70, 74))	('mesothelioma', 'Disease', 'MESH:D008654', (35, 47))	('mutations', 'Var', (75, 84))	('truncating', 'MPA', (59, 69))
34222	25803691	CDKN2A mutation carriers with MC1R variants had a hazard ratio of 3.39 for developing CM compared to CDKN2A mutation carriers with no MC1R variants.	('MC1R', 'Gene', '4157', (30, 34))	('MC1R', 'Gene', '4157', (134, 138))	('MC1R', 'Gene', (30, 34))	('MC1R', 'Gene', (134, 138))	('CDKN2A', 'Gene', (101, 107))	('variants', 'Var', (35, 43))	('CDKN2A', 'Gene', '1029', (101, 107))	('CM', 'Phenotype', 'HP:0012056', (86, 88))	('CDKN2A', 'Gene', (0, 6))	('developing CM', 'Disease', (75, 88))	('CDKN2A', 'Gene', '1029', (0, 6))
34223	25803691	CDKN2A mutation carriers with one or two R variants had a hazard ratio of 2.52, and CDKN2A mutation carriers with one or two r variants had a hazard ratio of 2.24 (Table 6).	('CDKN2A', 'Gene', (84, 90))	('CDKN2A', 'Gene', '1029', (84, 90))	('mutation', 'Var', (7, 15))	('CDKN2A', 'Gene', (0, 6))	('variants', 'Var', (43, 51))	('CDKN2A', 'Gene', '1029', (0, 6))
34224	25803691	CDKN2A mutation carriers with [R/R, R/r] MC1R genotypes had a statistically significant (p = 0.038) increased OR (6.16) for developing CM compared to CDKN2A mutation carriers with [R/wt, r/r, r/wt, wt/wt] MC1R genotypes, and a statistically significant (p = 0.025) increased risk of developing melanoma 10 years earlier, with an OR of 2.25.	('increased', 'PosReg', (100, 109))	('MC1R', 'Gene', (41, 45))	('CDKN2A', 'Gene', (150, 156))	('melanoma', 'Disease', 'MESH:D008545', (294, 302))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('melanoma', 'Disease', (294, 302))	('developing', 'CPA', (124, 134))	('MC1R', 'Gene', '4157', (205, 209))	('CDKN2A', 'Gene', '1029', (150, 156))	('CM', 'Phenotype', 'HP:0012056', (135, 137))	('MC1R', 'Gene', (205, 209))	('[R/R', 'Var', (30, 34))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', '1029', (0, 6))	('MC1R', 'Gene', '4157', (41, 45))
34225	25803691	We also found that CDKN2A mutation carriers with [R/R, R/r] MC1R genotypes, were 24 times more likely to have MPM compared to carriers with the [wt/wt] MC1R genotype (p = 0.033).	('CDKN2A', 'Gene', (19, 25))	('CDKN2A', 'Gene', '1029', (19, 25))	('MC1R', 'Gene', (60, 64))	('MC1R', 'Gene', '4157', (152, 156))	('MC1R', 'Gene', (152, 156))	('MC1R', 'Gene', '4157', (60, 64))	('[R/R', 'Var', (49, 53))	('MPM', 'Disease', (110, 113))
34226	25803691	The MITF p.E318K mutation was analysed in DNA from 276 participants with CM, and we found 4 carriers (Table 7).	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('p.E318K', 'Mutation', 'rs149617956', (9, 16))	('MITF', 'Gene', '4286', (4, 8))	('MITF', 'Gene', (4, 8))	('participants', 'Species', '9606', (55, 67))	('CM', 'Phenotype', 'HP:0012056', (73, 75))	('p.E318K', 'Var', (9, 16))
34227	25803691	In the Danish population the MAF of MITF p.E318K was 9/3930 = 0.0023.	('MITF', 'Gene', '4286', (36, 40))	('MITF', 'Gene', (36, 40))	('p.E318K', 'Var', (41, 48))	('p.E318K', 'Mutation', 'rs149617956', (41, 48))
34229	25803691	We identified CDKN2A mutations in 3.9% of unrelated high-risk Danish CM cases.	('CDKN2A', 'Gene', '1029', (14, 20))	('CM', 'Phenotype', 'HP:0012056', (69, 71))	('Danish CM', 'Disease', (62, 71))	('CDKN2A', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
34230	25803691	The frequency of CDKN2A mutations in population based CM cases is 2% in North America, Europe and Australia, so a frequency of 3.9% in high-risk CM cases is surprisingly low.	('CDKN2A', 'Gene', (17, 23))	('CM', 'Phenotype', 'HP:0012056', (145, 147))	('CDKN2A', 'Gene', '1029', (17, 23))	('mutations', 'Var', (24, 33))	('CM', 'Phenotype', 'HP:0012056', (54, 56))
34231	25803691	This is further illustrated by the fact that we only found CDKN2A mutations in 5.6% of 3-case CM families, where previous reports have found mutation in 30% and 40% of such families from North America and Europe, respectively.	('CDKN2A', 'Gene', (59, 65))	('CM', 'Phenotype', 'HP:0012056', (94, 96))	('mutations', 'Var', (66, 75))	('CDKN2A', 'Gene', '1029', (59, 65))
34232	25803691	However, in Australia, another high-risk country for CM like Denmark, only ~10% of 3-case CM families carried a CDKN2A mutation.	('mutation', 'Var', (119, 127))	('CDKN2A', 'Gene', (112, 118))	('CDKN2A', 'Gene', '1029', (112, 118))	('CM', 'Phenotype', 'HP:0012056', (90, 92))	('CM', 'Phenotype', 'HP:0012056', (53, 55))
34234	25803691	As reported in other studies we found that carriers of CDKN2A mutations generally develop CM earlier, mean age 42.8 years, than other high-risk CM cases, mean age 48.3 years.	('CDKN2A', 'Gene', '1029', (55, 61))	('CM', 'Phenotype', 'HP:0012056', (144, 146))	('CM', 'Phenotype', 'HP:0012056', (90, 92))	('CDKN2A', 'Gene', (55, 61))	('mutations', 'Var', (62, 71))	('develop', 'PosReg', (82, 89))
34235	25803691	The penetrance for CDKN2A mutation carriers was 50% at age 50 and 80% at age 70, which is in keeping with the previously observed penetrances in North America and Australia, but considerably higher than the penetrance observed in other European countries.	('CDKN2A', 'Gene', '1029', (19, 25))	('CDKN2A', 'Gene', (19, 25))	('mutation', 'Var', (26, 34))
34236	25803691	Previously, it has been shown that the penetrance of CDKN2A mutations is greater in a high-risk cohort, compared to cases identified through screening of an unselected sample of melanoma cases.	('CDKN2A', 'Gene', (53, 59))	('greater', 'PosReg', (73, 80))	('CDKN2A', 'Gene', '1029', (53, 59))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('mutations', 'Var', (60, 69))
34238	25803691	This is in contrast to other reports, where in North America and Europe CDKN2A mutations were observed in 70-80% of families with pancreatic caner and 3 cases of CM, and in Australia a CDKN2A mutation was only found in 30% of such families.	('CDKN2A', 'Gene', '1029', (185, 191))	('pancreatic caner', 'Disease', 'MESH:D010195', (130, 146))	('observed', 'Reg', (94, 102))	('CDKN2A', 'Gene', '1029', (72, 78))	('CM', 'Phenotype', 'HP:0012056', (162, 164))	('CDKN2A', 'Gene', (185, 191))	('pancreatic caner', 'Disease', (130, 146))	('CDKN2A', 'Gene', (72, 78))	('mutations', 'Var', (79, 88))
34240	25803691	It is unknown if pancreatic cancer among CDKN2A mutations carriers in different geographic regions is caused by life-style factors, environmental factors, or genetic modulators.	('pancreatic cancer', 'Disease', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('pancreatic cancer', 'Disease', 'MESH:D010190', (17, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))	('CDKN2A', 'Gene', (41, 47))	('CDKN2A', 'Gene', '1029', (41, 47))	('mutations', 'Var', (48, 57))	('caused', 'Reg', (102, 108))
34241	25803691	Alternatively, there may be a genotype-phenotype correlation between the position of mutations in CDKN2A and risk of pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('pancreatic cancer', 'Disease', (117, 134))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('CDKN2A', 'Gene', (98, 104))	('mutations', 'Var', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('CDKN2A', 'Gene', '1029', (98, 104))
34242	25803691	In families with pancreatic cancer only we did not find CDKN2A mutations, which is in contrast to observations in Dutch and Italian pancreatic cancer families, but in accordance with reports from North America and Germany.	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('pancreatic cancer', 'Disease', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('pancreatic cancer', 'Disease', 'MESH:D010190', (17, 34))	('pancreatic cancer', 'Disease', (132, 149))	('pancreatic cancer', 'Disease', 'MESH:D010190', (132, 149))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))	('CDKN2A', 'Gene', (56, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (132, 149))	('CDKN2A', 'Gene', '1029', (56, 62))
34244	25803691	In this study we examined BAP1 in 133 high-risk CM cases (Table 4) and found no mutations, but identified mutations in 4/16 (25%) UM-CM families, all of which had 2 or more cases of UM (Table 4).	('BAP1', 'Gene', (26, 30))	('UM', 'Phenotype', 'HP:0007716', (182, 184))	('CM', 'Phenotype', 'HP:0012056', (133, 135))	('CM', 'Phenotype', 'HP:0012056', (48, 50))	('UM-CM', 'Disease', (130, 135))	('BAP1', 'Gene', '8314', (26, 30))	('mutations', 'Var', (106, 115))	('UM', 'Phenotype', 'HP:0007716', (130, 132))
34245	25803691	This is in line with previous reports by Njauw et al, where they found BAP1 mutations in 0.5% of CM families, and in 28.5% of UM-CM families.	('mutations', 'Var', (76, 85))	('CM', 'Phenotype', 'HP:0012056', (129, 131))	('BAP1', 'Gene', '8314', (71, 75))	('CM', 'Phenotype', 'HP:0012056', (97, 99))	('UM', 'Phenotype', 'HP:0007716', (126, 128))	('found', 'Reg', (65, 70))	('BAP1', 'Gene', (71, 75))
34246	25803691	One of the weaknesses of the study is that we did not recruit UM patients in a systematic manner, however, we are in the process of examining 100 UM patients for germline BAP1 mutations.	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('BAP1', 'Gene', (171, 175))	('mutations', 'Var', (176, 185))	('patients', 'Species', '9606', (149, 157))	('UM', 'Phenotype', 'HP:0007716', (146, 148))	('patients', 'Species', '9606', (65, 73))	('BAP1', 'Gene', '8314', (171, 175))
34247	25803691	We found BAP1 mutations in 40% of families with CM and mesothelioma (Table 4).	('mesothelioma', 'Disease', (55, 67))	('CM', 'Phenotype', 'HP:0012056', (48, 50))	('BAP1', 'Gene', '8314', (9, 13))	('mesothelioma', 'Disease', 'MESH:D008654', (55, 67))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
34250	25803691	Whether BAP1 screening should be conducted in Danish families with CM and RCC remains unclear and further studies are needed to examine the frequency of BAP1 mutations in families with RCC, with and without CM.	('RCC', 'Disease', (185, 188))	('CM', 'Phenotype', 'HP:0012056', (207, 209))	('BAP1', 'Gene', '8314', (8, 12))	('RCC', 'Disease', (74, 77))	('BAP1', 'Gene', '8314', (153, 157))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('CM', 'Phenotype', 'HP:0012056', (67, 69))	('BAP1', 'Gene', (8, 12))	('BAP1', 'Gene', (153, 157))	('mutations', 'Var', (158, 167))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('RCC', 'Disease', 'MESH:C538614', (185, 188))
34251	25803691	In Danish CM cases the frequency of MC1R R variants is high (39%, almost twice the frequency of controls, MAF 0.2).	('variants', 'Var', (43, 51))	('MC1R', 'Gene', '4157', (36, 40))	('CM', 'Phenotype', 'HP:0012056', (10, 12))	('MC1R', 'Gene', (36, 40))
34252	25803691	In cohorts of CM cases from Southern Europe the OR for association with CM of MC1R r variants has been reported to be highly variable (between 0.84-3).	('variants', 'Var', (85, 93))	('CM', 'Phenotype', 'HP:0012056', (72, 74))	('CM', 'Phenotype', 'HP:0012056', (14, 16))	('association', 'Interaction', (55, 66))	('MC1R', 'Gene', '4157', (78, 82))	('MC1R', 'Gene', (78, 82))
34253	25803691	As Denmark is a high incidence country for melanoma, there is a distinct possibility of phenocopies in families, and since only one person from each family was examined for CDKN2A and CDK4 mutations, it cannot be ruled out that mutations in some families have not been identified.	('phenocopies', 'Disease', 'MESH:C580174', (88, 99))	('CDK4', 'Gene', (184, 188))	('CDKN2A', 'Gene', (173, 179))	('CDK', 'molecular_function', 'GO:0004693', ('184', '187'))	('CDK4', 'Gene', '1019', (184, 188))	('person', 'Species', '9606', (132, 138))	('CDKN2A', 'Gene', '1029', (173, 179))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('phenocopies', 'Disease', (88, 99))	('mutations', 'Var', (189, 198))
34254	25803691	Alternatively, mutations in other yet unknown predisposition genes could explain the low rate of CDKN2A mutations identified.	('CDKN2A', 'Gene', '1029', (97, 103))	('CDKN2A', 'Gene', (97, 103))	('mutations', 'Var', (104, 113))
34257	25803691	Mutations in CDK4, and the MITF p.E318K mutation, are rare in the Danish population examined here, and only explain a minority of CM cases.	('CM', 'Phenotype', 'HP:0012056', (130, 132))	('p.E318K', 'Var', (32, 39))	('p.E318K', 'Mutation', 'rs149617956', (32, 39))	('Mutations', 'Var', (0, 9))	('MITF', 'Gene', (27, 31))	('MITF', 'Gene', '4286', (27, 31))	('CDK4', 'Gene', (13, 17))	('CDK4', 'Gene', '1019', (13, 17))	('CDK', 'molecular_function', 'GO:0004693', ('13', '16'))
34258	25803691	The MAF of MITF p.E318K in Danish CM cases (0.0072) is lower than previously observed in UK CM cases (0.0176), Australian CM cases (0.0165), and Italian and French CM cases (MAF 0.011 and 0.014), respectively.	('CM', 'Phenotype', 'HP:0012056', (122, 124))	('CM', 'Phenotype', 'HP:0012056', (92, 94))	('p.E318K', 'Var', (16, 23))	('CM', 'Phenotype', 'HP:0012056', (34, 36))	('CM', 'Phenotype', 'HP:0012056', (164, 166))	('p.E318K', 'Mutation', 'rs149617956', (16, 23))	('lower', 'NegReg', (55, 60))	('MITF', 'Gene', '4286', (11, 15))	('MITF', 'Gene', (11, 15))
34259	25803691	MC1R is a modulator of CDKN2A mutations and we found a trend of carrying any MC1R variant being associated with increased risk of CM in CDKN2A mutation carriers (Table 6).	('CM', 'Phenotype', 'HP:0012056', (130, 132))	('MC1R', 'Gene', '4157', (0, 4))	('MC1R', 'Gene', (77, 81))	('associated', 'Reg', (96, 106))	('MC1R', 'Gene', (0, 4))	('CDKN2A', 'Gene', (23, 29))	('CDKN2A', 'Gene', (136, 142))	('CDKN2A', 'Gene', '1029', (136, 142))	('variant', 'Var', (82, 89))	('CDKN2A', 'Gene', '1029', (23, 29))	('MC1R', 'Gene', '4157', (77, 81))
34260	25803691	CDKN2A mutation carriers with [R/R, R/r] MC1R genotypes, had a significantly higher risk of developing melanoma compared to other carriers, and had an OR of 2.25 for developing CM 10 years earlier than carriers with [r/r, R/wt, r/wt, wt/wt] MC1R genotypes.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('MC1R', 'Gene', (41, 45))	('MC1R', 'Gene', '4157', (41, 45))	('MC1R', 'Gene', '4157', (241, 245))	('MC1R', 'Gene', (241, 245))	('developing CM', 'CPA', (166, 179))	('[R/R', 'Var', (30, 34))	('CDKN2A', 'Gene', (0, 6))	('CM', 'Phenotype', 'HP:0012056', (177, 179))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('CDKN2A', 'Gene', '1029', (0, 6))	('melanoma', 'Disease', (103, 111))
34261	25803691	It has previously been shown that MC1R variants increased the risk of melanoma in CDKN2A mutation carriers, however in Italian CDKN2A mutations carriers, who have few MC1R variants, other factors influence the risk of developing CM.	('melanoma', 'Disease', (70, 78))	('MC1R', 'Gene', '4157', (34, 38))	('MC1R', 'Gene', (167, 171))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('mutation', 'Var', (89, 97))	('MC1R', 'Gene', (34, 38))	('CDKN2A', 'Gene', (82, 88))	('CM', 'Phenotype', 'HP:0012056', (229, 231))	('increased', 'Reg', (48, 57))	('influence', 'Reg', (196, 205))	('CDKN2A', 'Gene', '1029', (82, 88))	('CDKN2A', 'Gene', (127, 133))	('MC1R', 'Gene', '4157', (167, 171))	('CDKN2A', 'Gene', '1029', (127, 133))	('variants', 'Var', (39, 47))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
34262	25803691	We found that CDKN2A mutation carriers with (R/R, R/r) MC1R genotypes had significantly higher risk of developing MPM compared to carriers with wt MC1R genotype.	('MPM', 'Disease', (114, 117))	('MC1R', 'Gene', '4157', (147, 151))	('MC1R', 'Gene', (147, 151))	('CDKN2A', 'Gene', '1029', (14, 20))	('MC1R', 'Gene', '4157', (55, 59))	('MC1R', 'Gene', (55, 59))	('R/R', 'Var', (45, 48))	('CDKN2A', 'Gene', (14, 20))
34264	25803691	The latter should be screened predominately when family history of CM or pancreatic cancer is unknown, since we identified three CDKN2A mutations in individuals with MPM and all had no or limited information about their family cancer history.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('MPM', 'Disease', (166, 169))	('pancreatic cancer', 'Disease', (73, 90))	('cancer', 'Disease', (84, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('CDKN2A', 'Gene', (129, 135))	('CDKN2A', 'Gene', '1029', (129, 135))	('mutations', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))	('CM', 'Phenotype', 'HP:0012056', (67, 69))
34265	25803691	The age-specific penetrance for CM in CDKN2A mutation carriers is high in Denmark, as in other high incidence melanoma countries, and MC1R variants modulate the penetrance of CM and the risk of MPM.	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('modulate', 'Reg', (148, 156))	('MC1R', 'Gene', '4157', (134, 138))	('MPM', 'Disease', (194, 197))	('MC1R', 'Gene', (134, 138))	('melanoma countries', 'Disease', (110, 128))	('CM', 'Phenotype', 'HP:0012056', (175, 177))	('penetrance', 'MPA', (161, 171))	('melanoma countries', 'Disease', 'MESH:D008545', (110, 128))	('CDKN2A', 'Gene', (38, 44))	('variants', 'Var', (139, 147))	('CDKN2A', 'Gene', '1029', (38, 44))	('CM', 'Phenotype', 'HP:0012056', (32, 34))
34267	25803691	The MITF p.E318K mutation is a rare moderate risk CM allele in the Danish population.	('p.E318K', 'Mutation', 'rs149617956', (9, 16))	('MITF', 'Gene', '4286', (4, 8))	('MITF', 'Gene', (4, 8))	('CM', 'Phenotype', 'HP:0012056', (50, 52))	('p.E318K', 'Var', (9, 16))
34268	25803691	At present, routine clinical testing of MITF p.E318K in CM patients does not appear warranted.	('p.E318K', 'Mutation', 'rs149617956', (45, 52))	('MITF', 'Gene', '4286', (40, 44))	('MITF', 'Gene', (40, 44))	('CM', 'Phenotype', 'HP:0012056', (56, 58))	('patients', 'Species', '9606', (59, 67))	('p.E318K', 'Var', (45, 52))
34276	25166211	Growth in hypoxia significantly increased cellular invasion of all 5 uveal melanoma lines tested, as did the introduction of an oxygen-insensitive HIF-1alpha mutant into Mel285 cells with low HIF-1alpha baseline levels.	('uveal melanoma lines', 'Disease', 'MESH:C536494', (69, 89))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('uveal melanoma lines', 'Disease', (69, 89))	('cellular invasion', 'CPA', (42, 59))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('hypoxia', 'Disease', 'MESH:D000860', (10, 17))	('oxygen', 'Chemical', 'MESH:D010100', (128, 134))	('increased', 'PosReg', (32, 41))	('hypoxia', 'Disease', (10, 17))	('mutant', 'Var', (158, 164))	('HIF-1alpha', 'Gene', (147, 157))
34286	25166211	The most significant single chromosomal marker of poor outcome in uveal melanoma is loss of one copy of chromosome 3, while activating mutations in the alpha subunit of heterotrimeric G proteins, GNAQ or GNA11, are considered an early event in the development of the disease.	('GNA11', 'Gene', (204, 209))	('uveal melanoma', 'Disease', (66, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('GNAQ', 'Gene', '2776', (196, 200))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('GNA11', 'Gene', '2767', (204, 209))	('mutations', 'Var', (135, 144))	('loss', 'NegReg', (84, 88))	('GNAQ', 'Gene', (196, 200))	('activating', 'PosReg', (124, 134))	('chromosome', 'cellular_component', 'GO:0005694', ('104', '114'))
34287	25166211	Recently, inactivating mutations in the tumor suppressor BRCA1-associated protein-1 (BAP1), located at 3p21.1, were shown to occur almost exclusively in metastatic uveal melanomas with monosomy 3.	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('BRCA1-associated protein-1', 'Gene', '8314', (57, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (164, 178))	('monosomy 3', 'Disease', (185, 195))	('inactivating mutations', 'Var', (10, 32))	('uveal melanomas', 'Disease', (164, 179))	('BRCA1-associated protein-1', 'Gene', (57, 83))	('uveal melanomas', 'Phenotype', 'HP:0007716', (164, 179))	('BAP1', 'Gene', '8314', (85, 89))	('melanomas', 'Phenotype', 'HP:0002861', (170, 179))	('occur', 'Reg', (125, 130))	('tumor', 'Disease', (40, 45))	('BAP1', 'Gene', (85, 89))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('uveal melanomas', 'Disease', 'MESH:C536494', (164, 179))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))
34304	25166211	Retroviruses were generated using a pBABE vector carrying an oxygen stable mutant of HIF-1alpha HA-tagged (HIF-1alphaPro402Ala/Pro564Ala), resistant to prolyl-hydroxylation and stably expressed in normoxia (Addgene, Cambridge, MA).	('oxygen', 'Chemical', 'MESH:D010100', (61, 67))	('Pro564Ala', 'SUBSTITUTION', 'None', (127, 136))	('prolyl', 'Chemical', '-', (152, 158))	('Pro564Ala', 'Var', (127, 136))	('HIF-1alpha', 'Gene', (85, 95))
34338	25166211	HIF-1alpha activity was induced in these cells by retroviral infection of an oxygen stable mutant of HIF-1alpha HA-tagged (HIF-1alphaPro402Ala/Pro564Ala), which is resistant to VHL-mediated degradation and its expression is not reduced in normoxia.	('VHL', 'Gene', (177, 180))	('Pro564Ala', 'SUBSTITUTION', 'None', (143, 152))	('activity', 'MPA', (11, 19))	('VHL', 'Gene', '7428', (177, 180))	('degradation', 'biological_process', 'GO:0009056', ('190', '201'))	('HIF-1alpha', 'Gene', (101, 111))	('Pro564Ala', 'Var', (143, 152))	('induced', 'Reg', (24, 31))	('oxygen', 'Chemical', 'MESH:D010100', (77, 83))
34339	25166211	We confirmed by Western blot the increase of HIF-1alpha protein in normoxia in Mel285 cells expressing the oxygen stable mutant of HIF-1alpha (Figure 2B), and we also observed by qPCR induction of VEGF and LOX mRNA expression in these cells as compared to the pBABE-infected cells (Figure 2C).	('VEGF', 'Gene', '7422', (197, 201))	('LOX', 'Gene', '4015', (206, 209))	('mutant', 'Var', (121, 127))	('HIF-1alpha', 'Gene', (131, 141))	('LOX', 'Gene', (206, 209))	('HIF-1alpha protein', 'Protein', (45, 63))	('VEGF', 'Gene', (197, 201))	('increase', 'PosReg', (33, 41))	('oxygen', 'Chemical', 'MESH:D010100', (107, 113))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))
34367	25166211	We used the Erk inhibitor SCH772984 to suppress the phosphorylation of Erk1-2 in 92.1 and OCM1 cells (Figure S7).	('phosphorylation', 'MPA', (52, 67))	('Erk', 'molecular_function', 'GO:0004707', ('12', '15'))	('Erk', 'Gene', (12, 15))	('Erk', 'Gene', (71, 74))	('SCH772984', 'Chemical', 'MESH:C587178', (26, 35))	('suppress', 'NegReg', (39, 47))	('Erk', 'Gene', '5594', (12, 15))	('Erk', 'Gene', '5594', (71, 74))	('phosphorylation', 'biological_process', 'GO:0016310', ('52', '67'))	('OCM1', 'Species', '83984', (90, 94))	('SCH772984', 'Var', (26, 35))	('Erk1', 'molecular_function', 'GO:0004707', ('71', '75'))
34368	25166211	Interestingly we observed that the treatment of these cells with SCH772984 at 500 nM for 24 hours significantly reduced the number of cells invading a Matrigel-coated membrane either in normoxic and in hypoxic conditions (Figure 7B).	('coated membrane', 'cellular_component', 'GO:0048475', ('160', '175'))	('SCH772984', 'Var', (65, 74))	('hypoxic conditions', 'Disease', (202, 220))	('hypoxic conditions', 'Disease', 'MESH:D009135', (202, 220))	('SCH772984', 'Chemical', 'MESH:C587178', (65, 74))	('reduced', 'NegReg', (112, 119))
34369	25166211	Based on these data, we propose a model in which GNAQ/GNA11 mutations, detected in the Galpha subunit of heterotrimeric G proteins in the majority of primary uveal melanomas, are responsible for the activation of MAPK pathway under normoxic conditions.	('MAPK', 'molecular_function', 'GO:0004707', ('213', '217'))	('uveal melanomas', 'Disease', (158, 173))	('GNA11', 'Gene', (54, 59))	('uveal melanomas', 'Phenotype', 'HP:0007716', (158, 173))	('GNAQ', 'Gene', '2776', (49, 53))	('melanomas', 'Phenotype', 'HP:0002861', (164, 173))	('GNA11', 'Gene', '2767', (54, 59))	('activation', 'PosReg', (199, 209))	('primary uveal melanoma', 'Disease', (150, 172))	('uveal melanoma', 'Phenotype', 'HP:0007716', (158, 172))	('GNAQ', 'Gene', (49, 53))	('mutations', 'Var', (60, 69))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (150, 172))	('MAPK pathway', 'Pathway', (213, 225))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('uveal melanomas', 'Disease', 'MESH:C536494', (158, 173))
34385	25166211	We performed HIF-1alpha loss-of-function studies in multiple uveal melanoma cell lines, since recent mutational profile studies have shown that BRAFV600E mutation, which is pretty rare in primary uveal melanomas, but more frequent in cutaneous melanomas, has been detected in a subset of uveal melanoma cell lines, including OCM1.	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('cutaneous melanomas', 'Disease', (234, 253))	('melanomas', 'Phenotype', 'HP:0002861', (244, 253))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (188, 210))	('uveal melanoma', 'Phenotype', 'HP:0007716', (196, 210))	('uveal melanomas', 'Disease', (196, 211))	('uveal melanomas', 'Phenotype', 'HP:0007716', (196, 211))	('uveal melanoma', 'Disease', 'MESH:C536494', (288, 302))	('uveal melanoma', 'Disease', (288, 302))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('BRAFV600E', 'Var', (144, 153))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (234, 252))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('uveal melanoma', 'Phenotype', 'HP:0007716', (288, 302))	('primary uveal melanoma', 'Disease', (188, 210))	('melanomas', 'Phenotype', 'HP:0002861', (202, 211))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (234, 253))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (234, 253))	('OCM1', 'Species', '83984', (325, 329))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('uveal melanoma', 'Disease', 'MESH:C536494', (61, 75))	('uveal melanomas', 'Disease', 'MESH:C536494', (196, 211))	('uveal melanoma', 'Disease', (61, 75))	('BRAFV600E', 'Mutation', 'rs113488022', (144, 153))	('uveal melanoma', 'Disease', 'MESH:C536494', (196, 210))
34405	25166211	Downstream pathways that we found activated by hypoxia exposure include Notch, Erk1-2 and Akt, and we found that activation of Notch and MAPK was required for full induction of cellular invasion under hypoxic conditions.	('Notch', 'Var', (127, 132))	('MAPK', 'Gene', (137, 141))	('Akt', 'Gene', (90, 93))	('cellular invasion', 'CPA', (177, 194))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('hypoxia', 'Disease', (47, 54))	('Downstream pathways', 'Pathway', (0, 19))	('hypoxic conditions', 'Disease', (201, 219))	('Erk1-2', 'Gene', (79, 85))	('Erk1', 'molecular_function', 'GO:0004707', ('79', '83'))	('Akt', 'Gene', '207', (90, 93))	('hypoxic conditions', 'Disease', 'MESH:D009135', (201, 219))	('MAPK', 'molecular_function', 'GO:0004707', ('137', '141'))
34407	23656586	Sturge-Weber Syndrome and Port-Wine Stains Caused by Somatic Mutation in GNAQ The Sturge-Weber syndrome is a sporadic congenital neurocutaneous disorder characterized by a port-wine stain affecting the skin in the distribution of the ophthalmic branch of the trigeminal nerve, abnormal capillary venous vessels in the leptomeninges of the brain and choroid, glaucoma, seizures, stroke, and intellectual disability.	('congenital neurocutaneous disorder', 'Disease', 'MESH:D020752', (118, 152))	('abnormal capillary', 'Phenotype', 'HP:0025016', (277, 295))	('stroke', 'Disease', (378, 384))	('seizures', 'Disease', 'MESH:D012640', (368, 376))	('Weber syndrome', 'Phenotype', 'HP:0002277', (89, 103))	('seizures', 'Phenotype', 'HP:0001250', (368, 376))	('intellectual disability', 'Disease', (390, 413))	('Mutation', 'Var', (61, 69))	('affecting', 'Reg', (188, 197))	('glaucoma', 'Phenotype', 'HP:0000501', (358, 366))	('Port-Wine Stains', 'Phenotype', 'HP:0001052', (26, 42))	('glaucoma', 'Disease', (358, 366))	('intellectual disability', 'Phenotype', 'HP:0001249', (390, 413))	('glaucoma', 'Disease', 'MESH:D005901', (358, 366))	('GNAQ', 'Gene', (73, 77))	('Weber Syndrome', 'Phenotype', 'HP:0002277', (7, 21))	('congenital neurocutaneous disorder', 'Disease', (118, 152))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (82, 103))	('port-wine stain', 'Phenotype', 'HP:0001052', (172, 187))	('stroke', 'Phenotype', 'HP:0001297', (378, 384))	('Sturge-Weber syndrome', 'Disease', (82, 103))	('seizures', 'Disease', (368, 376))	('stroke', 'Disease', 'MESH:D020521', (378, 384))
34408	23656586	It has been hypothesized that somatic mosaic mutations disrupting vascular development cause both the Sturge-Weber syndrome and port-wine stains, and the severity and extent of presentation are determined by the developmental time point at which the mutations occurred.	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (102, 123))	('mutations', 'Var', (45, 54))	('port-wine stains', 'Disease', (128, 144))	('port-wine stain', 'Phenotype', 'HP:0001052', (128, 143))	('cause', 'Reg', (87, 92))	('Weber syndrome', 'Phenotype', 'HP:0002277', (109, 123))	('port-wine stains', 'Phenotype', 'HP:0001052', (128, 144))	('Sturge-Weber syndrome', 'Disease', (102, 123))	('disrupting', 'NegReg', (55, 65))	('vascular development', 'CPA', (66, 86))
34410	23656586	We tested for the presence of a somatic mosaic mutation in 97 samples from 50 persons with the Sturge-Weber syndrome, a port-wine stain, or neither (controls), using amplicon sequencing and SNaPshot assays, and investigated the effects of the mutation on downstream signaling, using phosphorylation-specific antibodies for relevant effectors and a luciferase reporter assay.	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (95, 116))	('persons', 'Species', '9606', (78, 85))	('phosphorylation', 'biological_process', 'GO:0016310', ('283', '298'))	('mutation', 'Var', (47, 55))	('tested', 'Reg', (3, 9))	('Weber syndrome', 'Phenotype', 'HP:0002277', (102, 116))	('Sturge-Weber syndrome', 'Disease', (95, 116))	('signaling', 'biological_process', 'GO:0023052', ('266', '275'))	('port-wine stain', 'Phenotype', 'HP:0001052', (120, 135))
34411	23656586	We identified a nonsynonymous single-nucleotide variant (c.548G A, p.Arg183Gln) in GNAQ in samples of affected tissue from 88% of the participants (23 of 26) with the Sturge-Weber syndrome and from 92% of the participants (12 of 13) with apparently nonsyndromic port-wine stains, but not in any of the samples of affected tissue from 4 participants with an unrelated cerebrovascular malformation or in any of the samples from the 6 controls.	('port-wine stains', 'Disease', (262, 278))	('cerebrovascular malformation', 'Disease', 'MESH:D000014', (367, 395))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (167, 188))	('port-wine stain', 'Phenotype', 'HP:0001052', (262, 277))	('cerebrovascular malformation', 'Disease', (367, 395))	('participants', 'Species', '9606', (336, 348))	('participants', 'Species', '9606', (209, 221))	('participants', 'Species', '9606', (134, 146))	('Sturge-Weber syndrome', 'Disease', (167, 188))	('p.Arg183Gln', 'Var', (67, 78))	('Weber syndrome', 'Phenotype', 'HP:0002277', (174, 188))	('c.548G A', 'Var', (57, 65))	('p.Arg183Gln', 'Mutation', 'rs397514698', (67, 78))	('GNAQ', 'Gene', (83, 87))	('port-wine stains', 'Phenotype', 'HP:0001052', (262, 278))
34412	23656586	Extracellular signal-regulated kinase activity was modestly increased during transgenic expression of mutant Galphaq.	('mutant', 'Var', (102, 108))	('Extracellular signal-regulated kinase activity', 'molecular_function', 'GO:0004707', ('0', '46'))	('Extracellular signal-regulated kinase', 'Gene', (0, 37))	('Extracellular signal-regulated kinase', 'Gene', '5594', (0, 37))	('Extracellular', 'cellular_component', 'GO:0005576', ('0', '13'))	('Galphaq', 'Gene', (109, 116))	('Galphaq', 'Gene', '2776', (109, 116))	('increased', 'PosReg', (60, 69))
34423	23656586	When multiple samplings of biopsied tissue or multiple sequencing assays were performed, we considered the participant to be positive for the mutation if at least 1 tissue sample tested positive (>=1% mutant allele) and to be negative if every tissue sample tested negative for the mutation (<1% mutant allele).	('mutant', 'Var', (201, 207))	('positive', 'Reg', (125, 133))	('participant', 'Species', '9606', (107, 118))
34425	23656586	Two specific mutations, c.548G A (encoding p.Arg183Gln) and c.626A T (encoding p.Gln209 Leu), were introduced separately into GNAQ with the use of primers for site-directed mutagenesis (Table S4 in the Supplementary Appendix).	('p.Gln209 Leu', 'Var', (79, 91))	('mutagenesis', 'biological_process', 'GO:0006280', ('173', '184'))	('p.Arg183Gln', 'Var', (43, 54))	('p.Gln209 Leu', 'Mutation', 'rs121913492', (79, 91))	('p.Arg183Gln', 'Mutation', 'rs397514698', (43, 54))
34427	23656586	GNAQ, GNAQ p.Arg183Gln or GNAQ encoding p.Gln209Leu, pSRE-Luc, and pSV40-RL were transfected into HEK293T cells, which were lysed after 20 to 24 hours of incubation.	('p.Arg183Gln', 'Var', (11, 22))	('p.Arg183Gln', 'Mutation', 'rs397514698', (11, 22))	('pSV40-RL', 'Var', (67, 75))	('p.Gln209Leu', 'Mutation', 'rs121913492', (40, 51))	('HEK293T', 'CellLine', 'CVCL:0063', (98, 105))	('p.Gln209Leu', 'Var', (40, 51))
34430	23656586	This resulted in the identification of one nonsynonymous somatic single-nucleotide variant that was present in all three affected samples and was not present in the samples that were presumed to be normal : a c.548G A nucleotide transition in GNAQ on chromosome 9q21, encoding guanine nucleotide binding protein (G protein), q polypeptide (Galphaq).	('Galphaq', 'Gene', (340, 347))	('Galphaq', 'Gene', '2776', (340, 347))	('GNAQ', 'Gene', (243, 247))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (277, 295))	('protein', 'cellular_component', 'GO:0003675', ('304', '311'))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('285', '303'))	('protein', 'cellular_component', 'GO:0003675', ('315', '322'))	('chromosome', 'cellular_component', 'GO:0005694', ('251', '261'))	('c.548G A nucleotide', 'Var', (209, 228))
34431	23656586	The variant is predicted to result in the amino acid substitution p.Arg183Gln.	('result', 'Reg', (28, 34))	('p.Arg183Gln', 'Var', (66, 77))	('p.Arg183Gln', 'Mutation', 'rs397514698', (66, 77))
34433	23656586	The results of our studies of skin samples were as follows: 100% of participants (9 of 9) with the Sturge-Weber syndrome were positive for the c.548G A mutation in port-wine-stained skin, 86% of participants (6 of 7) with the syndrome were negative for the mutation in visibly normal skin, and 92% of participants (12 of 13) with apparently nonsyndromic port-wine stains were positive for the mutation (Table 1).	('port-wine-stained skin', 'Phenotype', 'HP:0001052', (164, 186))	('port-wine stain', 'Phenotype', 'HP:0001052', (354, 369))	('participants', 'Species', '9606', (301, 313))	('positive', 'Reg', (126, 134))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (99, 120))	('participants', 'Species', '9606', (68, 80))	('participants', 'Species', '9606', (195, 207))	('Weber syndrome', 'Phenotype', 'HP:0002277', (106, 120))	('port-wine stains', 'Phenotype', 'HP:0001052', (354, 370))	('Sturge-Weber syndrome', 'Disease', (99, 120))	('c.548G A', 'Var', (143, 151))
34436	23656586	In total, 88% of the participants (23 of 26) with the Sturge-Weber syndrome were positive for the c.548G A mutation in either port-wine-stained skin or brain tissue.	('positive', 'Reg', (81, 89))	('participants', 'Species', '9606', (21, 33))	('Sturge-Weber syndrome', 'Disease', (54, 75))	('Weber syndrome', 'Phenotype', 'HP:0002277', (61, 75))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (54, 75))	('c.548G A', 'Var', (98, 106))	('port-wine-stained skin', 'Phenotype', 'HP:0001052', (126, 148))
34437	23656586	GNA11 mutations have also been found in patients with uveal melanoma.	('patients', 'Species', '9606', (40, 48))	('GNA11', 'Gene', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('GNA11', 'Gene', '2767', (0, 5))	('uveal melanoma', 'Disease', (54, 68))	('uveal melanoma', 'Disease', 'MESH:C536494', (54, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('found', 'Reg', (31, 36))	('mutations', 'Var', (6, 15))
34438	23656586	We tested GNAQ Arg183Gln mutation-negative samples from participants with the Sturge-Weber syndrome and those with nonsyndromic port-wine stains for the presence of previously identified GNA11 mutations (p.Arg183Cys, c.547C T and c.546C T; p.Arg183His, c.548G A; p.Gln209Leu, c.626A T and c.627G A; and p.Gln209Pro, c.626A C) using SNaPshot analysis.	('Arg183Gln', 'SUBSTITUTION', 'None', (15, 24))	('GNA11', 'Gene', '2767', (187, 192))	('c.626A T', 'Var', (276, 284))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (78, 99))	('c.627G A', 'Var', (289, 297))	('port-wine stain', 'Phenotype', 'HP:0001052', (128, 143))	('c.626A C', 'Var', (316, 324))	('Sturge-Weber syndrome', 'Disease', (78, 99))	('p.Gln209Pro', 'Mutation', 'rs1057519742', (303, 314))	('c.548G A; p.Gln209Leu', 'Var', (253, 274))	('GNA11', 'Gene', (187, 192))	('Arg183Gln', 'Var', (15, 24))	('port-wine stains', 'Phenotype', 'HP:0001052', (128, 144))	('p.Gln209Leu', 'Mutation', 'rs121913492', (263, 274))	('Weber syndrome', 'Phenotype', 'HP:0002277', (85, 99))	('p.Arg183His', 'Var', (240, 251))	('participants', 'Species', '9606', (56, 68))	('p.Gln209Leu', 'Var', (263, 274))	('p.Gln209Pro', 'Var', (303, 314))	('p.Arg183Cys', 'Var', (204, 215))	('p.Arg183His', 'Mutation', 'p.R183H', (240, 251))	('c.547C T', 'Var', (217, 225))	('p.Arg183Cys', 'Mutation', 'p.R183C', (204, 215))	('c.546C T; p.Arg183His', 'Var', (230, 251))
34439	23656586	The somatic substitutions in GNAQ encoding p.Gln209Leu and p.Arg183Gln are found in patients with uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('p.Gln209Leu', 'Var', (43, 54))	('GNAQ', 'Gene', (29, 33))	('patients', 'Species', '9606', (84, 92))	('p.Arg183Gln', 'Var', (59, 70))	('p.Arg183Gln', 'Mutation', 'rs397514698', (59, 70))	('found', 'Reg', (75, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (98, 112))	('uveal melanoma', 'Disease', (98, 112))	('uveal melanoma', 'Disease', 'MESH:C536494', (98, 112))	('p.Gln209Leu', 'Mutation', 'rs121913492', (43, 54))
34440	23656586	The more common p.Gln209Leu has been shown to overactivate the mitogen-activated protein kinase (MAPK) pathway.	('MAPK', 'Gene', '5594', (97, 101))	('p.Gln209Leu', 'Mutation', 'rs121913492', (16, 27))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('MAPK', 'Gene', (97, 101))	('overactivate', 'PosReg', (46, 58))	('MAPK', 'molecular_function', 'GO:0004707', ('97', '101'))	('p.Gln209Leu', 'Var', (16, 27))
34441	23656586	We examined whether p.Arg183Gln would likewise overactivate the MAPK pathway.	('overactivate', 'PosReg', (47, 59))	('p.Arg183Gln', 'Var', (20, 31))	('p.Arg183Gln', 'Mutation', 'rs397514698', (20, 31))	('MAPK', 'molecular_function', 'GO:0004707', ('64', '68'))	('MAPK', 'Gene', '5594', (64, 68))	('MAPK', 'Gene', (64, 68))
34442	23656586	As shown in Figure 2A, cells transfected with GNAQ p.Gln209Leu or GNAQ p.Arg183Gln, as compared with cells transfected with nonmutant GNAQ, showed significant activation of extracellular signal-regulated kinase (ERK) (P<0.05).	('p.Gln209Leu', 'Mutation', 'rs121913492', (51, 62))	('activation', 'PosReg', (159, 169))	('ERK', 'molecular_function', 'GO:0004707', ('212', '215'))	('extracellular signal-regulated kinase', 'Gene', '5594', (173, 210))	('p.Gln209Leu', 'Var', (51, 62))	('ERK', 'Gene', '5594', (212, 215))	('extracellular signal-regulated kinase', 'Gene', (173, 210))	('p.Arg183Gln', 'Var', (71, 82))	('p.Arg183Gln', 'Mutation', 'rs397514698', (71, 82))	('ERK', 'Gene', (212, 215))	('extracellular', 'cellular_component', 'GO:0005576', ('173', '186'))
34444	23656586	Galphaq p.Gln209Leu strongly activated p38 and Jun N-terminal kinase (JNK), other MAPK pathway members, whereas p.Arg183Gln did not (Fig.	('JNK', 'Gene', (70, 73))	('p38', 'Gene', '5594', (39, 42))	('activated', 'PosReg', (29, 38))	('Galphaq', 'Gene', (0, 7))	('p.Arg183Gln', 'Mutation', 'rs397514698', (112, 123))	('Galphaq', 'Gene', '2776', (0, 7))	('Jun N-terminal kinase', 'Gene', '5599', (47, 68))	('p.Gln209Leu', 'Mutation', 'rs121913492', (8, 19))	('JNK', 'Gene', '5599', (70, 73))	('Jun N-terminal kinase', 'Gene', (47, 68))	('p38', 'Gene', (39, 42))	('MAPK', 'Gene', '5594', (82, 86))	('p.Gln209Leu', 'Var', (8, 19))	('JNK', 'molecular_function', 'GO:0004705', ('70', '73'))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))	('MAPK', 'Gene', (82, 86))
34446	23656586	These data show that p.Arg183Gln has a gain-of-function effect that activates downstream signaling pathways.	('p.Arg183Gln', 'Var', (21, 32))	('p.Arg183Gln', 'Mutation', 'rs397514698', (21, 32))	('gain-of-function', 'PosReg', (39, 55))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('downstream signaling pathways', 'Pathway', (78, 107))	('activates', 'PosReg', (68, 77))
34447	23656586	However, the effect of p.Arg183Gln in MAPK signal transduction appeared to be both weaker and less promiscuous with respect to the activation of downstream effectors than the effect of the substitution p.Gln209Leu that is found more commonly in uveal melanoma tissue.	('MAPK', 'Gene', (38, 42))	('uveal melanoma', 'Phenotype', 'HP:0007716', (245, 259))	('uveal melanoma', 'Disease', 'MESH:C536494', (245, 259))	('uveal melanoma', 'Disease', (245, 259))	('MAPK signal transduction', 'biological_process', 'GO:0000165', ('38', '62'))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('MAPK', 'Gene', '5594', (38, 42))	('p.Gln209Leu', 'Mutation', 'rs121913492', (202, 213))	('p.Arg183Gln', 'Var', (23, 34))	('p.Arg183Gln', 'Mutation', 'rs397514698', (23, 34))	('MAPK', 'molecular_function', 'GO:0004707', ('38', '42'))
34448	23656586	A different substitution in GNAQ encoding a variant at the same amino acid residue, p.Arg183Cys, was previously shown to overstimulate the serum response element (SRE) in a promoter reporter assay.	('p.Arg183Cys', 'Mutation', 'p.R183C', (84, 95))	('overstimulate', 'PosReg', (121, 134))	('p.Arg183Cys', 'Var', (84, 95))	('serum', 'MPA', (139, 144))	('GNAQ', 'Gene', (28, 32))
34449	23656586	We investigated whether the p.Arg183Gln substitution had the same stimulatory effect on SRE promoter activity.	('p.Arg183Gln', 'Mutation', 'rs397514698', (28, 39))	('p.Arg183Gln', 'Var', (28, 39))	('SRE promoter activity', 'MPA', (88, 109))
34450	23656586	We transfected HEK 293T cells with pSRE-Luc, pSV40-RL (reporter constructs), and GNAQ, GNAQ p.Arg183Gln, or GNAQ p.Gln209Leu plasmids and measured luciferase activity after 24 hours.	('luciferase activity', 'molecular_function', 'GO:0050397', ('147', '166'))	('p.Gln209Leu', 'Var', (113, 124))	('activity', 'MPA', (158, 166))	('luciferase activity', 'molecular_function', 'GO:0047712', ('147', '166'))	('HEK 293T', 'CellLine', 'CVCL:0063', (15, 23))	('luciferase activity', 'molecular_function', 'GO:0047077', ('147', '166'))	('p.Gln209Leu', 'Mutation', 'rs121913492', (113, 124))	('luciferase', 'Enzyme', (147, 157))	('p.Arg183Gln', 'Var', (92, 103))	('luciferase activity', 'molecular_function', 'GO:0045289', ('147', '166'))	('p.Arg183Gln', 'Mutation', 'rs397514698', (92, 103))	('measured', 'Reg', (138, 146))	('luciferase activity', 'molecular_function', 'GO:0050248', ('147', '166'))
34451	23656586	Both p.Gln209Leu and p.Arg183Gln showed significantly increased reporter activity as compared with nonmutant GNAQ (P<0.05), confirming that the p.Arg183Gln mutation is a gain-of-function or activating mutation (Fig.	('gain-of-function', 'PosReg', (170, 186))	('p.Arg183Gln', 'Mutation', 'rs397514698', (144, 155))	('p.Arg183Gln', 'Var', (21, 32))	('p.Arg183Gln', 'Mutation', 'rs397514698', (21, 32))	('reporter activity', 'MPA', (64, 81))	('increased', 'PosReg', (54, 63))	('p.Gln209Leu', 'Mutation', 'rs121913492', (5, 16))	('p.Gln209Leu', 'Var', (5, 16))	('p.Arg183Gln', 'Var', (144, 155))
34453	23656586	Rudolf Happle first suggested that sporadic asymmetric or scattered birth defects involving the skin are caused by somatic mosaic mutations that would be lethal if they occurred in very early embryonic development.	('birth defects', 'Disease', 'MESH:D000014', (68, 81))	('caused by', 'Reg', (105, 114))	('birth defects', 'Disease', (68, 81))	('mutations', 'Var', (130, 139))	('asymmetric', 'Disease', (44, 54))	('scattered', 'Disease', (58, 67))
34457	23656586	We have identified somatic mosaic GNAQ encoding p.Arg183Gln amino acid substitutions in skin and brain tissue from patients with the Sturge-Weber syndrome and in skin tissue with nonsyndromic port-wine stains and have shown that this mutation, much like the GNAQ variant encoding p.Gln209Leu, activates downstream MAPK signaling.	('patients', 'Species', '9606', (115, 123))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (133, 154))	('port-wine stains', 'Phenotype', 'HP:0001052', (192, 208))	('activates', 'PosReg', (293, 302))	('MAPK', 'molecular_function', 'GO:0004707', ('314', '318'))	('p.Gln209Leu', 'Mutation', 'rs121913492', (280, 291))	('Sturge-Weber syndrome', 'Disease', (133, 154))	('p.Arg183Gln', 'Mutation', 'rs397514698', (48, 59))	('MAPK', 'Gene', '5594', (314, 318))	('p.Arg183Gln amino acid', 'Var', (48, 70))	('Weber syndrome', 'Phenotype', 'HP:0002277', (140, 154))	('MAPK signaling', 'biological_process', 'GO:0000165', ('314', '328'))	('MAPK', 'Gene', (314, 318))	('p.Gln209Leu', 'Var', (280, 291))	('port-wine stain', 'Phenotype', 'HP:0001052', (192, 207))
34458	23656586	Galphaq Arg183 is conserved in the guanosine triphosphate (GTP) binding pocket of all human Galpha subunits, where it plays a critical role in the hydrolysis of GTP, the key step required for inactivation of the protein.	('GTP) binding', 'molecular_function', 'GO:0005525', ('59', '71'))	('Galphaq', 'Gene', (0, 7))	('Galphaq', 'Gene', '2776', (0, 7))	('Arg183', 'Var', (8, 14))	('guanosine triphosphate', 'Chemical', 'MESH:D006160', (35, 57))	('GTP', 'Chemical', 'MESH:D006160', (161, 164))	('hydrolysis', 'MPA', (147, 157))	('GTP', 'Chemical', 'MESH:D006160', (59, 62))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('human', 'Species', '9606', (86, 91))	('Galpha', 'Gene', '8802', (0, 6))	('Galpha', 'Gene', (0, 6))	('Arg183', 'Chemical', '-', (8, 14))	('Galpha', 'Gene', '8802', (92, 98))	('Galpha', 'Gene', (92, 98))
34459	23656586	Substitution of cysteine at this position results in a reduction in the intrinsic GTPase activity, leading to increased signaling activity.	('Substitution', 'Var', (0, 12))	('GTP', 'Chemical', 'MESH:D006160', (82, 85))	('reduction', 'NegReg', (55, 64))	('increased', 'PosReg', (110, 119))	('GTPase activity', 'molecular_function', 'GO:0003924', ('82', '97'))	('signaling activity', 'MPA', (120, 138))	('GTPase', 'Protein', (82, 88))	('cysteine', 'Chemical', 'MESH:D003545', (16, 24))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('intrinsic', 'MPA', (72, 81))	('activity', 'MPA', (89, 97))
34460	23656586	Activating mutations in genes encoding Galpha subunits have previously been shown to be associated with relevant phenotypes, including the McCune-Albright syndrome, which is characterized by skeletal abnormalities and abnormal skin pigmentation.	('skeletal abnormalities', 'Phenotype', 'HP:0000924', (191, 213))	('abnormal skin pigmentation', 'Disease', (218, 244))	('skin pigmentation', 'Phenotype', 'HP:0000953', (227, 244))	('abnormal skin pigmentation', 'Disease', 'MESH:D010859', (218, 244))	('pigmentation', 'biological_process', 'GO:0043473', ('232', '244'))	('skeletal abnormalities', 'Disease', 'MESH:C538496', (191, 213))	('abnormal skin', 'Phenotype', 'HP:0000951', (218, 231))	('Activating', 'Var', (0, 10))	('McCune-Albright syndrome', 'Disease', (139, 163))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (139, 163))	('abnormal skin pigmentation', 'Phenotype', 'HP:0001000', (218, 244))	('associated', 'Reg', (88, 98))	('skeletal abnormalities', 'Disease', (191, 213))	('Galpha', 'Gene', '8802', (39, 45))	('Galpha', 'Gene', (39, 45))
34462	23656586	Mutations in GNAQ were also identified in a chemical mutagenesis screen for a dark-skin phenotype in laboratory mice.	('dark-skin', 'Phenotype', 'HP:0000953', (78, 87))	('GNAQ', 'Gene', (13, 17))	('mutagenesis', 'biological_process', 'GO:0006280', ('53', '64'))	('Mutations', 'Var', (0, 9))	('mice', 'Species', '10090', (112, 116))
34463	23656586	Two of the dark-skin mutant alleles were identified at positions corresponding to human Galphaq p.Val179Met and p.Phe335Leu.	('p.Phe335Leu', 'Var', (112, 123))	('p.Phe335Leu', 'Mutation', 'p.F335L', (112, 123))	('p.Val179Met', 'Var', (96, 107))	('dark-skin', 'Phenotype', 'HP:0000953', (11, 20))	('p.Val179Met', 'Mutation', 'p.V179M', (96, 107))	('Galphaq', 'Gene', (88, 95))	('Galphaq', 'Gene', '2776', (88, 95))	('human', 'Species', '9606', (82, 87))
34464	23656586	Since endothelin also has important roles in vasculogenesis, dysregulation of this G-protein-coupled receptor as a result of the Galphaq p.Arg183Gln mutation in persons with the Sturge-Weber syndrome and those with nonsyndromic port-wine stains may also bring about vascular malformation.	('bring about', 'Reg', (254, 265))	('p.Arg183Gln', 'Var', (137, 148))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (178, 199))	('vascular', 'Disease', (266, 274))	('persons', 'Species', '9606', (161, 168))	('vasculogenesis', 'biological_process', 'GO:0001570', ('45', '59'))	('dysregulation', 'MPA', (61, 74))	('port-wine stain', 'Phenotype', 'HP:0001052', (228, 243))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))	('Weber syndrome', 'Phenotype', 'HP:0002277', (185, 199))	('Galphaq', 'Gene', (129, 136))	('Galphaq', 'Gene', '2776', (129, 136))	('p.Arg183Gln', 'Mutation', 'rs397514698', (137, 148))	('Sturge-Weber syndrome', 'Disease', (178, 199))	('port-wine stains', 'Phenotype', 'HP:0001052', (228, 244))
34465	23656586	In fact, somatic mutations of GNAQ in melanocytes are associated with uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('uveal melanoma', 'Disease', (70, 84))	('GNAQ', 'Gene', (30, 34))	('associated', 'Reg', (54, 64))	('somatic mutations', 'Var', (9, 26))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
34466	23656586	The most common mutation, causing Galphaq p.Gln209Leu, is an activating mutation that leads to increased downstream signaling through the MAPK pathway.	('MAPK', 'Gene', '5594', (138, 142))	('Galphaq', 'Gene', (34, 41))	('p.Gln209Leu', 'Mutation', 'rs121913492', (42, 53))	('Galphaq', 'Gene', '2776', (34, 41))	('MAPK', 'molecular_function', 'GO:0004707', ('138', '142'))	('p.Gln209Leu', 'Var', (42, 53))	('MAPK', 'Gene', (138, 142))	('increased', 'PosReg', (95, 104))	('downstream signaling', 'MPA', (105, 125))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))
34467	23656586	A few uveal melanomas have been reported to harbor a somatic mutation in GNAQ encoding p.Arg183Gln, although the functional consequence of this substitution has not been reported.	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanomas', 'Phenotype', 'HP:0002861', (12, 21))	('uveal melanomas', 'Disease', (6, 21))	('p.Arg183Gln', 'Var', (87, 98))	('p.Arg183Gln', 'Mutation', 'rs397514698', (87, 98))	('uveal melanomas', 'Phenotype', 'HP:0007716', (6, 21))	('GNAQ', 'Gene', (73, 77))	('uveal melanomas', 'Disease', 'MESH:C536494', (6, 21))	('uveal melanoma', 'Phenotype', 'HP:0007716', (6, 20))
34473	23656586	We have shown that the Galphaq p.Arg183Gln substitution can activate ERK and does not activate p38 or JNK in the same way that p.Gln209Leu does.	('Galphaq', 'Gene', '2776', (23, 30))	('p38', 'Gene', '5594', (95, 98))	('p.Arg183Gln', 'Var', (31, 42))	('p.Arg183Gln', 'Mutation', 'rs397514698', (31, 42))	('p38', 'Gene', (95, 98))	('JNK', 'molecular_function', 'GO:0004705', ('102', '105'))	('JNK', 'Gene', (102, 105))	('p.Gln209Leu', 'Mutation', 'rs121913492', (127, 138))	('ERK', 'molecular_function', 'GO:0004707', ('69', '72'))	('Galphaq', 'Gene', (23, 30))	('JNK', 'Gene', '5599', (102, 105))	('activate', 'PosReg', (60, 68))	('ERK', 'Gene', '5594', (69, 72))	('ERK', 'Gene', (69, 72))
34479	23656586	On examination of the ability of RGS4 to regulate Galphai1 with activating mutations in positions p.Arg178Cys and p.Gln204Leu, homologous to Galphaq p.Arg183Gln and p.Gln209Leu, it was found that all regulatory ability was lost for p.Gln204Leu, whereas GTPase activity was partially maintained for p.Arg178Cys.	('p.Gln209Leu', 'Var', (165, 176))	('p.Gln204Leu', 'Var', (232, 243))	('p.Arg183Gln', 'Mutation', 'rs397514698', (149, 160))	('GTPase activity', 'molecular_function', 'GO:0003924', ('253', '268'))	('lost', 'NegReg', (223, 227))	('Galpha', 'Gene', (50, 56))	('Galphaq', 'Gene', (141, 148))	('RGS4', 'Gene', (33, 37))	('Galpha', 'Gene', '8802', (50, 56))	('p.Arg178Cys', 'Mutation', 'p.R178C', (298, 309))	('Galphaq', 'Gene', '2776', (141, 148))	('regulatory ability', 'MPA', (200, 218))	('Galpha', 'Gene', (141, 147))	('p.Arg183Gln', 'Var', (149, 160))	('GTP', 'Chemical', 'MESH:D006160', (253, 256))	('RGS4', 'Gene', '5999', (33, 37))	('p.Arg178Cys', 'Mutation', 'p.R178C', (98, 109))	('p.Gln204Leu', 'Mutation', 'p.Q204L', (114, 125))	('Galpha', 'Gene', '8802', (141, 147))	('p.Gln204Leu', 'Mutation', 'p.Q204L', (232, 243))	('RGS', 'molecular_function', 'GO:0016299', ('33', '36'))	('p.Gln209Leu', 'Mutation', 'rs121913492', (165, 176))
34480	23656586	Thus, the weaker and less promiscuously activating effects of Galphaq p.Arg183Gln, as compared with Galphaq p.Gln209Leu, may be a result of partial regulation by a member of the RGS family.	('p.Gln209Leu', 'Mutation', 'rs121913492', (108, 119))	('Galphaq', 'Gene', (62, 69))	('p.Arg183Gln', 'Var', (70, 81))	('Galphaq', 'Gene', '2776', (62, 69))	('Galphaq', 'Gene', (100, 107))	('promiscuously activating effects', 'MPA', (26, 58))	('Galphaq', 'Gene', '2776', (100, 107))	('p.Arg183Gln', 'Mutation', 'rs397514698', (70, 81))	('regulation', 'biological_process', 'GO:0065007', ('148', '158'))	('weaker', 'NegReg', (10, 16))	('RGS', 'molecular_function', 'GO:0016299', ('178', '181'))
34482	23656586	It has been shown that Galphaq-mediated oncogenic proliferation, mediated through p38 and JNK, is significantly reduced after Trio knockdown without affecting PLC or ERK activation levels.	('ERK', 'Gene', '5594', (166, 169))	('JNK', 'Gene', (90, 93))	('oncogenic proliferation', 'CPA', (40, 63))	('knockdown', 'Var', (131, 140))	('JNK', 'Gene', '5599', (90, 93))	('p38', 'Gene', '5594', (82, 85))	('Galphaq', 'Gene', (23, 30))	('PLC', 'cellular_component', 'GO:0042824', ('159', '162'))	('ERK', 'Gene', (166, 169))	('PLC', 'Gene', '3339', (159, 162))	('Trio', 'Gene', '7204', (126, 130))	('PLC', 'Gene', (159, 162))	('ERK', 'molecular_function', 'GO:0004707', ('166', '169'))	('JNK', 'molecular_function', 'GO:0004705', ('90', '93'))	('Trio', 'Gene', (126, 130))	('reduced', 'NegReg', (112, 119))	('p38', 'Gene', (82, 85))	('Galphaq', 'Gene', '2776', (23, 30))
34484	23656586	We hypothesize that only the weaker effect of somatic Galphaq p.Arg183Gln would be compatible with the abnormal but nonlethal development of the cerebrovascular system seen in the Sturge-Weber syndrome.	('p.Arg183Gln', 'Var', (62, 73))	('p.Arg183Gln', 'Mutation', 'rs397514698', (62, 73))	('Sturge-Weber syndrome', 'Disease', (180, 201))	('Weber syndrome', 'Phenotype', 'HP:0002277', (187, 201))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (180, 201))	('Galphaq', 'Gene', (54, 61))	('Galphaq', 'Gene', '2776', (54, 61))
34485	23656586	We also hypothesize that during vulnerable periods in embryonic development, moderately increased baseline signaling downstream of Galphaq, or dysregulated signaling through G-protein-coupled receptors such as that for endothelin, may result in the malformed, progressively dilated, and abnormally innervated blood vessels underlying port-wine stains.	('port-wine stains', 'Disease', (334, 350))	('port-wine stain', 'Phenotype', 'HP:0001052', (334, 349))	('abnormally innervated blood vessels', 'CPA', (287, 322))	('result in', 'Reg', (235, 244))	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('progressively dilated', 'CPA', (260, 281))	('increased', 'PosReg', (88, 97))	('Galphaq', 'Gene', (131, 138))	('baseline signaling', 'MPA', (98, 116))	('Galphaq', 'Gene', '2776', (131, 138))	('malformed', 'CPA', (249, 258))	('port-wine stains', 'Phenotype', 'HP:0001052', (334, 350))	('signaling', 'MPA', (156, 165))	('G-protein-coupled', 'Protein', (174, 191))	('dysregulated', 'Var', (143, 155))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))
34487	23656586	The nonsyndromic port-wine stains may represent a late origin of the somatic GNAQ mutation in vascular endothelial cells, whereas the Sturge-Weber syndrome mutation may occur earlier in development, in progenitor cells that are precursors to a larger variety of cell types and tissues, leading to the syndromic phenotype.	('Weber syndrome', 'Phenotype', 'HP:0002277', (141, 155))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (134, 155))	('port-wine stains', 'Phenotype', 'HP:0001052', (17, 33))	('mutation', 'Var', (82, 90))	('GNAQ', 'Gene', (77, 81))	('Sturge-Weber syndrome', 'Disease', (134, 155))	('port-wine stain', 'Phenotype', 'HP:0001052', (17, 32))
34488	23656586	We found that 0.7% of samples of blood from the 1000 Genomes database (5 of 669 samples) that were tested for the presence of the GNAQ mutation encoding p.Arg183Gln were positive.	('GNAQ', 'Gene', (130, 134))	('p.Arg183Gln', 'Var', (153, 164))	('p.Arg183Gln', 'Mutation', 'rs397514698', (153, 164))
34490	23656586	The scientific and translational novelty of this discovery lies in the association of both apparently nonsyndromic port-wine stains and the Sturge-Weber syndrome with a mutation in a specific gene, a specific genetic mechanism, and a set of potential pathways, which provides a foundation for further scientific and clinical research.	('mutation', 'Var', (169, 177))	('gene', 'Gene', (192, 196))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (140, 161))	('port-wine stain', 'Phenotype', 'HP:0001052', (115, 130))	('association', 'Interaction', (71, 82))	('Weber syndrome', 'Phenotype', 'HP:0002277', (147, 161))	('port-wine stains', 'Phenotype', 'HP:0001052', (115, 131))	('Sturge-Weber syndrome', 'Disease', (140, 161))
34491	19654573	Oncogenic GNAQ mutations are not correlated with disease-free survival in uveal melanoma Recently, oncogenic G protein alpha subunit q (GNAQ) mutations have been described in about 50% of uveal melanomas and in the blue nevi of the skin.	('uveal melanoma', 'Phenotype', 'HP:0007716', (188, 202))	('nevi', 'Phenotype', 'HP:0003764', (220, 224))	('mutations', 'Var', (142, 151))	('uveal melanomas', 'Phenotype', 'HP:0007716', (188, 203))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('uveal melanomas', 'Disease', (188, 203))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('uveal melanoma', 'Disease', (74, 88))	('GNAQ', 'Gene', '2776', (10, 14))	('melanomas', 'Phenotype', 'HP:0002861', (194, 203))	('GNAQ', 'Gene', (10, 14))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('GNAQ', 'Gene', '2776', (136, 140))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('GNAQ', 'Gene', (136, 140))	('uveal melanomas', 'Disease', 'MESH:C536494', (188, 203))	('uveal melanoma', 'Disease', 'MESH:C536494', (188, 202))	('blue nevi', 'Phenotype', 'HP:0100814', (215, 224))
34493	19654573	Of the 75 tumour DNA samples analysed, 40 (53.3%) harboured oncogenic mutations in GNAQ codon 209.	('mutations', 'Var', (70, 79))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('tumour', 'Disease', (10, 16))	('tumour', 'Disease', 'MESH:D009369', (10, 16))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('GNAQ', 'Gene', (83, 87))	('harboured', 'Reg', (50, 59))
34494	19654573	Cutaneous melanocytic nevi and melanomas show frequent oncogenic mutations in BRAF and NRAS, and consequent constitutive activation of the MAP-kinase pathway (Davies et al, 2002; Pollock et al, 2003).	('NRAS', 'Gene', '4893', (87, 91))	('melanomas', 'Disease', 'MESH:D008545', (31, 40))	('BRAF', 'Gene', '673', (78, 82))	('MAP', 'molecular_function', 'GO:0004239', ('139', '142'))	('Cutaneous melanocytic', 'Disease', 'MESH:D009508', (0, 21))	('Cutaneous melanocytic', 'Disease', (0, 21))	('BRAF', 'Gene', (78, 82))	('MAP-kinase pathway', 'Pathway', (139, 157))	('Pollock', 'Species', '8060', (179, 186))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))	('activation', 'PosReg', (121, 131))	('nevi', 'Phenotype', 'HP:0003764', (22, 26))	('melanomas', 'Disease', (31, 40))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('NRAS', 'Gene', (87, 91))	('mutations', 'Var', (65, 74))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (10, 26))
34495	19654573	In contrast, melanocytic tumours such as uveal melanomas rarely show BRAF and NRAS mutations (Kilic et al, 2004; Saldanha et al, 2004; Janssen et al, 2008; Maat et al, 2008).	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('mutations', 'Var', (83, 92))	('melanocytic tumours', 'Disease', (13, 32))	('melanocytic tumours', 'Disease', 'MESH:D009508', (13, 32))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('uveal melanomas', 'Disease', (41, 56))	('uveal melanomas', 'Phenotype', 'HP:0007716', (41, 56))	('NRAS', 'Gene', (78, 82))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('BRAF', 'Gene', '673', (69, 73))	('uveal melanomas', 'Disease', 'MESH:C536494', (41, 56))	('NRAS', 'Gene', '4893', (78, 82))	('BRAF', 'Gene', (69, 73))
34497	19654573	In humans, GNAQ was found to be frequently mutated in the blue nevi of the skin (83%) and uveal melanoma (46%) (Van Raamsdonk et al, 2009).	('nevi', 'Phenotype', 'HP:0003764', (63, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (90, 104))	('blue nevi of the skin', 'Disease', (58, 79))	('uveal melanoma', 'Disease', (90, 104))	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('blue nevi', 'Phenotype', 'HP:0100814', (58, 67))	('humans', 'Species', '9606', (3, 9))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('GNAQ', 'Gene', (11, 15))	('mutated', 'Var', (43, 50))
34498	19654573	We asked whether oncogenic GNAQ mutations in uveal melanoma are associated with patient survival.	('associated', 'Reg', (64, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('uveal melanoma', 'Disease', (45, 59))	('GNAQ', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('patient', 'Species', '9606', (80, 87))	('uveal melanoma', 'Disease', 'MESH:C536494', (45, 59))
34517	19654573	All uveal melanomas were analysed for the oncogenic GNAQ mutation and chromosomal changes of chromosomes 3 and 8.	('mutation', 'Var', (57, 65))	('uveal melanoma', 'Phenotype', 'HP:0007716', (4, 18))	('uveal melanomas', 'Phenotype', 'HP:0007716', (4, 19))	('uveal melanomas', 'Disease', (4, 19))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('GNAQ', 'Gene', (52, 56))	('uveal melanomas', 'Disease', 'MESH:C536494', (4, 19))
34518	19654573	In detail, 29 cases showed a heterozygous Q209P mutation, 1 case a homozygous Q209P mutation, 9 cases a heterozygous Q209L and 1 case a Q209R mutation.	('Q209L', 'Mutation', 'rs121913492', (117, 122))	('Q209P', 'Var', (78, 83))	('Q209P', 'Mutation', 'rs121913492', (78, 83))	('Q209R', 'Mutation', 'rs121913492', (136, 141))	('Q209P', 'Var', (42, 47))	('Q209P', 'Mutation', 'rs121913492', (42, 47))
34520	19654573	Univariate analysis was performed for all parameters, showing a lower DFS for patients with loss of chromosome 3 and gain of chromosome 8q.	('chromosome', 'cellular_component', 'GO:0005694', ('125', '135'))	('lower', 'NegReg', (64, 69))	('gain', 'PosReg', (117, 121))	('patients', 'Species', '9606', (78, 86))	('loss', 'Var', (92, 96))	('DFS', 'MPA', (70, 73))	('chromosome', 'cellular_component', 'GO:0005694', ('100', '110'))	('chromosome', 'Gene', (100, 110))
34521	19654573	Univariate analysis of GNAQ mutated cases compared with wild-type tumours did not show a significantly decreased DFS (P=0.273) (Figure 1).	('DFS', 'MPA', (113, 116))	('mutated', 'Var', (28, 35))	('GNAQ', 'Gene', (23, 27))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('decreased', 'NegReg', (103, 112))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('tumours', 'Disease', (66, 73))
34522	19654573	To examine the possibility that GNAQ mutations may affect the prognosis of patients with loss of one copy of chromosome 3, we calculated Kaplan-Meier survival curves of GNAQ status stratified for chromosome 3 status and performed log rank tests (P=0.559) (Figure 2).	('GNAQ', 'Gene', (32, 36))	('chromosome', 'cellular_component', 'GO:0005694', ('196', '206'))	('affect', 'Reg', (51, 57))	('patients', 'Species', '9606', (75, 83))	('mutations', 'Var', (37, 46))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))
34523	19654573	In tumours with two copies of chromosome 3 the patients with a GNAQ mutation seemed to have a better prognosis, although it was not significant (P=0.097).	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('chromosome', 'cellular_component', 'GO:0005694', ('30', '40'))	('mutation', 'Var', (68, 76))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('patients', 'Species', '9606', (47, 55))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('tumours', 'Disease', (3, 10))	('GNAQ', 'Gene', (63, 67))
34525	19654573	The mutation frequency of GNAQ codon 209 (53%) was in the same range as that in a recent report by Onken et al (2008) (49%) and by Van Raamsdonk et al (2004) (46%), confirming the importance of oncogenic GNAQ mutations in uveal melanoma.	('GNAQ', 'Gene', (204, 208))	('GNAQ', 'Gene', (26, 30))	('uveal melanoma', 'Disease', 'MESH:C536494', (222, 236))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('uveal melanoma', 'Phenotype', 'HP:0007716', (222, 236))	('uveal melanoma', 'Disease', (222, 236))	('mutations', 'Var', (209, 218))
34526	19654573	However, GNAQ mutations have been shown to have similar frequencies at all clinical stages of uveal melanoma progression, and to be independent of chromosomal aberrations, hinting at GNAQ being an early or initiating oncogenic event (Onken et al, 2008).	('GNAQ', 'Gene', (9, 13))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('uveal melanoma', 'Disease', (94, 108))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (147, 170))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('mutations', 'Var', (14, 23))
34527	19654573	This is consistent with the assumption that frequent oncogenic mutations of BRAF and NRAS in cutaneous melanoma as well as in benign melanocytic nevi (Davies et al, 2002; Pollock et al, 2003), which also activate the MAP-kinase pathway, are early events and are not associated with clinical outcome (Shinozaki et al, 2004; Akslen et al, 2005; Edlundh-Rose et al, 2006).	('mutations', 'Var', (63, 72))	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('cutaneous melanoma', 'Disease', (93, 111))	('Pollock', 'Species', '8060', (171, 178))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (93, 111))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (93, 111))	('nevi', 'Phenotype', 'HP:0003764', (145, 149))	('activate', 'PosReg', (204, 212))	('MAP', 'molecular_function', 'GO:0004239', ('217', '220'))	('NRAS', 'Gene', (85, 89))	('NRAS', 'Gene', '4893', (85, 89))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (133, 149))	('benign melanocytic nevi', 'Disease', (126, 149))	('MAP-kinase pathway', 'Pathway', (217, 235))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
34528	19654573	In conclusion, we could show that oncogenic GNAQ mutations are not suitable to predict the clinical outcome in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (111, 125))	('uveal melanoma', 'Disease', 'MESH:C536494', (111, 125))	('GNAQ', 'Gene', (44, 48))	('mutations', 'Var', (49, 58))	('uveal melanoma', 'Disease', (111, 125))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
34532	33529461	BAP1 mutations are early and rare events in esophageal carcinoma, but the involvement of BAP1 in progression of esophageal carcinoma is unclear.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (44, 64))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (112, 132))	('BAP1', 'Gene', (0, 4))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (112, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('esophageal carcinoma', 'Disease', (44, 64))	('esophageal carcinoma', 'Disease', (112, 132))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (44, 64))
34533	33529461	Here, we report that cell proliferation and migration were significantly enhanced in esophageal carcinoma ECA109 cells overexpressing BAP1, while they were diminished upon BAP1 knockdown.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('cell proliferation', 'biological_process', 'GO:0008283', ('21', '39'))	('esophageal carcinoma', 'Disease', (85, 105))	('BAP1', 'Gene', (134, 138))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (85, 105))	('cell proliferation', 'CPA', (21, 39))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (85, 105))	('overexpressing', 'Var', (119, 133))	('enhanced', 'PosReg', (73, 81))
34549	33529461	Deletions, loss of heterozygosity, missense mutations, and large rearrangements in the BAP1 gene locus have been found in lung and sporadic breast tumors and lung cancer cell lines [7].	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('lung cancer', 'Disease', (158, 169))	('breast tumors', 'Phenotype', 'HP:0100013', (140, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('BAP1', 'Gene', (87, 91))	('rearrangements', 'Var', (65, 79))	('loss of heterozygosity', 'Var', (11, 33))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('found', 'Reg', (113, 118))	('sporadic breast tumors', 'Disease', (131, 153))	('missense mutations', 'Var', (35, 53))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('lung', 'Disease', (122, 126))	('Deletions', 'Var', (0, 9))	('sporadic breast tumors', 'Disease', 'MESH:D001943', (131, 153))
34568	33529461	Antibodies against BAP1 (ab245391, 1 : 2000), KLF5 (ab137676, 1 : 1000), CyclinD1 (ab134175, 1 : 10 000), and FGF-BP1 (ab215353, 1 : 500) were provided by Abcam (Cambridge, UK).	('ab245391', 'Var', (25, 33))	('ab215353', 'Var', (119, 127))	('FGF-BP1', 'Gene', '9982', (110, 117))	('CyclinD1', 'Gene', '595', (73, 81))	('FGF-BP1', 'Gene', (110, 117))	('KLF5', 'Gene', (46, 50))	('KLF5', 'Gene', '688', (46, 50))	('CyclinD1', 'Gene', (73, 81))
34575	33529461	As expected, the expression of KLF5 was enhanced in the BAP1 overexpression system compared with that in the control (Fig.	('overexpression system', 'Var', (61, 82))	('KLF5', 'Gene', (31, 35))	('expression', 'MPA', (17, 27))	('KLF5', 'Gene', '688', (31, 35))	('BAP1', 'Gene', (56, 60))	('enhanced', 'PosReg', (40, 48))
34576	33529461	KLF5 mRNA levels were also significantly reduced in ECA109 cells transfected with siRNA-BAP1 compared with those in the NC group (Fig.	('reduced', 'NegReg', (41, 48))	('siRNA-BAP1', 'Var', (82, 92))	('KLF5', 'Gene', (0, 4))	('KLF5', 'Gene', '688', (0, 4))
34577	33529461	Interestingly, we found that the expression of downstream genes, KLF5, CyclinD1, and FGF-BP1, was positively regulated by the expression of KLF5.	('FGF-BP1', 'Gene', (85, 92))	('KLF5', 'Gene', (65, 69))	('KLF5', 'Gene', '688', (140, 144))	('KLF5', 'Gene', '688', (65, 69))	('regulated', 'Reg', (109, 118))	('CyclinD1', 'Gene', (71, 79))	('expression', 'Var', (126, 136))	('expression', 'MPA', (33, 43))	('FGF-BP1', 'Gene', '9982', (85, 92))	('CyclinD1', 'Gene', '595', (71, 79))	('KLF5', 'Gene', (140, 144))
34586	33529461	first reported a meta-relationship between BAP1 deletion and the diagnoses and prognoses of various cancer types, and confirmed that BAP1 is a marker of poor prognosis in diverse cancer types, including uveal melanoma, renal cell carcinoma, cholangiocarcinoma, non-small cell lung cancer, and colorectal cancer [12].	('BAP1', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (261, 287))	('cancer', 'Disease', (304, 310))	('colorectal cancer', 'Phenotype', 'HP:0003003', (293, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('renal cell carcinoma', 'Disease', (219, 239))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (241, 259))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('lung cancer', 'Disease', (276, 287))	('deletion', 'Var', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('uveal melanoma', 'Phenotype', 'HP:0007716', (203, 217))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (219, 239))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (265, 287))	('cholangiocarcinoma', 'Disease', (241, 259))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (241, 259))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('uveal melanoma', 'Disease', (203, 217))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('colorectal cancer', 'Disease', 'MESH:D015179', (293, 310))	('lung cancer', 'Disease', 'MESH:D008175', (276, 287))	('cancer', 'Disease', (100, 106))	('colorectal cancer', 'Disease', (293, 310))	('lung cancer', 'Phenotype', 'HP:0100526', (276, 287))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (219, 239))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (281, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cancer', 'Disease', (179, 185))	('uveal melanoma', 'Disease', 'MESH:C536494', (203, 217))
34587	33529461	Inactivating BAP1 mutants were found in two patients with uveal melanoma by exon capture and large-scale sequencing, and BAP1 mutants were also found in 25 (45%) of 55 additional cases of uveal melanoma [13].	('BAP1', 'Gene', (13, 17))	('patients', 'Species', '9606', (44, 52))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('mutants', 'Var', (18, 25))	('BAP1', 'Gene', (121, 125))	('Inactivating', 'Var', (0, 12))	('uveal melanoma', 'Disease', 'MESH:C536494', (188, 202))	('uveal melanoma', 'Disease', 'MESH:C536494', (58, 72))	('found', 'Reg', (144, 149))	('uveal melanoma', 'Phenotype', 'HP:0007716', (188, 202))	('uveal melanoma', 'Disease', (188, 202))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('uveal melanoma', 'Disease', (58, 72))	('found', 'Reg', (31, 36))	('mutants', 'Var', (126, 133))
34588	33529461	suggested that the deletion of BAP1 is a diagnostic marker of mesothelioma in effusion cytology [14].	('mesothelioma in effusion', 'Disease', 'MESH:D008654', (62, 86))	('mesothelioma in effusion', 'Disease', (62, 86))	('deletion', 'Var', (19, 27))	('BAP1', 'Gene', (31, 35))
34590	33529461	BAP1 mutations have been reported as early and rare events in esophageal cancer [15].	('BAP1', 'Gene', (0, 4))	('esophageal cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (5, 14))	('esophageal cancer', 'Disease', 'MESH:D004938', (62, 79))
34594	33529461	Proliferation and migration of ECA109 cells were significantly inhibited by BAP1 knockdown, which is consistent with the results reported by Qin et al.	('Qin', 'Gene', (141, 144))	('migration', 'CPA', (18, 27))	('knockdown', 'Var', (81, 90))	('Qin', 'Gene', '2290', (141, 144))	('BAP1', 'Gene', (76, 80))	('inhibited', 'NegReg', (63, 72))	('Proliferation', 'CPA', (0, 13))
34596	33529461	Both mRNA expression and protein expression of KLF5 increased significantly in the BAP1 overexpression system, whereas the expression was impaired in the BAP1 knockdown system.	('increased', 'PosReg', (52, 61))	('mRNA expression', 'MPA', (5, 20))	('BAP1', 'Gene', (83, 87))	('protein expression', 'MPA', (25, 43))	('overexpression', 'Var', (88, 102))	('KLF5', 'Gene', (47, 51))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('KLF5', 'Gene', '688', (47, 51))
34605	32396633	Lower Levels of Adiponectin and Its Receptor Adipor1 in the Uveal Melanomas With Monosomy-3 Adiponectin is an insulin-sensitizing and anticarcinogenic hormone that is encoded by a gene on chromosome 3.	('Levels', 'MPA', (6, 12))	('Adiponectin', 'Gene', (16, 27))	('carcinogenic', 'Disease', (138, 150))	('Monosomy-3', 'Var', (81, 91))	('Adiponectin', 'Gene', '9370', (16, 27))	('Uveal Melanomas', 'Phenotype', 'HP:0007716', (60, 75))	('Melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('carcinogenic', 'Disease', 'MESH:D063646', (138, 150))	('Adipor1', 'Gene', (45, 52))	('insulin', 'Gene', '3630', (110, 117))	('Adipor1', 'Gene', '51094', (45, 52))	('Adiponectin', 'Gene', (92, 103))	('Melanomas', 'Disease', 'MESH:D008545', (66, 75))	('Melanomas', 'Disease', (66, 75))	('insulin', 'molecular_function', 'GO:0016088', ('110', '117'))	('chromosome', 'cellular_component', 'GO:0005694', ('188', '198'))	('Adiponectin', 'Gene', '9370', (92, 103))	('insulin', 'Gene', (110, 117))	('Lower Levels of Adiponectin', 'Phenotype', 'HP:0030685', (0, 27))
34612	32396633	UM with monosomy-3 exhibited a lower immunoreactivity for adiponectin and Adipor1, which was associated with monosomy-3-positive CMC and the development of extraocular growth or metastases.	('metastases', 'Disease', 'MESH:D009362', (178, 188))	('monosomy-3', 'Var', (8, 18))	('CMC', 'Disease', (129, 132))	('adiponectin', 'Gene', (58, 69))	('CMC', 'Chemical', '-', (129, 132))	('men', 'Species', '9606', (148, 151))	('Adipor1', 'Gene', '51094', (74, 81))	('lower', 'NegReg', (31, 36))	('Adipor1', 'Gene', (74, 81))	('associated', 'Reg', (93, 103))	('metastases', 'Disease', (178, 188))	('adiponectin', 'Gene', '9370', (58, 69))	('extraocular growth', 'CPA', (156, 174))	('lower immunoreactivity for adiponectin', 'Phenotype', 'HP:0030685', (31, 69))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('monosomy-3-positive', 'Var', (109, 128))
34616	32396633	Adiponectin deficiency appears to enhance the metastatic potential of the UM cells with monosomy-3 and the termination of tumor dormancy.	('monosomy-3', 'Var', (88, 98))	('metastatic potential', 'CPA', (46, 66))	('enhance', 'PosReg', (34, 41))	('dormancy', 'biological_process', 'GO:0030431', ('128', '136'))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('Adiponectin deficiency', 'Phenotype', 'HP:0030685', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('Adiponectin', 'Gene', (0, 11))	('Adiponectin', 'Gene', '9370', (0, 11))	('deficiency', 'Var', (12, 22))	('tumor', 'Disease', (122, 127))
34625	32396633	Knowledge of the pathophysiological factors that favor the survival of M3-positive CMC and their micrometastases over such long timeframes would also be indispensable for the development of a preventive therapy.	('metastases', 'Disease', (102, 112))	('CMC', 'Disease', (83, 86))	('M3-positive', 'Var', (71, 82))	('men', 'Species', '9606', (182, 185))	('CMC', 'Chemical', '-', (83, 86))	('metastases', 'Disease', 'MESH:D009362', (102, 112))
34640	32396633	However, it is not known yet whether the UM cells express adiponectin or its receptors, whether the presence of M3 leads to a decrease in tumor adiponectin levels, and whether adiponectin induces a physiological response in the UM cells.	('induces', 'Reg', (188, 195))	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('adiponectin', 'Gene', '9370', (176, 187))	('tumor', 'Disease', (138, 143))	('UM', 'Phenotype', 'HP:0007716', (228, 230))	('adiponectin', 'Gene', (176, 187))	('decrease', 'NegReg', (126, 134))	('adiponectin', 'Gene', '9370', (144, 155))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('adiponectin', 'Gene', '9370', (58, 69))	('physiological response', 'MPA', (198, 220))	('adiponectin', 'Gene', (144, 155))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('presence', 'Var', (100, 108))	('adiponectin', 'Gene', (58, 69))
34659	32396633	Sections were then incubated with the rabbit primary antibodies against adiponectin (Abcam, Cambridge, UK; ab62551; 1:150 dilution in blocking buffer), Adipor1 (Abcam; ab126611; 1:50 dilution in blocking buffer), or BAP1 (Abcam; ab199396; 1:20 dilution in blocking buffer) overnight at 4 C. The negative controls were incubated with the blocking buffer alone.	('Adipor1', 'Gene', '51094', (152, 159))	('BAP1', 'Gene', (216, 220))	('Adipor1', 'Gene', (152, 159))	('adiponectin', 'Gene', (72, 83))	('ab62551', 'Var', (107, 114))	('BAP1', 'Gene', '8314', (216, 220))	('adiponectin', 'Gene', '9370', (72, 83))
34664	32396633	The red (R), green (G), and blue (B) values that we could optimize for the deconvolution of our IHC samples were as follows: Magenta for nuclei (R1: 0.482, G1: 0.719, B1: 0.501); green for IHC (R2: 0.776, G2: 0.501, B2: 0.382); brown for the pigmentation (R3: 0.446, G3: 0.616, B3: 0.649).	('R1', 'Var', (145, 147))	('pigmentation', 'Disease', 'MESH:D010859', (242, 254))	('pigmentation', 'Disease', (242, 254))	('pigmentation', 'biological_process', 'GO:0043473', ('242', '254'))	('R2', 'Var', (194, 196))
34686	32396633	For the subsequent statistical analysis, the low and intermediate M3 tumors were combined and defined as "low M3 tumors."	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('low', 'Var', (45, 48))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
34740	32396633	Quantification of the IHC for adiponectin demonstrated the presence of this protein at significantly lower levels in the tumors that were classified as having a high degree of M3 (n = 16), compared to the tumors with a low to moderate degree of M3, which were collectively termed as "low M3" hereafter (n = 22; P = 0.02, please see the Methods for a detailed description of the M3 classification).	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('tumors', 'Disease', (205, 211))	('high', 'Var', (161, 165))	('lower', 'NegReg', (101, 106))	('adiponectin', 'Gene', '9370', (30, 41))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('adiponectin', 'Gene', (30, 41))
34746	32396633	Expression of Adipor1 followed a very similar pattern to adiponectin, being detected at significantly less levels in the high M3 tumors (n = 16) compared to the low M3 samples (n = 22; P = 0.02).	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('adiponectin', 'Gene', '9370', (57, 68))	('high M3', 'Var', (121, 128))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('adiponectin', 'Gene', (57, 68))	('less', 'NegReg', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('Adipor1', 'Gene', (14, 21))	('Adipor1', 'Gene', '51094', (14, 21))
34753	32396633	Adiponectin could be detected as a very faint band at a molecular weight of approximately 62 kDa only in the low M3 tumor.	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('low M3', 'Var', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('Adiponectin', 'Gene', (0, 11))	('Adiponectin', 'Gene', '9370', (0, 11))	('tumor', 'Disease', (116, 121))
34754	32396633	Likewise, the Adipor1 protein was highly abundant as an approximately 45- to 50-kDa band in the lysate of the low M3 sample, whereas the high M3 tumor revealed no signals (Fig.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('low M3', 'Var', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('Adipor1', 'Gene', (14, 21))	('Adipor1', 'Gene', '51094', (14, 21))
34755	32396633	To further verify the association of adiponectin and Adipor1 deficiency with the malignant potential of UM, we have evaluated the levels of these proteins with respect to the BAP1 status in 37 of the primary tumors of our patients, whereas one sample with low M3 was omitted due to the insufficient material amount.	('BAP1', 'Gene', (175, 179))	('Adipor1', 'Gene', (53, 60))	('UM', 'Phenotype', 'HP:0007716', (104, 106))	('Adipor1', 'Gene', '51094', (53, 60))	('patients', 'Species', '9606', (222, 230))	('adiponectin', 'Gene', '9370', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('BAP1', 'Gene', '8314', (175, 179))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('adiponectin', 'Gene', (37, 48))	('deficiency', 'Var', (61, 71))
34757	32396633	Cytoplasmic BAP1 was abundant in 16 of the 21 samples with low M3 (76.2%) compared to the expression of this protein in seven of the 16 tumors with high M3 (43.8%, P = 0.04, Pearson's Chi-Square test).	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Disease', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('BAP1', 'Gene', '8314', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('BAP1', 'Gene', (12, 16))	('low M3', 'Var', (59, 65))
34758	32396633	Likewise, the nuclear BAP1 was present in 11 of the 21 tumors with low M3 (52.4%) as opposed to its detection in two of the 16 samples with high M3 (12.5%, P = 0.01, Pearson's Chi-Square test).	('low M3', 'Var', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('BAP1', 'Gene', '8314', (22, 26))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('BAP1', 'Gene', (22, 26))
34804	32396633	The extent of Adipor1 expression was also very consistent with the amount of the adiponectin protein in the corresponding tumor, suggesting that the UM cells with adiponectin deficiency may be retracting the Adipor1 and already entering a state of local insulin resistance.	('insulin', 'molecular_function', 'GO:0016088', ('254', '261'))	('Adipor1', 'Gene', (208, 215))	('adiponectin', 'Gene', (81, 92))	('tumor', 'Disease', (122, 127))	('adiponectin', 'Gene', '9370', (163, 174))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('insulin', 'Gene', '3630', (254, 261))	('Adipor1', 'Gene', (14, 21))	('adiponectin', 'Gene', '9370', (81, 92))	('Adipor1', 'Gene', '51094', (208, 215))	('insulin resistance', 'Phenotype', 'HP:0000855', (254, 272))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('adiponectin deficiency', 'Phenotype', 'HP:0030685', (163, 185))	('deficiency', 'Var', (175, 185))	('UM', 'Phenotype', 'HP:0007716', (149, 151))	('adiponectin', 'Gene', (163, 174))	('entering', 'Reg', (228, 236))	('insulin', 'Gene', (254, 261))	('Adipor1', 'Gene', '51094', (14, 21))
34832	32396633	Interestingly, the inhibition of mutant GNAQ signaling could induce the AMPK-dependent autophagy of UM cells, providing further support to the central role of AMPK in the cellular adaptation efforts to cope with energy starvation.	('AMPK', 'molecular_function', 'GO:0050405', ('72', '76'))	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('UM', 'Phenotype', 'HP:0007716', (100, 102))	('AMPK', 'molecular_function', 'GO:0047322', ('159', '163'))	('mutant', 'Var', (33, 39))	('AMPK', 'molecular_function', 'GO:0004691', ('72', '76'))	('autophagy', 'biological_process', 'GO:0016236', ('87', '96'))	('AMPK', 'Gene', '5563', (72, 76))	('AMPK', 'Gene', '5563', (159, 163))	('AMPK', 'molecular_function', 'GO:0050405', ('159', '163'))	('AMPK', 'molecular_function', 'GO:0047322', ('72', '76'))	('autophagy', 'biological_process', 'GO:0006914', ('87', '96'))	('GNAQ', 'Gene', '2776', (40, 44))	('GNAQ', 'Gene', (40, 44))	('induce', 'PosReg', (61, 67))	('AMPK', 'Gene', (72, 76))	('AMPK', 'Gene', (159, 163))	('AMPK', 'molecular_function', 'GO:0004691', ('159', '163'))	('inhibition', 'NegReg', (19, 29))
34844	32396633	However, we could not find any information on whether BAP1 interacts with ERP44 and whether the loss of BAP1 contributes to the increased expression of ERP44 in the M3 tumors, which remain to be investigated.	('BAP1', 'Gene', '8314', (104, 108))	('ERP44', 'Gene', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('loss', 'Var', (96, 100))	('tumors', 'Disease', (168, 174))	('increased', 'PosReg', (128, 137))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('BAP1', 'Gene', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('BAP1', 'Gene', '8314', (54, 58))	('ERP44', 'Gene', '23071', (152, 157))	('expression', 'MPA', (138, 148))	('ERP44', 'Gene', '23071', (74, 79))	('BAP1', 'Gene', (54, 58))	('ERP44', 'Gene', (152, 157))
34875	32396633	In severe cases of adiponectin deficiency, therapeutic interventions with the type-2 diabetes drug Metformin, which could exert an inhibitory effect on cultured UM cells (de Andrade BDM et al., IOVS 2017;58:ARVO E-Abstract 3964), may also be beneficial to improve the circulating adiponectin levels, although there is to our knowledge no study reporting the efficacy of such drugs in UM patients.	('-2 diabetes', 'Phenotype', 'HP:0005978', (82, 93))	('improve', 'PosReg', (256, 263))	('adiponectin', 'Gene', '9370', (280, 291))	('adiponectin', 'Gene', '9370', (19, 30))	('patients', 'Species', '9606', (387, 395))	('adiponectin', 'Gene', (280, 291))	('adiponectin', 'Gene', (19, 30))	('Metformin', 'Chemical', 'MESH:D008687', (99, 108))	('deficiency', 'Var', (31, 41))	('UM', 'Phenotype', 'HP:0007716', (384, 386))	('type-2 diabetes', 'Phenotype', 'HP:0005978', (78, 93))	('type-2 diabetes', 'Disease', (78, 93))	('adiponectin deficiency', 'Phenotype', 'HP:0030685', (19, 41))	('UM', 'Phenotype', 'HP:0007716', (161, 163))	('type-2 diabetes', 'Disease', 'MESH:D003924', (78, 93))
34972	30956760	Previously, we have generated cell-based vaccines that consist of primary uveal melanoma cells genetically modified to express major histocompatibility class II (MHC II) alleles syngeneic to the recipient and the costimulatory molecule CD80 (B7.1).	('B7.1', 'CellLine', 'CVCL:U642', (242, 246))	('CD80', 'Gene', (236, 240))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('CD80', 'Gene', '941', (236, 240))	('MHC II', 'Gene', (162, 168))	('MHC II', 'Gene', '111364', (162, 168))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('alleles', 'Var', (170, 177))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('uveal melanoma', 'Disease', (74, 88))
34975	30956760	Moreover, the expression of CD80 blocked the interferon gamma (IFNgamma)-mediated upregulation of programmed-death-ligand 1 (PD-L1) and thereby prevented T cell suppression during vaccine priming and boosting of responding T cells.	('ligand', 'molecular_function', 'GO:0005488', ('115', '121'))	('expression', 'Var', (14, 24))	('interferon gamma', 'molecular_function', 'GO:0005133', ('45', '61'))	('prevented', 'NegReg', (144, 153))	('programmed-death-ligand 1', 'Gene', (98, 123))	('blocked', 'NegReg', (33, 40))	('CD80', 'Gene', (28, 32))	('T cell suppression', 'CPA', (154, 172))	('upregulation', 'PosReg', (82, 94))	('programmed-death-ligand 1', 'Gene', '29126', (98, 123))	('interferon gamma (IFNgamma)-', 'Gene', '3458', (45, 73))	('CD80', 'Gene', '941', (28, 32))	('interferon gamma (IFNgamma)-', 'Gene', (45, 73))
35027	30956760	Blocking of either ICAM-1 or LFA-1 resulted in a >10-fold decrease of IFNgamma-secretion (Figure 9C).	('IFNgamma', 'Gene', (70, 78))	('IFNgamma', 'Gene', '3458', (70, 78))	('Blocking', 'Var', (0, 8))	('LFA-1', 'Gene', (29, 34))	('secretion', 'biological_process', 'GO:0046903', ('79', '88'))	('decrease', 'NegReg', (58, 66))	('ICAM-1', 'Gene', '3383', (19, 25))	('LFA-1', 'Gene', '3683', (29, 34))	('ICAM-1', 'Gene', (19, 25))
35109	30883611	High GDF11 expression was associated with uveal melanoma in advanced stages (IV), epithelioid cell dominant subtype, as well as extrascleral extension.	('epithelioid cell dominant subtype', 'Disease', (82, 115))	('extrascleral extension', 'Disease', (128, 150))	('uveal melanoma', 'Disease', (42, 56))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('GDF11', 'Gene', (5, 10))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('associated', 'Reg', (26, 36))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
35111	30883611	Multivariate analysis confirmed that GDF11 expression was an independent prognostic indicator of unfavorable OS (HR: 1.704, 95%CI: 1.143-2.540, p = 0.009), after adjustment of age, histological subtypes and extrascleral extension.	('GDF11', 'Gene', (37, 42))	('expression', 'Var', (43, 53))	('unfavorable OS', 'Disease', (97, 111))	('OS', 'Chemical', '-', (109, 111))
35112	30883611	Among the 80 cases of uveal melanoma, only 3 cases had low-level copy gain (+1) and 2 cases had heterozygous loss (-1).	('uveal melanoma', 'Phenotype', 'HP:0007716', (22, 36))	('low-level copy gain', 'Var', (55, 74))	('uveal melanoma', 'Disease', 'MESH:C536494', (22, 36))	('uveal melanoma', 'Disease', (22, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
35113	30883611	The methylation of these four CpG sites had weakly (cg22950598 and cg23689080), moderately (cg09890930), or strongly (cg05511733) negative correlation with GDF11 expression.	('cg23689080', 'Var', (67, 77))	('cg05511733', 'Var', (118, 128))	('methylation', 'MPA', (4, 15))	('negative', 'NegReg', (130, 138))	('cg22950598', 'Chemical', '-', (52, 62))	('cg05511733', 'Chemical', '-', (118, 128))	('cg09890930', 'Var', (92, 102))	('expression', 'MPA', (162, 172))	('cg23689080', 'Chemical', '-', (67, 77))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('cg22950598', 'Var', (52, 62))	('GDF11', 'Gene', (156, 161))	('cg09890930', 'Chemical', '-', (92, 102))
35114	30883611	In addition, the patients with high methylation of these four sites had significantly better OS compared to the group with low methylation.	('OS', 'Chemical', '-', (93, 95))	('better', 'PosReg', (86, 92))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('patients', 'Species', '9606', (17, 25))	('high methylation', 'Var', (31, 47))	('methylation', 'biological_process', 'GO:0032259', ('127', '138'))
35115	30883611	Based on these findings, we infer that methylation modulated GDF11 expression might be a valuable prognostic biomarker regarding OS in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('uveal melanoma', 'Disease', 'MESH:C536494', (135, 149))	('methylation modulated', 'Var', (39, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (135, 149))	('uveal melanoma', 'Disease', (135, 149))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('expression', 'MPA', (67, 77))	('OS', 'Chemical', '-', (129, 131))	('GDF11', 'Gene', (61, 66))
35126	30883611	In addition, high GDF11 expression is associated with a higher risk of lymph node metastasis and poorer overall survival.	('GDF11', 'Gene', (18, 23))	('lymph node metastasis', 'Disease', (71, 92))	('high', 'Var', (13, 17))	('expression', 'MPA', (24, 34))	('lymph node metastasis', 'Disease', 'MESH:D009362', (71, 92))
35148	30883611	CNAs were calculated by gene-level thresholded Genomic Identification of Significant Targets in Cancer 2.0 (GISTIC2), which defines CNAs as homozygous deletion (-2), heterozygous loss (-1), copy-neutral (0), low-level copy gain (+1), high-level amplification (+2) were downloaded from the Xena browser.	('Cancer', 'Disease', 'MESH:D009369', (96, 102))	('Cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Cancer', 'Disease', (96, 102))	('deletion', 'Var', (151, 159))
35158	30883611	By performing ROC analysis regarding OS, GDF11 expression had an AUC value of 0.753 (Fig 3A), suggesting that high GDF11 expression might be a fair marker of unfavorable OS.	('expression', 'MPA', (121, 131))	('OS', 'Chemical', '-', (170, 172))	('OS', 'Chemical', '-', (37, 39))	('GDF11', 'Gene', (115, 120))	('high', 'Var', (110, 114))
35160	30883611	Results that the patients with high GDF11 expression had significantly shorter OS, compared to the patients with low GDF11 expression (p = 0.001, Fig 3B).	('OS', 'Chemical', '-', (79, 81))	('patients', 'Species', '9606', (99, 107))	('expression', 'Var', (42, 52))	('patients', 'Species', '9606', (17, 25))	('high', 'Var', (31, 35))	('shorter', 'NegReg', (71, 78))	('GDF11', 'Gene', (36, 41))
35161	30883611	By comparing the clinicopathological parameters between the high and low GDF11 expression groups, we found that the high expression group was significantly older (mean +- SD, 64.7+-12.45 vs. 58.60 +- 14.83, p = 0.05), had a higher proportion of epithelioid cell dominant subtype (25/40 vs. 9/40, p < 0.001), more patients in advanced stages, thicker tumors (> 10 mm vs. <= 10 mm, 27/40 vs. 16/40, p = 0.024) and a higher death rate (18/40 vs. 5/40, p = 0.003) (Table 1).	('tumors', 'Disease', (350, 356))	('tumors', 'Disease', 'MESH:D009369', (350, 356))	('death', 'Disease', 'MESH:D003643', (421, 426))	('death', 'Disease', (421, 426))	('tumors', 'Phenotype', 'HP:0002664', (350, 356))	('epithelioid cell dominant subtype', 'CPA', (245, 278))	('high expression', 'Var', (116, 131))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))	('higher', 'PosReg', (224, 230))	('patients', 'Species', '9606', (313, 321))
35166	30883611	Among the 80 cases of uveal melanoma, only 3 cases had low-level copy gain (+1) and 2 cases had heterozygous loss (-1) (Fig 4A).	('uveal melanoma', 'Phenotype', 'HP:0007716', (22, 36))	('low-level copy gain', 'Var', (55, 74))	('uveal melanoma', 'Disease', 'MESH:C536494', (22, 36))	('uveal melanoma', 'Disease', (22, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
35168	30883611	In the heatmap, we found that the methylation of some CpG sites (cg22950598, cg09890930, cg05511733 and cg23689080) were negatively correlated with GDF11 expression (Fig 5A).	('negatively', 'NegReg', (121, 131))	('cg09890930', 'Chemical', '-', (77, 87))	('GDF11', 'Gene', (148, 153))	('cg22950598', 'Chemical', '-', (65, 75))	('cg05511733', 'Var', (89, 99))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('cg23689080', 'Chemical', '-', (104, 114))	('cg09890930', 'Var', (77, 87))	('cg22950598', 'Var', (65, 75))	('cg05511733', 'Chemical', '-', (89, 99))	('methylation', 'MPA', (34, 45))	('cg23689080', 'Var', (104, 114))	('expression', 'MPA', (154, 164))
35169	30883611	By performing linear regression analysis, we confirmed that the methylation of these four CpG sites had weakly (cg22950598 and cg23689080), moderately (cg09890930), or strongly (cg05511733) negative correlation with GDF11 expression (Fig 5B).	('GDF11', 'Gene', (216, 221))	('cg22950598', 'Var', (112, 122))	('cg23689080', 'Chemical', '-', (127, 137))	('expression', 'MPA', (222, 232))	('cg09890930', 'Var', (152, 162))	('cg09890930', 'Chemical', '-', (152, 162))	('cg05511733', 'Var', (178, 188))	('cg23689080', 'Var', (127, 137))	('methylation', 'biological_process', 'GO:0032259', ('64', '75'))	('cg22950598', 'Chemical', '-', (112, 122))	('cg05511733', 'Chemical', '-', (178, 188))	('methylation', 'MPA', (64, 75))	('negative', 'NegReg', (190, 198))
35170	30883611	Although another CpG site cg15466281 also showed a moderately negative correlation with GDF11 expression (Pearson's r = -0.55), the average methylation of this site was low in uveal melanoma (mean +- SD: 0.04 +- 0.04) (Fig 5B).	('uveal melanoma', 'Phenotype', 'HP:0007716', (176, 190))	('uveal melanoma', 'Disease', (176, 190))	('cg15466281', 'Var', (26, 36))	('negative', 'NegReg', (62, 70))	('cg15466281', 'Chemical', '-', (26, 36))	('expression', 'MPA', (94, 104))	('methylation', 'biological_process', 'GO:0032259', ('140', '151'))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('GDF11', 'Gene', (88, 93))	('low', 'NegReg', (169, 172))	('uveal melanoma', 'Disease', 'MESH:C536494', (176, 190))	('methylation', 'MPA', (140, 151))
35171	30883611	Then, we assessed the association between the average methylation of cg22950598, cg09890930, cg05511733 and cg23689080 and OS of uveal melanoma.	('cg23689080', 'Var', (108, 118))	('cg05511733', 'Var', (93, 103))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('cg22950598', 'Chemical', '-', (69, 79))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('cg05511733', 'Chemical', '-', (93, 103))	('cg23689080', 'Chemical', '-', (108, 118))	('cg09890930', 'Var', (81, 91))	('OS of uveal melanoma', 'Disease', (123, 143))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('cg22950598', 'Var', (69, 79))	('OS of uveal melanoma', 'Disease', 'MESH:C536494', (123, 143))	('cg09890930', 'Chemical', '-', (81, 91))
35172	30883611	Kaplan-Meier showed that the group with high methylation had significantly better OS compared to the group with low methylation (Fig 5C).	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('better', 'PosReg', (75, 81))	('high methylation', 'Var', (40, 56))	('methylation', 'biological_process', 'GO:0032259', ('116', '127'))	('OS', 'Chemical', '-', (82, 84))
35173	30883611	This finding further confirmed that methylation modulated GDF11 expression was a valuable prognostic biomarker in uveal melanoma.	('expression', 'MPA', (64, 74))	('GDF11', 'Gene', (58, 63))	('methylation modulated', 'Var', (36, 57))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('uveal melanoma', 'Disease', (114, 128))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))
35174	30883611	Since the status of cg05511733 was strongly and negatively correlated with GDF11 expression, we compared the methylation level of this CpG site between the 19 primary tumor and adjacent normal tissues.	('negatively', 'NegReg', (48, 58))	('methylation', 'biological_process', 'GO:0032259', ('109', '120'))	('cg05511733', 'Var', (20, 30))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cg05511733', 'Chemical', '-', (20, 30))	('correlated', 'Reg', (59, 69))	('GDF11', 'Gene', (75, 80))	('tumor', 'Disease', (167, 172))	('expression', 'MPA', (81, 91))
35176	30883611	In this study, by using data from TCGA-UVM, we demonstrated that high GDF11 expression was associated with uveal melanoma in advanced stages (IV), epithelioid cell dominant subtype, as well as extrascleral extension.	('uveal melanoma', 'Disease', 'MESH:C536494', (107, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('uveal melanoma', 'Disease', (107, 121))	('GDF11', 'Gene', (70, 75))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('expression', 'MPA', (76, 86))	('high', 'Var', (65, 69))	('extrascleral extension', 'CPA', (193, 215))	('associated', 'Reg', (91, 101))
35177	30883611	More importantly, we confirmed that GDF11 expression was an independent prognostic indicator of unfavorable OS (HR: 1.704, 95%CI: 1.143-2.540, p = 0.009), after adjustment of age, histological subtypes and extrascleral extension.	('OS', 'Chemical', '-', (108, 110))	('GDF11', 'Gene', (36, 41))	('unfavorable OS', 'Disease', (96, 110))	('expression', 'Var', (42, 52))
35190	30883611	In this study, we explored the potential genetic and epigenetic (typically methylation) alterations in GDF11 DNA in uveal melanoma.	('methylation', 'biological_process', 'GO:0032259', ('75', '86'))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('GDF11', 'Gene', (103, 108))	('epigenetic', 'Var', (53, 63))	('alterations', 'Var', (88, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (116, 130))	('uveal melanoma', 'Disease', (116, 130))	('uveal melanoma', 'Disease', 'MESH:C536494', (116, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))
35192	30883611	However, we found that that the methylation of these four CpG sites had weakly (cg22950598 and cg23689080), moderately (cg09890930), or strongly (cg05511733) negative correlation with GDF11 expression.	('cg05511733', 'Var', (146, 156))	('cg09890930', 'Chemical', '-', (120, 130))	('cg23689080', 'Var', (95, 105))	('cg05511733', 'Chemical', '-', (146, 156))	('negative', 'NegReg', (158, 166))	('cg22950598', 'Chemical', '-', (80, 90))	('GDF11', 'Gene', (184, 189))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('methylation', 'MPA', (32, 43))	('cg09890930', 'Var', (120, 130))	('cg22950598', 'Var', (80, 90))	('expression', 'MPA', (190, 200))	('cg23689080', 'Chemical', '-', (95, 105))
35193	30883611	Also, we demonstrated that the patients with high methylation of these four sites had significantly better OS compared to the group with low methylation.	('OS', 'Chemical', '-', (107, 109))	('methylation', 'biological_process', 'GO:0032259', ('50', '61'))	('better', 'PosReg', (100, 106))	('patients', 'Species', '9606', (31, 39))	('high methylation', 'Var', (45, 61))	('methylation', 'biological_process', 'GO:0032259', ('141', '152'))
35194	30883611	In addition, using data from primary samples, we confirmed that the adjacent normal group had a significantly higher level of cg05511733 methylation than the tumor group.	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('tumor', 'Disease', (158, 163))	('cg05511733', 'Var', (126, 136))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('cg05511733', 'Chemical', '-', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('methylation', 'MPA', (137, 148))
35195	30883611	These findings indicated that methylation is an important mechanism of GDF11 dysregulation in uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('dysregulation', 'Var', (77, 90))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('uveal melanoma', 'Disease', (94, 108))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('GDF11', 'Gene', (71, 76))	('methylation', 'MPA', (30, 41))
35199	30883611	Methylation modulated GDF11 expression might be a valuable prognostic biomarker in terms of OS in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('expression', 'MPA', (28, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (98, 112))	('uveal melanoma', 'Disease', (98, 112))	('GDF11', 'Gene', (22, 27))	('uveal melanoma', 'Disease', 'MESH:C536494', (98, 112))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('OS', 'Chemical', '-', (92, 94))	('Methylation modulated', 'Var', (0, 21))
35202	28223438	Recent genomic studies have shown that mutations within components of G protein-coupled receptor (GPCR) signaling are early events associated with ~98% of UMs.	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('GPCR', 'Gene', (98, 102))	('associated', 'Reg', (131, 141))	('mutations', 'Var', (39, 48))	('UMs', 'Disease', (155, 158))	('G protein-coupled receptor', 'Gene', '10663', (70, 96))	('GPCR', 'Gene', '10663', (98, 102))	('G protein-coupled receptor', 'Gene', (70, 96))
35207	28223438	There is a low mutational burden in UM tumors, unlike cutaneous melanoma, but identification of mutations in components of GPCR signaling in UM tumors may uncover new therapeutic targets in UM.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (54, 72))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('GPCR', 'Gene', (123, 127))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cutaneous melanoma', 'Disease', (54, 72))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('GPCR', 'Gene', '10663', (123, 127))	('tumors', 'Disease', (39, 45))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (54, 72))	('mutations', 'Var', (96, 105))
35214	28223438	GNAQ and GNA11 mutations occur in a mutually exclusive manner in ~93% of UM tumors (The Cancer Genome Atlas (TCGA): GNAQ and GNA11 mutations detected in ~50% and ~43% of UM tumors, respectively).	('GNA11', 'Gene', (9, 14))	('Cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Cancer Genome Atlas', 'Disease', (88, 107))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (88, 107))	('mutations', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('GNAQ', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('GNA11', 'Gene', '2767', (125, 130))	('GNA11', 'Gene', (125, 130))	('GNA11', 'Gene', '2767', (9, 14))
35215	28223438	Common substitutions in GNAQ are glutamine-to-leucine (Q209L) and glutamine-to-proline (Q209P) whereas in GNA11, the most frequent substitution is Q209L.	('Q209P', 'Var', (88, 93))	('Q209P', 'Mutation', 'rs1057519742', (88, 93))	('GNA11', 'Gene', (106, 111))	('Q209L', 'SUBSTITUTION', 'None', (147, 152))	('Q209L', 'Var', (147, 152))	('glutamine-to-leucine', 'Chemical', '-', (33, 53))	('glutamine-to-proline', 'Chemical', '-', (66, 86))	('GNA11', 'Gene', '2767', (106, 111))	('Q209L', 'Var', (55, 60))	('Q209L', 'SUBSTITUTION', 'None', (55, 60))	('glutamine-to-proline', 'MPA', (66, 86))
35216	28223438	Q209 is crucial for the GTPase activity of G proteins; thus, hydrolysis of GTP is abolished in GNAQ and GNA11 mutants, leading to constitutive activation of the Galphaq and Galpha11 proteins in UM.	('GNA11', 'Gene', '2767', (104, 109))	('mutants', 'Var', (110, 117))	('GNAQ', 'Gene', (95, 99))	('GTP', 'Chemical', 'MESH:D006160', (24, 27))	('GTPase activity', 'molecular_function', 'GO:0003924', ('24', '39'))	('Galpha11 proteins', 'Protein', (173, 190))	('Galphaq', 'Protein', (161, 168))	('activation', 'PosReg', (143, 153))	('GNA11', 'Gene', (104, 109))	('abolished', 'NegReg', (82, 91))	('GTP', 'Chemical', 'MESH:D006160', (75, 78))	('hydrolysis', 'MPA', (61, 71))
35217	28223438	Interestingly, the levels of Galphaq Q209L mutant proteins may be regulated by Ric-8A, a molecular chaperone that contributes to folding of the G protein.	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('Ric-8A', 'Gene', (79, 85))	('proteins', 'Protein', (50, 58))	('Galphaq', 'Gene', (29, 36))	('Q209L', 'SUBSTITUTION', 'None', (37, 42))	('Q209L', 'Var', (37, 42))
35218	28223438	Deletion of Ric-8A in GNAQ Q209L mutant melanocytes grafted into NSG mice led to a marked reduction in levels of membrane-associated mutant Galphaq proteins and inhibition of GNAQ Q209L driven tumor progression.	('Q209L', 'SUBSTITUTION', 'None', (180, 185))	('membrane', 'cellular_component', 'GO:0016020', ('113', '121'))	('reduction', 'NegReg', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('Galphaq proteins', 'Protein', (140, 156))	('levels of membrane-associated mutant', 'MPA', (103, 139))	('mice', 'Species', '10090', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('Q209L', 'Var', (180, 185))	('Q209L', 'Var', (27, 32))	('Q209L', 'SUBSTITUTION', 'None', (27, 32))	('inhibition', 'NegReg', (161, 171))	('tumor', 'Disease', (193, 198))	('Ric-8A', 'Gene', (12, 18))	('Deletion', 'Var', (0, 8))
35220	28223438	GNAQ and GNA11 mutations occur at similar frequencies in metastasizing and non-metastasizing tumors.	('GNA11', 'Gene', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mutations', 'Var', (15, 24))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('GNAQ', 'Gene', (0, 4))	('tumors', 'Disease', (93, 99))	('metastasizing', 'Disease', (57, 70))	('GNA11', 'Gene', '2767', (9, 14))
35221	28223438	Similarly, these mutations are not associated with class 1 (low metastatic potential) or class 2 (high metastatic potential) of UM tumors.	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))	('mutations', 'Var', (17, 26))
35222	28223438	It has been shown that the Q209 mutation in GNAQ and GNA11 are found in benign nevi such as blue nevi in addition to primary and metastatic UM tumors.	('nevi', 'Phenotype', 'HP:0003764', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('GNA11', 'Gene', (53, 58))	('GNAQ', 'Gene', (44, 48))	('nevi', 'Phenotype', 'HP:0003764', (97, 101))	('tumors', 'Disease', (143, 149))	('GNA11', 'Gene', '2767', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('Q209', 'Var', (27, 31))	('blue nevi', 'Phenotype', 'HP:0100814', (92, 101))	('found', 'Reg', (63, 68))	('blue nevi', 'Disease', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
35223	28223438	Despite this notion, the GNA11 Q209 mutation is more commonly identified in UM metastases (~57%) and found only in ~7% of benign blue nevi, indicating that in comparison to GNAQ, alteration in GNA11 is associated with higher risk of metastasis of UM.	('metastases', 'Disease', 'MESH:D009362', (79, 89))	('Q209', 'Var', (31, 35))	('GNA11', 'Gene', (193, 198))	('alteration', 'Var', (179, 189))	('identified', 'Reg', (62, 72))	('GNA11', 'Gene', '2767', (193, 198))	('blue nevi', 'Phenotype', 'HP:0100814', (129, 138))	('metastases', 'Disease', (79, 89))	('GNA11', 'Gene', (25, 30))	('nevi', 'Phenotype', 'HP:0003764', (134, 138))	('metastasis', 'CPA', (233, 243))	('GNA11', 'Gene', '2767', (25, 30))
35225	28223438	Mutations in phospholipase C beta4 (PLCB4) and cysteinyl leukotriene receptor 2 (CYSLTR2) have been identified in 1% and 4 UM tumors, respectively and are mutually exclusive with GNAQ and GNA11 mutations.	('CYSLTR2', 'Gene', (81, 88))	('tumors', 'Disease', (126, 132))	('identified', 'Reg', (100, 110))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('phospholipase C beta4', 'Gene', '5332', (13, 34))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('phospholipase C beta4', 'Gene', (13, 34))	('PLCB4', 'Gene', (36, 41))	('GNA11', 'Gene', (188, 193))	('Mutations', 'Var', (0, 9))	('GNA11', 'Gene', '2767', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('CYSLTR2', 'Gene', '57105', (81, 88))	('PLCB4', 'Gene', '5332', (36, 41))
35226	28223438	The alteration in PLCbeta4, D630Y, affects the Y-domain of the highly conserved catalytic core of PLCbeta4 which controls signal transduction.	('controls', 'Reg', (113, 121))	('D630Y', 'Var', (28, 33))	('PLCbeta4', 'Gene', (98, 106))	('signal transduction', 'biological_process', 'GO:0007165', ('122', '141'))	('core', 'cellular_component', 'GO:0019013', ('90', '94'))	('PLCbeta4', 'Gene', '5332', (18, 26))	('affects', 'Reg', (35, 42))	('D630Y', 'Mutation', 'p.D630Y', (28, 33))	('Y-domain of the highly conserved catalytic core', 'MPA', (47, 94))	('PLCbeta4', 'Gene', (18, 26))	('signal transduction', 'MPA', (122, 141))	('PLCbeta4', 'Gene', '5332', (98, 106))
35230	28223438	IP3, particularly, translocates into the cytosol where it induces the release of calcium (Ca2+) from the endoplasmic reticulum to activate PKC.	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('105', '126'))	('IP3', 'Var', (0, 3))	('induces', 'Reg', (58, 65))	('PKC', 'molecular_function', 'GO:0004697', ('139', '142'))	('calcium', 'Chemical', 'MESH:D002118', (81, 88))	('Ca2+', 'Chemical', 'MESH:D000069285', (90, 94))	('PKC', 'Gene', (139, 142))	('PKC', 'Gene', '112476', (139, 142))	('cytosol', 'cellular_component', 'GO:0005829', ('41', '48'))	('IP3', 'Chemical', 'MESH:D015544', (0, 3))
35232	28223438	Out of 136 UM patient specimens analyzed by Moore and colleagues, 4 samples harbored a leucine to glutamine substitution at codon 129 (Leu129Gln) in the CYSLTR2 gene, and all four samples lacked mutations in GNAQ, GNA11 or PLCB4.	('GNAQ', 'Gene', (208, 212))	('GNA11', 'Gene', (214, 219))	('leucine to glutamine substitution at codon 129', 'Mutation', 'p.L129Q', (87, 133))	('CYSLTR2', 'Gene', '57105', (153, 160))	('GNA11', 'Gene', '2767', (214, 219))	('lacked', 'NegReg', (188, 194))	('PLCB4', 'Gene', '5332', (223, 228))	('Leu129Gln', 'SUBSTITUTION', 'None', (135, 144))	('patient', 'Species', '9606', (14, 21))	('CYSLTR2', 'Gene', (153, 160))	('PLCB4', 'Gene', (223, 228))	('leucine', 'Var', (87, 94))	('Leu129Gln', 'Var', (135, 144))
35235	28223438	The Leu129Gln mutation is located in the third transmembrane helix of the receptor and promotes ligand independent activation of the GPCR.	('Leu129Gln', 'SUBSTITUTION', 'None', (4, 13))	('activation', 'PosReg', (115, 125))	('transmembrane', 'cellular_component', 'GO:0016021', ('47', '60'))	('GPCR', 'Gene', (133, 137))	('ligand', 'molecular_function', 'GO:0005488', ('96', '102'))	('ligand independent', 'MPA', (96, 114))	('Leu129Gln', 'Var', (4, 13))	('promotes', 'PosReg', (87, 95))	('transmembrane', 'cellular_component', 'GO:0044214', ('47', '60'))	('GPCR', 'Gene', '10663', (133, 137))
35236	28223438	Expression of Leu129Gln CYSLTR2 in HEK293 cells increased basal levels of calcium and promoted the growth of melanocyte cell lines in vitro and in vivo.	('increased', 'PosReg', (48, 57))	('Leu129Gln', 'SUBSTITUTION', 'None', (14, 23))	('CYSLTR2', 'Gene', '57105', (24, 31))	('basal levels of calcium', 'MPA', (58, 81))	('CYSLTR2', 'Gene', (24, 31))	('calcium', 'Chemical', 'MESH:D002118', (74, 81))	('growth of melanocyte cell lines', 'CPA', (99, 130))	('Leu129Gln', 'Var', (14, 23))	('HEK293', 'CellLine', 'CVCL:0045', (35, 41))	('promoted', 'PosReg', (86, 94))
35237	28223438	Collectively, these findings raise the possibility of targeting mutant forms of GNAQ/GNA11, PLCB4 and CYSLTR2 in UMs as well as pathways downstream of mutant GNAQ/GNA11.	('GNA11', 'Gene', '2767', (163, 168))	('GNA11', 'Gene', (163, 168))	('CYSLTR2', 'Gene', (102, 109))	('mutant', 'Var', (151, 157))	('CYSLTR2', 'Gene', '57105', (102, 109))	('PLCB4', 'Gene', (92, 97))	('GNA11', 'Gene', '2767', (85, 90))	('GNA11', 'Gene', (85, 90))	('PLCB4', 'Gene', '5332', (92, 97))	('mutant', 'Var', (64, 70))
35238	28223438	Since the identification of mutations in GPCR signaling components in a high proportion of UM tumors, molecular understanding of pathways downstream of Galphaq and Galpha11 has become crucial for development or discovery of effective treatment options for metastatic UM.	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('GPCR', 'Gene', '10663', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('GPCR', 'Gene', (41, 45))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('mutations', 'Var', (28, 37))
35243	28223438	However, unlike cutaneous melanoma, in which BRAF is commonly mutated, mutations in RAS and BRAF are rare in UM tumors.	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('BRAF', 'Gene', '673', (92, 96))	('BRAF', 'Gene', (92, 96))	('cutaneous melanoma', 'Disease', (16, 34))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutations', 'Var', (71, 80))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('RAS', 'Gene', (84, 87))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (16, 34))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (16, 34))	('tumors', 'Disease', (112, 118))
35244	28223438	Only one patient with choroidal melanoma has been shown to harbor the BRAF V600E mutation.	('choroidal melanoma', 'Disease', 'MESH:D008545', (22, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('V600E', 'Mutation', 'rs113488022', (75, 80))	('choroidal melanoma', 'Disease', (22, 40))	('BRAF', 'Gene', '673', (70, 74))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (22, 40))	('V600E', 'Var', (75, 80))	('patient', 'Species', '9606', (9, 16))	('BRAF', 'Gene', (70, 74))
35245	28223438	MEK-ERK1/2 activation in UM is expected to be induced rather by mutant Galphaq/Galpha11 proteins.	('ERK1/2', 'Gene', (4, 10))	('Galphaq/Galpha11', 'Gene', (71, 87))	('ERK1', 'molecular_function', 'GO:0004707', ('4', '8'))	('MEK', 'Gene', (0, 3))	('ERK1/2', 'Gene', '5595;5594', (4, 10))	('MEK', 'Gene', '5609', (0, 3))	('proteins', 'Protein', (88, 96))	('activation', 'PosReg', (11, 21))	('mutant', 'Var', (64, 70))
35247	28223438	Transfection of GNAQ Q209L in human melanocytes enhanced phosphorylated ERK1/2 protein levels and was associated with increased anchorage-independent growth.	('human', 'Species', '9606', (30, 35))	('ERK1/2', 'Gene', (72, 78))	('ERK1/2', 'Gene', '5595;5594', (72, 78))	('enhanced', 'PosReg', (48, 56))	('ERK1', 'molecular_function', 'GO:0004707', ('72', '76'))	('increased', 'PosReg', (118, 127))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('Q209L', 'SUBSTITUTION', 'None', (21, 26))	('Q209L', 'Var', (21, 26))	('anchorage-independent growth', 'CPA', (128, 156))
35248	28223438	Consistently, these results were reversed by siRNA-mediated knockdown of GNAQ which decreased phospho-ERK1/2 levels.	('ERK1/2', 'Gene', '5595;5594', (102, 108))	('knockdown', 'Var', (60, 69))	('GNAQ', 'Protein', (73, 77))	('decreased', 'NegReg', (84, 93))	('ERK1/2', 'Gene', (102, 108))	('ERK1', 'molecular_function', 'GO:0004707', ('102', '106'))
35249	28223438	However, it is noteworthy that in some UM cases, ERK1/2 may not be activated by G proteins as a study of 22 UM patient tumors did not observe a correlation between GNAQ mutation and ERK1/2 activation although samples with GNAQ mutations had a higher average of the total ERK1/2 expression level compared to GNAQ wild-type tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('ERK1', 'molecular_function', 'GO:0004707', ('271', '275'))	('tumors', 'Phenotype', 'HP:0002664', (322, 328))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('ERK1/2', 'Gene', (271, 277))	('expression level', 'MPA', (278, 294))	('tumors', 'Disease', (119, 125))	('ERK1/2', 'Gene', '5595;5594', (271, 277))	('ERK1/2', 'Gene', (49, 55))	('ERK1/2', 'Gene', '5595;5594', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('patient', 'Species', '9606', (111, 118))	('tumors', 'Disease', (322, 328))	('ERK1/2', 'Gene', (182, 188))	('ERK1/2', 'Gene', '5595;5594', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('higher', 'PosReg', (243, 249))	('mutations', 'Var', (227, 236))	('tumors', 'Disease', 'MESH:D009369', (322, 328))	('ERK1', 'molecular_function', 'GO:0004707', ('49', '53'))	('ERK1', 'molecular_function', 'GO:0004707', ('182', '186'))
35251	28223438	Trio appears to be a key player in mediating mitogenic signals in UM since knockdown of Trio inhibited tumor growth and DNA synthesis in two UM cell line models.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('DNA synthesis', 'biological_process', 'GO:0071897', ('120', '133'))	('Trio', 'Gene', (88, 92))	('tumor', 'Disease', (103, 108))	('DNA synthesis', 'MPA', (120, 133))	('Trio', 'Gene', '7204', (0, 4))	('knockdown', 'Var', (75, 84))	('Trio', 'Gene', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('120', '123'))	('inhibited', 'NegReg', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('Trio', 'Gene', '7204', (88, 92))
35254	28223438	Multiple pathways downstream of Rho/Rac are likely to mediate Trio-dependent cell proliferation in mutant Galphaq/11 UM cells.	('Galphaq/11', 'Gene', (106, 116))	('Rac', 'Gene', '207', (36, 39))	('cell proliferation', 'biological_process', 'GO:0008283', ('77', '95'))	('Rac', 'Gene', (36, 39))	('Trio', 'Gene', '7204', (62, 66))	('mutant', 'Var', (99, 105))	('Trio', 'Gene', (62, 66))
35261	28223438	Another monomeric small GTPase, ARF6, has been proposed as a key mediator of most pathways activated by oncogenic Galphaq/11.	('ARF6', 'Gene', (32, 36))	('GTP', 'Chemical', 'MESH:D006160', (24, 27))	('ARF6', 'Gene', '382', (32, 36))	('Galphaq/11', 'Var', (114, 124))
35262	28223438	Inhibition or depletion of ARF6 in UM cells inhibited cell proliferation and the downstream signaling targets PLCbeta, ERK1/2, Rho, Rac and YAP.	('ERK1/2', 'Gene', '5595;5594', (119, 125))	('cell proliferation', 'CPA', (54, 72))	('ERK1', 'molecular_function', 'GO:0004707', ('119', '123'))	('inhibited', 'NegReg', (44, 53))	('Rac', 'Gene', (132, 135))	('signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('ARF6', 'Gene', (27, 31))	('depletion', 'Var', (14, 23))	('Inhibition', 'Var', (0, 10))	('cell proliferation', 'biological_process', 'GO:0008283', ('54', '72'))	('ARF6', 'Gene', '382', (27, 31))	('ERK1/2', 'Gene', (119, 125))	('Rac', 'Gene', '207', (132, 135))
35264	28223438	A provocative mechanism for the role of ARF6 in controlling Galphaq/11 signaling was proposed, in which ARF6 promoted localization of mutationally activated Galphaq/11 to cytoplasmic vesicles, rather than the plasma membrane, and these cytoplasmic vesicles are the site of oncogenic signaling by Galphaq/11 (Fig 1).	('ARF6', 'Gene', (40, 44))	('signaling', 'biological_process', 'GO:0023052', ('283', '292'))	('signaling', 'biological_process', 'GO:0023052', ('71', '80'))	('promoted', 'PosReg', (109, 117))	('ARF6', 'Gene', '382', (40, 44))	('localization', 'biological_process', 'GO:0051179', ('118', '130'))	('localization', 'MPA', (118, 130))	('ARF6', 'Gene', (104, 108))	('plasma membrane', 'cellular_component', 'GO:0005886', ('209', '224'))	('activated', 'PosReg', (147, 156))	('mutationally', 'Var', (134, 146))	('Galphaq/11', 'Gene', (157, 167))	('ARF6', 'Gene', '382', (104, 108))
35266	28223438	Phosphatidylinositol -bisphosphate 3-kinase (PI3K) catalyzes the formation of phosphatidylinositol -trisphosphate (PIP3) from PIP2, and PIP3 induces membrane translocation of AKT where it becomes active and signals to promote cell proliferation and survival.	('PIP3', 'Chemical', '-', (115, 119))	('promote', 'PosReg', (218, 225))	('induces', 'Reg', (141, 148))	('phosphatidylinositol -trisphosphate', 'Chemical', '-', (78, 113))	('PIP2', 'Chemical', 'MESH:D019269', (126, 130))	('active', 'MPA', (196, 202))	('cell proliferation', 'biological_process', 'GO:0008283', ('226', '244'))	('Phosphatidylinositol -bisphosphate 3-kinase', 'Gene', (0, 43))	('PIP3', 'Chemical', '-', (136, 140))	('PI3K', 'molecular_function', 'GO:0016303', ('45', '49'))	('AKT', 'Gene', '207', (175, 178))	('formation', 'biological_process', 'GO:0009058', ('65', '74'))	('PIP3', 'Var', (136, 140))	('survival', 'CPA', (249, 257))	('cell proliferation', 'CPA', (226, 244))	('membrane', 'cellular_component', 'GO:0016020', ('149', '157'))	('Phosphatidylinositol -bisphosphate 3-kinase', 'Gene', '5294', (0, 43))	('membrane translocation', 'MPA', (149, 171))	('AKT', 'Gene', (175, 178))
35271	28223438	Since activating mutations in either CYSLTR2, GNAQ, GNA11 or PLCB4 are found in ~98% of UMs, this signaling pathway represents a viable therapeutic target for the treatment of UM.	('CYSLTR2', 'Gene', (37, 44))	('activating', 'PosReg', (6, 16))	('GNA11', 'Gene', '2767', (52, 57))	('PLCB4', 'Gene', (61, 66))	('signaling pathway', 'biological_process', 'GO:0007165', ('98', '115'))	('GNA11', 'Gene', (52, 57))	('CYSLTR2', 'Gene', '57105', (37, 44))	('UMs', 'Disease', (88, 91))	('mutations', 'Var', (17, 26))	('PLCB4', 'Gene', '5332', (61, 66))
35274	28223438	A more compelling target is the activated G protein, either Galphaq or Galpha11, which together are mutated in ~93% of UM patients.	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('patients', 'Species', '9606', (122, 130))	('Galpha11', 'Var', (71, 79))	('Galphaq', 'Var', (60, 67))
35275	28223438	In this regard, there are two potent and specific inhibitors that have been reported for Galphaq, YM-254890 and FR900359 or UBO-QIC.	('YM-254890', 'Var', (98, 107))	('YM-254890', 'Chemical', 'MESH:C475455', (98, 107))	('FR900359', 'Var', (112, 120))	('FR900359', 'Chemical', 'MESH:C000607068', (112, 120))	('Galphaq', 'Gene', (89, 96))
35279	28223438	More recently, FR900359, a slightly different cyclic depsipeptide isolated from the Ardisia crenatasims plant, has shown similar pharmacological activity and specificity against Galphaq.	('FR900359', 'Var', (15, 23))	('FR900359', 'Chemical', 'MESH:C000607068', (15, 23))	('Ardisia crenatasims', 'Disease', 'None', (84, 103))	('Galphaq', 'Protein', (178, 185))	('Ardisia crenatasims', 'Disease', (84, 103))
35280	28223438	Docking models and molecular dynamics studies suggest FR900359 inhibits Galphaq in an identical manner to YM-254890.	('FR900359', 'Var', (54, 62))	('inhibits', 'NegReg', (63, 71))	('FR900359', 'Chemical', 'MESH:C000607068', (54, 62))	('YM-254890', 'Chemical', 'MESH:C475455', (106, 115))	('Galphaq', 'Protein', (72, 79))
35281	28223438	For example, while YM-254890 inhibited a Galphaq-R183C mutant, it was unable to inhibit Galphaq-Q209L.	('inhibited', 'NegReg', (29, 38))	('YM-254890', 'Chemical', 'MESH:C475455', (19, 28))	('YM-254890', 'Var', (19, 28))	('Q209L', 'SUBSTITUTION', 'None', (96, 101))	('Q209L', 'Var', (96, 101))	('Galphaq-R183C', 'Var', (41, 54))	('R183C', 'Mutation', 'p.R183C', (49, 54))
35282	28223438	Moreover, one also needs to consider Galphaq vs Galpha11 selectivity when inhibiting these proteins since a non-selective Galphaq/11 inhibitor would likely be toxic, as knockout of both Galphaq and Galpha11 in mice leads to death in utero.	('knockout', 'Var', (169, 177))	('mice', 'Species', '10090', (210, 214))	('Galpha11', 'Gene', (198, 206))	('Galphaq', 'Gene', (186, 193))	('leads to', 'Reg', (215, 223))	('death', 'Disease', (224, 229))	('death', 'Disease', 'MESH:D003643', (224, 229))
35284	28223438	However, PLCbeta4 is unlikely to be the only downstream target of activated Galphaq/11 in UM so such an inhibitor might only prove useful in the small number of patients that have a PLCbeta4 mutation.	('PLCbeta4', 'Gene', (9, 17))	('PLCbeta4', 'Gene', '5332', (182, 190))	('patients', 'Species', '9606', (161, 169))	('PLCbeta4', 'Gene', (182, 190))	('PLCbeta4', 'Gene', '5332', (9, 17))	('mutation', 'Var', (191, 199))
35286	28223438	Inhibition of MEK1/2 either by trametinib, selumetinib or PD0325901, induced growth arrest and apoptosis in GNAQ/GNA11 mutant UM cell lines and xenograft tumors.	('MEK1', 'molecular_function', 'GO:0004708', ('14', '18'))	('apoptosis', 'CPA', (95, 104))	('growth arrest', 'Disease', (77, 90))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('trametinib', 'Chemical', 'MESH:C560077', (31, 41))	('MEK1/2', 'Gene', '5604;5605', (14, 20))	('MEK1/2', 'Gene', (14, 20))	('GNA11', 'Gene', '2767', (113, 118))	('PD0325901', 'Chemical', 'MESH:C506614', (58, 67))	('selumetinib', 'Chemical', 'MESH:C517975', (43, 54))	('mutant', 'Var', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('xenograft tumors', 'Disease', (144, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('growth arrest', 'Phenotype', 'HP:0001510', (77, 90))	('xenograft tumors', 'Disease', 'MESH:D009369', (144, 160))	('growth arrest', 'Disease', 'MESH:D006323', (77, 90))	('GNA11', 'Gene', (113, 118))	('PD0325901', 'Gene', (58, 67))
35287	28223438	Trametinib is FDA-approved and used in combination with the BRAF inhibitor, dabrafenib for patients with unresectable or metastatic melanoma harboring BRAF V600E and V600K mutations.	('V600K', 'Var', (166, 171))	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('melanoma', 'Disease', (132, 140))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('patients', 'Species', '9606', (91, 99))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('BRAF', 'Gene', '673', (151, 155))	('V600E', 'Mutation', 'rs113488022', (156, 161))	('V600K', 'Mutation', 'rs121913227', (166, 171))	('BRAF', 'Gene', (151, 155))	('V600E', 'Var', (156, 161))	('dabrafenib', 'Chemical', 'MESH:C561627', (76, 86))
35294	28223438	Hepatocyte growth factor (HGF) provided resistance to trametinib growth inhibitory effects in metastatic UM cell lines and targeting of cMET (the receptor for HGF) enhanced the effects of trametinib in metastatic UM.	('HGF', 'Gene', '3082', (26, 29))	('Hepatocyte growth factor', 'Gene', '3082', (0, 24))	('trametinib', 'Chemical', 'MESH:C560077', (54, 64))	('enhanced', 'PosReg', (164, 172))	('trametinib', 'Chemical', 'MESH:C560077', (188, 198))	('HGF', 'Gene', (159, 162))	('Hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('0', '24'))	('targeting', 'Var', (123, 132))	('resistance', 'MPA', (40, 50))	('HGF', 'Gene', '3082', (159, 162))	('cMET', 'Gene', '4233', (136, 140))	('effects', 'MPA', (177, 184))	('growth inhibitory effects', 'MPA', (65, 90))	('cMET', 'Gene', (136, 140))	('Hepatocyte growth factor', 'Gene', (0, 24))	('HGF', 'Gene', (26, 29))
35299	28223438	These findings support an earlier study which reported the combination of MEK and PI3K inhibitors for UM and these agents induce marked early apoptosis in GNAQ mutant UM cell lines compared to the inhibitors alone which have moderate effects on apoptosis.	('MEK', 'Gene', '5609', (74, 77))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('apoptosis', 'biological_process', 'GO:0097194', ('245', '254'))	('PI3K', 'Gene', (82, 86))	('apoptosis', 'biological_process', 'GO:0006915', ('245', '254'))	('mutant', 'Var', (160, 166))	('apoptosis', 'biological_process', 'GO:0097194', ('142', '151'))	('apoptosis', 'biological_process', 'GO:0006915', ('142', '151'))	('GNAQ', 'Gene', (155, 159))	('MEK', 'Gene', (74, 77))
35302	28223438	However, these effects were not durable, whereas in combination with MEK inhibitors, PD0325901 or MEK162, sustained inhibition of the ERK1/2 pathway was observed.	('ERK1/2', 'Gene', '5595;5594', (134, 140))	('MEK', 'Gene', (98, 101))	('MEK', 'Gene', '5609', (98, 101))	('PD0325901', 'Var', (85, 94))	('MEK', 'Gene', (69, 72))	('MEK', 'Gene', '5609', (69, 72))	('inhibition', 'NegReg', (116, 126))	('PD0325901', 'Chemical', 'MESH:C506614', (85, 94))	('ERK1', 'molecular_function', 'GO:0004707', ('134', '138'))	('ERK1/2', 'Gene', (134, 140))	('MEK162', 'Chemical', 'MESH:C581313', (98, 104))
35306	28223438	AEB701 and CGM097 or AEB701 and RAD001 markedly reduced tumor growth and induced tumor regression.	('AEB701', 'Var', (21, 27))	('CGM097', 'Chemical', 'MESH:C000602644', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('reduced', 'NegReg', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('RAD001', 'Gene', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('RAD', 'biological_process', 'GO:1990116', ('32', '35'))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (81, 86))
35309	28223438	Whilst identification of driver mutations in UM such as GNAQ and GNA11 has shed light to potential therapeutic targets, alterations in GPCR signaling occur early in disease progression.	('GPCR', 'Gene', (135, 139))	('mutations', 'Var', (32, 41))	('GNA11', 'Gene', '2767', (65, 70))	('GNA11', 'Gene', (65, 70))	('GPCR', 'Gene', '10663', (135, 139))	('GNAQ', 'Gene', (56, 60))	('alterations', 'Reg', (120, 131))	('signaling', 'biological_process', 'GO:0023052', ('140', '149'))
35311	28223438	For example, inactivating mutations of BAP1 have been found in ~80% of aggressive UM while SF3B1 and EIF1AX were shown to correlate with a favorable prognosis.	('inactivating mutations', 'Var', (13, 35))	('SF3B1', 'Gene', (91, 96))	('EIF1AX', 'Gene', '1964', (101, 107))	('EIF1AX', 'Gene', (101, 107))	('SF3B1', 'Gene', '23451', (91, 96))	('found', 'Reg', (54, 59))	('BAP1', 'Gene', '8314', (39, 43))	('aggressive UM', 'Disease', (71, 84))	('BAP1', 'Gene', (39, 43))
35332	27790127	Incisional biopsy of one of these lesions demonstrated BRAF mutation-negative metastatic melanoma.	('BRAF', 'Gene', (55, 59))	('mutation-negative', 'Var', (60, 77))	('BRAF', 'Gene', '673', (55, 59))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
35380	26525215	Additionally, studies using alternative radioactive isotopes for brachytherapy (e.g., palladium-103 and ruthenium-106) have demonstrated superior preservation of visual acuity with long-term follow-up.	('palladium-103', 'Chemical', 'MESH:C000615531', (86, 99))	('ruthenium-106', 'Chemical', 'MESH:C000615522', (104, 117))	('palladium-103', 'Var', (86, 99))	('ruthenium-106', 'Var', (104, 117))	('visual', 'MPA', (162, 168))
35460	26525215	A recent report comparing smaller tumors treated with this 5 mm prescription point method to tumors treated with doses prescribed strictly to the apical height demonstrated increased visual complications in the 5 mm prescription point group.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('5 mm', 'Var', (211, 215))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('visual complications', 'CPA', (183, 203))	('tumors', 'Disease', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
35470	26525215	Studies describing visual acuity results in patients treated with 106Ru have also demonstrated good preservation of visual acuity, with one study reporting only 29% of patients developing visual loss greater than two Snellen lines after six years of follow-up.	('patients', 'Species', '9606', (44, 52))	('visual', 'MPA', (116, 122))	('visual loss', 'Disease', 'MESH:C531604', (188, 199))	('visual loss', 'Phenotype', 'HP:0000572', (188, 199))	('106Ru', 'Var', (66, 71))	('patients', 'Species', '9606', (168, 176))	('visual loss', 'Disease', (188, 199))
35564	23136044	Five of the melanomas that were studied by BLI were heavily pigmented (405, 487, 205, 514 and 214).	('melanomas', 'Phenotype', 'HP:0002861', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanomas', 'Disease', 'MESH:D008545', (12, 21))	('405', 'Var', (71, 74))	('melanomas', 'Disease', (12, 21))
35572	23136044	The other three melanomas were lymph node metastases obtained from patients with stage IIIB/C disease (651, 528, 530; Fig.	('metastases', 'Disease', 'MESH:D009362', (42, 52))	('patients', 'Species', '9606', (67, 75))	('C disease', 'Disease', 'MESH:C537418', (92, 101))	('melanomas', 'Disease', 'MESH:D008545', (16, 25))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanomas', 'Phenotype', 'HP:0002861', (16, 25))	('651', 'Var', (103, 106))	('C disease', 'Disease', (92, 101))	('metastases', 'Disease', (42, 52))	('melanomas', 'Disease', (16, 25))
35616	23136044	It is likely that the more highly immunocompromised environment within NSG mice, as compared to NOD/SCID or SCID mice, facilitates the modelling of human melanoma metastasis by attenuating the xenogeneic immune response to human cells.	('facilitates', 'PosReg', (119, 130))	('SCID', 'Gene', (108, 112))	('mice', 'Species', '10090', (75, 79))	('attenuating', 'NegReg', (177, 188))	('melanoma metastasis', 'Disease', 'MESH:D009362', (154, 173))	('NOD', 'Gene', (96, 99))	('human', 'Species', '9606', (223, 228))	('immune response', 'biological_process', 'GO:0006955', ('204', '219'))	('human', 'Species', '9606', (148, 153))	('NSG', 'Var', (71, 74))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('NOD', 'Gene', '1822', (96, 99))	('SCID', 'Gene', '19090', (100, 104))	('xenogeneic immune response to', 'CPA', (193, 222))	('mice', 'Species', '10090', (113, 117))	('melanoma metastasis', 'Disease', (154, 173))	('SCID', 'Gene', '19090', (108, 112))	('SCID', 'Gene', (100, 104))
35617	23136044	We have not yet encountered a melanoma that could not engraft in NSG mice and many more melanoma cells form subcutaneous tumors in NSG as compared to NOD/SCID mice.	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('mice', 'Species', '10090', (69, 73))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('NOD', 'Gene', '1822', (150, 153))	('NOD', 'Gene', (150, 153))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (108, 127))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (108, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('subcutaneous tumors', 'Disease', (108, 127))	('SCID', 'Gene', '19090', (154, 158))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Disease', (30, 38))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (108, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('NSG', 'Var', (131, 134))	('mice', 'Species', '10090', (159, 163))	('SCID', 'Gene', (154, 158))
35626	23136044	Melanoma specimens were obtained with informed consent from all patients according to protocols approved by the Institutional Review Board of the UM Medical School (IRBMED approvals HUM00050754 and HUM00050085).	('HUM00050754', 'Var', (182, 193))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('patients', 'Species', '9606', (64, 72))	('Melanoma', 'Disease', (0, 8))	('HUM00050085', 'Var', (198, 209))
35777	24688598	It differs from the study involving BRMS1 immunoexpression in breast cancer, which showed that the loss of BRMS1 protein expression predicts reduced disease-free survival.	('BRMS1', 'Gene', (36, 41))	('BRMS1', 'Gene', '25855', (107, 112))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('reduced', 'NegReg', (141, 148))	('BRMS1', 'Gene', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('BRMS1', 'Gene', '25855', (36, 41))	('protein', 'Protein', (113, 120))	('loss', 'Var', (99, 103))	('disease-free survival', 'CPA', (149, 170))
35786	22825583	Recent work has identified frequent inactivation of two tumor suppressor genes in MPM-- NF2 (Neurofibromatosis type 2) and BAP1 (BRCA associated protein 1).	('BAP1', 'Gene', (123, 127))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('56', '72'))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('NF2', 'Gene', '4771', (88, 91))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('tumor', 'Disease', (56, 61))	('NF2', 'Gene', (88, 91))	('MPM', 'Chemical', '-', (82, 85))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (93, 110))	('inactivation', 'Var', (36, 48))	('tumor suppressor', 'biological_process', 'GO:0051726', ('56', '72'))	('Neurofibromatosis type 2', 'Gene', (93, 117))	('Neurofibromatosis type 2', 'Gene', '4771', (93, 117))
35787	22825583	Additionally, germline mutations in BAP1 have been identified and an associated cancer syndrome which includes MPM, ocular melanoma and other cancers has been described.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('cancer syndrome', 'Disease', (80, 95))	('MPM', 'Chemical', '-', (111, 114))	('ocular melanoma', 'Phenotype', 'HP:0007716', (116, 131))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('associated', 'Reg', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('ocular melanoma', 'Disease', 'MESH:D008545', (116, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('BAP1', 'Gene', (36, 40))	('ocular melanoma', 'Disease', (116, 131))	('germline mutations', 'Var', (14, 32))	('cancer syndrome', 'Disease', 'MESH:D009369', (80, 95))	('MPM', 'Disease', (111, 114))
35797	22825583	This review calls attention to emerging data on the frequent inactivation of two genes in MPM: Neurofibromatosis Type 2 (NF2) and BRCA1 Associated Protein 1 (BAP1)-- that could help elucidate key pathways that drive tumorigenesis and which could subsequently be exploited as rational targets for drug development in this cancer.	('inactivation', 'Var', (61, 73))	('tumor', 'Disease', (216, 221))	('MPM', 'Gene', (90, 93))	('elucidate', 'Reg', (182, 191))	('Neurofibromatosis Type 2', 'Gene', (95, 119))	('MPM', 'Chemical', '-', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (321, 327))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (95, 112))	('NF2', 'Gene', (121, 124))	('cancer', 'Disease', (321, 327))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('NF2', 'Gene', '4771', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('BRCA1 Associated Protein 1', 'Gene', (130, 156))	('BRCA1 Associated Protein 1', 'Gene', '8314', (130, 156))	('Neurofibromatosis Type 2', 'Gene', '4771', (95, 119))
35798	22825583	About 35-40% of MPMs carry inactivating mutations at the neurofibromatosis 2 (NF2) locus, which encodes for the FERM domain protein Merlin.	('MPMs', 'Disease', (16, 20))	('inactivating mutations', 'Var', (27, 49))	('NF2', 'Gene', '4771', (78, 81))	('neurofibromatosis', 'Disease', (57, 74))	('MPM', 'Chemical', '-', (16, 19))	('neurofibromatosis', 'Disease', 'MESH:C537392', (57, 74))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (57, 74))	('NF2', 'Gene', (78, 81))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))
35801	22825583	Since loss of Merlin causes activation of multiple mitogenic signaling pathways, such as HER1/2, mTOR, ERK, and FAK, it has been postulated that Merlin inhibits signaling by negatively regulating multiple cell surface receptors.	('signaling', 'MPA', (161, 170))	('signaling', 'biological_process', 'GO:0023052', ('161', '170'))	('mitogenic signaling pathways', 'Pathway', (51, 79))	('loss', 'Var', (6, 10))	('cell', 'Protein', (205, 209))	('mTOR', 'Gene', (97, 101))	('FAK', 'molecular_function', 'GO:0004717', ('112', '115'))	('cell surface', 'cellular_component', 'GO:0009986', ('205', '217'))	('HER1/2', 'Protein', (89, 95))	('Merlin', 'Gene', (14, 20))	('mTOR', 'Gene', '2475', (97, 101))	('signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('FAK', 'Gene', (112, 115))	('negatively', 'NegReg', (174, 184))	('ERK', 'Gene', (103, 106))	('ERK', 'molecular_function', 'GO:0004707', ('103', '106'))	('FAK', 'Gene', '5747', (112, 115))	('inhibits', 'NegReg', (152, 160))	('activation', 'PosReg', (28, 38))	('ERK', 'Gene', '2048', (103, 106))
35807	22825583	However, it remains unclear whether loss of Merlin inactivates the Hippo kinase in the cytosol, as genetic studies in the fly suggest, or it deregulates the oncoprotein and transcriptional coactivator YAP through activation of CRL4DCAF1 .	('inactivates', 'NegReg', (51, 62))	('Merlin', 'Protein', (44, 50))	('Hippo kinase', 'Gene', (67, 79))	('DCAF1', 'Gene', '9730', (231, 236))	('oncoprotein', 'Enzyme', (157, 168))	('loss', 'Var', (36, 40))	('activation', 'PosReg', (213, 223))	('Hippo kinase', 'Gene', '37247', (67, 79))	('DCAF1', 'Gene', (231, 236))	('cytosol', 'cellular_component', 'GO:0005829', ('87', '94'))	('deregulates', 'NegReg', (141, 152))
35818	22825583	Preclinical evidence indicates that isolated mTOR inhibition alleviates feedback inhibition on PI3K and thereby allows restoration of PI3K and downstream AKT signaling.	('inhibition', 'Var', (50, 60))	('alleviates', 'NegReg', (61, 71))	('mTOR', 'Gene', '2475', (45, 49))	('AKT', 'Gene', '207', (154, 157))	('PI3K', 'Pathway', (95, 99))	('AKT', 'Gene', (154, 157))	('AKT signaling', 'biological_process', 'GO:0043491', ('154', '167'))	('PI3K', 'molecular_function', 'GO:0016303', ('134', '138'))	('feedback inhibition', 'MPA', (72, 91))	('PI3K', 'MPA', (134, 138))	('PI3K', 'molecular_function', 'GO:0016303', ('95', '99'))	('mTOR', 'Gene', (45, 49))
35825	22825583	The frequent occurrence of NF2 gene loss in MPM, as well as the very high prevalence of p16/CDKN2A deletions,have been known since the mid-1990s.	('NF2', 'Gene', (27, 30))	('p16', 'Gene', (88, 91))	('CDKN2A', 'Gene', (92, 98))	('deletions', 'Var', (99, 108))	('loss', 'NegReg', (36, 40))	('MPM', 'Disease', (44, 47))	('NF2', 'Gene', '4771', (27, 30))	('CDKN2A', 'Gene', '1029', (92, 98))	('MPM', 'Chemical', '-', (44, 47))	('p16', 'Gene', '1029', (88, 91))
35828	22825583	The 3 most common deletions noted were at 22q (which includes NF2), 9p21 (which includes CDKN2A), and 3p21.	('NF2', 'Gene', '4771', (62, 65))	('3p21', 'Var', (102, 106))	('CDKN2A', 'Gene', (89, 95))	('CDKN2A', 'Gene', '1029', (89, 95))	('NF2', 'Gene', (62, 65))
35830	22825583	Interestingly, 25% of tumors without identified BAP1 mutations did not display any IHC staining for BAP1 suggesting the possibility of another subset of tumors with functional BAP1 loss arising by other mechanisms.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('BAP1', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutations', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('BAP1', 'Gene', (176, 180))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('loss', 'NegReg', (181, 185))	('tumors', 'Disease', (22, 28))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
35836	22825583	Inactivating somatic mutations of BAP1 have been identified in 47% of uveal melanomas, primarily in the metastasizing subset, where the BAP1 mutation rate is close to 80%.	('uveal melanomas', 'Disease', 'MESH:C536494', (70, 85))	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('BAP1', 'Gene', (34, 38))	('identified', 'Reg', (49, 59))	('uveal melanomas', 'Disease', (70, 85))	('uveal melanomas', 'Phenotype', 'HP:0007716', (70, 85))	('Inactivating somatic mutations', 'Var', (0, 30))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
35842	22825583	Coming on the heels of the discovery of somatic BAP1 mutations is the recent discovery of germline BAP1 mutations in rare families predisposed to MPM.	('BAP1', 'Gene', (99, 103))	('MPM', 'Disease', (146, 149))	('mutations', 'Var', (104, 113))	('MPM', 'Chemical', '-', (146, 149))	('mutations', 'Var', (53, 62))
35850	22825583	Given these observations and reports of frequent gene loss at 3p21.1 in sporadic MPM, germline BAP1 sequencing was performed in both families and revealed concordance between mutation status and linkage analysis.	('MPM', 'Chemical', '-', (81, 84))	('gene loss', 'Var', (49, 58))	('MPM', 'Disease', (81, 84))
35851	22825583	Furthermore, those with germline mutations manifested other malignancies in addition to MPM including uveal melanoma, breast cancer, renal cancer, and skin cancer.	('renal cancer', 'Phenotype', 'HP:0009726', (133, 145))	('MPM', 'Disease', (88, 91))	('skin cancer', 'Disease', 'MESH:D012878', (151, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('renal cancer', 'Disease', 'MESH:D007680', (133, 145))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('manifested', 'Reg', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('skin cancer', 'Disease', (151, 162))	('uveal melanoma', 'Disease', (102, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (102, 116))	('malignancies', 'Disease', 'MESH:D009369', (60, 72))	('malignancies', 'Disease', (60, 72))	('skin cancer', 'Phenotype', 'HP:0008069', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('germline mutations', 'Var', (24, 42))	('MPM', 'Chemical', '-', (88, 91))	('renal cancer', 'Disease', (133, 145))
35852	22825583	reported an association between germline mutations in BAP1 and familial melanocytic tumors ranging from epithelioid nevi to atypical melanocytic proliferations with features of cutaneous melanoma.	('nevi to atypical melanocytic proliferations', 'Phenotype', 'HP:0000995', (116, 159))	('familial melanocytic tumors', 'Disease', (63, 90))	('familial melanocytic tumors', 'Disease', 'MESH:D009508', (63, 90))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('germline mutations', 'Var', (32, 50))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('epithelioid nevi', 'Disease', (104, 120))	('cutaneous melanoma', 'Disease', (177, 195))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (177, 195))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (177, 195))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('nevi', 'Phenotype', 'HP:0003764', (116, 120))	('atypical melanocytic proliferations', 'Disease', (124, 159))	('BAP1', 'Gene', (54, 58))	('atypical melanocytic proliferations', 'Phenotype', 'HP:0001062', (124, 159))
35853	22825583	Tumors were examined from two families and revealed biallelic somatic inactivation of BAP1.	('biallelic somatic inactivation', 'Var', (52, 82))	('BAP1', 'Gene', (86, 90))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
35857	22825583	Njauw and colleagues  have recently published additional melanocytic tumor-rich pedigrees of families with germline BAP1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('BAP1', 'Gene', (116, 120))	('mutations', 'Var', (121, 130))	('melanocytic tumor', 'Disease', 'MESH:D009508', (57, 74))	('melanocytic tumor', 'Disease', (57, 74))
35859	22825583	The recently published data reviewed above suggest that, together, a majority of MPM carry either NF2 or BAP1 mutations.	('mutations', 'Var', (110, 119))	('MPM', 'Disease', (81, 84))	('NF2', 'Gene', '4771', (98, 101))	('MPM', 'Chemical', '-', (81, 84))	('BAP1', 'Gene', (105, 109))	('NF2', 'Gene', (98, 101))
35861	22825583	Interestingly, total loss-of-function mutations in NF2 and BAP1, as assessed by immunoblotting, occur in largely non-overlapping subsets of MPM patients (see immunoblotting of cell lines for Merlin and for BAP1).	('NF2', 'Gene', (51, 54))	('BAP1', 'Gene', (59, 63))	('loss-of-function', 'NegReg', (21, 37))	('NF2', 'Gene', '4771', (51, 54))	('patients', 'Species', '9606', (144, 152))	('MPM', 'Disease', (140, 143))	('mutations', 'Var', (38, 47))	('MPM', 'Chemical', '-', (140, 143))
35864	22825583	If studies define a therapeutically accessible synthetic lethal target in the setting of BAP1 loss, this could eventually benefit the approximately 40% of MPM patients whose tumors have BAP1 loss or mutation.	('MPM', 'Chemical', '-', (155, 158))	('tumors', 'Disease', (174, 180))	('BAP1', 'Gene', (89, 93))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('loss', 'NegReg', (191, 195))	('loss', 'NegReg', (94, 98))	('mutation', 'Var', (199, 207))	('MPM', 'Disease', (155, 158))	('BAP1', 'Gene', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('patients', 'Species', '9606', (159, 167))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
35865	22825583	More speculatively, the same synthetic lethal target could be studied as chemoprevention drug targets in individuals (or, initially, mouse models) with germline BAP1 mutations that predispose to MPM development.	('BAP1', 'Gene', (161, 165))	('mutations', 'Var', (166, 175))	('MPM development', 'Disease', (195, 210))	('mouse', 'Species', '10090', (133, 138))	('MPM', 'Chemical', '-', (195, 198))
35867	22825583	Finally, the impact of the work may also extend to other cancers with BAP1 mutations such as melanoma and, as recently reported, clear cell renal cell carcinoma.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('clear cell renal cell carcinoma', 'Disease', (129, 160))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (129, 160))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('BAP1', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (140, 160))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (129, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
35868	21874000	Germline BAP1 mutations predispose to malignant mesothelioma Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors.	('malignant mesothelioma', 'Disease', (131, 153))	('mesothelioma', 'Disease', 'MESH:D008654', (167, 179))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (38, 60))	('mesothelioma', 'Disease', (48, 60))	('asbestos', 'Chemical', 'MESH:D001194', (94, 102))	('BAP1', 'Gene', '8314', (9, 13))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (131, 153))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (131, 153))	('mesothelioma', 'Disease', (141, 153))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (38, 60))	('mesothelioma', 'Disease', 'MESH:D008654', (48, 60))	('BAP1', 'Gene', (9, 13))	('predispose', 'Reg', (24, 34))	('mutations', 'Var', (14, 23))	('mesothelioma', 'Disease', (167, 179))	('malignant mesothelioma', 'Disease', (38, 60))
35869	21874000	We discovered germline mutations in BAP1 (BRCA1-associated protein 1) in two families with a high incidence of mesothelioma.	('BRCA1-associated protein 1', 'Gene', '8314', (42, 68))	('BRCA1-associated protein 1', 'Gene', (42, 68))	('BAP1', 'Gene', '8314', (36, 40))	('mesothelioma', 'Disease', (111, 123))	('BAP1', 'Gene', (36, 40))	('mesothelioma', 'Disease', 'MESH:D008654', (111, 123))	('germline mutations', 'Var', (14, 32))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
35871	21874000	Besides mesothelioma, some BAP1 mutation carriers developed uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('BAP1', 'Gene', (27, 31))	('mesothelioma', 'Disease', (8, 20))	('uveal melanoma', 'Disease', 'MESH:C536494', (60, 74))	('developed', 'Reg', (50, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('uveal melanoma', 'Disease', (60, 74))	('mutation', 'Var', (32, 40))	('mesothelioma', 'Disease', 'MESH:D008654', (8, 20))	('BAP1', 'Gene', '8314', (27, 31))
35872	21874000	Germline BAP1 mutations were also found in two of 26 sporadic mesotheliomas: both patients with mutant BAP1 were previously diagnosed with uveal melanoma.	('BAP1', 'Gene', '8314', (103, 107))	('sporadic mesotheliomas', 'Disease', (53, 75))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('mutant', 'Var', (96, 102))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (53, 75))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (53, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('uveal melanoma', 'Disease', 'MESH:C536494', (139, 153))	('patients', 'Species', '9606', (82, 90))	('BAP1', 'Gene', (103, 107))	('BAP1', 'Gene', '8314', (9, 13))	('uveal melanoma', 'Disease', (139, 153))	('BAP1', 'Gene', (9, 13))	('diagnosed', 'Reg', (124, 133))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (53, 75))
35873	21874000	Truncating mutations and aberrant BAP1 expression were common in sporadic mesotheliomas without germline mutations.	('Truncating mutations', 'Var', (0, 20))	('BAP1', 'Gene', (34, 38))	('common', 'Reg', (55, 61))	('aberrant', 'Var', (25, 33))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (65, 86))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (65, 87))	('expression', 'MPA', (39, 49))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (65, 87))	('BAP1', 'Gene', '8314', (34, 38))	('sporadic mesotheliomas', 'Disease', (65, 87))
35890	21874000	Array-CGH analysis of two tumors (one/family) uncovered alterations encompassing or adjacent to the BAP1 locus in 3p21.1.	('BAP1', 'Gene', '8314', (100, 104))	('alterations', 'Var', (56, 67))	('tumors', 'Disease', (26, 32))	('BAP1', 'Gene', (100, 104))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (26, 32))
35896	21874000	We sequenced BAP1 in germline DNA from family W and found that six affected members (four with mesothelioma; two with breast or renal cancer) had identical mutations, whereas unaffected family members did not (Fig.	('breast or renal cancer', 'Disease', 'MESH:D007680', (118, 140))	('BAP1', 'Gene', (13, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (95, 107))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('breast or renal cancer', 'Disease', (118, 140))	('mutations', 'Var', (156, 165))	('renal cancer', 'Phenotype', 'HP:0009726', (128, 140))	('BAP1', 'Gene', '8314', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mesothelioma', 'Disease', (95, 107))
35898	21874000	Transfection of mammalian cells with a genomic construct containing exons 6-8, and with the intron 6 splice site mutation, resulted in an aberrant splice product lacking exon 7 (Supplementary Fig.	('mammalian', 'Species', '9606', (16, 25))	('mutation', 'Var', (113, 121))	('splice product', 'MPA', (147, 161))	('exon 7', 'MPA', (170, 176))
35899	21874000	Besides the somatic genetic alteration detected by array-CGH in sample W-III-06T, in tumor W-III-08T only mutant BAP1 could be detected, consistent with loss of wild-type BAP1 on the other homologue.	('tumor', 'Disease', (85, 90))	('BAP1', 'Gene', (171, 175))	('mutant', 'Var', (106, 112))	('BAP1', 'Gene', '8314', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('BAP1', 'Gene', '8314', (171, 175))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('BAP1', 'Gene', (113, 117))
35900	21874000	Additionally, W-III-04T had both the splice site mutation and a 25-bp exon 4 deletion resulting in a frameshift and premature termination of BAP1 (p.I72fsX7) (Supplementary Fig.	('p.I72fsX7', 'Mutation', 'p.I72fsX7', (147, 156))	('frameshift', 'Var', (101, 111))	('BAP1', 'Gene', '8314', (141, 145))	('BAP1', 'Gene', (141, 145))
35901	21874000	Cloning of genomic PCR products encompassing exons 4-7 from tumor DNA suggested that the splice site mutation and deletion reside in different alleles, consistent with biallelic inactivation of BAP1.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('BAP1', 'Gene', '8314', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('BAP1', 'Gene', (194, 198))	('deletion', 'Var', (114, 122))
35902	21874000	In family L, germline DNA from three individuals with mesothelioma (one recently treated for uveal melanoma) and two with skin carcinomas exhibited a germline C/G to T/A transition in exon 16, creating a stop codon (p.Q684X) (Supplementary Fig.	('skin carcinomas', 'Disease', (122, 137))	('uveal melanoma', 'Phenotype', 'HP:0007716', (93, 107))	('uveal melanoma', 'Disease', 'MESH:C536494', (93, 107))	('mesothelioma', 'Disease', 'MESH:D008654', (54, 66))	('p.Q684X', 'Var', (216, 223))	('uveal melanoma', 'Disease', (93, 107))	('skin carcinomas', 'Phenotype', 'HP:0008069', (122, 137))	('skin carcinomas', 'Disease', 'MESH:D012878', (122, 137))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('p.Q684X', 'Mutation', 'rs387906848', (216, 223))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('mesothelioma', 'Disease', (54, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))
35903	21874000	There was complete concordance between BAP1 mutation status and linkage analysis.	('BAP1', 'Gene', '8314', (39, 43))	('mutation', 'Var', (44, 52))	('BAP1', 'Gene', (39, 43))
35909	21874000	Having linked BAP1 mutations to familial mesothelioma, we next sequenced BAP1 (17 exons/introns/promoter) in 26 germline DNAs from sporadic mesothelioma patients.	('linked', 'Reg', (7, 13))	('BAP1', 'Gene', '8314', (14, 18))	('BAP1', 'Gene', '8314', (73, 77))	('familial mesothelioma', 'Phenotype', 'HP:0100001', (32, 53))	('mesothelioma', 'Disease', (140, 152))	('patients', 'Species', '9606', (153, 161))	('mesothelioma', 'Disease', (41, 53))	('mesothelioma', 'Disease', 'MESH:D008654', (140, 152))	('BAP1', 'Gene', (14, 18))	('BAP1', 'Gene', (73, 77))	('mutations', 'Var', (19, 28))	('familial mesothelioma', 'Disease', (32, 53))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (131, 152))	('mesothelioma', 'Disease', 'MESH:D008654', (41, 53))	('familial mesothelioma', 'Disease', 'MESH:D008654', (32, 53))
35911	21874000	Two of 26 had BAP1 deletions: c.1832delC in exon 13 (p.P572fsX3) and c.2008-2011delTACT in exon 14 (p.Y627fsX9) (Supplementary Table 1).	('c.1832delC', 'Mutation', 'c.1832delC', (30, 40))	('BAP1', 'Gene', '8314', (14, 18))	('c.2008-2011delTACT', 'Var', (69, 87))	('BAP1', 'Gene', (14, 18))	('p.P572fsX3', 'Mutation', 'p.P572fsX3', (53, 63))	('c.2008-2011delTACT', 'Mutation', 'c.2008_2011delTACT', (69, 87))	('c.1832delC', 'Var', (30, 40))	('p.Y627fsX9', 'Mutation', 'p.Y627fsX9', (100, 110))
35912	21874000	Both mutations result in a frameshift leading to a stop codon upstream of the region encoding the BAP1 nuclear localization signal (Fig.	('BAP1', 'Gene', (98, 102))	('result', 'Reg', (15, 21))	('stop codon', 'MPA', (51, 61))	('BAP1', 'Gene', '8314', (98, 102))	('localization', 'biological_process', 'GO:0051179', ('111', '123'))	('frameshift', 'Var', (27, 37))
35915	21874000	Tumor DNA was available from 18 of the 26 sporadic mesothelioma patients: DNA sequencing revealed truncating BAP1 mutations in 4/18 (22%) tumors (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('patients', 'Species', '9606', (64, 72))	('mutations', 'Var', (114, 123))	('truncating', 'MPA', (98, 108))	('mesothelioma', 'Disease', (51, 63))	('BAP1', 'Gene', '8314', (109, 113))	('DNA', 'cellular_component', 'GO:0005574', ('6', '9'))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('mesothelioma', 'Disease', 'MESH:D008654', (51, 63))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (42, 63))	('BAP1', 'Gene', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
35923	21874000	A paper published while our manuscript was being reviewed reported somatic BAP1 mutations in 23% of sporadic mesotheliomas, which concurs with our findings in sporadic tumors.	('sporadic tumors', 'Disease', (159, 174))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('BAP1', 'Gene', (75, 79))	('mutations', 'Var', (80, 89))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (100, 122))	('sporadic tumors', 'Disease', 'MESH:D009369', (159, 174))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (100, 121))	('BAP1', 'Gene', '8314', (75, 79))	('sporadic mesotheliomas', 'Disease', (100, 122))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (100, 122))
35924	21874000	In addition, and most importantly, we demonstrate the presence of germline BAP1 mutations in members of U.S. families that experience an extremely high incidence of mesothelioma, in spite of very modest exposure to asbestos; thus, our results point to BAP1 as the first reported gene that may modulate mineral fiber carcinogenesis.	('BAP1', 'Gene', (252, 256))	('modulate', 'Reg', (293, 301))	('BAP1', 'Gene', (75, 79))	('mesothelioma', 'Disease', (165, 177))	('mutations', 'Var', (80, 89))	('asbestos', 'Chemical', 'MESH:D001194', (215, 223))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('carcinogenesis', 'Disease', 'MESH:D063646', (316, 330))	('BAP1', 'Gene', '8314', (252, 256))	('BAP1', 'Gene', '8314', (75, 79))	('carcinogenesis', 'Disease', (316, 330))
35925	21874000	Furthermore, we show that BAP1 mutations are associated with a novel hereditary cancer syndrome that predisposes to mesothelioma, uveal melanoma and potentially other cancers.	('BAP1', 'Gene', (26, 30))	('mesothelioma', 'Disease', (116, 128))	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('associated', 'Reg', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancers', 'Disease', (167, 174))	('uveal melanoma', 'Phenotype', 'HP:0007716', (130, 144))	('hereditary cancer syndrome', 'Disease', (69, 95))	('uveal melanoma', 'Disease', (130, 144))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('uveal melanoma', 'Disease', 'MESH:C536494', (130, 144))	('BAP1', 'Gene', '8314', (26, 30))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (69, 95))
35930	21874000	Altogether, we observed BAP1 mutations in four uveal melanoma patients, three of whom subsequently developed mesothelioma; the fourth (L-II-18) died of metastatic uveal melanoma to the liver (Fig.	('mesothelioma', 'Disease', 'MESH:D008654', (109, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (163, 177))	('uveal melanoma', 'Disease', 'MESH:C536494', (163, 177))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('BAP1', 'Gene', (24, 28))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('mutations', 'Var', (29, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('uveal melanoma to the liver', 'Disease', (163, 190))	('uveal melanoma', 'Disease', (47, 61))	('mesothelioma', 'Disease', (109, 121))	('uveal melanoma to the liver', 'Disease', 'MESH:C536494', (163, 190))	('patients', 'Species', '9606', (62, 70))	('BAP1', 'Gene', '8314', (24, 28))
35931	21874000	Thus, our findings suggest that uveal melanoma patients with germline BAP1 mutations are at high risk of developing mesothelioma and should be closely monitored.	('mesothelioma', 'Disease', (116, 128))	('germline', 'Var', (61, 69))	('BAP1', 'Gene', '8314', (70, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (32, 46))	('patients', 'Species', '9606', (47, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (32, 46))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('BAP1', 'Gene', (70, 74))	('uveal melanoma', 'Disease', (32, 46))	('mutations', 'Var', (75, 84))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))
35937	21874000	We hypothesize that when individuals with BAP1 mutations are exposed to asbestos, mesothelioma predominates.	('mesothelioma', 'Disease', (82, 94))	('BAP1', 'Gene', '8314', (42, 46))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('asbestos', 'Chemical', 'MESH:D001194', (72, 80))	('BAP1', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))
35938	21874000	Alternatively, BAP1 mutation alone may be sufficient to cause mesothelioma.	('mesothelioma', 'Disease', (62, 74))	('mutation', 'Var', (20, 28))	('BAP1', 'Gene', '8314', (15, 19))	('cause', 'Reg', (56, 61))	('mesothelioma', 'Disease', 'MESH:D008654', (62, 74))	('BAP1', 'Gene', (15, 19))
35939	19966562	The effect of pentamidine on melanoma Pentamidine is a small molecule inhibitor of the Ca2+ binding protein S100B and disrupts the S100B-p53 protein-protein interaction; this is thought to restore wild type p53 tumour suppressor function in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('melanoma', 'Disease', (241, 249))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('p53', 'Gene', '7157', (207, 210))	('disrupts', 'NegReg', (118, 126))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('p53', 'Gene', (137, 140))	('Pentamidine', 'Var', (38, 49))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('tumour', 'Disease', 'MESH:D009369', (211, 217))	('tumour', 'Disease', (211, 217))	('protein-protein', 'Protein', (141, 156))	('p53', 'Gene', '7157', (137, 140))	('restore', 'PosReg', (189, 196))	('S100B', 'Gene', '6285', (108, 113))	('p53', 'Gene', (207, 210))	('S100B', 'Gene', '6285', (131, 136))	('melanoma', 'Disease', 'MESH:D008545', (241, 249))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('Ca2+', 'Chemical', 'MESH:D000069285', (87, 91))	('pentamidine', 'Chemical', 'MESH:D010419', (14, 25))	('binding', 'molecular_function', 'GO:0005488', ('92', '99'))	('Pentamidine', 'Chemical', 'MESH:D010419', (38, 49))	('S100B', 'Gene', (108, 113))	('S100B', 'Gene', (131, 136))
35953	19966562	p53 has long been recognized as a vital transcriptional activator of many genes involved in apoptosis and cell cycle control; stabilization and activation of this protein (by tetramerisation and modifications such as C terminus phosphorylation) halts inappropriate growth and cell cycling; a tumour suppressor function.	('p53', 'Gene', (0, 3))	('C terminus', 'Var', (217, 227))	('p53', 'Gene', '7157', (0, 3))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('phosphorylation', 'biological_process', 'GO:0016310', ('228', '243'))	('protein', 'cellular_component', 'GO:0003675', ('163', '170'))	('tumour', 'Phenotype', 'HP:0002664', (292, 298))	('tumour', 'Disease', 'MESH:D009369', (292, 298))	('cell cycle control', 'biological_process', 'GO:1901987', ('106', '124'))	('activation', 'PosReg', (144, 154))	('inappropriate growth and cell cycling', 'CPA', (251, 288))	('halts', 'NegReg', (245, 250))	('tumour', 'Disease', (292, 298))
35957	19966562	have demonstrated a direct relationship between levels of p53 and S100B protein in 6 melanoma cell lines (LOX-IM, UACC-62, SK-MEL-5, UACC-2571, C8146A, Malme-3M) with a wild type p53 genotype, where a high S100B level is directly related to a low level of p53, and a low level of S100B is directly related to a high level of p53 as measured by western blot.	('p53', 'Gene', (179, 182))	('S100B', 'Gene', '6285', (206, 211))	('p53', 'Gene', '7157', (325, 328))	('C8146A', 'Var', (144, 150))	('S100B', 'Gene', (66, 71))	('p53', 'Gene', (256, 259))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('S100B', 'Gene', (280, 285))	('p53', 'Gene', (325, 328))	('SK-MEL-5', 'CellLine', 'CVCL:0527', (123, 131))	('S100B', 'Gene', '6285', (66, 71))	('C8146A', 'Mutation', 'g.8146C>A', (144, 150))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('S100B', 'Gene', (206, 211))	('melanoma', 'Disease', (85, 93))	('S100B', 'Gene', '6285', (280, 285))	('p53', 'Gene', '7157', (58, 61))	('p53', 'Gene', '7157', (179, 182))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('p53', 'Gene', '7157', (256, 259))	('p53', 'Gene', (58, 61))
35985	19966562	Indexsum<300 corresponding to 50% inhibition across the range of concentrations tested is a useful way to compare samples, and 78% (14/18) of the skin melanoma samples exhibited an Indexsum<300 indicating strong inhibition (Fig 2).	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('skin melanoma', 'Disease', (146, 159))	('Indexsum', 'Var', (181, 189))	('skin melanoma', 'Disease', 'MESH:D008545', (146, 159))
36000	19966562	A second potential mechanism, inhibition of PRL family phosphatases, may halt cell cycle progression; PRL-1 has been shown to be required for normal cell cycle progression, and Lee et al.	('inhibition', 'Var', (30, 40))	('cell cycle', 'biological_process', 'GO:0007049', ('149', '159'))	('PRL-1', 'Gene', (102, 107))	('cell cycle', 'biological_process', 'GO:0007049', ('78', '88'))	('halt', 'NegReg', (73, 77))	('PRL-1', 'Gene', '7803', (102, 107))	('cell cycle progression', 'CPA', (78, 100))
36020	31968535	Although radiation therapy may work for many patients, the type of cancer, genetic mutations, and age of the patient may limit any significant protective effects, as well as increase the risk for the development of a second primary cancer.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('second primary', 'CPA', (217, 231))	('patient', 'Species', '9606', (109, 116))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', (232, 238))	('genetic mutations', 'Var', (75, 92))	('protective effects', 'CPA', (143, 161))	('patient', 'Species', '9606', (45, 52))	('limit', 'NegReg', (121, 126))	('increase', 'PosReg', (174, 182))	('patients', 'Species', '9606', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))
36032	31968535	Strong oncolytic activity was evident with PDT using PdT4 and 405 nm, though was inversely correlated with cell confluency.	('PdT4', 'Var', (53, 57))	('Pd', 'Chemical', 'MESH:D010165', (53, 55))	('oncolytic activity', 'CPA', (7, 25))
36035	31968535	However, metalloporphyrin Pd(T4) (10 microM) diminished viability by 58% (Figure 2A, p < 0.05) as early as 5 min pre-illumination, followed by a fluence of 5 J/cm2 from a 405 nm portable light-emitting diode LED.	('pre', 'molecular_function', 'GO:0003904', ('113', '116'))	('10', 'Var', (34, 36))	('diminished', 'NegReg', (45, 55))	('viability', 'MPA', (56, 65))	('metalloporphyrin Pd(T4)', 'Chemical', '-', (9, 32))
36049	31968535	Although minimal PDT effects were evident at 30 microM with 10 J/cm2 (Table 1), drastic morphological impairment involving 50% lysis of vasculogenic mimicry-forming cells and 90% of epithelial cells residing below the Matrigel was evident with 100 microM of PdT4 and 15 J/cm2 of 405 nm irradiance (Figure 4B and Table 1).	('Pd', 'Chemical', 'MESH:D010165', (258, 260))	('drastic morphological impairment', 'Disease', 'MESH:D009422', (80, 112))	('lysis', 'CPA', (127, 132))	('lysis', 'biological_process', 'GO:0019835', ('127', '132'))	('drastic morphological impairment', 'Disease', (80, 112))	('PdT4', 'Var', (258, 262))
36071	31968535	However, Pd(T4)-PDT demonstrated the strongest apoptotic molecular signature, changing the Bax/Bcl-2 ratio from 1.0 (control cells) to 21.5, whereby ALA-PDT exhibited a 2.7 Bax/Bcl-2 ratio (Figure 8A,B).	('Bax', 'Gene', (173, 176))	('Pd(T4)', 'Chemical', '-', (9, 15))	('Bax', 'Gene', (91, 94))	('Pd(T4)-PDT', 'Var', (9, 19))	('Bcl-2', 'Gene', (177, 182))	('changing', 'Reg', (78, 86))	('Bcl-2', 'Gene', '596', (177, 182))	('Bax', 'Gene', '581', (173, 176))	('ALA', 'Chemical', 'MESH:D000409', (149, 152))	('Bax', 'Gene', '581', (91, 94))	('Bcl-2', 'Gene', (95, 100))	('Bcl-2', 'molecular_function', 'GO:0015283', ('177', '182'))	('Bcl-2', 'Gene', '596', (95, 100))	('Bcl-2', 'molecular_function', 'GO:0015283', ('95', '100'))
36075	31968535	Amongst the different treatments in this study, Pd(T4)-PDT diminished RIP expression the most with only 18% of control cells (Figure 8A,D).	('RIP', 'Gene', (70, 73))	('Pd(T4)-PDT', 'Var', (48, 58))	('diminished', 'NegReg', (59, 69))	('RIP', 'Gene', '8737', (70, 73))	('Pd(T4)', 'Chemical', '-', (48, 54))
36077	31968535	Figure 8A,D display a drastic reduction in both c-IAP1 and c-IAP2 (ratios of 0.09 and 0.04, respectively) after Pd(T4)-PDT, whereby ALA-PDT only reduced c-IAP-1 (ratio of 0.38).	('c-IAP2', 'Gene', '330', (59, 65))	('c-IAP1', 'Gene', '329', (48, 54))	('c-IAP-1', 'Gene', (153, 160))	('c-IAP2', 'Gene', (59, 65))	('Pd(T4)', 'Chemical', '-', (112, 118))	('c-IAP-1', 'Gene', '329', (153, 160))	('reduction', 'NegReg', (30, 39))	('ALA', 'Chemical', 'MESH:D000409', (132, 135))	('c-IAP1', 'Gene', (48, 54))	('Pd(T4)-PDT', 'Var', (112, 122))
36103	31968535	When grown on Matrigel, C918 develop a sub-population of cells expressing CD271, a cancer stem cell marker.	('C918', 'Var', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CD271', 'Gene', '4804', (74, 79))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))	('CD271', 'Gene', (74, 79))
36111	31968535	Utilizing the effects confirmed within this study along with the ability of TMPyP4, the base of Pd(T4), to distort G-Quadruplex structures could induce combinatorial or synergistic effects against cancer cells.	('Pd(T4)', 'Chemical', '-', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('combinatorial', 'Interaction', (152, 165))	('TMPyP4', 'Var', (76, 82))	('cancer', 'Disease', (197, 203))	('induce', 'Reg', (145, 151))	('distort', 'Reg', (107, 114))	('synergistic', 'Interaction', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('G-Quadruplex structures', 'MPA', (115, 138))	('TMPyP4', 'Chemical', 'MESH:C021096', (76, 82))
36130	31968535	Additionally, Pd(T4)-PDT upregulated endoplasmic reticulum chaperone protein disulfide isomerase (PDI), which also facilitates MOMP via the oligomerization of BAK in replacement of Bax.	('BAK', 'Gene', (159, 162))	('protein disulfide isomerase', 'Gene', (69, 96))	('Bax', 'Gene', '581', (181, 184))	('Pd(T4)', 'Chemical', '-', (14, 20))	('MOMP', 'biological_process', 'GO:0097345', ('127', '131'))	('oligomerization', 'MPA', (140, 155))	('Pd(T4)-PDT', 'Var', (14, 24))	('upregulated', 'PosReg', (25, 36))	('Bax', 'Gene', (181, 184))	('BAK', 'Gene', '578', (159, 162))	('PDI', 'Gene', '5034', (98, 101))	('PDI', 'Gene', (98, 101))	('protein disulfide isomerase', 'molecular_function', 'GO:0003756', ('69', '96'))	('protein disulfide isomerase', 'Gene', '5034', (69, 96))	('MOMP', 'MPA', (127, 131))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('37', '58'))	('facilitates', 'PosReg', (115, 126))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))
36143	31968535	In our study, PDT upregulated Zeb-1 compared to porphyrin or light alone.	('Zeb-1', 'Gene', '6935', (30, 35))	('PDT', 'Var', (14, 17))	('upregulated', 'PosReg', (18, 29))	('porphyrin', 'Chemical', 'MESH:D011166', (48, 57))	('Zeb-1', 'Gene', (30, 35))
36146	31968535	Additionally, our findings of Pd(T4)-PDT exhibiting oncolytic activity against vascular mimicry cells supports its use in combination with other chemotherapeutic agents.	('Pd(T4)-PDT', 'Var', (30, 40))	('oncolytic activity', 'MPA', (52, 70))	('Pd(T4)', 'Chemical', '-', (30, 36))
36190	31968535	The similar oncolytic effects of Pd(T4)-PDT compared to ALA-PDT, although at shorter pre-illumination times (5 min) and lower concentrations (10 microM), suggest Pd(T4)-PDT can reduce treatment durations, including for skin disorders such as actinic keratosis and basal cell carcinoma, thereby decreasing health care costs and patient stress responses.	('actinic keratosis', 'Disease', (242, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (264, 284))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (264, 284))	('basal cell carcinoma', 'Disease', (264, 284))	('Pd(T4)', 'Chemical', '-', (33, 39))	('actinic keratosis', 'Disease', 'MESH:D055623', (242, 259))	('skin disorders', 'Disease', (219, 233))	('skin disorders', 'Disease', 'MESH:D012871', (219, 233))	('Pd(T4)', 'Chemical', '-', (162, 168))	('Pd(T4)-PDT', 'Var', (162, 172))	('treatment durations', 'CPA', (184, 203))	('skin disorders', 'Phenotype', 'HP:0000951', (219, 233))	('ALA', 'Chemical', 'MESH:D000409', (56, 59))	('patient', 'Species', '9606', (327, 334))	('reduce', 'NegReg', (177, 183))	('actinic keratosis', 'Phenotype', 'HP:0025127', (242, 259))	('pre', 'molecular_function', 'GO:0003904', ('85', '88'))
36193	30773340	A Platform of Synthetic Lethal Gene Interaction Networks Reveals that the GNAQ Uveal Melanoma Oncogene Controls the Hippo Pathway through FAK Activating mutations in GNAQ/GNA11, encoding Galphaq G-proteins, are the cancer initiating oncogenes in uveal melanoma (UM).	('Melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('Hippo Pathway', 'Pathway', (116, 129))	('mutations', 'Var', (153, 162))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('Activating', 'PosReg', (142, 152))	('cancer', 'Disease', (215, 221))	('GNA11', 'Gene', (171, 176))	('GNAQ', 'Gene', '2776', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('FAK', 'molecular_function', 'GO:0004717', ('138', '141'))	('GNAQ', 'Gene', (74, 78))	('Melanoma', 'Disease', 'MESH:D008545', (85, 93))	('melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('Galphaq', 'Gene', (187, 194))	('uveal melanoma', 'Disease', (246, 260))	('uveal melanoma', 'Disease', 'MESH:C536494', (246, 260))	('Melanoma', 'Disease', (85, 93))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('GNA11', 'Gene', '2767', (171, 176))	('GNAQ', 'Gene', '2776', (166, 170))	('uveal melanoma', 'Phenotype', 'HP:0007716', (246, 260))	('Galphaq', 'Gene', '2776', (187, 194))	('GNAQ', 'Gene', (166, 170))
36195	30773340	We show that Galphaq activates FAK through TRIO-RhoA non-canonical Galphaq-signaling, and genetic ablation or pharmacological inhibition of FAK inhibits UM growth.	('FAK', 'Enzyme', (31, 34))	('Galphaq', 'Gene', (13, 20))	('inhibits', 'NegReg', (144, 152))	('TRIO', 'Gene', (43, 47))	('Galphaq', 'Gene', '2776', (13, 20))	('TRIO', 'Gene', '7204', (43, 47))	('UM growth', 'CPA', (153, 162))	('RhoA', 'Gene', '387', (48, 52))	('FAK', 'molecular_function', 'GO:0004717', ('140', '143'))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('genetic ablation', 'Var', (90, 106))	('FAK', 'Gene', (140, 143))	('FAK', 'molecular_function', 'GO:0004717', ('31', '34'))	('Galphaq', 'Gene', (67, 74))	('Galphaq', 'Gene', '2776', (67, 74))	('RhoA', 'Gene', (48, 52))
36200	30773340	Gaq, encoded by GNAQ, activates FAK by a non-canonical signaling pathway, and in turn FAK activates YAP by a novel mechanism suppressing the Hippo kinase cascade.	('Gaq', 'Gene', (0, 3))	('FAK', 'Gene', (32, 35))	('non-canonical signaling pathway', 'Pathway', (41, 72))	('activates', 'PosReg', (90, 99))	('FAK', 'molecular_function', 'GO:0004717', ('32', '35'))	('FAK', 'Var', (86, 89))	('GNAQ', 'Gene', (16, 20))	('Gaq', 'Gene', '2776', (0, 3))	('FAK', 'molecular_function', 'GO:0004717', ('86', '89'))	('signaling pathway', 'biological_process', 'GO:0007165', ('55', '72'))	('YAP', 'Disease', (100, 103))	('activates', 'PosReg', (22, 31))	('Hippo kinase cascade', 'Pathway', (141, 161))	('GNAQ', 'Gene', '2776', (16, 20))	('suppressing', 'NegReg', (125, 136))
36204	30773340	One such cancer, uveal melanoma (UM), is characterized by a gain of function mutation in the heterotrimeric G protein, Galphaq.	('cancer', 'Disease', (9, 15))	('gain of function', 'PosReg', (60, 76))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('mutation', 'Var', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('93', '117'))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('Galphaq', 'Gene', (119, 126))	('uveal melanoma', 'Disease', (17, 31))	('Galphaq', 'Gene', '2776', (119, 126))	('uveal melanoma', 'Disease', 'MESH:C536494', (17, 31))
36205	30773340	A hotspot mutation in GNAQ or GNA11 encodes constitutively active Galphaq proteins rendering them as driver oncogenes in approximately 93% of UM.	('Galphaq', 'Gene', (66, 73))	('GNA11', 'Gene', (30, 35))	('Galphaq', 'Gene', '2776', (66, 73))	('GNAQ', 'Gene', (22, 26))	('mutation', 'Var', (10, 18))	('GNA11', 'Gene', '2767', (30, 35))	('GNAQ', 'Gene', '2776', (22, 26))
36206	30773340	Another ~4% of UM harbor activating mutations in CYSLTR2, a Galphaq-linked G protein coupled receptor (GPCR) firmly establishing UM as a Galphaq-driven malignancy.	('Galphaq', 'Gene', '2776', (137, 144))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('CYSLTR2', 'Gene', '57105', (49, 56))	('activating', 'PosReg', (25, 35))	('mutations', 'Var', (36, 45))	('malignancy', 'Disease', 'MESH:D009369', (152, 162))	('CYSLTR2', 'Gene', (49, 56))	('malignancy', 'Disease', (152, 162))	('Galphaq', 'Gene', (60, 67))	('Galphaq', 'Gene', '2776', (60, 67))	('Galphaq', 'Gene', (137, 144))
36207	30773340	Aberrant activity of G proteins and GPCRs have been frequently associated with an oncogenic state and promotion of tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('associated', 'Reg', (63, 73))	('tumor', 'Disease', (115, 120))	('oncogenic state', 'Disease', (82, 97))	('Aberrant activity', 'Var', (0, 17))	('promotion', 'PosReg', (102, 111))	('GPCRs', 'Protein', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('G proteins', 'Protein', (21, 31))
36217	30773340	Finally, we demonstrate that targeting the Galphaq-FAK- Hippo/YAP signaling axis by inhibition of FAK blocks YAP-dependent growth in UM, thereby establishing FAK as a novel viable therapeutic target for the treatment of this aggressive human malignancy.	('human', 'Species', '9606', (236, 241))	('Galphaq', 'Gene', (43, 50))	('Galphaq', 'Gene', '2776', (43, 50))	('FAK', 'molecular_function', 'GO:0004717', ('158', '161'))	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('YAP-dependent growth in UM', 'MPA', (109, 135))	('blocks', 'NegReg', (102, 108))	('FAK', 'Gene', (98, 101))	('FAK', 'molecular_function', 'GO:0004717', ('98', '101'))	('malignancy', 'Disease', 'MESH:D009369', (242, 252))	('inhibition', 'Var', (84, 94))	('malignancy', 'Disease', (242, 252))	('FAK', 'molecular_function', 'GO:0004717', ('51', '54'))
36219	30773340	We denote a sample with mutations or gene amplification of GNAQ, GNA11 and CYSLTR2 as Galphaq+, while a sample with the absence of these GNAQ, GNA11 or CYSLTR2 gene alterations as Galphaq-.	('GNAQ', 'Gene', (137, 141))	('Galphaq', 'Gene', (86, 93))	('Galphaq', 'Gene', '2776', (86, 93))	('CYSLTR2', 'Gene', '57105', (152, 159))	('GNAQ', 'Gene', '2776', (137, 141))	('CYSLTR2', 'Gene', '57105', (75, 82))	('GNA11', 'Gene', '2767', (143, 148))	('mutations', 'Var', (24, 33))	('GNA11', 'Gene', '2767', (65, 70))	('GNAQ', 'Gene', (59, 63))	('GNA11', 'Gene', (143, 148))	('CYSLTR2', 'Gene', (152, 159))	('GNA11', 'Gene', (65, 70))	('CYSLTR2', 'Gene', (75, 82))	('gene amplification', 'Var', (37, 55))	('Galphaq', 'Gene', (180, 187))	('Galphaq', 'Gene', '2776', (180, 187))	('GNAQ', 'Gene', '2776', (59, 63))
36232	30773340	PTK2 itself is not mutated in UM, a disease that is characterized by mutations, primarily mutually-exclusive activating mutations in GNAQ, GNA11 and CYSLTR2, and mutually exclusive mutations in genes encoding two RNA splicing factors, EIF1AX and SF3B1, or a deubiquitinase BAP1.	('GNA11', 'Gene', '2767', (139, 144))	('RNA', 'cellular_component', 'GO:0005562', ('213', '216'))	('GNAQ', 'Gene', (133, 137))	('RNA splicing', 'biological_process', 'GO:0008380', ('213', '225'))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('258', '272'))	('PTK2', 'Gene', (0, 4))	('mutations', 'Var', (120, 129))	('CYSLTR2', 'Gene', (149, 156))	('PTK2', 'Gene', '5747', (0, 4))	('activating', 'PosReg', (109, 119))	('SF3B1', 'Gene', (246, 251))	('GNA11', 'Gene', (139, 144))	('EIF1AX', 'Gene', (235, 241))	('BAP1', 'Gene', '8314', (273, 277))	('SF3B1', 'Gene', '23451', (246, 251))	('EIF1AX', 'Gene', '1964', (235, 241))	('CYSLTR2', 'Gene', '57105', (149, 156))	('GNAQ', 'Gene', '2776', (133, 137))	('BAP1', 'Gene', (273, 277))
36235	30773340	In total 56% of UM patients have alterations in PTK2 resulting in gene amplification or mRNA upregulation (Fig.	('upregulation', 'PosReg', (93, 105))	('PTK2', 'Gene', '5747', (48, 52))	('patients', 'Species', '9606', (19, 27))	('mRNA', 'MPA', (88, 92))	('alterations', 'Var', (33, 44))	('gene amplification', 'MPA', (66, 84))	('PTK2', 'Gene', (48, 52))
36236	30773340	Interestingly, we found that expression of FAK is significantly correlated with reduced overall patient survival (Fig.	('expression', 'Var', (29, 39))	('FAK', 'Gene', (43, 46))	('patient', 'Species', '9606', (96, 103))	('reduced', 'NegReg', (80, 87))	('FAK', 'molecular_function', 'GO:0004717', ('43', '46'))	('expression', 'Species', '29278', (29, 39))
36238	30773340	We next tested the sensitivity of five representative UM cell lines, 92.1, OMM1.3, OMM1.5, Mel270, and Mel202, all of which harbor GNAQ mutations, to FAK inhibition using VS-4718, a new generation orally-bioavailable FAK inhibitor (FAKi), using an SKCM cell line SK-MEK-28 (BRAF mutant) as a control (Fig.	('tested', 'Reg', (8, 14))	('GNAQ', 'Gene', (131, 135))	('MEK', 'Gene', '5609', (266, 269))	('BRAF', 'Gene', (274, 278))	('BRAF', 'Gene', '673', (274, 278))	('FAK', 'molecular_function', 'GO:0004717', ('150', '153'))	('GNAQ', 'Gene', '2776', (131, 135))	('mutations', 'Var', (136, 145))	('MEK', 'Gene', (266, 269))	('FAK', 'molecular_function', 'GO:0004717', ('217', '220'))
36240	30773340	Instead, the SKCM cell line SK-MEK-28 (BRAF) was largely insensitive to FAKi, with an EC50>10muM for VS-4718 (Fig.	('VS-4718', 'Var', (101, 108))	('BRAF', 'Gene', '673', (39, 43))	('MEK', 'Gene', (31, 34))	('MEK', 'Gene', '5609', (31, 34))	('BRAF', 'Gene', (39, 43))	('EC50', 'MPA', (86, 90))
36241	30773340	siRNA knockdown of PTK2 reduced cell viability in two representative UM cells nearly as potently as GNAQ knock down (Fig.	('GNAQ', 'Gene', '2776', (100, 104))	('PTK2', 'Gene', (19, 23))	('cell viability in', 'CPA', (32, 49))	('reduced', 'NegReg', (24, 31))	('PTK2', 'Gene', '5747', (19, 23))	('GNAQ', 'Gene', (100, 104))	('knockdown', 'Var', (6, 15))
36242	30773340	GNAQ knock down reduced the accumulation of FAK in its active, tyrosine 397 phosphorylated form (pY397-FAK) (Fig.	('tyrosine', 'Chemical', 'MESH:D014443', (63, 71))	('GNAQ', 'Gene', '2776', (0, 4))	('reduced', 'NegReg', (16, 23))	('FAK', 'molecular_function', 'GO:0004717', ('103', '106'))	('accumulation', 'MPA', (28, 40))	('knock down', 'Var', (5, 15))	('GNAQ', 'Gene', (0, 4))	('FAK', 'molecular_function', 'GO:0004717', ('44', '47'))
36243	30773340	1F and S1G), and resulted in UM apoptosis as judged by the accumulation of cleaved PARP (Fig.	('accumulation', 'PosReg', (59, 71))	('apoptosis', 'CPA', (32, 41))	('apoptosis', 'biological_process', 'GO:0097194', ('32', '41'))	('apoptosis', 'biological_process', 'GO:0006915', ('32', '41'))	('PARP', 'Gene', '1302', (83, 87))	('PARP', 'Gene', (83, 87))	('S1G', 'Var', (7, 10))
36244	30773340	We further assessed whether inhibition of FAK impacted the oncogenic potential of UM cells by measuring their clonogenic capacity in semisolid media, an assay often used to assess cancer stem cell properties.	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('oncogenic potential', 'CPA', (59, 78))	('inhibition', 'Var', (28, 38))	('impacted', 'Reg', (46, 54))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('FAK', 'Gene', (42, 45))	('clonogenic capacity', 'CPA', (110, 129))	('cancer', 'Disease', (180, 186))	('FAK', 'molecular_function', 'GO:0004717', ('42', '45'))
36248	30773340	Immunoblotting against total and phosphorylated forms of FAK revealed that phosphorylation of FAK at Y397 was significantly increased after transfection with GalphaqQL (Fig.	('at Y397', 'Var', (98, 105))	('GalphaqQL', 'Chemical', '-', (158, 167))	('increased', 'PosReg', (124, 133))	('FAK', 'molecular_function', 'GO:0004717', ('57', '60'))	('FAK', 'molecular_function', 'GO:0004717', ('94', '97'))	('phosphorylation', 'biological_process', 'GO:0016310', ('75', '90'))	('phosphorylation', 'MPA', (75, 90))	('FAK', 'Protein', (94, 97))
36251	30773340	In UM cells, GNAQ siRNA knockdown or inhibition by FR900359 (FR), a potent Galphaq inhibitor, diminished FAK and ERK activation (Fig.	('ERK', 'molecular_function', 'GO:0004707', ('113', '116'))	('GNAQ', 'Gene', (13, 17))	('FAK', 'molecular_function', 'GO:0004717', ('105', '108'))	('ERK', 'Gene', '5594', (113, 116))	('ERK', 'Gene', (113, 116))	('FR900359', 'Var', (51, 59))	('Galphaq', 'Gene', (75, 82))	('diminished FAK', 'Phenotype', 'HP:0032341', (94, 108))	('Galphaq', 'Gene', '2776', (75, 82))	('diminished', 'NegReg', (94, 104))	('knockdown', 'Var', (24, 33))	('GNAQ', 'Gene', '2776', (13, 17))	('FAK', 'MPA', (105, 108))
36256	30773340	Similarly, inhibition of PKC blocked ERK activation but not FAK in UM cells (Fig.	('PKC', 'Gene', (25, 28))	('PKC', 'Gene', '112476', (25, 28))	('PKC', 'molecular_function', 'GO:0004697', ('25', '28'))	('ERK', 'Gene', '5594', (37, 40))	('ERK', 'Gene', (37, 40))	('FAK', 'molecular_function', 'GO:0004717', ('60', '63'))	('inhibition', 'Var', (11, 21))	('ERK', 'molecular_function', 'GO:0004707', ('37', '40'))	('activation', 'PosReg', (41, 51))
36260	30773340	In line with these findings, knockdown of RAC1 had no impact on FAK activation (Fig.	('RAC1', 'Gene', (42, 46))	('FAK activation', 'MPA', (64, 78))	('FAK', 'molecular_function', 'GO:0004717', ('64', '67'))	('knockdown', 'Var', (29, 38))	('RAC1', 'Gene', '5879', (42, 46))
36268	30773340	To validate these findings, we performed qPCR for the classical YAP-target genes CTGF and CYR61 in UM cells and found significant reduction in the presence of FAKi and knockdown of FAK or GNAQ (Fig.	('CYR61', 'Gene', (90, 95))	('GNAQ', 'Gene', (188, 192))	('CYR61', 'Gene', '3491', (90, 95))	('FAK', 'Gene', (181, 184))	('reduction', 'NegReg', (130, 139))	('CTGF', 'Gene', '1490', (81, 85))	('CTGF', 'Gene', (81, 85))	('FAK', 'molecular_function', 'GO:0004717', ('181', '184'))	('knockdown', 'Var', (168, 177))	('GNAQ', 'Gene', '2776', (188, 192))	('FAKi', 'Gene', (159, 163))
36269	30773340	We further confirmed the functional impact of FAKi and FAK knock down on YAP by performing YAP/TAZ luciferase reporter assays, and using GNAQ inhibition and knock down as a control (Fig.	('knock down', 'Var', (59, 69))	('TAZ', 'Gene', (95, 98))	('FAK', 'molecular_function', 'GO:0004717', ('55', '58'))	('GNAQ', 'Gene', (137, 141))	('GNAQ', 'Gene', '2776', (137, 141))	('TAZ', 'Gene', '6901', (95, 98))
36270	30773340	Interestingly, inhibition of Galphaq or FAK or siRNA-mediated FAK knockdown repressed YAP phosphorylation on tyrosine 357 (Y357), a residue that is associated with YAP activation, and increased phosphorylation on serine 127 (S127), which is one of the main repressive targets of Hippo signaling (Fig.	('FAK', 'molecular_function', 'GO:0004717', ('62', '65'))	('phosphorylation', 'MPA', (194, 209))	('serine', 'Chemical', 'MESH:D012694', (213, 219))	('repressed', 'NegReg', (76, 85))	('phosphorylation', 'biological_process', 'GO:0016310', ('90', '105'))	('FAK', 'molecular_function', 'GO:0004717', ('40', '43'))	('YAP', 'Protein', (86, 89))	('tyrosine', 'Chemical', 'MESH:D014443', (109, 117))	('increased', 'PosReg', (184, 193))	('Galphaq', 'Gene', '2776', (29, 36))	('FAK', 'Gene', (62, 65))	('Hippo signaling', 'biological_process', 'GO:0035329', ('279', '294'))	('phosphorylation', 'biological_process', 'GO:0016310', ('194', '209'))	('Galphaq', 'Gene', (29, 36))	('knockdown', 'Var', (66, 75))	('S127', 'Var', (225, 229))	('inhibition', 'Var', (15, 25))
36272	30773340	Inhibition of SRC in UM cells had no impact on YAP activity, measured by YAP/TAZ luciferase reporter assay, and failed to promote changes in YAP phosphorylation status (Fig.	('YAP activity', 'MPA', (47, 59))	('TAZ', 'Gene', '6901', (77, 80))	('TAZ', 'Gene', (77, 80))	('phosphorylation', 'biological_process', 'GO:0016310', ('145', '160'))	('Inhibition', 'Var', (0, 10))	('SRC', 'Gene', '6714', (14, 17))	('SRC', 'Gene', (14, 17))
36282	30773340	Consistent with our findings, scanning through large phosphoprotein databases (PhosphoSitePlus  PTM Resource, Cell signaling technology), we found that Y26 on MOB1A/B is conserved among mammals, and that this particular residue is phosphorylated in numerous high-throughput phosphoproteomic datasets (n=161) (Fig.	('Y26', 'Var', (152, 155))	('PTM', 'biological_process', 'GO:0043687', ('96', '99'))	('MOB1A/B', 'Gene', (159, 166))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('MOB1A/B', 'Gene', '55233', (159, 166))
36283	30773340	Firstly, we found that an antibody raised anti-pY26 MOB1 recognized MOB1 only when co-transfected with FAK, which was abolished upon mutation of Y26 residue on MOB1 to Y26F (Fig.	('antibody', 'cellular_component', 'GO:0019815', ('26', '34'))	('mutation', 'Var', (133, 141))	('antibody', 'cellular_component', 'GO:0019814', ('26', '34'))	('antibody', 'molecular_function', 'GO:0003823', ('26', '34'))	('FAK', 'molecular_function', 'GO:0004717', ('103', '106'))	('MOB1', 'Gene', (160, 164))	('Y26F', 'Mutation', 'p.Y26F', (168, 172))	('antibody', 'cellular_component', 'GO:0042571', ('26', '34'))	('Y26F', 'Var', (168, 172))
36284	30773340	Strikingly, mutation of Y26 residue on MOB1 to Y26F rescued the dissociation with LATS1 (Fig.	('Y26F', 'Mutation', 'p.Y26F', (47, 51))	('LATS1', 'Gene', (82, 87))	('LATS1', 'Gene', '9113', (82, 87))	('Y26F', 'Var', (47, 51))	('mutation', 'Var', (12, 20))	('dissociation', 'MPA', (64, 76))	('MOB1', 'Gene', (39, 43))	('rescued', 'PosReg', (52, 59))
36285	30773340	We observed an increase of pS127-YAP, p909-LATS1, p1079-LATS1, a dose-dependent decrease in pY26 MOB1, and in line with our previous data, enhanced MOB1/LATS interaction (Fig.	('LATS1', 'Gene', (43, 48))	('pS127-YAP', 'Var', (27, 36))	('LATS1', 'Gene', '9113', (43, 48))	('increase', 'PosReg', (15, 23))	('MOB1/LATS', 'CPA', (148, 157))	('pY26 MOB1', 'MPA', (92, 101))	('enhanced', 'PosReg', (139, 147))	('LATS1', 'Gene', (56, 61))	('LATS1', 'Gene', '9113', (56, 61))	('decrease', 'NegReg', (80, 88))
36286	30773340	In contrast, the MOB1-Y26F mutant demonstrated constitutively strong interaction with LATS independent of FAKi treatment (Fig.	('MOB1-Y26F', 'Var', (17, 26))	('interaction', 'Interaction', (69, 80))	('Y26F', 'Mutation', 'p.Y26F', (22, 26))
36287	30773340	S4B and C) and remarkably, expression of MOB1-Y26F in UM cells phenocopied FAKi treatment as it drastically diminished cell proliferation that could not be further reduced by FAKi (Fig.	('cell proliferation', 'CPA', (119, 137))	('expression', 'Species', '29278', (27, 37))	('cell proliferation', 'biological_process', 'GO:0008283', ('119', '137'))	('Y26F', 'Mutation', 'p.Y26F', (46, 50))	('expression', 'Var', (27, 37))	('diminished', 'NegReg', (108, 118))	('MOB1-Y26F', 'Var', (41, 50))	('FAKi', 'Disease', (75, 79))
36289	30773340	5A), nor a change in phosphorylation of MOB1 at T35, the main target of MST1 on MOB1 with FAKi or knockdown of FAK (Fig.	('FAK', 'molecular_function', 'GO:0004717', ('111', '114'))	('MST1', 'Gene', '4485', (72, 76))	('knockdown', 'Var', (98, 107))	('phosphorylation', 'MPA', (21, 36))	('MST1', 'Gene', (72, 76))	('phosphorylation', 'biological_process', 'GO:0016310', ('21', '36'))	('FAK', 'Gene', (111, 114))
36291	30773340	Furthermore, LATS1/2 knockdown was sufficient to rescue from the growth inhibition by FAKi in UM cells (Fig.	('knockdown', 'Var', (21, 30))	('growth inhibition', 'MPA', (65, 82))	('LATS1/2', 'Gene', '9113;26524', (13, 20))	('LATS1/2', 'Gene', (13, 20))
36296	30773340	We observed that FAK KO cells developed only very small tumors, clearly smaller than control cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('FAK', 'Var', (17, 20))	('smaller', 'NegReg', (72, 79))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('FAK', 'molecular_function', 'GO:0004717', ('17', '20'))
36298	30773340	We found that FAKi reduces both UM tumor size and cell proliferation in two different UM tumor models, the latter clearly visible by Ki67 staining that was nearly absent in VS-4718 treated mice (Fig.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('mice', 'Species', '10090', (189, 193))	('Ki67', 'Gene', (133, 137))	('Ki67', 'Gene', '17345', (133, 137))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('FAKi', 'Var', (14, 18))	('reduces', 'NegReg', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('cell proliferation', 'CPA', (50, 68))
36304	30773340	We thus hypothesized that focusing on a cancer type specifically driven by few activating (Galphaq) mutations may serve as a good testbed for studying such an approach, harnessing a novel SL-based integrated bioinformatics analysis to uncover novel oncogenic signaling mechanisms controlled by Galphaq and target them.	('signaling', 'biological_process', 'GO:0023052', ('259', '268'))	('mutations', 'Var', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('Galphaq', 'Gene', (91, 98))	('Galphaq', 'Gene', '2776', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Galphaq', 'Gene', (294, 301))	('Galphaq', 'Gene', '2776', (294, 301))
36306	30773340	We provide evidence that FAK destabilizes interactions between key core Hippo pathway members thereby activating YAP in an MST1 (Hippo)-independent manner.	('FAK', 'Var', (25, 28))	('core', 'cellular_component', 'GO:0019013', ('67', '71'))	('interactions', 'Interaction', (42, 54))	('MST1', 'Gene', '4485', (123, 127))	('destabilizes', 'NegReg', (29, 41))	('FAK', 'molecular_function', 'GO:0004717', ('25', '28'))	('YAP', 'MPA', (113, 116))	('MST1', 'Gene', (123, 127))	('activating', 'Reg', (102, 112))
36309	30773340	The activation of these second messenger systems and their direct targets, including ion channels and regulated kinases, such as PKC, CAMKs and MAPK are responsible for most of the rapid physiological responses elicited by GPCRs (; Sassone-Corsi).	('MAPK', 'molecular_function', 'GO:0004707', ('144', '148'))	('GPCRs', 'Var', (223, 228))	('PKC', 'molecular_function', 'GO:0004697', ('129', '132'))	('activation', 'PosReg', (4, 14))	('PKC', 'Gene', (129, 132))	('ion channels', 'molecular_function', 'GO:0022831', ('85', '97'))	('PKC', 'Gene', '112476', (129, 132))
36315	30773340	Unsurprisingly, dysregulation of the Hippo pathway is seen frequently in cancer; however, core components are rarely mutated.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('Hippo pathway', 'Pathway', (37, 50))	('core', 'cellular_component', 'GO:0019013', ('90', '94'))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('dysregulation', 'Var', (16, 29))
36316	30773340	Interestingly, inhibition of PLCbeta does not impact the activation of YAP after Galphaq stimulation.	('YAP', 'MPA', (71, 74))	('PLC', 'Gene', '3339', (29, 32))	('Galphaq', 'Gene', '2776', (81, 88))	('PLC', 'Gene', (29, 32))	('inhibition', 'Var', (15, 25))	('Galphaq', 'Gene', (81, 88))
36321	30773340	We found that FAK knock down and pharmacological inhibition is sufficient to reduce UM cell proliferation, and if prolonged, to trigger apoptotic cell death.	('knock down', 'Var', (18, 28))	('reduce', 'NegReg', (77, 83))	('cell proliferation', 'biological_process', 'GO:0008283', ('87', '105'))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('136', '156'))	('death', 'Disease', 'MESH:D003643', (151, 156))	('FAK', 'molecular_function', 'GO:0004717', ('14', '17'))	('death', 'Disease', (151, 156))	('FAK', 'Gene', (14, 17))	('UM cell proliferation', 'CPA', (84, 105))	('trigger', 'Reg', (128, 135))
36323	30773340	We hypothesized that as compared to other cancer types with FAK gene upregulation, the compounding impact of FAK copy number gain and gene upregulation and Galphaq-driven FAK activity in UM, creates a unique cellular state which may be highly dependent on the activity of FAK and therefore highly sensitive to FAK inhibition.	('FAK', 'molecular_function', 'GO:0004717', ('272', '275'))	('FAK', 'molecular_function', 'GO:0004717', ('109', '112'))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('FAK', 'molecular_function', 'GO:0004717', ('310', '313'))	('copy number', 'Var', (113, 124))	('upregulation', 'PosReg', (139, 151))	('gain', 'PosReg', (125, 129))	('FAK', 'Gene', (109, 112))	('FAK', 'molecular_function', 'GO:0004717', ('171', '174'))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('FAK', 'molecular_function', 'GO:0004717', ('60', '63'))	('Galphaq', 'Gene', (156, 163))	('Galphaq', 'Gene', '2776', (156, 163))
36326	30773340	In the case of YAP phosphorylation, these observations extend prior studies indicating the role of JAK2 and SRC tyrosine kinases in Y357 phosphorylation.	('phosphorylation', 'biological_process', 'GO:0016310', ('19', '34'))	('JAK', 'molecular_function', 'GO:0004713', ('99', '102'))	('JAK2', 'Gene', '3717', (99, 103))	('Y357', 'Var', (132, 136))	('JAK2', 'Gene', (99, 103))	('tyrosine', 'Chemical', 'MESH:D014443', (112, 120))	('SRC', 'Gene', (108, 111))	('phosphorylation', 'biological_process', 'GO:0016310', ('137', '152'))	('SRC', 'Gene', '6714', (108, 111))
36327	30773340	However, downstream from FAK, we observed both tyrosine-phosphorylated YAP and a decrease in pS127 YAP, the latter a direct target of the Hippo signaling pathway.	('decrease', 'NegReg', (81, 89))	('tyrosine-phosphorylated', 'Var', (47, 70))	('FAK', 'molecular_function', 'GO:0004717', ('25', '28'))	('pS127', 'Var', (93, 98))	('tyrosine', 'Chemical', 'MESH:D014443', (47, 55))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('138', '161'))
36328	30773340	Our interrogation of these complexes in response to FAK activation led to the finding that FAK phosphorylates MOB1 on Y26, resulting in the disassembly of the MOB1/LATS complex and disruption of the Hippo pathway downstream from MST1, effectively rewiring the cellular forces in control of YAP activity, and that mutation of this tyrosine residue is sufficient to abolish the effect of FAK.	('abolish', 'NegReg', (364, 371))	('tyrosine', 'Chemical', 'MESH:D014443', (330, 338))	('FAK', 'molecular_function', 'GO:0004717', ('91', '94'))	('MST1', 'Gene', '4485', (229, 233))	('FAK', 'molecular_function', 'GO:0004717', ('52', '55'))	('FAK', 'molecular_function', 'GO:0004717', ('386', '389'))	('MST1', 'Gene', (229, 233))	('disassembly', 'MPA', (140, 151))	('mutation', 'Var', (313, 321))	('Hippo pathway', 'Pathway', (199, 212))	('disruption', 'NegReg', (181, 191))	('FAK', 'Var', (91, 94))
36329	30773340	Whereas further work may be required to establish the structural basis for this inhibition, as well as alternative FAK-driven pathways in mechanotransduction and development, our findings support that disruption of the MOB1/LATS signaling complex by FAK is a key regulatory step resulting in YAP activation by Galphaq.	('disruption', 'Var', (201, 211))	('FAK', 'molecular_function', 'GO:0004717', ('115', '118'))	('YAP', 'Disease', (292, 295))	('Galphaq', 'Gene', (310, 317))	('signaling', 'biological_process', 'GO:0023052', ('229', '238'))	('Galphaq', 'Gene', '2776', (310, 317))	('FAK', 'molecular_function', 'GO:0004717', ('250', '253'))	('activation', 'PosReg', (296, 306))
36338	30773340	Plasmids pCMV-myc-MST1 (Addgene #8847, originally from Joseph Avruch's lab), pCMV2-FLAG-SAV1 (Addgene #18970, originally from Marius Sudol' lab), pcDNA3-HA-MOB1 (Addgene #32835, originally from Kunliang Guan's lab), p2xFLAG-CMV2-LATS1 (Addgene #18971, originally from Marius Sudol's lab) and 8xGTIIC-luciferase (Addgene #34615, originally from Stefano Piccolo's Lab).	('LATS1', 'Gene', (229, 234))	('SAV1', 'Gene', '60485', (88, 92))	('MST1', 'Gene', (18, 22))	('SAV1', 'Gene', (88, 92))	('LATS1', 'Gene', '9113', (229, 234))	('myc', 'Gene', (14, 17))	('Addgene', 'Var', (162, 169))	("Joseph Avruch's lab", 'Disease', (55, 74))	("Joseph Avruch's lab", 'Disease', 'MESH:D017827', (55, 74))	('myc', 'Gene', '4609', (14, 17))	('MST1', 'Gene', '4485', (18, 22))
36342	30773340	We denoted a tumor sample as Galphaq+ if any of the Galphaq-family genes (GNAQ, GNA11 and CYSLTR2) are either mutated or amplified in the given sample (amplification, if the Gistic score is greater than 0.35), and as Galphaq-if the sample lacks GNAQ, GNA11 and CYSLTR2 genes mutation and amplification.	('tumor', 'Disease', (13, 18))	('Galphaq', 'Gene', '2776', (217, 224))	('mutated', 'Var', (110, 117))	('CYSLTR2', 'Gene', (261, 268))	('Galphaq', 'Gene', '2776', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('amplified', 'Var', (121, 130))	('CYSLTR2', 'Gene', '57105', (90, 97))	('GNA11', 'Gene', (251, 256))	('GNAQ', 'Gene', '2776', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('GNAQ', 'Gene', (74, 78))	('GNA11', 'Gene', '2767', (80, 85))	('CYSLTR2', 'Gene', (90, 97))	('Galphaq', 'Gene', (29, 36))	('CYSLTR2', 'Gene', '57105', (261, 268))	('Galphaq', 'Gene', (217, 224))	('Galphaq', 'Gene', (52, 59))	('GNAQ', 'Gene', '2776', (245, 249))	('GNA11', 'Gene', '2767', (251, 256))	('Galphaq', 'Gene', '2776', (29, 36))	('GNA11', 'Gene', (80, 85))	('GNAQ', 'Gene', (245, 249))
36346	30773340	Second, we further selected the genes whose inactivation leads to better patient survival in UM, thus potential target of a therapy.	('patient survival', 'CPA', (73, 89))	('inactivation', 'Var', (44, 56))	('patient', 'Species', '9606', (73, 80))	('better', 'PosReg', (66, 72))
36348	30773340	The inactivation of 293 genes (out of 1,146 genes that passed the previous screen) show significant association with improved patient survival.	('inactivation', 'Var', (4, 16))	('patient', 'Species', '9606', (126, 133))	('improved', 'PosReg', (117, 125))	('patient survival', 'CPA', (126, 142))
36349	30773340	Third, we used gene essentiality and drug response screens in a wide panel of cancer cell lines to identify the genes whose knockdown/inhibition specifically reduces Galphaq+ cell viability.	('reduces', 'NegReg', (158, 165))	('knockdown/inhibition', 'Var', (124, 144))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('Galphaq', 'Gene', (166, 173))	('Galphaq', 'Gene', '2776', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
36369	30773340	The following antibodies were used for immunohistochemistry anti-Ki67 (DAKO) and anti-YAP (CST).	('Ki67', 'Gene', '17345', (65, 69))	('Ki67', 'Gene', (65, 69))	('CST', 'Gene', '106478911', (91, 94))	('CST', 'Gene', (91, 94))	('anti-YAP', 'Var', (81, 89))
36389	30073324	We also calculated the metastatic rate using an updated dataset of uveal melanoma patients with known mutations in BAP1, SF3B1 and EIF1AX provided by the Rotterdam Ocular Melanoma Study Group.	('Melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('EIF1AX', 'Gene', '1964', (131, 137))	('EIF1AX', 'Gene', (131, 137))	('Ocular Melanoma', 'Phenotype', 'HP:0007716', (164, 179))	('Rotterdam Ocular Melanoma', 'Disease', 'MESH:D008545', (154, 179))	('BAP1', 'Gene', '8314', (115, 119))	('patients', 'Species', '9606', (82, 90))	('uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('uveal melanoma', 'Disease', (67, 81))	('uveal melanoma', 'Disease', 'MESH:C536494', (67, 81))	('mutations', 'Var', (102, 111))	('BAP1', 'Gene', (115, 119))	('SF3B1', 'Gene', (121, 126))	('Rotterdam Ocular Melanoma', 'Disease', (154, 179))	('SF3B1', 'Gene', '23451', (121, 126))
36392	30073324	EIF1AX mutations were not exclusive of other mutations as two cases with EIF1AX mutations and metastasis also had BAP1 mutations.	('EIF1AX', 'Gene', '1964', (73, 79))	('EIF1AX', 'Gene', (73, 79))	('mutations', 'Var', (80, 89))	('BAP1', 'Gene', '8314', (114, 118))	('BAP1', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))
36393	30073324	None of the tumors with only an EIF1AX mutation metastasized.	('mutation', 'Var', (39, 47))	('EIF1AX', 'Gene', (32, 38))	('EIF1AX', 'Gene', '1964', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
36394	30073324	After plotting the yearly metastatic rate versus time after treatment, we observed a small peak at 1 year and a large peak at 3.5 years after treatment for BAP1 mutations, with peaks between 2 and 3 years and at 7 years for SF3B1 mutations.	('BAP1', 'Gene', '8314', (156, 160))	('mutations', 'Var', (230, 239))	('SF3B1', 'Gene', (224, 229))	('mutations', 'Var', (161, 170))	('BAP1', 'Gene', (156, 160))	('SF3B1', 'Gene', '23451', (224, 229))
36419	30073324	The Rotterdam Ocular Melanoma Study Group provided a large dataset of uveal melanoma patients with mutation analysis for BAP1, SF3B1 and EIF1AX.	('Rotterdam Ocular Melanoma', 'Disease', (4, 29))	('Melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('BAP1', 'Gene', '8314', (121, 125))	('uveal melanoma', 'Disease', (70, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('SF3B1', 'Gene', (127, 132))	('Rotterdam Ocular Melanoma', 'Disease', 'MESH:D008545', (4, 29))	('Ocular Melanoma', 'Phenotype', 'HP:0007716', (14, 29))	('BAP1', 'Gene', (121, 125))	('patients', 'Species', '9606', (85, 93))	('mutation analysis', 'Var', (99, 116))	('EIF1AX', 'Gene', (137, 143))	('EIF1AX', 'Gene', '1964', (137, 143))	('SF3B1', 'Gene', '23451', (127, 132))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
36428	30073324	The Rotterdam Ocular Melanoma Study Group investigated the mutation status for BAP1, SF3B1 and EIF1AX in uveal melanoma and compared this with survival.	('Rotterdam Ocular Melanoma', 'Disease', (4, 29))	('Melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('BAP1', 'Gene', '8314', (79, 83))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('SF3B1', 'Gene', (85, 90))	('Rotterdam Ocular Melanoma', 'Disease', 'MESH:D008545', (4, 29))	('EIF1AX', 'Gene', (95, 101))	('Ocular Melanoma', 'Phenotype', 'HP:0007716', (14, 29))	('BAP1', 'Gene', (79, 83))	('EIF1AX', 'Gene', '1964', (95, 101))	('mutation', 'Var', (59, 67))	('uveal melanoma', 'Disease', (105, 119))	('SF3B1', 'Gene', '23451', (85, 90))	('uveal melanoma', 'Disease', 'MESH:C536494', (105, 119))	('uveal melanoma', 'Phenotype', 'HP:0007716', (105, 119))
36429	30073324	In that study, there were 255 subjects, of which 162 had BAP1 mutations, 43 had SF3B1 mutations, 21 had EIF1AX mutations and 29 had no mutation.	('EIF1AX', 'Gene', (104, 110))	('mutations', 'Var', (86, 95))	('SF3B1', 'Gene', '23451', (80, 85))	('BAP1', 'Gene', '8314', (57, 61))	('SF3B1', 'Gene', (80, 85))	('BAP1', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('EIF1AX', 'Gene', '1964', (104, 110))
36433	30073324	Ninety-one subjects harbored BAP1 mutations, 31 had GNAQ mutations, 31 had GNA11 mutations, 2 had EIF1AX mutations and 12 had SF3B1 mutations.	('SF3B1', 'Gene', (126, 131))	('GNAQ', 'Gene', '2776', (52, 56))	('GNA11', 'Gene', '2767', (75, 80))	('GNA11', 'Gene', (75, 80))	('BAP1', 'Gene', '8314', (29, 33))	('SF3B1', 'Gene', '23451', (126, 131))	('EIF1AX', 'Gene', (98, 104))	('EIF1AX', 'Gene', '1964', (98, 104))	('GNAQ', 'Gene', (52, 56))	('BAP1', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))
36434	30073324	Two patients with metastatic uveal melanoma and mutated EIF1AX were excluded because they harbored a BAP1 mutation.	('mutated', 'Var', (48, 55))	('BAP1', 'Gene', '8314', (101, 105))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('mutation', 'Var', (106, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('harbored', 'Reg', (90, 98))	('BAP1', 'Gene', (101, 105))	('patients', 'Species', '9606', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('EIF1AX', 'Gene', '1964', (56, 62))	('EIF1AX', 'Gene', (56, 62))
36436	30073324	Twenty-five patients with mutated GNAQ harbored BAP1 mutations, and 5 with GNAQ mutations had SF3B1 mutations.	('SF3B1', 'Gene', '23451', (94, 99))	('patients', 'Species', '9606', (12, 20))	('BAP1', 'Gene', '8314', (48, 52))	('GNAQ', 'Gene', (75, 79))	('BAP1', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('mutated', 'Var', (26, 33))	('GNAQ', 'Gene', (34, 38))	('SF3B1', 'Gene', (94, 99))	('GNAQ', 'Gene', '2776', (75, 79))	('GNAQ', 'Gene', '2776', (34, 38))
36437	30073324	24 of subjects with GNA11 mutations harbored BAP1 mutations and 4 of them had SF3B1 mutations.	('BAP1', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('SF3B1', 'Gene', '23451', (78, 83))	('GNA11', 'Gene', (20, 25))	('mutations', 'Var', (26, 35))	('GNA11', 'Gene', '2767', (20, 25))	('harbored', 'Reg', (36, 44))	('BAP1', 'Gene', '8314', (45, 49))	('SF3B1', 'Gene', (78, 83))
36438	30073324	After plotting yearly metastatic rate against the time after treatment for the different mutations, we observed a small peak in metastases at 1 year after treatment and a large peak at 3.5 years for BAP1 mutations, with an early peak between 2 and 3 years and a late peak at 7 years for SF3B1 mutations (Figure 1B).	('metastases', 'Disease', (128, 138))	('BAP1', 'Gene', (199, 203))	('SF3B1', 'Gene', '23451', (287, 292))	('mutations', 'Var', (293, 302))	('mutations', 'Var', (204, 213))	('metastases', 'Disease', 'MESH:D009362', (128, 138))	('BAP1', 'Gene', '8314', (199, 203))	('SF3B1', 'Gene', (287, 292))
36439	30073324	There was a lack of metastases in patients with tumors that harbored EIF1AX mutations.	('EIF1AX', 'Gene', '1964', (69, 75))	('EIF1AX', 'Gene', (69, 75))	('mutations', 'Var', (76, 85))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('patients', 'Species', '9606', (34, 42))	('metastases', 'Disease', (20, 30))	('metastases', 'Disease', 'MESH:D009362', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
36460	30073324	Our results support the hypothesis that for uveal melanoma, tumor size correlating with metastatic rate can largely be explained by the number of neutral mutations in the tumors, consistent with the notion that tumor heterogeneity arises from subclonal accumulation of mutations.	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('metastatic', 'CPA', (88, 98))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('tumor', 'Disease', (211, 216))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('mutations', 'Var', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('uveal melanoma', 'Disease', (44, 58))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
36467	30073324	Williams et al highlighted that mutation rate and mutational timeline are the most important characteristics of tumors possessing neutral growth, whereas selection and the microenvironment may play a key role for non-neutral cancer types.	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', (225, 231))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutational', 'Var', (50, 60))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('mutation', 'Var', (32, 40))	('tumors', 'Disease', (112, 118))
36475	30073324	Mutations in GNAQ and GNA11 occur early in tumor formation while BAP1, SF3B1, and EIF1AX mutations likely occur later in tumor progression.	('SF3B1', 'Gene', (71, 76))	('BAP1', 'Gene', '8314', (65, 69))	('GNA11', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('formation', 'biological_process', 'GO:0009058', ('49', '58'))	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (121, 126))	('BAP1', 'Gene', (65, 69))	('SF3B1', 'Gene', '23451', (71, 76))	('Mutations', 'Var', (0, 9))	('EIF1AX', 'Gene', '1964', (82, 88))	('EIF1AX', 'Gene', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('GNAQ', 'Gene', '2776', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
36476	30073324	Mutation in EIF1AX is an indicator of good prognosis, whereas mutations in SF3B1 and BAP1 are associated with intermediate and poor prognosis.	('BAP1', 'Gene', (85, 89))	('EIF1AX', 'Gene', (12, 18))	('mutations', 'Var', (62, 71))	('Mutation', 'Var', (0, 8))	('EIF1AX', 'Gene', '1964', (12, 18))	('SF3B1', 'Gene', '23451', (75, 80))	('BAP1', 'Gene', '8314', (85, 89))	('SF3B1', 'Gene', (75, 80))
36477	30073324	GNAQ and GNA11 have recently shown to be mutated in choroidal nevi and they have not been proved to be associated with metastasis and survival in uveal melanoma.	('GNA11', 'Gene', (9, 14))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('mutated', 'Var', (41, 48))	('nevi', 'Phenotype', 'HP:0003764', (62, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (146, 160))	('GNAQ', 'Gene', '2776', (0, 4))	('associated', 'Reg', (103, 113))	('uveal melanoma', 'Phenotype', 'HP:0007716', (146, 160))	('uveal melanoma', 'Disease', (146, 160))	('choroidal nevi', 'Phenotype', 'HP:0025314', (52, 66))	('GNAQ', 'Gene', (0, 4))	('choroidal nevi', 'Disease', (52, 66))	('GNA11', 'Gene', '2767', (9, 14))
36480	30073324	The Rotterdam Ocular Melanoma Study Group investigated the association of EIF1AX, SF3B1 and BAP1 mutation with disease-free survival and metastatic risk of patients with uveal melanoma.	('patients', 'Species', '9606', (156, 164))	('Rotterdam Ocular Melanoma', 'Disease', (4, 29))	('SF3B1', 'Gene', (82, 87))	('uveal melanoma', 'Disease', 'MESH:C536494', (170, 184))	('Melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('association', 'Interaction', (59, 70))	('Rotterdam Ocular Melanoma', 'Disease', 'MESH:D008545', (4, 29))	('uveal melanoma', 'Disease', (170, 184))	('uveal melanoma', 'Phenotype', 'HP:0007716', (170, 184))	('SF3B1', 'Gene', '23451', (82, 87))	('EIF1AX', 'Gene', '1964', (74, 80))	('EIF1AX', 'Gene', (74, 80))	('Ocular Melanoma', 'Phenotype', 'HP:0007716', (14, 29))	('BAP1', 'Gene', '8314', (92, 96))	('mutation', 'Var', (97, 105))	('metastatic', 'CPA', (137, 147))	('BAP1', 'Gene', (92, 96))
36481	30073324	Three slopes on survival curves of patients treated for uveal melanoma could be identified, the first slope being at 3 years on the BAP1 mutation curve, the second slope being at 7-8 years on the SF3B1 mutation curve and the third slope being at 8 years on the EIF1AX mutation curve.	('BAP1', 'Gene', '8314', (132, 136))	('uveal melanoma', 'Disease', (56, 70))	('uveal melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('mutation', 'Var', (137, 145))	('SF3B1', 'Gene', (196, 201))	('BAP1', 'Gene', (132, 136))	('patients', 'Species', '9606', (35, 43))	('SF3B1', 'Gene', '23451', (196, 201))	('EIF1AX', 'Gene', '1964', (261, 267))	('EIF1AX', 'Gene', (261, 267))	('uveal melanoma', 'Disease', 'MESH:C536494', (56, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
36485	30073324	The third peak may coincide with the SF3B1 mutation effects on the metastasis and survival probability.	('SF3B1', 'Gene', '23451', (37, 42))	('mutation', 'Var', (43, 51))	('effects', 'Reg', (52, 59))	('metastasis', 'CPA', (67, 77))	('survival probability', 'CPA', (82, 102))	('SF3B1', 'Gene', (37, 42))
36487	30073324	In the original article, 24% of patients harbored an SF3B1 mutations and 21% of patients had an EIF1AX mutations.	('EIF1AX', 'Gene', '1964', (96, 102))	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (80, 88))	('SF3B1', 'Gene', '23451', (53, 58))	('mutations', 'Var', (59, 68))	('EIF1AX', 'Gene', (96, 102))	('SF3B1', 'Gene', (53, 58))
36489	30073324	Decatur et al reported a prevalence of BAP1 mutations in 45%, SF3B1 mutations in 24%, and EIF1AX mutations in 17% of uveal melanomas.	('EIF1AX', 'Gene', (90, 96))	('mutations', 'Var', (97, 106))	('EIF1AX', 'Gene', '1964', (90, 96))	('uveal melanomas', 'Disease', (117, 132))	('uveal melanomas', 'Phenotype', 'HP:0007716', (117, 132))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('SF3B1', 'Gene', (62, 67))	('mutations', 'Var', (44, 53))	('BAP1', 'Gene', '8314', (39, 43))	('uveal melanomas', 'Disease', 'MESH:C536494', (117, 132))	('mutations', 'Var', (68, 77))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('uveal melanoma', 'Phenotype', 'HP:0007716', (117, 131))	('SF3B1', 'Gene', '23451', (62, 67))	('BAP1', 'Gene', (39, 43))
36490	30073324	They found that BAP1, SF3B1, and EIF1AX mutations were usually mutually exclusive from one another.	('SF3B1', 'Gene', (22, 27))	('SF3B1', 'Gene', '23451', (22, 27))	('EIF1AX', 'Gene', '1964', (33, 39))	('EIF1AX', 'Gene', (33, 39))	('mutations', 'Var', (40, 49))	('BAP1', 'Gene', '8314', (16, 20))	('BAP1', 'Gene', (16, 20))
36491	30073324	After performing a meta-analysis of the Rotterdam data, we observed a peak of metastasis at 3.5 years for BAP1 mutations and a peak between 2 and 3 years and a late peak at 7 years for SF3B1 mutation after treatment for the primary uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('mutations', 'Var', (111, 120))	('BAP1', 'Gene', (106, 110))	('SF3B1', 'Gene', (185, 190))	('uveal melanoma', 'Phenotype', 'HP:0007716', (232, 246))	('uveal melanoma', 'Disease', 'MESH:C536494', (232, 246))	('uveal melanoma', 'Disease', (232, 246))	('SF3B1', 'Gene', '23451', (185, 190))	('BAP1', 'Gene', '8314', (106, 110))	('metastasis', 'CPA', (78, 88))
36492	30073324	SF3B1 mutations have been found to be associated with Preferentially Expressed Antigen in Melanoma (PRAME) expression.	('SF3B1', 'Gene', (0, 5))	('associated', 'Reg', (38, 48))	('Preferentially Expressed Antigen in Melanoma', 'Gene', '23532', (54, 98))	('PRAME', 'Gene', '23532', (100, 105))	('PRAME', 'Gene', (100, 105))	('Melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('SF3B1', 'Gene', '23451', (0, 5))	('Preferentially Expressed Antigen in Melanoma', 'Gene', (54, 98))	('mutations', 'Var', (6, 15))
36493	30073324	Since PRAME is an independent risk factor for the development of metastasis in disomy 3 tumors, PRAME expression might have an influence on the SF3B1 mutation related survival curve.	('PRAME', 'Gene', '23532', (96, 101))	('metastasis in disomy 3 tumors', 'Disease', (65, 94))	('PRAME', 'Gene', (6, 11))	('SF3B1', 'Gene', (144, 149))	('mutation', 'Var', (150, 158))	('PRAME', 'Gene', (96, 101))	('metastasis in disomy 3 tumors', 'Disease', 'MESH:D009362', (65, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('influence', 'Reg', (127, 136))	('SF3B1', 'Gene', '23451', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('PRAME', 'Gene', '23532', (6, 11))
36497	30073324	Disease-free survival of uveal melanoma patients with BAP1 and SF3B1 mutation may be influenced by the follow-up as survival is more favorable for patients with SF3B1 mutation in the earlier stages.	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('uveal melanoma', 'Disease', (25, 39))	('SF3B1', 'Gene', (161, 166))	('SF3B1', 'Gene', (63, 68))	('patients', 'Species', '9606', (40, 48))	('SF3B1', 'Gene', '23451', (161, 166))	('mutation', 'Var', (69, 77))	('BAP1', 'Gene', '8314', (54, 58))	('patients', 'Species', '9606', (147, 155))	('SF3B1', 'Gene', '23451', (63, 68))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('BAP1', 'Gene', (54, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (25, 39))
36501	30073324	Regarding time to clinically detected metastasis, the first two peaks appear to coincide with BAP1-mutated tumors and the late peak appears to coincide with the SF3B1 mutated tumors.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('SF3B1', 'Gene', (161, 166))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('BAP1', 'Gene', '8314', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('SF3B1', 'Gene', '23451', (161, 166))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('mutated', 'Var', (167, 174))	('BAP1', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
36553	27128983	conducted a meta-analysis in which they grouped uveal melanomas according to size into three categories based on tumor height and diameter: small (height <3 mm and diameter <10 mm), medium (height 3-8 mm and diameter <15 mm) and large (height >8 mm and diameter >15 mm).	('uveal melanomas', 'Disease', 'MESH:C536494', (48, 63))	('tumor', 'Disease', (113, 118))	('height 3-8 mm', 'Var', (190, 203))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('uveal melanomas', 'Disease', (48, 63))	('uveal melanomas', 'Phenotype', 'HP:0007716', (48, 63))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('height <3 mm', 'Var', (147, 159))
36560	27128983	conducted a retrospective analysis of 7,731 patients with posterior uveal melanoma, which revealed a two-fold increase in risk of both metastasis and death for each increase in AJCC category (e.g., T1, T2, T3, T4).	('metastasis', 'CPA', (135, 145))	('patients', 'Species', '9606', (44, 52))	('T4', 'Var', (210, 212))	('AJCC', 'Gene', (177, 181))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('uveal melanoma', 'Disease', 'MESH:C536494', (68, 82))	('uveal melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('uveal melanoma', 'Disease', (68, 82))
36568	27128983	Monosomy 3 is widely accepted as the most significant chromosomal abnormality with respect to patient prognosis.	('chromosomal abnormality', 'Disease', 'MESH:D002869', (54, 77))	('chromosomal abnormality', 'Disease', (54, 77))	('Monosomy 3', 'Var', (0, 10))	('patient', 'Species', '9606', (94, 101))
36573	27128983	This syndrome is the result of germline mutations in the BAP1 gene.	('BAP1', 'Gene', '8314', (57, 61))	('BAP1', 'Gene', (57, 61))	('result of', 'Reg', (21, 30))	('germline mutations', 'Var', (31, 49))
36575	27128983	BAP1 mutations can be either germline mutations, resulting in the familial cancer predisposition syndrome, or sporadic in the uveal melanoma tumor cells.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('BAP1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('resulting in', 'Reg', (49, 61))	('mutations', 'Var', (5, 14))	('familial cancer', 'Disease', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('familial cancer', 'Disease', 'MESH:D009369', (66, 81))	('uveal melanoma tumor', 'Disease', (126, 146))	('uveal melanoma', 'Phenotype', 'HP:0007716', (126, 140))	('uveal melanoma tumor', 'Disease', 'MESH:C536494', (126, 146))	('BAP1', 'Gene', '8314', (0, 4))
36576	27128983	Either type of recessive BAP1 mutation is unmasked by a loss of chromosome 3.	('BAP1', 'Gene', '8314', (25, 29))	('mutation', 'Var', (30, 38))	('BAP1', 'Gene', (25, 29))	('chromosome', 'cellular_component', 'GO:0005694', ('64', '74'))
36577	27128983	BAP1 mutations have been shown to relate to uveal melanoma metastatic potential and the classification of tumors as higher-risk, class 2 tumors (see section on gene expression profile that follows).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('BAP1', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('relate', 'Reg', (34, 40))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('mutations', 'Var', (5, 14))	('gene expression', 'biological_process', 'GO:0010467', ('160', '175'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('BAP1', 'Gene', '8314', (0, 4))	('uveal melanoma', 'Disease', (44, 58))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
36578	27128983	Such advances highlight the impact of isodisomy 3, which is associated with higher-risk, class 2 tumors and metastatic progression, and extend the story of alterations in chromosome 3 beyond simple haploinsufficiency.	('chromosome', 'cellular_component', 'GO:0005694', ('171', '181'))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('isodisomy 3', 'Var', (38, 49))	('haploinsufficiency', 'Disease', (198, 216))	('metastatic progression', 'CPA', (108, 130))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('haploinsufficiency', 'Disease', 'MESH:D058495', (198, 216))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('associated with', 'Reg', (60, 75))
36579	27128983	In addition to monosomy 3, alterations in chromosomes 6 and 8 influence uveal melanoma prognosis.	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('uveal melanoma', 'Disease', (72, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('influence', 'Reg', (62, 71))	('alterations', 'Var', (27, 38))
36581	27128983	Alternatively, chromosome 6q loss (also present in ~25% of uveal melanomas) is associated with increased risk of metastasis.	('uveal melanomas', 'Disease', 'MESH:C536494', (59, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('chromosome', 'cellular_component', 'GO:0005694', ('15', '25'))	('loss', 'NegReg', (29, 33))	('uveal melanomas', 'Disease', (59, 74))	('uveal melanomas', 'Phenotype', 'HP:0007716', (59, 74))	('metastasis', 'CPA', (113, 123))	('chromosome 6q', 'Var', (15, 28))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanomas', 'Phenotype', 'HP:0002861', (65, 74))
36585	27128983	Onken and colleagues identified LZT1 as a likely 8q "metastasis suppressor" and demonstrated that modulation of LZT1 mRNA expression in metastatic uveal melanoma cell lines effectively impacted in vitro measures of tumor cell motility and invasion.	('LZT1', 'Gene', (112, 116))	('uveal melanoma', 'Disease', (147, 161))	('impacted', 'Reg', (185, 193))	('invasion', 'CPA', (239, 247))	('modulation', 'Var', (98, 108))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('mRNA expression', 'MPA', (117, 132))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))	('uveal melanoma', 'Phenotype', 'HP:0007716', (147, 161))	('uveal melanoma', 'Disease', 'MESH:C536494', (147, 161))
36586	27128983	Recently, GNAQ or GNA11 mutations have been identified in over 80-90% of uveal melanomas in a mutually exclusive fashion.	('uveal melanomas', 'Disease', 'MESH:C536494', (73, 88))	('GNAQ', 'Gene', '2776', (10, 14))	('uveal melanoma', 'Phenotype', 'HP:0007716', (73, 87))	('GNAQ', 'Gene', (10, 14))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('GNA11', 'Gene', (18, 23))	('uveal melanomas', 'Disease', (73, 88))	('uveal melanomas', 'Phenotype', 'HP:0007716', (73, 88))	('identified', 'Reg', (44, 54))	('mutations', 'Var', (24, 33))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))	('GNA11', 'Gene', '2767', (18, 23))
36587	27128983	Activating mutations in either GNAQ or GNA11 interfere with the G-protein subunit's intrinsic GTPase activity, leading to activation of the MAPK/MEK/ERK pathway.	('mutations', 'Var', (11, 20))	('MAPK', 'Gene', (140, 144))	('GNA11', 'Gene', (39, 44))	('GNAQ', 'Gene', '2776', (31, 35))	('GTPase', 'Enzyme', (94, 100))	('activation', 'PosReg', (122, 132))	('GNAQ', 'Gene', (31, 35))	('MAPK', 'Gene', '5594', (140, 144))	('ERK', 'molecular_function', 'GO:0004707', ('149', '152'))	('MEK', 'Gene', '5609', (145, 148))	('ERK', 'Gene', '5594', (149, 152))	('interfere', 'NegReg', (45, 54))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('GNA11', 'Gene', '2767', (39, 44))	('intrinsic', 'MPA', (84, 93))	('MEK', 'Gene', (145, 148))	('G-protein subunit', 'Protein', (64, 81))	('ERK', 'Gene', (149, 152))	('MAPK', 'molecular_function', 'GO:0004707', ('140', '144'))	('GTPase activity', 'molecular_function', 'GO:0003924', ('94', '109'))
36589	27128983	The most common mutation in both GNAQ and GNA11 is at the Q209 residue.	('GNAQ', 'Gene', (33, 37))	('GNAQ', 'Gene', '2776', (33, 37))	('GNA11', 'Gene', (42, 47))	('Q209', 'Var', (58, 62))	('GNA11', 'Gene', '2767', (42, 47))
36590	27128983	Mutations in GNAQ and GNA11 are independent of prognostically relevant cytogenetic alterations or tumor gene expression profile (GEP) class.	('GNA11', 'Gene', (22, 27))	('GNAQ', 'Gene', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('GNA11', 'Gene', '2767', (22, 27))	('gene expression', 'biological_process', 'GO:0010467', ('104', '119'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (98, 103))	('GNAQ', 'Gene', '2776', (13, 17))
36592	27128983	Class 2 tumors have a higher risk of metastasis (five-year risk of metastasis is 72%) and death and are associated with BAP1 mutations.	('mutations', 'Var', (125, 134))	('metastasis', 'CPA', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('associated', 'Reg', (104, 114))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('BAP1', 'Gene', '8314', (120, 124))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('BAP1', 'Gene', (120, 124))
36593	27128983	Alternatively, class 1 tumors are associated with SF3B1 and EIF1AX mutations and are sub-divided into class 1A and class 1B, which have a five-year risk of metastasis of 2% and 21%, respectively.	('associated', 'Reg', (34, 44))	('tumors', 'Disease', (23, 29))	('SF3B1', 'Gene', (50, 55))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('EIF1AX', 'Gene', '1964', (60, 66))	('EIF1AX', 'Gene', (60, 66))	('mutations', 'Var', (67, 76))	('SF3B1', 'Gene', '23451', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
36598	27128983	Continued identification of specific pathway alterations in more aggressive class 2 tumors may lead to targeted therapies with the potential to reduce metastatic progression.	('alterations', 'Var', (45, 56))	('lead to', 'Reg', (95, 102))	('metastatic progression', 'CPA', (151, 173))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
36634	28350816	Furthermore, we validate our framework on a clinical dataset of T1w VIBE and T2w MRI from retinoblastoma patients and show that when EPSF are used, performance differences between state-of-the-art deep networks and other simpler classifiers such as Random Forests (RF) are minor and improvements are visible across all cases.	('T2w', 'Var', (77, 80))	('retinoblastoma', 'Disease', 'MESH:D012175', (90, 104))	('T1w VIBE', 'Gene', (64, 72))	('retinoblastoma', 'Disease', (90, 104))	('RF', 'Chemical', '-', (265, 267))	('patients', 'Species', '9606', (105, 113))	('retinoblastoma', 'Phenotype', 'HP:0009919', (90, 104))	('T1w VIBE', 'Gene', '9173', (64, 72))
36659	28350816	Now, to segment the eye tumor tissue, we make use of a MRF to model the joint distribution of all the voxels , where Y =  iYi, Yi   {0, 1} represents the presence of a tumor at location i, X is the MR volume and , represents the different healthy eye structures,  with normalization factor Z, likelihood model  and smoothness prior .	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Y =  iYi', 'Var', (117, 125))	('segment the eye tumor', 'Disease', (8, 29))	('tumor', 'Disease', (168, 173))	('RF', 'Chemical', '-', (56, 58))	('tumor', 'Disease', (24, 29))	('Yi   {', 'Var', (127, 133))	('eye tumor', 'Phenotype', 'HP:0100012', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('segment the eye tumor', 'Disease', 'MESH:C537538', (8, 29))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
36689	28350816	Here, we used two sequences for imaging the eyes (T1w VIBE and T2w) which were specifically selected in collaborations with expert radiologist from our clinical institution.	('T1w VIBE', 'Gene', (50, 58))	('T2w', 'Var', (63, 66))	('T1w VIBE', 'Gene', '9173', (50, 58))
36708	27166257	Minimal contribution of ERK1/2-MAPK signalling towards the maintenance of oncogenic GNAQQ209P-driven uveal melanomas in zebrafish Mutations affecting Galphaq proteins are pervasive in uveal melanoma (UM), suggesting they 'drive' UM pathogenesis.	("'drive", 'PosReg', (221, 227))	('uveal melanomas', 'Disease', 'MESH:C536494', (101, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (101, 115))	('Mutations', 'Var', (130, 139))	('GNAQQ209P', 'Mutation', 'rs121913492', (84, 93))	('pathogenesis', 'biological_process', 'GO:0009405', ('232', '244'))	('ERK1/2', 'Gene', (24, 30))	('MAPK signalling', 'biological_process', 'GO:0000165', ('31', '46'))	('uveal melanoma', 'Disease', 'MESH:C536494', (184, 198))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('uveal melanoma', 'Disease', (184, 198))	('uveal melanoma', 'Phenotype', 'HP:0007716', (101, 115))	('UM', 'Phenotype', 'HP:0007716', (200, 202))	('ERK1', 'molecular_function', 'GO:0004707', ('24', '28'))	('uveal melanomas', 'Disease', (101, 116))	('uveal melanomas', 'Phenotype', 'HP:0007716', (101, 116))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (184, 198))	('MAPK', 'molecular_function', 'GO:0004707', ('31', '35'))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('UM', 'Phenotype', 'HP:0007716', (229, 231))	('ERK1/2', 'Gene', '399480;360144', (24, 30))
36713	27166257	Combining expression of oncogenic GNAQQ209P with p53 inactivation resulted in earlier onset and even more extensive hyperplasia of uveal melanocytes that progressed to UM.	('hyperplasia', 'Disease', 'MESH:D006965', (116, 127))	('UM', 'Phenotype', 'HP:0007716', (168, 170))	('GNAQQ209P', 'Mutation', 'rs121913492', (34, 43))	('p53', 'Gene', (49, 52))	('uvea', 'Disease', (131, 135))	('GNAQQ209P', 'Var', (34, 43))	('uvea', 'Disease', 'MESH:C536494', (131, 135))	('hyperplasia', 'Disease', (116, 127))
36715	27166257	Moreover, no changes were observed in pERK1/2 levels upon transient knockdown of GNAQ or phospholipase C-beta (PLC-beta) inhibition in the majority of human UM cell lines we tested harbouring GNAQ mutations.	('C-beta', 'Species', '10703', (113, 119))	('human', 'Species', '9606', (151, 156))	('PLC', 'cellular_component', 'GO:0042824', ('111', '114'))	('GNAQ', 'Gene', (192, 196))	('mutations', 'Var', (197, 206))	('C-beta', 'Species', '10703', (103, 109))	('ERK1/2', 'Gene', (39, 45))	('ERK1/2', 'Gene', '399480;360144', (39, 45))	('UM', 'Phenotype', 'HP:0007716', (157, 159))	('GNAQ', 'Chemical', '-', (192, 196))	('GNAQ', 'Chemical', '-', (81, 85))
36720	27166257	However, mutations in well-known CM oncogenes such as BRAF or NRAS that are responsible for constitutive ERK activation are conspicuously rare in UM.	('ERK', 'molecular_function', 'GO:0004707', ('105', '108'))	('BRAF', 'Gene', (54, 58))	('ERK', 'Gene', '5594', (105, 108))	('UM', 'Phenotype', 'HP:0007716', (146, 148))	('mutations', 'Var', (9, 18))	('ERK', 'Gene', (105, 108))	('CM', 'Phenotype', 'HP:0012056', (33, 35))	('NRAS', 'Gene', (62, 66))
36722	27166257	Recurrent hypermorphic mutations of GNAQ or GNA11 (GNAQ/11), highly related Galphaq proteins, mainly affecting Glutamine 209 have been detected in UM and are proposed as indirect activators of ERK signalling via phospholipase C-beta (PLC-beta)-mediated activation of protein kinase C (PKC).	('PKC', 'Disease', 'MESH:C537180', (285, 288))	('C-beta', 'Species', '10703', (236, 242))	('GNAQ', 'Chemical', '-', (51, 55))	('affecting', 'Reg', (101, 110))	('UM', 'Phenotype', 'HP:0007716', (147, 149))	('GNAQ', 'Gene', (36, 40))	('ERK', 'Gene', (193, 196))	('C-beta', 'Species', '10703', (226, 232))	('mutations', 'Var', (23, 32))	('GNA11', 'Gene', (44, 49))	('Glutamine', 'Chemical', 'MESH:D005973', (111, 120))	('PKC', 'Disease', (285, 288))	('PLC', 'cellular_component', 'GO:0042824', ('234', '237'))	('ERK', 'molecular_function', 'GO:0004707', ('193', '196'))	('signalling', 'biological_process', 'GO:0023052', ('197', '207'))	('activators', 'PosReg', (179, 189))	('protein', 'cellular_component', 'GO:0003675', ('267', '274'))	('PKC', 'molecular_function', 'GO:0004697', ('285', '288'))	('Glutamine 209', 'MPA', (111, 124))	('GNAQ', 'Chemical', '-', (36, 40))	('ERK', 'Gene', '5594', (193, 196))
36725	27166257	GNAQ/11 mutations do not correlate with clinical, pathological, and genetic indicators of tumour progression, suggesting that they are early events in UM development and insufficient for malignant progression.	('UM', 'Phenotype', 'HP:0007716', (151, 153))	('GNAQ/11', 'Gene', (0, 7))	('GNAQ', 'Chemical', '-', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('mutations', 'Var', (8, 17))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('insufficient', 'Disease', (170, 182))	('insufficient', 'Disease', 'MESH:D000309', (170, 182))	('tumour', 'Disease', (90, 96))
36726	27166257	Consistent with this notion, forced expression of GNAQQ209L was insufficient to transform primary melanocytes.	('transform', 'Reg', (80, 89))	('insufficient', 'Disease', 'MESH:D000309', (64, 76))	('insufficient', 'Disease', (64, 76))	('GNAQ', 'Chemical', '-', (50, 54))	('GNAQQ209L', 'Var', (50, 59))
36727	27166257	In keeping with all other solid cancers, multiple genetic and epigenetic changes likely underlie progression of uveal melanocytic neoplasia from benign hyperproliferation to infiltrative and metastatic spread.	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('solid cancers', 'Disease', (26, 39))	('uveal melanocytic neoplasia', 'Disease', 'MESH:D014603', (112, 139))	('uveal melanocytic neoplasia', 'Phenotype', 'HP:0007716', (112, 139))	('solid cancers', 'Disease', 'MESH:D009369', (26, 39))	('epigenetic changes', 'Var', (62, 80))	('uveal melanocytic neoplasia', 'Disease', (112, 139))	('underlie', 'Reg', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('benign hyperproliferation', 'Disease', (145, 170))	('neoplasia', 'Phenotype', 'HP:0002664', (130, 139))
36728	27166257	In UM, loss-of-function BRCA1 associated protein-1 (BAP1) mutations correlate with metastatic behaviour.	('mutations', 'Var', (58, 67))	('BRCA1 associated protein-1', 'Gene', '558885', (24, 50))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('BRCA1 associated protein-1', 'Gene', (24, 50))	('loss-of-function', 'NegReg', (7, 23))	('BAP1', 'Gene', '558885', (52, 56))	('BAP1', 'Gene', (52, 56))	('metastatic behaviour', 'CPA', (83, 103))	('behaviour', 'biological_process', 'GO:0007610', ('94', '103'))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
36735	27166257	Herein, we describe the generation of transgenic zebrafish expressing oncogenic GNAQQ209P in the melanocyte lineage, yielding a model of benign uveal melanocytic hyperplasia which confirms the selective role of Galphaq proteins in driving the proliferation of uveal melanocytes.	('uvea', 'Disease', 'MESH:C536494', (260, 264))	('benign uveal melanocytic hyperplasia', 'Disease', (137, 173))	('uvea', 'Disease', 'MESH:C536494', (144, 148))	('GNAQQ209P', 'Mutation', 'rs121913492', (80, 89))	('benign uveal melanocytic hyperplasia', 'Disease', 'MESH:D014603', (137, 173))	('zebrafish', 'Species', '7955', (49, 58))	('uvea', 'Disease', (260, 264))	('uvea', 'Disease', (144, 148))	('GNAQQ209P', 'Var', (80, 89))
36747	27166257	Glutamine 209 of GNAQ is similar to Glutamine 61 of RAS proteins: substitution results in a conformational change, leading to the loss of intrinsic GTPase activity and sustained signalling.	('conformational change', 'MPA', (92, 113))	('Glutamine', 'Chemical', 'MESH:D005973', (0, 9))	('signalling', 'biological_process', 'GO:0023052', ('178', '188'))	('activity', 'MPA', (155, 163))	('sustained signalling', 'MPA', (168, 188))	('GTPase activity', 'molecular_function', 'GO:0003924', ('148', '163'))	('loss', 'NegReg', (130, 134))	('GTP', 'Chemical', 'MESH:D006160', (148, 151))	('Glutamine', 'Chemical', 'MESH:D005973', (36, 45))	('substitution', 'Var', (66, 78))	('intrinsic', 'MPA', (138, 147))	('GNAQ', 'Chemical', '-', (17, 21))
36752	27166257	This revealed a 4.1 fold increase in GNAQ expression in transgenic zebrafish, as compared to non-injected controls (Figure 1C).	('expression', 'MPA', (42, 52))	('GNAQ', 'Protein', (37, 41))	('increase', 'PosReg', (25, 33))	('zebrafish', 'Species', '7955', (67, 76))	('GNAQ', 'Chemical', '-', (37, 41))	('transgenic', 'Var', (56, 66))
36756	27166257	On the contrary, GNAQ mutations occur at a high frequency in UM, but are rarely detected in their cutaneous counterparts.	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('GNAQ', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('GNAQ', 'Chemical', '-', (17, 21))
36757	27166257	Using transgenic zebrafish lines expressing oncogenic BRAF (BRAFV600E), NRAS (NRASQ61L), or GNAQ (GNAQQ209P) in the melanocyte lineage under the control of mitfa promoter, we attempted to directly contrast the ability of oncogenic GNAQQ209P on the one hand and NRASQ61L and BRAFV600E on the other to induce proliferative responses in uveal versus cutaneous melanocytes.	('GNAQ', 'Chemical', '-', (98, 102))	('mitfa', 'Gene', '30080', (156, 161))	('zebrafish', 'Species', '7955', (17, 26))	('mitfa', 'Gene', (156, 161))	('uvea', 'Disease', 'MESH:C536494', (334, 338))	('NRASQ61L', 'Var', (261, 269))	('induce', 'PosReg', (300, 306))	('BRAFV600E', 'Var', (274, 283))	('GNAQQ209P', 'Mutation', 'rs121913492', (231, 240))	('GNAQQ209P', 'Mutation', 'rs121913492', (98, 107))	('GNAQ', 'Chemical', '-', (92, 96))	('uvea', 'Disease', (334, 338))	('GNAQQ209P', 'Var', (231, 240))	('GNAQ', 'Chemical', '-', (231, 235))
36762	27166257	Activation of ERK1/2-MAPK signalling by oncogenic GNAQ mutations was first demonstrated in vitro by transient expression of mutant GNAQQ209L construct in hTERT/CDK4R24C/p53DD melanocytes, which resulted in increased expression of phosphorylated ERK (pERK), as compared to the same melanocytes transfected with GNAQWT or empty vector.	('ERK', 'Gene', (14, 17))	('increased', 'PosReg', (206, 215))	('GNAQ', 'Chemical', '-', (131, 135))	('GNAQ', 'Chemical', '-', (50, 54))	('phosphorylated', 'MPA', (230, 244))	('GNAQQ209L', 'Gene', (131, 140))	('ERK', 'molecular_function', 'GO:0004707', ('245', '248'))	('expression', 'MPA', (216, 226))	('MAPK signalling', 'biological_process', 'GO:0000165', ('21', '36'))	('GNAQ', 'Gene', (50, 54))	('ERK', 'Gene', '5594', (245, 248))	('CDK4', 'Gene', (160, 164))	('mutations', 'Var', (55, 64))	('ERK1/2', 'Gene', '399480;360144', (14, 20))	('CDK', 'molecular_function', 'GO:0004693', ('160', '163'))	('ERK', 'Gene', '5594', (251, 254))	('Activation', 'PosReg', (0, 10))	('GNAQ', 'Chemical', '-', (310, 314))	('ERK', 'Gene', '5594', (14, 17))	('CDK4', 'Gene', '777730', (160, 164))	('ERK1/2', 'Gene', (14, 20))	('mutant', 'Var', (124, 130))	('ERK', 'Gene', (245, 248))	('ERK1', 'molecular_function', 'GO:0004707', ('14', '18'))	('MAPK', 'molecular_function', 'GO:0004707', ('21', '25'))	('ERK', 'Gene', (251, 254))
36765	27166257	For examining ERK status, hyperplastic lesions were stained with anti-pERK1/2 polyclonal antibody that detects activated ERK1 and ERK2 when phosphorylated at residues corresponding to Thr202/Tyr204 and Thr185/Tyr187 in man respectively.	('ERK', 'Gene', (14, 17))	('ERK1', 'Gene', (71, 75))	('antibody', 'cellular_component', 'GO:0019814', ('89', '97'))	('ERK', 'Gene', '5594', (130, 133))	('Thr185', 'Chemical', '-', (202, 208))	('ERK1/2', 'Gene', '399480;360144', (71, 77))	('ERK2', 'Gene', '5594', (130, 134))	('ERK1', 'molecular_function', 'GO:0004707', ('121', '125'))	('ERK', 'Gene', '5594', (121, 124))	('ERK2', 'Gene', (130, 134))	('ERK1', 'Gene', '5595', (71, 75))	('ERK', 'Gene', '5594', (71, 74))	('ERK1/2', 'Gene', (71, 77))	('antibody', 'molecular_function', 'GO:0003823', ('89', '97'))	('ERK', 'Gene', (130, 133))	('antibody', 'cellular_component', 'GO:0042571', ('89', '97'))	('ERK', 'Gene', (121, 124))	('Thr202/Tyr204', 'Var', (184, 197))	('ERK', 'molecular_function', 'GO:0004707', ('14', '17'))	('ERK', 'Gene', (71, 74))	('Thr202', 'Chemical', '-', (184, 190))	('ERK', 'Gene', '5594', (14, 17))	('ERK1', 'Gene', (121, 125))	('Tyr187', 'Chemical', '-', (209, 215))	('Thr185/Tyr187', 'Var', (202, 215))	('antibody', 'cellular_component', 'GO:0019815', ('89', '97'))	('man', 'Species', '9606', (219, 222))	('ERK1', 'Gene', '5595', (121, 125))	('ERK2', 'molecular_function', 'GO:0004707', ('130', '134'))	('Tyr204', 'Chemical', '-', (191, 197))
36768	27166257	Thus, the above findings indicate that zebrafish oncogenic GNAQQ209P can activate ERK1/2-MAPK and YAP signalling pathways, albeit restricted to melanocytes occupying a niche at the junction between the RPE and choroid.	('YAP', 'Gene', '561411', (98, 101))	('GNAQQ209P', 'Mutation', 'rs121913492', (59, 68))	('signalling', 'biological_process', 'GO:0023052', ('102', '112'))	('GNAQQ209P', 'Var', (59, 68))	('ERK1', 'molecular_function', 'GO:0004707', ('82', '86'))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('activate', 'PosReg', (73, 81))	('zebrafish', 'Species', '7955', (39, 48))	('ERK1/2', 'Gene', (82, 88))	('ERK1/2', 'Gene', '399480;360144', (82, 88))	('YAP', 'Gene', (98, 101))
36770	27166257	Concerned that IHC on any resultant pigmented neoplastic lesions might be compromised by the presence of melanin and the necessity to bleach sections, we injected the GNAQQ209P transgene construct into zebrafish zygotes of golden mutants characterized by delayed and reduced melanin pigmentation in skin melanocytes and RPE, as a result of a loss-of-function mutation in the slc24a5 gene.	('slc24a5', 'Gene', (375, 382))	('loss-of-function', 'NegReg', (342, 358))	('melanin', 'Chemical', 'MESH:D008543', (105, 112))	('zebrafish', 'Species', '7955', (202, 211))	('pigmentation', 'biological_process', 'GO:0043473', ('283', '295'))	('melanin pigmentation', 'MPA', (275, 295))	('slc24a5', 'Gene', '570312', (375, 382))	('pigmented neoplastic lesions', 'Disease', (36, 64))	('melanin', 'Chemical', 'MESH:D008543', (275, 282))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (46, 64))	('GNAQQ209P', 'Mutation', 'rs121913492', (167, 176))	('pigmented neoplastic lesions', 'Disease', 'MESH:D010859', (36, 64))	('reduced', 'NegReg', (267, 274))	('mutation', 'Var', (359, 367))
36771	27166257	To our initial surprise, pigmentation was restored in transgenic embryos (that is those with fluorescent green lenses) starting at day 2 post-fertilization (Figure 3C.I, 3C.II), and persisted in 49% of adult F0 transgenic zebrafish.	('pigmentation', 'MPA', (25, 37))	('fertilization', 'biological_process', 'GO:0009566', ('142', '155'))	('transgenic', 'Var', (54, 64))	('pigmentation', 'biological_process', 'GO:0043473', ('25', '37'))	('zebrafish', 'Species', '7955', (222, 231))
36772	27166257	Subsequent backcrossing from F0 founders to golden mutants resulted in an F1 generation with stable transgene incorporation, in which pigmentation was uniformly rescued (Figure 3F.I, 3G.I), and were visibly darker than non-injected golden (Figure 3E.I) and even wild-type (Figure 3D.I) zebrafish.	('pigmentation', 'MPA', (134, 146))	('mutants', 'Var', (51, 58))	('rescued', 'PosReg', (161, 168))	('zebrafish', 'Species', '7955', (286, 295))	('transgene', 'Var', (100, 109))	('darker', 'NegReg', (207, 213))	('pigmentation', 'biological_process', 'GO:0043473', ('134', '146'))
36773	27166257	Moreover, histological examination of transverse sections of eye tissues of 2-month-old GNAQQ209P-expressing zebrafish revealed pigmentation-rescued RPE (Figure 3F.II, 3G.II), as compared to non-injected golden mutants (Figure 3E.II).	('zebrafish', 'Species', '7955', (109, 118))	('pigmentation', 'biological_process', 'GO:0043473', ('128', '140'))	('GNAQQ209P-expressing', 'Gene', (88, 108))	('pigmentation-rescued', 'Var', (128, 148))	('GNAQQ209P', 'Mutation', 'rs121913492', (88, 97))	('RPE', 'Disease', (149, 152))
36774	27166257	Transmission electron microscopy (TEM) confirmed the presence of abundant melanin-rich melanosomes in the melanocytes of dissected tail fins of GNAQQ209P-expressing transgenics (Figure 3J.II, 3K.II), which as previously documented, were less densely pigmented in golden mutants (Figure I.II).	('less', 'NegReg', (237, 241))	('TEM', 'cellular_component', 'GO:0097197', ('34', '37'))	('GNAQQ209P-expressing transgenics', 'Var', (144, 176))	('melanin', 'Chemical', 'MESH:D008543', (74, 81))	('transgenics', 'Var', (165, 176))	('GNAQQ209P', 'Mutation', 'rs121913492', (144, 153))
36776	27166257	Thus, we concluded that forced expression of GNAQQ209P in zebrafish melanocytes stimulates melanin production, although the mechanism is still unclear.	('melanin', 'Chemical', 'MESH:D008543', (91, 98))	('GNAQQ209P', 'Mutation', 'rs121913492', (45, 54))	('zebrafish', 'Species', '7955', (58, 67))	('melanin production', 'MPA', (91, 109))	('GNAQQ209P', 'Var', (45, 54))	('stimulates', 'PosReg', (80, 90))
36780	27166257	Interaction between an oncogenic driver and inactivation of p53 signalling has been mooted for malignant transformation of uveal melanocytes.	('malignant transformation of uveal melanocytes', 'Phenotype', 'HP:0007716', (95, 140))	('signalling', 'biological_process', 'GO:0023052', ('64', '74'))	('uvea', 'Disease', (123, 127))	('inactivation', 'Var', (44, 56))	('uvea', 'Disease', 'MESH:C536494', (123, 127))
36781	27166257	To investigate this potential, we injected the oncogenic GNAQQ209P transgene construct into zygotes from homozygous p53M214K/M214K zebrafish mutants whose hypomorphic p53 closely resembles mutant forms isolated from human cancer.	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('human', 'Species', '9606', (216, 221))	('cancer', 'Disease', (222, 228))	('zebrafish', 'Species', '7955', (131, 140))	('M214K', 'Mutation', 'p.M214K', (125, 130))	('p53M214K/M214K', 'Var', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('GNAQQ209P', 'Mutation', 'rs121913492', (57, 66))	('M214K', 'Mutation', 'p.M214K', (119, 124))
36784	27166257	However, sectioning a cohort of fifteen F0 Tg (mitfa:GNAQQ209P;p53M214K/M214K) zebrafish at 5 months of age revealed five (33%) with uveal tumours co-existing with choroidal hyperplasia (Figure 4C.I, D.I), four (26%) displaying choroidal hyperplasia only without evidence of uveal malignancy, and two (13%) developing tumours in the leptomeninges surrounding the hindbrain (Supplementary Figure S4), while the remaining had normal phenotypes.	('choroidal hyperplasia', 'Disease', (228, 249))	('p53M214K/M214K', 'Var', (63, 77))	('mitfa', 'Gene', (47, 52))	('uveal tumours', 'Disease', 'MESH:D014604', (133, 146))	('M214K', 'Mutation', 'p.M214K', (72, 77))	('tumours', 'Disease', (139, 146))	('choroidal hyperplasia', 'Disease', (164, 185))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('GNAQQ209P', 'Mutation', 'rs121913492', (53, 62))	('uveal malignancy', 'Disease', (275, 291))	('uveal malignancy', 'Disease', 'MESH:D014603', (275, 291))	('tumours', 'Phenotype', 'HP:0002664', (139, 146))	('tumours', 'Disease', 'MESH:D009369', (139, 146))	('zebrafish', 'Species', '7955', (79, 88))	('uveal tumours', 'Disease', (133, 146))	('tumours', 'Disease', (318, 325))	('tumour', 'Phenotype', 'HP:0002664', (318, 324))	('tumours', 'Phenotype', 'HP:0002664', (318, 325))	('tumours', 'Disease', 'MESH:D009369', (318, 325))	('choroidal hyperplasia', 'Disease', 'MESH:D006965', (228, 249))	('M214K', 'Mutation', 'p.M214K', (66, 71))	('choroidal hyperplasia', 'Disease', 'MESH:D006965', (164, 185))	('mitfa', 'Gene', '30080', (47, 52))
36787	27166257	In contrast, sectioning twelve non-injected p53 mutant zebrafish at 5 months of age did not reveal any phenotypic changes in the uvea (Figure 4A.I).	('mutant', 'Var', (48, 54))	('uvea', 'Disease', (129, 133))	('zebrafish', 'Species', '7955', (55, 64))	('p53', 'Gene', (44, 47))	('uvea', 'Disease', 'MESH:C536494', (129, 133))
36788	27166257	However, zebrafish p53 mutants may occasionally develop malignant peripheral nerve sheath tumours (MPNSTs) starting at 8.5 months of age, thus it was crucial to verify the origin of the observed eye tumours.	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('peripheral nerve sheath tumours', 'Disease', 'MESH:D010524', (66, 97))	('MPNSTs', 'Phenotype', 'HP:0100697', (99, 105))	('malignant peripheral nerve sheath tumours', 'Phenotype', 'HP:0100697', (56, 97))	('peripheral nerve sheath tumours', 'Disease', (66, 97))	('develop', 'PosReg', (48, 55))	('tumours', 'Phenotype', 'HP:0002664', (199, 206))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('p53', 'Gene', (19, 22))	('eye tumours', 'Disease', 'MESH:D005134', (195, 206))	('zebrafish', 'Species', '7955', (9, 18))	('eye tumours', 'Disease', (195, 206))	('mutants', 'Var', (23, 30))
36789	27166257	To confirm that the malignancies observed following injection of GNAQQ209P transgene were linked to transgene expression, uveal tumour specimens were examined for GNAQ expression using IHC.	('GNAQQ209P', 'Mutation', 'rs121913492', (65, 74))	('linked', 'Reg', (90, 96))	('GNAQ', 'Chemical', '-', (65, 69))	('malignancies', 'Disease', 'MESH:D009369', (20, 32))	('uveal tumour', 'Disease', 'MESH:D014604', (122, 134))	('malignancies', 'Disease', (20, 32))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('GNAQQ209P', 'Var', (65, 74))	('GNAQ', 'Chemical', '-', (163, 167))	('uveal tumour', 'Disease', (122, 134))
36794	27166257	This contrasted with PCNA being restricted to the interface between the choroid and RPE in pre-malignant lesions expressing GNAQQ209P (Figure 5A.V).	('PCNA', 'molecular_function', 'GO:0003892', ('21', '25'))	('GNAQQ209P', 'Mutation', 'rs121913492', (124, 133))	('pre', 'molecular_function', 'GO:0003904', ('91', '94'))	('PCNA', 'Gene', (21, 25))	('PCNA', 'Gene', '30678', (21, 25))	('GNAQQ209P', 'Var', (124, 133))
36796	27166257	As revealed by IHC, pERK1/2-positive cells were sporadic in pre-malignant choroidal melanocytes expressing GNAQQ209P, again within the junctional zone (Figure 6A.II), and also in GNAQQ209P-expressing frank uveal tumours (Figure 6B.II, 6C.II).	('ERK1/2', 'Gene', (21, 27))	('ERK1/2', 'Gene', '399480;360144', (21, 27))	('frank uveal tumours', 'Disease', 'MESH:D014604', (200, 219))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('tumours', 'Phenotype', 'HP:0002664', (212, 219))	('GNAQQ209P', 'Mutation', 'rs121913492', (107, 116))	('pre', 'molecular_function', 'GO:0003904', ('60', '63'))	('GNAQQ209P', 'Var', (107, 116))	('frank uveal tumours', 'Disease', (200, 219))	('GNAQQ209P', 'Mutation', 'rs121913492', (179, 188))	('choroidal melanocytes', 'Phenotype', 'HP:0012054', (74, 95))
36799	27166257	To further explore the link between Galphaq hyperactivity and activation of ERK signalling, we transiently transfected human embryonic kidney (HEK) 293 cells with empty vector, or vector encoding wild-type GNAQ (GNAQWT), GNAQQ209P, or GNAQQ209L.	('GNAQQ209L', 'Var', (235, 244))	('HEK) 293', 'CellLine', 'CVCL:0045', (143, 151))	('GNAQ', 'Chemical', '-', (212, 216))	('GNAQ', 'Chemical', '-', (206, 210))	('ERK', 'molecular_function', 'GO:0004707', ('76', '79'))	('ERK', 'Gene', (76, 79))	('human', 'Species', '9606', (119, 124))	('GNAQQ209P', 'Mutation', 'rs121913492', (221, 230))	('hyperactivity', 'Disease', 'MESH:D006948', (44, 57))	('embryonic kidney', 'Disease', (125, 141))	('hyperactivity', 'Disease', (44, 57))	('hyperactivity', 'Phenotype', 'HP:0000752', (44, 57))	('GNAQ', 'Chemical', '-', (221, 225))	('signalling', 'biological_process', 'GO:0023052', ('80', '90'))	('GNAQQ209P', 'Var', (221, 230))	('GNAQ', 'Chemical', '-', (235, 239))	('embryonic kidney', 'Disease', 'MESH:D007674', (125, 141))	('ERK', 'Gene', '5594', (76, 79))
36800	27166257	Only the oncogenic forms (GNAQQ209P/L) resulted in ERK activation (Figure 7A), indicating that transient expression of oncogenic GNAQ can stimulate ERK.	('GNAQ', 'Chemical', '-', (26, 30))	('ERK', 'Gene', (51, 54))	('ERK', 'Gene', (148, 151))	('GNAQQ209P/L', 'Var', (26, 37))	('GNAQQ209P', 'Mutation', 'rs121913492', (26, 35))	('stimulate', 'PosReg', (138, 147))	('ERK', 'molecular_function', 'GO:0004707', ('148', '151'))	('ERK', 'Gene', '5594', (51, 54))	('GNAQ', 'Chemical', '-', (129, 133))	('ERK', 'molecular_function', 'GO:0004707', ('51', '54'))	('ERK', 'Gene', '5594', (148, 151))	('activation', 'PosReg', (55, 65))
36802	27166257	Following GNAQ knockdown, pERK1/2 levels remained unchanged in Mel202, Mel270, OMM1.3, and OMM1.5 cells, and as expected in OCM3 and OCM8, but it was only the 92.1 cell line that responded differently, showing a marked decrease in pERK1/2 levels (Figure 7B).	('ERK1/2', 'Gene', (27, 33))	('ERK1/2', 'Gene', '399480;360144', (27, 33))	('knockdown', 'Var', (15, 24))	('GNAQ', 'Chemical', '-', (10, 14))	('CM', 'Phenotype', 'HP:0012056', (125, 127))	('GNAQ', 'Gene', (10, 14))	('decrease', 'NegReg', (219, 227))	('ERK1/2', 'Gene', (232, 238))	('ERK1/2', 'Gene', '399480;360144', (232, 238))	('CM', 'Phenotype', 'HP:0012056', (134, 136))
36804	27166257	Moreover, treatment of UM cell lines with U-73122, a potent and selective PLC inhibitor, was not associated with any changes in pERK1/2 levels, excluding again 92.1 which showed reduced pERK1/2 levels (Figure 7D).	('PLC', 'cellular_component', 'GO:0042824', ('74', '77'))	('U-73122', 'Chemical', 'MESH:C060229', (42, 49))	('ERK1/2', 'Gene', (187, 193))	('ERK1/2', 'Gene', '399480;360144', (187, 193))	('U-73122', 'Var', (42, 49))	('UM', 'Phenotype', 'HP:0007716', (23, 25))	('ERK1/2', 'Gene', (129, 135))	('ERK1/2', 'Gene', '399480;360144', (129, 135))
36805	27166257	Using the Tol2-based transposon system, we genetically engineered zebrafish to express an oncogenic form of GNAQ (GNAQQ209P) under the control of the mitfa promoter to selectively target melanocytes.	('mitfa', 'Gene', '30080', (150, 155))	('GNAQ', 'Chemical', '-', (108, 112))	('zebrafish', 'Species', '7955', (66, 75))	('mitfa', 'Gene', (150, 155))	('GNAQQ209P', 'Mutation', 'rs121913492', (114, 123))	('GNAQ', 'Chemical', '-', (114, 118))	('GNAQQ209P', 'Var', (114, 123))
36806	27166257	Despite the transgene being expressed throughout the melanocyte lineage, including in the skin, it was uveal (choroidal) melanocytes that demonstrated hyperproliferation (and presumably leptomeningeal melanocytes), and interestingly, it is precisely this subset of melanocytes in humans that predominantly develops into melanoma in response to GNAQ mutation.	('uvea', 'Disease', (103, 107))	('melanoma', 'Disease', 'MESH:D008545', (320, 328))	('GNAQ', 'Gene', (344, 348))	('melanoma', 'Phenotype', 'HP:0002861', (320, 328))	('melanoma', 'Disease', (320, 328))	('uvea', 'Disease', 'MESH:C536494', (103, 107))	('mutation', 'Var', (349, 357))	('humans', 'Species', '9606', (280, 286))	('develops', 'Reg', (306, 314))	('GNAQ', 'Chemical', '-', (344, 348))
36807	27166257	Conversely, expression of oncogenic NRASQ61L or BRAFV600E from the same promoter resulted in hyperproliferation of cutaneous but not uveal melanocytes.	('hyperproliferation', 'CPA', (93, 111))	('BRAFV600E', 'Var', (48, 57))	('uvea', 'Disease', (133, 137))	('NRASQ61L', 'Var', (36, 44))	('uvea', 'Disease', 'MESH:C536494', (133, 137))
36808	27166257	Again, in humans, it is epidermal melanocytes that develop into melanoma in response to NRAS or BRAF mutations.	('mutations', 'Var', (101, 110))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('NRAS', 'Gene', (88, 92))	('melanoma', 'Disease', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('BRAF', 'Gene', (96, 100))	('humans', 'Species', '9606', (10, 16))
36809	27166257	Thus, despite being unable to target transgenes specifically to uveal melanocytes, nevertheless, owing to the intrinsic selective responses of anatomical subsets of melanocytes to various oncogenic drivers recurrently mutated in melanoma, we were able to induce an early oncogenic event within the uveal melanocytes, with no interference from the RPE or cutaneous melanocytes.	('melanoma', 'Phenotype', 'HP:0002861', (229, 237))	('melanoma', 'Disease', (229, 237))	('induce', 'Reg', (255, 261))	('melanoma', 'Disease', 'MESH:D008545', (229, 237))	('uvea', 'Disease', (64, 68))	('mutated', 'Var', (218, 225))	('uvea', 'Disease', 'MESH:C536494', (298, 302))	('uvea', 'Disease', (298, 302))	('uvea', 'Disease', 'MESH:C536494', (64, 68))
36810	27166257	Upon expression of GNAQQ209P in the melanocytes of zebrafish golden mutants, another effect we observed was its ability to rescue the reduced pigmentation caused by an inactivation of the slc24a5 gene required for melanosome formation and/or function.	('melanosome', 'cellular_component', 'GO:0042470', ('214', '224'))	('melanosome formation', 'biological_process', 'GO:1903232', ('214', '234'))	('inactivation', 'Var', (168, 180))	('pigmentation', 'MPA', (142, 154))	('zebrafish', 'Species', '7955', (51, 60))	('slc24a5', 'Gene', '570312', (188, 195))	('pigmentation', 'biological_process', 'GO:0043473', ('142', '154'))	('GNAQQ209P', 'Mutation', 'rs121913492', (19, 28))	('slc24a5', 'Gene', (188, 195))	('reduced', 'NegReg', (134, 141))	('GNAQQ209P', 'Var', (19, 28))
36813	27166257	In contrast, GNAQQ209L is compromised in GTP hydrolysis and is oncogenic.	('GNAQ', 'Chemical', '-', (13, 17))	('oncogenic', 'CPA', (63, 72))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('41', '55'))	('GTP', 'Chemical', 'MESH:D006160', (41, 44))	('GTP hydrolysis', 'MPA', (41, 55))	('GNAQQ209L', 'Var', (13, 22))	('compromised', 'NegReg', (26, 37))
36815	27166257	In zebrafish, despite the requirement for endothelin receptor B signalling in pigment pattern formation, forced expression of GNAQQ209P did not appear to affect the proliferation of cutaneous melanocytes.	('zebrafish', 'Species', '7955', (3, 12))	('pattern formation', 'biological_process', 'GO:0007389', ('86', '103'))	('pattern formation', 'biological_process', 'GO:0003002', ('86', '103'))	('endothelin receptor B', 'Gene', (42, 63))	('GNAQQ209P', 'Var', (126, 135))	('signalling', 'biological_process', 'GO:0023052', ('64', '74'))	('affect', 'Reg', (154, 160))	('GNAQQ209P', 'Mutation', 'rs121913492', (126, 135))	('endothelin receptor B', 'Gene', '30442', (42, 63))
36818	27166257	Oncogenic GNAQQ209P alone was not sufficient to drive malignant transformation of uveal melanocytes.	('GNAQQ209P', 'Var', (10, 19))	('uvea', 'Disease', (82, 86))	('GNAQQ209P', 'Mutation', 'rs121913492', (10, 19))	('uvea', 'Disease', 'MESH:C536494', (82, 86))	('malignant transformation of uveal melanocytes', 'Phenotype', 'HP:0007716', (54, 99))
36819	27166257	However, in co-operation with p53 loss-of-function, GNAQQ209P was able to promote uveal neoplasia.	('GNAQQ209P', 'Mutation', 'rs121913492', (52, 61))	('uveal neoplasia', 'Disease', (82, 97))	('promote', 'PosReg', (74, 81))	('loss-of-function', 'NegReg', (34, 50))	('p53', 'Gene', (30, 33))	('GNAQQ209P', 'Var', (52, 61))	('neoplasia', 'Phenotype', 'HP:0002664', (88, 97))	('uveal neoplasia', 'Disease', 'MESH:D014603', (82, 97))
36820	27166257	This is consistent with previous studies reporting the relatively weak oncogenic potential of mutant GNAQ/11 and their ability to transform only immortalized melanocytes that have been genetically altered to be deficient in the p53 and p16/CDK4/RB pathways.	('mutant', 'Var', (94, 100))	('GNAQ/11', 'Gene', (101, 108))	('GNAQ', 'Chemical', '-', (101, 105))	('CDK4', 'Gene', (240, 244))	('CDK4', 'Gene', '777730', (240, 244))	('CDK', 'molecular_function', 'GO:0004693', ('240', '243'))
36821	27166257	Further, the vast majority of uveal melanocytic neoplasms with GNAQ/11 mutations are benign, indicating that they require additional mutations to acquire metastatic potential.	('uveal melanocytic neoplasms', 'Disease', (30, 57))	('GNAQ/11', 'Gene', (63, 70))	('GNAQ', 'Chemical', '-', (63, 67))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (36, 57))	('mutations', 'Var', (71, 80))	('uveal melanocytic neoplasms', 'Phenotype', 'HP:0007716', (30, 57))	('neoplasms', 'Phenotype', 'HP:0002664', (48, 57))	('uveal melanocytic neoplasms', 'Disease', 'MESH:D014604', (30, 57))
36822	27166257	In the mouse, however, GNAQQ209L-expressing uveal melanocytes transformed readily and even developed distant metastases without the requirement to engineer further genetic modifications.	('mouse', 'Species', '10090', (7, 12))	('GNAQQ209L-expressing', 'Var', (23, 43))	('uvea', 'Disease', (44, 48))	('metastases', 'Disease', (109, 119))	('uvea', 'Disease', 'MESH:C536494', (44, 48))	('GNAQ', 'Chemical', '-', (23, 27))	('metastases', 'Disease', 'MESH:D009362', (109, 119))
36825	27166257	Of note, a commonality between mice and zebrafish genetically engineered UM models is the occurrence of melanocyte-derived neoplasms developing within the leptomeninges, which is consistent with the previously reported presence of GNAQ/11 mutations in human melanocytomas of the CNS.	('neoplasms', 'Disease', 'MESH:D009369', (123, 132))	('neoplasms', 'Disease', (123, 132))	('UM', 'Phenotype', 'HP:0007716', (73, 75))	('mutations', 'Var', (239, 248))	('mice', 'Species', '10090', (31, 35))	('neoplasms', 'Phenotype', 'HP:0002664', (123, 132))	('GNAQ/11', 'Gene', (231, 238))	('melanocytomas', 'Disease', (258, 271))	('GNAQ', 'Chemical', '-', (231, 235))	('zebrafish', 'Species', '7955', (40, 49))	('melanocytomas', 'Disease', 'None', (258, 271))	('human', 'Species', '9606', (252, 257))
36828	27166257	In contrast, oncogenic Galphaq drives UM in zebrafish and man and also dermal 'blue' naevi in man, but mutations in these proteins are all but absent in CM.	('naevi', 'Phenotype', 'HP:0003764', (85, 90))	('man', 'Species', '9606', (58, 61))	('oncogenic', 'Var', (13, 22))	('CM', 'Phenotype', 'HP:0012056', (153, 155))	("'blue' naevi", 'Phenotype', 'HP:0100814', (78, 90))	('man', 'Species', '9606', (94, 97))	('Galphaq', 'Gene', (23, 30))	('UM', 'Phenotype', 'HP:0007716', (38, 40))	('zebrafish', 'Species', '7955', (44, 53))
36829	27166257	Certainly, Galphaq proteins are expressed in cutaneous melanocytes, and as we and others demonstrate, hyperactivation of Galphaq proteins stimulates melanin synthesis in cutaneous melanocytes.	('melanin', 'Chemical', 'MESH:D008543', (149, 156))	('melanin synthesis', 'biological_process', 'GO:0042438', ('149', '166'))	('hyperactivation', 'Var', (102, 117))	('melanin synthesis', 'MPA', (149, 166))	('stimulates', 'PosReg', (138, 148))	('Galphaq proteins', 'Protein', (121, 137))
36830	27166257	Moreover, overexpression of GNAQQ209L in human cutaneous melanocytes stimulated ERK and contributed to in vitro transformation, so might be expected to substitute for NRAS or BRAF in CM.	('vitro transformation', 'CPA', (106, 126))	('stimulated', 'PosReg', (69, 79))	('ERK', 'Gene', '5594', (80, 83))	('ERK', 'Gene', (80, 83))	('GNAQ', 'Chemical', '-', (28, 32))	('human', 'Species', '9606', (41, 46))	('GNAQQ209L', 'Var', (28, 37))	('CM', 'Phenotype', 'HP:0012056', (183, 185))	('overexpression', 'PosReg', (10, 24))	('ERK', 'molecular_function', 'GO:0004707', ('80', '83'))
36831	27166257	What determines the differential sensitivity of uveal and cutaneous melanocytes to the various oncogenic driver mutations may ultimately be resolved by determining the developmental signalling networks operating in these anatomically and ontogenetically distinct melanocyte subsets.	('mutations', 'Var', (112, 121))	('uvea', 'Disease', (48, 52))	('signalling', 'biological_process', 'GO:0023052', ('182', '192'))	('uvea', 'Disease', 'MESH:C536494', (48, 52))
36833	27166257	Only a small percentage of uveal melanocytes benign and malignant expressing GNAQQ209P showed evidence of ERK activation, as revealed by immunoreactivity to pERK1/2.	('GNAQQ209P', 'Var', (77, 86))	('GNAQQ209P', 'Mutation', 'rs121913492', (77, 86))	('activation', 'PosReg', (110, 120))	('uvea', 'Disease', 'MESH:C536494', (27, 31))	('ERK', 'Gene', '5594', (158, 161))	('ERK', 'Gene', '5594', (106, 109))	('ERK', 'molecular_function', 'GO:0004707', ('106', '109'))	('ERK1/2', 'Gene', (158, 164))	('ERK', 'Gene', (158, 161))	('uvea', 'Disease', (27, 31))	('ERK', 'Gene', (106, 109))	('ERK1/2', 'Gene', '399480;360144', (158, 164))
36843	27166257	Transgenic zebrafish expressing oncogenic BRAFV600E [Tg (mitfa:BRAFV600E)] or HRASG12V[Tg (mitfa:HRASG12V)] in the melanocyte lineage have been previously described.	('mitfa', 'Gene', '30080', (57, 62))	('mitfa', 'Gene', (91, 96))	('BRAFV600E', 'Var', (42, 51))	('mitfa', 'Gene', '30080', (91, 96))	('mitfa', 'Gene', (57, 62))	('zebrafish', 'Species', '7955', (11, 20))	('HRASG12V[', 'Var', (78, 87))
36846	27166257	To generate mutant GNAQQ209P, the 872 bp insert was mutagenized using Quickchange II XL site-directed mutagenesis kit (Stratagene).	('mutant GNAQQ209P', 'Var', (12, 28))	('GNAQQ209P', 'Mutation', 'rs121913492', (19, 28))	('GNAQQ209P', 'Var', (19, 28))	('mutagenesis', 'biological_process', 'GO:0006280', ('102', '113'))
36847	27166257	Mutagenic oligonucleotides were designed using NEBase changer software (http://nebasechanger.neb.com), and were as follows: GNAQQ209P_Forward (Fwd): 5'-GATGTCGGGGGTCCACGATCAGAAAG-3' and GNAQQ209P_Reverse (Rev): 5'-CACCATCCTGAATATGACGCTTTG-3'.	('GNAQQ209P', 'Mutation', 'rs121913492', (124, 133))	('GNAQQ209P_Reverse', 'Var', (186, 203))	('GNAQQ209P_Forward', 'Var', (124, 141))	('GNAQQ209P', 'Mutation', 'rs121913492', (186, 195))
36866	27166257	Tissue samples were clipped from the caudal fins of wild-type, golden, and transgenic GNAQQ209P adult zebrafish.	('transgenic GNAQQ209P', 'Var', (75, 95))	('GNAQQ209P', 'Mutation', 'rs121913492', (86, 95))	('GNAQQ209P', 'Var', (86, 95))	('zebrafish', 'Species', '7955', (102, 111))
36886	27166257	The resulting supernatant (cell lysate) was then collected and analyzed for endogenous levels of ERK1/2 when phosphorylated at Thr202/Tyr204 using PathScan phospho-p44/42 MAPK (Thr202/Tyr204) sandwich ELISA kit (Cell Signalling Technology) following the manufacturer's instructions.	('Tyr204', 'Chemical', '-', (134, 140))	('MAPK', 'molecular_function', 'GO:0004707', ('171', '175'))	('Signalling', 'biological_process', 'GO:0023052', ('217', '227'))	('ERK1', 'molecular_function', 'GO:0004707', ('97', '101'))	('Thr202', 'Chemical', '-', (127, 133))	('ERK1/2', 'Gene', (97, 103))	('ERK1/2', 'Gene', '399480;360144', (97, 103))	('Thr202/Tyr204', 'Var', (177, 190))	('p44', 'Gene', (164, 167))	('man', 'Species', '9606', (254, 257))	('Tyr204', 'Chemical', '-', (184, 190))	('Thr202', 'Chemical', '-', (177, 183))	('p44', 'Gene', '323239', (164, 167))
36888	24460190	Neoplasms are initiated by gain of function mutations in one of several primary oncogenes, typically leading to benign melanocytic nevi with characteristic histologic features.	('Neoplasms', 'Phenotype', 'HP:0002664', (0, 9))	('benign melanocytic nevi', 'Disease', (112, 135))	('nevi', 'Phenotype', 'HP:0003764', (131, 135))	('Neoplasms', 'Disease', 'MESH:D009369', (0, 9))	('gain', 'Disease', (27, 31))	('gain', 'Disease', 'MESH:D015430', (27, 31))	('mutations', 'Var', (44, 53))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (119, 135))	('Neoplasms', 'Disease', (0, 9))
36890	24460190	Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories.	('override', 'PosReg', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('promote', 'PosReg', (58, 65))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('malignant tumors', 'Disease', (90, 106))	('Secondary genetic alterations', 'Var', (0, 29))	('malignant tumors', 'Disease', 'MESH:D018198', (90, 106))
36901	24460190	Over the last two decades tremendous progress has been made in uncovering genetic alterations in melanocytic neoplasia and an expanding panel or recurrent driver mutations that activate specific oncogenes or inactivate tumor suppressor genes is emerging.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('mutations', 'Var', (162, 171))	('tumor', 'Disease', (219, 224))	('melanocytic neoplasia', 'Disease', (97, 118))	('tumor suppressor', 'biological_process', 'GO:0051726', ('219', '235'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('219', '235'))	('oncogenes', 'Gene', (195, 204))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('neoplasia', 'Phenotype', 'HP:0002664', (109, 118))	('melanocytic neoplasia', 'Disease', 'MESH:D009369', (97, 118))	('activate', 'PosReg', (177, 185))	('inactivate', 'NegReg', (208, 218))
36902	24460190	Remarkably, many of the mutations are found in association with specific clinical or histopathological subsets of lesions, strongly supporting the notion of biologically distinct types of melanocytic neoplasms.	('melanocytic neoplasms', 'Disease', (188, 209))	('neoplasms', 'Phenotype', 'HP:0002664', (200, 209))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (188, 209))	('neoplasm', 'Phenotype', 'HP:0002664', (200, 208))	('mutations', 'Var', (24, 33))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (188, 209))
36913	24460190	Lesions of intraepithelial origin are distinct from melanocytic neoplasms, which consistently lack an epithelial involvement such as uveal melanoma and intradermal melanocytic proliferations, both of which share common mutations in the two G-protein alpha subunits GNAQ and GNA11.	('epithelia', 'Disease', 'None', (16, 25))	('epithelia', 'Disease', 'None', (102, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (133, 147))	('epithelia', 'Disease', (102, 111))	('epithelia', 'Disease', (16, 25))	('protein', 'cellular_component', 'GO:0003675', ('242', '249'))	('GNA11', 'Gene', (274, 279))	('neoplasm', 'Phenotype', 'HP:0002664', (64, 72))	('intradermal melanocytic proliferations', 'Disease', 'MESH:D059545', (152, 190))	('mutations', 'Var', (219, 228))	('GNAQ', 'Gene', (265, 269))	('uveal melanoma', 'Disease', 'MESH:C536494', (133, 147))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (52, 73))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('intradermal melanocytic proliferations', 'Disease', (152, 190))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (52, 73))	('neoplasms', 'Phenotype', 'HP:0002664', (64, 73))	('melanocytic neoplasms', 'Disease', (52, 73))	('uveal melanoma', 'Disease', (133, 147))
36918	24460190	Shortly after the discovery of frequent BRAF mutations in melanoma it became apparent that the mutations were unequally distributed across the phenotypic spectrum of melanocytic neoplasms.	('BRAF', 'Gene', '673', (40, 44))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('mutations', 'Var', (45, 54))	('BRAF', 'Gene', (40, 44))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (166, 187))	('neoplasms', 'Phenotype', 'HP:0002664', (178, 187))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (166, 187))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('neoplasm', 'Phenotype', 'HP:0002664', (178, 186))	('melanoma', 'Disease', (58, 66))	('melanocytic neoplasms', 'Disease', (166, 187))
36919	24460190	Mutations were more common in younger patients whose melanomas arose on skin that were sun-exposed, but not heavily sun-damaged as evidenced by the presence of marked solar elastosis, an accumulation of degenerated elastic fibers.	('melanomas', 'Disease', (53, 62))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('solar elastosis', 'Disease', 'MESH:D005148', (167, 182))	('melanomas', 'Disease', 'MESH:D008545', (53, 62))	('Mutations', 'Var', (0, 9))	('sun-damaged', 'Phenotype', 'HP:0000992', (116, 127))	('patients', 'Species', '9606', (38, 46))	('solar elastosis', 'Disease', (167, 182))	('common', 'Reg', (20, 26))
36920	24460190	Follow-up studies confirmed these associations and added additional distinguishing features of what emerges as a melanoma type that is characterized by a high frequency of specific BRAF mutations with associated clinical and histologic features such as increased pigmentation of the primary melanoma by clinical examination, and histopathological features such as a predominance of enlarged, hyperpigmented tumors cells of round rather than spindled shape, increased upward intraepidermal scatter, predominance of tumor cells nests over single cells, and thickening of the involved epidermis.	('pigmentation', 'biological_process', 'GO:0043473', ('263', '275'))	('tumor', 'Disease', 'MESH:D009369', (514, 519))	('melanoma', 'Disease', 'MESH:D008545', (291, 299))	('thickening', 'CPA', (555, 565))	('increased', 'PosReg', (457, 466))	('BRAF', 'Gene', (181, 185))	('upward intraepidermal scatter', 'CPA', (467, 496))	('BRAF', 'Gene', '673', (181, 185))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (514, 519))	('tumor', 'Disease', (407, 412))	('increased pigmentation', 'Phenotype', 'HP:0000953', (253, 275))	('tumor', 'Disease', 'MESH:D009369', (407, 412))	('melanoma', 'Phenotype', 'HP:0002861', (291, 299))	('melanoma', 'Disease', (291, 299))	('tumors', 'Phenotype', 'HP:0002664', (407, 413))	('hyperpigmented tumors', 'Disease', (392, 413))	('hyperpigmented tumors', 'Disease', 'MESH:C537836', (392, 413))	('mutations', 'Var', (186, 195))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (407, 412))	('increased', 'PosReg', (253, 262))	('tumor', 'Disease', (514, 519))
36921	24460190	Other genetic alterations associated with this melanoma type include copy number increases of chromosome 7, favoring the chromosome harboring the mutant BRAF allele, and loss of chromosome 10, primarily driven by PTEN.	('PTEN', 'Gene', '5728', (213, 217))	('BRAF', 'Gene', '673', (153, 157))	('BRAF', 'Gene', (153, 157))	('chromosome', 'cellular_component', 'GO:0005694', ('121', '131'))	('loss', 'NegReg', (170, 174))	('chromosome', 'cellular_component', 'GO:0005694', ('94', '104'))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('mutant', 'Var', (146, 152))	('chromosome', 'cellular_component', 'GO:0005694', ('178', '188'))	('copy number', 'Var', (69, 80))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('PTEN', 'Gene', (213, 217))	('increases', 'PosReg', (81, 90))
36926	24460190	The melanomas on skin without chronic sun-induced damage (non-CSD melanomas) were most commonly of the SSM type according to the WHO classification, but the features described above showed a stronger association with the BRAF mutation status than the WHO classification of SSM.	('BRAF', 'Gene', (221, 225))	('melanomas', 'Disease', 'MESH:D008545', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('SSM', 'cellular_component', 'GO:1990843', ('273', '276'))	('melanomas', 'Disease', (4, 13))	('SSM', 'Phenotype', 'HP:0012057', (273, 276))	('SSM', 'Phenotype', 'HP:0012057', (103, 106))	('non-CSD melanomas', 'Disease', (58, 75))	('melanomas', 'Disease', (66, 75))	('melanomas', 'Phenotype', 'HP:0002861', (4, 13))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('non-CSD melanomas', 'Disease', 'MESH:C562576', (58, 75))	('SSM', 'cellular_component', 'GO:1990843', ('103', '106'))	('BRAF', 'Gene', '673', (221, 225))	('melanomas', 'Disease', 'MESH:D008545', (4, 13))	('SSM', 'Disease', (103, 106))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('mutation status', 'Var', (226, 241))
36928	24460190	and others showed that BRAF mutations were also present in melanocytic nevi, with common acquired nevi being the type of nevus with the highest BRAF mutation frequency.	('BRAF', 'Gene', '673', (23, 27))	('BRAF', 'Gene', (23, 27))	('BRAF', 'Gene', '673', (144, 148))	('common acquired nevi', 'Disease', (82, 102))	('nevi', 'Phenotype', 'HP:0003764', (98, 102))	('BRAF', 'Gene', (144, 148))	('nevi', 'Phenotype', 'HP:0003764', (71, 75))	('melanocytic nevi', 'Disease', (59, 75))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (59, 75))	('mutations', 'Var', (28, 37))	('nevus', 'Phenotype', 'HP:0003764', (121, 126))
36929	24460190	While some studies have found that not all melanocytes within an acquired nevus may have detectable BRAF mutations and concluded that nevi may not be clonal or that BRAF mutations are not an initiating event, this finding may have been due to technical difficulties of quantifying mutant alleles in small numbers of cells.	('BRAF', 'Gene', '673', (165, 169))	('nevus', 'Phenotype', 'HP:0003764', (74, 79))	('BRAF', 'Gene', '673', (100, 104))	('BRAF', 'Gene', (165, 169))	('mutations', 'Var', (105, 114))	('BRAF', 'Gene', (100, 104))	('nevi', 'Phenotype', 'HP:0003764', (134, 138))
36930	24460190	Recent immunohistochemistry studies using a BRAF V600E specific antibody show labeling of the majority of neoplastic cells in melanocytic nevi harboring BRAF mutations but no labeling in nevi without BRAF mutations.	('BRAF', 'Gene', '673', (153, 157))	('BRAF', 'Gene', (200, 204))	('BRAF', 'Gene', (153, 157))	('BRAF', 'Gene', '673', (44, 48))	('nevi', 'Phenotype', 'HP:0003764', (138, 142))	('nevi', 'Phenotype', 'HP:0003764', (187, 191))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (126, 142))	('antibody', 'cellular_component', 'GO:0019814', ('64', '72'))	('BRAF', 'Gene', (44, 48))	('antibody', 'cellular_component', 'GO:0019815', ('64', '72'))	('antibody', 'molecular_function', 'GO:0003823', ('64', '72'))	('antibody', 'cellular_component', 'GO:0042571', ('64', '72'))	('melanocytic nevi', 'Disease', (126, 142))	('mutations', 'Var', (158, 167))	('BRAF', 'Gene', '673', (200, 204))	('V600E', 'Mutation', 'rs113488022', (49, 54))
36931	24460190	BRAF V600E mutations were also found to be fully clonal in neoplastic population of melanocytes using digital droplet PCR to quantify the mutant to wild type allelic ratios.	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('V600E', 'Var', (5, 10))	('V600E', 'Mutation', 'rs113488022', (5, 10))
36932	24460190	The finding of mutations in potent oncogenes in benign nevi such as NRAS in congenital nevi, HRAS in Spitz nevi, and later BRAF in acquired nevi, GNAQ or GNA11 in blue nevi originally came as a surprise, and the mechanisms suppressing the expansion of partially transformed melanocytes in nevi became of significant interest.	('nevi', 'Phenotype', 'HP:0003764', (87, 91))	('nevi', 'Phenotype', 'HP:0003764', (168, 172))	('HRAS', 'Gene', '3265', (93, 97))	('nevi', 'Phenotype', 'HP:0003764', (55, 59))	('nevi', 'Phenotype', 'HP:0003764', (107, 111))	('congenital nevi', 'Disease', (76, 91))	('mutations', 'Var', (15, 24))	('BRAF', 'Gene', (123, 127))	('NRAS', 'Gene', (68, 72))	('BRAF', 'Gene', '673', (123, 127))	('blue nevi', 'Phenotype', 'HP:0100814', (163, 172))	('melanocytes in nevi', 'Phenotype', 'HP:0000995', (274, 293))	('NRAS', 'Gene', '4893', (68, 72))	('HRAS', 'Gene', (93, 97))	('nevi', 'Phenotype', 'HP:0003764', (140, 144))
36933	24460190	Many of the studies have been performed in the context of BRAF mutations and therefore are discussed in this section.	('mutations', 'Var', (63, 72))	('BRAF', 'Gene', (58, 62))	('BRAF', 'Gene', '673', (58, 62))
36936	24460190	One, oncogene-induced senescence has been proposed as an immediate reaction in which a mutation within a critical signaling pathway such as the MAP-kinase pathway leads to non-physiologically high activation, which triggers a stress response leading to the induction of cyclin-dependent kinase inhibitors such as p21 and p16, leading to permanent G1 arrest.	('MAP', 'molecular_function', 'GO:0004239', ('144', '147'))	('senescence', 'biological_process', 'GO:0010149', ('22', '32'))	('activation', 'PosReg', (197, 207))	('p21', 'Gene', (313, 316))	('p16', 'Gene', '1029', (321, 324))	('cyclin', 'molecular_function', 'GO:0016538', ('270', '276'))	('p21', 'Gene', '644914', (313, 316))	('G1 arrest', 'CPA', (347, 356))	('signaling pathway', 'biological_process', 'GO:0007165', ('114', '131'))	('mutation', 'Var', (87, 95))	('p16', 'Gene', (321, 324))
36937	24460190	The critical role of p16 in melanoma is demonstrated by the fact that p16 is disabled by deletion, mutation, or silencing of CDKN2A in the majority of melanomas, and germline mutations in CDKN2A predispose to melanoma with high penetrance.	('p16', 'Gene', '1029', (70, 73))	('deletion', 'Var', (89, 97))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('CDKN2A', 'Gene', '1029', (188, 194))	('melanomas', 'Phenotype', 'HP:0002861', (151, 160))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('mutation', 'Var', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('silencing', 'NegReg', (112, 121))	('CDKN2A', 'Gene', (125, 131))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('melanomas', 'Disease', 'MESH:D008545', (151, 160))	('melanoma', 'Disease', (28, 36))	('p16', 'Gene', '1029', (21, 24))	('melanomas', 'Disease', (151, 160))	('p16', 'Gene', (21, 24))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('CDKN2A', 'Gene', (188, 194))	('disabled', 'NegReg', (77, 85))	('p16', 'Gene', (70, 73))	('melanoma', 'Disease', (209, 217))	('germline mutations', 'Var', (166, 184))	('CDKN2A', 'Gene', '1029', (125, 131))	('predispose', 'Reg', (195, 205))
36938	24460190	Ten percent of melanoma patients have a family history of melanoma and of these 20-40% carry germline mutations of CDKN2A, with mutations mostly in the exons or reading frame that affects p16 and not p14, which is also transcribed from this same gene.	('CDKN2A', 'Gene', (115, 121))	('affects', 'Reg', (180, 187))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('p16', 'Gene', (188, 191))	('melanoma', 'Disease', (15, 23))	('CDKN2A', 'Gene', '1029', (115, 121))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('mutations', 'Var', (102, 111))	('p14', 'Gene', (200, 203))	('p16', 'Gene', '1029', (188, 191))	('patients', 'Species', '9606', (24, 32))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('p14', 'Gene', '1029', (200, 203))	('melanoma', 'Disease', (58, 66))
36939	24460190	Approximately 2-3% of melanoma families have CDK4 mutations in the p16 binding domain, and a similar percentage has mutations that specifically disable p14/ARF, which acts upstream of p53, by inhibiting its ubiquitinase mdm2.	('ARF', 'Disease', 'MESH:D058186', (156, 159))	('p16', 'Gene', '1029', (67, 70))	('p53', 'Gene', '7157', (184, 187))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('CDK4', 'Gene', '1019', (45, 49))	('p53', 'Gene', (184, 187))	('mdm2', 'Gene', (220, 224))	('p14', 'Gene', '1029', (152, 155))	('inhibiting', 'NegReg', (192, 202))	('ARF', 'Disease', (156, 159))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('CDK', 'molecular_function', 'GO:0004693', ('45', '48'))	('melanoma', 'Disease', (22, 30))	('mutations', 'Var', (116, 125))	('p14', 'Gene', (152, 155))	('binding', 'Interaction', (71, 78))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))	('disable', 'NegReg', (144, 151))	('mutations', 'Var', (50, 59))	('mdm2', 'Gene', '4193', (220, 224))	('CDK4', 'Gene', (45, 49))	('p16', 'Gene', (67, 70))
36941	24460190	Patients with inherited CDKN2A mutations have more and larger nevi than their wild type relatives, indicating that p16 exerts its tumor suppressive function from nevus initiation to later phases of nevus growth.	('nevi', 'Phenotype', 'HP:0003764', (62, 66))	('mutations', 'Var', (31, 40))	('nevus', 'Phenotype', 'HP:0003764', (162, 167))	('nevi', 'CPA', (62, 66))	('p16', 'Gene', '1029', (115, 118))	('nevus', 'Phenotype', 'HP:0003764', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('CDKN2A', 'Gene', (24, 30))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('CDKN2A', 'Gene', '1029', (24, 30))	('p16', 'Gene', (115, 118))	('tumor', 'Disease', (130, 135))
36946	24460190	The more such barriers become disabled by inherited or by somatic mutations the larger the nevus will grow, and with it the probability of full transformation to melanoma.	('mutations', 'Var', (66, 75))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('nevus', 'Phenotype', 'HP:0003764', (91, 96))	('nevus', 'Disease', (91, 96))
36949	24460190	Amplification of the TERT gene has been reported as a common event in acral melanoma and observed to coincide with the transition to more advanced primaries.	('acral melanoma', 'Phenotype', 'HP:0012060', (70, 84))	('Amplification', 'Var', (0, 13))	('TERT', 'Gene', (21, 25))	('TERT', 'Gene', '7015', (21, 25))	('acral melanoma', 'Disease', 'MESH:D008545', (70, 84))	('acral melanoma', 'Disease', (70, 84))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
36950	24460190	Recently, frequent mutations in the telomerase promoter have been found in melanoma.	('found', 'Reg', (66, 71))	('mutations', 'Var', (19, 28))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))
36961	24460190	Such eruptive nevi also frequently have BRAF mutations and favor sun-exposed sites, indicating that the initiating mechanisms are identical to other acquired nevi.	('BRAF', 'Gene', '673', (40, 44))	('nevi', 'Phenotype', 'HP:0003764', (14, 18))	('mutations', 'Var', (45, 54))	('BRAF', 'Gene', (40, 44))	('nevi', 'Phenotype', 'HP:0003764', (158, 162))
36963	24460190	Epigenetic alterations are emerging as additional tumor suppressive mechanisms in melanoma as evidenced by recurrent mutations in genes involved in chromatin remodeling and dramatic changes in the chromatin state and DNA modifications in melanoma.	('Epigenetic alterations', 'Var', (0, 22))	('additional tumor', 'Disease', (39, 55))	('melanoma', 'Disease', (238, 246))	('mutations', 'Var', (117, 126))	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('chromatin', 'cellular_component', 'GO:0000785', ('148', '157'))	('melanoma', 'Disease', 'MESH:D008545', (238, 246))	('DNA', 'cellular_component', 'GO:0005574', ('217', '220'))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('changes', 'Reg', (182, 189))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('chromatin', 'cellular_component', 'GO:0000785', ('197', '206'))	('chromatin state', 'MPA', (197, 212))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('148', '168'))	('DNA modifications', 'MPA', (217, 234))	('additional tumor', 'Disease', 'MESH:D009369', (39, 55))
36964	24460190	Sequencing studies have revealed recurrent mutations in components of the SWI/SNF complex including ARID1A, ARID1B, and ARID2 as well as SMARCA4.	('SMARCA4', 'Gene', (137, 144))	('SMARCA4', 'Gene', '6597', (137, 144))	('ARID1B', 'Gene', (108, 114))	('ARID1A', 'Gene', '8289', (100, 106))	('ARID2', 'Gene', '196528', (120, 125))	('ARID1A', 'Gene', (100, 106))	('mutations', 'Var', (43, 52))	('SWI/SNF complex', 'Gene', (74, 89))	('ARID1B', 'Gene', '57492', (108, 114))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('74', '89'))	('ARID2', 'Gene', (120, 125))
36970	24460190	Genome-wide hypomethylation and hypermethylation of certain promoter regions has been observed in melanoma compared to normal melanocytes or neoplastic melanocytes of nevi.	('observed', 'Reg', (86, 94))	('hypermethylation', 'MPA', (32, 48))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('nevi', 'Phenotype', 'HP:0003764', (167, 171))	('melanoma', 'Disease', (98, 106))	('hypomethylation', 'Var', (12, 27))	('melanocytes of nevi', 'Phenotype', 'HP:0000995', (152, 171))	('neoplastic melanocytes', 'Phenotype', 'HP:0002861', (141, 163))
36973	24460190	In myelodysplastic syndrome and acute myeloid leukemia loss of 5-hmC is caused by loss of function of the 5-methyl-cytosine hydroxylating enzymes of the TET family, which can occur by inactivating mutations or functional inhibition via the production of 2-ketoglutarate caused by mutations in IDH1 or -2.	('IDH1', 'Gene', (293, 297))	('loss of function', 'NegReg', (82, 98))	('myelodysplastic syndrome', 'Disease', (3, 27))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (3, 27))	('inhibition', 'NegReg', (221, 231))	('IDH1', 'Gene', '3417', (293, 297))	('mutations', 'Var', (280, 289))	('2-ketoglutarate', 'Chemical', 'MESH:D007656', (254, 269))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (32, 54))	('inactivating mutations', 'Var', (184, 206))	('acute myeloid leukemia loss', 'Disease', (32, 59))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (38, 54))	('acute myeloid leukemia loss', 'Disease', 'MESH:D015470', (32, 59))	('5-hmC', 'Chemical', 'MESH:C011865', (63, 68))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (3, 27))	('leukemia', 'Phenotype', 'HP:0001909', (46, 54))	('TET', 'Chemical', 'MESH:C010349', (153, 156))	('cytosine', 'Chemical', 'MESH:D003596', (115, 123))
36974	24460190	While mutations in TET and IDH appear to be infrequent in melanoma, decreased expression levels of these proteins have been implicated as a mechanism underlying the loss of 5-hmC in melanoma progression.	('IDH', 'Gene', (27, 30))	('decreased', 'NegReg', (68, 77))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('5-hmC', 'Chemical', 'MESH:C011865', (173, 178))	('IDH', 'Gene', '3417', (27, 30))	('TET', 'Gene', (19, 22))	('melanoma', 'Disease', (182, 190))	('TET', 'Chemical', 'MESH:C010349', (19, 22))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('loss', 'NegReg', (165, 169))	('expression levels of these', 'MPA', (78, 104))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('mutations', 'Var', (6, 15))	('melanoma', 'Disease', (58, 66))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))
36975	24460190	Inactivating mutations in the deubiquitinase BAP1 have been found as frequent somatic events during the progression of uveal melanoma, as discussed below.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('BAP1', 'Gene', (45, 49))	('BAP1', 'Gene', '8314', (45, 49))	('Inactivating mutations', 'Var', (0, 22))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('30', '44'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (119, 133))	('uveal melanoma', 'Disease', 'MESH:C536494', (119, 133))	('uveal melanoma', 'Disease', (119, 133))
36976	24460190	Germline mutations in BAP1 were independently discovered in two families with uveal and cutaneous melanoma and atypical Spitz tumors.	('Germline mutations', 'Var', (0, 18))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('discovered', 'Reg', (46, 56))	('cutaneous melanoma', 'Disease', (88, 106))	('atypical Spitz tumors', 'Disease', (111, 132))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (88, 106))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (88, 106))	('BAP1', 'Gene', '8314', (22, 26))	('atypical Spitz tumors', 'Disease', 'MESH:D018332', (111, 132))	('uveal', 'Disease', (78, 83))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('BAP1', 'Gene', (22, 26))
36978	24460190	The resulting lesions show a bi-phasic morphology and represents an example of step-wise tumor progression, with a common acquired nevi initiated by BRAF mutation and promoted by loss of function of BAP1.	('BRAF', 'Gene', (149, 153))	('BAP1', 'Gene', '8314', (199, 203))	('BRAF', 'Gene', '673', (149, 153))	('loss of function', 'NegReg', (179, 195))	('BAP1', 'Gene', (199, 203))	('mutation', 'Var', (154, 162))	('nevi', 'Phenotype', 'HP:0003764', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
36979	24460190	BAP1 interacts with the polycomb factors ASXL1 and 2 and its substrates HCF-1 and OGT, but the precise mechanism how its loss of function bypasses growth arrest in BRAF mutated nevi remains to be elucidated.	('ASXL1 and 2', 'Gene', '171023;55252', (41, 52))	('BAP1', 'Gene', (0, 4))	('mutated', 'Var', (169, 176))	('OGT', 'Gene', (82, 85))	('growth arrest', 'Disease', (147, 160))	('HCF-1', 'Gene', '3054', (72, 77))	('OGT', 'Gene', '8473', (82, 85))	('HCF-1', 'Gene', (72, 77))	('BRAF', 'Gene', '673', (164, 168))	('growth arrest', 'Disease', 'MESH:D006323', (147, 160))	('nevi', 'Phenotype', 'HP:0003764', (177, 181))	('loss of function', 'NegReg', (121, 137))	('BRAF', 'Gene', (164, 168))	('growth arrest', 'Phenotype', 'HP:0001510', (147, 160))	('BAP1', 'Gene', '8314', (0, 4))
36992	24460190	The presence of clinically dysplastic nevi is thus a symptom of systemic melanoma susceptibility and reflects the inherited loss of genes functionally involved in restraining the proliferation of melanocytes that have acquired oncogenic mutations in genes like BRAF.	('loss', 'NegReg', (124, 128))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (27, 42))	('dysplastic', 'Disease', (27, 37))	('systemic melanoma', 'Disease', 'MESH:D008545', (64, 81))	('dysplastic', 'Disease', 'MESH:D004416', (27, 37))	('BRAF', 'Gene', (261, 265))	('systemic melanoma', 'Disease', (64, 81))	('BRAF', 'Gene', '673', (261, 265))	('mutations', 'Var', (237, 246))	('nevi', 'Phenotype', 'HP:0003764', (38, 42))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
36995	24460190	Nevi with histopathological dysplasia have been analyzed for allelic imbalance and found to have recurrent losses of heterozygosity of the CDKN2A and TP53 loci and BRAF V600E mutations.	('TP53', 'Gene', (150, 154))	('CDKN2A', 'Gene', '1029', (139, 145))	('dysplasia', 'Disease', 'MESH:D004476', (28, 37))	('V600E', 'Mutation', 'rs113488022', (169, 174))	('heterozygosity', 'MPA', (117, 131))	('dysplasia', 'Disease', (28, 37))	('Nevi', 'Phenotype', 'HP:0003764', (0, 4))	('V600E', 'Var', (169, 174))	('BRAF', 'Gene', '673', (164, 168))	('BRAF', 'Gene', (164, 168))	('TP53', 'Gene', '7157', (150, 154))	('CDKN2A', 'Gene', (139, 145))	('losses', 'NegReg', (107, 113))	('imbalance', 'Phenotype', 'HP:0002172', (69, 78))
36996	24460190	In summary the collective findings outlined above indicate that the neoplastic proliferation initiated by mutations in oncogenes is restrained by a multitude of independent mechanisms, which can be overridden by additional mutations that lead to loss of function in multiple tumor suppressor genes.	('tumor suppressor', 'biological_process', 'GO:0051726', ('275', '291'))	('neoplastic proliferation', 'Phenotype', 'HP:0002664', (68, 92))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('275', '291'))	('mutations', 'Var', (106, 115))	('oncogenes', 'Gene', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('neoplastic proliferation', 'CPA', (68, 92))
37009	24460190	Approximately 20% of cases show oncogenic mutations of HRAS, typically accompanied by copy number increases of the entire short arm of chromosome 11 as the only chromosomal aberration.	('HRAS', 'Gene', '3265', (55, 59))	('HRAS', 'Gene', (55, 59))	('short arm', 'Phenotype', 'HP:0009824', (122, 131))	('chromosome', 'cellular_component', 'GO:0005694', ('135', '145'))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (161, 183))	('copy number', 'MPA', (86, 97))	('increases', 'PosReg', (98, 107))	('mutations', 'Var', (42, 51))
37013	24460190	Recent studies have revealed a high frequency of rearrangements of kinases in the remainder of Spitz tumors.	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('Spitz tumors', 'Disease', (95, 107))	('rearrangements', 'Var', (49, 63))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('kinases', 'Protein', (67, 74))	('Spitz tumors', 'Disease', 'MESH:D018332', (95, 107))
37014	24460190	Rearrangements resulting in fusion kinases of ROS1, ALK, RET, NTRK1, and BRAF were observed in 60% of cases (Wiesner T, He J., Yelensky R, Esteve-Puig R., Botton T., Yeh I, Garrido M, et al., submitted).	('BRAF', 'Gene', '673', (73, 77))	('Rearrangements', 'Var', (0, 14))	('fusion kinases', 'MPA', (28, 42))	('NTRK1', 'Gene', (62, 67))	('ALK', 'Gene', '238', (52, 55))	('RET', 'Gene', (57, 60))	('ROS1', 'Gene', (46, 50))	('RET', 'Gene', '5979', (57, 60))	('BRAF', 'Gene', (73, 77))	('observed', 'Reg', (83, 91))	('NTRK1', 'Gene', '4914', (62, 67))	('ALK', 'Gene', (52, 55))	('ROS1', 'Gene', '6098', (46, 50))
37016	24460190	The 5' fusion partners in the majority have coiled-coil domains suggesting that they allow the kinase domains to dimerize and autophosphorylate, resulting in ligand-independent constitutive activation of multiple oncogenic signaling pathways including the MAP-kinase, PI3-kinase, STAT pathways with potent induction of proliferation.	('ligand', 'molecular_function', 'GO:0005488', ('158', '164'))	('activation', 'PosReg', (190, 200))	('PI3', 'Gene', (268, 271))	('signaling', 'biological_process', 'GO:0023052', ('223', '232'))	('STAT pathways', 'Pathway', (280, 293))	('MAP-kinase', 'Pathway', (256, 266))	('PI3', 'Gene', '5266', (268, 271))	('coiled-coil domains', 'Var', (44, 63))	('oncogenic signaling pathways', 'Pathway', (213, 241))	('MAP', 'molecular_function', 'GO:0004239', ('256', '259'))
37019	24460190	It is conceivable that Spitz tumors are not immortal and lack the high mutation burden that can make mutations in the telomerase promoter likely, as occurs in most lethal melanomas.	('Spitz tumors', 'Disease', (23, 35))	('mutations', 'Var', (101, 110))	('melanomas', 'Disease', (171, 180))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('melanomas', 'Disease', 'MESH:D008545', (171, 180))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanomas', 'Phenotype', 'HP:0002861', (171, 180))	('Spitz tumors', 'Disease', 'MESH:D018332', (23, 35))
37029	24460190	Whole genome and exome sequencing studies have revealed a high burden of mutations in the genomes of melanomas originating from sun-exposed sites, with cytosine to thymidine transitions prevailing, thereby providing compelling genetic validation for UV radiation as a major mutagenic factor.	('melanomas', 'Phenotype', 'HP:0002861', (101, 110))	('cytosine', 'Chemical', 'MESH:D003596', (152, 160))	('thymidine', 'Chemical', 'MESH:D013936', (164, 173))	('melanomas', 'Disease', 'MESH:D008545', (101, 110))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('cytosine to thymidine transitions', 'MPA', (152, 185))	('melanomas', 'Disease', (101, 110))	('mutations', 'Var', (73, 82))
37032	24460190	Some studies have found polymorphisms in DNA repair genes such as ERCC2 to be associated with melanoma risk and others have found high frequencies of somatic loss of function mutations of genes in the DNA damage response pathways including ERCC2.	('associated', 'Reg', (78, 88))	('DNA damage response', 'biological_process', 'GO:0006974', ('201', '220'))	('ERCC2', 'Gene', (240, 245))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('ERCC2', 'Gene', (66, 71))	('loss of function', 'NegReg', (158, 174))	('melanoma', 'Disease', (94, 102))	('DNA', 'cellular_component', 'GO:0005574', ('201', '204'))	('polymorphisms', 'Var', (24, 37))	('DNA repair', 'biological_process', 'GO:0006281', ('41', '51'))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('mutations', 'Var', (175, 184))	('ERCC2', 'Gene', '2068', (240, 245))	('ERCC2', 'Gene', '2068', (66, 71))
37034	24460190	BRAF mutations also arise in thyroid or colorectal cancer, indicating that UV is not required for their formation.	('colorectal cancer', 'Disease', (40, 57))	('thyroid', 'Disease', 'MESH:D013959', (29, 36))	('arise', 'Reg', (20, 25))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (40, 57))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('thyroid', 'Disease', (29, 36))	('colorectal cancer', 'Phenotype', 'HP:0003003', (40, 57))	('formation', 'biological_process', 'GO:0009058', ('104', '113'))
37036	24460190	While UV radiation primarily causes mutations at pyrimidine dimers it causes a broad range of other mutations as well.	('mutations', 'Var', (36, 45))	('causes', 'Reg', (70, 76))	('pyrimidine', 'Chemical', 'MESH:C030986', (49, 59))	('pyrimidine dimers', 'Var', (49, 66))	('causes', 'Reg', (29, 35))
37039	24460190	While the specific mutations that induced melanoma formation in this model are not yet known, the results clearly establish an interaction between UV radiation and melanin as a causative mechanism.	('melanoma', 'Disease', (42, 50))	('mutations', 'Var', (19, 28))	('melanin', 'Chemical', 'MESH:D008543', (164, 171))	('formation', 'biological_process', 'GO:0009058', ('51', '60'))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('interaction', 'Interaction', (127, 138))
37041	24460190	Using a mouse model in which mutant BRAF V600E can be conditionally activated in melanocytes, melanomas only developed if melanin, pheomelanin specifically, was present (Sidebar).	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('BRAF', 'Gene', (36, 40))	('melanin', 'Chemical', 'MESH:D008543', (135, 142))	('melanomas', 'Disease', 'MESH:D008545', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('mutant', 'Var', (29, 35))	('pheomelanin', 'Chemical', 'MESH:C018362', (131, 142))	('melanin', 'Chemical', 'MESH:D008543', (122, 129))	('mouse', 'Species', '10090', (8, 13))	('melanomas', 'Disease', (94, 103))	('BRAF', 'Gene', '673', (36, 40))	('V600E', 'Mutation', 'rs113488022', (41, 46))
37043	24460190	In this model, the BRAF mutations were already pre-engineered so that melanoma formation depended on additional, yet unknown mutations to occur.	('melanoma', 'Disease', (70, 78))	('BRAF', 'Gene', '673', (19, 23))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('pre', 'molecular_function', 'GO:0003904', ('47', '50'))	('BRAF', 'Gene', (19, 23))	('formation', 'biological_process', 'GO:0009058', ('79', '88'))	('mutations', 'Var', (24, 33))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
37054	24460190	The majority of individuals of European descent have inherited variants in MC1R, which blunt the receptor's ability to activate downstream signaling and to induce tanning in response to binding of MSH.	('tanning', 'CPA', (163, 170))	('MC1R', 'Gene', (75, 79))	('variants', 'Var', (63, 71))	('activate downstream signaling', 'MPA', (119, 148))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('response', 'MPA', (174, 182))	('MSH', 'Gene', (197, 200))	('induce', 'Reg', (156, 162))	('ability', 'MPA', (108, 115))	('MSH', 'Gene', '5443', (197, 200))	('binding', 'molecular_function', 'GO:0005488', ('186', '193'))	('binding', 'Interaction', (186, 193))	('blunt', 'NegReg', (87, 92))
37055	24460190	Several loss of function variants of MC1R are highly associated with red hair, poor tanning and freckling of the skin and increased melanoma risk.	('MC1R', 'Gene', (37, 41))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('variants', 'Var', (25, 33))	('red hair', 'Phenotype', 'HP:0002297', (69, 77))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('red hair', 'Disease', 'MESH:C567091', (69, 77))	('freckling of the skin', 'CPA', (96, 117))	('freckling', 'Phenotype', 'HP:0001480', (96, 105))	('poor tanning', 'CPA', (79, 91))	('loss of function', 'NegReg', (8, 24))	('red hair', 'Disease', (69, 77))
37056	24460190	Germline polymorphism in a range of other genes affecting skin pigmentation including ASIP, OCA2, SLC45A2, TYRP1, and TYR have been associated with melanoma risk, but inherited polymorphisms in MC1R are probably the most important genetic factor among risk alleles that occur at high frequency in populations.	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('ASIP', 'Gene', (86, 90))	('OCA2', 'Gene', (92, 96))	('OCA2', 'Gene', '4948', (92, 96))	('TYRP1', 'Gene', '7306', (107, 112))	('polymorphisms', 'Var', (177, 190))	('skin pigmentation', 'Phenotype', 'HP:0000953', (58, 75))	('TYR', 'Chemical', 'MESH:D014443', (118, 121))	('skin pigmentation', 'Disease', (58, 75))	('TYRP1', 'Gene', (107, 112))	('pigmentation', 'biological_process', 'GO:0043473', ('63', '75'))	('SLC45A2', 'Gene', '51151', (98, 105))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('skin pigmentation', 'Disease', 'MESH:D010859', (58, 75))	('associated', 'Reg', (132, 142))	('MC1R', 'Gene', (194, 198))	('TYR', 'Chemical', 'MESH:D014443', (107, 110))	('SLC45A2', 'Gene', (98, 105))	('ASIP', 'Gene', '434', (86, 90))
37058	24460190	In non-CSD melanomas MC1R variants were strongly associated with BRAF mutations in some studies, but not in others.	('mutations', 'Var', (70, 79))	('MC1R', 'Gene', (21, 25))	('associated', 'Reg', (49, 59))	('non-CSD melanomas', 'Disease', 'MESH:C562576', (3, 20))	('non-CSD melanomas', 'Disease', (3, 20))	('BRAF', 'Gene', '673', (65, 69))	('BRAF', 'Gene', (65, 69))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanomas', 'Phenotype', 'HP:0002861', (11, 20))	('variants', 'Var', (26, 34))
37060	24460190	CSD melanomas have a low frequency of BRAF mutations.	('CSD melanomas', 'Disease', (0, 13))	('CSD melanomas', 'Disease', 'MESH:C562576', (0, 13))	('BRAF', 'Gene', '673', (38, 42))	('mutations', 'Var', (43, 52))	('melanomas', 'Phenotype', 'HP:0002861', (4, 13))	('BRAF', 'Gene', (38, 42))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))
37061	24460190	Those that occur are primarily of the V600K rather than V600E type.	('V600E', 'Mutation', 'rs113488022', (56, 61))	('V600K', 'Var', (38, 43))	('V600E', 'Var', (56, 61))	('V600K', 'Mutation', 'rs121913227', (38, 43))
37062	24460190	In addition, BRAF mutations in CSD melanomas are associated with wild type MC1R alleles, indicating that any interactions between BRAF and MC1R may be complex.	('melanomas', 'Phenotype', 'HP:0002861', (35, 44))	('CSD melanomas', 'Disease', (31, 44))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', '673', (130, 134))	('BRAF', 'Gene', (130, 134))	('BRAF', 'Gene', (13, 17))	('CSD melanomas', 'Disease', 'MESH:C562576', (31, 44))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('mutations', 'Var', (18, 27))
37063	24460190	The consistent observation that melanocytic neoplasms with BRAF V600E mutations arise early in life and decrease in frequency later, while V600K show an opposite behavior is a puzzle to be solved.	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (32, 53))	('V600E', 'Var', (64, 69))	('neoplasms', 'Phenotype', 'HP:0002664', (44, 53))	('BRAF', 'Gene', (59, 63))	('V600E', 'Mutation', 'rs113488022', (64, 69))	('BRAF', 'Gene', '673', (59, 63))	('V600K', 'Mutation', 'rs121913227', (139, 144))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (32, 53))	('neoplasm', 'Phenotype', 'HP:0002664', (44, 52))	('melanocytic neoplasms', 'Disease', (32, 53))
37064	24460190	The early onset and multiplicity of nevi with BRAF mutations in some individuals suggests a genetically determined susceptibility that manifests itself in a high mutation rate in melanocytes.	('BRAF', 'Gene', (46, 50))	('mutation', 'MPA', (162, 170))	('BRAF', 'Gene', '673', (46, 50))	('mutations', 'Var', (51, 60))	('nevi', 'Phenotype', 'HP:0003764', (36, 40))	('nevi', 'Disease', (36, 40))
37065	24460190	The odds of mutating one of the single base pairs to generate the C.1799T>A mutation resulting in the V600E allele is exceedingly low so that the presence of multiple independent nevi with these mutations on the skin indicates a high mutation burden in normal melanocytes already at a young age.	('multiple independent nevi', 'Phenotype', 'HP:0001054', (158, 183))	('C.1799T>A', 'Var', (66, 75))	('1799T>A', 'Mutation', 'rs113488022', (68, 75))	('V600E', 'Mutation', 'rs113488022', (102, 107))	('nevi', 'Phenotype', 'HP:0003764', (179, 183))	('V600E', 'Var', (102, 107))
37074	24460190	Melanomas on chronic sun-exposed skin differ in the genetic alterations from non-CSD melanomas in that they have infrequent BRAF mutations, with BRAF V600K being more frequent than BRAF V600E mutations, inactivating mutations of NF1 in 30%, copy number increase of CCND1 in 20%, activating mutations of KIT in approximately 10%, increased mutational frequencies in TP53, and ARID2 and differences in the pattern of chromosomal aberrations as shown in table 1.	('ARID2', 'Gene', '196528', (375, 380))	('inactivating mutations', 'Var', (203, 225))	('non-CSD melanomas', 'Disease', (77, 94))	('BRAF', 'Gene', (145, 149))	('NF1', 'Gene', '4763', (229, 232))	('non-CSD melanomas', 'Disease', 'MESH:C562576', (77, 94))	('CCND1', 'Gene', '595', (265, 270))	('increase', 'PosReg', (253, 261))	('activating', 'PosReg', (279, 289))	('mutational frequencies', 'Var', (339, 361))	('CCND1', 'Gene', (265, 270))	('NF1', 'Gene', (229, 232))	('V600E', 'Mutation', 'rs113488022', (186, 191))	('ARID2', 'Gene', (375, 380))	('TP53', 'Gene', '7157', (365, 369))	('BRAF', 'Gene', (181, 185))	('BRAF', 'Gene', '673', (181, 185))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (415, 438))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('increased', 'PosReg', (329, 338))	('BRAF', 'Gene', (124, 128))	('BRAF', 'Gene', '673', (124, 128))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (415, 437))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('KIT', 'Gene', (303, 306))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('mutations', 'Var', (129, 138))	('Melanomas', 'Disease', (0, 9))	('KIT', 'molecular_function', 'GO:0005020', ('303', '306'))	('TP53', 'Gene', (365, 369))	('differences', 'Reg', (385, 396))	('copy number', 'Var', (241, 252))	('BRAF', 'Gene', '673', (145, 149))	('V600K', 'Mutation', 'rs121913227', (150, 155))
37078	24460190	They lack activating mutations of any of the known melanoma oncogenes BRAF, NRAS, KIT, GNAQ, GNA11 but have loss of function mutations in NF1 in approximately 25% of cases (unpublished observation).	('mutations', 'Var', (125, 134))	('NRAS', 'Gene', (76, 80))	('NRAS', 'Gene', '4893', (76, 80))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('activating', 'MPA', (10, 20))	('loss of function', 'NegReg', (108, 124))	('KIT', 'molecular_function', 'GO:0005020', ('82', '85'))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))	('BRAF', 'Gene', '673', (70, 74))	('NF1', 'Gene', (138, 141))	('melanoma', 'Disease', (51, 59))	('NF1', 'Gene', '4763', (138, 141))	('BRAF', 'Gene', (70, 74))
37090	24460190	These findings make UV radiation an unlikely pathogenetic factor, which is supported by whole genome sequencing studies, which do not reveal the high degree of UV signature mutations as found in melanomas originating from the non-glabrous skin.	('melanomas', 'Disease', (195, 204))	('non-glabrous skin', 'Phenotype', 'HP:0000973', (226, 243))	('melanomas', 'Disease', 'MESH:D008545', (195, 204))	('mutations', 'Var', (173, 182))	('melanomas', 'Phenotype', 'HP:0002861', (195, 204))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))
37093	24460190	In acral melanoma, mutations in BRAF occur in 15%, much less frequent than in non-CSD melanomas.	('BRAF', 'Gene', '673', (32, 36))	('acral melanoma', 'Disease', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('non-CSD melanomas', 'Disease', 'MESH:C562576', (78, 95))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('BRAF', 'Gene', (32, 36))	('acral melanoma', 'Disease', 'MESH:D008545', (3, 17))	('mutations', 'Var', (19, 28))	('occur', 'Reg', (37, 42))	('acral melanoma', 'Phenotype', 'HP:0012060', (3, 17))	('non-CSD melanomas', 'Disease', (78, 95))
37095	24460190	Activating mutations or amplifications of wild type KIT are found in 15-40% of acral melanoma and mucosal melanoma, and approximately 15% have NRAS mutations.	('mutations', 'Var', (148, 157))	('acral melanoma and mucosal melanoma', 'Disease', 'MESH:D008545', (79, 114))	('amplifications', 'Var', (24, 38))	('NRAS', 'Gene', (143, 147))	('KIT', 'molecular_function', 'GO:0005020', ('52', '55'))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('Activating', 'MPA', (0, 10))	('acral melanoma', 'Phenotype', 'HP:0012060', (79, 93))	('NRAS', 'Gene', '4893', (143, 147))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
37096	24460190	A unique feature of acral and mucosal melanomas is the high frequency of gene amplifications throughout the genome.	('mucosal melanomas', 'Disease', (30, 47))	('acral', 'Disease', (20, 25))	('gene amplifications', 'Var', (73, 92))	('mucosal melanomas', 'Disease', 'MESH:D008545', (30, 47))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))
37097	24460190	The majority of acral melanomas have multiple (5 on average) focused gene amplifications, most commonly involving the loci that include CCND1 (11q13), hTERT (5p15), CDK4 (12q14), RICTOR (5p13), and KIT and PDGFRA (4q12).	('RICTOR', 'Gene', '253260', (179, 185))	('PDGFRA', 'Gene', (206, 212))	('PDGFRA', 'Gene', '5156', (206, 212))	('CDK4', 'Gene', '1019', (165, 169))	('acral melanomas', 'Disease', 'MESH:D008545', (16, 31))	('RICTOR', 'Gene', (179, 185))	('CCND1', 'Gene', '595', (136, 141))	('hTERT', 'Gene', '7015', (151, 156))	('acral melanomas', 'Phenotype', 'HP:0012060', (16, 31))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('CCND1', 'Gene', (136, 141))	('5p15', 'Var', (158, 162))	('acral melanomas', 'Disease', (16, 31))	('hTERT', 'Gene', (151, 156))	('5p13', 'Var', (187, 191))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('acral melanoma', 'Phenotype', 'HP:0012060', (16, 30))	('KIT', 'molecular_function', 'GO:0005020', ('198', '201'))	('KIT', 'Gene', (198, 201))	('CDK4', 'Gene', (165, 169))	('CDK', 'molecular_function', 'GO:0004693', ('165', '168'))
37105	24460190	Preliminary studies suggest that KIT mutations may arise early and are followed by amplification of CCND1, and subsequently hTERT, which coincides with the development of substantial increase in the neoplastic cell population.	('CCND1', 'Gene', (100, 105))	('hTERT', 'Gene', '7015', (124, 129))	('KIT', 'molecular_function', 'GO:0005020', ('33', '36'))	('CCND1', 'Gene', '595', (100, 105))	('mutations', 'Var', (37, 46))	('KIT', 'Gene', (33, 36))	('hTERT', 'Gene', (124, 129))	('amplification', 'Var', (83, 96))
37106	24460190	Accordingly, KIT mutations may differ from BRAF mutations in that they are not sufficient to allow any significant proliferation that results in an equivalent of a nevus as seen with BRAF mutations.	('KIT', 'molecular_function', 'GO:0005020', ('13', '16'))	('BRAF', 'Gene', '673', (43, 47))	('BRAF', 'Gene', (43, 47))	('mutations', 'Var', (17, 26))	('BRAF', 'Gene', '673', (183, 187))	('nevus', 'Phenotype', 'HP:0003764', (164, 169))	('BRAF', 'Gene', (183, 187))
37107	24460190	The relatively high frequency of CCND1 amplifications in these melanoma types may indicate that additional genetic alterations that drive proliferation may be required.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('CCND1', 'Gene', (33, 38))	('CCND1', 'Gene', '595', (33, 38))	('melanoma', 'Disease', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('amplifications', 'Var', (39, 53))
37108	24460190	A low to moderate frequency of KIT mutations is common to acral, mucosal, and CSD melanomas, which all tend to share an often extensive lentiginous growth.	('mucosal', 'Disease', (65, 72))	('KIT', 'Gene', (31, 34))	('acral', 'Disease', (58, 63))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('CSD melanomas', 'Disease', (78, 91))	('KIT', 'molecular_function', 'GO:0005020', ('31', '34'))	('CSD melanomas', 'Disease', 'MESH:C562576', (78, 91))	('mutations', 'Var', (35, 44))
37111	24460190	However, in certain settings, KIT acts as an oncogene as patients whose melanomas harbor activating mutations in KIT can show dramatic responses to KIT inhibitors.	('mutations', 'Var', (100, 109))	('KIT', 'molecular_function', 'GO:0005020', ('148', '151'))	('melanomas', 'Disease', 'MESH:D008545', (72, 81))	('activating', 'PosReg', (89, 99))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('KIT', 'molecular_function', 'GO:0005020', ('30', '33'))	('patients', 'Species', '9606', (57, 65))	('KIT', 'molecular_function', 'GO:0005020', ('113', '116'))	('responses', 'MPA', (135, 144))	('KIT', 'Gene', (113, 116))	('melanomas', 'Disease', (72, 81))	('KIT inhibitors', 'MPA', (148, 162))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))
37120	24460190	In contrast to acquired nevi in which BRAF mutations predominate, large and giant congenital nevi carry NRAS mutations in over 80% of cases.	('large', 'Disease', (66, 71))	('NRAS', 'Gene', '4893', (104, 108))	('nevi', 'Phenotype', 'HP:0003764', (93, 97))	('BRAF', 'Gene', '673', (38, 42))	('BRAF', 'Gene', (38, 42))	('mutations', 'Var', (109, 118))	('giant congenital nevi', 'Disease', (76, 97))	('NRAS', 'Gene', (104, 108))	('giant congenital nevi', 'Phenotype', 'HP:0005600', (76, 97))	('nevi', 'Phenotype', 'HP:0003764', (24, 28))
37121	24460190	In patients with satellite lesions the same NRAS mutations are shared between anatomically separate lesions, indicating that they originate from a common ancestor.	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (49, 58))	('NRAS', 'Gene', '4893', (44, 48))	('NRAS', 'Gene', (44, 48))
37123	24460190	The founding NRAS mutation results in an expanded progenitor pool that exceeds the receiving capacity of the destination epithelia, with excess cells piling up in the dermis and other tissues along the way.	('expanded', 'PosReg', (41, 49))	('receiving', 'MPA', (83, 92))	('destination epithelia', 'Disease', (109, 130))	('NRAS', 'Gene', (13, 17))	('mutation', 'Var', (18, 26))	('destination epithelia', 'Disease', 'None', (109, 130))	('progenitor pool', 'CPA', (50, 65))	('NRAS', 'Gene', '4893', (13, 17))	('piling', 'Phenotype', 'HP:0032551', (150, 156))
37124	24460190	A similar phenomenon has been observed with hypermorphic mutations in GNAQ and GNA11 in mouse models.	('GNA11', 'Gene', (79, 84))	('GNAQ', 'Gene', (70, 74))	('hypermorphic mutations', 'Var', (44, 66))	('mouse', 'Species', '10090', (88, 93))
37125	24460190	Other oncogenic alterations reported in congenital nevi involve kinase fusions of BRAF, which have been reported in individual cases of congenital nevi.	('nevi', 'Phenotype', 'HP:0003764', (51, 55))	('BRAF', 'Gene', '673', (82, 86))	('BRAF', 'Gene', (82, 86))	('kinase fusions', 'Var', (64, 78))	('nevi', 'Phenotype', 'HP:0003764', (147, 151))	('congenital nevi', 'Disease', (40, 55))
37133	24460190	The molecular characteristics that are shared between neoplasms of this family are somatic mutations of GNAQ or GNA11, two close related alpha-subunits of the Galphaq family.	('neoplasms', 'Phenotype', 'HP:0002664', (54, 63))	('GNA11', 'Gene', (112, 117))	('Galphaq', 'Gene', '2776;14682;2767;14672', (159, 166))	('Galphaq', 'Gene', (159, 166))	('neoplasms', 'Disease', 'MESH:D009369', (54, 63))	('neoplasms', 'Disease', (54, 63))	('mutations', 'Var', (91, 100))	('GNAQ', 'Gene', (104, 108))	('neoplasm', 'Phenotype', 'HP:0002664', (54, 62))
37134	24460190	Mutations in GNAQ and GNA11 occur at the glutamine at position 209 or, in approximately 5% of cases, at the arginine at position 183.	('GNA11', 'Gene', (22, 27))	('occur', 'Reg', (28, 33))	('GNAQ', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('arginine', 'Chemical', 'MESH:D001120', (108, 116))	('glutamine', 'Chemical', 'MESH:D005973', (41, 50))
37135	24460190	The Q209 mutations complete abrogate the GTPase activity, locking them in a GTP-bound, constitutively activated state.	('GTPase', 'Enzyme', (41, 47))	('activity', 'MPA', (48, 56))	('GTP', 'Chemical', 'MESH:D006160', (41, 44))	('GTP', 'Chemical', 'MESH:D006160', (76, 79))	('Q209 mutations', 'Var', (4, 18))	('abrogate', 'NegReg', (28, 36))	('GTPase activity', 'molecular_function', 'GO:0003924', ('41', '56'))
37136	24460190	Mutations in these genes occur in a mutually exclusive pattern and are found in the majority of blue nevi including the segmental dermal melanocytoses.	('melanocytoses', 'Chemical', '-', (137, 150))	('blue nevi', 'Phenotype', 'HP:0100814', (96, 105))	('nevi', 'Phenotype', 'HP:0003764', (101, 105))	('blue nevi', 'Disease', (96, 105))	('found', 'Reg', (71, 76))	('segmental dermal melanocytoses', 'Disease', (120, 150))	('Mutations', 'Var', (0, 9))
37139	24460190	Blue nevi can also arise as part of Carney's complex, a tumor predisposition syndrome caused by germline loss of function mutations in PRKAR1A, one of the two regulatory subunits of protein kinase A, resulting in increased PKA activity.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('PRKAR1A', 'Gene', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('activity', 'MPA', (227, 235))	('tumor', 'Disease', (56, 61))	('PRKAR1A', 'Gene', '5573', (135, 142))	('PKA', 'Enzyme', (223, 226))	('PKA', 'molecular_function', 'GO:0004691', ('223', '226'))	('Blue nevi', 'Disease', (0, 9))	('Blue nevi', 'Phenotype', 'HP:0100814', (0, 9))	('nevi', 'Phenotype', 'HP:0003764', (5, 9))	('mutations', 'Var', (122, 131))	('PKA', 'cellular_component', 'GO:0005952', ('223', '226'))	('protein', 'cellular_component', 'GO:0003675', ('182', '189'))	('Carney', 'Disease', (36, 42))	('increased', 'PosReg', (213, 222))	('loss of function', 'NegReg', (105, 121))
37143	24460190	The genetic alterations in blue nevus-like melanoma have not been systematically studied but have similarities with blue nevi and uveal melanoma with frequent mutations in GNAQ or GNA11 and losses of chromosome 3.	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (32, 51))	('uveal melanoma', 'Disease', (130, 144))	('uveal melanoma', 'Disease', 'MESH:C536494', (130, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('blue nevi', 'Phenotype', 'HP:0100814', (116, 125))	('melanoma', 'Disease', (136, 144))	('GNA11', 'Gene', (180, 185))	('chromosome', 'cellular_component', 'GO:0005694', ('200', '210'))	('mutations', 'Var', (159, 168))	('nevus', 'Phenotype', 'HP:0003764', (32, 37))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('uveal melanoma', 'Phenotype', 'HP:0007716', (130, 144))	('GNAQ', 'Gene', (172, 176))	('losses', 'NegReg', (190, 196))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('blue nevus', 'Phenotype', 'HP:0100814', (27, 37))	('nevi', 'Phenotype', 'HP:0003764', (121, 125))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('blue nevi', 'Disease', (116, 125))
37153	24460190	Mutations in GNAQ or GNA11 occur in approximately 85% of uveal melanoma and are mutually exclusive.	('GNAQ', 'Gene', (13, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('occur', 'Reg', (27, 32))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Disease', (57, 71))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('GNA11', 'Gene', (21, 26))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))
37154	24460190	Loss of function mutations in the deubiquitinase BAP1 are found in 49% of uveal melanoma, with a significant higher frequency (85%) in tumors that become metastatic.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('34', '48'))	('BAP1', 'Gene', (49, 53))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('Loss of function', 'NegReg', (0, 16))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('uveal melanoma', 'Disease', (74, 88))	('mutations', 'Var', (17, 26))	('BAP1', 'Gene', '8314', (49, 53))
37156	24460190	The precise mechanisms underlying how elimination of BAP1 function promotes uveal melanoma growth are not fully understood.	('promotes', 'PosReg', (67, 75))	('elimination', 'Var', (38, 49))	('uveal melanoma', 'Disease', 'MESH:C536494', (76, 90))	('uveal melanoma', 'Phenotype', 'HP:0007716', (76, 90))	('uveal melanoma', 'Disease', (76, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('BAP1', 'Gene', '8314', (53, 57))	('BAP1', 'Gene', (53, 57))
37158	24460190	The disruption of this complex by loss of BAP1 is thought to result in altered histone modifications and a deregulated gene expression patter.	('BAP1', 'Gene', '8314', (42, 46))	('histone modifications', 'MPA', (79, 100))	('loss', 'Var', (34, 38))	('deregulated gene expression', 'MPA', (107, 134))	('BAP1', 'Gene', (42, 46))	('altered', 'Reg', (71, 78))	('gene expression', 'biological_process', 'GO:0010467', ('119', '134'))
37163	24460190	Mutations are found in 19% of uveal melanomas, primarily in class 1 tumors, and thus primarily affect melanomas without BAP1 mutations.	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('melanomas', 'Disease', 'MESH:D008545', (36, 45))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('melanomas', 'Disease', (36, 45))	('uveal melanomas', 'Disease', (30, 45))	('uveal melanomas', 'Phenotype', 'HP:0007716', (30, 45))	('BAP1', 'Gene', (120, 124))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('melanomas', 'Disease', 'MESH:D008545', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('melanomas', 'Disease', (102, 111))	('tumors', 'Disease', (68, 74))	('uveal melanomas', 'Disease', 'MESH:C536494', (30, 45))	('BAP1', 'Gene', '8314', (120, 124))
37165	24460190	In zebra fish, germline loss of function mutations of SF3B1 results in a pigmentation phenotype caused by a failure of neural crest development.	('SF3B1', 'Gene', (54, 59))	('mutations', 'Var', (41, 50))	('failure', 'NegReg', (108, 115))	('zebra fish', 'Species', '7955', (3, 13))	('pigmentation phenotype', 'Disease', (73, 95))	('loss of function', 'NegReg', (24, 40))	('pigmentation phenotype', 'Disease', 'MESH:D010859', (73, 95))	('pigmentation', 'biological_process', 'GO:0043473', ('73', '85'))
37166	24460190	Loss of SF3B1 in this model leads to mis-splicing of critical neural crest transcription factors such as sox10 and tfab2a.	('splicing', 'biological_process', 'GO:0045292', ('41', '49'))	('tfab2a', 'Gene', (115, 121))	('leads to', 'Reg', (28, 36))	('sox10', 'Gene', '6663', (105, 110))	('mis-splicing', 'MPA', (37, 49))	('transcription', 'biological_process', 'GO:0006351', ('75', '88'))	('Loss', 'Var', (0, 4))	('SF3B1', 'Gene', (8, 13))	('sox10', 'Gene', (105, 110))
37169	24460190	Melanocytic neoplasms are initiated by somatic mutations that activate oncogenes.	('neoplasms', 'Phenotype', 'HP:0002664', (12, 21))	('oncogenes', 'Gene', (71, 80))	('activate', 'PosReg', (62, 70))	('mutations', 'Var', (47, 56))	('neoplasm', 'Phenotype', 'HP:0002664', (12, 20))	('Melanocytic neoplasms', 'Disease', (0, 21))	('Melanocytic neoplasms', 'Disease', 'MESH:D009508', (0, 21))	('Melanocytic neoplasms', 'Phenotype', 'HP:0002861', (0, 21))
37172	24460190	Mutations in initiating oncogenes are not sufficient to form melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('Mutations', 'Var', (0, 9))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))
37173	24460190	Subsequent genetic alterations override the tumor suppressive mechanisms operative in melanocytic nevi and lead to the progressive evolution of cells with an increasingly malignant phenotype.	('lead to', 'Reg', (107, 114))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (86, 102))	('override', 'PosReg', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('nevi', 'Phenotype', 'HP:0003764', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('genetic alterations', 'Var', (11, 30))
37174	24460190	The subsequent genetic alterations differ among categories of melanocytic neoplasms.	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (62, 83))	('neoplasms', 'Phenotype', 'HP:0002664', (74, 83))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (62, 83))	('genetic alterations', 'Var', (15, 34))	('melanocytic neoplasms', 'Disease', (62, 83))	('neoplasm', 'Phenotype', 'HP:0002664', (74, 82))
37175	24460190	In concert, the combination of somatic mutations disrupt essential signaling pathways controlling cell proliferation, growth, motility, stromal interactions, differentiation status and interaction with the immune system, giving rise to distinct phenotypic presentations of neoplasms.	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('cell proliferation', 'biological_process', 'GO:0008283', ('98', '116'))	('interaction', 'Interaction', (185, 196))	('disrupt', 'Reg', (49, 56))	('neoplasms', 'Phenotype', 'HP:0002664', (273, 282))	('giving rise to', 'Reg', (221, 235))	('mutations', 'Var', (39, 48))	('neoplasm', 'Phenotype', 'HP:0002664', (273, 281))	('neoplasms', 'Disease', 'MESH:D009369', (273, 282))	('neoplasms', 'Disease', (273, 282))
37178	24460190	UV radiation can cause mutations by direct interaction with DNA or indirectly through the generation of ROS.	('cause', 'Reg', (17, 22))	('ROS', 'Chemical', 'MESH:D017382', (104, 107))	('mutations', 'Var', (23, 32))	('ROS', 'Protein', (104, 107))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('DNA', 'Protein', (60, 63))	('interaction', 'Interaction', (43, 54))
37181	23793026	Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3 Gene expression profiles and chromosome 3 copy number divide uveal melanomas into two distinct classes correlating with prognosis.	('EIF1AX', 'Gene', (59, 65))	('uveal melanomas', 'Disease', 'MESH:C536494', (169, 184))	('mutations', 'Var', (46, 55))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (169, 183))	('uveal melanoma', 'Phenotype', 'HP:0007716', (169, 183))	('melanomas', 'Phenotype', 'HP:0002861', (175, 184))	('SF3B1', 'Gene', (70, 75))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('chromosome', 'cellular_component', 'GO:0005694', ('137', '147'))	('Gene expression', 'biological_process', 'GO:0010467', ('108', '123'))	('uveal melanomas', 'Disease', (169, 184))	('uveal melanomas', 'Phenotype', 'HP:0007716', (169, 184))	('SF3B1', 'Gene', '23451', (70, 75))	('EIF1AX', 'Gene', '1964', (59, 65))	('uveal melanoma', 'Disease', (79, 93))
37182	23793026	Using exome sequencing, we identified recurrent somatic mutations in EIF1AX and SF3B1, specifically occurring in uveal melanomas with disomy 3, which rarely metastasize.	('SF3B1', 'Gene', '23451', (80, 85))	('EIF1AX', 'Gene', '1964', (69, 75))	('EIF1AX', 'Gene', (69, 75))	('mutations', 'Var', (56, 65))	('uveal melanomas', 'Disease', (113, 128))	('uveal melanomas', 'Phenotype', 'HP:0007716', (113, 128))	('uveal melanomas', 'Disease', 'MESH:C536494', (113, 128))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('uveal melanoma', 'Phenotype', 'HP:0007716', (113, 127))	('disomy 3', 'Disease', (134, 142))	('SF3B1', 'Gene', (80, 85))	('melanomas', 'Phenotype', 'HP:0002861', (119, 128))	('occurring', 'Reg', (100, 109))
37183	23793026	Targeted resequencing showed that 24 of 31 tumors with disomy 3 (77%) had mutations in either EIF1AX (15; 48%) or SF3B1 (9; 29%).	('SF3B1', 'Gene', '23451', (114, 119))	('EIF1AX', 'Gene', (94, 100))	('EIF1AX', 'Gene', '1964', (94, 100))	('mutations', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('SF3B1', 'Gene', (114, 119))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
37184	23793026	Mutations were infrequent (2/35; 5.7%) in uveal melanomas with monosomy 3, which are associated with poor prognosis.	('uveal melanomas', 'Disease', (42, 57))	('uveal melanomas', 'Phenotype', 'HP:0007716', (42, 57))	('monosomy 3', 'Var', (63, 73))	('uveal melanomas', 'Disease', 'MESH:C536494', (42, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
37185	23793026	Resequencing of 13 uveal melanomas with partial monosomy 3 identified 8 tumors with a mutation in either SF3B1 (7; 54%) or EIF1AX (1; 8%).	('uveal melanomas', 'Disease', (19, 34))	('uveal melanomas', 'Phenotype', 'HP:0007716', (19, 34))	('SF3B1', 'Gene', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('SF3B1', 'Gene', '23451', (105, 110))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('uveal melanoma', 'Phenotype', 'HP:0007716', (19, 33))	('uveal melanomas', 'Disease', 'MESH:C536494', (19, 34))	('EIF1AX', 'Gene', (123, 129))	('EIF1AX', 'Gene', '1964', (123, 129))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('mutation', 'Var', (86, 94))	('melanomas', 'Phenotype', 'HP:0002861', (25, 34))
37186	23793026	All EIF1AX mutations caused in-frame changes affecting the N terminus of the protein, whereas 17 of 19 SF3B1 mutations encoded an alteration of Arg625.	('Arg625', 'MPA', (144, 150))	('mutations', 'Var', (11, 20))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('changes', 'Var', (37, 44))	('affecting', 'Reg', (45, 54))	('SF3B1', 'Gene', (103, 108))	('alteration', 'Reg', (130, 140))	('encoded', 'Reg', (119, 126))	('mutations', 'Var', (109, 118))	('N terminus of the protein', 'MPA', (59, 84))	('EIF1AX', 'Gene', '1964', (4, 10))	('EIF1AX', 'Gene', (4, 10))	('Arg625', 'Chemical', '-', (144, 150))	('SF3B1', 'Gene', '23451', (103, 108))
37187	23793026	Resequencing of ten uveal melanomas with disomy 3 that developed metastases identified SF3B1 mutations in three tumors, none of which targeted Arg625.	('mutations', 'Var', (93, 102))	('metastases', 'Disease', 'MESH:D009362', (65, 75))	('SF3B1', 'Gene', (87, 92))	('tumors', 'Disease', (112, 118))	('melanomas', 'Phenotype', 'HP:0002861', (26, 35))	('uveal melanomas', 'Disease', (20, 35))	('uveal melanomas', 'Phenotype', 'HP:0007716', (20, 35))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (20, 34))	('SF3B1', 'Gene', '23451', (87, 92))	('uveal melanomas', 'Disease', 'MESH:C536494', (20, 35))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('Arg625', 'Chemical', '-', (143, 149))	('metastases', 'Disease', (65, 75))
37193	23793026	In contrast, tumors with disomy 3 rarely metastasize.	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('disomy 3', 'Var', (25, 33))
37194	23793026	The proportion of individuals with tumors showing partial monosomy 3 has been controversial, with figures varying from 0 to 48%.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('partial monosomy 3', 'Var', (50, 68))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
37197	23793026	On average, we identified 33 amino acid-changing sequence variations per tumor exome not present in either dbSNP, data from the 1000 Genomes Project or exomes from the matched blood samples (Supplementary Tables 1 and 2).	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('sequence variations', 'Var', (49, 68))
37198	23793026	Four of these genes (GNAQ, GNA11, BAP1 and SF3B1) are known targets of recurrent somatic mutations in uveal melanoma (Fig.	('SF3B1', 'Gene', (43, 48))	('GNAQ', 'Gene', '2776', (21, 25))	('BAP1', 'Gene', (34, 38))	('SF3B1', 'Gene', '23451', (43, 48))	('GNAQ', 'Gene', (21, 25))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('uveal melanoma', 'Disease', (102, 116))	('mutations', 'Var', (89, 98))	('GNA11', 'Gene', (27, 32))	('uveal melanoma', 'Disease', 'MESH:C536494', (102, 116))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('BAP1', 'Gene', '8314', (34, 38))	('GNA11', 'Gene', '2767', (27, 32))
37201	23793026	We also identified an inactivating hemizygous BAP1 mutation in four uveal melanomas with monosomy 3, a finding in line with that of a previous study focusing on chromosome 3 genes.	('uveal melanomas', 'Disease', (68, 83))	('uveal melanomas', 'Phenotype', 'HP:0007716', (68, 83))	('melanomas', 'Phenotype', 'HP:0002861', (74, 83))	('BAP1', 'Gene', '8314', (46, 50))	('inactivating', 'Reg', (22, 34))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('mutation', 'Var', (51, 59))	('BAP1', 'Gene', (46, 50))	('uveal melanomas', 'Disease', 'MESH:C536494', (68, 83))	('chromosome', 'cellular_component', 'GO:0005694', ('161', '171'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (68, 82))
37202	23793026	Exome sequencing also detected SF3B1 mutations in three tumors, two of which harbored a heterozygous missense mutation altering Arg625.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Arg625', 'Var', (128, 134))	('Arg625', 'Chemical', '-', (128, 134))	('tumors', 'Disease', (56, 62))	('mutations', 'Var', (37, 46))	('SF3B1', 'Gene', (31, 36))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('detected', 'Reg', (22, 30))	('SF3B1', 'Gene', '23451', (31, 36))
37203	23793026	Recently, mutations at this codon of SF3B1 have been identified in low-grade uveal melanoma with good prognosis.	('SF3B1', 'Gene', '23451', (37, 42))	('uveal melanoma', 'Disease', 'MESH:C536494', (77, 91))	('identified', 'Reg', (53, 63))	('uveal melanoma', 'Disease', (77, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (77, 91))	('mutations at', 'Var', (10, 22))	('SF3B1', 'Gene', (37, 42))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
37208	23793026	We detected a hemizygous EIF1AX missense mutation in three uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (59, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('uveal melanomas', 'Disease', (59, 74))	('uveal melanomas', 'Phenotype', 'HP:0007716', (59, 74))	('missense mutation', 'Var', (32, 49))	('EIF1AX', 'Gene', (25, 31))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanomas', 'Phenotype', 'HP:0002861', (65, 74))	('EIF1AX', 'Gene', '1964', (25, 31))
37210	23793026	To further explore the pattern and frequency of SF3B1, EIF1AX and EPB41L3 mutations in uveal melanoma, we resequenced these genes in tumor samples from another 66 affected individuals randomly chosen from our cohort of 374 individuals, excluding tumors with partial monosomy 3 and those with disomy 3 that had led to metastases.	('EPB41L3', 'Gene', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumors', 'Disease', (246, 252))	('EIF1AX', 'Gene', (55, 61))	('SF3B1', 'Gene', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('uveal melanoma', 'Disease', 'MESH:C536494', (87, 101))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('EIF1AX', 'Gene', '1964', (55, 61))	('uveal melanoma', 'Disease', (87, 101))	('metastases', 'Disease', 'MESH:D009362', (317, 327))	('tumor', 'Disease', (133, 138))	('SF3B1', 'Gene', '23451', (48, 53))	('tumor', 'Disease', (246, 251))	('uveal melanoma', 'Phenotype', 'HP:0007716', (87, 101))	('metastases', 'Disease', (317, 327))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('mutations', 'Var', (74, 83))	('EPB41L3', 'Gene', '23136', (66, 73))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))
37212	23793026	SF3B1 mutations have previously been detected in various hematological and lymphoid malignancies and have clear mutational hotspots at specific codons in the region encoding the HEAT repeats (HD) 4-9.	('SF3B1', 'Gene', (0, 5))	('HEAT repeats (HD) 4-9', 'Gene', (178, 199))	('lymphoid malignancies', 'Disease', 'MESH:D008223', (75, 96))	('lymphoid malignancies', 'Disease', (75, 96))	('SF3B1', 'Gene', '23451', (0, 5))	('HEAT repeats (HD) 4-9', 'Gene', '9759;10014;1671;51564;55869;9734', (178, 199))	('lymphoid malignancies', 'Phenotype', 'HP:0002665', (75, 96))	('detected', 'Reg', (37, 45))	('hematological', 'Disease', (57, 70))	('mutations', 'Var', (6, 15))
37215	23793026	Nine of these mutations resulted in a missense change at Arg625 to either cystine or histidine.	('histidine', 'MPA', (85, 94))	('cystine', 'MPA', (74, 81))	('Arg625', 'Var', (57, 63))	('Arg625', 'Chemical', '-', (57, 63))	('histidine', 'Chemical', 'MESH:D006639', (85, 94))	('resulted in', 'Reg', (24, 35))	('cystine', 'Chemical', 'MESH:D003553', (74, 81))
37217	23793026	It was suggested that missense mutations targeting the HEAT repeats do not impair the general function of the SF3B1 product but alter the splicing of numerous target genes.	('splicing', 'biological_process', 'GO:0045292', ('138', '146'))	('alter', 'Reg', (128, 133))	('missense mutations', 'Var', (22, 40))	('SF3B1', 'Gene', (110, 115))	('splicing', 'MPA', (138, 146))	('SF3B1', 'Gene', '23451', (110, 115))
37218	23793026	In uveal melanomas with disomy 3, the SF3B1 mutation pattern is uniform and distinct from that of neoplasms of hematopoietic and lymphoid origin, which involves a key mutational hotspot at codon 700 (reviewed in).	('neoplasms', 'Phenotype', 'HP:0002664', (98, 107))	('melanomas', 'Phenotype', 'HP:0002861', (9, 18))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('uveal melanomas', 'Disease', (3, 18))	('SF3B1', 'Gene', (38, 43))	('disomy 3', 'Var', (24, 32))	('uveal melanomas', 'Phenotype', 'HP:0007716', (3, 18))	('neoplasms of hematopoietic', 'Disease', (98, 124))	('uveal melanomas', 'Disease', 'MESH:C536494', (3, 18))	('SF3B1', 'Gene', '23451', (38, 43))	('neoplasms of hematopoietic', 'Disease', 'MESH:D019337', (98, 124))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))
37219	23793026	Resequencing of the coding regions and the flanking splice sites of all 7 EIF1AX exons identified mutations in another 16 of 66 tumors (24%), including in 15 of 31 uveal melanomas with disomy 3 (48%) and 1 of 35 uveal melanomas with monosomy 3 (3%) (Fig.	('EIF1AX', 'Gene', '1964', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('uveal melanoma', 'Phenotype', 'HP:0007716', (164, 178))	('uveal melanoma', 'Phenotype', 'HP:0007716', (212, 226))	('disomy 3', 'Disease', (185, 193))	('uveal melanomas', 'Disease', (164, 179))	('uveal melanomas', 'Disease', (212, 227))	('uveal melanomas', 'Phenotype', 'HP:0007716', (212, 227))	('uveal melanomas', 'Phenotype', 'HP:0007716', (164, 179))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('melanomas', 'Phenotype', 'HP:0002861', (170, 179))	('melanomas', 'Phenotype', 'HP:0002861', (218, 227))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('EIF1AX', 'Gene', (74, 80))	('mutations', 'Var', (98, 107))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('uveal melanomas', 'Disease', 'MESH:C536494', (164, 179))	('uveal melanomas', 'Disease', 'MESH:C536494', (212, 227))
37220	23793026	Most EIF1AX mutations resulted in amino acid substitutions.	('resulted in', 'Reg', (22, 33))	('mutations', 'Var', (12, 21))	('EIF1AX', 'Gene', '1964', (5, 11))	('EIF1AX', 'Gene', (5, 11))	('amino acid substitutions', 'Var', (34, 58))
37221	23793026	Altered splicing is also a potential consequence of substitutions of the last (D3-7, D3-8 and D3-13) or first (D3-3) base of an exon, which were found in four tumors.	('substitutions', 'Var', (52, 65))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('splicing', 'biological_process', 'GO:0045292', ('8', '16'))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('D3-13', 'Var', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('Altered', 'Reg', (0, 7))	('splicing', 'MPA', (8, 16))
37222	23793026	To evaluate the consequences of these mutations on EIF1AX mRNA and also to determine whether the active allele was mutated in tumors from females with uveal melanoma, we sequenced the entire EIF1AX coding region in cDNA from 20 tumors with disomy 3 from which mRNA was available (Supplementary Table 3).	('EIF1AX', 'Gene', (51, 57))	('tumors', 'Disease', (126, 132))	('uveal melanoma', 'Disease', (151, 165))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('EIF1AX', 'Gene', '1964', (191, 197))	('EIF1AX', 'Gene', (191, 197))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('tumors', 'Disease', (228, 234))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (38, 47))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('uveal melanoma', 'Phenotype', 'HP:0007716', (151, 165))	('uveal melanoma', 'Disease', 'MESH:C536494', (151, 165))	('EIF1AX', 'Gene', '1964', (51, 57))
37223	23793026	In all but the two uveal melanomas with mutations affecting the splice acceptor site (D3-4 and D3-15), only normally spliced transcripts were found.	('uveal melanomas', 'Disease', (19, 34))	('uveal melanomas', 'Phenotype', 'HP:0007716', (19, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (19, 33))	('mutations', 'Var', (40, 49))	('uveal melanomas', 'Disease', 'MESH:C536494', (19, 34))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanomas', 'Phenotype', 'HP:0002861', (25, 34))
37224	23793026	Both tumors with a splice-site mutation showed the same mutant EIF1AX cDNA with a deletion of the first six nucleotides of exon 2, which can be explained by activation of a cryptic splice acceptor site in exon 2.	('tumors', 'Disease', (5, 11))	('EIF1AX', 'Gene', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('EIF1AX', 'Gene', '1964', (63, 69))	('mutant', 'Var', (56, 62))	('mutation', 'Var', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('deletion', 'Var', (82, 90))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
37225	23793026	Therefore, all 16 EIF1AX mutations led to amino acid substitutions or short deletions of one or two amino acids in the unstructured N-terminal tail (NTT) of the EIF1AX product (Fig.	('EIF1AX', 'Gene', '1964', (18, 24))	('EIF1AX', 'Gene', (18, 24))	('mutations', 'Var', (25, 34))	('led to', 'Reg', (35, 41))	('EIF1AX', 'Gene', '1964', (161, 167))	('EIF1AX', 'Gene', (161, 167))	('amino acid substitutions', 'Var', (42, 66))
37226	23793026	In all tumors with EIF1AX mutation, including those with potential exonic splice-site mutations, cDNA sequencing only showed mutant EIF1AX transcript.	('EIF1AX', 'Gene', '1964', (132, 138))	('EIF1AX', 'Gene', (132, 138))	('mutation', 'Var', (26, 34))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('EIF1AX', 'Gene', '1964', (19, 25))	('EIF1AX', 'Gene', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
37227	23793026	This finding implies that all mutations in females with uveal melanoma target the active allele, whereas the other allele is silenced as the result of X-chromosome inactivation.	('uveal melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('uveal melanoma', 'Disease', (56, 70))	('X-chromosome inactivation', 'biological_process', 'GO:0009048', ('151', '176'))	('mutations', 'Var', (30, 39))	('active allele', 'MPA', (82, 95))	('X-chromosome', 'cellular_component', 'GO:0000805', ('151', '163'))	('uveal melanoma', 'Disease', 'MESH:C536494', (56, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
37228	23793026	The anticorrelation of SF3B1 and EIF1AX mutations (Fig.	('EIF1AX', 'Gene', '1964', (33, 39))	('EIF1AX', 'Gene', (33, 39))	('SF3B1', 'Gene', '23451', (23, 28))	('mutations', 'Var', (40, 49))	('SF3B1', 'Gene', (23, 28))
37229	23793026	Given the role of the SF3B1 protein in pre-mRNA splicing, mutant forms might induce alternative splicing of EIF1AX pre-mRNA.	('mutant', 'Var', (58, 64))	('EIF1AX', 'Gene', '1964', (108, 114))	('EIF1AX', 'Gene', (108, 114))	('pre', 'molecular_function', 'GO:0003904', ('39', '42'))	('SF3B1', 'Gene', '23451', (22, 27))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('39', '56'))	('pre', 'molecular_function', 'GO:0003904', ('115', '118'))	('alternative splicing', 'MPA', (84, 104))	('splicing', 'biological_process', 'GO:0045292', ('96', '104'))	('SF3B1', 'Gene', (22, 27))	('induce', 'Reg', (77, 83))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
37231	23793026	None of the tumors showed an overt loss-of-function mutation in EIF1AX.	('loss-of-function', 'NegReg', (35, 51))	('EIF1AX', 'Gene', '1964', (64, 70))	('EIF1AX', 'Gene', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mutation', 'Var', (52, 60))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
37235	23793026	The segment of EIF1AX harboring the mutations is highly conserved in eukaryotes (Supplementary Fig.	('EIF1AX', 'Gene', '1964', (15, 21))	('EIF1AX', 'Gene', (15, 21))	('mutations', 'Var', (36, 45))
37236	23793026	1), and substitutions in the corresponding portion of yeast eIF1A reduce bulk translation in a manner rescued by overexpressing eIF1, which binds cooperatively with eIF1A to the 40S subunit during the assembly of the preinitiation complex (PIC).	('eIF1A', 'Gene', '1964', (165, 170))	('preinitiation complex', 'cellular_component', 'GO:0097550', ('217', '238'))	('yeast', 'Species', '4932', (54, 59))	('translation', 'biological_process', 'GO:0006412', ('78', '89'))	('PIC', 'cellular_component', 'GO:0019035', ('240', '243'))	('overexpressing', 'PosReg', (113, 127))	('substitutions', 'Var', (8, 21))	('bulk translation', 'MPA', (73, 89))	('eIF1A', 'Gene', (60, 65))	('eIF1', 'Gene', (128, 132))	('eIF1A', 'Gene', '1964', (60, 65))	('reduce', 'NegReg', (66, 72))	('eIF1A', 'Gene', (165, 170))	('PIC', 'cellular_component', 'GO:0097550', ('240', '243'))
37238	23793026	Thus, EIF1AX mutations associated with uveal melanoma could diminish the rate of bulk translation and might also induce transcription factors whose mRNA translation is inversely coupled to ternary complex concentration by a specialized reinitiation mechanism.	('translation', 'biological_process', 'GO:0006412', ('153', '164'))	('transcription', 'MPA', (120, 133))	('translation', 'biological_process', 'GO:0006412', ('86', '97'))	('uveal melanoma', 'Disease', 'MESH:C536494', (39, 53))	('diminish', 'NegReg', (60, 68))	('bulk translation', 'MPA', (81, 97))	('EIF1AX', 'Gene', (6, 12))	('uveal melanoma', 'Phenotype', 'HP:0007716', (39, 53))	('uveal melanoma', 'Disease', (39, 53))	('rate', 'MPA', (73, 77))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('mutations', 'Var', (13, 22))	('transcription', 'biological_process', 'GO:0006351', ('120', '133'))	('induce', 'Reg', (113, 119))	('EIF1AX', 'Gene', '1964', (6, 12))	('mRNA', 'MPA', (148, 152))
37239	23793026	Other findings implicate yeast eIF1A NTT in regulating the accuracy of start codon recognition, as NTT substitutions suppress initiation at triplets with one-base mismatches from AUG and cause the PIC to bypass the first AUG encountered while scanning from the 5' end of the mRNA.	('NTT', 'Gene', (99, 102))	('PIC', 'cellular_component', 'GO:0019035', ('197', '200'))	('substitutions', 'Var', (103, 116))	('eIF1A', 'Gene', (31, 36))	('eIF1A', 'Gene', '1964', (31, 36))	('PIC', 'cellular_component', 'GO:0097550', ('197', '200'))	('initiation', 'MPA', (126, 136))	('yeast', 'Species', '4932', (25, 30))	('cause', 'Reg', (187, 192))	('suppress', 'NegReg', (117, 125))
37240	23793026	Hence, EIF1AX mutations might suppress the recognition of near-cognate initiation sites, which seem to be more prevalent than previously suspected, or of 5' proximal AUG codons to alter the relative use of different start codons in mRNAs encoded by tumor-promoting or tumor-suppressing genes.	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor', 'Disease', (268, 273))	('EIF1AX', 'Gene', '1964', (7, 13))	('tumor', 'Disease', (249, 254))	('suppress', 'NegReg', (30, 38))	('alter', 'Reg', (180, 185))	('recognition', 'MPA', (43, 54))	('EIF1AX', 'Gene', (7, 13))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
37242	23793026	We next sequenced SF3B1 (exons 12-16), EPB41L3 (entire coding region) and EIF1AX (exons 1 and 2) in 13 tumors with partial monosomy 3 and 10 tumors with disomy 3 that developed metastases.	('EPB41L3', 'Gene', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('EPB41L3', 'Gene', '23136', (39, 46))	('partial monosomy 3', 'Var', (115, 133))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (141, 147))	('metastases', 'Disease', (177, 187))	('EIF1AX', 'Gene', (74, 80))	('tumors', 'Disease', (103, 109))	('SF3B1', 'Gene', (18, 23))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('EIF1AX', 'Gene', '1964', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('metastases', 'Disease', 'MESH:D009362', (177, 187))	('SF3B1', 'Gene', '23451', (18, 23))
37244	23793026	We found SF3B1 mutations in 7 of 13 samples with partial monosomy 3 (54%), and all mutations changed codon 625.	('SF3B1', 'Gene', '23451', (9, 14))	('changed', 'Reg', (93, 100))	('mutations', 'Var', (15, 24))	('partial monosomy 3', 'Disease', (49, 67))	('codon 625', 'MPA', (101, 110))	('SF3B1', 'Gene', (9, 14))
37245	23793026	We detected an EIF1AX mutation affecting the intron 1 splice acceptor site in one tumor with partial monosomy 3 (8%) (Fig.	('mutation', 'Var', (22, 30))	('EIF1AX', 'Gene', '1964', (15, 21))	('EIF1AX', 'Gene', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
37246	23793026	Notably, mutations in SF3B1 or EIF1AX preferentially occurred in tumors with loss of 3q and retention of 3p.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('SF3B1', 'Gene', '23451', (22, 27))	('mutations', 'Var', (9, 18))	('occurred', 'Reg', (53, 61))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('retention', 'biological_process', 'GO:0051235', ('92', '101'))	('loss', 'NegReg', (77, 81))	('EIF1AX', 'Gene', (31, 37))	('SF3B1', 'Gene', (22, 27))	('EIF1AX', 'Gene', '1964', (31, 37))
37248	23793026	These results suggest that the biology of SF3B1- and EIF1AX-mutant uveal melanomas with partial monosomy 3, which comprise about 60% of all uveal melanomas with partial monosomy 3 in our cohort, is similar to that of uveal melanomas with disomy 3.	('uveal melanomas', 'Disease', 'MESH:C536494', (67, 82))	('SF3B1', 'Gene', (42, 47))	('uveal melanoma', 'Phenotype', 'HP:0007716', (140, 154))	('uveal melanomas', 'Disease', 'MESH:C536494', (217, 232))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('uveal melanomas', 'Disease', (140, 155))	('uveal melanomas', 'Phenotype', 'HP:0007716', (140, 155))	('EIF1AX', 'Gene', (53, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('SF3B1', 'Gene', '23451', (42, 47))	('uveal melanoma', 'Phenotype', 'HP:0007716', (217, 231))	('uveal melanomas', 'Disease', (67, 82))	('uveal melanomas', 'Phenotype', 'HP:0007716', (67, 82))	('melanomas', 'Phenotype', 'HP:0002861', (146, 155))	('EIF1AX', 'Gene', '1964', (53, 59))	('uveal melanomas', 'Disease', (217, 232))	('partial monosomy', 'Var', (88, 104))	('uveal melanomas', 'Phenotype', 'HP:0007716', (217, 232))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('uveal melanomas', 'Disease', 'MESH:C536494', (140, 155))	('melanomas', 'Phenotype', 'HP:0002861', (223, 232))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
37249	23793026	This observation agrees with our previous finding that both uveal melanomas with disomy 3 and those with partial monosomy 3 are associated with good prognosis.	('disomy 3', 'Var', (81, 89))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('uveal melanomas', 'Disease', (60, 75))	('uveal melanomas', 'Phenotype', 'HP:0007716', (60, 75))	('uveal melanomas', 'Disease', 'MESH:C536494', (60, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))
37250	23793026	Resequencing of SF3B1 and EIF1AX in ten uveal melanomas with disomy 3 leading to metastasis identified no mutation in EIF1AX; however, three tumors (30%) harbored a mutation in SF3B1 (Fig.	('uveal melanomas', 'Disease', (40, 55))	('uveal melanomas', 'Phenotype', 'HP:0007716', (40, 55))	('harbored', 'Reg', (154, 162))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('EIF1AX', 'Gene', '1964', (26, 32))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('SF3B1', 'Gene', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('EIF1AX', 'Gene', (118, 124))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('tumors', 'Disease', (141, 147))	('SF3B1', 'Gene', (16, 21))	('EIF1AX', 'Gene', '1964', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('SF3B1', 'Gene', '23451', (177, 182))	('uveal melanomas', 'Disease', 'MESH:C536494', (40, 55))	('SF3B1', 'Gene', '23451', (16, 21))	('EIF1AX', 'Gene', (26, 32))	('mutation', 'Var', (165, 173))	('uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))
37251	23793026	Notably, these mutations did not affect codon 625 of SF3B1.	('SF3B1', 'Gene', '23451', (53, 58))	('mutations', 'Var', (15, 24))	('SF3B1', 'Gene', (53, 58))
37252	23793026	This observation suggests that the spectrum of SF3B1 mutations in these rare tumors with disomy 3 leading to metastasis is distinct from that in the majority of uveal melanomas with disomy 3.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (161, 175))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('SF3B1', 'Gene', (47, 52))	('disomy 3', 'Var', (89, 97))	('uveal melanomas', 'Disease', (161, 176))	('uveal melanomas', 'Phenotype', 'HP:0007716', (161, 176))	('mutations', 'Var', (53, 62))	('SF3B1', 'Gene', '23451', (47, 52))	('melanomas', 'Phenotype', 'HP:0002861', (167, 176))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('metastasis', 'CPA', (109, 119))	('leading', 'Reg', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('uveal melanomas', 'Disease', 'MESH:C536494', (161, 176))
37253	23793026	In view of the distinct mutational spectra of SF3B1 in various malignancies, it is plausible that some functional diversity of the mutant protein depends on the location of the mutation.	('mutant', 'Var', (131, 137))	('malignancies', 'Disease', 'MESH:D009369', (63, 75))	('SF3B1', 'Gene', (46, 51))	('malignancies', 'Disease', (63, 75))	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('SF3B1', 'Gene', '23451', (46, 51))
37254	23793026	It is conceivable that spliceosomes with the various mutant forms of the SF3B1 protein act differently on pre-mRNAs from different genes, possibly depending on sequence features present in the pre-mRNAs that are to be processed.	('pre', 'molecular_function', 'GO:0003904', ('193', '196'))	('SF3B1', 'Gene', '23451', (73, 78))	('pre', 'molecular_function', 'GO:0003904', ('106', '109'))	('act', 'Reg', (87, 90))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('mutant', 'Var', (53, 59))	('SF3B1', 'Gene', (73, 78))
37255	23793026	As SF3B1 is part of a trans-acting complex, it is possible that the transcripts of many genes are affected by SF3B1 alterations.	('affected', 'Reg', (98, 106))	('SF3B1', 'Gene', (3, 8))	('SF3B1', 'Gene', (110, 115))	('SF3B1', 'Gene', '23451', (3, 8))	('alterations', 'Var', (116, 127))	('transcripts', 'MPA', (68, 79))	('SF3B1', 'Gene', '23451', (110, 115))
37256	23793026	We also found SF3B1 mutations outside of codon 625 in two uveal melanomas with disomy 3 that did not develop metastases.	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('SF3B1', 'Gene', (14, 19))	('uveal melanomas', 'Disease', (58, 73))	('uveal melanomas', 'Phenotype', 'HP:0007716', (58, 73))	('metastases', 'Disease', (109, 119))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('SF3B1', 'Gene', '23451', (14, 19))	('uveal melanomas', 'Disease', 'MESH:C536494', (58, 73))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('metastases', 'Disease', 'MESH:D009362', (109, 119))	('mutations', 'Var', (20, 29))
37257	23793026	It remains to be shown whether these non-Arg625 alterations in SF3B1 are also associated with a higher risk of metastatic disease.	('associated', 'Reg', (78, 88))	('SF3B1', 'Gene', (63, 68))	('non-Arg625', 'Var', (37, 47))	('SF3B1', 'Gene', '23451', (63, 68))	('metastatic disease', 'CPA', (111, 129))	('Arg625', 'Chemical', '-', (41, 47))
37258	23793026	We tested whether the mutation states of SF3B1 and EIF1AX were associated with clinical features of the affected individuals.	('EIF1AX', 'Gene', (51, 57))	('mutation', 'Var', (22, 30))	('associated', 'Reg', (63, 73))	('tested', 'Reg', (3, 9))	('SF3B1', 'Gene', (41, 46))	('SF3B1', 'Gene', '23451', (41, 46))	('EIF1AX', 'Gene', '1964', (51, 57))
37260	23793026	We also found that tumors with mutations in either of the two genes were more frequent among males with uveal melanoma (P = 0.0012, Fisher's exact test) (Supplementary Fig.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('mutations', 'Var', (31, 40))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('uveal melanoma', 'Disease', 'MESH:C536494', (104, 118))	('uveal melanoma', 'Disease', (104, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
37261	23793026	To evaluate whether alterations of EIF1AY, a Y-chromosomal paralog of EIF1AX, might contribute to this sex imbalance, we compared EIF1AX and EIF1AY expression in 24 tumors with disomy 3 or partial monosomy 3 from males and found that EIF1AY was expressed at levels comparable to those of EIF1AX in 16 of these tumors (Supplementary Table 3).	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('EIF1AX', 'Gene', '1964', (288, 294))	('tumors', 'Disease', (310, 316))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('EIF1AY', 'Gene', (234, 240))	('partial monosomy 3', 'Var', (189, 207))	('EIF1AY', 'Gene', (35, 41))	('EIF1AX', 'Gene', (70, 76))	('alterations', 'Var', (20, 31))	('EIF1AY', 'Gene', '9086', (234, 240))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('EIF1AY', 'Gene', '9086', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (310, 316))	('EIF1AX', 'Gene', '1964', (70, 76))	('tumors', 'Disease', (165, 171))	('EIF1AX', 'Gene', (130, 136))	('EIF1AY', 'Gene', (141, 147))	('disomy 3', 'Var', (177, 185))	('imbalance', 'Phenotype', 'HP:0002172', (107, 116))	('EIF1AY', 'Gene', '9086', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('EIF1AX', 'Gene', (288, 294))	('EIF1AX', 'Gene', '1964', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (310, 316))
37263	23793026	We also found SF3B1 or EIF1AX mutations in 2 of 47 uveal melanomas with monosomy 3 (4%); both tumors developed metastases and had a BAP1 mutation.	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('uveal melanomas', 'Disease', 'MESH:C536494', (51, 66))	('BAP1', 'Gene', '8314', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('metastases', 'Disease', 'MESH:D009362', (111, 121))	('developed', 'PosReg', (101, 110))	('EIF1AX', 'Gene', (23, 29))	('tumors', 'Disease', (94, 100))	('metastases', 'Disease', (111, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (51, 65))	('SF3B1', 'Gene', (14, 19))	('BAP1', 'Gene', (132, 136))	('uveal melanomas', 'Disease', (51, 66))	('uveal melanomas', 'Phenotype', 'HP:0007716', (51, 66))	('EIF1AX', 'Gene', '1964', (23, 29))	('mutations', 'Var', (30, 39))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('SF3B1', 'Gene', '23451', (14, 19))
37264	23793026	This finding shows that, in rare cases, mutations in both genes might also occur in the class of uveal melanoma characterized by monosomy 3.	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('monosomy', 'Var', (129, 137))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('uveal melanoma', 'Disease', (97, 111))	('mutations', 'Var', (40, 49))	('occur', 'Reg', (75, 80))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
37265	23793026	In summary, the newly identified driver mutations in EIF1AX and SF3B1, specifically found in uveal melanomas with disomy 3, confirm and extend the established classification model of uveal melanoma.	('uveal melanomas', 'Disease', 'MESH:C536494', (93, 108))	('SF3B1', 'Gene', (64, 69))	('uveal melanoma', 'Disease', 'MESH:C536494', (93, 107))	('uveal melanoma', 'Phenotype', 'HP:0007716', (93, 107))	('uveal melanoma', 'Disease', 'MESH:C536494', (183, 197))	('uveal melanoma', 'Phenotype', 'HP:0007716', (183, 197))	('found', 'Reg', (84, 89))	('EIF1AX', 'Gene', '1964', (53, 59))	('EIF1AX', 'Gene', (53, 59))	('uveal melanoma', 'Disease', (183, 197))	('mutations', 'Var', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanomas', 'Phenotype', 'HP:0002861', (99, 108))	('SF3B1', 'Gene', '23451', (64, 69))	('uveal melanomas', 'Disease', (93, 108))	('uveal melanomas', 'Phenotype', 'HP:0007716', (93, 108))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))
37266	23793026	Uveal melanomas with partial monosomy 3 also have mutations in these genes, placing this subgroup of tumors into the class of uveal melanomas with disomy 3.	('melanomas', 'Disease', 'MESH:D008545', (132, 141))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('melanomas', 'Disease', (132, 141))	('uveal melanomas', 'Phenotype', 'HP:0007716', (126, 141))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('uveal melanomas', 'Disease', (126, 141))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('partial monosomy 3', 'Var', (21, 39))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanomas', 'Phenotype', 'HP:0002861', (132, 141))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))	('tumors', 'Disease', (101, 107))	('mutations', 'Var', (50, 59))	('melanomas', 'Disease', (6, 15))	('uveal melanoma', 'Phenotype', 'HP:0007716', (126, 140))	('uveal melanomas', 'Disease', 'MESH:C536494', (126, 141))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
37267	23793026	Moreover, as SF3B1 mutations in metastasized and non-metastasized uveal melanomas with disomy 3 are distinct, a further subgrouping according to mutation type may help to identify high-risk patients.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('SF3B1', 'Gene', (13, 18))	('patients', 'Species', '9606', (190, 198))	('uveal melanomas', 'Phenotype', 'HP:0007716', (66, 81))	('mutations', 'Var', (19, 28))	('uveal melanomas', 'Disease', (66, 81))	('SF3B1', 'Gene', '23451', (13, 18))	('uveal melanomas', 'Disease', 'MESH:C536494', (66, 81))
37271	23793026	For validation by targeted Sanger sequencing, we randomly chose another 66 tumor samples from this cohort, initially excluding tumors with partial monosomy 3 or allelic imbalance and those with disomy 3 that developed metastases.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('partial monosomy 3', 'Var', (139, 157))	('tumor', 'Disease', (127, 132))	('metastases', 'Disease', (218, 228))	('imbalance', 'Phenotype', 'HP:0002172', (169, 178))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('metastases', 'Disease', 'MESH:D009362', (218, 228))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', (75, 80))
37272	23793026	In addition, we selected an additional 23 tumors from this cohort for resequencing, including 13 tumors with partial monosomy 3 and 10 tumors with disomy 3 from individuals who died from uveal melanoma metastases.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('uveal melanoma metastases', 'Disease', (187, 212))	('partial monosomy 3', 'Var', (109, 127))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (187, 212))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Disease', (97, 103))	('uveal melanoma', 'Phenotype', 'HP:0007716', (187, 201))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
37277	23793026	The following chromosome 3 polymorphic microsatellite loci were analyzed: D3S3050-HEX, D3S1263-FAM, D3S1481-FAM, D3S2406-TET, D3S3045-FAM, D3S1744-TET, D3S2421-FAM and D3S1311-HEX.	('D3S1481-FAM', 'Var', (100, 111))	('HEX', 'Gene', '3087', (82, 85))	('TET', 'Chemical', 'MESH:C010349', (147, 150))	('D3S2406-TET', 'Var', (113, 124))	('D3S1744-TET', 'Var', (139, 150))	('HEX', 'Gene', (176, 179))	('chromosome', 'cellular_component', 'GO:0005694', ('14', '24'))	('TET', 'Chemical', 'MESH:C010349', (121, 124))	('D3S1263-FAM', 'Var', (87, 98))	('D3S3045-FAM', 'Var', (126, 137))	('HEX', 'Gene', '3087', (176, 179))	('HEX', 'Gene', (82, 85))	('D3S2421-FAM', 'Var', (152, 163))
37281	23793026	Exome capture was performed on 13 tumor and matched blood DNA samples with the NimbleGen SeqCap EZ Human Exome Library SR kit (designated V1) (UM-E2, UM-E4, UM-E5, UM-E7, UM-E10, UM-E11, UM-E14, UM-E15, UM-E16, UM-E17, UM-E18, UM-E20 and UM-E22).	('UM-E20', 'Var', (227, 233))	('UM-E22', 'Var', (238, 244))	('tumor', 'Disease', (34, 39))	('Human', 'Species', '9606', (99, 104))	('UM-E10', 'Var', (171, 177))	('UM-E2', 'Var', (143, 148))	('UM-E11', 'Var', (179, 185))	('UM-E7', 'Var', (164, 169))	('UM-E16', 'Var', (203, 209))	('UM-E5', 'Var', (157, 162))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('UM-E18', 'Var', (219, 225))	('UM-E15', 'Var', (195, 201))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('UM-E14', 'Var', (187, 193))	('UM-E17', 'Var', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
37282	23793026	Nine tumor and matched blood samples were captured using NimbleGen SeqCap EZ Human Exome Library v2.0 (designated V2) (UM-E1, UM-E3, UM-E6, UM-E8, UM-E9, UM-E12, UM-E13, UM-E19 and UM-E21) (Roche NimbleGen).	('UM-E1', 'Var', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('UM-E21', 'Var', (181, 187))	('UM-E9', 'Var', (147, 152))	('UM-E12', 'Var', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('Human', 'Species', '9606', (77, 82))	('tumor', 'Disease', (5, 10))	('UM-E19', 'Var', (170, 176))	('UM-E13', 'Var', (162, 168))	('UM-E8', 'Var', (140, 145))	('UM-E6', 'Var', (133, 138))
37286	23793026	We filtered out all variants that occurred in the in-house database or in dbSNP135 (but did not filter out those marked as 'clinical', 'precious' or 'contained in a locus-specific database') and those occurring in mucin and mitochondrial genes or pseudogenes.	('variants', 'Var', (20, 28))	('dbSNP135', 'Chemical', '-', (74, 82))	('dbSNP135', 'Gene', (74, 82))	('mucin', 'Gene', '100508689', (214, 219))	('mucin', 'Gene', (214, 219))
37287	23793026	After filtering, a total of 832 sequence variations were identified in all 22 tumor DNA samples.	('sequence variations', 'Var', (32, 51))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
37298	24592138	The most common prognosis-affecting chromosomal disorders associated with the tumor include: loss of chromosome 1p, 3, 6q and 8p and an extra copy of chromosome 6p and 8q.	('chromosome', 'cellular_component', 'GO:0005694', ('101', '111'))	('extra copy', 'Var', (136, 146))	('chromosome', 'cellular_component', 'GO:0005694', ('150', '160'))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('loss', 'Var', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
37363	24270974	In recent years, certain chromosomal aberrations (most notably chromosome 3 monosomy) and the gene expression profile (GEP) of uveal melanoma cells have been shown to be far superior to clinical and histopathologic prognostic factors for classifying an individual patient's metastatic risk.	('uveal melanoma', 'Disease', (127, 141))	('gene expression', 'biological_process', 'GO:0010467', ('94', '109'))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (25, 48))	('metastatic', 'Disease', (274, 284))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('patient', 'Species', '9606', (264, 271))	('uveal melanoma', 'Phenotype', 'HP:0007716', (127, 141))	('uveal melanoma', 'Disease', 'MESH:C536494', (127, 141))	('chromosome', 'Var', (63, 73))
37422	23793989	Mice expressing PEDF exhibited significantly lower MVD and less type III collagen production in metastases.	('MVD', 'MPA', (51, 54))	('metastases', 'Disease', 'MESH:D009362', (96, 106))	('PEDF', 'Var', (16, 20))	('lower', 'NegReg', (45, 50))	('type III collagen production', 'MPA', (64, 92))	('less', 'NegReg', (59, 63))	('collagen', 'molecular_function', 'GO:0005202', ('73', '81'))	('Mice', 'Species', '10090', (0, 4))	('metastases', 'Disease', (96, 106))
37423	23793989	In conclusion, host PEDF inhibits the progression of hepatic metastases in a mouse model of UM, and loss of PEDF is accompanied by an increase in tumor blood vessel density and type III collagen.	('hepatic metastases', 'Disease', (53, 71))	('UM', 'Phenotype', 'HP:0007716', (92, 94))	('loss', 'Var', (100, 104))	('tumor blood vessel', 'Disease', (146, 164))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('PEDF', 'Gene', (108, 112))	('inhibits', 'NegReg', (25, 33))	('hepatic metastases', 'Disease', 'MESH:D009362', (53, 71))	('collagen', 'molecular_function', 'GO:0005202', ('186', '194'))	('tumor blood vessel', 'Disease', 'MESH:D009383', (146, 164))	('increase', 'PosReg', (134, 142))	('mouse', 'Species', '10090', (77, 82))	('type III collagen', 'CPA', (177, 194))
37434	23793989	Mutations in the deubiquitinating enzyme BRCA1-associated protein (BAP1) located on chromosome 3 are seen almost exclusively in patients with metastatic UM.	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('17', '40'))	('UM', 'Phenotype', 'HP:0007716', (153, 155))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('seen', 'Reg', (101, 105))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (67, 71))	('BRCA1-associated protein', 'Gene', (41, 65))	('patients', 'Species', '9606', (128, 136))	('BRCA1-associated protein', 'Gene', '8315', (41, 65))	('metastatic UM', 'Disease', (142, 155))	('BAP1', 'Gene', (67, 71))
37443	23793989	PEDF induces apoptosis of the endothelial cell, inhibiting angiogenesis, and this occurs through multiple pathways including Fas/FasL and cleavage of caspases 8 and 9.	('apoptosis', 'biological_process', 'GO:0097194', ('13', '22'))	('apoptosis', 'biological_process', 'GO:0006915', ('13', '22'))	('cleavage', 'Var', (138, 146))	('inhibiting', 'NegReg', (48, 58))	('apoptosis', 'CPA', (13, 22))	('caspases 8 and 9', 'Gene', '12370;12371', (150, 166))	('FasL', 'Gene', '14103', (129, 133))	('angiogenesis', 'biological_process', 'GO:0001525', ('59', '71'))	('PEDF', 'Var', (0, 4))	('angiogenesis', 'CPA', (59, 71))	('FasL', 'Gene', (129, 133))	('induces', 'Reg', (5, 12))
37482	23793989	Both assays demonstrated an abundance of PEDF protein in the livers of PEDF+/+ mice but not in livers of PEDF-/- mice.	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('mice', 'Species', '10090', (79, 83))	('mice', 'Species', '10090', (113, 117))	('PEDF protein', 'Protein', (41, 53))	('PEDF+/+', 'Var', (71, 78))
37489	23793989	PEDF+/- mice showed a 7.3 fold increase in mean vascular density (MVD), or blood vessels per 40x high-powered field of magnification (40HPF), versus PEDF+/+ controls, and the MVD of PEDF-/- mice was 20.8 fold greater than wild-type, both significantly greater (p<0.05) (Fig.	('PEDF+/-', 'Var', (0, 7))	('mice', 'Species', '10090', (8, 12))	('mice', 'Species', '10090', (190, 194))	('blood vessels', 'CPA', (75, 88))	('mean vascular density', 'CPA', (43, 64))	('greater', 'PosReg', (209, 216))	('increase', 'PosReg', (31, 39))
37490	23793989	Additionally, both PEDF-/- and PEDF+/- mice had significantly greater MVD in metastases than surrounding liver tissue, while WT mice did not.	('greater', 'PosReg', (62, 69))	('metastases', 'Disease', (77, 87))	('PEDF-/-', 'Var', (19, 26))	('PEDF+/-', 'Var', (31, 38))	('mice', 'Species', '10090', (128, 132))	('metastases', 'Disease', 'MESH:D009362', (77, 87))	('mice', 'Species', '10090', (39, 43))
37491	23793989	These findings corroborate a well-known function of PEDF, suggesting that PEDF may inhibit angiogenesis, or the formation of new blood vessels, in the metastases in mouse liver, but not vasculogenesis, or the formation of blood vessels during embryonic development.	('mouse', 'Species', '10090', (165, 170))	('angiogenesis', 'biological_process', 'GO:0001525', ('91', '103'))	('formation', 'biological_process', 'GO:0009058', ('112', '121'))	('angiogenesis', 'CPA', (91, 103))	('metastases', 'Disease', 'MESH:D009362', (151, 161))	('PEDF', 'Var', (74, 78))	('vasculogenesis', 'biological_process', 'GO:0001570', ('186', '200'))	('formation of new blood vessels', 'CPA', (112, 142))	('formation', 'biological_process', 'GO:0009058', ('209', '218'))	('inhibit', 'NegReg', (83, 90))	('metastases', 'Disease', (151, 161))
37493	23793989	A trend toward greater activated HSC density was found only in PEDF-/- mice but not PEDF+/- mice; however, this was not significantly different among the three groups (Fig.	('mice', 'Species', '10090', (71, 75))	('activated HSC density', 'CPA', (23, 44))	('HSC', 'cellular_component', 'GO:0035301', ('33', '36'))	('greater', 'PosReg', (15, 22))	('mice', 'Species', '10090', (92, 96))	('PEDF-/-', 'Var', (63, 70))
37494	23793989	There was however significantly less type III collagen, a marker for basement membrane production, in PEDF+/+ mice versus both PEDF+/- and PEDF-/- mice (Fig.	('mice', 'Species', '10090', (147, 151))	('less', 'NegReg', (32, 36))	('collagen', 'molecular_function', 'GO:0005202', ('46', '54'))	('mice', 'Species', '10090', (110, 114))	('PEDF+/+', 'Var', (102, 109))	('basement membrane', 'cellular_component', 'GO:0005604', ('69', '86'))	('type III collagen', 'CPA', (37, 54))
37501	23793989	Now we have shown that pigment epithelium-derived factor (PEDF) is also an important factor produced by the host that suppresses metastatic progression, and loss of PEDF is accompanied by an increase in angiogenesis and stromagenesis within the metastases.	('suppresses', 'NegReg', (118, 128))	('metastases', 'Disease', (245, 255))	('metastatic progression', 'CPA', (129, 151))	('PEDF', 'Gene', (165, 169))	('stromagenesis', 'CPA', (220, 233))	('angiogenesis', 'biological_process', 'GO:0001525', ('203', '215'))	('increase', 'PosReg', (191, 199))	('pigment epithelium-derived factor', 'Gene', (23, 56))	('metastases', 'Disease', 'MESH:D009362', (245, 255))	('pigment epithelium-derived factor', 'Gene', '20317', (23, 56))	('angiogenesis', 'CPA', (203, 215))	('loss', 'Var', (157, 161))
37512	23793989	PEDF+/+ contain mostly micrometastases and low-end intermediate metastases, thus we are unable to accurately compare vascular density and type III collagen production in large metastases across the three genotypes.	('metastases', 'Disease', (176, 186))	('metastases', 'Disease', 'MESH:D009362', (64, 74))	('metastases', 'Disease', 'MESH:D009362', (28, 38))	('metastases', 'Disease', 'MESH:D009362', (176, 186))	('PEDF+/+', 'Var', (0, 7))	('metastases', 'Disease', (64, 74))	('collagen', 'molecular_function', 'GO:0005202', ('147', '155'))	('metastases', 'Disease', (28, 38))
37519	21386838	Resistance of uveal melanoma to the interstrand cross-linking agent mitomycin C is associated with reduced expression of CYP450R Uveal melanoma (UM) is the most common primary intraocular tumour of adults, frequently metastasising to the liver.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('intraocular tumour', 'Disease', (176, 194))	('mitomycin C', 'Chemical', 'MESH:D016685', (68, 79))	('uveal melanoma', 'Disease', 'MESH:C536494', (14, 28))	('uveal melanoma', 'Phenotype', 'HP:0007716', (14, 28))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('uveal melanoma', 'Disease', (14, 28))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('expression', 'MPA', (107, 117))	('Uveal melanoma', 'Disease', 'MESH:C536494', (129, 143))	('intraocular tumour', 'Disease', 'MESH:D064090', (176, 194))	('CYP450R', 'Var', (121, 128))	('reduced', 'NegReg', (99, 106))	('Uveal melanoma', 'Disease', (129, 143))
37527	21386838	In all, 6 out of 6 UMs tested displayed reduced expression of the metabolising enzyme CYP450R and transient expression of CYP450R increased MMC sensitivity of UM.	('metabolising enzyme CYP450R', 'Enzyme', (66, 93))	('CYP450R', 'Var', (122, 129))	('expression', 'MPA', (48, 58))	('MMC', 'Chemical', 'MESH:D016685', (140, 143))	('reduced', 'NegReg', (40, 47))	('increased', 'PosReg', (130, 139))	('MMC sensitivity of UM', 'CPA', (140, 161))
37583	21386838	In control cell lines (WM793, HCT116 and SW480), MMC decreased migration of 40-50% of DNA out of cells (% decrease in TM).	('HCT116', 'CellLine', 'CVCL:0291', (30, 36))	('MMC', 'Var', (49, 52))	('decrease', 'NegReg', (106, 114))	('SW480', 'CellLine', 'CVCL:0546', (41, 46))	('MMC', 'Chemical', 'MESH:D016685', (49, 52))	('decreased', 'NegReg', (53, 62))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('migration', 'CPA', (63, 72))
37590	21386838	As a result of DNA damage, MMC causes cells to accumulate in G2 phase of the cell cycle.	('G2 phase', 'biological_process', 'GO:0051319', ('61', '69'))	('cell cycle', 'biological_process', 'GO:0007049', ('77', '87'))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('MMC', 'Chemical', 'MESH:D016685', (27, 30))	('accumulate', 'PosReg', (47, 57))	('damage', 'Var', (19, 25))
37599	21386838	To confirm the association between CYP450R expression and MMC resistance, the bicistronic CYP450R expressing vector pEF-P450R-IRES-P (CYP450R) or an empty vector control was transiently expressed in SOM 196b and WM793 cell lines (Figure 5).	('P450R', 'Var', (136, 141))	('P450R', 'SUBSTITUTION', 'None', (92, 97))	('P450R', 'SUBSTITUTION', 'None', (37, 42))	('P450R', 'SUBSTITUTION', 'None', (120, 125))	('P450R', 'Var', (92, 97))	('P450R', 'SUBSTITUTION', 'None', (136, 141))	('MMC', 'Chemical', 'MESH:D016685', (58, 61))	('P450R', 'Var', (37, 42))	('P450R', 'Var', (120, 125))
37602	21386838	In SOM 196b, however, complementation with CYP450R significantly increased the sensitivity to MMC compared with non-complemented and empty vector controls (P=0.02 and P=0.008, respectively) (Figures 5C and D).	('MMC', 'Chemical', 'MESH:D016685', (94, 97))	('increased', 'PosReg', (65, 74))	('CYP450R', 'Var', (43, 50))	('sensitivity to MMC', 'MPA', (79, 97))
37603	21386838	It is therefore likely that the resistance to MMC in UM is caused by defective CYP450R expression, altering the ability of these cells to metabolise MMC.	('MMC', 'Chemical', 'MESH:D016685', (46, 49))	('CYP450R', 'Enzyme', (79, 86))	('altering', 'Reg', (99, 107))	('metabolise MMC', 'MPA', (138, 152))	('ability', 'MPA', (112, 119))	('caused', 'Reg', (59, 65))	('defective', 'Var', (69, 78))	('MMC', 'Chemical', 'MESH:D016685', (149, 152))
37607	21386838	The induction of cross-links is lethal to cells because it blocks DNA replication, so cross-resistance to a different type of replication inhibitor, HU, was also tested.	('DNA replication', 'biological_process', 'GO:0006260', ('66', '81'))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('cross-links', 'Var', (17, 28))	('blocks', 'NegReg', (59, 65))	('HU', 'Chemical', 'MESH:D006918', (149, 151))	('DNA replication', 'MPA', (66, 81))
37612	21386838	Mitomycin C induces DNA ICLs, such lesions prevent DNA from unwinding and thus block replication and transcription.	('replication', 'MPA', (85, 96))	('block', 'NegReg', (79, 84))	('prevent', 'NegReg', (43, 50))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('transcription', 'biological_process', 'GO:0006351', ('101', '114'))	('DNA', 'MPA', (20, 23))	('transcription', 'MPA', (101, 114))	('lesions', 'Var', (35, 42))	('DNA', 'cellular_component', 'GO:0005574', ('20', '23'))	('Mitomycin C', 'Chemical', 'MESH:D016685', (0, 11))
37618	21386838	For example, using CHO cells expressing the bacterial MMC resistance-associated protein, it was found that the resistance to MMC could be reduced significantly by the overexpression of DTD and CYP450R.	('resistance', 'MPA', (111, 121))	('CHO', 'CellLine', 'CVCL:0213', (19, 22))	('reduced', 'NegReg', (138, 145))	('overexpression', 'PosReg', (167, 181))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('MMC', 'Chemical', 'MESH:D016685', (54, 57))	('CHO', 'molecular_function', 'GO:0043848', ('19', '22'))	('DTD', 'Var', (185, 188))	('CYP450R', 'Var', (193, 200))	('MMC', 'Chemical', 'MESH:D016685', (125, 128))
37619	21386838	Similarly, in human bladder tumours, the expression of DTD and CYP450R was positively correlated with MMC sensitivity in these tumours.	('correlated', 'Reg', (86, 96))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumours', 'Phenotype', 'HP:0002664', (127, 134))	('bladder tumours', 'Disease', 'MESH:D001749', (20, 35))	('human', 'Species', '9606', (14, 19))	('MMC', 'Chemical', 'MESH:D016685', (102, 105))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('tumours', 'Disease', 'MESH:D009369', (127, 134))	('DTD', 'Var', (55, 58))	('tumours', 'Disease', (127, 134))	('CYP450R', 'Var', (63, 70))	('MMC sensitivity', 'Disease', (102, 117))	('tumours', 'Disease', 'MESH:D009369', (28, 35))	('bladder tumours', 'Disease', (20, 35))	('tumours', 'Disease', (28, 35))
37643	21386838	However, our data demonstrating that the complementation of UM with CYP450R can restore sensitivity combined with the development of gene therapies to alter gene expression in cells, may offer hope that by restoring the metabolising gene, tumours may be successfully treated with cross-linking agents in the future.	('tumours', 'Phenotype', 'HP:0002664', (239, 246))	('CYP450R', 'Var', (68, 75))	('gene expression', 'biological_process', 'GO:0010467', ('157', '172'))	('complementation', 'Var', (41, 56))	('metabolising gene', 'MPA', (220, 237))	('tumours', 'Disease', 'MESH:D009369', (239, 246))	('tumours', 'Disease', (239, 246))	('restore', 'PosReg', (80, 87))	('tumour', 'Phenotype', 'HP:0002664', (239, 245))	('sensitivity', 'MPA', (88, 99))
37644	21386838	Indeed early studies have shown that intratumoral injection of a vector expressing CYP450R in an adenoviral context can sensitise previously resistant xenografts to MMC.	('sensitise', 'Reg', (120, 129))	('CYP450R', 'Var', (83, 90))	('MMC', 'Chemical', 'MESH:D016685', (165, 168))
37663	21111965	There is now evidence that the majority of melanomas harbor one or more mutations in critical kinase signaling pathways.	('mutations', 'Var', (72, 81))	('melanomas', 'Disease', (43, 52))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanomas', 'Phenotype', 'HP:0002861', (43, 52))	('melanomas', 'Disease', 'MESH:D008545', (43, 52))	('critical kinase signaling pathways', 'Pathway', (85, 119))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))
37671	21111965	Consistent with the hypothesis that these melanoma subtypes are caused by different factors, comparative genomic hybridization (CGH) analysis has demonstrated that these clinically-defined groups of tumors have markedly different patterns of DNA copy number changes, including subtype-specific gene amplifications and deletions.	('DNA', 'cellular_component', 'GO:0005574', ('242', '245'))	('melanoma subtypes', 'Disease', (42, 59))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('melanoma subtypes', 'Disease', 'MESH:D008545', (42, 59))	('gene amplifications', 'Var', (294, 313))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('deletions', 'Var', (318, 327))
37675	21111965	The identification of activating mutations in melanoma, combined with a growing appreciation of the different pattern of genetic changes in the anatomically defined melanoma subtypes, has become the focus of a concerted effort to translate these discoveries into personalized therapeutic approaches for this disease.	('melanoma subtypes', 'Disease', (165, 182))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('mutations', 'Var', (33, 42))	('melanoma subtypes', 'Disease', 'MESH:D008545', (165, 182))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('activating', 'PosReg', (22, 32))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
37676	21111965	In this article, we will review: (1) the known mutations, amplifications, and deletions in kinase signaling pathways that have been implicated in melanoma; (2) the prevalence of these genetic events in clinicopathologically defined melanoma subtypes; and (3) the results of clinical trials that utilize targeted therapy approaches to block aberrantly activated pathways resulting from such mutations.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('melanoma subtypes', 'Disease', 'MESH:D008545', (232, 249))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('mutations', 'Var', (390, 399))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('kinase signaling pathways', 'Pathway', (91, 116))	('mutations', 'Var', (47, 56))	('melanoma', 'Disease', (232, 240))	('melanoma', 'Disease', 'MESH:D008545', (232, 240))	('melanoma subtypes', 'Disease', (232, 249))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('deletions', 'Var', (78, 87))
37682	21111965	A variety of activating signals result in the exchange of GTP for GDP, which activates RAS.	('GDP', 'MPA', (66, 69))	('GTP', 'Chemical', 'MESH:D006160', (58, 61))	('GDP', 'Chemical', 'MESH:D006153', (66, 69))	('activates', 'PosReg', (77, 86))	('GTP', 'MPA', (58, 61))	('RAS', 'Protein', (87, 90))	('exchange', 'Var', (46, 54))
37683	21111965	RAS family members are also frequently affected by mutations in cancer that result in constitutive GTP-binding.	('GTP', 'Chemical', 'MESH:D006160', (99, 102))	('mutations', 'Var', (51, 60))	('affected', 'Reg', (39, 47))	('constitutive', 'MPA', (86, 98))	('cancer', 'Disease', (64, 70))	('RAS', 'Protein', (0, 3))	('GTP-binding', 'Interaction', (99, 110))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('GTP-binding', 'molecular_function', 'GO:0005525', ('99', '110'))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
37687	21111965	In 2002, an experimental screen for mutations in RAF family members in cancer cell lines and tumors identified point mutations in BRAF in approximately half of the melanomas that were examined in the study, as well as occasional (3-18%) colon, lung, breast, and ovarian cancer specimens.	('RAF', 'Gene', '22882', (49, 52))	('melanomas', 'Disease', (164, 173))	('RAF', 'Gene', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cancer', 'Disease', (71, 77))	('RAF', 'Gene', (49, 52))	('cancer', 'Disease', (270, 276))	('ovarian cancer', 'Disease', 'MESH:D010051', (262, 276))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('breast', 'Disease', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('melanomas', 'Phenotype', 'HP:0002861', (164, 173))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('tumors', 'Disease', (93, 99))	('ovarian cancer', 'Disease', (262, 276))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('ovarian cancer', 'Phenotype', 'HP:0100615', (262, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('RAF', 'Gene', '22882', (131, 134))	('colon', 'Disease', (237, 242))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('point mutations', 'Var', (111, 126))	('melanomas', 'Disease', 'MESH:D008545', (164, 173))
37688	21111965	Since this sentinel observation, the high frequency of point mutations in BRAF in melanoma has been confirmed in multiple studies.	('BRAF', 'Gene', (74, 78))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('point mutations', 'Var', (55, 70))
37689	21111965	A recent meta-analysis of over 200 published studies reported an overall mutation rate of 65% in melanoma cell lines and 42% in tumors.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('mutation', 'Var', (73, 81))
37690	21111965	Analysis of anatomic subtypes demonstrated that BRAF mutations are relatively common in CMs (42.5%), but uncommon in MuMs (5.6%) and rare in UvMs (<1%) [Table 1].	('UvM', 'Phenotype', 'HP:0007716', (141, 144))	('mutations', 'Var', (53, 62))	('common', 'Reg', (78, 84))	('BRAF', 'Gene', (48, 52))	('CM', 'Disease', 'MESH:D009202', (88, 90))	('MuMs', 'Species', '41568', (117, 121))	('CM', 'Phenotype', 'HP:0012056', (88, 90))
37691	21111965	Among CMs, BRAF mutations are common in superficial spreading melanomas (SSM) (53%), but are less prevalent in acral lentiginous (ALM) (18%) and lentigo maligna melanomas (LMM) (9%).	('LMM', 'Phenotype', 'HP:0012059', (172, 175))	('CM', 'Disease', 'MESH:D009202', (6, 8))	('SSM', 'Phenotype', 'HP:0012057', (73, 76))	('common', 'Reg', (30, 36))	('lentigo maligna', 'Phenotype', 'HP:0012059', (145, 160))	('melanomas', 'Disease', 'MESH:D008545', (161, 170))	('lentigo maligna melanomas', 'Disease', (145, 170))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('SSM', 'cellular_component', 'GO:1990843', ('73', '76'))	('melanomas', 'Disease', (161, 170))	('mutations', 'Var', (16, 25))	('acral lentiginous', 'Disease', (111, 128))	('lentigo maligna melanomas', 'Phenotype', 'HP:0012059', (145, 170))	('superficial spreading melanomas', 'Phenotype', 'HP:0012057', (40, 71))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('CM', 'Phenotype', 'HP:0012056', (6, 8))	('acral lentiginous', 'Disease', 'MESH:D007911', (111, 128))	('melanomas', 'Phenotype', 'HP:0002861', (161, 170))	('melanomas', 'Disease', 'MESH:D008545', (62, 71))	('lentigo maligna melanomas', 'Disease', 'MESH:D018327', (145, 170))	('melanomas', 'Disease', (62, 71))	('ALM', 'Phenotype', 'HP:0012060', (130, 133))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('BRAF', 'Gene', (11, 15))
37692	21111965	The low prevalence of BRAF mutations in these tumors is consistent with the different patterns of DNA copy number gains and losses observed in the CGH analysis of cutaneous melanomas with or without chronic sun damage.	('mutations', 'Var', (27, 36))	('DNA', 'Gene', (98, 101))	('losses', 'NegReg', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (163, 182))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (163, 182))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanomas', 'Phenotype', 'HP:0002861', (173, 182))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('BRAF', 'Gene', (22, 26))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('sun damage', 'Phenotype', 'HP:0000992', (207, 217))	('cutaneous melanomas', 'Disease', (163, 182))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
37693	21111965	Approximately 50 different point mutations in BRAF have been identified in cancer.	('BRAF', 'Gene', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('point mutations', 'Var', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('identified', 'Reg', (61, 71))
37694	21111965	A single substitution, the BRAF V600E mutation, comprises ~85% of the BRAF mutations detected in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('V600E', 'Mutation', 'rs113488022', (32, 37))	('V600E', 'Var', (32, 37))	('BRAF', 'Gene', (27, 31))
37695	21111965	The V600E mutation increases the in vitro kinase activity of the BRAF protein more than 400-fold.	('V600E', 'Var', (4, 9))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('BRAF protein', 'Protein', (65, 77))	('V600E', 'Mutation', 'rs113488022', (4, 9))	('increases', 'PosReg', (19, 28))	('ases', 'Chemical', '-', (24, 28))	('kinase activity', 'molecular_function', 'GO:0016301', ('42', '57'))
37696	21111965	Most of the other reported somatic BRAF mutations, particularly other changes involving the V600 residue, also increase BRAF's catalytic activity (5-fold to 700-fold).	('BRAF', 'Gene', (35, 39))	("increase BRAF's catalytic", 'Disease', 'MESH:D010300', (111, 136))	('V600', 'Var', (92, 96))	("increase BRAF's catalytic", 'Disease', (111, 136))	('catalytic activity', 'molecular_function', 'GO:0003824', ('127', '145'))
37697	21111965	Interestingly, a few of the BRAF mutations that have been detected in cancer cells (G466E, G466V, G596R, D594V) decrease the catalytic activity of the BRAF protein.	('G596R', 'Mutation', 'rs121913361', (98, 103))	('G466V', 'Var', (91, 96))	('decrease', 'NegReg', (112, 120))	('G466E', 'Mutation', 'rs121913351', (84, 89))	('D594V', 'Mutation', 'rs121913338', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('BRAF protein', 'Protein', (151, 163))	('G466E', 'Var', (84, 89))	('G466V', 'Mutation', 'rs121913351', (91, 96))	('catalytic activity', 'molecular_function', 'GO:0003824', ('125', '143'))	('BRAF', 'Gene', (28, 32))	('catalytic activity', 'MPA', (125, 143))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('G596R', 'Var', (98, 103))	('D594V', 'Var', (105, 110))
37698	21111965	As BRAF V600E is the predominant mutation identified in tumors, including melanoma, most functional studies have examined the function of the protein encoded by this change.	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('BRAF V600E', 'Var', (3, 13))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('V600E', 'Mutation', 'rs113488022', (8, 13))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
37700	21111965	Inhibition of BRAF V600E with small interfering RNA (siRNA, shRNA) inhibits MAPK activation, growth, and survival of human melanoma cell lines with this mutation.	('RNA', 'cellular_component', 'GO:0005562', ('48', '51'))	('activation', 'MPA', (81, 91))	('MAPK', 'Protein', (76, 80))	('V600E', 'Mutation', 'rs113488022', (19, 24))	('human', 'Species', '9606', (117, 122))	('BRAF', 'Var', (14, 18))	('MAPK activation', 'biological_process', 'GO:0000187', ('76', '91'))	('MAPK', 'molecular_function', 'GO:0004707', ('76', '80'))	('growth', 'CPA', (93, 99))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('inhibits', 'NegReg', (67, 75))	('survival', 'CPA', (105, 113))
37709	21111965	These results raised the possibility that mutant BRAF was not a good therapeutic target in melanoma.	('mutant', 'Var', (42, 48))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('BRAF', 'Gene', (49, 53))
37710	21111965	The observation that activating BRAF mutations are present in up to 80% of benign nevi - indolent lesions with almost no malignant potential - is certainly consistent with the hypothesis that this genetic alteration alone cannot fully explain the aggressive biology of melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (269, 277))	('melanoma', 'Disease', (269, 277))	('activating', 'PosReg', (21, 31))	('BRAF', 'Gene', (32, 36))	('benign nevi', 'Disease', (75, 86))	('melanoma', 'Disease', 'MESH:D008545', (269, 277))	('mutations', 'Var', (37, 46))	('nevi', 'Phenotype', 'HP:0003764', (82, 86))
37711	21111965	Similarly, introduction of the BRAF V600E mutation alone was not sufficient to transform melanocytes into invasive lesions in multiple models, but required complementation by other genetic events to transform cells.	('V600E', 'Var', (36, 41))	('V600E', 'Mutation', 'rs113488022', (36, 41))	('BRAF', 'Gene', (31, 35))
37712	21111965	An alternative explanation for the failure of sorafenib is that mutant BRAF is actually a good therapeutic target, but that the drug did not inhibit BRAF effectively.	('mutant', 'Var', (64, 70))	('BRAF', 'Gene', (71, 75))	('sorafenib', 'Chemical', 'MESH:D000077157', (46, 55))
37714	21111965	Of note, in the phase II trial of paclitaxel, carboplatin, and sorafenib, there was no association noted between the presence of BRAF mutations and clinical responses, but there was a positive association with expression of the VEGFR2 protein and clinical response.	('sorafenib', 'Chemical', 'MESH:D000077157', (63, 72))	('protein', 'cellular_component', 'GO:0003675', ('235', '242'))	('BRAF', 'Gene', (129, 133))	('carboplatin', 'Chemical', 'MESH:D016190', (46, 57))	('expression', 'MPA', (210, 220))	('VEGFR2', 'Gene', '3791', (228, 234))	('mutations', 'Var', (134, 143))	('protein', 'Protein', (235, 242))	('paclitaxel', 'Chemical', 'MESH:D017239', (34, 44))	('VEGFR2', 'Gene', (228, 234))	('positive', 'PosReg', (184, 192))
37715	21111965	The potential of the BRAF V600E protein as a therapeutic target for melanoma has now been validated by clinical trials with second-generation BRAF inhibitors.	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('V600E', 'Mutation', 'rs113488022', (26, 31))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('BRAF', 'Gene', (21, 25))	('V600E', 'Var', (26, 31))
37716	21111965	PLX4032 (also known as RG7204) is a more potent BRAF inhibitor than sorafenib, and it is selective for the V600E mutant form of the protein.	('V600E', 'Var', (107, 112))	('PLX4032', 'Chemical', 'MESH:D000077484', (0, 7))	('BRAF', 'MPA', (48, 52))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('sorafenib', 'Chemical', 'MESH:D000077157', (68, 77))	('V600E', 'Mutation', 'rs113488022', (107, 112))	('PLX4032', 'Gene', (0, 7))
37717	21111965	PLX4032 inhibits the catalytic activity of the BRAF V600E protein at an IC50 of 13 nM, which is more than 10-fold lower than the dose that inhibits the wild-type protein.	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('inhibits', 'NegReg', (8, 16))	('PLX4032', 'Chemical', 'MESH:D000077484', (0, 7))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('catalytic activity', 'MPA', (21, 39))	('catalytic activity', 'molecular_function', 'GO:0003824', ('21', '39'))	('BRAF V600E', 'Var', (47, 57))	('V600E', 'Mutation', 'rs113488022', (52, 57))
37718	21111965	In contrast to sorafenib, an inhibitor of multiple protein kinases at therapeutic drug levels, PLX4032 has minimal activity against most other protein kinases, with an IC50 >1,000 nM for many related proteins.	('PLX4032', 'Chemical', 'MESH:D000077484', (95, 102))	('PLX4032', 'Var', (95, 102))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('sorafenib', 'Chemical', 'MESH:D000077157', (15, 24))	('activity', 'MPA', (115, 123))	('ases', 'Chemical', '-', (154, 158))	('ases', 'Chemical', '-', (62, 66))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
37719	21111965	Preclinical studies demonstrated that PLX4032 inhibited the growth of melanoma cells with a BRAF mutation at 10x-100x lower concentrations than melanoma cell lines without a mutant BRAF.	('melanoma', 'Disease', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('BRAF', 'Gene', (92, 96))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('PLX4032', 'Chemical', 'MESH:D000077484', (38, 45))	('mutation', 'Var', (97, 105))	('melanoma', 'Disease', (144, 152))	('inhibited', 'NegReg', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('growth', 'CPA', (60, 66))
37730	21111965	The efficacy of targeting mutant BRAF is also supported by early results from the Phase I trial of GSK2118436, another potent, mutant-specific BRAF inhibitor.	('mutant', 'Var', (26, 32))	('BRAF', 'Gene', (33, 37))	('GSK2118436', 'Chemical', 'MESH:C561627', (99, 109))	('GSK', 'molecular_function', 'GO:0050321', ('99', '102'))
37733	21111965	The reported activities of PLX4032 and GSK2118436 in melanoma patients with BRAF V600 mutations suggests that a new standard of care will likely soon exist for these patients.	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('GSK2118436', 'Chemical', 'MESH:C561627', (39, 49))	('melanoma', 'Disease', (53, 61))	('GSK', 'molecular_function', 'GO:0050321', ('39', '42'))	('PLX4032', 'Chemical', 'MESH:D000077484', (27, 34))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('GSK2118436', 'Var', (39, 49))	('patients', 'Species', '9606', (62, 70))	('BRAF V600', 'Gene', (76, 85))	('patients', 'Species', '9606', (166, 174))	('activities', 'MPA', (13, 23))
37737	21111965	The lack of clinical response, and possible rapid progression, in patients not harboring a BRAF mutation is consistent with observations in preclinical models by four different groups suggesting potential promotion of tumor growth when mutant-selective BRAF inhibitors are used to treat BRAF wild-type melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (302, 310))	('melanomas', 'Phenotype', 'HP:0002861', (302, 311))	('melanomas', 'Disease', 'MESH:D008545', (302, 311))	('BRAF', 'Gene', (253, 257))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('mutation', 'Var', (96, 104))	('BRAF', 'Gene', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('promotion', 'PosReg', (205, 214))	('melanomas', 'Disease', (302, 311))	('tumor', 'Disease', (218, 223))	('patients', 'Species', '9606', (66, 74))
37739	21111965	While the results varied somewhat between the groups, the BRAF inhibitors promoted the formation of heterodimers of BRAF and CRAF that potently activate MEK in cells without a BRAF mutation.	('activate', 'PosReg', (144, 152))	('MEK', 'Pathway', (153, 156))	('CRAF', 'Gene', (125, 129))	('BRAF', 'Gene', (116, 120))	('CRAF', 'Gene', '5894', (125, 129))	('CRAF', 'molecular_function', 'GO:0004709', ('125', '129'))	('mutation', 'Var', (181, 189))	('formation', 'biological_process', 'GO:0009058', ('87', '96'))
37741	21111965	Interestingly, low catalytic activity BRAF mutants seem to activate MAPK similarly, and preclinical evidence suggests that melanoma cells with these mutations are sensitive to CRAF inhibition, including treatment with sorafenib.	('catalytic activity', 'molecular_function', 'GO:0003824', ('19', '37'))	('mutations', 'Var', (149, 158))	('activate', 'PosReg', (59, 67))	('CRAF', 'molecular_function', 'GO:0004709', ('176', '180'))	('CRAF', 'Gene', (176, 180))	('CRAF', 'Gene', '5894', (176, 180))	('MAPK', 'Pathway', (68, 72))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('catalytic activity', 'MPA', (19, 37))	('melanoma', 'Disease', (123, 131))	('BRAF', 'Gene', (38, 42))	('sorafenib', 'Chemical', 'MESH:D000077157', (218, 227))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('MAPK', 'molecular_function', 'GO:0004707', ('68', '72'))	('mutants', 'Var', (43, 50))	('low', 'NegReg', (15, 18))
37743	21111965	Mutations in the members of the RAS family of GTP-ases are one of the most frequent events in cancer.	('ases', 'Chemical', '-', (50, 54))	('frequent', 'Reg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Mutations', 'Var', (0, 9))	('GTP', 'Chemical', 'MESH:D006160', (46, 49))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
37744	21111965	While mutations of HRAS and KRAS are common in many cancer types, they are very rare in melanoma.	('KRAS', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('KRAS', 'Gene', '3845', (28, 32))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('HRAS', 'Gene', '3265', (19, 23))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('common', 'Reg', (37, 43))	('HRAS', 'Gene', (19, 23))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('mutations', 'Var', (6, 15))
37745	21111965	However, NRAS mutations have been reported in 14% of human melanoma cell lines and 15-25% of melanoma clinical specimens.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('reported', 'Reg', (34, 42))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('NRAS', 'Gene', (9, 13))	('NRAS', 'Gene', '4893', (9, 13))	('human', 'Species', '9606', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('mutations', 'Var', (14, 23))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
37746	21111965	The mutations affecting NRAS are highly conserved; mutations affecting positions 12 and 61 constitute approximately 90% of the mutations reported in melanoma.	('NRAS', 'Gene', '4893', (24, 28))	('mutations', 'Var', (51, 60))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('NRAS', 'Gene', (24, 28))
37747	21111965	The prevalence of NRAS mutations varies across the different anatomically-defined melanoma subgroups, although not as dramatically as is observed for BRAF mutations [Table 1].	('NRAS', 'Gene', '4893', (18, 22))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('mutations', 'Var', (23, 32))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('NRAS', 'Gene', (18, 22))
37748	21111965	NRAS mutations are detected in approximately 26% of CMs, 14% of MuMs, and <1% of UvMs.	('CM', 'Disease', 'MESH:D009202', (52, 54))	('MuMs', 'Species', '41568', (64, 68))	('CM', 'Phenotype', 'HP:0012056', (52, 54))	('mutations', 'Var', (5, 14))	('detected', 'Reg', (19, 27))	('UvM', 'Phenotype', 'HP:0007716', (81, 84))	('MuMs', 'Disease', (64, 68))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))
37749	21111965	Among CMs, 22% of superficial spreading melanomas and 28% of nodular melanomas have NRAS mutations, while significantly lower rates are observed in acral lentiginous (4%), spitzoid (10%), and lentigo maligna (0%) melanomas.	('CM', 'Disease', 'MESH:D009202', (6, 8))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('mutations', 'Var', (89, 98))	('nodular melanomas', 'Disease', (61, 78))	('melanomas', 'Phenotype', 'HP:0002861', (213, 222))	('melanomas', 'Phenotype', 'HP:0002861', (69, 78))	('lentigo maligna', 'Phenotype', 'HP:0012059', (192, 207))	('superficial spreading melanomas', 'Phenotype', 'HP:0012057', (18, 49))	('NRAS', 'Gene', '4893', (84, 88))	('nodular melanomas', 'Phenotype', 'HP:0012058', (61, 78))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('lentigo maligna', 'Disease', (192, 207))	('CM', 'Phenotype', 'HP:0012056', (6, 8))	('melanomas', 'Disease', 'MESH:D008545', (40, 49))	('acral lentiginous', 'Disease', (148, 165))	('melanomas', 'Disease', 'MESH:D008545', (213, 222))	('melanomas', 'Disease', 'MESH:D008545', (69, 78))	('melanomas', 'Disease', (40, 49))	('nodular melanomas', 'Disease', 'MESH:D020518', (61, 78))	('melanomas', 'Disease', (213, 222))	('NRAS', 'Gene', (84, 88))	('lentigo maligna', 'Disease', 'MESH:D018327', (192, 207))	('acral lentiginous', 'Disease', 'MESH:D007911', (148, 165))	('melanomas', 'Disease', (69, 78))	('spitzoid', 'Chemical', '-', (172, 180))
37750	21111965	NRAS mutations are also present in common acquired nevi (6-20%) at a similar rate as has been detected in melanomas, and potentially at an even higher rate in congenital nevi.	('nevi', 'Phenotype', 'HP:0003764', (51, 55))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanomas', 'Disease', (106, 115))	('nevi', 'Phenotype', 'HP:0003764', (170, 174))	('mutations', 'Var', (5, 14))	('congenital nevi', 'Disease', (159, 174))	('melanomas', 'Phenotype', 'HP:0002861', (106, 115))	('NRAS', 'Gene', (0, 4))	('melanomas', 'Disease', 'MESH:D008545', (106, 115))	('NRAS', 'Gene', '4893', (0, 4))	('acquired nevi', 'Disease', (42, 55))
37751	21111965	Interestingly, although rare in melanoma and other types of melanocytic nevi, HRAS mutations have been reported in 12 - 29% of Spitz nevi.	('mutations', 'Var', (83, 92))	('Spitz nevi', 'Disease', (127, 137))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('reported', 'Reg', (103, 111))	('nevi', 'Phenotype', 'HP:0003764', (72, 76))	('HRAS', 'Gene', '3265', (78, 82))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (60, 76))	('nevi', 'Phenotype', 'HP:0003764', (133, 137))	('HRAS', 'Gene', (78, 82))
37752	21111965	With very rare exceptions, the common activating BRAF and NRAS mutations are mutually exclusive in melanoma tumor and cell lines.	('mutations', 'Var', (63, 72))	('NRAS', 'Gene', '4893', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('activating', 'PosReg', (38, 48))	('melanoma tumor', 'Disease', (99, 113))	('melanoma tumor', 'Disease', 'MESH:D008545', (99, 113))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('NRAS', 'Gene', (58, 62))	('BRAF', 'Gene', (49, 53))
37753	21111965	In contrast, approximately 10% of melanomas with BRAF mutations that are catalytically inactive (i.e.	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('mutations', 'Var', (54, 63))	('melanomas', 'Disease', (34, 43))	('melanomas', 'Disease', 'MESH:D008545', (34, 43))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('BRAF', 'Gene', (49, 53))
37754	21111965	D594V) also have activating NRAS mutations.	('activating', 'Reg', (17, 27))	('NRAS', 'Gene', '4893', (28, 32))	('D594V', 'Mutation', 'rs121913338', (0, 5))	('D594V', 'Var', (0, 5))	('mutations', 'Var', (33, 42))	('NRAS', 'Gene', (28, 32))
37755	21111965	While the activated mutant forms of BRAF and NRAS both activate MEK and MAPK, the activation of these downstream elements is CRAF-dependent in melanomas with NRAS mutations, whereas it is BRAF-dependent in BRAF-mutant cells.	('NRAS', 'Gene', '4893', (158, 162))	('MAPK', 'molecular_function', 'GO:0004707', ('72', '76'))	('BRAF', 'Gene', (36, 40))	('mutations', 'Var', (163, 172))	('NRAS', 'Gene', '4893', (45, 49))	('MAPK', 'Pathway', (72, 76))	('MEK', 'Enzyme', (64, 67))	('CRAF', 'Gene', (125, 129))	('CRAF', 'Gene', '5894', (125, 129))	('melanomas', 'Disease', (143, 152))	('activate', 'PosReg', (55, 63))	('CRAF', 'molecular_function', 'GO:0004709', ('125', '129'))	('NRAS', 'Gene', (158, 162))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('NRAS', 'Gene', (45, 49))	('melanomas', 'Disease', 'MESH:D008545', (143, 152))	('melanomas', 'Phenotype', 'HP:0002861', (143, 152))	('mutant', 'Var', (20, 26))
37758	21111965	In addition, since over 60 cellular proteins have been shown to be farnesylated, FTIs will likely have off-target effects (and potentially dose-limiting toxicities) that compromise the ability to reach levels that effectively inhibit RAS.	('toxicities', 'Disease', (153, 163))	('farnesylated', 'Var', (67, 79))	('RAS', 'Protein', (234, 237))	('inhibit', 'NegReg', (226, 233))	('cellular proteins', 'Protein', (27, 44))	('toxicities', 'Disease', 'MESH:D064420', (153, 163))
37760	21111965	An alternative strategy to treat NRAS-mutant tumors is to inhibit pathways that are downstream of the mutant RAS protein.	('mutant', 'Var', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('NRAS', 'Gene', (33, 37))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('NRAS', 'Gene', '4893', (33, 37))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('inhibit', 'NegReg', (58, 65))
37761	21111965	Experiments in multiple tumor types have demonstrated that mutant RAS activates multiple pro-survival and proliferative pathways in addition to the RAF-MEK-MAPK cascade.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('activates', 'PosReg', (70, 79))	('MAPK', 'molecular_function', 'GO:0004707', ('156', '160'))	('multiple tumor', 'Disease', (15, 29))	('multiple tumor', 'Disease', 'MESH:D009369', (15, 29))	('RAS', 'Gene', (66, 69))	('mutant', 'Var', (59, 65))	('MAPK cascade', 'biological_process', 'GO:0000165', ('156', '168'))	('RAF', 'Gene', (148, 151))	('RAF', 'Gene', '22882', (148, 151))	('pro-survival', 'Pathway', (89, 101))	('pro-survival', 'biological_process', 'GO:0043066', ('89', '101'))
37765	21111965	PI3K is a lipid kinase that consists of a regulatory subunit (PIK3R; p85) and a catalytic subunit (PIK3C; p110).	('p85', 'Gene', (69, 72))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('PI3K', 'Var', (0, 4))	('p85', 'Gene', '5296', (69, 72))
37766	21111965	Activation of PI3K results in the phosphorylation of the 3'-OH of phosphatidylinositols (PI) in the plasma membrane, generating PI (3,4)P2 and PI(3,4,5)P3.	('phosphorylation', 'MPA', (34, 49))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('PI(3,4,5)P3', 'Chemical', '-', (143, 154))	('PI3K', 'Var', (14, 18))	('phosphatidylinositols', 'Chemical', 'MESH:D010716', (66, 87))	('PI (3,4)P2', 'Chemical', '-', (128, 138))	("3'-OH", 'Chemical', '-', (57, 62))	('PI3K', 'molecular_function', 'GO:0016303', ('14', '18'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('100', '115'))
37769	21111965	Upon recruitment to the plasma membrane, AKT is phosphorylated at two critical residues, Ser473 (by the mTORC2 complex) and Thr308 (by PDK1), which activates its serine-threonine kinase activity.	('activates', 'PosReg', (148, 157))	('Thr308', 'Var', (124, 130))	('kinase activity', 'molecular_function', 'GO:0016301', ('179', '194'))	('mTORC2', 'Gene', '74343', (104, 110))	('Ser', 'cellular_component', 'GO:0005790', ('89', '92'))	('Thr308', 'Chemical', '-', (124, 130))	('plasma membrane', 'cellular_component', 'GO:0005886', ('24', '39'))	('AKT', 'Gene', '207', (41, 44))	('serine-threonine kinase activity', 'MPA', (162, 194))	('mTORC2', 'Gene', (104, 110))	('Ser473', 'Var', (89, 95))	('Ser473', 'Chemical', '-', (89, 95))	('PDK1', 'molecular_function', 'GO:0004740', ('135', '139'))	('PDK1', 'Gene', '5163', (135, 139))	('mTORC2', 'cellular_component', 'GO:0031932', ('104', '110'))	('PDK1', 'Gene', (135, 139))	('AKT', 'Gene', (41, 44))
37772	21111965	The PI3K-AKT pathway is affected by mutations that activate it more than any other signaling pathway in cancer.	('AKT', 'Gene', '207', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('activate', 'PosReg', (51, 59))	('mutations', 'Var', (36, 45))	('signaling pathway', 'biological_process', 'GO:0007165', ('83', '100'))	('AKT', 'Gene', (9, 12))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
37773	21111965	The PI3K-AKT pathway was initially implicated in melanoma by the identification of activating NRAS mutations.	('NRAS', 'Gene', (94, 98))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('AKT', 'Gene', '207', (9, 12))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('NRAS', 'Gene', '4893', (94, 98))	('mutations', 'Var', (99, 108))	('AKT', 'Gene', (9, 12))	('activating', 'PosReg', (83, 93))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))	('implicated', 'Reg', (35, 45))
37776	21111965	Loss of PTEN results in constitutive activation of AKT in multiple cancer types, including melanoma.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('AKT', 'Gene', (51, 54))	('melanoma', 'Disease', (91, 99))	('activation', 'PosReg', (37, 47))	('PTEN', 'Gene', (8, 12))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('PTEN', 'Gene', '5728', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Loss', 'Var', (0, 4))	('AKT', 'Gene', '207', (51, 54))
37779	21111965	Nonetheless, loss of PTEN is frequently detected in melanoma tumors and cell lines with a concurrent BRAF mutation, but it appears to be mutually exclusive with NRAS mutations.	('BRAF', 'Gene', (101, 105))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma tumors', 'Disease', (52, 67))	('mutation', 'Var', (106, 114))	('melanoma tumors', 'Disease', 'MESH:D008545', (52, 67))	('NRAS', 'Gene', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('loss', 'NegReg', (13, 17))	('PTEN', 'Gene', (21, 25))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('PTEN', 'Gene', '5728', (21, 25))	('NRAS', 'Gene', '4893', (161, 165))
37780	21111965	While this pattern of mutations suggests that PTEN loss and NRAS mutations may have functional redundancy, quantitative analysis of AKT activation in melanoma tumors and cell lines showed that loss of PTEN correlated with much higher levels of activated AKT.	('AKT', 'Gene', (254, 257))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('PTEN', 'Gene', '5728', (46, 50))	('melanoma tumors', 'Disease', 'MESH:D008545', (150, 165))	('PTEN', 'Gene', (201, 205))	('melanoma tumors', 'Disease', (150, 165))	('AKT', 'Gene', (132, 135))	('NRAS', 'Gene', '4893', (60, 64))	('higher', 'PosReg', (227, 233))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('AKT', 'Gene', '207', (254, 257))	('PTEN loss', 'Disease', 'MESH:D006223', (46, 55))	('loss', 'Var', (193, 197))	('PTEN', 'Gene', '5728', (201, 205))	('mutations', 'Var', (22, 31))	('AKT', 'Gene', '207', (132, 135))	('PTEN', 'Gene', (46, 50))	('NRAS', 'Gene', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('PTEN loss', 'Disease', (46, 55))	('mutations', 'Var', (65, 74))
37781	21111965	This finding is similar to previous studies that showed non-equivalent activation of, and functional dependence upon, different PI3K-AKT pathway effectors by PTEN loss and PIK3CA mutations.	('PTEN loss', 'Disease', (158, 167))	('activation', 'PosReg', (71, 81))	('AKT', 'Gene', '207', (133, 136))	('PIK3CA', 'Gene', (172, 178))	('PI3K', 'molecular_function', 'GO:0016303', ('128', '132'))	('PIK3CA', 'Gene', '5290', (172, 178))	('PTEN loss', 'Disease', 'MESH:D006223', (158, 167))	('mutations', 'Var', (179, 188))	('AKT', 'Gene', (133, 136))
37782	21111965	P IK3CA mutations are relatively common in breast and colon cancer, but have been detected in <= 3% of melanomas.	('colon cancer', 'Phenotype', 'HP:0003003', (54, 66))	('breast and colon cancer', 'Disease', 'MESH:D001943', (43, 66))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('common', 'Reg', (33, 39))	('mutations', 'Var', (8, 17))	('melanomas', 'Disease', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('melanomas', 'Disease', 'MESH:D008545', (103, 112))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))
37784	21111965	Each melanoma with an AKT mutation also had a BRAF mutation.	('mutation', 'Var', (26, 34))	('AKT', 'Gene', '207', (22, 25))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('melanoma', 'Disease', (5, 13))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('AKT', 'Gene', (22, 25))	('mutation', 'Var', (51, 59))	('BRAF', 'Disease', (46, 50))
37785	21111965	While activating mutations of AKT in other cancers all involved the AKT1 isoform, some of the mutations in melanoma affected the AKT3 gene.	('AKT', 'Gene', '207', (129, 132))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', (43, 50))	('AKT1', 'Gene', '207', (68, 72))	('AKT', 'Gene', (30, 33))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('involved', 'Reg', (55, 63))	('AKT3', 'Gene', '10000', (129, 133))	('AKT', 'Gene', (68, 71))	('AKT1', 'Gene', (68, 72))	('mutations', 'Var', (94, 103))	('affected', 'Reg', (116, 124))	('activating', 'PosReg', (6, 16))	('AKT', 'Gene', '207', (30, 33))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('AKT3', 'Gene', (129, 133))	('AKT', 'Gene', (129, 132))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('AKT', 'Gene', '207', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
37791	21111965	In contrast to at least some other targeted therapies in which drug levels sufficient to significantly inhibit their intended target are not attained, it does appear that mTOR inhibitors reach levels that significantly inhibit their target in vivo.	('mTOR', 'Gene', (171, 175))	('inhibitors', 'Var', (176, 186))	('mTOR', 'Gene', '2475', (171, 175))	('inhibit', 'NegReg', (219, 226))
37792	21111965	However, studies in both clinical specimens and cell lines have demonstrated that rapalogs activate AKT, thus contributing to their lack of efficacy.	('AKT', 'Gene', '207', (100, 103))	('rapalogs', 'Var', (82, 90))	('activate', 'PosReg', (91, 99))	('AKT', 'Gene', (100, 103))
37797	21111965	In preclinical models, combined inhibition of the mTORC1 and mTORC2 complexes blocked the activation of P70S6K and AKT, and more effectively inhibited growth and survival of cancer cells, than inhibition of mTORC1 alone.	('AKT', 'Gene', '207', (115, 118))	('inhibition', 'NegReg', (32, 42))	('blocked', 'NegReg', (78, 85))	('P70S6K', 'Gene', '6198', (104, 110))	('complexes', 'Var', (68, 77))	('activation', 'PosReg', (90, 100))	('mTORC1', 'Gene', (50, 56))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('mTORC1', 'Gene', '382056', (50, 56))	('mTORC2', 'cellular_component', 'GO:0031932', ('61', '67'))	('mTORC2', 'Gene', (61, 67))	('mTORC1', 'Gene', (207, 213))	('mTORC1', 'cellular_component', 'GO:0031931', ('50', '56'))	('AKT', 'Gene', (115, 118))	('mTORC1', 'Gene', '382056', (207, 213))	('mTORC2', 'Gene', '74343', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('P70S6K', 'Gene', (104, 110))	('inhibited', 'NegReg', (141, 150))	('mTORC1', 'cellular_component', 'GO:0031931', ('207', '213'))
37799	21111965	However, preclinical experiments with RAS-mutant tumors, including melanomas, showed synergistic inhibition of tumor growth and survival when inhibitors against the RAS-RAF-MEK-MAPK and the PI3K-AKT pathways were combined.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('inhibition', 'NegReg', (97, 107))	('RAF', 'Gene', (169, 172))	('melanomas', 'Disease', 'MESH:D008545', (67, 76))	('tumors', 'Disease', (49, 55))	('melanomas', 'Disease', (67, 76))	('MAPK', 'molecular_function', 'GO:0004707', ('177', '181'))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('AKT', 'Gene', (195, 198))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', (111, 116))	('PI3K', 'molecular_function', 'GO:0016303', ('190', '194'))	('RAS-mutant', 'Gene', (38, 48))	('RAS-mutant', 'Var', (38, 48))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('RAF', 'Gene', '22882', (169, 172))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('AKT', 'Gene', '207', (195, 198))	('survival', 'CPA', (128, 136))
37800	21111965	The high frequency of BRAF mutations in melanomas with PTEN loss suggests that combinatorial regimens may be necessary in other melanoma genotypes as well.	('mutations', 'Var', (27, 36))	('melanomas', 'Disease', (40, 49))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('PTEN loss', 'Disease', 'MESH:D006223', (55, 64))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('melanoma', 'Disease', (40, 48))	('PTEN loss', 'Disease', (55, 64))	('BRAF', 'Gene', (22, 26))	('melanomas', 'Disease', 'MESH:D008545', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
37804	21111965	This region harbors a number of candidate genes, but detailed analysis demonstrated that the c-KIT gene was the focal target of copy number gain in this region.	('c-KIT', 'Gene', (93, 98))	('KIT', 'molecular_function', 'GO:0005020', ('95', '98'))	('c-KIT', 'Gene', '3815', (93, 98))	('copy', 'Var', (128, 132))
37805	21111965	Extra copies of c-KIT were identified in 8% of MuMs and 7% of ALMs.	('identified', 'Reg', (27, 37))	('Extra copies', 'Var', (0, 12))	('MuMs', 'Species', '41568', (47, 51))	('ALM', 'Phenotype', 'HP:0012060', (62, 65))	('c-KIT', 'Gene', (16, 21))	('MuMs', 'Disease', (47, 51))	('ALMs', 'Disease', (62, 66))	('KIT', 'molecular_function', 'GO:0005020', ('18', '21'))	('c-KIT', 'Gene', '3815', (16, 21))
37807	21111965	In addition, sequencing of c-KIT identified missense mutations in 21% of the mucosal, 11% of the acral, and 17% of the CSD cutaneous, but 0% of the non-CSD cutaneous melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanomas', 'Phenotype', 'HP:0002861', (166, 175))	('c-KIT', 'Gene', (27, 32))	('KIT', 'molecular_function', 'GO:0005020', ('29', '32'))	('CSD', 'Disease', (119, 122))	('missense mutations', 'Var', (44, 62))	('mucosal', 'Disease', (77, 84))	('c-KIT', 'Gene', '3815', (27, 32))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (156, 175))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (156, 175))	('acral', 'Disease', (97, 102))	('cutaneous melanomas', 'Disease', (156, 175))
37808	21111965	Subsequent studies have reported similar rates of c-KIT mutations in mucosal and acral melanomas, but they have reported lower rates of mutations in CSD cutaneous tumors, as well as different rates of gene copy number gain across the subtypes [Table 1].	('melanomas', 'Phenotype', 'HP:0002861', (87, 96))	('mutations', 'Var', (56, 65))	('CSD cutaneous tumors', 'Disease', 'MESH:C562576', (149, 169))	('acral melanomas', 'Disease', 'MESH:D008545', (81, 96))	('c-KIT', 'Gene', '3815', (50, 55))	('cutaneous tumors', 'Phenotype', 'HP:0008069', (153, 169))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('acral melanomas', 'Disease', (81, 96))	('CSD cutaneous tumors', 'Disease', (149, 169))	('lower', 'NegReg', (121, 126))	('gene copy number', 'Var', (201, 217))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('acral melanomas', 'Phenotype', 'HP:0012060', (81, 96))	('KIT', 'molecular_function', 'GO:0005020', ('52', '55'))	('c-KIT', 'Gene', (50, 55))	('gain', 'PosReg', (218, 222))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
37810	21111965	Mutations of c-KIT are the most common mutation detected in gastrointestinal stromal tumors (GISTs).	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (60, 91))	('c-KIT', 'Gene', (13, 18))	('c-KIT', 'Gene', '3815', (13, 18))	('GIST', 'Disease', 'MESH:D046152', (93, 97))	('GIST', 'Disease', (93, 97))	('GISTs', 'Phenotype', 'HP:0100723', (93, 98))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (60, 91))	('Mutations', 'Var', (0, 9))	('KIT', 'molecular_function', 'GO:0005020', ('15', '18'))	('gastrointestinal stromal tumors', 'Disease', (60, 91))	('GIST', 'Phenotype', 'HP:0100723', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
37811	21111965	These mutations result in constitutive activation of the c-KIT tyrosine kinase, and activation of multiple pro-survival signaling pathways, including the MAPK and PI3K-AKT pathways [Figure 1].	('c-KIT', 'Gene', '3815', (57, 62))	('PI3K', 'molecular_function', 'GO:0016303', ('163', '167'))	('KIT', 'molecular_function', 'GO:0005020', ('59', '62'))	('activation', 'PosReg', (39, 49))	('activation', 'PosReg', (84, 94))	('AKT', 'Gene', '207', (168, 171))	('MAPK', 'molecular_function', 'GO:0004707', ('154', '158'))	('c-KIT', 'Gene', (57, 62))	('pro-survival', 'biological_process', 'GO:0043066', ('107', '119'))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('pro-survival signaling pathways', 'Pathway', (107, 138))	('AKT', 'Gene', (168, 171))	('mutations', 'Var', (6, 15))
37812	21111965	GISTs exhibit oncogene addiction to the mutant c-KIT proteins, and c-KIT inhibitors (e.g., imatinib) have become the standard treatment for this disease.	('c-KIT', 'Gene', '3815', (67, 72))	('GIST', 'Disease', 'MESH:D046152', (0, 4))	('KIT', 'molecular_function', 'GO:0005020', ('69', '72'))	('GIST', 'Disease', (0, 4))	('GISTs', 'Phenotype', 'HP:0100723', (0, 5))	('c-KIT', 'Gene', '3815', (47, 52))	('imatinib', 'Chemical', 'MESH:D000068877', (91, 99))	('GIST', 'Phenotype', 'HP:0100723', (0, 4))	('KIT', 'molecular_function', 'GO:0005020', ('49', '52'))	('mutant', 'Var', (40, 46))	('c-KIT', 'Gene', (47, 52))	('c-KIT', 'Gene', (67, 72))
37813	21111965	The mutations that affect c-KIT in melanoma occur in the same regions of the gene as are observed in GIST.	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('GIST', 'Disease', 'MESH:D046152', (101, 105))	('c-KIT', 'Gene', '3815', (26, 31))	('KIT', 'molecular_function', 'GO:0005020', ('28', '31'))	('GIST', 'Disease', (101, 105))	('GIST', 'Phenotype', 'HP:0100723', (101, 105))	('mutations', 'Var', (4, 13))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('c-KIT', 'Gene', (26, 31))	('melanoma', 'Disease', (35, 43))
37814	21111965	The finding of activating mutations of c-KIT in melanoma was surprising, as previous studies had demonstrated that c-KIT protein expression is frequently lost in melanoma progression.	('c-KIT', 'Gene', '3815', (39, 44))	('melanoma', 'Disease', (48, 56))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('expression', 'MPA', (129, 139))	('melanoma', 'Disease', (162, 170))	('lost', 'NegReg', (154, 158))	('c-KIT', 'Gene', (115, 120))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('mutations', 'Var', (26, 35))	('c-KIT', 'Gene', (39, 44))	('c-KIT', 'Gene', '3815', (115, 120))	('KIT', 'molecular_function', 'GO:0005020', ('41', '44'))	('KIT', 'molecular_function', 'GO:0005020', ('117', '120'))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
37818	21111965	There are now multiple case reports of metastatic melanoma patients with c-KIT mutations achieving dramatic clinical responses to various c-KIT inhibitors.	('c-KIT', 'Gene', (138, 143))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('KIT', 'molecular_function', 'GO:0005020', ('75', '78'))	('c-KIT', 'Gene', (73, 78))	('c-KIT', 'Gene', '3815', (138, 143))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('KIT', 'molecular_function', 'GO:0005020', ('140', '143'))	('patients', 'Species', '9606', (59, 67))	('c-KIT', 'Gene', '3815', (73, 78))	('mutations', 'Var', (79, 88))
37819	21111965	Clinical trials that are restricted to metastatic melanoma patients with c-KIT mutations or amplifications are currently ongoing.	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('KIT', 'molecular_function', 'GO:0005020', ('75', '78'))	('c-KIT', 'Gene', (73, 78))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('patients', 'Species', '9606', (59, 67))	('c-KIT', 'Gene', '3815', (73, 78))	('amplifications', 'Var', (92, 106))	('mutations', 'Var', (79, 88))
37820	21111965	Mutations in BRAF, NRAS, and c-KIT are detected in <1% of uveal melanomas [Table 1].	('NRAS', 'Gene', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('uveal melanomas', 'Disease', (58, 73))	('NRAS', 'Gene', '4893', (19, 23))	('BRAF', 'Gene', (13, 17))	('uveal melanomas', 'Phenotype', 'HP:0007716', (58, 73))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('Mutations', 'Var', (0, 9))	('c-KIT', 'Gene', (29, 34))	('uveal melanomas', 'Disease', 'MESH:C536494', (58, 73))	('KIT', 'molecular_function', 'GO:0005020', ('31', '34'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('c-KIT', 'Gene', '3815', (29, 34))
37822	21111965	The mutations were highly conserved, affecting the RAS-like domain of the protein, and specifically occur at the Q209 residue that is analogous to the Q61 residue that is frequently mutated in NRAS.	('Q209', 'Var', (113, 117))	('NRAS', 'Gene', (193, 197))	('NRAS', 'Gene', '4893', (193, 197))	('occur', 'Reg', (100, 105))	('RAS-like domain of the', 'MPA', (51, 73))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('mutations', 'Var', (4, 13))	('affecting', 'Reg', (37, 46))
37823	21111965	Expression of the mutant GNalphaQ protein in melanocytes cooperated efficiently with other genes to induce both anchorage-independent growth and tumor formation in mice.	('GNalphaQ', 'Gene', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('protein', 'Protein', (34, 41))	('mice', 'Species', '10090', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('anchorage-independent growth', 'CPA', (112, 140))	('mutant', 'Var', (18, 24))	('formation', 'biological_process', 'GO:0009058', ('151', '160'))	('induce', 'PosReg', (100, 106))	('tumor', 'Disease', (145, 150))
37825	21111965	This finding suggests that inhibitors of this pathway, which were previously believed to be indicated for cutaneous melanomas only, may also have a role in uveal melanoma.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (106, 125))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (106, 125))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('cutaneous melanomas', 'Disease', (106, 125))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('uveal melanoma', 'Disease', (156, 170))	('inhibitors', 'Var', (27, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (156, 170))	('uveal melanoma', 'Phenotype', 'HP:0007716', (156, 170))
37830	21111965	The initial negative clinical trials with sorafenib have been followed by promising studies with PLX4032 and GSK2118436.	('GSK', 'molecular_function', 'GO:0050321', ('109', '112'))	('sorafenib', 'Chemical', 'MESH:D000077157', (42, 51))	('PLX4032', 'Gene', (97, 104))	('GSK2118436', 'Chemical', 'MESH:C561627', (109, 119))	('GSK2118436', 'Var', (109, 119))	('PLX4032', 'Chemical', 'MESH:D000077484', (97, 104))
37836	21111965	While targeted therapies against both BRAF and c-KIT have demonstrated marked activity in patients with mutations in these genes, secondary resistance has rapidly developed in many patients.	('mutations', 'Var', (104, 113))	('c-KIT', 'Gene', '3815', (47, 52))	('c-KIT', 'Gene', (47, 52))	('KIT', 'molecular_function', 'GO:0005020', ('49', '52'))	('patients', 'Species', '9606', (181, 189))	('BRAF', 'Gene', (38, 42))	('activity', 'MPA', (78, 86))	('patients', 'Species', '9606', (90, 98))
37839	21111965	The discovery of BRAF, NRAS, PTEN, and c-KIT alterations in melanoma has supported the development of a variety of rational therapeutic approaches.	('c-KIT', 'Gene', '3815', (39, 44))	('alterations', 'Var', (45, 56))	('KIT', 'molecular_function', 'GO:0005020', ('41', '44'))	('PTEN', 'Gene', (29, 33))	('NRAS', 'Gene', (23, 27))	('PTEN', 'Gene', '5728', (29, 33))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('BRAF', 'Gene', (17, 21))	('c-KIT', 'Gene', (39, 44))	('NRAS', 'Gene', '4893', (23, 27))
37841	21111965	In order to improve outcomes in these patients, it will be critical to determine if their tumors are activating similar pathways by as yet unidentified genetic alterations or if they are characterized by dependence on completely separate and heretofore underappreciated signaling cascades in this disease.	('genetic alterations', 'Var', (152, 171))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('activating', 'Reg', (101, 111))	('patients', 'Species', '9606', (38, 46))	('signaling', 'biological_process', 'GO:0023052', ('270', '279'))
37843	21111965	This study identified over 33,000 changes in the melanoma genome as compared to the germline, including almost 200 non-synonymous coding region substitutions.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))	('changes', 'Var', (34, 41))
37845	21111965	However, as the identification of c-KIT mutations has demonstrated, such analyses will need to incorporate the recognition of the possible molecular diversity of melanomas arising from different anatomic sites.	('c-KIT', 'Gene', (34, 39))	('melanomas', 'Disease', 'MESH:D008545', (162, 171))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('c-KIT', 'Gene', '3815', (34, 39))	('mutations', 'Var', (40, 49))	('melanomas', 'Disease', (162, 171))	('KIT', 'molecular_function', 'GO:0005020', ('36', '39'))	('melanomas', 'Phenotype', 'HP:0002861', (162, 171))
37873	19668458	Tumor height was measured and used to classify a tumor as small (1 mm to 2.5 mm in apical height), medium (>2.5 mm to 10 mm) or large (>10 mm in apical height).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('>2.5 mm to', 'Var', (107, 117))	('tumor', 'Disease', (49, 54))
37958	33903674	Estimation of the timing of BAP1 mutation in uveal melanoma progression Uveal melanoma is the most common primary intraocular malignancy.	('BAP1', 'Gene', '8314', (28, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('mutation', 'Var', (33, 41))	('BAP1', 'Gene', (28, 32))	('primary intraocular malignancy', 'Disease', 'MESH:D009798', (106, 136))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('primary intraocular malignancy', 'Disease', (106, 136))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
37959	33903674	A vast majority of metastasizing tumors have mutations in the BAP1 gene.	('BAP1', 'Gene', '8314', (62, 66))	('mutations', 'Var', (45, 54))	('metastasizing tumors', 'Disease', 'MESH:D009362', (19, 39))	('BAP1', 'Gene', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('metastasizing tumors', 'Disease', (19, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))
37962	33903674	Tumors with a BAP1 mutation had significantly larger volume (2109 vs. 1552 mm3, p = 0.025).	('BAP1', 'Gene', '8314', (14, 18))	('mutation', 'Var', (19, 27))	('volume', 'MPA', (53, 59))	('larger', 'PosReg', (46, 52))	('BAP1', 'Gene', (14, 18))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
37964	33903674	Using observations of the time elapsed between mitoses, the BAP1 mutation was calculated to occur when the primary tumor had a size of a few malignant cells to 6 mm3, 0.5 to 4.6 years after tumor initiation and at least 9 years before diagnosis.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (115, 120))	('tumor initiation', 'Disease', 'MESH:D009369', (190, 206))	('BAP1', 'Gene', '8314', (60, 64))	('tumor', 'Disease', (190, 195))	('mutation', 'Var', (65, 73))	('tumor initiation', 'Disease', (190, 206))	('BAP1', 'Gene', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
37965	33903674	We conclude that BAP1 mutations occur early in the growth of uveal melanoma, well before the average tumor is diagnosed.	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('uveal melanoma', 'Disease', 'MESH:C536494', (61, 75))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('uveal melanoma', 'Disease', (61, 75))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('BAP1', 'Gene', (17, 21))
37972	33903674	Further, mutations in the BRCA1 associated protein-1 gene (BAP1), a tumor suppressor located on chromosome 3p, is mutated in 47% of all UM and a vast majority of metastasizing UM.	('tumor', 'Disease', (68, 73))	('BRCA1 associated protein-1', 'Gene', (26, 52))	('BAP1', 'Gene', (59, 63))	('tumor suppressor', 'biological_process', 'GO:0051726', ('68', '84'))	('mutations', 'Var', (9, 18))	('mutated', 'Var', (114, 121))	('metastasizing', 'Disease', (162, 175))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('68', '84'))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('BRCA1 associated protein-1', 'Gene', '8314', (26, 52))	('metastasizing', 'Disease', 'MESH:D009362', (162, 175))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('UM', 'Phenotype', 'HP:0007716', (136, 138))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('BAP1', 'Gene', '8314', (59, 63))	('UM', 'Phenotype', 'HP:0007716', (176, 178))
37973	33903674	BAP1 is one of many genes that undergo mutations to confer increased epithelial to mesenchymal transition of the tumor.	('tumor', 'Disease', (113, 118))	('BAP1', 'Gene', (0, 4))	('BAP1', 'Gene', '8314', (0, 4))	('mutations', 'Var', (39, 48))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('69', '105'))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('increased', 'PosReg', (59, 68))
37974	33903674	In this mutation sequence, the BAP1 mutation has been assumed to occur relatively late in tumor progression, preceded by oncogenic mutations in G-protein subunits including GNA11 and GNAQ that are present in as high as 83-96% of UM.	('mutations', 'Var', (131, 140))	('GNA11', 'Gene', '2767', (173, 178))	('BAP1', 'Gene', '8314', (31, 35))	('GNAQ', 'Gene', '2776', (183, 187))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('BAP1', 'Gene', (31, 35))	('G-protein', 'Protein', (144, 153))	('UM', 'Phenotype', 'HP:0007716', (229, 231))	('GNAQ', 'Gene', (183, 187))	('mutation', 'Var', (36, 44))	('GNA11', 'Gene', (173, 178))
37975	33903674	BAP1 mutations are thought to appear after the GNA11 or GNAQ mutations, correlating with a gratly increased risk for tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('BAP1', 'Gene', (0, 4))	('tumor', 'Disease', (117, 122))	('GNA11', 'Gene', (47, 52))	('GNAQ', 'Gene', '2776', (56, 60))	('GNA11', 'Gene', '2767', (47, 52))	('mutations', 'Var', (5, 14))	('BAP1', 'Gene', '8314', (0, 4))	('GNAQ', 'Gene', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
37976	33903674	It is well-documented that larger UMs have a higher likelihood of harboring BAP1 mutations, supporting prognostic implications.	('BAP1', 'Gene', '8314', (76, 80))	('UM', 'Phenotype', 'HP:0007716', (34, 36))	('BAP1', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))
37977	33903674	However, there is also evidence that smaller UMs may harbor BAP1 mutations and seed metastases.	('metastases', 'Disease', (84, 94))	('harbor', 'Reg', (53, 59))	('metastases', 'Disease', 'MESH:D009362', (84, 94))	('BAP1', 'Gene', '8314', (60, 64))	('BAP1', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))	('UM', 'Phenotype', 'HP:0007716', (45, 47))
37981	33903674	These findings support the thought that BAP1 mutations can be present early in tumorigenesis and in small UMs.	('mutations', 'Var', (45, 54))	('tumor', 'Disease', (79, 84))	('BAP1', 'Gene', '8314', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('BAP1', 'Gene', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('UM', 'Phenotype', 'HP:0007716', (106, 108))
37982	33903674	Given the relationship between loss of BAP1 expression and poor prognosis, it is important to clarify the impact of tumor size and age on the likelihood of a BAP1 mutation.	('expression', 'MPA', (44, 54))	('tumor', 'Disease', (116, 121))	('loss', 'NegReg', (31, 35))	('BAP1', 'Gene', (158, 162))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('BAP1', 'Gene', '8314', (39, 43))	('BAP1', 'Gene', '8314', (158, 162))	('mutation', 'Var', (163, 171))	('BAP1', 'Gene', (39, 43))
37984	33903674	Thus, we aim to make estimations of the origin and dynamic evolution of the BAP1 mutated tumor cell clone in UM.	('BAP1', 'Gene', '8314', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mutated', 'Var', (81, 88))	('UM', 'Phenotype', 'HP:0007716', (109, 111))	('BAP1', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
37991	33903674	Of 76 sequenced tumors, 26 (34%) had a BAP1 mutation.	('tumors', 'Disease', (16, 22))	('mutation', 'Var', (44, 52))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('BAP1', 'Gene', '8314', (39, 43))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('BAP1', 'Gene', (39, 43))
37992	33903674	Tumors with a BAP1 mutation had significantly larger mean volume than those with wild-type BAP1 (2109 vs. 1552 mm3, p = 0.025).	('BAP1', 'Gene', '8314', (14, 18))	('BAP1', 'Gene', (91, 95))	('mutation', 'Var', (19, 27))	('mean volume', 'MPA', (53, 64))	('larger', 'PosReg', (46, 52))	('BAP1', 'Gene', (14, 18))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('BAP1', 'Gene', '8314', (91, 95))
38001	33903674	If the doubling time was 511 days instead, the first malignant cell appeared 39.1 years before diagnosis (SD 2.4, min 33.9, max 43.0), with the BAP1 mutation occurring 3 years later at 36.1 years before diagnosis (SD 4.5, min 27.3, max 42.6).	('BAP1', 'Gene', (144, 148))	('mutation', 'Var', (149, 157))	('BAP1', 'Gene', '8314', (144, 148))
38002	33903674	Next, we used these functions to estimate the tumor volume at which the proportion of BAP1 mutant cells is zero by setting the y value (proportion of tumor cells with loss of BAP1 expression) to 0.	('BAP1', 'Gene', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('BAP1', 'Gene', '8314', (86, 90))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('BAP1', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('BAP1', 'Gene', '8314', (175, 179))	('mutant', 'Var', (91, 97))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
38011	33903674	As shown above, the volume of BAP1 mutant cells can be described as a function of tumor volume.	('BAP1', 'Gene', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('mutant', 'Var', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BAP1', 'Gene', '8314', (30, 34))	('tumor', 'Disease', (82, 87))
38015	33903674	Consequently, the BAP1 mutation occurred after 1.3 to 1.5 cell doublings, when the malignant clone consisted of only 3 malignant cells.	('occurred', 'Reg', (32, 40))	('BAP1', 'Gene', (18, 22))	('BAP1', 'Gene', '8314', (18, 22))	('mutation', 'Var', (23, 31))
38021	33903674	Median patient metastasis-free survival after diagnosis of tumors with a BAP1 mutation was 2.4 years (standard error, SE 0.2, 95% confidence interval, CI 2.0 to 2.8), versus 16.0 years for tumors without a BAP1 mutation (SE 7.6, 95% CI 1.2 to 30.9, Log-Rank p < 0.0001, Fig.	('BAP1', 'Gene', '8314', (206, 210))	('BAP1', 'Gene', '8314', (73, 77))	('mutation', 'Var', (78, 86))	('patient', 'Species', '9606', (7, 14))	('BAP1', 'Gene', (206, 210))	('BAP1', 'Gene', (73, 77))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('patient metastasis-free survival', 'CPA', (7, 39))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
38025	33903674	Lastly, we examined patient survival with the concepts metastasis-free survival after tumor initiation and metastasis-free survival after BAP1 mutation.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('BAP1', 'Gene', '8314', (138, 142))	('tumor initiation', 'Disease', (86, 102))	('mutation', 'Var', (143, 151))	('BAP1', 'Gene', (138, 142))	('patient', 'Species', '9606', (20, 27))	('tumor initiation', 'Disease', 'MESH:D009369', (86, 102))
38026	33903674	In contrast to using the day of diagnosis as starting point for survival analysis, we added the estimated time that had elapsed from tumor initiation and BAP1 mutation before diagnosis.	('tumor initiation', 'Disease', (133, 149))	('BAP1', 'Gene', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('mutation', 'Var', (159, 167))	('tumor initiation', 'Disease', 'MESH:D009369', (133, 149))	('BAP1', 'Gene', '8314', (154, 158))
38030	33903674	Metastasis-free survival after BAP1 mutation was defined as the proportion of patients not having suffered symptomatic and/or radiologically detectable metastases at a specific time after the estimated appearance of the first tumor cell with loss of BAP1 expression.	('BAP1', 'Gene', '8314', (31, 35))	('tumor', 'Disease', (226, 231))	('metastases', 'Disease', (152, 162))	('patients', 'Species', '9606', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('metastases', 'Disease', 'MESH:D009362', (152, 162))	('BAP1', 'Gene', '8314', (250, 254))	('BAP1', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('BAP1', 'Gene', (250, 254))	('mutation', 'Var', (36, 44))
38032	33903674	With a doubling time of 292 days, the mean duration from BAP1 mutation to diagnosis was 20.6 years (SD 2.5).	('BAP1', 'Gene', '8314', (57, 61))	('mutation', 'Var', (62, 70))	('BAP1', 'Gene', (57, 61))
38033	33903674	Median Kaplan-Meier metastasis-free survival after BAP1 mutation was 31.0 years (SE 3.9, 95% CI 23.3 to 38.7, Fig.	('mutation', 'Var', (56, 64))	('BAP1', 'Gene', '8314', (51, 55))	('BAP1', 'Gene', (51, 55))
38034	33903674	This study provides an estimate of the timing of the BAP1 mutation in the growth of UM.	('mutation', 'Var', (58, 66))	('BAP1', 'Gene', '8314', (53, 57))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('BAP1', 'Gene', (53, 57))
38036	33903674	Our calculations showed that the first BAP1 mutant clone of an average UM appears when the tumor is 166 days to 1665 days old, within 2 cell doublings of the first UM clone.	('mutant', 'Var', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('UM', 'Phenotype', 'HP:0007716', (71, 73))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('BAP1', 'Gene', '8314', (39, 43))	('UM', 'Phenotype', 'HP:0007716', (164, 166))	('tumor', 'Disease', (91, 96))	('BAP1', 'Gene', (39, 43))
38038	33903674	Thus, we provide a mathematical explanation of the occurrence of micrometastases during the tumor's infancy and underscore the importance of BAP1 mutation in tumorigenesis.	('tumor', 'Disease', (158, 163))	('BAP1', 'Gene', '8314', (141, 145))	('metastases', 'Disease', 'MESH:D009362', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('BAP1', 'Gene', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutation', 'Var', (146, 154))	('metastases', 'Disease', (70, 80))
38040	33903674	Studies have shown that choroidal nevi, similar to UM, can harbor G-protein coupled receptor (GPCR) mutations in GNA11, GNAQ, and CYSLTR2.	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('mutations', 'Var', (100, 109))	('G-protein coupled receptor', 'Gene', (66, 92))	('choroidal nevi', 'Phenotype', 'HP:0025314', (24, 38))	('GNAQ', 'Gene', (120, 124))	('GNA11', 'Gene', '2767', (113, 118))	('GNA11', 'Gene', (113, 118))	('G-protein coupled receptor', 'Gene', '10663', (66, 92))	('GPCR', 'Gene', '10663', (94, 98))	('CYSLTR2', 'Gene', '57105', (130, 137))	('nevi', 'Phenotype', 'HP:0003764', (34, 38))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('choroidal nevi', 'Disease', (24, 38))	('GPCR', 'Gene', (94, 98))	('CYSLTR2', 'Gene', (130, 137))	('GNAQ', 'Gene', '2776', (120, 124))
38042	33903674	To our knowledge, there are no BAP1-deficient choroidal nevi reported in the literature, so our model was able to focus solely on BAP1 mutagenesis in the evolution of UM.	('BAP1', 'Gene', (130, 134))	('nevi', 'Phenotype', 'HP:0003764', (56, 60))	('BAP1', 'Gene', '8314', (31, 35))	('mutagenesis', 'biological_process', 'GO:0006280', ('135', '146'))	('deficient choroidal', 'Disease', 'MESH:D002833', (36, 55))	('deficient choroidal', 'Disease', (36, 55))	('mutagenesis', 'Var', (135, 146))	('UM', 'Phenotype', 'HP:0007716', (167, 169))	('BAP1', 'Gene', (31, 35))	('BAP1', 'Gene', '8314', (130, 134))	('choroidal nevi', 'Phenotype', 'HP:0025314', (46, 60))
38043	33903674	The early onset of the BAP1 mutation is likely promoted by evolutionary pressure.	('BAP1', 'Gene', (23, 27))	('mutation', 'Var', (28, 36))	('BAP1', 'Gene', '8314', (23, 27))
38046	33903674	Studies of primary fibroblasts from individuals heterozygous for the germline BAP1 mutation showed that these cells have increased anaerobic glycolysis and decreased mitochondrial respiration compared to fibroblasts from wild-type BAP1 individuals.	('anaerobic glycolysis', 'MPA', (131, 151))	('respiration', 'biological_process', 'GO:0045333', ('180', '191'))	('increased', 'PosReg', (121, 130))	('BAP1', 'Gene', '8314', (231, 235))	('mutation', 'Var', (83, 91))	('mitochondrial respiration', 'MPA', (166, 191))	('decreased', 'NegReg', (156, 165))	('BAP1', 'Gene', '8314', (78, 82))	('anaerobic glycolysis', 'biological_process', 'GO:0006096', ('131', '151'))	('BAP1', 'Gene', (231, 235))	('respiration', 'biological_process', 'GO:0007585', ('180', '191'))	('BAP1', 'Gene', (78, 82))
38047	33903674	This finding suggests that the BAP1 mutated clone can be favored under hypoxic conditions and gradually make up a larger proportion of the tumor.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('BAP1', 'Gene', '8314', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('mutated', 'Var', (36, 43))	('BAP1', 'Gene', (31, 35))	('hypoxic', 'Disease', (71, 78))	('hypoxic', 'Disease', 'MESH:D000860', (71, 78))
38048	33903674	Furthermore, if BAP1 mutated cells are more stem-like, they also have a higher capability of immune evasion, thereby outliving the wild types.	('immune evasion', 'biological_process', 'GO:0042783', ('93', '107'))	('immune evasion', 'biological_process', 'GO:0051842', ('93', '107'))	('BAP1', 'Gene', '8314', (16, 20))	('immune evasion', 'MPA', (93, 107))	('higher', 'PosReg', (72, 78))	('mutated', 'Var', (21, 28))	('BAP1', 'Gene', (16, 20))
38049	33903674	It has been documented that BAP1 mutations can downregulate the expression of genes responsible for immune checkpoints and increase inflammation in the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('expression of genes', 'MPA', (64, 83))	('BAP1', 'Gene', '8314', (28, 32))	('inflammation', 'Disease', 'MESH:D007249', (132, 144))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('downregulate', 'NegReg', (47, 59))	('inflammation', 'Disease', (132, 144))	('inflammation', 'biological_process', 'GO:0006954', ('132', '144'))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', (152, 157))	('increase', 'PosReg', (123, 131))
38052	33903674	Thus, both the hypoxic and stem-like properties would give BAP1 mutants an evolutionary advantage over wild type cells.	('BAP1', 'Gene', (59, 63))	('mutants', 'Var', (64, 71))	('hypoxic', 'Disease', (15, 22))	('hypoxic', 'Disease', 'MESH:D000860', (15, 22))	('BAP1', 'Gene', '8314', (59, 63))	('evolutionary advantage', 'CPA', (75, 97))
38054	33903674	BAP1 mutations tend to precede metastatic dissemination and they occur shortly after GPCR mutations in the UM evolutionary tree.	('UM', 'Phenotype', 'HP:0007716', (107, 109))	('GPCR', 'Gene', '10663', (85, 89))	('metastatic dissemination', 'CPA', (31, 55))	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('GPCR', 'Gene', (85, 89))	('BAP1', 'Gene', '8314', (0, 4))
38055	33903674	However, instances of monosomy 3 occurring after several UM mutations and cases in which metastases precede BAP1 loss have been reported.	('BAP1', 'Gene', '8314', (108, 112))	('monosomy 3', 'Disease', (22, 32))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('BAP1', 'Gene', (108, 112))	('metastases', 'Disease', (89, 99))	('mutations', 'Var', (60, 69))	('metastases', 'Disease', 'MESH:D009362', (89, 99))
38056	33903674	A recent study identified 2 cases where primary UM homozygous for the BAP1 mutation gave rise to BAP1 heterozygous metastases.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('metastases', 'Disease', (115, 125))	('gave rise', 'Reg', (84, 93))	('BAP1', 'Gene', '8314', (97, 101))	('BAP1', 'Gene', '8314', (70, 74))	('metastases', 'Disease', 'MESH:D009362', (115, 125))	('mutation', 'Var', (75, 83))	('BAP1', 'Gene', (97, 101))	('BAP1', 'Gene', (70, 74))
38058	33903674	This could be explained by BAP1 epigenetic silencing or the escape of the mutation from detection, as the authors suggest.	('BAP1', 'Gene', (27, 31))	('epigenetic silencing', 'Var', (32, 52))	('BAP1', 'Gene', '8314', (27, 31))
38063	33903674	It is important to note the role of tumor architecture and vascular framework, apart from the BAP1 mutation, in the promotion of metastasis in UM.	('BAP1', 'Gene', '8314', (94, 98))	('mutation', 'Var', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('metastasis', 'CPA', (129, 139))	('promotion', 'PosReg', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('BAP1', 'Gene', (94, 98))	('UM', 'Phenotype', 'HP:0007716', (143, 145))	('tumor', 'Disease', (36, 41))
38064	33903674	Our study suggests that a BAP1 mutation occurs early in tumorigenesis, possibly when the tumor consists of a few malignant cells.	('BAP1', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('mutation', 'Var', (31, 39))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('BAP1', 'Gene', '8314', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
38070	33903674	Thus, the requirements of the tumor microenvironment could explain the delay between the origination of the BAP1 mutant clone, the BAP1-GPCR double mutant clone, and micrometastatic spread.	('BAP1', 'Gene', (131, 135))	('BAP1', 'Gene', '8314', (108, 112))	('micrometastatic spread', 'CPA', (166, 188))	('BAP1', 'Gene', '8314', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('GPCR', 'Gene', (136, 140))	('BAP1', 'Gene', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutant', 'Var', (113, 119))	('tumor', 'Disease', (30, 35))	('GPCR', 'Gene', '10663', (136, 140))
38072	33903674	By formulating this mathematical model, this study provides an early snapshot of BAP1 mutagenesis and suggests micrometastases can occur as early as after the first few mitoses of primary UM.	('BAP1', 'Gene', (81, 85))	('mutagenesis', 'Var', (86, 97))	('UM', 'Phenotype', 'HP:0007716', (188, 190))	('metastases', 'Disease', (116, 126))	('metastases', 'Disease', 'MESH:D009362', (116, 126))	('BAP1', 'Gene', '8314', (81, 85))	('mutagenesis', 'biological_process', 'GO:0006280', ('86', '97'))
38074	33903674	Our model solely incorporated the BAP1 mutation.	('incorporated', 'Reg', (17, 29))	('BAP1', 'Gene', '8314', (34, 38))	('mutation', 'Var', (39, 47))	('BAP1', 'Gene', (34, 38))
38078	33903674	Furthermore, from the observation that larger tumors harbor a greater proportion of BAP1 mutant cells follows that BAP1 mutated clone should have either a faster growth rate or a slower death rate.	('death', 'Disease', 'MESH:D003643', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('BAP1', 'Gene', '8314', (115, 119))	('faster', 'PosReg', (155, 161))	('growth', 'CPA', (162, 168))	('BAP1', 'Gene', '8314', (84, 88))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('BAP1', 'Gene', (115, 119))	('tumors', 'Disease', (46, 52))	('BAP1', 'Gene', (84, 88))	('death', 'Disease', (186, 191))	('mutant', 'Var', (89, 95))	('mutated', 'Var', (120, 127))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
38079	33903674	Some authors may question our findings that UMs contains a ratio of BAP1 mutant-to-wild type cells, arguing that UM is more often composed exclusively of mutants or wild-types.	('mutant-to-wild', 'Var', (73, 87))	('BAP1', 'Gene', '8314', (68, 72))	('UM', 'Phenotype', 'HP:0007716', (113, 115))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('BAP1', 'Gene', (68, 72))
38080	33903674	In our study, we have alternately used loss of immunohistochemical expression of BAP1 in tumor cell nuclei and BAP1 mutations detected by DNA sequencing as a marker for the same genetic event, using methods replicated in our previous studies.	('BAP1', 'Gene', (81, 85))	('BAP1', 'Gene', '8314', (111, 115))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('BAP1', 'Gene', (111, 115))	('mutations', 'Var', (116, 125))	('BAP1', 'Gene', '8314', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
38083	33903674	In conclusion, the BAP1 mutation occurs early in the growth of UM, well before the average tumor is diagnosed and the timing coincides with previous calculations of the tumor size at which seeding of micrometastases start.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('UM', 'Phenotype', 'HP:0007716', (63, 65))	('metastases', 'Disease', (205, 215))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('BAP1', 'Gene', '8314', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('metastases', 'Disease', 'MESH:D009362', (205, 215))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (169, 174))	('mutation', 'Var', (24, 32))	('BAP1', 'Gene', (19, 23))	('tumor', 'Disease', (91, 96))
38084	33903674	At the time of primary tumor diagnosis, the primary tumor, the BAP1 mutation and the liver micrometastases are one to several decades old.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('BAP1', 'Gene', (63, 67))	('mutation', 'Var', (68, 76))	('BAP1', 'Gene', '8314', (63, 67))	('metastases', 'Disease', 'MESH:D009362', (96, 106))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('metastases', 'Disease', (96, 106))
38086	33903674	Further studies of BAP1 mutagenesis and on factors that promote micrometastasis dormancy and reduce the risk for a switch to proliferation could improve the prospects for development of effective therapies and improved survival.	('micrometastasis dormancy', 'CPA', (64, 88))	('mutagenesis', 'Var', (24, 35))	('mutagenesis', 'biological_process', 'GO:0006280', ('24', '35'))	('switch', 'MPA', (115, 121))	('BAP1', 'Gene', '8314', (19, 23))	('improve', 'PosReg', (145, 152))	('BAP1', 'Gene', (19, 23))	('promote', 'PosReg', (56, 63))	('dormancy', 'biological_process', 'GO:0030431', ('80', '88'))
38092	33903674	This data was downloaded to calculate the difference in tumor volume between tumors with and without a BAP1 mutation.	('tumors', 'Disease', (77, 83))	('BAP1', 'Gene', '8314', (103, 107))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('BAP1', 'Gene', (103, 107))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutation', 'Var', (108, 116))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
38103	33903674	The ANOVA F-test and coefficient of determination (R2) was used to optimize the computational model and goodness of fit of S, compound, logistic, growth, exponential, linear, logarithmic, inverse, quadratic and cubic curves of the proportion of BAP1 mutated cells as a function of tumor size.	('goodness', 'Disease', 'None', (104, 112))	('BAP1', 'Gene', '8314', (245, 249))	('mutated', 'Var', (250, 257))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('BAP1', 'Gene', (245, 249))	('goodness', 'Disease', (104, 112))	('tumor', 'Disease', (281, 286))
38104	33903674	We used binary logistic regression without x-centering of the tumor volume variable to predict the probability of a BAP1 mutation as a function of the tumor volume.	('BAP1', 'Gene', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('mutation', 'Var', (121, 129))	('BAP1', 'Gene', '8314', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
38138	31969914	Our Clinical Department of Ophthalmology and Ophthalmologic Oncology currently uses applicators containing 106Ru and 125I.	('Oncology', 'Phenotype', 'HP:0002664', (60, 68))	('125I', 'Chemical', 'MESH:C492712', (117, 121))	('106Ru', 'Chemical', 'MESH:C038365', (107, 112))	('106Ru', 'Var', (107, 112))	('men', 'Species', '9606', (19, 22))	('125I', 'Var', (117, 121))
38204	31969914	In the patients with dome-shaped tumours the relapse was more frequent than in those in whose case a mushroom-like shape was found in the ultrasound (p = 0.053).	('tumours', 'Phenotype', 'HP:0002664', (33, 40))	('dome-shaped', 'Var', (21, 32))	('tumours', 'Disease', 'MESH:D009369', (33, 40))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('tumours', 'Disease', (33, 40))	('mushroom', 'Species', '5341', (101, 109))	('relapse', 'CPA', (45, 52))	('patients', 'Species', '9606', (7, 15))
38206	31969914	evaluating 20-year results of the treatment of uveal melanoma observed that the necessity of enucleation of an eyeball occurs significantly more frequently in the case of dome-shaped tumours than in the case of a mushroom-like shape (p = 0.002).	('tumours', 'Disease', (183, 190))	('mushroom', 'Species', '5341', (213, 221))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('enucleation', 'biological_process', 'GO:0090601', ('93', '104'))	('uveal melanoma', 'Disease', (47, 61))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('men', 'Species', '9606', (39, 42))	('tumours', 'Phenotype', 'HP:0002664', (183, 190))	('dome-shaped', 'Var', (171, 182))	('tumours', 'Disease', 'MESH:D009369', (183, 190))
38224	31969914	The time of irradiation of uveal melanoma using 125I, as recommended by the Ophthalmic Oncology Task Force, is 5-7 days and for 106Ru: 3-7 days.	('men', 'Species', '9606', (62, 65))	('uveal melanoma', 'Disease', (27, 41))	('uveal melanoma', 'Disease', 'MESH:C536494', (27, 41))	('uveal melanoma', 'Phenotype', 'HP:0007716', (27, 41))	('125I', 'Chemical', 'MESH:C492712', (48, 52))	('Ophthalmic Oncology', 'Phenotype', 'HP:0100012', (76, 95))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('125I', 'Var', (48, 52))	('Oncology', 'Phenotype', 'HP:0002664', (87, 95))	('106Ru', 'Chemical', 'MESH:C038365', (128, 133))
38238	31969914	It was shown that vitamin D deficiency or dysregulated vitamin D signaling can play an important role in oncogenesis, clinical advancement and prognosis in such neoplasms as cutaneous melanomas, bladder, breast, lung, ovarian, pancreatic, thyroid, prostate and colorectal cancers.	('neoplasms', 'Disease', (161, 170))	('deficiency', 'Disease', (28, 38))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('vitamin', 'Gene', (55, 62))	('dysregulated vitamin D', 'Phenotype', 'HP:0100512', (42, 64))	('breast', 'Disease', (204, 210))	('colorectal cancers', 'Disease', (261, 279))	('thyroid', 'Disease', (239, 246))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (174, 193))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (174, 193))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (174, 192))	('pancreatic', 'Disease', (227, 237))	('vitamin D', 'Chemical', 'MESH:D014807', (18, 27))	('neoplasms', 'Phenotype', 'HP:0002664', (161, 170))	('oncogenesis', 'biological_process', 'GO:0007048', ('105', '116'))	('bladder', 'Disease', (195, 202))	('ovarian', 'Disease', (218, 225))	('ovarian', 'Disease', 'MESH:D010051', (218, 225))	('lung', 'Disease', (212, 216))	('dysregulated', 'Var', (42, 54))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))	('cutaneous melanomas', 'Disease', (174, 193))	('prostate', 'Disease', (248, 256))	('colorectal cancers', 'Disease', 'MESH:D015179', (261, 279))	('neoplasms', 'Disease', 'MESH:D009369', (161, 170))	('melanomas', 'Phenotype', 'HP:0002861', (184, 193))	('deficiency', 'Disease', 'MESH:D007153', (28, 38))	('vitamin D', 'Chemical', 'MESH:D014807', (55, 64))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (18, 38))	('pancreatic', 'Disease', 'MESH:D010195', (227, 237))
38241	31969914	The treatment of uveal melanomas with applicators containing 125I allows for a high rate of positive local results and in the majority of cases constitutes the treatment of first choice in the case of tumours with a height ranging from 5 to 12 mm and with the largest base up to 15 mm.	('men', 'Species', '9606', (165, 168))	('tumours', 'Disease', 'MESH:D009369', (201, 208))	('uveal melanomas', 'Disease', (17, 32))	('uveal melanomas', 'Phenotype', 'HP:0007716', (17, 32))	('tumours', 'Disease', (201, 208))	('125I', 'Var', (61, 65))	('men', 'Species', '9606', (9, 12))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('125I', 'Chemical', 'MESH:C492712', (61, 65))	('uveal melanomas', 'Disease', 'MESH:C536494', (17, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))	('tumours', 'Phenotype', 'HP:0002664', (201, 208))
38242	31969914	The treatment of uveal melanomas with applicators containing 125I allows for a high rate of positive local results.	('uveal melanomas', 'Disease', (17, 32))	('uveal melanomas', 'Phenotype', 'HP:0007716', (17, 32))	('125I', 'Var', (61, 65))	('men', 'Species', '9606', (9, 12))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('125I', 'Chemical', 'MESH:C492712', (61, 65))	('uveal melanomas', 'Disease', 'MESH:C536494', (17, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))
38248	31212861	Aberrant MicroRNA Expression and Its Implications for Uveal Melanoma Metastasis Uveal melanoma (UM) is the most frequently found primary intra-ocular tumor in adults.	('ocular tumor', 'Phenotype', 'HP:0100012', (143, 155))	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('intra-ocular tumor', 'Disease', (137, 155))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('Aberrant', 'Var', (0, 8))	('Melanoma Metastasis', 'Disease', 'MESH:D009362', (60, 79))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('intra-ocular tumor', 'Disease', 'MESH:D009369', (137, 155))	('Melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('MicroRNA Expression', 'Protein', (9, 28))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('Melanoma Metastasis', 'Disease', (60, 79))
38250	31212861	Many independent studies have reported somatic genetic changes associated with high metastatic risk, such as monosomy of chromosome 3 and mutations in BAP1.	('BAP1', 'Gene', (151, 155))	('chromosome', 'cellular_component', 'GO:0005694', ('121', '131'))	('monosomy of', 'Disease', (109, 120))	('BAP1', 'Gene', '8314', (151, 155))	('mutations', 'Var', (138, 147))
38253	31212861	Our findings demonstrate that aberrant microRNA expression in UM may affect the expression of genes in a variety of cancer-related pathways.	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('affect', 'Reg', (69, 75))	('aberrant microRNA', 'Var', (30, 47))	('cancer', 'Disease', (116, 122))	('microRNA', 'Var', (39, 47))	('expression of genes', 'MPA', (80, 99))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
38257	31212861	Most tumors carry a GNAQ or GNA11 mutation.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('GNAQ', 'Gene', '2776', (20, 24))	('mutation', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('GNA11', 'Gene', (28, 33))	('GNAQ', 'Gene', (20, 24))	('GNA11', 'Gene', '2767', (28, 33))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
38258	31212861	These mutations are considered to be tumor-initiating mutations and do not increase the risk of metastasis.	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mutations', 'Var', (6, 15))
38260	31212861	High-risk UM harbor a mutation in the tumor suppressor gene BRCA-associated protein (BAP1), located on chromosome 3.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('BAP1', 'Gene', (85, 89))	('UM', 'Phenotype', 'HP:0007716', (10, 12))	('mutation', 'Var', (22, 30))	('chromosome', 'cellular_component', 'GO:0005694', ('103', '113'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('BAP1', 'Gene', '8314', (85, 89))	('tumor suppressor', 'biological_process', 'GO:0051726', ('38', '54'))
38261	31212861	Mutations in this gene often coincide with monosomy 3, resulting in loss of expression of the BAP1 protein.	('BAP1', 'Gene', '8314', (94, 98))	('monosomy 3', 'Disease', (43, 53))	('Mutations', 'Var', (0, 9))	('expression', 'MPA', (76, 86))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('BAP1', 'Gene', (94, 98))	('protein', 'Protein', (99, 106))	('loss of', 'NegReg', (68, 75))
38263	31212861	Intermediate-risk tumors carry a mutation in the gene-encoding splicing factor 3 subunit 1 (SF3B1), which is part of a protein complex involved in pre-mRNA splicing.	('protein complex', 'cellular_component', 'GO:0032991', ('119', '134'))	('splicing factor 3 subunit 1', 'Gene', (63, 90))	('mutation', 'Var', (33, 41))	('pre', 'molecular_function', 'GO:0003904', ('147', '150'))	('splicing factor 3 subunit 1', 'Gene', '10291', (63, 90))	('splicing', 'biological_process', 'GO:0045292', ('63', '71'))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('147', '164'))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('SF3B1', 'Gene', '10291', (92, 97))	('SF3B1', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
38264	31212861	SF3B1 mutations in UM are known to result in aberrantly spliced transcripts that can either be degraded by nonsense-mediated decay or translated into unique, aberrant proteins.	('SF3B1', 'Gene', '10291', (0, 5))	('SF3B1', 'Gene', (0, 5))	('aberrantly', 'MPA', (45, 55))	('degraded', 'NegReg', (95, 103))	('UM', 'Phenotype', 'HP:0007716', (19, 21))	('mutations', 'Var', (6, 15))
38265	31212861	Low-risk UM often harbor a mutation in the eukaryotic translation initiation factor 1A (EIF1AX) gene, which is involved in the transfer of methionyl initiator tRNA to the small ribosomal subunit during translation.	('translation initiation', 'biological_process', 'GO:0006413', ('54', '76'))	('EIF1AX', 'Gene', '1964', (88, 94))	('EIF1AX', 'Gene', (88, 94))	('tRNA', 'molecular_function', 'GO:0030533', ('159', '163'))	('mutation', 'Var', (27, 35))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('small ribosomal subunit', 'cellular_component', 'GO:0015935', ('171', '194'))	('translation', 'biological_process', 'GO:0006412', ('202', '213'))
38273	31212861	Twelve patients with a mean DFS of 103 months and an SF3B1 mutated UM were included in the intermediate-risk group.	('SF3B1', 'Gene', (53, 58))	('UM', 'Phenotype', 'HP:0007716', (67, 69))	('SF3B1', 'Gene', '10291', (53, 58))	('patients', 'Species', '9606', (7, 15))	('mutated', 'Var', (59, 66))
38277	31212861	Specifically, miRNA 132-5p, 151a-3p, 17-5p, 16-5p, and 21-5p all had a higher expression in high-risk tumors, whereas miRNA 181b-5p, 101-3p, 378d, 181a-2-3p, 99a-5p, let-7c-5p, 1537-3p, and 99a-3p showed downregulation in the high-risk UM (Figure 2E).	('higher', 'PosReg', (71, 77))	('miRNA 181b-5p', 'Var', (118, 131))	('expression', 'MPA', (78, 88))	('high-risk', 'Disease', (92, 101))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('let-7c', 'Gene', (166, 172))	('UM', 'Phenotype', 'HP:0007716', (236, 238))	('let-7c', 'Gene', '406885', (166, 172))	('downregulation', 'NegReg', (204, 218))	('miRNA 132-5p', 'Var', (14, 26))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
38281	31212861	MiRNA-101-3p inhibits the cyclin-dependent kinase 6 (CDK6) which regulates the G1/S phase transition by inhibiting RB1.	('G1/S', 'MPA', (79, 83))	('MiRNA-101-3p', 'Var', (0, 12))	('CDK6', 'Gene', (53, 57))	('MiRNA-101-3p', 'Chemical', '-', (0, 12))	('RB1', 'Gene', (115, 118))	('CDK6', 'Gene', '1021', (53, 57))	('cyclin', 'molecular_function', 'GO:0016538', ('26', '32'))	('cyclin-dependent kinase 6', 'Gene', (26, 51))	('S phase', 'biological_process', 'GO:0051320', ('82', '89'))	('inhibiting', 'NegReg', (104, 114))	('regulates', 'MPA', (65, 74))	('RB1', 'Gene', '5925', (115, 118))	('cyclin-dependent kinase 6', 'Gene', '1021', (26, 51))	('CDK', 'molecular_function', 'GO:0004693', ('53', '56'))	('inhibits', 'NegReg', (13, 21))
38284	31212861	Histone deacetylase 4 (HDAC4) is being targeted by two different miRNAs; miRNA-1537-5p and microRNA-181a-2-3p.	('miRNA-1537-5p', 'Var', (73, 86))	('microRNA-181a-2-3p', 'Var', (91, 109))	('HDAC4', 'Gene', '9759', (23, 28))	('HDAC4', 'Gene', (23, 28))	('Histone deacetylase 4', 'Gene', '9759', (0, 21))	('Histone deacetylase 4', 'Gene', (0, 21))
38285	31212861	MiRNAs that are highly expressed in high-risk UM include several known oncomirs such as miRNA-17-5p, miRNA-151a-3p, and miRNA-21-5p.	('miRNA-17', 'Gene', (88, 96))	('miRNA-17', 'Gene', '406952', (88, 96))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('miRNA-21-5p', 'Gene', (120, 131))	('miRNA-151a-3p', 'Var', (101, 114))	('miRNA-21-5p', 'Gene', '406997', (120, 131))
38288	31212861	However, we also identified two new potential oncomirs; miRNA-16-5p and miRNA-132-5p.	('miRNA-16-5p', 'Chemical', '-', (56, 67))	('miRNA-132-5p', 'Var', (72, 84))	('miRNA-16-5p', 'Var', (56, 67))	('miRNA-132-5p', 'Chemical', '-', (72, 84))
38291	31212861	MiRNA-99a-5p has been shown to inhibit cell proliferation in bladder and breast cancer.	('MiRNA-99a-5p', 'Var', (0, 12))	('bladder and breast cancer', 'Disease', 'MESH:D001749', (61, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('inhibit', 'NegReg', (31, 38))	('cell proliferation', 'CPA', (39, 57))
38292	31212861	These studies already identified miRNAs that were shown to be differentially expressed in high-risk UM, such as miRNA-21, miRNA-146b, miRNA-143, miRNA-199a, and miRNA-134.	('miRNA-143', 'Var', (134, 143))	('miRNA-199a', 'Var', (145, 155))	('miRNA-146b', 'Gene', '574447', (122, 132))	('UM', 'Phenotype', 'HP:0007716', (100, 102))	('miRNA-146b', 'Gene', (122, 132))	('miRNA-21', 'Gene', '406991', (112, 120))	('miRNA-134', 'Var', (161, 170))	('miRNA-21', 'Gene', (112, 120))
38294	31212861	Comparing our dataset to The Cancer Genome Atlas (TCGA) dataset, which is the only study that performed miRNA analysis in UM by using next-generation sequencing, we did observe an overlap (e.g., miRNA-21-5p, miR-101-3p, miR-181a-2-3p, miR-181b-5p, let-7c-5p, and miRNA-17-5p).	('miRNA-17', 'Gene', (263, 271))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (29, 48))	('let-7c', 'Gene', (248, 254))	('miR-181b-5p', 'Var', (235, 246))	('miR-181a-2-3p', 'Var', (220, 233))	('let-7c', 'Gene', '406885', (248, 254))	('miRNA-21-5p', 'Gene', (195, 206))	('miR-101-3p', 'Var', (208, 218))	('miRNA-21-5p', 'Gene', '406997', (195, 206))	('miRNA-17', 'Gene', '406952', (263, 271))	('UM', 'Phenotype', 'HP:0007716', (122, 124))	('Cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Cancer Genome Atlas', 'Disease', (29, 48))
38301	31212861	Incorrect translation of oncogenes and tumor suppressor genes can promote abnormal proliferation in cancer cells.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('39', '55'))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('abnormal proliferation', 'CPA', (74, 96))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Incorrect', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('promote', 'PosReg', (66, 73))	('tumor suppressor', 'biological_process', 'GO:0051726', ('39', '55'))	('translation', 'MPA', (10, 21))	('tumor', 'Disease', (39, 44))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('translation', 'biological_process', 'GO:0006412', ('10', '21'))
38303	31212861	Several studies show involvement of aberrant EGF signaling in the development of several cancer types.	('EGF', 'Gene', '1950', (45, 48))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('EGF', 'molecular_function', 'GO:0005154', ('45', '48'))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('aberrant', 'Var', (36, 44))	('EGF', 'Gene', (45, 48))	('involvement', 'Reg', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
38321	31212861	We showed that differentially expressed miRNAs could play an important role in several oncogenic pathways, such as cell cycle regulation and EGF signaling, which could contribute to the early metastasis of UM.	('differentially', 'Var', (15, 29))	('EGF', 'Gene', '1950', (141, 144))	('miRNAs', 'Protein', (40, 46))	('play', 'Reg', (53, 57))	('contribute', 'Reg', (168, 178))	('oncogenic pathways', 'Pathway', (87, 105))	('EGF', 'Gene', (141, 144))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('115', '136'))	('cell cycle regulation', 'CPA', (115, 136))	('EGF', 'molecular_function', 'GO:0005154', ('141', '144'))	('UM', 'Phenotype', 'HP:0007716', (206, 208))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))
38330	30610113	PLX51107 was ineffective in vivo, but the combination of a FGFR inhibitor, AZD4547, and PLX51107 significantly suppressed the growth of xenograft UM tumors formed from subcutaneous inoculation of UM cells with HSCs and orthotopically in the liver.	('UM', 'Phenotype', 'HP:0007716', (196, 198))	('AZD4547', 'Chemical', 'MESH:C572463', (75, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('UM', 'Phenotype', 'HP:0007716', (146, 148))	('FGFR', 'Gene', (59, 63))	('PLX51107', 'Var', (88, 96))	('AZD4547', 'Var', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('HSC', 'Gene', (210, 213))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('suppressed', 'NegReg', (111, 121))	('HSC', 'Gene', '2523', (210, 213))	('growth', 'CPA', (126, 132))	('combination', 'Interaction', (42, 53))
38336	30610113	Inhibitors of BET proteins are potential anti-cancer agents and have been shown to suppress the growth of hematopoietic and solid tumors (Dawson et al, 2011; Lockwood et al, 2012; Ott et al, 2012; Segura et al, 2013; Ambrosini et al, 2015).	('solid tumors', 'Disease', 'MESH:D009369', (124, 136))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('Inhibitors', 'Var', (0, 10))	('BET proteins', 'Protein', (14, 26))	('solid tumors', 'Disease', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('suppress', 'NegReg', (83, 91))
38339	30610113	G-protein subunit alpha q/11 (GNAQ/11) mutations are identified in > 90% UM (Van Raamsdonk et al, 2009, 2010; Robertson et al, 2017) and induce constitutive activation of downstream signaling cascades such as the mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase/AKT (PI3K/AKT) and Yes-associated protein (YAP) pathways (Chua et al, 2017).	('PI3K/AKT', 'Gene', '5295;207', (285, 293))	('AKT', 'Gene', '207', (280, 283))	('Yes-associated protein', 'Gene', '10413', (299, 321))	('downstream signaling cascades', 'Pathway', (171, 200))	('GNAQ', 'Gene', '2776', (30, 34))	('YAP', 'Gene', (323, 326))	('GNAQ', 'Gene', (30, 34))	('mutations', 'Var', (39, 48))	('AKT', 'Gene', (290, 293))	('UM', 'Phenotype', 'HP:0007716', (73, 75))	('Yes-associated protein', 'Gene', (299, 321))	('AKT', 'Gene', (280, 283))	('YAP', 'Gene', '10413', (323, 326))	('PI3K', 'molecular_function', 'GO:0016303', ('285', '289'))	('signaling', 'biological_process', 'GO:0023052', ('182', '191'))	('AKT', 'Gene', '207', (290, 293))	('protein', 'cellular_component', 'GO:0003675', ('2', '9'))	('activation', 'PosReg', (157, 167))	('PI3K/AKT', 'Gene', (285, 293))	('protein', 'cellular_component', 'GO:0003675', ('314', '321'))	('protein', 'cellular_component', 'GO:0003675', ('231', '238'))	('MAPK', 'molecular_function', 'GO:0004707', ('247', '251'))
38341	30610113	Indeed, we have previously reported JQ1 to be highly effective in inhibiting the growth of GNAQ/GNA11 mutant UM cells associated with downregulation of DNA damage response genes, Bcl-xL and Rad51 (Ambrosini et al, 2015).	('mutant', 'Var', (102, 108))	('growth', 'MPA', (81, 87))	('downregulation', 'NegReg', (134, 148))	('GNAQ', 'Gene', (91, 95))	('Rad51', 'Gene', (190, 195))	('Bcl-xL', 'Gene', '598', (179, 185))	('inhibiting', 'NegReg', (66, 76))	('Rad51', 'Gene', '5888', (190, 195))	('DNA damage response', 'biological_process', 'GO:0006974', ('152', '171'))	('UM', 'Phenotype', 'HP:0007716', (109, 111))	('DNA', 'cellular_component', 'GO:0005574', ('152', '155'))	('DNA damage response genes', 'Gene', (152, 177))	('Rad', 'biological_process', 'GO:1990116', ('190', '193'))	('Bcl-xL', 'Gene', (179, 185))	('GNA11', 'Gene', '2767', (96, 101))	('GNA11', 'Gene', (96, 101))	('GNAQ', 'Gene', '2776', (91, 95))
38354	30610113	A related BET inhibitor, PLX72853, and JQ1, which inhibits the growth of UM cell lines (Ambrosini et al, 2015), were also included in our studies.	('PLX72853', 'Chemical', '-', (25, 33))	('UM', 'Phenotype', 'HP:0007716', (73, 75))	('PLX72853', 'Var', (25, 33))	('growth', 'CPA', (63, 69))	('inhibits', 'NegReg', (50, 58))
38355	30610113	Interestingly, PLX72853 was more potent than JQ1 and PLX51107 with inhibition of colony growth achieved at nanomolar concentrations (Fig 2A).	('PLX72853', 'Chemical', '-', (15, 23))	('colony growth', 'CPA', (81, 94))	('inhibition', 'NegReg', (67, 77))	('PLX72853', 'Var', (15, 23))
38356	30610113	From here onwards, according to the IC50 of the BET inhibitors, we treated UM001 and OMM1.3 cells with 1 muM JQ1, 1 muM PLX51107 and 100 nM PLX72853, and UM004 cells with 2 muM JQ1, 2 muM PLX51107 and 200 nM PLX72853.	('PLX72853', 'Var', (140, 148))	('PLX72853', 'Chemical', '-', (140, 148))	('muM', 'Gene', (116, 119))	('muM', 'Gene', '56925', (173, 176))	('JQ1', 'Var', (109, 112))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('PLX72853', 'Chemical', '-', (208, 216))	('muM', 'Gene', '56925', (184, 187))	('PLX51107', 'Var', (120, 128))	('muM', 'Gene', '56925', (105, 108))	('muM', 'Gene', (173, 176))	('UM', 'Phenotype', 'HP:0007716', (154, 156))	('muM', 'Gene', (105, 108))	('muM', 'Gene', '56925', (116, 119))	('muM', 'Gene', (184, 187))
38359	30610113	We further characterized effects of JQ1, PLX51107 and PLX72853 by performing reverse phase protein array (RPPA) which analyzes ~300 proteins and phospho-proteins (Fig EV1A).	('PLX72853', 'Chemical', '-', (54, 62))	('PLX51107', 'Var', (41, 49))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('PLX72853', 'Var', (54, 62))
38360	30610113	BET inhibitors downregulated the expression of proteins associated with cell cycle progression such as PLK1, cyclin B1, phospho-RB (S807/811), CDK1 and FOXM1 (Fig 2C).	('FOXM1', 'Gene', (152, 157))	('CDK', 'molecular_function', 'GO:0004693', ('143', '146'))	('FOXM1', 'Gene', '2305', (152, 157))	('PLK1', 'Gene', '5347', (103, 107))	('S807/811', 'Var', (132, 140))	('cell cycle', 'biological_process', 'GO:0007049', ('72', '82'))	('CDK1', 'Gene', '983', (143, 147))	('cyclin', 'molecular_function', 'GO:0016538', ('109', '115'))	('cell cycle', 'CPA', (72, 82))	('CDK1', 'Gene', (143, 147))	('expression', 'MPA', (33, 43))	('cyclin B1', 'Gene', '891', (109, 118))	('cyclin B1', 'Gene', (109, 118))	('downregulated', 'NegReg', (15, 28))	('PLK1', 'Gene', (103, 107))	('proteins', 'Protein', (47, 55))
38362	30610113	These data were validated by Western blotting which confirmed downregulation of PLK1, cyclin B1 and phospho-RB (S807/811) following 48 h of BET inhibitor treatment (Fig 2D).	('PLK1', 'Gene', (80, 84))	('cyclin B1', 'Gene', '891', (86, 95))	('cyclin B1', 'Gene', (86, 95))	('PLK1', 'Gene', '5347', (80, 84))	('cyclin', 'molecular_function', 'GO:0016538', ('86', '92'))	('S807/811', 'Var', (112, 120))	('downregulation', 'NegReg', (62, 76))
38364	30610113	Conversely, in all cell lines treated with the BET inhibitors, p27 levels were upregulated, indicating that inhibition of BET proteins induces cell cycle arrest (Fig 2D).	('cell cycle arrest', 'CPA', (143, 160))	('BET proteins', 'Protein', (122, 134))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('143', '160'))	('p27', 'Gene', '3429', (63, 66))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (143, 160))	('p27', 'Gene', (63, 66))	('upregulated', 'PosReg', (79, 90))	('inhibition', 'Var', (108, 118))	('induces', 'Reg', (135, 142))
38365	30610113	Consistent with the annexin V-APC assay, BET inhibitors increased the expression of cleaved PARP (Fig 2D).	('APC', 'Gene', (30, 33))	('APC', 'cellular_component', 'GO:0005680', ('30', '33'))	('APC', 'Gene', '324', (30, 33))	('increased', 'PosReg', (56, 65))	('cleaved', 'Var', (84, 91))	('expression', 'MPA', (70, 80))	('annexin V', 'Gene', (20, 29))	('annexin V', 'Gene', '308', (20, 29))
38372	30610113	In The Cancer Genome Atlas (TCGA), GNAQ Q209P and Q209L mutations are found in tumors of 32.5% and 12.5% UM patients, respectively.	('Q209L', 'Var', (50, 55))	('Q209P', 'Var', (40, 45))	('Q209P', 'Mutation', 'rs121913492', (40, 45))	('GNAQ', 'Gene', '2776', (35, 39))	('tumors', 'Disease', (79, 85))	('Cancer Genome Atlas', 'Disease', (7, 26))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (7, 26))	('Q209L', 'Mutation', 'rs121913492', (50, 55))	('Cancer', 'Phenotype', 'HP:0002664', (7, 13))	('patients', 'Species', '9606', (108, 116))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('GNAQ', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
38379	30610113	Additionally, JQ1, PLX51107, and PLX72853 decreased the percentage of EdU incorporation, indicating inhibition of DNA synthesis/S-phase entry (Fig 4A).	('DNA synthesis/S-phase entry', 'MPA', (114, 141))	('DNA synthesis', 'biological_process', 'GO:0071897', ('114', '127'))	('decreased', 'NegReg', (42, 51))	('EdU incorporation', 'MPA', (70, 87))	('EdU', 'Chemical', '-', (70, 73))	('PLX51107', 'Var', (19, 27))	('S-phase', 'biological_process', 'GO:0051320', ('128', '135'))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('PLX72853', 'Var', (33, 41))	('PLX72853', 'Chemical', '-', (33, 41))	('JQ1', 'Var', (14, 17))	('inhibition', 'NegReg', (100, 110))
38389	30610113	BET inhibitors increased the expression of pro-apoptotic proteins; cleaved PARP, BimEL and Bmf, and these changes were also reversed by FGF2 treatment (Fig 4C).	('FGF2', 'Gene', (136, 140))	('BimEL', 'Gene', (81, 86))	('PARP', 'Protein', (75, 79))	('increased', 'PosReg', (15, 24))	('cleaved', 'Var', (67, 74))	('FGF2', 'Gene', '2247', (136, 140))	('expression', 'MPA', (29, 39))	('Bmf', 'Gene', (91, 94))
38392	30610113	FGF2 protects UM cells from the growth inhibitory effects of BET inhibitors as before and AZD4547 significantly suppressed FGF2-induced resistance of cells to BET inhibitors (Fig 5).	('AZD4547', 'Var', (90, 97))	('suppressed', 'NegReg', (112, 122))	('FGF2', 'Gene', (123, 127))	('UM', 'Phenotype', 'HP:0007716', (14, 16))	('FGF2', 'Gene', (0, 4))	('resistance', 'MPA', (136, 146))	('growth inhibitory', 'MPA', (32, 49))	('AZD4547', 'Chemical', 'MESH:C572463', (90, 97))	('FGF2', 'Gene', '2247', (123, 127))	('FGF2', 'Gene', '2247', (0, 4))
38393	30610113	BLU9931 had a moderate effect in reversing resistance to BET inhibition conferred by FGF2 (Fig EV2).	('FGF2', 'Gene', (85, 89))	('resistance', 'MPA', (43, 53))	('BLU9931', 'Var', (0, 7))	('FGF2', 'Gene', '2247', (85, 89))	('reversing', 'NegReg', (33, 42))	('EV2', 'Gene', '147138', (95, 98))	('EV2', 'Gene', (95, 98))
38394	30610113	AZD4547 or BLU9931 alone at 1 muM had little effect on cell growth (Fig EV3).	('muM', 'Gene', (30, 33))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('BLU9931', 'Var', (11, 18))	('muM', 'Gene', '56925', (30, 33))	('AZD4547', 'Var', (0, 7))	('cell growth', 'biological_process', 'GO:0016049', ('55', '66'))	('cell growth', 'CPA', (55, 66))
38404	30610113	To investigate whether BET inhibitors alter FGF2/FGFR signaling, we determined effects of PLX51107, JQ1 and PLX72853 on FGF2 secretion by HSCs and FGFR expression in metastatic UM cell lines.	('signaling', 'biological_process', 'GO:0023052', ('54', '63'))	('FGF2', 'Gene', (44, 48))	('FGF2', 'Gene', (120, 124))	('PLX51107', 'Var', (90, 98))	('FGFR', 'Gene', (147, 151))	('PLX72853', 'Var', (108, 116))	('FGF2', 'Gene', '2247', (44, 48))	('PLX72853', 'Chemical', '-', (108, 116))	('UM', 'Phenotype', 'HP:0007716', (177, 179))	('secretion', 'biological_process', 'GO:0046903', ('125', '134'))	('FGFR', 'molecular_function', 'GO:0005007', ('147', '151'))	('secretion', 'MPA', (125, 134))	('HSC', 'Gene', (138, 141))	('FGF2', 'Gene', '2247', (120, 124))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('expression', 'MPA', (152, 162))	('HSC', 'Gene', '2523', (138, 141))
38408	30610113	These findings suggest that in addition to intrinsic resistance to BET inhibitors by FGF2 in the TME, BET inhibition induces adaptive response mechanisms that increase FGF2 production by HSCs and FGFR expression in UM cells.	('HSC', 'Gene', '2523', (187, 190))	('FGFR', 'Gene', (196, 200))	('FGF2', 'Gene', (85, 89))	('BET', 'Var', (102, 105))	('FGF2', 'Gene', (168, 172))	('UM', 'Phenotype', 'HP:0007716', (215, 217))	('FGFR', 'molecular_function', 'GO:0005007', ('196', '200'))	('FGF2', 'Gene', '2247', (85, 89))	('FGF2', 'Gene', '2247', (168, 172))	('HSC', 'Gene', (187, 190))	('increase', 'PosReg', (159, 167))
38414	30610113	Mice bearing UM001 xenograft tumors following subcutaneous injection of UM001 and LX-2 cells were treated with PLX51107 chow, AZD4547 or the combination of PLX51107 and AZD4547.	('PLX51107', 'Var', (111, 119))	('xenograft tumors', 'Disease', (19, 35))	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('AZD4547', 'Chemical', 'MESH:C572463', (126, 133))	('LX-2', 'CellLine', 'CVCL:5792', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('AZD4547', 'Chemical', 'MESH:C572463', (169, 176))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('xenograft tumors', 'Disease', 'MESH:D009369', (19, 35))	('Mice', 'Species', '10090', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (13, 15))
38416	30610113	Interestingly, PLX51107 increased UM001 tumor volume compared to controls (Fig 8A).	('PLX51107', 'Var', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('UM', 'Phenotype', 'HP:0007716', (34, 36))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('increased', 'PosReg', (24, 33))	('UM001', 'Gene', (34, 39))
38417	30610113	AZD4547 moderately decreased UM tumor volume, but the combination of PLX51107 and AZD4547 significantly suppressed tumor growth compared to the PLX51107 treatment arm (Fig 8A).	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('UM', 'Phenotype', 'HP:0007716', (29, 31))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('AZD4547', 'Var', (82, 89))	('suppressed', 'NegReg', (104, 114))	('PLX51107', 'Var', (69, 77))	('tumor', 'Disease', (32, 37))	('AZD4547', 'Chemical', 'MESH:C572463', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
38418	30610113	Additionally, BimEL and cleaved PARP protein levels increased more rapidly in tumors from PLX51107 and AZD4547-treated mice compared to either PLX51107-treated or control mice (Appendix Fig S6).	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('PLX51107', 'Var', (90, 98))	('increased', 'PosReg', (52, 61))	('AZD4547-treated', 'Var', (103, 118))	('mice', 'Species', '10090', (119, 123))	('mice', 'Species', '10090', (171, 175))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('AZD4547', 'Chemical', 'MESH:C572463', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))
38420	30610113	After 6-8 weeks, the animals were treated with PLX51107 chow, AZD4547 or the combination of PLX51107 and AZD4547 for a further 2 weeks.	('AZD4547', 'Var', (105, 112))	('AZD4547', 'Chemical', 'MESH:C572463', (105, 112))	('PLX51107', 'Var', (92, 100))	('AZD4547', 'Chemical', 'MESH:C572463', (62, 69))
38421	30610113	In comparison with the control, PLX51107 and AZD4547 alone suppressed tumor size moderately but the combination of PLX51107 and AZD4547 significantly decreased tumor size after 2 weeks of treatment (Fig 8B).	('PLX51107', 'Var', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('AZD4547', 'Var', (128, 135))	('AZD4547', 'Chemical', 'MESH:C572463', (45, 52))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('combination', 'Var', (100, 111))	('suppressed', 'NegReg', (59, 69))	('AZD4547', 'Chemical', 'MESH:C572463', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('decreased', 'NegReg', (150, 159))
38422	30610113	These findings indicate that effects of BET and FGFR inhibitors as monotherapies are poor in vivo but the combination of both inhibitors suppressed UM tumor growth.	('combination', 'Var', (106, 117))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('suppressed', 'NegReg', (137, 147))	('tumor', 'Disease', (151, 156))	('UM', 'Phenotype', 'HP:0007716', (148, 150))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
38423	30610113	Inhibition of BET proteins is emerging as a promising anti-cancer therapeutic strategy to block transcriptional dependencies.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('BET proteins', 'Protein', (14, 26))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
38430	30610113	We demonstrated that FGFR inhibitors, AZD4547 and BLU9931, reversed FGF2-induced protection against BET inhibitors, indicating that FGF2 effects are mediated by the canonical FGFRs.	('AZD4547', 'Var', (38, 45))	('FGF2', 'Gene', '2247', (132, 136))	('BLU9931', 'Var', (50, 57))	('AZD4547', 'Chemical', 'MESH:C572463', (38, 45))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('FGF2', 'Gene', (132, 136))	('FGF2', 'Gene', '2247', (68, 72))	('FGF2', 'Gene', (68, 72))
38431	30610113	AZD4547, a pan-FGFR1/2/3 inhibitor, had a more significant effect on reversing FGF2-induced resistance to BET inhibition in the UM cell lines compared to the FGFR4-specific inhibitor, BLU9931, indicating that FGFR1, 2, and/or 3 were the predominant receptors mediating FGF2 effects.	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('FGFR', 'molecular_function', 'GO:0005007', ('209', '213'))	('FGFR1', 'Gene', (15, 20))	('FGFR1/2/3', 'Gene', (15, 24))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('FGF2', 'Gene', '2247', (269, 273))	('FGF2', 'Gene', (79, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('158', '162'))	('FGFR1', 'Gene', '2260', (209, 214))	('FGFR4', 'Gene', '2264', (158, 163))	('resistance to BET inhibition', 'MPA', (92, 120))	('UM', 'Phenotype', 'HP:0007716', (128, 130))	('FGF2', 'Gene', (269, 273))	('FGFR4', 'Gene', (158, 163))	('FGFR1', 'Gene', '2260', (15, 20))	('FGFR1/2/3', 'Gene', '2260;2263;2261', (15, 24))	('reversing', 'NegReg', (69, 78))	('FGFR1', 'Gene', (209, 214))	('AZD4547', 'Var', (0, 7))	('FGF2', 'Gene', '2247', (79, 83))
38432	30610113	In two separate in vivo models, we also identified that PLX51107 either increased or had little effect on UM001 tumor growth.	('PLX51107', 'Var', (56, 64))	('increased', 'PosReg', (72, 81))	('UM', 'Phenotype', 'HP:0007716', (106, 108))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('UM001', 'Gene', (106, 111))
38433	30610113	This may indicate that the liver microenvironment including LX-2 cells plays a role in reducing the efficacy of BET inhibitors and co-inhibition of FGFRs by AZD4547 treatment significantly suppresses tumor growth compared to PLX51107-treated mice.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('AZD4547', 'Chemical', 'MESH:C572463', (157, 164))	('LX-2', 'CellLine', 'CVCL:5792', (60, 64))	('co-inhibition', 'Var', (131, 144))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('FGFRs', 'Gene', (148, 153))	('reducing', 'NegReg', (87, 95))	('tumor', 'Disease', (200, 205))	('suppresses', 'NegReg', (189, 199))	('efficacy', 'MPA', (100, 108))	('AZD4547', 'Var', (157, 164))	('mice', 'Species', '10090', (242, 246))
38435	30610113	Although we found that FGF2 provides resistance to the HDAC inhibitor vorinostat, the combination of BET inhibitors and vorinostat induced a greater inhibition of UM001 growth compared to single BET inhibitor and vorinostat treatments (Appendix Fig S7).	('inhibition', 'NegReg', (149, 159))	('inhibitors', 'Var', (105, 115))	('vorinostat', 'Gene', (120, 130))	('UM', 'Phenotype', 'HP:0007716', (163, 165))	('UM001 growth', 'CPA', (163, 175))	('vorinostat', 'Chemical', 'MESH:D000077337', (70, 80))	('FGF2', 'Gene', '2247', (23, 27))	('combination', 'Interaction', (86, 97))	('vorinostat', 'Chemical', 'MESH:D000077337', (120, 130))	('FGF2', 'Gene', (23, 27))	('vorinostat', 'Chemical', 'MESH:D000077337', (213, 223))
38439	30610113	The moderate resistance of OMM1.3 cells to BET inhibition following culture with LX2-conditioned media was also reversible by AZD4547, indicating involvement of FGFR1, 2, and/or 3 in mediating resistance.	('FGFR1', 'Gene', (161, 166))	('AZD4547', 'Chemical', 'MESH:C572463', (126, 133))	('BET', 'MPA', (43, 46))	('inhibition', 'NegReg', (47, 57))	('FGFR1', 'Gene', '2260', (161, 166))	('FGFR', 'molecular_function', 'GO:0005007', ('161', '165'))	('AZD4547', 'Var', (126, 133))
38455	30610113	UM001, UM004 and OMM1.3 were confirmed to harbor the Q209P mutation in GNAQ by Sanger sequencing; UM003 cells express the Q209L GNAQ mutation.	('Q209P', 'Var', (53, 58))	('UM', 'Phenotype', 'HP:0007716', (98, 100))	('Q209P', 'Mutation', 'rs121913492', (53, 58))	('Q209L', 'Var', (122, 127))	('GNAQ', 'Gene', (71, 75))	('GNAQ', 'Gene', '2776', (128, 132))	('UM', 'Phenotype', 'HP:0007716', (7, 9))	('GNAQ', 'Gene', (128, 132))	('GNAQ', 'Gene', '2776', (71, 75))	('Q209L', 'Mutation', 'rs121913492', (122, 127))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
38460	30610113	JQ1, AZD4547 and BLU9931 were purchased from Selleck Chemicals (Houston, TX).	('BLU9931', 'Var', (17, 24))	('AZD4547', 'Var', (5, 12))	('AZD4547', 'Chemical', 'MESH:C572463', (5, 12))
38489	30610113	Once tumor xenografts were established (100-200 mm3), the animals were divided into four arms: control (n = 8), PLX51107 (90 mg/kg, n = 8), AZD4547 (5 mg/kg, n = 8), or the combination of PLX51107 and AZD4547 (n = 10).	('AZD4547', 'Chemical', 'MESH:C572463', (140, 147))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('AZD4547', 'Chemical', 'MESH:C572463', (201, 208))	('tumor', 'Disease', (5, 10))	('AZD4547', 'Var', (140, 147))
38505	30610113	In addition, we identified that BET inhibitors increased FGF2 secretion by hepatic stellate cells.	('inhibitors', 'Var', (36, 46))	('secretion', 'biological_process', 'GO:0046903', ('62', '71'))	('secretion', 'MPA', (62, 71))	('FGF2', 'Gene', '2247', (57, 61))	('increased', 'PosReg', (47, 56))	('FGF2', 'Gene', (57, 61))
38510	28499758	Activating CYSLTR2 and PLCB4 mutations in primary leptomeningeal melanocytic tumors Melanocytic tumors arising in the central nervous system are also known as primary leptomeningeal melanocytic tumors (PLMTs).	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('Activating', 'PosReg', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Melanocytic tumors', 'Disease', (84, 102))	('PLCB4', 'Gene', (23, 28))	('mutations', 'Var', (29, 38))	('CYSLTR2', 'Gene', (11, 18))	('leptomeningeal melanocytic tumors', 'Disease', (50, 83))	('leptomeningeal melanocytic tumors', 'Disease', 'MESH:D008577', (167, 200))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('leptomeningeal melanocytic tumors', 'Disease', (167, 200))	('Melanocytic tumors', 'Disease', 'MESH:D009508', (84, 102))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumors arising in the central nervous system', 'Phenotype', 'HP:0100006', (96, 140))	('leptomeningeal melanocytic tumors', 'Disease', 'MESH:D008577', (50, 83))
38513	28499758	These mutations are very rare in cutaneous melanoma, but frequent in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('uveal melanoma', 'Disease', (69, 83))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('frequent', 'Reg', (57, 65))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('cutaneous melanoma', 'Disease', (33, 51))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (33, 51))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (33, 51))	('mutations', 'Var', (6, 15))
38514	28499758	The close molecular relationship between PMLTs and uveal melanomas was further demonstrated by the finding that EIF1AX, SF3B1 and BAP1 mutations, previously identified in uveal melanomas, can also occur in PMLT.	('uveal melanomas', 'Disease', 'MESH:C536494', (51, 66))	('PMLT', 'Disease', (206, 210))	('BAP1', 'Gene', (130, 134))	('uveal melanoma', 'Phenotype', 'HP:0007716', (51, 65))	('SF3B1', 'Gene', (120, 125))	('melanomas', 'Phenotype', 'HP:0002861', (177, 186))	('uveal melanomas', 'Disease', (171, 186))	('uveal melanomas', 'Phenotype', 'HP:0007716', (171, 186))	('mutations', 'Var', (135, 144))	('EIF1AX', 'Gene', (112, 118))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('uveal melanomas', 'Disease', (51, 66))	('uveal melanomas', 'Phenotype', 'HP:0007716', (51, 66))	('uveal melanoma', 'Phenotype', 'HP:0007716', (171, 185))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('uveal melanomas', 'Disease', 'MESH:C536494', (171, 186))	('occur', 'Reg', (197, 202))
38515	28499758	Similar to uveal melanomas, a proportion of PLMTs are not found to harbor activating mutations in GNAQ or GNA11.	('uveal melanoma', 'Phenotype', 'HP:0007716', (11, 25))	('melanomas', 'Phenotype', 'HP:0002861', (17, 26))	('GNA11', 'Gene', (106, 111))	('uveal melanomas', 'Disease', (11, 26))	('GNAQ', 'Gene', (98, 102))	('PLMTs', 'Disease', (44, 49))	('uveal melanomas', 'Phenotype', 'HP:0007716', (11, 26))	('mutations', 'Var', (85, 94))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('uveal melanomas', 'Disease', 'MESH:C536494', (11, 26))
38516	28499758	Recent studies have identified activating CYSLTR2 and PLCB4 mutations in uveal melanomas, occurring at the L129 and D630 hotspots, respectively.	('uveal melanomas', 'Disease', 'MESH:C536494', (73, 88))	('PLCB4', 'Gene', (54, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (73, 87))	('D630', 'Var', (116, 120))	('CYSLTR2', 'Gene', (42, 49))	('activating', 'PosReg', (31, 41))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('uveal melanomas', 'Disease', (73, 88))	('uveal melanomas', 'Phenotype', 'HP:0007716', (73, 88))	('mutations', 'Var', (60, 69))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))
38517	28499758	These mutations always occurred in tumors lacking GNAQ and GNA11 mutations, and have not yet been reported in cutaneous melanomas.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (110, 129))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (110, 129))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('occurred', 'Reg', (23, 31))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (110, 128))	('melanomas', 'Phenotype', 'HP:0002861', (120, 129))	('GNA11', 'Gene', (59, 64))	('tumors', 'Disease', (35, 41))	('cutaneous melanomas', 'Disease', (110, 129))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('mutations', 'Var', (65, 74))	('GNAQ', 'Gene', (50, 54))
38518	28499758	To determine whether CYSLTR2 and PLCB4 mutations also occur in PLMTs, we analyzed our previously published cohort of tumors, using a next-generation sequencing gene panel covering the mutational hot-spots in CYSLTR2 and PLCB4 as well as other gene mutations reported in uveal melanoma (described in Supplemental Material and previously reported).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('PLCB4', 'Gene', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('CYSLTR2', 'Gene', (21, 28))	('uveal melanoma', 'Phenotype', 'HP:0007716', (270, 284))	('mutations', 'Var', (39, 48))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('uveal melanoma', 'Disease', 'MESH:C536494', (270, 284))	('uveal melanoma', 'Disease', (270, 284))	('PLCB4', 'Gene', (220, 225))	('CYSLTR2', 'Gene', (208, 215))
38519	28499758	In 19 PLMTs, we found two tumors with activating L129Q (c.386T>A) mutations in CYSLTR2 and one tumor harboring an activating D630Y (c.1888G>T) mutation in PLCB4 (Figure 1, Table 1).	('L129Q (c.386T>A', 'Var', (49, 64))	('D630Y (c.1888G>T', 'Var', (125, 141))	('D630Y', 'Mutation', 'p.D630Y', (125, 130))	('activating', 'PosReg', (38, 48))	('tumors', 'Disease', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('PLCB4', 'Gene', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('CYSLTR2', 'Gene', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('c.386T>A', 'Mutation', 'c.386T>A', (56, 64))	('L129Q', 'Mutation', 'p.L129Q', (49, 54))	('c.1888G>T', 'Mutation', 'c.1888G>T', (132, 141))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', (95, 100))
38520	28499758	These mutations were identified at the same hotspots previously described in uveal melanoma and predicted to be activating.	('uveal melanoma', 'Disease', 'MESH:C536494', (77, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (77, 91))	('uveal melanoma', 'Disease', (77, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('mutations', 'Var', (6, 15))
38523	28499758	One EIF1AX mutation (R13C, c.37C>T) was identified in a tumor that also harbored an activating CYSLTR2 L129Q mutation (Supplemental Figure 1).	('CYSLTR2', 'Gene', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('c.37C>T', 'Mutation', 'c.37C>T', (27, 34))	('L129Q', 'Var', (103, 108))	('tumor', 'Disease', (56, 61))	('c.37C>T', 'Var', (27, 34))	('L129Q', 'Mutation', 'p.L129Q', (103, 108))	('activating', 'PosReg', (84, 94))	('R13C', 'Mutation', 'p.R13C', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
38524	28499758	In addition to a known SF3B1 R625H (c.1874G>A) and inactivating BAP1 R60* (c.178C>T) mutation, our targeted next-generation sequencing approach detected a BAP1 E31del (c.91_93delGAG) mutation in the PLMT sample also harboring a PLCB4 D630Y mutation (Supplemental Figure 1).	('c.1874G>A', 'Mutation', 'rs1057519961', (36, 45))	('PLCB4', 'Gene', (228, 233))	('D630Y', 'Var', (234, 239))	('R60*', 'SUBSTITUTION', 'None', (69, 73))	('D630Y', 'Mutation', 'p.D630Y', (234, 239))	('BAP1', 'Gene', (155, 159))	('PLMT', 'molecular_function', 'GO:0000773', ('199', '203'))	('c.91_93delGAG', 'Mutation', 'c.91_93delGAG', (168, 181))	('R60*', 'Var', (69, 73))	('c.178C>T', 'Mutation', 'c.178C>T', (75, 83))	('E31del', 'Mutation', 'p.31delE', (160, 166))	('R625H', 'Mutation', 'rs1057519961', (29, 34))
38525	28499758	However, copy number analysis (Supplemental Figure 3) demonstrated loss of chromosome 3 including the other wild-type BAP1 allele which means the mutation would be highly relevant if it resulted in loss or impairment of protein function.	('mutation', 'Var', (146, 154))	('loss or impairment of protein function', 'Disease', (198, 236))	('loss or impairment of protein function', 'Disease', 'MESH:D003072', (198, 236))	('protein', 'cellular_component', 'GO:0003675', ('220', '227'))	('loss', 'NegReg', (67, 71))	('BAP1', 'Gene', (118, 122))	('chromosome', 'cellular_component', 'GO:0005694', ('75', '85'))
38526	28499758	Activating mutations in these genes are exceedingly rare in other melanomas, with the exception of uveal melanomas.	('melanomas', 'Disease', 'MESH:D008545', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanomas', 'Disease', (105, 114))	('uveal melanomas', 'Disease', (99, 114))	('uveal melanomas', 'Phenotype', 'HP:0007716', (99, 114))	('Activating mutations', 'Var', (0, 20))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('uveal melanomas', 'Disease', 'MESH:C536494', (99, 114))	('melanomas', 'Phenotype', 'HP:0002861', (105, 114))	('melanomas', 'Disease', (66, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('melanomas', 'Disease', 'MESH:D008545', (105, 114))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))
38528	28499758	Presence of a PLCB4, CYSLTR2, GNAQ or GNA11 mutation is strong evidence in favor of a PLMT, but a rare CNS uveal melanoma metastasis should also be considered.	('uveal melanoma metastasis', 'Disease', (107, 132))	('mutation', 'Var', (44, 52))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('CYSLTR2', 'Gene', (21, 28))	('GNAQ', 'Gene', (30, 34))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('PLCB4', 'Gene', (14, 19))	('GNA11', 'Gene', (38, 43))	('PLMT', 'molecular_function', 'GO:0000773', ('86', '90'))	('uveal melanoma metastasis', 'Disease', 'MESH:C536494', (107, 132))
38529	28752853	Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation The Hippo pathway controls organ size, and tissue homeostasis with deregulation leading to cancer.	('MAPK', 'Gene', (61, 65))	('cancer', 'Disease', (191, 197))	('leading to', 'Reg', (180, 190))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('transcription', 'biological_process', 'GO:0006351', ('28', '41'))	('p38', 'Gene', '1432', (57, 60))	('transcription factor', 'molecular_function', 'GO:0000981', ('28', '48'))	('controls', 'Reg', (118, 126))	('Hippo', 'Gene', (104, 109))	('MAPK', 'molecular_function', 'GO:0004707', ('61', '65'))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('p38', 'Gene', (57, 60))	('MAPK', 'Gene', '5594', (61, 65))	('tissue homeostasis', 'biological_process', 'GO:0001894', ('143', '161'))	('deregulation', 'Var', (167, 179))	('organ', 'MPA', (127, 132))
38531	28752853	Inactivation of these upstream kinases leads to dephosphorylation, stabilization, nuclear translocation, and thus activation of the major functional transducers of the Hippo pathway, YAP and its paralog TAZ.	('activation', 'PosReg', (114, 124))	('stabilization', 'MPA', (67, 80))	('dephosphorylation', 'MPA', (48, 65))	('YAP', 'Gene', (183, 186))	('TAZ', 'Gene', '6901', (203, 206))	('dephosphorylation', 'biological_process', 'GO:0016311', ('48', '65'))	('TAZ', 'Gene', (203, 206))	('Hippo pathway', 'Pathway', (168, 181))	('nuclear translocation', 'MPA', (82, 103))	('Inactivation', 'Var', (0, 12))	('YAP', 'Gene', '10413', (183, 186))
38536	28752853	We set out to identify signals that may regulate TEAD subcellular localization by focusing on conditions known to inhibit YAP/TAZ such as serum starvation, energy stress by glucose starvation, PKA activation by forskolin, disruption of the actin cytoskeleton by latrunculin B, Src inhibition by dasatinib, and inhibition of mevalonate synthesis by cerivastatin.	('glucose', 'Chemical', 'MESH:D005947', (173, 180))	('latrunculin B', 'Chemical', 'MESH:C037068', (262, 275))	('disruption', 'Var', (222, 232))	('dasatinib', 'Chemical', 'MESH:D000069439', (295, 304))	('localization', 'biological_process', 'GO:0051179', ('66', '78'))	('TAZ', 'Gene', '6901', (126, 129))	('TAZ', 'Gene', (126, 129))	('YAP', 'Gene', '10413', (122, 125))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('240', '258'))	('PKA', 'Gene', (193, 196))	('mevalonate', 'Chemical', 'MESH:D008798', (324, 334))	('Src', 'Gene', (277, 280))	('PKA', 'cellular_component', 'GO:0005952', ('193', '196'))	('PKA', 'molecular_function', 'GO:0004691', ('193', '196'))	('mevalonate synthesis', 'MPA', (324, 344))	('inhibition', 'NegReg', (281, 291))	('Src', 'Gene', '6714', (277, 280))	('forskolin', 'Chemical', 'MESH:D005576', (211, 220))	('cerivastatin', 'Chemical', 'MESH:C086276', (348, 360))	('YAP', 'Gene', (122, 125))	('activation', 'PosReg', (197, 207))	('actin', 'MPA', (240, 245))	('synthesis', 'biological_process', 'GO:0009058', ('335', '344'))
38541	28752853	Treatment with p38 inhibitors (SB203580 or PH797840) blocked osmotic stress-induced, but not high density-induced, TEAD cytoplasmic localization, indicating that p38 is specifically involved in TEAD cytoplasmic translocation upon osmotic stress (Fig.	('localization', 'biological_process', 'GO:0051179', ('132', '144'))	('blocked', 'NegReg', (53, 60))	('osmotic', 'MPA', (61, 68))	('p38', 'Gene', (162, 165))	('SB203580', 'Var', (31, 39))	('SB203580', 'Chemical', 'MESH:C093642', (31, 39))	('p38', 'Gene', (15, 18))	('involved', 'Reg', (182, 190))	('PH797840', 'Var', (43, 51))	('p38', 'Gene', '1432', (162, 165))	('p38', 'Gene', '1432', (15, 18))
38542	28752853	Activation of p38 by ectopic expression of p38 and its upstream kinase MKK3 also induced cytoplasmic translocation of TEAD and this effect was blocked by p38 inhibitor treatment (Fig.	('p38', 'Gene', (14, 17))	('p38', 'Gene', (43, 46))	('p38', 'Gene', '1432', (154, 157))	('p38', 'Gene', '1432', (43, 46))	('MKK3', 'Gene', (71, 75))	('induced', 'Reg', (81, 88))	('cytoplasmic translocation', 'MPA', (89, 114))	('Activation', 'PosReg', (0, 10))	('p38', 'Gene', '1432', (14, 17))	('MKK', 'molecular_function', 'GO:0004708', ('71', '74'))	('p38', 'Gene', (154, 157))	('ectopic expression', 'Var', (21, 39))	('MKK3', 'Gene', '5606', (71, 75))
38544	28752853	Deletion of p38alpha/beta (p38 2KO) resulted in p38gamma/delta upregulation and did not impede TEAD cytoplasmic translocation (Supplementary Fig.	('p38', 'Gene', (48, 51))	('p38gamma', 'Gene', (48, 56))	('p38', 'Gene', (12, 15))	('p38alpha', 'Gene', '1432', (12, 20))	('p38', 'Gene', '1432', (27, 30))	('Deletion', 'Var', (0, 8))	('p38gamma', 'Gene', '6300', (48, 56))	('p38alpha', 'Gene', (12, 20))	('p38', 'Gene', '1432', (48, 51))	('upregulation', 'PosReg', (63, 75))	('p38', 'Gene', '1432', (12, 15))	('p38', 'Gene', (27, 30))
38546	28752853	When all four p38 genes were deleted in the p38alpha/beta/gamma/delta knockout (KO) (p38 4KO) cells, TEAD localization was insensitive to osmotic stress and largely retained in the nucleus (Fig.	('p38', 'Gene', (14, 17))	('localization', 'MPA', (106, 118))	('p38', 'Gene', '1432', (85, 88))	('p38', 'Gene', '1432', (44, 47))	('nucleus', 'cellular_component', 'GO:0005634', ('181', '188'))	('localization', 'biological_process', 'GO:0051179', ('106', '118'))	('p38alpha', 'Gene', '1432', (44, 52))	('p38', 'Gene', (44, 47))	('p38alpha', 'Gene', (44, 52))	('p38', 'Gene', '1432', (14, 17))	('p38', 'Gene', (85, 88))	('deleted', 'Var', (29, 36))
38547	28752853	Under basal conditions, deletion of p38 had no effect on TEAD localization and marginally increased YAP-TEAD activity, indicating that p38 plays a role in regulation of TEAD mainly under conditions of cellular stress.	('p38', 'Gene', '1432', (36, 39))	('YAP', 'Gene', (100, 103))	('TEAD localization', 'MPA', (57, 74))	('increased', 'PosReg', (90, 99))	('p38', 'Gene', (135, 138))	('p38', 'Gene', (36, 39))	('regulation', 'biological_process', 'GO:0065007', ('155', '165'))	('deletion', 'Var', (24, 32))	('YAP', 'Gene', '10413', (100, 103))	('p38', 'Gene', '1432', (135, 138))	('localization', 'biological_process', 'GO:0051179', ('62', '74'))
38548	28752853	The specific role of p38 in osmotic stress is further supported by the result that p38 inhibition or knockout had no effect on density-induced TEAD cytoplasmic localization (Supplementary Fig.	('inhibition', 'NegReg', (87, 97))	('knockout', 'Var', (101, 109))	('p38', 'Gene', (83, 86))	('p38', 'Gene', '1432', (21, 24))	('localization', 'biological_process', 'GO:0051179', ('160', '172'))	('p38', 'Gene', '1432', (83, 86))	('p38', 'Gene', (21, 24))
38561	28752853	Deletion of the D domain in TEAD abolished TEAD-p38 interaction (Fig.	('p38', 'Gene', (48, 51))	('p38', 'Gene', '1432', (48, 51))	('abolished', 'NegReg', (33, 42))	('TEAD', 'Gene', (28, 32))	('Deletion', 'Var', (0, 8))
38564	28752853	To determine whether TEAD cytoplasmic translocation is due to p38-mediated phosphorylation, we constructed TEAD4-4SP, in which the four putative p38 phosphorylation sites were mutated to alanine (Supplementary Fig.	('p38', 'Gene', (145, 148))	('TEAD4', 'Gene', (107, 112))	('mutated', 'Var', (176, 183))	('p38', 'Gene', '1432', (62, 65))	('alanine', 'Chemical', 'MESH:D000409', (187, 194))	('p38', 'Gene', '1432', (145, 148))	('phosphorylation', 'biological_process', 'GO:0016310', ('75', '90'))	('phosphorylation', 'biological_process', 'GO:0016310', ('149', '164'))	('p38', 'Gene', (62, 65))	('TEAD4', 'Gene', '7004', (107, 112))
38565	28752853	Using an in vitro kinase assay, we found TEAD4 to be a poor substrate for p38 phosphorylation with complete ablation of phosphorylation in the TEAD4-4SP mutant, indicating the absence of alternative phosphorylation sites (Supplementary Fig.	('TEAD4', 'Gene', '7004', (41, 46))	('TEAD4', 'Gene', (143, 148))	('p38', 'Gene', '1432', (74, 77))	('TEAD4', 'Gene', (41, 46))	('ablation', 'NegReg', (108, 116))	('phosphorylation', 'MPA', (120, 135))	('mutant', 'Var', (153, 159))	('phosphorylation', 'biological_process', 'GO:0016310', ('78', '93'))	('p38', 'Gene', (74, 77))	('TEAD4', 'Gene', '7004', (143, 148))	('phosphorylation', 'biological_process', 'GO:0016310', ('120', '135'))	('phosphorylation', 'biological_process', 'GO:0016310', ('199', '214'))
38568	28752853	Disruption of a putative TEAD nuclear export signal, as well as inhibition of Chromosomal Maintenance 1 (CRM1) using Leptomycin B (LMB), largely ablated TEAD translocation, indicating that TEAD cytoplasmic translocation is an active, CRM1-mediated process (Supplementary Fig.	('Chromosomal Maintenance 1', 'Gene', (78, 103))	('ablated', 'NegReg', (145, 152))	('Chromosomal Maintenance 1', 'Gene', '7514', (78, 103))	('CRM1', 'Gene', '7514', (105, 109))	('CRM1', 'Gene', (105, 109))	('inhibition', 'Var', (64, 74))	('TEAD translocation', 'MPA', (153, 171))	('Leptomycin B', 'Chemical', 'MESH:C038753', (117, 129))	('LMB', 'Chemical', 'MESH:C038753', (131, 134))	('CRM1', 'Gene', '7514', (234, 238))	('nuclear export', 'biological_process', 'GO:0051168', ('30', '44'))	('CRM1', 'Gene', (234, 238))	('Disruption', 'Var', (0, 10))
38576	28752853	Compared to WT cells, p38 inhibition enhanced YAP/TAZ nuclear accumulation and target gene expression in the absence of Lats (Fig.	('p38', 'Gene', '1432', (22, 25))	('TAZ', 'Gene', (50, 53))	('expression', 'MPA', (91, 101))	('YAP', 'Gene', '10413', (46, 49))	('gene expression', 'biological_process', 'GO:0010467', ('86', '101'))	('inhibition', 'Var', (26, 36))	('p38', 'Gene', (22, 25))	('YAP', 'Gene', (46, 49))	('enhanced', 'PosReg', (37, 45))	('TAZ', 'Gene', '6901', (50, 53))
38582	28752853	YAP is highly active in many cancers, particularly in uveal melanoma (UM) and mesothelioma, due to mutations in upstream components of the Hippo pathway.	('YAP', 'Gene', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('active', 'PosReg', (14, 20))	('cancers', 'Disease', 'MESH:D009369', (29, 36))	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancers', 'Disease', (29, 36))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('mutations', 'Var', (99, 108))	('uveal melanoma', 'Disease', (54, 68))	('YAP', 'Gene', '10413', (0, 3))	('uveal melanoma', 'Disease', 'MESH:C536494', (54, 68))	('mesothelioma', 'Disease', (78, 90))	('Hippo pathway', 'Pathway', (139, 152))
38583	28752853	YAP was constitutively hypophosphorylated and nuclear in mesothelioma cells MSTO-211H (Lats2 mutation) and H2373 (NF2 mutation), even under YAP-inhibitory conditions (Fig.	('MSTO-211H', 'CellLine', 'CVCL:1430', (76, 85))	('mesothelioma', 'Disease', (57, 69))	('YAP', 'Gene', (0, 3))	('Lats2', 'Gene', (87, 92))	('NF2', 'Gene', (114, 117))	('mesothelioma', 'Disease', 'MESH:D008654', (57, 69))	('YAP', 'Gene', '10413', (0, 3))	('NF2', 'Gene', '4771', (114, 117))	('YAP', 'Gene', '10413', (140, 143))	('Lats2', 'Gene', '26524', (87, 92))	('mutation', 'Var', (93, 101))	('YAP', 'Gene', (140, 143))
38587	28752853	To further examine whether stress-induced TEAD inhibition selectively suppresses YAP-driven cancer cell growth, we compared a series of UM cell lines with mutations in either GNAQ or BRAF.	('cancer', 'Disease', (92, 98))	('mutations', 'Var', (155, 164))	('YAP', 'Gene', '10413', (81, 84))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('UM', 'Phenotype', 'HP:0007716', (136, 138))	('GNAQ', 'Gene', (175, 179))	('cell growth', 'biological_process', 'GO:0016049', ('99', '110'))	('BRAF', 'Gene', '673', (183, 187))	('YAP', 'Gene', (81, 84))	('suppresses', 'NegReg', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('BRAF', 'Gene', (183, 187))	('GNAQ', 'Gene', '2776', (175, 179))
38603	28752853	Disruption of TEAD-p38 interaction abolishes TEAD cytoplasmic translocation, resulting in nuclear retention of transcriptionally active TEAD.	('retention', 'biological_process', 'GO:0051235', ('98', '107'))	('p38', 'Gene', '1432', (19, 22))	('p38', 'Gene', (19, 22))	('nuclear retention', 'CPA', (90, 107))	('abolishes', 'NegReg', (35, 44))	('TEAD cytoplasmic translocation', 'MPA', (45, 75))	('interaction', 'Interaction', (23, 34))	('Disruption', 'Var', (0, 10))
38606	28752853	Thus, inhibition of TEAD presents a Hippo pathway independent avenue of regulating YAP activity, thereby providing a mechanism of controlling its functional output without targeting Hippo core components Mst and Lats.	('YAP', 'Gene', '10413', (83, 86))	('YAP', 'Gene', (83, 86))	('functional output', 'MPA', (146, 163))	('core', 'cellular_component', 'GO:0019013', ('188', '192'))	('inhibition', 'Var', (6, 16))	('TEAD', 'Gene', (20, 24))
38607	28752853	Moreover, stress-induced TEAD nucleocytoplasmic shuttling is intact in cancer cells that harbor mutations in Hippo pathway upstream components and renders YAP-driven cancer cells highly susceptible to stress-induced growth inhibition.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('YAP', 'Gene', (155, 158))	('cancer', 'Disease', (71, 77))	('nucleocytoplasmic shuttling', 'biological_process', 'GO:0006913', ('30', '57'))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('Hippo pathway', 'Gene', (109, 122))	('mutations', 'Var', (96, 105))	('YAP', 'Gene', '10413', (155, 158))
38612	28752853	YAP inhibitory signals and environmental stresses included the following: serum starvation (16hr), glucose starvation (2-DG, 25mM, 2hr), PKA activation (forskolin, 10muM, 1hr), disruption of F-actin (latrunculin B, 0.1mug/ml, 1hr), Src inhibition (dasatinib, 5muM, 6hr), inhibition of the mevalonate synthesis (cerivastatin, 2muM, 6hr), NaCl (200mM, 6hr), sorbitol (0.5M, 6hr), high cell density (2 day post-confluent), and cell detachment (1hr).	('YAP', 'Gene', (0, 3))	('synthesis', 'biological_process', 'GO:0009058', ('300', '309'))	('mevalonate synthesis', 'MPA', (289, 309))	('high cell density', 'CPA', (378, 395))	('NaCl', 'Chemical', 'MESH:D012965', (337, 341))	('PKA', 'cellular_component', 'GO:0005952', ('137', '140'))	('F-actin', 'Protein', (191, 198))	('NaCl', 'MPA', (337, 341))	('F-actin', 'cellular_component', 'GO:0031941', ('191', '198'))	('PKA', 'molecular_function', 'GO:0004691', ('137', '140'))	('YAP', 'Gene', '10413', (0, 3))	('glucose', 'Chemical', 'MESH:D005947', (99, 106))	('cerivastatin', 'Chemical', 'MESH:C086276', (311, 323))	('mug', 'molecular_function', 'GO:0043739', ('218', '221'))	('mevalonate', 'Chemical', 'MESH:D008798', (289, 299))	('Src', 'Gene', (232, 235))	('disruption', 'Var', (177, 187))	('cell detachment', 'CPA', (424, 439))	('dasatinib', 'Chemical', 'MESH:D000069439', (248, 257))	('latrunculin B', 'Chemical', 'MESH:C037068', (200, 213))	('forskolin', 'Chemical', 'MESH:D005576', (153, 162))	('inhibition', 'NegReg', (271, 281))	('sorbitol', 'Chemical', 'MESH:D013012', (356, 364))	('Src', 'Gene', '6714', (232, 235))
38614	28752853	p38 inhibitors SB203580 (S1076) (40muM) and PH-797840 (S2726) (30muM) were purchased from Selleckchem and cells were treated 2 hr prior to osmotic stress exposure.	('p38', 'Gene', (0, 3))	('SB203580', 'Chemical', 'MESH:C093642', (15, 23))	('S2726', 'Var', (55, 60))	('p38', 'Gene', '1432', (0, 3))
38626	28752853	The following antibodies were purchased from Santa Cruz Biotechnology and used at the indicated dilution for western blot analysis and immunofluorescence: YAP (sc-101199, 1:1000), HA (sc-7392, 1:5000), Myc (sc-40, 1:5000), GAPDH (sc-25778, 1:1000).	('GAPDH', 'Gene', '2597', (223, 228))	('Myc', 'Gene', '4609', (202, 205))	('GAPDH', 'Gene', (223, 228))	('YAP', 'Gene', (155, 158))	('Myc', 'Gene', (202, 205))	('sc-25778', 'Var', (230, 238))	('YAP', 'Gene', '10413', (155, 158))
38654	27847622	Such novel tests include gene expression profiling, which analyzes the RNA expression patterns of tumor cells, and multiplex ligation-dependent probe amplification, which detects deletions or and amplifications of DNA in tumor cells.	('gene expression', 'biological_process', 'GO:0010467', ('25', '40'))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('amplifications', 'Var', (196, 210))	('deletions', 'Var', (179, 188))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('RNA', 'cellular_component', 'GO:0005562', ('71', '74'))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('DNA', 'cellular_component', 'GO:0005574', ('214', '217'))
38666	27847622	According to the authors, patients who retained both copies of chromosome 3 exhibited no metastatic disease within the median follow-up time of 3.4 years, whereas 57 % of patients with monosomy 3 developed metastases.	('monosomy 3', 'Var', (185, 195))	('metastases', 'Disease', 'MESH:D009362', (206, 216))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('metastatic disease', 'CPA', (89, 107))	('patients', 'Species', '9606', (171, 179))	('patients', 'Species', '9606', (26, 34))	('metastases', 'Disease', (206, 216))
38676	27847622	Analysis of tumor samples using FISH has identified monsomy 3 and amplification of 8q in PUM to be associated with poor disease-free 10-year survival in a study by van den Bosh et al..	('poor', 'NegReg', (115, 119))	('monsomy 3', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('amplification of', 'Var', (66, 82))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
38696	27847622	tumor sampling from different sites within the same tumor demonstrated discordance of GEP classification in 11.3 % of cases.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('GEP', 'Gene', (86, 89))	('discordance', 'Var', (71, 82))	('tumor', 'Disease', 'MESH:D009369', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (0, 5))
38713	27847622	Although not useful in prognostication of patients, detection of specific mutations in uveal melanomas may lead to improved therapeutic options in the future.	('uveal melanomas', 'Disease', 'MESH:C536494', (87, 102))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('mutations', 'Var', (74, 83))	('uveal melanomas', 'Disease', (87, 102))	('uveal melanomas', 'Phenotype', 'HP:0007716', (87, 102))	('patients', 'Species', '9606', (42, 50))	('uveal melanoma', 'Phenotype', 'HP:0007716', (87, 101))
38714	27847622	Through a search for mutations in the oncogenic pathway involving RAF, MEK, and ERK, Onken et al.	('ERK', 'Gene', '5594', (80, 83))	('RAF', 'Gene', (66, 69))	('ERK', 'Gene', (80, 83))	('ERK', 'molecular_function', 'GO:0004707', ('80', '83'))	('RAF', 'Gene', '22882', (66, 69))	('oncogenic pathway', 'Pathway', (38, 55))	('MEK', 'Gene', (71, 74))	('MEK', 'Gene', '5609', (71, 74))	('mutations', 'Var', (21, 30))
38715	27847622	first identified a mutation in the stimulatory alpha(q) G protein subunit known as GNAQ in approximately 50 % of PUM samples.	('GNAQ', 'Gene', (83, 87))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('GNAQ', 'Gene', '2776', (83, 87))	('mutation', 'Var', (19, 27))
38717	27847622	discovered that mutations in the protein GNA11, a paralogue of GNAQ, were found in 32 % of PUM samples and 57 % of PUM metastases.	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('found', 'Reg', (74, 79))	('GNAQ', 'Gene', '2776', (63, 67))	('mutations', 'Var', (16, 25))	('metastases', 'Disease', (119, 129))	('GNA11', 'Gene', (41, 46))	('GNAQ', 'Gene', (63, 67))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
38718	27847622	Furthermore, the authors found that mutations in GNA11 were sufficient to induce metastases in a mouse model.	('mutations', 'Var', (36, 45))	('metastases', 'Disease', (81, 91))	('mouse', 'Species', '10090', (97, 102))	('metastases', 'Disease', 'MESH:D009362', (81, 91))	('GNA11', 'Gene', (49, 54))	('induce', 'Reg', (74, 80))
38719	27847622	Mutations in GNAQ and GNA11 affect a critical oncogenic signaling cascade that affects the metastatic potential of tumors.	('affect', 'Reg', (28, 34))	('GNA11', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('oncogenic signaling cascade', 'Pathway', (46, 73))	('GNAQ', 'Gene', (13, 17))	('signaling cascade', 'biological_process', 'GO:0007165', ('56', '73'))	('tumors', 'Disease', (115, 121))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('affects', 'Reg', (79, 86))	('GNAQ', 'Gene', '2776', (13, 17))
38720	27847622	demonstrated that identification of specific mutations may have prognostic significance when combined with the chromosome 3 status of the tumor.	('mutations', 'Var', (45, 54))	('tumor', 'Disease', (138, 143))	('chromosome', 'cellular_component', 'GO:0005694', ('111', '121'))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
38721	27847622	In their study of 63 cases of PUM, GNA11 and BAP1 mutations were associated with a greater metastatic risk while a mutation in EIF1AX was associated with a lower metastatic risk within the 48 months of follow up.	('BAP1', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('BAP1', 'Gene', '8314', (45, 49))	('metastatic', 'CPA', (91, 101))	('EIF1AX', 'Gene', (127, 133))	('EIF1AX', 'Gene', '1964', (127, 133))	('GNA11', 'Gene', (35, 40))	('PUM', 'Disease', (30, 33))
38725	27847622	Although sensitive in detecting large chromosomal abnormalities such as monosomy 3, karyotype analysis, FISH, and CGH have largely been replaced by more recently developed prognostic tests like GEP and MLPA.	('large chromosomal abnormalities', 'Phenotype', 'HP:0040012', (32, 63))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (38, 63))	('monosomy 3', 'Var', (72, 82))	('chromosomal abnormalities', 'Disease', (38, 63))
38728	27847622	MLPA detects deletions and amplifications of DNA in tumor cells, and it offers information about the common chromosomal abnormalities associated with metastatic risk in PUM.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('amplifications', 'Var', (27, 41))	('deletions', 'Var', (13, 22))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('MLPA', 'Gene', (0, 4))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (108, 133))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('chromosomal abnormalities', 'Disease', (108, 133))
38745	23420605	Src tyrosine kinase family (SFK) members are known to be overexpressed and/or activated in many primary types of human cancer, typically through the mutational activation of upstream growth factor receptor tyrosine kinases.	('mutational', 'Var', (149, 159))	('activated', 'PosReg', (78, 87))	('activation', 'PosReg', (160, 170))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('Src', 'Gene', (0, 3))	('Src', 'Gene', '6714', (0, 3))	('cancer', 'Disease', (119, 125))	('overexpressed', 'PosReg', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('human', 'Species', '9606', (113, 118))
38755	23420605	The following primary antibodies (Ab) were used: Rabbit polyclonal antibody specific for GAPDH (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA); Src, phospho-SrcTyr416, phospho-ERK1/2Thr202/Tyr204 and ERK1/2 (Cell Signaling Technology, Inc., Beverly, MA, USA).	('Src', 'Gene', (150, 153))	('Src', 'Gene', '6714', (150, 153))	('Rabbit', 'Species', '9986', (49, 55))	('Src', 'Gene', '6714', (163, 166))	('antibody', 'cellular_component', 'GO:0042571', ('67', '75'))	('phospho-ERK1/2Thr202/Tyr204', 'Var', (174, 201))	('antibody', 'cellular_component', 'GO:0019815', ('67', '75'))	('Tyr204', 'Chemical', '-', (195, 201))	('antibody', 'cellular_component', 'GO:0019814', ('67', '75'))	('ERK1', 'molecular_function', 'GO:0004707', ('206', '210'))	('antibody', 'molecular_function', 'GO:0003823', ('67', '75'))	('ERK1', 'molecular_function', 'GO:0004707', ('182', '186'))	('Signaling', 'biological_process', 'GO:0023052', ('219', '228'))	('Src', 'Gene', (163, 166))	('GAPDH', 'Gene', '2597', (89, 94))	('GAPDH', 'Gene', (89, 94))
38765	23420605	Mel-p and A375 cells were plated overnight in 6-well dishes in the presence or absence of dasatinib (30 nM) or U0126 (10 muM).	('30 nM', 'Var', (101, 106))	('muM', 'Gene', '56925', (121, 124))	('A375', 'CellLine', 'CVCL:0132', (10, 14))	('U0126', 'Chemical', 'MESH:C113580', (111, 116))	('muM', 'Gene', (121, 124))	('dasatinib', 'Chemical', 'MESH:D000069439', (90, 99))
38774	23420605	Recently, Maat et al demonstrated that inhibition of Src led to the growth reduction of primary uveal melanoma cultures and cell lines, whereas metastatic cell line growth was only slightly reduced.	('Src', 'Gene', (53, 56))	('inhibition', 'Var', (39, 49))	('Src', 'Gene', '6714', (53, 56))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (88, 110))	('primary uveal melanoma', 'Disease', (88, 110))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('reduction', 'NegReg', (75, 84))	('growth', 'CPA', (68, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))
38794	23420605	Treatment with the MEK inhibitor, U0126, resulted in a significant decrease in cell proliferation in Mel-p cells compared with vehicle control-treated cells.	('U0126', 'Chemical', 'MESH:C113580', (34, 39))	('MEK', 'Gene', '5609', (19, 22))	('decrease', 'NegReg', (67, 75))	('cell proliferation', 'biological_process', 'GO:0008283', ('79', '97'))	('U0126', 'Var', (34, 39))	('cell proliferation in Mel-p cells', 'CPA', (79, 112))	('MEK', 'Gene', (19, 22))
38795	23420605	However, 20 muM U0126 did not significantly decrease the growth of A375 cells.	('U0126', 'Var', (16, 21))	('muM', 'Gene', '56925', (12, 15))	('U0126', 'Chemical', 'MESH:C113580', (16, 21))	('A375', 'CellLine', 'CVCL:0132', (67, 71))	('muM', 'Gene', (12, 15))
38799	23420605	Notably, U0126 induced a level of cell rounding in Mel-p cells similar to that induced by dasatinib treatment (Fig.	('cell rounding', 'CPA', (34, 47))	('U0126', 'Var', (9, 14))	('dasatinib', 'Chemical', 'MESH:D000069439', (90, 99))	('U0126', 'Chemical', 'MESH:C113580', (9, 14))
38807	23420605	Dasatinib caused complete or near-complete inhibition of Src activity, as measured by phosphorylation at Y416 in western blot analysis following treatment overnight with concentrations >=30 nM (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('86', '101'))	('Src', 'Gene', (57, 60))	('Src', 'Gene', '6714', (57, 60))	('inhibition', 'NegReg', (43, 53))	('Dasatinib', 'Chemical', 'MESH:D000069439', (0, 9))	('Y416', 'Var', (105, 109))
38815	23420605	Thus, nuclear translocation of activated pERK1/2 is impaired in dasatinib-treated cells, suggesting that dasatinib disrupts ERK1/2 signaling.	('ERK1/2 signaling', 'MPA', (124, 140))	('impaired', 'NegReg', (52, 60))	('dasatinib', 'Chemical', 'MESH:D000069439', (105, 114))	('dasatinib', 'Chemical', 'MESH:D000069439', (64, 73))	('nuclear translocation', 'MPA', (6, 27))	('dasatinib', 'Var', (105, 114))	('disrupts', 'NegReg', (115, 123))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('ERK1', 'molecular_function', 'GO:0004707', ('124', '128'))
38817	23420605	In the present study, we have demonstrated that dasatinib induces morphological (abored formation) differentiation in Mel-p cells.	('induces', 'Reg', (58, 65))	('dasatinib', 'Var', (48, 57))	('formation', 'biological_process', 'GO:0009058', ('88', '97'))	('dasatinib', 'Chemical', 'MESH:D000069439', (48, 57))
38820	22485156	Development of a Unique Small Molecule Modulator of CXCR4 Metastasis, the spread and growth of tumor cells to distant organ sites, represents the most devastating attribute and plays a major role in the morbidity and mortality of cancer.	('CXCR4', 'molecular_function', 'GO:0038147', ('52', '57'))	('Modulator', 'Var', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
38851	22485156	While AMD3100 can benefit patients with certain diseases, it can also induce lung or liver fibrosis, and the mobilized cells may act as potential cancer stem cells.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('AMD3100', 'Var', (6, 13))	('liver fibrosis', 'Disease', (85, 99))	('benefit', 'PosReg', (18, 25))	('patients', 'Species', '9606', (26, 34))	('induce', 'PosReg', (70, 76))	('liver fibrosis', 'Disease', 'MESH:D008103', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('lung', 'Disease', (77, 81))	('liver fibrosis', 'Phenotype', 'HP:0001395', (85, 99))
38854	22485156	In addition, we reported that TN14003 blocks bleomycin-induced lung fibrosis.	('TN14003', 'Var', (30, 37))	('bleomycin-induced', 'MPA', (45, 62))	('lung fibrosis', 'Disease', (63, 76))	('blocks', 'NegReg', (38, 44))	('lung fibrosis', 'Phenotype', 'HP:0002206', (63, 76))	('bleomycin', 'Chemical', 'MESH:D001761', (45, 54))	('lung fibrosis', 'Disease', 'MESH:D005355', (63, 76))
38857	22485156	Initially, we proposed that inclusion of a nitrogen atom in each of the terminal aromatic rings (i.e., pyridyl instead of phenyl) might impede rapid oxidative metabolism and improve inhibitor pharmacokinetic profiles.	('inhibitor pharmacokinetic profiles', 'MPA', (182, 216))	('rapid oxidative metabolism', 'MPA', (143, 169))	('improve', 'PosReg', (174, 181))	('nitrogen', 'Chemical', 'MESH:D009584', (43, 51))	('pyridyl', 'Var', (103, 110))	('impede', 'NegReg', (136, 142))	('oxidative metabolism', 'biological_process', 'GO:0045333', ('149', '169'))	('inclusion', 'Var', (28, 37))
38872	22485156	We previously reported that TN14003 effectively blocks CXCL12-mediated invasion of MDA-MB-231 cells in a Matrigel invasion assay using CXCL12 as a chemoattractant.	('blocks', 'NegReg', (48, 54))	('Matrigel invasion assay', 'CPA', (105, 128))	('CXCL12-mediated', 'MPA', (55, 70))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (83, 93))	('TN14003', 'Var', (28, 35))
38876	22485156	As a GPCR, CXCR4 binds CXCL12 and activates G-protein mediated signaling through the Galphai pathway that reduces cAMP levels within cells.	('reduces', 'NegReg', (106, 113))	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('cAMP', 'Chemical', 'MESH:D000242', (114, 118))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('CXCR4', 'Var', (11, 16))	('cAMP levels', 'MPA', (114, 125))	('CXCL12', 'MPA', (23, 29))	('CXCR4', 'molecular_function', 'GO:0038147', ('11', '16'))	('activates', 'PosReg', (34, 43))	('G-protein', 'MPA', (44, 53))	('Galphai pathway', 'Pathway', (85, 100))
38877	22485156	While MSX-122 counteracted CXCL12 function effectively at concentrations as low as 10 nM, 1000 nM AMD3100 was required to significantly block CXCL12 function ( Figure 3A ).	('block', 'NegReg', (136, 141))	('CXCL12 function', 'MPA', (142, 157))	('MSX-122', 'Chemical', 'MESH:C573792', (6, 13))	('AMD3100', 'Var', (98, 105))
38882	22485156	Two other in vitro assays demonstrated that MSX-122 exhibits a different profile than AMD3100 and other reported anti-CXCR4 compounds: (1) MSX-122 did not inhibit T-tropic HIV infection (via the formation of the CXCR4/CD4/GP120 complex), while AMD3100 did; and (2) unlike AMD3100, MSX-122 proved to be inactive in our calcium flux assay.	('CD', 'Phenotype', 'HP:0100280', (218, 220))	('HIV infection', 'Disease', (172, 185))	('MSX-122', 'Chemical', 'MESH:C573792', (44, 51))	('MSX-122', 'Chemical', 'MESH:C573792', (139, 146))	('CXCR4', 'molecular_function', 'GO:0038147', ('118', '123'))	('formation', 'biological_process', 'GO:0009058', ('195', '204'))	('calcium', 'Chemical', 'MESH:D002118', (318, 325))	('HIV infection', 'Disease', 'MESH:D015658', (172, 185))	('MSX-122', 'Chemical', 'MESH:C573792', (281, 288))	('CXCR4', 'molecular_function', 'GO:0038147', ('212', '217'))	('MSX-122', 'Var', (139, 146))	('CD4', 'Gene', (218, 221))	('inhibit', 'NegReg', (155, 162))	('CD4', 'Gene', '12504', (218, 221))
38890	22485156	Consistent with the histological differences, a marked decrease in neutrophil infiltration into the injured tissue (as assessed by myeloperoxidase (MPO) activity) was observed in DSS/MSX-122 treated mice when compared with DSS treated mice ( Figure 4C ).	('MSX-122', 'Chemical', 'MESH:C573792', (183, 190))	('mice', 'Species', '10090', (199, 203))	('myeloperoxidase', 'Gene', (131, 146))	('DSS/MSX-122', 'Var', (179, 190))	('DSS', 'Chemical', 'MESH:D016264', (179, 182))	('MPO', 'Gene', (148, 151))	('DSS', 'Chemical', 'MESH:D016264', (223, 226))	('decrease', 'NegReg', (55, 63))	('MPO', 'Gene', '17523', (148, 151))	('myeloperoxidase', 'Gene', '17523', (131, 146))	('mice', 'Species', '10090', (235, 239))	('neutrophil infiltration into the', 'MPA', (67, 99))	('MPO', 'molecular_function', 'GO:0004601', ('148', '151'))
38891	22485156	To elucidate whether MSX-122 action inhibits T-lymphocyte infiltration in colonic mucosa, we determined the number of CD4+ T-cells by immunohistochemical analysis and found it to be markedly decreased in DSS/MSX-122-treated mice relative to DSS-treated mice ( Figure 4D ).	('mice', 'Species', '10090', (253, 257))	('MSX-122', 'Gene', (21, 28))	('mice', 'Species', '10090', (224, 228))	('DSS', 'Chemical', 'MESH:D016264', (241, 244))	('T-lymphocyte infiltration in', 'CPA', (45, 73))	('MSX-122', 'Chemical', 'MESH:C573792', (208, 215))	('CD4', 'Gene', (118, 121))	('inhibits', 'NegReg', (36, 44))	('colonic mucosa', 'Disease', 'MESH:D015179', (74, 88))	('MSX-122', 'Chemical', 'MESH:C573792', (21, 28))	('DSS/MSX-122-treated', 'Var', (204, 223))	('decreased', 'NegReg', (191, 200))	('CD4', 'Gene', '12504', (118, 121))	('colonic mucosa', 'Disease', (74, 88))	('CD', 'Phenotype', 'HP:0100280', (118, 120))	('DSS', 'Chemical', 'MESH:D016264', (204, 207))
38892	22485156	These data clearly demonstrate that inflammation was far less severe in MSX-122-treated vs. DSS-treated mice.	('inflammation', 'biological_process', 'GO:0006954', ('36', '48'))	('DSS', 'Chemical', 'MESH:D016264', (92, 95))	('inflammation', 'Disease', 'MESH:D007249', (36, 48))	('mice', 'Species', '10090', (104, 108))	('inflammation', 'Disease', (36, 48))	('MSX-122-treated', 'Var', (72, 87))	('MSX-122', 'Chemical', 'MESH:C573792', (72, 79))
38895	22485156	By comparison, the number of CXCR4-positive cells was markedly decreased in DSS/MSX122 treated animals relative to the DSS-treated group ( Figures 4E, F ).	('DSS', 'Chemical', 'MESH:D016264', (119, 122))	('CXCR4', 'molecular_function', 'GO:0038147', ('29', '34'))	('decreased', 'NegReg', (63, 72))	('DSS/MSX122', 'Var', (76, 86))	('MSX122', 'Chemical', 'MESH:C573792', (80, 86))	('DSS', 'Chemical', 'MESH:D016264', (76, 79))
38901	22485156	As a consequence, we conclude that the inhibtion of CXCR4 alters the cytokine profiles within the mucosa of DSS-treated mice.	('mice', 'Species', '10090', (120, 124))	('cytokine profiles', 'MPA', (69, 86))	('alters', 'Reg', (58, 64))	('DSS', 'Chemical', 'MESH:D016264', (108, 111))	('CXCR4', 'molecular_function', 'GO:0038147', ('52', '57'))	('inhibtion', 'Var', (39, 48))
38903	22485156	To demonstrate that MSX-122 attenuates the level of TNF-alpha, a critical inflammatory cytokine, we assessed TNF-alpha secretion by J774A.1 macrophages infected with invasive E coli isolated from inflamed mucosa of patients with CD, LF82, and 13I, or non-pathogenic EFC-1 as a control.	('patients', 'Species', '9606', (215, 223))	('CD', 'Phenotype', 'HP:0100280', (229, 231))	('attenuates', 'NegReg', (28, 38))	('E coli', 'Species', '562', (175, 181))	('TNF-alpha secretion', 'biological_process', 'GO:1990774', ('109', '128'))	('LF82', 'Species', '591946', (233, 237))	('TNF-alpha', 'Gene', (52, 61))	('MSX-122', 'Var', (20, 27))	('LF82', 'Var', (233, 237))	('TNF-alpha', 'Gene', '21926', (109, 118))	('MSX-122', 'Chemical', 'MESH:C573792', (20, 27))	('TNF-alpha', 'Gene', (109, 118))	('TNF-alpha', 'Gene', '21926', (52, 61))
38912	22485156	Previously, we had studied the role of the CXCL12/CXCR4-axis in a rodent model of bleomycin-induced lung injury and reported that TN14003 blocked bleomycin-induced lung fibrosis.	('lung injury', 'Disease', (100, 111))	('TN14003', 'Var', (130, 137))	('lung fibrosis', 'Disease', (164, 177))	('bleomycin', 'Chemical', 'MESH:D001761', (146, 155))	('lung fibrosis', 'Phenotype', 'HP:0002206', (164, 177))	('lung fibrosis', 'Disease', 'MESH:D005355', (164, 177))	('CXCR4', 'molecular_function', 'GO:0038147', ('50', '55'))	('bleomycin', 'Chemical', 'MESH:D001761', (82, 91))	('lung injury', 'Disease', 'MESH:D055370', (100, 111))
38916	22485156	Thus, treatment with MSX-122ms completely prevented bleomycin-induced lung fibrosis, demonstrating superiority over TN14003.	('MSX-122ms', 'Var', (21, 30))	('lung fibrosis', 'Disease', 'MESH:D005355', (70, 83))	('MSX-122ms', 'Chemical', '-', (21, 30))	('bleomycin', 'Chemical', 'MESH:D001761', (52, 61))	('lung fibrosis', 'Disease', (70, 83))	('prevented', 'NegReg', (42, 51))	('lung fibrosis', 'Phenotype', 'HP:0002206', (70, 83))
38919	22485156	All untreated control mice developed lung metastases ( Figure 6A  top), while the group treated with MSX-122ms, i.p.	('MSX-122ms', 'Var', (101, 110))	('lung metastases', 'Disease', 'MESH:D009362', (37, 52))	('MSX-122ms', 'Chemical', '-', (101, 110))	('lung metastases', 'Disease', (37, 52))	('mice', 'Species', '10090', (22, 26))
38922	22485156	The anti-metastatic efficacy of MSX-122ms was confirmed in a model for SCCHN metastasis known for the critical role of CXCR4 in metastatic progression using [18F]FDG-PET which is a standard imaging tool to detect lung metastasis in clinic.	('CXCR4', 'molecular_function', 'GO:0038147', ('119', '124'))	('MSX-122ms', 'Chemical', '-', (32, 41))	('SCCHN metastasis', 'Disease', (71, 87))	('MSX-122ms', 'Var', (32, 41))
38925	22485156	By contrast, the arm administered with MSX-122ms showed no evidence of metastases, similar to TN14003.	('MSX-122ms', 'Chemical', '-', (39, 48))	('MSX-122ms', 'Var', (39, 48))	('metastases', 'Disease', (71, 81))	('metastases', 'Disease', 'MESH:D009362', (71, 81))
38940	22485156	We observed that DSS/MSX-122-treated mice had shown only moderate signs of inflammation compared to DSS-treated mice.	('inflammation', 'biological_process', 'GO:0006954', ('75', '87'))	('DSS/MSX-122-treated', 'Var', (17, 36))	('DSS', 'Chemical', 'MESH:D016264', (17, 20))	('DSS', 'Chemical', 'MESH:D016264', (100, 103))	('inflammation', 'Disease', 'MESH:D007249', (75, 87))	('inflammation', 'Disease', (75, 87))	('MSX-122', 'Chemical', 'MESH:C573792', (21, 28))	('mice', 'Species', '10090', (112, 116))	('mice', 'Species', '10090', (37, 41))
38950	22485156	As predicted, CXCL12 blocked binding of [18F]MSX-122F to CXCR4.	('binding', 'molecular_function', 'GO:0005488', ('29', '36'))	('MSX-122F', 'Chemical', '-', (45, 53))	('CXCR4', 'molecular_function', 'GO:0038147', ('57', '62'))	('[18F]', 'Var', (40, 45))	('MSX-122F', 'Gene', (45, 53))	('binding', 'Interaction', (29, 36))
39007	19553629	Human uveal melanoma cells were transfected with CXCR4 siRNA or control siRNA and tested in vitro for chemotactic and invasive behavior in response to soluble factors produced by human liver cells.	('Human', 'Species', '9606', (0, 5))	('human', 'Species', '9606', (179, 184))	('uveal melanoma', 'Disease', (6, 20))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('CXCR4', 'Var', (49, 54))	('soluble', 'cellular_component', 'GO:0005625', ('151', '158'))	('CXCR4', 'molecular_function', 'GO:0038147', ('49', '54'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (6, 20))	('uveal melanoma', 'Disease', 'MESH:C536494', (6, 20))
39010	19553629	Similarly, blocking CXCR4 gene expression by transfection with CXCR4 siRNA inhibited both the chemotactic and the invasive properties of uveal melanoma cells exposed to factors produced by human livers.	('CXCR4', 'molecular_function', 'GO:0038147', ('63', '68'))	('human', 'Species', '9606', (189, 194))	('CXCR4', 'Var', (63, 68))	('inhibited', 'NegReg', (75, 84))	('gene expression', 'biological_process', 'GO:0010467', ('26', '41'))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('uveal melanoma', 'Phenotype', 'HP:0007716', (137, 151))	('uveal melanoma', 'Disease', 'MESH:C536494', (137, 151))	('CXCR4', 'molecular_function', 'GO:0038147', ('20', '25'))	('chemotactic and', 'CPA', (94, 109))	('uveal melanoma', 'Disease', (137, 151))
39011	19553629	Uveal melanoma cells transfected with CXCR4 siRNA produced fewer liver metastases than untreated uveal melanoma cells or uveal melanoma cells transfected with control siRNA.	('CXCR4', 'Var', (38, 43))	('CXCR4', 'molecular_function', 'GO:0038147', ('38', '43'))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('fewer', 'NegReg', (59, 64))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('uveal melanoma', 'Disease', 'MESH:C536494', (121, 135))	('melanoma', 'Disease', (103, 111))	('uveal melanoma', 'Disease', (121, 135))	('liver metastases', 'Disease', (65, 81))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('uveal melanoma', 'Phenotype', 'HP:0007716', (121, 135))	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('uveal melanoma', 'Disease', (97, 111))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('liver metastases', 'Disease', 'MESH:D009362', (65, 81))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
39043	19553629	Primers used in the real-time RT-PCR were specific for human hypoxanthine phosphoribosyl transferase (hHPRT) sense primer 5'-GACCAGTCAACAGGGGACAT-3', antisense primer 5'-AAGCAGATGGCCACAGAACT-3', mouse glyceraldehyde 3-phosphate dehydrogenase (GAPDH) sense 5'-ACTCACGGCAAATTCAACGGC-3', and antisense 5'-ATCACAAACATGGGGGCATCG-3'.	('GAPDH', 'Gene', (243, 248))	("antisense 5'-ATCACAAACATGGGGGCATCG-3", 'Var', (289, 325))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '14433', (201, 241))	('hHPRT', 'Gene', '3251', (102, 107))	('human', 'Species', '9606', (55, 60))	('hHPRT', 'Gene', (102, 107))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (201, 241))	('GAPDH', 'Gene', '14433', (243, 248))	('mouse', 'Species', '10090', (195, 200))
39047	19553629	The average DeltaCt of each group was calculated with the following formula: DeltaCt = average hHPRT gene Ct - average mGAPDH gene Ct. DeltaDeltaCt was calculated by DeltaDeltaCt = DeltaCt of control SiRNA group - DeltaCt CXCR4 SiRNA group.	('GAPDH', 'Gene', (120, 125))	('DeltaDeltaCt', 'Var', (166, 178))	('CXCR4', 'molecular_function', 'GO:0038147', ('222', '227'))	('hHPRT', 'Gene', '3251', (95, 100))	('hHPRT', 'Gene', (95, 100))	('GAPDH', 'Gene', '14433', (120, 125))
39055	19553629	Liver metastases were induced by injecting OCM3 uveal melanoma cells, OCM3 cells transfected with CXCR4 siRNA, or OCM3 cells transfected with control SiRNA.	('uveal melanoma', 'Disease', (48, 62))	('metastases', 'Disease', 'MESH:D009362', (6, 16))	('induced', 'Reg', (22, 29))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('CXCR4 siRNA', 'Var', (98, 109))	('CXCR4', 'molecular_function', 'GO:0038147', ('98', '103'))	('metastases', 'Disease', (6, 16))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (48, 62))
39071	19553629	Therefore, OCM3 human uveal melanoma cells were selected for further study and were transfected with either CXCR4 siRNA or control siRNA.	('CXCR4 siRNA', 'Var', (108, 119))	('uveal melanoma', 'Phenotype', 'HP:0007716', (22, 36))	('uveal melanoma', 'Disease', 'MESH:C536494', (22, 36))	('CXCR4', 'molecular_function', 'GO:0038147', ('108', '113'))	('uveal melanoma', 'Disease', (22, 36))	('human', 'Species', '9606', (16, 21))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
39072	19553629	The results demonstrate that transfection with CXCR4 siRNA produced a profound reduction in CXCR4 gene expression in OCM3 uveal melanoma cells (Fig.	('CXCR4 gene expression', 'MPA', (92, 113))	('gene expression', 'biological_process', 'GO:0010467', ('98', '113'))	('CXCR4', 'molecular_function', 'GO:0038147', ('92', '97'))	('CXCR4', 'molecular_function', 'GO:0038147', ('47', '52'))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('CXCR4 siRNA', 'Var', (47, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (122, 136))	('uveal melanoma', 'Disease', (122, 136))	('uveal melanoma', 'Disease', 'MESH:C536494', (122, 136))	('reduction', 'NegReg', (79, 88))
39073	19553629	Flow cytometric analysis revealed that transfection with CXCR4 siRNA produced a significant reduction in the number of OCM3 uveal melanoma cells expressing CXCR4, whereas transfection with control siRNA had no effect on CXCR4 expression (Fig.	('CXCR4', 'MPA', (156, 161))	('uveal melanoma', 'Phenotype', 'HP:0007716', (124, 138))	('uveal melanoma', 'Disease', (124, 138))	('uveal melanoma', 'Disease', 'MESH:C536494', (124, 138))	('CXCR4', 'molecular_function', 'GO:0038147', ('220', '225'))	('CXCR4', 'molecular_function', 'GO:0038147', ('57', '62'))	('reduction', 'NegReg', (92, 101))	('CXCR4', 'molecular_function', 'GO:0038147', ('156', '161'))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('CXCR4', 'Var', (57, 62))
39077	19553629	OCM3 uveal melanoma cells transfected with CXCR4 siRNA demonstrated significantly (P < 0.001) reduced chemotactic responses to soluble factors produced by human liver cells (Fig.	('reduced', 'NegReg', (94, 101))	('human', 'Species', '9606', (155, 160))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('soluble', 'cellular_component', 'GO:0005625', ('127', '134'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (5, 19))	('uveal melanoma', 'Disease', (5, 19))	('uveal melanoma', 'Disease', 'MESH:C536494', (5, 19))	('CXCR4', 'molecular_function', 'GO:0038147', ('43', '48'))	('CXCR4', 'Var', (43, 48))
39087	19553629	Untreated OCM3 uveal melanoma cells and OCM3 melanoma cells transfected with CXCR4 siRNA or control siRNA were cultured for 48 hours, and cell proliferation was assessed by incorporation of tritiated thymidine.	('CXCR4', 'molecular_function', 'GO:0038147', ('77', '82'))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))	('uveal melanoma', 'Phenotype', 'HP:0007716', (15, 29))	('uveal melanoma', 'Disease', (15, 29))	('uveal melanoma', 'Disease', 'MESH:C536494', (15, 29))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('cell proliferation', 'biological_process', 'GO:0008283', ('138', '156'))	('melanoma', 'Disease', (21, 29))	('tritiated thymidine', 'Chemical', '-', (190, 209))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))	('CXCR4', 'Var', (77, 82))
39088	19553629	The results show that transfection with either CXCR4 siRNA or control siRNA had no affect on the proliferation of OCM3 uveal melanoma cells (Fig.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('CXCR4', 'molecular_function', 'GO:0038147', ('47', '52'))	('CXCR4 siRNA', 'Var', (47, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (119, 133))	('uveal melanoma', 'Phenotype', 'HP:0007716', (119, 133))	('uveal melanoma', 'Disease', (119, 133))
39096	19553629	Histopathologic examination of livers from the same mice confirmed that mice challenged with CXCR4 siRNA-treated OCM3 uveal melanoma cells had a reduced burden of liver metastases than mice challenged with either untreated OCM3 melanoma cells or OCM3 melanoma cells transfected with control siRNA (Fig.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('reduced', 'NegReg', (145, 152))	('uveal melanoma', 'Phenotype', 'HP:0007716', (118, 132))	('melanoma', 'Disease', 'MESH:D008545', (228, 236))	('mice', 'Species', '10090', (52, 56))	('liver metastases', 'Disease', 'MESH:D009362', (163, 179))	('CXCR4 siRNA-treated', 'Var', (93, 112))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('melanoma', 'Disease', (251, 259))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('mice', 'Species', '10090', (185, 189))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('melanoma', 'Disease', (228, 236))	('liver metastases', 'Disease', (163, 179))	('uveal melanoma', 'Disease', (118, 132))	('uveal melanoma', 'Disease', 'MESH:C536494', (118, 132))	('CXCR4', 'molecular_function', 'GO:0038147', ('93', '98'))	('mice', 'Species', '10090', (72, 76))	('melanoma', 'Disease', 'MESH:D008545', (251, 259))
39106	19553629	Inhibition of CXCR4 with antibodies or peptide antagonists has been reported to reduce tumor metastasis.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor metastasis', 'Disease', 'MESH:D009362', (87, 103))	('CXCR4', 'MPA', (14, 19))	('Inhibition', 'Var', (0, 10))	('tumor metastasis', 'Disease', (87, 103))	('reduce', 'NegReg', (80, 86))	('CXCR4', 'molecular_function', 'GO:0038147', ('14', '19'))
39108	19553629	However, a recent in vivo study in nude mice reported that instead of producing an antitumor effect, treatment with AMD3100 stimulated the growth of human epithelial carcinoma cells that were stably transfected with a mutant form of CXCR4.	('nude mice', 'Species', '10090', (35, 44))	('AMD3100', 'Gene', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('CXCR4', 'molecular_function', 'GO:0038147', ('233', '238'))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('tumor', 'Disease', (87, 92))	('human', 'Species', '9606', (149, 154))	('epithelial carcinoma', 'Disease', 'MESH:D002277', (155, 175))	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (155, 175))	('epithelial carcinoma', 'Disease', (155, 175))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mutant', 'Var', (218, 224))	('growth', 'MPA', (139, 145))	('stimulated', 'PosReg', (124, 134))
39109	19553629	By contrast, studies in mice have shown that the blockade of CXCR4 expression via siRNA or RNAi knockdown produced significant reductions in the metastasis of breast cancer.	('knockdown', 'Var', (96, 105))	('CXCR4', 'molecular_function', 'GO:0038147', ('61', '66'))	('mice', 'Species', '10090', (24, 28))	('RNAi', 'Gene', (91, 95))	('siRNA', 'Gene', (82, 87))	('RNAi', 'biological_process', 'GO:0016246', ('91', '95'))	('reductions', 'NegReg', (127, 137))	('blockade', 'Var', (49, 57))	('metastasis of breast cancer', 'Disease', 'MESH:D009362', (145, 172))	('CXCR4 expression', 'MPA', (61, 77))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('metastasis of breast cancer', 'Disease', (145, 172))
39123	19553629	Other evidence suggesting the limited efficacy of CXCR4-targeted therapy comes from studies showing that blockade of CXCR4/CXCL12 interactions can significantly reduce the initial seeding of pulmonary metastases of skin melanomas in mice but does not affect the growth of lung metastases once they have become established.	('blockade', 'Var', (105, 113))	('mice', 'Species', '10090', (233, 237))	('pulmonary metastases of skin melanomas', 'Disease', (191, 229))	('reduce', 'NegReg', (161, 167))	('CXCR4', 'molecular_function', 'GO:0038147', ('50', '55'))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('melanomas', 'Phenotype', 'HP:0002861', (220, 229))	('lung metastases', 'Disease', (272, 287))	('CXCR4', 'molecular_function', 'GO:0038147', ('117', '122'))	('lung metastases', 'Disease', 'MESH:D009362', (272, 287))	('pulmonary metastases of skin melanomas', 'Disease', 'MESH:D009362', (191, 229))
39132	19553629	The ligand for c-Met, HGF/SF, is present in the liver, and when it engages c-Met, it stimulates the growth and invasiveness of melanoma cells in the liver.	('c-Met', 'Var', (75, 80))	('stimulates', 'PosReg', (85, 95))	('ligand', 'molecular_function', 'GO:0005488', ('4', '10'))	('invasiveness of melanoma', 'Disease', (111, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('invasiveness of melanoma', 'Disease', 'MESH:D008545', (111, 135))	('HGF/SF', 'Gene', (22, 28))	('HGF/SF', 'Gene', '3082', (22, 28))
39136	19553629	Uveal melanoma cells also express c-Met, which engages HGF/SF in the liver and serves as the soil that promotes the growth and progression of liver metastases.	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('progression', 'CPA', (127, 138))	('liver metastases', 'Disease', (142, 158))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('HGF/SF', 'Gene', '3082', (55, 61))	('c-Met', 'Var', (34, 39))	('HGF/SF', 'Gene', (55, 61))	('promotes', 'PosReg', (103, 111))	('liver metastases', 'Disease', 'MESH:D009362', (142, 158))	('growth', 'CPA', (116, 122))	('melanoma', 'Disease', (6, 14))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
39210	32726977	Targeting Epigenetic Modifications in Uveal Melanoma Uveal melanoma (UM), the most common intraocular malignancy in adults, is a rare subset of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('intraocular malignancy', 'Disease', 'MESH:D009798', (90, 112))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('Targeting Epigenetic Modifications', 'Var', (0, 34))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('Melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (144, 152))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('intraocular malignancy', 'Disease', (90, 112))	('Melanoma', 'Disease', 'MESH:D008545', (44, 52))	('Melanoma', 'Disease', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
39213	32726977	Epigenetic dysregulation consisting of aberrant DNA methylation, histone modifications, and small non-coding RNA expression, silencing tumor suppressor genes, or activating oncogenes, have been shown to play a significant role in UM initiation and progression.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('135', '151'))	('histone', 'MPA', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('DNA', 'Protein', (48, 51))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('tumor', 'Disease', (135, 140))	('silencing', 'MPA', (125, 134))	('tumor suppressor', 'biological_process', 'GO:0051726', ('135', '151'))	('UM', 'Phenotype', 'HP:0007716', (230, 232))	('DNA methylation', 'biological_process', 'GO:0006306', ('48', '63'))	('RNA', 'cellular_component', 'GO:0005562', ('109', '112'))	('small', 'MPA', (92, 97))	('aberrant', 'Var', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
39218	32726977	G protein subunit alpha q (GNAQ) and G protein subunit alpha 11 (GNA11) hotspot mutations, present in 83% of UM, are considered to be initiating events in UM tumorigenesis.	('G protein subunit alpha q', 'Gene', (0, 25))	('tumor', 'Disease', (158, 163))	('GNAQ', 'Gene', '2776', (27, 31))	('UM', 'Phenotype', 'HP:0007716', (155, 157))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('mutations', 'Var', (80, 89))	('protein', 'cellular_component', 'GO:0003675', ('2', '9'))	('GNAQ', 'Gene', (27, 31))	('G protein subunit alpha 11', 'Gene', '2767', (37, 63))	('GNA11', 'Gene', '2767', (65, 70))	('GNA11', 'Gene', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('UM', 'Phenotype', 'HP:0007716', (109, 111))	('G protein subunit alpha 11', 'Gene', (37, 63))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('G protein subunit alpha q', 'Gene', '2776', (0, 25))
39219	32726977	Loss-of-function mutations in the BRCA1 associated protein 1 (BAP1) gene, located on 3p21, accompanied by decreased BAP1 mRNA and protein expression, have been identified in M3-UM, indicating that BAP1 abnormalities are highly correlated with the development of UM metastases.	('decreased', 'NegReg', (106, 115))	('Loss-of-function', 'NegReg', (0, 16))	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('metastases', 'Disease', (265, 275))	('p21', 'Gene', (86, 89))	('BAP1', 'Gene', (116, 120))	('UM', 'Phenotype', 'HP:0007716', (262, 264))	('metastases', 'Disease', 'MESH:D009362', (265, 275))	('BAP1', 'Gene', (62, 66))	('p21', 'Gene', '644914', (86, 89))	('UM', 'Phenotype', 'HP:0007716', (177, 179))	('mutations', 'Var', (17, 26))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
39220	32726977	Patients with BAP1 mutations are generally younger, between 30 and 59 years, compared to the mean age at diagnosis, 62 years.	('Patients', 'Species', '9606', (0, 8))	('BAP1', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))
39226	32726977	UM in DNA methylation clusters 2 and 3 were highly enriched (12 of 16 tumors) in SF3B1/SRFR2 mutations, whereas EIF1AX mutant tumors were only present in DNA methylation cluster 1.	('DNA', 'cellular_component', 'GO:0005574', ('154', '157'))	('DNA methylation', 'biological_process', 'GO:0006306', ('6', '21'))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (126, 132))	('SF3B1', 'Gene', (81, 86))	('mutations', 'Var', (93, 102))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('EIF1AX', 'Gene', '1964', (112, 118))	('EIF1AX', 'Gene', (112, 118))	('DNA', 'cellular_component', 'GO:0005574', ('6', '9'))	('tumors', 'Disease', (70, 76))	('SF3B1', 'Gene', '23451', (81, 86))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('DNA methylation', 'biological_process', 'GO:0006306', ('154', '169'))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
39227	32726977	Thus, D3 UM with EIF1AX versus SF3B1/SRFR2 mutations conveys diverse DNA methylation patterns.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('DNA methylation patterns', 'MPA', (69, 93))	('DNA methylation', 'biological_process', 'GO:0006306', ('69', '84'))	('SF3B1', 'Gene', (31, 36))	('mutations', 'Var', (43, 52))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('EIF1AX', 'Gene', '1964', (17, 23))	('EIF1AX', 'Gene', (17, 23))	('SF3B1', 'Gene', '23451', (31, 36))
39229	32726977	Epigenetic alterations can result in aberrant gene regulation, thereby playing an essential role in tumorigenesis.	('Epigenetic alterations', 'Var', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('regulation', 'biological_process', 'GO:0065007', ('51', '61'))	('tumor', 'Disease', (100, 105))	('aberrant gene regulation', 'MPA', (37, 61))	('result in', 'Reg', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
39230	32726977	Epigenetic changes that, for example, silence tumor suppressor genes or activate oncogenes include DNA methylation, histone modifications, and small non-coding RNAs.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor suppressor', 'biological_process', 'GO:0051726', ('46', '62'))	('DNA methylation', 'Var', (99, 114))	('activate', 'PosReg', (72, 80))	('silence tumor', 'Disease', 'MESH:D009369', (38, 51))	('oncogenes', 'Gene', (81, 90))	('DNA methylation', 'biological_process', 'GO:0006306', ('99', '114'))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('small non-coding RNAs', 'Var', (143, 164))	('silence tumor', 'Disease', (38, 51))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('46', '62'))	('histone modifications', 'MPA', (116, 137))
39234	32726977	It was shown that hypomethylation of specific CpG sites nearby the PRAME promoter resulted in its transcriptional activation, correlated with high metastatic risk in both classes 1 UMs.	('activation', 'PosReg', (114, 124))	('hypomethylation', 'Var', (18, 33))	('PRAME', 'Gene', '23532', (67, 72))	('PRAME', 'Gene', (67, 72))	('transcriptional', 'MPA', (98, 113))	('UM', 'Phenotype', 'HP:0007716', (181, 183))
39238	32726977	Aberrant promoter hypermethylation of CpG islands plays a critical role in the inactivation of tumor suppressor genes in cancer.	('inactivation', 'NegReg', (79, 91))	('Aberrant', 'Var', (0, 8))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('95', '111'))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('promoter', 'MPA', (9, 17))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Disease', (121, 127))	('tumor', 'Disease', (95, 100))	('tumor suppressor', 'biological_process', 'GO:0051726', ('95', '111'))
39239	32726977	Hypermethylation of p16, TIMP3, RASSF1A, RASEF, hTERT, and EFS genes have been reported in UM.	('RASSF1A', 'Gene', '11186', (32, 39))	('TIMP3', 'Gene', (25, 30))	('hTERT', 'Gene', (48, 53))	('reported', 'Reg', (79, 87))	('Hypermethylation', 'Var', (0, 16))	('p16', 'Gene', (20, 23))	('UM', 'Phenotype', 'HP:0007716', (91, 93))	('RASSF1A', 'Gene', (32, 39))	('RASEF', 'Gene', (41, 46))	('RASEF', 'Gene', '158158', (41, 46))	('p16', 'Gene', '1029', (20, 23))	('EFS', 'Gene', (59, 62))	('hTERT', 'Gene', '7015', (48, 53))
39241	32726977	Methylation of promoter sites of this gene control entry at the retinoblastoma checkpoint and inhibits cyclin D1 protein accumulation at the post-transcriptional level, leading to cell-cycle progression block from the G1 to the S phase.	('retinoblastoma', 'Phenotype', 'HP:0009919', (64, 78))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('block', 'NegReg', (203, 208))	('Methylation', 'Var', (0, 11))	('retinoblastoma', 'Disease', 'MESH:D012175', (64, 78))	('control', 'Reg', (43, 50))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('inhibits', 'NegReg', (94, 102))	('cyclin', 'molecular_function', 'GO:0016538', ('103', '109'))	('S phase', 'biological_process', 'GO:0051320', ('228', '235'))	('cyclin D1', 'Gene', '595', (103, 112))	('cell-cycle progression', 'CPA', (180, 202))	('retinoblastoma', 'Disease', (64, 78))	('cell-cycle', 'biological_process', 'GO:0007049', ('180', '190'))	('cyclin D1', 'Gene', (103, 112))
39242	32726977	Though the methylation of RASSF1A may not be wholly responsible for UM development, it could be a contributing factor in UM tumorigenesis.	('UM', 'Phenotype', 'HP:0007716', (121, 123))	('contributing factor', 'Reg', (98, 117))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('RASSF1A', 'Gene', '11186', (26, 33))	('methylation', 'biological_process', 'GO:0032259', ('11', '22'))	('tumor', 'Disease', (124, 129))	('methylation', 'Var', (11, 22))	('RASSF1A', 'Gene', (26, 33))	('UM', 'Phenotype', 'HP:0007716', (68, 70))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
39244	32726977	Considering the position of RASSF1A on the p21.3 region of chromosome 3, it could serve as a tumor suppressor gene whose silencing by methylation acts as a 'second hit' after monosomy occurs.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('chromosome', 'cellular_component', 'GO:0005694', ('59', '69'))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('methylation', 'Var', (134, 145))	('RASSF1A', 'Gene', (28, 35))	('tumor', 'Disease', (93, 98))	('methylation', 'biological_process', 'GO:0032259', ('134', '145'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('93', '109'))	('RASSF1A', 'Gene', '11186', (28, 35))	('p21', 'Gene', (43, 46))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('93', '109'))	('p21', 'Gene', '644914', (43, 46))	('silencing', 'NegReg', (121, 130))
39246	32726977	In 2007, UM cell lines and primary UM samples were screened for mutations in the RASEF gene region.	('RASEF', 'Gene', (81, 86))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('RASEF', 'Gene', '158158', (81, 86))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('mutations', 'Var', (64, 73))
39248	32726977	These findings propose that a combination of methylation and loss of heterozygosity may be the mechanism for loss of RASEF expression.	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('expression', 'MPA', (123, 133))	('loss', 'NegReg', (109, 113))	('RASEF', 'Gene', (117, 122))	('RASEF', 'Gene', '158158', (117, 122))	('methylation', 'Var', (45, 56))	('loss', 'Var', (61, 65))
39249	32726977	Homozygous tumors with a methylated RASEF promoter region tend to display reduced survival compared with heterozygous tumors without methylation, suggesting loss of heterozygosity might be related to the aggressive behavior of the tumor.	('methylation', 'biological_process', 'GO:0032259', ('133', '144'))	('aggressive behavior', 'Phenotype', 'HP:0000718', (204, 223))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('methylated', 'Var', (25, 35))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('survival', 'MPA', (82, 90))	('reduced', 'NegReg', (74, 81))	('RASEF', 'Gene', '158158', (36, 41))	('tumor', 'Disease', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (231, 236))	('tumors', 'Disease', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('RASEF', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('aggressive behavior', 'biological_process', 'GO:0002118', ('204', '223'))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumors', 'Disease', (11, 17))	('tumor', 'Disease', (118, 123))
39251	32726977	They demonstrated that epigenetic alterations in the P16INK4A and P14ARF (the alternative reading frame protein product of the CDKN2A locus) genes were frequently associated with cutaneous as well as UMs.	('P16INK4A', 'Gene', (53, 61))	('P14ARF', 'Gene', (66, 72))	('epigenetic alterations', 'Var', (23, 45))	('UM', 'Phenotype', 'HP:0007716', (200, 202))	('P16INK4A', 'Gene', '1029', (53, 61))	('associated', 'Reg', (163, 173))	('cutaneous', 'Disease', (179, 188))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('UMs', 'Disease', (200, 203))
39252	32726977	Moreover, it was demonstrated that P16INK4A is frequently inactivated by hypermethylation in both primary UM and UM cell lines, accompanied by a down-regulated expression of P16INK4A.	('expression', 'MPA', (160, 170))	('hypermethylation', 'Var', (73, 89))	('inactivated', 'NegReg', (58, 69))	('P16INK4A', 'Gene', (174, 182))	('down-regulated', 'NegReg', (145, 159))	('UM', 'Phenotype', 'HP:0007716', (113, 115))	('P16INK4A', 'Gene', (35, 43))	('P16INK4A', 'Gene', '1029', (174, 182))	('P16INK4A', 'Gene', '1029', (35, 43))	('UM', 'Phenotype', 'HP:0007716', (106, 108))
39254	32726977	Interestingly, in UM patients who possess a tumor with a methylated P16INK4A promoter, metastasis tends to be more common.	('metastasis', 'CPA', (87, 97))	('P16INK4A', 'Gene', (68, 76))	('UM', 'Phenotype', 'HP:0007716', (18, 20))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('P16INK4A', 'Gene', '1029', (68, 76))	('tumor', 'Disease', (44, 49))	('methylated', 'Var', (57, 67))	('common', 'PosReg', (115, 121))
39255	32726977	A recent study by Field and colleagues indicates that hypermethylation on chromosome 3 correlated with down-regulated gene expression at several loci, including 3p21 where BAP1 is located.	('chromosome', 'cellular_component', 'GO:0005694', ('74', '84'))	('down-regulated', 'NegReg', (103, 117))	('hypermethylation', 'Var', (54, 70))	('p21', 'Gene', (162, 165))	('p21', 'Gene', '644914', (162, 165))	('gene expression', 'biological_process', 'GO:0010467', ('118', '133'))
39256	32726977	All Class 2 tumors contained a novel hypermethylated site within the BAP1 locus, which reveals that BAP1 itself is epigenetically regulated.	('hypermethylated', 'Var', (37, 52))	('BAP1', 'Gene', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
39257	32726977	In functional validation experiments, Bap1 knockdown in UM cell lines consisted of a similar methylomic repatterning with UM tumors, enhanced for genes involved in axon guidance, melanogenesis, and development.	('axon', 'cellular_component', 'GO:0030424', ('164', '168'))	('Bap1', 'Gene', '8314', (38, 42))	('axon guidance', 'CPA', (164, 177))	('Bap1', 'Gene', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('knockdown', 'Var', (43, 52))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('UM tumors', 'Disease', (122, 131))	('axon guidance', 'biological_process', 'GO:0007411', ('164', '177'))	('UM', 'Phenotype', 'HP:0007716', (122, 124))	('enhanced', 'PosReg', (133, 141))	('UM tumors', 'Disease', 'MESH:D009369', (122, 131))	('UM', 'Phenotype', 'HP:0007716', (56, 58))
39258	32726977	Deciphering the role of epigenetic deregulation could explain the loss of melanocytic differentiation and gain of neural crest-like migratory behavior in Class 2 UMs.	('loss of melanocytic', 'Disease', 'MESH:D009508', (66, 85))	('neural crest-like migratory behavior', 'CPA', (114, 150))	('UM', 'Phenotype', 'HP:0007716', (162, 164))	('loss of melanocytic', 'Disease', (66, 85))	('epigenetic deregulation', 'Var', (24, 47))	('gain', 'PosReg', (106, 110))
39262	32726977	While Hdac4 is localized to the nucleus in BAP1-mutant UM cells and the cells in which a BAP1 mutation was introduced using CRISPR-Cas9, it is restricted mainly to the cytoplasm in BAP1 wild-type UM cells and in normal human uveal melanocytes.	('Hdac4', 'Gene', '9759', (6, 11))	('UM', 'Phenotype', 'HP:0007716', (196, 198))	('BAP1', 'Gene', (89, 93))	('human', 'Species', '9606', (219, 224))	('Cas', 'cellular_component', 'GO:0005650', ('131', '134'))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('cytoplasm', 'cellular_component', 'GO:0005737', ('168', '177'))	('BAP1-mutant', 'Var', (43, 54))	('nucleus', 'cellular_component', 'GO:0005634', ('32', '39'))	('mutation', 'Var', (94, 102))	('Hdac4', 'Gene', (6, 11))
39266	32726977	Their dysregulation has been ascertained to confer resistance to apoptosis, promote cell-cycle progression, and enhance invasiveness and metastasis of many cancers.	('promote', 'PosReg', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('dysregulation', 'Var', (6, 19))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cell-cycle', 'biological_process', 'GO:0007049', ('84', '94'))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('invasiveness', 'CPA', (120, 132))	('enhance', 'PosReg', (112, 119))	('cell-cycle progression', 'CPA', (84, 106))	('resistance to apoptosis', 'CPA', (51, 74))
39268	32726977	The expression level of let-7b, miR-143, miR-193b, miR-199a, and miR-652 were proved to be increased in Class 2 UMs, so they can be used to differentiate between Class 1 and Class 2 UM tumors.	('expression level', 'MPA', (4, 20))	('miR-143', 'Gene', (32, 39))	('UM tumors', 'Disease', 'MESH:D009369', (182, 191))	('UM', 'Phenotype', 'HP:0007716', (182, 184))	('Class 2 UMs', 'Disease', (104, 115))	('let-7b', 'Gene', '406884', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('let-7b', 'Gene', (24, 30))	('miR-652', 'Gene', '724022', (65, 72))	('miR-193b', 'Gene', '574455', (41, 49))	('UM', 'Phenotype', 'HP:0007716', (112, 114))	('miR-199a', 'Var', (51, 59))	('increased', 'PosReg', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('miR-652', 'Gene', (65, 72))	('miR-193b', 'Gene', (41, 49))	('UM tumors', 'Disease', (182, 191))	('miR-143', 'Gene', '406935', (32, 39))
39273	32726977	Treatment of UM cells with a DNA hypomethylating agent decitabine and HDACi trichostatin A (TSA), can regulate miR-124a expression level via epigenetic mechanisms.	('trichostatin A', 'Chemical', 'MESH:C012589', (76, 90))	('epigenetic', 'Var', (141, 151))	('TSA', 'Chemical', 'MESH:C012589', (92, 95))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('TSA', 'molecular_function', 'GO:0033984', ('92', '95'))	('HDAC', 'Gene', (70, 74))	('regulate', 'Reg', (102, 110))	('miR-124a', 'Gene', (111, 119))	('HDAC', 'Gene', '9734', (70, 74))	('decitabine', 'Chemical', 'MESH:D000077209', (55, 65))	('miR-124a', 'Gene', '406907', (111, 119))	('expression level', 'MPA', (120, 136))	('UM', 'Phenotype', 'HP:0007716', (13, 15))
39285	32726977	These include, for example sequential treatment with low-dose dacarbazine and interferon alfa-2b (NCT01100528), fotemustine (NCT02843386), adjuvant intra-arterial fotemustine, adjuvant interferon alfa-2a, or Bacillus Calmette-Guerin injections.	('fotemustine', 'Chemical', 'MESH:C054368', (112, 123))	('fotemustine', 'Chemical', 'MESH:C054368', (163, 174))	('Bacillus Calmette-Guerin', 'Species', '33892', (208, 232))	('dacarbazine', 'Chemical', 'MESH:D003606', (62, 73))	('NCT02843386', 'Var', (125, 136))	('NCT01100528', 'Var', (98, 109))
39288	32726977	Four adjuvant trials phase II/III are ongoing, focusing on combination immunotherapy (NCT02519322, NCT03528408), dendritic cells plus autologous tumor RNA (NCT01983748) and HDACi valproic acid (VPA) in comparison to sunitinib (NCT02068586).	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('valproic acid', 'Chemical', 'MESH:D014635', (179, 192))	('NCT02519322', 'Var', (86, 97))	('RNA', 'cellular_component', 'GO:0005562', ('151', '154'))	('dendritic cells plus autologous tumor', 'Disease', 'MESH:D054740', (113, 150))	('sunitinib', 'Chemical', 'MESH:D000077210', (216, 225))	('HDAC', 'Gene', (173, 177))	('HDAC', 'Gene', '9734', (173, 177))	('NCT03528408', 'Var', (99, 110))	('VPA', 'Chemical', 'MESH:D014635', (194, 197))	('dendritic cells plus autologous tumor', 'Disease', (113, 150))	('NCT01983748', 'Var', (156, 167))
39296	32726977	GNAQ/GNA11 mutations are fundamental for the activation of the RAS-ERK pathway.	('mutations', 'Var', (11, 20))	('GNA11', 'Gene', (5, 10))	('GNAQ', 'Gene', '2776', (0, 4))	('ERK', 'Gene', (67, 70))	('ERK', 'Gene', '5594', (67, 70))	('ERK', 'molecular_function', 'GO:0004707', ('67', '70'))	('GNA11', 'Gene', '2767', (5, 10))	('GNAQ', 'Gene', (0, 4))	('activation', 'PosReg', (45, 55))
39297	32726977	However, BRAF or NRAS mutations, which mediate sensitivity to the BRAF inhibitors vemurafenib and dabrafenib in cutaneous melanoma, are not common in UM.	('vemurafenib', 'Chemical', 'MESH:D000077484', (82, 93))	('BRAF', 'Gene', (9, 13))	('dabrafenib', 'Chemical', 'MESH:C561627', (98, 108))	('NRAS', 'Gene', (17, 21))	('cutaneous melanoma', 'Disease', (112, 130))	('mutations', 'Var', (22, 31))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (112, 130))	('BRAF', 'Gene', '673', (66, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('UM', 'Phenotype', 'HP:0007716', (150, 152))	('BRAF', 'Gene', (66, 70))	('BRAF', 'Gene', '673', (9, 13))
39299	32726977	Two clinical trials are currently underway assessing the safety and anti-tumor efficacy of orally available PKC inhibitor LXS196 in patients with solid tumors harboring GNAQ/11 mutations (NCT03947385) and metastatic UM (NCT02601378).	('PKC', 'Gene', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('patients', 'Species', '9606', (132, 140))	('tumor', 'Disease', (152, 157))	('solid tumors', 'Disease', (146, 158))	('UM', 'Phenotype', 'HP:0007716', (216, 218))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('LXS196', 'Chemical', '-', (122, 128))	('GNAQ', 'Gene', '2776', (169, 173))	('tumor', 'Disease', (73, 78))	('PKC', 'molecular_function', 'GO:0004697', ('108', '111'))	('GNAQ', 'Gene', (169, 173))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('solid tumors', 'Disease', 'MESH:D009369', (146, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('NCT03947385', 'Var', (188, 199))	('LXS196', 'Gene', (122, 128))	('PKC', 'Gene', '5584', (108, 111))
39303	32726977	Patients who received selumetinib gained significantly longer PFS than those who received standard chemotherapy (15.9 vs. 7 weeks, p < 0.001).	('PFS', 'MPA', (62, 65))	('selumetinib', 'Chemical', 'MESH:C517975', (22, 33))	('Patients', 'Species', '9606', (0, 8))	('longer', 'PosReg', (55, 61))	('selumetinib', 'Var', (22, 33))
39311	32726977	During DNA methylation, gene silencing occurs due to the adding methyl group to cytosine residue in CpG islands located principally in promoter regions.	('cytosine', 'Chemical', 'MESH:D003596', (80, 88))	('methyl group', 'MPA', (64, 76))	('adding', 'PosReg', (57, 63))	('DNA methylation', 'biological_process', 'GO:0006306', ('7', '22'))	('methylation', 'Var', (11, 22))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))	('gene silencing', 'biological_process', 'GO:0016458', ('24', '38'))	('gene', 'MPA', (24, 28))
39312	32726977	Aberrant gene silencing by DNA methylation has shown the ability to modulate cancer biology and cause drug resistance.	('drug resistance', 'CPA', (102, 117))	('drug resistance', 'Phenotype', 'HP:0020174', (102, 117))	('drug resistance', 'biological_process', 'GO:0042493', ('102', '117'))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))	('cause', 'Reg', (96, 101))	('modulate', 'Reg', (68, 76))	('gene silencing', 'biological_process', 'GO:0016458', ('9', '23'))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('DNA methylation', 'biological_process', 'GO:0006306', ('27', '42'))	('drug resistance', 'biological_process', 'GO:0009315', ('102', '117'))	('Aberrant gene', 'Var', (0, 13))
39330	32726977	Similarly, panobinostat has been demonstrated to induce morphological differentiation, G1 cell-cycle arrest, and a shift to a differentiated, melanocytic gene-expression profile in cultured UM cells.	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('90', '107'))	('panobinostat', 'Chemical', 'MESH:D000077767', (11, 23))	('UM', 'Phenotype', 'HP:0007716', (190, 192))	('arrest', 'Disease', 'MESH:D006323', (101, 107))	('gene-expression', 'biological_process', 'GO:0010467', ('154', '169'))	('morphological differentiation', 'CPA', (56, 85))	('panobinostat', 'Var', (11, 23))	('shift', 'Reg', (115, 120))	('arrest', 'Disease', (101, 107))	('differentiated', 'MPA', (126, 140))
39332	32726977	SAHA treatment-induced H3 and H4 hyperacetylation at the P14ARF promoter, followed by increased P14ARF expression, caused significant reduction in UM cell growth, migration, and invasion.	('increased', 'PosReg', (86, 95))	('P14ARF', 'Var', (96, 102))	('migration', 'CPA', (163, 172))	('expression', 'MPA', (103, 113))	('reduction', 'NegReg', (134, 143))	('invasion', 'CPA', (178, 186))	('UM', 'Phenotype', 'HP:0007716', (147, 149))	('cell growth', 'biological_process', 'GO:0016049', ('150', '161'))	('SAHA', 'Chemical', 'MESH:D000077337', (0, 4))	('UM cell growth', 'CPA', (147, 161))	('hyperacetylation', 'PosReg', (33, 49))
39338	32726977	Depsipeptide is a very potent HDACi that inhibits cell growth, induces apoptosis, and declines the migration of viable UM cells in both primary and metastatic UM cell lines.	('migration of viable UM cells', 'CPA', (99, 127))	('inhibits', 'NegReg', (41, 49))	('UM', 'Phenotype', 'HP:0007716', (159, 161))	('apoptosis', 'CPA', (71, 80))	('declines', 'NegReg', (86, 94))	('cell growth', 'CPA', (50, 61))	('induces', 'Reg', (63, 70))	('Depsipeptide', 'Chemical', 'MESH:D047630', (0, 12))	('cell growth', 'biological_process', 'GO:0016049', ('50', '61'))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('Depsipeptide', 'Var', (0, 12))	('HDAC', 'Gene', (30, 34))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('HDAC', 'Gene', '9734', (30, 34))	('UM', 'Phenotype', 'HP:0007716', (119, 121))
39348	32726977	At present, increasing attention is paid to the newly combined therapeutic approaches employing epigenetic drugs or new molecular inhibitors and other therapies to promote the efficacy of cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('promote', 'PosReg', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('epigenetic drugs', 'Var', (96, 112))
39361	32726977	Development of first-generation and second-generation epigenetic drugs, which are almost exclusively DNMTis or HDACis, following a 'one size fits all' approach together with the lack of predictive biomarkers for patient selection thereby, resulted in disappointingly low efficacy in patients with solid tumors.	('DNMT', 'Gene', '1786', (101, 105))	('solid tumors', 'Disease', (297, 309))	('DNMT', 'Gene', (101, 105))	('HDAC', 'Gene', (111, 115))	('fits', 'Disease', 'MESH:D012640', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('low', 'NegReg', (267, 270))	('patients', 'Species', '9606', (283, 291))	('patient', 'Species', '9606', (212, 219))	('HDAC', 'Gene', '9734', (111, 115))	('epigenetic drugs', 'Var', (54, 70))	('solid tumors', 'Disease', 'MESH:D009369', (297, 309))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))	('efficacy', 'MPA', (271, 279))	('fits', 'Disease', (141, 145))	('patient', 'Species', '9606', (283, 290))
39373	32726977	It was demonstrated that fusion of mutant form of Cas9 without endonuclease activity known as dCas9, with the Dnmt3a or Tet1 enzyme could provide a potent tool for targeted erasure or establishment of DNA methylation, respectively.	('DNA methylation', 'biological_process', 'GO:0006306', ('201', '216'))	('Cas9', 'Gene', (50, 54))	('DNA', 'cellular_component', 'GO:0005574', ('201', '204'))	('endonuclease activity', 'molecular_function', 'GO:0004519', ('63', '84'))	('mutant', 'Var', (35, 41))	('Tet1', 'Gene', '80312', (120, 124))	('Dnmt3a', 'Gene', '1788', (110, 116))	('Tet1', 'Gene', (120, 124))	('Dnmt3a', 'Gene', (110, 116))	('fusion', 'Interaction', (25, 31))	('Cas', 'cellular_component', 'GO:0005650', ('50', '53'))
39377	32726977	By gaining insight into the crucial role of molecular abnormalities, including epigenetic changes in cancer initiation, progression, and metastasis, there is a great demand for modern technologies to restore these aberrations.	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('epigenetic changes', 'Var', (79, 97))
39390	32099319	Local control of choroidal melanomas after 125I and 106Ru plaques implantation and vision changes are the main outcome measures.	('choroidal melanoma', 'Phenotype', 'HP:0012054', (17, 35))	('125I', 'Var', (43, 47))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (17, 36))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('vision', 'biological_process', 'GO:0007601', ('83', '89'))	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))	('choroidal melanomas', 'Disease', (17, 36))	('choroidal melanomas', 'Disease', 'MESH:D008545', (17, 36))
39393	32099319	A single patient treated with 106Ru had local tumor recurrence with no one in the 125I group.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('106Ru', 'Var', (30, 35))	('tumor', 'Disease', (46, 51))	('patient', 'Species', '9606', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
39394	32099319	The treatment with our 125I plaques is as effective as 106Ru plaques in controlling choroidal melanoma tumor and preserving the vision during the two and half year of follow-up.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('choroidal melanoma tumor', 'Disease', (84, 108))	('125I', 'Var', (23, 27))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('vision', 'MPA', (128, 134))	('vision', 'biological_process', 'GO:0007601', ('128', '134'))	('choroidal melanoma tumor', 'Disease', 'MESH:D008545', (84, 108))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (84, 102))
39395	32099319	It means that the effectiveness of 125I is not only comparable to 106Ru but also superior when the outcome of the interest is the thickness of the tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('125I', 'Var', (35, 39))
39397	32099319	Survival rates between patients managed by 125I brachytherapy compared to those managed by enucleation were not different in the COMS Group (Collaborative Ocular Melanoma Study Group) trial for medium-sized tumors, and a conservative approach is more appropriate for these cases.	('Collaborative Ocular Melanoma', 'Disease', 'MESH:D008545', (141, 170))	('Collaborative Ocular Melanoma', 'Disease', (141, 170))	('patients', 'Species', '9606', (23, 31))	('125I', 'Var', (43, 47))	('Ocular Melanoma', 'Phenotype', 'HP:0007716', (155, 170))	('Melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('COMS', 'Chemical', '-', (129, 133))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('enucleation', 'biological_process', 'GO:0090601', ('91', '102'))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('man', 'Species', '9606', (32, 35))	('man', 'Species', '9606', (80, 83))
39399	32099319	Since the first reports of using radon seeds radiation to treat choroidal melanoma back to 1930, physicians have used several isotopes as cobalt-60 (60Co), iodine-125 (125I), ruthenium-106 (106Ru), iridium-192 (192Ir), palladium-103 (103Pd) and strontium-90 (90Sr) to treat these tumors.	('choroidal melanoma back', 'Disease', 'MESH:D008545', (64, 87))	('iridium-192', 'Chemical', 'MESH:C000615087', (198, 209))	('tumors', 'Disease', 'MESH:D009369', (280, 286))	('192Ir', 'Var', (211, 216))	('iodine-125', 'Chemical', 'MESH:C000614960', (156, 166))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('choroidal melanoma back', 'Disease', (64, 87))	('strontium-90', 'Chemical', 'MESH:C000615490', (245, 257))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumors', 'Phenotype', 'HP:0002664', (280, 286))	('tumors', 'Disease', (280, 286))	('palladium-103', 'Chemical', 'MESH:C000615531', (219, 232))	('cobalt-60', 'Chemical', 'MESH:C000615395', (138, 147))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (64, 82))	('106Ru', 'Var', (190, 195))	('ruthenium-106', 'Chemical', 'MESH:C000615522', (175, 188))
39400	32099319	This study reports the achievement of local control of choroidal melanoma tumor during a short time follow-up period in both brachytherapy with 125I and 106Ru.	('choroidal melanoma tumor', 'Disease', 'MESH:D008545', (55, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (55, 73))	('125I', 'Var', (144, 148))	('choroidal melanoma tumor', 'Disease', (55, 79))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('106Ru', 'Var', (153, 158))
39401	32099319	We performed a chart review of patients treated with 125I and 106Ru for choroidal melanoma from September 2013 through August 2017 at Farabi Hospital, Tehran University of Medical Sciences.	('125I', 'Var', (53, 57))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (72, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('106Ru', 'Var', (62, 67))	('patients', 'Species', '9606', (31, 39))	('choroidal melanoma', 'Disease', 'MESH:D008545', (72, 90))	('choroidal melanoma', 'Disease', (72, 90))
39452	32099319	Table 2 shows that by applying MLR analysis to assess the effect of 125I compared to 106Ru on three different outcomes (visual acuity, thickness and diameter of ophthalmic tumors) adjusting for baseline differences, there is no priority between two interventions.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('125I', 'Var', (68, 72))	('ophthalmic tumors', 'Disease', (161, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('ophthalmic tumors', 'Disease', 'MESH:C535922', (161, 178))	('ophthalmic tumors', 'Phenotype', 'HP:0100012', (161, 178))
39454	32099319	To make it simple, it means that the effectiveness of 125I is not only comparable to 106Ru but also superior when the outcome of the interest is the thickness of the tumors.	('125I', 'Var', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
39455	32099319	The study showed that treatment with our 125I plaques was as effective as 106Ru brachytherapy to control choroidal melanoma basal diameter and vision preserving during a 30-month follow-up period.	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('vision', 'biological_process', 'GO:0007601', ('143', '149'))	('choroidal melanoma basal diameter', 'Disease', 'MESH:D008545', (105, 138))	('choroidal melanoma basal diameter', 'Disease', (105, 138))	('125I', 'Var', (41, 45))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (105, 123))
39456	32099319	In a retrospective study comparing the outcomes of patients with choroidal melanoma treated with 125I and 106Ru brachytherapy or proton beam radiation therapy (PBRT), patients treated with PBRT had a more rapid and substantial loss of vision than the ones treated with brachytherapy.	('loss', 'NegReg', (227, 231))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (65, 83))	('patients', 'Species', '9606', (167, 175))	('choroidal melanoma', 'Disease', 'MESH:D008545', (65, 83))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('loss of vision', 'Phenotype', 'HP:0000572', (227, 241))	('patients', 'Species', '9606', (51, 59))	('substantial loss of vision', 'Phenotype', 'HP:0001141', (215, 241))	('vision', 'biological_process', 'GO:0007601', ('235', '241'))	('125I', 'Var', (97, 101))	('vision', 'MPA', (235, 241))	('choroidal melanoma', 'Disease', (65, 83))
39457	32099319	The most commonly used radioactive sources to manage uveal melanoma with brachytherapy are beta emitters such as 106Ru or 90Sr plaques and low-energy gamma emitters such as 125I or 103Pd plaques.	('125I', 'Var', (173, 177))	('90Sr plaques', 'Var', (122, 134))	('106Ru', 'Var', (113, 118))	('103Pd plaques', 'Var', (181, 194))	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('uveal melanoma', 'Disease', (53, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (53, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('man', 'Species', '9606', (46, 49))
39458	32099319	Three years post-treatment, significant loss of visual acuity, defined as loss of six lines or more from baseline, was observed in 49% of the eyes treated with 125I (COMS), and 43% of them demonstrated the vision of 20/200 or worse.	('loss of visual acuity', 'Disease', (40, 61))	('COMS', 'Chemical', '-', (166, 170))	('loss of visual acuity', 'Phenotype', 'HP:0000529', (40, 61))	('loss', 'NegReg', (74, 78))	('loss of visual acuity', 'Disease', 'MESH:D014786', (40, 61))	('vision', 'biological_process', 'GO:0007601', ('206', '212'))	('125I', 'Var', (160, 164))
39461	32099319	According to the results, we observed a desirable trend in visual gain within 24 months post-treatment in the 125I group.	('visual gain', 'Disease', (59, 70))	('visual gain', 'Disease', 'MESH:D015430', (59, 70))	('125I', 'Var', (110, 114))
39467	32099319	A comparative study showed that five-year melanoma recurrence rates were 11% and 4% in 106Ru and 125I plaque brachytherapy, respectively.	('melanoma', 'Disease', (42, 50))	('106Ru', 'Var', (87, 92))	('125I plaque brachytherapy', 'Var', (97, 122))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
39474	32099319	In contrast, centers using 125I or 103Pd plaques do not restrict their treatments based on tumor thickness.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('125I', 'Var', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('103Pd', 'Var', (35, 40))	('tumor', 'Disease', (91, 96))
39480	32099319	Another study comparing the 125I with 106Ru plaques in the tumors less than 5 mm thickness reported the radiation retinopathy in 50% and 74%, respectively, at 5 years of follow up.	('radiation retinopathy', 'Disease', (104, 125))	('radiation retinopathy', 'Disease', 'MESH:D011832', (104, 125))	('retinopathy', 'Phenotype', 'HP:0000488', (114, 125))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Disease', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('125I', 'Var', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
39482	32099319	In our study, the rate of radiation retinopathy was 13.3% for the 125I and 10% for 1 6Ru plaques.	('retinopathy', 'Phenotype', 'HP:0000488', (36, 47))	('radiation retinopathy', 'Disease', (26, 47))	('radiation retinopathy', 'Disease', 'MESH:D011832', (26, 47))	('125I', 'Var', (66, 70))
39500	31659567	The most common mutations are found in genes encoding components of the RAS/RAF/MEK/ERK (MAPK) signaling pathway, and they lead to a constitutive activity of this cascade.	('MAPK) signaling', 'biological_process', 'GO:0000165', ('89', '104'))	('ERK', 'Gene', '5594', (84, 87))	('RAF', 'Gene', '22882', (76, 79))	('lead to', 'Reg', (123, 130))	('mutations', 'Var', (16, 25))	('ERK', 'Gene', (84, 87))	('RAF', 'Gene', (76, 79))	('signaling pathway', 'biological_process', 'GO:0007165', ('95', '112'))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('constitutive activity', 'MPA', (133, 154))	('ERK', 'molecular_function', 'GO:0004707', ('84', '87'))
39501	31659567	Algorithms for current treatment of melanoma patients include vemurafenib, dabrafenib and encorafenib, targeting mutated BRAF (B-RAF proto-oncogene, serine/threonine kinase); trametinib, cobimetinib and binimetinib that inhibit the activity of MEK1/2 (mitogen-activated protein kinase kinase), as well as immune checkpoint inhibitors including nivolumab and pembrolizumab binding to PD-1 (programmed cell death protein 1) and ipilimumab inhibiting CTLA-4 (cytotoxic T-lymphocyte antigen 4).	('BRAF', 'Gene', (121, 125))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('cobimetinib', 'Chemical', 'MESH:C574276', (187, 198))	('CTLA-4', 'Gene', (448, 454))	('cytotoxic T-lymphocyte antigen 4', 'Gene', '397286', (456, 488))	('MEK1/2', 'Enzyme', (244, 250))	('activity', 'MPA', (232, 240))	('patients', 'Species', '9606', (45, 53))	('lymphocyte antigen', 'molecular_function', 'GO:0005557', ('468', '486'))	('vemurafenib', 'Chemical', 'MESH:C551177', (62, 73))	('threonine', 'Chemical', 'MESH:C061951', (156, 165))	('binding', 'molecular_function', 'GO:0005488', ('372', '379'))	('cytotoxic T-lymphocyte antigen 4', 'Gene', (456, 488))	('protein', 'cellular_component', 'GO:0003675', ('411', '418'))	('PD-1', 'Gene', (383, 387))	('inhibit', 'NegReg', (220, 227))	('serine', 'Chemical', 'MESH:C047902', (149, 155))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('CTLA-4', 'Gene', '397286', (448, 454))	('MEK1', 'molecular_function', 'GO:0004708', ('244', '248'))	('protein', 'cellular_component', 'GO:0003675', ('270', '277'))	('mutated', 'Var', (113, 120))	('B-RAF proto-oncogene', 'Gene', (127, 147))	('binimetinib', 'Chemical', 'MESH:C581313', (203, 214))	('inhibiting', 'NegReg', (437, 447))	('programmed cell death protein 1', 'Gene', (389, 420))	('trametinib', 'Chemical', 'MESH:C560077', (175, 185))	('programmed cell death', 'biological_process', 'GO:0012501', ('389', '410'))	('dabrafenib', 'Chemical', 'MESH:C561627', (75, 85))	('binding', 'Interaction', (372, 379))	('B-RAF proto-oncogene', 'Gene', '673', (127, 147))	('encorafenib', 'Chemical', 'None', (90, 101))	('programmed cell death protein 1', 'Gene', '100533201', (389, 420))
39503	31659567	Resistance emerges through upregulation of expression of mutated BRAF, alternative splicing of BRAF transcript, secondary BRAF mutations, mutations in genes encoding MEK1/2 and RAS, reactivation of COT (cancer osaka thyroid oncogene) activity, dimerization of CRAF (RAF-1 proto-oncogene, serine/threonine kinase), which all can lead to the hyperactivation or recovery of the MAPK pathway activity.	('CRAF', 'molecular_function', 'GO:0004709', ('260', '264'))	('COT (cancer osaka thyroid oncogene', 'Gene', '1326', (198, 232))	('serine', 'Chemical', 'MESH:C047902', (288, 294))	('MEK1/2', 'Gene', (166, 172))	('hyperactivation', 'Disease', 'None', (340, 355))	('splicing', 'biological_process', 'GO:0045292', ('83', '91'))	('CRAF', 'Gene', (260, 264))	('MAPK pathway', 'Pathway', (375, 387))	('hyperactivation', 'Disease', (340, 355))	('MEK1', 'molecular_function', 'GO:0004708', ('166', '170'))	('BRAF', 'Gene', (95, 99))	('mutations', 'Var', (127, 136))	('dimerization', 'MPA', (244, 256))	('BRAF', 'Gene', (65, 69))	('activity', 'MPA', (388, 396))	('CRAF', 'Gene', '5894', (260, 264))	('expression', 'MPA', (43, 53))	('RAF-1', 'Gene', '5894', (266, 271))	('upregulation', 'PosReg', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('mutations', 'Var', (138, 147))	('MAPK', 'molecular_function', 'GO:0004707', ('375', '379'))	('RAF-1', 'Gene', (266, 271))	('threonine', 'Chemical', 'MESH:C061951', (295, 304))	('BRAF', 'Gene', (122, 126))	('reactivation', 'Var', (182, 194))	('mutated', 'Var', (57, 64))
39505	31659567	In addition to cell-intrinsic mechanisms, growth factors derived from stromal cells and hypoxia can modulate melanoma cell sensitivity to targeted drugs, and long-term therapy with BRAFV600E inhibitor can develop resistance to other drugs including dacarbazine.	('melanoma cell', 'Disease', 'MESH:D008545', (109, 122))	('dacarbazine', 'Chemical', 'MESH:D003606', (249, 260))	('hypoxia', 'Disease', 'MESH:D000860', (88, 95))	('hypoxia', 'Disease', (88, 95))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('resistance', 'MPA', (213, 223))	('develop', 'PosReg', (205, 212))	('melanoma cell', 'Disease', (109, 122))	('modulate', 'Reg', (100, 108))	('BRAFV600E', 'Mutation', 'rs113488022', (181, 190))	('BRAFV600E inhibitor', 'Var', (181, 200))
39506	31659567	Resistance to immunotherapy can also emerge, and melanoma cells resistant to PD-1 inhibitors show upregulation of receptors VISTA (V-domain Ig suppressor of T cell activation) and TIM-3 (T-cell immunoglobulin and mucin domain-containing 3), as well as acquisition of mutations in genes encoding JAK1 (Janus kinase 1), JAK2 (Janus kinase 2) and B2 M (beta-2-microglobulin), which results in reduced sensitivity to T-cell mediated killing.	('VISTA', 'Gene', '64115', (124, 129))	('melanoma cell', 'Disease', (49, 62))	('JAK1', 'Gene', (295, 299))	('TIM-3', 'Gene', '84868', (180, 185))	('Janus kinase 1', 'Gene', '3716', (301, 315))	('VISTA', 'Gene', (124, 129))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('194', '208'))	('sensitivity to T-cell mediated killing', 'MPA', (398, 436))	('JAK2', 'Gene', (318, 322))	('TIM-3', 'Gene', (180, 185))	('T-cell immunoglobulin and mucin domain-containing 3', 'Gene', '84868', (187, 238))	('reduced', 'NegReg', (390, 397))	('B2 M', 'Gene', (344, 348))	('mutations', 'Var', (267, 276))	('JAK1', 'Gene', '3716', (295, 299))	('JAK', 'molecular_function', 'GO:0004713', ('318', '321'))	('T cell activation', 'biological_process', 'GO:0042110', ('157', '174'))	('JAK', 'molecular_function', 'GO:0004713', ('295', '298'))	('upregulation', 'PosReg', (98, 110))	('melanoma cell', 'Disease', 'MESH:D008545', (49, 62))	('Janus kinase 1', 'Gene', (301, 315))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('JAK2', 'Gene', '3717', (318, 322))
39544	31659567	This signaling cascade is constitutively active in the majority of melanomas as a result of genetic alterations in BRAF, RAS or NF1 (neurofibromin 1).	('neurofibromin 1', 'Gene', (133, 148))	('melanomas', 'Disease', (67, 76))	('NF1', 'Gene', '4763', (128, 131))	('BRAF', 'Gene', (115, 119))	('result', 'Reg', (82, 88))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('neurofibromin 1', 'Gene', '4763', (133, 148))	('RAS', 'Gene', (121, 124))	('melanomas', 'Disease', 'MESH:D008545', (67, 76))	('signaling cascade', 'biological_process', 'GO:0007165', ('5', '22'))	('genetic alterations', 'Var', (92, 111))	('NF1', 'Gene', (128, 131))
39545	31659567	Most frequent mutations are found in BRAF (40-60% of melanoma patients) and NRAS (15-20%).	('NRAS', 'Gene', (76, 80))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('NRAS', 'Gene', '4893', (76, 80))	('melanoma', 'Disease', (53, 61))	('BRAF', 'Gene', (37, 41))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('patients', 'Species', '9606', (62, 70))	('mutations', 'Var', (14, 23))
39546	31659567	Mutations in BRAF are mainly associated with a substitution of valine in codon 600, and valine can be substituted with either glutamic acid or lysine in up to 90% and 10-20% of patients harboring mutation in BRAF, respectively.	('glutamic acid', 'Chemical', 'MESH:C030030', (126, 139))	('mutation', 'Var', (196, 204))	('BRAF', 'Gene', (208, 212))	('substitution', 'Var', (47, 59))	('patients', 'Species', '9606', (177, 185))	('valine', 'Chemical', 'MESH:C521924', (88, 94))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('lysine', 'Chemical', 'MESH:C114808', (143, 149))	('associated', 'Reg', (29, 39))	('valine', 'Chemical', 'MESH:C521924', (63, 69))
39547	31659567	Interestingly, HSP90 is required for folding of a protein product of mutated BRAF, whereas wild-type BRAF is not stabilized by HSP90 in cutaneous melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma cell', 'Disease', (146, 159))	('mutated', 'Var', (69, 76))	('HSP90', 'Gene', (127, 132))	('HSP90', 'Gene', '3320', (127, 132))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('BRAF', 'Gene', (77, 81))	('melanoma cell', 'Disease', 'MESH:D008545', (146, 159))	('cutaneous melanoma', 'Disease', (136, 154))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (136, 154))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (136, 154))	('HSP90', 'Gene', (15, 20))	('HSP90', 'Gene', '3320', (15, 20))
39560	31659567	In addition, HSP90 has been identified as a crucial regulator of melanoma cell phenotype, and inhibition of HSP90 has substantially affected both commercially available and primary melanoma cell lines, also those resistant to currently available therapeutics.	('melanoma cell', 'Disease', (65, 78))	('HSP90', 'Gene', '3320', (108, 113))	('melanoma cell', 'Disease', 'MESH:D008545', (181, 194))	('HSP90', 'Gene', (13, 18))	('HSP90', 'Gene', '3320', (13, 18))	('melanoma cell', 'Disease', 'MESH:D008545', (65, 78))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('HSP90', 'Gene', (108, 113))	('inhibition', 'Var', (94, 104))	('affected', 'Reg', (132, 140))	('melanoma cell', 'Disease', (181, 194))
39564	31659567	Inhibitors of the middle domain of HSP90 directly or allosterically disrupt interactions between HSP90 and C-terminal binding proteins.	('C', 'Chemical', 'MESH:D002244', (107, 108))	('C-terminal', 'Protein', (107, 117))	('Inhibitors', 'Var', (0, 10))	('HSP90', 'Gene', (35, 40))	('HSP90', 'Gene', (97, 102))	('interactions', 'Interaction', (76, 88))	('C-terminal binding', 'molecular_function', 'GO:0008022', ('107', '125'))	('HSP90', 'Gene', '3320', (35, 40))	('HSP90', 'Gene', '3320', (97, 102))	('disrupt', 'NegReg', (68, 75))
39572	31659567	It was demonstrated that 17-AAG induced degradation of BRAFV600E and other BRAF mutants, but not wild-type BRAF in cutaneous melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('17-AAG', 'Chemical', 'MESH:C112765', (25, 31))	('cutaneous melanoma', 'Disease', (115, 133))	('BRAFV600E', 'Var', (55, 64))	('melanoma cell', 'Disease', (125, 138))	('BRAFV600E', 'Mutation', 'rs113488022', (55, 64))	('degradation', 'MPA', (40, 51))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (115, 133))	('BRAF', 'Gene', (75, 79))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (115, 133))	('melanoma cell', 'Disease', 'MESH:D008545', (125, 138))	('degradation', 'biological_process', 'GO:0009056', ('40', '51'))
39575	31659567	This effect was similarly observed in melanoma cells harboring mutation in NRAS.	('melanoma cell', 'Disease', (38, 51))	('melanoma cell', 'Disease', 'MESH:D008545', (38, 51))	('NRAS', 'Gene', (75, 79))	('mutation', 'Var', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('NRAS', 'Gene', '4893', (75, 79))
39583	31659567	17-AG-mediated apoptosis was associated with attenuation of cytoprotective IRE1alpha-XBP1s (spliced X-Box binding protein 1) axis in melanoma cells harboring either BRAFV600E or NRASQ61R variant.	('apoptosis', 'CPA', (15, 24))	('IRE1alpha', 'Gene', (75, 84))	('apoptosis', 'biological_process', 'GO:0097194', ('15', '24'))	('XBP1', 'Gene', '7494', (85, 89))	('apoptosis', 'biological_process', 'GO:0006915', ('15', '24'))	('attenuation', 'NegReg', (45, 56))	('melanoma cell', 'Disease', (133, 146))	('BRAFV600E', 'Mutation', 'rs113488022', (165, 174))	('NRAS', 'Gene', (178, 182))	('X-Box binding protein 1', 'Gene', (100, 123))	('binding', 'molecular_function', 'GO:0005488', ('106', '113'))	('X-Box binding protein 1', 'Gene', '7494', (100, 123))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('XBP1', 'Gene', (85, 89))	('IRE1alpha', 'Gene', '2081', (75, 84))	('cytoprotective', 'MPA', (60, 74))	('BRAFV600E', 'Var', (165, 174))	('NRAS', 'Gene', '4893', (178, 182))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('melanoma cell', 'Disease', 'MESH:D008545', (133, 146))
39588	31659567	Geldanamycin-related HSP90 inhibitors upregulate co-chaperones and stress-related response genes that can affect cell sensitivity to these drugs.	('HSP90', 'Gene', (21, 26))	('inhibitors', 'Var', (27, 37))	('HSP90', 'Gene', '3320', (21, 26))	('upregulate', 'PosReg', (38, 48))	('co-chaperones', 'CPA', (49, 62))	('affect', 'Reg', (106, 112))	('cell sensitivity', 'MPA', (113, 129))	('stress-related response genes', 'Gene', (67, 96))	('Geldanamycin', 'Chemical', 'MESH:C001277', (0, 12))
39593	31659567	Cell sensitivity to ansamycin inhibitors of HSP90 was also associated with expression of NQO1 encoding NAD(P)H:quinone oxidoreductase 1 that converted these compounds to hydroquinone to enhance their activity by increasing hydrogen bonding.	('NQO1', 'molecular_function', 'GO:0003955', ('89', '93'))	('HSP90', 'Gene', (44, 49))	('HSP90', 'Gene', '3320', (44, 49))	('NAD(P)H:quinone oxidoreductase 1', 'Gene', '1728', (103, 135))	('expression', 'Var', (75, 85))	('associated', 'Reg', (59, 69))	('hydroquinone', 'Chemical', 'MESH:D006873', (170, 182))	('activity', 'MPA', (200, 208))	('ansamycin', 'Chemical', 'MESH:D047029', (20, 29))	('increasing', 'PosReg', (212, 222))	('NQO1', 'Gene', (89, 93))	('hydrogen', 'Chemical', 'MESH:D006859', (223, 231))	('hydrogen bonding', 'MPA', (223, 239))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('enhance', 'PosReg', (186, 193))	('NQO1', 'Gene', '1728', (89, 93))
39594	31659567	It was reported that NQO1P187S variant exerted diminished activity compared with wild-type NQO1, but genetic alterations affecting a His80 residue in this protein could compensate for P187S substitution.	('activity', 'MPA', (58, 66))	('diminished', 'NegReg', (47, 57))	('P187S', 'Mutation', 'rs1800566', (25, 30))	('NQO1', 'molecular_function', 'GO:0003955', ('21', '25'))	('genetic alterations', 'Var', (101, 120))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('NQO1', 'Gene', (21, 25))	('NQO1', 'Gene', (91, 95))	('P187S', 'Mutation', 'rs1800566', (184, 189))	('affecting', 'Reg', (121, 130))	('NQO1', 'Gene', '1728', (91, 95))	('NQO1', 'molecular_function', 'GO:0003955', ('91', '95'))	('NQO1', 'Gene', '1728', (21, 25))	('P187S', 'Var', (184, 189))
39598	31659567	Interestingly, melanoma cells harboring P187S variant of NQO1 were susceptible to 17-AG-induced apoptosis, although the occurrence of cell death was delayed compared with melanoma cells harboring wild-type NQO1.	('melanoma cell', 'Disease', 'MESH:D008545', (171, 184))	('susceptible', 'Reg', (67, 78))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('cell death', 'biological_process', 'GO:0008219', ('134', '144'))	('NQO1', 'Gene', (57, 61))	('P187S', 'Var', (40, 45))	('melanoma cell', 'Disease', (15, 28))	('NQO1', 'molecular_function', 'GO:0003955', ('206', '210'))	('NQO1', 'Gene', (206, 210))	('NQO1', 'Gene', '1728', (57, 61))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('P187S', 'Mutation', 'rs1800566', (40, 45))	('NQO1', 'molecular_function', 'GO:0003955', ('57', '61'))	('melanoma cell', 'Disease', (171, 184))	('melanoma cell', 'Disease', 'MESH:D008545', (15, 28))	('NQO1', 'Gene', '1728', (206, 210))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
39611	31659567	Lack of a benzoquinone moiety in CCT018159 may determine lower hepatotoxicity than this observed for ansamycin inhibitors of HSP90.	('ansamycin', 'Chemical', 'MESH:D047029', (101, 110))	('hepatotoxicity', 'Disease', (63, 77))	('benzoquinone', 'Chemical', 'MESH:C004532', (10, 22))	('CCT018159', 'Var', (33, 42))	('CCT018159', 'Chemical', 'MESH:C506244', (33, 42))	('HSP90', 'Gene', (125, 130))	('hepatotoxicity', 'Disease', 'MESH:D056486', (63, 77))	('HSP90', 'Gene', '3320', (125, 130))	('lower', 'NegReg', (57, 62))
39612	31659567	CCT018159 displayed a number of similar activities compared with geldanamycin and geldanamycin derivatives including induction of HSP70 expression, depletion of melanoma-related oncoproteins such as BRAFV600E, CRAF, CDK4 (cyclin-dependent kinase 4), ERBB2 (receptor tyrosine protein kinase ERBB2), attenuation of ERK1/2 activity and upregulation of genes involved in melanoma cell differentiation.	('receptor tyrosine protein kinase ERBB2', 'Gene', (257, 295))	('BRAFV600E', 'Mutation', 'rs113488022', (199, 208))	('ERK1', 'molecular_function', 'GO:0004707', ('313', '317'))	('ERBB2', 'Gene', '2064', (250, 255))	('ERK1/2', 'Gene', (313, 319))	('ERK1/2', 'Gene', '5595;5594', (313, 319))	('ERBB2', 'Gene', '2064', (290, 295))	('activity', 'MPA', (320, 328))	('upregulation', 'PosReg', (333, 345))	('HSP70', 'Gene', (130, 135))	('cyclin-dependent kinase 4', 'Gene', (222, 247))	('expression', 'MPA', (136, 146))	('CRAF', 'Gene', (210, 214))	('attenuation', 'NegReg', (298, 309))	('CDK4', 'Var', (216, 220))	('cyclin-dependent kinase 4', 'Gene', '1019', (222, 247))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('CCT018159', 'Var', (0, 9))	('melanoma', 'Disease', 'MESH:D008545', (367, 375))	('melanoma cell', 'Disease', 'MESH:D008545', (367, 380))	('BRAFV600E', 'Var', (199, 208))	('cyclin', 'molecular_function', 'GO:0016538', ('222', '228'))	('CRAF', 'Gene', '5894', (210, 214))	('receptor tyrosine protein kinase ERBB2', 'Gene', '2064', (257, 295))	('CRAF', 'molecular_function', 'GO:0004709', ('210', '214'))	('HSP70', 'Gene', '3308', (130, 135))	('melanoma cell', 'Disease', (367, 380))	('CCT018159', 'Chemical', 'MESH:C506244', (0, 9))	('depletion', 'MPA', (148, 157))	('geldanamycin', 'Chemical', 'MESH:C001277', (82, 94))	('ERBB2', 'Gene', (250, 255))	('ERBB2', 'Gene', (290, 295))	('CDK', 'molecular_function', 'GO:0004693', ('216', '219'))	('genes', 'Gene', (349, 354))	('protein', 'cellular_component', 'GO:0003675', ('275', '282'))	('geldanamycin', 'Chemical', 'MESH:C001277', (65, 77))	('melanoma', 'Phenotype', 'HP:0002861', (367, 375))	('melanoma', 'Disease', (367, 375))	('cell differentiation', 'biological_process', 'GO:0030154', ('376', '396'))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))
39613	31659567	In addition, CCT018159 caused a substantial accumulation of melanoma cells in the G1 phase of cell cycle, and induced apoptosis.	('apoptosis', 'CPA', (118, 127))	('CCT018159', 'Chemical', 'MESH:C506244', (13, 22))	('apoptosis', 'biological_process', 'GO:0097194', ('118', '127'))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('apoptosis', 'biological_process', 'GO:0006915', ('118', '127'))	('cell cycle', 'biological_process', 'GO:0007049', ('94', '104'))	('melanoma cell', 'Disease', (60, 73))	('G1 phase', 'biological_process', 'GO:0051318', ('82', '90'))	('induced', 'Reg', (110, 117))	('CCT018159', 'Var', (13, 22))	('melanoma cell', 'Disease', 'MESH:D008545', (60, 73))	('accumulation', 'PosReg', (44, 56))
39614	31659567	Melanoma cell response to CCT018159 was independent of NQO1 expression and the level of P-glycoprotein/ABCB1 (ATP binding cassette subfamily B member 1) involved in drug efflux.	('ATP binding cassette subfamily B member 1', 'Gene', '5243', (110, 151))	('NQO1', 'Gene', '1728', (55, 59))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('P-glycoprotein', 'molecular_function', 'GO:0008559', ('88', '102'))	('ATP binding cassette subfamily B member 1', 'Gene', (110, 151))	('efflux', 'biological_process', 'GO:0140115', ('170', '176'))	('ATP binding', 'molecular_function', 'GO:0005524', ('110', '121'))	('Melanoma', 'Disease', (0, 8))	('efflux', 'biological_process', 'GO:0140352', ('170', '176'))	('ABCB1', 'Gene', (103, 108))	('ABCB1', 'Gene', '5243', (103, 108))	('CCT018159', 'Var', (26, 35))	('NQO1', 'molecular_function', 'GO:0003955', ('55', '59'))	('CCT018159', 'Chemical', 'MESH:C506244', (26, 35))	('NQO1', 'Gene', (55, 59))
39615	31659567	AT13387 is a long-acting inhibitor that interacts with the N-terminal ATPase catalytic site of HSP90.	('HSP90', 'Gene', (95, 100))	('HSP90', 'Gene', '3320', (95, 100))	('interacts', 'Interaction', (40, 49))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('ATP', 'Gene', (70, 73))	('ATP', 'Gene', '51761', (70, 73))	('AT13387', 'Var', (0, 7))
39616	31659567	AT13387 exerted high activity against cancer cells addicted to several oncoproteins including receptor tyrosine kinases such as EGFR, ERBB2, c-MET (hepatocyte growth factor receptor) and FLT3 (Fms-related tyrosine kinase 3).	('Fms-related tyrosine kinase 3', 'Gene', (193, 222))	('FLT3', 'Gene', (187, 191))	('AT13387', 'Var', (0, 7))	('hepatocyte growth factor receptor', 'Gene', (148, 181))	('FLT3', 'Gene', '2322', (187, 191))	('EGFR', 'Gene', (128, 132))	('ERBB2', 'Gene', (134, 139))	('c-MET', 'Gene', '4233', (141, 146))	('cancer', 'Disease', (38, 44))	('activity', 'MPA', (21, 29))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('148', '172'))	('Fms', 'molecular_function', 'GO:0005011', ('193', '196'))	('EGFR', 'molecular_function', 'GO:0005006', ('128', '132'))	('c-MET', 'Gene', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('ERBB2', 'Gene', '2064', (134, 139))	('Fms-related tyrosine kinase 3', 'Gene', '2322', (193, 222))	('tyrosine', 'Chemical', 'None', (103, 111))	('tyrosine', 'Chemical', 'None', (205, 213))	('hepatocyte growth factor receptor', 'Gene', '4233', (148, 181))	('EGFR', 'Gene', '1956', (128, 132))	('cancer', 'Disease', 'MESH:D009369', (38, 44))
39617	31659567	AT13387 also depleted HSP90 client proteins including CRAF, BRAFV600E and AKT in a concentration-dependent manner leading to attenuation of MAPK and AKT signaling pathways, also in a three-dimensional model of melanoma.	('BRAFV600E', 'Var', (60, 69))	('HSP90', 'Gene', '3320', (22, 27))	('depleted', 'NegReg', (13, 21))	('BRAFV600E', 'Mutation', 'rs113488022', (60, 69))	('AKT signaling pathways', 'Pathway', (149, 171))	('melanoma', 'Disease', 'MESH:D008545', (210, 218))	('MAPK', 'molecular_function', 'GO:0004707', ('140', '144'))	('CRAF', 'molecular_function', 'GO:0004709', ('54', '58'))	('AT13387', 'Var', (0, 7))	('AKT signaling', 'biological_process', 'GO:0043491', ('149', '162'))	('AKT', 'Gene', (74, 77))	('CRAF', 'Gene', '5894', (54, 58))	('HSP90', 'Gene', (22, 27))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('CRAF', 'Gene', (54, 58))	('melanoma', 'Disease', (210, 218))	('attenuation', 'NegReg', (125, 136))
39619	31659567	AT13387 at low nanomolar concentration efficiently inhibited melanoma cell proliferation compared with other types of cancer cells, induced apoptosis and delayed tumor growth when used either alone or in combination with vemurafenib.	('melanoma cell', 'Disease', 'MESH:D008545', (61, 74))	('cancer', 'Disease', (118, 124))	('delayed', 'NegReg', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('vemurafenib', 'Chemical', 'MESH:C551177', (221, 232))	('cell proliferation', 'biological_process', 'GO:0008283', ('70', '88'))	('tumor', 'Disease', (162, 167))	('apoptosis', 'CPA', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('AT13387', 'Var', (0, 7))	('melanoma cell', 'Disease', (61, 74))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('inhibited', 'NegReg', (51, 60))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('induced', 'Reg', (132, 139))
39620	31659567	Notably, AT13387 delayed the emergence of resistance to vemurafenib in vitro and in vivo.	('delayed', 'NegReg', (17, 24))	('AT13387', 'Var', (9, 16))	('vemurafenib', 'Chemical', 'MESH:C551177', (56, 67))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('resistance', 'MPA', (42, 52))
39621	31659567	In addition, melanoma cells resistant to vemurafenib or resistant to a combination of BRAF and MEK inhibitors were sensitive to AT13387.	('AT13387', 'Var', (128, 135))	('melanoma cell', 'Disease', (13, 26))	('melanoma cell', 'Disease', 'MESH:D008545', (13, 26))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('vemurafenib', 'Chemical', 'MESH:C551177', (41, 52))
39622	31659567	Similarly to other N-terminal HSP90 inhibitors, AT13387 induced expression of chaperones, including HSP70.	('AT13387', 'Var', (48, 55))	('expression', 'MPA', (64, 74))	('HSP90', 'Gene', (30, 35))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('HSP90', 'Gene', '3320', (30, 35))	('HSP70', 'Gene', (100, 105))	('HSP70', 'Gene', '3308', (100, 105))	('induced', 'Reg', (56, 63))
39623	31659567	In a phase I study, AT13387 was tolerable in patients with advanced solid tumors and had acceptable safety profile.	('solid tumors', 'Disease', (68, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('solid tumors', 'Disease', 'MESH:D009369', (68, 80))	('patients', 'Species', '9606', (45, 53))	('AT13387', 'Var', (20, 27))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
39626	31659567	NVP-AUY922 is a resorcinol isoxazole amide compound with a high affinity to HSP90.	('NVP-AUY922', 'Var', (0, 10))	('resorcinol isoxazole amide', 'Chemical', 'MESH:C031389', (16, 42))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (0, 10))	('HSP90', 'Gene', (76, 81))	('HSP90', 'Gene', '3320', (76, 81))
39627	31659567	NVP-AUY922 affected proliferation and inhibited colony-forming capacity of melanoma cells.	('NVP-AUY922', 'Var', (0, 10))	('inhibited', 'NegReg', (38, 47))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma cell', 'Disease', (75, 88))	('affected', 'Reg', (11, 19))	('melanoma cell', 'Disease', 'MESH:D008545', (75, 88))
39628	31659567	NVP-AUY922 decreased protein level of cyclin D1, and decreased activity of ERK1/2 and NF-kappaB signaling pathway.	('activity', 'MPA', (63, 71))	('decreased', 'NegReg', (53, 62))	('NVP-AUY922', 'Var', (0, 10))	('decreased protein level', 'Phenotype', 'HP:0003075', (11, 34))	('decreased', 'NegReg', (11, 20))	('ERK1', 'molecular_function', 'GO:0004707', ('75', '79'))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (0, 10))	('cyclin', 'molecular_function', 'GO:0016538', ('38', '44'))	('ERK1/2', 'Gene', '5595;5594', (75, 81))	('NF-kappaB', 'Gene', '4790', (86, 95))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('cyclin D1', 'Gene', '595', (38, 47))	('ERK1/2', 'Gene', (75, 81))	('signaling pathway', 'biological_process', 'GO:0007165', ('96', '113'))	('cyclin D1', 'Gene', (38, 47))	('NF-kappaB', 'Gene', (86, 95))
39629	31659567	In addition to inducing apoptosis, NVP-AUY922 elevated LC3II/LC3I (microtubule-associated proteins 1A/1B light chain 3B) ratio in a time-dependent manner indicating activation of autophagy.	('C', 'Chemical', 'MESH:D002244', (62, 63))	('LC3II/LC3I', 'MPA', (55, 65))	('elevated', 'PosReg', (46, 54))	('C', 'Chemical', 'MESH:D002244', (56, 57))	('autophagy', 'biological_process', 'GO:0016236', ('179', '188'))	('apoptosis', 'CPA', (24, 33))	('NVP-AUY922', 'Var', (35, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('24', '33'))	('inducing', 'Reg', (15, 23))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (35, 45))	('autophagy', 'biological_process', 'GO:0006914', ('179', '188'))	('microtubule', 'cellular_component', 'GO:0005874', ('67', '78'))	('apoptosis', 'biological_process', 'GO:0006915', ('24', '33'))	('autophagy', 'CPA', (179, 188))	('activation', 'PosReg', (165, 175))
39631	31659567	NVP-AUY922 induced expression of HSP70, GRP78 and DDIT3 (DNA damage-inducible transcript 3) encoding CHOP, thereby increasing endoplasmic reticulum stress and activating unfolded protein response in melanoma cells.	('DNA damage-inducible transcript 3', 'Gene', '1649', (57, 90))	('melanoma cell', 'Disease', (199, 212))	('DNA damage-inducible transcript 3', 'Gene', (57, 90))	('unfolded protein response', 'MPA', (170, 195))	('activating', 'PosReg', (159, 169))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('126', '147'))	('expression', 'MPA', (19, 29))	('endoplasmic reticulum stress', 'MPA', (126, 154))	('HSP70', 'Gene', (33, 38))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (0, 10))	('CHOP', 'Gene', '1649', (101, 105))	('increasing', 'PosReg', (115, 125))	('DDIT3', 'Gene', '1649', (50, 55))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('DDIT3', 'Gene', (50, 55))	('HSP70', 'Gene', '3308', (33, 38))	('CHOP', 'Gene', (101, 105))	('melanoma cell', 'Disease', 'MESH:D008545', (199, 212))	('NVP-AUY922', 'Var', (0, 10))	('GRP78', 'Gene', (40, 45))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('GRP78', 'Gene', '3309', (40, 45))
39632	31659567	Co-treatment with PFT-mu (2-phenylethynesulphonamide), which acted as a dual inhibitor of HSP70 and autophagy, showed a synergistic anti-melanoma activity both in vitro and in vivo probably by deregulating redox balance.	('HSP70', 'Gene', (90, 95))	('PFT-mu', 'Var', (18, 24))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('2-phenylethynesulphonamide', 'Chemical', 'MESH:C021591', (26, 52))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('autophagy', 'biological_process', 'GO:0016236', ('100', '109'))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('autophagy', 'biological_process', 'GO:0006914', ('100', '109'))	('HSP70', 'Gene', '3308', (90, 95))
39640	31659567	Ganetespib inhibited tumor growth in mice xenografts, significantly potentiated the tumor growth inhibitory effect of BRAF and MEK inhibitors, and overcame mechanisms of primary and acquired resistance of melanoma cells to BRAF inhibitors.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('MEK', 'Gene', (127, 130))	('BRAF', 'Gene', (118, 122))	('tumor', 'Disease', (21, 26))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('potentiated', 'PosReg', (68, 79))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('melanoma cell', 'Disease', (205, 218))	('tumor', 'Disease', (84, 89))	('melanoma cell', 'Disease', 'MESH:D008545', (205, 218))	('inhibited', 'NegReg', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('inhibitors', 'Var', (131, 141))	('mice', 'Species', '10090', (37, 41))	('overcame', 'NegReg', (147, 155))
39642	31659567	More recently, ganetespib was demonstrated to potentiate anti-tumor effect of immunotherapy as it sensitized melanoma cells to T-cell-mediated killing by upregulating interferon response genes, IFIT1, IFIT2, IFIT3 (interferon-induced protein with tetratricopeptide repeats 1-3) in vitro and in vivo.	('ganetespib', 'Var', (15, 25))	('T-cell-mediated killing', 'CPA', (127, 150))	('melanoma cell', 'Disease', 'MESH:D008545', (109, 122))	('protein', 'cellular_component', 'GO:0003675', ('234', '241'))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('upregulating', 'PosReg', (154, 166))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('IFIT1', 'Gene', (194, 199))	('IFIT2', 'Gene', '3433', (201, 206))	('melanoma cell', 'Disease', (109, 122))	('ganetespib', 'Chemical', 'MESH:C533237', (15, 25))	('IFIT1', 'Gene', '3434', (194, 199))	('potentiate', 'PosReg', (46, 56))	('IFIT3', 'Gene', '3437', (208, 213))	('interferon-induced protein with tetratricopeptide repeats 1-3', 'Gene', '3437', (215, 276))	('IFIT2', 'Gene', (201, 206))	('tumor', 'Disease', (62, 67))	('sensitized', 'Reg', (98, 108))	('IFIT3', 'Gene', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
39646	31659567	PU-H71 exerted higher selectivity in targeting HSP90-oncoprotein complexes than several other N-terminal inhibitors of HSP90.	('HSP90', 'Gene', (119, 124))	('PU-H71', 'Var', (0, 6))	('HSP90', 'Gene', '3320', (47, 52))	('HSP90', 'Gene', '3320', (119, 124))	('N', 'Chemical', 'MESH:D009584', (94, 95))	('selectivity', 'MPA', (22, 33))	('targeting', 'MPA', (37, 46))	('HSP90', 'Gene', (47, 52))
39647	31659567	PU-H71 was shown to induce ER stress and activate UPR pathway involving upregulation of DDIT3 expression.	('upregulation', 'PosReg', (72, 84))	('induce', 'PosReg', (20, 26))	('PU-H71', 'Var', (0, 6))	('activate', 'PosReg', (41, 49))	('DDIT3', 'Gene', (88, 93))	('expression', 'MPA', (94, 104))	('UPR pathway', 'Pathway', (50, 61))	('DDIT3', 'Gene', '1649', (88, 93))	('ER stress', 'MPA', (27, 36))
39651	31659567	More recently, a first-in-human study revealed that PU-H71 was well tolerated in patients with refractory solid tumors, and exerted no dose-limiting toxicity with predominantly grade 1 adverse effects.	('solid tumors', 'Disease', (106, 118))	('PU-H71', 'Var', (52, 58))	('patients', 'Species', '9606', (81, 89))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('solid tumors', 'Disease', 'MESH:D009369', (106, 118))	('toxicity', 'Disease', 'MESH:D064420', (149, 157))	('toxicity', 'Disease', (149, 157))	('human', 'Species', '9606', (26, 31))
39655	31659567	SNX-2112 also induced apoptosis in melanoma cells, which was associated with an activation of caspase-3, caspase-7 and caspase-8, and PARP cleavage.	('caspase-8', 'Gene', (119, 128))	('caspase-3', 'Gene', (94, 103))	('caspase-7', 'Gene', '840', (105, 114))	('apoptosis', 'biological_process', 'GO:0006915', ('22', '31'))	('caspase-8', 'Gene', '841', (119, 128))	('melanoma cell', 'Disease', (35, 48))	('PARP', 'Gene', (134, 138))	('apoptosis', 'CPA', (22, 31))	('SNX-2112', 'Chemical', 'MESH:C534922', (0, 8))	('caspase-3', 'Gene', '836', (94, 103))	('activation', 'PosReg', (80, 90))	('PARP', 'Gene', '142', (134, 138))	('melanoma cell', 'Disease', 'MESH:D008545', (35, 48))	('SNX-2112', 'Var', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('apoptosis', 'biological_process', 'GO:0097194', ('22', '31'))	('caspase-7', 'Gene', (105, 114))
39669	31659567	XL888 induced G2/M phase accumulation of melanoma cells harboring unmutated BRAF, RAS and EGFR, and homozygous P72R variant of p53.	('melanoma cell', 'Disease', 'MESH:D008545', (41, 54))	('M phase', 'biological_process', 'GO:0000279', ('17', '24'))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('90', '94'))	('EGFR', 'Gene', (90, 94))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('G2/M phase accumulation', 'CPA', (14, 37))	('p53', 'Gene', '7157', (127, 130))	('melanoma cell', 'Disease', (41, 54))	('P72R', 'Mutation', 'rs1042522', (111, 115))	('p53', 'Gene', (127, 130))	('P72R', 'Var', (111, 115))
39670	31659567	In turn, the presence of a homozygous BRAFV600E variant was predominantly associated with accumulation of XL888-treated melanoma cells in G1 phase of cell cycle.	('BRAFV600E', 'Var', (38, 47))	('BRAFV600E', 'Mutation', 'rs113488022', (38, 47))	('melanoma cell', 'Disease', 'MESH:D008545', (120, 133))	('cell cycle', 'biological_process', 'GO:0007049', ('150', '160'))	('G1 phase of cell cycle', 'CPA', (138, 160))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('G1 phase', 'biological_process', 'GO:0051318', ('138', '146'))	('accumulation', 'PosReg', (90, 102))	('melanoma cell', 'Disease', (120, 133))
39672	31659567	In addition, XL888 diminished protein levels of ARAF (ARAF proto-oncogene, serine/threonine kinase) and CRAF leading to attenuation of ERK1/2 activity, and decreased activity of AKT and S6 kinases.	('XL888', 'Var', (13, 18))	('CRAF', 'molecular_function', 'GO:0004709', ('104', '108'))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('S6 kinases', 'Pathway', (186, 196))	('activity', 'MPA', (142, 150))	('diminished', 'NegReg', (19, 29))	('ERK1/2', 'Gene', (135, 141))	('activity', 'MPA', (166, 174))	('ERK1/2', 'Gene', '5595;5594', (135, 141))	('protein levels', 'MPA', (30, 44))	('ERK1', 'molecular_function', 'GO:0004707', ('135', '139'))	('threonine', 'Chemical', 'MESH:C061951', (82, 91))	('CRAF', 'Gene', (104, 108))	('decreased', 'NegReg', (156, 165))	('ARAF', 'Gene', '369', (48, 52))	('ARAF', 'Gene', (48, 52))	('ARAF', 'Gene', '369', (54, 58))	('ARAF', 'Gene', (54, 58))	('serine', 'Chemical', 'MESH:C047902', (75, 81))	('CRAF', 'Gene', '5894', (104, 108))	('attenuation', 'NegReg', (120, 131))
39675	31659567	Notably, XL888 efficiently exerted similar effects in three-dimensional spheroid cultures, and in a mouse xenograft model of melanoma with milder effect on the activity of MAPK signaling pathway but retaining its inhibitory potential on CDK4 and WEE1 expression, and activity of AKT and S6.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('MAPK', 'molecular_function', 'GO:0004707', ('172', '176'))	('melanoma', 'Disease', (125, 133))	('MAPK signaling pathway', 'Pathway', (172, 194))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('mouse', 'Species', '10090', (100, 105))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('CDK', 'molecular_function', 'GO:0004693', ('237', '240'))	('XL888', 'Var', (9, 14))	('activity', 'MPA', (267, 275))	('MAPK signaling', 'biological_process', 'GO:0000165', ('172', '186'))	('CDK4', 'Protein', (237, 241))	('AKT', 'Pathway', (279, 282))	('signaling pathway', 'biological_process', 'GO:0007165', ('177', '194'))
39676	31659567	In a panel of NRAS-mutated melanoma cell lines, XL888 caused degradation of IGF-1Rbeta, PDGFR-beta, c-MET and VEGFR1 (vascular endothelial growth factor receptor (1), although it surprisingly increased VEGFR2 (vascular endothelial growth factor receptor (2) level in one cell line.	('degradation', 'NegReg', (61, 72))	('VEGFR2', 'Gene', (202, 208))	('VEGFR2', 'Gene', '3791', (202, 208))	('NRAS', 'Gene', '4893', (14, 18))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('118', '152'))	('VEGFR1', 'Gene', '2321', (110, 116))	('IGF-1Rbeta', 'Gene', (76, 86))	('VEGFR1', 'Gene', (110, 116))	('PDGFR-beta', 'Gene', '5156', (88, 98))	('PDGFR-beta', 'Gene', (88, 98))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('210', '244'))	('XL888', 'Var', (48, 53))	('degradation', 'biological_process', 'GO:0009056', ('61', '72'))	('c-MET', 'Gene', '4233', (100, 105))	('melanoma cell', 'Disease', 'MESH:D008545', (27, 40))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('NRAS', 'Gene', (14, 18))	('vascular endothelial growth factor receptor (1)', 'Gene', '2321', (118, 165))	('c-MET', 'Gene', (100, 105))	('increased', 'PosReg', (192, 201))	('melanoma cell', 'Disease', (27, 40))	('vascular endothelial growth factor receptor (1', 'Gene', (118, 164))
39677	31659567	XL888 inhibited cell proliferation also in melanoma cells with intrinsic and acquired resistance to BRAF inhibitors that were dependent on different mechanisms including either overexpression of cyclin D1, PDGFR-beta or COT, or NRAS mutation.	('cyclin', 'molecular_function', 'GO:0016538', ('195', '201'))	('overexpression', 'PosReg', (177, 191))	('COT', 'Gene', '1326', (220, 223))	('NRAS', 'Gene', (228, 232))	('cell proliferation', 'biological_process', 'GO:0008283', ('16', '34'))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('mutation', 'Var', (233, 241))	('PDGFR-beta', 'Gene', (206, 216))	('PDGFR-beta', 'Gene', '5156', (206, 216))	('cyclin D1', 'Gene', '595', (195, 204))	('inhibited', 'NegReg', (6, 15))	('melanoma cell', 'Disease', (43, 56))	('NRAS', 'Gene', '4893', (228, 232))	('cyclin D1', 'Gene', (195, 204))	('melanoma cell', 'Disease', 'MESH:D008545', (43, 56))	('cell proliferation', 'CPA', (16, 34))	('COT', 'Gene', (220, 223))
39678	31659567	XL888 efficiently reduced levels of ARAF, CRAF and cyclin D1, and inhibited AKT, ERK1/2 and S6 activity in resistant melanoma cells.	('cyclin D1', 'Gene', (51, 60))	('ARAF', 'Gene', (36, 40))	('activity', 'MPA', (95, 103))	('melanoma cell', 'Disease', 'MESH:D008545', (117, 130))	('cyclin D1', 'Gene', '595', (51, 60))	('ERK1/2', 'Gene', '5595;5594', (81, 87))	('ERK1/2', 'Gene', (81, 87))	('AKT', 'Pathway', (76, 79))	('melanoma cell', 'Disease', (117, 130))	('reduced', 'NegReg', (18, 25))	('inhibited', 'NegReg', (66, 75))	('ERK1', 'molecular_function', 'GO:0004707', ('81', '85'))	('XL888', 'Var', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('CRAF', 'Gene', (42, 46))	('cyclin', 'molecular_function', 'GO:0016538', ('51', '57'))	('CRAF', 'molecular_function', 'GO:0004709', ('42', '46'))	('CRAF', 'Gene', '5894', (42, 46))	('levels', 'MPA', (26, 32))	('ARAF', 'Gene', '369', (36, 40))
39683	31659567	In addition, XL888-mediated inhibition of HSP90 was accompanied with induction of a compensatory mechanism involving HSP70 upregulation as shown in both in vitro and in vivo models of melanoma.	('HSP70', 'Gene', (117, 122))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanoma', 'Disease', (184, 192))	('XL888-mediated', 'Var', (13, 27))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('HSP90', 'Gene', (42, 47))	('HSP90', 'Gene', '3320', (42, 47))	('upregulation', 'PosReg', (123, 135))	('HSP70', 'Gene', '3308', (117, 122))	('inhibition', 'NegReg', (28, 38))
39685	31659567	In a clinical study, XL888 in combination with vemurafenib displayed a tolerable side-effect profile and promising activity in melanoma patients with BRAFV600E-mutant tumors.	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('BRAFV600E-mutant', 'Var', (150, 166))	('activity', 'MPA', (115, 123))	('BRAFV600E', 'Mutation', 'rs113488022', (150, 159))	('patients', 'Species', '9606', (136, 144))	('vemurafenib', 'Chemical', 'MESH:C551177', (47, 58))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('melanoma', 'Disease', (127, 135))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
39693	31659567	Additionally, LY-15 and H-10 induced mitochondrial pathway of apoptosis associated with activation of caspase-3 and caspase-9, but not caspase-8.	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('activation', 'PosReg', (88, 98))	('caspase-9', 'Gene', '842', (116, 125))	('H-10', 'Gene', '3005', (24, 28))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('caspase-8', 'Gene', (135, 144))	('caspase-3', 'Gene', (102, 111))	('caspase-9', 'Gene', (116, 125))	('LY-15', 'Var', (14, 19))	('H-10', 'Gene', (24, 28))	('caspase-8', 'Gene', '841', (135, 144))	('mitochondrial', 'CPA', (37, 50))	('caspase-3', 'Gene', '836', (102, 111))
39694	31659567	LY-15 increased BAX and diminished BCL-2 protein levels, and inhibited cell migration.	('increased', 'PosReg', (6, 15))	('inhibited', 'NegReg', (61, 70))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('LY-15', 'Var', (0, 5))	('diminished', 'NegReg', (24, 34))	('BCL-2', 'Gene', '596', (35, 40))	('BCL-2', 'molecular_function', 'GO:0015283', ('35', '40'))	('cell migration', 'biological_process', 'GO:0016477', ('71', '85'))	('BCL-2', 'Gene', (35, 40))	('cell migration', 'CPA', (71, 85))	('BAX', 'Gene', (16, 19))	('BAX', 'Gene', '581', (16, 19))
39695	31659567	H-15 increased melanin production and upregulated TYR (tyrosinase) expression suggesting that H-15 was capable of inducing differentiation in melanoma cells.	('melanoma cell', 'Disease', (142, 155))	('inducing', 'PosReg', (114, 122))	('melanin production', 'MPA', (15, 33))	('H-15', 'Var', (94, 98))	('tyrosinase', 'Gene', '7299', (55, 65))	('H-15', 'Chemical', 'MESH:D006859', (0, 4))	('melanoma cell', 'Disease', 'MESH:D008545', (142, 155))	('upregulated', 'PosReg', (38, 49))	('increased', 'PosReg', (5, 14))	('tyrosinase', 'Gene', (55, 65))	('expression', 'MPA', (67, 77))	('H-15', 'Gene', (0, 4))	('H-15', 'Chemical', 'MESH:D006859', (94, 98))	('differentiation', 'CPA', (123, 138))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))
39698	31659567	Novobiocin induced degradation of HSP90 client proteins including ERBB2, CRAF, mutated p53 and SRC (proto-oncogene tyrosine-protein kinase SRC), although only when used at relatively high concentrations.	('SRC', 'Gene', '6714', (95, 98))	('mutated', 'Var', (79, 86))	('SRC', 'Gene', (139, 142))	('HSP90', 'Gene', '3320', (34, 39))	('ERBB2', 'Gene', '2064', (66, 71))	('tyrosine', 'Chemical', 'None', (115, 123))	('SRC', 'Gene', (95, 98))	('p53', 'Gene', '7157', (87, 90))	('Novobiocin', 'Chemical', 'MESH:D009675', (0, 10))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('p53', 'Gene', (87, 90))	('CRAF', 'Gene', (73, 77))	('CRAF', 'molecular_function', 'GO:0004709', ('73', '77'))	('degradation', 'MPA', (19, 30))	('SRC', 'Gene', '6714', (139, 142))	('HSP90', 'Gene', (34, 39))	('CRAF', 'Gene', '5894', (73, 77))	('degradation', 'biological_process', 'GO:0009056', ('19', '30'))	('ERBB2', 'Gene', (66, 71))
39700	31659567	In one of them, KU135, the coumarin core was modified, and the noviose sugar was replaced with a methylated phenol that can participate in hydrogen bonding.	('hydrogen', 'Chemical', 'MESH:D006859', (139, 147))	('coumarin', 'Chemical', 'MESH:C030123', (27, 35))	('phenol', 'Chemical', 'MESH:D010636', (108, 114))	('core', 'cellular_component', 'GO:0019013', ('36', '40'))	('KU135', 'Var', (16, 21))	('sugar', 'Chemical', 'MESH:D002241', (71, 76))	('participate', 'Reg', (124, 135))
39701	31659567	KU135 arrested melanoma cells in the G2/M phase of cell cycle by increasing the phosphorylation of CDC25C (cell division cycle 25C) at Ser216 and diminishing cyclin B level in contrast to novobiocin that did not influence the level of both proteins.	('novobiocin', 'Chemical', 'MESH:D009675', (188, 198))	('melanoma cell', 'Disease', (15, 28))	('cell cycle', 'biological_process', 'GO:0007049', ('51', '61'))	('KU135', 'Var', (0, 5))	('phosphorylation', 'MPA', (80, 95))	('C', 'Chemical', 'MESH:D002244', (99, 100))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('phosphorylation', 'biological_process', 'GO:0016310', ('80', '95'))	('cell division cycle', 'biological_process', 'GO:0007049', ('107', '126'))	('diminishing', 'NegReg', (146, 157))	('Ser', 'cellular_component', 'GO:0005790', ('135', '138'))	('Ser', 'Chemical', 'MESH:C530429', (135, 138))	('C', 'Chemical', 'MESH:D002244', (129, 130))	('CDC25C', 'Gene', (99, 105))	('C', 'Chemical', 'MESH:D002244', (104, 105))	('CDC25C', 'Gene', '995', (99, 105))	('cyclin', 'molecular_function', 'GO:0016538', ('158', '164'))	('M phase', 'biological_process', 'GO:0000279', ('40', '47'))	('C', 'Chemical', 'MESH:D002244', (101, 102))	('cyclin B level', 'MPA', (158, 172))	('increasing', 'PosReg', (65, 75))	('melanoma cell', 'Disease', 'MESH:D008545', (15, 28))
39702	31659567	Moreover, KU135 reduced melanoma cell viability more potently than novobiocin and N-terminal inhibitor, 17-AAG.	('melanoma cell', 'Disease', (24, 37))	('17-AAG', 'Chemical', 'MESH:C112765', (104, 110))	('melanoma cell', 'Disease', 'MESH:D008545', (24, 37))	('N', 'Chemical', 'MESH:D009584', (82, 83))	('reduced', 'NegReg', (16, 23))	('novobiocin', 'Chemical', 'MESH:D009675', (67, 77))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('KU135', 'Var', (10, 15))
39703	31659567	KU135-induced apoptosis was associated with dissipation of mitochondrial membrane potential that led to the release of cytochrome c, activation of caspase-8, caspase-9 and caspase-3, and PARP cleavage.	('PARP', 'Gene', '142', (187, 191))	('dissipation', 'NegReg', (44, 55))	('apoptosis', 'CPA', (14, 23))	('apoptosis', 'biological_process', 'GO:0097194', ('14', '23'))	('apoptosis', 'biological_process', 'GO:0006915', ('14', '23'))	('caspase-9', 'Gene', (158, 167))	('PARP', 'Gene', (187, 191))	('cytochrome c', 'Gene', '54205', (119, 131))	('cytochrome c', 'molecular_function', 'GO:0045155', ('119', '131'))	('caspase-8', 'Gene', (147, 156))	('caspase-3', 'Gene', '836', (172, 181))	('cytochrome c', 'molecular_function', 'GO:0009461', ('119', '131'))	('cytochrome c', 'Gene', (119, 131))	('caspase-3', 'Gene', (172, 181))	('mitochondrial membrane potential', 'MPA', (59, 91))	('caspase-9', 'Gene', '842', (158, 167))	('caspase-8', 'Gene', '841', (147, 156))	('activation', 'PosReg', (133, 143))	('KU135-induced', 'Var', (0, 13))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('59', '81'))
39704	31659567	Interestingly, KU135 induced AKT phosphorylation after short incubation, but AKT activity was attenuated after 48 h. In addition, KU135 inhibited ERK1/2 activity that might be related to the reduction of HSP90 client proteins, BRAF and CRAF.	('CRAF', 'Gene', '5894', (236, 240))	('ERK1', 'molecular_function', 'GO:0004707', ('146', '150'))	('CRAF', 'molecular_function', 'GO:0004709', ('236', '240'))	('inhibited', 'NegReg', (136, 145))	('reduction', 'NegReg', (191, 200))	('ERK1/2', 'Gene', (146, 152))	('KU135', 'Var', (130, 135))	('activity', 'MPA', (153, 161))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('ERK1/2', 'Gene', '5595;5594', (146, 152))	('CRAF', 'Gene', (236, 240))	('HSP90', 'Gene', (204, 209))	('HSP90', 'Gene', '3320', (204, 209))
39705	31659567	Unlike N-terminal inhibitors, KU135 did not affect HSP27 (heat shock protein 27), HSP70 and GRP94 expression, and activity of HSF-1.	('activity', 'MPA', (114, 122))	('HSP27', 'Gene', (51, 56))	('HSP70', 'Gene', '3308', (82, 87))	('HSF-1', 'Gene', '3297', (126, 131))	('shock', 'Phenotype', 'HP:0031273', (63, 68))	('HSP27', 'Gene', '3315', (51, 56))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('GRP94', 'Gene', (92, 97))	('KU135', 'Var', (30, 35))	('HSF-1', 'Gene', (126, 131))	('N', 'Chemical', 'MESH:D009584', (7, 8))	('HSP70', 'Gene', (82, 87))	('heat shock protein 27', 'Gene', (58, 79))	('GRP94', 'Gene', '7184', (92, 97))	('heat shock protein 27', 'Gene', '3315', (58, 79))	('expression', 'MPA', (98, 108))
39706	31659567	Cancer cells are under constant stress due to the presence of mutant proteins and rapid cell proliferation that affects the control of proteostasis, and in turn elevates cell dependence on HSP90.	('elevates', 'PosReg', (161, 169))	('mutant', 'Var', (62, 68))	('proteins', 'Protein', (69, 77))	('proteostasis', 'Disease', 'MESH:D057165', (135, 147))	('affects', 'Reg', (112, 119))	('HSP90', 'Gene', (189, 194))	('HSP90', 'Gene', '3320', (189, 194))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cell proliferation', 'CPA', (88, 106))	('cell proliferation', 'biological_process', 'GO:0008283', ('88', '106'))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('cell dependence on', 'MPA', (170, 188))	('proteostasis', 'Disease', (135, 147))
39708	31659567	Several HSP90 inhibitors exerting anti-melanoma activity in pre-clinical in vitro and in vivo studies are currently evaluated in clinical trials (Table 1).	('HSP90', 'Gene', '3320', (8, 13))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('pre', 'molecular_function', 'GO:0003904', ('60', '63'))	('inhibitors', 'Var', (14, 24))	('HSP90', 'Gene', (8, 13))
39717	29988936	Patients and families with germline BAP1 mutation are predisposed to familial cancers including UM, mesothelioma, cutaneous melanoma (CM), renal cell carcinoma (RCC), and others.	('CM', 'Phenotype', 'HP:0012056', (134, 136))	('renal cell carcinoma', 'Disease', (139, 159))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (139, 159))	('BAP1', 'Gene', '8314', (36, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('mutation', 'Var', (41, 49))	('Patients', 'Species', '9606', (0, 8))	('RCC', 'Disease', (161, 164))	('predisposed', 'Reg', (54, 65))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('familial cancers', 'Disease', (69, 85))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('familial cancers', 'Disease', 'MESH:D009369', (69, 85))	('BAP1', 'Gene', (36, 40))	('CM', 'Disease', 'MESH:D009202', (134, 136))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('germline', 'Var', (27, 35))	('cutaneous melanoma', 'Disease', (114, 132))	('mesothelioma', 'Disease', (100, 112))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (114, 132))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (114, 132))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (139, 159))
39718	29988936	Clinicians should be aware of the implications of germline BAP1 mutation and advise genetic testing and assessment for BAP1 germline mutation in suspected patients and families.	('mutation', 'Var', (64, 72))	('BAP1', 'Gene', (59, 63))	('BAP1', 'Gene', '8314', (119, 123))	('patients', 'Species', '9606', (155, 163))	('BAP1', 'Gene', '8314', (59, 63))	('BAP1', 'Gene', (119, 123))
39719	29988936	The ability of BAP1 gene mutation to cause multiple tumor types and high penetrance in carriers suggests that this gene has an important role for influencing cancer cell growth.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutation', 'Var', (25, 33))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('multiple tumor', 'Disease', (43, 57))	('multiple tumor', 'Disease', 'MESH:D009369', (43, 57))	('BAP1', 'Gene', '8314', (15, 19))	('cancer', 'Disease', (158, 164))	('cell growth', 'biological_process', 'GO:0016049', ('165', '176'))	('BAP1', 'Gene', (15, 19))	('cause', 'Reg', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
39720	29988936	With progress in understanding the molecular landscape of UM and the development of treatments targeted to the pathways involving BAP1 and other gene mutations, it is possible to improve the outcome of this malignant cancer.	('BAP1', 'Gene', (130, 134))	('improve', 'PosReg', (179, 186))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('mutations', 'Var', (150, 159))	('BAP1', 'Gene', '8314', (130, 134))	('UM', 'Phenotype', 'HP:0007716', (58, 60))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
39734	29988936	Therefore, patients with BAP1 germline mutation are at risk for several malignant tumors and should be counseled regarding cancer risk for patient and family members as well as routinely monitored.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('BAP1', 'Gene', (25, 29))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('germline mutation', 'Var', (30, 47))	('patient', 'Species', '9606', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancer', 'Disease', (123, 129))	('risk', 'Reg', (55, 59))	('patients', 'Species', '9606', (11, 19))	('BAP1', 'Gene', '8314', (25, 29))	('patient', 'Species', '9606', (139, 146))
39755	29988936	Genetic assessment and chromosome microarray on the L and W families disclosed alteration in chromosome region 3p21 in both mesothelioma and UM cases.	('UM', 'Phenotype', 'HP:0007716', (141, 143))	('chromosome', 'cellular_component', 'GO:0005694', ('23', '33'))	('mesothelioma', 'Disease', (124, 136))	('alteration', 'Var', (79, 89))	('chromosome region', 'cellular_component', 'GO:0098687', ('93', '110'))	('mesothelioma', 'Disease', 'MESH:D008654', (124, 136))
39757	29988936	Since then, mutations in BAP1 gene has been confirmed in mesothelioma, UM, CM, and RCC.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('mesothelioma', 'Disease', (57, 69))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('BAP1', 'Gene', (25, 29))	('confirmed', 'Reg', (44, 53))	('mutations', 'Var', (12, 21))	('mesothelioma', 'Disease', 'MESH:D008654', (57, 69))	('UM', 'Phenotype', 'HP:0007716', (71, 73))	('CM', 'Disease', 'MESH:D009202', (75, 77))	('BAP1', 'Gene', '8314', (25, 29))	('CM', 'Phenotype', 'HP:0012056', (75, 77))
39762	29988936	recognized that germline BAP1 mutation was associated with a benign atypical skin melanocytic tumor.	('germline', 'Var', (16, 24))	('BAP1', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutation', 'Var', (30, 38))	('associated', 'Reg', (43, 53))	('BAP1', 'Gene', '8314', (25, 29))	('skin melanocytic tumor', 'Disease', (77, 99))	('skin melanocytic tumor', 'Disease', 'MESH:D012878', (77, 99))
39765	29988936	Unlike Spitz nevus, MBAIT nearly always demonstrate B-Raf Proto-Oncogene (BRAF) mutation.	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('mutation', 'Var', (80, 88))	('nevus', 'Phenotype', 'HP:0003764', (13, 18))	('B-Raf Proto-Oncogene', 'Gene', '673', (52, 72))	('B-Raf Proto-Oncogene', 'Gene', (52, 72))
39768	29988936	Instead of the term MBAITs, some employ the term "BAPomas" to describe this precursor skin lesion that occurs within families having germline BAP1 mutation.	('germline', 'Var', (133, 141))	('BAP1', 'Gene', '8314', (142, 146))	('skin lesion', 'Disease', 'MESH:D012871', (86, 97))	('mutation', 'Var', (147, 155))	('skin lesion', 'Disease', (86, 97))	('BAP1', 'Gene', (142, 146))
39770	29988936	reported 174 patients with germline BAP1 mutation and found that 130 (75%) developed at least one of the five main tumors, including UM (31%), MMe (22%), MBAIT (18%), CM (13%), and RCC (10%).	('MMe', 'Disease', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))	('MBAIT', 'Disease', (154, 159))	('CM', 'Disease', 'MESH:D009202', (167, 169))	('patients', 'Species', '9606', (13, 21))	('BAP1', 'Gene', '8314', (36, 40))	('UM', 'Phenotype', 'HP:0007716', (133, 135))	('mutation', 'Var', (41, 49))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('CM', 'Phenotype', 'HP:0012056', (167, 169))	('MMe', 'Phenotype', 'HP:0100001', (143, 146))	('developed', 'PosReg', (75, 84))	('BAP1', 'Gene', (36, 40))	('RCC', 'Disease', (181, 184))	('RCC', 'Disease', 'MESH:C538614', (181, 184))
39782	29988936	The survival rate in persons with BAP1-related MMe may be significantly longer compared to sporadic MMe as several reports have documented that patients with germline BAP1 mutation showed a sevenfold longer overall survival compared to those with sporadic MMe.	('BAP1', 'Gene', (34, 38))	('persons', 'Species', '9606', (21, 28))	('MMe', 'Phenotype', 'HP:0100001', (256, 259))	('mutation', 'Var', (172, 180))	('overall', 'MPA', (207, 214))	('patients', 'Species', '9606', (144, 152))	('BAP1', 'Gene', '8314', (167, 171))	('MMe', 'Phenotype', 'HP:0100001', (47, 50))	('longer', 'PosReg', (200, 206))	('MMe', 'Phenotype', 'HP:0100001', (100, 103))	('BAP1', 'Gene', '8314', (34, 38))	('BAP1', 'Gene', (167, 171))
39788	29988936	Several different alterations in the BAP1 gene have been described, including large deletions of exons leading to loss of the N-terminal region, focal deletions, frameshift mutations due to insertions or deletions, splice site mutations, and base substitutions leading to non-sense and missense mutations.	('focal deletions', 'Var', (145, 160))	('base substitutions', 'Var', (242, 260))	('loss', 'NegReg', (114, 118))	('non-sense', 'MPA', (272, 281))	('splice site mutations', 'Var', (215, 236))	('frameshift mutations', 'Var', (162, 182))	('BAP1', 'Gene', '8314', (37, 41))	('insertions', 'Var', (190, 200))	('missense mutations', 'Var', (286, 304))	('deletions', 'Var', (204, 213))	('BAP1', 'Gene', (37, 41))	('the N-terminal region', 'MPA', (122, 143))	('deletions', 'Var', (84, 93))
39789	29988936	In various tumors, including RCC, mesothelioma, metastasizing UM, and non-small cell lung cancer, the BAP1 gene is commonly lost by chromosomal deletion, and more than 70% of reported germline BAP1 mutations are truncation.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('RCC', 'Disease', (29, 32))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (70, 96))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (74, 96))	('BAP1', 'Gene', '8314', (102, 106))	('mesothelioma', 'Disease', (34, 46))	('mutations', 'Var', (198, 207))	('mesothelioma', 'Disease', 'MESH:D008654', (34, 46))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('lost', 'NegReg', (124, 128))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (70, 96))	('truncation', 'Var', (212, 222))	('BAP1', 'Gene', (102, 106))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('BAP1', 'Gene', '8314', (193, 197))	('non-small cell lung cancer', 'Disease', (70, 96))	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('tumors', 'Disease', (11, 17))	('BAP1', 'Gene', (193, 197))
39791	29988936	1), while missense mutations affect the ubiquitin hydrolase function of BAP1.	('ubiquitin hydrolase function', 'MPA', (40, 68))	('BAP1', 'Gene', '8314', (72, 76))	('affect', 'Reg', (29, 35))	('missense mutations', 'Var', (10, 28))	('BAP1', 'Gene', (72, 76))	('ubiquitin', 'molecular_function', 'GO:0031386', ('40', '49'))
39792	29988936	In fact, for reasons that are unclear, all four main cancers of BAP1-TPDS have been observed with all classes of mutations.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('observed', 'Reg', (84, 92))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('BAP1', 'Gene', '8314', (64, 68))	('BAP1', 'Gene', (64, 68))
39793	29988936	Therefore, available data suggest no distinct genotype-phenotype correlation between location or type of the mutations and the type of cancers in patients.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (109, 118))	('patients', 'Species', '9606', (146, 154))
39797	29988936	This cancer syndrome follows an AD inheritance pattern, and each child of an individual with BAP1-TPDS has a 50% chance of inheriting the BAP1 pathogenic variant; however, penetrance appears to be incomplete, and the types of BAP1-related tumors can vary among different members of the same family.	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('BAP1', 'Gene', '8314', (93, 97))	('BAP1', 'Gene', '8314', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('BAP1', 'Gene', (226, 230))	('cancer syndrome', 'Disease', 'MESH:D009369', (5, 20))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('BAP1', 'Gene', (138, 142))	('variant', 'Var', (154, 161))	('cancer syndrome', 'Disease', (5, 20))	('BAP1', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('child', 'Species', '9606', (65, 70))	('BAP1', 'Gene', '8314', (226, 230))
39799	29988936	Newer evidence suggests that penetrance of BAP1 mutation is fairly high, and more than 80% of gene carriers are ultimately affected by at least one type of cancer.	('BAP1', 'Gene', (43, 47))	('cancer', 'Disease', (156, 162))	('affected', 'Reg', (123, 131))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('BAP1', 'Gene', '8314', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('mutation', 'Var', (48, 56))
39801	29988936	The proportion of BAP1-TPDS caused by a de novo pathogenic variant is unknown.	('caused', 'Reg', (28, 34))	('BAP1', 'Gene', '8314', (18, 22))	('variant', 'Var', (59, 66))	('BAP1', 'Gene', (18, 22))
39804	29988936	Also, the mutational load in UM tumors is low.	('mutational', 'Var', (10, 20))	('UM', 'Phenotype', 'HP:0007716', (29, 31))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
39805	29988936	Therefore, recurrent mutations in genes and chromosomal abnormalities in UM are likely to be specific for tumor progression rather than random event.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (44, 69))	('UM', 'Phenotype', 'HP:0007716', (73, 75))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('chromosomal abnormalities', 'Disease', (44, 69))	('tumor', 'Disease', (106, 111))	('mutations', 'Var', (21, 30))
39806	29988936	The association between deletion in chromosome 3 (monosomy 3) and metastatic death in UM was first described by Prescher et al and later confirmed by our team in Philadelphia in a large cohort of 1059 patients.	('patients', 'Species', '9606', (201, 209))	('death', 'Disease', 'MESH:D003643', (77, 82))	('UM', 'Phenotype', 'HP:0007716', (86, 88))	('death', 'Disease', (77, 82))	('Philadelphia', 'Disease', 'MESH:D010677', (162, 174))	('Philadelphia', 'Disease', (162, 174))	('deletion', 'Var', (24, 32))	('chromosome', 'cellular_component', 'GO:0005694', ('36', '46'))
39808	29988936	This finding indicates that greater tumor size is correlated with greater single-chromosome mutational profile.	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('single-chromosome mutational', 'Var', (74, 102))	('tumor', 'Disease', (36, 41))
39810	29988936	The GEP of class 1A and 1B tumors resembles normal uveal melanocytes and low-grade uveal melanocytic tumors with 2 and 21% 5-years metastatic risk respectively, whereas the GEP of class 2 tumors is associated with a 72% 5-year metastatic risk, has correlated with chromosome 3 alterations, and has shown reduced expression of melanocytic genes.	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('reduced', 'NegReg', (304, 311))	('expression', 'MPA', (312, 322))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('1B tumors', 'Disease', 'MESH:C565748', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('uveal melanocytic tumors', 'Disease', (83, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('uveal melanocytic tumors', 'Phenotype', 'HP:0007716', (83, 107))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('1B tumors', 'Disease', (24, 33))	('tumors', 'Disease', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('melanocytic genes', 'Gene', (326, 343))	('tumors', 'Disease', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Disease', (27, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('264', '274'))	('alterations', 'Var', (277, 288))	('uveal melanocytic tumors', 'Disease', 'MESH:D014604', (83, 107))	('metastatic', 'CPA', (227, 237))
39811	29988936	Several gene mutations in UM have been described, and these do not resemble other melanoma subtypes such as CM.	('CM', 'Disease', 'MESH:D009202', (108, 110))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('CM', 'Phenotype', 'HP:0012056', (108, 110))	('UM', 'Phenotype', 'HP:0007716', (26, 28))	('mutations', 'Var', (13, 22))
39814	29988936	GNAQ/GNA11 mutations do not have known prognostic value, and they can be found in benign nevi and occur in similar frequencies in metastatic and non-metastatic tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('nevi', 'Phenotype', 'HP:0003764', (89, 93))	('mutations', 'Var', (11, 20))	('GNA11', 'Gene', (5, 10))	('GNAQ', 'Gene', '2776', (0, 4))	('GNA11', 'Gene', '2767', (5, 10))	('benign nevi', 'Disease', (82, 93))	('GNAQ', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('occur', 'Reg', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
39815	29988936	Mutations in other driver genes are likely to arise later in tumor development and have greater importance for patient outcome (Fig.	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('patient', 'Species', '9606', (111, 118))	('tumor', 'Disease', (61, 66))
39816	29988936	BAP1 mutation is associated with monosomy 3 or class 2 GEP tumors and impart poor survival.	('BAP1', 'Gene', (0, 4))	('associated', 'Reg', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('monosomy 3', 'Disease', (33, 43))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('BAP1', 'Gene', '8314', (0, 4))	('mutation', 'Var', (5, 13))
39817	29988936	The frequency of somatic BAP1 mutation in primary UM has been estimated to be approximately 40% which closely resembles chromosome 3 status and strongly correlates with metastatic disease in UM.	('BAP1', 'Gene', (25, 29))	('mutation', 'Var', (30, 38))	('UM', 'Phenotype', 'HP:0007716', (191, 193))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('BAP1', 'Gene', '8314', (25, 29))	('metastatic disease', 'Disease', (169, 187))	('chromosome', 'cellular_component', 'GO:0005694', ('120', '130'))	('correlates with', 'Reg', (153, 168))
39820	29988936	Mutations in this gene have not been detected in disomy 3 of UM, but other mutations including those in EIF1AX (48%) and/or SF3B1 (29%) genes have been identified.	('EIF1AX', 'Gene', (104, 110))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('Mutations', 'Var', (0, 9))	('SF3B1', 'Gene', (124, 129))	('EIF1AX', 'Gene', '1964', (104, 110))	('SF3B1', 'Gene', '23451', (124, 129))
39825	29988936	In the presence of BAP1 germline mutations, the risk for UM occurrence in carriers is estimated at up to 29%.	('BAP1', 'Gene', '8314', (19, 23))	('germline mutations', 'Var', (24, 42))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('BAP1', 'Gene', (19, 23))
39826	29988936	The prevalence of germline BAP1 mutations rate among the unselected population of UM cases is about 2-3%.	('BAP1', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('UM', 'Phenotype', 'HP:0007716', (82, 84))	('BAP1', 'Gene', '8314', (27, 31))
39827	29988936	It is predicted that germline BAP1 mutations are present in about 22% of FUM families overall.	('BAP1', 'Gene', '8314', (30, 34))	('BAP1', 'Gene', (30, 34))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('mutations', 'Var', (35, 44))
39830	29988936	Conversely, with additional family history of CM, MMe, and RCC, the chance of BAP1 germline mutations can be approximately 50%.	('MMe', 'Phenotype', 'HP:0100001', (50, 53))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))	('BAP1', 'Gene', '8314', (78, 82))	('CM', 'Disease', 'MESH:D009202', (46, 48))	('germline mutations', 'Var', (83, 101))	('CM', 'Phenotype', 'HP:0012056', (46, 48))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('BAP1', 'Gene', (78, 82))
39833	29988936	showed that FUM families without BAP1 mutation have lower rate of RCC and MMe compared to those with BAP1 mutations.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('MMe', 'CPA', (74, 77))	('BAP1', 'Gene', '8314', (101, 105))	('MMe', 'Phenotype', 'HP:0100001', (74, 77))	('BAP1', 'Gene', '8314', (33, 37))	('lower', 'NegReg', (52, 57))	('UM', 'Phenotype', 'HP:0007716', (13, 15))	('BAP1', 'Gene', (101, 105))	('mutation', 'Var', (38, 46))	('BAP1', 'Gene', (33, 37))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))
39834	29988936	Despite AD pattern inheritance of BAP1 gene mutations, FUM is indeed uncommon, and it rarely involve more than 2-3 family members.	('BAP1', 'Gene', (34, 38))	('FUM', 'Disease', (55, 58))	('mutations', 'Var', (44, 53))	('BAP1', 'Gene', '8314', (34, 38))	('UM', 'Phenotype', 'HP:0007716', (56, 58))
39836	29988936	While BAP1 is the most frequent known genetic cause of FUM, evidence shows less than 25% of families are positive for germline BAP1 mutations.	('BAP1', 'Gene', (127, 131))	('BAP1', 'Gene', (6, 10))	('mutations', 'Var', (132, 141))	('BAP1', 'Gene', '8314', (127, 131))	('BAP1', 'Gene', '8314', (6, 10))	('UM', 'Phenotype', 'HP:0007716', (56, 58))
39838	29988936	Patients with germline BAP1 mutations and UM are implicated in this hereditary cancer syndrome (BAP1-TPDS).	('BAP1', 'Gene', (23, 27))	('hereditary cancer syndrome', 'Disease', (68, 94))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('BAP1', 'Gene', (96, 100))	('BAP1', 'Gene', '8314', (23, 27))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (68, 94))	('Patients', 'Species', '9606', (0, 8))	('BAP1', 'Gene', '8314', (96, 100))	('mutations', 'Var', (28, 37))	('implicated', 'Reg', (49, 59))	('UM', 'Phenotype', 'HP:0007716', (42, 44))
39842	29988936	Ciliary body involvement is more often noted in patients with BAP1 mutations (75% vs 21.6%).	('BAP1', 'Gene', '8314', (62, 66))	('BAP1', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))	('Ciliary', 'Disease', (0, 7))	('patients', 'Species', '9606', (48, 56))
39844	29988936	Metastatic disease developed more frequently in BAP1 germline mutations group compared to the control group (71% vs 18%).	('BAP1', 'Gene', '8314', (48, 52))	('germline mutations', 'Var', (53, 71))	('BAP1', 'Gene', (48, 52))	('Metastatic disease', 'Disease', 'MESH:C538445', (0, 18))	('Metastatic disease', 'Disease', (0, 18))
39845	29988936	Generally, BAP1 germline mutation is associated with a 4-fold increased risk of metastasis and poor survival in patients.	('metastasis', 'CPA', (80, 90))	('poor survival', 'CPA', (95, 108))	('BAP1', 'Gene', '8314', (11, 15))	('germline mutation', 'Var', (16, 33))	('patients', 'Species', '9606', (112, 120))	('BAP1', 'Gene', (11, 15))
39848	29988936	In UM patients with germline BAP1 gene mutation, the mean survival is 4.74 years in comparison with 9.97 years in patients with normal BAP1 protein expression.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('BAP1', 'Gene', '8314', (135, 139))	('germline', 'Var', (20, 28))	('BAP1', 'Gene', '8314', (29, 33))	('patients', 'Species', '9606', (6, 14))	('BAP1', 'Gene', (135, 139))	('patients', 'Species', '9606', (114, 122))	('BAP1', 'Gene', (29, 33))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
39849	29988936	Patients at high risk for harboring germline BAP1 mutations are offered BAP1 sequencing and genetic counseling.	('BAP1', 'Gene', '8314', (72, 76))	('BAP1', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('BAP1', 'Gene', (72, 76))	('Patients', 'Species', '9606', (0, 8))	('germline', 'Var', (36, 44))	('BAP1', 'Gene', '8314', (45, 49))
39851	29988936	Genetic assessment and testing for BAP1 mutations should be taken into account for patients with two or more of primary tumors (UM, RCC, MMe, and CM) in themselves or first-degree relatives.	('primary tumors', 'Disease', 'MESH:D009369', (112, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('CM', 'Phenotype', 'HP:0012056', (146, 148))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('BAP1', 'Gene', '8314', (35, 39))	('UM', 'Phenotype', 'HP:0007716', (128, 130))	('mutations', 'Var', (40, 49))	('CM', 'Disease', 'MESH:D009202', (146, 148))	('BAP1', 'Gene', (35, 39))	('MMe', 'Phenotype', 'HP:0100001', (137, 140))	('patients', 'Species', '9606', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('primary tumors', 'Disease', (112, 126))	('MMe', 'Disease', (137, 140))
39853	29988936	Germline BAP1 mutation test should be advised when a patient is diagnosed with UM at an early age (younger than 30 years) or one of the following is present in the patients or first relatives: (1) history of two UM cases or more in a family, (2) patients with UM and history of at least one other primary tumor (CM, RCC, and MMe) in themselves, (3) patients with UM and history of at least 2 other primary tumors in first- or second-degree relatives (there is controversy about exclusion of families with only multiple CM cases, given its frequency in the general population).	('patients', 'Species', '9606', (246, 254))	('CM', 'Phenotype', 'HP:0012056', (312, 314))	('MMe', 'Phenotype', 'HP:0100001', (325, 328))	('BAP1', 'Gene', (9, 13))	('tumor', 'Disease', (305, 310))	('patient', 'Species', '9606', (246, 253))	('primary tumors', 'Disease', (398, 412))	('patient', 'Species', '9606', (349, 356))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('CM', 'Disease', 'MESH:D009202', (519, 521))	('tumor', 'Disease', (406, 411))	('patients', 'Species', '9606', (164, 172))	('UM', 'Phenotype', 'HP:0007716', (363, 365))	('patient', 'Species', '9606', (53, 60))	('CM', 'Disease', 'MESH:D009202', (312, 314))	('tumor', 'Disease', 'MESH:D009369', (406, 411))	('patient', 'Species', '9606', (164, 171))	('primary tumors', 'Disease', 'MESH:D009369', (398, 412))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('RCC', 'Phenotype', 'HP:0005584', (316, 319))	('RCC', 'Disease', (316, 319))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('patients', 'Species', '9606', (349, 357))	('tumor', 'Phenotype', 'HP:0002664', (406, 411))	('BAP1', 'Gene', '8314', (9, 13))	('CM', 'Phenotype', 'HP:0012056', (519, 521))	('mutation', 'Var', (14, 22))	('UM', 'Phenotype', 'HP:0007716', (260, 262))	('tumors', 'Phenotype', 'HP:0002664', (406, 412))	('RCC', 'Disease', 'MESH:C538614', (316, 319))	('UM', 'Phenotype', 'HP:0007716', (212, 214))
39854	29988936	Also, germline BAP1 mutations should be suspected when a patient has multifocal UM.	('patient', 'Species', '9606', (57, 64))	('UM', 'Phenotype', 'HP:0007716', (80, 82))	('BAP1', 'Gene', '8314', (15, 19))	('BAP1', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))
39856	29988936	Once the germline BAP1 pathogenic variant has been identified in a family, all family members should be informed about the details of this syndrome.	('BAP1', 'Gene', '8314', (18, 22))	('pathogenic', 'Reg', (23, 33))	('variant', 'Var', (34, 41))	('BAP1', 'Gene', (18, 22))
39862	29988936	If a UM is found in BAP1 mutation carriers, it should be managed as a high-risk tumor, and the ocular oncologist should monitor for systemic metastasis, including magnetic resonance imaging (MRI) of the abdomen and liver every 3-6 months and chest X-ray every 6-12 months.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('BAP1', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mutation', 'Var', (25, 33))	('tumor', 'Disease', (80, 85))	('UM', 'Phenotype', 'HP:0007716', (5, 7))	('BAP1', 'Gene', '8314', (20, 24))
39863	29988936	The discovery of GNAQ/11 and BAP1 mutations in UM provides an opportunity for targeted therapy of metastatic disease.	('metastatic disease', 'Disease', (98, 116))	('GNAQ', 'Gene', (17, 21))	('BAP1', 'Gene', '8314', (29, 33))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('BAP1', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))	('GNAQ', 'Gene', '2776', (17, 21))
39865	29988936	Therapeutic targeting of BAP1 mutation poses a different challenge.	('BAP1', 'Gene', '8314', (25, 29))	('mutation', 'Var', (30, 38))	('BAP1', 'Gene', (25, 29))
39870	29988936	About 80% of UM have oncogenic mutations for GNAQ or GNA11 genes, and it appears to be early or perhaps an initiating event for malignant transformation because these mutations can be found in nevus as well and do not correlate with survival.	('oncogenic', 'CPA', (21, 30))	('mutations', 'Var', (31, 40))	('GNA11', 'Gene', (53, 58))	('nevus', 'Phenotype', 'HP:0003764', (193, 198))	('GNA11', 'Gene', '2767', (53, 58))	('GNAQ', 'Gene', (45, 49))	('UM', 'Phenotype', 'HP:0007716', (13, 15))	('GNAQ', 'Gene', '2776', (45, 49))
39871	29988936	On the contrary, BAP1 inactivation mutation is a late event in tumor progression, beyond which metastasis and death await.	('tumor', 'Disease', (63, 68))	('inactivation mutation', 'Var', (22, 43))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('BAP1', 'Gene', '8314', (17, 21))	('death', 'Disease', 'MESH:D003643', (110, 115))	('death', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('BAP1', 'Gene', (17, 21))
39872	29988936	One strategy is to inhibit downstream signaling molecules that are activated by GNAQ/11 mutations.	('inhibit', 'NegReg', (19, 26))	('mutations', 'Var', (88, 97))	('GNAQ', 'Gene', '2776', (80, 84))	('signaling', 'biological_process', 'GO:0023052', ('38', '47'))	('GNAQ', 'Gene', (80, 84))
39873	29988936	These include mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (MEK) that is shown to be upregulated in GNAQ/GNA11 mutated tumors.	('MAPK', 'molecular_function', 'GO:0004707', ('48', '52'))	('mutated', 'Var', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('GNAQ', 'Gene', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('MEK', 'Gene', (93, 96))	('MEK', 'Gene', '5609', (93, 96))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('GNA11', 'Gene', (138, 143))	('upregulated', 'PosReg', (118, 129))	('tumors', 'Disease', (152, 158))	('mitogen-activated', 'Enzyme', (14, 31))	('GNA11', 'Gene', '2767', (138, 143))	('extracellular', 'cellular_component', 'GO:0005576', ('54', '67'))	('GNAQ', 'Gene', '2776', (133, 137))
39875	29988936	Clinician should be aware of the implications of germline BAP1 mutation and advise genetic testing and assessment for BAP1 germline mutation in suspected patients and families.	('BAP1', 'Gene', (58, 62))	('patients', 'Species', '9606', (154, 162))	('mutation', 'Var', (63, 71))	('BAP1', 'Gene', '8314', (118, 122))	('BAP1', 'Gene', (118, 122))	('BAP1', 'Gene', '8314', (58, 62))
39878	29988936	With progress in understanding the molecular landscape of UM and the development of treatments targeted to the pathways involving GNAQ/GNA11, BAP1, EIF1AX, SF3B1 mutations and epigenetic mechanisms, it is possible to improve the outcome of this malignant cancer.	('GNA11', 'Gene', '2767', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('mutations', 'Var', (162, 171))	('EIF1AX', 'Gene', '1964', (148, 154))	('EIF1AX', 'Gene', (148, 154))	('BAP1', 'Gene', '8314', (142, 146))	('improve', 'PosReg', (217, 224))	('SF3B1', 'Gene', '23451', (156, 161))	('GNAQ', 'Gene', (130, 134))	('BAP1', 'Gene', (142, 146))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('GNA11', 'Gene', (135, 140))	('GNAQ', 'Gene', '2776', (130, 134))	('UM', 'Phenotype', 'HP:0007716', (58, 60))	('SF3B1', 'Gene', (156, 161))	('epigenetic', 'Var', (176, 186))
39882	28018148	In particular, we focus upon the how epigenetic regulatory mechanisms impact five common ocular diseases: age related macular degeneration, age-related cataract, pterygium, retinoblastoma, and uveal melanoma.	('ocular diseases', 'Disease', 'MESH:D005128', (89, 104))	('retinoblastoma', 'Gene', '5925', (173, 187))	('retinoblastoma', 'Phenotype', 'HP:0009919', (173, 187))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('cataract', 'Phenotype', 'HP:0000518', (152, 160))	('uveal melanoma', 'Disease', 'MESH:C536494', (193, 207))	('age related macular degeneration', 'Disease', (106, 138))	('uveal melanoma', 'Disease', (193, 207))	('pterygium', 'Phenotype', 'HP:0001059', (162, 171))	('age-related cataract', 'Phenotype', 'HP:0011141', (140, 160))	('pterygium', 'Disease', (162, 171))	('cataract', 'Disease', (152, 160))	('epigenetic regulatory', 'Var', (37, 58))	('ocular diseases', 'Disease', (89, 104))	('uveal melanoma', 'Phenotype', 'HP:0007716', (193, 207))	('retinoblastoma', 'Gene', (173, 187))	('impact', 'Reg', (70, 76))	('cataract', 'Disease', 'MESH:D002386', (152, 160))	('ocular diseases', 'Phenotype', 'HP:0000478', (89, 104))	('macular degeneration', 'Phenotype', 'HP:0000608', (118, 138))
39885	28018148	Non-coding RNAs include small infrastructural RNAs: nuclear, nucleolar, ribosomal as well as regulatory RNAs: microRNAs, long non-coding RNAs, small-interfering RNAs, and Piwi-interacting RNAs.	('small-interfering', 'Var', (143, 160))	('Piwi', 'Gene', '9271', (171, 175))	('Piwi', 'Gene', (171, 175))
39887	28018148	This mini-review will focus on two areas of significant epigenetic research in human cell lines and tissues: DNA methylation and non-coding RNA molecules, in five common ophthalmic diseases.	('ophthalmic diseases', 'Disease', (170, 189))	('non-coding RNA', 'Var', (129, 143))	('ophthalmic diseases', 'Disease', 'MESH:C535922', (170, 189))	('human', 'Species', '9606', (79, 84))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('RNA', 'cellular_component', 'GO:0005562', ('140', '143'))	('methylation', 'Var', (113, 124))	('DNA methylation', 'biological_process', 'GO:0006306', ('109', '124'))	('DNA', 'Var', (109, 112))
39888	28018148	In the past decade, prior studies have identified epigenetic modifications in cancer, neurologic disease, and autoimmune disease.	('autoimmune disease', 'Disease', 'MESH:D001327', (110, 128))	('autoimmune disease', 'Phenotype', 'HP:0002960', (110, 128))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('neurologic disease', 'Disease', 'MESH:D019636', (86, 104))	('neurologic disease', 'Disease', (86, 104))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('autoimmune disease', 'Disease', (110, 128))	('neurologic disease', 'Phenotype', 'HP:0000707', (86, 104))	('epigenetic modifications', 'Var', (50, 74))
39889	28018148	Although the epigenetic findings of chromatin remodeling and modifications of histones have been noted in models of mice, Drosophila, and zebrafish, we will focus on the genes involved in abnormal DNA methylation and abnormal miRNA expression as these have been the two most significant areas of epigenetics applied to human ophthalmic disease.	('abnormal', 'Var', (188, 196))	('mice', 'Species', '10090', (116, 120))	('ophthalmic disease', 'Disease', 'MESH:C535922', (325, 343))	('chromatin', 'cellular_component', 'GO:0000785', ('36', '45'))	('miRNA', 'MPA', (226, 231))	('DNA', 'cellular_component', 'GO:0005574', ('197', '200'))	('Drosophila', 'Species', '7227', (122, 132))	('zebrafish', 'Species', '7955', (138, 147))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('36', '56'))	('DNA methylation', 'biological_process', 'GO:0006306', ('197', '212'))	('ophthalmic disease', 'Disease', (325, 343))	('human', 'Species', '9606', (319, 324))
39896	28018148	Researchers identified 231 genes with altered methylation patterns in the promoter regions in monozygotic AMD twin patients and dizygotic AMD twin patients.	('AMD', 'Disease', (138, 141))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('patients', 'Species', '9606', (115, 123))	('altered', 'Reg', (38, 45))	('methylation patterns', 'Var', (46, 66))	('patients', 'Species', '9606', (147, 155))	('AMD', 'Disease', 'MESH:D006009', (106, 109))	('AMD', 'Disease', (106, 109))	('AMD', 'Disease', 'MESH:D006009', (138, 141))
39897	28018148	described the DNA hypomethylation in the promoter region of IL17RC, the receptor for IL-17A and IL-17F in the AMD twin patients.	('AMD', 'Disease', (110, 113))	('IL-17A', 'Gene', '3605', (85, 91))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('14', '33'))	('patients', 'Species', '9606', (119, 127))	('IL-17F', 'Gene', '112744', (96, 102))	('hypomethylation', 'Var', (18, 33))	('IL17RC', 'Gene', '84818', (60, 66))	('IL-17', 'molecular_function', 'GO:0030367', ('85', '90'))	('IL-17A', 'Gene', (85, 91))	('IL-17', 'molecular_function', 'GO:0030367', ('96', '101'))	('IL17', 'molecular_function', 'GO:0030367', ('60', '64'))	('DNA', 'cellular_component', 'GO:0005574', ('14', '17'))	('IL-17F', 'Gene', (96, 102))	('IL17RC', 'Gene', (60, 66))	('AMD', 'Disease', 'MESH:D006009', (110, 113))
39901	28018148	Hypermethylation was identified in the promoter regions of two glutathione S transferase isoforms: GSTM1 and GSTM5; this correlated with decreased mRNA and protein levels.	('GSTM5', 'Gene', '2949', (109, 114))	('GSTM5', 'Gene', (109, 114))	('Hypermethylation', 'Var', (0, 16))	('GSTM1', 'Gene', '2944', (99, 104))	('GSTM1', 'Gene', (99, 104))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('decreased', 'NegReg', (137, 146))
39902	28018148	Of note, glutathione S transferases (GSTs) are a key part in the defense against oxidative stress; epigenetic downregulation of GSTs could contribute to increased vision loss due to the increased susceptibility to oxidative stress in AMD patients.	('GSTs', 'Gene', '373156', (37, 41))	('oxidative stress', 'Phenotype', 'HP:0025464', (214, 230))	('glutathione S transferases', 'Gene', '373156', (9, 35))	('glutathione S transferases', 'Gene', (9, 35))	('oxidative stress', 'Phenotype', 'HP:0025464', (81, 97))	('GSTs', 'Gene', (37, 41))	('vision', 'biological_process', 'GO:0007601', ('163', '169'))	('AMD', 'Disease', 'MESH:D006009', (234, 237))	('vision loss', 'Phenotype', 'HP:0000572', (163, 174))	('epigenetic', 'Var', (99, 109))	('GSTs', 'Gene', '373156', (128, 132))	('vision loss', 'Disease', 'MESH:D014786', (163, 174))	('downregulation', 'NegReg', (110, 124))	('patients', 'Species', '9606', (238, 246))	('AMD', 'Disease', (234, 237))	('GSTs', 'Gene', (128, 132))	('vision loss', 'Disease', (163, 174))
39915	28018148	Typically, patients with pterygium do not have central vision loss; however, the abnormal growth and proliferation of cells onto the peripheral cornea can induce astigmatism as well as disturb the tear film, contributing to dry eyes.	('vision loss', 'Phenotype', 'HP:0000572', (55, 66))	('dry eyes', 'Phenotype', 'HP:0001097', (224, 232))	('astigmatism', 'Disease', (162, 173))	('tear', 'Phenotype', 'HP:0009926', (197, 201))	('proliferation', 'CPA', (101, 114))	('dry eyes', 'Disease', (224, 232))	('astigmatism', 'Disease', 'MESH:D001251', (162, 173))	('vision loss', 'Disease', 'MESH:D014786', (55, 66))	('astigmatism', 'Phenotype', 'HP:0000483', (162, 173))	('abnormal growth', 'Phenotype', 'HP:0001507', (81, 96))	('patients', 'Species', '9606', (11, 19))	('dry eyes', 'Disease', 'MESH:D015352', (224, 232))	('tear film', 'MPA', (197, 206))	('vision loss', 'Disease', (55, 66))	('induce', 'Reg', (155, 161))	('pterygium', 'Phenotype', 'HP:0001059', (25, 34))	('vision', 'biological_process', 'GO:0007601', ('55', '61'))	('disturb', 'Reg', (185, 192))	('contributing to', 'Reg', (208, 223))	('abnormal', 'Var', (81, 89))
39919	28018148	In particular, hypermethylation at the promoter region of TGM2 indicated decreased transcript and protein levels while hypomethylation of regions of MMP2 and the promoter region of CD24 indicated increased transcript and protein levels.	('increased', 'PosReg', (196, 205))	('hypomethylation', 'Var', (119, 134))	('MMP2', 'Gene', '4313', (149, 153))	('protein', 'cellular_component', 'GO:0003675', ('221', '228'))	('decreased', 'NegReg', (73, 82))	('TGM2', 'Gene', (58, 62))	('MMP2', 'Gene', (149, 153))	('CD24', 'Gene', (181, 185))	('hypermethylation', 'Var', (15, 31))	('TGM2', 'Gene', '7052', (58, 62))	('CD24', 'Gene', '100133941', (181, 185))	('MMP2', 'molecular_function', 'GO:0004228', ('149', '153'))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))
39923	28018148	Researchers have identified hypermethylation in the promoter regions of ten genes: MSH6, CD44, PAX5, GATA5, TP53, VHL, GSTP1, MGMT, RB1, and CDKN2.	('TP53', 'Gene', (108, 112))	('CDKN2', 'Gene', (141, 146))	('RB1', 'Gene', (132, 135))	('MGMT', 'molecular_function', 'GO:0003908', ('126', '130'))	('CD44', 'Gene', '960', (89, 93))	('CD44', 'Gene', (89, 93))	('RB', 'Phenotype', 'HP:0009919', (132, 134))	('MGMT', 'Gene', '4255', (126, 130))	('VHL', 'Gene', (114, 117))	('MSH6', 'Gene', (83, 87))	('TP53', 'Gene', '7157', (108, 112))	('PAX5', 'Gene', (95, 99))	('GATA5', 'Gene', (101, 106))	('MSH6', 'Gene', '2956', (83, 87))	('GSTP1', 'Gene', '2950', (119, 124))	('RB1', 'Gene', '5925', (132, 135))	('CDKN2', 'Gene', '1029', (141, 146))	('GSTP1', 'Gene', (119, 124))	('hypermethylation', 'Var', (28, 44))	('VHL', 'Gene', '7428', (114, 117))	('PAX5', 'Gene', '5079', (95, 99))	('GATA5', 'Gene', '140628', (101, 106))	('MGMT', 'Gene', (126, 130))
39926	28018148	For the children diagnosed with RB, the dysregulation of methylation identified in these eleven genes is a further tool for targeted treatment to improve the prognosis of this ocular cancer.	('RB', 'Phenotype', 'HP:0009919', (32, 34))	('cancer', 'Disease', (183, 189))	('children', 'Species', '9606', (8, 16))	('dysregulation', 'Var', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('methylation', 'MPA', (57, 68))	('RB', 'Gene', '5925', (32, 34))	('ocular cancer', 'Phenotype', 'HP:0100012', (176, 189))	('improve', 'PosReg', (146, 153))	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
39927	28018148	In addition, microarray analysis reveals that several small non-coding RNA molecules are aberrant and are highly expressed in patients with RB: miR-494, let-7e, miR-513-1, miR-513-2, miR-518c, miR-129-1, miR-129-2.	('miR-129-1', 'Gene', '406917', (193, 202))	('miR-129-1', 'Gene', (193, 202))	('miR-494', 'Gene', '574452', (144, 151))	('let-7e', 'Gene', '406887', (153, 159))	('miR-494', 'Gene', (144, 151))	('miR-129-2', 'Gene', '100302138', (204, 213))	('miR-129-2', 'Gene', (204, 213))	('RB', 'Phenotype', 'HP:0009919', (140, 142))	('miR-518c', 'Gene', (183, 191))	('let-7e', 'Gene', (153, 159))	('miR-518c', 'Gene', '574477', (183, 191))	('RNA', 'cellular_component', 'GO:0005562', ('71', '74'))	('patients', 'Species', '9606', (126, 134))	('miR-513-1', 'Var', (161, 170))	('miR-513-2', 'Var', (172, 181))	('RB', 'Gene', '5925', (140, 142))
39928	28018148	Other researchers identified that miR-34a, miR-17/92, miR-I29-2 functions as a tumor-suppressor in RB cells.	('miR-34a', 'Gene', (34, 41))	('tumor', 'Disease', (79, 84))	('miR-17/92', 'Gene', (43, 52))	('RB', 'Phenotype', 'HP:0009919', (99, 101))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('79', '95'))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('miR-34a', 'Gene', '407040', (34, 41))	('RB', 'Gene', '5925', (99, 101))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('79', '95'))	('miR-17/92', 'Gene', '407975;406952;407047', (43, 52))	('miR-I29-2', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
39933	28018148	Researchers identified that the tumor suppressor gene, RASSF1A, was hypermethylated in 50 percent of the archived frozen tumor specimens and in 91 percent of the uveal melanoma cell lines.	('uveal melanoma', 'Phenotype', 'HP:0007716', (162, 176))	('uveal melanoma', 'Disease', (162, 176))	('uveal melanoma', 'Disease', 'MESH:C536494', (162, 176))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor suppressor', 'biological_process', 'GO:0051726', ('32', '48'))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (121, 126))	('RASSF1A', 'Gene', (55, 62))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('32', '48'))	('hypermethylated', 'Var', (68, 83))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('RASSF1A', 'Gene', '11186', (55, 62))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
39935	28018148	Furthermore, the EFS gene was noted to have bi-allelic methylation in uveal melanoma biopsies, with a poor prognosis for this cohort of patients.	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('uveal melanoma', 'Disease', (70, 84))	('EFS gene', 'Gene', (17, 25))	('bi-allelic methylation', 'Var', (44, 66))	('patients', 'Species', '9606', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
39938	28018148	Our mini-review of how the study of epigenetics has impacted five common ophthalmic diseases focused upon DNA methylation and non-coding RNAs.	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('DNA methylation', 'Disease', (106, 121))	('impacted', 'Reg', (52, 60))	('non-coding RNAs', 'Var', (126, 141))	('ophthalmic diseases', 'Disease', 'MESH:C535922', (73, 92))	('DNA methylation', 'biological_process', 'GO:0006306', ('106', '121'))	('ophthalmic diseases', 'Disease', (73, 92))
39939	28018148	With these epigenetic alterations, the progression of AMD, age-related cataracts, and pterygium will be better understood regarding the interactions between gene expression changes and environmental exposures.	('gene expression', 'biological_process', 'GO:0010467', ('157', '172'))	('AMD', 'Disease', 'MESH:D006009', (54, 57))	('AMD', 'Disease', (54, 57))	('cataract', 'Phenotype', 'HP:0000518', (71, 79))	('cataracts', 'Disease', 'MESH:D002386', (71, 80))	('cataracts', 'Disease', (71, 80))	('age-related cataracts', 'Phenotype', 'HP:0011141', (59, 80))	('pterygium', 'Phenotype', 'HP:0001059', (86, 95))	('age-related cataract', 'Phenotype', 'HP:0011141', (59, 79))	('epigenetic alterations', 'Var', (11, 33))	('cataracts', 'Phenotype', 'HP:0000518', (71, 80))
39943	28018148	In the future, our conversations with our patients will emphasize that specific therapeutics to epigenetic alterations will be a more effective treatment modality to provide hope to prevent irreversible vision loss.	('vision', 'biological_process', 'GO:0007601', ('203', '209'))	('vision loss', 'Phenotype', 'HP:0000572', (203, 214))	('vision loss', 'Disease', 'MESH:D014786', (203, 214))	('patients', 'Species', '9606', (42, 50))	('vision loss', 'Disease', (203, 214))	('epigenetic alterations', 'Var', (96, 118))
39969	27366747	Such a model should accurately mimic different characteristics of uveal melanoma such as genetics (monosomy 3, GNAQ/GNA11, and BAP1 mutations), hematogenous spread to the liver, (as the eye lacks lymphatics), an inflammatory tumor microenvironment, and other tumor growth characteristics.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('uveal melanoma', 'Disease', (66, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('BAP1', 'Gene', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('mutations', 'Var', (132, 141))	('tumor', 'Disease', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('BAP1', 'Gene', '104416', (127, 131))	('tumor', 'Disease', (259, 264))	('GNAQ/GNA11', 'Gene', (111, 121))
39998	27366747	Unlike cutaneous or conjunctival melanoma, mutations in B-RAF, RAS, or KIT genes occur rarely in uveal melanoma.	('KIT', 'molecular_function', 'GO:0005020', ('71', '74'))	('RAS', 'Gene', (63, 66))	('conjunctival melanoma', 'Disease', (20, 41))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (20, 41))	('KIT', 'Gene', (71, 74))	('B-RAF', 'Gene', '109880', (56, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('uveal melanoma', 'Disease', (97, 111))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (20, 41))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('mutations', 'Var', (43, 52))	('B-RAF', 'Gene', (56, 61))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
39999	27366747	Characteristic mutations differ between uveal and cutaneous melanoma and even among tumors itself, accounting for different progression and metastatic behavior.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('mutations', 'Var', (15, 24))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('cutaneous melanoma', 'Disease', (50, 68))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (50, 68))	('tumors', 'Disease', (84, 90))	('uveal', 'Disease', (40, 45))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (50, 68))
40008	27366747	However, recently, novel established permanent cell lines from primary and metastatic uveal melanomas exhibiting a characteristic genetic profile (including GNAQ, GNA11, or BAP1 mutations) allow for further investigations on genetic pathways and their influence on tumor progression and metastasis.	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('GNA11', 'Gene', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('influence', 'Reg', (252, 261))	('tumor', 'Disease', (265, 270))	('melanomas', 'Phenotype', 'HP:0002861', (92, 101))	('investigations', 'Reg', (207, 221))	('GNAQ', 'Gene', (157, 161))	('BAP1', 'Gene', '104416', (173, 177))	('uveal melanomas', 'Phenotype', 'HP:0007716', (86, 101))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('uveal melanomas', 'Disease', (86, 101))	('BAP1', 'Gene', (173, 177))	('mutations', 'Var', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('uveal melanomas', 'Disease', 'MESH:C536494', (86, 101))
40027	27366747	Several criteria have been suggested for such models; for example, mice must carry the same mutation that occurs in the human tumor and mutations should be engineered within the endogenous locus.	('human', 'Species', '9606', (120, 125))	('mutation', 'Var', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mice', 'Species', '10090', (67, 71))	('tumor', 'Disease', (126, 131))
40043	27366747	This breed represents the first transgenic mouse model of uveal melanocytic proliferation which is driven by a GNAQ gene alteration.	('uveal melanocytic proliferation', 'Disease', 'MESH:D059545', (58, 89))	('transgenic', 'Species', '10090', (32, 42))	('alteration', 'Var', (121, 131))	('mouse', 'Species', '10090', (43, 48))	('uveal melanocytic proliferation', 'Phenotype', 'HP:0007716', (58, 89))	('uveal melanocytic proliferation', 'Disease', (58, 89))
40044	27366747	By this means it genetically resembles human uveal melanomas, as about 80% of patients carry a G-protein (GNAQ and/or GNA11) mutation as an early event in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('GNA11', 'Gene', (118, 123))	('uveal melanomas', 'Disease', 'MESH:C536494', (45, 60))	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('GNAQ', 'Gene', (106, 110))	('tumor', 'Disease', (155, 160))	('G-protein', 'Protein', (95, 104))	('uveal melanomas', 'Disease', (45, 60))	('patients', 'Species', '9606', (78, 86))	('uveal melanomas', 'Phenotype', 'HP:0007716', (45, 60))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('human', 'Species', '9606', (39, 44))	('mutation', 'Var', (125, 133))
40047	27366747	Oncogenic resemblance with human uveal melanoma is given as uveal tumorigenesis is driven by an inserted plasmid with a mitfa:GNA11 Q209L overexpression (Rose, unpublished data).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('uveal melanoma', 'Disease', 'MESH:C536494', (33, 47))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('human', 'Species', '9606', (27, 32))	('driven by', 'Reg', (83, 92))	('uveal melanoma', 'Disease', (33, 47))	('uveal melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('Q209L', 'Mutation', 'rs1057519742', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('overexpression', 'PosReg', (138, 152))	('Q209L', 'Var', (132, 137))
40061	27366747	However, the generation of metastatic cell clones within a primary tumor requires genetic alterations and subsequent selection of such clones is heavily influenced by interactions with the surrounding microenvironment.	('primary tumor', 'Disease', (59, 72))	('primary tumor', 'Disease', 'MESH:D009369', (59, 72))	('genetic alterations', 'Var', (82, 101))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))
40069	27366747	The agent may be of chemical, radiational, physical, or biological origin and the impact may result in alterations and mutations that lead to uncontrolled cell growth.	('uncontrolled cell growth', 'MPA', (142, 166))	('lead to', 'Reg', (134, 141))	('alterations', 'Var', (103, 114))	('radiational', 'Disease', 'MESH:D004194', (30, 41))	('cell growth', 'biological_process', 'GO:0016049', ('155', '166'))	('radiational', 'Disease', (30, 41))	('mutations', 'Var', (119, 128))	('result in', 'Reg', (93, 102))
40072	27366747	However, treating transgenic mice which harbor a predisposing genetic alteration in an oncogene responsible for uveal melanocytic proliferation might provide an opportunity of a new animal model.	('transgenic mice', 'Species', '10090', (18, 33))	('uveal melanocytic proliferation', 'Disease', (112, 143))	('uveal melanocytic proliferation', 'Phenotype', 'HP:0007716', (112, 143))	('genetic alteration', 'Var', (62, 80))	('uveal melanocytic proliferation', 'Disease', 'MESH:D059545', (112, 143))
40096	27308390	UM often involves activating mutations in guanine nucleotide binding protein (G protein), q polypeptide (GQ), or G Protein, alpha 11 (G11).	('G Protein, alpha 11 (G11', 'Gene', (113, 137))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('G protein', 'Protein', (78, 87))	('mutations', 'Var', (29, 38))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('50', '68'))	('guanine nucleotide', 'Protein', (42, 60))	('activating', 'PosReg', (18, 28))	('q polypeptide', 'Protein', (90, 103))	('G Protein, alpha 11 (G11)', 'Gene', '319922', (113, 138))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('GQ', 'Gene', (105, 107))
40101	27308390	Instead of carrying mutations in v-raf murine sarcoma viral oncogene homolog B1 (BRAF) or neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), approximately 80% of cases of UM have activating mutations in either guanine nucleotide binding protein (G protein) q polypeptide (GNAQ), or G protein alpha 11 (GNA11).	('murine', 'Species', '10090', (39, 45))	('neuroblastoma', 'Phenotype', 'HP:0003006', (90, 103))	('GNA11', 'Gene', (308, 313))	('G protein alpha 11', 'Gene', '14672', (288, 306))	('BRAF', 'Gene', (81, 85))	('GNAQ', 'Gene', '14682', (278, 282))	('neuroblastoma RAS viral', 'Disease', (90, 113))	('GNA11', 'Gene', '14672', (308, 313))	('UM', 'Phenotype', 'HP:0007716', (177, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('224', '242'))	('G protein alpha 11', 'Gene', (288, 306))	('protein', 'cellular_component', 'GO:0003675', ('243', '250'))	('sarcoma viral', 'Disease', 'MESH:D001102', (46, 59))	('protein', 'cellular_component', 'GO:0003675', ('254', '261'))	('sarcoma viral', 'Disease', (46, 59))	('G protein) q polypeptide', 'Protein', (252, 276))	('mutations', 'Var', (196, 205))	('protein', 'cellular_component', 'GO:0003675', ('290', '297'))	('activating', 'PosReg', (185, 195))	('neuroblastoma RAS viral', 'Disease', 'MESH:D009447', (90, 113))	('BRAF', 'Gene', '109880', (81, 85))	('NRAS', 'Gene', '18176', (140, 144))	('NRAS', 'Gene', (140, 144))	('GNAQ', 'Gene', (278, 282))
40103	27308390	However, mutations at arginine 183 (R183) or glutamine 209 (Q209) of GQ/11 convert the G protein into a constitutively active and oncogenic form.	('R183', 'Var', (36, 40))	('glutamine', 'Chemical', 'MESH:D005973', (45, 54))	('arginine', 'Chemical', 'MESH:D001120', (22, 30))	('Q209', 'Var', (60, 64))	('mutations at arginine 183 (R183', 'Var', (9, 40))	('convert', 'Reg', (75, 82))	('GQ/11', 'Gene', (69, 74))	('G protein', 'Protein', (87, 96))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
40107	27308390	To explore this hypothesis, we tested whether YAP can be activated by the cancer-associated mutant form of GQ/11.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('mutant', 'Var', (92, 98))	('GQ/11', 'Gene', (107, 112))	('YAP', 'Disease', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
40108	27308390	We found that ectopic expression of mutant protein (GQR183Q, GQQ209L, or G11Q209L) in human embryonic kidney 293A cells caused dramatic dephosphorylation, nuclear localization, and activation of YAP.	('nuclear localization', 'MPA', (155, 175))	('localization', 'biological_process', 'GO:0051179', ('163', '175'))	('GQQ209L', 'Var', (61, 68))	('YAP', 'Gene', (195, 198))	('embryonic kidney', 'Disease', 'MESH:D007674', (92, 108))	('293A', 'CellLine', 'CVCL:6910', (109, 113))	('human', 'Species', '9606', (86, 91))	('G11Q209L', 'Var', (73, 81))	('activation', 'PosReg', (181, 191))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('GQR183Q', 'Var', (52, 59))	('embryonic kidney', 'Disease', (92, 108))	('dephosphorylation', 'biological_process', 'GO:0016311', ('136', '153'))	('dephosphorylation', 'MPA', (136, 153))
40110	27308390	In a collection of formalin-fixed, paraffin-embedded sections of enucleated tumors, we observed a strong correlation between mutated GQ/11 and YAP nuclear localization.	('GQ/11', 'Gene', (133, 138))	('paraffin', 'Chemical', 'MESH:D010232', (35, 43))	('mutated', 'Var', (125, 132))	('formalin', 'Chemical', 'MESH:D005557', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('localization', 'biological_process', 'GO:0051179', ('155', '167'))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('YAP nuclear localization', 'MPA', (143, 167))
40111	27308390	These findings indicate that YAP is activated by mutant GQ/11 widely present in UM, and also suggest a role of YAP oncoprotein in mutant GQ/11-induced tumorigenesis.	('GQ/11-induced', 'Reg', (137, 150))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('mutant', 'Var', (49, 55))	('UM', 'Phenotype', 'HP:0007716', (80, 82))	('tumor', 'Disease', (151, 156))	('GQ/11-induced', 'Gene', (137, 150))	('mutant', 'Var', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
40112	27308390	In a subcutaneous xenograft mouse model, UM cells (92.1, GqQ209L) were able to form solid tumors in immunocompromised mice.	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('mouse', 'Species', '10090', (28, 33))	('solid tumors', 'Disease', 'MESH:D009369', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('92.1, GqQ209L', 'Var', (51, 64))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('mice', 'Species', '10090', (118, 122))	('solid tumors', 'Disease', (84, 96))
40113	27308390	However, when Gq was knocked down by shRNA, 92.1 cells failed to develop tumors.	('knocked down', 'Var', (21, 33))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
40114	27308390	In contrast, melan-a cells (immortalized melanocytes) were unable to form tumors subcutaneously, whereas melan-a cells with GqQ209L expression were tumorigenic.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (74, 79))	('GqQ209L expression', 'Var', (124, 142))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
40115	27308390	These results proved that mutant Gq plays an important role in driving tumor formation.	('formation', 'biological_process', 'GO:0009058', ('77', '86'))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mutant', 'Var', (26, 32))	('tumor', 'Disease', (71, 76))
40116	27308390	To test the effect of Yap in mutant Gq/11-induced tumorigenesis, we knocked down Yap in 92.1 cells and melan-a (GqQ209L) cells.	('Gq/11-induced', 'Gene', (36, 49))	('Yap', 'Gene', '22601', (22, 25))	('mutant', 'Var', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('Gq/11', 'Chemical', '-', (36, 41))	('Yap', 'Gene', (22, 25))	('Yap', 'Gene', (81, 84))	('tumor', 'Disease', (50, 55))	('Yap', 'Gene', '22601', (81, 84))	('knocked', 'Reg', (68, 75))
40118	27308390	Therefore, Yap appears to be essential in mediating the oncogenic effect of mutant Gq/11.	('Gq/11', 'Chemical', '-', (83, 88))	('Yap', 'Gene', (11, 14))	('Gq/11', 'Gene', (83, 88))	('Yap', 'Gene', '22601', (11, 14))	('mutant', 'Var', (76, 82))
40122	27308390	These data suggest that inhibiting Yap activity may serve as a novel approach to the treatment of UM lesions driven by Gq/11 mutation.	('Gq/11', 'Gene', (119, 124))	('UM lesions', 'Disease', (98, 108))	('Yap', 'Gene', (35, 38))	('Yap', 'Gene', '22601', (35, 38))	('UM', 'Phenotype', 'HP:0007716', (98, 100))	('Gq/11', 'Chemical', '-', (119, 124))	('mutation', 'Var', (125, 133))
40123	27308390	One interesting discovery of this study is that Yap activation is required for UM lesions by caused Gq/11 mutation but not for those associated with another, less frequent, mutation in Braf.	('Gq/11', 'Chemical', '-', (100, 105))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('mutation', 'Var', (106, 114))	('Yap', 'Gene', (48, 51))	('Gq/11', 'Gene', (100, 105))	('Braf', 'Gene', '109880', (185, 189))	('Yap', 'Gene', '22601', (48, 51))	('Braf', 'Gene', (185, 189))
40124	27308390	YAP was hyperphosphorylated (inactivated) in Braf mutated cells, and YAP knockdown in these cells failed to reduce their tumorigenicity significantly.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('Braf', 'Gene', '109880', (45, 49))	('mutated', 'Var', (50, 57))	('Braf', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
40125	27308390	Moreover, Braf mutant UM cells were less sensitive to Yap inhibition, as a much higher dose of verteporfin was required to effectively kill these cells.	('Yap', 'Gene', '22601', (54, 57))	('verteporfin', 'Chemical', 'MESH:D000077362', (95, 106))	('Braf', 'Gene', '109880', (10, 14))	('UM', 'Phenotype', 'HP:0007716', (22, 24))	('mutant', 'Var', (15, 21))	('Yap', 'Gene', (54, 57))	('Braf', 'Gene', (10, 14))
40126	27308390	Therefore, the mutation background of UM lesions must be taken into consideration when Yap inhibitors are used for therapeutic interventions, and Yap inhibition may only applicable to the category of UM harboring Gq/11 mutation.	('Gq/11', 'Gene', (213, 218))	('UM', 'Phenotype', 'HP:0007716', (200, 202))	('mutation', 'Var', (219, 227))	('Yap', 'Gene', '22601', (87, 90))	('Yap', 'Gene', '22601', (146, 149))	('Yap', 'Gene', (87, 90))	('Yap', 'Gene', (146, 149))	('Gq/11', 'Chemical', '-', (213, 218))	('UM', 'Phenotype', 'HP:0007716', (38, 40))
40128	27308390	GQ/11 mutation functions as a cancer driver and is widely present in UM lesions, but a drug that targets constitutively active GQ/11 is currently not available.	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('mutation', 'Var', (6, 14))	('GQ/11', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
40132	27013893	Orchestrating epigenetic roles targeting ocular tumors Epigenetics is currently one of the most promising areas of study in the field of biomedical research.	('ocular tumors', 'Phenotype', 'HP:0100012', (41, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('ocular tumors', 'Disease', (41, 54))	('Epigenetics', 'Var', (55, 66))	('ocular tumors', 'Disease', 'MESH:D009369', (41, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
40136	27013893	Herein, we review the current understanding of epigenetic mechanisms in ocular tumors, including but not limited to retinoblastoma and uveal melanoma.	('ocular tumors', 'Disease', 'MESH:D009369', (72, 85))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('retinoblastoma', 'Phenotype', 'HP:0009919', (116, 130))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (135, 149))	('ocular tumors', 'Phenotype', 'HP:0100012', (72, 85))	('uveal melanoma', 'Disease', (135, 149))	('uveal melanoma', 'Phenotype', 'HP:0007716', (135, 149))	('epigenetic', 'Var', (47, 57))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('retinoblastoma', 'Gene', '5925', (116, 130))	('ocular tumors', 'Disease', (72, 85))	('retinoblastoma', 'Gene', (116, 130))
40145	27013893	However, with the discovery of disease-related epigenetic mechanisms, epigenetic disruptions have been increasingly found to affect tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('affect', 'Reg', (125, 131))	('epigenetic disruptions', 'Var', (70, 92))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))
40151	27013893	Recent findings suggest that many tumor suppressor genes are methylated, thus leading to tumorigenesis.	('methylated', 'Var', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('leading to', 'Reg', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))
40152	27013893	RB1 inactivation is the primary cause of retinoblastoma (RB); its inactivation is typically caused by loss-of-function mutations and the most recent study showed that RB function might be sexually dimorphic.	('RB', 'Phenotype', 'HP:0009919', (57, 59))	('inactivation', 'Var', (4, 16))	('loss-of-function', 'NegReg', (102, 118))	('RB', 'Gene', '5925', (0, 2))	('RB1', 'Gene', '5925', (0, 3))	('RB', 'Phenotype', 'HP:0009919', (167, 169))	('retinoblastoma', 'Gene', (41, 55))	('retinoblastoma', 'Gene', '5925', (41, 55))	('RB1', 'Gene', (0, 3))	('retinoblastoma', 'Phenotype', 'HP:0009919', (41, 55))	('RB', 'Phenotype', 'HP:0009919', (0, 2))	('RB', 'Gene', '5925', (57, 59))	('RB', 'Gene', '5925', (167, 169))	('mutations', 'Var', (119, 128))
40154	27013893	However, many differential gene expression profiles of RB tumors in comparison with normal retinas have recently been characterized, and many of these differences are caused by epigenetic changes.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('RB', 'Phenotype', 'HP:0009919', (55, 57))	('gene expression', 'biological_process', 'GO:0010467', ('27', '42'))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('RB tumors', 'Disease', 'MESH:D012175', (55, 64))	('caused by', 'Reg', (167, 176))	('RB tumors', 'Disease', (55, 64))	('differential gene expression profiles', 'MPA', (14, 51))	('epigenetic changes', 'Var', (177, 195))
40157	27013893	Another study also reported nine unilateral, sporadic RBs with hypermethylation in the 5' region of the RB1 gene.	('RB', 'Phenotype', 'HP:0009919', (54, 56))	('RB1', 'Gene', (104, 107))	('RBs', 'Disease', (54, 57))	('hypermethylation', 'Var', (63, 79))	('RB1', 'Gene', '5925', (104, 107))	('RB', 'Phenotype', 'HP:0009919', (104, 106))	('RBs', 'Chemical', 'MESH:D012413', (54, 57))
40159	27013893	Hypermethylation of the promoter region of the RASSF1A gene has been detected in 82% to 89% of RB cases, and promoter hypermethylation of the MGMT gene has been observed in lower stage RB patients.	('RASSF1A', 'Gene', (47, 54))	('MGMT', 'Gene', '4255', (142, 146))	('detected', 'Reg', (69, 77))	('MGMT', 'Gene', (142, 146))	('RB', 'Gene', '5925', (185, 187))	('RB', 'Phenotype', 'HP:0009919', (95, 97))	('Hypermethylation', 'Var', (0, 16))	('RASSF1A', 'Gene', '11186', (47, 54))	('patients', 'Species', '9606', (188, 196))	('RB', 'Phenotype', 'HP:0009919', (185, 187))	('MGMT', 'molecular_function', 'GO:0003908', ('142', '146'))	('RB', 'Gene', '5925', (95, 97))
40161	27013893	Hypermethylation of several cancer-related genes was detected: MGMT (58%), NEUROG1 (52%), MSH6 (50%), CD44 (42%), PAX5 (42%), and GATA5 (25%).	('PAX5', 'Gene', (114, 118))	('MGMT', 'Gene', '4255', (63, 67))	('MGMT', 'Gene', (63, 67))	('PAX5', 'Gene', '5079', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('NEUROG1', 'Gene', '4762', (75, 82))	('Hypermethylation', 'Var', (0, 16))	('MSH6', 'Gene', (90, 94))	('CD44', 'Gene', '960', (102, 106))	('GATA5', 'Gene', '140628', (130, 135))	('CD44', 'Gene', (102, 106))	('MSH6', 'Gene', '2956', (90, 94))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('NEUROG1', 'Gene', (75, 82))	('cancer', 'Disease', (28, 34))	('GATA5', 'Gene', (130, 135))	('MGMT', 'molecular_function', 'GO:0003908', ('63', '67'))
40162	27013893	Interestingly, deletions of some of these tumor suppressor genes may drive RB.	('tumor', 'Disease', (42, 47))	('RB', 'Phenotype', 'HP:0009919', (75, 77))	('tumor suppressor', 'biological_process', 'GO:0051726', ('42', '58'))	('drive', 'Reg', (69, 74))	('RB', 'Gene', '5925', (75, 77))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('42', '58'))	('deletions', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
40167	27013893	Furthermore, hypermethylation of the hTERT promoter and the TRAIL receptors DcR1 and DcR2 was detected at a relatively high frequency in cases of UM.	('DcR2', 'Gene', (85, 89))	('TRAIL', 'Gene', (60, 65))	('UM', 'Phenotype', 'HP:0007716', (146, 148))	('detected', 'Reg', (94, 102))	('hypermethylation', 'Var', (13, 29))	('DcR1', 'Gene', (76, 80))	('hTERT', 'Gene', '7015', (37, 42))	('DcR2', 'Gene', '8793', (85, 89))	('DcR1', 'Gene', '23405', (76, 80))	('hTERT', 'Gene', (37, 42))	('TRAIL', 'Gene', '8743', (60, 65))
40168	27013893	Another study demonstrated that CXCR4 and CCR7 expression in UM enabled directional migration of these tumor cells to the liver, and that the demethylating agent 5-aza-2'-deoxycytidine (5-Aza) upregulates the repressed CXCR4 gene via demethylation.	('CXCR4', 'Gene', '7852', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('upregulates', 'PosReg', (193, 204))	('CCR7', 'Gene', '1236', (42, 46))	('demethylation', 'biological_process', 'GO:0070988', ('234', '247'))	('CXCR4', 'Gene', (32, 37))	('CXCR4', 'molecular_function', 'GO:0038147', ('219', '224'))	('CXCR4', 'molecular_function', 'GO:0038147', ('32', '37'))	('CXCR4', 'Gene', '7852', (219, 224))	('CCR', 'molecular_function', 'GO:0043880', ('42', '45'))	('CXCR4', 'Gene', (219, 224))	('tumor', 'Disease', (103, 108))	('demethylation', 'Var', (234, 247))	('5-Aza', 'Chemical', 'MESH:D000077209', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (162, 184))	('CCR7', 'Gene', (42, 46))	('directional migration', 'CPA', (72, 93))	('UM', 'Phenotype', 'HP:0007716', (61, 63))
40169	27013893	Another recent study reported that 5-Aza causes significant decreases in growth, invasion, and clonogenicity in UM.	('clonogenicity', 'CPA', (95, 108))	('decreases', 'NegReg', (60, 69))	('invasion', 'CPA', (81, 89))	('5-Aza', 'Var', (35, 40))	('growth', 'CPA', (73, 79))	('5-Aza', 'Chemical', 'MESH:D000077209', (35, 40))	('UM', 'Phenotype', 'HP:0007716', (112, 114))
40170	27013893	In addition, 5-Aza decreased the number of metastases from the eye to the lung in a murine xenograft model.	('murine', 'Species', '10090', (84, 90))	('5-Aza', 'Chemical', 'MESH:D000077209', (13, 18))	('metastases', 'Disease', (43, 53))	('metastases', 'Disease', 'MESH:D009362', (43, 53))	('decreased', 'NegReg', (19, 28))	('5-Aza', 'Var', (13, 18))
40172	27013893	Methylation of the p16/INK4a gene promoter was noted in marginal zone lymphoma of the ocular adnexa, whereas hypermethylation of the CDKN2A gene promoter was demonstrated to have an effect on periocular sebaceous carcinoma and was associated with younger patient age.	('lymphoma', 'Phenotype', 'HP:0002665', (70, 78))	('carcinoma', 'Disease', (213, 222))	('p16', 'Gene', (19, 22))	('lymphoma of the ocular adnexa', 'Disease', 'MESH:D008223', (70, 99))	('Methylation', 'Var', (0, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('patient', 'Species', '9606', (255, 262))	('CDKN2A', 'Gene', (133, 139))	('sebaceous carcinoma', 'Phenotype', 'HP:0030410', (203, 222))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('p16', 'Gene', '1029', (19, 22))	('carcinoma', 'Disease', 'MESH:D002277', (213, 222))	('CDKN2A', 'Gene', '1029', (133, 139))	('hypermethylation', 'Var', (109, 125))	('lymphoma of the ocular adnexa', 'Disease', (70, 99))	('INK4a', 'Gene', '1029', (23, 28))	('effect', 'Reg', (182, 188))	('INK4a', 'Gene', (23, 28))
40173	27013893	Methylation of the E-cadherin promoter region was detected in 72% of eyelid sebaceous gland carcinoma, and this effect could contribute to the reduced disease-free survival of patients.	('patients', 'Species', '9606', (176, 184))	('disease-free survival', 'CPA', (151, 172))	('Methylation', 'Var', (0, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('E-cadherin', 'Gene', (19, 29))	('E-cadherin', 'Gene', '999', (19, 29))	('eyelid sebaceous gland carcinoma', 'Disease', 'MESH:D012626', (69, 101))	('sebaceous gland carcinoma', 'Phenotype', 'HP:0030410', (76, 101))	('detected', 'Reg', (50, 58))	('sebaceous gland', 'Phenotype', 'HP:0032227', (76, 91))	('cadherin', 'molecular_function', 'GO:0008014', ('21', '29'))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('eyelid sebaceous gland carcinoma', 'Disease', (69, 101))	('reduced', 'NegReg', (143, 150))
40174	27013893	Furthermore, a study in Drosophila suggested that the downregulation of Rbf due to DNA hypermethylation was associated with eye cancer, and a loss of methylation at the DNMT3L promoter was detected in ocular surface squamous neoplasia (Table 1).	('DNA', 'Gene', (83, 86))	('neoplasia', 'Phenotype', 'HP:0002664', (225, 234))	('squamous neoplasia', 'Disease', (216, 234))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('DNMT3L', 'Gene', (169, 175))	('eye cancer', 'Disease', (124, 134))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('83', '103'))	('methylation', 'biological_process', 'GO:0032259', ('150', '161'))	('hypermethylation', 'Var', (87, 103))	('squamous neoplasia', 'Disease', 'MESH:D009369', (216, 234))	('downregulation', 'NegReg', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('eye cancer', 'Phenotype', 'HP:0100012', (124, 134))	('Rbf', 'Gene', (72, 75))	('Rbf', 'Gene', '43231', (72, 75))	('Drosophila', 'Species', '7227', (24, 34))	('DNMT3L', 'Gene', '29947', (169, 175))	('squamous neoplasia', 'Phenotype', 'HP:0002860', (216, 234))	('eye cancer', 'Disease', 'MESH:D005134', (124, 134))
40176	27013893	HP1 can specifically recognize and bind to methylated histone H3K9 which leads to epigenetic silencing.	('bind', 'Interaction', (35, 39))	('leads to', 'Reg', (73, 81))	('histone H3K9', 'Protein', (54, 66))	('H3K9', 'Protein', (62, 66))	('HP1', 'Gene', '23468', (0, 3))	('epigenetic silencing', 'MPA', (82, 102))	('HP1', 'Gene', (0, 3))	('methylated', 'Var', (43, 53))
40179	27013893	With regard to eye cancer, by studying tumorigenesis in the Drosophila eye, it was noted that deacetylated H3K9 and methylated H3K27 of Pipsqueak and Lola contributed to the tumor phenotype.	('tumor', 'Disease', (174, 179))	('contributed', 'Reg', (155, 166))	('eye cancer', 'Phenotype', 'HP:0100012', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('Lola', 'Gene', '44548', (150, 154))	('Lola', 'Gene', (150, 154))	('eye cancer', 'Disease', 'MESH:D005134', (15, 25))	('Drosophila eye', 'Disease', (60, 74))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('Drosophila eye', 'Disease', 'MESH:D005124', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('eye cancer', 'Disease', (15, 25))	('tumor', 'Disease', (39, 44))	('H3K9', 'Protein', (107, 111))	('H3K27', 'Protein', (127, 132))	('methylated', 'Var', (116, 126))
40186	27013893	Furthermore, miR-24, 125b, 191, 181a, and 423 are also decreased in RB.	('RB', 'Gene', '5925', (68, 70))	('RB', 'Phenotype', 'HP:0009919', (68, 70))	('miR-24', 'Var', (13, 19))	('191', 'Var', (27, 30))	('decreased', 'NegReg', (55, 64))	('miR-24', 'Chemical', '-', (13, 19))
40188	27013893	miR-17~92 is a target of E2F, and loss of RB1 may lead to increased expression of miR-17~92 through depressed E2F activity.	('RB1', 'Gene', (42, 45))	('E2F', 'Enzyme', (110, 113))	('miR-17~92', 'Gene', '407975', (82, 91))	('loss', 'Var', (34, 38))	('increased', 'PosReg', (58, 67))	('activity', 'MPA', (114, 122))	('expression', 'MPA', (68, 78))	('miR-17~92', 'Gene', (82, 91))	('depressed', 'NegReg', (100, 109))	('miR-17~92', 'Gene', '407975', (0, 9))	('RB1', 'Gene', '5925', (42, 45))	('miR-17~92', 'Gene', (0, 9))	('RB', 'Phenotype', 'HP:0009919', (42, 44))
40199	27013893	Patients with increased lncRNA BANCR expression exhibited poorer survival, and knocking down lncRNA BANCR expression significantly suppressed RB cell proliferation, migration, and invasion in vitro.	('knocking down', 'Var', (79, 92))	('invasion', 'CPA', (180, 188))	('BANCR', 'Gene', '100885775', (31, 36))	('RB', 'Phenotype', 'HP:0009919', (142, 144))	('cell proliferation', 'biological_process', 'GO:0008283', ('145', '163'))	('BANCR', 'Gene', (100, 105))	('BANCR', 'Gene', (31, 36))	('RB', 'Gene', '5925', (142, 144))	('Patients', 'Species', '9606', (0, 8))	('suppressed', 'NegReg', (131, 141))	('migration', 'CPA', (165, 174))	('BANCR', 'Gene', '100885775', (100, 105))
40203	27013893	Epigenetic drugs can restore the normal epigenetic landscape in cancer cells by several modes, such as inhibiting enzymes of the epigenetic machinery.	('epigenetic landscape', 'MPA', (40, 60))	('inhibiting', 'Var', (103, 113))	('restore', 'PosReg', (21, 28))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('Epigenetic drugs', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
40204	27013893	Currently, several epigenetic drugs have been approved by the US Food and Drug Administration (FDA) for the treatment of cancer.	('epigenetic drugs', 'Var', (19, 35))	('cancer', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))
40211	27013893	Targeting SYK with the small-molecule inhibitor BAY61-3606 or R406 could remarkably induce RB tumor cell death in vitro and in vivo.	('RB tumor', 'Disease', 'MESH:D012175', (91, 99))	('SYK', 'Gene', '6850', (10, 13))	('RB', 'Phenotype', 'HP:0009919', (91, 93))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('BAY61-3606', 'Chemical', 'MESH:C477642', (48, 58))	('BAY61-3606', 'Var', (48, 58))	('cell death', 'biological_process', 'GO:0008219', ('100', '110'))	('SYK', 'Gene', (10, 13))	('R406', 'Var', (62, 66))	('RB tumor', 'Disease', (91, 99))	('induce', 'PosReg', (84, 90))	('R406', 'Chemical', '-', (62, 66))
40218	26631117	The purpose of this study was to: i) determine the mRNA amounts of IL-10, IL-10Ralpha, and IL-10Rbeta in cutaneous and uveal melanoma cells and specimens; ii) evaluate their post-transcriptional regulation by miRNAs; iii) ascertain whether miRNA dysregulation may affect IL-10-induced proliferation.	('IL-10', 'molecular_function', 'GO:0005141', ('91', '96'))	('IL-10Ralpha', 'Gene', '3587', (74, 85))	('dysregulation', 'Var', (246, 259))	('affect', 'Reg', (264, 270))	('IL-10Rbeta', 'Gene', '3588', (91, 101))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('IL-10Rbeta', 'Gene', (91, 101))	('IL-10', 'molecular_function', 'GO:0005141', ('74', '79'))	('regulation', 'biological_process', 'GO:0065007', ('195', '205'))	('IL-10', 'molecular_function', 'GO:0005141', ('271', '276'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (119, 133))	('uveal melanoma', 'Disease', 'MESH:C536494', (119, 133))	('IL-10Ralpha', 'Gene', (74, 85))	('uveal melanoma', 'Disease', (119, 133))	('IL-10', 'molecular_function', 'GO:0005141', ('67', '72'))
40225	26631117	miR-409-3p and miR-605were down-regulated exclusively in G361 cells.	('miR-605', 'Gene', '693190', (15, 22))	('miR-605', 'Gene', (15, 22))	('miR-409-3p', 'Var', (0, 10))	('down-regulated', 'NegReg', (27, 41))
40230	26631117	Moreover, specific knockdown of IL-10Ralpha prevented the proliferative effect of miRNA inhibitors.	('prevented', 'NegReg', (44, 53))	('knockdown', 'Var', (19, 28))	('proliferative effect of miRNA inhibitors', 'MPA', (58, 98))	('IL-10Ralpha', 'Gene', (32, 43))	('IL-10Ralpha', 'Gene', '3587', (32, 43))	('IL-10', 'molecular_function', 'GO:0005141', ('32', '37'))
40245	26631117	Emerging evidence suggests a role for epigenetic modulation in melanomagenesis.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('epigenetic modulation', 'Var', (38, 59))
40273	26631117	Two miRNAs (miR-513a-5p and miR-551b) were down-regulated exclusively in G361 cells.	('down-regulated', 'NegReg', (43, 57))	('miR-551b', 'Gene', (28, 36))	('miR-513a-5p', 'Var', (12, 23))	('miR-551b', 'Gene', '693136', (28, 36))
40274	26631117	Three out of the four miRNAs upregulated in G361 and OCM-1 and unchanged in GR-M were predicted to have seed regions able to bind to the 3'UTR of IL-10Ralpha (miR-15a was reported in all the miRNA target prediction systems, miR-185 in microRNA and PITA; miR-211 in microRNA and PITA).	('miR-15a', 'Gene', '406948', (159, 166))	('miR-211', 'Gene', '406993', (254, 261))	('upregulated', 'PosReg', (29, 40))	('miR-211', 'Gene', (254, 261))	('IL-10Ralpha', 'Gene', (146, 157))	('bind', 'Interaction', (125, 129))	('G361', 'Var', (44, 48))	('miR-15a', 'Gene', (159, 166))	('miR-185', 'Gene', '406961', (224, 231))	('IL-10', 'molecular_function', 'GO:0005141', ('146', '151'))	('IL-10Ralpha', 'Gene', '3587', (146, 157))	('miR-185', 'Gene', (224, 231))	('OCM-1', 'Species', '83984', (53, 58))
40303	26631117	Indeed, G361 showed a different behavior from GR-M in endogenous retrovirus K protein Rec expression upon exposure to UV and from several other cutaneous melanoma cell lines in the expression of ATP-binding cassette (ABC) B5 mRNA.	('G361', 'Var', (8, 12))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (144, 162))	('ATP-binding cassette (ABC) B5', 'Gene', '340273', (195, 224))	('Rec', 'Gene', (86, 89))	('Rec', 'Gene', '58163', (86, 89))	('ATP-binding', 'molecular_function', 'GO:0005524', ('195', '206'))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('ATP-binding cassette (ABC) B5', 'Gene', (195, 224))	('cutaneous melanoma', 'Disease', (144, 162))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (144, 162))
40304	26631117	On the other hand, G361 exhibited an expression pattern of DcR1 and DcR2 identical to that of uveal melanoma cell lines as a result of promoter hypermethylation and a likewise identical responsiveness to the demethylating agent 5-aza-dC.	('G361', 'Var', (19, 23))	('hypermethylation', 'Var', (144, 160))	('DcR2', 'Gene', (68, 72))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('uveal melanoma', 'Disease', (94, 108))	('DcR1', 'Gene', '8794', (59, 63))	('DcR2', 'Gene', '8793', (68, 72))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('expression', 'MPA', (37, 47))	('DcR1', 'Gene', (59, 63))
40387	26321866	These lines include one with a GNA11 mutation (OMM1), one with a GNAQ mutation (92.1), and one with a BRAF mutation (OCM1), which is uncommon in primary uveal melanoma.	('mutation', 'Var', (37, 45))	('BRAF', 'Gene', '673', (102, 106))	('uveal melanoma', 'Disease', (153, 167))	('GNAQ', 'Gene', '2776', (65, 69))	('uveal melanoma', 'Disease', 'MESH:C536494', (153, 167))	('uveal melanoma', 'Phenotype', 'HP:0007716', (153, 167))	('BRAF', 'Gene', (102, 106))	('GNAQ', 'Gene', (65, 69))	('OCM1', 'Species', '83984', (117, 121))	('GNA11', 'Gene', (31, 36))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))	('GNA11', 'Gene', '2767', (31, 36))
40394	26321866	However, metastases developed significantly more frequently in tumors with a high Twist1 gene expression (Appendix 4).	('gene expression', 'biological_process', 'GO:0010467', ('89', '104'))	('metastases', 'Disease', (9, 19))	('high', 'Var', (77, 81))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('metastases', 'Disease', 'MESH:D009362', (9, 19))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('Twist1', 'Gene', (82, 88))
40395	26321866	The univariate Cox regression analysis showed that the age at enucleation (p = 0.036), the largest basal diameter (p<0.0001), the presence of ciliary body involvement (p = 0.006), a mixed or epithelioid cell type (p = 0.031), the monosomy of chromosome 3 (p<0.0001), the gain or amplification of chromosome 8q (p = 0.025 and p = 0.002, respectively), and a high Twist1 gene expression (p<0.0001) were associated with an increased risk of death due to metastasis (Appendix 5).	('enucleation', 'biological_process', 'GO:0090601', ('62', '73'))	('death', 'Disease', (438, 443))	('expression', 'MPA', (374, 384))	('death', 'Disease', 'MESH:D003643', (438, 443))	('Twist1 gene', 'Gene', (362, 373))	('high', 'Var', (357, 361))	('metastasis', 'CPA', (451, 461))	('chromosome', 'cellular_component', 'GO:0005694', ('296', '306'))	('chromosome', 'cellular_component', 'GO:0005694', ('242', '252'))	('Cox', 'Gene', '1351', (15, 18))	('gain', 'Var', (271, 275))	('gene expression', 'biological_process', 'GO:0010467', ('369', '384'))	('Cox', 'Gene', (15, 18))
40397	26321866	Patients with a gain or amplification of chromosome 8q were more likely to develop metastases than patients without aberrations in chromosome 8q were (p = 0.046; p = 0.019 respectively).	('chromosome 8q', 'Gene', (41, 54))	('chromosome', 'cellular_component', 'GO:0005694', ('131', '141'))	('metastases', 'Disease', (83, 93))	('metastases', 'Disease', 'MESH:D009362', (83, 93))	('patients', 'Species', '9606', (99, 107))	('Patients', 'Species', '9606', (0, 8))	('amplification', 'Var', (24, 37))	('develop', 'PosReg', (75, 82))	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))	('gain', 'PosReg', (16, 20))
40408	26321866	Nevertheless, we observed that Snail1 shRNAs reduced by approximately 50% the number of 92.1 cells that moved through a Matrigel-coated filter after 24 h of incubation (Figure 5D), indicating that Snail1 can also promote invasion in uveal melanoma cells.	('uveal melanoma', 'Disease', (233, 247))	('reduced', 'NegReg', (45, 52))	('invasion', 'CPA', (221, 229))	('promote', 'PosReg', (213, 220))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('uveal melanoma', 'Phenotype', 'HP:0007716', (233, 247))	('uveal melanoma', 'Disease', 'MESH:C536494', (233, 247))	('Snail1', 'Var', (197, 203))
40420	26321866	In a different tumor cohort including a larger number of cases and more detailed clinical follow up, we found that the high expression of Twist1 was associated with worse survival, suggesting a role for an additional EMT factor in promoting metastatic behavior in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (264, 278))	('uveal melanoma', 'Disease', (264, 278))	('uveal melanoma', 'Disease', 'MESH:C536494', (264, 278))	('worse', 'NegReg', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('high expression', 'Var', (119, 134))	('EMT', 'biological_process', 'GO:0001837', ('217', '220'))	('melanoma', 'Phenotype', 'HP:0002861', (270, 278))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Twist1', 'Gene', (138, 144))	('tumor', 'Disease', (15, 20))	('survival', 'MPA', (171, 179))
40426	26321866	OMM1 cells carry GNA11 mutation, which is more commonly found in metastatic uveal melanoma cells, as compared to GNAQ mutation.	('GNAQ', 'Gene', (113, 117))	('uveal melanoma', 'Phenotype', 'HP:0007716', (76, 90))	('uveal melanoma', 'Disease', 'MESH:C536494', (76, 90))	('mutation', 'Var', (23, 31))	('uveal melanoma', 'Disease', (76, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('GNA11', 'Gene', (17, 22))	('GNAQ', 'Gene', '2776', (113, 117))	('GNA11', 'Gene', '2767', (17, 22))
40427	26321866	The presence of this mutation in OMM1 cells might be linked to a greater growth inhibition after the downregulation of ZEB1, as the other two lines, OCM1 and 92.1, contain BRAFV600E and GNAQ mutations, respectively.	('downregulation', 'NegReg', (101, 115))	('BRAFV600E', 'Var', (172, 181))	('BRAFV600E', 'Mutation', 'rs113488022', (172, 181))	('growth', 'CPA', (73, 79))	('GNAQ', 'Gene', '2776', (186, 190))	('OCM1', 'Species', '83984', (149, 153))	('GNAQ', 'Gene', (186, 190))
40429	26321866	In particular, no human uveal melanoma cell lines in common use contain mutations in BAP1, which are thought to play a key role in tumor spread.	('mutations', 'Var', (72, 81))	('BAP1', 'Gene', (85, 89))	('uveal melanoma', 'Disease', (24, 38))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('human', 'Species', '9606', (18, 23))	('tumor', 'Disease', (131, 136))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('BAP1', 'Gene', '8314', (85, 89))	('uveal melanoma', 'Phenotype', 'HP:0007716', (24, 38))	('uveal melanoma', 'Disease', 'MESH:C536494', (24, 38))
40430	26321866	In addition, the mutation profile of OCM1 challenges the assumption that this cell line is derived from a uveal melanoma; therefore, multiple cell lines, including those carrying GNAQ/GNA11 mutations, were used in this study.	('GNAQ', 'Gene', '2776', (179, 183))	('GNA11', 'Gene', '2767', (184, 189))	('OCM1', 'Species', '83984', (37, 41))	('mutation', 'Var', (17, 25))	('GNAQ', 'Gene', (179, 183))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('uveal melanoma', 'Disease', (106, 120))	('OCM1', 'Gene', (37, 41))	('GNA11', 'Gene', (184, 189))
40434	26321866	Comparison of clinical and histopathological features in low and high Twist1 gene expression in 64 cases of uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (108, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('uveal melanoma', 'Disease', (108, 122))	('low', 'Var', (57, 60))	('gene expression', 'biological_process', 'GO:0010467', ('77', '92'))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
40444	25184134	ERK1/2 inhibitors also reduced the migration and activity of MMP-2 in M17 cells.	('migration', 'CPA', (35, 44))	('activity', 'MPA', (49, 57))	('ERK1', 'molecular_function', 'GO:0004707', ('0', '4'))	('MMP-2', 'molecular_function', 'GO:0004228', ('61', '66'))	('MMP-2', 'Gene', '4313', (61, 66))	('inhibitors', 'Var', (7, 17))	('reduced', 'NegReg', (23, 30))	('MMP-2', 'Gene', (61, 66))
40462	25184134	observed that most of cell lines secreted MMP-2 in vitro and the expression of MMP-2 was associated with a poor prognosis.	('associated', 'Reg', (89, 99))	('MMP-2', 'Gene', (79, 84))	('MMP-2', 'Gene', (42, 47))	('MMP-2', 'molecular_function', 'GO:0004228', ('79', '84'))	('MMP-2', 'molecular_function', 'GO:0004228', ('42', '47'))	('MMP-2', 'Gene', '4313', (42, 47))	('MMP-2', 'Gene', '4313', (79, 84))	('expression', 'Var', (65, 75))
40482	25184134	Otherwise, cells were pretreated with an indicated concentration of specific inhibitors, 10 muM U0126 (ERK 1/2 inhibitor), for 60 min followed by incubation with or without 60 muM EGCG for an additional 24 hours.	('muM', 'Gene', (92, 95))	('U0126', 'Chemical', 'MESH:C113580', (96, 101))	('muM', 'Gene', '56925', (176, 179))	('ERK 1', 'molecular_function', 'GO:0004707', ('103', '108'))	('ERK 1/2', 'Gene', '5595;5594', (103, 110))	('U0126', 'Var', (96, 101))	('muM', 'Gene', (176, 179))	('muM', 'Gene', '56925', (92, 95))	('EGCG', 'Chemical', 'MESH:C045651', (180, 184))	('ERK 1/2', 'Gene', (103, 110))
40508	25184134	As we have shown that the treatment of EGCG to M17 cells inhibited the cell migration and activities of secreted MMP-2, the underlying mechanisms were further investigated.	('MMP-2', 'Gene', (113, 118))	('inhibited', 'NegReg', (57, 66))	('activities', 'MPA', (90, 100))	('EGCG', 'Var', (39, 43))	('EGCG', 'Chemical', 'MESH:C045651', (39, 43))	('MMP-2', 'Gene', '4313', (113, 118))	('cell migration', 'biological_process', 'GO:0016477', ('71', '85'))	('MMP-2', 'molecular_function', 'GO:0004228', ('113', '118'))	('cell migration', 'CPA', (71, 85))
40512	25184134	Results showed that U0126 treatment led to the inhibition of MMP-2 activity, similar to the EGCG treatment (Figure 6(a)).	('EGCG', 'Chemical', 'MESH:C045651', (92, 96))	('inhibition', 'NegReg', (47, 57))	('MMP-2', 'molecular_function', 'GO:0004228', ('61', '66'))	('MMP-2', 'Gene', '4313', (61, 66))	('U0126', 'Var', (20, 25))	('U0126', 'Chemical', 'MESH:C113580', (20, 25))	('MMP-2', 'Gene', (61, 66))
40524	25184134	Gene mutations in cutaneous melanoma (BRAF, N-Ras, etc.)	('cutaneous melanoma', 'Disease', (18, 36))	('N-Ras', 'Gene', '4893', (44, 49))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (18, 36))	('BRAF', 'Gene', '673', (38, 42))	('mutations', 'Var', (5, 14))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (18, 36))	('N-Ras', 'Gene', (44, 49))	('BRAF', 'Gene', (38, 42))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
40530	25184134	To our knowledge, this study provides the first demonstration that EGCG is capable of inhibiting invasive behaviors and MMP-2 activities in uveal melanoma cells.	('invasive behaviors', 'CPA', (97, 115))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('EGCG', 'Chemical', 'MESH:C045651', (67, 71))	('MMP-2', 'Gene', (120, 125))	('EGCG', 'Var', (67, 71))	('inhibiting', 'NegReg', (86, 96))	('MMP-2', 'Gene', '4313', (120, 125))	('MMP-2', 'molecular_function', 'GO:0004228', ('120', '125'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (140, 154))	('uveal melanoma', 'Disease', (140, 154))	('uveal melanoma', 'Disease', 'MESH:C536494', (140, 154))
40536	25184134	However, the present study showed that EGCG only inhibited ERK phosphorylation and no significant effects were detected on the JNK and p38 signaling pathways.	('ERK', 'Gene', (59, 62))	('JNK', 'Gene', '5599', (127, 130))	('phosphorylation', 'biological_process', 'GO:0016310', ('63', '78'))	('EGCG', 'Var', (39, 43))	('p38', 'Gene', (135, 138))	('EGCG', 'Chemical', 'MESH:C045651', (39, 43))	('JNK', 'molecular_function', 'GO:0004705', ('127', '130'))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('ERK', 'molecular_function', 'GO:0004707', ('59', '62'))	('JNK', 'Gene', (127, 130))	('ERK', 'Gene', '5594', (59, 62))	('inhibited', 'NegReg', (49, 58))	('p38', 'Gene', '5594', (135, 138))
40537	25184134	The involvement of the MAPK pathway in the modulation of MMP-2 activities was demonstrated by treating uveal melanoma cells by ERK inhibitor, which showed that ERK inhibitor could lead to an inhibition of MMP-2 secretion and cell invasion of uveal melanoma cells.	('MMP-2', 'Gene', (57, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (242, 256))	('inhibition', 'NegReg', (191, 201))	('MMP-2', 'Gene', '4313', (205, 210))	('uveal melanoma', 'Disease', (242, 256))	('MMP-2', 'molecular_function', 'GO:0004228', ('57', '62'))	('ERK', 'Gene', '5594', (160, 163))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('ERK', 'Gene', '5594', (127, 130))	('uveal melanoma', 'Phenotype', 'HP:0007716', (242, 256))	('MMP-2', 'Gene', (205, 210))	('uveal melanoma', 'Disease', 'MESH:C536494', (103, 117))	('MAPK', 'Gene', '5595;5594;5595', (23, 27))	('uveal melanoma', 'Disease', (103, 117))	('inhibitor', 'Var', (164, 173))	('MAPK', 'molecular_function', 'GO:0004707', ('23', '27'))	('MMP-2', 'Gene', '4313', (57, 62))	('secretion', 'biological_process', 'GO:0046903', ('211', '220'))	('ERK', 'Gene', (160, 163))	('ERK', 'Gene', (127, 130))	('MMP-2', 'molecular_function', 'GO:0004228', ('205', '210'))	('MAPK', 'Gene', (23, 27))	('ERK', 'molecular_function', 'GO:0004707', ('160', '163'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('ERK', 'molecular_function', 'GO:0004707', ('127', '130'))	('melanoma', 'Phenotype', 'HP:0002861', (248, 256))
40554	22275506	The overall rate of BRAF mutations in melanoma patients is approximately 45%.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('mutations', 'Var', (25, 34))	('patients', 'Species', '9606', (47, 55))	('BRAF', 'Gene', '673', (20, 24))	('BRAF', 'Gene', (20, 24))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))
40555	22275506	While this accurately reflects the rate in the common cutaneous melanomas that develop in areas with intermittent sun exposure, the rate of BRAF mutations is lower in acral, mucosal, and cutaneous melanomas with evidence of chronic sun damage (CSD), and are essentially absent in uveal melanomas [Table 1].	('melanomas', 'Phenotype', 'HP:0002861', (286, 295))	('mutations', 'Var', (145, 154))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('melanoma', 'Phenotype', 'HP:0002861', (286, 294))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('melanomas', 'Phenotype', 'HP:0002861', (197, 206))	('uveal melanomas', 'Disease', 'MESH:C536494', (280, 295))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (54, 73))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (54, 73))	('BRAF', 'Gene', '673', (140, 144))	('sun damage', 'Phenotype', 'HP:0000992', (232, 242))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (187, 206))	('uveal melanoma', 'Phenotype', 'HP:0007716', (280, 294))	('BRAF', 'Gene', (140, 144))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (187, 206))	('uveal melanomas', 'Disease', (280, 295))	('uveal melanomas', 'Phenotype', 'HP:0007716', (280, 295))	('cutaneous melanomas', 'Disease', (54, 73))	('lower', 'NegReg', (158, 163))	('cutaneous melanomas', 'Disease', (187, 206))
40556	22275506	The mutations in BRAF overwhelmingly occur in exon 15, which encodes the catalytic domain of the BRAF protein.	('BRAF', 'Gene', '673', (17, 21))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('BRAF', 'Gene', (17, 21))	('occur', 'Reg', (37, 42))	('mutations', 'Var', (4, 13))	('BRAF', 'Gene', '673', (97, 101))	('BRAF', 'Gene', (97, 101))
40557	22275506	Substitutions at the valine at position 600 (V600) represent ~95% of the reported point mutations in melanoma, most commonly V600E (~75% of V600 mutations), followed by V600K (20%).	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('V600K', 'Var', (169, 174))	('melanoma', 'Disease', (101, 109))	('V600E', 'Var', (125, 130))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('V600K', 'Mutation', 'rs121913227', (169, 174))	('valine', 'Chemical', 'MESH:D014633', (21, 27))	('V600E', 'Mutation', 'rs113488022', (125, 130))
40558	22275506	The V600 mutations increase the kinase activity of BRAF 130- to >700-fold.	('kinase activity', 'MPA', (32, 47))	('kinase activity', 'molecular_function', 'GO:0016301', ('32', '47'))	('increase', 'PosReg', (19, 27))	('BRAF', 'Gene', '673', (51, 55))	('V600', 'Var', (4, 8))	('BRAF', 'Gene', (51, 55))
40559	22275506	Other patient-derived mutations (G464E, G466V, D594V) decrease BRAF catalytic activity but promote dimerization with CRAF proteins, and thus still increase activation of MEK and ERK.	('D594V', 'Var', (47, 52))	('decrease', 'NegReg', (54, 62))	('increase activation', 'PosReg', (147, 166))	('G464E', 'Mutation', 'rs121913348', (33, 38))	('CRAF', 'Gene', (117, 121))	('catalytic activity', 'MPA', (68, 86))	('BRAF', 'Gene', '673', (63, 67))	('ERK', 'Gene', (178, 181))	('BRAF', 'Gene', (63, 67))	('G464E', 'Var', (33, 38))	('CRAF', 'Gene', '5894', (117, 121))	('ERK', 'Gene', '2048', (178, 181))	('CRAF', 'molecular_function', 'GO:0004709', ('117', '121'))	('catalytic activity', 'molecular_function', 'GO:0003824', ('68', '86'))	('D594V', 'Mutation', 'rs121913338', (47, 52))	('MEK', 'Gene', '5609', (170, 173))	('patient', 'Species', '9606', (6, 13))	('dimerization', 'MPA', (99, 111))	('G466V', 'Var', (40, 45))	('MEK', 'Gene', (170, 173))	('promote', 'PosReg', (91, 98))	('G466V', 'Mutation', 'rs121913351', (40, 45))	('ERK', 'molecular_function', 'GO:0004707', ('178', '181'))
40560	22275506	Several studies have identified a significant association of BRAF mutations with younger age, but there is no reproducible association with relapse-free survival (RFS) or overall survival (OS) from melanoma diagnosis.	('mutations', 'Var', (66, 75))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('BRAF', 'Gene', '673', (61, 65))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('BRAF', 'Gene', (61, 65))	('association', 'Interaction', (46, 57))
40561	22275506	Recently, two large retrospective studies identified significantly shorter OS from the diagnosis of stage IV disease for patients with an activating BRAF mutation.	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('mutation', 'Var', (154, 162))	('activating', 'PosReg', (138, 148))	('shorter', 'NegReg', (67, 74))	('patients', 'Species', '9606', (121, 129))
40563	22275506	Vemurafenib (also known as RG7204, or PLX4032; Roche) and GSK2118436 (GlaxoSmithKline) are potent BRAF inhibitors with increased affinity for V600-mutant over wild-type BRAF.	('BRAF', 'Gene', (169, 173))	('BRAF', 'Gene', '673', (169, 173))	('GSK', 'molecular_function', 'GO:0050321', ('58', '61'))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('V600-mutant', 'Var', (142, 153))	('GSK2118436', 'Chemical', 'MESH:C561627', (58, 68))
40565	22275506	No patients with a wild-type BRAF responded, which is consistent with pre-clinical studies showing that selective BRAF inhibitors actually increase the growth of such melanomas.	('BRAF', 'Gene', '673', (29, 33))	('growth', 'MPA', (152, 158))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('pre', 'molecular_function', 'GO:0003904', ('70', '73'))	('BRAF', 'Gene', (29, 33))	('inhibitors', 'Var', (119, 129))	('melanomas', 'Disease', 'MESH:D008545', (167, 176))	('increase', 'PosReg', (139, 147))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('patients', 'Species', '9606', (3, 11))	('clinical', 'Species', '191496', (74, 82))	('melanomas', 'Phenotype', 'HP:0002861', (167, 176))	('melanomas', 'Disease', (167, 176))
40566	22275506	In the BRIM3 phase III trial, vemurafenib treatment resulted in significant increases in ORR, progression-free survival (PFS), and OS as compared to dacarbazine in BRAF V600E-positive metastatic melanoma patients.	('vemurafenib', 'Chemical', 'MESH:D000077484', (30, 41))	('patients', 'Species', '9606', (204, 212))	('V600E', 'Mutation', 'rs113488022', (169, 174))	('dacarbazine', 'Chemical', 'MESH:D003606', (149, 160))	('increases', 'PosReg', (76, 85))	('BRAF', 'Gene', '673', (164, 168))	('progression-free survival', 'CPA', (94, 119))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('vemurafenib', 'Var', (30, 41))	('BRAF', 'Gene', (164, 168))	('melanoma', 'Disease', (195, 203))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('ORR', 'MPA', (89, 92))
40567	22275506	Clinical responses have also been reported with both vemurafenib and GSK2118436 in patients with BRAF V600K mutations, and with GSK2118436 with V600G mutations.	('V600G', 'Var', (144, 149))	('GSK', 'molecular_function', 'GO:0050321', ('128', '131'))	('GSK2118436', 'Chemical', 'MESH:C561627', (128, 138))	('Clinical', 'Species', '191496', (0, 8))	('V600K mutations', 'Var', (102, 117))	('patients', 'Species', '9606', (83, 91))	('GSK2118436', 'Var', (69, 79))	('GSK2118436', 'Var', (128, 138))	('GSK', 'molecular_function', 'GO:0050321', ('69', '72'))	('vemurafenib', 'Chemical', 'MESH:D000077484', (53, 64))	('BRAF', 'Gene', '673', (97, 101))	('V600G', 'Mutation', 'rs113488022', (144, 149))	('GSK2118436', 'Chemical', 'MESH:C561627', (69, 79))	('BRAF', 'Gene', (97, 101))	('V600K', 'Mutation', 'rs121913227', (102, 107))
40568	22275506	No clinical responses with GSK2118436 were achieved in two patients with BRAF K601E mutations.	('BRAF', 'Gene', '673', (73, 77))	('GSK2118436', 'Var', (27, 37))	('K601E', 'Mutation', 'rs121913364', (78, 83))	('GSK', 'molecular_function', 'GO:0050321', ('27', '30'))	('patients', 'Species', '9606', (59, 67))	('BRAF', 'Gene', (73, 77))	('GSK2118436', 'Chemical', 'MESH:C561627', (27, 37))	('clinical', 'Species', '191496', (3, 11))
40570	22275506	The RAS-RAF-MEK-ERK pathway is also activated in melanoma by point mutations in NRAS [Figure 1].	('NRAS', 'Gene', (80, 84))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('point mutations', 'Var', (61, 76))	('ERK', 'Gene', '2048', (16, 19))	('RAF', 'Gene', (8, 11))	('ERK', 'Gene', (16, 19))	('activated', 'PosReg', (36, 45))	('RAF', 'Gene', '22882', (8, 11))	('NRAS', 'Gene', '4893', (80, 84))	('ERK', 'molecular_function', 'GO:0004707', ('16', '19'))	('MEK', 'Gene', (12, 15))	('MEK', 'Gene', '5609', (12, 15))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
40571	22275506	Like BRAF, the prevalence of NRAS mutations is highest in cutaneous tumors without CSD, and they are not detected in uveal melanomas [Table 1].	('cutaneous tumors', 'Disease', 'MESH:D009369', (58, 74))	('BRAF', 'Gene', '673', (5, 9))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('highest', 'Reg', (47, 54))	('BRAF', 'Gene', (5, 9))	('cutaneous tumors', 'Disease', (58, 74))	('NRAS', 'Gene', (29, 33))	('uveal melanomas', 'Disease', (117, 132))	('uveal melanomas', 'Phenotype', 'HP:0007716', (117, 132))	('NRAS', 'Gene', '4893', (29, 33))	('cutaneous tumors', 'Phenotype', 'HP:0008069', (58, 74))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('uveal melanomas', 'Disease', 'MESH:C536494', (117, 132))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('uveal melanoma', 'Phenotype', 'HP:0007716', (117, 131))	('mutations', 'Var', (34, 43))
40573	22275506	Some melanoma clinical specimens and cell lines with secondary resistance to selective BRAF inhibitors have recently been reported with concurrent BRAF V600 and NRAS mutations; only the BRAF mutations were detectable prior to treatment.	('BRAF', 'Gene', (186, 190))	('clinical', 'Species', '191496', (14, 22))	('mutations', 'Var', (166, 175))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('melanoma', 'Disease', (5, 13))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('NRAS', 'Gene', (161, 165))	('BRAF', 'Gene', (87, 91))	('NRAS', 'Gene', '4893', (161, 165))	('BRAF', 'Gene', '673', (186, 190))	('BRAF', 'Gene', '673', (87, 91))
40575	22275506	NRAS mutations have been associated with increased Breslow (BT) thickness of primary melanomas in two independent series of >200 consecutive melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('melanomas', 'Disease', (85, 94))	('increased', 'PosReg', (41, 50))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (150, 158))	('Breslow', 'MPA', (51, 58))	('melanomas', 'Disease', 'MESH:D008545', (85, 94))	('NRAS', 'Gene', (0, 4))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('NRAS', 'Gene', '4893', (0, 4))
40576	22275506	One series also reported significantly shorter RFS and OS from primary melanoma diagnosis among patients with an NRAS mutation.	('NRAS', 'Gene', (113, 117))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('mutation', 'Var', (118, 126))	('NRAS', 'Gene', '4893', (113, 117))	('patients', 'Species', '9606', (96, 104))	('RFS', 'MPA', (47, 50))	('shorter', 'NegReg', (39, 46))
40578	22275506	Detailed analysis of the 4q12 chromosomal region in mucosal, acral, and CSD-cutaneous melanomas identified frequent increased copy number (~25%) and mutations (10-20%) of the KIT receptor tyrosine kinase gene in these subtypes [Table 1].	('receptor tyrosine kinase', 'Gene', (179, 203))	('CSD-cutaneous melanomas', 'Disease', 'MESH:C562576', (72, 95))	('copy', 'MPA', (126, 130))	('receptor tyrosine kinase', 'Gene', '5979', (179, 203))	('mutations', 'Var', (149, 158))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (76, 95))	('chromosomal region', 'cellular_component', 'GO:0098687', ('30', '48'))	('increased', 'PosReg', (116, 125))	('CSD-cutaneous melanomas', 'Disease', (72, 95))	('KIT', 'molecular_function', 'GO:0005020', ('175', '178'))
40579	22275506	KIT copy number changes and mutations are very rare in non-CSD cutaneous melanomas, but there are mixed data about the prevalence in tumors with CSD.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (63, 82))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (63, 82))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', (133, 139))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cutaneous melanomas', 'Disease', (63, 82))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('mutations', 'Var', (28, 37))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
40580	22275506	KIT genetic aberrations in melanoma differ from other cancers (i.e.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('genetic aberrations', 'Var', (4, 23))	('cancers', 'Disease', (54, 61))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('melanoma', 'Disease', (27, 35))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))
40581	22275506	gastrointestinal stromal tumors [GIST]) in the frequent occurrence of copy number gain, the preponderance of substitution mutations (deletions or insertions are rare), and the distribution of mutations (increased de novo prevalence of mutations in exons 13, 17, and 18).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (0, 31))	('substitution mutations', 'Var', (109, 131))	('copy', 'MPA', (70, 74))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (0, 31))	('gain', 'PosReg', (82, 86))	('gastrointestinal stromal tumors', 'Disease', (0, 31))
40583	22275506	In this cohort, KIT mutations correlated with shorter overall survival, but survival data specific to mucosal or acral melanomas was not reported.	('acral melanomas', 'Disease', 'MESH:D008545', (113, 128))	('KIT', 'molecular_function', 'GO:0005020', ('16', '19'))	('overall survival', 'MPA', (54, 70))	('KIT', 'Gene', (16, 19))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('acral melanomas', 'Disease', (113, 128))	('melanomas', 'Phenotype', 'HP:0002861', (119, 128))	('acral melanomas', 'Phenotype', 'HP:0012060', (113, 128))	('shorter', 'NegReg', (46, 53))	('mutations', 'Var', (20, 29))
40584	22275506	Omholt et al., reported the results of a Swedish cohort of 71 mucosal melanoma patients characterized for KIT (35%), NRAS (10%) and BRAF (6%) mutations.	('BRAF', 'Gene', (132, 136))	('mutations', 'Var', (142, 151))	('NRAS', 'Gene', (117, 121))	('NRAS', 'Gene', '4893', (117, 121))	('mucosal melanoma', 'Disease', (62, 78))	('KIT', 'molecular_function', 'GO:0005020', ('106', '109'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (62, 78))	('patients', 'Species', '9606', (79, 87))	('BRAF', 'Gene', '673', (132, 136))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
40585	22275506	Multiple reports have demonstrated impressive responses with FDA-approved KIT inhibitors in individual melanoma patients with KIT mutations.	('KIT', 'molecular_function', 'GO:0005020', ('74', '77'))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('patients', 'Species', '9606', (112, 120))	('KIT', 'molecular_function', 'GO:0005020', ('126', '129'))	('mutations', 'Var', (130, 139))	('KIT', 'Gene', (126, 129))	('melanoma', 'Disease', (103, 111))
40587	22275506	Although these were relatively small trials, the accompanying molecular studies suggest that clinical responses occurred at higher frequency in tumors with recurrent mutations in exons 11 and 13 (i.e.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('mutations in exons', 'Var', (166, 184))	('clinical', 'Species', '191496', (93, 101))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
40588	22275506	L576P, K642E), are more likely with increased mutant:wild-type allelic ratios, and tend not to occur with KIT increased copy number without mutation.	('L576P', 'Mutation', 'rs121913513', (0, 5))	('L576P', 'Var', (0, 5))	('KIT', 'molecular_function', 'GO:0005020', ('106', '109'))	('K642E', 'Var', (7, 12))	('increased', 'PosReg', (36, 45))	('mutant', 'Var', (46, 52))	('K642E', 'Mutation', 'rs121913512', (7, 12))
40589	22275506	Uveal melanomas have frequent mutations in the alpha subunits of the G-proteins GNAQ (~35%) and GNA11 (~45%).	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanomas', 'Disease', (6, 15))	('GNAQ', 'Gene', '2776', (80, 84))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))	('mutations', 'Var', (30, 39))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('GNA11', 'Gene', '2767', (96, 101))	('GNA11', 'Gene', (96, 101))	('GNAQ', 'Gene', (80, 84))
40590	22275506	Mutations in GNAQ and GNA11 are essentially absent in cutaneous and mucosal melanomas, but have also been detected in dermal melanocytic proliferations (e.g., blue nevi) and primary meningeal melanoma.	('mucosal melanomas', 'Disease', (68, 85))	('dermal melanocytic proliferations', 'Disease', (118, 151))	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('GNA11', 'Gene', (22, 27))	('meningeal melanoma', 'Disease', 'MESH:D008545', (182, 200))	('nevi', 'Phenotype', 'HP:0003764', (164, 168))	('GNAQ', 'Gene', (13, 17))	('mucosal melanomas', 'Disease', 'MESH:D008545', (68, 85))	('GNA11', 'Gene', '2767', (22, 27))	('blue nevi', 'Phenotype', 'HP:0100814', (159, 168))	('meningeal melanoma', 'Disease', (182, 200))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('Mutations', 'Var', (0, 9))	('meningeal melanoma', 'Phenotype', 'HP:0007716', (182, 200))	('dermal melanocytic proliferations', 'Disease', 'MESH:D059545', (118, 151))	('detected in', 'Reg', (106, 117))	('GNAQ', 'Gene', '2776', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
40591	22275506	Mutations in GNAQ and GNA11, which are mutually exclusive, involve the hotspot residues R183 and Q209 and, like RAS mutations, inactivate their intrinsic GTPase activity.	('GNA11', 'Gene', (22, 27))	('R183', 'Var', (88, 92))	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (22, 27))	('inactivate', 'NegReg', (127, 137))	('Mutations', 'Var', (0, 9))	('intrinsic', 'MPA', (144, 153))	('GTPase activity', 'molecular_function', 'GO:0003924', ('154', '169'))	('GNAQ', 'Gene', '2776', (13, 17))	('Q209', 'Var', (97, 101))
40592	22275506	Mutations in GNAQ and GNA11 activate the MEK/ERK pathway, although other pathways may also be affected.	('ERK', 'Gene', (45, 48))	('GNA11', 'Gene', (22, 27))	('ERK', 'molecular_function', 'GO:0004707', ('45', '48'))	('MEK', 'Gene', (41, 44))	('MEK', 'Gene', '5609', (41, 44))	('GNAQ', 'Gene', (13, 17))	('activate', 'PosReg', (28, 36))	('GNA11', 'Gene', '2767', (22, 27))	('Mutations', 'Var', (0, 9))	('ERK', 'Gene', '2048', (45, 48))	('GNAQ', 'Gene', '2776', (13, 17))	('affected', 'Reg', (94, 102))
40595	22275506	The risk of metastasis is also elevated in primary uveal melanoma tumors that demonstrate monosomy 3.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (51, 72))	('uveal melanoma', 'Phenotype', 'HP:0007716', (51, 65))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('metastasis', 'CPA', (12, 22))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('monosomy 3', 'Var', (90, 100))	('uveal melanoma tumors', 'Disease', (51, 72))
40596	22275506	The recent identification of inactivating mutations in uveal melanomas in BAP1 on chromosome 3p21 in ~80% of tumors with monosomy 3 implicates it as a tumor suppressor.	('uveal melanoma', 'Phenotype', 'HP:0007716', (55, 69))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('uveal melanomas', 'Disease', (55, 70))	('uveal melanomas', 'Phenotype', 'HP:0007716', (55, 70))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('chromosome', 'cellular_component', 'GO:0005694', ('82', '92'))	('tumor', 'Disease', (109, 114))	('monosomy 3', 'Var', (121, 131))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('BAP1', 'Gene', '8314', (74, 78))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('151', '167'))	('uveal melanomas', 'Disease', 'MESH:C536494', (55, 70))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor suppressor', 'biological_process', 'GO:0051726', ('151', '167'))	('inactivating mutations', 'Var', (29, 51))	('tumor', 'Disease', (151, 156))	('BAP1', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
40597	22275506	BAP1 mutations were present in 84% of tumors with a class 2 gene expression profile, and only 4% of tumors with a class 1 profile.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('BAP1', 'Gene', (0, 4))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('mutations', 'Var', (5, 14))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('gene expression', 'biological_process', 'GO:0010467', ('60', '75'))	('BAP1', 'Gene', '8314', (0, 4))
40601	22275506	Nonetheless, existing data has demonstrated high concordance (>=95%) for BRAF and NRAS mutation status between primary tumors and regional metastases.	('NRAS', 'Gene', '4893', (82, 86))	('BRAF', 'Gene', '673', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('metastases', 'Disease', (139, 149))	('primary tumors', 'Disease', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('NRAS', 'Gene', (82, 86))	('primary tumors', 'Disease', 'MESH:D009369', (111, 125))	('metastases', 'Disease', 'MESH:D009362', (139, 149))	('BRAF', 'Gene', (73, 77))	('mutation', 'Var', (87, 95))
40602	22275506	Thus, it is reasonable to perform BRAF/NRAS mutation testing on primary tumors if metastatic disease is not available; very little data is available at this time about the concordance of other mutations.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mutation', 'Var', (44, 52))	('primary tumors', 'Disease', 'MESH:D009369', (64, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('NRAS', 'Gene', (39, 43))	('BRAF', 'Gene', '673', (34, 38))	('NRAS', 'Gene', '4893', (39, 43))	('BRAF', 'Gene', (34, 38))	('primary tumors', 'Disease', (64, 78))
40605	22275506	Sanger sequencing, which was used in the initial identification of most melanoma-prevalent mutations, is an open method that detects virtually any genomic mutational event occurring between the sequencing primer pairs, including substitutions, deletions, and insertions.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('substitutions', 'Var', (229, 242))	('deletions', 'Var', (244, 253))	('mutations', 'Var', (91, 100))	('insertions', 'Var', (259, 269))
40607	22275506	BRAF, NRAS, GNAQ, GNA11) are altered by a limited number of mutations clustered at particular codons.	('GNAQ', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (0, 4))	('GNAQ', 'Gene', '2776', (12, 16))	('GNA11', 'Gene', (18, 23))	('NRAS', 'Gene', (6, 10))	('altered', 'Reg', (29, 36))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (60, 69))	('GNA11', 'Gene', '2767', (18, 23))	('NRAS', 'Gene', '4893', (6, 10))
40609	22275506	One of the most important and rapidly evolving areas in molecular testing centers around BRAF mutations.	('BRAF', 'Gene', (89, 93))	('BRAF', 'Gene', '673', (89, 93))	('mutations', 'Var', (94, 103))
40611	22275506	This real time PCR test is focused on the qualitative detection of the BRAF V600E mutation.	('V600E', 'Mutation', 'rs113488022', (76, 81))	('V600E', 'Var', (76, 81))	('BRAF', 'Gene', (71, 75))	('BRAF', 'Gene', '673', (71, 75))
40612	22275506	While full characterization of this test is forthcoming, data presented at research meetings suggest very high sensitivity (>99%) and specificity (88%) for the detection of the BRAF V600E mutation.	('BRAF', 'Gene', (177, 181))	('BRAF', 'Gene', '673', (177, 181))	('V600E', 'Mutation', 'rs113488022', (182, 187))	('V600E', 'Var', (182, 187))
40613	22275506	However, certain two nucleotide ("E2") mutations that result in a BRAF V600E mutation are not detected, and there is reduced sensitivity for other amino acid substitutions at the V600 site (i.e.	('V600E', 'Mutation', 'rs113488022', (71, 76))	('"E2"', 'Gene', '106478911', (33, 37))	('V600E', 'Var', (71, 76))	('BRAF', 'Gene', '673', (66, 70))	('BRAF', 'Gene', (66, 70))	('"E2"', 'Gene', (33, 37))
40614	22275506	estimated 66% sensitivity for BRAF V600K).	('BRAF', 'Gene', (30, 34))	('V600K', 'Mutation', 'rs121913227', (35, 40))	('BRAF', 'Gene', '673', (30, 34))	('V600K', 'Var', (35, 40))
40615	22275506	Currently, there is insufficient data to define the true response rates, but at least some patients with BRAF V600K mutations achieve clinical responses with BRAF inhibitors.	('BRAF', 'Gene', '673', (105, 109))	('patients', 'Species', '9606', (91, 99))	('BRAF', 'Gene', (105, 109))	('BRAF', 'Gene', '673', (158, 162))	('V600K', 'Mutation', 'rs121913227', (110, 115))	('BRAF', 'Gene', (158, 162))	('clinical', 'Species', '191496', (134, 142))	('V600K mutations', 'Var', (110, 125))
40618	22275506	Although the high sensitivity of the Cobas 4800 could lead to the detection of BRAF mutations lacking clinical relevance, the high rate of clinical benefit observed in the BRIM-3 trial, which used this platform, suggests that this may not be a significant problem.	('mutations', 'Var', (84, 93))	('clinical', 'Species', '191496', (139, 147))	('BRAF', 'Gene', '673', (79, 83))	('clinical', 'Species', '191496', (102, 110))	('BRAF', 'Gene', (79, 83))
40622	22275506	As both BRAF and NRAS are hotspot mutation tests, they can easily fit into panels, and the identification of an NRAS mutation in the setting of a BRAF wild-type result provides added confidence of the technical quality of the result.	('BRAF', 'Gene', (146, 150))	('BRAF', 'Gene', '673', (8, 12))	('BRAF', 'Gene', (8, 12))	('NRAS', 'Gene', (17, 21))	('NRAS', 'Gene', (112, 116))	('NRAS', 'Gene', '4893', (17, 21))	('NRAS', 'Gene', '4893', (112, 116))	('mutation', 'Var', (117, 125))	('BRAF', 'Gene', '673', (146, 150))
40625	22275506	If validated in additional studies, documentation of KIT locus copy gain may also have utility in tumors with KIT mutations.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('KIT', 'Gene', (110, 113))	('mutations', 'Var', (114, 123))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('KIT', 'Gene', (53, 56))	('KIT', 'molecular_function', 'GO:0005020', ('53', '56'))	('KIT', 'molecular_function', 'GO:0005020', ('110', '113'))
40626	22275506	In acral and mucosal melanomas, mutation frequencies support the simultaneous testing of BRAF and KIT mutations as a first step, preferably with NRAS testing.	('NRAS', 'Gene', (145, 149))	('mucosal melanomas', 'Disease', (13, 30))	('NRAS', 'Gene', '4893', (145, 149))	('BRAF', 'Gene', '673', (89, 93))	('mucosal melanomas', 'Disease', 'MESH:D008545', (13, 30))	('mutations', 'Var', (102, 111))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('KIT', 'Gene', (98, 101))	('BRAF', 'Gene', (89, 93))	('KIT', 'molecular_function', 'GO:0005020', ('98', '101'))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))
40629	22275506	Subsequent testing for other melanoma-prevalent mutations, including GNAQ/11 for diagnostic purposes, can then be performed if they are negative (Table 1).	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('GNAQ', 'Gene', '2776', (69, 73))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('GNAQ', 'Gene', (69, 73))	('mutations', 'Var', (48, 57))
40633	22275506	PTEN loss, MEK mutation, CDK4 mutation, CYCLIN D1 amplification) [Figure 1] in the future.	('mutation', 'Var', (15, 23))	('CYCLIN D1', 'Gene', '595', (40, 49))	('CYCLIN', 'molecular_function', 'GO:0016538', ('40', '46'))	('MEK', 'Gene', (11, 14))	('mutation', 'Var', (30, 38))	('MEK', 'Gene', '5609', (11, 14))	('loss', 'NegReg', (5, 9))	('CDK4', 'Gene', (25, 29))	('CYCLIN D1', 'Gene', (40, 49))	('CDK', 'molecular_function', 'GO:0004693', ('25', '28'))	('PTEN', 'Gene', (0, 4))	('CDK4', 'Gene', '1019', (25, 29))	('PTEN', 'Gene', '5728', (0, 4))
40637	22457788	In the present study, the effects of miR-34a on osteosarcoma and the possible mechanism by which miR-34a affected the tumor growth and metastasis of osteosarcoma were investigated.	('metastasis of osteosarcoma', 'Disease', (135, 161))	('affected', 'Reg', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('metastasis of osteosarcoma', 'Disease', 'MESH:D009362', (135, 161))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('osteosarcoma', 'Phenotype', 'HP:0002669', (48, 60))	('osteosarcoma', 'Disease', (48, 60))	('miR-34a', 'Var', (97, 104))	('osteosarcoma', 'Disease', 'MESH:D012516', (48, 60))	('tumor', 'Disease', (118, 123))	('osteosarcoma', 'Phenotype', 'HP:0002669', (149, 161))	('osteosarcoma', 'Disease', (149, 161))	('osteosarcoma', 'Disease', 'MESH:D012516', (149, 161))
40639	22457788	c-Met is a target of miR-34a, and regulates the migration and invasion of osteosarcoma cells.	('osteosarcoma', 'Disease', 'MESH:D012516', (74, 86))	('miR-34a', 'Var', (21, 28))	('migration', 'CPA', (48, 57))	('c-Met', 'Gene', '4233', (0, 5))	('regulates', 'Reg', (34, 43))	('invasion', 'CPA', (62, 70))	('osteosarcoma', 'Phenotype', 'HP:0002669', (74, 86))	('c-Met', 'Gene', (0, 5))	('osteosarcoma', 'Disease', (74, 86))
40640	22457788	Osteosarcoma cells over-expressing miR-34a exhibited a significant decrease in the expression levels of c-Met mRNA and protein simultaneously.	('decrease', 'NegReg', (67, 75))	('miR-34a', 'Var', (35, 42))	('c-Met', 'Gene', (104, 109))	('over-expressing', 'PosReg', (19, 34))	('c-Met', 'Gene', '4233', (104, 109))	('Osteosarcoma', 'Disease', (0, 12))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))
40644	22457788	Since pulmonary metastases are responsible for mortality of patient carrying osteosarcoma, miR-34a may prove to be a promising gene therapeutic agent.	('patient', 'Species', '9606', (60, 67))	('osteosarcoma', 'Disease', 'MESH:D012516', (77, 89))	('pulmonary metastases', 'Disease', 'MESH:D009362', (6, 26))	('pulmonary metastases', 'Disease', (6, 26))	('miR-34a', 'Var', (91, 98))	('osteosarcoma', 'Phenotype', 'HP:0002669', (77, 89))	('osteosarcoma', 'Disease', (77, 89))
40648	22457788	With a rapid expansion of our knowledge about stem cell biology, emerging evidence suggests osteosarcoma should be regarded as a kind of differentiation disease caused by genetic and epigenetic changes that interrupt osteoblast differentiation from mesenchymal stem cells.	('osteosarcoma', 'Disease', 'MESH:D012516', (92, 104))	('genetic', 'Var', (171, 178))	('osteoblast differentiation', 'CPA', (217, 243))	('osteoblast differentiation', 'biological_process', 'GO:0001649', ('217', '243'))	('caused by', 'Reg', (161, 170))	('osteosarcoma', 'Disease', (92, 104))	('interrupt', 'NegReg', (207, 216))	('epigenetic changes', 'Var', (183, 201))	('osteosarcoma', 'Phenotype', 'HP:0002669', (92, 104))
40666	22457788	The inactivating mutations of p53 often cause a decreased expression of miR-34a in tumors.	('inactivating mutations', 'Var', (4, 26))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('expression', 'MPA', (58, 68))	('tumors', 'Disease', (83, 89))	('decreased', 'NegReg', (48, 57))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('miR-34a', 'Protein', (72, 79))
40669	22457788	The inactivation and absence of miR-34a is related to the pathogenesis of a variety of tumors, including osteosarcoma.	('inactivation', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('pathogenesis', 'biological_process', 'GO:0009405', ('58', '70'))	('miR-34a', 'Gene', (32, 39))	('related', 'Reg', (43, 50))	('absence', 'NegReg', (21, 28))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('osteosarcoma', 'Phenotype', 'HP:0002669', (105, 117))	('tumors', 'Disease', (87, 93))	('osteosarcoma', 'Disease', (105, 117))	('osteosarcoma', 'Disease', 'MESH:D012516', (105, 117))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
40675	22457788	In addition, miR-34a could specifically down-regulate the expression of the metastasis related gene c-Met, indicating that miR-34a may function as a tumor gene suppressor through down-regulating c-Met oncogene.	('down-regulating', 'NegReg', (179, 194))	('c-Met', 'Gene', '4233', (195, 200))	('c-Met', 'Gene', (100, 105))	('down-regulate', 'NegReg', (40, 53))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('expression', 'MPA', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('c-Met', 'Gene', '4233', (100, 105))	('tumor', 'Disease', (149, 154))	('miR-34a', 'Var', (13, 20))	('c-Met', 'Gene', (195, 200))	('miR-34a', 'Var', (123, 130))
40677	22457788	We supposed that miR-34a may prove to be a promising gene therapeutic agent which functions as a tumor suppressor gene through down-regulating multiple target oncogenes in osteosarcoma.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('97', '113'))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (172, 184))	('tumor suppressor', 'biological_process', 'GO:0051726', ('97', '113'))	('osteosarcoma', 'Disease', (172, 184))	('osteosarcoma', 'Disease', 'MESH:D012516', (172, 184))	('tumor', 'Disease', (97, 102))	('down-regulating', 'NegReg', (127, 142))	('miR-34a', 'Var', (17, 24))
40684	22457788	The results demonstrated that cells in miR-34a group exhibited significant declines in proliferation capacity as compared with cells in control group and blank group, which exhibits a negative relationship with the exogenous miR-34a level (Figure 2A).	('declines', 'Disease', 'MESH:D060825', (75, 83))	('declines', 'Disease', (75, 83))	('proliferation capacity', 'CPA', (87, 109))	('miR-34a', 'Var', (39, 46))
40685	22457788	We also tested SAOS-2 cells transiently transfected with either pcDNA3.1 or pcDNA-miR34a (Figure 2B) and SOSP-9607 cells transiently transfected with either miR-34a mimics or inhibitors (Figure S2A, B).	('miR34a', 'Gene', (82, 88))	('SAOS-2', 'CellLine', 'CVCL:0548', (15, 21))	('miR34a', 'Gene', '407040', (82, 88))	('OS', 'Phenotype', 'HP:0002669', (106, 108))	('OS', 'Phenotype', 'HP:0002669', (17, 19))	('SOSP-9607', 'CellLine', 'CVCL:4V80', (105, 114))	('pcDNA3.1', 'Var', (64, 72))
40687	22457788	It has been reported that hepatocellular carcinoma cells transfected with miR-34a mimics are inhibited of both migration and invasion, and the expression of miR-34a is associated with the tumorigenesis of osteosacoma.	('miR-34a', 'Var', (157, 164))	('tumor', 'Disease', (188, 193))	('osteosacoma', 'Disease', 'None', (205, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('osteosacoma', 'Disease', (205, 216))	('associated with', 'Reg', (168, 183))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (26, 50))	('hepatocellular carcinoma', 'Disease', (26, 50))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (26, 50))	('miR-34a', 'Gene', (74, 81))	('inhibited', 'NegReg', (93, 102))
40690	22457788	The results demonstrated that cells in miR-34a group exhibited significant declines in migration and invasion capacities as compared with cells in control group and blank group respectively (Figure 3A, B, C, D).	('migration', 'CPA', (87, 96))	('declines', 'Disease', 'MESH:D060825', (75, 83))	('invasion capacities', 'CPA', (101, 120))	('miR-34a', 'Var', (39, 46))	('declines', 'Disease', (75, 83))
40698	22457788	By contrast, cells in miR-34a group produced much smaller tumors (Figure 4A, C).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('miR-34a', 'Var', (22, 29))	('smaller', 'NegReg', (50, 57))
40701	22457788	Meanwhile, the miR-34a expression levels in the orthotopic tumors were also tested, and the result showed that the orthotopic tumors in the miR-34a group expressed higher miR-34a levels as compared with control group (Figure 4E).	('orthotopic tumors', 'Disease', (115, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('miR-34a levels', 'MPA', (171, 185))	('orthotopic tumors', 'Disease', 'MESH:D009369', (48, 65))	('orthotopic tumors', 'Disease', 'MESH:D009369', (115, 132))	('higher', 'PosReg', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('orthotopic tumors', 'Disease', (48, 65))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('miR-34a', 'Var', (140, 147))
40702	22457788	Both of the results indicated that ectogenous miR-34a can significantly inhibit the tumor growth of osteosarcoma in vivo.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('osteosarcoma', 'Phenotype', 'HP:0002669', (100, 112))	('osteosarcoma', 'Disease', (100, 112))	('osteosarcoma', 'Disease', 'MESH:D012516', (100, 112))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('ectogenous miR-34a', 'Var', (35, 53))	('miR-34a', 'Var', (46, 53))	('inhibit', 'NegReg', (72, 79))
40704	22457788	An average of 26.2+-12.4 metastatic tumor nodules were detected per lung in miR-34a group, while mice in control group produced an average of 96.7+-20.5 metastatic tumor nodules per lung (Figure 5B), indicating that miR-34a significantly decreased tumor colonization in the lung.	('miR-34a', 'Var', (216, 223))	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('mice', 'Species', '10090', (97, 101))	('miR-34a', 'Var', (76, 83))	('decreased', 'NegReg', (238, 247))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Disease', (36, 41))
40707	22457788	The lungs of miR-34a group mice contained less and smaller spontaneous metastases as comparing with control group (Figure 5C).	('mice', 'Species', '10090', (27, 31))	('metastases', 'Disease', (71, 81))	('smaller', 'NegReg', (51, 58))	('miR-34a group', 'Var', (13, 26))	('metastases', 'Disease', 'MESH:D009362', (71, 81))
40708	22457788	Taken together, these results strongly suggest that miR-34a can inhibit osteosarcoma metastasis and might be prevention of metastasis and recurrence in osteosarcoma patients.	('miR-34a', 'Var', (52, 59))	('osteosarcoma metastasis', 'Disease', (72, 95))	('osteosarcoma metastasis', 'Disease', 'MESH:D009362', (72, 95))	('osteosarcoma', 'Disease', (72, 84))	('osteosarcoma', 'Phenotype', 'HP:0002669', (152, 164))	('inhibit', 'NegReg', (64, 71))	('osteosarcoma', 'Disease', (152, 164))	('osteosarcoma', 'Disease', 'MESH:D012516', (152, 164))	('osteosarcoma', 'Phenotype', 'HP:0002669', (72, 84))	('osteosarcoma', 'Disease', 'MESH:D012516', (72, 84))	('patients', 'Species', '9606', (165, 173))
40709	22457788	Studies have reported that miR-34a directly repressed the expression of c-Met in HeLa cells, suppressed brain tumor growth by targeting c-Met, and acted as a tumor suppressor in uveal melanoma cell proliferation and migration through the down-regulation of c-Met.	('down-regulation', 'NegReg', (238, 253))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('c-Met', 'Gene', '4233', (257, 262))	('regulation', 'biological_process', 'GO:0065007', ('243', '253'))	('uveal melanoma', 'Disease', 'MESH:C536494', (178, 192))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('uveal melanoma', 'Disease', (178, 192))	('brain tumor', 'Phenotype', 'HP:0030692', (104, 115))	('c-Met', 'Gene', '4233', (136, 141))	('miR-34a', 'Gene', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('c-Met', 'Gene', '4233', (72, 77))	('brain tumor', 'Disease', 'MESH:D001932', (104, 115))	('brain tumor', 'Disease', (104, 115))	('HeLa', 'CellLine', 'CVCL:0030', (81, 85))	('uveal melanoma', 'Phenotype', 'HP:0007716', (178, 192))	('c-Met', 'Gene', (257, 262))	('targeting', 'Var', (126, 135))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('158', '174'))	('cell proliferation', 'biological_process', 'GO:0008283', ('193', '211'))	('migration', 'CPA', (216, 225))	('suppressed', 'NegReg', (93, 103))	('c-Met', 'Gene', (136, 141))	('tumor', 'Disease', (158, 163))	('tumor suppressor', 'biological_process', 'GO:0051726', ('158', '174'))	('c-Met', 'Gene', (72, 77))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
40713	22457788	The results from RT-PCR demonstrated that the endogenous c-Met mRNA level in miR-34a group cells was also significantly decreased (Figure 6B).	('decreased', 'NegReg', (120, 129))	('c-Met', 'Gene', (57, 62))	('miR-34a', 'Var', (77, 84))	('c-Met', 'Gene', '4233', (57, 62))
40716	22457788	The results demonstrated that, in SOSP-9607 cells, the luciferase activity of the pmiR-Met UTR-Wt construct was significantly inhibited after the introduction of miR-34a, similar to those reported by others.	('luciferase activity', 'molecular_function', 'GO:0047077', ('55', '74'))	('activity', 'MPA', (66, 74))	('miR-34a', 'Var', (162, 169))	('inhibited', 'NegReg', (126, 135))	('luciferase activity', 'molecular_function', 'GO:0045289', ('55', '74'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('55', '74'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('55', '74'))	('OS', 'Phenotype', 'HP:0002669', (35, 37))	('luciferase activity', 'molecular_function', 'GO:0050397', ('55', '74'))	('SOSP-9607', 'CellLine', 'CVCL:4V80', (34, 43))	('luciferase', 'Enzyme', (55, 65))
40717	22457788	Meanwhile, mutations of the two c-Met 3'UTR-binding sites abolished the ability of miR-34a to regulate luciferase expression (Figure 6C).	('mutations', 'Var', (11, 20))	('abolished', 'NegReg', (58, 67))	('c-Met', 'Gene', '4233', (32, 37))	('ability', 'MPA', (72, 79))	('c-Met', 'Gene', (32, 37))	('luciferase', 'Enzyme', (103, 113))	('expression', 'MPA', (114, 124))	('regulate', 'MPA', (94, 102))	('binding', 'molecular_function', 'GO:0005488', ('44', '51'))
40724	22457788	We focused on miR-34a because not only previous reports demonstrated that the expression of miR-34a was significantly decreased in primary osteosarcoma samples as compared with adjacent normal tissues, but also the mutations of p53 tumor suppressor gene, which directly regulates the expression of miR-34a, was also found in 20-60% of sporadic osteosarcomas.	('primary osteosarcoma', 'Disease', (131, 151))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('232', '248'))	('expression', 'MPA', (78, 88))	('osteosarcoma', 'Phenotype', 'HP:0002669', (139, 151))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('p53', 'Gene', (228, 231))	('p53', 'Gene', '7157', (228, 231))	('osteosarcoma', 'Phenotype', 'HP:0002669', (344, 356))	('mutations', 'Var', (215, 224))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('primary osteosarcoma', 'Disease', 'MESH:D012516', (131, 151))	('osteosarcomas', 'Disease', (344, 357))	('decreased', 'NegReg', (118, 127))	('miR-34a', 'Gene', (92, 99))	('osteosarcomas', 'Phenotype', 'HP:0002669', (344, 357))	('osteosarcomas', 'Disease', 'MESH:D012516', (344, 357))	('tumor', 'Disease', (232, 237))	('tumor suppressor', 'biological_process', 'GO:0051726', ('232', '248'))
40725	22457788	Both of the previous reports suggested that miR-34a may function as a tumor suppressor in osteosarcoma.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', (70, 75))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('osteosarcoma', 'Disease', (90, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (90, 102))	('miR-34a', 'Var', (44, 51))	('osteosarcoma', 'Disease', 'MESH:D012516', (90, 102))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
40731	22457788	found that miR-34a inhibits migration and invasion of human hepatocellular carcinoma cells.	('miR-34a', 'Var', (11, 18))	('hepatocellular carcinoma', 'Disease', (60, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (60, 84))	('inhibits', 'NegReg', (19, 27))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (60, 84))	('human', 'Species', '9606', (54, 59))
40739	22457788	Therefore, we chose a mouse model to further investigate effects of miR-34a on tumor growth and pulmonary metastasis.	('tumor', 'Disease', (79, 84))	('mouse', 'Species', '10090', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('miR-34a', 'Var', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
40740	22457788	The results demonstrated that miR-34a also significantly inhibited the capacities of orthotopic tumor growth and lung metastasis in vivo.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('inhibited', 'NegReg', (57, 66))	('tumor', 'Disease', (96, 101))	('lung metastasis', 'CPA', (113, 128))	('miR-34a', 'Var', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
40741	22457788	Because we couldn't maintain the G418 selection in vivo, the selected cells may not maintain miR-34a over-expression as that in vitro.	('G418', 'Var', (33, 37))	('G418', 'Chemical', 'MESH:C010680', (33, 37))	('over-expression', 'MPA', (101, 116))	('miR-34a', 'Protein', (93, 100))
40743	22457788	The result showed that the miR-34a expression level of G418 sellected cells, in the orthotopic tumors after 6 weeks of inoculation, was indeed over-expressed as that in vitro.	('miR-34a', 'Gene', (27, 34))	('over-expressed', 'PosReg', (143, 157))	('orthotopic tumors', 'Disease', (84, 101))	('G418', 'Chemical', 'MESH:C010680', (55, 59))	('expression', 'MPA', (35, 45))	('orthotopic tumors', 'Disease', 'MESH:D009369', (84, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('G418', 'Var', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
40754	22457788	The Met oncogene is up-regulated in a variety of tumor cells similar in scope to p53 mutants.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('mutants', 'Var', (85, 92))	('up-regulated', 'PosReg', (20, 32))
40759	22457788	We examined the c-Met expression level of osteosarcoma cells in three groups SOSP-9607 cells, and observed a significant decrease of c-Met mRNA and protein levels in miR-34a group cells as compared with blank group and control group.	('c-Met', 'Gene', '4233', (16, 21))	('osteosarcoma', 'Disease', (42, 54))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('examined', 'Reg', (3, 11))	('OS', 'Phenotype', 'HP:0002669', (78, 80))	('miR-34a', 'Var', (166, 173))	('c-Met', 'Gene', (16, 21))	('osteosarcoma', 'Disease', 'MESH:D012516', (42, 54))	('osteosarcoma', 'Phenotype', 'HP:0002669', (42, 54))	('SOSP-9607', 'CellLine', 'CVCL:4V80', (77, 86))	('decrease', 'NegReg', (121, 129))	('c-Met', 'Gene', (133, 138))	('c-Met', 'Gene', '4233', (133, 138))
40761	22457788	These results indicated that miR-34a may suppress tumor growth and metastasis in osteosarcoma cells through down-regulating c-Met oncogene.	('osteosarcoma', 'Disease', (81, 93))	('down-regulating', 'NegReg', (108, 123))	('osteosarcoma', 'Disease', 'MESH:D012516', (81, 93))	('c-Met', 'Gene', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('c-Met', 'Gene', '4233', (124, 129))	('miR-34a', 'Var', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('suppress', 'NegReg', (41, 49))	('tumor', 'Disease', (50, 55))	('osteosarcoma', 'Phenotype', 'HP:0002669', (81, 93))
40770	22457788	The dysregulation of several evolutionarily conserved signaling pathways in osteosarcoma tumor samples and cell lines have been repeatedly found.	('signaling', 'biological_process', 'GO:0023052', ('54', '63'))	('osteosarcoma tumor', 'Disease', 'MESH:D012516', (76, 94))	('dysregulation', 'Var', (4, 17))	('osteosarcoma tumor', 'Disease', (76, 94))	('evolutionarily conserved signaling pathways', 'Pathway', (29, 72))	('osteosarcoma', 'Phenotype', 'HP:0002669', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
40772	22457788	Activation of Notch signaling contributes to the pathogenesis of human osteosarcomas andthe inhibition of the Notch signaling may be a therapeutic approach for the treatment of osteosarcoma.	('osteosarcoma', 'Disease', 'MESH:D012516', (71, 83))	('inhibition', 'Var', (92, 102))	('osteosarcoma', 'Disease', 'MESH:D012516', (177, 189))	('human', 'Species', '9606', (65, 70))	('pathogenesis', 'biological_process', 'GO:0009405', ('49', '61'))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))	('osteosarcomas', 'Phenotype', 'HP:0002669', (71, 84))	('osteosarcoma', 'Phenotype', 'HP:0002669', (177, 189))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))	('osteosarcomas', 'Disease', (71, 84))	('osteosarcoma', 'Phenotype', 'HP:0002669', (71, 83))	('osteosarcoma', 'Disease', (71, 83))	('osteosarcomas', 'Disease', 'MESH:D012516', (71, 84))	('osteosarcoma', 'Disease', (177, 189))
40774	22457788	Deregulation of Wnt signaling pathway has been implicated in many human diseases, ranging from cancers to skeletal disorders.	('Wnt', 'Gene', (16, 19))	('Deregulation', 'Var', (0, 12))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('implicated', 'Reg', (47, 57))	('human', 'Species', '9606', (66, 71))	('cancers to skeletal disorders', 'Disease', (95, 124))	('Wnt', 'Gene', '7471', (16, 19))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('16', '37'))	('skeletal disorders', 'Phenotype', 'HP:0000924', (106, 124))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancers to skeletal disorders', 'Disease', 'MESH:D009369', (95, 124))
40778	22457788	Therefore, we inferred that miR-34a may play an important role in inhibiting tumor metastasis and proliferation through down-regulating multiple target genes, including genes in Notch and Wnt signaling pathways.	('miR-34a', 'Var', (28, 35))	('tumor metastasis', 'Disease', (77, 93))	('tumor metastasis', 'Disease', 'MESH:D009362', (77, 93))	('Wnt', 'Gene', (188, 191))	('inhibiting', 'NegReg', (66, 76))	('signaling', 'biological_process', 'GO:0023052', ('192', '201'))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('down-regulating', 'NegReg', (120, 135))	('Wnt', 'Gene', '7471', (188, 191))
40779	22457788	In conclusion, the results presented here demonstrated that miR-34a has great biological effects on the growth and metastasis of osteosarcoma cells both in vitro and in vivo.	('growth', 'CPA', (104, 110))	('miR-34a', 'Var', (60, 67))	('osteosarcoma', 'Phenotype', 'HP:0002669', (129, 141))	('metastasis of osteosarcoma', 'Disease', (115, 141))	('metastasis of osteosarcoma', 'Disease', 'MESH:D009362', (115, 141))
40780	22457788	Over-expression of miR-34a down-regulated the expression of c-Met protein and mRNA simultaneously, suggesting that miR-34a functions as tumor suppressors probably through down-regulating c-Met in osteosarcoma.	('osteosarcoma', 'Phenotype', 'HP:0002669', (196, 208))	('osteosarcoma', 'Disease', (196, 208))	('osteosarcoma', 'Disease', 'MESH:D012516', (196, 208))	('mRNA', 'MPA', (78, 82))	('miR-34a', 'Var', (115, 122))	('down-regulated', 'NegReg', (27, 41))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('c-Met', 'Gene', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('miR-34a', 'Gene', (19, 26))	('c-Met', 'Gene', '4233', (187, 192))	('expression', 'MPA', (46, 56))	('c-Met', 'Gene', (60, 65))	('tumor', 'Disease', (136, 141))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('c-Met', 'Gene', '4233', (60, 65))	('down-regulating', 'NegReg', (171, 186))
40782	22457788	Finally, because pulmonary metastases are responsible for mortality of patient carrying osteosarcoma, miR-34a may prove to be a promising gene therapeutic agent.	('osteosarcoma', 'Disease', 'MESH:D012516', (88, 100))	('pulmonary metastases', 'Disease', 'MESH:D009362', (17, 37))	('miR-34a', 'Var', (102, 109))	('pulmonary metastases', 'Disease', (17, 37))	('patient', 'Species', '9606', (71, 78))	('osteosarcoma', 'Phenotype', 'HP:0002669', (88, 100))	('osteosarcoma', 'Disease', (88, 100))
40827	22253748	The Protein Kinase C Inhibitor Enzastaurin Exhibits Antitumor Activity against Uveal Melanoma GNAQ mutations at codon 209 have been recently identified in approximately 50% of uveal melanomas (UM) and are reported to be oncogenic through activating the MAPK/Erk1/2 pathway.	('Melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('GNAQ', 'Gene', '2776', (94, 98))	('activating', 'Reg', (238, 248))	('melanomas', 'Phenotype', 'HP:0002861', (182, 191))	('GNAQ', 'Gene', (94, 98))	('UM', 'Phenotype', 'HP:0007716', (193, 195))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('Erk1', 'molecular_function', 'GO:0004707', ('258', '262'))	('MAPK', 'molecular_function', 'GO:0004707', ('253', '257'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (176, 190))	('uveal melanomas', 'Disease', 'MESH:C536494', (176, 191))	('Melanoma', 'Disease', 'MESH:D008545', (85, 93))	('identified', 'Reg', (141, 151))	('Enzastaurin', 'Chemical', 'MESH:C504878', (31, 42))	('mutations at codon', 'Var', (99, 117))	('Melanoma', 'Disease', (85, 93))	('MAPK/Erk1/2 pathway', 'Pathway', (253, 272))	('uveal melanomas', 'Disease', (176, 191))	('uveal melanomas', 'Phenotype', 'HP:0007716', (176, 191))
40829	22253748	Inhibition of PKC might regulate GNAQ mutation-induced Erk1/2 activation, resulting in growth inhibition of UM cells carrying GNAQ mutations.	('GNAQ', 'Gene', '2776', (126, 130))	('mutations', 'Var', (131, 140))	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('GNAQ', 'Gene', (33, 37))	('PKC', 'Gene', (14, 17))	('PKC', 'Gene', '112476', (14, 17))	('Erk1', 'molecular_function', 'GO:0004707', ('55', '59'))	('GNAQ', 'Gene', (126, 130))	('PKC', 'molecular_function', 'GO:0004697', ('14', '17'))	('GNAQ', 'Gene', '2776', (33, 37))	('mutation-induced', 'Var', (38, 54))	('growth inhibition', 'CPA', (87, 104))	('activation', 'PosReg', (62, 72))	('Erk1/2', 'Enzyme', (55, 61))
40830	22253748	UM cells carrying wild type or mutant GNAQ were treated with the PKC inhibitor enzastaurin.	('GNAQ', 'Gene', '2776', (38, 42))	('mutant', 'Var', (31, 37))	('PKC', 'Gene', (65, 68))	('PKC', 'molecular_function', 'GO:0004697', ('65', '68'))	('PKC', 'Gene', '112476', (65, 68))	('GNAQ', 'Gene', (38, 42))	('enzastaurin', 'Chemical', 'MESH:C504878', (79, 90))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
40833	22253748	Enzastaurin exhibited greater antiproliferative effect on GNAQ mutant cells than wild type cells through induction of G1 arrest and apoptosis.	('apoptosis', 'CPA', (132, 141))	('arrest', 'Disease', 'MESH:D006323', (121, 127))	('apoptosis', 'biological_process', 'GO:0097194', ('132', '141'))	('mutant', 'Var', (63, 69))	('arrest', 'Disease', (121, 127))	('GNAQ', 'Gene', '2776', (58, 62))	('apoptosis', 'biological_process', 'GO:0006915', ('132', '141'))	('Enzastaurin', 'Chemical', 'MESH:C504878', (0, 11))	('antiproliferative effect', 'CPA', (30, 54))	('GNAQ', 'Gene', (58, 62))
40835	22253748	Furthermore, enzastaurin reduced the expression of antiapoptotic Bcl-2 and survivin in GNAQ mutant cells.	('reduced', 'NegReg', (25, 32))	('GNAQ', 'Gene', '2776', (87, 91))	('enzastaurin', 'Chemical', 'MESH:C504878', (13, 24))	('expression', 'MPA', (37, 47))	('GNAQ', 'Gene', (87, 91))	('mutant', 'Var', (92, 98))	('Bcl-2', 'molecular_function', 'GO:0015283', ('65', '70'))	('survivin', 'Protein', (75, 83))	('Bcl-2', 'Gene', (65, 70))	('antiapoptotic', 'MPA', (51, 64))	('Bcl-2', 'Gene', '596', (65, 70))
40836	22253748	Inhibition of Erk1/2 phosphorylation with a MEK specific inhibitor enhanced the sensitivity of GNAQ wild type cells to enzastaurin, accompanied by p27Kip1 accumulation and/or inhibition of enzastaurin-induced survivin and Bcl-2 upregulation.	('GNAQ', 'Gene', (95, 99))	('Bcl-2', 'Gene', '596', (222, 227))	('phosphorylation', 'biological_process', 'GO:0016310', ('21', '36'))	('sensitivity', 'MPA', (80, 91))	('enzastaurin', 'Chemical', 'MESH:C504878', (119, 130))	('Erk1', 'molecular_function', 'GO:0004707', ('14', '18'))	('GNAQ', 'Gene', '2776', (95, 99))	('survivin', 'CPA', (209, 217))	('p27Kip1', 'Gene', (147, 154))	('Bcl-2', 'molecular_function', 'GO:0015283', ('222', '227'))	('upregulation', 'PosReg', (228, 240))	('Erk1/2', 'Gene', (14, 20))	('Inhibition', 'Var', (0, 10))	('enzastaurin', 'Chemical', 'MESH:C504878', (189, 200))	('p27Kip1', 'Gene', '1027', (147, 154))	('accumulation', 'PosReg', (155, 167))	('Bcl-2', 'Gene', (222, 227))	('inhibition', 'NegReg', (175, 185))	('enhanced', 'PosReg', (67, 75))
40837	22253748	PKC inhibitors such as enzastaurin have activity against UM cells carrying GNAQ mutations through inhibition of the PKC/Erk1/2 pathway and induction of G1 arrest and apoptosis.	('PKC', 'Gene', '112476', (116, 119))	('apoptosis', 'biological_process', 'GO:0097194', ('166', '175'))	('apoptosis', 'biological_process', 'GO:0006915', ('166', '175'))	('activity', 'MPA', (40, 48))	('PKC', 'Gene', (116, 119))	('mutations', 'Var', (80, 89))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('arrest', 'Disease', (155, 161))	('PKC', 'molecular_function', 'GO:0004697', ('116', '119'))	('GNAQ', 'Gene', '2776', (75, 79))	('PKC', 'Gene', '112476', (0, 3))	('GNAQ', 'Gene', (75, 79))	('inhibition', 'NegReg', (98, 108))	('enzastaurin', 'Chemical', 'MESH:C504878', (23, 34))	('PKC', 'molecular_function', 'GO:0004697', ('0', '3'))	('PKC', 'Gene', (0, 3))	('arrest', 'Disease', 'MESH:D006323', (155, 161))	('Erk1', 'molecular_function', 'GO:0004707', ('120', '124'))	('apoptosis', 'CPA', (166, 175))
40849	22253748	GNAQ mutations occurring at codon 209 of the RAS-like domain result in constitutive activation of the MAPK/Erk1/2 pathway in melanocytes and confer dominantly acting oncogenic functions to GNAQ.	('GNAQ', 'Gene', '2776', (189, 193))	('GNAQ', 'Gene', '2776', (0, 4))	('Erk1', 'molecular_function', 'GO:0004707', ('107', '111'))	('activation', 'PosReg', (84, 94))	('oncogenic functions', 'CPA', (166, 185))	('MAPK', 'molecular_function', 'GO:0004707', ('102', '106'))	('mutations', 'Var', (5, 14))	('GNAQ', 'Gene', (189, 193))	('GNAQ', 'Gene', (0, 4))	('MAPK/Erk1/2 pathway', 'Pathway', (102, 121))
40858	22253748	Enzastaurin (LY317615) is a potent and selective competitive inhibitor of PKCbeta at low concentrations (IC50, 6 nmol/L) and inhibits other PKC isoenzymes at higher concentrations.	('PKCbeta', 'Gene', (74, 81))	('PKC', 'Gene', (140, 143))	('PKC', 'Gene', '112476', (140, 143))	('LY317615', 'Chemical', 'MESH:C504878', (13, 21))	('PKC', 'molecular_function', 'GO:0004697', ('140', '143'))	('Enzastaurin', 'Chemical', 'MESH:C504878', (0, 11))	('LY317615', 'Var', (13, 21))	('PKCbeta', 'Gene', '5579', (74, 81))	('inhibits', 'NegReg', (125, 133))	('PKCbeta', 'molecular_function', 'GO:0004697', ('74', '81'))	('PKC', 'Gene', (74, 77))	('PKC', 'Gene', '112476', (74, 77))
40859	22253748	In addition, enzastaurin targets the phosphatidylinositol 3-kinase/AKT pathway, and inhibits phosphorylation of GSK3beta (Ser9) and ribosomal protein S6 (Ser240/244).	('AKT', 'Gene', '207', (67, 70))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('ribosomal protein S6', 'Gene', (132, 152))	('phosphorylation', 'biological_process', 'GO:0016310', ('93', '108'))	('Ser240/244', 'Var', (154, 164))	('ribosomal protein S6', 'Gene', '6194', (132, 152))	('AKT', 'Gene', (67, 70))	('GSK3beta', 'Gene', (112, 120))	('GSK3beta', 'Gene', '2932', (112, 120))	('Ser', 'cellular_component', 'GO:0005790', ('154', '157'))	('Ser', 'cellular_component', 'GO:0005790', ('122', '125'))	('enzastaurin', 'Chemical', 'MESH:C504878', (13, 24))	('Ser9', 'Chemical', '-', (122, 126))	('GSK', 'molecular_function', 'GO:0050321', ('112', '115'))	('phosphorylation', 'MPA', (93, 108))	('inhibits', 'NegReg', (84, 92))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('132', '149'))	('Ser240', 'Chemical', '-', (154, 160))
40862	22253748	Given the importance of PKC in tumorigenesis and potentially in GNAQ mutation-induced MAPK activation, we hypothesized that PKC may provide new opportunities for therapeutic intervention of UM carrying GNAQ mutations.	('MAPK', 'molecular_function', 'GO:0004707', ('86', '90'))	('activation', 'PosReg', (91, 101))	('PKC', 'Gene', (124, 127))	('GNAQ', 'Gene', '2776', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('MAPK activation', 'biological_process', 'GO:0000187', ('86', '101'))	('GNAQ', 'Gene', (202, 206))	('mutations', 'Var', (207, 216))	('PKC', 'molecular_function', 'GO:0004697', ('24', '27'))	('PKC', 'molecular_function', 'GO:0004697', ('124', '127'))	('PKC', 'Gene', '112476', (24, 27))	('UM', 'Phenotype', 'HP:0007716', (190, 192))	('MAPK', 'Enzyme', (86, 90))	('GNAQ', 'Gene', '2776', (64, 68))	('PKC', 'Gene', (24, 27))	('GNAQ', 'Gene', (64, 68))	('tumor', 'Disease', (31, 36))	('PKC', 'Gene', '112476', (124, 127))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
40863	22253748	In the present study, we tested this hypothesis by examining the response of UM cells with wild type or mutant GNAQ toward the antiproliferative and proapoptotic action of enzastaurin and characterized the underlying signaling and molecular mechanisms.	('signaling', 'biological_process', 'GO:0023052', ('217', '226'))	('GNAQ', 'Gene', '2776', (111, 115))	('mutant', 'Var', (104, 110))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('antiproliferative', 'MPA', (127, 144))	('GNAQ', 'Gene', (111, 115))	('enzastaurin', 'Chemical', 'MESH:C504878', (172, 183))	('proapoptotic action', 'MPA', (149, 168))
40865	22253748	DNA sequencing confirmed that cell lines Omm1.3 (accession number JN184781), Mel202 (accession number JN184779) and 92.1 (accession number JN184780) carry a mutation at codon 209 of GNAQ while the remaining cell lines are wild type for GNAQ.	('GNAQ', 'Gene', '2776', (182, 186))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('GNAQ', 'Gene', (236, 240))	('mutation at codon 209', 'Var', (157, 178))	('GNAQ', 'Gene', (182, 186))	('GNAQ', 'Gene', '2776', (236, 240))
40867	22253748	Cell lines Ocm1 and Ocm3 have been reported to harbor BRAF V600E mutation.	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('V600E', 'Mutation', 'rs113488022', (59, 64))	('Ocm1', 'Species', '83984', (11, 15))	('V600E', 'Var', (59, 64))
40868	22253748	While a dose-dependent decrease in viability was seen in all eleven UM cell lines tested, greater inhibition was noted in the three cell lines harboring GNAQ mutations (Figure 1B).	('decrease', 'NegReg', (23, 31))	('GNAQ', 'Gene', (153, 157))	('GNAQ', 'Gene', '2776', (153, 157))	('mutations', 'Var', (158, 167))	('UM', 'Phenotype', 'HP:0007716', (68, 70))	('viability', 'MPA', (35, 44))
40874	22253748	In mutated cell lines, there was an estimated decrease of 21% (95% CI: 19.8% to 22.6%) in viability for each unit increase in enzastaurin concentration (Table S1).	('enzastaurin concentration', 'MPA', (126, 151))	('viability', 'MPA', (90, 99))	('increase', 'PosReg', (114, 122))	('decrease', 'NegReg', (46, 54))	('enzastaurin', 'Chemical', 'MESH:C504878', (126, 137))	('mutated', 'Var', (3, 10))
40877	22253748	Enzastaurin treatment for 48 hours significantly increased the G1 population while decreasing the S population in all three cell lines harboring GNAQ mutations (Figure 2).	('decreasing', 'NegReg', (83, 93))	('GNAQ', 'Gene', (145, 149))	('increased', 'PosReg', (49, 58))	('Enzastaurin', 'Chemical', 'MESH:C504878', (0, 11))	('GNAQ', 'Gene', '2776', (145, 149))	('mutations', 'Var', (150, 159))	('S population', 'MPA', (98, 110))	('G1 population', 'CPA', (63, 76))
40878	22253748	In agreement with these findings, enzastaurin significantly decreased BrdU incorporation in mutant cell lines (Figure 3).	('enzastaurin', 'Chemical', 'MESH:C504878', (34, 45))	('decreased', 'NegReg', (60, 69))	('mutant', 'Var', (92, 98))	('BrdU incorporation', 'MPA', (70, 88))
40879	22253748	These results suggest that enzastaurin induced G1 arrest in the cell lines harboring mutations.	('arrest', 'Disease', (50, 56))	('mutations', 'Var', (85, 94))	('arrest', 'Disease', 'MESH:D006323', (50, 56))	('enzastaurin', 'Chemical', 'MESH:C504878', (27, 38))
40880	22253748	In comparison, the G1 population of the wild type cell lines was either unaltered (C918 and Ocm3) or decreased by enzastaurin (Ocm1 and Mel285).	('enzastaurin', 'Chemical', 'MESH:C504878', (114, 125))	('C918', 'Var', (83, 87))	('Ocm3', 'Var', (92, 96))	('Ocm1', 'Species', '83984', (127, 131))	('decreased', 'NegReg', (101, 110))	('C918', 'CellLine', 'CVCL:8471', (83, 87))
40884	22253748	Treatment with 4 microM enzastaurin for 72 hours induced a slight increase (10.4%) in apoptosis in mutant cell line 92.1 but not in the wild type cell line C918 (Figure 4, left panel).	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('C918', 'CellLine', 'CVCL:8471', (156, 160))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('mutant', 'Var', (99, 105))	('apoptosis', 'CPA', (86, 95))	('enzastaurin', 'Chemical', 'MESH:C504878', (24, 35))
40886	22253748	In the presence of 1% serum, treatment with 5 microM enzastaurin for 72 hours induced substantial apoptosis in the cell lines Mel202, 92.1 and Omm1.3 harboring GNAQ mutations, and in the wild type cell lines Ocm1 (harboring a BRAF mutation), but failed to do so in cell line C918 which is wild type for GNAQ (Figure 4A, right panel).	('GNAQ', 'Gene', (160, 164))	('Ocm1', 'Species', '83984', (208, 212))	('apoptosis', 'CPA', (98, 107))	('enzastaurin', 'Chemical', 'MESH:C504878', (53, 64))	('GNAQ', 'Gene', '2776', (303, 307))	('BRAF', 'Gene', '673', (226, 230))	('GNAQ', 'Gene', '2776', (160, 164))	('BRAF', 'Gene', (226, 230))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('mutations', 'Var', (165, 174))	('GNAQ', 'Gene', (303, 307))	('C918', 'CellLine', 'CVCL:8471', (275, 279))
40887	22253748	An increase in cleaved caspase-3 fragments was also observed in enzastaurin-treated Mel202, 92.1 and Omm1.3 mutant cells and Ocm1 wild type cells, but not C918 cells (Figure 4B).	('C918', 'CellLine', 'CVCL:8471', (155, 159))	('Mel202', 'Gene', (84, 90))	('cleaved caspase-3 fragments', 'MPA', (15, 42))	('enzastaurin', 'Chemical', 'MESH:C504878', (64, 75))	('mutant', 'Var', (108, 114))	('Ocm1', 'Species', '83984', (125, 129))	('increase', 'PosReg', (3, 11))
40888	22253748	These findings suggest that UM cells carrying GNAQ mutations and some GNAQ wild type/BRAF mutant cells are more sensitive to the apoptotic activity of enzastaurin and that enzastaurin exerted increased antiproliferative effect on GNAQ mutant UM cells through induction of G1 arrest and apoptosis.	('GNAQ', 'Gene', (46, 50))	('mutations', 'Var', (51, 60))	('sensitive', 'MPA', (112, 121))	('UM', 'Phenotype', 'HP:0007716', (242, 244))	('mutant', 'Var', (90, 96))	('GNAQ', 'Gene', '2776', (70, 74))	('GNAQ', 'Gene', (70, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('286', '295'))	('UM', 'Phenotype', 'HP:0007716', (28, 30))	('apoptosis', 'biological_process', 'GO:0006915', ('286', '295'))	('arrest', 'Disease', (275, 281))	('antiproliferative effect', 'CPA', (202, 226))	('enzastaurin', 'Chemical', 'MESH:C504878', (151, 162))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('enzastaurin', 'Chemical', 'MESH:C504878', (172, 183))	('increased', 'PosReg', (192, 201))	('GNAQ', 'Gene', '2776', (230, 234))	('arrest', 'Disease', 'MESH:D006323', (275, 281))	('GNAQ', 'Gene', '2776', (46, 50))	('GNAQ', 'Gene', (230, 234))	('mutant', 'Var', (235, 241))	('apoptosis', 'CPA', (286, 295))
40889	22253748	To understand the molecular mechanisms underlying enzastaurin-induced G1 arrest in GNAQ mutant UM cells, we investigated the enzastaurin response of cell cycle regulatory molecules, including cyclin D1 and p27Kip1 that regulate cell cycle progression through G1 phase.	('G1 phase', 'biological_process', 'GO:0051318', ('259', '267'))	('GNAQ', 'Gene', '2776', (83, 87))	('cell cycle', 'biological_process', 'GO:0007049', ('228', '238'))	('arrest', 'Disease', 'MESH:D006323', (73, 79))	('p27Kip1', 'Gene', '1027', (206, 213))	('enzastaurin', 'Chemical', 'MESH:C504878', (125, 136))	('cell cycle', 'biological_process', 'GO:0007049', ('149', '159'))	('cyclin', 'molecular_function', 'GO:0016538', ('192', '198'))	('p27Kip1', 'Gene', (206, 213))	('enzastaurin', 'Chemical', 'MESH:C504878', (50, 61))	('cyclin D1', 'Gene', '595', (192, 201))	('mutant', 'Var', (88, 94))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('arrest', 'Disease', (73, 79))	('GNAQ', 'Gene', (83, 87))	('cyclin D1', 'Gene', (192, 201))
40892	22253748	These findings are in line with enzastaurin-induced G1 arrest occurring only in GNAQ mutant lines, and suggest that cyclin D1 and p27 dysregulation are molecular mechanisms for enzastaurin-induced G1 arrest.	('arrest', 'Disease', 'MESH:D006323', (200, 206))	('arrest', 'Disease', 'MESH:D006323', (55, 61))	('p27', 'Gene', (130, 133))	('p27', 'Gene', '3429', (130, 133))	('enzastaurin', 'Chemical', 'MESH:C504878', (177, 188))	('enzastaurin', 'Chemical', 'MESH:C504878', (32, 43))	('cyclin', 'molecular_function', 'GO:0016538', ('116', '122'))	('GNAQ', 'Gene', '2776', (80, 84))	('cyclin D1', 'Gene', '595', (116, 125))	('arrest', 'Disease', (55, 61))	('arrest', 'Disease', (200, 206))	('cyclin D1', 'Gene', (116, 125))	('mutant', 'Var', (85, 91))	('GNAQ', 'Gene', (80, 84))
40894	22253748	Enzastaurin significantly inhibited survivin expression in all three cell lines with GNAQ mutations and in GNAQ wild type cell line Mel285 (Figure 5B).	('mutations', 'Var', (90, 99))	('inhibited', 'NegReg', (26, 35))	('survivin', 'Protein', (36, 44))	('GNAQ', 'Gene', '2776', (107, 111))	('Enzastaurin', 'Chemical', 'MESH:C504878', (0, 11))	('GNAQ', 'Gene', (85, 89))	('expression', 'MPA', (45, 55))	('GNAQ', 'Gene', '2776', (85, 89))	('GNAQ', 'Gene', (107, 111))
40895	22253748	It is noteworthy that the mutant cell lines expressed significantly higher levels of Bcl-2 compared with wild type cell lines (Figure 5B and unpublished data).	('higher', 'PosReg', (68, 74))	('Bcl-2', 'molecular_function', 'GO:0015283', ('85', '90'))	('levels', 'MPA', (75, 81))	('Bcl-2', 'Gene', (85, 90))	('mutant', 'Var', (26, 32))	('Bcl-2', 'Gene', '596', (85, 90))
40896	22253748	Enzasaturin decreased Bcl-2 expression in the mutant cell lines and appeared to slightly increase (C918 and Ocm1 cells) or have little effect (Mel285) on its expression in the wild type cells.	('expression', 'MPA', (28, 38))	('Bcl-2', 'Gene', (22, 27))	('mutant', 'Var', (46, 52))	('decreased', 'NegReg', (12, 21))	('Enzasaturin', 'Chemical', '-', (0, 11))	('C918', 'CellLine', 'CVCL:8471', (99, 103))	('Bcl-2', 'Gene', '596', (22, 27))	('Ocm1', 'Species', '83984', (108, 112))	('Bcl-2', 'molecular_function', 'GO:0015283', ('22', '27'))	('increase', 'PosReg', (89, 97))
40897	22253748	The expression of p53, Bcl-xL, XIAP, Mcl-1, Bim and ARC were not significantly altered by enzastaurin in either wild type or mutant cell lines (Figure S2).	('p53', 'Gene', (18, 21))	('Mcl-1', 'Gene', (37, 42))	('Bcl-xL', 'Gene', '598', (23, 29))	('ARC', 'Gene', (52, 55))	('p53', 'Gene', '7157', (18, 21))	('mutant', 'Var', (125, 131))	('Bcl-xL', 'Gene', (23, 29))	('XIAP', 'Gene', (31, 35))	('XIAP', 'Gene', '331', (31, 35))	('Mcl-1', 'Gene', '4170', (37, 42))	('enzastaurin', 'Chemical', 'MESH:C504878', (90, 101))	('Bim', 'Gene', (44, 47))
40899	22253748	Erk1/2 activation has been reported to be induced by mutant GNAQ and has been found in UM independent of GNAQ, BRAF and RAS mutational status.	('GNAQ', 'Gene', (60, 64))	('GNAQ', 'Gene', (105, 109))	('UM', 'Phenotype', 'HP:0007716', (87, 89))	('Erk1/2', 'Gene', (0, 6))	('GNAQ', 'Gene', '2776', (60, 64))	('mutant', 'Var', (53, 59))	('activation', 'PosReg', (7, 17))	('GNAQ', 'Gene', '2776', (105, 109))	('BRAF', 'Gene', '673', (111, 115))	('BRAF', 'Gene', (111, 115))	('Erk1', 'molecular_function', 'GO:0004707', ('0', '4'))
40901	22253748	Interestingly, Erk1/2 phosphorylation was significantly suppressed in all three GNAQ mutant cell lines by enzastaurin but only in one GNAQ wild type cell line (Mel285) (Figure 6).	('GNAQ', 'Gene', (134, 138))	('suppressed', 'NegReg', (56, 66))	('GNAQ', 'Gene', '2776', (80, 84))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('enzastaurin', 'Chemical', 'MESH:C504878', (106, 117))	('Erk1', 'molecular_function', 'GO:0004707', ('15', '19'))	('mutant', 'Var', (85, 91))	('Erk1/2', 'Protein', (15, 21))	('phosphorylation', 'MPA', (22, 37))	('GNAQ', 'Gene', (80, 84))	('GNAQ', 'Gene', '2776', (134, 138))
40903	22253748	Total Akt and Erk1/2 levels were not significantly affected by enzastaurin in the wild type as well as the mutant cell lines.	('mutant', 'Var', (107, 113))	('Akt', 'Gene', '207', (6, 9))	('Erk1', 'molecular_function', 'GO:0004707', ('14', '18'))	('Erk1/2 levels', 'MPA', (14, 27))	('Akt', 'Gene', (6, 9))	('enzastaurin', 'Chemical', 'MESH:C504878', (63, 74))
40904	22253748	These findings suggest that enzastaurin may exert its antiproliferative action on GNAQ mutant cells in part through targeting the MAPK pathway.	('enzastaurin', 'Chemical', 'MESH:C504878', (28, 39))	('GNAQ', 'Gene', (82, 86))	('MAPK', 'molecular_function', 'GO:0004707', ('130', '134'))	('antiproliferative action', 'MPA', (54, 78))	('mutant', 'Var', (87, 93))	('MAPK pathway', 'Pathway', (130, 142))	('GNAQ', 'Gene', '2776', (82, 86))
40905	22253748	Enzastaurin inhibited GSK3beta phosphorylation and induced beta-catenin expression in both wild type and mutant cell lines (Figure S3), consistent with its known mechanism of activity.	('inhibited', 'NegReg', (12, 21))	('beta-catenin', 'Gene', '1499', (59, 71))	('induced', 'PosReg', (51, 58))	('GSK', 'molecular_function', 'GO:0050321', ('22', '25'))	('Enzastaurin', 'Chemical', 'MESH:C504878', (0, 11))	('expression', 'MPA', (72, 82))	('GSK3beta', 'Gene', (22, 30))	('GSK3beta', 'Gene', '2932', (22, 30))	('mutant', 'Var', (105, 111))	('beta-catenin', 'Gene', (59, 71))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))
40907	22253748	As expected, U0126 inhibited Erk1/2 phosphorylation, but had little effect on total Erk1/2 (Figure 7A).	('Erk1', 'molecular_function', 'GO:0004707', ('29', '33'))	('phosphorylation', 'biological_process', 'GO:0016310', ('36', '51'))	('inhibited', 'NegReg', (19, 28))	('U0126', 'Var', (13, 18))	('Erk1', 'molecular_function', 'GO:0004707', ('84', '88'))	('Erk1/2', 'Protein', (29, 35))	('phosphorylation', 'MPA', (36, 51))	('U0126', 'Chemical', 'MESH:C113580', (13, 18))
40908	22253748	U0126 reduced both basal and enzastaurin-induced expression of survivin in C918 and Ocm1 cells (Figure 7A).	('Ocm1', 'Species', '83984', (84, 88))	('survivin', 'Protein', (63, 71))	('reduced', 'NegReg', (6, 13))	('enzastaurin', 'Chemical', 'MESH:C504878', (29, 40))	('U0126', 'Var', (0, 5))	('expression', 'MPA', (49, 59))	('C918', 'CellLine', 'CVCL:8471', (75, 79))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))
40909	22253748	U0126 reduced basal expression of Bcl-2 in Ocm1 cells and enzastaurin-induced expression of Bcl-2 in C918 and Ocm1 cells.	('Ocm1', 'Species', '83984', (43, 47))	('enzastaurin', 'Chemical', 'MESH:C504878', (58, 69))	('expression', 'MPA', (78, 88))	('reduced', 'NegReg', (6, 13))	('C918', 'CellLine', 'CVCL:8471', (101, 105))	('U0126', 'Var', (0, 5))	('Bcl-2', 'molecular_function', 'GO:0015283', ('92', '97'))	('basal expression', 'MPA', (14, 30))	('Bcl-2', 'Gene', (92, 97))	('Bcl-2', 'Gene', '596', (92, 97))	('Ocm1', 'Species', '83984', (110, 114))	('Bcl-2', 'molecular_function', 'GO:0015283', ('34', '39'))	('Bcl-2', 'Gene', (34, 39))	('Bcl-2', 'Gene', '596', (34, 39))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))
40910	22253748	Furthermore, U0126 increased p27Kip1 expression in Ocm1 and C918 cells which was further augmented in the presence of enzastaurin in Ocm1 cells but not in C918 cells (Figure 7A).	('C918', 'CellLine', 'CVCL:8471', (155, 159))	('p27Kip1', 'Gene', (29, 36))	('Ocm1', 'Species', '83984', (133, 137))	('enzastaurin', 'Chemical', 'MESH:C504878', (118, 129))	('C918', 'CellLine', 'CVCL:8471', (60, 64))	('Ocm1', 'Species', '83984', (51, 55))	('increased', 'PosReg', (19, 28))	('U0126', 'Var', (13, 18))	('increased p27Kip1 expression', 'Phenotype', 'HP:0003240', (19, 47))	('p27Kip1', 'Gene', '1027', (29, 36))	('U0126', 'Chemical', 'MESH:C113580', (13, 18))	('expression', 'MPA', (37, 47))	('augmented', 'PosReg', (89, 98))
40911	22253748	The expression of cyclin D1 was repressed in Ocm1 cells treated with U0126 alone or in combination with enzastaurin (Figure 7A).	('cyclin D1', 'Gene', (18, 27))	('U0126', 'Chemical', 'MESH:C113580', (69, 74))	('Ocm1', 'Species', '83984', (45, 49))	('U0126', 'Var', (69, 74))	('cyclin', 'molecular_function', 'GO:0016538', ('18', '24'))	('cyclin D1', 'Gene', '595', (18, 27))	('enzastaurin', 'Chemical', 'MESH:C504878', (104, 115))
40912	22253748	Interestingly, U0126 increased the antiproliferative effects of enzastaurin on C918 cells, resulting in an IC50 comparable to that found in cells harboring GNAQ mutations (Figure 7B).	('GNAQ', 'Gene', (156, 160))	('C918', 'CellLine', 'CVCL:8471', (79, 83))	('increased', 'PosReg', (21, 30))	('U0126', 'Var', (15, 20))	('IC50', 'MPA', (107, 111))	('enzastaurin', 'Chemical', 'MESH:C504878', (64, 75))	('antiproliferative effects', 'MPA', (35, 60))	('U0126', 'Chemical', 'MESH:C113580', (15, 20))	('GNAQ', 'Gene', '2776', (156, 160))
40913	22253748	U0126 also enhanced the antiproliferation effects of enzastaurin on Ocm1 cells at lower concentrations (1-4 microM versus 6-10 microM) (Figure 7B).	('Ocm1', 'Species', '83984', (68, 72))	('antiproliferation effects', 'CPA', (24, 49))	('enzastaurin', 'Chemical', 'MESH:C504878', (53, 64))	('U0126', 'Var', (0, 5))	('enhanced', 'PosReg', (11, 19))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))
40915	22253748	As UM cells harboring GNAQ mutations concerned, only Mel202 cells showed increased sensitivity to enzastaurin in the presence of U0126 (Figure 7B).	('mutations', 'Var', (27, 36))	('increased', 'PosReg', (73, 82))	('GNAQ', 'Gene', (22, 26))	('enzastaurin', 'Chemical', 'MESH:C504878', (98, 109))	('U0126', 'Chemical', 'MESH:C113580', (129, 134))	('GNAQ', 'Gene', '2776', (22, 26))	('sensitivity to enzastaurin', 'MPA', (83, 109))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
40916	22253748	U0126 and AZD6244 alone showed varying inhibitory effects on proliferation of GNAQ wild type and mutant UM cell lines, with AZD6244 having greater inhibitory effects (Figure S5).	('AZD6244', 'Chemical', 'MESH:C517975', (124, 131))	('AZD6244', 'Chemical', 'MESH:C517975', (10, 17))	('GNAQ', 'Gene', (78, 82))	('UM', 'Phenotype', 'HP:0007716', (104, 106))	('mutant', 'Var', (97, 103))	('GNAQ', 'Gene', '2776', (78, 82))	('proliferation', 'CPA', (61, 74))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))	('inhibitory', 'NegReg', (39, 49))	('AZD6244', 'Var', (124, 131))
40926	22253748	While enzastaurin did not significantly alter PKCbetaII expression in C918 and Ocm1 cells, it did decrease PKCbetaII expression in Omm1.3, Mel202, and 92.1 cells harboring GNAQ mutations.	('PKCbeta', 'Gene', '5579', (107, 114))	('PKCbeta', 'Gene', (46, 53))	('C918', 'CellLine', 'CVCL:8471', (70, 74))	('decrease', 'NegReg', (98, 106))	('PKCbeta', 'Gene', '5579', (46, 53))	('expression', 'MPA', (117, 127))	('GNAQ', 'Gene', '2776', (172, 176))	('mutations', 'Var', (177, 186))	('Ocm1', 'Species', '83984', (79, 83))	('GNAQ', 'Gene', (172, 176))	('PKCbeta', 'Gene', (107, 114))	('enzastaurin', 'Chemical', 'MESH:C504878', (6, 17))
40929	22253748	As enzastaurin inhibited the expression and/or phosphorylation of PKCbeta, PKCepsilon, and PKCtheta in UM cells harboring GNAQ mutations, we investigated the functional importance of these PKC isoforms by shRNA-mediated downregulation.	('PKC', 'Gene', (189, 192))	('PKC', 'Gene', '112476', (66, 69))	('PKC', 'Gene', (91, 94))	('PKC', 'Gene', (75, 78))	('PKCepsilon', 'Gene', '5581', (75, 85))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('75', '85'))	('PKC', 'Gene', (66, 69))	('investigated', 'Reg', (141, 153))	('PKCbeta', 'Gene', '5579', (66, 73))	('downregulation', 'NegReg', (220, 234))	('mutations', 'Var', (127, 136))	('GNAQ', 'Gene', '2776', (122, 126))	('UM', 'Phenotype', 'HP:0007716', (103, 105))	('PKCbeta', 'molecular_function', 'GO:0004697', ('66', '73'))	('PKC', 'molecular_function', 'GO:0004697', ('189', '192'))	('phosphorylation', 'MPA', (47, 62))	('GNAQ', 'Gene', (122, 126))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('PKCbeta', 'Gene', (66, 73))	('PKCepsilon', 'Gene', (75, 85))	('expression', 'MPA', (29, 39))	('inhibited', 'NegReg', (15, 24))	('PKC', 'Gene', '112476', (189, 192))	('PKC', 'Gene', '112476', (75, 78))	('enzastaurin', 'Chemical', 'MESH:C504878', (3, 14))	('PKC', 'Gene', '112476', (91, 94))
40930	22253748	Infection of C918 and Mel202 cells with lentivirus expressing shRNA of PKCbeta, PKCepsilon or PKCtheta reduced the protein levels of corresponding isoforms in these cells (Figure 8C).	('PKCbeta, PKCepsilon or PKCtheta', 'Disease', 'None', (71, 102))	('PKCbeta', 'molecular_function', 'GO:0004697', ('71', '78'))	('reduced', 'NegReg', (103, 110))	('protein levels of corresponding isoforms', 'MPA', (115, 155))	('shRNA', 'Var', (62, 67))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('80', '90'))	('C918', 'CellLine', 'CVCL:8471', (13, 17))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))
40936	22253748	A reduction in viability was also seen in C918 cells expressing shRNA of PKCbeta, PKCepsilon or PKCtheta and in Mel285 cells expressing PKCbeta or PKCtheta, but to less extent compared to GNAQ mutated cells.	('PKC', 'Gene', '112476', (147, 150))	('GNAQ', 'Gene', (188, 192))	('PKCbeta, PKCepsilon or PKCtheta', 'Disease', 'None', (73, 104))	('PKC', 'Gene', '112476', (82, 85))	('PKC', 'Gene', (147, 150))	('PKCbeta', 'molecular_function', 'GO:0004697', ('73', '80'))	('PKC', 'Gene', '112476', (96, 99))	('PKC', 'Gene', '112476', (73, 76))	('PKCbeta', 'molecular_function', 'GO:0004697', ('136', '143'))	('PKC', 'Gene', (82, 85))	('PKC', 'Gene', '112476', (136, 139))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('82', '92'))	('viability', 'MPA', (15, 24))	('PKC', 'Gene', (96, 99))	('PKC', 'Gene', (73, 76))	('PKCbeta', 'Gene', '5579', (136, 143))	('reduction', 'NegReg', (2, 11))	('C918', 'CellLine', 'CVCL:8471', (42, 46))	('PKC', 'Gene', (136, 139))	('PKCbeta', 'Gene', '5579', (73, 80))	('PKCbeta', 'Gene', (136, 143))	('PKCbeta', 'Gene', (73, 80))	('GNAQ', 'Gene', '2776', (188, 192))	('shRNA', 'Var', (64, 69))
40938	22253748	These findings suggest that PKCtheta PKCbeta, and PKCepsilon may functionally be more important for UM cells harboring mutated than those with wild type GNAQ.	('PKCbeta', 'molecular_function', 'GO:0004697', ('37', '44'))	('UM', 'Phenotype', 'HP:0007716', (100, 102))	('GNAQ', 'Gene', '2776', (153, 157))	('PKCtheta PKCbeta', 'Disease', 'None', (28, 44))	('PKCtheta PKCbeta', 'Disease', (28, 44))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('50', '60'))	('PKCepsilon', 'Gene', '5581', (50, 60))	('mutated', 'Var', (119, 126))	('PKCepsilon', 'Gene', (50, 60))	('GNAQ', 'Gene', (153, 157))
40941	22253748	GNAQ mutations at codon 209 have been recently found in nearly 50% of UM patients.	('GNAQ', 'Gene', '2776', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('mutations', 'Var', (5, 14))	('found', 'Reg', (47, 52))	('GNAQ', 'Gene', (0, 4))	('patients', 'Species', '9606', (73, 81))
40942	22253748	In the present study, we demonstrate for the first time that UM cell lines harboring GNAQ mutations are more sensitive to the antiproliferative effects of the PKC inhibitor enzastaurin than those possessing wild type GNAQ.	('mutations', 'Var', (90, 99))	('GNAQ', 'Gene', '2776', (217, 221))	('PKC', 'Gene', (159, 162))	('enzastaurin', 'Chemical', 'MESH:C504878', (173, 184))	('PKC', 'Gene', '112476', (159, 162))	('GNAQ', 'Gene', (85, 89))	('antiproliferative effects of the', 'MPA', (126, 158))	('GNAQ', 'Gene', (217, 221))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('sensitive to', 'MPA', (109, 121))	('PKC', 'molecular_function', 'GO:0004697', ('159', '162'))	('GNAQ', 'Gene', '2776', (85, 89))
40943	22253748	Enzastaurin inhibits proliferation of mutant UM cells through induction of G1 cell cycle arrest and apoptosis.	('mutant', 'Var', (38, 44))	('arrest', 'Disease', (89, 95))	('proliferation', 'CPA', (21, 34))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('Enzastaurin', 'Chemical', 'MESH:C504878', (0, 11))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (78, 95))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('78', '95'))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('inhibits', 'NegReg', (12, 20))	('arrest', 'Disease', 'MESH:D006323', (89, 95))	('apoptosis', 'CPA', (100, 109))	('UM', 'Phenotype', 'HP:0007716', (45, 47))
40944	22253748	We have further characterized signaling and molecular mechanisms underlying differential responses of GNAQ wild type and mutant cells to enzastaurin.	('mutant', 'Var', (121, 127))	('GNAQ', 'Gene', (102, 106))	('signaling', 'biological_process', 'GO:0023052', ('30', '39'))	('enzastaurin', 'Chemical', 'MESH:C504878', (137, 148))	('GNAQ', 'Gene', '2776', (102, 106))
40947	22253748	GNAQ mutations have been reported to be oncogenic through activating the Erk1/2 pathway in UM cells.	('GNAQ', 'Gene', '2776', (0, 4))	('Erk1', 'molecular_function', 'GO:0004707', ('73', '77'))	('activating', 'PosReg', (58, 68))	('Erk1/2 pathway', 'Pathway', (73, 87))	('mutations', 'Var', (5, 14))	('UM', 'Phenotype', 'HP:0007716', (91, 93))	('GNAQ', 'Gene', (0, 4))
40948	22253748	In the current study, we show that enzastaurin reduced Erk1/2 phosphrylation in all three GNAQ mutant UM cell lines and in one wild type cell line (Mel285).	('Erk1', 'molecular_function', 'GO:0004707', ('55', '59'))	('GNAQ', 'Gene', '2776', (90, 94))	('phosphrylation', 'MPA', (62, 76))	('Erk1/2', 'Protein', (55, 61))	('UM', 'Phenotype', 'HP:0007716', (102, 104))	('mutant', 'Var', (95, 101))	('GNAQ', 'Gene', (90, 94))	('reduced', 'NegReg', (47, 54))	('enzastaurin', 'Chemical', 'MESH:C504878', (35, 46))
40953	22253748	In agreement with sensitivity to enzastaurin, inhibition of Erk1/2 phosphorylation was accompanied by increased p27Kip1 accumulation and decreased expression of cyclin D1, Bcl-2 and survivin in GNAQ mutant cells whereas only survivin was downregulated in Mel285 cells.	('Erk1', 'molecular_function', 'GO:0004707', ('60', '64'))	('p27Kip1', 'Gene', (112, 119))	('expression', 'MPA', (147, 157))	('cyclin D1', 'Gene', '595', (161, 170))	('p27Kip1', 'Gene', '1027', (112, 119))	('mutant', 'Var', (199, 205))	('survivin', 'Protein', (182, 190))	('increased', 'PosReg', (102, 111))	('Bcl-2', 'Gene', (172, 177))	('Bcl-2', 'molecular_function', 'GO:0015283', ('172', '177'))	('inhibition', 'NegReg', (46, 56))	('enzastaurin', 'Chemical', 'MESH:C504878', (33, 44))	('phosphorylation', 'biological_process', 'GO:0016310', ('67', '82'))	('GNAQ', 'Gene', '2776', (194, 198))	('Bcl-2', 'Gene', '596', (172, 177))	('GNAQ', 'Gene', (194, 198))	('accumulation', 'PosReg', (120, 132))	('cyclin', 'molecular_function', 'GO:0016538', ('161', '167'))	('phosphorylation', 'MPA', (67, 82))	('Erk1/2', 'Gene', (60, 66))	('increased p27Kip1 accumulation', 'Phenotype', 'HP:0003240', (102, 132))	('cyclin D1', 'Gene', (161, 170))	('decreased', 'NegReg', (137, 146))
40954	22253748	Furthermore, inhibition of Erk1/2 phosphorylation by MEK1/2 inhibitors increased sensitivity of GNAQ wild type cells to enzastaurin and was associated with similar alterations in the expression of p27Kip1, cyclin D1, Bcl-2 and/or survivin to GNAQ mutant cells treated with enzastaurin.	('MEK1/2', 'Gene', '5604;5605', (53, 59))	('alterations', 'Reg', (164, 175))	('MEK1/2', 'Gene', (53, 59))	('enzastaurin', 'Chemical', 'MESH:C504878', (273, 284))	('Bcl-2', 'molecular_function', 'GO:0015283', ('217', '222'))	('sensitivity', 'MPA', (81, 92))	('cyclin', 'molecular_function', 'GO:0016538', ('206', '212'))	('p27Kip1', 'Gene', (197, 204))	('expression', 'MPA', (183, 193))	('inhibition', 'NegReg', (13, 23))	('enzastaurin', 'Chemical', 'MESH:C504878', (120, 131))	('GNAQ', 'Gene', '2776', (242, 246))	('p27Kip1', 'Gene', '1027', (197, 204))	('Bcl-2', 'Gene', (217, 222))	('GNAQ', 'Gene', '2776', (96, 100))	('cyclin D1', 'Gene', (206, 215))	('GNAQ', 'Gene', (242, 246))	('Erk1/2', 'Protein', (27, 33))	('GNAQ', 'Gene', (96, 100))	('cyclin D1', 'Gene', '595', (206, 215))	('Bcl-2', 'Gene', '596', (217, 222))	('phosphorylation', 'MPA', (34, 49))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('MEK1', 'molecular_function', 'GO:0004708', ('53', '57'))	('inhibitors', 'Var', (60, 70))	('increased', 'PosReg', (71, 80))	('Erk1', 'molecular_function', 'GO:0004707', ('27', '31'))
40955	22253748	Our findings suggest that the suppression of Erk1/2 phosphorylation may be the major contributor to the increased sensitivity of GNAQ mutant UM cells to the antiproliferative action of enzastaurin through altering the expression of p27, ccyclin D1, Bcl-2 and survivn.	('sensitivity', 'MPA', (114, 125))	('enzastaurin', 'Chemical', 'MESH:C504878', (185, 196))	('Erk1/2', 'Protein', (45, 51))	('cyclin D1', 'Gene', (238, 247))	('Bcl-2', 'Gene', (249, 254))	('GNAQ', 'Gene', '2776', (129, 133))	('Bcl-2', 'molecular_function', 'GO:0015283', ('249', '254'))	('suppression', 'NegReg', (30, 41))	('mutant', 'Var', (134, 140))	('GNAQ', 'Gene', (129, 133))	('cyclin D1', 'Gene', '595', (238, 247))	('Erk1', 'molecular_function', 'GO:0004707', ('45', '49'))	('Bcl-2', 'Gene', '596', (249, 254))	('p27', 'Gene', '3429', (232, 235))	('phosphorylation', 'biological_process', 'GO:0016310', ('52', '67'))	('p27', 'Gene', (232, 235))	('UM', 'Phenotype', 'HP:0007716', (141, 143))	('altering', 'Reg', (205, 213))	('antiproliferative action', 'MPA', (157, 181))	('expression', 'MPA', (218, 228))	('phosphorylation', 'MPA', (52, 67))
40956	22253748	These observations further support the oncogenic role for GNAQ mutations via activation of MAPK.	('mutations', 'Var', (63, 72))	('MAPK', 'Gene', (91, 95))	('MAPK', 'molecular_function', 'GO:0004707', ('91', '95'))	('GNAQ', 'Gene', '2776', (58, 62))	('activation', 'PosReg', (77, 87))	('GNAQ', 'Gene', (58, 62))
40961	22253748	Nonetheless, some PKC isoforms were downregulated by enzastaurin in UM cell carrying GNAQ mutations.	('mutations', 'Var', (90, 99))	('enzastaurin', 'Chemical', 'MESH:C504878', (53, 64))	('PKC', 'Gene', (18, 21))	('PKC', 'Gene', '112476', (18, 21))	('PKC', 'molecular_function', 'GO:0004697', ('18', '21'))	('GNAQ', 'Gene', (85, 89))	('UM', 'Phenotype', 'HP:0007716', (68, 70))	('GNAQ', 'Gene', '2776', (85, 89))	('downregulated', 'NegReg', (36, 49))
40962	22253748	In particular, the expression and phosphorylation of PKCtheta, PKCepsilon, and PKCbeta were reduced by enzastaurin in GNAQ mutated cells.	('PKCbeta', 'Gene', (79, 86))	('PKC', 'Gene', (53, 56))	('GNAQ', 'Gene', '2776', (118, 122))	('GNAQ', 'Gene', (118, 122))	('expression', 'MPA', (19, 29))	('PKCepsilon', 'Gene', (63, 73))	('mutated', 'Var', (123, 130))	('enzastaurin', 'Chemical', 'MESH:C504878', (103, 114))	('PKC', 'Gene', '112476', (63, 66))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('63', '73'))	('PKC', 'Gene', '112476', (79, 82))	('PKCbeta', 'molecular_function', 'GO:0004697', ('79', '86'))	('PKC', 'Gene', (79, 82))	('phosphorylation', 'MPA', (34, 49))	('PKC', 'Gene', (63, 66))	('PKCepsilon', 'Gene', '5581', (63, 73))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('reduced', 'NegReg', (92, 99))	('PKCbeta', 'Gene', '5579', (79, 86))	('PKC', 'Gene', '112476', (53, 56))
40963	22253748	Our functional studies revealed that these PKC isoforms are indeed more critical for growth of UM cells harboring GNAQ mutations than those with wild type GNAQ.	('GNAQ', 'Gene', '2776', (155, 159))	('PKC', 'molecular_function', 'GO:0004697', ('43', '46'))	('GNAQ', 'Gene', '2776', (114, 118))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('PKC', 'Gene', (43, 46))	('PKC', 'Gene', '112476', (43, 46))	('mutations', 'Var', (119, 128))	('GNAQ', 'Gene', (155, 159))	('GNAQ', 'Gene', (114, 118))
40964	22253748	Together, our findings suggest that enzastaurin may exert increased antiproliferative action through inhibiting these PKC isoforms in GNAQ mutated UM cells.	('increased', 'PosReg', (58, 67))	('GNAQ', 'Gene', (134, 138))	('enzastaurin', 'Chemical', 'MESH:C504878', (36, 47))	('mutated', 'Var', (139, 146))	('PKC', 'Gene', (118, 121))	('PKC', 'Gene', '112476', (118, 121))	('GNAQ', 'Gene', '2776', (134, 138))	('PKC', 'molecular_function', 'GO:0004697', ('118', '121'))	('antiproliferative action', 'MPA', (68, 92))	('UM', 'Phenotype', 'HP:0007716', (147, 149))	('inhibiting', 'NegReg', (101, 111))
40966	22253748	In addition, the inhibition of PKCbetaII by enzastaurin or small interfering RNA decreased Erk1/2 phosphorylation in metastatic hepatocellular carcinoma cells.	('decreased', 'NegReg', (81, 90))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (128, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('phosphorylation', 'MPA', (98, 113))	('phosphorylation', 'biological_process', 'GO:0016310', ('98', '113'))	('hepatocellular carcinoma', 'Disease', (128, 152))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (128, 152))	('PKCbeta', 'Gene', '5579', (31, 38))	('small interfering', 'Var', (59, 76))	('Erk1/2', 'Enzyme', (91, 97))	('enzastaurin', 'Chemical', 'MESH:C504878', (44, 55))	('RNA', 'cellular_component', 'GO:0005562', ('77', '80'))	('PKCbeta', 'Gene', (31, 38))	('Erk1', 'molecular_function', 'GO:0004707', ('91', '95'))	('inhibition', 'NegReg', (17, 27))
40969	22253748	Complicating this interpretation, Ocm1 cells have been shown to carry the common V600E BRAF mutation that constitutively activates the MAPK pathway.	('activates', 'PosReg', (121, 130))	('MAPK', 'molecular_function', 'GO:0004707', ('135', '139'))	('MAPK pathway', 'Pathway', (135, 147))	('V600E', 'Mutation', 'rs113488022', (81, 86))	('Ocm1', 'Species', '83984', (34, 38))	('V600E', 'Var', (81, 86))	('BRAF', 'Gene', (87, 91))	('BRAF', 'Gene', '673', (87, 91))
40972	22253748	In the present study, we demonstrate that enzastaurin-induced antiproliferation of UM cells carrying GNAQ mutations is associated with G1 arrest.	('enzastaurin', 'Chemical', 'MESH:C504878', (42, 53))	('arrest', 'Disease', 'MESH:D006323', (138, 144))	('UM', 'Phenotype', 'HP:0007716', (83, 85))	('GNAQ', 'Gene', '2776', (101, 105))	('arrest', 'Disease', (138, 144))	('mutations', 'Var', (106, 115))	('GNAQ', 'Gene', (101, 105))	('antiproliferation', 'CPA', (62, 79))
40976	22253748	This recapitulates the Erk1/2 inhibition-induced G1 arrest by MEK inhibition that is characterized by decreased expression of cyclin D1 and accumulation of p27Kip1 .	('p27Kip1', 'Gene', (156, 163))	('MEK', 'Gene', (62, 65))	('accumulation', 'PosReg', (140, 152))	('cyclin', 'molecular_function', 'GO:0016538', ('126', '132'))	('arrest', 'Disease', (52, 58))	('inhibition', 'Var', (66, 76))	('p27Kip1', 'Gene', '1027', (156, 163))	('cyclin D1', 'Gene', '595', (126, 135))	('Erk1', 'molecular_function', 'GO:0004707', ('23', '27'))	('cyclin D1', 'Gene', (126, 135))	('arrest', 'Disease', 'MESH:D006323', (52, 58))	('decreased', 'NegReg', (102, 111))	('expression', 'MPA', (112, 122))
40984	22253748	It is intriguing that one of the GNAQ wild type UM cell lines was found to harbor a BRAF mutation and the implication of this biology to a PKC inhibitor such as enzastaurin remains to be investigated.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('GNAQ', 'Gene', (33, 37))	('BRAF', 'Gene', '673', (84, 88))	('mutation', 'Var', (89, 97))	('BRAF', 'Gene', (84, 88))	('PKC', 'molecular_function', 'GO:0004697', ('139', '142'))	('GNAQ', 'Gene', '2776', (33, 37))	('PKC', 'Gene', (139, 142))	('PKC', 'Gene', '112476', (139, 142))	('enzastaurin', 'Chemical', 'MESH:C504878', (161, 172))
40985	22253748	We have also demonstrated that enzastaurin induces apoptosis in UM cells carrying GNAQ mutation.	('GNAQ', 'Gene', (82, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('UM', 'Phenotype', 'HP:0007716', (64, 66))	('apoptosis', 'CPA', (51, 60))	('mutation', 'Var', (87, 95))	('GNAQ', 'Gene', '2776', (82, 86))	('enzastaurin', 'Chemical', 'MESH:C504878', (31, 42))
40988	22253748	As the Akt pathway was minimally affected by enzastaurin, the downregulation of Bcl-2 and survivin by enzastaurin may be the result of decreased activation of the MAPK pathway in cells carrying GNAQ mutations.	('activation', 'PosReg', (145, 155))	('mutations', 'Var', (199, 208))	('MAPK pathway', 'Pathway', (163, 175))	('GNAQ', 'Gene', (194, 198))	('Bcl-2', 'molecular_function', 'GO:0015283', ('80', '85'))	('enzastaurin', 'Var', (102, 113))	('survivin', 'Protein', (90, 98))	('Bcl-2', 'Gene', (80, 85))	('Bcl-2', 'Gene', '596', (80, 85))	('Akt', 'Gene', '207', (7, 10))	('downregulation', 'NegReg', (62, 76))	('MAPK', 'molecular_function', 'GO:0004707', ('163', '167'))	('decreased', 'NegReg', (135, 144))	('GNAQ', 'Gene', '2776', (194, 198))	('Akt', 'Gene', (7, 10))	('enzastaurin', 'Chemical', 'MESH:C504878', (102, 113))	('enzastaurin', 'Chemical', 'MESH:C504878', (45, 56))
40989	22253748	This is supported by our findings that MEK inhibition also downregulated the expression of Bcl-2 and/or survivin in the wild type cells.	('expression', 'MPA', (77, 87))	('inhibition', 'Var', (43, 53))	('survivin', 'Protein', (104, 112))	('downregulated', 'NegReg', (59, 72))	('Bcl-2', 'Gene', '596', (91, 96))	('Bcl-2', 'molecular_function', 'GO:0015283', ('91', '96'))	('MEK', 'Protein', (39, 42))	('Bcl-2', 'Gene', (91, 96))
40993	22253748	In summary, compared with UM cells with wild type GNAQ, the PKC inhibitor enzastaurin at low micromolar concentrations exerts significant antiproliferative effect on UM cells carrying GNAQ mutations through targeting PKC/MAPK pathways with induction of G1 arrest and apoptosis.	('arrest', 'Disease', 'MESH:D006323', (256, 262))	('enzastaurin', 'Chemical', 'MESH:C504878', (74, 85))	('PKC', 'Gene', (60, 63))	('PKC', 'Gene', '112476', (217, 220))	('GNAQ', 'Gene', '2776', (50, 54))	('UM', 'Phenotype', 'HP:0007716', (26, 28))	('mutations', 'Var', (189, 198))	('GNAQ', 'Gene', (50, 54))	('antiproliferative effect', 'CPA', (138, 162))	('PKC', 'Gene', (217, 220))	('GNAQ', 'Gene', '2776', (184, 188))	('arrest', 'Disease', (256, 262))	('targeting', 'Reg', (207, 216))	('GNAQ', 'Gene', (184, 188))	('PKC', 'molecular_function', 'GO:0004697', ('60', '63'))	('MAPK', 'molecular_function', 'GO:0004707', ('221', '225'))	('UM', 'Phenotype', 'HP:0007716', (166, 168))	('apoptosis', 'biological_process', 'GO:0097194', ('267', '276'))	('apoptosis', 'biological_process', 'GO:0006915', ('267', '276'))	('PKC', 'molecular_function', 'GO:0004697', ('217', '220'))	('PKC', 'Gene', '112476', (60, 63))
40997	22253748	It has been reported by Folberg and colleagues in studies authenticating cell lines that Ocm1 and Mum2C are from the same patient, and that M619, C918, and Mum2B are from the same patient.	('C918', 'CellLine', 'CVCL:8471', (146, 150))	('patient', 'Species', '9606', (122, 129))	('C918', 'Var', (146, 150))	('Ocm1', 'Species', '83984', (89, 93))	('M619', 'Var', (140, 144))	('patient', 'Species', '9606', (180, 187))
41000	22253748	Cells were then treated with enzastaurin (provided by Eli Lily and Company, Indianapolis, Indiana), MEK1/2 inhibitor U0126 (Cell Signaling Technology, Danvers, MA) or AZD6244 (Selleck Chemicals, Houston, TX) for three days.	('Signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('MEK1/2', 'Gene', '5604;5605', (100, 106))	('MEK1', 'molecular_function', 'GO:0004708', ('100', '104'))	('U0126', 'Chemical', 'MESH:C113580', (117, 122))	('MEK1/2', 'Gene', (100, 106))	('enzastaurin', 'Chemical', 'MESH:C504878', (29, 40))	('AZD6244', 'Var', (167, 174))	('U0126', 'Var', (117, 122))	('AZD6244', 'Chemical', 'MESH:C517975', (167, 174))
41001	22253748	For signaling pathway experiments, cells were treated with enzastaurin in the presence of U0126 (10 microM) or AZD6244 (2 microM).	('AZD6244', 'Var', (111, 118))	('signaling pathway', 'biological_process', 'GO:0007165', ('4', '21'))	('U0126', 'Chemical', 'MESH:C113580', (90, 95))	('AZD6244', 'Chemical', 'MESH:C517975', (111, 118))	('enzastaurin', 'Chemical', 'MESH:C504878', (59, 70))	('U0126', 'Var', (90, 95))
41027	29242243	This tropism is mediated through heparan sulfate modifications on cancer cells that mimic the modifications normally found on basement membrane proteoglycans but not the apical surfaces of intact tissues.	('heparan sulfate', 'Chemical', 'MESH:D006497', (33, 48))	('tropism', 'biological_process', 'GO:0009606', ('5', '12'))	('modifications', 'Var', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mediated through', 'Reg', (16, 32))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('heparan sulfate', 'Protein', (33, 48))	('cancer', 'Disease', (66, 72))	('basement membrane', 'cellular_component', 'GO:0005604', ('126', '143'))
41035	29242243	IR700 has been described to induce potent necrosis-mediated cell killing when delivered to a cancer cell membrane via conjugation to an antibody and has several advantages over traditional cytotoxic agents used for targeted cancer therapy.	('necrosis', 'Disease', (42, 50))	('cell membrane', 'cellular_component', 'GO:0005886', ('100', '113'))	('necrosis', 'biological_process', 'GO:0008220', ('42', '50'))	('antibody', 'cellular_component', 'GO:0019815', ('136', '144'))	('cancer', 'Disease', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('necrosis', 'biological_process', 'GO:0070265', ('42', '50'))	('necrosis', 'biological_process', 'GO:0019835', ('42', '50'))	('necrosis', 'biological_process', 'GO:0001906', ('42', '50'))	('cell killing', 'biological_process', 'GO:0001906', ('60', '72'))	('antibody', 'cellular_component', 'GO:0019814', ('136', '144'))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('antibody', 'molecular_function', 'GO:0003823', ('136', '144'))	('cancer', 'Disease', (93, 99))	('antibody', 'cellular_component', 'GO:0042571', ('136', '144'))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('necrosis', 'biological_process', 'GO:0008219', ('42', '50'))	('necrosis', 'Disease', 'MESH:D009336', (42, 50))	('IR700', 'Var', (0, 5))	('conjugation', 'biological_process', 'GO:0000746', ('118', '129'))	('IR700', 'Chemical', '-', (0, 5))
41036	29242243	First, IR700 is cytotoxic only during its activation by light, providing an additional level of specificity in addition to the targeting properties of an antibody or VLP.	('antibody', 'cellular_component', 'GO:0019815', ('154', '162'))	('VLP', 'cellular_component', 'GO:0000943', ('166', '169'))	('VLP', 'Gene', '391104', (166, 169))	('antibody', 'cellular_component', 'GO:0019814', ('154', '162'))	('VLP', 'Gene', (166, 169))	('antibody', 'molecular_function', 'GO:0003823', ('154', '162'))	('IR700', 'Var', (7, 12))	('antibody', 'cellular_component', 'GO:0042571', ('154', '162'))	('IR700', 'Chemical', '-', (7, 12))
41039	29242243	Although not yet fully understood, IR700-mediated cell killing is likely attributed to both local generation of reactive oxygen species and localized heating of cell-associated water, resulting in disruption and permeabilization of the cellular membrane.	('IR700-mediated', 'Var', (35, 49))	('IR700', 'Chemical', '-', (35, 40))	('water', 'Chemical', 'MESH:D014867', (177, 182))	('permeabilization', 'MPA', (212, 228))	('cell-associated', 'cellular_component', 'GO:0009986', ('161', '176'))	('cell killing', 'biological_process', 'GO:0001906', ('50', '62'))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (112, 135))	('disruption', 'MPA', (197, 207))	('cell killing', 'CPA', (50, 62))	('cellular membrane', 'cellular_component', 'GO:0005886', ('236', '253'))
41054	29242243	A mutant version of the HPV16L1 gene and the prototype HPV16 L2 gene were used to produce L1/L2 VLPs mammalian HEK293 cells as described previously.	('VLP', 'Gene', (96, 99))	('VLP', 'Gene', '391104', (96, 99))	('mammalian', 'Species', '9606', (101, 110))	('HPV16L1', 'Gene', (24, 31))	('HEK293', 'CellLine', 'CVCL:0045', (111, 117))	('mutant', 'Var', (2, 8))	('HPV16', 'Species', '333760', (24, 29))	('HPV16', 'Species', '333760', (55, 60))
41073	29242243	When tumors reached a size of 40 to 80 mm3, they were randomized into treatment groups: vehicle (PBS), 100 mug AU-011, or 200 mug AU-011.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('100 mug AU-011', 'Var', (103, 117))	('mug', 'molecular_function', 'GO:0043739', ('126', '129'))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('AU-011', 'Chemical', '-', (111, 117))	('mug', 'molecular_function', 'GO:0043739', ('107', '110'))	('200 mug AU-011', 'Var', (122, 136))	('PBS', 'Chemical', 'MESH:D007854', (97, 100))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('AU-011', 'Chemical', '-', (130, 136))
41083	29242243	Briefly, 1.5 x 106 92.1MEL human uveal melanoma cells, suspended in PBS, and in some cases PBS + 50% Matrigel (Corning), in a volume of 50 to 100 muL suspension was injected into the suprachoroidal space of one eye using a bent cannula.	('PBS +', 'Var', (91, 96))	('PBS', 'Chemical', 'MESH:D007854', (91, 94))	('uveal melanoma', 'Disease', 'MESH:C536494', (33, 47))	('PBS', 'Chemical', 'MESH:D007854', (68, 71))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('human', 'Species', '9606', (27, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('uveal melanoma', 'Disease', (33, 47))
41103	29242243	The membrane was then removed from the apparatus and imaged on an Odyssey CLx gel imager (LI-COR Biosciences) to detect the fluorescence of IR700, the conjugate in AU-011.	('AU-011', 'Chemical', '-', (164, 170))	('fluorescence', 'MPA', (124, 136))	('IR700', 'Var', (140, 145))	('IR700', 'Chemical', '-', (140, 145))	('membrane', 'cellular_component', 'GO:0016020', ('4', '12'))
41112	29242243	In addition, AU-011-mediated toxicity is directly proportional to light fluence, indicating that it may be plausible to use less AU-011 and more light should the experimental conditions require it (Supplementary Fig.	('toxicity', 'Disease', 'MESH:D064420', (29, 37))	('AU-011', 'Chemical', '-', (129, 135))	('AU-011', 'Chemical', '-', (13, 19))	('AU-011', 'Var', (129, 135))	('toxicity', 'Disease', (29, 37))
41132	29242243	Because AU-011 is fluorescent, a property imparted upon it by the IR700-conjugated molecule, we were able to directly image its presence in cancer tissue after a single intravitreal injection in the tumor-bearing rabbit eye.	('IR700', 'Chemical', '-', (66, 71))	('tumor', 'Disease', (199, 204))	('AU-011', 'Var', (8, 14))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('AU-011', 'Chemical', '-', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
41145	29242243	In this study, a total of 16 tumor-bearing rabbits were enrolled and randomized into four dose cohorts, specifically, 50 mug (n = 5), 20 mug (n = 4), 5 mug (n = 5), and vehicle control (n = 2).	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mug', 'molecular_function', 'GO:0043739', ('152', '155'))	('mug', 'molecular_function', 'GO:0043739', ('137', '140'))	('rabbits', 'Species', '9986', (43, 50))	('50 mug', 'Var', (118, 124))	('tumor', 'Disease', (29, 34))	('mug', 'molecular_function', 'GO:0043739', ('121', '124'))
41157	29242243	In the cohort receiving 5 mug of AU-011, there was evidence of necrosis following AU-011 and laser treatment, but to a lesser extent as illustrated in Fig.	('necrosis', 'biological_process', 'GO:0070265', ('63', '71'))	('necrosis', 'Disease', (63, 71))	('necrosis', 'biological_process', 'GO:0008219', ('63', '71'))	('necrosis', 'biological_process', 'GO:0019835', ('63', '71'))	('AU-011', 'Chemical', '-', (82, 88))	('necrosis', 'biological_process', 'GO:0008220', ('63', '71'))	('necrosis', 'Disease', 'MESH:D009336', (63, 71))	('AU-011', 'Var', (33, 39))	('necrosis', 'biological_process', 'GO:0001906', ('63', '71'))	('AU-011', 'Chemical', '-', (33, 39))	('AU-011', 'Var', (82, 88))	('mug', 'molecular_function', 'GO:0043739', ('26', '29'))
41173	29242243	The proposed use of AU-011 to treat uveal melanoma utilizing VLPs to deliver IR700 via intravitreal administration would require that AU-011 distributes throughout the ocular tumor tissue prior to activation with 690 nm light.	('ocular tumor', 'Disease', 'MESH:D005134', (168, 180))	('ocular tumor', 'Phenotype', 'HP:0100012', (168, 180))	('AU-011', 'Chemical', '-', (20, 26))	('AU-011', 'Chemical', '-', (134, 140))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('melanoma utilizing VLPs', 'Disease', 'MESH:D008545', (42, 65))	('uveal melanoma', 'Disease', 'MESH:C536494', (36, 50))	('uveal melanoma', 'Phenotype', 'HP:0007716', (36, 50))	('melanoma utilizing VLPs', 'Disease', (42, 65))	('IR700', 'Chemical', '-', (77, 82))	('uveal melanoma', 'Disease', (36, 50))	('AU-011', 'Var', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('ocular tumor', 'Disease', (168, 180))
41191	29242243	Ogawa and colleagues have reported that IR700-mediated killing has the potential to create antitumor immunogenicity, which we have similarly observed in immunocompetent mouse models (unpublished observations).	('create', 'PosReg', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('IR700-mediated killing', 'Var', (40, 62))	('mouse', 'Species', '10090', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('IR700', 'Chemical', '-', (40, 45))	('tumor', 'Disease', (95, 100))
41198	29242243	AU-011 binds to uveal melanoma cells through heparan sulfate modifications on the cancer cell surfaces and upon activation with 690 nm light elicits potent and selective anticancer activity in vitro.	('heparan sulfate', 'Protein', (45, 60))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('elicits', 'Reg', (141, 148))	('heparan sulfate', 'Chemical', 'MESH:D006497', (45, 60))	('AU-011', 'Chemical', '-', (0, 6))	('uveal melanoma', 'Disease', (16, 30))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', (82, 88))	('uveal melanoma', 'Disease', 'MESH:C536494', (16, 30))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('modifications', 'Var', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
41206	33572586	Results: High PARP-1 expression was associated with more frequent chromosome 3 loss, higher histopathological grade, bigger tumor size, and absence of intrascleral extension.	('loss', 'NegReg', (79, 83))	('chromosome', 'cellular_component', 'GO:0005694', ('66', '76'))	('chromosome 3', 'Protein', (66, 78))	('PARP-1', 'Gene', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('expression', 'MPA', (21, 31))	('High', 'Var', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
41207	33572586	Conclusions: The above findings indicate that high expression of PARP-1 can be considered as an unfavorable prognostic factor in uveal melanoma.	('PARP-1', 'Gene', (65, 71))	('high', 'Var', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('uveal melanoma', 'Disease', 'MESH:C536494', (129, 143))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('uveal melanoma', 'Disease', (129, 143))
41252	33572586	A similar association occurred in the case of total high expression of PARP-1 (IRS >= 4) (p = 0.089) (Figure 2C).	('IRS >= 4', 'Gene', (79, 87))	('high expression', 'Var', (52, 67))	('IRS >= 4', 'Gene', '8471', (79, 87))	('PARP-1', 'Gene', (71, 77))
41253	33572586	High percentage of positive cells, high reaction intensity, and total high expression significantly shortened disease-free survival time (DFS) (p = 0.012, p = 0.028, and p = 0.039, respectively) (Figure 3A-C).	('high reaction', 'Var', (35, 48))	('shortened', 'NegReg', (100, 109))	('disease-free survival time', 'CPA', (110, 136))	('high', 'Var', (70, 74))	('DFS', 'Chemical', '-', (138, 141))
41259	33572586	Moreover, loss of PARP-1 in mouse models may decrease tumor development.	('loss', 'Var', (10, 14))	('mouse', 'Species', '10090', (28, 33))	('PARP-1', 'Gene', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('men', 'Species', '9606', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('decrease', 'NegReg', (45, 53))	('tumor', 'Disease', (54, 59))
41260	33572586	Possibly PARP-1 inhibition can suppress damaged DNA repair and improve tumor killing.	('suppress', 'NegReg', (31, 39))	('PARP-1', 'Gene', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('damaged DNA repair', 'MPA', (40, 58))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('improve', 'PosReg', (63, 70))	('DNA repair', 'biological_process', 'GO:0006281', ('48', '58'))	('tumor', 'Disease', (71, 76))	('inhibition', 'Var', (16, 26))
41265	33572586	One study in gastric cancer patients showed that high PARP-1 expression was associated with poor prognosis, but only in patients with a more advanced disease stage.	('gastric cancer', 'Phenotype', 'HP:0012126', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('gastric cancer', 'Disease', (13, 27))	('advanced disease', 'Disease', (141, 157))	('PARP-1', 'Gene', (54, 60))	('high', 'Var', (49, 53))	('gastric cancer', 'Disease', 'MESH:D013274', (13, 27))	('patients', 'Species', '9606', (120, 128))	('patients', 'Species', '9606', (28, 36))	('expression', 'MPA', (61, 71))	('advanced disease', 'Disease', 'MESH:D020178', (141, 157))
41266	33572586	Patients with an advanced TNM stage (III-IV) and high PARP-1 expression had significantly reduced DFS and OS.	('reduced', 'NegReg', (90, 97))	('DFS', 'Chemical', '-', (98, 101))	('Patients', 'Species', '9606', (0, 8))	('PARP-1', 'Gene', (54, 60))	('high', 'Var', (49, 53))	('OS', 'Chemical', '-', (106, 108))	('expression', 'MPA', (61, 71))
41269	33572586	High PARP-1 expression was correlated with poor prognosis in lymph node negative early breast cancer.	('High', 'Var', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('PARP-1', 'Gene', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('expression', 'MPA', (12, 22))
41270	33572586	In addition, in more advanced stages of breast cancer, high PARP-1 expression helped in predicting survival: it correlated with shorter DFS and OS and increase risk of recurrence.	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('breast cancer', 'Disease', (40, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('DFS', 'MPA', (136, 139))	('shorter', 'NegReg', (128, 135))	('DFS', 'Chemical', '-', (136, 139))	('PARP-1', 'Gene', (60, 66))	('high', 'Var', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('increase', 'PosReg', (151, 159))	('OS', 'Chemical', '-', (144, 146))
41276	33572586	High PARP-1 expression alone and in combination with the expression of other DNA repair molecules (gammaH2AX, BRCA1, and BRCA2) is prognostic factor for shorter survival in soft tissue sarcoma patients.	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (173, 192))	('patients', 'Species', '9606', (193, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (185, 192))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('High', 'Var', (0, 4))	('BRCA2', 'Gene', (121, 126))	('BRCA2', 'Gene', '675', (121, 126))	('BRCA1', 'Gene', '672', (110, 115))	('shorter', 'NegReg', (153, 160))	('PARP-1', 'Gene', (5, 11))	('BRCA1', 'Gene', (110, 115))	('sarcoma', 'Disease', 'MESH:D012509', (185, 192))	('sarcoma', 'Disease', (185, 192))	('DNA repair', 'biological_process', 'GO:0006281', ('77', '87'))
41279	33572586	The demonstrated associations with recognized prognostic factors:loss of chromosome 3, tumor size, and histopathological grade:indicates that high PARP-1 expression can be considered an unfavorable prognostic factor in UM.	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('high', 'Var', (142, 146))	('UM', 'Phenotype', 'HP:0007716', (219, 221))	('PARP-1', 'Gene', (147, 153))	('expression', 'MPA', (154, 164))
41298	31479413	Among these, miR-155-5p, miR-9-5p, miR-142-5p, miR-19a-3p, miR-134-5p, and miR-301a-3p were upregulated, while miR-205-5p, miR-203a-3p, miR-27b-3p, miR-218-5p, and miR-23b-3p were downregulated.	('miR-134', 'Gene', (59, 66))	('miR-142', 'Gene', '406934', (35, 42))	('upregulated', 'PosReg', (92, 103))	('miR-205', 'Gene', (111, 118))	('miR-19a-3p', 'Var', (47, 57))	('miR-301a-3p', 'Var', (75, 86))	('miR-9-5p', 'Gene', (25, 33))	('miR-142', 'Gene', (35, 42))	('miR-155', 'Gene', (13, 20))	('miR-205', 'Gene', '406988', (111, 118))	('miR-9-5p', 'Gene', '407052', (25, 33))	('miR-203a', 'Chemical', '-', (123, 131))	('miR-134', 'Gene', '406924', (59, 66))	('miR-155', 'Gene', '406947', (13, 20))
41301	31479413	Among them, mir-9-5p, mir-203a-3p, mir-19a-3p, mir-27b-3p, and mir-218-5p showed altered expression in all three melanoma types vs. nevi.	('melanoma type', 'Disease', 'MESH:D008545', (113, 126))	('expression', 'MPA', (89, 99))	('mir-9-5p', 'Gene', (12, 20))	('nevi', 'Phenotype', 'HP:0003764', (132, 136))	('mir-203a-3p', 'Var', (22, 33))	('mir-19a-3p', 'Var', (35, 45))	('mir-27b-3p', 'Var', (47, 57))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('mir-218-5p', 'Var', (63, 73))	('melanoma type', 'Disease', (113, 126))	('altered', 'Reg', (81, 88))	('mir-9-5p', 'Gene', '407052', (12, 20))
41310	31479413	Numerous genomic studies showed different mutational patterns in melanoma, which was followed by the investigation of epigenetic factors involved in melanoma development.	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('mutational', 'Var', (42, 52))	('melanoma', 'Disease', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
41336	31479413	Among these miRNAs, only miR-155-5p, miR-142-5p, miR-205-5p, miR-23b-3p, miR-134-5p, and miR-301a-3p were previously studied in melanoma.	('miR-155', 'Gene', '406947', (25, 32))	('miR-134', 'Gene', '406924', (73, 80))	('melanoma', 'Disease', (128, 136))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('miR-134', 'Gene', (73, 80))	('miR-155', 'Gene', (25, 32))	('miR-301a-3p', 'Var', (89, 100))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('miR-142', 'Gene', '406934', (37, 44))	('miR-205', 'Gene', (49, 56))	('miR-205', 'Gene', '406988', (49, 56))	('miR-23b-3p', 'Var', (61, 71))	('miR-142', 'Gene', (37, 44))
41337	31479413	Thus, for the first time, here we reported altered expression of miR-9-5p, miR-203a-3p, miR-19a-3p, miR-27b-3p, and miR-218-5p in the three melanoma types vs. nevi.	('melanoma type', 'Disease', 'MESH:D008545', (140, 153))	('miR-203a-3p', 'Var', (75, 86))	('nevi', 'Phenotype', 'HP:0003764', (159, 163))	('miR-9-5p', 'Gene', (65, 73))	('miR-9-5p', 'Gene', '407052', (65, 73))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma type', 'Disease', (140, 153))	('expression', 'MPA', (51, 61))	('miR-203a', 'Chemical', '-', (75, 83))	('miR-218-5p', 'Var', (116, 126))	('miR-27b-3p', 'Var', (100, 110))	('miR-19a-3p', 'Var', (88, 98))	('altered', 'Reg', (43, 50))
41341	31479413	Nevertheless, in melanoma cell lines, ectopic expression of miR-155-5p had an anti-proliferative and pro-apoptotic effect, and higher miR-155-5p expression in metastatic melanoma could predict longer post-recurrence survival.	('miR-155', 'Gene', (134, 141))	('longer', 'PosReg', (193, 199))	('miR-155', 'Gene', (60, 67))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('post-recurrence survival', 'CPA', (200, 224))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('ectopic expression', 'Var', (38, 56))	('miR-155', 'Gene', '406947', (60, 67))	('melanoma', 'Disease', (17, 25))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('higher', 'PosReg', (127, 133))	('miR-155', 'Gene', '406947', (134, 141))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))
41355	31479413	In gastric cancer, miR-19a-3p had a negative prognostic impact and promoted cell malignancy.	('promoted', 'PosReg', (67, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('miR-19a-3p', 'Var', (19, 29))	('gastric cancer', 'Disease', (3, 17))	('malignancy', 'Disease', 'MESH:D009369', (81, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('malignancy', 'Disease', (81, 91))
41361	31479413	In addition, in hepatocellular carcinoma cell lines, miR-301a-3p overexpression was shown to stimulate cell proliferation, invasion, and chemoresistance.	('overexpression', 'Var', (65, 79))	('invasion', 'CPA', (123, 131))	('cell proliferation', 'CPA', (103, 121))	('miR-301a-3p overexpression', 'Var', (53, 79))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (16, 40))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (16, 40))	('hepatocellular carcinoma', 'Disease', (16, 40))	('stimulate', 'PosReg', (93, 102))	('chemoresistance', 'CPA', (137, 152))	('cell proliferation', 'biological_process', 'GO:0008283', ('103', '121'))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
41362	31479413	For the first time, we showed that miR-203a-3p was downregulated in melanoma compared with nevi.	('miR-203a', 'Chemical', '-', (35, 43))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('downregulated', 'NegReg', (51, 64))	('nevi', 'Phenotype', 'HP:0003764', (91, 95))	('miR-203a-3p', 'Var', (35, 46))
41363	31479413	The overexpression of miR-203a-3p in colorectal cancer cell lines inhibited cell proliferation and reduced chemoresistance and similarly, in nasopharyngeal carcinoma, overexpressed miR-203a-3p inhibited cell proliferation, migration, and invasion in vitro as well as xenograft tumor growth and lung metastasis in vivo.	('carcinoma', 'Disease', 'MESH:D009369', (156, 165))	('miR-203a', 'Chemical', '-', (181, 189))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('miR-203a', 'Chemical', '-', (22, 30))	('colorectal cancer', 'Phenotype', 'HP:0003003', (37, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('miR-203a-3p', 'Var', (22, 33))	('cell proliferation', 'biological_process', 'GO:0008283', ('76', '94'))	('inhibited', 'NegReg', (66, 75))	('miR-203a-3p', 'Var', (181, 192))	('overexpressed', 'PosReg', (167, 180))	('invasion', 'CPA', (238, 246))	('cell proliferation', 'biological_process', 'GO:0008283', ('203', '221'))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('chemoresistance', 'CPA', (107, 122))	('inhibited', 'NegReg', (193, 202))	('colorectal cancer', 'Disease', 'MESH:D015179', (37, 54))	('carcinoma', 'Disease', (156, 165))	('tumor', 'Disease', (277, 282))	('colorectal cancer', 'Disease', (37, 54))	('cell proliferation', 'CPA', (203, 221))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (141, 165))	('cell proliferation', 'CPA', (76, 94))	('lung metastasis', 'CPA', (294, 309))	('reduced', 'NegReg', (99, 106))
41365	31479413	MiR-27b-3p and miR-218-5p were another two downregulated miRNAs in our case study that are reported for the first time in melanoma.	('downregulated', 'NegReg', (43, 56))	('MiR-27b-3p', 'Var', (0, 10))	('miR-218-5p', 'Var', (15, 25))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))
41366	31479413	MiR-27b-3p was also downregulated in lung cancer tissues and in breast cancer tissues and cell lines, where it was associated with chemoresistance.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('lung cancer', 'Disease', (37, 48))	('MiR-27b-3p', 'Var', (0, 10))	('chemoresistance', 'CPA', (131, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('downregulated', 'NegReg', (20, 33))	('associated', 'Reg', (115, 125))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
41368	31479413	MiR-218-5p expression was reduced in gastric cancer, NSCLC, and gallbladder cancer (GBC) tissue; moreover, miR-218-5p overexpression reversed the resistance of GBC cells to gemcitabine.	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('overexpression', 'PosReg', (118, 132))	('miR-218-5p', 'Var', (107, 117))	('gastric cancer', 'Disease', (37, 51))	('resistance', 'MPA', (146, 156))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('gastric cancer', 'Phenotype', 'HP:0012126', (37, 51))	('NSCLC', 'Disease', (53, 58))	('gallbladder cancer', 'Disease', (64, 82))	('gallbladder cancer', 'Disease', 'MESH:D005706', (64, 82))	('gemcitabine', 'Chemical', 'MESH:C056507', (173, 184))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))
41370	31479413	Although some studies reported that miR-127-5p and miR-15a-5p were not significantly differently expressed in melanoma compared to melanocytic nevi, our results showed these miRNAs to be overexpressed in both cutaneous and mucosal melanomas vs. nevi.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (131, 147))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('melanomas', 'Phenotype', 'HP:0002861', (231, 240))	('melanoma', 'Disease', (231, 239))	('miR-127-5p', 'Gene', (36, 46))	('nevi', 'Phenotype', 'HP:0003764', (245, 249))	('cutaneous', 'Disease', (209, 218))	('overexpressed', 'PosReg', (187, 200))	('mucosal melanomas', 'Disease', (223, 240))	('mucosal melanomas', 'Disease', 'MESH:D008545', (223, 240))	('nevi', 'Phenotype', 'HP:0003764', (143, 147))	('miR-15a-5p', 'Var', (51, 61))	('miR-127-5p', 'Gene', '100302123', (36, 46))
41374	31479413	Mir-9-5p, miR-203a-3p, miR-19a-3p, miR-134-5p, miR-301a-3p, miR-155-5p, miR-142-5p, miR-205-5p, miR-23b-3p, miR-27b-3p, and miR-218-5p had altered expression in all three melanoma types.	('miR-142', 'Gene', '406934', (72, 79))	('miR-19a-3p', 'Var', (23, 33))	('expression', 'MPA', (147, 157))	('melanoma type', 'Disease', (171, 184))	('Mir-9-5p', 'Gene', (0, 8))	('miR-134', 'Gene', (35, 42))	('miR-205', 'Gene', '406988', (84, 91))	('miR-218-5p', 'Var', (124, 134))	('Mir-9-5p', 'Gene', '407052', (0, 8))	('miR-134', 'Gene', '406924', (35, 42))	('miR-27b-3p', 'Var', (108, 118))	('miR-203a', 'Chemical', '-', (10, 18))	('miR-155', 'Gene', (60, 67))	('miR-301a-3p', 'Var', (47, 58))	('miR-142', 'Gene', (72, 79))	('miR-155', 'Gene', '406947', (60, 67))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma type', 'Disease', 'MESH:D008545', (171, 184))	('miR-205', 'Gene', (84, 91))	('miR-23b-3p', 'Var', (96, 106))	('altered', 'Reg', (139, 146))	('miR-203a-3p', 'Var', (10, 21))
41393	31980913	The rationale to combine DC vaccination with cisplatin is based on the ability of cisplatin to not only cross-link DNA and inhibit mitosis, but also to have immunomodulatory effects.	('mitosis', 'CPA', (131, 138))	('cross-link', 'Reg', (104, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('cisplatin', 'Var', (82, 91))	('mitosis', 'biological_process', 'GO:0000278', ('131', '138'))	('DNA', 'Protein', (115, 118))	('DNA', 'cellular_component', 'GO:0005574', ('115', '118'))	('inhibit', 'NegReg', (123, 130))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))
41397	31980913	More recently, preclinical studies showed that cisplatin may upregulate MHC class I expression on tumor cells and upregulate the lytic activity of cytotoxic effector cells.	('upregulate', 'PosReg', (114, 124))	('upregulate MHC class I', 'Phenotype', 'HP:0031391', (61, 83))	('tumor', 'Disease', (98, 103))	('cisplatin', 'Var', (47, 56))	('upregulate', 'PosReg', (61, 71))	('lytic activity of cytotoxic effector cells', 'CPA', (129, 171))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('expression', 'MPA', (84, 94))	('MHC class I', 'Gene', (72, 83))
41398	31980913	Furthermore, it has been shown that cisplatin can improve recruitment of immune effector cells to the TME and enhances their proliferation and at the same time causes downregulation of immunosuppressive cells in the TME by reducing levels of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs).	('downregulation', 'NegReg', (167, 181))	('proliferation', 'CPA', (125, 138))	('cisplatin', 'Var', (36, 45))	('reducing', 'NegReg', (223, 231))	('regulatory T cells', 'CPA', (287, 305))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('recruitment', 'MPA', (58, 69))	('improve', 'PosReg', (50, 57))	('enhances', 'PosReg', (110, 118))
41400	31980913	Finally, it was recently observed that cisplatin can induce immunogenic cell death.	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('cell death', 'biological_process', 'GO:0008219', ('72', '82'))	('immunogenic cell death', 'CPA', (60, 82))	('cisplatin', 'Var', (39, 48))
41420	31980913	Monocytes were cultured in X-VIVO 15 medium (Lonza) supplemented with 2% human serum (HS; Sanquin), IL-4 (500 U/ml), GM-CSF (800 U/ml, both CellGenix) and KLH (10 mug/ml, Calbiochem).	('800 U/ml', 'Var', (125, 133))	('IL-4', 'molecular_function', 'GO:0005136', ('100', '104'))	('HS', 'Chemical', '-', (86, 88))	('human', 'Species', '9606', (73, 78))	('mug', 'molecular_function', 'GO:0043739', ('163', '166'))	('IL-4', 'Gene', (100, 104))	('GM-CSF', 'Gene', '1437', (117, 123))	('GM-CSF', 'Gene', (117, 123))	('IL-4', 'Gene', '3565', (100, 104))
41424	31980913	Phenotype of the ex vivo generated DCs was characterized by flow cytometry with the following monoclonal antibodies (mAbs): anti-HLA-ABC-PE, anti-HLA-DR-PE, anti-CD80-PE, anti-CD83-PE, anti-CD86-PE, anti-CD3-PE, anti-CD25-PE, anti-CD95-PE (all BD Biosciences), anti-CD14-PE (Sanquin Reagents), anti-HLA-DQ-PE, anti-CD20-PE (both BioLegend) and anti-CCR7-PE (Miltenyi Biotec).	('CD8', 'Gene', '925', (176, 179))	('CD20', 'Gene', (315, 319))	('anti-HLA-DR-PE', 'Var', (141, 155))	('BD Biosciences', 'Disease', (244, 258))	('anti-CCR7-PE', 'Var', (344, 356))	('CD8', 'Gene', (162, 165))	('CD14', 'Gene', (266, 270))	('anti-CD95-PE', 'Var', (226, 238))	('CD14', 'Gene', '929', (266, 270))	('CD8', 'Gene', '925', (190, 193))	('CD20', 'Gene', '54474', (315, 319))	('CD25', 'Gene', (217, 221))	('CCR', 'molecular_function', 'GO:0043880', ('349', '352'))	('CD8', 'Gene', (176, 179))	('anti-HLA-DQ-PE', 'Var', (294, 308))	('BD Biosciences', 'Disease', 'MESH:D001528', (244, 258))	('CD8', 'Gene', (190, 193))	('CD25', 'Gene', '3559', (217, 221))	('CD8', 'Gene', '925', (162, 165))
41427	31980913	The Treg antibody panel consisted of fixable viability dye 780, anti-FoxP3-Alexa488 (both eBioscience), anti-CD3-BV605 (BioLegend), anti-CD4-BV510 and anti-CD25-BV421 (both BD Biosciences).	('CD4', 'Gene', (137, 140))	('FoxP3', 'Gene', '50943', (69, 74))	('CD4', 'Gene', '920', (137, 140))	('BD Biosciences', 'Disease', 'MESH:D001528', (173, 187))	('antibody', 'cellular_component', 'GO:0019815', ('9', '17'))	('eBioscience', 'Disease', (90, 101))	('antibody', 'cellular_component', 'GO:0019814', ('9', '17'))	('FoxP3', 'Gene', (69, 74))	('antibody', 'molecular_function', 'GO:0003823', ('9', '17'))	('CD25', 'Gene', '3559', (156, 160))	('eBioscience', 'Disease', 'None', (90, 101))	('BD Biosciences', 'Disease', (173, 187))	('Alexa488', 'Chemical', '-', (75, 83))	('antibody', 'cellular_component', 'GO:0042571', ('9', '17'))	('anti-CD3-BV605', 'Var', (104, 118))	('CD25', 'Gene', (156, 160))
41428	31980913	M-MDSCs were analyzed with anti-CD33-APC (BioLegend), anti-CD14-BV421, anti-HLA-DR-BV510 and anti-CD11b-BV605 (all BD Biosciences) antibodies.	('APC', 'cellular_component', 'GO:0005680', ('37', '40'))	('BD Biosciences', 'Disease', (115, 129))	('anti-HLA-DR-BV510', 'Var', (71, 88))	('CD14', 'Gene', (59, 63))	('CD33', 'Gene', '945', (32, 36))	('CD14', 'Gene', '929', (59, 63))	('CD33', 'Gene', (32, 36))	('CD11b', 'Gene', (98, 103))	('CD11b', 'Gene', '3684', (98, 103))	('BD Biosciences', 'Disease', 'MESH:D001528', (115, 129))
41447	31980913	A seven-color mIHC for the detection of lymphocyte populations was applied using the BOND RX IHC & ISH Research Platform (Leica Biosystems) with mAbs for CD45RO, CD8, CD20, CD3, Foxp3 and a melanoma mix as listed in Supplementary Table 1b.	('mIHC', 'Gene', '432516', (14, 18))	('Foxp3', 'Gene', '50943', (178, 183))	('CD8', 'Gene', '925', (162, 165))	('Foxp3', 'Gene', (178, 183))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('CD20', 'Gene', (167, 171))	('melanoma', 'Disease', (190, 198))	('IHC', 'Gene', '432516', (15, 18))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('IHC', 'Gene', (93, 96))	('mIHC', 'Gene', (14, 18))	('CD8', 'Gene', (162, 165))	('IHC', 'Gene', (15, 18))	('CD4', 'Gene', '920', (154, 157))	('IHC', 'Gene', '432516', (93, 96))	('CD4', 'Gene', (154, 157))	('CD20', 'Gene', '54474', (167, 171))	('for', 'Var', (150, 153))
41451	31980913	A similar seven-color mIHC was performed on cryopreserved tissue with anti-granzyme B instead of CD20 (Supplementary Table 1c).	('anti-granzyme', 'Var', (70, 83))	('mIHC', 'Gene', (22, 26))	('CD20', 'Gene', '54474', (97, 101))	('CD20', 'Gene', (97, 101))	('mIHC', 'Gene', '432516', (22, 26))
41520	31980913	TM+CD8+ SKILs were induced in about half of the patients without difference between the treatment groups, although in stage III melanoma patients, combination therapy might have induced less TM+CD8+ T cells than monotherapy.	('CD8', 'Gene', (194, 197))	('CD8', 'Gene', '925', (194, 197))	('less', 'NegReg', (186, 190))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('combination', 'Var', (147, 158))	('CD8', 'Gene', (3, 6))	('CD8', 'Gene', '925', (3, 6))	('patients', 'Species', '9606', (137, 145))	('patients', 'Species', '9606', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
41573	31508890	Pristimerin (purity >99%) was obtained from Chengdu PureChem-Standard Co., Ltd; IGF-1, poly-L-lysine, bovine serum albumin, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and dimethyl sulfoxide (DMSO) were commercially obtained from Sigma; Antibiotics, Dulbecco's Modified Eagle's Medium (DMEM), trypsin and foetal bovine serum (FBS) were purchased from Gibco-BRL; Anti-beta-actin, anti-phospho-IGF-1R (Tyr1135/Tyr1136), anti-IGF-1R, anti-p21Waf1/Cip1 (p21) and anti-Cyclin D1 were from Signalway Antibody.	('p21', 'Gene', '1026', (474, 477))	('Pristimerin', 'Chemical', 'MESH:C009043', (0, 11))	('p21Waf1/Cip1', 'Gene', '1026', (460, 472))	('Tyr1135/Tyr1136', 'Var', (424, 439))	('p21', 'Gene', (460, 463))	('3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide', 'Chemical', 'MESH:C022616', (124, 185))	('bovine', 'Species', '9913', (336, 342))	('poly-L-lysine', 'Chemical', 'MESH:D011107', (87, 100))	('IGF-1R', 'Gene', (416, 422))	('p21Waf1/Cip1', 'Gene', (460, 472))	('p21', 'Gene', (474, 477))	('Cyclin', 'molecular_function', 'GO:0016538', ('488', '494'))	('Cyclin D1', 'Gene', '595', (488, 497))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (196, 214))	('p21', 'Gene', '1026', (460, 463))	('Cyclin D1', 'Gene', (488, 497))	('bovine', 'Species', '9913', (102, 108))	('MTT', 'Chemical', 'MESH:C022616', (187, 190))	('DMSO', 'Chemical', 'MESH:D004121', (216, 220))	('IGF-1R', 'Gene', '3480', (447, 453))	('IGF-1R', 'Gene', (447, 453))	('IGF-1R', 'Gene', '3480', (416, 422))	('Tyr1136', 'Chemical', 'MESH:C572500', (432, 439))
41574	31508890	Anti-phospho-Akt (Thr308), anti-ERK1/2, anti-phospho-Akt (Ser473), anti-phospho-mTOR (Ser338), anti-Akt and anti-phospho-ERK1/2 (Thr202/Tyr204) were from cell signalling technology.	('Thr308', 'Chemical', 'MESH:C015596', (18, 24))	('ERK1/2', 'Gene', (121, 127))	('ERK1/2', 'Gene', '5595;5594', (121, 127))	('Ser338', 'Chemical', 'MESH:C037244', (86, 92))	('Ser473', 'Var', (58, 64))	('Akt', 'Gene', (13, 16))	('ERK1', 'molecular_function', 'GO:0004707', ('121', '125'))	('Akt', 'Gene', (100, 103))	('Thr308', 'Var', (18, 24))	('Ser', 'cellular_component', 'GO:0005790', ('58', '61'))	('Akt', 'Gene', '207', (13, 16))	('Thr202/Tyr204', 'Var', (129, 142))	('Ser338', 'Var', (86, 92))	('Akt', 'Gene', '207', (100, 103))	('Akt', 'Gene', (53, 56))	('ERK1/2', 'Gene', (32, 38))	('ERK1/2', 'Gene', '5595;5594', (32, 38))	('Akt', 'Gene', '207', (53, 56))	('mTOR', 'Gene', (80, 84))	('Ser473', 'Chemical', 'MESH:C530429', (58, 64))	('mTOR', 'Gene', '2475', (80, 84))	('Ser', 'cellular_component', 'GO:0005790', ('86', '89'))	('signalling', 'biological_process', 'GO:0023052', ('159', '169'))	('ERK1', 'molecular_function', 'GO:0004707', ('32', '36'))
41592	31508890	As can be seen in Figure 1B, PRI can inhibit cell proliferation in a dose-dependent manner and significantly reduce the number of cultured live cells.	('reduce', 'NegReg', (109, 115))	('PRI', 'Var', (29, 32))	('inhibit', 'NegReg', (37, 44))	('cell proliferation', 'CPA', (45, 63))	('cell proliferation', 'biological_process', 'GO:0008283', ('45', '63'))	('PRI', 'Chemical', 'MESH:C009043', (29, 32))
41596	31508890	As shown in Figure 1E, PRI (1 mumol/L) significantly inhibited colony formation of UM cells and showed a very significant difference in comparison to the control group.	('inhibited', 'NegReg', (53, 62))	('UM', 'Disease', 'MESH:C536494', (83, 85))	('PRI', 'Var', (23, 26))	('formation', 'biological_process', 'GO:0009058', ('70', '79'))	('PRI', 'Chemical', 'MESH:C009043', (23, 26))
41602	31508890	From Figure 2A, it can be seen that IGF-1 induced S phase accumulation, but cells in the G1 phase were diminished, and PRI reversed the effect of IGF-1.	('G1 phase', 'biological_process', 'GO:0051318', ('89', '97'))	('IGF-1', 'Var', (36, 41))	('diminished', 'NegReg', (103, 113))	('S phase', 'biological_process', 'GO:0051320', ('50', '57'))	('PRI', 'Chemical', 'MESH:C009043', (119, 122))	('cells in the G1 phase', 'CPA', (76, 97))
41607	31508890	This demonstrated that PRI could affect UM cell cycle distribution as well as p21 and cyclin D1 expression.	('cyclin D1', 'Gene', (86, 95))	('cyclin', 'molecular_function', 'GO:0016538', ('86', '92'))	('affect', 'Reg', (33, 39))	('expression', 'MPA', (96, 106))	('PRI', 'Var', (23, 26))	('cyclin D1', 'Gene', '595', (86, 95))	('p21', 'Gene', '1026', (78, 81))	('cell cycle', 'biological_process', 'GO:0007049', ('43', '53'))	('PRI', 'Chemical', 'MESH:C009043', (23, 26))	('UM', 'Disease', 'MESH:C536494', (40, 42))	('p21', 'Gene', (78, 81))
41615	31508890	Furthermore, PRI inhibited IGF-1-induced IGF-1R phosphorylation of Tyr1135/Tyr1136 in a dose-dependent manner in UM cells.	('IGF-1-induced', 'Gene', (27, 40))	('PRI', 'Chemical', 'MESH:C009043', (13, 16))	('Tyr1136', 'Chemical', 'MESH:C572500', (75, 82))	('phosphorylation', 'MPA', (48, 63))	('inhibited', 'NegReg', (17, 26))	('Tyr1135/Tyr1136', 'Var', (67, 82))	('IGF-1R', 'Gene', '3480', (41, 47))	('IGF-1R', 'Gene', (41, 47))	('UM', 'Disease', 'MESH:C536494', (113, 115))	('phosphorylation', 'biological_process', 'GO:0016310', ('48', '63'))
41625	31508890	As shown in Figure 6C,D, PRI could attenuate the activation of mTOR, Akt and ERK1/2 in a dose-dependent manner.	('Akt', 'Gene', (69, 72))	('mTOR', 'Gene', (63, 67))	('ERK1', 'molecular_function', 'GO:0004707', ('77', '81'))	('mTOR', 'Gene', '2475', (63, 67))	('attenuate', 'NegReg', (35, 44))	('ERK1/2', 'Gene', '5595;5594', (77, 83))	('Akt', 'Gene', '207', (69, 72))	('ERK1/2', 'Gene', (77, 83))	('PRI', 'Var', (25, 28))	('PRI', 'Chemical', 'MESH:C009043', (25, 28))	('activation', 'PosReg', (49, 59))
41627	31508890	Both Akt and ERK1/2 phosphorylation were significantly blocked at 0.1 mumol/L and 0.3 mumol/L, respectively.	('Akt', 'Gene', '207', (5, 8))	('ERK1/2', 'Gene', '5595;5594', (13, 19))	('phosphorylation', 'biological_process', 'GO:0016310', ('20', '35'))	('ERK1', 'molecular_function', 'GO:0004707', ('13', '17'))	('0.3', 'Var', (82, 85))	('Akt', 'Gene', (5, 8))	('blocked', 'NegReg', (55, 62))	('ERK1/2', 'Gene', (13, 19))
41633	31508890	It was also stabilized by Van der Waals and hydrophobic interactions with Gly 1005, Leu 1002, Asp 1150, Gln 1004, Asn 1137, Arg 1136, and Gly 1149.	('hydrophobic', 'CPA', (44, 55))	('Gln', 'Chemical', 'MESH:C544323', (104, 107))	('Leu 1002', 'Var', (84, 92))	('Gly 1005', 'Var', (74, 82))	('Gly', 'Chemical', 'MESH:C070361', (138, 141))	('Asn 1137', 'Var', (114, 122))	('Leu', 'Chemical', 'MESH:C038361', (84, 87))	('Gly 1149', 'Var', (138, 146))	('Gln 1004', 'Var', (104, 112))	('Asn', 'Chemical', 'MESH:C528802', (114, 117))	('Asp', 'Chemical', 'MESH:C108952', (94, 97))	('Asp 1150', 'Var', (94, 102))	('Arg', 'Chemical', 'MESH:C076685', (124, 127))	('Gly', 'Chemical', 'MESH:C070361', (74, 77))	('Arg 1136', 'Var', (124, 132))
41636	31508890	Accordingly, IGF-1R signalling was regarded as a promising anti-tumour target, which has been widely studied in clinical trials for different types of tumours including lung cancer, prostate cancer and breast cancer.5 In recent years, using either IGF-1R targeting antibodies or small molecule inhibitors toward the IGF-1R kinase has been extensively studied.19, 20, 21 High levels of IGF-1R in UM are closely related to metastatic progression.22 Thus, suppression of IGF-1R provides an effective therapeutic approach to decrease the proliferation of UM cells, especially for cancer cells that have higher expression.	('lung cancer', 'Disease', 'MESH:D008175', (169, 180))	('cancer', 'Disease', 'MESH:D009369', (576, 582))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('IGF-1R', 'Gene', '3480', (248, 254))	('IGF-1R', 'Gene', (248, 254))	('cancer', 'Disease', (191, 197))	('UM', 'Disease', 'MESH:C536494', (395, 397))	('decrease', 'NegReg', (521, 529))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('IGF-1R', 'Gene', '3480', (316, 322))	('suppression', 'Var', (453, 464))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('IGF-1R', 'Gene', '3480', (468, 474))	('IGF-1R', 'Gene', (316, 322))	('tumours', 'Disease', (151, 158))	('prostate cancer', 'Disease', 'MESH:D011471', (182, 197))	('IGF-1R', 'Gene', (468, 474))	('prostate cancer', 'Phenotype', 'HP:0012125', (182, 197))	('cancer', 'Disease', (576, 582))	('UM', 'Disease', 'MESH:C536494', (551, 553))	('proliferation', 'CPA', (534, 547))	('tumours', 'Phenotype', 'HP:0002664', (151, 158))	('High levels of IGF-1R', 'Phenotype', 'HP:0030269', (370, 391))	('prostate cancer', 'Disease', (182, 197))	('IGF-1R', 'Gene', '3480', (13, 19))	('tumours', 'Disease', 'MESH:D009369', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (576, 582))	('lung cancer', 'Disease', (169, 180))	('IGF-1R', 'Gene', (13, 19))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('signalling', 'biological_process', 'GO:0023052', ('20', '30'))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('breast cancer', 'Disease', (202, 215))	('tumour', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', (209, 215))	('tumour', 'Disease', (151, 157))	('IGF-1R', 'Gene', '3480', (385, 391))	('IGF-1R', 'Gene', (385, 391))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
41638	31508890	These findings suggested that PRI targeting IGF-1R kinases simultaneously resulted in cell cycle arrest and potent anti-proliferative effects.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (86, 103))	('anti-proliferative effects', 'CPA', (115, 141))	('arrest', 'Disease', 'MESH:D006323', (97, 103))	('kinases', 'Gene', (51, 58))	('IGF-1R', 'Gene', '3480', (44, 50))	('PRI targeting', 'Var', (30, 43))	('arrest', 'Disease', (97, 103))	('IGF-1R', 'Gene', (44, 50))	('PRI', 'Chemical', 'MESH:C009043', (30, 33))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('86', '103'))
41642	31508890	Recent studies have shown that mTOR mutations usually occur in melanoma patients and show more negative therapeutic prognosis.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('mTOR', 'Gene', (31, 35))	('mTOR', 'Gene', '2475', (31, 35))	('mutations', 'Var', (36, 45))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('occur', 'Reg', (54, 59))	('patients', 'Species', '9606', (72, 80))
41656	31382450	Loss of BAP1 Is Associated with Upregulation of the NFkB Pathway and Increased HLA Class I Expression in Uveal Melanoma One of the characteristics of prognostically infaust uveal melanoma (UM) is an inflammatory phenotype, which is characterized by high numbers of infiltrating T cells and macrophages, and a high HLA Class I expression.	('Expression', 'MPA', (91, 101))	('Increased HLA Class', 'Phenotype', 'HP:0002853', (69, 88))	('UM', 'Phenotype', 'HP:0007716', (189, 191))	('NFkB Pathway', 'Pathway', (52, 64))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (105, 119))	('Melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('infaust uveal melanoma', 'Disease', (165, 187))	('uveal melanoma', 'Phenotype', 'HP:0007716', (173, 187))	('BAP1', 'Gene', '8314', (8, 12))	('BAP1', 'Gene', (8, 12))	('Melanoma', 'Disease', 'MESH:D008545', (111, 119))	('Upregulation', 'PosReg', (32, 44))	('infaust uveal melanoma', 'Disease', 'MESH:C536494', (165, 187))	('Melanoma', 'Disease', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('Loss', 'Var', (0, 4))	('HLA Class I', 'Protein', (79, 90))	('Increased', 'PosReg', (69, 78))
41665	31382450	It was recently noticed that an extra copy of chromosome 8q in the tumor is associated with an influx of macrophages, while loss of chromosome 3 (Monosomy 3, M3) correlates with an increased influx of T cells.	('loss', 'Var', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('increased influx of T cells', 'Phenotype', 'HP:0100828', (181, 208))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('associated with', 'Reg', (76, 91))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('T cells', 'MPA', (201, 208))	('influx', 'MPA', (191, 197))	('tumor', 'Disease', (67, 72))	('influx of macrophages', 'MPA', (95, 116))	('extra copy', 'Var', (32, 42))	('chromosome', 'cellular_component', 'GO:0005694', ('132', '142'))
41667	31382450	Almost all cases with M3 also show gain of chromosome 8q, but this may even occur in tumors with two chromosomes 3 (Disomy 3, D3); it is considered a bad prognostic sign.	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('chromosome', 'Var', (43, 53))	('chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('gain', 'PosReg', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
41668	31382450	Besides chromosomal changes, important genetic driver mutations have been identified: these include activating mutations in GNAQ and GNA11, which are thought to lead to the transformation of melanocytic cells by upregulation of YAP1.	('melanocytic cells', 'CPA', (191, 208))	('mutations', 'Var', (111, 120))	('GNA11', 'Gene', (133, 138))	('GNAQ', 'Gene', '2776', (124, 128))	('GNA11', 'Gene', '2767', (133, 138))	('upregulation', 'PosReg', (212, 224))	('transformation', 'CPA', (173, 187))	('lead to', 'Reg', (161, 168))	('GNAQ', 'Gene', (124, 128))	('YAP1', 'Gene', (228, 232))	('YAP1', 'Gene', '10413', (228, 232))
41669	31382450	These mutations are already seen in choroidal nevi, where YAP upregulation is also present.	('YAP', 'Gene', (58, 61))	('nevi', 'Phenotype', 'HP:0003764', (46, 50))	('choroidal nevi', 'Disease', (36, 50))	('YAP', 'Gene', '10413', (58, 61))	('choroidal nevi', 'Phenotype', 'HP:0025314', (36, 50))	('mutations', 'Var', (6, 15))
41673	31382450	Although in UM a relation is seen between M3/loss of BAP1 expression and the presence of an inflammatory phenotype, little is known about the pathways which regulate this inflammation.	('M3/loss', 'Var', (42, 49))	('expression', 'MPA', (58, 68))	('inflammation', 'biological_process', 'GO:0006954', ('171', '183'))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('inflammation', 'Disease', 'MESH:D007249', (171, 183))	('BAP1', 'Gene', '8314', (53, 57))	('inflammation', 'Disease', (171, 183))	('BAP1', 'Gene', (53, 57))
41678	31382450	P53 and PTEN proteins can function as negative regulators of NFkB signalling and mutations in these genes can affect the pathway's activity.	('affect', 'Reg', (110, 116))	('PTEN', 'Gene', (8, 12))	('activity', 'MPA', (131, 139))	('signalling', 'biological_process', 'GO:0023052', ('66', '76'))	('PTEN', 'Gene', '5728', (8, 12))	('P53', 'Gene', (0, 3))	('mutations', 'Var', (81, 90))	('P53', 'Gene', '7157', (0, 3))	('proteins', 'Protein', (13, 21))
41679	31382450	Other oncogenic mutations, such as amplifications and point mutations in RELA and other NFkB signalling genes, have been identified in several lymphoid malignancies, and give rise to inflammation.	('identified', 'Reg', (121, 131))	('inflammation', 'biological_process', 'GO:0006954', ('183', '195'))	('inflammation', 'Disease', (183, 195))	('point mutations', 'Var', (54, 69))	('NFkB signalling genes', 'Gene', (88, 109))	('amplifications', 'Var', (35, 49))	('lymphoid malignancies', 'Disease', 'MESH:D008223', (143, 164))	('lymphoid malignancies', 'Disease', (143, 164))	('signalling', 'biological_process', 'GO:0023052', ('93', '103'))	('RELA', 'Gene', (73, 77))	('RELA', 'Gene', '5970', (73, 77))	('lymphoid malignancies', 'Phenotype', 'HP:0002665', (143, 164))	('give rise to', 'Reg', (170, 182))	('inflammation', 'Disease', 'MESH:D007249', (183, 195))
41705	31382450	As M3 and loss of BAP1 expression are well known risk factors for the development of metastasis in UM, we determined whether these genetic aberrations might be associated with expression of the NFkB-related molecules directly and, therefore, with the generation of the inflammatory environment.	('loss', 'Var', (10, 14))	('BAP1', 'Gene', '8314', (18, 22))	('BAP1', 'Gene', (18, 22))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('metastasis', 'CPA', (85, 95))	('associated', 'Reg', (160, 170))
41721	31382450	We previously demonstrated that M3/loss of BAP1 is related to increased leukocytic infiltration, and now show an association between BAP1 loss and upregulation of the NFkB pathway.	('BAP1', 'Gene', (43, 47))	('loss', 'NegReg', (138, 142))	('increased leukocytic infiltration', 'Disease', 'MESH:D017254', (62, 95))	('BAP1', 'Gene', '8314', (43, 47))	('M3/loss', 'Var', (32, 39))	('BAP1', 'Gene', '8314', (133, 137))	('increased leukocytic infiltration', 'Disease', (62, 95))	('upregulation', 'PosReg', (147, 159))	('NFkB pathway', 'Pathway', (167, 179))	('BAP1', 'Gene', (133, 137))
41723	31382450	In this group, we similarly observed that the tumors with M3/loss of BAP1 had an increased NFkB and HLA Class I expression, indicating that the infiltrating leukocytes may enhance expression, but that the genetic basis determines expression in the first place.	('M3/loss', 'Var', (58, 65))	('BAP1', 'Gene', '8314', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('NFkB', 'Protein', (91, 95))	('enhance', 'PosReg', (172, 179))	('HLA Class I', 'Protein', (100, 111))	('BAP1', 'Gene', (69, 73))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('expression', 'MPA', (180, 190))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('tumors', 'Disease', (46, 52))	('increased', 'PosReg', (81, 90))	('expression', 'MPA', (112, 122))
41739	31382450	From this, we conclude that the genetic basis of the tumor, i.e., Monosomy 3 with BAP1 loss, determines the primary upregulation of the NFkB pathway, which leads to an increase in HLA Class I expression in the tumor cells and production of cytokines and chemokines, which then attracts immune cells, further upregulating expression of HLA Class I.	('increase', 'PosReg', (168, 176))	('loss', 'NegReg', (87, 91))	('BAP1', 'Gene', (82, 86))	('HLA Class I', 'Protein', (180, 191))	('Monosomy 3', 'Var', (66, 76))	('upregulating', 'PosReg', (308, 320))	('BAP1', 'Gene', '8314', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('expression', 'MPA', (192, 202))	('tumor', 'Disease', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('upregulation', 'PosReg', (116, 128))	('tumor', 'Disease', (53, 58))	('NFkB pathway', 'Pathway', (136, 148))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('expression', 'MPA', (321, 331))
41745	31382450	HPV-infected keratinocytes with a high UCHL1 expression showed greatly decreased HLA-A and -B levels.	('HLA-A', 'Gene', '3105', (81, 86))	('UCHL1', 'Gene', '7345', (39, 44))	('HLA-A', 'Gene', (81, 86))	('UCHL1', 'Gene', (39, 44))	('high', 'Var', (34, 38))	('decreased HLA', 'Phenotype', 'HP:0011905', (71, 84))	('HPV-infected', 'Disease', 'MESH:D030361', (0, 12))	('HPV-infected', 'Disease', (0, 12))	('expression', 'Var', (45, 55))	('decreased', 'NegReg', (71, 80))
41747	31382450	Taken together, our data suggest that the main regulator of the NFkB pathway in uveal melanoma is loss of chromosome 3 and BAP1: loss of chromosome 3/loss of BAP1 expression correlates with upregulation of the NFkB pathway and affects the activity of the NFkB pathway in UM tumors, which leads to upregulation of HLA Class I expression and attraction of infiltrating cells to the tumor environment which is a well known factor in the development of metastasis in this disease.	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('activity', 'MPA', (239, 247))	('BAP1', 'Gene', '8314', (158, 162))	('tumor', 'Disease', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (380, 385))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('upregulation', 'PosReg', (190, 202))	('BAP1', 'Gene', '8314', (123, 127))	('affects', 'Reg', (227, 234))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('NFkB pathway', 'Pathway', (210, 222))	('UM', 'Phenotype', 'HP:0007716', (271, 273))	('expression', 'MPA', (325, 335))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('uveal melanoma', 'Disease', (80, 94))	('uveal melanoma', 'Disease', 'MESH:C536494', (80, 94))	('BAP1', 'Gene', (158, 162))	('chromosome', 'cellular_component', 'GO:0005694', ('106', '116'))	('loss', 'Var', (129, 133))	('3/loss', 'Var', (148, 154))	('chromosome', 'cellular_component', 'GO:0005694', ('137', '147'))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('HLA Class I', 'Protein', (313, 324))	('tumors', 'Disease', (274, 280))	('tumor', 'Disease', (380, 385))	('BAP1', 'Gene', (123, 127))	('NFkB pathway', 'Pathway', (255, 267))	('uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('upregulation', 'PosReg', (297, 309))	('tumor', 'Disease', 'MESH:D009369', (380, 385))	('attraction', 'CPA', (340, 350))
41757	31382450	Immunofluorescence staining was performed for T cell and macrophage markers as described with anti-CD3 (ab828; Abcam, Cambridge, MA, USA), anti-CD8 (4B11, IgG2b; Novocastra Valkenswaard, The Netherlands), anti-CD68 (514H12; Abcam, Cambridge, UK) and anti-CD163 (Clone 10D6; Novocastra, Newcastle-upon-Tyne, UK).	('CD8', 'Gene', (144, 147))	('anti-CD3', 'Var', (94, 102))	('IgG2b', 'cellular_component', 'GO:0071735', ('155', '160'))	('CD8', 'Gene', '925', (144, 147))	('anti-CD163', 'Var', (250, 260))
41758	31382450	Affymetrix 250K Nsp array (Affymetrix, Santa Clara, CA, USA) was performed in order to obtain a genome-wide micro-array of single nucleotide polymorphisms (SNPs) as described previously for chromosome 3 abnormalities.	('single nucleotide polymorphisms', 'Var', (123, 154))	('Nsp', 'Gene', (16, 19))	('chromosome', 'cellular_component', 'GO:0005694', ('190', '200'))	('Nsp', 'Gene', '92521', (16, 19))
41760	31382450	Loss of chromosome 3/loss of nuclear BAP1 protein in UM is associated with upregulation of the main components of the NFkB pathway (NFkB1-NFkB2 and RELB) and downregulation of two negative regulators of this pathway (SPP1 and PPARgamma).	('protein', 'Protein', (42, 49))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('NFkB pathway', 'Pathway', (118, 130))	('downregulation', 'NegReg', (158, 172))	('RELB', 'Gene', '5971', (148, 152))	('BAP1', 'Gene', '8314', (37, 41))	('PPARgamma', 'Gene', '5468', (226, 235))	('NFkB2', 'Gene', '4791', (138, 143))	('NFkB2', 'Gene', (138, 143))	('3/loss', 'NegReg', (19, 25))	('NFkB1', 'Gene', (132, 137))	('SPP1', 'Gene', (217, 221))	('SPP', 'molecular_function', 'GO:0042499', ('217', '220'))	('BAP1', 'Gene', (37, 41))	('Loss', 'Var', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('RELB', 'Gene', (148, 152))	('nuclear', 'Gene', (29, 36))	('NFkB1', 'Gene', '4790', (132, 137))	('PPARgamma', 'Gene', (226, 235))	('SPP1', 'Gene', '6696', (217, 221))	('upregulation', 'PosReg', (75, 87))	('UM', 'Phenotype', 'HP:0007716', (53, 55))
41761	31382450	It seems that under normal conditions, BAP1 helps to keep the uveal pigment cells immunologically quiet, but that during evolution of a UM, loss of BAP1 expression results in lack of suppression of the NFkB pathway and subsequent inflammation.	('lack', 'NegReg', (175, 179))	('inflammation', 'Disease', (230, 242))	('inflammation', 'biological_process', 'GO:0006954', ('230', '242'))	('BAP1', 'Gene', '8314', (148, 152))	('suppression', 'NegReg', (183, 194))	('BAP1', 'Gene', (148, 152))	('BAP1', 'Gene', '8314', (39, 43))	('inflammation', 'Disease', 'MESH:D007249', (230, 242))	('UM', 'Phenotype', 'HP:0007716', (136, 138))	('NFkB pathway', 'Pathway', (202, 214))	('loss', 'Var', (140, 144))	('BAP1', 'Gene', (39, 43))
41771	31337000	Concluding, vascular density of UM relates to its genetic profile: Monosomy 3 and BAP1-loss are associated with an increased MVD, while an early event (gain of 8q) is not independently related to MVD, but may initiate a preparation phase towards development of vessels.	('BAP1', 'Gene', (82, 86))	('Monosomy 3', 'Var', (67, 77))	('MVD', 'MPA', (125, 128))	('UM', 'Phenotype', 'HP:0007716', (32, 34))	('8q', 'Chemical', '-', (160, 162))	('BAP1', 'Gene', '8314', (82, 86))	('initiate', 'Reg', (209, 217))
41788	31337000	As monosomy 3 and BAP1 loss are very important for prognosis in this disease, and they play a role in developing an inflammatory phenotype, we wondered if angiogenesis as demonstrated by MVD is similarly regulated by these genetic events.	('BAP1', 'Gene', '8314', (18, 22))	('angiogenesis', 'biological_process', 'GO:0001525', ('155', '167'))	('monosomy 3', 'Var', (3, 13))	('inflammatory', 'MPA', (116, 128))	('BAP1', 'Gene', (18, 22))	('loss', 'NegReg', (23, 27))	('play', 'Reg', (87, 91))
41810	31337000	Tumours with monosomy 3 (n = 21) had a higher MVD compared to tumours with disomy 3 (n = 22, p = 0.008).	('higher', 'PosReg', (39, 45))	('monosomy 3', 'Var', (13, 23))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('MVD', 'MPA', (46, 49))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('tumours', 'Disease', (62, 69))
41816	31337000	While monosomy 3 (or loss of BAP1) is considered a late event in the development of UM, gain of 8q is an early event.	('8q', 'Chemical', '-', (96, 98))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('monosomy 3', 'Var', (6, 16))	('BAP1', 'Gene', '8314', (29, 33))	('BAP1', 'Gene', (29, 33))	('loss', 'NegReg', (21, 25))
41827	31337000	Although we identified that gain of 8q is not independently related to MVD, a previous study demonstrated that gain of 8q is related to increased counts of (pro-angiogenic) macrophages.	('increased', 'PosReg', (136, 145))	('8q', 'Chemical', '-', (36, 38))	('gain', 'Var', (111, 115))	('8q', 'Chemical', '-', (119, 121))
41845	31337000	Indeed, a relation between high mRNA expression of VEGF-B and worse survival was found in patients with lung squamous cell carcinoma and non-ocular melanoma.	('mRNA expression', 'MPA', (32, 47))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (104, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('high', 'Var', (27, 31))	('lung squamous cell carcinoma', 'Disease', (104, 132))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (104, 132))	('non-ocular melanoma', 'Disease', 'MESH:D008545', (137, 156))	('ocular melanoma', 'Phenotype', 'HP:0007716', (141, 156))	('non-ocular melanoma', 'Disease', (137, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('VEGF-B', 'Gene', (51, 57))	('patients', 'Species', '9606', (90, 98))
41863	31337000	Makitie detected a weak correlation between MVD and increasing LBD as well as with prominence, but had a larger study group of 134 UM, and he did not know the BAP1 status.	('MVD', 'Var', (44, 47))	('UM', 'Phenotype', 'HP:0007716', (131, 133))	('BAP1', 'Gene', '8314', (159, 163))	('LBD', 'MPA', (63, 66))	('BAP1', 'Gene', (159, 163))
41946	30652059	Several chromosomal abnormalities associated with extranodal marginal zone B-cell lymphomas include trisomy 3, trisomy 18, and some chromosomal translocations (i.e., t[11;18]   API2-MALT1, t[14;18]   IGH-MALT1, t[1;14]   Bcl10-IGH, and t[3;14]   FoxP1-IGH).	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (8, 33))	('lymphoma', 'Phenotype', 'HP:0002665', (82, 90))	('IGH', 'Gene', (252, 255))	('FoxP1', 'Gene', (246, 251))	('FoxP1', 'Gene', '27086', (246, 251))	('MALT1', 'Gene', '10892', (182, 187))	('IGH', 'Gene', '3492', (200, 203))	('MALT1', 'Gene', '10892', (204, 209))	('trisomy', 'Disease', (100, 107))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (75, 91))	('lymphomas', 'Disease', 'MESH:D008223', (82, 91))	('Bcl10', 'Gene', (221, 226))	('lymphomas', 'Phenotype', 'HP:0002665', (82, 91))	('chromosomal abnormalities', 'Disease', (8, 33))	('IGH', 'Gene', (227, 230))	('API2', 'Gene', (177, 181))	('IGH', 'Gene', '3492', (252, 255))	('Bcl10', 'Gene', '8915', (221, 226))	('associated', 'Reg', (34, 44))	('API2', 'Gene', '330', (177, 181))	('MALT1', 'Gene', (182, 187))	('IGH', 'Gene', (200, 203))	('MALT1', 'Gene', (204, 209))	('trisomy 18', 'Var', (111, 121))	('lymphomas', 'Disease', (82, 91))	('IGH', 'Gene', '3492', (227, 230))
41947	30652059	Most of these chromosomal changes lead to an abnormal activation of the transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB).	('NF-kappaB', 'Gene', '4790', (158, 167))	('changes', 'Var', (26, 33))	('transcription factor', 'molecular_function', 'GO:0000981', ('72', '92'))	('NF-kappaB', 'Gene', (158, 167))	('activation', 'PosReg', (54, 64))	('transcription', 'biological_process', 'GO:0006351', ('72', '85'))
41953	30652059	Pathologic work-up includes cytomorphology and immunoprofiling with adjunctive tests, such as cytokine analysis, polymerase chain reaction (PCR) for immunoglobulin gene rearrangements, MYD88 mutational testing, and recently, bespoke next-generation sequencing panels.	('MYD88', 'Gene', '4615', (185, 190))	('MYD88', 'Gene', (185, 190))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('149', '163'))	('rearrangements', 'Var', (169, 183))	('mutational', 'Var', (191, 201))
41957	30652059	Skin and conjunctival melanomas share mutations that activate the mitogen-activated protein kinase (MAPK) pathway (i.e., BRAF, NRAS, NF1 genes), indicating skin and conjunctival melanocytes acquire similar ultraviolet radiation-induced mutations.	('BRAF', 'Gene', (121, 125))	('BRAF', 'Gene', '673', (121, 125))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('MAPK', 'molecular_function', 'GO:0004707', ('100', '104'))	('NF1', 'Gene', (133, 136))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('NRAS', 'Gene', (127, 131))	('NF1', 'Gene', '4763', (133, 136))	('activate', 'PosReg', (53, 61))	('mutations', 'Var', (38, 47))	('NRAS', 'Gene', '4893', (127, 131))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (9, 31))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (9, 30))	('conjunctival melanomas', 'Disease', (9, 31))
41959	30652059	By contrast, uveal melanomas have mutations in genes encoding G-coupled protein receptors (i.e., GNA11, GNAQ) or mutations in genes that signal through Galpha subunits (i.e., CYSLTR2, PLCB4).	('PLCB4', 'Gene', (184, 189))	('CYSLTR2', 'Gene', '57105', (175, 182))	('uveal melanomas', 'Disease', (13, 28))	('uveal melanomas', 'Phenotype', 'HP:0007716', (13, 28))	('GNAQ', 'Gene', '2776', (104, 108))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('CYSLTR2', 'Gene', (175, 182))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('mutations', 'Var', (113, 122))	('PLCB4', 'Gene', '5332', (184, 189))	('GNAQ', 'Gene', (104, 108))	('G-coupled protein receptors', 'Protein', (62, 89))	('uveal melanomas', 'Disease', 'MESH:C536494', (13, 28))	('Galpha', 'Gene', '8802', (152, 158))	('uveal melanoma', 'Phenotype', 'HP:0007716', (13, 27))	('Galpha', 'Gene', (152, 158))	('mutations', 'Var', (34, 43))
41961	30652059	A recent important new mouse uveal melanoma transgenic model confirms the contributions of GNA11 and BAP1 gene mutations in tumor growth, but also indicates our understanding of the genetic pathogenesis of uveal melanoma is not fully complete.	('mutations', 'Var', (111, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (206, 220))	('uveal melanoma', 'Disease', (206, 220))	('pathogenesis', 'biological_process', 'GO:0009405', ('190', '202'))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('GNA11', 'Gene', (91, 96))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('tumor', 'Disease', (124, 129))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('mouse', 'Species', '10090', (23, 28))	('BAP1', 'Gene', (101, 105))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (206, 220))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
41974	30652059	These include that there are random mutations in uveal melanoma, resulting in larger tumors giving rise to more metastases than smaller tumors, and that specific mutations are associated with peaks in uveal melanoma mortality at approximately 3 and 5 to 8 years after treatment.	('tumors', 'Disease', (136, 142))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('uveal melanoma', 'Disease', 'MESH:C536494', (201, 215))	('metastases', 'Disease', (112, 122))	('uveal melanoma', 'Disease', (201, 215))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Disease', (85, 91))	('uveal melanoma', 'Disease', 'MESH:C536494', (49, 63))	('uveal melanoma', 'Disease', (49, 63))	('uveal melanoma', 'Phenotype', 'HP:0007716', (201, 215))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (49, 63))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('mutations', 'Var', (162, 171))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
41999	30652059	The diagnosis is usually made by vitreous biopsy analyzed by cytology, including immunocytopathology, which considered to be a gold standard, by PCR for molecular analysis for the IGH gene rearrangement and mutated MYD88, and by cytokine analysis mainly by measuring the interleukin (IL)-10:IL-6 ratio.	('IGH', 'Gene', '3492', (180, 183))	('IL)-10', 'molecular_function', 'GO:0005141', ('284', '290'))	('IGH', 'Gene', (180, 183))	('mutated', 'Var', (207, 214))	('IL-6', 'Gene', (291, 295))	('MYD88', 'Gene', '4615', (215, 220))	('IL-6', 'Gene', '3569', (291, 295))	('IL-6', 'molecular_function', 'GO:0005138', ('291', '295'))	('MYD88', 'Gene', (215, 220))
42008	30652059	A number of highly effective cellular therapies have been developed, targeting overexpressed tumor-associated antigens and common mutations as well as the patients' personal 'mutanome', associated with the antigen processing and presentation machinery.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('mutations', 'Var', (130, 139))	('patients', 'Species', '9606', (155, 163))	('antigen processing and presentation', 'biological_process', 'GO:0019882', ('206', '241'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
42015	30652059	Unfortunately, uveal melanomas have the lowest number of mutations per megabase of solid cancers studied, and consequently the worst response to checkpoint inhibitors of any solid cancer.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('lowest', 'NegReg', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('response', 'MPA', (133, 141))	('uveal melanoma', 'Phenotype', 'HP:0007716', (15, 29))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('uveal melanomas', 'Disease', 'MESH:C536494', (15, 30))	('mutations', 'Var', (57, 66))	('cancer', 'Disease', (89, 95))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('solid cancers', 'Disease', (83, 96))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('uveal melanomas', 'Disease', (15, 30))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('cancer', 'Disease', (180, 186))	('uveal melanomas', 'Phenotype', 'HP:0007716', (15, 30))	('solid cancers', 'Disease', 'MESH:D009369', (83, 96))
42036	30652059	While the clinical results of agents targeting activated signaling pathways downstream of GNAQ, GNA11, PLCB4, and CYSLTR2 for the treatment of advanced uveal melanoma have been disappointing to date, novel therapeutic strategies addressing epigenetic aberrations in uveal melanoma have demonstrated promise preclinically, and now are being pursued in early phase clinical trials of bromodomain inhibitors and other epigenetic modifying agents.	('CYSLTR2', 'Gene', '57105', (114, 121))	('PLCB4', 'Gene', '5332', (103, 108))	('melanoma', 'Phenotype', 'HP:0002861', (272, 280))	('uveal melanoma', 'Disease', (152, 166))	('uveal melanoma', 'Disease', 'MESH:C536494', (152, 166))	('GNAQ', 'Gene', '2776', (90, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (152, 166))	('epigenetic aberrations', 'Var', (240, 262))	('CYSLTR2', 'Gene', (114, 121))	('uveal melanoma', 'Disease', (266, 280))	('uveal melanoma', 'Disease', 'MESH:C536494', (266, 280))	('uveal melanoma', 'Phenotype', 'HP:0007716', (266, 280))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('PLCB4', 'Gene', (103, 108))	('GNAQ', 'Gene', (90, 94))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))
42053	29982263	High expression of BNIP3 was demonstrated to be significantly associated with more pigment (P=0.018) and deeper scleral invasion (P=0.013).	('BNIP3', 'Gene', (19, 24))	('High expression', 'Var', (0, 15))	('deeper scleral invasion', 'CPA', (105, 128))	('more', 'PosReg', (78, 82))	('BNIP3', 'Gene', '664', (19, 24))	('associated', 'Reg', (62, 72))	('pigment', 'CPA', (83, 90))
42054	29982263	High expression of BNIP3 was also correlated with lower overall survival rate (P=0.006).	('BNIP3', 'Gene', (19, 24))	('lower', 'NegReg', (50, 55))	('High', 'Var', (0, 4))	('BNIP3', 'Gene', '664', (19, 24))	('overall survival rate', 'CPA', (56, 77))
42088	29982263	The correlation between BNIP3 high-/low-expression and clinicopathological factors was determined by the Fisher's test (Table 1).	('BNIP3', 'Gene', '664', (24, 29))	('BNIP3', 'Gene', (24, 29))	('high-/low-expression', 'Var', (30, 50))
42090	29982263	The high expression of BNIP3 was demonstrated to be significantly associated with more pigment (P=0.018) and deeper scleral invasion (P=0.013).	('BNIP3', 'Gene', '664', (23, 28))	('deeper scleral invasion', 'CPA', (109, 132))	('more', 'PosReg', (82, 86))	('associated', 'Reg', (66, 76))	('high expression', 'Var', (4, 19))	('pigment', 'CPA', (87, 94))	('BNIP3', 'Gene', (23, 28))
42091	29982263	The correlation between BNIP3 subgroups (high-/low-expression) and the 5-year overall survival (OS) rate of UM was analyzed with univariate analysis (Table 2).	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('BNIP3', 'Gene', (24, 29))	('high-/low-expression', 'NegReg', (41, 61))	('BNIP3', 'Gene', '664', (24, 29))	('high-/low-expression', 'Var', (41, 61))
42092	29982263	Patients with high expression of BNIP3 had poorer prognosis compared with those with low expression of BNIP3 (P=0.006, 5-year OS 25.0% vs. 82.7%) (Figure 2A).	('BNIP3', 'Gene', (33, 38))	('BNIP3', 'Gene', '664', (33, 38))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('BNIP3', 'Gene', (103, 108))	('poorer', 'NegReg', (43, 49))	('BNIP3', 'Gene', '664', (103, 108))
42100	29982263	In our study, we showed BNIP3 expression was predictive of unfavorable prognosis of UM with a very significant statistical difference (P=0.006).	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('BNIP3', 'Gene', '664', (24, 29))	('expression', 'Var', (30, 40))	('BNIP3', 'Gene', (24, 29))
42115	29303890	Comparative Outcomes and Toxicities for Ruthenium-106 versus Palladium-103 in the Treatment of Choroidal Melanoma For treatment of choroidal melanoma, Palladium-103 (103Pd) and Ruthenium-106 (106Ru) plaque brachytherapy demonstrates reduced toxicity compared to the historical standard Iodine-125 (125I).	('Ruthenium-106', 'Chemical', 'MESH:C000615522', (177, 190))	('toxicity', 'Disease', (241, 249))	('Melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('choroidal melanoma', 'Disease', 'MESH:D008545', (131, 149))	('Palladium-103', 'Var', (151, 164))	('Palladium-103', 'Chemical', 'MESH:C000615531', (151, 164))	('103Pd', 'Chemical', 'MESH:C000615531', (166, 171))	('Choroidal Melanoma', 'Disease', 'MESH:D008545', (95, 113))	('Palladium-103', 'Chemical', 'MESH:C000615531', (61, 74))	('Ruthenium-106', 'Chemical', 'MESH:C000615522', (40, 53))	('choroidal melanoma', 'Disease', (131, 149))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('Choroidal Melanoma', 'Phenotype', 'HP:0012054', (95, 113))	('Iodine', 'Chemical', 'MESH:D007455', (286, 292))	('Toxicities', 'Disease', (25, 35))	('Toxicities', 'Disease', 'MESH:D064420', (25, 35))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (131, 149))	('Choroidal Melanoma', 'Disease', (95, 113))	('toxicity', 'Disease', 'MESH:D064420', (241, 249))
42123	29303890	103Pd was associated with worse VA preservation (>=20/40) by year 3 (OR 3.8, 95% CI 1.01-14.31, p=0.048).	('VA preservation', 'CPA', (32, 47))	('103Pd', 'Chemical', 'MESH:C000615531', (0, 5))	('103Pd', 'Var', (0, 5))
42124	29303890	103Pd was associated with higher distant metastases-free survival (DMFS) in multivariate analysis (MVA) (HR 0.10, 95% CI 0.02-0.38, p<.001).	('higher', 'PosReg', (26, 32))	('103Pd', 'Var', (0, 5))	('metastases-free', 'Disease', 'MESH:D009362', (41, 56))	('metastases-free', 'Disease', (41, 56))	('103Pd', 'Chemical', 'MESH:C000615531', (0, 5))	('DMFS', 'Chemical', '-', (67, 71))
42139	29303890	The most commonly used radioisotopes for ocular melanoma brachytherapy are 106Ru, 103Pd, and 125I [please see Table 1 for a summary of the characteristics of these radioisotopes].	('ocular melanoma', 'Disease', (41, 56))	('106Ru', 'Var', (75, 80))	('103Pd', 'Var', (82, 87))	('ocular melanoma', 'Disease', 'MESH:D008545', (41, 56))	('ocular melanoma', 'Phenotype', 'HP:0007716', (41, 56))	('103Pd', 'Chemical', 'MESH:C000615531', (82, 87))	('125I', 'Var', (93, 97))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
42142	29303890	We recently reported an analysis of patients treated with plaque brachytherapy at Emory with either 103Pd vs 125I, which showed that 103Pd is independently associated with superior long term VA preservation and lower incidence of radiation retinopathy compared with 125I.	('patients', 'Species', '9606', (36, 44))	('retinopathy', 'Phenotype', 'HP:0000488', (240, 251))	('103Pd', 'Chemical', 'MESH:C000615531', (100, 105))	('radiation retinopathy', 'Disease', (230, 251))	('radiation retinopathy', 'Disease', 'MESH:D004194', (230, 251))	('VA preservation', 'CPA', (191, 206))	('103Pd', 'Chemical', 'MESH:C000615531', (133, 138))	('superior', 'PosReg', (172, 180))	('103Pd', 'Var', (133, 138))
42144	29303890	Dosimetric comparison of 106Ru and 125I for tumors <= 5mm shows translation of this sharp dose fall off to a clinically relevant reduction in radiation dose to normal eye structures.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('reduction', 'NegReg', (129, 138))	('radiation dose', 'MPA', (142, 156))	('fall', 'Phenotype', 'HP:0002527', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('fall off', 'NegReg', (95, 103))	('106Ru', 'Var', (25, 30))	('translation', 'biological_process', 'GO:0006412', ('64', '75'))
42145	29303890	Additionally, a recent retrospective report from MD Anderson demonstrates equivalent overall survival, improved enucleation free survival, and reduced radiation retinopathy in patients receiving 106Ru compared with patients receiving 125I plaque brachytherapy.	('patients', 'Species', '9606', (215, 223))	('patients', 'Species', '9606', (176, 184))	('106Ru', 'Var', (195, 200))	('improved', 'PosReg', (103, 111))	('radiation retinopathy', 'Disease', 'MESH:D004194', (151, 172))	('enucleation', 'biological_process', 'GO:0090601', ('112', '123'))	('radiation retinopathy', 'Disease', (151, 172))	('enucleation free survival', 'CPA', (112, 137))	('retinopathy', 'Phenotype', 'HP:0000488', (161, 172))	('reduced', 'NegReg', (143, 150))
42146	29303890	To date, there are no comparative reports of 106Ru and 103Pd brachytherapy for choroidal melanoma.	('choroidal melanoma', 'Phenotype', 'HP:0012054', (79, 97))	('103Pd', 'Chemical', 'MESH:C000615531', (55, 60))	('choroidal melanoma', 'Disease', 'MESH:D008545', (79, 97))	('choroidal melanoma', 'Disease', (79, 97))	('106Ru', 'Var', (45, 50))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))
42148	29303890	Therefore, in this multi-institutional study, we compare the visual acuity (VA), toxicity, and oncologic outcomes for patients with choroidal melanoma treated with 103Pd versus 106Ru plaque brachytherapy.	('choroidal melanoma', 'Disease', (132, 150))	('toxicity', 'Disease', 'MESH:D064420', (81, 89))	('103Pd', 'Chemical', 'MESH:C000615531', (164, 169))	('toxicity', 'Disease', (81, 89))	('103Pd', 'Var', (164, 169))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (132, 150))	('patients', 'Species', '9606', (118, 126))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('choroidal melanoma', 'Disease', 'MESH:D008545', (132, 150))
42158	29303890	Treatment data included date of plaque placement, radioisotope (106Ru or 103Pd), plaque size, RT dose, and distance of the tumor to the optic nerve (measured edge of tumor to center of disc) and macula (measured edge of tumor to fovea).	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('106Ru', 'Var', (64, 69))	('tumor', 'Disease', (220, 225))	('103Pd', 'Chemical', 'MESH:C000615531', (73, 78))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
42174	29303890	Five-year DMFS was higher in the 103Pd cohort, 96.5% vs 78.6% in the 106Ru cohort (p=0.0002) [Figure 1].	('103Pd', 'Var', (33, 38))	('higher', 'PosReg', (19, 25))	('DMFS', 'Chemical', '-', (10, 14))	('103Pd', 'Chemical', 'MESH:C000615531', (33, 38))	('DMFS', 'MPA', (10, 14))
42175	29303890	Five-year OS was also higher in the 103Pd cohort, 89.3% versus 80.2% in the 106Ru cohort (p=0.0347).	('103Pd', 'Chemical', 'MESH:C000615531', (36, 41))	('higher', 'PosReg', (22, 28))	('103Pd', 'Var', (36, 41))
42176	29303890	Fifteen patients (35.7%) treated with 106Ru and 56 patients (45.1%) treated with 103Pd developed radiation retinopathy.	('patients', 'Species', '9606', (8, 16))	('radiation retinopathy', 'Disease', (97, 118))	('106Ru', 'Var', (38, 43))	('retinopathy', 'Phenotype', 'HP:0000488', (107, 118))	('patients', 'Species', '9606', (51, 59))	('103Pd', 'Chemical', 'MESH:C000615531', (81, 86))	('radiation retinopathy', 'Disease', 'MESH:D004194', (97, 118))
42178	29303890	Table 3 summarizes rates of VA loss, preservation, and stability/improvement over 3 years for 106Ru and 103Pd.	('106Ru', 'Var', (94, 99))	('103Pd', 'Var', (104, 109))	('loss', 'NegReg', (31, 35))	('103Pd', 'Chemical', 'MESH:C000615531', (104, 109))
42189	29303890	In this multi-institutional analysis, we found that the 103Pd group had improved DMFS at 5 years (96.5% vs 78.6%, p=0.0002).	('DMFS', 'Chemical', '-', (81, 85))	('103Pd', 'Chemical', 'MESH:C000615531', (56, 61))	('improved', 'PosReg', (72, 80))	('DMFS', 'MPA', (81, 85))	('103Pd', 'Var', (56, 61))
42192	29303890	We report improved OS with 103Pd; however, we believe this is significant difference is confounded by the competing comorbidities and selection bias inherent to a retrospective analysis of all-cause mortality.	('103Pd', 'Var', (27, 32))	('103Pd', 'Chemical', 'MESH:C000615531', (27, 32))	('improved', 'PosReg', (10, 18))
42210	29303890	We compared oncologic, toxicity, VA acuity outcomes of patients treated with episcleral plaque brachytherapy for choroidal melanoma <=5mm in height, and found that 106Ru yielded similar rates but lower grades of radiation retinopathy, and superior VA preservation at 3 years, compared to 103Pd.	('toxicity', 'Disease', (23, 31))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (113, 131))	('VA preservation', 'CPA', (248, 263))	('lower', 'NegReg', (196, 201))	('choroidal melanoma', 'Disease', 'MESH:D008545', (113, 131))	('106Ru', 'Var', (164, 169))	('choroidal melanoma', 'Disease', (113, 131))	('retinopathy', 'Phenotype', 'HP:0000488', (222, 233))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('radiation retinopathy', 'Disease', 'MESH:D004194', (212, 233))	('patients', 'Species', '9606', (55, 63))	('radiation retinopathy', 'Disease', (212, 233))	('toxicity', 'Disease', 'MESH:D064420', (23, 31))	('103Pd', 'Chemical', 'MESH:C000615531', (288, 293))
42211	29303890	This advantage in terms of toxicity is perhaps compromised by lower DMFS compared to 103Pd, though the mechanism for this finding is unclear and most likely results from patient imbalances.	('toxicity', 'Disease', 'MESH:D064420', (27, 35))	('toxicity', 'Disease', (27, 35))	('imbalances', 'Phenotype', 'HP:0002172', (178, 188))	('lower', 'NegReg', (62, 67))	('103Pd', 'Chemical', 'MESH:C000615531', (85, 90))	('DMFS', 'Var', (68, 72))	('DMFS', 'Chemical', '-', (68, 72))	('patient', 'Species', '9606', (170, 177))
42214	29303890	Ruthenium-106 demonstrated lower grades of radiation retinopathy and improved 3-year visual acuity preservation--but also lower distant metastasis-free survival--compared to Palladium-103.	('lower', 'NegReg', (122, 127))	('Ruthenium-106', 'Chemical', 'MESH:C000615522', (0, 13))	('improved', 'PosReg', (69, 77))	('distant metastasis-free survival--', 'CPA', (128, 162))	('Ruthenium-106', 'Var', (0, 13))	('lower', 'NegReg', (27, 32))	('radiation retinopathy', 'Disease', 'MESH:D004194', (43, 64))	('visual acuity preservation', 'CPA', (85, 111))	('retinopathy', 'Phenotype', 'HP:0000488', (53, 64))	('radiation retinopathy', 'Disease', (43, 64))	('Palladium-103', 'Chemical', 'MESH:C000615531', (174, 187))
42220	28924151	We observed that hypermethylation of tumor suppressor genes is a frequent event in ocular tumors, but also unmethylation is associated with tumorogenesis.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('ocular tumors', 'Phenotype', 'HP:0100012', (83, 96))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumorogenesis', 'Disease', (140, 153))	('associated', 'Reg', (124, 134))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumorogenesis', 'Disease', 'MESH:D002471', (140, 153))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('37', '53'))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ocular tumors', 'Disease', (83, 96))	('tumor', 'Disease', (37, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('37', '53'))	('ocular tumors', 'Disease', 'MESH:D009369', (83, 96))	('hypermethylation', 'Var', (17, 33))	('tumor', 'Disease', (140, 145))
42221	28924151	Interestingly, unmethylation of the proto-oncogen RAB31 was a predictor of metastasis risk in uveal melanoma.	('RAB31', 'Gene', (50, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('uveal melanoma', 'Disease', (94, 108))	('RAB31', 'Gene', '11031', (50, 55))	('metastasis', 'CPA', (75, 85))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('unmethylation', 'Var', (15, 28))
42229	28924151	However, epigenetic studies are still in their infancy, and most of the research effort so far has focused on the role of epigenetics in regulating genes involved in retinal cell fate during embryogenesis, and the epigenetic alterations associated with tumoral disorders.	('tumoral disorders', 'Disease', 'MESH:D009369', (253, 270))	('associated', 'Reg', (237, 247))	('embryogenesis', 'biological_process', 'GO:0009792', ('191', '204'))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('epigenetic alterations', 'Var', (214, 236))	('embryogenesis', 'biological_process', 'GO:0009790', ('191', '204'))	('embryogenesis', 'biological_process', 'GO:0009793', ('191', '204'))	('tumoral disorders', 'Disease', (253, 270))
42231	28924151	In this study we assessed the epigenetic characterization of visual disorders from a broader perspective, investigating the involvement of genome-wide CpG methylation in ocular diseases associated with environmental factors, inflammation and aging (diabetic retinopathy, proliferative vitreoretinopathy), and in ocular tumors (uveal melanoma and retinoblastoma).	('proliferative vitreoretinopathy', 'Phenotype', 'HP:0007964', (271, 302))	('diabetic retinopathy', 'Disease', (249, 269))	('involvement', 'Reg', (124, 135))	('ocular tumors', 'Disease', (312, 325))	('visual disorders', 'Disease', (61, 77))	('ocular tumors', 'Disease', 'MESH:D009369', (312, 325))	('ocular tumors', 'Phenotype', 'HP:0100012', (312, 325))	('retinoblastoma', 'Phenotype', 'HP:0009919', (346, 360))	('methylation', 'Var', (155, 166))	('diabetic retinopathy', 'Disease', 'MESH:D003920', (249, 269))	('vitreoretinopathy', 'Phenotype', 'HP:0007773', (285, 302))	('melanoma', 'Phenotype', 'HP:0002861', (333, 341))	('proliferative vitreoretinopathy', 'Disease', (271, 302))	('retinopathy', 'Phenotype', 'HP:0000488', (291, 302))	('proliferative vitreoretinopathy', 'Disease', 'MESH:D018630', (271, 302))	('ocular diseases', 'Disease', (170, 185))	('associated', 'Reg', (186, 196))	('aging', 'biological_process', 'GO:0007568', ('242', '247'))	('visual disorders', 'Disease', 'MESH:D014786', (61, 77))	('tumors', 'Phenotype', 'HP:0002664', (319, 325))	('inflammation', 'biological_process', 'GO:0006954', ('225', '237'))	('uveal melanoma and retinoblastoma', 'Disease', 'MESH:C536494', (327, 360))	('retinopathy', 'Phenotype', 'HP:0000488', (258, 269))	('ocular diseases', 'Phenotype', 'HP:0000478', (170, 185))	('uveal melanoma', 'Phenotype', 'HP:0007716', (327, 341))	('ocular diseases', 'Disease', 'MESH:D005128', (170, 185))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('methylation', 'biological_process', 'GO:0032259', ('155', '166'))
42249	28924151	Finally, genetic mutations of more than 200 genes are known to be associated with retinal diseases (see RetNet database for additional details; https://sph.uth.edu/RetNet/home.html).	('retinal diseases', 'Disease', 'MESH:D012164', (82, 98))	('associated', 'Reg', (66, 76))	('retinal diseases', 'Phenotype', 'HP:0000479', (82, 98))	('retinal diseases', 'Disease', (82, 98))	('genetic mutations', 'Var', (9, 26))
42250	28924151	Indeed, gene set enrichment analysis (GSEA) revealed a statistically significant correlation (p < 0.001) between the hypomethylated ret-CpGs and the genes associated with retinal diseases (Fig.	('GSEA', 'Chemical', '-', (38, 42))	('retinal diseases', 'Disease', 'MESH:D012164', (171, 187))	('retinal diseases', 'Phenotype', 'HP:0000479', (171, 187))	('retinal diseases', 'Disease', (171, 187))	('significant correlation', 'Reg', (69, 92))	('hypomethylated', 'Var', (117, 131))	('ret-CpGs', 'Gene', (132, 140))
42254	28924151	The high sugar contents are associated with ischemic and exudative damage to retinal vessel causing visual loss and in latter stages of the disease, retinal detachment due to membrane formation and contraction.	('visual loss', 'Phenotype', 'HP:0000572', (100, 111))	('visual loss', 'Disease', (100, 111))	('retinal detachment', 'Disease', 'MESH:D012163', (149, 167))	('associated', 'Reg', (28, 38))	('membrane formation', 'CPA', (175, 193))	('membrane', 'cellular_component', 'GO:0016020', ('175', '183'))	('ischemic', 'Disease', 'MESH:D007511', (44, 52))	('retinal detachment', 'Phenotype', 'HP:0000541', (149, 167))	('high', 'Var', (4, 8))	('formation', 'biological_process', 'GO:0009058', ('184', '193'))	('sugar', 'Chemical', 'MESH:D000073893', (9, 14))	('visual loss', 'Disease', 'MESH:C531604', (100, 111))	('retinal detachment', 'Disease', (149, 167))	('ischemic', 'Disease', (44, 52))
42258	28924151	We observed a tendency towards hypomethylation in MAP3K1 promoter in NPDR (Supplementary Fig.	('MAP3K1', 'Gene', (50, 56))	('MAP3K', 'molecular_function', 'GO:0004709', ('50', '55'))	('MAP3K1', 'Gene', '4214', (50, 56))	('hypomethylation', 'Var', (31, 46))	('NPDR', 'Disease', (69, 73))
42264	28924151	As expected, genes associated with hematopoietic processes were hypomethylated in FVM with respect to PVR, including transcription factors (ETS1, HES5) or proteins required for hematopoietic stem cell renewal and differentiation (PRDM16) (Fig.	('ETS1', 'Gene', '2113', (140, 144))	('ETS1', 'Gene', (140, 144))	('PRDM16', 'Gene', (230, 236))	('HES5', 'Gene', (146, 150))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('PRDM16', 'Gene', '63976', (230, 236))	('hypomethylated', 'Var', (64, 78))	('stem cell renewal', 'biological_process', 'GO:0017145', ('191', '208'))	('FVM', 'Disease', (82, 85))	('HES5', 'Gene', '388585', (146, 150))
42265	28924151	3C) providing further evidence of the epigenetic control of angiogenesis in diabetic retinopathy progression.	('diabetic retinopathy', 'Disease', 'MESH:D003920', (76, 96))	('angiogenesis', 'biological_process', 'GO:0001525', ('60', '72'))	('epigenetic', 'Var', (38, 48))	('retinopathy', 'Phenotype', 'HP:0000488', (85, 96))	('diabetic retinopathy', 'Disease', (76, 96))
42273	28924151	In contrast to the methylation changes associated with non-tumoral diseases, 45% of the UM-PVRs were hypermethylated in cancer (829 hypermethylated and 1012 hypomethylated CpGs in uveal melanoma).	('UM-PVRs', 'Gene', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('hypermethylated', 'Var', (132, 147))	('non-tumoral diseases', 'Disease', 'MESH:D009369', (55, 75))	('uveal melanoma', 'Disease', (180, 194))	('uveal melanoma', 'Disease', 'MESH:C536494', (180, 194))	('uveal melanoma', 'Phenotype', 'HP:0007716', (180, 194))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('non-tumoral diseases', 'Disease', (55, 75))	('hypomethylated', 'Var', (157, 171))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
42274	28924151	GO annotations of the hypermethylated UM-CpGs in cancer showed an enrichment of functions associated with cell differentiation, cell development and signal regulation (Fig.	('UM-CpGs', 'Gene', (38, 45))	('cell development', 'biological_process', 'GO:0048468', ('128', '144'))	('hypermethylated', 'Var', (22, 37))	('cell differentiation', 'CPA', (106, 126))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cell differentiation', 'biological_process', 'GO:0030154', ('106', '126'))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('regulation', 'biological_process', 'GO:0065007', ('156', '166'))	('cancer', 'Disease', (49, 55))	('cell development', 'CPA', (128, 144))
42277	28924151	Notably, hypermethylation of ITGA7, NDRG2 and PITX2 was associated with decreased gene expression (Fig.	('ITGA7', 'Gene', (29, 34))	('PITX2', 'Gene', '5308', (46, 51))	('gene expression', 'MPA', (82, 97))	('decreased', 'NegReg', (72, 81))	('ITGA7', 'Gene', '3679', (29, 34))	('hypermethylation', 'Var', (9, 25))	('PITX2', 'Gene', (46, 51))	('NDRG2', 'Gene', '57447', (36, 41))	('gene expression', 'biological_process', 'GO:0010467', ('82', '97'))	('NDRG2', 'Gene', (36, 41))
42281	28924151	The widespread hypermethylation of ITGA7, NDRG2 and PITX2 observed prompted us to consider whether it was correlated with clinicopathological and molecular features.	('NDRG2', 'Gene', (42, 47))	('ITGA7', 'Gene', '3679', (35, 40))	('PITX2', 'Gene', (52, 57))	('hypermethylation', 'Var', (15, 31))	('NDRG2', 'Gene', '57447', (42, 47))	('ITGA7', 'Gene', (35, 40))	('PITX2', 'Gene', '5308', (52, 57))
42282	28924151	S4), suggesting that CpG hypermethylation of ITGA7, NDRG2 and PITX2 is an early phenomenon in uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('hypermethylation', 'Var', (25, 41))	('PITX2', 'Gene', '5308', (62, 67))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('uveal melanoma', 'Disease', (94, 108))	('ITGA7', 'Gene', '3679', (45, 50))	('PITX2', 'Gene', (62, 67))	('NDRG2', 'Gene', (52, 57))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('ITGA7', 'Gene', (45, 50))	('NDRG2', 'Gene', '57447', (52, 57))
42287	28924151	4G) demonstrated that RAB31 unmethylation is a predictor of poor outcome in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (76, 90))	('uveal melanoma', 'Disease', 'MESH:C536494', (76, 90))	('RAB31', 'Gene', '11031', (22, 27))	('uveal melanoma', 'Disease', (76, 90))	('unmethylation', 'Var', (28, 41))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('RAB31', 'Gene', (22, 27))
42291	28924151	Aging is an influent factor on the variance in the CpG methylation in our dataset of retinoblastoma patients (pediatric) and controls (adult retina) (Supplementary Fig.	('retinoblastoma', 'Phenotype', 'HP:0009919', (85, 99))	('Aging', 'biological_process', 'GO:0007568', ('0', '5'))	('patients', 'Species', '9606', (100, 108))	('retinoblastoma', 'Gene', '5925', (85, 99))	('methylation', 'Var', (55, 66))	('retinoblastoma', 'Gene', (85, 99))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))
42293	28924151	As the retina is a high methylated tissue, most of the CpG methylation changes were losses of methylation (169 hypermethylated and 385 hypomethylated CpGs in retinoblastoma).	('CpG', 'Gene', (55, 58))	('hypermethylated', 'Var', (111, 126))	('changes', 'Reg', (71, 78))	('methylation', 'biological_process', 'GO:0032259', ('94', '105'))	('retinoblastoma', 'Gene', (158, 172))	('methylation', 'MPA', (94, 105))	('losses', 'NegReg', (84, 90))	('retinoblastoma', 'Phenotype', 'HP:0009919', (158, 172))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('methylation', 'Var', (59, 70))	('retinoblastoma', 'Gene', '5925', (158, 172))
42294	28924151	GO annotations of the hypermethylated RB-CpGs in cancer showed an enrichment of the functions associated with DNA metabolic processes, DNA repair or response to DNA damage stimulus (Fig.	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('DNA repair', 'biological_process', 'GO:0006281', ('135', '145'))	('hypermethylated', 'Var', (22, 37))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('functions', 'MPA', (84, 93))	('DNA', 'cellular_component', 'GO:0005574', ('110', '113'))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('response to DNA damage stimulus', 'biological_process', 'GO:0006974', ('149', '180'))	('RB-CpGs', 'Gene', (38, 45))	('cancer', 'Disease', (49, 55))
42295	28924151	Taking this into consideration, we set out to identify how many of the CpG methylation detected in primary tumors could also be detected in blood samples from retinoblastoma patients.	('methylation', 'biological_process', 'GO:0032259', ('75', '86'))	('primary tumors', 'Disease', 'MESH:D009369', (99, 113))	('detected', 'Reg', (128, 136))	('methylation', 'Var', (75, 86))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('retinoblastoma', 'Gene', '5925', (159, 173))	('patients', 'Species', '9606', (174, 182))	('retinoblastoma', 'Gene', (159, 173))	('retinoblastoma', 'Phenotype', 'HP:0009919', (159, 173))	('primary tumors', 'Disease', (99, 113))
42303	28924151	Common CpG methylation changes in tumors and blood from patients with retinoblastoma relative to healthy controls reinforced the idea that the retinoblastoma has a specific methylation signature whose translational uses need to be explored.	('patients', 'Species', '9606', (56, 64))	('retinoblastoma', 'Gene', (143, 157))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('changes', 'Reg', (23, 30))	('retinoblastoma', 'Gene', '5925', (143, 157))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('methylation', 'biological_process', 'GO:0032259', ('11', '22'))	('methylation', 'biological_process', 'GO:0032259', ('173', '184'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (143, 157))	('retinoblastoma', 'Gene', (70, 84))	('retinoblastoma', 'Gene', '5925', (70, 84))	('methylation', 'Var', (11, 22))	('retinoblastoma', 'Phenotype', 'HP:0009919', (70, 84))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
42307	28924151	We found that CpG hypermethylation mediates silencing of PAX6 and its associated TFs in mature retina but not in the other eye tissues.	('silencing', 'Var', (44, 53))	('PAX6', 'Gene', '5080', (57, 61))	('hypermethylation', 'Var', (18, 34))	('PAX6', 'Gene', (57, 61))
42308	28924151	In accordance with this observation, silencing of Six6 or Rax occurs after the establishment of the eye field and prevents formation of ectopic eye structures.	('Six6', 'Gene', '4990', (50, 54))	('Rax', 'Gene', (58, 61))	('Six6', 'Gene', (50, 54))	('silencing', 'Var', (37, 46))	('Rax', 'Gene', '30062', (58, 61))	('prevents', 'NegReg', (114, 122))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))
42311	28924151	It has been previously described that low levels of serum folic acid and vitamin B12 (intermediates for DNA methylation that are found in many common nutrients) increase the risk of diabetic retinopathy and that global DNA methylation levels are associated with retinopathy in diabetic patients with progression in accordance with the severity of the disease.	('retinopathy', 'Disease', 'MESH:D012164', (191, 202))	('B12', 'Gene', '4709', (81, 84))	('retinopathy', 'Disease', (262, 273))	('DNA methylation', 'biological_process', 'GO:0006306', ('219', '234'))	('retinopathy', 'Phenotype', 'HP:0000488', (191, 202))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('retinopathy', 'Disease', 'MESH:D012164', (262, 273))	('DNA', 'cellular_component', 'GO:0005574', ('219', '222'))	('retinopathy', 'Phenotype', 'HP:0000488', (262, 273))	('diabetic retinopathy', 'Disease', (182, 202))	('associated with', 'Reg', (246, 261))	('diabetic', 'Disease', 'MESH:D003920', (277, 285))	('B12', 'Gene', (81, 84))	('diabetic', 'Disease', (277, 285))	('diabetic', 'Disease', 'MESH:D003920', (182, 190))	('folic acid', 'Chemical', 'MESH:D005492', (58, 68))	('diabetic', 'Disease', (182, 190))	('diabetic retinopathy', 'Disease', 'MESH:D003920', (182, 202))	('global DNA methylation levels', 'MPA', (212, 241))	('DNA methylation', 'biological_process', 'GO:0006306', ('104', '119'))	('retinopathy', 'Disease', (191, 202))	('low', 'Var', (38, 41))	('patients', 'Species', '9606', (286, 294))
42312	28924151	In this study, we found that CpG methylation regulates pathways that are used as pharmacological targets in diabetic retinopathy progression, such as angiogenesis (ETS1, HES5, PRDM16) (Fig.	('diabetic retinopathy', 'Disease', 'MESH:D003920', (108, 128))	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('HES5', 'Gene', '388585', (170, 174))	('methylation', 'Var', (33, 44))	('retinopathy', 'Phenotype', 'HP:0000488', (117, 128))	('ETS1', 'Gene', '2113', (164, 168))	('ETS1', 'Gene', (164, 168))	('PRDM16', 'Gene', (176, 182))	('HES5', 'Gene', (170, 174))	('pathways', 'Pathway', (55, 63))	('PRDM16', 'Gene', '63976', (176, 182))	('angiogenesis', 'Disease', (150, 162))	('regulates', 'Reg', (45, 54))	('diabetic retinopathy', 'Disease', (108, 128))	('angiogenesis', 'biological_process', 'GO:0001525', ('150', '162'))
42319	28924151	Specifically, unmethylation of the RAB31 promoter is a predictor of poor outcome in uveal melanoma.	('RAB31', 'Gene', '11031', (35, 40))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('uveal melanoma', 'Disease', (84, 98))	('RAB31', 'Gene', (35, 40))	('unmethylation', 'Var', (14, 27))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
42322	28924151	In addition, we demonstrate that CpG methylation changes are also found in the blood of retinoblastoma patients.	('methylation changes', 'Var', (37, 56))	('retinoblastoma', 'Gene', (88, 102))	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('retinoblastoma', 'Gene', '5925', (88, 102))	('patients', 'Species', '9606', (103, 111))	('retinoblastoma', 'Phenotype', 'HP:0009919', (88, 102))
42323	28924151	As the most notable example, we identify epigenetic deregulation of the mir-17-92 cluster in retinoblastoma in blood and primary tumors from patients (Fig.	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('primary tumors', 'Disease', (121, 135))	('patients', 'Species', '9606', (141, 149))	('retinoblastoma', 'Gene', (93, 107))	('primary tumors', 'Disease', 'MESH:D009369', (121, 135))	('epigenetic deregulation', 'Var', (41, 64))	('mir-17-92', 'Gene', '407975', (72, 81))	('retinoblastoma', 'Gene', '5925', (93, 107))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('retinoblastoma', 'Phenotype', 'HP:0009919', (93, 107))	('mir-17-92', 'Gene', (72, 81))
42325	28924151	Genetic inactivation of the miR-17-92 cluster is sufficient to prevent retinoblastoma formation in in vivo murine models, similarly to the effect of Rb, p53 or Dicer inactivation.	('Genetic inactivation', 'Var', (0, 20))	('p53', 'Gene', '22060', (153, 156))	('retinoblastoma', 'Phenotype', 'HP:0009919', (71, 85))	('miR-17-92', 'Gene', (28, 37))	('formation', 'biological_process', 'GO:0009058', ('86', '95'))	('Dicer', 'Gene', '23405', (160, 165))	('Dicer', 'Gene', (160, 165))	('p53', 'Gene', (153, 156))	('prevent', 'NegReg', (63, 70))	('retinoblastoma', 'Gene', '5925', (71, 85))	('murine', 'Species', '10090', (107, 113))	('retinoblastoma', 'Gene', (71, 85))
42360	28924151	The following expression data from the GEO Omnibus database were downloaded in order to extract the normalized expression values from the differentially methylated samples in each condition: GSE29801 (for normal retina and choroid), GSE51880 and GSE20986 (for uveal melanoma) and GSE5222 (for retinoblastoma).	('GSE51880', 'Var', (233, 241))	('melanoma', 'Phenotype', 'HP:0002861', (266, 274))	('retinoblastoma', 'Phenotype', 'HP:0009919', (293, 307))	('retinoblastoma', 'Gene', '5925', (293, 307))	('GSE5222', 'Var', (280, 287))	('uveal melanoma', 'Phenotype', 'HP:0007716', (260, 274))	('uveal melanoma', 'Disease', 'MESH:C536494', (260, 274))	('GSE29801', 'Var', (191, 199))	('retinoblastoma', 'Gene', (293, 307))	('uveal melanoma', 'Disease', (260, 274))	('GSE5222', 'Chemical', '-', (280, 287))	('GSE20986', 'Var', (246, 254))
42361	28924151	MirSeq data were downloaded from GEO Omnibus database under GSE18381 and GSE7072 for uveal melanoma and retinoblastoma samples, respectively.	('GSE7072', 'Chemical', '-', (73, 80))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('GSE18381', 'Var', (60, 68))	('GSE7072', 'Var', (73, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (85, 99))	('retinoblastoma', 'Phenotype', 'HP:0009919', (104, 118))	('uveal melanoma and retinoblastoma', 'Disease', 'MESH:C536494', (85, 118))
42388	26942004	High levels of MMP-2 are associated with an increased of invasion and metastasis in several types of cancer.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('MMP-2', 'Gene', '4313', (15, 20))	('High levels', 'Var', (0, 11))	('MMP-2', 'molecular_function', 'GO:0004228', ('15', '20'))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('increased', 'PosReg', (44, 53))	('MMP-2', 'Gene', (15, 20))
42396	26942004	C918 was provided by Dr. Robert Folberg (University of Illinois, Chicago) and Dr. Xiaoliang Leon Xu (Memorial Sloan Kettering Cancer Center, New York).	('Memorial Sloan Kettering Cancer', 'Disease', (101, 132))	('Memorial Sloan Kettering Cancer', 'Disease', 'MESH:D008569', (101, 132))	('Dr. Xiaoliang', 'Var', (78, 91))	('Cancer', 'Phenotype', 'HP:0002664', (126, 132))	('C918', 'CellLine', 'CVCL:8471', (0, 4))
42443	26942004	Secretion of MMP-2 by UM cells treated with zeaxanthin at 3.0 and 10.0 muM was significantly less than that from the negative control (cells not treated with zeaxanthin, P < 0.05).	('muM', 'Gene', (71, 74))	('less', 'NegReg', (93, 97))	('MMP-2', 'Gene', (13, 18))	('zeaxanthin', 'Chemical', 'MESH:D065146', (44, 54))	('MMP-2', 'molecular_function', 'GO:0004228', ('13', '18'))	('Secretion of', 'MPA', (0, 12))	('zeaxanthin', 'Chemical', 'MESH:D065146', (158, 168))	('MMP-2', 'Gene', '4313', (13, 18))	('UM', 'Phenotype', 'HP:0007716', (22, 24))	('muM', 'Gene', '56925', (71, 74))	('zeaxanthin', 'Var', (44, 54))
42445	26942004	The levels of NF-kappaB in nuclear extracts in cells cultured with zeaxanthin were only 42% of the control values (cells not treated with zeaxanthin).	('zeaxanthin', 'Chemical', 'MESH:D065146', (67, 77))	('NF-kappaB', 'Gene', '4790', (14, 23))	('zeaxanthin', 'Var', (67, 77))	('NF-kappaB', 'Gene', (14, 23))	('zeaxanthin', 'Chemical', 'MESH:D065146', (138, 148))
42468	26942004	NF-kappaB inhibitor BAY11-7082 markedly decreased the nuclear translocation of NF-kappaB and inhibits the migration of human UM cells.	('migration of human UM cells', 'CPA', (106, 133))	('UM', 'Phenotype', 'HP:0007716', (125, 127))	('NF-kappaB', 'Gene', '4790', (0, 9))	('NF-kappaB', 'Gene', (0, 9))	('BAY11-7082', 'Chemical', 'MESH:C434003', (20, 30))	('inhibits', 'NegReg', (93, 101))	('NF-kappaB', 'Gene', '4790', (79, 88))	('NF-kappaB inhibitor', 'biological_process', 'GO:0032088', ('0', '19'))	('BAY11-7082', 'Var', (20, 30))	('NF-kappaB', 'Gene', (79, 88))	('nuclear translocation', 'MPA', (54, 75))	('decreased', 'NegReg', (40, 49))	('human', 'Species', '9606', (119, 124))
42472	26942004	published their studies regarding the effects of zeaxanthin on the growth and invasion of UM in nude mice eyes and revealed that zeaxanthin significantly inhibited the invasion of uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('uveal melanoma', 'Phenotype', 'HP:0007716', (180, 194))	('uveal melanoma', 'Disease', (180, 194))	('uveal melanoma', 'Disease', 'MESH:C536494', (180, 194))	('invasion', 'CPA', (78, 86))	('UM', 'Phenotype', 'HP:0007716', (90, 92))	('inhibited', 'NegReg', (154, 163))	('zeaxanthin', 'Chemical', 'MESH:D065146', (129, 139))	('nude mice', 'Species', '10090', (96, 105))	('zeaxanthin', 'Var', (129, 139))	('zeaxanthin', 'Chemical', 'MESH:D065146', (49, 59))
42477	26942004	In conclusion, this study demonstrated that, in addition to the previously reported zeaxanthin-induced apoptosis effects on UM cells, zeaxanthin can also inhibit the cell migration and invasion of cultured human UM cells by the decrease of secretion of MMP-2.	('zeaxanthin', 'Chemical', 'MESH:D065146', (84, 94))	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('decrease', 'NegReg', (228, 236))	('secretion', 'biological_process', 'GO:0046903', ('240', '249'))	('human', 'Species', '9606', (206, 211))	('MMP-2', 'Gene', '4313', (253, 258))	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('MMP-2', 'molecular_function', 'GO:0004228', ('253', '258'))	('secretion', 'MPA', (240, 249))	('inhibit', 'NegReg', (154, 161))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('zeaxanthin', 'Chemical', 'MESH:D065146', (134, 144))	('cell migration', 'biological_process', 'GO:0016477', ('166', '180'))	('zeaxanthin', 'Var', (134, 144))	('MMP-2', 'Gene', (253, 258))	('UM', 'Phenotype', 'HP:0007716', (212, 214))
42480	22550165	Identification of unique MEK-dependent genes in GNAQ mutant uveal melanoma involved in cell growth, tumor cell invasion and MEK-resistance.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('cell growth', 'biological_process', 'GO:0016049', ('87', '98'))	('GNAQ', 'Gene', '2776', (48, 52))	('MEK', 'Gene', (25, 28))	('tumor', 'Disease', (100, 105))	('MEK', 'Gene', '5609', (25, 28))	('MEK', 'Gene', (124, 127))	('uveal melanoma', 'Disease', 'MESH:C536494', (60, 74))	('GNAQ', 'Gene', (48, 52))	('MEK', 'Gene', '5609', (124, 127))	('mutant', 'Var', (53, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('uveal melanoma', 'Disease', (60, 74))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
42482	22550165	Oncogenic mutations in the G protein alpha subunit q and 11 have been described in about 85% of uveal melanomas and confer constitutive activation.	('G protein alpha subunit q', 'Gene', (27, 52))	('described', 'Reg', (70, 79))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('uveal melanomas', 'Disease', (96, 111))	('uveal melanomas', 'Phenotype', 'HP:0007716', (96, 111))	('activation', 'PosReg', (136, 146))	('G protein alpha subunit q', 'Gene', '2776', (27, 52))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('mutations', 'Var', (10, 19))	('uveal melanomas', 'Disease', 'MESH:C536494', (96, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))
42485	22550165	We performed microarray analysis of UM cell lines with GNAQ mutations treated with the MEK inhibitor selumetinib.	('GNAQ', 'Gene', '2776', (55, 59))	('selumetinib', 'Chemical', 'MESH:C517975', (101, 112))	('MEK', 'Gene', (87, 90))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('MEK', 'Gene', '5609', (87, 90))	('GNAQ', 'Gene', (55, 59))	('mutations', 'Var', (60, 69))
42487	22550165	We found that GNAQ mutant cells have a MEK-dependent transcriptional output and identified a unique set of genes that are down-regulated by MEK inhibition, including the RNA helicase DDX21 and the cyclin dependent kinase regulator CDK5R1, while JUN was induced.	('DDX21', 'Gene', '9188', (183, 188))	('down-regulated', 'NegReg', (122, 136))	('MEK', 'Gene', (140, 143))	('CDK', 'molecular_function', 'GO:0004693', ('231', '234'))	('GNAQ', 'Gene', '2776', (14, 18))	('RNA helicase', 'Protein', (170, 182))	('cyclin', 'molecular_function', 'GO:0016538', ('197', '203'))	('CDK5R1', 'Gene', (231, 237))	('MEK', 'Gene', '5609', (140, 143))	('DDX21', 'Gene', (183, 188))	('RNA', 'cellular_component', 'GO:0005562', ('170', '173'))	('GNAQ', 'Gene', (14, 18))	('mutant', 'Var', (19, 25))	('CDK5R1', 'Gene', '8851', (231, 237))	('transcriptional output', 'MPA', (53, 75))	('inhibition', 'NegReg', (144, 154))	('MEK', 'Gene', (39, 42))	('MEK', 'Gene', '5609', (39, 42))
42490	22550165	Conclusions: Our findings define a subset of transcriptionally regulated genes by selumetinib in GNAQ mutant cells and provide new insights into understanding the biologic effect of MEK inhibition in this disease.	('mutant', 'Var', (102, 108))	('MEK', 'Gene', (182, 185))	('MEK', 'Gene', '5609', (182, 185))	('GNAQ', 'Gene', '2776', (97, 101))	('selumetinib', 'Gene', (82, 93))	('selumetinib', 'Chemical', 'MESH:C517975', (82, 93))	('GNAQ', 'Gene', (97, 101))
42491	22550165	The Ras/Raf/MEK/ERK pathway is often activated by genetic alterations in upstream signaling molecules, such as Ras and BRAF.	('Ras', 'Disease', (111, 114))	('ERK', 'Gene', '5594', (16, 19))	('signaling', 'biological_process', 'GO:0023052', ('82', '91'))	('activated', 'PosReg', (37, 46))	('BRAF', 'Gene', '673', (119, 123))	('ERK', 'Gene', (16, 19))	('Raf', 'Gene', '22882', (8, 11))	('genetic alterations', 'Var', (50, 69))	('BRAF', 'Gene', (119, 123))	('ERK', 'molecular_function', 'GO:0004707', ('16', '19'))	('MEK', 'Gene', (12, 15))	('MEK', 'Gene', '5609', (12, 15))	('Raf', 'Gene', (8, 11))
42492	22550165	Hyperactivation of this signaling cascade results in dysregulated cell proliferation and malignant transformation of a number of human tumors.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cell proliferation', 'CPA', (66, 84))	('Hyperactivation', 'Var', (0, 15))	('dysregulated', 'Var', (53, 65))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('results in', 'Reg', (42, 52))	('human', 'Species', '9606', (129, 134))	('signaling cascade', 'biological_process', 'GO:0007165', ('24', '41'))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))
42496	22550165	NRAS mutations have not been detected in UM, and BRAF mutations are considered rare; however, activation of the MAPK pathway by mutant GNAQ/11 appears to be critical for the development of this disease.	('GNAQ', 'Gene', (135, 139))	('MAPK', 'Gene', (112, 116))	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('NRAS', 'Gene', '4893', (0, 4))	('GNAQ', 'Gene', '2776', (135, 139))	('mutant', 'Var', (128, 134))	('MAPK', 'Gene', '5594', (112, 116))	('NRAS', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', (49, 53))	('MAPK', 'molecular_function', 'GO:0004707', ('112', '116'))	('activation', 'PosReg', (94, 104))
42499	22550165	The constitutively active mutant GNAQ and GNA11 have been reported to activate the ERK pathway, and knockdown of mutant GNAQ in UM cells resulted in MAP-kinase inhibition, reduced growth and induced apoptosis.	('inhibition', 'NegReg', (160, 170))	('apoptosis', 'biological_process', 'GO:0097194', ('199', '208'))	('activate', 'PosReg', (70, 78))	('GNA11', 'Gene', '2767', (42, 47))	('apoptosis', 'biological_process', 'GO:0006915', ('199', '208'))	('mutant', 'Var', (113, 119))	('induced', 'Reg', (191, 198))	('ERK', 'Gene', (83, 86))	('ERK', 'molecular_function', 'GO:0004707', ('83', '86'))	('MAP-kinase', 'MPA', (149, 159))	('growth', 'CPA', (180, 186))	('UM', 'Phenotype', 'HP:0007716', (128, 130))	('GNAQ', 'Gene', '2776', (33, 37))	('GNA11', 'Gene', (42, 47))	('GNAQ', 'Gene', '2776', (120, 124))	('reduced', 'NegReg', (172, 179))	('GNAQ', 'Gene', (33, 37))	('MAP', 'molecular_function', 'GO:0004239', ('149', '152'))	('GNAQ', 'Gene', (120, 124))	('apoptosis', 'CPA', (199, 208))	('ERK', 'Gene', '5594', (83, 86))
42500	22550165	However, the transcriptional output of ERK signaling downstream of mutant G proteins is not well characterized.	('ERK', 'Gene', '5594', (39, 42))	('G proteins', 'Protein', (74, 84))	('ERK', 'Gene', (39, 42))	('ERK', 'molecular_function', 'GO:0004707', ('39', '42'))	('mutant', 'Var', (67, 73))	('signaling', 'biological_process', 'GO:0023052', ('43', '52'))
42502	22550165	In particular, melanoma, thyroid and non-small cell lung cancer with mutant BRAFV600E have been shown to be sensitive to MEK inhibitors.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (37, 63))	('thyroid', 'Disease', (25, 32))	('mutant', 'Var', (69, 75))	('melanoma', 'Disease', (15, 23))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('BRAFV600E', 'Mutation', 'rs113488022', (76, 85))	('non-small cell lung cancer', 'Disease', (37, 63))	('MEK', 'Gene', (121, 124))	('BRAFV600E', 'Gene', (76, 85))	('MEK', 'Gene', '5609', (121, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (41, 63))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (37, 63))
42506	22550165	have found genes, including members of the dual specificity phosphatase and sprouty gene families, that were differentially regulated by MEK inhibition in BRAFV600E cells but not in receptor tyrosine kinase-driven tumor cells with similarly elevated levels of p-ERK.	('regulated', 'Reg', (124, 133))	('MEK', 'Gene', (137, 140))	('inhibition', 'NegReg', (141, 151))	('MEK', 'Gene', '5609', (137, 140))	('BRAFV600E', 'Var', (155, 164))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('BRAFV600E', 'Mutation', 'rs113488022', (155, 164))	('phosphatase', 'molecular_function', 'GO:0016791', ('60', '71'))	('sprouty gene families', 'Gene', (76, 97))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('p-ERK', 'Gene', '9451', (260, 265))	('tumor', 'Disease', (214, 219))	('p-ERK', 'Gene', (260, 265))	('ERK', 'molecular_function', 'GO:0004707', ('262', '265'))
42508	22550165	Here, we report that UM cells with GNAQ mutations are highly sensitive to MEK inhibition with selumetinib.	('MEK', 'Gene', '5609', (74, 77))	('selumetinib', 'Chemical', 'MESH:C517975', (94, 105))	('GNAQ', 'Gene', '2776', (35, 39))	('mutations', 'Var', (40, 49))	('UM', 'Phenotype', 'HP:0007716', (21, 23))	('GNAQ', 'Gene', (35, 39))	('sensitive', 'Reg', (61, 70))	('MEK', 'Gene', (74, 77))
42510	22550165	In addition, we identified several genes unique to GNAQ mutant cells, which are involved in proliferation and tumor cell invasion.	('GNAQ', 'Gene', '2776', (51, 55))	('mutant', 'Var', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('GNAQ', 'Gene', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
42513	22550165	UM cell lines have been sequenced for the presence of activating mutations in codons 209 (exon 5) and 183 (exon 4) of GNAQ and GNA11.	('activating', 'PosReg', (54, 64))	('GNAQ', 'Gene', (118, 122))	('GNAQ', 'Gene', '2776', (118, 122))	('GNA11', 'Gene', '2767', (127, 132))	('GNA11', 'Gene', (127, 132))	('mutations in', 'Var', (65, 77))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
42514	22550165	Two cell lines had Q209L mutation (92.1, Mel202), while Omm1.3 and Mel270 had Q209P mutation.	('Q209L mutation', 'Var', (19, 33))	('Q209L', 'Mutation', 'rs1057519742', (19, 24))	('Q209P', 'Mutation', 'rs1057519742', (78, 83))	('Q209P', 'Var', (78, 83))
42515	22550165	None had GNA11 mutations.	('GNA11', 'Gene', (9, 14))	('mutations', 'Var', (15, 24))	('GNA11', 'Gene', '2767', (9, 14))
42527	22550165	Using a panel of UM cell lines expressing GNAQQ209L/P, mutant BRAFV600E or WT for both, we investigated the effects of MEK inhibition on cell viability with selumetinib.	('MEK', 'Gene', (119, 122))	('selumetinib', 'Chemical', 'MESH:C517975', (157, 168))	('MEK', 'Gene', '5609', (119, 122))	('BRAFV600E', 'Mutation', 'rs113488022', (62, 71))	('BRAFV600E', 'Gene', (62, 71))	('mutant', 'Var', (55, 61))	('GNAQQ209L', 'Chemical', '-', (42, 51))	('GNAQQ209L/P', 'Var', (42, 53))	('UM', 'Phenotype', 'HP:0007716', (17, 19))
42528	22550165	As shown in Figure 1A, the GNAQQ209L/P cells exhibited dose dependent decrease in cell viability at nanomolar concentrations (IC50<0.1 muM).	('cell viability', 'CPA', (82, 96))	('muM', 'Gene', (135, 138))	('muM', 'Gene', '56925', (135, 138))	('GNAQQ209L/P', 'Var', (27, 38))	('GNAQQ209L', 'Chemical', '-', (27, 36))	('decrease', 'NegReg', (70, 78))
42532	22550165	The effect of MEK inhibition on GNAQ mutant UM demonstrated an accumulation in the G1 phase of the cell cycle (Supplemental Fig.	('inhibition', 'NegReg', (18, 28))	('GNAQ', 'Gene', (32, 36))	('G1 phase of the cell cycle', 'CPA', (83, 109))	('cell cycle', 'biological_process', 'GO:0007049', ('99', '109'))	('accumulation', 'PosReg', (63, 75))	('GNAQ', 'Gene', '2776', (32, 36))	('MEK', 'Gene', (14, 17))	('mutant', 'Var', (37, 43))	('MEK', 'Gene', '5609', (14, 17))	('G1 phase', 'biological_process', 'GO:0051318', ('83', '91'))	('UM', 'Phenotype', 'HP:0007716', (44, 46))
42535	22550165	Suppression of GNAQ in WT and BRAFV600E cells did not inhibit pERK (Supplemental Fig.	('GNAQ', 'Gene', (15, 19))	('pERK', 'Gene', (62, 66))	('pERK', 'Gene', '9451', (62, 66))	('GNAQ', 'Gene', '2776', (15, 19))	('BRAFV600E', 'Var', (30, 39))	('BRAFV600E', 'Mutation', 'rs113488022', (30, 39))
42537	22550165	In addition, overexpression of a GnaqQ209L plasmid in a WT cell line (Supplemental Fig.	('Q209L', 'Mutation', 'rs1057519742', (37, 42))	('GnaqQ209L', 'Var', (33, 42))	('overexpression', 'PosReg', (13, 27))
42539	22550165	These results confirm that GNAQQ209L/P signals to MEK and specifically renders mutant cells susceptible to MEK inhibition, as reported by Van Raamsdonk et al.	('mutant', 'Var', (79, 85))	('GNAQQ209L/P', 'Var', (27, 38))	('MEK', 'Gene', (107, 110))	('MEK', 'Gene', '5609', (107, 110))	('GNAQQ209L', 'Chemical', '-', (27, 36))	('signals', 'Reg', (39, 46))	('MEK', 'Gene', (50, 53))	('MEK', 'Gene', '5609', (50, 53))	('renders', 'Reg', (71, 78))
42544	22550165	Identical parameters were used to define the set of genes regulated differentially by MEK inhibitor in the BRAFV600E and WT cell lines, and a direct comparison was performed to evaluate common genes among the genetic subgroups.	('MEK', 'Gene', (86, 89))	('BRAFV600E', 'Mutation', 'rs113488022', (107, 116))	('MEK', 'Gene', '5609', (86, 89))	('BRAFV600E', 'Var', (107, 116))
42548	22550165	Of note, several of the genes that were shared between GNAQQ209L/P and BRAFV600E cells were previously described ERK targets, such as CCND1, transcription factors ETV5, MYC, and genes involved in the feedback inhibition of MEK/ERK signaling, i.e.	('MYC', 'Gene', (169, 172))	('ERK', 'Gene', '5594', (113, 116))	('MEK', 'Gene', (223, 226))	('GNAQQ209L/P', 'Var', (55, 66))	('BRAFV600E', 'Mutation', 'rs113488022', (71, 80))	('ERK', 'Gene', (227, 230))	('signaling', 'biological_process', 'GO:0023052', ('231', '240'))	('ETV5', 'Gene', (163, 167))	('ERK', 'Gene', (113, 116))	('ERK', 'molecular_function', 'GO:0004707', ('227', '230'))	('GNAQQ209L', 'Chemical', '-', (55, 64))	('CCND1', 'Gene', '595', (134, 139))	('MYC', 'Gene', '4609', (169, 172))	('CCND1', 'Gene', (134, 139))	('BRAFV600E', 'Var', (71, 80))	('ERK', 'molecular_function', 'GO:0004707', ('113', '116'))	('ETV5', 'Gene', '2119', (163, 167))	('MEK', 'Gene', '5609', (223, 226))	('transcription', 'biological_process', 'GO:0006351', ('141', '154'))	('ERK', 'Gene', '5594', (227, 230))
42552	22550165	In the less sensitive WT cell line, pERK was slightly downregulated at 2 hours and quickly rebounded at later time points, while its inhibition was more complete in cells with BRAFV600E and GNAQQ209L/P mutations.	('GNAQQ209L/P mutations', 'Var', (190, 211))	('BRAFV600E', 'Var', (176, 185))	('BRAFV600E', 'Mutation', 'rs113488022', (176, 185))	('pERK', 'Gene', (36, 40))	('pERK', 'Gene', '9451', (36, 40))	('downregulated', 'NegReg', (54, 67))	('GNAQQ209L', 'Chemical', '-', (190, 199))
42553	22550165	Basal expression levels of ETV5, DUSP6 and SPRY2 proteins were almost undetectable in the WT cell line, while they were highly expressed in the mutant cells (both BRAFV600E and GNAQQ209L/P), confirming elevated transcriptional output of MEK signaling in these cells.	('GNAQQ209L', 'Chemical', '-', (177, 186))	('proteins', 'Protein', (49, 57))	('MEK', 'Gene', (237, 240))	('MEK', 'Gene', '5609', (237, 240))	('DUSP6', 'Gene', (33, 38))	('SPRY2', 'Gene', (43, 48))	('BRAFV600E', 'Mutation', 'rs113488022', (163, 172))	('DUSP6', 'Gene', '1848', (33, 38))	('ETV5', 'Gene', '2119', (27, 31))	('SPRY2', 'Gene', '10253', (43, 48))	('signaling', 'biological_process', 'GO:0023052', ('241', '250'))	('elevated', 'PosReg', (202, 210))	('ETV5', 'Gene', (27, 31))	('GNAQQ209L/P', 'Var', (177, 188))	('expression levels', 'MPA', (6, 23))
42554	22550165	Cyclin D1 was durably downregulated in BRAFV600E cells, while its expression rebounded in GNAQQ209L/P and WT cells at later time points.	('GNAQQ209L', 'Chemical', '-', (90, 99))	('Cyclin D1', 'Gene', '595', (0, 9))	('expression', 'MPA', (66, 76))	('BRAFV600E', 'Mutation', 'rs113488022', (39, 48))	('Cyclin', 'molecular_function', 'GO:0016538', ('0', '6'))	('GNAQQ209L/P', 'Var', (90, 101))	('BRAFV600E', 'Var', (39, 48))	('Cyclin D1', 'Gene', (0, 9))	('downregulated', 'NegReg', (22, 35))
42557	22550165	The high basal expression of these transcripts and their downregulation by selumetinib confirmed that the MEK/ERK pathway is active in GNAQQ209L/P cells, and that the transcriptional events described in GNAQQ209L/P are at least, in part, similar to reported MEK functional activation signatures.	('downregulation', 'NegReg', (57, 71))	('GNAQQ209L', 'Chemical', '-', (135, 144))	('ERK', 'Gene', (110, 113))	('active', 'PosReg', (125, 131))	('MEK', 'Gene', (106, 109))	('MEK', 'Gene', '5609', (106, 109))	('MEK', 'Gene', (258, 261))	('ERK', 'molecular_function', 'GO:0004707', ('110', '113'))	('MEK', 'Gene', '5609', (258, 261))	('selumetinib', 'Chemical', 'MESH:C517975', (75, 86))	('GNAQQ209L', 'Chemical', '-', (203, 212))	('GNAQQ209L/P', 'Var', (203, 214))	('expression', 'MPA', (15, 25))	('ERK', 'Gene', '5594', (110, 113))	('GNAQQ209L/P', 'Var', (135, 146))
42558	22550165	reported a signature of 52 MEK-dependent genes in BRAFV600E cells, of which 19 are represented among our 345 genes (5.5%) and are significantly over-enriched (p<0.0001).	('MEK', 'Gene', '5609', (27, 30))	('BRAFV600E', 'Var', (50, 59))	('BRAFV600E', 'Mutation', 'rs113488022', (50, 59))	('MEK', 'Gene', (27, 30))
42561	22550165	Immunoblot detection showed that DDX21 and CDK5R1 protein levels were downregulated in GNAQQ209L/Pcells after MEK inhibition over time, but not in the BRAFV600E and WT cell lines (Fig.	('DDX21', 'Gene', '9188', (33, 38))	('BRAFV600E', 'Mutation', 'rs113488022', (151, 160))	('CDK5R1', 'Gene', (43, 49))	('protein levels', 'MPA', (50, 64))	('GNAQQ209L/Pcells', 'Var', (87, 103))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('CDK5R1', 'Gene', '8851', (43, 49))	('DDX21', 'Gene', (33, 38))	('downregulated', 'NegReg', (70, 83))	('MEK', 'Gene', (110, 113))	('MEK', 'Gene', '5609', (110, 113))	('GNAQQ209L', 'Chemical', '-', (87, 96))	('CDK', 'molecular_function', 'GO:0004693', ('43', '46'))
42564	22550165	In the BRAFV600E cells there was a decrease in mRNA levels, but generally to a lesser extent than the GNAQQ209L/P cells and this was associated with relatively minor changes in the protein levels of DDX21 and CDK5R1 (Fig.	('BRAFV600E', 'Var', (7, 16))	('BRAFV600E', 'Mutation', 'rs113488022', (7, 16))	('GNAQQ209L', 'Chemical', '-', (102, 111))	('decrease', 'NegReg', (35, 43))	('CDK5R1', 'Gene', (209, 215))	('protein levels', 'MPA', (181, 195))	('DDX21', 'Gene', '9188', (199, 204))	('mRNA levels', 'MPA', (47, 58))	('CDK5R1', 'Gene', '8851', (209, 215))	('DDX21', 'Gene', (199, 204))	('protein', 'cellular_component', 'GO:0003675', ('181', '188'))	('CDK', 'molecular_function', 'GO:0004693', ('209', '212'))
42565	22550165	Also, JUN was induced upon treatment in GNAQQ209L/P cells, while it was profoundly decreased in BRAFV600E (Fig.	('GNAQQ209L/P', 'Var', (40, 51))	('GNAQQ209L', 'Chemical', '-', (40, 49))	('BRAFV600E', 'Var', (96, 105))	('BRAFV600E', 'Mutation', 'rs113488022', (96, 105))	('decreased', 'NegReg', (83, 92))	('JUN', 'MPA', (6, 9))	('induced', 'Reg', (14, 21))
42566	22550165	To prove specificity of MEK-dependent signaling downstream of GNAQ and to exclude drug unrelated effects, the expression levels of these genes were analyzed in cells after GNAQ knock down.	('GNAQ', 'Gene', '2776', (62, 66))	('GNAQ', 'Gene', '2776', (172, 176))	('MEK', 'Gene', (24, 27))	('MEK', 'Gene', '5609', (24, 27))	('knock down', 'Var', (177, 187))	('GNAQ', 'Gene', (62, 66))	('GNAQ', 'Gene', (172, 176))	('signaling', 'biological_process', 'GO:0023052', ('38', '47'))
42569	22550165	Consistent with the effects of selumetinib, CDK5R1 and DDX21 were downregulated in the GNAQQ209L/P cells, while c-Jun was increased, though less than was observed with drug alone (Fig.	('c-Jun', 'Gene', '3725', (112, 117))	('DDX21', 'Gene', (55, 60))	('CDK5R1', 'Gene', (44, 50))	('downregulated', 'NegReg', (66, 79))	('GNAQQ209L', 'Chemical', '-', (87, 96))	('CDK5R1', 'Gene', '8851', (44, 50))	('c-Jun', 'Gene', (112, 117))	('GNAQQ209L/P', 'Var', (87, 98))	('increased', 'PosReg', (122, 131))	('DDX21', 'Gene', '9188', (55, 60))	('CDK', 'molecular_function', 'GO:0004693', ('44', '47'))	('selumetinib', 'Chemical', 'MESH:C517975', (31, 42))
42571	22550165	Both the GNAQQ209L/P and BRAFV600E cells were sensitive to increasing concentrations of the drug (Supplemental Fig.	('GNAQQ209L/P', 'Var', (9, 20))	('BRAFV600E', 'Var', (25, 34))	('BRAFV600E', 'Mutation', 'rs113488022', (25, 34))	('GNAQQ209L', 'Chemical', '-', (9, 18))
42572	22550165	In terms of protein expression, the change in c-jun (induction in GNAQQ209L/P, suppression in BRAFV600E, and no change in WT) was similar to selumetinib, but suppression of CDK5R1 and DDX21 was observed in both GNAQQ209L/P and BRAFV600E cell lines (Supplemental Fig.	('CDK', 'molecular_function', 'GO:0004693', ('173', '176'))	('selumetinib', 'Chemical', 'MESH:C517975', (141, 152))	('GNAQQ209L', 'Chemical', '-', (211, 220))	('protein', 'cellular_component', 'GO:0003675', ('12', '19'))	('DDX21', 'Gene', '9188', (184, 189))	('CDK5R1', 'Gene', (173, 179))	('BRAFV600E', 'Var', (227, 236))	('BRAFV600E', 'Mutation', 'rs113488022', (227, 236))	('GNAQQ209L/P', 'Var', (66, 77))	('BRAFV600E', 'Mutation', 'rs113488022', (94, 103))	('DDX21', 'Gene', (184, 189))	('CDK5R1', 'Gene', '8851', (173, 179))	('GNAQQ209L', 'Chemical', '-', (66, 75))	('suppression', 'NegReg', (158, 169))	('c-jun', 'Gene', '3725', (46, 51))	('c-jun', 'Gene', (46, 51))	('GNAQQ209L/P', 'Var', (211, 222))
42573	22550165	Interestingly, PD0325901 inhibited pERK in the WT cell line but this resulted in essentially no reduction in cell viability, nor a decrease in cyclin D1 expression.	('PD0325901', 'Var', (15, 24))	('PD0325901', 'Chemical', 'MESH:C506614', (15, 24))	('pERK', 'Gene', '9451', (35, 39))	('pERK', 'Gene', (35, 39))	('cyclin D1', 'Gene', '595', (143, 152))	('cyclin', 'molecular_function', 'GO:0016538', ('143', '149'))	('expression', 'MPA', (153, 163))	('inhibited', 'NegReg', (25, 34))	('decrease', 'NegReg', (131, 139))	('cyclin D1', 'Gene', (143, 152))	('reduction', 'NegReg', (96, 105))
42578	22550165	Three GNAQQ209L/P mutant cell lines, as well as BRAFV600E and WT cells, were transiently transfected with two different DDX21-specific or control siRNAs (Fig.	('BRAFV600E', 'Mutation', 'rs113488022', (48, 57))	('GNAQQ209L/P mutant', 'Var', (6, 24))	('DDX21', 'Gene', '9188', (120, 125))	('GNAQQ209L', 'Chemical', '-', (6, 15))	('DDX21', 'Gene', (120, 125))
42591	22550165	Interestingly, selumetinib inhibited migration of both GNAQQ209L/P and BRAFV600E, but not the WT cells (Supplemental Fig.	('migration', 'CPA', (37, 46))	('GNAQQ209L/P', 'Var', (55, 66))	('selumetinib', 'Chemical', 'MESH:C517975', (15, 26))	('BRAFV600E', 'Var', (71, 80))	('BRAFV600E', 'Mutation', 'rs113488022', (71, 80))	('inhibited', 'NegReg', (27, 36))	('GNAQQ209L', 'Chemical', '-', (55, 64))
42594	22550165	c-Jun was up-regulated in GNAQQ209L/P cells after selumetinib treatment, showing a differential regulation compared to cells with BRAFV600E.	('GNAQQ209L/P', 'Var', (26, 37))	('GNAQQ209L', 'Chemical', '-', (26, 35))	('c-Jun', 'Gene', '3725', (0, 5))	('selumetinib', 'Chemical', 'MESH:C517975', (50, 61))	('regulation', 'biological_process', 'GO:0065007', ('96', '106'))	('BRAFV600E', 'Mutation', 'rs113488022', (130, 139))	('c-Jun', 'Gene', (0, 5))	('up-regulated', 'PosReg', (10, 22))
42595	22550165	Knock down of c-Jun by two different siRNAs (Fig.	('c-Jun', 'Gene', (14, 19))	('Knock down', 'Var', (0, 10))	('c-Jun', 'Gene', '3725', (14, 19))
42598	22550165	In contrast, c-Jun did not seem to play a role in WT and BRAFV600E cells as its knockdown did not alter the sensitivity to the selumetinib when compared to control siRNA (Fig.	('knockdown', 'Var', (80, 89))	('c-Jun', 'Gene', '3725', (13, 18))	('sensitivity', 'MPA', (108, 119))	('BRAFV600E', 'Mutation', 'rs113488022', (57, 66))	('selumetinib', 'Chemical', 'MESH:C517975', (127, 138))	('c-Jun', 'Gene', (13, 18))
42600	22550165	Matched tumor biopsies are collected to examine target modulation between baseline and day 14 from patients with GNAQ/11 mutations receiving selumetinib.	('selumetinib', 'Chemical', 'MESH:C517975', (141, 152))	('GNAQ', 'Gene', (113, 117))	('mutations', 'Var', (121, 130))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('patients', 'Species', '9606', (99, 107))	('GNAQ', 'Gene', '2776', (113, 117))	('tumor', 'Disease', (8, 13))
42608	22550165	Here we report that cells with GNAQQ209L/P mutations are sensitive to MEK inhibition by selumetinib, and sensitization was associated with a MEK-dependent gene expression profile.	('gene expression', 'biological_process', 'GO:0010467', ('155', '170'))	('sensitive', 'MPA', (57, 66))	('MEK', 'Gene', (141, 144))	('MEK', 'Gene', '5609', (141, 144))	('inhibition', 'NegReg', (74, 84))	('MEK', 'Gene', (70, 73))	('selumetinib', 'Chemical', 'MESH:C517975', (88, 99))	('sensitization', 'biological_process', 'GO:0046960', ('105', '118'))	('MEK', 'Gene', '5609', (70, 73))	('GNAQQ209L', 'Chemical', '-', (31, 40))	('GNAQQ209L/P mutations', 'Var', (31, 52))
42609	22550165	Some features of this profile are overlapping with that elicited in BRAFV600E UM cells and other cell types, which supports the MEK dependence of GNAQQ209L/P cells.	('MEK', 'Gene', (128, 131))	('MEK', 'Gene', '5609', (128, 131))	('GNAQQ209L/P', 'Var', (146, 157))	('UM', 'Phenotype', 'HP:0007716', (78, 80))	('GNAQQ209L', 'Chemical', '-', (146, 155))	('BRAFV600E', 'Mutation', 'rs113488022', (68, 77))
42611	22550165	The Ets variant transcription factor ETV5 was also regulated by MEK inhibition, along with cell division cycle associated protein 7 (CDCA7), the proto-oncogene MYC, and the solute carrier family 16, member 6 (SLC16A6).	('MEK', 'Gene', (64, 67))	('transcription factor', 'molecular_function', 'GO:0000981', ('16', '36'))	('ETV5', 'Gene', (37, 41))	('regulated', 'Reg', (51, 60))	('variant', 'Var', (8, 15))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('cell division cycle associated protein 7', 'Gene', (91, 131))	('CDCA7', 'Gene', (133, 138))	('cell division cycle', 'biological_process', 'GO:0007049', ('91', '110'))	('carrier', 'molecular_function', 'GO:0005215', ('180', '187'))	('SLC16A6', 'Gene', '9120', (209, 216))	('MYC', 'Gene', (160, 163))	('SLC16A6', 'Gene', (209, 216))	('transcription', 'biological_process', 'GO:0006351', ('16', '29'))	('ETV5', 'Gene', '2119', (37, 41))	('cell division cycle associated protein 7', 'Gene', '83879', (91, 131))	('inhibition', 'NegReg', (68, 78))	('Ets', 'Gene', (4, 7))	('CDCA7', 'Gene', '83879', (133, 138))	('MEK', 'Gene', '5609', (64, 67))	('solute carrier family 16, member 6', 'Gene', '9120', (173, 207))	('MYC', 'Gene', '4609', (160, 163))
42612	22550165	Additional features of the MEK profile were identified as specific for GNAQQ209L/P cells.	('MEK', 'Gene', '5609', (27, 30))	('GNAQQ209L/P cells', 'Var', (71, 88))	('MEK', 'Gene', (27, 30))	('GNAQQ209L', 'Chemical', '-', (71, 80))
42615	22550165	Interestingly, it has been reported that mutant K-RAS regulates expression/stability of CDK5 and CDK5R1 (p35) to increase malignant progression and invasion of pancreatic cancer cells.	('p35', 'cellular_component', 'GO:0043514', ('105', '108'))	('malignant progression', 'CPA', (122, 143))	('CDK5', 'Gene', (97, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (160, 177))	('CDK', 'molecular_function', 'GO:0004693', ('97', '100'))	('CDK5R1', 'Gene', (97, 103))	('mutant', 'Var', (41, 47))	('CDK5', 'Gene', (88, 92))	('K-RAS', 'Gene', (48, 53))	('p35', 'Gene', '8851', (105, 108))	('CDK5', 'Gene', '1020', (97, 101))	('p35', 'Gene', (105, 108))	('CDK5', 'Gene', '1020', (88, 92))	('K-RAS', 'Gene', '3845', (48, 53))	('CDK5R1', 'Gene', '8851', (97, 103))	('pancreatic cancer', 'Disease', 'MESH:D010190', (160, 177))	('increase', 'PosReg', (113, 121))	('p35', 'cellular_component', 'GO:0070745', ('105', '108'))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('regulates', 'Reg', (54, 63))	('CDK', 'molecular_function', 'GO:0004693', ('88', '91'))	('expression/stability', 'MPA', (64, 84))	('pancreatic cancer', 'Disease', (160, 177))	('invasion', 'CPA', (148, 156))
42622	22550165	In contrast, c-Jun was induced by MEK inhibition in GNAQQ209L/P UM cells, suggesting a differential regulation of the ERK/JNK pathway.	('ERK', 'Gene', '5594', (118, 121))	('JNK', 'Gene', '5599', (122, 125))	('JNK', 'molecular_function', 'GO:0004705', ('122', '125'))	('UM', 'Phenotype', 'HP:0007716', (64, 66))	('c-Jun', 'Gene', '3725', (13, 18))	('MEK', 'Gene', (34, 37))	('ERK', 'Gene', (118, 121))	('MEK', 'Gene', '5609', (34, 37))	('ERK', 'molecular_function', 'GO:0004707', ('118', '121'))	('regulation', 'biological_process', 'GO:0065007', ('100', '110'))	('GNAQQ209L', 'Chemical', '-', (52, 61))	('inhibition', 'NegReg', (38, 48))	('GNAQQ209L/P', 'Var', (52, 63))	('JNK', 'Gene', (122, 125))	('c-Jun', 'Gene', (13, 18))
42624	22550165	The upregulation of c-Jun could represent an alternative route to cell proliferation, which would explain the relative lower sensitivity to selumetinib of GNAQQ209L/P cells as compared to BRAFV600E cells.	('lower', 'NegReg', (119, 124))	('cell proliferation', 'CPA', (66, 84))	('c-Jun', 'Gene', '3725', (20, 25))	('c-Jun', 'Gene', (20, 25))	('GNAQQ209L/P', 'Var', (155, 166))	('sensitivity', 'MPA', (125, 136))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('selumetinib', 'Chemical', 'MESH:C517975', (140, 151))	('upregulation', 'PosReg', (4, 16))	('BRAFV600E', 'Mutation', 'rs113488022', (188, 197))	('GNAQQ209L', 'Chemical', '-', (155, 164))
42625	22550165	Interestingly, increased expression of c-Jun has also been reported in colorectal cancer cells with KRAS or BRAF mutations after acquired resistance to selumetinib.	('KRAS', 'Gene', (100, 104))	('colorectal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('KRAS', 'Gene', '3845', (100, 104))	('expression', 'MPA', (25, 35))	('c-Jun', 'Gene', (39, 44))	('selumetinib', 'Chemical', 'MESH:C517975', (152, 163))	('increased', 'PosReg', (15, 24))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('mutations', 'Var', (113, 122))	('BRAF', 'Gene', '673', (108, 112))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('BRAF', 'Gene', (108, 112))	('c-Jun', 'Gene', '3725', (39, 44))
42627	22550165	This would suggest that targeting c-Jun in the presence of MEK inhibition would result in enhanced anti-tumor effects and may prevent selumetinib resistance.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('MEK', 'Gene', (59, 62))	('prevent', 'NegReg', (126, 133))	('tumor', 'Disease', (104, 109))	('MEK', 'Gene', '5609', (59, 62))	('c-Jun', 'Gene', '3725', (34, 39))	('enhanced', 'PosReg', (90, 98))	('selumetinib resistance', 'MPA', (134, 156))	('inhibition', 'Var', (63, 73))	('c-Jun', 'Gene', (34, 39))	('selumetinib', 'Chemical', 'MESH:C517975', (134, 145))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
42628	22550165	In conclusion, our findings define a unique molecular profile of MEK inhibition by selumetinib in UM cells with mutant GNAQ, and point to a set of transcriptionally modified genes that could have an impact on the activity of this agent in this disease.	('selumetinib', 'Chemical', 'MESH:C517975', (83, 94))	('MEK', 'Gene', (65, 68))	('GNAQ', 'Gene', (119, 123))	('MEK', 'Gene', '5609', (65, 68))	('mutant', 'Var', (112, 118))	('UM', 'Phenotype', 'HP:0007716', (98, 100))	('GNAQ', 'Gene', '2776', (119, 123))	('inhibition', 'NegReg', (69, 79))	('selumetinib', 'Gene', (83, 94))
42630	22550165	Recently, it has been demonstrated that 85% of uveal melanomas have oncogenic mutations in the GNAQ/11, which activate the MAPK pathway.	('MAPK', 'Gene', (123, 127))	('uveal melanomas', 'Disease', (47, 62))	('uveal melanomas', 'Phenotype', 'HP:0007716', (47, 62))	('MAPK', 'molecular_function', 'GO:0004707', ('123', '127'))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('GNAQ', 'Gene', (95, 99))	('activate', 'PosReg', (110, 118))	('mutations', 'Var', (78, 87))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanomas', 'Disease', 'MESH:C536494', (47, 62))	('MAPK', 'Gene', '5594', (123, 127))	('GNAQ', 'Gene', '2776', (95, 99))
42631	22550165	Here, we analyzed the transcriptional profile of GNAQ mutant cell lines treated with selumetinib, a MEK inhibitor, currently in clinical trial for uveal melanoma.	('uveal melanoma', 'Disease', (147, 161))	('MEK', 'Gene', (100, 103))	('GNAQ', 'Gene', '2776', (49, 53))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('MEK', 'Gene', '5609', (100, 103))	('selumetinib', 'Chemical', 'MESH:C517975', (85, 96))	('GNAQ', 'Gene', (49, 53))	('mutant', 'Var', (54, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (147, 161))	('uveal melanoma', 'Disease', 'MESH:C536494', (147, 161))
42659	19557412	As a result, in Ii- vaccine cells, MHC II molecules have an altered intracellular trafficking pattern relative to MHC II molecules in Ii+cells, consistent with our hypothesis that the absence of Ii facilitates T cell activation by re-directing MHC II molecules to different intracellular compartments where they bind atypical peptides.	('intracellular trafficking pattern', 'MPA', (68, 101))	('absence', 'Var', (184, 191))	('MHC II', 'Gene', (244, 250))	('MHC II', 'Gene', (35, 41))	('intracellular', 'cellular_component', 'GO:0005622', ('274', '287'))	('MHC II', 'Gene', (114, 120))	('MHC II', 'Gene', '111364', (244, 250))	('MHC II', 'Gene', '111364', (114, 120))	('MHC II', 'Gene', '111364', (35, 41))	('T cell', 'CPA', (210, 216))	('intracellular', 'cellular_component', 'GO:0005622', ('68', '81'))	('altered', 'Reg', (60, 67))	('T cell activation', 'biological_process', 'GO:0042110', ('210', '227'))	('facilitates', 'PosReg', (198, 209))
42662	19557412	SUM159PT mammary carcinoma cells were cultured as described.	('carcinoma', 'Disease', (17, 26))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (9, 26))	('carcinoma', 'Disease', 'MESH:D002277', (17, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('SUM159PT', 'Var', (0, 8))
42696	19557412	After 1 h, monensin (Golgistop, BD Biosciences) was added to each well and the cells cultured for an additional 5 h. Six hours later, cells were harvested, washed and stained for cell surface markers CD3-biotin, CD4-FITC, CD8-FITC or CD56-FITC and SA-PerCP, or isotype controls, and analyzed by flow cytometry (Epics XL flow cytometer and Expo 32 software, Beckman/Coulter, Fullerton, CA).	('CD4', 'Gene', (212, 215))	('CD3-biotin', 'Chemical', '-', (200, 210))	('CD56', 'Gene', '4684', (234, 238))	('cell surface', 'cellular_component', 'GO:0009986', ('179', '191'))	('CD8', 'Gene', (222, 225))	('CD56', 'Gene', (234, 238))	('CD8', 'Gene', '925', (222, 225))	('CD4', 'Gene', '920', (212, 215))	('CD3-biotin', 'Var', (200, 210))	('SA-PerCP', 'Chemical', '-', (248, 256))
42709	19557412	Therefore, HLA-DR1 wild-type and HLA-DR1-eGFP fusion proteins are stably expressed in the uveal melanoma transductants, and the absence of Ii does not significantly impact MHC II cell surface expression.	('MHC II', 'Gene', '111364', (172, 178))	('absence', 'Var', (128, 135))	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('uveal melanoma', 'Disease', (90, 104))	('uveal melanoma', 'Disease', 'MESH:C536494', (90, 104))	('HLA', 'Gene', '3123', (33, 36))	('cell surface', 'cellular_component', 'GO:0009986', ('179', '191'))	('DR1', 'Gene', '1810', (15, 18))	('HLA', 'Gene', '3123', (11, 14))	('HLA', 'Gene', (33, 36))	('DR1', 'Gene', '1810', (37, 40))	('DR1', 'Gene', (37, 40))	('DR1', 'Gene', (15, 18))	('HLA', 'Gene', (11, 14))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('MHC II', 'Gene', (172, 178))
42750	19557412	The confocal experiments presented here demonstrate that the absence of Ii allows MHC II molecules to preferentially enter Rab3b+ secretory vesicles in addition to trafficking through the endocytic pathway.	('Rab3b', 'Gene', '5865', (123, 128))	('absence', 'Var', (61, 68))	('Rab3b', 'Gene', (123, 128))	('preferentially', 'PosReg', (102, 116))	('MHC II', 'Gene', (82, 88))	('MHC II', 'Gene', '111364', (82, 88))
42763	19557412	Therefore, the absence of the Ii chain not only facilitates the presentation of peptides derived from endogenous sources, but also re-directs MHC II molecules to a variant pathway where they potentially encounter and bind a different repertoire of peptides.	('MHC II', 'Gene', (142, 148))	('Ii chain', 'Protein', (30, 38))	('absence', 'Var', (15, 22))	('presentation of peptides', 'MPA', (64, 88))	('MHC II', 'Gene', '111364', (142, 148))	('facilitates', 'PosReg', (48, 59))	('encounter', 'Interaction', (203, 212))	('re-directs', 'PosReg', (131, 141))	('bind', 'Interaction', (217, 221))
42764	19557412	The variant trafficking pattern combined with the advantages of vaccine cells made from tumors from an immune privileged site may explain the immunogenicity of the MHC II uveal melanoma vaccines.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('MHC II uveal melanoma vaccines', 'Disease', (164, 194))	('uveal melanoma', 'Phenotype', 'HP:0007716', (171, 185))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('MHC II uveal melanoma vaccines', 'Disease', 'MESH:C536494', (164, 194))	('variant', 'Var', (4, 11))	('tumors', 'Disease', (88, 94))
42766	19557412	Our finding that CD8+ T cells activated by the vaccines are cytolytic for MHC I mismatched, as well as syngeneic, uveal melanoma targets indicates that MHC I matching is not necessary.	('MHC I', 'Gene', (74, 79))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('CD8', 'Gene', (17, 20))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('CD8', 'Gene', '925', (17, 20))	('uveal melanoma', 'Disease', (114, 128))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('mismatched', 'Var', (80, 90))	('cytolytic', 'MPA', (60, 69))
42777	33648524	We identified nine splicing factors, including SNRPD2, SNRPD3 and NHP2L1, of which depletion inhibited proliferation in two TNBC cell lines by deregulation of sister chromatid cohesion (SCC) via increased sororin intron 1 retention and down-regulation of SMC1, MAU2 and ESPL1.	('proliferation', 'CPA', (103, 116))	('SNRPD2', 'Gene', '6633', (47, 53))	('SMC', 'cellular_component', 'GO:0016029', ('255', '258'))	('SNRPD3', 'Gene', '6634', (55, 61))	('depletion', 'Var', (83, 92))	('MAU2', 'Gene', (261, 265))	('increased', 'PosReg', (195, 204))	('SMC1', 'Gene', '8243', (255, 259))	('sister chromatid cohesion', 'biological_process', 'GO:0007062', ('159', '184'))	('sister chromatid cohesion', 'Protein', (159, 184))	('SMC1', 'Gene', (255, 259))	('ESPL1', 'Gene', '9700', (270, 275))	('SNRPD2', 'Gene', (47, 53))	('deregulation', 'PosReg', (143, 155))	('splicing factor', 'Gene', '10569', (19, 34))	('retention', 'biological_process', 'GO:0051235', ('222', '231'))	('down-regulation', 'NegReg', (236, 251))	('MAU2', 'Gene', '23383', (261, 265))	('ESPL1', 'Gene', (270, 275))	('sororin', 'Gene', (205, 212))	('chromatid', 'cellular_component', 'GO:0005694', ('166', '175'))	('regulation', 'biological_process', 'GO:0065007', ('241', '251'))	('SNRPD3', 'Gene', (55, 61))	('NHP2L1', 'Gene', (66, 72))	('NHP2L1', 'Gene', '4809', (66, 72))	('sororin', 'Gene', '113130', (205, 212))	('chromatid', 'cellular_component', 'GO:0005695', ('166', '175'))	('splicing', 'biological_process', 'GO:0045292', ('19', '27'))	('splicing factor', 'Gene', (19, 34))	('inhibited', 'NegReg', (93, 102))
42788	33648524	Many alternative splicing events have been linked to different pathways important in cancer development and progression, such as apoptosis (Bcl-x, caspase 2, Fas), metabolism (pyruvate kinase M), oncogenes (Ron, Rac1, FGFRs, CD44, BRAF), tumor suppressor genes (p53) and angiogenesis (VEGF).	('apoptosis', 'Disease', (129, 138))	('BRAF', 'Gene', (231, 235))	('BRAF', 'Gene', '673', (231, 235))	('CD44', 'Gene', (225, 229))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('Rac1', 'Gene', (212, 216))	('angiogenesis', 'CPA', (271, 283))	('Ron', 'Gene', '4486', (207, 210))	('Ron', 'Gene', (207, 210))	('metabolism', 'biological_process', 'GO:0008152', ('164', '174'))	('p53', 'Gene', '7157', (262, 265))	('caspase 2', 'Gene', (147, 156))	('p53', 'Gene', (262, 265))	('alternative splicing events', 'Var', (5, 32))	('Rac1', 'Gene', '5879', (212, 216))	('VEGF', 'Gene', '7422', (285, 289))	('caspase 2', 'Gene', '835', (147, 156))	('cancer', 'Disease', (85, 91))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('238', '254'))	('tumor', 'Disease', (238, 243))	('angiogenesis', 'biological_process', 'GO:0001525', ('271', '283'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Bcl-x', 'Gene', '598', (140, 145))	('VEGF', 'Gene', (285, 289))	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('splicing', 'biological_process', 'GO:0045292', ('17', '25'))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('238', '254'))	('Bcl-x', 'Gene', (140, 145))	('linked', 'Reg', (43, 49))
42790	33648524	Recently, some studies reported a link between splicing factor deficiency, defective splicing and aberrant chromosome segregation during mitosis, mediated by a premature loss of sister chromatid cohesion (SCC).	('defective', 'Var', (75, 84))	('sister chromatid cohesion', 'biological_process', 'GO:0007062', ('178', '203'))	('splicing', 'biological_process', 'GO:0045292', ('85', '93'))	('factor deficiency', 'Disease', 'MESH:D005171', (56, 73))	('sister chromatid cohesion', 'MPA', (178, 203))	('splicing factor', 'Gene', '10569', (47, 62))	('chromatid', 'cellular_component', 'GO:0005694', ('185', '194'))	('loss', 'NegReg', (170, 174))	('factor deficiency', 'Disease', (56, 73))	('chromosome', 'cellular_component', 'GO:0005694', ('107', '117'))	('splicing', 'MPA', (85, 93))	('mitosis', 'biological_process', 'GO:0000278', ('137', '144'))	('chromatid', 'cellular_component', 'GO:0005695', ('185', '194'))	('splicing', 'biological_process', 'GO:0045292', ('47', '55'))	('chromosome segregation', 'biological_process', 'GO:0007059', ('107', '129'))	('aberrant chromosome segregation', 'CPA', (98, 129))	('splicing factor', 'Gene', (47, 62))	('aberrant chromosome segregation', 'Phenotype', 'HP:0002916', (98, 129))
42792	33648524	Altogether these studies suggest a relation between splicing, mitosis and cancer growth, providing a potential strategy to combat cancer.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('mitosis', 'biological_process', 'GO:0000278', ('62', '69'))	('splicing', 'Var', (52, 60))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (130, 136))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('splicing', 'biological_process', 'GO:0045292', ('52', '60'))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
42794	33648524	We discovered nine splicing factors (AQR, CRNKL1, MFAP1, NHP2L1, PRPF8, SF3B1, SNRPD2, SNRPD3 and SNRPF), of which knockdown significantly impaired cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('148', '166'))	('MFAP1', 'Gene', '4236', (50, 55))	('PRPF8', 'Gene', '10594', (65, 70))	('SNRPD2', 'Gene', '6633', (79, 85))	('SNRPD3', 'Gene', '6634', (87, 93))	('knockdown', 'Var', (115, 124))	('CRNKL1', 'Gene', (42, 48))	('splicing factor', 'Gene', '10569', (19, 34))	('CRNKL1', 'Gene', '51340', (42, 48))	('impaired', 'NegReg', (139, 147))	('SF3B1', 'Gene', (72, 77))	('MFAP1', 'Gene', (50, 55))	('SNRPD2', 'Gene', (79, 85))	('SNRPF', 'Gene', (98, 103))	('SNRPD3', 'Gene', (87, 93))	('SNRPF', 'Gene', '6636', (98, 103))	('PRPF8', 'Gene', (65, 70))	('NHP2L1', 'Gene', (57, 63))	('SF3B1', 'Gene', '23451', (72, 77))	('NHP2L1', 'Gene', '4809', (57, 63))	('AQR', 'Gene', (37, 40))	('splicing', 'biological_process', 'GO:0045292', ('19', '27'))	('cell proliferation', 'CPA', (148, 166))	('AQR', 'Gene', '9716', (37, 40))	('splicing factor', 'Gene', (19, 34))
42804	33648524	Mouse anti-Cyclin B1 (#4135), rabbit anti-CDK9 (#2316), rabbit anti-Aurora A (#3092), rabbit anti-phospho-pRb (#9307), mouse anti-pRb (#2692S), rabbit anti-MCM2 (#3619) and rabbit anti-pHistone-H3 (#9701) were purchased from Cell Signaling.	('Cyclin B1', 'Gene', '891', (11, 20))	('Cyclin', 'molecular_function', 'GO:0016538', ('11', '17'))	('CDK', 'molecular_function', 'GO:0004693', ('42', '45'))	('MCM2', 'Gene', (156, 160))	('CDK9', 'Gene', '1025', (42, 46))	('Signaling', 'biological_process', 'GO:0023052', ('230', '239'))	('H3', 'Chemical', 'MESH:C012616', (194, 196))	('Aurora A', 'Gene', (68, 76))	('#4135', 'Var', (22, 27))	('Cyclin B1', 'Gene', (11, 20))	('pRb', 'Gene', (130, 133))	('pRb', 'Gene', (106, 109))	('#2316', 'Var', (48, 53))	('CDK9', 'Gene', (42, 46))	('pRb', 'Gene', '5925', (130, 133))	('pRb', 'Gene', '5925', (106, 109))	('MCM2', 'Gene', '4171', (156, 160))	('Aurora A', 'Gene', '6790', (68, 76))
42842	33648524	To enrich for the CDCA5 intron retained product, the procedure was repeated 3 days after NHP2L1 knockdown.	('knockdown', 'Var', (96, 105))	('NHP2L1', 'Gene', (89, 95))	('NHP2L1', 'Gene', '4809', (89, 95))	('CDCA5', 'Gene', (18, 23))	('CDCA5', 'Gene', '113130', (18, 23))
42864	33648524	Among our candidates was SF3B1, a splicing factor known to be a driver gene in breast cancer and often mutated in uveal melanoma and chronic lymphocytic leukemia (CLL).	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (133, 161))	('mutated', 'Var', (103, 110))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('splicing factor', 'Gene', '10569', (34, 49))	('chronic lymphocytic leukemia', 'Disease', (133, 161))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('splicing', 'biological_process', 'GO:0045292', ('34', '42'))	('uveal melanoma', 'Disease', (114, 128))	('SF3B1', 'Gene', (25, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('splicing factor', 'Gene', (34, 49))	('leukemia', 'Phenotype', 'HP:0001909', (153, 161))	('SF3B1', 'Gene', '23451', (25, 30))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (133, 161))
42865	33648524	FUCCI imaging-based cell cycle analysis demonstrated that splicing factor knockdown resulted in an increased cell fraction in G1-S transition accompanied by loss of cells in S-G2-M phase in Hs578T cells (Fig.	('splicing', 'biological_process', 'GO:0045292', ('58', '66'))	('Hs578T', 'CellLine', 'CVCL:0332', (190, 196))	('cell cycle', 'biological_process', 'GO:0007049', ('20', '30'))	('G1-S transition', 'CPA', (126, 141))	('cells in S-G2-M phase', 'MPA', (165, 186))	('cell fraction', 'CPA', (109, 122))	('knockdown', 'Var', (74, 83))	('splicing factor', 'Gene', '10569', (58, 73))	('M phase', 'biological_process', 'GO:0000279', ('179', '186'))	('increased', 'PosReg', (99, 108))	('cell fraction', 'cellular_component', 'GO:0000267', ('109', '122'))	('loss', 'NegReg', (157, 161))	('splicing factor', 'Gene', (58, 73))
42866	33648524	In conjunction, splicing factor knockdown also led to decreased levels of CDC7, a regulator of G1/S transition, and the phosphorylation of its downstream target p-MCM2 (Fig.	('splicing factor', 'Gene', '10569', (16, 31))	('MCM2', 'Gene', (163, 167))	('splicing', 'biological_process', 'GO:0045292', ('16', '24'))	('phosphorylation', 'MPA', (120, 135))	('CDC7', 'Gene', (74, 78))	('knockdown', 'Var', (32, 41))	('splicing factor', 'Gene', (16, 31))	('levels', 'MPA', (64, 70))	('decreased', 'NegReg', (54, 63))	('CDC7', 'Gene', '8317', (74, 78))	('phosphorylation', 'biological_process', 'GO:0016310', ('120', '135'))	('MCM2', 'Gene', '4171', (163, 167))
42867	33648524	Altogether, we selected nine splicing factors which depletion resulted in a strong decrease in cell proliferation and cell cycle arrest in G1-S phase with nuclei containing 4n DNA content.	('cell proliferation', 'CPA', (95, 113))	('DNA', 'cellular_component', 'GO:0005574', ('176', '179'))	('arrest', 'Disease', (129, 135))	('cell proliferation', 'biological_process', 'GO:0008283', ('95', '113'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('118', '135'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (118, 135))	('decrease', 'NegReg', (83, 91))	('S phase', 'biological_process', 'GO:0051320', ('142', '149'))	('splicing factor', 'Gene', (29, 44))	('arrest', 'Disease', 'MESH:D006323', (129, 135))	('depletion', 'Var', (52, 61))	('splicing', 'biological_process', 'GO:0045292', ('29', '37'))	('splicing factor', 'Gene', '10569', (29, 44))
42869	33648524	To investigate whether proliferative defects induced by loss of SNRPD2, SNRPD3 and NHP2L1 were TNBC and/or cell line specific, we performed knockdowns of these factors in four additional highly proliferative breast cancer cell lines covering different breast cancer subtypes (MDA-MB-468 and HCC1806 are from the TNBC basal A subtype, while T47D and MCF7 are from the luminal subtype).	('SNRPD2', 'Gene', '6633', (64, 70))	('loss', 'Var', (56, 60))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (276, 286))	('breast cancer', 'Phenotype', 'HP:0003002', (252, 265))	('SNRPD3', 'Gene', (72, 78))	('T47D', 'CellLine', 'CVCL:0553', (340, 344))	('HCC1806', 'CellLine', 'CVCL:1258', (291, 298))	('SNRPD2', 'Gene', (64, 70))	('proliferative defects', 'CPA', (23, 44))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('breast cancer', 'Disease', 'MESH:D001943', (252, 265))	('breast cancer', 'Disease', (252, 265))	('NHP2L1', 'Gene', (83, 89))	('NHP2L1', 'Gene', '4809', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('MCF7', 'CellLine', 'CVCL:0031', (349, 353))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))	('SNRPD3', 'Gene', '6634', (72, 78))	('breast cancer', 'Disease', 'MESH:D001943', (208, 221))	('breast cancer', 'Disease', (208, 221))
42870	33648524	All cell lines except T47D demonstrated decreased cell growth and a slight increase in cell death upon splicing factor knockdown (Suppl.	('splicing factor', 'Gene', (103, 118))	('splicing', 'biological_process', 'GO:0045292', ('103', '111'))	('cell growth', 'CPA', (50, 61))	('cell death', 'biological_process', 'GO:0008219', ('87', '97'))	('knockdown', 'Var', (119, 128))	('splicing factor', 'Gene', '10569', (103, 118))	('cell death', 'CPA', (87, 97))	('decreased', 'NegReg', (40, 49))	('cell growth', 'biological_process', 'GO:0016049', ('50', '61'))	('T47D', 'CellLine', 'CVCL:0553', (22, 26))
42872	33648524	3), the strongest effects were observed for NHP2L1 knockdown.	('NHP2L1', 'Gene', (44, 50))	('NHP2L1', 'Gene', '4809', (44, 50))	('knockdown', 'Var', (51, 60))
42873	33648524	Since SNRPD2, SNRPD3 and NHP2L1 knockdown halted proliferation due to G1-S arrest and showed the irregular nuclear phenotype, we hypothesized that knockdown of these splicing factors would lead to cell death on the long term.	('cell death', 'biological_process', 'GO:0008219', ('197', '207'))	('cell death', 'CPA', (197, 207))	('NHP2L1', 'Gene', (25, 31))	('proliferation', 'CPA', (49, 62))	('NHP2L1', 'Gene', '4809', (25, 31))	('splicing', 'biological_process', 'GO:0045292', ('166', '174'))	('SNRPD3', 'Gene', (14, 20))	('splicing factor', 'Gene', (166, 181))	('knockdown', 'Var', (32, 41))	('SNRPD2', 'Gene', '6633', (6, 12))	('halted', 'NegReg', (42, 48))	('SNRPD2', 'Gene', (6, 12))	('SNRPD3', 'Gene', '6634', (14, 20))	('G1-S arrest', 'Disease', (70, 81))	('lead to', 'Reg', (189, 196))	('G1-S arrest', 'Disease', 'MESH:D006323', (70, 81))	('splicing factor', 'Gene', '10569', (166, 181))	('knockdown', 'Var', (147, 156))
42875	33648524	The increased cell death was mediated by apoptosis, demonstrated by the significant increase in caspase activity upon splicing factor knockdown (Fig.	('apoptosis', 'biological_process', 'GO:0097194', ('41', '50'))	('apoptosis', 'biological_process', 'GO:0006915', ('41', '50'))	('splicing factor', 'Gene', (118, 133))	('caspase activity', 'molecular_function', 'GO:0097153', ('96', '112'))	('activity', 'MPA', (104, 112))	('caspase activity', 'molecular_function', 'GO:0030693', ('96', '112'))	('caspase', 'Gene', '835', (96, 103))	('cell death', 'biological_process', 'GO:0008219', ('14', '24'))	('knockdown', 'Var', (134, 143))	('increase', 'PosReg', (84, 92))	('caspase', 'Gene', (96, 103))	('caspase activity', 'molecular_function', 'GO:0004197', ('96', '112'))	('splicing factor', 'Gene', '10569', (118, 133))	('cell death', 'CPA', (14, 24))	('splicing', 'biological_process', 'GO:0045292', ('118', '126'))
42879	33648524	Yet for these 19 factors, a significant correlation between the percentage of abnormal nuclei in HeLa and proliferative defects was observed in MDA-MB-231, but not in Hs578T (Suppl.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (144, 154))	('Hs578T', 'CellLine', 'CVCL:0332', (167, 173))	('proliferative defects', 'CPA', (106, 127))	('HeLa', 'CellLine', 'CVCL:0030', (97, 101))	('MDA-MB-231', 'Var', (144, 154))
42880	33648524	This suggests that at least in MDA-MB-231 cells, the observed proliferative defect upon splicing factor knockdown could be mediated by mitotic defects.	('mitotic defects', 'Disease', (135, 150))	('mitotic defects', 'Disease', 'MESH:C536987', (135, 150))	('splicing factor', 'Gene', '10569', (88, 103))	('defect', 'NegReg', (76, 82))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (31, 41))	('splicing factor', 'Gene', (88, 103))	('splicing', 'biological_process', 'GO:0045292', ('88', '96'))	('proliferative', 'CPA', (62, 75))	('knockdown', 'Var', (104, 113))
42881	33648524	Interestingly, knockdown of all of nine selected splicing factors demonstrated an increase in poly-lobed irregular shaped nuclei, a marker for abnormal mitosis (Fig.	('splicing factor', 'Gene', (49, 64))	('splicing', 'biological_process', 'GO:0045292', ('49', '57'))	('knockdown', 'Var', (15, 24))	('mitosis', 'biological_process', 'GO:0000278', ('152', '159'))	('abnormal mitosis', 'Disease', (143, 159))	('splicing factor', 'Gene', '10569', (49, 64))	('increase', 'PosReg', (82, 90))	('poly-lobed irregular shaped nuclei', 'CPA', (94, 128))	('abnormal mitosis', 'Disease', 'MESH:D018376', (143, 159))
42882	33648524	Moreover, knockdown of SNRPD2, SNRPD3 and NHP2L1 in other breast cancer cell lines also resulted in a similar irregular shaped nuclear phenotype (Suppl.	('SNRPD2', 'Gene', (23, 29))	('SNRPD3', 'Gene', (31, 37))	('SNRPD2', 'Gene', '6633', (23, 29))	('NHP2L1', 'Gene', (42, 48))	('resulted in', 'Reg', (88, 99))	('NHP2L1', 'Gene', '4809', (42, 48))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('SNRPD3', 'Gene', '6634', (31, 37))	('irregular shaped nuclear phenotype', 'CPA', (110, 144))	('breast cancer', 'Disease', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('knockdown', 'Var', (10, 19))
42883	33648524	Figure 8B), suggesting that cell growth inhibition through splicing factor knockdown is mediated by a common mechanism irrespective of the BC subtype.	('cell growth', 'CPA', (28, 39))	('splicing factor', 'Gene', (59, 74))	('knockdown', 'Var', (75, 84))	('splicing', 'biological_process', 'GO:0045292', ('59', '67'))	('splicing factor', 'Gene', '10569', (59, 74))	('cell growth', 'biological_process', 'GO:0016049', ('28', '39'))
42889	33648524	Systematic evaluation of the changes in RNA expression levels of these sister chromatid cohesion factors demonstrated a consistent downregulation of ESPL1, SMC1 and MAU2 and upregulation of sororin levels upon SNRPD2, SNRPD3 and NHP2L1 knockdown in both MDA-MB-231 and Hs578T cell lines (Fig.	('MAU2', 'Gene', (165, 169))	('knockdown', 'Var', (236, 245))	('upregulation', 'PosReg', (174, 186))	('chromatid', 'cellular_component', 'GO:0005694', ('78', '87'))	('NHP2L1', 'Gene', (229, 235))	('NHP2L1', 'Gene', '4809', (229, 235))	('MAU2', 'Gene', '23383', (165, 169))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('chromatid', 'cellular_component', 'GO:0005695', ('78', '87'))	('downregulation', 'NegReg', (131, 145))	('ESPL1', 'Gene', '9700', (149, 154))	('SNRPD3', 'Gene', '6634', (218, 224))	('sororin', 'Gene', (190, 197))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (254, 264))	('RNA expression', 'MPA', (40, 54))	('SNRPD2', 'Gene', '6633', (210, 216))	('ESPL1', 'Gene', (149, 154))	('sororin', 'Gene', '113130', (190, 197))	('SMC', 'cellular_component', 'GO:0016029', ('156', '159'))	('SMC1', 'Gene', '8243', (156, 160))	('SMC1', 'Gene', (156, 160))	('SNRPD2', 'Gene', (210, 216))	('SNRPD3', 'Gene', (218, 224))	('sister chromatid cohesion', 'biological_process', 'GO:0007062', ('71', '96'))	('Hs578T', 'CellLine', 'CVCL:0332', (269, 275))
42890	33648524	Remarkably, whereas sororin RNA levels were upregulated upon splicing factor knockdown, we observed decreased sororin protein levels (Fig.	('splicing', 'biological_process', 'GO:0045292', ('61', '69'))	('splicing factor', 'Gene', '10569', (61, 76))	('RNA', 'cellular_component', 'GO:0005562', ('28', '31'))	('upregulated', 'PosReg', (44, 55))	('sororin', 'Gene', '113130', (20, 27))	('sororin', 'Gene', '113130', (110, 117))	('knockdown', 'Var', (77, 86))	('splicing factor', 'Gene', (61, 76))	('decreased', 'NegReg', (100, 109))	('sororin', 'Gene', (20, 27))	('sororin', 'Gene', (110, 117))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))
42892	33648524	We previously showed that knockdown of SNRPD2, SNRPD3 and NHP2L1 induced upregulation of sororin RNA expression (Fig.	('SNRPD2', 'Gene', '6633', (39, 45))	('SNRPD3', 'Gene', '6634', (47, 53))	('SNRPD2', 'Gene', (39, 45))	('NHP2L1', 'Gene', (58, 64))	('NHP2L1', 'Gene', '4809', (58, 64))	('sororin', 'Gene', (89, 96))	('knockdown', 'Var', (26, 35))	('RNA', 'cellular_component', 'GO:0005562', ('97', '100'))	('SNRPD3', 'Gene', (47, 53))	('sororin', 'Gene', '113130', (89, 96))	('upregulation', 'PosReg', (73, 85))
42894	33648524	Moreover, knockdown of sororin could recapitulate the nuclear phenotype observed upon splicing factor knockdown (Fig.	('splicing factor', 'Gene', (86, 101))	('sororin', 'Gene', (23, 30))	('splicing factor', 'Gene', '10569', (86, 101))	('splicing', 'biological_process', 'GO:0045292', ('86', '94'))	('sororin', 'Gene', '113130', (23, 30))	('knockdown', 'Var', (10, 19))
42897	33648524	Interestingly, SNRPD2, SNPRD3 and NHP2L1 knockdown consistently enhanced intron 1 and/or intron 2 retention in both TNBC cell lines (Suppl.	('retention', 'biological_process', 'GO:0051235', ('98', '107'))	('PR', 'Gene', '5241', (25, 27))	('SNRPD2', 'Gene', '6633', (15, 21))	('NHP2L1', 'Gene', (34, 40))	('NHP2L1', 'Gene', '4809', (34, 40))	('intron 2 retention', 'MPA', (89, 107))	('SNRPD2', 'Gene', (15, 21))	('intron 1', 'MPA', (73, 81))	('knockdown', 'Var', (41, 50))	('enhanced', 'PosReg', (64, 72))
42900	33648524	Analysis of the separate introns revealed that both intron 1 and 2 were retained upon splicing factor knockdown in both TNBC cell lines, while the other introns were not affected (Fig.	('splicing', 'biological_process', 'GO:0045292', ('86', '94'))	('splicing factor', 'Gene', (86, 101))	('splicing factor', 'Gene', '10569', (86, 101))	('knockdown', 'Var', (102, 111))
42902	33648524	Enhanced intron 2 retention was only observed after CRNKL1, PRPF8, SF3B1 and SNRPF depletion (Suppl.	('CRNKL1', 'Gene', (52, 58))	('SNRPF', 'Gene', (77, 82))	('SF3B1', 'Gene', '23451', (67, 72))	('PRPF8', 'Gene', '10594', (60, 65))	('PRPF8', 'Gene', (60, 65))	('CRNKL1', 'Gene', '51340', (52, 58))	('retention', 'biological_process', 'GO:0051235', ('18', '27'))	('depletion', 'Var', (83, 92))	('intron 2', 'Protein', (9, 17))	('SNRPF', 'Gene', '6636', (77, 82))	('SF3B1', 'Gene', (67, 72))	('Enhanced', 'PosReg', (0, 8))
42919	33648524	Intriguingly, depletion of nine of the fourteen tested genes including GEMIN6 and SNRNP35, showed a similar irregular nuclear phenotype as observed upon SNRPD2, SNRPD3 or NHP2L1 knockdown.	('NHP2L1', 'Gene', '4809', (171, 177))	('SNRNP35', 'Gene', '11066', (82, 89))	('SNRPD3', 'Gene', (161, 167))	('SNRNP', 'molecular_function', 'GO:0003734', ('82', '87'))	('SNRNP', 'cellular_component', 'GO:0030532', ('82', '87'))	('SNRPD3', 'Gene', '6634', (161, 167))	('SNRNP35', 'Gene', (82, 89))	('NHP2L1', 'Gene', (171, 177))	('GEMIN6', 'Gene', '79833', (71, 77))	('GEMIN6', 'Gene', (71, 77))	('knockdown', 'Var', (178, 187))	('SNRPD2', 'Gene', '6633', (153, 159))	('depletion', 'MPA', (14, 23))	('SNRPD2', 'Gene', (153, 159))
42925	33648524	Importantly, SUN2 knockdown also increased sororin intron 1 retention similarly as observed after depletion of SNRPD2, SNRPD3 and NHP2L1 (Fig.	('sororin', 'Gene', '113130', (43, 50))	('knockdown', 'Var', (18, 27))	('retention', 'biological_process', 'GO:0051235', ('60', '69'))	('SNRPD3', 'Gene', '6634', (119, 125))	('SUN2', 'Gene', (13, 17))	('sororin', 'Gene', (43, 50))	('depletion', 'MPA', (98, 107))	('increased', 'PosReg', (33, 42))	('SNRPD2', 'Gene', '6633', (111, 117))	('SNRPD2', 'Gene', (111, 117))	('NHP2L1', 'Gene', (130, 136))	('NHP2L1', 'Gene', '4809', (130, 136))	('SNRPD3', 'Gene', (119, 125))
42928	33648524	Given the overall critical connection between BC cell proliferation and correct splicing of sororin, we anticipated that overall sororin expression could be an indicative biomarker for highly proliferative human breast cancers.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('breast cancers', 'Phenotype', 'HP:0003002', (212, 226))	('human', 'Species', '9606', (206, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('sororin', 'Gene', (92, 99))	('breast cancers', 'Disease', 'MESH:D001943', (212, 226))	('sororin', 'Gene', (129, 136))	('breast cancers', 'Disease', (212, 226))	('cell proliferation', 'biological_process', 'GO:0008283', ('49', '67'))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('correct splicing', 'Var', (72, 88))	('splicing', 'biological_process', 'GO:0045292', ('80', '88'))	('sororin', 'Gene', '113130', (92, 99))	('sororin', 'Gene', '113130', (129, 136))
42930	33648524	6a), with all of these markers being higher expressed in TNBC compared to ER positive tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('TNBC', 'Var', (57, 61))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('higher expressed', 'PosReg', (37, 53))	('ER', 'Gene', '2099', (74, 76))
42945	33648524	For example, SF3B1 was identified as a breast cancer driver gene, mutated in 20% of uveal melanoma tumors and SF3B1 mutations have been related to adverse clinical outcome in CLL.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('CLL', 'Disease', (175, 178))	('mutated', 'Var', (66, 73))	('SF3B1', 'Gene', (13, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (84, 105))	('uveal melanoma tumors', 'Disease', (84, 105))	('mutations', 'Var', (116, 125))	('SF3B1', 'Gene', (110, 115))	('SF3B1', 'Gene', '23451', (13, 18))	('related to', 'Reg', (136, 146))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('breast cancer', 'Disease', (39, 52))	('SF3B1', 'Gene', '23451', (110, 115))
42946	33648524	Moreover, SNRPD2 and AQR knockdown inhibited proliferation in breast, pancreatic and ovarian cancer cell lines.	('pancreatic and ovarian cancer', 'Disease', 'MESH:D010195', (70, 99))	('ovarian cancer', 'Phenotype', 'HP:0100615', (85, 99))	('breast', 'Disease', (62, 68))	('proliferation', 'CPA', (45, 58))	('AQR', 'Gene', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('SNRPD2', 'Gene', '6633', (10, 16))	('inhibited', 'NegReg', (35, 44))	('SNRPD2', 'Gene', (10, 16))	('AQR', 'Gene', '9716', (21, 24))	('knockdown', 'Var', (25, 34))
42949	33648524	However, U2AF2 depletion only demonstrated mild proliferative defects in our primary screen.	('depletion', 'Var', (15, 24))	('proliferative defects', 'CPA', (48, 69))	('U2AF2', 'Gene', (9, 14))	('U2AF', 'cellular_component', 'GO:0089701', ('9', '13'))	('U2AF2', 'Gene', '11338', (9, 14))
42961	33648524	In the present study, we demonstrated that targeting SF3B1 using pladienolide B strongly affected breast cancer proliferation by increasing sororin alternative splicing and affecting the nuclear phenotype similar to our candidate splicing factor knockdown.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('splicing factor', 'Gene', (230, 245))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('sororin', 'Gene', '113130', (140, 147))	('breast cancer', 'Disease', (98, 111))	('targeting', 'Var', (43, 52))	('increasing', 'PosReg', (129, 139))	('SF3B1', 'Gene', '23451', (53, 58))	('splicing', 'biological_process', 'GO:0045292', ('160', '168'))	('affected', 'Reg', (89, 97))	('splicing factor', 'Gene', '10569', (230, 245))	('splicing', 'biological_process', 'GO:0045292', ('230', '238'))	('sororin', 'Gene', (140, 147))	('affecting', 'Reg', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('nuclear phenotype', 'MPA', (187, 204))	('pladienolide B', 'Chemical', 'MESH:C522342', (65, 79))	('SF3B1', 'Gene', (53, 58))
43184	32503466	High expression of TRIM44 protein in malignant tissues was found to be strongly associated with poor OS (HR = 1.94, 95% CI: 1.60-2.35, p < 0.0001), and the heterogeneity test revealed a mild heterogeneity (I2 = 32.6%; PQ = 0.139).	('High', 'Var', (0, 4))	('poor OS', 'Disease', (96, 103))	('TRIM44', 'Gene', '54765', (19, 25))	('associated', 'Reg', (80, 90))	('TRIM44', 'Gene', (19, 25))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('PQ', 'Chemical', '-', (218, 220))	('protein', 'Protein', (26, 33))
43198	32503466	When combined with all data from 33 different types of malignant tumors in GEPIA, the Kaplan-Meier analysis suggested that cancer patients with a high expression level of TRIM44 exhibited poorer OS, compared with cases expressing a low level of TRIM44 (Fig.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TRIM44', 'Gene', '54765', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('TRIM44', 'Gene', '54765', (171, 177))	('patients', 'Species', '9606', (130, 138))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('malignant tumors', 'Disease', (55, 71))	('TRIM44', 'Gene', (245, 251))	('cancer', 'Disease', (123, 129))	('TRIM44', 'Gene', (171, 177))	('malignant tumors', 'Disease', 'MESH:D009369', (55, 71))	('high expression', 'Var', (146, 161))
43206	32503466	TRIM44 amplification is correlated with unfavorable prognosis and advanced clinicopathological parameters of malignancies.	('TRIM44', 'Gene', (0, 6))	('malignancies', 'Disease', (109, 121))	('TRIM44', 'Gene', '54765', (0, 6))	('amplification', 'Var', (7, 20))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))
43216	32503466	Overexpression of TRIM44 has been shown to induce a similar change in hallmark characteristics of EMT in other cancers, such as ICC and HEC.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('ICC', 'Disease', (128, 131))	('TRIM44', 'Gene', '54765', (18, 24))	('HEC', 'CellLine', 'CVCL:N814', (136, 139))	('cancers', 'Disease', (111, 118))	('change', 'Reg', (60, 66))	('hallmark characteristics of', 'MPA', (70, 97))	('HEC', 'Disease', (136, 139))	('TRIM44', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Overexpression', 'Var', (0, 14))	('EMT', 'biological_process', 'GO:0001837', ('98', '101'))
43218	32503466	TRIM44 expression positively affects the expression of cyclins and CDKs, suggesting that TRIM44 is involved in the regulation of cell cycle G1/s transformation.	('TRIM44', 'Gene', (0, 6))	('affects', 'Reg', (29, 36))	('expression', 'MPA', (41, 51))	('regulation of cell cycle', 'biological_process', 'GO:0051726', ('115', '139'))	('involved', 'Reg', (99, 107))	('TRIM44', 'Gene', '54765', (0, 6))	('TRIM44', 'Gene', '54765', (89, 95))	('cyclin', 'Gene', '5111', (55, 61))	('expression', 'Var', (7, 17))	('CDKs', 'Gene', '23097', (67, 71))	('TRIM44', 'Gene', (89, 95))	('cyclin', 'Gene', (55, 61))	('CDKs', 'Gene', (67, 71))
43220	32503466	Indeed, ectopic expression of TRIM44 promotes cell proliferation by accelerating the G1/S-phase transition in HCC.	('accelerating', 'PosReg', (68, 80))	('HCC', 'Gene', '619501', (110, 113))	('ectopic expression', 'Var', (8, 26))	('G1/S-phase transition', 'CPA', (85, 106))	('S-phase', 'biological_process', 'GO:0051320', ('88', '95'))	('HCC', 'Gene', (110, 113))	('TRIM44', 'Gene', '54765', (30, 36))	('TRIM44', 'Gene', (30, 36))	('cell proliferation', 'CPA', (46, 64))	('promotes', 'PosReg', (37, 45))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))
43221	32503466	In colony formation assays, knockdown of TRIM44 in Huh7 cells significantly decreased the expression levels of cyclin D1 and cyclin E, which have been shown to play a crucial role in accelerating the G1/S-phase transition.	('cyclin', 'Gene', (111, 117))	('G1/S-phase transition', 'CPA', (200, 221))	('cyclin D1', 'Gene', (111, 120))	('formation', 'biological_process', 'GO:0009058', ('10', '19'))	('TRIM44', 'Gene', (41, 47))	('Huh7', 'CellLine', 'CVCL:0336', (51, 55))	('expression levels', 'MPA', (90, 107))	('decreased', 'NegReg', (76, 85))	('TRIM44', 'Gene', '54765', (41, 47))	('cyclin', 'Gene', '5111', (125, 131))	('cyclin', 'Gene', '5111', (111, 117))	('knockdown', 'Var', (28, 37))	('cyclin', 'molecular_function', 'GO:0016538', ('111', '117'))	('accelerating', 'PosReg', (183, 195))	('S-phase', 'biological_process', 'GO:0051320', ('203', '210'))	('cyclin', 'molecular_function', 'GO:0016538', ('125', '131'))	('cyclin D1', 'Gene', '595', (111, 120))	('cyclin', 'Gene', (125, 131))
43223	32503466	Knock-down of TRIM44 in glioma cells induces an increase in p21/p27 expression,and then it inhibited cell division.	('TRIM44', 'Gene', '54765', (14, 20))	('p27', 'Gene', '10671', (64, 67))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('cell division', 'CPA', (101, 114))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('p21', 'Gene', '644914', (60, 63))	('expression', 'MPA', (68, 78))	('p27', 'Gene', (64, 67))	('TRIM44', 'Gene', (14, 20))	('inhibited', 'NegReg', (91, 100))	('Knock-down', 'Var', (0, 10))	('cell division', 'biological_process', 'GO:0051301', ('101', '114'))	('glioma', 'Disease', (24, 30))	('p21', 'Gene', (60, 63))	('increase', 'PosReg', (48, 56))
43224	32503466	Further, the critical p21/p27 regulator AKT is inactivated after TRIM44 is knocked down, but it is activated in glioma cells that overexpress TRIM44.	('inactivated', 'NegReg', (47, 58))	('TRIM44', 'Gene', '54765', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('TRIM44', 'Gene', '54765', (142, 148))	('knocked', 'Var', (75, 82))	('AKT', 'Gene', '207', (40, 43))	('TRIM44', 'Gene', (65, 71))	('TRIM44', 'Gene', (142, 148))	('p21', 'Gene', (22, 25))	('glioma', 'Disease', (112, 118))	('activated', 'PosReg', (99, 108))	('p27', 'Gene', '10671', (26, 29))	('AKT', 'Gene', (40, 43))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('p21', 'Gene', '644914', (22, 25))	('p27', 'Gene', (26, 29))	('overexpress', 'PosReg', (130, 141))
43226	32503466	The phosphorylation of downstream mTOR substrates, including p-Akt (Ser473) and p-p70S6K (Thr389), in TRIM44-knockdown cells was markedly inhibited, indicating that TRIM44 functions upstream of the mTOR signaling pathway by phosphorylating mTOR.	('TRIM44', 'Gene', (102, 108))	('TRIM44', 'Gene', (165, 171))	('p70S6K', 'Gene', (82, 88))	('Ser473', 'Var', (68, 74))	('inhibited', 'NegReg', (138, 147))	('Akt', 'Gene', '207', (63, 66))	('Ser473', 'Chemical', '-', (68, 74))	('mTOR', 'Gene', (240, 244))	('mTOR', 'Gene', (34, 38))	('signaling pathway', 'biological_process', 'GO:0007165', ('203', '220'))	('mTOR', 'Gene', '2475', (34, 38))	('mTOR', 'Gene', '2475', (240, 244))	('Thr389', 'Var', (90, 96))	('p70S6K', 'Gene', '6198', (82, 88))	('mTOR', 'Gene', (198, 202))	('Thr389', 'Chemical', '-', (90, 96))	('phosphorylation', 'MPA', (4, 19))	('mTOR', 'Gene', '2475', (198, 202))	('TRIM44', 'Gene', '54765', (102, 108))	('TRIM44', 'Gene', '54765', (165, 171))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('Ser', 'cellular_component', 'GO:0005790', ('68', '71'))	('Akt', 'Gene', (63, 66))
43237	32503466	Microarray analysis showed that TRIM44 knockdown is associated with the dysregulation of NUPR1, CDK19, CADM1, INHBA, TNFSF10, and DDIT4, which could normally activate the apoptotic cell pathways.	('activate', 'PosReg', (158, 166))	('CADM1', 'Gene', '23705', (103, 108))	('INHBA', 'Gene', '3624', (110, 115))	('NUPR1', 'Gene', (89, 94))	('CDK19', 'Gene', (96, 101))	('dysregulation', 'MPA', (72, 85))	('TNFSF10', 'Gene', (117, 124))	('INHBA', 'Gene', (110, 115))	('TRIM44', 'Gene', '54765', (32, 38))	('TRIM44', 'Gene', (32, 38))	('CDK', 'molecular_function', 'GO:0004693', ('96', '99'))	('NUPR1', 'Gene', '26471', (89, 94))	('apoptotic cell pathways', 'Pathway', (171, 194))	('TNFSF10', 'Gene', '8743', (117, 124))	('knockdown', 'Var', (39, 48))	('DDIT4', 'Gene', (130, 135))	('CADM1', 'Gene', (103, 108))	('CDK19', 'Gene', '23097', (96, 101))	('DDIT4', 'Gene', '54541', (130, 135))
43246	32503466	A previous report has shown that the silencing of TRIM44 could decrease the c-IAP1, c-IAP2, and XIAP expression levels, especially in the presence of doxorubicin.	('c-IAP1', 'Gene', (76, 82))	('XIAP', 'Gene', '331', (96, 100))	('c-IAP1', 'Gene', '329', (76, 82))	('doxorubicin', 'Chemical', 'MESH:D004317', (150, 161))	('TRIM44', 'Gene', '54765', (50, 56))	('silencing', 'Var', (37, 46))	('c-IAP2', 'Gene', (84, 90))	('decrease', 'NegReg', (63, 71))	('c-IAP2', 'Gene', '330', (84, 90))	('TRIM44', 'Gene', (50, 56))	('XIAP', 'Gene', (96, 100))
43253	32503466	Moreover, miR-26b-5p is the upstream regulatory gene of TRIM44, which acts as a suppressor.	('miR-26b-5p', 'Var', (10, 20))	('TRIM44', 'Gene', '54765', (56, 62))	('TRIM44', 'Gene', (56, 62))
43268	31426461	SRSF2 Mutations in Uveal Melanoma: A Preference for In-Frame Deletions?	('SRSF2', 'Gene', (0, 5))	('Uveal Melanoma', 'Disease', (19, 33))	('Mutations', 'Var', (6, 15))	('SRSF2', 'Gene', '6427', (0, 5))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (19, 33))	('Uveal Melanoma', 'Disease', 'MESH:C536494', (19, 33))	('Melanoma', 'Phenotype', 'HP:0002861', (25, 33))
43270	31426461	UM with a mutation in SF3B1, a spliceosome gene, is characterized by three or more structural changes of chromosome 1, 6, 8, 9, or 11.	('SF3B1', 'Gene', '23451', (22, 27))	('chromosome', 'cellular_component', 'GO:0005694', ('105', '115'))	('mutation', 'Var', (10, 18))	('spliceosome', 'cellular_component', 'GO:0005681', ('31', '42'))	('SF3B1', 'Gene', (22, 27))
43271	31426461	Also UM without a mutation in SF3B1 harbors similar chromosomal aberrations.	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (52, 75))	('SF3B1', 'Gene', (30, 35))	('mutation', 'Var', (18, 26))	('SF3B1', 'Gene', '23451', (30, 35))
43272	31426461	Since, in addition to SF3B1, mutations in U2AF1 and SRSF2 have also been observed in hematological malignancies, UM without a SF3B1 mutation:but with the characteristic chromosomal pattern:might harbor mutations in one of these genes.	('U2AF1', 'Gene', '7307', (42, 47))	('SRSF2', 'Gene', '6427', (52, 57))	('U2AF', 'cellular_component', 'GO:0089701', ('42', '46'))	('hematological malignancies', 'Disease', (85, 111))	('SF3B1', 'Gene', (126, 131))	('observed', 'Reg', (73, 81))	('SF3B1', 'Gene', '23451', (22, 27))	('mutations', 'Var', (29, 38))	('hematological malignancies', 'Disease', 'MESH:D019337', (85, 111))	('harbor', 'Reg', (195, 201))	('SF3B1', 'Gene', '23451', (126, 131))	('hematological malignancies', 'Phenotype', 'HP:0004377', (85, 111))	('SRSF2', 'Gene', (52, 57))	('SF3B1', 'Gene', (22, 27))	('U2AF1', 'Gene', (42, 47))
43275	31426461	Data of three UM with an SRSF2 mutation was extracted from the The Cancer Genome Atlas (TCGA).	('Cancer Genome Atlas', 'Disease', (67, 86))	('SRSF2', 'Gene', '6427', (25, 30))	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (67, 86))	('mutation', 'Var', (31, 39))	('SRSF2', 'Gene', (25, 30))
43276	31426461	Results: Heterozygous in-frame SRSF2 deletions affecting amino acids 92-100 were detected in two UMs (5%) of 42 selected tumors and in three TGCA UM specimens.	('deletions', 'Var', (37, 46))	('SRSF2', 'Gene', '6427', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('SRSF2', 'Gene', (31, 36))	('detected', 'Reg', (81, 89))
43277	31426461	Both the UM with an SRSF2 mutation from our cohort and the UM samples from the TCGA showed more than four structural chromosomal aberrations including (partial) gain of chromosome 6 and 8, although in two TCGA UMs monosomy 3 was observed.	('mutation', 'Var', (26, 34))	('SRSF2', 'Gene', (20, 25))	('chromosome', 'cellular_component', 'GO:0005694', ('169', '179'))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (117, 140))	('SRSF2', 'Gene', '6427', (20, 25))	('gain', 'PosReg', (161, 165))
43278	31426461	Conclusions: Whereas in myelodysplastic syndrome predominantly missense SRSF2 mutations are described, the observed SRSF2 mutations in UM are all in-frame deletions of 8-9 amino acids.	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (24, 48))	('SRSF2', 'Gene', '6427', (72, 77))	('missense', 'Var', (63, 71))	('myelodysplastic syndrome', 'Disease', (24, 48))	('SRSF2', 'Gene', (116, 121))	('mutations', 'Var', (78, 87))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (24, 48))	('mutations', 'Var', (122, 131))	('SRSF2', 'Gene', '6427', (116, 121))	('SRSF2', 'Gene', (72, 77))
43279	31426461	This suggests that the R625 missense SF3B1 mutations and SRSF2 mutations in UM are different compared to the spliceosome gene mutations in hematological cancers, and probably target a different, as yet unknown, set of genes involved in uveal melanoma etiology.	('mutations', 'Var', (63, 72))	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('SF3B1', 'Gene', '23451', (37, 42))	('SRSF2', 'Gene', (57, 62))	('R625 missense', 'Var', (23, 36))	('target', 'Reg', (175, 181))	('uveal melanoma', 'Disease', 'MESH:C536494', (236, 250))	('mutations', 'Var', (43, 52))	('SRSF2', 'Gene', '6427', (57, 62))	('hematological cancers', 'Disease', 'MESH:D009369', (139, 160))	('uveal melanoma', 'Disease', (236, 250))	('uveal melanoma', 'Phenotype', 'HP:0007716', (236, 250))	('spliceosome', 'cellular_component', 'GO:0005681', ('109', '120'))	('SF3B1', 'Gene', (37, 42))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('hematological cancers', 'Disease', (139, 160))
43284	31426461	Several prognostic factors are described with mutations in BAP1, SF3B1, and EIF1AX, with or without loss of chromosome 3, as important predictors of survival.	('EIF1AX', 'Gene', (76, 82))	('mutations', 'Var', (46, 55))	('BAP1', 'Gene', (59, 63))	('SF3B1', 'Gene', (65, 70))	('chromosome', 'cellular_component', 'GO:0005694', ('108', '118'))	('SF3B1', 'Gene', '23451', (65, 70))	('BAP1', 'Gene', '8314', (59, 63))	('EIF1AX', 'Gene', '1964', (76, 82))
43285	31426461	Tumors of uveal melanoma (UM) patients with somatic BAP1, SF3B1, or EIF1AX mutations show a distinct chromosomal copy number variation (CNV) pattern.	('BAP1', 'Gene', '8314', (52, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (10, 24))	('Tumors of uveal melanoma', 'Disease', (0, 24))	('SF3B1', 'Gene', (58, 63))	('Tumors of uveal melanoma', 'Disease', 'MESH:C536494', (0, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('BAP1', 'Gene', (52, 56))	('patients', 'Species', '9606', (30, 38))	('EIF1AX', 'Gene', '1964', (68, 74))	('EIF1AX', 'Gene', (68, 74))	('mutations', 'Var', (75, 84))	('SF3B1', 'Gene', '23451', (58, 63))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
43288	31426461	However, not all UMs with a typical SF3B1mut CNV harbor a mutation in the SF3B1 component of the spliceosome complex.	('SF3B1', 'Gene', (36, 41))	('SF3B1', 'Gene', '23451', (74, 79))	('SF3B1', 'Gene', '23451', (36, 41))	('mutation', 'Var', (58, 66))	('SF3B1', 'Gene', (74, 79))	('spliceosome complex', 'cellular_component', 'GO:0005681', ('97', '116'))
43289	31426461	As in myelodysplastic syndrome (MDS) and MDS-related diseases (such as chronic myelomonocytic leukemia and acute myloid leukemia) in which mutations in other genes of the spliceosome complex such as SRSF2 and U2AF1 are described, mutations in SRSF2 and other spliceosome factors are also observed in UM.	('acute myloid leukemia', 'Disease', (107, 128))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (6, 30))	('leukemia', 'Phenotype', 'HP:0001909', (120, 128))	('mutations', 'Var', (230, 239))	('U2AF', 'cellular_component', 'GO:0089701', ('209', '213'))	('MDS', 'Disease', 'MESH:D009190', (41, 44))	('U2AF1', 'Gene', (209, 214))	('myloid leukemia', 'Phenotype', 'HP:0012324', (113, 128))	('chronic myelomonocytic leukemia', 'Disease', (71, 102))	('MDS', 'Disease', 'MESH:D009190', (32, 35))	('acute myloid leukemia', 'Disease', 'MESH:D015470', (107, 128))	('spliceosome complex', 'cellular_component', 'GO:0005681', ('171', '190'))	('acute myloid leukemia', 'Phenotype', 'HP:0004808', (107, 128))	('U2AF1', 'Gene', '7307', (209, 214))	('leukemia', 'Phenotype', 'HP:0001909', (94, 102))	('MDS', 'Disease', (41, 44))	('SRSF2', 'Gene', '6427', (243, 248))	('myelodysplastic syndrome', 'Disease', (6, 30))	('MDS', 'Disease', (32, 35))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (71, 102))	('SRSF2', 'Gene', (243, 248))	('SRSF2', 'Gene', '6427', (199, 204))	('spliceosome', 'cellular_component', 'GO:0005681', ('259', '270'))	('mutations', 'Var', (139, 148))	('SRSF2', 'Gene', (199, 204))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (71, 102))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (6, 30))
43290	31426461	Typical MDS-related mutations in SRSF2 involve codon 95 and are missense mutations resulting in an amino acid change (in 74% of patients with an SRSF2 mutation) or in-frame deletions starting at this codon (26%).	('SRSF2', 'Gene', (33, 38))	('amino acid change', 'MPA', (99, 116))	('MDS', 'Disease', (8, 11))	('MDS', 'Disease', 'MESH:D009190', (8, 11))	('SRSF2', 'Gene', '6427', (145, 150))	('resulting in', 'Reg', (83, 95))	('mutation', 'Var', (151, 159))	('SRSF2', 'Gene', '6427', (33, 38))	('patients', 'Species', '9606', (128, 136))	('SRSF2', 'Gene', (145, 150))	('mutations', 'Var', (20, 29))
43291	31426461	Missense mutations in U2AF1 in MDS are almost exclusively described in codon 34 (p.Ser34Phe and p.Ser34Tyr), 156 (Arg156His), or 157 (p.Gln157Arg and p.Gln157Pro).	('Arg156His', 'Var', (114, 123))	('MDS', 'Disease', (31, 34))	('p.Gln157Pro', 'Var', (150, 161))	('MDS', 'Disease', 'MESH:D009190', (31, 34))	('Ser', 'cellular_component', 'GO:0005790', ('83', '86'))	('Ser', 'cellular_component', 'GO:0005790', ('98', '101'))	('p.Ser34Tyr', 'Var', (96, 106))	('p.Gln157Pro', 'Mutation', 'rs371246226', (150, 161))	('Arg156His', 'SUBSTITUTION', 'None', (114, 123))	('p.Ser34Phe', 'Var', (81, 91))	('U2AF1', 'Gene', (22, 27))	('p.Ser34Phe', 'Mutation', 'rs371769427', (81, 91))	('U2AF1', 'Gene', '7307', (22, 27))	('U2AF', 'cellular_component', 'GO:0089701', ('22', '26'))	('p.Gln157Arg', 'Var', (134, 145))	('p.Gln157Arg', 'Mutation', 'rs371246226', (134, 145))	('p.Ser34Tyr', 'Mutation', 'rs371769427', (96, 106))
43292	31426461	Therefore, mutation analysis of SRSF2 and U2AF1 covering these hotspots was performed on UM tumors with no SF3B1 mutation but with an SF3B1-like chromosomal CNV pattern.	('U2AF1', 'Gene', '7307', (42, 47))	('U2AF', 'cellular_component', 'GO:0089701', ('42', '46'))	('mutation', 'Var', (113, 121))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('SF3B1', 'Gene', (134, 139))	('SRSF2', 'Gene', (32, 37))	('SF3B1', 'Gene', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('SF3B1', 'Gene', '23451', (134, 139))	('SRSF2', 'Gene', '6427', (32, 37))	('SF3B1', 'Gene', '23451', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('U2AF1', 'Gene', (42, 47))
43293	31426461	Heterozygous in-frame deletions starting at codon 92 of SRSF2 were identified in two of the selected 42 UM (p.(Tyr92_His99del); p.(Gly93_His100del)), (Figure 1).	('p.(Tyr92_His99del', 'Var', (108, 125))	('SRSF2', 'Gene', '6427', (56, 61))	('p.(Tyr92_His99del)', 'DELETION', 'None', (108, 126))	('p.(Gly93_His100del', 'Var', (128, 146))	('SRSF2', 'Gene', (56, 61))	('p.(Gly93_His100del)', 'Mutation', 'p.93,100del)', (128, 147))
43294	31426461	These mutations were mutually exclusive for BAP1, SF3B1, and EIF1AX but harbored a GNAQ p.(Gln209Leu) mutation (Table 1).	('GNAQ', 'Gene', '2776', (83, 87))	('SF3B1', 'Gene', (50, 55))	('p.(Gln209Leu)', 'Mutation', 'rs121913492', (88, 101))	('SF3B1', 'Gene', '23451', (50, 55))	('EIF1AX', 'Gene', '1964', (61, 67))	('EIF1AX', 'Gene', (61, 67))	('BAP1', 'Gene', '8314', (44, 48))	('GNAQ', 'Gene', (83, 87))	('p.(Gln209Leu', 'Var', (88, 100))	('BAP1', 'Gene', (44, 48))
43300	31426461	Three previously described SRSF2 mutations were found in the data from the The Cancer Genome Atlas (TCGA) database.	('SRSF2', 'Gene', '6427', (27, 32))	('mutations', 'Var', (33, 42))	('SRSF2', 'Gene', (27, 32))	('Cancer Genome Atlas', 'Disease', (79, 98))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (79, 98))
43301	31426461	Two UMs have a p.(Gln209Leu) mutation in GNAQ and one harbors a GNA11 mutation (p.(Gln209Leu)), (Table 2).	('GNAQ', 'Gene', '2776', (41, 45))	('p.(Gln209Leu)', 'Mutation', 'rs121913492', (80, 93))	('p.(Gln209Leu)', 'Mutation', 'rs121913492', (15, 28))	('GNAQ', 'Gene', (41, 45))	('GNA11', 'Gene', (64, 69))	('GNA11', 'Gene', '2767', (64, 69))	('p.(Gln209Leu', 'Var', (15, 27))
43302	31426461	No mutations in EIF1AX were detected, but one UM has BAP1 mutation (c.518A > G:p.(Tyr173Cys)).	('EIF1AX', 'Gene', '1964', (16, 22))	('EIF1AX', 'Gene', (16, 22))	('G:p.(Tyr173Cys', 'Var', (77, 91))	('BAP1', 'Gene', '8314', (53, 57))	('G:p.(Tyr173Cys)', 'SUBSTITUTION', 'None', (77, 92))	('BAP1', 'Gene', (53, 57))
43303	31426461	In this study we identified deletions in SRSF2 in two UM harboring an SF3B1 specific SNP array pattern albeit with no mutations of the SF3B1 hotspot regions.	('SRSF2', 'Gene', '6427', (41, 46))	('deletions', 'Var', (28, 37))	('SF3B1', 'Gene', (70, 75))	('SF3B1', 'Gene', (135, 140))	('SRSF2', 'Gene', (41, 46))	('SF3B1', 'Gene', '23451', (70, 75))	('SF3B1', 'Gene', '23451', (135, 140))
43304	31426461	Studies have shown that in myelodysplastic syndrome (MDS) SRSF2 was mutated in 12-14% of the cases and mutations in U2AF1 occur in 15% of the MDS cases.	('mutations', 'Var', (103, 112))	('MDS', 'Disease', (142, 145))	('MDS', 'Disease', 'MESH:D009190', (142, 145))	('SRSF2', 'Gene', '6427', (58, 63))	('U2AF', 'cellular_component', 'GO:0089701', ('116', '120'))	('myelodysplastic syndrome', 'Disease', (27, 51))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (27, 51))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (27, 51))	('MDS', 'Disease', (53, 56))	('MDS', 'Disease', 'MESH:D009190', (53, 56))	('SRSF2', 'Gene', (58, 63))	('U2AF1', 'Gene', (116, 121))	('U2AF1', 'Gene', '7307', (116, 121))	('mutated', 'Var', (68, 75))
43305	31426461	This is a higher frequency compared to UM, in which SRSF2 mutations are detected in less than 5% of the specimens and no U2AF1 mutations have been identified.	('mutations', 'Var', (58, 67))	('SRSF2', 'Gene', '6427', (52, 57))	('U2AF', 'cellular_component', 'GO:0089701', ('121', '125'))	('U2AF1', 'Gene', '7307', (121, 126))	('U2AF1', 'Gene', (121, 126))	('SRSF2', 'Gene', (52, 57))
43306	31426461	Three SRSF2 mutated UMs described in the literature are included in The Cancer Genome Atlas (TCGA, ).	('mutated', 'Var', (12, 19))	('SRSF2', 'Gene', (6, 11))	('Cancer Genome Atlas', 'Disease', (72, 91))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (72, 91))	('SRSF2', 'Gene', '6427', (6, 11))
43307	31426461	Two out of these harbor similar deletions (Table 2) as we have identified in our cohort, and are mutually exclusive with BAP1 and EIF1AX, similar to our own observations.	('deletions', 'Var', (32, 41))	('BAP1', 'Gene', '8314', (121, 125))	('EIF1AX', 'Gene', '1964', (130, 136))	('BAP1', 'Gene', (121, 125))	('EIF1AX', 'Gene', (130, 136))
43308	31426461	The third SRSF2 mutation from TCGA is a deletion of amino acid 174-179 and co-exists with a BAP1 mutation.	('SRSF2', 'Gene', '6427', (10, 15))	('mutation', 'Var', (16, 24))	('SRSF2', 'Gene', (10, 15))	('BAP1', 'Gene', '8314', (92, 96))	('BAP1', 'Gene', (92, 96))
43310	31426461	However, other spliceosome gene mutations can underlie UM pathogenesis but might not display the same chromosomal anomalies as described in SF3B1.	('pathogenesis', 'biological_process', 'GO:0009405', ('58', '70'))	('SF3B1', 'Gene', (140, 145))	('chromosomal anomalies', 'Disease', 'MESH:D002869', (102, 123))	('spliceosome', 'cellular_component', 'GO:0005681', ('15', '26'))	('SF3B1', 'Gene', '23451', (140, 145))	('mutations', 'Var', (32, 41))	('chromosomal anomalies', 'Disease', (102, 123))
43311	31426461	Furthermore, the low incidence of SRSF2 mutations in UM suggests that other genes of the splicing machinery, such as U2AF35 or ZRSR2, might be mutated.	('SRSF2', 'Gene', '6427', (34, 39))	('ZRSR2', 'Gene', '8233', (127, 132))	('SRSF2', 'Gene', (34, 39))	('mutations', 'Var', (40, 49))	('splicing', 'biological_process', 'GO:0045292', ('89', '97'))	('U2AF35', 'Gene', '7307', (117, 123))	('U2AF', 'cellular_component', 'GO:0089701', ('117', '121'))	('U2AF35', 'Gene', (117, 123))	('ZRSR2', 'Gene', (127, 132))
43312	31426461	Mutations in other splicing genes than SF3B1 could be less frequently involved in the development of UM compared to MDS in which mutations in several splicing genes have been identified.	('SF3B1', 'Gene', '23451', (39, 44))	('splicing', 'biological_process', 'GO:0045292', ('150', '158'))	('splicing', 'biological_process', 'GO:0045292', ('19', '27'))	('Mutations', 'Var', (0, 9))	('involved', 'Reg', (70, 78))	('MDS', 'Disease', (116, 119))	('MDS', 'Disease', 'MESH:D009190', (116, 119))	('SF3B1', 'Gene', (39, 44))
43315	31426461	Also, for SF3B1 in UM residue R625 is most commonly mutated residue, whereas in other tumors predominantly the K700 residue of SF3B1 is affected.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('SF3B1', 'Gene', (127, 132))	('K700', 'Var', (111, 115))	('tumors', 'Disease', (86, 92))	('SF3B1', 'Gene', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('SF3B1', 'Gene', '23451', (127, 132))	('SF3B1', 'Gene', '23451', (10, 15))
43316	31426461	Furthermore, studying the RNA expression of SRSF2 mutated UM from TGCA, we did not observe the same splicing effect as observed in SF3B1 mutated UM.	('SF3B1', 'Gene', '23451', (131, 136))	('splicing', 'biological_process', 'GO:0045292', ('100', '108'))	('SRSF2', 'Gene', (44, 49))	('mutated', 'Var', (50, 57))	('SRSF2', 'Gene', '6427', (44, 49))	('SF3B1', 'Gene', (131, 136))	('RNA', 'cellular_component', 'GO:0005562', ('26', '29'))
43317	31426461	These findings suggest that SF3B1 mutations compared to mutations in SRSF2 have, despite a similar chromosomal pattern, a different effect on splicing.	('SRSF2', 'Gene', '6427', (69, 74))	('effect', 'Reg', (132, 138))	('SF3B1', 'Gene', (28, 33))	('splicing', 'biological_process', 'GO:0045292', ('142', '150'))	('SRSF2', 'Gene', (69, 74))	('SF3B1', 'Gene', '23451', (28, 33))	('splicing', 'MPA', (142, 150))	('mutations', 'Var', (34, 43))
43318	31426461	Since we observed SRSF2 mutations in only two patients the clinical impact of this mutation remains unclear.	('SRSF2', 'Gene', '6427', (18, 23))	('mutations', 'Var', (24, 33))	('SRSF2', 'Gene', (18, 23))	('patients', 'Species', '9606', (46, 54))
43319	31426461	However, both patients with an SRSF2 mutation in our cohort did not develop metastasis within 6 and 10 years, neither did the patients from TCGA.	('metastasis', 'CPA', (76, 86))	('SRSF2', 'Gene', '6427', (31, 36))	('mutation', 'Var', (37, 45))	('patients', 'Species', '9606', (126, 134))	('SRSF2', 'Gene', (31, 36))	('patients', 'Species', '9606', (14, 22))	('develop', 'PosReg', (68, 75))
43330	31426461	In addition, UM with gain of chromosome 6p or loss of 6q in addition to one or two other anomalies were also included since these anomalies are also specific for SF3B1 mutated tumors, whereas this is not seen in EIF1AX or BAP1 mutated UM.	('mutated', 'Var', (168, 175))	('gain', 'PosReg', (21, 25))	('SF3B1', 'Gene', '23451', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('anomalies', 'Disease', 'MESH:D000014', (130, 139))	('chromosome', 'cellular_component', 'GO:0005694', ('29', '39'))	('anomalies', 'Disease', 'MESH:D000014', (89, 98))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('SF3B1', 'Gene', (162, 167))	('BAP1', 'Gene', '8314', (222, 226))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('EIF1AX', 'Gene', '1964', (212, 218))	('EIF1AX', 'Gene', (212, 218))	('anomalies', 'Disease', (130, 139))	('BAP1', 'Gene', (222, 226))	('anomalies', 'Disease', (89, 98))
43336	31426461	A BAP1 mutation was defined as a mutation in the BAP1 gene or lack of nuclear BAP1 expression (performed as described previously).	('mutation', 'Var', (33, 41))	('BAP1', 'Gene', (49, 53))	('lack', 'NegReg', (62, 66))	('BAP1', 'Gene', '8314', (2, 6))	('BAP1', 'Gene', '8314', (78, 82))	('mutation', 'Var', (7, 15))	('expression', 'MPA', (83, 93))	('BAP1', 'Gene', (2, 6))	('BAP1', 'Gene', '8314', (49, 53))	('BAP1', 'Gene', (78, 82))
43338	31426461	Mutations in SF3B1 and SRSF2, genes that are both involved in splicing, occur not only in UM but are described in MDS and MDS related diseases as well.	('MDS', 'Disease', (114, 117))	('MDS', 'Disease', 'MESH:D009190', (114, 117))	('SRSF2', 'Gene', (23, 28))	('splicing', 'biological_process', 'GO:0045292', ('62', '70'))	('SF3B1', 'Gene', (13, 18))	('described', 'Reg', (101, 110))	('occur', 'Reg', (72, 77))	('Mutations', 'Var', (0, 9))	('SRSF2', 'Gene', '6427', (23, 28))	('SF3B1', 'Gene', '23451', (13, 18))	('MDS', 'Disease', (122, 125))	('MDS', 'Disease', 'MESH:D009190', (122, 125))
43341	31426461	We identified in-frame deletions of SRSF2 in UM in the same genetic region, whereas most mutations in the same gene in MDS are missense mutations.	('deletions', 'Var', (23, 32))	('SRSF2', 'Gene', (36, 41))	('MDS', 'Disease', (119, 122))	('MDS', 'Disease', 'MESH:D009190', (119, 122))	('SRSF2', 'Gene', '6427', (36, 41))
43342	31426461	Therefore, we conclude that there might be a preference for in-frame deletions in SRSF2 in UM when this gene is involved.	('in-frame deletions', 'Var', (60, 78))	('SRSF2', 'Gene', '6427', (82, 87))	('SRSF2', 'Gene', (82, 87))
43343	31426461	We did not observe any mutation in U2AF1 in our selected cohort, and the incidence of mutations of SRSF2 is low.	('mutations', 'Var', (86, 95))	('U2AF', 'cellular_component', 'GO:0089701', ('35', '39'))	('U2AF1', 'Gene', (35, 40))	('U2AF1', 'Gene', '7307', (35, 40))	('SRSF2', 'Gene', (99, 104))	('SRSF2', 'Gene', '6427', (99, 104))
43360	31344957	Mutations in the GNAQ or GNA11 genes are often found in uveal but not in cutaneous melanoma.	('cutaneous melanoma', 'Disease', (73, 91))	('uveal', 'Disease', (56, 61))	('GNAQ', 'Gene', (17, 21))	('found', 'Reg', (47, 52))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (73, 91))	('Mutations', 'Var', (0, 9))	('GNA11', 'Gene', (25, 30))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('GNA11', 'Gene', '2767', (25, 30))	('GNAQ', 'Gene', '2776', (17, 21))
43361	31344957	In contrast, BRAF and NRAS mutations frequently occur in melanomas of the skin but are almost non-existent in uveal melanoma.	('mutations', 'Var', (27, 36))	('melanomas', 'Disease', (57, 66))	('uveal melanoma', 'Phenotype', 'HP:0007716', (110, 124))	('uveal melanoma', 'Disease', (110, 124))	('uveal melanoma', 'Disease', 'MESH:C536494', (110, 124))	('BRAF', 'Gene', '673', (13, 17))	('occur', 'Reg', (48, 53))	('melanomas', 'Disease', 'MESH:D008545', (57, 66))	('NRAS', 'Gene', (22, 26))	('BRAF', 'Gene', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('NRAS', 'Gene', '4893', (22, 26))
43366	31344957	Disease spread is associated with inactivating mutations in the tumor-suppressor gene BRCA1-associated protein 1 (BAP 1), which is present in 85% of metastatic uveal melanomas.	('Disease spread', 'CPA', (0, 14))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('uveal melanomas', 'Disease', (160, 175))	('melanomas', 'Phenotype', 'HP:0002861', (166, 175))	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('64', '80'))	('inactivating mutations', 'Var', (34, 56))	('BRCA1-associated protein 1', 'Gene', '8314', (86, 112))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('BRCA1-associated protein 1', 'Gene', (86, 112))	('uveal melanomas', 'Disease', 'MESH:C536494', (160, 175))	('uveal melanoma', 'Phenotype', 'HP:0007716', (160, 174))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('64', '80'))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('BAP 1', 'Gene', '8314', (114, 119))	('BAP 1', 'Gene', (114, 119))	('uveal melanomas', 'Phenotype', 'HP:0007716', (160, 175))
43367	31344957	Furthermore, monosomy 3 is the main risk factor for metastases, and strongly correlates with decreased survival: The three-year overall survival rate among patients with monosomy 3 is 60%, whereas patients with disomy 3 have a three-year overall survival rate of 95-100%.	('metastases', 'Disease', (52, 62))	('patients', 'Species', '9606', (156, 164))	('metastases', 'Disease', 'MESH:D009362', (52, 62))	('patients', 'Species', '9606', (197, 205))	('monosomy 3', 'Var', (170, 180))
43442	31344957	Results were recently published from a phase I/II study of an adjuvant therapy with ipilimumab among uveal melanoma patients, including those at risk as defined by a high-risk molecular gene signature, monosomy 3, or apical thickness >8 mm on baseline echography.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('patients', 'Species', '9606', (116, 124))	('uveal melanoma', 'Disease', 'MESH:C536494', (101, 115))	('monosomy 3', 'Var', (202, 212))	('uveal melanoma', 'Phenotype', 'HP:0007716', (101, 115))	('ipilimumab', 'Chemical', 'MESH:D000074324', (84, 94))	('uveal melanoma', 'Disease', (101, 115))
43456	31344957	Interestingly, patients with metastasized uveal melanoma and unusually high mutational loads have been successfully treated using checkpoint inhibition, experiencing prolonged survival or even complete remission.	('metastasized uveal melanoma', 'Disease', 'MESH:D009362', (29, 56))	('mutational', 'Var', (76, 86))	('patients', 'Species', '9606', (15, 23))	('metastasized uveal melanoma', 'Disease', (29, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
43457	31344957	In two of these cases, exome sequencing revealed a methyl-CpG-binding domain protein 4 (MBD4) loss-of-function mutation, resulting in a high mutational burden.	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('methyl-CpG-binding', 'molecular_function', 'GO:0008327', ('51', '69'))	('methyl-CpG-binding domain protein 4', 'Gene', (51, 86))	('MBD4', 'Gene', (88, 92))	('MBD4', 'Gene', '8930', (88, 92))	('methyl-CpG-binding domain protein 4', 'Gene', '8930', (51, 86))	('mutation', 'Var', (111, 119))	('mutational burden', 'MPA', (141, 158))	('loss-of-function', 'NegReg', (94, 110))
43490	31344957	To potentially increase efficacy and be independent of tumor material, genetically modified autologous T-cell receptors are investigated in ongoing clinical trials, e.g., against preferentially expressed antigen in melanoma (PRAME) (NCT02743611) or MART-1 (NCT02654821).	('NCT02743611', 'Var', (233, 244))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('NCT02654821', 'Var', (257, 268))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('melanoma', 'Disease', (215, 223))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('melanoma', 'Disease', 'MESH:D008545', (215, 223))	('PRAME', 'Gene', '23532', (225, 230))	('increase', 'PosReg', (15, 23))	('tumor', 'Disease', (55, 60))	('PRAME', 'Gene', (225, 230))	('MART-1', 'Gene', '2315', (249, 255))	('MART-1', 'Gene', (249, 255))	('efficacy', 'MPA', (24, 32))
43491	31344957	A trial with Ny-Eso TCR therapy in patients with melanoma was closed early because of a high mortality (NCT01350401).	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('NCT01350401', 'Var', (104, 115))	('TCR', 'cellular_component', 'GO:0042101', ('20', '23'))	('TCR', 'biological_process', 'GO:0006283', ('20', '23'))	('patients', 'Species', '9606', (35, 43))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))	('CR', 'Chemical', '-', (21, 23))
43492	31344957	However, another pilot trial combination of transgenic Ny-Eso TCR therapy with dentritic cell vaccination with or without ipilimumab was less toxic, but the two included melanoma patients did not benefit from the treatment.	('TCR', 'biological_process', 'GO:0006283', ('62', '65'))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('CR', 'Chemical', '-', (63, 65))	('melanoma', 'Disease', (170, 178))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('transgenic', 'Var', (44, 54))	('patients', 'Species', '9606', (179, 187))	('TCR', 'cellular_component', 'GO:0042101', ('62', '65'))	('ipilimumab', 'Chemical', 'MESH:D000074324', (122, 132))
43505	31344957	Several studies have therefore been initiated that combine checkpoint inhibition with local therapies such as SIRT (NCT02913417), intra-metastatic injection of oncolytic viruses combined with external-beam radiation (NCT02831933), or intravenous application of oncolytic viruses (NCT03408587).	('SIRT', 'Disease', (110, 114))	('SIRT', 'Disease', 'None', (110, 114))	('NCT03408587', 'Var', (280, 291))	('NCT02913417', 'Var', (116, 127))	('NCT02831933', 'Var', (217, 228))
43509	31344957	In fact, coinhibition of PD-1 and LAG-3 showed clinical activity in patients with previously treated metastatic or unresectable melanoma whose disease progressed during prior anti-PD(L)1 therapy.	('coinhibition', 'Var', (9, 21))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('metastatic', 'Disease', (101, 111))	('PD-1', 'Gene', (25, 29))	('PD-1', 'Gene', '5133', (25, 29))	('PD(L)1', 'Gene', (180, 186))	('patients', 'Species', '9606', (68, 76))	('LAG-3', 'Gene', (34, 39))	('LAG-3', 'Gene', '3902', (34, 39))	('PD(L)1', 'Gene', '29126', (180, 186))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
43520	31344957	However, at present the use of tebentafusp is restricted to patients with HLA-0201 positivity, which is expressed in approximately 50% of the Caucasian population.	('HLA-0201', 'Gene', (74, 82))	('patients', 'Species', '9606', (60, 68))	('tebentafusp', 'Chemical', '-', (31, 42))	('positivity', 'Var', (83, 93))
43552	30845981	The striking negative prognostic value of high ECP level is unanticipated and can guide patient management.	('negative', 'NegReg', (13, 21))	('patient', 'Species', '9606', (88, 95))	('ECP', 'Gene', (47, 50))	('ECP', 'Gene', '6037', (47, 50))	('high', 'Var', (42, 46))
43560	30845981	Regarding therapy with anti-PD-1 antibodies, eosinophil count at baseline also correlated with OS of melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('OS of melanoma', 'Disease', 'MESH:C567932', (95, 109))	('eosinophil count', 'MPA', (45, 61))	('correlated', 'Reg', (79, 89))	('anti-PD-1', 'Var', (23, 32))	('patients', 'Species', '9606', (110, 118))	('OS of melanoma', 'Disease', (95, 109))
43638	30845981	High serum ECP correlates with a poor prognosis, independently of the subsequent therapy.	('ECP', 'Gene', '6037', (11, 14))	('High', 'Var', (0, 4))	('ECP', 'Gene', (11, 14))
43681	30023461	Genetic testing using a 50-Gene Solid Tumor Cancer Panel by Next Generation Sequencing revealed that the patient had GNAQ exon 5 missense variant p Q209L (NM_002072.4:c.626A > T; NP_002063.2:p.Gln209Leu) in 60% of the alleles tested, suggestive of iris melanoma.	('patient', 'Species', '9606', (105, 112))	('Tumor Cancer', 'Disease', (38, 50))	('Tumor Cancer', 'Disease', 'MESH:D009369', (38, 50))	('iris melanoma', 'Disease', 'MESH:D007499', (248, 261))	('Tumor', 'Phenotype', 'HP:0002664', (38, 43))	('NM_002072.4:c.626A > T', 'Mutation', 'rs121913492', (155, 177))	('iris melanoma', 'Disease', (248, 261))	('GNAQ', 'Gene', '2776', (117, 121))	('NP_002063.2:p.Gln209Leu', 'Mutation', 'rs121913492', (179, 202))	('melanoma', 'Phenotype', 'HP:0002861', (253, 261))	('iris melanoma', 'Phenotype', 'HP:0011524', (248, 261))	('Q209L', 'SUBSTITUTION', 'None', (148, 153))	('Q209L', 'Var', (148, 153))	('GNAQ', 'Gene', (117, 121))
43809	29617659	The recently published sarcoma TCGA marker paper utilized automated feature extraction of nuclear properties for correlation with copy number load and genomic doubling.	('copy', 'Var', (130, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('sarcoma', 'Disease', 'MESH:D012509', (23, 30))	('sarcoma', 'Disease', (23, 30))
43818	29617659	Integrated analysis of TIL maps and molecular data reveals patterns and associations that can improve our understanding of the tumor microenvironment, and we illustrate some emerging relationships in this work.	('tumor', 'Disease', (127, 132))	('associations', 'Var', (72, 84))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))
43868	29617659	If over half of a 50x50 patch intersects with a necrotic region, the patch is classified as non-lymphocyte-infiltrated.	('necrotic', 'Disease', (48, 56))	('50x50', 'Var', (18, 23))	('necrotic', 'Disease', 'MESH:D009336', (48, 56))
43902	28757700	We present a case of iris melanoma with aggressive BAP-1 mutation, treated successfully with I-131 brachytherapy which was both characterized and followed with UBM and thereafter discuss the current state of these modalities.	('mutation', 'Var', (57, 65))	('iris melanoma', 'Disease', 'MESH:D007499', (21, 34))	('BAP-1', 'Gene', (51, 56))	('iris melanoma', 'Disease', (21, 34))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('iris melanoma', 'Phenotype', 'HP:0011524', (21, 34))	('BAP-1', 'Gene', '8314', (51, 56))
43904	28757700	The risk factors for uveal melanomas are predominantly nonmodifiable and include Caucasian descent, lighter iris color, and inactivation of the BAP1 gene occurring in 84% of metastasizing tumors.	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('BAP1', 'Gene', (144, 148))	('uveal melanomas', 'Disease', (21, 36))	('uveal melanomas', 'Phenotype', 'HP:0007716', (21, 36))	('inactivation', 'Var', (124, 136))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('uveal melanomas', 'Disease', 'MESH:C536494', (21, 36))	('lighter iris color', 'Phenotype', 'HP:0007730', (100, 118))	('BAP1', 'Gene', '8314', (144, 148))
43909	28757700	Fine-needle aspiration confirmed melanoma with a mix of the oval spindle and polyhedral epithelioid cells and inactivation of the BAP1 gene [Figures 4 and 5].	('spindle', 'cellular_component', 'GO:0005819', ('65', '72'))	('BAP1', 'Gene', (130, 134))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('aspiration', 'Phenotype', 'HP:0002835', (12, 22))	('melanoma', 'Disease', (33, 41))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('inactivation', 'Var', (110, 122))	('BAP1', 'Gene', '8314', (130, 134))
43913	28757700	Malignancies without BAP1 inactivation generally have a favorable prognosis due to their lower rates of visual morbidity and metastasis and 5-year mortality rate of 2-3%.	('lower', 'NegReg', (89, 94))	('inactivation', 'Var', (26, 38))	('BAP1', 'Gene', (21, 25))	('Malignancies', 'Disease', 'MESH:D009369', (0, 12))	('visual morbidity', 'CPA', (104, 120))	('Malignancies', 'Disease', (0, 12))	('BAP1', 'Gene', '8314', (21, 25))
43938	27574175	Risk factors for the development of uveal melanoma include Caucasian ethnicity, welding, light eye colour (green or blue), dysplastic naevus syndrome, ocular melanocytosis and presence of germline BRCA1-associated protein 1 (BAP1) mutations.	('dysplastic naevus syndrome', 'Disease', (123, 149))	('dysplastic naevus', 'Phenotype', 'HP:0001062', (123, 140))	('mutations', 'Var', (231, 240))	('naevus', 'Phenotype', 'HP:0003764', (134, 140))	('uveal melanoma', 'Disease', 'MESH:C536494', (36, 50))	('ocular melanocytosis', 'Disease', 'MESH:C535835', (151, 171))	('uveal melanoma', 'Disease', (36, 50))	('BRCA1-associated protein 1', 'Gene', (197, 223))	('dysplastic naevus syndrome', 'Disease', 'MESH:C580062', (123, 149))	('uveal melanoma', 'Phenotype', 'HP:0007716', (36, 50))	('ocular melanocytosis', 'Phenotype', 'HP:0025534', (151, 171))	('welding', 'Disease', (80, 87))	('BAP1', 'Gene', '8314', (225, 229))	('light eye colour', 'Phenotype', 'HP:0007730', (89, 105))	('BRCA1-associated protein 1', 'Gene', '8314', (197, 223))	('protein', 'cellular_component', 'GO:0003675', ('214', '221'))	('BAP1', 'Gene', (225, 229))	('ocular melanocytosis', 'Disease', (151, 171))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
43940	27574175	Monosomy 3, 1p loss, 1q gain, 6q loss, 6p gain, 8p loss and 8q gain are common chromosomal abnormalities in uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (108, 122))	('gain', 'PosReg', (24, 28))	('gain', 'PosReg', (42, 46))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('uveal melanoma', 'Disease', (108, 122))	('gain', 'PosReg', (63, 67))	('loss', 'NegReg', (33, 37))	('1p loss', 'Var', (12, 19))	('chromosomal abnormalities', 'Disease', (79, 104))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (79, 104))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('loss', 'NegReg', (51, 55))	('Monosomy 3', 'Var', (0, 10))
43941	27574175	Monosomy 3 is observed in ~50% of tumours and is associated with metastatic disease.	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('associated with', 'Reg', (49, 64))	('tumours', 'Disease', 'MESH:D009369', (34, 41))	('tumours', 'Disease', (34, 41))	('metastatic disease', 'Disease', (65, 83))	('Monosomy 3', 'Var', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
43942	27574175	Simultaneous monosomy 3 and chromosome 8 alterations are associated with a worse prognosis, while the outcome is more promising in patients with tumours harbouring partial monosomy 3.	('patients', 'Species', '9606', (131, 139))	('monosomy 3', 'Var', (13, 23))	('chromosome', 'cellular_component', 'GO:0005694', ('28', '38'))	('tumours', 'Phenotype', 'HP:0002664', (145, 152))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('chromosome 8', 'Gene', (28, 40))	('tumours', 'Disease', 'MESH:D009369', (145, 152))	('partial monosomy 3', 'Var', (164, 182))	('tumours', 'Disease', (145, 152))	('alterations', 'Var', (41, 52))
43943	27574175	Oncogenic mutations in genes associated with the G-protein-alpha subunits GNAQ or GNA11 are observed in >=80% of primary uveal melanomas and are associated with constitutive activation of signalling pathways including the central oncogenic RAS/RAF/MEK/ERK (RAS-ERK) pathway; thereby driving cell proliferation, tumour growth and progression  (figure 1).	('signalling', 'biological_process', 'GO:0023052', ('188', '198'))	('signalling pathways', 'Pathway', (188, 207))	('GNA11', 'Gene', '2767', (82, 87))	('cell proliferation', 'biological_process', 'GO:0008283', ('291', '309'))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('primary uveal melanoma', 'Disease', (113, 135))	('uveal melanomas', 'Disease', 'MESH:C536494', (121, 136))	('ERK', 'molecular_function', 'GO:0004707', ('252', '255'))	('ERK', 'molecular_function', 'GO:0004707', ('261', '264'))	('ERK', 'Gene', '5594', (261, 264))	('tumour', 'Phenotype', 'HP:0002664', (311, 317))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))	('GNAQ', 'Gene', (74, 78))	('tumour growth', 'Disease', 'MESH:D006130', (311, 324))	('RAF', 'Gene', '22882', (244, 247))	('uveal melanoma', 'Phenotype', 'HP:0007716', (121, 135))	('ERK', 'Gene', '5594', (252, 255))	('GNA11', 'Gene', (82, 87))	('uveal melanomas', 'Disease', (121, 136))	('uveal melanomas', 'Phenotype', 'HP:0007716', (121, 136))	('activation', 'PosReg', (174, 184))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (113, 135))	('ERK', 'Gene', (261, 264))	('cell proliferation', 'CPA', (291, 309))	('progression', 'CPA', (329, 340))	('ERK', 'Gene', (252, 255))	('RAF', 'Gene', (244, 247))	('associated', 'Reg', (145, 155))	('mutations', 'Var', (10, 19))	('driving', 'PosReg', (283, 290))	('tumour growth', 'Disease', (311, 324))
43944	27574175	Inactivating BAP1 mutations are found in ~50% of all cases, most frequently in class 2 metastasising disease.	('BAP1', 'Gene', (13, 17))	('Inactivating', 'Var', (0, 12))	('class 2 metastasising disease', 'Disease', (79, 108))	('BAP1', 'Gene', '8314', (13, 17))	('mutations', 'Var', (18, 27))
43946	27574175	Inactivating BAP1 mutations increase the prometastatic behaviour of uveal melanoma cells, although the mechanism by which this occurs remains unknown.	('BAP1', 'Gene', (13, 17))	('uveal melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('Inactivating', 'Var', (0, 12))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('behaviour', 'biological_process', 'GO:0007610', ('55', '64'))	('uveal melanoma', 'Disease', 'MESH:C536494', (68, 82))	('BAP1', 'Gene', '8314', (13, 17))	('uveal melanoma', 'Disease', (68, 82))	('increase', 'PosReg', (28, 36))	('mutations', 'Var', (18, 27))
43947	27574175	Mutations associated with a less aggressive behaviour include those found in splicing factor 3B subunit 1 (SF3B1) and eukaryotic translation initiation factor 1A, X-linked (EIF1AX).	('EIF1AX', 'Gene', '1964', (173, 179))	('EIF1AX', 'Gene', (173, 179))	('behaviour', 'biological_process', 'GO:0007610', ('44', '53'))	('translation initiation', 'biological_process', 'GO:0006413', ('129', '151'))	('splicing factor 3B subunit 1', 'Gene', '23451', (77, 105))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (33, 53))	('SF3B1', 'Gene', (107, 112))	('splicing factor 3B subunit 1', 'Gene', (77, 105))	('Mutations', 'Var', (0, 9))	('eukaryotic translation initiation factor 1A, X-linked', 'Gene', '1964', (118, 171))	('SF3B1', 'Gene', '23451', (107, 112))	('splicing', 'biological_process', 'GO:0045292', ('77', '85'))
43949	27574175	Despite this frequency, SF3B1 or EIF1AX mutations are found in just 3% of uveal melanomas with monosomy 3.	('melanomas', 'Phenotype', 'HP:0002861', (80, 89))	('uveal melanomas', 'Disease', (74, 89))	('SF3B1', 'Gene', (24, 29))	('EIF1AX', 'Gene', '1964', (33, 39))	('EIF1AX', 'Gene', (33, 39))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('uveal melanomas', 'Disease', 'MESH:C536494', (74, 89))	('found', 'Reg', (54, 59))	('mutations', 'Var', (40, 49))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('SF3B1', 'Gene', '23451', (24, 29))	('uveal melanomas', 'Phenotype', 'HP:0007716', (74, 89))
43950	27574175	Furthermore, preliminary whole genome single-nucleotide polymorphism microarray data showed that amplification of CNKSR3, the product of which is thought to be involved in transepithelial sodium transport, correlated with improved survival of patients with primary uveal melanoma.	('amplification', 'Var', (97, 110))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (257, 279))	('uveal melanoma', 'Phenotype', 'HP:0007716', (265, 279))	('patients', 'Species', '9606', (243, 251))	('sodium transport', 'biological_process', 'GO:0006814', ('188', '204'))	('sodium', 'Chemical', 'MESH:D012964', (188, 194))	('melanoma', 'Phenotype', 'HP:0002861', (271, 279))	('CNKSR3', 'Gene', '154043', (114, 120))	('improved', 'PosReg', (222, 230))	('survival', 'CPA', (231, 239))	('primary uveal melanoma', 'Disease', (257, 279))	('CNKSR3', 'Gene', (114, 120))
43974	27574175	GNAQ/GNA11 mutations drive the constitutive activation of the RAS-ERK pathway.	('mutations', 'Var', (11, 20))	('ERK', 'molecular_function', 'GO:0004707', ('66', '69'))	('GNA11', 'Gene', (5, 10))	('GNA11', 'Gene', '2767', (5, 10))	('activation', 'PosReg', (44, 54))	('ERK', 'Gene', '5594', (66, 69))	('ERK', 'Gene', (66, 69))
43977	27574175	Reduction of uveal melanoma cell viability with selumetinib (AZD6244, ARRY-142886), an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life,  was correlated with a MEK-dependent gene signature and found to be greater in tumour cells with GNAQ or BRAF mutations than in wild-type cells.	('uveal melanoma', 'Disease', (13, 27))	('tumour', 'Disease', 'MESH:D009369', (253, 259))	('tumour', 'Disease', (253, 259))	('uveal melanoma', 'Phenotype', 'HP:0007716', (13, 27))	('MEK1/2', 'Gene', '5604;5605', (133, 139))	('MEK1/2', 'Gene', (133, 139))	('mutations', 'Var', (284, 293))	('GNAQ', 'Disease', (271, 275))	('AZD6244', 'Chemical', 'MESH:C517975', (61, 68))	('Reduction', 'NegReg', (0, 9))	('selumetinib', 'Gene', (48, 59))	('MEK1', 'molecular_function', 'GO:0004708', ('133', '137'))	('ARRY-142886', 'Chemical', 'MESH:C517975', (70, 81))	('selumetinib', 'Chemical', 'MESH:C517975', (48, 59))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('BRAF', 'Gene', '673', (279, 283))	('BRAF', 'Gene', (279, 283))	('uveal melanoma', 'Disease', 'MESH:C536494', (13, 27))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))
43993	27574175	Phosphorylated AKT is observed in >50% of uveal melanomas and is associated with a higher risk of metastatic disease.	('Phosphorylated', 'Var', (0, 14))	('metastatic disease', 'CPA', (98, 116))	('uveal melanomas', 'Disease', (42, 57))	('uveal melanomas', 'Phenotype', 'HP:0007716', (42, 57))	('AKT', 'Protein', (15, 18))	('associated', 'Reg', (65, 75))	('uveal melanomas', 'Disease', 'MESH:C536494', (42, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
43995	27574175	As selumetinib in combination with the AKT inhibitor MK2206 reduced cell viability by >50% in multiple GNAQ-mutant uveal melanoma cell lines and reduced tumour volume in mouse xenograft models, the combination of MEK and AKT inhibition is a treatment strategy of interest.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('tumour', 'Disease', (153, 159))	('cell viability', 'CPA', (68, 82))	('reduced', 'NegReg', (145, 152))	('uveal melanoma', 'Phenotype', 'HP:0007716', (115, 129))	('uveal melanoma', 'Disease', (115, 129))	('uveal melanoma', 'Disease', 'MESH:C536494', (115, 129))	('GNAQ-mutant', 'Var', (103, 114))	('GNAQ-mutant', 'Gene', (103, 114))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('mouse', 'Species', '10090', (170, 175))	('reduced', 'NegReg', (60, 67))	('MK2206', 'Chemical', 'MESH:C548887', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (153, 159))	('selumetinib', 'Chemical', 'MESH:C517975', (3, 14))
44000	27574175	The multi-targeted tyrosine kinase inhibitor, sunitinib, inhibits driver mutations in the receptor tyrosine kinase, c-Kit.	('kinase inhibitor', 'biological_process', 'GO:0033673', ('28', '44'))	('c-Kit', 'Gene', (116, 121))	('receptor tyrosine kinase', 'Gene', (90, 114))	('receptor tyrosine kinase', 'Gene', '5979', (90, 114))	('c-Kit', 'Gene', '3815', (116, 121))	('sunitinib', 'Chemical', 'MESH:D000077210', (46, 55))	('inhibits', 'NegReg', (57, 65))	('mutations', 'Var', (73, 82))
44031	27574175	Delays may arise from slow referral times, misdiagnosis or failed detection of tumours, delays in imaging and administrative delays.	('misdiagnosis', 'Var', (43, 55))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('tumours', 'Disease', 'MESH:D009369', (79, 86))	('tumours', 'Disease', (79, 86))
44038	27574175	Biologically distinct from cutaneous melanoma, there are a number of underlying somatic gene alterations in uveal melanoma associated with a variable prognosis, which are currently being targeted in clinical drug development.	('uveal melanoma', 'Disease', 'MESH:C536494', (108, 122))	('associated', 'Reg', (123, 133))	('cutaneous melanoma', 'Disease', (27, 45))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (27, 45))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (27, 45))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('uveal melanoma', 'Disease', (108, 122))	('alterations', 'Var', (93, 104))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
44044	25147369	The presence of monosomy of chromosome 3 as identified by the different chromosome 3 tests showed significantly increased HRs (FISH on isolated nuclei cut-off 30%: HR 11.6, p=0.002; SNP analysis: HR 20.3, p=0.004) for death due to metastasis.	('death', 'Disease', 'MESH:D003643', (218, 223))	('death', 'Disease', (218, 223))	('monosomy', 'Var', (16, 24))	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('increased', 'PosReg', (112, 121))	('HRs', 'CPA', (122, 125))	('chromosome', 'cellular_component', 'GO:0005694', ('28', '38'))
44056	25147369	The pathophysiology of the importance of chromosome 3 loss was demonstrated by Harbour et al, who observed that loss of one copy of chromosome 3 together with inactivating mutations in the metastasis-suppressor gene encoding for BRCA1-asssociated protein 1 (BAP1) on the remaining copy of chromosome 3 was associated with the development of metastases.	('protein', 'cellular_component', 'GO:0003675', ('247', '254'))	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))	('BAP1', 'Gene', '8314', (258, 262))	('metastases', 'Disease', 'MESH:D009362', (341, 351))	('associated with', 'Reg', (306, 321))	('BAP1', 'Gene', (258, 262))	('BRCA1-asssociated protein 1', 'Gene', '8314', (229, 256))	('men', 'Species', '9606', (333, 336))	('loss', 'Var', (112, 116))	('BRCA1-asssociated protein 1', 'Gene', (229, 256))	('chromosome', 'cellular_component', 'GO:0005694', ('132', '142'))	('metastases', 'Disease', (341, 351))	('chromosome', 'cellular_component', 'GO:0005694', ('289', '299'))
44058	25147369	Inactivation of BAP1 at the chromosome level may be the driving force for the development of metastases, and BAP1 levels may therefore influence survival.	('influence', 'Reg', (135, 144))	('metastases', 'Disease', (93, 103))	('chromosome', 'cellular_component', 'GO:0005694', ('28', '38'))	('BAP1', 'Gene', '8314', (109, 113))	('metastases', 'Disease', 'MESH:D009362', (93, 103))	('BAP1', 'Gene', '8314', (16, 20))	('men', 'Species', '9606', (85, 88))	('survival', 'CPA', (145, 153))	('BAP1', 'Gene', (109, 113))	('BAP1', 'Gene', (16, 20))	('Inactivation', 'Var', (0, 12))
44090	25147369	With this technique, 15 out of the 16 monosomy 3 tumours had a gain of the long arm of chromosome 8 (8q) compared with four of the disomy 3 tumours.	('tumours', 'Disease', (49, 56))	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('chromosome', 'cellular_component', 'GO:0005694', ('87', '97'))	('monosomy 3', 'Var', (38, 48))	('gain', 'PosReg', (63, 67))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('disomy 3 tumours', 'Disease', 'MESH:D024182', (131, 147))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('disomy 3 tumours', 'Disease', (131, 147))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('tumours', 'Disease', 'MESH:D009369', (140, 147))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('tumours', 'Disease', (140, 147))
44095	25147369	Loss of chromosome 3 was associated with death due to metastasis (figure 2A).	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('death', 'Disease', 'MESH:D003643', (41, 46))	('death', 'Disease', (41, 46))	('metastasis', 'CPA', (54, 64))	('Loss', 'Var', (0, 4))
44096	25147369	Dividing the tumors in two groups based on chromsome 3 and 8q (either both disomic or both altered: loss of chromosome 3 together 8q gain), as determined by SNP analysis, associated with the 15-gene expression classes of Harbour (chi2 test p<0.001; one cell, had an expected count less than 5).	('loss', 'Var', (100, 104))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('chromosome', 'cellular_component', 'GO:0005694', ('108', '118'))	('gene expression', 'biological_process', 'GO:0010467', ('194', '209'))	('associated', 'Reg', (171, 181))
44103	25147369	The different methods that identify monosomy of chromosome 3 as well as the gene expression-based classifications had increased HRs for death due to metastasis.	('HRs', 'MPA', (128, 131))	('monosomy', 'Var', (36, 44))	('death', 'Disease', 'MESH:D003643', (136, 141))	('death', 'Disease', (136, 141))	('gene expression', 'biological_process', 'GO:0010467', ('76', '91'))	('chromosome', 'cellular_component', 'GO:0005694', ('48', '58'))
44105	25147369	Harbour et al identified an important role in the development of metastases in uveal melanomas for a specific gene on chromosome 3, that is, BAP1, and suggested that loss of one copy of chromosome 3 may unmask inactivating mutations in the metastasis-suppressor gene BAP1 on the remaining copy of chromosome 3.	('loss', 'Var', (166, 170))	('uveal melanomas', 'Disease', (79, 94))	('uveal melanomas', 'Phenotype', 'HP:0007716', (79, 94))	('BAP1', 'Gene', '8314', (141, 145))	('metastases', 'Disease', 'MESH:D009362', (65, 75))	('BAP1', 'Gene', '8314', (267, 271))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('men', 'Species', '9606', (57, 60))	('metastases', 'Disease', (65, 75))	('chromosome', 'cellular_component', 'GO:0005694', ('118', '128'))	('BAP1', 'Gene', (141, 145))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('BAP1', 'Gene', (267, 271))	('uveal melanomas', 'Disease', 'MESH:C536494', (79, 94))	('inactivating', 'MPA', (210, 222))	('chromosome', 'cellular_component', 'GO:0005694', ('186', '196'))	('chromosome', 'cellular_component', 'GO:0005694', ('297', '307'))	('unmask', 'Reg', (203, 209))
44108	25147369	Interestingly, one case was staged as stage IIA and still alive after 9 years' follow-up, despite having a monosomy of chromosome 3 together with gain of chromosome 8q and being a class 2 tumour (15-gene expression assay).	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('chromosome', 'cellular_component', 'GO:0005694', ('119', '129'))	('chromosome', 'cellular_component', 'GO:0005694', ('154', '164'))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('gain', 'PosReg', (146, 150))	('tumour', 'Disease', (188, 194))	('monosomy', 'Var', (107, 115))	('gene expression', 'biological_process', 'GO:0010467', ('199', '214'))
44111	25147369	As we observed an almost perfect association between the presence of monosomy of chromosome 3 plus 8q gain and the 15 gene expression profile class 2, we hypothesised that both should associate with loss of BAP1.	('BAP1', 'Gene', '8314', (207, 211))	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('monosomy', 'Var', (69, 77))	('BAP1', 'Gene', (207, 211))	('gene expression', 'biological_process', 'GO:0010467', ('118', '133'))	('loss', 'NegReg', (199, 203))	('gain', 'PosReg', (102, 106))
44112	25147369	We indeed noted a significant association for lower BAP1 gene expression (dichotomised and continuous data) and negative BAP1 immunostaining, with the combined presence of monosomy of chromosome 3 and chromosome 8q gain, as well as with the 15 gene expression prolife class 2.	('BAP1', 'Gene', '8314', (121, 125))	('negative', 'NegReg', (112, 120))	('BAP1', 'Gene', '8314', (52, 56))	('gene expression', 'biological_process', 'GO:0010467', ('244', '259'))	('BAP1', 'Gene', (121, 125))	('BAP1', 'Gene', (52, 56))	('chromosome', 'cellular_component', 'GO:0005694', ('184', '194'))	('lower', 'NegReg', (46, 51))	('gain', 'PosReg', (215, 219))	('monosomy', 'Var', (172, 180))	('chromosome', 'cellular_component', 'GO:0005694', ('201', '211'))	('gene expression', 'biological_process', 'GO:0010467', ('57', '72'))
44117	25147369	In large uveal melanoma, loss of one copy of chromosome 3, together with gain of chromosome 8q, clearly leads to this specific gene expression profile known as class 2, which is associated with loss of BAP1 gene expression, and with metastases formation.	('BAP1', 'Gene', (202, 206))	('loss', 'Var', (25, 29))	('metastases', 'Disease', 'MESH:D009362', (233, 243))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('chromosome', 'cellular_component', 'GO:0005694', ('45', '55'))	('leads to', 'Reg', (104, 112))	('uveal melanoma', 'Disease', (9, 23))	('expression', 'MPA', (212, 222))	('uveal melanoma', 'Disease', 'MESH:C536494', (9, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (9, 23))	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('loss', 'NegReg', (194, 198))	('gene expression', 'biological_process', 'GO:0010467', ('127', '142'))	('gene expression', 'biological_process', 'GO:0010467', ('207', '222'))	('BAP1', 'Gene', '8314', (202, 206))	('metastases', 'Disease', (233, 243))	('formation', 'biological_process', 'GO:0009058', ('244', '253'))
44121	25147369	Now that several prognostication techniques have been developed that work accurately in the highest risk patients, that is, those that undergo enucleation, the next challenge is to determine the exact way how these inactivation mutations in BAP1 lead to metastasis formation.	('patients', 'Species', '9606', (105, 113))	('BAP1', 'Gene', '8314', (241, 245))	('enucleation', 'biological_process', 'GO:0090601', ('143', '154'))	('BAP1', 'Gene', (241, 245))	('metastasis formation', 'CPA', (254, 274))	('inactivation mutations', 'Var', (215, 237))	('formation', 'biological_process', 'GO:0009058', ('265', '274'))	('lead to', 'Reg', (246, 253))
44122	25147369	In summary, our results show that monosomy 3/8q gain and the class 2 gene expression profile are both highly associated with lower BAP1 gene expression and negative BAP1 immunostaining, and that both methods for assessing BAP1 levels are predictive for death due to metastasis in uveal melanoma after enucleation.	('BAP1', 'Gene', '8314', (222, 226))	('negative', 'NegReg', (156, 164))	('BAP1', 'Gene', '8314', (165, 169))	('death', 'Disease', (253, 258))	('melanoma', 'Phenotype', 'HP:0002861', (286, 294))	('uveal melanoma', 'Disease', 'MESH:C536494', (280, 294))	('uveal melanoma', 'Disease', (280, 294))	('enucleation', 'biological_process', 'GO:0090601', ('301', '312'))	('gene expression', 'biological_process', 'GO:0010467', ('136', '151'))	('BAP1', 'Gene', (222, 226))	('gain', 'PosReg', (48, 52))	('BAP1', 'Gene', (165, 169))	('BAP1', 'Gene', '8314', (131, 135))	('metastasis', 'CPA', (266, 276))	('uveal melanoma', 'Phenotype', 'HP:0007716', (280, 294))	('death', 'Disease', 'MESH:D003643', (253, 258))	('gene expression', 'biological_process', 'GO:0010467', ('69', '84'))	('lower', 'NegReg', (125, 130))	('monosomy 3/8q', 'Var', (34, 47))	('BAP1', 'Gene', (131, 135))
44126	24880583	We reviewed our experience treating uveal melanoma with Ru-106 plaque brachytherapy using COMS planning techniques, hypothesizing we would observe similar outcomes to those in the COMS.	('COMS', 'Chemical', '-', (90, 94))	('COMS', 'Chemical', '-', (180, 184))	('Ru-106', 'Var', (56, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (36, 50))	('uveal melanoma', 'Phenotype', 'HP:0007716', (36, 50))	('uveal melanoma', 'Disease', (36, 50))	('Ru-106', 'Chemical', 'MESH:C000615522', (56, 62))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
44138	24880583	Among patients treated with Ru-106 plaque brachytherapy using COMS planning techniques, we found a greater than expected rate of local tumor recurrence.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('Ru-106', 'Var', (28, 34))	('tumor', 'Disease', (135, 140))	('patients', 'Species', '9606', (6, 14))	('Ru-106', 'Chemical', 'MESH:C000615522', (28, 34))	('COMS', 'Chemical', '-', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
44145	24880583	Although Co-60 was the original isotope used worldwide for more than 30 years, most prospective studies of plaque brachytherapy for uveal melanoma have used I-125 (or much less often Pd-103), despite the availability of many other radioisotopes for treatment.	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('men', 'Species', '9606', (254, 257))	('Co-60', 'Chemical', '-', (9, 14))	('uveal melanoma', 'Phenotype', 'HP:0007716', (132, 146))	('uveal melanoma', 'Disease', 'MESH:C536494', (132, 146))	('uveal melanoma', 'Disease', (132, 146))	('I-125', 'Chemical', 'MESH:C000614960', (157, 162))	('I-125', 'Var', (157, 162))
44147	24880583	Theoretical advantages of Ru-106 plaques include a thin profile that facilitates placement, as well as the limited depth of penetration by the emitted beta-particles.	('Ru-106', 'Chemical', 'MESH:C000615522', (26, 32))	('men', 'Species', '9606', (86, 89))	('Ru-106', 'Var', (26, 32))	('facilitates', 'PosReg', (69, 80))
44205	24880583	In this study, when using plaques of the same size (18 mm) and radiation doses prescribed to the same depth (3 or 5 mm), greater lateral constriction of isodoses at the edge of the plaque were observed with Ru-106.	('Ru-106', 'Chemical', 'MESH:C000615522', (207, 213))	('Ru-106', 'Var', (207, 213))	('lateral constriction', 'CPA', (129, 149))	('constriction', 'cellular_component', 'GO:0005702', ('137', '149'))
44206	24880583	At some isodose levels this difference was up to 20%, suggesting that for similarly sized plaques, with radiation prescribed to the same distance from the plaque, the dose at the edge of the plaque could be considerably lower with Ru-106 compared with I-125.	('Ru-106', 'Var', (231, 237))	('Ru-106', 'Chemical', 'MESH:C000615522', (231, 237))	('lower', 'NegReg', (220, 225))	('I-125', 'Chemical', 'MESH:C000614960', (252, 257))	('dose', 'MPA', (167, 171))
44212	24880583	This observation supports the dosimetric observations described above, specifically that the dose at the edge of Ru-106 is lower than a similarly designed I-125 plaque.	('dose', 'MPA', (93, 97))	('Ru-106', 'Var', (113, 119))	('I-125', 'Chemical', 'MESH:C000614960', (155, 160))	('lower', 'NegReg', (123, 128))	('Ru-106', 'Chemical', 'MESH:C000615522', (113, 119))
44218	24880583	These investigators observed a significantly higher rate of local tumor recurrence with Ru-106 (10.7%) compared with I-125 (4.2%).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('I-125', 'Chemical', 'MESH:C000614960', (117, 122))	('Ru-106', 'Chemical', 'MESH:C000615522', (88, 94))	('tumor', 'Disease', (66, 71))	('Ru-106', 'Var', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
44220	24880583	They observed a significantly higher risk of enucleation after brachytherapy with Ru-106, compared with I-125.	('enucleation', 'biological_process', 'GO:0090601', ('45', '56'))	('Ru-106', 'Var', (82, 88))	('I-125', 'Chemical', 'MESH:C000614960', (104, 109))	('Ru-106', 'Chemical', 'MESH:C000615522', (82, 88))	('enucleation', 'Disease', (45, 56))
44412	33540700	Ferroptosis is a double-edged sword in tumor development because ferroptotic cancer cells release a variety of signaling molecules, either to inhibit tumor growth or to promote tumor proliferation.	('inhibit', 'NegReg', (142, 149))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('Ferroptosis', 'biological_process', 'GO:0097707', ('0', '11'))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('signaling', 'biological_process', 'GO:0023052', ('111', '120'))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('ferroptotic', 'Var', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', (150, 155))	('promote', 'PosReg', (169, 176))
44439	33540700	Figure 4A,B showed poor metastasis-free survival in GSE22138 (p-value < 0.0001, Figure 4C) compared to specific low-risk patients.	('GSE22138', 'Var', (52, 60))	('poor', 'NegReg', (19, 23))	('patients', 'Species', '9606', (121, 129))	('metastasis-free survival', 'CPA', (24, 48))
44457	33540700	Zhang and colleagues showed that the role of ferroptosis regulation by miR-9 in melanoma, and the knocking-down of miR-9, induce ferroptosis in melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('ferroptosis', 'biological_process', 'GO:0097707', ('129', '140'))	('miR-9', 'Gene', (115, 120))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('ferroptosis', 'biological_process', 'GO:0097707', ('45', '56'))	('melanoma', 'Disease', (80, 88))	('miR-9', 'Gene', (71, 76))	('regulation', 'biological_process', 'GO:0065007', ('57', '67'))	('knocking-down', 'Var', (98, 111))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('induce', 'Reg', (122, 128))	('ferroptosis regulation', 'MPA', (45, 67))	('ferroptosis', 'CPA', (129, 140))
44458	33540700	miR-137 negatively affects necroptosis in melanoma cells and the inactivation of miR-137 enhances the antitumor activity of erastin by elevating ferroptosis.	('melanoma', 'Disease', (42, 50))	('miR-137', 'Gene', (0, 7))	('miR-137', 'Gene', '406928', (0, 7))	('tumor', 'Disease', (106, 111))	('ferroptosis', 'biological_process', 'GO:0097707', ('145', '156'))	('erastin', 'Chemical', 'MESH:C477224', (124, 131))	('ferroptosis', 'MPA', (145, 156))	('necroptosis', 'CPA', (27, 38))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('enhances', 'PosReg', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('necroptosis', 'biological_process', 'GO:0070266', ('27', '38'))	('inactivation', 'Var', (65, 77))	('necroptosis', 'biological_process', 'GO:0097528', ('27', '38'))	('miR-137', 'Gene', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('miR-137', 'Gene', '406928', (81, 88))	('elevating', 'PosReg', (135, 144))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
44471	33540700	Inactivation of ALOX12 can reduce p53-mediated ferroptosis, caused by active oxygen stress, and eliminate the dependence of p53 on tumor growth.	('eliminate', 'NegReg', (96, 105))	('p53', 'Gene', (34, 37))	('dependence', 'MPA', (110, 120))	('p53', 'Gene', (124, 127))	('ALOX12', 'Gene', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('p53', 'Gene', '7157', (34, 37))	('ALOX12', 'Gene', '239', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('p53', 'Gene', '7157', (124, 127))	('reduce', 'NegReg', (27, 33))	('tumor', 'Disease', (131, 136))	('ferroptosis', 'biological_process', 'GO:0097707', ('47', '58'))	('Inactivation', 'Var', (0, 12))	('oxygen', 'Chemical', 'MESH:D010100', (77, 83))
44472	33540700	ALOX12 plays an important role in inflammation and oxidation, while abnormal DNA methylation and genetic variants of ALOX12 are associated with various human diseases and pathological phenotypes, including cancer.	('DNA methylation', 'MPA', (77, 92))	('inflammation', 'Disease', (34, 46))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('ALOX12', 'Gene', '239', (0, 6))	('ALOX12', 'Gene', (0, 6))	('abnormal', 'Var', (68, 76))	('ALOX12', 'Gene', '239', (117, 123))	('human', 'Species', '9606', (152, 157))	('inflammation', 'biological_process', 'GO:0006954', ('34', '46'))	('associated', 'Reg', (128, 138))	('DNA methylation', 'biological_process', 'GO:0006306', ('77', '92'))	('ALOX12', 'Gene', (117, 123))	('genetic variants', 'Var', (97, 113))	('inflammation', 'Disease', 'MESH:D007249', (34, 46))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
44478	33540700	reported that ITGA6 is a hypoxia-inducible factor-dependent target gene, and high ITGA6 expression enhances invasion and tumor-initiating cell activities in models of metastatic breast cancer.	('ITGA6', 'Gene', '3655', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('high', 'Var', (77, 81))	('ITGA6', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('tumor', 'Disease', (121, 126))	('ITGA6', 'Gene', '3655', (14, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('breast cancer', 'Disease', (178, 191))	('ITGA6', 'Gene', (14, 19))	('enhances', 'PosReg', (99, 107))	('hypoxia', 'Disease', (25, 32))	('hypoxia', 'Disease', 'MESH:D000860', (25, 32))	('expression', 'MPA', (88, 98))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
44483	33540700	Notably, overexpression of the cancer-stem-cell-marker CD44 enhanced the stability of SLC7A11 by promoting the interaction between SLC7A11 and OTUB1; the depletion of CD44 partially abrogated this interaction.	('OTUB1', 'Gene', '55611', (143, 148))	('CD4', 'Gene', '920', (167, 170))	('SLC7A11', 'Gene', '23657', (131, 138))	('CD4', 'Gene', (55, 58))	('stability', 'MPA', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('promoting', 'PosReg', (97, 106))	('depletion', 'Var', (154, 163))	('CD4', 'Gene', '920', (55, 58))	('SLC7A11', 'Gene', (86, 93))	('OTUB1', 'Gene', (143, 148))	('interaction', 'Interaction', (111, 122))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('SLC7A11', 'Gene', '23657', (86, 93))	('cancer', 'Disease', (31, 37))	('enhanced', 'PosReg', (60, 68))	('SLC7A11', 'Gene', (131, 138))	('CD4', 'Gene', (167, 170))
44494	33540700	Several studies have confirmed that chromosome aberrations and gene mutations in UM patients are very closely linked to prognosis.	('gene mutations', 'Var', (63, 77))	('patients', 'Species', '9606', (84, 92))	('linked', 'Reg', (110, 116))	('UM', 'Phenotype', 'HP:0007716', (81, 83))	('chromosome', 'cellular_component', 'GO:0005694', ('36', '46'))
44516	33540700	7025 genes were significantly predicting the prognosis of UM patients by both Kaplan-Meier and univariate Cox regression analyses (p-value < 0.05); Table S5.	('7025', 'Var', (0, 4))	('predicting', 'Reg', (30, 40))	('patients', 'Species', '9606', (61, 69))	('UM', 'Phenotype', 'HP:0007716', (58, 60))
44523	33418925	Using a gene therapeutic approach, we demonstrated silencing of HuR reduced MITF protein expression and inhibited the growth of melanoma cells but not normal melanocytes.	('silencing', 'Var', (51, 60))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('expression', 'MPA', (89, 99))	('HuR', 'Gene', '1994', (64, 67))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('HuR', 'Gene', (64, 67))	('reduced', 'NegReg', (68, 75))	('inhibited', 'NegReg', (104, 113))	('MITF', 'Gene', '4286', (76, 80))	('MITF', 'Gene', (76, 80))	('melanoma', 'Disease', (128, 136))
44531	33418925	Methods: In this study, we tested the impact of siRNA-mediated gene silencing of HuR in human melanoma (MeWo, A375) and normal melanocyte cells in vitro.	('gene', 'Var', (63, 67))	('A375', 'CellLine', 'CVCL:0132', (110, 114))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('HuR', 'Gene', '1994', (81, 84))	('human', 'Species', '9606', (88, 93))	('HuR', 'Gene', (81, 84))	('tested', 'Reg', (27, 33))	('gene silencing', 'biological_process', 'GO:0016458', ('63', '77'))
44547	33418925	Therefore, a combination of B-RAFV600 and PI3K inhibitors were tested, but the clinical trial (NCT01616199, NCT01512251) showed no significant improvement of efficacy.	('B-RAF', 'Gene', '673', (28, 33))	('NCT01616199', 'Var', (95, 106))	('B-RAF', 'Gene', (28, 33))	('men', 'Species', '9606', (150, 153))	('NCT01512251', 'Var', (108, 119))	('PI3K', 'molecular_function', 'GO:0016303', ('42', '46'))
44551	33418925	Disrupting the interaction between the immune checkpoint proteins results in reactivating the immune system and eliminating tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('reactivating', 'MPA', (77, 89))	('tumor', 'Disease', (124, 129))	('immune', 'CPA', (94, 100))	('Disrupting', 'Var', (0, 10))	('eliminating', 'NegReg', (112, 123))	('interaction', 'Interaction', (15, 26))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
44563	33418925	Our study showed that inhibiting HuR reduced HuR-regulated oncoproteins, including MITF, inhibited cell proliferation and cell cycle, diminished melanoma cell's migration and invasion, and culminated in apoptotic cell death.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('HuR', 'Gene', '1994', (45, 48))	('apoptotic cell death', 'CPA', (203, 223))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('203', '223'))	('cell proliferation', 'biological_process', 'GO:0008283', ('99', '117'))	('culminated in', 'Reg', (189, 202))	('HuR', 'Gene', (33, 36))	('inhibiting', 'Var', (22, 32))	('diminished', 'NegReg', (134, 144))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('inhibited', 'NegReg', (89, 98))	('MITF', 'Gene', '4286', (83, 87))	('HuR', 'Gene', '1994', (33, 36))	('HuR', 'Gene', (45, 48))	('cell cycle', 'biological_process', 'GO:0007049', ('122', '132'))	('MITF', 'Gene', (83, 87))	('reduced', 'NegReg', (37, 44))	('cell cycle', 'CPA', (122, 132))
44577	33418925	Briefly, cells (MeWo, 7 x 104 cells/well; A375, 1 x 105 cells/well; melanocytes, 2 x 105 cells/well) were seeded in six-well plates and incubated overnight in a CO2 incubator at 37  C. The following day, the tissue culture medium from the plates was replaced with an appropriate fresh serum-free culture medium and treated with nanoparticles (NP) containing HuR-specific siRNA (100 nM; HuR-NP) or scrambled siRNA (100 nM; C-NP).	('C-NP', 'Chemical', '-', (422, 426))	('100 nM', 'Var', (414, 420))	('HuR', 'Gene', (358, 361))	('HuR', 'Gene', '1994', (358, 361))	('A375', 'CellLine', 'CVCL:0132', (42, 46))	('CO2', 'Chemical', 'MESH:D002245', (161, 164))	('HuR', 'Gene', (386, 389))	('HuR', 'Gene', '1994', (386, 389))
44584	33418925	For determining the combinatorial treatment effect of HuR-NP and MEK inhibitor (U0126), MeWo or MeWo-MITF cells (7 x 104) seeded in six-well plates were treated with DMSO, C-NP, HuR-NP (100 nM siRNA), U0126 (20 microM; Cell Signaling Technology Inc., Beverly, MA, USA), C-NP plus U0126, and HuR-NP plus U0126.	('C-NP', 'Chemical', '-', (172, 176))	('HuR', 'Gene', '1994', (291, 294))	('HuR', 'Gene', '1994', (178, 181))	('DMSO', 'Chemical', 'MESH:D004121', (166, 170))	('MITF', 'Gene', '4286', (101, 105))	('C-NP', 'Chemical', '-', (270, 274))	('MEK', 'Gene', '5609', (65, 68))	('HuR', 'Gene', (54, 57))	('U0126', 'Chemical', 'MESH:C113580', (201, 206))	('U0126', 'Chemical', 'MESH:C113580', (280, 285))	('men', 'Species', '9606', (39, 42))	('MITF', 'Gene', (101, 105))	('Signaling', 'biological_process', 'GO:0023052', ('224', '233'))	('MEK', 'Gene', (65, 68))	('U0126', 'Var', (280, 285))	('U0126', 'Chemical', 'MESH:C113580', (80, 85))	('U0126', 'Chemical', 'MESH:C113580', (303, 308))	('HuR', 'Gene', '1994', (54, 57))	('HuR', 'Gene', (291, 294))	('HuR', 'Gene', (178, 181))
44617	33418925	To validate HuR as a potential target for melanoma therapy, we first examined the expression pattern of HuR in a panel of human melanoma cell lines (A375.S2, WM39, SK-MEL-3, OCM-1, A375, WM1316A, OMM2.3, and MeWo) and primary normal human melanocytes.	('melanoma', 'Disease', (42, 50))	('human', 'Species', '9606', (122, 127))	('human', 'Species', '9606', (233, 238))	('OCM-1', 'Species', '83984', (174, 179))	('HuR', 'Gene', '1994', (12, 15))	('WM39', 'CellLine', 'CVCL:2240', (158, 162))	('HuR', 'Gene', (104, 107))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('HuR', 'Gene', '1994', (104, 107))	('WM1316A', 'Var', (187, 194))	('SK-MEL-3', 'Chemical', '-', (164, 172))	('A375', 'CellLine', 'CVCL:0132', (181, 185))	('WM39', 'Var', (158, 162))	('HuR', 'Gene', (12, 15))	('A375', 'CellLine', 'CVCL:0132', (149, 153))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('melanoma', 'Disease', (128, 136))
44620	33418925	Genetic knockdown of HuR using HuR-NP resulted in the attenuation of HuR mRNA in both MeWo and A375 cell lines at 24 h and 48 h (Figure 1A; p < 0.05).	('HuR', 'Gene', (21, 24))	('HuR', 'Gene', '1994', (69, 72))	('HuR', 'Gene', (31, 34))	('HuR', 'Gene', '1994', (31, 34))	('knockdown', 'Var', (8, 17))	('attenuation', 'NegReg', (54, 65))	('HuR', 'Gene', (69, 72))	('HuR', 'Gene', '1994', (21, 24))	('A375', 'CellLine', 'CVCL:0132', (95, 99))
44638	33418925	Since HuR knockdown reduced cyclin D1 and cyclin E1 and concomitantly increased the expression of p27, we evaluated the cell cycle profile of melanoma (MeWo and A375) and melanocytes with and without the HuR-NP exposure.	('HuR', 'Gene', '1994', (6, 9))	('reduced', 'NegReg', (20, 27))	('increased', 'PosReg', (70, 79))	('cyclin', 'molecular_function', 'GO:0016538', ('28', '34'))	('HuR', 'Gene', '1994', (204, 207))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma', 'Disease', (142, 150))	('cyclin E1', 'Gene', (42, 51))	('A375', 'CellLine', 'CVCL:0132', (161, 165))	('cell cycle', 'biological_process', 'GO:0007049', ('120', '130'))	('cyclin', 'molecular_function', 'GO:0016538', ('42', '48'))	('knockdown', 'Var', (10, 19))	('expression', 'MPA', (84, 94))	('evaluated', 'Reg', (106, 115))	('cyclin D1', 'Gene', (28, 37))	('p27', 'Gene', '3429', (98, 101))	('p27', 'Gene', (98, 101))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('HuR', 'Gene', (6, 9))	('cyclin E1', 'Gene', '898', (42, 51))	('HuR', 'Gene', (204, 207))	('cyclin D1', 'Gene', '595', (28, 37))
44641	33418925	In A375, about 5% and 8% increase in the number of cells in the G1 phase at 24 h and 48 h, respectively, was observed upon HuR-NP treatment compared to untreated and C-NP-treated cells (p < 0.05).	('A375', 'CellLine', 'CVCL:0132', (3, 7))	('treatment', 'Var', (130, 139))	('men', 'Species', '9606', (135, 138))	('increase', 'PosReg', (25, 33))	('G1 phase', 'biological_process', 'GO:0051318', ('64', '72'))	('HuR', 'Gene', (123, 126))	('C-NP', 'Chemical', '-', (166, 170))	('HuR', 'Gene', '1994', (123, 126))
44668	33418925	These results show that MITF is a molecular target of HuR and that inhibiting HuR concomitantly reduces MITF and its downstream BCL-2 expression.	('reduces', 'NegReg', (96, 103))	('expression', 'MPA', (134, 144))	('BCL-2', 'Gene', '596', (128, 133))	('MITF', 'Gene', '4286', (24, 28))	('inhibiting', 'Var', (67, 77))	('MITF', 'Gene', (24, 28))	('HuR', 'Gene', (54, 57))	('HuR', 'Gene', '1994', (54, 57))	('MITF', 'Gene', (104, 108))	('HuR', 'Gene', (78, 81))	('MITF', 'Gene', '4286', (104, 108))	('HuR', 'Gene', '1994', (78, 81))	('BCL-2', 'Gene', (128, 133))	('BCL-2', 'molecular_function', 'GO:0015283', ('128', '133'))
44670	33418925	Studies have shown that inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway is beneficial in melanoma treatment.	('MAPK) signaling', 'biological_process', 'GO:0000165', ('73', '88'))	('inhibiting', 'Var', (24, 34))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('signaling pathway', 'biological_process', 'GO:0007165', ('79', '96'))	('men', 'Species', '9606', (128, 131))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('MAPK', 'molecular_function', 'GO:0004707', ('73', '77'))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
44671	33418925	Clinical studies testing inhibitors targeting MEK1/2, such as Trametinib alone and in combination with B-RAF inhibitor, Dabrafenib, have demonstrated clinical benefit in melanoma patients.	('Trametinib', 'Chemical', '-', (62, 72))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('MEK1', 'Gene', (46, 50))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('B-RAF', 'Gene', '673', (103, 108))	('benefit', 'PosReg', (159, 166))	('MEK1', 'molecular_function', 'GO:0004708', ('46', '50'))	('Dabrafenib', 'Chemical', 'MESH:C561627', (120, 130))	('inhibitors', 'Var', (25, 35))	('patients', 'Species', '9606', (179, 187))	('B-RAF', 'Gene', (103, 108))	('MEK1', 'Gene', '5604', (46, 50))
44676	33418925	Treatment of MeWo cells with U0126 resulted in a dose-dependent reduction in cell viability at 24 h and 48 h compared to DMSO-treated control cells (Figure S9; p < 0.05).	('U0126', 'Var', (29, 34))	('cell viability at 24 h', 'CPA', (77, 99))	('U0126', 'Chemical', 'MESH:C113580', (29, 34))	('reduction', 'NegReg', (64, 73))	('men', 'Species', '9606', (5, 8))	('DMSO', 'Chemical', 'MESH:D004121', (121, 125))
44678	33418925	Next, we investigated whether HuR-NP treatment could override U0126-treatment-induced MITF and exhibit increased efficacy.	('MITF', 'Gene', '4286', (86, 90))	('men', 'Species', '9606', (42, 45))	('men', 'Species', '9606', (73, 76))	('U0126-treatment-induced', 'Var', (62, 85))	('U0126', 'Chemical', 'MESH:C113580', (62, 67))	('override', 'PosReg', (53, 61))	('HuR', 'Gene', (30, 33))	('HuR', 'Gene', '1994', (30, 33))	('MITF', 'Gene', (86, 90))
44680	33418925	However, a synergistic effect in reducing cell viability and reduction in MITF and p-MEK1/2Ser217/221 expression was observed when HuR-NP was combined with U0126 compared to all other treatment groups (Figure 7 and Figure S10; p < 0.05).	('reducing', 'NegReg', (33, 41))	('MEK1', 'molecular_function', 'GO:0004708', ('85', '89'))	('MITF', 'Gene', '4286', (74, 78))	('cell viability', 'CPA', (42, 56))	('MITF', 'Gene', (74, 78))	('combined', 'Interaction', (142, 150))	('U0126', 'Var', (156, 161))	('expression', 'MPA', (102, 112))	('men', 'Species', '9606', (189, 192))	('MEK1', 'Gene', '5604', (85, 89))	('reduction', 'NegReg', (61, 70))	('HuR', 'Gene', '1994', (131, 134))	('HuR', 'Gene', (131, 134))	('MEK1', 'Gene', (85, 89))	('U0126', 'Chemical', 'MESH:C113580', (156, 161))	('Ser', 'cellular_component', 'GO:0005790', ('91', '94'))
44682	33418925	Another important observation was that the increased MITF expression observed in C-NP and U0126 combination treatment and attributed to U0126 was almost completely eliminated in HuR-NP and U0126 combination treatment, especially at 48 h after treatment (Figure 7 and Figure S10; p < 0.05).	('HuR', 'Gene', '1994', (178, 181))	('U0126', 'Chemical', 'MESH:C113580', (189, 194))	('men', 'Species', '9606', (248, 251))	('MITF', 'Gene', '4286', (53, 57))	('MITF', 'Gene', (53, 57))	('expression', 'MPA', (58, 68))	('C-NP', 'Chemical', '-', (81, 85))	('combination', 'Var', (96, 107))	('U0126', 'Chemical', 'MESH:C113580', (90, 95))	('eliminated', 'NegReg', (164, 174))	('men', 'Species', '9606', (113, 116))	('increased', 'PosReg', (43, 52))	('U0126', 'Chemical', 'MESH:C113580', (136, 141))	('U0126 combination', 'Var', (90, 107))	('HuR', 'Gene', (178, 181))	('men', 'Species', '9606', (212, 215))
44683	33418925	Our study results showed the HuR-NP suppressed U0126 induced MITF and produced enhanced antitumor activity in the melanoma cell line.	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('U0126', 'Var', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('MITF', 'Gene', '4286', (61, 65))	('enhanced', 'PosReg', (79, 87))	('MITF', 'Gene', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('HuR', 'Gene', (29, 32))	('HuR', 'Gene', '1994', (29, 32))	('tumor', 'Disease', (92, 97))	('U0126', 'Chemical', 'MESH:C113580', (47, 52))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
44684	33418925	Since our results showed HuR-NP treatment alone reduced MITF and U0126 induced MITF, we investigated whether HuR-NP can suppress MITF when overexpressed in melanoma cells analogous to that seen in melanoma patients.	('MITF', 'Gene', (129, 133))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('MITF', 'Gene', '4286', (79, 83))	('MITF', 'Gene', '4286', (56, 60))	('HuR', 'Gene', (25, 28))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('melanoma', 'Disease', (197, 205))	('MITF', 'Gene', (79, 83))	('suppress', 'NegReg', (120, 128))	('MITF', 'Gene', (56, 60))	('HuR', 'Gene', '1994', (25, 28))	('U0126', 'Chemical', 'MESH:C113580', (65, 70))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('reduced', 'NegReg', (48, 55))	('U0126', 'Var', (65, 70))	('HuR', 'Gene', (109, 112))	('MITF', 'Gene', '4286', (129, 133))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('patients', 'Species', '9606', (206, 214))	('men', 'Species', '9606', (37, 40))	('HuR', 'Gene', '1994', (109, 112))
44688	33418925	Furthermore, MITF overexpression greatly increased BCL-2 and HIF1-alpha expression in MeWo-MITF-M cells (Figure S11), both of which are downstream transcriptional targets of MITF.	('increased', 'PosReg', (41, 50))	('BCL-2', 'molecular_function', 'GO:0015283', ('51', '56'))	('MITF', 'Gene', '4286', (91, 95))	('MITF', 'Gene', (13, 17))	('MITF', 'Gene', (91, 95))	('MITF', 'Gene', '4286', (13, 17))	('BCL-2', 'Gene', '596', (51, 56))	('expression', 'MPA', (72, 82))	('MITF', 'Gene', (174, 178))	('overexpression', 'Var', (18, 32))	('HIF1-alpha', 'Gene', (61, 71))	('MITF', 'Gene', '4286', (174, 178))	('BCL-2', 'Gene', (51, 56))	('HIF1-alpha', 'Gene', '3091', (61, 71))
44693	33418925	HuR-NP and U0126 combination treatment produced a significant and greater inhibitory effect on MeWo-MITF-M cell viability with approximately 64% reduction at 24 h and 86% reduction at 48 h after treatment compared to all other treatment groups (Figure 9).	('HuR', 'Gene', '1994', (0, 3))	('combination', 'Var', (17, 28))	('HuR', 'Gene', (0, 3))	('U0126', 'Chemical', 'MESH:C113580', (11, 16))	('reduction', 'NegReg', (145, 154))	('men', 'Species', '9606', (232, 235))	('reduction', 'NegReg', (171, 180))	('men', 'Species', '9606', (200, 203))	('U0126', 'Gene', (11, 16))	('MITF', 'Gene', '4286', (100, 104))	('MITF', 'Gene', (100, 104))	('inhibitory effect', 'NegReg', (74, 91))	('men', 'Species', '9606', (34, 37))
44694	33418925	The inhibitory effect on cell viability produced by U0126 treatment (46% inhibition) and C-NP and U0126 combination treatment (44% inhibition) was equivalent to the inhibitory effect produced by HuR-NP treatment alone (46% inhibition) at 48 h compared to DMSO-treated control cells (Figure 9).	('HuR', 'Gene', '1994', (195, 198))	('men', 'Species', '9606', (63, 66))	('U0126', 'Chemical', 'MESH:C113580', (52, 57))	('HuR', 'Gene', (195, 198))	('men', 'Species', '9606', (121, 124))	('cell viability', 'CPA', (25, 39))	('men', 'Species', '9606', (207, 210))	('C-NP', 'Chemical', '-', (89, 93))	('DMSO', 'Chemical', 'MESH:D004121', (255, 259))	('U0126', 'Chemical', 'MESH:C113580', (98, 103))	('U0126', 'Var', (52, 57))
44695	33418925	Molecular studies showed HuR-NP and U0126 combination treatment produced the greatest reduction in HuR, p-MEK1/2Ser217/221, BCL-2 protein expression, and most importantly, almost completely eliminated MITF expression in MeWo-MITF-M cells compared to all other treatment groups (Figure 9 and Figure S13).	('MITF', 'Gene', (225, 229))	('reduction', 'NegReg', (86, 95))	('men', 'Species', '9606', (265, 268))	('HuR', 'Gene', '1994', (99, 102))	('HuR', 'Gene', (25, 28))	('MEK1', 'Gene', '5604', (106, 110))	('HuR', 'Gene', (99, 102))	('Ser', 'cellular_component', 'GO:0005790', ('112', '115'))	('U0126', 'Chemical', 'MESH:C113580', (36, 41))	('HuR', 'Gene', '1994', (25, 28))	('MEK1', 'molecular_function', 'GO:0004708', ('106', '110'))	('expression', 'MPA', (206, 216))	('U0126 combination', 'Var', (36, 53))	('combination', 'Var', (42, 53))	('MITF', 'Gene', '4286', (201, 205))	('eliminated', 'NegReg', (190, 200))	('MITF', 'Gene', '4286', (225, 229))	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('BCL-2', 'molecular_function', 'GO:0015283', ('124', '129'))	('BCL-2', 'Gene', '596', (124, 129))	('MEK1', 'Gene', (106, 110))	('BCL-2', 'Gene', (124, 129))	('MITF', 'Gene', (201, 205))	('men', 'Species', '9606', (59, 62))
44699	33418925	While co-targeting B-RAF and MEK1/2 have shown to improve treatment response and provide clinical benefit, the manifestation of treatment-related acquired resistance continues to evolve.	('MEK1', 'Gene', '5604', (29, 33))	('men', 'Species', '9606', (63, 66))	('MEK1', 'Gene', (29, 33))	('improve', 'PosReg', (50, 57))	('co-targeting', 'Var', (6, 18))	('B-RAF', 'Gene', (19, 24))	('treatment response', 'CPA', (58, 76))	('MEK1', 'molecular_function', 'GO:0004708', ('29', '33'))	('men', 'Species', '9606', (133, 136))	('B-RAF', 'Gene', '673', (19, 24))	('clinical benefit', 'CPA', (89, 105))
44702	33418925	Studies have shown that HuR is a molecular target for therapy, and inhibiting HuR resulted in antitumor and antimetastatic activity.	('HuR', 'Gene', '1994', (24, 27))	('antimetastatic activity', 'CPA', (108, 131))	('HuR', 'Gene', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('inhibiting', 'Var', (67, 77))	('tumor', 'Disease', (98, 103))	('HuR', 'Gene', '1994', (78, 81))	('HuR', 'Gene', (78, 81))
44704	33418925	Activating B-RAF mutations are common and occur in approximately 50% of cutaneous melanomas.	('Activating', 'PosReg', (0, 10))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (72, 91))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (72, 91))	('B-RAF', 'Gene', '673', (11, 16))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (72, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('cutaneous melanomas', 'Disease', (72, 91))	('B-RAF', 'Gene', (11, 16))	('mutations', 'Var', (17, 26))
44711	33418925	HuR-NP-mediated inhibition led to a G1 phase cell cycle arrest that subsequently led to apoptotic cell death, as evidenced by the activation of the caspase cascade.	('HuR', 'Gene', '1994', (0, 3))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('88', '108'))	('G1 phase', 'biological_process', 'GO:0051318', ('36', '44'))	('HuR', 'Gene', (0, 3))	('apoptotic cell death', 'CPA', (88, 108))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('45', '62'))	('activation', 'PosReg', (130, 140))	('arrest', 'Disease', 'MESH:D006323', (56, 62))	('arrest', 'Disease', (56, 62))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (45, 62))	('caspase cascade', 'Pathway', (148, 163))	('inhibition', 'Var', (16, 26))
44718	33418925	To our surprise, a marked reduction in MITF and MITF-regulated BCL-2 and HIF-1alpha proteins was observed upon silencing of HuR.	('BCL-2', 'Gene', '596', (63, 68))	('silencing', 'Var', (111, 120))	('MITF', 'Gene', '4286', (39, 43))	('MITF', 'Gene', (39, 43))	('HuR', 'Gene', (124, 127))	('HuR', 'Gene', '1994', (124, 127))	('BCL-2', 'Gene', (63, 68))	('HIF-1alpha', 'Gene', (73, 83))	('reduction', 'NegReg', (26, 35))	('MITF', 'Gene', '4286', (48, 52))	('MITF', 'Gene', (48, 52))	('HIF-1alpha', 'Gene', '3091', (73, 83))	('BCL-2', 'molecular_function', 'GO:0015283', ('63', '68'))
44724	33418925	Therefore, we speculated that incorporating U0126 into HuR-NP treatment will result in enhanced antitumor activity.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('HuR', 'Gene', '1994', (55, 58))	('tumor', 'Disease', (100, 105))	('HuR', 'Gene', (55, 58))	('men', 'Species', '9606', (67, 70))	('U0126', 'Var', (44, 49))	('enhanced', 'PosReg', (87, 95))	('U0126', 'Chemical', 'MESH:C113580', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
44736	33418925	In addition, B-RAF and N-RAS are rarely mutated, instead GNAQ or GNA11 mutations are frequently detected and known to activate the MAPK pathway also.	('B-RAF', 'Gene', '673', (13, 18))	('N-RAS', 'Gene', (23, 28))	('GNAQ', 'Gene', (57, 61))	('MAPK pathway', 'Pathway', (131, 143))	('N-RAS', 'Gene', '4893', (23, 28))	('B-RAF', 'Gene', (13, 18))	('mutations', 'Var', (71, 80))	('GNA11', 'Gene', '2767', (65, 70))	('GNA11', 'Gene', (65, 70))	('activate', 'PosReg', (118, 126))	('MAPK', 'molecular_function', 'GO:0004707', ('131', '135'))	('GNAQ', 'Gene', '2776', (57, 61))
44739	33418925	We have established proof-of-concept and shown that targeting HuR represents a promising therapeutic option for melanoma treatment with or without oncogenic B-RAF mutation.	('HuR', 'Gene', (62, 65))	('men', 'Species', '9606', (126, 129))	('HuR', 'Gene', '1994', (62, 65))	('B-RAF', 'Gene', '673', (157, 162))	('B-RAF', 'Gene', (157, 162))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('targeting', 'Var', (52, 61))	('melanoma', 'Disease', (112, 120))
44740	33418925	Furthermore, inhibiting HuR offered the additional advantage of reducing MITF expression in melanoma cells, and combinatorial therapy targeting HuR and MEK1/2 produced synergistic antitumor activity.	('MEK1', 'Gene', (152, 156))	('reducing', 'NegReg', (64, 72))	('HuR', 'Gene', (144, 147))	('expression', 'MPA', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('HuR', 'Gene', '1994', (24, 27))	('HuR', 'Gene', '1994', (144, 147))	('HuR', 'Gene', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('tumor', 'Disease', (184, 189))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('MEK1', 'molecular_function', 'GO:0004708', ('152', '156'))	('MITF', 'Gene', '4286', (73, 77))	('MITF', 'Gene', (73, 77))	('MEK1', 'Gene', '5604', (152, 156))	('inhibiting', 'Var', (13, 23))
44747	33418925	This research was funded by the National Institutes of Health: R01 CA167516; National Institute of General Medical Sciences: P20 GM103639; National Cancer Institute: P30CA225520.	('P30CA225520', 'Var', (166, 177))	('Cancer', 'Phenotype', 'HP:0002664', (148, 154))	('P20', 'Gene', (125, 128))	('Cancer', 'Disease', (148, 154))	('P20', 'Gene', '51673', (125, 128))	('Cancer', 'Disease', 'MESH:D009369', (148, 154))
44808	33291752	While murine VEGF carries a mutation that may interfere with binding properties of conventional VEGF antibodies, human and porcine VEGF have high sequence homology and can conveniently be detected in the in cell culture supernatant by commercially available ELISA designed for human studies.	('binding', 'molecular_function', 'GO:0005488', ('61', '68'))	('human', 'Species', '9606', (113, 118))	('mutation', 'Var', (28, 36))	('murine', 'Species', '10090', (6, 12))	('interfere', 'NegReg', (46, 55))	('human', 'Species', '9606', (277, 282))	('binding', 'Interaction', (61, 68))
44879	33291752	The main difference for these fucoidans was their molecular weight; there was a high-molecular weight fucoidan (1548 KDa), a medium-molecular weight fucoidan (499 KDa), and a low-molecular weight fucoidan (26.9 KDa).	('fucoidan', 'Chemical', 'MESH:C007789', (149, 157))	('499', 'Var', (159, 162))	('fucoidans', 'Chemical', 'MESH:C007789', (30, 39))	('fucoidan', 'Chemical', 'MESH:C007789', (102, 110))	('fucoidan', 'Chemical', 'MESH:C007789', (196, 204))	('1548 KDa', 'Var', (112, 120))	('fucoidan', 'Chemical', 'MESH:C007789', (30, 38))
44952	32826455	Moreover, tube formation assay revealed that miR-145-transfected human microvascular endothelial cell line formed shorter tube length (36.10 +- 1.51 mm vs. 42.91 +- 0.94 mm, t = 6.603, P = 0.003) and less branch points (350.00 +- 19.97 vs. 406.67 +- 17.62, t = 3.685, P = 0.021) as compared with controls.	('human', 'Species', '9606', (65, 70))	('less', 'NegReg', (200, 204))	('branch points', 'CPA', (205, 218))	('shorter', 'NegReg', (114, 121))	('tube length', 'CPA', (122, 133))	('tube formation', 'biological_process', 'GO:0035148', ('10', '24'))	('miR-145-transfected', 'Var', (45, 64))
44954	32826455	In vivo, xenografts expressing miR-145 had smaller sizes (miR-145 vs. miR-scr, 717.41 +- 502.62 mm3vs.	('miR-145', 'Var', (31, 38))	('smaller', 'NegReg', (43, 50))	('scr', 'Gene', '109559', (74, 77))	('scr', 'Gene', (74, 77))
44959	32826455	Recent studies have demonstrated that miRNAs are differentially expressed in lung, nasopharyngeal, gastric and breast cancers, and may function as either oncogenes or tumor suppressors by controlling the expression of their target genes.	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('controlling', 'Reg', (188, 199))	('breast cancers', 'Phenotype', 'HP:0003002', (111, 125))	('function', 'Reg', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancers', 'Disease', 'MESH:D001943', (111, 125))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('breast cancers', 'Disease', (111, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('miRNAs', 'Var', (38, 44))	('expression', 'MPA', (204, 214))	('lung', 'Disease', (77, 81))	('nasopharyngeal', 'Disease', (83, 97))	('tumor', 'Disease', (167, 172))	('gastric', 'Disease', (99, 106))
44960	32826455	The overexpression of several miRNAs, such as miR-145 and miR-224-5p, has been demonstrated an inhibitory role in migration, proliferation, and invasion of UM cells.	('miR-145', 'Var', (46, 53))	('migration', 'CPA', (114, 123))	('proliferation', 'CPA', (125, 138))	('invasion', 'CPA', (144, 152))	('miR-224', 'Gene', (58, 65))	('UM', 'Phenotype', 'HP:0007716', (156, 158))	('miR-224', 'Gene', '407009', (58, 65))	('overexpression', 'PosReg', (4, 18))
44986	32826455	For the in vivo tumor growth assay, 12 four-week-old female BALB/c nude mice (six per group), maintained in pathogen-free conditions with standard diets, were injected subcutaneously in the right side of the axilla with 3 x 106 OCM-1 cells transfected with miR-145-5p mimic vector or its negative control vector.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('nude mice', 'Species', '10090', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('miR-145-5p', 'Chemical', '-', (257, 267))	('miR-145-5p mimic vector', 'Var', (257, 280))	('OCM-1', 'Species', '83984', (228, 233))
44996	32826455	In our previous study, we demonstrated that miR-145-5p was significantly downregulated in UM tissues compared with normal uveal tissues.	('miR-145-5p', 'Chemical', '-', (44, 54))	('miR-145-5p', 'Var', (44, 54))	('downregulated', 'NegReg', (73, 86))	('UM', 'Phenotype', 'HP:0007716', (90, 92))
44997	32826455	Thus, it could be speculated that miR-145-5p might directly modulate N-RAS and VEGF expression in UM.	('N-RAS', 'Gene', '4893', (69, 74))	('modulate', 'Reg', (60, 68))	('VEGF', 'Gene', '7422', (79, 83))	('miR-145-5p', 'Var', (34, 44))	('miR-145-5p', 'Chemical', '-', (34, 44))	('expression', 'MPA', (84, 94))	('UM', 'Phenotype', 'HP:0007716', (98, 100))	('VEGF', 'Gene', (79, 83))	('N-RAS', 'Gene', (69, 74))
45001	32826455	The luciferase activities of vectors carrying wild type VEGFA 3'-UTR (WT) and NRAS 3'-UTR (WT) were attenuated by co-transfection with miR-145-5p, while there was no significant difference in groups transfected with mutant 3'-UTR of VEGFA or NRAS and the negative control of miR-145-5p [Figure 2B].	('VEGFA', 'Gene', (233, 238))	('miR-145-5p', 'Chemical', '-', (135, 145))	('VEGFA', 'Gene', (56, 61))	('mutant', 'Var', (216, 222))	('NRAS', 'Gene', (242, 246))	('attenuated', 'NegReg', (100, 110))	('NRAS', 'Gene', (78, 82))	('activities', 'MPA', (15, 25))	('VEGFA', 'Gene', '7422', (233, 238))	('VEGFA', 'Gene', '7422', (56, 61))	('NRAS', 'Gene', '4893', (242, 246))	('NRAS', 'Gene', '4893', (78, 82))	('luciferase', 'Enzyme', (4, 14))	('miR-145-5p', 'Var', (135, 145))	('miR-145-5p', 'Chemical', '-', (275, 285))
45002	32826455	These data demonstrated that VEGFA and NRAS might be the direct targets of miR-145-5p.	('VEGFA', 'Gene', '7422', (29, 34))	('miR-145-5p', 'Chemical', '-', (75, 85))	('miR-145-5p', 'Var', (75, 85))	('VEGFA', 'Gene', (29, 34))	('NRAS', 'Gene', (39, 43))	('NRAS', 'Gene', '4893', (39, 43))
45003	32826455	Since our data demonstrated that VEGFA and N-RAS were directly targeted genes regulated by miR-145-5p, we next investigated the effects of miR-145 on tumor angiogenesis and invasion in vitro.	('miR-145-5p', 'Var', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('N-RAS', 'Gene', (43, 48))	('VEGFA', 'Gene', (33, 38))	('miR-145-5p', 'Chemical', '-', (91, 101))	('angiogenesis', 'biological_process', 'GO:0001525', ('156', '168'))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('N-RAS', 'Gene', '4893', (43, 48))	('tumor', 'Disease', (150, 155))	('VEGFA', 'Gene', '7422', (33, 38))
45005	32826455	Transwell assays were performed to investigate the effects of upregulation of miR-145-5p on the invasion of UM cells in vitro.	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('miR-145-5p', 'Chemical', '-', (78, 88))	('miR-145-5p', 'Var', (78, 88))	('upregulation', 'PosReg', (62, 74))
45013	32826455	In addition, the expression of N-RAS (0.20 +- 0.09 vs. 0.70 +- 0.09, t = 9.715, P < 0.001), p-AKT (0.18 +- 0.09 vs. 0.72 +- 0.11, t = 9.304, P < 0.001), m-TOR (0.07 +- 0.02 vs. 0.40 +- 0.02, t = 27.116, P < 0.001) and VEGF (0.36 +- 0.07 vs. 0.76 +- 0.29, t = 3.327, P = 0.018) were also reduced in stable miR-145 precursor transfected xenografts compared with controls, as examined by Western blotting.	('N-RAS', 'Gene', (31, 36))	('AKT', 'Gene', '207', (94, 97))	('TOR', 'Gene', (155, 158))	('TOR', 'Gene', '6097', (155, 158))	('miR-145', 'Gene', (305, 312))	('N-RAS', 'Gene', '4893', (31, 36))	('expression', 'MPA', (17, 27))	('AKT', 'Gene', (94, 97))	('VEGF', 'Gene', '7422', (218, 222))	('VEGF', 'Gene', (218, 222))	('reduced', 'NegReg', (287, 294))	('0.20', 'Var', (38, 42))
45022	32826455	However, the underlying mechanisms by which miR-145-5p regulates UM angiogenesis remain unknown.	('UM', 'Phenotype', 'HP:0007716', (65, 67))	('UM angiogenesis', 'CPA', (65, 80))	('miR-145-5p', 'Var', (44, 54))	('miR-145-5p', 'Chemical', '-', (44, 54))	('angiogenesis', 'biological_process', 'GO:0001525', ('68', '80'))	('regulates', 'Reg', (55, 64))
45023	32826455	The inhibitory effects of miR-145-5p on tumor cell lines have also been confirmed in several studies.	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('miR-145-5p', 'Chemical', '-', (26, 36))	('miR-145-5p', 'Var', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
45024	32826455	reported that VEGF expression in the miR-145 transfected group was significantly downregulated compared with that in the blank group in osteosarcoma cells.	('osteosarcoma', 'Disease', (136, 148))	('expression', 'MPA', (19, 29))	('transfected', 'Var', (45, 56))	('osteosarcoma', 'Phenotype', 'HP:0002669', (136, 148))	('downregulated', 'NegReg', (81, 94))	('osteosarcoma', 'Disease', 'MESH:D012516', (136, 148))	('VEGF', 'Gene', '7422', (14, 18))	('miR-145', 'Gene', (37, 44))	('VEGF', 'Gene', (14, 18))
45025	32826455	Boufraqech et al  suggested that miR-145 could regulate thyroid cancer growth by mediating the PI3K/Akt pathway and may serve as a useful diagnostic marker for thyroid cancer diagnosis.	('Akt', 'Gene', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('regulate', 'Reg', (47, 55))	('miR-145', 'Var', (33, 40))	('mediating', 'Reg', (81, 90))	('thyroid cancer', 'Disease', 'MESH:D013964', (56, 70))	('thyroid cancer', 'Disease', (160, 174))	('thyroid cancer', 'Phenotype', 'HP:0002890', (160, 174))	('PI3K', 'molecular_function', 'GO:0016303', ('95', '99'))	('Akt', 'Gene', '207', (100, 103))	('thyroid cancer', 'Disease', 'MESH:D013964', (160, 174))	('thyroid cancer', 'Phenotype', 'HP:0002890', (56, 70))	('thyroid cancer', 'Disease', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
45030	32826455	The bioinformatic analysis results indicated that VEGF and N-RAS might be the direct targets of miR-145-5p in UM angiogenesis.	('angiogenesis', 'biological_process', 'GO:0001525', ('113', '125'))	('VEGF', 'Gene', (50, 54))	('UM', 'Phenotype', 'HP:0007716', (110, 112))	('UM angiogenesis', 'CPA', (110, 125))	('N-RAS', 'Gene', (59, 64))	('VEGF', 'Gene', '7422', (50, 54))	('N-RAS', 'Gene', '4893', (59, 64))	('miR-145-5p', 'Chemical', '-', (96, 106))	('miR-145-5p', 'Var', (96, 106))
45033	32826455	The observed different effects of miR-145-5p in diverse tumors are very promising for application as diagnostic or prognostic biomarkers.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('miR-145-5p', 'Var', (34, 44))	('tumors', 'Disease', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('miR-145-5p', 'Chemical', '-', (34, 44))
45048	29416875	nBAP1 protein loss did not correlate with a BAP1 mutation in 23% (6/26) of the UMs analysed.	('protein', 'Protein', (6, 13))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('mutation', 'Var', (49, 57))	('BAP1', 'Gene', '8314', (1, 5))	('BAP1', 'Gene', '8314', (44, 48))	('BAP1', 'Gene', (1, 5))	('BAP1', 'Gene', (44, 48))	('loss', 'NegReg', (14, 18))
45050	29416875	These tumours tended to carry loss-of-function BAP1 mutations.	('mutations', 'Var', (52, 61))	('loss-of-function', 'NegReg', (30, 46))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('BAP1', 'Gene', '8314', (47, 51))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('tumours', 'Disease', (6, 13))	('BAP1', 'Gene', (47, 51))
45051	29416875	Our study demonstrates loss of nBAP1 expression to be the strongest prognostic marker in UM, confirming its importance in UM progression.	('BAP1', 'Gene', '8314', (32, 36))	('UM', 'Phenotype', 'HP:0007716', (89, 91))	('BAP1', 'Gene', (32, 36))	('UM', 'Phenotype', 'HP:0007716', (122, 124))	('loss', 'Var', (23, 27))	('expression', 'MPA', (37, 47))
45059	29416875	Further abnormalities described in UM include loss of 1p, which is associated with poor prognosis in the context of M3 15, and gains on 6p, which, in the absence of additional chromosomal abnormalities, correspond with a good prognosis 16, 17.	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('loss', 'Var', (46, 50))	('gains on 6p', 'Var', (127, 138))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (176, 201))	('chromosomal abnormalities', 'Disease', (176, 201))
45060	29416875	More recently, mutations occurring in UM have been identified in several genes, including GNAQ, GNA11, BAP1, SF3B1, EIF1AX, PLCB4, and CYSLTR2 11, 18, 19, 20, 21, 22.	('BAP1', 'Gene', '8314', (103, 107))	('SF3B1', 'Gene', (109, 114))	('GNA11', 'Gene', (96, 101))	('BAP1', 'Gene', (103, 107))	('mutations', 'Var', (15, 24))	('GNAQ', 'Gene', '2776', (90, 94))	('EIF1AX', 'Gene', '1964', (116, 122))	('EIF1AX', 'Gene', (116, 122))	('PLCB4', 'Gene', '5332', (124, 129))	('SF3B1', 'Gene', '23451', (109, 114))	('CYSLTR2', 'Gene', '57105', (135, 142))	('UM', 'Phenotype', 'HP:0007716', (38, 40))	('GNA11', 'Gene', '2767', (96, 101))	('GNAQ', 'Gene', (90, 94))	('CYSLTR2', 'Gene', (135, 142))	('PLCB4', 'Gene', (124, 129))
45061	29416875	In particular, inactivating BAP1 mutations are associated with a poor outcome, being present in ~84% of all UMs that went on to produce metastases 19, 23, 24.	('BAP1', 'Gene', '8314', (28, 32))	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('inactivating', 'Var', (15, 27))	('BAP1', 'Gene', (28, 32))	('metastases 19', 'Disease', 'MESH:D009362', (136, 149))	('mutations', 'Var', (33, 42))	('metastases 19', 'Disease', (136, 149))
45062	29416875	BAP1 mutations similarly correspond with a significantly worse prognosis in renal clear cell carcinoma 25 and cholangiocarcinoma 26, whilst in mesothelioma BAP1 inactivation is associated with a good prognosis 27.	('mesothelioma', 'Disease', (143, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('BAP1', 'Gene', (0, 4))	('BAP1', 'Gene', '8314', (156, 160))	('mesothelioma', 'Disease', 'MESH:D008654', (143, 155))	('mutations', 'Var', (5, 14))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (76, 102))	('renal clear cell carcinoma', 'Disease', (76, 102))	('cholangiocarcinoma', 'Disease', (110, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('BAP1', 'Gene', (156, 160))	('BAP1', 'Gene', '8314', (0, 4))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (110, 128))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (110, 128))
45063	29416875	Families with members carrying germline mutations in BAP1 have also been described, with individuals most often affected by mesothelioma, melanomas including UM, and renal cell carcinoma 28, 29.	('melanomas', 'Disease', 'MESH:D008545', (138, 147))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('renal cell carcinoma', 'Disease', (166, 186))	('affected', 'Reg', (112, 120))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (166, 186))	('mesothelioma', 'Disease', (124, 136))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (166, 186))	('melanomas', 'Disease', (138, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('BAP1', 'Gene', '8314', (53, 57))	('UM', 'Phenotype', 'HP:0007716', (158, 160))	('germline mutations', 'Var', (31, 49))	('mesothelioma', 'Disease', 'MESH:D008654', (124, 136))	('melanomas', 'Phenotype', 'HP:0002861', (138, 147))	('BAP1', 'Gene', (53, 57))
45067	29416875	Functionally, BAP1 nonsense or frameshift mutations lead to truncated BAP1 protein with loss of nuclear localisation and/or reduced protein or mRNA stability 23.	('protein', 'MPA', (132, 139))	('frameshift mutations', 'Var', (31, 51))	('BAP1', 'Gene', '8314', (14, 18))	('localisation', 'biological_process', 'GO:0051179', ('104', '116'))	('reduced', 'NegReg', (124, 131))	('truncated', 'MPA', (60, 69))	('BAP1', 'Gene', '8314', (70, 74))	('nonsense', 'Var', (19, 27))	('BAP1', 'Gene', (14, 18))	('loss', 'NegReg', (88, 92))	('N', 'Chemical', 'MESH:D009584', (145, 146))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('BAP1', 'Gene', (70, 74))	('protein', 'Protein', (75, 82))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('nuclear localisation', 'MPA', (96, 116))	('lead', 'Reg', (52, 56))	('mRNA stability 23', 'MPA', (143, 160))
45073	29416875	Indeed, in cell lines derived from mesothelioma patients, mutant BAP1 was associated with cytoplasmic sequestration of the protein due to loss of the NLS 45.	('mutant', 'Var', (58, 64))	('loss', 'NegReg', (138, 142))	('BAP1', 'Gene', '8314', (65, 69))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('mesothelioma', 'Disease', (35, 47))	('N', 'Chemical', 'MESH:D009584', (150, 151))	('BAP1', 'Gene', (65, 69))	('cytoplasmic sequestration of the protein', 'MPA', (90, 130))	('mesothelioma', 'Disease', 'MESH:D008654', (35, 47))	('NLS 45', 'Protein', (150, 156))	('patients', 'Species', '9606', (48, 56))
45089	29416875	We hypothesized that the phenomenon of 'focal perinuclear' cBAP1 may be due to distinct BAP1 mutations resulting in mis-localisation.	('localisation', 'biological_process', 'GO:0051179', ('120', '132'))	("'focal", 'PosReg', (39, 45))	('mutations', 'Var', (93, 102))	('BAP1', 'Gene', (88, 92))	('BAP1', 'Gene', '8314', (60, 64))	('BAP1', 'Gene', '8314', (88, 92))	('BAP1', 'Gene', (60, 64))	('mis-localisation', 'MPA', (116, 132))
45094	29416875	A second cohort of 14 UM samples had previously undergone direct sequencing for BAP1 alterations at OSU.	('UM', 'Phenotype', 'HP:0007716', (22, 24))	('BAP1', 'Gene', '8314', (80, 84))	('alterations', 'Var', (85, 96))	('BAP1', 'Gene', (80, 84))
45117	29416875	Both UMs negative for nBAP1 (Log Rank, p < 0.001) and M3 UMs (Log rank, p = 0.001) were significantly associated with a reduced survival time (Figure 1D,E).	('BAP1', 'Gene', (23, 27))	('M3 UMs', 'Var', (54, 60))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('BAP1', 'Gene', '8314', (23, 27))	('negative', 'NegReg', (9, 17))	('UM', 'Phenotype', 'HP:0007716', (5, 7))	('survival time', 'CPA', (128, 141))	('reduced', 'NegReg', (120, 127))
45139	29416875	Of the 17 nBAP1 negative cases examined, 3/7 cBAP1 diffuse UM were wild-type for BAP1and 1/7 harboured a splice acceptor mutation prior to exon 2, causing loss-of-function, while 3/7 had truncating, loss-of-function BAP1 mutations (Figure 4 and supplementary material, Table S4).	('BAP1', 'Gene', (216, 220))	('truncating', 'MPA', (187, 197))	('mutations', 'Var', (221, 230))	('BAP1', 'Gene', (81, 85))	('BAP1', 'Gene', '8314', (11, 15))	('loss-of-function', 'NegReg', (155, 171))	('BAP1', 'Gene', '8314', (46, 50))	('BAP1and 1', 'Gene', '8314', (81, 90))	('loss-of-function', 'NegReg', (199, 215))	('BAP1', 'Gene', (11, 15))	('mutation', 'Var', (121, 129))	('BAP1and 1', 'Gene', (81, 90))	('BAP1', 'Gene', (46, 50))	('BAP1', 'Gene', '8314', (216, 220))	('BAP1', 'Gene', '8314', (81, 85))	('UM', 'Phenotype', 'HP:0007716', (59, 61))
45140	29416875	In contrast, 7/9 cBAP1 'focal perinuclear' UM harboured loss-of-function BAP1 mutations.	('BAP1', 'Gene', '8314', (73, 77))	('BAP1', 'Gene', '8314', (18, 22))	('BAP1', 'Gene', (73, 77))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('mutations', 'Var', (78, 87))	('BAP1', 'Gene', (18, 22))	('loss-of-function', 'NegReg', (56, 72))
45142	29416875	In the independent OSU cohort, 6/9 nBAP1 negative UM harboured a BAP1 mutation, and 1/9 had a benign variant rs149499021.	('harboured', 'Reg', (53, 62))	('BAP1', 'Gene', '8314', (65, 69))	('negative', 'NegReg', (41, 49))	('rs149499021', 'Var', (109, 120))	('BAP1', 'Gene', (65, 69))	('BAP1', 'Gene', '8314', (36, 40))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('BAP1', 'Gene', (36, 40))	('mutation', 'Var', (70, 78))	('rs149499021', 'Mutation', 'rs149499021', (109, 120))
45143	29416875	In the nBAP1 positive UM, 4/5 showed no mutation with only one case having the benign variant rs149499021 [40].	('rs149499021 [', 'Var', (94, 107))	('rs149499021', 'Mutation', 'rs149499021', (94, 105))	('BAP1', 'Gene', '8314', (8, 12))	('UM', 'Phenotype', 'HP:0007716', (22, 24))	('BAP1', 'Gene', (8, 12))
45144	29416875	Of the three cases showing 'focal perinuclear' cBAP1, two had INDELs and one had a benign variant (supplementary material, Table S5).	('INDELs', 'Var', (62, 68))	('BAP1', 'Gene', '8314', (48, 52))	('had', 'Reg', (58, 61))	('BAP1', 'Gene', (48, 52))	('N', 'Chemical', 'MESH:D009584', (63, 64))
45149	29416875	We provide evidence to suggest that the subcellular localisation of cBAP1 in nBAP1-negative UM is associated with the presence of BAP1 mutations.	('UM', 'Phenotype', 'HP:0007716', (92, 94))	('BAP1', 'Gene', (130, 134))	('BAP1', 'Gene', '8314', (69, 73))	('localisation', 'biological_process', 'GO:0051179', ('52', '64'))	('BAP1', 'Gene', (69, 73))	('mutations', 'Var', (135, 144))	('BAP1', 'Gene', '8314', (78, 82))	('BAP1', 'Gene', '8314', (130, 134))	('associated', 'Reg', (98, 108))	('BAP1', 'Gene', (78, 82))
45150	29416875	That is, UM with 'focal perinuclear' cBAP1 tended to carry loss-of-function BAP1 mutations compared to UM with diffuse cytoplasmic BAP1.	('UM', 'Phenotype', 'HP:0007716', (103, 105))	('BAP1', 'Gene', (38, 42))	('BAP1', 'Gene', '8314', (76, 80))	('loss-of-function', 'NegReg', (59, 75))	('BAP1', 'Gene', '8314', (131, 135))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('BAP1', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('BAP1', 'Gene', (131, 135))	('BAP1', 'Gene', '8314', (38, 42))
45155	29416875	increasing age at primary management; ciliary body involvement; increasing tumour LBD; large tumour height; epithelioid cell morphology; PAS-positive connective tissue loops; and loss of chromosome 3 [6].	('epithelioid cell morphology', 'CPA', (108, 135))	('tumour height', 'Disease', 'MESH:D009369', (93, 106))	('increasing', 'PosReg', (64, 74))	('chromosome', 'cellular_component', 'GO:0005694', ('187', '197'))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('tumour LBD', 'Disease', (75, 85))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('ciliary body involvement', 'CPA', (38, 62))	('tumour height', 'Disease', (93, 106))	('PAS', 'cellular_component', 'GO:0000407', ('137', '140'))	('tumour LBD', 'Disease', 'MESH:D020192', (75, 85))	('loss', 'Var', (179, 183))
45156	29416875	Previous studies have indicated that there is a strong association between the absence of nBAP1 protein expression and mutations in BAP1 [23,39].	('BAP1', 'Gene', (91, 95))	('protein', 'Protein', (96, 103))	('BAP1', 'Gene', '8314', (132, 136))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('BAP1', 'Gene', (132, 136))	('absence', 'NegReg', (79, 86))	('expression', 'MPA', (104, 114))	('BAP1', 'Gene', '8314', (91, 95))	('mutations', 'Var', (119, 128))
45157	29416875	For example, Van de Nes et al demonstrated in a cohort of 66 UM that 33/37 (89%) M3 UM had a BAP1 mutation together with an absence of nBAP1 protein expression 23.	('BAP1', 'Gene', '8314', (93, 97))	('BAP1', 'Gene', (136, 140))	('mutation', 'Var', (98, 106))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('Nes', 'Gene', '10763', (20, 23))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('BAP1', 'Gene', (93, 97))	('BAP1', 'Gene', '8314', (136, 140))	('Nes', 'Gene', (20, 23))
45158	29416875	A similar proportion was reported by Koopmans et al in their study of 74 UM, with 88% of the M3 UM harbouring a BAP1 mutation together with loss of nuclear protein expression 39.	('BAP1', 'Gene', (112, 116))	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('UM', 'Phenotype', 'HP:0007716', (73, 75))	('BAP1', 'Gene', '8314', (112, 116))	('mutation', 'Var', (117, 125))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))
45159	29416875	In our current study of 26 nBAP1 negative UM, 20 (77%) harboured mutations in BAP1, which is similar to the previous reports detailed above.	('BAP1', 'Gene', '8314', (28, 32))	('BAP1', 'Gene', (28, 32))	('BAP1', 'Gene', '8314', (78, 82))	('UM', 'Phenotype', 'HP:0007716', (42, 44))	('harboured', 'Reg', (55, 64))	('mutations', 'Var', (65, 74))	('BAP1', 'Gene', (78, 82))
45160	29416875	Of particular interest in our current study was the identification of a subset of M3 UM (20/104; 19%) that showed nBAP1 positivity, correlating with a significantly increased survival time as compared with the M3/nBAP1-negative UM (p = 0.014) (Figure 2B).	('survival time', 'CPA', (175, 188))	('BAP1', 'Gene', '8314', (115, 119))	('UM', 'Phenotype', 'HP:0007716', (228, 230))	('BAP1', 'Gene', '8314', (214, 218))	('BAP1', 'Gene', (115, 119))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('increased', 'PosReg', (165, 174))	('positivity', 'Var', (120, 130))	('BAP1', 'Gene', (214, 218))
45162	29416875	More recently, BAP1 IHC performed at our centre showed nBAP1 positivity in metastatic UM cells within the liver of a patient who is alive 37 years after diagnosis of the primary UM.	('UM', 'Phenotype', 'HP:0007716', (86, 88))	('UM', 'Phenotype', 'HP:0007716', (178, 180))	('BAP1', 'Gene', '8314', (56, 60))	('BAP1', 'Gene', '8314', (15, 19))	('BAP1', 'Gene', (56, 60))	('patient', 'Species', '9606', (117, 124))	('BAP1', 'Gene', (15, 19))	('positivity', 'Var', (61, 71))
45164	29416875	Indeed, three M3/nBAP1 positive cases were analysed for BAP1 mutations and found to be wild type.	('BAP1', 'Gene', '8314', (18, 22))	('BAP1', 'Gene', '8314', (56, 60))	('mutations', 'Var', (61, 70))	('BAP1', 'Gene', (18, 22))	('BAP1', 'Gene', (56, 60))
45166	29416875	Overall, our data strongly suggest that bi-allelic inactivation of BAP1 is required to influence prognosis; on this basis, we would predict that the loss of other genes on chromosome 3 may have little or no additional effect on prognosis in this group.	('loss', 'Var', (149, 153))	('chromosome', 'cellular_component', 'GO:0005694', ('172', '182'))	('BAP1', 'Gene', '8314', (67, 71))	('bi-allelic inactivation', 'Var', (40, 63))	('influence', 'Reg', (87, 96))	('BAP1', 'Gene', (67, 71))
45171	29416875	Previous studies have suggested that D3 UM with a mutation in splicing Factor 3B Subunit 1A (SF3B1) have an increased risk of developing metastases 52.	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('splicing', 'biological_process', 'GO:0045292', ('62', '70'))	('SF3B1', 'Gene', (93, 98))	('UM', 'Phenotype', 'HP:0007716', (40, 42))	('metastases', 'Disease', (137, 147))	('splicing Factor 3B Subunit 1A', 'Gene', (62, 91))	('splicing Factor 3B Subunit 1A', 'Gene', '23451', (62, 91))	('mutation', 'Var', (50, 58))	('SF3B1', 'Gene', '23451', (93, 98))
45173	29416875	The remaining two cases were tested for BAP1 mutations, but were found to be wild type, suggesting alternative mechanisms of nBAP1 loss.	('mutations', 'Var', (45, 54))	('BAP1', 'Gene', (126, 130))	('loss', 'NegReg', (131, 135))	('BAP1', 'Gene', '8314', (40, 44))	('BAP1', 'Gene', (40, 44))	('BAP1', 'Gene', '8314', (126, 130))
45179	29416875	In fibroblasts and mesothelial cells derived from individuals with a heterozygous germline BAP1+/- mutation, they demonstrated a reduced Ca2+ flux that reduced the ability ofBAP1+/- mutant cells to undergo apoptosis following DNA damage.	('BAP1', 'Gene', (91, 95))	('undergo', 'Reg', (198, 205))	('BAP1', 'Gene', (174, 178))	('N', 'Chemical', 'MESH:D009584', (227, 228))	('reduced', 'NegReg', (152, 159))	('mutation', 'Var', (99, 107))	('Ca2+ flux', 'MPA', (137, 146))	('DNA', 'cellular_component', 'GO:0005574', ('226', '229'))	('BAP1', 'Gene', '8314', (91, 95))	('apoptosis', 'biological_process', 'GO:0097194', ('206', '215'))	('apoptosis', 'CPA', (206, 215))	('reduced', 'NegReg', (129, 136))	('Ca2+', 'Chemical', 'MESH:D000069285', (137, 141))	('BAP1', 'Gene', '8314', (174, 178))	('apoptosis', 'biological_process', 'GO:0006915', ('206', '215'))
45181	29416875	The preponderance of UM with 'focal perinuclear' cBAP1 that harbour truncating mutations is of interest as one might assume that mutations causing premature stop codons would trigger nonsense-mediated decay of the aberrant transcript, so that incorrect protein is not produced.	('protein', 'cellular_component', 'GO:0003675', ('253', '260'))	('mutations', 'Var', (129, 138))	('BAP1', 'Gene', '8314', (50, 54))	('trigger', 'Reg', (175, 182))	('nonsense-mediated decay', 'MPA', (183, 206))	('BAP1', 'Gene', (50, 54))	('UM', 'Phenotype', 'HP:0007716', (21, 23))	('mutations', 'Var', (79, 88))
45183	29416875	Bhattacharya and colleagues 59 suggested an alternative mechanism for the observation of 'focal perinuclear' cBAP1 in the form of cBAP1 aggregates promoted by BAP1 mutations, which expose hydrophobic regions of the protein, leading to beta amyloid aggregation.	('BAP1', 'Gene', (131, 135))	('amyloid aggregation', 'Disease', 'MESH:D017772', (240, 259))	('BAP1', 'Gene', '8314', (110, 114))	('BAP1', 'Gene', '8314', (159, 163))	('amyloid aggregation', 'Disease', (240, 259))	('BAP1', 'Gene', '8314', (131, 135))	('BAP1', 'Gene', (110, 114))	('promoted', 'PosReg', (147, 155))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('BAP1', 'Gene', (159, 163))	('mutations', 'Var', (164, 173))
45184	29416875	However, their study proposed that specific mis-sense mutations in the catalytic domain were responsible for the observed aggregation, whereas our sequencing results suggest that sporadic truncating mutations throughout BAP1 can induce the 'focal perinuclear' phenotype.	('truncating mutations', 'Var', (188, 208))	('BAP1', 'Gene', (220, 224))	("'focal perinuclear'", 'Disease', (240, 259))	('BAP1', 'Gene', '8314', (220, 224))	('induce', 'Reg', (229, 235))
45189	29416875	Finally, whilst our study found no link between cBAP1 expression and overall survival (Log rank; p = 0.33), it is of interest that Zhang et al 60 found that high expression of cBAP1 in gliomas was significantly associated with worse overall survival compared to low cBAP1 expression, although there was no mention of any specific localisation of the cBAP1 in this study.	('gliomas', 'Phenotype', 'HP:0009733', (185, 192))	('BAP1', 'Gene', '8314', (351, 355))	('localisation', 'biological_process', 'GO:0051179', ('330', '342'))	('BAP1', 'Gene', (49, 53))	('high expression', 'Var', (157, 172))	('worse', 'NegReg', (227, 232))	('BAP1', 'Gene', '8314', (49, 53))	('BAP1', 'Gene', '8314', (177, 181))	('BAP1', 'Gene', (351, 355))	('BAP1', 'Gene', '8314', (267, 271))	('gliomas', 'Disease', 'MESH:D005910', (185, 192))	('gliomas', 'Disease', (185, 192))	('BAP1', 'Gene', (177, 181))	('BAP1', 'Gene', (267, 271))	('overall', 'MPA', (233, 240))
45203	24650043	Using a BRAF-V600E-inducible mouse model, localized BRAF expression was induced by topical treatment with tamoxifen.	('men', 'Species', '9606', (96, 99))	('V600E', 'Var', (13, 18))	('V600E', 'SUBSTITUTION', 'None', (13, 18))	('tamoxifen', 'Chemical', 'MESH:D013629', (106, 115))	('topical', 'molecular_function', 'GO:0003809', ('83', '90'))	('mouse', 'Species', '10090', (29, 34))	('BRAF', 'Gene', (52, 56))
45206	24650043	Moreover, UV induced multiple tumors in BRAF-V600E mutant mice in the irradiated area, with 100% penetrance, and decreased latency compared to non-irradiated mice.	('latency', 'MPA', (123, 130))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('multiple tumors', 'Disease', 'MESH:D009369', (21, 36))	('mice', 'Species', '10090', (158, 162))	('multiple tumors', 'Disease', (21, 36))	('V600E', 'Var', (45, 50))	('induced', 'Reg', (13, 20))	('V600E', 'SUBSTITUTION', 'None', (45, 50))	('mice', 'Species', '10090', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('decreased', 'NegReg', (113, 122))
45208	24650043	Whole-exome sequencing of these tumors demonstrated a classical UV signature and gain-of-function p53 mutations.	('gain-of-function', 'PosReg', (81, 97))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mutations', 'Var', (102, 111))	('p53', 'Gene', (98, 101))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
45210	24650043	Whole-exome sequencing of these primary melanomas revealed very few mutations, including the known GNAQ and BAP1 mutations.	('melanomas', 'Disease', (40, 49))	('BAP1', 'Gene', '8314', (108, 112))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('GNAQ', 'Gene', (99, 103))	('BAP1', 'Gene', (108, 112))	('mutations', 'Var', (113, 122))	('melanomas', 'Disease', 'MESH:D008545', (40, 49))	('GNAQ', 'Gene', '2776', (99, 103))
45211	24650043	Mutations in SFB3B1, a component of the spliceosome, were also identified in approximately 15% of uveal melanoma samples.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('spliceosome', 'cellular_component', 'GO:0005681', ('40', '51'))	('identified', 'Reg', (63, 73))	('uveal melanoma', 'Phenotype', 'HP:0007716', (98, 112))	('uveal melanoma', 'Disease', (98, 112))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Disease', 'MESH:C536494', (98, 112))	('SFB3B1', 'Gene', (13, 19))
45212	24650043	RNA sequencing revealed that SF3B1 mutations were associated with alternative splicing of the long non-coding RNA CRNDE and of genes such as ABCC5 and UQCC.	('associated with', 'Reg', (50, 65))	('CRNDE', 'Gene', (114, 119))	('alternative splicing', 'MPA', (66, 86))	('CRNDE', 'Gene', '643911', (114, 119))	('ABCC5', 'Gene', (141, 146))	('SF3B1', 'Gene', '23451', (29, 34))	('splicing', 'biological_process', 'GO:0045292', ('78', '86'))	('RNA', 'cellular_component', 'GO:0005562', ('110', '113'))	('UQCC', 'Gene', '55245', (151, 155))	('ABCC5', 'Gene', '10057', (141, 146))	('UQCC', 'Gene', (151, 155))	('SF3B1', 'Gene', (29, 34))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('mutations', 'Var', (35, 44))
45213	24650043	Martin McMahon (Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA) described a new mouse model of melanoma carrying concurrent PI3Kalpha and BRAFV600E mutations.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', (121, 129))	('Cancer', 'Disease', (50, 56))	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('PI3Kalpha', 'Var', (150, 159))	('BRAFV600E', 'Var', (164, 173))	('BRAFV600E', 'Mutation', 'rs113488022', (164, 173))	('mouse', 'Species', '10090', (106, 111))
45214	24650043	Mice harboring one mutant Pik3CaH1047R allele developed melanomas that grew slower than those grown in Tyr::CRE-ERT2;BrafCA/+; PtenF/F mice.	('Braf', 'Gene', (117, 121))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('ERT2', 'Gene', '26417', (112, 116))	('Tyr', 'Chemical', 'MESH:D014443', (103, 106))	('mutant Pik3CaH1047R', 'Var', (19, 38))	('mice', 'Species', '10090', (135, 139))	('slower', 'NegReg', (76, 82))	('melanomas', 'Disease', (56, 65))	('ERT2', 'Gene', (112, 116))	('Mice', 'Species', '10090', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))	('Braf', 'Gene', '109880', (117, 121))	('melanomas', 'Disease', 'MESH:D008545', (56, 65))	('Pik3CaH1047R', 'Var', (26, 38))
45215	24650043	However, tumors from mice with homozygous Pik3CaH1047R mutations grew much more rapidly than BRafCA/+;PtenF/F tumors, suggesting that strong activation of PI3K can phenocopy the effects of PTEN silencing in murine models.	('Pik3CaH1047R', 'Gene', (42, 54))	('grew', 'CPA', (65, 69))	('murine', 'Species', '10090', (207, 213))	('F tumors', 'Disease', 'OMIM:102510', (108, 116))	('mutations', 'Var', (55, 64))	('F tumors', 'Disease', (108, 116))	('mice', 'Species', '10090', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('PI3K', 'molecular_function', 'GO:0016303', ('155', '159'))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('activation', 'PosReg', (141, 151))
45216	24650043	The potential relevance of PIK3Ca mutations or PTEN silencing in conferring sensitivity to PI3K blockade was evaluated using small-molecule inhibitors.	('silencing', 'NegReg', (52, 61))	('PIK3Ca', 'Gene', (27, 33))	('PTEN', 'Gene', (47, 51))	('PI3K', 'molecular_function', 'GO:0016303', ('91', '95'))	('mutations', 'Var', (34, 43))	('PIK3Ca', 'Gene', '5290', (27, 33))
45220	24650043	Similarly, combined inhibition of MEK and PI3K displayed cooperative effects blocking the proliferation of human melanoma cell lines.	('MEK', 'Gene', (34, 37))	('PI3K', 'Var', (42, 46))	('MEK', 'Gene', '5609', (34, 37))	('human', 'Species', '9606', (107, 112))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('inhibition', 'NegReg', (20, 30))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('blocking', 'NegReg', (77, 85))	('PI3K', 'molecular_function', 'GO:0016303', ('42', '46'))
45221	24650043	A lively discussion by Georgina Long (The University of Sydney, Sydney, Australia) emphasized the success of BRAF inhibitors in melanoma, what lessons have been learned from MAPK pathway inhibition (MAPKi), and how we can use this experience to develop better therapies.	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('BRAF', 'Gene', (109, 113))	('MAPK', 'molecular_function', 'GO:0004707', ('174', '178'))	('inhibitors', 'Var', (114, 124))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
45225	24650043	Ribas presented data demonstrating that combined treatment with PLX3397 and adoptive T-cell (ATC) transfer resulted in increased tumor growth inhibition compared to PLX3397 or ATC monotherapies.	('adoptive T-cell', 'CPA', (76, 91))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('men', 'Species', '9606', (54, 57))	('PLX3397', 'Var', (64, 71))	('tumor', 'Disease', (129, 134))	('increased', 'PosReg', (119, 128))
45226	24650043	He noted that treatment with PLX3397 decreased macrophage infiltration at the tumor site, allowing for increased functional activity of T cells.	('men', 'Species', '9606', (19, 22))	('functional', 'MPA', (113, 123))	('increased', 'PosReg', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('PLX3397', 'Var', (29, 36))	('decreased macrophage infiltration', 'Phenotype', 'HP:0012648', (37, 70))	('tumor', 'Disease', (78, 83))	('decreased', 'NegReg', (37, 46))
45231	24650043	Ahmed Samatar (MERCK Research Laboratories, Boston, MA) discussed the discovery and characterization of SCH772984, the first ERK inhibitor that has moved into early-phase clinical trials.	('ERK', 'Gene', '5594', (125, 128))	('ERK', 'molecular_function', 'GO:0004707', ('125', '128'))	('ERK', 'Gene', (125, 128))	('SCH772984', 'Var', (104, 113))	('clinical', 'Species', '191496', (171, 179))	('SCH772984', 'Chemical', 'MESH:C587178', (104, 113))
45232	24650043	SCH772984 was identified as a selective ERK1/2 inhibitor through a high-throughput screen.	('SCH772984', 'Chemical', 'MESH:C587178', (0, 9))	('ERK1/2', 'Gene', (40, 46))	('ERK1', 'molecular_function', 'GO:0004707', ('40', '44'))	('ERK1/2', 'Gene', '5595;5594', (40, 46))	('SCH772984', 'Var', (0, 9))
45234	24650043	SCH-77984 effectively blocked the MAPK pathway and decreased proliferation of a number of BRAF-V600E and KRAS mutant cells in vitro and in vivo.	('V600E', 'SUBSTITUTION', 'None', (95, 100))	('MAPK pathway', 'Pathway', (34, 46))	('SCH-77984', 'Chemical', '-', (0, 9))	('MAPK', 'molecular_function', 'GO:0004707', ('34', '38'))	('blocked', 'NegReg', (22, 29))	('KRAS', 'Gene', (105, 109))	('decreased', 'NegReg', (51, 60))	('KRAS', 'Gene', '3845', (105, 109))	('proliferation', 'CPA', (61, 74))	('V600E', 'Var', (95, 100))
45235	24650043	Furthermore, Dr. Samatar presented data demonstrating that SCH772984 overcomes resistance to BRAF and MEK inhibitors and that co-inhibition of BRAF and ERK results in enhanced antitumor activity.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('MEK', 'Gene', '5609', (102, 105))	('ERK', 'Gene', '5594', (152, 155))	('ERK', 'molecular_function', 'GO:0004707', ('152', '155'))	('enhanced', 'PosReg', (167, 175))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('SCH772984', 'Var', (59, 68))	('ERK', 'Gene', (152, 155))	('BRAF', 'Gene', (143, 147))	('tumor', 'Disease', (180, 185))	('overcomes', 'NegReg', (69, 78))	('co-inhibition', 'Var', (126, 139))	('SCH772984', 'Chemical', 'MESH:C587178', (59, 68))	('resistance', 'MPA', (79, 89))	('MEK', 'Gene', (102, 105))
45253	24650043	In a mouse model, anti-CTLA-4 therapy was combined with stereotactic body radiation therapy (SBRT) as a means to cause immunogenic cell death.	('stereotactic body', 'Phenotype', 'HP:0000733', (56, 73))	('anti-CTLA-4', 'Var', (18, 29))	('cell death', 'biological_process', 'GO:0008219', ('131', '141'))	('mouse', 'Species', '10090', (5, 10))	('immunogenic cell death', 'Disease', (119, 141))	('immunogenic cell death', 'Disease', 'MESH:D003643', (119, 141))
45256	24650043	Clinical trials of a combination of anti-CD40 antibodies, anti-CTLA-4 antibodies, and SBRT are planned.	('CD40', 'Gene', (41, 45))	('Clinical', 'Species', '191496', (0, 8))	('anti-CTLA-4', 'Var', (58, 69))	('anti-CTLA-4', 'Gene', (58, 69))	('CD40', 'Gene', '958', (41, 45))
45261	24650043	Clinically responding patients showed increased tumor infiltrates with gene expression of Th1 type in cases where on-treatment samples were obtained.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('Clinical', 'Species', '191496', (0, 8))	('Th1', 'Gene', (90, 93))	('patients', 'Species', '9606', (22, 30))	('gene expression', 'Var', (71, 86))	('gene expression', 'biological_process', 'GO:0010467', ('71', '86'))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('Th1', 'Gene', '51497', (90, 93))	('increased', 'PosReg', (38, 47))	('men', 'Species', '9606', (122, 125))
45262	24650043	Keith Flaherty (Massachusetts General Hospital, Boston, MA) presented an overview of the mutations found in melanoma, which were dominated by mutant BRAF.	('BRAF', 'Gene', (149, 153))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('mutant', 'Var', (142, 148))	('mutations', 'Var', (89, 98))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))
45263	24650043	The BRAF inhibitor vemurafenib was shown to remarkably reduce tumor burden in patients with mutant BRAF melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('patients', 'Species', '9606', (78, 86))	('BRAF melanoma', 'Disease', 'MESH:D008545', (99, 112))	('BRAF melanoma', 'Disease', (99, 112))	('vemurafenib', 'Chemical', 'MESH:D000077484', (19, 30))	('mutant', 'Var', (92, 98))	('reduce', 'NegReg', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
45271	24650043	These are subsequently transplanted in a mouse model that is pretolerized to GFP/ffLuc by virtue of transgenic expression of GFP and ffLuc in the pituitary gland under the control of the growth hormone promoter (Glowing Head mice).	('ffLuc', 'Var', (133, 138))	('mouse', 'Species', '10090', (41, 46))	('mice', 'Species', '10090', (225, 229))	('growth hormone', 'molecular_function', 'GO:0005131', ('187', '201'))	('GFP', 'Var', (125, 128))
45275	24650043	Administration of BRAFi PLX4720 was shown to increase infiltration of adoptively transferred T cells via inhibition of VEGF production by melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('VEGF', 'Gene', '7422', (119, 123))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('infiltration', 'CPA', (54, 66))	('inhibition', 'NegReg', (105, 115))	('BRAFi PLX4720', 'Var', (18, 31))	('VEGF', 'Gene', (119, 123))	('inhibition of VEGF production', 'biological_process', 'GO:1904046', ('105', '134'))	('increase', 'PosReg', (45, 53))
45290	24650043	He provided evidence for SNPs in PARP1 that have a functional effect.	('SNPs', 'Var', (25, 29))	('PARP1', 'Gene', '142', (33, 38))	('PARP1', 'Gene', (33, 38))
45293	24650043	Focusing on whole-exome sequencing data from a comprehensive set of melanoma tumors, she discussed the effect of a novel recurrent synonymous mutation in BCL2L12 that they subsequently showed to affect apoptosis via a miRNA-dependent mechanism.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('melanoma tumors', 'Disease', 'MESH:D008545', (68, 83))	('BCL2L12', 'Gene', (154, 161))	('BCL2L12', 'Gene', '83596', (154, 161))	('apoptosis', 'biological_process', 'GO:0097194', ('202', '211'))	('BCL2', 'molecular_function', 'GO:0015283', ('154', '158'))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('apoptosis', 'biological_process', 'GO:0006915', ('202', '211'))	('synonymous mutation', 'Var', (131, 150))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('melanoma tumors', 'Disease', (68, 83))	('apoptosis', 'CPA', (202, 211))	('affect', 'Reg', (195, 201))
45307	24650043	Lo then gave an overview of mechanisms of acquired resistance, noting that more than 50% of resistant tumors reactivate MAPK, about 4% engage the PTEN/PI3K/AKT pathway, and almost 20% display activation of both pathways.	('PTEN/PI3K/AKT pathway', 'Pathway', (146, 167))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('PI3K', 'molecular_function', 'GO:0016303', ('151', '155'))	('MAPK', 'molecular_function', 'GO:0004707', ('120', '124'))	('MAPK', 'Pathway', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('reactivate', 'Var', (109, 119))	('engage', 'Reg', (135, 141))
45308	24650043	Analysis of resistant tumors identified genetic alternations in the PTEN/PI3K/AKT axis, including a gain-of-function AKT1Q79K mutation, a loss-of-function PIK3R2 N561D mutation, and a novel PTEN M134 deletion, among others.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('deletion', 'Var', (200, 208))	('AKT1Q79K', 'Gene', (117, 125))	('PI3K', 'molecular_function', 'GO:0016303', ('73', '77'))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('PIK3R2', 'Gene', (155, 161))	('PIK3R2', 'Gene', '5296', (155, 161))	('N561D', 'Mutation', 'rs1057519801', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('loss-of-function', 'NegReg', (138, 154))	('PTEN/PI3K/AKT axis', 'Pathway', (68, 86))	('gain-of-function', 'PosReg', (100, 116))	('PTEN M134', 'Gene', (190, 199))	('N561D', 'Var', (162, 167))	('tumors', 'Disease', (22, 28))
45319	24650043	However, in uveal melanoma, where BRAF mutations are absent but mutations in GNAQ/11 predominate, single-agent MEK inhibitor selumetinib demonstrated significant responses (50%) and for the first time, markedly improved survival in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('selumetinib', 'Chemical', 'MESH:C517975', (125, 136))	('GNAQ', 'Gene', (77, 81))	('uveal melanoma', 'Disease', 'MESH:C536494', (232, 246))	('uveal melanoma', 'Disease', 'MESH:C536494', (12, 26))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('uveal melanoma', 'Phenotype', 'HP:0007716', (232, 246))	('uveal melanoma', 'Phenotype', 'HP:0007716', (12, 26))	('uveal melanoma', 'Disease', (232, 246))	('improved', 'PosReg', (211, 219))	('uveal melanoma', 'Disease', (12, 26))	('MEK', 'Gene', (111, 114))	('mutations', 'Var', (64, 73))	('MEK', 'Gene', '5609', (111, 114))	('survival', 'MPA', (220, 228))	('GNAQ', 'Gene', '2776', (77, 81))
45320	24650043	In contrast to single-agent MEK approaches, combination of targeted BRAF/MEK inhibition in BRAF-mutated melanoma continues to show a significant benefit with increased response rates (76%), lower resistance rates, and prolonged survival, while simultaneously displaying less toxicities, particularly cutaneous SCC formation (combination was FDA-approved for BRAF V600E or V600K disease on January 10, 2014).	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('toxicities', 'Disease', (275, 285))	('benefit', 'PosReg', (145, 152))	('resistance rates', 'MPA', (196, 212))	('formation', 'biological_process', 'GO:0009058', ('314', '323'))	('V600K', 'Var', (372, 377))	('inhibition', 'NegReg', (77, 87))	('MEK', 'Gene', '5609', (28, 31))	('response', 'MPA', (168, 176))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('MEK', 'Gene', (28, 31))	('MEK', 'Gene', '5609', (73, 76))	('lower', 'NegReg', (190, 195))	('BRAF-', 'Gene', '673', (91, 96))	('BRAF-', 'Gene', (91, 96))	('V600E', 'Mutation', 'rs113488022', (363, 368))	('V600K', 'Mutation', 'rs121913227', (372, 377))	('MEK', 'Gene', (73, 76))	('toxicities', 'Disease', 'MESH:D064420', (275, 285))	('cutaneous SCC formation', 'Disease', (300, 323))	('increased', 'PosReg', (158, 167))
45331	24650043	In a recent study on whole-exome sequencing of tumors from 45 patients treated with BRAF inhibitors (vemurafenib or dabrafenib), mutations in genes of the MAPK pathway (e.g., NRAS, MAP2K1 and MAP2K2) were identified to confer resistance to BRAF inhibition.	('MAP2K1', 'Gene', (181, 187))	('MAP2K2', 'Gene', (192, 198))	('MAPK pathway', 'Pathway', (155, 167))	('tumors', 'Disease', (47, 53))	('MAP2K2', 'Gene', '5605', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('MAP2K', 'molecular_function', 'GO:0004708', ('181', '186'))	('mutations', 'Var', (129, 138))	('dabrafenib', 'Chemical', 'MESH:C561627', (116, 126))	('MAP2K', 'molecular_function', 'GO:0004708', ('192', '197'))	('MAP2K1', 'Gene', '5604', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('vemurafenib', 'Chemical', 'MESH:D000077484', (101, 112))	('NRAS', 'Gene', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('MAPK', 'molecular_function', 'GO:0004707', ('155', '159'))	('patients', 'Species', '9606', (62, 70))	('resistance', 'MPA', (226, 236))
45339	24650043	In a set of 56 Italian melanoma pedigrees, a single missense mutation was found in five families suggesting it being a founder mutation in this population.	('missense mutation', 'Var', (52, 69))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))
45341	24650043	Interestingly, her mouse models developed brain melanomas and a subsequent follow-up in a primary CNS melanoma demonstrated a NRASQ61 mutation, suggesting the involvement of NRAS in the development of brain melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanoma', 'Disease', (207, 215))	('brain melanomas', 'Disease', (201, 216))	('men', 'Species', '9606', (193, 196))	('melanomas', 'Phenotype', 'HP:0002861', (207, 216))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanoma', 'Disease', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('involvement', 'Reg', (159, 170))	('melanoma', 'Disease', 'MESH:D008545', (207, 215))	('men', 'Species', '9606', (166, 169))	('mouse', 'Species', '10090', (19, 24))	('brain melanomas', 'Disease', 'MESH:D008545', (42, 57))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('brain melanomas', 'Disease', 'MESH:D008545', (201, 216))	('mutation', 'Var', (134, 142))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('NRASQ61', 'Gene', (126, 133))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('brain melanomas', 'Disease', (42, 57))
45382	24650043	TAB-cell derived IGF-1 induces therapy-resistant heterogeneous melanoma subpopulations, and neutralization of IGF-1 reverses this induction.	('IGF-1', 'Gene', (110, 115))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('neutralization', 'Var', (92, 106))	('induces', 'PosReg', (23, 30))	('IGF-1', 'Gene', '3479', (17, 22))	('IGF-1', 'Gene', (17, 22))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('IGF-1', 'Gene', '3479', (110, 115))
45383	24650043	Further, knockdown of FGFR-3 in tumor cells restores the sensitivity of melanoma cells to chemo- and targeted therapies.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('restores', 'PosReg', (44, 52))	('melanoma', 'Disease', (72, 80))	('knockdown', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('FGFR-3', 'Gene', (22, 28))	('sensitivity', 'MPA', (57, 68))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('tumor', 'Disease', (32, 37))	('FGFR-3', 'Gene', '2261', (22, 28))
45393	24650043	He went on to show that pyruvate dehydrogenase (PDH) plays an important role in mutant BRAF-induced senescence.	('pyruvate dehydrogenase', 'Gene', (24, 46))	('PDH', 'Gene', '54704', (48, 51))	('senescence', 'biological_process', 'GO:0010149', ('100', '110'))	('mutant', 'Var', (80, 86))	('PDH', 'molecular_function', 'GO:0004246', ('48', '51'))	('BRAF-', 'Gene', '673', (87, 92))	('BRAF-', 'Gene', (87, 92))	('PDH', 'molecular_function', 'GO:0004739', ('48', '51'))	('PDH', 'molecular_function', 'GO:0033718', ('48', '51'))	('PDH', 'Gene', (48, 51))	('pyruvate dehydrogenase', 'Gene', '54704', (24, 46))
45395	24650043	PDK1 knockdown inhibited melanoma tumor growth in a transplant model.	('inhibited', 'NegReg', (15, 24))	('knockdown', 'Var', (5, 14))	('PDK1', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma tumor', 'Disease', (25, 39))	('melanoma tumor', 'Disease', 'MESH:D008545', (25, 39))	('PDK1', 'molecular_function', 'GO:0004740', ('0', '4'))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
45413	24650043	A significant relationship was found between BRAF gain and limited response in patients with BRAF-V600E mutation.	('gain', 'PosReg', (50, 54))	('BRAF', 'Gene', (45, 49))	('limited', 'MPA', (59, 66))	('patients', 'Species', '9606', (79, 87))	('V600E', 'Var', (98, 103))	('V600E', 'SUBSTITUTION', 'None', (98, 103))
45416	24650043	Suzanne Topalian (John Hopkins University, Baltimore, MD) gave an update on the clinical activity of PD-1 (nivolumab and MK-3475) and PD-L1 (BMS-936559 and MPDL3280A) blocking antibodies in melanoma and other cancers.	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('PD-L1', 'Gene', (134, 139))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('clinical', 'Species', '191496', (80, 88))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('cancers', 'Disease', (209, 216))	('BMS-936559', 'Var', (141, 151))	('PD-1', 'Gene', (101, 105))	('nivolumab', 'Chemical', 'MESH:D000077594', (107, 116))	('MPDL3280A', 'Var', (156, 165))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
45423	24650043	Using a genetically engineered mouse model of BRAF and in vivo insertional mutagenesis, Daniele Perena (Beth Israel Deaconess Cancer Center, Boston, MA) showed that both Braf and ERas are top candidate genes playing a causal role in resistance to PLX4720.	('Braf', 'Gene', (170, 174))	('Cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mouse', 'Species', '10090', (31, 36))	('Beth Israel Deaconess Cancer', 'Disease', (104, 132))	('insertional mutagenesis', 'Var', (63, 86))	('Beth Israel Deaconess Cancer', 'Disease', 'MESH:D009369', (104, 132))	('mutagenesis', 'biological_process', 'GO:0006280', ('75', '86'))	('Braf', 'Gene', '109880', (170, 174))
45424	24650043	Katrina Meeth (Yale School of Medicine, New Haven, CT) discussed the in vivo inhibition of macrophages using PLX3397 or GW2580 (both specific inhibitors of CSF1R on macrophages) in combination with BRAF inhibitors, which delayed tumor growth.	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('CSF1', 'molecular_function', 'GO:0005011', ('156', '160'))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('CSF1R', 'Gene', (156, 161))	('GW2580', 'Chemical', 'MESH:C506269', (120, 126))	('tumor', 'Disease', (229, 234))	('delayed', 'NegReg', (221, 228))	('PLX3397', 'Var', (109, 116))	('GW2580', 'Var', (120, 126))	('CSF1R', 'Gene', '1436', (156, 161))
45428	24650043	In addition, they were able to predict when variations have deleterious effects on gene expression, giving IRF4 as an example.	('variations', 'Var', (44, 54))	('IRF4', 'Gene', '3662', (107, 111))	('IRF4', 'Gene', (107, 111))	('gene expression', 'biological_process', 'GO:0010467', ('83', '98'))	('gene expression', 'MPA', (83, 98))
45433	24650043	Rather, loss of PTEN increased Caveolin-1-mediated dissociation of membranous beta-catenin driving its nuclear translocation and inhibition of p16INK4A-induced senescence.	('increased', 'PosReg', (21, 30))	('Caveolin-1', 'Gene', '857', (31, 41))	('p16INK4A', 'Gene', (143, 151))	('nuclear translocation', 'MPA', (103, 124))	('Caveolin-1', 'Gene', (31, 41))	('PTEN', 'Gene', (16, 20))	('inhibition', 'NegReg', (129, 139))	('loss', 'Var', (8, 12))	('beta-catenin', 'Gene', (78, 90))	('p16INK4A', 'Gene', '1029', (143, 151))	('senescence', 'biological_process', 'GO:0010149', ('160', '170'))	('beta-catenin', 'Gene', '1499', (78, 90))
45434	24650043	These findings indicate that during multistep melanomagenesis, loss of PTEN cooperates with MAPK signaling by enabling a novel, Caveolin-1-mediated, mechanism of senescence suppression.	('MAPK', 'molecular_function', 'GO:0004707', ('92', '96'))	('senescence', 'biological_process', 'GO:0010149', ('162', '172'))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('loss', 'Var', (63, 67))	('Caveolin-1', 'Gene', '857', (128, 138))	('melanoma', 'Disease', (46, 54))	('enabling', 'PosReg', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('MAPK signaling', 'biological_process', 'GO:0000165', ('92', '106'))	('PTEN', 'Gene', (71, 75))	('senescence', 'MPA', (162, 172))	('Caveolin-1', 'Gene', (128, 138))
45438	24650043	Corine Bertolotto (INSERM, France) demonstrated that germline mutations in MITF (MITF 318K) leads to disrupted SUMOylation and predisposition to melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('predisposition', 'Reg', (127, 141))	('melanoma', 'Disease', (145, 153))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('SUMOylation', 'biological_process', 'GO:0016925', ('111', '122'))	('MITF', 'Gene', '4286', (75, 79))	('MITF', 'Gene', (75, 79))	('MITF', 'Gene', (81, 85))	('MITF', 'Gene', '4286', (81, 85))	('disrupted', 'NegReg', (101, 110))	('mutations', 'Var', (62, 71))	('SUMOylation', 'MPA', (111, 122))
45444	24650043	Dr. Cao demonstrated that DOT1L deficiency did not affect the expression of NER factors, but did impair the recruitment of NER factors to sites of DNA damage, indicating that DOT1L has a novel function in NER after UV irradiation.	('NER', 'biological_process', 'GO:0006289', ('76', '79'))	('DOT1L', 'Gene', (26, 31))	('recruitment of NER factors to sites of DNA damage', 'MPA', (108, 157))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('men', 'Species', '9606', (115, 118))	('NER', 'biological_process', 'GO:0006289', ('205', '208'))	('DOT1L', 'Gene', (175, 180))	('NER', 'biological_process', 'GO:0006289', ('123', '126'))	('DOT1L', 'Gene', '84444', (26, 31))	('impair', 'NegReg', (97, 103))	('DOT1L', 'Gene', '84444', (175, 180))	('deficiency', 'Var', (32, 42))
45449	24650043	Inactivation of PDK1 in the BRAF/PTEN/cdkn2a mouse delays melanomagenesis and prolongs survival of the mutant animals.	('cdkn2a', 'Gene', (38, 44))	('PDK1', 'Gene', (16, 20))	('mouse', 'Species', '10090', (45, 50))	('prolongs', 'PosReg', (78, 86))	('survival', 'CPA', (87, 95))	('delays melanomagenesis', 'Disease', (51, 73))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('PDK1', 'molecular_function', 'GO:0004740', ('16', '20'))	('cdkn2a', 'Gene', '12578', (38, 44))	('Inactivation', 'Var', (0, 12))	('delays melanomagenesis', 'Disease', 'MESH:D006968', (51, 73))
45450	24650043	Further, the top PDK1-dependent pathways altered in BRAF/PTEN melanomas reveal a FOXO signature with PDK1 mutant melanomas exhibiting decreased AKT phosphorylation and increased nuclear FOXO3.	('FOXO3', 'Gene', '2309', (186, 191))	('PTEN melanomas', 'Disease', 'MESH:D006223', (57, 71))	('phosphorylation', 'biological_process', 'GO:0016310', ('148', '163'))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('PDK1', 'Gene', (101, 105))	('mutant', 'Var', (106, 112))	('PDK1', 'molecular_function', 'GO:0004740', ('101', '105'))	('melanomas', 'Disease', 'MESH:D008545', (113, 122))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('decreased', 'NegReg', (134, 143))	('melanomas', 'Disease', (113, 122))	('AKT', 'Pathway', (144, 147))	('phosphorylation', 'MPA', (148, 163))	('melanomas', 'Disease', 'MESH:D008545', (62, 71))	('FOXO3', 'Gene', (186, 191))	('increased', 'PosReg', (168, 177))	('melanomas', 'Disease', (62, 71))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('PDK1', 'molecular_function', 'GO:0004740', ('17', '21'))	('PTEN melanomas', 'Disease', (57, 71))
45451	24650043	FOXO3A has been shown to be an important player in BRAF/PTEN melanomas and inhibition of FOXO3A in PDK KO/BRAFV600E/PTEN-knockout melanomas partially rescues proliferation and colony formation.	('rescues', 'PosReg', (150, 157))	('PDK', 'molecular_function', 'GO:0004740', ('99', '102'))	('inhibition', 'Var', (75, 85))	('PTEN melanomas', 'Disease', (56, 70))	('melanomas', 'Disease', 'MESH:D008545', (130, 139))	('FOXO3A', 'Gene', '2309', (89, 95))	('proliferation', 'CPA', (158, 171))	('PTEN melanomas', 'Disease', 'MESH:D006223', (56, 70))	('melanomas', 'Disease', (130, 139))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('FOXO3A', 'Gene', '2309', (0, 6))	('melanomas', 'Disease', (61, 70))	('melanomas', 'Phenotype', 'HP:0002861', (130, 139))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('FOXO3A', 'Gene', (89, 95))	('BRAFV600E', 'Mutation', 'rs113488022', (106, 115))	('melanomas', 'Disease', 'MESH:D008545', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('FOXO3A', 'Gene', (0, 6))	('formation', 'biological_process', 'GO:0009058', ('183', '192'))
45474	24650043	EZH2 expression is increased in melanomas from the Tyr:NRasQ61K Ink4a -/- mouse model.	('Ink4a', 'Gene', '12578', (64, 69))	('melanomas', 'Disease', (32, 41))	('expression', 'MPA', (5, 15))	('Tyr', 'Chemical', 'MESH:D014443', (51, 54))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('EZH2', 'Gene', (0, 4))	('Tyr:NRasQ61K', 'Var', (51, 63))	('melanomas', 'Phenotype', 'HP:0002861', (32, 41))	('Ink4a', 'Gene', (64, 69))	('increased', 'PosReg', (19, 28))	('melanomas', 'Disease', 'MESH:D008545', (32, 41))	('mouse', 'Species', '10090', (74, 79))
45475	24650043	Targeted EZH2 deletion, induced with tamoxifen, led to stabilization or regression of the disease and halted invasive behavior.	('tamoxifen', 'Chemical', 'MESH:D013629', (37, 46))	('invasive behavior', 'CPA', (109, 126))	('halted', 'NegReg', (102, 108))	('EZH2', 'Gene', (9, 13))	('deletion', 'Var', (14, 22))
45479	24650043	ATG5 is a central mediator in autophagy programs, and ATG5 deletion did not affect nevi formation; however, there was a delayed generation of cutaneous lesions in ATG5-null mice.	('formation', 'biological_process', 'GO:0009058', ('88', '97'))	('nevi', 'Phenotype', 'HP:0003764', (83, 87))	('autophagy', 'biological_process', 'GO:0016236', ('30', '39'))	('cutaneous lesions', 'CPA', (142, 159))	('autophagy', 'biological_process', 'GO:0006914', ('30', '39'))	('ATG5', 'Gene', (54, 58))	('deletion', 'Var', (59, 67))	('mice', 'Species', '10090', (173, 177))
45481	24650043	In sum, reduced ATG5 copy number in human melanoma cells shows no significant contribution to benign hyperplasia, while heterozygous deletion actually enhances metastatic development.	('melanoma', 'Disease', (42, 50))	('metastatic development', 'CPA', (160, 182))	('deletion', 'Var', (133, 141))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('reduced', 'NegReg', (8, 15))	('benign hyperplasia', 'Disease', (94, 112))	('enhances', 'PosReg', (151, 159))	('benign hyperplasia', 'Disease', 'MESH:D011470', (94, 112))	('ATG5', 'Protein', (16, 20))	('human', 'Species', '9606', (36, 41))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('men', 'Species', '9606', (178, 181))
45484	24650043	Notch 1 or MSX1 can reprogram mature melanocytes to neural crest-like multipotent stem cells and inhibition of Notch signaling reduced proliferation of neural crest-like spheres and induced cell death.	('inhibition', 'Var', (97, 107))	('proliferation of neural crest-like spheres', 'CPA', (135, 177))	('cell death', 'CPA', (190, 200))	('cell death', 'biological_process', 'GO:0008219', ('190', '200'))	('MSX1', 'Gene', (11, 15))	('Notch 1', 'Gene', '4851', (0, 7))	('Notch signaling', 'Gene', (111, 126))	('induced', 'Reg', (182, 189))	('MSX1', 'Gene', '4487', (11, 15))	('reduced', 'NegReg', (127, 134))	('Notch 1', 'Gene', (0, 7))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))
45497	24650043	Further, shutting down Wnt5A signaling by knocking out its receptor, ROR2, increased melanoma cells' response to BRAF inhibitor treatment in vitro and in vivo.	('signaling', 'biological_process', 'GO:0023052', ('29', '38'))	('response to BRAF inhibitor treatment', 'MPA', (101, 137))	('Wnt5A', 'Gene', (23, 28))	('Wnt5A', 'Gene', '7474', (23, 28))	('ROR2', 'Gene', (69, 73))	('ROR2', 'Gene', '4920', (69, 73))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('men', 'Species', '9606', (133, 136))	('increased', 'PosReg', (75, 84))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('knocking out', 'Var', (42, 54))
45500	24650043	MAPK-driven acetylation of MITF leads to distinctions between melanocyte differentiation and a more proliferative phenotype.	('leads to distinctions', 'Reg', (32, 53))	('melanocyte differentiation', 'biological_process', 'GO:0030318', ('62', '88'))	('acetylation', 'Var', (12, 23))	('melanocyte differentiation', 'CPA', (62, 88))	('MAPK', 'molecular_function', 'GO:0004707', ('0', '4'))	('MITF', 'Gene', '4286', (27, 31))	('MITF', 'Gene', (27, 31))
45504	24650043	When MITF is a high-affinity binder (non-acetylated), one gene set is upregulated; meanwhile, acetylated MITF becomes a lower-affinity binder and affects a different gene set.	('affects', 'Reg', (146, 153))	('MITF', 'Gene', '4286', (105, 109))	('MITF', 'Gene', (105, 109))	('MITF', 'Gene', (5, 9))	('MITF', 'Gene', '4286', (5, 9))	('lower-affinity', 'NegReg', (120, 134))	('acetylated', 'Var', (94, 104))	('upregulated', 'PosReg', (70, 81))
45512	24650043	Dr. Ballotti showed that loss of MITF, which can be induced by hypoxia, is sufficient to increase the tumorigenic potential of melanoma cells; meanwhile, the MITF-negative cell population is required for melanoma tumor formation.	('melanoma tumor', 'Disease', (204, 218))	('MITF', 'Gene', '4286', (33, 37))	('melanoma', 'Disease', 'MESH:D008545', (204, 212))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('MITF', 'Gene', (33, 37))	('MITF', 'Gene', '4286', (158, 162))	('hypoxia', 'Disease', (63, 70))	('formation', 'biological_process', 'GO:0009058', ('219', '228'))	('melanoma tumor', 'Disease', 'MESH:D008545', (204, 218))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('melanoma', 'Disease', (204, 212))	('MITF', 'Gene', (158, 162))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('hypoxia', 'Disease', 'MESH:D000860', (63, 70))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', (213, 218))	('loss', 'Var', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('increase', 'PosReg', (89, 97))
45517	24650043	The senescent phenotype was also shown to be induced by BRAF and combination BRAF/MEK inhibitors.	('senescent phenotype', 'CPA', (4, 23))	('MEK', 'Gene', '5609', (82, 85))	('induced', 'Reg', (45, 52))	('inhibitors', 'Var', (86, 96))	('MEK', 'Gene', (82, 85))
45526	24650043	Adil Daud (UCSF, San Francisco, CA) provided an update on a randomized phase II trial in BRAF V600E/K metastasized melanoma (n = 162) comparing monotherapy dabrafenib (D) 150 mg BID, D+ trametinib (T) 150/1QD, and D+T 150/2QD in 3 arms.	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('dabrafenib', 'Chemical', 'MESH:C561627', (156, 166))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('D+T', 'Chemical', 'MESH:D013936', (214, 217))	('V600E', 'Var', (94, 99))	('V600E', 'SUBSTITUTION', 'None', (94, 99))	('BID', 'Gene', '637', (178, 181))	('trametinib', 'Chemical', 'MESH:C560077', (186, 196))	('BID', 'Gene', (178, 181))
45568	26904454	ANSWER: C. Wiesner nevus Wiesner nevus is a benign epithelioid nevus with BAP1 mutation that represents a morphologically and genetically distinct variant in the spectrum of epithelioid Spitz nevi.	('nevi', 'Phenotype', 'HP:0003764', (192, 196))	('nevus', 'Phenotype', 'HP:0003764', (19, 24))	('nevus', 'Phenotype', 'HP:0003764', (33, 38))	('BAP1', 'Gene', '8314', (74, 78))	('epithelioid nevus', 'Phenotype', 'HP:0010816', (51, 68))	('mutation', 'Var', (79, 87))	('nevus', 'Phenotype', 'HP:0003764', (63, 68))	('BAP1', 'Gene', (74, 78))
45579	26904454	At the molecular level, Wiesner nevi frequently have BRAF mutation in addition to the characteristic BAP1 mutation, a genetic finding absent in Spitz nevi.	('BRAF', 'Gene', '673', (53, 57))	('BAP1', 'Gene', '8314', (101, 105))	('BRAF', 'Gene', (53, 57))	('mutation', 'Var', (58, 66))	('nevi', 'Phenotype', 'HP:0003764', (32, 36))	('Wiesner nevi', 'Disease', (24, 36))	('BAP1', 'Gene', (101, 105))	('nevi', 'Phenotype', 'HP:0003764', (150, 154))
45591	26904454	The increased susceptibility to develop uveal melanoma, mesothelioma, and renal cell carcinoma in patients with a germline mutation of BAP1is well documented.	('germline mutation', 'Var', (114, 131))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('renal cell carcinoma', 'Disease', (74, 94))	('BAP1', 'Gene', '8314', (135, 139))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (74, 94))	('patients', 'Species', '9606', (98, 106))	('uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))	('uveal melanoma', 'Disease', (40, 54))	('mesothelioma', 'Disease', (56, 68))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (74, 94))	('BAP1', 'Gene', (135, 139))	('uveal melanoma', 'Disease', 'MESH:C536494', (40, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('mesothelioma', 'Disease', 'MESH:D008654', (56, 68))
45596	26272168	Aberrant activation of the major effector and transcription co-activator YAP in the Hippo pathway causes drastic organ enlargement in development and underlies tumorigenesis in many human cancers.	('activation', 'PosReg', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('transcription', 'biological_process', 'GO:0006351', ('46', '59'))	('Aberrant', 'Var', (0, 8))	('human', 'Species', '9606', (182, 187))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('underlies', 'Reg', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('cancers', 'Disease', (188, 195))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Hippo', 'Gene', (84, 89))	('tumor', 'Disease', (160, 165))	('enlargement', 'PosReg', (119, 130))	('organ', 'CPA', (113, 118))
45597	26272168	Inhibition of miR-130a reversed liver size enlargement induced by Hippo pathway inactivation and blocked YAP-induced tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('blocked', 'NegReg', (97, 104))	('tumor', 'Disease', (117, 122))	('miR-130a', 'Gene', (14, 22))	('liver', 'MPA', (32, 37))	('enlargement', 'PosReg', (43, 54))	('inactivation', 'Var', (80, 92))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('Hippo pathway', 'Pathway', (66, 79))	('liver size enlargement', 'Phenotype', 'HP:0002240', (32, 54))
45600	26272168	Genetic manipulation of Hippo pathway genes leads to drastic change of organ size in Drosophila and mammals.	('change', 'Reg', (61, 67))	('Genetic manipulation', 'Var', (0, 20))	('Drosophila', 'Species', '7227', (85, 95))	('organ size in Drosophila', 'CPA', (71, 95))	('Hippo pathway', 'Gene', (24, 37))
45601	26272168	For instance, liver-specific expression of Yes-associated protein (YAP) transgene, the major effector of the Hippo pathway, leads to striking enlargement of liver up to one fourth of mouse body weight.	('mouse', 'Species', '10090', (183, 188))	('enlargement', 'PosReg', (142, 153))	('YAP', 'Gene', (67, 70))	('Yes-associated protein', 'Gene', '22601', (43, 65))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('transgene', 'Var', (72, 81))	('enlargement of liver', 'Phenotype', 'HP:0002240', (142, 162))	('liver up', 'MPA', (157, 165))	('Yes-associated protein', 'Gene', (43, 65))
45608	26272168	In human cancers, YAP is activated by genomic amplification and deregulation of the Hippo pathway.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('Hippo pathway', 'Pathway', (84, 97))	('cancers', 'Disease', (9, 16))	('genomic amplification', 'Var', (38, 59))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('YAP', 'Disease', (18, 21))	('deregulation', 'Var', (64, 76))	('activated', 'PosReg', (25, 34))
45614	26272168	Furthermore, miR-130a inhibition markedly reversed organ size enlargement and tumorigenesis induced by aberrant YAP activation.	('organ size enlargement', 'CPA', (51, 73))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('inhibition', 'NegReg', (22, 32))	('aberrant', 'Var', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('miR-130a', 'Gene', (13, 21))
45622	26272168	Furthermore, miR-130a promoted tumorigenesis induced by YAP-S127A in HepG2 cells (Figure 1G).	('HepG2', 'CellLine', 'CVCL:0027', (69, 74))	('S127A', 'Mutation', 'rs762471803', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('promoted', 'PosReg', (22, 30))	('YAP-S127A', 'Var', (56, 65))	('tumor', 'Disease', (31, 36))	('miR-130a', 'Gene', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
45624	26272168	Moreover, expression of the miR-130a sponge inhibited tumor formation induced by YAP-S127A in HepG2 cells (Figure 1H and Supplementary information, Figure S1C).	('HepG2', 'CellLine', 'CVCL:0027', (94, 99))	('S127A', 'Mutation', 'rs762471803', (85, 90))	('YAP-S127A', 'Var', (81, 90))	('inhibited', 'NegReg', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('formation', 'biological_process', 'GO:0009058', ('60', '69'))	('miR-130a', 'Var', (28, 36))
45626	26272168	To determine how YAP induces miR-130a, we checked whether the induction depends on TEADs.	('TEAD', 'Gene', (83, 87))	('miR-130a', 'Var', (29, 37))	('TEAD', 'Gene', '32536', (83, 87))
45627	26272168	Indeed, mutation of YAP serine 94 (S94), a residue critical for TEAD interaction, abrogated miR-130a induction (Figure 2A).	('serine', 'Chemical', 'MESH:D012694', (24, 30))	('TEAD', 'Gene', '32536', (64, 68))	('S94', 'Var', (35, 38))	('TEAD', 'Gene', (64, 68))	('abrogated', 'NegReg', (82, 91))	('mutation', 'Var', (8, 16))	('miR-130a induction', 'MPA', (92, 110))
45628	26272168	Furthermore, knockdown of TEADs strongly reduced miR-130a expression (Figure 2B and Supplementary information, Figure S2A, S2B).	('reduced', 'NegReg', (41, 48))	('miR-130a', 'Protein', (49, 57))	('TEAD', 'Gene', '32536', (26, 30))	('TEAD', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))
45638	26272168	Despite substantial repression and activation of the wild-type (WT) sensor by miR-130a mimic and inhibitor, respectively, the seed-matching region mutant sensor remained unresponsive (Figure 3B).	('mutant', 'Var', (147, 153))	('miR-130a', 'Gene', (78, 86))	('WT', 'Disease', 'MESH:C536751', (64, 66))	('repression', 'NegReg', (20, 30))	('activation', 'PosReg', (35, 45))
45641	26272168	More importantly, inhibition of miR-130a attenuated CTGF reporter activity in a VGLL4-dependent manner (Figure 4B and Supplementary information, Figure S4A), suggesting that YAP is regulated by endogenous miR-130a through VGLL4.	('attenuated', 'NegReg', (41, 51))	('CTGF', 'Gene', '1490', (52, 56))	('CTGF', 'Gene', (52, 56))	('miR-130a', 'Gene', (32, 40))	('inhibition', 'Var', (18, 28))
45643	26272168	Indeed, we observed an enhanced or suppressed binding of YAP to CTGF promoter by pre-miR-130a and the miR-130a sponge, respectively (Figure 4F).	('enhanced', 'PosReg', (23, 31))	('YAP', 'Protein', (57, 60))	('binding', 'molecular_function', 'GO:0005488', ('46', '53'))	('pre', 'molecular_function', 'GO:0003904', ('81', '84'))	('pre-miR-130a', 'Var', (81, 93))	('suppressed', 'NegReg', (35, 45))	('CTGF', 'Gene', '1490', (64, 68))	('miR-130a', 'Var', (102, 110))	('binding', 'Interaction', (46, 53))	('CTGF', 'Gene', (64, 68))
45645	26272168	The mechanism would also predict that miR-130a promotes the binding between YAP and TEADs.	('binding', 'molecular_function', 'GO:0005488', ('60', '67'))	('TEAD', 'Gene', '32536', (84, 88))	('promotes', 'PosReg', (47, 55))	('TEAD', 'Gene', (84, 88))	('YAP', 'Protein', (76, 79))	('miR-130a', 'Var', (38, 46))	('binding', 'Interaction', (60, 67))
45647	26272168	Indeed, knockdown of YAP and TAZ or TEADs substantially increased VGLL4 protein levels in cancer and noncancerous cell lines from various tissue origins (Figure 5A, 5B and Supplementary information, Figure S5A, S5B), suggesting widespread existence of the mechanism.	('S5B', 'Gene', (211, 214))	('cancerous', 'Disease', (104, 113))	('increased', 'PosReg', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('knockdown', 'Var', (8, 17))	('TEAD', 'Gene', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('cancer', 'Disease', (104, 110))	('cancerous', 'Disease', 'MESH:D009369', (104, 113))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('VGLL4 protein levels', 'MPA', (66, 86))	('S5B', 'Gene', '5711', (211, 214))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('TEAD', 'Gene', '32536', (36, 40))
45649	26272168	Thus YAP-TEAD actively represses VGLL4 level through miR-130a.	('TEAD', 'Gene', '32536', (9, 13))	('TEAD', 'Gene', (9, 13))	('miR-130a', 'Var', (53, 61))	('represses', 'NegReg', (23, 32))	('VGLL4 level', 'MPA', (33, 44))
45650	26272168	In contrast, inhibition of miR-130a enhanced anoikis in the liver cancer cell line HepG2, which is defective in anoikis under basal conditions (Figure 5K).	('liver cancer', 'Phenotype', 'HP:0002896', (60, 72))	('miR-130a', 'Gene', (27, 35))	('anoikis', 'biological_process', 'GO:0043276', ('112', '119'))	('anoikis', 'CPA', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('inhibition', 'Var', (13, 23))	('anoikis', 'biological_process', 'GO:0043276', ('45', '52'))	('enhanced', 'PosReg', (36, 44))	('liver cancer', 'Disease', 'MESH:D006528', (60, 72))	('HepG2', 'CellLine', 'CVCL:0027', (83, 88))	('liver cancer', 'Disease', (60, 72))
45654	26272168	This suggests that defects in this pathway in cancer are more commonly somatic and mosaic.	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('defects', 'Var', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
45655	26272168	Despite recent report using similar method suggesting that YAP-S127A alone was not tumorigenic, the YAP-5SA mutant induced large tumors 100 days post-injection (Figure 6B and Supplementary information, Figure S6A).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('YAP-5SA', 'Gene', (100, 107))	('tumor', 'Disease', (83, 88))	('S127A', 'Mutation', 'rs762471803', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('mutant', 'Var', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('induced', 'Reg', (115, 122))
45656	26272168	This result indicates that aberrant YAP activation alone is sufficient to drive liver tumorigenesis in a normal tissue microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('drive', 'PosReg', (74, 79))	('aberrant', 'Var', (27, 35))	('tumor', 'Disease', (86, 91))	('YAP', 'Gene', (36, 39))	('activation', 'PosReg', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
45658	26272168	To investigate the role of VGLL4 and miR-130a in YAP-induced liver tumorigenesis, we co-expressed YAP-5SA with VGLL4 or miR-130a.	('miR-130a', 'Var', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
45660	26272168	However, co-expression of VGLL4 eliminated tumors at D70 and small tumors were only occasionally seen at D110 (Figure 6D).	('small tumors', 'Disease', (61, 73))	('eliminated', 'NegReg', (32, 42))	('small tumors', 'Disease', 'MESH:D058405', (61, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('D70', 'Var', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('VGLL4', 'Protein', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', (67, 73))	('co-expression', 'Var', (9, 22))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
45661	26272168	The lack of VGLL4 expression in these tumors suggested an origin from cells expressing only YAP-5SA (Supplementary information, Figure S6C).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('VGLL4', 'Protein', (12, 17))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('YAP-5SA', 'Var', (92, 99))
45663	26272168	In contrast, co-injection of YAP-5SA and pre-miR-130a induced not only small tumors but also numerous hyperplastic foci by D70 (Figure 6D).	('small tumors', 'Disease', (71, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('hyperplastic foci', 'CPA', (102, 119))	('small tumors', 'Disease', 'MESH:D058405', (71, 83))	('D70', 'Var', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('pre', 'molecular_function', 'GO:0003904', ('41', '44'))	('pre-miR-130a', 'Var', (41, 53))	('YAP-5SA', 'Var', (29, 36))
45664	26272168	Consistently, these livers also showed much more tumors at D110 and some mice were moribund at the time (Figure 6D).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mice', 'Species', '10090', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('D110', 'Var', (59, 63))
45666	26272168	Indeed, liver-specific Mst1/2 knockout mediated by adenoviral Cre expression quickly led to liver enlargement within ten days (Figure 6E).	('Mst1/2', 'Gene', (23, 29))	('knockout', 'Var', (30, 38))	('liver enlargement', 'Disease', (92, 109))	('led to', 'Reg', (85, 91))	('liver enlargement', 'Phenotype', 'HP:0002240', (92, 109))	('liver enlargement', 'Disease', 'MESH:D006529', (92, 109))
45667	26272168	Taken together, the YAP-miR-130a-VGLL4 positive feedback loop plays a critical role in organ size regulation and tumorigenesis upon Hippo pathway deregulation.	('tumor', 'Disease', (113, 118))	('deregulation', 'Var', (146, 158))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('organ size regulation', 'CPA', (87, 108))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Hippo', 'Gene', (132, 137))	('regulation', 'biological_process', 'GO:0065007', ('98', '108'))
45673	26272168	However, deletion of the bantam-binding site largely abrogated the repression (Figure 7B).	('bantam', 'Species', '9031', (25, 31))	('deletion', 'Var', (9, 17))	('repression', 'MPA', (67, 77))	('abrogated', 'NegReg', (53, 62))	('binding', 'molecular_function', 'GO:0005488', ('32', '39'))
45680	26272168	Deregulation of the Hippo pathway leads to drastic change of organ size up to several folds in both Drosophila and mammals.	('Deregulation', 'Var', (0, 12))	('organ size', 'CPA', (61, 71))	('change', 'Reg', (51, 57))	('Hippo pathway', 'Pathway', (20, 33))	('Drosophila', 'Species', '7227', (100, 110))
45691	26272168	Indeed, it was recently suggested that Yki functions by relieving a default repression of Sd by SdBP/Tgi, although in situations such as hippo inactivation, the transcriptional activation activity of Yki itself plays a leading role.	('inactivation', 'Var', (143, 155))	('hippo', 'Disease', (137, 142))	('default repression', 'MPA', (68, 86))	('relieving', 'NegReg', (56, 65))	('Tgi', 'Gene', '39521', (101, 104))	('Tgi', 'Gene', (101, 104))
45695	26272168	More importantly, YAP activation has been found in human cancers such as HCC, neurofibromatosis 2 and uveal melanoma due to amplification of the YAP gene locus or mutations of NF2 or GNAQ/GNA11.	('NF2', 'Gene', (176, 179))	('human', 'Species', '9606', (51, 56))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('GNA11', 'Gene', (188, 193))	('cancers', 'Disease', (57, 64))	('YAP gene', 'Gene', (145, 153))	('HCC', 'Disease', (73, 76))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('GNAQ', 'Gene', '2776', (183, 187))	('uveal melanoma', 'Disease', (102, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (102, 116))	('GNAQ', 'Gene', (183, 187))	('neurofibromatosis 2', 'Disease', (78, 97))	('mutations', 'Var', (163, 172))	('activation', 'PosReg', (22, 32))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('GNA11', 'Gene', '2767', (188, 193))	('amplification', 'Var', (124, 137))	('neurofibromatosis 2', 'Disease', 'MESH:C537392', (78, 97))	('NF2', 'Gene', '4771', (176, 179))
45700	26272168	In this study, we show that miR-130a inhibition dampens Hippo pathway output and reverses organ size enlargement and tumorigenesis induced by Hippo pathway deregulation or YAP activation.	('Hippo pathway', 'Pathway', (56, 69))	('organ size enlargement', 'CPA', (90, 112))	('inhibition', 'Var', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('dampens', 'NegReg', (48, 55))	('tumor', 'Disease', (117, 122))	('miR-130a', 'Gene', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('deregulation', 'Var', (156, 168))	('Hippo pathway', 'Pathway', (142, 155))	('reverses', 'NegReg', (81, 89))
45703	26272168	Thus our identification of the remarkable role of miR-130a in sustaining YAP activity would suggest modulating miR-130a as an exciting new approach for pharmacological intervention of cancer.	('cancer', 'Disease', (184, 190))	('modulating', 'Var', (100, 110))	('YAP activity', 'MPA', (73, 85))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('miR-130a', 'Gene', (111, 119))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
45719	22653968	Protein kinase C inhibitor AEB071 targets ocular melanoma harboring GNAQ mutations via effects on the PKC/Erk1/2 and PKC/NF-kappaB pathways Somatic GNAQ mutations at codon 209 have been identified in approximately 50% of uveal melanomas (UM) and have been reported to be oncogenic through activating PLCbeta-PKC-Erk1/2 pathways.	('Erk1/2', 'Gene', (312, 318))	('PKC', 'Gene', (117, 120))	('mutations', 'Var', (153, 162))	('PKC', 'molecular_function', 'GO:0004697', ('308', '311'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (221, 235))	('Erk1/2', 'Gene', (106, 112))	('GNAQ', 'Gene', '2776', (148, 152))	('NF-kappaB', 'Gene', '4790', (121, 130))	('mutations', 'Var', (73, 82))	('Protein kinase C', 'Gene', (0, 16))	('GNAQ', 'Gene', (148, 152))	('PKC', 'Gene', (102, 105))	('uveal melanomas', 'Disease', (221, 236))	('GNAQ', 'Gene', '2776', (68, 72))	('uveal melanomas', 'Phenotype', 'HP:0007716', (221, 236))	('Erk1', 'molecular_function', 'GO:0004707', ('312', '316'))	('GNAQ', 'Gene', (68, 72))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('ocular melanoma', 'Phenotype', 'HP:0007716', (42, 57))	('PKC', 'molecular_function', 'GO:0004697', ('117', '120'))	('Erk1/2', 'Gene', '5595;5594', (312, 318))	('Erk1/2', 'Gene', '5595;5594', (106, 112))	('melanomas', 'Phenotype', 'HP:0002861', (227, 236))	('ocular melanoma', 'Disease', 'MESH:D008545', (42, 57))	('UM', 'Phenotype', 'HP:0007716', (238, 240))	('PKC', 'Gene', '112476', (102, 105))	('PKC', 'Gene', '112476', (308, 311))	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('uveal melanomas', 'Disease', 'MESH:C536494', (221, 236))	('identified', 'Reg', (186, 196))	('Erk1', 'molecular_function', 'GO:0004707', ('106', '110'))	('Protein kinase C', 'Gene', '112476', (0, 16))	('PKC', 'Gene', '112476', (117, 120))	('PKC', 'molecular_function', 'GO:0004697', ('102', '105'))	('activating', 'PosReg', (289, 299))	('PKC', 'Gene', (308, 311))	('NF-kappaB', 'Gene', (121, 130))	('ocular melanoma', 'Disease', (42, 57))
45720	22653968	We hypothesized that PKC may provide new opportunities for therapeutic targeting of UM carrying GNAQ mutations.	('GNAQ', 'Gene', '2776', (96, 100))	('mutations', 'Var', (101, 110))	('PKC', 'molecular_function', 'GO:0004697', ('21', '24'))	('PKC', 'Gene', '112476', (21, 24))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('GNAQ', 'Gene', (96, 100))	('PKC', 'Gene', (21, 24))
45721	22653968	To test this hypothesis, UM cells harboring wild type or mutant GNAQ were treated with the PKC inhibitor AEB071 (sotrastaurin) or infected with lentivirus expressing shRNAs targeting PKC isoforms.	('GNAQ', 'Gene', (64, 68))	('sotrastaurin', 'Chemical', 'MESH:C543528', (113, 125))	('PKC', 'Gene', (183, 186))	('PKC', 'Gene', '112476', (183, 186))	('PKC', 'molecular_function', 'GO:0004697', ('183', '186'))	('PKC', 'Gene', (91, 94))	('mutant', 'Var', (57, 63))	('AEB071', 'Chemical', 'MESH:C543528', (105, 111))	('GNAQ', 'Gene', '2776', (64, 68))	('PKC', 'Gene', '112476', (91, 94))	('UM', 'Phenotype', 'HP:0007716', (25, 27))	('PKC', 'molecular_function', 'GO:0004697', ('91', '94'))
45722	22653968	Notably, AEB071 at low micromolar concentrations significantly inhibited the growth of UM cells harboring GNAQ mutations through induction of G1 arrest and apoptosis.	('mutations', 'Var', (111, 120))	('arrest', 'Disease', 'MESH:D006323', (145, 151))	('UM', 'Phenotype', 'HP:0007716', (87, 89))	('AEB071', 'Chemical', 'MESH:C543528', (9, 15))	('arrest', 'Disease', (145, 151))	('GNAQ', 'Gene', (106, 110))	('apoptosis', 'biological_process', 'GO:0097194', ('156', '165'))	('inhibited', 'NegReg', (63, 72))	('apoptosis', 'biological_process', 'GO:0006915', ('156', '165'))	('growth', 'CPA', (77, 83))	('apoptosis', 'CPA', (156, 165))	('GNAQ', 'Gene', '2776', (106, 110))
45723	22653968	However, AEB071 had little effect on UM cells carrying wild type GNAQ.	('AEB071', 'Var', (9, 15))	('GNAQ', 'Gene', '2776', (65, 69))	('AEB071', 'Chemical', 'MESH:C543528', (9, 15))	('UM', 'Phenotype', 'HP:0007716', (37, 39))	('GNAQ', 'Gene', (65, 69))
45724	22653968	AEB071-mediated cell inhibition in the GNAQ mutated UM was accompanied by inhibition of Erk1/2 phosphorylation, NF-kappaB, decreased expression of cyclin D1, survivin, Bcl-xL and XIAP, and increased expression of cyclin-dependent kinase inhibitor p27Kip1.	('AEB071', 'Chemical', 'MESH:C543528', (0, 6))	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('cell', 'CPA', (16, 20))	('p27Kip1', 'Gene', '1027', (247, 254))	('GNAQ', 'Gene', (39, 43))	('decreased', 'NegReg', (123, 132))	('NF-kappaB', 'Gene', (112, 121))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('230', '246'))	('cyclin D1', 'Gene', '595', (147, 156))	('phosphorylation', 'MPA', (95, 110))	('XIAP', 'Gene', (179, 183))	('survivin', 'Protein', (158, 166))	('NF-kappaB', 'Gene', '4790', (112, 121))	('expression', 'MPA', (199, 209))	('mutated', 'Var', (44, 51))	('Bcl-xL', 'Gene', (168, 174))	('phosphorylation', 'biological_process', 'GO:0016310', ('95', '110'))	('cyclin', 'molecular_function', 'GO:0016538', ('147', '153'))	('Bcl-xL', 'Gene', '598', (168, 174))	('Erk1', 'molecular_function', 'GO:0004707', ('88', '92'))	('Erk1/2', 'Protein', (88, 94))	('XIAP', 'Gene', '331', (179, 183))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('213', '246'))	('expression', 'MPA', (133, 143))	('p27Kip1', 'Gene', (247, 254))	('increased expression of cyclin-dependent kinase', 'Phenotype', 'HP:0003236', (189, 236))	('inhibition', 'NegReg', (74, 84))	('GNAQ', 'Gene', '2776', (39, 43))	('cyclin D1', 'Gene', (147, 156))	('increased', 'PosReg', (189, 198))
45725	22653968	AEB071 suppressed the expression of PKC alpha, beta, delta, epsilon and theta in GNAQ mutated UM cells.	('AEB071', 'Chemical', 'MESH:C543528', (0, 6))	('mutated', 'Var', (86, 93))	('UM', 'Phenotype', 'HP:0007716', (94, 96))	('PKC alpha, beta, delta, epsilon and theta', 'Gene', '5578;5579;5580;5581', (36, 77))	('PKC', 'molecular_function', 'GO:0004697', ('36', '39'))	('suppressed', 'NegReg', (7, 17))	('GNAQ', 'Gene', (81, 85))	('AEB071', 'Var', (0, 6))	('expression', 'MPA', (22, 32))	('GNAQ', 'Gene', '2776', (81, 85))
45726	22653968	Our findings from shRNA-mediated knockdown studies revealed that these PKC isoforms are functionally important for UM cells harboring GNAQ mutations.	('mutations', 'Var', (139, 148))	('GNAQ', 'Gene', (134, 138))	('UM', 'Phenotype', 'HP:0007716', (115, 117))	('PKC', 'Gene', (71, 74))	('PKC', 'molecular_function', 'GO:0004697', ('71', '74'))	('PKC', 'Gene', '112476', (71, 74))	('GNAQ', 'Gene', '2776', (134, 138))
45728	22653968	Together, our findings demonstrate that AEB071 exerts antitumor action on UM cells carrying GNAQ mutations via targeting PKC/Erk1/2 and PKC/NF-kappaB pathways.	('PKC', 'Gene', (136, 139))	('mutations', 'Var', (97, 106))	('tumor', 'Disease', (58, 63))	('PKC', 'Gene', '112476', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Erk1', 'molecular_function', 'GO:0004707', ('125', '129'))	('GNAQ', 'Gene', (92, 96))	('NF-kappaB', 'Gene', '4790', (140, 149))	('PKC', 'molecular_function', 'GO:0004697', ('121', '124'))	('PKC', 'Gene', (121, 124))	('PKC', 'Gene', '112476', (121, 124))	('NF-kappaB', 'Gene', (140, 149))	('AEB071', 'Chemical', 'MESH:C543528', (40, 46))	('PKC', 'molecular_function', 'GO:0004697', ('136', '139'))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('targeting', 'Reg', (111, 120))	('GNAQ', 'Gene', '2776', (92, 96))
45729	22653968	Targeted PKC inhibition with drugs such as AEB071 offers novel therapeutic potential for UM harboring GNAQ mutations.	('PKC', 'molecular_function', 'GO:0004697', ('9', '12'))	('mutations', 'Var', (107, 116))	('GNAQ', 'Gene', (102, 106))	('AEB071', 'Chemical', 'MESH:C543528', (43, 49))	('PKC', 'Gene', (9, 12))	('inhibition', 'NegReg', (13, 23))	('PKC', 'Gene', '112476', (9, 12))	('UM', 'Phenotype', 'HP:0007716', (89, 91))	('GNAQ', 'Gene', '2776', (102, 106))
45733	22653968	Mutations in the GNAQ gene have been identified in approximately 50% of UM and 83% blue naevi.	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('blue naevi', 'Phenotype', 'HP:0100814', (83, 93))	('GNAQ', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (37, 47))	('blue', 'Disease', (83, 87))	('naevi', 'Phenotype', 'HP:0003764', (88, 93))	('GNAQ', 'Gene', '2776', (17, 21))
45737	22653968	The majority of GNAQ mutations occur at codon 209 within the GTPase catalytic domain, resulting in loss of the intrinsic GTPase activity and constitutively activation of GNAQ.	('GNAQ', 'Gene', (170, 174))	('GTP', 'Chemical', 'MESH:D006160', (61, 64))	('intrinsic', 'MPA', (111, 120))	('activity', 'MPA', (128, 136))	('activation', 'PosReg', (156, 166))	('GNAQ', 'Gene', (16, 20))	('GTPase activity', 'molecular_function', 'GO:0003924', ('121', '136'))	('GNAQ', 'Gene', '2776', (170, 174))	('GTP', 'Chemical', 'MESH:D006160', (121, 124))	('loss', 'NegReg', (99, 103))	('GTPase', 'Protein', (121, 127))	('GNAQ', 'Gene', '2776', (16, 20))	('mutations', 'Var', (21, 30))
45738	22653968	Expression of mutated GNAQ results in melanocyte transformation and increased Erk1/2 phosphorylation, indicating that mutant GNAQ behaves as a dominant acting oncogene.	('Erk1', 'molecular_function', 'GO:0004707', ('78', '82'))	('mutated', 'Var', (14, 21))	('phosphorylation', 'MPA', (85, 100))	('melanocyte transformation', 'CPA', (38, 63))	('GNAQ', 'Gene', '2776', (125, 129))	('GNAQ', 'Gene', (22, 26))	('mutant', 'Var', (118, 124))	('phosphorylation', 'biological_process', 'GO:0016310', ('85', '100'))	('GNAQ', 'Gene', '2776', (22, 26))	('GNAQ', 'Gene', (125, 129))	('increased', 'PosReg', (68, 77))	('Erk1/2', 'Protein', (78, 84))
45747	22653968	Using shRNA mediated downregulation of PKC isoforms beta, epsilon, and theta we have recently shown that these isoforms are functionally important for GNAQ mutated UM cells.	('GNAQ', 'Gene', '2776', (151, 155))	('GNAQ', 'Gene', (151, 155))	('downregulation', 'NegReg', (21, 35))	('mutated', 'Var', (156, 163))	('PKC isoforms beta, epsilon, and theta', 'Gene', '5581', (39, 76))	('UM', 'Phenotype', 'HP:0007716', (164, 166))	('PKC', 'molecular_function', 'GO:0004697', ('39', '42'))
45748	22653968	The oncogenic properties of mutant GNAQ and the important PKC roles in GNAQ-mediated Erk1/2 activation and GNAQ mutated UM cells suggested that PKC may provide new opportunities for therapeutic intervention of UM carrying GNAQ mutations.	('PKC', 'Gene', '112476', (58, 61))	('GNAQ', 'Gene', (71, 75))	('GNAQ', 'Gene', (222, 226))	('PKC', 'molecular_function', 'GO:0004697', ('144', '147'))	('PKC', 'Gene', (58, 61))	('UM', 'Phenotype', 'HP:0007716', (210, 212))	('GNAQ', 'Gene', '2776', (107, 111))	('UM', 'Phenotype', 'HP:0007716', (120, 122))	('GNAQ', 'Gene', (107, 111))	('PKC', 'Gene', '112476', (144, 147))	('GNAQ', 'Gene', '2776', (35, 39))	('GNAQ', 'Gene', (35, 39))	('mutations', 'Var', (227, 236))	('mutant', 'Var', (28, 34))	('PKC', 'molecular_function', 'GO:0004697', ('58', '61'))	('PKC', 'Gene', (144, 147))	('Erk1', 'molecular_function', 'GO:0004707', ('85', '89'))	('GNAQ', 'Gene', '2776', (71, 75))	('GNAQ', 'Gene', '2776', (222, 226))
45749	22653968	To test this hypothesis, UM cells carrying wild type GNAQ or GNAQ mutated at codon 209 were treated with the PKC inhibitor AEB071 (sotrastaurin), a PKC inhibitor that has potent activity against classical and novel PKC isotypes.	('sotrastaurin', 'Chemical', 'MESH:C543528', (131, 143))	('mutated', 'Var', (66, 73))	('GNAQ', 'Gene', (53, 57))	('GNAQ', 'Gene', (61, 65))	('PKC', 'Gene', (148, 151))	('PKC', 'Gene', (215, 218))	('PKC', 'Gene', '112476', (148, 151))	('PKC', 'molecular_function', 'GO:0004697', ('215', '218'))	('UM', 'Phenotype', 'HP:0007716', (25, 27))	('PKC', 'Gene', (109, 112))	('AEB071', 'Chemical', 'MESH:C543528', (123, 129))	('PKC', 'Gene', '112476', (215, 218))	('GNAQ', 'Gene', '2776', (53, 57))	('PKC', 'molecular_function', 'GO:0004697', ('148', '151'))	('PKC', 'molecular_function', 'GO:0004697', ('109', '112'))	('PKC', 'Gene', '112476', (109, 112))	('GNAQ', 'Gene', '2776', (61, 65))
45750	22653968	AEB071 selectively inhibited the growth of UM cells harboring GNAQ mutations by targeting PKC/Erk1/2 and PKC/NF-kappaB pathways.	('NF-kappaB', 'Gene', '4790', (109, 118))	('AEB071', 'Chemical', 'MESH:C543528', (0, 6))	('PKC', 'molecular_function', 'GO:0004697', ('105', '108'))	('inhibited', 'NegReg', (19, 28))	('growth', 'MPA', (33, 39))	('GNAQ', 'Gene', '2776', (62, 66))	('PKC', 'Gene', (90, 93))	('PKC', 'Gene', '112476', (90, 93))	('NF-kappaB', 'Gene', (109, 118))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('mutations', 'Var', (67, 76))	('Erk1', 'molecular_function', 'GO:0004707', ('94', '98'))	('PKC', 'Gene', (105, 108))	('GNAQ', 'Gene', (62, 66))	('PKC', 'Gene', '112476', (105, 108))	('PKC', 'molecular_function', 'GO:0004697', ('90', '93'))	('targeting', 'Reg', (80, 89))
45751	22653968	The sources and GNAQ mutational status of UM cell lines C918, Ocm1, Ocm3, Mel285, Mel202, 92.1 and Omm1.3 have been described previously.	('GNAQ', 'Gene', (16, 20))	('C918', 'Var', (56, 60))	('Ocm1', 'Species', '83984', (62, 66))	('GNAQ', 'Gene', '2776', (16, 20))	('UM', 'Phenotype', 'HP:0007716', (42, 44))
45768	22653968	Sequencing analysis confirmed that GNAQ is wild type in cell lines C918, Ocm1, Ocm3 and Mel285, while codon 209 of GNAQ is mutated from CAA (glutamine) to CTA (leucine) in cell lines Mel202 and 92.1 and to CCA (proline) in cell line Omm1.3.	('GNAQ', 'Gene', (115, 119))	('proline', 'Chemical', 'MESH:D011392', (211, 218))	('glutamine', 'Chemical', 'MESH:D005973', (141, 150))	('leucine', 'Chemical', 'MESH:D007930', (160, 167))	('CTA', 'Chemical', 'MESH:C569473', (155, 158))	('GNAQ', 'Gene', '2776', (115, 119))	('GNAQ', 'Gene', '2776', (35, 39))	('Ocm1', 'Species', '83984', (73, 77))	('mutated', 'Var', (123, 130))	('GNAQ', 'Gene', (35, 39))
45772	22653968	AEB071 had little effect on viability of three GNAQ wild type cells up to 10 muM (Figure 1C and Supplemental Figure S1).	('AEB071', 'Chemical', 'MESH:C543528', (0, 6))	('AEB071', 'Var', (0, 6))	('GNAQ', 'Gene', (47, 51))	('GNAQ', 'Gene', '2776', (47, 51))
45774	22653968	Along with decreased viability, microscopic examination found morphological alterations in AEB071 treated cells harboring GNAQ mutations but not wild type GNAQ or normal melanocytes (Figure 1D).	('GNAQ', 'Gene', '2776', (155, 159))	('GNAQ', 'Gene', (122, 126))	('GNAQ', 'Gene', '2776', (122, 126))	('AEB071', 'Chemical', 'MESH:C543528', (91, 97))	('mutations', 'Var', (127, 136))	('GNAQ', 'Gene', (155, 159))
45776	22653968	AEB071 markedly increased the G1 phase population while decreasing the S phase population in UM cells harboring GNAQ mutations (Figures 2A and 2B).	('AEB071', 'Chemical', 'MESH:C543528', (0, 6))	('mutations', 'Var', (117, 126))	('GNAQ', 'Gene', (112, 116))	('S phase', 'biological_process', 'GO:0051320', ('71', '78'))	('G1 phase', 'biological_process', 'GO:0051318', ('30', '38'))	('UM', 'Phenotype', 'HP:0007716', (93, 95))	('increased', 'PosReg', (16, 25))	('decreasing', 'NegReg', (56, 66))	('S phase population', 'MPA', (71, 89))	('GNAQ', 'Gene', '2776', (112, 116))	('AEB071', 'Var', (0, 6))
45777	22653968	There was no significant change in the cell cycle pattern for cell lines carrying wild type GNAQ (C918, Mel285 and Ocm3).	('GNAQ', 'Gene', '2776', (92, 96))	('cell cycle', 'biological_process', 'GO:0007049', ('39', '49'))	('C918', 'Var', (98, 102))	('GNAQ', 'Gene', (92, 96))
45779	22653968	In agreement with this G1 arrest, AEB071 also significantly increased the accumulation of p27Kip1, while decreasing the expression of cylin D1 in all three GNAQ mutated cell lines tested (Figures 2C).	('GNAQ', 'Gene', (156, 160))	('accumulation', 'MPA', (74, 86))	('decreasing', 'NegReg', (105, 115))	('expression', 'MPA', (120, 130))	('p27Kip1', 'Gene', '1027', (90, 97))	('cylin D1', 'MPA', (134, 142))	('arrest', 'Disease', 'MESH:D006323', (26, 32))	('AEB071', 'Var', (34, 40))	('GNAQ', 'Gene', '2776', (156, 160))	('AEB071', 'Chemical', 'MESH:C543528', (34, 40))	('p27Kip1', 'Gene', (90, 97))	('arrest', 'Disease', (26, 32))	('increased', 'PosReg', (60, 69))
45781	22653968	These findings suggest that AEB071 selectively induced G1 arrest in GNAQ mutated cells through altering the expression of regulators critical for the G1 to S transition.	('expression of regulators', 'MPA', (108, 132))	('arrest', 'Disease', (58, 64))	('GNAQ', 'Gene', (68, 72))	('AEB071', 'Chemical', 'MESH:C543528', (28, 34))	('induced', 'Reg', (47, 54))	('AEB071', 'Var', (28, 34))	('altering', 'Reg', (95, 103))	('GNAQ', 'Gene', '2776', (68, 72))	('arrest', 'Disease', 'MESH:D006323', (58, 64))
45782	22653968	We next examined whether AEB071 promoted apoptosis in UM cells.	('apoptosis', 'biological_process', 'GO:0097194', ('41', '50'))	('apoptosis', 'biological_process', 'GO:0006915', ('41', '50'))	('UM', 'Phenotype', 'HP:0007716', (54, 56))	('apoptosis', 'CPA', (41, 50))	('AEB071', 'Chemical', 'MESH:C543528', (25, 31))	('AEB071', 'Var', (25, 31))
45783	22653968	Treatment with 2 and 5 muM AEB071 for 72 hours significantly increased Annexin V positive (apoptotic) populations in GNAQ mutated 92.1 and Omm1.3 cells (Figure 3A).	('GNAQ', 'Gene', '2776', (117, 121))	('increased', 'PosReg', (61, 70))	('Annexin V', 'Gene', '308', (71, 80))	('GNAQ', 'Gene', (117, 121))	('Annexin V', 'Gene', (71, 80))	('mutated', 'Var', (122, 129))	('AEB071', 'Chemical', 'MESH:C543528', (27, 33))
45786	22653968	In contrast, AEB071 did not increase Annexin V positive cell populations or caspase-3 cleavage in UM cells harboring wild type GNAQ (Figures 3A and B).	('Annexin V', 'Gene', (37, 46))	('caspase-3', 'Gene', (76, 85))	('GNAQ', 'Gene', (127, 131))	('caspase-3', 'Gene', '836', (76, 85))	('AEB071', 'Var', (13, 19))	('Annexin V', 'Gene', '308', (37, 46))	('AEB071', 'Chemical', 'MESH:C543528', (13, 19))	('UM', 'Phenotype', 'HP:0007716', (98, 100))	('cleavage', 'MPA', (86, 94))	('GNAQ', 'Gene', '2776', (127, 131))
45787	22653968	AEB071 further inhibited the expression of the anti-apoptotic proteins survivin, Bcl-xL and XIAP in a dose-dependent manner in Mel202, 92.1 and Omm1.3 cells (Figure 3C).	('inhibited', 'NegReg', (15, 24))	('AEB071', 'Chemical', 'MESH:C543528', (0, 6))	('Bcl-xL', 'Gene', (81, 87))	('XIAP', 'Gene', (92, 96))	('survivin', 'Protein', (71, 79))	('XIAP', 'Gene', '331', (92, 96))	('expression', 'MPA', (29, 39))	('AEB071', 'Var', (0, 6))	('Bcl-xL', 'Gene', '598', (81, 87))
45789	22653968	These results indicate that AEB071 selectively induced apoptosis in UM cells harboring GNAQ mutations.	('AEB071', 'Gene', (28, 34))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('GNAQ', 'Gene', '2776', (87, 91))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('induced', 'Reg', (47, 54))	('mutations', 'Var', (92, 101))	('GNAQ', 'Gene', (87, 91))	('UM', 'Phenotype', 'HP:0007716', (68, 70))	('AEB071', 'Chemical', 'MESH:C543528', (28, 34))	('apoptosis', 'CPA', (55, 64))
45791	22653968	Immunoblotting demonstrated that treatment with AEB071 for 6 hours in the absence of serum resulted in decreased PKCdelta/thetaSer643/676 phosphorylation in Mel202, 92.1 and C918 cells, and PKCthetaThr538 phosphorylation in Mel202 cells (Figure 4A).	('phosphorylation', 'biological_process', 'GO:0016310', ('138', '153'))	('PKCdelta', 'molecular_function', 'GO:0004697', ('113', '121'))	('Thr538', 'Chemical', '-', (198, 204))	('phosphorylation', 'biological_process', 'GO:0016310', ('205', '220'))	('decreased', 'NegReg', (103, 112))	('PKC', 'Gene', '112476', (190, 193))	('PKCdelta', 'Gene', '5580', (113, 121))	('PKCdelta', 'Gene', (113, 121))	('phosphorylation', 'MPA', (138, 153))	('AEB071', 'Var', (48, 54))	('PKC', 'Gene', (190, 193))	('PKC', 'Gene', (113, 116))	('PKC', 'Gene', '112476', (113, 116))	('phosphorylation', 'MPA', (205, 220))	('AEB071', 'Chemical', 'MESH:C543528', (48, 54))	('Ser643', 'Chemical', '-', (127, 133))
45795	22653968	PKCalpha was reduced in some wild type (C918 and Ocm1) and in GNAQ mutated (92.1 and Omm1.3) cells, while PKCbeta was reduced only in mutated cells (Mel202 and 92.1).	('PKCalpha', 'molecular_function', 'GO:0004697', ('0', '8'))	('GNAQ', 'Gene', '2776', (62, 66))	('PKCbeta', 'molecular_function', 'GO:0004697', ('106', '113'))	('PKCbeta', 'Gene', (106, 113))	('C918', 'Var', (40, 44))	('mutated', 'Var', (67, 74))	('Ocm1', 'Var', (49, 53))	('PKCbeta', 'Gene', '5579', (106, 113))	('GNAQ', 'Gene', (62, 66))	('Ocm1', 'Species', '83984', (49, 53))	('PKCalpha', 'Gene', '5578', (0, 8))	('PKCalpha', 'Gene', (0, 8))	('reduced', 'NegReg', (13, 20))
45796	22653968	PKCtheta was decreased in all three GNAQ mutated but only in one wild type (Ocm3) cells.	('PKC', 'Gene', (0, 3))	('mutated', 'Var', (41, 48))	('decreased', 'NegReg', (13, 22))	('PKC', 'Gene', '112476', (0, 3))	('GNAQ', 'Gene', '2776', (36, 40))	('GNAQ', 'Gene', (36, 40))
45798	22653968	These findings suggest that AEB071 may have greater overall inhibitory effect on multiple PKC isoforms in UM cells with mutated GNAQ: PKCalpha, beta, delta, epsilon and/or theta expression was suppressed by AEB071 in GNAQ mutated cells while PKCalpha, and PKCdelta and PKCepsilon expression was affected in GNAQ wild type cells.	('PKCalpha', 'molecular_function', 'GO:0004697', ('134', '142'))	('PKC', 'Gene', (134, 137))	('AEB071', 'Var', (207, 213))	('PKCalpha', 'Gene', '5578', (242, 250))	('PKC', 'Gene', '112476', (90, 93))	('PKC', 'Gene', (242, 245))	('GNAQ', 'Gene', '2776', (307, 311))	('PKCalpha', 'molecular_function', 'GO:0004697', ('242', '250'))	('PKCalpha', 'Gene', (134, 142))	('GNAQ', 'Gene', (307, 311))	('mutated', 'Var', (222, 229))	('AEB071', 'Chemical', 'MESH:C543528', (28, 34))	('PKC', 'Gene', '112476', (256, 259))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('269', '279'))	('PKC', 'molecular_function', 'GO:0004697', ('90', '93'))	('PKCalpha, beta, delta, epsilon and/or theta', 'Gene', '112476', (134, 177))	('PKCalpha', 'Gene', (242, 250))	('PKCepsilon', 'Gene', (269, 279))	('PKC', 'Gene', (90, 93))	('PKC', 'Gene', (256, 259))	('UM', 'Phenotype', 'HP:0007716', (106, 108))	('GNAQ', 'Gene', '2776', (217, 221))	('GNAQ', 'Gene', '2776', (128, 132))	('PKC', 'Gene', '112476', (269, 272))	('GNAQ', 'Gene', (217, 221))	('PKCdelta', 'molecular_function', 'GO:0004697', ('256', '264'))	('PKCdelta', 'Gene', '5580', (256, 264))	('GNAQ', 'Gene', (128, 132))	('PKCdelta', 'Gene', (256, 264))	('PKC', 'Gene', '112476', (134, 137))	('PKC', 'Gene', (269, 272))	('PKCepsilon', 'Gene', '5581', (269, 279))	('AEB071', 'Chemical', 'MESH:C543528', (207, 213))	('inhibitory', 'MPA', (60, 70))	('PKC', 'Gene', '112476', (242, 245))	('PKCalpha', 'Gene', '5578', (134, 142))	('suppressed', 'NegReg', (193, 203))
45801	22653968	Interestingly, knockdown of PKCalpha or PKCdelta significantly decreased viability of Mel202 and Omm1.3 cells, but failed to significantly decrease the viability of C918 cells (Figure 4D), indicating that PKCalpha and PKCdelta are functionally important in UM cells harboring GNAQ mutations.	('GNAQ', 'Gene', (276, 280))	('PKCalpha', 'Gene', (28, 36))	('UM', 'Phenotype', 'HP:0007716', (257, 259))	('PKCdelta', 'molecular_function', 'GO:0004697', ('40', '48'))	('PKCalpha', 'molecular_function', 'GO:0004697', ('28', '36'))	('PKCdelta', 'molecular_function', 'GO:0004697', ('218', '226'))	('PKCalpha', 'Gene', '5578', (205, 213))	('PKCalpha', 'Gene', (205, 213))	('decreased', 'NegReg', (63, 72))	('PKCdelta', 'Gene', '5580', (40, 48))	('PKCdelta', 'Gene', (40, 48))	('GNAQ', 'Gene', '2776', (276, 280))	('PKCdelta', 'Gene', '5580', (218, 226))	('mutations', 'Var', (281, 290))	('PKCdelta', 'Gene', (218, 226))	('PKCalpha', 'molecular_function', 'GO:0004697', ('205', '213'))	('viability', 'MPA', (73, 82))	('PKCalpha', 'Gene', '5578', (28, 36))
45802	22653968	We have previously found that PKC isoforms beta, epsilon, and theta are functionally critical for GNAQ mutated UM cells.	('mutated', 'Var', (103, 110))	('UM', 'Phenotype', 'HP:0007716', (111, 113))	('GNAQ', 'Gene', (98, 102))	('PKC', 'molecular_function', 'GO:0004697', ('30', '33'))	('PKC isoforms beta, epsilon, and theta', 'Gene', '5581', (30, 67))	('GNAQ', 'Gene', '2776', (98, 102))
45803	22653968	These findings together suggest that AEB071 suppressed growth of GNAQ mutated UM cells via inhibition of multiple PKC isoforms.	('suppressed', 'NegReg', (44, 54))	('PKC', 'Gene', (114, 117))	('GNAQ', 'Gene', '2776', (65, 69))	('AEB071', 'Chemical', 'MESH:C543528', (37, 43))	('PKC', 'Gene', '112476', (114, 117))	('inhibition', 'NegReg', (91, 101))	('PKC', 'molecular_function', 'GO:0004697', ('114', '117'))	('GNAQ', 'Gene', (65, 69))	('UM', 'Phenotype', 'HP:0007716', (78, 80))	('growth', 'MPA', (55, 61))	('mutated', 'Var', (70, 77))
45804	22653968	To further define the molecular mechanisms underlying the anti-proliferative action of AEB071, we next assessed downstream effectors of PKC mediated pathways that were potentially affected by AEB071.	('PKC', 'Gene', (136, 139))	('PKC', 'Gene', '112476', (136, 139))	('AEB071', 'Chemical', 'MESH:C543528', (87, 93))	('PKC', 'molecular_function', 'GO:0004697', ('136', '139'))	('anti-proliferative', 'MPA', (58, 76))	('AEB071', 'Var', (192, 198))	('AEB071', 'Chemical', 'MESH:C543528', (192, 198))	('affected', 'Reg', (180, 188))
45807	22653968	Similarly, AEB071 decreased GSK3betaSer9 phsophorylation in all UM cell lines studied here (Supplemental Figure S2).	('AEB071', 'Chemical', 'MESH:C543528', (11, 17))	('GSK', 'molecular_function', 'GO:0050321', ('28', '31'))	('UM', 'Phenotype', 'HP:0007716', (64, 66))	('decreased', 'NegReg', (18, 27))	('GSK3betaSer9', 'Enzyme', (28, 40))	('AEB071', 'Var', (11, 17))
45808	22653968	However, AEB071 only significantly inhibited Erk1/2 phosphorylation in GNAQ mutant cells while it had minimal effect on Akt phosphorylation in both GNAQ wild type and mutated cells (Figure 5).	('AEB071', 'Var', (9, 15))	('Erk1', 'molecular_function', 'GO:0004707', ('45', '49'))	('GNAQ', 'Gene', (71, 75))	('AEB071', 'Chemical', 'MESH:C543528', (9, 15))	('mutant', 'Var', (76, 82))	('GNAQ', 'Gene', '2776', (148, 152))	('Akt', 'Gene', '207', (120, 123))	('phosphorylation', 'biological_process', 'GO:0016310', ('124', '139'))	('inhibited', 'NegReg', (35, 44))	('phosphorylation', 'biological_process', 'GO:0016310', ('52', '67'))	('GNAQ', 'Gene', (148, 152))	('GNAQ', 'Gene', '2776', (71, 75))	('Akt', 'Gene', (120, 123))	('Erk1/2', 'Pathway', (45, 51))
45809	22653968	Total Akt and Erk1/2 levels were not significantly altered by AEB071 in any of the cell lines examined.	('Akt', 'Gene', (6, 9))	('Akt', 'Gene', '207', (6, 9))	('Erk1', 'molecular_function', 'GO:0004707', ('14', '18'))	('AEB071', 'Var', (62, 68))	('Erk1/2 levels', 'MPA', (14, 27))	('AEB071', 'Chemical', 'MESH:C543528', (62, 68))
45810	22653968	These findings demonstrate AEB071-induced selective inhibition of the PKC/MAPK pathway in UM cells carrying GNAQ mutations.	('MAPK', 'molecular_function', 'GO:0004707', ('74', '78'))	('UM', 'Phenotype', 'HP:0007716', (90, 92))	('GNAQ', 'Gene', '2776', (108, 112))	('PKC', 'Gene', (70, 73))	('PKC', 'Gene', '112476', (70, 73))	('mutations', 'Var', (113, 122))	('GNAQ', 'Gene', (108, 112))	('PKC', 'molecular_function', 'GO:0004697', ('70', '73'))	('inhibition', 'NegReg', (52, 62))	('AEB071', 'Chemical', 'MESH:C543528', (27, 33))
45811	22653968	Therefore, AEB071 may exert its anti-proliferative effects in part through suppression of Erk1/2 activation in GNAQ mutated UM cells.	('AEB071', 'Chemical', 'MESH:C543528', (11, 17))	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('GNAQ', 'Gene', '2776', (111, 115))	('anti-proliferative effects', 'MPA', (32, 58))	('Erk1/2', 'Protein', (90, 96))	('suppression', 'NegReg', (75, 86))	('Erk1', 'molecular_function', 'GO:0004707', ('90', '94'))	('GNAQ', 'Gene', (111, 115))	('activation', 'MPA', (97, 107))	('mutated', 'Var', (116, 123))
45815	22653968	It is well known that aberrant NF-kappaB activity promotes tumorigenesis and metastasis.	('aberrant', 'Var', (22, 30))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('NF-kappaB', 'Gene', '4790', (31, 40))	('metastasis', 'CPA', (77, 87))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('NF-kappaB', 'Gene', (31, 40))	('promotes', 'PosReg', (50, 58))	('activity', 'MPA', (41, 49))
45817	22653968	In the absence of AEB071, nuclear p65 (RelA) levels are more or less similar among wild type and mutant cell lines (Figure 6A).	('AEB071', 'Chemical', 'MESH:C543528', (18, 24))	('RelA', 'Gene', (39, 43))	('RelA', 'Gene', '5970', (39, 43))	('mutant', 'Var', (97, 103))	('p65', 'Gene', (34, 37))	('p65', 'Gene', '5970', (34, 37))
45818	22653968	In contrast, in the presence of AEB071, nuclear p65 levels were significantly decreased in GNAQ mutated UM cells while they were minimally altered in wild type cells (Figure 6A).	('mutated', 'Var', (96, 103))	('p65', 'Gene', '5970', (48, 51))	('UM', 'Phenotype', 'HP:0007716', (104, 106))	('GNAQ', 'Gene', (91, 95))	('AEB071', 'Chemical', 'MESH:C543528', (32, 38))	('p65', 'Gene', (48, 51))	('decreased', 'NegReg', (78, 87))	('GNAQ', 'Gene', '2776', (91, 95))
45820	22653968	In agreement with decreased NF-kappaB activity, elevated IkappaBalpha levels were detected in AEB071-treated GNAQ mutated cells (Figure 6C).	('elevated IkappaBalpha', 'Phenotype', 'HP:0003261', (48, 69))	('AEB071', 'Chemical', 'MESH:C543528', (94, 100))	('GNAQ', 'Gene', (109, 113))	('decreased', 'NegReg', (18, 27))	('mutated', 'Var', (114, 121))	('NF-kappaB', 'Gene', '4790', (28, 37))	('IkappaBalpha', 'Gene', '4792', (57, 69))	('NF-kappaB', 'Gene', (28, 37))	('GNAQ', 'Gene', '2776', (109, 113))	('IkappaBalpha', 'Gene', (57, 69))	('elevated', 'PosReg', (48, 56))
45821	22653968	Besides, the secretion of IL-6, one of the target genes of NF-kappaB, was substantially inhibited by AEB071 in GNAQ mutated Omm1.3 cells but not GNAQ wild type C918 cells (Figure 6D).	('GNAQ', 'Gene', (145, 149))	('inhibited', 'NegReg', (88, 97))	('NF-kappaB', 'Gene', '4790', (59, 68))	('secretion', 'biological_process', 'GO:0046903', ('13', '22'))	('AEB071', 'Var', (101, 107))	('GNAQ', 'Gene', '2776', (111, 115))	('secretion', 'MPA', (13, 22))	('IL-6', 'Gene', (26, 30))	('AEB071', 'Chemical', 'MESH:C543528', (101, 107))	('IL-6', 'Gene', '3569', (26, 30))	('NF-kappaB', 'Gene', (59, 68))	('GNAQ', 'Gene', '2776', (145, 149))	('IL-6', 'molecular_function', 'GO:0005138', ('26', '30'))	('GNAQ', 'Gene', (111, 115))	('mutated', 'Var', (116, 123))
45822	22653968	These findings together indicate that AEB071 selectively inhibited NF-kappaB activation in UM cells harboring GNAQ mutations.	('NF-kappaB', 'Gene', '4790', (67, 76))	('mutations', 'Var', (115, 124))	('NF-kappaB', 'Gene', (67, 76))	('inhibited', 'NegReg', (57, 66))	('GNAQ', 'Gene', '2776', (110, 114))	('UM', 'Phenotype', 'HP:0007716', (91, 93))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('67', '87'))	('GNAQ', 'Gene', (110, 114))	('AEB071', 'Chemical', 'MESH:C543528', (38, 44))	('activation', 'MPA', (77, 87))
45823	22653968	This notion is also in agreement with the selective downregulation of NF-kappaB target genes including survivin, Bcl-xL, XIAP and cyclin D1, by AEB071 in GNAQ mutated cells (Figures 2C and 3C).	('GNAQ', 'Gene', '2776', (154, 158))	('Bcl-xL', 'Gene', '598', (113, 119))	('mutated', 'Var', (159, 166))	('survivin', 'Protein', (103, 111))	('XIAP', 'Gene', (121, 125))	('Bcl-xL', 'Gene', (113, 119))	('XIAP', 'Gene', '331', (121, 125))	('GNAQ', 'Gene', (154, 158))	('cyclin D1', 'Gene', '595', (130, 139))	('AEB071', 'Var', (144, 150))	('NF-kappaB', 'Gene', '4790', (70, 79))	('downregulation', 'NegReg', (52, 66))	('cyclin D1', 'Gene', (130, 139))	('AEB071', 'Chemical', 'MESH:C543528', (144, 150))	('NF-kappaB', 'Gene', (70, 79))	('cyclin', 'molecular_function', 'GO:0016538', ('130', '136'))
45825	22653968	This treatment resulted in the dramatic decrease in viability of both GNAQ wild type and mutant UM cell lines (Supplemental Figure S3).	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('decrease', 'NegReg', (40, 48))	('GNAQ', 'Gene', '2776', (70, 74))	('viability', 'CPA', (52, 61))	('GNAQ', 'Gene', (70, 74))	('mutant', 'Var', (89, 95))
45826	22653968	These findings suggest that NF-kappaB activity is critically important for UM cells and its suppression contributes to AEB071 induced growth inhibition of UM cells harboring GNAQ mutations.	('GNAQ', 'Gene', '2776', (174, 178))	('UM', 'Phenotype', 'HP:0007716', (155, 157))	('growth inhibition', 'CPA', (134, 151))	('NF-kappaB', 'Gene', '4790', (28, 37))	('GNAQ', 'Gene', (174, 178))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('NF-kappaB', 'Gene', (28, 37))	('suppression', 'NegReg', (92, 103))	('mutations', 'Var', (179, 188))	('AEB071', 'Chemical', 'MESH:C543528', (119, 125))
45828	22653968	In the present study we describe the first small molecule inhibitor that selectively exhibits antiproliferative activity of UM cells harboring GNAQ mutations: the novel PKC inhibitor AEB071 reduced viability of GNAQ mutated UM cell lines, but had little effect on those carrying wild type GNAQ.	('UM', 'Phenotype', 'HP:0007716', (224, 226))	('GNAQ', 'Gene', (211, 215))	('GNAQ', 'Gene', (143, 147))	('GNAQ', 'Gene', '2776', (143, 147))	('GNAQ', 'Gene', '2776', (289, 293))	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('AEB071', 'Gene', (183, 189))	('PKC', 'Gene', (169, 172))	('GNAQ', 'Gene', (289, 293))	('AEB071', 'Chemical', 'MESH:C543528', (183, 189))	('GNAQ', 'Gene', '2776', (211, 215))	('reduced', 'NegReg', (190, 197))	('PKC', 'Gene', '112476', (169, 172))	('PKC', 'molecular_function', 'GO:0004697', ('169', '172'))	('viability', 'CPA', (198, 207))	('mutated', 'Var', (216, 223))
45829	22653968	AEB071-induced growth inhibition is associated with reduced expression of PKC isoforms alpha, beta, delta, epsilon and/or theta, accompanied by inhibition of Erk1/2 phosphorylation, and NF-kappaB activation.	('expression', 'MPA', (60, 70))	('growth inhibition', 'CPA', (15, 32))	('AEB071', 'Chemical', 'MESH:C543528', (0, 6))	('AEB071-induced', 'Var', (0, 14))	('reduced', 'NegReg', (52, 59))	('phosphorylation', 'biological_process', 'GO:0016310', ('165', '180'))	('Erk1', 'molecular_function', 'GO:0004707', ('158', '162'))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('186', '206'))	('Erk1/2', 'Enzyme', (158, 164))	('phosphorylation', 'MPA', (165, 180))	('PKC', 'molecular_function', 'GO:0004697', ('74', '77'))	('NF-kappaB', 'Gene', '4790', (186, 195))	('activation', 'PosReg', (196, 206))	('inhibition', 'NegReg', (144, 154))	('PKC', 'Gene', (74, 77))	('PKC', 'Gene', '112476', (74, 77))	('NF-kappaB', 'Gene', (186, 195))
45830	22653968	We have previously shown that PKCtheta, PKCbeta and PKCepsilon are functionally important for GNAQ mutated UM cells and that inhibition of Erk1/2 by MEK1/2 inhibitors reduced UM cell viability.	('PKCbeta', 'Gene', (40, 47))	('UM', 'Phenotype', 'HP:0007716', (107, 109))	('MEK1/2', 'Gene', '5604;5605', (149, 155))	('PKCepsilon', 'Gene', '5581', (52, 62))	('MEK1', 'molecular_function', 'GO:0004708', ('149', '153'))	('MEK1/2', 'Gene', (149, 155))	('PKC', 'Gene', '112476', (52, 55))	('GNAQ', 'Gene', '2776', (94, 98))	('GNAQ', 'Gene', (94, 98))	('inhibition', 'NegReg', (125, 135))	('PKC', 'Gene', (52, 55))	('mutated', 'Var', (99, 106))	('PKCbeta', 'molecular_function', 'GO:0004697', ('40', '47'))	('PKC', 'Gene', '112476', (40, 43))	('reduced', 'NegReg', (167, 174))	('UM cell viability', 'CPA', (175, 192))	('PKCepsilon', 'Gene', (52, 62))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('52', '62'))	('PKC', 'Gene', (40, 43))	('PKC', 'Gene', '112476', (30, 33))	('UM', 'Phenotype', 'HP:0007716', (175, 177))	('PKCbeta', 'Gene', '5579', (40, 47))	('PKC', 'Gene', (30, 33))	('Erk1', 'molecular_function', 'GO:0004707', ('139', '143'))
45831	22653968	Here, we demonstrate that PKCalpha, PKCdelta and NF-kappaB are also functionally important for GNAQ mutated UM cells.	('PKCalpha', 'molecular_function', 'GO:0004697', ('26', '34'))	('mutated', 'Var', (100, 107))	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('PKCdelta', 'Gene', '5580', (36, 44))	('GNAQ', 'Gene', (95, 99))	('PKCdelta', 'Gene', (36, 44))	('PKCalpha', 'Gene', (26, 34))	('NF-kappaB', 'Gene', '4790', (49, 58))	('PKCalpha', 'Gene', '5578', (26, 34))	('NF-kappaB', 'Gene', (49, 58))	('PKCdelta', 'molecular_function', 'GO:0004697', ('36', '44'))	('GNAQ', 'Gene', '2776', (95, 99))
45832	22653968	Together, our findings suggest that AEB071 may selectively exert antiproliferative activity on GNAQ mutated UM cells via targeting the PKC/Erk1/2 and PKC/NF-kappaB pathways.	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('AEB071', 'Var', (36, 42))	('NF-kappaB', 'Gene', '4790', (154, 163))	('PKC', 'molecular_function', 'GO:0004697', ('150', '153'))	('NF-kappaB', 'Gene', (154, 163))	('GNAQ', 'Gene', (95, 99))	('AEB071', 'Chemical', 'MESH:C543528', (36, 42))	('PKC', 'Gene', (135, 138))	('PKC', 'Gene', '112476', (135, 138))	('targeting', 'Reg', (121, 130))	('Erk1', 'molecular_function', 'GO:0004707', ('139', '143'))	('PKC', 'molecular_function', 'GO:0004697', ('135', '138'))	('PKC', 'Gene', (150, 153))	('PKC', 'Gene', '112476', (150, 153))	('antiproliferative activity', 'MPA', (65, 91))	('GNAQ', 'Gene', '2776', (95, 99))
45833	22653968	AEB071 induced growth suppression of GNAQ mutant cells is associated with pronounced G1 arrest and induction of apoptosis.	('AEB071', 'Gene', (0, 6))	('AEB071', 'Chemical', 'MESH:C543528', (0, 6))	('mutant', 'Var', (42, 48))	('apoptosis', 'CPA', (112, 121))	('GNAQ', 'Gene', (37, 41))	('arrest', 'Disease', 'MESH:D006323', (88, 94))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('99', '121'))	('arrest', 'Disease', (88, 94))	('GNAQ', 'Gene', '2776', (37, 41))	('growth suppression', 'CPA', (15, 33))
45835	22653968	AEB071 induced apoptosis is associated with decreased expression of antiapoptotic proteins, yet the underlying molecular mechanisms remain to be revealed.	('apoptosis', 'CPA', (15, 24))	('AEB071', 'Chemical', 'MESH:C543528', (0, 6))	('expression of antiapoptotic proteins', 'MPA', (54, 90))	('apoptosis', 'biological_process', 'GO:0097194', ('15', '24'))	('apoptosis', 'biological_process', 'GO:0006915', ('15', '24'))	('AEB071', 'Var', (0, 6))	('decreased', 'NegReg', (44, 53))
45837	22653968	AEB071 inhibited Erk1/2 phosphorylation in GNAQ mutated but not GNAQ wild type UM cells, and had minimal impact on Akt phophorylation.	('Akt', 'Gene', '207', (115, 118))	('AEB071', 'Chemical', 'MESH:C543528', (0, 6))	('mutated', 'Var', (48, 55))	('GNAQ', 'Gene', (64, 68))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('GNAQ', 'Gene', (43, 47))	('Akt', 'Gene', (115, 118))	('GNAQ', 'Gene', '2776', (43, 47))	('Erk1', 'molecular_function', 'GO:0004707', ('17', '21'))	('phosphorylation', 'MPA', (24, 39))	('inhibited', 'NegReg', (7, 16))	('GNAQ', 'Gene', '2776', (64, 68))	('AEB071', 'Var', (0, 6))	('Erk1/2', 'Pathway', (17, 23))	('phosphorylation', 'biological_process', 'GO:0016310', ('24', '39'))
45839	22653968	The inhibition of Erk1/2 phosphorylation is therefore likely a common mechanism for the anti-proliferative action of PKC inhibitors in GNAQ mutated UM cells.	('Erk1/2', 'Enzyme', (18, 24))	('GNAQ', 'Gene', (135, 139))	('phosphorylation', 'biological_process', 'GO:0016310', ('25', '40'))	('PKC', 'Gene', (117, 120))	('anti-proliferative action', 'MPA', (88, 113))	('phosphorylation', 'MPA', (25, 40))	('UM', 'Phenotype', 'HP:0007716', (148, 150))	('Erk1', 'molecular_function', 'GO:0004707', ('18', '22'))	('GNAQ', 'Gene', '2776', (135, 139))	('PKC', 'Gene', '112476', (117, 120))	('PKC', 'molecular_function', 'GO:0004697', ('117', '120'))	('inhibition', 'NegReg', (4, 14))	('mutated', 'Var', (140, 147))
45840	22653968	Further studies are needed to identify the PKC isoform(s) which are most crucial for Erk1/2 phosphorylation in GNAQ mutant UM, and whose inhibition by AEB071 leads to decreased Erk1/2 phosphorylation.	('mutant UM', 'Var', (116, 125))	('Erk1/2', 'Gene', (85, 91))	('Erk1/2', 'Enzyme', (177, 183))	('phosphorylation', 'MPA', (92, 107))	('phosphorylation', 'biological_process', 'GO:0016310', ('92', '107'))	('GNAQ', 'Gene', '2776', (111, 115))	('PKC', 'molecular_function', 'GO:0004697', ('43', '46'))	('PKC', 'Gene', '112476', (43, 46))	('Erk1', 'molecular_function', 'GO:0004707', ('177', '181'))	('Erk1', 'molecular_function', 'GO:0004707', ('85', '89'))	('phosphorylation', 'biological_process', 'GO:0016310', ('184', '199'))	('PKC', 'Gene', (43, 46))	('GNAQ', 'Gene', (111, 115))	('UM', 'Phenotype', 'HP:0007716', (123, 125))	('AEB071', 'Chemical', 'MESH:C543528', (151, 157))	('decreased', 'NegReg', (167, 176))
45843	22653968	Overexpression of mutant GNAQ(Q209L) leads to constitutive activation of NF-kappaB which is mediated by PKCdelta and to a lesser extent PKCalpha and PKCepsilon in HUVEC.	('PKCdelta', 'Gene', '5580', (104, 112))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('149', '159'))	('PKCdelta', 'Gene', (104, 112))	('PKCdelta', 'molecular_function', 'GO:0004697', ('104', '112'))	('PKCepsilon', 'Gene', (149, 159))	('mutant', 'Var', (18, 24))	('PKCepsilon', 'Gene', '5581', (149, 159))	('NF-kappaB', 'Gene', '4790', (73, 82))	('GNAQ', 'Gene', (25, 29))	('Q209L', 'Mutation', 'rs121913492', (30, 35))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('59', '82'))	('PKCalpha', 'Gene', '5578', (136, 144))	('PKCalpha', 'Gene', (136, 144))	('NF-kappaB', 'Gene', (73, 82))	('activation', 'PosReg', (59, 69))	('GNAQ', 'Gene', '2776', (25, 29))	('PKCalpha', 'molecular_function', 'GO:0004697', ('136', '144'))
45845	22653968	Importantly, we demonstrate that AEB071 selectively repressed NF-kappaB activation in UM cells harboring GNAQ mutations and this is accompanied by downregulation of multiple PKC isoforms, in particular PKCalpha, PKCdelta, and PKCepsilon.	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('62', '82'))	('PKC', 'Gene', (212, 215))	('PKC', 'Gene', '112476', (226, 229))	('PKC', 'Gene', '112476', (202, 205))	('PKCalpha', 'Gene', '5578', (202, 210))	('PKC', 'Gene', (226, 229))	('PKCepsilon', 'Gene', '5581', (226, 236))	('PKC', 'Gene', (202, 205))	('GNAQ', 'Gene', '2776', (105, 109))	('NF-kappaB', 'Gene', (62, 71))	('PKCalpha', 'Gene', (202, 210))	('PKC', 'Gene', '112476', (174, 177))	('activation', 'PosReg', (72, 82))	('GNAQ', 'Gene', (105, 109))	('mutations', 'Var', (110, 119))	('AEB071', 'Chemical', 'MESH:C543528', (33, 39))	('NF-kappaB', 'Gene', '4790', (62, 71))	('downregulation', 'NegReg', (147, 161))	('PKCdelta', 'molecular_function', 'GO:0004697', ('212', '220'))	('PKCalpha', 'molecular_function', 'GO:0004697', ('202', '210'))	('PKC', 'Gene', (174, 177))	('PKCepsilon', 'Gene', (226, 236))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('226', '236'))	('PKC', 'Gene', '112476', (212, 215))	('UM', 'Phenotype', 'HP:0007716', (86, 88))	('PKC', 'molecular_function', 'GO:0004697', ('174', '177'))	('PKCdelta', 'Gene', '5580', (212, 220))	('PKCdelta', 'Gene', (212, 220))
45848	22653968	NF-kappaB inhibition might therefore be another mechanism for the antiproliferative action of AEB071 on UM cells harboring GNAQ mutations.	('inhibition', 'NegReg', (10, 20))	('antiproliferative action', 'MPA', (66, 90))	('GNAQ', 'Gene', (123, 127))	('mutations', 'Var', (128, 137))	('NF-kappaB', 'Gene', '4790', (0, 9))	('AEB071', 'Chemical', 'MESH:C543528', (94, 100))	('NF-kappaB', 'Gene', (0, 9))	('UM', 'Phenotype', 'HP:0007716', (104, 106))	('GNAQ', 'Gene', '2776', (123, 127))
45849	22653968	The association between PKC inhibition and decreased NF-kappaB activity in GNAQ mutated UM cells suggests that these cells might rely on GNAQ-PKC-NF-kappaB pathways for NF-kappaB activation.	('NF-kappaB', 'Gene', (169, 178))	('mutated', 'Var', (80, 87))	('NF-kappaB', 'Gene', '4790', (169, 178))	('activity', 'MPA', (63, 71))	('GNAQ', 'Gene', '2776', (137, 141))	('inhibition', 'NegReg', (28, 38))	('PKC', 'molecular_function', 'GO:0004697', ('24', '27'))	('GNAQ', 'Gene', '2776', (75, 79))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('169', '189'))	('NF-kappaB', 'Gene', (53, 62))	('PKC', 'Gene', '112476', (24, 27))	('GNAQ', 'Gene', (137, 141))	('GNAQ', 'Gene', (75, 79))	('PKC', 'Gene', '112476', (142, 145))	('UM', 'Phenotype', 'HP:0007716', (88, 90))	('PKC', 'molecular_function', 'GO:0004697', ('142', '145'))	('NF-kappaB', 'Gene', (146, 155))	('NF-kappaB', 'Gene', '4790', (53, 62))	('PKC', 'Gene', (24, 27))	('PKC', 'Gene', (142, 145))	('NF-kappaB', 'Gene', '4790', (146, 155))	('decreased', 'NegReg', (43, 52))
45851	22653968	For example, Ocm1 and Ocm3 cells have been shown to carry the common V600E BRAF mutation that constitutively activates the MAPK and NF-kappaB pathways.	('NF-kappaB', 'Gene', (132, 141))	('V600E', 'Var', (69, 74))	('MAPK', 'molecular_function', 'GO:0004707', ('123', '127'))	('Ocm1', 'Species', '83984', (13, 17))	('BRAF', 'Gene', '673', (75, 79))	('BRAF', 'Gene', (75, 79))	('activates', 'PosReg', (109, 118))	('V600E', 'Mutation', 'rs113488022', (69, 74))	('NF-kappaB', 'Gene', '4790', (132, 141))
45853	22653968	Our data indicate that multiple PKC isoforms including alpha, beta, delta, epsilon, and theta are suppressed by AEB071 in GNAQ mutated UM cells while only PKCalpha and PKCdelta were affected in GNAQ wild type cells.	('PKCalpha', 'Gene', '5578', (155, 163))	('PKC', 'Gene', (155, 158))	('PKCalpha', 'Gene', (155, 163))	('PKC', 'Gene', '112476', (168, 171))	('delta', 'Enzyme', (68, 73))	('beta', 'Enzyme', (62, 66))	('PKC', 'Gene', '112476', (32, 35))	('GNAQ', 'Gene', '2776', (194, 198))	('PKC', 'Gene', (168, 171))	('GNAQ', 'Gene', '2776', (122, 126))	('PKC', 'molecular_function', 'GO:0004697', ('32', '35'))	('GNAQ', 'Gene', (194, 198))	('theta', 'Enzyme', (88, 93))	('UM', 'Phenotype', 'HP:0007716', (135, 137))	('GNAQ', 'Gene', (122, 126))	('AEB071', 'Chemical', 'MESH:C543528', (112, 118))	('PKCdelta', 'molecular_function', 'GO:0004697', ('168', '176'))	('PKC', 'Gene', (32, 35))	('AEB071', 'Gene', (112, 118))	('PKCdelta', 'Gene', '5580', (168, 176))	('suppressed', 'NegReg', (98, 108))	('PKCdelta', 'Gene', (168, 176))	('epsilon', 'Enzyme', (75, 82))	('alpha', 'Enzyme', (55, 60))	('PKC', 'Gene', '112476', (155, 158))	('mutated', 'Var', (127, 134))	('PKCalpha', 'molecular_function', 'GO:0004697', ('155', '163'))
45858	22653968	These findings also provide a plausible explanation for the differential response/sensitivity of GNAQ wild type and mutated UM cells to AEB071.	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('GNAQ', 'Gene', '2776', (97, 101))	('AEB071', 'Chemical', 'MESH:C543528', (136, 142))	('mutated', 'Var', (116, 123))	('GNAQ', 'Gene', (97, 101))
45860	22653968	Frequent somatic mutations in GPCRs have been found in melanoma and mutations in GRM3, which is a glutamate receptor and a member of the metabolic GPCRs, activate the MAPK/ERK pathway and promote growth and migration of melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('GRM3', 'Gene', '2913', (81, 85))	('melanoma', 'Disease', (55, 63))	('GPCR', 'Gene', (147, 151))	('GPCR', 'Gene', (30, 34))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('melanoma', 'Disease', (220, 228))	('activate', 'PosReg', (154, 162))	('GRM3', 'Gene', (81, 85))	('promote', 'PosReg', (188, 195))	('ERK', 'molecular_function', 'GO:0004707', ('172', '175'))	('ERK', 'Gene', '5594', (172, 175))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('MAPK', 'molecular_function', 'GO:0004707', ('167', '171'))	('GPCR', 'Gene', '442206', (30, 34))	('mutations', 'Var', (68, 77))	('GPCR', 'Gene', '442206', (147, 151))	('melanoma', 'Disease', 'MESH:D008545', (220, 228))	('ERK', 'Gene', (172, 175))
45867	22653968	We demonstrate that PKC inhibitor AEB071 (sotrastaurin) at low micromolar concentrations exerts significant antiproliferative effect on GNAQ mutated UM cells through targeting the PKC/MAPK and PKC/NF-kappaB pathways.	('mutated', 'Var', (141, 148))	('PKC', 'Gene', '112476', (20, 23))	('PKC', 'Gene', (180, 183))	('PKC', 'Gene', '112476', (193, 196))	('sotrastaurin', 'Chemical', 'MESH:C543528', (42, 54))	('PKC', 'molecular_function', 'GO:0004697', ('193', '196'))	('PKC', 'Gene', (20, 23))	('PKC', 'Gene', (193, 196))	('AEB071', 'Chemical', 'MESH:C543528', (34, 40))	('NF-kappaB', 'Gene', (197, 206))	('PKC', 'molecular_function', 'GO:0004697', ('20', '23'))	('targeting', 'Reg', (166, 175))	('GNAQ', 'Gene', '2776', (136, 140))	('NF-kappaB', 'Gene', '4790', (197, 206))	('antiproliferative effect', 'MPA', (108, 132))	('UM', 'Phenotype', 'HP:0007716', (149, 151))	('GNAQ', 'Gene', (136, 140))	('PKC', 'molecular_function', 'GO:0004697', ('180', '183'))	('PKC', 'Gene', '112476', (180, 183))	('MAPK', 'molecular_function', 'GO:0004707', ('184', '188'))
45868	22653968	Our findings support PKCs as important targets for therapeutic intervention of UM harboring GNAQ mutations.	('mutations', 'Var', (97, 106))	('GNAQ', 'Gene', (92, 96))	('PKC', 'Gene', '112476', (21, 24))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('GNAQ', 'Gene', '2776', (92, 96))	('PKC', 'Gene', (21, 24))
45870	22653968	AEB071 could thus be of therapeutic potential for UM with GNAQ mutations.	('mutations', 'Var', (63, 72))	('AEB071', 'Chemical', 'MESH:C543528', (0, 6))	('GNAQ', 'Gene', '2776', (58, 62))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('GNAQ', 'Gene', (58, 62))
45876	22653968	MEK or PI3K) or immune therapy such as ipilimumab to improve the efficacy and durability of any clinical activity.	('PI3K', 'Var', (7, 11))	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('ipilimumab', 'Chemical', 'MESH:D000074324', (39, 49))	('PI3K', 'molecular_function', 'GO:0016303', ('7', '11'))	('improve', 'PosReg', (53, 60))
45877	22653968	It would be also of great interest to investigate antitumor effects of other specific PKC inhibitors in melanoma and other cancers with GPCR mutations that may activate MAPK/ERK and/or NF-kB pathways.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('melanoma', 'Disease', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('ERK', 'molecular_function', 'GO:0004707', ('174', '177'))	('ERK', 'Gene', '5594', (174, 177))	('PKC', 'molecular_function', 'GO:0004697', ('86', '89'))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('GPCR', 'Gene', '442206', (136, 140))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('mutations', 'Var', (141, 150))	('PKC', 'Gene', '112476', (86, 89))	('ERK', 'Gene', (174, 177))	('activate', 'PosReg', (160, 168))	('PKC', 'Gene', (86, 89))	('MAPK', 'molecular_function', 'GO:0004707', ('169', '173'))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('GPCR', 'Gene', (136, 140))	('cancers', 'Disease', (123, 130))	('tumor', 'Disease', (54, 59))
45880	22536370	We report here development, validation, and implementation of an assay designed to simultaneously detect 43 common somatic point mutations in 6 genes (BRAF, NRAS, KIT, GNAQ, GNA11, and CTNNB1) potentially relevant to existing and emerging targeted therapies specifically in melanoma.	('CTNNB1', 'Gene', '1499', (185, 191))	('KIT', 'Gene', (163, 166))	('GNAQ', 'Gene', '2776', (168, 172))	('point mutations', 'Var', (123, 138))	('mutations', 'Var', (129, 138))	('BRAF', 'Gene', '673', (151, 155))	('melanoma', 'Disease', 'MESH:D008545', (274, 282))	('GNA11', 'Gene', (174, 179))	('melanoma', 'Disease', (274, 282))	('melanoma', 'Phenotype', 'HP:0002861', (274, 282))	('CTNNB1', 'Gene', (185, 191))	('NRAS', 'Gene', (157, 161))	('BRAF', 'Gene', (151, 155))	('GNA11', 'Gene', '2767', (174, 179))	('GNAQ', 'Gene', (168, 172))	('KIT', 'molecular_function', 'GO:0005020', ('163', '166'))	('NRAS', 'Gene', '4893', (157, 161))
45883	22536370	Directing this test to a single disease, 90 of 150 (60%) melanomas from sites throughout the body harbored a mutation tested, including 57, 23, 6, 3, and 2 mutations in BRAF, NRAS, GNAQ, KIT, and CTNNB1, respectively.	('BRAF', 'Gene', (169, 173))	('melanomas', 'Disease', (57, 66))	('BRAF', 'Gene', '673', (169, 173))	('KIT', 'Gene', (187, 190))	('mutations', 'Var', (156, 165))	('CTNNB1', 'Gene', (196, 202))	('GNAQ', 'Gene', (181, 185))	('melanomas', 'Disease', 'MESH:D008545', (57, 66))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('KIT', 'molecular_function', 'GO:0005020', ('187', '190'))	('NRAS', 'Gene', (175, 179))	('NRAS', 'Gene', '4893', (175, 179))	('CTNNB1', 'Gene', '1499', (196, 202))	('GNAQ', 'Gene', '2776', (181, 185))	('mutation', 'Var', (109, 117))
45884	22536370	Among BRAF V600 mutations, 79%, 12%, 5%, and 4% were V600E, V600K, V600R, and V600M, respectively.	('V600 mutations', 'Var', (11, 25))	('V600M', 'Var', (78, 83))	('V600M', 'Mutation', 'rs121913378', (78, 83))	('V600E', 'Mutation', 'rs113488022', (53, 58))	('V600R', 'Mutation', 'rs121913227', (67, 72))	('V600E', 'Var', (53, 58))	('BRAF', 'Gene', '673', (6, 10))	('V600K', 'Var', (60, 65))	('BRAF', 'Gene', (6, 10))	('V600R', 'Var', (67, 72))	('V600K', 'Mutation', 'rs121913227', (60, 65))
45886	22536370	We present development of a simple mutational profiling screen for clinically relevant mutations in melanoma.	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('mutations', 'Var', (87, 96))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))
45892	22536370	More recently, mutation profiling studies have revealed that melanoma is further comprised of clinically relevant molecular subsets defined by specific 'driver' mutations.	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('mutations', 'Var', (161, 170))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))
45894	22536370	With the exception of CTNNB1, a tumor with an alteration in one of these genes rarely has a mutation in one of the other genes.	('CTNNB1', 'Gene', (22, 28))	('alteration', 'Var', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('CTNNB1', 'Gene', '1499', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
45895	22536370	Together, mutations in these genes can be found in approximately 70% of melanomas, depending on the site of origin of the primary lesion ( Table 1 ).	('melanomas', 'Disease', 'MESH:D008545', (72, 81))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanomas', 'Disease', (72, 81))	('found', 'Reg', (42, 47))	('mutations', 'Var', (10, 19))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))
45897	22536370	For example, in skin intermittently exposed to sun, approximately 80% of melanomas have mutations in BRAF or NRAS.	('BRAF', 'Gene', (101, 105))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('NRAS', 'Gene', (109, 113))	('mutations', 'Var', (88, 97))	('melanomas', 'Disease', (73, 82))	('NRAS', 'Gene', '4893', (109, 113))	('BRAF', 'Gene', '673', (101, 105))	('melanomas', 'Disease', 'MESH:D008545', (73, 82))
45898	22536370	On the other hand, 15-20% of melanomas occurring on mucosal, acral, and CSD skin have a KIT mutation while few have BRAF mutations (5-15%).	('mutation', 'Var', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanomas', 'Phenotype', 'HP:0002861', (29, 38))	('BRAF', 'Gene', '673', (116, 120))	('melanomas', 'Disease', 'MESH:D008545', (29, 38))	('KIT', 'molecular_function', 'GO:0005020', ('88', '91'))	('BRAF', 'Gene', (116, 120))	('KIT', 'Gene', (88, 91))	('melanomas', 'Disease', (29, 38))
45901	22536370	Tumors that harbor BRAF V600E mutations display high radiographic response rates to mutant-specific inhibitors such as PLX4032/RG7204/vemurafinib (Plexxikon/Roche) and GSK2118436 (GlaxoSmithKline), while patients whose tumors have certain KIT mutations (L576P, K642E, V559A) have disease sensitive to the KIT inhibitor, imatinib ( Table 1 ).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('K642E', 'Mutation', 'rs121913512', (261, 266))	('GSK2118436', 'Chemical', 'MESH:C561627', (168, 178))	('KIT', 'molecular_function', 'GO:0005020', ('239', '242'))	('patients', 'Species', '9606', (204, 212))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('Tumors', 'Disease', (0, 6))	('K642E', 'Var', (261, 266))	('V559A', 'Var', (268, 273))	('V559A', 'Mutation', 'rs121913517', (268, 273))	('vemurafinib', 'Chemical', '-', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('L576P', 'Mutation', 'rs121913513', (254, 259))	('GSK2118436', 'Var', (168, 178))	('tumors', 'Disease', (219, 225))	('GSK', 'molecular_function', 'GO:0050321', ('168', '171'))	('L576P', 'Var', (254, 259))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('V600E', 'Mutation', 'rs113488022', (24, 29))	('BRAF', 'Gene', '673', (19, 23))	('imatinib', 'Chemical', 'MESH:D000068877', (320, 328))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('BRAF', 'Gene', (19, 23))	('KIT', 'molecular_function', 'GO:0005020', ('305', '308'))
45902	22536370	Preclinical data suggest that MEK inhibition with drugs like AZD6244 or GSK1120212 may be effective for uveal melanomas carrying GNAQ or GNA11 mutations.	('uveal melanomas', 'Disease', 'MESH:C536494', (104, 119))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('GSK1120212', 'Chemical', 'MESH:C560077', (72, 82))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('GNAQ', 'Gene', (129, 133))	('GSK', 'molecular_function', 'GO:0050321', ('72', '75'))	('uveal melanomas', 'Disease', (104, 119))	('AZD6244', 'Chemical', 'MESH:C517975', (61, 68))	('GNA11', 'Gene', (137, 142))	('GNAQ', 'Gene', '2776', (129, 133))	('GSK1120212', 'Gene', (72, 82))	('uveal melanomas', 'Phenotype', 'HP:0007716', (104, 119))	('GNA11', 'Gene', '2767', (137, 142))	('MEK', 'Gene', (30, 33))	('AZD6244', 'Gene', (61, 68))	('MEK', 'Gene', '5609', (30, 33))	('mutations', 'Var', (143, 152))
45903	22536370	Tumors with NRAS mutations may respond to more potent MEK inhibitors (GSK1120212) or may require blockade of pathways mediated by both MEK and PI3K or other strategies directed at the MET receptor or ligand.	('MEK', 'Gene', '5609', (54, 57))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('NRAS', 'Gene', (12, 16))	('PI3K', 'molecular_function', 'GO:0016303', ('143', '147'))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('NRAS', 'Gene', '4893', (12, 16))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('GSK', 'molecular_function', 'GO:0050321', ('70', '73'))	('ligand', 'molecular_function', 'GO:0005488', ('200', '206'))	('MEK', 'Gene', (135, 138))	('MEK', 'Gene', '5609', (135, 138))	('mutations', 'Var', (17, 26))	('GSK1120212', 'Chemical', 'MESH:C560077', (70, 80))	('MEK', 'Gene', (54, 57))
45904	22536370	We report here the development, validation, and clinical implementation of a multiplexed assay designed to simultaneously detect 43 recurrent mutations in BRAF, KIT, NRAS, GNA11, GNAQ, and CTNNB1 using tumor-derived DNA from formalin-fixed paraffin-embedded (FFPE) tissues.	('formalin', 'Chemical', 'MESH:D005557', (225, 233))	('NRAS', 'Gene', '4893', (166, 170))	('CTNNB1', 'Gene', (189, 195))	('GNAQ', 'Gene', '2776', (179, 183))	('mutations', 'Var', (142, 151))	('tumor', 'Disease', (202, 207))	('GNAQ', 'Gene', (179, 183))	('GNA11', 'Gene', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('KIT', 'Gene', (161, 164))	('paraffin', 'Chemical', 'MESH:D010232', (240, 248))	('NRAS', 'Gene', (166, 170))	('BRAF', 'Gene', '673', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('CTNNB1', 'Gene', '1499', (189, 195))	('BRAF', 'Gene', (155, 159))	('DNA', 'cellular_component', 'GO:0005574', ('216', '219'))	('KIT', 'molecular_function', 'GO:0005020', ('161', '164'))	('GNA11', 'Gene', '2767', (172, 177))
45907	22536370	Our assay provides a robust and accessible approach for the rapid identification of important mutations in melanoma that can enable prioritization of specific targeted therapies.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('mutations', 'Var', (94, 103))
45910	22536370	The following cancer cell lines were generously provided by Dr. David Solit (Memorial Sloan Kettering Cancer Center): WM1361A, SK-MEL-238, SK-MEL-90, MEL270, and 92.1.	('cancer', 'Disease', (14, 20))	('Memorial Sloan Kettering Cancer', 'Disease', (77, 108))	('Memorial Sloan Kettering Cancer', 'Disease', 'MESH:D008569', (77, 108))	('SK-MEL-238', 'CellLine', 'CVCL:6121', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('SK-MEL-90', 'Var', (139, 148))	('Cancer', 'Phenotype', 'HP:0002664', (102, 108))	('SK-MEL-238', 'Var', (127, 137))	('SK-MEL-90', 'CellLine', 'CVCL:6227', (139, 148))	('WM1361A', 'Var', (118, 125))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
45911	22536370	The following cell lines were generously provided by Dr. Meenhard Herlyn (The Wistar Institute): WM1963, WM3682, WM115, WM266-4, and WM3211.	('WM3682', 'Var', (105, 111))	('WM266-4', 'Var', (120, 127))	('WM115', 'Var', (113, 118))	('WM3211', 'Var', (133, 139))	('WM266-4', 'CellLine', 'CVCL:2765', (120, 127))	('WM1963', 'Var', (97, 103))
45912	22536370	The following cancer cell lines were available in the Pao laboratory: H358, H2009, H460, H1975, H1666.	('cancer', 'Disease', (14, 20))	('H460', 'CellLine', 'CVCL:0459', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('H1666', 'Var', (96, 101))	('H2009', 'CellLine', 'CVCL:1514', (76, 81))	('H1975', 'CellLine', 'CVCL:1511', (89, 94))
45920	22536370	The current screen was designed to distinguish between BRAF mutations in cis or trans.	('mutations', 'Var', (60, 69))	('BRAF', 'Gene', (55, 59))	('BRAF', 'Gene', '673', (55, 59))
45926	22536370	The melanoma SNaPshot screen (v1.0) interrogates 43 somatic point mutations occurring at 20 different loci in 6 genes ( Table 2 ).	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))	('point mutations', 'Var', (60, 75))
45927	22536370	These mutations were originally selected in 2009 because they: 1) appear in melanomas, 2) could potentially be used to prioritize selection of existing or emerging targeted therapy, and 3) occur at mutational 'hotspots'.	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('melanomas', 'Disease', 'MESH:D008545', (76, 85))	('melanomas', 'Disease', (76, 85))	('mutations', 'Var', (6, 15))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
45931	22536370	According to the Catalogue of Somatic Mutations in Cancer (COSMIC), approximately 42% of melanomas harbor BRAF mutations, of which 36% are V600E and 3% are V600R/K/M/G/D.	('mutations', 'Var', (111, 120))	('melanomas', 'Disease', (89, 98))	('V600E', 'Mutation', 'rs113488022', (139, 144))	('BRAF', 'Gene', '673', (106, 110))	('V600E', 'Var', (139, 144))	('BRAF', 'Gene', (106, 110))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('V600R', 'SUBSTITUTION', 'None', (156, 161))	('melanomas', 'Disease', 'MESH:D008545', (89, 98))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('V600R', 'Var', (156, 161))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))
45932	22536370	Although mutant-specific inhibitors like vemurafenib and GSK2118436 are predicted to be equally efficacious against a variety of V600 mutants, clinical trials with the approved BRAF inhibitor, Vemurafenib, have thus far have focused on enrolling only those with V600E mutant melanoma.	('V600E', 'Var', (262, 267))	('BRAF', 'Gene', (177, 181))	('vemurafenib', 'Chemical', 'MESH:D000077484', (41, 52))	('BRAF', 'Gene', '673', (177, 181))	('GSK2118436', 'Chemical', 'MESH:C561627', (57, 67))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (193, 204))	('V600 mutants', 'Var', (129, 141))	('GSK', 'molecular_function', 'GO:0050321', ('57', '60'))	('GSK2118436', 'Var', (57, 67))	('V600E', 'Mutation', 'rs113488022', (262, 267))	('melanoma', 'Disease', 'MESH:D008545', (275, 283))	('melanoma', 'Phenotype', 'HP:0002861', (275, 283))	('melanoma', 'Disease', (275, 283))
45934	22536370	DNA from fresh-frozen or FFPE human melanoma tissue was used to show detection of multiple BRAF V600 mutations V600E/K/M/R/E (Figure S2).	('human', 'Species', '9606', (30, 35))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('BRAF', 'Gene', '673', (91, 95))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('BRAF', 'Gene', (91, 95))	('V600E/K/M/R/E', 'Var', (111, 124))	('V600E', 'Mutation', 'rs113488022', (111, 116))
45937	22536370	Thirteen tumors (54%) had BRAF mutations including 10 V600Es, 2 V600Ks, and 1 V600M.	('V600K', 'Mutation', 'rs121913227', (64, 69))	('V600M', 'Var', (78, 83))	('V600M', 'Mutation', 'rs121913378', (78, 83))	('BRAF', 'Gene', '673', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('BRAF', 'Gene', (26, 30))	('V600Ks', 'Var', (64, 70))	('V600E', 'Mutation', 'rs113488022', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('V600Es', 'Var', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
45938	22536370	Three samples (12.5%) had NRAS mutations: 2 Q61Rs and 1 G13A.	('Q61R', 'Mutation', 'rs11554290', (44, 48))	('NRAS', 'Gene', (26, 30))	('Q61Rs', 'Var', (44, 49))	('G13A', 'Mutation', 'rs121434596', (56, 60))	('NRAS', 'Gene', '4893', (26, 30))	('G13A', 'Var', (56, 60))
45940	22536370	As expected, BRAF, NRAS, and KIT mutations were mutually exclusive, and the distribution of mutations was consistent with that reported in the literature ( Table 1 ).	('KIT', 'molecular_function', 'GO:0005020', ('29', '32'))	('NRAS', 'Gene', (19, 23))	('BRAF', 'Gene', '673', (13, 17))	('mutations', 'Var', (33, 42))	('BRAF', 'Gene', (13, 17))	('NRAS', 'Gene', '4893', (19, 23))	('KIT', 'Gene', (29, 32))
45941	22536370	Six samples harbored KIT mutations, including 2 W557Rs, a V559A, a V559R, a L576P, and a K642E.	('V559R', 'Var', (67, 72))	('K642E', 'Var', (89, 94))	('K642E', 'Mutation', 'rs121913512', (89, 94))	('KIT', 'molecular_function', 'GO:0005020', ('21', '24'))	('L576P', 'Mutation', 'rs121913513', (76, 81))	('V559A', 'Var', (58, 63))	('V559R', 'Mutation', 'p.V559R', (67, 72))	('L576P', 'Var', (76, 81))	('V559A', 'Mutation', 'rs121913517', (58, 63))	('harbored', 'Reg', (12, 20))	('W557Rs', 'Var', (48, 54))
45942	22536370	Seven samples contained BRAF mutations, including 4 V600Es, 2 V600Ks, and 1 V600R.	('V600Es', 'Var', (52, 58))	('V600R', 'Mutation', 'rs121913227', (76, 81))	('V600K', 'Mutation', 'rs121913227', (62, 67))	('V600R', 'Var', (76, 81))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('V600Ks', 'Var', (62, 68))	('V600E', 'Mutation', 'rs113488022', (52, 57))
45944	22536370	A tumor with a mutation in one gene did not harbor a mutation in any other gene.	('mutation', 'Var', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('A tumor', 'Disease', (0, 7))	('A tumor', 'Disease', 'MESH:D009369', (0, 7))
45948	22536370	None of the 7 uveal melanomas contained BRAF mutations.	('BRAF', 'Gene', '673', (40, 44))	('uveal melanoma', 'Phenotype', 'HP:0007716', (14, 28))	('mutations', 'Var', (45, 54))	('BRAF', 'Gene', (40, 44))	('uveal melanomas', 'Disease', (14, 29))	('uveal melanomas', 'Phenotype', 'HP:0007716', (14, 29))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanomas', 'Phenotype', 'HP:0002861', (20, 29))	('uveal melanomas', 'Disease', 'MESH:C536494', (14, 29))
45949	22536370	NRAS mutations were found in disease from all sites except the uvea.	('found in', 'Reg', (20, 28))	('disease', 'Disease', (29, 36))	('mutations', 'Var', (5, 14))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))
45950	22536370	2 of 3 KIT changes were found in melanomas from acral and mucosal primary sites.	('melanomas', 'Disease', 'MESH:D008545', (33, 42))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('changes', 'Var', (11, 18))	('KIT', 'molecular_function', 'GO:0005020', ('7', '10'))	('melanomas', 'Disease', (33, 42))
45951	22536370	5 of 6 GNAQ mutations were found in melanomas from uveal sites.	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('GNAQ', 'Gene', '2776', (7, 11))	('mutations', 'Var', (12, 21))	('melanomas', 'Disease', 'MESH:D008545', (36, 45))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('GNAQ', 'Gene', (7, 11))	('found', 'Reg', (27, 32))	('melanomas', 'Disease', (36, 45))
45956	22536370	Importantly, 23 of 54 patients (43%) with metastatic disease containing a detectable mutation were subsequently enrolled on genotype-driven trials ( Table 4 ).	('metastatic disease', 'Disease', (42, 60))	('patients', 'Species', '9606', (22, 30))	('mutation', 'Var', (85, 93))
45958	22536370	Patient with NRAS, KIT, and GNAQ mutations were also enrolled on specific trials directed at their tumor mutation status.	('tumor', 'Disease', (99, 104))	('GNAQ', 'Gene', '2776', (28, 32))	('NRAS', 'Gene', '4893', (13, 17))	('mutations', 'Var', (33, 42))	('NRAS', 'Gene', (13, 17))	('KIT', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('GNAQ', 'Gene', (28, 32))	('Patient', 'Species', '9606', (0, 7))	('KIT', 'molecular_function', 'GO:0005020', ('19', '22'))
45963	22536370	Here, we present development, validation, and clinical implementation of a disease-specific SNaPshot-based screen to assess melanoma tumor samples simultaneously for 43 somatic recurrent point mutations in 6 genes with relevance to targeted therapy.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma tumor', 'Disease', 'MESH:D008545', (124, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('melanoma tumor', 'Disease', (124, 138))	('point mutations', 'Var', (187, 202))
45964	22536370	By comparison, direct dideoxynucleotide sequencing, used currently in many clinical molecular labs, requires that mutant DNA comprise >20-25% of the total DNA for mutation detection.	('dideoxynucleotide', 'Chemical', 'MESH:D054306', (22, 39))	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('DNA', 'cellular_component', 'GO:0005574', ('155', '158'))	('mutant', 'Var', (114, 120))	('DNA', 'Gene', (121, 124))
45965	22536370	In its present form, the SNaPshot assay can detect mutations that occur in the majority of melanomas.	('melanomas', 'Disease', (91, 100))	('mutations', 'Var', (51, 60))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('melanomas', 'Disease', 'MESH:D008545', (91, 100))
45966	22536370	Of the first 150 tumor samples tested in the clinical lab, 90 (60%) had an identifiable mutation, which were 38% BRAF, 15% NRAS, 4% GNAQ, 2% KIT, and ~1% CTNNB1.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('BRAF', 'Gene', '673', (113, 117))	('CTNNB1', 'Gene', (154, 160))	('tumor', 'Disease', (17, 22))	('KIT', 'molecular_function', 'GO:0005020', ('141', '144'))	('KIT', 'Var', (141, 144))	('BRAF', 'Gene', (113, 117))	('GNAQ', 'Gene', '2776', (132, 136))	('NRAS', 'Gene', (123, 127))	('CTNNB1', 'Gene', '1499', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('NRAS', 'Gene', '4893', (123, 127))	('GNAQ', 'Gene', (132, 136))
45967	22536370	The frequency of these mutations and the anatomic sites of origin for the primary tumor were consistent with previously published results.	('mutations', 'Var', (23, 32))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
45969	22536370	The percent of BRAF mutations that were V600E (79%) ( Figure 2 ) is also consistent with what has been reported in the literature.	('BRAF', 'Gene', '673', (15, 19))	('V600E', 'Var', (40, 45))	('V600E', 'Mutation', 'rs113488022', (40, 45))	('BRAF', 'Gene', (15, 19))
45970	22536370	Since our assay was designed to distinguish among various mutations that affect V600, our data further show that allele-specific molecular diagnostic assays designed to detect only the most common V600E mutation will miss ~20% of the total number of V600 mutations in melanoma.	('melanoma', 'Disease', (268, 276))	('miss', 'NegReg', (217, 221))	('V600E', 'Mutation', 'rs113488022', (197, 202))	('V600 mutations', 'Var', (250, 264))	('V600E', 'Var', (197, 202))	('melanoma', 'Disease', 'MESH:D008545', (268, 276))	('melanoma', 'Phenotype', 'HP:0002861', (268, 276))
45972	22536370	Of the 54 patients with metastatic disease and a detected tumor mutation, 23 (43%) were subsequently enrolled onto genotype-driven trials based upon the results from their tumor mutational profiling.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mutation', 'Var', (64, 72))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('patients', 'Species', '9606', (10, 18))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
45973	22536370	This is a dramatic advantage over a simple allele specific PCR for BRAF V600E.	('V600E', 'Var', (72, 77))	('BRAF', 'Gene', (67, 71))	('BRAF', 'Gene', '673', (67, 71))	('V600E', 'Mutation', 'rs113488022', (72, 77))
45974	22536370	In addition to BRAF inhibitors, patients are directed to trials for KIT mutations, GNAQ/11 mutations in uveal melanoma, and even NRAS mutant melanoma.	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('NRAS', 'Gene', (129, 133))	('KIT', 'molecular_function', 'GO:0005020', ('68', '71'))	('KIT', 'Gene', (68, 71))	('BRAF', 'Gene', '673', (15, 19))	('mutations', 'Var', (72, 81))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('GNAQ', 'Gene', '2776', (83, 87))	('BRAF', 'Gene', (15, 19))	('GNAQ', 'Gene', (83, 87))	('mutant', 'Var', (134, 140))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('uveal melanoma', 'Disease', (104, 118))	('uveal melanoma', 'Disease', 'MESH:C536494', (104, 118))	('NRAS', 'Gene', '4893', (129, 133))	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('patients', 'Species', '9606', (32, 40))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('mutations', 'Var', (91, 100))
45975	22536370	In addition, studies in patients who have disease progression following initial response to BRAF inhibitor therapy have revealed a secondary mutation in NRAS as the mechanism of resistance in nearly a quarter of this patient population.	('BRAF', 'Gene', '673', (92, 96))	('NRAS', 'Gene', (153, 157))	('patient', 'Species', '9606', (217, 224))	('BRAF', 'Gene', (92, 96))	('patient', 'Species', '9606', (24, 31))	('NRAS', 'Gene', '4893', (153, 157))	('patients', 'Species', '9606', (24, 32))	('mutation', 'Var', (141, 149))
45983	22536370	Finally, prospective tumor profiling may allow us to make previously unknown associations between a tumor mutation and clinical features and/or clinical activity of new drug combinations.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', (100, 105))	('mutation', 'Var', (106, 114))	('associations', 'Interaction', (77, 89))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
45998	12439722	Prescher et al (1996) reported metastases from 17 out of 30 (57%) tumours with monosomy 3 compared to none out of 24 (0%) patients without monosomy 3, after a median follow-up of 3.4 years.	('metastases', 'Disease', 'MESH:D009362', (31, 41))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('monosomy 3', 'Var', (79, 89))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('patients', 'Species', '9606', (122, 130))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('tumours', 'Disease', (66, 73))	('metastases', 'Disease', (31, 41))
46002	12439722	Using this technique, we have compared gene expression patterns between primary uveal melanomas with changes to chromosome 3, from patients with clinically evident metastasis, and melanomas without alterations to chromosome 3, from patients that have shown no evidence of metastatic disease (and whose tumours have favourable clinical and histological features).	('tumours', 'Disease', (302, 309))	('chromosome', 'cellular_component', 'GO:0005694', ('112', '122'))	('melanomas', 'Phenotype', 'HP:0002861', (180, 189))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('tumours', 'Phenotype', 'HP:0002664', (302, 309))	('chromosome', 'cellular_component', 'GO:0005694', ('213', '223'))	('tumours', 'Disease', 'MESH:D009369', (302, 309))	('patients', 'Species', '9606', (131, 139))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('primary uveal melanomas', 'Disease', (72, 95))	('tumour', 'Phenotype', 'HP:0002664', (302, 308))	('gene expression', 'biological_process', 'GO:0010467', ('39', '54'))	('changes to chromosome', 'Var', (101, 122))	('melanomas', 'Disease', 'MESH:D008545', (86, 95))	('uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('patients', 'Species', '9606', (232, 240))	('primary uveal melanomas', 'Disease', 'MESH:C536494', (72, 95))	('melanomas', 'Disease', 'MESH:D008545', (180, 189))	('melanomas', 'Disease', (86, 95))	('uveal melanomas', 'Phenotype', 'HP:0007716', (80, 95))	('melanomas', 'Disease', (180, 189))
46020	12439722	Allelic imbalance at ten loci on chromosome 3 (indicating probable monosomy 3) was seen in 22 tumours and 21 tumours showed allelic imbalance at position 8q24.1.	('tumours', 'Disease', (94, 101))	('chromosome', 'cellular_component', 'GO:0005694', ('33', '43'))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('imbalance', 'Phenotype', 'HP:0002172', (132, 141))	('imbalance', 'Phenotype', 'HP:0002172', (8, 17))	('Allelic imbalance', 'Var', (0, 17))	('tumours', 'Disease', (109, 116))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('tumours', 'Disease', 'MESH:D009369', (94, 101))
46035	12439722	The Mann-Whitney test was used to examine how EDNRB expression was associated with ciliary body involvement, epithelioid cells, closed loops, allelic imbalance on chromosome 3 and allelic imbalance on chromosome 8q.	('allelic', 'Var', (180, 187))	('epithelioid cells', 'Disease', (109, 126))	('chromosome', 'cellular_component', 'GO:0005694', ('163', '173'))	('EDNRB', 'Gene', '1910', (46, 51))	('ciliary body involvement', 'Disease', (83, 107))	('associated', 'Reg', (67, 77))	('EDNRB', 'Gene', (46, 51))	('chromosome', 'cellular_component', 'GO:0005694', ('201', '211'))	('allelic imbalance on chromosome', 'Var', (142, 173))	('imbalance', 'Phenotype', 'HP:0002172', (150, 159))	('closed loops', 'Disease', (128, 140))	('imbalance', 'Phenotype', 'HP:0002172', (188, 197))
46049	12439722	Reduced EDNRB was associated with allelic imbalance on chromosome 3 (P=<0.001), allelic imbalance on chromosome 8q (P=<0.001) and the presence of epithelioid cells (P=0.014).	('imbalance', 'Phenotype', 'HP:0002172', (42, 51))	('chromosome', 'cellular_component', 'GO:0005694', ('101', '111'))	('allelic imbalance', 'Var', (34, 51))	('Reduced', 'NegReg', (0, 7))	('EDNRB', 'Gene', '1910', (8, 13))	('imbalance', 'Phenotype', 'HP:0002172', (88, 97))	('allelic imbalance', 'Var', (80, 97))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))	('EDNRB', 'Gene', (8, 13))
46064	12439722	In this study, reduced EDNRB expression correlated with monosomy 3 (as determined by allelic imbalance at multiple, chromosome spanning markers), changes to chromosome 8q (at position 24.1) and the presence of epithelioid cells.	('monosomy 3', 'Disease', (56, 66))	('imbalance', 'Phenotype', 'HP:0002172', (93, 102))	('chromosome', 'cellular_component', 'GO:0005694', ('157', '167'))	('EDNRB', 'Gene', '1910', (23, 28))	('reduced', 'NegReg', (15, 22))	('chromosome', 'cellular_component', 'GO:0005694', ('116', '126'))	('expression', 'MPA', (29, 39))	('EDNRB', 'Gene', (23, 28))	('changes', 'Var', (146, 153))
46070	12439722	Mutations within the EDNRB gene, or within other genes in linked pathways, may explain this observation.	('EDNRB', 'Gene', '1910', (21, 26))	('Mutations', 'Var', (0, 9))	('EDNRB', 'Gene', (21, 26))
46081	12439722	We therefore investigated whether the observed reduced EDNRB levels were due to deletion of the EDNRB gene at 13q22.	('EDNRB', 'Gene', '1910', (96, 101))	('EDNRB', 'Gene', '1910', (55, 60))	('deletion', 'Var', (80, 88))	('EDNRB', 'Gene', (96, 101))	('EDNRB', 'Gene', (55, 60))	('reduced', 'NegReg', (47, 54))
46086	12439722	This region has been reported to be methylated in 70% of prostate cancer samples (including primary tissue and cell lines) analysed by Nelson et al (1997) but unmethylated in normal tissues.	('methylated', 'Var', (36, 46))	('prostate cancer', 'Disease', (57, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('prostate cancer', 'Disease', 'MESH:D011471', (57, 72))	('prostate cancer', 'Phenotype', 'HP:0012125', (57, 72))
46087	12439722	CpG island methylation of the EDNRB gene promoter may therefore be responsible for the reduction in EDNRB levels in metastatic uveal melanoma.	('uveal melanoma', 'Disease', (127, 141))	('EDNRB', 'Gene', '1910', (100, 105))	('EDNRB', 'Gene', (30, 35))	('methylation', 'biological_process', 'GO:0032259', ('11', '22'))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('EDNRB', 'Gene', (100, 105))	('methylation', 'Var', (11, 22))	('EDNRB', 'Gene', '1910', (30, 35))	('uveal melanoma', 'Phenotype', 'HP:0007716', (127, 141))	('uveal melanoma', 'Disease', 'MESH:C536494', (127, 141))	('reduction', 'NegReg', (87, 96))
46092	12439722	Similar to uveal melanoma, SCLC are neural crest derived tumours that exhibit changes to chromosome 3 (Sundaresan et al, 1992) and have a particularly aggressive clinical course, with frequent widespread metastases at diagnosis.	('SCLC', 'Gene', (27, 31))	('uveal melanoma', 'Phenotype', 'HP:0007716', (11, 25))	('metastases', 'Disease', (204, 214))	('uveal melanoma', 'Disease', (11, 25))	('uveal melanoma', 'Disease', 'MESH:C536494', (11, 25))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('changes', 'Var', (78, 85))	('metastases', 'Disease', 'MESH:D009362', (204, 214))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('tumours', 'Disease', (57, 64))	('chromosome', 'cellular_component', 'GO:0005694', ('89', '99'))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('SCLC', 'Gene', '7864', (27, 31))
46117	33858433	The antioxidant activity of chrysin is related to the presence of the double bond between C2-C3 and the carbonyl group on the C4 atom.	('antioxidant activity', 'MPA', (4, 24))	('chrysin', 'Chemical', 'MESH:C043561', (28, 35))	('C2-C3', 'Var', (90, 95))	('presence', 'Var', (54, 62))	('double bond', 'MPA', (70, 81))	('antioxidant activity', 'molecular_function', 'GO:0016209', ('4', '24'))
46123	33858433	The C30, C40-dichloro substituent in the chrysin molecule was responsible for the suppression of prostaglandin (PG) production.	('PG', 'Chemical', 'MESH:D011453', (112, 114))	('chrysin', 'Chemical', 'MESH:C043561', (41, 48))	('C40-dichloro', 'Var', (9, 21))	('C30', 'Var', (4, 7))	('mole', 'Phenotype', 'HP:0003764', (49, 53))	('prostaglandin', 'Chemical', 'MESH:D011453', (97, 110))	('C40-dichloro', 'Chemical', '-', (9, 21))	('suppression', 'NegReg', (82, 93))
46128	33858433	Methylation of both C5 and C7 resulted in higher effectiveness of this chrysin analog as a feasible chemotherapeutic agent for acute lymphoblastic leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('acute lymphoblastic leukemia', 'Disease', (127, 155))	('Methylation', 'Var', (0, 11))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (127, 155))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (133, 155))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('higher', 'PosReg', (42, 48))	('chrysin', 'Chemical', 'MESH:C043561', (71, 78))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (127, 155))	('effectiveness', 'MPA', (49, 62))
46130	33858433	By in silico screening, a series of C7-hydroxyproton substituted chrysin derivatives exhibited EGFR inhibiting possessions against breast cancer.	('chrysin', 'Chemical', 'MESH:C043561', (65, 72))	('inhibiting', 'NegReg', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('C7-hydroxyproton', 'Chemical', '-', (36, 52))	('EGFR', 'Gene', '1956', (95, 99))	('EGFR', 'molecular_function', 'GO:0005006', ('95', '99'))	('breast cancer', 'Disease', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('C7-hydroxyproton substituted', 'Var', (36, 64))	('EGFR', 'Gene', (95, 99))
46148	33858433	Doxorubicin loaded mPEG-PCL-chrysin micelles could significantly show potent anticancer activities in vitro, regarding the pi-pi stacking interactions among the mentioned micelles and doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (184, 195))	('pi-pi', 'Var', (123, 128))	('mice', 'Species', '10090', (171, 175))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('chrysin', 'Chemical', 'MESH:C043561', (28, 35))	('cancer', 'Disease', (81, 87))	('mPEG-PCL', 'Chemical', 'MESH:C439611', (19, 27))	('mice', 'Species', '10090', (36, 40))	('Doxorubicin', 'Chemical', 'MESH:D004317', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('men', 'Species', '9606', (161, 164))
46184	33858433	By substitution of benzyloxy, dimethylamino, nitro, and fluoro on chrysin structure, potent cytotoxic agents were synthetized that displayed considerable cytotoxicity against MDA-MB-231 and MCF-7.	('chrysin', 'Chemical', 'MESH:C043561', (66, 73))	('nitro', 'Chemical', '-', (45, 50))	('cytotoxicity', 'Disease', (154, 166))	('dimethylamino', 'Chemical', '-', (30, 43))	('MCF-7', 'CellLine', 'CVCL:0031', (190, 195))	('fluoro', 'Chemical', '-', (56, 62))	('benzyloxy', 'Chemical', '-', (19, 28))	('cytotoxicity', 'Disease', 'MESH:D064420', (154, 166))	('substitution', 'Var', (3, 15))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (175, 185))
46188	33858433	Various etiologies have participated in the initializations and progressions of gastric cancer including gene-environment dealings with Helicobacter pylori as the most prevailing reasons for the pathogenesis of gastric cancer, numerous genetic and epigenetic changes have been connected with its carcinogenesis moreover.	('genetic', 'Var', (236, 243))	('gastric cancer', 'Disease', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('gastric cancer', 'Disease', (211, 225))	('connected', 'Reg', (277, 286))	('men', 'Species', '9606', (117, 120))	('gastric cancer', 'Disease', 'MESH:D013274', (211, 225))	('carcinogenesis', 'Disease', 'MESH:D063646', (296, 310))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('Helicobacter pylori', 'Species', '210', (136, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (211, 225))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('epigenetic changes', 'Var', (248, 266))	('carcinogenesis', 'Disease', (296, 310))	('pathogenesis', 'biological_process', 'GO:0009405', ('195', '207'))
46195	33858433	CRISPR/Cas9 system was used to generate the TET1 gene knocked out.	('Cas', 'cellular_component', 'GO:0005650', ('7', '10'))	('knocked out', 'Var', (54, 65))	('TET1', 'Gene', (44, 48))	('rat', 'Species', '10116', (35, 38))	('TET1', 'Gene', '80312', (44, 48))
46257	33858433	Chrysin pretreatment led to an increase in mitochondrial ROS creation, swelling in isolated mitochondria from hepatocytes, collapse in MMP, and release cytochrome c. Furthermore, Chrysin could elevate caspase-3 activity in the HCC rats group.	('swelling', 'Disease', 'MESH:D004487', (71, 79))	('cytochrome c', 'Gene', '54205', (152, 164))	('ROS', 'Chemical', 'MESH:D017382', (57, 60))	('caspase-3 activity', 'molecular_function', 'GO:0030693', ('201', '219'))	('cytochrome c', 'molecular_function', 'GO:0009461', ('152', '164'))	('MMP', 'Gene', '4312;4313;17390;4318;17395;4319', (135, 138))	('men', 'Species', '9606', (16, 19))	('Chrysin', 'Chemical', 'MESH:C043561', (0, 7))	('MMP', 'molecular_function', 'GO:0004235', ('135', '138'))	('mitochondria', 'cellular_component', 'GO:0005739', ('92', '104'))	('rats', 'Species', '10116', (231, 235))	('caspase-3', 'Enzyme', (201, 210))	('cytochrome c', 'Gene', (152, 164))	('activity', 'MPA', (211, 219))	('Chrysin', 'Var', (179, 186))	('elevate', 'PosReg', (193, 200))	('caspase-3 activity', 'molecular_function', 'GO:0004208', ('201', '219'))	('mitochondrial ROS creation', 'MPA', (43, 69))	('MMP', 'Gene', (135, 138))	('Chrysin', 'Chemical', 'MESH:C043561', (179, 186))	('cytochrome c', 'molecular_function', 'GO:0045155', ('152', '164'))	('swelling', 'Disease', (71, 79))
46294	33858433	One of the main markers indicated the poor prognosis in patients with urinary bladder tumor that is mutation in tumor protein p53 (TP53) gene.	('patients', 'Species', '9606', (56, 64))	('p53', 'Gene', '7157', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('urinary bladder tumor', 'Disease', (70, 91))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('TP53', 'Gene', '7157', (131, 135))	('urinary bladder tumor', 'Disease', 'MESH:D001749', (70, 91))	('mutation', 'Var', (100, 108))	('TP53', 'Gene', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('bladder tumor', 'Phenotype', 'HP:0009725', (78, 91))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('p53', 'Gene', (126, 129))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))
46295	33858433	It was found that the progression of bladder tumor cell was inhibited by chrysin at doses 10-100 microM in mutated and wild type TP53 in grade 1-3.	('progression', 'CPA', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('chrysin', 'Chemical', 'MESH:C043561', (73, 80))	('bladder tumor', 'Disease', 'MESH:D001749', (37, 50))	('mutated', 'Var', (107, 114))	('inhibited', 'NegReg', (60, 69))	('TP53', 'Gene', '7157', (129, 133))	('bladder tumor', 'Phenotype', 'HP:0009725', (37, 50))	('TP53', 'Gene', (129, 133))	('bladder tumor', 'Disease', (37, 50))
46297	33858433	Chrysin could affect cell cycle at G2 and M phases and cell morphology following decrease in the expression of PLK1, HOXB3 and SRC genes in mutated TP53 cells,.	('PLK1', 'Gene', (111, 115))	('decrease', 'NegReg', (81, 89))	('affect', 'Reg', (14, 20))	('TP53', 'Gene', '7157', (148, 152))	('HOXB3', 'Gene', '3213', (117, 122))	('TP53', 'Gene', (148, 152))	('PLK1', 'Gene', '5347', (111, 115))	('cell morphology', 'CPA', (55, 70))	('SRC', 'Gene', '6714', (127, 130))	('SRC', 'Gene', (127, 130))	('HOXB3', 'Gene', (117, 122))	('Chrysin', 'Chemical', 'MESH:C043561', (0, 7))	('cell cycle', 'biological_process', 'GO:0007049', ('21', '31'))	('expression', 'MPA', (97, 107))	('mutated', 'Var', (140, 147))
46321	33858433	8-bromo-7-methoxychrysin led to cell fate in cisplatin-sensitive/resistant A2780 and A2780/DDP cells happened via the regulation of Akt/FOXO3a, resulting in transcription of Bim.	('transcription', 'MPA', (157, 170))	('FOXO3a', 'Gene', '2309', (136, 142))	('FOXO3a', 'Gene', (136, 142))	('8-bromo-7-methoxychrysin', 'Chemical', 'MESH:C552860', (0, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('transcription', 'biological_process', 'GO:0006351', ('157', '170'))	('regulation', 'biological_process', 'GO:0065007', ('118', '128'))	('Akt', 'Gene', (132, 135))	('Bim', 'MPA', (174, 177))	('A2780/DDP', 'Var', (85, 94))	('cell fate', 'CPA', (32, 41))	('Akt', 'Gene', '207', (132, 135))
46356	33858433	Any abnormality in the production and secretion of mucins causes a pathological condition in the airway such as mucoepidermoid carcinoma.	('mucoepidermoid carcinoma', 'Disease', (112, 136))	('mucin', 'Gene', '100508689', (51, 56))	('production', 'MPA', (23, 33))	('abnormality', 'Var', (4, 15))	('causes', 'Reg', (58, 64))	('secretion', 'MPA', (38, 47))	('secretion', 'biological_process', 'GO:0046903', ('38', '47'))	('mucin', 'Gene', (51, 56))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (112, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
46417	33858433	Pretreatment with chrysin exposed S/G2 phase arrest and apoptosis.	('S/G2', 'SUBSTITUTION', 'None', (34, 38))	('arrest', 'Disease', (45, 51))	('men', 'Species', '9606', (8, 11))	('chrysin', 'Chemical', 'MESH:C043561', (18, 25))	('G2 phase', 'biological_process', 'GO:0051319', ('36', '44'))	('S/G2', 'Var', (34, 38))	('apoptosis', 'CPA', (56, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('56', '65'))	('apoptosis', 'biological_process', 'GO:0097194', ('56', '65'))	('arrest', 'Disease', 'MESH:D006323', (45, 51))
46420	33858433	The findings suggested that inhibitory effect of chrysin on ASCL1 was effective for carcinoid management.	('carcinoid', 'Phenotype', 'HP:0100570', (84, 93))	('men', 'Species', '9606', (100, 103))	('carcinoid', 'Disease', 'MESH:D002276', (84, 93))	('chrysin', 'Chemical', 'MESH:C043561', (49, 56))	('inhibitory effect', 'Var', (28, 45))	('ASCL1', 'Gene', (60, 65))	('ASCL1', 'Gene', '429', (60, 65))	('carcinoid', 'Disease', (84, 93))
46436	33858433	Moreover due to this co-treatment declined Akt phosphorylation in addition to intracellular GSH content.	('Akt', 'Gene', '207', (43, 46))	('intracellular', 'cellular_component', 'GO:0005622', ('78', '91'))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('Akt', 'Gene', (43, 46))	('men', 'Species', '9606', (29, 32))	('GSH', 'Chemical', 'MESH:D005978', (92, 95))	('declined', 'NegReg', (34, 42))	('co-treatment', 'Var', (21, 33))
46525	31466473	PBRT induces DNA damage to tumour cells and late apoptosis, in a pattern that is different than the radionecrosis induced by other radiation modalities.	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('PBRT', 'Chemical', '-', (0, 4))	('PBRT', 'Var', (0, 4))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('apoptosis', 'biological_process', 'GO:0097194', ('49', '58'))	('apoptosis', 'biological_process', 'GO:0006915', ('49', '58'))	('tumour', 'Disease', (27, 33))	('induces', 'Reg', (5, 12))
46535	31466473	When performing treatment planning, this error can influence the size of designated target volume and thus treatment success.	('influence', 'Reg', (51, 60))	('men', 'Species', '9606', (112, 115))	('error', 'Var', (41, 46))	('men', 'Species', '9606', (21, 24))
46563	33173970	Further, the improved knowledge of tumour biology is giving rise to a more targeted approach to diagnosis, prognosis and treatment development; for example, epigenetics driven by microRNAs as a target for disease control.	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('epigenetics', 'Var', (157, 168))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Disease', (35, 41))
46575	33173970	When staging a primary uveal melanoma, besides considering its anatomical and pathological features (tumour base diameter, ciliary body involvement, and patterns of extravascular matrix growth, mitosis, and cell morphology), mutations with prognostic value along with their statistics have allowed for an individualized approach able to predict the response to treatment and outcome.	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('mutations', 'Var', (225, 234))	('mitosis', 'Disease', (194, 201))	('tumour', 'Disease', (101, 107))	('uveal melanoma', 'Disease', 'MESH:C536494', (23, 37))	('uveal melanoma', 'Phenotype', 'HP:0007716', (23, 37))	('mitosis', 'biological_process', 'GO:0000278', ('194', '201'))	('uveal melanoma', 'Disease', (23, 37))	('mitosis', 'Disease', 'None', (194, 201))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
46588	33173970	Hence, its association with an individual's phenotype may be a susceptibility factor for oncogenic melanocyte mutations and therefore, of the risk of developing uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (161, 175))	('uveal melanoma', 'Disease', (161, 175))	('mutations', 'Var', (110, 119))	('association', 'Interaction', (11, 22))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('susceptibility', 'Reg', (63, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (161, 175))
46618	33173970	Notably, the presence of HLA-B has been associated with the epithelioid subtype, which is the histological class exhibiting a lower survival.	('HLA-B', 'Gene', '3106', (25, 30))	('HLA-B', 'Gene', (25, 30))	('presence', 'Var', (13, 21))	('associated', 'Reg', (40, 50))	('epithelioid subtype', 'Disease', (60, 79))
46623	33173970	In addition, there is significant variation in cytogenetics and expression levels of some genes in the different subtypes; for example, chromosome 3 monosomy is characteristic of class 2 tumours.	('tumours', 'Disease', 'MESH:D009369', (187, 194))	('chromosome 3 monosomy', 'Var', (136, 157))	('tumours', 'Disease', (187, 194))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('chromosome', 'cellular_component', 'GO:0005694', ('136', '146'))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))
46625	33173970	For this reason, uveal melanoma classification has been extended to include 4 groups: 2 subclasses characterized by chromosome 3 monosomy (M3) with a worse prognosis, and a further 2 subtypes that lack this chromosome abnormality; i.e., with chromosome 3 disomy (D3), with a better prognosis.	('chromosome 3 disomy', 'Var', (242, 261))	('chromosome 3 monosomy', 'Var', (116, 137))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('chromosome', 'cellular_component', 'GO:0005694', ('207', '217'))	('chromosome abnormality', 'Phenotype', 'HP:0031411', (207, 229))	('chromosome', 'cellular_component', 'GO:0005694', ('116', '126'))	('chromosome', 'cellular_component', 'GO:0005694', ('242', '252'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))	('uveal melanoma', 'Disease', 'MESH:C536494', (17, 31))	('uveal melanoma', 'Disease', (17, 31))
46626	33173970	The first 2 subclasses are associated with a higher metastasis risk and exhibit a loss of or mutation of the gene encoding BRCA-associated protein 1 (BAP1) located on 3p21.1 (NCBI), and conferring a different methylation state to those without this monosomy.	('methylation', 'biological_process', 'GO:0032259', ('209', '220'))	('metastasis', 'CPA', (52, 62))	('BAP1', 'Gene', (150, 154))	('BRCA-associated protein 1', 'Gene', (123, 148))	('loss of or', 'NegReg', (82, 92))	('BAP1', 'Gene', '8314', (150, 154))	('BRCA-associated protein 1', 'Gene', '8314', (123, 148))	('mutation', 'Var', (93, 101))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))
46627	33173970	The former exhibits no aneuploidy, the least risk of spread and is characterized by a mutation in eukaryotic translation initiation factor 1A X-linked (EIF1AX).	('eukaryotic translation initiation factor 1A X-linked', 'Gene', '1964', (98, 150))	('aneuploidy', 'Disease', 'MESH:D000782', (23, 33))	('EIF1AX', 'Gene', '1964', (152, 158))	('EIF1AX', 'Gene', (152, 158))	('aneuploidy', 'Disease', (23, 33))	('mutation', 'Var', (86, 94))	('translation initiation', 'biological_process', 'GO:0006413', ('109', '131'))
46628	33173970	Subtype IB, characterized by the possible presence of a total or partial gain of 6p and a higher metastasis risk, features mutations in the splicing factor 3b subunit 1 (SF3B1) gene.	('SF3B1', 'Gene', '23451', (170, 175))	('gain', 'PosReg', (73, 77))	('splicing', 'biological_process', 'GO:0045292', ('140', '148'))	('metastasis', 'CPA', (97, 107))	('splicing factor 3b subunit 1', 'Gene', (140, 168))	('splicing factor 3b subunit 1', 'Gene', '23451', (140, 168))	('SF3B1', 'Gene', (170, 175))	('mutations', 'Var', (123, 132))
46629	33173970	Furthermore, Field et al highlighted the role of gene expression of preferentially expressed antigen in melanoma (PRAME) as an independent biomarker of metastasis frequently found in tumours with a mutation in SF3B1.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('tumours', 'Disease', (183, 190))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('PRAME', 'Gene', '23532', (114, 119))	('PRAME', 'Gene', (114, 119))	('SF3B1', 'Gene', (210, 215))	('gene expression', 'biological_process', 'GO:0010467', ('49', '64'))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('found', 'Reg', (174, 179))	('tumours', 'Phenotype', 'HP:0002664', (183, 190))	('SF3B1', 'Gene', '23451', (210, 215))	('tumours', 'Disease', 'MESH:D009369', (183, 190))	('mutation', 'Var', (198, 206))
46630	33173970	This marker may also appear in M3 tumours and is also inversely related to mutations in EIF1AX.	('EIF1AX', 'Gene', '1964', (88, 94))	('EIF1AX', 'Gene', (88, 94))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('tumours', 'Disease', 'MESH:D009369', (34, 41))	('mutations', 'Var', (75, 84))	('tumours', 'Disease', (34, 41))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
46631	33173970	Mutations in the genes EIF1AX, SF3B1 and BAP1 are mutually exclusive, as well as being key prognostic markers to understand the behaviour of each uveal melanoma subtype.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('uveal melanoma', 'Disease', 'MESH:C536494', (146, 160))	('BAP1', 'Gene', (41, 45))	('uveal melanoma', 'Phenotype', 'HP:0007716', (146, 160))	('uveal melanoma', 'Disease', (146, 160))	('Mutations', 'Var', (0, 9))	('SF3B1', 'Gene', (31, 36))	('EIF1AX', 'Gene', (23, 29))	('EIF1AX', 'Gene', '1964', (23, 29))	('behaviour', 'biological_process', 'GO:0007610', ('128', '137'))	('SF3B1', 'Gene', '23451', (31, 36))	('BAP1', 'Gene', '8314', (41, 45))
46632	33173970	Of note, both in D3 uveal melanomas which do not exhibit mutations in SF3B1 or EIF1AX and in M3, which exhibit gain of chromosome 8q, mutations in serine and arginine rich splicing factor 2 (SRSF2) have also been found, indicating a role for this marker in the metastasis of uveal melanoma and its functional analogy with SF3B1.	('chromosome', 'cellular_component', 'GO:0005694', ('119', '129'))	('metastasis of uveal melanoma', 'Disease', 'MESH:C536494', (261, 289))	('SRSF2', 'Gene', (191, 196))	('SF3B1', 'Gene', '23451', (322, 327))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('uveal melanomas', 'Disease', 'MESH:C536494', (20, 35))	('uveal melanoma', 'Phenotype', 'HP:0007716', (20, 34))	('EIF1AX', 'Gene', (79, 85))	('uveal melanoma', 'Phenotype', 'HP:0007716', (275, 289))	('metastasis of uveal melanoma', 'Disease', (261, 289))	('mutations', 'Var', (134, 143))	('serine and arginine rich splicing factor 2', 'Gene', '6427', (147, 189))	('EIF1AX', 'Gene', '1964', (79, 85))	('uveal melanomas', 'Disease', (20, 35))	('uveal melanomas', 'Phenotype', 'HP:0007716', (20, 35))	('SF3B1', 'Gene', (70, 75))	('splicing', 'biological_process', 'GO:0045292', ('172', '180'))	('SF3B1', 'Gene', (322, 327))	('melanomas', 'Phenotype', 'HP:0002861', (26, 35))	('melanoma', 'Phenotype', 'HP:0002861', (281, 289))	('SRSF2', 'Gene', '6427', (191, 196))	('SF3B1', 'Gene', '23451', (70, 75))
46637	33173970	However, mutations found in both types of melanoma differ.	('melanoma', 'Disease', (42, 50))	('mutations', 'Var', (9, 18))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
46638	33173970	In the skin form, most frequent abnormalities are found in molecules directly involved in this pathway especially the B-RAF mutation (in 40-60% of cases).	('B-RAF', 'Gene', '673', (118, 123))	('B-RAF', 'Gene', (118, 123))	('mutation', 'Var', (124, 132))	('abnormalities', 'Reg', (32, 45))
46639	33173970	In addition, are mutations in other genes, such as NRAS (15-25%) and KIT (39%) are frequent.	('KIT', 'Gene', (69, 72))	('KIT', 'molecular_function', 'GO:0005020', ('69', '72'))	('NRAS', 'Gene', (51, 55))	('KIT', 'Gene', '3815', (69, 72))	('mutations', 'Var', (17, 26))	('NRAS', 'Gene', '4893', (51, 55))
46641	33173970	The mutations found in this tumour type appear mainly in the genes that code for the alpha subunit of G, mainly G protein subunit alpha (GNA)11 or GNAQ, detected in up to 90% of cases of uveal melanoma.	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('alpha subunit of G, mainly G protein subunit alpha (GNA)11', 'Gene', '2767', (85, 143))	('uveal melanoma', 'Disease', 'MESH:C536494', (187, 201))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('uveal melanoma', 'Disease', (187, 201))	('GNAQ', 'Gene', (147, 151))	('uveal melanoma', 'Phenotype', 'HP:0007716', (187, 201))	('tumour', 'Disease', (28, 34))	('mutations', 'Var', (4, 13))	('GNAQ', 'Gene', '2776', (147, 151))
46642	33173970	Furthermore, these mutations seem to play an important role in the onset and progression of uveal melanoma as it has been observed that both abnormalities are not associated with a worse prognosis.	('mutations', 'Var', (19, 28))	('uveal melanoma', 'Phenotype', 'HP:0007716', (92, 106))	('uveal melanoma', 'Disease', (92, 106))	('uveal melanoma', 'Disease', 'MESH:C536494', (92, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))
46644	33173970	The mechanisms through which all these alterations affect tumour biology are described below.	('affect', 'Reg', (51, 57))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour', 'Disease', (58, 64))	('alterations', 'Var', (39, 50))
46645	33173970	In some cases of uveal melanoma, mutations in the telomerase reverse transcriptase (TERT) gene have been described.	('TERT', 'Gene', (84, 88))	('TERT', 'Gene', '7015', (84, 88))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('mutations', 'Var', (33, 42))	('transcriptase', 'molecular_function', 'GO:0003899', ('69', '82'))	('telomerase reverse transcriptase', 'Gene', (50, 82))	('telomerase reverse transcriptase', 'Gene', '7015', (50, 82))	('transcriptase', 'molecular_function', 'GO:0003968', ('69', '82'))	('transcriptase', 'molecular_function', 'GO:0034062', ('69', '82'))	('described', 'Reg', (105, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))	('uveal melanoma', 'Disease', (17, 31))	('uveal melanoma', 'Disease', 'MESH:C536494', (17, 31))
46647	33173970	Furthermore, this mutation appeared to be associated with a tumour with variations in GNA11 and EIF1AX, that is, it appeared in the least aggressive profile.	('EIF1AX', 'Gene', '1964', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('associated', 'Reg', (42, 52))	('tumour', 'Disease', (60, 66))	('variations', 'Var', (72, 82))	('GNA11', 'Gene', (86, 91))	('EIF1AX', 'Gene', (96, 102))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('GNA11', 'Gene', '2767', (86, 91))
46650	33173970	These authors found that up to 32% of conjunctival melanomas had a mutated TERT promotor, while this polymorphism was absent in 47 uveal melanomas examined.	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))	('TERT', 'Gene', (75, 79))	('TERT', 'Gene', '7015', (75, 79))	('melanomas', 'Phenotype', 'HP:0002861', (137, 146))	('mutated', 'Var', (67, 74))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (38, 60))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('conjunctival melanomas', 'Disease', (38, 60))	('uveal melanomas', 'Disease', (131, 146))	('uveal melanomas', 'Phenotype', 'HP:0007716', (131, 146))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('uveal melanomas', 'Disease', 'MESH:C536494', (131, 146))
46667	33173970	As described above, the most frequent mutations that appear in the early development of uveal melanoma are those affecting GPCR receptors, particularly variants of GNA11 or GNAQ.	('GNAQ', 'Gene', '2776', (173, 177))	('GNAQ', 'Gene', (173, 177))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (88, 102))	('GNA11', 'Gene', (164, 169))	('variants', 'Var', (152, 160))	('uveal melanoma', 'Disease', (88, 102))	('GNA11', 'Gene', '2767', (164, 169))	('mutations', 'Var', (38, 47))	('GPCR receptors', 'Protein', (123, 137))
46669	33173970	Receptor 5-HT2B mutations are often found in a wide variety of tumours and have been linked to a greater metastasis risk.	('tumours', 'Disease', (63, 70))	('5-HT2B', 'Gene', (9, 15))	('5-HT2B', 'Gene', '3357', (9, 15))	('mutations', 'Var', (16, 25))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('metastasis', 'CPA', (105, 115))	('linked to', 'Reg', (85, 94))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('tumours', 'Disease', 'MESH:D009369', (63, 70))
46670	33173970	Furthermore, GNAQ and GNA11 mutations trigger a wide range of cell signalling cascades, including the PI3K/Akt/mTOR, YAP/TAZ, Wnt/beta-catenin, Rac/Rho, Notch and MAPK pathways.	('signalling', 'biological_process', 'GO:0023052', ('67', '77'))	('GNAQ', 'Gene', (13, 17))	('trigger', 'Reg', (38, 45))	('GNA11', 'Gene', (22, 27))	('YAP', 'Gene', (117, 120))	('Rac/Rho', 'Pathway', (144, 151))	('Akt', 'Gene', (107, 110))	('mTOR', 'Gene', (111, 115))	('TAZ', 'Gene', '6901', (121, 124))	('TAZ', 'Gene', (121, 124))	('Akt', 'Gene', '207', (107, 110))	('mutations', 'Var', (28, 37))	('YAP', 'Gene', '10413', (117, 120))	('mTOR', 'Gene', '2475', (111, 115))	('GNA11', 'Gene', '2767', (22, 27))	('MAPK', 'molecular_function', 'GO:0004707', ('163', '167'))	('MAPK pathways', 'Pathway', (163, 176))	('cell signalling cascades', 'Pathway', (62, 86))	('beta-catenin', 'Gene', (130, 142))	('GNAQ', 'Gene', '2776', (13, 17))	('PI3K', 'molecular_function', 'GO:0016303', ('102', '106'))	('beta-catenin', 'Gene', '1499', (130, 142))
46673	33173970	As previously described, one of the most important mutations found in uveal melanoma and a key point for understanding its biology, particularly its metastasis, is BAP1.	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('uveal melanoma', 'Disease', (70, 84))	('mutations', 'Var', (51, 60))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('BAP1', 'Gene', (164, 168))	('BAP1', 'Gene', '8314', (164, 168))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
46674	33173970	BAP1 is a tumour suppressor gene that appears mutated in up to 84% of cases of metastasized uveal melanoma and in 38% of primary uveal melanomas.	('uveal melanomas', 'Disease', (129, 144))	('uveal melanomas', 'Phenotype', 'HP:0007716', (129, 144))	('metastasized uveal melanoma', 'Disease', (79, 106))	('BAP1', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanomas', 'Phenotype', 'HP:0002861', (135, 144))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('metastasized uveal melanoma', 'Disease', 'MESH:D009362', (79, 106))	('mutated', 'Var', (46, 53))	('uveal melanoma', 'Phenotype', 'HP:0007716', (92, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('tumour', 'Disease', 'MESH:D009369', (10, 16))	('uveal melanomas', 'Disease', 'MESH:C536494', (129, 144))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('tumour', 'Disease', (10, 16))	('BAP1', 'Gene', '8314', (0, 4))
46676	33173970	It has been observed that mutations in the BAP1 germline are associated with a large variety of tumours, including lung adenocarcinoma, menangioma and uveal melanoma.	('BAP1', 'Gene', (43, 47))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('lung adenocarcinoma', 'Disease', (115, 134))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (115, 134))	('BAP1', 'Gene', '8314', (43, 47))	('mutations', 'Var', (26, 35))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('menangioma and uveal melanoma', 'Disease', 'MESH:C536494', (136, 165))	('tumours', 'Disease', 'MESH:D009369', (96, 103))	('tumours', 'Disease', (96, 103))	('associated', 'Reg', (61, 71))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (115, 134))	('uveal melanoma', 'Phenotype', 'HP:0007716', (151, 165))
46679	33173970	However, this mechanism has not been detected in melanocyte lines and it has been described that the loss of BAP-1 leads to defective DNA repair, thus favouring later mutations and cytogenetic aberrations, promoting the metastasis and aggressiveness of tumour cells.	('aggressiveness of tumour', 'Disease', (235, 259))	('promoting', 'PosReg', (206, 215))	('DNA repair', 'MPA', (134, 144))	('aggressiveness', 'Phenotype', 'HP:0000718', (235, 249))	('loss', 'Var', (101, 105))	('BAP-1', 'Gene', '8314', (109, 114))	('mutations', 'Var', (167, 176))	('favouring', 'PosReg', (151, 160))	('aggressiveness of tumour', 'Disease', 'MESH:D009369', (235, 259))	('DNA repair', 'biological_process', 'GO:0006281', ('134', '144'))	('BAP-1', 'Gene', (109, 114))	('defective', 'NegReg', (124, 133))	('tumour', 'Phenotype', 'HP:0002664', (253, 259))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))	('metastasis', 'CPA', (220, 230))
46681	33173970	Furthermore, it has been proposed that the loss of BAP1 can lead to an inflammatory tumour microenvironment.	('tumour', 'Disease', (84, 90))	('lead to', 'Reg', (60, 67))	('BAP1', 'Gene', (51, 55))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('inflammatory', 'CPA', (71, 83))	('loss', 'Var', (43, 47))	('BAP1', 'Gene', '8314', (51, 55))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
46683	33173970	Szalai et al reported no nuclear immunodetection of BAP1 in approximately 50% of patients with metastatic uveal melanoma, hence supporting the relevance of BAP1 mutations in metastasis.	('BAP1', 'Gene', '8314', (52, 56))	('BAP1', 'Gene', '8314', (156, 160))	('patients', 'Species', '9606', (81, 89))	('BAP1', 'Gene', (52, 56))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('mutations', 'Var', (161, 170))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('uveal melanoma', 'Disease', (106, 120))	('BAP1', 'Gene', (156, 160))
46685	33173970	SF3B1 encodes a component of the spliceosome and its gaining function mutations affect the splicing of several transcripts with effects at different levels.	('mutations', 'Var', (70, 79))	('affect', 'Reg', (80, 86))	('SF3B1', 'Gene', (0, 5))	('splicing of several transcripts', 'MPA', (91, 122))	('spliceosome', 'cellular_component', 'GO:0005681', ('33', '44'))	('SF3B1', 'Gene', '23451', (0, 5))	('splicing', 'biological_process', 'GO:0045292', ('91', '99'))
46686	33173970	Yavuzyigitoglu et al confirmed that SF3B1 mutations were important in late metastasis, due to their effects on splicing, which in turn has been associated with a wide range of carcinogenic processes in a number of tumours, including invasion and metastasis.	('tumours', 'Phenotype', 'HP:0002664', (214, 221))	('carcinogenic processes', 'Disease', (176, 198))	('SF3B1', 'Gene', (36, 41))	('associated with', 'Reg', (144, 159))	('effects', 'Reg', (100, 107))	('tumours', 'Disease', 'MESH:D009369', (214, 221))	('metastasis', 'CPA', (246, 256))	('tumours', 'Disease', (214, 221))	('SF3B1', 'Gene', '23451', (36, 41))	('carcinogenic processes', 'Disease', 'MESH:D016301', (176, 198))	('splicing', 'biological_process', 'GO:0045292', ('111', '119'))	('invasion', 'CPA', (233, 241))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('splicing', 'MPA', (111, 119))	('mutations', 'Var', (42, 51))
46687	33173970	In uveal melanoma, SF3B1 splicing defects may play an important role in different processes, probably sharing common oncogenic mechanisms with BAP1 and EIF1AX.	('BAP1', 'Gene', (143, 147))	('uveal melanoma', 'Disease', (3, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('play', 'Reg', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('EIF1AX', 'Gene', '1964', (152, 158))	('EIF1AX', 'Gene', (152, 158))	('SF3B1', 'Gene', '23451', (19, 24))	('role', 'Reg', (64, 68))	('splicing defects', 'Var', (25, 41))	('splicing', 'biological_process', 'GO:0045292', ('25', '33'))	('BAP1', 'Gene', '8314', (143, 147))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('SF3B1', 'Gene', (19, 24))
46688	33173970	Mutant SF3B1 is considered to recognise intronic sequences in the bromodomain containing 9 (BRD9), degrading them and affecting the non-canonical barrier-to-autointegration factor complex (ncBAF), thus resulting in the development of myelodysplastic syndrome and uveal melanoma.	('affecting', 'Reg', (118, 127))	('melanoma', 'Phenotype', 'HP:0002861', (269, 277))	('resulting in', 'Reg', (202, 214))	('myelodysplastic syndrome', 'Disease', (234, 258))	('BRD9', 'Gene', '65980', (92, 96))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (234, 258))	('uveal melanoma', 'Disease', (263, 277))	('uveal melanoma', 'Disease', 'MESH:C536494', (263, 277))	('SF3B1', 'Gene', (7, 12))	('degrading', 'NegReg', (99, 108))	('development', 'Reg', (219, 230))	('uveal melanoma', 'Phenotype', 'HP:0007716', (263, 277))	('BRD9', 'Gene', (92, 96))	('them', 'MPA', (109, 113))	('Mutant', 'Var', (0, 6))	('SF3B1', 'Gene', '23451', (7, 12))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (234, 258))
46689	33173970	In addition, mutations in SRSF2, U2AF1 and ZRSR2 have also been linked to defective splicing in uveal melanoma.	('U2AF', 'cellular_component', 'GO:0089701', ('33', '37'))	('defective splicing', 'MPA', (74, 92))	('uveal melanoma', 'Disease', (96, 110))	('SRSF2', 'Gene', '6427', (26, 31))	('SRSF2', 'Gene', (26, 31))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('U2AF1', 'Gene', (33, 38))	('U2AF1', 'Gene', '7307', (33, 38))	('splicing', 'biological_process', 'GO:0045292', ('84', '92'))	('ZRSR2', 'Gene', '8233', (43, 48))	('linked', 'Reg', (64, 70))	('mutations', 'Var', (13, 22))	('ZRSR2', 'Gene', (43, 48))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('uveal melanoma', 'Disease', 'MESH:C536494', (96, 110))
46690	33173970	Furthermore, in tumours with mutations in both BAP1 and SF3B1, elevated levels may appear of PRAME, which act as a repressor of retinoic acid signalling and of its receptor, two known tumour suppressors, whose inhibition has been incriminated in a wide variety of cancers.	('retinoic', 'MPA', (128, 136))	('levels', 'MPA', (72, 78))	('BAP1', 'Gene', '8314', (47, 51))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('PRAME', 'Gene', '23532', (93, 98))	('cancers', 'Disease', (264, 271))	('tumours', 'Disease', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('PRAME', 'Gene', (93, 98))	('SF3B1', 'Gene', (56, 61))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('repressor', 'MPA', (115, 124))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))	('tumour', 'Disease', (184, 190))	('BAP1', 'Gene', (47, 51))	('retinoic acid', 'Chemical', 'MESH:D014212', (128, 141))	('tumours', 'Disease', 'MESH:D009369', (16, 23))	('mutations', 'Var', (29, 38))	('signalling', 'biological_process', 'GO:0023052', ('142', '152'))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('elevated', 'PosReg', (63, 71))	('SF3B1', 'Gene', '23451', (56, 61))	('cancers', 'Disease', 'MESH:D009369', (264, 271))	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('tumour', 'Disease', (16, 22))
46691	33173970	Mutations affecting EIF1AX, which participate in the onset of translation, has no influence on metastases and more work is needed to establish possible relations between both.	('metastases', 'Disease', (95, 105))	('EIF1AX', 'Gene', '1964', (20, 26))	('Mutations', 'Var', (0, 9))	('EIF1AX', 'Gene', (20, 26))	('metastases', 'Disease', 'MESH:D009362', (95, 105))	('translation', 'biological_process', 'GO:0006412', ('62', '73'))
46692	33173970	Of note, EIF1AX mutations seem to exert a synergistic effect on Ras mutations in certain types of tumours, such as ovary and thyroid.	('synergistic effect', 'Reg', (42, 60))	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('EIF1AX', 'Gene', '1964', (9, 15))	('EIF1AX', 'Gene', (9, 15))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (68, 77))	('mutations', 'Var', (16, 25))	('tumours', 'Disease', 'MESH:D009369', (98, 105))	('tumours', 'Disease', (98, 105))	('thyroid', 'Disease', (125, 132))	('ovary', 'Disease', (115, 120))	('ovary', 'Disease', 'MESH:D010051', (115, 120))	('Ras', 'Gene', (64, 67))
46698	33173970	Urtatiz and Van Raamsdonk proposed that reduced EDNRB receptor expression causes signalling dysregulation mediated by Wt variants and GNAQ/GNA11 mutants.	('mutants', 'Var', (145, 152))	('GNA11', 'Gene', '2767', (139, 144))	('GNA11', 'Gene', (139, 144))	('variants', 'Var', (121, 129))	('GNAQ', 'Gene', (134, 138))	('signalling dysregulation', 'MPA', (81, 105))	('EDNRB', 'Gene', (48, 53))	('expression', 'MPA', (63, 73))	('EDNRB', 'Gene', '1910', (48, 53))	('reduced', 'NegReg', (40, 47))	('signalling', 'biological_process', 'GO:0023052', ('81', '91'))	('GNAQ', 'Gene', '2776', (134, 138))
46699	33173970	However, in the study by Van Raamsdonk et al, it was observed that patients without GNAQ or GNA11 mutations exhibited a worse prognosis.	('GNA11', 'Gene', (92, 97))	('patients', 'Species', '9606', (67, 75))	('GNAQ', 'Gene', (84, 88))	('GNA11', 'Gene', '2767', (92, 97))	('mutations', 'Var', (98, 107))	('GNAQ', 'Gene', '2776', (84, 88))
46700	33173970	Thus, lower EDNRB expression could be beneficial for patients with mutations in both proteins through their interference with the cell signalling cascade.	('lower', 'NegReg', (6, 11))	('patients', 'Species', '9606', (53, 61))	('EDNRB', 'Gene', '1910', (12, 17))	('mutations', 'Var', (67, 76))	('cell signalling cascade', 'Pathway', (130, 153))	('signalling cascade', 'biological_process', 'GO:0007165', ('135', '153'))	('expression', 'MPA', (18, 28))	('interference', 'NegReg', (108, 120))	('EDNRB', 'Gene', (12, 17))
46721	33173970	These authors also noted that the inhibition of the Notch pathway partially reduced Erk and Akt phosphorylation, suggesting a need to gain further insight into these targets to delay or avoid tumour dissemination.	('reduced Erk', 'Phenotype', 'HP:0000654', (76, 87))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('inhibition', 'Var', (34, 44))	('Akt', 'Gene', '207', (92, 95))	('phosphorylation', 'biological_process', 'GO:0016310', ('96', '111'))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('Erk', 'Gene', (84, 87))	('Erk', 'molecular_function', 'GO:0004707', ('84', '87'))	('reduced', 'NegReg', (76, 83))	('tumour', 'Disease', (192, 198))	('Akt', 'Gene', (92, 95))	('Erk', 'Gene', '5594', (84, 87))	('Notch pathway', 'Pathway', (52, 65))
46724	33173970	In their study, the inhibition of this molecule and of VEGF was found to reduce the angiogenic potential of these tumours.	('tumours', 'Disease', 'MESH:D009369', (114, 121))	('VEGF', 'Gene', (55, 59))	('tumours', 'Disease', (114, 121))	('inhibition', 'Var', (20, 30))	('VEGF', 'Gene', '7422', (55, 59))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('reduce', 'NegReg', (73, 79))
46736	33173970	To date, it has been established that oxidative stress can induce a carcinogenic process in early disease stages.	('oxidative stress', 'Var', (38, 54))	('oxidative stress', 'Phenotype', 'HP:0025464', (38, 54))	('induce', 'Reg', (59, 65))	('carcinogenic process', 'Disease', 'MESH:D016301', (68, 88))	('carcinogenic process', 'Disease', (68, 88))
46745	33173970	The hypermethylation of the most significant CpG islands through tumour gene suppressor inactivation takes place in numerous cancers including uveal melanoma.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('numerous cancers', 'Disease', 'MESH:D009369', (116, 132))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('numerous cancers', 'Disease', (116, 132))	('hypermethylation', 'Var', (4, 20))	('uveal melanoma', 'Disease', 'MESH:C536494', (143, 157))	('uveal melanoma', 'Phenotype', 'HP:0007716', (143, 157))	('tumour', 'Disease', (65, 71))	('inactivation', 'Var', (88, 100))	('uveal melanoma', 'Disease', (143, 157))
46746	33173970	For example, it is common to observe the hypermethylation of the RASSF1a (Ras association domain family 1 isoform A) gene promotor region in uveal melanoma tumours.	('hypermethylation', 'Var', (41, 57))	('uveal melanoma tumours', 'Disease', (141, 163))	('uveal melanoma', 'Phenotype', 'HP:0007716', (141, 155))	('RASSF1a', 'Gene', '11186', (65, 72))	('RASSF1a', 'Gene', (65, 72))	('uveal melanoma tumours', 'Disease', 'MESH:C536494', (141, 163))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumours', 'Phenotype', 'HP:0002664', (156, 163))
46747	33173970	This gene also appears methylated in a wide variety of tumours, such as cutaneous melanoma, and lung, liver, breast or head and neck cancer, among others, and is a factor for a worse prognosis directly correlated with tumour progression.	('tumour', 'Disease', (55, 61))	('cutaneous melanoma', 'Disease', (72, 90))	('lung', 'Disease', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('liver', 'Disease', (102, 107))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (72, 90))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (72, 90))	('breast', 'Disease', (109, 115))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('tumour', 'Disease', 'MESH:D009369', (218, 224))	('tumour', 'Disease', (218, 224))	('tumours', 'Disease', (55, 62))	('methylated', 'Var', (23, 33))	('cancer', 'Disease', (133, 139))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('head and neck cancer', 'Phenotype', 'HP:0012288', (119, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumours', 'Disease', 'MESH:D009369', (55, 62))	('neck', 'cellular_component', 'GO:0044326', ('128', '132'))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))
46748	33173970	Maat et al examined the role of Ras and EF-hand domain containing (RASEF) as a tumour suppressor gene in 11 uveal melanoma cell lines and 35 samples of primary uveal melanoma, and found that homozygosity in conjunction with hypermethylation was the mechanism whereby RASEF expression was lost, which was associated with a lower survival rate.	('lower', 'NegReg', (322, 327))	('uveal melanoma', 'Disease', 'MESH:C536494', (108, 122))	('RASEF', 'Gene', '158158', (267, 272))	('uveal melanoma', 'Disease', (108, 122))	('survival', 'MPA', (328, 336))	('homozygosity', 'Var', (191, 203))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('RASEF', 'Gene', '158158', (67, 72))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('RASEF', 'Gene', (267, 272))	('uveal melanoma', 'Disease', 'MESH:C536494', (160, 174))	('uveal melanoma', 'Disease', (160, 174))	('RASEF', 'Gene', (67, 72))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('lost', 'NegReg', (288, 292))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('uveal melanoma', 'Phenotype', 'HP:0007716', (160, 174))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))	('expression', 'MPA', (273, 283))
46750	33173970	Of note, it has been observed that this hypermethylation of p16 leads to the phosphorylation of the retinoblastoma protein, which is key for controlling the cell cycle.	('phosphorylation', 'MPA', (77, 92))	('p16', 'Gene', (60, 63))	('retinoblastoma', 'Disease', 'MESH:D012175', (100, 114))	('retinoblastoma', 'Disease', (100, 114))	('cell cycle', 'biological_process', 'GO:0007049', ('157', '167'))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('p16', 'Gene', '1029', (60, 63))	('hypermethylation', 'Var', (40, 56))	('retinoblastoma', 'Phenotype', 'HP:0009919', (100, 114))	('leads to', 'Reg', (64, 72))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))
46752	33173970	Gene hypomethylation is a less frequent epigenetic mechanism than hypermethylation and yet has been related to increased gene expression involved in these PRAME mechanisms or those of the gene deleted in split hand/split foot 1 (DSS1).	('split foot', 'Phenotype', 'HP:0001839', (215, 225))	('increased', 'PosReg', (111, 120))	('split hand', 'Phenotype', 'HP:0001171', (204, 214))	('PRAME', 'Gene', '23532', (155, 160))	('Gene hypomethylation', 'Var', (0, 20))	('PRAME', 'Gene', (155, 160))	('deleted in split hand/split foot 1', 'Gene', (193, 227))	('DSS1', 'Gene', '7979', (229, 233))	('gene expression', 'MPA', (121, 136))	('deleted in split hand/split foot 1', 'Gene', '7979', (193, 227))	('gene expression', 'biological_process', 'GO:0010467', ('121', '136'))	('DSS1', 'Gene', (229, 233))
46753	33173970	Notably, it is known that the DNA methylation patterns present in M3 tumours with abnormal BAP1 differ from those of D3, which, in turn, also differ between each other according to whether their mutation affects EIF1AX or SF3B1/SRFR2.	('tumours', 'Disease', (69, 76))	('BAP1', 'Gene', (91, 95))	('affects', 'Reg', (204, 211))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('differ', 'Reg', (142, 148))	('SF3B1', 'Gene', '23451', (222, 227))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('mutation', 'Var', (195, 203))	('BAP1', 'Gene', '8314', (91, 95))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('DNA methylation', 'biological_process', 'GO:0006306', ('30', '45'))	('EIF1AX', 'Gene', '1964', (212, 218))	('EIF1AX', 'Gene', (212, 218))	('abnormal', 'Var', (82, 90))	('SF3B1', 'Gene', (222, 227))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
46754	33173970	The dysregulation of these mechanisms can lead to the inappropriate activation of oncogenes or in the inactivation of tumour suppressor genes making this an important line of study in the field of cancer.	('inactivation', 'NegReg', (102, 114))	('tumour', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('dysregulation', 'Var', (4, 17))	('cancer', 'Disease', (197, 203))	('activation', 'PosReg', (68, 78))	('oncogenes', 'Protein', (82, 91))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('tumour', 'Disease', 'MESH:D009369', (118, 124))
46755	33173970	In uveal melanoma, the overexpression of transcription factors, such as HES1 has been directly involved in the metastatic capacity of uveal melanoma, suggesting the methylation of the promotor region of histone H3K4 is an inducer of this over-expression.	('transcription', 'biological_process', 'GO:0006351', ('41', '54'))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('methylation', 'biological_process', 'GO:0032259', ('165', '176'))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('HES1', 'Gene', '3280', (72, 76))	('methylation', 'Var', (165, 176))	('uveal melanoma', 'Disease', 'MESH:C536494', (134, 148))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Phenotype', 'HP:0007716', (134, 148))	('uveal melanoma', 'Disease', (134, 148))	('HES1', 'Gene', (72, 76))	('involved', 'Reg', (95, 103))	('uveal melanoma', 'Disease', (3, 17))
46759	33173970	For example, it is known that miRNAs are a key epigenetic mechanism for the control of gene transcription and may act in some cancer types as tumour suppressors and in others as oncogenes.	('tumour', 'Disease', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('act', 'Reg', (114, 117))	('gene transcription', 'MPA', (87, 105))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('miRNAs', 'Var', (30, 36))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('transcription', 'biological_process', 'GO:0006351', ('92', '105'))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('control', 'MPA', (76, 83))
46775	33173970	In addition, Liu et al described the role of miR-216a-5p as an indicator of a better prognosis due to its inhibitory effect on hexokinase 2, an enzyme overexpressed in a wide array of tumours that is directly related to induction of the Warburg effect.	('array of tumours', 'Disease', 'MESH:D009369', (175, 191))	('miR-216a-5p', 'Var', (45, 56))	('hexokinase 2', 'Gene', (127, 139))	('inhibitory effect', 'NegReg', (106, 123))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('array of tumours', 'Disease', (175, 191))	('hexokinase 2', 'Gene', '3099', (127, 139))	('tumours', 'Phenotype', 'HP:0002664', (184, 191))
46776	33173970	Therapy, pursuing the dysregulation of these miRNAs is a promising approach for the treatment of this type of cancer.	('dysregulation', 'Var', (22, 35))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))
46795	33173970	The results served to define a panel of 6 miRNAs (miR-16, miR-145, miR-146a, miR-204, miR-211 and miR-363-3p) that could be used for a precision diagnosis of uveal melanoma with 93% sensitivity and 100% specificity.	('miR-146a', 'Gene', (67, 75))	('miR-211', 'Gene', (86, 93))	('miR-204', 'Gene', (77, 84))	('miR-363-3p', 'Var', (98, 108))	('miR-211', 'Gene', '406993', (86, 93))	('miR-146a', 'Gene', '406938', (67, 75))	('uveal melanoma', 'Disease', 'MESH:C536494', (158, 172))	('miR-145', 'Gene', (58, 65))	('miR-16', 'Gene', (50, 56))	('miR-204', 'Gene', '406987', (77, 84))	('miR-145', 'Gene', '406937', (58, 65))	('uveal melanoma', 'Phenotype', 'HP:0007716', (158, 172))	('uveal melanoma', 'Disease', (158, 172))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('miR-16', 'Gene', '51573', (50, 56))
46818	33173970	The genetic analysis of melanocyte lesions has identified that extraocular invasion is related to both the inactivation of the tumour suppressor gene, BAP1 (detected in 85% of cases), and to monosomy 3, as the main risk factors for disease spread.	('BAP1', 'Gene', (151, 155))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('extraocular invasion', 'CPA', (63, 83))	('inactivation', 'Var', (107, 119))	('monosomy 3', 'Var', (191, 201))	('tumour', 'Disease', (127, 133))	('BAP1', 'Gene', '8314', (151, 155))
46824	33173970	As previously stated, genetic mutations and chromosome abnormalities are also directly associated with patient outcomes and shed light into the prognosis of uveal melanoma.	('chromosome abnormalities', 'Disease', 'MESH:D002869', (44, 68))	('chromosome', 'cellular_component', 'GO:0005694', ('44', '54'))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('genetic mutations', 'Var', (22, 39))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (44, 68))	('associated', 'Reg', (87, 97))	('chromosome abnormalities', 'Disease', (44, 68))	('patient', 'Species', '9606', (103, 110))	('uveal melanoma', 'Disease', 'MESH:C536494', (157, 171))	('uveal melanoma', 'Phenotype', 'HP:0007716', (157, 171))	('uveal melanoma', 'Disease', (157, 171))
46827	33173970	FISH, such as CGH is more accurate in detecting chromosome aberrations in uveal melanoma; however, it is still insufficient for the detection of all chromosome modifications.	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('chromosome', 'cellular_component', 'GO:0005694', ('48', '58'))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('uveal melanoma', 'Disease', (74, 88))	('chromosome aberrations', 'Var', (48, 70))	('chromosome', 'cellular_component', 'GO:0005694', ('149', '159'))
46830	33173970	Additionally, whole genome sequencing (WGS) can provide substantial information in uveal melanoma and microarray analysis can also offer whole genome data, partial chromosome defects, loss of heterozygosity or additional challenges not detected by FISH.	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('uveal melanoma', 'Disease', (83, 97))	('loss of heterozygosity', 'Var', (184, 206))	('chromosome', 'cellular_component', 'GO:0005694', ('164', '174'))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('chromosome defects', 'Disease', 'MESH:D002869', (164, 182))	('chromosome defects', 'Disease', (164, 182))	('uveal melanoma', 'Disease', 'MESH:C536494', (83, 97))
46850	33173970	This poor response may be attributed to resistance due to the high tumour burden or to a low mutation rate conferring scarce antigenic induction and therefore a poor immune response.	('antigenic induction', 'MPA', (125, 144))	('high tumour', 'Disease', (62, 73))	('high tumour', 'Disease', 'MESH:D009369', (62, 73))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('poor immune', 'Phenotype', 'HP:0002721', (161, 172))	('immune response', 'biological_process', 'GO:0006955', ('166', '181'))	('mutation', 'Var', (93, 101))
46857	33173970	Likewise, molecular targeting mayh be one of the most promising therapies for the management of uveal melanoma.	('uveal melanoma', 'Disease', (96, 110))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('molecular targeting', 'Var', (10, 29))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('uveal melanoma', 'Disease', 'MESH:C536494', (96, 110))
46864	33173970	Importantly, by inhibiting the acetylation of histones, it is possible to reverse the effects of the loss of BAP1 through its effects on the cell cycle, leading to a less aggressive differentiated state.	('histones', 'Protein', (46, 54))	('loss', 'Var', (101, 105))	('less aggressive differentiated state', 'CPA', (166, 202))	('BAP1', 'Gene', '8314', (109, 113))	('cell cycle', 'CPA', (141, 151))	('cell cycle', 'biological_process', 'GO:0007049', ('141', '151'))	('acetylation', 'MPA', (31, 42))	('BAP1', 'Gene', (109, 113))	('inhibiting', 'NegReg', (16, 26))
46869	33173970	Of note, spliceosome inhibitors may also be useful in BAP1 mutant tumours, as they promote c-Myc expression, increasing susceptibility to this therapy.	('spliceosome', 'cellular_component', 'GO:0005681', ('9', '20'))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('mutant', 'Var', (59, 65))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('c-Myc', 'Gene', '4609', (91, 96))	('BAP1', 'Gene', '8314', (54, 58))	('c-Myc', 'Gene', (91, 96))	('promote', 'PosReg', (83, 90))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('tumours', 'Disease', (66, 73))	('BAP1', 'Gene', (54, 58))	('expression', 'MPA', (97, 107))
46871	33173970	Another undergoing clinical trial involves studying the role of niraparib in patients with uveal melanoma and other tumours featuring BAP1 mutations (NCT03207347), and PRAME is also being targeted in metastatic uveal melanoma through a PRAME-TCR construct (NCT02743611).	('PRAME', 'Gene', '23532', (168, 173))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('PRAME', 'Gene', (168, 173))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('uveal melanoma', 'Disease', 'MESH:C536494', (91, 105))	('uveal melanoma', 'Disease', (211, 225))	('uveal melanoma', 'Disease', 'MESH:C536494', (211, 225))	('tumours', 'Disease', 'MESH:D009369', (116, 123))	('uveal melanoma', 'Disease', (91, 105))	('BAP1', 'Gene', '8314', (134, 138))	('uveal melanoma', 'Phenotype', 'HP:0007716', (211, 225))	('patients', 'Species', '9606', (77, 85))	('uveal melanoma', 'Phenotype', 'HP:0007716', (91, 105))	('PRAME', 'Gene', '23532', (236, 241))	('PRAME', 'Gene', (236, 241))	('BAP1', 'Gene', (134, 138))	('mutations', 'Var', (139, 148))	('TCR', 'cellular_component', 'GO:0042101', ('242', '245'))	('tumours', 'Disease', (116, 123))	('niraparib', 'Chemical', 'MESH:C545685', (64, 73))	('TCR', 'biological_process', 'GO:0006283', ('242', '245'))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))
46875	33173970	The study of novel biological mechanisms possibly involved in uveal melanoma is also a key point for the design of new drugs directed towards targets, such as tumour hypoxia responses mediated by HIF-1alpha or epigenetic regulation driven by miRNAs.	('HIF-1alpha', 'Gene', (196, 206))	('regulation', 'biological_process', 'GO:0065007', ('221', '231'))	('uveal melanoma', 'Disease', (62, 76))	('tumour hypoxia', 'Disease', (159, 173))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('tumour hypoxia', 'Disease', 'MESH:D000860', (159, 173))	('HIF-1alpha', 'Gene', '3091', (196, 206))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('epigenetic regulation', 'Var', (210, 231))	('uveal melanoma', 'Phenotype', 'HP:0007716', (62, 76))	('uveal melanoma', 'Disease', 'MESH:C536494', (62, 76))
46885	33138697	MiR-9-5p Inhibits the Proliferation, Migration and Invasion of Choroidal Melanoma by Targeting BRAF According to different reports, miR-9-5p either facilitates or suppresses the occurrence of tumors.	('Choroidal Melanoma', 'Disease', (63, 81))	('Inhibits', 'NegReg', (9, 17))	('suppresses', 'NegReg', (163, 173))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('Choroidal Melanoma', 'Disease', 'MESH:D008545', (63, 81))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('MiR-9-5p', 'Chemical', '-', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('Invasion', 'CPA', (51, 59))	('Migration', 'CPA', (37, 46))	('facilitates', 'PosReg', (148, 159))	('BRAF', 'Gene', (95, 99))	('Choroidal Melanoma', 'Phenotype', 'HP:0012054', (63, 81))	('Proliferation', 'CPA', (22, 35))	('miR-9-5p', 'Var', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
46887	33138697	The present study aimed to reveal the mechanism of action of miR-9-5p and BRAF in choroidal melanoma (CM).	('CM', 'Chemical', '-', (102, 104))	('BRAF', 'Gene', (74, 78))	('miR-9-5p', 'Var', (61, 69))	('choroidal melanoma', 'Disease', 'MESH:D008545', (82, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('choroidal melanoma', 'Disease', (82, 100))	('CM', 'Phenotype', 'HP:0012054', (102, 104))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (82, 100))
46889	33138697	EdU assay and Transwell assay, respectively, showed the proliferation, migration and invasion of CM cells after transfection with miR-9-5p mimics and inhibitor.	('invasion of CM cells', 'CPA', (85, 105))	('miR-9-5p', 'Var', (130, 138))	('CM', 'Phenotype', 'HP:0012054', (97, 99))	('proliferation', 'CPA', (56, 69))	('migration', 'CPA', (71, 80))	('CM', 'Chemical', '-', (97, 99))
46891	33138697	Overexpressing BRAF and transfecting miR-9-5p mimics into choroidal melanoma cells confirmed the interaction between miR-9-5p and BRAF.	('choroidal melanoma', 'Phenotype', 'HP:0012054', (58, 76))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('choroidal melanoma', 'Disease', 'MESH:D008545', (58, 76))	('BRAF', 'Gene', (130, 134))	('interaction', 'Interaction', (97, 108))	('miR-9-5p', 'Var', (117, 125))	('choroidal melanoma', 'Disease', (58, 76))
46892	33138697	miR-9-5p could bind to the BRAF mRNA 3'UTR and inhibit the transcription and translation of BRAF, thereby suppressing the proliferation, migration and invasion of CM cell lines.	('translation', 'biological_process', 'GO:0006412', ('77', '88'))	('CM', 'Phenotype', 'HP:0012054', (163, 165))	('transcription', 'biological_process', 'GO:0006351', ('59', '72'))	('UTR', 'Gene', '2837', (39, 42))	('miR-9-5p', 'Var', (0, 8))	('suppressing', 'NegReg', (106, 117))	('translation', 'MPA', (77, 88))	('BRAF', 'Gene', (92, 96))	('transcription', 'MPA', (59, 72))	('invasion of CM cell lines', 'CPA', (151, 176))	('UTR', 'Gene', (39, 42))	('CM', 'Chemical', '-', (163, 165))	('inhibit', 'NegReg', (47, 54))	('migration', 'CPA', (137, 146))	('proliferation', 'CPA', (122, 135))
46893	33138697	Moreover, silencing BRAF inhibited the progression of CM cells.	('progression of CM cells', 'CPA', (39, 62))	('CM', 'Chemical', '-', (54, 56))	('CM', 'Phenotype', 'HP:0012054', (54, 56))	('inhibited', 'NegReg', (25, 34))	('BRAF', 'Gene', (20, 24))	('silencing', 'Var', (10, 19))
46896	33138697	Thus, our study suggests that miR-9-5p, BRAF and their interaction may act as potential therapeutic targets for CM.	('CM', 'Chemical', '-', (112, 114))	('interaction', 'Interaction', (55, 66))	('CM', 'Phenotype', 'HP:0012054', (112, 114))	('miR-9-5p', 'Var', (30, 38))
46899	33138697	Choroidal melanoma (CM) is fatal in approximately 50% of patients, and while the mechanism of CM is not yet clear, numerous researchers infer that chromosomal aberrations, genetic mutations and activation of cell signaling pathways may initiate this tumor.	('signaling', 'biological_process', 'GO:0023052', ('213', '222'))	('CM', 'Phenotype', 'HP:0012054', (94, 96))	('chromosomal aberrations', 'Var', (147, 170))	('patients', 'Species', '9606', (57, 65))	('Choroidal melanoma', 'Phenotype', 'HP:0012054', (0, 18))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (147, 170))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('CM', 'Chemical', '-', (94, 96))	('Choroidal melanoma', 'Disease', (0, 18))	('CM', 'Phenotype', 'HP:0012054', (20, 22))	('cell signaling pathways', 'Pathway', (208, 231))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('Choroidal melanoma', 'Disease', 'MESH:D008545', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('tumor', 'Disease', (250, 255))	('genetic mutations', 'Var', (172, 189))	('CM', 'Chemical', '-', (20, 22))
46911	33138697	Since 2002, scholars have successively shown that high frequency BRAF mutations exist in melanoma, and the most common mutation is the mutation from T to A at a single site in the exon 15 kinase domain.	('mutations', 'Var', (70, 79))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('mutation', 'Var', (135, 143))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
46923	33138697	The above RNA sequences were as follows: si-BRAF-1, 5'-GCAGAUUACAG UGGGACAATT-3'; si-BRAF-2, 5'-CCAUAUCAUUGAGACCAAATT-3'; miR-9-5p mimics, 5'-UCUUUGGUUAUCUAGCUGUAUGA-3'; miR-9-5p NC, 5'-UUCUCCGAA CGUGUCACGUTT-3'; miR-9-5p inhibitor, 5'-UCAUACAGCUAGAUAACCAAAGA-3'; and miR-9-5p inhibitor NC, 5'-CAGUACUUUUGUGUAGUACAA-3'.	('RNA', 'cellular_component', 'GO:0005562', ('10', '13'))	('BRAF-2', 'Gene', '286494', (85, 91))	('BRAF-1', 'Gene', (44, 50))	('miR-9-5p inhibitor', 'Var', (268, 286))	('BRAF-2', 'Gene', (85, 91))	('BRAF-1', 'Gene', '673', (44, 50))
46929	33138697	5174s, CST, USA) antibodies overnight at 4 C. The membranes were washed with TBST 3 times for 5 min and incubated with the appropriate secondary antibody for 1 h at 37 C. After the membranes were washed 3 times with TBST, the specific proteins were detected by microchemistry 4.2 (Bio-Rad, CA, USA).	('antibody', 'cellular_component', 'GO:0019815', ('145', '153'))	('antibody', 'cellular_component', 'GO:0019814', ('145', '153'))	('antibody', 'molecular_function', 'GO:0003823', ('145', '153'))	('Rad', 'biological_process', 'GO:1990116', ('285', '288'))	('CST', 'Gene', (7, 10))	('5174s', 'Var', (0, 5))	('antibody', 'cellular_component', 'GO:0042571', ('145', '153'))	('CST', 'Gene', '106478911', (7, 10))
46939	33138697	These results confirm that miR-9-5p inhibits the proliferation of CM cells.	('CM', 'Chemical', '-', (66, 68))	('miR-9-5p', 'Var', (27, 35))	('inhibits', 'NegReg', (36, 44))	('proliferation of CM cells', 'CPA', (49, 74))	('CM', 'Phenotype', 'HP:0012054', (66, 68))
46942	33138697	This evidence strongly suggests that miR-9-5p inhibits the migration and invasion of CM cells.	('CM', 'Phenotype', 'HP:0012054', (85, 87))	('CM', 'Chemical', '-', (85, 87))	('miR-9-5p', 'Var', (37, 45))	('inhibits', 'NegReg', (46, 54))
46944	33138697	Through the TargetScan algorithm (http://www.targetscan.org/vert_71/), a conserved binding site for miR-9-5p within the BRAF mRNA 3'UTR was found.	('UTR', 'Gene', (132, 135))	('binding', 'Interaction', (83, 90))	('miR-9-5p', 'Var', (100, 108))	('binding', 'molecular_function', 'GO:0005488', ('83', '90'))	('UTR', 'Gene', '2837', (132, 135))
46945	33138697	To further explore the relationship between miR-9-5p and BRAF, we constructed BRAF 3'UTR wild-type (WT) and mutant (MUT) luciferase reporter vectors (Figure 3A).	("BRAF 3'UTR", 'Gene', '2837', (78, 88))	("BRAF 3'UTR", 'Gene', (78, 88))	('mutant', 'Var', (108, 114))
46952	33138697	Compared to the NC group, knockdown of BRAF with 2 siRNAs significantly suppressed the proliferation ability of MUM-2B (P < 0.05) (Figure 4C and E) and MUM-2C cells (P < 0.05) (Figure 4D and E).	('MUM-2B', 'Gene', (112, 118))	('proliferation ability', 'CPA', (87, 108))	('UM', 'Phenotype', 'HP:0007716', (153, 155))	('knockdown', 'Var', (26, 35))	('MUM-2C', 'CellLine', 'CVCL:3448', (152, 158))	('suppressed', 'NegReg', (72, 82))	('UM', 'Phenotype', 'HP:0007716', (113, 115))
46953	33138697	Then, Transwell assays were carried out to reveal the changes in the migration and invasion of MUM-2B and MUM-2C cells with BRAF knockdown.	('UM', 'Phenotype', 'HP:0007716', (107, 109))	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('knockdown', 'Var', (129, 138))	('migration', 'CPA', (69, 78))	('invasion', 'CPA', (83, 91))	('MUM-2C', 'CellLine', 'CVCL:3448', (106, 112))
46959	33138697	Taking the above results into account, we confirmed that miR-9-5p inhibits the proliferation and migration of CM cells by targeting BRAF.	('BRAF', 'Gene', (132, 136))	('CM', 'Phenotype', 'HP:0012054', (110, 112))	('targeting', 'Reg', (122, 131))	('inhibits', 'NegReg', (66, 74))	('CM', 'Chemical', '-', (110, 112))	('miR-9-5p', 'Var', (57, 65))
46968	33138697	In addition, accumulating reports have also found that miRNAs play a key role in the proliferation, metabolism and apoptosis of UM ; for example, miR-296-3p and FOXCUT act as tumor supressor of CM by jointly targeting MMP-2 and MMP-9.	('MMP-9', 'Gene', '4318', (228, 233))	('MMP-9', 'Gene', (228, 233))	('FOXCUT', 'Gene', '101927703', (161, 167))	('MMP-2', 'Gene', '4313', (218, 223))	('apoptosis', 'biological_process', 'GO:0097194', ('115', '124'))	('apoptosis', 'biological_process', 'GO:0006915', ('115', '124'))	('CM', 'Chemical', '-', (194, 196))	('targeting', 'Reg', (208, 217))	('tumor', 'Disease', (175, 180))	('miR-296-3p', 'Var', (146, 156))	('UM', 'Phenotype', 'HP:0007716', (128, 130))	('CM', 'Phenotype', 'HP:0012054', (194, 196))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('MMP-9', 'molecular_function', 'GO:0004229', ('228', '233'))	('MMP-2', 'Gene', (218, 223))	('FOXCUT', 'Gene', (161, 167))	('metabolism', 'biological_process', 'GO:0008152', ('100', '110'))	('MMP-2', 'molecular_function', 'GO:0004228', ('218', '223'))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
46969	33138697	Recent reports have indicated that miR-9-5p plays an important role in numerous tumors, such as gastric cancer, metastatic renal cell carcinoma and pancreatic cancer, regulating the proliferation, migration, invasion and other functions of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('renal cell carcinoma', 'Disease', (123, 143))	('pancreatic cancer', 'Disease', 'MESH:D010190', (148, 165))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (123, 143))	('tumors', 'Disease', (80, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))	('proliferation', 'CPA', (182, 195))	('tumor', 'Disease', (240, 245))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('pancreatic cancer', 'Disease', (148, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('migration', 'CPA', (197, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('invasion', 'CPA', (208, 216))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('tumor', 'Disease', (80, 85))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (123, 143))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (148, 165))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('regulating', 'Reg', (167, 177))	('miR-9-5p', 'Var', (35, 43))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('gastric cancer', 'Disease', (96, 110))
46971	33138697	In addition, miR-9-5p could inhibit the migration and invasion of colorectal cancer by targeting FOXP2 and then inhibit metastasis and the EMT process.	('EMT process', 'CPA', (139, 150))	('invasion', 'CPA', (54, 62))	('miR-9-5p', 'Var', (13, 21))	('inhibit', 'NegReg', (112, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('EMT', 'biological_process', 'GO:0001837', ('139', '142'))	('targeting', 'Reg', (87, 96))	('metastasis', 'CPA', (120, 130))	('migration', 'CPA', (40, 49))	('FOXP2', 'Gene', (97, 102))	('colorectal cancer', 'Disease', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('FOXP2', 'Gene', '93986', (97, 102))	('inhibit', 'NegReg', (28, 35))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
46972	33138697	Studies have shown that miR-9-5p has dual functions in different tumors.	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('miR-9-5p', 'Var', (24, 32))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
46973	33138697	So far, the regulatory effect of miR-9-5p in CM has not been reported, so we hypothesized that miR-9-5p may play a key role in CM cell proliferation, migration and invasion.	('CM', 'Chemical', '-', (127, 129))	('CM', 'Phenotype', 'HP:0012054', (45, 47))	('cell proliferation', 'biological_process', 'GO:0008283', ('130', '148'))	('CM', 'Chemical', '-', (45, 47))	('invasion', 'CPA', (164, 172))	('CM', 'Phenotype', 'HP:0012054', (127, 129))	('migration', 'CPA', (150, 159))	('miR-9-5p', 'Var', (95, 103))
46974	33138697	In the present study, we discovered that miR-9-5p influenced the progression of CM cells.	('CM', 'Phenotype', 'HP:0012054', (80, 82))	('influenced', 'Reg', (50, 60))	('miR-9-5p', 'Var', (41, 49))	('CM', 'Chemical', '-', (80, 82))	('progression of CM cells', 'CPA', (65, 88))
46975	33138697	The EdU assay showed that miR-9-5p mimics could inhibit the proliferation of CM cells, while the miR-9-5p inhibitor could enhance the proliferation of CM cells.	('CM', 'Chemical', '-', (151, 153))	('enhance', 'PosReg', (122, 129))	('proliferation of CM cells', 'CPA', (60, 85))	('CM', 'Phenotype', 'HP:0012054', (77, 79))	('CM', 'Phenotype', 'HP:0012054', (151, 153))	('miR-9-5p', 'Var', (97, 105))	('proliferation', 'CPA', (134, 147))	('CM', 'Chemical', '-', (77, 79))	('inhibit', 'NegReg', (48, 55))
46976	33138697	Consequently, miR-9-5p may suppress the proliferation, migration and invasion of CM.	('migration', 'CPA', (55, 64))	('invasion of CM', 'CPA', (69, 83))	('miR-9-5p', 'Var', (14, 22))	('CM', 'Phenotype', 'HP:0012054', (81, 83))	('suppress', 'NegReg', (27, 35))	('proliferation', 'CPA', (40, 53))	('CM', 'Chemical', '-', (81, 83))
46978	33138697	Comprehensive analysis of the above evidence suggests that miR-9-5p is likely to exert a regulatory effect on CM cells by directly targeting BRAF.	('BRAF', 'Gene', (141, 145))	('CM', 'Phenotype', 'HP:0012054', (110, 112))	('CM', 'Chemical', '-', (110, 112))	('miR-9-5p', 'Var', (59, 67))	('targeting', 'Reg', (131, 140))
46979	33138697	The most common mutation of BRAF is V600E, which is most frequently present in melanoma.	('V600E', 'Mutation', 'rs113488022', (36, 41))	('V600E', 'Var', (36, 41))	('BRAF', 'Gene', (28, 32))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
46981	33138697	Colorectal cancer with the BRAF V600E mutation can be effectively treated by combining inhibitors of BRAF, MEK and EGFR proteins.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('BRAF', 'Protein', (101, 105))	('V600E', 'Mutation', 'rs113488022', (32, 37))	('EGFR', 'Gene', '1956', (115, 119))	('MEK', 'Protein', (107, 110))	('EGFR', 'molecular_function', 'GO:0005006', ('115', '119'))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('V600E', 'Var', (32, 37))	('EGFR', 'Gene', (115, 119))	('BRAF', 'Gene', (27, 31))	('Colorectal cancer', 'Disease', (0, 17))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))
46982	33138697	Then, we explored the effect of BRAF on CM cells by transfecting siRNAs into cells and detected the proliferation, migration and invasion of cells.	('migration', 'CPA', (115, 124))	('invasion', 'CPA', (129, 137))	('transfecting', 'Var', (52, 64))	('CM', 'Phenotype', 'HP:0012054', (40, 42))	('CM', 'Chemical', '-', (40, 42))
46983	33138697	The results indicated that silencing BRAF inhibited the progression of CM cells.	('silencing', 'Var', (27, 36))	('CM', 'Phenotype', 'HP:0012054', (71, 73))	('BRAF', 'Gene', (37, 41))	('inhibited', 'NegReg', (42, 51))	('CM', 'Chemical', '-', (71, 73))	('progression of CM cells', 'CPA', (56, 79))
46985	33138697	This further indicated that miR-9-5p may possess negative regulatory functions in CM cells by targeting BRAF.	('negative regulatory', 'MPA', (49, 68))	('CM', 'Chemical', '-', (82, 84))	('miR-9-5p', 'Var', (28, 36))	('CM', 'Phenotype', 'HP:0012054', (82, 84))	('BRAF', 'Gene', (104, 108))	('targeting', 'Reg', (94, 103))
46986	33138697	In conclusion, our study proved that miR-9-5p may function as a tumor suppressor, inhibiting the proliferation, migration and invasion of CM cells by targeting BRAF.	('invasion of CM cells', 'CPA', (126, 146))	('BRAF', 'Gene', (160, 164))	('CM', 'Phenotype', 'HP:0012054', (138, 140))	('tumor', 'Disease', (64, 69))	('tumor suppressor', 'biological_process', 'GO:0051726', ('64', '80'))	('inhibiting', 'NegReg', (82, 92))	('targeting', 'Reg', (150, 159))	('proliferation', 'CPA', (97, 110))	('CM', 'Chemical', '-', (138, 140))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('64', '80'))	('migration', 'CPA', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('miR-9-5p', 'Var', (37, 45))
46989	33138697	Furthermore, due to the lack of clinical tissue samples, in subsequent experiments, we will focus on investigating the expression of miR-9-5p in choroidal melanoma tissues and its correlation with clinical characteristics.	('miR-9-5p', 'Var', (133, 141))	('choroidal melanoma', 'Disease', (145, 163))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (145, 163))	('choroidal melanoma', 'Disease', 'MESH:D008545', (145, 163))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))
46991	32481544	Inhibition of ATM Increases the Radiosensitivity of Uveal Melanoma Cells to Photons and Protons Treatment of uveal melanoma (UM) is generally successful, with local primary tumour control being at 90-95%.	('tumour', 'Disease', (173, 179))	('UM', 'Phenotype', 'HP:0007716', (125, 127))	('ATM', 'Gene', '472', (14, 17))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('Melanoma', 'Disease', 'MESH:D008545', (58, 66))	('Melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('Melanoma', 'Disease', (58, 66))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('Inhibition', 'Var', (0, 10))	('Radiosensitivity', 'MPA', (32, 48))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('ATM', 'Gene', (14, 17))	('Increases', 'PosReg', (18, 27))	('tumour', 'Disease', 'MESH:D009369', (173, 179))
47006	32481544	The important protein kinases that co-ordinate the signaling cascade and repair of DNA DSBs are ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR), and the DNA-dependent protein kinase (DNA-Pk), which stimulate repair through either non-homologous end-joining (ATM and DNA-Pk) or homologous recombination.	('ataxia', 'Phenotype', 'HP:0001251', (133, 139))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('telangiectasia', 'Phenotype', 'HP:0001009', (103, 117))	('DNA-Pk', 'Gene', '5591', (217, 223))	('DSBs', 'Chemical', '-', (87, 91))	('ATR', 'Gene', (173, 176))	('DNA', 'cellular_component', 'GO:0005574', ('217', '220'))	('DNA', 'cellular_component', 'GO:0005574', ('187', '190'))	('ATM', 'Gene', (127, 130))	('ataxia telangiectasia mutated', 'Gene', '472', (96, 125))	('ATM', 'Gene', (292, 295))	('DNA-Pk', 'Gene', (300, 306))	('signaling cascade', 'biological_process', 'GO:0007165', ('51', '68'))	('ataxia', 'Phenotype', 'HP:0001251', (96, 102))	('non-homologous', 'Var', (264, 278))	('telangiectasia', 'Phenotype', 'HP:0001009', (140, 154))	('DNA-dependent protein kinase', 'Gene', (187, 215))	('ATR', 'Gene', '545', (173, 176))	('homologous recombination', 'biological_process', 'GO:0035825', ('311', '335'))	('DNA', 'cellular_component', 'GO:0005574', ('300', '303'))	('protein', 'cellular_component', 'GO:0003675', ('201', '208'))	('DNA-Pk', 'Gene', '5591', (300, 306))	('DNA-dependent protein kinase', 'Gene', '5591', (187, 215))	('ataxia telangiectasia mutated', 'Gene', (96, 125))	('ataxia telangiectasia and Rad3 related', 'Gene', '545', (133, 171))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('ATM', 'Gene', '472', (127, 130))	('ATM', 'Gene', '472', (292, 295))	('DNA-Pk', 'Gene', (217, 223))	('Rad', 'biological_process', 'GO:1990116', ('159', '162'))
47008	32481544	Interestingly, in UM, there is recent evidence demonstrating that the DNA-Pk inhibitor, NU7026, can decrease the survival of UM cell lines (OMM1, OMM2.5, Mel270 and MM28) as a monotherapy.	('survival', 'CPA', (113, 121))	('UM', 'Phenotype', 'HP:0007716', (125, 127))	('DNA-Pk', 'Gene', '5591', (70, 76))	('DNA-Pk', 'Gene', (70, 76))	('UM', 'Phenotype', 'HP:0007716', (18, 20))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('decrease', 'NegReg', (100, 108))	('NU7026', 'Chemical', 'MESH:C479235', (88, 94))	('NU7026', 'Var', (88, 94))	('Mel270', 'Chemical', '-', (154, 160))
47009	32481544	Similarly, the survival of UM cells (SOM 157D and SOM 196B) was also significantly reduced using inhibitors of DNA-Pk (NU7026 and NU7441) alone, and there was limited data presented that SOM 196B displayed increased radiosensitivity in the presence of NU7026.	('radiosensitivity', 'CPA', (216, 232))	('UM', 'Phenotype', 'HP:0007716', (27, 29))	('DNA-Pk', 'Gene', (111, 117))	('NU7441', 'Chemical', 'MESH:C499693', (130, 136))	('reduced', 'NegReg', (83, 90))	('DNA-Pk', 'Gene', '5591', (111, 117))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (206, 232))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('NU7026', 'Chemical', 'MESH:C479235', (252, 258))	('NU7026', 'Chemical', 'MESH:C479235', (119, 125))	('NU7026', 'Var', (252, 258))	('survival', 'CPA', (15, 23))
47021	32481544	The same trend was observed in response to proton irradiation, where OMM2.5 and Mel270 were ~1.8-4.3-fold more radioresistant than OMM1 and 92.1 (Figure 1D,E).	('Mel270', 'Chemical', '-', (80, 86))	('Mel270', 'Var', (80, 86))	('more', 'PosReg', (106, 110))	('radioresistant', 'CPA', (111, 125))
47039	32481544	Inhibition of ATM using the inhibitor KU-59933 alone had no impact on the survival of UM cell lines by clonogenic assays (Figure 3A).	('UM', 'Phenotype', 'HP:0007716', (86, 88))	('ATM', 'Gene', '472', (14, 17))	('KU-59933', 'Var', (38, 46))	('KU-59933', 'Chemical', '-', (38, 46))	('ATM', 'Gene', (14, 17))
47040	32481544	This demonstrated that inhibiting ATM had no significant impact on the survival of UM cells as a monotherapy (p = 0.33-0.72; one-sample t-test).	('UM', 'Phenotype', 'HP:0007716', (83, 85))	('inhibiting', 'Var', (23, 33))	('ATM', 'Gene', '472', (34, 37))	('ATM', 'Gene', (34, 37))
47047	32481544	However, Mel270 also displayed a ~1.8-fold elevation in proton radiosensitivity (from 0-4 Gy).	('elevation', 'PosReg', (43, 52))	('Mel270', 'Chemical', '-', (9, 15))	('proton radiosensitivity', 'MPA', (56, 79))	('Mel270', 'Var', (9, 15))	('proton radiosensitivity', 'Phenotype', 'HP:0010997', (56, 79))
47060	32481544	Interestingly, there are recent studies suggesting that the inhibition of another kinase involved in DSB repair, DNA-Pk, as a monotherapy can reduce the survival of UM cell lines.	('UM', 'Phenotype', 'HP:0007716', (165, 167))	('DNA', 'cellular_component', 'GO:0005574', ('113', '116'))	('inhibition', 'Var', (60, 70))	('DSB', 'Chemical', '-', (101, 104))	('survival of UM cell lines', 'CPA', (153, 178))	('reduce', 'NegReg', (142, 148))	('DNA-Pk', 'Gene', '5591', (113, 119))	('DNA-Pk', 'Gene', (113, 119))
47091	32481544	For inhibition experiments, media containing 10 microM ATM inhibitor (KU-55933; Selleck Chemicals, Munich, Germany) or DMSO as a vehicle only control were added onto the monolayer cells for 1 h prior to irradiation.	('ATM', 'Gene', '472', (55, 58))	('DMSO', 'Chemical', 'MESH:D004121', (119, 123))	('KU-55933;', 'Var', (70, 79))	('KU-55933', 'Chemical', 'MESH:C495818', (70, 78))	('ATM', 'Gene', (55, 58))
47094	32481544	For inhibitor experiments, media containing 10 microM ATM inhibitor (KU-55933) or DMSO as a vehicle only control was added to the cells 1 h prior to trypsinization.	('ATM', 'Gene', (54, 57))	('DMSO', 'Chemical', 'MESH:D004121', (82, 86))	('KU-55933', 'Chemical', 'MESH:C495818', (69, 77))	('ATM', 'Gene', '472', (54, 57))	('KU-55933', 'Var', (69, 77))
47103	32481544	Whilst no correlation between ATM protein expression in UM tissue samples and an adverse patient outcome was found, inhibition of ATM in vitro was shown to be effective in potentiating the effects of photons and protons in reducing clonogenic survival.	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('patient', 'Species', '9606', (89, 96))	('inhibition', 'Var', (116, 126))	('ATM', 'Gene', (30, 33))	('reducing', 'NegReg', (223, 231))	('ATM', 'Gene', (130, 133))	('clonogenic survival', 'CPA', (232, 251))	('ATM', 'Gene', '472', (30, 33))	('ATM', 'Gene', '472', (130, 133))	('UM', 'Phenotype', 'HP:0007716', (56, 58))
47108	32429485	Melanoma develops as result of a number of genetic mutations, with UV radiation often acting as a mutagenic risk factor.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('mutations', 'Var', (51, 60))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanoma', 'Disease', (0, 8))	('result', 'Reg', (21, 27))
47109	32429485	Rapid detection of genetic alterations is also significant for choosing appropriate treatment and developing targeted therapies for melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('genetic alterations', 'Var', (19, 38))
47131	32429485	Cutaneous melanomagenesis can generally be traced to mutations in signaling pathways critical to cell survival.	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('Cutaneous melanomagenesis', 'Phenotype', 'HP:0012056', (0, 25))	('mutations', 'Var', (53, 62))	('traced', 'Reg', (43, 49))	('Cutaneous melanomagenesis', 'Disease', 'MESH:D017577', (0, 25))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('Cutaneous melanomagenesis', 'Disease', (0, 25))
47138	32429485	Mutations to these regulatory signals such as the oncogene NRAS or the tumor suppressor PTEN can occur alone or even in addition to other mutations in melanoma.	('tumor suppressor', 'biological_process', 'GO:0051726', ('71', '87'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('71', '87'))	('tumor suppressor', 'Gene', (71, 87))	('PTEN', 'Gene', (88, 92))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('PTEN', 'Gene', '5728', (88, 92))	('NRAS', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor suppressor', 'Gene', '7248', (71, 87))	('NRAS', 'Gene', '4893', (59, 63))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))
47139	32429485	In contrast to cutaneous melanoma, uveal melanoma tends to develop from different mutations along the MAPK or PI3K/AKT pathways.	('uveal melanoma', 'Disease', 'MESH:C536494', (35, 49))	('AKT', 'Gene', '207', (115, 118))	('uveal melanoma', 'Disease', (35, 49))	('PI3K', 'molecular_function', 'GO:0016303', ('110', '114'))	('MAPK', 'molecular_function', 'GO:0004707', ('102', '106'))	('cutaneous melanoma', 'Disease', (15, 33))	('AKT', 'Gene', (115, 118))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (15, 33))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (15, 33))	('mutations', 'Var', (82, 91))	('MAPK', 'Pathway', (102, 106))	('develop from', 'Reg', (59, 71))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))
47140	32429485	The most common mutations are in GNAQ or GNA11, which can lead to overactivation of both pathways.	('GNAQ', 'Gene', (33, 37))	('mutations', 'Var', (16, 25))	('overactivation', 'PosReg', (66, 80))	('GNAQ', 'Gene', '2776', (33, 37))	('GNA11', 'Gene', (41, 46))	('GNA11', 'Gene', '2767', (41, 46))
47142	32429485	GNAQ and GNA11 mutations may also increase activity through the Hippo pathway.	('GNA11', 'Gene', (9, 14))	('Hippo pathway', 'Pathway', (64, 77))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('GNAQ', 'Gene', (0, 4))	('activity', 'MPA', (43, 51))	('increase', 'PosReg', (34, 42))	('GNA11', 'Gene', '2767', (9, 14))
47144	32429485	GNAQ and GNA11 mutations result in downstream activation of YAP/TAZ to stimulate melanomagenesis.	('GNA11', 'Gene', (9, 14))	('TAZ', 'Gene', '6901', (64, 67))	('stimulate', 'PosReg', (71, 80))	('GNAQ', 'Gene', '2776', (0, 4))	('TAZ', 'Gene', (64, 67))	('activation', 'PosReg', (46, 56))	('mutations', 'Var', (15, 24))	('YAP', 'Gene', '10413', (60, 63))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('GNAQ', 'Gene', (0, 4))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('YAP', 'Gene', (60, 63))	('GNA11', 'Gene', '2767', (9, 14))
47145	32429485	Uveal melanoma has been thought to result from an initiating GNAQ/GNA11 mutation, followed by a secondary BSE event from mutations in the genes BAP1, SF3B1, and EIF1AX.	('SF3B1', 'Gene', (150, 155))	('mutations', 'Var', (121, 130))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('GNAQ', 'Gene', '2776', (61, 65))	('BAP1', 'Gene', (144, 148))	('GNAQ', 'Gene', (61, 65))	('SF3B1', 'Gene', '23451', (150, 155))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('EIF1AX', 'Gene', '1964', (161, 167))	('EIF1AX', 'Gene', (161, 167))	('mutation', 'Var', (72, 80))	('GNA11', 'Gene', (66, 71))	('result from', 'Reg', (35, 46))	('melanoma', 'Disease', (6, 14))	('GNA11', 'Gene', '2767', (66, 71))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))	('BAP1', 'Gene', '8314', (144, 148))
47148	32429485	Sequencing studies have illuminated the role of UV exposure in different mutations that lead to melanoma.	('lead to', 'Reg', (88, 95))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))	('mutations', 'Var', (73, 82))
47150	32429485	Whole-genome sequencing has revealed the different mutations that contribute to the development of UV-dependent and -independent melanomas.	('mutations', 'Var', (51, 60))	('melanomas', 'Disease', 'MESH:D008545', (129, 138))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanomas', 'Phenotype', 'HP:0002861', (129, 138))	('UV-dependent', 'Disease', (99, 111))	('contribute', 'Reg', (66, 76))	('melanomas', 'Disease', (129, 138))
47153	32429485	These markers can be represented by melanoma mutations, gene polymorphisms, signaling receptors, and melanin pigment.	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('mutations', 'Var', (45, 54))	('melanoma', 'Disease', (36, 44))	('melanin', 'Chemical', 'MESH:D008543', (101, 108))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))
47155	32429485	GNAQ and GNA11 mutations result in overamplification of signaling through the MAPK and PI3K pathways via blocking GTPase activity.	('GTPase', 'Protein', (114, 120))	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('activity', 'MPA', (121, 129))	('mutations', 'Var', (15, 24))	('MAPK', 'molecular_function', 'GO:0004707', ('78', '82'))	('blocking', 'NegReg', (105, 113))	('GTP', 'Chemical', 'MESH:D006160', (114, 117))	('overamplification', 'PosReg', (35, 52))	('signaling', 'MPA', (56, 65))	('GNAQ', 'Gene', (0, 4))	('GTPase activity', 'molecular_function', 'GO:0003924', ('114', '129'))	('PI3K', 'molecular_function', 'GO:0016303', ('87', '91'))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))	('GNA11', 'Gene', '2767', (9, 14))
47157	32429485	With GNAQ and GNA11 mutations, GTP is persistently bound to the G protein and lead to constitutive downstream signaling.	('GNAQ', 'Gene', (5, 9))	('lead to', 'Reg', (78, 85))	('GTP', 'Chemical', 'MESH:D006160', (31, 34))	('bound', 'Interaction', (51, 56))	('G protein', 'Protein', (64, 73))	('GNA11', 'Gene', (14, 19))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('GNAQ', 'Gene', '2776', (5, 9))	('signaling', 'biological_process', 'GO:0023052', ('110', '119'))	('constitutive downstream signaling', 'MPA', (86, 119))	('GNA11', 'Gene', '2767', (14, 19))	('mutations', 'Var', (20, 29))
47159	32429485	However, they are known to occur with BAP1 and SF3B1 mutations, with GNAQ/GNA11 mutation representing the initial event.	('GNA11', 'Gene', (74, 79))	('SF3B1', 'Gene', (47, 52))	('GNA11', 'Gene', '2767', (74, 79))	('BAP1', 'Gene', (38, 42))	('GNAQ', 'Gene', '2776', (69, 73))	('occur', 'Reg', (27, 32))	('mutations', 'Var', (53, 62))	('SF3B1', 'Gene', '23451', (47, 52))	('GNAQ', 'Gene', (69, 73))	('BAP1', 'Gene', '8314', (38, 42))
47162	32429485	While GNAQ and GNA11 mutations can also be found in cutaneous melanoma, these cases are extremely rare.	('GNA11', 'Gene', (15, 20))	('cutaneous melanoma', 'Disease', (52, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('GNAQ', 'Gene', '2776', (6, 10))	('GNA11', 'Gene', '2767', (15, 20))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (52, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('found', 'Reg', (43, 48))	('GNAQ', 'Gene', (6, 10))	('mutations', 'Var', (21, 30))
47163	32429485	The evidence for the prognostic value of GNAQ and GNA11 mutations is limited.	('GNAQ', 'Gene', '2776', (41, 45))	('mutations', 'Var', (56, 65))	('GNA11', 'Gene', '2767', (50, 55))	('GNA11', 'Gene', (50, 55))	('GNAQ', 'Gene', (41, 45))
47164	32429485	Multiple studies have shown that the presence of GNAQ or GNA11 mutations is not associated with metastatic progression or patient outcomes.	('mutations', 'Var', (63, 72))	('GNA11', 'Gene', (57, 62))	('metastatic progression', 'CPA', (96, 118))	('patient', 'Species', '9606', (122, 129))	('GNAQ', 'Gene', '2776', (49, 53))	('GNA11', 'Gene', '2767', (57, 62))	('GNAQ', 'Gene', (49, 53))
47166	32429485	Mutations in the CDKN2A gene are the most common alteration in hereditary melanoma, with presence in 40% of families with strong family history.	('hereditary melanoma', 'Disease', (63, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('CDKN2A', 'Gene', (17, 23))	('Mutations', 'Var', (0, 9))	('hereditary melanoma', 'Disease', 'MESH:D008545', (63, 82))	('common', 'Reg', (42, 48))
47168	32429485	Mutations in CDKN2A thus result in hyperphosphorylation of retinoblastoma protein (RB1), releasing the E2F1 transcription factor to promote cell cycle progression from G1 to S. In addition, loss of p14ARF function promotes the ubiquitination of p53, subsequently reducing cell cycle arrest and apoptosis.	('promotes', 'PosReg', (214, 222))	('cell cycle', 'biological_process', 'GO:0007049', ('140', '150'))	('hyperphosphorylation', 'MPA', (35, 55))	('retinoblastoma protein', 'Gene', (59, 81))	('apoptosis', 'CPA', (294, 303))	('loss', 'Var', (190, 194))	('arrest', 'Disease', (283, 289))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (272, 289))	('cell cycle progression', 'CPA', (140, 162))	('reducing', 'NegReg', (263, 271))	('E2F1', 'Gene', (103, 107))	('transcription factor', 'molecular_function', 'GO:0000981', ('108', '128'))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', '7157', (245, 248))	('hyperphosphorylation', 'biological_process', 'GO:0048151', ('35', '55'))	('transcription', 'biological_process', 'GO:0006351', ('108', '121'))	('p14ARF', 'Gene', '1029', (198, 204))	('p53', 'Gene', (245, 248))	('arrest', 'Disease', 'MESH:D006323', (283, 289))	('retinoblastoma', 'Phenotype', 'HP:0009919', (59, 73))	('retinoblastoma protein', 'Gene', '108709804', (59, 81))	('promote', 'PosReg', (132, 139))	('result in', 'Reg', (25, 34))	('E2F1', 'Gene', '100036852', (103, 107))	('ubiquitination', 'MPA', (227, 241))	('apoptosis', 'biological_process', 'GO:0097194', ('294', '303'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('272', '289'))	('CDKN2A', 'Gene', (13, 19))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('apoptosis', 'biological_process', 'GO:0006915', ('294', '303'))	('p14ARF', 'Gene', (198, 204))
47169	32429485	Those with the CDKN2A mutation have been shown to develop multiple melanomas and significantly more dysplastic nevi, including presentations consistent with dysplastic nevus syndrome.	('melanomas', 'Disease', (67, 76))	('mutation', 'Var', (22, 30))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (100, 115))	('CDKN2A', 'Gene', (15, 21))	('dysplastic nevus syndrome', 'Disease', 'MESH:D004416', (157, 182))	('nevi', 'Phenotype', 'HP:0003764', (111, 115))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('more', 'PosReg', (95, 99))	('melanomas', 'Disease', 'MESH:D008545', (67, 76))	('dysplastic nevus syndrome', 'Disease', (157, 182))	('develop', 'PosReg', (50, 57))	('nevus', 'Phenotype', 'HP:0003764', (168, 173))	('dysplastic nevi', 'Disease', (100, 115))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (157, 173))	('dysplastic nevi', 'Disease', 'MESH:D004416', (100, 115))
47171	32429485	Furthermore, in a Swedish study, familial melanoma cases with the CDKN2A mutation were associated with a younger age at onset and worse survival than those without the mutation.	('familial melanoma', 'Disease', (33, 50))	('familial melanoma', 'Disease', 'MESH:C562393', (33, 50))	('mutation', 'Var', (73, 81))	('CDKN2A', 'Gene', (66, 72))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
47172	32429485	That study suggested that dysregulation of the cell cycle with CDKN2A mutations may exacerbate mutational load and increase tumor aggression.	('mutational load', 'MPA', (95, 110))	('mutations', 'Var', (70, 79))	('dysregulation', 'Var', (26, 39))	('increase tumor aggression', 'Disease', 'MESH:D006974', (115, 140))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('aggression', 'Phenotype', 'HP:0000718', (130, 140))	('aggression', 'biological_process', 'GO:0002118', ('130', '140'))	('cell cycle', 'biological_process', 'GO:0007049', ('47', '57'))	('dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (26, 57))	('exacerbate', 'PosReg', (84, 94))	('increase tumor aggression', 'Disease', (115, 140))	('cell cycle', 'CPA', (47, 57))	('CDKN2A', 'Gene', (63, 69))
47174	32429485	BAP1 mutations are associated with monosomy 3, which is associated with metastatic uveal melanoma.	('associated', 'Reg', (19, 29))	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('uveal melanoma', 'Disease', (83, 97))	('BAP1', 'Gene', (0, 4))	('monosomy 3', 'Disease', (35, 45))	('mutations', 'Var', (5, 14))	('associated', 'Reg', (56, 66))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('BAP1', 'Gene', '8314', (0, 4))	('uveal melanoma', 'Disease', 'MESH:C536494', (83, 97))
47175	32429485	Multiple other studies since have confirmed the correlation of BAP1 mutations with metastasis, tumor aggression, and worse prognosis in uveal melanoma.	('metastasis', 'CPA', (83, 93))	('aggression', 'Phenotype', 'HP:0000718', (101, 111))	('tumor aggression', 'Disease', (95, 111))	('BAP1', 'Gene', (63, 67))	('tumor aggression', 'Disease', 'MESH:D001523', (95, 111))	('aggression', 'biological_process', 'GO:0002118', ('101', '111'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (136, 150))	('uveal melanoma', 'Disease', (136, 150))	('uveal melanoma', 'Disease', 'MESH:C536494', (136, 150))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutations', 'Var', (68, 77))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('BAP1', 'Gene', '8314', (63, 67))
47176	32429485	Notably, BAP1 was found to be mutated in early tumorigenesis and not with progression to metastasis.	('BAP1', 'Gene', '8314', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mutated', 'Var', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('BAP1', 'Gene', (9, 13))	('tumor', 'Disease', (47, 52))
47177	32429485	Germline mutations of BAP1 have also been identified, suggesting a hereditary form of uveal melanoma.	('Germline mutations', 'Var', (0, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('uveal melanoma', 'Disease', 'MESH:C536494', (86, 100))	('uveal melanoma', 'Disease', (86, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', (22, 26))
47179	32429485	Similar to somatic mutations, germline mutation of BAP1 was highly associated with metastasis as compared with uveal melanoma without BAP1 mutation.	('uveal melanoma', 'Phenotype', 'HP:0007716', (111, 125))	('uveal melanoma', 'Disease', 'MESH:C536494', (111, 125))	('metastasis', 'CPA', (83, 93))	('BAP1', 'Gene', (134, 138))	('BAP1', 'Gene', (51, 55))	('uveal melanoma', 'Disease', (111, 125))	('germline mutation', 'Var', (30, 47))	('associated with', 'Reg', (67, 82))	('BAP1', 'Gene', '8314', (134, 138))	('BAP1', 'Gene', '8314', (51, 55))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
47181	32429485	The BAP1 tumor predisposition syndrome caused by germline BAP1 mutations is not only associated with cutaneous melanoma.	('mutations', 'Var', (63, 72))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('BAP1', 'Gene', (4, 8))	('BAP1', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('cutaneous melanoma', 'Disease', (101, 119))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (101, 119))	('germline', 'Var', (49, 57))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (101, 119))	('tumor', 'Disease', (9, 14))	('caused', 'Reg', (39, 45))	('BAP1', 'Gene', '8314', (4, 8))	('associated', 'Reg', (85, 95))	('BAP1', 'Gene', '8314', (58, 62))
47184	32429485	In contrast to its role as a tumor suppressor gene, BAP1 expression in cutaneous melanoma was found to promote growth and survival of cells.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (71, 89))	('tumor suppressor', 'Gene', (29, 45))	('BAP1', 'Gene', '8314', (52, 56))	('growth', 'CPA', (111, 117))	('expression', 'Var', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor suppressor', 'biological_process', 'GO:0051726', ('29', '45'))	('BAP1', 'Gene', (52, 56))	('tumor suppressor', 'Gene', '7248', (29, 45))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('29', '45'))	('cutaneous melanoma', 'Disease', (71, 89))	('survival of cells', 'CPA', (122, 139))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (71, 89))	('promote', 'PosReg', (103, 110))
47188	32429485	Mutations in BAP1 thus have been hypothesized to rely on alternative mechanisms of DNA repair with poly (ADP-ribose) polymerase (PARP) emerging as a target for its role in base-excision and nucleotide excision repair.	('BAP1', 'Gene', (13, 17))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('190', '216'))	('DNA repair', 'biological_process', 'GO:0006281', ('83', '93'))	('poly (ADP-ribose) polymerase', 'Gene', '142', (99, 127))	('PARP', 'Gene', '142', (129, 133))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('Mutations', 'Var', (0, 9))	('poly (ADP-ribose) polymerase', 'Gene', (99, 127))	('BAP1', 'Gene', '8314', (13, 17))	('PARP', 'Gene', (129, 133))
47190	32429485	SF3B1 encodes a subunit of splicing factor 3b, and mutations therefore result in aberrant splicing of pre-mRNA into mature mRNA.	('splicing', 'biological_process', 'GO:0045292', ('27', '35'))	('mutations', 'Var', (51, 60))	('SF3B1', 'Gene', (0, 5))	('result in', 'Reg', (71, 80))	('splicing of pre-mRNA into mature mRNA', 'MPA', (90, 127))	('SF3B1', 'Gene', '23451', (0, 5))	('pre', 'molecular_function', 'GO:0003904', ('102', '105'))	('splicing', 'biological_process', 'GO:0045292', ('90', '98'))
47191	32429485	SF3B1 mutations are characterized by disomy 3 and noted to be a marker of good prognosis for uveal melanoma and found in younger patients.	('SF3B1', 'Gene', (0, 5))	('uveal melanoma', 'Disease', 'MESH:C536494', (93, 107))	('uveal melanoma', 'Phenotype', 'HP:0007716', (93, 107))	('patients', 'Species', '9606', (129, 137))	('uveal melanoma', 'Disease', (93, 107))	('SF3B1', 'Gene', '23451', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('mutations', 'Var', (6, 15))
47192	32429485	While tumors bearing the mutation often metastasize, this can take many years and they are thus thought to have intermediate risk for metastasis.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('mutation', 'Var', (25, 33))	('metastasize', 'CPA', (40, 51))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
47193	32429485	In one study sequencing melanoma samples, the SF3B1 R625 mutation was found in two out of 231 cutaneous melanoma samples.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('melanoma', 'Disease', (104, 112))	('SF3B1', 'Gene', '23451', (46, 51))	('cutaneous melanoma', 'Disease', (94, 112))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (94, 112))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (94, 112))	('SF3B1', 'Gene', (46, 51))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))	('R625', 'Var', (52, 56))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
47196	32429485	Cases of uveal melanoma with positive EIF1AX mutations rarely metastasize and other genetic alterations are thought to occur when metastasis does occur.	('mutations', 'Var', (45, 54))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (9, 23))	('uveal melanoma', 'Disease', (9, 23))	('uveal melanoma', 'Disease', 'MESH:C536494', (9, 23))	('EIF1AX', 'Gene', '1964', (38, 44))	('EIF1AX', 'Gene', (38, 44))	('metastasize', 'CPA', (62, 73))
47198	32429485	Further, 1,25(OH)2D3 has been shown to protect against melanoma by inhibiting proliferation, regulating growth factor activity, and promoting apoptosis.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (9, 20))	('promoting', 'PosReg', (132, 141))	('growth factor activity', 'MPA', (104, 126))	('growth factor activity', 'molecular_function', 'GO:0008083', ('104', '126'))	('proliferation', 'CPA', (78, 91))	('apoptosis', 'CPA', (142, 151))	('apoptosis', 'biological_process', 'GO:0097194', ('142', '151'))	('apoptosis', 'biological_process', 'GO:0006915', ('142', '151'))	('regulating', 'Reg', (93, 103))	('1,25(OH)2D3', 'Var', (9, 20))	('inhibiting', 'NegReg', (67, 77))	('melanoma', 'Disease', (55, 63))
47204	32429485	Various polymorphisms of VDR have also been found to affect the risk and prognosis of melanoma, but a consistent pattern has not been identified.	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('VDR', 'Gene', '7421', (25, 28))	('melanoma', 'Disease', (86, 94))	('affect', 'Reg', (53, 59))	('VDR', 'Gene', (25, 28))	('polymorphisms', 'Var', (8, 21))
47205	32429485	first studied 38 common VDR single-nucleotide polymorphisms (SNPs) and discovered six of these to be associated with increased risk of melanoma development and two with decreased risk.	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('VDR', 'Gene', '7421', (24, 27))	('melanoma', 'Disease', (135, 143))	('associated', 'Reg', (101, 111))	('single-nucleotide polymorphisms', 'Var', (28, 59))	('VDR', 'Gene', (24, 27))
47208	32429485	However, a 2009 study analyzing six VDR SNPs found no significant change in outcomes with the exception of worse outcome in patients with the BsmI polymorphism and low vitamin D levels.	('polymorphism', 'Var', (147, 159))	('vitamin D', 'Chemical', 'MESH:D014807', (168, 177))	('BsmI', 'Gene', (142, 146))	('low', 'NegReg', (164, 167))	('VDR', 'Gene', (36, 39))	('vitamin D levels', 'MPA', (168, 184))	('low vitamin D', 'Phenotype', 'HP:0100512', (164, 177))	('VDR', 'Gene', '7421', (36, 39))	('patients', 'Species', '9606', (124, 132))
47209	32429485	Overall, the understanding of VDR variants in melanoma remains poor.	('variants', 'Var', (34, 42))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('VDR', 'Gene', (30, 33))	('VDR', 'Gene', '7421', (30, 33))
47214	32429485	were the first to discover that 1,25(OH)2D3 inhibits the proliferation of human melanoma cells.	('human', 'Species', '9606', (74, 79))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (32, 43))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('inhibits', 'NegReg', (44, 52))	('1,25(OH)2D3', 'Var', (32, 43))
47220	32429485	Analogs with modified side chains, such as calcipotriol, have been demonstrated to inhibit proliferation with low calcemic activity.	('calcipotriol', 'Chemical', 'MESH:C055085', (43, 55))	('inhibit', 'NegReg', (83, 90))	('modified', 'Var', (13, 21))	('proliferation', 'CPA', (91, 104))
47232	32429485	Variants in the MC1R gene have been shown to directly and indirectly induce melanomagenesis.	('melanoma', 'Disease', (76, 84))	('Variants', 'Var', (0, 8))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('induce', 'Reg', (69, 75))	('MC1R', 'Gene', '4157', (16, 20))	('MC1R', 'Gene', (16, 20))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
47234	32429485	Thus, MC1R polymorphisms can exacerbate the UV-induced DNA damage and promote tumor formation.	('MC1R', 'Gene', '4157', (6, 10))	('formation', 'biological_process', 'GO:0009058', ('84', '93'))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('MC1R', 'Gene', (6, 10))	('UV-induced DNA damage', 'CPA', (44, 65))	('exacerbate', 'PosReg', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('polymorphisms', 'Var', (11, 24))	('promote', 'PosReg', (70, 77))	('tumor', 'Disease', (78, 83))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))
47235	32429485	In addition, variants of MC1R upregulate pheomelanin production, which is characterized by a phenotype of fair skin and red hair and susceptibility to UV light.	('variants', 'Var', (13, 21))	('MC1R', 'Gene', '4157', (25, 29))	('pheomelanin production', 'MPA', (41, 63))	('MC1R', 'Gene', (25, 29))	('upregulate', 'PosReg', (30, 40))	('susceptibility to UV light', 'Phenotype', 'HP:0003224', (133, 159))	('fair skin', 'Phenotype', 'HP:0007513', (106, 115))	('red hair', 'Phenotype', 'HP:0002297', (120, 128))	('pheomelanin', 'Chemical', 'MESH:C018362', (41, 52))
47236	32429485	Multiple studies have demonstrated that MC1R variation confers increased risk for melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('MC1R', 'Gene', '4157', (40, 44))	('variation', 'Var', (45, 54))	('risk', 'Reg', (73, 77))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('MC1R', 'Gene', (40, 44))
47237	32429485	While this association was thought to be driven by the predisposition to fair skin, multiple large studies have shown that the presence of a MC1R variant was associated with development of melanoma, independent of all other risk factors including skin type.	('fair skin', 'Phenotype', 'HP:0007513', (73, 82))	('associated with', 'Reg', (158, 173))	('variant', 'Var', (146, 153))	('MC1R', 'Gene', '4157', (141, 145))	('MC1R', 'Gene', (141, 145))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', (189, 197))	('presence', 'Var', (127, 135))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))
47238	32429485	While the presence of MC1R variation has not been associated with histopathologic characteristics, it was found to correlate with tumor presentation on the arms, which may provide additional support for its UV-risk independence.	('MC1R', 'Gene', (22, 26))	('MC1R', 'Gene', '4157', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('variation', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('presence', 'Var', (10, 18))	('tumor', 'Disease', (130, 135))
47239	32429485	Melanomas associated with germline mutations of MC1R have also been shown to have a significantly higher somatic mutational burden, suggesting a higher susceptibility to tumorigenesis in these patients.	('patients', 'Species', '9606', (193, 201))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('MC1R', 'Gene', '4157', (48, 52))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('Melanomas', 'Disease', (0, 9))	('MC1R', 'Gene', (48, 52))	('germline mutations', 'Var', (26, 44))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('higher', 'PosReg', (98, 104))	('somatic mutational burden', 'MPA', (105, 130))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('susceptibility', 'Reg', (152, 166))
47240	32429485	Notably, MC1R variants have been shown to increase the penetrance of CDKN2A mutations, doubling the risk for melanoma.	('mutations', 'Var', (76, 85))	('variants', 'Var', (14, 22))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('penetrance', 'MPA', (55, 65))	('MC1R', 'Gene', '4157', (9, 13))	('MC1R', 'Gene', (9, 13))	('CDKN2A', 'Gene', (69, 75))	('increase', 'PosReg', (42, 50))
47243	32429485	MITF has also been found to regulate phenotype switching, wherein low expression leads to increased invasiveness of melanoma cells and high expression leads to decreased invasiveness.	('increased', 'PosReg', (90, 99))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('invasiveness', 'CPA', (170, 182))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('decreased', 'NegReg', (160, 169))	('low', 'Var', (66, 69))
47244	32429485	showed that MITF silencing in mouse and human melanoma cells enhanced tumorigenicity and metastasis.	('MITF', 'Gene', (12, 16))	('human', 'Species', '9606', (40, 45))	('enhanced', 'PosReg', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('metastasis', 'CPA', (89, 99))	('silencing', 'Var', (17, 26))	('mouse', 'Species', '10090', (30, 35))
47247	32429485	The presence of the Mi-E318K germline mutation in MITF was associated with a fivefold increase in the risk of developing melanoma as compared to patients without the mutation.	('patients', 'Species', '9606', (145, 153))	('MITF', 'Gene', (50, 54))	('melanoma', 'Disease', (121, 129))	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('Mi-E318K', 'Var', (20, 28))	('E318K', 'Mutation', 'rs149617956', (23, 28))
47249	32429485	In cases of familial melanoma, testing for the MITF mutation may be helpful.	('MITF', 'Gene', (47, 51))	('familial melanoma', 'Disease', (12, 29))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('familial melanoma', 'Disease', 'MESH:C562393', (12, 29))	('mutation', 'Var', (52, 60))
47251	32429485	One explanation is that age-related changes degrade the extracellular matrix (ECM) in the skin and thus promote the growth and migration of melanoma.	('extracellular matrix', 'cellular_component', 'GO:0031012', ('56', '76'))	('degrade', 'NegReg', (44, 51))	('changes', 'Var', (36, 43))	('extracellular', 'MPA', (56, 69))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('promote', 'PosReg', (104, 111))	('melanoma', 'Disease', (140, 148))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('growth', 'CPA', (116, 122))	('migration', 'CPA', (127, 136))
47265	32429485	showed that inhibition of melanogenesis by N-phenylthiourea (PTU) or D-penicillamine in human melanoma cells increased the sensitivity to killing by gamma rays.	('N-phenylthiourea', 'Chemical', '-', (43, 59))	('sensitivity', 'MPA', (123, 134))	('melanogenesis', 'Enzyme', (26, 39))	('inhibition', 'NegReg', (12, 22))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('D-penicillamine', 'Chemical', 'MESH:D010396', (69, 84))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('PTU', 'Chemical', '-', (61, 64))	('human', 'Species', '9606', (88, 93))	('D-penicillamine', 'Var', (69, 84))	('increased', 'PosReg', (109, 118))
47266	32429485	Soon after, melanogenesis inhibition was also shown to amplify the cytotoxicity of cyclophosphamide chemotherapy in human melanoma cells.	('cyclophosphamide', 'Chemical', 'MESH:D003520', (83, 99))	('cytotoxicity', 'Disease', (67, 79))	('melanogenesis', 'Gene', (12, 25))	('inhibition', 'Var', (26, 36))	('amplify', 'PosReg', (55, 62))	('cytotoxicity', 'Disease', 'MESH:D064420', (67, 79))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('human', 'Species', '9606', (116, 121))
47270	32429485	Interestingly, inhibition of melanogenesis also potentiates the efficacy of vitamin D therapy.	('potentiates', 'PosReg', (48, 59))	('efficacy', 'MPA', (64, 72))	('melanogenesis', 'CPA', (29, 42))	('vitamin D', 'Chemical', 'MESH:D014807', (76, 85))	('inhibition', 'Var', (15, 25))
47274	32429485	Melanin is synthesized in melanocytes from L-tyrosine through a series of enzymatic reactions leading to production of variety of intermediates of melanogenesis that are biologically active.	('Melanin', 'Chemical', 'MESH:D008543', (0, 7))	('L-tyrosine', 'Chemical', 'MESH:D014443', (43, 53))	('production', 'MPA', (105, 115))	('L-tyrosine', 'Var', (43, 53))
47281	32429485	BRAF mutations comprise the most common genetic alteration in cutaneous melanoma with its presence ranging from 40% to 60% of cases.	('cutaneous melanoma', 'Disease', (62, 80))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (62, 80))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (62, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))
47282	32429485	The most common BRAF mutation is V600E, which represents 80% of alterations in the gene.	('V600E', 'Var', (33, 38))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('V600E', 'Mutation', 'rs113488022', (33, 38))
47283	32429485	The V600K and V600R mutations are other known BRAF mutations.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('V600K', 'Mutation', 'rs121913227', (4, 9))	('V600R', 'Var', (14, 19))	('V600R', 'Mutation', 'rs121913227', (14, 19))	('V600K', 'Var', (4, 9))
47284	32429485	Studies have shown that V600E expression is associated with the superficial spreading subtype, younger patient age, and skin sites without chronic sun-induced damage, such as the extremities.	('associated', 'Reg', (44, 54))	('V600E', 'Var', (24, 29))	('patient', 'Species', '9606', (103, 110))	('V600E', 'Mutation', 'rs113488022', (24, 29))	('superficial', 'Disease', (64, 75))
47285	32429485	In contrast, V600K mutations are correlated with skin sites with CSD, such as the head and neck, and patients of older age.	('patients', 'Species', '9606', (101, 109))	('V600K', 'Mutation', 'rs121913227', (13, 18))	('V600K mutations', 'Var', (13, 28))	('skin sites', 'Disease', (49, 59))	('correlated', 'Reg', (33, 43))	('CSD', 'Disease', (65, 68))	('neck', 'cellular_component', 'GO:0044326', ('91', '95'))
47287	32429485	Recently, whole-genome sequencing of benign melanocytic nevi showed the presence of BRAF mutations, in addition to NRAS mutations, with mutational load positively correlated with UV exposure; lower mutational loads were observed in congenital nevi.	('NRAS', 'Gene', (115, 119))	('BRAF', 'Gene', '673', (84, 88))	('correlated', 'Reg', (163, 173))	('nevi', 'Phenotype', 'HP:0003764', (56, 60))	('NRAS', 'Gene', '4893', (115, 119))	('BRAF', 'Gene', (84, 88))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (44, 60))	('mutations', 'Var', (89, 98))	('nevi', 'Phenotype', 'HP:0003764', (243, 247))	('congenital nevi', 'Disease', (232, 247))	('UV exposure', 'MPA', (179, 190))	('mutational', 'MPA', (136, 146))
47288	32429485	Similar observations were found in dysplastic nevi with high mutational load as a key distinction between the benign tumors and melanoma.	('dysplastic nevi', 'Phenotype', 'HP:0001062', (35, 50))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('dysplastic nevi', 'Disease', 'MESH:D004416', (35, 50))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('nevi', 'Phenotype', 'HP:0003764', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('benign tumors', 'Disease', (110, 123))	('dysplastic nevi', 'Disease', (35, 50))	('benign tumors', 'Disease', 'MESH:D009369', (110, 123))	('high mutational load', 'Var', (56, 76))	('melanoma', 'Disease', (128, 136))
47289	32429485	BRAF mutations were thought to be independent of UV exposure due to the absence of UV signature mutations but the consideration of "noninformative" mutations has shifted that belief.	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('mutations', 'Var', (5, 14))
47290	32429485	showed that BRAF mutations could not be detected in congenital melanocytic nevi, further suggesting the role of moderate UV exposure in introducing such mutations in the skin.	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', (12, 16))	('congenital melanocytic nevi', 'Phenotype', 'HP:0100814', (52, 79))	('nevi', 'Phenotype', 'HP:0003764', (75, 79))	('mutations', 'Var', (17, 26))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (63, 79))
47291	32429485	Accordingly, BRAF mutations are associated with melanomas from anatomic locations with intermittent sun exposure, such as the trunk and extremities.	('BRAF', 'Gene', '673', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanomas', 'Disease', (48, 57))	('BRAF', 'Gene', (13, 17))	('associated with', 'Reg', (32, 47))	('trunk', 'cellular_component', 'GO:0043198', ('126', '131'))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('mutations', 'Var', (18, 27))
47292	32429485	Better understanding of the development of these mutations can help to track the rare transformation of benign nevi to malignant melanoma and distinguish the two when histology is equivocal.	('malignant melanoma', 'Phenotype', 'HP:0002861', (119, 137))	('nevi', 'Phenotype', 'HP:0003764', (111, 115))	('mutations', 'Var', (49, 58))	('malignant melanoma', 'Disease', (119, 137))	('malignant melanoma', 'Disease', 'MESH:D008545', (119, 137))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('benign nevi', 'Disease', (104, 115))
47293	32429485	Refined sequencing technology is also critical for determining the mutational load, which may help evaluate tumor malignancy.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor malignancy', 'Disease', (108, 124))	('mutational', 'Var', (67, 77))	('tumor malignancy', 'Disease', 'MESH:D009369', (108, 124))
47294	32429485	Previously, it had been thought that the presence of BRAF mutations were not associated with worsening prognosis or tumor proliferation.	('mutations', 'Var', (58, 67))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
47295	32429485	showed that cellular localization of the BRAF mutation to either the nucleus or cytoplasm was associated with different clinicopathological features.	('nucleus', 'cellular_component', 'GO:0005634', ('69', '76'))	('cellular localization', 'biological_process', 'GO:0051641', ('12', '33'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('80', '89'))	('BRAF', 'Gene', '673', (41, 45))	('BRAF', 'Gene', (41, 45))	('mutation', 'Var', (46, 54))
47296	32429485	Positive expression of V600E in the nucleus as compared to the cytoplasm was correlated with worse tumor stage, lymph node metastasis, and depth of invasion.	('tumor', 'Disease', (99, 104))	('V600E', 'Mutation', 'rs113488022', (23, 28))	('nucleus', 'cellular_component', 'GO:0005634', ('36', '43'))	('lymph node metastasis', 'CPA', (112, 133))	('V600E', 'Var', (23, 28))	('depth of invasion', 'CPA', (139, 156))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cytoplasm', 'cellular_component', 'GO:0005737', ('63', '72'))
47304	32429485	identified RhoA GTPases as a potential pathway for BRAF resistance and that inhibition of the pathway by Rho kinase (ROCK) inhibitors promotes resensitization to BRAF-targeting therapy.	('promotes', 'PosReg', (134, 142))	('inhibitors', 'Var', (123, 133))	('BRAF', 'Gene', '673', (51, 55))	('GTP', 'Chemical', 'MESH:D006160', (16, 19))	('inhibition', 'Var', (76, 86))	('BRAF', 'Gene', '673', (162, 166))	('BRAF', 'Gene', (51, 55))	('resensitization', 'CPA', (143, 158))	('BRAF', 'Gene', (162, 166))
47307	32429485	In turn, this paradoxical upregulation had been linked to increased incidence in cutaneous SCCs that harbor RAS mutation, as well as reported cases of dysplastic nevi and wild-type BRAF melanomas, in patients after vemurafenib treatment.	('dysplastic nevi', 'Phenotype', 'HP:0001062', (151, 166))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanomas', 'Phenotype', 'HP:0002861', (186, 195))	('patients', 'Species', '9606', (200, 208))	('mutation', 'Var', (112, 120))	('nevi', 'Phenotype', 'HP:0003764', (162, 166))	('BRAF melanomas', 'Disease', 'MESH:D008545', (181, 195))	('RAS', 'Gene', (108, 111))	('vemurafenib', 'Chemical', 'MESH:D000077484', (215, 226))	('upregulation', 'PosReg', (26, 38))	('dysplastic nevi', 'Disease', (151, 166))	('BRAF melanomas', 'Disease', (181, 195))	('cutaneous SCCs', 'Disease', (81, 95))	('dysplastic nevi', 'Disease', 'MESH:D004416', (151, 166))
47309	32429485	When the oncogene is mutated, GTPase activity is reduced, resulting in a constitutively active GTP-bound G protein to propagate downstream signals.	('constitutively active GTP-bound', 'MPA', (73, 104))	('reduced', 'NegReg', (49, 56))	('GTPase', 'Protein', (30, 36))	('G protein', 'Protein', (105, 114))	('propagate downstream signals', 'MPA', (118, 146))	('activity', 'MPA', (37, 45))	('GTPase activity', 'molecular_function', 'GO:0003924', ('30', '45'))	('mutated', 'Var', (21, 28))	('GTP', 'Chemical', 'MESH:D006160', (30, 33))	('GTP', 'Chemical', 'MESH:D006160', (95, 98))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
47310	32429485	Generally, NRAS mutations occur independently of BRAF mutations but dual expression has been reported.	('NRAS', 'Gene', '4893', (11, 15))	('mutations', 'Var', (16, 25))	('BRAF', 'Gene', '673', (49, 53))	('NRAS', 'Gene', (11, 15))	('BRAF', 'Gene', (49, 53))
47314	32429485	The prognostic value of identification of NRAS mutation is unclear.	('mutation', 'Var', (47, 55))	('NRAS', 'Gene', (42, 46))	('NRAS', 'Gene', '4893', (42, 46))
47317	32429485	Along with BRAF mutations, NRAS mutations are among mutations found in melanocytic and dysplastic nevi and melanomas, with high mutational load as a notable discriminant favoring the latter in diagnosis.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('NRAS', 'Gene', '4893', (27, 31))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('dysplastic nevi and melanomas', 'Disease', 'MESH:D004416', (87, 116))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (87, 102))	('melanocytic and dysplastic nevi', 'Phenotype', 'HP:0000995', (71, 102))	('mutations', 'Var', (32, 41))	('nevi', 'Phenotype', 'HP:0003764', (98, 102))	('BRAF', 'Gene', '673', (11, 15))	('melanocytic', 'Disease', (71, 82))	('NRAS', 'Gene', (27, 31))	('BRAF', 'Gene', (11, 15))
47318	32429485	Notably, NRAS mutations were also commonly found in congenital melanocytic nevi, suggesting mutagenesis independent of UV radiation.	('NRAS', 'Gene', (9, 13))	('found', 'Reg', (43, 48))	('NRAS', 'Gene', '4893', (9, 13))	('congenital melanocytic nevi', 'Phenotype', 'HP:0100814', (52, 79))	('nevi', 'Phenotype', 'HP:0003764', (75, 79))	('congenital melanocytic nevi', 'Disease', (52, 79))	('mutations', 'Var', (14, 23))	('mutagenesis', 'biological_process', 'GO:0006280', ('92', '103'))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (63, 79))
47319	32429485	The contrast between this observation and the association of NRAS mutation with skin with CSD suggests that detecting the UV signature mutations can help diagnose melanoma.	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('NRAS', 'Gene', (61, 65))	('mutation', 'Var', (66, 74))	('skin with CSD', 'Disease', (80, 93))	('NRAS', 'Gene', '4893', (61, 65))
47320	32429485	In melanomas bearing NRAS mutations, targeted therapy has shown limited effectiveness and thus immune therapies and chemotherapy are generally used.	('NRAS', 'Gene', '4893', (21, 25))	('melanomas', 'Disease', (3, 12))	('mutations', 'Var', (26, 35))	('NRAS', 'Gene', (21, 25))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanomas', 'Phenotype', 'HP:0002861', (3, 12))	('melanomas', 'Disease', 'MESH:D008545', (3, 12))
47325	32429485	MEK inhibitors have been identified as potential therapy for NRAS mutants.	('mutants', 'Var', (66, 73))	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('NRAS', 'Gene', (61, 65))	('NRAS', 'Gene', '4893', (61, 65))
47326	32429485	In particular, binimetinib has been shown in phase 3 trials to have improved survival and response rate compared to dacarbazine in NRAS-mutant melanoma.	('response', 'CPA', (90, 98))	('survival', 'CPA', (77, 85))	('NRAS', 'Gene', (131, 135))	('binimetinib', 'Chemical', 'MESH:C581313', (15, 26))	('binimetinib', 'Var', (15, 26))	('NRAS', 'Gene', '4893', (131, 135))	('dacarbazine', 'Chemical', 'MESH:D003606', (116, 127))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('improved', 'PosReg', (68, 76))
47330	32429485	The majority of c-KIT mutations are found in mucosal and acral melanomas, as well as in melanomas arising from skin with CSD.	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('acral melanomas', 'Phenotype', 'HP:0012060', (57, 72))	('KIT', 'molecular_function', 'GO:0005020', ('18', '21'))	('mucosal and acral melanomas', 'Disease', 'MESH:D008545', (45, 72))	('found', 'Reg', (36, 41))	('melanomas', 'Disease', 'MESH:D008545', (88, 97))	('melanomas', 'Disease', (63, 72))	('mutations', 'Var', (22, 31))	('c-KIT', 'Gene', (16, 21))	('melanomas', 'Disease', 'MESH:D008545', (63, 72))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))	('melanomas', 'Disease', (88, 97))	('c-KIT', 'Gene', '3815', (16, 21))
47331	32429485	Presence of these mutations has also been associated with worse survival as compared with wild-type melanomas.	('melanomas', 'Disease', 'MESH:D008545', (100, 109))	('melanomas', 'Disease', (100, 109))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))	('mutations', 'Var', (18, 27))
47332	32429485	Because of the relative rarity of c-KIT mutations, the understanding of targeted therapy to treat melanoma is scarce.	('c-KIT', 'Gene', (34, 39))	('c-KIT', 'Gene', '3815', (34, 39))	('mutations', 'Var', (40, 49))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('KIT', 'molecular_function', 'GO:0005020', ('36', '39'))
47334	32429485	In a pair of phase 2 trials, imatinib was shown to have significant clinical response in tumors bearing c-KIT mutations as compared with wild-type tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('mutations', 'Var', (110, 119))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('imatinib', 'Chemical', 'MESH:D000068877', (29, 37))	('KIT', 'molecular_function', 'GO:0005020', ('106', '109'))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('c-KIT', 'Gene', (104, 109))	('c-KIT', 'Gene', '3815', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
47335	32429485	Nilotinib has similarly shown promise in the treatment of patients with c-KIT mutations in phase 2 trials.	('KIT', 'molecular_function', 'GO:0005020', ('74', '77'))	('c-KIT', 'Gene', (72, 77))	('Nilotinib', 'Chemical', 'MESH:C498826', (0, 9))	('mutations', 'Var', (78, 87))	('c-KIT', 'Gene', '3815', (72, 77))	('patients', 'Species', '9606', (58, 66))
47338	32429485	The main targeted signals are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1).	('CTLA-4', 'Gene', '397286', (64, 70))	('PD-1', 'Gene', (96, 100))	('PD-1', 'Gene', '5133', (96, 100))	('death', 'Disease', 'MESH:D003643', (87, 92))	('lymphocyte antigen', 'molecular_function', 'GO:0005557', ('42', '60'))	('programmed', 'Var', (76, 86))	('cytotoxic T-lymphocyte antigen-4', 'Gene', (30, 62))	('death', 'Disease', (87, 92))	('CTLA-4', 'Gene', (64, 70))	('cytotoxic T-lymphocyte antigen-4', 'Gene', '397286', (30, 62))
47350	32429485	An Italian study also found that serum CTLA-4 may serve as a novel biomarker in predicting favorable response to ipilimumab.	('CTLA-4', 'Gene', '397286', (39, 45))	('ipilimumab', 'Chemical', 'MESH:D000074324', (113, 123))	('CTLA-4', 'Gene', (39, 45))	('serum', 'Var', (33, 38))
47359	32267900	Interplay between TERT promoter mutations and methylation culminates in chromatin accessibility and TERT expression The telomerase reverse transcriptase (TERT) gene is responsible for telomere maintenance in germline and stem cells, and is re-expressed in 90% of human cancers.	('telomere', 'cellular_component', 'GO:0000781', ('184', '192'))	('telomere maintenance', 'biological_process', 'GO:0000723', ('184', '204'))	('TERT', 'Gene', (100, 104))	('chromatin', 'cellular_component', 'GO:0000785', ('72', '81'))	('telomere', 'cellular_component', 'GO:0005696', ('184', '192'))	('transcriptase', 'molecular_function', 'GO:0003968', ('139', '152'))	('human', 'Species', '9606', (263, 268))	('TERT', 'Gene', '7015', (100, 104))	('transcriptase', 'molecular_function', 'GO:0034062', ('139', '152'))	('mutations', 'Var', (32, 41))	('cancers', 'Phenotype', 'HP:0002664', (269, 276))	('cancers', 'Disease', (269, 276))	('telomerase reverse transcriptase', 'Gene', (120, 152))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('TERT', 'Gene', (154, 158))	('TERT', 'Gene', (18, 22))	('responsible', 'Reg', (168, 179))	('TERT', 'Gene', '7015', (154, 158))	('transcriptase', 'molecular_function', 'GO:0003899', ('139', '152'))	('TERT', 'Gene', '7015', (18, 22))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('telomerase reverse transcriptase', 'Gene', '7015', (120, 152))	('cancers', 'Disease', 'MESH:D009369', (269, 276))
47360	32267900	CpG methylation in the TERT promoter (TERTp) was correlated with TERT mRNA expression.	('correlated', 'Reg', (49, 59))	('TERTp', 'Gene', (38, 43))	('TERT', 'Gene', (23, 27))	('TERTp', 'Gene', '7015', (38, 43))	('TERT', 'Gene', '7015', (23, 27))	('TERT', 'Gene', (38, 42))	('methylation', 'Var', (4, 15))	('TERT', 'Gene', (65, 69))	('TERT', 'Gene', '7015', (65, 69))	('TERT', 'Gene', '7015', (38, 42))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))
47361	32267900	Furthermore, two hotspot mutations in TERTp, dubbed C228T and C250T, have been revealed to facilitate binding of transcription factor ETS/TCF and subsequent TERT expression.	('TERTp', 'Gene', (38, 43))	('C228T', 'Var', (52, 57))	('binding', 'Interaction', (102, 109))	('TERTp', 'Gene', '7015', (38, 43))	('C250T', 'Mutation', 'rs1184821004', (62, 67))	('TERT', 'Gene', (157, 161))	('TERT', 'Gene', (38, 42))	('TERT', 'Gene', '7015', (157, 161))	('binding', 'molecular_function', 'GO:0005488', ('102', '109'))	('C250T', 'Var', (62, 67))	('ETS/TCF', 'Gene', (134, 141))	('transcription factor', 'molecular_function', 'GO:0000981', ('113', '133'))	('facilitate', 'PosReg', (91, 101))	('TERT', 'Gene', '7015', (38, 42))	('ETS/TCF', 'Gene', '3172', (134, 141))	('transcription', 'biological_process', 'GO:0006351', ('113', '126'))	('C228T', 'Mutation', 'rs763756456', (52, 57))
47364	32267900	In spite of the high promoter methylation fraction in wild-type (WT) samples, TERT mRNA was only expressed in the melanoma cell lines with either high methylation or intermediate methylation in combination with TERT mutations.	('TERT', 'Gene', (78, 82))	('TERT', 'Gene', '7015', (211, 215))	('TERT', 'Gene', '7015', (78, 82))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('melanoma cell', 'Disease', (114, 127))	('intermediate', 'Var', (166, 178))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma cell', 'Disease', 'MESH:D008545', (114, 127))	('TERT', 'Gene', (211, 215))	('methylation', 'biological_process', 'GO:0032259', ('179', '190'))	('high methylation', 'Var', (146, 162))	('methylation', 'biological_process', 'GO:0032259', ('151', '162'))
47366	32267900	Combined, these results suggest a complex model in which TERT expression requires either a widely open chromatin state in TERTp-WT samples due to high methylation throughout the promoter or a combination of moderate methylation fraction/chromatin accessibility in the presence of the C228T or C250T mutations.	('chromatin', 'cellular_component', 'GO:0000785', ('103', '112'))	('methylation', 'MPA', (151, 162))	('TERT', 'Gene', (57, 61))	('TERT', 'Gene', (122, 126))	('TERT', 'Gene', '7015', (57, 61))	('TERT', 'Gene', '7015', (122, 126))	('C228T', 'Mutation', 'rs763756456', (284, 289))	('C250T', 'Mutation', 'rs1184821004', (293, 298))	('chromatin', 'cellular_component', 'GO:0000785', ('237', '246'))	('methylation', 'biological_process', 'GO:0032259', ('216', '227'))	('C250T', 'Var', (293, 298))	('C228T', 'Var', (284, 289))	('TERTp', 'Gene', (122, 127))	('methylation', 'biological_process', 'GO:0032259', ('151', '162'))	('TERTp', 'Gene', '7015', (122, 127))
47370	32267900	Since the MYC oncogene has firstly been identified to activate telomerase, a variety of epigenetic or genetic mechanisms in the gene body or TERT promoter (TERTp) have followed, such as CpG methylation, histone modifications, mutations, germline genetic variations, structural variations, DNA amplification or chromosomal rearrangements.	('methylation', 'Var', (190, 201))	('histone', 'Protein', (203, 210))	('MYC', 'Gene', (10, 13))	('methylation', 'biological_process', 'GO:0032259', ('190', '201'))	('structural variations', 'Var', (266, 287))	('chromosomal rearrangements', 'Var', (310, 336))	('TERTp', 'Gene', '7015', (156, 161))	('MYC', 'Gene', '4609', (10, 13))	('DNA amplification', 'biological_process', 'GO:0006277', ('289', '306'))	('mutations', 'Var', (226, 235))	('DNA', 'cellular_component', 'GO:0005574', ('289', '292'))	('TERTp', 'Gene', (156, 161))	('TERT', 'Gene', (141, 145))	('activate', 'PosReg', (54, 62))	('TERT', 'Gene', '7015', (141, 145))	('TERT', 'Gene', (156, 160))	('TERT', 'Gene', '7015', (156, 160))
47371	32267900	A widely investigated mechanism that could induce TERT reactivation is the presence of mutations in the gene promoter.	('TERT', 'Gene', (50, 54))	('TERT', 'Gene', '7015', (50, 54))	('mutations', 'Var', (87, 96))
47372	32267900	identified two mutually exclusive TERTp point mutations that are correlated to TERT mRNA expression by creating binding motifs for the transcription factor E26 transformation-specific/ternary complex factor (ETS/TCF).	('binding', 'Interaction', (112, 119))	('transcription factor', 'molecular_function', 'GO:0000981', ('135', '155'))	('transcription', 'biological_process', 'GO:0006351', ('135', '148'))	('mutations', 'Var', (46, 55))	('TERTp', 'Gene', '7015', (34, 39))	('TERT', 'Gene', (34, 38))	('ETS/TCF', 'Gene', (208, 215))	('TERT', 'Gene', (79, 83))	('TERT', 'Gene', '7015', (34, 38))	('TERT', 'Gene', '7015', (79, 83))	('binding', 'molecular_function', 'GO:0005488', ('112', '119'))	('ETS/TCF', 'Gene', '3172', (208, 215))	('TERTp', 'Gene', (34, 39))
47373	32267900	These mutations, chr5:1,295,228 C>T and chr5:1,295,250 C>T in hg19 (-124 bp and -146 bp from the translation start site, respectively), henceforth respectively dubbed C228T and C250T, were first identified in melanoma.	('250 C>T', 'Mutation', 'rs1184821004', (51, 58))	('hg19', 'Gene', (62, 66))	('C228T', 'Mutation', 'rs763756456', (167, 172))	('228 C>T', 'Mutation', 'rs763756456', (28, 35))	('C250T', 'Mutation', 'rs1184821004', (177, 182))	('translation', 'biological_process', 'GO:0006412', ('97', '108'))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('C228T', 'Var', (167, 172))	('melanoma', 'Disease', (209, 217))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('C250T', 'Var', (177, 182))
47374	32267900	Furthermore, these mutations showed high prevalence in and were correlated with poor prognosis of cutaneous melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (108, 117))	('cutaneous melanomas', 'Disease', (98, 117))	('mutations', 'Var', (19, 28))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (98, 116))	('correlated', 'Reg', (64, 74))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (98, 117))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (98, 117))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))
47376	32267900	As such, in combination with transcription factor binding, dissociation of the repressor may result in TERT expression.	('dissociation', 'Var', (59, 71))	('TERT', 'Gene', (103, 107))	('TERT', 'Gene', '7015', (103, 107))	('transcription', 'biological_process', 'GO:0006351', ('29', '42'))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('29', '57'))	('result in', 'Reg', (93, 102))
47377	32267900	proposed that methylation of a specific CpG site in TERTp, cg11625005 (position 1,295,737 in hg19) was associated with paediatric brain tumours progression and poor prognosis.	('cg11625005', 'Chemical', '-', (59, 69))	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('TERTp', 'Gene', (52, 57))	('TERTp', 'Gene', '7015', (52, 57))	('hg19', 'Gene', (93, 97))	('cg11625005', 'Gene', (59, 69))	('methylation', 'Var', (14, 25))	('associated with', 'Reg', (103, 118))	('brain tumours', 'Disease', 'MESH:D001932', (130, 143))	('brain tumours', 'Phenotype', 'HP:0030692', (130, 143))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))	('brain tumours', 'Disease', (130, 143))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
47378	32267900	This finding was later supported by the study from Barthel et al., in which the CpG methylation was found to be correlated with TERT expression in samples lacking somatic TERT alterations and to be generally absent in normal samples adjacent to tumour tissue.	('tumour', 'Disease', 'MESH:D009369', (245, 251))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('methylation', 'Var', (84, 95))	('tumour', 'Disease', (245, 251))	('TERT', 'Gene', (171, 175))	('correlated', 'Reg', (112, 122))	('CpG', 'Gene', (80, 83))	('TERT', 'Gene', '7015', (171, 175))	('methylation', 'biological_process', 'GO:0032259', ('84', '95'))	('TERT', 'Gene', (128, 132))	('TERT', 'Gene', '7015', (128, 132))
47383	32267900	The TERTp mutational status was assessed along with the absolute presence of methylation in the TERTp at a CpG-specific resolution.	('TERTp', 'Gene', (4, 9))	('methylation', 'biological_process', 'GO:0032259', ('77', '88'))	('methylation', 'Var', (77, 88))	('TERTp', 'Gene', '7015', (4, 9))	('TERTp', 'Gene', (96, 101))	('TERTp', 'Gene', '7015', (96, 101))
47390	32267900	In order to validate the TERTp MF obtained through NGS in a quantitative manner, we have developed a ddPCR assay (Fig 2A) using methylation-sensitive restriction enzymes (MSREs) HgaI and AvaI, which recognise the CpG on position 1,295,737 (cg11625005) and 1,295,731 in hg19, respectively.	('cg11625005', 'Var', (240, 250))	('cg11625005', 'Chemical', '-', (240, 250))	('TERTp', 'Gene', (25, 30))	('TERTp', 'Gene', '7015', (25, 30))	('hg19', 'Gene', (269, 273))	('methylation', 'biological_process', 'GO:0032259', ('128', '139'))
47391	32267900	showed that methylation of the cg11625005 in TERTp, was associated with tumour progression and poor prognosis of childhood brain tumours.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('methylation', 'biological_process', 'GO:0032259', ('12', '23'))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('cg11625005', 'Chemical', '-', (31, 41))	('childhood brain tumours', 'Disease', 'MESH:D001932', (113, 136))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('TERTp', 'Gene', (45, 50))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('TERTp', 'Gene', '7015', (45, 50))	('associated', 'Reg', (56, 66))	('tumour', 'Disease', (129, 135))	('cg11625005', 'Gene', (31, 41))	('methylation', 'Var', (12, 23))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('brain tumours', 'Phenotype', 'HP:0030692', (123, 136))	('childhood brain tumours', 'Disease', (113, 136))	('tumour', 'Disease', (72, 78))
47395	32267900	Cancer cells are commonly characterised by hypermethylation of promoter CpG islands resulting in repression of tumour suppressor genes.	('repression', 'NegReg', (97, 107))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('hypermethylation', 'Var', (43, 59))	('tumour', 'Disease', (111, 117))
47396	32267900	However, in TERT, promoter hypermethylation was found to be associated with higher expression, since CTCF repressors of TERT transcription do not bind methylated sequences.	('TERT', 'Gene', '7015', (12, 16))	('TERT', 'Gene', (120, 124))	('TERT', 'Gene', '7015', (120, 124))	('CTCF', 'Gene', (101, 105))	('transcription', 'biological_process', 'GO:0006351', ('125', '138'))	('expression', 'MPA', (83, 93))	('CTCF', 'Gene', '10664', (101, 105))	('higher', 'PosReg', (76, 82))	('promoter hypermethylation', 'Var', (18, 43))	('TERT', 'Gene', (12, 16))
47400	32267900	Sanger sequencing on one naevus, fresh skin and cutaneous melanoma cell lines 518A2, 607B, A375, 94.07 and 93.08 revealed melanoma-associated TERT C250T and C228T mutations (Fig 4A).	('cutaneous melanoma', 'Disease', (48, 66))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('melanoma cell', 'Disease', (58, 71))	('A375', 'CellLine', 'CVCL:0132', (91, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (48, 66))	('C250T', 'Mutation', 'rs1184821004', (147, 152))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 66))	('melanoma cell', 'Disease', 'MESH:D008545', (58, 71))	('C228T', 'Mutation', 'rs763756456', (157, 162))	('naevus', 'Phenotype', 'HP:0003764', (25, 31))	('C228T', 'Var', (157, 162))	('TERT', 'Gene', (142, 146))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('TERT', 'Gene', '7015', (142, 146))	('melanoma', 'Disease', (122, 130))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('melanoma', 'Disease', (58, 66))
47401	32267900	Aiming to use the ddPCR method to evaluate the mutational load of the samples, the TERT C250T and C228T mutation assays were validated in three samples of which the mutation was identified in sequencing analysis, 518A2, 607B and A375 (Fig 4B).	('607B', 'Var', (220, 224))	('C228T', 'Mutation', 'rs763756456', (98, 103))	('A375', 'CellLine', 'CVCL:0132', (229, 233))	('C228T', 'Var', (98, 103))	('TERT', 'Gene', (83, 87))	('518A2', 'Var', (213, 218))	('TERT', 'Gene', '7015', (83, 87))	('C250T', 'Mutation', 'rs1184821004', (88, 93))	('A375', 'Var', (229, 233))
47402	32267900	Following the test runs, the C228T and C250T assays were used on the extended sample cohort (n = 61) (S5 Table and Fig 7C).	('C250T', 'Var', (39, 44))	('C228T', 'Mutation', 'rs763756456', (29, 34))	('C250T', 'Mutation', 'rs1184821004', (39, 44))	('C228T', 'Var', (29, 34))
47404	32267900	The C250T mutation was not present in combination with the C228T mutation in any sample, confirming that the mutations are mutually exclusive.	('C228T', 'Var', (59, 64))	('C250T', 'Var', (4, 9))	('C228T', 'Mutation', 'rs763756456', (59, 64))	('C250T', 'Mutation', 'rs1184821004', (4, 9))
47405	32267900	As the presence of mutations in the gene promoter induces TERT reactivation, we assessed the correlation between mutational status with TERT mRNA expression (n = 31).	('presence', 'Var', (7, 15))	('TERT', 'Gene', (136, 140))	('TERT', 'Gene', '7015', (136, 140))	('mutations', 'Var', (19, 28))	('TERT', 'Gene', (58, 62))	('TERT', 'Gene', '7015', (58, 62))	('induces', 'Reg', (50, 57))
47406	32267900	When WT and mutated samples (either C228T or C250T) were compared, regardless of origin of the tissue, no significant differences for TERT mRNA expression were found (Fig 5).	('TERT', 'Gene', (134, 138))	('C250T', 'Mutation', 'rs1184821004', (45, 50))	('C228T', 'Mutation', 'rs763756456', (36, 41))	('TERT', 'Gene', '7015', (134, 138))	('C250T', 'Var', (45, 50))	('C228T', 'Var', (36, 41))
47407	32267900	Moreover, TERT expression was exclusive to the melanoma cell lines, either with or without TERTp mutations (Fig 7B).	('mutations', 'Var', (97, 106))	('TERT', 'Gene', (91, 95))	('melanoma cell', 'Disease', 'MESH:D008545', (47, 60))	('TERT', 'Gene', (10, 14))	('TERT', 'Gene', '7015', (91, 95))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('TERTp', 'Gene', (91, 96))	('TERT', 'Gene', '7015', (10, 14))	('melanoma cell', 'Disease', (47, 60))	('TERTp', 'Gene', '7015', (91, 96))
47412	32267900	The accessibility in the region around cg11625005 shows a high variability, being over 90% in uveal cell lines while being intermediate to low in cutaneous melanoma cell lines (Figs 6A and 7D and S6 Table).	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma cell', 'Disease', (156, 169))	('cg11625005', 'Chemical', '-', (39, 49))	('cutaneous melanoma', 'Disease', (146, 164))	('cg11625005', 'Var', (39, 49))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (146, 164))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (146, 164))	('melanoma cell', 'Disease', 'MESH:D008545', (156, 169))
47417	32267900	In addition, we investigated whether the TERT accessibility originated from the mutant or the wild-type allele.	('TERT', 'Gene', (41, 45))	('TERT', 'Gene', '7015', (41, 45))	('mutant', 'Var', (80, 86))
47424	32267900	Moreover, in our study, methylation of cg11625005 did not stand out across the CpGs in TERTp but seemed to be affected along with adjacent CpGs in this genomic region in all samples (Fig 7A).	('methylation', 'MPA', (24, 35))	('TERTp', 'Gene', (87, 92))	('TERTp', 'Gene', '7015', (87, 92))	('cg11625005', 'Chemical', '-', (39, 49))	('cg11625005', 'Var', (39, 49))	('affected', 'Reg', (110, 118))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('did not stand out', 'Phenotype', 'HP:0003698', (50, 67))
47426	32267900	TERTp mutations has been described as a genetic mechanism responsible for induction of TERT reactivation.	('TERTp', 'Gene', '7015', (0, 5))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', (87, 91))	('TERT', 'Gene', '7015', (0, 4))	('TERT', 'Gene', '7015', (87, 91))	('mutations', 'Var', (6, 15))	('TERTp', 'Gene', (0, 5))
47427	32267900	Over the years that followed, a variety of epigenetic or genetic alterations in the gene body or TERTp have been identified, such as promoter methylation, mutations, structural variations, DNA amplification, or promoter rearrangements.	('promoter rearrangements', 'Var', (211, 234))	('mutations', 'Var', (155, 164))	('methylation', 'biological_process', 'GO:0032259', ('142', '153'))	('TERTp', 'Gene', (97, 102))	('DNA', 'cellular_component', 'GO:0005574', ('189', '192'))	('structural variations', 'Var', (166, 187))	('TERTp', 'Gene', '7015', (97, 102))	('DNA amplification', 'biological_process', 'GO:0006277', ('189', '206'))
47430	32267900	A plethora of histone modifications result in chromatin remodelling that may change accessibility of the TERTp to transcription factors, such as ETS/TCF.	('chromatin remodelling', 'MPA', (46, 67))	('transcription', 'biological_process', 'GO:0006351', ('114', '127'))	('plethora', 'Phenotype', 'HP:0001050', (2, 10))	('ETS/TCF', 'Gene', '3172', (145, 152))	('result in', 'Reg', (36, 45))	('modifications', 'Var', (22, 35))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('46', '67'))	('TERTp', 'Gene', (105, 110))	('chromatin', 'cellular_component', 'GO:0000785', ('46', '55'))	('ETS/TCF', 'Gene', (145, 152))	('TERTp', 'Gene', '7015', (105, 110))	('change', 'Reg', (77, 83))
47433	32267900	We could infer that, mutated alleles are more accessible, possibly favouring the binding of transcription factors and consequently TERT mono-allelic expression.	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('transcription', 'Protein', (92, 105))	('transcription', 'biological_process', 'GO:0006351', ('92', '105'))	('binding', 'Interaction', (81, 88))	('mutated', 'Var', (21, 28))	('TERT', 'Gene', (131, 135))	('favouring', 'PosReg', (67, 76))	('TERT', 'Gene', '7015', (131, 135))
47434	32267900	Our findings in the 518A2 cell line, harbouring the C228T TERTp mutation, are similar to the results from a study by Stern et al., in which it was found that the active mutant allele is hypomethylated.	('TERTp', 'Gene', (58, 63))	('C228T', 'Var', (52, 57))	('TERTp', 'Gene', '7015', (58, 63))	('hypomethylated', 'MPA', (186, 200))	('C228T', 'Mutation', 'rs763756456', (52, 57))
47441	32267900	Furthermore, Huang and colleagues reported that some cancer cell lines show mono-allelic expression of TERT even in the absence of TERTp mutations.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('TERTp', 'Gene', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mono-allelic', 'Var', (76, 88))	('TERT', 'Gene', (103, 107))	('TERTp', 'Gene', '7015', (131, 136))	('TERT', 'Gene', '7015', (103, 107))	('TERT', 'Gene', (131, 135))	('TERT', 'Gene', '7015', (131, 135))
47449	32267900	WM1361A, WM3506, WM1960 cell lines were a kind gift from Dr. KL Scott (Baylor College of Medicine, Houston, USA).	('WM3506', 'CellLine', 'CVCL:AP93', (9, 15))	('WM1361A', 'Var', (0, 7))	('WM1960', 'Var', (17, 23))	('WM1960', 'CellLine', 'CVCL:AP76', (17, 23))	('WM3506', 'Var', (9, 15))
47465	32267900	The presence of the C228T and C250T TERTp mutations in some samples was evaluated by conventional Sanger sequencing.	('TERTp', 'Gene', '7015', (36, 41))	('C250T', 'Var', (30, 35))	('C228T', 'Mutation', 'rs763756456', (20, 25))	('TERTp', 'Gene', (36, 41))	('C228T', 'Var', (20, 25))	('C250T', 'Mutation', 'rs1184821004', (30, 35))
47466	32267900	DNA samples were amplified through the PCRX Enhancer System (Thermo Fisher Scientific) using primers (Sigma-Aldrich) and amplification program described by McEvoy et al.. For most of the samples, the TERTp mutations were detected by the ddPCR technique according to protocol described by Corless et al., using the TERT C250T_113 Assay and C228T_113 Assay (unique assay ID dHsaEXD46675715 and dHsaEXD72405942, respectively; Bio-Rad).	('TERT', 'Gene', '7015', (314, 318))	('dHsaEXD72405942', 'Var', (392, 407))	('Rad', 'Gene', '6236', (427, 430))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('C228T_113', 'Var', (339, 348))	('Rad', 'Gene', (427, 430))	('TERTp', 'Gene', (200, 205))	('TERTp', 'Gene', '7015', (200, 205))	('TERT', 'Gene', '7015', (200, 204))	('C228T', 'Mutation', 'rs763756456', (339, 344))	('TERT', 'Gene', (200, 204))	('TERT', 'Gene', (314, 318))	('Rad', 'biological_process', 'GO:1990116', ('427', '430'))	('C250T', 'Mutation', 'rs1184821004', (319, 324))
47467	32267900	Both assays include FAM-labelled probes for the C250T and C228T mutations respectively, HEX-labelled wild-type (WT) probes, and primers for a 113-bp amplicon that encompasses the mutational sites.	('HEX', 'Gene', '3087', (88, 91))	('C250T', 'Mutation', 'rs1184821004', (48, 53))	('C250T', 'Var', (48, 53))	('HEX', 'Gene', (88, 91))	('C228T', 'Mutation', 'rs763756456', (58, 63))	('C228T', 'Var', (58, 63))
47477	32267900	The mutational fraction upon digestion with nuclease (EpiQ  Chromatin Analysis Kit aforementioned) was assessed in cutaneous melanoma cell lines with heterozygous TERTp mutations, 518A2, 94.07, A375 and 93.08.	('518A2', 'Var', (180, 185))	('A375', 'Var', (194, 198))	('Kit', 'Gene', (79, 82))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('mutations', 'Var', (169, 178))	('cutaneous melanoma', 'Disease', (115, 133))	('Kit', 'Gene', '3815', (79, 82))	('melanoma cell', 'Disease', (125, 138))	('TERTp', 'Gene', (163, 168))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (115, 133))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (115, 133))	('melanoma cell', 'Disease', 'MESH:D008545', (125, 138))	('digestion', 'biological_process', 'GO:0007586', ('29', '38'))	('A375', 'CellLine', 'CVCL:0132', (194, 198))	('TERTp', 'Gene', '7015', (163, 168))	('Chromatin', 'cellular_component', 'GO:0000785', ('60', '69'))
47478	32267900	The analysis was performed by ddPCR using the TERT C250T_113 Assay and C228T_113 Assay (unique assay ID dHsaEXD46675715 and dHsaEXD72405942, respectively; Bio-Rad) as described above.	('Rad', 'Gene', '6236', (159, 162))	('TERT', 'Gene', '7015', (46, 50))	('C228T_113', 'Var', (71, 80))	('Rad', 'Gene', (159, 162))	('C250T', 'Mutation', 'rs1184821004', (51, 56))	('C228T', 'Mutation', 'rs763756456', (71, 76))	('TERT', 'Gene', (46, 50))	('Rad', 'biological_process', 'GO:1990116', ('159', '162'))
47488	32267900	31 Dec 2019  PONE-D-19-33667 Interplay between TERT promoter mutations and methylation culminates in chromatin accessibility and TERT expression PLOS ONE Dear Ms Salgado, Thank you for submitting your manuscript to PLOS ONE.	('TERT', 'Gene', (47, 51))	('PONE-D-19-33667', 'Chemical', '-', (13, 28))	('methylation', 'biological_process', 'GO:0032259', ('75', '86'))	('TERT', 'Gene', '7015', (129, 133))	('Dear', 'Gene', (154, 158))	('TERT', 'Gene', '7015', (47, 51))	('mutations', 'Var', (61, 70))	('chromatin', 'cellular_component', 'GO:0000785', ('101', '110'))	('Dear', 'Gene', '102191832', (154, 158))	('chromatin accessibility', 'MPA', (101, 124))	('TERT', 'Gene', (129, 133))
47494	32267900	(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Summary: The authors study genetic and epigenetic contribution to TERT gene reactivation in the context of normal skin cells and melanomas.	('reactivation', 'Var', (166, 178))	('melanomas', 'Phenotype', 'HP:0002861', (219, 228))	('melanomas', 'Disease', (219, 228))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('melanomas', 'Disease', 'MESH:D008545', (219, 228))	('TERT', 'Gene', (156, 160))	('TERT', 'Gene', '7015', (156, 160))
47496	32267900	Interestingly, though the authors found that previously characterized mutations in TERT gene were unique to melanoma cell-lines, they did not seem to be correlated to expression.	('mutations', 'Var', (70, 79))	('melanoma cell', 'Disease', (108, 121))	('TERT', 'Gene', (83, 87))	('TERT', 'Gene', '7015', (83, 87))	('melanoma cell', 'Disease', 'MESH:D008545', (108, 121))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))
47502	32267900	Provide the raw tables that were used to make the box plots and other graphs Reviewer #2: Salgado et al report on the association between TERT promoter mutations, DNA methylation, and chromatin accessibility in melanoma and normal cells.	('mutations', 'Var', (152, 161))	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Disease', (211, 219))	('chromatin', 'cellular_component', 'GO:0000785', ('184', '193'))	('TERT', 'Gene', '7015', (138, 142))	('TERT', 'Gene', (138, 142))	('chromatin accessibility', 'MPA', (184, 207))	('association', 'Interaction', (118, 129))	('DNA methylation', 'biological_process', 'GO:0006306', ('163', '178'))	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))	('DNA', 'MPA', (163, 166))
47514	32267900	10.1371/journal.pone.0231418.r002  18 Feb 2020  Dear Editor,  First we would like to express our appreciation for considering our manuscript entitled "Interplay between TERT promoter mutations and methylation culminates in chromatin accessibility and TERT expression" for publication in PLOS ONE and for the thoughtful reviews provided by the referees.	('TERT', 'Gene', '7015', (169, 173))	('mutations', 'Var', (183, 192))	('TERT', 'Gene', (251, 255))	('Dear', 'Gene', (48, 52))	('TERT', 'Gene', '7015', (251, 255))	('TERT', 'Gene', (169, 173))	('Dear', 'Gene', '102191832', (48, 52))
47515	32267900	Please find our responses below: Reviewer #1:  The authors study genetic and epigenetic contribution to TERT gene reactivation in the context of normal skin cells and melanomas.	('melanomas', 'Disease', 'MESH:D008545', (167, 176))	('TERT', 'Gene', (104, 108))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('TERT', 'Gene', '7015', (104, 108))	('melanomas', 'Phenotype', 'HP:0002861', (167, 176))	('reactivation', 'Var', (114, 126))	('melanomas', 'Disease', (167, 176))
47519	32267900	Moreover, in accordance to previous studies none of the human-derived benign samples neither harbour TERTp mutation nor expressed TERT, thereby supporting the basic oncological concept that a benign cell does not undergo undefined proliferation.	('TERT', 'Gene', '7015', (101, 105))	('TERT', 'Gene', (130, 134))	('TERT', 'Gene', '7015', (130, 134))	('TERTp', 'Gene', (101, 106))	('human', 'Species', '9606', (56, 61))	('TERTp', 'Gene', '7015', (101, 106))	('TERT', 'Gene', (101, 105))	('mutation', 'Var', (107, 115))
47523	32267900	While 12 out of 25 showed C250T mutation and 5 the C228T mutations, 8 out of 25 were WT.	('C228T', 'Mutation', 'rs763756456', (51, 56))	('C250T mutation', 'Var', (26, 40))	('C250T', 'Mutation', 'rs1184821004', (26, 31))	('C228T', 'Var', (51, 56))
47524	32267900	All melanoma cell lines showed TERT expression, (n=25) irrespective of mutation and methylation status, supporting that there are additional telomerase-activating mechanisms involved in cancer besides methylation and mutations in TERTp [1-3].	('melanoma cell', 'Disease', (4, 17))	('TERTp', 'Gene', '7015', (230, 235))	('melanoma cell', 'Disease', 'MESH:D008545', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('mutations', 'Var', (217, 226))	('TERT', 'Gene', (230, 234))	('TERT', 'Gene', '7015', (230, 234))	('methylation', 'biological_process', 'GO:0032259', ('201', '212'))	('methylation', 'biological_process', 'GO:0032259', ('84', '95'))	('TERT', 'Gene', (31, 35))	('TERT', 'Gene', '7015', (31, 35))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('TERTp', 'Gene', (230, 235))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
47525	32267900	This holistic model in which mutation, methylation of TERTp and other unidentified mechanisms might explain TERT expression in WT melanoma cell lines.	('mutation', 'Var', (29, 37))	('melanoma cell', 'Disease', 'MESH:D008545', (130, 143))	('methylation', 'Var', (39, 50))	('WT melanoma', 'Disease', (127, 138))	('TERT', 'Gene', '7015', (54, 58))	('WT melanoma', 'Disease', 'MESH:D008545', (127, 138))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('TERT', 'Gene', (108, 112))	('melanoma cell', 'Disease', (130, 143))	('TERT', 'Gene', '7015', (108, 112))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('TERTp', 'Gene', (54, 59))	('TERTp', 'Gene', '7015', (54, 59))	('TERT', 'Gene', (54, 58))
47529	32267900	Interestingly, these results suggest a complex model in which TERT expression requires either a widely open chromatin state in TERTp-WT samples due to hypermethylation throughout the promoter leading to biallelically TERT activation or mono-allelic expression of the accessible mutated allele in combination with moderate (probably allele-specific) methylation fraction.	('TERTp', 'Gene', (127, 132))	('TERTp', 'Gene', '7015', (127, 132))	('chromatin', 'cellular_component', 'GO:0000785', ('108', '117'))	('TERT', 'Gene', (127, 131))	('mono-allelic expression', 'MPA', (236, 259))	('TERT', 'Gene', '7015', (127, 131))	('TERT', 'Gene', (217, 221))	('TERT', 'Gene', (62, 66))	('TERT', 'Gene', '7015', (217, 221))	('TERT', 'Gene', '7015', (62, 66))	('methylation', 'biological_process', 'GO:0032259', ('349', '360'))	('hypermethylation', 'Var', (151, 167))
47530	32267900	Reviewer #2:  Salgado et al report on the association between TERT promoter mutations, DNA methylation, and chromatin accessibility in melanoma and normal cells.	('mutations', 'Var', (76, 85))	('chromatin', 'cellular_component', 'GO:0000785', ('108', '117'))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('melanoma', 'Disease', (135, 143))	('association', 'Interaction', (42, 53))	('TERT', 'Gene', (62, 66))	('chromatin accessibility', 'MPA', (108, 131))	('DNA methylation', 'biological_process', 'GO:0006306', ('87', '102'))	('TERT', 'Gene', '7015', (62, 66))
47531	32267900	Answer: Throughout the last 20 years many processes have been identified as having an effect in the regulation of TERT gene, namely histone modifications, such as acetylation, methylation, phosphorylation, and ubiquitinization [8], CpG methylation at TERTp and TERTp mutations.	('regulation', 'MPA', (100, 110))	('effect', 'Reg', (86, 92))	('TERTp', 'Gene', (261, 266))	('TERT', 'Gene', (251, 255))	('TERTp', 'Gene', '7015', (261, 266))	('methylation', 'biological_process', 'GO:0032259', ('176', '187'))	('TERT', 'Gene', '7015', (251, 255))	('TERT', 'Gene', (261, 265))	('methylation', 'biological_process', 'GO:0032259', ('236', '247'))	('TERT', 'Gene', '7015', (261, 265))	('TERTp', 'Gene', (251, 256))	('TERTp', 'Gene', '7015', (251, 256))	('CpG', 'Var', (232, 235))	('acetylation', 'MPA', (163, 174))	('ubiquitinization', 'MPA', (210, 226))	('histone', 'MPA', (132, 139))	('mutations', 'Var', (267, 276))	('phosphorylation', 'MPA', (189, 204))	('methylation', 'MPA', (176, 187))	('regulation', 'biological_process', 'GO:0065007', ('100', '110'))	('phosphorylation', 'biological_process', 'GO:0016310', ('189', '204'))	('TERT', 'Gene', (114, 118))	('TERT', 'Gene', '7015', (114, 118))
47533	32267900	Methylation at lysine 9 of histone H3 (H3K9) and lysine 20 of H4 (H4K20) were features of telomerase-negative immortal cells, whereas methylation at lysine 4 of histone H3 (H3K4) was usual in telomerase-positive cells [11].	('lysine', 'Chemical', 'MESH:D008239', (49, 55))	('lysine', 'Chemical', 'MESH:D008239', (149, 155))	('Methylation', 'Var', (0, 11))	('lysine', 'Var', (49, 55))	('lysine', 'Chemical', 'MESH:D008239', (15, 21))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('methylation', 'biological_process', 'GO:0032259', ('134', '145'))
47534	32267900	Depletion of the histone methyltransferase SMYD3 leading to reduction of histone H3K4 methylation at TERTp led to downregulation of TERT [12] and inhibition of demethylase LSD1 led to increase of methylation at H3K4 and an TERT upregulation [13].	('TERTp', 'Gene', (101, 106))	('TERTp', 'Gene', '7015', (101, 106))	('TERT', 'Gene', (101, 105))	('TERT', 'Gene', (132, 136))	('histone H3K4 methylation', 'biological_process', 'GO:0051568', ('73', '97'))	('TERT', 'Gene', '7015', (132, 136))	('inhibition', 'Var', (146, 156))	('TERT', 'Gene', '7015', (101, 105))	('reduction', 'NegReg', (60, 69))	('SMYD3', 'Gene', (43, 48))	('H3K4', 'Protein', (211, 215))	('LSD1', 'Gene', (172, 176))	('LSD1', 'Gene', '23028', (172, 176))	('methylation', 'biological_process', 'GO:0032259', ('196', '207'))	('histone H3K4', 'Protein', (73, 85))	('downregulation', 'NegReg', (114, 128))	('methylation', 'MPA', (86, 97))	('increase', 'PosReg', (184, 192))	('TERT', 'Gene', (223, 227))	('TERT', 'Gene', '7015', (223, 227))	('methylation', 'MPA', (196, 207))
47536	32267900	It has been suggested that hypermethylation was implicated in the positive regulation of the TERTp [16] possibly due to the hampering of binding of transcriptional repressors [17].	('binding', 'Interaction', (137, 144))	('hypermethylation', 'Var', (27, 43))	('positive regulation', 'PosReg', (66, 85))	('TERTp', 'Gene', (93, 98))	('TERTp', 'Gene', '7015', (93, 98))	('binding', 'molecular_function', 'GO:0005488', ('137', '144'))	('regulation', 'biological_process', 'GO:0065007', ('75', '85'))
47537	32267900	Only few years ago with the advent of NGS-technologies, namely NGS-based bisulfite sequencing and nowadays the emerging techniques, as ddPCR that we present in our study, it became possible to draw robust conclusions on how TERTp methylation affects TERT gene regulation [6].	('methylation', 'biological_process', 'GO:0032259', ('230', '241'))	('regulation', 'biological_process', 'GO:0065007', ('260', '270'))	('TERT', 'Gene', (250, 254))	('TERTp', 'Gene', (224, 229))	('TERT', 'Gene', '7015', (250, 254))	('TERT', 'Gene', (224, 228))	('methylation', 'Var', (230, 241))	('TERTp', 'Gene', '7015', (224, 229))	('TERT', 'Gene', '7015', (224, 228))	('affects', 'Reg', (242, 249))
47538	32267900	Within the last decade with the discovery of TERTp mutations and the correlation with TERT upregulation, due to the generation of new transcription factors binding motifs, another layer of complexity arose and allowed to clarify the mechanism in some types of cancer [2, 3].	('mutations', 'Var', (51, 60))	('TERT', 'Gene', (45, 49))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('TERTp', 'Gene', (45, 50))	('TERTp', 'Gene', '7015', (45, 50))	('cancer', 'Disease', (260, 266))	('TERT', 'Gene', '7015', (45, 49))	('TERT', 'Gene', (86, 90))	('binding', 'molecular_function', 'GO:0005488', ('156', '163'))	('transcription', 'biological_process', 'GO:0006351', ('134', '147'))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('TERT', 'Gene', '7015', (86, 90))
47543	32267900	However, in accordance to previous studies none of the human-derived benign samples neither harbour TERTp mutation nor expressed TERT, thereby supporting the basic oncological concept that a benign cell does not undergo undefined proliferation.	('TERT', 'Gene', '7015', (129, 133))	('TERTp', 'Gene', (100, 105))	('mutation', 'Var', (106, 114))	('human', 'Species', '9606', (55, 60))	('TERT', 'Gene', (100, 104))	('TERTp', 'Gene', '7015', (100, 105))	('TERT', 'Gene', '7015', (100, 104))	('TERT', 'Gene', (129, 133))
47544	32267900	Analysis of tumour cell lines revealed a wide range of promoter methylation levels (from 5% to 100%) and different TERTp mutational status: 12 out of 25 showed C250T mutation, 5 the C228T mutations and 8 out of 25 were WT.	('C228T', 'Var', (182, 187))	('C250T mutation', 'Var', (160, 174))	('tumour', 'Disease', (12, 18))	('TERTp', 'Gene', (115, 120))	('TERTp', 'Gene', '7015', (115, 120))	('promoter methylation levels', 'MPA', (55, 82))	('C250T', 'Mutation', 'rs1184821004', (160, 165))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('methylation', 'biological_process', 'GO:0032259', ('64', '75'))	('C228T', 'Mutation', 'rs763756456', (182, 187))	('tumour', 'Disease', 'MESH:D009369', (12, 18))
47547	32267900	In the present study, from the chromatin accessibility assay, we could observe an interplay between DNA methylation and presence of TERTp mutations culminates in different levels of accessibility and thus TERT expression.	('DNA methylation', 'biological_process', 'GO:0006306', ('100', '115'))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('chromatin', 'cellular_component', 'GO:0000785', ('31', '40'))	('accessibility', 'MPA', (182, 195))	('TERTp', 'Gene', (132, 137))	('TERTp', 'Gene', '7015', (132, 137))	('TERT', 'Gene', (132, 136))	('TERT', 'Gene', (205, 209))	('TERT', 'Gene', '7015', (132, 136))	('TERT', 'Gene', '7015', (205, 209))	('mutations', 'Var', (138, 147))
47549	32267900	These results suggest a complex model in which TERT expression requires either a widely open chromatin state in TERTp-WT samples due to hypermethylation throughout the promoter leading to biallelically TERT activation or mono-allelic expression of the accessible mutated allele in combination with moderate (probably allele-specific) methylation fraction.	('TERT', 'Gene', (47, 51))	('TERTp', 'Gene', '7015', (112, 117))	('TERT', 'Gene', (112, 116))	('biallelically', 'MPA', (188, 201))	('TERT', 'Gene', '7015', (47, 51))	('TERT', 'Gene', (202, 206))	('TERT', 'Gene', '7015', (112, 116))	('TERT', 'Gene', '7015', (202, 206))	('chromatin', 'cellular_component', 'GO:0000785', ('93', '102'))	('methylation', 'biological_process', 'GO:0032259', ('334', '345'))	('TERTp', 'Gene', (112, 117))	('hypermethylation', 'Var', (136, 152))	('mono-allelic expression', 'MPA', (221, 244))
47562	32267900	DNA hypermethylation within TERT promoter upregulates TERT expression in cancer.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('TERT', 'Gene', '7015', (54, 58))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TERT', 'Gene', (28, 32))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('0', '20'))	('hypermethylation', 'Var', (4, 20))	('TERT', 'Gene', '7015', (28, 32))	('TERT', 'Gene', (54, 58))	('upregulates', 'PosReg', (42, 53))
47564	32267900	TERT promoter mutations in familial and sporadic melanoma.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('mutations', 'Var', (14, 23))	('melanoma', 'Disease', (49, 57))
47566	32267900	Highly recurrent TERT promoter mutations in human melanoma.	('human', 'Species', '9606', (44, 49))	('mutations', 'Var', (31, 40))	('TERT', 'Gene', (17, 21))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('TERT', 'Gene', '7015', (17, 21))	('melanoma', 'Disease', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))
47569	32267900	Allele-Specific DNA Methylation and Its Interplay with Repressive Histone Marks at Promoter-Mutant TERT Genes.	('TERT', 'Gene', (99, 103))	('DNA', 'cellular_component', 'GO:0005574', ('16', '19'))	('Methylation', 'Var', (20, 31))	('TERT', 'Gene', '7015', (99, 103))	('DNA Methylation', 'biological_process', 'GO:0006306', ('16', '31'))	('Promoter-Mutant', 'PosReg', (83, 98))
47571	32267900	Zhu J, Zhao Y, Wang S. Chromatin and epigenetic regulation of the telomerase reverse transcriptase gene.	('telomerase reverse transcriptase', 'Gene', (66, 98))	('transcriptase', 'molecular_function', 'GO:0003899', ('85', '98'))	('epigenetic regulation', 'Var', (37, 58))	('transcriptase', 'molecular_function', 'GO:0003968', ('85', '98'))	('telomerase reverse transcriptase', 'Gene', '7015', (66, 98))	('transcriptase', 'molecular_function', 'GO:0034062', ('85', '98'))	('regulation', 'biological_process', 'GO:0065007', ('48', '58'))	('Chromatin', 'cellular_component', 'GO:0000785', ('23', '32'))
47582	32267900	Guilleret I, Yan P, Grange F, Braunschweig R, Bosman FT, Benhattar J. Hypermethylation of the human telomerase catalytic subunit (hTERT) gene correlates with telomerase activity.	('telomerase activity', 'molecular_function', 'GO:0003720', ('158', '177'))	('telomerase catalytic subunit', 'Gene', (100, 128))	('human', 'Species', '9606', (94, 99))	('telomerase activity', 'MPA', (158, 177))	('hTERT', 'Gene', '7015', (130, 135))	('Hypermethylation', 'Var', (70, 86))	('hTERT', 'Gene', (130, 135))	('telomerase catalytic subunit', 'Gene', '7015', (100, 128))
47590	32267900	Methylation of the TERT promoter and risk stratification of childhood brain tumours: an integrative genomic and molecular study.	('TERT', 'Gene', (19, 23))	('TERT', 'Gene', '7015', (19, 23))	('brain tumours', 'Phenotype', 'HP:0030692', (70, 83))	('Methylation', 'Var', (0, 11))	('childhood brain tumours', 'Disease', 'MESH:D001932', (60, 83))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('childhood brain tumours', 'Disease', (60, 83))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))
47598	31173078	Heterogeneity in Mitogen-Activated Protein Kinase (MAPK) Pathway Activation in Uveal Melanoma With Somatic GNAQ and GNA11 Mutations The activation of the mitogen-activated protein kinase (MAPK) pathway has been suggested as the major downstream target when GNAQ and GNA11 (GNAQ/11) are mutated in uveal melanoma (UM).	('Melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('mutated', 'Var', (286, 293))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('uveal melanoma', 'Disease', 'MESH:C536494', (297, 311))	('Mutations', 'Var', (122, 131))	('uveal melanoma', 'Disease', (297, 311))	('GNAQ', 'Gene', '2776', (257, 261))	('UM', 'Phenotype', 'HP:0007716', (313, 315))	('GNA11', 'Gene', (116, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (297, 311))	('GNAQ', 'Gene', (257, 261))	('GNAQ', 'Gene', '2776', (107, 111))	('GNAQ', 'Gene', '2776', (273, 277))	('Activation', 'PosReg', (65, 75))	('GNAQ', 'Gene', (107, 111))	('GNAQ', 'Gene', (273, 277))	('MAPK', 'molecular_function', 'GO:0004707', ('188', '192'))	('Uveal Melanoma', 'Disease', (79, 93))	('Uveal Melanoma', 'Disease', 'MESH:C536494', (79, 93))	('MAPK', 'molecular_function', 'GO:0004707', ('51', '55'))	('melanoma', 'Phenotype', 'HP:0002861', (303, 311))
47599	31173078	However, clinical trials with single agent MEK inhibitor showed no clinical significance in altering the overall outcome of the disease in UM; therefore, we investigated the correlation between naturally occurring mutations in GNAQ/11 and activation of MAPK pathway in vivo in primary UM.	('MEK', 'Gene', '5609', (43, 46))	('MAPK', 'molecular_function', 'GO:0004707', ('253', '257'))	('UM', 'Phenotype', 'HP:0007716', (285, 287))	('GNAQ', 'Gene', '2776', (227, 231))	('UM', 'Phenotype', 'HP:0007716', (139, 141))	('mutations', 'Var', (214, 223))	('MAPK pathway', 'Pathway', (253, 265))	('GNAQ', 'Gene', (227, 231))	('MEK', 'Gene', (43, 46))
47600	31173078	Screening for activating mutations in codons 183 and 209 of GNAQ/11 was carried out by sequencing and restriction fragment length polymorphism (RFLP) in a cohort of 42 primary UM.	('mutations', 'Var', (25, 34))	('GNAQ', 'Gene', (60, 64))	('activating', 'PosReg', (14, 24))	('GNAQ', 'Gene', '2776', (60, 64))	('UM', 'Phenotype', 'HP:0007716', (176, 178))
47601	31173078	Potential downstream signaling of mutant and wild type GNAQ/11 was studied by transient transfection assay in nonmutant cell lines.	('GNAQ', 'Gene', (55, 59))	('GNAQ', 'Gene', '2776', (55, 59))	('signaling', 'biological_process', 'GO:0023052', ('21', '30'))	('mutant', 'Var', (34, 40))
47603	31173078	Tumors with GNAQ/11 mutations showed variations in the activation of ERK1/2 with significant tumor heterogeneity.	('GNAQ', 'Gene', (12, 16))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('ERK1/2', 'Gene', (69, 75))	('ERK1/2', 'Gene', '5595;5594', (69, 75))	('tumor', 'Disease', (93, 98))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('GNAQ', 'Gene', '2776', (12, 16))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('ERK1', 'molecular_function', 'GO:0004707', ('69', '73'))	('mutations', 'Var', (20, 29))	('activation', 'PosReg', (55, 65))
47604	31173078	Weak and undetectable ERK1/2 activation was observed in 4/35 (11.4%) and 8/35 (22.9%) of the GNAQ/11 mutant UM, respectively.	('activation', 'PosReg', (29, 39))	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('ERK1', 'molecular_function', 'GO:0004707', ('22', '26'))	('GNAQ', 'Gene', '2776', (93, 97))	('mutant', 'Var', (101, 107))	('ERK1/2', 'Gene', (22, 28))	('ERK1/2', 'Gene', '5595;5594', (22, 28))	('GNAQ', 'Gene', (93, 97))
47605	31173078	Tumor heterogeneity of GNAQ/11 mutations was also observed in a subset of tumors.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (31, 40))	('GNAQ', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('GNAQ', 'Gene', '2776', (23, 27))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
47606	31173078	Our results indicate that there is marked variation in MAPK activation in UM with GNAQ/11 mutations.	('MAPK', 'molecular_function', 'GO:0004707', ('55', '59'))	('mutations', 'Var', (90, 99))	('MAPK activation', 'biological_process', 'GO:0000187', ('55', '70'))	('GNAQ', 'Gene', (82, 86))	('activation', 'PosReg', (60, 70))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('MAPK', 'Protein', (55, 59))	('GNAQ', 'Gene', '2776', (82, 86))
47608	31173078	It has been suggested that such activation is mostly due to somatic mutations in GNAQ and GNA11 (GNAQ/11).	('GNA11', 'Gene', (90, 95))	('activation', 'PosReg', (32, 42))	('GNAQ', 'Gene', '2776', (97, 101))	('GNAQ', 'Gene', (81, 85))	('mutations', 'Var', (68, 77))	('GNAQ', 'Gene', '2776', (81, 85))	('GNAQ', 'Gene', (97, 101))
47610	31173078	With the exception of blue nevi and melanomas of the central nervous system, somatic mutations in GNAQ/11 are unique to UM and have not been reported in other cancers.	('cancers', 'Disease', (159, 166))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanomas of the central nervous system', 'Disease', 'MESH:D008545', (36, 75))	('GNAQ', 'Gene', (98, 102))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('mutations', 'Var', (85, 94))	('melanomas of the central nervous system', 'Disease', (36, 75))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('UM', 'Phenotype', 'HP:0007716', (120, 122))	('blue nevi', 'Phenotype', 'HP:0100814', (22, 31))	('GNAQ', 'Gene', '2776', (98, 102))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('nevi', 'Phenotype', 'HP:0003764', (27, 31))
47611	31173078	Mutations in another two genes PLCB4 and CYSLTR2 leading to constitutively activated G-protein signaling have also been reported in UM, although at much lower frequencies than GNAQ/11.	('CYSLTR2', 'Gene', '57105', (41, 48))	('CYSLTR2', 'Gene', (41, 48))	('GNAQ', 'Gene', '2776', (176, 180))	('PLCB4', 'Gene', '5332', (31, 36))	('constitutively activated G-protein signaling', 'MPA', (60, 104))	('UM', 'Phenotype', 'HP:0007716', (132, 134))	('Mutations', 'Var', (0, 9))	('signaling', 'biological_process', 'GO:0023052', ('95', '104'))	('GNAQ', 'Gene', (176, 180))	('PLCB4', 'Gene', (31, 36))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
47612	31173078	Mutations in GNAQ, GNA11, PLCB4, and CYSLTR2 are mostly mutually exclusive.	('CYSLTR2', 'Gene', (37, 44))	('PLCB4', 'Gene', '5332', (26, 31))	('GNA11', 'Gene', (19, 24))	('GNAQ', 'Gene', (13, 17))	('PLCB4', 'Gene', (26, 31))	('Mutations', 'Var', (0, 9))	('CYSLTR2', 'Gene', '57105', (37, 44))	('GNAQ', 'Gene', '2776', (13, 17))
47618	31173078	It has been suggested that resistance genes such as the RNA helixase DDX21 and the cyclin-dependent kinase regulator CDK5R1 could play an important role in lack of response to selumetinib in GNAQ/11 mutant UM.	('CDK5R1', 'Gene', '8851', (117, 123))	('cyclin', 'molecular_function', 'GO:0016538', ('83', '89'))	('CDK', 'molecular_function', 'GO:0004693', ('117', '120'))	('RNA', 'cellular_component', 'GO:0005562', ('56', '59'))	('DDX21', 'Gene', (69, 74))	('response', 'MPA', (164, 172))	('selumetinib', 'Chemical', 'MESH:C517975', (176, 187))	('GNAQ', 'Gene', '2776', (191, 195))	('CDK5R1', 'Gene', (117, 123))	('DDX21', 'Gene', '9188', (69, 74))	('GNAQ', 'Gene', (191, 195))	('UM', 'Phenotype', 'HP:0007716', (206, 208))	('mutant', 'Var', (199, 205))
47620	31173078	A study on primary UM with GNAQQ209L/P mutation suggested that a subset of tumors with the mutation showed weak or no activation in MAPK.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('mutation', 'Var', (91, 99))	('activation', 'PosReg', (118, 128))	('GNAQ', 'Gene', '2776', (27, 31))	('MAPK', 'molecular_function', 'GO:0004707', ('132', '136'))	('GNAQ', 'Gene', (27, 31))	('MAPK', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('UM', 'Phenotype', 'HP:0007716', (19, 21))	('tumors', 'Disease', (75, 81))
47622	31173078	Our current study was conceived prior to the two clinical trials and was carried out to validate our preliminary findings that there was a lack of MAPK activation in a significant number of UM primary tumors with somatic GNAQ/11 mutations.	('MAPK', 'molecular_function', 'GO:0004707', ('147', '151'))	('UM', 'Phenotype', 'HP:0007716', (190, 192))	('MAPK', 'Gene', (147, 151))	('mutations', 'Var', (229, 238))	('MAPK activation', 'biological_process', 'GO:0000187', ('147', '162'))	('GNAQ', 'Gene', '2776', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('primary tumors', 'Disease', (193, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('GNAQ', 'Gene', (221, 225))	('primary tumors', 'Disease', 'MESH:D009369', (193, 207))
47634	31173078	Both UM7007 and ARPE-19 were confirmed to have no GNAQ/11, mutations, whereas MEL202, 92.1 and MEL270 all were confirmed to have GNAQ codon 209 mutation.	('GNAQ', 'Gene', (129, 133))	('GNAQ', 'Gene', '2776', (50, 54))	('GNAQ', 'Gene', '2776', (129, 133))	('mutations', 'Var', (59, 68))	('UM7007', 'Var', (5, 11))	('UM', 'Phenotype', 'HP:0007716', (5, 7))	('ARPE-19', 'CellLine', 'CVCL:0145', (16, 23))	('GNAQ', 'Gene', (50, 54))
47636	31173078	Direct (Sanger) sequencing was used for confirmation of mutations in GNAQ/11 and mutational screening for hotspot mutations in PLCB4 (codon 630) and CYSLTR2 (codon 129).	('mutations', 'Var', (56, 65))	('codon 630', 'Var', (134, 143))	('mutations', 'Var', (114, 123))	('codon 129', 'Var', (158, 167))	('PLCB4', 'Gene', '5332', (127, 132))	('GNAQ', 'Gene', '2776', (69, 73))	('CYSLTR2', 'Gene', '57105', (149, 156))	('CYSLTR2', 'Gene', (149, 156))	('GNAQ', 'Gene', (69, 73))	('PLCB4', 'Gene', (127, 132))
47638	31173078	The sequence results were read by aligning with the reference sequence provided in Genebank accession numbers NM_002072.2 (GNAQ), NM_002067 (GNA11), NM_000933 (PLCB4), and NM_001308471 (CYSLTR2) utilizing the Sequencher software (version 4.8; Gene Codes Corp, Ann Arbor, MI, USA).	('NM_002067', 'Var', (130, 139))	('GNAQ', 'Gene', (123, 127))	('PLCB4', 'Gene', (160, 165))	('CYSLTR2', 'Gene', '57105', (186, 193))	('GNAQ', 'Gene', '2776', (123, 127))	('CYSLTR2', 'Gene', (186, 193))	('NM_001308471', 'Var', (172, 184))	('PLCB4', 'Gene', '5332', (160, 165))	('NM_000933', 'Var', (149, 158))
47639	31173078	Plasmids containing the GNAQ (wild type), GNA11 (wild type), GNAQQ209L, and GNA11Q209L cDNAs were obtained from the Missouri S&T cDNA Resource Center.	('GNAQ', 'Gene', '2776', (24, 28))	('GNAQ', 'Gene', (61, 65))	('GNAQ', 'Gene', (24, 28))	('GNA11Q209L', 'Var', (76, 86))	('GNAQ', 'Gene', '2776', (61, 65))
47643	31173078	Then they were transiently transfected with 4 mug of plasmid pcDNA3.1+ constructed with complete coding regions of wild type GNAQ, and GNA11, and mutant GNAQQ209L, and GNA11Q209L genes using a transfection reagent (Lipofectamine 2000; Invitrogen, Carlsbad, CA, USA).	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (215, 233))	('GNAQ', 'Gene', '2776', (125, 129))	('GNAQ', 'Gene', '2776', (153, 157))	('GNA11Q209L', 'Gene', (168, 178))	('mutant', 'Var', (146, 152))	('GNAQ', 'Gene', (125, 129))	('mug', 'molecular_function', 'GO:0043739', ('46', '49'))	('GNA11', 'Gene', (135, 140))	('GNAQ', 'Gene', (153, 157))
47658	31173078	Allele frequencies of mutations in GNAQ/11 were extracted using the query function within BCF tools of SAM (Sequence Alignment/Map) format and tools.	('GNAQ', 'Gene', (35, 39))	('mutations', 'Var', (22, 31))	('GNAQ', 'Gene', '2776', (35, 39))
47659	31173078	The Table summarizes the frequency of GNAQ/11 mutations observed in primary UM included in our study.	('primary UM', 'Disease', (68, 78))	('GNAQ', 'Gene', '2776', (38, 42))	('mutations', 'Var', (46, 55))	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('GNAQ', 'Gene', (38, 42))
47660	31173078	Out of the 42 primary UM evaluated, 34 (80.9%) had mutations in only one of the GNAQ/11 genes.	('GNAQ', 'Gene', '2776', (80, 84))	('UM', 'Phenotype', 'HP:0007716', (22, 24))	('mutations', 'Var', (51, 60))	('GNAQ', 'Gene', (80, 84))
47661	31173078	One (2.3%) UM tumor had mutations in both genes and one tumor had two different mutations in GNA11, while seven (16.7%) were GNAQ/11 wild type.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (14, 19))	('UM', 'Phenotype', 'HP:0007716', (11, 13))	('GNAQ', 'Gene', '2776', (125, 129))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('GNAQ', 'Gene', (125, 129))	('mutations', 'Var', (24, 33))	('GNA11', 'Gene', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
47662	31173078	Most mutations (30/35) were in codon 209 of GNAQ/11.	('GNAQ', 'Gene', (44, 48))	('mutations', 'Var', (5, 14))	('GNAQ', 'Gene', '2776', (44, 48))
47663	31173078	Seven of the GNAQ mutations were A>T GNAQQ209L and six were A>C GNAQQ209P.	('GNAQ', 'Gene', (64, 68))	('GNAQ', 'Gene', (37, 41))	('GNAQ', 'Gene', (13, 17))	('GNAQ', 'Gene', '2776', (37, 41))	('GNAQ', 'Gene', '2776', (64, 68))	('GNAQQ209P', 'Mutation', 'rs121913492', (64, 73))	('GNAQ', 'Gene', '2776', (13, 17))	('mutations', 'Var', (18, 27))
47669	31173078	Out of the 15 tumors with mutation in either GNAQ/11, 14 (93.3%) showed detectable but highly variable pERK1/2, 10 (66.7%) showed pMEK1/2 and 15 (100%) showed pAKT levels.	('AKT', 'Gene', '207', (160, 163))	('mutation', 'Var', (26, 34))	('ERK1/2', 'Gene', (104, 110))	('ERK1/2', 'Gene', '5595;5594', (104, 110))	('15 tumors', 'Disease', 'MESH:C567447', (11, 20))	('MEK1/2', 'Gene', '5604;5605', (131, 137))	('pERK', 'Gene', '9451', (103, 107))	('MEK1/2', 'Gene', (131, 137))	('pERK', 'Gene', (103, 107))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('15 tumors', 'Disease', (11, 20))	('GNAQ', 'Gene', (45, 49))	('AKT', 'Gene', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('GNAQ', 'Gene', '2776', (45, 49))
47670	31173078	The tumor with CYSLTR2 mutation showed detectable pMEK1/2 but no pERK1/2.	('tumor', 'Disease', (4, 9))	('ERK1/2', 'Gene', (66, 72))	('MEK1/2', 'Gene', '5604;5605', (51, 57))	('mutation', 'Var', (23, 31))	('MEK1/2', 'Gene', (51, 57))	('pERK', 'Gene', (65, 69))	('ERK1/2', 'Gene', '5595;5594', (66, 72))	('pERK', 'Gene', '9451', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('CYSLTR2', 'Gene', '57105', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CYSLTR2', 'Gene', (15, 22))
47676	31173078	UM cell lines with GNAQQ209 mutations (92.1, MEL202 and Mel270) showed variable pERK1/2 and pMEK1/2 levels, Figure 1B.	('GNAQ', 'Gene', (19, 23))	('ERK1/2', 'Gene', '5595;5594', (81, 87))	('MEK1/2', 'Gene', '5604;5605', (93, 99))	('MEK1/2', 'Gene', (93, 99))	('pERK', 'Gene', (80, 84))	('GNAQ', 'Gene', '2776', (19, 23))	('pERK', 'Gene', '9451', (80, 84))	('ERK1/2', 'Gene', (81, 87))	('mutations', 'Var', (28, 37))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
47677	31173078	The activation of ERK1/2 was also assessed by immunohistochemistry using the same pERK/2 antibody in 39 primary tumors and correlated with GNAQ/11 status (13 with GNAQ mutation, 18 with GNA11 mutation, one with GNAQ and GNA11 mutations, and seven with no mutation in both genes).	('antibody', 'cellular_component', 'GO:0019814', ('89', '97'))	('GNAQ', 'Gene', '2776', (211, 215))	('pERK', 'Gene', (82, 86))	('pERK', 'Gene', '9451', (82, 86))	('GNAQ', 'Gene', (211, 215))	('ERK1/2', 'Gene', (18, 24))	('primary tumors', 'Disease', (104, 118))	('GNAQ', 'Gene', '2776', (163, 167))	('ERK1/2', 'Gene', '5595;5594', (18, 24))	('GNAQ', 'Gene', '2776', (139, 143))	('antibody', 'molecular_function', 'GO:0003823', ('89', '97'))	('antibody', 'cellular_component', 'GO:0042571', ('89', '97'))	('GNAQ', 'Gene', (163, 167))	('GNA11', 'Gene', (186, 191))	('GNAQ', 'Gene', (139, 143))	('ERK1', 'molecular_function', 'GO:0004707', ('18', '22'))	('mutation', 'Var', (168, 176))	('primary tumors', 'Disease', 'MESH:D009369', (104, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('antibody', 'cellular_component', 'GO:0019815', ('89', '97'))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))
47679	31173078	Of the UM tumors with GNAQ/11 mutation, 23/35 (65.7%) showed strong to moderate staining for pERK1/2 (in >=10% of tumor cells) with only (28.6%) showing staining in >50% of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('mutation', 'Var', (30, 38))	('tumors', 'Disease', (10, 16))	('GNAQ', 'Gene', '2776', (22, 26))	('staining', 'MPA', (80, 88))	('tumor', 'Disease', (10, 15))	('GNAQ', 'Gene', (22, 26))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumor', 'Disease', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('ERK1/2', 'Gene', (94, 100))	('ERK1/2', 'Gene', '5595;5594', (94, 100))	('UM', 'Phenotype', 'HP:0007716', (7, 9))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('pERK', 'Gene', '9451', (93, 97))	('tumor', 'Disease', (173, 178))	('pERK', 'Gene', (93, 97))
47683	31173078	No statistically significant difference was observed between tumors with and without GNAQ/11 mutations (P = 0.49).	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('mutations', 'Var', (93, 102))	('GNAQ', 'Gene', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('GNAQ', 'Gene', '2776', (85, 89))
47684	31173078	Through reviewing the RFLP and sequencing results we observed variations in the mutant/wild type allele ratios in different tumors.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (124, 130))	('mutant/wild', 'Var', (80, 91))
47685	31173078	Such variations strongly suggested tumor heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('variations', 'Var', (5, 15))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('suggested', 'Reg', (25, 34))
47687	31173078	Two of these tumors had the GNA11Q209P, one had the GNA11R183C and one had the GNAQQ209P mutations.	('GNAQQ209P', 'Mutation', 'rs121913492', (79, 88))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('GNA11Q209P', 'Var', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
47688	31173078	Variation in GNA11 mutation status was observed in two out of the four tumors, Figure 2.	('mutation', 'Var', (19, 27))	('GNA11', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
47689	31173078	In the remaining two tumors both the stained and unstained areas of the tumor showed heterozygous mutation.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('heterozygous mutation', 'Var', (85, 106))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', (72, 77))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
47690	31173078	Interestingly, in the two tumors showing variation in GNA11 mutation, the areas with strong pERK1/2 immunostaining showed no detectable GNA11 mutation, while the tumor areas with no pERK1/2 immunostaining showed heterozygous GNA11 mutation, Figure 2A.	('pERK', 'Gene', '9451', (92, 96))	('mutation', 'Var', (60, 68))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('GNA11', 'Gene', (54, 59))	('ERK1/2', 'Gene', (183, 189))	('ERK1/2', 'Gene', '5595;5594', (183, 189))	('tumor', 'Disease', (26, 31))	('mutation', 'Var', (231, 239))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('GNA11', 'Gene', (136, 141))	('pERK', 'Gene', (182, 186))	('variation', 'Var', (41, 50))	('ERK1/2', 'Gene', (93, 99))	('ERK1/2', 'Gene', '5595;5594', (93, 99))	('pERK', 'Gene', '9451', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('pERK', 'Gene', (92, 96))	('tumors', 'Disease', (26, 32))
47692	31173078	The average allele frequency of mutations in GNAQ was 0.42 (range, 0.07-0.65) and of GNA11 was 0.41 (range, 0.05-0.56).	('GNAQ', 'Gene', '2776', (45, 49))	('mutations', 'Var', (32, 41))	('GNAQ', 'Gene', (45, 49))	('GNA11', 'Gene', (85, 90))
47694	31173078	The two tumors with very low mutation allele frequencies (0.05 and 0.07) were those with mutations in both genes.	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('mutations', 'Var', (89, 98))
47697	31173078	Variations in downstream signaling between UM (UM7007) and control cell lines (ARPE-19) were observed after transfection of wild-type or mutant GNAQ/11, Figure 3.	('GNAQ', 'Gene', '2776', (144, 148))	('downstream signaling', 'MPA', (14, 34))	('Variations', 'Reg', (0, 10))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('GNAQ', 'Gene', (144, 148))	('ARPE-19', 'CellLine', 'CVCL:0145', (79, 86))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('signaling', 'biological_process', 'GO:0023052', ('25', '34'))	('mutant', 'Var', (137, 143))
47698	31173078	Activation of ERK1/2 was observed in UM7007 cells transfected with both mutant and wild-type GNAQ/11, while ARPE-19 control cells did not show ERK1/2 activation with transfection of either constructs.	('ERK1/2', 'Gene', (143, 149))	('ERK1/2', 'Gene', '5595;5594', (143, 149))	('ERK1/2', 'Gene', (14, 20))	('mutant', 'Var', (72, 78))	('ERK1', 'molecular_function', 'GO:0004707', ('143', '147'))	('ERK1/2', 'Gene', '5595;5594', (14, 20))	('GNAQ', 'Gene', '2776', (93, 97))	('UM', 'Phenotype', 'HP:0007716', (37, 39))	('Activation', 'PosReg', (0, 10))	('ARPE-19', 'CellLine', 'CVCL:0145', (108, 115))	('ERK1', 'molecular_function', 'GO:0004707', ('14', '18'))	('GNAQ', 'Gene', (93, 97))
47700	31173078	Suppression of AKT activation was observed in the ARPE-19 cells in particular with the mutant constructs but not in UM7007 which showed activation of AKT.	('AKT', 'Gene', '207', (15, 18))	('ARPE-19', 'CellLine', 'CVCL:0145', (50, 57))	('activation', 'PosReg', (19, 29))	('AKT', 'Gene', '207', (150, 153))	('mutant', 'Var', (87, 93))	('AKT', 'Gene', (15, 18))	('Suppression', 'NegReg', (0, 11))	('UM', 'Phenotype', 'HP:0007716', (116, 118))	('AKT', 'Gene', (150, 153))
47703	31173078	Our study supports the reported high frequency of GNAQ/11 mutations in primary UM tumors but also identifies that a significant subset (34.3%) of these primary UM tumors with GNAQ/11 mutation have absent or low-level activation of the MAPK pathway with considerable tumor heterogeneity.	('mutations', 'Var', (58, 67))	('tumors', 'Disease', (82, 88))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', (266, 271))	('tumor', 'Disease', (82, 87))	('activation', 'PosReg', (217, 227))	('low-level', 'NegReg', (207, 216))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('GNAQ', 'Gene', '2776', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('mutation', 'Var', (183, 191))	('GNAQ', 'Gene', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('UM', 'Phenotype', 'HP:0007716', (160, 162))	('tumors', 'Disease', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('GNAQ', 'Gene', '2776', (175, 179))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('GNAQ', 'Gene', (175, 179))	('MAPK pathway', 'Pathway', (235, 247))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('MAPK', 'molecular_function', 'GO:0004707', ('235', '239'))
47704	31173078	Tumor areas with confirmed mutation in GNAQ/11 showed variation in activation of the MAPK pathway suggesting that these mutations are not sufficient for MAPK activation in vivo.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('MAPK activation', 'biological_process', 'GO:0000187', ('153', '168'))	('GNAQ', 'Gene', (39, 43))	('activation', 'PosReg', (67, 77))	('MAPK', 'molecular_function', 'GO:0004707', ('85', '89'))	('mutation', 'Var', (27, 35))	('MAPK', 'molecular_function', 'GO:0004707', ('153', '157'))	('GNAQ', 'Gene', '2776', (39, 43))	('MAPK pathway', 'Pathway', (85, 97))
47705	31173078	This lack of direct MAPK activation resulting from GNAQ/11 mutation in UM was also evident in our transfection experiments that indicate that there may be cell-specific differences in the levels of MAPK activation due to in GNAQ/11 mutation.	('GNAQ', 'Gene', '2776', (51, 55))	('GNAQ', 'Gene', '2776', (224, 228))	('MAPK', 'molecular_function', 'GO:0004707', ('198', '202'))	('MAPK', 'molecular_function', 'GO:0004707', ('20', '24'))	('MAPK', 'Gene', (20, 24))	('MAPK activation', 'biological_process', 'GO:0000187', ('20', '35'))	('UM', 'Phenotype', 'HP:0007716', (71, 73))	('GNAQ', 'Gene', (224, 228))	('MAPK activation', 'biological_process', 'GO:0000187', ('198', '213'))	('mutation', 'Var', (59, 67))	('GNAQ', 'Gene', (51, 55))	('MAPK', 'MPA', (198, 202))	('activation', 'PosReg', (25, 35))	('activation', 'PosReg', (203, 213))
47706	31173078	The low-level of MAPK activation in primary UM with GNAQ mutation has been reported by Populo et al.	('mutation', 'Var', (57, 65))	('MAPK', 'Gene', (17, 21))	('MAPK activation', 'biological_process', 'GO:0000187', ('17', '32'))	('GNAQ', 'Gene', '2776', (52, 56))	('MAPK', 'molecular_function', 'GO:0004707', ('17', '21'))	('activation', 'PosReg', (22, 32))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('GNAQ', 'Gene', (52, 56))	('primary UM', 'Disease', (36, 46))
47708	31173078	showed that UM cell lines with mutation in GNAQ/11 had lower baseline activation of MAPK compared to cell lines (MEL285 and MEL290) with wild-type GNAQ/11.	('MAPK', 'molecular_function', 'GO:0004707', ('84', '88'))	('MAPK', 'Protein', (84, 88))	('GNAQ', 'Gene', (43, 47))	('mutation', 'Var', (31, 39))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('GNAQ', 'Gene', (147, 151))	('baseline activation', 'MPA', (61, 80))	('lower', 'NegReg', (55, 60))	('GNAQ', 'Gene', '2776', (43, 47))	('GNAQ', 'Gene', '2776', (147, 151))
47711	31173078	Also, no changes were observed in pERK1/2 levels upon transient knockdown of GNAQ in the Mel270, OMM1.3, OMM1.5 (GNAQQ209P) and the MEL202 (GNAQQ209L) mutant UM cell lines and only the 92.1 (GNAQQ209L) showed significant inhibition.	('GNAQ', 'Gene', '2776', (140, 144))	('GNAQ', 'Gene', (113, 117))	('mutant', 'Var', (151, 157))	('pERK', 'Gene', '9451', (34, 38))	('ERK1/2', 'Gene', (35, 41))	('pERK', 'Gene', (34, 38))	('GNAQ', 'Gene', (77, 81))	('ERK1/2', 'Gene', '5595;5594', (35, 41))	('GNAQ', 'Gene', (140, 144))	('GNAQ', 'Gene', '2776', (191, 195))	('GNAQQ209P', 'Mutation', 'rs121913492', (113, 122))	('GNAQ', 'Gene', '2776', (113, 117))	('UM', 'Phenotype', 'HP:0007716', (158, 160))	('MEL202', 'Gene', (132, 138))	('GNAQ', 'Gene', '2776', (77, 81))	('GNAQ', 'Gene', (191, 195))
47713	31173078	Taken together, these studies indicate that the activation of the MAPK pathway is not a major downstream target in a subset of UM with GNAQ/11 mutation.	('GNAQ', 'Gene', (135, 139))	('MAPK pathway', 'Pathway', (66, 78))	('GNAQ', 'Gene', '2776', (135, 139))	('mutation', 'Var', (143, 151))	('UM', 'Phenotype', 'HP:0007716', (127, 129))	('MAPK', 'molecular_function', 'GO:0004707', ('66', '70'))
47714	31173078	Targeted therapy utilizing selective MEK inhibition appears promising for uveal melanoma based on preliminary results of a phase II clinical trial; however, a subset of patients with GNAQ/11 mutation are resistant to this therapy.	('patients', 'Species', '9606', (169, 177))	('GNAQ', 'Gene', '2776', (183, 187))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('GNAQ', 'Gene', (183, 187))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('uveal melanoma', 'Disease', (74, 88))	('mutation', 'Var', (191, 199))	('MEK', 'Gene', (37, 40))	('MEK', 'Gene', '5609', (37, 40))
47715	31173078	It has been suggested that the resistance is due to existence of a unique subset of "MEK-resistant genes" in a subset of GNAQ mutant tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('MEK', 'Gene', '5609', (85, 88))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('GNAQ', 'Gene', '2776', (121, 125))	('GNAQ', 'Gene', (121, 125))	('mutant', 'Var', (126, 132))	('MEK', 'Gene', (85, 88))
47716	31173078	Our findings provide another possible explanation and suggest that tumor heterogeneity and variability of MAPK activation could be an important cause for therapy resistance.	('MAPK', 'Gene', (106, 110))	('variability', 'Var', (91, 102))	('MAPK', 'molecular_function', 'GO:0004707', ('106', '110'))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('MAPK activation', 'biological_process', 'GO:0000187', ('106', '121'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
47717	31173078	We speculate that patients with GNAQ/11 mutation who are resistant to selective MEK inhibitors have a greater proportion of tumor cells that lack MAPK activation.	('mutation', 'Var', (40, 48))	('GNAQ', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('GNAQ', 'Gene', '2776', (32, 36))	('MAPK', 'molecular_function', 'GO:0004707', ('146', '150'))	('patients', 'Species', '9606', (18, 26))	('MAPK activation', 'biological_process', 'GO:0000187', ('146', '161'))	('MEK', 'Gene', (80, 83))	('MEK', 'Gene', '5609', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
47718	31173078	In vitro studies of UM cell lines with GNAQ mutations show weaker response to the B-Raf inhibitor PLX4720 and the MEK inhibitor selumetinib than BRAF mutant cells.	('BRAF', 'Gene', (145, 149))	('GNAQ', 'Gene', (39, 43))	('B-Raf', 'Gene', '673', (82, 87))	('B-Raf', 'Gene', (82, 87))	('selumetinib', 'Chemical', 'MESH:C517975', (128, 139))	('MEK', 'Gene', (114, 117))	('MEK', 'Gene', '5609', (114, 117))	('weaker', 'NegReg', (59, 65))	('mutations', 'Var', (44, 53))	('PLX4720', 'Chemical', 'MESH:C528407', (98, 105))	('GNAQ', 'Gene', '2776', (39, 43))	('UM', 'Phenotype', 'HP:0007716', (20, 22))	('BRAF', 'Gene', '673', (145, 149))	('response', 'MPA', (66, 74))
47720	31173078	Given the potential clinical implications of a lack of correlation of GNAQ/11 mutation with ERK1/2 activation, our study highlights the need to develop additional biomarkers to assay MAPK activity in the tumor, rather than GNAQ/11 mutation status alone.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('mutation', 'Var', (78, 86))	('GNAQ', 'Gene', '2776', (223, 227))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('GNAQ', 'Gene', '2776', (70, 74))	('tumor', 'Disease', (204, 209))	('GNAQ', 'Gene', (223, 227))	('ERK1/2', 'Gene', (92, 98))	('ERK1/2', 'Gene', '5595;5594', (92, 98))	('ERK1', 'molecular_function', 'GO:0004707', ('92', '96'))	('MAPK', 'molecular_function', 'GO:0004707', ('183', '187'))	('GNAQ', 'Gene', (70, 74))
47722	31173078	In vitro studies have shown that combinations of MAPK and PI3K pathways inhibition are more effective in controlling GNAQ mutant UM and reducing the proliferation of UM cells.	('PI3K', 'molecular_function', 'GO:0016303', ('58', '62'))	('MAPK', 'molecular_function', 'GO:0004707', ('49', '53'))	('reducing', 'NegReg', (136, 144))	('GNAQ', 'Gene', '2776', (117, 121))	('PI3K pathways', 'Pathway', (58, 71))	('UM', 'Phenotype', 'HP:0007716', (166, 168))	('proliferation', 'CPA', (149, 162))	('UM', 'Phenotype', 'HP:0007716', (129, 131))	('GNAQ', 'Gene', (117, 121))	('mutant', 'Var', (122, 128))	('inhibition', 'NegReg', (72, 82))	('MAPK', 'Pathway', (49, 53))
47724	31173078	It has been suggested that GNAQ mutation occurs early in the tumorigenesis of UM.	('GNAQ', 'Gene', '2776', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('GNAQ', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('UM', 'Phenotype', 'HP:0007716', (78, 80))	('mutation', 'Var', (32, 40))	('tumor', 'Disease', (61, 66))
47725	31173078	This was based in large part on the lack of association between GNAQ and any clinical, pathologic, or molecular features associated with late-tumor progression and the identification of these mutations in uveal nevi.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('GNAQ', 'Gene', (64, 68))	('uveal nevi', 'Disease', (205, 215))	('nevi', 'Phenotype', 'HP:0003764', (211, 215))	('late-tumor', 'Disease', 'MESH:D009369', (137, 147))	('late-tumor', 'Disease', (137, 147))	('GNAQ', 'Gene', '2776', (64, 68))	('mutations', 'Var', (192, 201))	('association', 'Interaction', (44, 55))
47726	31173078	Since initiating tumor mutations should be observed as a clonal genetic alteration in all tumor cells, our study suggest that although GNAQ/11 mutations occur early in tumor development in the majority of UM tumors, a small subset of patients develop these mutations as later events in tumor progression.	('GNAQ', 'Gene', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('tumor', 'Disease', (90, 95))	('patients', 'Species', '9606', (234, 242))	('tumor', 'Disease', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('mutations', 'Var', (143, 152))	('develop', 'Reg', (243, 250))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Disease', (286, 291))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('GNAQ', 'Gene', '2776', (135, 139))	('UM', 'Phenotype', 'HP:0007716', (205, 207))	('tumors', 'Disease', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
47727	31173078	The lack of association between the GNAQ/11 mutations and any clinical, pathologic, or molecular prognostic features of UM is likely because of the high frequency of these mutations in UM.	('UM', 'Phenotype', 'HP:0007716', (185, 187))	('GNAQ', 'Gene', '2776', (36, 40))	('UM', 'Phenotype', 'HP:0007716', (120, 122))	('mutations', 'Var', (44, 53))	('GNAQ', 'Gene', (36, 40))
47728	31173078	In addition, the variation in the downstream signaling of wild-type and mutant GNAQ/11 in different cell lines suggests that the downstream molecular effects depend on other genetic alterations in the tumors.	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('variation', 'Reg', (17, 26))	('GNAQ', 'Gene', '2776', (79, 83))	('mutant', 'Var', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('GNAQ', 'Gene', (79, 83))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))
47729	31173078	Our study focused on GNAQ/11 mutations; however, mutations in two additional genes PLCB4 and CYSLTR2 have been reported as additional G-protein signaling activators.	('GNAQ', 'Gene', '2776', (21, 25))	('mutations', 'Var', (49, 58))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('PLCB4', 'Gene', '5332', (83, 88))	('CYSLTR2', 'Gene', '57105', (93, 100))	('GNAQ', 'Gene', (21, 25))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('CYSLTR2', 'Gene', (93, 100))	('activators', 'PosReg', (154, 164))	('PLCB4', 'Gene', (83, 88))	('G-protein signaling', 'MPA', (134, 153))
47730	31173078	The impact of mutations in PLCB4 and CYSLTR2 on MAPK pathway activation has not been reported.	('MAPK', 'molecular_function', 'GO:0004707', ('48', '52'))	('CYSLTR2', 'Gene', (37, 44))	('MAPK pathway', 'Pathway', (48, 60))	('PLCB4', 'Gene', '5332', (27, 32))	('PLCB4', 'Gene', (27, 32))	('CYSLTR2', 'Gene', '57105', (37, 44))	('mutations', 'Var', (14, 23))
47731	31173078	In our cohort we identified one tumor with CYSLTR2 mutation.	('CYSLTR2', 'Gene', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mutation', 'Var', (51, 59))	('CYSLTR2', 'Gene', '57105', (43, 50))	('tumor', 'Disease', (32, 37))
47734	31173078	In conclusion, our study indicates that primary UM tumors have heterogeneity in MAPK activation and GNAQ/11 mutation.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('GNAQ', 'Gene', '2776', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('MAPK', 'molecular_function', 'GO:0004707', ('80', '84'))	('MAPK activation', 'biological_process', 'GO:0000187', ('80', '95'))	('tumors', 'Disease', (51, 57))	('GNAQ', 'Gene', (100, 104))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('MAPK', 'Gene', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('mutation', 'Var', (108, 116))
47735	31173078	In contrast to the dogma that GNAQ/11 mutation leads directly to MAPK activation and tumor survival, there is a subset of GNAQ/11 mutated UM tumors which lack significant MAPK activity.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', (85, 90))	('MAPK', 'Enzyme', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('GNAQ', 'Gene', '2776', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('UM', 'Phenotype', 'HP:0007716', (138, 140))	('GNAQ', 'Gene', (30, 34))	('tumors', 'Disease', (141, 147))	('mutated', 'Var', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('GNAQ', 'Gene', '2776', (122, 126))	('GNAQ', 'Gene', (122, 126))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('MAPK activation', 'biological_process', 'GO:0000187', ('65', '80'))	('activation', 'PosReg', (70, 80))	('MAPK', 'molecular_function', 'GO:0004707', ('171', '175'))	('tumor', 'Disease', (141, 146))	('MAPK', 'molecular_function', 'GO:0004707', ('65', '69'))
47737	31173078	The lack of MAPK activation in a subset of GNAQ/11 mutated UM should also be explored as a potential major resistance factor to targeted therapy.	('MAPK activation', 'biological_process', 'GO:0000187', ('12', '27'))	('MAPK', 'molecular_function', 'GO:0004707', ('12', '16'))	('GNAQ', 'Gene', (43, 47))	('mutated', 'Var', (51, 58))	('GNAQ', 'Gene', '2776', (43, 47))	('MAPK', 'Gene', (12, 16))	('UM', 'Phenotype', 'HP:0007716', (59, 61))
47796	27507190	UM is characterized by mutations in the genes GNAQ and GNA11 which activate the PKC pathway, leading to the use of PKC inhibitors as a rational strategy to treat UM tumors.	('PKC', 'molecular_function', 'GO:0004697', ('115', '118'))	('PKC', 'molecular_function', 'GO:0004697', ('80', '83'))	('GNAQ', 'Gene', (46, 50))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('UM', 'Phenotype', 'HP:0007716', (162, 164))	('GNAQ', 'Gene', '2776', (46, 50))	('PKC', 'Gene', (115, 118))	('mutations', 'Var', (23, 32))	('PKC', 'Gene', '112476', (115, 118))	('PKC', 'Gene', (80, 83))	('PKC', 'Gene', '112476', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('GNA11', 'Gene', '2767', (55, 60))	('GNA11', 'Gene', (55, 60))	('activate', 'PosReg', (67, 75))
47806	27507190	Metastatic risk has been associated with monosomy of chromosome 3 and loss of expression of the protein BAP1 .	('Metastatic risk', 'Disease', (0, 15))	('BAP1', 'Gene', '8314', (104, 108))	('loss of expression', 'NegReg', (70, 88))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('BAP1', 'Gene', (104, 108))	('monosomy', 'Var', (41, 49))	('chromosome', 'cellular_component', 'GO:0005694', ('53', '63'))
47807	27507190	More than 80% of UM have mutations in the genes GNAQ and GNA11, which encode for small GTPases.	('mutations', 'Var', (25, 34))	('GNAQ', 'Gene', '2776', (48, 52))	('GNA11', 'Gene', (57, 62))	('GNA11', 'Gene', '2767', (57, 62))	('GNAQ', 'Gene', (48, 52))	('UM', 'Phenotype', 'HP:0007716', (17, 19))
47808	27507190	Oncogenic signaling as a result of GNAQ/11 mutations is reported to hyperactivate the PLCbeta/PKC/MAPK pathway .	('signaling', 'biological_process', 'GO:0023052', ('10', '19'))	('MAPK', 'molecular_function', 'GO:0004707', ('98', '102'))	('PKC', 'Gene', (94, 97))	('PKC', 'Gene', '112476', (94, 97))	('GNAQ', 'Gene', '2776', (35, 39))	('mutations', 'Var', (43, 52))	('PKC', 'molecular_function', 'GO:0004697', ('94', '97'))	('hyperactivate', 'PosReg', (68, 81))	('GNAQ', 'Gene', (35, 39))	('Oncogenic signaling', 'MPA', (0, 19))
47810	27507190	While the PKCi AEB071 could induce a GNAQQ209L-dependent tumor growth inhibition in vivo, no sustained MAPK pathway inhibition could be achieved and inhibition of PKC alone was unable to trigger cell death in vitro and/or tumor regression in vivo.	('PKC', 'Gene', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('GNAQ', 'Gene', '2776', (37, 41))	('PKC', 'Gene', '112476', (10, 13))	('cell death', 'biological_process', 'GO:0008219', ('195', '205'))	('GNAQ', 'Gene', (37, 41))	('AEB071', 'Var', (15, 21))	('tumor', 'Disease', (57, 62))	('PKC', 'Gene', (10, 13))	('MAPK pathway', 'Pathway', (103, 115))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (222, 227))	('PKCi', 'Gene', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('MAPK', 'molecular_function', 'GO:0004707', ('103', '107'))	('PKC', 'Gene', '112476', (163, 166))	('PKCi', 'Gene', '5584', (10, 14))	('PKC', 'molecular_function', 'GO:0004697', ('163', '166'))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))
47814	27507190	Our current knowledge of UM biology has led us to consider novel combination approaches, such as co-targeting PKC and the PI3K/AKT/mTOR pathway, MDM2/p53 signaling or cell cycle regulation.	('MDM2', 'Gene', (145, 149))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('167', '188'))	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('mTOR', 'Gene', (131, 135))	('PKC', 'Gene', (110, 113))	('mTOR', 'Gene', '2475', (131, 135))	('PKC', 'Gene', '112476', (110, 113))	('PKC', 'molecular_function', 'GO:0004697', ('110', '113'))	('p53', 'Gene', (150, 153))	('AKT', 'Gene', '207', (127, 130))	('p53', 'Gene', '7157', (150, 153))	('UM', 'Phenotype', 'HP:0007716', (25, 27))	('PI3K', 'molecular_function', 'GO:0016303', ('122', '126'))	('co-targeting', 'Var', (97, 109))	('AKT', 'Gene', (127, 130))	('MDM2', 'Gene', '4193', (145, 149))
47822	27507190	We first evaluated the anti-tumor efficacy of AEB071 in five UM PDXs: MP42, MP46, MP55, MM33 and MM52 (Supplementary Figure S1A; Tables S1 and S2).	('tumor', 'Disease', (28, 33))	('MM33', 'Var', (88, 92))	('MP42', 'Var', (70, 74))	('MP55', 'Var', (82, 86))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('MP46', 'Var', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
47827	27507190	As shown in Supplementary Figure S1B and Table S3, treatment with MEK162 or LEE011 showed a modest TGI in the five PDX models from 13-50% for MEK162 or around 35% for LEE011.	('LEE011', 'Chemical', 'MESH:C000589651', (167, 173))	('MEK162', 'Chemical', 'MESH:C581313', (66, 72))	('MEK162', 'Chemical', 'MESH:C581313', (142, 148))	('LEE011', 'Var', (76, 82))	('MEK162', 'Var', (66, 72))	('LEE011', 'Var', (167, 173))	('MEK162', 'Var', (142, 148))	('LEE011', 'Chemical', 'MESH:C000589651', (76, 82))
47830	27507190	When looking at the overall response rate (ORR; see Supplementary Materials), AEB071, MEK162, LEE011, RAD001, CGM097 induced an ORR lower than -0.5 in 32%, 22%, 13%, 34%, and 70% respectively, confirming CGM097 as the most efficient agent (Supplementary Figure S2 and Table S3).	('LEE011', 'Chemical', 'MESH:C000589651', (94, 100))	('MEK162', 'Chemical', 'MESH:C581313', (86, 92))	('LEE011', 'Var', (94, 100))	('CGM097', 'Chemical', 'MESH:C000602644', (204, 210))	('CGM097', 'Chemical', 'MESH:C000602644', (110, 116))	('AEB071', 'Var', (78, 84))	('MEK162', 'Var', (86, 92))	('RAD', 'biological_process', 'GO:1990116', ('102', '105'))	('ORR', 'MPA', (128, 131))	('RAD001', 'Var', (102, 108))	('lower', 'NegReg', (132, 137))	('CGM097', 'Var', (110, 116))
47831	27507190	We next compared the overall efficacy across all tested compounds except LEE011.	('compared', 'Reg', (8, 16))	('LEE011', 'Chemical', 'MESH:C000589651', (73, 79))	('LEE011', 'Var', (73, 79))
47834	27507190	When comparing the efficacy of all combinations across the five PDX models, two combinations showed higher anti-tumor responses: AEB071 + RAD001 and AEB071 + CGM097 (Figures 1 and 2; Supplementary Table S5).	('AEB071 + RAD001', 'Var', (129, 144))	('AEB071 + CGM097', 'Var', (149, 164))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('higher', 'PosReg', (100, 106))	('RAD', 'biological_process', 'GO:1990116', ('138', '141'))	('tumor', 'Disease', (112, 117))	('CGM097', 'Chemical', 'MESH:C000602644', (158, 164))
47835	27507190	Indeed, AEB071 + RAD001 co-treatment induced a significant TGI in three models with two tumor regressions (MP42, MM33) and one tumor stabilization (MM52).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('RAD', 'biological_process', 'GO:1990116', ('17', '20'))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (127, 132))	('AEB071 +', 'Var', (8, 16))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('TGI', 'MPA', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', (88, 93))	('RAD001', 'Gene', (17, 23))
47836	27507190	Strikingly, the AEB071 + CGM097 combination strongly reduced tumor growth, leading to tumor regression or stasis in all five PDX models.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('CGM097', 'Chemical', 'MESH:C000602644', (25, 31))	('AEB071', 'Var', (16, 22))	('tumor', 'Disease', (86, 91))	('stasis', 'CPA', (106, 112))	('CGM097', 'Gene', (25, 31))	('reduced', 'NegReg', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (61, 66))
47839	27507190	Treatment with AEB071 + LEE011 did not significantly enhance the effect of either AEB071 or LEE011 used alone (Figure 1 and Supplementary Figure S5).	('LEE011', 'Chemical', 'MESH:C000589651', (92, 98))	('LEE011', 'Var', (92, 98))	('LEE011', 'Chemical', 'MESH:C000589651', (24, 30))	('LEE011', 'Var', (24, 30))
47841	27507190	Combinations of AEB071 + MEK162, AEB071 + RAD001 and AEB071 + CGM097 scored as 13, 9 and 8 respectively (Supplementary Table S4).	('MEK162', 'Chemical', 'MESH:C581313', (25, 31))	('AEB071 + CGM097', 'Var', (53, 68))	('AEB071 + MEK162', 'Var', (16, 31))	('AEB071 +', 'Var', (33, 41))	('RAD', 'biological_process', 'GO:1990116', ('42', '45'))	('CGM097', 'Chemical', 'MESH:C000602644', (62, 68))
47844	27507190	Overall, our in vivo findings show that targeting of PKC and p53-MDM2 or PKC and mTORC1 are effective combination strategies for GNAQ/11 mutated UM PDXs, with tumor regressions often observed after PKC and p53-MDM2 inhibition.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('PKC', 'molecular_function', 'GO:0004697', ('53', '56'))	('MDM2', 'Gene', (210, 214))	('PKC', 'Gene', (53, 56))	('p53', 'Gene', '7157', (206, 209))	('PKC', 'molecular_function', 'GO:0004697', ('198', '201'))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('mTORC1', 'Gene', (81, 87))	('MDM2', 'Gene', '4193', (210, 214))	('PKC', 'Gene', '112476', (73, 76))	('GNAQ', 'Gene', '2776', (129, 133))	('MDM2', 'Gene', (65, 69))	('mTORC1', 'Gene', '382056', (81, 87))	('p53', 'Gene', (206, 209))	('GNAQ', 'Gene', (129, 133))	('PKC', 'Gene', (73, 76))	('PKC', 'molecular_function', 'GO:0004697', ('73', '76'))	('tumor', 'Disease', (159, 164))	('MDM2', 'Gene', '4193', (65, 69))	('mutated', 'Var', (137, 144))	('p53', 'Gene', '7157', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('PKC', 'Gene', '112476', (198, 201))	('mTORC1', 'cellular_component', 'GO:0031931', ('81', '87'))	('PKC', 'Gene', (198, 201))	('p53', 'Gene', (61, 64))	('PKC', 'Gene', '112476', (53, 56))
47846	27507190	In the three models that are sensitive to RAD001 (MM33, MM52, MP42), we observed a decreased in phospho-S6 (pS6) levels after RAD001 treatment, confirming that RAD001 blocked mTORC1 activity in these models.	('RAD', 'biological_process', 'GO:1990116', ('160', '163'))	('mTORC1', 'Gene', '382056', (175, 181))	('mTORC1', 'cellular_component', 'GO:0031931', ('175', '181'))	('mTORC1', 'Gene', (175, 181))	('decreased', 'NegReg', (83, 92))	('RAD001', 'Var', (126, 132))	('RAD', 'biological_process', 'GO:1990116', ('42', '45'))	('RAD', 'biological_process', 'GO:1990116', ('126', '129'))
47848	27507190	Given that CGM097 blocks protein-protein interaction between p53 and MDM2 and MDM2 is an E3 ubiquitin ligase that targets p53 for degradation by the proteasome, CGM097 treatment should lead to increased expression of p53, which in turn should result in increased expression of p21 (a direct transcriptional target of p53).	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('MDM2', 'Gene', '4193', (78, 82))	('protein-protein', 'Protein', (25, 40))	('p53', 'Gene', '7157', (217, 220))	('CGM097', 'Var', (161, 167))	('MDM2', 'Gene', '4193', (69, 73))	('expression', 'MPA', (263, 273))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('p53', 'Gene', (122, 125))	('CGM097', 'Chemical', 'MESH:C000602644', (11, 17))	('p53', 'Gene', '7157', (317, 320))	('p53', 'Gene', (217, 220))	('proteasome', 'molecular_function', 'GO:0004299', ('149', '159'))	('degradation', 'biological_process', 'GO:0009056', ('130', '141'))	('p21', 'Gene', (277, 280))	('CGM097', 'Chemical', 'MESH:C000602644', (161, 167))	('p53', 'Gene', (317, 320))	('p21', 'Gene', '644914', (277, 280))	('proteasome', 'cellular_component', 'GO:0000502', ('149', '159'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('92', '101'))	('blocks', 'NegReg', (18, 24))	('increased', 'PosReg', (193, 202))	('p53', 'Gene', '7157', (61, 64))	('MDM2', 'Gene', (78, 82))	('expression', 'MPA', (203, 213))	('increased', 'PosReg', (253, 262))	('p53', 'Gene', (61, 64))	('MDM2', 'Gene', (69, 73))	('p53', 'Gene', '7157', (122, 125))
47856	27507190	Notably and as expected, AEB071 did not affect the proliferation of control cells that do not harbor GNAQ/11mutation.	('AEB071', 'Var', (25, 31))	('GNAQ', 'Gene', (101, 105))	('GNAQ', 'Gene', '2776', (101, 105))
47861	27507190	Indeed, AEB071 + MEK162 and AEB071 + RAD001 treatments resulted in synergy scores higher than 2 for 63.6 % (7 out of 11) and 54.5 % (6 out of 11) of GNAQ/11 mutated UM cell lines respectively.	('UM', 'Phenotype', 'HP:0007716', (165, 167))	('GNAQ', 'Gene', (149, 153))	('AEB071 + MEK162', 'Var', (8, 23))	('synergy scores', 'MPA', (67, 81))	('GNAQ', 'Gene', '2776', (149, 153))	('RAD001', 'Gene', (37, 43))	('AEB071', 'Var', (28, 34))	('RAD', 'biological_process', 'GO:1990116', ('37', '40'))	('MEK162', 'Chemical', 'MESH:C581313', (17, 23))
47862	27507190	In contrast, AEB071 + CGM097 co-treatment gave rise to synergy scores around 1 for all GNAQ/11 mutated UM models, indicating that this combination was rather additive.	('synergy scores', 'MPA', (55, 69))	('GNAQ', 'Gene', '2776', (87, 91))	('mutated', 'Var', (95, 102))	('AEB071', 'Var', (13, 19))	('GNAQ', 'Gene', (87, 91))	('CGM097', 'Chemical', 'MESH:C000602644', (22, 28))	('UM', 'Phenotype', 'HP:0007716', (103, 105))
47863	27507190	Results from two representative cell lines in which combination activity was observed (Mel202 and MM66) and two cell lines in which no combination activity was observed (Mel290 and RPE1) are presented in Figure 3C and 3D and Supplementary Figure S15B.	('S15B', 'Var', (246, 250))	('combination', 'Interaction', (52, 63))	('S15B', 'SUBSTITUTION', 'None', (246, 250))
47865	27507190	This observation highlights the value of these combinations for GNAQ/11 mutated UM models and reveals a potential for achieving a therapeutic window using these drug combination approaches.	('GNAQ', 'Gene', '2776', (64, 68))	('UM', 'Phenotype', 'HP:0007716', (80, 82))	('mutated', 'Var', (72, 79))	('GNAQ', 'Gene', (64, 68))
47867	27507190	Indeed, taking all mice and all models together, 29% of mice had an ORR inferior to -0.75 after AEB071 + MEK162 treatment, whereas 49% and 79% of mice showed similar response under AEB071 + RAD001 and AEB071 + CGM097 associations respectively (Figure 1B and Supplementary Table S5).	('AEB071 + MEK162', 'Var', (96, 111))	('AEB071', 'Var', (201, 207))	('CGM097', 'Chemical', 'MESH:C000602644', (210, 216))	('RAD', 'biological_process', 'GO:1990116', ('190', '193'))	('mice', 'Species', '10090', (56, 60))	('MEK162', 'Chemical', 'MESH:C581313', (105, 111))	('ORR inferior to -0.75', 'MPA', (68, 89))	('mice', 'Species', '10090', (146, 150))	('mice', 'Species', '10090', (19, 23))
47870	27507190	We observed that co-treatment of AEB071 and RAD001 led to an enhanced loss of viability compared to monotherapies only in GNAQ/11 mutated models.	('loss', 'NegReg', (70, 74))	('AEB071', 'Var', (33, 39))	('GNAQ', 'Gene', (122, 126))	('RAD', 'biological_process', 'GO:1990116', ('44', '47'))	('RAD001', 'Var', (44, 50))	('GNAQ', 'Gene', '2776', (122, 126))	('viability', 'CPA', (78, 87))
47871	27507190	Overall, the combination treatment led to a loss of viability in all GNAQ/11 mutated lines (Figure 4A and Supplementary Figure S16A).	('viability', 'MPA', (52, 61))	('GNAQ', 'Gene', '2776', (69, 73))	('mutated', 'Var', (77, 84))	('loss', 'NegReg', (44, 48))	('S16A', 'Mutation', 'p.S16A', (127, 131))	('GNAQ', 'Gene', (69, 73))
47872	27507190	We next measured apoptosis using western blot analyses for cleaved PARP (cPARP) after three days of treatment (Figure 4B and Supplementary Figure S16B).	('S16B', 'SUBSTITUTION', 'None', (146, 150))	('PARP', 'Gene', (67, 71))	('cPARP', 'Chemical', '-', (73, 78))	('S16B', 'Var', (146, 150))	('apoptosis', 'biological_process', 'GO:0097194', ('17', '26'))	('apoptosis', 'biological_process', 'GO:0006915', ('17', '26'))	('PARP', 'Gene', '1302', (74, 78))	('PARP', 'Gene', '1302', (67, 71))	('PARP', 'Gene', (74, 78))
47873	27507190	In all of the six representative GNAQ/11 mutated cell lines, AEB071 slightly induced cPARP.	('GNAQ', 'Gene', (33, 37))	('induced', 'Reg', (77, 84))	('AEB071', 'Var', (61, 67))	('GNAQ', 'Gene', '2776', (33, 37))	('cPARP', 'Chemical', '-', (85, 90))	('cPARP', 'MPA', (85, 90))
47880	27507190	In all models, GNAQ/11 mutated and wt, AEB071 treatment led to decreased pMARCKS and pPKCdelta.	('GNAQ', 'Gene', (15, 19))	('PKCdelta', 'Gene', '5580', (86, 94))	('PKCdelta', 'Gene', (86, 94))	('decreased', 'NegReg', (63, 72))	('MARCKS', 'Gene', (74, 80))	('mutated', 'Var', (23, 30))	('GNAQ', 'Gene', '2776', (15, 19))	('MARCKS', 'Gene', '4082', (74, 80))
47881	27507190	Like the combination of AEB071 + RAD001, combination of AEB071 and CGM097 further blocked cell proliferation compared to single agent treatment in most GNAQ/11 mutated cell lines (Figure 5A and Supplementary Figure S17A).	('S17A', 'Mutation', 'p.S17A', (215, 219))	('combination', 'Var', (41, 52))	('AEB071', 'Gene', (56, 62))	('blocked', 'NegReg', (82, 89))	('cell proliferation', 'CPA', (90, 108))	('GNAQ', 'Gene', '2776', (152, 156))	('CGM097', 'Chemical', 'MESH:C000602644', (67, 73))	('RAD', 'biological_process', 'GO:1990116', ('33', '36'))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))	('CGM097', 'Gene', (67, 73))	('GNAQ', 'Gene', (152, 156))
47882	27507190	The control lines did respond to CGM097 but not to AEB071, and their combination of both did not enhance the effect of CGM097 monotherapy in these models.	('CGM097', 'Chemical', 'MESH:C000602644', (119, 125))	('CGM097', 'Var', (33, 39))	('respond', 'MPA', (22, 29))	('CGM097', 'Chemical', 'MESH:C000602644', (33, 39))
47889	27507190	AnnexinV staining was used to better quantify apoptosis and confirmed that the combination treatment strongly induced apoptosis in five cellular models (92.1, Mel202, MP46, MM66, Mel270) compared to DMSO or monotherapies (Supplementary Figures 21-23).	('apoptosis', 'CPA', (118, 127))	('MP46', 'Var', (167, 171))	('apoptosis', 'biological_process', 'GO:0097194', ('118', '127'))	('apoptosis', 'biological_process', 'GO:0006915', ('118', '127'))	('DMSO', 'Chemical', 'MESH:D004121', (199, 203))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))	('induced', 'Reg', (110, 117))
47890	27507190	Interestingly, when comparing all cell lines together, the induction of apoptosis by AEB071 + CGM097 was much stronger than the one observed with AEB071 + RAD001 (see quantification of cPARP/GAPDH in Figures 4B and 5B; AnnexinV staining in Supplementary Figures S15-18 and S20-21), reinforcing our previous finding of the higher in vivo efficacy of AEB071 + CGM097 combination on AEB071 + RAD001 treatment.	('CGM097', 'Chemical', 'MESH:C000602644', (94, 100))	('AEB071', 'Var', (85, 91))	('CGM097', 'Chemical', 'MESH:C000602644', (358, 364))	('RAD', 'biological_process', 'GO:1990116', ('389', '392'))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('59', '81'))	('RAD', 'biological_process', 'GO:1990116', ('155', '158'))	('GAPDH', 'Gene', '2597', (191, 196))	('cPARP', 'Chemical', '-', (185, 190))	('GAPDH', 'Gene', (191, 196))	('apoptosis', 'CPA', (72, 81))
47891	27507190	In conclusion, our in vitro findings show that co-inhibition of PKC and mTORC1 or PKC and p53-MDM2 are effective combination strategies for GNAQ/11 mutated UM models.	('MDM2', 'Gene', (94, 98))	('GNAQ', 'Gene', '2776', (140, 144))	('p53', 'Gene', (90, 93))	('PKC', 'molecular_function', 'GO:0004697', ('82', '85'))	('mTORC1', 'cellular_component', 'GO:0031931', ('72', '78'))	('PKC', 'molecular_function', 'GO:0004697', ('64', '67'))	('PKC', 'Gene', '112476', (82, 85))	('p53', 'Gene', '7157', (90, 93))	('mutated', 'Var', (148, 155))	('GNAQ', 'Gene', (140, 144))	('mTORC1', 'Gene', '382056', (72, 78))	('co-inhibition', 'Var', (47, 60))	('UM', 'Phenotype', 'HP:0007716', (156, 158))	('PKC', 'Gene', (64, 67))	('PKC', 'Gene', '112476', (64, 67))	('MDM2', 'Gene', '4193', (94, 98))	('PKC', 'Gene', (82, 85))	('mTORC1', 'Gene', (72, 78))
47894	27507190	Due to mutations in GNAQ/11 genes and subsequent activation of the PKC pathway, the PKC inhibitor AEB071 has been tested in preclinical and clinical settings.	('GNAQ', 'Gene', '2776', (20, 24))	('PKC', 'molecular_function', 'GO:0004697', ('67', '70'))	('PKC', 'molecular_function', 'GO:0004697', ('84', '87'))	('PKC', 'Gene', (67, 70))	('PKC', 'Gene', '112476', (67, 70))	('GNAQ', 'Gene', (20, 24))	('PKC', 'Gene', (84, 87))	('PKC', 'Gene', '112476', (84, 87))	('activation', 'PosReg', (49, 59))	('mutations', 'Var', (7, 16))
47899	27507190	In our study, treatment of AEB071 + MEK162 showed good synergy in our panel of UM cellular models and led to a significant reduction of tumor growth in all PDXs, but without clear tumor stabilization or regression as opposed to what was described in UM xenograft models.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('MEK162', 'Var', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('AEB071 + MEK162', 'Var', (27, 42))	('good synergy', 'Disease', (50, 62))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('tumor', 'Disease', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('UM', 'Phenotype', 'HP:0007716', (250, 252))	('good synergy', 'Disease', 'None', (50, 62))	('MEK162', 'Chemical', 'MESH:C581313', (36, 42))	('reduction', 'NegReg', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
47903	27507190	Only a limited efficacy of LEE011 was observed and no clear evidence of increased efficacy combining it with AEB071 was detected, indicating that co-inhibition of PKC and CDK4/6 is not an optimal strategy for treating UM.	('CDK4/6', 'Gene', '1019;1021', (171, 177))	('LEE011', 'Var', (27, 33))	('PKC', 'Gene', (163, 166))	('PKC', 'Gene', '112476', (163, 166))	('UM', 'Phenotype', 'HP:0007716', (218, 220))	('CDK', 'molecular_function', 'GO:0004693', ('171', '174'))	('CDK4/6', 'Gene', (171, 177))	('PKC', 'molecular_function', 'GO:0004697', ('163', '166'))	('LEE011', 'Chemical', 'MESH:C000589651', (27, 33))
47904	27507190	The absence of increased efficacy after AEB071 + LEE011 combination could be in part explained by the fact that AEB071 decreases expression of cyclin D1 and Rb proteins and induces G1/S cell cycle arrest , effects that are specific to CDK4/6 targeting.	('Rb proteins', 'Protein', (157, 168))	('decreases', 'NegReg', (119, 128))	('expression', 'MPA', (129, 139))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (186, 203))	('CDK4/6', 'Gene', (235, 241))	('AEB071', 'Var', (112, 118))	('LEE011', 'Chemical', 'MESH:C000589651', (49, 55))	('arrest', 'Disease', 'MESH:D006323', (197, 203))	('cyclin D1', 'Gene', '595', (143, 152))	('cyclin', 'molecular_function', 'GO:0016538', ('143', '149'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('186', '203'))	('arrest', 'Disease', (197, 203))	('induces', 'Reg', (173, 180))	('cyclin D1', 'Gene', (143, 152))	('CDK', 'molecular_function', 'GO:0004693', ('235', '238'))	('CDK4/6', 'Gene', '1019;1021', (235, 241))
47910	27507190	To further understand the mechanism of combination activity, we evaluated the synergy between AEB071 + RAD001 and AEB071 + CGM097.	('AEB071', 'Var', (94, 100))	('RAD', 'biological_process', 'GO:1990116', ('103', '106'))	('RAD001', 'Gene', (103, 109))	('CGM097', 'Chemical', 'MESH:C000602644', (123, 129))
47911	27507190	We observed that, for most GNAQ/11 mutated UM cell lines, the AEB071 + RAD001 combination was synergistic while AEB071 + CGM097 co-treatment was additive.	('GNAQ', 'Gene', '2776', (27, 31))	('CGM097', 'Chemical', 'MESH:C000602644', (121, 127))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('GNAQ', 'Gene', (27, 31))	('RAD', 'biological_process', 'GO:1990116', ('71', '74'))	('RAD001', 'Gene', (71, 77))	('AEB071', 'Var', (62, 68))
47918	27507190	In contrast, the effects of the combinations were associated with GNAQ/11 status, indicating that mutated GNAQ/11 proteins are likely to be UM drivers.	('GNAQ', 'Gene', '2776', (66, 70))	('proteins', 'Protein', (114, 122))	('GNAQ', 'Gene', (106, 110))	('GNAQ', 'Gene', (66, 70))	('mutated', 'Var', (98, 105))	('UM', 'Phenotype', 'HP:0007716', (140, 142))	('GNAQ', 'Gene', '2776', (106, 110))
47929	27507190	AEB071, MEK162, RAD001, CGM097 and LEE011 are selective inhibitors of PKC, MEK1/2, mTORC1, MDM2 and CDK4/6 respectively.	('PKC', 'Gene', (70, 73))	('LEE011', 'Chemical', 'MESH:C000589651', (35, 41))	('PKC', 'molecular_function', 'GO:0004697', ('70', '73'))	('mTORC1', 'Gene', (83, 89))	('RAD001', 'Var', (16, 22))	('MDM2', 'Gene', (91, 95))	('MEK162', 'Chemical', 'MESH:C581313', (8, 14))	('mTORC1', 'Gene', '382056', (83, 89))	('MEK1', 'molecular_function', 'GO:0004708', ('75', '79'))	('MEK1/2', 'Gene', '5604;5605', (75, 81))	('CDK4/6', 'Gene', (100, 106))	('CGM097', 'Chemical', 'MESH:C000602644', (24, 30))	('MEK1/2', 'Gene', (75, 81))	('MDM2', 'Gene', '4193', (91, 95))	('CDK', 'molecular_function', 'GO:0004693', ('100', '103'))	('RAD', 'biological_process', 'GO:1990116', ('16', '19'))	('LEE011', 'Var', (35, 41))	('CDK4/6', 'Gene', '1019;1021', (100, 106))	('PKC', 'Gene', '112476', (70, 73))	('mTORC1', 'cellular_component', 'GO:0031931', ('83', '89'))
47975	25065585	The aberrant expression and function of miRNAs has been linked to the development and progression of many human diseases, including various cancers, not least melanoma.	('melanoma', 'Disease', (159, 167))	('and', 'Gene', '387572', (82, 85))	('human', 'Species', '9606', (106, 111))	('miR', 'Gene', '220972', (40, 43))	('and', 'Gene', (82, 85))	('miR', 'Gene', (40, 43))	('linked', 'Reg', (56, 62))	('expression', 'MPA', (13, 23))	('function', 'MPA', (28, 36))	('aberrant', 'Var', (4, 12))	('and', 'Gene', '387572', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('and', 'Gene', (24, 27))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
47977	25065585	Ectopic expression of miR-211 in melanoma cell lines results in significant inhibition of growth and invasion compared to parental cells, suggesting that miR-211 normally functions as a tumor suppressor in melanocytes.	('inhibition', 'NegReg', (76, 86))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('186', '202'))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('Ectopic expression', 'Var', (0, 18))	('tumor', 'Disease', (186, 191))	('miR-211', 'Gene', (22, 29))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('and', 'Gene', (97, 100))	('miR-211', 'Gene', '406993', (22, 29))	('and', 'Gene', '387572', (97, 100))	('miR-211', 'Gene', '406993', (154, 161))	('miR-211', 'Gene', (154, 161))	('tumor suppressor', 'biological_process', 'GO:0051726', ('186', '202'))	('inhibition of growth', 'biological_process', 'GO:0045926', ('76', '96'))
47988	25065585	Functional validation showed that knockdown of 'central node genes' had the same effect on melanoma cell invasion as up-regulation of miR-211.	('up-regulation', 'PosReg', (117, 130))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('miR-211', 'Gene', (134, 141))	('miR-211', 'Gene', '406993', (134, 141))	('knockdown', 'Var', (34, 43))	('regulation', 'biological_process', 'GO:0065007', ('120', '130'))
48011	25065585	In another study, ectopic expression of miR-30b and miR-30 enhanced melanoma metastasis by creating an immunosuppressive environment via GALNT7 and increased synthesis of immunosuppressive molecules such asIL-10, and consequent reduced immune cell activation and recruitment.	('and', 'Gene', (213, 216))	('increased', 'PosReg', (148, 157))	('and', 'Gene', (144, 147))	('and', 'Gene', (48, 51))	('miR', 'Gene', '220972', (52, 55))	('synthesis', 'MPA', (158, 167))	('and', 'Gene', '387572', (213, 216))	('and', 'Gene', '387572', (144, 147))	('and', 'Gene', '387572', (48, 51))	('miR', 'Gene', (52, 55))	('melanoma metastasis', 'Disease', (68, 87))	('reduced immune cell', 'Phenotype', 'HP:0002721', (228, 247))	('recruitment', 'CPA', (263, 274))	('and', 'Gene', (259, 262))	('miR', 'Gene', '220972', (40, 43))	('melanoma metastasis', 'Disease', 'MESH:D009362', (68, 87))	('immune cell activation', 'biological_process', 'GO:0045321', ('236', '258'))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('synthesis', 'biological_process', 'GO:0009058', ('158', '167'))	('reduced', 'NegReg', (228, 235))	('miR-30b', 'Gene', '407030', (40, 47))	('miR-30b', 'Gene', (40, 47))	('immune cell activation', 'CPA', (236, 258))	('and', 'Gene', '387572', (259, 262))	('ectopic expression', 'Var', (18, 36))	('miR', 'Gene', (40, 43))	('enhanced', 'PosReg', (59, 67))	('reduced immune cell activation', 'Phenotype', 'HP:0005419', (228, 258))	('immunosuppressive environment', 'MPA', (103, 132))
48032	25065585	studied 106 primary melanomas and metastases and showed that inhibition of miR-21 was significantly associated with increased apoptosis and growth of human cutaneous melanoma, via inhibition of PTEN, Akt phosphorylation, Bax upregulation, and Bcl-2 inhibition.	('and', 'Gene', (239, 242))	('Bax', 'CPA', (221, 224))	('miR', 'Gene', '220972', (75, 78))	('PTEN', 'Protein', (194, 198))	('and', 'Gene', (136, 139))	('apoptosis', 'CPA', (126, 135))	('melanomas', 'Disease', (20, 29))	('metastases', 'Disease', (34, 44))	('increased', 'PosReg', (116, 125))	('inhibition', 'NegReg', (180, 190))	('and', 'Gene', '387572', (239, 242))	('Bcl-2', 'molecular_function', 'GO:0015283', ('243', '248'))	('and', 'Gene', (30, 33))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('miR', 'Gene', (75, 78))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('and', 'Gene', '387572', (136, 139))	('phosphorylation', 'biological_process', 'GO:0016310', ('204', '219'))	('and', 'Gene', (45, 48))	('melanomas', 'Phenotype', 'HP:0002861', (20, 29))	('and', 'Gene', '387572', (30, 33))	('human', 'Species', '9606', (150, 155))	('and', 'Gene', '387572', (45, 48))	('Akt', 'Pathway', (200, 203))	('cutaneous melanoma', 'Disease', (156, 174))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (156, 174))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (156, 174))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('growth', 'CPA', (140, 146))	('primary melanoma', 'Disease', (12, 28))	('Bcl-2', 'CPA', (243, 248))	('primary melanoma', 'Disease', 'MESH:D008545', (12, 28))	('inhibition', 'Var', (61, 71))	('upregulation', 'PosReg', (225, 237))	('inhibition', 'NegReg', (249, 259))	('melanomas', 'Disease', 'MESH:D008545', (20, 29))	('metastases', 'Disease', 'MESH:D009362', (34, 44))
48033	25065585	similarly determined that miR-21 is upregulated in primary melanomas and melanoma cell lines, and miR-21 knockdown in melanoma cell lines induced apoptosis, but not proliferation.	('melanoma', 'Disease', (73, 81))	('melanomas', 'Disease', (59, 68))	('and', 'Gene', (94, 97))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('upregulated', 'PosReg', (36, 47))	('melanoma', 'Disease', (118, 126))	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', '220972', (98, 101))	('and', 'Gene', '387572', (94, 97))	('and', 'Gene', (69, 72))	('melanomas', 'Phenotype', 'HP:0002861', (59, 68))	('apoptosis', 'CPA', (146, 155))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('miR', 'Gene', (26, 29))	('miR', 'Gene', (98, 101))	('knockdown', 'Var', (105, 114))	('and', 'Gene', '387572', (69, 72))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('apoptosis', 'biological_process', 'GO:0097194', ('146', '155'))	('apoptosis', 'biological_process', 'GO:0006915', ('146', '155'))	('primary melanoma', 'Disease', 'MESH:D008545', (51, 67))	('melanomas', 'Disease', 'MESH:D008545', (59, 68))	('induced', 'Reg', (138, 145))	('primary melanoma', 'Disease', (51, 67))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
48052	25065585	Treatment of mice with anti-miR-182 resulted in significantly fewer liver metastases compared to controls.	('fewer', 'NegReg', (62, 67))	('mice', 'Species', '10090', (13, 17))	('anti-miR-182', 'Var', (23, 35))	('metastases', 'Disease', (74, 84))	('metastases', 'Disease', 'MESH:D009362', (74, 84))
48055	25065585	Moreover, mRNA expression profiles of anti-miR-182-treated tumors differed from those of controls, supporting the notion that anti-miR-182 has a transcriptional impact on gene expression.	('gene expression', 'biological_process', 'GO:0010467', ('171', '186'))	('transcriptional', 'MPA', (145, 160))	('gene expression', 'MPA', (171, 186))	('tumors', 'Disease', (59, 65))	('anti-miR-182', 'Var', (126, 138))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('mRNA expression', 'MPA', (10, 25))	('differed', 'Reg', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
48069	25065585	miR-199 and miR-34b/c have been shown to target MET and decrease its mRNA and protein expression, and inhibition of miR-199 and miR-34b/c increase expression of MET and increased cell adhesion and migration.	('miR-34b', 'Gene', (128, 135))	('and', 'Gene', '387572', (98, 101))	('expression', 'MPA', (147, 157))	('miR', 'Gene', '220972', (116, 119))	('and', 'Gene', '387572', (193, 196))	('and', 'Gene', '387572', (8, 11))	('miR', 'Gene', (12, 15))	('miR-34b', 'Gene', '407041', (12, 19))	('miR', 'Gene', (116, 119))	('and', 'Gene', (165, 168))	('and', 'Gene', (124, 127))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('miR', 'Gene', '220972', (128, 131))	('increase', 'PosReg', (138, 146))	('miR-34b', 'Gene', (12, 19))	('cell adhesion', 'CPA', (179, 192))	('increased', 'PosReg', (169, 178))	('and', 'Gene', '387572', (165, 168))	('miR', 'Gene', '220972', (0, 3))	('and', 'Gene', '387572', (124, 127))	('miR', 'Gene', (128, 131))	('and', 'Gene', (193, 196))	('and', 'Gene', (52, 55))	('and', 'Gene', (74, 77))	('miR-34b', 'Gene', '407041', (128, 135))	('and', 'Gene', (98, 101))	('MET', 'Protein', (161, 164))	('cell adhesion', 'biological_process', 'GO:0007155', ('179', '192'))	('inhibition', 'Var', (102, 112))	('miR', 'Gene', (0, 3))	('and', 'Gene', (8, 11))	('and', 'Gene', '387572', (52, 55))	('decrease', 'NegReg', (56, 64))	('and', 'Gene', '387572', (74, 77))	('miR', 'Gene', '220972', (12, 15))
48076	25065585	Cellular epigenetic events occur at greater frequency than mutations, may be sustained during the life of the cell, and can be transmitted to progeny.	('epigenetic events', 'Var', (9, 26))	('and', 'Gene', '387572', (116, 119))	('and', 'Gene', (116, 119))
48077	25065585	Our group has conducted the most comprehensive characterization of the role of epigenetics in melanoma development.	('epigenetics', 'Var', (79, 90))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Disease', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))
48083	25065585	miR-182 has been shown to be overexpressed in human melanoma cells after epigenetic modulation, and CpG islands upstream of mature miR-182 were hypermethylated in melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('epigenetic', 'Var', (73, 83))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('melanoma', 'Disease', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('and', 'Gene', (96, 99))	('hypermethylated', 'Var', (144, 159))	('and', 'Gene', '387572', (96, 99))	('miR-182', 'Gene', (0, 7))	('human', 'Species', '9606', (46, 51))	('overexpressed', 'PosReg', (29, 42))	('and', 'Gene', '387572', (107, 110))	('and', 'Gene', (107, 110))	('miR-182', 'Gene', (131, 138))
48084	25065585	Similar work was carried out by Lodygin et al, which demonstrated that expression of miR-34a, target of the tumor suppressor gene p53, was highly reduced in various cancers due to aberrant CpG methylation of miR-34a promoter.	('expression', 'MPA', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor suppressor', 'biological_process', 'GO:0051726', ('108', '124'))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CpG methylation', 'Var', (189, 204))	('miR-34a', 'Gene', '407040', (208, 215))	('methylation', 'biological_process', 'GO:0032259', ('193', '204'))	('reduced', 'NegReg', (146, 153))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('108', '124'))	('tumor', 'Disease', (108, 113))	('miR-34a', 'Gene', '407040', (85, 92))	('miR-34a', 'Gene', (208, 215))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('miR-34a', 'Gene', (85, 92))	('cancers', 'Disease', (165, 172))
48085	25065585	Apart of other cancers, CpG methylation of miR-34a promoter was detected in melanoma cell lines (19/44; 43.2%) and primary melanoma (20/32 samples; 62.5%).	('primary melanoma', 'Disease', (115, 131))	('primary melanoma', 'Disease', 'MESH:D008545', (115, 131))	('CpG methylation', 'Var', (24, 39))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))	('and', 'Gene', (111, 114))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('and', 'Gene', '387572', (111, 114))	('miR-34a', 'Gene', (43, 50))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancers', 'Disease', (15, 22))	('miR-34a', 'Gene', '407040', (43, 50))	('detected', 'Reg', (64, 72))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('melanoma', 'Disease', (76, 84))
48092	25065585	One reason was the genomic loss in a subset of samples, second reason was the epigenetic silencing by DNA methylation and third reason was EZH2-mediated histone methylation.	('epigenetic', 'MPA', (78, 88))	('histone methylation', 'biological_process', 'GO:0016571', ('153', '172'))	('methylation', 'Var', (106, 117))	('DNA methylation', 'biological_process', 'GO:0006306', ('102', '117'))	('and', 'Gene', '387572', (118, 121))	('and', 'Gene', (118, 121))	('loss', 'NegReg', (27, 31))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
48123	25065585	A more detailed study was carried out on SPRY4-IT1, an intronic lncRNA of the SPRY4 gene, and knockdown of SPRY4-IT1 in the melanoma cell lines A375 and WM1552C resulted in significant cell death, invasion, and induction of apoptosis.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('WM1552C', 'CellLine', 'CVCL:6472', (153, 160))	('knockdown', 'Var', (94, 103))	('cell death', 'CPA', (185, 195))	('and', 'Gene', (149, 152))	('SPRY4-IT1', 'Gene', (107, 116))	('and', 'Gene', '387572', (207, 210))	('and', 'Gene', '387572', (149, 152))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('211', '233'))	('-IT1', 'Chemical', '-', (112, 116))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('A375', 'CellLine', 'CVCL:0132', (144, 148))	('melanoma', 'Disease', (124, 132))	('and', 'Gene', (90, 93))	('apoptosis', 'CPA', (224, 233))	('-IT1', 'Chemical', '-', (46, 50))	('cell death', 'biological_process', 'GO:0008219', ('185', '195'))	('invasion', 'CPA', (197, 205))	('and', 'Gene', '387572', (90, 93))	('induction', 'Reg', (211, 220))	('and', 'Gene', (207, 210))
48124	25065585	Dysregulation of SPRY4-IT1 may therefore have an important role in melanomagenesis, be used as an early biomarker, and be a key regulator for melanoma pathogenesis in humans.	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('Dysregulation', 'Var', (0, 13))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('humans', 'Species', '9606', (167, 173))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('pathogenesis', 'biological_process', 'GO:0009405', ('151', '163'))	('SPRY4-IT1', 'Gene', (17, 26))	('and', 'Gene', (115, 118))	('role', 'Reg', (59, 63))	('and', 'Gene', '387572', (115, 118))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('-IT1', 'Chemical', '-', (22, 26))	('melanoma', 'Disease', (142, 150))
48131	25065585	Llme23 knockdown suppressed the malignant properties of the human melanoma cell line YUSAC and repressed expression of the proto-oncogene Rab23.	('and', 'Gene', (91, 94))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('Llme23', 'Gene', (0, 6))	('melanoma', 'Disease', (66, 74))	('suppressed', 'NegReg', (17, 27))	('knockdown', 'Var', (7, 16))	('expression', 'MPA', (105, 115))	('and', 'Gene', '387572', (91, 94))	('human', 'Species', '9606', (60, 65))
48132	25065585	in BRAF V600E melanomas cells, and the BANCR lncRNA was found to be overexpressed and associated with malignant melanoma.	('overexpressed', 'PosReg', (68, 81))	('and', 'Gene', '387572', (82, 85))	('BRAF V600E', 'Var', (3, 13))	('and', 'Gene', (82, 85))	('malignant melanoma', 'Disease', (102, 120))	('and', 'Gene', '387572', (31, 34))	('melanomas', 'Disease', (14, 23))	('associated', 'Reg', (86, 96))	('and', 'Gene', (31, 34))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('V600E', 'Mutation', 'p.V600E', (8, 13))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('melanomas', 'Phenotype', 'HP:0002861', (14, 23))	('malignant melanoma', 'Phenotype', 'HP:0002861', (102, 120))	('melanomas', 'Disease', 'MESH:D008545', (14, 23))
48133	25065585	BANCR knockdown reduced melanoma cell migration by upregulating the chemokine CXCL11, a mediator of cell migration.	('cell migration', 'biological_process', 'GO:0016477', ('100', '114'))	('chemokine CXCL11', 'MPA', (68, 84))	('cell migration', 'biological_process', 'GO:0016477', ('33', '47'))	('reduced', 'NegReg', (16, 23))	('upregulating', 'PosReg', (51, 63))	('melanoma cell migration', 'Disease', 'MESH:D008545', (24, 47))	('knockdown', 'Var', (6, 15))	('melanoma cell migration', 'Disease', (24, 47))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('BANCR', 'Gene', (0, 5))
48135	25065585	identified single nucleotide polymorphisms (SNPs) on chromosome 9p21 that were associated with melanoma and other diseases through the allelic expression of the lncRNA ANRIL .	('associated', 'Reg', (79, 89))	('single nucleotide polymorphisms', 'Var', (11, 42))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('and', 'Gene', (104, 107))	('and', 'Gene', '387572', (104, 107))	('chromosome', 'cellular_component', 'GO:0005694', ('53', '63'))
48136	25065585	Expression studies have confirmed the coregulation of p15/CDKN2B, p16/CDKN2A, p14/ARF, and ANRIL.	('p16/CDKN2A', 'Var', (66, 76))	('ARF', 'Disease', 'MESH:D058186', (82, 85))	('p15/CDKN2B', 'Var', (54, 64))	('ARF', 'Disease', (82, 85))	('and', 'Gene', '387572', (87, 90))	('and', 'Gene', (87, 90))
48138	25065585	Modulation in ANRIL expression mediated susceptibility to several important human diseases, including melanoma.	('Modulation', 'Var', (0, 10))	('susceptibility', 'Reg', (40, 54))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('human', 'Species', '9606', (76, 81))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('ANRIL expression', 'Protein', (14, 30))
48139	25065585	Similarly, genetic aberrations of the GAS5 locus have been found in several tumors, including melanoma, breast, and prostate cancers.	('and', 'Gene', (112, 115))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('prostate cancers', 'Phenotype', 'HP:0012125', (116, 132))	('prostate cancers', 'Disease', (116, 132))	('and', 'Gene', '387572', (112, 115))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('GAS5', 'Gene', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('GAS', 'molecular_function', 'GO:0034005', ('38', '41'))	('tumors', 'Disease', (76, 82))	('prostate cancers', 'Disease', 'MESH:D011471', (116, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('breast', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('found', 'Reg', (59, 64))	('genetic aberrations', 'Var', (11, 30))
48142	25065585	An increased understanding of the molecular and cellular biology of non-coding RNAs shows promise for the diagnosis, prognosis, and treatment of patients with melanoma.	('melanoma', 'Disease', (159, 167))	('and', 'Gene', (44, 47))	('patients', 'Species', '9606', (145, 153))	('RNAs', 'Gene', (79, 83))	('and', 'Gene', '387572', (20, 23))	('and', 'Gene', (20, 23))	('and', 'Gene', '387572', (128, 131))	('and', 'Gene', (128, 131))	('and', 'Gene', '387572', (44, 47))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))	('non-coding', 'Var', (68, 78))
48153	21876842	Aberrant CDKN2A gene products have been implicated in a great many cases of familial cutaneous melanoma.	('familial cutaneous melanoma', 'Disease', 'MESH:C562393', (76, 103))	('CDKN2A', 'Gene', '1029', (9, 15))	('Aberrant', 'Var', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('implicated', 'Reg', (40, 50))	('familial cutaneous melanoma', 'Disease', (76, 103))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))	('CDKN2A', 'Gene', (9, 15))
48154	21876842	Sporadic cases, on the other hand, often involve constitutive signal transduction along the mitogen-activated protein kinase (MAPK) pathway, with particular focus falling upon mutated RAS and RAF protooncogenes.	('MAPK', 'molecular_function', 'GO:0004707', ('126', '130'))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('falling', 'Phenotype', 'HP:0002527', (163, 170))	('mutated', 'Var', (176, 183))	('RAS', 'Gene', (184, 187))	('signal transduction', 'biological_process', 'GO:0007165', ('62', '81'))	('constitutive signal transduction', 'MPA', (49, 81))	('RAF', 'Gene', '22882', (192, 195))	('involve', 'Reg', (41, 48))	('RAF', 'Gene', (192, 195))
48177	21876842	Mutated p14/ARF, on the other hand, is unable to bind and suppress HDM2, allowing it to mark p53 for destruction.	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('ARF', 'Disease', (12, 15))	('p14', 'Gene', (8, 11))	('p14', 'Gene', '1029', (8, 11))	('Mutated', 'Var', (0, 7))	('ARF', 'Disease', 'MESH:D058186', (12, 15))	('HDM2', 'Gene', '4193', (67, 71))	('HDM2', 'Gene', (67, 71))
48185	21876842	Germline mutations that activate this gene occur at codon 24 (Arg24Cys and Arg24His) and render the CDK4/6 complex resistant to p16 inhibition.	('Arg24Cys', 'Var', (62, 70))	('Arg24His', 'Var', (75, 83))	('p16', 'Gene', '1029', (128, 131))	('Arg24His', 'SUBSTITUTION', 'None', (75, 83))	('CDK', 'molecular_function', 'GO:0004693', ('100', '103'))	('Arg24Cys', 'SUBSTITUTION', 'None', (62, 70))	('activate', 'PosReg', (24, 32))	('p16', 'Gene', (128, 131))
48186	21876842	Similar to the case of aberrations in the CDKN2A gene, mutations in CDK4 lend to an increased risk for cutaneous melanomagenesis.	('cutaneous melanomagenesis', 'Disease', 'MESH:D018366', (103, 128))	('mutations', 'Var', (55, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (103, 121))	('cutaneous melanomagenesis', 'Phenotype', 'HP:0012056', (103, 128))	('CDK', 'molecular_function', 'GO:0004693', ('68', '71'))	('CDK4', 'Gene', (68, 72))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('CDKN2A', 'Gene', (42, 48))	('CDK4', 'Gene', '1019', (68, 72))	('CDKN2A', 'Gene', '1029', (42, 48))	('cutaneous melanomagenesis', 'Disease', (103, 128))
48191	21876842	Through phosphorylation, RAS activates RAF, which in turn phosphorylates and activates MEK.	('phosphorylation', 'Var', (8, 23))	('activates', 'PosReg', (29, 38))	('phosphorylation', 'biological_process', 'GO:0016310', ('8', '23'))	('MEK', 'Gene', (87, 90))	('activates', 'PosReg', (77, 86))	('MEK', 'Gene', '5609', (87, 90))	('RAF', 'Gene', '22882', (39, 42))	('RAF', 'Gene', (39, 42))
48195	21876842	Activating mutations and/or gene amplification of KIT are now being described in significant subsets of melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanomas', 'Phenotype', 'HP:0002861', (104, 113))	('gene amplification', 'Var', (28, 46))	('melanomas', 'Disease', 'MESH:D008545', (104, 113))	('Activating mutations', 'Var', (0, 20))	('KIT', 'molecular_function', 'GO:0005020', ('50', '53'))	('KIT', 'Gene', (50, 53))	('melanomas', 'Disease', (104, 113))
48196	21876842	One study, in particular, recognized such aberrations in 39% of mucosal melanomas, 36% of acral melanomas, and 28% of melanomas arising in chronically sun-damaged skin (as defined by the presence of solar elastosis on review of histopathology):anatomic sites at which BRAF mutations occur far less frequently.	('acral melanomas', 'Phenotype', 'HP:0012060', (90, 105))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('sun-damaged', 'Phenotype', 'HP:0000992', (151, 162))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('acral melanomas', 'Disease', (90, 105))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanomas', 'Phenotype', 'HP:0002861', (118, 127))	('elastosis', 'Disease', 'MESH:D005148', (205, 214))	('BRAF', 'Gene', '673', (268, 272))	('BRAF', 'Gene', (268, 272))	('melanomas', 'Disease', 'MESH:D008545', (96, 105))	('melanomas', 'Disease', 'MESH:D008545', (72, 81))	('mucosal melanomas', 'Disease', 'MESH:D008545', (64, 81))	('melanomas', 'Disease', (96, 105))	('melanomas', 'Disease', (72, 81))	('elastosis', 'Disease', (205, 214))	('mucosal melanomas', 'Disease', (64, 81))	('melanomas', 'Disease', 'MESH:D008545', (118, 127))	('mutations', 'Var', (273, 282))	('acral melanomas', 'Disease', 'MESH:D008545', (90, 105))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanomas', 'Disease', (118, 127))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))
48197	21876842	The most prevalent KIT mutations are L576P (exon 11), K642E (exon 13), V559A (exon 11), and D816H (exon 17).	('K642E', 'Var', (54, 59))	('V559A', 'Var', (71, 76))	('K642E', 'Mutation', 'rs121913512', (54, 59))	('V559A', 'Mutation', 'rs121913517', (71, 76))	('D816H', 'Mutation', 'rs121913506', (92, 97))	('L576P', 'Mutation', 'rs121913513', (37, 42))	('KIT', 'Disease', (19, 22))	('L576P', 'Var', (37, 42))	('D816H', 'Var', (92, 97))	('KIT', 'molecular_function', 'GO:0005020', ('19', '22'))
48198	21876842	These mutations are thought to promote the constitutive activation of KIT either through precluding the protein from assuming its default autoinhibited conformation, or by promoting its dimerization in the absence of SCF.	('SCF', 'Gene', '4254', (217, 220))	('SCF', 'Gene', (217, 220))	('promoting', 'PosReg', (172, 181))	('KIT', 'Gene', (70, 73))	('dimerization', 'MPA', (186, 198))	('KIT', 'molecular_function', 'GO:0005020', ('70', '73'))	('SCF', 'molecular_function', 'GO:0005173', ('217', '220'))	('promote', 'PosReg', (31, 38))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('activation', 'PosReg', (56, 66))	('mutations', 'Var', (6, 15))
48202	21876842	Of these three protooncogenes, activating mutations in NRAS occur most frequently in melanocytes and have been identified in nearly one-third of all melanomas.	('melanomas', 'Disease', 'MESH:D008545', (149, 158))	('NRAS', 'Gene', '4893', (55, 59))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanomas', 'Phenotype', 'HP:0002861', (149, 158))	('identified', 'Reg', (111, 121))	('melanomas', 'Disease', (149, 158))	('activating mutations', 'Var', (31, 51))	('NRAS', 'Gene', (55, 59))
48203	21876842	The most commonly documented NRAS aberration in melanoma is a missense mutation at codon 61 (Q61R), which results in the substitution of arginine in place of glutamine and impairs GTP hydrolysis locking the protein in a state of constitutive activation.	('substitution', 'Var', (121, 133))	('melanoma', 'Disease', (48, 56))	('protein', 'cellular_component', 'GO:0003675', ('207', '214'))	('Q61R', 'Mutation', 'rs11554290', (93, 97))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('180', '194'))	('arginine', 'Chemical', 'MESH:D001120', (137, 145))	('GTP hydrolysis locking the', 'MPA', (180, 206))	('NRAS', 'Gene', (29, 33))	('protein', 'Protein', (207, 214))	('impairs', 'NegReg', (172, 179))	('NRAS', 'Gene', '4893', (29, 33))	('GTP', 'Chemical', 'MESH:D006160', (180, 183))	('glutamine', 'Chemical', 'MESH:D005973', (158, 167))	('arginine', 'Protein', (137, 145))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
48204	21876842	In comparison to other solid tumors, mutations in RAS do not occur with as high as a frequency in melanoma.	('solid tumors', 'Disease', 'MESH:D009369', (23, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mutations', 'Var', (37, 46))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('RAS', 'Gene', (50, 53))	('solid tumors', 'Disease', (23, 35))
48207	21876842	While ARAF and CRAF mutations are rare in human cancers, a significant percentage of human malignancies have been shown to harbor activating mutations in BRAF, with the highest rate occurring in melanoma.	('human cancers', 'Disease', (42, 55))	('human', 'Species', '9606', (42, 47))	('CRAF', 'molecular_function', 'GO:0004709', ('15', '19'))	('human cancers', 'Disease', 'MESH:D009369', (42, 55))	('CRAF', 'Gene', '5894', (15, 19))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('mutations', 'Var', (141, 150))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('malignancies', 'Disease', 'MESH:D009369', (91, 103))	('melanoma', 'Disease', (195, 203))	('human', 'Species', '9606', (85, 90))	('activating', 'PosReg', (130, 140))	('malignancies', 'Disease', (91, 103))	('BRAF', 'Gene', '673', (154, 158))	('CRAF', 'Gene', (15, 19))	('BRAF', 'Gene', (154, 158))	('ARAF', 'Gene', '369', (6, 10))	('ARAF', 'Gene', (6, 10))
48208	21876842	BRAF mutations in melanoma tend to occur at anatomic sites exposed to intermittent, rather than chronic, sun damage.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('occur', 'Reg', (35, 40))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('sun damage', 'Phenotype', 'HP:0000992', (105, 115))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))
48209	21876842	With approximately 70% of cases harboring such a mutation, BRAF is the most commonly mutated protooncogene in cutaneous melanoma.	('mutation', 'Var', (49, 57))	('cutaneous melanoma', 'Disease', (110, 128))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (110, 128))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (110, 128))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('harboring', 'Reg', (32, 41))
48210	21876842	Furthermore, a significant proportion of both benign and dysplastic melanocytic nevi have been shown to harbor mutation of BRAF as well, suggesting a relatively early event in melanomagenesis.	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))	('dysplastic melanocytic', 'Disease', 'MESH:D009508', (57, 79))	('nevi', 'Phenotype', 'HP:0003764', (80, 84))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('dysplastic melanocytic', 'Disease', (57, 79))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (68, 84))	('mutation', 'Var', (111, 119))
48211	21876842	Greater than 90% of BRAF mutations in melanoma result from a single base missense mutation (T A) at codon 1799 that leads to the substitution of valine in favor of glutamic acid at position 600 of the BRAF protein.	('valine', 'MPA', (145, 151))	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('mutations', 'Var', (25, 34))	('valine', 'Chemical', 'MESH:D014633', (145, 151))	('substitution', 'Var', (129, 141))	('BRAF', 'Gene', '673', (201, 205))	('protein', 'cellular_component', 'GO:0003675', ('206', '213'))	('result from', 'Reg', (47, 58))	('BRAF', 'Gene', '673', (20, 24))	('BRAF', 'Gene', (20, 24))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('glutamic acid', 'Chemical', 'MESH:D018698', (164, 177))	('melanoma', 'Disease', (38, 46))	('BRAF', 'Gene', (201, 205))
48212	21876842	This alteration introduces a conformational change in BRAF's kinase domain, which can lead to a 480-fold increase in kinase activity when compared to that of wild-type BRAF.	('alteration', 'Var', (5, 15))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('increase', 'PosReg', (105, 113))	('kinase activity', 'molecular_function', 'GO:0016301', ('117', '132'))	('BRAF', 'Gene', '673', (168, 172))	('conformational', 'MPA', (29, 43))	('kinase activity', 'MPA', (117, 132))	('BRAF', 'Gene', (168, 172))
48213	21876842	While mutated BRAF induces uncontrolled proliferation in melanoma, it lends to senescence in benign melanocytic nevi.	('melanocytic nevi', 'Phenotype', 'HP:0000995', (100, 116))	('senescence', 'MPA', (79, 89))	('benign melanocytic nevi', 'Disease', (93, 116))	('senescence', 'biological_process', 'GO:0010149', ('79', '89'))	('uncontrolled proliferation', 'MPA', (27, 53))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('BRAF', 'Gene', '673', (14, 18))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('nevi', 'Phenotype', 'HP:0003764', (112, 116))	('BRAF', 'Gene', (14, 18))	('induces', 'Reg', (19, 26))	('mutated', 'Var', (6, 13))
48216	21876842	PIP3 then recruits the serine/threonine kinase AKT, also known as protein kinase B, to the cell membrane.	('AKT', 'Gene', (47, 50))	('cell membrane', 'cellular_component', 'GO:0005886', ('91', '104'))	('AKT', 'Gene', '207', (47, 50))	('recruits', 'PosReg', (10, 18))	('PIP3', 'Chemical', '-', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('PIP3', 'Var', (0, 4))
48220	21876842	Inactivation of the TSC1/TSC2 complex stimulates activity of mammalian target of rapamycin (mTOR), a kinase that promotes the uptake of nutrients necessary for cellular growth.	('promotes', 'PosReg', (113, 121))	('TSC2', 'Gene', '7249', (25, 29))	('TSC2', 'Gene', (25, 29))	('activity', 'MPA', (49, 57))	('TSC1/TSC2 complex', 'cellular_component', 'GO:0033596', ('20', '37'))	('uptake', 'biological_process', 'GO:0098657', ('126', '132'))	('mammalian target of rapamycin', 'Gene', '2475', (61, 90))	('mammalian target of rapamycin', 'Gene', (61, 90))	('uptake', 'biological_process', 'GO:0098739', ('126', '132'))	('cellular growth', 'biological_process', 'GO:0016049', ('160', '175'))	('stimulates', 'PosReg', (38, 48))	('uptake of nutrients necessary', 'MPA', (126, 155))	('TSC1', 'Gene', '7248', (20, 24))	('mTOR', 'Gene', (92, 96))	('mTOR', 'Gene', '2475', (92, 96))	('TSC1', 'Gene', (20, 24))	('Inactivation', 'Var', (0, 12))
48225	21876842	Frequency of mutations and deletions only partly account for PTEN loss in melanoma samples, suggesting epigenetic mechanisms.	('loss', 'NegReg', (66, 70))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('PTEN', 'Gene', (61, 65))	('deletions', 'Var', (27, 36))	('PTEN', 'Gene', '5728', (61, 65))	('mutations', 'Var', (13, 22))
48237	21876842	Screening of potential oncogenes that may activate the MAPK pathway has led to the discovery of mutations in GNAQ, a stimulatory alphaq subunit of heterotrimeric G proteins (Galphabetagamma).	('MAPK', 'molecular_function', 'GO:0004707', ('55', '59'))	('Galpha', 'Gene', '8802', (174, 180))	('GNAQ', 'Gene', (109, 113))	('Galpha', 'Gene', (174, 180))	('GNAQ', 'Gene', '2776', (109, 113))	('mutations', 'Var', (96, 105))
48244	21876842	Mutation of GNAQ at codon 209 prevents the hydrolysis of GTP and locks GNAQ in its active, GTP-bound state.	('GTP', 'Chemical', 'MESH:D006160', (57, 60))	('GNAQ', 'Gene', (12, 16))	('GNAQ', 'Gene', '2776', (71, 75))	('GNAQ', 'Gene', (71, 75))	('Mutation', 'Var', (0, 8))	('prevents', 'NegReg', (30, 38))	('GNAQ', 'Gene', '2776', (12, 16))	('GTP', 'Chemical', 'MESH:D006160', (91, 94))	('hydrolysis', 'MPA', (43, 53))
48248	21876842	Just as researchers are beginning to understand the mechanisms by which activating mutations in the RAS and RAF protooncogenes lead to proliferative and antiapoptotic effects, evidence is mounting for the role of constitutive MAPK activity in tumor evasion of immune surveillance, suppression of immune response, tumor angiogenesis, and metastatic dissemination.	('tumor', 'Disease', (313, 318))	('proliferative', 'MPA', (135, 148))	('activating', 'PosReg', (72, 82))	('activity', 'MPA', (231, 239))	('immune response', 'CPA', (296, 311))	('immune response', 'biological_process', 'GO:0006955', ('296', '311'))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('MAPK', 'molecular_function', 'GO:0004707', ('226', '230'))	('tumor', 'Disease', (243, 248))	('RAS', 'Gene', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('angiogenesis', 'biological_process', 'GO:0001525', ('319', '331'))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('RAF', 'Gene', '22882', (108, 111))	('metastatic dissemination', 'CPA', (337, 361))	('suppression of immune response', 'Phenotype', 'HP:0002721', (281, 311))	('MAPK', 'Enzyme', (226, 230))	('antiapoptotic effects', 'MPA', (153, 174))	('suppression', 'CPA', (281, 292))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('mutations', 'Var', (83, 92))	('RAF', 'Gene', (108, 111))
48249	21876842	Furthermore, approximately 40% of melanoma kindreds harbor CDKN2A mutations, and significantly less perpetuate CDK4 mutations, thus the genetic basis of a substantial proportion of cases of familial cutaneous melanoma clearly remains unresolved.	('mutations', 'Var', (66, 75))	('CDK4', 'Gene', (111, 115))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('familial cutaneous melanoma', 'Disease', (190, 217))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (199, 217))	('CDK4', 'Gene', '1019', (111, 115))	('CDK', 'molecular_function', 'GO:0004693', ('111', '114'))	('familial cutaneous melanoma', 'Disease', 'MESH:C562393', (190, 217))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('CDKN2A', 'Gene', (59, 65))	('melanoma', 'Disease', (209, 217))	('melanoma', 'Disease', (34, 42))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('CDKN2A', 'Gene', '1029', (59, 65))
48253	21876842	While clinical trials are under way to determine if aberrations in the aforementioned molecules and pathways can be manipulated to stifle and/or reverse uveal melanomagenesis, the need for intervention at more than just one critical junction will likely be needed.	('uveal melanomagenesis', 'Disease', (153, 174))	('aberrations', 'Var', (52, 63))	('uveal melanomagenesis', 'Disease', 'MESH:D014603', (153, 174))	('uveal melanomagenesis', 'Phenotype', 'HP:0007716', (153, 174))	('uveal melanoma', 'Phenotype', 'HP:0007716', (153, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
48258	19052061	Results: Here, we present the heterogeneous hidden conditional random field, a new integrated array-CGH analysis method for jointly classifying tumors, inferring copy numbers and identifying clinically relevant positions in recurrent alteration regions.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('copy numbers', 'Var', (162, 174))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('ran', 'Gene', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('ran', 'Gene', '5901', (63, 66))	('CGH', 'Gene', (100, 103))	('CGH', 'Gene', '3342', (100, 103))
48314	19052061	The desired grouping effect can be provided by a hybrid L1+L2 extension of Gradient LASSO, analogous to the Elastic Net (Zou and Hastie,) extension of LASSO (Tibshirani,), which will select all similarly important genes simultaneously due to the L2 component.	('ran', 'Gene', '5901', (164, 167))	('hybrid L1+L2', 'Var', (49, 61))	('ran', 'Gene', (164, 167))
48323	33912157	Here we characterize a mouse line with a selective deletion of BAP1 within the B cell lineage (Bap1 fl/fl mb1-Cre) and establish a cell intrinsic role of BAP1 in the regulation of B cell development.	('Bap1', 'Gene', (95, 99))	('BAP1', 'Gene', (63, 67))	('mb1', 'Gene', (106, 109))	('mouse', 'Species', '10090', (23, 28))	('Bap1', 'Gene', '104416', (95, 99))	('regulation of B cell development', 'biological_process', 'GO:0045577', ('166', '198'))	('deletion', 'Var', (51, 59))	('mb1', 'Gene', '12518', (106, 109))
48329	33912157	Monoubiquitination of histone H2A (H2AK119ub) is a highly abundant histone modification, associated with gene silencing.	('H2AK119ub', 'Var', (35, 44))	('gene silencing', 'biological_process', 'GO:0016458', ('105', '119'))	('histone H2A', 'Gene', (22, 33))	('H2AK119ub', 'Chemical', '-', (35, 44))	('histone H2A', 'Gene', '624153', (22, 33))	('histone modification', 'biological_process', 'GO:0016570', ('67', '87'))	('Monoubiquitination', 'MPA', (0, 18))
48331	33912157	The role of PRC1 in B cell development and lymphomagenesis is well established, and the loss of PRC1 complex components in conditional knockout mouse models impairs B cell differentiation and disrupts B cell specific transcriptional programs.	('B cell differentiation', 'CPA', (165, 187))	('mouse', 'Species', '10090', (144, 149))	('B cell development', 'biological_process', 'GO:0030183', ('20', '38'))	('PRC1 complex', 'cellular_component', 'GO:0035102', ('96', '108'))	('disrupts', 'NegReg', (192, 200))	('impairs', 'NegReg', (157, 164))	('PRC1', 'Gene', (96, 100))	('B cell specific transcriptional programs', 'CPA', (201, 241))	('lymphomagenesis', 'Disease', 'None', (43, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (43, 51))	('lymphomagenesis', 'Disease', (43, 58))	('loss', 'Var', (88, 92))	('B cell differentiation', 'biological_process', 'GO:0030183', ('165', '187'))
48339	33912157	BAP1 also interacts with forkhead transcription factors FOXK1 and FOXK2, and promotes the transcriptional repression of FOXK2-regulated genes through mechanisms involving H2AK119ub deubiquitination.	('BAP1', 'Gene', (0, 4))	('FOXK2', 'Gene', '68837', (66, 71))	('promotes', 'PosReg', (77, 85))	('FOXK1', 'Gene', '17425', (56, 61))	('FOXK1', 'Gene', (56, 61))	('transcriptional repression', 'MPA', (90, 116))	('H2AK119ub', 'Var', (171, 180))	('FOXK2', 'Gene', '68837', (120, 125))	('deubiquitination', 'biological_process', 'GO:0016579', ('181', '197'))	('FOXK2', 'Gene', (120, 125))	('interacts', 'Interaction', (10, 19))	('transcription', 'biological_process', 'GO:0006351', ('34', '47'))	('deubiquitination', 'MPA', (181, 197))	('H2AK119ub', 'Chemical', '-', (171, 180))	('FOXK2', 'Gene', (66, 71))
48341	33912157	BAP1 is an important tumor suppressor in human, with somatic or germinal BAP1 mutations being common in mesothelioma, uveal melanoma, renal cell carcinoma, and other cancers, while mutations in BAP1 interacting Polycomb proteins ASXL1/2 are prevalent in myeloid leukemia.	('prevalent', 'Reg', (241, 250))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('common', 'Reg', (94, 100))	('tumor', 'Disease', (21, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('tumor suppressor', 'biological_process', 'GO:0051726', ('21', '37'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (118, 132))	('BAP1', 'Gene', (73, 77))	('myeloid leukemia', 'Disease', 'MESH:D007951', (254, 270))	('leukemia', 'Phenotype', 'HP:0001909', (262, 270))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (254, 270))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('Polycomb', 'Gene', '12416', (211, 219))	('mesothelioma', 'Disease', (104, 116))	('human', 'Species', '9606', (41, 46))	('mutations', 'Var', (78, 87))	('mesothelioma', 'Disease', 'MESH:D008654', (104, 116))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (134, 154))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('cancers', 'Disease', (166, 173))	('Polycomb', 'Gene', (211, 219))	('ASXL1/2', 'Gene', (229, 236))	('myeloid leukemia', 'Disease', (254, 270))	('ASXL1/2', 'Gene', '171023;55252', (229, 236))	('uveal melanoma', 'Disease', (118, 132))	('uveal melanoma', 'Disease', 'MESH:C536494', (118, 132))	('renal cell carcinoma', 'Disease', (134, 154))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('21', '37'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (134, 154))
48343	33912157	Importantly, an inducible systemic deletion of Bap1 in Bap1 fl/fl CreERT2 mice resulted in broad spectrum hematologic pathology, with an expansion of myeloid leukocytes, and a depletion of platelet and red blood cells, resembling myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML).	('MDS', 'Disease', 'MESH:D009190', (256, 259))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (265, 296))	('myelodysplastic syndrome', 'Disease', (230, 254))	('Bap1', 'Gene', '104416', (55, 59))	('expansion', 'PosReg', (137, 146))	('MDS', 'Disease', (256, 259))	('Bap1', 'Gene', '104416', (47, 51))	('mice', 'Species', '10090', (74, 78))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (265, 296))	('myeloid leukocytes', 'MPA', (150, 168))	('Bap1', 'Gene', (55, 59))	('CMML', 'Disease', 'MESH:D054429', (298, 302))	('deletion', 'Var', (35, 43))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (230, 254))	('leukemia', 'Phenotype', 'HP:0001909', (288, 296))	('Bap1', 'Gene', (47, 51))	('CMML', 'Disease', (298, 302))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (230, 254))	('chronic myelomonocytic leukemia', 'Disease', (265, 296))
48345	33912157	Importantly, depletion of B cells was also observed following the systemic inducible deletion of Bap1 in Bap1 fl/f lCreERT2 mice.	('Bap1', 'Gene', '104416', (97, 101))	('mice', 'Species', '10090', (124, 128))	('Bap1', 'Gene', (97, 101))	('Bap1', 'Gene', '104416', (105, 109))	('deletion', 'Var', (85, 93))	('Bap1', 'Gene', (105, 109))
48349	33912157	RNA-Seq analyses of Bap1 fl/flmb1-Cre pre-B cells demonstrated a downregulation of genes involved in cell proliferation and cell cycle progression, consistent with both the depletion of the proliferative large pre-B cell subset and impaired cell cycle progression in BAP1 deficiency.	('Bap1', 'Gene', (20, 24))	('pre', 'molecular_function', 'GO:0003904', ('38', '41'))	('pre-B', 'Gene', '50907', (210, 215))	('pre-B', 'Gene', (210, 215))	('cell cycle progression', 'CPA', (124, 146))	('cell proliferation', 'biological_process', 'GO:0008283', ('101', '119'))	('cell cycle', 'biological_process', 'GO:0007049', ('241', '251'))	('mb1', 'Gene', '12518', (30, 33))	('pre', 'molecular_function', 'GO:0003904', ('210', '213'))	('cell cycle progression', 'CPA', (241, 263))	('deficiency', 'Var', (272, 282))	('impaired', 'NegReg', (232, 240))	('pre-B', 'Gene', (38, 43))	('pre-B', 'Gene', '50907', (38, 43))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('BAP1', 'Gene', (267, 271))	('Bap1', 'Gene', '104416', (20, 24))	('cell cycle', 'biological_process', 'GO:0007049', ('124', '134'))	('mb1', 'Gene', (30, 33))	('downregulation', 'NegReg', (65, 79))	('cell proliferation', 'CPA', (101, 119))
48356	33912157	The Bap1 Delta allele is predicted to disrupt Bap1 protein coding sequence from amino acid 126 onward, precluding the expression of full N-terminal UCH catalytic domain and all downstream domains of BAP1 protein.	('disrupt', 'NegReg', (38, 45))	('Bap1', 'Gene', (4, 8))	('protein', 'Protein', (51, 58))	('Bap1', 'Gene', '104416', (46, 50))	('Delta', 'Var', (9, 14))	('protein', 'cellular_component', 'GO:0003675', ('204', '211'))	('Bap1', 'Gene', (46, 50))	('expression', 'MPA', (118, 128))	('Bap1', 'Gene', '104416', (4, 8))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
48362	33912157	Cell suspensions of mouse tissues were prepared in RPMI-1640 (Wisent) with 2% (v/v) FCS, 100mug/ml streptomycin and 100U/ml penicillin (Wisent).	('100mug/ml', 'Var', (89, 98))	('mug', 'molecular_function', 'GO:0043739', ('92', '95'))	('streptomycin', 'Chemical', 'MESH:D013307', (99, 111))	('100U/ml', 'Var', (116, 123))	('penicillin', 'Chemical', 'MESH:D010406', (124, 134))	('RPMI-1640', 'Chemical', '-', (51, 60))	('mouse', 'Species', '10090', (20, 25))
48383	33912157	Ba/F3 cell lines stably expressing triple-FLAG-tagged murine BAP1 were derived as previously described, and maintained under 2mug/mL puromycin selection (Wisent).	('triple-FLAG-tagged', 'Var', (35, 53))	('BAP1', 'Gene', (61, 65))	('mug', 'molecular_function', 'GO:0043739', ('126', '129'))	('murine', 'Species', '10090', (54, 60))	('puromycin', 'Chemical', 'MESH:D011691', (133, 142))
48385	33912157	The loss of BAP1 protein expression in the cell line clones was validated via Western blotting, with the following antibodies: anti-BAP1 (D7W7O, Cell Signaling Technology), anti-beta-Actin (D6A8, Cell Signaling Technology), HRP-conjugated anti-mouse-Ig (eB144, Rockland), and HRP-conjugated anti-rabbit-Ig (eB182, Rockland).	('protein', 'Protein', (17, 24))	('mouse', 'Species', '10090', (244, 249))	('beta-Actin', 'Gene', '11461', (178, 188))	('Signaling', 'biological_process', 'GO:0023052', ('150', '159'))	('Signaling', 'biological_process', 'GO:0023052', ('201', '210'))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('anti-BAP1', 'Var', (127, 136))	('beta-Actin', 'Gene', (178, 188))	('BAP1', 'Gene', (12, 16))	('loss', 'NegReg', (4, 8))
48398	33912157	Beads immunocomplexes were prepared overnight by conjugating 40muL of Dynabeads Protein G (Invitrogen, Life Technologies) with antibodies: anti-BAP1 (Cell Signaling Technology, D1W9B, 52.8 mug), anti-FLAG M2 (Sigma, F1804, 5 mug) or anti-H2AK119Ub (Cell Signaling Technology, D27C4, 5 mug).	('anti-BAP1', 'Var', (139, 148))	('mug', 'molecular_function', 'GO:0043739', ('225', '228'))	('mug', 'molecular_function', 'GO:0043739', ('189', '192'))	('mug', 'molecular_function', 'GO:0043739', ('285', '288'))	('H2A', 'Gene', '8337', (238, 241))	('H2A', 'Gene', (238, 241))	('Signaling', 'biological_process', 'GO:0023052', ('254', '263'))	('Signaling', 'biological_process', 'GO:0023052', ('155', '164'))
48404	33912157	To study the role of BAP1 in the B cell lineage, a B cell specific conditional knockout mouse model was generated by crossing the Bap1-floxed mouse line Bap1 fl/fl to the mb1-Cre line expressing Cre-recombinase under the control of the B cell lineage specific Cd79a gene promoter, from the pre-pro-B cell stage in development.	('Bap1', 'Gene', (130, 134))	('Cd79a', 'Gene', (260, 265))	('mouse', 'Species', '10090', (142, 147))	('mb1', 'Gene', (171, 174))	('Bap1', 'Gene', '104416', (153, 157))	('mouse', 'Species', '10090', (88, 93))	('Bap1', 'Gene', (153, 157))	('pre', 'molecular_function', 'GO:0003904', ('290', '293'))	('Bap1', 'Gene', '104416', (130, 134))	('fl/fl', 'Var', (158, 163))	('Cd79a', 'Gene', '12518', (260, 265))	('mb1', 'Gene', '12518', (171, 174))
48406	33912157	Loss of BAP1 transcript and protein expression was validated in B cells isolated from the spleen of Bap1 fl/fl Cre and control mice, using qRT-PCR and Western blotting, respectively ( Figures 1A, B ).	('mice', 'Species', '10090', (127, 131))	('Bap1', 'Gene', '104416', (100, 104))	('Bap1', 'Gene', (100, 104))	('transcript', 'MPA', (13, 23))	('Loss', 'NegReg', (0, 4))	('BAP1', 'Gene', (8, 12))	('fl/fl Cre', 'Var', (105, 114))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
48407	33912157	To assess the effects of BAP1-loss on the B cell lineage, spleens and mesenteric lymph nodes of Bap1 fl/fl Cre, Bap1 fl/+ Cre, and control Bap1 fl/+ mice were analyzed by flow cytometry, gating on CD19+ B cells.	('Bap1', 'Gene', (96, 100))	('fl/fl', 'Var', (101, 106))	('BAP1-loss', 'Gene', (25, 34))	('Bap1', 'Gene', '104416', (96, 100))	('Bap1', 'Gene', '104416', (139, 143))	('mice', 'Species', '10090', (149, 153))	('Bap1', 'Gene', (139, 143))	('Bap1', 'Gene', '104416', (112, 116))	('Bap1', 'Gene', (112, 116))
48409	33912157	The absolute numbers of B cells were also significantly reduced in the spleen of Bap1 fl/fl Cre mice and showed a trend toward reduction in the lymph nodes ( Figures 1C-E ).	('fl/fl', 'Var', (86, 91))	('Bap1', 'Gene', (81, 85))	('mice', 'Species', '10090', (96, 100))	('reduced', 'NegReg', (56, 63))	('lymph nodes', 'CPA', (144, 155))	('reduction', 'NegReg', (127, 136))	('Bap1', 'Gene', '104416', (81, 85))
48432	33912157	To further understand the functional impact of BAP1 loss on B cell development, RNA-Seq gene expression analysis was conducted on live pre-B and immature B cells, isolated from the bone marrow of Bap1 fl/fl Cre, Bap1 fl/+ Cre, and control Bap1 fl/+ mice through FACS-sorting ( Figure 4A ,  Table S1A, B ).	('pre', 'molecular_function', 'GO:0003904', ('135', '138'))	('gene expression', 'biological_process', 'GO:0010467', ('88', '103'))	('Bap1', 'Gene', (212, 216))	('pre-B', 'Gene', '50907', (135, 140))	('Bap1', 'Gene', (196, 200))	('RNA', 'cellular_component', 'GO:0005562', ('80', '83'))	('B cell development', 'biological_process', 'GO:0030183', ('60', '78'))	('fl/fl', 'Var', (201, 206))	('Bap1', 'Gene', '104416', (196, 200))	('Bap1', 'Gene', '104416', (239, 243))	('mice', 'Species', '10090', (249, 253))	('Bap1', 'Gene', '104416', (212, 216))	('Bap1', 'Gene', (239, 243))	('pre-B', 'Gene', (135, 140))	('BAP1', 'Gene', (47, 51))
48439	33912157	This demonstrates the very limited effects of Cre or heterozygous Bap1 loss on the transcriptome, and confirms that the major transcriptional changes in Bap1 fl/fl Cre are due to the loss of BAP1 function.	('loss', 'NegReg', (183, 187))	('Bap1', 'Gene', '104416', (66, 70))	('function', 'MPA', (196, 204))	('Bap1', 'Gene', (66, 70))	('Bap1', 'Gene', '104416', (153, 157))	('BAP1', 'Protein', (191, 195))	('loss', 'NegReg', (71, 75))	('Bap1', 'Gene', (153, 157))	('fl/fl', 'Var', (158, 163))	('transcriptional', 'MPA', (126, 141))
48448	33912157	Cell clones were screened by PCR for deletions within the Bap1 locus, and six clones were selected and further analyzed by Western blotting to confirm the loss of BAP1 protein ( Figure 5B ).	('deletions', 'Var', (37, 46))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('loss', 'NegReg', (155, 159))	('protein', 'Protein', (168, 175))	('Bap1', 'Gene', '104416', (58, 62))	('Bap1', 'Gene', (58, 62))	('BAP1', 'Gene', (163, 167))
48450	33912157	Both approaches demonstrated a reduction in cell proliferation for all the Bap1 Delta/Delta clones tested, reaching statistical significance for the majority of the clones ( Figures 5D-F ).	('Delta/Delta', 'Var', (80, 91))	('reduction', 'NegReg', (31, 40))	('Bap1', 'Gene', (75, 79))	('cell proliferation', 'CPA', (44, 62))	('Bap1', 'Gene', '104416', (75, 79))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))
48453	33912157	To gain insights into the mechanisms of BAP1 transcriptional and epigenetic regulation in the B cell lineage, we performed ChIP-Seq analysis for the repressive histone mark H2AK119ub, comparing the Bap1 Delta/Delta and control Ba/F3 B cell precursor cell lines.	('Delta/Delta', 'Var', (203, 214))	('regulation', 'biological_process', 'GO:0065007', ('76', '86'))	('Bap1', 'Gene', '104416', (198, 202))	('H2AK119ub', 'Chemical', '-', (173, 182))	('Bap1', 'Gene', (198, 202))	('BAP1', 'Gene', (40, 44))
48456	33912157	Importantly, the levels of histone H2AK119ub at these BAP1-bound genomic sites were significantly elevated in Bap1 Delta/Delta relative to wild-type cells ( Figures 6C, D ,  Supplemental Figure S7B ).	('Bap1', 'Gene', '104416', (110, 114))	('Delta/Delta', 'Var', (115, 126))	('histone H2A', 'Gene', (27, 38))	('Bap1', 'Gene', (110, 114))	('H2AK119ub', 'Chemical', '-', (35, 44))	('elevated', 'PosReg', (98, 106))	('levels', 'MPA', (17, 23))	('histone H2A', 'Gene', '624153', (27, 38))
48469	33912157	Importantly, a significant increase in histone H2AK119ub levels was observed in Bap1 Delta/Delta relative to control cells at these promoters ( Figures 7D, E ).	('Bap1', 'Gene', '104416', (80, 84))	('histone H2A', 'Gene', (39, 50))	('Delta/Delta', 'Var', (85, 96))	('Bap1', 'Gene', (80, 84))	('histone H2A', 'Gene', '624153', (39, 50))	('H2AK119ub', 'Chemical', '-', (47, 56))	('increase', 'PosReg', (27, 35))
48472	33912157	B cell dysfunction was previously reported by Arenzana et.al., following an inducible deletion of Bap1 in the Bap1 fl/fl CreERT2 mouse model, showing a depletion of pre-pro-B, small pre-B, immature, and mature B cell subsets.	('depletion', 'MPA', (152, 161))	('Bap1', 'Gene', '104416', (110, 114))	('B cell dysfunction', 'Phenotype', 'HP:0005372', (0, 18))	('B cell', 'CPA', (0, 6))	('Bap1', 'Gene', (110, 114))	('pre-B', 'Gene', '50907', (182, 187))	('Bap1', 'Gene', (98, 102))	('pre', 'molecular_function', 'GO:0003904', ('165', '168'))	('pre-B', 'Gene', (182, 187))	('Bap1', 'Gene', '104416', (98, 102))	('pre', 'molecular_function', 'GO:0003904', ('182', '185'))	('mouse', 'Species', '10090', (129, 134))	('immature', 'CPA', (189, 197))	('deletion', 'Var', (86, 94))
48473	33912157	The full mechanisms leading to the depletion of large pre-B cells in Bap1 Delta/Delta mice remain to be further explored.	('Bap1', 'Gene', '104416', (69, 73))	('pre-B', 'Gene', (54, 59))	('Bap1', 'Gene', (69, 73))	('pre-B', 'Gene', '50907', (54, 59))	('mice', 'Species', '10090', (86, 90))	('Delta/Delta', 'Var', (74, 85))	('pre', 'molecular_function', 'GO:0003904', ('54', '57'))
48479	33912157	While our study links the depletion of large pre-B cells in Bap1 fl/fl mb1-Cre mice to the disruption in cell proliferation and the direct role of BAP1 in the regulation of genes required for cell cycle progression, the expansion of Fraction B pro-B cells also seen in Bap1 fl/fl mb1-Cre mice is not linked to changes in cell cycle or cell survival, and remains to be further explored in future work.	('regulation', 'biological_process', 'GO:0065007', ('159', '169'))	('mb1', 'Gene', '12518', (71, 74))	('cell proliferation', 'CPA', (105, 123))	('cell cycle', 'biological_process', 'GO:0007049', ('192', '202'))	('cell cycle', 'biological_process', 'GO:0007049', ('321', '331'))	('mb1', 'Gene', (280, 283))	('mice', 'Species', '10090', (288, 292))	('mb1', 'Gene', (71, 74))	('Bap1', 'Gene', '104416', (269, 273))	('pre', 'molecular_function', 'GO:0003904', ('45', '48'))	('Bap1', 'Gene', '104416', (60, 64))	('fl/fl', 'Var', (274, 279))	('cell proliferation', 'biological_process', 'GO:0008283', ('105', '123'))	('Fraction B pro-B cells', 'CPA', (233, 255))	('pre-B', 'Gene', (45, 50))	('mice', 'Species', '10090', (79, 83))	('mb1', 'Gene', '12518', (280, 283))	('Bap1', 'Gene', (269, 273))	('expansion', 'PosReg', (220, 229))	('pre-B', 'Gene', '50907', (45, 50))	('Bap1', 'Gene', (60, 64))
48482	33912157	Although our transcriptional analyses of Bap1 fl/fl Cre pre-B cells is somewhat confounded by the depletion of the more proliferative large pre-B cell subset from the analyzed cell population, it is important to note that the dysregulation in cell cycle was observed in both large pre-B and small pre-B cell subsets that make up the pre-B cell pool sorted for the transcriptional profiling.	('Bap1', 'Gene', '104416', (41, 45))	('cell cycle', 'CPA', (243, 253))	('pre-B', 'Gene', (297, 302))	('fl/fl', 'Var', (46, 51))	('pre-B', 'Gene', (281, 286))	('pre-B', 'Gene', '50907', (297, 302))	('pre-B', 'Gene', '50907', (281, 286))	('Bap1', 'Gene', (41, 45))	('pre-B', 'Gene', '50907', (56, 61))	('pre-B', 'Gene', (56, 61))	('pre', 'molecular_function', 'GO:0003904', ('281', '284'))	('pre', 'molecular_function', 'GO:0003904', ('333', '336'))	('pre-B', 'Gene', (333, 338))	('pre-B', 'Gene', '50907', (333, 338))	('pre', 'molecular_function', 'GO:0003904', ('297', '300'))	('pre', 'molecular_function', 'GO:0003904', ('56', '59'))	('pre', 'molecular_function', 'GO:0003904', ('140', '143'))	('pre-B', 'Gene', (140, 145))	('pre-B', 'Gene', '50907', (140, 145))	('cell cycle', 'biological_process', 'GO:0007049', ('243', '253'))
48483	33912157	Furthermore, there was a highly significant overrepresentation of BAP1 binding sites in proximity of the genes dysregulated in our transcriptional data from Bap1 fl/fl Cre pre-B cells, providing further support for our conclusions.	('fl/fl', 'Var', (162, 167))	('pre-B', 'Gene', '50907', (172, 177))	('Bap1', 'Gene', (157, 161))	('overrepresentation', 'PosReg', (44, 62))	('BAP1', 'Gene', (66, 70))	('pre', 'molecular_function', 'GO:0003904', ('172', '175'))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))	('binding', 'Interaction', (71, 78))	('pre-B', 'Gene', (172, 177))	('Bap1', 'Gene', '104416', (157, 161))
48484	33912157	The overrepresentation of BAP1 binding sites was especially significant at the downregulated genes involved in cell proliferation and cycle progression, and the loss of BAP1 resulted in increased H2AK119ub levels at these sites, supporting a direct role of BAP1 and its deubiquitinase catalytic activity for histone H2A in their transcriptional regulation.	('BAP1', 'Gene', (26, 30))	('catalytic activity', 'molecular_function', 'GO:0003824', ('285', '303'))	('H2AK119ub', 'Chemical', '-', (196, 205))	('H2AK119ub levels', 'MPA', (196, 212))	('cell proliferation', 'biological_process', 'GO:0008283', ('111', '129'))	('regulation', 'biological_process', 'GO:0065007', ('345', '355'))	('increased', 'PosReg', (186, 195))	('overrepresentation', 'PosReg', (4, 22))	('histone H2A', 'Gene', (308, 319))	('cell proliferation', 'CPA', (111, 129))	('binding', 'molecular_function', 'GO:0005488', ('31', '38'))	('BAP1', 'Gene', (169, 173))	('downregulated genes', 'Gene', (79, 98))	('histone H2A', 'Gene', '624153', (308, 319))	('loss', 'Var', (161, 165))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('270', '284'))
48486	33912157	As already discussed, an inducible systemic deletion of Bap1 in mice results in impaired proliferation of thymocytes and peripheral CD4 T cells, suggesting shared BAP1 function across the different cell types of the lymphoid lineage.	('proliferation', 'CPA', (89, 102))	('Bap1', 'Gene', '104416', (56, 60))	('impaired', 'NegReg', (80, 88))	('deletion', 'Var', (44, 52))	('CD4', 'Gene', (132, 135))	('Bap1', 'Gene', (56, 60))	('CD4', 'Gene', '12504', (132, 135))	('mice', 'Species', '10090', (64, 68))
48488	33912157	Importantly, however, the role of BAP1 as a positive regulator of cell maintenance and proliferation is not universal, and Bap1 deletion in mice results in an expansion of myeloid leukocytes and progenitor cells, resembling the pathology of MDS and CMML.	('CMML', 'Disease', 'MESH:D054429', (249, 253))	('mice', 'Species', '10090', (140, 144))	('expansion', 'PosReg', (159, 168))	('myeloid leukocytes and', 'CPA', (172, 194))	('MDS', 'Disease', (241, 244))	('Bap1', 'Gene', '104416', (123, 127))	('CMML', 'Disease', (249, 253))	('MDS', 'Disease', 'MESH:D009190', (241, 244))	('Bap1', 'Gene', (123, 127))	('deletion', 'Var', (128, 136))
48490	33912157	We demonstrate that the loss of BAP1 results in an increase in histone H2AK119ub levels at BAP1 genomic binding sites in B cell precursor cells, both globally across the genome and also locally at the promoters of BAP1-target genes involved in the regulation of B cell proliferation.	('increase', 'PosReg', (51, 59))	('loss', 'Var', (24, 28))	('BAP1', 'Gene', (91, 95))	('histone H2A', 'Gene', '624153', (63, 74))	('regulation of B cell proliferation', 'biological_process', 'GO:0030888', ('248', '282'))	('binding', 'molecular_function', 'GO:0005488', ('104', '111'))	('BAP1', 'Gene', (32, 36))	('H2AK119ub', 'Chemical', '-', (71, 80))	('histone H2A', 'Gene', (63, 74))
48492	33912157	Deposition of the repressive histone mark H2AK119ub on chromatin by PRC1 is traditionally linked to long-term silencing of developmentally regulated genes, to control the pathways of cellular differentiation and lineage specification.	('chromatin', 'cellular_component', 'GO:0000785', ('55', '64'))	('linked', 'Reg', (90, 96))	('silencing', 'NegReg', (110, 119))	('H2AK119ub', 'Chemical', '-', (42, 51))	('cellular differentiation', 'CPA', (183, 207))	('PRC1', 'Gene', (68, 72))	('H2AK119ub', 'Var', (42, 51))	('control', 'Reg', (159, 166))
48493	33912157	More recently the role of PRC1 and H2AK119ub in the regulation of other transcriptional programs has emerged, such as the pro-survival and pro-apoptosis transcriptional programs, and the programs of cell proliferation and cell cycle progression across different cell types.	('H2AK119ub', 'Var', (35, 44))	('cell cycle', 'biological_process', 'GO:0007049', ('222', '232'))	('H2AK119ub', 'Chemical', '-', (35, 44))	('cell proliferation', 'biological_process', 'GO:0008283', ('199', '217'))	('pro-apoptosis', 'biological_process', 'GO:0043065', ('139', '152'))	('cell cycle', 'CPA', (222, 232))	('PRC1', 'Gene', (26, 30))	('pro-survival', 'biological_process', 'GO:0043066', ('122', '134'))	('regulation', 'biological_process', 'GO:0065007', ('52', '62'))
48495	33912157	BAP1 is an important tumor suppressor, and germline BAP1 mutations in human result in a strong predisposition to a range of cancers, including mesothelioma, uveal melanoma, renal cell carcinoma, and others.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('tumor', 'Disease', (21, 26))	('tumor suppressor', 'biological_process', 'GO:0051726', ('21', '37'))	('mutations', 'Var', (57, 66))	('uveal melanoma', 'Phenotype', 'HP:0007716', (157, 171))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (173, 193))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('mesothelioma', 'Disease', (143, 155))	('predisposition', 'Reg', (95, 109))	('mesothelioma', 'Disease', 'MESH:D008654', (143, 155))	('human', 'Species', '9606', (70, 75))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('renal cell carcinoma', 'Disease', (173, 193))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (173, 193))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('BAP1', 'Gene', (52, 56))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('21', '37'))	('uveal melanoma', 'Disease', 'MESH:C536494', (157, 171))	('uveal melanoma', 'Disease', (157, 171))
48496	33912157	Although B cell lymphomas are not commonly associated with BAP1 mutations, cases of non-Hodgkin lymphoma have been reported in carriers of germline BAP1 mutations.	('B cell lymphomas', 'Disease', (9, 25))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (88, 104))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (9, 25))	('BAP1', 'Gene', (59, 63))	('B cell lymphomas', 'Disease', 'MESH:D016393', (9, 25))	('mutations', 'Var', (153, 162))	('lymphoma', 'Phenotype', 'HP:0002665', (16, 24))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (84, 104))	('non-Hodgkin lymphoma', 'Disease', (84, 104))	('BAP1', 'Gene', (148, 152))	('mutations', 'Var', (64, 73))	('lymphoma', 'Phenotype', 'HP:0002665', (96, 104))	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (84, 104))	('lymphomas', 'Phenotype', 'HP:0002665', (16, 25))
48497	33912157	Furthermore, lymphomas that carry other genetic aberrations have been shown to acquire BAP1 gene silencing via epigenetic mechanisms.	('lymphomas', 'Disease', 'MESH:D008223', (13, 22))	('epigenetic', 'Var', (111, 121))	('lymphomas', 'Phenotype', 'HP:0002665', (13, 22))	('lymphoma', 'Phenotype', 'HP:0002665', (13, 21))	('gene silencing', 'biological_process', 'GO:0016458', ('92', '106'))	('BAP1 gene', 'Gene', (87, 96))	('lymphomas', 'Disease', (13, 22))
48508	33912157	We have demonstrated that the loss of BAP1 results in impaired B lymphocyte development, and suggested the link of this phenotype to the altered transcriptional profile and the defects in proliferation in BAP1-deficient pre-B cells.	('lymphocyte development', 'biological_process', 'GO:0030098', ('65', '87'))	('transcriptional', 'MPA', (145, 160))	('impaired B lymphocyte', 'Phenotype', 'HP:0010976', (54, 75))	('pre', 'molecular_function', 'GO:0003904', ('220', '223'))	('BAP1', 'Gene', (38, 42))	('B lymphocyte development', 'CPA', (63, 87))	('impaired', 'NegReg', (54, 62))	('pre-B', 'Gene', (220, 225))	('pre-B', 'Gene', '50907', (220, 225))	('loss', 'Var', (30, 34))	('proliferation', 'CPA', (188, 201))
48516	32341551	Although oncoproteins were discovered many years ago and have been widely studied in the context of cancer, the recent use of high-throughput sequencing techniques has led to the identification of cancer-associated mutations in other conditions, including many congenital disorders.	('congenital disorders', 'Disease', (261, 281))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutations', 'Var', (215, 224))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('congenital disorders', 'Disease', 'MESH:D009358', (261, 281))
48522	32341551	For instance, an emerging number of congenital disorders caused by either somatic or germline pathogenic variants have been reported to be caused by mutations in genes that are well-known cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('mutations', 'Var', (149, 158))	('congenital disorders', 'Disease', 'MESH:D009358', (36, 56))	('caused', 'Reg', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('congenital disorders', 'Disease', (36, 56))	('caused', 'Reg', (57, 63))	('variants', 'Var', (105, 113))	('cancer', 'Disease', (188, 194))
48528	32341551	In this Review, we provide a comprehensive catalogue of oncoproteins that are known to cause cancer and congenital disorders (a property that we have termed 'oncoprotein duality').	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('congenital disorders', 'Disease', (104, 124))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cause', 'Reg', (87, 92))	('oncoproteins', 'Var', (56, 68))	('congenital disorders', 'Disease', 'MESH:D009358', (104, 124))
48530	32341551	Intrinsic factors can include the role of gene dosage, such as amplifications of a cancer-associated gene that result in increased activity and downstream signalling.	('age', 'Gene', (50, 53))	('increased', 'PosReg', (121, 130))	('age', 'Gene', '5973', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('activity', 'MPA', (131, 139))	('signalling', 'biological_process', 'GO:0023052', ('155', '165'))	('amplifications', 'Var', (63, 77))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('downstream signalling', 'MPA', (144, 165))	('cancer', 'Disease', (83, 89))
48537	32341551	Because the expression of some of these oncoproteins leads to cell cycle arrest, terminal differentiation or senescence, it is not surprising that genetic epistatic interactions often occur with tumour suppressors involved in these cellular processes.	('arrest', 'Disease', 'MESH:D006323', (73, 79))	('expression', 'Var', (12, 22))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('terminal differentiation', 'CPA', (81, 105))	('tumour', 'Disease', (195, 201))	('senescence', 'CPA', (109, 119))	('arrest', 'Disease', (73, 79))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('62', '79'))	('terminal differentiation', 'biological_process', 'GO:0048468', ('81', '105'))	('senescence', 'biological_process', 'GO:0010149', ('109', '119'))	('leads to', 'Reg', (53, 61))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (62, 79))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
48541	32341551	For instance, in the skin, the presence of HRAS mutations (which are characteristic of squamous carcinomas), does not lead to abnormal growth because tissue architecture preserves homeostasis by correcting the mutant clones or because of compartmentalization in the hair follicle.	('HRAS', 'Gene', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('homeostasis', 'MPA', (180, 191))	('squamous carcinomas', 'Disease', (87, 106))	('mutant', 'Var', (210, 216))	('squamous carcinomas', 'Disease', 'MESH:D002294', (87, 106))	('HRAS', 'Gene', '3265', (43, 47))	('homeostasis', 'biological_process', 'GO:0042592', ('180', '191'))	('abnormal growth', 'Phenotype', 'HP:0001507', (126, 141))	('mutations', 'Var', (48, 57))
48543	32341551	In a similar context, the ability of the immune cells to detect and remove populations of mutant cells could be compromised in cases in which the mutant population was present from birth, as seen in many congenital disorders and tumour predisposition syndromes.	('tumour', 'Disease', 'MESH:D009369', (229, 235))	('tumour', 'Disease', (229, 235))	('mutant', 'Var', (90, 96))	('congenital disorders', 'Disease', 'MESH:D009358', (204, 224))	('congenital disorders', 'Disease', (204, 224))	('tumour', 'Phenotype', 'HP:0002664', (229, 235))
48546	32341551	To add another layer of complexity, different variants of the same oncogene can lead to signi ficant variations in phenotypic outcomes as well; this phenomenon leads to the allele bias observed in tumours and congenital disorders.	('leads', 'Reg', (160, 165))	('congenital disorders', 'Disease', (209, 229))	('tumours', 'Disease', 'MESH:D009369', (197, 204))	('tumours', 'Disease', (197, 204))	('tumours', 'Phenotype', 'HP:0002664', (197, 204))	('variants', 'Var', (46, 54))	('congenital disorders', 'Disease', 'MESH:D009358', (209, 229))	('lead', 'Reg', (80, 84))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))
48548	32341551	The age of the father can have a direct impact on the germline transmission of certain oncogenic variants, because these 'selfish' variants give a growth advantage to cells producing sperm in these individuals.	('impact', 'Reg', (40, 46))	('age', 'Gene', (4, 7))	('age', 'Gene', '5973', (160, 163))	('variants', 'Var', (97, 105))	('variants', 'Var', (131, 139))	('age', 'Gene', '5973', (4, 7))	('age', 'Gene', (160, 163))
48549	32341551	For instance, germline oncogenic mutations in the fibroblast growth factor receptor 3 gene (FGFR3) lead to a disorder termed 'achondroplasia', which results in dwarfism and macrocephaly, yet is compatible with life.	('FGFR3', 'Gene', (92, 97))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('50', '74'))	('lead to', 'Reg', (99, 106))	('dwarfism', 'Disease', (160, 168))	('fibroblast growth factor receptor 3', 'Gene', '2261', (50, 85))	('macrocephaly', 'Disease', (173, 185))	('macrocephaly', 'Phenotype', 'HP:0000256', (173, 185))	('mutations', 'Var', (33, 42))	('achondroplasia', 'Disease', 'MESH:D000130', (126, 140))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('fibroblast growth factor receptor 3', 'Gene', (50, 85))	('achondroplasia', 'Disease', (126, 140))	('dwarfism', 'Phenotype', 'HP:0003510', (160, 168))	('macrocephaly', 'Disease', 'MESH:D058627', (173, 185))	('results in', 'Reg', (149, 159))
48551	32341551	This is exemplified by the oncoprotein KRAS; mutations in the classical hotspots found in cancer (that is, G12, G13 and Q61) are highly transforming in cellbased assays, and the expression of such mutants in the germline results in embryonic lethality due to a severe phenotype that includes cardiomegaly and abnormal brain development.	('G13', 'Gene', (112, 115))	('mutations', 'Var', (45, 54))	('cardiomegaly', 'Disease', (292, 304))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('brain development', 'biological_process', 'GO:0007420', ('318', '335'))	('results in', 'Reg', (221, 231))	('cardiomegaly', 'Disease', 'MESH:D006332', (292, 304))	('abnormal brain development', 'CPA', (309, 335))	('mutants', 'Var', (197, 204))	('embryonic lethality', 'Disease', (232, 251))	('abnormal brain', 'Phenotype', 'HP:0012443', (309, 323))	('KRAS', 'Gene', '3845', (39, 43))	('KRAS', 'Gene', (39, 43))	('Q61', 'Gene', (120, 123))	('embryonic lethality', 'Disease', 'MESH:D020964', (232, 251))	('cardiomegaly', 'Phenotype', 'HP:0001640', (292, 304))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
48552	32341551	However, KRAS mutations have been found in the germline of individuals with Noonan syndrome.	('KRAS', 'Gene', (9, 13))	('Noonan syndrome', 'Disease', (76, 91))	('Noonan syndrome', 'Disease', 'MESH:D009634', (76, 91))	('KRAS', 'Gene', '3845', (9, 13))	('mutations', 'Var', (14, 23))
48553	32341551	These mutations never occur in the cancer hotspot alleles, but rather occur in secondary alleles such as KRASV14I, KRAST58I and KRASD153V (REF.).	('KRAS', 'Gene', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('KRAS', 'Gene', (115, 119))	('KRAS', 'Gene', (105, 109))	('KRAS', 'Gene', '3845', (128, 132))	('KRAS', 'Gene', '3845', (115, 119))	('occur', 'Reg', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('KRAS', 'Gene', '3845', (105, 109))	('cancer', 'Disease', (35, 41))	('mutations', 'Var', (6, 15))
48554	32341551	Such mutations render KRAS active, but to an intermediate point where there is a balance between embryo survival and hyperactive signalling that results in a specific congenital disorder.	('signalling', 'biological_process', 'GO:0023052', ('129', '139'))	('hyperactive', 'Disease', (117, 128))	('mutations', 'Var', (5, 14))	('hyperactive', 'Disease', 'MESH:D006948', (117, 128))	('KRAS', 'Gene', (22, 26))	('congenital disorder', 'Disease', 'MESH:D009358', (167, 186))	('KRAS', 'Gene', '3845', (22, 26))	('congenital disorder', 'Disease', (167, 186))	('results in', 'Reg', (145, 155))
48555	32341551	Examples of such pedigrees have been described in cardiofaciocutaneous syndrome, carrying oncogenic mutations in the MAPK/ERK kinase 1 gene (MEK1, also known as MAP2K1) or MEK2 (also known as MAP2K2).	('MAP2K1', 'Gene', (161, 167))	('MAP2K2', 'Gene', (192, 198))	('MEK2', 'molecular_function', 'GO:0004708', ('172', '176'))	('cardiofaciocutaneous syndrome', 'Disease', (50, 79))	('MAPK', 'molecular_function', 'GO:0004707', ('117', '121'))	('ERK', 'molecular_function', 'GO:0004707', ('122', '125'))	('MAP2K2', 'Gene', '5605', (192, 198))	('MAP2K', 'molecular_function', 'GO:0004708', ('161', '166'))	('MEK1', 'Gene', (141, 145))	('MEK2', 'Gene', (172, 176))	('MAP2K', 'molecular_function', 'GO:0004708', ('192', '197'))	('MEK2', 'Gene', '5605', (172, 176))	('cardiofaciocutaneous syndrome', 'Disease', 'MESH:C535579', (50, 79))	('mutations', 'Var', (100, 109))	('MEK1', 'molecular_function', 'GO:0004708', ('141', '145'))	('MAP2K1', 'Gene', '5604', (161, 167))	('MAPK/ERK kinase 1', 'Gene', '5604', (117, 134))	('MEK1', 'Gene', '5604', (141, 145))	('MAPK/ERK kinase 1', 'Gene', (117, 134))
48557	32341551	The resulting clonal mosaicisms are relatively frequent in healthy individuals and could contribute to genetic conditions such as cancer or congenital disorders.	('congenital disorders', 'Disease', (140, 160))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('contribute', 'Reg', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('clonal mosaicisms', 'Var', (14, 31))	('congenital disorders', 'Disease', 'MESH:D009358', (140, 160))
48559	32341551	Consistently, Schimmelpenning-Feuerstein-Mims syndrome, a disorder characterized by the presence of sebaceous nevi and cataracts, is caused by KRASG12V and KRASG12D mutations in the neuroectodermal lineage as a result of mosaicism.	('KRASG12V', 'Var', (143, 151))	('age', 'Gene', '5973', (202, 205))	('nevi', 'Phenotype', 'HP:0003764', (110, 114))	('cataracts', 'Phenotype', 'HP:0000518', (119, 128))	('Schimmelpenning-Feuerstein-Mims syndrome', 'Disease', (14, 54))	('age', 'Gene', (202, 205))	('Schimmelpenning-Feuerstein-Mims syndrome', 'Disease', 'MESH:D054000', (14, 54))	('caused by', 'Reg', (133, 142))	('sebaceous nevi', 'Phenotype', 'HP:0010815', (100, 114))	('cataracts', 'Disease', 'MESH:D002386', (119, 128))	('KRASG12D', 'Var', (156, 164))	('cataracts', 'Disease', (119, 128))
48560	32341551	These lines represent the vestigial route of cell migration during skin development and become highly evident in mosaicism involving melanocytic lesions, such as the epidermal nevi driven by postzygotic FGFR3, HRAS or PIK3CA mutations.	('HRAS', 'Gene', '3265', (210, 214))	('HRAS', 'Gene', (210, 214))	('mutations', 'Var', (225, 234))	('nevi', 'Phenotype', 'HP:0003764', (176, 180))	('cell migration', 'biological_process', 'GO:0016477', ('45', '59'))	('skin development', 'biological_process', 'GO:0043588', ('67', '83'))	('melanocytic lesions', 'Disease', (133, 152))	('FGFR3', 'Gene', (203, 208))	('epidermal nevi', 'Disease', (166, 180))	('melanocytic lesions', 'Disease', 'MESH:D009508', (133, 152))	('epidermal nevi', 'Phenotype', 'HP:0010816', (166, 180))	('FGFR', 'molecular_function', 'GO:0005007', ('203', '207'))	('PIK3CA', 'Gene', (218, 224))
48561	32341551	The degree and lineage specificity of the mosaicism will be the result of the precise moment at which the oncogenic mutation occurs during embryonic development and whether the mutation might exhibit a positive or a negative advantage to the developing embryo.	('age', 'Gene', (19, 22))	('mutation', 'Var', (116, 124))	('age', 'Gene', '5973', (231, 234))	('age', 'Gene', '5973', (19, 22))	('age', 'Gene', (231, 234))
48562	32341551	Mutations arising as early as the morula stage will give rise to highdegree mosaicisms affecting all tissue lineages, while mutations that occur during or after gastrulation will likely be restricted to a specific germ layer and/or cell fate.	('age', 'Gene', (112, 115))	('age', 'Gene', (43, 46))	('age', 'Gene', '5973', (43, 46))	('gastrulation', 'biological_process', 'GO:0007369', ('161', '173'))	('age', 'Gene', '5973', (112, 115))	('give rise to', 'Reg', (52, 64))	('affecting', 'Reg', (87, 96))	('Mutations', 'Var', (0, 9))	('highdegree', 'Var', (65, 75))
48564	32341551	The presence of large areas of tissue affected by carcinogenic mutations, which often contribute to malignant transformation.	('malignant transformation', 'CPA', (100, 124))	('mutations', 'Var', (63, 72))	('carcinogenic', 'Disease', 'MESH:D063646', (50, 62))	('carcinogenic', 'Disease', (50, 62))
48566	32341551	The current model for sporadic cancer initiation relies on this idea, where a single cell acquires an oncogenic mutation that drives tumour formation (FIG.	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('mutation', 'Var', (112, 120))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumour', 'Disease', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('formation', 'biological_process', 'GO:0009058', ('140', '149'))
48568	32341551	It was later proposed that, to promote cancer formation, cells require several additional mutations, or multiple hits, that would facilitate transformation.	('mutations', 'Var', (90, 99))	('transformation', 'CPA', (141, 155))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('promote', 'PosReg', (31, 38))	('formation', 'biological_process', 'GO:0009058', ('46', '55'))	('facilitate', 'PosReg', (130, 140))
48569	32341551	This concept, introduced by Nordling, and later known as the Knudson hypothesis, is exemplified by experiments in which the deletion of the tumour suppressor Trp highly accelerates the formation of tumours in mice expressing different oncoproteins.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('tumour', 'Disease', (198, 204))	('mice', 'Species', '10090', (209, 213))	('tumours', 'Phenotype', 'HP:0002664', (198, 205))	('formation', 'biological_process', 'GO:0009058', ('185', '194'))	('tumours', 'Disease', 'MESH:D009369', (198, 205))	('Trp', 'Gene', (158, 161))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('Trp', 'Chemical', 'MESH:D014364', (158, 161))	('tumours', 'Disease', (198, 205))	('tumour', 'Disease', (140, 146))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('accelerates', 'PosReg', (169, 180))	('deletion', 'Var', (124, 132))	('tumour', 'Disease', 'MESH:D009369', (198, 204))
48570	32341551	Loss of heterozygosity at the RB1 locus was one of the first examples supporting the Knudson hypothesis in human cancers.	('Loss of heterozygosity', 'Var', (0, 22))	('human', 'Species', '9606', (107, 112))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('RB1', 'Gene', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('RB1', 'Gene', '5925', (30, 33))
48571	32341551	Additional genetic hits can also be boosted by a permissive microenvironment (that is, as a result of radiation or inflammation), as seen in the pancreatitis-induced models that cooperate with Kras mutations to induce pancreatic adenocarcinoma progression.	('inflammation', 'Disease', 'MESH:D007249', (115, 127))	('Kras', 'Gene', '3845', (193, 197))	('pancreatitis', 'Phenotype', 'HP:0001733', (145, 157))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (218, 243))	('pancreatitis', 'Disease', 'MESH:D010195', (145, 157))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (218, 243))	('inflammation', 'biological_process', 'GO:0006954', ('115', '127'))	('inflammation', 'Disease', (115, 127))	('mutations', 'Var', (198, 207))	('pancreatitis', 'Disease', (145, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('Kras', 'Gene', (193, 197))	('induce', 'PosReg', (211, 217))	('pancreatic adenocarcinoma', 'Disease', (218, 243))
48572	32341551	Therefore, a combination of a driver oncogenic mutation and secondary mutations is likely to result in tumour formation when present in a tissue susceptible to transformation.	('mutations', 'Var', (70, 79))	('formation', 'biological_process', 'GO:0009058', ('110', '119'))	('mutation', 'Var', (47, 55))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('tumour', 'Disease', (103, 109))	('result in', 'Reg', (93, 102))
48573	32341551	For example, mutations in the G protein subunit alphaq gene (GNAQ) are drivers of uveal melanoma and congenital capillary malformations but are unlikely to transform other tissues.	('capillary malformations', 'Phenotype', 'HP:0025104', (112, 135))	('congenital capillary malformations', 'Disease', (101, 135))	('congenital capillary malformations', 'Disease', 'MESH:C535816', (101, 135))	('capillary malformation', 'Phenotype', 'HP:0025104', (112, 134))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('GNAQ', 'Gene', (61, 65))	('uveal melanoma', 'Disease', (82, 96))	('uveal melanoma', 'Disease', 'MESH:C536494', (82, 96))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('mutations', 'Var', (13, 22))	('GNAQ', 'Gene', '2776', (61, 65))
48584	32341551	RTK genes are commonly mutated in cancer and the encoded proteins are considered bona fide oncoproteins, constitutively activated by point mutation, amplification, translocation or deletion of autoinhibitory regions.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('point mutation', 'Var', (133, 147))	('translocation', 'Var', (164, 177))	('amplification', 'Var', (149, 162))	('RTK', 'Gene', '5979', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('deletion', 'Var', (181, 189))	('RTK', 'Gene', (0, 3))
48585	32341551	In general, weakly activating mutations in these RTK genes are compatible with development and give rise to tumour predisposition syndromes rather than clinically unique syndromes (FIG.	('tumour', 'Disease', (108, 114))	('give rise to', 'Reg', (95, 107))	('activating', 'PosReg', (19, 29))	('RTK', 'Gene', '5979', (49, 52))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (30, 39))	('tumour', 'Disease', 'MESH:D009369', (108, 114))	('RTK', 'Gene', (49, 52))
48587	32341551	While EGFR mutations occur in a large number of lung adenocarcinomas (mostly L858R and E746-750del), ERBB2 variants are less frequent in the lung, but can be found in some patients with breast cancer.	('mutations', 'Var', (11, 20))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (48, 68))	('L858R', 'Mutation', 'rs121434568', (77, 82))	('variants', 'Var', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('EGFR', 'Gene', '1956', (6, 10))	('EGFR', 'molecular_function', 'GO:0005006', ('6', '10'))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (48, 68))	('E746-750del', 'Var', (87, 98))	('patients', 'Species', '9606', (172, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('ERBB2', 'Gene', (101, 106))	('L858R', 'Var', (77, 82))	('lung adenocarcinomas', 'Disease', (48, 68))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('found', 'Reg', (158, 163))	('breast cancer', 'Disease', (186, 199))	('ERBB2', 'Gene', '2064', (101, 106))	('E746-750del', 'Mutation', 'c.746,750delE,-', (87, 98))	('EGFR', 'Gene', (6, 10))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
48588	32341551	Gene amplification and/or protein overexpression of ERBB2 is a very common and subtype-defining event, and is found in breast and gastric adenocarcinomas.	('breast', 'Disease', (119, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('gastric adenocarcinomas', 'Disease', (130, 153))	('found', 'Reg', (110, 115))	('overexpression', 'PosReg', (34, 48))	('Gene amplification', 'Var', (0, 18))	('ERBB2', 'Gene', '2064', (52, 57))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('ERBB2', 'Gene', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('protein', 'Protein', (26, 33))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (130, 153))
48589	32341551	Most of these mutations are gain-of-function mutations because they promote ligand-independent activation of the receptor, but they have not been found in other congenital disorders.	('ligand', 'molecular_function', 'GO:0005488', ('76', '82'))	('promote', 'PosReg', (68, 75))	('congenital disorders', 'Disease', 'MESH:D009358', (161, 181))	('ligand-independent activation', 'MPA', (76, 105))	('mutations', 'Var', (14, 23))	('congenital disorders', 'Disease', (161, 181))
48591	32341551	An autosomal dominant syndrome that is the most common form of skeletal dysplasia in humans and is caused by the FGFR3 mutation G380R.	('skeletal dysplasia', 'Phenotype', 'HP:0002652', (63, 81))	('FGFR', 'molecular_function', 'GO:0005007', ('113', '117'))	('G380R', 'Mutation', 'rs28931614', (128, 133))	('G380R', 'Var', (128, 133))	('FGFR3', 'Gene', (113, 118))	('skeletal dysplasia', 'Disease', 'MESH:C535858', (63, 81))	('humans', 'Species', '9606', (85, 91))	('skeletal dysplasia', 'Disease', (63, 81))	('caused by', 'Reg', (99, 108))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (3, 30))	('autosomal dominant syndrome', 'Disease', (3, 30))
48595	32341551	Somatic events often result from translocation of the ALK kinase domain and other partners (for example, EML4 in lung cancer and TPM3 and/or TPM4 in anaplastic large B cell lymphoma) or as a result of gain-offunction alterations in the kinase domain that result in constitutive activation of the receptor, most frequently seen in neuroblastomas.	('ALK', 'Gene', (54, 57))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('alterations', 'Var', (217, 228))	('gain-offunction', 'PosReg', (201, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('TPM3', 'Gene', (129, 133))	('TPM4', 'Gene', '7171', (141, 145))	('EML4', 'Gene', (105, 109))	('neuroblastomas', 'Phenotype', 'HP:0003006', (330, 344))	('B cell lymphoma', 'Disease', 'MESH:D016393', (166, 181))	('translocation', 'MPA', (33, 46))	('EML4', 'Gene', '27436', (105, 109))	('neuroblastomas', 'Disease', (330, 344))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('result', 'Reg', (21, 27))	('neuroblastomas', 'Disease', 'MESH:D009447', (330, 344))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (166, 181))	('lung cancer', 'Disease', (113, 124))	('lymphoma', 'Phenotype', 'HP:0002665', (173, 181))	('large B cell', 'Phenotype', 'HP:0005404', (160, 172))	('neuroblastoma', 'Phenotype', 'HP:0003006', (330, 343))	('constitutive activation', 'MPA', (265, 288))	('TPM4', 'Gene', (141, 145))	('ALK', 'Gene', '238', (54, 57))	('TPM3', 'Gene', '7170', (129, 133))	('B cell lymphoma', 'Disease', (166, 181))
48596	32341551	In cases of family predisposition to neuroblastoma, ALK kinase domain alterations have been described in the germline, although these alleles do generally not overlap with those seen in sporadic cases.	('neuroblastoma', 'Disease', 'MESH:D009447', (37, 50))	('ALK', 'Gene', '238', (52, 55))	('neuroblastoma', 'Disease', (37, 50))	('kinase domain alterations', 'Var', (56, 81))	('neuroblastoma', 'Phenotype', 'HP:0003006', (37, 50))	('ALK', 'Gene', (52, 55))
48600	32341551	Strong activating variants in these genes are present in sporadic gastrointestinal stromal tumours, with PDGFRAD842V, KITD816N/V/Y/H and KITN822K as the main hotspots.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('KIT', 'Gene', '3815', (118, 121))	('sporadic gastrointestinal stromal tumours', 'Disease', (57, 98))	('activating', 'PosReg', (7, 17))	('PDGFRAD842V', 'Mutation', 'rs121908585', (105, 116))	('sporadic gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (57, 98))	('KIT', 'Gene', (118, 121))	('KIT', 'Gene', '3815', (137, 140))	('gastrointestinal stromal tumour', 'Phenotype', 'HP:0100723', (66, 97))	('KIT', 'Gene', (137, 140))	('PDGFRAD842V', 'Var', (105, 116))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
48602	32341551	In addition to gastrointestinal stromal tumours, patients with germline PDGFRA and KIT mutations exhibit cutaneous mastocytosis.	('tumours', 'Phenotype', 'HP:0002664', (40, 47))	('gastrointestinal stromal tumours', 'Disease', (15, 47))	('gastrointestinal stromal tumour', 'Phenotype', 'HP:0100723', (15, 46))	('KIT', 'Gene', (83, 86))	('PDGFRA', 'Gene', '5156', (72, 78))	('mastocytosis', 'Phenotype', 'HP:0100495', (115, 127))	('PDGFRA', 'Gene', (72, 78))	('cutaneous mastocytosis', 'Disease', (105, 127))	('exhibit', 'Reg', (97, 104))	('KIT', 'molecular_function', 'GO:0005020', ('83', '86'))	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (15, 47))	('cutaneous mastocytosis', 'Phenotype', 'HP:0200151', (105, 127))	('cutaneous mastocytosis', 'Disease', 'MESH:D034701', (105, 127))	('patients', 'Species', '9606', (49, 57))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('mutations', 'Var', (87, 96))	('KIT', 'Gene', '3815', (83, 86))
48603	32341551	Other neoplasms driven by KIT oncogenic mutations include acute leukaemia and germ cell tumours.	('neoplasms', 'Disease', 'MESH:D009369', (6, 15))	('neoplasms', 'Disease', (6, 15))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('KIT', 'Gene', '3815', (26, 29))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('KIT', 'molecular_function', 'GO:0005020', ('26', '29'))	('leukaemia', 'Disease', 'MESH:D007938', (64, 73))	('acute leukaemia', 'Phenotype', 'HP:0002488', (58, 73))	('KIT', 'Gene', (26, 29))	('mutations', 'Var', (40, 49))	('tumours', 'Disease', (88, 95))	('neoplasms', 'Phenotype', 'HP:0002664', (6, 15))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('leukaemia', 'Disease', (64, 73))
48604	32341551	The case of somatic and germline mutations in the fibroblast growth factor receptor (FGFR) gene family is of particular interest, given the gene-and allele-specific phenotypes resulting from gain-of-function mutations.	('FGF', 'Gene', (85, 88))	('mutations', 'Var', (208, 217))	('mutations', 'Var', (33, 42))	('FGF', 'Gene', '8074', (85, 88))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))	('gain-of-function', 'PosReg', (191, 207))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('50', '74'))
48606	32341551	The latter becomes apparent when one is studying the phenotypes of individuals carry ing germline gain-of-function mutations in FGFR1, FGFR2 or FGFR3, as these are generally characterized by dysmorphic features, such as craniosynostosis, and short limbs.	('FGFR1', 'Gene', (128, 133))	('FGFR1', 'Gene', '2260', (128, 133))	('short limbs', 'Phenotype', 'HP:0009826', (242, 253))	('mutations', 'Var', (115, 124))	('gain-of-function', 'PosReg', (98, 114))	('dysmorphic features', 'Disease', (191, 210))	('short limbs', 'Disease', (242, 253))	('FGFR2', 'Gene', (135, 140))	('FGFR2', 'Gene', '2263', (135, 140))	('craniosynostosis', 'Phenotype', 'HP:0001363', (220, 236))	('FGFR3', 'Gene', (144, 149))	('FGFR', 'molecular_function', 'GO:0005007', ('128', '132'))	('FGFR', 'molecular_function', 'GO:0005007', ('144', '148'))	('craniosynostosis', 'Disease', 'MESH:D003398', (220, 236))	('craniosynostosis', 'Disease', (220, 236))	('FGFR', 'molecular_function', 'GO:0005007', ('135', '139'))
48607	32341551	Activating mutations in FGFR3 give rise to clinically overlapping, but different, forms of bone affections, including achondroplasia (G380R), Muenke syndrome (P250R), thanatophoric dysplasia I and II (R248C and K650E, respectively), severe achondroplasia with developmental delay and acanthosis nigricans (K650M) and Crouzon syndrome with acanthosis nigricans (A391E).	('mutations', 'Var', (11, 20))	('achondroplasia', 'Disease', 'MESH:D000130', (118, 132))	('G380R', 'Var', (134, 139))	('acanthosis', 'Disease', (284, 294))	('acanthosis', 'Disease', (339, 349))	('P250R', 'Var', (159, 164))	('Muenke syndrome', 'Disease', (142, 157))	('A391E', 'Mutation', 'rs28931615', (361, 366))	('dysplasia I', 'Disease', (181, 192))	('achondroplasia', 'Disease', (240, 254))	('acanthosis', 'Disease', 'MESH:D000052', (284, 294))	('developmental delay', 'Phenotype', 'HP:0001263', (260, 279))	('acanthosis', 'Disease', 'MESH:D000052', (339, 349))	('developmental delay and acanthosis', 'Disease', 'MESH:D000130', (260, 294))	('R248C', 'Var', (201, 206))	('R248C', 'Mutation', 'rs121913482', (201, 206))	('Crouzon syndrome', 'Disease', 'MESH:D003394', (317, 333))	('dysplasia I', 'Disease', 'MESH:C538215', (181, 192))	('Crouzon syndrome', 'Phenotype', 'HP:0004439', (317, 333))	('achondroplasia', 'Disease', (118, 132))	('Crouzon syndrome', 'Disease', (317, 333))	('achondroplasia', 'Disease', 'MESH:D000130', (240, 254))	('K650E', 'Mutation', 'rs78311289', (211, 216))	('K650M', 'Mutation', 'rs121913105', (306, 311))	('bone affections', 'Disease', (91, 106))	('acanthosis', 'Phenotype', 'HP:0025092', (284, 294))	('Muenke syndrome', 'Disease', 'MESH:C537369', (142, 157))	('K650E', 'Var', (211, 216))	('acanthosis nigricans', 'Phenotype', 'HP:0000956', (284, 304))	('acanthosis', 'Phenotype', 'HP:0025092', (339, 349))	('FGFR3', 'Gene', (24, 29))	('P250R', 'Mutation', 'rs4647924', (159, 164))	('acanthosis nigricans', 'Phenotype', 'HP:0000956', (339, 359))	('G380R', 'Mutation', 'rs28931614', (134, 139))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))
48608	32341551	Some of these alterations occurat different functional domains of the protein (P250R at the extracellular immunoglobulin- like domain, G380R at the transmembrane domain and K650E at the intracellular kinase domain), which could potentially explain the differential traits of these patients.	('immunoglobulin', 'molecular_function', 'GO:0003823', ('106', '120'))	('K650E', 'Var', (173, 178))	('G380R', 'Mutation', 'rs28931614', (135, 140))	('P250R', 'Mutation', 'rs4647924', (79, 84))	('transmembrane', 'cellular_component', 'GO:0016021', ('148', '161'))	('transmembrane', 'cellular_component', 'GO:0044214', ('148', '161'))	('P250R', 'Var', (79, 84))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('patients', 'Species', '9606', (281, 289))	('occurat', 'Reg', (26, 33))	('extracellular', 'cellular_component', 'GO:0005576', ('92', '105'))	('intracellular', 'cellular_component', 'GO:0005622', ('186', '199'))	('G380R', 'Var', (135, 140))	('K650E', 'Mutation', 'rs78311289', (173, 178))
48609	32341551	Somatic mutations in FGFR3 are very common in urothelial bladder carcinoma, with two main hotspots, R248C and S249C, that are also found in patients with thanatophoric dysplasia I.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('R248C', 'Var', (100, 105))	('dysplasia I', 'Disease', (168, 179))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('urothelial bladder carcinoma', 'Disease', (46, 74))	('FGFR3', 'Gene', (21, 26))	('R248C', 'Mutation', 'rs121913482', (100, 105))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (57, 74))	('common', 'Reg', (36, 42))	('S249C', 'Var', (110, 115))	('thanatophoric', 'Disease', (154, 167))	('patients', 'Species', '9606', (140, 148))	('S249C', 'Mutation', 'rs121913483', (110, 115))	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (46, 74))	('dysplasia I', 'Disease', 'MESH:C538215', (168, 179))
48610	32341551	Such mutations also appear to be common in epidermal nevi and seborrheic keratosis, two frequent benign skin lesions characterized by, among other conditions, acanthosis.	('benign skin lesions', 'Disease', 'MESH:D012871', (97, 116))	('seborrheic keratosis', 'Disease', (62, 82))	('benign skin lesions', 'Disease', (97, 116))	('seborrheic keratosis', 'Phenotype', 'HP:0031287', (62, 82))	('common', 'Reg', (33, 39))	('mutations', 'Var', (5, 14))	('seborrheic keratosis', 'Disease', 'MESH:D017492', (62, 82))	('nevi', 'Phenotype', 'HP:0003764', (53, 57))	('epidermal nevi', 'Phenotype', 'HP:0010816', (43, 57))	('acanthosis', 'Phenotype', 'HP:0025092', (159, 169))	('acanthosis', 'Disease', 'MESH:D000052', (159, 169))	('acanthosis', 'Disease', (159, 169))	('epidermal nevi', 'Disease', (43, 57))
48611	32341551	Germline mutations in FGFR1 and FGFR2 are also a frequent cause of skeletal pathologies within this spectrum, for which Pfeiffer syndrome, Apert syndrome and Crouzon syndrome are widely recognized.	('Germline mutations', 'Var', (0, 18))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('Pfeiffer syndrome', 'Disease', (120, 137))	('FGFR1', 'Gene', '2260', (22, 27))	('Apert syndrome', 'Disease', (139, 153))	('cause', 'Reg', (58, 63))	('FGFR2', 'Gene', (32, 37))	('skeletal pathologies', 'Disease', (67, 87))	('skeletal pathologies', 'Phenotype', 'HP:0000924', (67, 87))	('Crouzon syndrome', 'Disease', (158, 174))	('FGFR2', 'Gene', '2263', (32, 37))	('Pfeiffer syndrome', 'Disease', 'MESH:C538582', (120, 137))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))	('Crouzon syndrome', 'Disease', 'MESH:D003394', (158, 174))	('Crouzon syndrome', 'Phenotype', 'HP:0004439', (158, 174))	('FGFR1', 'Gene', (22, 27))
48612	32341551	Although some uterine adenocarcinomas have FGFR2 hypermorphs similar to those in Apert syndrome, FGFR1 and FGFR2 mutations are relatively uncommon in cancer.	('FGFR1', 'Gene', '2260', (97, 102))	('FGFR2', 'Gene', (107, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('carcinomas', 'Phenotype', 'HP:0030731', (27, 37))	('FGFR2', 'Gene', '2263', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('FGFR', 'molecular_function', 'GO:0005007', ('97', '101'))	('FGFR', 'molecular_function', 'GO:0005007', ('107', '111'))	('cancer', 'Disease', (150, 156))	('mutations', 'Var', (113, 122))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('adenocarcinomas', 'Disease', 'MESH:D000230', (22, 37))	('FGFR2', 'Gene', (43, 48))	('FGFR2', 'Gene', '2263', (43, 48))	('FGFR1', 'Gene', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('adenocarcinomas', 'Disease', (22, 37))
48613	32341551	Although many other RTKs are known to be oncogenic, and often altered in tumours, they have not been discussed in this section because of limited evidence regarding gain-of-function mutations in congenital disorders and, hence, do not fall within the category of dual oncoproteins.	('fall', 'Phenotype', 'HP:0002527', (235, 239))	('tumours', 'Disease', (73, 80))	('congenital disorders', 'Disease', (195, 215))	('RTK', 'Gene', '5979', (20, 23))	('tumours', 'Disease', 'MESH:D009369', (73, 80))	('gain-of-function', 'PosReg', (165, 181))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('congenital disorders', 'Disease', 'MESH:D009358', (195, 215))	('RTK', 'Gene', (20, 23))	('mutations', 'Var', (182, 191))
48618	32341551	An increasing number of cancers and congenital disorders have been found to be driven by gain-of-function mutations in RAS, RAF or MEK gene isoforms (FIG.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('RAF', 'Gene', '22882', (124, 127))	('RAF', 'Gene', (124, 127))	('congenital disorders', 'Disease', 'MESH:D009358', (36, 56))	('gain-of-function', 'PosReg', (89, 105))	('congenital disorders', 'Disease', (36, 56))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('MEK', 'Gene', (131, 134))	('mutations', 'Var', (106, 115))	('MEK', 'Gene', '5609', (131, 134))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('RAS', 'Gene', (119, 122))	('cancers', 'Disease', (24, 31))
48619	32341551	Mutations in the RAS oncogenes are very frequent across all human cancers.	('frequent', 'Reg', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('RAS oncogenes', 'Gene', (17, 30))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('human', 'Species', '9606', (60, 65))
48620	32341551	KRAS mutations are found as a main driver in pancreatic adenocarcinoma, lung adenocarcinoma, colorectal adenocarcinoma, uterine carcinoma and carcinosarcoma, testicular germ tumours, multiple myeloma and gastric adeno carcinoma.	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (45, 70))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (120, 137))	('gastric adeno carcinoma', 'Disease', 'MESH:D013274', (204, 227))	('carcinoma', 'Disease', 'MESH:D009369', (61, 70))	('carcinoma', 'Disease', 'MESH:D009369', (109, 118))	('multiple myeloma', 'Disease', (183, 199))	('carcinosarcoma', 'Disease', 'MESH:D002296', (142, 156))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (45, 70))	('carcinoma', 'Disease', 'MESH:D009369', (218, 227))	('carcinoma', 'Disease', 'MESH:D009369', (82, 91))	('gastric adeno carcinoma', 'Disease', (204, 227))	('carcinoma', 'Disease', (218, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('colorectal adenocarcinoma', 'Disease', (93, 118))	('tumours', 'Disease', (174, 181))	('carcinoma', 'Disease', (128, 137))	('KRAS', 'Gene', '3845', (0, 4))	('lung adenocarcinoma', 'Disease', (72, 91))	('tumours', 'Phenotype', 'HP:0002664', (174, 181))	('multiple myeloma', 'Phenotype', 'HP:0006775', (183, 199))	('pancreatic adenocarcinoma', 'Disease', (45, 70))	('mutations', 'Var', (5, 14))	('tumours', 'Disease', 'MESH:D009369', (174, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (93, 118))	('carcinoma', 'Disease', (61, 70))	('KRAS', 'Gene', (0, 4))	('carcinoma', 'Disease', 'MESH:D009369', (128, 137))	('carcinoma', 'Disease', (109, 118))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (72, 91))	('multiple myeloma', 'Disease', 'MESH:D009101', (183, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('carcinosarcoma', 'Disease', (142, 156))	('carcinoma', 'Disease', (82, 91))
48621	32341551	HRAS mutations instead are mostly found in pheochromocytomas, paragangliomas, head and neck tumours, bladder and thyroid cancers, and melanoma.	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('bladder and thyroid cancers', 'Disease', 'MESH:D001749', (101, 128))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (43, 60))	('neck tumours', 'Disease', 'MESH:D006258', (87, 99))	('found', 'Reg', (34, 39))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('paragangliomas', 'Disease', 'MESH:D010235', (62, 76))	('paragangliomas, head and neck', 'Phenotype', 'HP:0002864', (62, 91))	('paragangliomas', 'Phenotype', 'HP:0002668', (62, 76))	('neck', 'cellular_component', 'GO:0044326', ('87', '91'))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('mutations', 'Var', (5, 14))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (43, 59))	('neck tumours', 'Disease', (87, 99))	('HRAS', 'Gene', '3265', (0, 4))	('pheochromocytomas', 'Disease', (43, 60))	('pheochromocytomas', 'Disease', 'MESH:D010673', (43, 60))	('HRAS', 'Gene', (0, 4))	('paragangliomas', 'Disease', (62, 76))	('thyroid cancer', 'Phenotype', 'HP:0002890', (113, 127))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
48622	32341551	Mutations in NRAS are found in melanoma, acute myeloid leukaemias, and thyroid and colorectal cancers.	('myeloid leukaemias', 'Phenotype', 'HP:0012324', (47, 65))	('colorectal cancers', 'Disease', 'MESH:D015179', (83, 101))	('acute myeloid leukaemias', 'Disease', (41, 65))	('NRAS', 'Gene', '4893', (13, 17))	('colorectal cancers', 'Disease', (83, 101))	('found', 'Reg', (22, 27))	('acute myeloid leukaemias', 'Disease', 'MESH:D015470', (41, 65))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', (13, 17))	('thyroid', 'Disease', (71, 78))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('melanoma', 'Disease', (31, 39))	('acute myeloid leukaemias', 'Phenotype', 'HP:0004808', (41, 65))
48623	32341551	Mechanistically, such mutations result in the loss of GTPase-activating protein-mediated hydrolysis, which results in constitutive RAS activation and signalling.	('constitutive RAS', 'MPA', (118, 134))	('activation', 'PosReg', (135, 145))	('GTPase-activating protein-mediated', 'Protein', (54, 88))	('loss', 'NegReg', (46, 50))	('signalling', 'biological_process', 'GO:0023052', ('150', '160'))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('mutations', 'Var', (22, 31))	('signalling', 'MPA', (150, 160))	('GTP', 'Chemical', 'MESH:D006160', (54, 57))
48624	32341551	Most of the mutations that activate NRAS in melanoma are at codon 61, while in leukaemias they are at codon 12 (REF.).	('leukaemias', 'Disease', (79, 89))	('NRAS', 'Gene', (36, 40))	('activate', 'PosReg', (27, 35))	('mutations', 'Var', (12, 21))	('melanoma', 'Disease', (44, 52))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('NRAS', 'Gene', '4893', (36, 40))	('leukaemias', 'Disease', 'MESH:D007938', (79, 89))
48626	32341551	Extracranial arteriovenous malformations can also carry mosaic KRAS mutations, although in a lower proportion.	('KRAS', 'Gene', '3845', (63, 67))	('arteriovenous malformations', 'Disease', (13, 40))	('arteriovenous malformations', 'Disease', 'MESH:D001165', (13, 40))	('venous malformations', 'Phenotype', 'HP:0012721', (20, 40))	('mosaic', 'Var', (56, 62))	('arteriovenous malformations', 'Phenotype', 'HP:0100026', (13, 40))	('KRAS', 'Gene', (63, 67))
48627	32341551	KRAS mutations have also been identified in the form of mosaicism in nevus sebaceous and both oculoectodermal syndrome and Schimmelpenning-Feuerstein-Mims syndrome.	('KRAS', 'Gene', '3845', (0, 4))	('nevus sebaceous', 'Disease', (69, 84))	('Schimmelpenning-Feuerstein-Mims syndrome', 'Disease', 'MESH:D054000', (123, 163))	('mosaicism', 'Var', (56, 65))	('nevus sebaceous', 'Phenotype', 'HP:0010815', (69, 84))	('mutations', 'Var', (5, 14))	('oculoectodermal syndrome', 'Disease', (94, 118))	('identified', 'Reg', (30, 40))	('nevus', 'Phenotype', 'HP:0003764', (69, 74))	('KRAS', 'Gene', (0, 4))	('Schimmelpenning-Feuerstein-Mims syndrome', 'Disease', (123, 163))
48629	32341551	Within this group, other mosaic forms driven by oncogenic HRAS or NRAS mutations have also been described, including epidermal nevi, phacomatosis pigmentokeratotica, nevus spilus, woolly hair nevus, neurocutaneous melanosis/congenital giant melanocytic nevus and cutaneous-skeletal hypophosphataemia syndrome.	('nevus spilus', 'Disease', (166, 178))	('epidermal nevi', 'Phenotype', 'HP:0010816', (117, 131))	('phacomatosis pigmentokeratotica', 'Disease', (133, 164))	('epidermal nevi', 'Disease', (117, 131))	('woolly hair nevus', 'Disease', (180, 197))	('nevus', 'Phenotype', 'HP:0003764', (192, 197))	('nevus spilus', 'Phenotype', 'HP:0025510', (166, 178))	('nevus', 'Phenotype', 'HP:0003764', (166, 171))	('melanosis', 'Disease', (214, 223))	('NRAS', 'Gene', (66, 70))	('melanosis', 'Disease', 'MESH:D008548', (214, 223))	('nevus', 'Phenotype', 'HP:0003764', (253, 258))	('woolly hair', 'Phenotype', 'HP:0002224', (180, 191))	('mutations', 'Var', (71, 80))	('cutaneous-skeletal hypophosphataemia syndrome', 'Disease', 'MESH:D017577', (263, 308))	('hypophosphataemia', 'Phenotype', 'HP:0002148', (282, 299))	('HRAS', 'Gene', '3265', (58, 62))	('HRAS', 'Gene', (58, 62))	('phacomatosis pigmentokeratotica', 'Disease', 'MESH:C537893', (133, 164))	('cutaneous-skeletal hypophosphataemia syndrome', 'Disease', (263, 308))	('NRAS', 'Gene', '4893', (66, 70))	('melanocytic nevus', 'Phenotype', 'HP:0000995', (241, 258))	('nevi', 'Phenotype', 'HP:0003764', (127, 131))	('congenital giant melanocytic nevus', 'Phenotype', 'HP:0005600', (224, 258))
48633	32341551	On GPCR stimulation, conformational changes in the receptor lead to Gbetagamma dissociation and Galpha GTP loading and activation, resulting in the production of second messengers; for Galphas (encoded by GNAS) adenylate cyclase and production of cAMP, and for Galphaq and Galphall (encoded by GNAQ and GNA11, respectively) phospholipase C, resulting in diacylglycerol and inositol trisphosphate.	('Galphas', 'Gene', '79447', (185, 192))	('inositol trisphosphate', 'MPA', (373, 395))	('inositol trisphosphate', 'Chemical', '-', (373, 395))	('GNAS', 'Gene', (205, 209))	('Galpha', 'Gene', '8802', (273, 279))	('cAMP', 'MPA', (247, 251))	('diacylglycerol', 'MPA', (354, 368))	('diacylglycerol', 'Chemical', 'MESH:D004075', (354, 368))	('lead to', 'Reg', (60, 67))	('GNAS', 'Gene', '2778', (205, 209))	('Galpha', 'Gene', (185, 191))	('Gbetagamma', 'Protein', (68, 78))	('Galpha', 'Gene', (96, 102))	('cAMP', 'Chemical', '-', (247, 251))	('GNA11', 'Gene', '2767', (303, 308))	('conformational changes', 'Var', (21, 43))	('Galphas', 'Gene', (185, 192))	('production of second messengers', 'MPA', (148, 179))	('Galpha', 'Gene', (261, 267))	('activation', 'PosReg', (119, 129))	('GTP', 'Chemical', 'MESH:D006160', (103, 106))	('Galpha', 'Gene', '8802', (96, 102))	('GNAQ', 'Gene', '2776', (294, 298))	('Galpha', 'Gene', '8802', (185, 191))	('phospholipase C', 'Enzyme', (324, 339))	('dissociation', 'MPA', (79, 91))	('GNAQ', 'Gene', (294, 298))	('Galpha', 'Gene', '8802', (261, 267))	('GNA11', 'Gene', (303, 308))	('Galpha', 'Gene', (273, 279))
48637	32341551	Mutant bone exhibits dysplastic features and elevated secretion of FGF23, a hormone that regulates phosphorus homeostasis in the kidney (autonomous effect).	('dysplastic', 'Disease', (21, 31))	('phosphorus', 'Chemical', 'MESH:D010758', (99, 109))	('FGF23', 'Gene', (67, 72))	('dysplastic', 'Disease', 'MESH:D004416', (21, 31))	('homeostasis', 'biological_process', 'GO:0042592', ('110', '121'))	('elevated', 'PosReg', (45, 53))	('secretion', 'biological_process', 'GO:0046903', ('54', '63'))	('Mutant', 'Var', (0, 6))	('secretion', 'MPA', (54, 63))	('FGF23', 'Gene', '8074', (67, 72))
48638	32341551	These patients develop rickets in bones that do not contain the mutation as a result of paracrine and endocrine action of RAS mutant bone-derived FGF23 (non-autonomous effects), in a similar fashion as the paraneoplastic phenomenon observed in oncogenic osteomalacia.	('rickets', 'Disease', (23, 30))	('FGF23', 'Gene', '8074', (146, 151))	('paraneoplastic', 'Disease', 'MESH:D010257', (206, 220))	('RAS mutant', 'Var', (122, 132))	('patients', 'Species', '9606', (6, 14))	('rickets', 'Phenotype', 'HP:0002748', (23, 30))	('osteomalacia', 'Phenotype', 'HP:0002749', (254, 266))	('oncogenic osteomalacia', 'Disease', (244, 266))	('oncogenic osteomalacia', 'Disease', 'MESH:C537751', (244, 266))	('paraneoplastic', 'Disease', (206, 220))	('develop', 'Reg', (15, 22))	('FGF23', 'Gene', (146, 151))
48639	32341551	Another mosaic RASopathy characterized by an extensive bone phenotype is melorheostosis, a rare disorder that causes excess bone growth with a classic 'dripping candle wax' pattern and is caused by activating mutations in MEK1 (REF.).	('MEK1', 'Gene', '5604', (222, 226))	('bone growth', 'biological_process', 'GO:0098868', ('124', '135'))	('RASopathy', 'Disease', (15, 24))	('activating mutations', 'Var', (198, 218))	('MEK1', 'Gene', (222, 226))	('caused by', 'Reg', (188, 197))	('excess bone growth', 'Phenotype', 'HP:0100774', (117, 135))	('melorheostosis', 'Disease', (73, 87))	('RASopathy', 'Disease', 'None', (15, 24))	('melorheostosis', 'Disease', 'MESH:D008557', (73, 87))	('MEK1', 'molecular_function', 'GO:0004708', ('222', '226'))
48640	32341551	The effect of MAPK activation in the bone due to oncogenic mutations is not restricted to these syndromes, since skeletal abnormalities have been observed in other germline RASopathies, such as Noonan syndrome, cardiofaciocutaneous syndrome and Costello syndrome.	('cardiofaciocutaneous syndrome', 'Disease', (211, 240))	('skeletal abnormalities', 'Disease', (113, 135))	('Noonan syndrome', 'Disease', 'MESH:D009634', (194, 209))	('skeletal abnormalities', 'Phenotype', 'HP:0000924', (113, 135))	('MAPK', 'Gene', (14, 18))	('activation', 'PosReg', (19, 29))	('Costello syndrome', 'Disease', (245, 262))	('RASopathies', 'Disease', (173, 184))	('MAPK', 'molecular_function', 'GO:0004707', ('14', '18'))	('skeletal abnormalities', 'Disease', 'MESH:C538496', (113, 135))	('cardiofaciocutaneous syndrome', 'Disease', 'MESH:C535579', (211, 240))	('MAPK', 'Gene', '5604', (14, 18))	('mutations', 'Var', (59, 68))	('MAPK activation', 'biological_process', 'GO:0000187', ('14', '29'))	('Costello syndrome', 'Disease', 'MESH:D056685', (245, 262))	('RASopathies', 'Disease', 'None', (173, 184))	('Noonan syndrome', 'Disease', (194, 209))
48642	32341551	Costello syndrome is the most seve of the germline RASopathies and is caused by de novo mutations in HRAS, mostly G12S.	('Costello syndrome', 'Disease', 'MESH:D056685', (0, 17))	('RASopathies', 'Disease', (51, 62))	('HRAS', 'Gene', '3265', (101, 105))	('G12S', 'Mutation', 'rs104894229', (114, 118))	('mutations', 'Var', (88, 97))	('HRAS', 'Gene', (101, 105))	('Costello syndrome', 'Disease', (0, 17))	('RASopathies', 'Disease', 'None', (51, 62))	('G12S', 'Var', (114, 118))	('caused by', 'Reg', (70, 79))
48643	32341551	Although other mutations have been described, it is worth noting that strong alleles (that is, HRASG12V and HRASG12D) are rarely found in these patients, most likely due to embryonic lethality, but if found, they are associated with a severe phenotype.	('associated with', 'Reg', (217, 232))	('HRASG12V', 'Var', (95, 103))	('patients', 'Species', '9606', (144, 152))	('HRASG12D', 'Var', (108, 116))	('embryonic lethality', 'Disease', 'MESH:D020964', (173, 192))	('embryonic lethality', 'Disease', (173, 192))
48645	32341551	In the case of Noonan syndrome, several genes have been shown to contribute to the disorder due to gain-of-function mutations.	('Noonan syndrome', 'Disease', 'MESH:D009634', (15, 30))	('Noonan syndrome', 'Disease', (15, 30))	('mutations', 'Var', (116, 125))	('gain-of-function', 'PosReg', (99, 115))
48650	32341551	RIT1 mutations have been seen in a subset of patients with lung adenocarcinoma who do not harbour other typical driver mutations and these alleles are often the same as in patients with Noonan syndrome.	('Noonan syndrome', 'Disease', 'MESH:D009634', (186, 201))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (59, 78))	('mutations', 'Var', (5, 14))	('RIT1', 'Gene', '6016', (0, 4))	('patients', 'Species', '9606', (45, 53))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('patients', 'Species', '9606', (172, 180))	('Noonan syndrome', 'Disease', (186, 201))	('RIT1', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('lung adenocarcinoma', 'Disease', (59, 78))	('seen', 'Reg', (25, 29))
48656	32341551	These mutations were postulated to affect the GTP hydrolysis and promote effector activation due to constitutive GTP loading; however, recent structural studies suggest otherwise.	('GTP hydrolysis', 'MPA', (46, 60))	('GTP', 'Chemical', 'MESH:D006160', (113, 116))	('affect', 'Reg', (35, 41))	('GTP loading', 'MPA', (113, 124))	('promote', 'PosReg', (65, 72))	('effector activation', 'MPA', (73, 92))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('46', '60'))	('GTP', 'Chemical', 'MESH:D006160', (46, 49))	('mutations', 'Var', (6, 15))
48657	32341551	Such mutations can subvert the GDP state, activating adenylate cyclase when it is bound to GDP.	('activating', 'PosReg', (42, 52))	('GDP', 'Chemical', 'MESH:D006153', (31, 34))	('adenylate cyclase', 'Enzyme', (53, 70))	('mutations', 'Var', (5, 14))	('GDP', 'Chemical', 'MESH:D006153', (91, 94))
48658	32341551	Mutations in GNAQ and GNA11 are frequent in uveal melanomas and have also been described in other dermatological conditions.	('uveal melanomas', 'Disease', (44, 59))	('uveal melanomas', 'Phenotype', 'HP:0007716', (44, 59))	('GNA11', 'Gene', (22, 27))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (22, 27))	('frequent', 'Reg', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('uveal melanomas', 'Disease', 'MESH:C536494', (44, 59))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('GNAQ', 'Gene', '2776', (13, 17))	('described', 'Reg', (79, 88))
48659	32341551	For instance, in congenital haemangioma, patients exhibit the same variant found in uveal melanoma, Q209L/P, although the expression of the oncoprotein is restricted to the endothelial cells.	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma', 'Disease', (84, 98))	('congenital haemangioma', 'Disease', 'MESH:D000013', (17, 39))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('patients', 'Species', '9606', (41, 49))	('Q209L', 'SUBSTITUTION', 'None', (100, 105))	('Q209L', 'Var', (100, 105))	('congenital haemangioma', 'Disease', (17, 39))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
48660	32341551	It is likely that these mutations exhibit a similar mechanism as described for Galphas.	('Galphas', 'Gene', (79, 86))	('mutations', 'Var', (24, 33))	('Galphas', 'Gene', '79447', (79, 86))
48661	32341551	The R183Q variant, which is never seen in uveal melanomas, is the driver of Sturge-Weber syndrome, a neuroectodermal mosaicism characterized by port-wine stains, glaucoma and leptomeningeal angiomatosis.	('glaucoma', 'Phenotype', 'HP:0000501', (162, 170))	('Sturge-Weber syndrome', 'Disease', (76, 97))	('glaucoma', 'Disease', (162, 170))	('uveal melanomas', 'Disease', (42, 57))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('port-wine stains', 'Phenotype', 'HP:0001052', (144, 160))	('uveal melanomas', 'Phenotype', 'HP:0007716', (42, 57))	('leptomeningeal angiomatosis', 'Disease', 'MESH:D000798', (175, 202))	('Weber syndrome', 'Phenotype', 'HP:0002277', (83, 97))	('glaucoma', 'Disease', 'MESH:D005901', (162, 170))	('R183Q', 'Var', (4, 9))	('uveal melanomas', 'Disease', 'MESH:C536494', (42, 57))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (76, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('R183Q', 'Mutation', 'rs397514698', (4, 9))	('leptomeningeal angiomatosis', 'Disease', (175, 202))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
48663	32341551	A central component of the pathway is the lipid kinase PI3K, encoded by the PIK3CA, PIK3CB, PIK3CG and PIK3CD genes; while PI3Kalpha and PI3Kbeta are widely expressed in most tissues, the other isoforms are restricted to immune cell lineages.	('age', 'Gene', '5973', (237, 240))	('age', 'Gene', (237, 240))	('PIK3CD', 'Gene', '5293', (103, 109))	('PI3K', 'molecular_function', 'GO:0016303', ('55', '59'))	('PI3Kbeta', 'Gene', '5291', (137, 145))	('PIK3CB', 'Gene', (84, 90))	('PIK3CG', 'Gene', (92, 98))	('PI3Kbeta', 'Gene', (137, 145))	('PIK3CD', 'Gene', (103, 109))	('PI3Kalpha', 'Var', (123, 132))	('PIK3CB', 'Gene', '5291', (84, 90))	('PIK3CG', 'Gene', '5294', (92, 98))
48664	32341551	PI3K activation results in the activation of dowsntream AKT kinases, among others, to promote cell survival.	('AKT', 'Gene', '207', (56, 59))	('PI3K', 'Var', (0, 4))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('dowsntream', 'Enzyme', (45, 55))	('AKT', 'Gene', (56, 59))	('promote', 'PosReg', (86, 93))	('cell survival', 'CPA', (94, 107))	('activation', 'PosReg', (31, 41))
48665	32341551	Gain-offunction mutations in PIK3CA were described in different tumour types and have been characterized at the cellular, biochemical and structural levels.	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('mutations', 'Var', (16, 25))	('tumour', 'Disease', (64, 70))	('PIK3CA', 'Gene', (29, 35))	('Gain-offunction', 'PosReg', (0, 15))
48666	32341551	While alterations in the helical domain have been shown to interfere with the inhibitory interaction of the regulatory subunit p85 (encoded by PIK3R1), alterations in the catalytic domain appear to promote kinase activity by increasing substrate availability.	('kinase activity', 'molecular_function', 'GO:0016301', ('206', '221'))	('alterations', 'Var', (6, 17))	('p85', 'Gene', (127, 130))	('increasing', 'PosReg', (225, 235))	('PIK3R1', 'Gene', '5295', (143, 149))	('promote', 'PosReg', (198, 205))	('PIK3R1', 'Gene', (143, 149))	('inhibitory interaction', 'MPA', (78, 100))	('alterations', 'Var', (152, 163))	('helical', 'MPA', (25, 32))	('interfere', 'NegReg', (59, 68))	('substrate availability', 'MPA', (236, 258))	('p85', 'Gene', '5296', (127, 130))	('kinase activity', 'MPA', (206, 221))
48668	32341551	An emerging number of congenital disorders characterized by overgrowth and vascular malformations have also been found to harbour monogenic mutations in PIK3CA.	('overgrowth', 'Phenotype', 'HP:0001548', (60, 70))	('congenital disorders', 'Disease', 'MESH:D009358', (22, 42))	('overgrowth and vascular malformations', 'Disease', 'MESH:D000014', (60, 97))	('congenital disorders', 'Disease', (22, 42))	('mutations', 'Var', (140, 149))	('PIK3CA', 'Gene', (153, 159))
48670	32341551	All these syndromes are likely the result of different degrees of PIK3CA mutation mosaicism and, therefore, have been grouped under the umbrella term 'PIK3CA-related overgrowth spectrum' (PROS).	('mutation mosaicism', 'Var', (73, 91))	('PROS', 'Chemical', '-', (188, 192))	('PIK3CA', 'Gene', (66, 72))	('mosaicism', 'Var', (82, 91))	('result', 'Reg', (35, 41))	('overgrowth', 'Phenotype', 'HP:0001548', (166, 176))
48671	32341551	While these somatic events occur in a postzygotic manner, the affected tissue lineage and the time of the mutation will determine the extent of the lesion, ranging from severe forms of CLOVES to localized overgrowth such as megadactyly, a disproportionate growth of one or multiple fingers Somatic mutations in PIK3CA have also been described in vascular malformations, including venous and lymphatic malformations.	('PIK3CA', 'Gene', (311, 317))	('described', 'Reg', (333, 342))	('age', 'Gene', (82, 85))	('vascular malformations', 'Disease', (346, 368))	('lymphatic malformations', 'Disease', (391, 414))	('lymphatic malformations', 'Phenotype', 'HP:0100763', (391, 414))	('megadactyly', 'Disease', (224, 235))	('lymphatic malformations', 'Disease', 'MESH:D000014', (391, 414))	('age', 'Gene', '5973', (82, 85))	('CLOVES', 'Species', '219868', (185, 191))	('mutations', 'Var', (298, 307))	('CLOVES', 'Disease', (185, 191))	('vascular malformations', 'Disease', 'MESH:D000014', (346, 368))	('overgrowth', 'Phenotype', 'HP:0001548', (205, 215))
48672	32341551	Germline PIK3CA mutations in the main hotspots have never been reported in humans, probably due to embryonic lethality.	('embryonic lethality', 'Disease', 'MESH:D020964', (99, 118))	('embryonic lethality', 'Disease', (99, 118))	('humans', 'Species', '9606', (75, 81))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (9, 15))
48673	32341551	However, other less common mutations may be associated with a disorder resembling Cowden syndrome, which is classically caused by mutations in PTEN, which encodes the phosphatase that antagonizes PI3K enzymatic function.	('associated', 'Reg', (44, 54))	('mutations', 'Var', (27, 36))	('Cowden syndrome', 'Disease', 'MESH:D006223', (82, 97))	('phosphatase', 'molecular_function', 'GO:0016791', ('167', '178'))	('Cowden syndrome', 'Disease', (82, 97))	('PI3K', 'molecular_function', 'GO:0016303', ('196', '200'))	('caused by', 'Reg', (120, 129))	('mutations', 'Var', (130, 139))	('PTEN', 'Gene', (143, 147))	('PTEN', 'Gene', '5728', (143, 147))
48674	32341551	Such PIK3CA mutations are weakly active, in contrast to the mutations found in patients with PROS.	('PIK3CA', 'Gene', (5, 11))	('mutations', 'Var', (12, 21))	('active', 'MPA', (33, 39))	('patients', 'Species', '9606', (79, 87))	('PROS', 'Chemical', '-', (93, 97))
48675	32341551	Strong germline gain-of-function mutations in PIK3CD (mostly E1021K) can be found in patients with a specific immunodeficiency, which has now been termed 'activated PI3Kd syndrome'.	('immunodeficiency', 'Phenotype', 'HP:0002721', (110, 126))	('E1021K', 'Mutation', 'rs397518423', (61, 67))	('immunodeficiency', 'Disease', 'MESH:D007153', (110, 126))	('PIK3CD', 'Gene', (46, 52))	('E1021K', 'Var', (61, 67))	('immunodeficiency', 'Disease', (110, 126))	('patients', 'Species', '9606', (85, 93))	("'activated PI3Kd syndrome'", 'Disease', (154, 180))	('PIK3CD', 'Gene', '5293', (46, 52))	('gain-of-function', 'PosReg', (16, 32))
48678	32341551	The most common AKT1 mutant is the E17K variant, which promotes constitutive membrane targeting as a result of the charge switch at the phosphoinositidebinding domain.	('membrane', 'cellular_component', 'GO:0016020', ('77', '85'))	('E17K', 'Mutation', 'rs121434592', (35, 39))	('constitutive membrane targeting', 'MPA', (64, 95))	('promotes', 'PosReg', (55, 63))	('E17K', 'Var', (35, 39))	('AKT1', 'Gene', '207', (16, 20))	('AKT1', 'Gene', (16, 20))	('charge switch', 'MPA', (115, 128))
48679	32341551	Analogous mutations have also been described in the AKT2 and AKT3 genes, although at a lower frequency.	('AKT2', 'Gene', '208', (52, 56))	('AKT3', 'Gene', (61, 65))	('mutations', 'Var', (10, 19))	('AKT3', 'Gene', '10000', (61, 65))	('AKT2', 'Gene', (52, 56))
48680	32341551	AKT1E17K mutations are mostly found in breast and uterine endometrioid carcinomas and have been shown to be transforming in cell culture assays.	('endometrioid carcinomas', 'Disease', (58, 81))	('mutations', 'Var', (9, 18))	('found', 'Reg', (30, 35))	('endometrioid carcinomas', 'Disease', 'MESH:D016889', (58, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('endometrioid carcinomas', 'Phenotype', 'HP:0012114', (58, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('AKT1E17K', 'Gene', (0, 8))
48681	32341551	High-degree mosaicism of AKT1E17K leads to Proteus syndrome, a rare and severe progressive disorder characterized by asymmetric overgrowth of bone and adipose tissue, as well as vascular malformations and predisposition to benign and malignant tumours.	('vascular malformations', 'Disease', 'MESH:D000014', (178, 200))	('Proteus syndrome', 'Disease', 'MESH:D016715', (43, 59))	('Proteus syndrome', 'Disease', (43, 59))	('overgrowth of bone', 'Phenotype', 'HP:0100774', (128, 146))	('leads to', 'Reg', (34, 42))	('vascular malformations', 'Disease', (178, 200))	('severe progressive disorder', 'Disease', (72, 99))	('severe progressive disorder', 'Disease', 'MESH:D045169', (72, 99))	('malignant tumours', 'Disease', 'MESH:D009369', (234, 251))	('tumour', 'Phenotype', 'HP:0002664', (244, 250))	('malignant tumours', 'Disease', (234, 251))	('tumours', 'Phenotype', 'HP:0002664', (244, 251))	('mosaicism', 'Var', (12, 21))	('overgrowth', 'Phenotype', 'HP:0001548', (128, 138))	('asymmetric overgrowth', 'Phenotype', 'HP:0001528', (117, 138))	('AKT1E17K', 'Gene', (25, 33))
48682	32341551	Germline heterozygous E17K mutations in the AKT2 gene have been shown in two individuals with hypoglycaemia and mild overgrowth, AKT3E17K somatic mutations are found in children with hemimegalencephaly and germline mutations are found in syndromic diffuse megalencephaly.	('hemimegalencephaly', 'Phenotype', 'HP:0007206', (183, 201))	('AKT3E17K', 'Var', (129, 137))	('AKT2', 'Gene', (44, 48))	('overgrowth', 'Phenotype', 'HP:0001548', (117, 127))	('hypoglycaemia', 'Phenotype', 'HP:0001943', (94, 107))	('syndromic diffuse megalencephaly', 'Disease', (238, 270))	('syndromic diffuse megalencephaly', 'Disease', 'MESH:D058627', (238, 270))	('megalencephaly', 'Phenotype', 'HP:0001355', (187, 201))	('hemimegalencephaly', 'Disease', (183, 201))	('children', 'Species', '9606', (169, 177))	('E17K', 'Mutation', 'rs121434592', (133, 137))	('E17K', 'Var', (22, 26))	('found', 'Reg', (160, 165))	('E17K', 'Mutation', 'rs121434592', (22, 26))	('megalencephaly', 'Phenotype', 'HP:0001355', (256, 270))	('hemimegalencephaly', 'Disease', 'MESH:D065705', (183, 201))	('hypoglycaemia', 'Disease', 'None', (94, 107))	('AKT2', 'Gene', '208', (44, 48))	('hypoglycaemia', 'Disease', (94, 107))
48683	32341551	The phenotypic difference of these mutations suggests non-redundant roles between the AKT isoforms.	('AKT', 'Gene', '207', (86, 89))	('AKT', 'Gene', (86, 89))	('mutations', 'Var', (35, 44))
48686	32341551	One can predict that the use of these tools is highly convenient when one is addressing fundamental questions in the context of oncoprotein biology, including cell lineage tracing, cell competition between wild-type and mutant clones, and cell-autonomous versus cell-non-autonomous effects of the oncoprotein.	('mutant', 'Var', (220, 226))	('age', 'Gene', '5973', (168, 171))	('age', 'Gene', (168, 171))
48689	32341551	Examples of these include the KrasG12D, Pik3caH1047R, GnasR201H and Akt1E17K variants.	('Akt1E17K', 'Var', (68, 76))	('GnasR201H', 'Var', (54, 63))	('Pik3', 'Gene', (40, 44))	('Pik3', 'Gene', '5294', (40, 44))	('KrasG12D', 'Var', (30, 38))
48701	32341551	Infigratinib is also being tested in cancers driven by mutant FGFR and, while it is likely that treatment of these tumours will require complete inhibition of FGFR signalling to promote tumour regression, reduced FGFR signalling might be sufficient to reverse the effects of hyperactive FGFR3 in achondroplasia, as proposed in a study that used a mouse model of dwarfism.	('FGF', 'Gene', '8074', (159, 162))	('tumours', 'Disease', (115, 122))	('achondroplasia', 'Disease', (296, 310))	('FGFR', 'molecular_function', 'GO:0005007', ('62', '66'))	('FGF', 'Gene', (287, 290))	('hyperactive', 'Disease', 'MESH:D006948', (275, 286))	('FGF', 'Gene', (213, 216))	('hyperactive', 'Disease', (275, 286))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('FGF', 'Gene', (62, 65))	('FGF', 'Gene', '8074', (287, 290))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('FGF', 'Gene', '8074', (62, 65))	('FGF', 'Gene', '8074', (213, 216))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('tumour', 'Disease', (115, 121))	('tumour', 'Disease', (186, 192))	('tumours', 'Disease', 'MESH:D009369', (115, 122))	('FGFR', 'molecular_function', 'GO:0005007', ('159', '163'))	('mouse', 'Species', '10090', (347, 352))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('achondroplasia', 'Disease', 'MESH:D000130', (296, 310))	('Infigratinib', 'Chemical', 'MESH:C568950', (0, 12))	('reduced', 'NegReg', (205, 212))	('mutant', 'Var', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('signalling', 'biological_process', 'GO:0023052', ('218', '228'))	('FGFR', 'molecular_function', 'GO:0005007', ('287', '291'))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancers', 'Disease', (37, 44))	('FGFR', 'molecular_function', 'GO:0005007', ('213', '217'))	('dwarfism', 'Phenotype', 'HP:0003510', (362, 370))	('FGF', 'Gene', (159, 162))	('signalling', 'biological_process', 'GO:0023052', ('164', '174'))
48713	32341551	In oncology trials, AKT inhibitors and PI3K inhibitors have both shown adverse events, with the most significant being hyperglycaemia However, because the doses given to patients with PROS are expected to be lower, such secondary effects might not be an issue, even in long-term treatments.	('patients', 'Species', '9606', (170, 178))	('AKT', 'Gene', (20, 23))	('PI3K', 'molecular_function', 'GO:0016303', ('39', '43'))	('hyperglycaemia', 'Disease', (119, 133))	('hyperglycaemia', 'Disease', 'None', (119, 133))	('oncology', 'Phenotype', 'HP:0002664', (3, 11))	('PI3K inhibitors', 'Var', (39, 54))	('AKT', 'Gene', '207', (20, 23))	('PROS', 'Chemical', '-', (184, 188))
48729	32341551	The Cre-loxP system allows us to conditionally express oncoproteins somatically, while CRISPR-Cas9 facilitates the generation of germline mutations by editing mouse zygotes.	('germline', 'Var', (129, 137))	('oncoproteins', 'Protein', (55, 67))	('mouse', 'Species', '10090', (159, 164))	('editing', 'Var', (151, 158))	('Cas', 'cellular_component', 'GO:0005650', ('94', '97'))	('facilitates', 'PosReg', (99, 110))
48730	32341551	In the Cre-loxP system, insertion of a loxP-STOP-loxP cassette in front of the oncogene prevents its expression until it is removed by Cre recombinase, for example in the KrasG12D conditional mouse model.	('prevents', 'NegReg', (88, 96))	('expression', 'MPA', (101, 111))	('mouse', 'Species', '10090', (192, 197))	('insertion', 'Var', (24, 33))
48733	32341551	This is particularly useful in mutations that are found in the last coding exons, such as in the Pik3caH1047R mouse model.	('Pik3', 'Gene', (97, 101))	('mouse', 'Species', '10090', (110, 115))	('Pik3', 'Gene', '5294', (97, 101))	('mutations', 'Var', (31, 40))
48735	32341551	Here, the degree of mosaicism can be dependent on the tamoxifen concentration achieved in the tissues of interest or the time at which recombination was induced.	('mosaicism', 'Var', (20, 29))	('tamoxifen', 'Chemical', 'MESH:D013629', (54, 63))	('dependent', 'Reg', (37, 46))
48744	31835485	The identification of the most frequent putative driver mutations, which occur in a mutually exclusive manner in two genes encoding alpha subunits of G proteins, namely G protein subunit alpha Q (GNAQ) and G protein subunit alpha 11 (GNA11), has indicated G protein signaling and the activation of MAP kinases as potential targets, but MEK inhibitors have failed to show major effects in clinical trials.	('GNAQ', 'Gene', '2776', (196, 200))	('G protein subunit alpha 11', 'Gene', '2767', (206, 232))	('mutations', 'Var', (56, 65))	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('G protein subunit alpha Q', 'Gene', (169, 194))	('MEK', 'Gene', (336, 339))	('MEK', 'Gene', '5609', (336, 339))	('G protein subunit alpha 11', 'Gene', (206, 232))	('G protein subunit alpha Q', 'Gene', '2776', (169, 194))	('MAP', 'molecular_function', 'GO:0004239', ('298', '301'))	('GNAQ', 'Gene', (196, 200))	('GNA11', 'Gene', (234, 239))	('GNA11', 'Gene', '2767', (234, 239))	('protein', 'cellular_component', 'GO:0003675', ('208', '215'))	('signaling', 'biological_process', 'GO:0023052', ('266', '275'))	('protein', 'cellular_component', 'GO:0003675', ('258', '265'))
48745	31835485	More recently, the HIPPO-independent activation of the YAP/TAZ signaling pathway by mutated GNAQ and GNA11 has been described but, at present, no specific inhibitors have been tested in the clinics.	('GNA11', 'Gene', '2767', (101, 106))	('GNA11', 'Gene', (101, 106))	('signaling pathway', 'biological_process', 'GO:0007165', ('63', '80'))	('GNAQ', 'Gene', (92, 96))	('YAP', 'Gene', (55, 58))	('activation', 'PosReg', (37, 47))	('mutated', 'Var', (84, 91))	('GNAQ', 'Gene', '2776', (92, 96))	('YAP', 'Gene', '10413', (55, 58))
48746	31835485	Recent reports on a specific inhibitor of the mutated form of GNAQ must be confirmed and translated into clinical applications.	('GNAQ', 'Gene', (62, 66))	('mutated', 'Var', (46, 53))	('GNAQ', 'Gene', '2776', (62, 66))
48755	31835485	analyze a more extended cohort of 139 cases whose exomes have been sequenced and identify secondary somatic mutations delivering evidence that some of the apparently sporadic mutations that occur in very few or even single cases might contribute to tumor development.	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('mutations', 'Var', (108, 117))	('contribute', 'Reg', (235, 245))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor', 'Disease', (249, 254))	('mutations', 'Var', (175, 184))
48756	31835485	Van Poppelen and coworkers analyze somatic mutations in the serine/arginine-rich splicing factor 2 gene (SRSF2) and show a mutational pattern that differs from that observed in myelodysplastic syndrome, where SRSF2 is frequently mutated, likely related to different sets of genes that show aberrant splicing.	('splicing', 'biological_process', 'GO:0045292', ('299', '307'))	('SRSF2', 'Gene', (105, 110))	('serine/arginine-rich splicing factor 2', 'Gene', (60, 98))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (177, 201))	('serine/arginine-rich splicing factor 2', 'Gene', '6427', (60, 98))	('SRSF2', 'Gene', (209, 214))	('mutations', 'Var', (43, 52))	('myelodysplastic syndrome', 'Disease', (177, 201))	('SRSF2', 'Gene', '6427', (105, 110))	('Van Poppelen', 'Chemical', 'MESH:C488457', (0, 12))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (177, 201))	('splicing', 'biological_process', 'GO:0045292', ('81', '89'))	('SRSF2', 'Gene', '6427', (209, 214))
48758	31835485	who show that differences in the inflammatory phenotype and major histocompatibility complex (HLA) expression rely on chromosome 3 status but not on G protein subunit alpha Q (GNAQ) versus G protein subunit alpha 11 (GNA11), mutations in uveal melanoma.	('G protein subunit alpha 11', 'Gene', (189, 215))	('G protein subunit alpha 11', 'Gene', '2767', (189, 215))	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('60', '92'))	('G protein subunit alpha Q', 'Gene', (149, 174))	('G protein subunit alpha Q', 'Gene', '2776', (149, 174))	('mutations', 'Var', (225, 234))	('protein', 'cellular_component', 'GO:0003675', ('191', '198'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (238, 252))	('uveal melanoma', 'Disease', (238, 252))	('uveal melanoma', 'Disease', 'MESH:C536494', (238, 252))	('GNAQ', 'Gene', '2776', (176, 180))	('chromosome', 'cellular_component', 'GO:0005694', ('118', '128'))	('GNA11', 'Gene', (217, 222))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('GNA11', 'Gene', '2767', (217, 222))	('GNAQ', 'Gene', (176, 180))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))
48764	31835485	show that knockdown of the hypoxia mediators cAMP response element-binding protein (CREB) or HIF1alpha in UM cells by means of replication-competent retroviral vectors dramatically decreases UM tumor progression.	('decreases', 'NegReg', (181, 190))	('CREB', 'Gene', '1385', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('cAMP response element-binding protein', 'Gene', '1385', (45, 82))	('HIF1alpha', 'Gene', (93, 102))	('hypoxia', 'Disease', (27, 34))	('cAMP response element-binding protein', 'Gene', (45, 82))	('hypoxia', 'Disease', 'MESH:D000860', (27, 34))	('tumor', 'Disease', (194, 199))	('UM', 'Disease', 'MESH:C536494', (191, 193))	('cAMP response element-binding', 'molecular_function', 'GO:0035497', ('45', '74'))	('knockdown', 'Var', (10, 19))	('HIF1alpha', 'Gene', '3091', (93, 102))	('CREB', 'Gene', (84, 88))	('UM', 'Disease', 'MESH:C536494', (106, 108))
48765	31835485	also address tumor angiogenesis and show that the monosomy 3 and the loss of BAP1 is associated with an increased microvascular density.	('monosomy 3', 'Var', (50, 60))	('tumor', 'Disease', (13, 18))	('microvascular density', 'CPA', (114, 135))	('increased', 'PosReg', (104, 113))	('loss', 'Var', (69, 73))	('angiogenesis', 'biological_process', 'GO:0001525', ('19', '31'))	('BAP1', 'Gene', '8314', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('BAP1', 'Gene', (77, 81))
48768	31835485	show that the DNA-activated protein kinase PRKDC is overexpressed in high-risk uveal melanoma and that the inhibition of such kinases reduces the survival of the tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('overexpressed', 'PosReg', (52, 65))	('PRKDC', 'Gene', '5591', (43, 48))	('tumor', 'Disease', (162, 167))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('reduces', 'NegReg', (134, 141))	('inhibition', 'Var', (107, 117))	('DNA', 'cellular_component', 'GO:0005574', ('14', '17'))	('PRKDC', 'Gene', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('uveal melanoma', 'Disease', (79, 93))
48829	31765784	Moreover, high MW chitosan is often associated with poor water solubility under physiological environment, which may hamper its complexion ability with siRNA.	('hamper', 'NegReg', (117, 123))	('water', 'Chemical', 'MESH:D014867', (57, 62))	('chitosan', 'Protein', (18, 26))	('complexion ability', 'MPA', (128, 146))	('high MW', 'Var', (10, 17))	('poor water solubility', 'MPA', (52, 73))	('N', 'Chemical', 'MESH:D009584', (155, 156))
48887	31765784	The primer used was a Taqman  Gene Expression Assay (FAM), GAPDH (Hs02786624_g1) and HIF-1alpha (Hs00153153_m1).	('GAPDH', 'Gene', (59, 64))	('Hs00153153_m1', 'Var', (97, 110))	('HIF-1alpha', 'Gene', '3091', (85, 95))	('Hs02786624_g1', 'Var', (66, 79))	('HIF-1alpha', 'Gene', (85, 95))	('Gene Expression', 'biological_process', 'GO:0010467', ('30', '45'))	('GAPDH', 'Gene', '2597', (59, 64))
48910	31765784	The surface charge of the complexes changed from positive to negative (~-16 mV to -24 mV) after coated with HA at various C/P ratios, which suggested the successful coating of polyanion HA.	('surface charge', 'MPA', (4, 18))	('HA', 'Chemical', 'MESH:D006820', (108, 110))	('changed', 'Reg', (36, 43))	('HA', 'Chemical', 'MESH:D006820', (186, 188))	('polyanion', 'Var', (176, 185))	('polyanion', 'Chemical', 'MESH:C009791', (176, 185))	('P', 'Chemical', 'MESH:D010758', (124, 125))	('C', 'Chemical', 'MESH:D002244', (122, 123))
48930	31765784	The complexes with a higher Chi or HA amount (a higher N/P or C/P ratio) appeared to have higher toxicity against MP-38 cells at both 48 and 72 hr (Figure 4A).	('C', 'Chemical', 'MESH:D002244', (28, 29))	('C', 'Chemical', 'MESH:D002244', (62, 63))	('Chi', 'Var', (28, 31))	('P', 'Chemical', 'MESH:D010758', (64, 65))	('HA', 'Chemical', 'MESH:D006820', (35, 37))	('Chi', 'Chemical', 'MESH:D048271', (28, 31))	('toxicity', 'Disease', 'MESH:D064420', (97, 105))	('P', 'Chemical', 'MESH:D010758', (115, 116))	('toxicity', 'Disease', (97, 105))	('N', 'Chemical', 'MESH:D009584', (55, 56))	('higher', 'PosReg', (90, 96))	('P', 'Chemical', 'MESH:D010758', (57, 58))
48935	31765784	This could be explained by increased cytotoxicity associated with high concentration polycations.	('cytotoxicity', 'Disease', (37, 49))	('polycations', 'Var', (85, 96))	('increased', 'PosReg', (27, 36))	('cytotoxicity', 'Disease', 'MESH:D064420', (37, 49))
48944	31765784	Therefore, a high amount of HA coating (C/P: 40/1) can lead to enhanced receptor-mediated endocytosis, thus better cellular uptake.	('receptor-mediated endocytosis', 'MPA', (72, 101))	('enhanced', 'PosReg', (63, 71))	('P: 40', 'cellular_component', 'GO:0070743', ('42', '47'))	('HA', 'Chemical', 'MESH:D006820', (28, 30))	('P', 'Chemical', 'MESH:D010758', (42, 43))	('P: 40', 'cellular_component', 'GO:0043514', ('42', '47'))	('uptake', 'biological_process', 'GO:0098657', ('124', '130'))	('uptake', 'biological_process', 'GO:0098739', ('124', '130'))	('receptor-mediated endocytosis', 'biological_process', 'GO:0006898', ('72', '101'))	('better', 'PosReg', (108, 114))	('cellular uptake', 'CPA', (115, 130))	('C', 'Chemical', 'MESH:D002244', (40, 41))	('C/P: 40/1', 'Var', (40, 49))
48967	31765784	Moreover, the polyanionic HA can loosen the tight Chi-siRNA binding, which may promote siRNA release from the complexes, thus improving siRNA silencing effect.	('N', 'Chemical', 'MESH:D009584', (139, 140))	('polyanionic', 'Var', (14, 25))	('N', 'Chemical', 'MESH:D009584', (57, 58))	('polyanion', 'Chemical', 'MESH:C009791', (14, 23))	('loosen', 'NegReg', (33, 39))	('N', 'Chemical', 'MESH:D009584', (90, 91))	('siRNA binding', 'molecular_function', 'GO:0035197', ('54', '67'))	('complexes', 'Interaction', (110, 119))	('Chi', 'Chemical', 'MESH:D048271', (50, 53))	('siRNA', 'MPA', (136, 141))	('promote', 'PosReg', (79, 86))	('improving', 'PosReg', (126, 135))	('HA', 'Chemical', 'MESH:D006820', (26, 28))	('silencing', 'NegReg', (142, 151))	('tight Chi-siRNA binding', 'Interaction', (44, 67))	('siRNA release from', 'MPA', (87, 105))
48970	31765784	The complexes with high HA coating (C/N/P: 40/20/1 and 40/40/1) showed the best HIF-1alpha protein downregulation efficiency (55.1% +- 6.41 and 56.3% +- 5.45%, respectively), which was lower than the commercial siRNA delivery reagent DF (62.0% +- 5.61%) (p>0.05).	('P: 40', 'cellular_component', 'GO:0043514', ('40', '45'))	('P', 'Chemical', 'MESH:D010758', (40, 41))	('40/40/1', 'Var', (55, 62))	('downregulation', 'NegReg', (99, 113))	('HA', 'Chemical', 'MESH:D006820', (24, 26))	('HIF-1alpha', 'Gene', (80, 90))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('C', 'Chemical', 'MESH:D002244', (36, 37))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('P: 40', 'cellular_component', 'GO:0070743', ('40', '45'))	('HIF-1alpha', 'Gene', '3091', (80, 90))	('N', 'Chemical', 'MESH:D009584', (214, 215))
48976	31765784	The ternary complexes with high HA coating (C/N/P: 40/20/1 and 40/40/1) resulted in 47.4% +- 7.58% and 46.8% +- 2.87% VEGF protein expression relative to the control, which was slightly lower than the DF-siRNA group (49.6% +- 9.12%).	('C/N/P: 40/20/1', 'Var', (44, 58))	('N', 'Chemical', 'MESH:D009584', (207, 208))	('N', 'Chemical', 'MESH:D009584', (46, 47))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('P: 40', 'cellular_component', 'GO:0043514', ('48', '53'))	('VEGF', 'Gene', (118, 122))	('P', 'Chemical', 'MESH:D010758', (48, 49))	('expression', 'MPA', (131, 141))	('C', 'Chemical', 'MESH:D002244', (44, 45))	('HA', 'Chemical', 'MESH:D006820', (32, 34))	('VEGF', 'Gene', '7422', (118, 122))	('P: 40', 'cellular_component', 'GO:0070743', ('48', '53'))
49002	30631354	They included gender, age, melanoma subtype, stage, site(s) of metastatic disease at the initiation of systemic treatment, presence of BRAF, NRAS, or KIT mutations, treatment regimen, response to first-line chemotherapy or immunotherapy, and survival status at the last follow-up visit.	('melanoma subtype', 'Disease', 'MESH:D008545', (27, 43))	('NRAS', 'Gene', '4893', (141, 145))	('BRAF', 'Gene', (135, 139))	('NRAS', 'Gene', (141, 145))	('KIT', 'Gene', (150, 153))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('mutations', 'Var', (154, 163))	('KIT', 'molecular_function', 'GO:0005020', ('150', '153'))	('melanoma subtype', 'Disease', (27, 43))
49016	29441098	Nomogram for predicting radiation maculopathy in patients treated with Ruthenium-106 plaque brachytherapy for uveal melanoma To develop a predictive model and nomogram for maculopathy occurrence at 3 years after 106Ru/106Rh plaque brachytherapy in uveal melanoma.	('radiation maculopathy', 'Phenotype', 'HP:0031420', (24, 45))	('uveal melanoma', 'Disease', 'MESH:C536494', (248, 262))	('maculopathy', 'Disease', (34, 45))	('uveal melanoma', 'Disease', (110, 124))	('uveal melanoma', 'Disease', 'MESH:C536494', (110, 124))	('Ruthenium-106', 'Chemical', 'MESH:C000615522', (71, 84))	('maculopathy', 'Disease', (172, 183))	('uveal melanoma', 'Disease', (248, 262))	('uveal melanoma', 'Phenotype', 'HP:0007716', (110, 124))	('106Ru/106Rh', 'Var', (212, 223))	('uveal melanoma', 'Phenotype', 'HP:0007716', (248, 262))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('patients', 'Species', '9606', (49, 57))	('melanoma', 'Phenotype', 'HP:0002861', (254, 262))	('maculopathy', 'Disease', 'MESH:D008268', (34, 45))	('maculopathy', 'Disease', 'MESH:D008268', (172, 183))
49017	29441098	Clinical records of patients affected by choroidal melanoma and treated with 106Ru/106Rh plaque from December 2006 to December 2014 were retrospectively reviewed.	('106Ru/106Rh', 'Var', (77, 88))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (41, 59))	('choroidal melanoma', 'Disease', 'MESH:D008545', (41, 59))	('patients', 'Species', '9606', (20, 28))	('choroidal melanoma', 'Disease', (41, 59))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))
49033	29441098	Nevertheless, many European institutions have gained experience using 106Ru/106Rh, a beta emitter, mainly for the treatment of small and medium-sized choroidal melanomas, reporting comparable outcomes in terms of overall survival.	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanomas', 'Phenotype', 'HP:0002861', (160, 169))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (150, 169))	('106Ru/106Rh', 'Var', (70, 81))	('choroidal melanomas', 'Disease', (150, 169))	('choroidal melanomas', 'Disease', 'MESH:D008545', (150, 169))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (150, 168))	('a beta', 'Gene', '351', (83, 89))	('a beta', 'Gene', (83, 89))
49034	29441098	106Ru/106Rh is a beta emitter with more restricted range in comparison to gamma sources, and offers some advantages with respect to 125I, such us a better radiation protection for the operators and less side effects for adjacent healthy tissues.	('a beta', 'Gene', '351', (15, 21))	('a beta', 'Gene', (15, 21))	('106Ru/106Rh', 'Var', (0, 11))	('radiation protection', 'CPA', (155, 175))	('better', 'PosReg', (148, 154))
49035	29441098	Excellent local control outcomes have been reported by a number of groups using 106Ru/106Rh plaques for small-medium sized uveal melanoma with acceptable rates of radiation-induced complications.	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('106Ru/106Rh', 'Var', (80, 91))	('uveal melanoma', 'Disease', (123, 137))	('uveal melanoma', 'Disease', 'MESH:C536494', (123, 137))	('uveal melanoma', 'Phenotype', 'HP:0007716', (123, 137))	('local control', 'CPA', (10, 23))
49037	29441098	Furthermore, a dosimetric comparison of 125I versus 106Ru/106Rh plaques demonstrated that 106Ru/106Rh plaques can provide adequate dose coverage to small tumors, sparing critical nearby structures more effectively than 125I.	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('small tumors', 'Disease', 'MESH:D058405', (148, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('small tumors', 'Disease', (148, 160))	('106Ru/106Rh plaques', 'Var', (90, 109))
49038	29441098	However, brachytherapy with 106Ru/106Rh plaques is not free from local toxicity, and the benefits of saving the eye may be reduced by visual function impairment, secondary to radiation-induced toxicity (such as cataract, optic neuropathy or retinopathy).	('cataract', 'Disease', (211, 219))	('toxicity', 'Disease', (71, 79))	('cataract', 'Phenotype', 'HP:0000518', (211, 219))	('retinopathy', 'Phenotype', 'HP:0000488', (241, 252))	('optic neuropathy', 'Phenotype', 'HP:0001138', (221, 237))	('visual function impairment', 'Disease', 'MESH:D014786', (134, 160))	('106Ru/106Rh plaques', 'Var', (28, 47))	('optic neuropathy or retinopathy', 'Disease', (221, 252))	('visual function impairment', 'Phenotype', 'HP:0000505', (134, 160))	('neuropathy', 'Phenotype', 'HP:0009830', (227, 237))	('toxicity', 'Disease', 'MESH:D064420', (193, 201))	('toxicity', 'Disease', 'MESH:D064420', (71, 79))	('toxicity', 'Disease', (193, 201))	('optic neuropathy or retinopathy', 'Disease', 'MESH:D009901', (221, 252))	('visual function impairment', 'Disease', (134, 160))	('reduced', 'NegReg', (123, 130))	('cataract', 'Disease', 'MESH:D002386', (211, 219))
49041	29441098	Primary aim of this study is to develop a nomogram for the prediction of such complication in patients affected by uveal melanoma who underwent 106Ru/106Rh brachytherapy.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('uveal melanoma', 'Phenotype', 'HP:0007716', (115, 129))	('uveal melanoma', 'Disease', (115, 129))	('uveal melanoma', 'Disease', 'MESH:C536494', (115, 129))	('patients', 'Species', '9606', (94, 102))	('106Ru/106Rh', 'Var', (144, 155))
49042	29441098	For this analysis, we considered all consecutive patients who underwent 106Ru/106Rh plaque brachytherapy for uveal melanoma at the Gemelli Advanced Radiation Therapy Center from December 2006 to December 2014.	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('uveal melanoma', 'Disease', (109, 123))	('uveal melanoma', 'Disease', 'MESH:C536494', (109, 123))	('106Ru/106Rh', 'Var', (72, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('patients', 'Species', '9606', (49, 57))
49095	26896281	Bap1 is a bona fide tumor suppressor: genetic evidence from mouse models carrying heterozygous germline Bap1 mutations Individuals harboring inherited heterozygous germline mutations in BAP1 are predisposed to a range of benign and malignant tumor types, including malignant mesothelioma, melanoma, and kidney carcinoma.	('malignant mesothelioma', 'Disease', (265, 287))	('Bap1', 'Gene', '104416', (104, 108))	('kidney carcinoma', 'Disease', (303, 319))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (265, 287))	('tumor', 'Disease', (242, 247))	('kidney carcinoma', 'Disease', 'MESH:C538614', (303, 319))	('Bap1', 'Gene', '104416', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (289, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('kidney carcinoma', 'Phenotype', 'HP:0005584', (303, 319))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('Bap1', 'Gene', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('Bap1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('20', '36'))	('malignant tumor', 'Disease', (232, 247))	('mutations', 'Var', (109, 118))	('mouse', 'Species', '10090', (60, 65))	('malignant tumor', 'Disease', 'MESH:D018198', (232, 247))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (265, 287))	('predisposed', 'Reg', (195, 206))	('melanoma', 'Phenotype', 'HP:0002861', (289, 297))	('melanoma', 'Disease', (289, 297))	('tumor suppressor', 'biological_process', 'GO:0051726', ('20', '36'))	('BAP1', 'Gene', (186, 190))	('tumor', 'Disease', (20, 25))
49097	26896281	To test experimentally whether BAP1 behaves as a tumor suppressor, we monitored spontaneous tumor development in three different mouse models with germline heterozygous mutations in Bap1, including two models in which the knock-in mutations are identical to those reported in human BAP1 cancer syndrome families.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('mutations', 'Var', (169, 178))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('Bap1', 'Gene', (182, 186))	('cancer syndrome', 'Disease', 'MESH:D009369', (287, 302))	('tumor', 'Disease', (49, 54))	('cancer syndrome', 'Disease', (287, 302))	('human', 'Species', '9606', (276, 281))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('49', '65'))	('tumor', 'Disease', (92, 97))	('mouse', 'Species', '10090', (129, 134))	('tumor suppressor', 'biological_process', 'GO:0051726', ('49', '65'))
49102	26896281	Additional studies revealed that asbestos exposure induced a highly significant increase in the incidence of aggressive mesotheliomas in the two mouse models carrying clinically relevant Bap1 mutations compared with asbestos-exposed wild-type littermates.	('asbestos', 'Chemical', 'MESH:D001194', (216, 224))	('aggressive mesotheliomas', 'Disease', 'MESH:D008654', (109, 133))	('aggressive mesotheliomas', 'Disease', (109, 133))	('mouse', 'Species', '10090', (145, 150))	('Bap1', 'Gene', (187, 191))	('asbestos', 'Chemical', 'MESH:D001194', (33, 41))	('mutations', 'Var', (192, 201))
49105	26896281	This tumor susceptibility disorder is inherited in an autosomal dominant manner, with BAP1 mutation carriers being at high risk for the development of a spectrum of tumor types, including atypical benign melanocytic lesions, malignant mesothelioma (MM), uveal melanoma, cutaneous melanoma, basal cell carcinoma, meningioma, paraganglioma and carcinomas of the kidney, lung, breast and potentially other organs.	('mutation', 'Var', (91, 99))	('paraganglioma and carcinomas of the kidney', 'Disease', 'MESH:D010235', (324, 366))	('benign melanocytic lesions', 'Disease', (197, 223))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (342, 351))	('carcinomas', 'Phenotype', 'HP:0030731', (342, 352))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (290, 310))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cutaneous melanoma', 'Disease', (270, 288))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (270, 288))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (270, 288))	('benign melanocytic lesions', 'Phenotype', 'HP:0000995', (197, 223))	('meningioma', 'Disease', (312, 322))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('meningioma', 'Phenotype', 'HP:0002858', (312, 322))	('carcinoma', 'Phenotype', 'HP:0030731', (301, 310))	('paraganglioma', 'Phenotype', 'HP:0002668', (324, 337))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (290, 310))	('uveal melanoma', 'Disease', 'MESH:C536494', (254, 268))	('uveal melanoma', 'Disease', (254, 268))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (225, 247))	('BAP1', 'Gene', (86, 90))	('melanoma', 'Phenotype', 'HP:0002861', (260, 268))	('benign melanocytic lesions', 'Disease', 'MESH:D009508', (197, 223))	('basal cell carcinoma', 'Disease', (290, 310))	('meningioma', 'Disease', 'MESH:D008577', (312, 322))	('uveal melanoma', 'Phenotype', 'HP:0007716', (254, 268))	('tumor', 'Disease', (165, 170))	('malignant mesothelioma', 'Disease', (225, 247))	('melanoma', 'Phenotype', 'HP:0002861', (280, 288))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', (5, 10))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (225, 247))
49106	26896281	Genomic analysis of tumors from BAP1 mutation carriers often show loss of the remaining wild-type (WT) BAP1 allele as the second hit, strongly suggesting that BAP1 acts as a classical 2-hit tumor suppressor gene.	('tumors', 'Disease', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('mutation', 'Var', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor suppressor', 'biological_process', 'GO:0051726', ('190', '206'))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', (190, 195))	('BAP1', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('190', '206'))	('tumor', 'Disease', (20, 25))
49107	26896281	The latter idea has been further supported by in vivo evidence using a conditional whole-body knockout mouse model, which demonstrated that somatic biallelic (homozygous) deletion of Bap1 in adult mice recapitulates features of human myelodysplastic syndrome.	('myelodysplastic syndrome', 'Disease', (234, 258))	('mouse', 'Species', '10090', (103, 108))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (234, 258))	('Bap1', 'Gene', (183, 187))	('deletion', 'Var', (171, 179))	('human', 'Species', '9606', (228, 233))	('mice', 'Species', '10090', (197, 201))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (234, 258))
49109	26896281	Although MM is generally associated with occupational exposure to asbestos, this does not appear to be the case in MM patients carrying BAP1 mutations.	('BAP1', 'Gene', (136, 140))	('mutations', 'Var', (141, 150))	('asbestos', 'Chemical', 'MESH:D001194', (66, 74))	('associated', 'Reg', (25, 35))	('patients', 'Species', '9606', (118, 126))
49110	26896281	Normal mesothelial cells and MM cells obtained from Bap1+/- mice show down regulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of Bap1+/- mice to MM is facilitated, in part, by cooperation between loss of Bap1 and Rb function.	('Bap1+/-', 'Var', (170, 177))	('down regulation', 'NegReg', (70, 85))	('Ink4a', 'Gene', '12578', (106, 111))	('p16', 'Gene', (102, 105))	('mice', 'Species', '10090', (178, 182))	('Ink4a', 'Gene', (106, 111))	('regulation', 'biological_process', 'GO:0065007', ('75', '85'))	('mice', 'Species', '10090', (60, 64))	('p16', 'Gene', '12578', (102, 105))
49111	26896281	Bap1+/- mice exposed to asbestos have also been reported to have inherent alterations of the peritoneal inflammatory response, as well as a significantly higher incidence of MM after exposure to low doses of asbestos that rarely induced the disease in the WT control mice.	('asbestos', 'Chemical', 'MESH:D001194', (24, 32))	('peritoneal inflammatory response', 'CPA', (93, 125))	('alterations', 'Reg', (74, 85))	('Bap1+/-', 'Var', (0, 7))	('asbestos', 'Chemical', 'MESH:D001194', (208, 216))	('mice', 'Species', '10090', (8, 12))	('inflammatory response', 'biological_process', 'GO:0006954', ('104', '125'))	('mice', 'Species', '10090', (267, 271))
49112	26896281	While inherited inactivating mutations of BAP1 predispose to a wide spectrum of tumors in humans and is frequently mutated in sporadic MM, uveal melanoma, and other cancers, the function of BAP1 in cancer is controversial.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('uveal melanoma', 'Disease', 'MESH:C536494', (139, 153))	('BAP1', 'Gene', (42, 46))	('uveal melanoma', 'Disease', (139, 153))	('tumors', 'Disease', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancer', 'Disease', (198, 204))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (165, 171))	('inactivating mutations', 'Var', (16, 38))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('predispose', 'Reg', (47, 57))	('cancers', 'Disease', (165, 172))	('humans', 'Species', '9606', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))
49113	26896281	reported that MM cell lines containing wild-type BAP1 showed decreased proliferation upon BAP1 knockdown, and that the reintroduction of wild-type BAP1 in BAP1-null MM cell lines resulted in an increase in cell proliferation, perplexing findings for a putative tumor suppressor gene.	('BAP1', 'Gene', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('cell proliferation', 'biological_process', 'GO:0008283', ('206', '224'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('261', '277'))	('cell proliferation', 'CPA', (206, 224))	('BAP1-null', 'Gene', (155, 164))	('increase', 'PosReg', (194, 202))	('knockdown', 'Var', (95, 104))	('BAP1', 'Gene', (90, 94))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('261', '277'))	('proliferation', 'CPA', (71, 84))	('reintroduction', 'Var', (119, 133))	('decreased', 'NegReg', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (261, 266))
49114	26896281	showed that knockdown of BAP1 in several breast cancer cell lines inhibited cell proliferation, tumorigenicity and metastasis.	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('BAP1', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('metastasis', 'CPA', (115, 125))	('breast cancer', 'Disease', (41, 54))	('cell proliferation', 'biological_process', 'GO:0008283', ('76', '94'))	('knockdown', 'Var', (12, 21))	('tumor', 'Disease', (96, 101))	('cell proliferation', 'CPA', (76, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('inhibited', 'NegReg', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
49116	26896281	We monitored spontaneous tumor development for up to 31 months in three heterozygous mouse models with different inactivating mutations in Bap1.	('mouse', 'Species', '10090', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('Bap1', 'Gene', (139, 143))	('inactivating mutations', 'Var', (113, 135))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
49117	26896281	The Bap1-mutant mouse models included one with knockout of Bap1 exons 6 and 7, and two others with point mutations identical to those found in two human BAP1 cancer syndrome families (W and L), i.e., a Bap1 intron 6 splice site mutation leading to a frameshift and predicted premature stop codon and an exon 16 nonsense mutation, respectively.	('Bap1', 'Gene', (59, 63))	('mutation', 'Var', (228, 236))	('human', 'Species', '9606', (147, 152))	('Bap1', 'Gene', (202, 206))	('frameshift', 'Var', (250, 260))	('cancer syndrome', 'Disease', 'MESH:D009369', (158, 173))	('premature stop codon', 'MPA', (275, 295))	('mouse', 'Species', '10090', (16, 21))	('cancer syndrome', 'Disease', (158, 173))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
49118	26896281	We report that aged mice with a germline inactivating mutation of Bap1 are susceptible to a spectrum of spontaneous tumors, which generally differ from that observed in the human BAP1 cancer syndrome, although two Bap1-mutant mice did develop MM.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('susceptible', 'Reg', (75, 86))	('mice', 'Species', '10090', (226, 230))	('cancer syndrome', 'Disease', 'MESH:D009369', (184, 199))	('mice', 'Species', '10090', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('germline inactivating mutation', 'Var', (32, 62))	('cancer syndrome', 'Disease', (184, 199))	('Bap1', 'Gene', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('human', 'Species', '9606', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
49121	26896281	We also generated two new mouse models with inactivating Bap1 mutations identical to those observed in the first two reported MM families with germline BAP1 mutations, i.e., families W and L. Bap1 W and Bap1 L knock-in mice were created in a FVB genetic background using zinc finger nuclease (ZFN) technology, with the assistance of the Fox Chase Cancer Center (FCCC) Transgenic Mouse Facility, according to a strategy described previously.	('Bap1', 'Gene', (57, 61))	('mice', 'Species', '10090', (219, 223))	('inactivating', 'NegReg', (44, 56))	('Mouse', 'Species', '10090', (379, 384))	('mutations', 'Var', (157, 166))	('Cancer', 'Disease', 'MESH:D009369', (347, 353))	('Cancer', 'Disease', (347, 353))	('Cancer', 'Phenotype', 'HP:0002664', (347, 353))	('BAP1', 'Gene', (152, 156))	('mouse', 'Species', '10090', (26, 31))	('mutations', 'Var', (62, 71))
49124	26896281	Note that while the Bap1 L knock-in mutation creates the identical stop codon seen in human family L, the Bap1 W knock-in mouse generates a mRNA that differs from that observed in human family W (due to sequence divergence in exon 7 in human and mouse genomes); nevertheless, both encoded mRNAs result in loss of at least a portion of exon 7, and the net result is the same, i.e., premature truncation of the predicted gene product.	('human', 'Species', '9606', (236, 241))	('mouse', 'Species', '10090', (122, 127))	('human', 'Species', '9606', (180, 185))	('human', 'Species', '9606', (86, 91))	('mouse', 'Species', '10090', (246, 251))	('loss', 'NegReg', (305, 309))	('exon', 'Protein', (335, 339))	('premature truncation', 'MPA', (381, 401))	('mutation', 'Var', (36, 44))
49136	26896281	Markers used to confirm the diagnosis of MM included mesothelin antibody D-16: sc-27702 and WT1 antibody C-19: sc-192, both from Santa Cruz Biotechnology (Dallas, TX), and pan-cytokeratin antibody Z0622 from Dako (Carpinteria, CA).	('WT1', 'Gene', (92, 95))	('mesothelin', 'Gene', (53, 63))	('WT1', 'Gene', '22431', (92, 95))	('antibody', 'cellular_component', 'GO:0019814', ('64', '72'))	('antibody', 'cellular_component', 'GO:0042571', ('188', '196'))	('antibody', 'molecular_function', 'GO:0003823', ('64', '72'))	('antibody', 'cellular_component', 'GO:0019815', ('188', '196'))	('antibody', 'cellular_component', 'GO:0019815', ('96', '104'))	('mesothelin', 'Gene', '56047', (53, 63))	('antibody', 'cellular_component', 'GO:0019814', ('188', '196'))	('antibody', 'cellular_component', 'GO:0042571', ('64', '72'))	('sc-27702', 'Var', (79, 87))	('antibody', 'molecular_function', 'GO:0003823', ('96', '104'))	('antibody', 'cellular_component', 'GO:0019814', ('96', '104'))	('antibody', 'molecular_function', 'GO:0003823', ('188', '196'))	('antibody', 'cellular_component', 'GO:0019815', ('64', '72'))	('antibody', 'cellular_component', 'GO:0042571', ('96', '104'))
49137	26896281	Bap1 expression in the mouse was assessed using an antibody A302-242A from Bethyl Laboratories (Montgomery, TX), whereas BAP1 expression in human ovarian sex cord stromal tumors (SCSTs) was determined using antibody C-4: sc-28383 (Santa Cruz Biotechnology).	('ovarian sex cord stromal tumors', 'Phenotype', 'HP:0031918', (146, 177))	('antibody', 'cellular_component', 'GO:0042571', ('207', '215'))	('human', 'Species', '9606', (140, 145))	('A302-242A', 'Var', (60, 69))	('antibody', 'cellular_component', 'GO:0042571', ('51', '59'))	('Bap1', 'Gene', (0, 4))	('antibody', 'cellular_component', 'GO:0019815', ('51', '59'))	('antibody', 'cellular_component', 'GO:0019815', ('207', '215'))	('ovarian sex cord stromal tumors', 'Disease', (146, 177))	('ovarian sex cord stromal tumors', 'Disease', 'MESH:D018312', (146, 177))	('antibody', 'cellular_component', 'GO:0019814', ('51', '59'))	('antibody', 'cellular_component', 'GO:0019814', ('207', '215'))	('mouse', 'Species', '10090', (23, 28))	('antibody', 'molecular_function', 'GO:0003823', ('207', '215'))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('antibody', 'molecular_function', 'GO:0003823', ('51', '59'))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
49150	26896281	To assess Bap1 allelic loss in LCM-isolated tumor cells from a spontaneous MM, DNA was extracted using an AllPrep DNA/RNA FFPE Kit from Qiagen (Valencia, CA).	('allelic', 'Var', (15, 22))	('Bap1', 'Gene', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('RNA', 'cellular_component', 'GO:0005562', ('118', '121'))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('tumor', 'Disease', (44, 49))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))
49152	26896281	To identify genomic imbalances in frozen ovarian SCSTs from Bap1-mutant mice, array-CGH (aCGH) analysis was performed with 244K genomic DNA arrays from Agilent (Santa Clara, CA), as previously described.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('Bap1-mutant', 'Var', (60, 71))	('imbalances', 'Phenotype', 'HP:0002172', (20, 30))	('array-CGH', 'Disease', (78, 87))	('Bap1-mutant', 'Gene', (60, 71))	('ovarian SCSTs', 'Phenotype', 'HP:0000138', (41, 54))	('ovarian SCST', 'Phenotype', 'HP:0000138', (41, 53))	('mice', 'Species', '10090', (72, 76))	('array-CGH', 'Disease', 'MESH:C538388', (78, 87))
49156	26896281	We also generated two new knock-in mouse models with inactivating Bap1 mutations identical to those observed in the first two reported MM families with germline BAP1 mutations, i.e., families W and L. Unexposed WT mice and animals with the three different germline Bap1 mutations were followed for up to 31 months.	('mutations', 'Var', (166, 175))	('inactivating', 'Reg', (53, 65))	('Bap1', 'Gene', (66, 70))	('mouse', 'Species', '10090', (35, 40))	('mutations', 'Var', (71, 80))	('mice', 'Species', '10090', (214, 218))
49159	26896281	Most tumors in mutant mice developed late in life (median age at time of detection: 19.7 months).	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mutant', 'Var', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('mice', 'Species', '10090', (22, 26))
49161	26896281	All three Bap1 mouse models exhibited an increased incidence and similar spectrum of tumor types, with ovarian SCSTs, lung adenocarcinomas, mammary gland carcinomas, and spindle cell tumors of the skin being seen in each of the Bap1-mutant models.	('tumor', 'Disease', (85, 90))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (118, 138))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('mouse', 'Species', '10090', (15, 20))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))	('Bap1', 'Gene', (10, 14))	('spindle cell tumors', 'Disease', 'MESH:D002277', (170, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (118, 138))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('tumors of the skin', 'Phenotype', 'HP:0008069', (183, 201))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ovarian SCST', 'Phenotype', 'HP:0000138', (103, 115))	('spindle', 'cellular_component', 'GO:0005819', ('170', '177'))	('Bap1-mutant', 'Gene', (228, 239))	('lung adenocarcinomas', 'Disease', (118, 138))	('tumors of the skin', 'Disease', 'MESH:D012878', (183, 201))	('spindle cell tumors', 'Disease', (170, 189))	('ovarian SCSTs', 'Disease', (103, 116))	('tumor', 'Disease', (183, 188))	('tumors of the skin', 'Disease', (183, 201))	('ovarian SCSTs', 'Phenotype', 'HP:0000138', (103, 116))	('Bap1-mutant', 'Var', (228, 239))	('gland carcinomas', 'Disease', (148, 164))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('gland carcinomas', 'Disease', 'MESH:D004701', (148, 164))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))
49189	26896281	To determine if mice with clinically relevant germline mutations of Bap1 show increased susceptibility to asbestos, cohorts of Bap1+/W and Bap1+/L knock-in animals, and their WT littermates, were chronically injected i.p.	('Bap1', 'Gene', (68, 72))	('germline mutations', 'Var', (46, 64))	('susceptibility', 'MPA', (88, 102))	('mice', 'Species', '10090', (16, 20))	('asbestos', 'Chemical', 'MESH:D001194', (106, 114))
49194	26896281	The Bap1-mutant mice were found to succumb to disease much earlier than their WT littermates, with a median survival of 48 weeks in Bap1+/W mice and 46 weeks in Bap1+/L mice from the time of the first asbestos injection versus 60 weeks in WT mice (Fig.	('Bap1+/W', 'Var', (132, 139))	('mice', 'Species', '10090', (140, 144))	('asbestos', 'Chemical', 'MESH:D001194', (201, 209))	('mice', 'Species', '10090', (169, 173))	('Bap1-mutant', 'Gene', (4, 15))	('mice', 'Species', '10090', (16, 20))	('mice', 'Species', '10090', (242, 246))
49196	26896281	Peritoneal MMs occurred in 74% of Bap1+/W mice and 71% of Bap1+/L mice compared to 35% of WT animals.	('MMs', 'Chemical', 'MESH:D008741', (11, 14))	('mice', 'Species', '10090', (42, 46))	('Peritoneal MMs', 'CPA', (0, 14))	('mice', 'Species', '10090', (66, 70))	('Bap1+/W', 'Var', (34, 41))	('Bap1+/L', 'Var', (58, 65))
49203	26896281	Carriers of heterozygous BAP1 mutations are at high risk for the development of a variety of tumors, including benign melanocytic tumors and various malignant tumors, including MM, uveal and cutaneous melanomas, as well as other cancer types, such as lung adenocarcinoma, meningioma, and renal cell carcinoma.	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('BAP1', 'Gene', (25, 29))	('malignant tumors', 'Disease', 'MESH:D018198', (149, 165))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('meningioma', 'Disease', (272, 282))	('tumors', 'Disease', (159, 165))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (191, 210))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (191, 210))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (191, 209))	('benign melanocytic tumors', 'Disease', (111, 136))	('meningioma', 'Phenotype', 'HP:0002858', (272, 282))	('malignant tumors', 'Disease', (149, 165))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (251, 270))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('renal cell carcinoma', 'Disease', (288, 308))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (288, 308))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (251, 270))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('cutaneous melanomas', 'Disease', (191, 210))	('meningioma', 'Disease', 'MESH:D008577', (272, 282))	('melanomas', 'Phenotype', 'HP:0002861', (201, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (299, 308))	('uveal', 'Disease', (181, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('cancer', 'Disease', (229, 235))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mutations', 'Var', (30, 39))	('tumors', 'Disease', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('tumors', 'Disease', (130, 136))	('benign melanocytic tumors', 'Disease', 'MESH:D009508', (111, 136))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (288, 308))	('lung adenocarcinoma', 'Disease', (251, 270))
49205	26896281	Moreover, the spectrum of tumors observed in the three different Bap1-mutant mouse models, all in the same FVB background, was similar irrespective of the type or location of the inactivating mutation.	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('Bap1-mutant', 'Var', (65, 76))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('mouse', 'Species', '10090', (77, 82))	('Bap1-mutant', 'Gene', (65, 76))	('tumors', 'Disease', (26, 32))
49206	26896281	However, the generally distinct spectrum of tumors observed in our Bap1-mutant mice highlights differences in target tissue susceptibility between mice and humans.	('tumors', 'Disease', (44, 50))	('mice', 'Species', '10090', (147, 151))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('humans', 'Species', '9606', (156, 162))	('Bap1-mutant', 'Gene', (67, 78))	('mice', 'Species', '10090', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Bap1-mutant', 'Var', (67, 78))
49207	26896281	With the exception of two MMs, other malignancies commonly observed in the BAP1 cancer syndrome, i.e., uveal and cutaneous melanomas and renal cell carcinomas, were not seen in mice with a germline Bap1 mutation.	('cancer syndrome', 'Disease', (80, 95))	('malignancies', 'Disease', (37, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (137, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (113, 131))	('mutation', 'Var', (203, 211))	('uveal and cutaneous melanomas and renal cell carcinomas', 'Disease', 'MESH:C536494', (103, 158))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (137, 157))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (113, 132))	('Bap1', 'Gene', (198, 202))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('MMs', 'Chemical', 'MESH:D008741', (26, 29))	('mice', 'Species', '10090', (177, 181))	('malignancies', 'Disease', 'MESH:D009369', (37, 49))	('cancer syndrome', 'Disease', 'MESH:D009369', (80, 95))
49211	26896281	Similarly, while germline mutations of RB1 predispose to hereditary retinoblastoma in humans, Rb+/- mice instead exhibit a high incidence (60-80%) of thyroid cancer and pituitary adenocarcinoma.	('RB1', 'Gene', '5925', (39, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('retinoblastoma', 'Phenotype', 'HP:0009919', (68, 82))	('mice', 'Species', '10090', (100, 104))	('pituitary adenocarcinoma', 'Disease', 'MESH:D000230', (169, 193))	('hereditary retinoblastoma', 'Disease', 'MESH:D012175', (57, 82))	('predispose', 'Reg', (43, 53))	('thyroid cancer', 'Disease', (150, 164))	('germline mutations', 'Var', (17, 35))	('hereditary retinoblastoma', 'Disease', (57, 82))	('RB1', 'Gene', (39, 42))	('thyroid cancer', 'Phenotype', 'HP:0002890', (150, 164))	('pituitary adenocarcinoma', 'Disease', (169, 193))	('thyroid cancer', 'Disease', 'MESH:D013964', (150, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('humans', 'Species', '9606', (86, 92))
49215	26896281	Thus, collectively, these data suggest that the finding of MMs in both the human BAP1 syndrome and in Bap1-mutant mice is noteworthy.	('MMs', 'Chemical', 'MESH:D008741', (59, 62))	('Bap1-mutant', 'Var', (102, 113))	('mice', 'Species', '10090', (114, 118))	('human', 'Species', '9606', (75, 80))	('BAP1 syndrome', 'Disease', (81, 94))
49222	26896281	A similar highly increased incidence of MM has been observed in asbestos-exposed Bap1 knockout mice compared to WT mice.	('knockout', 'Var', (86, 94))	('mice', 'Species', '10090', (95, 99))	('Bap1', 'Gene', (81, 85))	('asbestos', 'Chemical', 'MESH:D001194', (64, 72))	('mice', 'Species', '10090', (115, 119))
49223	26896281	For example, in mice with deletion of Bap1 exons 6 and 7, asbestos-induced MMs were observed in 73% of these knockout mice versus 32% in WT littermates.	('Bap1', 'Gene', (38, 42))	('asbestos', 'Chemical', 'MESH:D001194', (58, 66))	('observed', 'Reg', (84, 92))	('deletion', 'Var', (26, 34))	('asbestos-induced MMs', 'Disease', (58, 78))	('MMs', 'Chemical', 'MESH:D008741', (75, 78))	('mice', 'Species', '10090', (118, 122))	('mice', 'Species', '10090', (16, 20))
49229	26896281	While the incidence of frank spontaneous MMs in Bap1-mutant animals was low (2/93; 2.2%), the penetrance of aggressive MMs was very high (>70%) in Bap1-mutant mice exposed to asbestos, indicative of a strong geneenvironment interaction.	('MMs', 'Chemical', 'MESH:D008741', (41, 44))	('asbestos', 'Chemical', 'MESH:D001194', (175, 183))	('penetrance', 'CPA', (94, 104))	('Bap1-mutant', 'Gene', (147, 158))	('Bap1-mutant', 'Var', (48, 59))	('mice', 'Species', '10090', (159, 163))	('MMs', 'Chemical', 'MESH:D008741', (119, 122))	('Bap1-mutant', 'Gene', (48, 59))	('high', 'PosReg', (132, 136))
49230	26896281	The overall findings are consistent with the notion that BAP1 mutation carriers are inherently at elevated risk of MM, and that risk in these individuals increases greatly upon exposure to carcinogenic fibers.	('carcinogenic fibers', 'Disease', 'MESH:D000071075', (189, 208))	('mutation', 'Var', (62, 70))	('BAP1', 'Gene', (57, 61))	('carcinogenic fibers', 'Disease', (189, 208))
49242	24596511	The CTLA-4 blockade results in the enhancement of the T-cell mediated antitumor immune response.	('CTLA-4', 'Gene', (4, 10))	('enhancement', 'PosReg', (35, 46))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('CTLA-4', 'Gene', '1493', (4, 10))	('blockade', 'Var', (11, 19))	('immune response', 'biological_process', 'GO:0006955', ('80', '95'))
49294	24596511	The prognosis of patients with stage IV melanoma is very poor, with 1-year survival rates for those with M1a, M1b, and M1c being 62%, 53%, and 33%, respectively.	('M1c', 'Var', (119, 122))	('M1a', 'Var', (105, 108))	('M1b', 'Var', (110, 113))	('IV melanoma', 'Disease', 'MESH:D008545', (37, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('patients', 'Species', '9606', (17, 25))	('IV melanoma', 'Disease', (37, 48))
49352	18922120	Later, the growing tumor encounters a critical bifurcation point, where it progresses along one of two genetic pathways with very distinct genetic signatures (monosomy 3 vs 6p gain) and metastatic propensity.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('monosomy 3 vs 6p gain', 'Var', (159, 180))	('progresses', 'PosReg', (75, 85))
49354	18922120	However, specific chromosomal alterations, such as loss of chromosome 8p, can hasten the onset of metastasis in susceptible tumors.	('loss of chromosome', 'Var', (51, 69))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('hasten', 'NegReg', (78, 84))	('onset of metastasis', 'CPA', (89, 108))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('chromosome', 'cellular_component', 'GO:0005694', ('59', '69'))
49369	18922120	More recently, oncogenic mutations in GNAQ, a Galphaq stimulatory subunit involved in activating the RAF/MEK/ERK pathway in melanocytes, have been identified in both class 1 and 2 tumors, suggesting that this is an early or initiating event that occurs before the divergence of these two signatures.	('mutations', 'Var', (25, 34))	('GNAQ', 'Gene', '2776', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('ERK', 'Gene', '5594', (109, 112))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('GNAQ', 'Gene', (38, 42))	('RAF', 'Gene', '22882', (101, 104))	('tumors', 'Disease', (180, 186))	('ERK', 'Gene', (109, 112))	('Galphaq', 'Gene', (46, 53))	('RAF', 'Gene', (101, 104))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('Galphaq', 'Gene', '2776', (46, 53))	('MEK', 'Gene', (105, 108))	('MEK', 'Gene', '5609', (105, 108))	('ERK', 'molecular_function', 'GO:0004707', ('109', '112'))
49372	18922120	The retinoblastoma protein inhibits cell-cycle progression through the G1-S phase transition point, so inactivation of retinoblastoma leads to unregulated proliferation.	('leads to', 'Reg', (134, 142))	('unregulated', 'MPA', (143, 154))	('inhibits', 'NegReg', (27, 35))	('cell-cycle', 'biological_process', 'GO:0007049', ('36', '46'))	('retinoblastoma', 'Gene', (4, 18))	('retinoblastoma', 'Gene', '5925', (119, 133))	('retinoblastoma', 'Gene', '5925', (4, 18))	('cell-cycle progression through the G1-S', 'CPA', (36, 75))	('inactivation', 'Var', (103, 115))	('retinoblastoma', 'Phenotype', 'HP:0009919', (119, 133))	('retinoblastoma', 'Phenotype', 'HP:0009919', (4, 18))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))	('S phase', 'biological_process', 'GO:0051320', ('74', '81'))	('retinoblastoma', 'Gene', (119, 133))
49374	18922120	One mechanism for retinoblastoma hyperphosphorylation is via methylation and inactivation of the INK4A gene, which encodes the p16Ink4a tumor suppressor that activates retinoblastoma by blocking its phosphorylation by cyclin D/CDK4.	('retinoblastoma hyperphosphorylation', 'Disease', 'MESH:D012175', (18, 53))	('blocking', 'NegReg', (186, 194))	('p16Ink4a', 'Gene', (127, 135))	('activates', 'PosReg', (158, 167))	('phosphorylation', 'biological_process', 'GO:0016310', ('199', '214'))	('inactivation', 'Var', (77, 89))	('CDK4', 'Gene', (227, 231))	('INK4A', 'Gene', '1029', (97, 102))	('CDK', 'molecular_function', 'GO:0004693', ('227', '230'))	('retinoblastoma', 'Gene', (168, 182))	('phosphorylation', 'MPA', (199, 214))	('retinoblastoma', 'Gene', (18, 32))	('cyclin', 'Protein', (218, 224))	('tumor', 'Disease', (136, 141))	('CDK4', 'Gene', '1019', (227, 231))	('INK4A', 'Gene', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('136', '152'))	('cyclin', 'molecular_function', 'GO:0016538', ('218', '224'))	('hyperphosphorylation', 'biological_process', 'GO:0048151', ('33', '53'))	('p16Ink4a', 'Gene', '1029', (127, 135))	('retinoblastoma', 'Gene', '5925', (168, 182))	('tumor suppressor', 'biological_process', 'GO:0051726', ('136', '152'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (168, 182))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('retinoblastoma hyperphosphorylation', 'Disease', (18, 53))	('retinoblastoma', 'Gene', '5925', (18, 32))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('retinoblastoma', 'Phenotype', 'HP:0009919', (18, 32))
49375	18922120	We have shown that INK4A is a direct transcriptional target of the master melanocyte differentiation factor MITF, and that loss of p16Ink4a allows melanocytes to escape MITF-induced growth inhibition and to re-enter the cell cycle.	('cell cycle', 'biological_process', 'GO:0007049', ('220', '230'))	('p16Ink4a', 'Gene', (131, 139))	('INK4A', 'Gene', '1029', (19, 24))	('melanocyte differentiation', 'biological_process', 'GO:0030318', ('74', '100'))	('INK4A', 'Gene', (19, 24))	('MITF', 'Gene', '4286', (108, 112))	('re-enter the cell cycle', 'CPA', (207, 230))	('loss', 'Var', (123, 127))	('escape', 'MPA', (162, 168))	('MITF', 'Gene', (108, 112))	('p16Ink4a', 'Gene', '1029', (131, 139))	('MITF', 'Gene', '4286', (169, 173))	('MITF', 'Gene', (169, 173))
49379	18922120	In some types of cancer, this can be due to gene amplification, but this does not appear to be the case for uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (108, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('uveal melanoma', 'Disease', (108, 122))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('gene amplification', 'Var', (44, 62))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
49380	18922120	Cyclin D overexpression can also occur through oncogenic mutations that constitutively activate the RAF/MEK/ERK pathway and its downstream target cyclin D. In skin melanoma, for example, such mutations occur commonly in BRAF, RAS and KIT.	('ERK', 'Gene', (108, 111))	('KIT', 'Disease', (234, 237))	('ERK', 'molecular_function', 'GO:0004707', ('108', '111'))	('RAS', 'Disease', (226, 229))	('mutations', 'Var', (192, 201))	('skin melanoma', 'Disease', 'MESH:D008545', (159, 172))	('RAF', 'Gene', '22882', (221, 224))	('BRAF', 'Gene', '673', (220, 224))	('BRAF', 'Gene', (220, 224))	('RAF', 'Gene', '22882', (100, 103))	('Cyclin', 'molecular_function', 'GO:0016538', ('0', '6'))	('MEK', 'Gene', '5609', (104, 107))	('RAF', 'Gene', (221, 224))	('cyclin', 'molecular_function', 'GO:0016538', ('146', '152'))	('skin melanoma', 'Disease', (159, 172))	('ERK', 'Gene', '5594', (108, 111))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('RAF', 'Gene', (100, 103))	('MEK', 'Gene', (104, 107))	('KIT', 'molecular_function', 'GO:0005020', ('234', '237'))
49385	18922120	Normally, tumor suppressor mechanisms eliminate damaged cells that have sustained oncogenic mutations through senescence or apoptosis.	('apoptosis', 'CPA', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('senescence', 'biological_process', 'GO:0010149', ('110', '120'))	('senescence', 'CPA', (110, 120))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('tumor', 'Disease', (10, 15))	('tumor suppressor', 'biological_process', 'GO:0051726', ('10', '26'))	('mutations', 'Var', (92, 101))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('10', '26'))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
49396	18922120	Thus, uveal melanomas often harbor defects at multiple points in the Bcl2 pathway, thereby contributing to the apoptosis-resistant phenotype of these tumors.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('Bcl2', 'Gene', (69, 73))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanomas', 'Phenotype', 'HP:0002861', (12, 21))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('Bcl2', 'molecular_function', 'GO:0015283', ('69', '73'))	('uveal melanomas', 'Disease', 'MESH:C536494', (6, 21))	('uveal melanomas', 'Disease', (6, 21))	('uveal melanomas', 'Phenotype', 'HP:0007716', (6, 21))	('contributing', 'Reg', (91, 103))	('apoptosis-resistant phenotype', 'MPA', (111, 140))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('Bcl2', 'Gene', '596', (69, 73))	('uveal melanoma', 'Phenotype', 'HP:0007716', (6, 20))	('defects', 'Var', (35, 42))
49402	18922120	The IGF1R is strongly expressed in many uveal melanomas, and inhibition of this receptor induces growth arrest and cell death in uveal melanoma cell lines.	('uveal melanomas', 'Disease', (40, 55))	('growth arrest', 'Phenotype', 'HP:0001510', (97, 110))	('uveal melanomas', 'Phenotype', 'HP:0007716', (40, 55))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('death', 'Disease', (120, 125))	('growth arrest', 'Disease', 'MESH:D006323', (97, 110))	('cell death', 'biological_process', 'GO:0008219', ('115', '125'))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('uveal melanoma', 'Disease', 'MESH:C536494', (129, 143))	('uveal melanoma', 'Disease', (129, 143))	('growth arrest', 'Disease', (97, 110))	('death', 'Disease', 'MESH:D003643', (120, 125))	('uveal melanomas', 'Disease', 'MESH:C536494', (40, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (40, 54))	('IGF1R', 'Gene', '3480', (4, 9))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('induces', 'Reg', (89, 96))	('inhibition', 'Var', (61, 71))	('IGF1R', 'Gene', (4, 9))	('uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))
49411	18922120	In general, tumors with monosomy 3 contain greater numbers of chromosomal abnormalities (aneuploidy) than tumors with disomy 3, suggesting that loss of chromosome 3 leads to increased genomic instability.	('chromosome 3', 'Gene', (152, 164))	('loss', 'Var', (144, 148))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('genomic instability', 'MPA', (184, 203))	('chromosome', 'cellular_component', 'GO:0005694', ('152', '162'))	('chromosomal abnormalities (aneuploidy) than tumors', 'Disease', 'MESH:D000782', (62, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('increased', 'PosReg', (174, 183))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
49414	18922120	It seems likely that chromosome 8q gain is not an independent risk factor for metastasis, but that it is more common in tumors with monosomy 3, which is a strong metastatic risk factor.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('monosomy 3', 'Var', (132, 142))	('chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))
49417	18922120	We have shown that loss of LZTS1 is associated with increased invasion and migration of uveal melanoma cells.	('increased', 'PosReg', (52, 61))	('LZTS1', 'Gene', '11178', (27, 32))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (88, 102))	('uveal melanoma', 'Disease', (88, 102))	('loss', 'Var', (19, 23))	('invasion', 'CPA', (62, 70))	('LZTS1', 'Gene', (27, 32))
49429	18922120	If this hypothesis is correct, then 6p gain may lead to a phenotype that remains competent for melanocytic differentiation (class 1), whereas monosomy 3 may result in at least a relative block to melanocyte differentiation (class 2).	('melanocyte differentiation', 'biological_process', 'GO:0030318', ('196', '222'))	('block', 'NegReg', (187, 192))	('6p gain', 'Var', (36, 43))	('melanocyte differentiation', 'CPA', (196, 222))	('monosomy 3', 'Var', (142, 152))	('lead to', 'Reg', (48, 55))	('melanocytic', 'Disease', 'MESH:D009508', (95, 106))	('melanocytic', 'Disease', (95, 106))
49436	18922120	The result is a bifurcation in further tumor progression, with gain of chromosome 6p or loss of chromosome 3 somehow relieving this selective pressure.	('gain', 'PosReg', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('loss', 'Var', (88, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('71', '81'))	('tumor', 'Disease', (39, 44))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))
49437	18922120	Loss of chromosome 3 leads to further genomic instability, accumulation of further aneuploidy, a loss of differentiation competence and a gain of metastatic competence.	('differentiation competence', 'CPA', (105, 131))	('loss', 'NegReg', (97, 101))	('accumulation', 'PosReg', (59, 71))	('gain', 'PosReg', (138, 142))	('aneuploidy', 'Disease', (83, 93))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('aneuploidy', 'Disease', 'MESH:D000782', (83, 93))	('metastatic competence', 'CPA', (146, 167))	('Loss', 'Var', (0, 4))	('genomic instability', 'CPA', (38, 57))
49439	18922120	For example, a strategy aimed at inhibiting early events in the RAF/MEK/ERK pathway may have little or no effect on metastasizing tumor cells that have accumulated other mutations that render the early mutations irrelevant for further tumor progression.	('ERK', 'Gene', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('MEK', 'Gene', '5609', (68, 71))	('mutations', 'Var', (170, 179))	('ERK', 'Gene', '5594', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('metastasizing', 'CPA', (116, 129))	('tumor', 'Disease', (235, 240))	('RAF', 'Gene', '22882', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('ERK', 'molecular_function', 'GO:0004707', ('72', '75'))	('RAF', 'Gene', (64, 67))	('tumor', 'Disease', (130, 135))	('inhibiting', 'NegReg', (33, 43))	('MEK', 'Gene', (68, 71))
49445	18922120	Activating mutations in GNAQ occur in approximately half of all primary uveal melanomas and can activate the RAF/MEK/ERK pathway.	('MEK', 'Gene', '5609', (113, 116))	('mutations', 'Var', (11, 20))	('Activating', 'PosReg', (0, 10))	('GNAQ', 'Gene', '2776', (24, 28))	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('ERK', 'Gene', (117, 120))	('activate', 'PosReg', (96, 104))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('GNAQ', 'Gene', (24, 28))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('ERK', 'molecular_function', 'GO:0004707', ('117', '120'))	('RAF', 'Gene', '22882', (109, 112))	('primary uveal melanomas', 'Disease', 'MESH:C536494', (64, 87))	('uveal melanomas', 'Phenotype', 'HP:0007716', (72, 87))	('RAF', 'Gene', (109, 112))	('primary uveal melanomas', 'Disease', (64, 87))	('ERK', 'Gene', '5594', (117, 120))	('MEK', 'Gene', (113, 116))
49452	18922120	Monosomy 3 leads to further genomic instability, accumulation of aneuploidy, a loss of differentiation competence and a gain of metastatic competence.	('aneuploidy', 'Disease', (65, 75))	('loss', 'NegReg', (79, 83))	('genomic instability', 'CPA', (28, 47))	('accumulation', 'PosReg', (49, 61))	('aneuploidy', 'Disease', 'MESH:D000782', (65, 75))	('differentiation competence', 'CPA', (87, 113))	('metastatic competence', 'CPA', (128, 149))	('Monosomy 3', 'Var', (0, 10))	('gain', 'PosReg', (120, 124))
49454	18922120	Tumors can be further divided into genetically and prognostically relevant subgroups: class 1A (minimal aneuploidy), class 1B (6p gain), class 2A (diploid for 8p) and class 2B (8p loss).	('6p', 'Var', (127, 129))	('aneuploidy', 'Disease', (104, 114))	('aneuploidy', 'Disease', 'MESH:D000782', (104, 114))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('diploid', 'Var', (147, 154))	('gain', 'PosReg', (130, 134))
49468	9820172	The presence of these antigens was a little lower in metastases.	('metastases', 'Disease', (53, 63))	('presence', 'Var', (4, 12))	('lower', 'NegReg', (44, 49))	('metastases', 'Disease', 'MESH:D009362', (53, 63))
49472	28921907	Dual MAPK / PI3K pathway inhibition with trametinib and GSK2141795 does not yield clinical benefit in metastatic NRAS mutant and wild type melanoma Aberrant MAPK and PI3K pathway signaling may drive the malignant phenotype in NRAS mutant and BRAFWT NRASWT metastatic melanoma.	('NRAS', 'Gene', (249, 253))	('NRAS', 'Gene', (113, 117))	('melanoma', 'Disease', 'MESH:D008545', (267, 275))	('drive', 'PosReg', (193, 198))	('signaling', 'biological_process', 'GO:0023052', ('179', '188'))	('MAPK', 'molecular_function', 'GO:0004707', ('5', '9'))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('mutant', 'Var', (231, 237))	('NRAS', 'Gene', '4893', (226, 230))	('MAPK', 'molecular_function', 'GO:0004707', ('157', '161'))	('PI3K', 'molecular_function', 'GO:0016303', ('166', '170'))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('melanoma', 'Disease', (267, 275))	('BRAFWT', 'Gene', '673', (242, 248))	('mutant', 'Var', (118, 124))	('NRAS', 'Gene', '4893', (249, 253))	('NRAS', 'Gene', '4893', (113, 117))	('PI3K', 'molecular_function', 'GO:0016303', ('12', '16'))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('trametinib', 'Chemical', 'MESH:C560077', (41, 51))	('NRAS', 'Gene', (226, 230))	('BRAFWT', 'Gene', (242, 248))	('GSK2141795', 'Chemical', 'MESH:C000595149', (56, 66))	('GSK', 'molecular_function', 'GO:0050321', ('56', '59'))
49473	28921907	To target these pathways NRAS mutant and BRAFWT NRASWT patients received oral trametinib at 1.5 mg daily and GSK2141795 at 50 mg daily in a 2-cohort Simon 2-stage design.	('GSK', 'molecular_function', 'GO:0050321', ('109', '112'))	('BRAFWT', 'Gene', '673', (41, 47))	('BRAFWT', 'Gene', (41, 47))	('NRAS', 'Gene', '4893', (48, 52))	('GSK2141795', 'Chemical', 'MESH:C000595149', (109, 119))	('trametinib', 'Chemical', 'MESH:C560077', (78, 88))	('NRAS', 'Gene', (25, 29))	('patients', 'Species', '9606', (55, 63))	('mutant', 'Var', (30, 36))	('NRAS', 'Gene', '4893', (25, 29))	('NRAS', 'Gene', (48, 52))
49476	28921907	The median PFS and OS were 2.3 and 4.0 months in the NRAS mutant cohort 2.8 and 3.5 months in the wild-type cohort.	('mutant', 'Var', (58, 64))	('NRAS', 'Gene', '4893', (53, 57))	('NRAS', 'Gene', (53, 57))
49478	28921907	We conclude that the combination of trametinib and GSK2141795 does not have significant clinical activity in NRAS mutant or BRAFWT NRASWT melanoma.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('trametinib', 'Chemical', 'MESH:C560077', (36, 46))	('BRAFWT', 'Gene', '673', (124, 130))	('BRAFWT', 'Gene', (124, 130))	('NRAS', 'Gene', (109, 113))	('GSK2141795', 'Var', (51, 61))	('NRAS', 'Gene', (131, 135))	('NRAS', 'Gene', '4893', (131, 135))	('NRAS', 'Gene', '4893', (109, 113))	('GSK2141795', 'Chemical', 'MESH:C000595149', (51, 61))	('GSK', 'molecular_function', 'GO:0050321', ('51', '54'))
49480	28921907	In BRAF mutant melanoma, which accounts for approximately 50% of cases overall, BRAF plus MEK inhibitor combinations yield rapid objective response in 64 to 68% of patients with a median PFS of 9.9 to 11.4 months (e. g.), but there are limited options for patients with BRAF wild type melanoma who do benefit from immune therapy.	('melanoma', 'Phenotype', 'HP:0002861', (285, 293))	('BRAF', 'Gene', (80, 84))	('BRAF', 'Gene', (270, 274))	('BRAF', 'Gene', '673', (270, 274))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('combinations', 'Interaction', (104, 116))	('patients', 'Species', '9606', (256, 264))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('mutant', 'Var', (8, 14))	('MEK', 'Gene', (90, 93))	('BRAF', 'Gene', '673', (3, 7))	('MEK', 'Gene', '5609', (90, 93))	('BRAF', 'Gene', (3, 7))	('patients', 'Species', '9606', (164, 172))	('melanoma', 'Disease', (285, 293))	('BRAF', 'Gene', '673', (80, 84))	('melanoma', 'Disease', 'MESH:D008545', (285, 293))
49482	28921907	NRAS exon 1 and 2 mutations, observed in approximately 30% of BRAF wild type melanoma metastases, are associated with poor overall survival (e. g.).	('NRAS', 'Gene', '4893', (0, 4))	('poor', 'NegReg', (118, 122))	('melanoma metastases', 'Disease', 'MESH:D009362', (77, 96))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('NRAS', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('overall', 'MPA', (123, 130))	('melanoma metastases', 'Disease', (77, 96))	('mutations', 'Var', (18, 27))
49483	28921907	ATP-competitive BRAF inhibitors lead to paradoxical activation of the MAP kinase pathway in NRAS mutant melanoma, but MEK inhibitors induce objective responses in about 20% of NRAS mutant melanoma patients, with a median progression free survival of 3.6 months.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('patients', 'Species', '9606', (197, 205))	('MEK', 'Gene', (118, 121))	('MAP', 'molecular_function', 'GO:0004239', ('70', '73'))	('NRAS', 'Gene', (176, 180))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('mutant', 'Var', (97, 103))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('melanoma', 'Disease', (188, 196))	('NRAS', 'Gene', '4893', (92, 96))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('mutant', 'Var', (181, 187))	('NRAS', 'Gene', (92, 96))	('NRAS', 'Gene', '4893', (176, 180))	('ATP', 'Chemical', 'MESH:D000255', (0, 3))	('MAP kinase pathway', 'Pathway', (70, 88))	('melanoma', 'Disease', 'MESH:D008545', (188, 196))	('MEK', 'Gene', '5609', (118, 121))	('activation', 'PosReg', (52, 62))
49484	28921907	Increased signaling through the MAPK and PI3K pathways as assessed by pERK, pAKT, and pS6 levels has also been identified in melanoma lesions harboring either BRAF or NRAS mutations, suggesting that inhibition of these pathways could have clinical activity in wild type melanoma patients as well.	('pS6', 'Gene', (86, 89))	('PI3K', 'molecular_function', 'GO:0016303', ('41', '45'))	('PI3K pathways', 'Pathway', (41, 54))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('melanoma', 'Phenotype', 'HP:0002861', (270, 278))	('MAPK', 'Pathway', (32, 36))	('melanoma', 'Disease', (270, 278))	('signaling', 'MPA', (10, 19))	('AKT', 'Gene', (77, 80))	('BRAF', 'Gene', '673', (159, 163))	('BRAF', 'Gene', (159, 163))	('NRAS', 'Gene', (167, 171))	('MAPK', 'molecular_function', 'GO:0004707', ('32', '36'))	('pS6', 'Gene', '338413', (86, 89))	('melanoma lesions', 'Disease', 'MESH:D008545', (125, 141))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('AKT', 'Gene', '207', (77, 80))	('melanoma', 'Disease', 'MESH:D008545', (270, 278))	('Increased', 'PosReg', (0, 9))	('patients', 'Species', '9606', (279, 287))	('mutations', 'Var', (172, 181))	('melanoma lesions', 'Disease', (125, 141))	('signaling', 'biological_process', 'GO:0023052', ('10', '19'))	('pERK', 'Gene', (70, 74))	('pERK', 'Gene', '9451', (70, 74))	('NRAS', 'Gene', '4893', (167, 171))
49486	28921907	Trametinib is an allosteric inhibitor of MEK1/2 that decreases MAPK signaling in RAS mutant melanoma and GSK2141795 is an ATP competitive pan-AKT inhibitor with preliminary evidence of activity in patients whose tumors demonstrated significant PI3K pathway activity.	('patients', 'Species', '9606', (197, 205))	('AKT', 'Gene', (142, 145))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('MAPK', 'molecular_function', 'GO:0004707', ('63', '67'))	('decreases', 'NegReg', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('PI3K pathway', 'Pathway', (244, 256))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('RAS', 'Disease', (81, 84))	('AKT', 'Gene', '207', (142, 145))	('MAPK signaling', 'biological_process', 'GO:0000165', ('63', '77'))	('MAPK signaling', 'MPA', (63, 77))	('GSK', 'molecular_function', 'GO:0050321', ('105', '108'))	('tumors', 'Disease', (212, 218))	('ATP', 'Chemical', 'MESH:D000255', (122, 125))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('mutant', 'Var', (85, 91))	('GSK2141795', 'Chemical', 'MESH:C000595149', (105, 115))	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('MEK1/2', 'Gene', '5604;5605', (41, 47))	('MEK1/2', 'Gene', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('PI3K', 'molecular_function', 'GO:0016303', ('244', '248'))	('MEK1', 'molecular_function', 'GO:0004708', ('41', '45'))	('GSK2141795', 'Var', (105, 115))
49487	28921907	The combination of trametinib and GSK2141795 shows evidence of clinical activity at tolerable doses in gynecologic malignancies.	('trametinib', 'Chemical', 'MESH:C560077', (19, 29))	('GSK2141795', 'Chemical', 'MESH:C000595149', (34, 44))	('GSK', 'molecular_function', 'GO:0050321', ('34', '37'))	('malignancies', 'Disease', 'MESH:D009369', (115, 127))	('malignancies', 'Disease', (115, 127))	('GSK2141795', 'Var', (34, 44))
49488	28921907	In the current phase II clinical trial, we test the hypothesis that the combination of trametinib and GSK2141795 will overcome the resistance associated with single agent MEK inhibitors by decreasing PI3K pathway activity in NRAS mutant melanoma.	('melanoma', 'Disease', (237, 245))	('activity', 'MPA', (213, 221))	('resistance', 'MPA', (131, 141))	('MEK', 'Gene', (171, 174))	('melanoma', 'Disease', 'MESH:D008545', (237, 245))	('MEK', 'Gene', '5609', (171, 174))	('NRAS', 'Gene', (225, 229))	('PI3K pathway', 'Pathway', (200, 212))	('GSK2141795', 'Chemical', 'MESH:C000595149', (102, 112))	('GSK', 'molecular_function', 'GO:0050321', ('102', '105'))	('NRAS', 'Gene', '4893', (225, 229))	('trametinib', 'Chemical', 'MESH:C560077', (87, 97))	('decreasing', 'NegReg', (189, 199))	('PI3K', 'molecular_function', 'GO:0016303', ('200', '204'))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('GSK2141795', 'Var', (102, 112))
49490	28921907	This was a nonrandomized, multicenter phase II study of trametinib in combination with GSK2141795 accrued at UCSF and MSKCC with 2 separate cohorts: Patients with NRAS exon 1 and 2 mutations (NRAS mutant) identified by Sanger sequencing or exon-capture next-generation sequencing and patients without these mutations (wild-type).	('Patients', 'Species', '9606', (149, 157))	('NRAS', 'Gene', (163, 167))	('patients', 'Species', '9606', (284, 292))	('NRAS', 'Gene', '4893', (163, 167))	('trametinib', 'Chemical', 'MESH:C560077', (56, 66))	('NRAS', 'Gene', (192, 196))	('mutations', 'Var', (181, 190))	('GSK2141795', 'Chemical', 'MESH:C000595149', (87, 97))	('GSK', 'molecular_function', 'GO:0050321', ('87', '90'))	('NRAS', 'Gene', '4893', (192, 196))
49493	28921907	Patients with tumors harboring BRAF exon 15 mutations, significant heart disease, retinal or fundal disease, prior treatment and an AKT or MEK inhibitor, or untreated central nervous metastases were excluded from the study.	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('retinal or fundal disease', 'Disease', 'MESH:D012164', (82, 107))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('AKT', 'Gene', (132, 135))	('Patients', 'Species', '9606', (0, 8))	('metastases', 'Disease', 'MESH:D009362', (183, 193))	('BRAF', 'Gene', '673', (31, 35))	('retinal or fundal disease', 'Disease', (82, 107))	('retinal or fundal disease', 'Phenotype', 'HP:0000479', (82, 107))	('MEK', 'Gene', '5609', (139, 142))	('BRAF', 'Gene', (31, 35))	('metastases', 'Disease', (183, 193))	('heart disease', 'Disease', 'MESH:D006331', (67, 80))	('tumors', 'Disease', (14, 20))	('MEK', 'Gene', (139, 142))	('heart disease', 'Disease', (67, 80))	('AKT', 'Gene', '207', (132, 135))	('mutations', 'Var', (44, 53))	('tumors', 'Disease', 'MESH:D009369', (14, 20))
49496	28921907	Enrollment was completed in April 2014 after 10 patients in the NRAS mutant cohort and 10 patients in the NRAS wild-type cohort were enrolled and futility endpoints were met in both cohorts.	('mutant', 'Var', (69, 75))	('NRAS', 'Gene', (64, 68))	('NRAS', 'Gene', (106, 110))	('patients', 'Species', '9606', (48, 56))	('NRAS', 'Gene', '4893', (64, 68))	('patients', 'Species', '9606', (90, 98))	('NRAS', 'Gene', '4893', (106, 110))
49499	28921907	In the NRAS mutant cohort, 4 patients had transient stabilization of disease, all lasting less than 6 months including 2 patients with mucosal melanoma.	('patients', 'Species', '9606', (29, 37))	('mutant', 'Var', (12, 18))	('mucosal melanoma', 'Disease', (135, 151))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('NRAS', 'Gene', (7, 11))	('patients', 'Species', '9606', (121, 129))	('mucosal melanoma', 'Disease', 'MESH:D008545', (135, 151))	('NRAS', 'Gene', '4893', (7, 11))
49501	28921907	The median PFS estimates in the NRAS mutant and wild type cohorts were 2.3 months (95% CI 2.1 to 2.5 months) and 2.8 months (95% CI 2.6 to 2.9 months) and the median OS estimates were 4.0 months (95% CI 0.9 to 7.0 months) and 3.5 months (95% CI 0.6 to 6.4 months) respectively.	('mutant', 'Var', (37, 43))	('PFS', 'MPA', (11, 14))	('NRAS', 'Gene', '4893', (32, 36))	('NRAS', 'Gene', (32, 36))
49504	28921907	The combination of trametinib and GSK2141795 failed to produce objective responses in patients with either NRAS mutant or wild-type melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('trametinib', 'Chemical', 'MESH:C560077', (19, 29))	('GSK2141795', 'Chemical', 'MESH:C000595149', (34, 44))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('NRAS', 'Gene', '4893', (107, 111))	('GSK', 'molecular_function', 'GO:0050321', ('34', '37'))	('mutant', 'Var', (112, 118))	('NRAS', 'Gene', (107, 111))	('patients', 'Species', '9606', (86, 94))
49508	28921907	Efforts to block oncogenic signaling in NRAS-mutated melanoma is further complicated by the potential for escape through the PI3 kinase pathway, but the recommended phase 2 doses of trametinib and GSK2141795 when administered in combination are lower than the doses for either drug when administered as monotherapy.	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('GSK', 'molecular_function', 'GO:0050321', ('197', '200'))	('NRAS', 'Gene', (40, 44))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('trametinib', 'Chemical', 'MESH:C560077', (182, 192))	('melanoma', 'Disease', (53, 61))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('NRAS', 'Gene', '4893', (40, 44))	('GSK2141795', 'Var', (197, 207))	('GSK2141795', 'Chemical', 'MESH:C000595149', (197, 207))
49518	28921907	In summary, the combination of trametinib and GSK2141795 did not induce objective responses in NRAS mutant melanoma nor in uveal and cutaneous melanoma patients whose tumors harbored neither BRAF nor NRAS mutations.	('BRAF', 'Gene', (191, 195))	('uveal', 'Disease', (123, 128))	('trametinib', 'Chemical', 'MESH:C560077', (31, 41))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('GSK2141795', 'Chemical', 'MESH:C000595149', (46, 56))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('NRAS', 'Gene', '4893', (95, 99))	('GSK', 'molecular_function', 'GO:0050321', ('46', '49'))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('NRAS', 'Gene', (200, 204))	('cutaneous melanoma', 'Disease', (133, 151))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (133, 151))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (133, 151))	('NRAS', 'Gene', (95, 99))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('patients', 'Species', '9606', (152, 160))	('BRAF', 'Gene', '673', (191, 195))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('mutant', 'Var', (100, 106))	('NRAS', 'Gene', '4893', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))
49519	28921907	NRAS mutations leading to aberrant MAP kinase and PI3 kinase pathway activity are observed in 15% of patients with advanced melanoma and signaling through these pathways may also contribute to the malignant phenotype in BRAFwt / NRASwt melanoma patients.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('patients', 'Species', '9606', (245, 253))	('contribute', 'Reg', (179, 189))	('NRAS', 'Gene', '4893', (229, 233))	('melanoma', 'Disease', 'MESH:D008545', (236, 244))	('patients', 'Species', '9606', (101, 109))	('BRAFwt', 'Gene', '673', (220, 226))	('MAP kinase', 'Pathway', (35, 45))	('signaling', 'biological_process', 'GO:0023052', ('137', '146'))	('NRAS', 'Gene', (0, 4))	('MAP', 'molecular_function', 'GO:0004239', ('35', '38'))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('activity', 'MPA', (69, 77))	('NRAS', 'Gene', (229, 233))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('melanoma', 'Disease', (236, 244))	('PI3 kinase pathway', 'Pathway', (50, 68))	('BRAFwt', 'Gene', (220, 226))	('NRAS', 'Gene', '4893', (0, 4))
49520	28921907	This is the first study to examine the safety and efficacy of combined MAPK / PI3K pathway blockade with MEK and AKT inhibitors in NRAS mutant and BRAFwt / NRASwt populations.	('NRAS', 'Gene', (156, 160))	('MAPK / PI3K pathway', 'Pathway', (71, 90))	('NRAS', 'Gene', (131, 135))	('AKT', 'Gene', '207', (113, 116))	('BRAFwt', 'Gene', '673', (147, 153))	('MAPK', 'molecular_function', 'GO:0004707', ('71', '75'))	('NRAS', 'Gene', '4893', (131, 135))	('NRAS', 'Gene', '4893', (156, 160))	('MEK', 'Gene', '5609', (105, 108))	('blockade', 'NegReg', (91, 99))	('AKT', 'Gene', (113, 116))	('BRAFwt', 'Gene', (147, 153))	('MEK', 'Gene', (105, 108))	('mutant', 'Var', (136, 142))	('PI3K', 'molecular_function', 'GO:0016303', ('78', '82'))
49575	32911759	Unlike skin melanomas, BRAF mutations are extremely rare in uveal melanomas, where the vast majority show mutations in the genes GNAQ and GNA11 that activate the mitogen-activated protein kinase (MAPK) pathway and, consequently, result in increased cell proliferation.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('uveal melanomas', 'Disease', 'MESH:C536494', (60, 75))	('activate', 'PosReg', (149, 157))	('MAPK', 'molecular_function', 'GO:0004707', ('196', '200'))	('BRAF', 'Gene', '673', (23, 27))	('skin melanomas', 'Disease', (7, 21))	('BRAF', 'Gene', (23, 27))	('GNAQ', 'Gene', '2776', (129, 133))	('skin melanomas', 'Disease', 'MESH:D008545', (7, 21))	('GNA11', 'Gene', (138, 143))	('cell proliferation', 'biological_process', 'GO:0008283', ('249', '267'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('uveal melanomas', 'Disease', (60, 75))	('uveal melanomas', 'Phenotype', 'HP:0007716', (60, 75))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('GNAQ', 'Gene', (129, 133))	('melanomas', 'Phenotype', 'HP:0002861', (12, 21))	('increased', 'PosReg', (239, 248))	('mutations', 'Var', (28, 37))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('cell proliferation', 'CPA', (249, 267))	('mutations', 'Var', (106, 115))	('GNA11', 'Gene', '2767', (138, 143))	('protein', 'cellular_component', 'GO:0003675', ('180', '187'))
49584	32911759	Preclinical data have shown that in both in vitro and in vivo systems, ganetespib exhibits potent cytotoxicity and anti-tumor activity.	('ganetespib', 'Chemical', 'MESH:C533237', (71, 81))	('cytotoxicity', 'Disease', (98, 110))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cytotoxicity', 'Disease', 'MESH:D064420', (98, 110))	('ganetespib', 'Var', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
49600	32911759	In UM, the expression of tumor IGF1R has been associated with disease progression, and the in-vitro inhibition of IGF1R results in tumor regression of UM.	('UM', 'Phenotype', 'HP:0007716', (151, 153))	('IGF1R', 'Gene', '3480', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('IGF1R', 'Gene', '3480', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (25, 30))	('expression', 'MPA', (11, 21))	('tumor', 'Disease', (131, 136))	('inhibition', 'Var', (100, 110))	('associated', 'Reg', (46, 56))	('IGF1R', 'Gene', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('IGF1R', 'Gene', (31, 36))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
49607	32911759	A phase II study has already found favorable results at the preventive level when evaluating their use in patients with primary UM and chromosome 3 monosomy, comparing their survival results with historical controls.	('primary UM', 'Disease', (120, 130))	('UM', 'Phenotype', 'HP:0007716', (128, 130))	('chromosome', 'cellular_component', 'GO:0005694', ('135', '145'))	('patients', 'Species', '9606', (106, 114))	('chromosome 3 monosomy', 'Var', (135, 156))
49636	32911759	In contrast, prognostically unfavorable UMs are highly lethal; these UMs show monosomy 3, a GEP class 2, BAP1 inactivation, multiple copies of chromosome 8q.	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('BAP1', 'Gene', '8314', (105, 109))	('chromosome', 'cellular_component', 'GO:0005694', ('143', '153'))	('inactivation', 'Var', (110, 122))	('UM', 'Phenotype', 'HP:0007716', (40, 42))	('monosomy 3', 'Disease', (78, 88))	('BAP1', 'Gene', (105, 109))
49637	32911759	have suggested that molecular genetic alterations of the tumor, in particular, the lack of monosomy 3, are associated with such prolonged survival.	('associated', 'Reg', (107, 117))	('monosomy', 'Gene', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('lack', 'Var', (83, 87))	('tumor', 'Disease', (57, 62))
49665	31330784	UM is driven by recurrent activating mutations in Galphaq pathway, which are associated with a second mutation in BRCA1 associated protein 1 (BAP1), splicing factor 3b subunit 1 (SF3B1), or eukaryotic translation initiation factor 1A X-linked (EIF1AX), occurring in an almost mutually exclusive manner.	('activating', 'PosReg', (26, 36))	('BRCA1 associated protein 1', 'Gene', (114, 140))	('splicing factor 3b subunit 1', 'Gene', '23451', (149, 177))	('SF3B1', 'Gene', (179, 184))	('BAP1', 'Gene', '8314', (142, 146))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('mutation', 'Var', (102, 110))	('splicing', 'biological_process', 'GO:0045292', ('149', '157'))	('translation initiation', 'biological_process', 'GO:0006413', ('201', '223'))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('mutations', 'Var', (37, 46))	('BAP1', 'Gene', (142, 146))	('SF3B1', 'Gene', '23451', (179, 184))	('BRCA1 associated protein 1', 'Gene', '8314', (114, 140))	('eukaryotic translation initiation factor 1A X-linked', 'Gene', '1964', (190, 242))	('Galphaq', 'Gene', (50, 57))	('Galphaq', 'Gene', '2776', (50, 57))	('splicing factor 3b subunit 1', 'Gene', (149, 177))
49673	31330784	Germline inactivating mutations in BAP1 (BRCA1 associated protein 1) also represent a genetic risk factor in rare familial and bilateral UM cases, accounting for 2-5% of cases.	('Germline inactivating mutations', 'Var', (0, 31))	('BAP1', 'Gene', '8314', (35, 39))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('BRCA1 associated protein 1', 'Gene', '8314', (41, 67))	('UM', 'Phenotype', 'HP:0007716', (137, 139))	('BAP1', 'Gene', (35, 39))	('BRCA1 associated protein 1', 'Gene', (41, 67))	('risk', 'Reg', (94, 98))
49674	31330784	Recently, two UM cases have been reported to harbor germline loss-of-function mutations in MBD4 (methyl-CpG binding domain 4).	('UM', 'Phenotype', 'HP:0007716', (14, 16))	('loss-of-function', 'NegReg', (61, 77))	('MBD4', 'Gene', '8930', (91, 95))	('methyl-CpG binding domain 4', 'Gene', '8930', (97, 124))	('methyl-CpG binding', 'molecular_function', 'GO:0008327', ('97', '115'))	('mutations', 'Var', (78, 87))	('MBD4', 'Gene', (91, 95))	('methyl-CpG binding domain 4', 'Gene', (97, 124))
49675	31330784	MBD4 plays a role in repairing DNA mismatches and its inactivation leads to a hypermutated tumor profile that is sensitive to immune checkpoint inhibitors.	('DNA', 'Var', (31, 34))	('leads to', 'Reg', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('MBD4', 'Gene', '8930', (0, 4))	('MBD4', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('tumor', 'Disease', (91, 96))	('inactivation', 'Var', (54, 66))
49680	31330784	For instance, treatment with inhibitors of the apoptotic proteins Bcl2/xL coupled with alkylating agents has been shown to trigger tumor growth inhibition in UM PDXs (Patient-Derived Xenografts).	('inhibitors', 'Var', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('Bcl2', 'Gene', (66, 70))	('tumor', 'Disease', (131, 136))	('apoptotic', 'Protein', (47, 56))	('Bcl2', 'molecular_function', 'GO:0015283', ('66', '70'))	('Patient', 'Species', '9606', (167, 174))	('UM', 'Phenotype', 'HP:0007716', (158, 160))	('Bcl2', 'Gene', '596', (66, 70))
49681	31330784	Clinical studies have failed to provide a therapeutic benefit due to strong adverse effects, although preclinical investigations of Bcl2 and Mdm2 inhibitors have confirmed their antitumorigenic effect in UM.	('inhibitors', 'Var', (146, 156))	('tumor', 'Disease', (182, 187))	('Mdm2', 'Gene', '4193', (141, 145))	('UM', 'Phenotype', 'HP:0007716', (204, 206))	('Bcl2', 'molecular_function', 'GO:0015283', ('132', '136'))	('Bcl2', 'Gene', (132, 136))	('Bcl2', 'Gene', '596', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('Mdm2', 'Gene', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
49682	31330784	Evaluation of other strategies to re-activate p53, including inhibitors of Mdm4, a homolog of Mdm2, may offer good alternatives.	('Mdm4', 'Gene', '4194', (75, 79))	('inhibitors', 'Var', (61, 71))	('Mdm2', 'Gene', '4193', (94, 98))	('p53', 'Gene', (46, 49))	('p53', 'Gene', '7157', (46, 49))	('Mdm4', 'Gene', (75, 79))	('Mdm2', 'Gene', (94, 98))
49688	31330784	Cotherapy with HDACi and CDKi has been shown to induce cell death in UM cell lines.	('Cotherapy', 'Var', (0, 9))	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('cell death', 'biological_process', 'GO:0008219', ('55', '65'))	('HDAC', 'Gene', (15, 19))	('HDAC', 'Gene', '9734', (15, 19))	('cell death', 'CPA', (55, 65))	('CD', 'Chemical', 'MESH:D002104', (25, 27))
49698	31330784	Therefore, blocking HGF-cMET signaling can resensitize the tumor cells to MEK inhibitors.	('signaling', 'biological_process', 'GO:0023052', ('29', '38'))	('cMET', 'Gene', (24, 28))	('MEK', 'Gene', '5609', (74, 77))	('tumor', 'Disease', (59, 64))	('HGF', 'Gene', (20, 23))	('HGF', 'Gene', '3082', (20, 23))	('blocking', 'Var', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('cMET', 'Gene', '4233', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('MEK', 'Gene', (74, 77))
49702	31330784	There is growing evidence that PTEN is downregulated by miRNAs in UM.	('miRNAs', 'Var', (56, 62))	('PTEN', 'Gene', (31, 35))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('PTEN', 'Gene', '5728', (31, 35))	('downregulated', 'NegReg', (39, 52))
49705	31330784	Inhibitors of NF-kB signaling synergized with BET inhibition in vitro and in vivo, which suggested that the inhibition of NF-kB signaling may improve the efficacy of BET inhibition in patients with advanced UM.	('signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('patients', 'Species', '9606', (184, 192))	('UM', 'Phenotype', 'HP:0007716', (207, 209))	('efficacy', 'MPA', (154, 162))	('improve', 'PosReg', (142, 149))	('NF-kB', 'Protein', (122, 127))	('inhibition', 'Var', (108, 118))	('BET inhibition', 'MPA', (166, 180))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))
49711	31330784	As previously stated, these cases are characterized by a hypermutated profile due to the presence of a germline loss-of-function mutation in MBD4.	('loss-of-function', 'NegReg', (112, 128))	('MBD4', 'Gene', '8930', (141, 145))	('MBD4', 'Gene', (141, 145))	('mutation', 'Var', (129, 137))
49712	31330784	First, a Galphaq-pathway activating mutation in either GNAQ, GNA11, CYSLTR2 (cysteinyl leukotriene receptor 2), or PLCbeta4 (phospholipase C beta4),.	('CYSLTR2', 'Gene', (68, 75))	('GNAQ', 'Gene', (55, 59))	('GNA11', 'Gene', '2767', (61, 66))	('GNA11', 'Gene', (61, 66))	('Galphaq', 'Gene', (9, 16))	('PLCbeta4', 'Gene', '5332', (115, 123))	('cysteinyl leukotriene receptor 2', 'Gene', '57105', (77, 109))	('Galphaq', 'Gene', '2776', (9, 16))	('phospholipase C beta4', 'Gene', (125, 146))	('cysteinyl leukotriene receptor 2', 'Gene', (77, 109))	('phospholipase C beta4', 'Gene', '5332', (125, 146))	('CYSLTR2', 'Gene', '57105', (68, 75))	('mutation', 'Var', (36, 44))	('PLCbeta4', 'Gene', (115, 123))
49713	31330784	Second, a mutation in either BAP1, SF3B1 (splicing factor 3b subunit 1), SRSF2 (serine/arginine-rich splicing factor 2), or EIF1AX (eukaryotic translation initiation factor 1A X-linked) (Figure 1a,b).	('SF3B1', 'Gene', '23451', (35, 40))	('EIF1AX', 'Gene', (124, 130))	('serine/arginine-rich splicing factor 2', 'Gene', (80, 118))	('serine/arginine-rich splicing factor 2', 'Gene', '6427', (80, 118))	('splicing', 'biological_process', 'GO:0045292', ('42', '50'))	('splicing', 'biological_process', 'GO:0045292', ('101', '109'))	('SRSF2', 'Gene', '6427', (73, 78))	('mutation', 'Var', (10, 18))	('BAP1', 'Gene', '8314', (29, 33))	('splicing factor 3b subunit 1', 'Gene', '23451', (42, 70))	('SF3B1', 'Gene', (35, 40))	('eukaryotic translation initiation factor 1A X-linked', 'Gene', '1964', (132, 184))	('splicing factor 3b subunit 1', 'Gene', (42, 70))	('SRSF2', 'Gene', (73, 78))	('BAP1', 'Gene', (29, 33))	('translation initiation', 'biological_process', 'GO:0006413', ('143', '165'))
49715	31330784	The first UM driver event consists of mutations that activate the Galphaq pathway.	('mutations', 'Var', (38, 47))	('UM', 'Phenotype', 'HP:0007716', (10, 12))	('Galphaq', 'Gene', '2776', (66, 73))	('Galphaq', 'Gene', (66, 73))
49716	31330784	GNAQ/11 mutations are reported in approximately 96% of UM patients, mainly at codon Q209 and less recurrently at R183 or G48.	('GNAQ/11', 'Gene', (0, 7))	('R183', 'Var', (113, 117))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('G48', 'Var', (121, 124))	('codon Q209', 'Var', (78, 88))	('patients', 'Species', '9606', (58, 66))
49718	31330784	PLCbeta4 hotspot mutation is located at p.D630, the region corresponding to the phospholipase C beta-4 catalytic domain, and CYSLTR2 mutation encodes an L129 substitution.	('PLCbeta4', 'Gene', '5332', (0, 8))	('phospholipase C beta-4', 'Gene', '5332', (80, 102))	('phospholipase C beta-4', 'Gene', (80, 102))	('PLCbeta4', 'Gene', (0, 8))	('CYSLTR2', 'Gene', '57105', (125, 132))	('L129', 'Var', (153, 157))	('CYSLTR2', 'Gene', (125, 132))	('p.D630', 'Var', (40, 46))
49719	31330784	These mutations are mutually exclusive hotspot mutations that activate the Galphaq signaling, thereby stressing the importance of this pathway in UM oncogenesis (Figure 2).	('oncogenesis', 'biological_process', 'GO:0007048', ('149', '160'))	('UM', 'Phenotype', 'HP:0007716', (146, 148))	('activate', 'PosReg', (62, 70))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('Galphaq', 'Gene', (75, 82))	('Galphaq', 'Gene', '2776', (75, 82))	('mutations', 'Var', (6, 15))
49723	31330784	GNAQ/11 mutations lead to a constitutively active alpha subunit, which results in a dysregulation of several downstream pathways including Akt/mTOR, Wnt/beta-catenin, Rac/Rho, MAPK, and PI3K pathways.	('GNAQ/11', 'Gene', (0, 7))	('dysregulation', 'MPA', (84, 97))	('Akt', 'Gene', '207', (139, 142))	('MAPK', 'Pathway', (176, 180))	('results in', 'Reg', (71, 81))	('MAPK', 'molecular_function', 'GO:0004707', ('176', '180'))	('Akt', 'Gene', (139, 142))	('beta-catenin', 'Gene', (153, 165))	('mutations', 'Var', (8, 17))	('Rac', 'Gene', '207', (167, 170))	('PI3K pathways', 'Pathway', (186, 199))	('mTOR', 'Gene', '2475', (143, 147))	('PI3K', 'molecular_function', 'GO:0016303', ('186', '190'))	('lead', 'Reg', (18, 22))	('mTOR', 'Gene', (143, 147))	('beta-catenin', 'Gene', '1499', (153, 165))	('Rac', 'Gene', (167, 170))	('alpha subunit', 'Protein', (50, 63))
49725	31330784	Moreover, mouse models that harbor GNAQ/11 mutations develop multiple tumors, which confirms the oncogenic impact of these mutations.	('mouse', 'Species', '10090', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('GNAQ/11', 'Gene', (35, 42))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('mutations', 'Var', (43, 52))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('develop', 'PosReg', (53, 60))
49726	31330784	Mice with melanocyte-specific expression of GNA11Q209L recapitulated human Gq-associated melanomas and developed pigmented neoplastic lesions from the melanocytes of the skin and non-cutaneous organs, including the eye and leptomeninges, as well as atypical sites, such as the lymph nodes and lungs.	('neoplastic lesions', 'Phenotype', 'HP:0002664', (123, 141))	('GNA11Q209L', 'Var', (44, 54))	('developed', 'PosReg', (103, 112))	('melanomas', 'Disease', (89, 98))	('human', 'Species', '9606', (69, 74))	('neoplastic lesions from the melanocytes of the skin', 'Phenotype', 'HP:0002861', (123, 174))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('melanomas', 'Disease', 'MESH:D008545', (89, 98))	('pigmented neoplastic', 'Disease', (113, 133))	('pigmented neoplastic', 'Disease', 'MESH:D010859', (113, 133))	('Mice', 'Species', '10090', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('Gq-associated', 'Gene', (75, 88))
49727	31330784	Galphaq/11 inhibitors development has been a major concern over the last two decades, given the high recurrence of GNAQ and GNA11 mutations in UM.	('GNA11', 'Gene', '2767', (124, 129))	('GNAQ', 'Gene', (115, 119))	('Galphaq', 'Gene', (0, 7))	('Galphaq', 'Gene', '2776', (0, 7))	('mutations', 'Var', (130, 139))	('UM', 'Phenotype', 'HP:0007716', (143, 145))	('GNA11', 'Gene', (124, 129))
49729	31330784	Interestingly, YM was shown to inhibit R183 Galphaq mutant rather than Q209L Galphaq mutant.	('Q209L', 'Var', (71, 76))	('R183', 'Var', (39, 43))	('Q209L', 'Mutation', 'rs121913492', (71, 76))	('Galphaq', 'Gene', (77, 84))	('Galphaq', 'Gene', (44, 51))	('Galphaq', 'Gene', '2776', (77, 84))	('inhibit', 'NegReg', (31, 38))	('Galphaq', 'Gene', '2776', (44, 51))
49731	31330784	FR mainly inhibits Q209L, Q209P, and Q209L Galphaq/11 mutants, promoting UM cell cycle arrest and cell death.	('cell death', 'CPA', (98, 108))	('Galphaq', 'Gene', (43, 50))	('Q209L', 'Var', (19, 24))	('promoting', 'PosReg', (63, 72))	('inhibits', 'NegReg', (10, 18))	('Galphaq', 'Gene', '2776', (43, 50))	('arrest', 'Disease', 'MESH:D006323', (87, 93))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (76, 93))	('UM', 'Phenotype', 'HP:0007716', (73, 75))	('Q209P', 'Var', (26, 31))	('Q209P', 'Mutation', 'rs121913492', (26, 31))	('Q209L', 'Mutation', 'rs121913492', (19, 24))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('76', '93'))	('Q209L', 'Mutation', 'rs121913492', (37, 42))	('arrest', 'Disease', (87, 93))	('cell death', 'biological_process', 'GO:0008219', ('98', '108'))	('Q209L', 'Var', (37, 42))
49732	31330784	Despite the promising results of Galphaq/11 inhibitors in vitro, such inhibitors have not yet been evaluated for clinical application.	('Galphaq', 'Gene', '2776', (33, 40))	('inhibitors', 'Var', (44, 54))	('Galphaq', 'Gene', (33, 40))
49735	31330784	The inhibitors of MEK and PI3K (MEKi, PI3Ki) separately show a modest apoptotic effect on GNAQ/11-mutated UM cell lines that is significantly increased upon combination.	('increased', 'PosReg', (142, 151))	('UM', 'Phenotype', 'HP:0007716', (106, 108))	('MEK', 'Gene', (18, 21))	('PI3K', 'molecular_function', 'GO:0016303', ('26', '30'))	('MEK', 'Gene', '5609', (18, 21))	('apoptotic', 'CPA', (70, 79))	('MEK', 'Gene', (32, 35))	('MEK', 'Gene', '5609', (32, 35))	('PI3K', 'Var', (26, 30))
49736	31330784	Similarly, PI3Ki and mTORi exhibit an apoptotic effect in a wide range of UM cells and tumor growth inhibition in vivo.	('PI3Ki', 'Var', (11, 16))	('apoptotic effect', 'CPA', (38, 54))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mTOR', 'Gene', (21, 25))	('mTOR', 'Gene', '2475', (21, 25))
49742	31330784	In UM, inhibiting ARF6 induces a decrease in proliferation in vitro and tumorigenesis in vivo.	('ARF6', 'Gene', '382', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('inhibiting', 'Var', (7, 17))	('decrease', 'NegReg', (33, 41))	('proliferation', 'CPA', (45, 58))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('ARF6', 'Gene', (18, 22))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
49743	31330784	Moreover, activated ARF6 triggers the transport of beta-catenin to the nucleus, where it can activate transcription factors, thereby promoting invasion and metastasis.	('transcription', 'biological_process', 'GO:0006351', ('102', '115'))	('activated', 'Var', (10, 19))	('nucleus', 'cellular_component', 'GO:0005634', ('71', '78'))	('ARF6', 'Gene', '382', (20, 24))	('beta-catenin', 'Gene', '1499', (51, 63))	('transport of', 'MPA', (38, 50))	('transport', 'biological_process', 'GO:0006810', ('38', '47'))	('ARF6', 'Gene', (20, 24))	('triggers', 'Reg', (25, 33))	('activate', 'PosReg', (93, 101))	('transcription', 'Protein', (102, 115))	('promoting', 'PosReg', (133, 142))	('beta-catenin', 'Gene', (51, 63))
49744	31330784	beta-catenin is the main node in the canonical Wnt pathway, which plays a vital role in embryonic development and it is known to be mutated in various cancers.	('canonical Wnt pathway', 'Pathway', (37, 58))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('beta-catenin', 'Gene', '1499', (0, 12))	('mutated', 'Var', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancers', 'Disease', (151, 158))	('beta-catenin', 'Gene', (0, 12))
49746	31330784	Moreover, beta-catenin inhibition was shown to induce apoptosis and inhibit cell growth, invasion, and migration in vitro.	('apoptosis', 'CPA', (54, 63))	('beta-catenin', 'Gene', (10, 22))	('inhibition', 'Var', (23, 33))	('cell growth', 'biological_process', 'GO:0016049', ('76', '87'))	('beta-catenin', 'Gene', '1499', (10, 22))	('inhibit', 'NegReg', (68, 75))	('invasion', 'CPA', (89, 97))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))	('cell growth', 'CPA', (76, 87))
49752	31330784	All the UM cell lines harboring GNAQ/11 mutations exhibit low YAP phosphorylation and nuclear localization, which indicates YAP activation.	('nuclear localization', 'MPA', (86, 106))	('YAP', 'Gene', '10413', (124, 127))	('localization', 'biological_process', 'GO:0051179', ('94', '106'))	('UM', 'Phenotype', 'HP:0007716', (8, 10))	('YAP', 'Gene', (124, 127))	('low', 'NegReg', (58, 61))	('mutations', 'Var', (40, 49))	('GNAQ/11', 'Gene', (32, 39))	('YAP', 'Gene', '10413', (62, 65))	('phosphorylation', 'biological_process', 'GO:0016310', ('66', '81'))	('YAP', 'Gene', (62, 65))
49753	31330784	The cell growth of GNAQ/11-mutated UM cells is significantly decreased upon YAP knockdown or inhibition.	('inhibition', 'NegReg', (93, 103))	('knockdown', 'Var', (80, 89))	('YAP', 'Gene', '10413', (76, 79))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('YAP', 'Gene', (76, 79))	('cell growth', 'biological_process', 'GO:0016049', ('4', '15'))	('decreased', 'NegReg', (61, 70))	('cell growth', 'CPA', (4, 15))
49762	31330784	The second oncogenic event of UM consists of mutations in BAP1, EIF1AX, SF3B1, or SRSF2.	('mutations', 'Var', (45, 54))	('SRSF2', 'Gene', (82, 87))	('BAP1', 'Gene', (58, 62))	('SF3B1', 'Gene', (72, 77))	('EIF1AX', 'Gene', (64, 70))	('SRSF2', 'Gene', '6427', (82, 87))	('UM', 'Phenotype', 'HP:0007716', (30, 32))	('SF3B1', 'Gene', '23451', (72, 77))	('BAP1', 'Gene', '8314', (58, 62))
49763	31330784	BAP1 mutations are recurrently found to be associated with chromosome 3 monosomy in early metastatic risk cases.	('early metastatic risk', 'Disease', (84, 105))	('BAP1', 'Gene', (0, 4))	('chromosome 3', 'Disease', (59, 71))	('mutations', 'Var', (5, 14))	('associated', 'Reg', (43, 53))	('BAP1', 'Gene', '8314', (0, 4))	('chromosome', 'cellular_component', 'GO:0005694', ('59', '69'))
49764	31330784	Mutations on SF3B1 and SRSF2 are mainly associated with chromosome 3 disomy and a late-onset metastatic risk, while EIF1AX mutations are associated with chromosome 3 disomy and a low risk of metastasis (Figure 1a).	('SRSF2', 'Gene', (23, 28))	('disomy', 'Disease', (69, 75))	('disomy', 'Disease', 'MESH:D024182', (69, 75))	('SF3B1', 'Gene', (13, 18))	('disomy', 'Disease', (166, 172))	('disomy', 'Disease', 'MESH:D024182', (166, 172))	('chromosome', 'cellular_component', 'GO:0005694', ('153', '163'))	('chromosome', 'cellular_component', 'GO:0005694', ('56', '66'))	('Mutations', 'Var', (0, 9))	('SF3B1', 'Gene', '23451', (13, 18))	('SRSF2', 'Gene', '6427', (23, 28))	('associated', 'Reg', (40, 50))
49766	31330784	The expression of BAP1 is lost in up to 84% cases of metastatic UM, due to inactivating mutations.	('BAP1', 'Gene', '8314', (18, 22))	('lost', 'NegReg', (26, 30))	('metastatic UM', 'Disease', (53, 66))	('expression', 'MPA', (4, 14))	('BAP1', 'Gene', (18, 22))	('inactivating mutations', 'Var', (75, 97))	('UM', 'Phenotype', 'HP:0007716', (64, 66))
49767	31330784	BAP1 is mutated in 38% of primary UMs, mainly in tumors with monosomy 3, thereby being characteristic of belligerent tumors.	('monosomy 3', 'Var', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('BAP1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('mutated', 'Var', (8, 15))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('UM', 'Phenotype', 'HP:0007716', (34, 36))	('BAP1', 'Gene', '8314', (0, 4))	('primary UMs', 'Disease', (26, 37))
49769	31330784	Hence, BAP1 alterations are strongly correlated with a higher metastatic risk and reduced survival rate.	('metastatic', 'CPA', (62, 72))	('BAP1', 'Gene', (7, 11))	('alterations', 'Var', (12, 23))	('survival rate', 'CPA', (90, 103))	('reduced', 'NegReg', (82, 89))	('BAP1', 'Gene', '8314', (7, 11))
49772	31330784	Thus, the loss of BAP1 increases ubiquitinated expression and it may sensitize tumor cells to HDAC (histone deacetylase) inhibitors, like valproic acid, trichostatin A, LBH-589, and syberynalide hydroxamic acid.	('loss', 'Var', (10, 14))	('LBH', 'Gene', '81606', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('BAP1', 'Gene', '8314', (18, 22))	('trichostatin A', 'Chemical', 'MESH:C012589', (153, 167))	('tumor', 'Disease', (79, 84))	('syberynalide hydroxamic acid', 'Chemical', '-', (182, 210))	('HDAC', 'Gene', (94, 98))	('BAP1', 'Gene', (18, 22))	('HDAC', 'Gene', '9734', (94, 98))	('histone deacetylase', 'Gene', '9734', (100, 119))	('valproic acid', 'Chemical', 'MESH:D014635', (138, 151))	('LBH', 'Gene', (169, 172))	('histone deacetylase', 'Gene', (100, 119))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('sensitize', 'Reg', (69, 78))	('increases', 'PosReg', (23, 32))	('ubiquitinated expression', 'MPA', (33, 57))
49773	31330784	HDAC inhibition has been shown to stop cell proliferation, induce cell cycle arrest, trigger apoptosis, block migration, promote cell differentiation, and impact the gene expression profile in preclinical UM models.	('inhibition', 'Var', (5, 15))	('trigger', 'Reg', (85, 92))	('induce', 'PosReg', (59, 65))	('stop', 'NegReg', (34, 38))	('apoptosis', 'CPA', (93, 102))	('promote', 'PosReg', (121, 128))	('arrest', 'Disease', (77, 83))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (66, 83))	('cell differentiation', 'biological_process', 'GO:0030154', ('129', '149'))	('HDAC', 'Gene', '9734', (0, 4))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('migration', 'CPA', (110, 119))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('cell proliferation', 'CPA', (39, 57))	('HDAC', 'Gene', (0, 4))	('gene expression', 'biological_process', 'GO:0010467', ('166', '181'))	('gene expression profile', 'MPA', (166, 189))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('66', '83'))	('arrest', 'Disease', 'MESH:D006323', (77, 83))	('block', 'NegReg', (104, 109))	('UM', 'Phenotype', 'HP:0007716', (205, 207))	('cell differentiation', 'CPA', (129, 149))	('impact', 'Reg', (155, 161))
49784	31330784	These mutations are mainly associated with disomy 3 and present a low metastatic risk.	('disomy', 'Disease', (43, 49))	('disomy', 'Disease', 'MESH:D024182', (43, 49))	('associated', 'Reg', (27, 37))	('mutations', 'Var', (6, 15))
49785	31330784	EIF1AX encodes eukaryotic translation initiation factor 1A (eIF1A) and it is essential in the recruitment of the ternary complex and for assembling the 43S preinitiation complex (PIC).	('recruitment', 'MPA', (94, 105))	('EIF1AX', 'Var', (0, 6))	('translation initiation', 'biological_process', 'GO:0006413', ('26', '48'))	('ternary complex', 'MPA', (113, 128))	('PIC', 'cellular_component', 'GO:0019035', ('179', '182'))	('eIF1A', 'Gene', (60, 65))	('eIF1A', 'Gene', '1964', (60, 65))	('preinitiation complex', 'cellular_component', 'GO:0097550', ('156', '177'))	('eukaryotic translation initiation factor 1A', 'Gene', '1964', (15, 58))	('PIC', 'cellular_component', 'GO:0097550', ('179', '182'))	('eukaryotic translation initiation factor 1A', 'Gene', (15, 58))
49789	31330784	Very recently, EIF1AX and RAS mutations have been shown to cooperate to induce tumorigenesis in isogenic cell lines and mice.	('mice', 'Species', '10090', (120, 124))	('tumor', 'Disease', (79, 84))	('induce', 'Reg', (72, 78))	('EIF1AX', 'Gene', (15, 21))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('RAS', 'Gene', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
49790	31330784	EIF1AX-A113splice variants, which are recurrent in advanced thyroid cancer, stabilize the PIC and enable a general increase in protein synthesis through ATF4-induced dephosphorylation of EIF2alpha.	('stabilize', 'Reg', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('PIC', 'cellular_component', 'GO:0097550', ('90', '93'))	('thyroid cancer', 'Disease', (60, 74))	('protein synthesis', 'MPA', (127, 144))	('protein synthesis', 'biological_process', 'GO:0006412', ('127', '144'))	('EIF2alpha', 'Gene', '83939', (187, 196))	('EIF2alpha', 'Gene', (187, 196))	('PIC', 'MPA', (90, 93))	('thyroid cancer', 'Disease', 'MESH:D013964', (60, 74))	('EIF1AX-A113splice variants', 'Var', (0, 26))	('ATF4', 'Gene', (153, 157))	('increase', 'PosReg', (115, 123))	('dephosphorylation', 'biological_process', 'GO:0016311', ('166', '183'))	('dephosphorylation', 'MPA', (166, 183))	('ATF4', 'Gene', '468', (153, 157))	('thyroid cancer', 'Phenotype', 'HP:0002890', (60, 74))	('EIF2', 'cellular_component', 'GO:0005850', ('187', '191'))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('PIC', 'cellular_component', 'GO:0019035', ('90', '93'))
49793	31330784	The splicing factor (SF) genes SF3B1, U2AF35, ZRSR2, and SRSF2 are recurrently mutated in hematological malignancies and solid tumors, which include UM.	('mutated', 'Var', (79, 86))	('solid tumors', 'Disease', 'MESH:D009369', (121, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('splicing factor', 'Gene', '10569', (4, 19))	('U2AF35', 'Gene', '7307', (38, 44))	('U2AF', 'cellular_component', 'GO:0089701', ('38', '42'))	('SF', 'Gene', '10569', (31, 33))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('ZRSR2', 'Gene', '8233', (46, 51))	('SF', 'Gene', '10569', (21, 23))	('hematological malignancies', 'Disease', 'MESH:D019337', (90, 116))	('splicing', 'biological_process', 'GO:0045292', ('4', '12'))	('hematological malignancies', 'Phenotype', 'HP:0004377', (90, 116))	('SF3B1', 'Gene', (31, 36))	('U2AF35', 'Gene', (38, 44))	('SRSF2', 'Gene', '6427', (57, 62))	('solid tumors', 'Disease', (121, 133))	('SF', 'Gene', '10569', (59, 61))	('splicing factor', 'Gene', (4, 19))	('SRSF2', 'Gene', (57, 62))	('UM', 'Phenotype', 'HP:0007716', (149, 151))	('ZRSR2', 'Gene', (46, 51))	('hematological malignancies', 'Disease', (90, 116))	('SF3B1', 'Gene', '23451', (31, 36))
49794	31330784	It is noteworthy that the SF hotspot mutations take place in a mutually exclusive manner and they affect proteins that are involved in the 3' splice site (3'ss) recognition, an early step of splicing, resulting in specific aberrant splicing patterns.	('splicing', 'biological_process', 'GO:0045292', ('191', '199'))	('SF', 'Gene', '10569', (26, 28))	('proteins', 'Protein', (105, 113))	('mutations', 'Var', (37, 46))	('aberrant splicing patterns', 'MPA', (223, 249))	('affect', 'Reg', (98, 104))	('splicing', 'biological_process', 'GO:0045292', ('232', '240'))
49795	31330784	SF3B1 and SRSF2 mutations are recurrent in UMs and they lead to a change of function of the SF.	('UMs', 'Disease', (43, 46))	('SRSF2', 'Gene', '6427', (10, 15))	('SF3B1', 'Gene', (0, 5))	('SF', 'Gene', '10569', (12, 14))	('change', 'Reg', (66, 72))	('mutations', 'Var', (16, 25))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('SF3B1', 'Gene', '23451', (0, 5))	('SF', 'Gene', '10569', (92, 94))	('SRSF2', 'Gene', (10, 15))	('function', 'MPA', (76, 84))	('SF', 'Gene', '10569', (0, 2))
49796	31330784	Such events highlight the involvement of splicing aberrations in oncogenesis and the relevance of SF therapeutic targeting.	('splicing', 'biological_process', 'GO:0045292', ('41', '49'))	('splicing aberrations', 'Var', (41, 61))	('involvement', 'Reg', (26, 37))	('SF', 'Gene', '10569', (98, 100))	('oncogenesis', 'biological_process', 'GO:0007048', ('65', '76'))
49800	31330784	SRSF2 is most commonly mutated in chronic myelomonocytic leukemia (CMML) (47%) and myelodysplastic syndromes (MDS) (15%).	('MDS', 'Disease', (110, 113))	('MDS', 'Disease', 'MESH:D009190', (110, 113))	('MDS', 'Phenotype', 'HP:0002863', (110, 113))	('CMML', 'Disease', 'MESH:D054429', (67, 71))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (34, 65))	('SRSF2', 'Gene', (0, 5))	('chronic myelomonocytic leukemia', 'Disease', (34, 65))	('mutated', 'Var', (23, 30))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (83, 108))	('myelodysplastic syndromes', 'Disease', (83, 108))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (83, 108))	('SRSF2', 'Gene', '6427', (0, 5))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (34, 65))	('leukemia', 'Phenotype', 'HP:0001909', (57, 65))	('CMML', 'Disease', (67, 71))	('CMML', 'Phenotype', 'HP:0012325', (67, 71))
49801	31330784	Recently, SRSF2 has also been found to be mutated in 4% of UMs.	('SRSF2', 'Gene', '6427', (10, 15))	('mutated', 'Var', (42, 49))	('UMs', 'Disease', (59, 62))	('SRSF2', 'Gene', (10, 15))	('UM', 'Phenotype', 'HP:0007716', (59, 61))
49802	31330784	Upon hotspot mutations at P95m which is located downstream the RRM, SRSF2 undergoes a conformational change on the RRM, and consequently acquires more affinity for G-rich versus C-rich ESEs motifs, differently from the WT, which has an equal affinity for these motifs.	('P95m', 'Var', (26, 30))	('SRSF2', 'Gene', (68, 73))	('affinity', 'MPA', (151, 159))	('conformational change', 'MPA', (86, 107))	('SRSF2', 'Gene', '6427', (68, 73))	('more', 'PosReg', (146, 150))	('C-rich', 'MPA', (178, 184))	('undergoes', 'Reg', (74, 83))	('G-rich', 'Protein', (164, 170))	('mutations', 'Var', (13, 22))
49803	31330784	The resulting misregulated exon inclusion causes an aberrant splicing pattern of a broad range of genes comprising the tumor suppressor ARMC10 or EZH2.	('splicing', 'biological_process', 'GO:0045292', ('61', '69'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('119', '135'))	('causes', 'Reg', (42, 48))	('tumor suppressor', 'Gene', (119, 135))	('EZH2', 'Gene', '2146', (146, 150))	('splicing pattern', 'MPA', (61, 77))	('ARMC10', 'Gene', '83787', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('EZH2', 'Gene', (146, 150))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('119', '135'))	('tumor suppressor', 'Gene', '7248', (119, 135))	('aberrant', 'MPA', (52, 60))	('ARMC10', 'Gene', (136, 142))	('misregulated', 'Reg', (14, 26))	('exon inclusion', 'Var', (27, 41))
49804	31330784	The mis-spliced form of EZH2 is sensitive to nonsense-mediated RNA decay (NMD), which implies a decrease in EZH2 levels which has already been observed in MDS progression.	('MDS', 'Disease', (155, 158))	('MDS', 'Disease', 'MESH:D009190', (155, 158))	('MDS', 'Phenotype', 'HP:0002863', (155, 158))	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))	('EZH2', 'Gene', '2146', (24, 28))	('EZH2', 'Gene', (24, 28))	('decrease', 'NegReg', (96, 104))	('EZH2', 'Gene', (108, 112))	('EZH2', 'Gene', '2146', (108, 112))	('nonsense-mediated', 'Var', (45, 62))
49805	31330784	In fact, EZH2 and SRSF2 mutations take place in a mutually exclusive manner.	('SRSF2', 'Gene', '6427', (18, 23))	('EZH2', 'Gene', '2146', (9, 13))	('SRSF2', 'Gene', (18, 23))	('EZH2', 'Gene', (9, 13))	('mutations', 'Var', (24, 33))
49806	31330784	Even though the SRSF2 mutation rate is low in UM, it may be a significant event, given the cascade effect of misrecognition of ESEs on a large number of target genes.	('SRSF2', 'Gene', (16, 21))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('mutation', 'Var', (22, 30))	('SRSF2', 'Gene', '6427', (16, 21))
49807	31330784	SF3B1 encodes the U2 small nuclear riboprotein complex (U2-snRNP) that is responsible for branchpoint (BP) recognition and it is mutated in 23% of UMs.	('BP', 'Chemical', '-', (103, 105))	('SF3B1', 'Gene', (0, 5))	('SF3B1', 'Gene', '23451', (0, 5))	('snRNP', 'molecular_function', 'GO:0003734', ('59', '64'))	('mutated', 'Var', (129, 136))	('UM', 'Phenotype', 'HP:0007716', (147, 149))	('U2-snRNP', 'cellular_component', 'GO:0005686', ('56', '64'))
49811	31330784	Hotspot mutations target the HEAT repeats at codons R625, K666, and K700.	('K700', 'Var', (68, 72))	('HEAT', 'Disease', (29, 33))	('HEAT', 'Disease', 'None', (29, 33))	('K666', 'Var', (58, 62))
49812	31330784	Hotspot mutation K700 prevails in hematological malignancies, whereas the R625 and K666 mutations prevail in UM and they are frequently associated with disomy 3 and a late metastatic risk.	('K666', 'Var', (83, 87))	('hematological malignancies', 'Disease', (34, 60))	('R625', 'Var', (74, 78))	('disomy', 'Disease', (152, 158))	('disomy', 'Disease', 'MESH:D024182', (152, 158))	('hematological malignancies', 'Disease', 'MESH:D019337', (34, 60))	('UM', 'Phenotype', 'HP:0007716', (109, 111))	('hematological malignancies', 'Phenotype', 'HP:0004377', (34, 60))	('K700', 'Var', (17, 21))	('associated with', 'Reg', (136, 151))
49813	31330784	SF3B1 mutations have been thoroughly investigated and were reported to induce an aberrant splicing pattern by an alternative 3'ss usage upstream the canonical 3'ss in breast cancer, CLL, and UM.	('aberrant splicing pattern', 'MPA', (81, 106))	('SF3B1', 'Gene', (0, 5))	('breast cancer', 'Disease', (167, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('splicing', 'biological_process', 'GO:0045292', ('90', '98'))	('SF3B1', 'Gene', '23451', (0, 5))	('UM', 'Phenotype', 'HP:0007716', (191, 193))	('CLL', 'Disease', 'MESH:D015451', (182, 185))	('induce', 'Reg', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('mutations', 'Var', (6, 15))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))	('CLL', 'Disease', (182, 185))
49814	31330784	SF3B1 mutations generate change-of-function mutants, leading to aberrant splicing of less than 1% of all splice junctions by recognizing an alternative BP localized at 11-14 nts upstream the canonical site.	('SF3B1', 'Gene', (0, 5))	('splicing', 'biological_process', 'GO:0045292', ('73', '81'))	('BP', 'Chemical', '-', (152, 154))	('SF3B1', 'Gene', '23451', (0, 5))	('splicing', 'MPA', (73, 81))	('mutations', 'Var', (6, 15))
49816	31330784	Microbial and natural metabolites that inhibit splicing were the first candidates, including FR901464 and derivatives.	('splicing', 'biological_process', 'GO:0045292', ('47', '55'))	('splicing', 'MPA', (47, 55))	('FR901464', 'Chemical', 'MESH:C104486', (93, 101))	('FR901464', 'Var', (93, 101))
49824	31330784	E7107 has been tested on clinical trials in various solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('solid tumors', 'Disease', 'MESH:D009369', (52, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('E7107', 'Var', (0, 5))	('solid tumors', 'Disease', (52, 64))
49827	31330784	Cells harboring SF3B1 mutations presented higher sensitivity to this inhibitor than cells with WT SF3B1, a feature that may overcome the high cytotoxicity of splicing inhibition.	('cytotoxicity', 'Disease', 'MESH:D064420', (142, 154))	('SF3B1', 'Gene', '23451', (16, 21))	('SF3B1', 'Gene', '23451', (98, 103))	('sensitivity', 'MPA', (49, 60))	('splicing', 'biological_process', 'GO:0045292', ('158', '166'))	('higher', 'PosReg', (42, 48))	('mutations', 'Var', (22, 31))	('cytotoxicity', 'Disease', (142, 154))	('SF3B1', 'Gene', (16, 21))	('SF3B1', 'Gene', (98, 103))
49828	31330784	The preferential inhibition is associated with an enrichment of alternative 3'ss in SF3B1 mutant cells as compared to WT cells.	('SF3B1', 'Gene', (84, 89))	('mutant', 'Var', (90, 96))	('SF3B1', 'Gene', '23451', (84, 89))
49829	31330784	Further studies are ongoing to confirm the specificity of H3B-8800 in vivo and in a clinical trial in patients with advanced myeloid malignancies, including MDS, AML, and CMML (NCT02841540).	('MDS', 'Disease', 'MESH:D009190', (157, 160))	('CMML', 'Disease', (171, 175))	('CMML', 'Phenotype', 'HP:0012325', (171, 175))	('myeloid malignancies', 'Disease', 'MESH:D009369', (125, 145))	('patients', 'Species', '9606', (102, 110))	('AML', 'Disease', (162, 165))	('H3B-8800', 'Var', (58, 66))	('CMML', 'Disease', 'MESH:D054429', (171, 175))	('NCT02841540', 'Var', (177, 188))	('myeloid malignancies', 'Disease', (125, 145))	('MDS', 'Disease', (157, 160))	('H3', 'Chemical', 'MESH:C012616', (58, 60))	('AML', 'Disease', 'MESH:D015470', (162, 165))	('MDS', 'Phenotype', 'HP:0002863', (157, 160))
49830	31330784	New perspectives also emerged from the studies of neopeptides that were generated by the aberrant transcripts in SF3B1-mutant cells.	('aberrant', 'Var', (89, 97))	('SF3B1', 'Gene', '23451', (113, 118))	('SF3B1', 'Gene', (113, 118))
49833	31330784	Recently-reported exceptional immune responses in UM patients harboring MBD4 mutations point up the importance of deciphering cancer mechanisms in order to determine the oncogenic actors and develop the appropriate therapeutic strategies.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('immune responses', 'CPA', (30, 46))	('patients', 'Species', '9606', (53, 61))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('mutations', 'Var', (77, 86))	('MBD4', 'Gene', '8930', (72, 76))	('MBD4', 'Gene', (72, 76))
49876	30867659	The coupled beads were counted using a Coulter Z2 counter, validated using biotinylated rabbit anti-mouse (B8520) or rabbit anti-goat (B7014) IgG antibodies (Sigma-Aldrich, St. Louis, MO), and stored in storage buffer at 4oC in the dark.	('rabbit', 'Species', '9986', (117, 123))	('IgG antibodies', 'Protein', (142, 156))	('goat', 'Species', '9925', (129, 133))	('rabbit', 'Species', '9986', (88, 94))	('mouse', 'Species', '10090', (100, 105))	('B8520', 'Var', (107, 112))	('IgG antibodies', 'Phenotype', 'HP:0003237', (142, 156))	('storage', 'biological_process', 'GO:0051235', ('203', '210'))
49964	30092184	Further, Class 1 tumors have been shown to harbor mutations in the translation elongation factor EIF1AX and the splicing factor SF3B1, whereas Class 2 tumors are strongly associated with mutations in the tumor suppressor gene BAP1.	('EIF1AX', 'Gene', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumors', 'Disease', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('translation elongation', 'biological_process', 'GO:0006414', ('67', '89'))	('splicing', 'biological_process', 'GO:0045292', ('112', '120'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('204', '220'))	('EIF1AX', 'Gene', '1964', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor suppressor', 'biological_process', 'GO:0051726', ('204', '220'))	('SF3B1', 'Gene', (128, 133))	('BAP1', 'Gene', '8314', (226, 230))	('associated', 'Reg', (171, 181))	('tumor', 'Disease', (17, 22))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('SF3B1', 'Gene', '23451', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('BAP1', 'Gene', (226, 230))	('mutations', 'Var', (50, 59))	('tumor', 'Disease', (151, 156))	('mutations', 'Var', (187, 196))	('tumor', 'Disease', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
49999	30092184	For patients without metastasis after >=5 years follow-up (n=45), a false positive "high risk" result would have been given in 16 (35.6%) patients using the TNM, compared to 3 (6.7%) using GEP/PRAME.	('false', 'biological_process', 'GO:0071878', ('68', '73'))	('TNM', 'Var', (157, 160))	('false', 'biological_process', 'GO:0071877', ('68', '73'))	('PRAME', 'Gene', '23532', (193, 198))	('patients', 'Species', '9606', (4, 12))	('PRAME', 'Gene', (193, 198))	('patients', 'Species', '9606', (138, 146))
50015	30092184	This study will also formally compare the new GEP/PRAME model described here to the existing Class 1A/1B/2 system, as well as mutations in BAP1, SF3B1 and EIF1AX and chromosomal copy number changes.	('EIF1AX', 'Gene', '1964', (155, 161))	('EIF1AX', 'Gene', (155, 161))	('SF3B1', 'Gene', '23451', (145, 150))	('BAP1', 'Gene', '8314', (139, 143))	('SF3B1', 'Gene', (145, 150))	('mutations', 'Var', (126, 135))	('BAP1', 'Gene', (139, 143))	('PRAME', 'Gene', '23532', (50, 55))	('PRAME', 'Gene', (50, 55))
50072	29375706	The deviations between CT-1 and CT-2 (Delta1) and between CT-1 and CT-3 (Delta2) were calculated using the following formula: , where Deltax, Deltay and Deltaz represent the left-right, up-down and forward-back deviations, respectively.	('CT-1', 'Gene', (58, 62))	('Deltaz', 'Var', (153, 159))	('CT-2', 'Gene', '30848', (32, 36))	('Delta1', 'Mutation', 'c.del1', (38, 44))	('Deltax', 'Var', (134, 140))	('CT-1', 'Gene', '1489', (23, 27))	('CT-1', 'Gene', (23, 27))	('CT-2', 'Gene', (32, 36))	('Deltay', 'Var', (142, 148))	('CT-1', 'Gene', '1489', (58, 62))	('CT-1 and CT-3', 'Gene', '1489;285782', (58, 71))
50141	28903377	Recent inhibitors of the interaction of programmed cell death protein 1 (PD-1) and its ligand PD-L1 are associated with good clinical responses in many malignancies.	('interaction', 'Interaction', (25, 36))	('programmed cell death protein 1', 'Gene', (40, 71))	('programmed cell death', 'biological_process', 'GO:0012501', ('40', '61'))	('PD-1', 'Gene', (73, 77))	('inhibitors', 'Var', (7, 17))	('malignancies', 'Disease', 'MESH:D009369', (152, 164))	('ligand', 'molecular_function', 'GO:0005488', ('87', '93'))	('programmed cell death protein 1', 'Gene', '5133', (40, 71))	('malignancies', 'Disease', (152, 164))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
50174	28903377	Kaplan-Meier analysis and log rank testing similarly showed that PD-L1 positive staining in the tumor was associated with a worse melanoma-related survival (p = 0.045; Figure 4).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('positive staining', 'Var', (71, 88))	('tumor', 'Disease', (96, 101))	('worse', 'NegReg', (124, 129))	('PD-L1', 'Gene', (65, 70))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Disease', (130, 138))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
50177	28903377	In order to see whether specific types of infiltrating leukocytes contributed to PD-L1 and PD-1 expression on tumor cells, we determined the presence of different subsets of T cells and myeloid cells in the same CM, by performing immunofluorescence (IF) staining according to previously described techniques: we measured the numbers of CD3, CD3+CD8+, CD3+CD8-, CD3+CD8-Foxp3+ and CD3+CD8-Foxp3- T cells, and CD68 (macrophages) and CD68+CD163+ (M2 macrophages) within tumor areas of 26 primary CM sections.	('CD3', 'Gene', '397455', (351, 354))	('CD68', 'Var', (408, 412))	('CD3+CD8', 'Gene', '925', (341, 348))	('CD3+CD8', 'Gene', (361, 368))	('CD3', 'Gene', (361, 364))	('CD3', 'Gene', '397455', (380, 383))	('CM', 'Phenotype', 'HP:0007716', (493, 495))	('tumor', 'Phenotype', 'HP:0002664', (467, 472))	('CD3', 'Gene', '397455', (341, 344))	('CD3', 'Gene', (336, 339))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('CD3', 'Gene', (351, 354))	('CD3+CD8', 'Gene', (351, 358))	('CD3+CD8', 'Gene', (380, 387))	('CD3', 'Gene', (380, 383))	('CD68+CD163+', 'Var', (431, 442))	('CD3', 'Gene', (341, 344))	('CD3+CD8', 'Gene', (341, 348))	('CD3+CD8', 'Gene', '925', (361, 368))	('tumor', 'Disease', (467, 472))	('CD3', 'Gene', '397455', (361, 364))	('tumor', 'Disease', (110, 115))	('CD3+CD8', 'Gene', '925', (351, 358))	('CM', 'Phenotype', 'HP:0007716', (212, 214))	('CD3+CD8', 'Gene', '925', (380, 387))	('tumor', 'Disease', 'MESH:D009369', (467, 472))	('CD3', 'Gene', '397455', (336, 339))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
50218	28903377	Compared to one study of cutaneous melanoma metastasis, the density of CD3 and CD68CD163 was similar, with a higher density of CD4 and Foxp3, and lower density of CD8 cells.	('CD4', 'Gene', '920', (127, 130))	('CD68CD163', 'Chemical', '-', (79, 88))	('Foxp3', 'Var', (135, 140))	('cutaneous melanoma metastasis', 'Disease', (25, 54))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (25, 43))	('higher', 'PosReg', (109, 115))	('cutaneous melanoma metastasis', 'Disease', 'MESH:D009362', (25, 54))	('CD3', 'Gene', '397455', (71, 74))	('CD8', 'Gene', (163, 166))	('CD3', 'Gene', (71, 74))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('CD8', 'Gene', '925', (163, 166))	('CD4', 'Gene', (127, 130))
50219	28903377	We find no association between tumoral or stromal PD-L1 positivity and the density of TILs.	('tumoral', 'Disease', (31, 38))	('tumoral', 'Disease', 'MESH:D009369', (31, 38))	('positivity', 'Var', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))
50252	27827359	VM vessels are also observed in 9/10 CTC patient-derived explants (CDX), where molecular analysis of fractionated VE-cadherin-positive cells uncovered copy-number alterations and mutated TP53, confirming human tumour origin.	('copy-number alterations', 'Var', (151, 174))	('TP53', 'Gene', '7157', (187, 191))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('patient', 'Species', '9606', (41, 48))	('TP53', 'Gene', (187, 191))	('tumour', 'Disease', 'MESH:D009369', (210, 216))	('human', 'Species', '9606', (204, 209))	('rat', 'Species', '10116', (167, 170))	('cadherin', 'molecular_function', 'GO:0008014', ('117', '125'))	('CDX', 'Chemical', '-', (67, 70))	('tumour', 'Disease', (210, 216))	('mutated', 'Var', (179, 186))
50284	27827359	For 24 of the ES SCLC patients' blood samples assessed by ISET, we were able to access a matched needle-core biopsy in which to evaluate VM using PAS and anti-human anti-CD31 IHC.	('anti-human', 'Var', (154, 164))	('PAS', 'Chemical', '-', (146, 149))	('patients', 'Species', '9606', (22, 30))	('human', 'Species', '9606', (159, 164))	('PAS', 'cellular_component', 'GO:0000407', ('146', '149'))	('core', 'cellular_component', 'GO:0019013', ('104', '108'))	('SCLC', 'Gene', '7864', (17, 21))	('SCLC', 'Phenotype', 'HP:0030357', (17, 21))	('SCLC', 'Gene', (17, 21))
50319	27827359	Although some differences were seen between CDX3a and CDX3b, there was striking similarity across all CNA profiles and all harboured characteristic chromosome 17p loss, a hallmark of SCLC (Fig.	('SCLC', 'Gene', '7864', (183, 187))	('SCLC', 'Phenotype', 'HP:0030357', (183, 187))	('SCLC', 'Gene', (183, 187))	('loss', 'NegReg', (163, 167))	('chromosome 17p', 'Var', (148, 162))	('chromosome', 'cellular_component', 'GO:0005694', ('148', '158'))
50331	27827359	Although loss of chromosome 17p (harbouring TP53, seen in 50-60% of SCLC) was not seen in this patient, targeted sequencing of their ctDNA identified non-synonymous TP53 and RB1 mutations (Supplementary Table 5) in keeping with the frequent mutation of these genes in SCLC.	('RB1', 'Gene', '5925', (174, 177))	('SCLC', 'Gene', (268, 272))	('patient', 'Species', '9606', (95, 102))	('TP53', 'Gene', (165, 169))	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('SCLC', 'Gene', '7864', (268, 272))	('SCLC', 'Phenotype', 'HP:0030357', (268, 272))	('SCLC', 'Gene', '7864', (68, 72))	('SCLC', 'Gene', (68, 72))	('TP53', 'Gene', '7157', (165, 169))	('TP53', 'Gene', '7157', (44, 48))	('RB1', 'Gene', (174, 177))	('SCLC', 'Phenotype', 'HP:0030357', (68, 72))	('mutations', 'Var', (178, 187))	('TP53', 'Gene', (44, 48))
50339	27827359	VE-cadherin KD cells grown as xenografts maintained a significant reduction in VE-cadherin expression (using the human-specific antibody) throughout the study (91.0 versus 1.5% of tumour cells stain for human VE-cadherin for H446 parental versus H446 VE-cadherin KD, P<0.0001; Fig.	('expression', 'MPA', (91, 101))	('cadherin', 'molecular_function', 'GO:0008014', ('82', '90'))	('antibody', 'cellular_component', 'GO:0019814', ('128', '136'))	('stain', 'Reg', (193, 198))	('human', 'Species', '9606', (113, 118))	('H446', 'Var', (246, 250))	('antibody', 'molecular_function', 'GO:0003823', ('128', '136'))	('reduction', 'NegReg', (66, 75))	('antibody', 'cellular_component', 'GO:0042571', ('128', '136'))	('cadherin', 'molecular_function', 'GO:0008014', ('3', '11'))	('VE-cadherin', 'Protein', (79, 90))	('H446 parental', 'Var', (225, 238))	('human', 'Species', '9606', (203, 208))	('cadherin', 'molecular_function', 'GO:0008014', ('212', '220'))	('antibody', 'cellular_component', 'GO:0019815', ('128', '136'))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('cadherin', 'molecular_function', 'GO:0008014', ('254', '262'))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('tumour', 'Disease', (180, 186))
50340	27827359	The reduction of tumour VE-cadherin expression correlated with reduction in VM vessels (9.36 versus 2.49 VM scores for parental H446 versus H446 VE-cadherin KD P=0.0005; Fig.	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('cadherin', 'molecular_function', 'GO:0008014', ('148', '156'))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('H446', 'Var', (140, 144))	('tumour', 'Disease', (17, 23))	('reduction', 'NegReg', (4, 13))	('reduction', 'NegReg', (63, 72))	('cadherin', 'molecular_function', 'GO:0008014', ('27', '35'))	('VM vessels', 'CPA', (76, 86))
50342	27827359	We hypothesized that the presence of VM might increase the delivery of chemotherapy into tumours.	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('increase', 'PosReg', (46, 54))	('tumours', 'Disease', 'MESH:D009369', (89, 96))	('tumours', 'Disease', (89, 96))	('presence', 'Var', (25, 33))
50346	27827359	8, left panel); 8.4 versus 4.0% of nuclei stained positively for cisplatin adducts in H446 parental versus H446 VE-cadherin KD xenografts (P=0.0052; Fig.	('H446 parental', 'Var', (86, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('cadherin', 'molecular_function', 'GO:0008014', ('115', '123'))	('cisplatin adducts', 'MPA', (65, 82))	('H446', 'Var', (107, 111))
50349	27827359	Knockdown of VE-cadherin led to a significant increase in sensitivity to cisplatin in vitro (IC50 12.29 versus 3.23 nM, for H446 parental versus H446 VE-cadherin KD, P<0.0001; Supplementary Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('cadherin', 'molecular_function', 'GO:0008014', ('16', '24'))	('H446 parental', 'Var', (124, 137))	('increase', 'PosReg', (46, 54))	('cadherin', 'molecular_function', 'GO:0008014', ('153', '161'))	('sensitivity to cisplatin', 'MPA', (58, 82))	('H446', 'Var', (145, 149))
50352	27827359	We next sought to investigate the impact of VE-cadherin knockdown with attendant reduced VM on tumour responses in vivo to the standard of care chemotherapy doublet, cisplatin and etoposide.	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('etoposide', 'Chemical', 'MESH:D005047', (180, 189))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('tumour', 'Disease', (95, 101))	('cadherin', 'molecular_function', 'GO:0008014', ('47', '55'))	('VE-cadherin', 'Protein', (44, 55))	('knockdown', 'Var', (56, 65))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
50355	27827359	Mice were implanted with H446 parental or H446 VE-cadherin KD cells and tumours were allowed to grow to 200 mm3 before being randomised and dosed with a single dose of 5 mg per kg cisplatin and 8 mg per kg etoposide on 3 consecutive days (i.p.	('etoposide', 'Chemical', 'MESH:D005047', (206, 215))	('cisplatin', 'Chemical', 'MESH:D002945', (180, 189))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('cadherin', 'molecular_function', 'GO:0008014', ('50', '58'))	('H446', 'Var', (42, 46))	('Mice', 'Species', '10090', (0, 4))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('tumours', 'Disease', (72, 79))
50357	27827359	In contrast, a reduction in tumour volume (percentage of tumour volume change relative to size at randomization) occurred with H446 VE-cadherin KD tumours following cisplatin/etoposide treatment (mean -43.4% reduction, median -47.9% reduction, range -9.4% to -68.1% reduction; Fig.	('tumour', 'Disease', (57, 63))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumours', 'Phenotype', 'HP:0002664', (147, 154))	('H446', 'Var', (127, 131))	('reduction', 'NegReg', (15, 24))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('KD tumours', 'Disease', 'MESH:C537017', (144, 154))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('KD tumours', 'Disease', (144, 154))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('cadherin', 'molecular_function', 'GO:0008014', ('135', '143'))	('tumour', 'Disease', (28, 34))	('etoposide', 'Chemical', 'MESH:D005047', (175, 184))	('tumour', 'Disease', (147, 153))	('cisplatin', 'Chemical', 'MESH:D002945', (165, 174))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
50359	27827359	Treatment of H446 VE-cadherin KD with cisplatin/etoposide resulted in an 18.50-day median increase in survival (P=0.0003) compared with vehicle-treated mice (Fig.	('etoposide', 'Chemical', 'MESH:D005047', (48, 57))	('increase', 'PosReg', (90, 98))	('survival', 'CPA', (102, 110))	('H446', 'Var', (13, 17))	('cadherin', 'molecular_function', 'GO:0008014', ('21', '29'))	('mice', 'Species', '10090', (152, 156))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))
50360	27827359	No significant difference in survival was seen between vehicle-treated H446 parental and H446 VE-cadherin KD tumours following randomization (P=0.84; Fig.	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('cadherin', 'molecular_function', 'GO:0008014', ('97', '105'))	('H446', 'Var', (89, 93))	('H446 parental', 'Var', (71, 84))	('KD tumours', 'Disease', 'MESH:C537017', (106, 116))	('KD tumours', 'Disease', (106, 116))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
50376	27827359	Mutations in Notch family genes have been recently reported in 25% SCLC and whilst these signalling networks are complex, it is notable that inhibitors of Notch signalling are reported to preferentially target 'stem-like' VM tumour cells.	('signalling', 'biological_process', 'GO:0023052', ('89', '99'))	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('tumour', 'Disease', (225, 231))	('reported', 'Reg', (51, 59))	('Notch', 'Gene', (13, 18))	('Notch', 'Gene', '4851', (155, 160))	('Notch', 'Gene', (155, 160))	('Mutations', 'Var', (0, 9))	('SCLC', 'Gene', '7864', (67, 71))	('SCLC', 'Phenotype', 'HP:0030357', (67, 71))	('preferentially', 'PosReg', (188, 202))	('inhibitors', 'Var', (141, 151))	('SCLC', 'Gene', (67, 71))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('signalling', 'biological_process', 'GO:0023052', ('161', '171'))	('Notch', 'Gene', '4851', (13, 18))
50417	27827359	Fisher's exact t-test was used to evaluate for association between the TMA VM score and prognostic factors (hemoglobin <9 g per l, white blood cell >10 x 109 per l, platelets <150 x 109 per l, Na <135 mmol per l and LDH >550 IU per l11).	('TMA', 'Disease', 'MESH:D000783', (71, 74))	('TMA', 'Disease', (71, 74))	('LDH', 'MPA', (216, 219))	('<150 x 109 per', 'Var', (175, 189))
50470	27827359	Polyclonal mixes for each shRNA plus control were generated and screened for knockdown of VE-cadherin by western blot.	('rat', 'Species', '10116', (54, 57))	('VE-cadherin', 'Protein', (90, 101))	('knockdown', 'Var', (77, 86))	('cadherin', 'molecular_function', 'GO:0008014', ('93', '101'))
50486	27467964	Inhibition of the PD1-PDL1 axis has shown promise in the management of CM and we here report a two center experience of UM patients receiving pembrolizumab.	('pembrolizumab', 'Chemical', 'MESH:C582435', (142, 155))	('CM', 'Phenotype', 'HP:0012056', (71, 73))	('PD1', 'Gene', '6622', (18, 21))	('PDL1', 'Gene', (22, 26))	('PD1', 'Gene', (18, 21))	('patients', 'Species', '9606', (123, 131))	('UM', 'Phenotype', 'HP:0007716', (120, 122))	('Inhibition', 'Var', (0, 10))	('PDL1', 'Gene', '29126', (22, 26))
50500	27467964	The absence of activating BRAF mutations in the majority of UM patients limits the use of BRAF inhibitors.	('BRAF', 'Gene', (90, 94))	('mutations', 'Var', (31, 40))	('BRAF', 'Gene', '673', (26, 30))	('BRAF', 'Gene', (26, 30))	('activating', 'Reg', (15, 25))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('patients', 'Species', '9606', (63, 71))	('BRAF', 'Gene', '673', (90, 94))
50506	27467964	Furthermore, the overall mutational load is significantly lower compared to CM and expression of cancer-testis antigens is significantly rarer.	('mutational', 'Var', (25, 35))	('cancer-testis', 'Disease', 'MESH:D013736', (97, 110))	('lower', 'NegReg', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('CM', 'Phenotype', 'HP:0012056', (76, 78))	('cancer-testis', 'Disease', (97, 110))	('rarer', 'NegReg', (137, 142))
50513	27467964	Inclusion criteria included AST and ALT <=2.5 x upper limit of normal (ULN) or <=5 x ULN with liver metastases, serum total bilirubin <=1.5 x ULN or direct bilirubin <=ULN for patients with total bilirubin level >1.5 ULN.	('patients', 'Species', '9606', (176, 184))	('bilirubin', 'Chemical', 'MESH:D001663', (196, 205))	('<=1.5', 'Var', (134, 139))	('direct bilirubin', 'MPA', (149, 165))	('AST', 'Gene', (28, 31))	('bilirubin', 'Chemical', 'MESH:D001663', (124, 133))	('ALT', 'molecular_function', 'GO:0004021', ('36', '39'))	('bilirubin', 'Chemical', 'MESH:D001663', (156, 165))	('liver metastases', 'Disease', (94, 110))	('<=5', 'Var', (79, 82))	('AST', 'Gene', '26503', (28, 31))	('liver metastases', 'Disease', 'MESH:D009362', (94, 110))
50524	27467964	All seven patients with available cytogenetic results had chromosome three losses and chromosome eight gains in the primary tumors.	('gains', 'PosReg', (103, 108))	('primary tumors', 'Disease', 'MESH:D009369', (116, 130))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))	('losses', 'NegReg', (75, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('86', '96'))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('patients', 'Species', '9606', (10, 18))	('chromosome', 'Var', (58, 68))	('primary tumors', 'Disease', (116, 130))	('chromosome', 'Var', (86, 96))
50553	27467964	Finally, the pattern of metastatic spread may reflect underlying biological differences:e.g., mutational load, underlying immune escape mechanisms:that influence the ability of checkpoint inhibitors such as pembrolizumab to drive an effective immune response.	('pembrolizumab', 'Chemical', 'MESH:C582435', (207, 220))	('mutational load', 'Var', (94, 109))	('immune response', 'biological_process', 'GO:0006955', ('243', '258'))	('metastatic spread', 'CPA', (24, 41))	('influence', 'Reg', (152, 161))	('ability', 'MPA', (166, 173))
50584	27138736	Moreover, pigmented cutaneous tumors arose in a high percentage of the transgenic mice, further complicating its utility as a model of UM.	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('pigmented cutaneous tumors', 'Disease', (10, 36))	('UM', 'Phenotype', 'HP:0007716', (135, 137))	('transgenic', 'Var', (71, 81))	('cutaneous tumors', 'Phenotype', 'HP:0008069', (20, 36))	('transgenic mice', 'Species', '10090', (71, 86))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('pigmented cutaneous tumors', 'Disease', 'MESH:D010859', (10, 36))
50592	27138736	Moreover, B16LS9 melanomas display a propensity to metastasize to the liver, which recapitulates the metastatic behavior of human UM.	('metastasize', 'CPA', (51, 62))	('B16LS9', 'CellLine', 'CVCL:2105', (10, 16))	('B16LS9', 'Var', (10, 16))	('melanomas', 'Disease', (17, 26))	('human', 'Species', '9606', (124, 129))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('UM', 'Phenotype', 'HP:0007716', (130, 132))	('melanomas', 'Phenotype', 'HP:0002861', (17, 26))	('melanomas', 'Disease', 'MESH:D008545', (17, 26))
50640	27138736	Within 24 hours, C12MDP-LIP (100 muL) typically induced 85% to 90% cytotoxicity of 1 x 105 RAW 264.7 cells.	('cytotoxicity', 'Disease', (67, 79))	('RAW 264.7', 'CellLine', 'CVCL:0493', (91, 100))	('MDP', 'molecular_function', 'GO:0004237', ('20', '23'))	('cytotoxicity', 'Disease', 'MESH:D064420', (67, 79))	('C12MDP-LIP', 'Var', (17, 27))	('C12MDP-LIP', 'Chemical', '-', (17, 27))
50641	27138736	Previous studies have shown that subconjunctival injection of C12MDP-LIP (clodronate-containing liposomes; Sigma-Aldrich Corp.) induces the elimination of more than 95% of the conjunctival macrophages and more than 99% depletion of F4/80+ macrophages that infiltrate intraocular Ad5E1 tumors.	('Sigma-Aldrich Corp', 'Disease', 'MESH:D014923', (107, 125))	('MDP', 'molecular_function', 'GO:0004237', ('65', '68'))	('C12MDP-LIP', 'Var', (62, 72))	('Sigma-Aldrich Corp', 'Disease', (107, 125))	('C12MDP-LIP', 'Chemical', '-', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('F4/80', 'Gene', '13733', (232, 237))	('subconjunctival injection', 'Phenotype', 'HP:0011896', (33, 58))	('tumors', 'Disease', (285, 291))	('tumors', 'Disease', 'MESH:D009369', (285, 291))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('F4/80', 'Gene', (232, 237))	('elimination', 'NegReg', (140, 151))	('depletion', 'MPA', (219, 228))	('clodronate', 'Chemical', 'MESH:D004002', (74, 84))
50643	27138736	Injection of the C12MDP-LIP suspension resulted in a bleb around the injection site.	('bleb around the injection site', 'CPA', (53, 83))	('MDP', 'molecular_function', 'GO:0004237', ('20', '23'))	('C12MDP-LIP', 'Var', (17, 27))	('C12MDP-LIP', 'Chemical', '-', (17, 27))	('bleb', 'cellular_component', 'GO:0032059', ('53', '57'))
50650	27138736	Red blood cells were lysed using ACT lysis buffer (NH4Cl, 140 mM; C4H11NO3, 17 mM; pH 7.2).	('lysis', 'biological_process', 'GO:0019835', ('37', '42'))	('NH4Cl', 'Var', (51, 56))	('C4H11NO3', 'Chemical', '-', (66, 74))	('NH4Cl', 'Chemical', 'MESH:D000643', (51, 56))	('C4H11NO3', 'Var', (66, 74))	('4Cl', 'molecular_function', 'GO:0016207', ('53', '56'))
50699	27138736	Several studies have reported that MDSCs strongly suppress human and murine NK cytolytic activity.	('human', 'Species', '9606', (59, 64))	('human and', 'CPA', (59, 68))	('suppress', 'NegReg', (50, 58))	('MDSCs', 'Var', (35, 40))	('murine', 'Species', '10090', (69, 75))
50727	27138736	There is a growing awareness that MDSCs suppress both innate and adaptive tumor immune responses.	('MDSCs', 'Var', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('suppress', 'NegReg', (40, 48))	('tumor', 'Disease', (74, 79))
50729	27138736	Importantly, MDSCs strongly suppress human and murine NK cytolytic activity.	('suppress', 'NegReg', (28, 36))	('MDSCs', 'Var', (13, 18))	('murine', 'Species', '10090', (47, 53))	('human', 'Species', '9606', (37, 42))
50752	26605361	Another concern regarding the role of changes in functional TRP expression to visual processing stems from a more recent study showing that loss of TRP function instead inhibits optic nerve function.	('TRP', 'Gene', (148, 151))	('TRP', 'Chemical', '-', (148, 151))	('TRP', 'Chemical', '-', (60, 63))	('inhibits', 'NegReg', (169, 177))	('optic nerve function', 'CPA', (178, 198))	('loss', 'Var', (140, 144))
50756	26605361	In addition, the possible association between TRP channel mutations and some ocular diseases is considered.	('mutations', 'Var', (58, 67))	('ocular diseases', 'Disease', (77, 92))	('TRP', 'Chemical', '-', (46, 49))	('TRP channel', 'Gene', (46, 57))	('association', 'Reg', (26, 37))	('ocular diseases', 'Phenotype', 'HP:0000478', (77, 92))	('ocular diseases', 'Disease', 'MESH:D005128', (77, 92))
50781	26605361	However, it is not yet known if the TRP conformational changes induced by Ca2+ or Mg2+ are the same as those induced by a thermal transition known to activate these different TRP channel subtypes.	('TRP', 'Chemical', '-', (36, 39))	('Mg2', 'Gene', '57192', (82, 85))	('TRP', 'Protein', (36, 39))	('Ca2+', 'Var', (74, 78))	('TRP', 'Chemical', '-', (175, 178))	('Mg2', 'Gene', (82, 85))
50808	26605361	A recent report suggests that differences in TRP channel protein sequence endow thermal sensitivity, which could mean that this property is ascribable to specific structural changes.	('TRP', 'Chemical', '-', (45, 48))	('thermal sensitivity', 'MPA', (80, 99))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('differences', 'Var', (30, 41))	('TRP channel', 'Gene', (45, 56))
50827	26605361	Furthermore, in CPZ-treated rats, anterograde retrograde transport of markers were inhibited, which was associated with axonal loss and astrogliosis.	('axonal loss', 'Phenotype', 'HP:0003447', (120, 131))	('CPZ', 'Chemical', 'MESH:C071423', (16, 19))	('anterograde retrograde transport of markers', 'MPA', (34, 77))	('rats', 'Species', '10116', (28, 32))	('inhibited', 'NegReg', (83, 92))	('transport', 'biological_process', 'GO:0006810', ('57', '66'))	('axonal loss and astrogliosis', 'Disease', 'MESH:D012183', (120, 148))	('CPZ-treated', 'Var', (16, 27))
50844	26605361	Furthermore, the mitogenic response to epidermal growth factor receptor (EGFR) phosphorylation by EGF is dependent on increases in plasma membrane Ca2+ influx elicited by a SOC composed of TRPC4 subunits.	('EGF', 'Var', (98, 101))	('plasma membrane', 'cellular_component', 'GO:0005886', ('131', '146'))	('SOC', 'biological_process', 'GO:0031578', ('173', '176'))	('EGFR', 'Gene', '1956', (73, 77))	('epidermal growth factor receptor', 'Gene', '1956', (39, 71))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('39', '62'))	('EGF', 'molecular_function', 'GO:0005154', ('98', '101'))	('phosphorylation', 'biological_process', 'GO:0016310', ('79', '94'))	('EGFR', 'Gene', (73, 77))	('Ca2', 'Gene', '760', (147, 150))	('phosphorylation', 'MPA', (79, 94))	('increases', 'PosReg', (118, 127))	('mitogenic', 'MPA', (17, 26))	('response to epidermal growth factor', 'biological_process', 'GO:0070849', ('27', '62'))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('Ca2', 'Gene', (147, 150))	('epidermal growth factor receptor', 'Gene', (39, 71))
50845	26605361	This dependence is evident since knockdown of TRPC4 expression in human corneal epithelial cells (HCEC) markedly reduced cell proliferation and migration.	('TRPC4', 'Gene', (46, 51))	('corneal epithelia', 'Disease', (72, 89))	('cell proliferation', 'biological_process', 'GO:0008283', ('121', '139'))	('knockdown', 'Var', (33, 42))	('human', 'Species', '9606', (66, 71))	('corneal epithelia', 'Disease', 'MESH:D003316', (72, 89))	('reduced', 'NegReg', (113, 120))
50847	26605361	The HCEC mitogenic response to capsaicin is consistent with a mouse study in which corneal re-epithelialization following debridement was delayed in TRPV1-/- knockout mice compared to their wildtype counterparts.	('corneal re-epithelialization', 'CPA', (83, 111))	('mouse', 'Species', '10090', (62, 67))	('TRPV1-/-', 'Gene', (149, 157))	('capsaicin', 'Chemical', 'MESH:D002211', (31, 40))	('mitogenic', 'CPA', (9, 18))	('delayed', 'NegReg', (138, 145))	('knockout', 'Var', (158, 166))	('mice', 'Species', '10090', (167, 171))
50853	26605361	Subsequent to the breaching of the corneal epithelial basement membrane by a severe injury, transforming growth factor-beta (TGFbeta) infiltrates into the stroma and activates its cognate receptor on human fibroblasts also expressing TRPV1.	('transforming growth factor-beta', 'Gene', '7040', (92, 123))	('activates', 'PosReg', (166, 175))	('breaching', 'Var', (18, 27))	('corneal epithelia', 'Disease', (35, 52))	('TGFbeta', 'Gene', '7040', (125, 132))	('corneal epithelia', 'Disease', 'MESH:D003316', (35, 52))	('transforming growth factor-beta', 'Gene', (92, 123))	('transforming growth factor-beta', 'molecular_function', 'GO:0005160', ('92', '123'))	('human', 'Species', '9606', (200, 205))	('TRPV1', 'Gene', (234, 239))	('injury', 'Disease', (84, 90))	('injury', 'Disease', 'MESH:D058186', (84, 90))	('basement membrane', 'cellular_component', 'GO:0005604', ('54', '71'))	('TGFbeta', 'Gene', (125, 132))
50856	26605361	This result is pertinent for efforts to reduce corneal opacification and inflammation following a chemical burn since it suggests that in a clinical setting treatment, a TRPV1 antagonist could promote restoration of corneal transparency by inhibiting TGFbeta-induced myofibroblast transdifferentiation.	('promote', 'PosReg', (193, 200))	('TRPV1', 'Gene', (170, 175))	('inflammation', 'Disease', (73, 85))	('inflammation', 'Disease', 'MESH:D007249', (73, 85))	('transdifferentiation', 'biological_process', 'GO:0060290', ('281', '301'))	('corneal opacification', 'Disease', 'MESH:C537775', (47, 68))	('TGFbeta', 'Gene', (251, 258))	('corneal opacification', 'Phenotype', 'HP:0007957', (47, 68))	('corneal transparency', 'CPA', (216, 236))	('inhibiting', 'NegReg', (240, 250))	('inflammation', 'biological_process', 'GO:0006954', ('73', '85'))	('corneal opacification', 'Disease', (47, 68))	('TGFbeta', 'Gene', '7040', (251, 258))	('antagonist', 'Var', (176, 186))
50866	26605361	Besides TRPM8 expression in human corneal endothelial cells, there might also be other TRPs expressed in human corneal endothelium since H2O2 induced significant increase in [Ca2+].	('TRPs', 'Chemical', 'MESH:D014364', (87, 91))	('increase', 'PosReg', (162, 170))	('human', 'Species', '9606', (28, 33))	('TRPM8', 'Gene', (8, 13))	('Ca2', 'Gene', '760', (175, 178))	('H2O2', 'Chemical', 'MESH:D006861', (137, 141))	('H2O2', 'Var', (137, 141))	('human', 'Species', '9606', (105, 110))	('Ca2', 'Gene', (175, 178))
50870	26605361	TRP gene mutations underlie numerous inherited diseases in humans including the eye.	('numerous inherited diseases', 'Disease', 'MESH:D030342', (28, 55))	('mutations', 'Var', (9, 18))	('TRP gene', 'Gene', (0, 8))	('underlie', 'Reg', (19, 27))	('numerous inherited diseases', 'Disease', (28, 55))	('TRP', 'Chemical', '-', (0, 3))	('humans', 'Species', '9606', (59, 65))
50874	26605361	It is an autosomal recessive, neurodegenerative lysosomal storage disorder, which is due to mutations in the gene MCOLN1.	('MCOLN1', 'Gene', '57192', (114, 120))	('due to', 'Reg', (85, 91))	('autosomal recessive', 'Disease', (9, 28))	('MCOLN1', 'Gene', (114, 120))	('mutations', 'Var', (92, 101))	('neurodegenerative lysosomal storage disorder', 'Disease', 'MESH:D016464', (30, 74))	('storage', 'biological_process', 'GO:0051235', ('58', '65'))	('neurodegenerative lysosomal storage disorder', 'Disease', (30, 74))
50877	26605361	In addition, human TRPM1 mutations are associated with congenital stationary night blindness (CSNB), whose patients lack rod function and suffer from night blindness starting in early childhood.	('blindness', 'Disease', (83, 92))	('blindness', 'Disease', 'MESH:D001766', (83, 92))	('mutations', 'Var', (25, 34))	('congenital stationary night blindness', 'Disease', 'MESH:C536122', (55, 92))	('night blindness starting in early childhood', 'Phenotype', 'HP:0007642', (150, 193))	('human', 'Species', '9606', (13, 18))	('TRPM1', 'Gene', (19, 24))	('blindness', 'Disease', (156, 165))	('blindness', 'Disease', 'MESH:D001766', (156, 165))	('blindness', 'Phenotype', 'HP:0000618', (83, 92))	('blindness starting in early childhood', 'Phenotype', 'HP:0007875', (156, 193))	('night blindness', 'Phenotype', 'HP:0000662', (77, 92))	('associated', 'Reg', (39, 49))	('congenital stationary night blindness', 'Disease', (55, 92))	('night blindness', 'Phenotype', 'HP:0000662', (150, 165))	('blindness', 'Phenotype', 'HP:0000618', (156, 165))	('patients', 'Species', '9606', (107, 115))	('congenital stationary night blindness', 'Phenotype', 'HP:0007642', (55, 92))
50911	26605361	Its incidence is low but is the most common ocular tumour of the eye in children and is associated with a RB mutation.	('RB', 'Gene', '5925', (106, 108))	('children', 'Species', '9606', (72, 80))	('ocular tumour', 'Disease', 'MESH:D005134', (44, 57))	('tumour of the eye', 'Phenotype', 'HP:0100012', (51, 68))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('associated', 'Reg', (88, 98))	('ocular tumour', 'Disease', (44, 57))	('mutation', 'Var', (109, 117))
50921	26605361	Therefore, modulation of TRP expression and/or function could provide a critically needed therapeutic option.	('modulation', 'Var', (11, 21))	('function', 'MPA', (47, 55))	('TRP', 'Protein', (25, 28))	('TRP', 'Chemical', '-', (25, 28))	('expression', 'MPA', (29, 39))
50925	26605361	As there is an association between aberrant TRP channel expression and human disease, these regulators of Ca2+ influx may be potential drug targets for usage in a clinical setting.	('Ca2', 'Gene', (106, 109))	('aberrant', 'Var', (35, 43))	('TRP', 'Chemical', '-', (44, 47))	('Ca2', 'Gene', '760', (106, 109))	('association', 'Interaction', (15, 26))	('human disease', 'Disease', (71, 84))	('human', 'Species', '9606', (71, 76))	('TRP channel', 'Protein', (44, 55))
50933	25030020	GNAQ mutation in a patient with metastatic mucosal melanoma Mucosal melanomas represent about 1% of all melanoma cases and classically have a worse prognosis than cutaneous melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('mucosal melanoma', 'Disease', 'MESH:D008545', (43, 59))	('patient', 'Species', '9606', (19, 26))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))	('mucosal melanoma', 'Disease', (43, 59))	('Mucosal melanomas', 'Disease', (60, 77))	('melanomas', 'Phenotype', 'HP:0002861', (173, 182))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (163, 182))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (163, 182))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (163, 181))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('melanomas', 'Phenotype', 'HP:0002861', (68, 77))	('Mucosal melanomas', 'Disease', 'MESH:D008545', (60, 77))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('GNAQ', 'Gene', '2776', (0, 4))	('GNAQ', 'Gene', (0, 4))	('cutaneous melanomas', 'Disease', (163, 182))	('mutation', 'Var', (5, 13))
50935	25030020	Mucosal melanomas most commonly contain mutations in the gene CKIT, and treatments have been investigated using targeted therapy for this gene.	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('CKIT', 'Gene', (62, 66))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('Mucosal melanomas', 'Disease', (0, 17))	('mutations', 'Var', (40, 49))	('CKIT', 'Gene', '3815', (62, 66))	('Mucosal melanomas', 'Disease', 'MESH:D008545', (0, 17))
50936	25030020	Mutations in mucosal melanoma are less common than in cutaneous or uveal melanomas and occur in descending order of frequency as: CKIT (20%), NRAS (5%) or BRAF (3%).	('mucosal melanoma', 'Disease', (13, 29))	('BRAF', 'Gene', (155, 159))	('NRAS', 'Gene', (142, 146))	('mucosal melanoma', 'Disease', 'MESH:D008545', (13, 29))	('uveal melanomas', 'Disease', 'MESH:C536494', (67, 82))	('NRAS', 'Gene', '4893', (142, 146))	('uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('CKIT', 'Gene', '3815', (130, 134))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('CKIT', 'Gene', (130, 134))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('BRAF', 'Gene', '673', (155, 159))	('uveal melanomas', 'Disease', (67, 82))	('uveal melanomas', 'Phenotype', 'HP:0007716', (67, 82))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
50937	25030020	Mutations in G-alpha proteins, which are associated with activation of the mitogen-activated protein kinase pathway, have not been reported in mucosal melanomas.	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('mucosal melanomas', 'Disease', (143, 160))	('mucosal melanomas', 'Disease', 'MESH:D008545', (143, 160))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('G-alpha', 'Gene', '8802', (13, 20))	('mitogen-activated protein kinase pathway', 'Pathway', (75, 115))	('melanomas', 'Phenotype', 'HP:0002861', (151, 160))	('G-alpha', 'Gene', (13, 20))
50938	25030020	These G-alpha protein mutations occur in the genes GNAQ and GNA11 and are seen at a high frequency in uveal melanomas, those melanomas that begin in the eye.	('melanomas', 'Disease', 'MESH:D008545', (108, 117))	('GNA11', 'Gene', '2767', (60, 65))	('melanomas', 'Disease', (108, 117))	('melanomas', 'Phenotype', 'HP:0002861', (125, 134))	('GNAQ', 'Gene', '2776', (51, 55))	('uveal melanomas', 'Disease', (102, 117))	('uveal melanomas', 'Phenotype', 'HP:0007716', (102, 117))	('GNAQ', 'Gene', (51, 55))	('G-alpha', 'Gene', '8802', (6, 13))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('G-alpha', 'Gene', (6, 13))	('melanomas', 'Phenotype', 'HP:0002861', (108, 117))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('GNA11', 'Gene', (60, 65))	('mutations', 'Var', (22, 31))	('melanomas', 'Disease', 'MESH:D008545', (125, 134))	('melanomas', 'Disease', (125, 134))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('uveal melanomas', 'Disease', 'MESH:C536494', (102, 117))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))
50942	25030020	Here we report, to our knowledge, the first known case of GNAQ mutation in a patient with metastatic mucosal melanoma.	('GNAQ', 'Gene', '2776', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('mutation', 'Var', (63, 71))	('mucosal melanoma', 'Disease', (101, 117))	('GNAQ', 'Gene', (58, 62))	('patient', 'Species', '9606', (77, 84))	('mucosal melanoma', 'Disease', 'MESH:D008545', (101, 117))
50948	25030020	Although the discovery of BRAF gene mutation and the advancement of immunotherapy in melanoma have led to the development of highly effective targeted therapy such as vemurafenib, dabrafenib, and trametinib and durable immunotherapy such as interleukin-2 and ipilimumab, the efficacy of these treatments in metastatic mucosal melanoma is not clear due to limited number of these patients included in clinical trials.	('dabrafenib', 'Chemical', 'MESH:C561627', (180, 190))	('mucosal melanoma', 'Disease', 'MESH:D008545', (318, 334))	('interleukin-2', 'Gene', '3558', (241, 254))	('patients', 'Species', '9606', (379, 387))	('BRAF', 'Gene', '673', (26, 30))	('interleukin-2', 'Gene', (241, 254))	('trametinib', 'Chemical', 'MESH:C560077', (196, 206))	('BRAF', 'Gene', (26, 30))	('ipilimumab', 'Chemical', 'MESH:D000074324', (259, 269))	('melanoma', 'Disease', 'MESH:D008545', (326, 334))	('melanoma', 'Phenotype', 'HP:0002861', (326, 334))	('melanoma', 'Disease', (326, 334))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('mucosal melanoma', 'Disease', (318, 334))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('vemurafenib', 'Chemical', 'MESH:D000077484', (167, 178))	('mutation', 'Var', (36, 44))
50949	25030020	Recently, several clinical trials reported promising results with targeting of CKIT mutation in mucosal melanoma.	('CKIT', 'Gene', (79, 83))	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('mucosal melanoma', 'Disease', (96, 112))	('mucosal melanoma', 'Disease', 'MESH:D008545', (96, 112))	('CKIT', 'Gene', '3815', (79, 83))	('mutation', 'Var', (84, 92))
50950	25030020	CKIT mutations are reported in 21% of mucosal melanoma, and only patients with mucosal melanoma harboring a special subset of CKIT mutations such as L576P and K642E in exon 11 and 13 may have a clinical benefit from c-KIT inhibitors.	('CKIT', 'Gene', (126, 130))	('mucosal melanoma', 'Disease', (38, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('KIT', 'molecular_function', 'GO:0005020', ('218', '221'))	('c-KIT', 'Gene', '3815', (216, 221))	('mucosal melanoma', 'Disease', (79, 95))	('mucosal melanoma', 'Disease', 'MESH:D008545', (79, 95))	('mucosal melanoma', 'Disease', 'MESH:D008545', (38, 54))	('L576P', 'Mutation', 'rs121913513', (149, 154))	('CKIT', 'Gene', '3815', (0, 4))	('K642E', 'Var', (159, 164))	('patients', 'Species', '9606', (65, 73))	('CKIT', 'Gene', '3815', (126, 130))	('K642E', 'Mutation', 'rs121913512', (159, 164))	('L576P', 'Var', (149, 154))	('c-KIT', 'Gene', (216, 221))	('CKIT', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
50954	25030020	Mutations in the genes GNAQ and GNA11 are critical for development and progression of uveal melanoma and are associated with activation of the mitogen-activated protein kinase (MAPK) pathway.	('activation', 'PosReg', (125, 135))	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('associated', 'Reg', (109, 119))	('uveal melanoma', 'Disease', 'MESH:C536494', (86, 100))	('MAPK', 'molecular_function', 'GO:0004707', ('177', '181'))	('GNA11', 'Gene', '2767', (32, 37))	('GNAQ', 'Gene', (23, 27))	('uveal melanoma', 'Disease', (86, 100))	('GNA11', 'Gene', (32, 37))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', '2776', (23, 27))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))
50955	25030020	This same pathway is activated by oncogenic BRAF mutations in cutaneous melanoma.	('cutaneous melanoma', 'Disease', (62, 80))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (62, 80))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (62, 80))	('BRAF', 'Gene', '673', (44, 48))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('mutations', 'Var', (49, 58))	('BRAF', 'Gene', (44, 48))
50956	25030020	Approximately, 80% of primary uveal melanomas have GNAQ or GNA11 mutations.	('uveal melanomas', 'Disease', (30, 45))	('GNAQ', 'Gene', '2776', (51, 55))	('uveal melanomas', 'Phenotype', 'HP:0007716', (30, 45))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('uveal melanomas', 'Disease', 'MESH:C536494', (30, 45))	('GNA11', 'Gene', '2767', (59, 64))	('GNA11', 'Gene', (59, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('GNAQ', 'Gene', (51, 55))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('mutations', 'Var', (65, 74))
50957	25030020	However, GNAQ or GNA11 mutations have not been reported in mucosal melanoma.	('GNAQ', 'Gene', (9, 13))	('mucosal melanoma', 'Disease', (59, 75))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('mucosal melanoma', 'Disease', 'MESH:D008545', (59, 75))	('mutations', 'Var', (23, 32))	('GNA11', 'Gene', (17, 22))	('GNAQ', 'Gene', '2776', (9, 13))	('GNA11', 'Gene', '2767', (17, 22))
50958	25030020	Here, we present a patient with metastatic mucosal melanoma harboring a classic GNAQ mutation.	('patient', 'Species', '9606', (19, 26))	('mucosal melanoma', 'Disease', 'MESH:D008545', (43, 59))	('mutation', 'Var', (85, 93))	('GNAQ', 'Gene', '2776', (80, 84))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('GNAQ', 'Gene', (80, 84))	('mucosal melanoma', 'Disease', (43, 59))
50965	25030020	The GNAQ gene mutation of the patient was the substitution of glutamine to proline in codon 209 (Q209P) which has been reported in uveal melanoma at a frequency of 20.8% but not in cutaneous melanoma or other subtypes of the disease.	('Q209P', 'Mutation', 'rs121913492', (97, 102))	('GNAQ', 'Gene', '2776', (4, 8))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (181, 199))	('uveal melanoma', 'Disease', 'MESH:C536494', (131, 145))	('patient', 'Species', '9606', (30, 37))	('uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('uveal melanoma', 'Disease', (131, 145))	('GNAQ', 'Gene', (4, 8))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (181, 199))	('cutaneous melanoma', 'Disease', (181, 199))	('Q209P', 'Var', (97, 102))	('glutamine to proline in codon 209', 'Mutation', 'rs121913492', (62, 95))
50971	25030020	GNAQ and GNA11 mutations, which are potential drivers of MAPK activation, have been reported in blue nevi and in up to 85% of cases of uveal melanoma.	('GNA11', 'Gene', (9, 14))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('blue nevi', 'Phenotype', 'HP:0100814', (96, 105))	('MAPK activation', 'biological_process', 'GO:0000187', ('57', '72'))	('GNAQ', 'Gene', '2776', (0, 4))	('uveal melanoma', 'Disease', 'MESH:C536494', (135, 149))	('nevi', 'Phenotype', 'HP:0003764', (101, 105))	('MAPK', 'molecular_function', 'GO:0004707', ('57', '61'))	('blue nevi', 'Disease', (96, 105))	('mutations', 'Var', (15, 24))	('uveal melanoma', 'Phenotype', 'HP:0007716', (135, 149))	('uveal melanoma', 'Disease', (135, 149))	('GNAQ', 'Gene', (0, 4))	('reported', 'Reg', (84, 92))	('GNA11', 'Gene', '2767', (9, 14))
50972	25030020	Although GNAQ and GNA11 mutations have been reported in a cutaneous melanoma case and a cell line from cutaneous melanoma, there are no data to demonstrate GNAQ or GNA11 mutations in mucosal melanoma.	('cutaneous melanoma', 'Disease', (103, 121))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (103, 121))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (103, 121))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('GNAQ', 'Gene', '2776', (156, 160))	('mucosal melanoma', 'Disease', 'MESH:D008545', (183, 199))	('mutations', 'Var', (24, 33))	('GNA11', 'Gene', '2767', (18, 23))	('GNAQ', 'Gene', (156, 160))	('mucosal melanoma', 'Disease', (183, 199))	('GNA11', 'Gene', (164, 169))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('GNAQ', 'Gene', '2776', (9, 13))	('GNA11', 'Gene', (18, 23))	('GNAQ', 'Gene', (9, 13))	('cutaneous melanoma', 'Disease', (58, 76))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (58, 76))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (58, 76))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('reported', 'Reg', (44, 52))	('GNA11', 'Gene', '2767', (164, 169))
50973	25030020	It is possible that our patient may have had an undetected or spontaneously regressed primary uveal melanoma since his melanoma harbored the GNAQ mutation and metastasized to liver which is the most common metastatic site of uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('melanoma', 'Disease', (231, 239))	('GNAQ', 'Gene', '2776', (141, 145))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('harbored', 'Reg', (128, 136))	('melanoma', 'Disease', (119, 127))	('mutation', 'Var', (146, 154))	('GNAQ', 'Gene', (141, 145))	('uveal melanoma', 'Disease', (225, 239))	('patient', 'Species', '9606', (24, 31))	('uveal melanoma', 'Disease', 'MESH:C536494', (225, 239))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('uveal melanoma', 'Phenotype', 'HP:0007716', (225, 239))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('metastasized', 'CPA', (159, 171))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('uveal melanoma', 'Disease', (94, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))
50979	25030020	Since GNAQ mutations are potential drivers of MAPK activation similar to oncogenic BRAF, and a recent clinical study demonstrated a significant clinical benefit of selumetinib (a selective MEK inhibitor) in metastatic uveal melanoma with GNAQ or GNA11 mutations, our patient might have achieved clinical response with selumetinib.	('GNAQ', 'Gene', (238, 242))	('GNAQ', 'Gene', '2776', (6, 10))	('GNA11', 'Gene', (246, 251))	('uveal melanoma', 'Disease', 'MESH:C536494', (218, 232))	('MEK', 'Gene', '5609', (189, 192))	('uveal melanoma', 'Disease', (218, 232))	('GNAQ', 'Gene', (6, 10))	('MEK', 'Gene', (189, 192))	('uveal melanoma', 'Phenotype', 'HP:0007716', (218, 232))	('GNA11', 'Gene', '2767', (246, 251))	('selumetinib', 'Chemical', 'MESH:C517975', (318, 329))	('mutations', 'Var', (252, 261))	('MAPK', 'molecular_function', 'GO:0004707', ('46', '50'))	('BRAF', 'Gene', '673', (83, 87))	('BRAF', 'Gene', (83, 87))	('patient', 'Species', '9606', (267, 274))	('MAPK activation', 'biological_process', 'GO:0000187', ('46', '61'))	('GNAQ', 'Gene', '2776', (238, 242))	('selumetinib', 'Chemical', 'MESH:C517975', (164, 175))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))
50981	25030020	To our knowledge, this is the first case report to demonstrate mucosal melanoma harboring a GNAQ mutation.	('mucosal melanoma', 'Disease', (63, 79))	('GNAQ', 'Gene', (92, 96))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('mucosal melanoma', 'Disease', 'MESH:D008545', (63, 79))	('mutation', 'Var', (97, 105))	('GNAQ', 'Gene', '2776', (92, 96))
51012	24599420	Overall, UBM provided superior tumour visualisation (69% vs 31%) and better resolution of the posterior margin (74% vs 27%) compared to AS-OCT.	('AS-OCT', 'Chemical', '-', (136, 142))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumour visualisation', 'Disease', 'MESH:D009369', (31, 51))	('AS-OCT', 'Phenotype', 'HP:0007700', (136, 142))	('UBM', 'Chemical', '-', (9, 12))	('UBM', 'Var', (9, 12))	('tumour visualisation', 'Disease', (31, 51))
51065	21941004	Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers To investigate the potential contribution of germline sequence alterations in the BAP1 gene in uveal melanoma (UM) patients with possible predisposition to hereditary cancer.	('meningioma', 'Disease', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('meningioma', 'Phenotype', 'HP:0002858', (75, 85))	('hereditary cancer', 'Disease', (261, 278))	('patients', 'Species', '9606', (220, 228))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (54, 73))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('BAP1', 'Gene', (9, 13))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('hereditary cancer', 'Disease', 'MESH:D009369', (261, 278))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (54, 73))	('cancers', 'Disease', (97, 104))	('uveal melanoma', 'Disease', (200, 214))	('BAP1', 'Gene', '8314', (187, 191))	('uveal melanoma', 'Disease', 'MESH:C536494', (200, 214))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('meningioma', 'Disease', 'MESH:D008577', (75, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('UM', 'Phenotype', 'HP:0007716', (216, 218))	('uveal melanoma', 'Phenotype', 'HP:0007716', (200, 214))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('predisposes', 'Reg', (23, 34))	('BAP1', 'Gene', (187, 191))	('uveal melanoma', 'Disease', 'MESH:C536494', (38, 52))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('uveal melanoma', 'Disease', (38, 52))	('BAP1', 'Gene', '8314', (9, 13))	('mutation', 'Var', (14, 22))	('lung adenocarcinoma', 'Disease', (54, 73))	('uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))
51068	21941004	Biallelic inactivation of BAP1 and decreased BAP1 expression were identified in the UM, lung adenocarcinoma and meningioma tumours from three family members with this germline BAP1 mutation.	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('decreased', 'NegReg', (35, 44))	('BAP1', 'Gene', (176, 180))	('BAP1', 'Gene', '8314', (45, 49))	('expression', 'MPA', (50, 60))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('BAP1', 'Gene', (26, 30))	('meningioma', 'Phenotype', 'HP:0002858', (112, 122))	('meningioma tumours', 'Disease', (112, 130))	('BAP1', 'Gene', (45, 49))	('lung adenocarcinoma', 'Disease', (88, 107))	('BAP1', 'Gene', '8314', (176, 180))	('meningioma tumours', 'Disease', 'MESH:D008577', (112, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('mutation', 'Var', (181, 189))	('BAP1', 'Gene', '8314', (26, 30))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (88, 107))
51069	21941004	Germline BAP1 variants of uncertain significance, likely non-pathogenic, were also identified in two additional UM patients.	('patients', 'Species', '9606', (115, 123))	('variants', 'Var', (14, 22))	('BAP1', 'Gene', '8314', (9, 13))	('UM', 'Phenotype', 'HP:0007716', (112, 114))	('BAP1', 'Gene', (9, 13))
51070	21941004	This study reports a novel hereditary cancer syndrome caused by a germline BAP1 mutation that predisposes patients to UM, lung carcinoma, meningioma, and possibly other cancers.	('cancers', 'Disease', (169, 176))	('BAP1', 'Gene', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('germline', 'Var', (66, 74))	('meningioma', 'Disease', (138, 148))	('meningioma', 'Phenotype', 'HP:0002858', (138, 148))	('hereditary cancer syndrome', 'Disease', (27, 53))	('lung carcinoma', 'Disease', (122, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('cancers', 'Disease', 'MESH:D009369', (169, 176))	('predisposes', 'Reg', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('caused by', 'Reg', (54, 63))	('meningioma', 'Disease', 'MESH:D008577', (138, 148))	('patients', 'Species', '9606', (106, 114))	('BAP1', 'Gene', '8314', (75, 79))	('mutation', 'Var', (80, 88))	('UM', 'Phenotype', 'HP:0007716', (118, 120))	('lung carcinoma', 'Disease', 'MESH:D008175', (122, 136))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (27, 53))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
51079	21941004	Monosomy of chromosome 3 is the most common somatic alteration in UM, reported in about 50% of primary tumours, and it is associated with aggressive tumours.	('associated', 'Reg', (122, 132))	('Monosomy', 'Var', (0, 8))	('primary tumours', 'Disease', (95, 110))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('aggressive tumours', 'Disease', 'MESH:D001523', (138, 156))	('aggressive tumours', 'Disease', (138, 156))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('tumours', 'Phenotype', 'HP:0002664', (149, 156))	('primary tumours', 'Disease', 'MESH:D009369', (95, 110))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))
51081	21941004	The mutations were almost exclusively identified in tumours with a gene expression profile pattern strongly associated with early development of metastatic disease (class 2 tumours) and were seen more commonly in UM with monosomy 3.	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('tumours', 'Disease', (173, 180))	('tumours', 'Disease', (52, 59))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('gene expression', 'biological_process', 'GO:0010467', ('67', '82'))	('associated with', 'Reg', (108, 123))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('mutations', 'Var', (4, 13))	('UM', 'Phenotype', 'HP:0007716', (213, 215))	('tumours', 'Disease', 'MESH:D009369', (52, 59))
51082	21941004	A germline mutation in BAP1 was also detected in a single patient (1.7%) with no available family history.	('BAP1', 'Gene', (23, 27))	('germline mutation', 'Var', (2, 19))	('patient', 'Species', '9606', (58, 65))	('BAP1', 'Gene', '8314', (23, 27))
51087	21941004	In the following study we investigated the frequency of germline sequence alterations in the BAP1 gene in 53 unrelated UM patients with a strong hereditary cancer risk.	('BAP1', 'Gene', '8314', (93, 97))	('hereditary cancer', 'Disease', 'MESH:D009369', (145, 162))	('germline sequence alterations', 'Var', (56, 85))	('hereditary cancer', 'Disease', (145, 162))	('patients', 'Species', '9606', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('BAP1', 'Gene', (93, 97))	('UM', 'Phenotype', 'HP:0007716', (119, 121))
51094	21941004	All patients tested negative for pathogenic mutations in the familial cutaneous melanoma predisposition genes CDKN2A, p14/ARF, and exon 2 of CDK4.	('CDKN2A', 'Gene', (110, 116))	('familial cutaneous melanoma', 'Disease', (61, 88))	('CDK4', 'Gene', '1019', (141, 145))	('CDKN2A', 'Gene', '1029', (110, 116))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (70, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('ARF', 'Disease', 'MESH:D058186', (122, 125))	('p14', 'Gene', (118, 121))	('mutations', 'Var', (44, 53))	('familial cutaneous melanoma', 'Disease', 'MESH:C562393', (61, 88))	('patients', 'Species', '9606', (4, 12))	('p14', 'Gene', '1029', (118, 121))	('ARF', 'Disease', (122, 125))	('CDK', 'molecular_function', 'GO:0004693', ('141', '144'))	('CDK4', 'Gene', (141, 145))
51095	21941004	Five patients with apparent breast cancer predisposition were negative for pathogenic BRCA1 and BRCA2 gene mutations based on clinical testing.	('patients', 'Species', '9606', (5, 13))	('mutations', 'Var', (107, 116))	('BRCA1', 'Gene', '672', (86, 91))	('BRCA2', 'Gene', '675', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('BRCA1', 'Gene', (86, 91))	('breast cancer', 'Disease', (28, 41))	('BRCA2', 'Gene', (96, 101))
51102	21941004	The three patients had germline mutation in BAP1.	('germline mutation', 'Var', (23, 40))	('BAP1', 'Gene', '8314', (44, 48))	('BAP1', 'Gene', (44, 48))	('patients', 'Species', '9606', (10, 18))
51103	21941004	A total of 15 micro-satellite markers on chromosome 3 were used for genotyping, including three markers (D3S3026, D3S3561, and D3S1578) flanking the BAP1 gene (figure 2).	('S3561', 'CellLine', 'CVCL:Z231', (116, 121))	('BAP1', 'Gene', '8314', (149, 153))	('D3S3561', 'Var', (114, 121))	('D3S3026', 'Var', (105, 112))	('BAP1', 'Gene', (149, 153))	('D3S1578', 'Var', (127, 134))	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))
51112	21941004	One of the BAP1 variants identified is a truncating mutation (c. 799 C T, p.Q267X), another variant is a synonymous single nucleotide polymorphism (SNP)rs28997577(c1002 A T), while the remaining four variants are intronic variants (c.650-26T A, c.931+70A G, c.931+117_118delCC, and c.1891-30G C) of uncertain significance.	('c.931+117_118delCC', 'Var', (258, 276))	('BAP1', 'Gene', '8314', (11, 15))	('rs28997577', 'Mutation', 'rs28997577', (152, 162))	('c.1891-30G C', 'Var', (282, 294))	('p.Q267X', 'Mutation', 'rs387906849', (74, 81))	('c. 799 C T', 'Var', (62, 72))	('BAP1', 'Gene', (11, 15))	('c.931+70A G', 'Var', (245, 256))	('c.931+117_118delCC', 'Mutation', 'c.931+117_118delCC', (258, 276))	('variants', 'Var', (16, 24))	('c.650-26T A', 'Var', (232, 243))
51114	21941004	The same BAP1 variants, including the p.Q267X mutation, were identified in four of those individuals and were inherited as a single linkage disequilibrium block (figure 1).	('p.Q267X', 'Var', (38, 45))	('BAP1', 'Gene', (9, 13))	('p.Q267X', 'Mutation', 'rs387906849', (38, 45))	('BAP1', 'Gene', '8314', (9, 13))
51115	21941004	The mutation and variants were detected in patients with cutaneous melanoma (individual II.2), meningioma (individual III.2), UM and neuroendocrine carcinoma (individual III.6), and in one individual who was cancer-free at the age of 55 years (individual III.9).	('detected', 'Reg', (31, 39))	('cancer', 'Disease', (208, 214))	('variants', 'Var', (17, 25))	('meningioma', 'Disease', (95, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('patients', 'Species', '9606', (43, 51))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('meningioma', 'Phenotype', 'HP:0002858', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (133, 157))	('UM', 'Phenotype', 'HP:0007716', (126, 128))	('meningioma', 'Disease', 'MESH:D008577', (95, 105))	('cutaneous melanoma', 'Disease', (57, 75))	('neuroendocrine carcinoma', 'Disease', (133, 157))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (57, 75))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (57, 75))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (133, 157))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
51116	21941004	In addition, two patients from family FUM036 are obligate carriers for the BAP1 mutation, one with abdominal adenocarcinoma, suspected to be ovarian per the patient's clinical notes (individual II.1), and one with mesothelioma (individual II.3).	('abdominal adenocarcinoma', 'Disease', (99, 123))	('BAP1', 'Gene', (75, 79))	('abdominal adenocarcinoma', 'Disease', 'MESH:D000008', (99, 123))	('patient', 'Species', '9606', (157, 164))	('mesothelioma', 'Disease', 'MESH:D008654', (214, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('patient', 'Species', '9606', (17, 24))	('UM', 'Phenotype', 'HP:0007716', (39, 41))	('mesothelioma', 'Disease', (214, 226))	('patients', 'Species', '9606', (17, 25))	('BAP1', 'Gene', '8314', (75, 79))	('carriers', 'Reg', (58, 66))	('mutation', 'Var', (80, 88))
51117	21941004	One individual (individual III.11) tested negative for the truncating mutation and the other BAP1 variants and had no history of cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('BAP1', 'Gene', '8314', (93, 97))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('negative', 'NegReg', (42, 50))	('BAP1', 'Gene', (93, 97))	('truncating mutation', 'MPA', (59, 78))	('variants', 'Var', (98, 106))
51122	21941004	Sequencing of the tumour tissues showed loss of the normal allele, indicating biallelic inactivation of BAP1 in these tumours (figure 2).	('BAP1', 'Gene', '8314', (104, 108))	('tumour', 'Disease', (118, 124))	('tumours', 'Disease', (118, 125))	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('BAP1', 'Gene', (104, 108))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('biallelic inactivation', 'Var', (78, 100))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('tumour', 'Disease', (18, 24))
51125	21941004	We report a novel cancer predisposition syndrome caused by a germline truncating mutation in the BAP1 gene.	('caused by', 'Reg', (49, 58))	('germline truncating mutation', 'Var', (61, 89))	('BAP1', 'Gene', '8314', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('BAP1', 'Gene', (97, 101))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
51126	21941004	Cancers segregating with the mutation in this family included UM plus lung adenocarcinoma, UM plus neuroendocrine carcinoma, as well as meningioma, abdominal adenocarcinoma, and cutaneous melanoma (figure 1).	('mutation', 'Var', (29, 37))	('Cancers', 'Disease', (0, 7))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (70, 89))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('UM', 'Phenotype', 'HP:0007716', (91, 93))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (99, 123))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (70, 89))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (99, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('meningioma', 'Disease', (136, 146))	('meningioma', 'Phenotype', 'HP:0002858', (136, 146))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('abdominal adenocarcinoma', 'Disease', 'MESH:D000008', (148, 172))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('neuroendocrine carcinoma', 'Disease', (99, 123))	('meningioma', 'Disease', 'MESH:D008577', (136, 146))	('cutaneous melanoma', 'Disease', (178, 196))	('lung adenocarcinoma', 'Disease', (70, 89))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (178, 196))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (178, 196))	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('abdominal adenocarcinoma', 'Disease', (148, 172))
51127	21941004	The biallelic inactivation of BAP1 in the UM, meningioma and lung adenocarcinoma confirms that these tumours are part of the cancer phenotype in the family.	('tumours', 'Disease', 'MESH:D009369', (101, 108))	('BAP1', 'Gene', (30, 34))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (61, 80))	('meningioma', 'Phenotype', 'HP:0002858', (46, 56))	('tumours', 'Disease', (101, 108))	('BAP1', 'Gene', '8314', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('meningioma and lung adenocarcinoma', 'Disease', 'MESH:D000077192', (46, 80))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('biallelic inactivation', 'Var', (4, 26))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))	('UM', 'Phenotype', 'HP:0007716', (42, 44))
51128	21941004	A recent report identified two families with germline BAP1 mutations that presented with UM, cutaneous melanoma, and multiple naevi indicating that cutaneous melanoma and naevi may be part of the cancer phenotype in patients with germline BAP1 mutations.	('presented', 'Reg', (74, 83))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('BAP1', 'Gene', '8314', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('BAP1', 'Gene', (239, 243))	('cutaneous melanoma', 'Disease', (93, 111))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (93, 111))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (93, 111))	('UM', 'Phenotype', 'HP:0007716', (89, 91))	('BAP1', 'Gene', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('naevi', 'Phenotype', 'HP:0003764', (126, 131))	('cutaneous melanoma', 'Disease', (148, 166))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (148, 166))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (148, 166))	('patients', 'Species', '9606', (216, 224))	('cancer', 'Disease', (196, 202))	('mutations', 'Var', (59, 68))	('naevi', 'Phenotype', 'HP:0003764', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('multiple naevi', 'Phenotype', 'HP:0001054', (117, 131))	('BAP1', 'Gene', '8314', (239, 243))
51129	21941004	Whether other cancers observed in our family, such as mesothelioma, testicular cancer, and adrenocortical carcinoma, are part of the cancer phenotype caused by germline BAP1 alteration remains to be investigated.	('testicular cancer', 'Phenotype', 'HP:0010788', (68, 85))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (91, 115))	('BAP1', 'Gene', (169, 173))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('germline', 'Var', (160, 168))	('adrenocortical carcinoma', 'Disease', (91, 115))	('cancer', 'Disease', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('caused by', 'Reg', (150, 159))	('testicular cancer', 'Disease', 'MESH:D013736', (68, 85))	('cancer', 'Disease', (133, 139))	('mesothelioma', 'Disease', (54, 66))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Disease', (14, 20))	('cancers', 'Disease', (14, 21))	('mesothelioma', 'Disease', 'MESH:D008654', (54, 66))	('BAP1', 'Gene', '8314', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (91, 115))	('testicular cancer', 'Disease', (68, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
51131	21941004	Only one out of seven individuals with the mutation was cancer-free (individual III.9).	('mutation', 'Var', (43, 51))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))
51134	21941004	Germline BAP1 mutations have been analysed in a series of 47 French and 96 French Canadian families with high risk for breast and/or ovarian cancers that did not have detectable mutations in the BRCA1 and BRCA2 genes.	('BRCA1', 'Gene', '672', (195, 200))	('breast and/or ovarian cancers', 'Disease', (119, 148))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('BRCA1', 'Gene', (195, 200))	('breast and/or ovarian cancers', 'Disease', 'MESH:D010051', (119, 148))	('BRCA2', 'Gene', (205, 210))	('ovarian cancers', 'Phenotype', 'HP:0100615', (133, 148))	('BAP1', 'Gene', '8314', (9, 13))	('BRCA2', 'Gene', '675', (205, 210))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
51136	21941004	BAP1 is located in the tumour suppressor cluster at the 3p21 chromosomal region which shows deletion in many cancers including lung, breast, ovarian, pancreatic, and head and neck cancers.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('tumour', 'Disease', (23, 29))	('lung', 'Disease', (127, 131))	('neck', 'cellular_component', 'GO:0044326', ('175', '179'))	('BAP1', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('head and neck cancers', 'Phenotype', 'HP:0012288', (166, 187))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('deletion', 'Var', (92, 100))	('cancers', 'Disease', (109, 116))	('breast, ovarian, pancreatic', 'Disease', 'MESH:D010051', (133, 160))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('chromosomal region', 'cellular_component', 'GO:0098687', ('61', '79'))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('neck cancers', 'Disease', (175, 187))	('cancers', 'Disease', (180, 187))	('neck cancers', 'Disease', 'MESH:D006258', (175, 187))	('BAP1', 'Gene', '8314', (0, 4))
51139	21941004	In UM, somatic mutations in BAP1 were highly correlated with monosomy of chromosome 3 in tumours, suggesting that either mutation in BAP1 is a primary hit in tumours with monosomy 3 or that monosomy 3 is the primary hit in these tumours and BAP1 mutation is a secondary hit.	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('BAP1', 'Gene', (241, 245))	('tumours', 'Disease', (89, 96))	('BAP1', 'Gene', '8314', (133, 137))	('UM', 'Phenotype', 'HP:0007716', (3, 5))	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('tumours', 'Disease', 'MESH:D009369', (89, 96))	('mutation', 'Var', (121, 129))	('tumours', 'Disease', (158, 165))	('BAP1', 'Gene', (133, 137))	('BAP1', 'Gene', '8314', (28, 32))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('tumours', 'Disease', (229, 236))	('tumours', 'Disease', 'MESH:D009369', (158, 165))	('tumours', 'Phenotype', 'HP:0002664', (229, 236))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('BAP1', 'Gene', '8314', (241, 245))	('tumours', 'Disease', 'MESH:D009369', (229, 236))	('BAP1', 'Gene', (28, 32))	('tumour', 'Phenotype', 'HP:0002664', (229, 235))
51140	21941004	A previous study has identified a germline mutation of BAP1 in a female patient with UM who was diagnosed at the age of 53 years.	('BAP1', 'Gene', (55, 59))	('patient', 'Species', '9606', (72, 79))	('germline mutation', 'Var', (34, 51))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('BAP1', 'Gene', '8314', (55, 59))
51144	21941004	Taken together with the results of our study, it appears that germline mutations in BAP1 are the cause of hereditary cancer predisposition in a small subset of UM patients.	('patients', 'Species', '9606', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('BAP1', 'Gene', '8314', (84, 88))	('UM', 'Phenotype', 'HP:0007716', (160, 162))	('germline mutations', 'Var', (62, 80))	('BAP1', 'Gene', (84, 88))	('cause', 'Reg', (97, 102))	('hereditary cancer', 'Disease', (106, 123))	('hereditary cancer', 'Disease', 'MESH:D009369', (106, 123))
51146	21941004	The frequency of germline mutations in other known candidate genes in UM patients, including BRCA2, CDKN2A, p14/ARF, and CDK4, is extremely low, suggesting the existence of one or more additional genes.	('CDK', 'molecular_function', 'GO:0004693', ('121', '124'))	('CDK4', 'Gene', '1019', (121, 125))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('ARF', 'Disease', 'MESH:D058186', (112, 115))	('BRCA2', 'Gene', '675', (93, 98))	('CDK4', 'Gene', (121, 125))	('p14', 'Gene', (108, 111))	('germline mutations', 'Var', (17, 35))	('CDKN2A', 'Gene', (100, 106))	('ARF', 'Disease', (112, 115))	('p14', 'Gene', '1029', (108, 111))	('patients', 'Species', '9606', (73, 81))	('CDKN2A', 'Gene', '1029', (100, 106))	('BRCA2', 'Gene', (93, 98))
51147	21941004	In conclusion, we report a novel hereditary cancer syndrome caused by a germline BAP1 mutation that predisposes patients to UM, lung carcinoma, meningioma, and possibly other cancers.	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (33, 59))	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('caused by', 'Reg', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('BAP1', 'Gene', (81, 85))	('lung carcinoma', 'Disease', 'MESH:D008175', (128, 142))	('meningioma', 'Disease', (144, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('hereditary cancer syndrome', 'Disease', (33, 59))	('meningioma', 'Phenotype', 'HP:0002858', (144, 154))	('cancers', 'Disease', (175, 182))	('germline', 'Var', (72, 80))	('predisposes', 'Reg', (100, 111))	('meningioma', 'Disease', 'MESH:D008577', (144, 154))	('lung carcinoma', 'Disease', (128, 142))	('patients', 'Species', '9606', (112, 120))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('mutation', 'Var', (86, 94))	('BAP1', 'Gene', '8314', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
51209	23378737	VEGF levels have also been found to have a positive association with increased apical height and basal diameter.	('increased', 'PosReg', (69, 78))	('basal diameter', 'CPA', (97, 111))	('VEGF', 'Gene', '7422', (0, 4))	('apical height', 'CPA', (79, 92))	('levels', 'Var', (5, 11))	('VEGF', 'Gene', (0, 4))
51218	23378737	Following combined treatment with I-125 plaque brachytherapy and intravitreal bevacizumab, there was a significant decrease in tumor burden at all time points compared with baseline (P < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('men', 'Species', '9606', (24, 27))	('I-125', 'Var', (34, 39))	('tumor', 'Disease', (127, 132))	('bevacizumab', 'Chemical', 'MESH:D000068258', (78, 89))	('I', 'Chemical', 'MESH:D007455', (34, 35))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('decrease', 'NegReg', (115, 123))
51245	20697348	Advances in the understanding of the prevalence and patterns of mutations in melanoma have recently led to impressive results in trials of personalized, targeted therapies for this disease.	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('mutations', 'Var', (64, 73))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))
51258	20697348	The management of many cancers is entering into an era in which treatments are being used to inhibit pathways activated by mutations in the tumors.	('inhibit', 'NegReg', (93, 100))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('mutations', 'Var', (123, 132))
51262	20697348	There is growing evidence that the majority of melanomas harbor genetic changes in key protein kinase signaling pathways (Figure 1).	('melanomas', 'Disease', 'MESH:D008545', (47, 56))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('genetic changes', 'Var', (64, 79))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('melanomas', 'Disease', (47, 56))
51265	20697348	In 2002, investigators from the Sanger Institute published the identification of point mutations in BRAF in tumors and cell lines.	('point mutations', 'Var', (81, 96))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('BRAF', 'Gene', '673', (100, 104))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('BRAF', 'Gene', (100, 104))
51266	20697348	Although mutations were identified in 1-10% of a variety of tumor types, including colon, lung and ovarian cancers, strikingly over half of the tested melanomas had a mutation in the BRAF gene.	('colon, lung and ovarian cancers', 'Disease', 'MESH:D008175', (83, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('mutation', 'Var', (167, 175))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('ovarian cancers', 'Phenotype', 'HP:0100615', (99, 114))	('melanomas', 'Disease', (151, 160))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('BRAF', 'Gene', '673', (183, 187))	('melanomas', 'Phenotype', 'HP:0002861', (151, 160))	('tumor', 'Disease', (60, 65))	('BRAF', 'Gene', (183, 187))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('melanomas', 'Disease', 'MESH:D008545', (151, 160))
51267	20697348	The high prevalence of BRAF mutations in melanoma has been validated in multiple studies.	('BRAF', 'Gene', '673', (23, 27))	('BRAF', 'Gene', (23, 27))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('mutations', 'Var', (28, 37))
51268	20697348	A recent meta-analysis of sequencing results for over 2700 samples reported a mutation rate of 65% in melanoma cell lines and 42% in uncultured cutaneous melanomas.	('mutation', 'Var', (78, 86))	('melanoma cell lines', 'Disease', (102, 121))	('cutaneous melanomas', 'Disease', (144, 163))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma cell lines', 'Disease', 'MESH:D008545', (102, 121))	('melanomas', 'Phenotype', 'HP:0002861', (154, 163))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (144, 163))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (144, 163))
51269	20697348	Mutations in BRAF are the most common somatic mutations in this disease.	('BRAF', 'Gene', '673', (13, 17))	('common', 'Reg', (31, 37))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (13, 17))
51272	20697348	Activation of this signaling pathway had previously been implicated in melanoma by the identification of activating mutations in NRAS, which occur in 15-25% of melanomas.	('melanomas', 'Disease', 'MESH:D008545', (160, 169))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('NRAS', 'Gene', (129, 133))	('melanomas', 'Phenotype', 'HP:0002861', (160, 169))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('NRAS', 'Gene', '4893', (129, 133))	('mutations', 'Var', (116, 125))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('melanomas', 'Disease', (160, 169))	('activating', 'PosReg', (105, 115))	('signaling pathway', 'biological_process', 'GO:0007165', ('19', '36'))
51273	20697348	Over 40 different point mutations in BRAF have been identified in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('identified', 'Reg', (52, 62))	('melanoma', 'Disease', (66, 74))	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', (37, 41))	('point mutations', 'Var', (18, 33))
51274	20697348	Approximately 90% of the BRAF mutations in melanoma affect a single site, the valine at position 600 (V600).	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('valine', 'Chemical', 'MESH:D014633', (78, 84))	('melanoma', 'Disease', (43, 51))	('BRAF', 'Gene', '673', (25, 29))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('mutations', 'Var', (30, 39))	('BRAF', 'Gene', (25, 29))	('affect', 'Reg', (52, 58))
51275	20697348	The most common mutation, V600E (89% of BRAF mutations), markedly increases the in vitro catalytic activity of BRAF, and results in constitutive activation of both MEK and MAPK.	('MAPK', 'Pathway', (172, 176))	('MEK', 'Gene', (164, 167))	('activation', 'PosReg', (145, 155))	('MEK', 'Gene', '5609', (164, 167))	('BRAF', 'Gene', '673', (40, 44))	('MAPK', 'molecular_function', 'GO:0004707', ('172', '176'))	('catalytic activity', 'molecular_function', 'GO:0003824', ('89', '107'))	('BRAF', 'Gene', (40, 44))	('increases', 'PosReg', (66, 75))	('constitutive', 'MPA', (132, 144))	('V600E', 'Mutation', 'rs113488022', (26, 31))	('BRAF', 'Gene', '673', (111, 115))	('V600E', 'Var', (26, 31))	('BRAF', 'Gene', (111, 115))
51276	20697348	The BRAF V600E mutations are mutually exclusive with activating NRAS mutations.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('V600E', 'Var', (9, 14))	('NRAS', 'Gene', (64, 68))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('NRAS', 'Gene', '4893', (64, 68))
51277	20697348	However, overlap of NRAS mutations has been observed with BRAF mutations that do not increase BRAF catalytic activity.	('mutations', 'Var', (25, 34))	('BRAF', 'Gene', (94, 98))	('catalytic activity', 'molecular_function', 'GO:0003824', ('99', '117'))	('BRAF', 'Gene', '673', (58, 62))	('NRAS', 'Gene', (20, 24))	('BRAF', 'Gene', '673', (94, 98))	('BRAF', 'Gene', (58, 62))	('NRAS', 'Gene', '4893', (20, 24))
51278	20697348	The identification of frequent activating BRAF mutations in melanoma was rapidly followed by functional testing.	('BRAF', 'Gene', '673', (42, 46))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('mutations', 'Var', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('activating', 'PosReg', (31, 41))	('BRAF', 'Gene', (42, 46))
51279	20697348	Knock down of the V600E mutant BRAF in melanoma cell lines by small interfering RNA inhibited MEK activation, decreased cell proliferation and invasion, and induced cell death.	('melanoma cell lines', 'Disease', 'MESH:D008545', (39, 58))	('MEK', 'Gene', (94, 97))	('melanoma cell lines', 'Disease', (39, 58))	('cell proliferation', 'CPA', (120, 138))	('RNA', 'Gene', (80, 83))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('BRAF', 'Gene', '673', (31, 35))	('activation', 'MPA', (98, 108))	('cell death', 'biological_process', 'GO:0008219', ('165', '175'))	('BRAF', 'Gene', (31, 35))	('induced', 'Reg', (157, 164))	('invasion', 'CPA', (143, 151))	('decreased', 'NegReg', (110, 119))	('V600E', 'Var', (18, 23))	('MEK', 'Gene', '5609', (94, 97))	('cell death', 'CPA', (165, 175))	('cell proliferation', 'biological_process', 'GO:0008283', ('120', '138'))	('RNA', 'cellular_component', 'GO:0005562', ('80', '83'))	('inhibited', 'NegReg', (84, 93))
51280	20697348	Sorafenib is a small molecule inhibitor of wild-type BRAF, V600E BRAF, CRAF and a number of tyrosine kinase receptors.	('BRAF', 'Gene', '673', (53, 57))	('CRAF', 'molecular_function', 'GO:0004709', ('71', '75'))	('BRAF', 'Gene', (53, 57))	('BRAF', 'Gene', '673', (65, 69))	('V600E', 'Mutation', 'rs113488022', (59, 64))	('CRAF', 'Gene', (71, 75))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('BRAF', 'Gene', (65, 69))	('CRAF', 'Gene', '5894', (71, 75))	('V600E', 'Var', (59, 64))
51285	20697348	The disappointing clinical results with sorafenib raised the question of whether mutant BRAF was a good therapeutic target in melanoma.	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('sorafenib', 'Chemical', 'MESH:D000077157', (40, 49))	('mutant', 'Var', (81, 87))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))
51286	20697348	The BRAF V600E mutation is present in up to 80% of benign nevi, which have virtually no malignant potential.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('nevi', 'Phenotype', 'HP:0003764', (58, 62))	('V600E', 'Var', (9, 14))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('benign nevi', 'Disease', (51, 62))
51287	20697348	Studies in human cell lines, zebrafish and transgenic mice also demonstrated that expression of the BRAF V600E mutation alone failed to fully transform melanocytes.	('expression', 'Species', '29278', (82, 92))	('human', 'Species', '9606', (11, 16))	('V600E', 'Mutation', 'rs113488022', (105, 110))	('BRAF', 'Gene', '673', (100, 104))	('transgenic mice', 'Species', '10090', (43, 58))	('V600E', 'Var', (105, 110))	('zebrafish', 'Species', '7955', (29, 38))	('BRAF', 'Gene', (100, 104))
51288	20697348	Thus, it was possible that although BRAF mutations are prevalent in melanoma, they were not essential.	('mutations', 'Var', (41, 50))	('BRAF', 'Gene', (36, 40))	('prevalent', 'Reg', (55, 64))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('BRAF', 'Gene', '673', (36, 40))
51289	20697348	The validity of mutant BRAF as a therapeutic target has now been demonstrated by clinical trials with a new, mutant-specific BRAF inhibitor.	('BRAF', 'Gene', '673', (23, 27))	('BRAF', 'Gene', (23, 27))	('BRAF', 'Gene', (125, 129))	('mutant', 'Var', (16, 22))	('BRAF', 'Gene', '673', (125, 129))
51290	20697348	PLX4032 (also known as RO5185426) is a small molecule inhibitor with selective activity against V600-mutant BRAF.	('RO5185426', 'Chemical', 'MESH:D000077484', (23, 32))	('V600-mutant', 'Var', (96, 107))	('PLX4032', 'Chemical', 'MESH:D000077484', (0, 7))	('BRAF', 'Gene', '673', (108, 112))	('BRAF', 'Gene', (108, 112))
51291	20697348	PLX4032 inhibits V600E BRAF catalytic activity with an IC50 of 13nm, as compared with 160nm for wild-type BRAF, and >1000nm for several other related kinases (CSK, SRC, focal adhesion kinase, KDR).	('V600E', 'Var', (17, 22))	('BRAF', 'Gene', '673', (23, 27))	('inhibits', 'NegReg', (8, 16))	('PLX4032', 'Chemical', 'MESH:D000077484', (0, 7))	('BRAF', 'Gene', (23, 27))	('CSK', 'Gene', (159, 162))	('BRAF', 'Gene', '673', (106, 110))	('PLX4032', 'Var', (0, 7))	('KDR', 'Gene', '3791', (192, 195))	('BRAF', 'Gene', (106, 110))	('SRC', 'Gene', '6714', (164, 167))	('catalytic activity', 'MPA', (28, 46))	('SRC', 'Gene', (164, 167))	('catalytic activity', 'molecular_function', 'GO:0003824', ('28', '46'))	('focal adhesion', 'cellular_component', 'GO:0005925', ('169', '183'))	('V600E', 'Mutation', 'rs113488022', (17, 22))	('KDR', 'Gene', (192, 195))	('CSK', 'Gene', '1445', (159, 162))
51292	20697348	Similarly, the IC50 for the antiproliferative effect of PLX4032 is significantly lower in cells with V600-mutant BRAF (0.3-1.7 microm) versus cells with wild-type BRAF (>10 microm).	('antiproliferative effect', 'MPA', (28, 52))	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (113, 117))	('lower', 'NegReg', (81, 86))	('BRAF', 'Gene', '673', (163, 167))	('BRAF', 'Gene', (113, 117))	('PLX4032', 'Gene', (56, 63))	('V600-mutant', 'Var', (101, 112))	('PLX4032', 'Chemical', 'MESH:D000077484', (56, 63))
51294	20697348	No responses were seen in patients without a BRAF V600E mutation.	('V600E', 'Mutation', 'rs113488022', (50, 55))	('patients', 'Species', '9606', (26, 34))	('BRAF', 'Gene', '673', (45, 49))	('BRAF', 'Gene', (45, 49))	('V600E', 'Var', (50, 55))
51298	20697348	Recently, a number of studies have demonstrated that BRAF inhibitors, including PLX4032, activate MEK and MAPK in melanoma cell lines with wild-type BRAF, including cell lines with mutant NRAS.	('BRAF', 'Gene', (149, 153))	('mutant', 'Var', (181, 187))	('MEK', 'Gene', (98, 101))	('activate', 'PosReg', (89, 97))	('BRAF', 'Gene', '673', (149, 153))	('MEK', 'Gene', '5609', (98, 101))	('BRAF', 'Gene', '673', (53, 57))	('MAPK', 'molecular_function', 'GO:0004707', ('106', '110'))	('BRAF', 'Gene', (53, 57))	('NRAS', 'Gene', (188, 192))	('melanoma cell lines', 'Disease', (114, 133))	('PLX4032', 'Gene', (80, 87))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('MAPK', 'Pathway', (106, 110))	('NRAS', 'Gene', '4893', (188, 192))	('melanoma cell lines', 'Disease', 'MESH:D008545', (114, 133))	('PLX4032', 'Chemical', 'MESH:D000077484', (80, 87))
51299	20697348	These studies showed that inhibition of the catalytic activity of wild-type BRAF promotes the formation of a complex between BRAF and CRAF, which increases CRAF catalytic activity.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('CRAF', 'Gene', (134, 138))	('CRAF', 'Gene', '5894', (134, 138))	('complex', 'Interaction', (109, 116))	('formation', 'biological_process', 'GO:0009058', ('94', '103'))	('increases', 'PosReg', (146, 155))	('inhibition', 'Var', (26, 36))	('catalytic activity', 'MPA', (44, 62))	('CRAF', 'Gene', (156, 160))	('catalytic activity', 'MPA', (161, 179))	('BRAF', 'Gene', '673', (125, 129))	('CRAF', 'Gene', '5894', (156, 160))	('catalytic activity', 'molecular_function', 'GO:0003824', ('44', '62'))	('CRAF', 'molecular_function', 'GO:0004709', ('134', '138'))	('CRAF', 'molecular_function', 'GO:0004709', ('156', '160'))	('BRAF', 'Gene', (125, 129))	('catalytic activity', 'molecular_function', 'GO:0003824', ('161', '179'))
51302	20697348	Interestingly, the recent studies in the cell lines with wild-type BRAF reported different complexes and pathways that are activated by different BRAF inhibitors.	('BRAF', 'Gene', (146, 150))	('BRAF', 'Gene', '673', (67, 71))	('complexes', 'Interaction', (91, 100))	('BRAF', 'Gene', (67, 71))	('inhibitors', 'Var', (151, 161))	('BRAF', 'Gene', '673', (146, 150))	('pathways', 'Pathway', (105, 113))
51306	20697348	A number of the BRAF mutations that have been identified in melanoma, including D594V, G596R and G466V, do not activate the catalytic activity of BRAF, but do result in activation of MEK and ERK.	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('activation', 'PosReg', (169, 179))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('G466V', 'Var', (97, 102))	('D594V', 'Mutation', 'rs121913338', (80, 85))	('ERK', 'molecular_function', 'GO:0004707', ('191', '194'))	('catalytic activity', 'molecular_function', 'GO:0003824', ('124', '142'))	('ERK', 'Gene', (191, 194))	('G466V', 'Mutation', 'rs121913351', (97, 102))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('MEK', 'Gene', '5609', (183, 186))	('BRAF', 'Gene', '673', (146, 150))	('BRAF', 'Gene', (146, 150))	('ERK', 'Gene', '2048', (191, 194))	('catalytic', 'MPA', (124, 133))	('G596R', 'Mutation', 'rs121913361', (87, 92))	('G596R', 'Var', (87, 92))	('MEK', 'Gene', (183, 186))	('D594V', 'Var', (80, 85))
51307	20697348	Studies have demonstrated that melanoma cell lines with these mutations are critically dependent upon CRAF, and are sensitive in vitro and in vivo to sorafenib.	('CRAF', 'Gene', '5894', (102, 106))	('sensitive', 'Reg', (116, 125))	('CRAF', 'molecular_function', 'GO:0004709', ('102', '106'))	('melanoma cell lines', 'Disease', (31, 50))	('melanoma cell lines', 'Disease', 'MESH:D008545', (31, 50))	('sorafenib', 'Chemical', 'MESH:D000077157', (150, 159))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('mutations', 'Var', (62, 71))	('CRAF', 'Gene', (102, 106))
51310	20697348	The observed effects of the mutant-specific BRAF inhibitors in cell lines without BRAF mutations strongly support that these agents should not be used in patients with wild-type BRAF.	('BRAF', 'Gene', '673', (44, 48))	('BRAF', 'Gene', '673', (82, 86))	('BRAF', 'Gene', (44, 48))	('BRAF', 'Gene', (82, 86))	('patients', 'Species', '9606', (154, 162))	('BRAF', 'Gene', (178, 182))	('BRAF', 'Gene', '673', (178, 182))	('mutations', 'Var', (87, 96))
51317	20697348	In parallel, the investigators demonstrated that the prevalence of BRAF and NRAS mutations varied markedly between the anatomically defined groups (Table 1).	('NRAS', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (67, 71))	('NRAS', 'Gene', '4893', (76, 80))	('BRAF', 'Gene', (67, 71))	('mutations', 'Var', (81, 90))
51318	20697348	Whereas activating BRAF mutations were highly prevalent in cutaneous tumors without chronic sun damage (59%), the mutation rate was much lower in cutaneous tumors with chronic sun damage (11%), acral melanomas (23%) and mucosal melanomas (11%).	('acral melanomas', 'Disease', 'MESH:D008545', (194, 209))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('mucosal melanomas', 'Disease', (220, 237))	('acral melanomas', 'Phenotype', 'HP:0012060', (194, 209))	('sun damage', 'Phenotype', 'HP:0000992', (92, 102))	('activating', 'PosReg', (8, 18))	('mutations', 'Var', (24, 33))	('cutaneous tumors', 'Disease', 'MESH:D009369', (59, 75))	('cutaneous tumors', 'Disease', (59, 75))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('acral melanoma', 'Phenotype', 'HP:0012060', (194, 208))	('cutaneous tumors', 'Disease', 'MESH:D009369', (146, 162))	('melanomas', 'Phenotype', 'HP:0002861', (228, 237))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('cutaneous tumors', 'Disease', (146, 162))	('acral melanomas', 'Disease', (194, 209))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('sun damage', 'Phenotype', 'HP:0000992', (176, 186))	('lower', 'NegReg', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('BRAF', 'Gene', '673', (19, 23))	('melanomas', 'Phenotype', 'HP:0002861', (200, 209))	('cutaneous tumor', 'Phenotype', 'HP:0008069', (59, 74))	('BRAF', 'Gene', (19, 23))	('cutaneous tumors', 'Phenotype', 'HP:0008069', (59, 75))	('cutaneous tumor', 'Phenotype', 'HP:0008069', (146, 161))	('mucosal melanomas', 'Disease', 'MESH:D008545', (220, 237))	('cutaneous tumors', 'Phenotype', 'HP:0008069', (146, 162))
51319	20697348	Other studies have shown that BRAF mutations are essentially undetectable in uveal melanomas by traditional technologies.	('uveal melanomas', 'Phenotype', 'HP:0007716', (77, 92))	('BRAF', 'Gene', (30, 34))	('uveal melanomas', 'Disease', 'MESH:C536494', (77, 92))	('BRAF', 'Gene', '673', (30, 34))	('uveal melanomas', 'Disease', (77, 92))	('uveal melanoma', 'Phenotype', 'HP:0007716', (77, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('mutations', 'Var', (35, 44))
51320	20697348	Analysis with more sensitive technologies suggests that a subpopulation of cells in uveal melanomas may harbor BRAF mutations.	('harbor', 'Reg', (104, 110))	('melanomas', 'Phenotype', 'HP:0002861', (90, 99))	('uveal melanomas', 'Disease', (84, 99))	('uveal melanomas', 'Phenotype', 'HP:0007716', (84, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanomas', 'Disease', 'MESH:C536494', (84, 99))	('mutations', 'Var', (116, 125))	('BRAF', 'Gene', '673', (111, 115))	('BRAF', 'Gene', (111, 115))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
51321	20697348	The lower prevalence of BRAF mutations in the less common melanomas led to investigations to identify other driver mutations.	('mutations', 'Var', (29, 38))	('melanomas', 'Disease', (58, 67))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanomas', 'Disease', 'MESH:D008545', (58, 67))	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))
51323	20697348	Characterization of candidate genes in this region led to the finding of focal copy number gain and mutations in the c-KIT gene in melanoma.	('mutations', 'Var', (100, 109))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('c-KIT', 'Gene', (117, 122))	('KIT', 'molecular_function', 'GO:0005020', ('119', '122'))	('focal copy number gain', 'Disease', (73, 95))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('focal copy number gain', 'Disease', 'MESH:D015430', (73, 95))	('c-KIT', 'Gene', '3815', (117, 122))
51325	20697348	In melanoma, c-KIT mutations were identified in 17% chronic sun-damaged cutaneous, 11% acral and 21% mucosal melanomas.	('mucosal melanomas', 'Disease', (101, 118))	('c-KIT', 'Gene', (13, 18))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('c-KIT', 'Gene', '3815', (13, 18))	('sun-damaged', 'Phenotype', 'HP:0000992', (60, 71))	('melanoma', 'Disease', (109, 117))	('mutations', 'Var', (19, 28))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('KIT', 'molecular_function', 'GO:0005020', ('15', '18'))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('identified', 'Reg', (34, 44))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('mucosal melanomas', 'Disease', 'MESH:D008545', (101, 118))
51327	20697348	Subsequent studies in other panels of melanomas have identified similar rates of c-KIT alterations in acral and mucosal tumors, but lower rates (~2%) in chronic sun-damaged cutaneous tumors.	('acral', 'Disease', (102, 107))	('mucosal tumors', 'Disease', 'MESH:D052016', (112, 126))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('mucosal tumors', 'Disease', (112, 126))	('lower', 'NegReg', (132, 137))	('KIT', 'molecular_function', 'GO:0005020', ('83', '86'))	('cutaneous tumor', 'Phenotype', 'HP:0008069', (173, 188))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('cutaneous tumors', 'Phenotype', 'HP:0008069', (173, 189))	('c-KIT', 'Gene', (81, 86))	('melanomas', 'Disease', 'MESH:D008545', (38, 47))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('c-KIT', 'Gene', '3815', (81, 86))	('alterations', 'Var', (87, 98))	('melanomas', 'Disease', (38, 47))	('cutaneous tumors', 'Disease', 'MESH:D009369', (173, 189))	('cutaneous tumors', 'Disease', (173, 189))	('sun-damaged', 'Phenotype', 'HP:0000992', (161, 172))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
51328	20697348	In vitro studies demonstrated that point mutations in c-KIT result in constitutive activation of the c-KIT protein in melanoma cells, and the activation of downstream proliferative and prosurvival signaling pathways.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('c-KIT', 'Gene', '3815', (101, 106))	('c-KIT', 'Gene', '3815', (54, 59))	('activation', 'PosReg', (142, 152))	('KIT', 'molecular_function', 'GO:0005020', ('56', '59'))	('melanoma cell', 'Disease', (118, 131))	('signaling', 'biological_process', 'GO:0023052', ('197', '206'))	('c-KIT', 'Gene', (101, 106))	('point mutations', 'Var', (35, 50))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('KIT', 'molecular_function', 'GO:0005020', ('103', '106'))	('c-KIT', 'Gene', (54, 59))	('melanoma cell', 'Disease', 'MESH:D008545', (118, 131))	('activation', 'PosReg', (83, 93))
51329	20697348	The identification of activating c-KIT mutations was surprising, as a number of lines of research previously rejected a role for c-KIT function in melanoma.	('KIT', 'molecular_function', 'GO:0005020', ('131', '134'))	('c-KIT', 'Gene', '3815', (129, 134))	('mutations', 'Var', (39, 48))	('c-KIT', 'Gene', (33, 38))	('KIT', 'molecular_function', 'GO:0005020', ('35', '38'))	('c-KIT', 'Gene', (129, 134))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('activating', 'PosReg', (22, 32))	('c-KIT', 'Gene', '3815', (33, 38))
51332	20697348	However, these trials were conducted before the identification of c-KIT aberrations in rare melanoma subtypes and, thus, they likely were overwhelmingly composed of patients with cutaneous melanomas.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (179, 198))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (179, 198))	('melanomas', 'Phenotype', 'HP:0002861', (189, 198))	('melanoma subtypes', 'Disease', 'MESH:D008545', (92, 109))	('aberrations', 'Var', (72, 83))	('c-KIT', 'Gene', (66, 71))	('cutaneous melanomas', 'Disease', (179, 198))	('KIT', 'molecular_function', 'GO:0005020', ('68', '71'))	('c-KIT', 'Gene', '3815', (66, 71))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('patients', 'Species', '9606', (165, 173))	('melanoma subtypes', 'Disease', (92, 109))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))
51334	20697348	There are now several case reports of individual melanoma patients with c-KIT mutations who have achieved dramatic clinical responses to c-KIT small molecule inhibitors, including imatinib, sorafenib and dasatinib.	('c-KIT', 'Gene', (137, 142))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('KIT', 'molecular_function', 'GO:0005020', ('74', '77'))	('imatinib', 'Chemical', 'MESH:D000068877', (180, 188))	('c-KIT', 'Gene', (72, 77))	('sorafenib', 'Chemical', 'MESH:D000077157', (190, 199))	('c-KIT', 'Gene', '3815', (137, 142))	('mutations', 'Var', (78, 87))	('c-KIT', 'Gene', '3815', (72, 77))	('dasatinib', 'Chemical', 'MESH:D000069439', (204, 213))	('patients', 'Species', '9606', (58, 66))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('KIT', 'molecular_function', 'GO:0005020', ('139', '142'))	('melanoma', 'Disease', (49, 57))
51336	20697348	In GIST, mutations in c-KIT, but not protein expression levels, are predictive of response to c-KIT inhibitors.	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('KIT', 'molecular_function', 'GO:0005020', ('24', '27'))	('mutations', 'Var', (9, 18))	('expression', 'Species', '29278', (45, 55))	('GIST', 'Phenotype', 'HP:0100723', (3, 7))	('response', 'MPA', (82, 90))	('c-KIT', 'Gene', (94, 99))	('KIT', 'molecular_function', 'GO:0005020', ('96', '99'))	('c-KIT', 'Gene', '3815', (94, 99))	('c-KIT', 'Gene', (22, 27))	('c-KIT', 'Gene', '3815', (22, 27))
51337	20697348	In melanoma, imatinib resulted in a 50% clinical response rate among 10 patients with c-KIT mutations, but in none of the 10 patients with c-KIT amplification of the wild-type gene.	('c-KIT', 'Gene', '3815', (139, 144))	('patients', 'Species', '9606', (125, 133))	('KIT', 'molecular_function', 'GO:0005020', ('141', '144'))	('c-KIT', 'Gene', (86, 91))	('KIT', 'molecular_function', 'GO:0005020', ('88', '91'))	('mutations', 'Var', (92, 101))	('clinical response', 'MPA', (40, 57))	('c-KIT', 'Gene', (139, 144))	('c-KIT', 'Gene', '3815', (86, 91))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('imatinib', 'Chemical', 'MESH:D000068877', (13, 21))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('patients', 'Species', '9606', (72, 80))
51339	20697348	In addition, the c-KIT mutations associated with imatinibresistance in GIST (exons 13, 17 and 18) are more prevalent in melanoma (~15%) as compared with GIST (~1%).	('KIT', 'molecular_function', 'GO:0005020', ('19', '22'))	('imatinibresistance', 'MPA', (49, 67))	('prevalent', 'Reg', (107, 116))	('GIST', 'Phenotype', 'HP:0100723', (71, 75))	('c-KIT', 'Gene', (17, 22))	('c-KIT', 'Gene', '3815', (17, 22))	('mutations', 'Var', (23, 32))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('GIST', 'Phenotype', 'HP:0100723', (153, 157))	('imatinib', 'Chemical', 'MESH:D000068877', (49, 57))	('associated with', 'Reg', (33, 48))
51341	20697348	However, the initial demonstration of activity in melanoma patients with c-KIT mutations supports further research to build upon this activity.	('activity', 'MPA', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('KIT', 'molecular_function', 'GO:0005020', ('75', '78'))	('c-KIT', 'Gene', (73, 78))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('patients', 'Species', '9606', (59, 67))	('c-KIT', 'Gene', '3815', (73, 78))	('mutations', 'Var', (79, 88))
51344	20697348	These mutations lock RAS in the guanosine triphosphate-bound active state.	('guanosine triphosphate', 'Chemical', 'MESH:D006160', (32, 54))	('lock', 'Reg', (16, 20))	('mutations', 'Var', (6, 15))
51345	20697348	Mutant RAS activates the RAS-RAF-MEK-MAPK pathway, similar to mutant BRAF.	('MAPK', 'molecular_function', 'GO:0004707', ('37', '41'))	('activates', 'PosReg', (11, 20))	('RAS', 'Gene', (7, 10))	('RAF', 'Gene', '22882', (70, 73))	('RAF', 'Gene', (70, 73))	('RAF', 'Gene', (29, 32))	('BRAF', 'Gene', '673', (69, 73))	('RAF', 'Gene', '22882', (29, 32))	('Mutant', 'Var', (0, 6))	('MEK', 'Gene', (33, 36))	('MEK', 'Gene', '5609', (33, 36))	('BRAF', 'Gene', (69, 73))
51347	20697348	Mutations in NRAS have since been identified in ~15-20% of melanomas with 90% of mutations localizing to codon 61.	('identified', 'Reg', (34, 44))	('melanomas', 'Disease', (59, 68))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', (13, 17))	('melanomas', 'Disease', 'MESH:D008545', (59, 68))	('melanomas', 'Phenotype', 'HP:0002861', (59, 68))	('NRAS', 'Gene', '4893', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))
51348	20697348	NRAS mutations are mutually exclusive with activating BRAF mutations, and their prevalence is relatively consistent across the non-uveal anatomical subtypes.	('BRAF', 'Gene', '673', (54, 58))	('BRAF', 'Gene', (54, 58))	('mutations', 'Var', (5, 14))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))
51352	20697348	Studies in several systems, including melanoma, have shown increased efficacy with combined inhibition of targets in multiple RAS effector pathways, such as MEK and PI3K.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('PI3K', 'molecular_function', 'GO:0016303', ('165', '169'))	('MEK', 'Gene', (157, 160))	('PI3K', 'Var', (165, 169))	('RAS effector pathways', 'Pathway', (126, 147))	('MEK', 'Gene', '5609', (157, 160))	('inhibition', 'NegReg', (92, 102))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))
51353	20697348	At this time, the efficacy of targeted therapies in melanoma patients with NRAS mutations is yet to be reported, but this will be an important area of study in the future.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('mutations', 'Var', (80, 89))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('patients', 'Species', '9606', (61, 69))	('NRAS', 'Gene', (75, 79))	('NRAS', 'Gene', '4893', (75, 79))
51356	20697348	Class IA PI3Ks are heterodimers comprised of a catalytic subunit encoded by three p110 genes (p110alpha, p110beta and p110delta) and five different regulatory subunits (p85alpha, p85beta, p85gamma, p50alpha and p55alpha).	('p50alpha', 'Var', (198, 206))	('p110delta', 'Gene', (118, 127))	('p110alpha', 'Gene', '5290', (94, 103))	('p110alpha', 'Gene', (94, 103))	('p85alpha', 'Gene', '5295', (169, 177))	('p110beta', 'Gene', (105, 113))	('p85beta', 'Gene', '5296', (179, 186))	('p110', 'Gene', (94, 98))	('p110', 'Gene', (118, 122))	('p85beta', 'Gene', (179, 186))	('p110beta', 'Gene', '5291', (105, 113))	('p85alpha', 'Gene', (169, 177))	('p110delta', 'Gene', '5293', (118, 127))	('p110', 'Gene', '100616443', (94, 98))	('p110', 'Gene', '100616443', (118, 122))	('p110', 'Gene', (105, 109))	('p110', 'Gene', (82, 86))	('p55alpha', 'Var', (211, 219))	('p110', 'Gene', '100616443', (105, 109))	('p110', 'Gene', '100616443', (82, 86))	('p85gamma', 'Var', (188, 196))
51357	20697348	The enzymatic product generated by the PI3Ks, PI-(3,4,5)P3, activates AKT, a serine/ threonine kinase that induces a variety of responses including increased cell growth and proliferation.	('PI3Ks', 'Var', (39, 44))	('AKT', 'Gene', '207', (70, 73))	('increased', 'PosReg', (148, 157))	('AKT', 'Gene', (70, 73))	('cell growth', 'CPA', (158, 169))	('induces', 'Reg', (107, 114))	('PI-(3,4,5)P3', 'Chemical', 'MESH:C118303', (46, 58))	('cell growth', 'biological_process', 'GO:0016049', ('158', '169'))	('activates', 'PosReg', (60, 69))	('PI-', 'Var', (46, 49))	('proliferation', 'CPA', (174, 187))
51361	20697348	PTEN loss usually occurs in melanomas that also harbor a BRAF mutation, but it is mutually exclusive with NRAS mutation.	('BRAF', 'Gene', '673', (57, 61))	('melanomas', 'Disease', (28, 37))	('BRAF', 'Gene', (57, 61))	('NRAS', 'Gene', (106, 110))	('PTEN', 'Gene', '5728', (0, 4))	('loss', 'NegReg', (5, 9))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('mutation', 'Var', (62, 70))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('PTEN', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (106, 110))	('melanomas', 'Disease', 'MESH:D008545', (28, 37))
51362	20697348	Thus, melanomas frequently have genetic activation of both the PI3K and ERK signaling pathways, either by combined BRAF mutation and PTEN loss, or by NRAS mutation.	('ERK', 'Gene', '2048', (72, 75))	('PI3K', 'molecular_function', 'GO:0016303', ('63', '67'))	('PTEN', 'Gene', '5728', (133, 137))	('PI3K', 'Pathway', (63, 67))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('NRAS', 'Gene', '4893', (150, 154))	('loss', 'NegReg', (138, 142))	('ERK', 'molecular_function', 'GO:0004707', ('72', '75'))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('mutation', 'Var', (120, 128))	('activation', 'PosReg', (40, 50))	('NRAS', 'Gene', (150, 154))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('BRAF', 'Gene', '673', (115, 119))	('ERK', 'Gene', (72, 75))	('BRAF', 'Gene', (115, 119))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('melanomas', 'Disease', (6, 15))	('PTEN', 'Gene', (133, 137))
51363	20697348	However, quantitative measurement of activation-specific markers has demonstrated that PTEN loss and NRAS mutations may not have equivalent effects on AKT activation.	('PTEN', 'Gene', (87, 91))	('AKT', 'Gene', (151, 154))	('NRAS', 'Gene', (101, 105))	('PTEN', 'Gene', '5728', (87, 91))	('NRAS', 'Gene', '4893', (101, 105))	('loss', 'NegReg', (92, 96))	('mutations', 'Var', (106, 115))	('AKT', 'Gene', '207', (151, 154))
51370	20697348	Recently, a rare point mutation (E17K) in the regulatory pleckstrin homology domain of AKT3 was identified in melanoma cell lines and clinical specimens.	('AKT3', 'Gene', (87, 91))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('AKT3', 'Gene', '10000', (87, 91))	('E17K', 'Mutation', 'rs397514606', (33, 37))	('melanoma cell lines', 'Disease', (110, 129))	('melanoma cell lines', 'Disease', 'MESH:D008545', (110, 129))	('E17K', 'Var', (33, 37))
51372	20697348	Similar to AKT1 mutations, the AKT3 E17K mutation results in constitutive activation of AKT.	('AKT', 'Gene', (11, 14))	('AKT3', 'Gene', (31, 35))	('AKT', 'Gene', (31, 34))	('AKT1', 'Gene', '207', (11, 15))	('AKT3', 'Gene', '10000', (31, 35))	('AKT', 'Gene', '207', (88, 91))	('E17K', 'Mutation', 'rs397514606', (36, 40))	('AKT1', 'Gene', (11, 15))	('AKT', 'Gene', '207', (11, 14))	('E17K', 'Var', (36, 40))	('AKT', 'Gene', (88, 91))	('constitutive activation', 'MPA', (61, 84))	('AKT', 'Gene', '207', (31, 34))
51383	20697348	To identify new targets that may contribute to this disease, we recently investigated 86 protein tyrosine kinases for sequence variations in a set of cutaneous melanomas.	('cutaneous melanomas', 'Disease', (150, 169))	('variations', 'Var', (127, 137))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanomas', 'Phenotype', 'HP:0002861', (160, 169))	('investigated', 'Reg', (73, 85))	('protein tyrosine kinases', 'Enzyme', (89, 113))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (150, 169))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (150, 169))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
51386	20697348	Other family members, including ERBB1 (epidermal growth factor receptor) and ERBB2 (HER2), have been implicated by mutations and/or amplifications in a number of cancers, including lung, colon and breast cancers.	('cancers', 'Disease', (162, 169))	('HER2', 'Gene', (84, 88))	('implicated', 'Reg', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancers', 'Phenotype', 'HP:0003002', (197, 211))	('epidermal growth factor receptor', 'Gene', (39, 71))	('colon and breast cancers', 'Disease', 'MESH:D001943', (187, 211))	('epidermal growth factor receptor', 'Gene', '1956', (39, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('39', '62'))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('lung', 'Disease', (181, 185))	('ERBB1', 'Gene', (32, 37))	('ERBB2', 'Gene', (77, 82))	('HER2', 'Gene', '2064', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('amplifications', 'Var', (132, 146))	('ERBB1', 'Gene', '1956', (32, 37))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('mutations', 'Var', (115, 124))	('ERBB2', 'Gene', '2064', (77, 82))	('cancers', 'Disease', (204, 211))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
51390	20697348	As mutations that arise during tumorigenesis may provide a selective advantage to the tumor cell (driver mutations) or have no functional effect on tumor growth (passenger mutations), it is important to capture both the nonsynonymous and the synonymous alterations for further analysis.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (31, 36))	('advantage', 'PosReg', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('mutations', 'Var', (3, 12))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
51393	20697348	This supports that the frequent ERBB4 mutations were not random events, but may be functional, driver mutations that contribute to melanoma development or progression.	('ERBB4', 'Gene', (32, 37))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('ERBB4', 'Gene', '2066', (32, 37))	('mutations', 'Var', (38, 47))
51394	20697348	There was overlap with both BRAF and NRAS in the tumors with ERBB4 mutations, suggesting that these genes may operate through independent pathways.	('BRAF', 'Gene', '673', (28, 32))	('ERBB4', 'Gene', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('NRAS', 'Gene', (37, 41))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('NRAS', 'Gene', '4893', (37, 41))	('mutations', 'Var', (67, 76))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('BRAF', 'Gene', (28, 32))	('ERBB4', 'Gene', '2066', (61, 66))
51395	20697348	Indeed, this same scenario is seen for activating mutations in other genes, such as PIK3CA.	('mutations', 'Var', (50, 59))	('PIK3CA', 'Gene', '5290', (84, 90))	('PIK3CA', 'Gene', (84, 90))
51396	20697348	The ERBB4 mutations were localized in several different functional domains of the protein.	('ERBB4', 'Gene', (4, 9))	('mutations', 'Var', (10, 19))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('ERBB4', 'Gene', '2066', (4, 9))
51397	20697348	On the basis of bioinformatics, analyses that localized the identified mutations on the protein crystal structure and evaluated their proximity to the previously identified mutations in ERBB1 and ERBB2, seven of the mutations were cloned into expression vectors for functional experiments.	('ERBB1', 'Gene', (186, 191))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('expression vectors', 'Species', '29278', (243, 261))	('ERBB2', 'Gene', '2064', (196, 201))	('mutations', 'Var', (71, 80))	('ERBB2', 'Gene', (196, 201))	('ERBB1', 'Gene', '1956', (186, 191))
51398	20697348	Although these seven mutations affected several different functional domains, all of the mutations induced increased ERBB4 catalytic activity (as measured by autophosphorylation), kinase activity (measured using an in vitro kinase assay) and anchorage-independent growth.	('kinase activity', 'molecular_function', 'GO:0016301', ('180', '195'))	('catalytic activity', 'molecular_function', 'GO:0003824', ('123', '141'))	('ERBB4', 'Gene', '2066', (117, 122))	('kinase activity', 'MPA', (180, 195))	('increased', 'PosReg', (107, 116))	('affected', 'Reg', (31, 39))	('catalytic activity', 'MPA', (123, 141))	('ERBB4', 'Gene', (117, 122))	('mutations', 'Var', (89, 98))	('anchorage-independent growth', 'CPA', (242, 270))
51400	20697348	We also examined the effects of inhibiting ERBB4 in melanoma cell lines with the gene mutations.	('inhibiting', 'NegReg', (32, 42))	('mutations', 'Var', (86, 95))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('ERBB4', 'Gene', (43, 48))	('melanoma cell lines', 'Disease', (52, 71))	('melanoma cell lines', 'Disease', 'MESH:D008545', (52, 71))	('ERBB4', 'Gene', '2066', (43, 48))
51402	20697348	In contrast, cell lines with various ERBB4 mutations were markedly inhibited by knock down of the gene.	('ERBB4', 'Gene', (37, 42))	('knock down', 'Var', (80, 90))	('inhibited', 'NegReg', (67, 76))	('mutations', 'Var', (43, 52))	('ERBB4', 'Gene', '2066', (37, 42))
51404	20697348	Although lapatinib has been shown to have greatest inhibitory activity against ERBB1 and ERBB2, it showed selective growth inhibition in the melanoma cell lines expressing mutant ERBB4.	('mutant', 'Var', (172, 178))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('inhibitory activity', 'MPA', (51, 70))	('ERBB4', 'Gene', '2066', (179, 184))	('growth', 'MPA', (116, 122))	('melanoma cell lines', 'Disease', (141, 160))	('ERBB2', 'Gene', (89, 94))	('lapatinib', 'Chemical', 'MESH:D000077341', (9, 18))	('ERBB2', 'Gene', '2064', (89, 94))	('ERBB4', 'Gene', (179, 184))	('ERBB1', 'Gene', (79, 84))	('ERBB1', 'Gene', '1956', (79, 84))	('melanoma cell lines', 'Disease', 'MESH:D008545', (141, 160))
51405	20697348	The mechanism that lies behind this selectivity is as yet unknown, but it could be because of the inhibition of the mutant ERBB4 protein itself, or alternatively to a preferential heterodimerization of mutant ERBB4 with ERBB2.	('heterodimerization', 'MPA', (180, 198))	('ERBB4', 'Gene', '2066', (209, 214))	('ERBB4', 'Gene', '2066', (123, 128))	('protein', 'Protein', (129, 136))	('ERBB4', 'Gene', (209, 214))	('ERBB4', 'Gene', (123, 128))	('inhibition', 'NegReg', (98, 108))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('ERBB2', 'Gene', (220, 225))	('ERBB2', 'Gene', '2064', (220, 225))	('mutant', 'Var', (116, 122))	('preferential', 'PosReg', (167, 179))	('mutant', 'Var', (202, 208))
51407	20697348	Taken together, these findings have identified a novel melanoma 'driver' that causes 'oncogene addiction' allowing for the investigation of applying targeted therapeutics for melanoma patients harboring ERBB4 mutations.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('patients', 'Species', '9606', (184, 192))	('ERBB4', 'Gene', '2066', (203, 208))	("'oncogene addiction'", 'Disease', (85, 105))	('ERBB4', 'Gene', (203, 208))	('mutations', 'Var', (209, 218))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('melanoma', 'Disease', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
51408	20697348	Interestingly ERBB4 mutations are dispersed throughout its domains.	('ERBB4', 'Gene', '2066', (14, 19))	('ERBB4', 'Gene', (14, 19))	('mutations', 'Var', (20, 29))
51409	20697348	This is reminiscent to the mutations reported in PIK3CA; although it has two major mutational hotspots, it harbors mutations throughout its domains.	('PIK3CA', 'Gene', '5290', (49, 55))	('PIK3CA', 'Gene', (49, 55))	('mutations', 'Var', (115, 124))	('harbors', 'Reg', (107, 114))
51410	20697348	A similar observation is seen for p85alpha, whose identified mutations mainly lie in the iSH2 domain, but are also found in the cSH2, nSH2, iSH2cSH and BCR domains,, as well as FLT3 (http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=gene&ln=FLT3).	('FLT3', 'Gene', '2322', (177, 181))	('cSH2', 'Gene', (128, 132))	('p85alpha', 'Gene', (34, 42))	('mutations', 'Var', (61, 70))	('FLT3', 'Gene', '2322', (247, 251))	('FLT3', 'Gene', (177, 181))	('FLT3', 'Gene', (247, 251))	('p85alpha', 'Gene', '5295', (34, 42))	('cSH2', 'Gene', '1443', (128, 132))
51411	20697348	As described previously, uveal melanomas are notable for an almost complete absence of BRAF and NRAS mutations by conventional sequencing approaches.	('absence', 'NegReg', (76, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('mutations', 'Var', (101, 110))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('uveal melanomas', 'Disease', (25, 40))	('uveal melanomas', 'Phenotype', 'HP:0007716', (25, 40))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))	('NRAS', 'Gene', (96, 100))	('BRAF', 'Gene', (87, 91))	('uveal melanomas', 'Disease', 'MESH:C536494', (25, 40))	('BRAF', 'Gene', '673', (87, 91))	('NRAS', 'Gene', '4893', (96, 100))
51412	20697348	Previous experiments using a forward genetic screen had identified that hypermorphic mutations in two different G-protein-coupled receptors, GNalphaQ and GNalpha11, produced increased proliferation of dermal melanocytes.	('proliferation of dermal melanocytes', 'CPA', (184, 219))	('GNalphaQ', 'Gene', (141, 149))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('GNalphaQ', 'Chemical', '-', (141, 149))	('GNalpha11', 'Gene', (154, 163))	('hypermorphic mutations', 'Var', (72, 94))	('increased', 'PosReg', (174, 183))
51414	20697348	The team lead by Dr. Boris Bastian identified a recurrent point mutation in the GNalphaQ gene in 46% of uveal melanomas and 27% of uveal melanoma cell lines.	('uveal melanomas', 'Disease', 'MESH:C536494', (104, 119))	('melanoma cell lines', 'Disease', (137, 156))	('uveal melanoma', 'Disease', 'MESH:C536494', (131, 145))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('uveal melanoma', 'Disease', 'MESH:C536494', (104, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('point mutation', 'Var', (58, 72))	('uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))	('uveal melanoma', 'Disease', (131, 145))	('melanoma cell lines', 'Disease', 'MESH:D008545', (137, 156))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('GNalphaQ', 'Chemical', '-', (80, 88))	('GNalphaQ', 'Gene', (80, 88))	('uveal melanomas', 'Disease', (104, 119))	('uveal melanomas', 'Phenotype', 'HP:0007716', (104, 119))
51416	20697348	A study by an independent group of investigators similarly reported a 49% incidence of GNalphaQ mutations in primary uveal melanomas.	('GNalphaQ', 'Gene', (87, 95))	('uveal melanomas', 'Disease', (117, 132))	('uveal melanomas', 'Phenotype', 'HP:0007716', (117, 132))	('GNalphaQ', 'Chemical', '-', (87, 95))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('uveal melanomas', 'Disease', 'MESH:C536494', (117, 132))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('uveal melanoma', 'Phenotype', 'HP:0007716', (117, 131))	('mutations', 'Var', (96, 105))
51417	20697348	All the mutations occurred at the Q209 residue, which is analogous to the Q61 residue in NRAS, and all were somatic.	('NRAS', 'Gene', '4893', (89, 93))	('mutations', 'Var', (8, 17))	('Q209', 'Var', (34, 38))	('NRAS', 'Gene', (89, 93))	('occurred', 'Reg', (18, 26))
51422	20697348	In addition, expression of GNalphaQ Q209L activated protein kinase C signaling and increased expression of P-ERK.	('expression', 'Species', '29278', (13, 23))	('increased', 'PosReg', (83, 92))	('GNalphaQ', 'Chemical', '-', (27, 35))	('GNalphaQ Q209L', 'Var', (27, 41))	('protein kinase C signaling', 'biological_process', 'GO:0070528', ('52', '78'))	('Q209L', 'Mutation', 'p.Q209L', (36, 41))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))	('ERK', 'Gene', '2048', (109, 112))	('expression', 'Species', '29278', (93, 103))	('expression', 'MPA', (93, 103))	('ERK', 'Gene', (109, 112))	('ERK', 'molecular_function', 'GO:0004707', ('109', '112'))	('activated', 'PosReg', (42, 51))	('protein kinase', 'MPA', (52, 66))
51423	20697348	A preliminary report has also described point mutations in GNalpha11 in uveal melanomas, which were mutually exclusive with the GNalphaQ mutations.	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('point mutations', 'Var', (40, 55))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('GNalphaQ', 'Chemical', '-', (128, 136))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('GNalpha11', 'Gene', (59, 68))	('uveal melanomas', 'Disease', (72, 87))	('uveal melanomas', 'Phenotype', 'HP:0007716', (72, 87))	('uveal melanomas', 'Disease', 'MESH:C536494', (72, 87))
51424	20697348	Future investigation of this promising target should encompass further functional assays to understand the signaling mechanisms regulated by mutant GNalphaQ and GNalpha11.	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('mutant', 'Var', (141, 147))	('GNalphaQ', 'Chemical', '-', (148, 156))	('GNalphaQ', 'Gene', (148, 156))	('GNalpha11', 'Gene', (161, 170))
51425	20697348	In addition, directed therapy against the mutant GNalphaQ/GNalpha11 or the signaling pathways activated by these mutations may open up new therapeutic strategies for melanocytic tumors, particularly uveal tumors.	('mutant', 'Var', (42, 48))	('uveal tumors', 'Disease', 'MESH:D014604', (199, 211))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('uveal tumors', 'Disease', (199, 211))	('GNalphaQ', 'Chemical', '-', (49, 57))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('melanocytic tumors', 'Disease', 'MESH:D009508', (166, 184))	('melanocytic tumors', 'Disease', (166, 184))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('GNalphaQ/GNalpha11', 'Gene', (49, 67))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
51427	20697348	The promising results with PLX4032 and c-KIT inhibitors in melanoma patients with BRAF and c-KIT mutations, respectively, add to the growing list of successful clinical strategies exploiting activating genetic events in cancer.	('c-KIT', 'Gene', '3815', (39, 44))	('mutations', 'Var', (97, 106))	('c-KIT', 'Gene', '3815', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('BRAF', 'Gene', '673', (82, 86))	('KIT', 'molecular_function', 'GO:0005020', ('93', '96'))	('KIT', 'molecular_function', 'GO:0005020', ('41', '44'))	('BRAF', 'Gene', (82, 86))	('PLX4032', 'Chemical', 'MESH:D000077484', (27, 34))	('patients', 'Species', '9606', (68, 76))	('c-KIT', 'Gene', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('c-KIT', 'Gene', (91, 96))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('cancer', 'Disease', (220, 226))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
51430	20697348	Although the majority of patients with BRAF and c-KIT mutations have responded to inhibitors against these targets, both primary and secondary resistance have been observed.	('BRAF', 'Gene', '673', (39, 43))	('c-KIT', 'Gene', (48, 53))	('BRAF', 'Gene', (39, 43))	('responded', 'Reg', (69, 78))	('mutations', 'Var', (54, 63))	('c-KIT', 'Gene', '3815', (48, 53))	('inhibitors', 'MPA', (82, 92))	('KIT', 'molecular_function', 'GO:0005020', ('50', '53'))	('patients', 'Species', '9606', (25, 33))
51432	20697348	However, the pattern of mutations in melanoma, such as the frequent co-occurrence of BRAF mutations and PTEN loss, suggests that combinatorial approaches against multiple pathways may be more effective.	('mutations', 'Var', (90, 99))	('loss', 'NegReg', (109, 113))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('PTEN', 'Gene', (104, 108))	('PTEN', 'Gene', '5728', (104, 108))
51433	20697348	The recent identification of ERBB4 mutations in tumors with both BRAF and NRAS mutations suggests other combinatorial approaches.	('ERBB4', 'Gene', (29, 34))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('NRAS', 'Gene', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('NRAS', 'Gene', '4893', (74, 78))	('BRAF', 'Gene', '673', (65, 69))	('ERBB4', 'Gene', '2066', (29, 34))	('BRAF', 'Gene', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mutations', 'Var', (79, 88))	('mutations', 'Var', (35, 44))
51443	20697348	In addition to BRAF and c-KIT, there is ongoing research to identify therapeutic strategies to apply to melanoma patients with NRAS, AKT, ERBB4, GNalphaQ and GNalpha11 mutations.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('GNalpha11', 'Gene', (158, 167))	('AKT', 'Gene', (133, 136))	('mutations', 'Var', (168, 177))	('BRAF', 'Gene', '673', (15, 19))	('BRAF', 'Gene', (15, 19))	('KIT', 'molecular_function', 'GO:0005020', ('26', '29'))	('NRAS', 'Gene', (127, 131))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('patients', 'Species', '9606', (113, 121))	('AKT', 'Gene', '207', (133, 136))	('ERBB4', 'Gene', '2066', (138, 143))	('GNalphaQ', 'Gene', (145, 153))	('ERBB4', 'Gene', (138, 143))	('c-KIT', 'Gene', (24, 29))	('c-KIT', 'Gene', '3815', (24, 29))	('GNalphaQ', 'Chemical', '-', (145, 153))	('NRAS', 'Gene', '4893', (127, 131))
51446	20697348	As the cumulative prevalence of mutations in BRAF and NRAS is so high in this disease, it is possible that these tumors harbor other mutations that activate the RAS-RAF-MEK-MAPK signaling pathway.	('tumors', 'Disease', (113, 119))	('MAPK', 'molecular_function', 'GO:0004707', ('173', '177'))	('activate', 'PosReg', (148, 156))	('NRAS', 'Gene', '4893', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('signaling pathway', 'biological_process', 'GO:0007165', ('178', '195'))	('RAF', 'Gene', '22882', (46, 49))	('mutations', 'Var', (32, 41))	('BRAF', 'Gene', (45, 49))	('mutations', 'Var', (133, 142))	('BRAF', 'Gene', '673', (45, 49))	('MEK', 'Gene', '5609', (169, 172))	('RAF', 'Gene', '22882', (165, 168))	('MAPK signaling', 'biological_process', 'GO:0000165', ('173', '187'))	('NRAS', 'Gene', (54, 58))	('RAF', 'Gene', (46, 49))	('MEK', 'Gene', (169, 172))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('RAF', 'Gene', (165, 168))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
51461	33287369	One of the hits showed inverse agonism at the L129Q constitutively active mutant of CysLT2R, with potential utility against uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (124, 138))	('uveal melanoma', 'Disease', (124, 138))	('uveal melanoma', 'Disease', 'MESH:C536494', (124, 138))	('CysLT2R', 'Gene', '57105', (84, 91))	('L129Q', 'Var', (46, 51))	('L129Q', 'Mutation', 'p.L129Q', (46, 51))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('hits', 'Gene', '83641', (11, 15))	('agonism', 'MPA', (31, 38))	('CysLT2R', 'Gene', (84, 91))	('hits', 'Gene', (11, 15))
51467	33287369	Recently, a single nucleotide polymorphism L129Q in human CysLT2R was discovered as a driver oncogenic mutation leading to uveal melanoma and potentially some other melanocytic tumors.	('L129Q', 'Mutation', 'p.L129Q', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('CysLT2R', 'Gene', (58, 65))	('leading to', 'Reg', (112, 122))	('melanocytic tumors', 'Disease', (165, 183))	('melanocytic tumors', 'Disease', 'MESH:D009508', (165, 183))	('human', 'Species', '9606', (52, 57))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('single nucleotide polymorphism L129Q', 'Var', (12, 48))	('CysLT2R', 'Gene', '57105', (58, 65))	('uveal melanoma', 'Disease', 'MESH:C536494', (123, 137))	('L129Q', 'Var', (43, 48))	('uveal melanoma', 'Phenotype', 'HP:0007716', (123, 137))	('uveal melanoma', 'Disease', (123, 137))
51468	33287369	Further studies suggested that this mutation causes constitutive CysLT2R activation with a high bias towards Gq signaling, which was not effectively inhibited by known CysLT antagonists.	('activation', 'PosReg', (73, 83))	('CysLT2R', 'Gene', (65, 72))	('signaling', 'biological_process', 'GO:0023052', ('112', '121'))	('Gq signaling', 'MPA', (109, 121))	('CysLT2R', 'Gene', '57105', (65, 72))	('mutation', 'Var', (36, 44))
51488	33287369	Moreover, BRI-12359 and BRI-12417 demonstrated potent inverse agonism behavior against the constitutively active CysLT2R L129Q mutant involved in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('inverse agonism', 'MPA', (54, 69))	('BRI-12359', 'Chemical', '-', (10, 19))	('BRI-12359', 'Var', (10, 19))	('uveal melanoma', 'Disease', 'MESH:C536494', (146, 160))	('uveal melanoma', 'Phenotype', 'HP:0007716', (146, 160))	('uveal melanoma', 'Disease', (146, 160))	('BRI-12417', 'Chemical', '-', (24, 33))	('CysLT2R', 'Gene', '57105', (113, 120))	('BRI-12417', 'Var', (24, 33))	('L129Q', 'Mutation', 'p.L129Q', (121, 126))	('CysLT2R', 'Gene', (113, 120))
51505	33287369	Human Embryonic Kidney (HEK) 293 cells (ATCC CRL-1573) between passages 5 and 25 were seeded onto poly-L-Lysine-coated 384-well plates at 20,000 cells/well and transfected with 30 ng of cDNA coding for the wild-type CysLT1R or CysLT2R receptors or for the CysLT2R mutant L129Q, using the Lipofectamine 3000 (Thermo Fisher Scientific) transfection agent.	('CysLT1R', 'Gene', '10800', (216, 223))	('Human', 'Species', '9606', (0, 5))	('HEK) 293', 'CellLine', 'CVCL:0045', (24, 32))	('Embryonic Kidney', 'Disease', 'MESH:D007674', (6, 22))	('poly-L-Lysine', 'Chemical', '-', (98, 111))	('CysLT2R', 'Gene', '57105', (227, 234))	('L129Q', 'Var', (271, 276))	('CysLT2R', 'Gene', '57105', (256, 263))	('Lipofectamine', 'Chemical', 'MESH:C086724', (288, 301))	('CysLT2R', 'Gene', (227, 234))	('CysLT1R', 'Gene', (216, 223))	('Embryonic Kidney', 'Disease', (6, 22))	('L129Q', 'Mutation', 'p.L129Q', (271, 276))	('CysLT2R', 'Gene', (256, 263))
51510	33287369	For CysLT1R, the compounds retained were BRI-12328, BRI-12334, BRI-12359, BRI-12410, BRI-12411, BRI-12417, BRI-12424, BRI-12435, BRI-12450, and BRI-12458; for CysLT2R, these were BRI-12328, BRI-12334, BRI-12359, BRI-12401, BRI-12402, BRI-12405, BRI-12410, BRI-413, BRI-12417, BRI-12424, BRI-426, BRI-427, BRI-450, BRI-453, BRI-454, BRI-458, and BRI-466.	('BRI-12410', 'Chemical', '-', (245, 254))	('BRI', 'Chemical', 'MESH:D013459', (323, 326))	('BRI-12402', 'Var', (223, 232))	('BRI', 'Chemical', 'MESH:D013459', (305, 308))	('CysLT2R', 'Gene', (159, 166))	('BRI-12359', 'Var', (201, 210))	('BRI-12359', 'Chemical', '-', (201, 210))	('BRI', 'Chemical', 'MESH:D013459', (234, 237))	('BRI-413', 'Var', (256, 263))	('BRI-12417', 'Var', (265, 274))	('BRI-12424', 'Var', (276, 285))	('BRI-12410', 'Var', (245, 254))	('CysLT2R', 'Gene', '57105', (159, 166))	('BRI', 'Chemical', 'MESH:D013459', (179, 182))	('BRI', 'Chemical', 'MESH:D013459', (296, 299))	('BRI', 'Chemical', 'MESH:D013459', (265, 268))	('BRI', 'Chemical', 'MESH:D013459', (107, 110))	('BRI', 'Chemical', 'MESH:D013459', (52, 55))	('BRI-12401', 'Var', (212, 221))	('BRI-12424', 'Chemical', '-', (107, 116))	('BRI', 'Chemical', 'MESH:D013459', (201, 204))	('BRI', 'Chemical', 'MESH:D013459', (345, 348))	('BRI', 'Chemical', 'MESH:D013459', (314, 317))	('BRI', 'Chemical', 'MESH:D013459', (256, 259))	('BRI-454', 'Var', (323, 330))	('BRI', 'Chemical', 'MESH:D013459', (129, 132))	('BRI', 'Chemical', 'MESH:D013459', (74, 77))	('BRI-12417', 'Var', (96, 105))	('BRI', 'Chemical', 'MESH:D013459', (41, 44))	('BRI', 'Chemical', 'MESH:D013459', (96, 99))	('CysLT1R', 'Gene', '10800', (4, 11))	('BRI-12405', 'Var', (234, 243))	('BRI-12334', 'Var', (190, 199))	('BRI-12359', 'Chemical', '-', (63, 72))	('BRI-12410', 'Chemical', '-', (74, 83))	('BRI-453', 'Var', (314, 321))	('BRI-450', 'Var', (305, 312))	('CysLT1R', 'Gene', (4, 11))	('BRI-12411', 'Chemical', '-', (85, 94))	('BRI', 'Chemical', 'MESH:D013459', (287, 290))	('BRI-12328', 'Var', (179, 188))	('BRI-12417', 'Chemical', '-', (265, 274))	('BRI', 'Chemical', 'MESH:D013459', (63, 66))	('BRI', 'Chemical', 'MESH:D013459', (144, 147))	('BRI', 'Chemical', 'MESH:D013459', (223, 226))	('BRI-427', 'Var', (296, 303))	('BRI', 'Chemical', 'MESH:D013459', (276, 279))	('BRI-12424', 'Chemical', '-', (276, 285))	('BRI', 'Chemical', 'MESH:D013459', (118, 121))	('BRI-426', 'Var', (287, 294))	('BRI', 'Chemical', 'MESH:D013459', (245, 248))	('BRI', 'Chemical', 'MESH:D013459', (190, 193))	('BRI', 'Chemical', 'MESH:D013459', (85, 88))	('BRI-12417', 'Chemical', '-', (96, 105))	('BRI', 'Chemical', 'MESH:D013459', (332, 335))	('BRI', 'Chemical', 'MESH:D013459', (212, 215))
51512	33287369	The three best hits (BRI-12359, BRI-417, and BRI-424) were also tested using the LTC4 ligand (EC80 concentration) and in cells transiently expressing the constitutively active CysLT2R mutant L129Q.	('L129Q', 'Mutation', 'p.L129Q', (191, 196))	('BRI-12359', 'Chemical', '-', (21, 30))	('hits', 'Gene', (15, 19))	('BRI', 'Chemical', 'MESH:D013459', (32, 35))	('ligand', 'molecular_function', 'GO:0005488', ('86', '92'))	('L129Q', 'Var', (191, 196))	('CysLT2R', 'Gene', (176, 183))	('BRI', 'Chemical', 'MESH:D013459', (21, 24))	('BRI', 'Chemical', 'MESH:D013459', (45, 48))	('CysLT2R', 'Gene', '57105', (176, 183))	('hits', 'Gene', '83641', (15, 19))
51516	33287369	In those cases where reliable IC50 values could be obtained from the fits, we estimated functional inhibitory constants (Ki) using the Cheng-Prusoff equation: Ki = IC50 x ([A]/EC50 + 1)-1, in which [A] is the fixed concentration used of the LTD4 or LTC4 agonist, and EC50 the concentration of this agonist that produces a half-maximal response at the receptor.	('EC50', 'Var', (267, 271))	('[A]', 'Var', (198, 201))	('fits', 'Disease', 'MESH:D012640', (69, 73))	('LTD', 'biological_process', 'GO:0060292', ('241', '244'))	('fits', 'Disease', (69, 73))	('LTD4', 'Chemical', 'MESH:D017998', (241, 245))
51523	33287369	Thus, in the CysLT1R LiBERO-optimized structure, a water molecule in between residues Y261.35, Y301.39, R792.60 and Y832.64 was kept.	('Y832.64', 'Var', (116, 123))	('Y301.39', 'Var', (95, 102))	('CysLT1R', 'Gene', (13, 20))	('water', 'Chemical', 'MESH:D014867', (51, 56))	('Y832', 'Chemical', '-', (116, 120))	('R792.60', 'Var', (104, 111))	('Y261.35', 'Var', (86, 93))	('CysLT1R', 'Gene', '10800', (13, 20))	('Y261', 'CellLine', 'CVCL:2490', (86, 90))
51524	33287369	In the CysLT2R crystal structure and LiBERO-optimized structure, water molecule in between residues T902.56, R942.60 and S1173.31 was present during VLS.	('CysLT2R', 'Gene', (7, 14))	('S1173.31', 'Var', (121, 129))	('T902.56', 'Var', (100, 107))	('R942.60', 'Var', (109, 116))	('water', 'Chemical', 'MESH:D014867', (65, 70))	('CysLT2R', 'Gene', '57105', (7, 14))
51536	33287369	BRI-12359 was the most effective at inhibiting LTD4-induced IP1 production, with inhibitory efficacies of 94 +- 17% and 64 +- 10% for CysLT1R and CysLT2R, respectively.	('BRI-12359', 'Chemical', '-', (0, 9))	('BRI-12359', 'Var', (0, 9))	('CysLT1R', 'Gene', (134, 141))	('inhibiting', 'NegReg', (36, 46))	('CysLT2R', 'Gene', '57105', (146, 153))	('LTD4', 'Chemical', 'MESH:D017998', (47, 51))	('IP1', 'Gene', '8517', (60, 63))	('LTD', 'biological_process', 'GO:0060292', ('47', '50'))	('CysLT2R', 'Gene', (146, 153))	('CysLT1R', 'Gene', '10800', (134, 141))	('IP1', 'Gene', (60, 63))
51537	33287369	For the CysLT1R, five hits with robust dose response were identified: BRI-12359, BRI-12410, BRI-12411, BRI-12417, and BRI-12424.	('BRI-12411', 'Var', (92, 101))	('BRI-12410', 'Var', (81, 90))	('hits', 'Gene', '83641', (22, 26))	('hits', 'Gene', (22, 26))	('BRI-12359', 'Chemical', '-', (70, 79))	('BRI-12359', 'Var', (70, 79))	('CysLT1R', 'Gene', '10800', (8, 15))	('BRI-12410', 'Chemical', '-', (81, 90))	('BRI-12411', 'Chemical', '-', (92, 101))	('BRI-12424', 'Chemical', '-', (118, 127))	('BRI-12417', 'Chemical', '-', (103, 112))	('CysLT1R', 'Gene', (8, 15))	('BRI-12417', 'Var', (103, 112))	('BRI-12424', 'Var', (118, 127))
51538	33287369	Of these, BRI-12359 and BRI-12417 were able to completely inhibit the agonist-mediated response, with BRI-12359 being the more potent of the two (Figure 3a; Table 2).	('BRI-12359', 'Chemical', '-', (10, 19))	('BRI-12359', 'Var', (10, 19))	('BRI-12417', 'Chemical', '-', (24, 33))	('BRI-12417', 'Var', (24, 33))	('inhibit', 'NegReg', (58, 65))	('agonist-mediated response', 'MPA', (70, 95))	('BRI-12359', 'Chemical', '-', (102, 111))	('BRI-12359', 'Var', (102, 111))
51540	33287369	Compounds BRI-12410, BRI-12411, and BRI-12424 showed partial antagonism with Ki values in the 0.2 to 0.7 microM range.	('BRI-12424', 'Var', (36, 45))	('antagonism', 'MPA', (61, 71))	('BRI-12411', 'Var', (21, 30))	('BRI-12410', 'Var', (10, 19))	('BRI-12410', 'Chemical', '-', (10, 19))	('BRI-12424', 'Chemical', '-', (36, 45))	('BRI-12411', 'Chemical', '-', (21, 30))
51541	33287369	For CysLT2R, only BRI-12359 fully abolished the LTD4-induced response (Ki = 6.46 +- 0.43 microM), while BRI-12417 displayed partial inhibition (54 +- 6%) at 100 microM (Supplementary Table S1 and Figure S3).	('LTD4-induced response', 'MPA', (48, 69))	('abolished', 'NegReg', (34, 43))	('CysLT2R', 'Gene', (4, 11))	('BRI-12359', 'Var', (18, 27))	('BRI-12359', 'Chemical', '-', (18, 27))	('LTD', 'biological_process', 'GO:0060292', ('48', '51'))	('LTD4', 'Chemical', 'MESH:D017998', (48, 52))	('BRI-12417', 'Chemical', '-', (104, 113))	('CysLT2R', 'Gene', '57105', (4, 11))	('BRI-12417', 'Var', (104, 113))
51542	33287369	Considering that LTC4 is another prominent endogenous leukotriene that activates both CysLT1R and CysLT2R, we tested the three most promising hits (BRI-12359, BRI-12417 and BRI-12424) in the IP1 assay using LTC4 as agonist.	('BRI-12417', 'Var', (159, 168))	('CysLT2R', 'Gene', (98, 105))	('CysLT1R', 'Gene', '10800', (86, 93))	('BRI-12359', 'Chemical', '-', (148, 157))	('BRI-12359', 'Var', (148, 157))	('activates', 'PosReg', (71, 80))	('BRI-12424', 'Chemical', '-', (173, 182))	('CysLT2R', 'Gene', '57105', (98, 105))	('CysLT1R', 'Gene', (86, 93))	('leukotriene', 'Chemical', 'MESH:D015289', (54, 65))	('hits', 'Gene', '83641', (142, 146))	('BRI-12417', 'Chemical', '-', (159, 168))	('IP1', 'Gene', (191, 194))	('IP1', 'Gene', '8517', (191, 194))	('BRI-12424', 'Var', (173, 182))	('tested', 'Reg', (110, 116))	('hits', 'Gene', (142, 146))
51543	33287369	As one can see in Figure 3b, the compounds showed similar profiles with LTC4 vs LTD4 at the CysLT1R, with even slightly better sub-micromolar potencies (Ki = 0.7 +- 0.2 microM for both BRI-12417 and BRI-12359).	('BRI-12359', 'Chemical', '-', (199, 208))	('better', 'PosReg', (120, 126))	('CysLT1R', 'Gene', (92, 99))	('LTD', 'biological_process', 'GO:0060292', ('80', '83'))	('BRI-12417', 'Chemical', '-', (185, 194))	('CysLT1R', 'Gene', '10800', (92, 99))	('LTD4', 'Chemical', 'MESH:D017998', (80, 84))	('LTC4', 'Var', (72, 76))
51544	33287369	However, BRI-12359 and BRI-12417 were less effective at inhibiting the LTC4-induced response at CysLT2R at the EC80 concentration of LTC4 (Table 2), and their Ki values could not be calculated.	('BRI-12417', 'Chemical', '-', (23, 32))	('CysLT2R', 'Gene', (96, 103))	('BRI-12417', 'Var', (23, 32))	('inhibiting', 'NegReg', (56, 66))	('BRI-12359', 'Chemical', '-', (9, 18))	('BRI-12359', 'Var', (9, 18))	('CysLT2R', 'Gene', '57105', (96, 103))
51545	33287369	Recognizing that the sensitivity of the above assays depends on the concentration of agonist used, we also tested compound BRI-12359 in a more elaborate experimental paradigm designed to ascertain its pA2 values in Schild analysis as a more robust estimate of functional potency.	('BRI-12359', 'Chemical', '-', (123, 132))	('BRI-12359', 'Var', (123, 132))	('tested', 'Reg', (107, 113))
51547	33287369	As shown in Figure 4, BRI-12359 inhibited LTD4 signaling in a concentration-dependent manner.	('LTD4 signaling', 'MPA', (42, 56))	('inhibited', 'NegReg', (32, 41))	('LTD', 'biological_process', 'GO:0060292', ('42', '45'))	('LTD4', 'Chemical', 'MESH:D017998', (42, 46))	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))	('BRI-12359', 'Chemical', '-', (22, 31))	('BRI-12359', 'Var', (22, 31))
51548	33287369	Schild analysis revealed that the pA2 values for BRI-12359 are 6.5 +- 0.1 and 4.0 +- 0.2 (KB = 0.34 +- 0.09 microM and 105 +- 37 microM) for the CysLT1R and CysLT2R, respectively.	('CysLT1R', 'Gene', '10800', (145, 152))	('CysLT2R', 'Gene', (157, 164))	('BRI-12359', 'Chemical', '-', (49, 58))	('BRI-12359', 'Var', (49, 58))	('CysLT2R', 'Gene', '57105', (157, 164))	('CysLT1R', 'Gene', (145, 152))
51550	33287369	Given the efficient antagonism of the novel BRI-12359, BRI-12417 and BRI-12424 compounds, we hypothesized that these compounds might also inhibit receptor signaling at constitutively active CysLTR mutants, thereby acting as inverse agonists.	('BRI-12359', 'Var', (44, 53))	('BRI-12424', 'Chemical', '-', (69, 78))	('BRI-12359', 'Chemical', '-', (44, 53))	('BRI-12417', 'Chemical', '-', (55, 64))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('mutants', 'Var', (197, 204))	('receptor signaling', 'MPA', (146, 164))	('CysLTR', 'Gene', '10800', (190, 196))	('inhibit', 'NegReg', (138, 145))	('BRI-12424', 'Gene', (69, 78))	('CysLTR', 'Gene', (190, 196))
51551	33287369	This effect would be particularly interesting in the case of the L129Q CysLT2R mutant identified in uveal melanoma patients.	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('patients', 'Species', '9606', (115, 123))	('L129Q', 'Var', (65, 70))	('CysLT2R', 'Gene', '57105', (71, 78))	('uveal melanoma', 'Disease', (100, 114))	('L129Q', 'Mutation', 'p.L129Q', (65, 70))	('CysLT2R', 'Gene', (71, 78))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
51552	33287369	We tested these three compounds in the functional IP1 assay using cells transiently expressing the L129Q CysLT2R mutant, directly stimulated with a range of compound concentrations (1.6 to 100 muM).	('L129Q', 'Var', (99, 104))	('L129Q', 'Mutation', 'p.L129Q', (99, 104))	('CysLT2R', 'Gene', '57105', (105, 112))	('IP1', 'Gene', (50, 53))	('IP1', 'Gene', '8517', (50, 53))	('CysLT2R', 'Gene', (105, 112))
51556	33287369	Compounds BRI-12359 and BRI-12417 have the same polar amide group, but the predicted binding poses show that these two ligands have different critical interactions with the CysLT1R binding pocket (Figure 6).	('binding', 'molecular_function', 'GO:0005488', ('181', '188'))	('BRI-12359', 'Chemical', '-', (10, 19))	('BRI-12359', 'Var', (10, 19))	('interactions', 'Interaction', (151, 163))	('CysLT1R', 'Gene', '10800', (173, 180))	('amide', 'Chemical', 'MESH:D000577', (54, 59))	('BRI-12417', 'Chemical', '-', (24, 33))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('BRI-12417', 'Var', (24, 33))	('CysLT1R', 'Gene', (173, 180))	('binding', 'Interaction', (85, 92))
51557	33287369	The amide of BRI-12359 creates H-bond with the Y832.64, while amide of the BRI-12417 forms H-bond with the Y1043.33.	('amide', 'Chemical', 'MESH:D000577', (62, 67))	('H-bond', 'MPA', (31, 37))	('Y1043', 'Chemical', '-', (107, 112))	('Y832.64', 'Var', (47, 54))	('BRI-12359', 'Chemical', '-', (13, 22))	('BRI-12359', 'Var', (13, 22))	('BRI-12417', 'Chemical', '-', (75, 84))	('BRI-12417', 'Var', (75, 84))	('amide', 'Chemical', 'MESH:D000577', (4, 9))	('Y832', 'Chemical', '-', (47, 51))	('Y1043.33', 'Var', (107, 115))
51558	33287369	Moreover, compound BRI-12359 occupies the upper part of the binding pocket, while compound BRI-12417 leaves this area empty.	('binding', 'molecular_function', 'GO:0005488', ('60', '67'))	('BRI-12417', 'Chemical', '-', (91, 100))	('BRI-12417', 'Var', (91, 100))	('BRI-12359', 'Chemical', '-', (19, 28))	('BRI-12359', 'Var', (19, 28))
51559	33287369	BRI-12411 and BRI-12424 contain carboxy groups that interact with the R792.60 and Y1043.33 anchor residues in the CysLT1R binding pocket.	('BRI-12424', 'Chemical', '-', (14, 23))	('binding', 'molecular_function', 'GO:0005488', ('122', '129'))	('Y1043.33', 'Var', (82, 90))	('CysLT1R', 'Gene', '10800', (114, 121))	('Y1043', 'Chemical', '-', (82, 87))	('BRI-12424', 'Var', (14, 23))	('BRI-12411', 'Chemical', '-', (0, 9))	('R792.60', 'Var', (70, 77))	('CysLT1R', 'Gene', (114, 121))
51568	33287369	Compound BRI-12359 showed full antagonism at both CysLT1R and CysLT2R receptors, while compounds BRI-12410, BRI-12411, BRI-12417, and BRI-12424 showed partial antagonism at CysLT1R receptor with strong selectivity.	('CysLT1R', 'Gene', (50, 57))	('BRI-12424', 'Var', (134, 143))	('BRI-12411', 'Chemical', '-', (108, 117))	('CysLT2R', 'Gene', (62, 69))	('CysLT1R', 'Gene', '10800', (173, 180))	('BRI-12417', 'Chemical', '-', (119, 128))	('CysLT1R', 'Gene', '10800', (50, 57))	('BRI-12417', 'Var', (119, 128))	('BRI-12411', 'Var', (108, 117))	('BRI-12410', 'Chemical', '-', (97, 106))	('BRI-12359', 'Var', (9, 18))	('BRI-12359', 'Chemical', '-', (9, 18))	('BRI-12410', 'Var', (97, 106))	('CysLT2R', 'Gene', '57105', (62, 69))	('BRI-12424', 'Chemical', '-', (134, 143))	('antagonism', 'MPA', (31, 41))	('CysLT1R', 'Gene', (173, 180))
51569	33287369	The potencies of these compounds were verified in assays where CysLT1 was stimulated by a different endogenous agonist, LTC4, with functional affinities consistent between LTD4 and LTC4, and in the case of BRI-12359, BRI-12417, and BRI-12424 with some improvement in the Ki values, supporting activity of all five compounds in submicromolar range.	('BRI-12424', 'Var', (232, 241))	('LTD4', 'Var', (172, 176))	('CysLT1', 'Gene', '10800', (63, 69))	('stimulated', 'PosReg', (74, 84))	('improvement', 'PosReg', (252, 263))	('BRI-12359', 'Var', (206, 215))	('CysLT1', 'Gene', (63, 69))	('BRI-12359', 'Chemical', '-', (206, 215))	('BRI-12417', 'Chemical', '-', (217, 226))	('LTC4', 'Gene', (120, 124))	('BRI-12417', 'Var', (217, 226))	('LTD4', 'Chemical', 'MESH:D017998', (172, 176))	('BRI-12424', 'Chemical', '-', (232, 241))	('LTD', 'biological_process', 'GO:0060292', ('172', '175'))
51571	33287369	Importantly, the predicted physicochemical properties of identified hits, such as molecular weight MW < 460 Da, hydrophobicity clogP < 3.6, and solubility logS > -4.3 (see Table 1), make them promising candidates for further lead optimization to improve their antagonistic potencies.	('hits', 'Gene', '83641', (68, 72))	('hits', 'Gene', (68, 72))	('solubility', 'MPA', (144, 154))	('hydrophobicity', 'MPA', (112, 126))	('MW < 460 Da', 'Var', (99, 110))	('antagonistic potencies', 'MPA', (260, 282))	('improve', 'PosReg', (246, 253))
51579	33287369	Unlike previous drugs and drug candidates for CysLTRs, these new chemotypes are small (360 < MW < 460 Da) and hydrophilic (logP < 4), which makes them potential candidates for lead optimization with new drug-like properties.	('CysLTR', 'Gene', (46, 52))	('CysLTR', 'Gene', '10800', (46, 52))	('360 <', 'Var', (87, 92))
51589	33170593	In contrast with cutaneous melanoma, UM lacks BRAF mutations and demonstrates very low response rates to immune-checkpoint blockade.	('BRAF', 'Gene', (46, 50))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (17, 35))	('BRAF', 'Gene', '673', (46, 50))	('mutations', 'Var', (51, 60))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (17, 35))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('cutaneous melanoma', 'Disease', (17, 35))
51598	33170593	In contrast to cutaneous melanoma where mutations in BRAF, NRAS, NF1 and KIT genes are hallmarks of disease, pUM rarely if ever harbors these and instead commonly carries mutations in the G-protein alpha proteins q (GNAQ) or 11 (GNA11).	('GNA11', 'Gene', (229, 234))	('G-protein alpha proteins q', 'Protein', (188, 214))	('cutaneous melanoma', 'Disease', (15, 33))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (15, 33))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (15, 33))	('KIT', 'molecular_function', 'GO:0005020', ('73', '76'))	('mutations', 'Var', (40, 49))	('GNAQ', 'Gene', '2776', (216, 220))	('NRAS', 'Gene', '4893', (59, 63))	('KIT', 'Gene', (73, 76))	('BRAF', 'Gene', '673', (53, 57))	('GNA11', 'Gene', '2767', (229, 234))	('BRAF', 'Gene', (53, 57))	('hallmarks of disease', 'Disease', (87, 107))	('protein', 'cellular_component', 'GO:0003675', ('190', '197'))	('GNAQ', 'Gene', (216, 220))	('mutations', 'Var', (171, 180))	('NF1', 'Gene', '4763', (65, 68))	('hallmarks of disease', 'Disease', 'MESH:D003141', (87, 107))	('NRAS', 'Gene', (59, 63))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('NF1', 'Gene', (65, 68))	('KIT', 'Gene', '3815', (73, 76))	('carries', 'Reg', (163, 170))
51603	33170593	More specifically poor-prognosis M3-UM is associated with BAP1 loss, aberrant DNA methylation, somatic copy number aberrations and RNA alterations relative to good-prognosis D3-UM, where alternative genomic and transcriptional changes are observed.	('RNA', 'Gene', (131, 134))	('DNA', 'Gene', (78, 81))	('DNA methylation', 'biological_process', 'GO:0006306', ('78', '93'))	('RNA', 'cellular_component', 'GO:0005562', ('131', '134'))	('poor-prognosis M3-UM', 'Disease', (18, 38))	('M3-UM', 'Disease', (33, 38))	('BAP1', 'Gene', (58, 62))	('aberrant', 'Var', (69, 77))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))	('loss', 'NegReg', (63, 67))	('BAP1', 'Gene', '8314', (58, 62))
51608	33170593	From a study of 52 metastatic samples obtained in a prospective clinical trial of metastatic disease, massively parallel sequencing of clinically relevant cancer genes identified mutations known from pUM within TCGA and other databases including GNAQ, GNA11, BAP1, PLCB4, and amplification of chromosome arm 8q.	('amplification', 'Var', (276, 289))	('GNAQ', 'Gene', (246, 250))	('GNA11', 'Gene', (252, 257))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('PLCB4', 'Gene', '5332', (265, 270))	('BAP1', 'Gene', '8314', (259, 263))	('GNA11', 'Gene', '2767', (252, 257))	('chromosome', 'cellular_component', 'GO:0005694', ('293', '303'))	('mutations', 'Var', (179, 188))	('BAP1', 'Gene', (259, 263))	('GNAQ', 'Gene', '2776', (246, 250))	('PLCB4', 'Gene', (265, 270))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
51610	33170593	More recently, targeted sequencing of 500 genes in pUM and matched metastases from 35 patients revealed new driver mutations in genes such as CDKN2A, PBRM1, EZH2, PIK3R2, PIK3CA, PTEN, and MED12 with clonal and subclonal events.	('EZH2', 'Gene', '2146', (157, 161))	('PBRM1', 'Gene', (150, 155))	('mutations', 'Var', (115, 124))	('EZH2', 'Gene', (157, 161))	('PIK3CA', 'Gene', (171, 177))	('metastases', 'Disease', (67, 77))	('CDKN2A', 'Gene', '1029', (142, 148))	('PIK3R2', 'Gene', (163, 169))	('PIK3CA', 'Gene', '5290', (171, 177))	('patients', 'Species', '9606', (86, 94))	('PBRM1', 'Gene', '55193', (150, 155))	('PIK3R2', 'Gene', '5296', (163, 169))	('MED12', 'Gene', (189, 194))	('metastases', 'Disease', 'MESH:D009362', (67, 77))	('MED12', 'Gene', '9968', (189, 194))	('PTEN', 'Gene', (179, 183))	('CDKN2A', 'Gene', (142, 148))	('PTEN', 'Gene', '5728', (179, 183))
51633	33170593	OCM3 Uveal melanoma cell lines have been sequenced for the presence of activating mutations in codons 209 (exon 5) and 183 (exon 4) of GNAQ and GNA11.	('GNAQ', 'Gene', (135, 139))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (5, 19))	('GNAQ', 'Gene', '2776', (135, 139))	('GNA11', 'Gene', (144, 149))	('mutations in', 'Var', (82, 94))	('GNA11', 'Gene', '2767', (144, 149))	('activating', 'PosReg', (71, 81))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
51662	33170593	Considering the overall lower tumor purity in the metastatic samples from A091201 compared to primary tumors from TCGA, we sought to confirm that differences observed in NRP1 gene expression were not due to tumor purity differences between groups and observed no significant tumor purity differences between mUM patient OS groups (P=0.182, Student's t-test, two-sided).	('patient', 'Species', '9606', (312, 319))	('tumor', 'Disease', (275, 280))	('gene expression', 'biological_process', 'GO:0010467', ('175', '190'))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('primary tumors', 'Disease', 'MESH:D001932', (94, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('A091201', 'Var', (74, 81))	('lower', 'NegReg', (24, 29))	('expression', 'MPA', (180, 190))	('primary tumors', 'Disease', (94, 108))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (102, 107))	('NRP', 'biological_process', 'GO:0085015', ('170', '173'))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (30, 35))	('NRP1', 'Gene', (170, 174))
51667	33170593	In our study, siRNA knockdown of NRP1 markedly induced p27Kip1 expression compared to the scramble transfected control.	('induced', 'PosReg', (47, 54))	('NRP1', 'Gene', (33, 37))	('NRP', 'biological_process', 'GO:0085015', ('33', '36'))	('p27Kip1', 'Gene', '1027', (55, 62))	('expression', 'MPA', (63, 73))	('knockdown', 'Var', (20, 29))	('p27Kip1', 'Gene', (55, 62))
51684	33170593	In our analysis we observed that expression of NRP1 was associated with survival of patients of less than one year.	('NRP1', 'Gene', (47, 51))	('NRP', 'biological_process', 'GO:0085015', ('47', '50'))	('patients', 'Species', '9606', (84, 92))	('expression', 'Var', (33, 43))	('associated', 'Reg', (56, 66))
51697	33266349	No correlation between PD-L1 expression (in tumour and/or immune cells) and BRAF or NRAS mutations was observed.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('PD-L1', 'Gene', (23, 28))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('NRAS', 'Gene', (84, 88))	('tumour', 'Disease', (44, 50))	('PD-L1', 'Gene', '29126', (23, 28))	('NRAS', 'Gene', '4893', (84, 88))	('mutations', 'Var', (89, 98))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
51705	33266349	Notably, genetic studies have reported mutations in BRAF, NRAS, and KIT, and implication of ultraviolet radiation as a risk factor for CM.	('NRAS', 'Gene', '4893', (58, 62))	('reported', 'Reg', (30, 38))	('risk', 'Reg', (119, 123))	('KIT', 'molecular_function', 'GO:0005020', ('68', '71'))	('mutations', 'Var', (39, 48))	('KIT', 'Gene', '3815', (68, 71))	('BRAF', 'Gene', '673', (52, 56))	('KIT', 'Gene', (68, 71))	('NRAS', 'Gene', (58, 62))	('BRAF', 'Gene', (52, 56))
51706	33266349	Indeed, large cohorts of CM patients have identified BRAF and NRAS mutations in 29-50% and in 18%, respectively.	('NRAS', 'Gene', '4893', (62, 66))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('mutations', 'Var', (67, 76))	('patients', 'Species', '9606', (28, 36))	('NRAS', 'Gene', (62, 66))
51724	33266349	The inter-observer coefficient of agreement (Cohen Kappa) was performed to compare the expression of PD-L1 in IC with SP142 and SP263 Abs.	('SP142', 'Chemical', '-', (118, 123))	('PD-L1', 'Gene', '29126', (101, 106))	('SP263', 'Chemical', '-', (128, 133))	('SP142', 'Var', (118, 123))	('IC', 'Chemical', '-', (110, 112))	('SP263 Abs', 'Var', (128, 137))	('PD-L1', 'Gene', (101, 106))
51725	33266349	A good correlation was observed for IC between the SP263 and SP142 Abs (0.74).	('SP263', 'Var', (51, 56))	('SP263', 'Chemical', '-', (51, 56))	('SP142 Abs', 'Var', (61, 70))	('SP142', 'Chemical', '-', (61, 66))	('IC', 'Chemical', '-', (36, 38))
51737	33266349	The mutations BRAFV600E and NRASQ61R were mutually exclusive.	('NRASQ61R', 'Var', (28, 36))	('BRAFV600E', 'Var', (14, 23))	('BRAFV600E', 'Mutation', 'rs113488022', (14, 23))
51739	33266349	SP142/PD-L1-IC and SP263/PD-L1-IC positivity (>=1%) correlated with CD8+ TILs and with PD-1+ TILs (p = 0.04 and p < 0.001, respectively for SP142, and p = 0.0006 and p = 0.0002 for SP263, respectively).	('IC', 'Chemical', '-', (12, 14))	('PD-1+ TILs', 'Disease', (87, 97))	('CD8', 'Gene', (68, 71))	('CD8', 'Gene', '925', (68, 71))	('PD-L1', 'Gene', '29126', (25, 30))	('SP263', 'Chemical', '-', (19, 24))	('IC', 'Chemical', '-', (31, 33))	('PD-1+ TILs', 'Disease', 'MESH:D010300', (87, 97))	('PD-L1', 'Gene', (6, 11))	('SP142', 'Chemical', '-', (0, 5))	('SP142', 'Chemical', '-', (140, 145))	('SP263', 'Chemical', '-', (181, 186))	('SP142', 'Var', (140, 145))	('PD-L1', 'Gene', '29126', (6, 11))	('PD-L1', 'Gene', (25, 30))
51741	33266349	No correlation was found between PD-L1 expression (SP142 or SP263) or PD-1+ or CD8+ TILs and BRAF or NRAS mutations.	('BRAF', 'Gene', (93, 97))	('PD-L1', 'Gene', (33, 38))	('SP142', 'Chemical', '-', (51, 56))	('NRAS', 'Gene', (101, 105))	('SP142', 'Var', (51, 56))	('NRAS', 'Gene', '4893', (101, 105))	('PD-L1', 'Gene', '29126', (33, 38))	('CD8', 'Gene', (79, 82))	('CD8', 'Gene', '925', (79, 82))	('PD-1', 'Gene', (70, 74))	('mutations', 'Var', (106, 115))	('SP263', 'Chemical', '-', (60, 65))	('PD-1', 'Gene', '5133', (70, 74))	('BRAF', 'Gene', '673', (93, 97))	('SP263', 'Var', (60, 65))
51754	33266349	Finally, negative or weak staining of IC with SP142 and with CD8 was significantly associated with a pathological-Tumour 1 (pT1) stage and a bulbar localization.	('SP142', 'Chemical', '-', (46, 51))	('bulbar', 'Disease', (141, 147))	('SP142', 'Var', (46, 51))	('CD8', 'Gene', (61, 64))	('CD8', 'Gene', '925', (61, 64))	('IC', 'Chemical', '-', (38, 40))	('localization', 'biological_process', 'GO:0051179', ('148', '160'))	('associated', 'Reg', (83, 93))	('negative', 'NegReg', (9, 17))	('Tumour', 'Phenotype', 'HP:0002664', (114, 120))	('weak', 'NegReg', (21, 25))
51757	33266349	No significant association with DFS was noted with SP142 IC and SP263 IC or TC.	('SP263', 'Chemical', '-', (64, 69))	('SP142', 'Chemical', '-', (51, 56))	('SP142', 'Var', (51, 56))	('TC', 'Chemical', '-', (76, 78))	('IC', 'Chemical', '-', (70, 72))	('SP263 IC', 'Var', (64, 72))	('IC', 'Chemical', '-', (57, 59))
51758	33266349	No significant association with DSS was noted with SP142 and SP263 IC.	('SP142', 'Chemical', '-', (51, 56))	('SP142', 'Var', (51, 56))	('SP263', 'Chemical', '-', (61, 66))	('DSS', 'Chemical', '-', (32, 35))	('DSS', 'Disease', (32, 35))	('IC', 'Chemical', '-', (67, 69))	('SP263 IC', 'Var', (61, 69))
51759	33266349	No significant association was found for BRAFV600E or NRASQ61R mutations and clinical or pathological parameters.	('BRAFV600E', 'Mutation', 'rs113488022', (41, 50))	('NRASQ61R', 'Var', (54, 62))	('BRAFV600E', 'Gene', (41, 50))
51760	33266349	There was no significant association of a BRAF mutation with DSS or DFS but a NRAS mutation was significantly associated with shorter DSS (p = 0.03).	('BRAF', 'Gene', '673', (42, 46))	('shorter DSS', 'Disease', (126, 137))	('DSS', 'Chemical', '-', (61, 64))	('DSS', 'Chemical', '-', (134, 137))	('NRAS', 'Gene', (78, 82))	('mutation', 'Var', (83, 91))	('NRAS', 'Gene', '4893', (78, 82))	('BRAF', 'Gene', (42, 46))
51761	33266349	Finally, a multifactorial analysis showed that metastasis (pM1) was independently associated with worse DFS (p = 0.01, hazard ratio = 5.54, IC95% OR (1.31-23.30)).	('IC', 'Chemical', '-', (140, 142))	('pM1', 'Gene', '8834', (59, 62))	('pM1', 'Gene', (59, 62))	('DFS', 'Disease', (104, 107))	('metastasis', 'Var', (47, 57))
51764	33266349	The purpose of our study was to analyse PD-L1 expression alone or in combination with CD8 and PD-1 expression and the BRAFV600E and NRASQ61R status, as a prognostic factor in CM.	('PD-L1', 'Gene', (40, 45))	('BRAFV600E', 'Var', (118, 127))	('BRAFV600E', 'Mutation', 'rs113488022', (118, 127))	('CD8', 'Gene', (86, 89))	('CD8', 'Gene', '925', (86, 89))	('PD-L1', 'Gene', '29126', (40, 45))	('PD-1', 'Gene', (94, 98))	('PD-1', 'Gene', '5133', (94, 98))
51765	33266349	We tested 2 PD-L1 clones (SP142 and SP263) on 65 CM.	('PD-L1', 'Gene', (12, 17))	('SP142', 'Chemical', '-', (26, 31))	('PD-L1', 'Gene', '29126', (12, 17))	('SP263', 'Chemical', '-', (36, 41))	('SP142', 'Var', (26, 31))	('SP263', 'Var', (36, 41))
51769	33266349	Finally, the administration of therapeutic molecules targeting PD1/PD-L1 for some solid tumours is linked to specific biomarkers used as FDA approved companion diagnostic tests (SP142 for atezolizumab and SP263 for pembrolizumab treatment).	('atezolizumab', 'Chemical', 'MESH:C000594389', (188, 200))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('PD-L1', 'Gene', (67, 72))	('solid tumours', 'Disease', 'MESH:D009369', (82, 95))	('SP263', 'Chemical', '-', (205, 210))	('solid tumours', 'Disease', (82, 95))	('PD-L1', 'Gene', '29126', (67, 72))	('SP263', 'Var', (205, 210))	('pembrolizumab', 'Chemical', 'MESH:C582435', (215, 228))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('SP142', 'Chemical', '-', (178, 183))	('SP142', 'Var', (178, 183))
51771	33266349	The tumours with PD-L1/IC+ were practically the same with the SP142 and SP263 clones.	('SP142', 'Chemical', '-', (62, 67))	('SP263', 'Chemical', '-', (72, 77))	('SP142', 'Var', (62, 67))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('SP263', 'Var', (72, 77))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('PD-L1/IC', 'Gene', (17, 25))	('PD-L1/IC', 'Gene', '29126', (17, 25))	('tumours', 'Disease', (4, 11))
51776	33266349	We also found preferential labelling on IC, with clone SP142 (44%) and clone SP263 (58%).	('IC', 'Chemical', '-', (40, 42))	('preferential', 'PosReg', (14, 26))	('SP142', 'Chemical', '-', (55, 60))	('clone SP263', 'Var', (71, 82))	('SP263', 'Chemical', '-', (77, 82))	('labelling', 'MPA', (27, 36))
51782	33266349	We found a significant correlation between the positivity to PD-L1 (SP142 and SP263 clones) and CD8+ TILs and between the positivity of PD-L1 (SP142 and SP263 clones) and PD-1+ TILs.	('SP142', 'Var', (143, 148))	('PD-L1', 'Gene', (61, 66))	('CD8', 'Gene', (96, 99))	('SP263', 'Chemical', '-', (153, 158))	('PD-L1', 'Gene', (136, 141))	('PD-1+ TILs', 'Disease', (171, 181))	('SP263', 'Chemical', '-', (78, 83))	('PD-L1', 'Gene', '29126', (61, 66))	('CD8', 'Gene', '925', (96, 99))	('SP142', 'Chemical', '-', (68, 73))	('PD-1+ TILs', 'Disease', 'MESH:D010300', (171, 181))	('PD-L1', 'Gene', '29126', (136, 141))	('SP142', 'Chemical', '-', (143, 148))
51792	33266349	showed that PD-L1 positive staining in the tumour was associated with worse CM-related survival.	('CM-related survival', 'CPA', (76, 95))	('PD-L1', 'Gene', (12, 17))	('worse', 'NegReg', (70, 75))	('tumour', 'Disease', (43, 49))	('PD-L1', 'Gene', '29126', (12, 17))	('positive staining', 'Var', (18, 35))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
51798	33266349	In addition to immunotherapy, patients with melanoma can also benefit from anti-BRAF therapy when a mutation is detected.	('BRAF', 'Gene', (80, 84))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('mutation', 'Var', (100, 108))	('patients', 'Species', '9606', (30, 38))	('BRAF', 'Gene', '673', (80, 84))
51801	33266349	Moreover, some BRAF and NRAS mutations could be missed by using IHC alone since the anti-BRAF and anti-NRAS antibodies allow detecting only some specific BRAF and NRAS mutations.	('NRAS', 'Gene', '4893', (24, 28))	('BRAF', 'Gene', '673', (15, 19))	('NRAS', 'Gene', '4893', (103, 107))	('NRAS', 'Gene', (163, 167))	('BRAF', 'Gene', (15, 19))	('BRAF', 'Gene', '673', (154, 158))	('NRAS', 'Gene', '4893', (163, 167))	('BRAF', 'Gene', '673', (89, 93))	('BRAF', 'Gene', (154, 158))	('BRAF', 'Gene', (89, 93))	('NRAS', 'Gene', (24, 28))	('NRAS', 'Gene', (103, 107))	('mutations', 'Var', (168, 177))
51813	33266349	Formalin-Fixed Paraffin Embedded (FFPE) freshly cut serial tissue sections of 3microm thickness, mounted on positively charged slides were stained for PD-L1 with two anti-human PD-L1 rabbit monoclonal Ab, according to the manufacturer's recommendations: SP263 and SP142 antibodies (Abs) (Ventana, Tucson, AZ, USA).	('SP263', 'Var', (254, 259))	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('PD-L1', 'Gene', '29126', (151, 156))	('PD-L1', 'Gene', (177, 182))	('SP142 antibodies', 'Var', (264, 280))	('PD-L1', 'Gene', '29126', (177, 182))	('Paraffin', 'Chemical', 'MESH:D010232', (15, 23))	('PD-L1', 'Gene', (151, 156))	('SP263', 'Chemical', '-', (254, 259))	('SP142', 'Chemical', '-', (264, 269))
51826	33266349	NRASQ61R and BRAFV600E IHC expression was evaluated as previously described.	('BRAFV600E', 'Var', (13, 22))	('BRAFV600E', 'Mutation', 'rs113488022', (13, 22))	('NRASQ61R', 'Var', (0, 8))
51831	33266349	The impact of the following factors: patient age, gender, localization, NRAS status, BRAF status, associated lesion, histological type, thickness, mitosis, pTNM stage, and immunohistochemical markers SP142 IC and TC, SP263 IC and TC, PD-1 TILs, CD8+ TILs, NKP46 TILs were investigated by univariate and multivariate analysis.	('SP142', 'Chemical', '-', (200, 205))	('NRAS', 'Gene', '4893', (72, 76))	('IC', 'Chemical', '-', (223, 225))	('localization', 'biological_process', 'GO:0051179', ('58', '70'))	('mitosis', 'biological_process', 'GO:0000278', ('147', '154'))	('CD8', 'Gene', '925', (245, 248))	('IC', 'Chemical', '-', (206, 208))	('NRAS', 'Gene', (72, 76))	('TC', 'Chemical', '-', (213, 215))	('BRAF', 'Gene', (85, 89))	('TC', 'Chemical', '-', (230, 232))	('BRAF', 'Gene', '673', (85, 89))	('PD-1 TILs', 'Disease', 'MESH:D010300', (234, 243))	('SP142 IC', 'Var', (200, 208))	('PD-1 TILs', 'Disease', (234, 243))	('CD8', 'Gene', (245, 248))	('NKP46', 'Gene', (256, 261))	('SP263', 'Chemical', '-', (217, 222))	('NKP46', 'Gene', '9437', (256, 261))	('patient', 'Species', '9606', (37, 44))
51876	32971703	Recent studies have shown that Chromosome 3 deletion, BAP1 loss, chromosome 8q gain, chromosome 1p loss, and chromosome 6q loss are associated with poor prognosis.	('Chromosome', 'Gene', (31, 41))	('chromosome', 'Var', (65, 75))	('gain', 'PosReg', (79, 83))	('chromosome', 'cellular_component', 'GO:0005694', ('85', '95'))	('deletion', 'Var', (44, 52))	('Chromosome', 'cellular_component', 'GO:0005694', ('31', '41'))	('chromosome', 'Var', (85, 95))	('BAP1', 'Gene', '8314', (54, 58))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('loss', 'NegReg', (123, 127))	('loss', 'NegReg', (99, 103))	('loss', 'NegReg', (59, 63))	('BAP1', 'Gene', (54, 58))	('chromosome 6q', 'Var', (109, 122))	('chromosome', 'cellular_component', 'GO:0005694', ('65', '75'))
51877	32971703	In fact, it is now recognized that genetic changes play a very significant role in the growth, as well as metastatic potential of these tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('genetic changes', 'Var', (35, 50))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('metastatic potential', 'CPA', (106, 126))
51885	32532044	Oncogenic mutations in both GPCRs and G proteins (GNAS, GNAQ or GNA11) encoding genes have been identified in a significant number of tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('GPCR', 'Gene', '23566', (28, 32))	('identified', 'Reg', (96, 106))	('GPCR', 'Gene', (28, 32))	('GNA11', 'Gene', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('mutations', 'Var', (10, 19))	('GNAS', 'Gene', (50, 54))	('GNAQ', 'Gene', (56, 60))
51886	32532044	Interestingly, uveal melanoma driver mutations in GNAQ/GNA11 were identified for a decade, but their discovery did not lead to mutation-specific drug development, unlike it the case for BRAF mutations in cutaneous melanoma which saw enormous success.	('BRAF', 'Gene', (186, 190))	('GNAQ/GNA11', 'Gene', (50, 60))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('uveal melanoma', 'Phenotype', 'HP:0007716', (15, 29))	('uveal melanoma', 'Disease', (15, 29))	('cutaneous melanoma', 'Disease', (204, 222))	('uveal melanoma', 'Disease', 'MESH:C536494', (15, 29))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (204, 222))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (204, 222))	('mutations', 'Var', (37, 46))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('BRAF', 'Gene', '673', (186, 190))
51887	32532044	In this review, we summarize the current knowledge on cancer-associated alterations of GPCRs and G proteins and we focus on the case of uveal melanoma.	('alterations', 'Var', (72, 83))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('GPCR', 'Gene', '23566', (87, 91))	('G proteins', 'Protein', (97, 107))	('cancer', 'Disease', (54, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (136, 150))	('uveal melanoma', 'Disease', (136, 150))	('uveal melanoma', 'Disease', 'MESH:C536494', (136, 150))	('GPCR', 'Gene', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))
51895	32532044	In this review, we describe first the G protein-encoding gene alterations that have been identified in malignancies.	('malignancies', 'Disease', (103, 115))	('alterations', 'Var', (62, 73))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('malignancies', 'Disease', 'MESH:D009369', (103, 115))
51896	32532044	Second, we focus on the role of alterations in GNAQ/11 specifically in uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (71, 85))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('alterations', 'Var', (32, 43))	('uveal melanoma', 'Phenotype', 'HP:0007716', (71, 85))	('uveal melanoma', 'Disease', (71, 85))	('GNAQ/11', 'Gene', (47, 54))
51901	32532044	In the case of GPCRs stimulation and after conformation change of the receptors, the Galpha unit will load GTP instead of GDP, leading to its release from the Gbetagamma unit and from the receptor.	('GPCR', 'Gene', (15, 19))	('Galpha', 'Gene', (85, 91))	('GDP', 'Chemical', 'MESH:D006153', (122, 125))	('GPCR', 'Gene', '23566', (15, 19))	('GTP', 'Chemical', 'MESH:D006160', (107, 110))	('conformation change', 'Var', (43, 62))	('Gbeta', 'Gene', (159, 164))	('Galpha', 'Gene', '8802', (85, 91))	('release', 'MPA', (142, 149))	('Gbeta', 'Gene', '8801', (159, 164))
51907	32532044	Oncogenic mutations in these genes usually impair their GTPase activity, leading to constitutively active forms of GTP-bound proteins and to extended downstream signaling.	('extended', 'PosReg', (141, 149))	('activity', 'MPA', (63, 71))	('GTPase', 'Enzyme', (56, 62))	('GTP', 'Chemical', 'MESH:D006160', (56, 59))	('signaling', 'biological_process', 'GO:0023052', ('161', '170'))	('GTPase activity', 'molecular_function', 'GO:0003924', ('56', '71'))	('GTP-bound', 'Protein', (115, 124))	('GTP', 'Chemical', 'MESH:D006160', (115, 118))	('mutations', 'Var', (10, 19))	('impair', 'NegReg', (43, 49))	('downstream signaling', 'MPA', (150, 170))	('constitutively active forms of', 'MPA', (84, 114))
51909	32532044	Nonetheless, it was recently suggested that Galphas gain-of-function mutation can bypass the need for GTP binding and directly activate GDP-bound Galphas.	('Galphas', 'Gene', (44, 51))	('GTP', 'Chemical', 'MESH:D006160', (102, 105))	('activate', 'PosReg', (127, 135))	('GDP', 'Chemical', 'MESH:D006153', (136, 139))	('GTP', 'Protein', (102, 105))	('mutation', 'Var', (69, 77))	('Galphas', 'Gene', '79447', (146, 153))	('Galphas', 'Gene', (146, 153))	('gain-of-function', 'PosReg', (52, 68))	('GTP binding', 'molecular_function', 'GO:0005525', ('102', '113'))	('Galphas', 'Gene', '79447', (44, 51))
51910	32532044	Based on deep sequencing studies, it is known that mutations in GNAS occur in a wide range of tumors.	('GNAS', 'Gene', (64, 68))	('mutations', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('occur', 'Reg', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
51915	32532044	Interestingly, GNAS is described as a driver oncogene in a subset of colon adenomas and adenocarcinomas, and mutations in this gene can promote hyperplasia of endocrine cells in thyroid and pituitary tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('hyperplasia', 'Disease', 'MESH:D006965', (144, 155))	('adenocarcinomas', 'Disease', (88, 103))	('promote', 'PosReg', (136, 143))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('colon adenomas', 'Disease', (69, 83))	('pituitary tumors', 'Disease', 'MESH:D010911', (190, 206))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('hyperplasia', 'Disease', (144, 155))	('mutations', 'Var', (109, 118))	('adenocarcinomas', 'Disease', 'MESH:D000230', (88, 103))	('colon adenomas', 'Disease', 'MESH:D000236', (69, 83))	('pituitary tumors', 'Disease', (190, 206))
51917	32532044	Since COX2 has a known protumorigenic role in colon neoplasia, oncogenic mutations in GNAS may therefore activate a proinflammatory response, which favors tumor development.	('colon neoplasia', 'Disease', (46, 61))	('favors', 'PosReg', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('colon neoplasia', 'Disease', 'MESH:D003110', (46, 61))	('neoplasia', 'Phenotype', 'HP:0002664', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (155, 160))	('mutations', 'Var', (73, 82))	('COX2', 'Gene', '5743', (6, 10))	('COX2', 'Gene', (6, 10))	('colon neoplasia', 'Phenotype', 'HP:0100273', (46, 61))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('GNAS', 'Gene', (86, 90))	('activate', 'PosReg', (105, 113))	('proinflammatory response', 'MPA', (116, 140))
51918	32532044	GNAQ and GNA11 mutations are mutually exclusives and occur in about 2% of human cancers.	('GNA11', 'Gene', (9, 14))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (15, 24))	('cancers', 'Disease', (80, 87))	('GNAQ', 'Gene', (0, 4))	('human', 'Species', '9606', (74, 79))	('occur', 'Reg', (53, 58))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
51919	32532044	Mutations in GNAQ and GNA11 were mostly identified at residues involved in GTPase activity (Q209 or R183).	('Q209', 'Var', (92, 96))	('GNA11', 'Gene', (22, 27))	('GNAQ', 'Gene', (13, 17))	('GTPase activity', 'molecular_function', 'GO:0003924', ('75', '90'))	('GTPase', 'Protein', (75, 81))	('Mutations', 'Var', (0, 9))	('R183', 'Var', (100, 104))	('activity', 'MPA', (82, 90))	('GTP', 'Chemical', 'MESH:D006160', (75, 78))
51921	32532044	Details on the role of these mutations in uveal melanoma will be discussed in the next paragraph.	('mutations', 'Var', (29, 38))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('uveal melanoma', 'Disease', (42, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
51922	32532044	Several mutations in other Galpha encoding genes have been identified at a much lower frequency in human cancers and might not be activating.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('Galpha', 'Gene', '8802', (27, 33))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('mutations', 'Var', (8, 17))	('Galpha', 'Gene', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('human', 'Species', '9606', (99, 104))
51923	32532044	As an example, GNA15 (encoding Galphaq subunits) is significantly mutated in skin melanomas that do not often carry GNAQ or GNA11 mutations.	('mutated', 'Var', (66, 73))	('Galphaq', 'Gene', '2776', (31, 38))	('skin melanomas', 'Disease', 'MESH:D008545', (77, 91))	('Galphaq', 'Gene', (31, 38))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('skin melanomas', 'Disease', (77, 91))	('GNA15', 'Gene', '2769', (15, 20))	('GNA15', 'Gene', (15, 20))
51925	32532044	However, mutations in GPCRs encoding genes were identified in almost 20% human cancers.	('identified', 'Reg', (48, 58))	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutations', 'Var', (9, 18))	('GPCR', 'Gene', (22, 26))	('human', 'Species', '9606', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('GPCR', 'Gene', '23566', (22, 26))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
51926	32532044	Although many of these mutations are still uncharacterized regarding the impact on tumorigenesis, the most frequent were found in the thyroid-stimulating hormone receptor (TSHR), smoothened (SMO), glutamate metabotropic receptors (GRMs), the lysophosphatidic acid receptor (LPA) and the sphingosine-1-phosphate (S1P) receptor.	('sphingosine-1-phosphate', 'Chemical', 'MESH:C060506', (287, 310))	('TSHR', 'Gene', '7253', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('smoothened', 'Gene', (179, 189))	('thyroid-stimulating hormone receptor', 'Gene', (134, 170))	('tumor', 'Disease', (83, 88))	('smoothened', 'Gene', '6608', (179, 189))	('GRMs', 'Gene', (231, 235))	('TSHR', 'Gene', (172, 176))	('SMO', 'Gene', '6608', (191, 194))	('SMO', 'Gene', (191, 194))	('mutations', 'Var', (23, 32))	('thyroid-stimulating hormone receptor', 'Gene', '7253', (134, 170))	('LPA', 'Gene', (274, 277))	('lysophosphatidic acid', 'Chemical', 'MESH:C032881', (242, 263))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('frequent', 'Reg', (107, 115))
51929	32532044	In sum, hotspot mutations in GNAS, GNAQ and GNA11 have been identified in human tumors; however, a better characterization of the mutations on the other G protein-encoding genes is still needed.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('GNA11', 'Gene', (44, 49))	('mutations', 'Var', (16, 25))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('human', 'Species', '9606', (74, 79))	('GNAQ', 'Gene', (35, 39))	('GNAS', 'Gene', (29, 33))
51934	32532044	Moreover, by using different Galpha variants in which GTPase activity was lost, they could observe the formation of stable complexes with Gbetagamma and a prevention of its downstream interaction with PREX1.	('lost', 'NegReg', (74, 78))	('prevention', 'NegReg', (155, 165))	('GTP', 'Chemical', 'MESH:D006160', (54, 57))	('GTPase activity', 'molecular_function', 'GO:0003924', ('54', '69'))	('PREX1', 'Gene', '57580', (201, 206))	('GTPase', 'Protein', (54, 60))	('complexes', 'Interaction', (123, 132))	('Galpha', 'Gene', '8802', (29, 35))	('formation', 'biological_process', 'GO:0009058', ('103', '112'))	('interaction', 'Interaction', (184, 195))	('variants', 'Var', (36, 44))	('Gbeta', 'Gene', (138, 143))	('activity', 'MPA', (61, 69))	('Gbeta', 'Gene', '8801', (138, 143))	('Galpha', 'Gene', (29, 35))	('PREX1', 'Gene', (201, 206))
51937	32532044	Silencing of Gialpha2 in pancreatic cancer cells reduced the migration dependent on TGFbeta, oxytocin, SDF-1alpha, and EGF.	('TGFbeta', 'Gene', (84, 91))	('oxytocin', 'Gene', (93, 101))	('pancreatic cancer', 'Disease', (25, 42))	('reduced', 'NegReg', (49, 56))	('pancreatic cancer', 'Disease', 'MESH:D010190', (25, 42))	('EGF', 'Gene', (119, 122))	('oxytocin', 'Gene', '5020', (93, 101))	('TGFbeta', 'Gene', '7039', (84, 91))	('Gialpha2', 'Gene', (13, 21))	('EGF', 'Gene', '1950', (119, 122))	('migration', 'CPA', (61, 70))	('EGF', 'molecular_function', 'GO:0005154', ('119', '122'))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (25, 42))	('Silencing', 'Var', (0, 9))
51938	32532044	In addition, silencing of Gialpha2 in cells that overexpressed active RAC1 abolished their migration without affecting the basal RAC1 activation.	('Gialpha2', 'Protein', (26, 34))	('RAC1', 'Gene', '5879', (129, 133))	('RAC1', 'Gene', (70, 74))	('abolished', 'NegReg', (75, 84))	('RAC1', 'Gene', (129, 133))	('active', 'Var', (63, 69))	('migration', 'CPA', (91, 100))	('RAC1', 'Gene', '5879', (70, 74))	('silencing', 'Var', (13, 22))
51940	32532044	Indeed, genetically engineered mouse models could show cooperation between GnasR201C and KrasG12D mutations to promote the initiation of intraductal papillary mucinous neoplasms (IPMNs), the latter progressing into pancreatic ductal adenocarcinomas (PDAs) after additional Tp53 loss.	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (215, 248))	('papillary mucinous neoplasms', 'Disease', (149, 177))	('loss', 'NegReg', (278, 282))	('GnasR201C', 'Var', (75, 84))	('mouse', 'Species', '10090', (31, 36))	('KrasG12D', 'Gene', (89, 97))	('mucinous neoplasms', 'Phenotype', 'HP:0031495', (159, 177))	('progressing', 'Reg', (198, 209))	('mutations', 'Var', (98, 107))	('pancreatic ductal adenocarcinomas', 'Disease', (215, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('papillary mucinous neoplasms', 'Disease', 'MESH:D000077779', (149, 177))	('Tp53', 'Gene', (273, 277))	('neoplasms', 'Phenotype', 'HP:0002664', (168, 177))	('promote', 'PosReg', (111, 118))
51941	32532044	The authors not only observed an essential role of mutant Gnas in tumor maintenance but also a mechanism of protein kinase A-mediated suppression of salt-inducible kinases (Sik1-3), in association with lipid remodeling.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Gnas', 'Gene', (58, 62))	('tumor', 'Disease', (66, 71))	('lipid', 'Chemical', 'MESH:D008055', (202, 207))	('mutant', 'Var', (51, 57))	('suppression', 'NegReg', (134, 145))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('Sik1-3', 'Gene', (173, 179))
51942	32532044	As increased intracellular ROS levels are known to induce cell cycle arrest, senescence, and apoptosis, the deregulation of ROS levels may lead to tumorigenesis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (58, 75))	('apoptosis', 'CPA', (93, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))	('tumor', 'Disease', (147, 152))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('deregulation', 'Var', (108, 120))	('senescence', 'CPA', (77, 87))	('arrest', 'Disease', (69, 75))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('58', '75'))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('increased', 'PosReg', (3, 12))	('lead to', 'Reg', (139, 146))	('increased intracellular ROS levels', 'Phenotype', 'HP:0025464', (3, 37))	('ROS', 'Chemical', 'MESH:D017382', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('arrest', 'Disease', 'MESH:D006323', (69, 75))	('ROS', 'Chemical', 'MESH:D017382', (27, 30))	('senescence', 'biological_process', 'GO:0010149', ('77', '87'))	('intracellular ROS levels', 'MPA', (13, 37))	('intracellular', 'cellular_component', 'GO:0005622', ('13', '26'))
51958	32532044	In sum, multiple recent studies indicate a key role of GNA mutations in processes such as cell migration, promoter hypermethylation and ultimately tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('cell migration', 'biological_process', 'GO:0016477', ('90', '104'))	('cell migration', 'CPA', (90, 104))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('mutations', 'Var', (59, 68))	('promoter', 'MPA', (106, 114))	('GNA', 'Gene', (55, 58))
51960	32532044	Four main groups have been proposed as follows: mutant BRAF, mutant RAS, mutant NF1, and triple BRAF/RAS/NF1 wildtype (which includes mutations in other genes such as GNA).	('mutant', 'Var', (48, 54))	('NF1', 'Gene', (105, 108))	('NF1', 'Gene', (80, 83))	('NF1', 'Gene', '4763', (105, 108))	('NF1', 'Gene', '4763', (80, 83))	('mutant', 'Var', (73, 79))	('BRAF', 'Gene', (96, 100))	('mutant', 'Var', (61, 67))	('BRAF', 'Gene', '673', (55, 59))	('BRAF', 'Gene', '673', (96, 100))	('BRAF', 'Gene', (55, 59))
51961	32532044	For example, several zebrafish models of uveal melanoma have shown that melanocyte-specific expression of driver mutations GNAQ/GNA11(Q209L) led to considerable changes in the melanocyte biology of the fish.	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('uveal melanoma', 'Disease', (41, 55))	('zebrafish', 'Species', '7955', (21, 30))	('uveal melanoma', 'Disease', 'MESH:C536494', (41, 55))	('melanocyte biology of the fish', 'CPA', (176, 206))	('GNAQ/GNA11', 'Gene', (123, 133))	('Q209L', 'SUBSTITUTION', 'None', (134, 139))	('Q209L', 'Var', (134, 139))	('changes', 'Reg', (161, 168))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('mutations', 'Var', (113, 122))
51965	32532044	In a mouse model of leptomeningeal melanocytic neoplasms, the inducible expression of Gnaq(Q209L) variant at the neural crest stage before melanocyte differentiation, could favor the development of blue nevus-like lesions in the dermis, various melanocytic neoplasms in the cranium and spine but also melanoma of the central nervous system.	('Q209L', 'SUBSTITUTION', 'None', (91, 96))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (35, 56))	('leptomeningeal melanocytic neoplasms', 'Disease', (20, 56))	('blue nevus', 'Phenotype', 'HP:0100814', (198, 208))	('variant', 'Var', (98, 105))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (35, 56))	('leptomeningeal melanocytic neoplasms', 'Disease', 'MESH:D008577', (20, 56))	('spine', 'cellular_component', 'GO:0044309', ('286', '291'))	('favor', 'PosReg', (173, 178))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (245, 266))	('melanoma', 'Phenotype', 'HP:0002861', (301, 309))	('blue nevus-like lesions', 'Disease', (198, 221))	('mouse', 'Species', '10090', (5, 10))	('melanocyte differentiation', 'biological_process', 'GO:0030318', ('139', '165'))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (245, 266))	('neoplasms', 'Phenotype', 'HP:0002664', (257, 266))	('melanocytic neoplasms', 'Disease', (245, 266))	('melanoma of the central nervous system', 'Disease', (301, 339))	('melanoma of the central nervous system', 'Disease', 'MESH:D002493', (301, 339))	('nevus', 'Phenotype', 'HP:0003764', (203, 208))	('Q209L', 'Var', (91, 96))	('neoplasms', 'Phenotype', 'HP:0002664', (47, 56))	('melanoma of the central nervous system', 'Phenotype', 'HP:0100836', (301, 339))
51967	32532044	Thus, these results suggest an essential role of GNAQ mutations in the tumorigenesis of the melanocyte lineage.	('mutations', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('GNAQ', 'Gene', (49, 53))	('tumor', 'Disease', (71, 76))
51968	32532044	Nevertheless, these data do not explain the GNAQ/GNA11 selective mutational pressure observed in uveal melanoma compared to cutaneous melanoma or why they are considered to be oncogenic.	('mutational', 'Var', (65, 75))	('GNAQ/GNA11', 'Gene', (44, 54))	('cutaneous melanoma', 'Disease', (124, 142))	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('uveal melanoma', 'Disease', (97, 111))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (124, 142))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (124, 142))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
51970	32532044	GNAQ and GNA11 mutations were amplified by real-time PCR in the circulating DNA from the plasma of 22 patients with uveal melanoma, and Q209 mutations were detected by ultradeep sequencing in 9 of these.	('GNA11', 'Gene', (9, 14))	('patients', 'Species', '9606', (102, 110))	('mutations', 'Var', (15, 24))	('GNAQ', 'Gene', (0, 4))	('uveal melanoma', 'Disease', (116, 130))	('uveal melanoma', 'Disease', 'MESH:C536494', (116, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('uveal melanoma', 'Phenotype', 'HP:0007716', (116, 130))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))
51971	32532044	More recently, the identification of additional somatic mutations in uveal melanoma which could not be detected by classical NGS led to a tumor classification in four molecular and clinical subgroups that will allow a stratification of uveal melanoma patient management.	('mutations', 'Var', (56, 65))	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('tumor', 'Disease', (138, 143))	('uveal melanoma', 'Disease', (69, 83))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('patient', 'Species', '9606', (251, 258))	('uveal melanoma', 'Disease', 'MESH:C536494', (236, 250))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (236, 250))	('uveal melanoma', 'Disease', (236, 250))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
51972	32532044	Moreover, "secondary" driver mutations in the GNA pathway have also been detected in uveal melanoma at low frequencies, but might account for tumor development and progression.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('tumor', 'Disease', (142, 147))	('account', 'Reg', (130, 137))	('mutations', 'Var', (29, 38))	('GNA pathway', 'Pathway', (46, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (85, 99))	('uveal melanoma', 'Disease', 'MESH:C536494', (85, 99))	('uveal melanoma', 'Disease', (85, 99))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
51973	32532044	Of note, a retrospective study identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma, which showed lower tumor mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas.	('metastatic GNAQ/11', 'Gene', (59, 77))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (194, 213))	('tumor', 'Disease', (123, 128))	('ultraviolet', 'MPA', (157, 168))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('melanomas', 'Phenotype', 'HP:0002861', (204, 213))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (88, 102))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (194, 212))	('uveal melanoma', 'Disease', (88, 102))	('patients', 'Species', '9606', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (194, 213))	('mutant', 'Var', (78, 84))	('cutaneous melanomas', 'Disease', (194, 213))
51975	32532044	The authors concluded that primary GNAQ/11 mutant nonuveal melanoma is a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (161, 175))	('uveal melanoma', 'Disease', (161, 175))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('uveal melanoma', 'Disease', (53, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (53, 67))	('melanoma', 'Disease', (167, 175))	('mutant', 'Var', (43, 49))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (161, 175))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
51977	32532044	In uveal melanoma, hot spot somatic mutations in GNAQ/GNA11 lead to amino acid substitutions in exon 5 (p.Q209L or p.Q209P) or in exon 4 (p.R183C).	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('p.Q209L', 'SUBSTITUTION', 'None', (104, 111))	('p.R183C', 'SUBSTITUTION', 'None', (138, 145))	('p.R183C', 'Var', (138, 145))	('lead', 'Reg', (60, 64))	('p.Q209P', 'SUBSTITUTION', 'None', (115, 122))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('p.Q209P', 'Var', (115, 122))	('GNAQ/GNA11', 'Gene', (49, 59))	('p.Q209L', 'Var', (104, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
51978	32532044	While the first group of mutations prevents the intrinsic GTPase activity and therefore constitutively activates the protein, the second group leads to only a partial loss of GTPase activity.	('activity', 'MPA', (65, 73))	('mutations', 'Var', (25, 34))	('activity', 'MPA', (182, 190))	('activates', 'PosReg', (103, 112))	('GTP', 'Chemical', 'MESH:D006160', (175, 178))	('GTP', 'Chemical', 'MESH:D006160', (58, 61))	('GTPase', 'Protein', (175, 181))	('protein', 'Protein', (117, 124))	('GTPase activity', 'molecular_function', 'GO:0003924', ('58', '73'))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('GTPase', 'Protein', (58, 64))	('prevents', 'NegReg', (35, 43))	('GTPase activity', 'molecular_function', 'GO:0003924', ('175', '190'))
51979	32532044	In the first described uveal melanoma mouse model, an oncogenic Gnaq mutant under the control of the Rosa26 promoter was conditionally expressed by the cre recombinase under the control of melanocyte specific-promoter Mitf, and could initiate tumors which progressed to intravasation and metastases in 100% offspring.	('Mitf', 'Gene', '17342', (218, 222))	('mouse', 'Species', '10090', (38, 43))	('tumors', 'Disease', (243, 249))	('Gnaq', 'Gene', (64, 68))	('Mitf', 'Gene', (218, 222))	('mutant', 'Var', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('Rosa26', 'Gene', '14910', (101, 107))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (23, 37))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('uveal melanoma', 'Phenotype', 'HP:0007716', (23, 37))	('metastases', 'Disease', (288, 298))	('uveal melanoma', 'Disease', (23, 37))	('Rosa26', 'Gene', (101, 107))	('metastases', 'Disease', 'MESH:D009362', (288, 298))	('initiate', 'PosReg', (234, 242))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
51981	32532044	Interestingly, the overexpression of mutant Gnaq(Q209L) led to a loss of cutaneous melanocytes in adult mice, which could explain why this mutation is not found in cutaneous melanoma.	('overexpression', 'PosReg', (19, 33))	('loss', 'NegReg', (65, 69))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (164, 182))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (164, 182))	('Gnaq', 'Gene', (44, 48))	('mice', 'Species', '10090', (104, 108))	('mutant', 'Var', (37, 43))	('Q209L', 'Var', (49, 54))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('Q209L', 'SUBSTITUTION', 'None', (49, 54))	('cutaneous melanoma', 'Disease', (164, 182))	('cutaneous melanocytes', 'CPA', (73, 94))
51982	32532044	In another mouse model, melanocyte-specific expression of Gna11(Q209L) led to pigmented neoplastic lesions from melanocytes of the skin and noncutaneous organs, including the eye and leptomeninges.	('Gna11', 'Gene', (58, 63))	('pigmented neoplastic lesions', 'Disease', 'MESH:D010859', (78, 106))	('mouse', 'Species', '10090', (11, 16))	('Q209L', 'Var', (64, 69))	('led to', 'Reg', (71, 77))	('Q209L', 'SUBSTITUTION', 'None', (64, 69))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (88, 106))	('Gna11', 'Gene', '14672', (58, 63))	('pigmented neoplastic lesions', 'Disease', (78, 106))	('pigmented neoplastic lesions from melanocytes of the skin', 'Phenotype', 'HP:0002861', (78, 135))
51987	32532044	Interestingly, other members in the GNA signaling have also been identified with mutations specifically in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('uveal melanoma', 'Disease', (107, 121))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('mutations', 'Var', (81, 90))	('uveal melanoma', 'Disease', 'MESH:C536494', (107, 121))
51989	32532044	Recurrent mutations on codon 129 and 136 have been identified in uveal melanoma, but only the first one is oncogenic.	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('uveal melanoma', 'Disease', (65, 79))	('identified', 'Reg', (51, 61))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('mutations', 'Var', (10, 19))	('uveal melanoma', 'Disease', 'MESH:C536494', (65, 79))
51992	32532044	Mutations in members of this family, PLCB4 and PLCB3, were identified in patient-derived uveal melanoma samples.	('identified', 'Reg', (59, 69))	('PLCB3', 'Gene', (47, 52))	('PLCB4', 'Gene', (37, 42))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('Mutations', 'Var', (0, 9))	('patient', 'Species', '9606', (73, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (89, 103))	('uveal melanoma', 'Disease', (89, 103))	('uveal melanoma', 'Disease', 'MESH:C536494', (89, 103))	('PLCB4', 'Gene', '5332', (37, 42))	('PLCB3', 'Gene', '5331', (47, 52))
52001	32532044	The combination of BRAF/MEK inhibitors is not possible due to the absence of BRAF mutations in uveal melanoma.	('BRAF', 'Gene', '673', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (19, 23))	('MEK', 'Gene', (24, 27))	('MEK', 'Gene', '5609', (24, 27))	('BRAF', 'Gene', (77, 81))	('absence', 'NegReg', (66, 73))	('uveal melanoma', 'Disease', 'MESH:C536494', (95, 109))	('mutations', 'Var', (82, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (95, 109))	('uveal melanoma', 'Disease', (95, 109))
52002	32532044	Clinical trials for MEK inhibitors in combination with chemotherapy or other candidate targets (PKC, AKT) have shown no significant improvement in the progression free survival.	('AKT', 'Gene', '207', (101, 104))	('PKC', 'Gene', (96, 99))	('PKC', 'Gene', '112476', (96, 99))	('MEK', 'Gene', (20, 23))	('PKC', 'molecular_function', 'GO:0004697', ('96', '99'))	('MEK', 'Gene', '5609', (20, 23))	('AKT', 'Gene', (101, 104))	('inhibitors', 'Var', (24, 34))
52003	32532044	Indeed, the observed heterogeneity of MAPK activation in uveal melanoma with GNAQ/11 mutations could explain at least in part this phenomenon and, therefore, it does not allow this mutational status to be an efficient biomarker of MEK inhibitors' sensitivity.	('MAPK activation', 'biological_process', 'GO:0000187', ('38', '53'))	('MAPK', 'Gene', (38, 42))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('activation', 'PosReg', (43, 53))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('mutations', 'Var', (85, 94))	('GNAQ/11', 'Gene', (77, 84))	('uveal melanoma', 'Disease', (57, 71))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('MEK', 'Gene', (231, 234))	('MEK', 'Gene', '5609', (231, 234))	('MAPK', 'molecular_function', 'GO:0004707', ('38', '42'))
52005	32532044	Nevertheless, in light of the data discussed above, it appears quite obvious that the inhibition of oncogenic G proteins and their downstream targets should lead to the efficient killing of tumors that developed from driver GNA mutations.	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('oncogenic', 'Protein', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('mutations', 'Var', (228, 237))	('killing', 'CPA', (179, 186))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('inhibition', 'NegReg', (86, 96))
52007	32532044	Of these, GNAQ family-specific inhibitors FR900359 (FR) and YM254890 (YM) were described to block the downstream signaling of GNAQ variants in cancer cells with high GNAQ activity.	('downstream signaling', 'MPA', (102, 122))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('GNAQ', 'Gene', (126, 130))	('variants', 'Var', (131, 139))	('YM254890', 'Chemical', 'MESH:C475455', (60, 68))	('block', 'NegReg', (92, 97))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('FR900359', 'Chemical', 'MESH:C000607068', (42, 50))
52009	32532044	In uveal melanoma-specific mutations, both identified hotspots are located in the GTPase domain and play a key role in stabilizing the transition state for GTP hydrolysis.	('mutations', 'Var', (27, 36))	('GTP', 'Chemical', 'MESH:D006160', (82, 85))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('GTP hydrolysis', 'MPA', (156, 170))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('156', '170'))	('GTP', 'Chemical', 'MESH:D006160', (156, 159))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
52010	32532044	As discussed above, these variants differ because the R183C variant is still able to be regulated by receptor stimulation, whereas Q209L/P variants are uncoupled from GPCRs.	('GPCR', 'Gene', (167, 171))	('R183C', 'SUBSTITUTION', 'None', (54, 59))	('Q209L', 'Var', (131, 136))	('R183C', 'Var', (54, 59))	('Q209L', 'SUBSTITUTION', 'None', (131, 136))	('GPCR', 'Gene', '23566', (167, 171))
52017	32532044	It is therefore likely that these inhibitors will be tested in uveal melanoma with GPCR mutations in the future.	('GPCR', 'Gene', '23566', (83, 87))	('uveal melanoma', 'Disease', 'MESH:C536494', (63, 77))	('uveal melanoma', 'Disease', (63, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (63, 77))	('mutations', 'Var', (88, 97))	('GPCR', 'Gene', (83, 87))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))
52018	32532044	GDIs such as FR or YM are also expected to have an impact on tumors with aberrant activation of the G proteins, whether they carry a mutation on GNA genes or upstream their receptor.	('G proteins', 'Protein', (100, 110))	('tumors', 'Disease', (61, 67))	('mutation', 'Var', (133, 141))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('GNA genes', 'Gene', (145, 154))	('activation', 'PosReg', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('impact', 'Reg', (51, 57))
52019	32532044	Mutations in GNAQ and CYSTR2 represent the vast majority of uveal melanoma tumors and they activate downstream targets such as TRIO or ARF6.	('ARF6', 'Gene', (135, 139))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma tumors', 'Disease', (66, 81))	('TRIO', 'Gene', (127, 131))	('TRIO', 'Gene', '7204', (127, 131))	('ARF6', 'Gene', '382', (135, 139))	('melanoma tumors', 'Disease', 'MESH:D008545', (66, 81))	('GNAQ', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Disease', 'MESH:C536494', (60, 74))	('activate', 'PosReg', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('uveal melanoma', 'Disease', (60, 74))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('CYSTR2', 'Gene', (22, 28))
52020	32532044	Inhibitors of these two proteins have been developed, and it would make sense to test them in uveal melanoma  The observation that one of the direct causes for cancer development is the alteration of genes encoding for G proteins, leading to inactivate their GTPase function, has been known for a while.	('GTPase', 'Protein', (259, 265))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('inactivate', 'NegReg', (242, 252))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('uveal melanoma', 'Disease', (94, 108))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('alteration', 'Var', (186, 196))	('function', 'MPA', (266, 274))	('GTP', 'Chemical', 'MESH:D006160', (259, 262))
52022	32532044	The development of specific inhibitors for GNAQ, efficacy of which was shown in vitro and in vivo, has paved the road for a rational therapeutic approach in cancers carrying alterations in this particular protein.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('GNAQ', 'Protein', (43, 47))	('cancers', 'Disease', (157, 164))	('alterations', 'Var', (174, 185))
52027	32532044	The vast majority of tumors carry activating mutations in GNAQ/11, which leads to the overactivation of signaling such as ARF6/TRIO/RHO/RAC/YAP and PLCB/PKC/ERK.	('RAC', 'Gene', (136, 139))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('overactivation', 'PosReg', (86, 100))	('signaling', 'MPA', (104, 113))	('ARF6', 'Gene', '382', (122, 126))	('PKC', 'Gene', '112476', (153, 156))	('GNAQ/11', 'Gene', (58, 65))	('YAP', 'Gene', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('TRIO', 'Gene', (127, 131))	('RAC', 'Gene', '5879', (136, 139))	('tumors', 'Disease', (21, 27))	('ARF6', 'Gene', (122, 126))	('ERK', 'Gene', '5594', (157, 160))	('PKC', 'Gene', (153, 156))	('mutations', 'Var', (45, 54))	('ERK', 'molecular_function', 'GO:0004707', ('157', '160'))	('activating', 'PosReg', (34, 44))	('TRIO', 'Gene', '7204', (127, 131))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('PKC', 'molecular_function', 'GO:0004697', ('153', '156'))	('ERK', 'Gene', (157, 160))	('YAP', 'Gene', '10413', (140, 143))
52028	32532044	In addition, 40% uveal melanoma present genetic alterations in BAP1, which are associated with metastasis.	('associated', 'Reg', (79, 89))	('BAP1', 'Gene', (63, 67))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('genetic alterations', 'Var', (40, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))	('uveal melanoma', 'Disease', (17, 31))	('BAP1', 'Gene', '8314', (63, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (17, 31))
52047	32330128	Successful molecular subdivision of tumors originating from the same tissue may result in different treatments targeting a specific tumor type, as is found in the case of ERBB2-amplified breast cancer and EGFR mutant lung carcinoma.	('mutant', 'Var', (210, 216))	('EGFR', 'Gene', '1956', (205, 209))	('EGFR', 'molecular_function', 'GO:0005006', ('205', '209'))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('lung carcinoma', 'Disease', (217, 231))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('ERBB2', 'Gene', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('EGFR', 'Gene', (205, 209))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('tumors', 'Disease', (36, 42))	('breast cancer', 'Disease', (187, 200))	('result in', 'Reg', (80, 89))	('ERBB2', 'Gene', '2064', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('lung carcinoma', 'Disease', 'MESH:D008175', (217, 231))	('tumors', 'Disease', 'MESH:D009369', (36, 42))
52140	28680759	For example, driver mutations in BRAF and NRAS commonly detected in CM rarely appear in UM, whereas GNAQ and GNA11 mutations are found in approximately 80-90% of UM and are rarely seen in CM.	('NRAS', 'Gene', '4893', (42, 46))	('GNAQ', 'Gene', '2776', (100, 104))	('BRAF', 'Gene', '673', (33, 37))	('CM', 'Phenotype', 'HP:0012056', (68, 70))	('CM', 'Phenotype', 'HP:0012056', (188, 190))	('BRAF', 'Gene', (33, 37))	('GNA11', 'Gene', (109, 114))	('UM', 'Phenotype', 'HP:0007716', (162, 164))	('GNAQ', 'Gene', (100, 104))	('GNA11', 'Gene', '2767', (109, 114))	('UM', 'Phenotype', 'HP:0007716', (88, 90))	('NRAS', 'Gene', (42, 46))	('mutations', 'Var', (20, 29))
52195	28680759	Recently, an increasing number of studies have attributed checkpoint blockade efficacy to high mutation rates in CM and lung cancer, a process suggested to increase tumor immunogenicity through generation of neoantigens.	('tumor', 'Disease', (165, 170))	('lung cancer', 'Disease', (120, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('increase', 'PosReg', (156, 164))	('CM', 'Phenotype', 'HP:0012056', (113, 115))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('mutation', 'Var', (95, 103))
52196	28680759	However, UM presents a limited mutational load compared with CM, which has been purported to contribute to the poor success of trials investigating checkpoint blockade in this type of cancer.	('cancer', 'Disease', (184, 190))	('mutational load', 'Var', (31, 46))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('CM', 'Phenotype', 'HP:0012056', (61, 63))
52197	28680759	Different checkpoint blocking regimens act through distinct mechanisms, with CTLA-4 blockade suggested to act in the periphery causing increased infiltration of CD8+ lymphocytes into tumors, and PD-1 blockade mediating effects within the tumor microenvironment on T cells in the immediate vicinity.	('infiltration', 'CPA', (145, 157))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('PD-1', 'Gene', (195, 199))	('CD8', 'Gene', (161, 164))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('CTLA-4', 'Gene', '1493', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('PD-1', 'Gene', '5133', (195, 199))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('increased', 'PosReg', (135, 144))	('CD8', 'Gene', '925', (161, 164))	('tumor', 'Disease', (238, 243))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', (183, 188))	('CTLA-4', 'Gene', (77, 83))	('tumors', 'Disease', (183, 189))	('blockade', 'Var', (84, 92))
52199	28680759	Furthermore, combination CTLA-4 and PD-1 blockade improves recruitment of peripheral T cells and blocks the inhibitory resistance mechanisms within the tumor microenvironment resulting in greater objective response rates in CM.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('improves', 'PosReg', (50, 58))	('objective response', 'CPA', (196, 214))	('PD-1', 'Gene', '5133', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('blockade', 'Var', (41, 49))	('CTLA-4', 'Gene', '1493', (25, 31))	('CM', 'Phenotype', 'HP:0012056', (224, 226))	('blocks', 'NegReg', (97, 103))	('PD-1', 'Gene', (36, 40))	('recruitment', 'MPA', (59, 70))	('inhibitory resistance mechanisms', 'MPA', (108, 140))	('CTLA-4', 'Gene', (25, 31))	('greater', 'PosReg', (188, 195))
52219	26748926	Germline BAP1 mutations misreported as somatic based on tumor-only testing We present three unrelated patients with germline mutations in BAP1 misreported as somatic mutations.	('mutations', 'Var', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('BAP1', 'Gene', '8314', (138, 142))	('patients', 'Species', '9606', (102, 110))	('tumor', 'Disease', (56, 61))	('BAP1', 'Gene', (138, 142))	('BAP1', 'Gene', '8314', (9, 13))	('BAP1', 'Gene', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
52221	26748926	One of these patients presented with an invasive breast cancer with the tumor tissue showing partial loss of the mutant rather than the wild type allele, suggesting that the germline BAP1 mutation didn't contribute to breast cancer development in this patient.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('loss', 'NegReg', (101, 105))	('invasive breast cancer', 'Disease', 'MESH:D001943', (40, 62))	('patients', 'Species', '9606', (13, 21))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('BAP1', 'Gene', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('patient', 'Species', '9606', (252, 259))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('patient', 'Species', '9606', (13, 20))	('tumor', 'Disease', (72, 77))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('breast cancer', 'Disease', (218, 231))	('BAP1', 'Gene', '8314', (183, 187))	('mutation', 'Var', (188, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('invasive breast cancer', 'Disease', (40, 62))
52223	26748926	In patients with somatic mutations reported from laboratories carrying out tumor-only genomic testing, the possibility that a variant may be a germline mutation should be considered, especially if the personal and/or family history suggests hereditary cancer predisposition.	('hereditary cancer', 'Disease', 'MESH:D009369', (241, 258))	('hereditary cancer', 'Disease', (241, 258))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('patients', 'Species', '9606', (3, 11))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('variant', 'Var', (126, 133))	('tumor', 'Disease', (75, 80))
52224	26748926	Since tumor-only testing can reveal germline mutations, ethical issues for patients being tested should be considered including proper consent and genetic counseling.	('germline mutations', 'Var', (36, 54))	('patients', 'Species', '9606', (75, 83))	('reveal', 'Reg', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
52227	26748926	Results are based on in-house developed calling algorithms based on tumor cellularity and minor allele frequency (MAF) of the mutation.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('mutation', 'Var', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
52229	26748926	Based on the strong personal and family histories of cancer we reevaluated them in our laboratory and determined that the reported mutations were germline.	('mutations', 'Var', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))
52234	26748926	A non-synonymous c.604T>C, p.W202R variant of uncertain significance was reported as somatic with a tumor content estimated at 75 %, minor allele frequency of 35.2 % and sequencing allele depth of 500.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('c.604T>C', 'Mutation', 'c.604T>C', (17, 25))	('p.W202R', 'Mutation', 'p.W202R', (27, 34))	('p.W202R', 'Var', (27, 34))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
52236	26748926	Briefly, FUM152-III.2 presented with a metastatic UM to the breast with family history of a father with UM and a grandfather with a tumor of unknown origin.	('UM', 'Phenotype', 'HP:0007716', (10, 12))	('metastatic UM to the breast', 'Disease', (39, 66))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('UM', 'Phenotype', 'HP:0007716', (104, 106))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('tumor', 'Disease', (132, 137))	('FUM152-III.2', 'Var', (9, 21))
52241	26748926	Direct sequencing and genotyping were carried out on DNA extracted from peripheral blood leukocytes in all patients and from tumor tissues on FUM103-III.1 and FUM153-III.4 according to our previously published protocol.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('FUM153-III.4', 'Var', (159, 171))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('UM', 'Phenotype', 'HP:0007716', (160, 162))	('tumor', 'Disease', (125, 130))	('UM', 'Phenotype', 'HP:0007716', (143, 145))	('patients', 'Species', '9606', (107, 115))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))
52243	26748926	Sequencing confirmed the germline origin for three (FUM152-III.2, FUM103-III.1, and FUM153-III.4) out of the four tested patients, Table 1.	('FUM103-III.1', 'Var', (66, 78))	('FUM153-III.4', 'Var', (84, 96))	('FUM152-III.2', 'Var', (52, 64))	('UM', 'Phenotype', 'HP:0007716', (53, 55))	('UM', 'Phenotype', 'HP:0007716', (67, 69))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('patients', 'Species', '9606', (121, 129))
52244	26748926	Similar allele heights of both mutant and wild type alleles were observed in both tumor and germline DNA in FUM103-III.1.	('mutant', 'Var', (31, 37))	('germline DNA', 'CPA', (92, 104))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('DNA', 'cellular_component', 'GO:0005574', ('101', '104'))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('UM', 'Phenotype', 'HP:0007716', (109, 111))	('tumor', 'Disease', (82, 87))
52245	26748926	In the tumor tissue the wild type allele was more predominant suggesting partial deletion of the mutant allele in the tumor, Fig.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mutant', 'Var', (97, 103))	('partial deletion', 'Var', (73, 89))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
52247	26748926	The mutation is located in the ubiquitin carboxyl-terminal hydrolase domain of BAP1 and predicted to be pathogenic by both SIFT, Mutation Taster, and PolyPhen software.	('pathogenic', 'Reg', (104, 114))	('BAP1', 'Gene', '8314', (79, 83))	('BAP1', 'Gene', (79, 83))	('mutation', 'Var', (4, 12))	('SIFT', 'Disease', (123, 127))	('ubiquitin', 'molecular_function', 'GO:0031386', ('31', '40'))	('SIFT', 'Disease', 'None', (123, 127))
52248	26748926	We and others have characterized a novel hereditary cancer predisposition syndrome caused by germline mutation in BAP1.	('hereditary cancer', 'Disease', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('BAP1', 'Gene', '8314', (114, 118))	('hereditary cancer', 'Disease', 'MESH:D009369', (41, 58))	('BAP1', 'Gene', (114, 118))	('germline mutation', 'Var', (93, 110))	('caused by', 'Reg', (83, 92))
52251	26748926	This would indicate that tumor testing of many of these patients could be positive for mutation in BAP1.	('patients', 'Species', '9606', (56, 64))	('BAP1', 'Gene', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('BAP1', 'Gene', '8314', (99, 103))	('mutation', 'Var', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
52253	26748926	Given the high frequency of copy number variation or large chromosomal deletions in chromosome 3 in many of these tumors assessment of minor allele frequency and tumor content may not be sufficient to differentiate between somatic and germline origin of the mutation with tumor only testing.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (162, 167))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('tumor', 'Disease', (114, 119))	('copy number variation', 'Var', (28, 49))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
52255	26748926	However, our assessment of both germline and tumor DNAs showed that the lost allele fraction in the tumor is the mutant rather than the wild type.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (45, 50))	('mutant', 'Var', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
52258	26748926	The lack of evidence of biallelic inactivation in breast cancer tumor tissue suggests that the germline BAP1 mutation didn't contribute to breast cancer development in this patient.	('BAP1', 'Gene', '8314', (104, 108))	('breast cancer tumor', 'Disease', 'MESH:D001943', (50, 69))	('breast cancer tumor', 'Disease', (50, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('BAP1', 'Gene', (104, 108))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Disease', (139, 152))	('patient', 'Species', '9606', (173, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mutation', 'Var', (109, 117))
52259	26748926	Characterization of the germline origin of the mutation in BAP1 will have significant impact on the management including screening for additional cancers in the patients and their family members.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('BAP1', 'Gene', (59, 63))	('mutation', 'Var', (47, 55))	('patients', 'Species', '9606', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('impact', 'Reg', (86, 92))	('BAP1', 'Gene', '8314', (59, 63))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
52261	26748926	Personal and family history could be an important guide for selection of patients with reported somatic BAP1 mutation for further germline testing.	('BAP1', 'Gene', '8314', (104, 108))	('patients', 'Species', '9606', (73, 81))	('BAP1', 'Gene', (104, 108))	('mutation', 'Var', (109, 117))
52262	26748926	Based on reported families about 90 % of patients with germline BAP1 mutation will have family history suggestive of BAP1-TPDS.	('BAP1', 'Gene', '8314', (117, 121))	('germline', 'Var', (55, 63))	('BAP1', 'Gene', (117, 121))	('patients', 'Species', '9606', (41, 49))	('BAP1', 'Gene', '8314', (64, 68))	('BAP1', 'Gene', (64, 68))
52268	26748926	In patients with reported somatic mutations from laboratories carrying out tumor-only genomic testing, consideration of the possibility that a variant may be a germline mutation is warranted especially if personal and/or family history suggest hereditary cancer predisposition.	('hereditary cancer', 'Disease', 'MESH:D009369', (244, 261))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('hereditary cancer', 'Disease', (244, 261))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('variant', 'Var', (143, 150))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
52269	23933888	Checkpoint Modulation in Melanoma: An Update on Ipilimumab and Future Directions Ipilimumab, an anti-cytotoxic T-lymphocyte antigen 4 antibody, was the first therapy demonstrated to improve overall survival in melanoma.	('antibody', 'cellular_component', 'GO:0019814', ('134', '142'))	('Ipilimumab', 'Var', (81, 91))	('antibody', 'cellular_component', 'GO:0019815', ('134', '142'))	('Melanoma', 'Disease', 'MESH:D008545', (25, 33))	('antibody', 'molecular_function', 'GO:0003823', ('134', '142'))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (81, 91))	('improve', 'PosReg', (182, 189))	('Melanoma', 'Disease', (25, 33))	('cytotoxic T-lymphocyte antigen 4', 'Gene', '1493', (101, 133))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (48, 58))	('cytotoxic T-lymphocyte antigen 4', 'Gene', (101, 133))	('antibody', 'cellular_component', 'GO:0042571', ('134', '142'))	('overall', 'MPA', (190, 197))	('melanoma', 'Disease', 'MESH:D008545', (210, 218))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('lymphocyte antigen', 'molecular_function', 'GO:0005557', ('113', '131'))	('melanoma', 'Disease', (210, 218))	('Melanoma', 'Phenotype', 'HP:0002861', (25, 33))
52275	23933888	Following these positive phase III studies, ipilimumab became a new standard of care, and was soon joined by vemurafenib, a selective B-Raf inhibitor that improves overall survival among patients with the activating V600E BRAF mutation.	('patients', 'Species', '9606', (187, 195))	('BRAF', 'Gene', '673', (222, 226))	('B-Raf', 'Gene', '673', (134, 139))	('B-Raf', 'Gene', (134, 139))	('BRAF', 'Gene', (222, 226))	('V600E', 'Mutation', 'rs113488022', (216, 221))	('ipilimumab', 'Chemical', 'MESH:D000074324', (44, 54))	('vemurafenib', 'Chemical', 'MESH:D000077484', (109, 120))	('improves', 'PosReg', (155, 163))	('overall survival', 'MPA', (164, 180))	('activating V600E', 'Var', (205, 221))
52302	23933888	Preclinical studies indicate that B-Raf inhibitors can increase melanoma antigen expression, decrease secretion of immunosuppressive cytokines, and induce T-cell infiltration of tumor sites while preserving T-cell function.	('tumor', 'Disease', (178, 183))	('increase', 'PosReg', (55, 63))	('inhibitors', 'Var', (40, 50))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('melanoma', 'Disease', (64, 72))	('secretion', 'biological_process', 'GO:0046903', ('102', '111'))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('B-Raf', 'Gene', '673', (34, 39))	('induce', 'Reg', (148, 154))	('B-Raf', 'Gene', (34, 39))	('decrease', 'NegReg', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('secretion of immunosuppressive cytokines', 'MPA', (102, 142))	('expression', 'MPA', (81, 91))
52345	23933888	This indicates that ipilimumab is a reasonable choice to consider in patients with mucosal melanoma, especially in patients for whom a targetable mutation such as a c-KIT mutation cannot be identified.	('c-KIT', 'Gene', (165, 170))	('patients', 'Species', '9606', (115, 123))	('mutation', 'Var', (171, 179))	('mucosal melanoma', 'Disease', (83, 99))	('c-KIT', 'Gene', '3815', (165, 170))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('KIT', 'molecular_function', 'GO:0005020', ('167', '170'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (83, 99))	('patients', 'Species', '9606', (69, 77))	('ipilimumab', 'Chemical', 'MESH:D000074324', (20, 30))
52378	23933888	Inhibition of these interactions can enhance T-cell response in vitro and stimulate antitumor activity in preclinical models.	('stimulate', 'PosReg', (74, 83))	('interactions', 'Interaction', (20, 32))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('T-cell response', 'CPA', (45, 60))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (88, 93))	('enhance', 'PosReg', (37, 44))
52400	23933888	The rationale is similar: antibodies against PD-L1 impede the inhibitory interactions of PD-1 with PD-L1.	('impede', 'NegReg', (51, 57))	('antibodies', 'Var', (26, 36))	('PD-1', 'Gene', (89, 93))	('PD-L1', 'Gene', '29126', (45, 50))	('PD-1', 'Gene', '5133', (89, 93))	('PD-L1', 'Gene', (99, 104))	('inhibitory interactions', 'MPA', (62, 85))	('PD-L1', 'Gene', '29126', (99, 104))	('PD-L1', 'Gene', (45, 50))
52439	33428593	High ALKBH5 expression predicted worse outcome in patients with UM.	('patients', 'Species', '9606', (50, 58))	('High', 'Var', (0, 4))	('ALKBH5', 'Gene', (5, 11))	('UM', 'Phenotype', 'HP:0007716', (64, 66))	('expression', 'MPA', (12, 22))
52441	33428593	Besides, ALKBH5 may promote UM metastasis by inducing epithelial-to-mesenchymal transition (EMT) via demethylation of FOXM1 mRNA, which increases its expression and stability.	('inducing', 'PosReg', (45, 53))	('stability', 'MPA', (165, 174))	('expression', 'MPA', (150, 160))	('mRNA', 'Protein', (124, 128))	('UM', 'Phenotype', 'HP:0007716', (28, 30))	('ALKBH5', 'Gene', (9, 15))	('FOXM1', 'Gene', '2305', (118, 123))	('EMT', 'biological_process', 'GO:0001837', ('92', '95'))	('FOXM1', 'Gene', (118, 123))	('UM metastasis', 'CPA', (28, 41))	('epithelial-to-mesenchymal transition', 'CPA', (54, 90))	('promote', 'PosReg', (20, 27))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('54', '90'))	('demethylation', 'biological_process', 'GO:0070988', ('101', '114'))	('increases', 'PosReg', (136, 145))	('demethylation', 'Var', (101, 114))
52442	33428593	In sum, our study indicates that AKLBH5-induced m6A demethylation of FOXM1 mRNA promotes UM progression.	('UM progression', 'CPA', (89, 103))	('m6A', 'Gene', '56339', (48, 51))	('demethylation', 'biological_process', 'GO:0070988', ('52', '65'))	('AKLBH5-induced', 'Var', (33, 47))	('UM', 'Phenotype', 'HP:0007716', (89, 91))	('promotes', 'PosReg', (80, 88))	('FOXM1', 'Gene', (69, 74))	('m6A', 'Gene', (48, 51))	('FOXM1', 'Gene', '2305', (69, 74))
52447	33428593	N6-methyladenosine (m6A) methylation is the most prevalent modification in RNA, including mRNAs, LncRNAs, and circRNAs.	('prevalent', 'Reg', (49, 58))	('m6A', 'Gene', '56339', (20, 23))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('N6-methyladenosine', 'Var', (0, 18))	('methylation', 'Var', (25, 36))	('RNA', 'Disease', (75, 78))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('RNA', 'cellular_component', 'GO:0005562', ('75', '78'))	('m6A', 'Gene', (20, 23))
52450	33428593	m6A modifications have been reported to affect multiple biological processes, such as RNA stability, splicing, transport, subcellular localization and translation efficiency, and RNA-protein interactions.	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('RNA stability', 'MPA', (86, 99))	('modifications', 'Var', (4, 17))	('m6A', 'Gene', '56339', (0, 3))	('subcellular localization', 'MPA', (122, 146))	('splicing', 'biological_process', 'GO:0045292', ('101', '109'))	('RNA', 'cellular_component', 'GO:0005562', ('86', '89'))	('transport', 'MPA', (111, 120))	('m6A', 'Gene', (0, 3))	('RNA', 'cellular_component', 'GO:0005562', ('179', '182'))	('transport', 'biological_process', 'GO:0006810', ('111', '120'))	('affect', 'Reg', (40, 46))	('interactions', 'Interaction', (191, 203))	('translation', 'biological_process', 'GO:0006412', ('151', '162'))	('translation efficiency', 'MPA', (151, 173))	('splicing', 'MPA', (101, 109))	('localization', 'biological_process', 'GO:0051179', ('134', '146'))	('RNA-protein', 'Protein', (179, 190))
52451	33428593	Recently, RNA methylation was shown to inhibit the progression of UM and ocular melanoma (OM), and decreased m6A levels were associated with a poor outcome in OM.	('RNA', 'cellular_component', 'GO:0005562', ('10', '13'))	('decreased', 'NegReg', (99, 108))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('inhibit', 'NegReg', (39, 46))	('ocular melanoma', 'Disease', (73, 88))	('m6A', 'Gene', (109, 112))	('RNA', 'Protein', (10, 13))	('methylation', 'Var', (14, 25))	('ocular melanoma', 'Disease', 'MESH:D008545', (73, 88))	('ocular melanoma', 'Phenotype', 'HP:0007716', (73, 88))	('OM', 'Phenotype', 'HP:0007716', (90, 92))	('m6A', 'Gene', '56339', (109, 112))	('OM', 'Phenotype', 'HP:0007716', (159, 161))	('RNA methylation', 'biological_process', 'GO:0001510', ('10', '25'))
52452	33428593	Conversely, METTL3-mediated m6A modification may promote UM progression by targeting c-Met and increasing its expression.	('METTL3', 'Gene', (12, 18))	('m6A', 'Gene', (28, 31))	('increasing', 'PosReg', (95, 105))	('UM progression', 'CPA', (57, 71))	('targeting', 'Reg', (75, 84))	('m6A', 'Gene', '56339', (28, 31))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('expression', 'MPA', (110, 120))	('promote', 'PosReg', (49, 56))	('METTL3', 'Gene', '56339', (12, 18))	('c-Met', 'Gene', (85, 90))	('c-Met', 'Gene', '4233', (85, 90))	('modification', 'Var', (32, 44))
52456	33428593	m6A modifications have been shown to cause tumor progression via EMT and tumorigenesis.	('EMT', 'CPA', (65, 68))	('modifications', 'Var', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('m6A', 'Gene', '56339', (0, 3))	('cause', 'Reg', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('EMT', 'biological_process', 'GO:0001837', ('65', '68'))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('m6A', 'Gene', (0, 3))
52458	33428593	In addition, METTL3-provoked m6A methylation of ZMYM1 mRNA facilitated EMT and gastric cancer metastasis.	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('methylation', 'Var', (33, 44))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('METTL3', 'Gene', (13, 19))	('EMT', 'biological_process', 'GO:0001837', ('71', '74'))	('ZMYM1', 'Gene', '79830', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('EMT', 'CPA', (71, 74))	('m6A', 'Gene', (29, 32))	('facilitated', 'PosReg', (59, 70))	('gastric cancer metastasis', 'Disease', 'MESH:D013274', (79, 104))	('ZMYM1', 'Gene', (48, 53))	('m6A', 'Gene', '56339', (29, 32))	('gastric cancer metastasis', 'Disease', (79, 104))	('METTL3', 'Gene', '56339', (13, 19))
52460	33428593	However, the effect of m6A modifications on EMT in UM has yet to be explored.	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('modifications', 'Var', (27, 40))	('m6A', 'Gene', (23, 26))	('m6A', 'Gene', '56339', (23, 26))	('EMT', 'biological_process', 'GO:0001837', ('44', '47'))
52462	33428593	In addition, ALKBH5 promotes EMT of UM by upregulating FOXM1 expression via demethylating the m6A modification and further increasing the stability of FOXM1 mRNA.	('m6A', 'Gene', (94, 97))	('FOXM1', 'Gene', (55, 60))	('FOXM1', 'Gene', '2305', (151, 156))	('FOXM1', 'Gene', '2305', (55, 60))	('EMT', 'biological_process', 'GO:0001837', ('29', '32'))	('stability', 'MPA', (138, 147))	('m6A', 'Gene', '56339', (94, 97))	('promotes', 'PosReg', (20, 28))	('EMT of UM', 'CPA', (29, 38))	('upregulating', 'PosReg', (42, 54))	('increasing', 'PosReg', (123, 133))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('demethylating', 'Var', (76, 89))	('ALKBH5', 'Var', (13, 19))	('expression', 'MPA', (61, 71))	('FOXM1', 'Gene', (151, 156))
52471	33428593	In addition, IHC staining revealed that, compared with the normal control group, Ki-67 expression was dramatically suppressed and cleaved-caspase3 was increased in the C918-shALKBH5#2 group (Figure 1G).	('C918', 'CellLine', 'CVCL:8471', (168, 172))	('increased', 'PosReg', (151, 160))	('caspase3', 'Gene', '836', (138, 146))	('expression', 'MPA', (87, 97))	('C918-shALKBH5', 'Var', (168, 181))	('suppressed', 'NegReg', (115, 125))	('Ki-67', 'Gene', (81, 86))	('caspase3', 'Gene', (138, 146))
52473	33428593	To determine the cause of high ALKBH5 expression in UM cells, we analyzed melanoma data from the UCSC Genome Bioinformatics Site (http://genome.ucsc.edu) and found high enrichment and overlap of H3K27ac peaks at the promoter region of ALKBH5 in melanoma (Figure 2A), which suggests that ALKBH5 may be regulated by chromatin acetylation.	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('H3K27ac', 'Var', (195, 202))	('melanoma', 'Disease', 'MESH:D008545', (245, 253))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('melanoma', 'Disease', (245, 253))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('ALKBH5', 'Gene', (235, 241))	('chromatin', 'cellular_component', 'GO:0000785', ('314', '323'))	('H3K27ac', 'Chemical', '-', (195, 202))
52479	33428593	Furthermore, the ChIP assay results indicated that the promoter region of ALKBH5 was enriched in EP300 binding and H3K27ac signals, and inhibition of EP300 by C646 treatment could significantly decrease the enrichment of H3K27ac signals in the promoter of ALKBH5 (Figure 2F).	('enrichment', 'MPA', (207, 217))	('EP300', 'Gene', '2033', (150, 155))	('C646', 'Chemical', '-', (159, 163))	('H3K27ac', 'Protein', (221, 228))	('EP300', 'Gene', (150, 155))	('ALKBH5', 'Gene', (256, 262))	('H3K27ac', 'Chemical', '-', (115, 122))	('H3K27ac', 'Chemical', '-', (221, 228))	('binding', 'molecular_function', 'GO:0005488', ('103', '110'))	('ALKBH5', 'Gene', (74, 80))	('EP300', 'Gene', (97, 102))	('EP300', 'Gene', '2033', (97, 102))	('C646', 'Var', (159, 163))	('decrease', 'NegReg', (194, 202))
52481	33428593	Loss of ALKBH5 caused a significant decrease in cell viability in MuM-2B and C918 cells (Figure 3A) and induced G1 to S phase transition arrest (Figure 3B).	('arrest', 'Disease', (137, 143))	('cell viability', 'CPA', (48, 62))	('ALKBH5', 'Gene', (8, 14))	('S phase', 'biological_process', 'GO:0051320', ('118', '125'))	('C918', 'CellLine', 'CVCL:8471', (77, 81))	('induced', 'Reg', (104, 111))	('arrest', 'Disease', 'MESH:D006323', (137, 143))	('Loss', 'Var', (0, 4))	('decrease', 'NegReg', (36, 44))
52482	33428593	The protein expression of the G1 to S phase checkpoint regulators cyclin D1 and cyclin E1 was downregulated in shALKBH5-transfected cells compared with the control vector-transfected cells (Figure 3D).	('protein expression', 'MPA', (4, 22))	('cyclin D1', 'Gene', (66, 75))	('cyclin', 'molecular_function', 'GO:0016538', ('66', '72'))	('cyclin E1', 'Gene', (80, 89))	('S phase checkpoint', 'biological_process', 'GO:0033314', ('36', '54'))	('cyclin', 'molecular_function', 'GO:0016538', ('80', '86'))	('shALKBH5-transfected', 'Var', (111, 131))	('S phase checkpoint', 'biological_process', 'GO:0031573', ('36', '54'))	('downregulated', 'NegReg', (94, 107))	('cyclin E1', 'Gene', '898', (80, 89))	('cyclin D1', 'Gene', '595', (66, 75))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
52484	33428593	Downregulation of ALKBH5 significantly increased cell apoptosis in MuM-2B and C918 cells (Figure 3C).	('ALKBH5', 'Gene', (18, 24))	('Downregulation', 'Var', (0, 14))	('C918', 'CellLine', 'CVCL:8471', (78, 82))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('increased', 'PosReg', (39, 48))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))	('cell apoptosis', 'CPA', (49, 63))
52485	33428593	Moreover, loss of ALKBH5 in MuM-2B and C918 cells significantly increased apoptosis marker protein levels, cleaved caspase-3, and decreased the expression of BCL-2, which is an antiapoptosis marker (Figure 3D).	('loss', 'Var', (10, 14))	('apoptosis marker protein levels', 'MPA', (74, 105))	('BCL-2', 'Gene', '596', (158, 163))	('ALKBH5', 'Gene', (18, 24))	('BCL-2', 'molecular_function', 'GO:0015283', ('158', '163'))	('expression', 'MPA', (144, 154))	('BCL-2', 'Gene', (158, 163))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('caspase-3', 'Gene', '836', (115, 124))	('C918', 'CellLine', 'CVCL:8471', (39, 43))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('increased', 'PosReg', (64, 73))	('decreased', 'NegReg', (130, 139))	('caspase-3', 'Gene', (115, 124))
52486	33428593	As shown in Figure 4A, knockdown of ALKBH5 significantly inhibited migration and invasion of MuM-2B and C918 cells.	('inhibited', 'NegReg', (57, 66))	('C918', 'CellLine', 'CVCL:8471', (104, 108))	('knockdown', 'Var', (23, 32))	('ALKBH5', 'Gene', (36, 42))
52490	33428593	Moreover, IHC staining was used to detect EMT markers expression in tumors of nude mice assay of C918-shALKBH5#2 group and C918-shControl group.	('C918-shALKBH5', 'Var', (97, 110))	('C918', 'CellLine', 'CVCL:8471', (97, 101))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('C918-shControl', 'Var', (123, 137))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('nude mice', 'Species', '10090', (78, 87))	('EMT', 'biological_process', 'GO:0001837', ('42', '45'))	('C918', 'CellLine', 'CVCL:8471', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
52491	33428593	We found that Vimentin and Snail expressions were dramatically suppressed in the C918-shALKBH5#2 group than that in C918-shControl group (Supplementary Figure 2B).	('Vimentin', 'Gene', (14, 22))	('Vimentin', 'cellular_component', 'GO:0045099', ('14', '22'))	('Vimentin', 'Gene', '7431', (14, 22))	('Snail', 'Gene', '6615', (27, 32))	('Snail', 'Gene', (27, 32))	('C918-shALKBH5#2', 'Var', (81, 96))	('suppressed', 'NegReg', (63, 73))	('C918', 'CellLine', 'CVCL:8471', (81, 85))	('C918', 'CellLine', 'CVCL:8471', (116, 120))	('Vimentin', 'cellular_component', 'GO:0045098', ('14', '22'))
52494	33428593	The reported catalytic inactive mutation ALKBH5 H204A (ALKBH5MUT) plasmid and the wild-type ALKBH5 (ALKBH5WT) plasmid were transfected into C918 and MuM-2B cells (Figure 4F).	('H204A', 'Var', (48, 53))	('H204A', 'Mutation', 'p.H204A', (48, 53))	('ALKBH5WT', 'Gene', (100, 108))	('ALKBH5WT', 'Gene', '54890', (100, 108))	('C918', 'CellLine', 'CVCL:8471', (140, 144))	('ALKBH5', 'Gene', (41, 47))
52496	33428593	Furthermore, cells with the catalytic inactive mutation of ALKBH5 showed lower N-cadherin, Vimentin, Snail, Slug, and beta-catenin expression and higher E-cadherin expression (Figure 4I).	('ALKBH5', 'Gene', (59, 65))	('Vimentin', 'cellular_component', 'GO:0045099', ('91', '99'))	('cadherin', 'molecular_function', 'GO:0008014', ('155', '163'))	('cadherin', 'molecular_function', 'GO:0008014', ('81', '89'))	('beta-catenin', 'Gene', (118, 130))	('beta-catenin', 'Gene', '1499', (118, 130))	('Slug', 'Gene', (108, 112))	('Vimentin', 'cellular_component', 'GO:0045098', ('91', '99'))	('Vimentin', 'Gene', '7431', (91, 99))	('Snail', 'Gene', '6615', (101, 106))	('E-cadherin', 'Gene', (153, 163))	('E-cadherin', 'Gene', '999', (153, 163))	('N-cadherin', 'Gene', (79, 89))	('N-cadherin', 'Gene', '1000', (79, 89))	('Vimentin', 'Gene', (91, 99))	('lower', 'NegReg', (73, 78))	('higher', 'PosReg', (146, 152))	('mutation', 'Var', (47, 55))	('Slug', 'Gene', '6591', (108, 112))	('expression', 'MPA', (131, 141))	('Snail', 'Gene', (101, 106))
52498	33428593	ALKBH5 has been reported to demethylate FOXM1 nascent transcripts and promote FOXM1 expression in glioblastoma.	('glioblastoma', 'Disease', (98, 110))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('FOXM1', 'Gene', '2305', (78, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('FOXM1', 'Gene', '2305', (40, 45))	('FOXM1', 'Gene', (78, 83))	('demethylate', 'Var', (28, 39))	('FOXM1', 'Gene', (40, 45))	('promote', 'PosReg', (70, 77))	('expression', 'MPA', (84, 94))
52502	33428593	In addition, IHC staining also demonstrated that knockdown ALKBH5 could decrease FOXM1 expression in vivo (Supplementary Figure 3D).	('knockdown', 'Var', (49, 58))	('ALKBH5', 'Gene', (59, 65))	('FOXM1', 'Gene', '2305', (81, 86))	('FOXM1', 'Gene', (81, 86))	('expression', 'MPA', (87, 97))	('decrease', 'NegReg', (72, 80))
52506	33428593	Moreover, knockdown of ALKBH5 decreased the expression of FOXM1 (Figure 5B).	('expression', 'MPA', (44, 54))	('ALKBH5', 'Gene', (23, 29))	('FOXM1', 'Gene', '2305', (58, 63))	('knockdown', 'Var', (10, 19))	('FOXM1', 'Gene', (58, 63))	('decreased', 'NegReg', (30, 39))
52509	33428593	In addition, m6A levels of FOXM1 mRNA were significantly increased in cells transfected with ALKBH5MUT plasmids compared with wild-type plasmids (Figure 5C, right panel).	('FOXM1', 'Gene', '2305', (27, 32))	('ALKBH5MUT plasmids', 'Var', (93, 111))	('m6A', 'Gene', (13, 16))	('increased', 'PosReg', (57, 66))	('FOXM1', 'Gene', (27, 32))	('m6A', 'Gene', '56339', (13, 16))	('plasmids', 'Var', (103, 111))
52511	33428593	Investigators have found that ALKBH5-induced m6A demethylation on mRNAs affects mRNA stability and translation.	('translation', 'biological_process', 'GO:0006412', ('99', '110'))	('m6A', 'Gene', '56339', (45, 48))	('translation', 'MPA', (99, 110))	('mRNA stability', 'MPA', (80, 94))	('ALKBH5-induced', 'Gene', (30, 44))	('affects', 'Reg', (72, 79))	('demethylation', 'biological_process', 'GO:0070988', ('49', '62'))	('demethylation', 'Var', (49, 62))	('m6A', 'Gene', (45, 48))
52512	33428593	To investigate whether ALKBH5 increases FOMX1 expression by increasing its mRNA stability, we treated cells with the transcription inhibitor dactinomycin and detected the level of FOXM1 mRNA.	('FOXM1', 'Gene', (180, 185))	('FOXM1', 'Gene', '2305', (180, 185))	('increasing', 'PosReg', (60, 70))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('OM', 'Phenotype', 'HP:0007716', (41, 43))	('dactinomycin', 'Chemical', 'MESH:D003609', (141, 153))	('ALKBH5', 'Var', (23, 29))	('mRNA stability', 'MPA', (75, 89))	('expression', 'MPA', (46, 56))	('increases', 'PosReg', (30, 39))	('FOMX1', 'Gene', (40, 45))
52513	33428593	As shown in Figure 5D (left panel), knockdown of ALKBH5 in C918 cells significantly decreased the FOXM1 mRNA level compared with control cells.	('ALKBH5', 'Gene', (49, 55))	('FOXM1', 'Gene', (98, 103))	('FOXM1', 'Gene', '2305', (98, 103))	('knockdown', 'Var', (36, 45))	('C918', 'CellLine', 'CVCL:8471', (59, 63))	('decreased', 'NegReg', (84, 93))
52514	33428593	Furthermore, the level of FOXM1 mRNA was notably reduced in C918 cells with catalytic inactive mutation of ALKBH5 after dactinomycin treatment (Figure 5D, right panel).	('dactinomycin', 'Chemical', 'MESH:D003609', (120, 132))	('reduced', 'NegReg', (49, 56))	('level', 'MPA', (17, 22))	('C918', 'CellLine', 'CVCL:8471', (60, 64))	('FOXM1', 'Gene', '2305', (26, 31))	('FOXM1', 'Gene', (26, 31))	('ALKBH5', 'Gene', (107, 113))	('mutation', 'Var', (95, 103))
52515	33428593	Thus, these results demonstrated that ALKBH5 may upregulate FOXM1 expression and increase the stability of FOXM1 mRNA via demethylating m6A modification.	('FOXM1', 'Gene', (107, 112))	('demethylating', 'Var', (122, 135))	('m6A', 'Gene', '56339', (136, 139))	('mRNA', 'MPA', (113, 117))	('upregulate', 'PosReg', (49, 59))	('expression', 'MPA', (66, 76))	('stability', 'MPA', (94, 103))	('FOXM1', 'Gene', '2305', (60, 65))	('FOXM1', 'Gene', (60, 65))	('increase', 'PosReg', (81, 89))	('ALKBH5', 'Var', (38, 44))	('m6A', 'Gene', (136, 139))	('FOXM1', 'Gene', '2305', (107, 112))
52518	33428593	Downregulation of FOXM1 significantly suppressed cell migration (Figure 6B) and invasion (Figure 6C).	('cell migration', 'biological_process', 'GO:0016477', ('49', '63'))	('invasion', 'CPA', (80, 88))	('cell migration', 'CPA', (49, 63))	('Downregulation', 'Var', (0, 14))	('suppressed', 'NegReg', (38, 48))	('FOXM1', 'Gene', (18, 23))	('FOXM1', 'Gene', '2305', (18, 23))
52519	33428593	In addition, inhibition of FOXM1 in UM cells increased E-cadherin expression and decreased N-cadherin, vimentin, Snail, Slug, and beta-catenin expression (Figure 6D).	('E-cadherin', 'Gene', (55, 65))	('E-cadherin', 'Gene', '999', (55, 65))	('vimentin', 'cellular_component', 'GO:0045099', ('103', '111'))	('Slug', 'Gene', (120, 124))	('Snail', 'Gene', '6615', (113, 118))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('N-cadherin', 'Gene', (91, 101))	('decreased', 'NegReg', (81, 90))	('N-cadherin', 'Gene', '1000', (91, 101))	('increased', 'PosReg', (45, 54))	('cadherin', 'molecular_function', 'GO:0008014', ('57', '65'))	('cadherin', 'molecular_function', 'GO:0008014', ('93', '101'))	('FOXM1', 'Gene', (27, 32))	('Slug', 'Gene', '6591', (120, 124))	('vimentin', 'Gene', '7431', (103, 111))	('vimentin', 'Gene', (103, 111))	('Snail', 'Gene', (113, 118))	('vimentin', 'cellular_component', 'GO:0045098', ('103', '111'))	('inhibition', 'Var', (13, 23))	('beta-catenin', 'Gene', (130, 142))	('FOXM1', 'Gene', '2305', (27, 32))	('beta-catenin', 'Gene', '1499', (130, 142))
52525	33428593	Taken together, our results suggest that ALKBH5 may promote UM EMT by upregulating FOXM1 expression in an m6A modification-dependent manner.	('ALKBH5', 'Var', (41, 47))	('expression', 'MPA', (89, 99))	('upregulating', 'PosReg', (70, 82))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('m6A', 'Gene', (106, 109))	('EMT', 'biological_process', 'GO:0001837', ('63', '66'))	('UM EMT', 'CPA', (60, 66))	('FOXM1', 'Gene', (83, 88))	('promote', 'PosReg', (52, 59))	('m6A', 'Gene', '56339', (106, 109))	('FOXM1', 'Gene', '2305', (83, 88))
52528	33428593	In lung cancer, gastric cancer, and epithelial ovarian cancer, ALKBH5 may act as an oncogene, whereas in colon cancer and pancreatic cancer, ALKBH5 may inhibit tumor progression.	('inhibit', 'NegReg', (152, 159))	('gastric cancer', 'Disease', (16, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (122, 139))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('colon cancer', 'Disease', 'MESH:D015179', (105, 117))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (36, 61))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (16, 30))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('ALKBH5', 'Var', (141, 147))	('pancreatic cancer', 'Disease', 'MESH:D010190', (122, 139))	('ALKBH5', 'Gene', (63, 69))	('lung cancer', 'Disease', (3, 14))	('colon cancer', 'Disease', (105, 117))	('epithelial ovarian cancer', 'Disease', (36, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('gastric cancer', 'Phenotype', 'HP:0012126', (16, 30))	('tumor', 'Disease', (160, 165))	('pancreatic cancer', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (36, 61))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('colon cancer', 'Phenotype', 'HP:0003003', (105, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (47, 61))
52529	33428593	In this study, we demonstrated that inhibition of ALKBH5 suppresses tumor growth in vivo and that EP300-induced H3K27ac activation promotes ALKBH5 expression.	('tumor', 'Disease', (68, 73))	('EP300', 'Gene', (98, 103))	('suppresses', 'NegReg', (57, 67))	('inhibition', 'Var', (36, 46))	('expression', 'MPA', (147, 157))	('H3K27ac', 'Protein', (112, 119))	('ALKBH5', 'Gene', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('ALKBH5', 'Gene', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('H3K27ac', 'Chemical', '-', (112, 119))	('EP300', 'Gene', '2033', (98, 103))	('promotes', 'PosReg', (131, 139))
52531	33428593	Western blot assay results showed that knockdown or loss of m6A catalytic activity of ALKBH5 increased the epithelial cell phenotype marker E-cadherin and decreased mesenchymal phenotype markers (N-cadherin and Vimentin) compared with controls.	('increased', 'PosReg', (93, 102))	('Vimentin', 'cellular_component', 'GO:0045099', ('211', '219'))	('N-cadherin', 'Gene', (196, 206))	('E-cadherin', 'Gene', (140, 150))	('E-cadherin', 'Gene', '999', (140, 150))	('cadherin', 'molecular_function', 'GO:0008014', ('142', '150'))	('N-cadherin', 'Gene', '1000', (196, 206))	('epithelial cell phenotype', 'CPA', (107, 132))	('cadherin', 'molecular_function', 'GO:0008014', ('198', '206'))	('catalytic activity', 'molecular_function', 'GO:0003824', ('64', '82'))	('m6A', 'Gene', '56339', (60, 63))	('Vimentin', 'Gene', '7431', (211, 219))	('ALKBH5', 'Gene', (86, 92))	('Vimentin', 'cellular_component', 'GO:0045098', ('211', '219'))	('loss', 'Var', (52, 56))	('Vimentin', 'Gene', (211, 219))	('m6A', 'Gene', (60, 63))	('catalytic activity', 'MPA', (64, 82))	('mesenchymal phenotype', 'CPA', (165, 186))	('decreased', 'NegReg', (155, 164))
52534	33428593	ALKBH5 inhibits tumor motility and stemness by demethylating TIMP3, LncRNA NEAT1, WIF1, and LncRNA KCNK15-AS1.	('NEAT1', 'Gene', '283131', (75, 80))	('ALKBH5', 'Gene', (0, 6))	('WIF1', 'Gene', '11197', (82, 86))	('demethylating', 'Var', (47, 60))	('NEAT1', 'Gene', (75, 80))	('tumor motility', 'Disease', (16, 30))	('TIMP3', 'Gene', (61, 66))	('inhibits', 'NegReg', (7, 15))	('TIMP3', 'Gene', '7078', (61, 66))	('tumor motility', 'Disease', 'MESH:D015835', (16, 30))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('AS1', 'Gene', '5729', (106, 109))	('AS1', 'Gene', (106, 109))	('KCNK15', 'Gene', (99, 105))	('WIF1', 'Gene', (82, 86))	('KCNK15', 'Gene', '60598', (99, 105))
52535	33428593	ALKBH5 regulates FOXM1 expression by demethylating the nascent transcripts of FOXM1 in glioblastoma stem-like cells.	('demethylating', 'Var', (37, 50))	('FOXM1', 'Gene', '2305', (78, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('FOXM1', 'Gene', (78, 83))	('glioblastoma', 'Disease', (87, 99))	('regulates', 'Reg', (7, 16))	('glioblastoma', 'Disease', 'MESH:D005909', (87, 99))	('FOXM1', 'Gene', '2305', (17, 22))	('FOXM1', 'Gene', (17, 22))
52537	33428593	In the present study, we demonstrated that ALKBH5 knockdown or loss of m6A catalytic activity had significantly decreased m6A enrichment of FOXM1 mRNA.	('m6A', 'Gene', '56339', (122, 125))	('knockdown', 'Var', (50, 59))	('ALKBH5', 'Gene', (43, 49))	('m6A', 'Gene', (71, 74))	('catalytic activity', 'MPA', (75, 93))	('catalytic activity', 'molecular_function', 'GO:0003824', ('75', '93'))	('FOXM1', 'Gene', (140, 145))	('m6A', 'Gene', '56339', (71, 74))	('FOXM1', 'Gene', '2305', (140, 145))	('decreased', 'NegReg', (112, 121))	('m6A', 'Gene', (122, 125))	('loss', 'NegReg', (63, 67))
52539	33428593	To further explore the relationship between histone modification and elevated ALKBH5 expression in UM, we analyzed the data from UCSC Genome Bioinformatics Site and found high enrichments of H3K27ac peaks at the promoter of ALKBH5.	('expression', 'MPA', (85, 95))	('H3K27ac', 'Chemical', '-', (191, 198))	('H3K27ac', 'Var', (191, 198))	('ALKBH5', 'Gene', (78, 84))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('histone modification', 'biological_process', 'GO:0016570', ('44', '64'))	('elevated', 'PosReg', (69, 77))	('ALKBH5', 'Gene', (224, 230))
52547	33428593	In the current study, we observed that FOXM1 knockdown not only decreased the invasion and migration of UM cells, but also induced the downregulation of Snail, Slug, and beta-catenin.	('UM', 'Phenotype', 'HP:0007716', (104, 106))	('FOXM1', 'Gene', (39, 44))	('FOXM1', 'Gene', '2305', (39, 44))	('Snail', 'Gene', '6615', (153, 158))	('beta-catenin', 'Gene', (170, 182))	('Slug', 'Gene', '6591', (160, 164))	('beta-catenin', 'Gene', '1499', (170, 182))	('Snail', 'Gene', (153, 158))	('downregulation', 'NegReg', (135, 149))	('Slug', 'Gene', (160, 164))	('knockdown', 'Var', (45, 54))	('decreased', 'NegReg', (64, 73))
52550	33428593	In conclusion, we demonstrate that ALKBH5, which is positively regulated by epigenetic modifications of H3K27 acetylation, promotes tumor progression by inducing tumor EMT and increasing FOXM1 expression via m6A demethylation (Figure 7).	('H3K27', 'Protein', (104, 109))	('ALKBH5', 'Gene', (35, 41))	('tumor', 'Disease', (162, 167))	('m6A', 'Gene', (208, 211))	('tumor', 'Disease', (132, 137))	('expression', 'MPA', (193, 203))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('promotes', 'PosReg', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('FOXM1', 'Gene', (187, 192))	('inducing', 'PosReg', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('epigenetic modifications', 'Var', (76, 100))	('increasing', 'PosReg', (176, 186))	('FOXM1', 'Gene', '2305', (187, 192))	('m6A', 'Gene', '56339', (208, 211))	('demethylation', 'biological_process', 'GO:0070988', ('212', '225'))	('EMT', 'biological_process', 'GO:0001837', ('168', '171'))
52559	33428593	The antibodies used in this study were as follows: ALKBH5 (ab195377, Abcam), H3K27ac (#8173, Cell Signaling Technology [CST]), cyclin D1 (#2978, CST), cyclin E1 (ab33911, Abcam), c-Myc (#5605, CST), caspase-3 (19677-1-AP, Proteintech), BCL-2 (12789-1-AP, Proteintech), MMP2 (#87809, CST), MMP7 (#71031, CST), MMP9 (#13667, CST), E-cadherin (#3195, CST), N-cadherin (#13116, CST), vimentin (#5741, CST), beta-catenin (#8480, CST), Snail (ab53519, Abcam), Slug (ab27568, Abcam), beta-actin (ab8227, Abcam), and GAPDH (#8884, CST).	('caspase-3', 'Gene', '836', (199, 208))	('MMP9', 'Gene', '4318', (309, 313))	('vimentin', 'cellular_component', 'GO:0045099', ('380', '388'))	('MMP9', 'Gene', (309, 313))	('#8480', 'Var', (417, 422))	('Snail', 'Gene', '6615', (430, 435))	('MMP2', 'molecular_function', 'GO:0004228', ('269', '273'))	('N-cadherin', 'Gene', (354, 364))	('cadherin', 'molecular_function', 'GO:0008014', ('356', '364'))	('cyclin', 'molecular_function', 'GO:0016538', ('151', '157'))	('H3K27ac', 'Chemical', '-', (77, 84))	('N-cadherin', 'Gene', '1000', (354, 364))	('caspase-3', 'Gene', (199, 208))	('MMP2', 'Gene', '4313', (269, 273))	('#13116', 'Var', (366, 372))	('Slug', 'Gene', '6591', (454, 458))	('GAPDH', 'Gene', '2597', (509, 514))	('cadherin', 'molecular_function', 'GO:0008014', ('331', '339'))	('Signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('E-cadherin', 'Gene', (329, 339))	('E-cadherin', 'Gene', '999', (329, 339))	('cyclin E1', 'Gene', '898', (151, 160))	('MMP7', 'Gene', '4316', (289, 293))	('cyclin D1', 'Gene', (127, 136))	('GAPDH', 'Gene', (509, 514))	('cyclin', 'molecular_function', 'GO:0016538', ('127', '133'))	('BCL-2', 'molecular_function', 'GO:0015283', ('236', '241'))	('beta-catenin', 'Gene', (403, 415))	('Snail', 'Gene', (430, 435))	('#5741', 'Var', (390, 395))	('MMP7', 'molecular_function', 'GO:0004235', ('289', '293'))	('vimentin', 'cellular_component', 'GO:0045098', ('380', '388'))	('vimentin', 'Gene', '7431', (380, 388))	('cyclin D1', 'Gene', '595', (127, 136))	('beta-catenin', 'Gene', '1499', (403, 415))	('vimentin', 'Gene', (380, 388))	('BCL-2', 'Gene', '596', (236, 241))	('c-Myc', 'Gene', (179, 184))	('cyclin E1', 'Gene', (151, 160))	('MMP9', 'molecular_function', 'GO:0004229', ('309', '313'))	('BCL-2', 'Gene', (236, 241))	('Slug', 'Gene', (454, 458))	('MMP7', 'Gene', (289, 293))	('MMP2', 'Gene', (269, 273))	('c-Myc', 'Gene', '4609', (179, 184))
52563	33428593	The catalytic inactive mutation site of ALKBH5 H204A was obtained from a previously published study.	('ALKBH5', 'Gene', (40, 46))	('H204A', 'Var', (47, 52))	('H204A', 'Mutation', 'p.H204A', (47, 52))
52603	32455885	More recently, combination therapy trials revealed that patients positive for oncogenic BRAF mutations treated with the BRAF inhibitor dabrafenib plus the dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1/MEK) inhibitor trametinib had improved survival.	('MEK', 'Gene', (222, 225))	('mitogen-activated protein kinase kinase 1', 'Gene', (172, 213))	('MEK', 'Gene', '5609', (222, 225))	('patients', 'Species', '9606', (56, 64))	('MAP2K', 'molecular_function', 'GO:0004708', ('215', '220'))	('mutations', 'Var', (93, 102))	('MAP2K1', 'Gene', '5604', (215, 221))	('BRAF', 'Gene', (88, 92))	('survival', 'CPA', (261, 269))	('protein', 'cellular_component', 'GO:0003675', ('190', '197'))	('MAP2K1', 'Gene', (215, 221))	('trametinib', 'Chemical', 'MESH:C560077', (237, 247))	('improved', 'PosReg', (252, 260))	('mitogen-activated protein kinase kinase 1', 'Gene', '5604', (172, 213))	('dabrafenib', 'Chemical', 'MESH:C561627', (135, 145))
52632	32455885	For instance, zebrafish with a mutation in tyrosinase fail to produce melanin, mirroring the mechanism for human albinism.	('produce melanin', 'MPA', (62, 77))	('zebrafish', 'Species', '7955', (14, 23))	('tyrosinase', 'Gene', '30207', (43, 53))	('human', 'Species', '9606', (107, 112))	('mutation', 'Var', (31, 39))	('albinism', 'Phenotype', 'HP:0001022', (113, 121))	('fail', 'NegReg', (54, 58))	('melanin', 'Chemical', 'MESH:D008543', (70, 77))	('tyrosinase', 'Gene', (43, 53))
52634	32455885	Activating mutations in BRAF, most commonly BRAFV600E, occur in nearly 50% of human melanoma and lead to overactivation of the MAPK pathway.	('overactivation', 'PosReg', (105, 119))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('BRAF', 'Gene', (24, 28))	('MAPK pathway', 'Pathway', (127, 139))	('human', 'Species', '9606', (78, 83))	('MAPK', 'molecular_function', 'GO:0004707', ('127', '131'))	('BRAFV600E', 'Var', (44, 53))
52635	32455885	However, these mutations alone are not sufficient to give rise to malignancy, as human nevi frequently express BRAFV600E.	('nevi', 'Phenotype', 'HP:0003764', (87, 91))	('malignancy', 'Disease', 'MESH:D009369', (66, 76))	('BRAFV600E', 'Var', (111, 120))	('malignancy', 'Disease', (66, 76))	('human', 'Species', '9606', (81, 86))
52637	32455885	However, injection into p53 loss-of-function mutants, p53(lf), gave rise to tumors that histopathologically mirrored human melanomas.	('p53', 'Gene', (24, 27))	('mutants', 'Var', (45, 52))	('human', 'Species', '9606', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('loss-of-function', 'NegReg', (28, 44))	('melanomas', 'Disease', (123, 132))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('melanomas', 'Disease', 'MESH:D008545', (123, 132))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))
52642	32455885	Uveal melanomas are biologically distinct from their cutaneous counterparts and often contain driver mutations in the G protein subunits GNAQ or GNA11.	('mutations', 'Var', (101, 110))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('GNAQ', 'Gene', (137, 141))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('GNA11', 'Gene', '563953', (145, 150))	('contain', 'Reg', (86, 93))	('melanomas', 'Disease', (6, 15))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('GNAQ', 'Gene', '570108', (137, 141))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))	('GNA11', 'Gene', (145, 150))
52648	32455885	This is not unexpected, as human melanomas retain a history of UV-induced mutations present in the cell of origin prior to transformation, and such UV exposure is not present in zebrafish housing tanks.	('zebrafish', 'Species', '7955', (178, 187))	('melanomas', 'Disease', 'MESH:D008545', (33, 42))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('human', 'Species', '9606', (27, 32))	('mutations', 'Var', (74, 83))	('melanomas', 'Disease', (33, 42))
52649	32455885	By contrast, the high degree of copy number variation in human melanomas is also observed in zebrafish tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('zebrafish', 'Species', '7955', (93, 102))	('melanomas', 'Disease', (63, 72))	('tumors', 'Disease', (103, 109))	('melanomas', 'Disease', 'MESH:D008545', (63, 72))	('copy number variation', 'Var', (32, 53))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))	('human', 'Species', '9606', (57, 62))
52650	32455885	Because of their preponderance, it is likely that these copy number variations are important in the initiation and further progression of zebrafish melanomas.	('important', 'Reg', (83, 92))	('melanomas', 'Disease', 'MESH:D008545', (148, 157))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('zebrafish', 'Species', '7955', (138, 147))	('melanomas', 'Disease', (148, 157))	('copy number variations', 'Var', (56, 78))	('melanomas', 'Phenotype', 'HP:0002861', (148, 157))
52651	32455885	In support of this possibility, many genes subject to copy number variation in zebrafish melanoma are similarly varied in their copy number in human melanoma.	('copy number variation', 'Var', (54, 75))	('human', 'Species', '9606', (143, 148))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('zebrafish', 'Species', '7955', (79, 88))	('melanoma', 'Disease', (149, 157))	('copy', 'MPA', (128, 132))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
52652	32455885	A high degree of copy number alterations may be a common feature of zebrafish tumor models, as malignant peripheral nerve sheath tumors caused by loss of p53 also have frequent copy number alterations.	('copy number', 'MPA', (177, 188))	('malignant peripheral nerve sheath tumors', 'Disease', (95, 135))	('zebrafish', 'Species', '7955', (68, 77))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('loss', 'Var', (146, 150))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (95, 135))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (95, 135))	('p53', 'Gene', (154, 157))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', (129, 134))
52659	32455885	This indicates the need for additional genetic or epigenetic alterations for tumor formation and presents the opportunity for zebrafish tumorigenic models to serve as poised backgrounds for the discovery of new melanoma modifier genes.	('zebrafish', 'Species', '7955', (126, 135))	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Disease', (211, 219))	('formation', 'biological_process', 'GO:0009058', ('83', '92'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('epigenetic', 'Var', (50, 60))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (136, 141))
52661	32455885	However, melanomas have among the highest mutation burdens of any cancer, and most of the detected mutations and copy number variations in human melanomas are likely to be passenger alterations.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanomas', 'Phenotype', 'HP:0002861', (9, 18))	('melanomas', 'Phenotype', 'HP:0002861', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('melanomas', 'Disease', 'MESH:D008545', (145, 154))	('melanomas', 'Disease', 'MESH:D008545', (9, 18))	('copy number variations', 'Var', (113, 135))	('mutations', 'Var', (99, 108))	('human', 'Species', '9606', (139, 144))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('melanomas', 'Disease', (145, 154))	('melanomas', 'Disease', (9, 18))	('cancer', 'Disease', (66, 72))
52664	32455885	In this study, a 'MiniCoopR' screening strategy was developed that utilized a strain in which a mitfa loss-of-function mutation was introduced into a tumor-prone Tg(mitfa:BRAFV600E); p53(lf) background.	('loss-of-function', 'NegReg', (102, 118))	('mutation', 'Var', (119, 127))	('mitfa', 'Gene', '30080', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('mitfa', 'Gene', (165, 170))	('mitfa', 'Gene', '30080', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('mitfa', 'Gene', (96, 101))	('tumor', 'Disease', (150, 155))
52665	32455885	The mitfa mutation abrogated melanocyte development and melanoma formation.	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('mitfa', 'Gene', '30080', (4, 9))	('abrogated', 'NegReg', (19, 28))	('mutation', 'Var', (10, 18))	('melanocyte development', 'CPA', (29, 51))	('mitfa', 'Gene', (4, 9))	('formation', 'biological_process', 'GO:0009058', ('65', '74'))
52679	32455885	Since KIT mutations predominate over BRAF or NRAS mutations in mucosal melanomas, this result suggests a special cooperativity between KIT gain of function and SPRED1 loss.	('gain of function', 'PosReg', (139, 155))	('KIT', 'molecular_function', 'GO:0005020', ('135', '138'))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('mucosal melanomas', 'Disease', (63, 80))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('loss', 'NegReg', (167, 171))	('mucosal melanomas', 'Disease', 'MESH:D008545', (63, 80))	('KIT', 'molecular_function', 'GO:0005020', ('6', '9'))	('NRAS', 'Gene', (45, 49))	('mutations', 'Var', (10, 19))	('NRAS', 'Gene', '30380', (45, 49))	('KIT', 'Gene', (6, 9))
52681	32455885	Venkatesan and colleagues compared genes subject to copy number amplification in human melanomas to those subject to copy number amplification in zebrafish melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanomas', 'Phenotype', 'HP:0002861', (156, 165))	('zebrafish', 'Species', '7955', (146, 155))	('copy number amplification', 'Var', (52, 77))	('melanomas', 'Disease', 'MESH:D008545', (156, 165))	('melanomas', 'Disease', (87, 96))	('melanomas', 'Phenotype', 'HP:0002861', (87, 96))	('melanomas', 'Disease', (156, 165))	('human', 'Species', '9606', (81, 86))	('melanomas', 'Disease', 'MESH:D008545', (87, 96))
52684	32455885	GDF6-dependent BMP signaling was found to be critical for maintaining neural crest identity, and withdrawal of BMP signaling led to differentiation and death of melanoma cells.	('death of melanoma', 'Disease', 'MESH:D003643', (152, 169))	('BMP', 'Gene', '649', (111, 114))	('death of melanoma', 'Disease', (152, 169))	('BMP', 'Gene', '649', (15, 18))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('GDF6', 'Gene', (0, 4))	('BMP', 'Gene', (111, 114))	('differentiation', 'CPA', (132, 147))	('BMP', 'Gene', (15, 18))	('GDF6', 'Gene', '392255', (0, 4))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('withdrawal', 'Var', (97, 107))
52692	32455885	In 2017, Scahill and colleagues found that loss of kdm2aa, an ortholog of the histone demethylase KDM2A, led to the formation of spontaneous melanomas at high frequency.	('melanomas', 'Disease', 'MESH:D008545', (141, 150))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanomas', 'Phenotype', 'HP:0002861', (141, 150))	('formation', 'biological_process', 'GO:0009058', ('116', '125'))	('KDM2A', 'Gene', '799441', (98, 103))	('kdm2aa', 'Gene', (51, 57))	('kdm2aa', 'Gene', '571851', (51, 57))	('melanomas', 'Disease', (141, 150))	('loss', 'Var', (43, 47))	('KDM2A', 'Gene', (98, 103))
52693	32455885	These tumors arose independently of BRAFV600E and other common driver mutations as well as common tumor suppressor losses.	('losses', 'NegReg', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor suppressor', 'biological_process', 'GO:0051726', ('98', '114'))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('98', '114'))	('BRAFV600E', 'Var', (36, 45))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
52694	32455885	Gene expression profiling showed a concerted response of genes related to translation, DNA replication, and chromatin regulation upon knockdown of kdm2aa, suggesting a role for aberrant chromatin methylation in melanomagenesis.	('chromatin', 'cellular_component', 'GO:0000785', ('108', '117'))	('kdm2aa', 'Gene', '571851', (147, 153))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('kdm2aa', 'Gene', (147, 153))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Disease', (211, 219))	('regulation', 'biological_process', 'GO:0065007', ('118', '128'))	('methylation', 'biological_process', 'GO:0032259', ('196', '207'))	('knockdown', 'Var', (134, 143))	('DNA replication', 'biological_process', 'GO:0006260', ('87', '102'))	('translation', 'biological_process', 'GO:0006412', ('74', '85'))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('chromatin', 'cellular_component', 'GO:0000785', ('186', '195'))
52697	32455885	Subsequent cell culture assays revealed that inhibition of RSK1 led to downregulation of a transcriptional program that supports cell motility.	('cell motility', 'CPA', (129, 142))	('downregulation', 'NegReg', (71, 85))	('RSK1', 'Gene', (59, 63))	('cell motility', 'biological_process', 'GO:0048870', ('129', '142'))	('inhibition', 'Var', (45, 55))	('RSK1', 'Gene', '6195', (59, 63))
52698	32455885	Constitutive activation of RSK1 in zebrafish accelerated melanoma onset and promoted invasion, whereas inactivation of RSK1 delayed tumor initiation.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('zebrafish', 'Species', '7955', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('RSK1', 'Gene', '6195', (27, 31))	('inactivation', 'Var', (103, 115))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('activation', 'PosReg', (13, 23))	('RSK1', 'Gene', (119, 123))	('tumor', 'Disease', (132, 137))	('invasion', 'CPA', (85, 93))	('accelerated', 'PosReg', (45, 56))	('RSK1', 'Gene', '6195', (119, 123))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('promoted', 'PosReg', (76, 84))	('RSK1', 'Gene', (27, 31))
52703	32455885	Follow up in vitro knockdowns of PGC1alpha resulted in downregulation of transcriptional signatures associated with melanoma progression.	('PGC1alpha', 'Gene', (33, 42))	('knockdowns', 'Var', (19, 29))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('PGC1alpha', 'Gene', '10891', (33, 42))	('transcriptional signatures', 'MPA', (73, 99))	('downregulation', 'NegReg', (55, 69))
52714	32455885	More severe mutations have been isolated in mice and zebrafish, and MITF-null mutations in both species cause a complete loss of melanocytes.	('loss', 'NegReg', (121, 125))	('mutations', 'Var', (78, 87))	('MITF-null', 'Gene', (68, 77))	('zebrafish', 'Species', '7955', (53, 62))	('mice', 'Species', '10090', (44, 48))
52718	32455885	They found that mitfa(vc7); p53(lf) animals develop superficial melanomas enriched for stem and invasive gene signatures, similar to what is observed in human MITF-low melanomas.	('melanomas', 'Disease', 'MESH:D008545', (168, 177))	('mitfa', 'Gene', (16, 21))	('melanomas', 'Disease', (64, 73))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanomas', 'Phenotype', 'HP:0002861', (168, 177))	('MITF-low melanomas', 'Disease', (159, 177))	('melanomas', 'Disease', (168, 177))	('superficial melanomas', 'Phenotype', 'HP:0012057', (52, 73))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('MITF-low melanomas', 'Disease', 'MESH:D008545', (159, 177))	('human', 'Species', '9606', (153, 158))	('melanomas', 'Disease', 'MESH:D008545', (64, 73))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('p53', 'Var', (28, 31))	('mitfa', 'Gene', '30080', (16, 21))
52723	32455885	In humans, heterozygous loss of the KIT gene results in piebaldism, a pigmentation disorder characterized by a white forelock.	('heterozygous loss', 'Var', (11, 28))	('piebaldism', 'Phenotype', 'HP:0007544', (56, 66))	('pigmentation disorder', 'Disease', 'MESH:D010859', (70, 91))	('KIT', 'Gene', (36, 39))	('pigmentation disorder', 'Phenotype', 'HP:0001000', (70, 91))	('pigmentation', 'biological_process', 'GO:0043473', ('70', '82'))	('white forelock', 'Phenotype', 'HP:0002211', (111, 125))	('humans', 'Species', '9606', (3, 9))	('KIT', 'molecular_function', 'GO:0005020', ('36', '39'))	('piebaldism', 'Disease', 'MESH:D016116', (56, 66))	('results in', 'Reg', (45, 55))	('piebaldism', 'Disease', (56, 66))	('pigmentation disorder', 'Disease', (70, 91))
52724	32455885	Mice deficient in Kit and its cognate ligand, stem cell factor (SCF), develop a similar pigmentation phenotype of white spotting.	('stem cell factor', 'molecular_function', 'GO:0005173', ('46', '62'))	('Kit', 'Gene', (18, 21))	('pigmentation', 'biological_process', 'GO:0043473', ('88', '100'))	('SCF', 'Gene', '17311', (64, 67))	('stem cell factor', 'Gene', (46, 62))	('Kit', 'Gene', '16590', (18, 21))	('stem cell factor', 'Gene', '17311', (46, 62))	('SCF', 'Gene', (64, 67))	('Mice', 'Species', '10090', (0, 4))	('pigmentation', 'Disease', 'MESH:D010859', (88, 100))	('ligand', 'molecular_function', 'GO:0005488', ('38', '44'))	('pigmentation', 'Disease', (88, 100))	('SCF', 'molecular_function', 'GO:0005173', ('64', '67'))	('white spotting', 'Disease', (114, 128))	('deficient', 'Var', (5, 14))
52726	32455885	KIT gain-of-function mutations have been shown to drive the formation of rare acral and mucosal melanoma subtypes.	('mucosal melanoma', 'Disease', 'MESH:D008545', (88, 104))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('gain-of-function', 'PosReg', (4, 20))	('mucosal melanoma', 'Disease', (88, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('KIT', 'Gene', (0, 3))	('formation', 'biological_process', 'GO:0009058', ('60', '69'))	('mutations', 'Var', (21, 30))
52728	32455885	The effect of KIT loss was investigated in zebrafish by introducing a kita-null mutation into the Tg(mitfa:BRAFV600E); p53(lf) melanoma-prone strain.	('zebrafish', 'Species', '7955', (43, 52))	('kita', 'Gene', '30256', (70, 74))	('KIT', 'molecular_function', 'GO:0005020', ('14', '17'))	('introducing', 'Reg', (56, 67))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('KIT loss', 'Disease', 'MESH:D014786', (14, 22))	('mitfa', 'Gene', '30080', (101, 106))	('melanoma', 'Disease', (127, 135))	('kita', 'Gene', (70, 74))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('mitfa', 'Gene', (101, 106))	('mutation', 'Var', (80, 88))	('KIT loss', 'Disease', (14, 22))
52729	32455885	Loss of kita caused accelerated melanoma onset, with increased BRAFV600E-driven MAPK pathway signaling evident in tumors.	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('melanoma', 'Disease', (32, 40))	('BRAFV600E-driven', 'Var', (63, 79))	('MAPK', 'molecular_function', 'GO:0004707', ('80', '84'))	('kita', 'Gene', '30256', (8, 12))	('Loss', 'NegReg', (0, 4))	('signaling', 'biological_process', 'GO:0023052', ('93', '102'))	('increased', 'PosReg', (53, 62))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('accelerated', 'PosReg', (20, 31))	('kita', 'Gene', (8, 12))
52739	32455885	Crucially, treatment with leflunomide caused a decrease in melanoma cell growth in vitro, in addition to inhibiting the growth of autochthonous zebrafish melanomas and xenografted melanomas in mice.	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('decrease', 'NegReg', (47, 55))	('melanomas', 'Disease', 'MESH:D008545', (154, 163))	('growth', 'CPA', (120, 126))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('melanomas', 'Phenotype', 'HP:0002861', (180, 189))	('zebrafish', 'Species', '7955', (144, 153))	('cell growth', 'biological_process', 'GO:0016049', ('68', '79'))	('melanomas', 'Disease', (154, 163))	('mice', 'Species', '10090', (193, 197))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('inhibiting', 'NegReg', (105, 115))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('melanomas', 'Phenotype', 'HP:0002861', (154, 163))	('leflunomide', 'Chemical', 'MESH:D000077339', (26, 37))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('melanomas', 'Disease', 'MESH:D008545', (180, 189))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('melanomas', 'Disease', (180, 189))	('leflunomide', 'Var', (26, 37))
52761	32455885	Consistent with a role in promoting differentiation and proliferation upon metastatic spread, ZMEL1-GFP secondary metastases in zebrafish mutant for edn3 and its biosynthetic enzyme ece2b were smaller and less pigmented.	('ece2b', 'Gene', (182, 187))	('metastases', 'Disease', (114, 124))	('pigmented', 'Disease', (210, 219))	('edn3', 'Gene', (149, 153))	('less', 'NegReg', (205, 209))	('pigmented', 'Disease', 'MESH:D010859', (210, 219))	('edn3', 'Gene', '101884385', (149, 153))	('mutant', 'Var', (138, 144))	('metastases', 'Disease', 'MESH:D009362', (114, 124))	('ece2b', 'Gene', '793465', (182, 187))	('zebrafish', 'Species', '7955', (128, 137))
52770	32455885	Furthermore, more aggressive melanomas were observed in a SPINT1-deficient background in zebrafish, suggesting that SPINT1 deficiency accelerates melanoma formation via altered immune cell recruitment and activity.	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('aggressive melanomas', 'Disease', (18, 38))	('zebrafish', 'Species', '7955', (89, 98))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('SPINT1', 'Gene', '6692', (58, 64))	('accelerates', 'PosReg', (134, 145))	('aggressive melanomas', 'Disease', 'MESH:D008545', (18, 38))	('melanomas', 'Phenotype', 'HP:0002861', (29, 38))	('SPINT1', 'Gene', (116, 122))	('immune cell recruitment', 'CPA', (177, 200))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('deficiency', 'Var', (123, 133))	('melanoma', 'Disease', (29, 37))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('SPINT1', 'Gene', (58, 64))	('formation', 'biological_process', 'GO:0009058', ('155', '164'))	('altered', 'Reg', (169, 176))	('activity', 'CPA', (205, 213))	('SPINT1', 'Gene', '6692', (116, 122))
52782	32455885	Furthermore, elevated expression of FATP1 expression in melanocytes accelerated BRAFV600E-driven melanoma development in both zebrafish and murine models.	('zebrafish', 'Species', '7955', (126, 135))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('BRAFV600E-driven', 'Var', (80, 96))	('elevated', 'PosReg', (13, 21))	('accelerated', 'PosReg', (68, 79))	('murine', 'Species', '10090', (140, 146))	('FATP1', 'Gene', (36, 41))	('expression', 'MPA', (22, 32))
52798	32455885	Complementing the discovery that GDF6-activated BMP signaling suppresses differentiation to promote invasive melanoma, Gramann and colleagues found that loss of the zebrafish ortholog gdf6a in development leads to an excess of melanocytes specified from the neural crest.	('zebrafish', 'Species', '7955', (165, 174))	('GDF6', 'Gene', '392255', (33, 37))	('gdf6a', 'Gene', '566470', (184, 189))	('promote', 'PosReg', (92, 99))	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('BMP', 'Gene', '649', (48, 51))	('differentiation', 'CPA', (73, 88))	('BMP', 'Gene', (48, 51))	('invasive melanoma', 'Disease', 'MESH:D008545', (100, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('loss', 'Var', (153, 157))	('excess', 'PosReg', (217, 223))	('suppresses', 'NegReg', (62, 72))	('invasive melanoma', 'Disease', (100, 117))	('GDF6', 'Gene', (33, 37))	('gdf6a', 'Gene', (184, 189))
52819	32455885	was supported by NIH AR063850, NIH CA228120.	('NIH', 'Var', (31, 34))	('CA228120', 'Chemical', '-', (35, 43))	('NIH', 'Var', (17, 20))
52822	32236611	A number of reports have demonstrated that HOXA11-AS functions as a protein scaffold for polycomb repressive complex 2 (PRC2), lysine-specific histone demethylase 1 (LSD1) and DNA methyltransferase 1 (DNMT1) to perform epigenetic modifications on chromosomes in the nucleus.	('DNA', 'cellular_component', 'GO:0005574', ('176', '179'))	('DNA methyltransferase 1', 'Gene', (176, 199))	('DNMT1', 'Gene', (201, 206))	('LSD1', 'Gene', (166, 170))	('lysine-specific histone demethylase 1', 'Gene', (127, 164))	('DNA methyltransferase 1', 'Gene', '1786', (176, 199))	('RC', 'Phenotype', 'HP:0009726', (121, 123))	('LSD1', 'Gene', '23028', (166, 170))	('DNMT1', 'Gene', '1786', (201, 206))	('methyltransferase 1', 'molecular_function', 'GO:0047152', ('180', '199'))	('epigenetic', 'Var', (219, 229))	('PR', 'Gene', '5241', (120, 122))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('nucleus', 'cellular_component', 'GO:0005634', ('266', '273'))	('lysine-specific histone demethylase 1', 'Gene', '23028', (127, 164))	('AS', 'Phenotype', 'HP:0002621', (50, 52))
52823	32236611	In addition, HOXA11-AS may be useful as a biomarker for the diagnosis and prognosis of cancer.	('cancer', 'Disease', (87, 93))	('HOXA11-AS', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('AS', 'Phenotype', 'HP:0002621', (20, 22))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
52847	32236611	The dosage compensation effect of the X chromosome in mammals provides a striking instance of lncRNA-mediated chromatin regulation.	('chromatin', 'cellular_component', 'GO:0000785', ('110', '119'))	('dosage compensation', 'biological_process', 'GO:0007549', ('4', '23'))	('dosage compensation', 'Var', (4, 23))	('ncRNA', 'Gene', (95, 100))	('X chromosome', 'cellular_component', 'GO:0000805', ('38', '50'))	('ncRNA', 'Gene', '220202', (95, 100))	('regulation', 'biological_process', 'GO:0065007', ('120', '130'))
52853	32236611	The interaction between DNA and lncRNA is achieved either via sequence complementation or via combination in helical structures.	('helical', 'MPA', (109, 116))	('interaction', 'Interaction', (4, 15))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('ncRNA', 'Gene', '220202', (33, 38))	('men', 'Species', '9606', (77, 80))	('sequence complementation', 'Var', (62, 86))	('combination', 'Interaction', (94, 105))	('ncRNA', 'Gene', (33, 38))
52860	32236611	Findings demonstrated that improvements in cell invasion and proliferation mediated by HOXA11-AS were reversed by miR-124.	('HOXA11-AS', 'Var', (87, 96))	('improvements', 'PosReg', (27, 39))	('AS', 'Phenotype', 'HP:0002621', (94, 96))	('cell invasion', 'CPA', (43, 56))	('men', 'Species', '9606', (34, 37))
52862	32236611	For instance, lncRNA LOC554202 was shown to be the putative precursor of miR-31, exerting an important role in preventing metastasis of BC.	('miR-31', 'Gene', '407035', (73, 79))	('ncRNA', 'Gene', (15, 20))	('LOC554202', 'Var', (21, 30))	('preventing', 'NegReg', (111, 121))	('BC', 'Phenotype', 'HP:0003002', (136, 138))	('miR-31', 'Gene', (73, 79))	('ncRNA', 'Gene', '220202', (15, 20))	('BC', 'Phenotype', 'HP:0009725', (136, 138))	('metastasis', 'CPA', (122, 132))
52870	32236611	When exosomes containing lncARSR reached the sensitive RCC cells, lncARSR was released into the cytoplasm.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('CC', 'Phenotype', 'HP:0002664', (56, 58))	('lncARSR', 'Var', (25, 32))	('RC', 'Phenotype', 'HP:0009726', (55, 57))	('cytoplasm', 'cellular_component', 'GO:0005737', ('96', '105'))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
52871	32236611	The expression of the receptor tyrosine kinases AXL and c-MET in RCC cells was promoted by lncARSR competitively binding miR-34/miR-449, thus promoting sunitinib resistance.	('miR-34', 'Gene', (121, 127))	('AXL', 'Gene', (48, 51))	('expression', 'MPA', (4, 14))	('c-MET', 'Gene', '4233', (56, 61))	('promoted', 'PosReg', (79, 87))	('c-MET', 'Gene', (56, 61))	('binding', 'molecular_function', 'GO:0005488', ('113', '120'))	('CC', 'Phenotype', 'HP:0002664', (66, 68))	('binding', 'Interaction', (113, 120))	('RCC', 'Disease', (65, 68))	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('miR-34', 'Gene', '407040', (121, 127))	('lncARSR', 'Var', (91, 98))	('AXL', 'Gene', '558', (48, 51))	('sunitinib resistance', 'MPA', (152, 172))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('promoting', 'PosReg', (142, 151))	('sunitinib', 'Chemical', 'MESH:D000077210', (152, 161))	('RC', 'Phenotype', 'HP:0009726', (65, 67))
52872	32236611	AXL and c-MET are responsible for lncARSR-mediated sunitinib resistance in RCC.	('RC', 'Phenotype', 'HP:0009726', (75, 77))	('sunitinib', 'Chemical', 'MESH:D000077210', (51, 60))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('c-MET', 'Gene', (8, 13))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('AXL', 'Gene', '558', (0, 3))	('RCC', 'Disease', (75, 78))	('lncARSR-mediated', 'Var', (34, 50))	('CC', 'Phenotype', 'HP:0002664', (76, 78))	('AXL', 'Gene', (0, 3))	('c-MET', 'Gene', '4233', (8, 13))
52888	32236611	HOXA11-AS is a novel lncRNA that functions as an oncogene or tumor-suppressor gene in diverse types of tumor.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('61', '77'))	('ncRNA', 'Gene', (22, 27))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('AS', 'Phenotype', 'HP:0002621', (7, 9))	('ncRNA', 'Gene', '220202', (22, 27))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('61', '77'))	('HOXA11-AS', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (61, 66))
52889	32236611	For example, HOXA11-AS can serve as an oncogene in non-small cell lung cancer (NSCLC), HCC, glioma, BC, GC, renal cancer (RC), uveal melanoma (UM), laryngeal squamous cell carcinoma (LSCC), cervical cancer (CC), ESCC and osteosarcoma.	('renal cancer', 'Disease', (108, 120))	('GC', 'Phenotype', 'HP:0012126', (104, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('renal cancer', 'Phenotype', 'HP:0009726', (108, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (158, 181))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (199, 205))	('SCC', 'Phenotype', 'HP:0002860', (184, 187))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('HCC', 'Disease', (87, 90))	('HCC', 'Phenotype', 'HP:0001402', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('SCC', 'Phenotype', 'HP:0002860', (213, 216))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('cancer', 'Disease', (71, 77))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('renal cancer', 'Disease', 'MESH:D007680', (108, 120))	('osteosarcoma', 'Phenotype', 'HP:0002669', (221, 233))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (158, 181))	('HOXA11-AS', 'Var', (13, 22))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('RC', 'Phenotype', 'HP:0009726', (122, 124))	('lung cancer', 'Disease', (66, 77))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (51, 77))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('CC', 'Phenotype', 'HP:0002664', (185, 187))	('CC', 'Phenotype', 'HP:0002664', (214, 216))	('UM', 'Phenotype', 'HP:0007716', (143, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('squamous cell carcinoma', 'Disease', (158, 181))	('CC', 'Phenotype', 'HP:0002664', (207, 209))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (55, 77))	('BC', 'Phenotype', 'HP:0009725', (100, 102))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('CC', 'Phenotype', 'HP:0002664', (88, 90))	('ESCC', 'Disease', (212, 216))	('SCLC', 'Phenotype', 'HP:0030357', (80, 84))	('AS', 'Phenotype', 'HP:0002621', (20, 22))	('glioma', 'Disease', (92, 98))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('BC', 'Phenotype', 'HP:0003002', (100, 102))	('osteosarcoma', 'Disease', (221, 233))	('osteosarcoma', 'Disease', 'MESH:D012516', (221, 233))	('uveal melanoma', 'Phenotype', 'HP:0007716', (127, 141))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))	('NSCLC', 'Disease', (79, 84))	('cancer', 'Disease', (114, 120))
52890	32236611	By contrast, HOXA11-AS functions as a tumor suppressor in epithelial ovarian cancer (EOC).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('HOXA11-AS', 'Var', (13, 22))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('AS', 'Phenotype', 'HP:0002621', (20, 22))	('tumor suppressor', 'biological_process', 'GO:0051726', ('38', '54'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (69, 83))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (58, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('epithelial ovarian cancer', 'Disease', (58, 83))
52897	32236611	Zhang et al reported that the expression of HOXA11-AS is higher in both squamous cell carcinoma (SCC) and lung adenocarcinoma (LUAD) compared with that in normal lung tissues, and HOXA11-AS knockdown suppresses tumorigenesis, angiogenesis, proliferation, migration and invasion of NSCLC cells, inducing apoptosis by impeding the cell cycle at the G0/G1 or the G2/M phase.	('invasion', 'CPA', (269, 277))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('AS', 'Phenotype', 'HP:0002621', (187, 189))	('migration', 'CPA', (255, 264))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('AS', 'Phenotype', 'HP:0002621', (51, 53))	('tumor', 'Disease', (211, 216))	('suppresses', 'NegReg', (200, 210))	('LUAD', 'Phenotype', 'HP:0030078', (127, 131))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 95))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('SCLC', 'Phenotype', 'HP:0030357', (282, 286))	('M phase', 'biological_process', 'GO:0000279', ('363', '370'))	('apoptosis', 'biological_process', 'GO:0097194', ('303', '312'))	('lung adenocarcinoma', 'Disease', (106, 125))	('cell cycle at the G0/G1', 'CPA', (329, 352))	('apoptosis', 'biological_process', 'GO:0006915', ('303', '312'))	('HOXA11-AS', 'Gene', (44, 53))	('NSCLC', 'Disease', 'MESH:D002289', (281, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('CC', 'Phenotype', 'HP:0002664', (98, 100))	('squamous cell carcinoma', 'Disease', (72, 95))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('NSCLC', 'Disease', (281, 286))	('apoptosis', 'CPA', (303, 312))	('inducing', 'NegReg', (294, 302))	('HOXA11-AS knockdown', 'Var', (180, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('angiogenesis', 'biological_process', 'GO:0001525', ('226', '238'))	('proliferation', 'CPA', (240, 253))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (106, 125))	('expression', 'MPA', (30, 40))	('impeding', 'NegReg', (316, 324))	('knockdown', 'Var', (190, 199))	('higher', 'PosReg', (57, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (281, 286))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (106, 125))	('angiogenesis', 'CPA', (226, 238))	('cell cycle', 'biological_process', 'GO:0007049', ('329', '339'))
52898	32236611	Moreover, Chen et al identified that high levels of HOXA11-AS predict poor prognosis in patients with NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('high', 'Var', (37, 41))	('SCLC', 'Phenotype', 'HP:0030357', (103, 107))	('patients', 'Species', '9606', (88, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('AS', 'Phenotype', 'HP:0002621', (59, 61))	('HOXA11-AS', 'Protein', (52, 61))	('NSCLC', 'Disease', (102, 107))
52901	32236611	Those authors conjectured that HOXA11-AS could have an oncogenic role in the development and progression of NSCLC by modulating various pathways, such as the transforming growth factor (TGF)-beta pathway, the phosphoinositide 3-kinase (PI3K)-Akt pathway and the Hippo signaling pathway, and genes, such as DOCK8 gene.	('Hippo signaling pathway', 'Pathway', (262, 285))	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('HOXA11-AS', 'Var', (31, 40))	('phosphoinositide 3-kinase', 'Gene', '5295', (209, 234))	('AS', 'Phenotype', 'HP:0002621', (38, 40))	('modulating', 'Reg', (117, 127))	('NSCLC', 'Disease', (108, 113))	('phosphoinositide 3-kinase', 'Gene', (209, 234))	('Akt', 'Gene', (242, 245))	('DOCK8', 'Gene', '81704', (306, 311))	('transforming growth factor (TGF)-beta', 'Gene', '7039', (158, 195))	('men', 'Species', '9606', (84, 87))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('SCLC', 'Phenotype', 'HP:0030357', (109, 113))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('262', '285'))	('Akt', 'Gene', '207', (242, 245))	('PI3K', 'molecular_function', 'GO:0016303', ('236', '240'))	('DOCK8', 'Gene', (306, 311))
52902	32236611	In other studies, the same authors demonstrated that the expression of HOXA11-AS co-expressed genes in NSCLC may be partly regulated by the NSCLC pathway and that HOXA11-AS could affect various biological processes of NSCLC via regulation of the expression of miR-642b-3p by targeting the expression of phosphodiesterase 4D (PDE4D) or other target genes.	('HOXA11-AS', 'Gene', (71, 80))	('NSCLC', 'Disease', (103, 108))	('SCLC', 'Phenotype', 'HP:0030357', (141, 145))	('targeting', 'Reg', (275, 284))	('expression', 'MPA', (289, 299))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('phosphodiesterase 4D', 'Gene', '5144', (303, 323))	('phosphodiesterase', 'molecular_function', 'GO:0008081', ('303', '320'))	('AS', 'Phenotype', 'HP:0002621', (170, 172))	('expression', 'MPA', (57, 67))	('PDE4D', 'Gene', '5144', (325, 330))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('PDE', 'molecular_function', 'GO:0004114', ('325', '328'))	('SCLC', 'Phenotype', 'HP:0030357', (219, 223))	('NSCLC', 'Disease', 'MESH:D002289', (218, 223))	('NSCLC', 'Disease', (140, 145))	('affect', 'Reg', (179, 185))	('SCLC', 'Phenotype', 'HP:0030357', (104, 108))	('PDE4D', 'Gene', (325, 330))	('HOXA11-AS', 'Var', (163, 172))	('NSCLC', 'Disease', (218, 223))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('miR-642b-3p', 'Gene', (260, 271))	('regulation', 'biological_process', 'GO:0065007', ('228', '238'))	('phosphodiesterase 4D', 'Gene', (303, 323))	('NSCLC', 'Phenotype', 'HP:0030358', (218, 223))	('AS', 'Phenotype', 'HP:0002621', (78, 80))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))
52903	32236611	Additionally, Chen et al found that HOXA11-AS interacts with DNA (cytosine-5)-methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2), recruiting these proteins to the promoter regions of miR-200b and mediating methylation silencing of miR-200b in NSCLC cells, a process that promotes both NSCLC cell epithelial-mesenchymal transition (EMT) via regulation of the protein levels of E-cadherin, N-cadherin, Snail1/2 and ZEB1/2 and tumor progression.	('AS', 'Phenotype', 'HP:0002621', (43, 45))	('N-cadherin', 'Gene', '1000', (404, 414))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('312', '345'))	('cadherin', 'molecular_function', 'GO:0008014', ('394', '402'))	('miR-200b', 'Gene', (199, 207))	('NSCLC', 'Disease', (301, 306))	('silencing', 'NegReg', (234, 243))	('NSCLC', 'Disease', 'MESH:D002289', (259, 264))	('E-cadherin', 'Gene', (392, 402))	('DNMT1', 'Gene', '1786', (99, 104))	('protein', 'cellular_component', 'GO:0003675', ('374', '381'))	('SCLC', 'Phenotype', 'HP:0030357', (260, 264))	('E-cadherin', 'Gene', '999', (392, 402))	('EMT', 'biological_process', 'GO:0001837', ('347', '350'))	('miR-200b', 'Gene', '406984', (247, 255))	('Snail1/2', 'Gene', (416, 424))	('NSCLC', 'Phenotype', 'HP:0030358', (301, 306))	('methylation', 'Var', (222, 233))	('tumor', 'Disease', (440, 445))	('cadherin', 'molecular_function', 'GO:0008014', ('406', '414'))	('NSCLC', 'Disease', (259, 264))	('ZEB1/2', 'Gene', (429, 435))	('tumor', 'Disease', 'MESH:D009369', (440, 445))	('NSCLC', 'Phenotype', 'HP:0030358', (259, 264))	('regulation', 'biological_process', 'GO:0065007', ('356', '366'))	('DNA (cytosine-5)-methyltransferase 1', 'Gene', '1786', (61, 97))	('enhancer of zeste homolog 2', 'Gene', '2146', (110, 137))	('miR-200b', 'Gene', '406984', (199, 207))	('Snail1/2', 'Gene', '6615;6591', (416, 424))	('methylation', 'biological_process', 'GO:0032259', ('222', '233'))	('DNMT1', 'Gene', (99, 104))	('methyltransferase 1', 'molecular_function', 'GO:0047152', ('78', '97'))	('promotes', 'PosReg', (287, 295))	('ZEB1/2', 'Gene', '6935;9839', (429, 435))	('tumor', 'Phenotype', 'HP:0002664', (440, 445))	('SCLC', 'Phenotype', 'HP:0030357', (302, 306))	('miR-200b', 'Gene', (247, 255))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('enhancer of zeste homolog 2', 'Gene', (110, 137))	('EZH2', 'Gene', '2146', (139, 143))	('NSCLC', 'Disease', 'MESH:D002289', (301, 306))	('EZH2', 'Gene', (139, 143))	('N-cadherin', 'Gene', (404, 414))
52904	32236611	Futhermore, those authors found that HOXA11-AS can serve as an oncogene by promoting EMT via regulation of the protein levels of E-cadherin, beta-catenin, vimentin and the EMT-mediating transcription factors Slug and Snail in NSCLC.	('AS', 'Phenotype', 'HP:0002621', (44, 46))	('regulation', 'MPA', (93, 103))	('cadherin', 'molecular_function', 'GO:0008014', ('131', '139'))	('transcription', 'biological_process', 'GO:0006351', ('186', '199'))	('vimentin', 'cellular_component', 'GO:0045098', ('155', '163'))	('EMT', 'CPA', (85, 88))	('NSCLC', 'Disease', 'MESH:D002289', (226, 231))	('Snail', 'Gene', (217, 222))	('SCLC', 'Phenotype', 'HP:0030357', (227, 231))	('HOXA11-AS', 'Var', (37, 46))	('Slug', 'Gene', '6591', (208, 212))	('promoting', 'PosReg', (75, 84))	('NSCLC', 'Disease', (226, 231))	('regulation', 'biological_process', 'GO:0065007', ('93', '103'))	('vimentin', 'cellular_component', 'GO:0045099', ('155', '163'))	('beta-catenin', 'Gene', (141, 153))	('E-cadherin', 'Gene', (129, 139))	('E-cadherin', 'Gene', '999', (129, 139))	('beta-catenin', 'Gene', '1499', (141, 153))	('NSCLC', 'Phenotype', 'HP:0030358', (226, 231))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('vimentin', 'Gene', '7431', (155, 163))	('vimentin', 'Gene', (155, 163))	('EMT', 'biological_process', 'GO:0001837', ('85', '88'))	('Snail', 'Gene', '6615', (217, 222))	('EMT', 'biological_process', 'GO:0001837', ('172', '175'))	('Slug', 'Gene', (208, 212))	('protein levels', 'MPA', (111, 125))
52905	32236611	Zhao et al discovered that, in human LUAD cells, HOXA11-AS can function as a ceRNA to facilitate cisplatin tolerance through the miR-454-3p/Stat3 pathway (the abovementioned mechanisms are shown in Fig.	('HOXA11-AS', 'Var', (49, 58))	('facilitate', 'PosReg', (86, 96))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('human', 'Species', '9606', (31, 36))	('Stat3', 'Gene', '6774', (140, 145))	('AS', 'Phenotype', 'HP:0002621', (56, 58))	('cisplatin tolerance', 'MPA', (97, 116))	('LUAD', 'Phenotype', 'HP:0030078', (37, 41))	('Stat3', 'Gene', (140, 145))	('men', 'Species', '9606', (164, 167))
52907	32236611	These findings indicate that HOXA11-AS has several functions associated with oncogenesis, regulating various physiological activities in NSCLC.	('NSCLC', 'Disease', (137, 142))	('AS', 'Phenotype', 'HP:0002621', (36, 38))	('oncogenesis', 'biological_process', 'GO:0007048', ('77', '88'))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('HOXA11-AS', 'Var', (29, 38))	('SCLC', 'Phenotype', 'HP:0030357', (138, 142))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))
52912	32236611	Liu et al found that high expression levels of HOXA11-AS are significantly correlated with vascular invasion, cirrhosis, tumor size and Edmondson grade.	('AS', 'Phenotype', 'HP:0002621', (54, 56))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cirrhosis', 'Disease', (110, 119))	('cirrhosis', 'Disease', 'MESH:D005355', (110, 119))	('tumor', 'Disease', (121, 126))	('correlated', 'Reg', (75, 85))	('Edmondson', 'Disease', (136, 145))	('HOXA11-AS', 'Var', (47, 56))	('vascular invasion', 'CPA', (91, 108))	('expression levels', 'MPA', (26, 43))	('cirrhosis', 'Phenotype', 'HP:0001394', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
52913	32236611	The overall survival (OS) rate of patients with high levels of HOXA11-AS expression is markedly shorter compared with those with lower levels of HOXA11-AS expression.	('HOXA11-AS expression', 'Var', (63, 83))	('shorter', 'NegReg', (96, 103))	('high levels', 'Var', (48, 59))	('AS', 'Phenotype', 'HP:0002621', (70, 72))	('patients', 'Species', '9606', (34, 42))	('overall survival', 'MPA', (4, 20))	('AS', 'Phenotype', 'HP:0002621', (152, 154))
52914	32236611	Yu et al reported that HOXA11-AS recruits PRC2 to the promoter region of large tumor suppressor 1 (LATS1) to obstruct its transcription, thereby promoting HCC growth and inhibiting apoptosis and cell cycle progression at the G0/G1 phase.	('HCC growth', 'CPA', (155, 165))	('LATS1', 'Gene', (99, 104))	('apoptosis', 'CPA', (181, 190))	('HOXA11-AS', 'Var', (23, 32))	('LATS1', 'Gene', '9113', (99, 104))	('CC', 'Phenotype', 'HP:0002664', (156, 158))	('large tumor suppressor 1', 'Gene', '9113', (73, 97))	('G1 phase', 'biological_process', 'GO:0051318', ('228', '236'))	('cell cycle progression at the G0/G1 phase', 'CPA', (195, 236))	('RC', 'Phenotype', 'HP:0009726', (43, 45))	('HCC', 'Phenotype', 'HP:0001402', (155, 158))	('inhibiting', 'NegReg', (170, 180))	('obstruct', 'NegReg', (109, 117))	('promoting', 'PosReg', (145, 154))	('large tumor suppressor 1', 'Gene', (73, 97))	('PR', 'Gene', '5241', (42, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('181', '190'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('79', '95'))	('transcription', 'biological_process', 'GO:0006351', ('122', '135'))	('transcription', 'MPA', (122, 135))	('AS', 'Phenotype', 'HP:0002621', (30, 32))	('apoptosis', 'biological_process', 'GO:0006915', ('181', '190'))	('cell cycle', 'biological_process', 'GO:0007049', ('195', '205'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('79', '95'))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
52916	32236611	Zhan et al showed that the overexpression of HOXA11-AS is able to facilitate HCC proliferation and invasion, and induce EMT by repressing the expression of miR-214-3p.	('HOXA11-AS', 'Var', (45, 54))	('induce', 'PosReg', (113, 119))	('facilitate', 'PosReg', (66, 76))	('CC', 'Phenotype', 'HP:0002664', (78, 80))	('HCC', 'Phenotype', 'HP:0001402', (77, 80))	('HCC proliferation', 'CPA', (77, 94))	('miR-214-3p', 'Chemical', '-', (156, 166))	('AS', 'Phenotype', 'HP:0002621', (52, 54))	('invasion', 'CPA', (99, 107))	('miR-214-3p', 'Var', (156, 166))	('EMT', 'biological_process', 'GO:0001837', ('120', '123'))	('overexpression', 'PosReg', (27, 41))	('EMT', 'CPA', (120, 123))
52917	32236611	In addition, these authors demonstrated that the expression of miR-214-3p in early clinical stages (I-II) was higher than that in advanced clinical stages (III-IV).	('miR-214-3p', 'Chemical', '-', (63, 73))	('higher', 'PosReg', (110, 116))	('miR-214-3p', 'Var', (63, 73))	('expression', 'MPA', (49, 59))
52919	32236611	HOXA11-AS performs an oncogenic role in HCC by interacting with PRC2 (the abovementioned mechanisms are shown in Fig.	('men', 'Species', '9606', (79, 82))	('HCC', 'Disease', (40, 43))	('RC', 'Phenotype', 'HP:0009726', (65, 67))	('HCC', 'Phenotype', 'HP:0001402', (40, 43))	('AS', 'Phenotype', 'HP:0002621', (7, 9))	('interacting', 'Interaction', (47, 58))	('CC', 'Phenotype', 'HP:0002664', (41, 43))	('PR', 'Gene', '5241', (64, 66))	('HOXA11-AS', 'Var', (0, 9))
52920	32236611	HOXA11-AS may function as an oncogene in HCC development.	('men', 'Species', '9606', (52, 55))	('AS', 'Phenotype', 'HP:0002621', (7, 9))	('CC', 'Phenotype', 'HP:0002664', (42, 44))	('HCC', 'Disease', (41, 44))	('HCC', 'Phenotype', 'HP:0001402', (41, 44))	('HOXA11-AS', 'Var', (0, 9))
52926	32236611	Wang et al discovered that high levels of HOXA11-AS expression are closely correlated with OS in high-grade glioma, and HOXA11-AS may be an independent prognostic factor for GBM.	('glioma', 'Disease', (108, 114))	('AS', 'Phenotype', 'HP:0002621', (127, 129))	('expression', 'MPA', (52, 62))	('correlated', 'Reg', (75, 85))	('glioma', 'Disease', 'MESH:D005910', (108, 114))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('AS', 'Phenotype', 'HP:0002621', (49, 51))	('HOXA11-AS', 'Var', (120, 129))
52928	32236611	Those authors reported that the expression levels of HOTTIP, HOXA9, HOXA10, and HOXA13 are prominently correlated with HOXA11-AS expression, and HOXA11-AS can alter the expression of cell cycle-associated proteins, thus regulating cell cycle progression.	('HOXA13', 'Gene', (80, 86))	('HOXA10', 'Gene', (68, 74))	('expression', 'MPA', (169, 179))	('cell cycle-associated proteins', 'Protein', (183, 213))	('regulating', 'Reg', (220, 230))	('HOTTIP', 'Gene', (53, 59))	('expression', 'MPA', (32, 42))	('AS', 'Phenotype', 'HP:0002621', (152, 154))	('alter', 'Reg', (159, 164))	('cell cycle', 'biological_process', 'GO:0007049', ('183', '193'))	('HOXA10', 'Gene', '3206', (68, 74))	('HOXA9', 'Gene', (61, 66))	('AS', 'Phenotype', 'HP:0002621', (126, 128))	('HOTTIP', 'Gene', '100316868', (53, 59))	('HOXA9', 'Gene', '3205', (61, 66))	('cell cycle', 'biological_process', 'GO:0007049', ('231', '241'))	('HOXA11-AS', 'Var', (145, 154))	('HOXA13', 'Gene', '3209', (80, 86))	('cell cycle progression', 'CPA', (231, 253))
52930	32236611	In addition, Xu et al found that the overexpression of HOXA11-AS is associated with advanced stages of glioma and poor prognosis.	('overexpression', 'PosReg', (37, 51))	('associated', 'Reg', (68, 78))	('HOXA11-AS', 'Var', (55, 64))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('AS', 'Phenotype', 'HP:0002621', (62, 64))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('glioma', 'Disease', (103, 109))
52931	32236611	Authors of that study reported that knocking down the expression of HOXA11-AS leads to suppression of the proliferation, migration, and invasion rates of glioma cells in vitro, with the consequent further enhancement of cell cycle arrest at the G0/G1 stage and improved apoptotic responses.	('glioma', 'Disease', 'MESH:D005910', (154, 160))	('migration', 'CPA', (121, 130))	('glioma', 'Phenotype', 'HP:0009733', (154, 160))	('improved', 'PosReg', (261, 269))	('HOXA11-AS', 'Gene', (68, 77))	('suppression', 'NegReg', (87, 98))	('enhancement', 'PosReg', (205, 216))	('apoptotic responses', 'CPA', (270, 289))	('invasion rates', 'CPA', (136, 150))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('220', '237'))	('glioma', 'Disease', (154, 160))	('arrest', 'Disease', 'MESH:D006323', (231, 237))	('knocking down', 'Var', (36, 49))	('arrest', 'Disease', (231, 237))	('AS', 'Phenotype', 'HP:0002621', (75, 77))	('men', 'Species', '9606', (212, 215))
52932	32236611	Cui et al showed that miR-140-5p is able to directly target the 3'-UTR of HOXA11-AS, and the effects of HOXA11-AS knockdown are shown to be reversed by an miR-140-5p inhibitor, as determined by its effects on cell cycle arrest, proliferation and apoptosis.	('AS', 'Phenotype', 'HP:0002621', (111, 113))	('miR-140-5p', 'Chemical', '-', (22, 32))	('apoptosis', 'CPA', (246, 255))	('AS', 'Phenotype', 'HP:0002621', (81, 83))	('knockdown', 'Var', (114, 123))	('arrest', 'Disease', (220, 226))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('209', '226'))	('apoptosis', 'biological_process', 'GO:0097194', ('246', '255'))	('proliferation', 'CPA', (228, 241))	('HOXA11-AS', 'Gene', (104, 113))	('apoptosis', 'biological_process', 'GO:0006915', ('246', '255'))	('miR-140-5p', 'Chemical', '-', (155, 165))	('arrest', 'Disease', 'MESH:D006323', (220, 226))
52934	32236611	It was thereby confirmed that HOXA11-AS may serve in an oncogenic role by regulating the miR-214-3p/EZH2 pathway.	('AS', 'Phenotype', 'HP:0002621', (37, 39))	('regulating', 'Reg', (74, 84))	('EZH2', 'Gene', '2146', (100, 104))	('EZH2', 'Gene', (100, 104))	('miR-214-3p', 'Chemical', '-', (89, 99))	('HOXA11-AS', 'Var', (30, 39))
52935	32236611	Yang et al found that HOXA11-AS leads to a marked increase in proliferation, invasion and migration rates, while inhibiting apoptosis by absorbing miR-124-3p in glioma cells.	('apoptosis', 'CPA', (124, 133))	('miR-124-3p', 'Gene', (147, 157))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('migration rates', 'CPA', (90, 105))	('inhibiting', 'NegReg', (113, 123))	('proliferation', 'CPA', (62, 75))	('glioma', 'Disease', 'MESH:D005910', (161, 167))	('glioma', 'Phenotype', 'HP:0009733', (161, 167))	('invasion', 'CPA', (77, 85))	('increase', 'PosReg', (50, 58))	('HOXA11-AS', 'Var', (22, 31))	('miR-124-3p', 'Gene', '406909', (147, 157))	('glioma', 'Disease', (161, 167))	('AS', 'Phenotype', 'HP:0002621', (29, 31))	('absorbing', 'NegReg', (137, 146))
52936	32236611	Furthermore, Xu et al found that HOXA11-AS can exert its oncogenic role by directly binding to miR-130a-5p as a ceRNA, which inhibits the inhibitory effect of miR-130a-5p on HMGB2 expression.	('HMGB2', 'Gene', '3148', (174, 179))	('AS', 'Phenotype', 'HP:0002621', (40, 42))	('-130a', 'Chemical', '-', (162, 167))	('HMGB2', 'Gene', (174, 179))	('expression', 'MPA', (180, 190))	('HOXA11-AS', 'Var', (33, 42))	('binding', 'molecular_function', 'GO:0005488', ('84', '91'))	('inhibits', 'NegReg', (125, 133))	('-130a', 'Chemical', '-', (98, 103))	('binding', 'Interaction', (84, 91))	('inhibitory effect', 'MPA', (138, 155))
52944	32236611	Moreover, Chen et al reported that the level of HOXA11-AS was markedly upregulated in CRC patients with liver metastasis, and the migration and invasion of CRC cells was facilitated by HOXA11-AS.	('HOXA11-AS', 'Var', (185, 194))	('HOXA11-AS', 'MPA', (48, 57))	('RC', 'Phenotype', 'HP:0009726', (157, 159))	('invasion of CRC cells', 'CPA', (144, 165))	('facilitated', 'PosReg', (170, 181))	('liver metastasis', 'Disease', 'MESH:D009362', (104, 120))	('CRC', 'Phenotype', 'HP:0003003', (86, 89))	('liver metastasis', 'Disease', (104, 120))	('AS', 'Phenotype', 'HP:0002621', (192, 194))	('CRC', 'Phenotype', 'HP:0003003', (156, 159))	('RC', 'Phenotype', 'HP:0009726', (87, 89))	('AS', 'Phenotype', 'HP:0002621', (55, 57))	('patients', 'Species', '9606', (90, 98))	('CRC', 'Disease', (86, 89))	('upregulated', 'PosReg', (71, 82))
52945	32236611	In addition, Chen et al found that HOXA11-AS can act as a ceRNA sequestering miR-125a-5p to modulate the expression of protein-arginine deiminase type-2 (PADI2), which was shown to facilitate metastasis and the invasion of CRC (the abovementioned mechanisms are shown in Fig.	('invasion', 'CPA', (211, 219))	('AS', 'Phenotype', 'HP:0002621', (42, 44))	('modulate', 'Reg', (92, 100))	('miR-125a', 'Gene', (77, 85))	('expression', 'MPA', (105, 115))	('PADI2', 'Gene', (154, 159))	('sequestering', 'biological_process', 'GO:0051235', ('64', '76'))	('protein-arginine deiminase type-2', 'Gene', '11240', (119, 152))	('men', 'Species', '9606', (237, 240))	('PADI2', 'Gene', '11240', (154, 159))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('facilitate', 'PosReg', (181, 191))	('CRC', 'Disease', (223, 226))	('protein-arginine deiminase type-2', 'Gene', (119, 152))	('HOXA11-AS', 'Var', (35, 44))	('CRC', 'Phenotype', 'HP:0003003', (223, 226))	('RC', 'Phenotype', 'HP:0009726', (224, 226))	('metastasis', 'CPA', (192, 202))	('miR-125a', 'Gene', '406910', (77, 85))
52949	32236611	Su and Hu discovered that lncRNA HOXA11-AS is overexpressed in human BC, and the expression of HOXA11-AS is markedly associated with metastasis, tumor size and TNM staging.	('BC', 'Phenotype', 'HP:0009725', (69, 71))	('AS', 'Phenotype', 'HP:0002621', (40, 42))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('HOXA11-AS', 'Var', (95, 104))	('human', 'Species', '9606', (63, 68))	('AS', 'Phenotype', 'HP:0002621', (102, 104))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('associated with', 'Reg', (117, 132))	('expression', 'Var', (81, 91))	('tumor', 'Disease', (145, 150))	('BC', 'Phenotype', 'HP:0003002', (69, 71))	('metastasis', 'CPA', (133, 143))	('ncRNA', 'Gene', (27, 32))	('TNM staging', 'CPA', (160, 171))	('ncRNA', 'Gene', '220202', (27, 32))
52950	32236611	Clinical statistics revealed that the expression of HOXA11-AS was correlated with Ki-67 protein and human epidermal growth factor receptor (HER2), but not with estrogen receptor (ER) or progesterone receptor (PR).	('progesterone receptor', 'Gene', (186, 207))	('progesterone receptor', 'Gene', '5241', (186, 207))	('AS', 'Phenotype', 'HP:0002621', (59, 61))	('HER2', 'Gene', (140, 144))	('estrogen receptor', 'Gene', '2099', (160, 177))	('correlated', 'Reg', (66, 76))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('ER', 'Gene', '2099', (141, 143))	('Ki-67 protein', 'Protein', (82, 95))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('106', '129'))	('expression', 'MPA', (38, 48))	('HOXA11-AS', 'Var', (52, 61))	('PR', 'Gene', '5241', (209, 211))	('estrogen receptor', 'Gene', (160, 177))	('HER2', 'Gene', '2064', (140, 144))	('epidermal growth factor receptor', 'Gene', (106, 138))	('ER', 'Gene', '2099', (179, 181))	('human', 'Species', '9606', (100, 105))	('epidermal growth factor receptor', 'Gene', '1956', (106, 138))
52951	32236611	Their results indicated that decreased expression levels of HOXA11-AS in human BC led to suppression in the rates of cell proliferation, migration and invasion, and cell cycle arrest at the G0/G1 phase.	('arrest', 'Disease', 'MESH:D006323', (176, 182))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('165', '182'))	('HOXA11-AS', 'Var', (60, 69))	('arrest', 'Disease', (176, 182))	('human', 'Species', '9606', (73, 78))	('cell proliferation', 'biological_process', 'GO:0008283', ('117', '135'))	('decreased', 'NegReg', (29, 38))	('G1 phase', 'biological_process', 'GO:0051318', ('193', '201'))	('expression levels', 'MPA', (39, 56))	('BC', 'Phenotype', 'HP:0003002', (79, 81))	('suppression', 'NegReg', (89, 100))	('BC', 'Phenotype', 'HP:0009725', (79, 81))	('AS', 'Phenotype', 'HP:0002621', (67, 69))
52952	32236611	Li et al also reported that low levels of HOXA11-AS expression inhibited cell proliferation and induced tumor cell apoptosis by inducing cell cycle arrest at the G0/G1 stage.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('137', '154'))	('cell proliferation', 'biological_process', 'GO:0008283', ('73', '91'))	('HOXA11-AS', 'Var', (42, 51))	('induced', 'PosReg', (96, 103))	('arrest', 'Disease', 'MESH:D006323', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('inducing', 'NegReg', (128, 136))	('tumor', 'Disease', (104, 109))	('apoptosis', 'biological_process', 'GO:0097194', ('115', '124'))	('apoptosis', 'biological_process', 'GO:0006915', ('115', '124'))	('arrest', 'Disease', (148, 154))	('cell proliferation', 'CPA', (73, 91))	('inhibited', 'NegReg', (63, 72))	('AS', 'Phenotype', 'HP:0002621', (49, 51))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
52953	32236611	By contrast, high levels of HOXA11-AS expression facilitated metastasis and invasion both in vitro and in vivo by exerting an influence on EMT in BC (the abovementioned mechanisms are shown in Fig.	('BC', 'Phenotype', 'HP:0009725', (146, 148))	('men', 'Species', '9606', (159, 162))	('EMT', 'biological_process', 'GO:0001837', ('139', '142'))	('influence', 'Reg', (126, 135))	('metastasis', 'CPA', (61, 71))	('AS', 'Phenotype', 'HP:0002621', (35, 37))	('invasion', 'CPA', (76, 84))	('BC', 'Phenotype', 'HP:0003002', (146, 148))	('HOXA11-AS', 'Var', (28, 37))	('facilitated', 'PosReg', (49, 60))
52955	32236611	These studies, however, have confirmed that HOXA11-AS exerts carcinogenic effects in BC, thereby providing some novel insights for even earlier diagnosis in the future, and for the therapy of BC.	('carcinogenic', 'Disease', 'MESH:D063646', (61, 73))	('BC', 'Phenotype', 'HP:0003002', (85, 87))	('carcinogenic', 'Disease', (61, 73))	('BC', 'Phenotype', 'HP:0003002', (192, 194))	('BC', 'Phenotype', 'HP:0009725', (85, 87))	('BC', 'Phenotype', 'HP:0009725', (192, 194))	('AS', 'Phenotype', 'HP:0002621', (51, 53))	('HOXA11-AS', 'Var', (44, 53))
52962	32236611	By contrast, Liu et al reported that HOXA11-AS knockdown induces G0/G1 phase arrest in GC cells and decreases GC cell metastasis, migration and invasion, both in vitro and in vivo.	('GC cell metastasis', 'CPA', (110, 128))	('induces', 'Reg', (57, 64))	('AS', 'Phenotype', 'HP:0002621', (44, 46))	('GC', 'Phenotype', 'HP:0012126', (87, 89))	('GC', 'Phenotype', 'HP:0012126', (110, 112))	('invasion', 'CPA', (144, 152))	('decreases', 'NegReg', (100, 109))	('knockdown', 'Var', (47, 56))	('arrest', 'Disease', 'MESH:D006323', (77, 83))	('HOXA11-AS', 'Var', (37, 46))	('G1 phase', 'biological_process', 'GO:0051318', ('68', '76'))	('migration', 'CPA', (130, 139))	('arrest', 'Disease', (77, 83))
52963	32236611	In terms of the underlying mechanism, Sun et al demonstrated that HOXA11-AS acts as a protein scaffold to recruit EZH2, accompanied by DNMT1 or LSD1.	('LSD1', 'Gene', (144, 148))	('DNMT1', 'Gene', (135, 140))	('DNMT1', 'Gene', '1786', (135, 140))	('HOXA11-AS', 'Var', (66, 75))	('EZH2', 'Gene', '2146', (114, 118))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('AS', 'Phenotype', 'HP:0002621', (73, 75))	('recruit', 'PosReg', (106, 113))	('EZH2', 'Gene', (114, 118))	('LSD1', 'Gene', '23028', (144, 148))
52968	32236611	Knockdown of HOXA11-AS suppresses the binding capability of DNA with several chromatin modification factors (namely, PRC2, LSD1 and DNMT1).	('HOXA11-AS', 'Var', (13, 22))	('PR', 'Gene', '5241', (117, 119))	('DNMT1', 'Gene', (132, 137))	('binding', 'Interaction', (38, 45))	('suppresses', 'NegReg', (23, 33))	('DNMT1', 'Gene', '1786', (132, 137))	('AS', 'Phenotype', 'HP:0002621', (20, 22))	('chromatin', 'cellular_component', 'GO:0000785', ('77', '86'))	('LSD1', 'Gene', (123, 127))	('binding', 'molecular_function', 'GO:0005488', ('38', '45'))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('chromatin modification', 'biological_process', 'GO:0006325', ('77', '99'))	('RC', 'Phenotype', 'HP:0009726', (118, 120))	('LSD1', 'Gene', '23028', (123, 127))	('chromatin modification', 'biological_process', 'GO:0016569', ('77', '99'))
52971	32236611	Liu et al identified that HOXA11-AS enhances beta-catenin transcription by interacting with WD repeat-containing protein 5 (WDR5), and p21 transcription is subsequently inhibited via binding with EZH2.	('WD repeat-containing protein 5', 'Gene', '11091', (92, 122))	('transcription', 'biological_process', 'GO:0006351', ('58', '71'))	('WDR5', 'Gene', '11091', (124, 128))	('WDR5', 'Gene', (124, 128))	('AS', 'Phenotype', 'HP:0002621', (33, 35))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('p21', 'Gene', (135, 138))	('p21', 'Gene', '644914', (135, 138))	('inhibited', 'NegReg', (169, 178))	('beta-catenin', 'Gene', (45, 57))	('EZH2', 'Gene', '2146', (196, 200))	('EZH2', 'Gene', (196, 200))	('beta-catenin', 'Gene', '1499', (45, 57))	('binding', 'Interaction', (183, 190))	('transcription', 'MPA', (139, 152))	('WD repeat-containing protein 5', 'Gene', (92, 122))	('enhances', 'PosReg', (36, 44))	('binding', 'molecular_function', 'GO:0005488', ('183', '190'))	('transcription', 'MPA', (58, 71))	('interacting', 'Interaction', (75, 86))	('transcription', 'biological_process', 'GO:0006351', ('139', '152'))	('HOXA11-AS', 'Var', (26, 35))
52972	32236611	In addition, HOXA11-AS can interact with double-stranded RNA-binding protein staufen homolog 1 (STAU1) to promote KLF2 mRNA degradation.	('interact', 'Interaction', (27, 35))	('HOXA11-AS', 'Var', (13, 22))	('double-stranded RNA-binding protein staufen homolog 1', 'Gene', '6780', (41, 94))	('STAU1', 'Gene', '6780', (96, 101))	('double-stranded RNA-binding', 'molecular_function', 'GO:0003725', ('41', '68'))	('promote', 'PosReg', (106, 113))	('KLF2', 'Gene', '10365', (114, 118))	('AS', 'Phenotype', 'HP:0002621', (20, 22))	('RNA', 'cellular_component', 'GO:0005562', ('57', '60'))	('KLF2', 'Gene', (114, 118))	('mRNA degradation', 'biological_process', 'GO:0006402', ('119', '135'))	('STAU1', 'Gene', (96, 101))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))
52980	32236611	Regarding the mechanism, Yang et al discovered that HOXA11-AS functions as a ceRNA to suppress the expression of miR-146b-5p, which subsequently modulates the expression of its downstream target, matrix metalloproteinase-16 (MMP16) in RC.	('RC', 'Phenotype', 'HP:0009726', (235, 237))	('expression', 'MPA', (99, 109))	('MMP', 'molecular_function', 'GO:0004235', ('225', '228'))	('miR-146b-5p', 'Var', (113, 124))	('suppress', 'NegReg', (86, 94))	('matrix metalloproteinase-16', 'Gene', (196, 223))	('MMP16', 'Gene', (225, 230))	('matrix metalloproteinase-16', 'Gene', '4325', (196, 223))	('expression', 'MPA', (159, 169))	('modulates', 'Reg', (145, 154))	('AS', 'Phenotype', 'HP:0002621', (59, 61))	('MMP16', 'Gene', '4325', (225, 230))
52981	32236611	Therefore, HOXA11-AS promotes RC cell invasion and proliferation by regulating the miR-146b-5p/MMP16 pathway (Fig.	('HOXA11-AS', 'Var', (11, 20))	('RC', 'Phenotype', 'HP:0009726', (30, 32))	('regulating', 'Reg', (68, 78))	('promotes', 'PosReg', (21, 29))	('RC cell invasion', 'CPA', (30, 46))	('proliferation', 'CPA', (51, 64))	('MMP16', 'Gene', '4325', (95, 100))	('AS', 'Phenotype', 'HP:0002621', (18, 20))	('MMP16', 'Gene', (95, 100))	('MMP', 'molecular_function', 'GO:0004235', ('95', '98'))
52986	32236611	Authors of that study also reported that HOXA11-AS recruits EZH2 to the promoter region of p21 and mediates H3K27me3 to suppress its transcription.	('EZH2', 'Gene', (60, 64))	('transcription', 'biological_process', 'GO:0006351', ('133', '146'))	('p21', 'Gene', '644914', (91, 94))	('AS', 'Phenotype', 'HP:0002621', (48, 50))	('p21', 'Gene', (91, 94))	('H3K27me3', 'Var', (108, 116))	('suppress', 'NegReg', (120, 128))	('EZH2', 'Gene', '2146', (60, 64))	('transcription', 'MPA', (133, 146))
52987	32236611	Furthermore, HOXA11-AS acts as a ceRNA for miR-124, which directly targets EZH2, and the cell proliferation and invasion-increasing effects of HOXA11-AS were attenuated upon miR-124 overexpression (Fig.	('invasion-increasing', 'CPA', (112, 131))	('EZH2', 'Gene', (75, 79))	('miR-124', 'Gene', (43, 50))	('attenuated', 'NegReg', (158, 168))	('cell proliferation', 'CPA', (89, 107))	('AS', 'Phenotype', 'HP:0002621', (150, 152))	('AS', 'Phenotype', 'HP:0002621', (20, 22))	('cell proliferation', 'biological_process', 'GO:0008283', ('89', '107'))	('overexpression', 'PosReg', (182, 196))	('EZH2', 'Gene', '2146', (75, 79))	('HOXA11-AS', 'Var', (143, 152))
52992	32236611	A large number of studies have shown that not only HOXA11-AS, but also many other lncRNAs act as oncogenes or tumor suppressor genes in different cancers.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('HOXA11-AS', 'Var', (51, 60))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('AS', 'Phenotype', 'HP:0002621', (58, 60))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ncRNA', 'Gene', (83, 88))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('ncRNA', 'Gene', '220202', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
52994	32236611	HOXA11-AS exerts opposing effects in different types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('AS', 'Phenotype', 'HP:0002621', (7, 9))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('HOXA11-AS', 'Var', (0, 9))
52996	32236611	For example, in EOC, HOXA11-AS can act as a tumor suppressor gene, which is different from the tumor mentioned above.	('HOXA11-AS', 'Var', (21, 30))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('men', 'Species', '9606', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('AS', 'Phenotype', 'HP:0002621', (28, 30))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', (95, 100))
52997	32236611	It has been reported that common germline genetic variants or single nucleotide polymorphisms (SNPs) affecting lncRNAs are conducive to the development of various types of cancer, such as EOC.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('single nucleotide polymorphisms', 'Var', (62, 93))	('ncRNA', 'Gene', (112, 117))	('EOC', 'Disease', (188, 191))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('ncRNA', 'Gene', '220202', (112, 117))	('conducive to', 'Reg', (123, 135))	('variants', 'Var', (50, 58))	('cancer', 'Disease', (172, 178))	('men', 'Species', '9606', (147, 150))
52998	32236611	Richards et al reported that overexpression of HOXA11-AS results in a clear reduction in cell proliferation and survival, which are two main cellular processes associated with EOC development in both common and minor allele constructs.	('AS', 'Phenotype', 'HP:0002621', (54, 56))	('reduction', 'NegReg', (76, 85))	('overexpression', 'PosReg', (29, 43))	('cell proliferation', 'CPA', (89, 107))	('men', 'Species', '9606', (187, 190))	('cell proliferation', 'biological_process', 'GO:0008283', ('89', '107'))	('HOXA11-AS', 'Var', (47, 56))
53000	32236611	The finding has identified a greatly decreased risk of EOC among women who have the HOXA11-AS rs17427875 T allele.	('rs17427875 T', 'Var', (94, 106))	('AS', 'Phenotype', 'HP:0002621', (91, 93))	('EOC', 'Disease', (55, 58))	('women', 'Species', '9606', (65, 70))	('rs17427875', 'Mutation', 'rs17427875', (94, 104))	('decreased', 'NegReg', (37, 46))
53006	32236611	Qu et al found that the expression levels of HOXA11-AS are closely correlated with pathological grade, T (tumor) grade, clinical stage, neck nodal metastasis and advanced tumors of grade T3 to T4 in LSCC.	('HOXA11-AS', 'Var', (45, 54))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('neck', 'cellular_component', 'GO:0044326', ('136', '140'))	('expression levels', 'MPA', (24, 41))	('neck nodal metastasis', 'CPA', (136, 157))	('correlated', 'Reg', (67, 77))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('AS', 'Phenotype', 'HP:0002621', (52, 54))	('tumor', 'Disease', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('SCC', 'Phenotype', 'HP:0002860', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('CC', 'Phenotype', 'HP:0002664', (201, 203))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
53013	32236611	In terms of the underlying mechanism, HOXA11-AS promotes CC cell migration and invasion by upregulating the levels of MMP-9, MMP-2, and vascular endothelial growth factor (VEGF), and disordering of the EMT-associated genes suggested that HOXA11-AS may be involved in cell migration and invasion in CC (Fig.	('MMP-2', 'Gene', '4313', (125, 130))	('vascular endothelial growth factor', 'Gene', (136, 170))	('MMP-2', 'molecular_function', 'GO:0004228', ('125', '130'))	('involved', 'Reg', (255, 263))	('VEGF', 'Gene', '7422', (172, 176))	('MMP-9', 'Gene', '4318', (118, 123))	('cell migration', 'biological_process', 'GO:0016477', ('60', '74'))	('MMP-9', 'Gene', (118, 123))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('136', '170'))	('VEGF', 'Gene', (172, 176))	('HOXA11-AS', 'Var', (38, 47))	('CC', 'Phenotype', 'HP:0002664', (298, 300))	('MMP-2', 'Gene', (125, 130))	('CC', 'Phenotype', 'HP:0002664', (57, 59))	('invasion', 'CPA', (79, 87))	('invasion', 'CPA', (286, 294))	('AS', 'Phenotype', 'HP:0002621', (245, 247))	('disordering', 'Var', (183, 194))	('EMT', 'biological_process', 'GO:0001837', ('202', '205'))	('vascular endothelial growth factor', 'Gene', '7422', (136, 170))	('MMP-9', 'molecular_function', 'GO:0004229', ('118', '123'))	('CC cell migration', 'CPA', (57, 74))	('promotes', 'PosReg', (48, 56))	('AS', 'Phenotype', 'HP:0002621', (45, 47))	('EMT-associated', 'Gene', (202, 216))	('cell migration', 'CPA', (267, 281))	('upregulating', 'PosReg', (91, 103))	('cell migration', 'biological_process', 'GO:0016477', ('267', '281'))
53020	32236611	Taking all these findings into consideration, HOXA11-AS may have an oncogenic role in ESCC, and therefore HOXA11-AS may also represent a predictive marker in postoperative ESCC patients.	('AS', 'Phenotype', 'HP:0002621', (113, 115))	('CC', 'Phenotype', 'HP:0002664', (88, 90))	('patients', 'Species', '9606', (177, 185))	('CC', 'Phenotype', 'HP:0002664', (174, 176))	('HOXA11-AS', 'Var', (46, 55))	('HOXA11-AS', 'Var', (106, 115))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('SCC', 'Phenotype', 'HP:0002860', (173, 176))	('ESCC', 'Disease', (172, 176))	('ESCC', 'Disease', (86, 90))	('AS', 'Phenotype', 'HP:0002621', (53, 55))
53024	32236611	Their study suggested that HOXA11-AS knockdown in osteosarcoma induces cell cycle arrest at the G0/G1 phase, and HOXA11-AS overexpression led to a substantial improvement in cell invasion and growth rates in osteosarcoma cells via the competitive binding of miR-124-3p, which targets Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) (Fig.	('miR-124-3p', 'Gene', (258, 268))	('knockdown', 'Var', (37, 46))	('AS', 'Phenotype', 'HP:0002621', (34, 36))	('ROCK1', 'Gene', '6093', (341, 346))	('arrest', 'Disease', 'MESH:D006323', (82, 88))	('osteosarcoma', 'Phenotype', 'HP:0002669', (208, 220))	('AS', 'Phenotype', 'HP:0002621', (120, 122))	('osteosarcoma', 'Disease', (50, 62))	('growth rates', 'CPA', (192, 204))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('71', '88'))	('osteosarcoma', 'Disease', 'MESH:D012516', (50, 62))	('binding', 'molecular_function', 'GO:0005488', ('247', '254'))	('binding', 'Interaction', (247, 254))	('protein', 'cellular_component', 'GO:0003675', ('323', '330'))	('osteosarcoma', 'Phenotype', 'HP:0002669', (50, 62))	('men', 'Species', '9606', (166, 169))	('G1 phase', 'biological_process', 'GO:0051318', ('99', '107'))	('osteosarcoma', 'Disease', (208, 220))	('ROCK1', 'Gene', (341, 346))	('miR-124-3p', 'Gene', '406909', (258, 268))	('cell invasion', 'CPA', (174, 187))	('osteosarcoma', 'Disease', 'MESH:D012516', (208, 220))	('arrest', 'Disease', (82, 88))	('improvement', 'PosReg', (159, 170))	('Rho-associated, coiled-coil-containing protein kinase 1', 'Gene', '6093', (284, 339))
53025	32236611	In this manner, HOXA11-AS may exert oncogenic functions by regulating the miR-124-3p/ROCK1 pathway.	('AS', 'Phenotype', 'HP:0002621', (23, 25))	('ROCK1', 'Gene', '6093', (85, 90))	('ROCK1', 'Gene', (85, 90))	('miR-124-3p', 'Gene', '406909', (74, 84))	('regulating', 'Reg', (59, 69))	('HOXA11-AS', 'Var', (16, 25))	('miR-124-3p', 'Gene', (74, 84))
53031	32236611	In addition, HOXA11-AS can act as a ceRNA by sequestering miR-124-3p to inhibit cell proliferation and enhance apoptosis (Fig.	('HOXA11-AS', 'Var', (13, 22))	('sequestering', 'MPA', (45, 57))	('miR-124-3p', 'Gene', (58, 68))	('sequestering', 'biological_process', 'GO:0051235', ('45', '57'))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('AS', 'Phenotype', 'HP:0002621', (20, 22))	('enhance', 'PosReg', (103, 110))	('cell proliferation', 'CPA', (80, 98))	('cell proliferation', 'biological_process', 'GO:0008283', ('80', '98'))	('inhibit', 'NegReg', (72, 79))	('miR-124-3p', 'Gene', '406909', (58, 68))	('apoptosis', 'CPA', (111, 120))
53035	32236611	Mechanistically, those authors revealed that HOXA11-AS recruits LSD1 and EZH2 proteins to the RND3 gene promoter region in the nucleus to repress its expression in trophoblast cells.	('expression', 'MPA', (150, 160))	('HOXA11-AS', 'Var', (45, 54))	('RND3', 'Gene', '390', (94, 98))	('repress', 'NegReg', (138, 145))	('LSD1', 'Gene', '23028', (64, 68))	('EZH2', 'Gene', '2146', (73, 77))	('AS', 'Phenotype', 'HP:0002621', (52, 54))	('EZH2', 'Gene', (73, 77))	('LSD1', 'Gene', (64, 68))	('proteins', 'Protein', (78, 86))	('RND3', 'Gene', (94, 98))	('nucleus', 'cellular_component', 'GO:0005634', ('127', '134'))
53038	32236611	These studies revealed that HOXA11-AS may have an oncogenic function via modulating the LSD1/EZH2-RND3 and HOXA11-AS/miR-15b-5p/HOXA7 pathways.	('RND3', 'Gene', (98, 102))	('miR-15b', 'Gene', (117, 124))	('HOXA7', 'Gene', (128, 133))	('EZH2', 'Gene', '2146', (93, 97))	('HOXA7', 'Gene', '3204', (128, 133))	('RND3', 'Gene', '390', (98, 102))	('LSD1', 'Gene', (88, 92))	('EZH2', 'Gene', (93, 97))	('modulating', 'Reg', (73, 83))	('miR-15b', 'Gene', '406949', (117, 124))	('AS', 'Phenotype', 'HP:0002621', (35, 37))	('LSD1', 'Gene', '23028', (88, 92))	('AS', 'Phenotype', 'HP:0002621', (114, 116))	('HOXA11-AS', 'Var', (28, 37))
53039	32236611	Consequently, these results have verified that abnormal expression of HOXA11-AS is involved in the occurrence and development of PE, and that this lncRNA may function as a putative target for diagnosis and treatment in PE.	('PE', 'Phenotype', 'HP:0100602', (219, 221))	('AS', 'Phenotype', 'HP:0002621', (77, 79))	('ncRNA', 'Gene', '220202', (148, 153))	('men', 'Species', '9606', (121, 124))	('involved', 'Reg', (83, 91))	('men', 'Species', '9606', (211, 214))	('HOXA11-AS', 'Gene', (70, 79))	('PE', 'Phenotype', 'HP:0100602', (129, 131))	('ncRNA', 'Gene', (148, 153))	('abnormal', 'Var', (47, 55))
53045	32236611	Mechanistically, HOXA11-AS knockdown reduces the expression of proliferation-associated gene (PCNA), the cell cycle-related genes p21 and p53, and platelet-derived growth factor (PDGF)-induced growth and migration of vascular smooth muscle cells (VSMCs) is repressed, significantly downregulating the expression of inflammation-associated genes in VSMCs induced by tumor necrosis factor-alpha (TNF-alpha).	('p21', 'Gene', (130, 133))	('p53', 'Gene', (138, 141))	('p21', 'Gene', '644914', (130, 133))	('PCNA', 'Gene', '5111', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('tumor necrosis factor-alpha', 'Gene', '7124', (365, 392))	('inflammation', 'Disease', 'MESH:D007249', (315, 327))	('necrosis', 'biological_process', 'GO:0008220', ('371', '379'))	('TNF-alpha', 'Gene', '7124', (394, 403))	('PDGF', 'molecular_function', 'GO:0005161', ('179', '183'))	('downregulating', 'NegReg', (282, 296))	('TNF-alpha', 'Gene', (394, 403))	('PCNA', 'molecular_function', 'GO:0003892', ('94', '98'))	('expression', 'MPA', (49, 59))	('necrosis', 'biological_process', 'GO:0070265', ('371', '379'))	('cell cycle', 'biological_process', 'GO:0007049', ('105', '115'))	('necrosis', 'biological_process', 'GO:0019835', ('371', '379'))	('inflammation', 'Disease', (315, 327))	('necrosis', 'biological_process', 'GO:0001906', ('371', '379'))	('expression', 'MPA', (301, 311))	('knockdown', 'Var', (27, 36))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('147', '177'))	('tumor necrosis factor-alpha', 'Gene', (365, 392))	('AS', 'Phenotype', 'HP:0002621', (24, 26))	('PCNA', 'Gene', (94, 98))	('p53', 'Gene', '7157', (138, 141))	('inflammation', 'biological_process', 'GO:0006954', ('315', '327'))	('necrosis', 'biological_process', 'GO:0008219', ('371', '379'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('365', '386'))	('reduces', 'NegReg', (37, 44))
53047	32236611	Low expression levels of HOXA11-AS inhibited the PDGF-induced stimulation of the PI3K/AKT pathway by inhibiting the phosphorylation of PI3K and AKT in VSMCs and VECs (Fig.	('PI3K', 'molecular_function', 'GO:0016303', ('81', '85'))	('AS', 'Phenotype', 'HP:0002621', (32, 34))	('HOXA11-AS', 'Var', (25, 34))	('PI3K', 'Pathway', (135, 139))	('AKT', 'Gene', (144, 147))	('AKT', 'Gene', (86, 89))	('phosphorylation', 'MPA', (116, 131))	('phosphorylation', 'biological_process', 'GO:0016310', ('116', '131'))	('PDGF', 'molecular_function', 'GO:0005161', ('49', '53'))	('inhibited', 'NegReg', (35, 44))	('PI3K', 'molecular_function', 'GO:0016303', ('135', '139'))	('AKT', 'Gene', '207', (144, 147))	('AKT', 'Gene', '207', (86, 89))	('PDGF-induced', 'Gene', (49, 61))	('stimulation', 'MPA', (62, 73))	('inhibiting', 'NegReg', (101, 111))
53049	32236611	In conclusion, an increasing number of studies have shown that lncRNAs are dysregulated in various types of cancer, and aberrant expression of lncRNAs is involved in the occurrence, development, and metastasis of cancer.	('aberrant', 'Var', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('men', 'Species', '9606', (189, 192))	('expression', 'MPA', (129, 139))	('involved', 'Reg', (154, 162))	('ncRNA', 'Gene', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ncRNA', 'Gene', (144, 149))	('cancer', 'Disease', (213, 219))	('ncRNA', 'Gene', '220202', (64, 69))	('ncRNA', 'Gene', '220202', (144, 149))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
53063	32277165	Unlike mesothelioma cells harboring a mutation of negative regulators of YAP, the survival of multiple UM cell lines was not significantly reduced by YAP/TAZ depletion.	('YAP', 'Gene', '10413', (73, 76))	('survival', 'CPA', (82, 90))	('YAP', 'Gene', (73, 76))	('YAP', 'Gene', '10413', (150, 153))	('mesothelioma', 'Disease', (7, 19))	('depletion', 'Var', (158, 167))	('mesothelioma', 'Disease', 'MESH:D008654', (7, 19))	('YAP', 'Gene', (150, 153))	('reduced', 'NegReg', (139, 146))	('UM', 'Phenotype', 'HP:0007716', (103, 105))
53068	32277165	Most UM tumors harbor the GNAQ or GNA11 mutations; these mutants have been shown to activate oncogenic pathways, including the mitogen-activated protein kinase (MAPK) and Hippo-Yes-associated protein (YAP) pathways.	('YAP', 'Gene', '10413', (201, 204))	('GNAQ', 'Gene', (26, 30))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('UM', 'Phenotype', 'HP:0007716', (5, 7))	('mutations', 'Var', (40, 49))	('YAP', 'Gene', (201, 204))	('GNA11', 'Gene', (34, 39))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('oncogenic pathways', 'Pathway', (93, 111))	('activate', 'PosReg', (84, 92))	('GNA11', 'Gene', '2767', (34, 39))	('GNAQ', 'Gene', '2776', (26, 30))	('protein', 'cellular_component', 'GO:0003675', ('192', '199'))	('MAPK', 'molecular_function', 'GO:0004707', ('161', '165'))	('mitogen-activated protein kinase', 'Pathway', (127, 159))
53080	32277165	The mean RNA-seq by Expectation Maximization (RSEM)-normalized YAP mRNA levels were 1430.5 +- 362.4 and 2719.4 +- 700.8 for the low expression and high expression groups, respectively (P < 0.001).	('YAP', 'Gene', '10413', (63, 66))	('RNA', 'cellular_component', 'GO:0005562', ('9', '12'))	('2719.4', 'Var', (104, 110))	('YAP', 'Gene', (63, 66))
53081	32277165	The mean Gene Set Variant Analysis (GSVA) scores for the YAP signature were 0.162 +- 0.115 and 0.168 +- 0.124 in the low YAP signature and high YAP signature groups, respectively (P < 0.001; Fig.	('0.168 +-', 'Var', (95, 103))	('GSVA', 'Chemical', '-', (36, 40))	('YAP', 'Gene', (144, 147))	('YAP', 'Gene', (121, 124))	('YAP', 'Gene', '10413', (57, 60))	('YAP', 'Gene', (57, 60))	('YAP', 'Gene', '10413', (144, 147))	('YAP', 'Gene', '10413', (121, 124))
53082	32277165	When compared with the YAP-downregulated group, the YAP signature gene sets were significantly upregulated in the high YAP signature group (normalized enrichment score: 2.30; P < 0.001; Fig.	('upregulated', 'PosReg', (95, 106))	('high', 'Var', (114, 118))	('YAP', 'Gene', '10413', (23, 26))	('YAP', 'Gene', '10413', (119, 122))	('YAP', 'Gene', (52, 55))	('YAP', 'Gene', (23, 26))	('YAP', 'Gene', (119, 122))	('YAP', 'Gene', '10413', (52, 55))
53096	32277165	UM-specific survival also did not differ between the low YAP signature and high YAP signature groups (HR: 1.272; 95% CI: 0.523-3.093; P = 0.62; Fig.	('YAP', 'Gene', '10413', (80, 83))	('low', 'Var', (53, 56))	('YAP', 'Gene', '10413', (57, 60))	('YAP', 'Gene', (80, 83))	('YAP', 'Gene', (57, 60))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
53103	32277165	The siRNA-mediated knockdown of YAP and its paralog, TAZ, significantly suppressed expression of YAP mRNA (Supplementary Fig.	('YAP', 'Gene', '10413', (97, 100))	('YAP', 'Gene', '10413', (32, 35))	('knockdown', 'Var', (19, 28))	('YAP', 'Gene', (97, 100))	('YAP', 'Gene', (32, 35))	('suppressed', 'NegReg', (72, 82))	('expression', 'MPA', (83, 93))
53106	32277165	YAP/TAZ knockdown exhibited smaller effects on survival in multiple UM cell lines (92.1, MP41, MP46, and MP65).	('YAP', 'Gene', (0, 3))	('MP41', 'Var', (89, 93))	('MP46', 'Var', (95, 99))	('MP65', 'Var', (105, 109))	('YAP', 'Gene', '10413', (0, 3))	('UM', 'Phenotype', 'HP:0007716', (68, 70))
53110	32277165	Remarkably, GNAQ and GNA11 are mutated in most UM tumors (~93%) with hotspot mutations (Q209P/L).	('GNAQ', 'Gene', (12, 16))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('Q209P', 'Var', (88, 93))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('Q209P', 'SUBSTITUTION', 'None', (88, 93))	('GNAQ', 'Gene', '2776', (12, 16))	('GNA11', 'Gene', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('GNA11', 'Gene', '2767', (21, 26))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
53111	32277165	Recent studies have highlighted the roles of GNAQ and GNA11 mutations in UM development.	('UM', 'Phenotype', 'HP:0007716', (73, 75))	('GNA11', 'Gene', (54, 59))	('GNAQ', 'Gene', '2776', (45, 49))	('GNA11', 'Gene', '2767', (54, 59))	('GNAQ', 'Gene', (45, 49))	('mutations', 'Var', (60, 69))	('UM development', 'CPA', (73, 87))
53112	32277165	GNAQ and GNA11 mutations result in constitutive activation of oncogenic Gq/G11 subunits, leading to UM tumorigenesis by sequential activation of YAP.	('GNA11', 'Gene', (9, 14))	('activation', 'PosReg', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('UM', 'Phenotype', 'HP:0007716', (100, 102))	('GNAQ', 'Gene', '2776', (0, 4))	('YAP', 'Gene', (145, 148))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', (103, 108))	('GNAQ', 'Gene', (0, 4))	('Gq/G11', 'Protein', (72, 78))	('activation', 'PosReg', (48, 58))	('leading to', 'Reg', (89, 99))	('YAP', 'Gene', '10413', (145, 148))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('GNA11', 'Gene', '2767', (9, 14))
53130	32277165	To confirm this possibility, we investigated whether siRNA-mediated YAP knockdown affected the survival of UM cell lines.	('UM', 'Phenotype', 'HP:0007716', (107, 109))	('affected', 'Reg', (82, 90))	('YAP', 'Gene', '10413', (68, 71))	('YAP', 'Gene', (68, 71))	('knockdown', 'Var', (72, 81))
53131	32277165	YAP knockdown slightly reduced the survival of 92.1, MP41, MP46, and MP65 UM cell lines.	('YAP', 'Gene', (0, 3))	('survival', 'CPA', (35, 43))	('MP46', 'Var', (59, 63))	('YAP', 'Gene', '10413', (0, 3))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('MP65', 'Var', (69, 73))	('reduced', 'NegReg', (23, 30))	('knockdown', 'Var', (4, 13))	('MP41', 'Var', (53, 57))
53132	32277165	However, these effects were much smaller than the effects observed for the two mesothelioma cell types, MSTO-211H (LATS2 mutation) and H2373 (NF2 mutation), which harbor mutations in negative regulators of YAP.	('YAP', 'Gene', (206, 209))	('mesothelioma', 'Disease', (79, 91))	('mutations', 'Var', (170, 179))	('NF2', 'Gene', (142, 145))	('H2373', 'CellLine', 'CVCL:A533', (135, 140))	('mesothelioma', 'Disease', 'MESH:D008654', (79, 91))	('NF2', 'Gene', '4771', (142, 145))	('YAP', 'Gene', '10413', (206, 209))	('LATS2', 'Gene', (115, 120))	('LATS2', 'Gene', '26524', (115, 120))
53133	32277165	In the TCGA mesothelioma cohort, 35 (42%) of 83 patients had mutations in MST1/2, LAST1/2, or NF (negative upstream regulators of YAP).	('YAP', 'Gene', (130, 133))	('LAST1/2', 'Gene', (82, 89))	('MST1/2', 'Gene', (74, 80))	('mutations', 'Var', (61, 70))	('YAP', 'Gene', '10413', (130, 133))	('mesothelioma', 'Disease', (12, 24))	('patients', 'Species', '9606', (48, 56))	('MST1/2', 'Gene', '4485;6788', (74, 80))	('mesothelioma', 'Disease', 'MESH:D008654', (12, 24))
53134	32277165	In another analysis, a high YAP signature was associated with poor prognoses in the TCGA mesothelioma cohort (HR: 2.675; 95% CI: 1.63-4.389; P < 0.001).	('mesothelioma', 'Disease', (89, 101))	('high', 'Var', (23, 27))	('YAP', 'Gene', (28, 31))	('mesothelioma', 'Disease', 'MESH:D008654', (89, 101))	('YAP', 'Gene', '10413', (28, 31))
53137	32277165	It has been shown that YAP is important for acquisition of resistance to targeted therapy in tumors with KRAS and BRAF mutations, and that YAP can induce immune evasion by increasing the expression of PD-L1.	('BRAF', 'Gene', (114, 118))	('induce', 'Reg', (147, 153))	('PD-L1', 'Gene', (201, 206))	('immune evasion', 'MPA', (154, 168))	('YAP', 'Gene', '10413', (139, 142))	('BRAF', 'Gene', '673', (114, 118))	('PD-L1', 'Gene', '29126', (201, 206))	('KRAS', 'Gene', '3845', (105, 109))	('YAP', 'Gene', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('KRAS', 'Gene', (105, 109))	('increasing', 'PosReg', (172, 182))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('mutations', 'Var', (119, 128))	('immune evasion', 'biological_process', 'GO:0042783', ('154', '168'))	('YAP', 'Gene', '10413', (23, 26))	('immune evasion', 'biological_process', 'GO:0051842', ('154', '168'))	('YAP', 'Gene', (139, 142))	('tumors', 'Disease', (93, 99))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('expression', 'MPA', (187, 197))
53138	32277165	YAP activation by the GNAQ and GNA11 mutations may explain the failure of MEK1/2 inhibitors or immunotherapy in patients with UM.	('YAP', 'Gene', (0, 3))	('GNAQ', 'Gene', (22, 26))	('MEK1', 'molecular_function', 'GO:0004708', ('74', '78'))	('patients', 'Species', '9606', (112, 120))	('mutations', 'Var', (37, 46))	('UM', 'Phenotype', 'HP:0007716', (126, 128))	('MEK1/2', 'Gene', '5604;5605', (74, 80))	('YAP', 'Gene', '10413', (0, 3))	('GNAQ', 'Gene', '2776', (22, 26))	('MEK1/2', 'Gene', (74, 80))	('GNA11', 'Gene', (31, 36))	('activation', 'PosReg', (4, 14))	('GNA11', 'Gene', '2767', (31, 36))
53150	32277165	The normalized count data calculated by expectation maximization analysis were incorporated as a matrix in R. The enrichment score was then calculated by GSVA for each tumor sample in the matrix data using the following arguments: kcdf = "Poisson", min.sz = 5, max_sz = 500, mx.diff = TRUE.	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('GSVA', 'Chemical', '-', (154, 158))	('kcdf = "Poisson', 'Var', (231, 246))	('max_sz = 500', 'Var', (261, 273))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
53151	32277165	GSEA was performed using the C6 MSigDB gene set database to test whether the YAP signature was enriched in the high YAP signature group, compared with the low YAP signature group.	('YAP', 'Gene', (116, 119))	('YAP', 'Gene', (159, 162))	('YAP', 'Gene', '10413', (77, 80))	('YAP', 'Gene', '10413', (116, 119))	('YAP', 'Gene', (77, 80))	('YAP', 'Gene', '10413', (159, 162))	('GSEA', 'Chemical', '-', (0, 4))	('high', 'Var', (111, 115))
53162	32277165	UM cells (MP41 MP46, and MP65) and RPE1 cells were acquired from the American Type Culture Collection (ATCC, Manassas, VA, USA).	('MP65', 'Var', (25, 29))	('MP41 MP46', 'Var', (10, 19))	('RPE1', 'CellLine', 'CVCL:4388', (35, 39))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
53169	32277165	performed the cell viability tests using multiple cancer cells; Y.J.K., S.C.L., S.K.K.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('Y.J.K.', 'Var', (64, 70))	('S.C.L.', 'Var', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
53175	32300551	We found that cinobufagin could induce cell apoptosis and upregulate the expression of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase (PARP), and cleaved caspase-9 in vivo and in vitro.	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('PARP', 'Gene', (143, 147))	('cell apoptosis', 'CPA', (39, 53))	('PARP', 'Gene', '11545', (143, 147))	('cinobufagin', 'Chemical', 'MESH:C002471', (14, 25))	('cinobufagin', 'Var', (14, 25))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('cleaved', 'MPA', (106, 113))	('cleaved', 'MPA', (154, 161))	('expression', 'MPA', (73, 83))	('upregulate', 'PosReg', (58, 68))	('induce', 'PosReg', (32, 38))	('cleaved', 'MPA', (87, 94))	('caspase-9', 'Gene', (162, 171))
53177	32300551	Taken together, the results of this preclinical study suggest that cinobufagin can both inhibit cell survival and induce cell apoptosis in a dose-dependent manner in UM cells, which provides new insights into the biochemical mechanism of cinobufagin and its potential as a future chemotherapeutic agent for UM.	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('cell survival', 'CPA', (96, 109))	('UM', 'Phenotype', 'HP:0007716', (307, 309))	('inhibit', 'NegReg', (88, 95))	('UM', 'Phenotype', 'HP:0007716', (166, 168))	('cinobufagin', 'Chemical', 'MESH:C002471', (238, 249))	('induce', 'Reg', (114, 120))	('cinobufagin', 'Chemical', 'MESH:C002471', (67, 78))	('cinobufagin', 'Var', (67, 78))	('cell apoptosis', 'CPA', (121, 135))
53188	32300551	Another report showed that cinobufagin could induce cell apoptosis through the intrinsic, mitochondrion-dependent apoptosis pathway via the aggregation of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential (DeltaPsim) in FOB1.19 and U2OS osteosarcoma cells.	('intrinsic', 'Pathway', (79, 88))	('cinobufagin', 'Chemical', 'MESH:C002471', (27, 38))	('osteosarcoma', 'Disease', (266, 278))	('osteosarcoma', 'Disease', 'MESH:D012516', (266, 278))	('OS', 'Phenotype', 'HP:0002669', (181, 183))	('apoptosis', 'biological_process', 'GO:0097194', ('57', '66'))	('loss', 'NegReg', (193, 197))	('apoptosis', 'biological_process', 'GO:0006915', ('57', '66'))	('cinobufagin', 'Var', (27, 38))	('DeltaPsim', 'Disease', (235, 244))	('reactive oxygen species', 'MPA', (155, 178))	('mitochondrion', 'cellular_component', 'GO:0005739', ('90', '103'))	('OS', 'Phenotype', 'HP:0002669', (263, 265))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('201', '223'))	('U2OS', 'CellLine', 'CVCL:0042', (261, 265))	('ROS', 'Chemical', 'MESH:D017382', (180, 183))	('osteosarcoma', 'Phenotype', 'HP:0002669', (266, 278))	('apoptosis', 'biological_process', 'GO:0097194', ('114', '123'))	('apoptosis', 'biological_process', 'GO:0006915', ('114', '123'))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (155, 178))	('mitochondrion-dependent apoptosis pathway', 'Pathway', (90, 131))	('induce', 'PosReg', (45, 51))	('mitochondrial membrane potential', 'MPA', (201, 233))	('cell apoptosis', 'CPA', (52, 66))	('DeltaPsim', 'Disease', 'None', (235, 244))
53205	32300551	Primary antibodies were incubated overnight at 4 C. The primary antibodies used were anticleaved caspase-9 (1:1,000), anticleaved caspase-3 (1:1,000), anti-PARP (1:1,000), anti-Bcl-2 (1:1,000), anti-Bcl-xl (1:1,000), anti-Bad (1:1,000), anti-Bax (1:1,000), and anti-beta-actin (1:5,000).	('anti-Bcl-2', 'Var', (172, 182))	('Bcl-xl', 'Gene', (199, 205))	('anti-Bax', 'Var', (237, 245))	('PARP', 'Gene', (156, 160))	('PARP', 'Gene', '11545', (156, 160))	('Bcl-xl', 'Gene', '12048', (199, 205))	('Bcl-2', 'molecular_function', 'GO:0015283', ('177', '182'))
53221	32300551	After treatment with different concentrations (0, 0.03, 0.1, and 0.3 muM) of cinobufagin for 1 week, the number of colonies decreased in a dose-dependent manner (Figure 1B).	('cinobufagin', 'Chemical', 'MESH:C002471', (77, 88))	('cinobufagin', 'Gene', (77, 88))	('0.1', 'Var', (56, 59))	('decreased', 'NegReg', (124, 133))
53231	32300551	Our results showed that cinobufagin could induce OCM1 cell apoptosis with apoptosis rates of approximately 12.6, 56.4, and 63.6% after treatment with different concentrations of cinobufagin (0.3, 1, and 3 muM), while the percentage of apoptotic cells showed no statistically significant difference at a concentration of 0.3 muM compared with that in the control group (Figures 3A,B).	('apoptosis', 'biological_process', 'GO:0097194', ('59', '68'))	('cinobufagin', 'Chemical', 'MESH:C002471', (178, 189))	('apoptosis', 'biological_process', 'GO:0006915', ('59', '68'))	('OCM1 cell apoptosis', 'CPA', (49, 68))	('induce', 'Reg', (42, 48))	('cinobufagin', 'Var', (24, 35))	('cinobufagin', 'Chemical', 'MESH:C002471', (24, 35))	('OCM1', 'Species', '83984', (49, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))
53265	32300551	Excessive ROS production and oxidative damage to mitochondrial membrane trigger apoptosis and other a series of mitochondrion-associated biological events.	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('ROS', 'Protein', (10, 13))	('oxidative', 'Var', (29, 38))	('mitochondrion', 'cellular_component', 'GO:0005739', ('112', '125'))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('49', '71'))	('trigger', 'Reg', (72, 79))	('Excessive ROS production', 'Phenotype', 'HP:0025464', (0, 24))	('OS', 'Phenotype', 'HP:0002669', (11, 13))	('apoptosis', 'CPA', (80, 89))
53286	30563937	Arylsulfonamide 64B inhibits hypoxia/HIF-induced expression of c-Met and CXCR4 and reduces primary tumor growth and metastasis of uveal melanoma Uveal melanoma (UM) is the most prevalent and lethal intraocular malignancy in adults.	('hypoxia', 'Disease', 'MESH:D000860', (29, 36))	('CXCR4', 'Gene', (73, 78))	('reduces', 'NegReg', (83, 90))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (145, 159))	('Arylsulfonamide', 'Var', (0, 15))	('tumor', 'Disease', (99, 104))	('expression', 'MPA', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('uveal melanoma', 'Phenotype', 'HP:0007716', (130, 144))	('metastasis', 'CPA', (116, 126))	('intraocular malignancy', 'Disease', (198, 220))	('inhibits', 'NegReg', (20, 28))	('intraocular malignancy', 'Disease', 'MESH:D009798', (198, 220))	('CXCR4', 'molecular_function', 'GO:0038147', ('73', '78'))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('c-Met', 'Gene', (63, 68))	('hypoxia', 'Disease', (29, 36))	('expression', 'Species', '29278', (49, 59))	('c-Met', 'Gene', '17295', (63, 68))	('CXCR4', 'Gene', '12767', (73, 78))	('Arylsulfonamide 64B', 'Chemical', '-', (0, 19))
53307	30563937	Active HIF is composed of a heterodimer of an oxygen-regulated alpha (HIF-1alpha or 2alpha) subunit and a beta subunit (HIF-1beta) and recruits its co-activators p300/CBP to form an active transcription factor complex that transactivates target genes by binding to hypoxia response elements (HRE) in their promoters.	('p300/CBP', 'Var', (162, 170))	('HIF-1beta', 'Gene', (120, 129))	('HIF-1alpha', 'Gene', '15251', (70, 80))	('HIF-1alpha', 'Gene', (70, 80))	('transcription factor', 'molecular_function', 'GO:0000981', ('189', '209'))	('transcription', 'biological_process', 'GO:0006351', ('189', '202'))	('binding', 'Interaction', (254, 261))	('CBP', 'molecular_function', 'GO:0008140', ('167', '170'))	('transcription factor complex', 'cellular_component', 'GO:0005667', ('189', '217'))	('HIF-1beta', 'Gene', '15251', (120, 129))	('binding', 'molecular_function', 'GO:0005488', ('254', '261'))	('hypoxia', 'Disease', (265, 272))	('hypoxia', 'Disease', 'MESH:D000860', (265, 272))	('oxygen', 'Chemical', 'MESH:D010100', (46, 52))	('transactivates', 'MPA', (223, 237))
53313	30563937	CXCR4 is the receptor for stromal cell-derived factor 1 (SDF-1/CXCL12), and can increase cancer cell migration and tumor metastasis.	('stromal cell-derived factor 1', 'Gene', (26, 55))	('cell migration', 'biological_process', 'GO:0016477', ('96', '110'))	('SDF-1', 'Gene', '20315', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('CXCL12', 'Gene', (63, 69))	('CXCR4', 'Var', (0, 5))	('CXCL12', 'Gene', '20315', (63, 69))	('increase', 'PosReg', (80, 88))	('stromal cell-derived factor 1', 'Gene', '20315', (26, 55))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('CXCR4', 'molecular_function', 'GO:0038147', ('0', '5'))	('cancer', 'Disease', (89, 95))	('tumor metastasis', 'Disease', 'MESH:D009362', (115, 131))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumor metastasis', 'Disease', (115, 131))	('SDF-1', 'Gene', (57, 62))
53378	30563937	Treatment of the cells with siRNA for CXCR4 and c-Met also inhibited cell migration under hypoxia, supporting their role in this process (Fig.	('CXCR4', 'Var', (38, 43))	('inhibited', 'NegReg', (59, 68))	('CXCR4', 'molecular_function', 'GO:0038147', ('38', '43'))	('cell migration', 'biological_process', 'GO:0016477', ('69', '83'))	('hypoxia', 'Disease', 'MESH:D000860', (90, 97))	('hypoxia', 'Disease', (90, 97))	('c-Met', 'Var', (48, 53))
53387	30563937	Co-immunoprecipitation (co-IP) experiments showed 64B could disrupt the interaction between HIF-1alpha and both p300 and CBP paralogs, but not with HIF-1beta (Fig.	('HIF-1beta', 'Gene', '15251', (148, 157))	('CBP', 'Gene', '12914', (121, 124))	('p300', 'Gene', (112, 116))	('interaction', 'Interaction', (72, 83))	('CBP', 'Gene', (121, 124))	('HIF-1beta', 'Gene', (148, 157))	('64B', 'Var', (50, 53))	('HIF-1alpha', 'Gene', (92, 102))	('HIF-1alpha', 'Gene', '15251', (92, 102))	('64B', 'Chemical', '-', (50, 53))	('disrupt', 'NegReg', (60, 67))	('p300', 'Gene', '328572', (112, 116))	('CBP', 'molecular_function', 'GO:0008140', ('121', '124'))
53388	30563937	Levels of hypoxia-induced HIF-1alpha, and constitutive expression of p300, and CBP were unaffected by 64B (Fig.	('CBP', 'Gene', (79, 82))	('expression', 'Species', '29278', (55, 65))	('p300', 'Gene', '328572', (69, 73))	('p300', 'Gene', (69, 73))	('hypoxia', 'Disease', 'MESH:D000860', (10, 17))	('HIF-1alpha', 'Gene', '15251', (26, 36))	('HIF-1alpha', 'Gene', (26, 36))	('hypoxia', 'Disease', (10, 17))	('CBP', 'Gene', '12914', (79, 82))	('CBP', 'molecular_function', 'GO:0008140', ('79', '82'))	('64B', 'Var', (102, 105))	('64B', 'Chemical', '-', (102, 105))
53392	30563937	Altogether, these results show that 64B can disrupt the recruitment of p300/CBP co-factors to the HIF transcription complex in a FIH-independent manner.	('transcription', 'biological_process', 'GO:0006351', ('102', '115'))	('FIH', 'Gene', '319594', (129, 132))	('recruitment', 'MPA', (56, 67))	('p300/CBP', 'Var', (71, 79))	('64B', 'Var', (36, 39))	('64B', 'Chemical', '-', (36, 39))	('CBP', 'molecular_function', 'GO:0008140', ('76', '79'))	('disrupt', 'NegReg', (44, 51))	('FIH', 'Gene', (129, 132))
53402	30563937	To test this, we used chromatin immunoprecipitation (ChIP), and found that 64B reduced p300 binding to both genes under hypoxia (Fig.	('reduced', 'NegReg', (79, 86))	('p300', 'Gene', '328572', (87, 91))	('p300', 'Gene', (87, 91))	('hypoxia', 'Disease', (120, 127))	('hypoxia', 'Disease', 'MESH:D000860', (120, 127))	('binding', 'molecular_function', 'GO:0005488', ('92', '99'))	('64B', 'Var', (75, 78))	('64B', 'Chemical', '-', (75, 78))	('chromatin', 'cellular_component', 'GO:0000785', ('22', '31'))
53421	30563937	Mice treated with 64B showed a ~50% reduction in metastatic foci (Fig.	('64B', 'Var', (18, 21))	('64B', 'Chemical', '-', (18, 21))	('metastatic foci', 'CPA', (49, 64))	('reduction', 'NegReg', (36, 45))	('Mice', 'Species', '10090', (0, 4))
53430	30563937	Eyes were enucleated on day 9, and sections showed reduced tumor size in 64B treatment group (Fig.	('tumor', 'Disease', (59, 64))	('reduced', 'NegReg', (51, 58))	('64B', 'Var', (73, 76))	('64B', 'Chemical', '-', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
53431	30563937	Immunofluorescence analysis of eye tumor sections showed CXCR4 and c-Met expression was strongly reduced in 64B treated mice compared to vehicle controls (Fig.	('mice', 'Species', '10090', (120, 124))	('CXCR4', 'MPA', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('eye tumor', 'Disease', (31, 40))	('64B', 'Var', (108, 111))	('expression', 'Species', '29278', (73, 83))	('64B', 'Chemical', '-', (108, 111))	('eye tumor', 'Phenotype', 'HP:0100012', (31, 40))	('reduced', 'NegReg', (97, 104))	('c-Met expression', 'MPA', (67, 83))	('eye tumor', 'Disease', 'MESH:D000853', (31, 40))	('CXCR4', 'molecular_function', 'GO:0038147', ('57', '62'))
53433	30563937	Flow cytometry of blood collected on day 9 showed that mice treated with 64B exhibited reduced amounts of circulating tumor cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('64B', 'Var', (73, 76))	('reduced', 'NegReg', (87, 94))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mice', 'Species', '10090', (55, 59))	('64B', 'Chemical', '-', (73, 76))	('tumor', 'Disease', (118, 123))
53434	30563937	Mice were sacrificed on day 56, and livers from mice treated with 64B had a reduced metastatic burden and showed the number of micrometastases was also dramatically decreased in the 64B treatment group (Supplementary Fig.	('decreased', 'NegReg', (165, 174))	('64B', 'Var', (66, 69))	('64B', 'Chemical', '-', (66, 69))	('metastatic burden', 'CPA', (84, 101))	('metastases', 'Disease', (132, 142))	('mice', 'Species', '10090', (48, 52))	('metastases', 'Disease', 'MESH:D009362', (132, 142))	('reduced', 'NegReg', (76, 83))	('Mice', 'Species', '10090', (0, 4))	('64B', 'Chemical', '-', (182, 185))
53443	30563937	The HIF transcription factor pathway is an attractive cancer target as HIF upregulates a wide range of tumor survival and metastasis related genes, including CXCR4 and MET.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('CXCR4', 'molecular_function', 'GO:0038147', ('158', '163'))	('MET', 'Disease', (168, 171))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Disease', (103, 108))	('upregulates', 'PosReg', (75, 86))	('transcription', 'biological_process', 'GO:0006351', ('8', '21'))	('cancer', 'Disease', (54, 60))	('CXCR4', 'Disease', (158, 163))	('transcription factor', 'molecular_function', 'GO:0000981', ('8', '28'))	('metastasis', 'CPA', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('HIF', 'Var', (71, 74))
53461	30563937	CXCL12 (SDF-1) binding to CXCR4 elicits signaling that facilitates cancer cell survival, proliferation, chemotaxis, invasion and adhesion.	('proliferation', 'CPA', (89, 102))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('CXCL12', 'Gene', (0, 6))	('CXCL12', 'Gene', '20315', (0, 6))	('cancer', 'Disease', (67, 73))	('binding', 'molecular_function', 'GO:0005488', ('15', '22'))	('chemotaxis', 'CPA', (104, 114))	('binding', 'Var', (15, 22))	('chemotaxis', 'biological_process', 'GO:0006935', ('104', '114'))	('facilitates', 'PosReg', (55, 66))	('elicits', 'Reg', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('CXCR4', 'molecular_function', 'GO:0038147', ('26', '31'))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('adhesion', 'CPA', (129, 137))	('SDF-1', 'Gene', (8, 13))	('SDF-1', 'Gene', '20315', (8, 13))
53462	30563937	Blockade of CXCR4 signaling inhibits chemotaxis in skin melanomas, a pre-requisite for metastasis.	('CXCR4', 'molecular_function', 'GO:0038147', ('12', '17'))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('inhibits', 'NegReg', (28, 36))	('Blockade', 'Var', (0, 8))	('skin melanomas', 'Disease', (51, 65))	('signaling', 'biological_process', 'GO:0023052', ('18', '27'))	('chemotaxis', 'biological_process', 'GO:0006935', ('37', '47'))	('skin melanomas', 'Disease', 'MESH:D008545', (51, 65))	('pre', 'molecular_function', 'GO:0003904', ('69', '72'))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
53464	30563937	CXCR4 and c-Met promote uveal melanoma cell proliferation, migration, invasion and metastasis.	('uveal melanoma', 'Disease', (24, 38))	('metastasis', 'CPA', (83, 93))	('CXCR4', 'Var', (0, 5))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('CXCR4', 'molecular_function', 'GO:0038147', ('0', '5'))	('c-Met', 'Var', (10, 15))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (24, 38))	('migration', 'CPA', (59, 68))	('uveal melanoma', 'Disease', 'MESH:C536494', (24, 38))	('promote', 'PosReg', (16, 23))	('invasion', 'CPA', (70, 78))
53466	30563937	In summary, our findings demonstrate that arylsulfonamide 64B has strong anti-cancer activity in syngeneic and xenogeneic orthotopic UM mouse models.	('arylsulfonamide 64B', 'Chemical', '-', (42, 61))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mouse', 'Species', '10090', (136, 141))	('arylsulfonamide 64B', 'Var', (42, 61))
53487	30045986	For example, talimogene laherparepvec (T-VEC), an FDA-approved modified HSV-1 oncolytic virus, has been shown to suppress the growth of advanced malignant melanoma in humans, and G47delta, a third-generation oncolytic herpesvirus, exhibited efficiency in numerous in vivo solid tumor models, including glioma, breast, and prostate cancers.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('prostate cancers', 'Phenotype', 'HP:0012125', (322, 338))	('prostate cancers', 'Disease', (322, 338))	('HSV-1 oncolytic virus', 'Disease', 'MESH:C536395', (72, 93))	('herpesvirus', 'Species', '39059', (218, 229))	('suppress', 'NegReg', (113, 121))	('malignant melanoma', 'Phenotype', 'HP:0002861', (145, 163))	('G47delta', 'Var', (179, 187))	('solid tumor', 'Disease', (272, 283))	('malignant melanoma', 'Disease', 'MESH:D008545', (145, 163))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('growth', 'CPA', (126, 132))	('solid tumor', 'Disease', 'MESH:D009369', (272, 283))	('glioma', 'Disease', (302, 308))	('HSV-1 oncolytic virus', 'Disease', (72, 93))	('glioma', 'Disease', 'MESH:D005910', (302, 308))	('malignant melanoma', 'Disease', (145, 163))	('prostate cancers', 'Disease', 'MESH:D011471', (322, 338))	('cancers', 'Phenotype', 'HP:0002664', (331, 338))	('humans', 'Species', '9606', (167, 173))	('glioma', 'Phenotype', 'HP:0009733', (302, 308))	('breast', 'Disease', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))
53489	30045986	In T-VEC, deletions of wild-type gamma34.5 and alpha47 viral genes promote targeting tumor cells over nonneoplastic cells and enhance the body's natural antitumor response.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', (85, 90))	('enhance', 'PosReg', (126, 133))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('gamma34.5', 'Gene', (33, 42))	('deletions', 'Var', (10, 19))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('alpha47 viral genes', 'Gene', (47, 66))	('promote', 'PosReg', (67, 74))
53498	30045986	Recombinant HSV-1 K26GFP was derived from wild-type HSV-1 strain KOS and grows as a wild-type virus in cell culture.	('KOS', 'Disease', 'MESH:C537013', (65, 68))	('K26GFP', 'Var', (18, 24))	('HSV-1', 'Gene', (12, 17))	('HSV-1', 'Species', '10298', (12, 17))	('KOS', 'Disease', (65, 68))	('HSV-1', 'Species', '10298', (52, 57))
53500	30045986	After OCM1 uveal melanoma cells were placed on the surface of Matrigel matrix, the cells grew on the Matrigel surface and began invading the matrix, where they formed spherical tumor cell aggregates, termed spheroids.	('uveal melanoma', 'Phenotype', 'HP:0007716', (11, 25))	('uveal melanoma', 'Disease', (11, 25))	('uveal melanoma', 'Disease', 'MESH:C536494', (11, 25))	('OCM1', 'Species', '83984', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('melanoma cells', 'Disease', (17, 31))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('OCM1', 'Var', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('melanoma cells', 'Disease', 'MESH:D008545', (17, 31))	('tumor', 'Disease', (177, 182))
53509	30045986	In cultures that were infected with HSV-1 K26GFP and were also treated with acyclovir, spread of HSV-1 within the 3D cultures was reduced and delayed (Table 1; Fig.	('HSV-1', 'Species', '10298', (97, 102))	('HSV-1', 'Gene', (36, 41))	('acyclovir', 'Chemical', 'MESH:D000212', (76, 85))	('HSV-1', 'Species', '10298', (36, 41))	('spread', 'CPA', (87, 93))	('reduced', 'NegReg', (130, 137))	('delayed', 'NegReg', (142, 149))	('K26GFP', 'Var', (42, 48))	('HSV-1', 'Gene', (97, 102))
53515	30045986	In contrast, in HSV-1-inoculated cultures, the average spheroid number was 0.503546 +- 0.080 per 0.25-mm2 culture area and the average spheroid was 7,036.967 +- 473.617 square micrometers (Table 2).	('0.503546 +- 0.080', 'Var', (75, 92))	('HSV-1-inoculated', 'Disease', (16, 32))	('HSV-1-inoculated', 'Disease', 'MESH:C536395', (16, 32))	('spheroid number', 'CPA', (55, 70))
53577	30045986	Cells infected with HSV-1 strain K26GFP exhibit punctate nuclear fluorescence at early times in the replication cycle, and at later times during infection, a generalized cytoplasmic and nuclear fluorescence, including fluorescence at the cell membranes, can be observed.	('HSV-1', 'Species', '10298', (20, 25))	('punctate nuclear fluorescence', 'MPA', (48, 77))	('K26GFP', 'Var', (33, 39))	('fluorescence', 'MPA', (218, 230))
53616	29333944	Furthermore, ectopic expression of NDFIP1 restored the effects of miR-155 on proliferation and invasion of uveal melanoma cells.	('uveal melanoma', 'Disease', 'MESH:C536494', (107, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('uveal melanoma', 'Disease', (107, 121))	('restored', 'PosReg', (42, 50))	('NDFIP1', 'Gene', (35, 41))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('miR-155', 'Gene', (66, 73))	('NDFIP1', 'Gene', '80762', (35, 41))	('effects', 'MPA', (55, 62))	('ectopic expression', 'Var', (13, 31))	('proliferation', 'CPA', (77, 90))	('miR-155', 'Gene', '406947', (66, 73))
53644	29333944	As shown in Figure 2C and D, the invasive ability of the miR-155 mimic-transfected cells increased significantly compared with that of the negative control-transfected cells.	('miR-155', 'Gene', (57, 64))	('invasive ability', 'CPA', (33, 49))	('miR-155', 'Gene', '406947', (57, 64))	('mimic-transfected', 'Var', (65, 82))	('increased', 'PosReg', (89, 98))
53649	29333944	After transfection of MUM-2B and C918 cells with miR-155 inhibitor or negative control, the invasive capacity of the miR-155 inhibitor-transfected cells was found to be significantly lower than that of the negative control-transfected cells (Figure 3C and D).	('miR-155', 'Gene', '406947', (49, 56))	('miR-155', 'Gene', '406947', (117, 124))	('C918', 'CellLine', 'CVCL:8471', (33, 37))	('MUM-2', 'Gene', (22, 27))	('MUM-2', 'Gene', '9589', (22, 27))	('miR-155', 'Gene', (49, 56))	('miR-155', 'Gene', (117, 124))	('invasive capacity', 'CPA', (92, 109))	('lower', 'NegReg', (183, 188))	('inhibitor-transfected', 'Var', (125, 146))
53654	29333944	The mutant pLuc-NDFIP1 3'UTR construct completely abolished the ability of miR-155 to regulate the expression of luciferase (Figure 4B and C).	('expression', 'MPA', (99, 109))	('NDFIP1', 'Gene', '80762', (16, 22))	('mutant', 'Var', (4, 10))	('ability', 'MPA', (64, 71))	('luciferase', 'Enzyme', (113, 123))	('abolished', 'NegReg', (50, 59))	('regulate', 'MPA', (86, 94))	('miR-155', 'Gene', '406947', (75, 82))	('NDFIP1', 'Gene', (16, 22))	('miR-155', 'Gene', (75, 82))
53674	29333944	Our results demonstrated that ectopic expression of NDFIP1 restored the effects of miR-155 on proliferation and invasion of uveal melanoma cells.	('uveal melanoma', 'Phenotype', 'HP:0007716', (124, 138))	('NDFIP1', 'Gene', (52, 58))	('uveal melanoma', 'Disease', (124, 138))	('miR-155', 'Gene', '406947', (83, 90))	('uveal melanoma', 'Disease', 'MESH:C536494', (124, 138))	('restored', 'PosReg', (59, 67))	('effects', 'MPA', (72, 79))	('proliferation', 'CPA', (94, 107))	('ectopic expression', 'Var', (30, 48))	('NDFIP1', 'Gene', '80762', (52, 58))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('miR-155', 'Gene', (83, 90))
53694	28912895	For example, recent studies have demonstrated that long noncoding RNAs, circular RNAs, circulating tumor DNAs, and non-essential amino acids that support numerous metabolic processes crucial for the growth and survival of proliferating cells can serve as biomarkers for cancers.	('N', 'Chemical', 'MESH:D009584', (67, 68))	('tumor', 'Disease', (99, 104))	('cancers', 'Disease', 'MESH:D009369', (270, 277))	('cancers', 'Phenotype', 'HP:0002664', (270, 277))	('long noncoding', 'Var', (51, 65))	('N', 'Chemical', 'MESH:D009584', (82, 83))	('cancers', 'Disease', (270, 277))	('N', 'Chemical', 'MESH:D009584', (106, 107))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
53844	27800275	Familial uveal melanoma: Recently, an autosomal dominant hereditary cancer syndrome has been described in some patients with germline BAP1 mutation.	('Familial uveal melanoma', 'Disease', 'MESH:C536494', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutation', 'Var', (139, 147))	('BAP1', 'Gene', (134, 138))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (9, 23))	('autosomal dominant hereditary cancer syndrome', 'Disease', 'MESH:D009386', (38, 83))	('autosomal dominant hereditary cancer syndrome', 'Disease', (38, 83))	('Familial uveal melanoma', 'Disease', (0, 23))	('germline', 'Var', (125, 133))	('BAP1', 'Gene', '8314', (134, 138))	('patients', 'Species', '9606', (111, 119))
53845	27800275	Patients with this mutation have higher incidences of uveal melanoma, cutaneous melanoma, atypical Spitz tumors, mesothelioma, meningioma, adenocarcinoma of the lung and many other cancer types.	('tumors', 'Disease', (105, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('mesothelioma', 'Disease', (113, 125))	('adenocarcinoma of the lung', 'Disease', (139, 165))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('mutation', 'Var', (19, 27))	('cutaneous melanoma', 'Disease', (70, 88))	('mesothelioma', 'Disease', 'MESH:D008654', (113, 125))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (70, 88))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (70, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('Patients', 'Species', '9606', (0, 8))	('meningioma', 'Disease', (127, 137))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('meningioma', 'Phenotype', 'HP:0002858', (127, 137))	('cancer', 'Disease', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (139, 165))	('higher', 'PosReg', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('uveal melanoma', 'Disease', (54, 68))	('uveal melanoma', 'Disease', 'MESH:C536494', (54, 68))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('meningioma', 'Disease', 'MESH:D008577', (127, 137))
53942	27800275	The first reported chromosomal alteration to be associated with poor prognosis in uveal melanoma was chromosome 3 monosomy.	('chromosome', 'cellular_component', 'GO:0005694', ('101', '111'))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('uveal melanoma', 'Disease', 'MESH:C536494', (82, 96))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('uveal melanoma', 'Disease', (82, 96))	('chromosome 3 monosomy', 'Var', (101, 122))
53945	27800275	used multiplex ligation-dependent probe amplification to compare patients with disomy 3, monosomy 3 and both monosomy 3 and 8q gain, and reported 10-year melanoma-related mortality rates of 0%, 55% and 71% in the three groups, respectively.	('monosomy 3', 'Var', (89, 99))	('monosomy 3', 'Var', (109, 119))	('disomy 3', 'Var', (79, 87))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('patients', 'Species', '9606', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))
53951	27800275	Although less than 1% of all uveal melanoma cases are familial, studies have demonstrated that these patients carry many mutations, primarily germline mutation of BAP1, and have suggested that these mutations may be responsible for transmission in familes.	('familes', 'Disease', (248, 255))	('patients', 'Species', '9606', (101, 109))	('BAP1', 'Gene', '8314', (163, 167))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('responsible', 'Reg', (216, 227))	('BAP1', 'Gene', (163, 167))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('germline mutation', 'Var', (142, 159))
53953	27800275	This pathway can be activated by various mechanisms, and activation via RAS and B-RAF gene mutations is common in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('activation', 'PosReg', (57, 67))	('cutaneous melanoma', 'Disease', (114, 132))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (114, 132))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (114, 132))	('RAS', 'Gene', (72, 75))	('B-RAF', 'Gene', '673', (80, 85))	('mutations', 'Var', (91, 100))	('B-RAF', 'Gene', (80, 85))
53955	27800275	However, some studies have attributed this to limitations in the techniques used and claim to have detected B-RAF mutations in uveal melanoma.	('uveal melanoma', 'Disease', (127, 141))	('mutations', 'Var', (114, 123))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('B-RAF', 'Gene', '673', (108, 113))	('uveal melanoma', 'Phenotype', 'HP:0007716', (127, 141))	('uveal melanoma', 'Disease', 'MESH:C536494', (127, 141))	('detected', 'Reg', (99, 107))	('B-RAF', 'Gene', (108, 113))
53957	27800275	found that 91% of patients with large melanoma had GNAQ (47%) or GNA11 (44%) mutations, and Van Raamsdonk et al.	('GNAQ', 'Gene', '2776', (51, 55))	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('GNA11', 'Gene', '2767', (65, 70))	('mutations', 'Var', (77, 86))	('GNA11', 'Gene', (65, 70))	('GNAQ', 'Gene', (51, 55))	('patients', 'Species', '9606', (18, 26))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))
53958	27800275	detected GNAQ mutations in patients with Nevus of Ota and uveal melanoma.	('GNAQ', 'Gene', (9, 13))	('Nevus of Ota', 'Phenotype', 'HP:0009920', (41, 53))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('Nevus of Ota', 'Disease', (41, 53))	('patients', 'Species', '9606', (27, 35))	('uveal melanoma', 'Disease', 'MESH:C536494', (58, 72))	('GNAQ', 'Gene', '2776', (9, 13))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('uveal melanoma', 'Disease', (58, 72))	('mutations', 'Var', (14, 23))	('Nevus', 'Phenotype', 'HP:0003764', (41, 46))
53959	27800275	Somatic mutations in GNAQ or GNA11 activate mitogen-activated kinase (MEK), phosphoinositide 3-kinase/protein kinase B, protein kinase C and yes-associated protein related pathways, which has led to an increasing number of clinical trials targeting these pathways for patients with metastatic uveal melanoma.	('GNAQ', 'Gene', '2776', (21, 25))	('uveal melanoma', 'Phenotype', 'HP:0007716', (293, 307))	('GNAQ', 'Gene', (21, 25))	('protein kinase B', 'Gene', (102, 118))	('mitogen-activated kinase', 'Gene', (44, 68))	('MEK', 'Gene', '5609', (70, 73))	('patients', 'Species', '9606', (268, 276))	('GNA11', 'Gene', (29, 34))	('mitogen-activated kinase', 'Gene', '5609', (44, 68))	('mutations', 'Var', (8, 17))	('activate', 'PosReg', (35, 43))	('MEK', 'Gene', (70, 73))	('melanoma', 'Phenotype', 'HP:0002861', (299, 307))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('yes-associated protein related pathways', 'Pathway', (141, 180))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('protein kinase C', 'Pathway', (120, 136))	('uveal melanoma', 'Disease', 'MESH:C536494', (293, 307))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('GNA11', 'Gene', '2767', (29, 34))	('uveal melanoma', 'Disease', (293, 307))	('protein kinase B', 'Gene', '2185', (102, 118))
53960	27800275	These oncogenic mutations are seen in the early stages of tumorigenesis, as in benign uveal nevi, and are not associated with molecular class (class 1 or 2) or with metastasis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('uvea', 'Disease', (86, 90))	('uvea', 'Disease', 'MESH:C536494', (86, 90))	('mutations', 'Var', (16, 25))	('nevi', 'Phenotype', 'HP:0003764', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
53964	27800275	Somatic mutation in this gene is observed in many cancers including breast, lung and mesothelioma and germline mutations have been found in familial uveal melanoma and mesothelioma cases.86,87 It has been shown that BAP1 mutation appears in the late stages of tumorigenesis, causes changes in phenotype, and is associated with metastatic behavior and class 2 genetic structure in 84% of patients.	('tumor', 'Disease', (260, 265))	('mesothelioma', 'Disease', (85, 97))	('BAP1', 'Gene', (216, 220))	('uveal melanoma', 'Phenotype', 'HP:0007716', (149, 163))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('cancers', 'Disease', (50, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (85, 97))	('metastatic behavior', 'CPA', (327, 346))	('patients', 'Species', '9606', (387, 395))	('familial uveal melanoma', 'Disease', (140, 163))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('familial uveal melanoma', 'Disease', 'MESH:C536494', (140, 163))	('associated with', 'Reg', (311, 326))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('mesothelioma', 'Disease', (168, 180))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('phenotype', 'MPA', (293, 302))	('mesothelioma', 'Disease', 'MESH:D008654', (168, 180))	('BAP1', 'Gene', '8314', (216, 220))	('changes', 'Reg', (282, 289))	('mutation', 'Var', (221, 229))
53965	27800275	In contrast to the previously described mutations, splicing factor 3b subunit 1 (SF3B1) gene mutations have been found at a rate of 19% in uveal melanomas and are associated with good prognosis.90 Mutations in this gene also occur later in tumor progression and are relatively specific to class 1 tumors.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('splicing', 'biological_process', 'GO:0045292', ('51', '59'))	('tumor', 'Disease', (297, 302))	('tumor', 'Disease', (240, 245))	('SF3B1', 'Gene', (81, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('uveal melanomas', 'Disease', 'MESH:C536494', (139, 154))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('splicing factor 3b subunit 1', 'Gene', '23451', (51, 79))	('SF3B1', 'Gene', '23451', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumors', 'Disease', (297, 303))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('uveal melanomas', 'Disease', (139, 154))	('uveal melanomas', 'Phenotype', 'HP:0007716', (139, 154))	('melanomas', 'Phenotype', 'HP:0002861', (145, 154))	('Mutations', 'Var', (197, 206))	('splicing factor 3b subunit 1', 'Gene', (51, 79))	('tumors', 'Disease', 'MESH:D009369', (297, 303))
53966	27800275	However, it was shown that patients with disomy 3 tumors and SF3B1 mutations have increased risk of metastatic disease at a longer follow-up time (Koopmans AE, Prognostic implications of acquired genetic changes in uveal melanoma.	('SF3B1', 'Gene', (61, 66))	('melanoma', 'Phenotype', 'HP:0002861', (221, 229))	('disomy 3 tumors', 'Disease', (41, 56))	('mutations', 'Var', (67, 76))	('SF3B1', 'Gene', '23451', (61, 66))	('patients', 'Species', '9606', (27, 35))	('uveal melanoma', 'Disease', 'MESH:C536494', (215, 229))	('uveal melanoma', 'Phenotype', 'HP:0007716', (215, 229))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('metastatic disease', 'Disease', (100, 118))	('uveal melanoma', 'Disease', (215, 229))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('disomy 3 tumors', 'Disease', 'MESH:D024182', (41, 56))
53967	27800275	Another mutation associated with good prognosis is the eukaryotic translation initiation factor 1A (EIF1AX) gene mutation, which has been reported in 24% of uveal melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (163, 172))	('mutation', 'Var', (113, 121))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('uveal melanomas', 'Disease', (157, 172))	('uveal melanomas', 'Phenotype', 'HP:0007716', (157, 172))	('uveal melanomas', 'Disease', 'MESH:C536494', (157, 172))	('translation initiation', 'biological_process', 'GO:0006413', ('66', '88'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (157, 171))	('EIF1AX', 'Gene', '1964', (100, 106))	('EIF1AX', 'Gene', (100, 106))
53999	27800275	Melanoma-related mortality rates at 5, 10 and 12 years were 10%, 18% and 21% in the brachytherapy group, versus 11%, 17% and 17% in the enucleation group.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanoma', 'Disease', (0, 8))	('brachytherapy', 'Var', (84, 97))	('enucleation', 'biological_process', 'GO:0090601', ('136', '147'))
54001	27800275	Another study evaluating patients treated with Ru-106 plaques observed local tumor recurrence in 3.9% and reported estimated metastasis rates at 5 and 10 years of 30.9% and 68.2%.	('Ru-106', 'Var', (47, 53))	('metastasis', 'CPA', (125, 135))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('Ru-106', 'Chemical', 'MESH:C000615522', (47, 53))	('patients', 'Species', '9606', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
54087	27800275	The MAPK pathway, activated by GNAQ mutations plays an important role in the pathogenesis of uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (93, 107))	('uveal melanoma', 'Disease', 'MESH:C536494', (93, 107))	('uveal melanoma', 'Disease', (93, 107))	('GNAQ', 'Gene', '2776', (31, 35))	('mutations', 'Var', (36, 45))	('pathogenesis', 'biological_process', 'GO:0009405', ('77', '89'))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('MAPK', 'molecular_function', 'GO:0004707', ('4', '8'))	('GNAQ', 'Gene', (31, 35))	('MAPK pathway', 'Pathway', (4, 16))
54088	27800275	Although the MEK-inhibitor selumetinib did not improve survival in cutaneous melanoma, when administered to uveal melanoma patients with GNAQ mutation it extended progression-free survival.	('MEK', 'Gene', '5609', (13, 16))	('uveal melanoma', 'Disease', 'MESH:C536494', (108, 122))	('selumetinib', 'Chemical', 'MESH:C517975', (27, 38))	('GNAQ', 'Gene', (137, 141))	('uveal melanoma', 'Disease', (108, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('patients', 'Species', '9606', (123, 131))	('progression-free survival', 'CPA', (163, 188))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('cutaneous melanoma', 'Disease', (67, 85))	('extended', 'PosReg', (154, 162))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (67, 85))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (67, 85))	('mutation', 'Var', (142, 150))	('GNAQ', 'Gene', '2776', (137, 141))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('MEK', 'Gene', (13, 16))
54090	27800275	Ipilimumab is being evaluated as a systemic adjuvant therapy following treatment of the primary tumor in patients identified as class 2 by RNA analysis, exhibiting monosomy 3 on DNA analysis, or having a tumor over 8 mm in thickness.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('patients', 'Species', '9606', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('monosomy 3', 'Var', (164, 174))	('RNA', 'cellular_component', 'GO:0005562', ('139', '142'))	('DNA', 'cellular_component', 'GO:0005574', ('178', '181'))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (96, 101))	('men', 'Species', '9606', (76, 79))	('tumor', 'Disease', (204, 209))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
54091	27800275	Patient enrollment has concluded for a clinical trial evaluating treatment response to dacarbazine and recombinant interferon alpha-2b in patients who exhibit monosomy 3 or 8q gain without any metastasis, but results have not been published yet.	('interferon alpha-2b', 'Gene', '3440', (115, 134))	('patients', 'Species', '9606', (138, 146))	('men', 'Species', '9606', (14, 17))	('gain', 'PosReg', (176, 180))	('monosomy 3 or 8q', 'Var', (159, 175))	('men', 'Species', '9606', (70, 73))	('Patient', 'Species', '9606', (0, 7))	('dacarbazine', 'Chemical', 'MESH:D003606', (87, 98))	('interferon alpha-2b', 'Gene', (115, 134))
54098	27800275	With progress in understanding the molecular landscape of the tumor and the development of treatments targeting the pathways involving GNAQ/GNA11, BAP1, EIF1AX, SF3B1 mutations and epigenetic mechanisms, in the near future it may be possible to prevent the progression of micrometastases.	('GNAQ', 'Gene', (135, 139))	('SF3B1', 'Gene', (161, 166))	('EIF1AX', 'Gene', '1964', (153, 159))	('men', 'Species', '9606', (83, 86))	('mutations', 'Var', (167, 176))	('men', 'Species', '9606', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('GNA11', 'Gene', (140, 145))	('SF3B1', 'Gene', '23451', (161, 166))	('metastases', 'Disease', 'MESH:D009362', (277, 287))	('BAP1', 'Gene', '8314', (147, 151))	('metastases', 'Disease', (277, 287))	('epigenetic mechanisms', 'Var', (181, 202))	('BAP1', 'Gene', (147, 151))	('EIF1AX', 'Gene', (153, 159))	('tumor', 'Disease', (62, 67))	('GNAQ', 'Gene', '2776', (135, 139))	('GNA11', 'Gene', '2767', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
54106	23292925	Poor prognosis is associated with large tumours (>10-mm diameter, >2-mm height), epithelioid histology, vascular, highly proliferative and necrotic tumours, monosomy 3, and trisomy 8 or 8q.	('tumours', 'Disease', 'MESH:D009369', (148, 155))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('tumours', 'Disease', (148, 155))	('tumours', 'Disease', 'MESH:D009369', (40, 47))	('monosomy 3', 'Var', (157, 167))	('tumours', 'Disease', (40, 47))	('epithelioid histology', 'CPA', (81, 102))	('vascular', 'CPA', (104, 112))	('highly proliferative', 'CPA', (114, 134))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))	('necrotic tumours', 'Disease', (139, 155))	('necrotic tumours', 'Disease', 'MESH:D009369', (139, 155))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))	('trisomy 8 or 8q', 'Var', (173, 188))
54112	23292925	Single nucleotide polymorphism analysis was performed for chromosome 3, a hotspot for uveal melanoma abnormalities.	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('uveal melanoma abnormalities', 'Disease', (86, 114))	('uveal melanoma abnormalities', 'Disease', 'MESH:C536494', (86, 114))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('Single nucleotide', 'Var', (0, 17))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))
54124	23292925	Tumour karyotype by G-band analysis showed rearrangements of chromosomes 9, 19 and 22, and deletion of chromosome 13: (45,XX,der(9)t(9;22)(p13;?q13),13,der(19)t(13;19)(q12;p13), der(22)t(9;22)(p13;q11.2)[3]/46,XX[7]).	('chromosome', 'cellular_component', 'GO:0005694', ('103', '113'))	('deletion', 'Var', (91, 99))	('p13', 'Gene', '440926', (139, 142))	('p13', 'Gene', (172, 175))	('45,XX', 'Var', (119, 124))	('45,XX,der(9)', 'STRUCTURAL_ABNORMALITY', 'None', (119, 131))	('p13', 'Gene', '440926', (172, 175))	('p13', 'Gene', (193, 196))	('der(19)t(13;19)(q12;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (152, 176))	('p13', 'Gene', (139, 142))	('der(22)t(9;22)(p13;q11.2)', 'STRUCTURAL_ABNORMALITY', 'None', (178, 203))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('p13', 'Gene', '440926', (193, 196))
54136	23292925	Recurrent chromosomal abnormalities identified in uveal melanoma include monosomy 3, trisomy 8 or 8q, loss of a sex chromosome and loss of 6q.	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('loss of', 'Var', (131, 138))	('trisomy 8 or 8q', 'Var', (85, 100))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (10, 35))	('chromosomal abnormalities', 'Disease', (10, 35))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('uveal melanoma', 'Disease', 'MESH:C536494', (50, 64))	('sex chromosome', 'cellular_component', 'GO:0000803', ('112', '126'))	('Recurrent chromosomal abnormalities', 'Phenotype', 'HP:0040012', (0, 35))	('uveal melanoma', 'Disease', (50, 64))	('monosomy 3', 'Var', (73, 83))	('loss', 'Var', (102, 106))
54139	23292925	The history of melanoma in the cousin and grandparent of our patient may suggest the presence a familial mutation in the NF1 gene, which has been correlated to a higher risk of skin and ocular melanomas; however this gene was not studied in our patient.	('mutation', 'Var', (105, 113))	('patient', 'Species', '9606', (61, 68))	('NF1', 'Gene', '4763', (121, 124))	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (193, 201))	('melanoma', 'Disease', (15, 23))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('ocular melanomas', 'Phenotype', 'HP:0025534', (186, 202))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('correlated to', 'Reg', (146, 159))	('melanomas', 'Phenotype', 'HP:0002861', (193, 202))	('skin and ocular melanomas', 'Disease', 'MESH:D008545', (177, 202))	('patient', 'Species', '9606', (245, 252))	('NF1', 'Gene', (121, 124))
54158	27446211	In particular, the presence of monosomy 3 in primary tumor cells is a significant factor for predicting metastatic risk, and fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), multiplex ligation-dependent probe amplification (MLPA), and loss of heterozygosity (LOH) have been developed to identify chromosome abnormalities.	('loss of heterozygosity', 'Var', (270, 292))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (331, 355))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('metastatic', 'CPA', (104, 114))	('chromosome abnormalities', 'Disease', (331, 355))	('monosomy 3', 'Var', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('chromosome abnormalities', 'Disease', 'MESH:D002869', (331, 355))	('chromosome', 'cellular_component', 'GO:0005694', ('331', '341'))
54219	27386847	Psychosocial impact of prognostic genetic testing in the care of uveal melanoma patients: protocol of a controlled prospective clinical observational study Uveal melanoma patients with a poor prognosis can be detected through genetic analysis of the tumor, which has a very high sensitivity.	('Uveal melanoma', 'Phenotype', 'HP:0007716', (156, 170))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('uveal melanoma', 'Disease', (65, 79))	('patients', 'Species', '9606', (80, 88))	('melanoma', 'Disease', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('genetic analysis', 'Var', (226, 242))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('melanoma', 'Disease', (71, 79))	('patients', 'Species', '9606', (171, 179))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Disease', (250, 255))	('uveal melanoma', 'Disease', 'MESH:C536494', (65, 79))
54228	27386847	Both tumor classes can be determined either through detection of monosomy 3 in tumor DNA, or by a multi-gene expression profile of tumor RNA.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('RNA', 'cellular_component', 'GO:0005562', ('137', '140'))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('gene expression', 'biological_process', 'GO:0010467', ('104', '119'))	('monosomy 3', 'Var', (65, 75))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
54229	27386847	Due to the tumor class, the risk of developing metastases varies pronouncedly: In a current study, the mortality rates due to metastasis were 13.2 % for tumors with disomy 3 and 75.1 % for tumors with monosomy 3 (median follow-up time of 5.2 years).	('disomy 3', 'Var', (165, 173))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('tumor', 'Disease', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('tumors', 'Disease', (189, 195))	('metastases', 'Disease', (47, 57))	('tumor', 'Disease', (153, 158))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('metastases', 'Disease', 'MESH:D009362', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
54257	27386847	Sociodemographic and psychological features will moderate the utilization of prognostic genetic testing: Patients with high education, high social support, high resilience, and a previous history of cancer will utilize genetic testing more often than patients with low levels of education, or low social support, or a previous history of cancer.	('cancer', 'Disease', (338, 344))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('Patients', 'Species', '9606', (105, 113))	('genetic', 'Var', (219, 226))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('low levels of education', 'Phenotype', 'HP:0001249', (265, 288))	('patients', 'Species', '9606', (251, 259))	('cancer', 'Disease', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (338, 344))
54262	27386847	At T3 (communication of the result, 6-12 weeks after surgery), IG-patients with poor prognosis (IGpp) will have the highest levels of psychological distress and the lowest mental quality of life compared to IG-patients with good prognosis (IGgp) and OG-patients.	('psychological', 'CPA', (134, 147))	('patients', 'Species', '9606', (253, 261))	('lowest', 'NegReg', (165, 171))	('mental quality of life', 'MPA', (172, 194))	('patients', 'Species', '9606', (210, 218))	('IG-patients', 'Disease', (63, 74))	('poor', 'Var', (80, 84))	('patients', 'Species', '9606', (66, 74))
54285	27386847	In two meta-analyses, a significant impact of genetic counseling for familial cancer on anxiety (reduction), and on accuracy of perceived risk and knowledge (both improved) was found, suggesting genetic counseling had no adverse psychological effects.	('reduction', 'NegReg', (97, 106))	('anxiety', 'Disease', 'MESH:D001008', (88, 95))	('familial cancer', 'Disease', (69, 84))	('improved', 'PosReg', (163, 171))	('anxiety', 'Phenotype', 'HP:0000739', (88, 95))	('anxiety', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('familial cancer', 'Disease', 'MESH:D009369', (69, 84))	('genetic', 'Var', (46, 53))
54286	27386847	Comparably, beneficial effects of multidisciplinary genetic risk counseling for familial colorectal cancer on psychosocial outcome were found: General anxiety, familial cancer-specific distress and general cancer worries were significantly reduced after genetic counseling.	('familial cancer', 'Disease', (160, 175))	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('anxiety', 'Phenotype', 'HP:0000739', (151, 158))	('reduced', 'NegReg', (240, 247))	('familial colorectal cancer', 'Disease', (80, 106))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('genetic counseling', 'Var', (254, 272))	('familial colorectal cancer', 'Disease', 'MESH:D015179', (80, 106))	('familial cancer', 'Disease', 'MESH:D009369', (160, 175))	('general', 'CPA', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Disease', (100, 106))	('anxiety', 'Disease', (151, 158))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('anxiety', 'Disease', 'MESH:D001008', (151, 158))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
54288	27386847	Furthermore, the authors found passive and palliative coping styles, excessive breast self-examination, and overestimation of breast cancer risk to be predictive of increased long-term distress.	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', (126, 139))	('breast self-examination', 'CPA', (79, 102))	('overestimation', 'Var', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
54330	25037857	Table 1 contains values of alpha and beta parameters derived from the LQ formula, the SFs at 2 Gy (SF2), and RBE values calculated at three survival levels, SF = 0.01, 0.1, or 0.37, corresponding to the doses of about 5, 3, and 1 Gy, respectively.	('SF2', 'Gene', '6426', (99, 102))	('SF2', 'Gene', (99, 102))	('SF = 0.01', 'Var', (157, 166))
54335	25037857	using 67-MeV protons found an RBE-dose dependence (RBE 1.15 at SF = 0.01 increased to 1.63 at SF = 0.5) only for radioresistant V79-379A hamster cells (characterised by survival curves with a shoulder) but not for radiosensitive human colon carcinoma LS174T cells (described by survival curves without such a shoulder).	('colon carcinoma', 'Disease', (235, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('LS174T', 'CellLine', 'CVCL:1384', (251, 257))	('hamster', 'Species', '10034', (137, 144))	('V79-379A', 'Var', (128, 136))	('colon carcinoma', 'Disease', 'MESH:D015179', (235, 250))
54353	24441583	A low pre-treatment TGA (<225 g) was associated with a significantly longer median OS than was a TGA >=225 g (17.2 vs. 9.7 mos., p=0.01) 90Y microsphere brachytherapy provided favorable survival times in patients with unresectable liver metastases from uveal melanoma.	('patients', 'Species', '9606', (204, 212))	('OS', 'Chemical', '-', (83, 85))	('pre', 'molecular_function', 'GO:0003904', ('6', '9'))	('TGA', 'MPA', (20, 23))	('melanoma', 'Phenotype', 'HP:0002861', (259, 267))	('men', 'Species', '9606', (15, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (253, 267))	('<225 g', 'Var', (25, 31))	('uveal melanoma', 'Disease', 'MESH:C536494', (253, 267))	('uveal melanoma', 'Disease', (253, 267))	('longer', 'PosReg', (69, 75))	('liver metastases', 'Disease', (231, 247))	('liver metastases', 'Disease', 'MESH:D009362', (231, 247))
54409	24441583	Extra-hepatic metastases and monosomy 3 genetic aberrations were common.	('monosomy 3 genetic aberrations', 'Var', (29, 59))	('metastases', 'Disease', 'MESH:D009362', (14, 24))	('metastases', 'Disease', (14, 24))
54418	24441583	Non-hepatic toxicities were frequent but self-limiting: grade <=2 fatigue in 31 (44%), grade <=2 nausea in 11 (15%), and grade <=2 abdominal discomfort in 18 (25%).	('fatigue', 'Disease', (66, 73))	('Non-hepatic toxicities', 'Disease', (0, 22))	('abdominal discomfort', 'Phenotype', 'HP:0002027', (131, 151))	('Non-hepatic toxicities', 'Disease', 'MESH:D056486', (0, 22))	('fatigue', 'Phenotype', 'HP:0012378', (66, 73))	('grade <=2', 'Var', (121, 130))	('grade <=2', 'Var', (87, 96))	('nausea', 'Phenotype', 'HP:0002018', (97, 103))	('nausea', 'Disease', (97, 103))	('nausea', 'Disease', 'MESH:D009325', (97, 103))	('abdominal discomfort', 'Disease', (131, 151))	('fatigue', 'Disease', 'MESH:D005221', (66, 73))
54450	24441583	Furthermore, the observed median OS of 12.3 months following microsphere brachytherapy is especially encouraging when compared with a second institutional historic control from a phase II trial of liver chemoembolization in which median OS was 5.2 months for all patients and 9.8 months in those patients with limited tumor burden.	('microsphere', 'Var', (61, 72))	('patients', 'Species', '9606', (263, 271))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('OS', 'Chemical', '-', (33, 35))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('tumor', 'Disease', (318, 323))	('patients', 'Species', '9606', (296, 304))	('OS', 'Chemical', '-', (237, 239))
54459	24441583	On univariate analysis, pre-treatment MTV was found to be a negative predictive factor for OS and PFS, which is consistent with findings in a separate small series of seven patients with liver metastases from uveal melanoma.	('negative', 'NegReg', (60, 68))	('pre', 'molecular_function', 'GO:0003904', ('24', '27'))	('MTV', 'Chemical', '-', (38, 41))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('patients', 'Species', '9606', (173, 181))	('liver metastases', 'Disease', 'MESH:D009362', (187, 203))	('liver metastases', 'Disease', (187, 203))	('MTV', 'Var', (38, 41))	('OS', 'Chemical', '-', (91, 93))	('uveal melanoma', 'Phenotype', 'HP:0007716', (209, 223))	('uveal melanoma', 'Disease', 'MESH:C536494', (209, 223))	('men', 'Species', '9606', (33, 36))	('PFS', 'Disease', (98, 101))	('uveal melanoma', 'Disease', (209, 223))
54479	24441583	Additional study is also necessary on the subject of non-random karyotypic abnormalities like monosomy 3, duplications in 8q and other aneuploidy which are commonly identified in uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (179, 193))	('monosomy 3', 'Disease', (94, 104))	('duplications in', 'Var', (106, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (179, 193))	('uveal melanoma', 'Disease', (179, 193))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))
54487	24795358	The 50% inhibition concentration (IC50) in PBMC was < 20 nM compared to > 600 nM in melanoma cell lines; > 40% apoptotic cell death in PBMC versus < 10% in melanoma cell lines was seen at the same concentration.	('PBMC', 'Chemical', '-', (135, 139))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('PBMC', 'Chemical', '-', (43, 47))	('melanoma', 'Disease', (84, 92))	('PBMC', 'Var', (135, 139))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('111', '131'))	('apoptotic cell death', 'CPA', (111, 131))
54491	24795358	In human lymphocytes, panobinostat alters key lymphocyte activation signaling pathways and is cytotoxic at concentrations much lower than that required for melanoma antitumor activity, resulting in an adverse therapeutic window.	('lymphocyte activation', 'biological_process', 'GO:0046649', ('46', '67'))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('key lymphocyte activation signaling pathways', 'Pathway', (42, 86))	('melanoma', 'Disease', (156, 164))	('human', 'Species', '9606', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('panobinostat', 'Var', (22, 34))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('panobinostat', 'Chemical', 'MESH:D000077767', (22, 34))	('alters', 'Reg', (35, 41))	('signaling', 'biological_process', 'GO:0023052', ('68', '77'))
54512	24795358	Combining vorinostat or panobinostat with antibodies to CD40, which stimulates antigen presenting cells, or to CD137, which co-stimulates cytotoxic T-lymphocytes (CTL), led to enhanced tumor regression in mouse models of breast, renal and colon carcinomas.	('tumor', 'Disease', (185, 190))	('panobinostat', 'Chemical', 'MESH:D000077767', (24, 36))	('CD137', 'Gene', (111, 116))	('CD40', 'Gene', (56, 60))	('carcinomas', 'Phenotype', 'HP:0030731', (245, 255))	('vorinostat', 'Chemical', 'MESH:D000077337', (10, 20))	('breast, renal and colon carcinomas', 'Disease', 'MESH:D007680', (221, 255))	('antibodies', 'Var', (42, 52))	('enhanced', 'PosReg', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('mouse', 'Species', '10090', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('CD137', 'Gene', '21942', (111, 116))
54514	24795358	The ability of LAQ824 to augment the effects of immune therapy was also demonstrated in a prophylactic prime-boost vaccination mouse model of melanoma using the melanoma antigen tyrosinase-related protein-2.	('mouse', 'Species', '10090', (127, 132))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('LAQ824', 'Chemical', 'MESH:C477361', (15, 21))	('LAQ824', 'Var', (15, 21))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))	('protein', 'cellular_component', 'GO:0003675', ('197', '204'))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma', 'Disease', (142, 150))
54525	24795358	The human melanoma cell lines M202, M229, M233, M249, M263, M285, M308, M370, M376, M395, M408, and M417 were established from patient biopsies under UCLA IRB #02-08-067 as described.	('M408', 'Var', (90, 94))	('human', 'Species', '9606', (4, 9))	('M308', 'Var', (66, 70))	('patient', 'Species', '9606', (127, 134))	('M417', 'Var', (100, 104))	('M285', 'Var', (60, 64))	('melanoma', 'Disease', 'MESH:D008545', (10, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanoma', 'Disease', (10, 18))	('M395', 'Var', (84, 88))
54540	24795358	As shown in Figure 1, the human PBMC and melanoma cell lines tested fell into 3 categories with respect to sensitivity to panobinostat: IC50 of 20 nM or less (defined as sensitive), IC50 of 21-50 nM (intermediately sensitive), and IC50 of greater than 50 nM (resistant), consistent with previous published reports.	('PBMC', 'Chemical', '-', (32, 36))	('less', 'NegReg', (153, 157))	('panobinostat', 'Chemical', 'MESH:D000077767', (122, 134))	('IC50 of 20 nM', 'Var', (136, 149))	('IC50 of 21-50 nM', 'Var', (182, 198))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('human', 'Species', '9606', (26, 31))
54542	24795358	Twelve of seventeen anti-CD3 and IL2-activated PBMC were sensitive, with an additional three activated PBMC samples showing intermediate sensitivity.	('IL2', 'Gene', '3558', (33, 36))	('anti-CD3', 'Var', (20, 28))	('PBMC', 'Chemical', '-', (47, 51))	('IL2', 'Gene', (33, 36))	('PBMC', 'Chemical', '-', (103, 107))	('IL2', 'molecular_function', 'GO:0005134', ('33', '36'))
54545	24795358	For MD9, the IC50 of the resting PBMC was less than two times greater than that of the activated PBMC, though both samples were highly sensitive to panobinostat (16 and 12 nM, respectively).	('PBMC', 'Chemical', '-', (97, 101))	('MD9', 'Var', (4, 7))	('PBMC', 'Chemical', '-', (33, 37))	('panobinostat', 'Chemical', 'MESH:D000077767', (148, 160))	('IC50', 'MPA', (13, 17))
54552	24795358	In contrast to results for PBMC, only 2 of 12 human melanoma cells were sensitive to panobinostat, including M308, a BRAFV600E-mutant melanoma cell line highly resistant to vemurafenib.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('BRAFV600E', 'Mutation', 'rs113488022', (117, 126))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('BRAFV600E-mutant', 'Var', (117, 133))	('human', 'Species', '9606', (46, 51))	('vemurafenib', 'Chemical', 'MESH:D000077484', (173, 184))	('melanoma', 'Disease', (134, 142))	('PBMC', 'Chemical', '-', (27, 31))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('panobinostat', 'Chemical', 'MESH:D000077767', (85, 97))
54554	24795358	Neither the BRAF wild-type (M285) nor the NRAS-mutated melanoma cell lines (M202, M408 and M376) were sensitive to panobinostat.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('NRAS', 'Gene', '4893', (42, 46))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('panobinostat', 'Chemical', 'MESH:D000077767', (115, 127))	('panobinostat', 'MPA', (115, 127))	('melanoma', 'Disease', (55, 63))	('NRAS', 'Gene', (42, 46))	('M376', 'Var', (91, 95))
54562	24795358	Only at 10 microM was cleaved PARP about 30% for M229 while approximately 10% cleaved PARP was observed for M370 at this this concentration (Figure 2C).	('PARP', 'Gene', (30, 34))	('PARP', 'Gene', '142', (86, 90))	('M229', 'Var', (49, 53))	('PARP', 'Gene', (86, 90))	('PARP', 'Gene', '142', (30, 34))
54565	24795358	For M370, pH2A.X increased by less than 2-fold, even at 10 microM.	('H2A.X', 'Gene', '3014', (11, 16))	('H2A.X', 'Gene', (11, 16))	('M370', 'Var', (4, 8))
54573	24795358	Similarly, for MD2 CD4 T cells, pSTAT1, pSTAT3, pSTAT6, pAKT, pERK1/2, CyD3 and pH3 were increased by 4-fold compared to controls.	('pSTAT6', 'Gene', (48, 54))	('STAT3', 'Gene', (41, 46))	('ERK1/2', 'Gene', (63, 69))	('ERK1/2', 'Gene', '5595;5594', (63, 69))	('MD2', 'Var', (15, 18))	('AKT', 'Gene', '207', (57, 60))	('CD4', 'Gene', (19, 22))	('increased', 'PosReg', (89, 98))	('CD4', 'Gene', '920', (19, 22))	('STAT3', 'Gene', '6774', (41, 46))	('AKT', 'Gene', (57, 60))
54593	24795358	In contrast to treatment with vemurafenib, which resulted in little change in phosphoproteins or lymphocyte function at concentrations below 50 microM, panobinostat upregulated proteins in key signaling pathways in all cells tested.	('panobinostat', 'Chemical', 'MESH:D000077767', (152, 164))	('key signaling pathways', 'Pathway', (189, 211))	('upregulated', 'PosReg', (165, 176))	('proteins', 'Protein', (177, 185))	('signaling', 'biological_process', 'GO:0023052', ('193', '202'))	('vemurafenib', 'Chemical', 'MESH:D000077484', (30, 41))	('panobinostat', 'Var', (152, 164))
54594	24795358	Therefore, we hypothesize that panobinostat exerts its toxic effect on lymphocytes by upregulating signaling molecules that lead to decreased function and increased cytotoxicity.	('signaling', 'biological_process', 'GO:0023052', ('99', '108'))	('increased', 'PosReg', (155, 164))	('cytotoxicity', 'Disease', (165, 177))	('function', 'MPA', (142, 150))	('upregulating', 'PosReg', (86, 98))	('decreased', 'NegReg', (132, 141))	('panobinostat', 'Var', (31, 43))	('cytotoxicity', 'Disease', 'MESH:D064420', (165, 177))	('signaling molecules', 'MPA', (99, 118))	('panobinostat', 'Chemical', 'MESH:D000077767', (31, 43))
54596	24795358	Despite promising mouse data demonstrating synergy of HDACi with anti-CD40 and anti-CD137 or in combination with ACT therapy, our data with panobinostat in human lymphocytes should temper enthusiasm for combining HDACi with immunotherapy given the cytotoxic effect of panobinostat on lymphocytes at concentrations lower than that required to inhibit most melanoma cell lines.	('panobinostat', 'Chemical', 'MESH:D000077767', (140, 152))	('melanoma', 'Disease', (355, 363))	('panobinostat', 'Chemical', 'MESH:D000077767', (268, 280))	('CD137', 'Gene', (84, 89))	('mouse', 'Species', '10090', (18, 23))	('HD', 'Disease', 'MESH:D006816', (54, 56))	('melanoma', 'Disease', 'MESH:D008545', (355, 363))	('melanoma', 'Phenotype', 'HP:0002861', (355, 363))	('HD', 'Disease', 'MESH:D006816', (213, 215))	('anti-CD40', 'Var', (65, 74))	('human', 'Species', '9606', (156, 161))	('CD137', 'Gene', '21942', (84, 89))
54613	24613808	There were no differences in outcome (LC, DM, OS) when dose was stratified by apex dose quartile (<69 Gy, 69-81 Gy, 81-89 Gy, >89 Gy).	('apex', 'cellular_component', 'GO:0097683', ('78', '82'))	('<69 Gy', 'Var', (98, 104))	('apex', 'Gene', '328', (78, 82))	('DM', 'Disease', 'MESH:D009223', (42, 44))	('apex', 'Gene', (78, 82))
54619	24613808	The Collaborative Ocular Melanoma Study (COMS) Medium-sized melanoma trial was a North American, multi-institutional, prospective randomized study involving over 1300 patients between 1987-1998, which found that overall survival was similar in patients that received enucleation compared to those patients that underwent globe preserving therapy with 125I episcleral plaques.	('Ocular Melanoma', 'Disease', 'MESH:D008545', (18, 33))	('patients', 'Species', '9606', (297, 305))	('enucleation', 'Var', (267, 278))	('patients', 'Species', '9606', (167, 175))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('enucleation', 'biological_process', 'GO:0090601', ('267', '278'))	('melanoma', 'Disease', (60, 68))	('Ocular Melanoma', 'Phenotype', 'HP:0007716', (18, 33))	('Ocular Melanoma', 'Disease', (18, 33))	('patients', 'Species', '9606', (244, 252))	('COMS', 'Chemical', '-', (41, 45))	('Melanoma', 'Phenotype', 'HP:0002861', (25, 33))
54637	24613808	All patients were initially evaluated and diagnosed with uveal melanoma by an ophthalmologist with expertise in ocular oncology (J.J.D, E.G.B., and P.M.).	('ocular oncology', 'Phenotype', 'HP:0100012', (112, 127))	('oncology', 'Phenotype', 'HP:0002664', (119, 127))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('P.M.', 'Var', (148, 152))	('uveal melanoma', 'Disease', (57, 71))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('patients', 'Species', '9606', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))
54692	24613808	There was no significant relationship between tumor apex dose and likelihood of overall survival when the tumors were distributed and evaluated by quartile, though there was a trend towards the highest quartile (>89 Gy) being less likely to survive over time (p=0.13, Figure 1C).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('apex', 'Gene', (52, 56))	('tumor', 'Disease', (46, 51))	('>89 Gy', 'Var', (212, 218))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('less', 'NegReg', (226, 230))	('apex', 'cellular_component', 'GO:0097683', ('52', '56'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('apex', 'Gene', '328', (52, 56))	('tumor', 'Disease', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
54813	16236162	Cells that were directly exposed imatinib mesylate showed a decrease in proliferation for all five human cell lines (92.1, MKT-BR, OCM-1, SP6.5, UW-1) as compared to control (p value of 0.001354991, 0.012655861, 9.47698 x 10-7, 0.002754018 and 5.79576 x 10-6 respectively).	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (33, 50))	('decrease', 'NegReg', (60, 68))	('proliferation', 'CPA', (72, 85))	('as c', 'Gene', '29108', (151, 155))	('MKT-BR', 'Chemical', '-', (123, 129))	('0.012655861', 'Var', (199, 210))	('OCM-1', 'Species', '83984', (131, 136))	('as c', 'Gene', (151, 155))	('human', 'Species', '9606', (99, 104))
54835	16236162	GIST is a sarcoma arising from the interstitial cells of Cajal, harbouring mutation of c-kit.	('sarcoma', 'Disease', (10, 17))	('c-kit', 'Gene', (87, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('mutation', 'Var', (75, 83))	('c-kit', 'Gene', '3815', (87, 92))	('GIST', 'Phenotype', 'HP:0100723', (0, 4))	('sarcoma', 'Disease', 'MESH:D012509', (10, 17))
54836	16236162	Mutations are detected in approximately 71% of tumors, the majority (over 60%) involving exon 11, and less exons 9 and 13.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('involving', 'Reg', (79, 88))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
54916	31382494	Recently, mutations in specific genes such as BAP1 (BRCA1-associated protein-1), SF3B1 (splicing factor 3b subunit 1), and EIF1AX (eukaryotic translation initiation factor 1A, X-linked) have been reported to have prognostic value.	('SF3B1', 'Gene', (81, 86))	('BRCA1-associated protein-1', 'Gene', '8314', (52, 78))	('BAP1', 'Gene', '8314', (46, 50))	('splicing factor 3b subunit 1', 'Gene', (88, 116))	('splicing factor 3b subunit 1', 'Gene', '23451', (88, 116))	('eukaryotic translation initiation factor 1A, X-linked', 'Gene', (131, 184))	('EIF1AX', 'Gene', '1964', (123, 129))	('EIF1AX', 'Gene', (123, 129))	('SF3B1', 'Gene', '23451', (81, 86))	('BAP1', 'Gene', (46, 50))	('BRCA1-associated protein-1', 'Gene', (52, 78))	('splicing', 'biological_process', 'GO:0045292', ('88', '96'))	('mutations', 'Var', (10, 19))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('eukaryotic translation initiation factor 1A, X-linked)', 'Gene', '1964', (131, 185))	('translation initiation', 'biological_process', 'GO:0006413', ('142', '164'))
54917	31382494	Aberrant DNA repair during the evolution of many malignancies and, accordingly, genomic instability is considered a hallmark of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('DNA repair', 'biological_process', 'GO:0006281', ('9', '19'))	('Aberrant', 'Var', (0, 8))	('malignancies', 'Disease', 'MESH:D009369', (49, 61))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('malignancies', 'Disease', (49, 61))	('cancer', 'Disease', (128, 134))
54926	31382494	Monosomy 3 was detected in 63% of the tumors.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('Monosomy 3', 'Var', (0, 10))
54941	31382494	We divided tumors into three groups: no aberration in the specified chromosome area, duplication in the specified region or deletion of the region of interest.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('duplication', 'Var', (85, 96))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('deletion', 'Var', (124, 132))
54943	31382494	As we expected, the four genes located on chromosome 3p (BAP1, MLH1, WDR48, XPC) showed an association between a decreased expression and presence of monosomy 3, while a trend towards decreased expression was noted for MBD4 (chromosome 3q) (Table 3).	('presence', 'Var', (138, 146))	('monosomy 3', 'Var', (150, 160))	('WDR48', 'Gene', (69, 74))	('XPC', 'Gene', (76, 79))	('expression', 'MPA', (123, 133))	('XPC', 'Gene', '7508', (76, 79))	('chromosome', 'cellular_component', 'GO:0005694', ('42', '52'))	('BAP1', 'Gene', '8314', (57, 61))	('MLH1', 'Gene', '4292', (63, 67))	('MLH1', 'Gene', (63, 67))	('MBD4', 'Gene', '8930', (219, 223))	('MBD4', 'Gene', (219, 223))	('chromosome', 'cellular_component', 'GO:0005694', ('225', '235'))	('WDR48', 'Gene', '57599', (69, 74))	('BAP1', 'Gene', (57, 61))	('decreased', 'NegReg', (113, 122))
54945	31382494	The expression of POLB (chromosome 8p) was significantly decreased in tumors with loss of 8p, while an increased expression of NBN and PRKDC, which are located on the long arm of chromosome 8, was related to a gain of genetic material in that chromosome region.	('chromosome', 'cellular_component', 'GO:0005694', ('24', '34'))	('gain', 'PosReg', (210, 214))	('chromosome region', 'cellular_component', 'GO:0098687', ('243', '260'))	('chromosome', 'cellular_component', 'GO:0005694', ('179', '189'))	('expression', 'MPA', (4, 14))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('decreased', 'NegReg', (57, 66))	('NBN', 'Gene', (127, 130))	('expression', 'MPA', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('PRKDC', 'Gene', '5591', (135, 140))	('POLB', 'Gene', '5423', (18, 22))	('tumors', 'Disease', (70, 76))	('PRKDC', 'Gene', (135, 140))	('loss of 8p', 'Var', (82, 92))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('POLB', 'Gene', (18, 22))	('increased', 'PosReg', (103, 112))	('NBN', 'Gene', '4683', (127, 130))
54949	31382494	A high expression of PRKDC was associated with poor survival, as well as a low expression of BAP1, WDR48, and XPC (Table 4).	('low', 'NegReg', (75, 78))	('BAP1', 'Gene', '8314', (93, 97))	('XPC', 'Gene', (110, 113))	('PRKDC', 'Gene', (21, 26))	('high', 'Var', (2, 6))	('XPC', 'Gene', '7508', (110, 113))	('WDR48', 'Gene', '57599', (99, 104))	('BAP1', 'Gene', (93, 97))	('PRKDC', 'Gene', '5591', (21, 26))	('WDR48', 'Gene', (99, 104))
54955	31382494	A higher chromosome 8q copy number was significantly correlated to a higher expression of PRKDC in the LUMC cohort (correlation coefficient: 0.67, p < 0.001) as well as the TCGA cohort (correlation coefficient: 0.61, p < 0.001) (Figure 3).	('PRKDC', 'Gene', '5591', (90, 95))	('UM', 'Phenotype', 'HP:0007716', (104, 106))	('chromosome 8q copy number', 'Var', (9, 34))	('chromosome', 'cellular_component', 'GO:0005694', ('9', '19'))	('expression', 'MPA', (76, 86))	('PRKDC', 'Gene', (90, 95))	('higher', 'PosReg', (69, 75))
54962	31382494	As the expression of ZEB1, TWIST1 and SNAIL1 have been proposed to play a role in invasion of UM cells, we evaluated whether inhibition of DNA-PKcs with NU7026 would influence the expression of these genes.	('UM', 'Phenotype', 'HP:0007716', (94, 96))	('TWIST1', 'Gene', (27, 33))	('DNA-PKcs', 'Gene', '5591', (139, 147))	('invasion', 'CPA', (82, 90))	('TWIST1', 'Gene', '7291', (27, 33))	('play', 'Reg', (67, 71))	('expression', 'MPA', (180, 190))	('DNA-PKcs', 'Gene', (139, 147))	('NU7026', 'Chemical', 'MESH:C479235', (153, 159))	('SNAIL1', 'Gene', (38, 44))	('SNAIL1', 'Gene', '6615', (38, 44))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('ZEB1', 'Gene', '6935', (21, 25))	('ZEB1', 'Gene', (21, 25))	('NU7026', 'Var', (153, 159))	('influence', 'Reg', (166, 175))
54963	31382494	NU7026 is an inhibitor of DNA-dependent protein kinase (DNA-PK), an enzyme involved in the non-homologous end-joining (NHEJ) DNA-repair pathway.	('NU7026', 'Chemical', 'MESH:C479235', (0, 6))	('DNA-dependent protein kinase', 'Gene', (26, 54))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('DNA-PK', 'Gene', (56, 62))	('DNA-repair', 'biological_process', 'GO:0006281', ('125', '135'))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('NU7026', 'Var', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('DNA-PK', 'Gene', '5591', (56, 62))	('NHEJ', 'biological_process', 'GO:0006303', ('119', '123'))	('DNA-dependent protein kinase', 'Gene', '5591', (26, 54))	('DNA', 'cellular_component', 'GO:0005574', ('125', '128'))
54964	31382494	NU7026 sensitizes cells to radiation and has potential for use in anticancer therapies.	('NU7026', 'Chemical', 'MESH:C479235', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('NU7026', 'Var', (0, 6))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('sensitizes', 'Reg', (7, 17))
54966	31382494	Inhibition of DNA-PKcs by NU7026 led to a downregulation of SNAIL1 in Mel270 as well as MM28 cells (Figure 5).	('DNA-PKcs', 'Gene', (14, 22))	('MM28', 'Gene', (88, 92))	('SNAIL1', 'Gene', (60, 66))	('SNAIL1', 'Gene', '6615', (60, 66))	('downregulation', 'NegReg', (42, 56))	('DNA-PKcs', 'Gene', '5591', (14, 22))	('NU7026', 'Chemical', 'MESH:C479235', (26, 32))	('DNA', 'cellular_component', 'GO:0005574', ('14', '17'))	('NU7026', 'Var', (26, 32))	('MM28', 'Gene', '79148', (88, 92))
54968	31382494	To analyze the effect of DNA-PKcs inhibition on cell proliferation, we treated four cell lines (OMM1, OMM2.5, Mel270, MM28) with increasing doses of NU7026 up to 10 microM for a period of 5 days (Figure 6).	('MM28', 'Gene', (118, 122))	('NU7026', 'Chemical', 'MESH:C479235', (149, 155))	('DNA-PKcs', 'Gene', '5591', (25, 33))	('NU7026', 'Var', (149, 155))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('MM28', 'Gene', '79148', (118, 122))	('DNA-PKcs', 'Gene', (25, 33))	('cell proliferation', 'biological_process', 'GO:0008283', ('48', '66'))
54975	31382494	Chromosome 3 loss does not occur in a single step since small tumors with partial monosomy have been observed, but apparently, loss of the entire chromosome confers a selective advantage that might be mediated by the DNA-repair genes identified here.	('DNA-repair', 'biological_process', 'GO:0006281', ('217', '227'))	('advantage', 'PosReg', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('DNA', 'cellular_component', 'GO:0005574', ('217', '220'))	('chromosome', 'cellular_component', 'GO:0005694', ('146', '156'))	('tumors', 'Disease', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('loss', 'Var', (127, 131))
54980	31382494	Loss of BAP1 has been shown to be related to a poor clinical outcome in UM.	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('Loss', 'Var', (0, 4))	('BAP1', 'Gene', '8314', (8, 12))	('BAP1', 'Gene', (8, 12))
54982	31382494	In accordance, BAP1 has been shown to play a role in the repair of DNA double-strand breaks by homologous recombination.	('DNA', 'Var', (67, 70))	('homologous recombination', 'biological_process', 'GO:0035825', ('95', '119'))	('BAP1', 'Gene', '8314', (15, 19))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('BAP1', 'Gene', (15, 19))
54994	31382494	Mutations in XPC that impair the production of the XPC protein are related to Xeroderma Pigmentosum (XP), a rare recessive disorder, which makes patients extremely sensitive to ultraviolet light.	('patients', 'Species', '9606', (145, 153))	('rare recessive disorder', 'Disease', 'MESH:D035583', (108, 131))	('impair', 'NegReg', (22, 28))	('related', 'Reg', (67, 74))	('XPC', 'Gene', '7508', (51, 54))	('XPC', 'Gene', '7508', (13, 16))	('XPC', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('Xeroderma Pigmentosum', 'Disease', 'MESH:D014983', (78, 99))	('Xeroderma Pigmentosum', 'Disease', (78, 99))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('XPC', 'Gene', (51, 54))	('production', 'MPA', (33, 43))	('rare recessive disorder', 'Disease', (108, 131))
54998	31382494	However, XPC may play a role that is independent of its direct function related to UV-damage, as evidenced by the association of epigenetic silencing of XPC with shorter survival in bladder cancer.	('UV-damage', 'Disease', 'MESH:C563466', (83, 92))	('bladder cancer', 'Phenotype', 'HP:0009725', (182, 196))	('XPC', 'Gene', (9, 12))	('XPC', 'Gene', (153, 156))	('shorter', 'NegReg', (162, 169))	('UV-damage', 'Disease', (83, 92))	('XPC', 'Gene', '7508', (9, 12))	('XPC', 'Gene', '7508', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('bladder cancer', 'Disease', 'MESH:D001749', (182, 196))	('bladder cancer', 'Disease', (182, 196))	('epigenetic silencing', 'Var', (129, 149))
55009	31382494	Targeting DNA-PKcs has been suggested as a novel sensitization therapy of OSCC, and it has been shown to increase anticancer drug sensitivity in osteosarcoma cell lines.	('DNA-PKcs', 'Gene', (10, 18))	('cancer', 'Disease', (118, 124))	('drug sensitivity', 'Phenotype', 'HP:0020174', (125, 141))	('OSCC', 'Disease', (74, 78))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('increase', 'PosReg', (105, 113))	('OSCC', 'CellLine', 'CVCL:L894', (74, 78))	('DNA-PKcs', 'Gene', '5591', (10, 18))	('osteosarcoma', 'Phenotype', 'HP:0002669', (145, 157))	('osteosarcoma', 'Disease', (145, 157))	('osteosarcoma', 'Disease', 'MESH:D012516', (145, 157))	('Targeting', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('sensitization', 'biological_process', 'GO:0046960', ('49', '62'))
55011	31382494	While some preliminary results indicate that inhibition of DNA-PKcs by NU7026 sensitizes UM cell lines for the topoisomerase I inhibitor, Topotecan, studies on cervical and breast cancer cells, as well as on lung cancer cells, have shown that this treatment sensitizes tumor cells to radiation treatment.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('topoisomerase', 'molecular_function', 'GO:0003918', ('111', '124'))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('lung cancer', 'Disease', 'MESH:D008175', (208, 219))	('DNA-PKcs', 'Gene', '5591', (59, 67))	('UM', 'Phenotype', 'HP:0007716', (89, 91))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('lung cancer', 'Disease', (208, 219))	('breast cancer', 'Disease', (173, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('Topotecan', 'Chemical', 'MESH:D019772', (138, 147))	('NU7026', 'Chemical', 'MESH:C479235', (71, 77))	('sensitizes', 'Reg', (78, 88))	('sensitizes', 'Reg', (258, 268))	('tumor', 'Disease', (269, 274))	('topoisomerase', 'molecular_function', 'GO:0003917', ('111', '124'))	('NU7026', 'Var', (71, 77))	('DNA-PKcs', 'Gene', (59, 67))
55012	31382494	showed that the combination of hyperthermia and treatment with NU7441 led to an even better sensitization.	('hyperthermia', 'Phenotype', 'HP:0001945', (31, 43))	('sensitization', 'biological_process', 'GO:0046960', ('92', '105'))	('NU7441', 'Var', (63, 69))	('hyperthermia', 'Disease', (31, 43))	('sensitization', 'MPA', (92, 105))	('NU7441', 'Chemical', 'MESH:C499693', (63, 69))	('hyperthermia', 'Disease', 'MESH:D005334', (31, 43))
55016	31382494	In addition, activated DNA-PKcs has been correlated with increased proliferation, decreased apoptosis and poor survival in hepatocellular carcinoma.	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('activated', 'Var', (13, 22))	('apoptosis', 'CPA', (92, 101))	('DNA-PKcs', 'Gene', '5591', (23, 31))	('DNA-PKcs', 'Gene', (23, 31))	('proliferation', 'CPA', (67, 80))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (123, 147))	('increased', 'PosReg', (57, 66))	('hepatocellular carcinoma', 'Disease', (123, 147))	('decreased', 'NegReg', (82, 91))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (123, 147))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))
55018	31382494	In this study, we show that inhibition of DNA-PKcs results in decreased proliferation of UM cells.	('DNA-PKcs', 'Gene', (42, 50))	('proliferation of UM cells', 'CPA', (72, 97))	('decreased', 'NegReg', (62, 71))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('inhibition', 'Var', (28, 38))	('DNA-PKcs', 'Gene', '5591', (42, 50))	('UM', 'Phenotype', 'HP:0007716', (89, 91))
55022	31382494	Although the basal expression of these factors was low in the UM cell lines, we observed a decrease in the expression of the pro-metastatic SNAIL1 upon DNA-PKcs inhibition.	('DNA-PKcs', 'Gene', '5591', (152, 160))	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('SNAIL1', 'Gene', '6615', (140, 146))	('inhibition', 'Var', (161, 171))	('expression', 'MPA', (107, 117))	('DNA-PKcs', 'Gene', (152, 160))	('SNAIL1', 'Gene', (140, 146))	('DNA', 'cellular_component', 'GO:0005574', ('152', '155'))	('decrease', 'NegReg', (91, 99))
55024	31382494	Considering the suggested pro-metastatic functions of DNA-PKcs, it is conceivable that an increased expression of PRKDC, as a result of amplification of 8q, may contribute to the malignant progression in UM.	('PRKDC', 'Gene', '5591', (114, 119))	('DNA-PKcs', 'Gene', '5591', (54, 62))	('UM', 'Phenotype', 'HP:0007716', (204, 206))	('increased', 'PosReg', (90, 99))	('malignant progression', 'CPA', (179, 200))	('expression', 'MPA', (100, 110))	('contribute', 'Reg', (161, 171))	('PRKDC', 'Gene', (114, 119))	('DNA-PKcs', 'Gene', (54, 62))	('amplification', 'Var', (136, 149))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))
55034	31382494	Sixty-three untreated uveal melanoma provided by the Biological Resource Centre of Institut Curie (GSE2213840) and 48 UM samples from the Genoa cohort (GSE2783141 and GSE5188042) were obtained from the Gene Expression Omnibus .	('GSE5188042', 'Var', (167, 177))	('UM', 'Phenotype', 'HP:0007716', (118, 120))	('uveal melanoma', 'Disease', 'MESH:C536494', (22, 36))	('uveal melanoma', 'Phenotype', 'HP:0007716', (22, 36))	('GSE2213840', 'Var', (99, 109))	('Gene Expression', 'biological_process', 'GO:0010467', ('202', '217'))	('uveal melanoma', 'Disease', (22, 36))	('GSE2783141', 'Var', (152, 162))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
55049	31382494	To evaluate the effect of DNA-PKcs inhibition on the expression of pro-metastatic factors, the expression of these factors was evaluated in a primary UM cell line (Mel270) and in a metastatic UM cell line (MM28) before and after treating the cells with 10 microM NU7026 (#13308, Cayman Chemical, Ann Arbor, MI, USA, stock concentration 20 mM in DMSO) for 5 days.	('DMSO', 'Chemical', 'MESH:D004121', (345, 349))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('MM28', 'Gene', '79148', (206, 210))	('NU7026', 'Chemical', 'MESH:C479235', (263, 269))	('DNA-PKcs', 'Gene', '5591', (26, 34))	('NU7026', 'Var', (263, 269))	('UM', 'Phenotype', 'HP:0007716', (150, 152))	('MM28', 'Gene', (206, 210))	('DNA-PKcs', 'Gene', (26, 34))	('UM', 'Phenotype', 'HP:0007716', (192, 194))
55067	31187000	Other than being Caucasian, the host susceptibility factors include fair skin, light eye color, inability to tan, ocular or oculodermal melanocytosis, cutaneous, iris, or choroidal nevus, and BRCA1-associated protein-1 mutation .	('BRCA1-associated protein-1', 'Gene', '8314', (192, 218))	('oculodermal melanocytosis', 'Disease', (124, 149))	('ocular', 'Disease', (114, 120))	('oculodermal melanocytosis', 'Disease', 'MESH:C535835', (124, 149))	('inability', 'Disease', 'MESH:D016388', (96, 105))	('light eye color', 'Phenotype', 'HP:0007730', (79, 94))	('light eye color', 'Disease', (79, 94))	('BRCA1-associated protein-1', 'Gene', (192, 218))	('mutation', 'Var', (219, 227))	('inability', 'Disease', (96, 105))	('choroidal nevus', 'Phenotype', 'HP:0025314', (171, 186))	('nevus', 'Phenotype', 'HP:0003764', (181, 186))	('iris', 'Disease', (162, 166))	('oculodermal melanocytosis', 'Phenotype', 'HP:0009920', (124, 149))	('cutaneous', 'Disease', (151, 160))	('protein', 'cellular_component', 'GO:0003675', ('209', '216'))	('fair skin', 'Phenotype', 'HP:0007513', (68, 77))
55124	31065009	Direct photon irradiation of a tumor from radioisotopes such as 125I or 106Ru is the main form of treatment in the management of uveal melanoma known as brachytherapy.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('tumor', 'Disease', (31, 36))	('uveal melanoma', 'Disease', 'MESH:C536494', (129, 143))	('106Ru', 'Var', (72, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('uveal melanoma', 'Disease', (129, 143))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
55133	31065009	A similar effect was also observed in the case of endothelial cells irradiated with X-rays, in which these modifications lead to lower motile activity of the cells.	('modifications', 'Var', (107, 120))	('lower', 'NegReg', (129, 134))	('motile activity of the cells', 'CPA', (135, 163))	('rays', 'Species', '255564', (86, 90))
55144	31065009	Untreated Mel270 and BLM cells exhibited a normal distribution of the Young's modulus values, although the mean value of Mel270 cells was almost two times higher than that of BLM cells (1.5 vs 0.8 kPa, respectively, Fig.	('BLM', 'Gene', '641', (175, 178))	('BLM', 'Gene', '641', (21, 24))	('Mel270', 'Var', (121, 127))	('BLM', 'Gene', (175, 178))	('higher', 'PosReg', (155, 161))	('BLM', 'Gene', (21, 24))
55146	31065009	For the highest dose of the low-LET proton beam, Mel270 were approximately 1.5-times more elastic and BLM 5 times more elastic than control (at 20 days post-radiation).	('more', 'PosReg', (85, 89))	('BLM', 'Gene', '641', (102, 105))	('elastic', 'MPA', (90, 97))	('elastic', 'MPA', (119, 126))	('BLM', 'Gene', (102, 105))	('Mel270', 'Var', (49, 55))
55169	31065009	Mechanical softening of cancer cells and modification of their adhesion to extracellular matrix increased their capacity to escape the primary tumor.	('increased', 'PosReg', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('adhesion', 'CPA', (63, 71))	('tumor', 'Disease', (143, 148))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('modification', 'Var', (41, 53))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('75', '95'))	('capacity', 'MPA', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
55175	31065009	In general, the changes in cellular elasticity in Mel270 choroidal melanoma were much less pronounced.	('Mel270', 'Var', (50, 56))	('choroidal melanoma', 'Disease', (57, 75))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('cellular elasticity', 'MPA', (27, 46))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (57, 75))	('choroidal melanoma', 'Disease', 'MESH:D008545', (57, 75))
55193	31065009	GNAQ mutation induces viability and migration of uveal melanoma cells via Notch signaling activation, which is mediated by YAP dephosphorylation and nuclear translocation.	('uveal melanoma', 'Disease', 'MESH:C536494', (49, 63))	('activation', 'PosReg', (90, 100))	('dephosphorylation', 'biological_process', 'GO:0016311', ('127', '144'))	('GNAQ', 'Gene', '2776', (0, 4))	('uveal melanoma', 'Disease', (49, 63))	('induces', 'PosReg', (14, 21))	('YAP', 'Gene', '10413', (123, 126))	('migration', 'CPA', (36, 45))	('GNAQ', 'Gene', (0, 4))	('Notch signaling', 'Gene', (74, 89))	('signaling', 'biological_process', 'GO:0023052', ('80', '89'))	('viability', 'CPA', (22, 31))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('mutation', 'Var', (5, 13))	('YAP', 'Gene', (123, 126))	('uveal melanoma', 'Phenotype', 'HP:0007716', (49, 63))
55210	31065009	The primary antibodies used for staining were Vimentin (D21H3) Rabbit mAbs (Cell Signaling Technology, USA) in 0.1% BSA at a concentration 1:300.	('D21H3', 'Var', (56, 61))	('Rabbit', 'Species', '9986', (63, 69))	('Vimentin', 'cellular_component', 'GO:0045098', ('46', '54'))	('Vimentin', 'Protein', (46, 54))	('Vimentin', 'cellular_component', 'GO:0045099', ('46', '54'))	('Signaling', 'biological_process', 'GO:0023052', ('81', '90'))
55213	31065009	The membranes were blocked with 5% skim milk or in 5% BSA in a TBS buffer with 1% of Tween 20 for 1 h and incubated with primary antibodies against ICAM-1 and Tenascin C (D16C4) (Cell Signaling Technology, MA, USA), LAMB3 (CL3363) (Thermo Fisher Scientific) at 4  C overnight.	('TBS', 'Chemical', 'MESH:D013725', (63, 66))	('LAMB3', 'Gene', (216, 221))	('Tween 20', 'Chemical', 'MESH:D011136', (85, 93))	('LAMB3', 'Gene', '3914', (216, 221))	('Signaling', 'biological_process', 'GO:0023052', ('184', '193'))	('D16C4', 'Var', (171, 176))	('Tenascin C', 'cellular_component', 'GO:0090733', ('159', '169'))
55223	30662476	This tumor develops from melanocytes of the iris, ciliary body, or choroid, which, as a result of genetic mutation, undergo neoplastic transformation.	('neoplastic transformation', 'CPA', (124, 149))	('undergo', 'Reg', (116, 123))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('genetic mutation', 'Var', (98, 114))	('tumor', 'Disease', (5, 10))
55230	30662476	Additionally, a genetic profile - chromosome 3 monosomy in the tumor cells, the aberrations of chromosomes 1, 3, 6, and 8 as well as mutation in GNAQ/GNA11 genes in connection with BAP1 mutation worsen the prognoses.	('GNAQ', 'Gene', (145, 149))	('tumor', 'Disease', (63, 68))	('mutation', 'Var', (133, 141))	('BAP1', 'Gene', (181, 185))	('chromosome', 'cellular_component', 'GO:0005694', ('34', '44'))	('GNA11', 'Gene', (150, 155))	('worsen', 'NegReg', (195, 201))	('GNA11', 'Gene', '2767', (150, 155))	('GNAQ', 'Gene', '2776', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('prognoses', 'CPA', (206, 215))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('BAP1', 'Gene', '8314', (181, 185))	('mutation', 'Var', (186, 194))
55318	30662476	when creating regression models of uveal melanomas after brachytherapy: Ru-106 median apex dose was 102 Gy (range, 62-194 Gy), and I-125 median apex dose was 80 Gy (range, 49-164 Gy), did not observe influence of the level dose on tumor regression.	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('I-125', 'Chemical', 'MESH:C000614960', (131, 136))	('Ru-106', 'Var', (72, 78))	('apex', 'cellular_component', 'GO:0097683', ('144', '148'))	('tumor', 'Disease', (231, 236))	('uveal melanomas', 'Disease', (35, 50))	('uveal melanomas', 'Phenotype', 'HP:0007716', (35, 50))	('apex', 'cellular_component', 'GO:0097683', ('86', '90'))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('Ru-106', 'Chemical', 'MESH:C000615522', (72, 78))	('uveal melanomas', 'Disease', 'MESH:C536494', (35, 50))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))
55339	30662476	showed that the tumor regression (between 12 and 15 months after the treatment) is faster in the melanoma with monosomy of chromosome 3, than in case of a disomy.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('disomy', 'Disease', (155, 161))	('melanoma', 'Disease', (97, 105))	('faster', 'PosReg', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('disomy', 'Disease', 'MESH:D024182', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('monosomy of chromosome 3', 'Var', (111, 135))	('men', 'Species', '9606', (74, 77))	('chromosome', 'cellular_component', 'GO:0005694', ('123', '133'))
55350	30662476	(p < 0.001) who analyzed the tumors in three categories determined by the size of the tumor base (< 10 mm, 10-15 mm, and > 15 mm).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('< 10', 'Var', (98, 102))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Disease', (29, 34))	('tumors', 'Disease', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
55355	30662476	In our study, no significant differences between both dose groups (low 80-100 Gy and high 100-120 Gy) in the influence of tumor regression, number of complications, metastasis appearing, number of removed eyeballs (in a second line treatment), and patient survival were found.	('low 80-100 Gy', 'Var', (67, 80))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('metastasis appearing', 'CPA', (165, 185))	('patient', 'Species', '9606', (248, 255))	('tumor', 'Disease', (122, 127))	('men', 'Species', '9606', (237, 240))
55450	30652028	There is evidence that geographic miss, where a tumor edge remains incompletely covered either due to misalignment or inadequate plaque size, is the leading cause of tumor recurrence.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('geographic miss', 'Disease', (23, 38))	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('misalignment', 'Var', (102, 114))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
55474	29899845	We have previously shown that CREB knockdown enhances sensitivity to DOX.	('knockdown', 'Var', (35, 44))	('CREB', 'Gene', (30, 34))	('DOX', 'Chemical', 'MESH:D004317', (69, 72))	('enhances', 'PosReg', (45, 53))	('sensitivity to DOX', 'MPA', (54, 72))
55476	29899845	We found that CREB knockdown increases the sensitivity of these cells to both DOX and DTIC in normoxia and more so in hypoxia as measured by cell survival and Caspase 3 activation.	('activation', 'PosReg', (169, 179))	('DTIC', 'Chemical', 'MESH:D003606', (86, 90))	('hypoxia', 'Disease', (118, 125))	('hypoxia', 'Disease', 'MESH:D000860', (118, 125))	('knockdown', 'Var', (19, 28))	('CREB', 'Gene', (14, 18))	('Caspase 3', 'Gene', '836', (159, 168))	('DOX', 'Chemical', 'MESH:D004317', (78, 81))	('increases', 'PosReg', (29, 38))	('Caspase 3', 'Gene', (159, 168))	('sensitivity', 'MPA', (43, 54))
55486	29899845	On the other hand, CREB knockdown increased HCC cell sensitivity to hypoxia as well as to doxorubicin (DOX) in normoxia and hypoxia.	('HCC', 'Gene', (44, 47))	('hypoxia', 'Disease', 'MESH:D000860', (124, 131))	('DOX', 'Chemical', 'MESH:D004317', (103, 106))	('hypoxia', 'Disease', (68, 75))	('HCC', 'Gene', '619501', (44, 47))	('hypoxia', 'Disease', 'MESH:D000860', (68, 75))	('increased HCC', 'Phenotype', 'HP:0001899', (34, 47))	('HCC', 'Phenotype', 'HP:0001402', (44, 47))	('hypoxia', 'Disease', (124, 131))	('doxorubicin', 'Chemical', 'MESH:D004317', (90, 101))	('increased', 'PosReg', (34, 43))	('CREB', 'Gene', (19, 23))	('knockdown', 'Var', (24, 33))
55487	29899845	Recently, it was demonstrated that CREB blockade by decoy oligonucleotides functionally inhibited transactivation of CREB, and significantly increased radio-sensitivity of multiple human cancer cell lines.	('decoy oligonucleotides', 'Var', (52, 74))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('inhibited', 'NegReg', (88, 97))	('human', 'Species', '9606', (181, 186))	('cancer', 'Disease', (187, 193))	('increased', 'PosReg', (141, 150))	('CREB', 'Protein', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('radio-sensitivity', 'CPA', (151, 168))	('oligonucleotides', 'Chemical', 'MESH:D009841', (58, 74))	('blockade', 'NegReg', (40, 48))	('rat', 'Species', '10116', (24, 27))	('transactivation', 'MPA', (98, 113))	('transactivation', 'biological_process', 'GO:2000144', ('98', '113'))
55499	29899845	In this work, we infected the cells with a MuLV-based recombinant replication competent retrovirus (RCR) which expresses shRNA targeting CREB (vACE-CREB) prior to treatment of the tumors with chemotherapeutic drugs.	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('shRNA', 'Var', (121, 126))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumors', 'Disease', (180, 186))
55522	29899845	At normoxic conditions, CREB knockdown did not increase the apoptotic (sub-G1) fraction (flow cytometry, Table 1, lines 1 and 2) and barely affected cell viability and Caspase 3 activity (cell viability and activation of the Caspase-3 assay, Figure 5).	('Caspase 3', 'Gene', (168, 177))	('knockdown', 'Var', (29, 38))	('Caspase 3 activity', 'molecular_function', 'GO:0030693', ('168', '186'))	('CREB', 'Gene', (24, 28))	('affected', 'Reg', (140, 148))	('cell viability', 'CPA', (149, 163))	('Caspase-3', 'Gene', (225, 234))	('Caspase-3', 'Gene', '836', (225, 234))	('activity', 'MPA', (178, 186))	('Caspase 3 activity', 'molecular_function', 'GO:0004208', ('168', '186'))	('Caspase 3', 'Gene', '836', (168, 177))
55525	29899845	In hypoxia, CREB knockdown increased the apoptotic (sub-G1) fraction in both tested cell lines by about 50% (Table 1, lines 1 and 2).	('increased', 'PosReg', (27, 36))	('hypoxia', 'Disease', (3, 10))	('hypoxia', 'Disease', 'MESH:D000860', (3, 10))	('knockdown', 'Var', (17, 26))	('CREB', 'Gene', (12, 16))
55537	29899845	The combined effect of DOX and CREB-knockdown on induction of apoptosis was determined by flow cytometry (Table 1, lines 5-6) where Mel270 cells had a two-fold increase in apoptosis in either normoxia or hypoxia.	('normoxia or hypoxia', 'Disease', (192, 211))	('apoptosis', 'biological_process', 'GO:0006915', ('172', '181'))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('49', '71'))	('normoxia or hypoxia', 'Disease', 'MESH:D000860', (192, 211))	('increase', 'PosReg', (160, 168))	('apoptosis', 'biological_process', 'GO:0097194', ('172', '181'))	('apoptosis', 'CPA', (172, 181))	('DOX', 'Chemical', 'MESH:D004317', (23, 26))	('Mel270', 'Var', (132, 138))
55540	29899845	We used the higher dose of DOX for testing the survival and activation of Caspase 3 (Figure 8) and found an about 20% additive reduction in survival and a 14-26-fold increase in activation of Caspase 3 in vACE-CREB infected cells vs. vACE-NT infected cells.	('DOX', 'Chemical', 'MESH:D004317', (27, 30))	('Caspase 3', 'Gene', (74, 83))	('increase', 'PosReg', (166, 174))	('vACE-CREB', 'Var', (205, 214))	('survival', 'CPA', (140, 148))	('Caspase 3', 'Gene', '836', (74, 83))	('vACE-NT', 'Chemical', '-', (234, 241))	('activation', 'PosReg', (178, 188))	('Caspase 3', 'Gene', (192, 201))	('reduction', 'NegReg', (127, 136))	('Caspase 3', 'Gene', '836', (192, 201))
55542	29899845	We used DTIC to test whether the ability of CREB knockdown to increase the sensitivity of cells to DOX can be generalized to other chemotherapeutic agents.	('knockdown', 'Var', (49, 58))	('DTIC', 'Chemical', 'MESH:D003606', (8, 12))	('sensitivity of cells to DOX', 'MPA', (75, 102))	('CREB', 'Protein', (44, 48))	('DOX', 'Chemical', 'MESH:D004317', (99, 102))	('increase', 'PosReg', (62, 70))
55543	29899845	To test if knockdown of CREB increases the cellular sensitivity to DTIC, we used two sub-lethal concentrations of DTIC (400 and 600 mug/ml).	('rat', 'Species', '10116', (103, 106))	('mug', 'molecular_function', 'GO:0043739', ('132', '135'))	('DTIC', 'Chemical', 'MESH:D003606', (114, 118))	('DTIC', 'Chemical', 'MESH:D003606', (67, 71))	('increases', 'PosReg', (29, 38))	('cellular sensitivity to DTIC', 'MPA', (43, 71))	('knockdown', 'Var', (11, 20))
55552	29899845	In previous work, we have shown that knockdown of CREB prevents the cellular responses to hypoxia in hepatocellular carcinoma, increase cell death in hypoxia, and lead to increased sensitivity to treatment with doxorubicin in normoxia and hypoxia, in vitro and in vivo.	('increase cell death in hypoxia', 'Disease', (127, 157))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (101, 125))	('knockdown', 'Var', (37, 46))	('hypoxia', 'Disease', 'MESH:D000860', (90, 97))	('increased', 'PosReg', (171, 180))	('hypoxia in hepatocellular carcinoma', 'Disease', 'MESH:D000860', (90, 125))	('hypoxia', 'Disease', (239, 246))	('hypoxia', 'Disease', (150, 157))	('increase cell death in hypoxia', 'Disease', 'MESH:D000860', (127, 157))	('hypoxia', 'Disease', 'MESH:D000860', (150, 157))	('hypoxia', 'Disease', 'MESH:D000860', (239, 246))	('sensitivity to treatment with doxorubicin', 'MPA', (181, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('CREB', 'Gene', (50, 54))	('doxorubicin', 'Chemical', 'MESH:D004317', (211, 222))	('cell death', 'biological_process', 'GO:0008219', ('136', '146'))	('hypoxia in hepatocellular carcinoma', 'Disease', (90, 125))	('hypoxia', 'Disease', (90, 97))	('prevents', 'NegReg', (55, 63))
55556	29899845	Since we demonstrated that CREB plays a pivotal role in the cellular responses to hypoxia, we knocked down CREB in two UM cell lines and found a 50% increase in the apoptotic fraction following knockdown of CREB (Table 1, line 2).	('apoptotic fraction', 'CPA', (165, 183))	('increase', 'PosReg', (149, 157))	('knockdown', 'Var', (194, 203))	('rat', 'Species', '10116', (16, 19))	('hypoxia', 'Disease', (82, 89))	('hypoxia', 'Disease', 'MESH:D000860', (82, 89))	('CREB', 'Gene', (107, 111))	('knocked', 'Var', (94, 101))	('UM', 'Phenotype', 'HP:0007716', (119, 121))
55561	29899845	Thus, infection with vACE-CREB will, on the one hand, increase the hypoxic regions, and on the other hand, prevent the tumor cells from responding to the hypoxia cue.	('tumor', 'Disease', (119, 124))	('hypoxia', 'Disease', (154, 161))	('hypoxia', 'Disease', 'MESH:D000860', (154, 161))	('increase', 'PosReg', (54, 62))	('infection', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('hypoxic', 'Disease', (67, 74))	('prevent', 'NegReg', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('hypoxic', 'Disease', 'MESH:D000860', (67, 74))
55574	29899845	We hypothesize that the increase in cell sensitivity to DOX, resulting from CREB knockdown, may result in a decrease in the required active dose of the drug and thus to a reduction in DOX cardiotoxicity.	('increase', 'PosReg', (24, 32))	('cardiotoxicity', 'Disease', (188, 202))	('cell sensitivity to DOX', 'MPA', (36, 59))	('decrease', 'NegReg', (108, 116))	('reduction', 'NegReg', (171, 180))	('knockdown', 'Var', (81, 90))	('DOX', 'Chemical', 'MESH:D004317', (56, 59))	('DOX', 'Chemical', 'MESH:D004317', (184, 187))	('CREB', 'Gene', (76, 80))	('required active dose of the drug', 'MPA', (124, 156))	('cardiotoxicity', 'Disease', 'MESH:D066126', (188, 202))
55580	29899845	Knockdown of CREB increased the sensitivity to DOX (Table 1 and Figures 8 and 9) and could allow the use of lower concentrations of DOX to avoid its toxicity in patients.	('increased', 'PosReg', (18, 27))	('Knockdown', 'Var', (0, 9))	('patients', 'Species', '9606', (161, 169))	('DOX', 'Chemical', 'MESH:D004317', (132, 135))	('sensitivity to DOX', 'MPA', (32, 50))	('toxicity', 'Disease', 'MESH:D064420', (149, 157))	('toxicity', 'Disease', (149, 157))	('DOX', 'Chemical', 'MESH:D004317', (47, 50))	('rat', 'Species', '10116', (121, 124))
55581	29899845	Moreover, the unique properties of our system in which the MuLV-based RCR recombinant vectors which generate an ongoing infectious knockdown of CERB in tumor growing cells have specificity to tumor cells more than the above-mentioned approaches of Latorre and Dong.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', (192, 197))	('knockdown', 'Var', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('CERB', 'Gene', (144, 148))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('specificity', 'MPA', (177, 188))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('rat', 'Species', '10116', (104, 107))
55582	29899845	In this work we demonstrated that the RCR vector expressing shRNA could infect UM cell lines and spread efficiently to knock down the expression of CREB in these cells, resulting in diminished expression of downstream CREB-mediated genes (Figure 4).	('expression', 'MPA', (134, 144))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('rat', 'Species', '10116', (23, 26))	('knock', 'Var', (119, 124))	('CREB', 'Gene', (148, 152))	('diminished', 'NegReg', (182, 192))	('expression', 'MPA', (193, 203))	('shRNA', 'Gene', (60, 65))
55585	29899845	Despite the less efficient knockdown of CREB in OMM2.5 vs. Mel270 (Figure 3), OMM2.5 showed a higher dependence on CREB in their response to DOX.	('knockdown', 'Var', (27, 36))	('dependence', 'MPA', (101, 111))	('DOX', 'Chemical', 'MESH:D004317', (141, 144))	('OMM2.5', 'Var', (78, 84))	('response to DOX', 'MPA', (129, 144))	('higher', 'PosReg', (94, 100))
55587	29899845	In this work, we found that knocking down CREB increases the sensitivity of Mel270 and less so of OMM2.5 to DTIC.	('knocking down', 'Var', (28, 41))	('CREB', 'Protein', (42, 46))	('increases', 'PosReg', (47, 56))	('sensitivity', 'MPA', (61, 72))	('DTIC', 'Chemical', 'MESH:D003606', (108, 112))
55589	29899845	The results presented here bring hope that infection with vACE-CREB can increase the sensitivity of some of the tumors to DTIC or DOX and by which, increase the treatment efficacy.	('DOX', 'Chemical', 'MESH:D004317', (130, 133))	('increase', 'PosReg', (72, 80))	('increase', 'PosReg', (148, 156))	('infection', 'Var', (43, 52))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('treatment efficacy', 'CPA', (161, 179))	('DTIC', 'Chemical', 'MESH:D003606', (122, 126))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))	('sensitivity', 'MPA', (85, 96))
55591	29899845	We have shown that knocking down CREB can increase the sensitivity of some UMs to DOX.	('DOX', 'Chemical', 'MESH:D004317', (82, 85))	('sensitivity', 'MPA', (55, 66))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('CREB', 'Protein', (33, 37))	('knocking down', 'Var', (19, 32))	('increase', 'PosReg', (42, 50))
55592	29899845	The increased sensitivity also to DTIC may indicate that combining CREB knockdown with chemotherapeutic agents may be a general mechanism to improve the sensitivity of solid tumors to chemotherapy.	('sensitivity', 'MPA', (14, 25))	('solid tumors', 'Disease', (168, 180))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('improve', 'PosReg', (141, 148))	('sensitivity', 'MPA', (153, 164))	('CREB', 'Protein', (67, 71))	('solid tumors', 'Disease', 'MESH:D009369', (168, 180))	('DTIC', 'Chemical', 'MESH:D003606', (34, 38))	('knockdown', 'Var', (72, 81))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
55647	29236046	The overall survival of advanced-stage melanoma patients has improved dramatically in the last 5 years with development of immunotherapy by monoclonal antibodies blocking cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell-death protein 1 (PD-1) and with application of B-Raf or MEK kinase inhibitors in BRAF gene mutant tumours.	('cytotoxic T-lymphocyte-associated antigen 4', 'Gene', (171, 214))	('blocking', 'NegReg', (162, 170))	('programmed cell-death protein 1', 'Gene', '5133', (228, 259))	('MEK', 'Gene', '5609', (300, 303))	('programmed cell-death', 'biological_process', 'GO:0012501', ('228', '249'))	('mutant', 'Var', (335, 341))	('programmed cell-death protein 1', 'Gene', (228, 259))	('BRAF', 'Gene', '673', (325, 329))	('B-Raf', 'Gene', '673', (291, 296))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('BRAF', 'Gene', (325, 329))	('MEK', 'Gene', (300, 303))	('tumours', 'Disease', (342, 349))	('CTLA-4', 'Gene', '1493', (216, 222))	('tumour', 'Phenotype', 'HP:0002664', (342, 348))	('CTLA-4', 'Gene', (216, 222))	('tumours', 'Phenotype', 'HP:0002664', (342, 349))	('protein', 'cellular_component', 'GO:0003675', ('250', '257'))	('tumours', 'Disease', 'MESH:D009369', (342, 349))	('cytotoxic T-lymphocyte-associated antigen 4', 'Gene', '1493', (171, 214))	('improved', 'PosReg', (61, 69))	('B-Raf', 'Gene', (291, 296))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('PD-1', 'Gene', (261, 265))	('PD-1', 'Gene', '5133', (261, 265))	('patients', 'Species', '9606', (48, 56))
55731	29236046	MIF was firstly enriched by MIF antibodies and then measured by MALDI-TOF (Matrix-assisted laser desorption ionisation-Time-of-flight) MS instrument.	('MIF', 'Gene', (28, 31))	('antibodies', 'Var', (32, 42))	('MIF', 'Gene', (0, 3))	('MIF', 'Gene', '4282', (0, 3))	('flight', 'biological_process', 'GO:0060361', ('127', '133'))	('MIF', 'Gene', '4282', (28, 31))
55829	29236046	Two types of tumour antigen-specific cytotoxic T-cell were evaluated: (i) T-cells transgenic for T-cell receptor specific for melanoma-associated antigen recognized by T-cells 1 (MART-1) protein and (ii) ex vivo-expanded tyrosinase-specific T-cells.	('MART-1', 'Gene', '2315', (179, 185))	('MART-1', 'Gene', (179, 185))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('tumour', 'Disease', (13, 19))	('transgenic', 'Var', (82, 92))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma-associated antigen recognized by T-cells 1', 'Gene', '2315', (126, 177))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))
55845	28938534	The presence of BRAF V600E mutation and expression of phosphorylated (p)-ERK and p-AKT were assessed by immunohistochemistry.	('AKT', 'Gene', '207', (83, 86))	('V600E', 'Var', (21, 26))	('ERK', 'molecular_function', 'GO:0004707', ('73', '76'))	('ERK', 'Gene', (73, 76))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('AKT', 'Gene', (83, 86))	('V600E', 'Mutation', 'rs113488022', (21, 26))	('ERK', 'Gene', '5594', (73, 76))
55847	28938534	The BRAF V600E mutation was present in 19% of nevi and 26% of melanomas, but not in primary acquired melanosis (PAM).	('nevi', 'Disease', (46, 50))	('V600E', 'Mutation', 'rs113488022', (9, 14))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('nevi', 'Phenotype', 'HP:0003764', (46, 50))	('V600E', 'Var', (9, 14))	('melanomas', 'Disease', (62, 71))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('melanosis', 'Disease', 'MESH:D008548', (101, 110))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('melanosis', 'Disease', (101, 110))	('melanomas', 'Disease', 'MESH:D008545', (62, 71))
55849	28938534	Both BRAF inhibitors suppressed growth of both BRAF mutant CM cell lines, but only one induced cell death.	('growth', 'MPA', (32, 38))	('BRAF', 'Gene', '673', (5, 9))	('mutant', 'Var', (52, 58))	('BRAF', 'Gene', (5, 9))	('BRAF', 'Gene', (47, 51))	('suppressed', 'NegReg', (21, 31))	('BRAF', 'Gene', '673', (47, 51))	('CM', 'Phenotype', 'HP:0007716', (59, 61))	('cell death', 'biological_process', 'GO:0008219', ('95', '105'))
55850	28938534	MEK162 and MK2206 inhibited proliferation of CM cells in a dose-dependent manner, and the combination of these two drugs led to synergistic growth inhibition and cell death in all CM cell lines.	('MEK162', 'Chemical', 'MESH:C581313', (0, 6))	('CM', 'Phenotype', 'HP:0007716', (45, 47))	('proliferation', 'CPA', (28, 41))	('MK2206', 'Chemical', 'MESH:C548887', (11, 17))	('cell death', 'biological_process', 'GO:0008219', ('162', '172'))	('cell death', 'CPA', (162, 172))	('inhibited', 'NegReg', (18, 27))	('MEK162', 'Gene', (0, 6))	('inhibition', 'NegReg', (147, 157))	('MK2206', 'Var', (11, 17))	('combination', 'Interaction', (90, 101))	('growth', 'CPA', (140, 146))	('CM', 'Phenotype', 'HP:0007716', (180, 182))
55852	28938534	While BRAF inhibitors prohibited cell growth, they were not always cytotoxic.	('prohibited', 'NegReg', (22, 32))	('cell growth', 'CPA', (33, 44))	('BRAF', 'Gene', '673', (6, 10))	('inhibitors', 'Var', (11, 21))	('cell growth', 'biological_process', 'GO:0016049', ('33', '44'))	('BRAF', 'Gene', (6, 10))
55863	28938534	Like cutaneous melanoma, CM frequently harbors a BRAF mutation, as opposed to GNAQ/GNA11 mutations which are found in most cases of uveal melanoma.	('mutation', 'Var', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('GNAQ', 'Gene', (78, 82))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('harbors', 'Reg', (39, 46))	('uveal melanoma', 'Phenotype', 'HP:0007716', (132, 146))	('uveal melanoma', 'Disease', (132, 146))	('GNA11', 'Gene', (83, 88))	('uveal melanoma', 'Disease', 'MESH:C536494', (132, 146))	('CM', 'Phenotype', 'HP:0007716', (25, 27))	('BRAF', 'Gene', '673', (49, 53))	('cutaneous melanoma', 'Disease', (5, 23))	('GNAQ', 'Gene', '2776', (78, 82))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (5, 23))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (5, 23))	('BRAF', 'Gene', (49, 53))	('GNA11', 'Gene', '2767', (83, 88))
55864	28938534	In a recent study, a BRAF V600E mutation was found in 29% of CM, and an NRAS mutation in 18%.	('NRAS', 'Gene', (72, 76))	('CM', 'Phenotype', 'HP:0007716', (61, 63))	('NRAS', 'Gene', '4893', (72, 76))	('BRAF', 'Gene', '673', (21, 25))	('V600E', 'Mutation', 'rs113488022', (26, 31))	('BRAF', 'Gene', (21, 25))	('V600E', 'Var', (26, 31))
55865	28938534	C-KIT mutations are seldom found in CM.	('CM', 'Phenotype', 'HP:0007716', (36, 38))	('C-KIT', 'Gene', '3815', (0, 5))	('C-KIT', 'Gene', (0, 5))	('KIT', 'molecular_function', 'GO:0005020', ('2', '5'))	('mutations', 'Var', (6, 15))
55866	28938534	Mutant BRAF and NRAS are both known to activate the downstream kinases MEK1/2 and ERK1/2, thereby promoting tumor proliferation.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('ERK1/2', 'Gene', '5595;5594', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('ERK1', 'molecular_function', 'GO:0004707', ('82', '86'))	('NRAS', 'Gene', (16, 20))	('MEK1/2', 'Gene', '5604;5605', (71, 77))	('tumor', 'Disease', (108, 113))	('MEK1', 'molecular_function', 'GO:0004708', ('71', '75'))	('MEK1/2', 'Gene', (71, 77))	('promoting', 'PosReg', (98, 107))	('BRAF', 'Gene', '673', (7, 11))	('NRAS', 'Gene', '4893', (16, 20))	('Mutant', 'Var', (0, 6))	('BRAF', 'Gene', (7, 11))	('ERK1/2', 'Gene', (82, 88))	('activate', 'PosReg', (39, 47))
55871	28938534	Overactivity of PI3K/AKT pathway can be induced by loss of activity of PTEN or by activating mutations in oncogene NRAS.	('Overactivity', 'PosReg', (0, 12))	('loss of activity', 'NegReg', (51, 67))	('NRAS', 'Gene', (115, 119))	('mutations', 'Var', (93, 102))	('NRAS', 'Gene', '4893', (115, 119))	('PTEN', 'Gene', (71, 75))	('AKT', 'Gene', '207', (21, 24))	('PTEN', 'Gene', '5728', (71, 75))	('activating', 'Reg', (82, 92))	('AKT', 'Gene', (21, 24))	('PI3K', 'molecular_function', 'GO:0016303', ('16', '20'))
55873	28938534	To determine whether the above-mentioned inhibitors are of use in CM, we tested the effect of several potentially useful drugs on three CM cell lines, each of which has either a BRAF or NRAS mutation.	('BRAF', 'Gene', (178, 182))	('tested', 'Reg', (73, 79))	('NRAS', 'Gene', (186, 190))	('CM', 'Phenotype', 'HP:0007716', (136, 138))	('NRAS', 'Gene', '4893', (186, 190))	('BRAF', 'Gene', '673', (178, 182))	('CM', 'Phenotype', 'HP:0007716', (66, 68))	('mutation', 'Var', (191, 199))
55875	28938534	We determined the presence of BRAF V600E mutation in 131 pigmented conjunctival lesions from 129 patients and analyzed the expression of phosphorylated (p)-ERK and p-AKT by immunohistochemistry (Table 1).	('ERK', 'Gene', '5594', (156, 159))	('AKT', 'Gene', '207', (166, 169))	('ERK', 'Gene', (156, 159))	('V600E', 'Var', (35, 40))	('BRAF', 'Gene', (30, 34))	('AKT', 'Gene', (166, 169))	('BRAF', 'Gene', '673', (30, 34))	('ERK', 'molecular_function', 'GO:0004707', ('156', '159'))	('V600E', 'Mutation', 'rs113488022', (35, 40))	('patients', 'Species', '9606', (97, 105))
55876	28938534	We observed BRAF V600E mutation in 19% of nevi (n=51) and 26% of melanoma (n=42) (Figure 1G).	('nevi', 'Phenotype', 'HP:0003764', (42, 46))	('V600E', 'Var', (17, 22))	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', (12, 16))	('nevi', 'Disease', (42, 46))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('V600E', 'Mutation', 'rs113488022', (17, 22))	('melanoma', 'Disease', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
55877	28938534	No BRAF V600E mutation was seen in any case of PAM without atypia (n=20) or PAM with atypia (n=18).	('V600E', 'Mutation', 'rs113488022', (8, 13))	('V600E', 'Var', (8, 13))	('BRAF', 'Gene', '673', (3, 7))	('PAM', 'Disease', (47, 50))	('BRAF', 'Gene', (3, 7))
55878	28938534	One of the BRAF mutated melanomas evolved from a background of PAM.	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanomas', 'Disease', (24, 33))	('mutated', 'Var', (16, 23))	('melanomas', 'Phenotype', 'HP:0002861', (24, 33))	('BRAF', 'Gene', '673', (11, 15))	('melanomas', 'Disease', 'MESH:D008545', (24, 33))	('BRAF', 'Gene', (11, 15))
55885	28938534	In groups of nevi and CM, neither cytoplasmic nor nuclear expression was associated with the presence of a BRAF mutation.	('BRAF', 'Gene', (107, 111))	('CM', 'Phenotype', 'HP:0007716', (22, 24))	('mutation', 'Var', (112, 120))	('nevi', 'Disease', (13, 17))	('nevi', 'Phenotype', 'HP:0003764', (13, 17))	('BRAF', 'Gene', '673', (107, 111))
55896	28938534	Low concentrations of MK2206 (CRMM1 0.5 muM, CRMM2 2muM and CM2005.1 4muM) reduced the level of p-AKT, but higher concentrations were needed to suppress cell growth (Figure 3).	('MK2206', 'Var', (22, 28))	('CM2005.1', 'Var', (60, 68))	('level', 'MPA', (87, 92))	('reduced', 'NegReg', (75, 82))	('AKT', 'Gene', '207', (98, 101))	('CM', 'Phenotype', 'HP:0007716', (60, 62))	('cell growth', 'biological_process', 'GO:0016049', ('153', '164'))	('MK2206', 'Chemical', 'MESH:C548887', (22, 28))	('AKT', 'Gene', (98, 101))
55897	28938534	To investigate whether the AKT pathway was effectively inhibited by MK2206, we determined the p-PRAS40 level, since PRAS40 is a direct downstream target molecule of AKT.	('AKT', 'Gene', (165, 168))	('MK2206', 'Chemical', 'MESH:C548887', (68, 74))	('PRAS40', 'Gene', '84335', (116, 122))	('AKT', 'Gene', (27, 30))	('PRAS40', 'Gene', (116, 122))	('MK2206', 'Var', (68, 74))	('PRAS40', 'Gene', '84335', (96, 102))	('AKT', 'Gene', '207', (27, 30))	('AKT', 'Gene', '207', (165, 168))	('PRAS40', 'Gene', (96, 102))
55898	28938534	As shown in Figure 3E, levels of p-PRAS40 were strongly reduced in all three cell lines upon MK2206 treatment at relative low concentrations, indicating that AKT activity was decreased by MK2206; however, this inhibition was not sufficient to decrease the cell growth of CRMM2 and CM2005.1.	('MK2206', 'Var', (93, 99))	('MK2206', 'Chemical', 'MESH:C548887', (188, 194))	('reduced', 'NegReg', (56, 63))	('activity', 'MPA', (162, 170))	('MK2206', 'Var', (188, 194))	('cell growth', 'biological_process', 'GO:0016049', ('256', '267'))	('AKT', 'Gene', '207', (158, 161))	('levels', 'MPA', (23, 29))	('MK2206', 'Chemical', 'MESH:C548887', (93, 99))	('CM', 'Phenotype', 'HP:0007716', (281, 283))	('PRAS40', 'Gene', '84335', (35, 41))	('PRAS40', 'Gene', (35, 41))	('decreased', 'NegReg', (175, 184))	('AKT', 'Gene', (158, 161))
55900	28938534	MEK162 and MK2206 inhibited growth of all CM cell lines in a dose-dependent manner, although only high concentrations of MK2206 were able to suppress the proliferation of CRMM2 and CM2005.1.	('MEK162', 'Chemical', 'MESH:C581313', (0, 6))	('growth', 'CPA', (28, 34))	('MK2206', 'Chemical', 'MESH:C548887', (121, 127))	('suppress', 'NegReg', (141, 149))	('MK2206', 'Chemical', 'MESH:C548887', (11, 17))	('CM', 'Phenotype', 'HP:0007716', (42, 44))	('inhibited', 'NegReg', (18, 27))	('MK2206', 'Var', (11, 17))	('CM', 'Phenotype', 'HP:0007716', (181, 183))	('proliferation', 'CPA', (154, 167))	('MK2206', 'Var', (121, 127))
55901	28938534	Although CRMM1 and CM2005.1 both harbor the BRAF V600E mutation, their sensitivity to BRAFi differed very much.	('BRAF', 'Gene', '673', (44, 48))	('V600E', 'Var', (49, 54))	('BRAF', 'Gene', (44, 48))	('CM', 'Phenotype', 'HP:0007716', (19, 21))	('BRAF', 'Gene', (86, 90))	('BRAF', 'Gene', '673', (86, 90))	('V600E', 'Mutation', 'rs113488022', (49, 54))
55903	28938534	However, we did find a deletion in exon 2 of PTEN in the NRAS mutant cell line CRMM2.	('deletion', 'Var', (23, 31))	('NRAS', 'Gene', (57, 61))	('NRAS', 'Gene', '4893', (57, 61))	('PTEN', 'Gene', (45, 49))	('PTEN', 'Gene', '5728', (45, 49))
55905	28938534	MEK162 and MK2206 increased the sub-G1 fraction, indicating that these two drugs were able to induce cell death.	('MEK162', 'Chemical', 'MESH:C581313', (0, 6))	('cell death', 'CPA', (101, 111))	('increased', 'PosReg', (18, 27))	('MK2206', 'Chemical', 'MESH:C548887', (11, 17))	('MEK162', 'Var', (0, 6))	('cell death', 'biological_process', 'GO:0008219', ('101', '111'))	('sub-G1 fraction', 'MPA', (32, 47))	('MK2206', 'Var', (11, 17))
55907	28938534	Both MEK162 and MK2206 treatment led to G1 arrest, a modest increase in the sub-G1 fraction and a reduced number of S-phase cells (Supplementary Figure S2), although the effect of MK2206 was not very strong.	('MEK162', 'Var', (5, 11))	('MK2206', 'Var', (16, 22))	('increase', 'PosReg', (60, 68))	('arrest', 'Disease', 'MESH:D006323', (43, 49))	('MK2206', 'Chemical', 'MESH:C548887', (180, 186))	('S-phase', 'biological_process', 'GO:0051320', ('116', '123'))	('MEK162', 'Chemical', 'MESH:C581313', (5, 11))	('arrest', 'Disease', (43, 49))	('reduced', 'NegReg', (98, 105))	('sub-G1 fraction', 'CPA', (76, 91))	('MK2206', 'Chemical', 'MESH:C548887', (16, 22))
55908	28938534	In CM2005.1, G1 arrest and depletion of S-phase cells were found after all drug treatments, although MK2206 treatment did not result in a reduced G2/M phase.	('G2/M phase', 'CPA', (146, 156))	('arrest', 'Disease', 'MESH:D006323', (16, 22))	('M phase', 'biological_process', 'GO:0000279', ('149', '156'))	('CM2005.1', 'Var', (3, 11))	('CM', 'Phenotype', 'HP:0007716', (3, 5))	('S-phase', 'biological_process', 'GO:0051320', ('40', '47'))	('arrest', 'Disease', (16, 22))	('MK2206', 'Chemical', 'MESH:C548887', (101, 107))	('depletion', 'MPA', (27, 36))
55910	28938534	Poly (ADP-ribose) polymerase (PARP) cleavage is often associated with apoptotic cell death and has served as a marker for apoptosis and caspase activity.	('caspase activity', 'molecular_function', 'GO:0030693', ('136', '152'))	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('PARP', 'Gene', (30, 34))	('Poly (ADP-ribose) polymerase', 'Gene', '142', (0, 28))	('cleavage', 'Var', (36, 44))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('70', '90'))	('PARP', 'Gene', '142', (30, 34))	('caspase activity', 'molecular_function', 'GO:0097153', ('136', '152'))	('caspase activity', 'molecular_function', 'GO:0004197', ('136', '152'))	('Poly (ADP-ribose) polymerase', 'Gene', (0, 28))	('associated', 'Reg', (54, 64))	('apoptotic cell death', 'CPA', (70, 90))
55917	28938534	We treated CRMM1, CRMM2 and CM2005.1 with varied concentrations of MEK162, MK2206 or the combination of MEK162 and MK2206 for 72 hours, and evaluated cell growth.	('MK2206', 'Var', (115, 121))	('MEK162', 'Chemical', 'MESH:C581313', (104, 110))	('MEK162', 'Chemical', 'MESH:C581313', (67, 73))	('MK2206', 'Chemical', 'MESH:C548887', (115, 121))	('cell growth', 'biological_process', 'GO:0016049', ('150', '161'))	('cell growth', 'CPA', (150, 161))	('MK2206', 'Chemical', 'MESH:C548887', (75, 81))	('CM', 'Phenotype', 'HP:0007716', (28, 30))	('evaluated', 'Reg', (140, 149))
55918	28938534	Figure 5 shows that MEK162 and MK2206 were synergistic in all cell lines, with synergy confirmed by CI values.	('MK2206', 'Var', (31, 37))	('MEK162', 'Chemical', 'MESH:C581313', (20, 26))	('MEK162', 'Var', (20, 26))	('MK2206', 'Chemical', 'MESH:C548887', (31, 37))
55919	28938534	In all cell lines, the combination of MEK162 and MK2206 at low concentrations caused slightly stronger G1 arrest and depletion of S-phase compared to single treatments (Figure 6).	('MEK162', 'Var', (38, 44))	('arrest', 'Disease', (106, 112))	('S-phase', 'biological_process', 'GO:0051320', ('130', '137'))	('depletion of S-phase', 'MPA', (117, 137))	('MK2206', 'Chemical', 'MESH:C548887', (49, 55))	('arrest', 'Disease', 'MESH:D006323', (106, 112))	('stronger', 'PosReg', (94, 102))	('MK2206', 'Var', (49, 55))	('MEK162', 'Chemical', 'MESH:C581313', (38, 44))
55920	28938534	Uveal melanomas, in contrast to conjunctival melanomas, lack BRAF or NRAS mutations but frequently have mutations in GNAQ, GNA11, BAP1, SF3B1 or EIF1AX.	('BAP1', 'Gene', (130, 134))	('EIF1AX', 'Gene', '1964', (145, 151))	('conjunctival melanomas', 'Disease', (32, 54))	('GNAQ', 'Gene', '2776', (117, 121))	('melanomas', 'Disease', (45, 54))	('GNA11', 'Gene', '2767', (123, 128))	('GNAQ', 'Gene', (117, 121))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('NRAS', 'Gene', '4893', (69, 73))	('SF3B1', 'Gene', (136, 141))	('mutations', 'Var', (104, 113))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (32, 53))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))	('BRAF', 'Gene', '673', (61, 65))	('SF3B1', 'Gene', '23451', (136, 141))	('BRAF', 'Gene', (61, 65))	('GNA11', 'Gene', (123, 128))	('BAP1', 'Gene', '8314', (130, 134))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('NRAS', 'Gene', (69, 73))	('EIF1AX', 'Gene', (145, 151))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (32, 54))	('melanomas', 'Disease', (6, 15))	('melanomas', 'Disease', 'MESH:D008545', (45, 54))
55923	28938534	In our series, BRAF V600E mutations occur in 19% of nevi and 26% of CM, but not in PAM, which confirms previous results.	('BRAF', 'Gene', '673', (15, 19))	('nevi', 'Phenotype', 'HP:0003764', (52, 56))	('BRAF', 'Gene', (15, 19))	('CM', 'Phenotype', 'HP:0007716', (68, 70))	('V600E', 'Mutation', 'rs113488022', (20, 25))	('nevi', 'Disease', (52, 56))	('V600E', 'Var', (20, 25))
55925	28938534	Furthermore, similar to the findings in melanocytic nevi and cutaneous melanoma, we report that BRAF mutations do not determine the tumor's ERK phosphorylation status.	('ERK', 'molecular_function', 'GO:0004707', ('140', '143'))	('mutations', 'Var', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (61, 79))	('nevi', 'Phenotype', 'HP:0003764', (52, 56))	('phosphorylation', 'biological_process', 'GO:0016310', ('144', '159'))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (40, 56))	('ERK', 'Gene', '5594', (140, 143))	('tumor', 'Disease', (132, 137))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('cutaneous melanoma', 'Disease', (61, 79))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))	('ERK', 'Gene', (140, 143))
55927	28938534	Recently, loss of function mutations in NF1 have been described in a high percentage of cutaneous melanoma.	('mutations', 'Var', (27, 36))	('loss of function', 'NegReg', (10, 26))	('NF1', 'Gene', (40, 43))	('cutaneous melanoma', 'Disease', (88, 106))	('NF1', 'Gene', '4763', (40, 43))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (88, 106))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (88, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))
55935	28938534	Although CRMM1 and CM2005.1 both harbor a BRAF V600E mutation, their sensitivity to BRAFi differed greatly: CRMM1 required a much higher dose of Dabrafenib to inhibit cell growth compared to CM2005.1.	('BRAF', 'Gene', '673', (42, 46))	('CM', 'Phenotype', 'HP:0007716', (191, 193))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('V600E', 'Mutation', 'rs113488022', (47, 52))	('CM', 'Phenotype', 'HP:0007716', (19, 21))	('Dabrafenib', 'Chemical', 'MESH:C561627', (145, 155))	('cell growth', 'CPA', (167, 178))	('V600E', 'Var', (47, 52))	('BRAF', 'Gene', (42, 46))	('cell growth', 'biological_process', 'GO:0016049', ('167', '178'))	('inhibit', 'NegReg', (159, 166))
55940	28938534	This finding is in agreement with other preclinical studies in other malignancies, in which selective BRAFi stimulated cell growth and ERK phosphorylation in BRAF WT and NRAS mutant cutaneous melanoma cell lines.	('NRAS', 'Gene', (170, 174))	('mutant', 'Var', (175, 181))	('cutaneous melanoma', 'Disease', (182, 200))	('stimulated', 'PosReg', (108, 118))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (182, 200))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (182, 200))	('BRAF', 'Gene', '673', (102, 106))	('BRAF', 'Gene', (102, 106))	('BRAF', 'Gene', '673', (158, 162))	('cell growth', 'CPA', (119, 130))	('ERK', 'molecular_function', 'GO:0004707', ('135', '138'))	('BRAF', 'Gene', (158, 162))	('ERK', 'Gene', '5594', (135, 138))	('malignancies', 'Disease', 'MESH:D009369', (69, 81))	('NRAS', 'Gene', '4893', (170, 174))	('malignancies', 'Disease', (69, 81))	('phosphorylation', 'biological_process', 'GO:0016310', ('139', '154'))	('ERK', 'Gene', (135, 138))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('cell growth', 'biological_process', 'GO:0016049', ('119', '130'))
55944	28938534	Furthermore, the data of cell cycle profiles and PARP cleavage show that in addition to cytostatic effects, MEK162 alone can prompt apoptosis, regardless of BRAF or NRAS mutations.	('apoptosis', 'CPA', (132, 141))	('PARP', 'Gene', '142', (49, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('132', '141'))	('MEK162', 'Chemical', 'MESH:C581313', (108, 114))	('BRAF', 'Gene', '673', (157, 161))	('apoptosis', 'biological_process', 'GO:0006915', ('132', '141'))	('PARP', 'Gene', (49, 53))	('BRAF', 'Gene', (157, 161))	('MEK162', 'Var', (108, 114))	('cell cycle', 'biological_process', 'GO:0007049', ('25', '35'))	('NRAS', 'Gene', (165, 169))	('prompt', 'PosReg', (125, 131))	('NRAS', 'Gene', '4893', (165, 169))
55948	28938534	The PI3K/AKT signal transduction pathway is considered a potential co-target for BRAF and NRAS mutant cutaneous melanoma.	('AKT', 'Gene', '207', (9, 12))	('NRAS', 'Gene', (90, 94))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('NRAS', 'Gene', '4893', (90, 94))	('BRAF', 'Gene', '673', (81, 85))	('AKT signal transduction', 'biological_process', 'GO:0043491', ('9', '32'))	('BRAF', 'Gene', (81, 85))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('AKT', 'Gene', (9, 12))	('mutant', 'Var', (95, 101))	('cutaneous melanoma', 'Disease', (102, 120))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))
55950	28938534	Our results show that MK2206 inhibited proliferation in all CM cell lines, but at variable doses, and independent of their effect on p-AKT and p-PRAS40, indicating that the growth inhibitory effect induced by MK2206 is not specific or at least partly caused by off-target effects.	('inhibited', 'NegReg', (29, 38))	('AKT', 'Gene', '207', (135, 138))	('MK2206', 'Var', (22, 28))	('MK2206', 'Chemical', 'MESH:C548887', (209, 215))	('AKT', 'Gene', (135, 138))	('CM', 'Phenotype', 'HP:0007716', (60, 62))	('MK2206', 'Var', (209, 215))	('proliferation', 'CPA', (39, 52))	('PRAS40', 'Gene', '84335', (145, 151))	('MK2206', 'Chemical', 'MESH:C548887', (22, 28))	('PRAS40', 'Gene', (145, 151))	('growth', 'MPA', (173, 179))
55951	28938534	With the clinical availability of PI3K, AKT and mTOR inhibitors, a number of trials are now ongoing in cutaneous melanoma.	('mTOR', 'Gene', '2475', (48, 52))	('PI3K', 'Var', (34, 38))	('cutaneous melanoma', 'Disease', (103, 121))	('mTOR', 'Gene', (48, 52))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (103, 121))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (103, 121))	('AKT', 'Gene', '207', (40, 43))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('PI3K', 'molecular_function', 'GO:0016303', ('34', '38'))	('AKT', 'Gene', (40, 43))
55952	28938534	Our studies show that combining MEK162 with MK2206 has a synergistic inhibitory effect on proliferation of three CM cell lines, regardless of their sensitivity to the individual agents.	('proliferation', 'CPA', (90, 103))	('CM', 'Phenotype', 'HP:0007716', (113, 115))	('MK2206', 'Var', (44, 50))	('inhibitory', 'NegReg', (69, 79))	('MEK162', 'Chemical', 'MESH:C581313', (32, 38))	('MEK162', 'Var', (32, 38))	('MK2206', 'Chemical', 'MESH:C548887', (44, 50))
55953	28938534	Mutations in the G-alpha-proteins GNAQ and GNA11 that occur in 91% of uveal melanoma also activate MAPK and PI3K/AKT pathways, which implies that the combination of MEK and AKT inhibitors may also be profitable for this patient group.	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('AKT', 'Gene', '207', (113, 116))	('MEK', 'Gene', '5609', (165, 168))	('AKT', 'Gene', (173, 176))	('GNA11', 'Gene', '2767', (43, 48))	('MAPK', 'molecular_function', 'GO:0004707', ('99', '103'))	('G-alpha-proteins', 'Protein', (17, 33))	('MEK', 'Gene', (165, 168))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', '2776', (34, 38))	('AKT', 'Gene', '207', (173, 176))	('GNA11', 'Gene', (43, 48))	('patient', 'Species', '9606', (220, 227))	('activate', 'PosReg', (90, 98))	('GNAQ', 'Gene', (34, 38))	('AKT', 'Gene', (113, 116))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('uveal melanoma', 'Disease', (70, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('PI3K', 'molecular_function', 'GO:0016303', ('108', '112'))
55966	28938534	Briefly, following deparaffinization and heat-induced antigen retrieval for 60 minutes, the tissue sections were incubated with primary antibody anti-MAP kinase diphosphorylated ERK 1/2 (1:1000; M8159, Sigma-Aldrich, St. Louis, MO, USA), p-AKT Ser473 (sc-135651; 1:25, Santa Cruz Biotechnology; Dallas, TX, USA), p-AKT Thr 308 (sc-135650, 1:50, Santa Cruz Biotechnology), BRAF-V600E (26039, 1:50, NewEast Biosciences, Malvern, PA, USA) or Melan A (clone A103, Ventana) for 1 hour at 36 C. A subsequent amplification step was followed by incubation with hematoxylin II counter stain for 8 minutes and then bluing reagent for 8 minutes according to the manufacturer's instructions (Ventana).	('paraffin', 'Chemical', 'MESH:D010232', (21, 29))	('Ser473', 'Chemical', '-', (244, 250))	('Ser', 'cellular_component', 'GO:0005790', ('244', '247'))	('ERK 1/2', 'Gene', (178, 185))	('hematoxylin', 'Chemical', 'MESH:D006416', (553, 564))	('antibody', 'cellular_component', 'GO:0019815', ('136', '144'))	('BRAF', 'Gene', (372, 376))	('BRAF', 'Gene', '673', (372, 376))	('AKT', 'Gene', (315, 318))	('AKT', 'Gene', '207', (240, 243))	('ERK 1', 'molecular_function', 'GO:0004707', ('178', '183'))	('V600E', 'Mutation', 'rs113488022', (377, 382))	('antibody', 'cellular_component', 'GO:0019814', ('136', '144'))	('MAP', 'molecular_function', 'GO:0004239', ('150', '153'))	('sc-135650', 'Var', (328, 337))	('ERK 1/2', 'Gene', '5595;5594', (178, 185))	('Thr', 'Chemical', 'MESH:D013912', (319, 322))	('AKT', 'Gene', '207', (315, 318))	('antibody', 'molecular_function', 'GO:0003823', ('136', '144'))	('AKT', 'Gene', (240, 243))	('antibody', 'cellular_component', 'GO:0042571', ('136', '144'))
55968	28938534	Vemurafenib (PLX4032, S1267), Dabrafenib (GSK2118436, S2807), MEK162 (ARRY-162, S7007) and MK2206 (S1078) were purchased from Selleck Chemicals (Huissen, The Netherlands).	('GSK2118436', 'Var', (42, 52))	('MEK162', 'Chemical', 'MESH:C581313', (62, 68))	('PLX4032', 'Var', (13, 20))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('Dabrafenib', 'Chemical', 'MESH:C561627', (30, 40))	('GSK2118436', 'Chemical', 'MESH:C561627', (42, 52))	('MK2206', 'Chemical', 'MESH:C548887', (91, 97))	('GSK', 'molecular_function', 'GO:0050321', ('42', '45'))
55972	28938534	Our previous studies have shown that CRMM1 and CM2005.1 harbor a BRAF V600E mutation, and CRMM2 contains an NRAS Q61L mutation.	('NRAS', 'Gene', (108, 112))	('V600E', 'Var', (70, 75))	('NRAS', 'Gene', '4893', (108, 112))	('Q61L', 'Mutation', 'rs11554290', (113, 117))	('BRAF', 'Gene', '673', (65, 69))	('CM', 'Phenotype', 'HP:0007716', (47, 49))	('V600E', 'Mutation', 'rs113488022', (70, 75))	('BRAF', 'Gene', (65, 69))
55973	28938534	Inactivating molecular changes in PTEN were tested by NGS as decribed before.	('PTEN', 'Gene', '5728', (34, 38))	('PTEN', 'Gene', (34, 38))	('Inactivating', 'Var', (0, 12))
55974	28938534	Cells were lysed in M-PER Mammalian Protein Extraction Reagent (78501, Thermo Scientific, OH, USA), supplemented with protease and phosphatase inhibitors (78415 and 78420, Thermo Scientific).	('phosphatase', 'molecular_function', 'GO:0016791', ('131', '142'))	('78501', 'Var', (64, 69))	('Mammalian', 'Species', '9606', (26, 35))	('78415', 'Var', (155, 160))
55982	28380455	Targeted next generation sequencing of mucosal melanomas identifies frequent NF1 and RAS mutations Mucosal melanoma represents ~1% of all melanomas, frequently having a poor prognosis due to diagnosis at a late stage of disease.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanomas', 'Disease', 'MESH:D008545', (138, 147))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('Mucosal melanoma', 'Disease', 'MESH:D008545', (99, 115))	('NF1', 'Gene', (77, 80))	('mucosal melanomas', 'Disease', 'MESH:D008545', (39, 56))	('NF1', 'Gene', '4763', (77, 80))	('Mucosal melanoma', 'Disease', (99, 115))	('melanomas', 'Phenotype', 'HP:0002861', (138, 147))	('melanomas', 'Disease', (138, 147))	('melanomas', 'Disease', 'MESH:D008545', (47, 56))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('mutations', 'Var', (89, 98))	('RAS', 'Gene', (85, 88))	('mucosal melanomas', 'Disease', (39, 56))	('melanomas', 'Disease', (47, 56))
55984	28380455	less BRAF and more frequent KIT mutations than cutaneous melanomas.	('cutaneous melanomas', 'Disease', 'MESH:C562393', (47, 66))	('KIT', 'Gene', (28, 31))	('BRAF', 'Gene', '673', (5, 9))	('cutaneous melanomas', 'Disease', (47, 66))	('BRAF', 'Gene', (5, 9))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('KIT', 'molecular_function', 'GO:0005020', ('28', '31'))	('mutations', 'Var', (32, 41))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (47, 65))	('less', 'NegReg', (0, 4))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (47, 66))
55988	28380455	Mutations in BRAF were identified in 8.4% and KIT in 7.0% of tumor samples.	('BRAF', 'Gene', '673', (13, 17))	('KIT', 'molecular_function', 'GO:0005020', ('46', '49'))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
55992	28380455	Our data indicate that in mucosal melanomas RAS/NF1 alterations are frequent, implying a significant pathogenetic role for MAPK and potentially PI3K pathway activation in these tumors.	('NF1', 'Gene', '4763', (48, 51))	('alterations', 'Var', (52, 63))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('MAPK', 'molecular_function', 'GO:0004707', ('123', '127'))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('PI3K', 'molecular_function', 'GO:0016303', ('144', '148'))	('activation', 'PosReg', (157, 167))	('mucosal melanomas RAS', 'Disease', (26, 47))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('tumors', 'Disease', (177, 183))	('mucosal melanomas RAS', 'Disease', 'MESH:D008545', (26, 47))	('NF1', 'Gene', (48, 51))
55999	28380455	gene amplifications or gain-of-function mutations of KIT are more frequently detected in mucosal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanomas', 'Phenotype', 'HP:0002861', (97, 106))	('gain-of-function', 'PosReg', (23, 39))	('mucosal melanomas', 'Disease', (89, 106))	('mutations', 'Var', (40, 49))	('mucosal melanomas', 'Disease', 'MESH:D008545', (89, 106))	('KIT', 'Gene', (53, 56))	('KIT', 'molecular_function', 'GO:0005020', ('53', '56'))
56002	28380455	NRAS mutations are somewhat less frequent in mucosal (10-20%) than cutaneous melanomas (20-30%).	('mucosal', 'Disease', (45, 52))	('mutations', 'Var', (5, 14))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (67, 86))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (67, 86))	('NRAS', 'Gene', (0, 4))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (67, 85))	('NRAS', 'Gene', '4893', (0, 4))	('cutaneous melanomas', 'Disease', (67, 86))
56005	28380455	Our study aimed to identify additional oncogenic driver mutations in mucosal melanoma in a larger cohort of patients to recognize additional molecular pathways with the potential to be exploited for establishing future therapeutic strategies.	('mutations', 'Var', (56, 65))	('mucosal melanoma', 'Disease', (69, 85))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('mucosal melanoma', 'Disease', 'MESH:D008545', (69, 85))	('patients', 'Species', '9606', (108, 116))
56008	28380455	NF1 and RAS were the most frequently mutated genes (Figure 2, Supplementary Figure 1 and 2, Table 2, Supplementary Table 1), with 15 NF1 mutations identified in 13 samples (18.3.%) and 12 RAS mutations identified in 12 samples (16.9%).	('identified', 'Reg', (147, 157))	('NF1', 'Gene', (133, 136))	('mutations', 'Var', (137, 146))	('NF1', 'Gene', '4763', (133, 136))	('NF1', 'Gene', (0, 3))	('NF1', 'Gene', '4763', (0, 3))
56009	28380455	In 9 out of 13 samples (69.2%) a clearly inactivating NF1 mutation was present resulting in non-sense (synthesis stop) or frameshift mutations.	('frameshift mutations', 'Var', (122, 142))	('NF1', 'Gene', '4763', (54, 57))	('NF1', 'Gene', (54, 57))	('inactivating', 'NegReg', (41, 53))	('synthesis', 'biological_process', 'GO:0009058', ('103', '112'))
56010	28380455	Examples of some inactivating NF1 mutations detected in our cohort are shown in Supplementary Figure 1.	('NF1', 'Gene', (30, 33))	('NF1', 'Gene', '4763', (30, 33))	('mutations', 'Var', (34, 43))	('inactivating', 'Reg', (17, 29))
56011	28380455	Two samples harbored multiple NF1 mutations (Table 2, Supplementary Table 1); one of them having two inactivating mutations, the other one having an inactivating and a D896N missense mutation.	('NF1', 'Gene', (30, 33))	('NF1', 'Gene', '4763', (30, 33))	('D896N missense', 'Var', (168, 182))	('mutations', 'Var', (34, 43))	('D896N', 'Mutation', 'rs1189816828', (168, 173))
56012	28380455	RAS gene alterations were found in 12 out of 71 samples (16.9%), including 8 NRAS and 4 KRAS mutations.	('NRAS', 'Gene', (77, 81))	('RAS gene', 'Gene', (0, 8))	('alterations', 'Var', (9, 20))	('found', 'Reg', (26, 31))	('KRAS', 'Gene', (88, 92))	('NRAS', 'Gene', '4893', (77, 81))	('KRAS', 'Gene', '3845', (88, 92))
56013	28380455	Sanger sequencing was performed to validate the identified KRAS mutations (Supplementary Figure 3).	('KRAS', 'Gene', '3845', (59, 63))	('KRAS', 'Gene', (59, 63))	('mutations', 'Var', (64, 73))
56014	28380455	Six samples (8.4%) harbored BRAF mutations, 5 of which were activating V600 mutations (4 V600E and 1 V600K) and 1 N188S mutation (Supplementary Table 2).	('activating', 'PosReg', (60, 70))	('BRAF', 'Gene', '673', (28, 32))	('V600K', 'Var', (101, 106))	('N188S', 'Mutation', 'rs770678769', (114, 119))	('V600', 'Gene', (71, 75))	('V600K', 'Mutation', 'rs121913227', (101, 106))	('V600E', 'Mutation', 'rs113488022', (89, 94))	('BRAF', 'Gene', (28, 32))	('V600E', 'Var', (89, 94))
56015	28380455	The mutation pattern on protein level for the identified NRAS, KRAS and NF1 mutations are shown in Figure 2.	('NF1', 'Gene', (72, 75))	('KRAS', 'Gene', '3845', (63, 67))	('mutations', 'Var', (76, 85))	('NF1', 'Gene', '4763', (72, 75))	('NRAS', 'Gene', (57, 61))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('NRAS', 'Gene', '4893', (57, 61))	('KRAS', 'Gene', (63, 67))
56016	28380455	Another 4 samples carried known activating TERT-promoter mutations.	('mutations', 'Var', (57, 66))	('TERT', 'Gene', (43, 47))	('TERT', 'Gene', '7015', (43, 47))
56017	28380455	One GNA11 S267F mutation and 1 GNAQ R183Q mutation were identified.	('GNAQ', 'Gene', (31, 35))	('S267F', 'Mutation', 'rs765491785', (10, 15))	('GNAQ', 'Gene', '2776', (31, 35))	('GNA11', 'Gene', (4, 9))	('R183Q', 'Mutation', 'rs397514698', (36, 41))	('GNA11', 'Gene', '2767', (4, 9))	('S267F', 'Var', (10, 15))
56018	28380455	Three samples harboring KRAS mutations also had concurrent NF1 mutations, 2 of which were clearly functionally inactivating.	('mutations', 'Var', (63, 72))	('KRAS', 'Gene', '3845', (24, 28))	('mutations', 'Var', (29, 38))	('NF1', 'Gene', (59, 62))	('NF1', 'Gene', '4763', (59, 62))	('KRAS', 'Gene', (24, 28))
56019	28380455	Additionally, 5 TP53, 7 SF3B1, 4 MITF and 3 PTEN mutations were identified.	('MITF', 'Gene', (33, 37))	('mutations', 'Var', (49, 58))	('MITF', 'Gene', '4286', (33, 37))	('SF3B1', 'Gene', (24, 29))	('PTEN', 'Gene', (44, 48))	('TP53', 'Gene', '7157', (16, 20))	('PTEN', 'Gene', '5728', (44, 48))	('SF3B1', 'Gene', '23451', (24, 29))	('TP53', 'Gene', (16, 20))
56020	28380455	Other less frequent mutations were identified in various genes including SMARC, BAP1, TERT, WT1, PIK3CA, MAP2K2, CDK4, CTNNB1, RAC1, ARID2 and ARID1A.	('WT1', 'Gene', (92, 95))	('BAP1', 'Gene', '8314', (80, 84))	('TERT', 'Gene', (86, 90))	('TERT', 'Gene', '7015', (86, 90))	('WT1', 'Gene', '7490', (92, 95))	('PIK3CA', 'Gene', '5290', (97, 103))	('ARID2', 'Gene', '196528', (133, 138))	('CDK4', 'Gene', (113, 117))	('MAP2K2', 'Gene', '5605', (105, 111))	('BAP1', 'Gene', (80, 84))	('CTNNB1', 'Gene', '1499', (119, 125))	('RAC1', 'Gene', (127, 131))	('CDK', 'molecular_function', 'GO:0004693', ('113', '116'))	('CDK4', 'Gene', '1019', (113, 117))	('SMARC', 'Gene', (73, 78))	('RAC1', 'Gene', '5879', (127, 131))	('ARID1A', 'Gene', (143, 149))	('ARID2', 'Gene', (133, 138))	('MAP2K', 'molecular_function', 'GO:0004708', ('105', '110'))	('PIK3CA', 'Gene', (97, 103))	('mutations', 'Var', (20, 29))	('CTNNB1', 'Gene', (119, 125))	('ARID1A', 'Gene', '8289', (143, 149))	('MAP2K2', 'Gene', (105, 111))
56021	28380455	We performed a statistical analysis to assess possible associations of clinical parameters such as gender, location of the primary tumor and sample type (primary, metastasis or recurrence) with the NF1, RAS and RAF mutational status.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('metastasis', 'Disease', 'MESH:D009362', (163, 173))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('NF1', 'Gene', (198, 201))	('RAS', 'Protein', (203, 206))	('mutational', 'Var', (215, 225))	('metastasis', 'Disease', (163, 173))	('RAF', 'Gene', (211, 214))	('tumor', 'Disease', (131, 136))	('NF1', 'Gene', '4763', (198, 201))	('RAF', 'Gene', '22882', (211, 214))
56022	28380455	In this study, 71 mucosal melanoma samples were screened for mutations in known recurrently mutated genes in cutaneous and uveal melanoma.	('mucosal melanoma', 'Disease', (18, 34))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('mutations', 'Var', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('uveal melanoma', 'Disease', 'MESH:C536494', (123, 137))	('mucosal melanoma', 'Disease', 'MESH:D008545', (18, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (123, 137))	('uveal melanoma', 'Disease', (123, 137))
56023	28380455	The most frequent mutations were identified in the NF1 gene and RAS gene family members, indicating that mucosal melanomas have a genetic mutation profile which is different from that of cutaneous or uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (200, 215))	('mucosal melanomas', 'Disease', 'MESH:D008545', (105, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (200, 214))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('uveal melanomas', 'Phenotype', 'HP:0007716', (200, 215))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('NF1', 'Gene', (51, 54))	('uveal melanomas', 'Disease', (200, 215))	('mucosal melanomas', 'Disease', (105, 122))	('NF1', 'Gene', '4763', (51, 54))	('melanomas', 'Phenotype', 'HP:0002861', (206, 215))	('mutations', 'Var', (18, 27))
56024	28380455	Our study identified an unexpectedly high number of NF1 mutations.	('NF1', 'Gene', (52, 55))	('mutations', 'Var', (56, 65))	('NF1', 'Gene', '4763', (52, 55))
56025	28380455	In 13 (18.3,%) out of 71 samples, NF1 mutations were identified.	('mutations', 'Var', (38, 47))	('NF1', 'Gene', '4763', (34, 37))	('NF1', 'Gene', (34, 37))
56026	28380455	To our knowledge, there is no previous data demonstrating that mucosal melanomas express such a high frequency of NF1 mutations.	('NF1', 'Gene', '4763', (114, 117))	('mutations', 'Var', (118, 127))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('mucosal melanomas', 'Disease', (63, 80))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('mucosal melanomas', 'Disease', 'MESH:D008545', (63, 80))	('NF1', 'Gene', (114, 117))
56027	28380455	recently conducted a targeted sequencing analysis on 15 anorectal melanomas and identified that 3 of these tumors harbored an NF1 mutation.	('melanomas', 'Disease', 'MESH:D008545', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('anorectal', 'Disease', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('mutation', 'Var', (130, 138))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('harbored', 'Reg', (114, 122))	('melanomas', 'Disease', (66, 75))	('NF1', 'Gene', (126, 129))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('NF1', 'Gene', '4763', (126, 129))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))
56029	28380455	In cutaneous melanomas, more than half of the mutations reported are loss-of-function (LoF) events.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (3, 22))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (3, 22))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('mutations', 'Var', (46, 55))	('cutaneous melanomas', 'Disease', (3, 22))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('loss-of-function', 'NegReg', (69, 85))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))
56030	28380455	In the mucosal melanomas studied here, 9 out of 13 cases carried NF1 LoF mutations (69.2%).	('LoF', 'NegReg', (69, 72))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('mucosal melanomas', 'Disease', (7, 24))	('NF1', 'Gene', '4763', (65, 68))	('NF1', 'Gene', (65, 68))	('mucosal melanomas', 'Disease', 'MESH:D008545', (7, 24))	('mutations', 'Var', (73, 82))
56032	28380455	As such, LoF mutations in NF1 are an important genetic mechanism for constitutive MAPK pathway activation.	('LoF', 'NegReg', (9, 12))	('NF1', 'Gene', (26, 29))	('activation', 'PosReg', (95, 105))	('NF1', 'Gene', '4763', (26, 29))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))	('mutations', 'Var', (13, 22))
56033	28380455	A relevant role for NF1 mutations in cutaneous melanomas lacking conventional (i.e.	('cutaneous melanomas', 'Disease', (37, 56))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (37, 56))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (37, 56))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (37, 55))	('NF1', 'Gene', (20, 23))	('mutations', 'Var', (24, 33))	('NF1', 'Gene', '4763', (20, 23))
56035	28380455	demonstrated that desmoplastic melanomas frequently harbor NF1 mutations.	('mutations', 'Var', (63, 72))	('desmoplastic melanomas', 'Disease', (18, 40))	('desmoplastic melanomas', 'Disease', 'MESH:D008545', (18, 40))	('NF1', 'Gene', (59, 62))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('NF1', 'Gene', '4763', (59, 62))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))
56036	28380455	Desmoplastic melanomas are typically associated with high UV-exposure and high mutational loads.	('Desmoplastic melanomas', 'Disease', (0, 22))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('Desmoplastic melanomas', 'Disease', 'MESH:D008545', (0, 22))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('associated', 'Reg', (37, 47))	('mutational loads', 'Var', (79, 95))
56037	28380455	described NF1 mutations in association with mutations in RASopathy genes (e.g.	('RASopathy', 'Disease', (57, 66))	('mutations', 'Var', (44, 53))	('NF1', 'Gene', '4763', (10, 13))	('RASopathy', 'Disease', 'None', (57, 66))	('NF1', 'Gene', (10, 13))	('association', 'Reg', (27, 38))	('mutations', 'Var', (14, 23))
56040	28380455	The association of UV-exposure with NF1 mutations observed in cutaneous melanoma is not to be expected in mucosal melanoma.	('cutaneous melanoma', 'Disease', (62, 80))	('NF1', 'Gene', (36, 39))	('mucosal melanoma', 'Disease', (106, 122))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (62, 80))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (62, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('NF1', 'Gene', '4763', (36, 39))	('mucosal melanoma', 'Disease', 'MESH:D008545', (106, 122))	('mutations', 'Var', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
56041	28380455	Although mutational mechanisms may differ, these studies and our data support NF1 mutations being highly relevant in melanoma subgroups that rarely harbor BRAF or NRAS mutations.	('BRAF', 'Gene', (155, 159))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('NRAS', 'Gene', (163, 167))	('NRAS', 'Gene', '4893', (163, 167))	('NF1', 'Gene', (78, 81))	('mutations', 'Var', (82, 91))	('NF1', 'Gene', '4763', (78, 81))	('BRAF', 'Gene', '673', (155, 159))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
56042	28380455	Twelve out of 71 (16.9%) mucosal melanomas analyzed harbored RAS mutations, 8 in the NRAS and 4 in the KRAS gene.	('KRAS', 'Gene', (103, 107))	('KRAS', 'Gene', '3845', (103, 107))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('mucosal melanomas', 'Disease', (25, 42))	('NRAS', 'Gene', (85, 89))	('harbored', 'Reg', (52, 60))	('NRAS', 'Gene', '4893', (85, 89))	('mucosal melanomas', 'Disease', 'MESH:D008545', (25, 42))	('RAS', 'Gene', (61, 64))	('mutations', 'Var', (65, 74))
56044	28380455	The frequency of NRAS mutations detected in our study with 11.2% is comparable.	('mutations', 'Var', (22, 31))	('NRAS', 'Gene', '4893', (17, 21))	('NRAS', 'Gene', (17, 21))
56045	28380455	KRAS mutations have not been assessed in most previous studies of mucosal melanoma, however, accounted for one third of the mutations in RAS genes observed in our cohort.	('mutations', 'Var', (124, 133))	('mucosal melanoma', 'Disease', (66, 82))	('RAS genes', 'Gene', (137, 146))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('mucosal melanoma', 'Disease', 'MESH:D008545', (66, 82))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
56047	28380455	Of the 6 mutations (8.4%) identified, 5 were well known V600 activating mutations, consisting of 4 V600E and 1 V600K mutation.	('V600K', 'Var', (111, 116))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('V600K', 'Mutation', 'rs121913227', (111, 116))	('V600', 'Gene', (56, 60))	('V600E', 'Var', (99, 104))
56049	28380455	These findings are in accordance with reports stating that activating BRAF mutations in mucosal melanomas are rare with a frequency between 5 and 17%.	('mucosal melanomas', 'Disease', (88, 105))	('mucosal melanomas', 'Disease', 'MESH:D008545', (88, 105))	('mutations', 'Var', (75, 84))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('BRAF', 'Gene', '673', (70, 74))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('BRAF', 'Gene', (70, 74))
56052	28380455	Genetic alterations of KIT, including mutations and copy number increases, have been reported to occur in up to 39% of mucosal melanomas.	('mucosal melanomas', 'Disease', (119, 136))	('copy number increases', 'Var', (52, 73))	('occur', 'Reg', (97, 102))	('KIT', 'Gene', (23, 26))	('mucosal melanomas', 'Disease', 'MESH:D008545', (119, 136))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('mutations', 'Var', (38, 47))	('KIT', 'molecular_function', 'GO:0005020', ('23', '26'))
56053	28380455	In our study, 5 out of 71 (7.0%) samples had a KIT mutation; 2 mutations in tumors of the head and neck region and 2 in vulvar melanomas.	('vulvar melanomas', 'Phenotype', 'HP:0030418', (120, 136))	('KIT', 'molecular_function', 'GO:0005020', ('47', '50'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('vulvar melanomas', 'Disease', (120, 136))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('vulvar melanomas', 'Disease', 'MESH:D008545', (120, 136))	('KIT', 'Gene', (47, 50))	('mutation', 'Var', (51, 59))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('neck', 'cellular_component', 'GO:0044326', ('99', '103'))
56054	28380455	reported KIT mutations in 17% (n=12) of primary mucosal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mucosal melanomas', 'Disease', (48, 65))	('KIT', 'molecular_function', 'GO:0005020', ('9', '12'))	('mucosal melanomas', 'Disease', 'MESH:D008545', (48, 65))	('mutations', 'Var', (13, 22))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
56055	28380455	They found that 35% (8 out of 23) of vulvar melanomas harbored KIT mutations.	('vulvar melanomas', 'Phenotype', 'HP:0030418', (37, 53))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('vulvar melanomas', 'Disease', (37, 53))	('vulvar melanomas', 'Disease', 'MESH:D008545', (37, 53))	('mutations', 'Var', (67, 76))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('KIT', 'molecular_function', 'GO:0005020', ('63', '66'))	('harbored', 'Reg', (54, 62))	('KIT', 'Gene', (63, 66))
56057	28380455	Generally, our findings support existing literature stating that KIT mutations are more frequent in melanomas of the genital area followed by melanomas of the head and neck and the anorectal area.	('mutations', 'Var', (69, 78))	('melanomas', 'Disease', 'MESH:D008545', (100, 109))	('KIT', 'Gene', (65, 68))	('melanomas', 'Disease', 'MESH:D008545', (142, 151))	('frequent', 'Reg', (88, 96))	('anorectal area', 'Phenotype', 'HP:0012732', (181, 195))	('neck', 'cellular_component', 'GO:0044326', ('168', '172'))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanomas', 'Disease', (100, 109))	('melanomas', 'Disease', (142, 151))	('KIT', 'molecular_function', 'GO:0005020', ('65', '68'))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))	('melanomas', 'Phenotype', 'HP:0002861', (142, 151))
56058	28380455	TERT promoter mutations resulting in increased transcription of the TERT gene have been identified as the most common mutation in cutaneous melanoma.	('transcription', 'biological_process', 'GO:0006351', ('47', '60'))	('transcription', 'MPA', (47, 60))	('TERT', 'Gene', (68, 72))	('TERT', 'Gene', '7015', (68, 72))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('increased', 'PosReg', (37, 46))	('cutaneous melanoma', 'Disease', (130, 148))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (130, 148))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (130, 148))	('mutations', 'Var', (14, 23))
56060	28380455	All TERT mutations were C>T mutations.	('C>T mutations', 'Var', (24, 37))	('TERT', 'Gene', '7015', (4, 8))	('TERT', 'Gene', (4, 8))
56061	28380455	As C>T alterations are classically associated with UV-exposure, the lower TERT mutation frequency may be due to the very limited UV-exposure of tumors arising in mucosal locations.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('TERT', 'Gene', '7015', (74, 78))	('C>T alterations', 'Var', (3, 18))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('TERT', 'Gene', (74, 78))
56063	28380455	Of those, only the GNAQ R183Q mutation is known to be functionally activating, resulting in increased mitogenic signaling in melanocytic tumors and rare vascular diseases such as Sturge-Weber syndrome and phakomatosis pigmentovascularis.	('Weber syndrome', 'Phenotype', 'HP:0002277', (186, 200))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('GNAQ', 'Gene', (19, 23))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (179, 200))	('phakomatosis pigmentovascularis', 'Disease', 'MESH:D020752', (205, 236))	('melanocytic tumors', 'Disease', (125, 143))	('vascular diseases', 'Disease', (153, 170))	('mitogenic signaling', 'MPA', (102, 121))	('vascular diseases', 'Disease', 'MESH:D000783', (153, 170))	('GNAQ', 'Gene', '2776', (19, 23))	('increased', 'PosReg', (92, 101))	('melanocytic tumors', 'Disease', 'MESH:D009508', (125, 143))	('signaling', 'biological_process', 'GO:0023052', ('112', '121'))	('phakomatosis pigmentovascularis', 'Disease', (205, 236))	('R183Q', 'Var', (24, 29))	('Sturge-Weber syndrome', 'Disease', (179, 200))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('R183Q', 'Mutation', 'rs397514698', (24, 29))
56065	28380455	While GNAQ and GNA11 mutations were recently reported to occur in 9.5% of mucosal melanomas, our study suggests these mutations are less frequent in this tumor entity.	('GNA11', 'Gene', (15, 20))	('tumor', 'Disease', (154, 159))	('mucosal melanomas', 'Disease', 'MESH:D008545', (74, 91))	('GNAQ', 'Gene', '2776', (6, 10))	('GNA11', 'Gene', '2767', (15, 20))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('GNAQ', 'Gene', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mucosal melanomas', 'Disease', (74, 91))	('mutations', 'Var', (21, 30))
56066	28380455	In out cohort, 31 samples presented mutations in the MAPK pathway (some of them harboring more than one mutation): 13 NF1, 12 RAS, 6 RAF, 5 KIT, 1 GNAQ and 1 GNA11 mutation.	('MAPK', 'molecular_function', 'GO:0004707', ('53', '57'))	('mutations', 'Var', (36, 45))	('GNA11', 'Gene', (158, 163))	('NF1, 12 RAS, 6 RAF, 5 KIT, 1 GNAQ and 1', 'Gene', '4763', (118, 157))	('MAPK pathway', 'Pathway', (53, 65))	('KIT', 'molecular_function', 'GO:0005020', ('140', '143'))	('GNA11', 'Gene', '2767', (158, 163))
56067	28380455	In 23 of those samples mutations resulting in MAPK activation were found suggesting that this is a critical event in the pathogenesis of mucosal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('MAPK activation', 'biological_process', 'GO:0000187', ('46', '61'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (137, 153))	('mutations', 'Var', (23, 32))	('MAPK', 'molecular_function', 'GO:0004707', ('46', '50'))	('pathogenesis', 'biological_process', 'GO:0009405', ('121', '133'))	('MAPK', 'Gene', (46, 50))	('activation', 'PosReg', (51, 61))	('mucosal melanoma', 'Disease', (137, 153))
56071	28380455	Our results underline that mucosal melanomas are genetically distinct from cutaneous and uveal melanomas with frequent inactivating mutations in NF1 and activating mutations in RAS genes.	('NF1', 'Gene', '4763', (145, 148))	('melanomas', 'Phenotype', 'HP:0002861', (35, 44))	('uveal melanomas', 'Disease', (89, 104))	('uveal melanomas', 'Phenotype', 'HP:0007716', (89, 104))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('mucosal melanomas', 'Disease', (27, 44))	('RAS', 'Gene', (177, 180))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('uveal melanomas', 'Disease', 'MESH:C536494', (89, 104))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('uveal melanoma', 'Phenotype', 'HP:0007716', (89, 103))	('activating', 'PosReg', (153, 163))	('mucosal melanomas', 'Disease', 'MESH:D008545', (27, 44))	('inactivating mutations', 'Var', (119, 141))	('NF1', 'Gene', (145, 148))
56073	28380455	Taken into consideration that both NF1 and RAS alterations can additionally activate PI3K signaling, this pathway could be of particular significance in mucosal melanomas.	('PI3K signaling', 'Pathway', (85, 99))	('mucosal melanomas', 'Disease', 'MESH:D008545', (153, 170))	('PI3K', 'molecular_function', 'GO:0016303', ('85', '89'))	('activate', 'PosReg', (76, 84))	('PI3K signaling', 'biological_process', 'GO:0014065', ('85', '99'))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanomas', 'Phenotype', 'HP:0002861', (161, 170))	('alterations', 'Var', (47, 58))	('NF1', 'Gene', (35, 38))	('mucosal melanomas', 'Disease', (153, 170))	('NF1', 'Gene', '4763', (35, 38))
56074	28380455	It stands to reason that other, so far unidentified, mutations are present in mucosal melanomas and future whole-exome or whole-genome studies of larger tumor cohorts will be required to fully elucidate the landscape of genetic alterations involved.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('mucosal melanomas', 'Disease', (78, 95))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('mucosal melanomas', 'Disease', 'MESH:D008545', (78, 95))	('mutations', 'Var', (53, 62))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
56083	28380455	All known recurrent mutations in melanoma (incl.	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('mutations', 'Var', (20, 29))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))
56084	28380455	BRAF V600, NRAS G12, G13 and Q61 and KIT L576, K642 and N822) were repeatedly picked up by our NGS panel which showed a 100% concordance with mutations identified by Sanger sequencing, however demonstrated a higher level of sensitivity.	('Q61', 'Var', (29, 32))	('N822', 'Var', (56, 60))	('NRAS', 'Gene', '4893', (11, 15))	('KIT', 'molecular_function', 'GO:0005020', ('37', '40'))	('K642 and N822', 'Var', (47, 60))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('NRAS', 'Gene', (11, 15))	('G13', 'Var', (21, 24))
56088	28380455	The CLC generated csv files were further analyzed manually with mutations affecting the protein-coding portion of the gene considered if predicted to result in non-synonymous amino acid changes.	('CLC', 'Gene', '1178', (4, 7))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('mutations', 'Var', (64, 73))	('CLC', 'Gene', (4, 7))
56092	24755198	Melanomas were characterized according to an in-house clinical assay that identifies well-known specific recurrent mutations in five driver genes: BRAF (affecting V600), NRAS (G12, G13, and Q61), KIT (W557, V559, L576, K642, and D816), GNAQ (Q209), and GNA11 (Q209).	('NRAS', 'Gene', (170, 174))	('Q209', 'Var', (242, 246))	('GNA11', 'Gene', (253, 258))	('V600', 'Var', (163, 167))	('GNAQ', 'Gene', '2776', (236, 240))	('K642', 'Var', (219, 223))	('GNAQ', 'Gene', (236, 240))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('GNA11', 'Gene', '2767', (253, 258))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('NRAS', 'Gene', '4893', (170, 174))	('D816', 'Var', (229, 233))	('KIT', 'molecular_function', 'GO:0005020', ('196', '199'))	('Q61', 'Var', (190, 193))	('mutations', 'Var', (115, 124))	('L576', 'Var', (213, 217))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('Melanomas', 'Disease', (0, 9))	('V559', 'Var', (207, 211))
56093	24755198	Tumors with none of these mutations are termed "pan-negative".	('mutations', 'Var', (26, 35))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
56094	24755198	We then mined the driver mutation-positive and pan-negative melanoma NGS data for mutations in 632 cancer genes that could influence existing or emerging targeted therapies.	('melanoma NGS', 'Disease', (60, 72))	('melanoma NGS', 'Disease', 'MESH:D008545', (60, 72))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('cancer', 'Disease', (99, 105))	('influence', 'Reg', (123, 132))	('mutations', 'Var', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
56095	24755198	First, we uncovered several genes whose mutations were more likely associated with BRAF- or NRAS-driven melanomas, including TP53 and COL1A1 with BRAF, and PPP6C, KALRN, PIK3R4, TRPM6, GUCY2C, and PRKAA2 with NRAS.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanomas', 'Phenotype', 'HP:0002861', (104, 113))	('TP53', 'Gene', (125, 129))	('COL1A1', 'Gene', (134, 140))	('NRAS', 'Gene', (209, 213))	('KALRN', 'Gene', (163, 168))	('mutations', 'Var', (40, 49))	('KALRN', 'Gene', '8997', (163, 168))	('NRAS', 'Gene', '4893', (92, 96))	('PRKAA2', 'Gene', (197, 203))	('GUCY2C', 'Gene', (185, 191))	('PPP6C', 'Gene', '5537', (156, 161))	('PRKAA2', 'Gene', '5563', (197, 203))	('melanomas', 'Disease', 'MESH:D008545', (104, 113))	('TP53', 'Gene', '7157', (125, 129))	('PPP6C', 'Gene', (156, 161))	('BRAF-', 'Gene', '673', (83, 88))	('TRPM6', 'Gene', (178, 183))	('TRPM6', 'Gene', '140803', (178, 183))	('BRAF-', 'Gene', (83, 88))	('associated', 'Reg', (67, 77))	('melanomas', 'Disease', (104, 113))	('BRAF', 'Gene', '673', (83, 87))	('PIK3R4', 'Gene', '30849', (170, 176))	('BRAF', 'Gene', '673', (146, 150))	('NRAS', 'Gene', '4893', (209, 213))	('BRAF', 'Gene', (83, 87))	('BRAF', 'Gene', (146, 150))	('GUCY2C', 'Gene', '2984', (185, 191))	('NRAS', 'Gene', (92, 96))	('COL1A1', 'Gene', '1277', (134, 140))	('PIK3R4', 'Gene', (170, 176))
56096	24755198	Second, we found that the 69 "pan-negative" melanoma genomes harbored alternate infrequent mutations in the 5 known driver genes along with many mutations in genes encoding guanine nucleotide binding protein alpha-subunits.	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('mutations', 'Var', (91, 100))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('179', '197'))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))
56104	24755198	More recently, driver mutations in genes encoding signaling proteins that activate the mitogen-activated protein kinase (MAPK) pathway have been implicated in the pathogenesis of a majority of melanomas.	('implicated', 'Reg', (145, 155))	('melanomas', 'Disease', (193, 202))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('MAPK', 'Gene', '5594', (121, 125))	('melanomas', 'Disease', 'MESH:D008545', (193, 202))	('melanomas', 'Phenotype', 'HP:0002861', (193, 202))	('MAPK', 'molecular_function', 'GO:0004707', ('121', '125'))	('pathogenesis', 'biological_process', 'GO:0009405', ('163', '175'))	('MAPK', 'Gene', (121, 125))	('mutations', 'Var', (22, 31))	('activate', 'PosReg', (74, 82))
56105	24755198	Accordingly, we recently developed a melanoma-specific multiplex mutational profiling assay to detect 43 recurrent mutations in 6 genes relevant to targeted therapy for the disease.	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('mutations', 'Var', (115, 124))	('melanoma', 'Disease', (37, 45))
56106	24755198	This SNaPshot assay, used routinely in our clinic, detects mutations in BRAF (at position V600), NRAS (G12/13, Q61), KIT (W557, V559, L576, K642, D816), GNAQ (Q209) and GNA11 (Q209) in tumors.	('KIT', 'Gene', (117, 120))	('tumors', 'Disease', (185, 191))	('D816', 'Var', (146, 150))	('K642', 'Var', (140, 144))	('BRAF', 'Gene', '673', (72, 76))	('NRAS', 'Gene', (97, 101))	('GNA11', 'Gene', '2767', (169, 174))	('BRAF', 'Gene', (72, 76))	('W557', 'Var', (122, 126))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('GNAQ', 'Gene', '2776', (153, 157))	('mutations', 'Var', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('GNAQ', 'Gene', (153, 157))	('L576', 'Var', (134, 138))	('GNA11', 'Gene', (169, 174))	('NRAS', 'Gene', '4893', (97, 101))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('V559', 'Var', (128, 132))	('KIT', 'molecular_function', 'GO:0005020', ('117', '120'))
56107	24755198	We chose these specific mutations because 1) they occur in melanoma at a frequency of greater than 1% and 2) they have relevance to emerging or targeted therapies such as the BRAF inhibitors, vemurafenib and dabrafenib, the MEK inhibitor, trametinib, and the KIT inhibitor, imatinib.	('dabrafenib', 'Chemical', 'MESH:C561627', (208, 218))	('vemurafenib', 'Chemical', 'MESH:D000077484', (192, 203))	('trametinib', 'Chemical', 'MESH:C560077', (239, 249))	('MEK', 'Gene', (224, 227))	('KIT', 'molecular_function', 'GO:0005020', ('259', '262'))	('MEK', 'Gene', '5609', (224, 227))	('BRAF', 'Gene', (175, 179))	('BRAF', 'Gene', '673', (175, 179))	('imatinib', 'Chemical', 'MESH:D000068877', (274, 282))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('mutations', 'Var', (24, 33))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
56108	24755198	Using this assay, we have found that one-third of tumors lack any of these mutations and are herein referred to as "pan-negative".	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('mutations', 'Var', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('lack', 'NegReg', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
56110	24755198	For example, we recently found that ~8% of "pan-negative" cases harbor non-V600 exon 15 BRAF mutations and 4-8% contain activating BRAF fusions, both of which may be sensitive to MEK inhibition.	('BRAF', 'Gene', '673', (131, 135))	('mutations', 'Var', (93, 102))	('BRAF', 'Gene', (131, 135))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('MEK', 'Gene', (179, 182))	('fusions', 'Var', (136, 143))	('MEK', 'Gene', '5609', (179, 182))	('activating', 'PosReg', (120, 130))
56114	24755198	BRAF and NRAS) and those without known recurrent BRAF, NRAS, KIT, GNAQ, or GNA11 mutations.	('NRAS', 'Gene', '4893', (55, 59))	('GNAQ', 'Gene', '2776', (66, 70))	('NRAS', 'Gene', (9, 13))	('GNA11', 'Gene', (75, 80))	('GNA11', 'Gene', '2767', (75, 80))	('BRAF', 'Gene', '673', (0, 4))	('NRAS', 'Gene', '4893', (9, 13))	('KIT', 'molecular_function', 'GO:0005020', ('61', '64'))	('KIT', 'Gene', (61, 64))	('BRAF', 'Gene', '673', (49, 53))	('mutations', 'Var', (81, 90))	('GNAQ', 'Gene', (66, 70))	('BRAF', 'Gene', (0, 4))	('NRAS', 'Gene', (55, 59))	('BRAF', 'Gene', (49, 53))
56125	24755198	The mutation rate is high in melanoma tumor genomes compared to other types of tumor genomes.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('melanoma tumor', 'Disease', (29, 43))	('tumor', 'Disease', (79, 84))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma tumor', 'Disease', 'MESH:D008545', (29, 43))	('mutation', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('high', 'Reg', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
56127	24755198	In total, we analyzed NGS data from 241 tumor samples with mutation information, along with their matched normal samples (Figure 1, Table 1).	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('mutation', 'Var', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (40, 45))
56128	24755198	For the current analysis, we primarily focused on somatic single nucleotide variants (SNVs) because they constitute the largest fraction of oncogenic drivers identified in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('single nucleotide variants', 'Var', (58, 84))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanoma', 'Disease', (172, 180))
56129	24755198	For these SNVs, we collected all non-silent parts, including missense, nonsense, nonstop, and splice site mutations, as well as accompanying information such as tumor name, tumor type, and gene name.	('missense', 'Var', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('nonsense', 'Var', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))
56131	24755198	As a result, sifting through these mutations to pin down the few driver mutations present in melanoma is a challenge; therefore we generated a list of candidate genes to further analyze in the published data sets.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('mutations', 'Var', (35, 44))
56133	24755198	Since mutations in protein kinase genes have been frequently reported in cancers, and they are often the targets in the design of antitumor therapies, we also included the 612 genes from Agilent's SureSelect Human Kinome targeted NGS kit (http://www.genomics.agilent.com/en/home.jsp) in our candidate gene list.	('cancers', 'Disease', (73, 80))	('protein kinase', 'Enzyme', (19, 33))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Human', 'Species', '9606', (208, 213))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('reported', 'Reg', (61, 69))	('tumor', 'Disease', (134, 139))	('mutations', 'Var', (6, 15))
56135	24755198	Excluding CTNNB1 (CTNNB1 mutations commonly co-occur with mutations in the other 5 genes), we analyzed the melanoma NGS data against these drivers to determine mutations associated with these 5 driver genes, as well as to uncover potential novel drivers in "pan-negative" samples [i.e., samples which lack all the known, recurrent mutations in BRAF (V600), NRAS (G12, G13, and Q61), KIT (W557, V559, L576, K642, D816), GNAQ (Q209), and GNA11 (Q209)].	('BRAF', 'Gene', '673', (344, 348))	('BRAF', 'Gene', (344, 348))	('GNAQ', 'Gene', '2776', (419, 423))	('Q61', 'Var', (377, 380))	('L576', 'Var', (400, 404))	('GNA11', 'Gene', (436, 441))	('GNAQ', 'Gene', (419, 423))	('melanoma NGS', 'Disease', (107, 119))	('melanoma NGS', 'Disease', 'MESH:D008545', (107, 119))	('CTNNB1', 'Gene', '1499', (10, 16))	('CTNNB1', 'Gene', '1499', (18, 24))	('NRAS', 'Gene', (357, 361))	('K642', 'Var', (406, 410))	('V559', 'Var', (394, 398))	('CTNNB1', 'Gene', (10, 16))	('KIT', 'Gene', (383, 386))	('CTNNB1', 'Gene', (18, 24))	('GNA11', 'Gene', '2767', (436, 441))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('KIT', 'molecular_function', 'GO:0005020', ('381', '384'))	('W557', 'Var', (388, 392))	('D816', 'Var', (412, 416))	('NRAS', 'Gene', '4893', (357, 361))
56136	24755198	To classify melanoma genomes according to our clinical SNaPshot-based assay, we queried WGS and WES data from 241 melanoma samples for known driver mutations in BRAF (V600), NRAS (G12/13, Q61), KIT (W557, V559, L576, K642, and D816), GNAQ (Q209) and GNA11 (Q209).	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('GNA11', 'Gene', '2767', (250, 255))	('D816', 'Var', (227, 231))	('V559', 'Var', (205, 209))	('NRAS', 'Gene', '4893', (174, 178))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('GNAQ', 'Gene', '2776', (234, 238))	('KIT', 'molecular_function', 'GO:0005020', ('194', '197'))	('KIT', 'Gene', (194, 197))	('GNAQ', 'Gene', (234, 238))	('K642', 'Var', (217, 221))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', (12, 20))	('GNA11', 'Gene', (250, 255))	('NRAS', 'Gene', (174, 178))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))	('Q61', 'Var', (188, 191))	('BRAF', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (161, 165))	('L576', 'Var', (211, 215))
56141	24755198	Forty-seven samples (19.5%) had NRAS mutations, including Q61 mutations [44/47 (93.6%): Q61R (22/47, 46.8%), Q61K (12/47, 25.5%), Q61L (6/47, 12.8%), and Q61H (4/47, 8.5%)] and G12 mutations [3/47 (6.4%): G12V (2/47, 4.3%) and G12D (1/47, 2.1%)].	('Q61K', 'Var', (109, 113))	('Q61H', 'Var', (154, 158))	('Q61R', 'Var', (88, 92))	('NRAS', 'Gene', (32, 36))	('G12D', 'Mutation', 'rs121913237', (227, 231))	('Q61K', 'Mutation', 'rs121913254', (109, 113))	('G12V', 'Mutation', 'rs121913237', (205, 209))	('Q61R', 'SUBSTITUTION', 'None', (88, 92))	('NRAS', 'Gene', '4893', (32, 36))	('Q61L', 'Mutation', 'rs11554290', (130, 134))	('G12 mutations', 'Var', (177, 190))	('Q61L', 'Var', (130, 134))	('Q61H', 'Mutation', 'rs121913255', (154, 158))	('Q61 mutations', 'Var', (58, 71))	('G12D', 'Var', (227, 231))	('G12V', 'Var', (205, 209))
56142	24755198	Three uveal melanoma samples (3/241, 1.2%) had GNA11 Q209L mutations.	('uveal melanoma', 'Disease', (6, 20))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('GNA11', 'Gene', '2767', (47, 52))	('GNA11', 'Gene', (47, 52))	('Q209L', 'Mutation', 'rs1057519742', (53, 58))	('Q209L mutations', 'Var', (53, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (6, 20))	('uveal melanoma', 'Disease', 'MESH:C536494', (6, 20))
56143	24755198	Only one tumor (1/241, 0.4%) had a KIT mutation (V559A).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('KIT', 'molecular_function', 'GO:0005020', ('35', '38'))	('V559A', 'Var', (49, 54))	('V559A', 'Mutation', 'rs121913517', (49, 54))
56146	24755198	We next sought to identify mutations that co-occurred with mutant BRAF in this dataset.	('mutant', 'Var', (59, 65))	('BRAF', 'Gene', (66, 70))	('BRAF', 'Gene', '673', (66, 70))
56148	24755198	Genes were ranked according to their p-values for different frequencies between samples with and without BRAF mutations.	('BRAF', 'Gene', (105, 109))	('BRAF', 'Gene', '673', (105, 109))	('mutations', 'Var', (110, 119))
56149	24755198	Mutations in the gene TTN were the most significantly associated with BRAF mutation, occurring in 64.6% of samples (p = 0.009).	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (54, 64))	('BRAF', 'Gene', '673', (70, 74))	('TTN', 'Gene', (22, 25))	('BRAF', 'Gene', (70, 74))
56151	24755198	TTN mutations are often seen in cancer NGS studies and are likely passenger mutations due to gene length bias.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('TTN', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('mutations', 'Var', (4, 13))
56153	24755198	Although TP53 is a highly recognized tumor suppressor gene harboring numerous mutations, it is rarely mutated in melanoma relative to other cancers.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('mutations', 'Var', (78, 87))	('melanoma', 'Disease', (113, 121))	('TP53', 'Gene', '7157', (9, 13))	('tumor', 'Disease', (37, 42))	('TP53', 'Gene', (9, 13))	('cancers', 'Disease', (140, 147))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('37', '53'))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('37', '53'))
56154	24755198	The association between BRAF and TP53 mutations supports a previous report based on Sanger resequencing of selected genes in melanoma cell lines.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('TP53', 'Gene', '7157', (33, 37))	('BRAF', 'Gene', (24, 28))	('TP53', 'Gene', (33, 37))	('BRAF', 'Gene', '673', (24, 28))	('mutations', 'Var', (38, 47))
56155	24755198	We used MutationAssessor to predict the functional relevance of these TP53 mutations to melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('TP53', 'Gene', '7157', (70, 74))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('TP53', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))
56156	24755198	All missense mutations in TP53 were predicted to have a medium impact on the protein function.	('TP53', 'Gene', (26, 30))	('protein function', 'MPA', (77, 93))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('missense mutations', 'Var', (4, 22))	('impact', 'Reg', (63, 69))	('TP53', 'Gene', '7157', (26, 30))
56158	24755198	BRAF mutant samples harbored more nonsense mutations than BRAF wild-type samples (5.4% vs. 2.7%).	('BRAF', 'Gene', '673', (0, 4))	('nonsense mutations', 'Var', (34, 52))	('mutant', 'Var', (5, 11))	('BRAF', 'Gene', '673', (58, 62))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', (58, 62))
56161	24755198	Table 2 shows the mutated genes associated with NRAS mutations (occurred in at least 10% of NRAS-mutated melanomas and p-value < 0.05, Fisher's exact test).	('melanomas', 'Disease', (105, 114))	('NRAS', 'Gene', '4893', (48, 52))	('NRAS', 'Gene', (92, 96))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('mutations', 'Var', (53, 62))	('melanomas', 'Phenotype', 'HP:0002861', (105, 114))	('melanomas', 'Disease', 'MESH:D008545', (105, 114))	('NRAS', 'Gene', '4893', (92, 96))	('NRAS', 'Gene', (48, 52))
56162	24755198	Aside from TTN, this list of mutated genes was surprisingly very different from the list associated with BRAF mutant tumors.	('BRAF', 'Gene', '673', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('BRAF', 'Gene', (105, 109))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('mutated', 'Var', (29, 36))
56165	24755198	The genes encoding the Rho-GEF kinase, KALRN, and the phosphoinositide-3 kinase, PIK3R4, which ranked third and fourth in this association list based on p-values, were mutated in 27.5% and 11.8% of NRAS-mutated melanomas, respectively.	('mutated', 'Var', (168, 175))	('PIK3R4', 'Gene', (81, 87))	('KALRN', 'Gene', (39, 44))	('NRAS', 'Gene', (198, 202))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanomas', 'Phenotype', 'HP:0002861', (211, 220))	('melanomas', 'Disease', 'MESH:D008545', (211, 220))	('NRAS', 'Gene', '4893', (198, 202))	('GEF', 'molecular_function', 'GO:0005085', ('27', '30'))	('PIK3R4', 'Gene', '30849', (81, 87))	('KALRN', 'Gene', '8997', (39, 44))	('melanomas', 'Disease', (211, 220))
56168	24755198	The enterotoxin receptor, GUCY2C, which is an emerging prognostic molecular biomarker in colorectal cancer, was also found to co-occur with NRAS mutations (13.7%, p-value = 0.021) in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('melanoma', 'Disease', (183, 191))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('mutations', 'Var', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Disease', (89, 106))	('GUCY2C', 'Gene', (26, 32))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('NRAS', 'Gene', (140, 144))	('GUCY2C', 'Gene', '2984', (26, 32))	('NRAS', 'Gene', '4893', (140, 144))
56169	24755198	Finally, we observed that 13.7% of all NRAS mutations identified were coincident with mutations in PRKAA2 (p = 0.043), which encodes the catalytic subunit of AMP-activated protein kinase (AMPK).	('mutations', 'Var', (86, 95))	('AMPK', 'Gene', '5563', (188, 192))	('PRKAA2', 'Gene', (99, 105))	('AMP-activated protein kinase', 'Gene', (158, 186))	('PRKAA2', 'Gene', '5563', (99, 105))	('AMPK', 'molecular_function', 'GO:0047322', ('188', '192'))	('AMPK', 'Gene', (188, 192))	('AMPK', 'molecular_function', 'GO:0004691', ('188', '192'))	('NRAS', 'Gene', (39, 43))	('AMPK', 'molecular_function', 'GO:0050405', ('188', '192'))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('mutations', 'Var', (44, 53))	('NRAS', 'Gene', '4893', (39, 43))	('AMP-activated protein kinase', 'Gene', '5563', (158, 186))
56170	24755198	We further assessed the functional impact of the 8 PRKAA2 missense mutations that were found to be associated with the NRAS mutations.	('NRAS', 'Gene', (119, 123))	('missense mutations', 'Var', (58, 76))	('NRAS', 'Gene', '4893', (119, 123))	('PRKAA2', 'Gene', (51, 57))	('PRKAA2', 'Gene', '5563', (51, 57))	('associated', 'Reg', (99, 109))
56171	24755198	Four missense mutations in PRKAA2 were predicted to have a medium impact on the protein function by MutationAssessor.	('missense mutations', 'Var', (5, 23))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('PRKAA2', 'Gene', (27, 33))	('PRKAA2', 'Gene', '5563', (27, 33))	('impact', 'Reg', (66, 72))	('protein function', 'MPA', (80, 96))
56173	24755198	BRAF phosphorylation by PRKAA2 could attenuate BRAF signaling and inhibit cell proliferation.	('cell proliferation', 'CPA', (74, 92))	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('PRKAA2', 'Gene', (24, 30))	('phosphorylation', 'Var', (5, 20))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('PRKAA2', 'Gene', '5563', (24, 30))	('BRAF', 'Gene', '673', (0, 4))	('inhibit', 'NegReg', (66, 73))	('BRAF', 'Gene', (0, 4))	('cell proliferation', 'biological_process', 'GO:0008283', ('74', '92'))	('attenuate', 'NegReg', (37, 46))
56176	24755198	For the above genes that were found to be significantly associated with BRAF or NRAS mutations, we manually reviewed their results in individual studies for reliability.	('NRAS', 'Gene', (80, 84))	('BRAF', 'Gene', (72, 76))	('NRAS', 'Gene', '4893', (80, 84))	('associated', 'Reg', (56, 66))	('mutations', 'Var', (85, 94))	('BRAF', 'Gene', '673', (72, 76))
56178	24755198	(89 paired tumor-normal samples), we examined the mutations that co-occurred with mutant BRAF or NRAS only in these two studies (the details are available in Supplementary Tables S3-S10).	('NRAS', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('S10', 'Gene', (182, 185))	('NRAS', 'Gene', '4893', (97, 101))	('tumor', 'Disease', (11, 16))	('S10', 'Gene', '6204', (182, 185))	('BRAF', 'Gene', '673', (89, 93))	('BRAF', 'Gene', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('mutant', 'Var', (82, 88))
56181	24755198	We explored whether the observed mutation association was due to ultraviolet (UV) induction or a specific driver mutation in genes such as BRAF and NRAS.	('mutation', 'Var', (113, 121))	('NRAS', 'Gene', (148, 152))	('BRAF', 'Gene', (139, 143))	('NRAS', 'Gene', '4893', (148, 152))	('BRAF', 'Gene', '673', (139, 143))
56186	24755198	Interestingly, almost all genes associated with NRAS mutation (except PRKAA2) in melanomas (Table 2) were consistently observed in cutaneous melanoma (Supplementary Table S12).	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('NRAS', 'Gene', '4893', (48, 52))	('mutation', 'Var', (53, 61))	('melanomas', 'Disease', (81, 90))	('S12', 'Gene', (171, 174))	('S12', 'Gene', '6268', (171, 174))	('cutaneous melanoma', 'Disease', (131, 149))	('observed', 'Reg', (119, 127))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (131, 149))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (131, 149))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanomas', 'Phenotype', 'HP:0002861', (81, 90))	('PRKAA2', 'Gene', (70, 76))	('PRKAA2', 'Gene', '5563', (70, 76))	('melanomas', 'Disease', 'MESH:D008545', (81, 90))	('NRAS', 'Gene', (48, 52))
56188	24755198	C changes to T), we further compared C>T mutation frequency in NRAS mutant samples versus NRAS wild-type samples.	('NRAS', 'Gene', '4893', (63, 67))	('NRAS', 'Gene', (90, 94))	('C>T', 'Var', (37, 40))	('NRAS', 'Gene', '4893', (90, 94))	('NRAS', 'Gene', (63, 67))	('mutant', 'Var', (68, 74))
56189	24755198	The C>T frequency in NRAS mutant samples (80.7%) was slightly larger than that in NRAS wild-type samples (78.9%).	('NRAS', 'Gene', '4893', (21, 25))	('larger', 'Reg', (62, 68))	('NRAS', 'Gene', (21, 25))	('NRAS', 'Gene', (82, 86))	('mutant', 'Var', (26, 32))	('NRAS', 'Gene', '4893', (82, 86))
56190	24755198	For the purpose of comparison, the C>T frequency in BRAF mutant samples (78.3%) was slightly smaller than that in BRAF wild-type samples (80.5%).	('BRAF', 'Gene', '673', (114, 118))	('BRAF', 'Gene', (114, 118))	('mutant', 'Var', (57, 63))	('smaller', 'NegReg', (93, 100))	('BRAF', 'Gene', '673', (52, 56))	('BRAF', 'Gene', (52, 56))
56191	24755198	Further studies are needed to determine the influence of sun exposure on the association of mutations in NRAS-mutant melanomas.	('melanomas', 'Disease', 'MESH:D008545', (117, 126))	('NRAS', 'Gene', (105, 109))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('mutations', 'Var', (92, 101))	('melanomas', 'Disease', (117, 126))	('NRAS', 'Gene', '4893', (105, 109))	('association', 'Interaction', (77, 88))	('melanomas', 'Phenotype', 'HP:0002861', (117, 126))
56192	24755198	As stated above, our clinical SNaPshot-based assay examines tumors for mutations in BRAF (V600), NRAS (G12/13, Q61), KIT (W557, V559, L576, K642, D816), GNAQ (Q209) and GNA11 (Q209).	('KIT', 'Gene', (117, 120))	('D816', 'Var', (146, 150))	('K642', 'Var', (140, 144))	('NRAS', 'Gene', (97, 101))	('GNA11', 'Gene', '2767', (169, 174))	('W557', 'Var', (122, 126))	('mutations', 'Var', (71, 80))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('GNAQ', 'Gene', '2776', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', (60, 66))	('GNAQ', 'Gene', (153, 157))	('L576', 'Var', (134, 138))	('GNA11', 'Gene', (169, 174))	('NRAS', 'Gene', '4893', (97, 101))	('V559', 'Var', (128, 132))	('KIT', 'molecular_function', 'GO:0005020', ('117', '120'))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
56194	24755198	To identify other potential mutations in these genes, we interrogated the 69 tumor/normal pairs for non-hotspot mutations in BRAF, NRAS, KIT, GNAQ, and GNA11 (Table 3, Figure 2, and Supplementary Figures S1-S4).	('GNA11', 'Gene', '2767', (152, 157))	('NRAS', 'Gene', (131, 135))	('GNAQ', 'Gene', '2776', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mutations', 'Var', (112, 121))	('NRAS', 'Gene', '4893', (131, 135))	('BRAF', 'Gene', '673', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('KIT', 'molecular_function', 'GO:0005020', ('137', '140'))	('KIT', 'Gene', (137, 140))	('GNAQ', 'Gene', (142, 146))	('tumor', 'Disease', (77, 82))	('GNA11', 'Gene', (152, 157))	('BRAF', 'Gene', (125, 129))
56195	24755198	Two samples with distinct BRAF L597 mutations were identified.	('BRAF', 'Gene', '673', (26, 30))	('BRAF', 'Gene', (26, 30))	('mutations', 'Var', (36, 45))
56196	24755198	This frequency (2/69 = 2.9%) is consistent with our previous report, in which we identified two BRAF L597 mutations in 49 SNaPshot pan-negative samples (4.1%) upon screening of BRAF exon 15.	('BRAF', 'Gene', (177, 181))	('BRAF', 'Gene', '673', (177, 181))	('BRAF', 'Gene', '673', (96, 100))	('BRAF', 'Gene', (96, 100))	('mutations', 'Var', (106, 115))
56197	24755198	Six additional non-V600 BRAF mutations were found in these 69 pan-negative melanoma samples, including K601E (2 samples), P75L (1 sample), G469R (1 sample), N581T (1 sample), G593S (1 sample), and P731S (1 sample).	('G469R', 'Var', (139, 144))	('P75L', 'Mutation', 'p.P75L', (122, 126))	('K601E', 'Var', (103, 108))	('G593S', 'Var', (175, 180))	('G593S', 'Mutation', 'p.G593S', (175, 180))	('N581T', 'Var', (157, 162))	('N581T', 'Mutation', 'rs121913370', (157, 162))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('P731S', 'Var', (197, 202))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('G469R', 'Mutation', 'rs121913357', (139, 144))	('P731S', 'Mutation', 'p.P731S', (197, 202))	('K601E', 'Mutation', 'rs121913364', (103, 108))	('P75L', 'Var', (122, 126))
56201	24755198	In addition, 3.3% (4 of 121) and 4.3% (2 of 47) of melanomas with BRAF V600 and NRAS G12/G13/Q61 mutations, respectively, harbored non-V600 BRAF mutations.	('NRAS', 'Gene', (80, 84))	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('melanomas', 'Disease', 'MESH:D008545', (51, 60))	('harbored', 'Reg', (122, 130))	('BRAF', 'Gene', '673', (140, 144))	('NRAS', 'Gene', '4893', (80, 84))	('BRAF', 'Gene', (140, 144))	('melanomas', 'Disease', (51, 60))	('BRAF', 'Gene', '673', (66, 70))	('non-V600', 'Var', (131, 139))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('BRAF', 'Gene', (66, 70))
56203	24755198	The rate of non-V600 BRAF mutations in the whole cohort is 5.4% (13 of 241).	('non-V600', 'Var', (12, 20))	('BRAF', 'Gene', (21, 25))	('BRAF', 'Gene', '673', (21, 25))
56204	24755198	Two somatic nonsynonymous mutations were identified in NRAS (Q22K and H131R), and three somatic nonsynonymous mutations were identified in KIT (L572P, K638E, and N818Y).	('Q22K', 'Mutation', 'p.Q22K', (61, 65))	('H131R', 'Mutation', 'p.H131R', (70, 75))	('N818Y', 'Var', (162, 167))	('NRAS', 'Gene', '4893', (55, 59))	('L572P', 'Mutation', 'rs121913513', (144, 149))	('L572P', 'Var', (144, 149))	('K638E', 'Mutation', 'rs121913512', (151, 156))	('H131R', 'Var', (70, 75))	('N818Y', 'Mutation', 'p.N818Y', (162, 167))	('NRAS', 'Gene', (55, 59))	('K638E', 'Var', (151, 156))	('KIT', 'molecular_function', 'GO:0005020', ('139', '142'))
56205	24755198	The NRAS mutations were found in disease from sun damaged skin, and all KIT mutations were found in melanomas from acral sites.	('melanomas', 'Disease', 'MESH:D008545', (100, 109))	('KIT', 'molecular_function', 'GO:0005020', ('72', '75'))	('mutations', 'Var', (9, 18))	('found', 'Reg', (91, 96))	('melanomas', 'Disease', (100, 109))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('NRAS', 'Gene', (4, 8))	('found', 'Reg', (24, 29))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))	('sun damaged skin', 'Phenotype', 'HP:0000992', (46, 62))	('NRAS', 'Gene', '4893', (4, 8))
56206	24755198	Additional GNAQ mutations included R183X, P185S, S211L, and A302G, of which P185S and A302G were present in a single patient.	('P185S', 'Var', (42, 47))	('A302G', 'Var', (60, 65))	('R183X', 'Var', (35, 40))	('A302G', 'Mutation', 'c.302A>G', (86, 91))	('P185S', 'Var', (76, 81))	('GNAQ', 'Gene', '2776', (11, 15))	('S211L', 'Mutation', 'p.S211L', (49, 54))	('P185S', 'Mutation', 'p.P185S', (42, 47))	('S211L', 'Var', (49, 54))	('R183X', 'Mutation', 'p.R183X', (35, 40))	('A302G', 'Var', (86, 91))	('A302G', 'Mutation', 'c.302A>G', (60, 65))	('patient', 'Species', '9606', (117, 124))	('GNAQ', 'Gene', (11, 15))	('P185S', 'Mutation', 'p.P185S', (76, 81))
56207	24755198	Interestingly, only one of these four GNAQ mutations originated from a uveal site; the other three GNAQ mutations were found in sun damaged skin.	('GNAQ', 'Gene', '2776', (38, 42))	('GNAQ', 'Gene', (38, 42))	('GNAQ', 'Gene', (99, 103))	('mutations', 'Var', (43, 52))	('sun damaged skin', 'Phenotype', 'HP:0000992', (128, 144))	('GNAQ', 'Gene', '2776', (99, 103))
56208	24755198	Only one GNA11 mutation (R183C) was identified in a uveal melanoma.	('GNA11', 'Gene', (9, 14))	('uveal melanoma', 'Disease', (52, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (52, 66))	('uveal melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('R183C', 'Var', (25, 30))	('R183C', 'Mutation', 'p.R183C', (25, 30))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('GNA11', 'Gene', '2767', (9, 14))
56210	24755198	Recently, activating mutations in GNAS (another GNA) in breast cancer, colorectal cancer, and ovarian cancer were reported.	('ovarian cancer', 'Disease', (94, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('colorectal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('GNAS', 'Gene', (34, 38))	('ovarian cancer', 'Phenotype', 'HP:0100615', (94, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('ovarian cancer', 'Disease', 'MESH:D010051', (94, 108))	('breast cancer', 'Disease', (56, 69))	('activating mutations', 'Var', (10, 30))	('GNAS', 'Gene', '2778', (34, 38))
56211	24755198	Further interrogation of the "pan-negative" melanoma samples revealed 19 mutations in 9 genes encoding GNAs other than GNAQ and GNA11 (Supplementary Table S13).	('GNA11', 'Gene', '2767', (128, 133))	('GNA11', 'Gene', (128, 133))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('GNAQ', 'Gene', (119, 123))	('melanoma', 'Disease', (44, 52))	('GNAs', 'Gene', '2778', (103, 107))	('GNAs', 'Gene', (103, 107))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('GNAQ', 'Gene', '2776', (119, 123))	('mutations', 'Var', (73, 82))
56212	24755198	Interestingly, 17 of the 19 GNA mutations were found in cutaneous melanomas, unlike the known recurrent mutations in GNAQ and GNA11, which are primarily associated with uveal melanomas.	('GNA', 'Gene', (28, 31))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (56, 74))	('GNAQ', 'Gene', '2776', (117, 121))	('GNA11', 'Gene', (126, 131))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('GNAQ', 'Gene', (117, 121))	('uveal melanomas', 'Disease', 'MESH:C536494', (169, 184))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (56, 75))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (56, 75))	('mutations', 'Var', (32, 41))	('uveal melanoma', 'Phenotype', 'HP:0007716', (169, 183))	('found', 'Reg', (47, 52))	('GNA11', 'Gene', '2767', (126, 131))	('cutaneous melanomas', 'Disease', (56, 75))	('uveal melanomas', 'Disease', (169, 184))	('uveal melanomas', 'Phenotype', 'HP:0007716', (169, 184))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('melanomas', 'Phenotype', 'HP:0002861', (175, 184))	('associated', 'Reg', (153, 163))
56213	24755198	Notably, 13 of these 19 GNA mutations are caused by C>T (G>A) mutations that are compatible with UV-mediated damage, providing evidence for UV exposure in melanoma pathogenesis.	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('caused', 'Reg', (42, 48))	('mutations', 'Var', (62, 71))	('pathogenesis', 'biological_process', 'GO:0009405', ('164', '176'))	('GNA', 'Gene', (24, 27))	('C>T', 'Var', (52, 55))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('mutations', 'Var', (28, 37))	('melanoma', 'Disease', (155, 163))
56214	24755198	Among these 19 GNA-encoding genes, GNAI2 had 6 missense changes, of which 2 were present in a single sample.	('GNAI2', 'Gene', (35, 40))	('GNAI2', 'Gene', '2771', (35, 40))	('missense changes', 'Var', (47, 63))
56215	24755198	Taken together, these data indicate that GNA mutations potentially have a more significant role in cutaneous melanomas than previously thought.	('cutaneous melanomas', 'Disease', (99, 118))	('mutations', 'Var', (45, 54))	('GNA', 'Gene', (41, 44))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (99, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (99, 118))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (99, 118))
56216	24755198	To identify other potential novel driver mutations in pan-negative melanomas, we identified gene mutations that were enriched in the pan-negative samples (69) compared to the driver-positive samples (172).	('melanomas', 'Disease', (67, 76))	('mutations', 'Var', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('melanomas', 'Disease', 'MESH:D008545', (67, 76))
56217	24755198	Twelve genes had statistically significant mutations in the pan-negative samples (mutated in >= 10% of pan-negative melanomas and p-value < 0.05, Fisher's exact test) (Table 4, Supplementary Table S14) including ALK, STK31, DGKI, RAC1, EPHA4, ADAMTS18, EPHA7, ERBB4, TAF1L, NF1, SYK, and KDR (Supplementary Figures S5-S16).	('ALK', 'Gene', '238', (212, 215))	('melanomas', 'Disease', (116, 125))	('STK31', 'Gene', '56164', (217, 222))	('ALK', 'Gene', (212, 215))	('EPHA4', 'Gene', '2043', (236, 241))	('EPHA7', 'Gene', '2045', (253, 258))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('NF1', 'Gene', '4763', (274, 277))	('SYK', 'Gene', (279, 282))	('TAF1L', 'Gene', (267, 272))	('KDR', 'Gene', (288, 291))	('RAC1', 'Gene', (230, 234))	('ERBB4', 'Gene', '2066', (260, 265))	('S14', 'Gene', '6208', (197, 200))	('ADAMTS18', 'Gene', (243, 251))	('ERBB4', 'Gene', (260, 265))	('DGKI', 'Gene', (224, 228))	('NF1', 'Gene', (274, 277))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('RAC1', 'Gene', '5879', (230, 234))	('S16', 'Gene', '6217', (318, 321))	('SYK', 'Gene', '6850', (279, 282))	('S14', 'Gene', (197, 200))	('KDR', 'Gene', '3791', (288, 291))	('STK31', 'Gene', (217, 222))	('S16', 'Gene', (318, 321))	('TAF1L', 'Gene', '138474', (267, 272))	('mutations', 'Var', (43, 52))	('STK31', 'molecular_function', 'GO:0050321', ('217', '222'))	('EPHA4', 'Gene', (236, 241))	('DGKI', 'Gene', '9162', (224, 228))	('melanomas', 'Disease', 'MESH:D008545', (116, 125))	('ADAMTS18', 'Gene', '170692', (243, 251))	('EPHA7', 'Gene', (253, 258))
56220	24755198	Among the 13 ALK missense mutations in 12 samples, one (E1197K) was predicted to have a high impact on the protein function by MutationAssessor and four were predicted to have a medium impact on the protein function.	('missense', 'Var', (17, 25))	('ALK', 'Gene', (13, 16))	('protein', 'cellular_component', 'GO:0003675', ('199', '206'))	('E1197K', 'Mutation', 'rs1295056005', (56, 62))	('ALK', 'Gene', '238', (13, 16))	('protein function', 'MPA', (107, 123))	('impact', 'Reg', (93, 99))	('E1197K', 'Var', (56, 62))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
56221	24755198	Considering that activating ALK rearrangements are found in lung cancer and more recently in colorectal cancer, and a subset of lung cancer patients with ALK fusion genes are sensitive to the kinase inhibitor crizotinib, the role of ALK in melanoma and the clinical efficacy of ALK inhibition in ALK mutation-positive melanoma warrants further investigation.	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('activating', 'PosReg', (17, 27))	('melanoma', 'Phenotype', 'HP:0002861', (318, 326))	('melanoma', 'Disease', (318, 326))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('ALK', 'Gene', '238', (154, 157))	('rearrangements', 'Var', (32, 46))	('ALK', 'Gene', '238', (233, 236))	('ALK', 'Gene', '238', (296, 299))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('ALK', 'Gene', '238', (28, 31))	('ALK', 'Gene', (154, 157))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('crizotinib', 'Chemical', 'MESH:D000077547', (209, 219))	('ALK', 'Gene', (233, 236))	('ALK', 'Gene', (28, 31))	('ALK', 'Gene', (296, 299))	('patients', 'Species', '9606', (140, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('melanoma', 'Disease', 'MESH:D008545', (240, 248))	('lung cancer', 'Disease', (60, 71))	('melanoma', 'Disease', 'MESH:D008545', (318, 326))	('colorectal cancer', 'Disease', (93, 110))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('192', '208'))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('ALK', 'Gene', '238', (278, 281))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('lung cancer', 'Disease', (128, 139))	('ALK', 'Gene', (278, 281))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('melanoma', 'Disease', (240, 248))
56223	24755198	Mutations in the GTPase RAC1 occurred in 8 (11.6%) of the 69 pan-negative tumors compared to 5 of the 172 (2.9%) driver-positive tumors (p = 0.011) (Supplementary Figure S5).	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('occurred', 'Reg', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('Mutations', 'Var', (0, 9))	('RAC1', 'Gene', '5879', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('RAC1', 'Gene', (24, 28))	('tumors', 'Disease', (74, 80))
56224	24755198	Seven of these 8 RAC1 mutations were the alteration P29S, which was previously shown to activate RAC1 and increase melanocyte proliferation; therefore, RAC1 P29S may be a potential therapeutic target in melanoma.	('RAC1', 'Gene', '5879', (152, 156))	('P29S', 'Var', (157, 161))	('P29S', 'Mutation', 'rs1057519874', (157, 161))	('RAC1', 'Gene', (97, 101))	('melanocyte proliferation', 'CPA', (115, 139))	('P29S', 'Var', (52, 56))	('RAC1', 'Gene', (152, 156))	('increase', 'PosReg', (106, 114))	('RAC1', 'Gene', '5879', (17, 21))	('RAC1', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('P29S', 'Mutation', 'rs1057519874', (52, 56))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('RAC1', 'Gene', '5879', (97, 101))	('melanocyte proliferation', 'biological_process', 'GO:0097325', ('115', '139'))	('activate', 'PosReg', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))
56226	24755198	ADAMTS18 (ADAM metallopeptidase with thrombospondin type I motif, 18), which typically acts as a tumor-suppressor, was recently found to be mutated in melanoma, and mutant ADAMTS18 could increase melanoma cell migration and metastasis.	('ADAMTS18', 'Gene', '170692', (172, 180))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('97', '113'))	('ADAMTS18', 'Gene', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('increase', 'PosReg', (187, 195))	('tumor', 'Disease', (97, 102))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('melanoma', 'Disease', (196, 204))	('cell migration', 'biological_process', 'GO:0016477', ('205', '219'))	('ADAMTS18', 'Gene', '170692', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('melanoma cell migration', 'Disease', 'MESH:D008545', (196, 219))	('ADAMTS18', 'Gene', (172, 180))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('mutant', 'Var', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('melanoma cell migration', 'Disease', (196, 219))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('97', '113'))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))
56227	24755198	We found ADAMTS18 mutations in 23.2% of the 69 pan-negative melanomas (Supplementary Table S14), with a hotspot R172Q mutation in three pan-negative tumors (Supplementary Figure S6).	('mutations', 'Var', (18, 27))	('S14', 'Gene', (91, 94))	('S14', 'Gene', '6208', (91, 94))	('melanomas', 'Disease', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('R172Q', 'Mutation', 'rs770516167', (112, 117))	('ADAMTS18', 'Gene', '170692', (9, 17))	('R172Q', 'Var', (112, 117))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('melanomas', 'Disease', 'MESH:D008545', (60, 69))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('ADAMTS18', 'Gene', (9, 17))
56230	24755198	We observed 14 EPHA7 mutations in 12 pan-negative tumors (17.4%, p = 0.017).	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('EPHA7', 'Gene', '2045', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('EPHA7', 'Gene', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('mutations', 'Var', (21, 30))
56231	24755198	Among them, a G642E mutation, present in the tyrosine kinase domain of EPHA7, occurred in two tumors (Supplementary Figure S7).	('EPHA7', 'Gene', (71, 76))	('G642E', 'Var', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('G642E', 'Mutation', 'rs766856886', (14, 19))	('EPHA7', 'Gene', '2045', (71, 76))	('occurred', 'Reg', (78, 86))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
56232	24755198	This mutation may impact kinase activity of EPHA7, making it a potential clinical target.	('EPHA7', 'Gene', (44, 49))	('kinase activity', 'molecular_function', 'GO:0016301', ('25', '40'))	('impact', 'Reg', (18, 24))	('EPHA7', 'Gene', '2045', (44, 49))	('kinase activity', 'MPA', (25, 40))	('mutation', 'Var', (5, 13))
56235	24755198	In TAF1L (TAF1 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 210kDa-like), we observed 15 mutations in 11 of the 69 pan-negative samples (15.9%, p = 0.022, Supplementary Figure S8).	('TAF1L', 'Gene', (3, 8))	('mutations', 'Var', (113, 122))	('binding', 'molecular_function', 'GO:0005488', ('43', '50'))	('TAF1L', 'Gene', '138474', (3, 8))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))	('RNA', 'cellular_component', 'GO:0005562', ('15', '18'))
56237	24755198	Many loss-of-function mutations were observed in the genes STK31 (serine/threonine kinase 31) and NF1 (neurofibromin 1).	('neurofibromin 1', 'Gene', '4763', (103, 118))	('STK31', 'Gene', (59, 64))	('serine/threonine kinase 31', 'Gene', (66, 92))	('STK31', 'Gene', '56164', (59, 64))	('NF1', 'Gene', (98, 101))	('mutations', 'Var', (22, 31))	('neurofibromin 1', 'Gene', (103, 118))	('NF1', 'Gene', '4763', (98, 101))	('serine/threonine kinase 31', 'Gene', '56164', (66, 92))	('STK31', 'molecular_function', 'GO:0050321', ('59', '64'))	('loss-of-function', 'NegReg', (5, 21))
56238	24755198	We found 22 STK31 mutations in 18 pan-negative tumors (26.1%, p = 0.001, Supplementary Figure S11), including 3 nonsense, 1 splice-site, and 18 missense mutations.	('tumors', 'Disease', (47, 53))	('S11', 'Gene', '6267', (94, 97))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('missense mutations', 'Var', (144, 162))	('S11', 'Gene', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('STK31', 'Gene', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('STK31', 'molecular_function', 'GO:0050321', ('12', '17'))	('STK31', 'Gene', '56164', (12, 17))	('mutations', 'Var', (18, 27))
56242	24755198	Moreover, 22 NF1 mutations, including 6 nonsense (include one recurrent mutation W784X), 4 splice-site, and 12 missense mutations, were observed in 12 pan-negative tumors (17.4%, p = 0.024, Supplementary Figure S9).	('W784X', 'Mutation', 'rs199474778', (81, 86))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('NF1', 'Gene', (13, 16))	('NF1', 'Gene', '4763', (13, 16))	('observed', 'Reg', (136, 144))	('W784X', 'Var', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
56243	24755198	Four of these 12 missense mutations in NF1 were predicted to have a medium impact on the protein function by MutationAssessor.	('impact', 'Reg', (75, 81))	('NF1', 'Gene', (39, 42))	('protein function', 'MPA', (89, 105))	('missense mutations', 'Var', (17, 35))	('NF1', 'Gene', '4763', (39, 42))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
56244	24755198	As a negative regulator of RAS signaling, NF1 inactivation was recently reported to promote BRAF inhibitor resistance in the context of BRAF-V600 mutant melanoma.	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('BRAF', 'Gene', '673', (92, 96))	('promote', 'PosReg', (84, 91))	('BRAF-', 'Gene', (136, 141))	('BRAF', 'Gene', '673', (136, 140))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('BRAF', 'Gene', (92, 96))	('melanoma', 'Disease', (153, 161))	('BRAF-', 'Gene', '673', (136, 141))	('BRAF', 'Gene', (136, 140))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('inactivation', 'Var', (46, 58))	('NF1', 'Gene', '4763', (42, 45))	('NF1', 'Gene', (42, 45))
56245	24755198	In pan-negative melanoma, NF1 inactivating mutations (nonsense mutations) may also play a role in promoting MAPK pathway activation.	('MAPK', 'Gene', '5594', (108, 112))	('NF1', 'Gene', (26, 29))	('MAPK', 'Gene', (108, 112))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanoma', 'Disease', (16, 24))	('NF1', 'Gene', '4763', (26, 29))	('promoting', 'PosReg', (98, 107))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('inactivating mutations', 'Var', (30, 52))	('activation', 'PosReg', (121, 131))
56246	24755198	Therefore, melanomas with NF1 inactivating mutations may respond to MEK1/2 inhibition.	('melanomas', 'Disease', 'MESH:D008545', (11, 20))	('melanomas', 'Phenotype', 'HP:0002861', (11, 20))	('inhibition', 'NegReg', (75, 85))	('NF1', 'Gene', (26, 29))	('MEK1', 'molecular_function', 'GO:0004708', ('68', '72'))	('NF1', 'Gene', '4763', (26, 29))	('melanomas', 'Disease', (11, 20))	('respond', 'MPA', (57, 64))	('MEK1/2', 'Gene', '5604;5605', (68, 74))	('inactivating mutations', 'Var', (30, 52))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('MEK1/2', 'Gene', (68, 74))
56250	24755198	Two genes, KIT (mutated in 3 samples) and PREX2 (2 samples), were mutated in acral melanoma, however, this result did not reach statistical significance (KIT: p = 0.535; PREX2: p = 0.669).	('KIT', 'molecular_function', 'GO:0005020', ('154', '157'))	('PREX2', 'Gene', (170, 175))	('mutated', 'Var', (66, 73))	('PREX2', 'Gene', '80243', (170, 175))	('KIT', 'Gene', (11, 14))	('acral melanoma', 'Phenotype', 'HP:0012060', (77, 91))	('acral melanoma', 'Disease', (77, 91))	('KIT', 'molecular_function', 'GO:0005020', ('11', '14'))	('PREX2', 'Gene', '80243', (42, 47))	('acral melanoma', 'Disease', 'MESH:D008545', (77, 91))	('PREX2', 'Gene', (42, 47))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
56258	24755198	In this study, we systematically examined mutations from recently published melanoma NGS data encompassing 241 paired tumor-normal samples, aiming to identify potential, clinically-relevant mutations in melanomas that did not present with any of the well-established and -characterized driver mutations in BRAF, NRAS, KIT, GNAQ, and GNA11, which we describe as "pan-negative" tumors.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', (376, 381))	('GNAQ', 'Gene', '2776', (323, 327))	('melanomas', 'Disease', (203, 212))	('KIT', 'molecular_function', 'GO:0005020', ('318', '321'))	('GNA11', 'Gene', (333, 338))	('NRAS', 'Gene', (312, 316))	('GNAQ', 'Gene', (323, 327))	('tumors', 'Disease', 'MESH:D009369', (376, 382))	('tumor', 'Disease', 'MESH:D009369', (376, 381))	('melanoma NGS', 'Disease', (76, 88))	('melanoma NGS', 'Disease', 'MESH:D008545', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('melanomas', 'Phenotype', 'HP:0002861', (203, 212))	('tumor', 'Phenotype', 'HP:0002664', (376, 381))	('mutations', 'Var', (293, 302))	('GNA11', 'Gene', '2767', (333, 338))	('tumors', 'Phenotype', 'HP:0002664', (376, 382))	('KIT', 'Gene', (318, 321))	('NRAS', 'Gene', '4893', (312, 316))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('BRAF', 'Gene', '673', (306, 310))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('BRAF', 'Gene', (306, 310))	('tumor', 'Disease', (118, 123))	('tumors', 'Disease', (376, 382))	('melanomas', 'Disease', 'MESH:D008545', (203, 212))
56260	24755198	Through our statistical analyses, we identified several genes with non-silent mutations that were likely to co-occur with BRAF- and NRAS-driven melanomas.	('NRAS', 'Gene', '4893', (132, 136))	('BRAF-', 'Gene', (122, 127))	('melanomas', 'Disease', (144, 153))	('mutations', 'Var', (78, 87))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanomas', 'Phenotype', 'HP:0002861', (144, 153))	('melanomas', 'Disease', 'MESH:D008545', (144, 153))	('BRAF-', 'Gene', '673', (122, 127))	('NRAS', 'Gene', (132, 136))
56263	24755198	Subsequent analysis of the sequence data from 69 pan-negative samples revealed less common mutations in BRAF, NRAS, KIT, GNAQ, and GNA11 along with many mutations in other genes encoding guanine nucleotide binding protein alpha-subunits.	('NRAS', 'Gene', '4893', (110, 114))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('195', '213'))	('KIT', 'molecular_function', 'GO:0005020', ('116', '119'))	('GNAQ', 'Gene', '2776', (121, 125))	('mutations', 'Var', (91, 100))	('BRAF', 'Gene', '673', (104, 108))	('protein', 'cellular_component', 'GO:0003675', ('214', '221'))	('NRAS', 'Gene', (110, 114))	('KIT', 'Gene', (116, 119))	('BRAF', 'Gene', (104, 108))	('GNAQ', 'Gene', (121, 125))	('GNA11', 'Gene', '2767', (131, 136))	('GNA11', 'Gene', (131, 136))
56266	24755198	Interestingly, somatic nonsense mutations were frequently found in 2 genes: 6 nonsense mutations (including one recurrent mutation, W784X) in NF1 and 3 nonsense mutations in STK31 (for details, see Supplementary Table S14).	('NF1', 'Gene', '4763', (142, 145))	('W784X', 'Mutation', 'rs199474778', (132, 137))	('STK31', 'Gene', '56164', (174, 179))	('STK31', 'Gene', (174, 179))	('S14', 'Gene', (218, 221))	('STK31', 'molecular_function', 'GO:0050321', ('174', '179'))	('S14', 'Gene', '6208', (218, 221))	('W784X', 'Var', (132, 137))	('found', 'Reg', (58, 63))	('NF1', 'Gene', (142, 145))
56268	24755198	If tumors containing these mutations are activated and inhibition of the mutation(s) leads to cell death or attenuated growth, then clinically targeting them through pharmacological approaches may be a useful strategy.	('mutations', 'Var', (27, 36))	('cell death', 'biological_process', 'GO:0008219', ('94', '104'))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('death', 'Disease', 'MESH:D003643', (99, 104))	('death', 'Disease', (99, 104))	('attenuated', 'NegReg', (108, 118))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('inhibition', 'NegReg', (55, 65))	('growth', 'CPA', (119, 125))
56269	24755198	For example, the kinase inhibitor crizotinib might be tested in tumors with ALK mutations; STK inhibitors could be tested in tumors with STK31 mutations; and MEK1/2 inhibitors may be tested in tumors with NF1 mutations.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('STK31', 'Gene', (137, 142))	('STK31', 'molecular_function', 'GO:0050321', ('137', '142'))	('NF1', 'Gene', '4763', (205, 208))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('STK', 'molecular_function', 'GO:0050359', ('91', '94'))	('NF1', 'Gene', (205, 208))	('mutations', 'Var', (80, 89))	('ALK', 'Gene', '238', (76, 79))	('STK31', 'Gene', '56164', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('crizotinib', 'Chemical', 'MESH:D000077547', (34, 44))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('17', '33'))	('ALK', 'Gene', (76, 79))	('mutations', 'Var', (143, 152))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('MEK1', 'molecular_function', 'GO:0004708', ('158', '162'))	('MEK1/2', 'Gene', '5604;5605', (158, 164))	('tumors', 'Disease', (193, 199))	('MEK1/2', 'Gene', (158, 164))
56270	24755198	Moreover, the rare mutations in the 5 known driver genes (BRAF, NRAS, KIT, GNAQ, and GNA11) in this pan-negative melanoma panel clearly demonstrated that the commonly used SNaPshot screen could overlook a subset of melanoma patients that might also respond to the currently available, effective BRAF, NRAS, KIT, GNAQ, and GNA11 targeting inhibitors, or at least their effector pathways (MEK1/2 inhibitors).	('KIT', 'Gene', (307, 310))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('melanoma', 'Disease', (215, 223))	('BRAF', 'Gene', '673', (295, 299))	('BRAF', 'Gene', (295, 299))	('KIT', 'molecular_function', 'GO:0005020', ('307', '310'))	('NRAS', 'Gene', '4893', (301, 305))	('MEK1', 'molecular_function', 'GO:0004708', ('387', '391'))	('MEK1/2', 'Gene', '5604;5605', (387, 393))	('MEK1/2', 'Gene', (387, 393))	('GNA11', 'Gene', (322, 327))	('NRAS', 'Gene', (64, 68))	('GNA11', 'Gene', (85, 90))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('GNAQ', 'Gene', '2776', (312, 316))	('GNAQ', 'Gene', '2776', (75, 79))	('melanoma', 'Disease', 'MESH:D008545', (215, 223))	('GNAQ', 'Gene', (75, 79))	('GNAQ', 'Gene', (312, 316))	('NRAS', 'Gene', (301, 305))	('patients', 'Species', '9606', (224, 232))	('respond', 'PosReg', (249, 256))	('GNA11', 'Gene', '2767', (322, 327))	('KIT', 'molecular_function', 'GO:0005020', ('70', '73'))	('mutations', 'Var', (19, 28))	('GNA11', 'Gene', '2767', (85, 90))	('melanoma', 'Disease', (113, 121))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('BRAF', 'Gene', '673', (58, 62))	('NRAS', 'Gene', '4893', (64, 68))	('BRAF', 'Gene', (58, 62))
56271	24755198	For example, non-V600E BRAF mutations, including L597R/S/Q/V and K601E, are actionable in melanoma with MEK1/2 inhibition.	('K601E', 'Var', (65, 70))	('melanoma', 'Disease', (90, 98))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('non-V600E', 'Var', (13, 22))	('BRAF', 'Gene', '673', (23, 27))	('MEK1/2', 'Gene', '5604;5605', (104, 110))	('MEK1/2', 'Gene', (104, 110))	('L597R', 'SUBSTITUTION', 'None', (49, 54))	('BRAF', 'Gene', (23, 27))	('MEK1', 'molecular_function', 'GO:0004708', ('104', '108'))	('L597R', 'Var', (49, 54))	('K601E', 'Mutation', 'rs121913364', (65, 70))	('V600E', 'Mutation', 'rs113488022', (17, 22))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
56272	24755198	A recent WGS study has detected a recurrent functional synonymous mutation in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('synonymous mutation', 'Var', (55, 74))
56275	24755198	In summary, different from each individual NGS study, which attempted to identify mutations and genes involved in melanoma as a whole, our study uniquely provides a roadmap of potentially druggable mutations and genes in specific melanoma subtypes, especially those lacking any known driver mutations (pan-negative samples).	('melanoma subtypes', 'Disease', (230, 247))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('melanoma subtypes', 'Disease', 'MESH:D008545', (230, 247))	('mutations', 'Var', (198, 207))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('melanoma', 'Disease', (230, 238))	('melanoma', 'Disease', 'MESH:D008545', (230, 238))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
56276	24755198	In future work, we will extend our analysis to other types of mutations, such as insertions and deletions (indels), copy number variations (CNVs), and structural variants (SVs), for a more comprehensive map of genetic alterations in melanoma.	('deletions', 'Var', (96, 105))	('melanoma', 'Disease', 'MESH:D008545', (233, 241))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))	('melanoma', 'Disease', (233, 241))	('insertions', 'Var', (81, 91))
56277	24755198	We will attempt to identify genetic variants as the predictors of drug sensitivity by mining datasets from the Cancer Cell Line Encyclopedia (CCLE, http://www.broadinstitute.org/ccle/home) project, the Genomics of Drug Sensitivity in Cancer project (GDSC, http://www.cancerrxgene.org), and other large-scale pharmacogenomic datasets in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (111, 140))	('Cancer', 'Disease', (234, 240))	('cancer', 'Disease', (336, 342))	('cancer', 'Disease', 'MESH:D009369', (336, 342))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('Cancer', 'Disease', 'MESH:D009369', (111, 117))	('variants', 'Var', (36, 44))	('Cancer', 'Disease', (111, 117))	('Cancer', 'Disease', 'MESH:D009369', (234, 240))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (214, 230))	('drug sensitivity', 'Phenotype', 'HP:0020174', (66, 82))	('Cancer Cell Line Encyclopedia', 'Disease', (111, 140))	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Cancer', 'Phenotype', 'HP:0002664', (234, 240))
56278	24755198	To our knowledge, this study represents the largest effort to-date that characterizes potentially clinically-relevant mutations in melanomas without known BRAF, NRAS, KIT, GNAQ, and GNA11 driver mutations (i.e.	('BRAF', 'Gene', (155, 159))	('melanomas', 'Disease', 'MESH:D008545', (131, 140))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('GNAQ', 'Gene', '2776', (172, 176))	('mutations', 'Var', (118, 127))	('KIT', 'molecular_function', 'GO:0005020', ('167', '170'))	('melanomas', 'Disease', (131, 140))	('GNA11', 'Gene', (182, 187))	('NRAS', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (155, 159))	('GNAQ', 'Gene', (172, 176))	('GNA11', 'Gene', '2767', (182, 187))	('NRAS', 'Gene', '4893', (161, 165))	('melanomas', 'Phenotype', 'HP:0002861', (131, 140))
56280	24755198	Our comprehensive analyses of the mutation patterns in 69 pan-negative melanoma genomes, along with 172 melanoma genomes harboring known driver mutations, demonstrated the effectiveness of discovering underrepresented somatic mutations potentially relevant to targeted therapies in melanoma patients who otherwise could not receive targeted therapies.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (282, 290))	('melanoma', 'Disease', (104, 112))	('melanoma', 'Disease', 'MESH:D008545', (282, 290))	('melanoma', 'Phenotype', 'HP:0002861', (282, 290))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('patients', 'Species', '9606', (291, 299))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('mutations', 'Var', (226, 235))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
56281	24755198	As clinical NGS rapidly emerges, the high capacity and low cost of these platforms will soon allow routine screening of more comprehensive sets of tumor mutations in CLIA-certified laboratories, and thus, will benefit numerous cancer patients.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('mutations', 'Var', (153, 162))	('numerous cancer', 'Disease', 'MESH:D009369', (218, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('patients', 'Species', '9606', (234, 242))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('benefit', 'Reg', (210, 217))	('numerous cancer', 'Disease', (218, 233))
56282	24755198	In summary, we used existing published NGS data from 241 tumor-normal pairs to identify mutations that could influence existing and emerging targeted therapies in both driver mutation positive and pan-negative melanomas.	('melanomas', 'Disease', 'MESH:D008545', (210, 219))	('melanomas', 'Phenotype', 'HP:0002861', (210, 219))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('influence', 'Reg', (109, 118))	('mutations', 'Var', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('melanomas', 'Disease', (210, 219))	('tumor', 'Disease', (57, 62))
56283	24755198	Future preclinical studies will need to be conducted to determine whether these mutations are driver or passenger mutations and how they will affect response to targeted therapies specifically in melanoma.	('affect', 'Reg', (142, 148))	('mutations', 'Var', (80, 89))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('melanoma', 'Disease', (196, 204))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))
56320	24212610	About 80% of human melanocytic nevi contain an activating mutation (V600E) in the BRAF Ser/Thr kinase.	('V600E', 'Var', (68, 73))	('human', 'Species', '9606', (13, 18))	('BRAF', 'Gene', '673', (82, 86))	('nevi', 'Phenotype', 'HP:0003764', (31, 35))	('Ser', 'cellular_component', 'GO:0005790', ('87', '90'))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (19, 35))	('BRAF', 'Gene', (82, 86))	('human melanocytic nevi', 'Disease', (13, 35))	('V600E', 'Mutation', 'rs113488022', (68, 73))	('activating', 'PosReg', (47, 57))
56435	24212610	Depletion of this population of T cells can accelerate progression of metastatic melanoma in mouse models.	('mouse', 'Species', '10090', (93, 98))	('Depletion', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('progression', 'CPA', (55, 66))	('accelerate', 'PosReg', (44, 54))
56465	24212610	Taube and colleagues recently have identified the BRAFV600E mutation in a substantial subset of nodal nevi.	('BRAFV600E', 'Var', (50, 59))	('BRAFV600E', 'Mutation', 'rs113488022', (50, 59))	('nodal nevi', 'Disease', (96, 106))	('nevi', 'Phenotype', 'HP:0003764', (102, 106))
56466	24212610	As this same activating mutation is found in the majority of normal cutaneous nevi and roughly half of melanomas, it is possible that nodal nevi may arise from the "metastasis" of normal cutaneous nevi.	('activating', 'PosReg', (13, 23))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('nevi', 'Phenotype', 'HP:0003764', (197, 201))	('melanomas', 'Disease', (103, 112))	('nevi', 'Phenotype', 'HP:0003764', (78, 82))	('mutation', 'Var', (24, 32))	('nevi', 'Phenotype', 'HP:0003764', (140, 144))	('nodal', 'Disease', (134, 139))	('melanomas', 'Disease', 'MESH:D008545', (103, 112))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))
56519	24212610	Less metastatic B16 variants did not adhere to the lung endothelium suggesting tumor cell intrinsic mechanisms mediate specific adherence to the lung.	('variants', 'Var', (20, 28))	('tumor', 'Disease', (79, 84))	('B16', 'Gene', (16, 19))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
56598	24212610	In addition to high-throughput expression analysis, next-generation sequencing of cancer genomes and/or exomes is likely to be very informative and identify mutations that drive tumor formation and even metastasis in melanoma.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', (178, 183))	('melanoma', 'Disease', 'MESH:D008545', (217, 225))	('melanoma', 'Disease', (217, 225))	('cancer', 'Disease', (82, 88))	('mutations', 'Var', (157, 166))	('drive', 'PosReg', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('formation', 'biological_process', 'GO:0009058', ('184', '193'))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('metastasis', 'CPA', (203, 213))
56600	24212610	In uveal melanoma, exome sequencing has recently identified inactivating mutations to BAP1 in 84% of metastasizing tumors.	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('BAP1', 'Gene', '8314', (86, 90))	('identified', 'Reg', (49, 59))	('BAP1', 'Gene', (86, 90))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('inactivating mutations', 'Var', (60, 82))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
56604	24212610	BRAF, a mitogenic Ser/Thr kinase in the MAPK/ERK pathway, has an activating mutation, V600E, in at least 50% of melanomas and is thought to be a central oncogenic driver in melanoma.	('ERK', 'Gene', (45, 48))	('activating', 'PosReg', (65, 75))	('MAPK', 'molecular_function', 'GO:0004707', ('40', '44'))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('BRAF', 'Gene', (0, 4))	('V600E', 'Var', (86, 91))	('Ser', 'cellular_component', 'GO:0005790', ('18', '21'))	('melanomas', 'Disease', 'MESH:D008545', (112, 121))	('MAPK', 'Gene', (40, 44))	('melanomas', 'Disease', (112, 121))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('MAPK', 'Gene', '5594', (40, 44))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('ERK', 'Gene', '5594', (45, 48))	('ERK', 'molecular_function', 'GO:0004707', ('45', '48'))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('V600E', 'Mutation', 'rs113488022', (86, 91))
56606	24212610	BRAF-mutant tumors have been reported to have a worse prognosis than, for example, NRAS mutants, another oncogenic mutation that is thought to drive melanoma formation in a smaller subset of tumors.	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('NRAS', 'Gene', '4893', (83, 87))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('BRAF', 'Gene', '673', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (12, 18))	('BRAF', 'Gene', (0, 4))	('tumors', 'Disease', (191, 197))	('mutants', 'Var', (88, 95))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('formation', 'biological_process', 'GO:0009058', ('158', '167'))	('NRAS', 'Gene', (83, 87))
56608	24212610	Some preliminary evidence suggests that inhibition of targets downstream of mutant BRAF in melanoma can inhibit lung metastasis.	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('mutant', 'Var', (76, 82))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('lung metastasis', 'CPA', (112, 127))	('BRAF', 'Gene', '673', (83, 87))	('inhibit', 'NegReg', (104, 111))	('BRAF', 'Gene', (83, 87))
56611	24212610	The discrepancies in these early studies suggest the implications of the BRAFV600E mutational status with respect to survival and metastasis in melanoma are likely complex.	('BRAFV600E', 'Var', (73, 82))	('BRAFV600E', 'Mutation', 'rs113488022', (73, 82))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))
56613	24212610	This pathway is often dysregulated in melanoma through various mechanisms including inactivation of PTEN phosphatase, which is mutated in 5-20% of primary melanomas.	('PTEN', 'Gene', (100, 104))	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('melanomas', 'Disease', 'MESH:D008545', (155, 164))	('PTEN', 'Gene', '5728', (100, 104))	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('melanomas', 'Phenotype', 'HP:0002861', (155, 164))	('dysregulated', 'Reg', (22, 34))	('melanoma', 'Disease', (155, 163))	('phosphatase', 'molecular_function', 'GO:0016791', ('105', '116'))	('melanomas', 'Disease', (155, 164))	('inactivation', 'Var', (84, 96))	('melanoma', 'Disease', (38, 46))
56614	24212610	Protein expression of PTEN is lost through other mechanisms including epigenetic changes in a larger subset of melanomas.	('melanomas', 'Disease', 'MESH:D008545', (111, 120))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('lost', 'NegReg', (30, 34))	('Protein expression', 'MPA', (0, 18))	('melanomas', 'Disease', (111, 120))	('PTEN', 'Gene', (22, 26))	('epigenetic changes', 'Var', (70, 88))	('PTEN', 'Gene', '5728', (22, 26))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))
56627	24212610	The dysregulation of several miRNAs has already been proposed to have functionally important consequences in melanoma.	('dysregulation', 'Var', (4, 17))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Disease', (109, 117))	('consequences', 'Reg', (93, 105))
56640	24212610	For example, the relevance of EMT in melanoma could be directly tested by either inactivating E-cadherin or over-expressing particular transcription factors in these models.	('E-cadherin', 'Gene', (94, 104))	('E-cadherin', 'Gene', '999', (94, 104))	('transcription', 'biological_process', 'GO:0006351', ('135', '148'))	('EMT', 'biological_process', 'GO:0001837', ('30', '33'))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('inactivating', 'Var', (81, 93))	('cadherin', 'molecular_function', 'GO:0008014', ('96', '104'))	('over-expressing', 'PosReg', (108, 123))
56649	24212610	Individual melanomas are driven by diverse genetic and epigenetic alterations.	('epigenetic alterations', 'Var', (55, 77))	('melanomas', 'Disease', 'MESH:D008545', (11, 20))	('melanomas', 'Disease', (11, 20))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanomas', 'Phenotype', 'HP:0002861', (11, 20))
56716	22419851	Specifically, a CD271+ cell population isolated directly from aggressive melanoma samples and transplanted into T-, B- and natural-killer cell deficient mice resulted in melanoma formation at a markedly higher rate than CD271- cells.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('melanoma', 'Disease', (170, 178))	('CD271', 'Chemical', '-', (16, 21))	('formation', 'biological_process', 'GO:0009058', ('179', '188'))	('natural-killer cell deficient', 'Phenotype', 'HP:0012178', (123, 152))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('higher', 'PosReg', (203, 209))	('aggressive melanoma', 'Disease', 'MESH:D008545', (62, 81))	('CD271', 'Chemical', '-', (220, 225))	('CD271+', 'Var', (16, 22))	('mice', 'Species', '10090', (153, 157))	('rat', 'Species', '10116', (210, 213))	('aggressive melanoma', 'Disease', (62, 81))
56721	22419851	In our experiments, C918 uveal melanoma cells did not express CD271 in traditional 2D cultures; however, in 3D cultures, VM-forming C918 uveal melanoma cells expressed CD271.	('C918', 'CellLine', 'CVCL:8471', (132, 136))	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('uveal melanoma', 'Disease', (25, 39))	('CD271', 'Var', (168, 173))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('CD271', 'Chemical', '-', (168, 173))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('uveal melanoma', 'Disease', 'MESH:C536494', (137, 151))	('uveal melanoma', 'Phenotype', 'HP:0007716', (137, 151))	('CD271', 'Chemical', '-', (62, 67))	('C918', 'CellLine', 'CVCL:8471', (20, 24))	('uveal melanoma', 'Disease', 'MESH:C536494', (25, 39))	('uveal melanoma', 'Disease', (137, 151))
56758	18470571	Eligibility criteria included a WHO performance status of 0 or 1, leukocyte count >=3.0 x 109/L, platelet count >=100 x 109/L, maximum serum creatinine level 135 mumol/L, maximum bilirubin level 17 mumol/L, and minimum albumin level 40 g/L.	('>=100', 'Var', (112, 117))	('minimum albumin level', 'Phenotype', 'HP:0003073', (211, 232))	('creatinine', 'Chemical', 'MESH:D003404', (141, 151))	('maximum serum creatinine level', 'Phenotype', 'HP:0003259', (127, 157))	('serum creatinine level 135 mumol/L', 'MPA', (135, 169))
56836	18470571	reported the response after peptide receptor radionuclide therapy with [90Y-DOTA0, Tyr3] octreotide in 56 patients with advanced neuroendocrine tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('[90Y-DOTA0, Tyr3] octreotide', 'Chemical', 'MESH:C496730', (71, 99))	('neuroendocrine tumors', 'Disease', (129, 150))	('[90Y-DOTA0', 'Var', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('patients', 'Species', '9606', (106, 114))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (129, 150))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (129, 149))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (129, 150))
56846	18470571	GISTs have characteristic gain-of-function mutations in the KIT oncogene that results in overexpression of the KIT-protein (CD117).	('gain-of-function', 'PosReg', (26, 42))	('CD117', 'Gene', '3815', (124, 129))	('KIT', 'molecular_function', 'GO:0005020', ('111', '114'))	('overexpression', 'PosReg', (89, 103))	('CD117', 'Gene', (124, 129))	('GIST', 'Phenotype', 'HP:0100723', (0, 4))	('KIT', 'Gene', (60, 63))	('mutations', 'Var', (43, 52))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('KIT', 'molecular_function', 'GO:0005020', ('60', '63'))
56874	33046735	It is well known that CM is often associated with mutations in BRAF, representing a potential therapeutic target.	('mutations', 'Var', (50, 59))	('associated', 'Reg', (34, 44))	('BRAF', 'Gene', (63, 67))	('BRAF', 'Gene', '673', (63, 67))
56881	33046735	Pathologic T (pT) categories according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual (eighth edition) were pT1a in 9 (75.0%), pT1b in 1 (8.3%) and pT3b in 2 (16.6%) cases.	('Cancer', 'Disease', 'MESH:D009369', (88, 94))	('Cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Cancer', 'Disease', (74, 80))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))	('pT1b', 'Var', (151, 155))	('pT1a', 'Disease', (132, 136))	('Cancer', 'Disease', (88, 94))
56918	33046735	siRNA-mediated knockdown of linc-POU3F3 reduces tumor cell proliferation and invasion and increase apoptosis in colorectal cancer cells and may therefore represent a therapeutic approach for the treatment of CM.	('colorectal cancer', 'Disease', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Disease', (48, 53))	('knockdown', 'Var', (15, 24))	('POU3F3', 'Gene', (33, 39))	('increase', 'PosReg', (90, 98))	('POU3F3', 'Gene', '5455', (33, 39))	('invasion', 'CPA', (77, 85))	('apoptosis', 'CPA', (99, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('cell proliferation', 'biological_process', 'GO:0008283', ('54', '72'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('reduces', 'NegReg', (40, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
56960	32756477	Despite the biological potential of pericytes, their dysfunction can contribute to the pathogenesis of atherosclerosis, fibrosis, vascular calcification, diabetic retinopathy, and tumor progression.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('atherosclerosis', 'Disease', (103, 118))	('vascular calcification', 'Phenotype', 'HP:0004934', (130, 152))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('diabetic retinopathy', 'Disease', (154, 174))	('fibrosis', 'Disease', (120, 128))	('vascular calcification', 'Disease', (130, 152))	('fibrosis', 'Disease', 'MESH:D005355', (120, 128))	('retinopathy', 'Phenotype', 'HP:0000488', (163, 174))	('tumor', 'Disease', (180, 185))	('diabetic retinopathy', 'Disease', 'MESH:D003920', (154, 174))	('vascular calcification', 'Disease', 'MESH:D061205', (130, 152))	('pathogenesis', 'biological_process', 'GO:0009405', ('87', '99'))	('dysfunction', 'Var', (53, 64))	('contribute', 'Reg', (69, 79))	('atherosclerosis', 'Disease', 'MESH:D050197', (103, 118))	('atherosclerosis', 'Phenotype', 'HP:0002621', (103, 118))
56969	32756477	PDGF and/or PDGF receptors are overexpressed or mutated in different solid tumors and participate in tumor progression through autocrine stimulation of tumor cell growth and paracrine stimulation on stromal cells to generate a favorable microenvironment for tumor survival.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('mutated', 'Var', (48, 55))	('tumor', 'Disease', (258, 263))	('cell growth', 'biological_process', 'GO:0016049', ('158', '169'))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Disease', (75, 80))	('PDGF', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('PDGF', 'molecular_function', 'GO:0005161', ('12', '16'))	('PDGF', 'molecular_function', 'GO:0005161', ('0', '4'))	('PDGF', 'Gene', '5154;5155;56034;80310', (12, 16))	('participate', 'Reg', (86, 97))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('PDGF', 'Gene', '5154;5155;56034;80310', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (101, 106))	('overexpressed', 'PosReg', (31, 44))	('PDGF', 'Gene', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
56971	32756477	Moreover, STAT3 activation was described to be strongly induced by PDGF-mediated phosphorylation of conserved serine residue at position 727.	('phosphorylation', 'Var', (81, 96))	('PDGF', 'molecular_function', 'GO:0005161', ('67', '71'))	('STAT3', 'Gene', '6774', (10, 15))	('PDGF', 'Gene', '5154;5155;56034;80310', (67, 71))	('serine', 'Chemical', 'MESH:D012694', (110, 116))	('PDGF', 'Gene', (67, 71))	('phosphorylation', 'biological_process', 'GO:0016310', ('81', '96'))	('STAT3', 'Gene', (10, 15))
56980	32756477	Inhibition of pericytes in NG2 knockout mice decreased neovascularization and tumor volume, indicating an important role of pericytes in the progression of uveal melanoma.	('NG2', 'Gene', (27, 30))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('neovascularization', 'CPA', (55, 73))	('decreased', 'NegReg', (45, 54))	('uveal melanoma', 'Phenotype', 'HP:0007716', (156, 170))	('uveal melanoma', 'Disease', (156, 170))	('uveal melanoma', 'Disease', 'MESH:C536494', (156, 170))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (78, 83))	('mice', 'Species', '10090', (40, 44))
56996	32756477	Real-time RT-PCR analysis showed a significant increase in PDGF-B mRNA levels of about 0.9- and 1.7-fold in c92.1 and c/IMA92.1, respectively (p < 0.05) compared to control cells.	('PDGF-B', 'Gene', (59, 65))	('PDGF-B', 'Gene', '5155', (59, 65))	('c92.1', 'Var', (108, 113))	('c/IMA92.1', 'Var', (118, 127))	('increase', 'PosReg', (47, 55))	('PDGF', 'molecular_function', 'GO:0005161', ('59', '63'))	('mRNA levels', 'MPA', (66, 77))
57008	32756477	The presence of 5 muM of imatinib in coculture completely prevented the increase of both the anti-inflammatory cytokines induced by 92.1UM as evidenced by mRNA levels of TGF- beta1 and IL10 in c/IMAHRPC similar to control HRPC.	('92.1UM', 'Var', (132, 138))	('TGF- beta1', 'Gene', '7040', (170, 180))	('IL10', 'Gene', (185, 189))	('mRNA levels', 'MPA', (155, 166))	('TGF- beta1', 'Gene', (170, 180))	('increase', 'PosReg', (72, 80))	('IL10', 'Gene', '3586', (185, 189))	('muM', 'Gene', '56925', (18, 21))	('prevented', 'NegReg', (58, 67))	('1UM', 'Chemical', '-', (135, 138))	('muM', 'Gene', (18, 21))	('IL10', 'molecular_function', 'GO:0005141', ('185', '189'))	('UM', 'Phenotype', 'HP:0007716', (136, 138))	('imatinib', 'Chemical', 'MESH:D000068877', (25, 33))	('anti-inflammatory cytokines', 'MPA', (93, 120))
57009	32756477	Interestingly, 6 days of coculture with 92.1UM triggered a significant increase of pro-inflammatory cytokine TNF-alpha mRNA of about 3.5-fold (p < 0.05) and a reduction of IL-1beta and IFN- gamma mRNA levels of about 75% and 85%, respectively (p < 0.05, Figure 3C-E).	('IFN- gamma', 'Gene', '3458', (185, 195))	('reduction', 'NegReg', (159, 168))	('IL-1', 'molecular_function', 'GO:0005149', ('172', '176'))	('IFN- gamma', 'Gene', (185, 195))	('92.1UM', 'Var', (40, 46))	('IL-1beta', 'Gene', '3552', (172, 180))	('increase', 'PosReg', (71, 79))	('TNF-alpha', 'Gene', '7124', (109, 118))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('IL-1beta', 'Gene', (172, 180))	('TNF-alpha', 'Gene', (109, 118))	('1UM', 'Chemical', '-', (43, 46))
57017	32756477	High-content screening analysis showed a slight but significant increase of immunoreactivity for phospho-PDGFRbeta in HRPC cocultured with 92.1UM compared to control HRPC as indicated by the increased green fluorescence (Figure 4A).	('immunoreactivity', 'MPA', (76, 92))	('1UM', 'Chemical', '-', (142, 145))	('PDGFRbeta', 'Gene', '5156', (105, 114))	('increased', 'PosReg', (191, 200))	('increase', 'PosReg', (64, 72))	('cocultured', 'Var', (123, 133))	('PDGFRbeta', 'Gene', (105, 114))	('green fluorescence', 'MPA', (201, 219))	('UM', 'Phenotype', 'HP:0007716', (143, 145))
57020	32756477	These data indicate the involvement of PDGFRbeta in retinal pericyte-CAF transition induced by 92.1UM.	('92.1UM', 'Var', (95, 101))	('retinal pericyte-CAF transition', 'CPA', (52, 83))	('PDGFRbeta', 'Gene', '5156', (39, 48))	('PDGFRbeta', 'Gene', (39, 48))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('involvement', 'Reg', (24, 35))	('1UM', 'Chemical', '-', (98, 101))
57022	32756477	Immunostaining for the phospho-STAT3 (Y702) in cHRPC showed an increase of positive nuclei for the active isoform STAT3 (about 5-fold, p < 0.05) in comparison to control HRPC.	('increase', 'PosReg', (63, 71))	('STAT3', 'Gene', '6774', (114, 119))	('STAT3', 'Gene', (31, 36))	('Y702', 'Var', (38, 42))	('STAT3', 'Gene', (114, 119))	('positive nuclei', 'MPA', (75, 90))	('cHRPC', 'Gene', (47, 52))	('STAT3', 'Gene', '6774', (31, 36))
57034	32756477	CAF infiltration in the tumor microenvironment has been correlated with increased invasiveness and poor prognosis of cancer.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('increased', 'PosReg', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (24, 29))	('infiltration', 'Var', (4, 16))	('invasiveness', 'CPA', (82, 94))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
57052	32756477	In particular, increased cell motility of HRPC induced by 92.1UM can be attributed to chemotaxis that is specifically mediated only by betabeta homodimers and alphabeta heterodimers in smooth muscle cells and fibroblasts.	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('HRPC', 'Protein', (42, 46))	('chemotaxis', 'biological_process', 'GO:0006935', ('86', '96'))	('increased', 'PosReg', (15, 24))	('92.1UM', 'Var', (58, 64))	('cell motility', 'biological_process', 'GO:0048870', ('25', '38'))	('cell motility', 'CPA', (25, 38))	('1UM', 'Chemical', '-', (61, 64))
57076	32756477	Moreover, we do not address the role of physical contact with endothelial cells in the activation of HRPC induced by 92.1UM as it modulates pericyte phenotype and the response to different growth factors present in their environment.	('UM', 'Phenotype', 'HP:0007716', (121, 123))	('HRPC', 'Protein', (101, 105))	('pericyte phenotype', 'CPA', (140, 158))	('response', 'MPA', (167, 175))	('92.1UM', 'Var', (117, 123))	('modulates', 'Reg', (130, 139))	('1UM', 'Chemical', '-', (120, 123))
57079	32756477	Rabbit monoclonal antibody (EP1255Y) against MMP9, rabbit polyclonal antibody against NG2 (catalog num.	('antibody', 'cellular_component', 'GO:0019814', ('18', '26'))	('MMP9', 'Gene', '4318', (45, 49))	('antibody', 'cellular_component', 'GO:0019815', ('69', '77'))	('MMP9', 'Gene', (45, 49))	('antibody', 'cellular_component', 'GO:0019814', ('69', '77'))	('antibody', 'molecular_function', 'GO:0003823', ('18', '26'))	('antibody', 'molecular_function', 'GO:0003823', ('69', '77'))	('antibody', 'cellular_component', 'GO:0019815', ('18', '26'))	('antibody', 'cellular_component', 'GO:0042571', ('18', '26'))	('antibody', 'cellular_component', 'GO:0042571', ('69', '77'))	('EP1255Y', 'Var', (28, 35))	('MMP9', 'molecular_function', 'GO:0004229', ('45', '49'))
57119	32756477	Immunoblot was preceded by 30 min incubation with Odyssey Blocking Buffer (LI-COR Biosciences, Lincoln, NE, USA), and subsequently, the membranes were incubated at 4  C overnight with an antibody against TGF-beta1 (1:200), IL-10 (1:800), vimentin (1:2000), MMP9 (1:1000), NG2 (1:500), and phosphor-PDGFRbeta (1:250).	('1:200', 'Var', (215, 220))	('IL-10', 'Gene', '3586', (223, 228))	('PDGFRbeta', 'Gene', '5156', (298, 307))	('antibody', 'cellular_component', 'GO:0019814', ('187', '195'))	('vimentin', 'cellular_component', 'GO:0045099', ('238', '246'))	('IL-10', 'Gene', (223, 228))	('PDGFRbeta', 'Gene', (298, 307))	('vimentin', 'Gene', '7431', (238, 246))	('IL-10', 'molecular_function', 'GO:0005141', ('223', '228'))	('MMP9', 'molecular_function', 'GO:0004229', ('257', '261'))	('vimentin', 'Gene', (238, 246))	('antibody', 'molecular_function', 'GO:0003823', ('187', '195'))	('antibody', 'cellular_component', 'GO:0042571', ('187', '195'))	('MMP9', 'Gene', '4318', (257, 261))	('MMP9', 'Gene', (257, 261))	('TGF-beta1', 'Gene', (204, 213))	('vimentin', 'cellular_component', 'GO:0045098', ('238', '246'))	('1:800', 'Var', (230, 235))	('antibody', 'cellular_component', 'GO:0019815', ('187', '195'))	('TGF-beta1', 'Gene', '7040', (204, 213))	('1:2000', 'Var', (248, 254))
57184	32304183	Among the 42 patients, 10 primary tumours and 17 liver metastases underwent mutation analysis and the results recorded (not done, BRAF, NRAS, KIT, other) (Tables 1 and 2).	('KIT', 'molecular_function', 'GO:0005020', ('142', '145'))	('KIT', 'Gene', (142, 145))	('BRAF', 'Gene', '673', (130, 134))	('patients', 'Species', '9606', (13, 21))	('liver metastases', 'Disease', (49, 65))	('primary tumour', 'Disease', (26, 40))	('BRAF', 'Gene', (130, 134))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('NRAS', 'Gene', (136, 140))	('primary tumour', 'Disease', 'MESH:D009369', (26, 40))	('liver metastases', 'Disease', 'MESH:D009362', (49, 65))	('tumours', 'Disease', 'MESH:D009369', (34, 41))	('KIT', 'Gene', '3815', (142, 145))	('NRAS', 'Gene', '4893', (136, 140))	('mutation analysis', 'Var', (76, 93))	('tumours', 'Disease', (34, 41))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
57193	32304183	Six patients had BRAF V600E mutations; a KIT mutation; and three were not mutated in BRAF, NRAS or KIT.	('KIT', 'molecular_function', 'GO:0005020', ('99', '102'))	('KIT', 'Gene', '3815', (99, 102))	('BRAF', 'Gene', '673', (17, 21))	('V600E', 'Mutation', 'rs113488022', (22, 27))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('KIT', 'Gene', '3815', (41, 44))	('KIT', 'Gene', (99, 102))	('NRAS', 'Gene', (91, 95))	('BRAF', 'Gene', (17, 21))	('patients', 'Species', '9606', (4, 12))	('KIT', 'molecular_function', 'GO:0005020', ('41', '44'))	('KIT', 'Gene', (41, 44))	('NRAS', 'Gene', '4893', (91, 95))	('V600E mutations', 'Var', (22, 37))
57221	32304183	Nine patients had BRAF V600E mutations; two NRAS mutations; and six were not mutated in BRAF, NRAS or KIT (Table 2).	('NRAS', 'Gene', (94, 98))	('patients', 'Species', '9606', (5, 13))	('BRAF', 'Gene', (88, 92))	('V600E mutations', 'Var', (23, 38))	('V600E', 'Mutation', 'rs113488022', (23, 28))	('BRAF', 'Gene', '673', (88, 92))	('NRAS', 'Gene', (44, 48))	('NRAS', 'Gene', '4893', (94, 98))	('KIT', 'Gene', '3815', (102, 105))	('BRAF', 'Gene', '673', (18, 22))	('NRAS', 'Gene', '4893', (44, 48))	('KIT', 'Gene', (102, 105))	('BRAF', 'Gene', (18, 22))	('KIT', 'molecular_function', 'GO:0005020', ('102', '105'))
57222	32304183	The BRAF and NRAS mutations showed no association with HGP.	('HGP', 'Disease', (55, 58))	('NRAS', 'Gene', (13, 17))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('NRAS', 'Gene', '4893', (13, 17))	('mutations', 'Var', (18, 27))
57231	32304183	It is important to emphasise that pure dHGP conferred unique survival advantage apart from other HGP variants 10.	('dHGP', 'Gene', (39, 43))	('pure', 'Var', (34, 38))	('pure', 'molecular_function', 'GO:0034023', ('34', '38'))	('dHGP', 'Chemical', '-', (39, 43))	('survival advantage', 'CPA', (61, 79))
57252	32304183	In a similar fashion to UM, CRC, and breast carcinoma, 6, 8, 11, the presence of any replacement pattern significantly predicted diminished overall survival while the desmoplastic pattern correlated with increased survival.	('presence', 'Var', (69, 77))	('breast carcinoma', 'Disease', 'MESH:D001943', (37, 53))	('CRC', 'Phenotype', 'HP:0030731', (28, 31))	('UM', 'Phenotype', 'HP:0007716', (24, 26))	('diminished', 'NegReg', (129, 139))	('men', 'Species', '9606', (92, 95))	('breast carcinoma', 'Phenotype', 'HP:0003002', (37, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('overall survival', 'MPA', (140, 156))	('breast carcinoma', 'Disease', (37, 53))
57278	31635116	Herein, we focused specifically on uveal melanoma (UM) in which BAP1 mutations are associated with a metastasizing phenotype and decreased survival rates.	('uveal melanoma', 'Disease', 'MESH:C536494', (35, 49))	('mutations', 'Var', (69, 78))	('UM', 'Disease', 'MESH:C536494', (51, 53))	('uveal melanoma', 'Disease', (35, 49))	('survival rates', 'CPA', (139, 153))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))	('BAP1', 'Gene', '8314', (64, 68))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('decreased', 'NegReg', (129, 138))	('BAP1', 'Gene', (64, 68))
57279	31635116	We identified the ubiquitin carboxyl hydrolase (UCH) domain as a major hotspot region for the pathogenic mutations with a high evolutionary action (EA) score.	('ubiquitin', 'molecular_function', 'GO:0031386', ('18', '27'))	('mutations', 'Var', (105, 114))	('pathogenic', 'Reg', (94, 104))	('carboxyl', 'Chemical', 'MESH:C041069', (28, 36))
57280	31635116	Computational protein interaction studies revealed that distant BAP1-associated protein complexes (FOXK2, ASXL1, BARD1, BRCA1) could be directly impacted by this mutation paradigm.	('BRCA1', 'Gene', (120, 125))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('ASXL1', 'Gene', '171023', (106, 111))	('FOXK2', 'Gene', '3607', (99, 104))	('BARD1', 'Gene', '580', (113, 118))	('impacted', 'Reg', (145, 153))	('BARD1', 'Gene', (113, 118))	('BAP1', 'Gene', '8314', (64, 68))	('ASXL1', 'Gene', (106, 111))	('FOXK2', 'Gene', (99, 104))	('mutation', 'Var', (162, 170))	('BRCA1', 'Gene', '672', (120, 125))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('BAP1', 'Gene', (64, 68))
57282	31635116	The mutations affect - independent of being somatic or germline - the binding affinity of miRNAs embedded within the BAP1 locus, thereby altering the unique regulatory network.	('unique regulatory network', 'MPA', (150, 175))	('affect', 'Reg', (14, 20))	('binding', 'Interaction', (70, 77))	('BAP1', 'Gene', '8314', (117, 121))	('binding', 'molecular_function', 'GO:0005488', ('70', '77'))	('BAP1', 'Gene', (117, 121))	('miRNAs', 'Protein', (90, 96))	('N', 'Chemical', 'MESH:D009584', (93, 94))	('mutations', 'Var', (4, 13))	('altering', 'Reg', (137, 145))
57286	31635116	BAP1 (BRCA1-associated protein 1) with its gene product acting as a deubiquitinating enzyme, is a critical tumor suppressor gene that is mutated in various human cancers, including metastatic uveal melanoma, pleural mesothelioma, and renal cell carcinoma.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (208, 228))	('BRCA1-associated protein 1', 'Gene', (6, 32))	('human', 'Species', '9606', (156, 161))	('tumor', 'Disease', (107, 112))	('cancers', 'Disease', (162, 169))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumor suppressor', 'biological_process', 'GO:0051726', ('107', '123'))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('renal cell carcinoma', 'Disease', (234, 254))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (234, 254))	('BAP1', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('uveal melanoma', 'Disease', 'MESH:C536494', (192, 206))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('uveal melanoma', 'Disease', (192, 206))	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('68', '91'))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('pleural mesothelioma', 'Disease', (208, 228))	('mutated', 'Var', (137, 144))	('uveal melanoma', 'Phenotype', 'HP:0007716', (192, 206))	('BRCA1-associated protein 1', 'Gene', '8314', (6, 32))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (234, 254))	('BAP1', 'Gene', '8314', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('107', '123'))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (208, 228))
57287	31635116	Germline BAP1 mutations define the recently identified BAP1 cancer syndrome with affected patients developing different tumor entities, such as uveal and cutaneous melanoma, malignant mesothelioma, atypical Spitz tumors and others.	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('Spitz tumors', 'Disease', 'MESH:D018332', (207, 219))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (174, 196))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('BAP1', 'Gene', (9, 13))	('uveal', 'Disease', (144, 149))	('BAP1', 'Gene', (55, 59))	('mutations', 'Var', (14, 23))	('malignant mesothelioma', 'Disease', (174, 196))	('tumor', 'Disease', (120, 125))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (174, 196))	('cancer syndrome', 'Disease', 'MESH:D009369', (60, 75))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cutaneous melanoma', 'Disease', (154, 172))	('patients', 'Species', '9606', (90, 98))	('Spitz tumors', 'Disease', (207, 219))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (154, 172))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (154, 172))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('tumor', 'Disease', (213, 218))	('BAP1', 'Gene', '8314', (9, 13))	('cancer syndrome', 'Disease', (60, 75))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('BAP1', 'Gene', '8314', (55, 59))
57288	31635116	The apparent ability of BAP1 mutations, both somatic and germline variants, to cause multiple tumor types suggests that this gene has a major role in influencing cancer cell growth.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Disease', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('BAP1', 'Gene', (24, 28))	('cell growth', 'biological_process', 'GO:0016049', ('169', '180'))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', (94, 99))	('cause', 'Reg', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('BAP1', 'Gene', '8314', (24, 28))
57290	31635116	Particularly, in uveal melanoma (UM), the most frequent intraocular tumor of the eye, BAP1 mutations were identified in 84% of tumors with a metastasizing phenotype.	('identified', 'Reg', (106, 116))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('intraocular tumor', 'Disease', (56, 73))	('tumors', 'Disease', (127, 133))	('BAP1', 'Gene', '8314', (86, 90))	('intraocular tumor', 'Disease', 'MESH:D064090', (56, 73))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumor of the eye', 'Phenotype', 'HP:0100012', (68, 84))	('UM', 'Disease', 'MESH:C536494', (33, 35))	('BAP1', 'Gene', (86, 90))	('mutations', 'Var', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))	('uveal melanoma', 'Disease', (17, 31))	('uveal melanoma', 'Disease', 'MESH:C536494', (17, 31))
57291	31635116	While a wild type BAP1 is associated with disomy of chromosome 3 (D3) and a low risk for metastasis in UM BAP1 mutations follow the appearance of monsomy of chromosome 3 (M3) and with a high probability for metastasis.	('chromosome', 'cellular_component', 'GO:0005694', ('52', '62'))	('mutations', 'Var', (111, 120))	('UM', 'Disease', 'MESH:C536494', (103, 105))	('BAP1', 'Gene', '8314', (18, 22))	('BAP1', 'Gene', (106, 110))	('BAP1', 'Gene', (18, 22))	('BAP1', 'Gene', '8314', (106, 110))	('disomy', 'Disease', (42, 48))	('disomy', 'Disease', 'MESH:D024182', (42, 48))	('chromosome', 'cellular_component', 'GO:0005694', ('157', '167'))
57292	31635116	Immunohistochemically, BAP1 mutations are characterized by absence of nuclear staining (but commonly cytoplasmic staining), while BAP1 wildtype shows a strong nuclear staining reaction in the tumor cells.	('BAP1', 'Gene', (23, 27))	('tumor', 'Disease', (192, 197))	('BAP1', 'Gene', (130, 134))	('BAP1', 'Gene', '8314', (23, 27))	('absence', 'NegReg', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('BAP1', 'Gene', '8314', (130, 134))	('nuclear staining', 'MPA', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('mutations', 'Var', (28, 37))
57295	31635116	Other genetic alterations, such as deletion/duplication of driver genes (GNAQ, GNA11, EIFAX, SF3B1, and BPA1) also act as additional contributors towards the UM specific clinical evaluations.	('GNAQ', 'Gene', '2776', (73, 77))	('BPA1', 'Gene', (104, 108))	('BPA1', 'Chemical', 'MESH:C436045', (104, 108))	('SF3B1', 'Gene', (93, 98))	('EIFAX', 'Gene', (86, 91))	('deletion/duplication', 'Var', (35, 55))	('GNA11', 'Gene', '2767', (79, 84))	('GNA11', 'Gene', (79, 84))	('GNAQ', 'Gene', (73, 77))	('UM', 'Disease', 'MESH:C536494', (158, 160))	('SF3B1', 'Gene', '23451', (93, 98))
57296	31635116	Aberrant miRNA expression was found in UM and allowed for a differentiation between high risk and low-/intermediate-risk tumors in a recent study.	('N', 'Chemical', 'MESH:D009584', (12, 13))	('miRNA', 'Protein', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Aberrant', 'Var', (0, 8))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('UM', 'Disease', 'MESH:C536494', (39, 41))	('tumors', 'Disease', 'MESH:D009369', (121, 127))
57300	31635116	Although somatic mutations of the BAP1 gene are quite prevalent in UM, the impact of these mutations on the structural architecture of the BAP1 protein and its associated complexes has not been reported, yet.	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('BAP1', 'Gene', (34, 38))	('BAP1', 'Gene', '8314', (139, 143))	('UM', 'Disease', 'MESH:C536494', (67, 69))	('BAP1', 'Gene', (139, 143))	('BAP1', 'Gene', '8314', (34, 38))	('mutations', 'Var', (17, 26))
57301	31635116	Herein, we have created a comprehensive map of all reported UM-associated somatic and germline missense mutations located in the BAP1 gene and have analyzed their structural and evolutionary impact.	('BAP1', 'Gene', (129, 133))	('UM', 'Disease', 'MESH:C536494', (60, 62))	('missense mutations', 'Var', (95, 113))	('BAP1', 'Gene', '8314', (129, 133))
57314	31635116	To determine the pathogenic probability of BAP1 mutations, we used the Evolutionary Action (EA) scores.	('BAP1', 'Gene', '8314', (43, 47))	('BAP1', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
57315	31635116	Usually, the loss of function mutations typically have high EA scores (e.g., >70), benign mutations have low EA scores (e.g., <30), while intermediate EA scores (~30-70) may not deactivate the protein, but rather have either detrimental or gain of function effect to the overall function.	('loss of function', 'NegReg', (13, 29))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('protein', 'Protein', (193, 200))	('detrimental', 'Disease', (225, 236))	('EA scores', 'MPA', (60, 69))	('mutations', 'Var', (30, 39))	('gain of function', 'PosReg', (240, 256))	('detrimental', 'Disease', 'MESH:D008569', (225, 236))
57316	31635116	To define the binding affinity of the miRNAs embedded in its 3' UTR towards BAP1 mutations, we implemented an RNA sequence-based statistical approach (RNA hybrid).	('N', 'Chemical', 'MESH:D009584', (152, 153))	('binding', 'molecular_function', 'GO:0005488', ('14', '21'))	('BAP1', 'Gene', '8314', (76, 80))	('RNA', 'cellular_component', 'GO:0005562', ('110', '113'))	('binding', 'Interaction', (14, 21))	('RNA', 'cellular_component', 'GO:0005562', ('151', '154'))	('BAP1', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('N', 'Chemical', 'MESH:D009584', (111, 112))
57317	31635116	Briefly, the energetically most favorable binding conformations were predicted, and minimum free energy (mfe) of the BAP1 mutants:miRNAs were calculated (units:kcal/mol).	('mutants', 'Var', (122, 129))	('BAP1', 'Gene', '8314', (117, 121))	('N', 'Chemical', 'MESH:D009584', (133, 134))	('binding', 'Interaction', (42, 49))	('BAP1', 'Gene', (117, 121))	('binding', 'molecular_function', 'GO:0005488', ('42', '49'))
57326	31635116	Herein, we focused on 34 BAP1 specific missense mutations which were previously shown to be associated with UM (Figure 1B).	('BAP1', 'Gene', (25, 29))	('UM', 'Disease', 'MESH:C536494', (108, 110))	('BAP1', 'Gene', '8314', (25, 29))	('associated', 'Reg', (92, 102))	('missense mutations', 'Var', (39, 57))
57327	31635116	The ubiquitin carboxyl hydrolase (UCH) domain (including the BARD1 interaction region) of the BAP1 protein emerged as a hotspot region for missense mutations.	('BAP1', 'Gene', '8314', (94, 98))	('carboxyl', 'Chemical', 'MESH:C041069', (14, 22))	('missense mutations', 'Var', (139, 157))	('BARD1', 'Gene', '580', (61, 66))	('BARD1', 'Gene', (61, 66))	('BAP1', 'Gene', (94, 98))	('ubiquitin', 'molecular_function', 'GO:0031386', ('4', '13'))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))
57328	31635116	Importantly, among the conserved UCH residues (C91, H169, and D184), two mutations (C91G, H169P) showed a high EA score.	('C91G', 'Mutation', 'c.91C>G', (84, 88))	('C91G', 'Var', (84, 88))	('H169P', 'Var', (90, 95))	('H169', 'Chemical', 'MESH:C005718', (52, 56))	('H169', 'Chemical', 'MESH:C005718', (90, 94))	('H169P', 'SUBSTITUTION', 'None', (90, 95))	('C91', 'Var', (47, 50))	('D184', 'Chemical', 'MESH:C101289', (62, 66))
57329	31635116	A comparison to 4,772 missense BAP1 variants resulting from all possible nucleotide changes, the observed BAP1 variants were significantly skewed (Kolmogorov-Smirnov p-value of 10-4) to EA scores of 80-100 predicting them to be highly pathogenic (Figure1D, Table S1).	('BAP1', 'Gene', (106, 110))	('BAP1', 'Gene', '8314', (31, 35))	('pathogenic', 'Reg', (235, 245))	('variants', 'Var', (111, 119))	('BAP1', 'Gene', (31, 35))	('BAP1', 'Gene', '8314', (106, 110))	('variants', 'Var', (36, 44))
57331	31635116	Three mutations (S63C, S98R, T117R) were found to be overlapping with these phosphorylation sites (Figure 1B, Figure S2, Table S1).	('T117R', 'Mutation', 'p.T117R', (29, 34))	('phosphorylation', 'biological_process', 'GO:0016310', ('76', '91'))	('S98R', 'Mutation', 'p.S98R', (23, 27))	('S63C', 'SUBSTITUTION', 'None', (17, 21))	('S98R', 'Var', (23, 27))	('S63C', 'Var', (17, 21))	('T117R', 'Var', (29, 34))
57332	31635116	BAP1 model obtained from the ITASSER (C-score: -0.52) showed a clear structural division into ordered N and C terminal regions linked by a disordered 74 amino acid long stretch (residues 336-410) (Figure 1C).	('BAP1', 'Gene', (0, 4))	('amino', 'Chemical', 'MESH:D000596', (153, 158))	('N', 'Chemical', 'MESH:D009584', (102, 103))	('residues 336-410', 'Var', (178, 194))	('BAP1', 'Gene', '8314', (0, 4))
57341	31635116	A high percentage of the BAP1 mutations were observed in the UCH domain.	('BAP1', 'Gene', '8314', (25, 29))	('mutations', 'Var', (30, 39))	('BAP1', 'Gene', (25, 29))	('observed', 'Reg', (45, 53))
57342	31635116	A number of these mutations comprise substitutions to amino acids like glycine and proline (D68G, Q85P, C91G, L100P, H169P, L180, PE182G) that will result in disruption of the helices and exposure of the hydrophobic core to solvents, thereby leading to the unfolding of this domain.	('L180', 'Var', (124, 128))	('L100P', 'Var', (110, 115))	('PE182G', 'Chemical', 'MESH:C096583', (130, 136))	('Q85P', 'Mutation', 'p.Q85P', (98, 102))	('amino', 'Chemical', 'MESH:D000596', (54, 59))	('PE182G', 'Var', (130, 136))	('Q85P', 'Var', (98, 102))	('C91G', 'Var', (104, 108))	('glycine', 'Chemical', 'MESH:D005998', (71, 78))	('unfolding', 'MPA', (257, 266))	('proline', 'Chemical', 'MESH:C489032', (83, 90))	('core', 'cellular_component', 'GO:0019013', ('216', '220'))	('H169P', 'Var', (117, 122))	('D68G', 'Mutation', 'rs1194652468', (92, 96))	('helices', 'Protein', (176, 183))	('disruption', 'NegReg', (158, 168))	('leading to', 'Reg', (242, 252))	('H169P', 'SUBSTITUTION', 'None', (117, 122))	('exposure', 'MPA', (188, 196))	('D68G', 'Var', (92, 96))	('C91G', 'Mutation', 'c.91C>G', (104, 108))	('L100P', 'Mutation', 'p.L100P', (110, 115))
57343	31635116	The mutation C91 in the UCH region is substituted to cysteines which could result in the formation of native disulfide bonds and alters the conformational landscape of the UCH domain, therefore, deleteriously affecting the enzymatic efficiency.	('enzymatic', 'MPA', (223, 232))	('formation', 'MPA', (89, 98))	('result', 'Reg', (75, 81))	('alters', 'Reg', (129, 135))	('conformational landscape of', 'MPA', (140, 167))	('affecting', 'Reg', (209, 218))	('cysteines', 'Chemical', 'MESH:D003545', (53, 62))	('C91', 'Var', (13, 16))	('native disulfide bonds', 'MPA', (102, 124))	('disulfide', 'Chemical', 'MESH:D004220', (109, 118))	('formation', 'biological_process', 'GO:0009058', ('89', '98'))
57344	31635116	C91 has been previously shown to ablate enzymatic activity without interfering with its interactions with BRCA1 or with FOXK1/FOXK2.	('FOXK1', 'Gene', (120, 125))	('BRCA1', 'Gene', (106, 111))	('ablate', 'NegReg', (33, 39))	('FOXK2', 'Gene', '3607', (126, 131))	('C91', 'Var', (0, 3))	('enzymatic activity', 'MPA', (40, 58))	('FOXK2', 'Gene', (126, 131))	('FOXK1', 'Gene', '221937', (120, 125))	('BRCA1', 'Gene', '672', (106, 111))	('interactions', 'Interaction', (88, 100))
57345	31635116	The three germline mutations (L100P, R146K, L180P) occurring on the UCH domain are semi-conserved in their biophysical and biochemical nature, and therefore, are expected to have less deleterious consequences on this domain.	('L100P', 'Var', (30, 35))	('L100P', 'Mutation', 'p.L100P', (30, 35))	('R146K', 'Var', (37, 42))	('R146K', 'Mutation', 'p.R146K', (37, 42))	('L180P', 'Mutation', 'p.L180P', (44, 49))	('L180P', 'Var', (44, 49))
57346	31635116	A number of mutations also involve the substitution of a hydrophobic residue to a large polar charged residue like arginine (G45R, S98R, L112R, G128R, H141R, S172R, P175R, T177R, G185R) which will disturb the closely packed hydrophobic core of the UCH domain and contribute to the unfolding of the domain structure.	('G45R', 'Var', (125, 129))	('H141R', 'Var', (151, 156))	('arginine', 'Chemical', 'MESH:D001127', (115, 123))	('disturb', 'Reg', (197, 204))	('G185R', 'Var', (179, 184))	('unfolding', 'MPA', (281, 290))	('core', 'cellular_component', 'GO:0019013', ('236', '240'))	('closely packed hydrophobic core of the', 'MPA', (209, 247))	('H141R', 'Mutation', 'p.H141R', (151, 156))	('G185R', 'Mutation', 'p.G185R', (179, 184))	('G128R', 'Mutation', 'p.G128R', (144, 149))	('S172R', 'Var', (158, 163))	('G128R', 'Var', (144, 149))	('contribute', 'Reg', (263, 273))	('S172R', 'Mutation', 'p.S172R', (158, 163))	('domain structure', 'MPA', (298, 314))	('G45R', 'Mutation', 'p.G45R', (125, 129))	('P175R', 'Mutation', 'p.P175R', (165, 170))	('P175R', 'Var', (165, 170))	('L112R', 'Var', (137, 142))	('S98R', 'Mutation', 'p.S98R', (131, 135))	('T177R', 'Var', (172, 177))	('L112R', 'Mutation', 'p.L112R', (137, 142))	('T177R', 'Mutation', 'p.T177R', (172, 177))
57347	31635116	As compared to the mutations in the N-terminus, the mutations at the C-terminus (D672G, E602D) are few and occur mostly on the structurally disordered regions, and their impact most likely would be on either structural flexibility or on the interaction of BAP1 with other proteins.	('impact', 'Reg', (170, 176))	('D672G', 'Var', (81, 86))	('E602D', 'Var', (88, 93))	('structural flexibility', 'MPA', (208, 230))	('interaction', 'Interaction', (241, 252))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('BAP1', 'Gene', '8314', (256, 260))	('E602D', 'Mutation', 'rs759423683', (88, 93))	('D672G', 'SUBSTITUTION', 'None', (81, 86))	('BAP1', 'Gene', (256, 260))
57348	31635116	We had earlier reported one C-terminal mutation (c.2001delG; p.[Thr668Profs*24] close to the nuclear localization signals (NLS) region and have shown the structural changes in the BAP1 protein.	('protein', 'Protein', (185, 192))	('c.2001delG', 'Mutation', 'c.2001delG', (49, 59))	('BAP1', 'Gene', '8314', (180, 184))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('BAP1', 'Gene', (180, 184))	('c.2001delG;', 'Var', (49, 60))	('structural', 'MPA', (154, 164))	('localization', 'biological_process', 'GO:0051179', ('101', '113'))
57349	31635116	To define the consequences of these mutations, we also generated protein models from BAP1 associated proteins and performed docking studies.	('BAP1', 'Gene', (85, 89))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('mutations', 'Var', (36, 45))	('BAP1', 'Gene', '8314', (85, 89))
57350	31635116	To begin with, the poses generated by docking the BRCA1-BARD1 heterodimeric crystal structure on the BAP1 model resulted in an interesting pattern which further implicates the disordered amino stretch between the ordered regions of BAP1 as a critical region for protein flexibility (Figure 2, Figure S1).	('BAP1', 'Gene', (232, 236))	('BRCA1', 'Gene', (50, 55))	('amino', 'Chemical', 'MESH:D000596', (187, 192))	('disordered amino stretch', 'Var', (176, 200))	('BAP1', 'Gene', '8314', (101, 105))	('implicates', 'Reg', (161, 171))	('BAP1', 'Gene', (101, 105))	('BAP1', 'Gene', '8314', (232, 236))	('BARD1', 'Gene', '580', (56, 61))	('BRCA1', 'Gene', '672', (50, 55))	('BARD1', 'Gene', (56, 61))	('protein', 'cellular_component', 'GO:0003675', ('262', '269'))
57357	31635116	This conformational transition could have critical implications for mutations especially at the docking interfaces of all three proteins, or even at the domain boundaries of BAP1 that could potentially hinder the complex formation (E182G, G185R, E212D, N229D, S278L, S280T, E602D).	('formation', 'biological_process', 'GO:0009058', ('221', '230'))	('S278L', 'Var', (260, 265))	('N229D', 'Var', (253, 258))	('E182G', 'Mutation', 'rs876658395', (232, 237))	('S278L', 'Mutation', 'p.S278L', (260, 265))	('BAP1', 'Gene', '8314', (174, 178))	('E602D', 'Var', (274, 279))	('hinder', 'NegReg', (202, 208))	('S280T', 'Mutation', 'p.S280T', (267, 272))	('N229D', 'Mutation', 'p.N229D', (253, 258))	('BAP1', 'Gene', (174, 178))	('E602D', 'Mutation', 'rs759423683', (274, 279))	('G185R', 'Var', (239, 244))	('E212D', 'Var', (246, 251))	('S280T', 'Var', (267, 272))	('E182G', 'Var', (232, 237))	('G185R', 'Mutation', 'p.G185R', (239, 244))	('E212D', 'SUBSTITUTION', 'None', (246, 251))	('complex formation', 'Interaction', (213, 230))
57358	31635116	At the N-terminus, two mutations (E182G, G185R) showed specificity towards the BARD1 interaction site (Figure 2B).	('G185R', 'Mutation', 'p.G185R', (41, 46))	('BARD1', 'Gene', '580', (79, 84))	('E182G', 'Var', (34, 39))	('specificity', 'Reg', (55, 66))	('G185R', 'Var', (41, 46))	('BARD1', 'Gene', (79, 84))	('E182G', 'Mutation', 'rs876658395', (34, 39))	('N', 'Chemical', 'MESH:D009584', (7, 8))
57359	31635116	The C-terminus harbors very few mutations; however, three among them were located on the positions used by BAP1 to interact with other distant proteins, such as D672 (YY1), E602D (BRCA1), and S482L (FOXK2).	('S482L', 'Mutation', 'rs753329341', (192, 197))	('BAP1', 'Gene', '8314', (107, 111))	('YY1', 'Gene', '7528', (167, 170))	('BRCA1', 'Gene', '672', (180, 185))	('BAP1', 'Gene', (107, 111))	('YY1', 'Gene', (167, 170))	('FOXK2', 'Gene', (199, 204))	('E602D', 'Mutation', 'rs759423683', (173, 178))	('S482L', 'Var', (192, 197))	('BRCA1', 'Gene', (180, 185))	('FOXK2', 'Gene', '3607', (199, 204))	('D672', 'Var', (161, 165))	('interact', 'Reg', (115, 123))	('E602D', 'Var', (173, 178))
57360	31635116	A very limited number of mutations (S482L, D672G, E182G, G185R, E602D) were observed in the putative interface regions of BAP1 (Figure 2C,D, Figure S1).	('E602D', 'Mutation', 'rs759423683', (64, 69))	('D672G', 'Var', (43, 48))	('BAP1', 'Gene', (122, 126))	('E602D', 'Var', (64, 69))	('G185R', 'Var', (57, 62))	('E182G', 'Var', (50, 55))	('S482L', 'Var', (36, 41))	('E182G', 'Mutation', 'rs876658395', (50, 55))	('G185R', 'Mutation', 'p.G185R', (57, 62))	('D672G', 'SUBSTITUTION', 'None', (43, 48))	('BAP1', 'Gene', '8314', (122, 126))	('S482L', 'Mutation', 'rs753329341', (36, 41))
57361	31635116	These mutations also either act as a helix breaker or result in the changes in electrostatic polarity (except E602D).	('result', 'Reg', (54, 60))	('E602D', 'Mutation', 'rs759423683', (110, 115))	('helix', 'CPA', (37, 42))	('changes', 'Reg', (68, 75))	('electrostatic polarity', 'MPA', (79, 101))	('E602D', 'Var', (110, 115))
57363	31635116	Only one of the C-terminal BAP1 mutations lies in the BRCA1 interaction domain and might have implications in its putative interaction with BRCA1, even though the wild type and the substituted amino acid, in this case, are similar in nature.	('BRCA1', 'Gene', (140, 145))	('amino', 'Chemical', 'MESH:D000596', (193, 198))	('BAP1', 'Gene', (27, 31))	('BAP1', 'Gene', '8314', (27, 31))	('implications', 'Reg', (94, 106))	('mutations', 'Var', (32, 41))	('BRCA1', 'Gene', '672', (54, 59))	('lies', 'Reg', (42, 46))	('BRCA1', 'Gene', '672', (140, 145))	('interaction', 'Interaction', (123, 134))	('BRCA1', 'Gene', (54, 59))
57365	31635116	To determine the impact of BAP1 mutants on these miRNAs, we calculated the respective binding affinities for each variant versus individual miRNAs.	('variant', 'Var', (114, 121))	('BAP1', 'Gene', (27, 31))	('binding', 'Interaction', (86, 93))	('N', 'Chemical', 'MESH:D009584', (143, 144))	('binding', 'molecular_function', 'GO:0005488', ('86', '93'))	('N', 'Chemical', 'MESH:D009584', (52, 53))	('BAP1', 'Gene', '8314', (27, 31))
57367	31635116	However, D672G and E602D were found to have a higher minimum free binding energy (mfe) as compared to other mutations (Figure 3A, Table S2).	('minimum free binding energy', 'MPA', (53, 80))	('E602D', 'Var', (19, 24))	('binding', 'molecular_function', 'GO:0005488', ('66', '73'))	('higher', 'PosReg', (46, 52))	('D672G', 'SUBSTITUTION', 'None', (9, 14))	('E602D', 'Mutation', 'rs759423683', (19, 24))	('D672G', 'Var', (9, 14))
57368	31635116	The binding affinity of C-terminal mutations was stronger than for mutations at the N-terminus which was evident from the seven mutations (G45R, Q85P, S98R, G128R, H141R, S172R, G185R) located in the UCH domain showing a varying range of the mfe.	('G185R', 'Mutation', 'p.G185R', (178, 183))	('N', 'Chemical', 'MESH:D009584', (84, 85))	('Q85P', 'Var', (145, 149))	('G45R', 'Var', (139, 143))	('binding', 'molecular_function', 'GO:0005488', ('4', '11'))	('S172R', 'Var', (171, 176))	('H141R', 'Var', (164, 169))	('G185R', 'Var', (178, 183))	('stronger', 'PosReg', (49, 57))	('H141R', 'Mutation', 'p.H141R', (164, 169))	('S172R', 'Mutation', 'p.S172R', (171, 176))	('G45R', 'Mutation', 'p.G45R', (139, 143))	('G128R', 'Var', (157, 162))	('binding affinity', 'Interaction', (4, 20))	('S98R', 'Mutation', 'p.S98R', (151, 155))	('S98R', 'Var', (151, 155))	('G128R', 'Mutation', 'p.G128R', (157, 162))	('Q85P', 'Mutation', 'p.Q85P', (145, 149))
57374	31635116	Hence, one may speculate about the local impact of these mutations on the BAP1-associated miRNA network.	('BAP1', 'Gene', '8314', (74, 78))	('mutations', 'Var', (57, 66))	('BAP1', 'Gene', (74, 78))	('N', 'Chemical', 'MESH:D009584', (93, 94))
57381	31635116	By virtue of the complex regulation of the BAP1 gene and its associated proteins, it can be assumed that the specific type of genetic rearrangements (mutations, polymorphisms) in this gene will lead to disease-specific functional consequences.	('rearrangements', 'Var', (134, 148))	('genetic rearrangements', 'Var', (126, 148))	('BAP1', 'Gene', (43, 47))	('lead to', 'Reg', (194, 201))	('regulation', 'biological_process', 'GO:0065007', ('25', '35'))	('polymorphisms', 'Var', (161, 174))	('BAP1', 'Gene', '8314', (43, 47))
57382	31635116	Considering this, we conducted this study to determine the potential impact of UM-associated mutations in BAP1-related protein complexes.	('mutations', 'Var', (93, 102))	('BAP1', 'Gene', (106, 110))	('UM', 'Disease', 'MESH:C536494', (79, 81))	('BAP1', 'Gene', '8314', (106, 110))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))
57385	31635116	Interestingly, most of the mutations showed a very high evolutionary action (EA) score, which is consistent with the fact that BAP1 acts as tumor suppressor and harbors metastatic potential in combination with other factors.	('mutations', 'Var', (27, 36))	('BAP1', 'Gene', (127, 131))	('metastatic potential', 'CPA', (169, 189))	('evolutionary', 'MPA', (56, 68))	('tumor suppressor', 'biological_process', 'GO:0051726', ('140', '156'))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('140', '156'))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('BAP1', 'Gene', '8314', (127, 131))	('tumor', 'Disease', (140, 145))
57387	31635116	In context to the functional impact of these mutations, one study has previously described the structural destabilization of BAP1 after mutations in the catalytic domain leading to aggregation, cytoplasmic sequestration and subsequent functional loss.	('functional', 'MPA', (235, 245))	('destabilization', 'NegReg', (106, 121))	('cytoplasmic sequestration', 'MPA', (194, 219))	('BAP1', 'Gene', '8314', (125, 129))	('aggregation', 'MPA', (181, 192))	('BAP1', 'Gene', (125, 129))	('mutations in', 'Var', (136, 148))	('structural', 'MPA', (95, 105))
57392	31635116	Our structural analysis clearly showed closer interactions of neighboring residues of the S482L mutation with the forkhead-associated domain of FOXK2.	('S482L', 'Var', (90, 95))	('S482L', 'Mutation', 'rs753329341', (90, 95))	('FOXK2', 'Gene', '3607', (144, 149))	('interactions', 'Interaction', (46, 58))	('FOXK2', 'Gene', (144, 149))
57394	31635116	The potential involvement of HCF-1 is also evident from the D672G mutation, which is located in the BAP1 region essential for interactions with transcription factor YY1.	('HCF-1', 'Gene', (29, 34))	('BAP1', 'Gene', '8314', (100, 104))	('transcription factor', 'molecular_function', 'GO:0000981', ('144', '164'))	('D672G', 'Var', (60, 65))	('transcription', 'biological_process', 'GO:0006351', ('144', '157'))	('interactions', 'Interaction', (126, 138))	('YY1', 'Gene', '7528', (165, 168))	('BAP1', 'Gene', (100, 104))	('HCF-1', 'Gene', '3054', (29, 34))	('YY1', 'Gene', (165, 168))	('involvement', 'Reg', (14, 25))	('D672G', 'SUBSTITUTION', 'None', (60, 65))
57397	31635116	In our structural analysis, the neighboring residues of mutation D672 were found to be directly involved in ASXL1-BAP1 interactions; hence, alterations in the activity of PR-DUB complex can be predicted.	('D672', 'Var', (65, 69))	('PR-DUB', 'Enzyme', (171, 177))	('activity', 'MPA', (159, 167))	('ASXL1', 'Gene', (108, 113))	('involved', 'Reg', (96, 104))	('BAP1', 'Gene', '8314', (114, 118))	('PR-DUB complex', 'cellular_component', 'GO:0035517', ('171', '185'))	('mutation D672', 'Var', (56, 69))	('alterations', 'Reg', (140, 151))	('BAP1', 'Gene', (114, 118))	('ASXL1', 'Gene', '171023', (108, 113))
57402	31635116	Since BARD1 directly interacts with BAP1, the major impact of mutations in BARD1 (E182G, G185R) as compared to BRCA1 (E602D) can be seen in the structural analysis.	('BARD1', 'Gene', '580', (75, 80))	('E182G', 'Var', (82, 87))	('BARD1', 'Gene', '580', (6, 11))	('G185R', 'Var', (89, 94))	('BAP1', 'Gene', '8314', (36, 40))	('BRCA1', 'Gene', '672', (111, 116))	('E182G', 'Mutation', 'rs876658395', (82, 87))	('BARD1', 'Gene', (75, 80))	('BARD1', 'Gene', (6, 11))	('E602D', 'Mutation', 'rs759423683', (118, 123))	('interacts', 'Interaction', (21, 30))	('BRCA1', 'Gene', (111, 116))	('BAP1', 'Gene', (36, 40))	('G185R', 'Mutation', 'p.G185R', (89, 94))	('E602D', 'Var', (118, 123))
57403	31635116	It is also noteworthy to mention that we found 15 phosphorylation sites solely in the UCH domain of BAP1 and three mutations (S63C, S98R, T117R) were found to be overlapping with these sites.	('BAP1', 'Gene', '8314', (100, 104))	('S98R', 'Mutation', 'p.S98R', (132, 136))	('S98R', 'Var', (132, 136))	('BAP1', 'Gene', (100, 104))	('T117R', 'Var', (138, 143))	('phosphorylation', 'biological_process', 'GO:0016310', ('50', '65'))	('S63C', 'SUBSTITUTION', 'None', (126, 130))	('T117R', 'Mutation', 'p.T117R', (138, 143))	('phosphorylation sites', 'MPA', (50, 71))	('S63C', 'Var', (126, 130))
57404	31635116	There is concrete evidence in the literature that disruptions of phosphorylation sites are associated with cancer.	('phosphorylation sites', 'MPA', (65, 86))	('disruptions', 'Var', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('phosphorylation', 'biological_process', 'GO:0016310', ('65', '80'))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('associated', 'Reg', (91, 101))
57411	31635116	Likewise, miR-200a-3p (renal carcinoma, pancreatic cancer), miR-423-5p (gastric cancer), miR-31-5p(Oral Cancer), miR-141-3p (rectal cancer) and miR-140-3p.1 (breast cancer) have also been implicated in different types of cancer.	('miR-423-5p', 'Var', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('renal carcinoma', 'Disease', (23, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('renal carcinoma', 'Phenotype', 'HP:0005584', (23, 38))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('miR-141-3p', 'Var', (113, 123))	('pancreatic cancer', 'Disease', (40, 57))	('miR-140-3p.1', 'Var', (144, 156))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (80, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('Oral Cancer', 'Disease', (99, 110))	('breast cancer', 'Disease', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('miR-31', 'Gene', '407035', (89, 95))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('rectal cancer', 'Disease', (125, 138))	('rectal cancer', 'Phenotype', 'HP:0100743', (125, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('cancer', 'Disease', (221, 227))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (40, 57))	('cancer', 'Disease', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Oral Cancer', 'Disease', 'MESH:D009062', (99, 110))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('renal carcinoma', 'Disease', 'MESH:D002292', (23, 38))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('miR-200a-3p', 'Var', (10, 21))	('rectal cancer', 'Disease', 'MESH:D012004', (125, 138))	('implicated', 'Reg', (188, 198))	('423-5p', 'Chemical', 'MESH:C072935', (64, 70))	('cancer', 'Disease', (51, 57))	('gastric cancer', 'Disease', (72, 86))	('pancreatic cancer', 'Disease', 'MESH:D010190', (40, 57))	('miR-31', 'Gene', (89, 95))
57413	31635116	This, in turn, suggests that the BAP1-miRNAs associated network (in combination with respective BAP1 mutations) might have an independent impact in UM.	('mutations', 'Var', (101, 110))	('impact', 'Reg', (138, 144))	('BAP1', 'Gene', (96, 100))	('BAP1', 'Gene', '8314', (33, 37))	('UM', 'Disease', 'MESH:C536494', (148, 150))	('BAP1', 'Gene', (33, 37))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('BAP1', 'Gene', '8314', (96, 100))
57416	31635116	Considering this, we checked the BAP1 gene expression from the TCGA dataset and found that regardless of the mutation type, an alteration of the BAP1 gene expression can be used for the prognosis in 29 tumor types.	('gene expression', 'biological_process', 'GO:0010467', ('150', '165'))	('tumor', 'Disease', (202, 207))	('BAP1', 'Gene', '8314', (33, 37))	('BAP1', 'Gene', '8314', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('alteration', 'Var', (127, 137))	('BAP1', 'Gene', (33, 37))	('BAP1', 'Gene', (145, 149))	('gene expression', 'biological_process', 'GO:0010467', ('38', '53'))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
57421	31635116	The following are available online at , Figure S1: BAP1 variants and stability of multiprotein complexes.	('variants', 'Var', (56, 64))	('BAP1', 'Gene', '8314', (51, 55))	('BAP1', 'Gene', (51, 55))
57427	31186267	This analysis revealed a clonal PLCB4 mutation in the melanocytosis, confirming that this is indeed a neoplastic condition and explaining why it predisposes to UM.	('PLCB4', 'Gene', (32, 37))	('melanocytosis', 'Disease', (54, 67))	('neoplastic condition', 'Phenotype', 'HP:0002664', (102, 122))	('UM', 'Phenotype', 'HP:0007716', (160, 162))	('melanocytosis', 'Disease', 'MESH:C535835', (54, 67))	('mutation', 'Var', (38, 46))	('PLCB4', 'Gene', '5332', (32, 37))
57430	31186267	A mutation in BAP1 arose later on the other copy of Chromosome 3 in a tumor subclone, followed by a gain of Chromosome 8q.	('BAP1', 'Gene', '8314', (14, 18))	('Chromosome', 'cellular_component', 'GO:0005694', ('108', '118'))	('mutation', 'Var', (2, 10))	('gain', 'PosReg', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('BAP1', 'Gene', (14, 18))	('Chromosome', 'cellular_component', 'GO:0005694', ('52', '62'))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
57435	31186267	Ocular melanocytosis is the strongest predisposing factor for uveal melanoma (UM), increasing its risk from ~1 in 230,000 to ~1 in 400, and its presence doubles the risk of metastasis from UM.	('UM', 'Phenotype', 'HP:0007716', (189, 191))	('uveal melanoma', 'Disease', (62, 76))	('metastasis', 'CPA', (173, 183))	('Ocular melanocytosis', 'Disease', 'MESH:C535835', (0, 20))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('Ocular melanocytosis', 'Disease', (0, 20))	('UM', 'Phenotype', 'HP:0007716', (78, 80))	('presence', 'Var', (144, 152))	('uveal melanoma', 'Phenotype', 'HP:0007716', (62, 76))	('uveal melanoma', 'Disease', 'MESH:C536494', (62, 76))	('Ocular melanocytosis', 'Phenotype', 'HP:0025534', (0, 20))
57437	31186267	The first is characterized by mutually exclusive gain-of-function point mutations in members of the Gq signaling pathway (GNAQ, GNA11, CYSLTR2, and PLCB4), which trigger constitutive activation of proliferative and survival signals.	('Gq signaling pathway', 'Pathway', (100, 120))	('GNA11', 'Gene', '2767', (128, 133))	('GNA11', 'Gene', (128, 133))	('activation', 'PosReg', (183, 193))	('signaling pathway', 'biological_process', 'GO:0007165', ('103', '120'))	('GNAQ', 'Gene', (122, 126))	('PLCB4', 'Gene', '5332', (148, 153))	('proliferative', 'CPA', (197, 210))	('point mutations', 'Var', (66, 81))	('CYSLTR2', 'Gene', '57105', (135, 142))	('gain-of-function', 'PosReg', (49, 65))	('PLCB4', 'Gene', (148, 153))	('CYSLTR2', 'Gene', (135, 142))	('GNAQ', 'Gene', '2776', (122, 126))
57438	31186267	The second mutational node consists of near-mutually exclusive mutations in the tumor suppressor BAP1, the splicing factors SF3B1, SF3A1, SRSF2, SRSF7, and RBM10, and the translational initiation factor EIF1AX.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('BAP1', 'Gene', (97, 101))	('RBM10', 'Gene', (156, 161))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))	('SF3B1', 'Gene', '23451', (124, 129))	('mutations', 'Var', (63, 72))	('SRSF2', 'Gene', '6427', (138, 143))	('RBM10', 'Gene', '8241', (156, 161))	('SRSF2', 'Gene', (138, 143))	('translational initiation', 'biological_process', 'GO:0006413', ('171', '195'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('EIF1AX', 'Gene', (203, 209))	('SF3A1', 'Gene', '10291', (131, 136))	('tumor', 'Disease', (80, 85))	('EIF1AX', 'Gene', '1964', (203, 209))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('splicing', 'biological_process', 'GO:0045292', ('107', '115'))	('SF3A1', 'Gene', (131, 136))	('BAP1', 'Gene', '8314', (97, 101))	('SRSF7', 'Gene', (145, 150))	('SF3B1', 'Gene', (124, 129))	('SRSF7', 'Gene', '6432', (145, 150))
57439	31186267	Notably, mutations in BAP1, located on Chromosome 3p21, are associated with loss of heterozygosity for Chromosome 3 (LOH3), leading to biallelic inactivation of BAP1 and poor prognosis.	('BAP1', 'Gene', (161, 165))	('Chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))	('mutations', 'Var', (9, 18))	('Chromosome', 'cellular_component', 'GO:0005694', ('103', '113'))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', '8314', (161, 165))	('biallelic', 'MPA', (135, 144))	('BAP1', 'Gene', (22, 26))
57440	31186267	By the time UMs are detected, the most recent common ancestral tumor clone usually contains a full complement of mutations and CNAs, indicating that these canonical aberrations occur early during tumor evolution.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (196, 201))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('mutations', 'Var', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
57449	31186267	Whole-exome sequencing (WES) followed by mutational analysis revealed a deleterious somatic single-nucleotide alteration (p.D630Y) in PLCB4 in both the tumor and melanocytosis but not in the blood (Fig.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('melanocytosis', 'Disease', (162, 175))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('melanocytosis', 'Disease', 'MESH:C535835', (162, 175))	('tumor', 'Disease', (152, 157))	('PLCB4', 'Gene', (134, 139))	('p.D630Y', 'Var', (122, 129))	('p.D630Y', 'Mutation', 'p.D630Y', (122, 129))	('PLCB4', 'Gene', '5332', (134, 139))
57450	31186267	An in-frame deletion (p.C320_D311del) that extended into the intronic region was detected in BAP1 in the tumor but not in the melanocytosis or blood (Table 1; Fig.	('BAP1', 'Gene', '8314', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('p.C320_D311del', 'Mutation', 'p.320_,311delC,D', (22, 36))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('BAP1', 'Gene', (93, 97))	('melanocytosis', 'Disease', (126, 139))	('tumor', 'Disease', (105, 110))	('melanocytosis', 'Disease', 'MESH:C535835', (126, 139))	('p.C320_D311del', 'Var', (22, 36))
57456	31186267	Although limitations in methodology did not allow detailed conclusions regarding genomic evolution, these findings imply that the BAP1 mutation and 8q gain occurred after LOH3, which is consistent with previous reports.	('gain', 'PosReg', (151, 155))	('BAP1', 'Gene', (130, 134))	('LOH3', 'Gene', (171, 175))	('BAP1', 'Gene', '8314', (130, 134))	('mutation', 'Var', (135, 143))
57457	31186267	Gq pathway mutations have been reported in UM, cutaneous blue nevi, and central nervous system melanocytic neoplasms.	('cutaneous blue nevi', 'Disease', (47, 66))	('nevi', 'Phenotype', 'HP:0003764', (62, 66))	('mutations', 'Var', (11, 20))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (95, 116))	('reported', 'Reg', (31, 39))	('Gq pathway', 'Pathway', (0, 10))	('central nervous system melanocytic neoplasms', 'Disease', (72, 116))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('blue nevi', 'Phenotype', 'HP:0100814', (57, 66))	('neoplasms', 'Phenotype', 'HP:0002664', (107, 116))	('central nervous system melanocytic neoplasms', 'Disease', 'MESH:D016543', (72, 116))
57458	31186267	However, this is the first direct demonstration of a Gq pathway mutation in the nonmalignant uveal tissue giving rise to melanoma in an eye with ocular melanocytosis.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('ocular melanocytosis', 'Phenotype', 'HP:0025534', (145, 165))	('melanoma', 'Disease', (121, 129))	('mutation', 'Var', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('ocular melanocytosis', 'Disease', (145, 165))	('Gq pathway', 'Gene', (53, 63))	('giving rise to', 'Reg', (106, 120))	('ocular melanocytosis', 'Disease', 'MESH:C535835', (145, 165))
57459	31186267	Further, it is the first report of a PLCB4 mutation in any form of ocular or oculodermal melanocytosis.	('mutation', 'Var', (43, 51))	('PLCB4', 'Gene', (37, 42))	('oculodermal melanocytosis', 'Phenotype', 'HP:0009920', (77, 102))	('ocular or oculodermal melanocytosis', 'Disease', (67, 102))	('ocular or oculodermal melanocytosis', 'Disease', 'MESH:C535835', (67, 102))	('PLCB4', 'Gene', '5332', (37, 42))
57461	31186267	Recently, we identified a second case of ocular melanocytosis in which the nonmalignant uveal tissue harbored a somatic GNA11 mutation (data not shown), suggesting that Gq pathway mutations may be characteristic of this condition.	('GNA11', 'Gene', (120, 125))	('mutation', 'Var', (126, 134))	('ocular melanocytosis', 'Disease', 'MESH:C535835', (41, 61))	('GNA11', 'Gene', '2767', (120, 125))	('ocular melanocytosis', 'Phenotype', 'HP:0025534', (41, 61))	('ocular melanocytosis', 'Disease', (41, 61))
57462	31186267	This oncogenic "first hit" mutation could explain the increased risk of UM associated with ocular melanocytosis and confirms that this condition represents a congenital nevus rather than simply an excess of normal melanocytes.	('ocular melanocytosis', 'Disease', 'MESH:C535835', (91, 111))	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('ocular melanocytosis', 'Phenotype', 'HP:0025534', (91, 111))	('nevus', 'Phenotype', 'HP:0003764', (169, 174))	('ocular melanocytosis', 'Disease', (91, 111))	('mutation', 'Var', (27, 35))
57464	31186267	We recently analyzed 151 primary UMs and showed that all of the canonical mutations and CNAs usually arose early in tumor evolution, making it difficult to discriminate the relative order in which these aberrations accrued.	('CNAs', 'Gene', (88, 92))	('UM', 'Phenotype', 'HP:0007716', (33, 35))	('mutations', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
57465	31186267	The PLCB4 mutation in the precursor melanocytosis was clearly the initiating event but could not effectuate malignant transformation without additional aberrations.	('PLCB4', 'Gene', '5332', (4, 9))	('melanocytosis', 'Disease', (36, 49))	('mutation', 'Var', (10, 18))	('PLCB4', 'Gene', (4, 9))	('melanocytosis', 'Disease', 'MESH:C535835', (36, 49))
57466	31186267	This finding is particularly interesting because mutant GNAQ signals to PKC through PLCbeta and thereby activates the MAPK pathway.	('activates', 'PosReg', (104, 113))	('mutant', 'Var', (49, 55))	('MAPK pathway', 'Pathway', (118, 130))	('PLCbeta', 'Enzyme', (84, 91))	('GNAQ', 'Gene', '2776', (56, 60))	('MAPK', 'molecular_function', 'GO:0004707', ('118', '122'))	('PKC', 'Enzyme', (72, 75))	('PKC', 'molecular_function', 'GO:0004697', ('72', '75'))	('GNAQ', 'Gene', (56, 60))	('signals', 'Reg', (61, 68))
57468	31186267	Additionally, by producing haploinsufficiency for BAP1, LOH3 may have created a selective pressure to inactivate the other BAP1 allele, a requisite event for conversion to the highly metastatic class 2 GEP.	('BAP1', 'Gene', (123, 127))	('BAP1', 'Gene', '8314', (50, 54))	('inactivate', 'NegReg', (102, 112))	('haploinsufficiency', 'Disease', 'MESH:D058495', (27, 45))	('BAP1', 'Gene', '8314', (123, 127))	('BAP1', 'Gene', (50, 54))	('LOH3', 'Var', (56, 60))	('haploinsufficiency', 'Disease', (27, 45))
57469	31186267	Gain of 8q was a late event and, hence, apparently not required for malignant transformation but likely providing a selective advantage during tumor progression.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', (143, 148))	('Gain', 'Var', (0, 4))
57470	31186267	For example, the failure of targeted therapies aimed at inhibiting the Gq pathway might be explained by the inability of these mutations to drive malignant tumor growth without additional genomic aberrations.	('malignant tumor', 'Disease', (146, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('inhibiting', 'NegReg', (56, 66))	('Gq pathway', 'Pathway', (71, 81))	('malignant tumor', 'Disease', 'MESH:D018198', (146, 161))	('mutations', 'Var', (127, 136))
57471	31186267	Further, some UMs with good prognosis exhibit LOH3 yet retain a wild-type BAP1 allele and class 1 GEP, suggesting that biallelic loss of BAP1 is required for conversion to the class 2 GEP and that LOH3 alone is insufficient to confer high metastatic risk.	('BAP1', 'Gene', (137, 141))	('UM', 'Phenotype', 'HP:0007716', (14, 16))	('loss', 'NegReg', (129, 133))	('BAP1', 'Gene', '8314', (74, 78))	('BAP1', 'Gene', '8314', (137, 141))	('BAP1', 'Gene', (74, 78))	('LOH3', 'Var', (46, 50))
57486	30305285	EIF1AX and RAS mutations cooperate to drive thyroid tumorigenesis through ATF4 and c-MYC Translation initiation is orchestrated by the cap binding and 43S pre-initiation complexes (PIC).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('RAS', 'Gene', (11, 14))	('ATF4', 'Gene', (74, 78))	('mutations', 'Var', (15, 24))	('thyroid tumorigenesis', 'Disease', (44, 65))	('c-MYC Translation initiation', 'MPA', (83, 111))	('drive', 'PosReg', (38, 43))	('Translation initiation', 'biological_process', 'GO:0006413', ('89', '111'))	('PIC', 'cellular_component', 'GO:0019035', ('181', '184'))	('ATF4', 'Gene', '468', (74, 78))	('PIC', 'cellular_component', 'GO:0097550', ('181', '184'))	('binding', 'molecular_function', 'GO:0005488', ('139', '146'))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('pre', 'molecular_function', 'GO:0003904', ('155', '158'))
57488	30305285	Recurrent EIF1AX mutations in papillary thyroid cancers are mutually exclusive with other drivers, including RAS.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('thyroid cancer', 'Phenotype', 'HP:0002890', (40, 54))	('mutations', 'Var', (17, 26))	('papillary thyroid cancers', 'Disease', 'MESH:C536915', (30, 55))	('papillary thyroid cancers', 'Disease', (30, 55))	('papillary thyroid cancers', 'Phenotype', 'HP:0002895', (30, 55))	('EIF1AX', 'Gene', (10, 16))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))
57489	30305285	EIF1AX is enriched in advanced thyroid cancers, where it displays a striking co-occurrence with RAS, which cooperates to induce tumorigenesis in mice and isogenic cell lines.	('EIF1AX', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('thyroid cancer', 'Phenotype', 'HP:0002890', (31, 45))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('thyroid cancers', 'Disease', (31, 46))	('spl', 'Gene', '8879', (59, 62))	('spl', 'Gene', (59, 62))	('induce', 'PosReg', (121, 127))	('mice', 'Species', '10090', (145, 149))	('thyroid cancers', 'Disease', 'MESH:D013964', (31, 46))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Disease', (128, 133))
57490	30305285	The C-terminal EIF1AX-A113splice mutation is the most prevalent in advanced thyroid cancer.	('spl', 'Gene', (26, 29))	('thyroid cancer', 'Phenotype', 'HP:0002890', (76, 90))	('thyroid cancer', 'Disease', (76, 90))	('prevalent', 'Reg', (54, 63))	('C-terminal', 'Var', (4, 14))	('thyroid cancer', 'Disease', 'MESH:D013964', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('spl', 'Gene', '8879', (26, 29))
57491	30305285	EIF1AX-A113spl variants stabilize the PIC and induce ATF4, a sensor of cellular stress, which is co-opted to suppress EIF2alpha phosphorylation, enabling a general increase in protein synthesis.	('phosphorylation', 'biological_process', 'GO:0016310', ('128', '143'))	('protein synthesis', 'MPA', (176, 193))	('EIF2', 'cellular_component', 'GO:0005850', ('118', '122'))	('protein synthesis', 'biological_process', 'GO:0006412', ('176', '193'))	('ATF4', 'Gene', (53, 57))	('PIC', 'MPA', (38, 41))	('spl', 'Gene', (11, 14))	('spl', 'Gene', '8879', (11, 14))	('suppress', 'NegReg', (109, 117))	('EIF2alpha', 'Gene', '83939', (118, 127))	('PIC', 'cellular_component', 'GO:0019035', ('38', '41'))	('PIC', 'cellular_component', 'GO:0097550', ('38', '41'))	('EIF2alpha', 'Gene', (118, 127))	('phosphorylation', 'MPA', (128, 143))	('stabilize', 'Reg', (24, 33))	('variants', 'Var', (15, 23))	('increase', 'PosReg', (164, 172))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))
57493	30305285	ATF4 and c-MYC induce expression of aminoacid transporters and enhance sensitivity of mTOR to aminoacid supply.	('amino', 'Chemical', 'MESH:D000596', (94, 99))	('sensitivity of mTOR to aminoacid supply', 'MPA', (71, 110))	('enhance', 'PosReg', (63, 70))	('amino', 'Chemical', 'MESH:D000596', (36, 41))	('c-MYC', 'Gene', (9, 14))	('aminoacid transporters', 'MPA', (36, 58))	('expression', 'Species', '29278', (22, 32))	('c-MYC', 'Gene', '4609', (9, 14))	('expression', 'MPA', (22, 32))	('ATF4', 'Var', (0, 4))
57496	30305285	They are usually indolent tumors that harbor mutually exclusive mutations in BRAF, RAS or fusions of RET, NTRK or BRAF.	('RET', 'Gene', (101, 104))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('BRAF', 'Gene', '673', (77, 81))	('RAS', 'Gene', (83, 86))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('N', 'Chemical', 'MESH:D009584', (106, 107))	('BRAF', 'Gene', (77, 81))	('RET', 'Gene', '5979', (101, 104))	('mutations', 'Var', (64, 73))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
57497	30305285	The TCGA study of PTC identified additional driver alterations present at lower frequency, including EIF1AX, PPM1D and CHEK2 .	('CHEK2', 'Gene', (119, 124))	('PPM1D', 'Gene', (109, 114))	('EIF1AX', 'Var', (101, 107))	('PPM1D', 'Gene', '8493', (109, 114))	('CHEK2', 'Gene', '11200', (119, 124))
57499	30305285	Although BRAF and RAS mutations are also the main drivers, as compared to PTC they are more frequently associated with mutations of the TERT promoter, TP53, genes encoding PI3K/AKT/mTOR pathway effectors or chromatin modifiers.	('AKT', 'Gene', '207', (177, 180))	('TP53', 'Gene', (151, 155))	('TERT', 'Gene', (136, 140))	('associated', 'Reg', (103, 113))	('RAS', 'Gene', (18, 21))	('BRAF', 'Gene', (9, 13))	('TERT', 'Gene', '7015', (136, 140))	('AKT', 'Gene', (177, 180))	('mutations', 'Var', (22, 31))	('PI3K', 'molecular_function', 'GO:0016303', ('172', '176'))	('chromatin', 'cellular_component', 'GO:0000785', ('207', '216'))	('mutations', 'Var', (119, 128))	('TP53', 'Gene', '7157', (151, 155))	('BRAF', 'Gene', '673', (9, 13))
57504	30305285	Deregulation of translation initiation is common in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Deregulation', 'Var', (0, 12))	('tumor', 'Disease', (52, 57))	('translation initiation', 'biological_process', 'GO:0006413', ('16', '38'))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('translation initiation', 'MPA', (16, 38))
57505	30305285	Increased expression of components of the EIF4F cap binding complex (EIF4E, EIF4A, EIF4G) is seen in many cancers.	('EIF4G', 'Var', (83, 88))	('binding', 'molecular_function', 'GO:0005488', ('52', '59'))	('EIF4F', 'cellular_component', 'GO:0016281', ('42', '47'))	('EIF4E', 'Gene', '1977', (69, 74))	('EIF4A', 'Gene', '1973', (76, 81))	('EIF4A', 'Gene', (76, 81))	('expression', 'MPA', (10, 20))	('expression', 'Species', '29278', (10, 20))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('EIF4E', 'Gene', (69, 74))	('cancers', 'Disease', (106, 113))	('Increased', 'PosReg', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('EIF4', 'cellular_component', 'GO:0008304', ('83', '87'))	('EIF4', 'cellular_component', 'GO:0008304', ('76', '80'))	('EIF4', 'cellular_component', 'GO:0008304', ('69', '73'))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
57508	30305285	To our knowledge EIF1AX is the only example of a PIC subunit recurrently mutated in cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('PIC', 'cellular_component', 'GO:0097550', ('49', '52'))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('EIF1AX', 'Var', (17, 23))	('PIC', 'cellular_component', 'GO:0019035', ('49', '52'))
57509	30305285	Mutations of EIF1AX were first reported in uveal melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('uveal melanomas', 'Disease', (43, 58))	('reported', 'Reg', (31, 39))	('uveal melanomas', 'Phenotype', 'HP:0007716', (43, 58))	('uveal melanomas', 'Disease', 'MESH:C536494', (43, 58))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('EIF1AX', 'Gene', (13, 19))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
57512	30305285	EIF1AX mutations have been reported in benign thyroid adenomas , follicular carcinomas as well as in ~1% of PTC in a mutually exclusive manner with other drivers.	('thyroid adenomas', 'Phenotype', 'HP:0000854', (46, 62))	('reported', 'Reg', (27, 35))	('follicular carcinomas', 'Phenotype', 'HP:0031548', (65, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('follicular carcinomas', 'Disease', (65, 86))	('follicular carcinomas', 'Disease', 'MESH:C572845', (65, 86))	('benign thyroid adenomas', 'Disease', (39, 62))	('benign thyroid adenomas', 'Disease', 'MESH:D013964', (39, 62))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
57514	30305285	The striking co-evolution of EIF1AX and RAS mutations in advanced disease suggests that they may cooperate to drive tumor progression.	('tumor', 'Disease', (116, 121))	('EIF1AX', 'Gene', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutations', 'Var', (44, 53))	('RAS', 'Gene', (40, 43))	('drive', 'PosReg', (110, 115))
57516	30305285	EIF1AX mutations identified in several cancers encode somatic substitutions in the first 2-15 amino acids of the NTT, whereas thyroid cancers harbour an additional hotspot splice site mutation (EIF1AX-A113splice) in the CTT that is private to this disease .	('thyroid cancers', 'Disease', 'MESH:D013964', (126, 141))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('thyroid cancer', 'Phenotype', 'HP:0002890', (126, 140))	('2-15 amino acids', 'Chemical', 'MESH:D000596', (89, 105))	('EIF1AX', 'Gene', (0, 6))	('substitutions', 'Var', (62, 75))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('spl', 'Gene', '8879', (205, 208))	('spl', 'Gene', (205, 208))	('mutations', 'Var', (7, 16))	('thyroid cancers', 'Disease', (126, 141))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('spl', 'Gene', '8879', (172, 175))	('spl', 'Gene', (172, 175))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('cancers', 'Disease', (39, 46))	('NTT', 'Disease', (113, 116))	('cancers', 'Disease', 'MESH:D009369', (134, 141))
57517	30305285	Structure-function studies in yeast revealed that mutating any of the NTT residues between 7 and 16 amino acid were lethal and resulted in leaky scanning of the initiation AUG codon, and discriminated against AUGs with poor context.	('yeast', 'Species', '4932', (30, 35))	('resulted in', 'Reg', (127, 138))	('leaky scanning', 'MPA', (139, 153))	('mutating', 'Var', (50, 58))	('NTT', 'Gene', (70, 73))	('N', 'Chemical', 'MESH:D009584', (70, 71))	('amino', 'Chemical', 'MESH:D000596', (100, 105))
57519	30305285	Here we describe the identification of the key signaling drivers of transformation by EIF1AX mutants, particularly EIF1AX-A113splice, alone and in the context of RAS, and the therapeutic dependencies they confer.	('spl', 'Gene', '8879', (126, 129))	('spl', 'Gene', (126, 129))	('mutants', 'Var', (93, 100))	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))	('EIF1AX', 'Gene', (86, 92))
57520	30305285	Analysis of our institutional clinical genomics database of 148 advanced thyroid cancers coupled to data from two previously published studies  showed that 26/246 (11%) tumors harbored EIF1AX mutations, 25 of which were associated with mutant RAS (25/26; p=3.15x10E-13) (Fig.	('RAS', 'Protein', (243, 246))	('thyroid cancer', 'Phenotype', 'HP:0002890', (73, 87))	('associated', 'Reg', (220, 230))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('thyroid cancers', 'Disease', (73, 88))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('mutant', 'Var', (236, 242))	('thyroid cancers', 'Disease', 'MESH:D013964', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('EIF1AX', 'Gene', (185, 191))	('mutations', 'Var', (192, 201))	('tumors', 'Disease', (169, 175))
57521	30305285	The EIF1AX mutations clustered within the first 15 amino acids of the N-terminal tail (NTT), as reported in uveal melanomas , or more frequently at a hotspot splice acceptor site upstream of exon 6 (A113splice) in the C-terminal tail (CTT) (17/26) (Fig.	('spl', 'Gene', '8879', (158, 161))	('mutations', 'Var', (11, 20))	('spl', 'Gene', (158, 161))	('uveal melanomas', 'Disease', 'MESH:C536494', (108, 123))	('melanomas', 'Phenotype', 'HP:0002861', (114, 123))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('spl', 'Gene', '8879', (203, 206))	('spl', 'Gene', (203, 206))	('uveal melanomas', 'Disease', (108, 123))	('uveal melanomas', 'Phenotype', 'HP:0007716', (108, 123))	('N', 'Chemical', 'MESH:D009584', (87, 88))	('amino', 'Chemical', 'MESH:D000596', (51, 56))	('EIF1AX', 'Gene', (4, 10))	('N', 'Chemical', 'MESH:D009584', (70, 71))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
57527	30305285	To explore the biological consequences of the EIF1AX-A113splice mutation, either alone or in the context of mutant RAS, we generated isogenic thyroid cancer cell lines by CRISPR-Cas9 knock-in of heterozygous mutations of A113splice into KRASG12R-mutant CAL62 or RAS-wild type TTA1 cells, and by reversing the endogenous A113splice mutation in HRASG13R and EIF1AXA113spl-mutant C643 cells (Fig.	('KRAS', 'Gene', (237, 241))	('mutations', 'Var', (208, 217))	('thyroid cancer', 'Disease', 'MESH:D013964', (142, 156))	('spl', 'Gene', '8879', (57, 60))	('spl', 'Gene', (57, 60))	('C643', 'Chemical', 'MESH:C040977', (377, 381))	('spl', 'Gene', '8879', (366, 369))	('spl', 'Gene', (366, 369))	('thyroid cancer', 'Phenotype', 'HP:0002890', (142, 156))	('spl', 'Gene', '8879', (324, 327))	('spl', 'Gene', (324, 327))	('HRAS', 'Gene', '3265', (343, 347))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('HRAS', 'Gene', (343, 347))	('KRAS', 'Gene', '3845', (237, 241))	('thyroid cancer', 'Disease', (142, 156))	('spl', 'Gene', '8879', (225, 228))	('Cas', 'cellular_component', 'GO:0005650', ('178', '181'))	('spl', 'Gene', (225, 228))
57533	30305285	We next investigated the interaction of oncogenic Hras and EIF1AX-c'spl in vivo.	('Hras', 'Gene', (50, 54))	('Hras', 'Gene', '3265', (50, 54))	("EIF1AX-c'spl", 'Var', (59, 71))
57537	30305285	These findings closely phenocopy the human thyroid histologies associated with an isolated EIF1AX mutation.	('human', 'Species', '9606', (37, 42))	('mutation', 'Var', (98, 106))	('EIF1AX', 'Gene', (91, 97))
57542	30305285	IP of HEK293T cells expressing HA-tagged wild-type (WT) EIF1AX, NTT mutants (G8R, G9R, G15V) or EIF1AX-c'spl with an antibody to HA showed pulldown of the TC component eukaryotic initiation factor 2alpha (EIF2alpha) by all EIF1AX proteins, with EIF1AX-c'spl showing greater affinity (Fig.	('antibody', 'cellular_component', 'GO:0042571', ('117', '125'))	("EIF1AX-c'spl", 'Var', (96, 108))	('antibody', 'cellular_component', 'GO:0019815', ('117', '125'))	('antibody', 'molecular_function', 'GO:0003823', ('117', '125'))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('antibody', 'cellular_component', 'GO:0019814', ('117', '125'))	('EIF2alpha', 'Gene', '83939', (205, 214))	('G15V', 'Mutation', 'rs1228670098', (87, 91))	('HEK293T', 'CellLine', 'CVCL:0063', (6, 13))	('pulldown', 'NegReg', (139, 147))	('EIF2alpha', 'Gene', (205, 214))	('G9R', 'Mutation', 'p.G9R', (82, 85))	('EIF2', 'cellular_component', 'GO:0005850', ('205', '209'))
57544	30305285	By contrast, EIF1AX mutants, particularly G8R, G9R and c'spl, exhibited increased affinity for EIF5 (Fig.	('EIF5', 'Gene', '1983', (95, 99))	('spl', 'Gene', (57, 60))	('increased', 'PosReg', (72, 81))	('affinity', 'Interaction', (82, 90))	('EIF5', 'Gene', (95, 99))	('G9R', 'Var', (47, 50))	('EIF1AX', 'Gene', (13, 19))	('G8R', 'Var', (42, 45))	('G9R', 'Mutation', 'p.G9R', (47, 50))	('spl', 'Gene', '8879', (57, 60))
57546	30305285	3C), and in thyroid cancer cells with endogenous EIF1AX mutations (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('EIF1AX', 'Gene', (49, 55))	('mutations', 'Var', (56, 65))	('thyroid cancer', 'Phenotype', 'HP:0002890', (12, 26))	('thyroid cancer', 'Disease', (12, 26))	('thyroid cancer', 'Disease', 'MESH:D013964', (12, 26))
57548	30305285	NthyOri cells stably expressing EIF1AX-G8R, G9R or EIF1AX-c'spl also showed an increase in nascent protein synthesis compared to WT, with c'spl having the greatest effect (Fig.	('increase', 'PosReg', (79, 87))	('EIF1AX-G8R', 'Var', (32, 42))	('spl', 'Gene', (60, 63))	('protein synthesis', 'biological_process', 'GO:0006412', ('99', '116'))	('spl', 'Gene', '8879', (140, 143))	('spl', 'Gene', (140, 143))	('spl', 'Gene', '8879', (60, 63))	('G9R', 'Var', (44, 47))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('G9R', 'Mutation', 'p.G9R', (44, 47))	('nascent protein synthesis', 'MPA', (91, 116))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))
57554	30305285	ATF4 is a key transcription factor that integrates responses to cell stressors, such as amino acid deficiency or ER protein folding defects.	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('transcription', 'biological_process', 'GO:0006351', ('14', '27'))	('defects', 'Var', (132, 139))	('amino acid deficiency', 'Disease', 'MESH:D000592', (88, 109))	('ATF4', 'Gene', (0, 4))	('transcription factor', 'molecular_function', 'GO:0000981', ('14', '34'))	('amino acid deficiency', 'Disease', (88, 109))	('protein folding', 'biological_process', 'GO:0006457', ('116', '131'))
57560	30305285	Expression of EIF1AX-WT or EIF1AX-c'spl in HEK293T cells co-transfected with appropriate reporters showed that the inhibitory uORF2 led to less efficient translation in EIF1AX mutant-expressing cells (Supplementary Fig.	("EIF1AX-c'spl", 'Var', (27, 39))	('less', 'NegReg', (139, 143))	('translation', 'biological_process', 'GO:0006412', ('154', '165'))	('mutant-expressing', 'Var', (176, 193))	('HEK293T', 'CellLine', 'CVCL:0063', (43, 50))	('translation', 'MPA', (154, 165))	('EIF1AX mutant-expressing', 'Var', (169, 193))	('Expression', 'Species', '29278', (0, 10))
57562	30305285	Expression of EIF1AX NTT or c'spl mutants in HEK293T cells co-transfected with TCRS showed higher S.P.	('mutants', 'Var', (34, 41))	('EIF1AX', 'Var', (14, 20))	('higher', 'PosReg', (91, 97))	('NTT', 'Gene', (21, 24))	('S.P', 'MPA', (98, 101))	('Expression', 'Species', '29278', (0, 10))	('HEK293T', 'CellLine', 'CVCL:0063', (45, 52))	('N', 'Chemical', 'MESH:D009584', (21, 22))	('spl', 'Gene', '8879', (30, 33))	('spl', 'Gene', (30, 33))
57566	30305285	Serine 51 phosphorylation of EIF2alpha in response to cellular stress represses global translation, but increases translational efficiency of ATF4 .	('phosphorylation', 'biological_process', 'GO:0016310', ('10', '25'))	('Serine', 'Var', (0, 6))	('EIF2alpha', 'Gene', '83939', (29, 38))	('represses', 'NegReg', (70, 79))	('EIF2', 'cellular_component', 'GO:0005850', ('29', '33'))	('increases', 'PosReg', (104, 113))	('translation', 'biological_process', 'GO:0006412', ('87', '98'))	('translational efficiency', 'MPA', (114, 138))	('EIF2alpha', 'Gene', (29, 38))	('Serine', 'Chemical', 'MESH:C047902', (0, 6))	('global translation', 'MPA', (80, 98))
57575	30305285	Accordingly, the mTOR substrates P70-S6 kinase and 4EBP1 were activated by expression of the EIF1AX-splice products in both RAS-WT and RAS mutant cell lines (Fig.	('spl', 'Gene', '8879', (100, 103))	('4EBP1', 'Gene', (51, 56))	('spl', 'Gene', (100, 103))	('mutant', 'Var', (139, 145))	('expression', 'Species', '29278', (75, 85))	('P70-S6 kinase', 'Enzyme', (33, 46))	('activated', 'PosReg', (62, 71))	('expression', 'MPA', (75, 85))
57576	30305285	The EIF1AX mutant induction of mTOR signaling was not associated with PI3K pathway activation in RAS-WT cells, whereas AKT and PRAS40 phosphorylation were increased in RAS-mutant cells.	('mutant', 'Var', (11, 17))	('mTOR signaling', 'MPA', (31, 45))	('increased', 'PosReg', (155, 164))	('EIF1AX mutant', 'Var', (4, 17))	('AKT', 'Gene', '207', (119, 122))	('PRAS40', 'Gene', '84335', (127, 133))	('signaling', 'biological_process', 'GO:0023052', ('36', '45'))	('PRAS40', 'Gene', (127, 133))	('phosphorylation', 'biological_process', 'GO:0016310', ('134', '149'))	('AKT', 'Gene', (119, 122))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))
57577	30305285	Despite this, the activation of mTOR by the aberrant EIF1AX gene products was neither PI3K- nor RSK-dependent, as treatment with the pan-PI3K inhibitor GDC0941, the pan-AKT kinase inhibitor MK-2206 or the pan-RSK inhibitor LJI308 did not impair the induction of p4EBP1 in the parental C643 compared to splice-reverted cells (Supplementary Fig.	('RSK', 'Gene', (96, 99))	('C643', 'Chemical', 'MESH:C040977', (285, 289))	('PI3K', 'molecular_function', 'GO:0016303', ('137', '141'))	('EIF1AX', 'Gene', (53, 59))	('AKT', 'Gene', (169, 172))	('RSK', 'Gene', '6196', (209, 212))	('MK-2206', 'Chemical', 'MESH:C548887', (190, 197))	('spl', 'Gene', '8879', (302, 305))	('impair', 'NegReg', (238, 244))	('spl', 'Gene', (302, 305))	('GDC0941', 'Chemical', 'MESH:C532162', (152, 159))	('RSK', 'Gene', '6196', (96, 99))	('aberrant', 'Var', (44, 52))	('PI3K', 'molecular_function', 'GO:0016303', ('86', '90'))	('RSK', 'Gene', (209, 212))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('173', '189'))	('AKT', 'Gene', '207', (169, 172))
57579	30305285	Based on these findings, we hypothesized that c-MYC and ATF4 could be key oncogenic clients of EIF1AX.	('c-MYC', 'Gene', (46, 51))	('EIF1AX', 'Var', (95, 101))	('ATF4', 'Gene', (56, 60))	('c-MYC', 'Gene', '4609', (46, 51))
57583	30305285	The differential expression of these transporters in RAS mutant thyroid cancer cell lines with endogenous EIF1AX mutations compared to those that were EIF1AX WT was particularly striking (Supplementary Fig.	('thyroid cancer', 'Disease', 'MESH:D013964', (64, 78))	('expression', 'Species', '29278', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (113, 122))	('thyroid cancer', 'Phenotype', 'HP:0002890', (64, 78))	('thyroid cancer', 'Disease', (64, 78))	('EIF1AX', 'Gene', (106, 112))
57586	30305285	Silencing of ATF4 or c-MYC alone modestly decreased ASCT2 abundance in C643 cells, with minimal effects on LAT1.	('ASCT2', 'Gene', '6510', (52, 57))	('c-MYC', 'Gene', (21, 26))	('ASCT2', 'Gene', (52, 57))	('LAT1', 'Gene', '8140', (107, 111))	('decreased', 'NegReg', (42, 51))	('LAT1', 'Gene', (107, 111))	('c-MYC', 'Gene', '4609', (21, 26))	('Silencing', 'Var', (0, 9))	('C643', 'Chemical', 'MESH:C040977', (71, 75))
57592	30305285	Deregulated expression of c-MYC in cancer is commonly due to increased protein stability.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('Deregulated', 'Var', (0, 11))	('c-MYC', 'Gene', '4609', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('increased', 'PosReg', (61, 70))	('expression', 'Species', '29278', (12, 22))	('c-MYC', 'Gene', (26, 31))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('expression', 'MPA', (12, 22))	('protein stability', 'MPA', (71, 88))	('cancer', 'Disease', (35, 41))
57595	30305285	Silencing of oncogenic KRAS also decreased c-MYC protein levels (Fig.	('c-MYC', 'Gene', '4609', (43, 48))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('KRAS', 'Gene', (23, 27))	('c-MYC', 'Gene', (43, 48))	('decreased', 'NegReg', (33, 42))	('Silencing', 'Var', (0, 9))	('KRAS', 'Gene', '3845', (23, 27))
57598	30305285	In these cells HRAS silencing or MEK inhibition decreased c-MYC and ASCT2 expression, whereas the pan-PI3K inhibitor GDC-0941 was without effect (Supplementary Fig.	('GDC-0941', 'Chemical', 'MESH:C532162', (117, 125))	('expression', 'MPA', (74, 84))	('inhibition', 'Var', (37, 47))	('HRAS', 'Gene', '3265', (15, 19))	('expression', 'Species', '29278', (74, 84))	('decreased', 'NegReg', (48, 57))	('c-MYC', 'Gene', '4609', (58, 63))	('ASCT2', 'Gene', (68, 73))	('ASCT2', 'Gene', '6510', (68, 73))	('HRAS', 'Gene', (15, 19))	('MEK', 'Gene', (33, 36))	('silencing', 'Var', (20, 29))	('MEK', 'Gene', '5609', (33, 36))	('PI3K', 'molecular_function', 'GO:0016303', ('102', '106'))	('c-MYC', 'Gene', (58, 63))
57600	30305285	To explore potential therapeutic dependencies of RAS + EIF1AX mutant thyroid cancers, we investigated the effects of the MEK inhibitor trametinib, the mTOR kinase inhibitor AZD8055 or the BRD4 inhibitor JQ1 (to target c-MYC transcription, with the caveat that JQ1 also inhibits other bromodomain proteins) alone and in various combinations in xenografts of CAL62-splice and parental cells.	('c-MYC', 'Gene', '4609', (218, 223))	('thyroid cancers', 'Disease', 'MESH:D013964', (69, 84))	('c-MYC', 'Gene', (218, 223))	('inhibits', 'NegReg', (269, 277))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('156', '172'))	('spl', 'Gene', '8879', (363, 366))	('spl', 'Gene', (363, 366))	('mutant', 'Var', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('thyroid cancer', 'Phenotype', 'HP:0002890', (69, 83))	('BRD4', 'Gene', (188, 192))	('thyroid cancers', 'Disease', (69, 84))	('MEK', 'Gene', '5609', (121, 124))	('transcription', 'biological_process', 'GO:0006351', ('224', '237'))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('AZD8055', 'Chemical', 'MESH:C546624', (173, 180))	('MEK', 'Gene', (121, 124))	('BRD4', 'Gene', '23476', (188, 192))	('trametinib', 'Chemical', 'MESH:C560077', (135, 145))
57601	30305285	CAL62-splice xenografts grew to a larger size and were more sensitive to the growth inhibitory effects of AZD8055 or JQ1 than the parental controls, whereas trametinib had equivalent efficacy in both contexts (Fig.	('AZD8055', 'Var', (106, 113))	('AZD8055', 'Chemical', 'MESH:C546624', (106, 113))	('spl', 'Gene', '8879', (6, 9))	('spl', 'Gene', (6, 9))	('trametinib', 'Chemical', 'MESH:C560077', (157, 167))	('growth inhibitory effects', 'MPA', (77, 102))	('sensitive to', 'MPA', (60, 72))
57602	30305285	The combination of AZD8055 with either trametinib or JQ1 induced tumor shrinkage in CAL62-splice but not in parental cells, and was superior to either drug alone (Fig.	('tumor', 'Disease', (65, 70))	('spl', 'Gene', '8879', (90, 93))	('spl', 'Gene', (90, 93))	('JQ1', 'Gene', (53, 56))	('AZD8055', 'Chemical', 'MESH:C546624', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('combination', 'Interaction', (4, 15))	('AZD8055', 'Var', (19, 26))	('trametinib', 'Chemical', 'MESH:C560077', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
57603	30305285	Consistent with their effects on growth, Western blots of tumor lysates from mice treated with each condition showed that AZD8055 in combination with either trametinib or JQ1 showed the most profound inhibition of c-MYC and mTOR substrates (Fig.	('mice', 'Species', '10090', (77, 81))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('inhibition', 'NegReg', (200, 210))	('AZD8055', 'Var', (122, 129))	('AZD8055', 'Chemical', 'MESH:C546624', (122, 129))	('trametinib', 'Chemical', 'MESH:C560077', (157, 167))	('c-MYC', 'Gene', (214, 219))	('mTOR substrates', 'MPA', (224, 239))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('c-MYC', 'Gene', '4609', (214, 219))
57604	30305285	However, despite comparable inhibition of these signaling nodes in EIF1AX WT and mutant cells, the latter show preferential tumor shrinkage, consistent with heightened dependency on the pathways activated by these mutant proteins.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('EIF1AX', 'Gene', (67, 73))	('tumor', 'Disease', (124, 129))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('mutant', 'Var', (81, 87))	('inhibition', 'NegReg', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
57605	30305285	EIF1AX is the only PIC component that is recurrently mutated in cancers.	('EIF1AX', 'Var', (0, 6))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('PIC', 'cellular_component', 'GO:0019035', ('19', '22'))	('PIC', 'cellular_component', 'GO:0097550', ('19', '22'))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
57606	30305285	EIF1AX mutations have been presumed to result in a change- or gain-of-function because of their predilection for specific substitutions in the N- and C-terminal tails.	('gain-of-function', 'PosReg', (62, 78))	('N', 'Chemical', 'MESH:D009584', (143, 144))	('substitutions', 'Var', (122, 135))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
57607	30305285	However, functional insights so far have been primarily confined to how EIF1AX mutants alter usage of initiation codons with varying contexts in yeast.	('usage of initiation codons', 'MPA', (93, 119))	('mutants', 'Var', (79, 86))	('alter', 'Reg', (87, 92))	('yeast', 'Species', '4932', (145, 150))	('EIF1AX', 'Gene', (72, 78))
57608	30305285	In uveal melanomas, EIF1AX-NTT mutants are associated with relatively indolent disease.	('relatively indolent disease', 'Disease', (59, 86))	('associated with', 'Reg', (43, 58))	('mutants', 'Var', (31, 38))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanomas', 'Phenotype', 'HP:0002861', (9, 18))	('uveal melanomas', 'Disease', (3, 18))	('uveal melanomas', 'Phenotype', 'HP:0007716', (3, 18))	('EIF1AX-NTT mutants', 'Var', (20, 38))	('uveal melanomas', 'Disease', 'MESH:C536494', (3, 18))	('N', 'Chemical', 'MESH:D009584', (27, 28))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))
57609	30305285	Isolated EIF1AX mutations are also found in low-risk thyroid tumors.	('found', 'Reg', (35, 40))	('thyroid tumors', 'Disease', (53, 67))	('EIF1AX', 'Gene', (9, 15))	('mutations', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('thyroid tumors', 'Disease', 'MESH:D013966', (53, 67))
57610	30305285	When coupled to RAS mutations they mark aggressive and often lethal forms of PDTC and ATC.	('ATC', 'Disease', (86, 89))	('mutations', 'Var', (20, 29))	('PDTC', 'Disease', (77, 81))	('PDTC', 'Chemical', 'MESH:C066229', (77, 81))
57613	30305285	In that respect, most human EIF1AX/RAS PDTCs and ATCs harbored either TERT promoter or TP53 mutations, which are major drivers of tumor progression in this disease.	('TP53', 'Gene', '7157', (87, 91))	('EIF1AX/RAS', 'Gene', (28, 38))	('TP53', 'Gene', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('mutations', 'Var', (92, 101))	('PDTC', 'Chemical', 'MESH:C066229', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('TERT', 'Gene', (70, 74))	('human', 'Species', '9606', (22, 27))	('tumor', 'Disease', (130, 135))	('TERT', 'Gene', '7015', (70, 74))
57615	30305285	This modification of EIF2alpha prevents its recycling into the TC, thereby inhibiting global protein synthesis, which helps cells to adapt by conserving nutrients and relieving ER stress.	('modification', 'Var', (5, 17))	('inhibiting', 'NegReg', (75, 85))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('EIF2', 'cellular_component', 'GO:0005850', ('21', '25'))	('EIF2alpha', 'Gene', (21, 30))	('global protein synthesis', 'MPA', (86, 110))	('adapt', 'MPA', (133, 138))	('recycling into the TC', 'MPA', (44, 65))	('prevents', 'NegReg', (31, 39))	('protein synthesis', 'biological_process', 'GO:0006412', ('93', '110'))	('helps', 'PosReg', (118, 123))	('EIF2alpha', 'Gene', '83939', (21, 30))	('conserving nutrients', 'MPA', (142, 162))
57620	30305285	Hence, this mutated translation initiation component attains a gain-of-function by deregulating the stringent control of the rate of global protein synthesis by EIF2alpha dephosphorylation.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('initiation component', 'Disease', 'MESH:D007319', (32, 52))	('EIF2alpha', 'Gene', (161, 170))	('mutated', 'Var', (12, 19))	('EIF2', 'cellular_component', 'GO:0005850', ('161', '165'))	('deregulating', 'Reg', (83, 95))	('translation initiation', 'biological_process', 'GO:0006413', ('20', '42'))	('dephosphorylation', 'biological_process', 'GO:0016311', ('171', '188'))	('protein synthesis', 'biological_process', 'GO:0006412', ('140', '157'))	('initiation component', 'Disease', (32, 52))	('EIF2alpha', 'Gene', '83939', (161, 170))	('dephosphorylation', 'MPA', (171, 188))
57622	30305285	RAS mutations are found along the entire spectrum of thyroid cancer, although the frequency is markedly enriched in PDTC and ATC.	('RAS', 'Gene', (0, 3))	('thyroid cancer', 'Disease', (53, 67))	('ATC', 'Disease', (125, 128))	('thyroid cancer', 'Phenotype', 'HP:0002890', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('PDTC', 'Disease', (116, 120))	('PDTC', 'Chemical', 'MESH:C066229', (116, 120))	('mutations', 'Var', (4, 13))	('thyroid cancer', 'Disease', 'MESH:D013964', (53, 67))
57627	30305285	Interestingly, transcription-independent MYC-MAX activation was seen in the uveal melanoma (UM) TCGA study in the context of EIF1AX-NTT mutations.	('N', 'Chemical', 'MESH:D009584', (132, 133))	('uveal melanoma', 'Phenotype', 'HP:0007716', (76, 90))	('uveal melanoma', 'Disease', 'MESH:C536494', (76, 90))	('uveal melanoma', 'Disease', (76, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('transcription', 'biological_process', 'GO:0006351', ('15', '28'))	('mutations', 'Var', (136, 145))	('MYC', 'Gene', '4609', (41, 44))	('EIF1AX-NTT', 'Var', (125, 135))	('activation', 'PosReg', (49, 59))	('MYC', 'Gene', (41, 44))
57628	30305285	Consistent with this, the EIF1AX mutations in uveal melanoma display mutual exclusivity to tumors with chromosome 8q gain, which harbors the MYC gene locus (8q24.21).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('chromosome', 'cellular_component', 'GO:0005694', ('103', '113'))	('MYC', 'Gene', (141, 144))	('uveal melanoma', 'Disease', 'MESH:C536494', (46, 60))	('EIF1AX', 'Gene', (26, 32))	('mutations', 'Var', (33, 42))	('spl', 'Gene', (63, 66))	('spl', 'Gene', '8879', (63, 66))	('uveal melanoma', 'Phenotype', 'HP:0007716', (46, 60))	('uveal melanoma', 'Disease', (46, 60))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('MYC', 'Gene', '4609', (141, 144))
57629	30305285	Conceivably, by analogy to the RAS-EIF1AX cooperativity on MYC in thyroid cancer, a potential mechanistic basis of MYC-MAX activation in uveal melanomas may involve interactions with constitutive G-protein oncogenic signaling mediated by the co-occurring GNAQ/GNA11 mutations in EIF1AX-mutant uveal melanomas.	('MYC', 'Gene', (59, 62))	('uveal melanoma', 'Phenotype', 'HP:0007716', (293, 307))	('MYC', 'Gene', (115, 118))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))	('uveal melanomas', 'Disease', (293, 308))	('uveal melanomas', 'Phenotype', 'HP:0007716', (293, 308))	('melanomas', 'Phenotype', 'HP:0002861', (143, 152))	('thyroid cancer', 'Disease', (66, 80))	('melanomas', 'Phenotype', 'HP:0002861', (299, 308))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('GNA11', 'Gene', (260, 265))	('uveal melanomas', 'Disease', 'MESH:C536494', (137, 152))	('signaling', 'biological_process', 'GO:0023052', ('216', '225'))	('MYC', 'Gene', '4609', (59, 62))	('melanoma', 'Phenotype', 'HP:0002861', (299, 307))	('MYC', 'Gene', '4609', (115, 118))	('GNAQ', 'Gene', '2776', (255, 259))	('thyroid cancer', 'Disease', 'MESH:D013964', (66, 80))	('GNAQ', 'Gene', (255, 259))	('uveal melanoma', 'Phenotype', 'HP:0007716', (137, 151))	('thyroid cancer', 'Phenotype', 'HP:0002890', (66, 80))	('interactions', 'Interaction', (165, 177))	('uveal melanomas', 'Disease', 'MESH:C536494', (293, 308))	('uveal melanomas', 'Disease', (137, 152))	('uveal melanomas', 'Phenotype', 'HP:0007716', (137, 152))	('GNA11', 'Gene', '2767', (260, 265))	('mutations', 'Var', (266, 275))	('EIF1AX-mutant', 'Gene', (279, 292))	('EIF1AX-mutant', 'Var', (279, 292))
57632	30305285	Accordingly, expression of ATF4, c-MYC and amino acid transporters in a panel of RAS-mutant human thyroid cancer cell lines displayed a striking concordance with EIF1AX mutation.	('expression', 'Species', '29278', (13, 23))	('spl', 'Gene', '8879', (126, 129))	('spl', 'Gene', (126, 129))	('amino acid transporters', 'MPA', (43, 66))	('expression', 'MPA', (13, 23))	('amino', 'Chemical', 'MESH:D000596', (43, 48))	('thyroid cancer', 'Disease', (98, 112))	('RAS-mutant', 'Gene', (81, 91))	('RAS-mutant', 'Var', (81, 91))	('c-MYC', 'Gene', (33, 38))	('ATF4', 'Gene', (27, 31))	('human', 'Species', '9606', (92, 97))	('thyroid cancer', 'Disease', 'MESH:D013964', (98, 112))	('thyroid cancer', 'Phenotype', 'HP:0002890', (98, 112))	('EIF1AX mutation', 'Var', (162, 177))	('c-MYC', 'Gene', '4609', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
57636	30305285	Whether increased PI3K contributions to tumorigenesis through alternative mechanisms in this context cannot be ruled out.	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('PI3K', 'Var', (18, 22))	('PI3K', 'molecular_function', 'GO:0016303', ('18', '22'))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
57638	30305285	The mutant EIF1AX, in concert with oncogenic RAS, also increases c-MYC protein stability.	('EIF1AX', 'Var', (11, 17))	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('c-MYC', 'Gene', (65, 70))	('c-MYC', 'Gene', '4609', (65, 70))	('mutant EIF1AX', 'Var', (4, 17))	('increases', 'PosReg', (55, 64))
57641	30305285	Besides the ~ 11% of advanced thyroid cancers harboring EIF1AX and RAS mutations, these two oncogenes also co-occur in low grade serous ovarian cancers and in some widely invasive Hurthle cell carcinomas.	('thyroid cancers', 'Disease', 'MESH:D013964', (30, 45))	('EIF1AX', 'Var', (56, 62))	('serous ovarian cancers', 'Disease', (129, 151))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('ovarian cancers', 'Phenotype', 'HP:0100615', (136, 151))	('serous ovarian cancers', 'Disease', 'MESH:D010051', (129, 151))	('invasive Hurthle cell carcinomas', 'Disease', 'MESH:C536913', (171, 203))	('RAS', 'Gene', (67, 70))	('mutations', 'Var', (71, 80))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('co-occur', 'Reg', (107, 115))	('thyroid cancer', 'Phenotype', 'HP:0002890', (30, 44))	('carcinomas', 'Phenotype', 'HP:0030731', (193, 203))	('invasive Hurthle cell carcinomas', 'Disease', (171, 203))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('thyroid cancers', 'Disease', (30, 45))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
57649	30305285	EIF1AX N-terminal tail (NTT) mutants were generated from pLVX-puro-EIF1AX-WT by site-directed mutagenesis (Strategene protocol).	('mutagenesis', 'biological_process', 'GO:0006280', ('94', '105'))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('mutants', 'Var', (29, 36))	('N', 'Chemical', 'MESH:D009584', (7, 8))	('EIF1AX', 'Gene', (0, 6))
57653	30305285	The PCR primers used to amplify EIF1AX-WT, to generate NTT mutants by site-directed mutagenesis, or to amplify the specific splice variants in cell lines harboring endogenous EIF1AX mutations are shown in Supplementary Table S5.	('mutants', 'Var', (59, 66))	('NTT', 'Disease', (55, 58))	('spl', 'Gene', '8879', (124, 127))	('EIF1AX', 'Gene', (175, 181))	('spl', 'Gene', (124, 127))	('N', 'Chemical', 'MESH:D009584', (55, 56))	('mutagenesis', 'biological_process', 'GO:0006280', ('84', '95'))	('mutations', 'Var', (182, 191))
57655	30305285	The targeting plasmid ColA1-TRE (ColA-CHC system for cDNA expression) used to clone the EIF1AX-c'spl cDNA was provided by Dr. Luke Dow (Weill Cornell College of Medicine, NY).	('expression', 'Species', '29278', (58, 68))	('CHC', 'Disease', (38, 41))	('N', 'Chemical', 'MESH:D009584', (171, 172))	('CHC', 'Disease', 'MESH:D019698', (38, 41))	('ColA1', 'Gene', '12842', (22, 27))	('ColA1', 'Gene', (22, 27))	('N', 'Chemical', 'MESH:D009584', (55, 56))	('N', 'Chemical', 'MESH:D009584', (103, 104))	("EIF1AX-c'spl", 'Var', (88, 100))
57656	30305285	CAL62 and TTA1 cells, which are WT for EIF1AX, were modified to endogenously express EIF1AX splice variants (cryptic and truncated splice) by targeted disruption of the splice acceptor site by CRISPR-Cas9.	('spl', 'Gene', '8879', (92, 95))	('spl', 'Gene', (92, 95))	('cryptic', 'Gene', '55997', (109, 116))	('cryptic', 'Gene', (109, 116))	('EIF1AX', 'Gene', (85, 91))	('Cas', 'cellular_component', 'GO:0005650', ('200', '203'))	('spl', 'Gene', '8879', (169, 172))	('spl', 'Gene', (169, 172))	('disruption', 'Var', (151, 161))	('spl', 'Gene', (131, 134))	('spl', 'Gene', '8879', (131, 134))
57662	30305285	The substitutions introduced in CAL62 and TTA1 cells effectively disrupted the splice acceptor site but were not identical to the naturally occurring endogenous EIF1AX-A113spl mutations.	('spl', 'Gene', '8879', (172, 175))	('spl', 'Gene', (172, 175))	('spl', 'Gene', '8879', (79, 82))	('spl', 'Gene', (79, 82))	('disrupted', 'NegReg', (65, 74))	('substitutions', 'Var', (4, 17))
57664	30305285	The parental C643 cell line, which harbors an endogenous EIF1AX-A113splice mutation, was used to revert the mutant allele by CRISPR-Cas9 knock-in of the corresponding WT sequence through use of a homologous directed repair template (HDR).	('spl', 'Gene', (68, 71))	('Cas', 'cellular_component', 'GO:0005650', ('132', '135'))	('HDR', 'biological_process', 'GO:0000724', ('233', '236'))	('mutant', 'Var', (108, 114))	('HD', 'Disease', 'MESH:D006816', (233, 235))	('C643', 'Chemical', 'MESH:C040977', (13, 17))	('spl', 'Gene', '8879', (68, 71))
57672	30305285	Nthy-Ori 3-1 cells (hereafter referred to as NthyOri, derived from wild-type human thyroid cells immortalized with large T-antigen) were used to generate stable and dox-inducible lines expressing EIF1AX-WT, NTT-mutants or the splice variants.	('N', 'Chemical', 'MESH:D009584', (207, 208))	('EIF1AX-WT', 'Var', (196, 205))	('spl', 'Gene', '8879', (226, 229))	('spl', 'Gene', (226, 229))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('NTT-mutants', 'Gene', (207, 218))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('human', 'Species', '9606', (77, 82))
57673	30305285	The pLVX-puro vector cloned with the respective various EIF1AX cDNA's were used for constitutive expression, whereas the pLVX-Tet-On Advanced vector system (Clontech) was used to generate dox-inducible EIF1AX or bicistronically expressed EIF1AX-splice variants, as described in 'Plasmids and Constructs' section.	('spl', 'Gene', '8879', (245, 248))	('expression', 'Species', '29278', (97, 107))	('N', 'Chemical', 'MESH:D009584', (65, 66))	('EIF1AX', 'Var', (202, 208))	('spl', 'Gene', (245, 248))
57693	30305285	c-MYC (5605), ATF4 (11815), LAT1 (5347), ASCT2 (5100), pEIF2alpha-S51 (9721), pAKT-S473 (4051), pAKT-T308 (4056), AKT (2920), pP70S6K-T389 (9234), P70S6K (2708), p4EBP1-S65 (9451), p4EBP1-T37/46 (2855), 4EBP1 (9452), pYB1-S102 (2900), pRPS6-S240/244 (2215), pRPS6-S235/236 (2211), RPS6 (2317), pERK (9101), ERK (4696), HA-Tag (3724), Biotin (5597), ER stress antibody sampler kit (9956) were from Cell Signaling, pPRAS40-T246 (441100G), GADD34 (PA1-139) from Invitrogen, ASCT2 (HPA035240) and beta-actin (A2228; 1: 10000) from Sigma Aldrich.	('beta-actin', 'Gene', '728378', (493, 503))	('AKT', 'Gene', '207', (114, 117))	('ERK', 'molecular_function', 'GO:0004707', ('307', '310'))	('Signaling', 'biological_process', 'GO:0023052', ('402', '411'))	('ERK', 'Gene', (307, 310))	('AKT', 'Gene', (79, 82))	('HPA035240', 'Chemical', 'MESH:C047158', (478, 487))	('GADD34', 'Gene', (437, 443))	('PRAS40', 'Gene', '84335', (414, 420))	('antibody', 'cellular_component', 'GO:0019814', ('359', '367'))	('ASCT2', 'Gene', '6510', (471, 476))	('AKT', 'Gene', '207', (97, 100))	('S235', 'Chemical', 'MESH:C056056', (264, 268))	('ASCT2', 'Gene', (41, 46))	('c-MYC', 'Gene', '4609', (0, 5))	('441100G', 'Chemical', 'MESH:C058999', (427, 434))	('ERK', 'Gene', '5594', (295, 298))	('AKT', 'Gene', '207', (79, 82))	('c-MYC', 'Gene', (0, 5))	('LAT1', 'Gene', '8140', (28, 32))	('antibody', 'molecular_function', 'GO:0003823', ('359', '367'))	('pERK', 'Gene', '9451', (294, 298))	('LAT1', 'Gene', (28, 32))	('pERK', 'Gene', (294, 298))	('Biotin', 'Chemical', 'MESH:D001710', (334, 340))	('ASCT2', 'Gene', '6510', (41, 46))	('beta-actin', 'Gene', (493, 503))	('GADD34', 'Gene', '23645', (437, 443))	('antibody', 'cellular_component', 'GO:0042571', ('359', '367'))	('AKT', 'Gene', (114, 117))	('ERK', 'Gene', (295, 298))	('ERK', 'Gene', '5594', (307, 310))	('PRAS40', 'Gene', (414, 420))	('EIF2alpha', 'Gene', '83939', (56, 65))	('441100G', 'Var', (427, 434))	('AKT', 'Gene', (97, 100))	('EIF2alpha', 'Gene', (56, 65))	('antibody', 'cellular_component', 'GO:0019815', ('359', '367'))	('ASCT2', 'Gene', (471, 476))
57713	30305285	Tumor-bearing mice were randomly assigned into 5 treatment arms: Controls (vehicle-4% DMSO in 30% PEG 300); AZD8055 (10 mg/kg); Trametinib (0.75 mg/kg); JQ1 (40 mg/kg); AZD8055 + Trametinib and AZD8055 + JQ1 (all drugs were from Selleckchem).	('AZD8055 +', 'Var', (169, 178))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Trametinib', 'Chemical', 'MESH:C560077', (128, 138))	('PEG', 'Chemical', 'MESH:C499599', (98, 101))	('mice', 'Species', '10090', (14, 18))	('AZD8055', 'Chemical', 'MESH:C546624', (108, 115))	('AZD8055', 'Chemical', 'MESH:C546624', (169, 176))	('Trametinib', 'Chemical', 'MESH:C560077', (179, 189))	('AZD8055', 'Chemical', 'MESH:C546624', (194, 201))	('DMSO', 'Chemical', 'MESH:D004121', (86, 90))	('AZD8055 + JQ1', 'Var', (194, 207))
57733	30305285	The normalized counts of each replicate (GEO accession GSE113695) derived from the RNA-seq of C643 vs C643-spl-rev and CAL62-splice vs CA62 cells were used as a dataset to run GSEA analysis (Identification-Gene symbol; permutations-1000 and permutation type-gene sets).	('N', 'Chemical', 'MESH:D009584', (84, 85))	('RNA', 'cellular_component', 'GO:0005562', ('83', '86'))	('CA62', 'CellLine', 'CVCL:E319', (135, 139))	('C643', 'Chemical', 'MESH:C040977', (94, 98))	('spl', 'Gene', '8879', (107, 110))	('C643', 'Var', (94, 98))	('spl', 'Gene', (107, 110))	('spl', 'Gene', '8879', (125, 128))	('spl', 'Gene', (125, 128))	('C643', 'Chemical', 'MESH:C040977', (102, 106))
57737	30305285	HEK293T cells were co-transfected with EIF1AX-WT, G9R or c'splice expression vectors along with the engineered firefly vectors using Fugene HD.	('spl', 'Gene', '8879', (59, 62))	('spl', 'Gene', (59, 62))	('G9R', 'Mutation', 'p.G9R', (50, 53))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('expression vectors', 'Species', '29278', (66, 84))	('HD', 'Disease', 'MESH:D006816', (140, 142))	('EIF1AX-WT', 'Var', (39, 48))
57738	30305285	HEK293T cells co-transfected with TCRS and EIF1AX-WT, -NTT mutants or EIF1AX-c'spl expression vectors.	("EIF1AX-c'spl", 'Var', (70, 82))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('expression vectors', 'Species', '29278', (83, 101))	('N', 'Chemical', 'MESH:D009584', (55, 56))	('EIF1AX-WT', 'Var', (43, 52))
57740	30305285	Mutations of EIF1AX, a component of the translation preinitiation complex, co-occur with RAS in advanced thyroid cancers and promote tumorigenesis.	('translation preinitiation complex', 'cellular_component', 'GO:0070993', ('40', '73'))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Mutations', 'Var', (0, 9))	('thyroid cancer', 'Phenotype', 'HP:0002890', (105, 119))	('tumor', 'Disease', (133, 138))	('EIF1AX', 'Gene', (13, 19))	('translation', 'biological_process', 'GO:0006412', ('40', '51'))	('thyroid cancers', 'Disease', (105, 120))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('promote', 'PosReg', (125, 132))	('thyroid cancers', 'Disease', 'MESH:D013964', (105, 120))
57743	30558566	Detection of mutations in SF3B1, EIF1AX and GNAQ in primary orbital melanoma by candidate gene analysis Ocular melanoma is a rare but often deadly malignancy that arises in the uvea (commonest primary site), conjunctiva or the orbit.	('Ocular melanoma', 'Disease', (104, 119))	('SF3B1', 'Gene', (26, 31))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('deadly malignancy', 'Disease', 'MESH:D009369', (140, 157))	('GNAQ', 'Gene', (44, 48))	('primary orbital melanoma', 'Disease', 'MESH:D008545', (52, 76))	('EIF1AX', 'Gene', '1964', (33, 39))	('EIF1AX', 'Gene', (33, 39))	('SF3B1', 'Gene', '23451', (26, 31))	('GNAQ', 'Gene', '2776', (44, 48))	('deadly malignancy', 'Disease', (140, 157))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('primary orbital melanoma', 'Disease', (52, 76))	('uvea', 'Disease', (177, 181))	('Ocular melanoma', 'Phenotype', 'HP:0007716', (104, 119))	('uvea', 'Disease', 'MESH:C536494', (177, 181))	('mutations', 'Var', (13, 22))	('Ocular melanoma', 'Disease', 'MESH:D008545', (104, 119))
57748	30558566	Sequencing of melanoma driver genes revealed GNAQ (p.Q209L) mutations in two samples; although it is possible that these samples represent extraocular spread of an occult uveal melanoma.	('melanoma', 'Disease', (14, 22))	('p.Q209L', 'Mutation', 'rs121913492', (51, 58))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('melanoma', 'Disease', (177, 185))	('uveal melanoma', 'Phenotype', 'HP:0007716', (171, 185))	('uveal melanoma', 'Disease', (171, 185))	('uveal melanoma', 'Disease', 'MESH:C536494', (171, 185))	('GNAQ', 'Gene', (45, 49))	('mutations', 'Var', (60, 69))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
57749	30558566	A recurrent mutation in SF3B1 (p.R625H) was observed in indolent, but not aggressive, tumours; a mutation in EIF1AX (p.N4S) was detected in one patient with non-aggressive disease.	('p.N4S', 'Mutation', 'rs1367788342', (117, 122))	('non-aggressive disease', 'Disease', 'MESH:D001523', (157, 179))	('SF3B1', 'Gene', (24, 29))	('EIF1AX', 'Gene', '1964', (109, 115))	('EIF1AX', 'Gene', (109, 115))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('patient', 'Species', '9606', (144, 151))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('p.R625H', 'Mutation', 'rs1057519961', (31, 38))	('SF3B1', 'Gene', '23451', (24, 29))	('tumours', 'Disease', (86, 93))	('p.R625H', 'Var', (31, 38))	('non-aggressive disease', 'Disease', (157, 179))
57750	30558566	EIF1AX and SF3B1 mutations appear have a role in determining the clinical course of POM and detection of these changes could have clinical significance.	('POM', 'Disease', (84, 87))	('SF3B1', 'Gene', (11, 16))	('SF3B1', 'Gene', '23451', (11, 16))	('mutations', 'Var', (17, 26))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))
57759	30558566	Mutations in the RAS pathway are found in > 75% of CM and have also been described in conjunctival melanoma, whereas mutations in GNAQ and GNA11 are found in ~ 85% of UM.	('mutations', 'Var', (117, 126))	('GNA11', 'Gene', '2767', (139, 144))	('GNA11', 'Gene', (139, 144))	('described', 'Reg', (73, 82))	('GNAQ', 'Gene', (130, 134))	('RAS pathway', 'Pathway', (17, 28))	('Mutations', 'Var', (0, 9))	('conjunctival melanoma', 'Disease', (86, 107))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (86, 107))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (86, 107))
57761	30558566	In this study, we examined POM for alterations in candidate melanoma driver genes (BRAF, NRAS, KRAS, GNA11, GNAQ) and genes implicated in UM prognosis (EIF1AX, SF3B1, BAP1).	('KRAS', 'Gene', '3845', (95, 99))	('SF3B1', 'Gene', (160, 165))	('GNA11', 'Gene', (101, 106))	('NRAS', 'Gene', '4893', (89, 93))	('alterations', 'Var', (35, 46))	('GNA11', 'Gene', '2767', (101, 106))	('EIF1AX', 'Gene', '1964', (152, 158))	('EIF1AX', 'Gene', (152, 158))	('SF3B1', 'Gene', '23451', (160, 165))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('BAP1', 'Gene', '8314', (167, 171))	('KRAS', 'Gene', (95, 99))	('NRAS', 'Gene', (89, 93))	('BRAF', 'Gene', '673', (83, 87))	('BRAF', 'Gene', (83, 87))	('BAP1', 'Gene', (167, 171))
57768	30558566	Copy number alterations were obtained for 7/11 tumour samples (Table 3).	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('tumour', 'Disease', (47, 53))	('Copy number alterations', 'Var', (0, 23))
57772	30558566	In two patients (numbers 4 and 5), a change in GNAQ was found: c.A626T, p.Q209L (Fig.	('c.A626T', 'Mutation', 'rs121913492', (63, 70))	('c.A626T', 'Var', (63, 70))	('p.Q209L', 'Var', (72, 79))	('patients', 'Species', '9606', (7, 15))	('GNAQ', 'MPA', (47, 51))	('p.Q209L', 'Mutation', 'rs121913492', (72, 79))
57773	30558566	GNAQ mutations account for approximately 50% of UM driver changes, and p.Q209L is found in 33% of GNAQ mutant tumours.	('p.Q209L', 'Var', (71, 78))	('mutant', 'Var', (103, 109))	('GNAQ', 'Gene', (98, 102))	('changes', 'Var', (58, 65))	('p.Q209L', 'Mutation', 'rs121913492', (71, 78))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('tumours', 'Phenotype', 'HP:0002664', (110, 117))	('GNAQ', 'Gene', (0, 4))	('tumours', 'Disease', 'MESH:D009369', (110, 117))	('tumours', 'Disease', (110, 117))
57778	30558566	Sequencing of exon 14 of SF3B1 revealed that four patients (cases 4, 9, 11, 12) harboured the same mutation; c.G1874A, p.R625H (Fig.	('patients', 'Species', '9606', (50, 58))	('p.R625H', 'Mutation', 'rs1057519961', (119, 126))	('SF3B1', 'Gene', (25, 30))	('c.G1874A', 'Mutation', 'rs1057519961', (109, 117))	('p.R625H', 'Var', (119, 126))	('SF3B1', 'Gene', '23451', (25, 30))	('c.G1874A', 'Var', (109, 117))
57779	30558566	One patient (case 10) was found to harbour a change in exon 1 of EIF1AX; c.A11T, p.N4S (Fig.	('EIF1AX', 'Gene', (65, 71))	('c.A11T', 'Var', (73, 79))	('c.A11T', 'Mutation', 'rs1367788342', (73, 79))	('patient', 'Species', '9606', (4, 11))	('p.N4S', 'Var', (81, 86))	('p.N4S', 'Mutation', 'rs1367788342', (81, 86))	('EIF1AX', 'Gene', '1964', (65, 71))
57781	30558566	It was noted that the patients harbouring the recurrent SF3B1 mutation all had highly favourable prognosis (Table 4).	('SF3B1', 'Gene', (56, 61))	('mutation', 'Var', (62, 70))	('patients', 'Species', '9606', (22, 30))	('SF3B1', 'Gene', '23451', (56, 61))
57782	30558566	The mean survival to-date of those patients harbouring the SF3B1 mutation is 104.8 months (range = 22-188 months), whilst the mean survival of patients without the SF3B1 mutation is 29.8 months (range = 3-91 months).	('SF3B1', 'Gene', '23451', (59, 64))	('SF3B1', 'Gene', (164, 169))	('SF3B1', 'Gene', (59, 64))	('patients', 'Species', '9606', (143, 151))	('mutation', 'Var', (65, 73))	('SF3B1', 'Gene', '23451', (164, 169))	('patients', 'Species', '9606', (35, 43))
57783	30558566	Furthermore, it should be noted that of the seven patients with systemic and/or orbital progression of disease, only one carried the SF3B1 mutation - and this patient remained without disease progression for over 13 years prior to sudden recurrence, deterioration and death.	('patients', 'Species', '9606', (50, 58))	('SF3B1', 'Gene', '23451', (133, 138))	('mutation -', 'Var', (139, 149))	('patient', 'Species', '9606', (159, 166))	('deterioration and death', 'Disease', 'MESH:D003643', (250, 273))	('SF3B1', 'Gene', (133, 138))	('patient', 'Species', '9606', (50, 57))
57787	30558566	Of the two nBAP1 negative cases, one showed disomy of chromosome 3 and the presence of SF3B1 and GNAQ mutations, whilst in the second case MLPA had not yielded any results and no mutations were detected.	('disomy', 'Var', (44, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('54', '64'))	('GNAQ', 'Gene', (97, 101))	('SF3B1', 'Gene', (87, 92))	('BAP1', 'Gene', '8314', (12, 16))	('mutations', 'Var', (102, 111))	('SF3B1', 'Gene', '23451', (87, 92))	('BAP1', 'Gene', (12, 16))	('presence', 'Reg', (75, 83))
57788	30558566	In this study we examined the largest reported clinical series of POM for mutations implicated in melanoma, giving the first report of genetic alterations in this rare tumour.	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('mutations', 'Var', (74, 83))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('tumour', 'Disease', (168, 174))
57789	30558566	Furthermore, mutations in SF3B1 and EIF1AX might influence prognosis.	('SF3B1', 'Gene', (26, 31))	('EIF1AX', 'Gene', '1964', (36, 42))	('EIF1AX', 'Gene', (36, 42))	('SF3B1', 'Gene', '23451', (26, 31))	('prognosis', 'CPA', (59, 68))	('mutations', 'Var', (13, 22))	('influence', 'Reg', (49, 58))
57793	30558566	In addition, although polysomy 8q was observed in 4/7 POM in this cohort, all were associated with patients who had a good prognosis, which again is contrary to its association with a poor outcome in UM.	('patients', 'Species', '9606', (99, 107))	('associated with', 'Reg', (83, 98))	('polysomy 8q', 'Var', (22, 33))
57794	30558566	Similarly, loss of nBAP1, which is associated with a poor prognosis and monosomy of chromosome 3 in UM was noted in only two cases and was neither associated with a poor outcome nor with monosomy of chromosome 3.	('BAP1', 'Gene', (20, 24))	('loss', 'Var', (11, 15))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('BAP1', 'Gene', '8314', (20, 24))	('chromosome', 'cellular_component', 'GO:0005694', ('199', '209'))
57795	30558566	Mutations in BRAF account for the majority of driver mutations (up to 60%).	('BRAF', 'Gene', '673', (13, 17))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (13, 17))
57796	30558566	However, mutations in NRAS and KRAS are also relatively frequent (13-25 and 2%, respectively).	('KRAS', 'Gene', (31, 35))	('mutations', 'Var', (9, 18))	('KRAS', 'Gene', '3845', (31, 35))	('NRAS', 'Gene', (22, 26))	('NRAS', 'Gene', '4893', (22, 26))
57797	30558566	Mutations in two Gq alpha sub-unit genes, which interact indirectly with the MAPK pathway, are found frequently in UM: GNAQ (~ 45%) and GNA11 (~ 35%).	('Gq alpha sub-unit', 'Gene', (17, 34))	('GNA11', 'Gene', (136, 141))	('GNA11', 'Gene', '2767', (136, 141))	('MAPK', 'molecular_function', 'GO:0004707', ('77', '81'))	('Mutations', 'Var', (0, 9))	('MAPK pathway', 'Pathway', (77, 89))
57798	30558566	In our cohort, two cases (patients 4 and 5) were found to carry a heterozygous mutation in GNAQ (p.Q209L).	('GNAQ', 'Gene', (91, 95))	('p.Q209L', 'Mutation', 'rs121913492', (97, 104))	('p.Q209L', 'Var', (97, 104))	('patients', 'Species', '9606', (26, 34))
57799	30558566	Expression of GNAQ p.Q209L in mice resulted in malignant transformation of melanocytes and increased signalling through the MAPK pathway.	('mice', 'Species', '10090', (30, 34))	('MAPK pathway', 'Pathway', (124, 136))	('signalling', 'biological_process', 'GO:0023052', ('101', '111'))	('transformation of melanocytes', 'Phenotype', 'HP:0002861', (57, 86))	('p.Q209L', 'Var', (19, 26))	('signalling', 'MPA', (101, 111))	('MAPK', 'molecular_function', 'GO:0004707', ('124', '128'))	('p.Q209L', 'Mutation', 'rs121913492', (19, 26))	('increased', 'PosReg', (91, 100))	('malignant transformation of melanocytes', 'CPA', (47, 86))
57801	30558566	It was considered necessary, therefore, to assess whether these two cases could be occult uveal tumours, given the frequency of GNAQ p.Q209L in UM.	('occult uveal tumours', 'Disease', (83, 103))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('p.Q209L', 'Var', (133, 140))	('p.Q209L', 'Mutation', 'rs121913492', (133, 140))	('GNAQ', 'Gene', (128, 132))	('occult uveal tumours', 'Disease', 'MESH:D014604', (83, 103))
57804	30558566	In one case harbouring the GNAQ change, there was evidence of very minor choroidal pigmentary changes which could represent a possible uveal source; in the other case, there was insufficient biopsy material to fully exclude a uveal source.	('uvea', 'Disease', 'MESH:C536494', (226, 230))	('insufficient', 'Disease', (178, 190))	('insufficient', 'Disease', 'MESH:D000309', (178, 190))	('uvea', 'Disease', (135, 139))	('choroidal pigmentary', 'Disease', 'MESH:D015862', (73, 93))	('pigmentary changes', 'Phenotype', 'HP:0001000', (83, 101))	('uvea', 'Disease', 'MESH:C536494', (135, 139))	('uvea', 'Disease', (226, 230))	('choroidal pigmentary', 'Disease', (73, 93))	('change', 'Var', (32, 38))
57806	30558566	Mutations in other G protein genes, such as CYSLTR2 and PLCB4 have been reported in a small number of UM patients and these could be sequenced in our cohort to extend the study further.	('patients', 'Species', '9606', (105, 113))	('PLCB4', 'Gene', '5332', (56, 61))	('Mutations', 'Var', (0, 9))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('CYSLTR2', 'Gene', '57105', (44, 51))	('PLCB4', 'Gene', (56, 61))	('CYSLTR2', 'Gene', (44, 51))
57807	30558566	Next, it was considered whether mutations in SF3B1 or EIF1AX contributed to the pathogenesis of disease and/or variable prognosis seen within our cohort.	('EIF1AX', 'Gene', '1964', (54, 60))	('EIF1AX', 'Gene', (54, 60))	('mutations', 'Var', (32, 41))	('SF3B1', 'Gene', (45, 50))	('contributed', 'Reg', (61, 72))	('pathogenesis', 'biological_process', 'GO:0009405', ('80', '92'))	('SF3B1', 'Gene', '23451', (45, 50))
57808	30558566	Sequencing of exon 14 of SF3B1 revealed a recurrent heterozygous mutation (c.G1874A, p.R625H) in four patients - cases 4, 9, 11 and 12.	('c.G1874A', 'Mutation', 'rs1057519961', (75, 83))	('c.G1874A', 'Var', (75, 83))	('patients', 'Species', '9606', (102, 110))	('p.R625H', 'Mutation', 'rs1057519961', (85, 92))	('SF3B1', 'Gene', (25, 30))	('p.R625H', 'Var', (85, 92))	('SF3B1', 'Gene', '23451', (25, 30))
57811	30558566	One patient - case 9 - harbouring the SF3B1 mutation had systemic progression and has since died, however, this was after a remarkable disease-free period of 13 years.	('mutation', 'Var', (44, 52))	('SF3B1', 'Gene', (38, 43))	('patient', 'Species', '9606', (4, 11))	('SF3B1', 'Gene', '23451', (38, 43))	('systemic', 'CPA', (57, 65))
57814	30558566	This would suggest that the observed mutation in SF3B1 confers a favourable prognosis in POM.	('POM', 'Disease', (89, 92))	('SF3B1', 'Gene', '23451', (49, 54))	('SF3B1', 'Gene', (49, 54))	('mutation', 'Var', (37, 45))
57816	30558566	Mutations in SF3B1 have been implicated as a common driver mutation in myelodysplatic syndromes (MDS), myelofibrosis and chronic myeloid leukaemia.	('myelofibrosis', 'Disease', 'MESH:D055728', (103, 116))	('myelodysplatic syndromes', 'Disease', (71, 95))	('MDS', 'Disease', (97, 100))	('SF3B1', 'Gene', (13, 18))	('chronic myeloid leukaemia', 'Disease', (121, 146))	('MDS', 'Disease', 'MESH:D009190', (97, 100))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (129, 146))	('myelofibrosis', 'Phenotype', 'HP:0011974', (103, 116))	('chronic myeloid leukaemia', 'Disease', 'MESH:D015464', (121, 146))	('Mutations', 'Var', (0, 9))	('SF3B1', 'Gene', '23451', (13, 18))	('myelodysplatic syndromes', 'Disease', 'MESH:D013577', (71, 95))	('chronic myeloid leukaemia', 'Phenotype', 'HP:0005506', (121, 146))	('myelofibrosis', 'Disease', (103, 116))
57817	30558566	In MDS, SF3B1 mutations have been associated with favourable overall survival and a lower likelihood of transformation into acute leukaemia.	('acute leukaemia', 'Phenotype', 'HP:0002488', (124, 139))	('SF3B1', 'Gene', '23451', (8, 13))	('leukaemia', 'Disease', 'MESH:D007938', (130, 139))	('MDS', 'Disease', (3, 6))	('leukaemia', 'Disease', (130, 139))	('mutations', 'Var', (14, 23))	('SF3B1', 'Gene', (8, 13))	('MDS', 'Disease', 'MESH:D009190', (3, 6))
57818	30558566	More recently, mutations in SF3B1 (particularly at codon 625) have been identified in various pigmented tumours, including UM, mucosal melanoma, leptomeningeal melanoma and blue naevi-like cutaneous melanoma.	('pigmented tumours', 'Disease', (94, 111))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('naevi', 'Phenotype', 'HP:0003764', (178, 183))	('leptomeningeal melanoma', 'Disease', 'MESH:D008545', (145, 168))	('SF3B1', 'Gene', '23451', (28, 33))	('pigmented tumours', 'Disease', 'MESH:D010859', (94, 111))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('cutaneous melanoma', 'Disease', (189, 207))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (189, 207))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (189, 207))	('mucosal melanoma', 'Disease', 'MESH:D008545', (127, 143))	('identified', 'Reg', (72, 82))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('mutations', 'Var', (15, 24))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('mucosal melanoma', 'Disease', (127, 143))	('leptomeningeal melanoma', 'Disease', (145, 168))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('blue naevi', 'Phenotype', 'HP:0100814', (173, 183))	('SF3B1', 'Gene', (28, 33))
57819	30558566	As with MDS, SF3B1 mutations confer a favourable prognosis in UM, with lower age of onset and concurrent disomy 3.	('MDS', 'Disease', (8, 11))	('SF3B1', 'Gene', (13, 18))	('disomy 3', 'Disease', (105, 113))	('MDS', 'Disease', 'MESH:D009190', (8, 11))	('mutations', 'Var', (19, 28))	('SF3B1', 'Gene', '23451', (13, 18))
57820	30558566	However, it should be noted that SF3B1 mutant UM are reported to give rise to late metastasis (median 8.2 years after initial diagnosis).	('SF3B1', 'Gene', '23451', (33, 38))	('give rise', 'Reg', (65, 74))	('mutant UM', 'Var', (39, 48))	('SF3B1', 'Gene', (33, 38))
57821	30558566	Furthermore, The Cancer Genome Atlas project reported that UM cases with SF3B1 mutations have an intermediate prognosis.	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('SF3B1', 'Gene', (73, 78))	('SF3B1', 'Gene', '23451', (73, 78))	('mutations', 'Var', (79, 88))
57824	30558566	One patient, case 10, was found to harbour a heterozygous mutation in exon 1 of EIF1AX (c.A11T, p.N4S).	('EIF1AX', 'Gene', '1964', (80, 86))	('EIF1AX', 'Gene', (80, 86))	('p.N4S', 'Mutation', 'rs1367788342', (96, 101))	('c.A11T', 'Var', (88, 94))	('c.A11T', 'Mutation', 'rs1367788342', (88, 94))	('patient', 'Species', '9606', (4, 11))	('p.N4S', 'Var', (96, 101))
57827	30558566	Mutations in exon 1 or 2 of this gene have been frequently reported in UM, but also rarer melanoma types including blue-nevus associated melanoma and leptomeningeal melanoma.	('melanoma', 'Disease', (90, 98))	('reported', 'Reg', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('blue-nevus', 'Phenotype', 'HP:0100814', (115, 125))	('nevus', 'Phenotype', 'HP:0003764', (120, 125))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('melanoma', 'Disease', (137, 145))	('Mutations in', 'Var', (0, 12))	('leptomeningeal melanoma', 'Disease', (150, 173))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('leptomeningeal melanoma', 'Disease', 'MESH:D008545', (150, 173))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
57828	30558566	EIF1AX mutations are associated with good prognosis disomy 3 UM, and usually occur in non-metastatic cases.	('disomy 3 UM', 'Disease', (52, 63))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
57830	30558566	It is highly plausible, therefore, that mutations in EIF1AX also correspond to good prognosis in POM.	('mutations', 'Var', (40, 49))	('POM', 'Disease', (97, 100))	('EIF1AX', 'Gene', (53, 59))	('EIF1AX', 'Gene', '1964', (53, 59))
57831	30558566	It must be considered whether the changes seen in SF3B1 and EIF1AX are the driver mutation of POM, or a secondary change in the tumour.	('tumour', 'Disease', (128, 134))	('SF3B1', 'Gene', (50, 55))	('EIF1AX', 'Gene', '1964', (60, 66))	('EIF1AX', 'Gene', (60, 66))	('SF3B1', 'Gene', '23451', (50, 55))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('changes', 'Var', (34, 41))	('POM', 'Disease', (94, 97))	('tumour', 'Disease', 'MESH:D009369', (128, 134))
57832	30558566	It is thought that mutations in SF3B1 arise as a second genetic change in UM and blue nevus-like melanoma, after initial mutation in GNAQ or GNA11; however, SF3B1 changes can be driver mutations in MDS.	('SF3B1', 'Gene', (157, 162))	('nevus', 'Phenotype', 'HP:0003764', (86, 91))	('GNA11', 'Gene', '2767', (141, 146))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('SF3B1', 'Gene', '23451', (157, 162))	('SF3B1', 'Gene', '23451', (32, 37))	('mutations', 'Var', (19, 28))	('MDS', 'Disease', 'MESH:D009190', (198, 201))	('blue nevus', 'Phenotype', 'HP:0100814', (81, 91))	('MDS', 'Disease', (198, 201))	('SF3B1', 'Gene', (32, 37))	('GNA11', 'Gene', (141, 146))
57833	30558566	Indeed, in UM, mutations in either gene (SF3B1 or EIF1AX) are almost never seen in the absence of a GNAQ or GNA11 mutation.	('GNA11', 'Gene', '2767', (108, 113))	('EIF1AX', 'Gene', '1964', (50, 56))	('EIF1AX', 'Gene', (50, 56))	('mutations', 'Var', (15, 24))	('SF3B1', 'Gene', (41, 46))	('SF3B1', 'Gene', '23451', (41, 46))	('GNA11', 'Gene', (108, 113))
57837	30558566	Furthermore, we have shown that mutations in either SF3B1 or EIF1AX are likely to be associated with a favourable prognosis in POM cases.	('POM', 'Disease', (127, 130))	('SF3B1', 'Gene', (52, 57))	('EIF1AX', 'Gene', '1964', (61, 67))	('EIF1AX', 'Gene', (61, 67))	('mutations', 'Var', (32, 41))	('SF3B1', 'Gene', '23451', (52, 57))	('associated', 'Reg', (85, 95))
57839	30558566	However, it is possible that SF3B1 mutations are associated with late recurrence of disease, and so long-term follow-up and high index of suspicion should be maintained in all cases of orbital melanoma.	('SF3B1', 'Gene', '23451', (29, 34))	('orbital melanoma', 'Disease', 'MESH:D008545', (185, 201))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('associated', 'Reg', (49, 59))	('orbital melanoma', 'Disease', (185, 201))	('SF3B1', 'Gene', (29, 34))	('mutations', 'Var', (35, 44))
57853	29977240	PD-1 inhibition in melanoma promotes tumor regression and prolonged overall survival in 30-40% of patients with advanced disease.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('inhibition', 'Var', (5, 15))	('PD-1', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('prolonged', 'PosReg', (58, 67))	('melanoma', 'Disease', (19, 27))	('PD-1', 'Gene', '5133', (0, 4))	('patients', 'Species', '9606', (98, 106))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('promotes', 'PosReg', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('overall survival', 'CPA', (68, 84))
57862	29977240	Genetic alterations affecting IFNGR1, IFNGR2, IRF1, and JAK2, and amplifications of the IFNgamma inhibitor genes, SOCS1 and PIAS4, are also enriched in patients not responding to checkpoint inhibition.	('JAK2', 'Gene', (56, 60))	('Genetic alterations', 'Var', (0, 19))	('SOCS1', 'Gene', '8651', (114, 119))	('IFNgamma', 'Gene', (88, 96))	('IFNGR2', 'Gene', '3460', (38, 44))	('JAK2', 'Gene', '3717', (56, 60))	('IFNgamma', 'Gene', '3458', (88, 96))	('IFNGR1', 'Gene', (30, 36))	('SOCS1', 'Gene', (114, 119))	('patients', 'Species', '9606', (152, 160))	('JAK', 'molecular_function', 'GO:0004713', ('56', '59'))	('IFNGR2', 'Gene', (38, 44))	('IRF1', 'Gene', '3659', (46, 50))	('PIAS4', 'Gene', (124, 129))	('PIAS4', 'Gene', '51588', (124, 129))	('IRF1', 'Gene', (46, 50))
57863	29977240	Furthermore, loss-of-function mutations in the upstream IFNgamma-signaling regulators JAK1 and JAK2, concurrent with deletion of the wild type alleles, have been identified in two melanoma patients who failed anti-PD-1 therapy.	('IFNgamma', 'Gene', (56, 64))	('PD-1', 'Gene', (214, 218))	('JAK1', 'Gene', (86, 90))	('melanoma', 'Disease', (180, 188))	('loss-of-function', 'NegReg', (13, 29))	('JAK2', 'Gene', '3717', (95, 99))	('IFNgamma', 'Gene', '3458', (56, 64))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('PD-1', 'Gene', '5133', (214, 218))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('JAK', 'molecular_function', 'GO:0004713', ('86', '89'))	('JAK2', 'Gene', (95, 99))	('mutations', 'Var', (30, 39))	('patients', 'Species', '9606', (189, 197))	('JAK', 'molecular_function', 'GO:0004713', ('95', '98'))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))
57864	29977240	The loss of IFNgamma signaling limits immune cell recruitment and immune recognition of tumor cells by suppressing the production of IFNgamma-dependent chemokines and diminishing antigen presentation.	('IFNgamma', 'Gene', (12, 20))	('limits', 'NegReg', (31, 37))	('diminishing', 'NegReg', (167, 178))	('antigen presentation', 'biological_process', 'GO:0019882', ('179', '199'))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('IFNgamma', 'Gene', '3458', (12, 20))	('immune', 'CPA', (66, 72))	('IFNgamma', 'Gene', (133, 141))	('antigen presentation', 'MPA', (179, 199))	('IFNgamma', 'Gene', '3458', (133, 141))	('immune cell recruitment', 'CPA', (38, 61))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('signaling', 'biological_process', 'GO:0023052', ('21', '30'))	('tumor', 'Disease', (88, 93))	('suppressing', 'NegReg', (103, 114))	('loss', 'Var', (4, 8))
57869	29977240	Furthermore, our data confirm that measuring IFNgamma output with a select number of targets may be useful for detecting intrinsic defects in the IFNgamma/JAK/STAT pathway, including JAK and STAT mutations which are associated with PD-1 inhibitor resistance.	('IFNgamma', 'Gene', (146, 154))	('PD-1', 'Gene', (232, 236))	('defects', 'NegReg', (131, 138))	('JAK', 'molecular_function', 'GO:0004713', ('183', '186'))	('PD-1', 'Gene', '5133', (232, 236))	('IFNgamma', 'Gene', '3458', (146, 154))	('associated', 'Reg', (216, 226))	('JAK', 'molecular_function', 'GO:0004713', ('155', '158'))	('JAK', 'Var', (183, 186))	('IFNgamma', 'Gene', (45, 53))	('IFNgamma', 'Gene', '3458', (45, 53))
57886	29977240	Expression of five well-defined IFNgamma targets, the PD-1 ligands PD-L1 and PD-L2, NGFR, antigen-presenting HLA-A, -B, and -C (HLA-ABC), and HLA-DR molecules was examined in a panel of 39 human melanoma cell lines with defined oncogenic driver mutations (Figure 1A; Figure S1 in Supplementary Material).	('HLA-DR', 'Gene', (142, 148))	('HLA-A', 'Gene', (109, 114))	('PD-L2', 'Gene', (77, 82))	('HLA-A, -B, and -C', 'Gene', '3105;3106;3107', (109, 126))	('HLA-A', 'Gene', '3105', (128, 133))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('NGFR', 'Gene', (84, 88))	('mutations', 'Var', (245, 254))	('HLA-A', 'Gene', '3105', (109, 114))	('human', 'Species', '9606', (189, 194))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('PD-1', 'Gene', (54, 58))	('HLA-A', 'Gene', (128, 133))	('PD-1', 'Gene', '5133', (54, 58))	('IFNgamma', 'Gene', (32, 40))	('HLA-DR', 'Gene', '3122', (142, 148))	('IFNgamma', 'Gene', '3458', (32, 40))	('PD-L1', 'Gene', (67, 72))	('NGFR', 'Gene', '4804', (84, 88))	('PD-L2', 'Gene', '80380', (77, 82))	('PD-L1', 'Gene', '29126', (67, 72))
57892	29977240	Three cell lines, the BRAFV600-mutant C060M1 and BRAF/NRASWT D24M and SMU15-0217, had a bimodal expression of both HLA-DR and NGFR (data not shown).	('D24M', 'Mutation', 'p.D24M', (61, 65))	('NGFR', 'Gene', (126, 130))	('HLA-DR', 'Gene', '3122', (115, 121))	('BRAF', 'Gene', '673', (22, 26))	('NRAS', 'Gene', (54, 58))	('HLA-DR', 'Gene', (115, 121))	('C060M1', 'Var', (38, 44))	('BRAF', 'Gene', (22, 26))	('NGFR', 'Gene', '4804', (126, 130))	('NRAS', 'Gene', '4893', (54, 58))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', (49, 53))
57919	29977240	Whole exome sequencing of this cell line identified a damaging missense mutation resulting in a P44R substitution in the extracellular portion of the IFNGR1 (Figure 6B).	('P44R', 'Mutation', 'rs587776853', (96, 100))	('extracellular', 'cellular_component', 'GO:0005576', ('121', '134'))	('P44R', 'Var', (96, 100))	('IFNGR1', 'Gene', (150, 156))
57924	29977240	The remaining 23 melanoma cell lines, including the IFNGR1-mutant D22M1 cells, showed minimal cell cycle profile changes when exposed to IFNgamma (Table 2).	('cell cycle profile', 'CPA', (94, 112))	('D22M1', 'Gene', (66, 71))	('IFNgamma', 'Gene', (137, 145))	('cell cycle', 'biological_process', 'GO:0007049', ('94', '104'))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('IFNgamma', 'Gene', '3458', (137, 145))	('melanoma', 'Disease', (17, 25))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('IFNGR1-mutant', 'Var', (52, 65))	('IFNGR1-mutant D22M1', 'Gene', (52, 71))
57939	29977240	In particular, nuclear expression of the IFNgamma transcription factor IRF1 is associated with better response to anti-PD-1 therapy in melanoma and loss-of-function mutations in IFNgamma pathway modulators (JAK1, JAK2) are associated with resistance to anti-PD-1 treatment.	('transcription', 'biological_process', 'GO:0006351', ('50', '63'))	('PD-1', 'Gene', (258, 262))	('PD-1', 'Gene', '5133', (258, 262))	('nuclear expression', 'MPA', (15, 33))	('JAK', 'molecular_function', 'GO:0004713', ('213', '216'))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('JAK2', 'Gene', '3717', (213, 217))	('IFNgamma', 'Gene', (178, 186))	('JAK', 'molecular_function', 'GO:0004713', ('207', '210'))	('IFNgamma', 'Gene', '3458', (178, 186))	('mutations', 'Var', (165, 174))	('PD-1', 'Gene', (119, 123))	('PD-1', 'Gene', '5133', (119, 123))	('IRF1', 'Gene', (71, 75))	('IFNgamma', 'Gene', '3458', (41, 49))	('JAK2', 'Gene', (213, 217))	('IFNgamma', 'Gene', (41, 49))	('transcription factor', 'molecular_function', 'GO:0000981', ('50', '70'))	('better', 'PosReg', (95, 101))	('IRF1', 'Gene', '3659', (71, 75))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('loss-of-function', 'NegReg', (148, 164))
57951	29977240	Loss of MHC class I expression is another established mechanism of immune escape, often involving genetic alterations in the B2M gene and we noted that the SMU15-0217 melanoma cell line showed loss of B2M expression, concurrent with loss of HLA-ABC expression.	('MHC class I', 'Gene', (8, 19))	('expression', 'MPA', (249, 259))	('B2M', 'Gene', '567', (125, 128))	('loss', 'NegReg', (193, 197))	('B2M', 'Gene', (201, 204))	('B2M', 'Gene', (125, 128))	('HLA-A', 'Gene', '3105', (241, 246))	('Loss', 'NegReg', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanoma', 'Disease', (167, 175))	('B2M', 'Gene', '567', (201, 204))	('HLA-A', 'Gene', (241, 246))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('genetic alterations', 'Var', (98, 117))	('alterations', 'Var', (106, 117))	('expression', 'MPA', (205, 215))	('loss', 'NegReg', (233, 237))
57952	29977240	Only one cell line (i.e., D22M1) failed to respond to IFNgamma, and this was associated with a homozygous, predicted loss-of-function mutation in the IFNGR1 gene.	('IFNgamma', 'Gene', (54, 62))	('mutation', 'Var', (134, 142))	('IFNgamma', 'Gene', '3458', (54, 62))	('IFNGR1', 'Gene', (150, 156))	('loss-of-function', 'NegReg', (117, 133))	('respond', 'MPA', (43, 50))
57954	29977240	We show that incomplete IFNgamma signaling occurs in almost 70% of immunotherapy-naive melanoma, and previous reports have confirmed that pre-existing alterations affecting IFNgamma signaling have the potential to confer resistance to immune checkpoint inhibitors.	('melanoma', 'Disease', (87, 95))	('pre', 'molecular_function', 'GO:0003904', ('138', '141'))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('IFNgamma', 'Gene', (173, 181))	('signaling', 'biological_process', 'GO:0023052', ('182', '191'))	('resistance', 'MPA', (221, 231))	('IFNgamma', 'Gene', '3458', (173, 181))	('IFNgamma', 'Gene', '3458', (24, 32))	('signaling', 'biological_process', 'GO:0023052', ('33', '42'))	('IFNgamma', 'Gene', (24, 32))	('alterations', 'Var', (151, 162))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
57955	29977240	In fact, we identified two well-recognized mechanisms of immunotherapy resistance; the loss of B2M expression, resulting in absence of cell surface HLA-ABC, and a missense mutation in the IFNGR1 gene, resulting in loss of cell surface IFNGR1.	('B2M', 'Gene', (95, 98))	('expression', 'MPA', (99, 109))	('cell surface IFNGR1', 'MPA', (222, 241))	('loss', 'NegReg', (87, 91))	('B2M', 'Gene', '567', (95, 98))	('missense mutation', 'Var', (163, 180))	('loss', 'NegReg', (214, 218))	('cell surface', 'cellular_component', 'GO:0009986', ('222', '234'))	('IFNGR1', 'Gene', (188, 194))	('absence', 'NegReg', (124, 131))	('HLA-A', 'Gene', '3105', (148, 153))	('cell surface', 'cellular_component', 'GO:0009986', ('135', '147'))	('HLA-A', 'Gene', (148, 153))
58011	29095823	FTH1P3 overexpression enhanced Rac1 expression in the MUM-2B cell (Fig 4B).	('overexpression', 'Var', (7, 21))	('FTH1P3', 'Gene', '2498', (0, 6))	('MUM-2', 'Gene', '58485', (54, 59))	('MUM-2', 'Gene', (54, 59))	('Rac1', 'Gene', '5879', (31, 35))	('FTH1P3', 'Gene', (0, 6))	('enhanced', 'PosReg', (22, 30))	('Rac1', 'Gene', (31, 35))
58051	29095823	In conclusion, we demonstrated that lncRNA FTH1P3 was commonly up-regulated in uveal melanoma cell lines and tissues and acted as an oncogene in uveal melanoma progression by inhibiting miR-224-5p expression.	('inhibiting', 'NegReg', (175, 185))	('uveal melanoma', 'Disease', 'MESH:C536494', (145, 159))	('uveal melanoma', 'Phenotype', 'HP:0007716', (145, 159))	('miR-224', 'Gene', (186, 193))	('FTH1P3', 'Gene', (43, 49))	('uveal melanoma', 'Disease', (145, 159))	('lncRNA', 'Var', (36, 42))	('up-regulated', 'PosReg', (63, 75))	('miR-224', 'Gene', '407009', (186, 193))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('FTH1P3', 'Gene', '2498', (43, 49))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('uveal melanoma', 'Disease', (79, 93))
58063	26991400	While certain somatic mutations are associated with neoplastic growth and distant metastasis (see below) the malignancy is not inherited in a traditional genetic fashion although individuals with germline BAP1 mutations are thought to be at higher risk for uveal and cutaneous melanoma as well as mesothelioma and renal cancers.	('uveal and cutaneous melanoma', 'Disease', 'MESH:C536494', (257, 285))	('malignancy', 'Disease', (109, 119))	('mutations', 'Var', (210, 219))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('cancers', 'Phenotype', 'HP:0002664', (320, 327))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (267, 285))	('melanoma', 'Phenotype', 'HP:0002861', (277, 285))	('BAP1', 'Gene', (205, 209))	('malignancy', 'Disease', 'MESH:D009369', (109, 119))	('associated', 'Reg', (36, 46))	('mesothelioma and renal cancers', 'Disease', 'MESH:D007680', (297, 327))	('neoplastic growth', 'Disease', (52, 69))	('neoplastic growth', 'Disease', 'MESH:D006130', (52, 69))
58115	26991400	Those whose primary tumors have a Class 2 gene expression profile, monosomy 3 or were greater than 8 mm in apical dimension are in the highest risk group.	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('primary tumors', 'Disease', (12, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('gene expression', 'biological_process', 'GO:0010467', ('42', '57'))	('monosomy 3', 'Var', (67, 77))	('primary tumors', 'Disease', 'MESH:D009369', (12, 26))
58165	26991400	The ligation of PD-1 and PD-L1 inhibits T cell proliferation and activation and induces apoptosis of antigen specific T cells to suppress anti-tumor immunity.	('apoptosis', 'CPA', (88, 97))	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))	('tumor', 'Disease', (143, 148))	('inhibits', 'NegReg', (31, 39))	('T cell proliferation', 'CPA', (40, 60))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('suppress', 'NegReg', (129, 137))	('T cell proliferation', 'biological_process', 'GO:0042098', ('40', '60'))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('ligation', 'Var', (4, 12))	('activation', 'PosReg', (65, 75))	('PD-L1', 'Gene', (25, 30))	('induces', 'Reg', (80, 87))	('PD-1', 'Gene', (16, 20))
58171	26991400	Since there are many differences in the tumor-immune microenvironment (nearly always the liver) as well as tumor biology (far fewer mutations and different mutational spectrum) of uveal melanoma compared with cutaneous (and other, such as mucosal) sites of primary melanoma, it is likely that outcomes reported for metastatic cutaneous melanoma will not be replicated in uveal melanoma, and that other trial designs will need to be considered.	('tumor', 'Disease', (107, 112))	('uveal melanoma', 'Phenotype', 'HP:0007716', (180, 194))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('melanoma', 'Disease', 'MESH:D008545', (377, 385))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('uveal melanoma', 'Phenotype', 'HP:0007716', (371, 385))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('melanoma', 'Disease', 'MESH:D008545', (186, 194))	('melanoma', 'Disease', 'MESH:D008545', (336, 344))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('melanoma', 'Phenotype', 'HP:0002861', (377, 385))	('melanoma', 'Disease', (377, 385))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('tumor', 'Disease', (40, 45))	('melanoma', 'Disease', (265, 273))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanoma', 'Disease', (186, 194))	('uveal melanoma', 'Disease', (180, 194))	('uveal melanoma', 'Disease', 'MESH:C536494', (180, 194))	('mutations', 'Var', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cutaneous melanoma', 'Disease', (326, 344))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (326, 344))	('melanoma', 'Phenotype', 'HP:0002861', (336, 344))	('melanoma', 'Disease', (336, 344))	('fewer', 'NegReg', (126, 131))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (326, 344))	('uveal melanoma', 'Disease', (371, 385))	('uveal melanoma', 'Disease', 'MESH:C536494', (371, 385))
58172	26991400	Uveal melanomas are not known to harbor BRAF or NRAS mutations.	('BRAF', 'Gene', '673', (40, 44))	('NRAS', 'Gene', '4893', (48, 52))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('BRAF', 'Gene', (40, 44))	('melanomas', 'Disease', (6, 15))	('mutations', 'Var', (53, 62))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('NRAS', 'Gene', (48, 52))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))
58173	26991400	Instead, 80% of uveal melanomas have oncogenic mutations in GNAQ or GNA11, which are potential drivers of MAPK activation similar to oncogenic BRAF mutations in cutaneous melanoma.	('uveal melanomas', 'Disease', (16, 31))	('cutaneous melanoma', 'Disease', (161, 179))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (161, 179))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (161, 179))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('GNA11', 'Gene', '2767', (68, 73))	('GNAQ', 'Gene', '2776', (60, 64))	('GNAQ', 'Gene', (60, 64))	('mutations', 'Var', (47, 56))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('uveal melanomas', 'Disease', 'MESH:C536494', (16, 31))	('MAPK activation', 'biological_process', 'GO:0000187', ('106', '121'))	('GNA11', 'Gene', (68, 73))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('MAPK', 'molecular_function', 'GO:0004707', ('106', '110'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('uveal melanomas', 'Phenotype', 'HP:0007716', (16, 31))
58184	26991400	Cytogenetic changes in uveal melanoma are nonrandom and are characterized by monosomy 3, trisomy 8, deletions in chromosome 1 and structural or numerical abnormalities of chromosome 6.	('chromosome', 'cellular_component', 'GO:0005694', ('171', '181'))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('uveal melanoma', 'Phenotype', 'HP:0007716', (23, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (23, 37))	('structural', 'Var', (130, 140))	('trisomy 8', 'Disease', (89, 98))	('uveal melanoma', 'Disease', (23, 37))	('monosomy 3', 'Disease', (77, 87))	('deletions', 'Var', (100, 109))	('chromosome', 'cellular_component', 'GO:0005694', ('113', '123'))
58185	26991400	Cytogenetic investigation of uveal melanoma has revealed that monosomy 3 is the most frequent karyotypic abnormality, present in approximately 50-60% of cases.	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('monosomy 3', 'Var', (62, 72))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))
58186	26991400	The pattern of loss of heterozygosity in these tumors indicates the presence of deletions around 3p25-26 and on 3q, and a region at 3p11-14 is preferentially deleted.	('tumors', 'Disease', (47, 53))	('3p25-26', 'Gene', (97, 104))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('deletions', 'Var', (80, 89))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
58189	26991400	The loss of the entire short arm of chromosome 1 was only observed in tumors with monosomy 3 and 1p31 was proposed to be involved in progression of monosomy 3 uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (159, 173))	('monosomy 3', 'Var', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (159, 173))	('uveal melanoma', 'Disease', (159, 173))	('short arm', 'Phenotype', 'HP:0009824', (23, 32))	('p31', 'Gene', (98, 101))	('tumors', 'Disease', (70, 76))	('involved', 'Reg', (121, 129))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('p31', 'Gene', '529', (98, 101))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('chromosome', 'cellular_component', 'GO:0005694', ('36', '46'))
58191	26991400	The combination of monosomy 3 with cell type analysis or tumor diameter has been shown to have a greater prognostic impact than monosomy 3 alone.	('monosomy 3', 'Var', (19, 29))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))
58193	26991400	Abdel-Rahman et.al., in their study of 47 uveal melanomas and median follow-up of 36 months, showed that partial chromosome 3 alteration is not associated with the highly aggressive uveal melanoma that metastasizes within the first 3 years post treatment.	('associated', 'Reg', (144, 154))	('uveal melanomas', 'Disease', (42, 57))	('uveal melanomas', 'Phenotype', 'HP:0007716', (42, 57))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('chromosome', 'cellular_component', 'GO:0005694', ('113', '123'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (182, 196))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('partial chromosome', 'Var', (105, 123))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('uveal melanomas', 'Disease', 'MESH:C536494', (42, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('uveal melanoma', 'Disease', 'MESH:C536494', (182, 196))	('uveal melanoma', 'Disease', (182, 196))
58202	26991400	Oncogene and tumor suppressor mutations that are common in other cancers are mostly absent in uveal melanoma, a disease characterized by low mutation burden.	('tumor', 'Disease', (13, 18))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('uveal melanoma', 'Disease', (94, 108))	('absent', 'NegReg', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor suppressor', 'biological_process', 'GO:0051726', ('13', '29'))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('mutations', 'Var', (30, 39))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('Oncogene', 'Gene', (0, 8))	('cancers', 'Disease', (65, 72))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('13', '29'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
58204	26991400	These "driver" mutations that control the biology of up to 70% of cutaneous melanomas are absent/rare in uveal melanoma.	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (66, 85))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (66, 85))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('mutations', 'Var', (15, 24))	('cutaneous melanomas', 'Disease', (66, 85))	('uveal melanoma', 'Phenotype', 'HP:0007716', (105, 119))	('uveal melanoma', 'Disease', 'MESH:C536494', (105, 119))	('uveal melanoma', 'Disease', (105, 119))	('to 7', 'Species', '1214577', (56, 60))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
58206	26991400	analyzed 50 cases of primary uveal melanoma obtained from enucleation for mutations in the genes GNAQ, GNA11, BAP1, SF3B1, EIFAX1 and TERT.	('primary uveal melanoma', 'Disease', (21, 43))	('SF3B1', 'Gene', (116, 121))	('TERT', 'Gene', (134, 138))	('GNAQ', 'Gene', '2776', (97, 101))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('mutations', 'Var', (74, 83))	('SF3B1', 'Gene', '23451', (116, 121))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('BAP1', 'Gene', (110, 114))	('enucleation', 'biological_process', 'GO:0090601', ('58', '69'))	('TERT', 'Gene', '7015', (134, 138))	('GNA11', 'Gene', (103, 108))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (21, 43))	('GNA11', 'Gene', '2767', (103, 108))	('GNAQ', 'Gene', (97, 101))
58207	26991400	They found that 42.2% of uveal melanomas harbored mutated GNAQ, 32.6% GNA11, 31.5% BAP1, 9.7% SF3B1, 18.9% EIF1AX and 1% TERT.	('SF3B1', 'Gene', '23451', (94, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('GNAQ', 'Gene', '2776', (58, 62))	('TERT', 'Gene', '7015', (121, 125))	('uveal melanomas', 'Disease', (25, 40))	('uveal melanomas', 'Phenotype', 'HP:0007716', (25, 40))	('mutated', 'Var', (50, 57))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))	('SF3B1', 'Gene', (94, 99))	('GNAQ', 'Gene', (58, 62))	('TERT', 'Gene', (121, 125))	('GNA11', 'Gene', (70, 75))	('uveal melanomas', 'Disease', 'MESH:C536494', (25, 40))	('EIF1AX and 1', 'Gene', '1964;10209', (107, 119))	('GNA11', 'Gene', '2767', (70, 75))
58208	26991400	Of these, GNAQ and GNA11 are usually mutually exclusive but both can co-exist with BAP1 or SF3B1 mutations.	('mutations', 'Var', (97, 106))	('SF3B1', 'Gene', (91, 96))	('GNAQ', 'Gene', '2776', (10, 14))	('GNA11', 'Gene', (19, 24))	('BAP1', 'Gene', (83, 87))	('GNA11', 'Gene', '2767', (19, 24))	('SF3B1', 'Gene', '23451', (91, 96))	('GNAQ', 'Gene', (10, 14))	('co-exist', 'Reg', (69, 77))
58209	26991400	Likewise, BAP1 and SF3B1 are mutually exclusive as are EIF1AX and SF3B1 mutations, TERT mutations appear to co-exist specifically with GNA11 or EIF1AX mutations.	('mutations', 'Var', (72, 81))	('GNA11', 'Gene', '2767', (135, 140))	('EIF1AX', 'Gene', (55, 61))	('EIF1AX', 'Gene', '1964', (55, 61))	('SF3B1', 'Gene', '23451', (19, 24))	('EIF1AX', 'Gene', (144, 150))	('SF3B1', 'Gene', (66, 71))	('TERT', 'Gene', (83, 87))	('EIF1AX', 'Gene', '1964', (144, 150))	('TERT', 'Gene', '7015', (83, 87))	('SF3B1', 'Gene', '23451', (66, 71))	('GNA11', 'Gene', (135, 140))	('SF3B1', 'Gene', (19, 24))
58210	26991400	The majority of uveal melanomas have one of two mutually exclusive activating mutations in the very homologous genes encoding Galpha subunits, GNAQ (Galphaq) and GNA11 (Galpha11) (19-21).	('uveal melanomas', 'Disease', (16, 31))	('Galpha', 'Gene', (169, 175))	('Galpha11', 'Gene', (169, 177))	('Galphaq', 'Gene', (149, 156))	('mutations', 'Var', (78, 87))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('Galpha', 'Gene', '8802', (169, 175))	('GNA11', 'Gene', (162, 167))	('Galpha', 'Gene', (126, 132))	('uveal melanomas', 'Disease', 'MESH:C536494', (16, 31))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('Galpha', 'Gene', (149, 155))	('Galphaq', 'Gene', '2776;2767', (149, 156))	('activating', 'PosReg', (67, 77))	('GNAQ', 'Gene', '2776', (143, 147))	('Galpha', 'Gene', '8802', (126, 132))	('GNAQ', 'Gene', (143, 147))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('Galpha11', 'Gene', '2767', (169, 177))	('Galpha', 'Gene', '8802', (149, 155))	('uveal melanomas', 'Phenotype', 'HP:0007716', (16, 31))	('GNA11', 'Gene', '2767', (162, 167))
58211	26991400	Interestingly, the GNAQ mutation is more frequently found in benign blue nevi, while the GNA11 mutation is frequent in malignant uveal melanoma.	('found', 'Reg', (52, 57))	('nevi', 'Phenotype', 'HP:0003764', (73, 77))	('malignant uveal melanoma', 'Disease', 'MESH:C536494', (119, 143))	('GNAQ', 'Gene', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('benign blue nevi', 'Disease', (61, 77))	('malignant uveal melanoma', 'Disease', (119, 143))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('GNA11', 'Gene', '2767', (89, 94))	('GNA11', 'Gene', (89, 94))	('mutation', 'Var', (24, 32))	('GNAQ', 'Gene', '2776', (19, 23))	('blue nevi', 'Phenotype', 'HP:0100814', (68, 77))
58212	26991400	showed that the GNAQ/11 mutations activate YAP, a major effector of the Hippo tumor suppressor pathway, and YAP mediates the oncogenic properties of GNAQ/GNA11 mutations.	('YAP', 'Gene', '10413', (108, 111))	('GNAQ', 'Gene', (149, 153))	('activate', 'PosReg', (34, 42))	('YAP', 'Gene', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('YAP', 'Gene', '10413', (43, 46))	('GNAQ', 'Gene', (16, 20))	('GNA11', 'Gene', (154, 159))	('GNAQ', 'Gene', '2776', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor suppressor', 'biological_process', 'GO:0051726', ('78', '94'))	('mutations', 'Var', (24, 33))	('GNA11', 'Gene', '2767', (154, 159))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('78', '94'))	('GNAQ', 'Gene', '2776', (16, 20))	('tumor', 'Disease', (78, 83))	('YAP', 'Gene', (43, 46))
58213	26991400	first described inactivating somatic mutations in BAP1 gene (BRCA1-associated protein 1), on chromosome 3p21.1 in 26 of 31 (84%) metastasizing tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('inactivating', 'Var', (16, 28))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('mutations', 'Var', (37, 46))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('BRCA1-associated protein 1', 'Gene', '8314', (61, 87))	('BAP1', 'Gene', (50, 54))	('BRCA1-associated protein 1', 'Gene', (61, 87))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
58214	26991400	One tumor had a germ line frame-shift mutation representing a susceptibility allele.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('frame-shift mutation', 'Var', (26, 46))	('tumor', 'Disease', 'MESH:D009369', (4, 9))
58217	26991400	Subsequently, more germline mutations of BAP1 have been described in uveal melanoma patients suggesting that BAP1 screening can identify people with predisposition to uveal melanoma.	('described', 'Reg', (56, 65))	('patients', 'Species', '9606', (84, 92))	('uveal melanoma', 'Disease', (69, 83))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('BAP1', 'Gene', (41, 45))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (167, 181))	('uveal melanoma', 'Disease', 'MESH:C536494', (167, 181))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('uveal melanoma', 'Disease', (167, 181))	('people', 'Species', '9606', (137, 143))	('germline', 'Var', (19, 27))
58218	26991400	These reports of mutation screens in patients with uveal melanoma suggest younger patients may harbor a germline BAP1 mutation.	('uveal melanoma', 'Phenotype', 'HP:0007716', (51, 65))	('uveal melanoma', 'Disease', (51, 65))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (82, 90))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('mutation', 'Var', (118, 126))	('BAP1', 'Gene', (113, 117))	('uveal melanoma', 'Disease', 'MESH:C536494', (51, 65))
58222	26991400	Uveal melanoma is among a small group of cancers associated with SF3B1 mutations.	('melanoma', 'Disease', 'MESH:D008545', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('associated', 'Reg', (49, 59))	('SF3B1', 'Gene', (65, 70))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('mutations', 'Var', (71, 80))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('SF3B1', 'Gene', '23451', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('melanoma', 'Disease', (6, 14))	('cancers', 'Disease', (41, 48))
58223	26991400	These mutations define a genetic subset of uveal melanoma that have been reported by Harbour et al.	('uveal melanoma', 'Disease', 'MESH:C536494', (43, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('uveal melanoma', 'Disease', (43, 57))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('mutations', 'Var', (6, 15))
58224	26991400	SF3B1 mutations are observed in codon 65 and mostly in tumors without loss of all or part of chromosome 3.	('SF3B1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('SF3B1', 'Gene', '23451', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('mutations', 'Var', (6, 15))
58227	26991400	EIF1AX mutations are infrequent in monosomy 3 uveal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('uveal melanomas', 'Disease', 'MESH:C536494', (46, 61))	('uveal melanomas', 'Phenotype', 'HP:0007716', (46, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (46, 60))	('EIF1AX', 'Gene', (0, 6))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))	('EIF1AX', 'Gene', '1964', (0, 6))	('uveal melanomas', 'Disease', (46, 61))	('mutations', 'Var', (7, 16))
58231	26991400	Molecular prognostic testing for genetic mutations, chromosomal abnormalities, and gene expression profiling, as discussed above, are becoming more common in uveal melanoma and have led to the identification and enrollment of high risk patients in adjuvant therapy trials.	('common', 'Reg', (148, 154))	('genetic mutations', 'Var', (33, 50))	('patients', 'Species', '9606', (236, 244))	('chromosomal abnormalities', 'Disease', (52, 77))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (52, 77))	('gene expression', 'biological_process', 'GO:0010467', ('83', '98'))	('uveal melanoma', 'Disease', 'MESH:C536494', (158, 172))	('uveal melanoma', 'Phenotype', 'HP:0007716', (158, 172))	('uveal melanoma', 'Disease', (158, 172))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('led to', 'Reg', (182, 188))
58233	26991400	GNAQ and GNA11 mutations activate pathways that may provide a rationale for the use of a MEK or Akt inhibitor, while HDAC inhibitors may be the choice for treating BAP1-mutated uveal melanoma.	('GNA11', 'Gene', (9, 14))	('MEK', 'Gene', (89, 92))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('activate', 'PosReg', (25, 33))	('GNAQ', 'Gene', '2776', (0, 4))	('MEK', 'Gene', '5609', (89, 92))	('pathways', 'Pathway', (34, 42))	('mutations', 'Var', (15, 24))	('uveal melanoma', 'Disease', 'MESH:C536494', (177, 191))	('uveal melanoma', 'Phenotype', 'HP:0007716', (177, 191))	('GNAQ', 'Gene', (0, 4))	('uveal melanoma', 'Disease', (177, 191))	('Akt', 'Gene', '207', (96, 99))	('Akt', 'Gene', (96, 99))	('GNA11', 'Gene', '2767', (9, 14))
58234	26991400	The identification of downstream effectors of GNAQ/11 mutations, like the components of the Hippo pathway, gives us an alternative to targeting the MAPK pathway, which, to date, has been disappointing.	('GNAQ', 'Gene', (46, 50))	('MAPK', 'molecular_function', 'GO:0004707', ('148', '152'))	('MAPK pathway', 'Pathway', (148, 160))	('mutations', 'Var', (54, 63))	('GNAQ', 'Gene', '2776', (46, 50))
58244	26991400	Mice treated with crizotinib showed a significant reduction in the development of metastasis as compared to untreated control mice.	('mice', 'Species', '10090', (126, 130))	('reduction', 'NegReg', (50, 59))	('crizotinib', 'Var', (18, 28))	('Mice', 'Species', '10090', (0, 4))	('development of metastasis', 'CPA', (67, 92))	('crizotinib', 'Chemical', 'MESH:D000077547', (18, 28))
58245	26991400	Thus, inhibition of MET may prevent uveal melanoma metastasis and crizotinib could represent a potential adjuvant therapy strategy for patients with primary uveal melanoma at risk for distant disease.	('patients', 'Species', '9606', (135, 143))	('uveal melanoma metastasis', 'Disease', (36, 61))	('uveal melanoma metastasis', 'Disease', 'MESH:C536494', (36, 61))	('primary uveal melanoma', 'Disease', (149, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (149, 171))	('MET', 'Gene', (20, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (36, 50))	('prevent', 'NegReg', (28, 35))	('inhibition', 'Var', (6, 16))	('uveal melanoma', 'Phenotype', 'HP:0007716', (157, 171))	('crizotinib', 'Chemical', 'MESH:D000077547', (66, 76))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
58252	27453164	Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations.	('mutations', 'Var', (112, 121))	('BRCA1 associated protein 1', 'Gene', '8314', (85, 111))	('BRCA1 associated protein 1', 'Gene', (85, 111))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))
58253	27453164	Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers.	('asbestos', 'Chemical', 'MESH:D001194', (203, 211))	('variants', 'Var', (103, 111))	('BRCA1 associated protein 1', 'Gene', '8314', (49, 75))	('BRCA1 associated protein 1', 'Gene', (49, 75))	('influence', 'Reg', (121, 130))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
58275	27453164	Multiple tumor types develop in family members who inherit BAP1 mutations; in addition, laboratory studies suggest that the incidence of MM may be increased upon exposure to asbestos, possibly even at levels too low to cause MM among the population at large.	('Multiple tumor', 'Disease', 'MESH:D009369', (0, 14))	('increased', 'PosReg', (147, 156))	('BAP1', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (64, 73))	('asbestos', 'Chemical', 'MESH:D001194', (174, 182))	('Multiple tumor', 'Disease', (0, 14))
58286	27453164	In subsequent studies, the team found that germline mutations in the BAP1 gene caused a novel cancer syndrome characterized by extremely high incidences of MM and uveal melanoma (UM) and, less frequently, other cancers.	('uveal melanoma', 'Phenotype', 'HP:0007716', (163, 177))	('cancer syndrome', 'Disease', (94, 109))	('germline mutations', 'Var', (43, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (163, 177))	('cancers', 'Disease', 'MESH:D009369', (211, 218))	('BAP1', 'Gene', (69, 73))	('cancers', 'Disease', (211, 218))	('caused', 'Reg', (79, 85))	('uveal melanoma', 'Disease', (163, 177))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer syndrome', 'Disease', 'MESH:D009369', (94, 109))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))
58289	27453164	At least one malignancy has developed in all carriers of germline BAP1 mutations who are older than 55 years studied so far, and multiple cancers have developed in many of them.	('germline', 'Var', (57, 65))	('malignancy', 'Disease', (13, 23))	('man', 'Species', '9606', (164, 167))	('multiple cancers', 'Disease', (129, 145))	('BAP1', 'Gene', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (71, 80))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('multiple cancers', 'Disease', 'MESH:D009369', (129, 145))	('malignancy', 'Disease', 'MESH:D009369', (13, 23))
58296	27453164	In the 18th century, the couple immigrated to the United States and their descendants spread throughout the country, with carriers of the mutation affected by multiple malignancies.	('multiple malignancies', 'Disease', 'MESH:D009369', (159, 180))	('mutation', 'Var', (138, 146))	('multiple malignancies', 'Disease', (159, 180))
58329	27453164	MM caused by environmental exposure and/or reported in those with BAP1 genetic mutations are more likely to be found in younger individuals and to have equal sex and pleural/peritoneal distributions.	('BAP1', 'Gene', (66, 70))	('pleura', 'Disease', 'MESH:D054363', (166, 172))	('genetic mutations', 'Var', (71, 88))	('pleura', 'Disease', (166, 172))
58340	27453164	in China reported a similar or higher percentage of erroneous diagnoses of MM that were often related to inadequate specimens: diagnoses based on cytologic examination or fine-needle aspiration rather than larger biopsy, diagnoses that were not supported by an adequate set of immunostains, or diagnoses made by pathologists or coroners (in the United States) who rarely see these malignancies.	('erroneous', 'Var', (52, 61))	('malignancies', 'Disease', (381, 393))	('aspiration', 'Phenotype', 'HP:0002835', (183, 193))	('malignancies', 'Disease', 'MESH:D009369', (381, 393))
58386	27453164	A retrospective review of 663 patients who underwent an operation at three MM centers in the United States compared EPP with P/D and found that patients who underwent P/D had better survival than those who underwent EPP and that perioperative morbidity and mortality was greater after EPP.	('better', 'PosReg', (175, 181))	('patients', 'Species', '9606', (144, 152))	('survival', 'CPA', (182, 190))	('patients', 'Species', '9606', (30, 38))	('P/D', 'Var', (167, 170))
58394	27453164	PCB improved both progression-free survival (hazard risk = 0.61, p < 0.0001) and OS over PC (hazard risk = 0.77, p = 0.0167).	('improved', 'PosReg', (4, 12))	('OS over PC', 'CPA', (81, 91))	('progression-free survival', 'CPA', (18, 43))	('PCB', 'Var', (0, 3))	('PC', 'Chemical', '-', (89, 91))	('PC', 'Chemical', '-', (0, 2))	('PCB', 'Chemical', '-', (0, 3))
58409	27453164	The finding that BAP1 heterozygosity renders mice susceptible to low amounts of asbestos that rarely cause MM in wild-type mice supports the biologic plausibility for a similar activity in humans.	('heterozygosity', 'Var', (22, 36))	('mice', 'Species', '10090', (45, 49))	('asbestos', 'Chemical', 'MESH:D001194', (80, 88))	('BAP1', 'Gene', (17, 21))	('mice', 'Species', '10090', (123, 127))	('humans', 'Species', '9606', (189, 195))
58410	27453164	To date, none of the patients with MM who are germline carriers of BAP1 mutations have had a history of occupational exposure to asbestos, indicating that MM can develop in these individuals with undetectable levels of exposure.	('patients', 'Species', '9606', (21, 29))	('mutations', 'Var', (72, 81))	('asbestos', 'Chemical', 'MESH:D001194', (129, 137))	('BAP1', 'Gene', (67, 71))
58412	27453164	showing that BAP1+/- mice exposed to 3 microg of asbestos have a higher incidence of MM than control mice, it is anticipated that carriers of germline BAP1 mutations may be more sensitive than the population at large to low amounts of asbestos and NOA.	('mice', 'Species', '10090', (21, 25))	('BAP1', 'Gene', (151, 155))	('mutations', 'Var', (156, 165))	('asbestos', 'Chemical', 'MESH:D001194', (49, 57))	('asbestos', 'Chemical', 'MESH:D001194', (235, 243))	('mice', 'Species', '10090', (101, 105))	('NOA', 'Chemical', '-', (248, 251))
58413	27453164	It is therefore a reasonable precaution for germline carriers of the BAP1 mutation to consider avoiding jobs associated with any possible asbestos exposure, including low levels of exposure, and avoiding residing in areas where asbestos and NOA are known to be present in the environment.	('mutation', 'Var', (74, 82))	('asbestos', 'Chemical', 'MESH:D001194', (138, 146))	('BAP1', 'Gene', (69, 73))	('asbestos', 'Chemical', 'MESH:D001194', (228, 236))	('NOA', 'Chemical', '-', (241, 244))
58437	27453164	are independently validated, total HMGB1 could provide a useful blood biomarker to identify individuals who have been exposed to asbestos and are thus at risk for development of MM, and, among them, hyperacetylated HMGB1 could provide a blood biomarker to detect those in whom MM has developed.	('HMGB1', 'Gene', (215, 220))	('HMGB1', 'Gene', '3146', (215, 220))	('hyperacetylated', 'Var', (199, 214))	('asbestos', 'Chemical', 'MESH:D001194', (129, 137))	('HMGB1', 'Gene', (35, 40))	('HMGB1', 'Gene', '3146', (35, 40))
58442	27453164	The group supported screening for BAP1 germline mutations in families with high-risk features, such as three or more cases of any of the following cancers within two generations: MM, UM, renal cell carcinoma, and cholangiocarcinoma.	('renal cell carcinoma', 'Disease', (187, 207))	('germline mutations', 'Var', (39, 57))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (187, 207))	('BAP1', 'Gene', (34, 38))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (187, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (213, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (213, 231))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('cholangiocarcinoma', 'Disease', (213, 231))
58445	27453164	Thus, it was proposed that children may benefit from genetic testing, as those who are found to have inherited BAP1 mutations may benefit from screening for melanoma.	('BAP1', 'Gene', (111, 115))	('mutations', 'Var', (116, 125))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('benefit', 'PosReg', (130, 137))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('children', 'Species', '9606', (27, 35))
58446	27453164	In summary, the group was in support of medical screening for at-risk people who are carriers of BAP1 germline mutations as follows: (1) annual dermatological screening for early detection of melanoma at age 18 or younger; (2) annual eye examination/ophthalmoscopy for UM at age 18 or younger; and (3) skin and eye examinations every 6 months after age of 30, when the frequency of cancer among carriers of germline BAP1 mutations starts to increase.	('mutations', 'Var', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (382, 388))	('cancer', 'Disease', (382, 388))	('people', 'Species', '9606', (70, 76))	('BAP1', 'Gene', (416, 420))	('mutations', 'Var', (421, 430))	('BAP1', 'Gene', (97, 101))	('melanoma', 'Disease', (192, 200))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))
58466	28350068	Specific genetic alterations can predict the development of metastasis and survival in patients with UM.	('genetic alterations', 'Var', (9, 28))	('UM', 'Phenotype', 'HP:0007716', (101, 103))	('predict', 'Reg', (33, 40))	('metastasis', 'CPA', (60, 70))	('patients', 'Species', '9606', (87, 95))
58467	28350068	Monosomy 3 strongly predicts metastatic risk and other chromosomal abnormalities, also correlated with metastatic diseases.	('metastatic diseases', 'Disease', (103, 122))	('correlated', 'Reg', (87, 97))	('chromosomal abnormalities', 'Disease', (55, 80))	('Monosomy 3', 'Var', (0, 10))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (55, 80))	('predicts', 'Reg', (20, 28))	('metastatic risk', 'Disease', (29, 44))
58471	28350068	Monosomy 3 is present in 50-60% of tumors, which is associated with isochromosome 8q and high level of 8q gain.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('isochromosome 8q', 'Var', (68, 84))	('gain', 'PosReg', (106, 110))
58474	28350068	UM can be classified into 2 groups based on the status of chromosome 3: class 1 tumors with 2 copies, and class 2 tumors, with monosomy of chromosome 3.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('monosomy', 'Var', (127, 135))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('chromosome', 'cellular_component', 'GO:0005694', ('139', '149'))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))
58475	28350068	The characteristics of these tumors basically differ; class 1 tumors have been characterized by gain of 6p and 8q while class 2 tumors by monosomy 3 and gain of entire 8q.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('gain', 'PosReg', (96, 100))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('gain', 'PosReg', (153, 157))	('monosomy 3', 'Var', (138, 148))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', (29, 35))
58518	28350068	Both agonists and antagonists of LH-RH may serve as potential therapeutic agents, acting directly on the target cancer cells.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('antagonists', 'Var', (18, 29))	('LH-RH', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('LH-RH', 'Gene', '2798', (33, 38))
58528	28350068	For example, aberrations of chromosome 4 have been demonstrated in cervical cancer, small cell lung cancer, glioblastoma and chronic lymphocytic leukemia.	('glioblastoma', 'Disease', (108, 120))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))	('small cell lung cancer', 'Disease', 'MESH:D055752', (84, 106))	('aberrations', 'Var', (13, 24))	('small cell lung cancer', 'Disease', (84, 106))	('chromosome', 'cellular_component', 'GO:0005694', ('28', '38'))	('demonstrated', 'Reg', (51, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (125, 153))	('cancer', 'Disease', (100, 106))	('chronic lymphocytic leukemia', 'Disease', (125, 153))	('cancer', 'Disease', (76, 82))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (84, 106))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (125, 153))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('leukemia', 'Phenotype', 'HP:0001909', (145, 153))	('glioblastoma', 'Disease', 'MESH:D005909', (108, 120))
58529	28350068	Chromosome 4 hyperploidy is the most prominent alteration found in Barrett's metaplasia and 89% of the patients display this aberration.	('hyperploidy', 'Var', (13, 24))	('metaplasia', 'biological_process', 'GO:0036074', ('77', '87'))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('Chromosome', 'Var', (0, 10))	("Barrett's metaplasia", 'Disease', 'MESH:D001471', (67, 87))	('patients', 'Species', '9606', (103, 111))	("Barrett's metaplasia", 'Disease', (67, 87))
58531	28350068	It was reported that monosomy 3 strongly predicts metastatic risk and other chromosomal abnormalities correlate with metastatic disease.	('metastatic risk', 'Disease', (50, 65))	('monosomy 3', 'Var', (21, 31))	('predicts', 'Reg', (41, 49))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (76, 101))	('metastatic disease', 'Disease', (117, 135))	('chromosomal abnormalities', 'Disease', (76, 101))
58532	28350068	Monosomy 3 in choroidal melanoma is a significant predictor of metastasis-related death and has been associated with a 70% decrease in 5-year survival.	('death', 'Disease', 'MESH:D003643', (82, 87))	('death', 'Disease', (82, 87))	('decrease', 'NegReg', (123, 131))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (14, 32))	('choroidal melanoma', 'Disease', 'MESH:D008545', (14, 32))	('choroidal melanoma', 'Disease', (14, 32))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('Monosomy 3', 'Var', (0, 10))
58536	28350068	FISH can detect chromosomal alterations that are consistent with a diagnosis of neoplasia.	('chromosomal alterations', 'Var', (16, 39))	('neoplasia', 'Phenotype', 'HP:0002664', (80, 89))	('neoplasia', 'Disease', 'MESH:D009369', (80, 89))	('neoplasia', 'Disease', (80, 89))
58538	28350068	According to our statistical analysis, there is a moderate, statistically significant correlation between the copy numbers of chromosome 3 and 4, but no correlation was found with LH-RH-R expression and chromosome aberrations.	('LH-RH-R', 'Gene', (180, 187))	('LH-RH-R', 'Gene', '2798', (180, 187))	('copy', 'Var', (110, 114))	('chromosome', 'cellular_component', 'GO:0005694', ('126', '136'))	('chromosome', 'cellular_component', 'GO:0005694', ('203', '213'))
58584	26518678	In both cases, patients have mutations of the retinoblastoma tumour suppressor gene on chromosome 13q14.	('retinoblastoma', 'Phenotype', 'HP:0009919', (46, 60))	('patients', 'Species', '9606', (15, 23))	('chromosome', 'cellular_component', 'GO:0005694', ('87', '97'))	('retinoblastoma tumour', 'Disease', 'MESH:D012175', (46, 67))	('retinoblastoma tumour', 'Disease', (46, 67))	('mutations', 'Var', (29, 38))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
58625	26518678	In highly myopic patients, the globe can be elongated and the resulting chemical shift artefact can lead to asymmetric thickening of the outline of the globe mimicking the presence of a tumour while, on the contrary, retinal detachment may mask small tumours.	('tumour', 'Disease', (186, 192))	('highly myopic', 'Phenotype', 'HP:0011003', (3, 16))	('retinal detachment may mask small tumours', 'Disease', 'MESH:D012163', (217, 258))	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('asymmetric thickening', 'Phenotype', 'HP:0001528', (108, 129))	('artefact', 'Var', (87, 95))	('retinal detachment', 'Phenotype', 'HP:0000541', (217, 235))	('tumours', 'Phenotype', 'HP:0002664', (251, 258))	('tumour', 'Disease', 'MESH:D009369', (251, 257))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('chemical shift', 'MPA', (72, 86))	('tumour', 'Disease', (251, 257))	('retinal detachment may mask small tumours', 'Disease', (217, 258))	('lead to', 'Reg', (100, 107))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('patients', 'Species', '9606', (17, 25))
58659	26518678	Nevertheless, de Blank et al found that decreased FA of the optic radiations in patients with ONG was predictive of visual acuity loss during the following year and, therefore, suggested that DTI may be used as a non-invasive tool to prospectively identify those patients who will require therapy.	('patients', 'Species', '9606', (80, 88))	('visual acuity loss', 'Phenotype', 'HP:0000572', (116, 134))	('visual acuity loss', 'Disease', 'MESH:D014786', (116, 134))	('patients', 'Species', '9606', (263, 271))	('FA of', 'MPA', (50, 55))	('ONG', 'Var', (94, 97))	('radiations', 'Disease', 'MESH:D004194', (66, 76))	('radiations', 'Disease', (66, 76))	('decreased', 'NegReg', (40, 49))	('visual acuity loss', 'Disease', (116, 134))
58715	26518678	On MRI, dermoids typically appear hyperintense on T1W and T2W and hypointense on STIR (Fig.	('hypo', 'Disease', (66, 70))	('hypo', 'Disease', 'MESH:D052456', (66, 70))	('T1W', 'Var', (50, 53))	('T2W', 'Var', (58, 61))
58736	26518678	Thus, ADC values appear to be highly sensitive and specific in differentiating BMT from malignant tumours of the lacrimal gland.	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('BMT', 'Disease', (79, 82))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('malignant tumours', 'Disease', 'MESH:D009369', (88, 105))	('malignant tumours', 'Disease', (88, 105))	('ADC', 'Var', (6, 9))
58923	26334521	Various host factors that may increase the risk of uveal melanoma include Caucasian race, light skin and eye color, and propensity to sunburn.	('light skin', 'Phenotype', 'HP:0001010', (90, 100))	('uveal melanoma', 'Disease', (51, 65))	('Caucasian race', 'Var', (74, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (51, 65))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('uveal melanoma', 'Disease', 'MESH:C536494', (51, 65))
58994	26334521	The differential diagnosis of T1 hyperintense lesions includes haemorrhage in primary nasal lesions such as haemangioma and juvenile angiofibroma, proteinaceous secretions in mucoceles, fat-containing lesions and haemorrhagic metastases.	('T1 hyperintense lesions', 'Var', (30, 53))	('haemorrhage', 'Disease', (63, 74))	('haemangioma and juvenile angiofibroma', 'Disease', 'MESH:D018322', (108, 145))	('haemorrhage', 'Disease', 'MESH:D006470', (63, 74))	('haemorrhagic metastases', 'Disease', 'MESH:D006470', (213, 236))	('haemorrhagic metastases', 'Disease', (213, 236))
59009	26334521	8b); however, amelanotic melanomas, which comprise approximately 10 to 29 % of anorectal melanomas, are hypointense on T1- and hyperintense on T2-weighted sequences.	('T2-weighted', 'MPA', (143, 154))	('hypointense', 'Var', (104, 115))	('amelanotic melanomas', 'Disease', (14, 34))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('T1-', 'MPA', (119, 122))	('amelanotic melanomas', 'Disease', 'MESH:D018328', (14, 34))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('anorectal melanomas', 'Disease', (79, 98))	('anorectal melanomas', 'Disease', 'MESH:D008545', (79, 98))	('melanomas', 'Phenotype', 'HP:0002861', (25, 34))
59038	26334521	BRAF mutations are seen in about 10 % of mucosal melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('mucosal melanomas', 'Disease', (41, 58))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('mucosal melanomas', 'Disease', 'MESH:D008545', (41, 58))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
59042	26334521	The US Food and Drug Administration (FDA) has approved drugs for BRAF mutant melanoma including the BRAF inhibitors vemurafenib (August 2011) and dabrafenib (May 2013) as well as the MEK inhibitor trametinib (May 2013).	('vemurafenib', 'Chemical', 'MESH:D000077484', (116, 127))	('trametinib', 'Chemical', 'MESH:C560077', (197, 207))	('dabrafenib', 'Chemical', 'MESH:C561627', (146, 156))	('mutant', 'Var', (70, 76))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('BRAF', 'Gene', '673', (100, 104))	('MEK', 'Gene', (183, 186))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('MEK', 'Gene', '5609', (183, 186))	('BRAF', 'Gene', '673', (65, 69))	('BRAF', 'Gene', (100, 104))	('BRAF', 'Gene', (65, 69))
59044	26334521	Mutations in BRAF, KIT and NRAS are rarely seen in uveal melanoma; however more than 80 percent of uveal melanomas have mutations in GNAQ or GNA11.	('GNAQ', 'Gene', (133, 137))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('uveal melanomas', 'Disease', 'MESH:C536494', (99, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (99, 113))	('mutations', 'Var', (120, 129))	('GNA11', 'Gene', (141, 146))	('uveal melanoma', 'Disease', 'MESH:C536494', (51, 65))	('KIT', 'molecular_function', 'GO:0005020', ('19', '22'))	('uveal melanoma', 'Disease', (51, 65))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('NRAS', 'Gene', '4893', (27, 31))	('uveal melanoma', 'Phenotype', 'HP:0007716', (51, 65))	('uveal melanomas', 'Disease', (99, 114))	('uveal melanomas', 'Phenotype', 'HP:0007716', (99, 114))	('GNA11', 'Gene', '2767', (141, 146))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanomas', 'Phenotype', 'HP:0002861', (105, 114))	('NRAS', 'Gene', (27, 31))	('GNAQ', 'Gene', '2776', (133, 137))
59045	26334521	The GNAQ and GNA11 mutations lead to the activation of the downstream MAPK pathway, which may be a potential target for therapeutic intervention.	('GNAQ', 'Gene', '2776', (4, 8))	('MAPK', 'molecular_function', 'GO:0004707', ('70', '74'))	('mutations', 'Var', (19, 28))	('GNAQ', 'Gene', (4, 8))	('GNA11', 'Gene', (13, 18))	('GNA11', 'Gene', '2767', (13, 18))	('activation', 'PosReg', (41, 51))	('downstream MAPK pathway', 'Pathway', (59, 82))
59047	26334521	Mucosal melanomas have an increased prevalence of c-KIT mutations, seen in about 20-25 % cases.	('mutations', 'Var', (56, 65))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('c-KIT', 'Gene', '3815', (50, 55))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('Mucosal melanomas', 'Disease', (0, 17))	('KIT', 'molecular_function', 'GO:0005020', ('52', '55'))	('c-KIT', 'Gene', (50, 55))	('Mucosal melanomas', 'Disease', 'MESH:D008545', (0, 17))
59048	26334521	Imatinib is a small molecule inhibitor of KIT that inhibits proliferation and induces apoptosis in melanoma cells harbouring KIT mutations, associated with significant clinical response in these patients.	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('induces', 'Reg', (78, 85))	('KIT', 'Gene', (125, 128))	('inhibits', 'NegReg', (51, 59))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('mutations', 'Var', (129, 138))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('KIT', 'molecular_function', 'GO:0005020', ('42', '45'))	('patients', 'Species', '9606', (195, 203))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('proliferation', 'CPA', (60, 73))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('KIT', 'molecular_function', 'GO:0005020', ('125', '128'))	('apoptosis', 'CPA', (86, 95))
59052	26334521	CTLA-4 is a key downregulator of the immune system and blockade of CTLA-4 potentiates the T cell-mediated anti-tumour immune response.	('CTLA-4', 'Gene', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('immune response', 'biological_process', 'GO:0006955', ('118', '133'))	('potentiates', 'PosReg', (74, 85))	('CTLA-4', 'Gene', (67, 73))	('CTLA-4', 'Gene', '1493', (0, 6))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('blockade', 'Var', (55, 63))	('tumour', 'Disease', (111, 117))	('CTLA-4', 'Gene', '1493', (67, 73))
59053	26334521	Inhibition of CTLA-4 by ipilimumab can lead to unique immune-related adverse events (irAEs) such as a rash, colitis, hepatitis, hypophysitis, thyroiditis and pancreatitis.	('lead to', 'Reg', (39, 46))	('rash', 'Disease', 'MESH:D005076', (102, 106))	('CTLA-4', 'Gene', (14, 20))	('hypophysitis', 'Disease', 'MESH:D000072659', (128, 140))	('thyroiditis', 'Disease', (142, 153))	('colitis', 'Phenotype', 'HP:0002583', (108, 115))	('pancreatitis', 'Phenotype', 'HP:0001733', (158, 170))	('ipilimumab', 'Chemical', 'MESH:D000074324', (24, 34))	('pancreatitis', 'Disease', 'MESH:D010195', (158, 170))	('thyroiditis', 'Disease', 'MESH:D013959', (142, 153))	('immune-related adverse events', 'Disease', (54, 83))	('hepatitis', 'Phenotype', 'HP:0012115', (117, 126))	('pancreatitis', 'Disease', (158, 170))	('colitis', 'Disease', (108, 115))	('rash', 'Phenotype', 'HP:0000988', (102, 106))	('Inhibition', 'Var', (0, 10))	('hepatitis', 'Disease', 'MESH:D056486', (117, 126))	('hypophysitis', 'Disease', (128, 140))	('thyroiditis', 'Phenotype', 'HP:0100646', (142, 153))	('colitis', 'Disease', 'MESH:D003092', (108, 115))	('hepatitis', 'Disease', (117, 126))	('rash', 'Disease', (102, 106))	('CTLA-4', 'Gene', '1493', (14, 20))
59059	26368812	Distribution of GNAQ and GNA11 Mutation Signatures in Uveal Melanoma Points to a Light Dependent Mutation Mechanism Uveal melanomas (UM) originate from melanocytes in the interior wall of the eye, namely from the iris, ciliary body and the choroid with marked differences in light exposure (from dark anterior to illuminated posterior).	('Melanoma', 'Disease', (60, 68))	('melanomas', 'Disease', (122, 131))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (116, 130))	('GNAQ', 'Gene', (16, 20))	('Mutation', 'Var', (31, 39))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('Melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (116, 131))	('melanomas', 'Disease', 'MESH:D008545', (122, 131))	('GNAQ', 'Gene', '2776', (16, 20))	('GNA11', 'Gene', (25, 30))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('Melanoma', 'Disease', 'MESH:D008545', (60, 68))	('UM', 'Phenotype', 'HP:0007716', (133, 135))	('GNA11', 'Gene', '2767', (25, 30))
59060	26368812	In this report choroidal, ciliochoroidal and iridociliary melanomas were analyzed for GNAQ and GNA11 mutations which were subsequently correlated to the location of tumor origin.	('tumor', 'Disease', (165, 170))	('mutations', 'Var', (101, 110))	('GNAQ', 'Gene', '2776', (86, 90))	('GNA11', 'Gene', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('GNA11', 'Gene', '2767', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('iridociliary melanomas', 'Disease', (45, 67))	('iridociliary melanomas', 'Disease', 'MESH:D008545', (45, 67))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))	('GNAQ', 'Gene', (86, 90))
59061	26368812	Hotspot mutations in GNAQ and GNA11 can be divided in A>T and in A>C mutation signatures.	('GNAQ', 'Gene', '2776', (21, 25))	('GNA11', 'Gene', (30, 35))	('mutations', 'Var', (8, 17))	('GNAQ', 'Gene', (21, 25))	('GNA11', 'Gene', '2767', (30, 35))
59062	26368812	The GNAQ A626C mutation (Q209P) was almost exclusively observed in choroidal melanomas from the illuminated posterior side.	('GNAQ', 'Gene', '2776', (4, 8))	('A626C', 'Mutation', 'rs121913492', (9, 14))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (67, 86))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('GNAQ', 'Gene', (4, 8))	('choroidal melanomas', 'Disease', (67, 86))	('A626C', 'Var', (9, 14))	('choroidal melanomas', 'Disease', 'MESH:D008545', (67, 86))	('Q209P', 'Var', (25, 30))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (67, 85))	('Q209P', 'Mutation', 'rs121913492', (25, 30))
59068	26368812	Whereas mutations in the BRAF and NRAS genes have been shown to be present in most of the CM, GNAQ and GNA11 mutations are involved in the development of UM.	('involved', 'Reg', (123, 131))	('GNA11', 'Gene', (103, 108))	('GNA11', 'Gene', '2767', (103, 108))	('mutations', 'Var', (8, 17))	('GNAQ', 'Gene', '2776', (94, 98))	('BRAF', 'Gene', '673', (25, 29))	('CM', 'Phenotype', 'HP:0012056', (90, 92))	('NRAS', 'Gene', (34, 38))	('mutations', 'Var', (109, 118))	('BRAF', 'Gene', (25, 29))	('UM', 'Phenotype', 'HP:0007716', (154, 156))	('NRAS', 'Gene', '4893', (34, 38))	('GNAQ', 'Gene', (94, 98))
59069	26368812	The BRAF hotspot mutation in CM (1799T>A V600E) does not bear the typical "UV signature" (C>T in dipyrimidine sites) and therefore does not reflect sun exposure as a risk factor.	('1799T>A', 'Var', (33, 40))	('V600E', 'Var', (41, 46))	('dipyrimidine', 'Chemical', '-', (97, 109))	('V600E', 'SUBSTITUTION', 'None', (41, 46))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('CM', 'Phenotype', 'HP:0012056', (29, 31))	('1799T>A', 'SUBSTITUTION', 'None', (33, 40))
59070	26368812	A>T and T>A) are observed in BRAF, GNA11 and GNAQ, a common mechanism may lead to these mutations.	('BRAF', 'Gene', '673', (29, 33))	('T>A', 'Var', (8, 11))	('lead', 'Reg', (74, 78))	('BRAF', 'Gene', (29, 33))	('GNAQ', 'Gene', (45, 49))	('GNA11', 'Gene', '2767', (35, 40))	('GNA11', 'Gene', (35, 40))	('GNAQ', 'Gene', '2776', (45, 49))
59090	26368812	GNAQ mutations were found in choroid, ciliochoroidal and iridociliary melanoma in respectively 50%, 34% and 45% of the cases.	('iridociliary melanoma', 'Disease', (57, 78))	('ciliochoroidal', 'Disease', (38, 52))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (5, 14))	('GNAQ', 'Gene', (0, 4))	('choroid', 'Disease', (29, 36))	('found', 'Reg', (20, 25))	('iridociliary melanoma', 'Disease', 'MESH:D008545', (57, 78))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
59091	26368812	GNA11 mutations were found in choroid, ciliochoroidal and iridociliary melanoma in respectively 45%, 63% and 27% of the cases per location.	('iridociliary melanoma', 'Disease', 'MESH:D008545', (58, 79))	('GNA11', 'Gene', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('iridociliary melanoma', 'Disease', (58, 79))	('GNA11', 'Gene', '2767', (0, 5))	('choroid', 'Disease', (30, 37))	('found', 'Reg', (21, 26))	('ciliochoroidal', 'Disease', (39, 53))	('mutations', 'Var', (6, 15))
59094	26368812	Subsequently, we subdivided UM based on type of base substitution as A>T and A>C underlie all GNAQ and GNA11 mutations.	('GNA11', 'Gene', '2767', (103, 108))	('UM', 'Phenotype', 'HP:0007716', (28, 30))	('A>C', 'Var', (77, 80))	('A>T', 'Var', (69, 72))	('GNAQ', 'Gene', '2776', (94, 98))	('mutations', 'Var', (109, 118))	('GNA11', 'Gene', (103, 108))	('GNAQ', 'Gene', (94, 98))
59096	26368812	The choroid melanomas that present the A>C mutation originate from the light-exposed area of the eye.	('choroid melanomas', 'Disease', 'MESH:D008545', (4, 21))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanomas', 'Phenotype', 'HP:0002861', (12, 21))	('choroid melanomas', 'Phenotype', 'HP:0012054', (4, 21))	('choroid melanomas', 'Disease', (4, 21))	('A>C', 'Var', (39, 42))
59098	26368812	Half (53%) of the UM with lipofuscin tested positive for the A>C mutation while approximately a quarter of the lipofuscin negative UM presented the A>C mutation (p = 0.078) (Table 3).	('lipofuscin', 'Chemical', 'MESH:D008062', (111, 121))	('A>C', 'Var', (148, 151))	('UM', 'Phenotype', 'HP:0007716', (131, 133))	('UM', 'Phenotype', 'HP:0007716', (18, 20))	('lipofuscin', 'Chemical', 'MESH:D008062', (26, 36))	('A>C', 'Var', (61, 64))	('positive', 'Reg', (44, 52))
59102	26368812	Remarkably, UM bearing the GNAQ Q209L mutation were most commonly found in light eyes (p = 0.002) but this did not hold for the GNA11 Q209L mutation which is characterized by the same base substitution (A>T) (Table 2).	('GNAQ', 'Gene', '2776', (27, 31))	('GNA11', 'Gene', '2767', (128, 133))	('GNA11', 'Gene', (128, 133))	('Q209L', 'Var', (134, 139))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('GNAQ', 'Gene', (27, 31))	('Q209L', 'Mutation', 'rs121913492', (32, 37))	('Q209L', 'Mutation', 'rs121913492', (134, 139))
59103	26368812	UM is a rare tumor for which only recently the first step in the molecular etiology was revealed with the identification of GNAQ and GNA11 mutations.	('tumor', 'Disease', (13, 18))	('GNA11', 'Gene', (133, 138))	('mutations', 'Var', (139, 148))	('GNAQ', 'Gene', '2776', (124, 128))	('GNA11', 'Gene', '2767', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('GNAQ', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
59105	26368812	Apparently, the regulation of uveal melanocytes determines oncogene dependence of UM on mutant GNAQ/GNA11, in contrast to mutant BRAF/NRAS in CM.	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('GNAQ', 'Gene', (95, 99))	('GNA11', 'Gene', '2767', (100, 105))	('UM', 'Phenotype', 'HP:0007716', (82, 84))	('regulation', 'biological_process', 'GO:0065007', ('16', '26'))	('mutant', 'Var', (88, 94))	('CM', 'Phenotype', 'HP:0012056', (142, 144))	('NRAS', 'Gene', (134, 138))	('GNA11', 'Gene', (100, 105))	('uvea', 'Disease', (30, 34))	('GNAQ', 'Gene', '2776', (95, 99))	('NRAS', 'Gene', '4893', (134, 138))	('uvea', 'Disease', 'MESH:C536494', (30, 34))
59106	26368812	The molecular mechanisms that lead to GNAQ and GNA11 mutations are, however, unknown.	('GNAQ', 'Gene', '2776', (38, 42))	('GNA11', 'Gene', '2767', (47, 52))	('GNA11', 'Gene', (47, 52))	('mutations', 'Var', (53, 62))	('GNAQ', 'Gene', (38, 42))
59111	26368812	A2E induced 8-oxo-deoxyguanosine that is incorporated in DNA replication, may lead to the GNAQ Q209P (A>C) mutation in a successive round of replication.	('DNA replication', 'biological_process', 'GO:0006260', ('57', '72'))	('8-oxo-deoxyguanosine', 'Chemical', 'MESH:C067134', (12, 32))	('lead to', 'Reg', (78, 85))	('GNAQ', 'Gene', '2776', (90, 94))	('Q209P', 'Mutation', 'rs121913492', (95, 100))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('GNAQ', 'Gene', (90, 94))	('Q209P (A>C', 'Var', (95, 105))
59112	26368812	In esophageal adenocarcinoma the A>C mutation was the most common mutation signature which has a homologous context to GNAQ.	('GNAQ', 'Gene', (119, 123))	('A>C', 'Var', (33, 36))	('esophageal adenocarcinoma', 'Disease', (3, 28))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (3, 28))	('GNAQ', 'Gene', '2776', (119, 123))
59113	26368812	The mutation is correlated with acid reflux disease but no specific carcinogenic compound has been identified.	('carcinogenic', 'Disease', 'MESH:D063646', (68, 80))	('carcinogenic', 'Disease', (68, 80))	('mutation', 'Var', (4, 12))	('correlated', 'Reg', (16, 26))	('acid reflux', 'Phenotype', 'HP:0002020', (32, 43))	('acid reflux disease', 'Disease', (32, 51))
59115	26368812	As lipofuscin and focused visible light (blue light in particular) are unique to the macular region it may explain the preferential occurrence of the Q209P mutation in choroidal melanoma.	('choroidal melanoma', 'Phenotype', 'HP:0012054', (168, 186))	('Q209P', 'Mutation', 'rs121913492', (150, 155))	('Q209P', 'Var', (150, 155))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('choroidal melanoma', 'Disease', 'MESH:D008545', (168, 186))	('lipofuscin', 'Chemical', 'MESH:D008062', (3, 13))	('choroidal melanoma', 'Disease', (168, 186))
59116	26368812	The role of lipofuscin depositions in UM development should ideally be studied clinically in high-risk uveal nevi and correlated with the GNAQ/GNA11 mutations in the succeeding UM.	('uvea', 'Disease', (103, 107))	('mutations', 'Var', (149, 158))	('uvea', 'Disease', 'MESH:C536494', (103, 107))	('GNAQ', 'Gene', '2776', (138, 142))	('lipofuscin', 'Chemical', 'MESH:D008062', (12, 22))	('nevi', 'Phenotype', 'HP:0003764', (109, 113))	('UM', 'Phenotype', 'HP:0007716', (177, 179))	('GNA11', 'Gene', (143, 148))	('GNAQ', 'Gene', (138, 142))	('GNA11', 'Gene', '2767', (143, 148))	('UM', 'Phenotype', 'HP:0007716', (38, 40))
59121	26368812	S-adenosyl methionine can also act as methyl donor in DNA-alkylating reactions and can cause A>T transversions due to methyl-adenosine adduct formation.	('methyl', 'MPA', (38, 44))	('S-adenosyl methionine', 'Chemical', 'MESH:D012436', (0, 21))	('>T transversions', 'MPA', (94, 110))	('donor', 'Species', '9606', (45, 50))	('DNA-alkylating reactions', 'Enzyme', (54, 78))	('cause', 'Reg', (87, 92))	('methyl-adenosine adduct formation', 'MPA', (118, 151))	('methyl-adenosine', 'Chemical', '-', (118, 134))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('formation', 'biological_process', 'GO:0009058', ('142', '151'))	('S-adenosyl methionine', 'Var', (0, 21))
59122	26368812	The observation that ciliochoroidal melanoma is almost exclusively correlated with A>T mutations in GNAQ Q209L and GNA11 Q209L (16/21) in patients with light eyes (11/14) supports this hypothesis (Tables 2 and 3).	('GNA11', 'Gene', '2767', (115, 120))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('GNAQ', 'Gene', '2776', (100, 104))	('choroidal melanoma', 'Disease', 'MESH:D008545', (26, 44))	('Q209L', 'Mutation', 'rs121913492', (121, 126))	('Q209L', 'Var', (105, 110))	('choroidal melanoma', 'Disease', (26, 44))	('correlated', 'Reg', (67, 77))	('A>T', 'Var', (83, 86))	('GNAQ', 'Gene', (100, 104))	('Q209L', 'Mutation', 'rs121913492', (105, 110))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (26, 44))	('GNA11', 'Gene', (115, 120))	('patients', 'Species', '9606', (138, 146))
59127	26368812	We propose that light-induced damage may underlie the almost exclusive presence of the GNAQ Q209P mutation in choroidal melanoma.	('choroidal melanoma', 'Disease', (110, 128))	('GNAQ', 'Gene', '2776', (87, 91))	('Q209P', 'Var', (92, 97))	('Q209P', 'Mutation', 'rs121913492', (92, 97))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (110, 128))	('GNAQ', 'Gene', (87, 91))	('choroidal melanoma', 'Disease', 'MESH:D008545', (110, 128))
59147	26217116	There are many polymorphisms of the MC1R gene, resulting in the numerous skin-colour phenotypes seen in humans; variants such as the red hair, fair-skinned phenotype express low pigmentation, with a consequent increased sensitivity to ultraviolet (UV) light and associated increased melanoma risk.	('pigmentation', 'biological_process', 'GO:0043473', ('178', '190'))	('increased', 'PosReg', (210, 219))	('melanoma', 'Disease', 'MESH:D008545', (283, 291))	('melanoma', 'Phenotype', 'HP:0002861', (283, 291))	('melanoma', 'Disease', (283, 291))	('increased', 'PosReg', (273, 282))	('red hair', 'Phenotype', 'HP:0002297', (133, 141))	('MC1R', 'Gene', (36, 40))	('humans', 'Species', '9606', (104, 110))	('low pigmentation', 'Disease', (174, 190))	('variants', 'Var', (112, 120))	('low pigmentation', 'Disease', 'MESH:D010859', (174, 190))
59168	26217116	Observational studies suggest a strong association between high naevus counts and melanoma.	('naevus', 'Phenotype', 'HP:0003764', (64, 70))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('high', 'Var', (59, 63))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))
59172	26217116	This gene locus undergoes complex transcription (from alternate reading frames) and thus encodes two proteins, p16 and p14ARF; the majority of mutations affect the former protein.	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('p14ARF', 'Gene', (119, 125))	('p16', 'Gene', '1029', (111, 114))	('affect', 'Reg', (153, 159))	('transcription', 'biological_process', 'GO:0006351', ('34', '47'))	('p14ARF', 'Gene', '1029', (119, 125))	('p16', 'Gene', (111, 114))	('mutations', 'Var', (143, 152))
59176	26217116	Evidence also exists for a pro-melanomagenic effect of germline mutations affecting CDK4 and Rb1 directly.	('Rb', 'Phenotype', 'HP:0009919', (93, 95))	('Rb1', 'Gene', (93, 96))	('CDK4', 'Gene', (84, 88))	('CDK', 'molecular_function', 'GO:0004693', ('84', '87'))	('CDK4', 'Gene', '1019', (84, 88))	('Rb1', 'Gene', '5925', (93, 96))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('germline mutations', 'Var', (55, 73))
59177	26217116	p14ARF also has an important role in down-regulating p53 activity (through increased activation of MDM2), thus also acting as a tumour suppressor; disruption of this activity through mutations could also be tumourigenic.	('tumour', 'Disease', (128, 134))	('tumour', 'Disease', (207, 213))	('p14ARF', 'Gene', '1029', (0, 6))	('mutations', 'Var', (183, 192))	('MDM2', 'Gene', '4193', (99, 103))	('MDM2', 'Gene', (99, 103))	('activation', 'PosReg', (85, 95))	('p14ARF', 'Gene', (0, 6))	('disruption', 'Var', (147, 157))	('down-regulating', 'NegReg', (37, 52))	('activity', 'MPA', (57, 65))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('tumour', 'Disease', 'MESH:D009369', (207, 213))
59178	26217116	The actual prevalence of CDKN2A mutations is difficult to quantify.	('mutations', 'Var', (32, 41))	('CDKN2A', 'Gene', '1029', (25, 31))	('CDKN2A', 'Gene', (25, 31))
59181	26217116	There may also be interaction between genetic mutations to modulate melanoma risk further; for example, some MC1R gene variants can increase the penetrance of CDKN2A mutations, thus increasing risk further.	('CDKN2A', 'Gene', '1029', (159, 165))	('mutations', 'Var', (166, 175))	('increase', 'PosReg', (132, 140))	('risk', 'MPA', (193, 197))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('increasing', 'PosReg', (182, 192))	('melanoma', 'Disease', (68, 76))	('penetrance', 'MPA', (145, 155))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('MC1R', 'Gene', (109, 113))	('variants', 'Var', (119, 127))	('CDKN2A', 'Gene', (159, 165))
59185	26217116	Given that some studies suggest an increased risk of melanoma in the presence of mutations in this gene, whereas others have been unable to demonstrate this, no sound conclusions can be drawn regarding this gene.	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('mutations', 'Var', (81, 90))
59187	26217116	Genetic mutations affecting protagonists of the mitogen-activated protein kinase (MAPK) pathway have been found in many tumour types.	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('tumour', 'Disease', (120, 126))	('found', 'Reg', (106, 111))	('Genetic mutations', 'Var', (0, 17))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
59191	26217116	Homo- or hetero-dimer formation of RAF molecules ultimately leads to the activation of extracellular signal-regulated kinase (ERK) which in turn acts on numerous targets to promote cell growth and survival, as well as controlling further MAPK pathway signalling by inducing the expression of negative regulators, and directly inhibiting proteins such as CRAF.	('inducing', 'PosReg', (265, 273))	('extracellular signal-regulated kinase', 'Gene', '5594', (87, 124))	('CRAF', 'Gene', (354, 358))	('RAF', 'Gene', (35, 38))	('controlling', 'Reg', (218, 229))	('extracellular', 'cellular_component', 'GO:0005576', ('87', '100'))	('ERK', 'molecular_function', 'GO:0004707', ('126', '129'))	('expression', 'MPA', (278, 288))	('proteins', 'Protein', (337, 345))	('CRAF', 'molecular_function', 'GO:0004709', ('354', '358'))	('CRAF', 'Gene', '5894', (354, 358))	('promote', 'PosReg', (173, 180))	('inhibiting', 'NegReg', (326, 336))	('Homo-', 'Var', (0, 5))	('activation', 'PosReg', (73, 83))	('RAF', 'Gene', '22882', (355, 358))	('mole', 'Phenotype', 'HP:0003764', (39, 43))	('ERK', 'Gene', '5594', (126, 129))	('negative regulators', 'MPA', (292, 311))	('MAPK pathway signalling', 'Pathway', (238, 261))	('cell growth', 'CPA', (181, 192))	('signalling', 'biological_process', 'GO:0023052', ('251', '261'))	('RAF', 'Gene', '22882', (35, 38))	('cell growth', 'biological_process', 'GO:0016049', ('181', '192'))	('formation', 'biological_process', 'GO:0009058', ('22', '31'))	('extracellular signal-regulated kinase', 'Gene', (87, 124))	('MAPK', 'molecular_function', 'GO:0004707', ('238', '242'))	('RAF', 'Gene', (355, 358))	('hetero-dimer formation', 'Var', (9, 31))	('ERK', 'Gene', (126, 129))
59192	26217116	Mutations affecting this pathway are present in the vast majority of cutaneous melanomas, predominantly affecting the NRAS (approximately 20%) or BRAF (approximately 40-50%) proteins.	('BRAF', 'Gene', (146, 150))	('NRAS', 'Gene', (118, 122))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (69, 88))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (69, 87))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (69, 88))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', '4893', (118, 122))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('cutaneous melanomas', 'Disease', (69, 88))	('affecting', 'Reg', (104, 113))	('BRAF', 'Gene', '673', (146, 150))	('proteins', 'Protein', (174, 182))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))
59193	26217116	In the case of BRAF, the vast majority of mutations constitute a single amino acid substitution from valine to glutamic acid at codon 600 (V600E), resulting in a constitutively active BRAF protein that is consequently able to signal in a continuous and unopposed fashion down the MAPK pathway, thus promoting melanomagenesis and preventing apoptosis.	('promoting', 'PosReg', (299, 308))	('BRAF', 'Gene', (184, 188))	('apoptosis', 'CPA', (340, 349))	('MAPK pathway', 'Pathway', (280, 292))	('melanomagenesis', 'Disease', 'None', (309, 324))	('melanoma', 'Phenotype', 'HP:0002861', (309, 317))	('BRAF', 'Gene', '673', (15, 19))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('V600E', 'Mutation', 'rs113488022', (139, 144))	('BRAF', 'Gene', (15, 19))	('apoptosis', 'biological_process', 'GO:0097194', ('340', '349'))	('apoptosis', 'biological_process', 'GO:0006915', ('340', '349'))	('preventing', 'NegReg', (329, 339))	('MAPK', 'molecular_function', 'GO:0004707', ('280', '284'))	('protein', 'Protein', (189, 196))	('V600E', 'Var', (139, 144))	('valine to glutamic acid at codon 600', 'Mutation', 'rs113488022', (101, 137))	('melanomagenesis', 'Disease', (309, 324))	('mutations', 'Var', (42, 51))	('BRAF', 'Gene', '673', (184, 188))
59194	26217116	Interestingly, a similar proportion of naevi also contain BRAF mutations, implying that these alone are not sufficient for malignant transformation.	('mutations', 'Var', (63, 72))	('naevi', 'Disease', (39, 44))	('BRAF', 'Gene', '673', (58, 62))	('naevi', 'Phenotype', 'HP:0003764', (39, 44))	('BRAF', 'Gene', (58, 62))
59195	26217116	It is hypothesised that whilst melanocyte acquisition of a BRAF mutation is not the founder event for oncogenesis, it occurs early in the development of invasive melanoma and further enhances the effects of other oncogenic stimuli; thus it facilitates malignant transformation, rather than initiating it.	('invasive melanoma', 'Disease', (153, 170))	('mutation', 'Var', (64, 72))	('men', 'Species', '9606', (145, 148))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('oncogenesis', 'biological_process', 'GO:0007048', ('102', '113'))	('facilitates', 'PosReg', (240, 251))	('effects', 'MPA', (196, 203))	('malignant transformation', 'CPA', (252, 276))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('invasive melanoma', 'Disease', 'MESH:D008545', (153, 170))	('enhances', 'PosReg', (183, 191))
59196	26217116	BRAF mutations are more commonly seen in melanomas arising in intermittently sun-exposed sites, implying that UV light (as described earlier) may be one such stimulus.	('melanomas', 'Disease', 'MESH:D008545', (41, 50))	('mutations', 'Var', (5, 14))	('seen', 'Reg', (33, 37))	('BRAF', 'Gene', '673', (0, 4))	('melanomas', 'Disease', (41, 50))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))
59197	26217116	Additionally, as there is significant interaction between intracellular signalling pathways, further genetic aberrations affecting the PI3 kinase pathway, for example, may also be sufficient to induce melanoma development.	('melanoma', 'Disease', (201, 209))	('interaction', 'Reg', (38, 49))	('men', 'Species', '9606', (217, 220))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('signalling', 'biological_process', 'GO:0023052', ('72', '82'))	('genetic aberrations', 'Var', (101, 120))	('intracellular', 'cellular_component', 'GO:0005622', ('58', '71'))	('PI3 kinase pathway', 'Pathway', (135, 153))	('induce', 'PosReg', (194, 200))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))
59199	26217116	Prognostic factors in cutaneous melanoma have been closely studied; they include histopathological characteristics, patient characteristics, biochemical measures and most recently genetic mutations.	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('patient', 'Species', '9606', (116, 123))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (22, 40))	('cutaneous melanoma', 'Disease', (22, 40))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (22, 40))	('genetic mutations', 'Var', (180, 197))
59217	26217116	The BRAF gene mutation - which as previously described is integral to melanoma pathogenesis - has been investigated as a prognostic marker too.	('melanoma', 'Disease', (70, 78))	('pathogenesis', 'biological_process', 'GO:0009405', ('79', '91'))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('mutation', 'Var', (14, 22))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
59218	26217116	In advanced disease, meta-analyses have demonstrated that the presence of a BRAF mutation is independently associated with a worse survival outcome.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('mutation', 'Var', (81, 89))	('presence', 'Var', (62, 70))
59227	26217116	Disruptions in a number of tumour suppressor genes and/or activation of oncogenes have been implicated in the development of uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (125, 139))	('uveal melanoma', 'Disease', 'MESH:C536494', (125, 139))	('Disruptions', 'Var', (0, 11))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('uveal melanoma', 'Disease', (125, 139))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('men', 'Species', '9606', (117, 120))	('implicated', 'Reg', (92, 102))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('activation', 'PosReg', (58, 68))	('tumour', 'Disease', (27, 33))	('oncogenes', 'Gene', (72, 81))
59228	26217116	Disruption of the activity of the retinoblastoma (Rb) tumour suppressor gene leads to uninhibited progression of melanocytes through the G1-S phase of the cell cycle, resulting in deregulated cell proliferation.	('retinoblastoma', 'Gene', (34, 48))	('activity', 'MPA', (18, 26))	('deregulated', 'MPA', (180, 191))	('retinoblastoma', 'Gene', '5925', (34, 48))	('cell proliferation', 'CPA', (192, 210))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('Rb', 'Gene', '5925', (50, 52))	('Rb', 'Phenotype', 'HP:0009919', (50, 52))	('uninhibited', 'MPA', (86, 97))	('tumour', 'Disease', (54, 60))	('S phase', 'biological_process', 'GO:0051320', ('140', '147'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (34, 48))	('cell cycle', 'biological_process', 'GO:0007049', ('155', '165'))	('cell proliferation', 'biological_process', 'GO:0008283', ('192', '210'))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('Disruption', 'Var', (0, 10))
59232	26217116	More recently mutually exclusive mutations in GNAQ and GNA11, genes encoding the alpha subunit of heterotrimeric cell surface G proteins, have been reported.	('GNAQ', 'Gene', (46, 50))	('cell surface', 'cellular_component', 'GO:0009986', ('113', '125'))	('mutations', 'Var', (33, 42))	('GNAQ', 'Gene', '2776', (46, 50))	('GNA11', 'Gene', '2767', (55, 60))	('GNA11', 'Gene', (55, 60))
59233	26217116	These alpha subunits are involved in mediating signals between G-protein-coupled receptors and downstream effectors such as protein kinases A and C. Mutations in codon 209 of GNAQ and GNA11 have been reported in approximately 46-49% and 32% of patients, respectively, and lead to constitutive activation of the G protein alpha subunit and activation of the MAPK signalling pathway (in human melanocyte cell lines), driving cell proliferation.	('Mutations in', 'Var', (149, 161))	('human', 'Species', '9606', (385, 390))	('cell proliferation', 'CPA', (423, 441))	('signalling pathway', 'biological_process', 'GO:0007165', ('362', '380'))	('patients', 'Species', '9606', (244, 252))	('GNA11', 'Gene', '2767', (184, 189))	('MAPK signalling pathway', 'Pathway', (357, 380))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('cell proliferation', 'biological_process', 'GO:0008283', ('423', '441'))	('driving', 'PosReg', (415, 422))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('protein', 'cellular_component', 'GO:0003675', ('313', '320'))	('GNAQ', 'Gene', '2776', (175, 179))	('GNA11', 'Gene', (184, 189))	('activation', 'PosReg', (293, 303))	('MAPK', 'molecular_function', 'GO:0004707', ('357', '361'))	('MAPK signalling', 'biological_process', 'GO:0000165', ('357', '372'))	('GNAQ', 'Gene', (175, 179))	('activation', 'PosReg', (339, 349))
59234	26217116	The majority of substitutions at codon 209 of GNAQ and GNA11 involve substitutions of glutamine by leucine or glutamine by proline.	('leucine', 'Chemical', 'MESH:D007930', (99, 106))	('GNAQ', 'Gene', (46, 50))	('substitutions', 'Var', (69, 82))	('leucine', 'MPA', (99, 106))	('glutamine', 'Chemical', 'MESH:D005973', (110, 119))	('glutamine', 'Chemical', 'MESH:D005973', (86, 95))	('proline', 'Chemical', 'MESH:D011392', (123, 130))	('GNAQ', 'Gene', '2776', (46, 50))	('substitutions', 'Var', (16, 29))	('glutamine', 'MPA', (110, 119))	('GNA11', 'Gene', '2767', (55, 60))	('GNA11', 'Gene', (55, 60))	('glutamine', 'Protein', (86, 95))
59235	26217116	Mutations at codon 183 of GNAQ and GNA11 also occur, although less frequently, and involve the substitution of cytosine by thymine which is characteristic of ultraviolet-radiation-induced mutations, thereby supporting the role of UV-B radiation in the pathogenesis of a minority of uveal melanomas.	('cytosine', 'Chemical', 'MESH:D003596', (111, 119))	('uveal melanomas', 'Disease', 'MESH:C536494', (282, 297))	('GNAQ', 'Gene', (26, 30))	('thymine', 'MPA', (123, 130))	('GNA11', 'Gene', '2767', (35, 40))	('substitution', 'Var', (95, 107))	('cytosine', 'MPA', (111, 119))	('thymine', 'Chemical', 'MESH:D013941', (123, 130))	('melanoma', 'Phenotype', 'HP:0002861', (288, 296))	('Mutations', 'Var', (0, 9))	('melanomas', 'Phenotype', 'HP:0002861', (288, 297))	('pathogenesis', 'biological_process', 'GO:0009405', ('252', '264'))	('uveal melanomas', 'Disease', (282, 297))	('uveal melanomas', 'Phenotype', 'HP:0007716', (282, 297))	('GNAQ', 'Gene', '2776', (26, 30))	('involve', 'Reg', (83, 90))	('GNA11', 'Gene', (35, 40))	('uveal melanoma', 'Phenotype', 'HP:0007716', (282, 296))
59236	26217116	As mutations in GNAQ and GNA11 are common in uveal melanoma, targeting these or downstream effectors such as protein kinase C or members of the MAPK signalling pathway are promising potential therapeutic options.	('MAPK', 'molecular_function', 'GO:0004707', ('144', '148'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('uveal melanoma', 'Disease', (45, 59))	('common', 'Reg', (35, 41))	('signalling pathway', 'biological_process', 'GO:0007165', ('149', '167'))	('GNAQ', 'Gene', (16, 20))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('MAPK signalling', 'biological_process', 'GO:0000165', ('144', '159'))	('GNAQ', 'Gene', '2776', (16, 20))	('GNA11', 'Gene', (25, 30))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('mutations', 'Var', (3, 12))	('uveal melanoma', 'Disease', 'MESH:C536494', (45, 59))	('GNA11', 'Gene', '2767', (25, 30))
59238	26217116	Inactivating somatic mutations of the gene coding for BRCA1-associated protein-1 (BAP1) have been found in up to 85% of metastasising uveal melanomas.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('uveal melanomas', 'Disease', (134, 149))	('BAP1', 'Gene', (82, 86))	('uveal melanomas', 'Phenotype', 'HP:0007716', (134, 149))	('BRCA1-associated protein-1', 'Gene', (54, 80))	('found', 'Reg', (98, 103))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('uveal melanomas', 'Disease', 'MESH:C536494', (134, 149))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('uveal melanoma', 'Phenotype', 'HP:0007716', (134, 148))	('BAP1', 'Gene', '8314', (82, 86))	('BRCA1-associated protein-1', 'Gene', '8314', (54, 80))	('Inactivating somatic mutations', 'Var', (0, 30))
59241	26217116	Also families with germ-line mutations of BAP1 have been identified with an increased incidence of both uveal and cutaneous melanoma, as well as other malignancies.	('BAP1', 'Gene', '8314', (42, 46))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('malignancies', 'Disease', 'MESH:D009369', (151, 163))	('uveal', 'Disease', (104, 109))	('mutations', 'Var', (29, 38))	('BAP1', 'Gene', (42, 46))	('cutaneous melanoma', 'Disease', (114, 132))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (114, 132))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (114, 132))	('malignancies', 'Disease', (151, 163))
59249	26217116	Such patients with monosomy 3 uveal melanoma have a poor 5-year survival.	('monosomy 3', 'Var', (19, 29))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('patients', 'Species', '9606', (5, 13))	('uveal melanoma', 'Disease', 'MESH:C536494', (30, 44))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('uveal melanoma', 'Disease', (30, 44))
59251	26217116	It is likely that loss of chromosome 3 is an early event in tumourigenesis, predisposing to other cytogenetic aberrations such as gain of 8q.	('loss', 'Var', (18, 22))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('tumour', 'Disease', (60, 66))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('gain', 'PosReg', (130, 134))
59274	26217116	Unlike cutaneous melanoma, V600E BRAF or NRAS mutations are rare in mucosal melanoma.	('NRAS', 'Gene', '4893', (41, 45))	('cutaneous melanoma', 'Disease', (7, 25))	('V600E', 'Var', (27, 32))	('mucosal melanoma', 'Disease', 'MESH:D008545', (68, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (7, 25))	('BRAF', 'Gene', '673', (33, 37))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (7, 25))	('BRAF', 'Gene', (33, 37))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('NRAS', 'Gene', (41, 45))	('V600E', 'Mutation', 'rs113488022', (27, 32))	('mucosal melanoma', 'Disease', (68, 84))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
59278	26217116	Although the exact mechanism of KIT signalling in melanocytes is not fully understood, studies have demonstrated that inactivating mutations in KIT can lead to amelanotic disorders and prevent normal melanocyte development and survival.	('KIT', 'Gene', (144, 147))	('signalling', 'biological_process', 'GO:0023052', ('36', '46'))	('amelanotic disorders', 'Disease', (160, 180))	('amelanotic disorders', 'Disease', 'MESH:D018328', (160, 180))	('normal melanocyte development', 'CPA', (193, 222))	('prevent', 'NegReg', (185, 192))	('KIT', 'molecular_function', 'GO:0005020', ('32', '35'))	('inactivating mutations', 'Var', (118, 140))	('men', 'Species', '9606', (218, 221))	('lead to', 'Reg', (152, 159))	('KIT', 'molecular_function', 'GO:0005020', ('144', '147'))
59281	26217116	Subsequently, detailed studies comparing melanomas derived from different anatomical sites demonstrated gain-of-function mutations (such as K642E, D816H and V559A), amplifications or over-expression of c-KIT in 39% of mucosal melanomas.	('melanomas', 'Disease', (226, 235))	('KIT', 'molecular_function', 'GO:0005020', ('204', '207'))	('D816H', 'Var', (147, 152))	('V559A', 'Var', (157, 162))	('mucosal melanomas', 'Disease', 'MESH:D008545', (218, 235))	('K642E', 'Mutation', 'rs121913512', (140, 145))	('V559A', 'Mutation', 'rs121913517', (157, 162))	('D816H', 'Mutation', 'rs121913506', (147, 152))	('melanomas', 'Phenotype', 'HP:0002861', (226, 235))	('mucosal melanomas', 'Disease', (218, 235))	('melanomas', 'Disease', 'MESH:D008545', (41, 50))	('K642E', 'Var', (140, 145))	('c-KIT', 'Gene', (202, 207))	('amplifications', 'Var', (165, 179))	('c-KIT', 'Gene', '3815', (202, 207))	('melanomas', 'Disease', (41, 50))	('over-expression', 'PosReg', (183, 198))	('gain-of-function', 'PosReg', (104, 120))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanomas', 'Disease', 'MESH:D008545', (226, 235))	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))
59282	26217116	This frequency is reported to vary markedly by site of melanoma; in one study 88% of oral mucosal melanomas were reported as expressing aberrant c-KIT, while others reported their highest rates (35%) amongst genital tract melanomas.	('expressing', 'Reg', (125, 135))	('melanomas', 'Phenotype', 'HP:0002861', (222, 231))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))	('aberrant', 'Var', (136, 144))	('KIT', 'molecular_function', 'GO:0005020', ('147', '150'))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('melanoma', 'Disease', (222, 230))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('genital tract melanomas', 'Disease', 'MESH:D060737', (208, 231))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('c-KIT', 'Gene', (145, 150))	('genital tract melanomas', 'Disease', (208, 231))	('oral mucosal melanomas', 'Disease', 'MESH:D013280', (85, 107))	('c-KIT', 'Gene', '3815', (145, 150))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('oral mucosal melanomas', 'Disease', (85, 107))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('melanoma', 'Disease', 'MESH:D008545', (222, 230))
59284	26217116	Exon 11 mutations (including point mutations, in-frame deletions and insertions) are the most common KIT mutations; the L576P mutation in particular is found in approximately one third of these melanomas.	('L576P', 'Var', (120, 125))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanomas', 'Phenotype', 'HP:0002861', (194, 203))	('melanomas', 'Disease', 'MESH:D008545', (194, 203))	('KIT', 'molecular_function', 'GO:0005020', ('101', '104'))	('L576P', 'Mutation', 'rs121913513', (120, 125))	('melanomas', 'Disease', (194, 203))	('found', 'Reg', (152, 157))
59286	26217116	There is clearly still much to learn about the biology of mucosal melanoma, but the knowledge gained thus far about KIT mutations is encouraging further research in this area, focused particularly on exploiting this mutation in the pursuit of effective treatment options for this condition.	('men', 'Species', '9606', (258, 261))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('mucosal melanoma', 'Disease', (58, 74))	('KIT', 'molecular_function', 'GO:0005020', ('116', '119'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (58, 74))	('mutations', 'Var', (120, 129))	('KIT', 'Gene', (116, 119))
59287	26217116	KIT mutations have been successfully targeted in the treatment of other malignancies such as gastrointestinal stromal tumours (GIST), which also demonstrate an increased prevalence of KIT mutations.	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (93, 125))	('mutations', 'Var', (188, 197))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('KIT', 'molecular_function', 'GO:0005020', ('184', '187'))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('KIT', 'Gene', (184, 187))	('malignancies', 'Disease', (72, 84))	('malignancies', 'Disease', 'MESH:D009369', (72, 84))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))	('men', 'Species', '9606', (58, 61))	('gastrointestinal stromal tumours', 'Disease', (93, 125))
59289	26217116	Interestingly, patients with KIT mutations appear to have a poorer prognosis than wild-type patients.	('patients', 'Species', '9606', (15, 23))	('KIT', 'molecular_function', 'GO:0005020', ('29', '32'))	('patients', 'Species', '9606', (92, 100))	('mutations', 'Var', (33, 42))	('KIT', 'Gene', (29, 32))
59307	22484192	This strategy is exemplified by the use of imatinib in chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST) and erlotinib in subsets of non-small cell lung cancer (NSCLC) that harbor activating EGFR mutations .	('CML', 'Disease', (81, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('215', '219'))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (55, 79))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (63, 79))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (55, 79))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (161, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('gastrointestinal stromal tumors', 'Disease', (90, 121))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (157, 183))	('GIST', 'Phenotype', 'HP:0100723', (123, 127))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('activating', 'PosReg', (204, 214))	('EGFR', 'Gene', (215, 219))	('mutations', 'Var', (220, 229))	('CML', 'Phenotype', 'HP:0005506', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('NSCLC', 'Disease', 'MESH:D002289', (185, 190))	('non-small cell lung cancer', 'Disease', (157, 183))	('erlotinib', 'Chemical', 'MESH:D000069347', (133, 142))	('chronic myeloid leukemia', 'Disease', (55, 79))	('imatinib', 'Chemical', 'MESH:D000068877', (43, 51))	('NSCLC', 'Disease', (185, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('EGFR', 'Gene', '1956', (215, 219))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (90, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (185, 190))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (90, 121))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (157, 183))	('CML', 'Disease', 'MESH:D015464', (81, 84))
59311	22484192	Of these, the BRAF V600E mutation, resulting from a valine to glutamic acid substitution, is by far the most common and accounts for over 80% of all reported BRAF mutations .	('V600E', 'Mutation', 'rs113488022', (19, 24))	('V600E', 'Var', (19, 24))	('BRAF', 'Gene', (14, 18))	('valine', 'Chemical', 'MESH:D014633', (52, 58))	('glutamic acid', 'Chemical', 'MESH:D018698', (62, 75))
59312	22484192	Other less common, but clinically relevant variants identified from melanoma specimens are the V600K mutation (16% of all BRAF mutations) and V600D/V600R (3% of all BRAF mutations).	('V600K', 'Mutation', 'rs121913227', (95, 100))	('V600D', 'Var', (142, 147))	('V600R', 'SUBSTITUTION', 'None', (148, 153))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('V600R', 'Var', (148, 153))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('V600K', 'Var', (95, 100))	('V600D', 'SUBSTITUTION', 'None', (142, 147))
59313	22484192	Most of the oncogenic activity of mutant BRAF is mediated through activation of the mitogen activated protein kinase (MAPK) cascade, which regulates the cell cycle entry through control of cyclin D1 expression, and the suppression of p27KIP1  as well as through effects upon invasion and survival .	('p27KIP1', 'Gene', '1027', (234, 241))	('MAPK) cascade', 'biological_process', 'GO:0000165', ('118', '131'))	('cyclin', 'molecular_function', 'GO:0016538', ('189', '195'))	('cell cycle entry', 'CPA', (153, 169))	('oncogenic activity', 'CPA', (12, 30))	('MAPK', 'molecular_function', 'GO:0004707', ('118', '122'))	('p27KIP1', 'Gene', (234, 241))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('cell cycle', 'biological_process', 'GO:0007049', ('153', '163'))	('suppression', 'NegReg', (219, 230))	('invasion', 'CPA', (275, 283))	('BRAF', 'Gene', (41, 45))	('cyclin D1', 'Gene', '595', (189, 198))	('regulates', 'Reg', (139, 148))	('mutant', 'Var', (34, 40))	('cyclin D1', 'Gene', (189, 198))	('activation', 'PosReg', (66, 76))
59314	22484192	In experimental systems, the role of mutated BRAF in melanoma seems convincing with in vitro studies showing that the BRAF V600E mutation is an oncogene in immortalized mouse melanocytes  and that selective downregulation of the BRAF V600E mutation using RNAi leads to reversal of the melanoma phenotype .	('downregulation', 'NegReg', (207, 221))	('melanoma', 'Phenotype', 'HP:0002861', (285, 293))	('BRAF', 'Gene', (229, 233))	('mutation', 'Var', (129, 137))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('RNAi', 'biological_process', 'GO:0016246', ('255', '259'))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('BRAF V600E', 'Gene', (118, 128))	('V600E', 'Mutation', 'rs113488022', (234, 239))	('V600E', 'Mutation', 'rs113488022', (123, 128))	('mouse', 'Species', '10090', (169, 174))	('mutated', 'Var', (37, 44))	('melanoma', 'Disease', (285, 293))	('melanoma', 'Disease', 'MESH:D008545', (285, 293))
59315	22484192	Although mutated BRAF is undoubtedly important for melanomagenesis, introduction of BRAF V600E alone is not sufficient for the transformation of primary human or mouse melanocytes.	('melanomagenesis', 'Disease', (51, 66))	('BRAF', 'Gene', (84, 88))	('mouse', 'Species', '10090', (162, 167))	('BRAF', 'Gene', (17, 21))	('V600E', 'Mutation', 'rs113488022', (89, 94))	('human', 'Species', '9606', (153, 158))	('melanomagenesis', 'Disease', 'None', (51, 66))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('V600E', 'Var', (89, 94))
59316	22484192	Instead, melanoma development seems to require both BRAF/MAPK and activity in the PI3K/AKT pathway.	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma', 'Disease', (9, 17))	('AKT', 'Gene', (87, 90))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('MAPK', 'molecular_function', 'GO:0004707', ('57', '61'))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('BRAF/MAPK', 'Var', (52, 61))	('AKT', 'Gene', '207', (87, 90))
59318	22484192	There is also evidence that intermittent, rather than chronic sun-exposure is predictive for BRAF mutational status with BRAF mutant melanoma patients tending to be younger in age (<55 years old) with a lower cumulative UV exposure .	('BRAF', 'Gene', (121, 125))	('BRAF', 'Gene', (93, 97))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('patients', 'Species', '9606', (142, 150))	('mutant', 'Var', (126, 132))
59319	22484192	BRAF mutational status is also of prognostic value and is associated with inferior survival in the metastatic setting (8.5 months in BRAF wild-type vs 5.7 months for BRAF mutant melanoma).	('inferior', 'NegReg', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('mutational', 'Var', (5, 15))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('BRAF', 'Gene', (0, 4))	('survival', 'MPA', (83, 91))
59320	22484192	Since the discovery of activating BRAF mutations in melanoma, a number of BRAF inhibitors have been developed and subjected to extensive in vitro testing .	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('mutations', 'Var', (39, 48))	('BRAF', 'Gene', (34, 38))	('activating', 'PosReg', (23, 33))
59327	22484192	These drugs show higher potency against mutated BRAF and have fewer off-target effects; the list of those currently under pre-clinical investigation includes: SB590885, dabrafenib (GSK2118436), AZ628, XL281, GDC-0879 and vemurafenib (RG704, PLX4032/4720) .	('GSK2118436', 'Var', (181, 191))	('mutated', 'MPA', (40, 47))	('pre', 'molecular_function', 'GO:0003904', ('122', '125'))	('dabrafenib', 'Chemical', 'MESH:C561627', (169, 179))	('GDC-0879', 'Chemical', 'MESH:C540167', (208, 216))	('PLX4032', 'Chemical', 'MESH:D000077484', (241, 248))	('AZ628', 'Chemical', 'MESH:C000592454', (194, 199))	('higher', 'PosReg', (17, 23))	('vemurafenib', 'Chemical', 'MESH:D000077484', (221, 232))	('potency', 'MPA', (24, 31))	('GSK', 'molecular_function', 'GO:0050321', ('181', '184'))	('GSK2118436', 'Chemical', 'MESH:C561627', (181, 191))	('SB590885', 'Chemical', 'MESH:C508204', (159, 167))	('RG704', 'Var', (234, 239))
59330	22484192	Responses to PLX4032 in melanoma xenograft models were BRAF V600E specific and impressive; with either partial or complete responses observed in all cases with a close relationship observed between drug exposure and response within individual xenograft models .	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('PLX4032', 'Chemical', 'MESH:D000077484', (13, 20))	('BRAF V600E', 'Var', (55, 65))	('V600E', 'Mutation', 'rs113488022', (60, 65))	('PLX4032', 'Gene', (13, 20))	('melanoma', 'Disease', (24, 32))
59331	22484192	Interestingly, not all BRAF mutated melanoma cell lines were similarly sensitive to PLX4032 and PLX4720, with a significant proportion showing varying degrees of intrinsic resistance .	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('PLX4032', 'Var', (84, 91))	('melanoma', 'Disease', (36, 44))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('PLX4720', 'Var', (96, 103))	('PLX4720', 'Chemical', 'MESH:C528407', (96, 103))	('PLX4032', 'Chemical', 'MESH:D000077484', (84, 91))
59332	22484192	Current data suggests that PLX4032/4720 induces both cell cycle arrest and apoptosis in the most sensitive cell lines and cell cycle arrest only in resistant less sensitive cell lines .	('induces', 'Reg', (40, 47))	('apoptosis', 'biological_process', 'GO:0006915', ('75', '84'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (53, 70))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('53', '70'))	('apoptosis', 'CPA', (75, 84))	('PLX4032', 'Chemical', 'MESH:D000077484', (27, 34))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('122', '139'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (122, 139))	('PLX4032/4720', 'Var', (27, 39))	('cell cycle arrest', 'CPA', (53, 70))	('apoptosis', 'biological_process', 'GO:0097194', ('75', '84'))
59337	22484192	A minor sub-group of melanomas have been identified with BRAF mutations in positions other than 600.	('BRAF', 'Gene', (57, 61))	('melanomas', 'Disease', (21, 30))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('mutations', 'Var', (62, 71))
59338	22484192	Analysis of a large panel of melanoma cell lines and tissues revealed that ~1% of melanoma cell lines had either D594G or G469E mutation in BRAF, respectively and that 1% of melanoma specimens harbored a G469A mutation in BRAF .	('G469A', 'Var', (204, 209))	('G469E', 'Mutation', 'rs121913355', (122, 127))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('D594G', 'Var', (113, 118))	('G469A', 'Mutation', 'rs121913355', (204, 209))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('BRAF', 'Gene', (140, 144))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('melanoma', 'Disease', (174, 182))	('G469E', 'Var', (122, 127))	('D594G', 'Mutation', 'rs121913338', (113, 118))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))
59339	22484192	These non-V600 BRAF mutated cell lines differed in their signaling from the BRAF V600E mutants and showed high levels of phospho-ERK, low levels of phospho-MEK and resistance to MEK inhibition .	('signaling', 'MPA', (57, 66))	('phospho-MEK', 'MPA', (148, 159))	('BRAF', 'Gene', (76, 80))	('ERK', 'molecular_function', 'GO:0004707', ('129', '132'))	('differed', 'Reg', (39, 47))	('ERK', 'Gene', '5594', (129, 132))	('V600E', 'Mutation', 'rs113488022', (81, 86))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('ERK', 'Gene', (129, 132))	('V600E', 'Var', (81, 86))
59340	22484192	Interestingly, these non-V600 BRAF mutants seem to form part of a broader sub-group of melanoma cell lines, including some that are BRAF wild-type and BRAF V600K mutated, that are reliant upon CRAF for their survival .	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('non-V600', 'Var', (21, 29))	('V600K', 'Var', (156, 161))	('BRAF', 'Gene', (151, 155))	('V600K', 'Mutation', 'rs121913227', (156, 161))	('CRAF', 'molecular_function', 'GO:0004709', ('193', '197'))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
59341	22484192	Studies from two independent groups have now demonstrated that shRNA knockdown of CRAF in the CRAF-dependent melanoma groups leads to MEK-independent effects upon BAD phosphorylation and Bcl-2 expression, leading in turn to apoptosis and impaired tumor growth in a mouse xenograft model .	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('impaired tumor', 'Disease', (238, 252))	('Bcl-2', 'molecular_function', 'GO:0015283', ('187', '192'))	('impaired tumor', 'Disease', 'MESH:D015417', (238, 252))	('apoptosis', 'biological_process', 'GO:0097194', ('224', '233'))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('apoptosis', 'biological_process', 'GO:0006915', ('224', '233'))	('CRAF', 'Gene', (82, 86))	('MEK-independent effects', 'MPA', (134, 157))	('CRAF', 'molecular_function', 'GO:0004709', ('82', '86'))	('apoptosis', 'CPA', (224, 233))	('CRAF', 'molecular_function', 'GO:0004709', ('94', '98'))	('BAD phosphorylation', 'MPA', (163, 182))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('mouse', 'Species', '10090', (265, 270))	('Bcl-2 expression', 'MPA', (187, 203))	('phosphorylation', 'biological_process', 'GO:0016310', ('167', '182'))	('knockdown', 'Var', (69, 78))
59343	22484192	There is pre-clinical evidence demonstrating that sorafenib has good pro-apoptotic activity against melanoma cell lines with low-activity BRAF mutations, and leads to regression of these cell lines grown as mouse xenografts .	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('pre', 'molecular_function', 'GO:0003904', ('9', '12'))	('sorafenib', 'Chemical', 'MESH:D000077157', (50, 59))	('low-activity', 'NegReg', (125, 137))	('pro-apoptotic activity', 'MPA', (69, 91))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('mouse', 'Species', '10090', (207, 212))	('BRAF', 'Gene', (138, 142))	('regression', 'CPA', (167, 177))	('mutations', 'Var', (143, 152))
59347	22484192	Mutations in NRAS, KRAS and HRAS have been identified in 20%, 2% and 1% of all melanomas, respectively .	('melanomas', 'Disease', 'MESH:D008545', (79, 88))	('HRAS', 'Disease', 'None', (28, 32))	('HRAS', 'Disease', (28, 32))	('KRAS', 'Gene', (19, 23))	('melanomas', 'Disease', (79, 88))	('KRAS', 'Gene', '3845', (19, 23))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', (13, 17))	('identified', 'Reg', (43, 53))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))
59348	22484192	Mutations in NRAS are most commonly the result of a point-change leading to the substitution of leucine to glutamine at position 61 , with mutations at positions 12 and 13 being reported less frequently .	('point-change', 'Var', (52, 64))	('result', 'Reg', (40, 46))	('substitution', 'Var', (80, 92))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', (13, 17))	('leucine to glutamine at position 61', 'Mutation', 'rs11554290', (96, 131))
59349	22484192	Large-scale analysis of melanoma samples and cell lines have shown that although BRAF V600E and NRAS mutations are mutually exclusive, there is overlap between low activity BRAF mutations and NRAS mutations .	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('V600E', 'Var', (86, 91))	('BRAF', 'Gene', (81, 85))	('NRAS', 'Gene', (96, 100))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))	('V600E', 'Mutation', 'rs113488022', (86, 91))
59350	22484192	Mechanistically, mutations in NRAS lead to impairment of GTPase activity, so that the GTPase is locked into its "On" position.	('GTP', 'Chemical', 'MESH:D006160', (57, 60))	('GTP', 'Chemical', 'MESH:D006160', (86, 89))	('GTPase', 'Protein', (57, 63))	('GTPase activity', 'molecular_function', 'GO:0003924', ('57', '72'))	('activity', 'MPA', (64, 72))	('impairment', 'NegReg', (43, 53))	('NRAS', 'Gene', (30, 34))	('mutations', 'Var', (17, 26))
59352	22484192	Thus, melanomas harboring activating NRAS mutations differ from melanomas with BRAF mutations in that they rely upon CRAF to induce their MAPK pathway activity .	('activating', 'PosReg', (26, 36))	('MAPK pathway', 'Pathway', (138, 150))	('melanomas', 'Disease', (64, 73))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('NRAS', 'Gene', (37, 41))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('MAPK', 'molecular_function', 'GO:0004707', ('138', '142'))	('melanomas', 'Disease', (6, 15))	('induce', 'PosReg', (125, 131))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('CRAF', 'molecular_function', 'GO:0004709', ('117', '121'))	('melanomas', 'Disease', 'MESH:D008545', (64, 73))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('activity', 'MPA', (151, 159))	('mutations', 'Var', (42, 51))
59353	22484192	RAS is also known to activate the phospho inositide-3-kinase (PI3K)/AKT pathway, which contributes to tumor progression via the modulation of growth and survival of transformed cells .	('PI3K', 'molecular_function', 'GO:0016303', ('62', '66'))	('phospho inositide-3-kinase', 'Gene', '5293', (34, 60))	('tumor', 'Disease', (102, 107))	('activate', 'PosReg', (21, 29))	('growth', 'CPA', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('AKT', 'Gene', '207', (68, 71))	('contributes', 'Reg', (87, 98))	('RAS', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('phospho inositide-3-kinase', 'Gene', (34, 60))	('AKT', 'Gene', (68, 71))
59354	22484192	In addition to MAPK and PI3K/AKT, mutated NRAS can also activate other intracellular signaling pathways important for malignant transformation.	('intracellular signaling pathways', 'Pathway', (71, 103))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('intracellular', 'cellular_component', 'GO:0005622', ('71', '84'))	('AKT', 'Gene', '207', (29, 32))	('MAPK', 'molecular_function', 'GO:0004707', ('15', '19'))	('activate', 'PosReg', (56, 64))	('PI3K', 'molecular_function', 'GO:0016303', ('24', '28'))	('AKT', 'Gene', (29, 32))	('NRAS', 'Gene', (42, 46))	('mutated', 'Var', (34, 41))
59356	22484192	A role for RAS mutations in melanoma initiation has been confirmed in animal models, where the introduction of mutated HRAS or NRAS (Q61K) leads to melanoma in transgenic mice lacking expression of the CDK inhibitor p16INK4A .	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma initiation', 'Disease', (28, 47))	('mutated', 'Var', (111, 118))	('transgenic mice', 'Species', '10090', (160, 175))	('p16INK4A', 'Gene', (216, 224))	('HRAS', 'Disease', 'None', (119, 123))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('mutations', 'Var', (15, 24))	('NRAS', 'Gene', (127, 131))	('melanoma initiation', 'Disease', 'MESH:D008545', (28, 47))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('lacking', 'NegReg', (176, 183))	('HRAS', 'Disease', (119, 123))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('melanoma', 'Disease', (28, 36))	('Q61K', 'Mutation', 'rs121913254', (133, 137))	('p16INK4A', 'Gene', '12578', (216, 224))	('CDK inhibitor', 'molecular_function', 'GO:0004861', ('202', '215'))	('leads to', 'Reg', (139, 147))
59363	22484192	Although NRAS mutated melanomas are known to rely upon CRAF for their MAPK signaling, there is little evidence that sorafenib is any more effective on the NRAS mutants than melanoma cell lines with BRAF mutations .	('melanomas', 'Disease', (22, 31))	('MAPK signaling', 'biological_process', 'GO:0000165', ('70', '84'))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('MAPK', 'molecular_function', 'GO:0004707', ('70', '74'))	('melanoma', 'Disease', (173, 181))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanomas', 'Disease', 'MESH:D008545', (22, 31))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('melanoma', 'Disease', (22, 30))	('mutants', 'Var', (160, 167))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('sorafenib', 'Chemical', 'MESH:D000077157', (116, 125))	('CRAF', 'molecular_function', 'GO:0004709', ('55', '59'))	('NRAS', 'Gene', (155, 159))
59364	22484192	Melanomas developing on body sites with low-levels of environmental ultraviolet radiation exposure, such as on the soles of the feet or subungual sites (acral melanomas) or the mucous membranes (mucosal melanomas) are known to have a low incidence of BRAF mutations .	('melanomas', 'Phenotype', 'HP:0002861', (203, 212))	('mucous', 'cellular_component', 'GO:0070701', ('177', '183'))	('melanomas', 'Phenotype', 'HP:0002861', (159, 168))	('acral melanoma', 'Phenotype', 'HP:0012060', (153, 167))	('acral melanomas', 'Disease', (153, 168))	('acral melanomas', 'Phenotype', 'HP:0012060', (153, 168))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('mucosal melanomas', 'Disease', (195, 212))	('Melanomas', 'Disease', (0, 9))	('BRAF', 'Gene', (251, 255))	('mutations', 'Var', (256, 265))	('mucosal melanomas', 'Disease', 'MESH:D008545', (195, 212))	('acral melanomas', 'Disease', 'MESH:D008545', (153, 168))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
59365	22484192	Instead, these more rare histological sub-types of melanoma are often associated with genetic amplification of and/or activating mutations in the receptor tyrosine kinase KIT.	('genetic amplification', 'Var', (86, 107))	('associated', 'Reg', (70, 80))	('KIT', 'molecular_function', 'GO:0005020', ('171', '174'))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('activating', 'PosReg', (118, 128))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
59366	22484192	A recent landmark study showed that 21% of mucosal melanomas, 11% of acral melanomas and 17% of melanomas arising on sun-damaged skin harbor activating mutations in KIT, with many of these occurring at the imatinib-sensitive juxatmembrane position .	('imatinib', 'Chemical', 'MESH:D000068877', (206, 214))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('melanomas', 'Disease', 'MESH:D008545', (75, 84))	('sun-damaged', 'Phenotype', 'HP:0000992', (117, 128))	('acral melanoma', 'Phenotype', 'HP:0012060', (69, 83))	('KIT', 'molecular_function', 'GO:0005020', ('165', '168'))	('melanomas', 'Disease', (75, 84))	('melanomas', 'Disease', 'MESH:D008545', (51, 60))	('activating mutations', 'Var', (141, 161))	('mucosal melanomas', 'Disease', 'MESH:D008545', (43, 60))	('melanomas', 'Disease', (51, 60))	('mucosal melanomas', 'Disease', (43, 60))	('melanomas', 'Disease', 'MESH:D008545', (96, 105))	('melanomas', 'Disease', (96, 105))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('juxatmembrane', 'Chemical', '-', (225, 238))	('acral melanomas', 'Disease', 'MESH:D008545', (69, 84))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('acral melanomas', 'Phenotype', 'HP:0012060', (69, 84))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('KIT', 'Gene', (165, 168))	('acral melanomas', 'Disease', (69, 84))
59367	22484192	Sequencing of c-KIT exons 11, 13, 17 and 18 revealed the most prevalent mutations to be K642E, L576P, D816H and V559A, that interestingly are enriched at different locations from KIT mutations in GIST or hematological malignancies .	('D816H', 'Var', (102, 107))	('V559A', 'Var', (112, 117))	('K642E', 'Mutation', 'rs121913512', (88, 93))	('L576P', 'Mutation', 'rs121913513', (95, 100))	('KIT', 'molecular_function', 'GO:0005020', ('179', '182'))	('L576P', 'Var', (95, 100))	('c-KIT', 'Gene', (14, 19))	('D816H', 'Mutation', 'rs121913506', (102, 107))	('hematological malignancies', 'Phenotype', 'HP:0004377', (204, 230))	('GIST', 'Phenotype', 'HP:0100723', (196, 200))	('V559A', 'Mutation', 'rs121913517', (112, 117))	('KIT', 'molecular_function', 'GO:0005020', ('16', '19'))	('c-KIT', 'Gene', '3815', (14, 19))	('hematological malignancies', 'Disease', (204, 230))	('hematological malignancies', 'Disease', 'MESH:D019337', (204, 230))	('K642E', 'Var', (88, 93))
59368	22484192	Since the initial report of KIT aberrations in melanoma, a number of further studies have validated this finding .	('KIT', 'Gene', (28, 31))	('KIT', 'molecular_function', 'GO:0005020', ('28', '31'))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('aberrations', 'Var', (32, 43))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))
59370	22484192	Given that acral and mucosal melanomas each represent only 2% of all melanomas, the total percentage of melanomas with KIT mutations is likely to be quite low.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('acral and', 'Disease', (11, 20))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanomas', 'Phenotype', 'HP:0002861', (104, 113))	('melanomas', 'Disease', 'MESH:D008545', (104, 113))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanomas', 'Phenotype', 'HP:0002861', (29, 38))	('KIT', 'molecular_function', 'GO:0005020', ('119', '122'))	('mucosal melanomas', 'Disease', (21, 38))	('melanomas', 'Disease', 'MESH:D008545', (29, 38))	('melanomas', 'Phenotype', 'HP:0002861', (69, 78))	('melanomas', 'Disease', (69, 78))	('melanomas', 'Disease', 'MESH:D008545', (69, 78))	('melanomas', 'Disease', (104, 113))	('mucosal melanomas', 'Disease', 'MESH:D008545', (21, 38))	('melanomas', 'Disease', (29, 38))	('mutations', 'Var', (123, 132))
59371	22484192	Moreover in an Australian population where over 40% of melanomas are associated with chronic sun damaged skin KIT mutations were observed at a similar low frequency of 2% .	('melanomas', 'Phenotype', 'HP:0002861', (55, 64))	('mutations', 'Var', (114, 123))	('melanomas', 'Disease', 'MESH:D008545', (55, 64))	('associated', 'Reg', (69, 79))	('sun damaged skin', 'Phenotype', 'HP:0000992', (93, 109))	('melanomas', 'Disease', (55, 64))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('KIT', 'molecular_function', 'GO:0005020', ('110', '113'))
59372	22484192	In experimental studies, introduction of the D814Y mutant of KIT into non-tumorigenic immortalized melanocytes did not lead to either oncogenic transformation or enhanced proliferation .	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('oncogenic transformation', 'CPA', (134, 158))	('D814Y', 'Mutation', 'p.D814Y', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('KIT', 'molecular_function', 'GO:0005020', ('61', '64'))	('enhanced', 'PosReg', (162, 170))	('KIT', 'Gene', (61, 64))	('tumor', 'Disease', (74, 79))	('proliferation', 'CPA', (171, 184))	('D814Y', 'Var', (45, 50))
59373	22484192	In agreement with this idea, it was recently shown that the two most common c-KIT mutations found in melanoma (K642E and L576P) were only able to transform melanocytes when grown under hypoxia or following the introduction of exogenous hypoxia-inducible factor 1alpha(HIF-1alpha) .	('hypoxia', 'Disease', (236, 243))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('L576P', 'Mutation', 'rs121913513', (121, 126))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('c-KIT', 'Gene', (76, 81))	('hypoxia', 'Disease', (185, 192))	('hypoxia', 'Disease', 'MESH:D000860', (185, 192))	('L576P', 'Var', (121, 126))	('transform', 'Reg', (146, 155))	('hypoxia-inducible factor 1alpha(HIF-1alpha', 'Gene', '3091', (236, 278))	('K642E', 'Var', (111, 116))	('c-KIT', 'Gene', '3815', (76, 81))	('K642E', 'Mutation', 'rs121913512', (111, 116))	('KIT', 'molecular_function', 'GO:0005020', ('78', '81'))	('hypoxia', 'Disease', 'MESH:D000860', (236, 243))
59374	22484192	Mechanistically, it seemed that introduction of mutated c-KIT activated PI3K/AKT signaling but not MEK/ERK and that the combination of hypoxia and mutated c-KIT was required to fully activate both pathways.	('hypoxia', 'Disease', (135, 142))	('mutated', 'Var', (48, 55))	('ERK', 'Gene', (103, 106))	('hypoxia', 'Disease', 'MESH:D000860', (135, 142))	('AKT', 'Gene', '207', (77, 80))	('AKT signaling', 'biological_process', 'GO:0043491', ('77', '90'))	('c-KIT', 'Gene', (155, 160))	('ERK', 'molecular_function', 'GO:0004707', ('103', '106'))	('c-KIT', 'Gene', (56, 61))	('KIT', 'molecular_function', 'GO:0005020', ('157', '160'))	('PI3K', 'molecular_function', 'GO:0016303', ('72', '76'))	('c-KIT', 'Gene', '3815', (56, 61))	('KIT', 'molecular_function', 'GO:0005020', ('58', '61'))	('c-KIT', 'Gene', '3815', (155, 160))	('AKT', 'Gene', (77, 80))	('activated', 'PosReg', (62, 71))	('ERK', 'Gene', '5594', (103, 106))
59376	22484192	The relative scarcity of melanoma cell lines harboring activating KIT mutations has made pre-clinical studies a challenge.	('KIT', 'Gene', (66, 69))	('mutations', 'Var', (70, 79))	('KIT', 'molecular_function', 'GO:0005020', ('66', '69'))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))	('pre', 'molecular_function', 'GO:0003904', ('89', '92'))
59378	22484192	The first of these characterized 3 primary mucosal melanoma cell lines, of which one was noted to have an exon-11 V559D mutation in c-KIT .	('V559D', 'Mutation', 'rs121913517', (114, 119))	('mucosal melanoma', 'Disease', 'MESH:D008545', (43, 59))	('c-KIT', 'Gene', (132, 137))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('V559D', 'Var', (114, 119))	('c-KIT', 'Gene', '3815', (132, 137))	('KIT', 'molecular_function', 'GO:0005020', ('134', '137'))	('mucosal melanoma', 'Disease', (43, 59))
59380	22484192	A second study reported the identification of a mucosal melanoma cell line with a D820Y exon-17 mutation in c-KIT (the mutation often associated with imatinib resistance in GIST) with sensitivity to sunitinib (only at high concentrations) .	('associated with', 'Reg', (134, 149))	('sunitinib', 'Chemical', 'MESH:D000077210', (199, 208))	('D820Y exon-17', 'Var', (82, 95))	('GIST', 'Phenotype', 'HP:0100723', (173, 177))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mucosal melanoma', 'Disease', (48, 64))	('imatinib resistance', 'MPA', (150, 169))	('c-KIT', 'Gene', (108, 113))	('sensitivity', 'MPA', (184, 195))	('mucosal melanoma', 'Disease', 'MESH:D008545', (48, 64))	('c-KIT', 'Gene', '3815', (108, 113))	('imatinib', 'Chemical', 'MESH:D000068877', (150, 158))	('KIT', 'molecular_function', 'GO:0005020', ('110', '113'))	('D820Y', 'Mutation', 'rs1057519710', (82, 87))
59381	22484192	One other recent publication reported the identification of a non-acral/non-mucosal melanoma cell lines harboring an L576P KIT mutation .	('L576P', 'Mutation', 'rs121913513', (117, 122))	('KIT', 'molecular_function', 'GO:0005020', ('123', '126'))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('mucosal melanoma', 'Disease', (76, 92))	('L576P', 'Var', (117, 122))	('KIT', 'Gene', (123, 126))	('mucosal melanoma', 'Disease', 'MESH:D008545', (76, 92))
59386	22484192	Although unlike acral and mucosal melanomas, uveal melanomas typically lack activating c-KIT mutations .	('uveal melanomas', 'Disease', 'MESH:C536494', (45, 60))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('mutations', 'Var', (93, 102))	('mucosal melanomas', 'Disease', (26, 43))	('c-KIT', 'Gene', (87, 92))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('activating', 'MPA', (76, 86))	('uveal melanomas', 'Disease', (45, 60))	('uveal melanomas', 'Phenotype', 'HP:0007716', (45, 60))	('mucosal melanomas', 'Disease', 'MESH:D008545', (26, 43))	('c-KIT', 'Gene', '3815', (87, 92))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('lack', 'NegReg', (71, 75))	('KIT', 'molecular_function', 'GO:0005020', ('89', '92'))
59387	22484192	Cell culture experiments have demonstrated that uveal melanoma cell lines harbor phospho-KIT expression and undergo imatinib-mediated cell cycle arrest .	('uveal melanoma', 'Disease', (48, 62))	('phospho-KIT', 'Var', (81, 92))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('imatinib-mediated cell cycle arrest', 'CPA', (116, 151))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (134, 151))	('imatinib', 'Chemical', 'MESH:D000068877', (116, 124))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('134', '151'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (48, 62))	('KIT', 'molecular_function', 'GO:0005020', ('89', '92'))
59390	22484192	In uveal melanomas, most of which lack BRAF and RAS mutations, there is emerging evidence that MAPK activity is driven through activating Q209 mutations in the heterotrimeric G-protein alpha subunit GNAQ  or the equivalent residue in the closely related G-protein alpha subunit GNA11.	('GNAQ', 'Gene', '2776', (199, 203))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanomas', 'Phenotype', 'HP:0002861', (9, 18))	('activating', 'PosReg', (127, 137))	('uveal melanomas', 'Disease', (3, 18))	('uveal melanomas', 'Phenotype', 'HP:0007716', (3, 18))	('MAPK', 'molecular_function', 'GO:0004707', ('95', '99'))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('heterotrimeric G-protein', 'molecular_function', 'GO:0005065', ('160', '184'))	('uveal melanomas', 'Disease', 'MESH:C536494', (3, 18))	('GNA11', 'Gene', '2767', (278, 283))	('protein', 'cellular_component', 'GO:0003675', ('256', '263'))	('GNAQ', 'Gene', (199, 203))	('GNA11', 'Gene', (278, 283))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('Q209 mutations', 'Var', (138, 152))	('activity', 'MPA', (100, 108))
59391	22484192	Mutations at Q209 of GNAQ are analogous to those seen in NRAS (at Q61), and result in impaired GTPase activity leading to constitutive signaling.	('constitutive signaling', 'MPA', (122, 144))	('GNAQ', 'Gene', '2776', (21, 25))	('GTPase activity', 'molecular_function', 'GO:0003924', ('95', '110'))	('impaired', 'NegReg', (86, 94))	('signaling', 'biological_process', 'GO:0023052', ('135', '144'))	('GTPase', 'Protein', (95, 101))	('GNAQ', 'Gene', (21, 25))	('Mutations at Q209', 'Var', (0, 17))	('activity', 'MPA', (102, 110))	('GTP', 'Chemical', 'MESH:D006160', (95, 98))
59392	22484192	Large scale molecular profiling has identified GNAQ Q209 mutations in 46-49% of uveal melanoma samples and 27% of uveal melanoma cell lines .	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('uveal melanoma', 'Disease', 'MESH:C536494', (80, 94))	('uveal melanoma', 'Disease', (80, 94))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('GNAQ', 'Gene', (47, 51))	('uveal melanoma', 'Disease', (114, 128))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('mutations', 'Var', (57, 66))	('GNAQ', 'Gene', '2776', (47, 51))
59394	22484192	Although no small molecule inhibitors of GNAQ currently exist, the potential therapeutic relevance of this G-protein was demonstrated by that fact that siRNA knockdown of GNAQ led to increased cell death in uveal melanoma cell lines that harbored the mutation .	('cell death', 'CPA', (193, 203))	('GNAQ', 'Gene', '2776', (171, 175))	('GNAQ', 'Gene', '2776', (41, 45))	('cell death', 'biological_process', 'GO:0008219', ('193', '203'))	('increased', 'PosReg', (183, 192))	('uveal melanoma', 'Disease', 'MESH:C536494', (207, 221))	('mutation', 'Var', (251, 259))	('uveal melanoma', 'Phenotype', 'HP:0007716', (207, 221))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('GNAQ', 'Gene', (171, 175))	('GNAQ', 'Gene', (41, 45))	('uveal melanoma', 'Disease', (207, 221))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))
59398	22484192	The findings of frequent mutations in BRAF and NRAS in melanoma led to the evaluation of MEK inhibitors in melanoma including AZD6244, CI-1040 and PD0325901.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('mutations', 'Var', (25, 34))	('melanoma', 'Disease', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('NRAS', 'Gene', (47, 51))	('CI-1040', 'Chemical', 'MESH:C120227', (135, 142))	('BRAF', 'Gene', (38, 42))	('PD0325901', 'Chemical', 'MESH:C506614', (147, 156))	('AZD6244', 'Chemical', 'MESH:C517975', (126, 133))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
59402	22484192	Recently the MEK inhibitor GSK1120212 with more reliable and sustained inhibition of MEK and pERK at clinically achievable doses has been evaluated in melanoma patients harboring BRAF V600E mutations with preliminary data indicating response rates in excess of 20% .	('V600E', 'Mutation', 'rs113488022', (184, 189))	('patients', 'Species', '9606', (160, 168))	('V600E', 'Var', (184, 189))	('inhibition', 'NegReg', (71, 81))	('GSK1120212', 'Var', (27, 37))	('MEK', 'Pathway', (85, 88))	('pERK', 'Gene', (93, 97))	('BRAF', 'Gene', (179, 183))	('melanoma', 'Disease', (151, 159))	('pERK', 'Gene', '9451', (93, 97))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('GSK', 'molecular_function', 'GO:0050321', ('27', '30'))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('GSK1120212', 'Chemical', 'MESH:C560077', (27, 37))
59406	22484192	Due to its poor selectivity for the active conformation of BRAF induced by the V600E mutation, coupled with significant "off-target" activity, results were disappointing with very low response rates .	('V600E', 'Var', (79, 84))	('V600E', 'Mutation', 'rs113488022', (79, 84))	('BRAF', 'Disease', (59, 63))
59409	22484192	In a recent phase III trial of individuals with previously untreated BRAF V600E mutant melanoma (n=675) vemurafenib treatment (960mg BID twice daily) led to responses in 48% of patients .	('melanoma', 'Disease', (87, 95))	('V600E', 'Mutation', 'rs113488022', (74, 79))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('BID', 'Gene', '637', (133, 136))	('patients', 'Species', '9606', (177, 185))	('vemurafenib', 'Chemical', 'MESH:D000077484', (104, 115))	('BRAF V600E', 'Var', (69, 79))	('responses', 'MPA', (157, 166))	('BID', 'Gene', (133, 136))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
59412	22484192	Similar impressive effects on signaling and response have been observed with another selective BRAF inhibitor GSK2118436  that has also entered phase III clinical trials.	('GSK2118436', 'Chemical', 'MESH:C561627', (110, 120))	('signaling', 'MPA', (30, 39))	('signaling', 'biological_process', 'GO:0023052', ('30', '39'))	('GSK2118436', 'Var', (110, 120))	('GSK', 'molecular_function', 'GO:0050321', ('110', '113'))
59413	22484192	Interestingly all BRAF inhibitors including sorafenib, vemurafenib, GSK2118436 and XL281 that have been evaluated clinically have induced proliferative squamous lesions in the skin that closely resemble squamous cell carcinomas of the keratoacanthoma type .	('squamous cell carcinomas of the keratoacanthoma type', 'Disease', 'MESH:D002294', (203, 255))	('GSK', 'molecular_function', 'GO:0050321', ('68', '71'))	('induced', 'Reg', (130, 137))	('sorafenib', 'Chemical', 'MESH:D000077157', (44, 53))	('vemurafenib', 'Chemical', 'MESH:D000077484', (55, 66))	('XL281', 'Var', (83, 88))	('keratoacanthoma', 'Phenotype', 'HP:0031525', (235, 250))	('squamous lesions', 'Disease', 'MESH:D002294', (152, 168))	('GSK2118436', 'Chemical', 'MESH:C561627', (68, 78))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (203, 227))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (203, 226))	('BRAF', 'Gene', (18, 22))	('squamous lesions', 'Disease', (152, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('GSK2118436', 'Var', (68, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (217, 227))
59414	22484192	Although the mechanism by which inhibition of RAF kinases induces these lesions remains to be fully elucidated there is now clinical evidence that the paradoxical activation of MAPK signaling, arising as a result of BRAF inhibition, may play a role in SCC development (see below) .	('activation', 'PosReg', (163, 173))	('inhibition', 'Var', (32, 42))	('MAPK', 'molecular_function', 'GO:0004707', ('177', '181'))	('inhibition', 'NegReg', (221, 231))	('RAF', 'Gene', '22882', (217, 220))	('RAF', 'Gene', (217, 220))	('RAF', 'Gene', (46, 49))	('MAPK signaling', 'Pathway', (177, 191))	('RAF', 'Gene', '22882', (46, 49))	('MAPK signaling', 'biological_process', 'GO:0000165', ('177', '191'))	('SCC', 'Disease', (252, 255))
59415	22484192	Inhibition of KIT by tyrosine kinase inhibitors has been reported to induce clinical responses in melanomas harboring KIT mutations.	('melanomas', 'Disease', (98, 107))	('KIT', 'Gene', (14, 17))	('KIT', 'molecular_function', 'GO:0005020', ('118', '121'))	('Inhibition', 'NegReg', (0, 10))	('KIT', 'Gene', (118, 121))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('melanomas', 'Disease', 'MESH:D008545', (98, 107))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('mutations', 'Var', (122, 131))	('KIT', 'molecular_function', 'GO:0005020', ('14', '17'))
59419	22484192	Indeed clinical response has been reported to sorafenib in a case of metastatic anal melanoma with the imatinib resistant mutation D820Y.	('imatinib', 'Chemical', 'MESH:D000068877', (103, 111))	('D820Y', 'Var', (131, 136))	('sorafenib', 'Chemical', 'MESH:D000077157', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('D820Y', 'Mutation', 'rs1057519710', (131, 136))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('anal melanoma', 'Phenotype', 'HP:0030444', (80, 93))
59420	22484192	Although the presence of an activating BRAF V600E mutation generally predicts for sensitivity to BRAF inhibition, not all patients with BRAF V600E mutant melanoma respond to vemurafenib and there is evidence that some patients may be intrinsically resistant .	('vemurafenib', 'Chemical', 'MESH:D000077484', (174, 185))	('sensitivity', 'MPA', (82, 93))	('patients', 'Species', '9606', (218, 226))	('activating', 'PosReg', (28, 38))	('BRAF', 'Gene', (39, 43))	('V600E', 'Mutation', 'rs113488022', (44, 49))	('BRAF', 'Gene', (136, 140))	('patients', 'Species', '9606', (122, 130))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('V600E', 'Mutation', 'rs113488022', (141, 146))	('predicts', 'Reg', (69, 77))	('V600E', 'Var', (44, 49))
59421	22484192	Recent preclinical studies have demonstrated that amplification of cyclin D1 (in up to 17% of BRAF V600E mutant melanomas) or loss of the tumor suppressor RB together with loss of the tumor suppressor phosphatase and tensin homolog (PTEN) may both contribute to intrinsic BRAF inhibitor resistance .	('cyclin D1', 'Gene', '595', (67, 76))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('mutant', 'Var', (105, 111))	('amplification', 'Var', (50, 63))	('loss of the tumor', 'Disease', 'MESH:D009369', (126, 143))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('138', '154'))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('melanomas', 'Disease', 'MESH:D008545', (112, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('184', '200'))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('melanomas', 'Disease', (112, 121))	('BRAF', 'Gene', (94, 98))	('tumor suppressor', 'biological_process', 'GO:0051726', ('138', '154'))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('201', '231'))	('loss of the tumor', 'Disease', (126, 143))	('phosphatase', 'molecular_function', 'GO:0016791', ('201', '212'))	('loss of the tumor', 'Disease', 'MESH:D009369', (172, 189))	('cyclin', 'molecular_function', 'GO:0016538', ('67', '73'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('184', '200'))	('contribute', 'Reg', (248, 258))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('cyclin D1', 'Gene', (67, 76))	('loss of the tumor', 'Disease', (172, 189))	('V600E mutant', 'Var', (99, 111))
59422	22484192	In the case of PTEN loss, BRAF inhibition was found to paradoxically activate AKT which prevented cell death by suppressing the levels of the pro-apoptotic protein BIM .	('cell death', 'CPA', (98, 108))	('PTEN loss', 'Disease', 'MESH:D006223', (15, 24))	('activate', 'PosReg', (69, 77))	('suppressing', 'NegReg', (112, 123))	('AKT', 'Gene', '207', (78, 81))	('BIM', 'Gene', '10018', (164, 167))	('PTEN loss', 'Disease', (15, 24))	('inhibition', 'Var', (31, 41))	('cell death', 'biological_process', 'GO:0008219', ('98', '108'))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('AKT', 'Gene', (78, 81))	('BIM', 'Gene', (164, 167))
59423	22484192	Almost all BRAF mutant melanoma patients who respond to vemurafenib ultimately fail therapy and become resistant.	('therapy', 'MPA', (84, 91))	('patients', 'Species', '9606', (32, 40))	('fail', 'NegReg', (79, 83))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('vemurafenib', 'Chemical', 'MESH:D000077484', (56, 67))	('mutant', 'Var', (16, 22))	('BRAF', 'Gene', (11, 15))
59425	22484192	Even before the development of BRAF specific inhibitors it was already known that both growth factors and cytokines could rescue melanoma cells from apoptosis following the siRNA-induced knockdown of BRAF.	('apoptosis', 'CPA', (149, 158))	('BRAF', 'Gene', (200, 204))	('knockdown', 'Var', (187, 196))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('apoptosis', 'biological_process', 'GO:0097194', ('149', '158'))	('rescue', 'PosReg', (122, 128))	('apoptosis', 'biological_process', 'GO:0006915', ('149', '158'))
59426	22484192	A number of studies have now begun to address the mechanisms of acquired BRAF inhibitor resistance in both melanoma cell lines and specimens from BRAF mutant melanoma patients failing vemurafenib therapy.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('BRAF', 'Gene', (146, 150))	('melanoma', 'Disease', (107, 115))	('mutant', 'Var', (151, 157))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('patients', 'Species', '9606', (167, 175))	('vemurafenib', 'Chemical', 'MESH:D000077484', (184, 195))	('BRAF', 'Gene', (73, 77))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (158, 166))
59427	22484192	So far a large number of potential acquired resistance mechanisms have been reported; these include upregulated receptor tyrosine kinase signaling (both PDGFRbeta and IGF1R), the emergence of apparently de novo mutations in NRAS, acquisition of novel mutations in MEK1 and the increased expression of MAP3K8 (otherwise known as COT) .	('IGF1R', 'Gene', '3480', (167, 172))	('upregulated', 'PosReg', (100, 111))	('NRAS', 'Gene', (224, 228))	('MEK1', 'molecular_function', 'GO:0004708', ('264', '268'))	('IGF1R', 'Gene', (167, 172))	('PDGFRbeta', 'Gene', (153, 162))	('signaling', 'biological_process', 'GO:0023052', ('137', '146'))	('MEK1', 'Gene', '5604', (264, 268))	('MAP3K', 'molecular_function', 'GO:0004709', ('301', '306'))	('MAP3K8', 'Gene', (301, 307))	('PDGFRbeta', 'Gene', '5159', (153, 162))	('receptor tyrosine kinase signaling', 'MPA', (112, 146))	('COT', 'Gene', (328, 331))	('COT', 'Gene', '1326', (328, 331))	('mutations', 'Var', (251, 260))	('MAP3K8', 'Gene', '1326', (301, 307))	('mutations', 'Var', (211, 220))	('increased', 'PosReg', (277, 286))	('MEK1', 'Gene', (264, 268))
59429	22484192	There is already preclinical data showing that dual BRAF + MEK inhibition may prevent or delay the onset of resistance to PLX4720 and may overcome resistance mediated by MEK1 mutations, COT overexpression and the acquisition of de novo NRAS mutations .	('resistance', 'MPA', (108, 118))	('MEK1', 'Gene', (170, 174))	('overcome', 'PosReg', (138, 146))	('MEK1', 'molecular_function', 'GO:0004708', ('170', '174'))	('delay', 'NegReg', (89, 94))	('PLX4720', 'Chemical', 'MESH:C528407', (122, 129))	('NRAS', 'Gene', (236, 240))	('onset', 'MPA', (99, 104))	('COT', 'Gene', (186, 189))	('mutations', 'Var', (175, 184))	('COT', 'Gene', '1326', (186, 189))	('resistance', 'MPA', (147, 157))	('overexpression', 'PosReg', (190, 204))	('MEK1', 'Gene', '5604', (170, 174))	('mutations', 'Var', (241, 250))
59432	22484192	In a recent presentation at ASCO, the phase I/II trial of the GSK112012 + GSK2118436 combination was associated with objective response rates (complete response + partial response) of 77% at a dose level of 150mg GSK118436/1mg GSK112012 and 74% at the dose level of 150mg GSK118436/2mg GSK1120212 .	('GSK', 'molecular_function', 'GO:0050321', ('272', '275'))	('GSK118436', 'Chemical', '-', (213, 222))	('GSK', 'molecular_function', 'GO:0050321', ('62', '65'))	('GSK112012', 'Chemical', '-', (62, 71))	('GSK2118436', 'Chemical', 'MESH:C561627', (74, 84))	('GSK112012', 'Chemical', '-', (227, 236))	('GSK118436', 'Chemical', '-', (272, 281))	('GSK', 'molecular_function', 'GO:0050321', ('213', '216'))	('GSK', 'molecular_function', 'GO:0050321', ('286', '289'))	('GSK112012 + GSK2118436', 'Var', (62, 84))	('GSK', 'molecular_function', 'GO:0050321', ('74', '77'))	('GSK2118436', 'Var', (74, 84))	('GSK118436/1mg', 'Var', (213, 226))	('GSK1120212', 'Chemical', 'MESH:C560077', (286, 296))	('GSK', 'molecular_function', 'GO:0050321', ('227', '230'))
59433	22484192	Even more significantly, the combination of the BRAF + MEK inhibitor was associated with significantly reduced levels of squamous cell carcinoma (<1%, n=109) .	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('squamous cell carcinoma', 'Disease', (121, 144))	('reduced', 'NegReg', (103, 110))	('BRAF + MEK inhibitor', 'Gene', (48, 68))	('combination', 'Var', (29, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))
59436	22484192	The most well known examples of this phenomenon are imatinib resistance in CML and GIST that arises as the result of de novo "gatekeeper" mutations in BCR-ABL and c-KIT, respectively .	('imatinib', 'Chemical', 'MESH:D000068877', (52, 60))	('BCR-ABL', 'Gene', '25', (151, 158))	('CML', 'Disease', (75, 78))	('KIT', 'molecular_function', 'GO:0005020', ('163', '166'))	('c-KIT', 'Gene', (163, 168))	('BCR-ABL', 'Gene', (151, 158))	('gatekeeper', 'Species', '111938', (126, 136))	('GIST', 'Phenotype', 'HP:0100723', (83, 87))	('imatinib resistance', 'MPA', (52, 71))	('CML', 'Disease', 'MESH:D015464', (75, 78))	('c-KIT', 'Gene', '3815', (163, 168))	('CML', 'Phenotype', 'HP:0005506', (75, 78))	('mutations', 'Var', (138, 147))
59437	22484192	Although preclinical studies identified Threonine-529 to be the BRAF gatekeeper site, there is currently little evidence that chronic treatment of melanoma patients with vemurafenib leads to acquisition of secondary mutations in BRAF at the gatekeeper site or at any others .	('patients', 'Species', '9606', (156, 164))	('BRAF', 'Gene', (229, 233))	('Threonine', 'Chemical', 'MESH:D013912', (40, 49))	('vemurafenib', 'Chemical', 'MESH:D000077484', (170, 181))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('mutations', 'Var', (216, 225))	('gatekeeper', 'Species', '111938', (241, 251))	('gatekeeper', 'Species', '111938', (69, 79))	('acquisition', 'Reg', (191, 202))
59439	22484192	The importance of matching the right targeted therapy to the correct melanoma genotype is illustrated by recent pre-clinical studies showing that inhibitors of BRAF paradoxically activate MAPK signaling in tumors that lack activating BRAF mutations.	('BRAF', 'Gene', (160, 164))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('inhibitors', 'Var', (146, 156))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('activate', 'PosReg', (179, 187))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('MAPK', 'molecular_function', 'GO:0004707', ('188', '192'))	('MAPK signaling', 'MPA', (188, 202))	('pre', 'molecular_function', 'GO:0003904', ('112', '115'))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))	('MAPK signaling', 'biological_process', 'GO:0000165', ('188', '202'))
59440	22484192	Reports from at least 6 independent groups have shown that BRAF inhibition activates MAPK in cell lines with NRAS and KRAS mutations as well as those cell lines where the MAPK pathway is activated through other oncogenes such as HER2 .	('MAPK', 'molecular_function', 'GO:0004707', ('171', '175'))	('MAPK', 'Gene', (85, 89))	('NRAS', 'Gene', (109, 113))	('HER2', 'Gene', (229, 233))	('KRAS', 'Gene', (118, 122))	('MAPK', 'molecular_function', 'GO:0004707', ('85', '89'))	('inhibition', 'Var', (64, 74))	('HER2', 'Gene', '2064', (229, 233))	('BRAF', 'Gene', (59, 63))	('activates', 'PosReg', (75, 84))	('KRAS', 'Gene', '3845', (118, 122))	('mutations', 'Var', (123, 132))
59441	22484192	Mechanistic studies showed that although vemurafenib and other BRAF inhibitors were able to profoundly inhibit the activity of BRAF V600E containing complexes in melanoma cells they instead promoted the activity of CRAF-CRAF dimers in cells with RAS mutations, leading in turn to MEK activation .	('V600E', 'Mutation', 'rs113488022', (132, 137))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('vemurafenib', 'Chemical', 'MESH:D000077484', (41, 52))	('activation', 'PosReg', (284, 294))	('activity', 'MPA', (115, 123))	('BRAF', 'Gene', (127, 131))	('RAS', 'Gene', (246, 249))	('mutations', 'Var', (250, 259))	('MEK', 'CPA', (280, 283))	('CRAF', 'molecular_function', 'GO:0004709', ('220', '224'))	('CRAF', 'molecular_function', 'GO:0004709', ('215', '219'))	('inhibit', 'NegReg', (103, 110))	('activity', 'MPA', (203, 211))	('promoted', 'PosReg', (190, 198))
59442	22484192	There is also evidence that PLX4032 increases the invasive potential of NRAS-mutated melanoma cells through the through the activation of ERK and FAK signaling .	('ERK', 'Gene', '5594', (138, 141))	('ERK', 'Gene', (138, 141))	('activation', 'PosReg', (124, 134))	('signaling', 'biological_process', 'GO:0023052', ('150', '159'))	('FAK', 'molecular_function', 'GO:0004717', ('146', '149'))	('increases', 'PosReg', (36, 45))	('PLX4032', 'Chemical', 'MESH:D000077484', (28, 35))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('PLX4032', 'Var', (28, 35))	('invasive potential', 'CPA', (50, 68))	('ERK', 'molecular_function', 'GO:0004707', ('138', '141'))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))
59443	22484192	Additional studies demonstrated that BRAF inhibitors may even contribute to the progression of NRAS mutated melanomas in part by suppressing apoptosis through the modulation of Mcl-1 expression .	('modulation', 'Reg', (163, 173))	('apoptosis', 'biological_process', 'GO:0097194', ('141', '150'))	('melanomas', 'Disease', 'MESH:D008545', (108, 117))	('mutated', 'Var', (100, 107))	('melanomas', 'Phenotype', 'HP:0002861', (108, 117))	('Mcl-1', 'Gene', (177, 182))	('apoptosis', 'biological_process', 'GO:0006915', ('141', '150'))	('suppressing', 'NegReg', (129, 140))	('BRAF', 'Gene', (37, 41))	('NRAS', 'Gene', (95, 99))	('Mcl-1', 'Gene', '4170', (177, 182))	('expression', 'MPA', (183, 193))	('melanomas', 'Disease', (108, 117))	('apoptosis', 'CPA', (141, 150))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))
59462	18958307	However, one must keep in mind that SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation.	('SV40', 'Species', '1891767', (36, 40))	('elicit', 'Reg', (95, 101))	('targets', 'Reg', (57, 64))	('cellular transformation', 'CPA', (102, 125))	('SV40 large T antigen', 'Var', (36, 56))
59479	18958307	Expression of the SV40 T antigen began at E10.5 and the first abnormalities in the RPE were observed at E15.5.	('E15.5', 'Var', (104, 109))	('SV40', 'Species', '1891767', (18, 22))	('SV40', 'Gene', (18, 22))	('SV40 T antigen', 'molecular_function', 'GO:0016887', ('18', '32'))
59483	18958307	However, several previous studies have shown that early oncogenic sequences of SV40 under transcriptional control of the tyrosinase promoter genetically predispose normal melanocytes to their transformation into malignant melanocytes.	('transformation', 'CPA', (192, 206))	('sequences', 'Var', (66, 75))	('predispose', 'Reg', (153, 163))	('transcriptional control', 'biological_process', 'GO:0006355', ('90', '113'))	('SV40', 'Species', '1891767', (79, 83))	('SV40', 'Gene', (79, 83))
59486	18958307	Indeed, the promoter of the tyrosinase-related family gene, Tyrp1, drives detectable transgene expression only in the RPE, even though the gene is also expressed in melanocytes as observed in Tyrp1 mutant mice.	('Tyrp1', 'Gene', (60, 65))	('Tyrp1', 'Gene', '22178', (192, 197))	('Tyrp1', 'Gene', (192, 197))	('mutant', 'Var', (198, 204))	('mice', 'Species', '10090', (205, 209))	('expression', 'MPA', (95, 105))	('Tyrp1', 'Gene', '22178', (60, 65))
59497	18958307	It remains unclear why proliferation in these melanomas is driven by mutant B-Raf rather than mutant Ras.	('driven', 'Reg', (59, 65))	('mutant', 'Var', (69, 75))	('melanomas', 'Disease', 'MESH:D008545', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('melanomas', 'Disease', (46, 55))	('B-Raf', 'Gene', (76, 81))	('B-Raf', 'Gene', '109880', (76, 81))
59508	18958307	The presence of ETS-1 is associated with a high incidence of lymph node metastasis in the lung, colorectal, and squamous cell carcinoma.	('colorectal', 'Disease', (96, 106))	('associated', 'Reg', (25, 35))	('ETS-1', 'Gene', (16, 21))	('lymph node metastasis', 'CPA', (61, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (112, 135))	('presence', 'Var', (4, 12))	('squamous cell carcinoma', 'Disease', (112, 135))
59514	18958307	Indeed, oligonucleotides or transdominant mutant ETS-1 molecules with dominant negative effects inhibit angiogenesis, consistent with a critical role for ETS-1 in angiogenesis.	('ETS-1', 'Gene', (49, 54))	('mutant', 'Var', (42, 48))	('oligonucleotides', 'Var', (8, 24))	('angiogenesis', 'biological_process', 'GO:0001525', ('104', '116'))	('angiogenesis', 'CPA', (104, 116))	('angiogenesis', 'biological_process', 'GO:0001525', ('163', '175'))	('inhibit', 'NegReg', (96, 103))	('oligonucleotides', 'Chemical', 'MESH:D009841', (8, 24))
59516	18958307	ETS-1 regulates several downstream effectors of angiotensin II including p21CIP, plasminogen activator inhibitor-1 (PAI-1), vascular cell adhesion molecule 1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) and plays a very important role in inflammation and vascular remodeling in response to angiotensine 2 (Ang II) as shown by in vitro and in vivo experiments.	('PAI-1', 'Gene', '18787', (116, 121))	('monocyte chemoattractant protein-1', 'Gene', '20296', (172, 206))	('inflammation', 'Disease', 'MESH:D007249', (250, 262))	('p21CIP', 'Var', (73, 79))	('plasminogen activator inhibitor-1', 'Gene', '18787', (81, 114))	('ETS-1', 'Gene', (0, 5))	('cell adhesion', 'biological_process', 'GO:0007155', ('133', '146'))	('VCAM-1', 'Gene', (159, 165))	('inflammation', 'Disease', (250, 262))	('vascular cell adhesion molecule 1', 'Gene', (124, 157))	('plasminogen activator inhibitor-1', 'Gene', (81, 114))	('inflammation', 'biological_process', 'GO:0006954', ('250', '262'))	('PAI-1', 'Gene', (116, 121))	('MCP', 'molecular_function', 'GO:0004298', ('208', '211'))	('VCAM-1', 'Gene', '22329', (159, 165))	('monocyte chemoattractant protein-1', 'Gene', (172, 206))	('regulates', 'Reg', (6, 15))	('vascular cell adhesion molecule 1', 'Gene', '22329', (124, 157))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('133', '155'))	('protein', 'cellular_component', 'GO:0003675', ('197', '204'))
59524	18958307	Levels of mRNA and protein for these two transcription factors were higher in abnormal mouse eyes during the development of tumors than in normal control eyes of the same age.	('transcription', 'biological_process', 'GO:0006351', ('41', '54'))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mouse', 'Species', '10090', (87, 92))	('higher', 'PosReg', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))	('abnormal', 'Var', (78, 86))
59573	18958307	These results show a marked increase in protein levels for ETS-1 and ETS-2 after P25 in transgenic mice compared to the control mice.	('mice', 'Species', '10090', (99, 103))	('transgenic', 'Var', (88, 98))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('transgenic mice', 'Species', '10090', (88, 103))	('protein levels', 'MPA', (40, 54))	('mice', 'Species', '10090', (128, 132))	('ETS-2', 'Gene', (69, 74))	('P25', 'Gene', '12569', (81, 84))	('P25', 'Gene', (81, 84))	('increase', 'PosReg', (28, 36))
59581	18958307	Like ETS-1, ETS-2 was produced in the MTC at the posterior pole at P25 at higher levels in the transgenic mice than in control (WT) mice (Figure 4E,F).	('mice', 'Species', '10090', (106, 110))	('transgenic mice', 'Species', '10090', (95, 110))	('transgenic', 'Var', (95, 105))	('P25', 'Gene', '12569', (67, 70))	('P25', 'Gene', (67, 70))	('mice', 'Species', '10090', (132, 136))
59610	18958307	During malignant transformation, cancer cells acquire genetic mutations that override the normal mechanisms controlling cellular proliferation.	('override', 'PosReg', (77, 85))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (62, 71))
59611	18958307	Importantly, malignant progression has been shown to be triggered and/or accelerated by epigenetic mutations caused by alterations of DNA Methyltransferase-1 (DNMT), histone acetyltransferase (HAT), Histone deacetylases (HDACs) genes, and other mutator or modifier genes.	('DNA Methyltransferase-1', 'Gene', '13433', (134, 157))	('epigenetic mutations', 'Var', (88, 108))	('malignant progression', 'CPA', (13, 34))	('DNMT', 'Gene', (159, 163))	('DNMT', 'Gene', '13433', (159, 163))	('DNA Methyltransferase-1', 'Gene', (134, 157))	('Methyltransferase-1', 'molecular_function', 'GO:0047152', ('138', '157'))	('alterations', 'Var', (119, 130))	('accelerated', 'PosReg', (73, 84))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))	('triggered', 'PosReg', (56, 65))
59615	18958307	previously developed a transgenic mouse model in which the SV40 T antigen induces RPE tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('induces', 'Reg', (74, 81))	('formation', 'biological_process', 'GO:0009058', ('92', '101'))	('mouse', 'Species', '10090', (34, 39))	('transgenic', 'Species', '10090', (23, 33))	('RPE tumor', 'Disease', 'MESH:D009369', (82, 91))	('SV40', 'Species', '1891767', (59, 63))	('SV40 T', 'Var', (59, 65))	('SV40 T antigen', 'molecular_function', 'GO:0016887', ('59', '73'))	('RPE tumor', 'Disease', (82, 91))
59629	18958307	Our observations could also be explained by epigenetic changes in tumor cells having differential effects on the regulation of genes encoding transcription factors and/or cotranscriptional regulators of ETS-1 and ETS-2.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('transcription', 'biological_process', 'GO:0006351', ('142', '155'))	('epigenetic changes', 'Var', (44, 62))	('tumor', 'Disease', (66, 71))	('regulation', 'MPA', (113, 123))	('regulation', 'biological_process', 'GO:0065007', ('113', '123'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('effects', 'Reg', (98, 105))
59655	18958307	The coupling of PAI-1 to vitronectin prevents vitronectin-integrin interaction, which downregulates cell adhesion.	('prevents', 'NegReg', (37, 45))	('vitronectin', 'Gene', '22370', (25, 36))	('vitronectin', 'Gene', (25, 36))	('cell adhesion', 'CPA', (100, 113))	('vitronectin', 'Gene', '22370', (46, 57))	('PAI-1', 'Gene', '18787', (16, 21))	('cell adhesion', 'biological_process', 'GO:0007155', ('100', '113'))	('coupling', 'Var', (4, 12))	('downregulates', 'NegReg', (86, 99))	('vitronectin', 'Gene', (46, 57))	('PAI-1', 'Gene', (16, 21))
59661	18958307	Indeed, high levels of PAI-1 expression are correlated with a poor prognosis in various types of cancer (gastric, breast, and lung).	('cancer', 'Disease', (97, 103))	('PAI-1', 'Gene', (23, 28))	('high levels', 'Var', (8, 19))	('correlated', 'Reg', (44, 54))	('breast', 'Disease', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('PAI-1', 'Gene', '18787', (23, 28))	('gastric', 'Disease', (105, 112))	('expression', 'MPA', (29, 39))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
59665	18958307	For example, a high level of MCP-1 in breast cancer patients is associated with a significantly shorter relapse-free survival period than low levels of MCP-1.	('shorter', 'NegReg', (96, 103))	('relapse-free survival period', 'CPA', (104, 132))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('MCP', 'molecular_function', 'GO:0004298', ('29', '32'))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('breast cancer', 'Disease', (38, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('MCP', 'molecular_function', 'GO:0004298', ('152', '155'))	('MCP-1', 'Var', (29, 34))	('patients', 'Species', '9606', (52, 60))	('low levels of MCP', 'Phenotype', 'HP:0025066', (138, 155))
59686	18958307	Recent work based on the use of a mouse antibody against ICAM-1 has shown that blocking this adhesion molecule inhibits the growth of uveal melanoma in a severe combined immunideficient (SCID) mouse model.	('SCID', 'Disease', (187, 191))	('mouse', 'Species', '10090', (34, 39))	('antibody', 'cellular_component', 'GO:0042571', ('40', '48'))	('growth', 'CPA', (124, 130))	('inhibits', 'NegReg', (111, 119))	('blocking', 'Var', (79, 87))	('uveal melanoma', 'Disease', 'MESH:C536494', (134, 148))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('antibody', 'cellular_component', 'GO:0019814', ('40', '48'))	('antibody', 'cellular_component', 'GO:0019815', ('40', '48'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (134, 148))	('uveal melanoma', 'Disease', (134, 148))	('ICAM-1', 'Gene', (57, 63))	('mouse', 'Species', '10090', (193, 198))	('antibody', 'molecular_function', 'GO:0003823', ('40', '48'))	('SCID', 'Disease', 'MESH:D053632', (187, 191))	('ICAM-1', 'Gene', '15894', (57, 63))
59702	33578810	Integrative Genomic Analyses of Patient-Matched Intracranial and Extracranial Metastases Reveal a Novel Brain-Specific Landscape of Genetic Variants in Driver Genes of Malignant Melanoma Melanoma is the third most common cause of brain metastasis with a reported incidence of up to 80% leading to patients' early mortality.	('Malignant Melanoma', 'Phenotype', 'HP:0002861', (168, 186))	('Melanoma', 'Disease', 'MESH:D008545', (178, 186))	('Melanoma', 'Disease', (178, 186))	('Variants', 'Var', (140, 148))	('Patient', 'Species', '9606', (32, 39))	('patients', 'Species', '9606', (297, 305))	('Melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('Malignant Melanoma', 'Disease', (168, 186))	('mortality', 'Disease', 'MESH:D003643', (313, 322))	('Metastases', 'Disease', (78, 88))	('Malignant Melanoma', 'Disease', 'MESH:D008545', (168, 186))	('Melanoma', 'Disease', 'MESH:D008545', (187, 195))	('Metastases', 'Disease', 'MESH:D009362', (78, 88))	('Melanoma', 'Disease', (187, 195))	('mortality', 'Disease', (313, 322))	('Melanoma', 'Phenotype', 'HP:0002861', (178, 186))
59704	33578810	Thus, the identification of genetic alterations may provide new insights into the pathogenesis of brain metastases and this will facilitate the improvement of precision oncology.	('oncology', 'Phenotype', 'HP:0002664', (169, 177))	('genetic alterations', 'Var', (28, 47))	('pathogenesis', 'biological_process', 'GO:0009405', ('82', '94'))	('brain metastases', 'Disease', (98, 114))	('brain metastases', 'Disease', 'MESH:D009362', (98, 114))
59707	33578810	Therapeutic targeting of the new-identified genetic variants could help to facilitate novel, more effective therapies for prevention and/or treatment of melanoma brain metastases.	('melanoma brain metastases', 'Disease', 'MESH:D009362', (153, 178))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma brain metastases', 'Disease', (153, 178))	('variants', 'Var', (52, 60))
59711	33578810	Experimental Design and Results: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma metastases', 'Disease', 'MESH:D009362', (97, 116))	('melanoma', 'Disease', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (229, 237))	('melanoma', 'Disease', (229, 237))	('melanoma', 'Disease', 'MESH:D008545', (229, 237))	('mutations', 'Var', (135, 144))	('melanoma metastases', 'Disease', (97, 116))
59712	33578810	In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites.	('metastases', 'Disease', (113, 123))	('metastases', 'Disease', (74, 84))	('metastases', 'Disease', 'MESH:D009362', (74, 84))	('brain metastases', 'Disease', 'MESH:D009362', (68, 84))	('brain metastases', 'Disease', (68, 84))	('metastases', 'Disease', 'MESH:D009362', (113, 123))	('nucleotide modifications', 'Var', (40, 64))
59713	33578810	Moreover, we identified novel genetic variants in ARID1A, ARID2, SMARCA4 and BAP1, genes that have not been linked to brain metastases before; albeit most frequent mutations were found in ARID1A, ARID2 and BRAF.	('ARID1A', 'Gene', '8289', (188, 194))	('variants', 'Var', (38, 46))	('ARID1A', 'Gene', (188, 194))	('SMARCA4', 'Gene', (65, 72))	('brain metastases', 'Disease', 'MESH:D009362', (118, 134))	('SMARCA4', 'Gene', '6597', (65, 72))	('brain metastases', 'Disease', (118, 134))	('BAP1', 'Gene', '8314', (77, 81))	('ARID1A', 'Gene', '8289', (50, 56))	('BAP1', 'Gene', (77, 81))	('ARID1A', 'Gene', (50, 56))	('ARID2', 'Gene', (58, 63))
59728	33578810	However, genomic sequencing of primary tumors and intracranial metastases from different types of solid cancers revealed remarkable genetic heterogeneity but also further genetic modifications from primary tumors to metastases at distant sites, or BM specific mutations, implicating that intracerebral metastases develop from "branched genetic evolution".	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('tumors', 'Disease', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('metastases', 'Disease', 'MESH:D009362', (216, 226))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('metastases', 'Disease', 'MESH:D009362', (302, 312))	('tumors', 'Disease', (206, 212))	('metastases', 'Disease', (216, 226))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('metastases', 'Disease', (302, 312))	('metastases', 'Disease', 'MESH:D009362', (63, 73))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('intracerebral metastases', 'Disease', 'MESH:D009362', (288, 312))	('intracerebral metastases', 'Disease', (288, 312))	('mutations', 'Var', (260, 269))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('metastases', 'Disease', (63, 73))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
59729	33578810	Several large-scale sequencing studies in melanoma identified significantly mutated melanoma genes, such as NF), ARID2, TERT or RAC beside the well-established oncogenes including NRAS, BRAF or KIT.	('melanoma', 'Disease', (42, 50))	('RAC', 'Gene', (128, 131))	('KIT', 'Gene', '3815', (194, 197))	('KIT', 'molecular_function', 'GO:0005020', ('194', '197'))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('KIT', 'Gene', (194, 197))	('melanoma', 'Disease', (84, 92))	('mutated', 'Var', (76, 83))	('RAC', 'Gene', '6035;5879', (128, 131))	('NF', 'Gene', '23114', (108, 110))	('ARID2', 'Gene', (113, 118))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
59735	33578810	The aim of this study was to identify BM-associated driver mutations in melanoma with potential for translation into future therapeutic strategies.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('mutations', 'Var', (59, 68))	('translation', 'biological_process', 'GO:0006412', ('100', '111'))
59744	33578810	We called single nucleotide variants including known mutations and rare single-nucleotide-polymorphisms (SNPs) in 47 of 54 intracerebral and in 15 of 18 extracranial metastases (Figure 1).	('single nucleotide variants', 'Var', (10, 36))	('intracerebral', 'Disease', (123, 136))	('intracerebral', 'Disease', 'MESH:D002543', (123, 136))	('metastases', 'Disease', (166, 176))	('metastases', 'Disease', 'MESH:D009362', (166, 176))	('single-nucleotide-polymorphisms', 'Var', (72, 103))
59745	33578810	SMARCA4 mutations significantly co-occurred with ARID2 (p = 0.001, log2 odds ratio [OR] >3, n = 9) and ARID1A (p < 0.0001, log2 OR > 3, n = 7) mutations.	('co-occurred', 'Reg', (32, 43))	('SMARCA4', 'Gene', (0, 7))	('ARID2', 'Gene', (49, 54))	('SMARCA4', 'Gene', '6597', (0, 7))	('mutations', 'Var', (8, 17))	('ARID1A', 'Gene', '8289', (103, 109))	('ARID1A', 'Gene', (103, 109))
59746	33578810	Similarly, TERT mutations significantly co-occurred with NRAS and MAP2K2 (both: p = 0.046, log2 OR = 2.373, n = 9), RAC1 (p = 0.004, log2 OR > 3, n = 8), and NF1 (p = 0.035, log2 OR > 3, n = 7) mutations.	('MAP2K', 'molecular_function', 'GO:0004708', ('66', '71'))	('MAP2K2', 'Gene', '5605', (66, 72))	('MAP2K2', 'Gene', (66, 72))	('NRAS', 'Gene', (57, 61))	('mutations', 'Var', (194, 203))	('NF1', 'Gene', (158, 161))	('RAC1', 'Gene', '5879', (116, 120))	('RAC1', 'Gene', (116, 120))	('co-occurred', 'Reg', (40, 51))
59747	33578810	ARID2 was mutated in samples that also carried ARID1A (p < 0.0001, log2 OR > 3, n = 8) or NF1 mutations (p < 0.0001, log2 OR > 3, n = 8).	('ARID1A', 'Gene', '8289', (47, 53))	('ARID1A', 'Gene', (47, 53))	('mutations', 'Var', (94, 103))	('ARID2', 'Gene', (0, 5))	('NF1', 'Gene', (90, 93))
59748	33578810	Finally, TP53 mutations were highly likely present in NRAS mutated samples (p = 0.005, log2 OR > 3, n = 8).	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
59750	33578810	In 11 of the 16 pairs, we detected genetic variants in BM that were absent in the corresponding metastases obtained from other sites of the body.	('variants', 'Var', (43, 51))	('metastases', 'Disease', 'MESH:D009362', (96, 106))	('metastases', 'Disease', (96, 106))
59751	33578810	These included mutations in 12 well-known cancer genes associated with cutaneous and/or uveal melanomas: BRAF, NRAS, PIK3CA, TERT, IDH1, EZH2, NF1, PTEN, TP53, MAP2K1, GNAQ and GNA11.	('PTEN', 'Gene', (148, 152))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('MAP2K1', 'Gene', '5604', (160, 166))	('NF1', 'Gene', (143, 146))	('MAP2K1', 'Gene', (160, 166))	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('mutations', 'Var', (15, 24))	('associated', 'Reg', (55, 65))	('uveal melanoma', 'Disease', 'MESH:C536494', (88, 102))	('uveal melanoma', 'Disease', (88, 102))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('NRAS', 'Gene', (111, 115))	('TP53', 'Gene', (154, 158))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('BRAF', 'Gene', (105, 109))	('melanomas', 'Disease', 'MESH:D008545', (94, 103))	('PIK3CA', 'Gene', (117, 123))	('cancer', 'Disease', (42, 48))	('MAP2K', 'molecular_function', 'GO:0004708', ('160', '165'))	('melanomas', 'Disease', (94, 103))	('TP53', 'Gene', '7157', (154, 158))	('uveal melanomas', 'Phenotype', 'HP:0007716', (88, 103))
59752	33578810	Interestingly, we identified variants in five new candidate genes, i.e., ARID1A, ARID2, SMARCA4, PIK3R1 and BAP1, which neither have been previously identified in melanoma BM nor reported in CNS metastases from other cancers (Figure 2A).	('PIK3R1', 'Gene', '5295', (97, 103))	('SMARCA4', 'Gene', (88, 95))	('BAP1', 'Gene', '8314', (108, 112))	('ARID2', 'Gene', (81, 86))	('cancers', 'Disease', 'MESH:D009369', (217, 224))	('ARID1A', 'Gene', (73, 79))	('CNS', 'Disease', (191, 194))	('BAP1', 'Gene', (108, 112))	('PIK3R1', 'Gene', (97, 103))	('ARID1A', 'Gene', '8289', (73, 79))	('melanoma BM', 'Disease', (163, 174))	('metastases', 'Disease', 'MESH:D009362', (195, 205))	('SMARCA4', 'Gene', '6597', (88, 95))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('variants', 'Var', (29, 37))	('metastases', 'Disease', (195, 205))	('cancers', 'Disease', (217, 224))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('melanoma BM', 'Disease', 'MESH:D008545', (163, 174))
59753	33578810	Mutations in ARID1A (p = 0.0205), ARID2 (p = 0.0207), BRAF (p = 0.023) SMARCA4 (p = 0.015), TERT (p = 0.0041), and IDH1 (p = 0.0041) were significantly exclusive to BM while the same variants remained undetected in the corresponding extracranial tumor tissues.	('ARID1A', 'Gene', '8289', (13, 19))	('IDH1', 'Gene', (115, 119))	('ARID1A', 'Gene', (13, 19))	('SMARCA4', 'Gene', '6597', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('Mutations', 'Var', (0, 9))	('SMARCA4', 'Gene', (71, 78))	('tumor', 'Disease', (246, 251))	('ARID2', 'Gene', (34, 39))
59754	33578810	Overall, the most frequently mutated genes in BM included ARID1A, ARID2, BRAF, and SMARCA4 (Figure 2B, Table 2).	('ARID1A', 'Gene', '8289', (58, 64))	('ARID1A', 'Gene', (58, 64))	('SMARCA4', 'Gene', (83, 90))	('SMARCA4', 'Gene', '6597', (83, 90))	('mutated', 'Var', (29, 36))
59755	33578810	ARID1A variants (P650S, P1568S, L2119S, P1562L, G831A, G423E4) and ARID2 variants (D239N, S1489L, P1022S, S297F) were detected in 4 intracerebral melanoma tissues.	('D239N', 'Mutation', 'rs876660807', (83, 88))	('P650S', 'Var', (17, 22))	('D239N', 'Var', (83, 88))	('ARID2', 'Gene', (67, 72))	('P1022S', 'Mutation', 'rs575874753', (98, 104))	('P1568S', 'Mutation', 'rs113718290', (24, 30))	('P1562L', 'Mutation', 'p.P1562L', (40, 46))	('S1489L', 'Mutation', 'rs1257231753', (90, 96))	('L2119S', 'Var', (32, 38))	('P1022S', 'Var', (98, 104))	('intracerebral melanoma', 'Disease', (132, 154))	('P650S', 'Mutation', 'rs758533417', (17, 22))	('intracerebral melanoma', 'Disease', 'MESH:D002543', (132, 154))	('P1562L', 'Var', (40, 46))	('G831A', 'Mutation', 'rs781896082', (48, 53))	('ARID1A', 'Gene', (0, 6))	('S297F', 'Mutation', 'p.S297F', (106, 111))	('P1568S', 'Var', (24, 30))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('G423E4', 'Var', (55, 61))	('L2119S', 'Mutation', 'p.L2119S', (32, 38))	('ARID1A', 'Gene', '8289', (0, 6))	('S297F', 'Var', (106, 111))	('G831A', 'Var', (48, 53))	('intracerebral melanoma', 'Phenotype', 'HP:0007716', (132, 154))
59756	33578810	BRAF variants (P336L, G73E and V207E) and SMARCA4 variants (P262L, P919S, E1113K, H884Y) were detected in 3 melanoma BM.	('V207E', 'Var', (31, 36))	('SMARCA4', 'Gene', (42, 49))	('detected', 'Reg', (94, 102))	('V207E', 'Mutation', 'rs1237829645', (31, 36))	('BRAF', 'Gene', (0, 4))	('P262L', 'Var', (60, 65))	('E1113K', 'Var', (74, 80))	('E1113K', 'Mutation', 'p.E1113K', (74, 80))	('G73E', 'Mutation', 'p.G73E', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('P262L', 'Mutation', 'rs756531500', (60, 65))	('G73E', 'Var', (22, 26))	('P336L', 'Var', (15, 20))	('SMARCA4', 'Gene', '6597', (42, 49))	('H884Y', 'Mutation', 'p.H884Y', (82, 87))	('melanoma BM', 'Disease', (108, 119))	('P336L', 'Mutation', 'rs765058736', (15, 20))	('H884Y', 'Var', (82, 87))	('P919S', 'Var', (67, 72))	('melanoma BM', 'Disease', 'MESH:D008545', (108, 119))	('P919S', 'Mutation', 'p.P919S', (67, 72))
59757	33578810	We also detected nucleotide transitions resulting in gene activation in NRAS (Q61K, Q61R), in the promoter region of TERT (chr5:1295250 G > A), and in GNA11 (R183C), the latter being frequent in uveal melanoma and primary meningeal melanocytic tumors.	('meningeal melanocytic tumors', 'Disease', (222, 250))	('NRAS', 'Gene', (72, 76))	('Q61R', 'Var', (84, 88))	('chr5:1295250 G > A', 'Var', (123, 141))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('Q61K', 'Mutation', 'rs121913254', (78, 82))	('Q61R', 'Mutation', 'rs11554290', (84, 88))	('1295250 G > A', 'Mutation', 'g.1295250G>A', (128, 141))	('meningeal melanocytic tumors', 'Disease', 'MESH:D009508', (222, 250))	('gene', 'MPA', (53, 57))	('R183C', 'Mutation', 'p.R183C', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('uveal melanoma', 'Phenotype', 'HP:0007716', (195, 209))	('uveal melanoma', 'Disease', 'MESH:C536494', (195, 209))	('activation', 'PosReg', (58, 68))	('uveal melanoma', 'Disease', (195, 209))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))
59758	33578810	Moreover, recurrence was seen for three brain-specific variants, in BRAF (V207E), and TP53 (E171G) in 2 of 16 tested pairs.	('V207E', 'Var', (74, 79))	('E171G', 'Mutation', 'rs1299176017', (92, 97))	('TP53', 'Gene', '7157', (86, 90))	('E171G', 'Var', (92, 97))	('TP53', 'Gene', (86, 90))	('V207E', 'Mutation', 'rs1237829645', (74, 79))
59759	33578810	These genetic variants include a typical cancer driver mutations in BRAF.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (55, 64))	('variants', 'Var', (14, 22))	('BRAF', 'Gene', (68, 72))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
59760	33578810	Brain-specific loss-of-function mutations were detected in PIK3CA (Y1157*) and in PTEN (Q219*, A328fs).	('Q219*', 'Var', (88, 93))	('Q219*', 'SUBSTITUTION', 'None', (88, 93))	('A328fs', 'Mutation', 'p.A328fsX', (95, 101))	('PIK3CA', 'Gene', (59, 65))	('Y1157*', 'SUBSTITUTION', 'None', (67, 73))	('Y1157*', 'Var', (67, 73))	('PTEN', 'Gene', (82, 86))	('loss-of-function', 'NegReg', (15, 31))	('A328fs', 'Var', (95, 101))
59761	33578810	Previously not described variants in PIK3R1 (S43R, F41C) were detected private to BM.	('F41C', 'Mutation', 'p.F41C', (51, 55))	('S43R', 'Mutation', 'p.S43R', (45, 49))	('F41C', 'Var', (51, 55))	('PIK3R1', 'Gene', (37, 43))	('S43R', 'Var', (45, 49))	('PIK3R1', 'Gene', '5295', (37, 43))
59762	33578810	SMARCA4 significantly co-occurred with IDH1 and PIK3CA mutations (both: p = 0.042, log2 OR > 3, n = 2).	('SMARCA4', 'Gene', (0, 7))	('co-occurred', 'Reg', (22, 33))	('mutations', 'Var', (55, 64))	('PIK3CA', 'Gene', (48, 54))	('IDH1', 'Gene', (39, 43))	('SMARCA4', 'Gene', '6597', (0, 7))
59763	33578810	As seen before, SMARCA4 tended to co-occurred with ARID1A and ARID2 mutations, however, here significance was not reached (p = 0.083 and p = 0.583, respectively).	('ARID2', 'Gene', (62, 67))	('ARID1A', 'Gene', '8289', (51, 57))	('ARID1A', 'Gene', (51, 57))	('SMARCA4', 'Gene', (16, 23))	('SMARCA4', 'Gene', '6597', (16, 23))	('mutations', 'Var', (68, 77))
59764	33578810	We also searched in 180 different cancer sequencing studies (including over 47000 samples using the cBioPortal site) for evidence of BM associated variants, and while all of the detected variants in the 17 genes were found in different cancer types, only 4 variants (NRAS Q61, TP53 E171G, PTEN A328*, ARID2 S297F) were detected corresponding to CNS cancers (n = 10 tumor tissues).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('NRAS Q61', 'Var', (267, 275))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('corresponding', 'Reg', (328, 341))	('E171G', 'Mutation', 'rs1299176017', (282, 287))	('cancers', 'Phenotype', 'HP:0002664', (349, 356))	('cancer', 'Disease', (349, 355))	('A328*', 'Var', (294, 299))	('cancers', 'Disease', (349, 356))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('TP53', 'Gene', '7157', (277, 281))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('S297F', 'Mutation', 'p.S297F', (307, 312))	('cancer', 'Disease', (236, 242))	('A328*', 'SUBSTITUTION', 'None', (294, 299))	('tumor', 'Disease', (365, 370))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Disease', 'MESH:D009369', (365, 370))	('ARID2 S297F', 'Var', (301, 312))	('cancer', 'Disease', 'MESH:D009369', (349, 355))	('cancers', 'Disease', 'MESH:D009369', (349, 356))	('cancer', 'Disease', (34, 40))	('TP53', 'Gene', (277, 281))
59765	33578810	The presence of these mutations in primary CNS tumors further support their significance in brain metastases.	('CNS tumors', 'Disease', (43, 53))	('mutations', 'Var', (22, 31))	('brain metastases', 'Disease', 'MESH:D009362', (92, 108))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('brain metastases', 'Disease', (92, 108))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('CNS tumors', 'Disease', 'MESH:D016543', (43, 53))
59766	33578810	Metastases located in sun-exposed areas of the skin might accumulate more mutations compared to metastases located of sun-protected areas of the body, such as metastases of the CNS.	('metastases', 'Disease', (159, 169))	('metastases', 'Disease', 'MESH:D009362', (96, 106))	('mutations', 'Var', (74, 83))	('metastases', 'Disease', 'MESH:D009362', (159, 169))	('Metastases', 'Disease', (0, 10))	('Metastases', 'Disease', 'MESH:D009362', (0, 10))	('metastases', 'Disease', (96, 106))
59771	33578810	Next, we analyzed C > T transitions in four mutational subtypes of melanoma, BRAF-, NRAS-, NF1-mutant samples and triple-wildtype samples.	('BRAF-', 'Disease', (77, 82))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('NF1-mutant', 'Var', (91, 101))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('NRAS-', 'Gene', (84, 89))
59776	33578810	Intracranial response rates for BRAF inhibitors in patients harboring mutant BRAF (V600E) have been reported in the range of 30-50%, with an increased response in asymptomatic patients and patients without previous local BM therapy.	('patients', 'Species', '9606', (176, 184))	('mutant', 'Var', (70, 76))	('BRAF', 'Gene', (77, 81))	('patients', 'Species', '9606', (51, 59))	('V600E', 'Mutation', 'rs113488022', (83, 88))	('patients', 'Species', '9606', (189, 197))
59785	33578810	While only 16 genes overlapped between our gene panel and the gene panel by Fischer et al., in 5 of those genes (BRAF, GNAQ, NF1, BAP1, PIK3CA, PIK3R1) mutations private to BM were confirmed.	('PIK3CA', 'Gene', (136, 142))	('NF1', 'Gene', (125, 128))	('BAP1', 'Gene', (130, 134))	('PIK3R1', 'Gene', '5295', (144, 150))	('PIK3R1', 'Gene', (144, 150))	('mutations', 'Var', (152, 161))	('BRAF', 'Gene', (113, 117))	('BAP1', 'Gene', '8314', (130, 134))
59787	33578810	Moreover, we detected single nucleotide transitions in ARID1A, ARID2, SMARCA4 and BAP1, all genes which have not been associated before with CNS metastases of melanomas.	('metastases of melanomas', 'Disease', 'MESH:D009362', (145, 168))	('BAP1', 'Gene', (82, 86))	('melanomas', 'Phenotype', 'HP:0002861', (159, 168))	('BAP1', 'Gene', '8314', (82, 86))	('single nucleotide transitions', 'Var', (22, 51))	('SMARCA4', 'Gene', (70, 77))	('SMARCA4', 'Gene', '6597', (70, 77))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))	('ARID1A', 'Gene', '8289', (55, 61))	('detected', 'Reg', (13, 21))	('ARID1A', 'Gene', (55, 61))	('metastases of melanomas', 'Disease', (145, 168))	('ARID2', 'Gene', (63, 68))
59788	33578810	However, beside modifications in ARID1A, genetic variants in BRAF were detected most frequently compared to alterations in other genes.	('genetic variants', 'Var', (41, 57))	('BRAF', 'Gene', (61, 65))	('modifications', 'Reg', (16, 29))	('ARID1A', 'Gene', '8289', (33, 39))	('ARID1A', 'Gene', (33, 39))
59789	33578810	Point mutations in BRAF, mostly resulting by the substitution of valine for glutamin acid at codon 600 (VAL600 Glu or V600E) but also NRAS are the most frequent activating somatic events in melanoma and have been extensively studied in large cohorts of clinical trials for their impact on disease progression and therapeutic intervention.	('resulting by', 'Reg', (32, 44))	('valine', 'Chemical', 'MESH:D014633', (65, 71))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('activating', 'PosReg', (161, 171))	('BRAF', 'Gene', (19, 23))	('VAL600 Glu', 'Var', (104, 114))	('V600E', 'Mutation', 'rs113488022', (118, 123))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('glutamin acid', 'Chemical', '-', (76, 89))	('VAL600 Glu', 'Mutation', 'rs113488022', (104, 114))	('V600E', 'Var', (118, 123))	('NRAS', 'Gene', (134, 138))	('substitution', 'Reg', (49, 61))	('Point mutations', 'Var', (0, 15))	('valine', 'MPA', (65, 71))
59790	33578810	In line with previous studies of extracranial melanomas, none of our 16 sample pairs presented coexistence of BRAF and NRAS mutations.	('mutations', 'Var', (124, 133))	('melanomas', 'Disease', 'MESH:D008545', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('NRAS', 'Gene', (119, 123))	('melanomas', 'Disease', (46, 55))	('BRAF', 'Gene', (110, 114))
59791	33578810	However, the clinical correlates of BRAF and NRAS mutations in melanoma BM are limited.	('BRAF', 'Gene', (36, 40))	('mutations', 'Var', (50, 59))	('NRAS', 'Gene', (45, 49))	('melanoma BM', 'Disease', (63, 74))	('melanoma BM', 'Disease', 'MESH:D008545', (63, 74))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))
59792	33578810	Fang and colleagues recently described the relationship between tumor BRAF/NRAS mutation status, clinical characteristics and response to conventional therapy in patients with melanoma BM.	('melanoma BM', 'Disease', (176, 187))	('patients', 'Species', '9606', (162, 170))	('melanoma BM', 'Disease', 'MESH:D008545', (176, 187))	('tumor BRAF', 'Disease', (64, 74))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('tumor BRAF', 'Disease', 'MESH:D009369', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mutation', 'Var', (80, 88))
59793	33578810	The authors resumed that either an activating BRAF mutation or an NRAS mutation significantly increases the local failure rate compared to patients who carried tumors that were wildtype for both genes.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('BRAF', 'Gene', (46, 50))	('patients', 'Species', '9606', (139, 147))	('activating', 'PosReg', (35, 45))	('increases', 'PosReg', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mutation', 'Var', (51, 59))	('local failure rate', 'CPA', (108, 126))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
59795	33578810	ARID1A mutations were first reported in ovarian clear cell carcinoma and subsequently described in endometrium-derived carcinomas.	('carcinomas', 'Disease', (119, 129))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (40, 68))	('ARID1A', 'Gene', '8289', (0, 6))	('described', 'Reg', (86, 95))	('reported', 'Reg', (28, 36))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('ARID1A', 'Gene', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinomas', 'Disease', 'MESH:D009369', (119, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('ovarian clear cell carcinoma', 'Disease', (40, 68))	('mutations', 'Var', (7, 16))
59798	33578810	Moreover, recent data reported by Shen and colleagues correlate loss-of-function mutations in ARID1A with the efficacy of anti-PD1 therapy, as a result of enhanced intratumoral lymphocyte recruitment and up-regulation of PD-L1 in preclinical models of ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (252, 266))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('PD-L1', 'Gene', '29126', (221, 226))	('ovarian cancer', 'Disease', (252, 266))	('up-regulation', 'PosReg', (204, 217))	('loss-of-function', 'NegReg', (64, 80))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('enhanced', 'PosReg', (155, 163))	('ovarian cancer', 'Phenotype', 'HP:0100615', (252, 266))	('regulation', 'biological_process', 'GO:0065007', ('207', '217'))	('ARID1A', 'Gene', '8289', (94, 100))	('tumor', 'Disease', (169, 174))	('mutations', 'Var', (81, 90))	('ARID1A', 'Gene', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('PD-L1', 'Gene', (221, 226))
59800	33578810	In addition to ARID1A mutations, our data also indicated variants of unknown significance in other components of the SWI/SNF complex, such as ARID2 and SMARCA4.	('ARID1A', 'Gene', (15, 21))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('117', '132'))	('SMARCA4', 'Gene', (152, 159))	('mutations', 'Var', (22, 31))	('SMARCA4', 'Gene', '6597', (152, 159))	('variants', 'Var', (57, 65))	('NF', 'Gene', '23114', (122, 124))	('ARID1A', 'Gene', '8289', (15, 21))
59801	33578810	Single nucleotide modifications in ARID2 and SMARCA4, all of unknown function but together with mutated splice site and frameshifts events often summarized and reviewed as "loss-of-function mutations", have already been reported in extracranial melanomas.	('ARID2', 'Gene', (35, 40))	('melanomas', 'Phenotype', 'HP:0002861', (245, 254))	('SMARCA4', 'Gene', (45, 52))	('melanomas', 'Disease', 'MESH:D008545', (245, 254))	('SMARCA4', 'Gene', '6597', (45, 52))	('Single nucleotide modifications', 'Var', (0, 31))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('melanomas', 'Disease', (245, 254))	('loss-of-function', 'NegReg', (173, 189))
59802	33578810	In summary, 11/54 (20%, Figure 2A) and 6 of the 11 patient-matched brain pairs (55%, Figure 2B) of our discovery samples harbored genetic modifications in a component of the SWI/SNF machinery, implicating a potential role for dysregulation of chromatin remodeling in promoting the formation of melanoma CNS metastases.	('modifications', 'Var', (138, 151))	('NF', 'Gene', '23114', (179, 181))	('chromatin', 'cellular_component', 'GO:0000785', ('243', '252'))	('dysregulation', 'Var', (226, 239))	('genetic modifications', 'Var', (130, 151))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('melanoma CNS metastases', 'Disease', (294, 317))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('243', '263'))	('patient', 'Species', '9606', (51, 58))	('harbored', 'Reg', (121, 129))	('formation', 'biological_process', 'GO:0009058', ('281', '290'))	('promoting', 'PosReg', (267, 276))	('melanoma CNS metastases', 'Disease', 'MESH:D009362', (294, 317))
59806	33578810	In 2 of 16 paired patient samples, we found mutations of unknown relevance in BAP1 which were absent in the corresponding extracranial metastases.	('metastases', 'Disease', (135, 145))	('metastases', 'Disease', 'MESH:D009362', (135, 145))	('patient', 'Species', '9606', (18, 25))	('mutations', 'Var', (44, 53))	('BAP1', 'Gene', '8314', (78, 82))	('BAP1', 'Gene', (78, 82))
59807	33578810	In both cases, we detected single nucleotide changes A > T or C > T in position 52436829 (protein change V295M and L650H).	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('A > T', 'Var', (53, 58))	('V295M', 'Mutation', 'rs746925345', (105, 110))	('L650H', 'Mutation', 'p.L650H', (115, 120))	('L650H', 'Var', (115, 120))	('C > T', 'Var', (62, 67))
59808	33578810	Germline pathogenic variants and somatic mutations in the BAP1 gene have been described in ocular and cutaneous melanoma and paralleled with a highly aggressive ocular melanoma phenotype but also detected in several other cancer subtypes.	('variants', 'Var', (20, 28))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('BAP1', 'Gene', (58, 62))	('cancer', 'Disease', (222, 228))	('ocular melanoma', 'Phenotype', 'HP:0007716', (161, 176))	('aggressive ocular melanoma', 'Disease', 'MESH:D008545', (150, 176))	('described', 'Reg', (78, 87))	('ocular', 'Disease', (91, 97))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('aggressive ocular melanoma', 'Disease', (150, 176))	('cutaneous melanoma', 'Disease', (102, 120))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('BAP1', 'Gene', '8314', (58, 62))
59828	33578810	Mutations in ARID1A, ARID2, BRAF, SMARCA4, TERT and IDH1 were significantly exclusive to intracranial metastases while the same variants remained undetected in the corresponding extracranial tumor tissues.	('ARID2', 'Gene', (21, 26))	('ARID1A', 'Gene', '8289', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('ARID1A', 'Gene', (13, 19))	('SMARCA4', 'Gene', (34, 41))	('SMARCA4', 'Gene', '6597', (34, 41))	('metastases', 'Disease', (102, 112))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('BRAF', 'Gene', (28, 32))	('IDH1', 'Gene', (52, 56))	('metastases', 'Disease', 'MESH:D009362', (102, 112))
59829	33578810	We also detected previously not described genetic variants in the "hot spot" oncogenic driver genes private to melanoma brain metastases.	('melanoma brain metastases', 'Disease', (111, 136))	('melanoma brain metastases', 'Disease', 'MESH:D009362', (111, 136))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('variants', 'Var', (50, 58))
59830	33578810	Analyses of large cancer sequencing data sets of primary CNS tumors point the significance of our novel variants for tumor establishment in the brain.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('CNS tumors', 'Disease', 'MESH:D016543', (57, 67))	('tumor', 'Disease', (117, 122))	('variants', 'Var', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('CNS tumors', 'Disease', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (18, 24))	('tumor', 'Disease', (61, 66))
59839	33393969	Diagnostic sensitivity and specificity were highest for abnormalities in digital fundus photography, visual field loss within the central 10 , and decrease in vessel density.	('visual field loss', 'Disease', 'MESH:D014786', (101, 118))	('abnormalities', 'Var', (56, 69))	('decrease', 'NegReg', (147, 155))	('visual field loss', 'Disease', (101, 118))	('vessel', 'MPA', (159, 165))	('digital fundus photography', 'CPA', (73, 99))	('abnormalities in digital', 'Phenotype', 'HP:0011297', (56, 80))
59926	33393969	Importantly, by the latest time point, more patients were classed as having abnormalities by fundus photograph evaluation (64%), loss of visual function by 10-2 visual field (52%), and deep learning-derived vascularity (48%), whereas far fewer subjects were classed abnormal by FAZ area, parafoveal density, and change in visual acuity by ETDRS (24%, 24%, and 16%, respectively).	('patients', 'Species', '9606', (44, 52))	('deep learning-derived vascularity', 'CPA', (185, 218))	('abnormalities', 'Var', (76, 89))	('loss', 'NegReg', (129, 133))	('abnormalities by fundus', 'Phenotype', 'HP:0001098', (76, 99))	('FAZ', 'cellular_component', 'GO:0120119', ('278', '281'))	('visual function', 'MPA', (137, 152))
59946	33393969	Not surprisingly, because of our combined use of a control cohort and normalization to the fellow, untreated eye, changes in the FAZ area and parafoveal density, previously proposed as signs of early microvasculopathy, were significantly less sensitive in detecting early abnormalities than our other readouts of capillary drop-out.	('less', 'NegReg', (238, 242))	('capillary drop', 'Phenotype', 'HP:0030005', (313, 327))	('FAZ', 'cellular_component', 'GO:0120119', ('129', '132'))	('microvasculopathy', 'Disease', (200, 217))	('changes', 'Var', (114, 121))	('microvasculopathy', 'Disease', 'None', (200, 217))
59975	33203661	For example, BRAF and NRAS mutations commonly detected in CM, rarely appear in UM, while GNAQ and GNA11 mutations are found in approximately 80% of UM.	('mutations', 'Var', (27, 36))	('GNAQ', 'Gene', '2776', (89, 93))	('GNA11', 'Gene', (98, 103))	('BRAF', 'Gene', '673', (13, 17))	('GNA11', 'Gene', '2767', (98, 103))	('NRAS', 'Gene', (22, 26))	('BRAF', 'Gene', (13, 17))	('GNAQ', 'Gene', (89, 93))	('NRAS', 'Gene', '4893', (22, 26))
60016	33203661	CD3+, CD8+, CD68+, and FoxP3+ infiltrates were detected in all available treatment-naive metastatic UM tumors (table 1).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('UM tumors', 'Disease', (100, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('CD3', 'Gene', (0, 3))	('UM tumors', 'Disease', 'MESH:D009369', (100, 109))	('CD8', 'Gene', (6, 9))	('CD68+', 'Var', (12, 17))	('CD8', 'Gene', '925', (6, 9))	('CD3', 'Gene', '397455', (0, 3))
60085	33203661	UM has been shown to present a limited mutational load compared with CM, which may contribute to low tumor immunogenicity in UM.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('low tumor', 'Disease', (97, 106))	('mutational load', 'Var', (39, 54))	('low tumor', 'Disease', 'MESH:D009800', (97, 106))
60094	33203661	A study from Coupland's group showed that CD68+ and CD163+ tumor-associated macrophages were seen in all tested UM metastases.	('metastases', 'Disease', (115, 125))	('tumor', 'Disease', (59, 64))	('metastases', 'Disease', 'MESH:D009362', (115, 125))	('CD163', 'Gene', '9332', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('CD163', 'Gene', (52, 57))	('CD68+', 'Var', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
60096	33203661	CD8+ TILs were few in number within metastatic UMs but were predominantly seen peritumorally at the interface of tumor and normal liver, whereas CD4+ TIL showed a high perivascular density within metastatic UMs.	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('CD8', 'Gene', (0, 3))	('CD8', 'Gene', '925', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('high perivascular density', 'Phenotype', 'HP:0012520', (163, 188))	('CD4+', 'Var', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
60100	33203661	Several studies have indicated that tumor-infiltrating CD4+CD25+FoxP3+Tregs are associated with decreased survival of various malignancies.	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('CD4+CD25+FoxP3+Tregs', 'Gene', (55, 75))	('decreased', 'NegReg', (96, 105))	('survival', 'CPA', (106, 114))	('CD4+CD25+FoxP3+Tregs', 'Var', (55, 75))	('malignancies', 'Disease', (126, 138))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Tregs', 'Chemical', '-', (70, 75))	('tumor', 'Disease', (36, 41))
60102	33203661	Tregs can also induce an immunosuppressive phenotype in other cell types such as macrophages.	('Tregs', 'Chemical', '-', (0, 5))	('Tregs', 'Var', (0, 5))	('induce', 'Reg', (15, 21))	('immunosuppressive phenotype', 'MPA', (25, 52))
60103	33203661	Our analysis found that FoxP3+ infiltrates in UM tumors were positively associated with CD3+ and CD8+ infiltrates (online supplemental figure S2A, B).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('UM tumors', 'Disease', (46, 55))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('associated', 'Reg', (72, 82))	('CD3', 'Gene', '397455', (88, 91))	('UM tumors', 'Disease', 'MESH:D009369', (46, 55))	('CD8', 'Gene', (97, 100))	('CD3', 'Gene', (88, 91))	('FoxP3+ infiltrates', 'Var', (24, 42))	('CD8', 'Gene', '925', (97, 100))
60107	33203661	In a pilot study analyzing one UM responder's tumor tissue to anti-PD-1 therapy, Stern's group identified that germline MBD4 mutation might correlate with response to immune checkpoint inhibitor; this data needs to be validated in a larger cohort of UM patients.	('correlate with', 'Reg', (140, 154))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('MBD4', 'Gene', '8930', (120, 124))	('MBD4', 'Gene', (120, 124))	('tumor', 'Disease', (46, 51))	('patients', 'Species', '9606', (253, 261))	('response to', 'MPA', (155, 166))	('mutation', 'Var', (125, 133))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
60111	33203661	For example, immunization with SOCS1-/- dendritic cells induces a hyper Th1 immune response, lupus-like autoimmune disease, and anti-tumor activity.	('lupus-like autoimmune disease', 'Disease', 'MESH:D001327', (93, 122))	('autoimmune disease', 'Phenotype', 'HP:0002960', (104, 122))	('SOCS1-/-', 'Var', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('hyper', 'CPA', (66, 71))	('induces', 'Reg', (56, 63))	('Th1 immune response', 'biological_process', 'GO:0042088', ('72', '91'))	('tumor', 'Disease', (133, 138))	('lupus-like autoimmune disease', 'Disease', (93, 122))
60113	33203661	Various in vivo studies showed that deletion or suppression of SOCS1 in either myeloid cells or T cells enhanced anti-tumor immunity.	('SOCS1', 'Gene', (63, 68))	('deletion', 'Var', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('suppression', 'NegReg', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('enhanced', 'PosReg', (104, 112))	('tumor', 'Disease', (118, 123))
60117	33203661	A couple of studies showed that SOCS1 gene methylation and histone H3K9 methylation caused gene silencing of SOCS1 in myeloid leukemia cells.	('SOCS1', 'Gene', (109, 114))	('histone H3K9', 'Protein', (59, 71))	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))	('methylation', 'Var', (43, 54))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('myeloid leukemia', 'Disease', (118, 134))	('histone H3K9 methylation', 'biological_process', 'GO:0051567', ('59', '83'))	('gene', 'MPA', (91, 95))	('SOCS1', 'Gene', (32, 37))	('myeloid leukemia', 'Disease', 'MESH:D007951', (118, 134))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (118, 134))	('gene silencing', 'biological_process', 'GO:0016458', ('91', '105'))
60179	32681390	The risk of male breast cancer was increased for trichloroethylene; OR 1.4 (95% CI 0.7-2.5) for low, and OR 1.9 (95% CI 1.1-3.3) for high score.	('trichloroethylene', 'Var', (49, 66))	('OR 1.4', 'Gene', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('trichloroethylene', 'Chemical', 'MESH:D014241', (49, 66))	('male breast cancer', 'Disease', 'MESH:D018567', (12, 30))	('OR 1.9', 'Gene', '391110', (105, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('OR 1.4', 'Gene', '391107', (68, 74))	('low', 'Var', (96, 99))	('male breast cancer', 'Disease', (12, 30))	('high score', 'Var', (133, 143))	('OR 1.9', 'Gene', (105, 111))
60197	32681390	Alcohol consumption is high in countries included in the Rare Cancer Study, and the risk of male breast cancer increased with alcohol consumption, being more than fivefold for 9 + drinks/day compared with < 1.5 drinks/day; OR 5.62 (95% 1.54-20.52),, Table 3.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('9 + drinks/day', 'Var', (176, 190))	('Cancer', 'Disease', (62, 68))	('alcohol', 'Chemical', 'MESH:D000438', (126, 133))	('Cancer', 'Disease', 'MESH:D009369', (62, 68))	('male breast cancer', 'Disease', 'MESH:D018567', (92, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))	('male breast cancer', 'Disease', (92, 110))
60217	32681390	A French JEM was used in the male breast cancer study to aggregate persons from occupations exposed to organic solvents; indicating an association with trichloroethylene; high exposure OR 1.9 (95% CI 1.1-3.3).	('persons', 'Species', '9606', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('trichloroethylene', 'Var', (152, 169))	('OR 1.9', 'Gene', (185, 191))	('OR 1.9', 'Gene', '391110', (185, 191))	('male breast cancer', 'Disease', 'MESH:D018567', (29, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('trichloroethylene', 'Chemical', 'MESH:D014241', (152, 169))	('male breast cancer', 'Disease', (29, 47))	('association', 'Interaction', (135, 146))
60279	32681390	Glutathione S-transferase genotype and p53 mutations in adenocarcinoma of the small intestine.	('Glutathione', 'Chemical', 'MESH:D005978', (0, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('mutations', 'Var', (43, 52))	('p53', 'Gene', (39, 42))	('adenocarcinoma', 'Disease', (56, 70))	('p53', 'Gene', '7157', (39, 42))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))	('adenocarcinoma of the small intestine', 'Phenotype', 'HP:0040274', (56, 93))
60321	31861092	Moreover, the genetic deletion of both PDGF-B and PDGFR-beta in mice leads to perinatal death due to vascular dysfunction, and the ablation of endothelial-derived PDGF-B causes the reduction of retinal pericyte coverage, resulting in the change of capillary and venous diameter, microaneurysms, and proliferative retinopathy, thus confirming the key role played by pericytes in angiogenesis and vessel stabilization.	('PDGF-B', 'Gene', (39, 45))	('angiogenesis', 'biological_process', 'GO:0001525', ('378', '390'))	('microaneurysms', 'CPA', (279, 293))	('ret', 'Gene', '19713', (313, 316))	('ablation', 'Var', (131, 139))	('proliferative retinopathy', 'Disease', 'OMIM:612623', (299, 324))	('ret', 'Gene', '19713', (194, 197))	('proliferative retinopathy', 'Disease', (299, 324))	('PDGF', 'molecular_function', 'GO:0005161', ('163', '167'))	('ret', 'Gene', (313, 316))	('vascular dysfunction', 'Disease', (101, 121))	('PDGFR-beta', 'Gene', (50, 60))	('PDGF-B', 'Gene', (163, 169))	('ret', 'Gene', (194, 197))	('PDGF', 'molecular_function', 'GO:0005161', ('39', '43'))	('mice', 'Species', '10090', (64, 68))	('vascular dysfunction', 'Disease', 'MESH:D014652', (101, 121))	('retinopathy', 'Phenotype', 'HP:0000488', (313, 324))	('reduction', 'NegReg', (181, 190))	('change', 'Reg', (238, 244))
60337	31861092	VEGFR-2 activation is transduced mainly through the phosphorylation of several tyrosines such as the selective tyrosine Y951 (in the kinase insert domain) and tyrosines Y1175 and Y1214 (in the carboxy-terminal domain), mediating endothelial permeability and proliferation.	('carboxy', 'Chemical', 'MESH:C015732', (193, 200))	('activation', 'PosReg', (8, 18))	('tyrosine Y951', 'Var', (111, 124))	('VEGFR-2', 'Gene', (0, 7))	('tyrosines Y1175', 'Var', (159, 174))	('tyrosines', 'Chemical', 'None', (159, 168))	('mediating', 'Reg', (219, 228))	('tyrosine', 'Chemical', 'None', (159, 167))	('tyrosine', 'Chemical', 'None', (79, 87))	('phosphorylation', 'biological_process', 'GO:0016310', ('52', '67'))	('tyrosine', 'Chemical', 'None', (111, 119))	('phosphorylation', 'MPA', (52, 67))	('VEGFR-2', 'Gene', '3791', (0, 7))	('tyrosines', 'Chemical', 'None', (79, 88))	('Y1214', 'Var', (179, 184))
60343	31861092	An in vitro study showed that membrane permeabilization and the following administration of adenosine triphosphate (ATP) caused selective contraction of pericytes but not of other cells (i.e., endothelial and epithelial cells) under the same conditions, thus confirming the contractile properties of pericytes.	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (92, 114))	('pericytes', 'CPA', (153, 162))	('contraction', 'NegReg', (138, 149))	('ATP', 'Chemical', 'MESH:D000255', (116, 119))	('membrane permeabilization', 'Var', (30, 55))	('membrane', 'cellular_component', 'GO:0016020', ('30', '38'))
60356	31861092	In an in vitro model of a bacterial infection of the BBB, on the basis of co-culturing endothelial cells and pericytes, E. coli invasion induced pericyte loss, and consequently a TEER decrease and BBB permeability increase.	('decrease', 'NegReg', (184, 192))	('BBB', 'CPA', (197, 200))	('TEER', 'MPA', (179, 183))	('bacterial infection', 'Phenotype', 'HP:0002718', (26, 45))	('increase', 'PosReg', (214, 222))	('pericyte', 'CPA', (145, 153))	('E. coli', 'Species', '562', (120, 127))	('E. coli', 'Var', (120, 127))	('loss', 'NegReg', (154, 158))	('bacterial infection', 'Disease', 'MESH:D001424', (26, 45))	('bacterial infection', 'Disease', (26, 45))
60360	31861092	Pericyte coverage is crucial during embryogenesis, in fact, in PDGFR-beta mouse mutants, the permeability through the BBB dramatically increases in the CNS.	('embryogenesis', 'biological_process', 'GO:0009793', ('36', '49'))	('mutants', 'Var', (80, 87))	('increases', 'PosReg', (135, 144))	('embryogenesis', 'biological_process', 'GO:0009792', ('36', '49'))	('PDGFR-beta', 'Gene', (63, 73))	('mouse', 'Species', '10090', (74, 79))	('embryogenesis', 'biological_process', 'GO:0009790', ('36', '49'))	('permeability through the BBB', 'MPA', (93, 121))
60361	31861092	In PDGF-B transgenic mice, the loss of pericyte coverage in the BRB is associated with reduced neuronal layers and a folding photoreceptor layer, signs that can be compared to diabetic retinopathy.	('transgenic', 'Var', (10, 20))	('diabetic retinopathy', 'Disease', 'MESH:D003930', (176, 196))	('loss', 'NegReg', (31, 35))	('PDGF', 'molecular_function', 'GO:0005161', ('3', '7'))	('retinopathy', 'Phenotype', 'HP:0000488', (185, 196))	('reduced', 'NegReg', (87, 94))	('transgenic mice', 'Species', '10090', (10, 25))	('pericyte coverage', 'CPA', (39, 56))	('PDGF-B', 'Gene', (3, 9))	('neuronal layers', 'CPA', (95, 110))	('diabetic retinopathy', 'Disease', (176, 196))
60366	31861092	The fact that MSCs have a perivascular origin has been demonstrated by the expression of the surface molecules commonly used as MSC markers, CD44, CD73, CD90, and CD105, in perivascular cells that are natively expressed.	('CD73', 'Gene', '4907', (147, 151))	('CD90', 'Gene', '7070', (153, 157))	('CD105', 'Var', (163, 168))	('CD90', 'Gene', (153, 157))	('CD73', 'Gene', (147, 151))	('CD44', 'Gene', '960', (141, 145))	('MSCs', 'molecular_function', 'GO:0043854', ('14', '18'))	('CD44', 'Gene', (141, 145))
60436	31861092	In this regard, it has been reported that the loss of pericytes leads to an unexpected increase in tumor growth in mouse models.	('tumor', 'Disease', (99, 104))	('increase', 'PosReg', (87, 95))	('loss', 'Var', (46, 50))	('mouse', 'Species', '10090', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('pericytes', 'Protein', (54, 63))
60437	31861092	In pancreatic tumor-bearing mice, the deficiency of pericyte marker G-protein signaling 5 (Rgs5, a gene responsible for the aberrant tumor vasculature in mice), results in pericyte maturation, vascular normalization, and a marked reduction of hypoxia.	('deficiency', 'Var', (38, 48))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('aberrant tumor vasculature', 'Disease', (124, 150))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('reduction of hypoxia', 'Disease', (230, 250))	('vascular normalization', 'CPA', (193, 215))	('mice', 'Species', '10090', (28, 32))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (3, 19))	('Rgs5', 'Gene', (91, 95))	('mice', 'Species', '10090', (154, 158))	('pancreatic tumor', 'Disease', (3, 19))	('Rgs', 'molecular_function', 'GO:0016299', ('91', '94'))	('Rgs5', 'Gene', '19737', (91, 95))	('aberrant tumor vasculature', 'Disease', 'MESH:C565633', (124, 150))	('pancreatic tumor', 'Disease', 'MESH:D010190', (3, 19))	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('pericyte maturation', 'CPA', (172, 191))	('reduction of hypoxia', 'Disease', 'MESH:D000860', (230, 250))
60460	31861092	After pericyte-specific deletion of Tie-2, the amount of pericytes covering the retinal microvessel is strongly reduced, leading to delayed retinal vascularization.	('ret', 'Gene', '19713', (80, 83))	('retinal vascularization', 'Phenotype', 'HP:0030666', (140, 163))	('ret', 'Gene', (140, 143))	('Tie-2', 'Gene', '7010', (36, 41))	('Tie-2', 'Gene', (36, 41))	('deletion', 'Var', (24, 32))	('delayed', 'NegReg', (132, 139))	('reduced', 'NegReg', (112, 119))	('ret', 'Gene', '19713', (140, 143))	('ret', 'Gene', (80, 83))
60479	31861092	In particular, in PDGF-Bret/ret transgenic mice (PDGF-B mutant), characterized by microvessels with defective pericyte coverage, no invasion by melanoma cells in bone marrow and liver was observed, demonstrating that the presence of pericytes is required for the extravasation of melanoma cells.	('ret', 'Gene', '19713', (28, 31))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('Bret', 'Gene', '227325', (23, 27))	('transgenic mice', 'Species', '10090', (32, 47))	('melanoma', 'Phenotype', 'HP:0002861', (280, 288))	('melanoma', 'Disease', (280, 288))	('mutant', 'Var', (56, 62))	('PDGF', 'molecular_function', 'GO:0005161', ('18', '22'))	('PDGF', 'molecular_function', 'GO:0005161', ('49', '53'))	('melanoma', 'Disease', 'MESH:D008545', (280, 288))	('Bret', 'Gene', (23, 27))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('ret', 'Gene', (24, 27))	('ret', 'Gene', (28, 31))	('ret', 'Gene', '19713', (24, 27))	('PDGF-B', 'Gene', (49, 55))
60503	31839882	Consistent with that study were previous publications showing that high expression of immune gene signatures was associated with favorable prognosis in breast and colorectal cancer.	('high', 'Var', (67, 71))	('breast and colorectal cancer', 'Disease', 'MESH:D001943', (152, 180))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('immune gene signatures', 'Gene', (86, 108))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
60528	31839882	CTNNB1 gene mutation has been shown to be associated with low immune response.	('CTNNB1', 'Gene', '1499', (0, 6))	('low immune response', 'CPA', (58, 77))	('low immune response', 'Phenotype', 'HP:0002721', (58, 77))	('CTNNB1', 'Gene', (0, 6))	('immune response', 'biological_process', 'GO:0006955', ('62', '77'))	('mutation', 'Var', (12, 20))
60529	31839882	On the other hand, patients with POLE gene mutations had higher immune activity and were associated with favorable prognosis compared with patients without POLE mutations.	('patients', 'Species', '9606', (19, 27))	('immune activity', 'MPA', (64, 79))	('higher', 'PosReg', (57, 63))	('patients', 'Species', '9606', (139, 147))	('mutations', 'Var', (43, 52))	('POLE gene', 'Gene', (33, 42))
60566	31839882	MHC class I molecules, including HLA-A, -B, and -C, present peptides from inside the cell to T lymphocytes, while MHC class II molecules (HLA-DP, -DM, -DO, -DQ, and -DR) present antigens from outside the cell.	('peptides', 'MPA', (60, 68))	('HLA-DP', 'Var', (138, 144))	('HLA-A, -B, and -C', 'Gene', '3105;3106;3107', (33, 50))
60631	31146793	In a small subset of select cases, resection of hepatic lesions may offer enhanced long-term survival; however, very few cases are likely to benefit from resection overall.	('resection', 'Var', (35, 44))	('enhanced', 'PosReg', (74, 82))	('hepatic lesions', 'Disease', (48, 63))	('hepatic lesions', 'Disease', 'MESH:D056486', (48, 63))
60637	31146793	In hepatic metastases of uveal melanoma, CS-PHP with melphalan has been reported to have response rates of up to 83% as well as improved local tumor control.	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('tumor', 'Disease', (143, 148))	('CS-PHP', 'Chemical', '-', (41, 47))	('melphalan', 'Chemical', 'MESH:D008558', (53, 62))	('improved', 'PosReg', (128, 136))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('CS-PHP', 'Var', (41, 47))	('hepatic metastases of uveal melanoma', 'Disease', (3, 39))	('hepatic metastases of uveal melanoma', 'Disease', 'MESH:D009362', (3, 39))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
60638	31146793	Recently, a large trial with 93 enrolled patients additionally reported superior rates of hepatic progression-free survival (hPFS) in patients with liver-predominant ocular or cutaneous melanoma treated with CS-PHP compared to best alternative care (arterial embolization, systemic chemotherapy, and symptomatic care via supportive measure only).	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('superior', 'PosReg', (72, 80))	('liver-predominant ocular', 'Disease', (148, 172))	('cutaneous melanoma', 'Disease', (176, 194))	('CS-PHP', 'Chemical', '-', (208, 214))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (176, 194))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (176, 194))	('arterial embolization', 'Phenotype', 'HP:0004420', (250, 271))	('patients', 'Species', '9606', (134, 142))	('patients', 'Species', '9606', (41, 49))	('hepatic progression-free survival', 'MPA', (90, 123))	('CS-PHP', 'Var', (208, 214))
60710	31146793	However, it is particularly important to recognize that CS-PHP causes substantial stress on the cardiovascular system.	('stress', 'MPA', (82, 88))	('CS-PHP', 'Var', (56, 62))	('CS-PHP', 'Chemical', '-', (56, 62))
60737	30702560	M2-type was considered to have a tumor-promoting role rather than an effective immune response.	('immune response', 'biological_process', 'GO:0006955', ('79', '94'))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('M2-type', 'Var', (0, 7))
60829	29033534	Ki-67 staining was performed using the Envision + Dual Link HRP (K4065, Dako, Glostrup, Denmark) and AEC + Substrate chromogen ready-to-use (k3461, Dako).	('K4065', 'Var', (65, 70))	('k3461', 'Var', (141, 146))	('K4065', 'Chemical', '-', (65, 70))	('AEC', 'Chemical', 'MESH:C020702', (101, 104))
60905	29033534	The link between ANGPTL4 and EMT has recently been highlighted as a decrease in EMT markers and aggressiveness after silencing of ANGPTL4 in non-small cell lung cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (145, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('silencing', 'Var', (117, 126))	('EMT', 'biological_process', 'GO:0001837', ('29', '32'))	('decrease', 'NegReg', (68, 76))	('aggressiveness', 'Disease', 'MESH:D001523', (96, 110))	('EMT', 'Protein', (80, 83))	('EMT', 'biological_process', 'GO:0001837', ('80', '83'))	('aggressiveness', 'Disease', (96, 110))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (141, 167))	('aggressiveness', 'Phenotype', 'HP:0000718', (96, 110))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (141, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('ANGPTL4', 'Gene', (130, 137))	('non-small cell lung cancer', 'Disease', (141, 167))
60977	28125874	Once the tumor was located and its dimensions and distance to the optic nerve and fovea checked to be suitable for plaque BT, the Ru-106 plaque was sewn onto the sclera to cover the tumor's base with a minimal margin of 1 mm around the tumor borders (Figure 2).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('Ru-106', 'Chemical', 'MESH:C000615522', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Disease', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (236, 241))	('Ru-106', 'Var', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
61004	28125874	In a retrospective study comparing outcomes of patients with choroidal melanoma treated with I-125, Ru-106 BT, or proton beam radiation therapy (PBRT) (Wilson and Hungerford, 1999), patients treated with PBRT had a more rapid and substantial loss of vision than those treated with BT.	('Wilson', 'Disease', (152, 158))	('PBRT', 'Var', (204, 208))	('I-125', 'Chemical', 'MESH:C000614960', (93, 98))	('choroidal melanoma', 'Disease', 'MESH:D008545', (61, 79))	('Wilson', 'Disease', 'MESH:D006527', (152, 158))	('loss of vision', 'Disease', 'MESH:D014786', (242, 256))	('choroidal melanoma', 'Disease', (61, 79))	('patients', 'Species', '9606', (47, 55))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('vision', 'biological_process', 'GO:0007601', ('250', '256'))	('patients', 'Species', '9606', (182, 190))	('substantial loss of vision', 'Phenotype', 'HP:0001141', (230, 256))	('loss of vision', 'Phenotype', 'HP:0000572', (242, 256))	('Ru-106', 'Chemical', 'MESH:C000615522', (100, 106))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (61, 79))	('loss of vision', 'Disease', (242, 256))
61011	28125874	In patients treated with Ru-106 plaques (as compared to I-125 or Pd-103), the dose deposition close to the plaque can be more than nine times the apex dose (table 3).	('dose deposition', 'MPA', (78, 93))	('Ru-106 plaques', 'Var', (25, 39))	('I-125', 'Chemical', 'MESH:C000614960', (56, 61))	('patients', 'Species', '9606', (3, 11))	('Ru-106', 'Chemical', 'MESH:C000615522', (25, 31))	('Pd-103', 'Chemical', 'MESH:C000615531', (65, 71))	('apex', 'cellular_component', 'GO:0097683', ('146', '150'))
61020	28125874	In a recent retrospective study including 143 eyes with UM treated with RU-106 plaque BT, the estimated local tumor recurrence rate at 12, 24 and 48 months after irradiation was 3%, 8.4% and 14.7%, respectively (Tarmann et al., 2015).	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('RU-106 plaque BT', 'Var', (72, 88))	('UM', 'Phenotype', 'HP:0007716', (56, 58))
61109	26960380	Five hours after surgery, the patient suddenly developed cyanosis, dyspnea, and lost consciousness, electrocardiogram (ECG) examination showed SIQIII [Figure 1, a2, a3] and incomplete right bundle branch block.	('cyanosis', 'Phenotype', 'HP:0000961', (57, 65))	('developed', 'Reg', (47, 56))	('patient', 'Species', '9606', (30, 37))	('dyspnea', 'Disease', (67, 74))	('cyanosis', 'Disease', (57, 65))	('SIQIII [', 'Var', (143, 151))	('lost consciousness', 'Phenotype', 'HP:0007185', (80, 98))	('dyspnea', 'Disease', 'MESH:D004417', (67, 74))	('bundle branch block', 'Phenotype', 'HP:0011710', (190, 209))	('lost', 'NegReg', (80, 84))	('right bundle branch block', 'Phenotype', 'HP:0011712', (184, 209))	('cyanosis', 'Disease', 'MESH:D003490', (57, 65))	('right bundle branch block', 'Disease', 'MESH:D002037', (184, 209))	('right bundle branch block', 'Disease', (184, 209))	('dyspnea', 'Phenotype', 'HP:0002094', (67, 74))
61162	26305875	Mutations in GNAQ/11 and in the BRCA1-associated protein-1 (BAP1) and disruption of epigenetic regulators have been suggested as possible events in UM metastasis.	('BRCA1-associated protein-1', 'Gene', (32, 58))	('GNAQ', 'Gene', (13, 17))	('GNAQ', 'Gene', '2776', (13, 17))	('UM', 'Phenotype', 'HP:0007716', (148, 150))	('disruption of epigenetic regulators', 'MPA', (70, 105))	('BAP1', 'Gene', '8314', (60, 64))	('Mutations', 'Var', (0, 9))	('BRCA1-associated protein-1', 'Gene', '8314', (32, 58))	('UM metastasis', 'CPA', (148, 161))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('BAP1', 'Gene', (60, 64))
61186	26305875	In this study, tryptic digests of each of the 15 tumors (~100 mug/specimen) were labeled individually with iTRAQ tags 115, 116, or 117 and mixed individually with an equal amount of tryptic digest from the pooled control sample labeled with iTRAQ tag 114.	('mug', 'molecular_function', 'GO:0043739', ('62', '65'))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('15 tumors', 'Disease', 'MESH:C567447', (46, 55))	('iTRAQ', 'Var', (107, 112))	('15 tumors', 'Disease', (46, 55))
61190	26305875	Fixed protein modifications included N-terminal and epsilon-Lys iTRAQ modifications and S-methyl-Cys.	('Cys', 'Chemical', 'MESH:D003545', (97, 100))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('N-terminal', 'MPA', (37, 47))	('epsilon-Lys iTRAQ modifications', 'MPA', (52, 83))	('S-methyl-Cys', 'Var', (88, 100))
61251	26305875	In addition, autoantibodies to cathepsin D, macrophage-capping protein and melanocyte protein PMEL have been reported in sera from UM patients.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('macrophage-capping protein', 'Gene', '822', (44, 70))	('UM', 'Phenotype', 'HP:0007716', (131, 133))	('melanocyte protein PMEL', 'Gene', '6490', (75, 98))	('melanocyte protein PMEL', 'Gene', (75, 98))	('macrophage-capping protein', 'Gene', (44, 70))	('cathepsin D', 'Gene', '1509', (31, 42))	('patients', 'Species', '9606', (134, 142))	('reported', 'Reg', (109, 117))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('sera', 'molecular_function', 'GO:0004617', ('121', '125'))	('autoantibodies', 'Var', (13, 27))	('cathepsin D', 'Gene', (31, 42))
61276	26305875	Alternative splicing of the collagen alpha-3(VI) gene has been suggested to have a mechanistic role in pancreatic cancer, and elevated serum protein levels to possibly offer biomarker potential.	('splicing', 'biological_process', 'GO:0045292', ('12', '20'))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('serum protein levels', 'MPA', (135, 155))	('pancreatic cancer', 'Disease', (103, 120))	('pancreatic cancer', 'Disease', 'MESH:D010190', (103, 120))	('collagen', 'molecular_function', 'GO:0005202', ('28', '36'))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('elevated', 'PosReg', (126, 134))	('Alternative splicing', 'Var', (0, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (103, 120))	('collagen alpha-3(VI', 'Gene', (28, 47))
61286	25903059	Characterization and identification of hidden rare variants in the human genome By examining the genotype calls generated by the 1000 Genomes Project we discovered that the human reference genome GRCh37 contains almost 20,000 loci in which the reference allele has never been observed in healthy individuals and around 70,000 loci in which it has been observed only in the heterozygous state.	('GRCh37', 'Gene', (196, 202))	('human', 'Species', '9606', (67, 72))	('variants', 'Var', (51, 59))	('human', 'Species', '9606', (173, 178))
61288	25903059	By using a small cancer dataset we compared our tool with two state-of-the-art callers and we found that RAREVATOR identified more than 1,500 germline and 22 somatic RRA variants missed by the two methods and which belong to significantly mutated pathways.	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('belong', 'Reg', (215, 221))	('variants', 'Var', (170, 178))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('mutated', 'Reg', (239, 246))
61290	25903059	Moreover, the investigation of the latest version of the human reference genome, GRCh38, showed that although the GRC corrected almost all insertions and a small part of SNVs and deletions, a large number of functionally relevant RRAs still remain unchanged.	('RRAs', 'Gene', '6237', (230, 234))	('deletions', 'Var', (179, 188))	('RRAs', 'Gene', (230, 234))	('insertions', 'Var', (139, 149))	('human', 'Species', '9606', (57, 62))
61295	25903059	Loss-of-function variants in homozygous state are the most common cause of autosomal recessive Mendelian disorders, while gain-of-function variants that change the gene product to a new and abnormal function usually lead to dominant Mendelian disorders.	('Mendelian disorders', 'Disease', (233, 252))	('Loss-of-function', 'NegReg', (0, 16))	('Mendelian disorders', 'Disease', 'MESH:D030342', (95, 114))	('autosomal recessive Mendelian disorders', 'Disease', (75, 114))	('variants', 'Var', (17, 25))	('Mendelian disorders', 'Disease', 'MESH:D030342', (233, 252))	('gain-of-function', 'PosReg', (122, 138))	('autosomal recessive Mendelian disorders', 'Disease', 'MESH:D030342', (75, 114))	('variants', 'Var', (139, 147))
61296	25903059	Moreover, both loss-of-function and gain-of-function mutations inherited in germline cells or acquired in somatic cells are often the starting events of cancer evolution and proliferation.	('gain-of-function', 'PosReg', (36, 52))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('mutations', 'Var', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('loss-of-function', 'NegReg', (15, 31))
61297	25903059	Functionally relevant variants responsible for mendelian disorders and cancer have been successfully identified by using the re-sequencing strategy.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('mendelian disorders', 'Disease', (47, 66))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mendelian disorders', 'Disease', 'MESH:D030342', (47, 66))	('variants', 'Var', (22, 30))
61304	25903059	In this work, we re-analyzed the complete set of these variant calls, and we found that more than 96000 loci of the GRCh37 assembly have a reference allele frequency smaller than 1% (here called Rare Reference Alleles, RRAs).	('variant', 'Var', (55, 62))	('RRAs', 'Gene', '6237', (219, 223))	('RRAs', 'Gene', (219, 223))	('GRCh37', 'Gene', (116, 122))
61307	25903059	We further searched for significantly mutated genes and pathways and showed that some of these RRA variants belong to signicantly mutated pathways and can thus have a role in human development and tumorigenesis.	('human', 'Species', '9606', (175, 180))	('belong', 'Reg', (108, 114))	('have', 'Reg', (160, 164))	('variants', 'Var', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('human development', 'CPA', (175, 192))	('role', 'Reg', (167, 171))	('RRA', 'Gene', (95, 98))	('tumor', 'Disease', (197, 202))
61315	25903059	Exonic SNVs such as missense mutations resulting in amino acid substitutions and nonsense mutations introducing new stop codons can seriously disrupt the function of human protein-coding genes.	('function', 'MPA', (154, 162))	('human', 'Species', '9606', (166, 171))	('missense mutations', 'Var', (20, 38))	('disrupt', 'NegReg', (142, 149))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('substitutions', 'Var', (63, 76))	('amino acid', 'MPA', (52, 62))
61316	25903059	This is particularly evident for microRNAs for which it has been shown that genetic changes are hallmark of cancers, but also variants in large intergenic non-coding RNAs (lincRNAs), small nucleolar RNAs (snoRNAs) and other ncRNAs might contribute to the development of many different human disorders.	('lincRNA', 'Chemical', '-', (172, 179))	('variants', 'Var', (126, 134))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('human', 'Species', '9606', (285, 290))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('contribute', 'Reg', (237, 247))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))
61321	25903059	For both SNVs and InDels, the most represented GAD class is Psychiatric followed by Chemdependency, Neurological, Metabolic, Immune and Cardiovascular classes.	('Psychiatric', 'Disease', (60, 71))	('SNVs', 'Var', (9, 13))	('Psychiatric', 'Disease', 'MESH:D001523', (60, 71))	('InDels', 'Var', (18, 24))
61326	25903059	To date, they have been mainly applied in cancer studies and the basic idea behind these methods consists in finding variant alleles that are present in the tumor sample but not in the matched control.	('tumor', 'Disease', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('variant', 'Var', (117, 124))
61329	25903059	Since these methods are devised to detect every kind of differences between normal and tumor samples, in principle, they are able to identify somatic variants that belong to RRA loci.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('variants', 'Var', (150, 158))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
61330	25903059	RAREVATOR is able to call germline RRA variants in single- and multi-samples experiments (germline mode) as well as somatic RRA variants in pairs of matched tumor and normal samples (somatic mode).	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('variants', 'Var', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
61332	25903059	Among the RRAs calls we also found variants that lead to protein functional consequences (missense and splicing) and variants that have a positive association with a complex phenotype annotated at the GAD (25 SNVs are associated with CANCER phenotype).	('CANCER', 'Phenotype', 'HP:0002664', (234, 240))	('variants', 'Var', (35, 43))	('CANCER', 'Disease', (234, 240))	('RRAs', 'Gene', (10, 14))	('RRAs', 'Gene', '6237', (10, 14))	('variants', 'Var', (117, 125))	('associated', 'Reg', (218, 228))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('protein functional consequences', 'MPA', (57, 88))	('splicing', 'biological_process', 'GO:0045292', ('103', '111'))
61333	25903059	Then we used RAREVATOR on the 18 matched tumor-normal pairs to identify somatic variants in RRA loci and we compared these results to those obtained by Mutect and VarScan2.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('variants', 'Var', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('RRA loci', 'Gene', (92, 100))
61334	25903059	RRA missense mutations affected five different genes: DCC, CR1, FAT2, GCC2 and CLCN1.	('FAT2', 'Gene', (64, 68))	('RRA', 'Gene', (0, 3))	('affected', 'Reg', (23, 31))	('CR1', 'Gene', (59, 62))	('DCC', 'Gene', (54, 57))	('missense mutations', 'Var', (4, 22))	('CR1', 'Gene', '1378', (59, 62))	('CLCN1', 'Gene', '1180', (79, 84))	('CLCN1', 'Gene', (79, 84))	('DCC', 'Gene', '1630', (54, 57))	('DCC', 'cellular_component', 'GO:0120206', ('54', '57'))	('GCC2', 'Gene', '9648', (70, 74))	('GCC2', 'Gene', (70, 74))	('FAT2', 'Gene', '2196', (64, 68))
61338	25903059	Surprisingly, four of the genes containing RRA missense mutaions in Uveal Melanoma (DCC, CR1, GCC2 and CLCN1) were predicted as diver genes in TCGA skin cutaneous melanoma dataset.	('Uveal Melanoma', 'Disease', (68, 82))	('CR1', 'Gene', '1378', (89, 92))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('Uveal Melanoma', 'Disease', 'MESH:C536494', (68, 82))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('DCC', 'Gene', (84, 87))	('DCC', 'cellular_component', 'GO:0120206', ('84', '87'))	('cutaneous melanoma', 'Disease', (153, 171))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (153, 171))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (153, 171))	('DCC', 'Gene', '1630', (84, 87))	('GCC2', 'Gene', '9648', (94, 98))	('missense mutaions', 'Var', (47, 64))	('GCC2', 'Gene', (94, 98))	('CLCN1', 'Gene', (103, 108))	('CLCN1', 'Gene', '1180', (103, 108))	('Melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('CR1', 'Gene', (89, 92))
61340	25903059	To evaluate the potential involvement of the RRA somatic mutations on the uveal melanoma tumorigenesis, we searched for significantly mutated genes (SMG) and pathways (SMP) that contain the RRA mutations.	('SMP', 'molecular_function', 'GO:0004193', ('168', '171'))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('mutations', 'Var', (194, 203))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('uveal melanoma', 'Disease', (74, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
61345	25903059	These results do not demonstrate at all that RRA mutations actively participate to the tumorigenesis in the Uveal Melanoma cancer, but the missing of these variants can seriously affect the identification of genes and pathways that might have an important role in tumorigenesis and cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RRA', 'Gene', (45, 48))	('Melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('mutations', 'Var', (49, 58))	('tumor', 'Disease', (264, 269))	('Uveal Melanoma', 'Disease', (108, 122))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('Uveal Melanoma', 'Disease', 'MESH:C536494', (108, 122))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('affect', 'Reg', (179, 185))	('Melanoma cancer', 'Disease', (114, 129))	('tumor', 'Disease', (87, 92))	('Melanoma cancer', 'Disease', 'MESH:C563985', (114, 129))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cancer', 'Disease', (282, 288))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('variants', 'Var', (156, 164))	('participate', 'Reg', (68, 79))	('cancer', 'Disease', (123, 129))
61346	25903059	The results described in previous section on a small cancer dataset demonstrated that the identification of mutations in RRA loci can affect the discovery of driver genes and pathways in cancer studies.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', (187, 193))	('mutations', 'Var', (108, 117))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('RRA loci', 'Gene', (121, 129))	('discovery', 'MPA', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('affect', 'Reg', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
61347	25903059	To obtain a global picture of the potential impact of RRA loci on biological processes and functional pathways, we selected all the genes in the human genome that contains at least one functionally relevant RRA loci (602 genes with at least one splicing, missense, nonsense or frameshift variant) and we searched for enriched gene sets.	('splicing', 'biological_process', 'GO:0045292', ('245', '253'))	('nonsense or frameshift variant', 'Var', (265, 295))	('missense', 'Var', (255, 263))	('human', 'Species', '9606', (145, 150))
61349	25903059	Strikingly, adhesion and interaction with extracellular matrix and surrounding cells are extremely important for integrity and homeostasis maintenance in normal tissues, and alterations in microenvironment and related functions are notoriously associated with cancer transformation and metastasis.	('metastasis', 'CPA', (286, 296))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('homeostasis', 'biological_process', 'GO:0042592', ('127', '138'))	('cancer', 'Disease', (260, 266))	('associated', 'Reg', (244, 254))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('42', '62'))	('alterations', 'Var', (174, 185))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))
61350	25903059	Strictly connected to cell cycle checkpoints, alterations of genes involved in this pathway support genetic instability and DNA damage tolerance, typically leading to death escape for tumor cells.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('death', 'Disease', 'MESH:D003643', (167, 172))	('leading to', 'Reg', (156, 166))	('death', 'Disease', (167, 172))	('genetic instability', 'CPA', (100, 119))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cell cycle', 'biological_process', 'GO:0007049', ('22', '32'))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('alterations', 'Var', (46, 57))	('tumor', 'Disease', (184, 189))	('DNA damage tolerance', 'CPA', (124, 144))	('support', 'Reg', (92, 99))
61355	25903059	All these genes with a missense or splicing RRA locus were predicted to be common driver genes in at least 11 or all the 12 cancer types taken into consideration, thus emphasizing their involvement in essential tumorigenic processes (Additional file 1: Table S6).	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('splicing', 'biological_process', 'GO:0045292', ('35', '43'))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('missense', 'Var', (23, 31))
61360	25903059	In the announcement (http://genomeref.blogspot.it), the GRC reports that "large scale studies of human variation, such as the 1000 Genomes Project, identified a number of bases and indels in GRCh37 that were never seen in any individuals, suggesting they may represent errors in the assembly."	('indels', 'Var', (181, 187))	('human', 'Species', '9606', (97, 102))	('bases', 'Var', (171, 176))	('GRCh37', 'Gene', (191, 197))
61364	25903059	The identification of variants with these technologies is based on comparing the reads produced by HTS platforms with the haploid sequence of the human reference genome and finding the bases that differ from the reference genome sequence.	('HTS', 'Disease', 'MESH:C537160', (99, 102))	('human', 'Species', '9606', (146, 151))	('variants', 'Var', (22, 30))	('HTS', 'Disease', (99, 102))
61365	25903059	HTS-based approaches have been successfully used to identify disease causing variants in mendelian disorders as well as in the study of genomic instability in cancer samples.	('cancer', 'Disease', (159, 165))	('variants', 'Var', (77, 85))	('mendelian disorders', 'Disease', (89, 108))	('HTS', 'Disease', 'MESH:C537160', (0, 3))	('disease causing', 'Reg', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('HTS', 'Disease', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('mendelian disorders', 'Disease', 'MESH:D030342', (89, 108))
61367	25903059	We studied the genomic complexity of the regions surrounding these loci and the geographical origins of their alleles and we found that their presence in the human reference assembly can be due to both sequencing errors and rare/private variants of the anonymous individuals used by the Human Genome Project.	('variants', 'Var', (237, 245))	('Human', 'Species', '9606', (287, 292))	('due', 'Reg', (190, 193))	('human', 'Species', '9606', (158, 163))
61370	25903059	To emphasize the impact that many of these loci could have on human health, we report some examples of RRA variants present in genes that have been demonstrated to be causative of neurological disorders and cancer.	('causative', 'Reg', (167, 176))	('neurological disorders', 'Disease', (180, 202))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('human', 'Species', '9606', (62, 67))	('RRA', 'Gene', (103, 106))	('variants', 'Var', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('neurological disorders', 'Disease', 'MESH:D009422', (180, 202))
61371	25903059	The ASPM gene, that is associated with primary autosomal recessive microcephaly type 5 and seizures, contains a missense RRA SNV of class B.	('autosomal recessive microcephaly type', 'Disease', 'MESH:C579935', (47, 84))	('seizures', 'Disease', (91, 99))	('seizures', 'Phenotype', 'HP:0001250', (91, 99))	('microcephaly type 5', 'Phenotype', 'HP:0005484', (67, 86))	('ASPM', 'Gene', '259266', (4, 8))	('microcephaly', 'Phenotype', 'HP:0000252', (67, 79))	('autosomal recessive microcephaly type', 'Disease', (47, 84))	('seizures', 'Disease', 'MESH:D012640', (91, 99))	('ASPM', 'Gene', (4, 8))	('associated', 'Reg', (23, 33))	('missense', 'Var', (112, 120))
61372	25903059	Another missense RRA SNV of class B belongs to FAT4 gene, whose biallelic disruption was recently associated with a human recessive syndrome including periventricular neuronal heterotopia.	('neuronal heterotopia', 'Phenotype', 'HP:0002282', (167, 187))	('periventricular neuronal heterotopia', 'Phenotype', 'HP:0007165', (151, 187))	('periventricular neuronal heterotopia', 'Disease', (151, 187))	('periventricular neuronal heterotopia', 'Disease', 'MESH:D054091', (151, 187))	('FAT4', 'Gene', (47, 51))	('FAT4', 'Gene', '79633', (47, 51))	('biallelic', 'Var', (64, 73))	('recessive syndrome', 'Disease', (122, 140))	('associated', 'Reg', (98, 108))	('recessive syndrome', 'Disease', 'OMIM:600791', (122, 140))	('human', 'Species', '9606', (116, 121))
61373	25903059	GRIA3, that is an important gene associated with a X-linked intellectual disability known as lissencephaly, and RECQL4, that is responsible for some cases of the autosomal recessive Rothmund-Thomson syndrome, contain a frameshift insertion and a splicing insertion of class B, respectively.	('GRIA3', 'Gene', '2892', (0, 5))	('RECQL4', 'Gene', '9401', (112, 118))	('lissencephaly', 'Disease', (93, 106))	('lissencephaly', 'Disease', 'MESH:D054082', (93, 106))	('GRIA3', 'Gene', (0, 5))	('autosomal recessive Rothmund-Thomson syndrome', 'Disease', 'MESH:D011038', (162, 207))	('lissencephaly', 'Phenotype', 'HP:0001339', (93, 106))	('frameshift insertion', 'Var', (219, 239))	('intellectual disability', 'Disease', (60, 83))	('autosomal recessive Rothmund-Thomson syndrome', 'Disease', (162, 207))	('splicing', 'MPA', (246, 254))	('intellectual disability', 'Disease', 'MESH:D008607', (60, 83))	('intellectual disability', 'Phenotype', 'HP:0001249', (60, 83))	('RECQL4', 'Gene', (112, 118))	('splicing', 'biological_process', 'GO:0045292', ('246', '254'))	('responsible', 'Reg', (128, 139))
61374	25903059	Among class A variants, we found missense, splicing and frameshift RRA loci in COL4A1, PIGN and ATM genes.	('ATM', 'Gene', '472', (96, 99))	('frameshift RRA', 'Var', (56, 70))	('COL4A1', 'Gene', '1282', (79, 85))	('variants', 'Var', (14, 22))	('splicing', 'biological_process', 'GO:0045292', ('43', '51'))	('PIGN', 'Gene', '23556', (87, 91))	('PIGN', 'Gene', (87, 91))	('splicing', 'Var', (43, 51))	('ATM', 'Gene', (96, 99))	('COL4A1', 'Gene', (79, 85))	('missense', 'Var', (33, 41))
61376	25903059	PIGN encodes a protein involved in glycosylphosphatidylinositol-anchor biosynthesis, and recently a missense mutation has been found in patients with an autosomal recessive syndrome characterized by dysmorphic features and multiple congenital anomalies together with severe neurological impairment, chorea and seizures leading to early death.	('missense mutation', 'Var', (100, 117))	('glycosylphosphatidylinositol', 'Chemical', 'MESH:D017261', (35, 63))	('congenital anomalies', 'Disease', (232, 252))	('autosomal recessive syndrome', 'Disease', (153, 181))	('death', 'Disease', 'MESH:D003643', (336, 341))	('multiple congenital anomalies', 'Phenotype', 'HP:0002804', (223, 252))	('PIGN', 'Gene', (0, 4))	('biosynthesis', 'biological_process', 'GO:0009058', ('71', '83'))	('seizures', 'Disease', (310, 318))	('chorea', 'Phenotype', 'HP:0002072', (299, 305))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('autosomal recessive syndrome', 'Disease', 'MESH:D030342', (153, 181))	('seizures', 'Disease', 'MESH:D012640', (310, 318))	('found', 'Reg', (127, 132))	('neurological impairment', 'Phenotype', 'HP:0000707', (274, 297))	('seizures', 'Phenotype', 'HP:0001250', (310, 318))	('death', 'Disease', (336, 341))	('PIGN', 'Gene', '23556', (0, 4))	('congenital anomalies', 'Disease', 'MESH:D000013', (232, 252))	('neurological impairment, chorea', 'Disease', 'MESH:D009422', (274, 305))	('patients', 'Species', '9606', (136, 144))
61378	25903059	Somatic mutations in this gene have been identified in T-cell prolymphocytic leukemia, mantle cell lymphoma, and B-cell chronic lymphocytic leukemia, while germline mutations have been found associated to increased susceptibility to early-onset breast cancer and risk of glioma and meningioma.	('lymphoma', 'Phenotype', 'HP:0002665', (99, 107))	('cell lymphoma', 'Phenotype', 'HP:0012191', (94, 107))	('breast cancer', 'Disease', 'MESH:D001943', (245, 258))	('breast cancer', 'Disease', (245, 258))	('meningioma', 'Disease', 'MESH:D008577', (282, 292))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (65, 85))	('identified', 'Reg', (41, 51))	('-cell chronic lymphocytic leukemia', 'Phenotype', 'HP:0005539', (114, 148))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (128, 148))	('mutations', 'Var', (8, 17))	('glioma', 'Disease', (271, 277))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (120, 148))	('leukemia', 'Phenotype', 'HP:0001909', (77, 85))	('leukemia', 'Phenotype', 'HP:0001909', (140, 148))	('glioma', 'Disease', 'MESH:D005910', (271, 277))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (87, 107))	('mantle cell lymphoma', 'Disease', (87, 107))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('lymphocytic leukemia', 'Disease', (128, 148))	('glioma', 'Phenotype', 'HP:0009733', (271, 277))	('T-cell prolymphocytic leukemia', 'Disease', 'MESH:D015461', (55, 85))	('meningioma', 'Disease', (282, 292))	('T-cell prolymphocytic leukemia', 'Disease', (55, 85))	('meningioma', 'Phenotype', 'HP:0002858', (282, 292))	('breast cancer', 'Phenotype', 'HP:0003002', (245, 258))
61379	25903059	Failure to identify these RRA could seriously limit the identification of disease-causing variants in Mendelian and polygenic disorders and driver genes in cancer studies.	('Mendelian', 'Disease', (102, 111))	('polygenic disorders', 'Disease', (116, 135))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('polygenic disorders', 'Disease', 'MESH:D030342', (116, 135))	('variants', 'Var', (90, 98))	('limit', 'NegReg', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
61380	25903059	RAREVATOR is able to identify germline variants in single- and multi-samples experiments (germline mode) as well as somatic variants in pairs of matched tumor and normal samples (somatic mode).	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('variants', 'Var', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
61381	25903059	The use of our tool on a publicly available whole-exome sequencing cancer dataset demonstrated its uniqueness in the identification of germline and somatic variants: RAREVATOR was able to identify more than 1500 germline and 22 somatic RRA variants that we demonstrated to participate to significantly mutated pathways.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('variants', 'Var', (240, 248))	('cancer', 'Disease', (67, 73))	('mutated', 'Reg', (302, 309))	('participate', 'Reg', (273, 284))	('RRA', 'Gene', (236, 239))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
61383	25903059	Moreover, although the GRC corrected almost all the RRA insertions and a significant fraction of SNVs and deletions for which the reference allele has never been observed, a large number of functionally relevant RRAs still remain unchanged in the latest version of the human reference genome.	('RRAs', 'Gene', (212, 216))	('RRAs', 'Gene', '6237', (212, 216))	('insertions', 'Var', (56, 66))	('human', 'Species', '9606', (269, 274))	('RRA', 'Disease', (52, 55))
61391	25903059	Positive scores represent a substitution deficit and thus indicate that a site may be under evolutionary constraint, while negative scores indicate that a site is probably evolving neutrally.	('deficit', 'Disease', (41, 48))	('Positive scores', 'Var', (0, 15))	('deficit', 'Disease', 'MESH:D009461', (41, 48))
61417	25903059	Colors nodes are assigned according to the class of RRA variant they contain and color border according to the cancer type for which the gene was predicted as driver.	('variant', 'Var', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('RRA', 'Gene', (52, 55))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
61434	25210967	In addition to asbestos exposure, risk factors for the development of MM include erionite exposure, simian virus 40, and germline BAP1 mutations.	('BAP1', 'Gene', '8314', (130, 134))	('BAP1', 'Gene', (130, 134))	('mutations', 'Var', (135, 144))
61435	25210967	Between 1980 and 1995, the authors of that study used the International Classification of Diseases, 9th revision (ICD-9), codes 163.0, 163.1, 163.8, and 163.9, and all cases of pleural neoplasm were considered to be cases of mesothelioma.	('pleural neoplasm', 'Phenotype', 'HP:0100527', (177, 193))	('neoplasm', 'Phenotype', 'HP:0002664', (185, 193))	('codes 163.0', 'Var', (122, 133))	('mesothelioma', 'Disease', (225, 237))	('pleural neoplasm', 'Disease', 'MESH:D010997', (177, 193))	('pleural neoplasm', 'Disease', (177, 193))
61443	25210967	The p16INK4a protein is a cyclin-dependent kinase inhibitor and plays a role in the hyperphosphorylation of the retinoblastoma protein.	('hyperphosphorylation', 'biological_process', 'GO:0048151', ('84', '104'))	('p16INK4a', 'Var', (4, 12))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('43', '59'))	('retinoblastoma', 'Disease', 'MESH:D012175', (112, 126))	('retinoblastoma', 'Disease', (112, 126))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (112, 126))	('hyperphosphorylation', 'MPA', (84, 104))	('plays', 'Reg', (64, 69))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('26', '59'))	('protein', 'Protein', (13, 20))
61444	25210967	In contrast, the p14ARF protein inhibits the degradation of p53 through its interaction with murine double minute 2 protein (MDM2).	('degradation', 'MPA', (45, 56))	('double minute 2 protein', 'Gene', (100, 123))	('murine', 'Species', '10090', (93, 99))	('protein', 'Protein', (24, 31))	('degradation', 'biological_process', 'GO:0009056', ('45', '56'))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('double minute 2 protein', 'Gene', '17246', (100, 123))	('interaction', 'Interaction', (76, 87))	('p53', 'Protein', (60, 63))	('inhibits', 'NegReg', (32, 40))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('p14ARF', 'Var', (17, 23))
61446	25210967	Approximately 70% of all cases of epithelial MM and nearly 100% of all cases of biphasic or sarcomatoid MM show changes in p16 INK4a and p14  ARF.	('p14', 'Var', (137, 140))	('biphasic or sarcomatoid MM', 'Disease', 'MESH:C538614', (80, 106))	('changes', 'Reg', (112, 119))	('biphasic or sarcomatoid MM', 'Disease', (80, 106))	('p16', 'Var', (123, 126))
61448	25210967	Germline BAP1 mutations have recently been detected in families with a high incidence of MM, characterizing a syndrome that predisposes to MM, uveal melanoma, and, possibly, other cancers.	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('uveal melanoma', 'Disease', 'MESH:C536494', (143, 157))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (143, 157))	('uveal melanoma', 'Disease', (143, 157))
61449	25210967	In individuals suspected of having BAP1 cancer syndrome, early diagnosis is essential to prevent the onset of diseases associated with BAP1 mutations.	('cancer syndrome', 'Disease', 'MESH:D009369', (40, 55))	('cancer syndrome', 'Disease', (40, 55))	('BAP1', 'Gene', (135, 139))	('mutations', 'Var', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
61451	25210967	Monoallelic mutations are common in various types of cancer; however, homozygous PTEN mutations are frequently found in advanced cancers, such as endometrial cancer and glioblastoma.	('found', 'Reg', (111, 116))	('mutations', 'Var', (86, 95))	('glioblastoma', 'Disease', (169, 181))	('glioblastoma', 'Disease', 'MESH:D005909', (169, 181))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('glioblastoma', 'Phenotype', 'HP:0012174', (169, 181))	('endometrial cancer', 'Disease', (146, 164))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('PTEN', 'Gene', (81, 85))	('endometrial cancer', 'Phenotype', 'HP:0012114', (146, 164))	('endometrial cancer', 'Disease', 'MESH:D016889', (146, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
61502	25210967	Todavia, a delecao completa de PTEN associada com TP53 com mutacao foi associada a uma forma mais grave de cancer de prostata.	('uma forma mais grave de cancer de prostata', 'Disease', (83, 125))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('TP53', 'Var', (50, 54))	('uma forma mais grave de cancer de prostata', 'Disease', 'MESH:D005862', (83, 125))
61523	25058347	Lack of nBAP1 expression importantly identified a subset of 'atypical' PUM patients with disomy of chromosome 3 but with unexpected metastatic relapse.	('chromosome', 'cellular_component', 'GO:0005694', ('99', '109'))	('Lack', 'NegReg', (0, 4))	('nBAP1', 'Gene', (8, 13))	('patients', 'Species', '9606', (75, 83))	('disomy of chromosome', 'Var', (89, 109))
61534	25058347	In PUM, an absence of BAP1 protein was recently shown to be strongly correlated with BAP1 gene mutations, and was significantly associated with metastatic progression and reduced survival in these patients.	('correlated', 'Reg', (69, 79))	('metastatic progression', 'CPA', (144, 166))	('BAP1 gene', 'Gene', (85, 94))	('protein', 'Protein', (27, 34))	('patients', 'Species', '9606', (197, 205))	('survival', 'CPA', (179, 187))	('absence', 'NegReg', (11, 18))	('associated', 'Reg', (128, 138))	('mutations', 'Var', (95, 104))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))	('BAP1', 'Gene', (22, 26))	('reduced', 'NegReg', (171, 178))
61579	25058347	Univariate analysis of all cases demonstrated that lack of nBAP1 protein expression was strongly associated with clinicopathological and genetic features of increased metastatic risk, namely: increased age at primary management (P=0.002); ciliary body involvement (P=0.001); presence of periodic acid Schiff+ closed connective tissue loops (P=0.001); presence of epithelioid cells (P=0.011) and M3 (P=0.001; Table 1).	('periodic acid Schiff', 'Chemical', '-', (287, 307))	('protein', 'Protein', (65, 72))	('ciliary body involvement', 'CPA', (239, 263))	('lack', 'Var', (51, 55))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('nBAP1', 'Gene', (59, 64))
61588	25058347	Moreover, we report the results of nBAP1 protein expression in MUM to the liver, demonstrating not only complete concordance between matched PUM and metastatic liver lesions, but also that the presence of nBAP1 positivity tended to be associated with increased metastatic latency in M3 tumours.	('increased', 'PosReg', (251, 260))	('presence', 'Var', (193, 201))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('tumour', 'Phenotype', 'HP:0002664', (286, 292))	('nBAP1', 'Gene', (205, 210))	('M3 tumours', 'Disease', 'MESH:D015473', (283, 293))	('M3 tumours', 'Disease', (283, 293))	('liver lesions', 'Disease', 'MESH:D017093', (160, 173))	('tumours', 'Phenotype', 'HP:0002664', (286, 293))	('positivity', 'Var', (211, 221))	('liver lesions', 'Disease', (160, 173))	('nBAP1', 'Gene', (35, 40))
61591	25058347	In another study, three cases without metastases (disease-free survival of 32, 40 and 81 months) despite monosomy 3 and BAP1 mutation are described.	('metastases', 'Disease', (38, 48))	('metastases', 'Disease', 'MESH:D009362', (38, 48))	('mutation', 'Var', (125, 133))	('BAP1', 'Gene', (120, 124))
61592	25058347	Newly identified driver mutations in splicing factor 3b subunit 1 (SF3B1) and eukaryotic translation initiation factor 1A, X-linked (EIF1AX) have been described in about 20-30% and 48% of UM patients with disomy 3, respectively, and are associated with a favourable prognosis.	('patients', 'Species', '9606', (191, 199))	('described', 'Reg', (151, 160))	('eukaryotic translation initiation factor 1A, X-linked', 'Gene', '1964', (78, 131))	('SF3B1', 'Gene', '23451', (67, 72))	('disomy 3', 'Disease', (205, 213))	('splicing factor 3b subunit 1', 'Gene', (37, 65))	('splicing factor 3b subunit 1', 'Gene', '23451', (37, 65))	('translation initiation', 'biological_process', 'GO:0006413', ('89', '111'))	('EIF1AX', 'Gene', '1964', (133, 139))	('EIF1AX', 'Gene', (133, 139))	('splicing', 'biological_process', 'GO:0045292', ('37', '45'))	('mutations', 'Var', (24, 33))	('SF3B1', 'Gene', (67, 72))
61593	25058347	Although it is not yet clear how these mutations promote UM, it is of interest that BAP1, SF3B1 and EIF1AX mutations occur in a largely mutually exclusive manner.	('mutations', 'Var', (107, 116))	('mutations', 'Var', (39, 48))	('SF3B1', 'Gene', (90, 95))	('promote', 'PosReg', (49, 56))	('BAP1', 'Gene', (84, 88))	('EIF1AX', 'Gene', '1964', (100, 106))	('EIF1AX', 'Gene', (100, 106))	('SF3B1', 'Gene', '23451', (90, 95))
61594	25058347	Moreover, although the majority of SF3B1 mutations detected result in a missense change at Arg625, distinct SF3B1 mutations in 30% (3 out of 10) of disomy 3 patients who developed metastatic disease were also reported.	('missense change', 'Var', (72, 87))	('mutations', 'Var', (41, 50))	('SF3B1', 'Gene', '23451', (35, 40))	('SF3B1', 'Gene', '23451', (108, 113))	('disomy 3', 'Disease', (148, 156))	('mutations', 'Var', (114, 123))	('patients', 'Species', '9606', (157, 165))	('Arg625', 'Var', (91, 97))	('Arg625', 'Chemical', '-', (91, 97))	('result in', 'Reg', (60, 69))	('SF3B1', 'Gene', (35, 40))	('SF3B1', 'Gene', (108, 113))	('metastatic disease', 'CPA', (180, 198))
61595	25058347	Further subgrouping of the UM according to SF3B1 and EIF1AX mutations may enhance prognostication for these patients and also be incorporated into the prognostic workflow proposed in Figure 3.	('SF3B1', 'Gene', (43, 48))	('EIF1AX', 'Gene', '1964', (53, 59))	('EIF1AX', 'Gene', (53, 59))	('SF3B1', 'Gene', '23451', (43, 48))	('prognostication', 'MPA', (82, 97))	('patients', 'Species', '9606', (108, 116))	('mutations', 'Var', (60, 69))	('enhance', 'PosReg', (74, 81))
61597	25058347	These data are consistent with those of) for both patient survival based on the BAP1 mutational status (32 vs 133 months for BAP1 mutation-positive vs BAP1 mutation-negative tumours) or BAP1 protein expression (31 vs 133 months for tumours showing negative BAP1 expression by IHC vs those with positive BAP1 expression) and thus the proposed role of BAP1 in the pathogenesis of UM with an aggressive phenotype.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumours', 'Disease', 'MESH:D009369', (232, 239))	('tumours', 'Phenotype', 'HP:0002664', (174, 181))	('pathogenesis', 'biological_process', 'GO:0009405', ('362', '374'))	('protein', 'cellular_component', 'GO:0003675', ('191', '198'))	('tumours', 'Disease', (232, 239))	('BAP1', 'Gene', (186, 190))	('mutation-positive', 'Var', (130, 147))	('BAP1', 'Gene', (125, 129))	('tumours', 'Disease', (174, 181))	('tumours', 'Disease', 'MESH:D009369', (174, 181))	('BAP1', 'Gene', (80, 84))	('mutational', 'Var', (85, 95))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('patient', 'Species', '9606', (50, 57))	('tumours', 'Phenotype', 'HP:0002664', (232, 239))
61598	25058347	Nonetheless, three patients within subgroup 1 displayed nBAP1 staining and yet died within 5 years of primary management of their UM.	('staining', 'Var', (62, 70))	('patients', 'Species', '9606', (19, 27))	('displayed', 'Reg', (46, 55))	('nBAP1', 'Protein', (56, 61))
61600	25058347	More recently, BAP1 mutations were identified in 58% (11 out of 19) of UM patients who had developed metastasis, and loss of BAP1 immunohistochemical staining was observed in the tumour cells of all but 2 of those 11 cases.	('tumour', 'Disease', (179, 185))	('patients', 'Species', '9606', (74, 82))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('metastasis', 'CPA', (101, 111))	('BAP1', 'Gene', (125, 129))	('tumour', 'Disease', 'MESH:D009369', (179, 185))	('BAP1', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))
61601	25058347	We were unable to conduct mutational analysis of the BAP1 gene in this cohort of patient samples because of insufficient material remaining for this study; however, there is mounting evidence in the literature that lack of BAP1 protein expression is strongly associated with the presence of inactivating BAP1 mutations in UM, mesothelioma and Spitz melanomas.	('melanomas', 'Disease', 'MESH:D008545', (349, 358))	('patient', 'Species', '9606', (81, 88))	('protein', 'cellular_component', 'GO:0003675', ('228', '235'))	('melanomas', 'Disease', (349, 358))	('mesothelioma', 'Disease', 'MESH:D008654', (326, 338))	('BAP1', 'Gene', (223, 227))	('melanoma', 'Phenotype', 'HP:0002861', (349, 357))	('inactivating', 'Var', (291, 303))	('insufficient', 'Disease', (108, 120))	('insufficient', 'Disease', 'MESH:D000309', (108, 120))	('protein', 'Protein', (228, 235))	('melanomas', 'Phenotype', 'HP:0002861', (349, 358))	('lack', 'NegReg', (215, 219))	('BAP1', 'Gene', (304, 308))	('mutations', 'Var', (309, 318))	('expression', 'MPA', (236, 246))	('mesothelioma', 'Disease', (326, 338))
61604	25058347	It is important to acknowledge, however, that in a human NSCLC cell line, missense mutations introduced into the catalytic domain of BAP1 reduced its tumour-suppressor function, but BAP1 protein expression was unaltered.	('reduced', 'NegReg', (138, 145))	('missense mutations', 'Var', (74, 92))	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('tumour', 'Disease', (150, 156))	('human', 'Species', '9606', (51, 56))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))	('NSCLC', 'Disease', (57, 62))	('BAP1', 'Gene', (133, 137))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
61606	25058347	It should be recognised, however, that the MUM is likely to have undergone additional genetic alterations that could further influence the therapeutic response, as seen in other tumours.	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('influence', 'Reg', (125, 134))	('tumours', 'Phenotype', 'HP:0002664', (178, 185))	('tumours', 'Disease', 'MESH:D009369', (178, 185))	('therapeutic response', 'CPA', (139, 159))	('tumours', 'Disease', (178, 185))	('genetic alterations', 'Var', (86, 105))
61608	25058347	In functional studies, depletion of BAP1 protein in the 92.1 UM cell line using siRNAs led to a change in cell morphology from spindle to a more epithelioid phenotype, loss of melanocytic differentiation and transition from a 'class 1' to a 'class 2' gene expression profile.	('loss of melanocytic', 'Disease', 'MESH:D009508', (168, 187))	('spindle', 'cellular_component', 'GO:0005819', ('127', '134'))	('gene expression', 'biological_process', 'GO:0010467', ('251', '266'))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('depletion', 'Var', (23, 32))	('loss of melanocytic', 'Disease', (168, 187))	('protein', 'Protein', (41, 48))	('cell morphology', 'CPA', (106, 121))	('change', 'Reg', (96, 102))	('BAP1', 'Gene', (36, 40))	('spindle', 'CPA', (127, 134))	('transition', 'Reg', (208, 218))
61611	25058347	Moreover, our finding that lack of BAP1 protein can identify a subgroup of 'atypical' poor prognosis D3 patients warrants the introduction of this test into the routine pathological work-up of all UM specimens.	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('lack', 'Var', (27, 31))	("'atypical' poor prognosis", 'Disease', (75, 100))	('BAP1', 'Gene', (35, 39))	('protein', 'Protein', (40, 47))	('patients', 'Species', '9606', (104, 112))
61671	22613358	There is emerging evidence supporting the role of BAP1 mutations in the pathogenesis of these two neoplasias.	('neoplasias', 'Disease', (98, 108))	('mutations', 'Var', (55, 64))	('BAP1', 'Gene', '8314', (50, 54))	('neoplasias', 'Phenotype', 'HP:0002664', (98, 108))	('BAP1', 'Gene', (50, 54))	('pathogenesis', 'biological_process', 'GO:0009405', ('72', '84'))	('neoplasias', 'Disease', 'MESH:D009369', (98, 108))
61723	22613358	All cases were found to have a BAP1 mutation.	('BAP1', 'Gene', '8314', (31, 35))	('BAP1', 'Gene', (31, 35))	('mutation', 'Var', (36, 44))
61725	22613358	Mutations in BAP1 are infrequent in the general population but high in mesothelioma (20.1%) and uveal melanoma (44.1%).	('mesothelioma', 'Disease', (71, 83))	('BAP1', 'Gene', (13, 17))	('uveal melanoma', 'Disease', (96, 110))	('mesothelioma', 'Disease', 'MESH:D008654', (71, 83))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('BAP1', 'Gene', '8314', (13, 17))	('high', 'Reg', (63, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (96, 110))
61727	22613358	In that study, the authors found germline BAP1 mutations in 2 of 26 patients diagnosed with mesothelioma and both patients were previously diagnosed with uveal melanoma.	('BAP1', 'Gene', '8314', (42, 46))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('mesothelioma', 'Disease', 'MESH:D008654', (92, 104))	('BAP1', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('patients', 'Species', '9606', (68, 76))	('uveal melanoma', 'Phenotype', 'HP:0007716', (154, 168))	('uveal melanoma', 'Disease', (154, 168))	('uveal melanoma', 'Disease', 'MESH:C536494', (154, 168))	('mesothelioma', 'Disease', (92, 104))	('patients', 'Species', '9606', (114, 122))
61728	22613358	Three of their four patients with uveal melanoma and BAP1 mutations subsequently developed mesothelioma.	('mutations', 'Var', (58, 67))	('mesothelioma', 'Disease', 'MESH:D008654', (91, 103))	('developed', 'Reg', (81, 90))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('patients', 'Species', '9606', (20, 28))	('mesothelioma', 'Disease', (91, 103))	('BAP1', 'Gene', '8314', (53, 57))	('uveal melanoma', 'Disease', 'MESH:C536494', (34, 48))	('uveal melanoma', 'Phenotype', 'HP:0007716', (34, 48))	('uveal melanoma', 'Disease', (34, 48))	('BAP1', 'Gene', (53, 57))
61731	22613358	Clinicians should be aware of this entity since individuals who carry germline BAP1 mutations may be at increased risk of developing metachronously both OM and DMPM.	('DMPM', 'Disease', (160, 164))	('BAP1', 'Gene', '8314', (79, 83))	('BAP1', 'Gene', (79, 83))	('mutations', 'Var', (84, 93))	('germline', 'Var', (70, 78))	('OM', 'Phenotype', 'HP:0007716', (153, 155))	('DMPM', 'Chemical', '-', (160, 164))
61732	22613358	Patients found with BAP1 mutations and their families should be closely monitored for the development of any or both of these malignancies for the possibility of early detection and intervention.	('mutations', 'Var', (25, 34))	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('BAP1', 'Gene', (20, 24))	('malignancies', 'Disease', (126, 138))	('Patients', 'Species', '9606', (0, 8))	('BAP1', 'Gene', '8314', (20, 24))
61737	22613358	Genetic testing for BAP1 mutations in this patient and his family is currently in progress and the results will be the subject of another publication.	('mutations', 'Var', (25, 34))	('BAP1', 'Gene', '8314', (20, 24))	('BAP1', 'Gene', (20, 24))	('patient', 'Species', '9606', (43, 50))
61778	33542896	After the membranes were blocked with 5% skim milk dissolved in Tris-buffered saline containing 0.1% Tween20, they were incubated with primary antibodies overnight at 4 C, including anti-TDO2 (NOVUS, USA), anti-AhR (Abcam, UK), anti-Cyp1b1(Abcam, UK), anti-E Cadherin(CST, USA), anti-N Cadherin(CST, USA), anti-MMP9 (CST, USA), or anti-Vimentin antibodies(CST, USA).	('anti-E', 'Var', (252, 258))	('anti-MMP9', 'Var', (306, 315))	('MMP9', 'molecular_function', 'GO:0004229', ('311', '315'))	('CST', 'Gene', '106478911', (295, 298))	('Cadherin', 'molecular_function', 'GO:0008014', ('259', '267'))	('CST', 'Gene', '106478911', (317, 320))	('Cadherin', 'molecular_function', 'GO:0008014', ('286', '294'))	('Vimentin', 'cellular_component', 'GO:0045098', ('336', '344'))	('AhR', 'Gene', '196', (211, 214))	('CST', 'Gene', '106478911', (356, 359))	('Cyp1b1', 'Gene', (233, 239))	('N Cadherin', 'Gene', (284, 294))	('N Cadherin', 'Gene', '1000', (284, 294))	('CST', 'Gene', '106478911', (268, 271))	('CST', 'Gene', (295, 298))	('TDO', 'molecular_function', 'GO:0004833', ('187', '190'))	('CST', 'Gene', (317, 320))	('anti-TDO2', 'Var', (182, 191))	('CST', 'Gene', (356, 359))	('AhR', 'Gene', (211, 214))	('Vimentin', 'cellular_component', 'GO:0045099', ('336', '344'))	('CST', 'Gene', (268, 271))	('Cyp1b1', 'Gene', '1545', (233, 239))
61804	33542896	And the analysis of co-relationship of TDO2 expression level and overall survival of HCC patients showed a shorter survival time in high TDO2 group than in low TDO2 group, while no statistical significance reached (Figure 1D).	('TDO', 'molecular_function', 'GO:0004833', ('160', '163'))	('TDO', 'molecular_function', 'GO:0004833', ('39', '42'))	('HCC', 'Phenotype', 'HP:0001402', (85, 88))	('shorter', 'NegReg', (107, 114))	('patients', 'Species', '9606', (89, 97))	('high TDO2', 'Var', (132, 141))	('survival time', 'CPA', (115, 128))	('TDO', 'molecular_function', 'GO:0004833', ('137', '140'))
61807	33542896	Then two shRNA sequences packed with effective lentivirus were designed and utilized to knockdown Tdo2 gene in Huh7 and LM3 cells, while only one of them showed knockdown effects (Figure 2B).	('LM3', 'CellLine', 'CVCL:5998', (120, 123))	('Tdo2 gene', 'Gene', (98, 107))	('knockdown', 'Var', (88, 97))	('Huh7', 'CellLine', 'CVCL:0336', (111, 115))	('Tdo', 'molecular_function', 'GO:0004833', ('98', '101'))
61808	33542896	Scratch wound assays and Transwell assay showed that sh-Tdo2 groups in both Huh7 and LM3 cells has significantly reduced capabilities of the migration and invasion than sh-scramble groups (P < 0.01, Figures 2C, D).	('LM3', 'CellLine', 'CVCL:5998', (85, 88))	('Tdo', 'molecular_function', 'GO:0004833', ('56', '59'))	('sh-Tdo2', 'Var', (53, 60))	('Huh7', 'CellLine', 'CVCL:0336', (76, 80))	('reduced', 'NegReg', (113, 120))
61809	33542896	In addition, to inhibit the TDO2 in these cells, we applied 680C91, a specific inhibitor used for suppressing TDO2 activity to these cells at 10 or 20 muM concentrations.	('inhibit', 'NegReg', (16, 23))	('TDO', 'molecular_function', 'GO:0004833', ('28', '31'))	('activity', 'MPA', (115, 123))	('680C91', 'Chemical', 'MESH:C093792', (60, 66))	('TDO', 'molecular_function', 'GO:0004833', ('110', '113'))	('680C91', 'Var', (60, 66))
61810	33542896	Consistently, the inhibition of TDO2 also suppressed the migration and invasion capabilities of Huh7 and LM3 (P < 0.01, Figures 2E, F).	('invasion capabilities', 'CPA', (71, 92))	('Huh7', 'CellLine', 'CVCL:0336', (96, 100))	('TDO2', 'Gene', (32, 36))	('LM3', 'CPA', (105, 108))	('suppressed', 'NegReg', (42, 52))	('migration', 'CPA', (57, 66))	('TDO', 'molecular_function', 'GO:0004833', ('32', '35'))	('inhibition', 'Var', (18, 28))	('LM3', 'CellLine', 'CVCL:5998', (105, 108))
61813	33542896	Both knockdown of TDO2 in Huh7sh-Tdo2 cells and inhibition of TDO2 in the Huh7 cell lines treated with 680C91 group developed less metastatic nodules than their respective control groups (Figures 3A, B).	('680C91', 'Chemical', 'MESH:C093792', (103, 109))	('Huh7', 'CellLine', 'CVCL:0336', (26, 30))	('Tdo', 'molecular_function', 'GO:0004833', ('33', '36'))	('inhibition', 'Var', (48, 58))	('TDO', 'molecular_function', 'GO:0004833', ('62', '65'))	('metastatic nodules', 'CPA', (131, 149))	('less', 'NegReg', (126, 130))	('Huh7', 'CellLine', 'CVCL:0336', (74, 78))	('TDO', 'molecular_function', 'GO:0004833', ('18', '21'))	('TDO2', 'Gene', (62, 66))	('TDO2', 'Gene', (18, 22))
61817	33542896	We documented that in sh-Tdo2 and inhibitory groups of Huh7 and LM3 cells, an increased expression of E-cadherin, as well as decreased expressions of N-cadherin, MMP9, and Vimentin, was observed compared to negative control groups (Figures 4A, B).	('cadherin', 'molecular_function', 'GO:0008014', ('152', '160'))	('cadherin', 'molecular_function', 'GO:0008014', ('104', '112'))	('MMP9', 'molecular_function', 'GO:0004229', ('162', '166'))	('Vimentin', 'Protein', (172, 180))	('N-cadherin', 'Protein', (150, 160))	('decreased', 'NegReg', (125, 134))	('expression', 'MPA', (88, 98))	('Huh7', 'CellLine', 'CVCL:0336', (55, 59))	('Vimentin', 'cellular_component', 'GO:0045098', ('172', '180'))	('MMP9', 'Protein', (162, 166))	('increased', 'PosReg', (78, 87))	('sh-Tdo2', 'Var', (22, 29))	('Vimentin', 'cellular_component', 'GO:0045099', ('172', '180'))	('expressions', 'MPA', (135, 146))	('E-cadherin', 'Protein', (102, 112))	('Tdo', 'molecular_function', 'GO:0004833', ('25', '28'))	('LM3', 'CellLine', 'CVCL:5998', (64, 67))
61820	33542896	We tested whether TDO2 knockdown or inhibition affected Kyn production in Huh7 cell line.	('Kyn production', 'MPA', (56, 70))	('inhibition', 'NegReg', (36, 46))	('knockdown', 'Var', (23, 32))	('tested', 'Reg', (3, 9))	('Huh7', 'CellLine', 'CVCL:0336', (74, 78))	('Kyn', 'Chemical', 'MESH:D007737', (56, 59))	('TDO', 'molecular_function', 'GO:0004833', ('18', '21'))	('TDO2', 'Gene', (18, 22))
61821	33542896	TDO2 knockdown increased Trp accumulation and decreased Kyn level.	('Trp accumulation', 'MPA', (25, 41))	('knockdown', 'Var', (5, 14))	('Trp', 'Chemical', 'MESH:D014364', (25, 28))	('TDO', 'molecular_function', 'GO:0004833', ('0', '3'))	('increased', 'PosReg', (15, 24))	('decreased', 'NegReg', (46, 55))	('Kyn', 'Chemical', 'MESH:D007737', (56, 59))	('TDO2', 'Gene', (0, 4))	('Kyn level', 'MPA', (56, 65))
61823	33542896	TDO2 knockdown or inhibition abrogated the abundance of CYP1b1, which indicated weakened activity of AhR (Figure 5C).	('weakened', 'NegReg', (80, 88))	('knockdown', 'Var', (5, 14))	('AhR', 'Gene', (101, 104))	('abrogated', 'NegReg', (29, 38))	('AhR', 'Gene', '196', (101, 104))	('TDO', 'molecular_function', 'GO:0004833', ('0', '3'))	('CYP1b1', 'Gene', (56, 62))	('inhibition', 'Var', (18, 28))	('CYP1b1', 'Gene', '1545', (56, 62))	('TDO2', 'Gene', (0, 4))	('activity', 'MPA', (89, 97))
61825	33542896	Besides, public data showed a positive correlation between the level of TDO2 and that of AhR in malignant tumors, including colon (Spearman r = 0.33, P = 3.2e-08) and rectum adenocarcinoma (Spearman r = 0.32, P = 0.0019), thymoma (Spearman r = 0.51, P = 3.4e-09), testicular Germ Cell Tumors (Spearman r = 0.53, P = 4.4e-11), and Uveal melanoma (UM) (Spearman r = 0.50, P = 2.2e-06) (Supplementary Figure 1C).	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (167, 188))	('Tumors', 'Phenotype', 'HP:0002664', (285, 291))	('AhR', 'Gene', (89, 92))	('colon', 'Disease', (124, 129))	('Germ Cell Tumors', 'Phenotype', 'HP:0100728', (275, 291))	('Tumors', 'Disease', (285, 291))	('melanoma', 'Disease', 'MESH:D008545', (336, 344))	('rectum adenocarcinoma', 'Disease', (167, 188))	('TDO', 'molecular_function', 'GO:0004833', ('72', '75'))	('thymoma', 'Disease', 'MESH:D013945', (222, 229))	('malignant tumors', 'Disease', (96, 112))	('malignant tumors', 'Disease', 'MESH:D009369', (96, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('AhR', 'Gene', '196', (89, 92))	('TDO2', 'Var', (72, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('Tumors', 'Disease', 'MESH:D009369', (285, 291))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('thymoma', 'Disease', (222, 229))	('thymoma', 'Phenotype', 'HP:0100522', (222, 229))	('UM', 'Phenotype', 'HP:0007716', (346, 348))	('melanoma', 'Phenotype', 'HP:0002861', (336, 344))	('melanoma', 'Disease', (336, 344))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (330, 344))
61826	33542896	Further Western Blot examining the expression of AhR and its downstream target gene CYP1b1 in LO2 and HCC cell lines showed that cell lines with TDO2 overexpression express relative higher level of AhR and CYP1b1 than the cell line with low expression of TDO2 (Supplementary Figure 1D), providing a clue that TDO2 probably regulated AhR in a translational level, which needs further work to explore.	('CYP1b1', 'Gene', '1545', (84, 90))	('AhR', 'Gene', '196', (49, 52))	('AhR', 'Gene', '196', (198, 201))	('TDO2', 'Gene', (145, 149))	('LO2', 'CellLine', 'CVCL:6926', (94, 97))	('TDO', 'molecular_function', 'GO:0004833', ('145', '148'))	('TDO', 'molecular_function', 'GO:0004833', ('255', '258'))	('TDO', 'molecular_function', 'GO:0004833', ('309', '312'))	('CYP1b1', 'Gene', (206, 212))	('AhR', 'Gene', (333, 336))	('higher', 'PosReg', (182, 188))	('AhR', 'Gene', '196', (333, 336))	('AhR', 'Gene', (198, 201))	('HCC', 'Phenotype', 'HP:0001402', (102, 105))	('CYP1b1', 'Gene', (84, 90))	('CYP1b1', 'Gene', '1545', (206, 212))	('overexpression', 'Var', (150, 164))	('AhR', 'Gene', (49, 52))
61828	33542896	Sh-Tdo2 Huh7 cells treated with exogenous Kyn showed decreased expression of E-cadherin and increased expression of N-Cadherin, MMP9 and Vimentin to different levels.	('MMP9', 'molecular_function', 'GO:0004229', ('128', '132'))	('cadherin', 'molecular_function', 'GO:0008014', ('79', '87'))	('N-Cadherin', 'Gene', (116, 126))	('N-Cadherin', 'Gene', '1000', (116, 126))	('MMP9', 'Gene', (128, 132))	('expression', 'MPA', (102, 112))	('Vimentin', 'cellular_component', 'GO:0045099', ('137', '145'))	('E-cadherin', 'Protein', (77, 87))	('exogenous', 'Var', (32, 41))	('expression', 'MPA', (63, 73))	('Kyn', 'Chemical', 'MESH:D007737', (42, 45))	('Cadherin', 'molecular_function', 'GO:0008014', ('118', '126'))	('increased', 'PosReg', (92, 101))	('Huh7', 'CellLine', 'CVCL:0336', (8, 12))	('decreased', 'NegReg', (53, 62))	('Vimentin', 'Protein', (137, 145))	('Tdo', 'molecular_function', 'GO:0004833', ('3', '6'))	('Vimentin', 'cellular_component', 'GO:0045098', ('137', '145'))
61835	33542896	Overexpression of TDO2 in triple negative breast cancer facilitated anoikis resistance and enhanced the metastatic capability of breast cancer cells in vivo.	('breast cancer', 'Disease', (129, 142))	('facilitated', 'PosReg', (56, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('anoikis', 'biological_process', 'GO:0043276', ('68', '75'))	('TDO', 'molecular_function', 'GO:0004833', ('18', '21'))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('anoikis resistance', 'CPA', (68, 86))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('Overexpression', 'Var', (0, 14))	('metastatic capability of', 'CPA', (104, 128))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('enhanced', 'PosReg', (91, 99))	('TDO2', 'Gene', (18, 22))
61845	33542896	AhR was involved in the induction of EMT by Polychlorinated biphenyls in HCC cells.	('HCC', 'Phenotype', 'HP:0001402', (73, 76))	('EMT', 'biological_process', 'GO:0001837', ('37', '40'))	('Polychlorinated biphenyls', 'Chemical', 'MESH:D011078', (44, 69))	('Polychlorinated biphenyls', 'Var', (44, 69))	('AhR', 'Gene', (0, 3))	('AhR', 'Gene', '196', (0, 3))
61850	33542896	Our in vitro results revealed that TDO2 was the main enzyme catalyzing Trp to Kyn in HCC cell lines, and Kyn activated AhR promoted migration and invasion capabilities through regulating EMT of HCC cell lines.	('Kyn', 'Chemical', 'MESH:D007737', (105, 108))	('Trp', 'Chemical', 'MESH:D014364', (71, 74))	('EMT of HCC cell lines', 'CPA', (187, 208))	('HCC', 'Phenotype', 'HP:0001402', (194, 197))	('Kyn', 'Chemical', 'MESH:D007737', (78, 81))	('Kyn', 'Var', (105, 108))	('promoted', 'PosReg', (123, 131))	('EMT', 'biological_process', 'GO:0001837', ('187', '190'))	('migration', 'CPA', (132, 141))	('HCC', 'Phenotype', 'HP:0001402', (85, 88))	('TDO', 'molecular_function', 'GO:0004833', ('35', '38'))	('AhR', 'Gene', (119, 122))	('regulating', 'Reg', (176, 186))	('invasion capabilities', 'CPA', (146, 167))	('AhR', 'Gene', '196', (119, 122))
61876	33256089	UV signatures were detected in cutaneous melanoma, and consist of C > T transitions at dipyrimidine sites and CC > TT or (C/T)C > (C/T)T mutations.	('C > T transitions', 'Var', (66, 83))	('cutaneous melanoma', 'Disease', (31, 49))	('CC > TT', 'Var', (110, 117))	('C/T)C > (C/T)T mutations', 'Var', (122, 146))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (31, 49))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (31, 49))	('dipyrimidine', 'Chemical', '-', (87, 99))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))
61878	33256089	Melanoma is a disease of old age and the stochastic accumulation of mutations within melanocytes either inherited or acquired, result in melanocyte transformation into melanoma.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanoma', 'Disease', (0, 8))	('result in', 'Reg', (127, 136))	('mutations', 'Var', (68, 77))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))	('melanoma', 'Disease', (168, 176))	('melanocyte transformation', 'CPA', (137, 162))
61903	33256089	The genetic abnormalities commonly associated with these two subtypes of cutaneous melanoma are neurofibromin 1 (NF1), NRAS, BRAF non-V600E mutations, or KIT in CSID, while non-CSID is associated with BRAF V600E mutations, suggesting that the non-CSID might originate from nevi (Figure 1).	('cutaneous melanoma', 'Disease', (73, 91))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('KIT', 'Gene', (154, 157))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (73, 91))	('NRAS', 'Gene', (119, 123))	('non-V600E mutations', 'Var', (130, 149))	('BRAF', 'Gene', (125, 129))	('KIT', 'Gene', '3815', (154, 157))	('genetic abnormalities', 'Disease', 'MESH:D030342', (4, 25))	('BRAF', 'Var', (201, 205))	('genetic abnormalities', 'Disease', (4, 25))	('NF1', 'Gene', '4763', (113, 116))	('nevi', 'Phenotype', 'HP:0003764', (273, 277))	('neurofibromin 1', 'Gene', '4763', (96, 111))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('KIT', 'molecular_function', 'GO:0005020', ('154', '157'))	('associated', 'Reg', (35, 45))	('neurofibromin 1', 'Gene', (96, 111))	('NF1', 'Gene', (113, 116))	('V600E', 'Mutation', 'rs113488022', (134, 139))	('NRAS', 'Gene', '4893', (119, 123))	('V600E', 'Mutation', 'rs113488022', (206, 211))
61905	33256089	The BRAF subtype is characterized by the presence of BRAF hot-spot mutations (V600E, V600K, V600R, and K601E) and is mutually exclusive with NRAS hot spot mutations.	('K601E', 'Var', (103, 108))	('V600K', 'Mutation', 'rs121913227', (85, 90))	('NRAS', 'Gene', '4893', (141, 145))	('BRAF', 'Gene', (53, 57))	('V600R', 'Mutation', 'rs121913227', (92, 97))	('V600E', 'Mutation', 'rs113488022', (78, 83))	('BRAF', 'Disease', (4, 8))	('V600K', 'Var', (85, 90))	('V600E', 'Var', (78, 83))	('V600R', 'Var', (92, 97))	('K601E', 'Mutation', 'rs121913364', (103, 108))	('NRAS', 'Gene', (141, 145))
61906	33256089	Additionally, non-hotspot mutations in BRAF occurred together with N/H/K-RAS hotspot mutations and NF1 mutations.	('mutations', 'Var', (103, 112))	('BRAF', 'Gene', (39, 43))	('NF1', 'Gene', (99, 102))	('mutations', 'Var', (26, 35))	('NF1', 'Gene', '4763', (99, 102))	('K-RAS', 'Gene', '3845', (71, 76))	('K-RAS', 'Gene', (71, 76))
61907	33256089	Hot-spot mutations in BRAF and N/H/K-RAS show increased MAPK and PI3K/AKT signaling cascade activation.	('AKT', 'Gene', '207', (70, 73))	('activation', 'PosReg', (92, 102))	('K-RAS', 'Gene', '3845', (35, 40))	('increased', 'PosReg', (46, 55))	('mutations', 'Var', (9, 18))	('PI3K', 'molecular_function', 'GO:0016303', ('65', '69'))	('AKT signaling cascade', 'biological_process', 'GO:0043491', ('70', '91'))	('MAPK', 'molecular_function', 'GO:0004707', ('56', '60'))	('AKT', 'Gene', (70, 73))	('K-RAS', 'Gene', (35, 40))	('BRAF', 'Gene', (22, 26))
61908	33256089	NF1 mutations are detected in 15% of melanoma and the majority of them are from older patients with a higher mutational burden.	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('NF1', 'Gene', '4763', (0, 3))	('patients', 'Species', '9606', (86, 94))
61909	33256089	More than half of the NF1 mutations are associated with a loss of function.	('mutations', 'Var', (26, 35))	('NF1', 'Gene', (22, 25))	('NF1', 'Gene', '4763', (22, 25))	('loss of function', 'NegReg', (58, 74))
61910	33256089	Mutations in NF1 also lead to the activation of the MAPK pathway.	('MAPK pathway', 'Pathway', (52, 64))	('NF1', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('NF1', 'Gene', '4763', (13, 16))	('MAPK', 'molecular_function', 'GO:0004707', ('52', '56'))	('activation', 'PosReg', (34, 44))
61920	33256089	Common mutations found in uveal melanoma include CYSLTR2, PLCB4, and GNAQ/GNA11; all promote activation of the MAPK and PI3K/AKT signaling cascades (Figure 1).	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('GNA11', 'Gene', '2767', (74, 79))	('PLCB4', 'Gene', '5332', (58, 63))	('GNAQ', 'Gene', '2776', (69, 73))	('GNAQ', 'Gene', (69, 73))	('MAPK', 'molecular_function', 'GO:0004707', ('111', '115'))	('AKT signaling', 'biological_process', 'GO:0043491', ('125', '138'))	('AKT', 'Gene', (125, 128))	('uveal melanoma', 'Disease', (26, 40))	('uveal melanoma', 'Disease', 'MESH:C536494', (26, 40))	('mutations', 'Var', (7, 16))	('GNA11', 'Gene', (74, 79))	('CYSLTR2', 'Gene', '57105', (49, 56))	('PI3K', 'molecular_function', 'GO:0016303', ('120', '124'))	('promote activation', 'PosReg', (85, 103))	('uveal melanoma', 'Phenotype', 'HP:0007716', (26, 40))	('PLCB4', 'Gene', (58, 63))	('AKT', 'Gene', '207', (125, 128))	('CYSLTR2', 'Gene', (49, 56))
61921	33256089	Activating mutations in GNAQ/GNA11 also lead to activation of several transcriptional factors associated with RNA splicing, DNA damage response, and cellular proliferation.	('GNA11', 'Gene', (29, 34))	('mutations', 'Var', (11, 20))	('GNAQ', 'Gene', '2776', (24, 28))	('GNA11', 'Gene', '2767', (29, 34))	('RNA', 'cellular_component', 'GO:0005562', ('110', '113'))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('GNAQ', 'Gene', (24, 28))	('RNA splicing', 'biological_process', 'GO:0008380', ('110', '122'))	('transcriptional factors', 'MPA', (70, 93))	('DNA damage response', 'biological_process', 'GO:0006974', ('124', '143'))	('activation', 'PosReg', (48, 58))
61926	33256089	Amplification or deletion of many genes is a common carcinogenic process involved in acral melanoma.	('acral melanoma', 'Disease', 'MESH:D008545', (85, 99))	('Amplification', 'Var', (0, 13))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('acral melanoma', 'Phenotype', 'HP:0012060', (85, 99))	('carcinogenic', 'Disease', 'MESH:D063646', (52, 64))	('acral melanoma', 'Disease', (85, 99))	('carcinogenic', 'Disease', (52, 64))
61927	33256089	Genetic alterations commonly found within acral melanoma are correlated with the signaling pathways associated with cell cycle progression and cell growth.	('Genetic alterations', 'Var', (0, 19))	('signaling pathways', 'Pathway', (81, 99))	('cell growth', 'biological_process', 'GO:0016049', ('143', '154'))	('acral melanoma', 'Disease', 'MESH:D008545', (42, 56))	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('correlated', 'Reg', (61, 71))	('acral melanoma', 'Phenotype', 'HP:0012060', (42, 56))	('cell cycle', 'biological_process', 'GO:0007049', ('116', '126'))	('acral melanoma', 'Disease', (42, 56))	('cell cycle', 'CPA', (116, 126))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
61928	33256089	Interestingly, like cutaneous melanoma, mutations in the TERT promoter and TERT amplification might upregulate telomerase activity in acral melanoma cells, allowing them to become replicative immortal (Figure 1).	('melanoma cells', 'Disease', (140, 154))	('acral melanoma', 'Disease', (134, 148))	('mutations', 'Var', (40, 49))	('telomerase activity', 'molecular_function', 'GO:0003720', ('111', '130'))	('cutaneous melanoma', 'Disease', (20, 38))	('upregulate', 'PosReg', (100, 110))	('telomerase', 'Enzyme', (111, 121))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (20, 38))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (20, 38))	('TERT', 'Gene', (75, 79))	('TERT', 'Gene', '7015', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma cells', 'Disease', 'MESH:D008545', (140, 154))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('acral melanoma', 'Disease', 'MESH:D008545', (134, 148))	('TERT', 'Gene', (57, 61))	('TERT', 'Gene', '7015', (57, 61))	('acral melanoma', 'Phenotype', 'HP:0012060', (134, 148))	('activity', 'MPA', (122, 130))
61931	33256089	Similar to other non-cutaneous melanoma subtypes, mucosal melanoma is characterized by a low mutational burden (2.64 mutations per Mb compared to cutaneous melanoma with 49.17 mutations per Mb), high copy number variations, and increased chromosomal structural variations.	('mucosal melanoma', 'Disease', 'MESH:D008545', (50, 66))	('cutaneous melanoma', 'Disease', (21, 39))	('mutations', 'Var', (117, 126))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (21, 39))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (21, 39))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('cutaneous melanoma', 'Disease', (146, 164))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (146, 164))	('high', 'Var', (195, 199))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (146, 164))	('mucosal melanoma', 'Disease', (50, 66))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
61935	33256089	identified mutations that were not previously identified in mucosal melanoma: MUC2, UBE4A, PTPRT, NRK, NALCN, MUC4, MAP4K4, LRRC7, LRP1B, FURIN, CNBD1, CDH13, CACNA1C, AHNAK, ABH1B, KIR2DL1, MGAM, and SELPLG.	('mutations', 'Var', (11, 20))	('MAP4K4', 'Gene', (116, 122))	('FURIN', 'Gene', '5045', (138, 143))	('KIR2DL1', 'Gene', (182, 189))	('MUC2', 'Gene', '4583', (78, 82))	('SELPLG', 'Gene', '6404', (201, 207))	('NRK', 'Gene', '203447', (98, 101))	('CDH13', 'Gene', (152, 157))	('CACNA1C', 'Gene', '775', (159, 166))	('PTPRT', 'Gene', (91, 96))	('LRRC7', 'Gene', (124, 129))	('LRRC7', 'Gene', '57554', (124, 129))	('LRP1B', 'Gene', (131, 136))	('MAP', 'molecular_function', 'GO:0004239', ('116', '119'))	('NALCN', 'Gene', (103, 108))	('MUC2', 'Gene', (78, 82))	('MGAM', 'Gene', '8972', (191, 195))	('CNBD1', 'Gene', '168975', (145, 150))	('NALCN', 'Gene', '259232', (103, 108))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('CACNA1C', 'Gene', (159, 166))	('UBE4A', 'Gene', (84, 89))	('SELPLG', 'Gene', (201, 207))	('AHNAK', 'Gene', '79026', (168, 173))	('UBE4A', 'Gene', '9354', (84, 89))	('FURIN', 'Gene', (138, 143))	('CNBD1', 'Gene', (145, 150))	('MGAM', 'Gene', (191, 195))	('LRP1B', 'Gene', '53353', (131, 136))	('MAP4K4', 'Gene', '9448', (116, 122))	('mucosal melanoma', 'Disease', 'MESH:D008545', (60, 76))	('MUC4', 'Gene', '4585', (110, 114))	('PTPRT', 'Gene', '11122', (91, 96))	('KIR2DL1', 'Gene', '3802', (182, 189))	('MUC4', 'Gene', (110, 114))	('CDH13', 'Gene', '1012', (152, 157))	('AHNAK', 'Gene', (168, 173))	('ABH1B', 'Gene', (175, 180))	('NRK', 'Gene', (98, 101))	('mucosal melanoma', 'Disease', (60, 76))
61939	33256089	In the course of constructing transgenic mice with a fragment of genomic DNA (Clone B), which demonstrated adipocyte differentiation in vitro, resulted in concomitant deletion of 70 kb of host DNA and insertion of Clone B.	('adipocyte', 'MPA', (107, 116))	('DNA', 'cellular_component', 'GO:0005574', ('193', '196'))	('adipocyte differentiation', 'biological_process', 'GO:0045444', ('107', '132'))	('transgenic mice', 'Species', '10090', (30, 45))	('deletion', 'Var', (167, 175))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('insertion', 'Var', (201, 210))	('men', 'Species', '9606', (57, 60))	('host DNA', 'Gene', (188, 196))
61943	33256089	To confirm that the aberrant mGluR1 expression in melanocytes drives the tumor phenotype, a second transgenic line was made with GRM1 cDNA, under a melanocyte-specific promoter, dopachrome tautomerase (DCT).	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('aberrant', 'Var', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('DC', 'Gene', '13179', (202, 204))	('dopachrome tautomerase', 'Gene', '13190', (178, 200))	('transgenic', 'Species', '10090', (99, 109))	('tumor', 'Disease', (73, 78))	('dopachrome tautomerase', 'Gene', (178, 200))	('drives', 'Reg', (62, 68))	('mGluR1', 'Gene', (29, 35))
61944	33256089	This second transgenic line displays similar tumor onset and progression as the first one, confirming that the aberrant expression of mGluR1 in melanocytes was sufficient to promote melanocyte hyperplasia and transformation into malignant melanoma, similar to human melanoma development.	('transgenic', 'Species', '10090', (12, 22))	('tumor', 'Disease', (45, 50))	('men', 'Species', '9606', (282, 285))	('melanoma', 'Disease', 'MESH:D008545', (266, 274))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('melanoma', 'Disease', (239, 247))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('mGluR1', 'Gene', (134, 140))	('malignant melanoma', 'Disease', (229, 247))	('promote', 'PosReg', (174, 181))	('aberrant', 'Var', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('melanoma', 'Phenotype', 'HP:0002861', (266, 274))	('melanoma', 'Disease', (266, 274))	('melanoma', 'Disease', 'MESH:D008545', (239, 247))	('malignant melanoma', 'Phenotype', 'HP:0002861', (229, 247))	('transformation', 'CPA', (209, 223))	('human', 'Species', '9606', (260, 265))	('malignant melanoma', 'Disease', 'MESH:D008545', (229, 247))	('hyperplasia', 'Disease', (193, 204))	('hyperplasia', 'Disease', 'MESH:D006965', (193, 204))
61964	33256089	Chemotherapy induces mitotic catastrophe in cancer cells and if not repaired rapidly, it can induce apoptosis or necrosis, depending on the extent of the damage.	('necrosis', 'Disease', 'MESH:D009336', (113, 121))	('necrosis', 'biological_process', 'GO:0070265', ('113', '121'))	('necrosis', 'biological_process', 'GO:0019835', ('113', '121'))	('induces', 'Reg', (13, 20))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('necrosis', 'biological_process', 'GO:0008220', ('113', '121'))	('induce', 'Reg', (93, 99))	('mitotic catastrophe', 'CPA', (21, 40))	('necrosis', 'biological_process', 'GO:0001906', ('113', '121'))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('Chemotherapy', 'Var', (0, 12))	('necrosis', 'Disease', (113, 121))	('necrosis', 'biological_process', 'GO:0008219', ('113', '121'))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('21', '40'))	('apoptosis', 'CPA', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
61970	33256089	In 2011, the FDA approved the first in-class targeted therapy for melanoma, vemurafenib.. Vemurafenib was specifically approved for melanomas with BRAF V600E-activating mutation, this agent inhibits the kinase activity that is responsible for hyperactivating the MAPK pathway.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('melanomas', 'Disease', 'MESH:D008545', (132, 141))	('inhibits', 'NegReg', (190, 198))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (90, 101))	('melanomas', 'Disease', (132, 141))	('BRAF V600E-activating mutation', 'Var', (147, 177))	('MAPK pathway', 'Pathway', (263, 275))	('MAPK', 'molecular_function', 'GO:0004707', ('263', '267'))	('V600E', 'Mutation', 'rs113488022', (152, 157))	('kinase activity', 'MPA', (203, 218))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Disease', (132, 140))	('melanomas', 'Phenotype', 'HP:0002861', (132, 141))	('kinase activity', 'molecular_function', 'GO:0016301', ('203', '218'))	('vemurafenib', 'Chemical', 'MESH:D000077484', (76, 87))	('hyperactivating', 'PosReg', (243, 258))
61973	33256089	Dabrafenib is approved for melanoma tumors with BRAF V600E/K mutations.	('melanoma tumors', 'Disease', 'MESH:D008545', (27, 42))	('V600E', 'Mutation', 'rs113488022', (53, 58))	('BRAF V600E/K', 'Var', (48, 60))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('melanoma tumors', 'Disease', (27, 42))
61975	33256089	The mutated BRAF melanomas had a 33% response while the wild-type BRAF tumors only had a 10% response.	('mutated', 'Var', (4, 11))	('BRAF melanomas', 'Disease', (12, 26))	('BRAF tumors', 'Disease', 'MESH:D009369', (66, 77))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('BRAF tumors', 'Disease', (66, 77))	('melanomas', 'Phenotype', 'HP:0002861', (17, 26))	('BRAF melanomas', 'Disease', 'MESH:D008545', (12, 26))
61976	33256089	In 2012, the FDA approved trametinib for mutated BRAF melanoma, based on the improved patient survival in the trametinib arm, compared to the standard of care.	('BRAF melanoma', 'Disease', (49, 62))	('mutated', 'Var', (41, 48))	('trametinib', 'Chemical', 'MESH:C560077', (26, 36))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('patient', 'Species', '9606', (86, 93))	('trametinib', 'Chemical', 'MESH:C560077', (110, 120))	('BRAF melanoma', 'Disease', 'MESH:D008545', (49, 62))	('improved', 'PosReg', (77, 85))
61977	33256089	Evidence suggests that in patients with mutated BRAF, the combination of BRAF and MEK inhibitors yields greater benefit and prolongs the development of resistance.	('BRAF', 'Gene', (73, 77))	('men', 'Species', '9606', (144, 147))	('MEK', 'Gene', '5609', (82, 85))	('patients', 'Species', '9606', (26, 34))	('mutated', 'Var', (40, 47))	('development of resistance', 'MPA', (137, 162))	('prolongs', 'NegReg', (124, 132))	('BRAF', 'Gene', (48, 52))	('MEK', 'Gene', (82, 85))
61981	33256089	A small subset of melanoma patients have DNA alterations in KIT that manifest as point mutations and amplifications in less than 7% of cutaneous melanoma patients, and in approximately 40% of mucosal and acral melanoma patients.	('acral melanoma', 'Phenotype', 'HP:0012060', (204, 218))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('cutaneous melanoma', 'Disease', (135, 153))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (135, 153))	('KIT', 'Gene', (60, 63))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (135, 153))	('melanoma', 'Disease', 'MESH:D008545', (210, 218))	('amplifications', 'MPA', (101, 115))	('patients', 'Species', '9606', (27, 35))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('patients', 'Species', '9606', (219, 227))	('KIT', 'molecular_function', 'GO:0005020', ('60', '63'))	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('point mutations', 'Var', (81, 96))	('acral melanoma', 'Disease', (204, 218))	('KIT', 'Gene', '3815', (60, 63))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('patients', 'Species', '9606', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('melanoma', 'Disease', (210, 218))	('acral melanoma', 'Disease', 'MESH:D008545', (204, 218))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))
61982	33256089	KIT, a tyrosine kinase, when stimulated by binding of stem cell factor (SCF) or when mutated, activates the MAPK and PI3K/AKT pathway.	('binding', 'Interaction', (43, 50))	('stimulated', 'PosReg', (29, 39))	('activates', 'PosReg', (94, 103))	('SCF', 'Gene', (72, 75))	('SCF', 'Gene', '4254', (72, 75))	('stem cell factor', 'Gene', (54, 70))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('stem cell factor', 'Gene', '4254', (54, 70))	('stem cell factor', 'molecular_function', 'GO:0005173', ('54', '70'))	('binding', 'molecular_function', 'GO:0005488', ('43', '50'))	('KIT', 'Gene', '3815', (0, 3))	('AKT', 'Gene', '207', (122, 125))	('mutated', 'Var', (85, 92))	('PI3K', 'molecular_function', 'GO:0016303', ('117', '121'))	('SCF', 'molecular_function', 'GO:0005173', ('72', '75'))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('KIT', 'Gene', (0, 3))	('AKT', 'Gene', (122, 125))
61996	33256089	In cancer, the interactions between PD-1 on cytotoxic T-lymphocytes and PD-L1 on tumor cells or tumor macrophages, NK cells, dendritic cells, and various other immune cells, result in an exhausted T-cell phenotype, rendering the immune system unable to detect and eliminate tumors via epigenetic changes within T-cells (Figure 3).	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (274, 279))	('PD-L1', 'Gene', (72, 77))	('T-cell phenotype', 'CPA', (197, 213))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('epigenetic changes', 'Var', (285, 303))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('interactions', 'Interaction', (15, 27))	('tumors', 'Disease', (274, 280))	('cancer', 'Disease', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('PD-1', 'Gene', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
62001	33256089	Furthermore, glycosylation in PD-L1 was shown to improve the half-life of PD-L1, and strengthen its engagement with PD-1, thereby improving its ability to exhaust T-cells.	('strengthen', 'PosReg', (85, 95))	('PD-L1', 'Gene', (74, 79))	('glycosylation', 'Var', (13, 26))	('engagement', 'Interaction', (100, 110))	('PD-L1', 'Gene', (30, 35))	('improving', 'PosReg', (130, 139))	('glycosylation', 'biological_process', 'GO:0070085', ('13', '26'))	('improve', 'PosReg', (49, 56))	('men', 'Species', '9606', (106, 109))	('half-life', 'MPA', (61, 70))	('exhaust T-cells', 'MPA', (155, 170))	('PD-1', 'Protein', (116, 120))
62006	33256089	However, in the context of cancer, when PD-L1/PD-L2 interact with PD-1 on cytotoxic T-cells, it leads to SHP1/2 recruitment to the TCR and modulates numerous phosphorylation activities, resulting in defective cytolytic T-cell function and metabolism.	('cytolytic T-cell function', 'CPA', (209, 234))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('modulates', 'Reg', (139, 148))	('phosphorylation', 'biological_process', 'GO:0016310', ('158', '173'))	('leads to', 'Reg', (96, 104))	('phosphorylation activities', 'MPA', (158, 184))	('TCR', 'biological_process', 'GO:0006283', ('131', '134'))	('metabolism', 'biological_process', 'GO:0008152', ('239', '249'))	('SHP1/2', 'Gene', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('PD-L1/PD-L2', 'Var', (40, 51))	('defective', 'NegReg', (199, 208))	('recruitment', 'MPA', (112, 123))	('cancer', 'Disease', (27, 33))	('men', 'Species', '9606', (119, 122))	('metabolism', 'CPA', (239, 249))	('TCR', 'cellular_component', 'GO:0042101', ('131', '134'))
62008	33256089	Disruption between PD-1 and one or more of these molecules result in defective development of cytotoxic memory T-cells and exhaustion of CD8+ T cells.	('men', 'Species', '9606', (86, 89))	('CD8', 'Gene', (137, 140))	('cytotoxic memory T', 'Disease', (94, 112))	('CD8', 'Gene', '925', (137, 140))	('cytotoxic memory T', 'Disease', 'MESH:D064420', (94, 112))	('memory', 'biological_process', 'GO:0007613', ('104', '110'))	('mole', 'Phenotype', 'HP:0003764', (49, 53))	('defective', 'NegReg', (69, 78))	('PD-1', 'Gene', (19, 23))	('Disruption', 'Var', (0, 10))
62023	33256089	MDSCs are critical in cancer progression, as they support tumor cell dissemination, and inhibit T-cell function.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('MDSCs', 'Var', (0, 5))	('support', 'PosReg', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('T-cell function', 'CPA', (96, 111))	('inhibit', 'NegReg', (88, 95))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
62025	33256089	MDSCs reduce cytotoxic T-cell function in the tumor microenvironment by disrupting key metabolic pathways required for proper T cell function, which eventually result in T-cell apoptosis.	('MDSCs', 'Var', (0, 5))	('T-cell apoptosis', 'CPA', (170, 186))	('result in', 'Reg', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('key metabolic', 'MPA', (83, 96))	('cytotoxic T-cell function', 'CPA', (13, 38))	('reduce', 'NegReg', (6, 12))	('disrupting', 'NegReg', (72, 82))	('men', 'Species', '9606', (64, 67))	('T-cell apoptosis', 'biological_process', 'GO:0070231', ('170', '186'))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
62026	33256089	Depletion of MDSCs might improve anti-melanoma immunity, since MDSCs were shown to negative correlate with survival.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('MDSCs', 'Gene', (13, 18))	('Depletion', 'Var', (0, 9))	('improve', 'PosReg', (25, 32))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))
62055	33256089	During genetic/epigenetic changes or immune editing, melanoma subclones can successfully downregulate key components of their MHC I antigen presentation pathways, and effectively escape immune surveillance (Figure 3).	('escape', 'Reg', (179, 185))	('antigen presentation', 'biological_process', 'GO:0019882', ('132', '152'))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('immune editing', 'Var', (37, 51))	('downregulate', 'NegReg', (89, 101))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('MHC I antigen presentation pathways', 'Pathway', (126, 161))	('immune', 'MPA', (186, 192))	('genetic/epigenetic changes', 'Var', (7, 33))
62060	33256089	Our lab developed various spontaneous melanoma-prone mouse models, driven by aberrant mGluR1 expression in melanocytes, which mimic melanoma development and progression in humans.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('melanoma', 'Disease', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('men', 'Species', '9606', (148, 151))	('mGluR1', 'Gene', (86, 92))	('humans', 'Species', '9606', (172, 178))	('mouse', 'Species', '10090', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))	('aberrant', 'Var', (77, 85))
62069	33256089	UV-induced accumulation of stochastic mutations in melanocytes leads to cell transformation and tumor formation.	('cell transformation', 'CPA', (72, 91))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('leads to', 'Reg', (63, 71))	('tumor', 'Disease', (96, 101))	('formation', 'biological_process', 'GO:0009058', ('102', '111'))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('stochastic mutations', 'Var', (27, 47))
62088	33256089	MiR-125b-5p detected in the melanoma exosome cargo can induce TAM formation, to support melanoma growth.	('melanoma', 'Disease', (28, 36))	('MiR-125b-5p', 'Var', (0, 11))	('melanoma growth', 'Disease', (88, 103))	('formation', 'biological_process', 'GO:0009058', ('66', '75'))	('support', 'PosReg', (80, 87))	('melanoma growth', 'Disease', 'MESH:D008545', (88, 103))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('exosome', 'cellular_component', 'GO:0070062', ('37', '44'))	('cargo', 'molecular_function', 'GO:0140355', ('45', '50'))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('TAM', 'Chemical', '-', (62, 65))	('MiR-125b-5p', 'Chemical', '-', (0, 11))	('induce', 'PosReg', (55, 61))	('TAM formation', 'CPA', (62, 75))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
62091	33256089	Our lab demonstrated that inhibition of mGluR1 expression or function by genetic or pharmacological inhibitors in melanoma cells, did not modulate the number of exosomes released, but rather reduced the functions of the exosomes on the recipient cells in cell migration, invasion, and anchorage-independent growth, perhaps through cargo sorting into exosomes.	('mGluR1', 'Gene', (40, 46))	('melanoma cells', 'Disease', 'MESH:D008545', (114, 128))	('melanoma cells', 'Disease', (114, 128))	('cell migration', 'CPA', (255, 269))	('cell migration', 'biological_process', 'GO:0016477', ('255', '269'))	('inhibition', 'Var', (26, 36))	('reduced', 'NegReg', (191, 198))	('invasion', 'CPA', (271, 279))	('cargo', 'molecular_function', 'GO:0140355', ('331', '336'))	('anchorage-independent growth', 'CPA', (285, 313))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('functions', 'MPA', (203, 212))
62111	33256089	The triple combination of atezolizumab, vemurafenib (BRAF V600E inhibitor), and cobimetnib (MEK inhibitor) was approved by the FDA as a first line therapy for BRAF V600 unresectable or metastatic melanoma.	('MEK', 'Gene', (92, 95))	('MEK', 'Gene', '5609', (92, 95))	('atezolizumab', 'Chemical', 'MESH:C000594389', (26, 38))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('BRAF V600', 'Var', (159, 168))	('melanoma', 'Disease', (196, 204))	('V600E', 'Mutation', 'rs113488022', (58, 63))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))	('vemurafenib', 'Chemical', 'MESH:D000077484', (40, 51))	('cobimetnib', 'Chemical', '-', (80, 90))	('metastatic', 'CPA', (185, 195))
62116	33256089	PD-1 antibodies show response rates in the range of 30%-40% which are higher than ipilimumab and showed improved overall survival.	('ipilimumab', 'Chemical', 'MESH:D000074324', (82, 92))	('improved', 'PosReg', (104, 112))	('antibodies', 'Var', (5, 15))	('PD-1', 'Gene', (0, 4))
62120	33256089	Furthermore, detailed characterization of melanoma patients who are sensitive to immune checkpoint therapy would improve response rates and survival outcomes for future patients, given anti-CTLA-4/anti-PD-1/anti-PD-L1 antibodies.	('melanoma', 'Disease', (42, 50))	('patients', 'Species', '9606', (169, 177))	('response rates', 'CPA', (121, 135))	('anti-CTLA-4/anti-PD-1/anti-PD-L1', 'Var', (185, 217))	('patients', 'Species', '9606', (51, 59))	('survival outcomes', 'CPA', (140, 157))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('improve', 'PosReg', (113, 120))
62141	33256089	Genomic instability is associated with treatment responses to anti-PD-1/anti-PD-L1 antibodies in melanoma (and other cancers), specifically by examining the tumor mutational burden.	('tumor', 'Disease', (157, 162))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('men', 'Species', '9606', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('Genomic instability', 'Var', (0, 19))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('anti-PD-1/anti-PD-L1', 'Var', (62, 82))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('associated', 'Reg', (23, 33))	('cancers', 'Disease', (117, 124))
62142	33256089	This concept revolves around the fact that these tumors have a higher mutation rate that increases their likelihood of presenting neoepitopes for surveying immune cells, to recognize and mount an anti-tumor immune response.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('presenting neoepitopes for surveying immune cells', 'MPA', (119, 168))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('immune response', 'biological_process', 'GO:0006955', ('207', '222'))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Disease', (201, 206))	('mutation', 'Var', (70, 78))	('increases', 'PosReg', (89, 98))
62144	33256089	proposed that if there are specific mutations that make a tumor more responsive to immune checkpoint therapy, "immune checkpoint activating mutation threshold (iCAM)".	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('activating', 'PosReg', (129, 139))
62156	33256089	Similar results were observed when the patients were stratified based on the PD-L1 positivity of their tumors, high tumor mutational burden or high T-cell inflamed gene expression profiles showed improved responses and survival.	('responses', 'CPA', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('patients', 'Species', '9606', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('survival', 'CPA', (219, 227))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('gene expression', 'biological_process', 'GO:0010467', ('164', '179'))	('tumor', 'Disease', (116, 121))	('improved', 'PosReg', (196, 204))	('high', 'Var', (111, 115))
62160	33256089	These subtypes can be divided into cutaneous melanoma; CSID and non-CSID with a higher mutational burden, as compared to non-cutaneous melanoma that include acral, mucosal, and uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('cutaneous melanoma', 'Disease', (125, 143))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (125, 143))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (125, 143))	('mutational', 'Var', (87, 97))	('cutaneous melanoma', 'Disease', (35, 53))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (35, 53))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (35, 53))	('uveal melanoma', 'Disease', 'MESH:C536494', (177, 191))	('uveal melanoma', 'Phenotype', 'HP:0007716', (177, 191))	('uveal melanoma', 'Disease', (177, 191))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))
62183	33256089	CAR T cell therapy was shown to be remarkably successful in treating patients with B-cell malignancies, however, for solid tumors like melanoma, it was met with low response rates (19% for CARs targeting gp100 and 30% for CARs targeting DMF5), and the toxicities associated with the destruction of normal melanocytes.	('CARs', 'Gene', '833', (189, 193))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('patients', 'Species', '9606', (69, 77))	('malignancies', 'Disease', (90, 102))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('solid tumors like melanoma', 'Disease', (117, 143))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('CAR', 'Gene', (0, 3))	('CAR', 'Gene', '9970', (0, 3))	('solid tumors like melanoma', 'Disease', 'MESH:D008545', (117, 143))	('toxicities', 'Disease', 'MESH:D064420', (252, 262))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('CAR', 'Gene', (222, 225))	('gp100', 'Gene', (204, 209))	('CAR', 'Gene', '9970', (222, 225))	('CARs', 'Gene', (222, 226))	('gp100', 'Gene', '6490', (204, 209))	('CAR', 'cellular_component', 'GO:0005826', ('0', '3'))	('toxicities', 'Disease', (252, 262))	('CAR', 'Gene', (189, 192))	('CARs', 'Gene', (189, 193))	('CAR', 'Gene', '9970', (189, 192))	('DMF5', 'Var', (237, 241))	('CARs', 'Gene', '833', (222, 226))
62196	33256089	Preclinical studies suggest that oncolytic viruses can induce an abscopal-like effect; with tumor regression occurring at the site of injection, and induction of a systemic anti-tumor immune response that affects distant tumors.	('tumor', 'Disease', (178, 183))	('abscopal-like effect', 'Disease', (65, 85))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('immune response', 'biological_process', 'GO:0006955', ('184', '199'))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('oncolytic viruses', 'Var', (33, 50))	('tumors', 'Disease', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
62205	33256089	The rationale for combining these two immune checkpoint blockade therapies is to expand anti-tumor cytotoxic T-cells within the lymph nodes through anti-CTLA-4 treatment, and anti-PD-1 releases the "breaks" of these effector T-cells at the tumor site to overcome the immune suppressive environment created by tumor cells (Figure 7).	('men', 'Species', '9606', (165, 168))	('expand', 'PosReg', (81, 87))	('tumor', 'Disease', (309, 314))	('tumor', 'Disease', (240, 245))	('tumor cytotoxic', 'Disease', (93, 108))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor cytotoxic', 'Disease', 'MESH:D064420', (93, 108))	('men', 'Species', '9606', (293, 296))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('anti-PD-1', 'Var', (175, 184))
62211	33256089	Similarly, the rational of sequential administration of T-VEC, anti-CTLA-4, and anti-PD-1, radiation therapy could be given first to promote tumor necrosis, and to induce an anti-tumor adaptive immune response.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor necrosis', 'Disease', 'MESH:D009336', (141, 155))	('adaptive immune response', 'biological_process', 'GO:0002250', ('185', '209'))	('induce', 'Reg', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('necrosis', 'biological_process', 'GO:0070265', ('147', '155'))	('promote', 'PosReg', (133, 140))	('necrosis', 'biological_process', 'GO:0008219', ('147', '155'))	('necrosis', 'biological_process', 'GO:0019835', ('147', '155'))	('tumor', 'Disease', (141, 146))	('anti-CTLA-4', 'Var', (63, 74))	('necrosis', 'biological_process', 'GO:0008220', ('147', '155'))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('anti-PD-1', 'Var', (80, 89))	('tumor necrosis', 'Disease', (141, 155))	('necrosis', 'biological_process', 'GO:0001906', ('147', '155'))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
62214	33256089	Preclinical evidence suggest that adoptive T-cell transfer along with the dual treatment of anti-CTLA-4 and anti-PD-1, can improve tumor-antigen-specific cytotoxic T-cell infiltration and function within the tumor site, corresponding to the improved survival in experimental animal models (Figure 7).	('tumor-antigen', 'molecular_function', 'GO:0008222', ('131', '144'))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('function within the', 'CPA', (188, 207))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('improved', 'PosReg', (241, 249))	('anti-CTLA-4', 'Gene', (92, 103))	('adoptive T-cell transfer', 'CPA', (34, 58))	('improve', 'PosReg', (123, 130))	('men', 'Species', '9606', (268, 271))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (131, 136))	('anti-PD-1', 'Var', (108, 117))	('men', 'Species', '9606', (84, 87))	('tumor', 'Disease', (208, 213))
62218	33256089	Interestingly, vemurafenib, the inhibitor for mutated BRAF, paradoxically activates the MAPK pathway in adoptively transferred T-cells in a mutant BRAF-driven mouse melanoma model.	('MAPK', 'molecular_function', 'GO:0004707', ('88', '92'))	('BRAF', 'Gene', (54, 58))	('activates', 'PosReg', (74, 83))	('mouse', 'Species', '10090', (159, 164))	('mutated', 'Var', (46, 53))	('MAPK pathway', 'Pathway', (88, 100))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('vemurafenib', 'Chemical', 'MESH:D000077484', (15, 26))	('melanoma', 'Disease', (165, 173))	('mutant', 'Var', (140, 146))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
62219	33256089	In this model, the inhibitor, vemurafenib, acts within its canonical function to inhibit mutant BRAF in melanoma cells but also paradoxically activates the MAPK pathway in T-cells to enhance the anti-tumor cytotoxic function of the tumor recognizing T-cells.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('activates', 'PosReg', (142, 151))	('MAPK', 'molecular_function', 'GO:0004707', ('156', '160'))	('mutant', 'Var', (89, 95))	('melanoma cells', 'Disease', 'MESH:D008545', (104, 118))	('tumor cytotoxic', 'Disease', 'MESH:D064420', (200, 215))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('vemurafenib', 'Chemical', 'MESH:D000077484', (30, 41))	('tumor cytotoxic', 'Disease', (200, 215))	('melanoma cells', 'Disease', (104, 118))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('inhibit', 'NegReg', (81, 88))	('MAPK pathway', 'Pathway', (156, 168))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('enhance', 'PosReg', (183, 190))	('BRAF', 'Gene', (96, 100))
62226	33256089	However, with the ongoing biomarker studies uncovering key molecular markers such as tumor mutational burden, molecular marker expression on tumor or immune cells, circulating soluble markers, and pro- or anti-tumor immune cell populations, at baseline or on treatment, would advance the identification of responders vs. non-responders.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', (85, 90))	('advance', 'PosReg', (276, 283))	('men', 'Species', '9606', (264, 267))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', (141, 146))	('mutational', 'Var', (91, 101))	('mole', 'Phenotype', 'HP:0003764', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('responders', 'Disease', (306, 316))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mole', 'Phenotype', 'HP:0003764', (110, 114))	('soluble', 'cellular_component', 'GO:0005625', ('176', '183'))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
62255	33008022	Strong genetic prognosticators for increased metastatic risk in UM include monosomy 3 (M3), polysomy 8q, inactivating somatic mutations of BAP1, and somatic mutations in SF3B1/SRSF2.	('metastatic', 'CPA', (45, 55))	('SF3B1', 'Gene', '23451', (170, 175))	('BAP1', 'Gene', (139, 143))	('SRSF2', 'Gene', '6427', (176, 181))	('polysomy 8q', 'Var', (92, 103))	('BAP1', 'Gene', '8314', (139, 143))	('monosomy 3', 'Disease', (75, 85))	('SRSF2', 'Gene', (176, 181))	('inactivating somatic', 'Var', (105, 125))	('SF3B1', 'Gene', (170, 175))
62276	33008022	For instance, ITGB4 (integrin ss4; CD104) expression was 16 times lower (log2 fold change: 4) (Figure 2A) in mUM with high total immunoscores compared to those with low immunoscores (adjusted p < 0.01).	('high', 'Var', (118, 122))	('ITGB4', 'Gene', '3691', (14, 19))	('expression', 'MPA', (42, 52))	('CD104', 'Gene', '3691', (35, 40))	('lower', 'NegReg', (66, 71))	('CD104', 'Gene', (35, 40))	('ITGB4', 'Gene', (14, 19))
62294	33008022	There was no difference in the expression of the above proteins between nBAP+ve or nBAP1-ve mUM.	('nBAP+ve', 'Var', (72, 79))	('BAP1', 'Gene', (84, 88))	('BAP1', 'Gene', '8314', (84, 88))
62328	33008022	Although there are no trials targeting DUSP4, siRNA depletion of DUSP4 sensitizes cancer cell lines to drugs to which they were otherwise resistant, a strategy that may be of value in mUM.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('DUSP4', 'Gene', '1846', (65, 70))	('cancer', 'Disease', (82, 88))	('sensitizes', 'Reg', (71, 81))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('DUSP4', 'Gene', (39, 44))	('depletion', 'Var', (52, 61))	('DUSP4', 'Gene', (65, 70))	('DUSP4', 'Gene', '1846', (39, 44))
62390	33008022	For mUM versus control liver, QC flags were raised in three of the mUM and these RNA samples were excluded from the analyses: R15 and R31 (normalization flags) and R38 (binding density flag).	('flags', 'Species', '34205', (153, 158))	('R31', 'Var', (134, 137))	('R15', 'Var', (126, 129))	('flags', 'Species', '34205', (33, 38))	('binding', 'molecular_function', 'GO:0005488', ('169', '176'))	('R38', 'Var', (164, 167))	('RNA', 'cellular_component', 'GO:0005562', ('81', '84'))
62407	32953248	Monosomy 3 and BAP1 mutation are strong prognostic factors predicting metastatic risk in UM.	('predicting', 'Reg', (59, 69))	('metastatic risk', 'CPA', (70, 85))	('mutation', 'Var', (20, 28))	('BAP1', 'Gene', '8314', (15, 19))	('UM', 'Phenotype', 'HP:0007716', (89, 91))	('BAP1', 'Gene', (15, 19))	('Monosomy 3', 'Var', (0, 10))
62422	32953248	BAP1 mutations are associated with cancers, such as clear cell renal carcinoma, mesothelioma, and non-small cell lung cancer as well as UM.	('associated', 'Reg', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancers', 'Disease', (35, 42))	('BAP1', 'Gene', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('clear cell renal carcinoma', 'Disease', (52, 78))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('UM', 'Phenotype', 'HP:0007716', (136, 138))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (98, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('cancer', 'Disease', (118, 124))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (52, 78))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (102, 124))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (52, 78))	('mesothelioma', 'Disease', (80, 92))	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('BAP1', 'Gene', '8314', (0, 4))	('renal carcinoma', 'Phenotype', 'HP:0005584', (63, 78))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Disease', (35, 41))
62424	32953248	The bi-allelic inactivation of BAP1 frequently leads to a loss of nuclear BAP1 protein expression (nBAP1) on immunohistochemistry (IHC; i.e.	('BAP1', 'Gene', '8314', (100, 104))	('bi-allelic inactivation', 'Var', (4, 27))	('loss', 'NegReg', (58, 62))	('BAP1', 'Gene', '8314', (31, 35))	('BAP1', 'Gene', (100, 104))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('BAP1', 'Gene', '8314', (74, 78))	('BAP1', 'Gene', (31, 35))	('BAP1', 'Gene', (74, 78))
62425	32953248	it can be used as a surrogate marker because its nuclear expression corresponds to a high degree with both BAP1 mutational and chromosome 3 status).	('BAP1', 'Gene', '8314', (107, 111))	('BAP1', 'Gene', (107, 111))	('mutational', 'Var', (112, 122))	('chromosome', 'cellular_component', 'GO:0005694', ('127', '137'))	('nuclear expression', 'MPA', (49, 67))
62441	32953248	both the training and test sets), 539848, 130471, and 30677 tumor patches were cropped in 3 different dimensions, respectively (Table 1).	('539848', 'Var', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('130471', 'Var', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('30677', 'Var', (54, 59))	('tumor', 'Disease', (60, 65))
62489	32509949	Next Generation Sequence analysis of BAP1 detected a germline, monoallelic single base substitution c.2188T>C, leading to loss of a stop codon, p.X730Arg.	('c.2188T>C', 'Mutation', 'c.2188T>C', (100, 109))	('p.X730Arg', 'Mutation', 'p.X730R', (144, 153))	('BAP1', 'Gene', '8314', (37, 41))	('stop codon', 'MPA', (132, 142))	('p.X730Arg', 'Var', (144, 153))	('loss', 'NegReg', (122, 126))	('BAP1', 'Gene', (37, 41))	('c.2188T>C', 'Var', (100, 109))
62503	32509949	Patients with germline BAP1 pathogenic variants tend to have more aggressive class 2 tumors with increased risk for metastasis and poorer prognosis.	('BAP1', 'Gene', (23, 27))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('BAP1', 'Gene', '8314', (23, 27))	('Patients', 'Species', '9606', (0, 8))	('metastasis', 'CPA', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('variants', 'Var', (39, 47))	('tumors', 'Disease', (85, 91))
62510	32509949	BAP1 pathogenic variant status correlates well with protein expression on immunohistochemistry.	('BAP1', 'Gene', (0, 4))	('variant', 'Var', (16, 23))	('protein expression', 'MPA', (52, 70))	('BAP1', 'Gene', '8314', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
62513	32509949	It has been estimated that perhaps 10%-20% of patients with BAP1-inactivated nevi could have pathogenic germline variations in BAP1, although prospective studies are warranted in this area.	('patients', 'Species', '9606', (46, 54))	('BAP1', 'Gene', (127, 131))	('pathogenic', 'Reg', (93, 103))	('BAP1', 'Gene', '8314', (60, 64))	('nevi', 'Phenotype', 'HP:0003764', (77, 81))	('BAP1', 'Gene', '8314', (127, 131))	('BAP1', 'Gene', (60, 64))	('variations', 'Var', (113, 123))
62521	32509949	To date, there are no evidence-based screening recommendations for detection of germline BAP1 mutations.	('BAP1', 'Gene', '8314', (89, 93))	('BAP1', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))
62527	32230715	Using a CRISPR-Cas9 approach, we observed that the inhibition of ADAMTS1 in an aggressive uveal melanoma model compromised its endothelial-like properties, and more importantly, caused a robust blockade on the progression of tumor xenografts.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('Cas', 'cellular_component', 'GO:0005650', ('15', '18'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('endothelial-like', 'MPA', (127, 143))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', (225, 230))	('ADAMTS1', 'Gene', (65, 72))	('compromised', 'NegReg', (111, 122))	('blockade', 'NegReg', (194, 202))	('aggressive uveal melanoma', 'Disease', (79, 104))	('inhibition', 'Var', (51, 61))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('aggressive uveal melanoma', 'Disease', 'MESH:C536494', (79, 104))
62549	32230715	While MUM-2B, SK-MEL-28, SK-MEL-103, SK-MEL-147 and C8161 generated clear endothelial-like networks in Matrigel, MUM-2C, A-375 and G-361 formed cell clusters (Figure 1a).	('SK-MEL-147', 'CellLine', 'CVCL:3876', (37, 47))	('SK-MEL', 'Chemical', '-', (25, 31))	('MUM-2', 'Gene', '58485', (113, 118))	('SK-MEL-147', 'Var', (37, 47))	('SK-MEL', 'Chemical', '-', (14, 20))	('MUM-2', 'Gene', '58485', (6, 11))	('MUM-2', 'Gene', (6, 11))	('SK-MEL', 'Chemical', '-', (37, 43))	('MUM-2', 'Gene', (113, 118))	('cell clusters', 'CPA', (144, 157))	('SK-MEL-103', 'CellLine', 'CVCL:6069', (25, 35))	('C8161', 'Var', (52, 57))
62580	32230715	In line with the impaired progression, ATS1-KO tumors showed an overall downregulation of stemness markers compared with WT samples, especially significant for the more abundant NANOG and POU5F1 (Figure 4d and Figure S2d).	('stemness markers', 'CPA', (90, 106))	('NANOG', 'Var', (178, 183))	('ATS1-KO tumors', 'Disease', 'OMIM:301050', (39, 53))	('ATS1-KO tumors', 'Disease', (39, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('downregulation', 'NegReg', (72, 86))	('POU5F1', 'Var', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
62599	32230715	All these data demonstrated that ADAMTS1 inhibition also compromises stemness capacities in MUM-2B UVM cells.	('ADAMTS1', 'Gene', (33, 40))	('compromises', 'NegReg', (57, 68))	('stemness capacities', 'CPA', (69, 88))	('MUM-2', 'Gene', (92, 97))	('inhibition', 'Var', (41, 51))	('UVM', 'Phenotype', 'HP:0007716', (99, 102))	('MUM-2', 'Gene', '58485', (92, 97))
62601	32230715	Indeed, the size and number of spheres of ATS1-KO cells with ADAMTS1+ CM was comparable to that of WT cells with normal CSC medium (Figure 5f,g), suggesting that secreted ADAMTS1 have a positive effect on the recovery of stemness capacities of MUM-2B cells.	('CSC medium', 'Chemical', '-', (120, 130))	('ADAMTS1+ CM', 'Var', (61, 72))	('positive', 'PosReg', (186, 194))	('ADAMTS1', 'Gene', (171, 178))	('MUM-2', 'Gene', '58485', (244, 249))	('stemness capacities', 'CPA', (221, 240))	('MUM-2', 'Gene', (244, 249))
62652	32230715	Uveal melanoma MUM-2B and MUM-2C, and skin melanoma C8161 cell lines were kindly provided by Dr. Arjan W. Griffioen (VUmc, Amsterdam, The Netherlands); skin melanoma SK-MEL-28, SK-MEL-103, SK-MEL-147 by Dr. Juan A. Recio (VHIR, Barcelona, Spain); A-375 and G-361 by Dr. Javier Oliver (IPBLN-CSIC, Granada, Spain); and HEK293T by Dr. Pablo Menendez (IJC, Barcelona, Spain).	('MUM-2', 'Gene', '58485', (26, 31))	('HEK293T', 'CellLine', 'CVCL:0063', (318, 325))	('SK-MEL', 'Chemical', '-', (189, 195))	('skin melanoma', 'Disease', 'MESH:D008545', (152, 165))	('HEK293T', 'Var', (318, 325))	('MUM-2', 'Gene', '58485', (15, 20))	('SK-MEL-103', 'CellLine', 'CVCL:6069', (177, 187))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('skin melanoma', 'Disease', (152, 165))	('melanoma', 'Disease', (157, 165))	('SK-MEL', 'Chemical', '-', (177, 183))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('skin melanoma', 'Disease', 'MESH:D008545', (38, 51))	('SK-MEL-147', 'CellLine', 'CVCL:3876', (189, 199))	('MUM-2', 'Gene', (26, 31))	('MUM-2', 'Gene', (15, 20))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('skin melanoma', 'Disease', (38, 51))	('melanoma', 'Disease', (43, 51))	('SK-MEL', 'Chemical', '-', (166, 172))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
62654	32230715	Specific media were: RPMI 1640 with stable glutamine (Biowest, Nuaille, France) for MUM-2B, MUM-2C and C8161; High Glucose Dulbecco's Modified Eagle Medium (DMEM) with stable glutamine and sodium pyruvate (Biowest, Nuaille, France) for A-375, G-361, SK-MEL-28, SK-MEL-103, SK-MEL-147 and HEK293T.	('MUM-2', 'Gene', (84, 89))	('MUM-2', 'Gene', (92, 97))	('glutamine', 'Chemical', 'MESH:D005973', (43, 52))	('SK-MEL-103', 'Var', (261, 271))	('SK-MEL', 'Chemical', '-', (250, 256))	('SK-MEL', 'Chemical', '-', (273, 279))	('High Glucose Dulbecco', 'Disease', (110, 131))	('High Glucose', 'Phenotype', 'HP:0003074', (110, 122))	('glutamine', 'Chemical', 'MESH:D005973', (175, 184))	('MUM-2', 'Gene', '58485', (92, 97))	('MUM-2', 'Gene', '58485', (84, 89))	('sodium pyruvate', 'Chemical', '-', (189, 204))	('High Glucose Dulbecco', 'Disease', 'MESH:D044882', (110, 131))	('G-361', 'Var', (243, 248))	('DMEM', 'Chemical', '-', (157, 161))	('SK-MEL-103', 'CellLine', 'CVCL:6069', (261, 271))	('SK-MEL-147', 'CellLine', 'CVCL:3876', (273, 283))	('SK-MEL', 'Chemical', '-', (261, 267))	('HEK293T', 'CellLine', 'CVCL:0063', (288, 295))	('HEK293T', 'Var', (288, 295))	('SK-MEL-147', 'Var', (273, 283))
62662	32230715	For the morphometric analysis of vasculature, tumor paraffin sections were subjected to immunofluorescence (IF) with a rat anti-mouse EMCN (endomucin) antibody (V.7C7, SC-65495, SCBT) and Alexa Fluor 488 donkey anti-rat secondary antibody (A21208, ThermoFisher Scientific, Waltham, MA, USA).	('antibody', 'molecular_function', 'GO:0003823', ('230', '238'))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('antibody', 'cellular_component', 'GO:0042571', ('151', '159'))	('antibody', 'cellular_component', 'GO:0019815', ('230', '238'))	('antibody', 'cellular_component', 'GO:0019815', ('151', '159'))	('tumor', 'Disease', (46, 51))	('A21208', 'Var', (240, 246))	('endomucin', 'Gene', '59308', (140, 149))	('endomucin', 'Gene', (140, 149))	('paraffin', 'Chemical', 'MESH:D010232', (52, 60))	('mouse', 'Species', '10090', (128, 133))	('antibody', 'cellular_component', 'GO:0042571', ('230', '238'))	('antibody', 'cellular_component', 'GO:0019814', ('151', '159'))	('antibody', 'molecular_function', 'GO:0003823', ('151', '159'))	('antibody', 'cellular_component', 'GO:0019814', ('230', '238'))	('Alexa Fluor 488', 'Chemical', '-', (188, 203))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
62663	32230715	CDH5 and NANOG were detected with rabbit anti-human CDH5 (160840, Cayman Chemical, Ann Arbor, MI, USA) or NANOG (4903, Cell Signaling Technology, Danvers, MA, USA) antibodies, respectively.	('CDH5', 'Gene', (0, 4))	('160840', 'Var', (58, 64))	('human', 'Species', '9606', (46, 51))	('CDH5', 'Gene', '1003', (0, 4))	('CDH5', 'Gene', (52, 56))	('CDH5', 'Gene', '1003', (52, 56))	('Signaling', 'biological_process', 'GO:0023052', ('124', '133'))
62667	32230715	PAS staining was performed with Periodic acid solution (3951, Sigma-Aldrich, St. Louis, MO, USA) and Schiff's reagent (3952016, Sigma-Aldrich, St. Louis, MO, USA).	('Periodic acid', 'Chemical', 'MESH:D010504', (32, 45))	('3952016', 'Var', (119, 126))	('PAS', 'cellular_component', 'GO:0000407', ('0', '3'))	('3951', 'Var', (56, 60))
62684	32230715	The inhibition of this protease reveals a new link between stemness and endothelial-like features of uveal melanoma cells, and the evaluation of gene expression data of human samples shows its relevance at early stages, also implying the contribution of further ADAMTS members during more advance stages.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('uveal melanoma', 'Phenotype', 'HP:0007716', (101, 115))	('gene expression', 'biological_process', 'GO:0010467', ('145', '160'))	('inhibition', 'Var', (4, 14))	('human', 'Species', '9606', (169, 174))
62796	26225580	One potential explanation for these results might be BRAF inhibitors, as a new treatment option for controlling BRAF mutant melanoma metastasizing to the brain, becoming widely available for use outside of trials.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('BRAF', 'Gene', '673', (53, 57))	('mutant', 'Var', (117, 123))	('BRAF', 'Gene', (53, 57))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))
62814	26225580	In terms of safety, a consistent theme with ipilimumab across multiple clinical trials is risk for irAEs, and, rarely, death due to colitis.	('colitis', 'Disease', 'MESH:D003092', (132, 139))	('ipilimumab', 'Var', (44, 54))	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('irAEs', 'Disease', (99, 104))	('colitis', 'Disease', (132, 139))	('ipilimumab', 'Chemical', 'MESH:D000074324', (44, 54))	('colitis', 'Phenotype', 'HP:0002583', (132, 139))
62833	25587217	The majority offered molecular analyses of UM tumor samples to most patients.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('molecular', 'Var', (21, 30))	('patients', 'Species', '9606', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
62846	25587217	Loss of chromosome 3 is one of the key early cytogenetic alterations associated with more aggressive UM, and monosomy of chromosome 3 in as little as 6% of tumor cells significantly increases the risk of UM metastasis.	('monosomy', 'Var', (109, 117))	('increases', 'PosReg', (182, 191))	('more', 'PosReg', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('chromosome', 'cellular_component', 'GO:0005694', ('121', '131'))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('associated', 'Reg', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('Loss', 'Var', (0, 4))	('UM metastasis', 'CPA', (204, 217))
62847	25587217	However, intratumoral heterogeneity for monosomy 3 is a frequent occurrence that complicates accurate detection and is understandable, given that the majority of tumor specimens are obtained from a single pass fine-needle aspiration biopsy (FNAB).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', (162, 167))	('aspiration', 'Phenotype', 'HP:0002835', (222, 232))	('monosomy 3', 'Var', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
62923	25587217	In both survey groups, more than 75% of respondents offered molecular testing of tumor biopsy samples to most or all of their UM patients.	('patients', 'Species', '9606', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('molecular testing', 'Var', (60, 77))	('tumor', 'Disease', (81, 86))
62950	23637769	Using tumour cell lines, primary human cells and primary human breast cancer (BC) xenografts, we investigated the capacity of DPT-C9h to provoke apoptosis in vitro and inhibition of tumour growth (TGI) in vivo.	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('breast cancer', 'Disease', (63, 76))	('tumour', 'Disease', 'MESH:D009369', (6, 12))	('human', 'Species', '9606', (33, 38))	('tumour', 'Disease', (6, 12))	('human', 'Species', '9606', (57, 62))	('tumour growth', 'Disease', (182, 195))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('provoke', 'PosReg', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('DPT-C9h', 'Chemical', '-', (126, 133))	('apoptosis', 'CPA', (145, 154))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('tumour growth', 'Disease', 'MESH:D006130', (182, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('inhibition', 'NegReg', (168, 178))	('tumour', 'Disease', (182, 188))	('DPT-C9h', 'Var', (126, 133))
62952	23637769	We demonstrated that DPT-C9h specifically target caspase-9/PP2A interaction in vitro and in vivo and induced caspase-9-dependent apoptosis in cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('DPT-C9h', 'Var', (21, 28))	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('DPT-C9h', 'Chemical', '-', (21, 28))	('apoptosis', 'CPA', (129, 138))	('caspase-9/PP2A', 'Protein', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('caspase-9-dependent', 'MPA', (109, 128))	('caspase-9/PP2A', 'Gene', (49, 63))	('induced', 'PosReg', (101, 108))	('interaction', 'Interaction', (64, 75))	('cancer', 'Disease', (142, 148))
62953	23637769	DPT-C9h also induced significant TGI in BC xenografts models.	('TGI', 'CPA', (33, 36))	('DPT-C9h', 'Var', (0, 7))	('BC xenografts models', 'CPA', (40, 60))	('DPT-C9h', 'Chemical', '-', (0, 7))
62957	23637769	Using the cell-penetrating peptides blocking caspase-9/PP2A interactions, we have demonstrated that DPT-C9h had a strong therapeutic effect in vitro and in vivo in mouse models of tumour progression.	('mouse', 'Species', '10090', (164, 169))	('therapeutic effect', 'CPA', (121, 139))	('DPT-C9h', 'Var', (100, 107))	('DPT-C9h', 'Chemical', '-', (100, 107))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('interactions', 'Interaction', (60, 72))	('tumour', 'Disease', (180, 186))
62963	23637769	Conversely, the inhibition of PP1, PP2A, or PP2C triggers cell death, indicating also a potential anti-apoptotic function of these phosphatases, and pointing to a complex interplay of phosphatase actions.	('anti-apoptotic', 'CPA', (98, 112))	('PP2C', 'Gene', (44, 48))	('inhibition', 'NegReg', (16, 26))	('phosphatase', 'molecular_function', 'GO:0016791', ('184', '195'))	('cell death', 'biological_process', 'GO:0008219', ('58', '68'))	('cell death', 'CPA', (58, 68))	('PP1', 'Gene', '19047', (30, 33))	('PP2C', 'Gene', '242083', (44, 48))	('PP1', 'Gene', (30, 33))	('triggers', 'Reg', (49, 57))	('PP2A', 'Var', (35, 39))
62968	23637769	On these bases, we decided to analyze whether modulation of the PP2A and caspase-9 interaction might have an impact on the induction of tumour cell deathing without effecting healthy cells, and demonstrated DPT-C9h and DPT-C9 corresponding to the binding sites between human and mouse caspase-9 and PP2A respectively, have a specific anti-tumour effect.	('tumour', 'Phenotype', 'HP:0002664', (339, 345))	('impact', 'Reg', (109, 115))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Disease', 'MESH:D009369', (339, 345))	('DPT-C9', 'Chemical', '-', (207, 213))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('mouse', 'Species', '10090', (279, 284))	('interaction', 'Interaction', (83, 94))	('tumour', 'Disease', (136, 142))	('human', 'Species', '9606', (269, 274))	('tumour', 'Disease', (339, 345))	('DPT-C9h', 'Var', (207, 214))	('modulation', 'Var', (46, 56))	('DPT-C9h', 'Chemical', '-', (207, 214))	('DPT-C9', 'Var', (219, 225))	('DPT-C9', 'Chemical', '-', (219, 225))	('binding', 'molecular_function', 'GO:0005488', ('247', '254'))
62991	23637769	They carry a latent K-ras allele with two copies of exon 1: one was the wild-type and the other the G12D mutant (Tyler Jacks).	('K-ras', 'Gene', (20, 25))	('G12D', 'Mutation', 'rs121913529', (100, 104))	('K-ras', 'Gene', '16653', (20, 25))	('G12D', 'Var', (100, 104))
62992	23637769	The latent allele is stochastically activated in cells through homologous recombination, which results in deletion of the wild-type copy of exon 1 and the expression of an oncogenic form of the K-ras gene.	('K-ras', 'Gene', (194, 199))	('K-ras', 'Gene', '16653', (194, 199))	('deletion', 'Var', (106, 114))	('homologous recombination', 'biological_process', 'GO:0035825', ('63', '87'))
63014	23637769	As controls, we generated the shuttle DPT-sh1 alone, the peptides C9 and C9h, which did not contain the shuttle and the peptide DPT-C9h mut, with a mutation in the caspase-9/PP2A binding sequence and that does not bind PP2A (data not shown).	('DPT', 'Chemical', '-', (38, 41))	('DPT', 'Chemical', '-', (128, 131))	('binding', 'molecular_function', 'GO:0005488', ('179', '186'))	('sh1', 'Gene', '100125848', (42, 45))	('caspase-9/PP2A', 'Protein', (164, 178))	('binding', 'Interaction', (179, 186))	('sh1', 'Gene', (42, 45))	('DPT-C9h', 'Chemical', '-', (128, 135))	('C9h', 'Chemical', '-', (73, 76))	('mutation', 'Var', (148, 156))	('C9h', 'Chemical', '-', (132, 135))
63018	23637769	Figure 1A shows that the amount of complex detected in DPT-C9h-treated cells was strongly reduced compared to non-treated control cells.	('DPT-C9h-treated', 'Var', (55, 70))	('DPT-C9h', 'Chemical', '-', (55, 62))	('reduced', 'NegReg', (90, 97))	('amount of complex', 'MPA', (25, 42))
63019	23637769	For the in vitro competition assay, lysates from HBCx-8 cells were immunoprecipitated with an anti-caspase-9 antibody and the interaction with PP2A competed with the DPT-C9h peptide (Fig 1A).	('antibody', 'cellular_component', 'GO:0019815', ('109', '117'))	('interaction', 'Interaction', (126, 137))	('antibody', 'cellular_component', 'GO:0019814', ('109', '117'))	('antibody', 'molecular_function', 'GO:0003823', ('109', '117'))	('PP2A', 'Var', (143, 147))	('DPT-C9h', 'Chemical', '-', (166, 173))	('antibody', 'cellular_component', 'GO:0042571', ('109', '117'))
63023	23637769	We analyzed the ability of the two penetrating peptides DPT-C9h and DPT-C9, as well as the negative control peptides C9, C9h and DPT-Sh1 to induce apoptosis.	('C9h', 'Chemical', '-', (60, 63))	('induce', 'Reg', (140, 146))	('DPT-C9', 'Chemical', '-', (56, 62))	('DPT-C9', 'Chemical', '-', (68, 74))	('DPT-C9h', 'Var', (56, 63))	('DPT', 'Chemical', '-', (56, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('147', '156'))	('DPT', 'Chemical', '-', (129, 132))	('C9h', 'Chemical', '-', (121, 124))	('DPT', 'Chemical', '-', (68, 71))	('DPT-C9h', 'Chemical', '-', (56, 63))	('apoptosis', 'CPA', (147, 156))	('apoptosis', 'biological_process', 'GO:0006915', ('147', '156'))	('DPT-C9', 'Var', (68, 74))	('Sh1', 'Gene', (133, 136))	('Sh1', 'Gene', '100125848', (133, 136))
63024	23637769	As shown in Figure 2A, DPT-C9h induced apoptosis, as detected by Annexin-V staining in human Daudi, Jurkat, and HeLa cell lines upon 20 h of treatment, whereas the C9 and C9h peptides without shuttle and the shuttle alone, did not induce apoptosis in human cell lines.	('apoptosis', 'biological_process', 'GO:0006915', ('238', '247'))	('apoptosis', 'CPA', (39, 48))	('Jurkat', 'CellLine', 'CVCL:0065', (100, 106))	('C9h', 'Chemical', '-', (171, 174))	('apoptosis', 'biological_process', 'GO:0097194', ('39', '48'))	('human', 'Species', '9606', (251, 256))	('human', 'Species', '9606', (87, 92))	('HeLa', 'CellLine', 'CVCL:0030', (112, 116))	('C9h', 'Chemical', '-', (27, 30))	('apoptosis', 'biological_process', 'GO:0006915', ('39', '48'))	('Annexin-V', 'Gene', (65, 74))	('DPT-C9h', 'Var', (23, 30))	('DPT-C9h', 'Chemical', '-', (23, 30))	('Annexin-V', 'Gene', '308', (65, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('238', '247'))
63025	23637769	Similarly, the DPT-C9h peptide did not have any apoptotic effect on the mouse lung cancer cell lines LKR10 and LKR13, while the peptide DPT-C9, specific for mouse caspase-9, induced apoptosis in both cell lines upon 24 h of treatment (Fig 2B).	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('peptide DPT-C9', 'Var', (128, 142))	('mouse', 'Species', '10090', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('induced', 'Reg', (174, 181))	('DPT-C9', 'Chemical', '-', (15, 21))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('apoptosis', 'CPA', (182, 191))	('DPT-C9', 'Chemical', '-', (136, 142))	('apoptosis', 'biological_process', 'GO:0097194', ('182', '191'))	('apoptosis', 'biological_process', 'GO:0006915', ('182', '191'))	('mouse', 'Species', '10090', (157, 162))	('DPT-C9', 'Var', (136, 142))	('DPT-C9h', 'Chemical', '-', (15, 22))
63027	23637769	Using the human breast, uveal melanoma, non-small cell lung and small-cell lung cancer cell lines obtained from primary human xenograft models, we tested the apoptotic effect of both DPT-C9h and C9h peptides.	('uveal melanoma', 'Disease', (24, 38))	('human', 'Species', '9606', (120, 125))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (64, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('apoptotic effect', 'CPA', (158, 174))	('human', 'Species', '9606', (10, 15))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (64, 86))	('small-cell lung cancer', 'Disease', (64, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('DPT-C9h', 'Var', (183, 190))	('C9h', 'Chemical', '-', (195, 198))	('DPT-C9h', 'Chemical', '-', (183, 190))	('tested', 'Reg', (147, 153))	('C9h', 'Var', (195, 198))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('C9h', 'Chemical', '-', (187, 190))	('uveal melanoma', 'Phenotype', 'HP:0007716', (24, 38))	('uveal melanoma', 'Disease', 'MESH:C536494', (24, 38))
63029	23637769	In all cell lines analyzed, DPT-C9h induced apoptosis, ranging from 20 to 75% upon 24 h of culture (Fig 2C) while no effect was observed after C9h treatment of breast cancer cell lines (Fig 2D).	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('DPT-C9h', 'Var', (28, 35))	('apoptosis', 'CPA', (44, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('C9h', 'Chemical', '-', (143, 146))	('DPT-C9h', 'Chemical', '-', (28, 35))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('C9h', 'Chemical', '-', (32, 35))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('to 7', 'Species', '1214577', (71, 75))
63030	23637769	Supplementary addition of DPT-C9h peptide 27h after the initial treatment strongly increased the level of apoptosis (data not shown).	('increased', 'PosReg', (83, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('DPT-C9h peptide', 'Var', (26, 41))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('DPT-C9h', 'Chemical', '-', (26, 33))
63032	23637769	Taken together, these results show a strong in vitro anti-tumoral effect of the DPT-C9h peptide in various human cell lines.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('human', 'Species', '9606', (107, 112))	('DPT-C9h peptide', 'Var', (80, 95))	('tumoral', 'Disease', (58, 65))	('tumoral', 'Disease', 'MESH:D009369', (58, 65))	('DPT-C9h', 'Chemical', '-', (80, 87))
63034	23637769	We have observed an increase of caspase-9 activity in DPT-C9h treated cell line (Fig 3A).	('caspase-9 activity', 'molecular_function', 'GO:0030693', ('32', '50'))	('activity', 'MPA', (42, 50))	('caspase-9 activity', 'molecular_function', 'GO:0004211', ('32', '50'))	('DPT-C9h', 'Var', (54, 61))	('caspase-9', 'Enzyme', (32, 41))	('DPT-C9h', 'Chemical', '-', (54, 61))	('increase', 'PosReg', (20, 28))
63040	23637769	Using mitochondrial proteins from control non-treated or peptide-treated cells, we observed the release of cytochrome c from the mitochondria in DPT-C9h treated cells while in non-treated control cells, cytochrome c is retained in the mitochondrial fraction (Fig 3D).	('cytochrome c', 'Gene', (203, 215))	('cytochrome c', 'molecular_function', 'GO:0009461', ('203', '215'))	('cytochrome c', 'Gene', (107, 119))	('cytochrome c', 'Gene', '54205', (203, 215))	('mitochondria', 'cellular_component', 'GO:0005739', ('129', '141'))	('cytochrome c', 'Gene', '54205', (107, 119))	('DPT-C9h', 'Var', (145, 152))	('cytochrome c', 'molecular_function', 'GO:0009461', ('107', '119'))	('DPT-C9h', 'Chemical', '-', (145, 152))	('release', 'MPA', (96, 103))	('cytochrome c', 'molecular_function', 'GO:0045155', ('203', '215'))	('cytochrome c', 'molecular_function', 'GO:0045155', ('107', '119'))
63041	23637769	The ratio of cytochrome c/Tim 23 is used as internal control for normalization and quantification of the amount of liberated Cyt c. These results confirm the mitochondrial implication in DPT-C9h-induced apoptosis.	('cytochrome c', 'molecular_function', 'GO:0045155', ('13', '25'))	('Tim 23', 'Gene', (26, 32))	('apoptosis', 'biological_process', 'GO:0006915', ('203', '212'))	('apoptosis', 'CPA', (203, 212))	('DPT-C9h-induced', 'Var', (187, 202))	('Tim 23', 'Gene', '53600', (26, 32))	('DPT-C9h', 'Chemical', '-', (187, 194))	('cytochrome c', 'Gene', (13, 25))	('cytochrome c', 'molecular_function', 'GO:0009461', ('13', '25'))	('apoptosis', 'biological_process', 'GO:0097194', ('203', '212'))	('cytochrome c', 'Gene', '54205', (13, 25))
63043	23637769	Using in vitro sub-apoptotic dose of peptide, we showed that DPT-C9h did not induce accumulation of tumour cells in any phase of the cell cycle, whatever concentration used and time analyzed (Fig 3E).	('DPT-C9h', 'Chemical', '-', (61, 68))	('cell cycle', 'biological_process', 'GO:0007049', ('133', '143'))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('tumour', 'Disease', (100, 106))	('DPT-C9h', 'Var', (61, 68))
63046	23637769	PBMC from healthy donors or CLL patients were treated for 3h with DPT-C9h peptide, washed, resuspended in complete medium without peptide for 6h and then analyzed for apoptosis.	('patients', 'Species', '9606', (32, 40))	('DPT-C9h peptide', 'Var', (66, 81))	('3h', 'Chemical', 'MESH:D014316', (58, 60))	('CLL', 'Disease', (28, 31))	('DPT-C9h', 'Chemical', '-', (66, 73))	('apoptosis', 'biological_process', 'GO:0097194', ('167', '176'))	('apoptosis', 'biological_process', 'GO:0006915', ('167', '176'))	('CLL', 'Disease', 'MESH:D015451', (28, 31))
63047	23637769	Fig 4A shows that DPT-C9h has an apoptotic effect on B cells from CLL patients but not on B cells from healthy donors relative to control non treated cells.	('patients', 'Species', '9606', (70, 78))	('CLL', 'Disease', (66, 69))	('DPT-C9h', 'Var', (18, 25))	('DPT-C9h', 'Chemical', '-', (18, 25))	('apoptotic effect', 'CPA', (33, 49))	('CLL', 'Disease', 'MESH:D015451', (66, 69))
63050	23637769	Finally, a similar pro-apoptotic effect of DPT-C9h peptide was observed when B cells were isolated from bone marrow of CLL patients (Fig 4B).	('DPT-C9h', 'Chemical', '-', (43, 50))	('CLL', 'Disease', 'MESH:D015451', (119, 122))	('patients', 'Species', '9606', (123, 131))	('DPT-C9h', 'Var', (43, 50))	('CLL', 'Disease', (119, 122))
63051	23637769	This result strongly suggests that only tumour B cells are affected by DPT-C9h treatment without any effect on cells from healthy donors, underscoring the specific tumoural effect of DPT-C9h.	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('tumour', 'Disease', (40, 46))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('DPT-C9h', 'Chemical', '-', (183, 190))	('DPT-C9h', 'Var', (71, 78))	('tumour', 'Disease', (164, 170))	('DPT-C9h', 'Chemical', '-', (71, 78))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))
63052	23637769	Given that our final interest is to prove an anti-tumour effect of DPT-C9h on human cancers, we decided to analyze the in vivo immunogenic activity of the peptide.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', (50, 56))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('DPT-C9h', 'Chemical', '-', (67, 74))	('DPT-C9h', 'Var', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('human', 'Species', '9606', (78, 83))
63053	23637769	Nude immunodeficient T-cell mice were treated five days per week during 6 weeks by intraperitoneal injections of DPT-C9h.	('immunodeficient', 'Disease', 'MESH:D007153', (5, 20))	('immunodeficient', 'Disease', (5, 20))	('mice', 'Species', '10090', (28, 32))	('DPT-C9h', 'Var', (113, 120))	('DPT-C9h', 'Chemical', '-', (113, 120))
63056	23637769	Similarly, the antibody response was also analyzed using immunocompetent mice, again showing lack of antibody production neither against DPT-C9h nor DPT-Sh1 peptides (Fig 5B).	('DPT-C9h', 'Chemical', '-', (137, 144))	('antibody', 'cellular_component', 'GO:0019814', ('15', '23'))	('antibody production', 'biological_process', 'GO:0002377', ('101', '120'))	('antibody', 'molecular_function', 'GO:0003823', ('101', '109'))	('DPT', 'Chemical', '-', (149, 152))	('Sh1', 'Gene', '100125848', (153, 156))	('antibody', 'cellular_component', 'GO:0042571', ('15', '23'))	('mice', 'Species', '10090', (73, 77))	('antibody', 'cellular_component', 'GO:0019815', ('15', '23'))	('antibody', 'cellular_component', 'GO:0042571', ('101', '109'))	('Sh1', 'Gene', (153, 156))	('DPT', 'Chemical', '-', (137, 140))	('antibody', 'molecular_function', 'GO:0003823', ('15', '23'))	('antibody', 'cellular_component', 'GO:0019814', ('101', '109'))	('antibody', 'cellular_component', 'GO:0019815', ('101', '109'))	('DPT-C9h', 'Var', (137, 144))
63063	23637769	Administered intraperitoneally at a dose of 5 mg/kg for 5 days/7 for 4 weeks, DTC-C9 induced a significant decrease in lung tumour burden as the number of tumours per mouse was 24.6+-2.8 (mean+-SEM) in the placebo group compared to 15.4+-1.9 in the treated group (p = 0.01) (Fig 6A).	('tumours', 'Disease', (155, 162))	('DTC-C9', 'Chemical', '-', (78, 84))	('lung tumour', 'Phenotype', 'HP:0100526', (119, 130))	('decrease in lung tumour', 'Disease', 'MESH:D008175', (107, 130))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('DTC-C9', 'Var', (78, 84))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('tumours', 'Disease', 'MESH:D009369', (155, 162))	('mouse', 'Species', '10090', (167, 172))	('decrease in lung tumour', 'Disease', (107, 130))
63066	23637769	Despite a very fast spontaneously tumor growth, DPT-C9 induced a significant TGI of 46% (p<0.03) (Fig 6C).	('TGI', 'MPA', (77, 80))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('DPT-C9', 'Chemical', '-', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('DPT-C9', 'Var', (48, 54))
63071	23637769	At the end of the treatment, we observed that DPT-C9h induced significant tumour growth inhibition (TGI) of 50% (p<0.04), 37% (p<0.11), and 48% (p<0.04) according to previously defined doses and, compared to control mice treated with the formulating vehicle alone (Fig 6D).	('tumour growth inhibition', 'Disease', 'MESH:D006130', (74, 98))	('mice', 'Species', '10090', (216, 220))	('tumour growth inhibition', 'Disease', (74, 98))	('DPT-C9h', 'Var', (46, 53))	('DPT-C9h', 'Chemical', '-', (46, 53))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
63075	23637769	Using optical imaging, we showed that DPT-C9h inhibited tumor growth of HBCx-12A cell line compared to control non-treated group that receive only the formulating vehicle (Fig 6F), as previously observed (Fig 6D).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('DPT-C9h', 'Var', (38, 45))	('DPT-C9h', 'Chemical', '-', (38, 45))	('tumor', 'Disease', (56, 61))	('HBCx-12A', 'Chemical', '-', (72, 80))	('inhibited', 'NegReg', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
63078	23637769	DPT-C9h induced an optimal and significant TGI in the luminal B breast cancer HBCx-3 model (85%; p<0.02) (Fig 6G).	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('DPT-C9h', 'Var', (0, 7))	('DPT-C9h', 'Chemical', '-', (0, 7))	('TGI', 'MPA', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
63079	23637769	Interestingly, in this luminal breast cancer model, DPT-C9h induced 12 complete remissions in the 39 treated mice (31%) (p<0.01), in which 5 were prolonged after 2 months.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('DPT-C9h', 'Var', (52, 59))	('breast cancer', 'Disease', (31, 44))	('DPT-C9h', 'Chemical', '-', (52, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('mice', 'Species', '10090', (109, 113))
63082	23637769	When considering positive ratio (resistant tumours) and negative ratio (sensitive tumours), we observed that 72% (41%+31%) of all 198 DPT-C9h/DPT-C9-treated mice had a negative ratio.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('mice', 'Species', '10090', (157, 161))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('DPT-C9', 'Chemical', '-', (142, 148))	('tumours', 'Disease', 'MESH:D009369', (43, 50))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('tumours', 'Disease', (43, 50))	('tumours', 'Disease', (82, 89))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('DPT-C9', 'Chemical', '-', (134, 140))	('DPT-C9h/DPT-C9-treated', 'Var', (134, 156))	('DPT-C9h', 'Chemical', '-', (134, 141))
63084	23637769	Taken together, our results show that breast cancer models, triple negative, luminal, lung K-Ras mutated and PyMT respond to DPT-C9h or DPT-9 treatment showing considerable tumour growth inhibition.	('DPT-9', 'Chemical', '-', (136, 141))	('K-Ras', 'Gene', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumour growth inhibition', 'Disease', (173, 197))	('mutated', 'Var', (97, 104))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('K-Ras', 'Gene', '16653', (91, 96))	('breast cancer', 'Disease', (38, 51))	('DPT-C9h', 'Var', (125, 132))	('DPT-9', 'Var', (136, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('respond', 'Reg', (114, 121))	('DPT-C9h', 'Chemical', '-', (125, 132))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumour growth inhibition', 'Disease', 'MESH:D006130', (173, 197))
63086	23637769	In addition, the peptide specifically induces apoptosis in tumour cells, without effect on healthy primary cells.	('apoptosis', 'CPA', (46, 55))	('peptide', 'Var', (17, 24))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('induces', 'Reg', (38, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))	('tumour', 'Disease', (59, 65))
63087	23637769	DPT-C9 and DPT-C9h also inhibit tumour growth in mouse or primary human breast cancer models.	('DPT-C9', 'Var', (0, 6))	('tumour growth', 'Disease', 'MESH:D006130', (32, 45))	('DPT-C9h', 'Var', (11, 18))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('DPT-C9', 'Chemical', '-', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('human', 'Species', '9606', (66, 71))	('DPT-C9h', 'Chemical', '-', (11, 18))	('mouse', 'Species', '10090', (49, 54))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('DPT-C9', 'Chemical', '-', (11, 17))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('inhibit', 'NegReg', (24, 31))	('tumour growth', 'Disease', (32, 45))
63090	23637769	Similarly, several CPP are under clinical development, such as peptides targeting protein kinase c, Hsp20, and c-Jun-N-terminal kinase.	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('Hsp20', 'Gene', (100, 105))	('Hsp20', 'Gene', '243912', (100, 105))	('peptides', 'Var', (63, 71))	('c-Jun-N-terminal kinase', 'MPA', (111, 134))	('protein', 'Protein', (82, 89))
63091	23637769	In this report, we demonstrated that DPT-C9h targets the interaction between PP2A and caspase-9, without apparently affecting the rest of cellular PP2A, whose modulation might possibly induce toxicity.	('toxicity', 'Disease', 'MESH:D064420', (192, 200))	('DPT-C9h', 'Chemical', '-', (37, 44))	('toxicity', 'Disease', (192, 200))	('induce', 'Reg', (185, 191))	('modulation', 'Var', (159, 169))	('PP2A', 'Gene', (77, 81))	('interaction', 'Interaction', (57, 68))	('DPT-C9h', 'Var', (37, 44))	('caspase-9', 'Protein', (86, 95))
63093	23637769	In breast cancers, PP2A has been reported to be involved in progression through various important signalling pathways; indeed, it has been reported that Her-2 receptor induced PP2A phosphorylation that PP2A induced ERalpha dephosphorylation and ERalpha mRNA instability, and that PP2A induced Akt dephosphorylation.	('Akt', 'Gene', (293, 296))	('ERalpha', 'Gene', '13982', (245, 252))	('PP2A', 'Var', (202, 206))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('Akt', 'Gene', '11651', (293, 296))	('ERalpha', 'Gene', (215, 222))	('phosphorylation', 'biological_process', 'GO:0016310', ('181', '196'))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancers', 'Disease', 'MESH:D001943', (3, 17))	('breast cancers', 'Disease', (3, 17))	('dephosphorylation', 'biological_process', 'GO:0016311', ('223', '240'))	('induced', 'Reg', (285, 292))	('ERalpha', 'Gene', (245, 252))	('dephosphorylation', 'biological_process', 'GO:0016311', ('297', '314'))	('breast cancers', 'Phenotype', 'HP:0003002', (3, 17))	('PP2A', 'Gene', (176, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('phosphorylation', 'MPA', (181, 196))	('ERalpha', 'Gene', '13982', (215, 222))	('signalling', 'biological_process', 'GO:0023052', ('98', '108'))
63106	16189526	Tumour control is achieved by radiation-induced damage to DNA, which ultimately causes tumour cell death.	('damage', 'Var', (48, 54))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('causes', 'Reg', (80, 86))	('tumour cell death', 'Disease', (87, 104))	('cell death', 'biological_process', 'GO:0008219', ('94', '104'))	('tumour cell death', 'Disease', 'MESH:D003643', (87, 104))
63144	16189526	Actuarial rates (5-year) of endocrinopathy in patients with base of skull lesions were as follows: 72% for hyperprolactinaemia, 30% for hypothyroidism, 29% for hypogonadism, 19% for hypoadrenalism, and no incidence of diabetes insipidus (Pai et al, 2001), reflective of the proximity of the pituitary to the sarcoma.	('patients', 'Species', '9606', (46, 54))	('hypogonadism', 'Disease', (160, 172))	('sarcoma', 'Disease', 'MESH:D012509', (308, 315))	('hyperprolactinaemia', 'Disease', (107, 126))	('hypoadrenalism', 'Phenotype', 'HP:0000846', (182, 196))	('diabetes insipidus', 'Disease', 'MESH:D003919', (218, 236))	('sarcoma', 'Disease', (308, 315))	('hypogonadism', 'Phenotype', 'HP:0000135', (160, 172))	('diabetes insipidus', 'Phenotype', 'HP:0000873', (218, 236))	('lesions', 'Var', (74, 81))	('hyperprolactinaemia', 'Phenotype', 'HP:0000870', (107, 126))	('Pai', 'Gene', (238, 241))	('hypothyroidism', 'Disease', (136, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (308, 315))	('hypogonadism', 'Disease', 'MESH:D007006', (160, 172))	('Pai', 'Gene', '5054', (238, 241))	('hypothyroidism', 'Disease', 'MESH:D007037', (136, 150))	('hypothyroidism', 'Phenotype', 'HP:0000821', (136, 150))	('hypoadrenalism', 'Disease', (182, 196))	('endocrinopathy', 'Disease', 'MESH:C567425', (28, 42))	('hyperprolactinaemia', 'Disease', 'MESH:D002640', (107, 126))	('diabetes insipidus', 'Disease', (218, 236))	('hypoadrenalism', 'Disease', 'MESH:D000309', (182, 196))	('endocrinopathy', 'Disease', (28, 42))
63249	33234846	Twenty-four-month OS rates were 63% in patients aged >=75 years, 56% in patients with elevated lactate dehydrogenase levels, 73% in patients with BRAF wild-type tumors, 70% in patients with BRAF mutant tumors, and 56% in patients with mucosal melanoma.	('elevated', 'PosReg', (86, 94))	('patients', 'Species', '9606', (221, 229))	('patients', 'Species', '9606', (39, 47))	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('patients', 'Species', '9606', (132, 140))	('BRAF', 'Gene', '673', (190, 194))	('BRAF', 'Gene', (190, 194))	('lactate dehydrogenase levels', 'MPA', (95, 123))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('elevated lactate dehydrogenase levels', 'Phenotype', 'HP:0025435', (86, 123))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('melanoma', 'Phenotype', 'HP:0002861', (243, 251))	('BRAF', 'Gene', '673', (146, 150))	('mutant', 'Var', (195, 201))	('BRAF', 'Gene', (146, 150))	('patients', 'Species', '9606', (176, 184))	('mucosal melanoma', 'Disease', 'MESH:D008545', (235, 251))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', (202, 208))	('mucosal melanoma', 'Disease', (235, 251))	('patients', 'Species', '9606', (72, 80))
63295	33234846	Patients with BRAF mutant tumors comprised less than half of the EAP population [329 (44%) patients].	('patients', 'Species', '9606', (91, 99))	('EAP', 'Chemical', '-', (65, 68))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('BRAF', 'Gene', '673', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('mutant', 'Var', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('BRAF', 'Gene', (14, 18))	('tumors', 'Disease', (26, 32))
63317	33234846	3a] and between patients with BRAF wild-type [73% (95% CI 67-78)] and mutant tumors [70% (95% CI 63-75); Fig.	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Disease', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('mutant', 'Var', (70, 76))	('patients', 'Species', '9606', (16, 24))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))
63319	33234846	3d]; patients with LDH levels that were <=upper limit of normal (ULN; 77% (95% CI 72-81)], >ULN [56% (95% CI 49-63)], and >2 x ULN [39% (95% CI 26-53); Fig.	('LDH', 'MPA', (19, 22))	('>2 x ULN', 'Var', (122, 130))	('patients', 'Species', '9606', (5, 13))	('>ULN', 'Var', (91, 95))
63327	33234846	For example, in contrast to CheckMate 067, which exclusively enrolled untreated patients, this EAP included patients who had previously received systemic treatment, including BRAF/MEK inhibitors in patients with BRAF mutant disease.	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (198, 206))	('BRAF', 'Gene', '673', (212, 216))	('mutant disease', 'Var', (217, 231))	('BRAF', 'Gene', (175, 179))	('BRAF', 'Gene', '673', (175, 179))	('BRAF', 'Gene', (212, 216))	('MEK', 'Gene', (180, 183))	('MEK', 'Gene', '5609', (180, 183))	('patients', 'Species', '9606', (108, 116))	('EAP', 'Chemical', '-', (95, 98))
63328	33234846	As a result, the EAP population had a greater proportion of patients with BRAF mutant disease (44% or more) than the study group treated with the combination in CheckMate 067 (32%).	('EAP', 'Chemical', '-', (17, 20))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('patients', 'Species', '9606', (60, 68))	('mutant', 'Var', (79, 85))
63340	33234846	Interestingly, 24-month OS rates in this EAP were similar in patients with BRAF wild-type and mutant disease (73% vs. 70%), suggesting that BRAF mutation status may not be predictive of survival outcomes with the combination.	('EAP', 'Chemical', '-', (41, 44))	('BRAF', 'Gene', '673', (75, 79))	('patients', 'Species', '9606', (61, 69))	('BRAF', 'Gene', '673', (140, 144))	('mutant', 'Var', (94, 100))	('BRAF', 'Gene', (75, 79))	('BRAF', 'Gene', (140, 144))
63341	33234846	In CheckMate 067, the 24-month OS rate was 64% in patients treated with the combination, and there appeared to be a long-term survival benefit in patients with BRAF mutant disease treated with the combination compared with those treated with nivolumab monotherapy [5-year OS rate: 60% vs. 46%; unstratified hazard ratio 0.70 (95% CI 0.46-1.05)].	('BRAF', 'Gene', (160, 164))	('BRAF', 'Gene', '673', (160, 164))	('mutant', 'Var', (165, 171))	('patients', 'Species', '9606', (50, 58))	('benefit', 'PosReg', (135, 142))	('patients', 'Species', '9606', (146, 154))	('nivolumab', 'Chemical', 'MESH:D000077594', (242, 251))
63375	32218990	Concurrent germline and somatic pathogenic BAP1 variants in a patient with metastatic bladder cancer Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1 tumor predisposition syndrome (TPDS).	('BAP1', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('BAP1', 'Gene', '8314', (165, 169))	('BRCA1-associated protein-1', 'Gene', '8314', (137, 163))	('variants', 'Var', (121, 129))	('patient', 'Species', '9606', (62, 69))	('BRCA1-associated protein-1', 'Gene', (137, 163))	('bladder cancer', 'Disease', 'MESH:D001749', (86, 100))	('bladder cancer', 'Disease', (86, 100))	('BAP1', 'Gene', (165, 169))	('variants', 'Var', (48, 56))	('BAP1', 'Gene', '8314', (186, 190))	('BAP1', 'Gene', '8314', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('tumor', 'Disease', (191, 196))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('cause', 'Reg', (176, 181))	('BAP1', 'Gene', (186, 190))
63376	32218990	BAP1 TPDS is associated with an increased risk of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma, and several other cancer subtypes.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (60, 78))	('mesothelioma', 'Disease', 'MESH:D008654', (80, 92))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (94, 114))	('BAP1', 'Gene', (0, 4))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (94, 114))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('TPDS', 'Var', (5, 9))	('cutaneous melanoma', 'Disease', (60, 78))	('mesothelioma', 'Disease', (80, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('BAP1', 'Gene', '8314', (0, 4))	('uveal', 'Disease', (50, 55))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (60, 78))	('renal cell carcinoma', 'Disease', (94, 114))
63377	32218990	Here, we report a germline nonsense BAP1 variant (c.850G>T, p.Glu284Ter) in a patient with bladder cancer and a strong family history of malignancy.	('malignancy', 'Disease', (137, 147))	('patient', 'Species', '9606', (78, 85))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('c.850G>T', 'Mutation', 'rs1240260385', (50, 58))	('c.850G>T', 'Var', (50, 58))	('p.Glu284Ter', 'Mutation', 'rs1240260385', (60, 71))	('BAP1', 'Gene', '8314', (36, 40))	('bladder cancer', 'Disease', (91, 105))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('BAP1', 'Gene', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Ter', 'cellular_component', 'GO:0097047', ('68', '71'))	('malignancy', 'Disease', 'MESH:D009369', (137, 147))
63378	32218990	Concurrently, we identified a somatic frameshift BAP1 variant, and as expected, immunostaining validated the loss of BAP1 protein in patient-derived tumor specimens.	('protein', 'Protein', (122, 129))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('BAP1', 'Gene', '8314', (117, 121))	('BAP1', 'Gene', (49, 53))	('patient', 'Species', '9606', (133, 140))	('loss', 'NegReg', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('BAP1', 'Gene', (117, 121))	('tumor', 'Disease', (149, 154))	('frameshift', 'Var', (38, 48))	('BAP1', 'Gene', '8314', (49, 53))
63379	32218990	With the addition of bladder cancer to the tumor types reported with germline BAP1 mutations, our understanding of the BAP1 TPDS continues to evolve, and may affect future screening and surveillance guidelines.	('mutations', 'Var', (83, 92))	('bladder cancer', 'Phenotype', 'HP:0009725', (21, 35))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('BAP1', 'Gene', '8314', (119, 123))	('bladder cancer', 'Disease', 'MESH:D001749', (21, 35))	('BAP1', 'Gene', '8314', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('affect', 'Reg', (158, 164))	('tumor', 'Disease', (43, 48))	('bladder cancer', 'Disease', (21, 35))	('BAP1', 'Gene', (119, 123))	('BAP1', 'Gene', (78, 82))
63387	32218990	For example, germline pathogenic variants in the BRCA1-associated protein 1 (BAP1) tumor suppressor gene are the genetic cause of the BAP1 tumor predisposition syndrome (TPDS; OMIM: 614327; also known as the BAP1 cancer syndrome).	('tumor suppressor', 'biological_process', 'GO:0051726', ('83', '99'))	('tumor', 'Disease', (83, 88))	('cancer syndrome', 'Disease', 'MESH:D009369', (213, 228))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('BAP1', 'Gene', '8314', (134, 138))	('BAP1', 'Gene', (208, 212))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('BAP1', 'Gene', '8314', (77, 81))	('cancer syndrome', 'Disease', (213, 228))	('variants', 'Var', (33, 41))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('BRCA1-associated protein 1', 'Gene', '8314', (49, 75))	('BAP1', 'Gene', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('BAP1', 'Gene', (77, 81))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('83', '99'))	('BRCA1-associated protein 1', 'Gene', (49, 75))	('BAP1', 'Gene', '8314', (208, 212))	('cause', 'Reg', (121, 126))
63388	32218990	BAP1 TPDS is associated with an increased risk of uveal melanoma, cutaneous melanoma, mesothelioma, renal cell carcinoma, and several other cancer subtypes.	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('BAP1', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('uveal melanoma', 'Disease', 'MESH:C536494', (50, 64))	('uveal melanoma', 'Disease', (50, 64))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (100, 120))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (100, 120))	('cancer', 'Disease', (140, 146))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('cutaneous melanoma', 'Disease', (66, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (66, 84))	('mesothelioma', 'Disease', (86, 98))	('TPDS', 'Var', (5, 9))	('renal cell carcinoma', 'Disease', (100, 120))	('BAP1', 'Gene', '8314', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (86, 98))
63389	32218990	Herein, we report a bladder cancer case with a germline BAP1 variant, which was detected incidentally during analysis of plasma circulating tumor DNA (ctDNA).	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (20, 34))	('BAP1', 'Gene', '8314', (56, 60))	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('variant', 'Var', (61, 68))	('bladder cancer', 'Disease', 'MESH:D001749', (20, 34))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('BAP1', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('bladder cancer', 'Disease', (20, 34))	('tumor', 'Disease', (140, 145))
63403	32218990	Analysis of leukocyte and plasma cell-free DNA (cfDNA) suggested a ctDNA fraction of 34.7% and revealed a hotspot somatic variant in FGFR3 (c.746C>G, p.Ser249Cys), which is present in ~14% of all bladder cases.	('FGFR3', 'Gene', (133, 138))	('p.Ser249Cys', 'Mutation', 'rs121913483', (150, 161))	('c.746C>G', 'Mutation', 'rs121913483', (140, 148))	('Ser', 'cellular_component', 'GO:0005790', ('152', '155'))	('c.746C>G', 'Var', (140, 148))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('FGFR', 'molecular_function', 'GO:0005007', ('133', '137'))	('FGFR3', 'Gene', '2261', (133, 138))
63405	32218990	Interestingly, a germline nonsense BAP1 variant, c.850G>T (p.Glu284Ter), was incidentally detected in both leukocyte DNA and cfDNA, with coverage of approximately 300x and 1600x, respectively, and is not present in the gnomAD database.	('Ter', 'cellular_component', 'GO:0097047', ('67', '70'))	('BAP1', 'Gene', '8314', (35, 39))	('p.Glu284Ter', 'Mutation', 'rs1240260385', (59, 70))	('BAP1', 'Gene', (35, 39))	('c.850G>T', 'Mutation', 'rs1240260385', (49, 57))	('c.850G>T', 'Var', (49, 57))	('DNA', 'cellular_component', 'GO:0005574', ('117', '120'))
63411	32218990	As such, BAP1 c.850G>T may be classified as a pathogenic variant, as per the American College of Medical Genetics (ACMG) guidelines (PVS1, PS3, PM2).	('pathogenic', 'Reg', (46, 56))	('BAP1', 'Gene', '8314', (9, 13))	('c.850G>T', 'Var', (14, 22))	('PS3', 'Gene', '448990', (139, 142))	('BAP1', 'Gene', (9, 13))	('c.850G>T', 'Mutation', 'rs1240260385', (14, 22))	('PS3', 'Gene', (139, 142))
63412	32218990	The patient was referred to our hereditary cancer program for counseling regarding the pathogenic germline BAP1 variant.	('BAP1', 'Gene', '8314', (107, 111))	('patient', 'Species', '9606', (4, 11))	('BAP1', 'Gene', (107, 111))	('variant', 'Var', (112, 119))	('hereditary cancer', 'Disease', 'MESH:D009369', (32, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('hereditary cancer', 'Disease', (32, 49))
63418	32218990	We identified a germline pathogenic variant in BAP1 in a patient with lethal bladder cancer.	('patient', 'Species', '9606', (57, 64))	('variant', 'Var', (36, 43))	('bladder cancer', 'Disease', 'MESH:D001749', (77, 91))	('bladder cancer', 'Disease', (77, 91))	('BAP1', 'Gene', '8314', (47, 51))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('pathogenic', 'Reg', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('BAP1', 'Gene', (47, 51))
63419	32218990	In addition, ctDNA analysis revealed a somatic BAP1 frameshift mutation, also likely to result in NMD or protein truncation.	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('frameshift mutation', 'Var', (52, 71))	('NMD', 'MPA', (98, 101))	('BAP1', 'Gene', '8314', (47, 51))	('protein truncation', 'MPA', (105, 123))	('result', 'Reg', (88, 94))	('BAP1', 'Gene', (47, 51))
63421	32218990	Matched exome and transcriptome data from almost 10,000 human tumors revealed that BAP1 was among the category of tumor suppressor genes exhibiting frequent NMD-triggering of heterozygous deletions, leading to biallelic inactivation by a classical "two-hit" mechanism, as seen in neurofibromatosis type-1 and malignant peripheral nerve sheath tumors.	('tumors', 'Disease', (343, 349))	('neurofibromatosis type-1 and malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (280, 349))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('deletions', 'Var', (188, 197))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('114', '130'))	('tumors', 'Disease', 'MESH:D009369', (343, 349))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor suppressor', 'biological_process', 'GO:0051726', ('114', '130'))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (309, 349))	('tumors', 'Disease', (62, 68))	('human', 'Species', '9606', (56, 61))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', (343, 348))	('BAP1', 'Gene', '8314', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (280, 297))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('biallelic inactivation', 'MPA', (210, 232))	('tumors', 'Phenotype', 'HP:0002664', (343, 349))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('BAP1', 'Gene', (83, 87))	('tumor', 'Disease', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
63422	32218990	Indeed, IHC validated the functional biallelic loss of BAP1 protein, indicating that these alleles are in trans in the metastatic bladder cancer of this individual.	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('biallelic', 'Var', (37, 46))	('BAP1', 'Gene', (55, 59))	('bladder cancer', 'Disease', 'MESH:D001749', (130, 144))	('bladder cancer', 'Disease', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('loss', 'NegReg', (47, 51))	('protein', 'Protein', (60, 67))	('bladder cancer', 'Phenotype', 'HP:0009725', (130, 144))	('BAP1', 'Gene', '8314', (55, 59))
63425	32218990	BAP1 has been implicated in several cellular processes, including cell cycle regulation, differentiation, apoptosis, DNA repair, and epigenetic histone modification.	('implicated', 'Reg', (14, 24))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('66', '87'))	('BAP1', 'Gene', (0, 4))	('histone modification', 'biological_process', 'GO:0016570', ('144', '164'))	('cell cycle', 'CPA', (66, 76))	('apoptosis', 'CPA', (106, 115))	('epigenetic histone modification', 'Var', (133, 164))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('BAP1', 'Gene', '8314', (0, 4))	('DNA repair', 'biological_process', 'GO:0006281', ('117', '127'))	('DNA', 'cellular_component', 'GO:0005574', ('117', '120'))
63428	32218990	In addition, cells carrying heterozygous germline BAP1 mutations have impaired mitochondrial respiration secondary to reduced Ca2+ levels and switch to aerobic glycolysis, which is known to promote malignant transformation and growth.	('glycolysis', 'biological_process', 'GO:0006096', ('160', '170'))	('Ca2+', 'Chemical', 'MESH:D000069285', (126, 130))	('mutations', 'Var', (55, 64))	('Ca2+ levels', 'MPA', (126, 137))	('respiration', 'biological_process', 'GO:0007585', ('93', '104'))	('mitochondrial respiration', 'MPA', (79, 104))	('reduced', 'NegReg', (118, 125))	('BAP1', 'Gene', '8314', (50, 54))	('respiration', 'biological_process', 'GO:0045333', ('93', '104'))	('switch', 'Reg', (142, 148))	('BAP1', 'Gene', (50, 54))	('impaired', 'NegReg', (70, 78))
63429	32218990	Germline alterations in BAP1 predispose to the BAP1 TPDS, an autosomal dominant syndrome encompassing uveal melanoma, cutaneous melanoma, mesothelioma and, most recently, renal cell carcinoma.	('mesothelioma', 'Disease', (138, 150))	('BAP1', 'Gene', '8314', (47, 51))	('renal cell carcinoma', 'Disease', (171, 191))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (171, 191))	('mesothelioma', 'Disease', 'MESH:D008654', (138, 150))	('BAP1', 'Gene', (24, 28))	('cutaneous melanoma', 'Disease', (118, 136))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (118, 136))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (118, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('BAP1', 'Gene', (47, 51))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (61, 88))	('uveal melanoma', 'Disease', (102, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (102, 116))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (171, 191))	('predispose', 'Reg', (29, 39))	('autosomal dominant syndrome', 'Disease', (61, 88))	('Germline alterations', 'Var', (0, 20))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('BAP1', 'Gene', '8314', (24, 28))
63430	32218990	Other cancers, such as breast and lung carcinomas, have also been reported in germline BAP1 mutation carriers but there is insufficient data to support their inclusion in the BAP1 TPDS.	('BAP1', 'Gene', '8314', (87, 91))	('BAP1', 'Gene', (175, 179))	('mutation', 'Var', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('BAP1', 'Gene', (87, 91))	('breast and lung carcinomas', 'Disease', 'MESH:D001943', (23, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (39, 49))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('BAP1', 'Gene', '8314', (175, 179))	('cancers', 'Disease', (6, 13))
63431	32218990	There were no germline BAP1 pathogenic variants identified in an analysis of 412 bladder cancer cases in The Cancer Genome Atlas.	('BAP1', 'Gene', (23, 27))	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Cancer', 'Disease', (109, 115))	('Cancer', 'Disease', 'MESH:D009369', (109, 115))	('BAP1', 'Gene', '8314', (23, 27))	('bladder cancer', 'Disease', 'MESH:D001749', (81, 95))	('bladder cancer', 'Disease', (81, 95))	('bladder cancer', 'Phenotype', 'HP:0009725', (81, 95))	('variants', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
63432	32218990	However, a germline BAP1 splice-site variant (c.67-1G>T) has been previously reported in a patient with metastatic uveal melanoma and prior diagnosis of bladder cancer.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('bladder cancer', 'Disease', 'MESH:D001749', (153, 167))	('bladder cancer', 'Disease', (153, 167))	('uveal melanoma', 'Disease', (115, 129))	('BAP1', 'Gene', (20, 24))	('uveal melanoma', 'Disease', 'MESH:C536494', (115, 129))	('BAP1', 'Gene', '8314', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('uveal melanoma', 'Phenotype', 'HP:0007716', (115, 129))	('c.67-1G>T', 'Mutation', 'c.67-1G>T', (46, 55))	('patient', 'Species', '9606', (91, 98))	('c.67-1G>T', 'Var', (46, 55))	('bladder cancer', 'Phenotype', 'HP:0009725', (153, 167))	('reported', 'Reg', (77, 85))
63435	32218990	While the strong family history of cancers on the proband's paternal side is suggestive of an autosomal dominance inheritance pattern, BAP1 c.850G>T cosegregation analysis across this family would be required to validate this assumption.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('BAP1', 'Gene', '8314', (135, 139))	('c.850G>T', 'Var', (140, 148))	('BAP1', 'Gene', (135, 139))	('c.850G>T', 'Mutation', 'rs1240260385', (140, 148))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))
63436	32218990	Identification of germline pathogenic BAP1 variants in affected patients and families is of great clinical importance for screening and surveillance recommendations, given the diverse array of associated cancer subtypes and tendency toward tumors that are more aggressive in nature, occur at younger ages compared to the general population, and have a greater likelihood of metastasis.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('patients', 'Species', '9606', (64, 72))	('BAP1', 'Gene', (38, 42))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('BAP1', 'Gene', '8314', (38, 42))	('tumors', 'Disease', (240, 246))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('variants', 'Var', (43, 51))	('metastasis', 'CPA', (374, 384))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('pathogenic', 'Reg', (27, 37))
63441	32218990	In addition, because BAP1 mutations lead to a deficient homologous recombination repair pathway and increase the reliance on PARP1-mediated DNA repair pathways, PARP inhibitors could induce synthetic lethality in BAP1-mutant cancers similar to BRCA1/2-mutant breast and ovarian cancers.	('cancers', 'Disease', 'MESH:D009369', (278, 285))	('PARP', 'Gene', '142', (125, 129))	('cancers', 'Disease', (225, 232))	('homologous recombination repair pathway', 'Pathway', (56, 95))	('mutations', 'Var', (26, 35))	('homologous recombination', 'biological_process', 'GO:0035825', ('56', '80'))	('PARP', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('DNA repair', 'biological_process', 'GO:0006281', ('140', '150'))	('reliance', 'MPA', (113, 121))	('increase', 'PosReg', (100, 108))	('BAP1', 'Gene', '8314', (213, 217))	('BAP1', 'Gene', '8314', (21, 25))	('PARP1', 'Gene', '142', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('PARP', 'Gene', '142', (161, 165))	('cancers', 'Phenotype', 'HP:0002664', (278, 285))	('cancers', 'Disease', (278, 285))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('PARP', 'Gene', (161, 165))	('BAP1', 'Gene', (213, 217))	('BAP1', 'Gene', (21, 25))	('ovarian cancers', 'Phenotype', 'HP:0100615', (270, 285))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (259, 285))	('deficient', 'NegReg', (46, 55))	('BRCA1', 'Gene', '672', (244, 249))	('PARP1', 'Gene', (125, 130))	('BRCA1', 'Gene', (244, 249))	('synthetic lethality', 'CPA', (190, 209))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
63443	32218990	A phase II trial investigating the use of the PARP inhibitor, niraparib, in patients with tumors harboring BAP1 and other select DNA damage response mutations is currently recruiting (NCT03207347).	('patients', 'Species', '9606', (76, 84))	('BAP1', 'Gene', '8314', (107, 111))	('mutations', 'Var', (149, 158))	('DNA damage response', 'biological_process', 'GO:0006974', ('129', '148'))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('PARP', 'Gene', '142', (46, 50))	('DNA', 'cellular_component', 'GO:0005574', ('129', '132'))	('BAP1', 'Gene', (107, 111))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('PARP', 'Gene', (46, 50))	('niraparib', 'Chemical', 'MESH:C545685', (62, 71))
63445	32218990	In conclusion, we present a germline nonsense BAP1 variant in a patient with bladder cancer and a strong family history of malignancy.	('malignancy', 'Disease', (123, 133))	('patient', 'Species', '9606', (64, 71))	('bladder cancer', 'Disease', 'MESH:D001749', (77, 91))	('bladder cancer', 'Phenotype', 'HP:0009725', (77, 91))	('BAP1', 'Gene', '8314', (46, 50))	('bladder cancer', 'Disease', (77, 91))	('BAP1', 'Gene', (46, 50))	('variant', 'Var', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('with', 'Reg', (72, 76))	('malignancy', 'Disease', 'MESH:D009369', (123, 133))
63446	32218990	The patient's concurrent somatic BAP1 variant and the loss of BAP1 protein provides strong evidence of pathogenicity.	('BAP1', 'Gene', '8314', (62, 66))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('BAP1', 'Gene', '8314', (33, 37))	('BAP1', 'Gene', (62, 66))	('loss', 'NegReg', (54, 58))	('patient', 'Species', '9606', (4, 11))	('protein', 'Protein', (67, 74))	('BAP1', 'Gene', (33, 37))	('variant', 'Var', (38, 45))
63509	31357439	Lower circulating CD3-CD56dim NK cells, CD8+, and NK T cells, as well as an increase in Tregs and MSDCs have been detected during the metastatic phase.	('MSDCs', 'CPA', (98, 103))	('Tregs', 'CPA', (88, 93))	('increase', 'PosReg', (76, 84))	('CD8', 'Gene', '925', (40, 43))	('CD3-CD56dim', 'Var', (18, 29))	('CD8', 'Gene', (40, 43))
63524	31357439	Among PD-1/PD-L1 patterns, in UM samples the two more frequent patterns are PD-1-/PD-L1- and PD-1+/PD-L1-, representing immunological tolerance, with, respectively, absence or functional suppression of TILs in the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('PD-1+/PD-L1-', 'Var', (93, 105))	('tumor', 'Disease', (214, 219))	('PD-1-/PD-L1-', 'Var', (76, 88))
63525	31357439	Differently, in cutaneous melanoma the dominant subgroup is the PD-1+/PD-L1+, resulting in immune-competent and active TILs.	('PD-1+/PD-L1+', 'Var', (64, 76))	('immune-competent', 'CPA', (91, 107))	('cutaneous melanoma', 'Disease', (16, 34))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (16, 34))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (16, 34))
63536	31357439	Uveal melanoma is a relatively simple genetic disease characterized by recurrent chromosomal losses and gains determining a low mutational rate.	('genetic disease', 'Disease', (38, 53))	('gains', 'PosReg', (104, 109))	('genetic disease', 'Disease', 'MESH:D030342', (38, 53))	('Uveal melanoma', 'Disease', 'MESH:C536494', (0, 14))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('Uveal melanoma', 'Disease', (0, 14))	('chromosomal losses', 'Var', (81, 99))
63537	31357439	Monosomy 3, 1p loss, 1q gain, 6q loss, 6p gain, 8p loss, and 8q gain are the most frequent chromosomal abnormalities in uveal melanoma.	('chromosomal abnormalities', 'Disease', (91, 116))	('gain', 'PosReg', (24, 28))	('gain', 'PosReg', (42, 46))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (91, 116))	('loss', 'NegReg', (33, 37))	('1p loss', 'Var', (12, 19))	('uveal melanoma', 'Disease', 'MESH:C536494', (120, 134))	('8q gain', 'Var', (61, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (120, 134))	('uveal melanoma', 'Disease', (120, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('loss', 'NegReg', (51, 55))	('Monosomy 3', 'Var', (0, 10))
63538	31357439	It has been supposed that the inactivation of the peroxisome proliferator-activated receptor (PPARgamma) located on chromosome 3 can increase factors that favor the inflammatory microenvironment.	('favor', 'PosReg', (155, 160))	('inactivation', 'Var', (30, 42))	('PPARgamma', 'Gene', '5468', (94, 103))	('chromosome', 'cellular_component', 'GO:0005694', ('116', '126'))	('peroxisome', 'cellular_component', 'GO:0005777', ('50', '60'))	('increase', 'PosReg', (133, 141))	('PPARgamma', 'Gene', (94, 103))
63541	31357439	SF3B1 mutations are evident in approximately 15% of cases, associated with better prognosis.	('SF3B1', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('SF3B1', 'Gene', '23451', (0, 5))
63543	31357439	Recently, it has been described that a defect of MBD4, a transcriptional factor of gene promoters, is associated with a hyper-mutated CpG>TpG pattern, which generates multiple sub-clones of the primary UM with more heterogeneous metastases and high mutational burden.	('associated', 'Reg', (102, 112))	('defect', 'Var', (39, 45))	('metastases', 'Disease', (229, 239))	('MBD4', 'Gene', '8930', (49, 53))	('MBD4', 'Gene', (49, 53))	('metastases', 'Disease', 'MESH:D009362', (229, 239))
63570	30651788	of the UM samples were GSM1082563, GSM1082565-GSM1082566, GSM1082568-GSM1082575, GSM1082577-GSM1082584, GSM1082586-GSM1082596 and GSM1082598-GSM1082625.	('GSM1082563', 'Chemical', '-', (23, 33))	('GSM1082598-GSM1082625', 'Var', (130, 151))	('GSM1082565-GSM1082566', 'Var', (35, 56))	('GSM1082575', 'Chemical', '-', (69, 79))	('GSM1082625', 'Chemical', '-', (141, 151))	('GSM1082565', 'Chemical', '-', (35, 45))	('GSM1082598', 'Chemical', '-', (130, 140))	('GSM1082566', 'Chemical', '-', (46, 56))	('GSM1082577', 'Chemical', '-', (81, 91))	('GSM1082586', 'Chemical', '-', (104, 114))	('GSM1082584', 'Chemical', '-', (92, 102))	('GSM1082563', 'Var', (23, 33))	('GSM1082568', 'Chemical', '-', (58, 68))	('GSM1082596', 'Chemical', '-', (115, 125))	('UM', 'Phenotype', 'HP:0007716', (7, 9))	('GSM1082586-GSM1082596', 'Var', (104, 125))	('GSM1082577-GSM1082584', 'Var', (81, 102))	('GSM1082568-GSM1082575', 'Var', (58, 79))
63571	30651788	A total of 38 samples were included in the first cluster, where sample GSM1082605 had the highest expression value.	('GSM1082605', 'Chemical', '-', (71, 81))	('GSM1082605', 'Var', (71, 81))	('expression', 'MPA', (98, 108))
63572	30651788	Genes in module 7 were mainly enriched in biological processes involving immune responses, including the type I interferon signaling pathway (GO:0060337), the interferon-gamma-mediated signaling pathway (GO:0060333) and immune responses (GO:0006955).	('type I interferon signaling pathway', 'Pathway', (105, 140))	('interferon-gamma', 'Gene', (159, 175))	('immune responses', 'CPA', (220, 236))	('type I interferon signaling pathway', 'biological_process', 'GO:0060337', ('105', '140'))	('GO:0060337', 'Var', (142, 152))	('GO:0060333', 'Var', (204, 214))	('interferon-gamma-mediated signaling pathway', 'biological_process', 'GO:0060333', ('159', '202'))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('159', '175'))	('interferon-gamma', 'Gene', '3458', (159, 175))
63573	30651788	Genes in module 1 were mainly enriched in metabolic pathways such as the ribosome (hsa03010) and oxidative phosphorylation (hsa00190), while genes in module 2 were mainly enriched in the notch signaling pathway (hsa04330), the RNA degradation pathway (hsa03018), cancer progression pathways (hsa05200) and ubiquitin mediated proteolysis (hsa04120).	('ubiquitin', 'molecular_function', 'GO:0031386', ('306', '315'))	('ribosome', 'cellular_component', 'GO:0005840', ('73', '81'))	('cancer', 'Disease', (263, 269))	('hsa04120', 'Var', (338, 346))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('hsa04330', 'Var', (212, 220))	('notch signaling pathway', 'biological_process', 'GO:0007219', ('187', '210'))	('oxidative phosphorylation', 'MPA', (97, 122))	('metabolic', 'MPA', (42, 51))	('proteolysis', 'biological_process', 'GO:0006508', ('325', '336'))	('ubiquitin mediated proteolysis', 'MPA', (306, 336))	('RNA degradation', 'biological_process', 'GO:0006401', ('227', '242'))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('RNA degradation pathway', 'Pathway', (227, 250))	('notch signaling pathway', 'Pathway', (187, 210))	('enriched', 'Reg', (171, 179))	('enriched', 'Reg', (30, 38))	('hsa05200', 'Var', (292, 300))	('RNA', 'cellular_component', 'GO:0005562', ('227', '230'))	('hsa03018', 'Var', (252, 260))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('97', '122'))
63574	30651788	Genes in module 7 were mainly enriched in pathways associated with antigen processing and presentation (hsa04612), and herpes simplex infection (hsa05168).	('hsa04612', 'Var', (104, 112))	('infection', 'Disease', 'MESH:D007239', (134, 143))	('hsa05168', 'Var', (145, 153))	('herpes simplex', 'Phenotype', 'HP:0012302', (119, 133))	('antigen processing and presentation', 'biological_process', 'GO:0019882', ('67', '102'))	('infection', 'Disease', (134, 143))
63580	30651788	Mutation of the cellular tumor antigen p53 gene has been reported to be associated with the occurrence of the majority of different types of cancer.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cellular tumor antigen p53', 'Gene', (16, 42))	('Mutation', 'Var', (0, 8))	('associated', 'Reg', (72, 82))	('cellular tumor antigen p53', 'Gene', '7157', (16, 42))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('tumor antigen', 'molecular_function', 'GO:0008222', ('25', '38'))	('cancer', 'Disease', (141, 147))
63585	30068939	Hippo signaling dysfunction induces cancer cell addiction to YAP Over the past decades, the Hippo has been established as a crucial pathway involved in organ size control and cancer suppression.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('induces', 'Reg', (28, 35))	('Hippo signaling', 'biological_process', 'GO:0035329', ('0', '15'))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('dysfunction', 'Var', (16, 27))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
63586	30068939	Dysregulation of Hippo signaling and hyperactivation of its downstream effector YAP are frequently associated with various human cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Hippo', 'Protein', (17, 22))	('Hippo signaling', 'biological_process', 'GO:0035329', ('17', '32'))	('Dysregulation', 'Var', (0, 13))	('human', 'Species', '9606', (123, 128))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('YAP', 'Gene', (80, 83))	('hyperactivation', 'PosReg', (37, 52))	('associated', 'Reg', (99, 109))
63588	30068939	In this study, we reported that the Hippo signaling deficiency can lead to a YAP-dependent oncogene addiction for cancer cells.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('lead to', 'Reg', (67, 74))	('Hippo signaling', 'biological_process', 'GO:0035329', ('36', '51'))	('deficiency', 'Var', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('YAP-dependent', 'MPA', (77, 90))	('Hippo', 'Protein', (36, 41))	('cancer', 'Disease', (114, 120))
63601	30068939	In KRAS mutated pancreatic cancer, YAP activation can drive KRAS-independent tumor relapse.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('KRAS', 'Gene', '3845', (3, 7))	('mutated', 'Var', (8, 15))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (16, 33))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('KRAS', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('pancreatic cancer', 'Disease', (16, 33))	('KRAS', 'Gene', '3845', (60, 64))	('pancreatic cancer', 'Disease', 'MESH:D010190', (16, 33))	('tumor', 'Disease', (77, 82))	('KRAS', 'Gene', (3, 7))
63602	30068939	Notably, in all these documented cancer types, YAP is highly activated and targeting YAP significantly suppresses the related tumorigenesis.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('targeting', 'Var', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('suppresses', 'NegReg', (103, 113))	('YAP', 'Gene', (85, 88))	('tumor', 'Disease', (126, 131))
63603	30068939	These evidences suggest that YAP could be indispensable in the cancers with Hippo signaling dysfunction.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Hippo signaling', 'biological_process', 'GO:0035329', ('76', '91'))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('dysfunction', 'Var', (92, 103))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
63604	30068939	In this study, we demonstrated that Hippo signaling deficiency enables the development of an active YAP addiction in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Hippo signaling', 'biological_process', 'GO:0035329', ('36', '51'))	('deficiency', 'Var', (52, 62))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('Hippo', 'Protein', (36, 41))
63610	30068939	In concordance with the previous studies, loss of Hippo pathway components, LATS1/2, MOB1A/B and NF2, dramatically induced a nuclear accumulation of YAP (Figure 1A) and significantly decreased the YAP phosphorylation (Figure 1B); deficiency of MST1/2 kinases only showed mild effect on YAP activity, because YAP is still mostly localized in the cytoplasm (Figure 1A) and had only a slight decrease of its phosphorylation (Figure 1B) in MST1/2 DKO cells.	('YAP phosphorylation', 'MPA', (197, 216))	('NF2', 'Gene', (97, 100))	('MST1/2', 'Gene', '4485;6788', (244, 250))	('MST1/2', 'Gene', (244, 250))	('MST1/2', 'Gene', (436, 442))	('phosphorylation', 'MPA', (405, 420))	('cytoplasm', 'cellular_component', 'GO:0005737', ('345', '354'))	('decreased', 'NegReg', (183, 192))	('phosphorylation', 'biological_process', 'GO:0016310', ('201', '216'))	('LATS1/2', 'Gene', '9113;26524', (76, 83))	('MOB1A', 'Gene', (85, 90))	('LATS1/2', 'Gene', (76, 83))	('nuclear accumulation', 'CPA', (125, 145))	('phosphorylation', 'biological_process', 'GO:0016310', ('405', '420'))	('decrease', 'NegReg', (389, 397))	('loss', 'Var', (42, 46))	('MST1/2', 'Gene', '4485;6788', (436, 442))	('MOB1A', 'Gene', '55233', (85, 90))	('NF2', 'Gene', '4771', (97, 100))	('induced', 'Reg', (115, 122))
63611	30068939	Interestingly, cell proliferation assay revealed that loss of YAP resulted in a dramatic inhibitory effect on the growth of LATS1/2 DKO cells compared to that of wild-type cells (Figure S1).	('LATS1/2', 'Gene', '9113;26524', (124, 131))	('cell proliferation', 'biological_process', 'GO:0008283', ('15', '33'))	('inhibitory effect', 'NegReg', (89, 106))	('YAP', 'Gene', (62, 65))	('loss', 'Var', (54, 58))	('LATS1/2', 'Gene', (124, 131))	('growth', 'MPA', (114, 120))
63612	30068939	In addition, we used shRNA to downregulate YAP in each Hippo pathway component KO cells (Figure 1B) and found that loss of YAP specifically suppressed the viability of the LATS1/2 DKO, MOB1A/B DKO and NF2 KO cells, in which YAP is constitutively active, but only had a mild growth effect on both wild-type and MST1/2 DKO cells (Figures 1C and 1D).	('LATS1/2', 'Gene', '9113;26524', (172, 179))	('suppressed', 'NegReg', (140, 150))	('MOB1A', 'Gene', (185, 190))	('NF2', 'Gene', (201, 204))	('viability', 'CPA', (155, 164))	('downregulate', 'NegReg', (30, 42))	('LATS1/2', 'Gene', (172, 179))	('MOB1A', 'Gene', '55233', (185, 190))	('loss', 'Var', (115, 119))	('MST1/2', 'Gene', '4485;6788', (310, 316))	('NF2', 'Gene', '4771', (201, 204))	('Hippo pathway', 'Pathway', (55, 68))	('YAP', 'Gene', (123, 126))	('MST1/2', 'Gene', (310, 316))
63614	30068939	Although YAP and TAZ are both constitutively active in the LATS1/2 DKO cells, loss of YAP but not TAZ (Figure 1E) dramatically suppressed the LATS1/2 DKO cell viability (Figures 1F and 1G).	('TAZ', 'Gene', '6901', (98, 101))	('LATS1/2', 'Gene', '9113;26524', (59, 66))	('YAP', 'Gene', (86, 89))	('TAZ', 'Gene', (98, 101))	('TAZ', 'Gene', '6901', (17, 20))	('suppressed', 'NegReg', (127, 137))	('TAZ', 'Gene', (17, 20))	('LATS1/2', 'Gene', '9113;26524', (142, 149))	('LATS1/2', 'Gene', (59, 66))	('loss', 'Var', (78, 82))	('LATS1/2', 'Gene', (142, 149))
63615	30068939	Notably, a recent gene inactivation study comparing both YAP KO and TAZ KO cells further supports this finding, where loss of YAP showed greater effect on cell physiology than TAZ inactivation.	('cell physiology', 'biological_process', 'GO:0009987', ('155', '170'))	('cell physiology', 'MPA', (155, 170))	('YAP', 'Gene', (126, 129))	('TAZ', 'Gene', '6901', (68, 71))	('TAZ', 'Gene', (68, 71))	('loss', 'Var', (118, 122))	('TAZ', 'Gene', '6901', (176, 179))	('TAZ', 'Gene', (176, 179))
63628	30068939	Interestingly, loss of YAP dramatically suppressed the viability for the cancer cells with YAP dominantly localized in the nucleus (e.g.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('suppressed', 'NegReg', (40, 50))	('nucleus', 'cellular_component', 'GO:0005634', ('123', '130'))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('loss', 'Var', (15, 19))	('viability', 'CPA', (55, 64))	('YAP', 'Gene', (23, 26))
63630	30068939	SUM159, T47D, SKOV3, Huh-7) (Figures 2E and 2F).	('Huh-7', 'Gene', '284424', (21, 26))	('SKOV3', 'CellLine', 'CVCL:0532', (14, 19))	('T47D', 'Var', (8, 12))	('Huh-7', 'Gene', (21, 26))
63631	30068939	These results suggest that Hippo inactivation/YAP activation is associated with a YAP-dependent oncogene addiction in the tested cancer cells, which is consistent with our previous findings by using the Hippo KO cells (Figures 1C and 1D).	('associated', 'Reg', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('activation', 'PosReg', (50, 60))	('Hippo', 'Gene', (27, 32))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('inactivation/YAP', 'Var', (33, 49))	('YAP-dependent oncogene addiction', 'Disease', (82, 114))
63633	30068939	Through it, we identified that several HDAC inhibitors, including LBH589 (Panobinostat), JNJ26481585 (Quisinostat), LAQ824 (Dacinostat) and Trichostatin A, can dramatically suppress the YAP expression in all the tested cancer cells (Figure 3B).	('JNJ26481585', 'Chemical', 'MESH:C541788', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('Dacinostat', 'Chemical', '-', (124, 134))	('Panobinostat', 'Chemical', 'MESH:D000077767', (74, 86))	('JNJ26481585', 'Var', (89, 100))	('LBH589', 'Chemical', 'MESH:D000077767', (66, 72))	('suppress', 'NegReg', (173, 181))	('HDAC', 'Gene', '9734', (39, 43))	('Quisinostat', 'Chemical', 'MESH:C541788', (102, 113))	('LAQ824', 'Chemical', 'MESH:C477361', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('HDAC', 'Gene', (39, 43))	('LAQ824', 'Var', (116, 122))	('YAP', 'Gene', (186, 189))	('cancer', 'Disease', (219, 225))	('LBH589', 'Var', (66, 72))	('Trichostatin A', 'Chemical', 'MESH:C012589', (140, 154))
63639	30068939	As for the Hippo KO cells, HDAC inhibitors LBH589 and SAHA dramatically suppressed the viability of the LATS1/2 DKO, MOB1A/B DKO and NF2 KO cells, in which YAP is constitutively active; but only showed a certain extent of inhibitory effect on both wild-type and MST1/2 DKO cells, in which YAP is still normally controlled by the Hippo pathway (Figures 3E and 3F).	('HDAC', 'Gene', '9734', (27, 31))	('LBH589', 'Var', (43, 49))	('SAHA', 'Chemical', 'MESH:D000077337', (54, 58))	('NF2', 'Gene', '4771', (133, 136))	('MOB1A', 'Gene', (117, 122))	('viability', 'CPA', (87, 96))	('LATS1/2', 'Gene', '9113;26524', (104, 111))	('LBH589', 'Chemical', 'MESH:D000077767', (43, 49))	('suppressed', 'NegReg', (72, 82))	('MST1/2', 'Gene', '4485;6788', (262, 268))	('inhibitors LBH589', 'Var', (32, 49))	('MOB1A', 'Gene', '55233', (117, 122))	('LATS1/2', 'Gene', (104, 111))	('NF2', 'Gene', (133, 136))	('MST1/2', 'Gene', (262, 268))	('HDAC', 'Gene', (27, 31))
63648	30068939	Interestingly, although the wild-type 4T1-derived xenograft tumor growth was significantly suppressed by LBH589 and SAHA, loss of Lats1/2 further enhanced the tumor vulnerability in response to the treatment of LBH589 and SAHA (Figures 4B and 4C).	('suppressed', 'NegReg', (91, 101))	('Lats1/2', 'Gene', '8140;7462', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('SAHA', 'Chemical', 'MESH:D000077337', (116, 120))	('SAHA', 'Chemical', 'MESH:D000077337', (222, 226))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('Lats1/2', 'Gene', (130, 137))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('enhanced', 'PosReg', (146, 154))	('LBH589', 'Chemical', 'MESH:D000077767', (211, 217))	('tumor', 'Disease', (60, 65))	('loss', 'Var', (122, 126))	('LBH589', 'Chemical', 'MESH:D000077767', (105, 111))
63651	30068939	Moreover, LBH589 and SAHA treatment further enhanced the cell apoptosis (cleaved-caspase 3 staining) in the Lats1/2 DKO tumors compared to the wild-type 4T1 tumors under the same compound treated condition (Figure 4D).	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('cell apoptosis', 'CPA', (57, 71))	('Lats1/2', 'Gene', '8140;7462', (108, 115))	('LBH589', 'Chemical', 'MESH:D000077767', (10, 16))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('SAHA', 'Chemical', 'MESH:D000077337', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('LBH589', 'Var', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('Lats1/2', 'Gene', (108, 115))	('enhanced', 'PosReg', (44, 52))
63652	30068939	Taken together, these results suggest that Hippo signaling deficiency is able to sensitize tumors to HDAC inhibitors.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('HDAC', 'Gene', (101, 105))	('Hippo signaling', 'biological_process', 'GO:0035329', ('43', '58'))	('HDAC', 'Gene', '9734', (101, 105))	('sensitize', 'Reg', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('deficiency', 'Var', (59, 69))	('Hippo', 'Protein', (43, 48))
63657	30068939	Moreover, expression of YAP-5SA significantly rescued the MDA-MB-231 tumor growth compared to the vector control cells upon LBH589 and SAHA treatment (Figures 4H and 4I).	('rescued', 'PosReg', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('SAHA', 'Chemical', 'MESH:D000077337', (135, 139))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (58, 68))	('tumor', 'Disease', (69, 74))	('YAP-5SA', 'Gene', (24, 31))	('MDA-MB-231', 'Gene', (58, 68))	('LBH589', 'Chemical', 'MESH:D000077767', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('expression', 'Var', (10, 20))
63658	30068939	Consistently, the transcription of YAP was largely decreased in the vector control tumors treated by LBH589 and SAHA, while YAP level was relatively stable in the YAP-5SA overexpressed tumors under the same treated conditions (Figure 4J).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('LBH589', 'Var', (101, 107))	('YAP', 'Gene', (35, 38))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Disease', (83, 89))	('transcription', 'MPA', (18, 31))	('decreased', 'NegReg', (51, 60))	('SAHA', 'Chemical', 'MESH:D000077337', (112, 116))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('LBH589', 'Chemical', 'MESH:D000077767', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('transcription', 'biological_process', 'GO:0006351', ('18', '31'))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
63661	30068939	The Hippo has been established as a tumor suppressor pathway and its downstream effector YAP is known as an oncoprotein; however, compared to multiple genetic and epigenetic abnormalities during cancer development, role of Hippo signaling dysfunction/YAP activation in cancer has not been fully elucidated.	('tumor suppressor', 'biological_process', 'GO:0051726', ('36', '52'))	('epigenetic abnormalities', 'Disease', (163, 187))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('36', '52'))	('cancer', 'Disease', (269, 275))	('epigenetic abnormalities', 'Disease', 'MESH:D000014', (163, 187))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('dysfunction/YAP', 'Var', (239, 254))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Hippo signaling', 'biological_process', 'GO:0035329', ('223', '238'))	('tumor', 'Disease', (36, 41))	('cancer', 'Disease', 'MESH:D009369', (269, 275))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
63662	30068939	In this study, we revealed an unexpected YAP addiction in the cancers driven by the Hippo inactivation.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Hippo', 'Gene', (84, 89))	('inactivation', 'Var', (90, 102))	('driven by', 'Reg', (70, 79))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('YAP addiction', 'Disease', (41, 54))
63664	30068939	Genetic mouse studies demonstrated that inhibition of YAP expression or activity dramatically targeted the liver cancer formation as generated by the loss of Hippo component Nf2 or Mst1/2.	('inhibition', 'Var', (40, 50))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Nf2', 'Gene', (174, 177))	('liver cancer', 'Phenotype', 'HP:0002896', (107, 119))	('activity', 'MPA', (72, 80))	('liver cancer', 'Disease', 'MESH:D006528', (107, 119))	('Nf2', 'Gene', '18016', (174, 177))	('formation', 'biological_process', 'GO:0009058', ('120', '129'))	('Mst1/2', 'Gene', (181, 187))	('liver cancer', 'Disease', (107, 119))	('Mst1/2', 'Gene', '15235;56274', (181, 187))	('targeted', 'NegReg', (94, 102))	('mouse', 'Species', '10090', (8, 13))	('loss', 'NegReg', (150, 154))
63665	30068939	Inactivation of YAP dramatically inhibited the oncogenic activities of the NF2-deficient mesothelioma cells.	('inhibited', 'NegReg', (33, 42))	('NF2-deficient mesothelioma', 'Disease', (75, 101))	('oncogenic activities', 'CPA', (47, 67))	('NF2-deficient mesothelioma', 'Disease', 'MESH:C537392', (75, 101))	('YAP', 'Gene', (16, 19))	('Inactivation', 'Var', (0, 12))
63666	30068939	Moreover, YAP is dominantly localized in the nucleus of the uveal melanoma cells with GNAQ/GNA11 mutations.	('mutations', 'Var', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('GNA11', 'Gene', (91, 96))	('GNAQ', 'Gene', '2776', (86, 90))	('GNA11', 'Gene', '2767', (91, 96))	('uveal melanoma', 'Disease', 'MESH:C536494', (60, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('uveal melanoma', 'Disease', (60, 74))	('nucleus', 'cellular_component', 'GO:0005634', ('45', '52'))	('GNAQ', 'Gene', (86, 90))
63667	30068939	Similarly, loss of YAP dramatically suppressed the cell viability and tumor formation for the uveal melanoma cells carrying GNAQ/GNA11 mutations, but did not affect the BRAF-mutated cells with the functional Hippo signaling.	('BRAF', 'Gene', (169, 173))	('BRAF', 'Gene', '673', (169, 173))	('GNA11', 'Gene', '2767', (129, 134))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('GNAQ', 'Gene', '2776', (124, 128))	('cell viability', 'CPA', (51, 65))	('GNAQ', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mutations', 'Var', (135, 144))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('GNA11', 'Gene', (129, 134))	('YAP', 'Gene', (19, 22))	('Hippo signaling', 'biological_process', 'GO:0035329', ('208', '223'))	('formation', 'biological_process', 'GO:0009058', ('76', '85'))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('suppressed', 'NegReg', (36, 46))	('uveal melanoma', 'Disease', (94, 108))	('loss', 'Var', (11, 15))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
63668	30068939	These genetic and pathological evidences further support our current hypothesis that deficient Hippo signaling can result in a YAP addiction in cancers.	('YAP addiction', 'Disease', (127, 140))	('Hippo signaling', 'Protein', (95, 110))	('deficient', 'Var', (85, 94))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('Hippo signaling', 'biological_process', 'GO:0035329', ('95', '110'))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('result in', 'Reg', (115, 124))
63691	30068939	For HDAC inhibitors, JNJ26481585 (Quisinostat), LAQ824 (Dacinostat), LBH589 (Panobinostat) and Trichostatin A were purchased from SelleckChem.	('HDAC', 'Gene', '9734', (4, 8))	('Dacinostat', 'Chemical', '-', (56, 66))	('Panobinostat', 'Chemical', 'MESH:D000077767', (77, 89))	('JNJ26481585', 'Chemical', 'MESH:C541788', (21, 32))	('JNJ26481585', 'Var', (21, 32))	('LBH589', 'Chemical', 'MESH:D000077767', (69, 75))	('Quisinostat', 'Chemical', 'MESH:C541788', (34, 45))	('Trichostatin A', 'Chemical', 'MESH:C012589', (95, 109))	('LAQ824', 'Chemical', 'MESH:C477361', (48, 54))	('HDAC', 'Gene', (4, 8))
63756	29801433	The discovery uveal melanoma dataset (GSE22138) consists of gene expression profiles of 42,346 genes for 63 untreated patients, chromosome 3 monosomy status and follow-up metastasis-free survival information.	('uveal melanoma', 'Phenotype', 'HP:0007716', (14, 28))	('uveal melanoma', 'Disease', 'MESH:C536494', (14, 28))	('chromosome', 'cellular_component', 'GO:0005694', ('128', '138'))	('uveal melanoma', 'Disease', (14, 28))	('gene expression', 'biological_process', 'GO:0010467', ('60', '75'))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('patients', 'Species', '9606', (118, 126))	('monosomy', 'Var', (141, 149))
63786	29801433	FDR-corrected p-values between bHC1 and bNMF5/bKM4 were 11-14 orders of magnitude larger than those between bHC1 and bNMF3/bKM1 (despite still being significant).	('bNMF5/bKM4', 'Var', (40, 50))	('bKM4', 'Chemical', '-', (46, 50))	('p-values', 'MPA', (14, 22))	('bHC1', 'Var', (31, 35))	('larger', 'PosReg', (82, 88))
63796	29801433	Two of the remaining three communities showed less significant associations with chromosome 3 disomy (mHYP4) and monosomy (mHYP1; hypergeometric test; FDR < 0.2) respectively, while the final community (mHYP3) was not significantly enriched for either.	('HYP', 'Gene', (124, 127))	('HYP', 'Gene', '18675', (124, 127))	('monosomy', 'Var', (113, 121))	('HYP', 'Gene', (103, 106))	('disomy', 'Disease', (94, 100))	('HYP', 'Gene', '18675', (103, 106))	('disomy', 'Disease', 'MESH:D024182', (94, 100))	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('chromosome', 'Var', (81, 91))	('HYP', 'Gene', (204, 207))	('HYP', 'Gene', '18675', (204, 207))
63817	29801433	Two classes were discovered - class 1, with good prognosis and association with chromosome 3 disomy; and class 2, with poor prognosis, associated with chromosome 3 monosomy and metastasis.	('disomy', 'Disease', (93, 99))	('disomy', 'Disease', 'MESH:D024182', (93, 99))	('chromosome 3 monosomy', 'Var', (151, 172))	('association', 'Interaction', (63, 74))	('associated', 'Reg', (135, 145))	('metastasis', 'CPA', (177, 187))	('chromosome', 'cellular_component', 'GO:0005694', ('80', '90'))	('chromosome', 'cellular_component', 'GO:0005694', ('151', '161'))
63826	29760383	Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors Metastatic uveal melanoma is a deadly disease with no proven standard of care.	('Metastatic uveal melanoma', 'Disease', 'MESH:C536494', (102, 127))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('PD1', 'Gene', '5133', (25, 28))	('tumors', 'Disease', (95, 101))	('uveal melanoma', 'Disease', 'MESH:C536494', (113, 127))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('Metastatic uveal melanoma', 'Disease', (102, 127))	('mutations', 'Var', (69, 78))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('MBD4', 'Gene', '8930', (64, 68))	('uveal melanoma', 'Disease', 'MESH:C536494', (32, 46))	('uveal melanoma', 'Phenotype', 'HP:0007716', (113, 127))	('uveal melanoma', 'Disease', (32, 46))	('PD1', 'Gene', (25, 28))	('deadly disease', 'Disease', (133, 147))	('MBD4', 'Gene', (64, 68))	('deadly disease', 'Disease', 'MESH:D004194', (133, 147))	('uveal melanoma', 'Phenotype', 'HP:0007716', (32, 46))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
63827	29760383	Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor.	('high sensitivity', 'MPA', (72, 88))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('patient', 'Species', '9606', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('CpG>', 'Gene', (133, 137))	('uveal melanoma', 'Disease', (29, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('MBD4', 'Gene', '8930', (158, 162))	('MBD4', 'Gene', (158, 162))	('tumor', 'Disease', (231, 236))	('MBD4', 'Gene', (206, 210))	('MBD4', 'Gene', '8930', (206, 210))	('germline', 'Var', (163, 171))	('inactivation', 'Var', (211, 223))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('mutation', 'Var', (141, 149))
63828	29760383	We identify additional tumors in The Cancer Genome Atlas (TCGA) cohorts with similar hypermutator profiles in patients carrying germline deleterious MBD4 mutations and somatic loss of heterozygosity.	('MBD4', 'Gene', '8930', (149, 153))	('Cancer Genome Atlas', 'Disease', (37, 56))	('MBD4', 'Gene', (149, 153))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('loss', 'NegReg', (176, 180))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (37, 56))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutations', 'Var', (154, 163))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('patients', 'Species', '9606', (110, 118))	('Cancer', 'Phenotype', 'HP:0002664', (37, 43))
63831	29760383	Here, the authors describe a new hypermutated phenotype due to germline mutations and subsequent somatic loss of heterozygosity of MBD4, and a dramatic response to the PD-1 inhibitor pembrolizumab in a patient with a MBD4-inactivated hypermutated uveal melanoma.	('mutations', 'Var', (72, 81))	('uveal melanoma', 'Disease', (247, 261))	('response', 'MPA', (152, 160))	('melanoma', 'Phenotype', 'HP:0002861', (253, 261))	('pembrolizumab', 'Chemical', 'MESH:C582435', (183, 196))	('patient', 'Species', '9606', (202, 209))	('MBD4', 'Gene', '8930', (217, 221))	('loss of', 'NegReg', (105, 112))	('MBD4', 'Gene', (217, 221))	('uveal melanoma', 'Phenotype', 'HP:0007716', (247, 261))	('uveal melanoma', 'Disease', 'MESH:C536494', (247, 261))	('MBD4', 'Gene', '8930', (131, 135))	('MBD4', 'Gene', (131, 135))
63833	29760383	Inactivation of BAP1 (3p21), through both deleterious mutations and monosomy 3, is frequent in UM and is associated with a high risk of metastasis.	('monosomy 3', 'Var', (68, 78))	('metastasis', 'CPA', (136, 146))	('BAP1', 'Gene', '8314', (16, 20))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('associated', 'Reg', (105, 115))	('Inactivation', 'Var', (0, 12))	('BAP1', 'Gene', (16, 20))
63848	29760383	We identified a germline deleterious frameshift deletion of MBD4 (3q21.3; c.1441delT:p.F481Dfs*9) with loss of the second allele by monosomy 3 in all tumor samples (Fig.	('p.F481Dfs*9', 'FRAMESHIFT', 'None', (85, 96))	('MBD4', 'Gene', '8930', (60, 64))	('MBD4', 'Gene', (60, 64))	('frameshift deletion', 'Var', (37, 56))	('p.F481Dfs*9', 'Var', (85, 96))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('c.1441delT', 'Var', (74, 84))	('c.1441delT', 'Mutation', 'c.1441delT', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('loss', 'NegReg', (103, 107))
63849	29760383	No other sample in our UM series carried a MBD4 or TDG mutation.	('MBD4', 'Gene', '8930', (43, 47))	('MBD4', 'Gene', (43, 47))	('TDG', 'Gene', (51, 54))	('mutation', 'Var', (55, 63))	('UM', 'Phenotype', 'HP:0007716', (23, 25))	('TDG', 'Gene', '6996', (51, 54))
63855	29760383	2a).This tumor was carrying a BAP1 mutation and monosomy 3 as well as 474 SNVs (305 non-synonymous SNVs) corresponding to a 36-fold increase of SNVs as compared to the overall TCGA UM series.	('BAP1', 'Gene', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('increase', 'PosReg', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('SNVs', 'MPA', (144, 148))	('tumor', 'Disease', (9, 14))	('mutation', 'Var', (35, 43))	('BAP1', 'Gene', '8314', (30, 34))	('UM', 'Phenotype', 'HP:0007716', (181, 183))
63856	29760383	This patient furthermore carried a germline c.1562-1G>T:p.D521Pfs*4 MBD4 splice-site variant and somatic loss of the wild-type allele due to tumor monosomy 3.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('patient', 'Species', '9606', (5, 12))	('p.D521Pfs*4', 'Var', (56, 67))	('c.1562-1G>T', 'Mutation', 'rs778697654', (44, 55))	('MBD4', 'Gene', '8930', (68, 72))	('MBD4', 'Gene', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('p.D521Pfs*4', 'FRAMESHIFT', 'None', (56, 67))	('tumor', 'Disease', (141, 146))	('loss', 'NegReg', (105, 109))
63858	29760383	We further analyzed the pan-cancer TCGA series (>10,000 tumors; Supplementary Table 1) and identified 4831 hypermutated tumors (>200 SNVs per tumor) of which 20 cases, including UVM_1, were enriched in CpG>TpG mutations ( > 0.6; Fig.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Disease', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('000 tumors', 'Disease', 'MESH:D009369', (52, 62))	('tumor', 'Disease', (120, 125))	('000 tumors', 'Disease', (52, 62))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancer', 'Disease', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('CpG>TpG mutations', 'Var', (202, 219))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
63859	29760383	Of these 20 cases, patient GBM_4 presented a glioblastoma carrying 1149 SNVs (440 non-synonymous SNVs) and a germline c.335+1G>A:p.R83Pfs*5 MBD4 mutation with somatic loss of heterozygosity leading to the use of a cryptic splice donor site, loss of 88 bases, and a premature stop codon (Fig.	('loss', 'NegReg', (241, 245))	('patient', 'Species', '9606', (19, 26))	('c.335+1G>A', 'Mutation', 'rs552296498', (118, 128))	('donor', 'Species', '9606', (229, 234))	('MBD4', 'Gene', '8930', (140, 144))	('88 bases', 'MPA', (249, 257))	('p.R83Pfs*5', 'FRAMESHIFT', 'None', (129, 139))	('glioblastoma', 'Disease', (45, 57))	('glioblastoma', 'Disease', 'MESH:D005909', (45, 57))	('MBD4', 'Gene', (140, 144))	('p.R83Pfs*5', 'Var', (129, 139))	('glioblastoma', 'Phenotype', 'HP:0012174', (45, 57))	('loss of', 'NegReg', (167, 174))
63861	29760383	The germline MBD4 mutations identified in patients UVM_IC, UVM_1, and GBM_4 are rare in the general population with minor allele frequencies ranging from ~0.000008 to ~0.00002.	('MBD4', 'Gene', '8930', (13, 17))	('MBD4', 'Gene', (13, 17))	('patients', 'Species', '9606', (42, 50))	('mutations', 'Var', (18, 27))
63862	29760383	To be noticed, three of these 20 hypermutated cases carried somatic MBD4 indels together with mismatch repair deficiency (two colorectal and one endometrial adenocarcinomas); the molecular mechanism of hypermutation in the other cases remains undetermined.	('indels', 'Var', (73, 79))	('mismatch repair', 'biological_process', 'GO:0006298', ('94', '109'))	('MBD4', 'Gene', '8930', (68, 72))	('MBD4', 'Gene', (68, 72))	('endometrial adenocarcinomas', 'Disease', 'MESH:D016889', (145, 172))	('endometrial adenocarcinomas', 'Disease', (145, 172))	('colorectal', 'Disease', (126, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
63863	29760383	A role for MBD4 germline mutations in cancer predisposition was hypothesized 18 years ago.	('cancer', 'Disease', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('germline mutations', 'Var', (16, 34))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('MBD4', 'Gene', '8930', (11, 15))	('MBD4', 'Gene', (11, 15))
63864	29760383	The identification of two UM cases with MBD4 germline mutations is intriguing, and possibly related to the frequent monosomy 3:where MBD4 is located:in this disease.	('MBD4', 'Gene', '8930', (40, 44))	('MBD4', 'Gene', (40, 44))	('MBD4', 'Gene', '8930', (133, 137))	('MBD4', 'Gene', (133, 137))	('germline', 'Var', (45, 53))	('UM', 'Phenotype', 'HP:0007716', (26, 28))
63869	29760383	Thus, MBD4 inactivation may not be sufficient to initiate tumorigenesis but may play a significant role in tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('inactivation', 'Var', (11, 23))	('MBD4', 'Gene', '8930', (6, 10))	('MBD4', 'Gene', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('play', 'Reg', (80, 84))
63884	29760383	Pathological examinations showed CD3+ peri- and intra-tumoral lymphocytic infiltrates in both samples (Fig.	('CD3+', 'Var', (33, 37))	('intra-tumoral lymphocytic infiltrates', 'Disease', 'None', (48, 85))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('intra-tumoral lymphocytic infiltrates', 'Disease', (48, 85))
63901	29760383	Union of variants detected with these three algorithms were annotated using ANNOVAR with the following databases: ensGene, avsnp147, cosmic80, popfreq_all_20150413, and dbnsfp33a.	('variants', 'Var', (9, 17))	('algorithms', 'Disease', (44, 54))	('algorithms', 'Disease', 'None', (44, 54))
63915	29760383	Bi-PAP real-time PCR assays were done using primers with dideoxynucleotide 3' ends, specific for GNAQ and GNA11 mutations.	('dideoxynucleotide', 'Chemical', 'MESH:D054306', (57, 74))	('GNAQ', 'Gene', '2776', (97, 101))	('GNA11', 'Gene', (106, 111))	('mutations', 'Var', (112, 121))	('GNA11', 'Gene', '2767', (106, 111))	('PAP', 'molecular_function', 'GO:0043751', ('3', '6'))	('GNAQ', 'Gene', (97, 101))
64044	29244840	Results showed that high PVT1 expression group had a higher proportion of epithelioid cell dominant disease (a more malignant histological subtype than spindle cell dominant disease) and more cases of extrascleral extension (a risk factor for metastasis) compared with the low PVT1 expression group.	('PVT1', 'Gene', (277, 281))	('PVT1', 'Gene', (25, 29))	('epithelioid cell dominant disease', 'Disease', (74, 107))	('PVT1', 'Gene', '5820', (277, 281))	('high', 'Var', (20, 24))	('spindle', 'cellular_component', 'GO:0005819', ('152', '159'))	('PVT1', 'Gene', '5820', (25, 29))	('extrascleral extension', 'CPA', (201, 223))	('epithelioid cell dominant disease', 'Disease', 'MESH:D012509', (74, 107))
64047	29244840	By performing univariate and multivariate analysis, we found that high PVT1 expression was an independent predictor of poor OS in patients with uveal melanoma (HR: 12.015, 95%CI: 1.854-77.876, p = 0.009).	('PVT1', 'Gene', (71, 75))	('OS', 'Chemical', '-', (124, 126))	('PVT1', 'Gene', '5820', (71, 75))	('patients', 'Species', '9606', (130, 138))	('expression', 'MPA', (76, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (144, 158))	('high', 'Var', (66, 70))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('uveal melanoma', 'Phenotype', 'HP:0007716', (144, 158))	('uveal melanoma', 'Disease', (144, 158))	('poor OS', 'Disease', (119, 126))
64050	29244840	Some recent studies found that dysregulated lncRNAs are involved in the pathological development of uveal melanoma.	('dysregulated', 'Var', (31, 43))	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('lncRNAs', 'Protein', (44, 51))	('uveal melanoma', 'Disease', (100, 114))	('involved', 'Reg', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
64051	29244840	For example, hypermethylated in cancer 1 (HIC1) can induce uveal melanoma progression by activating lncRNA-numb.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('activating', 'PosReg', (89, 99))	('uveal melanoma', 'Disease', (59, 73))	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('cancer', 'Disease', (32, 38))	('numb', 'Gene', '8650', (107, 111))	('hypermethylated', 'Var', (13, 28))	('numb', 'Gene', (107, 111))	('induce', 'PosReg', (52, 58))	('HIC1', 'Gene', '3090', (42, 46))	('HIC1', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('uveal melanoma', 'Disease', 'MESH:C536494', (59, 73))
64055	29244840	In gastric cancer, high PVT1 expression is an independent prognostic marker for poor overall survival (OS) and disease-free survival (DFS).	('high', 'Var', (19, 23))	('OS', 'Chemical', '-', (103, 105))	('poor', 'NegReg', (80, 84))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('PVT1', 'Gene', (24, 28))	('gastric cancer', 'Disease', (3, 17))	('PVT1', 'Gene', '5820', (24, 28))	('disease-free survival', 'CPA', (111, 132))	('overall', 'MPA', (85, 92))	('expression', 'MPA', (29, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
64056	29244840	PVT1 overexpression promotes melanoma cells proliferation, cell cycle progression, and migration.	('migration', 'CPA', (87, 96))	('cell cycle progression', 'CPA', (59, 81))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('cell cycle', 'biological_process', 'GO:0007049', ('59', '69'))	('promotes', 'PosReg', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('PVT1', 'Gene', (0, 4))	('PVT1', 'Gene', '5820', (0, 4))	('overexpression', 'Var', (5, 19))
64070	29244840	Compared with the low PVT1 expression group, the high PVT1 expression was associated with older age (66.80 +- 11.55 vs. 56.50 +- 14.36, p = 0.0007), a higher proportion of epithelioid cell dominant disease (22/40 vs. 12/40, p = 0.024), more cases of distant metastasis (4/28 vs. 0/27, p = 0.043) and extrascleral extension (6/37 vs. 1/38, p = 0.043) and a higher death rate (20/40 vs. 3/40, p<0.0001) (Table 1).	('epithelioid cell dominant disease', 'Disease', (172, 205))	('PVT1', 'Gene', (22, 26))	('death', 'Disease', 'MESH:D003643', (363, 368))	('death', 'Disease', (363, 368))	('PVT1', 'Gene', '5820', (54, 58))	('distant metastasis', 'CPA', (250, 268))	('epithelioid cell dominant disease', 'Disease', 'MESH:D012509', (172, 205))	('extrascleral extension', 'CPA', (300, 322))	('PVT1', 'Gene', '5820', (22, 26))	('high', 'Var', (49, 53))	('PVT1', 'Gene', (54, 58))
64073	29244840	Among the 80 cases of primary uveal melanoma, 14 cases (17.5%) had PVT1 high-amplification (+2) and 47 cases (58.8%) had amplification (+1) (Fig 1A).	('amplification', 'Var', (121, 134))	('PVT1', 'Gene', (67, 71))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('PVT1', 'Gene', '5820', (67, 71))	('primary uveal melanoma', 'Disease', (22, 44))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (22, 44))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('high-amplification', 'PosReg', (72, 90))
64074	29244840	The amplification was associated with significantly higher expression of PVT1 RNA (Fig 1B).	('PVT1', 'Gene', (73, 77))	('RNA', 'cellular_component', 'GO:0005562', ('78', '81'))	('expression', 'MPA', (59, 69))	('amplification', 'Var', (4, 17))	('higher', 'PosReg', (52, 58))	('PVT1', 'Gene', '5820', (73, 77))
64078	29244840	By generating Kaplan-Meier curves of OS, we found that high PVT1 expression was associated with significantly shorter OS (p<0.0001) (Fig 2A).	('PVT1', 'Gene', '5820', (60, 64))	('shorter', 'NegReg', (110, 117))	('OS', 'Chemical', '-', (118, 120))	('OS', 'Chemical', '-', (37, 39))	('expression', 'MPA', (65, 75))	('high', 'Var', (55, 59))	('PVT1', 'Gene', (60, 64))
64080	29244840	In univariate analysis, we found that epithelioid cell dominant uveal melanoma, extrascleral extension, high PVT1 expression and low PVT1 DNA methylation were associated with unfavorable OS (Table 2).	('extrascleral', 'Disease', (80, 92))	('low', 'NegReg', (129, 132))	('PVT1', 'Gene', '5820', (109, 113))	('PVT1', 'Gene', (133, 137))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('DNA methylation', 'biological_process', 'GO:0006306', ('138', '153'))	('epithelioid cell dominant uveal melanoma', 'Disease', 'MESH:C536494', (38, 78))	('OS', 'Chemical', '-', (187, 189))	('unfavorable OS', 'Disease', (175, 189))	('high', 'Var', (104, 108))	('epithelioid cell dominant uveal melanoma', 'Disease', (38, 78))	('PVT1', 'Gene', '5820', (133, 137))	('uveal melanoma', 'Phenotype', 'HP:0007716', (64, 78))	('expression', 'MPA', (114, 124))	('PVT1', 'Gene', (109, 113))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
64081	29244840	Multivariate analysis showed that older age (>60) (HR: 2.599, 95%CI: 1.049-6.437, p = 0.039), epithelioid cell dominant uveal melanoma (HR: 4.385, 95%CI: 1.514-12.703, p = 0.006) and high PVT1 expression (HR: 12.015, 95%CI: 1.854-77.876, p = 0.009) were independent predictors for poor OS (Table 2).	('poor OS', 'Disease', (281, 288))	('PVT1', 'Gene', (188, 192))	('OS', 'Chemical', '-', (286, 288))	('PVT1', 'Gene', '5820', (188, 192))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('high', 'Var', (183, 187))	('epithelioid cell dominant uveal melanoma', 'Disease', 'MESH:C536494', (94, 134))	('uveal melanoma', 'Phenotype', 'HP:0007716', (120, 134))	('expression', 'MPA', (193, 203))	('epithelioid cell dominant uveal melanoma', 'Disease', (94, 134))
64085	29244840	21 cases even had PVT1 heterozygous loss (Fig 3A).	('PVT1', 'Gene', (18, 22))	('heterozygous loss', 'Var', (23, 40))	('PVT1', 'Gene', '5820', (18, 22))
64087	29244840	In comparison, heterozygous loss did not necessarily result in PVT1 decrease (Fig 3B).	('PVT1', 'Gene', (63, 67))	('heterozygous', 'Var', (15, 27))	('decrease', 'NegReg', (68, 76))	('PVT1', 'Gene', '5820', (63, 67))
64088	29244840	DNA methylation was weakly and negatively correlated with PVT1 expression in skin melanoma (Pearson's r = -0.352, Spearman's r = -0.480) (Fig 3C).	('skin melanoma', 'Disease', (77, 90))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('negatively', 'NegReg', (31, 41))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('methylation', 'Var', (4, 15))	('expression', 'MPA', (63, 73))	('PVT1', 'Gene', (58, 62))	('correlated', 'Reg', (42, 52))	('skin melanoma', 'Disease', 'MESH:D008545', (77, 90))	('PVT1', 'Gene', '5820', (58, 62))
64092	29244840	The high PVT1 expression group had a higher ratio of primary tumor (67/230) compared with the low PVT1 expression group (35/229) (p = 0.0004) (Table 3).	('PVT1', 'Gene', (98, 102))	('PVT1', 'Gene', '5820', (9, 13))	('PVT1', 'Gene', '5820', (98, 102))	('high', 'Var', (4, 8))	('primary tumor', 'Disease', (53, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('primary tumor', 'Disease', 'MESH:D009369', (53, 66))	('PVT1', 'Gene', (9, 13))
64101	29244840	In this study, we found that high PVT1 expression was associated with a higher proportion of epithelioid cell dominant disease (a more malignant histological subtype than spindle cell dominant disease) and more cases of extrascleral extension (a risk factor for metastasis), suggesting that high PVT1 expression may confer some malignant phenotypes to uveal melanoma.	('high', 'Var', (29, 33))	('melanoma', 'Phenotype', 'HP:0002861', (358, 366))	('expression', 'Var', (39, 49))	('PVT1', 'Gene', (34, 38))	('PVT1', 'Gene', '5820', (34, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (352, 366))	('uveal melanoma', 'Disease', (352, 366))	('extrascleral extension', 'CPA', (220, 242))	('uveal melanoma', 'Disease', 'MESH:C536494', (352, 366))	('epithelioid cell dominant disease', 'Disease', 'MESH:D012509', (93, 126))	('PVT1', 'Gene', (296, 300))	('spindle', 'cellular_component', 'GO:0005819', ('171', '178'))	('PVT1', 'Gene', '5820', (296, 300))	('epithelioid cell dominant disease', 'Disease', (93, 126))
64103	29244840	The mechanisms of PVT1 dysregulation in these cancers are quite complex and far from being fully understood.	('dysregulation', 'Var', (23, 36))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', (46, 53))	('PVT1', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PVT1', 'Gene', '5820', (18, 22))
64107	29244840	These findings indicate that dysregulated PVT1 may be caused by both genetic and epigenetic alterations.	('caused by', 'Reg', (54, 63))	('epigenetic alterations', 'Var', (81, 103))	('PVT1', 'Gene', (42, 46))	('dysregulated', 'Var', (29, 41))	('PVT1', 'Gene', '5820', (42, 46))
64108	29244840	By examining copy number alterations in TCGA-UVM, we found that 61 out of 80 cases (76.3%) of primary uveal melanoma had PVT1 amplification.	('PVT1', 'Gene', '5820', (121, 125))	('numb', 'Gene', '8650', (18, 22))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (94, 116))	('copy', 'Var', (13, 17))	('primary uveal melanoma', 'Disease', (94, 116))	('numb', 'Gene', (18, 22))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('PVT1', 'Gene', (121, 125))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))
64109	29244840	In addition, the amplification was associated with significantly higher PVT1 RNA expression.	('PVT1', 'Gene', '5820', (72, 76))	('RNA', 'cellular_component', 'GO:0005562', ('77', '80'))	('PVT1', 'Gene', (72, 76))	('amplification', 'Var', (17, 30))	('higher', 'PosReg', (65, 71))
64110	29244840	These findings supported our hypothesis that genetic amplification is a mechanism of aberrant PVT1 expression in uveal melanoma.	('expression', 'MPA', (99, 109))	('PVT1', 'Gene', '5820', (94, 98))	('aberrant', 'Var', (85, 93))	('PVT1', 'Gene', (94, 98))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('uveal melanoma', 'Phenotype', 'HP:0007716', (113, 127))	('uveal melanoma', 'Disease', 'MESH:C536494', (113, 127))	('uveal melanoma', 'Disease', (113, 127))	('genetic amplification', 'Var', (45, 66))
64112	29244840	In addition, we also observed different levels of copy number alterations and methylation status between uveal melanoma and skin cutaneous melanoma, which indicate that PVT1 dysregulation might be cancer-specific.	('PVT1', 'Gene', '5820', (169, 173))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('numb', 'Gene', '8650', (55, 59))	('numb', 'Gene', (55, 59))	('dysregulation', 'Var', (174, 187))	('cancer', 'Disease', (197, 203))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (124, 147))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('uveal melanoma', 'Phenotype', 'HP:0007716', (105, 119))	('uveal melanoma', 'Disease', (105, 119))	('uveal melanoma', 'Disease', 'MESH:C536494', (105, 119))	('methylation', 'biological_process', 'GO:0032259', ('78', '89'))	('skin cutaneous melanoma', 'Disease', (124, 147))	('PVT1', 'Gene', (169, 173))	('methylation status', 'Var', (78, 96))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (129, 147))
64122	29244840	Inhibition of melanogenesis might enhance the efficacy of radiotherapy and chemotherapy in advanced melanomas.	('melanomas', 'Disease', 'MESH:D008545', (100, 109))	('enhance', 'PosReg', (34, 41))	('melanomas', 'Disease', (100, 109))	('chemotherapy', 'CPA', (75, 87))	('Inhibition', 'Var', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanogenesis', 'Gene', (14, 27))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))	('radiotherapy', 'CPA', (58, 70))
64125	29244840	Aberrant PVT1 expression is associated with malignant behaviors of uveal melanoma and might independently predict poor OS.	('Aberrant', 'Var', (0, 8))	('PVT1', 'Gene', '5820', (9, 13))	('malignant behaviors of uveal melanoma', 'Disease', (44, 81))	('associated with', 'Reg', (28, 43))	('OS', 'Chemical', '-', (119, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('poor OS', 'Disease', (114, 121))	('expression', 'MPA', (14, 24))	('malignant behaviors of uveal melanoma', 'Disease', 'MESH:C536494', (44, 81))	('predict', 'Reg', (106, 113))	('PVT1', 'Gene', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
64143	28744147	Further elaborative research and clinical trials concluded that the mutation of p53 gene could result in tumorigenesis or cell transformation.	('mutation', 'Var', (68, 76))	('p53', 'Gene', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('result in', 'Reg', (95, 104))	('p53', 'Gene', '7157', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('cell transformation', 'CPA', (122, 141))
64144	28744147	The mutant protein of p53 can be considered as a uveal melanoma promoter.	('uveal melanoma', 'Disease', 'MESH:C536494', (49, 63))	('mutant', 'Var', (4, 10))	('uveal melanoma', 'Disease', (49, 63))	('protein', 'Protein', (11, 18))	('p53', 'Gene', (22, 25))	('p53', 'Gene', '7157', (22, 25))	('protein', 'cellular_component', 'GO:0003675', ('11', '18'))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('uveal melanoma', 'Phenotype', 'HP:0007716', (49, 63))
64145	28744147	In addition, the wild-type p53 gene is a kind of tumor suppressor gene; hence, mutation of p53 gene will induce tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('induce', 'PosReg', (105, 111))	('p53', 'Gene', '7157', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('49', '65'))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('mutation', 'Var', (79, 87))	('tumor', 'Disease', (112, 117))	('p53', 'Gene', (27, 30))	('tumor suppressor', 'biological_process', 'GO:0051726', ('49', '65'))
64150	28744147	Studies have found that p53 mutant protein is highly expressed in the cell lines and tissues of uveal melanoma.	('mutant', 'Var', (28, 34))	('p53', 'Gene', (24, 27))	('protein', 'Protein', (35, 42))	('uveal melanoma', 'Disease', (96, 110))	('p53', 'Gene', '7157', (24, 27))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('uveal melanoma', 'Disease', 'MESH:C536494', (96, 110))
64172	28744147	According to the following grading standard, positive cell staining number was classified (no staining or <5% as 0 point, <40% staining as 1 point, >40% as 2 points, >60% as 3 points) into two groups: low p53 expression group (<=1 point) and high p53 expression group (>=2 points).	('low', 'Var', (201, 204))	('p53', 'Gene', (205, 208))	('p53', 'Gene', '7157', (205, 208))	('p53', 'Gene', '7157', (247, 250))	('p53', 'Gene', (247, 250))
64203	28744147	However, the short half-life of mutant p53 protein is relatively long and highly expressed, and is also easy to be detected.	('mutant', 'Var', (32, 38))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('protein', 'Protein', (43, 50))
64209	28744147	Research and correlation analysis of survival prognosis have found that the high expression of p53 and the prognosis of uveal melanoma were negatively correlated.	('uveal melanoma', 'Disease', 'MESH:C536494', (120, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('uveal melanoma', 'Phenotype', 'HP:0007716', (120, 134))	('uveal melanoma', 'Disease', (120, 134))	('high', 'Var', (76, 80))	('negatively', 'NegReg', (140, 150))
64212	28744147	Patients with high expression of p53 showed worse prognosis.	('Patients', 'Species', '9606', (0, 8))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('high expression', 'Var', (14, 29))
64245	28115829	A total of 8,165 cases with a primary diagnosis of OM were identified using the SEER International Classification of Disease for Oncology (ICD-O-3) codes, code C69.0 (CM) for the CM group, and C69.3 (choroid) and C69.4 (ciliary body and iris) for the UM group.	('Oncology', 'Phenotype', 'HP:0002664', (129, 137))	('CM', 'Phenotype', 'HP:0007716', (167, 169))	('CM', 'Disease', 'MESH:D009202', (179, 181))	('CM', 'Disease', 'MESH:D009202', (167, 169))	('CM', 'Phenotype', 'HP:0007716', (179, 181))	('C69.4', 'Var', (213, 218))	('OM', 'Phenotype', 'HP:0007716', (51, 53))	('C69.3', 'Var', (193, 198))	('C69.0', 'Var', (160, 165))	('UM', 'Phenotype', 'HP:0007716', (251, 253))
64327	28115829	Genetic counseling to identify BAP1 mutations are also currently under investigation.	('BAP1', 'Gene', '8314', (31, 35))	('BAP1', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))
64389	27386120	To characterize the tumor cells in all analyzed tissues the following three primary antibodies were used: Melan A (reference M 7196; Dako, Queluz de Baixo, Lisbon, Portugal), c-Kit (reference A 4502; Dako), and Ki67 (reference NCL-L-Ki67-MM1; NK, Newcastle, UK).	('c-Kit', 'Gene', '403811', (175, 180))	('Melan A', 'Gene', (106, 113))	('Melan A', 'Gene', '403495', (106, 113))	('c-Kit', 'Gene', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('Ki67', 'Var', (211, 215))	('tumor', 'Disease', (20, 25))
64422	27386120	Recently C-kit expression has also been considered a prognostic marker as its expression may reveal mutations on tyrosine kinase receptor protein, although there is no consensus in the literature 8.	('mutations', 'Var', (100, 109))	('C-kit', 'Gene', (9, 14))	('reveal', 'Reg', (93, 99))	('tyrosine', 'Protein', (113, 121))	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('C-kit', 'Gene', '403811', (9, 14))
64426	27386120	As more cases will be studied in the future, Ki-67 proliferation index may also prove to be an interesting prognostic indicator in ocular melanomas, and is the case of other melanomas 18.	('melanomas', 'Disease', 'MESH:D008545', (138, 147))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('ocular melanomas', 'Phenotype', 'HP:0025534', (131, 147))	('Ki-67', 'Var', (45, 50))	('melanomas', 'Disease', (174, 183))	('ocular melanomas', 'Disease', 'MESH:D008545', (131, 147))	('melanomas', 'Disease', (138, 147))	('ocular melanomas', 'Disease', (131, 147))	('ocular melanoma', 'Phenotype', 'HP:0007716', (131, 146))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanomas', 'Phenotype', 'HP:0002861', (174, 183))	('melanomas', 'Disease', 'MESH:D008545', (174, 183))	('melanomas', 'Phenotype', 'HP:0002861', (138, 147))
64433	25280020	Oncogenic GNAQ and GNA11 Mutations in Uveal Melanoma in Chinese To examine whether GNAQ and GNA11 somatic mutations previously identified in uveal melanomas of Caucasians are associated with uveal melanomas in Chinese patients.	('associated', 'Reg', (175, 185))	('uveal melanomas', 'Phenotype', 'HP:0007716', (191, 206))	('uveal melanoma', 'Phenotype', 'HP:0007716', (141, 155))	('GNA11', 'Gene', '2767', (19, 24))	('uveal melanomas', 'Disease', (141, 156))	('uveal melanomas', 'Phenotype', 'HP:0007716', (141, 156))	('GNAQ', 'Gene', '2776', (83, 87))	('GNA11', 'Gene', (92, 97))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('melanomas', 'Phenotype', 'HP:0002861', (197, 206))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('Mutations', 'Var', (25, 34))	('GNAQ', 'Gene', (83, 87))	('Melanoma', 'Disease', 'MESH:D008545', (44, 52))	('GNAQ', 'Gene', '2776', (10, 14))	('GNA11', 'Gene', (19, 24))	('patients', 'Species', '9606', (218, 226))	('uveal melanomas', 'Disease', 'MESH:C536494', (191, 206))	('GNAQ', 'Gene', (10, 14))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('Melanoma', 'Disease', (44, 52))	('melanomas', 'Phenotype', 'HP:0002861', (147, 156))	('uveal melanomas', 'Disease', 'MESH:C536494', (141, 156))	('GNA11', 'Gene', '2767', (92, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (191, 205))	('Melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('uveal melanomas', 'Disease', (191, 206))
64434	25280020	Uveal melanomas treated by primary enucleation in Chinese patients underwent a mutation analysis of GNAQ and GNA11 with sequencing of exon 5 and exon 4.	('patients', 'Species', '9606', (58, 66))	('GNAQ', 'Gene', '2776', (100, 104))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('Uveal melanoma', 'Disease', 'MESH:C536494', (0, 14))	('GNA11', 'Gene', (109, 114))	('melanomas', 'Disease', (6, 15))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('GNAQ', 'Gene', (100, 104))	('GNA11', 'Gene', '2767', (109, 114))	('mutation analysis', 'Var', (79, 96))	('enucleation', 'biological_process', 'GO:0090601', ('35', '46'))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('Uveal melanoma', 'Disease', (0, 14))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))
64438	25280020	Mutations affecting codon 209 in GNAQ were c.626A>C(Q209P) (78%) and c.626A>T(Q209L) (22%).	('c.626A>T(Q209L', 'Var', (69, 83))	('GNAQ', 'Gene', (33, 37))	('c.626A>C', 'Mutation', 'rs121913492', (43, 51))	('c.626A>T', 'Mutation', 'rs121913492', (69, 77))	('c.626A>C(Q209P', 'Var', (43, 57))	('GNAQ', 'Gene', '2776', (33, 37))	('Q209L', 'Mutation', 'rs121913492', (78, 83))	('Q209P', 'Mutation', 'rs121913492', (52, 57))
64441	25280020	GNAQ/11 mutations were marginally (P = 0.045) associated with optic disc involvement.	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (8, 17))	('GNAQ', 'Gene', (0, 4))	('associated', 'Reg', (46, 56))	('optic disc involvement', 'Disease', (62, 84))
64442	25280020	In Kaplan-Meier analysis, metastasis-free survival was not significantly (P = 0.94) associated with GNAQ/11 mutations.	('GNAQ', 'Gene', (100, 104))	('GNAQ', 'Gene', '2776', (100, 104))	('mutations', 'Var', (108, 117))
64443	25280020	Mutations of GNAQ and GNA11 can be found in Chinese patients as in Caucasian patients with uveal melanoma, with a higher frequency reported for Caucasian patients.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('GNA11', 'Gene', (22, 27))	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (22, 27))	('uveal melanoma', 'Disease', 'MESH:C536494', (91, 105))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (77, 85))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Phenotype', 'HP:0007716', (91, 105))	('uveal melanoma', 'Disease', (91, 105))	('GNAQ', 'Gene', '2776', (13, 17))	('patients', 'Species', '9606', (52, 60))
64449	25280020	Previous studies have revealed that cutaneous melanomas showed oncogenic mutations in some components of the MAPKinase cascade, particularly in BRAF and NRAS .	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('NRAS', 'Gene', (153, 157))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('BRAF', 'Gene', '673', (144, 148))	('MAPK', 'Gene', (109, 113))	('NRAS', 'Gene', '4893', (153, 157))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (36, 55))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (36, 55))	('MAPK', 'Gene', '5594', (109, 113))	('BRAF', 'Gene', (144, 148))	('mutations', 'Var', (73, 82))	('cutaneous melanomas', 'Disease', (36, 55))
64450	25280020	In contrast, uveal melanomas did not exhibit mutations in BRAF and NRAS .	('mutations', 'Var', (45, 54))	('uveal melanomas', 'Disease', (13, 28))	('uveal melanomas', 'Phenotype', 'HP:0007716', (13, 28))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('NRAS', 'Gene', (67, 71))	('BRAF', 'Gene', '673', (58, 62))	('uveal melanomas', 'Disease', 'MESH:C536494', (13, 28))	('NRAS', 'Gene', '4893', (67, 71))	('uveal melanoma', 'Phenotype', 'HP:0007716', (13, 27))	('BRAF', 'Gene', (58, 62))
64454	25280020	Recently, oncogenic mutations in the G-protein alpha-subunit q class were found in about 83% of uveal melanomas with constitutive an activation of downstream MAPK signaling.	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('found', 'Reg', (74, 79))	('MAPK signaling', 'biological_process', 'GO:0000165', ('158', '172'))	('MAPK', 'Gene', (158, 162))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('uveal melanomas', 'Disease', (96, 111))	('activation', 'PosReg', (133, 143))	('uveal melanomas', 'Phenotype', 'HP:0007716', (96, 111))	('G-protein alpha-subunit', 'Protein', (37, 60))	('MAPK', 'molecular_function', 'GO:0004707', ('158', '162'))	('uveal melanomas', 'Disease', 'MESH:C536494', (96, 111))	('mutations', 'Var', (20, 29))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('MAPK', 'Gene', '5594', (158, 162))
64455	25280020	Glu209 and Arg183 are conserved in the guanosine triphosphate (GTP) binding site of Galpha subunits and essential in GTP hydrolysis.	('GTP) binding', 'molecular_function', 'GO:0005525', ('63', '75'))	('Arg183', 'Chemical', '-', (11, 17))	('Glu209', 'Chemical', '-', (0, 6))	('GTP', 'Chemical', 'MESH:D006160', (63, 66))	('GTP', 'Chemical', 'MESH:D006160', (117, 120))	('Glu209', 'Var', (0, 6))	('Galpha', 'Gene', '8802', (84, 90))	('guanosine triphosphate', 'Chemical', 'MESH:D006160', (39, 61))	('Galpha', 'Gene', (84, 90))	('Arg183', 'Var', (11, 17))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('117', '131'))
64456	25280020	The substitutions of glutamine or arginine in GNAQ or GNA11 mutations cause constitutive G-protein activation due to a reduced GTP hydrolysis.	('arginine', 'Var', (34, 42))	('GNAQ', 'Gene', (46, 50))	('substitutions', 'Var', (4, 17))	('GTP hydrolysis', 'MPA', (127, 141))	('GNA11', 'Gene', (54, 59))	('GTP', 'Chemical', 'MESH:D006160', (127, 130))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('127', '141'))	('arginine', 'Chemical', 'MESH:D001120', (34, 42))	('GNA11', 'Gene', '2767', (54, 59))	('GNAQ', 'Gene', '2776', (46, 50))	('activation', 'PosReg', (99, 109))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('constitutive', 'MPA', (76, 88))	('reduced', 'NegReg', (119, 126))	('glutamine', 'Var', (21, 30))	('glutamine', 'Chemical', 'MESH:D005973', (21, 30))
64457	25280020	GNAQ or GNA11 mutations lead to an upregulating activation of the MAPKinase pathway and appear to be major contributors to the development of uveal melanomas.	('GNA11', 'Gene', (8, 13))	('GNAQ', 'Gene', '2776', (0, 4))	('uveal melanomas', 'Disease', 'MESH:C536494', (142, 157))	('MAPK', 'Gene', '5594', (66, 70))	('uveal melanoma', 'Phenotype', 'HP:0007716', (142, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('GNA11', 'Gene', '2767', (8, 13))	('MAPK', 'Gene', (66, 70))	('upregulating activation', 'PosReg', (35, 58))	('GNAQ', 'Gene', (0, 4))	('uveal melanomas', 'Disease', (142, 157))	('uveal melanomas', 'Phenotype', 'HP:0007716', (142, 157))	('melanomas', 'Phenotype', 'HP:0002861', (148, 157))	('mutations', 'Var', (14, 23))	('contributors', 'Reg', (107, 119))
64458	25280020	The landmark studies on the association of uveal melanoma with GNAQ and GNA11 mutations were conducted in Caucasian populations while the status of GNAQ and GNA11 mutations in uveal melanomas of Chinese has not been investigated yet.	('GNAQ', 'Gene', '2776', (148, 152))	('uveal melanoma', 'Disease', 'MESH:C536494', (43, 57))	('GNA11', 'Gene', (157, 162))	('uveal melanoma', 'Disease', (43, 57))	('GNAQ', 'Gene', (148, 152))	('melanomas', 'Phenotype', 'HP:0002861', (182, 191))	('uveal melanoma', 'Disease', 'MESH:C536494', (176, 190))	('GNA11', 'Gene', (72, 77))	('mutations', 'Var', (78, 87))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('GNA11', 'Gene', '2767', (72, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (176, 190))	('uveal melanomas', 'Disease', 'MESH:C536494', (176, 191))	('GNA11', 'Gene', '2767', (157, 162))	('GNAQ', 'Gene', '2776', (63, 67))	('GNAQ', 'Gene', (63, 67))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('uveal melanomas', 'Disease', (176, 191))	('uveal melanomas', 'Phenotype', 'HP:0007716', (176, 191))
64459	25280020	Considering the genetic variations and their role in tumor genesis in different ethnic groups, we investigated the status of GNAQ and GNA11 mutations in uveal melanoma of Chinese patients to decrypt potential oncogenic differences between Caucasian and Chinese populations.	('uveal melanoma', 'Phenotype', 'HP:0007716', (153, 167))	('uveal melanoma', 'Disease', (153, 167))	('uveal melanoma', 'Disease', 'MESH:C536494', (153, 167))	('GNAQ', 'Gene', '2776', (125, 129))	('GNA11', 'Gene', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('GNA11', 'Gene', '2767', (134, 139))	('tumor', 'Disease', (53, 58))	('patients', 'Species', '9606', (179, 187))	('mutations', 'Var', (140, 149))	('GNAQ', 'Gene', (125, 129))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
64468	25280020	To detect hotspot mutations, exon 4 and exon 5 of both GNAQ and GNA11 were amplified by polymerase chain reaction (PCR) in at least two separate preparations of genomic DNA.	('DNA', 'cellular_component', 'GO:0005574', ('169', '172'))	('GNAQ', 'Gene', '2776', (55, 59))	('GNA11', 'Gene', '2767', (64, 69))	('GNA11', 'Gene', (64, 69))	('GNAQ', 'Gene', (55, 59))	('mutations', 'Var', (18, 27))
64469	25280020	The associations between the clinical or pathologic parameters and the mutation types (mutated GNAQ, mutated GNA11, or neither mutated) were evaluated and the mutational status was categorized into 2 categories (mutated GNAQ/11 or neither mutated).	('GNAQ', 'Gene', '2776', (220, 224))	('GNA11', 'Gene', (109, 114))	('GNAQ', 'Gene', (95, 99))	('mutated', 'Var', (101, 108))	('GNA11', 'Gene', '2767', (109, 114))	('GNAQ', 'Gene', (220, 224))	('GNAQ', 'Gene', '2776', (95, 99))
64475	25280020	In detail, the metastasis free survival was 94% for 1-year, 90% for 2-years and 87% for 3-years follow-up in the wild type group, 89% for 1-year, 78% for 2-years and 78% for 3-years follow-up in the GNAQ mutation group, and 90% for 1-year, 80% for 2-years and 80% for 3-years follow-up in the GNA11 mutation group.	('GNA11', 'Gene', (293, 298))	('mutation', 'Var', (204, 212))	('GNAQ', 'Gene', '2776', (199, 203))	('GNA11', 'Gene', '2767', (293, 298))	('GNAQ', 'Gene', (199, 203))	('metastasis free survival', 'CPA', (15, 39))
64478	25280020	Among the 50 samples screened for GNAQ and GNA11 mutations, the overall mutation frequency was 38% (19/50), with 18% (9/50) for GNAQ and 20% (10/50)for GNA11, respectively.	('GNA11', 'Gene', '2767', (152, 157))	('mutations', 'Var', (49, 58))	('GNA11', 'Gene', (43, 48))	('GNAQ', 'Gene', '2776', (128, 132))	('GNA11', 'Gene', '2767', (43, 48))	('GNAQ', 'Gene', (34, 38))	('GNAQ', 'Gene', (128, 132))	('GNA11', 'Gene', (152, 157))	('GNAQ', 'Gene', '2776', (34, 38))
64481	25280020	These mutations predicted substitution by proline (Q209P) in 78% of samples that were analyzed and by leucine (Q209L) in 22% of the samples.	('leucine', 'Chemical', 'MESH:D007930', (102, 109))	('Q209L', 'Mutation', 'rs121913492', (111, 116))	('proline', 'Chemical', 'MESH:D011392', (42, 49))	('Q209L', 'Var', (111, 116))	('Q209P', 'Var', (51, 56))	('predicted', 'Reg', (16, 25))	('Q209P', 'Mutation', 'rs121913492', (51, 56))
64482	25280020	Mutations affecting codon 209 in GNA11 were exclusively c.626A>T(Q209L) (100%) (Tables 3).	('GNA11', 'Gene', (33, 38))	('c.626A>T', 'Mutation', 'rs121913492', (56, 64))	('GNA11', 'Gene', '2767', (33, 38))	('c.626A>T(Q209L', 'Var', (56, 70))	('Q209L', 'Mutation', 'rs121913492', (65, 70))
64485	25280020	Examining correlations between GNAQ mutations or GNA11 mutations and the clinical-pathologic features in univariate analysis revealed a statistically association between the presence of GNAQ/11 mutations and optic disc involvement (P = 0.045) and a statistically weak association between male gender and presence of GNAQ/11 mutations (P = 0.04) (Table 4).	('optic disc', 'Disease', (208, 218))	('GNAQ', 'Gene', '2776', (31, 35))	('mutations', 'Var', (194, 203))	('GNAQ', 'Gene', '2776', (316, 320))	('GNAQ', 'Gene', '2776', (186, 190))	('presence', 'Var', (174, 182))	('GNAQ', 'Gene', (31, 35))	('GNA11', 'Gene', '2767', (49, 54))	('GNAQ', 'Gene', (316, 320))	('GNA11', 'Gene', (49, 54))	('GNAQ', 'Gene', (186, 190))
64486	25280020	In a logistic multivariate analysis with GNAQ/11 mutations as the dependent variable and gender and optic disc involvement as independent variables showed that GNAQ/11 mutations remained to be significantly (P = 0.034; Odds ratio (OR): 4.76; 95% Confidence Interval (CI): 1.12, 20.2) associated with an optic disc involvement while gender was no longer significantly associated (P = 0.07; OR: 3.26; 95%CI: 0.92, 11.5).	('associated with', 'Reg', (284, 299))	('GNAQ', 'Gene', (160, 164))	('GNAQ', 'Gene', '2776', (41, 45))	('optic disc involvement', 'Disease', (303, 325))	('GNAQ', 'Gene', '2776', (160, 164))	('GNAQ', 'Gene', (41, 45))	('mutations', 'Var', (168, 177))
64487	25280020	In the Kaplan-Meier analysis, the difference in metastasis-free survival among patients with GNAQ or GNA11 mutations and patients without the mutations was not statistically significant (P = 0.94), indicating that GNAQ and GNA11 mutations were not significantly associated with metastasis (Fig.	('GNA11', 'Gene', '2767', (101, 106))	('GNA11', 'Gene', (101, 106))	('GNAQ', 'Gene', (214, 218))	('mutations', 'Var', (107, 116))	('GNAQ', 'Gene', '2776', (93, 97))	('patients', 'Species', '9606', (79, 87))	('GNAQ', 'Gene', '2776', (214, 218))	('GNA11', 'Gene', '2767', (223, 228))	('GNA11', 'Gene', (223, 228))	('GNAQ', 'Gene', (93, 97))	('metastasis', 'CPA', (278, 288))	('patients', 'Species', '9606', (121, 129))
64489	25280020	Our hospital-based study showed that mutation frequency of GNAQ and GNA11 in Chinese patients with uveal melanomas was 18% (9/50) for GNAQ and 20% (10/50) for GNA11 with an overall frequency of 38% (19/50).	('GNAQ', 'Gene', '2776', (59, 63))	('uveal melanomas', 'Disease', (99, 114))	('uveal melanomas', 'Phenotype', 'HP:0007716', (99, 114))	('mutation', 'Var', (37, 45))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('GNAQ', 'Gene', (134, 138))	('GNA11', 'Gene', (68, 73))	('uveal melanomas', 'Disease', 'MESH:C536494', (99, 114))	('patients', 'Species', '9606', (85, 93))	('melanomas', 'Phenotype', 'HP:0002861', (105, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('GNAQ', 'Gene', '2776', (134, 138))	('GNAQ', 'Gene', (59, 63))	('GNA11', 'Gene', '2767', (68, 73))	('GNA11', 'Gene', '2767', (159, 164))	('GNA11', 'Gene', (159, 164))
64490	25280020	These results on a relatively low percentage of uveal melanomas showing mutations in GNAQ and GNA11 are different from the findings obtained in previous studies on Caucasian patients.	('uveal melanomas', 'Disease', 'MESH:C536494', (48, 63))	('mutations', 'Var', (72, 81))	('GNA11', 'Gene', '2767', (94, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('GNAQ', 'Gene', (85, 89))	('patients', 'Species', '9606', (174, 182))	('uveal melanomas', 'Disease', (48, 63))	('uveal melanomas', 'Phenotype', 'HP:0007716', (48, 63))	('GNAQ', 'Gene', '2776', (85, 89))	('GNA11', 'Gene', (94, 99))
64492	25280020	The study sample of our investigation was relatively small and was not obtained in a population-based manner to allow a direct comparison of the frequency of GNAQ and GNA11 mutations between different studies.	('GNAQ', 'Gene', '2776', (158, 162))	('GNA11', 'Gene', '2767', (167, 172))	('GNA11', 'Gene', (167, 172))	('mutations', 'Var', (173, 182))	('GNAQ', 'Gene', (158, 162))
64493	25280020	In Caucasian patients with uveal melanomas, the reported GNAQ mutation frequency varied between 36% and 53%.	('uveal melanoma', 'Phenotype', 'HP:0007716', (27, 41))	('GNAQ', 'Gene', (57, 61))	('patients', 'Species', '9606', (13, 21))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('uveal melanomas', 'Disease', (27, 42))	('uveal melanomas', 'Phenotype', 'HP:0007716', (27, 42))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('mutation', 'Var', (62, 70))	('GNAQ', 'Gene', '2776', (57, 61))	('uveal melanomas', 'Disease', 'MESH:C536494', (27, 42))
64494	25280020	Van Raamsdonk and her colleagues detected GNAQ mutations in 46% of uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (67, 82))	('GNAQ', 'Gene', '2776', (42, 46))	('mutations', 'Var', (47, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('GNAQ', 'Gene', (42, 46))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('uveal melanomas', 'Disease', (67, 82))	('uveal melanomas', 'Phenotype', 'HP:0007716', (67, 82))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
64496	25280020	In our study, the GNAQ mutation frequency was 18%, which was lower than the frequency in studies on Caucasian patients.	('GNAQ', 'Gene', '2776', (18, 22))	('patients', 'Species', '9606', (110, 118))	('GNAQ', 'Gene', (18, 22))	('mutation', 'Var', (23, 31))
64498	25280020	Interestingly with respect to cutaneous melanomas, the frequency of BRAF mutations was 66% in Caucasian patients with cutaneous melanomas while the frequency was only 25.5% in Chinese patients with cutaneous melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (128, 137))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('mutations', 'Var', (73, 82))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (118, 137))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (118, 137))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (30, 49))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (30, 49))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (198, 217))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (198, 217))	('BRAF', 'Gene', '673', (68, 72))	('BRAF', 'Gene', (68, 72))	('cutaneous melanomas', 'Disease', (118, 137))	('patients', 'Species', '9606', (104, 112))	('cutaneous melanomas', 'Disease', (30, 49))	('cutaneous melanomas', 'Disease', (198, 217))	('patients', 'Species', '9606', (184, 192))	('melanomas', 'Phenotype', 'HP:0002861', (208, 217))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))
64499	25280020	reported that mutations of KIT gene were detected in 29% of Caucasian patients with cutaneous melanomas while the frequency was only 11% in a Chinese cohort with cutaneous melanomas.	('KIT', 'molecular_function', 'GO:0005020', ('27', '30'))	('patients', 'Species', '9606', (70, 78))	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (162, 181))	('KIT', 'Gene', (27, 30))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (162, 181))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (84, 103))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (84, 103))	('melanomas', 'Phenotype', 'HP:0002861', (172, 181))	('cutaneous melanomas', 'Disease', (162, 181))	('mutations', 'Var', (14, 23))	('detected', 'Reg', (41, 49))	('cutaneous melanomas', 'Disease', (84, 103))
64503	25280020	Most of the reported GNAQ and GNA11 mutations occurred at codon 209, which was located in the activation domain of this kinase.	('GNAQ', 'Gene', '2776', (21, 25))	('occurred', 'Reg', (46, 54))	('GNA11', 'Gene', (30, 35))	('mutations', 'Var', (36, 45))	('GNAQ', 'Gene', (21, 25))	('GNA11', 'Gene', '2767', (30, 35))
64504	25280020	Van Raamsdonk and her colleagues reported that most of GNAQ and GNA11 mutations occurred at codon 209, and few others occurred at codon 183.	('mutations', 'Var', (70, 79))	('GNAQ', 'Gene', '2776', (55, 59))	('occurred', 'Reg', (80, 88))	('GNA11', 'Gene', '2767', (64, 69))	('GNA11', 'Gene', (64, 69))	('GNAQ', 'Gene', (55, 59))
64505	25280020	In a similar manner, Onken and his colleagues found that 49% of primary uveal melanomas harbored activating mutations in GNAQ at codon 209.	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('mutations', 'Var', (108, 117))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('GNAQ', 'Gene', '2776', (121, 125))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('uveal melanomas', 'Disease', (72, 87))	('uveal melanomas', 'Phenotype', 'HP:0007716', (72, 87))	('activating', 'PosReg', (97, 107))	('GNAQ', 'Gene', (121, 125))	('uveal melanomas', 'Disease', 'MESH:C536494', (72, 87))
64506	25280020	Consistent with previous studies, our data confirmed that GNAQ and GNA11 mutations in exon 5 occurred exclusively in codon 209.	('occurred', 'Reg', (93, 101))	('GNA11', 'Gene', (67, 72))	('GNAQ', 'Gene', '2776', (58, 62))	('GNA11', 'Gene', '2767', (67, 72))	('GNAQ', 'Gene', (58, 62))	('mutations', 'Var', (73, 82))
64508	25280020	In previous studies, associations between GNAQ and GNA11 mutations and clinical-pathologic features and prognosis were examined intensively.	('GNA11', 'Gene', '2767', (51, 56))	('GNAQ', 'Gene', '2776', (42, 46))	('mutations', 'Var', (57, 66))	('GNAQ', 'Gene', (42, 46))	('GNA11', 'Gene', (51, 56))
64509	25280020	Van Raamsdonk and her colleagues reported that GNA11 mutations were more common in locally advanced primary tumors and in melanomas originating from the peripheral choroid or ciliary body.	('melanomas', 'Disease', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('common', 'Reg', (73, 79))	('GNA11', 'Gene', '2767', (47, 52))	('GNA11', 'Gene', (47, 52))	('mutations', 'Var', (53, 62))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('melanomas', 'Disease', 'MESH:D008545', (122, 131))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
64510	25280020	In the study of Onken and colleagues, GNAQ mutations were not significantly associated with any clinical or histopathological parameter nor correlated with tumor progression.	('GNAQ', 'Gene', '2776', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('GNAQ', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('correlated', 'Reg', (140, 150))	('tumor', 'Disease', (156, 161))
64511	25280020	Onken and coworkers concluded that the GNAQ mutation may be an early or initiating event in the tumorgenesis.	('mutation', 'Var', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('GNAQ', 'Gene', (39, 43))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('GNAQ', 'Gene', '2776', (39, 43))
64512	25280020	Koopmans and his colleagues reported that patient survival in uveal melanoma was not correlated with oncogenic mutations in GNAQ and GNA11 .	('mutations', 'Var', (111, 120))	('GNA11', 'Gene', (133, 138))	('uveal melanoma', 'Disease', (62, 76))	('GNAQ', 'Gene', '2776', (124, 128))	('GNA11', 'Gene', '2767', (133, 138))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('patient', 'Species', '9606', (42, 49))	('GNAQ', 'Gene', (124, 128))	('uveal melanoma', 'Phenotype', 'HP:0007716', (62, 76))	('uveal melanoma', 'Disease', 'MESH:C536494', (62, 76))
64513	25280020	It is in agreement with our study in which GNAQ/11 mutations were not significantly associated with age, largest tumor basis diameter, tumor thickness, tumor cell type, scleral invasion or ciliary body involvement, with these parameters being associated with a poor prognosis of uveal melanomas.	('associated with', 'Reg', (243, 258))	('mutations', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('melanoma', 'Phenotype', 'HP:0002861', (285, 293))	('melanomas', 'Phenotype', 'HP:0002861', (285, 294))	('tumor', 'Disease', (152, 157))	('associated', 'Reg', (84, 94))	('GNAQ', 'Gene', '2776', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', (113, 118))	('uveal melanomas', 'Disease', 'MESH:C536494', (279, 294))	('GNAQ', 'Gene', (43, 47))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('uveal melanoma', 'Phenotype', 'HP:0007716', (279, 293))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('uveal melanomas', 'Disease', (279, 294))	('uveal melanomas', 'Phenotype', 'HP:0007716', (279, 294))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
64514	25280020	Consequently, we also did not find statistically significant associations of GNAQ/11 mutations with metastasis.	('GNAQ', 'Gene', (77, 81))	('mutations', 'Var', (85, 94))	('associations', 'Interaction', (61, 73))	('GNAQ', 'Gene', '2776', (77, 81))	('metastasis', 'CPA', (100, 110))
64515	25280020	Interestingly, GNAQ/11 mutations were associated with uveal melanomas involving optic disc in our study.	('GNAQ', 'Gene', (15, 19))	('uveal melanomas', 'Disease', (54, 69))	('associated', 'Reg', (38, 48))	('uveal melanomas', 'Phenotype', 'HP:0007716', (54, 69))	('uveal melanomas', 'Disease', 'MESH:C536494', (54, 69))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('mutations', 'Var', (23, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('GNAQ', 'Gene', '2776', (15, 19))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))
64516	25280020	Specific windows for GNAQ signaling in terms of location, cell type and developmental time were previously reported, such as that GNAQ mutations induced melanocytic proliferations spared epithelial structures.	('GNAQ', 'Gene', '2776', (21, 25))	('GNAQ', 'Gene', (130, 134))	('melanocytic proliferations', 'Disease', 'MESH:D059545', (153, 179))	('mutations', 'Var', (135, 144))	('GNAQ', 'Gene', (21, 25))	('signaling', 'biological_process', 'GO:0023052', ('26', '35'))	('melanocytic proliferations', 'Disease', (153, 179))	('induced', 'Reg', (145, 152))	('GNAQ', 'Gene', '2776', (130, 134))
64517	25280020	Our study did not allow addressing whether the association between GNAQ/11 mutations and uveal melanomas involving optic disc would be a parallel to the previous observation of two choroidal melanocytomas harboring mutations in GNAQ with one of them transforming into uveal melanoma.	('choroidal melanocytomas', 'Disease', 'MESH:D002833', (181, 204))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('choroidal melanocytomas', 'Disease', (181, 204))	('GNAQ', 'Gene', '2776', (228, 232))	('transforming', 'Reg', (250, 262))	('GNAQ', 'Gene', (228, 232))	('mutations', 'Var', (215, 224))	('uveal melanomas', 'Disease', 'MESH:C536494', (89, 104))	('uveal melanoma', 'Disease', 'MESH:C536494', (89, 103))	('GNAQ', 'Gene', '2776', (67, 71))	('choroidal melanocytomas', 'Phenotype', 'HP:0012054', (181, 204))	('GNAQ', 'Gene', (67, 71))	('melanoma', 'Phenotype', 'HP:0002861', (274, 282))	('uveal melanoma', 'Phenotype', 'HP:0007716', (89, 103))	('uveal melanoma', 'Disease', 'MESH:C536494', (268, 282))	('uveal melanoma', 'Disease', (268, 282))	('uveal melanomas', 'Disease', (89, 104))	('uveal melanomas', 'Phenotype', 'HP:0007716', (89, 104))	('mutations', 'Var', (75, 84))	('uveal melanoma', 'Phenotype', 'HP:0007716', (268, 282))
64518	25280020	Strength of the study was that it was the first study to investigate the frequency of GNAQ/11 mutations in uveal melanomas of Chinese patients.	('uveal melanomas', 'Disease', 'MESH:C536494', (107, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('mutations', 'Var', (94, 103))	('GNAQ', 'Gene', '2776', (86, 90))	('patients', 'Species', '9606', (134, 142))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('uveal melanomas', 'Disease', (107, 122))	('uveal melanomas', 'Phenotype', 'HP:0007716', (107, 122))	('GNAQ', 'Gene', (86, 90))
64519	25280020	In conclusion, mutations of GNAQ and GNA11 can be found in Chinese patients as in Caucasian patients with uveal melanoma, with the reported frequency being higher in Caucasian patients.	('patients', 'Species', '9606', (176, 184))	('GNAQ', 'Gene', '2776', (28, 32))	('patients', 'Species', '9606', (67, 75))	('GNA11', 'Gene', (37, 42))	('GNA11', 'Gene', '2767', (37, 42))	('mutations', 'Var', (15, 24))	('patients', 'Species', '9606', (92, 100))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('uveal melanoma', 'Disease', (106, 120))	('GNAQ', 'Gene', (28, 32))
64522	24124368	In this study, we constructed recombinant DNA plasmids (early growth response-1 tumor necrosis factor-alpha [pEgr1-TNFalpha], pEgr1 thymidine kinase [TK], and pEgr1-TNFalpha-TK) according to the Egr1 promoter sequence.	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('80', '101'))	('thymidine kinase', 'Gene', '24271467', (132, 148))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('necrosis', 'biological_process', 'GO:0008220', ('86', '94'))	('TNFalpha', 'Gene', '7124', (165, 173))	('tumor necrosis factor-alpha', 'Gene', '7124', (80, 107))	('necrosis', 'biological_process', 'GO:0070265', ('86', '94'))	('necrosis', 'biological_process', 'GO:0019835', ('86', '94'))	('thymidine kinase', 'Gene', (132, 148))	('necrosis', 'biological_process', 'GO:0001906', ('86', '94'))	('TK', 'Gene', '24271467', (150, 152))	('TK', 'Gene', '24271467', (174, 176))	('TNFalpha', 'Gene', '7124', (115, 123))	('pEgr1', 'Var', (126, 131))	('TNFalpha', 'Gene', (165, 173))	('tumor necrosis factor-alpha', 'Gene', (80, 107))	('necrosis', 'biological_process', 'GO:0008219', ('86', '94'))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('TNFalpha', 'Gene', (115, 123))
64600	24124368	As shown in Figure 7A, irradiation only and transfection can suppress OCM-1 cell growth compared with the negative-control group and blank-control group, respectively.	('transfection', 'Var', (44, 56))	('cell growth', 'biological_process', 'GO:0016049', ('76', '87'))	('suppress', 'NegReg', (61, 69))	('OCM-1 cell growth', 'CPA', (70, 87))	('OCM-1', 'Species', '83984', (70, 75))
64611	24124368	The properties of the dendriplexes suggest that they can perform the transfection appropriately and affect tumor-cell proliferation and apoptosis.	('affect', 'Reg', (100, 106))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('apoptosis', 'CPA', (136, 145))	('apoptosis', 'biological_process', 'GO:0097194', ('136', '145'))	('transfection', 'Var', (69, 81))	('apoptosis', 'biological_process', 'GO:0006915', ('136', '145'))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cell proliferation', 'biological_process', 'GO:0008283', ('113', '131'))
64612	24124368	Numerous studies have reported that nanotechnology accelerates various regenerative therapies, such as those for the bone, vascular, heart, cartilage, bladder, and brain tissue.	('nanotechnology', 'Var', (36, 50))	('cartilage, bladder', 'Disease', 'MESH:D001749', (140, 158))	('regenerative therapies', 'CPA', (71, 93))	('accelerates', 'PosReg', (51, 62))
64621	24124368	As a result, we hypothesize the combination of gene therapy and radiotherapy will have a better antitumor coeffect.	('gene therapy', 'Var', (47, 59))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))
64622	24124368	Egr-1 played an important role in combining gene therapy and radiotherapy effectively.	('Egr-1', 'Gene', (0, 5))	('gene', 'Var', (44, 48))	('Egr-1', 'Gene', '1958', (0, 5))
64632	24124368	Also, our study proved that radiation can increase the efficiency of gene transfer to ameliorate the effect of gene therapy, and gene therapy can increase radiosensitivity, reduce radiation injury to normal tissue, and change oxygenation of tumor cells.	('radiation injury', 'Disease', (180, 196))	('reduce', 'NegReg', (173, 179))	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (146, 171))	('radiosensitivity', 'MPA', (155, 171))	('change', 'Reg', (219, 225))	('increase', 'PosReg', (146, 154))	('tumor', 'Disease', (241, 246))	('radiation injury', 'Disease', 'MESH:D011832', (180, 196))	('oxygenation', 'MPA', (226, 237))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('gene transfer', 'CPA', (69, 82))	('gene therapy', 'Var', (129, 141))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
64656	24130723	Here we survey three known PKC inhibitors, enzastaurin, Go6976 and sotrastaurin and investigate their ability to enhance the killing of an immunotoxin directed to the cell surface antigen, mesothelin.	('Go6976', 'Var', (56, 62))	('PKC', 'Gene', '112476', (27, 30))	('PKC', 'molecular_function', 'GO:0004697', ('27', '30'))	('enhance', 'PosReg', (113, 120))	('sotrastaurin', 'Chemical', 'MESH:C543528', (67, 79))	('killing', 'MPA', (125, 132))	('enzastaurin', 'Chemical', 'MESH:C504878', (43, 54))	('mesothelin', 'Gene', '10232', (189, 199))	('cell surface', 'cellular_component', 'GO:0009986', ('167', '179'))	('cell surface antigen', 'molecular_function', 'GO:0016171', ('167', '187'))	('mesothelin', 'Gene', (189, 199))	('Go6976', 'Chemical', 'MESH:C081021', (56, 62))	('PKC', 'Gene', (27, 30))
64664	24130723	Enhancement was noted with SS1P and to a lesser extent with a model immunotoxin targeting the transferrin receptor.	('Enhancement', 'PosReg', (0, 11))	('transferrin receptor', 'Gene', (94, 114))	('SS1P', 'Chemical', 'MESH:C474515', (27, 31))	('transferrin receptor', 'Gene', '7037', (94, 114))	('SS1P', 'Var', (27, 31))
64680	24130723	However, when added in combination, the toxicity of SS1P was greatly enhanced (Fig.	('toxicity', 'Disease', (40, 48))	('enhanced', 'PosReg', (69, 77))	('toxicity', 'Disease', 'MESH:D064420', (40, 48))	('SS1P', 'Chemical', 'MESH:C474515', (52, 56))	('SS1P', 'Var', (52, 56))
64682	24130723	The combination of SS1P and 10 uM of enzastaurin caused a ~80% reduction (Fig.	('SS1P', 'Chemical', 'MESH:C474515', (19, 23))	('SS1P', 'Var', (19, 23))	('enzastaurin', 'Chemical', 'MESH:C504878', (37, 48))	('enzastaurin', 'Protein', (37, 48))	('reduction', 'NegReg', (63, 72))
64683	24130723	As single agents, sotrastaurin (10 uM) and G06976 (10 uM) exhibited a 50-70% reduction in growth (Figs.	('growth', 'MPA', (90, 96))	('reduction', 'NegReg', (77, 86))	('G06976', 'Var', (43, 49))	('sotrastaurin', 'Chemical', 'MESH:C543528', (18, 30))
64685	24130723	Specifically, the activity of both PKC inhibitors was reduced when co-incubated with SS1P.	('activity', 'MPA', (18, 26))	('PKC', 'molecular_function', 'GO:0004697', ('35', '38'))	('PKC', 'Gene', (35, 38))	('PKC', 'Gene', '112476', (35, 38))	('reduced', 'NegReg', (54, 61))	('SS1P', 'Chemical', 'MESH:C474515', (85, 89))	('SS1P', 'Var', (85, 89))
64693	24130723	KLM1 cells, a pancreatic cancer line, also exhibited resistance to SS1P, with an IC50 greater than 100 ng/ml.	('pancreatic cancer', 'Disease', (14, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('resistance', 'MPA', (53, 63))	('pancreatic cancer', 'Disease', 'MESH:D010190', (14, 31))	('SS1P', 'Chemical', 'MESH:C474515', (67, 71))	('SS1P', 'Var', (67, 71))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (14, 31))
64702	24130723	To determine if combinations of SS1P and enzastaurin enhanced apoptosis we conducted similar combination experiments and assayed for caspase activation.	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('SS1P', 'Chemical', 'MESH:C474515', (32, 36))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('caspase activation', 'biological_process', 'GO:0006919', ('133', '151'))	('SS1P', 'Gene', (32, 36))	('apoptosis', 'CPA', (62, 71))	('enzastaurin', 'Chemical', 'MESH:C504878', (41, 52))	('combinations', 'Var', (16, 28))	('enhanced', 'PosReg', (53, 61))
64705	24130723	From these results we conclude that combining SS1P with enzastaurin leads to greater cell death.	('SS1P', 'Chemical', 'MESH:C474515', (46, 50))	('enzastaurin', 'Chemical', 'MESH:C504878', (56, 67))	('SS1P', 'Var', (46, 50))	('cell death', 'CPA', (85, 95))	('cell death', 'biological_process', 'GO:0008219', ('85', '95'))
64710	24130723	HB21-PE40 is a PE-based immunotoxin directed to the transferrin receptor.	('transferrin receptor', 'Gene', (52, 72))	('transferrin receptor', 'Gene', '7037', (52, 72))	('HB21-PE40', 'Var', (0, 9))
64712	24130723	When plotting a single concentration of HB21-PE40 (1.25 ng/ml), with and without enzastaurin (0, 2, 4, 8, and 16 uM) the trend of enhanced cytoxicity was again evident (Fig.	('enhanced', 'PosReg', (130, 138))	('enzastaurin', 'Chemical', 'MESH:C504878', (81, 92))	('HB21-PE40', 'Var', (40, 49))	('toxicity', 'Disease', 'MESH:D064420', (141, 149))	('toxicity', 'Disease', (141, 149))
64715	24130723	Inhibition of PKC can lead to the inactivation of AKT resulting in the re-activation of GSK beta that results in the phosphorylation and degradation of Mcl-1.	('GSK', 'molecular_function', 'GO:0050321', ('88', '91'))	('inactivation', 'NegReg', (34, 46))	('degradation', 'biological_process', 'GO:0009056', ('137', '148'))	('AKT', 'Gene', '207', (50, 53))	('PKC', 'Gene', (14, 17))	('PKC', 'Gene', '112476', (14, 17))	('phosphorylation', 'biological_process', 'GO:0016310', ('117', '132'))	('Mcl-1', 'Gene', '4170', (152, 157))	('PKC', 'molecular_function', 'GO:0004697', ('14', '17'))	('phosphorylation', 'MPA', (117, 132))	('AKT', 'Gene', (50, 53))	('results in', 'Reg', (102, 112))	('Inhibition', 'Var', (0, 10))	('degradation', 'MPA', (137, 148))	('Mcl-1', 'Gene', (152, 157))	('GSK beta', 'Protein', (88, 96))	('re-activation', 'MPA', (71, 84))	('activation of GSK', 'biological_process', 'GO:1902949', ('74', '91'))
64732	24130723	Using cytotoxicity assays that detect energy stores, mitochondrial 'health' and the activation of the apoptotic pathway we have shown synergistic action of SS1P and enzastaurin.	('SS1P', 'Chemical', 'MESH:C474515', (156, 160))	('SS1P', 'Var', (156, 160))	('cytotoxicity', 'Disease', (6, 18))	('energy', 'MPA', (38, 44))	('apoptotic pathway', 'Pathway', (102, 119))	('enzastaurin', 'Chemical', 'MESH:C504878', (165, 176))	('cytotoxicity', 'Disease', 'MESH:D064420', (6, 18))
64739	24130723	Inhibiting PKC is one of many potential strategies to improve cancer treatment outcomes.	('PKC', 'Gene', (11, 14))	('PKC', 'Gene', '112476', (11, 14))	('PKC', 'molecular_function', 'GO:0004697', ('11', '14'))	('Inhibiting', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
64741	24130723	Therefore it is likely that inhibitors of PKC will have a variable beneficial action depending on the cancer cell type and the activity being targeted.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('PKC', 'Gene', (42, 45))	('PKC', 'Gene', '112476', (42, 45))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('inhibitors', 'Var', (28, 38))	('PKC', 'molecular_function', 'GO:0004697', ('42', '45'))
64743	24130723	Two of these, sotrastaurin and Go6976, exhibited some antagonism, whereby immunotoxin treatment rendered these inhibitors less potent (Fig.	('less', 'NegReg', (122, 126))	('sotrastaurin', 'Chemical', 'MESH:C543528', (14, 26))	('Go6976', 'Var', (31, 37))	('Go6976', 'Chemical', 'MESH:C081021', (31, 37))
64818	33142712	However, there was a trend suggesting an increased proportion of European ancestry associated with expression of the PRAME oncogene (q = 0.06).	('expression', 'MPA', (99, 109))	('PRAME', 'Gene', (117, 122))	('European ancestry', 'Var', (65, 82))	('PRAME', 'Gene', '23532', (117, 122))
64825	33142712	Class 1 tumors tend to harbor mutations in SF3B1 or EIF1AX and have low metastatic risk, whereas class 2 tumors harbor inactivating mutations in BAP1 and have a high metastatic risk.	('tumors', 'Disease', (105, 111))	('SF3B1', 'Gene', (43, 48))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('metastatic', 'CPA', (72, 82))	('SF3B1', 'Gene', '23451', (43, 48))	('BAP1', 'Gene', '8314', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mutations', 'Var', (30, 39))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('BAP1', 'Gene', (145, 149))	('EIF1AX', 'Gene', '1964', (52, 58))	('EIF1AX', 'Gene', (52, 58))
64841	33142712	The variants found within the top five significant segments after admixture mapping of class 1 versus class 2 tumors affected expression of 15 target genes in cis and 110 target genes in trans (Figure 4A; Supplementary Table S4).	('expression', 'MPA', (126, 136))	('variants', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('affected', 'Reg', (117, 125))
64843	33142712	Using HaploReg v4.1, these variants were enriched at enhancers associated with neural cells (q = 0.03), suggesting a potential link to the stem-like neural crest reprogramming in class 2 UM.	('variants', 'Var', (27, 35))	('UM', 'Phenotype', 'HP:0007716', (187, 189))	('v4.1', 'Gene', '28783', (15, 19))	('v4.1', 'Gene', (15, 19))	('enhancers', 'PosReg', (53, 62))
64844	33142712	These variants were predicted to affect transcription factor binding sites at greater than expected frequency for GABPA, EGR2, ELK4, and NRF1, suggesting that local ancestry may impact gene regulation.	('variants', 'Var', (6, 14))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('40', '68'))	('NRF1', 'Gene', (137, 141))	('affect', 'Reg', (33, 39))	('GABPA', 'Gene', '2551', (114, 119))	('gene regulation', 'MPA', (185, 200))	('regulation', 'biological_process', 'GO:0065007', ('190', '200'))	('ELK4', 'Gene', (127, 131))	('impact', 'Reg', (178, 184))	('EGR2', 'Gene', (121, 125))	('EGR2', 'Gene', '1959', (121, 125))	('transcription', 'biological_process', 'GO:0006351', ('40', '53'))	('GABPA', 'Gene', (114, 119))	('NRF1', 'Gene', '4899', (137, 141))	('ELK4', 'Gene', '2005', (127, 131))	('transcription factor', 'MPA', (40, 60))
64858	33142712	Indeed, mutational inactivation of BAP1, the most relevant genomic aberration in UM, may be influenced by an unusually complex local chromatin structure, which our findings suggest to be influenced by ancestry.	('chromatin', 'cellular_component', 'GO:0000785', ('133', '142'))	('influenced', 'Reg', (92, 102))	('BAP1', 'Gene', '8314', (35, 39))	('mutational', 'Var', (8, 18))	('BAP1', 'Gene', (35, 39))	('UM', 'Phenotype', 'HP:0007716', (81, 83))
64868	33142712	Variants were lifted to the human genome build hg38/GRCH38 and were removed if they were non-biallelic, were poorly imputed (info < 0.3), or imputed variants with a minor allele frequency (MAF) < 5%.	('Variants', 'Var', (0, 8))	('human', 'Species', '9606', (28, 33))	('variants', 'Var', (149, 157))	('hg38', 'Gene', (47, 51))	('hg38', 'Gene', '8549', (47, 51))
64871	33142712	HaploReg v4.1, was used to identify if enhancers were impacted by these variants.	('v4.1', 'Gene', '28783', (9, 13))	('v4.1', 'Gene', (9, 13))	('enhancers', 'PosReg', (39, 48))	('variants', 'Var', (72, 80))
64874	33142712	Admixture mapping was performed using a generalized linear model with binomial logistic regression to test the association between biomarkers and local ancestry at each variant, correcting for sex, age, and global European and Native American ancestry.	('variant', 'Var', (169, 176))	('mark', 'Gene', (134, 138))	('mark', 'Gene', '4139', (134, 138))
64879	33142712	and P30CA240139 (Sylvester Comprehensive Cancer Center), NIH Core Grant P30EY014801 (Bascom Palmer Eye Institute), Research to Prevent Blindness Unrestricted Grant (Bascom Palmer Eye Institute), and a generous gift from Mark J.	('Mark', 'Gene', '4139', (220, 224))	('P30EY014801', 'Var', (72, 83))	('Cancer', 'Disease', (41, 47))	('Blindness', 'Phenotype', 'HP:0000618', (135, 144))	('Cancer', 'Disease', 'MESH:D009369', (41, 47))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Mark', 'Gene', (220, 224))	('P30CA240139', 'Var', (4, 15))
64985	31253872	Neratinib inhibits Hippo/YAP signaling, reduces mutant K-RAS expression, ONCOGENE and kills pancreatic and blood cancer cells Prior studies demonstrated that the irreversible ERBB1/2/4 inhibitor neratinib caused plasma membrane-associated mutant K-RAS to localize in intracellular vesicles, concomitant with its degradation.	('signaling', 'biological_process', 'GO:0023052', ('29', '38'))	('si', 'Chemical', 'MESH:D012825', (169, 171))	('degradation', 'biological_process', 'GO:0009056', ('312', '323'))	('neratinib', 'Chemical', 'MESH:C487932', (195, 204))	('YAP', 'Gene', '10413', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('plasma membrane', 'cellular_component', 'GO:0005886', ('212', '227'))	('intracellular', 'cellular_component', 'GO:0005622', ('267', '280'))	('mutant', 'Var', (48, 54))	('localize', 'MPA', (255, 263))	('reduces', 'NegReg', (40, 47))	('K-RAS', 'Gene', (246, 251))	('mutant', 'Var', (239, 245))	('blood cancer', 'Phenotype', 'HP:0001909', (107, 119))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('si', 'Chemical', 'MESH:D012825', (283, 285))	('K-RAS', 'Gene', (55, 60))	('ERBB1/2/4', 'Gene', (175, 184))	('K-RAS', 'Gene', '3845', (246, 251))	('Neratinib', 'Chemical', 'MESH:C487932', (0, 9))	('expression', 'MPA', (61, 71))	('YAP', 'Gene', (25, 28))	('inhibits', 'NegReg', (10, 18))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('ERBB1/2/4', 'Gene', '1956;2064;2066', (175, 184))	('K-RAS', 'Gene', '3845', (55, 60))	('pancreatic and blood cancer', 'Disease', 'MESH:D010190', (92, 119))
64988	31253872	Knock down of ATM-AMPK suppressed vesicle formation and knock down of cathepsin B-AIF significantly reduced neratinib lethality.	('knock down', 'Var', (56, 66))	('AMPK', 'molecular_function', 'GO:0047322', ('18', '22'))	('AMPK', 'Gene', '5563', (18, 22))	('neratinib', 'Chemical', 'MESH:C487932', (108, 117))	('ATM', 'Gene', '472', (14, 17))	('neratinib lethality', 'MPA', (108, 127))	('AMPK', 'Gene', (18, 22))	('AMPK', 'molecular_function', 'GO:0050405', ('18', '22'))	('si', 'Chemical', 'MESH:D012825', (86, 88))	('vesicle formation', 'biological_process', 'GO:0106038', ('34', '51'))	('suppressed', 'NegReg', (23, 33))	('vesicle', 'cellular_component', 'GO:0031982', ('34', '41'))	('AIF', 'Gene', '9131', (82, 85))	('AIF', 'Gene', (82, 85))	('ATM', 'Gene', (14, 17))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('vesicle formation', 'MPA', (34, 51))	('AMPK', 'molecular_function', 'GO:0004691', ('18', '22'))	('cathepsin B', 'Gene', (70, 81))	('reduced', 'NegReg', (100, 107))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('vesicle formation', 'biological_process', 'GO:0006900', ('34', '51'))	('cathepsin B', 'Gene', '1508', (70, 81))
64993	31253872	Neratinib lethality was enhanced by knock down of YAP.	('Neratinib', 'Protein', (0, 9))	('enhanced', 'PosReg', (24, 32))	('knock down', 'Var', (36, 46))	('YAP', 'Gene', (50, 53))	('Neratinib', 'Chemical', 'MESH:C487932', (0, 9))
64995	31253872	Our data demonstrate that neratinib coordinately suppresses both mutant K-RAS and YAP function to kill pancreatic tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('YAP function', 'Gene', (82, 94))	('mutant', 'Var', (65, 71))	('K-RAS', 'Protein', (72, 77))	('neratinib', 'Chemical', 'MESH:C487932', (26, 35))	('pancreatic tumor', 'Disease', 'MESH:D010190', (103, 119))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (103, 119))	('suppresses', 'NegReg', (49, 59))	('pancreatic tumor', 'Disease', (103, 119))
64996	31253872	Inhibition of mutant RAS signaling has been a "holy grail" in the field of cancer therapeutics for over thirty years.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('mutant', 'Var', (14, 20))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('si', 'Chemical', 'MESH:D012825', (25, 27))	('signaling', 'biological_process', 'GO:0023052', ('25', '34'))
64997	31253872	We discovered that the FDA approved drug neratinib is not only an irreversible ERBB1/2/4 inhibitor but is a drug that can act to rapidly down-regulate the expression of other RTKs as well as mutant RAS proteins.	('si', 'Chemical', 'MESH:D012825', (73, 75))	('down-regulate', 'NegReg', (137, 150))	('expression', 'MPA', (155, 165))	('ERBB1/2/4', 'Gene', '1956;2064;2066', (79, 88))	('mutant', 'Var', (191, 197))	('si', 'Chemical', 'MESH:D012825', (161, 163))	('neratinib', 'Chemical', 'MESH:C487932', (41, 50))	('RAS proteins', 'Protein', (198, 210))	('ERBB1/2/4', 'Gene', (79, 88))
64999	31253872	The three RAS isoforms, H-, N-, and K-RAS are expressed in mammalian cells; K-RAS is mutated in ~90% of pancreatic tumors.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('pancreatic tumors', 'Disease', 'MESH:D010190', (104, 121))	('K-RAS', 'Protein', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('pancreatic tumors', 'Disease', (104, 121))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (104, 121))	('mutated', 'Var', (85, 92))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (104, 120))	('mammalian', 'Species', '9606', (59, 68))
65018	31253872	Thus, neratinib may be able to prevent signaling by mutant K-RAS and by the Hippo Pathway; events that collectively are detrimental to the growth and viability of pancreatic cancer cells.	('K-RAS', 'Protein', (59, 64))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (163, 180))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('mutant', 'Var', (52, 58))	('neratinib', 'Chemical', 'MESH:C487932', (6, 15))	('prevent', 'NegReg', (31, 38))	('pancreatic cancer', 'Disease', 'MESH:D010190', (163, 180))	('pancreatic cancer', 'Disease', (163, 180))	('signaling', 'biological_process', 'GO:0023052', ('39', '48'))	('Hippo Pathway', 'Pathway', (76, 89))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('signaling', 'MPA', (39, 48))
65022	31253872	The irreversible ERBB1/2/4 inhibitor neratinib as a single agent, and at low clinically relevant concentrations, causes ~15-20% cell killing of mutant K-RAS expressing tumor cells in 12 hours; this is comparable to the level of killing induced within this time-frame in a BT474 HER2+ mammary carcinoma cell (Figure 1A, not shown).	('neratinib', 'Chemical', 'MESH:C487932', (37, 46))	('mutant', 'Var', (144, 150))	('HER2', 'Gene', '2064', (278, 282))	('K-RAS', 'Protein', (151, 156))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (284, 301))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('tumor', 'Disease', (168, 173))	('carcinoma', 'Disease', (292, 301))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('HER2', 'Gene', (278, 282))	('ERBB1/2/4', 'Gene', (17, 26))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('ERBB1/2/4', 'Gene', '1956;2064;2066', (17, 26))	('cell killing', 'biological_process', 'GO:0001906', ('128', '140'))	('cell killing', 'CPA', (128, 140))	('carcinoma', 'Disease', 'MESH:D009369', (292, 301))	('si', 'Chemical', 'MESH:D012825', (11, 13))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
65025	31253872	Knock down of Beclin1 or cathepsin B significantly reduced the ability of neratinib to lower the expression of ERBB1, ERBB2 and of K-RAS (Figure 1C).	('si', 'Chemical', 'MESH:D012825', (31, 33))	('Beclin1', 'Gene', '8678', (14, 21))	('ERBB2', 'Gene', (118, 123))	('reduced', 'NegReg', (51, 58))	('cathepsin B', 'Gene', (25, 36))	('neratinib', 'Chemical', 'MESH:C487932', (74, 83))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('lower', 'NegReg', (87, 92))	('K-RAS', 'Protein', (131, 136))	('Beclin1', 'Gene', (14, 21))	('ERBB2', 'Gene', '2064', (118, 123))	('ERBB1', 'Gene', '1956', (111, 116))	('cathepsin B', 'Gene', '1508', (25, 36))	('ERBB1', 'Gene', (111, 116))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('Knock down', 'Var', (0, 10))	('expression', 'MPA', (97, 107))
65026	31253872	Cathepsin B is localized in endosomes/lysosomes, and knock down of ATM, AMPKalpha or Beclin1 significantly reduced the ability of neratinib to cause acidic endosome/lysosome formation as measured using an LC3-GFP-RFP construct (Figure 1D).	('reduced', 'NegReg', (107, 114))	('LC3', 'Gene', (205, 208))	('RFP', 'Gene', (213, 216))	('endosome', 'cellular_component', 'GO:0005768', ('156', '164'))	('neratinib', 'Chemical', 'MESH:C487932', (130, 139))	('ATM', 'Gene', '472', (67, 70))	('knock down', 'Var', (53, 63))	('acidic endosome/lysosome formation', 'MPA', (149, 183))	('cause', 'Reg', (143, 148))	('AMPK', 'Gene', '5563', (72, 76))	('Beclin1', 'Gene', '8678', (85, 92))	('Cathepsin B', 'Gene', (0, 11))	('RFP', 'Gene', '2358', (213, 216))	('formation', 'biological_process', 'GO:0009058', ('174', '183'))	('si', 'Chemical', 'MESH:D012825', (197, 199))	('LC3', 'Gene', '84557', (205, 208))	('si', 'Chemical', 'MESH:D012825', (6, 8))	('lysosome', 'cellular_component', 'GO:0005764', ('165', '173'))	('ATM', 'Gene', (67, 70))	('Beclin1', 'Gene', (85, 92))	('si', 'Chemical', 'MESH:D012825', (93, 95))	('AMPK', 'Gene', (72, 76))	('Cathepsin B', 'Gene', '1508', (0, 11))
65028	31253872	Together with data from our prior studies, this information links an ATM-AMPKalpha-ULK1-autophagosome-autolysosome pathway to the degradation of ERBB1 and mutant K-RAS and to pancreatic tumor cell death.	('AMPK', 'Gene', '5563', (73, 77))	('pancreatic tumor', 'Disease', (175, 191))	('ERBB1', 'Gene', (145, 150))	('ATM', 'Gene', '472', (69, 72))	('pancreatic tumor', 'Disease', 'MESH:D010190', (175, 191))	('autophagosome', 'cellular_component', 'GO:0005776', ('88', '101'))	('ULK1', 'Gene', '8408', (83, 87))	('degradation', 'biological_process', 'GO:0009056', ('130', '141'))	('autolysosome', 'cellular_component', 'GO:0044754', ('102', '114'))	('degradation', 'MPA', (130, 141))	('ERBB1', 'Gene', '1956', (145, 150))	('AMPK', 'Gene', (73, 77))	('ULK1', 'Gene', (83, 87))	('K-RAS', 'Protein', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('cell death', 'biological_process', 'GO:0008219', ('192', '202'))	('ATM', 'Gene', (69, 72))	('mutant', 'Var', (155, 161))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (175, 191))
65036	31253872	In PANC1 pancreatic adenocarcinoma cells transfected to express K-RAS V12 - GFP and K-RAS V12 - RFP, neratinib caused the proteins to colocalize in small and large intracellular vesicles (Figure 3A).	('colocalize', 'MPA', (134, 144))	('RFP', 'Gene', (96, 99))	('PANC1', 'CellLine', 'CVCL:0480', (3, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('neratinib', 'Chemical', 'MESH:C487932', (101, 110))	('intracellular', 'cellular_component', 'GO:0005622', ('164', '177'))	('K-RAS V12 - GFP', 'Var', (64, 79))	('pancreatic adenocarcinoma', 'Disease', (9, 34))	('RFP', 'Gene', '2358', (96, 99))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (9, 34))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (9, 34))	('proteins', 'Protein', (122, 130))	('si', 'Chemical', 'MESH:D012825', (180, 182))
65037	31253872	Neratinib down-regulated mutant K-RAS in NSCLC cells (Figure 3B).	('mutant', 'Var', (25, 31))	('NSCLC', 'Disease', (41, 46))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('down-regulated', 'NegReg', (10, 24))	('Neratinib', 'Chemical', 'MESH:C487932', (0, 9))
65038	31253872	In head & neck squamous carcinoma cells, neratinib was also competent to cause K-RAS V12 - GFP and K-RAS V12 - RFP to become vesicularized (Figure 3C).	('and K-RAS V12 -', 'Var', (95, 110))	('neck', 'cellular_component', 'GO:0044326', ('10', '14'))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (15, 33))	('head & neck squamous carcinoma', 'Phenotype', 'HP:0012288', (3, 33))	('cause K-RAS V12 -', 'Var', (73, 90))	('neck squamous carcinoma', 'Disease', (10, 33))	('RFP', 'Gene', (111, 114))	('neck squamous carcinoma', 'Disease', 'MESH:D000077195', (10, 33))	('si', 'Chemical', 'MESH:D012825', (127, 129))	('neratinib', 'Chemical', 'MESH:C487932', (41, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('RFP', 'Gene', '2358', (111, 114))
65039	31253872	As previously reported by us, exposure of a K-RAS V12 / p53 K275H GEMM cell line (FC1199, also known as KPC) and a PDX model of pancreatic cancer (J000077973) that also expresses mutant K-RAS and mutant p53 to the proteasome inhibitor Velcade prevented the neratinib-induced degradation of ERBB1 but did not alter degradation of K-RAS (Figure 3D).	('Velcade', 'Chemical', 'MESH:D000069286', (235, 242))	('mutant', 'Var', (179, 185))	('ERBB1', 'Gene', (290, 295))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (128, 145))	('ERBB1', 'Gene', '1956', (290, 295))	('proteasome', 'molecular_function', 'GO:0004299', ('214', '224'))	('neratinib', 'Chemical', 'MESH:C487932', (257, 266))	('FC1199', 'Chemical', '-', (82, 88))	('degradation', 'biological_process', 'GO:0009056', ('275', '286'))	('prevented', 'NegReg', (243, 252))	('pancreatic cancer', 'Disease', 'MESH:D010190', (128, 145))	('proteasome', 'cellular_component', 'GO:0000502', ('214', '224'))	('degradation', 'biological_process', 'GO:0009056', ('314', '325'))	('K275H', 'Var', (60, 65))	('mutant', 'Var', (196, 202))	('K275H', 'Mutation', 'p.K275H', (60, 65))	('neratinib-induced degradation', 'MPA', (257, 286))	('pancreatic cancer', 'Disease', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('p53', 'Gene', (203, 206))
65040	31253872	As a positive control, knock down of the lysosomal protease cathepsin B prevented the degradation of both ERBB1 and K-RAS.	('ERBB1', 'Gene', '1956', (106, 111))	('ERBB1', 'Gene', (106, 111))	('cathepsin B', 'Gene', '1508', (60, 71))	('degradation', 'biological_process', 'GO:0009056', ('86', '97'))	('prevented', 'NegReg', (72, 81))	('knock down', 'Var', (23, 33))	('si', 'Chemical', 'MESH:D012825', (7, 9))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('cathepsin B', 'Gene', (60, 71))	('K-RAS', 'Protein', (116, 121))	('degradation', 'MPA', (86, 97))
65042	31253872	K-RAS mislocalization from the plasma membrane was quantified as the colocalization of K-RAS V12 - GFP and mCherry-CAAX using Manders coefficients.	('plasma membrane', 'cellular_component', 'GO:0005886', ('31', '46'))	('V12 -', 'Var', (93, 98))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('colocalization', 'MPA', (69, 83))
65057	31253872	K-RAS and ERBB1 appeared to be held in discrete pools in the PDX tumor cells; neratinib caused the formation of intracellular vesicles, some of which stained for either K-RAS or ERBB1, and some that stained for both proteins.	('neratinib', 'Chemical', 'MESH:C487932', (78, 87))	('formation', 'MPA', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('ERBB1', 'Gene', '1956', (10, 15))	('ERBB1', 'Gene', '1956', (178, 183))	('intracellular', 'cellular_component', 'GO:0005622', ('112', '125'))	('ERBB1', 'Gene', (178, 183))	('K-RAS', 'Protein', (169, 174))	('ERBB1', 'Gene', (10, 15))	('stained', 'Reg', (150, 157))	('neratinib', 'Var', (78, 87))	('formation', 'biological_process', 'GO:0009058', ('99', '108'))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
65068	31253872	Neratinib reduced MST3/4 autophosphorylation (T174 + T178 + T190), and phosphorylation of their direct substrate Ezrin T567.	('phosphorylation', 'MPA', (71, 86))	('MST3/4', 'Gene', (18, 24))	('reduced', 'NegReg', (10, 17))	('Ezrin', 'Gene', (113, 118))	('MST3/4', 'Gene', '8428;51765', (18, 24))	('phosphorylation', 'biological_process', 'GO:0016310', ('71', '86'))	('T174 + T178 + T190', 'Var', (46, 64))	('Neratinib', 'Chemical', 'MESH:C487932', (0, 9))	('Ezrin', 'Gene', '7430', (113, 118))
65084	31253872	Neratinib caused YAP expression to both decline and for YAP to leave the nucleus and become punctate within the cytoplasm.	('YAP expression', 'MPA', (17, 31))	('cytoplasm', 'cellular_component', 'GO:0005737', ('112', '121'))	('nucleus', 'cellular_component', 'GO:0005634', ('73', '80'))	('Neratinib', 'Var', (0, 9))	('decline', 'NegReg', (40, 47))	('Neratinib', 'Chemical', 'MESH:C487932', (0, 9))	('si', 'Chemical', 'MESH:D012825', (27, 29))
65086	31253872	In addition to inhibiting MST3/MST4 autophosphorylation, neratinib also reduced MST1/2 phosphorylation (T183/T180) (Figure 7).	('reduced', 'NegReg', (72, 79))	('MST4', 'Gene', (31, 35))	('MST3', 'Gene', (26, 30))	('neratinib', 'Chemical', 'MESH:C487932', (57, 66))	('MST4', 'Gene', '51765', (31, 35))	('MST3', 'Gene', '8428', (26, 30))	('T183/T180', 'Var', (104, 113))	('MST1/2', 'Gene', '4485;6788', (80, 86))	('inhibiting', 'NegReg', (15, 25))	('MST1/2', 'Gene', (80, 86))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))
65089	31253872	Dephosphorylation of MOB1 T35 would be predicted to reduce upstream MST kinase signaling into LATS1.	('LATS1', 'Gene', '9113', (94, 99))	('si', 'Chemical', 'MESH:D012825', (79, 81))	('MOB1', 'Gene', (21, 25))	('T35', 'Var', (26, 29))	('MOB1', 'Gene', '3627', (21, 25))	('Dephosphorylation', 'biological_process', 'GO:0016311', ('0', '17'))	('reduce', 'NegReg', (52, 58))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('upstream MST kinase signaling into', 'MPA', (59, 93))	('Dephosphorylation', 'Var', (0, 17))	('LATS1', 'Gene', (94, 99))
65090	31253872	Although MST1/2 and MST3/4 phosphorylation were reduced by neratinib, the phosphorylation of their direct substrate, LATS1, at regulatory and auto-phosphorylation sites (S909, T1079), was significantly enhanced by the drug.	('phosphorylation', 'MPA', (74, 89))	('neratinib', 'Chemical', 'MESH:C487932', (59, 68))	('T1079', 'Var', (176, 181))	('MST3/4', 'Gene', (20, 26))	('phosphorylation', 'biological_process', 'GO:0016310', ('74', '89'))	('MST1/2', 'Gene', '4485;6788', (9, 15))	('MST1/2', 'Gene', (9, 15))	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('MST3/4', 'Gene', '8428;51765', (20, 26))	('reduced', 'NegReg', (48, 55))	('si', 'Chemical', 'MESH:D012825', (188, 190))	('LATS1', 'Gene', (117, 122))	('LATS1', 'Gene', '9113', (117, 122))	('neratinib', 'Gene', (59, 68))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('enhanced', 'PosReg', (202, 210))	('phosphorylation', 'MPA', (27, 42))	('S909', 'Var', (170, 174))	('phosphorylation', 'biological_process', 'GO:0016310', ('147', '162'))
65092	31253872	activity, the phosphorylation of YAP at multiple sites and that of TAZ were increased after neratinib exposure (S109, S127, S397; S89).	('S127', 'Var', (118, 122))	('neratinib', 'Chemical', 'MESH:C487932', (92, 101))	('increased', 'PosReg', (76, 85))	('S397; S89', 'Var', (124, 133))	('phosphorylation', 'biological_process', 'GO:0016310', ('14', '29'))	('phosphorylation', 'MPA', (14, 29))	('S109', 'Var', (112, 116))	('TAZ', 'Gene', '6901', (67, 70))	('TAZ', 'Gene', (67, 70))	('si', 'Chemical', 'MESH:D012825', (49, 51))	('YAP', 'Protein', (33, 36))	('activity', 'MPA', (0, 8))
65098	31253872	We made use of previously described HCT116 colorectal carcinoma cells that lack ATG16L1 or that express the ATG16L1 T300A isoform, and of FC1199 GEMM mouse pancreatic cancer cells that express mutant K-RAS and mutant p53 (Figures 8A and 8B).	('HCT116', 'CellLine', 'CVCL:0291', (36, 42))	('mutant', 'Var', (210, 216))	('ATG16L1', 'Gene', '55054', (80, 87))	('pancreatic cancer', 'Disease', 'MESH:D010190', (156, 173))	('mutant', 'Var', (193, 199))	('ATG16L1', 'Gene', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('ATG16L1', 'Gene', '55054', (108, 115))	('mouse', 'Species', '10090', (150, 155))	('p53', 'Gene', (217, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('ATG16L1', 'Gene', (108, 115))	('pancreatic cancer', 'Disease', (156, 173))	('FC1199', 'Chemical', '-', (138, 144))	('colorectal carcinoma', 'Disease', (43, 63))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (43, 63))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (156, 173))	('T300A', 'Mutation', 'rs2241880', (116, 121))	('K-RAS', 'Protein', (200, 205))
65099	31253872	The ATG16L1 T300A variant, more commonly found in European Americans than in African Americans, predisposes persons to develop Crohn's Disease.	('T300A', 'Var', (12, 17))	('ATG16L1', 'Gene', (4, 11))	("Crohn's Disease", 'Phenotype', 'HP:0100280', (127, 142))	("Crohn's Disease", 'Disease', 'MESH:D003424', (127, 142))	('persons', 'Species', '9606', (108, 115))	("Crohn's Disease", 'Disease', (127, 142))	('T300A', 'Mutation', 'rs2241880', (12, 17))	('ATG16L1', 'Gene', '55054', (4, 11))	('predisposes', 'Reg', (96, 107))
65100	31253872	The expression of one ATG16L1 A300 allele significantly increased the risk for Crohn's disease.	('increased', 'PosReg', (56, 65))	('ATG16L1', 'Gene', '55054', (22, 29))	("Crohn's disease", 'Disease', 'MESH:D003424', (79, 94))	("Crohn's disease", 'Disease', (79, 94))	('A300', 'Var', (30, 34))	('ATG16L1', 'Gene', (22, 29))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('si', 'Chemical', 'MESH:D012825', (10, 12))	("Crohn's disease", 'Phenotype', 'HP:0100280', (79, 94))
65102	31253872	Knock-down of Rubicon significantly reduced the ability of neratinib to lower ERBB1 and K-RAS levels.	('Rubicon', 'Gene', (14, 21))	('ERBB1', 'Gene', (78, 83))	('Knock-down', 'Var', (0, 10))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('lower', 'NegReg', (72, 77))	('neratinib', 'Chemical', 'MESH:C487932', (59, 68))	('reduced', 'NegReg', (36, 43))	('Rubicon', 'Gene', '9711', (14, 21))	('ERBB1', 'Gene', '1956', (78, 83))
65104	31253872	In cells lacking ATG16L1 expression or expressing the variant ATG16L1 T300A, the ability of neratinib to suppress ERBB1 and K-RAS levels was also blocked.	('blocked', 'NegReg', (146, 153))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('neratinib', 'Chemical', 'MESH:C487932', (92, 101))	('ATG16L1', 'Gene', (17, 24))	('ATG16L1', 'Gene', (62, 69))	('suppress', 'NegReg', (105, 113))	('variant', 'Var', (54, 61))	('T300A', 'Mutation', 'rs2241880', (70, 75))	('ATG16L1', 'Gene', '55054', (17, 24))	('ERBB1', 'Gene', '1956', (114, 119))	('ATG16L1', 'Gene', '55054', (62, 69))	('ERBB1', 'Gene', (114, 119))	('si', 'Chemical', 'MESH:D012825', (45, 47))
65105	31253872	Neratinib caused K-RAS staining to become vesicular, which was absent in cells lacking Rubicon expression.	('Rubicon', 'Gene', (87, 94))	('staining', 'MPA', (23, 31))	('Rubicon', 'Gene', '9711', (87, 94))	('K-RAS', 'Protein', (17, 22))	('Neratinib', 'Var', (0, 9))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('Neratinib', 'Chemical', 'MESH:C487932', (0, 9))
65106	31253872	Knock down of Rubicon or expression of ATG16L1 T300A both significantly reduced the ability of [neratinib + valproate] to kill HCT116 colon cancer cells (Figure 8C).	('reduced', 'NegReg', (72, 79))	('Rubicon', 'Gene', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('T300A', 'Var', (47, 52))	('ATG16L1', 'Gene', '55054', (39, 46))	('HCT116', 'CellLine', 'CVCL:0291', (127, 133))	('colon cancer', 'Disease', 'MESH:D015179', (134, 146))	('colon cancer', 'Phenotype', 'HP:0003003', (134, 146))	('ATG16L1', 'Gene', (39, 46))	('neratinib', 'Chemical', 'MESH:C487932', (96, 105))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('colon cancer', 'Disease', (134, 146))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('valproate', 'Chemical', 'MESH:D014635', (108, 117))	('T300A', 'Mutation', 'rs2241880', (47, 52))	('Rubicon', 'Gene', '9711', (14, 21))
65107	31253872	Knock down of Rubicon was significantly better at suppressing neratinib and [neratinib + valproate] lethality than expression of ATG16L1 A300.	('Rubicon', 'Gene', (14, 21))	('suppressing', 'NegReg', (50, 61))	('neratinib', 'Chemical', 'MESH:C487932', (77, 86))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('valproate', 'Chemical', 'MESH:D014635', (89, 98))	('ATG16L1', 'Gene', '55054', (129, 136))	('neratinib', 'MPA', (62, 71))	('[neratinib + valproate] lethality', 'MPA', (76, 109))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('neratinib', 'Chemical', 'MESH:C487932', (62, 71))	('ATG16L1', 'Gene', (129, 136))	('Knock down', 'Var', (0, 10))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('Rubicon', 'Gene', '9711', (14, 21))
65110	31253872	Knock down of Rubicon, Beclin1 or ATG5 suppressed neratinib lethality as a single agent and when it was combined with either the PKG activator sildenafil or the HDAC inhibitor valproate (Figure 8E).	('Rubicon', 'Gene', (14, 21))	('PKG', 'Gene', '5592', (129, 132))	('ATG5', 'Gene', '9474', (34, 38))	('HDAC', 'Gene', (161, 165))	('suppressed', 'NegReg', (39, 49))	('neratinib', 'Chemical', 'MESH:C487932', (50, 59))	('PKG', 'Gene', (129, 132))	('ATG5', 'Gene', (34, 38))	('Beclin1', 'Gene', '8678', (23, 30))	('sildenafil', 'Chemical', 'MESH:D000068677', (143, 153))	('si', 'Chemical', 'MESH:D012825', (143, 145))	('Knock down', 'Var', (0, 10))	('valproate', 'Chemical', 'MESH:D014635', (176, 185))	('Beclin1', 'Gene', (23, 30))	('Rubicon', 'Gene', '9711', (14, 21))	('neratinib lethality', 'MPA', (50, 69))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('PKG', 'molecular_function', 'GO:0004692', ('129', '132'))	('HDAC', 'Gene', '9734', (161, 165))
65111	31253872	Rubicon knock down was more protective than that of either Beclin1 or ATG5.	('Beclin1', 'Gene', (59, 66))	('ATG5', 'Gene', '9474', (70, 74))	('knock down', 'Var', (8, 18))	('ATG5', 'Gene', (70, 74))	('Rubicon', 'Gene', '9711', (0, 7))	('Beclin1', 'Gene', '8678', (59, 66))	('Rubicon', 'Gene', (0, 7))
65113	31253872	Our first, unexpected, observation was under control conditions examining the impact of Rubicon knock down on the expression of total YAP, YAP S127 phosphorylation and YAP S397 phosphorylation: knock down of Rubicon in FCC1199 cells increased basal YAP expression by 2.60-fold; basal S127 phosphorylation by 1.20-fold; and basal S397 phosphorylation by 3.10-fold (all p < 0.05 greater than siSCR control values).	('phosphorylation', 'biological_process', 'GO:0016310', ('177', '192'))	('si', 'Chemical', 'MESH:D012825', (259, 261))	('si', 'Chemical', 'MESH:D012825', (390, 392))	('knock down', 'Var', (194, 204))	('phosphorylation', 'biological_process', 'GO:0016310', ('289', '304'))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('Rubicon', 'Gene', '9711', (208, 215))	('basal S397 phosphorylation', 'MPA', (323, 349))	('Rubicon', 'Gene', (88, 95))	('Rubicon', 'Gene', (208, 215))	('phosphorylation', 'biological_process', 'GO:0016310', ('148', '163'))	('Rubicon', 'Gene', '9711', (88, 95))	('phosphorylation', 'biological_process', 'GO:0016310', ('334', '349'))	('basal S127 phosphorylation', 'MPA', (278, 304))	('increased', 'PosReg', (233, 242))
65114	31253872	Rubicon knock down in PDX pancreatic cancer cells elevated basal total YAP expression 4.00-fold; basal S127 phosphorylation by 1.15-fold; and basal S397 phosphorylation by 4.85-fold (all p < 0.05 greater than siSCR control values).	('elevated', 'PosReg', (50, 58))	('knock down', 'Var', (8, 18))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (26, 43))	('phosphorylation', 'biological_process', 'GO:0016310', ('108', '123'))	('basal S397 phosphorylation', 'MPA', (142, 168))	('si', 'Chemical', 'MESH:D012825', (209, 211))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Rubicon', 'Gene', '9711', (0, 7))	('pancreatic cancer', 'Disease', (26, 43))	('basal S127 phosphorylation', 'MPA', (97, 123))	('Rubicon', 'Gene', (0, 7))	('YAP', 'Protein', (71, 74))	('pancreatic cancer', 'Disease', 'MESH:D010190', (26, 43))	('phosphorylation', 'biological_process', 'GO:0016310', ('153', '168'))
65116	31253872	In contrast, in cells with their Rubicon expression knocked down, neratinib treatment more modestly enhanced the phosphorylation of PAK1 and Merlin and lowered the phosphorylation of LATS1/2 and YAP S127.	('Merlin', 'Gene', '4771', (141, 147))	('phosphorylation', 'MPA', (113, 128))	('LATS1/2', 'Protein', (183, 190))	('phosphorylation', 'MPA', (164, 179))	('enhanced', 'PosReg', (100, 108))	('neratinib', 'Chemical', 'MESH:C487932', (66, 75))	('phosphorylation', 'biological_process', 'GO:0016310', ('113', '128'))	('Rubicon', 'Gene', '9711', (33, 40))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('Rubicon', 'Gene', (33, 40))	('Merlin', 'Gene', (141, 147))	('knocked down', 'Var', (52, 64))	('PAK1', 'Gene', '5058', (132, 136))	('lowered', 'NegReg', (152, 159))	('PAK1', 'Gene', (132, 136))	('phosphorylation', 'biological_process', 'GO:0016310', ('164', '179'))
65119	31253872	Knock-down of Rubicon prevented this localization and expression effect.	('expression', 'MPA', (54, 64))	('localization', 'biological_process', 'GO:0051179', ('37', '49'))	('Rubicon', 'Gene', (14, 21))	('Knock-down', 'Var', (0, 10))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('localization', 'MPA', (37, 49))	('Rubicon', 'Gene', '9711', (14, 21))	('prevented', 'NegReg', (22, 31))
65120	31253872	Knock down of YAP expression enhanced the lethality of neratinib as a single agent and when combined with either sildenafil or valproate (Supplementary Figure 7B).	('si', 'Chemical', 'MESH:D012825', (70, 72))	('sildenafil', 'Chemical', 'MESH:D000068677', (113, 123))	('YAP', 'Gene', (14, 17))	('valproate', 'Chemical', 'MESH:D014635', (127, 136))	('lethality', 'MPA', (42, 51))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('neratinib', 'Chemical', 'MESH:C487932', (55, 64))	('Knock down', 'Var', (0, 10))	('enhanced', 'PosReg', (29, 37))	('si', 'Chemical', 'MESH:D012825', (24, 26))
65121	31253872	So far, our studies have been examining cells wherein the mutated GTPase protein has been of the RAS family.	('GTP', 'Chemical', 'MESH:D006160', (66, 69))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('mutated', 'Var', (58, 65))	('GTPase protein', 'Protein', (66, 80))
65122	31253872	We recently demonstrated that neratinib combined with the HDAC inhibitor entinostat could kill uveal melanoma cells; cells that express mutated GTPase inactive forms of G alpha Q or G alpha 11.	('G alpha 11', 'Gene', '2767', (182, 192))	('HDAC', 'Gene', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('HDAC', 'Gene', '9734', (58, 62))	('GTP', 'Chemical', 'MESH:D006160', (144, 147))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('neratinib', 'Chemical', 'MESH:C487932', (30, 39))	('entinostat', 'Chemical', 'MESH:C118739', (73, 83))	('G alpha Q', 'Gene', (169, 178))	('mutated', 'Var', (136, 143))	('GTPase', 'Gene', (144, 150))	('uveal melanoma', 'Phenotype', 'HP:0007716', (95, 109))	('G alpha Q', 'Gene', '2776', (169, 178))	('G alpha 11', 'Gene', (182, 192))
65127	31253872	Phosphorylated YAP/TAZ leaves the nucleus and, based on S397 phosphorylation, YAP will then be ubiquitinated and degraded.	('S397', 'Var', (56, 60))	('TAZ', 'Gene', '6901', (19, 22))	('nucleus', 'cellular_component', 'GO:0005634', ('34', '41'))	('TAZ', 'Gene', (19, 22))	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))
65129	31253872	We have previously shown that the degradation of both G alpha proteins as well as K-RAS was prevented by knock down of Beclin1 or ATG5 and thus hypothesized that LAP also plays a key role in controlling mutant G alpha protein degradation.	('ATG5', 'Gene', (130, 134))	('mutant', 'Var', (203, 209))	('protein degradation', 'biological_process', 'GO:0030163', ('218', '237'))	('G alpha proteins', 'Protein', (54, 70))	('G alpha protein', 'Protein', (210, 225))	('degradation', 'biological_process', 'GO:0009056', ('34', '45'))	('knock down', 'Var', (105, 115))	('Beclin1', 'Gene', '8678', (119, 126))	('ATG5', 'Gene', '9474', (130, 134))	('degradation', 'MPA', (34, 45))	('protein', 'cellular_component', 'GO:0003675', ('218', '225'))	('prevented', 'NegReg', (92, 101))	('degradation', 'MPA', (226, 237))	('si', 'Chemical', 'MESH:D012825', (151, 153))	('Beclin1', 'Gene', (119, 126))
65131	31253872	As was observed in the pancreatic cancer cells expressing a mutant K-RAS, so in the uveal melanoma cells expressing a mutant G alpha protein (see Supplemental Figure S1), knock down of Rubicon enhanced the basal expression of YAP and the levels of YAP S397 phosphorylation, that again argues that a cell lacking LC3 associated phagocytosis / Rubicon has higher YAP levels and that it attempts to reduce this elevated expression by elevating S397 phosphorylation and ubiquitination (Supplemental Figure 10).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('melanoma', 'Disease', (90, 98))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('phosphorylation', 'biological_process', 'GO:0016310', ('446', '461'))	('pancreatic cancer', 'Disease', (23, 40))	('si', 'Chemical', 'MESH:D012825', (336, 338))	('Rubicon', 'Gene', '9711', (185, 192))	('LC3', 'Gene', '84557', (312, 315))	('si', 'Chemical', 'MESH:D012825', (423, 425))	('phosphorylation', 'biological_process', 'GO:0016310', ('257', '272'))	('Rubicon', 'Gene', '9711', (342, 349))	('Rubicon', 'Gene', (185, 192))	('higher', 'PosReg', (354, 360))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (23, 40))	('mutant', 'Var', (118, 124))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('elevating', 'PosReg', (431, 440))	('Rubicon', 'Gene', (342, 349))	('ubiquitination', 'MPA', (466, 480))	('LC3', 'Gene', (312, 315))	('si', 'Chemical', 'MESH:D012825', (218, 220))	('enhanced', 'PosReg', (193, 201))	('pancreatic cancer', 'Disease', 'MESH:D010190', (23, 40))	('S397 phosphorylation', 'MPA', (441, 461))	('mutant', 'Var', (60, 66))	('phagocytosis', 'biological_process', 'GO:0006909', ('327', '339'))	('YAP levels', 'MPA', (361, 371))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
65132	31253872	Prior data had shown that neratinib could cause K-RAS V12-GFP and K-RAS V12-RFP to rapidly colocalize into intracellular vesicles of varying sizes.	('intracellular', 'cellular_component', 'GO:0005622', ('107', '120'))	('K-RAS V12-GFP', 'Var', (48, 61))	('neratinib', 'Chemical', 'MESH:C487932', (26, 35))	('cause', 'Reg', (42, 47))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('RFP', 'Gene', (76, 79))	('RFP', 'Gene', '2358', (76, 79))	('si', 'Chemical', 'MESH:D012825', (141, 143))
65133	31253872	Knock down of Rubicon considerably reduced the ability of RAS-tagged proteins from localizing inside the cell as vesicles (Supplemental Figure 11).	('Rubicon', 'Gene', (14, 21))	('reduced', 'NegReg', (35, 42))	('ability', 'MPA', (47, 54))	('si', 'Chemical', 'MESH:D012825', (115, 117))	('RAS-tagged', 'Protein', (58, 68))	('localizing', 'MPA', (83, 93))	('si', 'Chemical', 'MESH:D012825', (25, 27))	('Knock down', 'Var', (0, 10))	('si', 'Chemical', 'MESH:D012825', (96, 98))	('Rubicon', 'Gene', '9711', (14, 21))
65135	31253872	We had previously published in H1975 NSCLC cells that express a mutant active ERBB1 that the irreversible ERBB1/2/4 inhibitor neratinib had greater potential to down-regulate the expression of ERBB1 than another irreversible ERBB1/2/4 inhibitor, afatinib.	('ERBB1', 'Gene', (225, 230))	('ERBB1', 'Gene', (106, 111))	('ERBB1', 'Gene', '1956', (225, 230))	('si', 'Chemical', 'MESH:D012825', (185, 187))	('afatinib', 'Chemical', 'MESH:D000077716', (246, 254))	('ERBB1', 'Gene', (193, 198))	('ERBB1/2/4', 'Gene', (225, 234))	('ERBB1', 'Gene', '1956', (106, 111))	('ERBB1/2/4', 'Gene', (106, 115))	('ERBB1/2/4', 'Gene', '1956;2064;2066', (225, 234))	('mutant', 'Var', (64, 70))	('ERBB1', 'Gene', '1956', (193, 198))	('ERBB1/2/4', 'Gene', '1956;2064;2066', (106, 115))	('down-regulate', 'NegReg', (161, 174))	('ERBB1', 'Gene', (78, 83))	('si', 'Chemical', 'MESH:D012825', (219, 221))	('ERBB1', 'Gene', '1956', (78, 83))	('si', 'Chemical', 'MESH:D012825', (100, 102))	('expression', 'MPA', (179, 189))	('neratinib', 'Chemical', 'MESH:C487932', (126, 135))	('H1975 NSCLC', 'CellLine', 'CVCL:1511', (31, 42))
65154	31253872	Knock out of LATS1/2, but not of MST1/2, abolishes YAP/TAZ phosphorylation.	('MST1/2', 'Gene', (33, 39))	('Knock out', 'Var', (0, 9))	('TAZ', 'Gene', '6901', (55, 58))	('LATS1/2', 'Gene', (13, 20))	('phosphorylation', 'biological_process', 'GO:0016310', ('59', '74'))	('TAZ', 'Gene', (55, 58))	('MST1/2', 'Gene', '4485;6788', (33, 39))	('abolishes', 'NegReg', (41, 50))
65156	31253872	Thus, combined deletion of the MAP4Ks and MST1/2, but neither subset alone, can suppress the phosphorylation of LATS1/2 and YAP/TAZ i.e.	('phosphorylation', 'biological_process', 'GO:0016310', ('93', '108'))	('deletion', 'Var', (15, 23))	('MST1/2', 'Gene', '4485;6788', (42, 48))	('suppress', 'NegReg', (80, 88))	('MAP', 'molecular_function', 'GO:0004239', ('31', '34'))	('MAP4', 'Gene', (31, 35))	('MAP4', 'Gene', '4134', (31, 35))	('TAZ', 'Gene', '6901', (128, 131))	('MST1/2', 'Gene', (42, 48))	('LATS1/2', 'Protein', (112, 119))	('phosphorylation', 'MPA', (93, 108))	('TAZ', 'Gene', (128, 131))
65159	31253872	MST1/2/3 phosphorylate NDR1/2 on T444/T442, and the binding of the scaffold MOB1 to NDR1/2 is required to support the auto-phosphorylation of NDR1/2 on S281/S282.	('NDR1/2', 'Gene', '11329;23012', (23, 29))	('NDR1/2', 'Gene', (84, 90))	('auto-phosphorylation', 'MPA', (118, 138))	('binding', 'molecular_function', 'GO:0005488', ('52', '59'))	('NDR1/2', 'Gene', (23, 29))	('MOB1', 'Gene', (76, 80))	('T444/T442', 'Var', (33, 42))	('MST1/2/3', 'Gene', (0, 8))	('MST1/2/3', 'Gene', '4485;6788;8428', (0, 8))	('NDR1/2', 'Gene', '11329;23012', (142, 148))	('NDR1/2', 'Gene', '11329;23012', (84, 90))	('MOB1', 'Gene', '3627', (76, 80))	('phosphorylation', 'biological_process', 'GO:0016310', ('123', '138'))	('NDR1/2', 'Gene', (142, 148))	('S281/S282', 'Var', (152, 161))
65160	31253872	The activation of NDR1/2 can be mediated via different pathways: the inhibition of protein phosphatase 2A; the mutation of an autoinhibitory segment; and membrane targeting of NDR1/2.	('NDR1/2', 'Gene', (18, 24))	('protein phosphatase 2A', 'molecular_function', 'GO:0050115', ('83', '105'))	('protein', 'Protein', (83, 90))	('membrane', 'MPA', (154, 162))	('NDR1/2', 'Gene', '11329;23012', (176, 182))	('NDR1/2', 'Gene', '11329;23012', (18, 24))	('membrane', 'cellular_component', 'GO:0016020', ('154', '162'))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('mutation', 'Var', (111, 119))	('inhibition', 'NegReg', (69, 79))	('NDR1/2', 'Gene', (176, 182))
65165	31253872	It has been shown that oncogenic RAS can alter signaling by the Hippo pathway.	('signaling', 'MPA', (47, 56))	('Hippo pathway', 'Pathway', (64, 77))	('oncogenic RAS', 'Var', (23, 36))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('alter', 'Reg', (41, 46))	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))
65170	31253872	In myoblasts expressing a mutant K-RAS, YAP cooperates to enhance proliferation and prevent death in vitro and in vivo.	('enhance', 'PosReg', (58, 65))	('proliferation', 'CPA', (66, 79))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('K-RAS', 'Protein', (33, 38))	('death', 'CPA', (92, 97))	('mutant', 'Var', (26, 32))
65174	31253872	Silencing of Rubicon prevents ERBB1 activation; in our systems, this would be caused by neratinib exposure.	('ERBB1', 'Gene', '1956', (30, 35))	('neratinib', 'Chemical', 'MESH:C487932', (88, 97))	('ERBB1', 'Gene', (30, 35))	('Rubicon', 'Gene', '9711', (13, 20))	('Rubicon', 'Gene', (13, 20))	('Silencing', 'Var', (0, 9))
65175	31253872	At least in our short-term assays, loss of Rubicon also enhanced YAP expression, arguing that the YAP/Rubicon axis could play an important role in tumor cells with altered phagocytosis.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('loss', 'Var', (35, 39))	('YAP', 'Protein', (65, 68))	('phagocytosis', 'biological_process', 'GO:0006909', ('172', '184'))	('enhanced', 'PosReg', (56, 64))	('si', 'Chemical', 'MESH:D012825', (181, 183))	('Rubicon', 'Gene', '9711', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('Rubicon', 'Gene', '9711', (43, 50))	('Rubicon', 'Gene', (43, 50))	('Rubicon', 'Gene', (102, 109))
65178	31253872	The T300A variant has been linked to an enhanced risk of gastric cancer.	('T300A', 'Mutation', 'rs2241880', (4, 9))	('gastric cancer', 'Disease', (57, 71))	('T300A', 'Var', (4, 9))	('gastric cancer', 'Disease', 'MESH:D013274', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))
65179	31253872	It has been shown that selective autophagy is lowered in many cell types using T300A knock-in mice compared to T300 mice, which agrees with our findings showing a reduced autophagic down-regulation of K-RAS and ERBB1 (Supplemental Figure 11).	('mice', 'Species', '10090', (116, 120))	('ERBB1', 'Gene', (211, 216))	('T300A', 'Mutation', 'rs2241880', (79, 84))	('regulation', 'biological_process', 'GO:0065007', ('187', '197'))	('reduced', 'NegReg', (163, 170))	('T300A', 'Var', (79, 84))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('autophagic', 'CPA', (171, 181))	('selective autophagy', 'CPA', (23, 42))	('down-regulation', 'NegReg', (182, 197))	('mice', 'Species', '10090', (94, 98))	('selective autophagy', 'biological_process', 'GO:0061912', ('23', '42'))	('ERBB1', 'Gene', '1956', (211, 216))	('lowered', 'NegReg', (46, 53))
65180	31253872	The ATG16L1 T300A isoform is associated with elevated production of IL-1beta.	('T300A', 'Var', (12, 17))	('IL-1beta', 'Gene', '3552', (68, 76))	('ATG16L1', 'Gene', (4, 11))	('IL-1beta', 'Gene', (68, 76))	('elevated', 'PosReg', (45, 53))	('IL-1', 'molecular_function', 'GO:0005149', ('68', '72'))	('T300A', 'Mutation', 'rs2241880', (12, 17))	('ATG16L1', 'Gene', '55054', (4, 11))
65188	31253872	Based on data from Waters et al, we used two validated siRNA tools to knock down K-RAS or N-RAS for antibody validation purposes; custom made NRAS-5 CCUGAGUACUGACCUAAGAdTdT and K-RAS Silencer s7940.	('N-RAS', 'Gene', (90, 95))	('antibody', 'molecular_function', 'GO:0003823', ('100', '108'))	('N-RAS', 'Gene', '4893', (90, 95))	('antibody', 'cellular_component', 'GO:0019814', ('100', '108'))	('antibody', 'cellular_component', 'GO:0042571', ('100', '108'))	('antibody', 'cellular_component', 'GO:0019815', ('100', '108'))	('K-RAS', 'Protein', (81, 86))	('knock', 'Var', (70, 75))	('si', 'Chemical', 'MESH:D012825', (55, 57))
65189	31253872	Knock down of K-RAS or N- RAS reduced fluorescent staining by ~80%.	('fluorescent staining', 'MPA', (38, 58))	('K-RAS', 'Protein', (14, 19))	('reduced', 'NegReg', (30, 37))	('N- RAS', 'Gene', '4893', (23, 29))	('Knock down', 'Var', (0, 10))	('N- RAS', 'Gene', (23, 29))
65206	31013837	This is linked to the capacity of melanoma cells to mutate very quickly and/or activate alternative signaling pathways.	('alternative signaling pathways', 'Pathway', (88, 118))	('activate', 'PosReg', (79, 87))	('mutate', 'Var', (52, 58))	('melanoma cells', 'Disease', 'MESH:D008545', (34, 48))	('melanoma cells', 'Disease', (34, 48))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))
65209	31013837	Regarding the fact that many melanoma patients carry a BRAF mutation, and that they develop resistance to BRAF inhibitors, this observation is very interesting as MIF inhibitors could be used to treat many patients in relapse after treatment with an inhibitor of the mutant BRAF protein.	('mutation', 'Var', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('BRAF', 'Gene', (274, 278))	('melanoma', 'Disease', (29, 37))	('BRAF', 'Gene', '673', (274, 278))	('BRAF', 'Gene', '673', (106, 110))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('BRAF', 'Gene', (106, 110))	('patients', 'Species', '9606', (206, 214))	('BRAF', 'Gene', '673', (55, 59))	('patients', 'Species', '9606', (38, 46))	('protein', 'cellular_component', 'GO:0003675', ('279', '286'))	('BRAF', 'Gene', (55, 59))
65215	31013837	The most used targeted therapies act on the MAPK pathway, which is mutated in NRAS and BRAF in about 25 and 60% of melanoma patients, respectively.	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('MAPK', 'molecular_function', 'GO:0004707', ('44', '48'))	('NRAS', 'Gene', (78, 82))	('mutated', 'Var', (67, 74))	('MAPK pathway', 'Pathway', (44, 56))	('NRAS', 'Gene', '4893', (78, 82))	('BRAF', 'Gene', (87, 91))	('patients', 'Species', '9606', (124, 132))	('BRAF', 'Gene', '673', (87, 91))
65223	31013837	For the purpose of this study, we analyzed the rate of mutations and copy number variations in 479 melanomas using the cBioPortal for Cancer Genomics .	('copy number variations', 'Var', (69, 91))	('melanomas', 'Disease', (99, 108))	('Cancer', 'Disease', (134, 140))	('Cancer', 'Disease', 'MESH:D009369', (134, 140))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('melanomas', 'Disease', 'MESH:D008545', (99, 108))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanomas', 'Phenotype', 'HP:0002861', (99, 108))
65224	31013837	We found molecular alterations in only 1% of cases for MIF, 3% for CD74, and 2.4% for CD44, mainly including gene amplifications and missense mutations.	('CD44', 'Gene', (86, 90))	('MIF', 'Gene', (55, 58))	('missense mutations', 'Var', (133, 151))	('gene amplifications', 'Var', (109, 128))	('CD44', 'Gene', '960', (86, 90))	('CD74', 'Gene', (67, 71))
65241	31013837	A study performed at the University of Texas on metastasis of melanoma patients with stage III disease indicated that the presence of MIF protein expression in tumors was associated with poor survival parameters in both overall survival and relapse-free survival.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('melanoma', 'Disease', (62, 70))	('relapse-free survival', 'CPA', (241, 262))	('poor', 'NegReg', (187, 191))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('patients', 'Species', '9606', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('MIF protein', 'Protein', (134, 145))	('tumors', 'Disease', (160, 166))	('presence', 'Var', (122, 130))	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('overall survival', 'CPA', (220, 236))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
65243	31013837	Furthermore, their study indicated that the signature CD74+/MIF- could be a more powerful prognostic marker in the case of stage III melanoma.	('CD74+/MIF-', 'Var', (54, 64))	('III melanoma', 'Disease', (129, 141))	('III melanoma', 'Disease', 'MESH:D008545', (129, 141))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))
65248	31013837	This binding triggers the sustained activation of the MAPK and the PI3K/AKT pathways, which are frequently upregulated in melanomas through NRAS or BRAF mutation, or PTEN loss, respectively.	('AKT', 'Gene', (72, 75))	('activation', 'PosReg', (36, 46))	('PTEN', 'Gene', '5728', (166, 170))	('melanomas', 'Disease', 'MESH:D008545', (122, 131))	('loss', 'NegReg', (171, 175))	('MAPK', 'molecular_function', 'GO:0004707', ('54', '58'))	('melanomas', 'Disease', (122, 131))	('MAPK', 'Pathway', (54, 58))	('upregulated', 'PosReg', (107, 118))	('BRAF', 'Gene', '673', (148, 152))	('NRAS', 'Gene', '4893', (140, 144))	('mutation', 'Var', (153, 161))	('AKT', 'Gene', '207', (72, 75))	('PI3K', 'molecular_function', 'GO:0016303', ('67', '71'))	('BRAF', 'Gene', (148, 152))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('PTEN', 'Gene', (166, 170))	('binding', 'molecular_function', 'GO:0005488', ('5', '12'))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('NRAS', 'Gene', (140, 144))
65249	31013837	In vitro analysis conducted in human melanoma cell lines showed that MIF acts upstream of the PI3K/AKT pathway, as MIF knock-down decreased AKT phosphorylation.	('AKT', 'Gene', (140, 143))	('knock-down', 'Var', (119, 129))	('phosphorylation', 'biological_process', 'GO:0016310', ('144', '159'))	('AKT', 'Gene', '207', (99, 102))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('MIF', 'Gene', (115, 118))	('human', 'Species', '9606', (31, 36))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('PI3K', 'molecular_function', 'GO:0016303', ('94', '98'))	('AKT', 'Gene', '207', (140, 143))	('AKT', 'Gene', (99, 102))	('decreased', 'NegReg', (130, 139))
65250	31013837	A correlation between the degree of sensitivity of cell lines to MIF depletion and the inhibition of AKT activity has also been reported.	('inhibition', 'NegReg', (87, 97))	('AKT', 'Gene', '207', (101, 104))	('depletion', 'Var', (69, 78))	('AKT', 'Gene', (101, 104))
65251	31013837	Notably, the effect of MIF on AKT leads to modifications in the proteins regulated by its pathway, including a decrease of cyclin D1 and CDK4 expression, as well as an increase of the p27 level.	('increase', 'PosReg', (168, 176))	('cyclin', 'molecular_function', 'GO:0016538', ('123', '129'))	('CDK', 'molecular_function', 'GO:0004693', ('137', '140'))	('expression', 'MPA', (142, 152))	('AKT', 'Gene', '207', (30, 33))	('proteins', 'MPA', (64, 72))	('CDK4', 'Gene', (137, 141))	('modifications', 'Reg', (43, 56))	('CDK4', 'Gene', '1019', (137, 141))	('cyclin D1', 'Gene', '595', (123, 132))	('MIF', 'Var', (23, 26))	('AKT', 'Gene', (30, 33))	('decrease', 'NegReg', (111, 119))	('cyclin D1', 'Gene', (123, 132))	('p27', 'Gene', '3429', (184, 187))	('p27', 'Gene', (184, 187))
65253	31013837	Indeed, CD74 expression is associated with melanoma progression but, as previously seen (Section 2.1), high levels of CD74 in melanoma metastasis are associated with a better overall and recurrence-free survival, in the absence of MIF in the tumor microenvironment.	('melanoma metastasis', 'Disease', (126, 145))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('better', 'PosReg', (168, 174))	('melanoma metastasis', 'Disease', 'MESH:D009362', (126, 145))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('high levels', 'Var', (103, 114))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('CD74', 'Gene', (118, 122))	('tumor', 'Disease', (242, 247))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))	('recurrence-free survival', 'CPA', (187, 211))
65260	31013837	For example, the treatment of melanoma bearing mice with anti-MIF antibodies led to a significantly reduced angiogenesis.	('reduced', 'NegReg', (100, 107))	('anti-MIF antibodies', 'Var', (57, 76))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('antibodies', 'Var', (66, 76))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Disease', (30, 38))	('angiogenesis', 'biological_process', 'GO:0001525', ('108', '120'))	('angiogenesis', 'CPA', (108, 120))	('mice', 'Species', '10090', (47, 51))
65267	31013837	Indeed, MIF enhances Jab1/CSN5-dependent stabilization of HIF-1alpha which leads to the activation of hypoxia-responsive genes.	('CSN5', 'Gene', '10987', (26, 30))	('CSN', 'cellular_component', 'GO:0008180', ('26', '29'))	('activation', 'PosReg', (88, 98))	('MIF', 'Var', (8, 11))	('CSN5', 'Gene', (26, 30))	('Jab1', 'Gene', (21, 25))	('hypoxia', 'Disease', 'MESH:D000860', (102, 109))	('HIF-1alpha', 'Gene', '3091', (58, 68))	('stabilization', 'MPA', (41, 54))	('hypoxia', 'Disease', (102, 109))	('Jab1', 'Gene', '10987', (21, 25))	('HIF-1alpha', 'Gene', (58, 68))	('enhances', 'PosReg', (12, 20))
65268	31013837	In vitro studies on melanoma cell lines also showed that MIF knock-down resulted in a reduced expression of VEGF, and this was associated with a decreased response to hypoxia.	('knock-down', 'Var', (61, 71))	('VEGF', 'Gene', (108, 112))	('reduced', 'NegReg', (86, 93))	('response to hypoxia', 'biological_process', 'GO:0001666', ('155', '174'))	('hypoxia', 'Disease', (167, 174))	('hypoxia', 'Disease', 'MESH:D000860', (167, 174))	('VEGF', 'Gene', '7422', (108, 112))	('decreased', 'NegReg', (145, 154))	('MIF', 'Gene', (57, 60))	('expression', 'MPA', (94, 104))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanoma', 'Disease', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))
65270	31013837	Actually, in vivo experiments on wild-type and MIF-/- mice, in which MIF deficient tumor cells were implanted, showed a decreased angiogenesis in the MIF-/- mice but not in the wild-type individuals.	('decreased', 'NegReg', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mice', 'Species', '10090', (157, 161))	('angiogenesis', 'CPA', (130, 142))	('MIF deficient tumor', 'Disease', 'MESH:D009369', (69, 88))	('angiogenesis', 'biological_process', 'GO:0001525', ('130', '142'))	('mice', 'Species', '10090', (54, 58))	('MIF-/-', 'Var', (150, 156))	('MIF deficient tumor', 'Disease', (69, 88))
65271	31013837	Indeed, MIF has many ways to modulate angiogenesis by acting on many factors implied in this phenomenon, such as the anti-angiogenic factor TSP-1, the growth factor VEGF, pro-angiogenic chemokines, and the transcription factor HIF-1alpha, which modulates the activity of hypoxia responsive genes, as well as pro-inflammatory cells (Figure 1).	('transcription', 'biological_process', 'GO:0006351', ('206', '219'))	('transcription factor', 'molecular_function', 'GO:0000981', ('206', '226'))	('HIF-1alpha', 'Gene', (227, 237))	('VEGF', 'Gene', '7422', (165, 169))	('MIF', 'Var', (8, 11))	('TSP-1', 'Gene', '7057', (140, 145))	('modulate', 'Reg', (29, 37))	('TSP-1', 'molecular_function', 'GO:0004277', ('140', '145'))	('acting', 'Reg', (54, 60))	('hypoxia', 'Disease', 'MESH:D000860', (271, 278))	('HIF-1alpha', 'Gene', '3091', (227, 237))	('hypoxia', 'Disease', (271, 278))	('VEGF', 'Gene', (165, 169))	('angiogenesis', 'biological_process', 'GO:0001525', ('38', '50'))	('angiogenesis', 'CPA', (38, 50))	('TSP-1', 'Gene', (140, 145))
65286	31013837	They also showed that patients with late stage melanoma in an immunotherapy trial, consisting of autologous GM-CSF secreting tumor cell vaccines and CTLA-4 blockade, developed auto-antibodies against MIF while they responded to their combined therapies.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('CTLA-4', 'Gene', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('MIF', 'Gene', (200, 203))	('patients', 'Species', '9606', (22, 30))	('auto-antibodies', 'Var', (176, 191))	('tumor', 'Disease', (125, 130))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('CTLA-4', 'Gene', '1493', (149, 155))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('GM-CSF', 'Gene', (108, 114))	('GM-CSF', 'Gene', '1437', (108, 114))
65299	31013837	showed a promotion of alternative activation markers, and a reduction of classical activation markers, of peripheral macrophage polarization by MIF in mouse models of melanoma.	('mouse', 'Species', '10090', (151, 156))	('peripheral macrophage polarization', 'CPA', (106, 140))	('promotion', 'PosReg', (9, 18))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('reduction', 'NegReg', (60, 69))	('melanoma', 'Disease', (167, 175))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('macrophage polarization', 'biological_process', 'GO:0042116', ('117', '140'))	('MIF', 'Var', (144, 147))
65300	31013837	They also showed that MIF inhibition reduces splenic MDSC immune suppression in melanoma mouse models, and is well-known that MDSCs act on immune-dependent and immune-independent mechanisms to promote tumor progression.	('promote', 'PosReg', (193, 200))	('MIF', 'Protein', (22, 25))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('inhibition', 'Var', (26, 36))	('melanoma', 'Disease', (80, 88))	('splenic MDSC immune suppression', 'MPA', (45, 76))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('mouse', 'Species', '10090', (89, 94))	('tumor', 'Disease', (201, 206))	('reduces', 'NegReg', (37, 44))
65301	31013837	These observations, associated with other results showing that MIF neutralization in tumor bearing hosts induces cytotoxic T lymphocyte activities, suggest that MIF plays an important role in tumor-induced immune tolerance, both innate and adaptive, and immunosuppression in cancer, and more specifically in melanoma.	('tumor', 'Disease', (85, 90))	('induces', 'Reg', (105, 112))	('MIF', 'Gene', (63, 66))	('tumor', 'Disease', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('neutralization', 'Var', (67, 81))	('melanoma', 'Phenotype', 'HP:0002861', (308, 316))	('melanoma', 'Disease', (308, 316))	('cytotoxic T lymphocyte activities', 'CPA', (113, 146))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('melanoma', 'Disease', 'MESH:D008545', (308, 316))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('cancer', 'Disease', (275, 281))
65303	31013837	reported that the blockade of MIF-CD74 interaction reduces the expression of pro-tumorigenic molecules implied in immune and inflammatory mechanisms, such as interleukin-6 and interleukin-8.	('interleukin-6', 'Gene', (158, 171))	('interleukin-8', 'Gene', '3576', (176, 189))	('reduces', 'NegReg', (51, 58))	('expression of', 'MPA', (63, 76))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('MIF-CD74', 'Gene', (30, 38))	('interleukin-6', 'Gene', '3569', (158, 171))	('blockade', 'Var', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('interleukin-8', 'Gene', (176, 189))	('interaction', 'Interaction', (39, 50))	('tumor', 'Disease', (81, 86))
65313	31013837	demonstrated that MIF deletion in melanoma-bearing mice protects them against lung metastatic colonization by improving the immunosuppressive response against melanoma cells and enhancing the peripheral macrophage pro-inflammatory responses.	('melanoma', 'Disease', (159, 167))	('improving', 'PosReg', (110, 119))	('MIF', 'Gene', (18, 21))	('lung metastatic colonization', 'CPA', (78, 106))	('mice', 'Species', '10090', (51, 55))	('melanoma cells', 'Disease', (159, 173))	('peripheral macrophage pro-inflammatory responses', 'MPA', (192, 240))	('deletion', 'Var', (22, 30))	('enhancing', 'PosReg', (178, 187))	('immunosuppressive response', 'MPA', (124, 150))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))	('melanoma cells', 'Disease', 'MESH:D008545', (159, 173))
65314	31013837	They also showed that MIF inhibition leads to a reprogramming of TAM polarization, which allows the attenuation of melanoma progression and pulmonary metastases.	('pulmonary metastases', 'Disease', 'MESH:D009362', (140, 160))	('pulmonary metastases', 'Disease', (140, 160))	('MIF', 'Protein', (22, 25))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('inhibition', 'Var', (26, 36))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('TAM', 'Chemical', '-', (65, 68))	('attenuation', 'NegReg', (100, 111))
65316	31013837	When melanomas develop, the tumors can release factors which prevent these healthy melanocytes from entering the circulation, but instead melanoma cells expressing MLANA and MIF enter the blood circulation where they become circulating tumor cells (CTCs) which play a key role in metastasis development.	('melanoma cells', 'Disease', 'MESH:D008545', (138, 152))	('tumor', 'Disease', (28, 33))	('MLANA', 'Gene', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('MLANA', 'Gene', '2315', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('MIF', 'Var', (174, 177))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('melanomas', 'Phenotype', 'HP:0002861', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('melanoma cells', 'Disease', (138, 152))	('tumors', 'Disease', (28, 34))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('blood circulation', 'biological_process', 'GO:0008015', ('188', '205'))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('melanomas', 'Disease', 'MESH:D008545', (5, 14))	('tumor', 'Disease', (236, 241))	('melanomas', 'Disease', (5, 14))
65323	31013837	Keeping in mind that many melanoma patients carry a BRAF mutation, and that they develop resistance to BRAF inhibitors, this observation is very interesting as MIF inhibitors could be used to treat many patients in relapse after a treatment with a mutant BRAF inhibitor.	('mutation', 'Var', (57, 65))	('BRAF', 'Gene', '673', (103, 107))	('BRAF', 'Gene', '673', (255, 259))	('patients', 'Species', '9606', (203, 211))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('BRAF', 'Gene', (255, 259))	('melanoma', 'Disease', (26, 34))	('BRAF', 'Gene', '673', (52, 56))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))	('BRAF', 'Gene', (52, 56))	('patients', 'Species', '9606', (35, 43))	('BRAF', 'Gene', (103, 107))
65324	31013837	Besides patients carrying a BRAF mutation, MIF inhibitors could technically be effective on many tumor types harboring different mutation profiles, providing therapeutic alternatives to patients whose tumors do not correspond to classical targeted therapies.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('BRAF', 'Gene', (28, 32))	('mutation', 'Var', (33, 41))	('BRAF', 'Gene', '673', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumor', 'Disease', (201, 206))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('patients', 'Species', '9606', (186, 194))	('patients', 'Species', '9606', (8, 16))
65325	31013837	Indeed, as shown earlier, MIF acts on TSP-1 and promotes angiogenesis.	('TSP-1', 'molecular_function', 'GO:0004277', ('38', '43'))	('TSP-1', 'Gene', (38, 43))	('angiogenesis', 'CPA', (57, 69))	('promotes', 'PosReg', (48, 56))	('TSP-1', 'Gene', '7057', (38, 43))	('angiogenesis', 'biological_process', 'GO:0001525', ('57', '69'))	('MIF', 'Var', (26, 29))
65326	31013837	Experiments have shown that knocking down MIF expression in cells inoculated in mice led to similar-sized tumors establishing horizontally, but the vertical growth was strongly decreased, compared to mice inoculated with no-knock down melanoma cells.	('MIF', 'Gene', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('knocking down', 'Var', (28, 41))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('melanoma cells', 'Disease', 'MESH:D008545', (235, 249))	('melanoma cells', 'Disease', (235, 249))	('mice', 'Species', '10090', (200, 204))	('decreased', 'NegReg', (177, 186))	('mice', 'Species', '10090', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('vertical growth', 'CPA', (148, 163))
65327	31013837	In addition, TAM polarization following MIF blockade is another source of proof that targeting MIF could help in restoring immune response, attenuating melanoma progression and pulmonary metastases in patients.	('patients', 'Species', '9606', (201, 209))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('TAM', 'Chemical', '-', (13, 16))	('MIF', 'Gene', (95, 98))	('targeting', 'Var', (85, 94))	('immune response', 'MPA', (123, 138))	('attenuating', 'NegReg', (140, 151))	('pulmonary metastases', 'Disease', 'MESH:D009362', (177, 197))	('pulmonary metastases', 'Disease', (177, 197))	('immune response', 'biological_process', 'GO:0006955', ('123', '138'))
65330	31013837	Research is now focusing on more attractive approaches to decrease MIF activity by using small inhibitors, such as ISO-1 or ISO-66, which ligate the tautomerase active site of MIF, which plays a role in many of its biological functions.	('tautomerase', 'MPA', (149, 160))	('MIF', 'Gene', (176, 179))	('ISO-1', 'Gene', '10209', (115, 120))	('ISO-66', 'Var', (124, 130))	('activity', 'MPA', (71, 79))	('ISO-1', 'Gene', (115, 120))	('ligate', 'NegReg', (138, 144))	('ISO-66', 'Chemical', 'MESH:C000598426', (124, 130))
65331	31013837	A study performed on colon cancer and melanoma showed that ISO-66 enhanced specific and non-specific immune responses in vitro, and its administration in vivo was nontoxic and resulted in decreased tumor burdens.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('ISO-66', 'Var', (59, 65))	('colon cancer', 'Phenotype', 'HP:0003003', (21, 33))	('decreased tumor', 'Disease', 'MESH:D009369', (188, 203))	('enhanced', 'PosReg', (66, 74))	('colon cancer', 'Disease', 'MESH:D015179', (21, 33))	('specific', 'MPA', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('ISO-66', 'Chemical', 'MESH:C000598426', (59, 65))	('colon cancer', 'Disease', (21, 33))	('melanoma', 'Disease', (38, 46))	('decreased tumor', 'Disease', (188, 203))
65334	31013837	A study performed on melanoma bearing mice showed that 4-IPP attenuates tumor polarized macrophage alternative activation, immunosuppression, neoangiogenesis, and melanoma tumor outgrowth.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mice', 'Species', '10090', (38, 42))	('tumor', 'Disease', (172, 177))	('immunosuppression', 'CPA', (123, 140))	('neoangiogenesis', 'CPA', (142, 157))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('melanoma tumor', 'Disease', (163, 177))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Disease', (21, 29))	('4-IPP', 'Var', (55, 60))	('4-IPP', 'Chemical', 'MESH:C532251', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('melanoma tumor', 'Disease', 'MESH:D008545', (163, 177))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('attenuates', 'NegReg', (61, 71))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))
65345	31013837	All these data indicate that MIF targeting could be a therapy of choice in the future of melanoma treatment.	('targeting', 'Var', (33, 42))	('MIF', 'Protein', (29, 32))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
65354	29774094	The identification of near-ubiquitous GNAQ/GNA11 mutations and the activation of MAPK signaling in UM have raised hopes of more effective, targeted therapies, based on MEK inhibition, for example.	('GNAQ', 'Gene', '2776', (38, 42))	('MEK', 'Gene', (168, 171))	('mutations', 'Var', (49, 58))	('activation', 'PosReg', (67, 77))	('GNA11', 'Gene', (43, 48))	('MEK', 'Gene', '5609', (168, 171))	('GNA11', 'Gene', '2767', (43, 48))	('MAPK', 'molecular_function', 'GO:0004707', ('81', '85'))	('GNAQ', 'Gene', (38, 42))	('MAPK signaling', 'Pathway', (81, 95))	('MAPK signaling', 'biological_process', 'GO:0000165', ('81', '95'))
65364	29774094	Thus, GNAQ/11 mutations induce the constitutive activation of the PKC/MAPK pathways involved in oncogenesis.	('PKC', 'molecular_function', 'GO:0004697', ('66', '69'))	('GNAQ', 'Gene', '2776', (6, 10))	('PKC', 'Gene', (66, 69))	('PKC', 'Gene', '112476', (66, 69))	('MAPK', 'molecular_function', 'GO:0004707', ('70', '74'))	('GNAQ', 'Gene', (6, 10))	('activation', 'PosReg', (48, 58))	('oncogenesis', 'biological_process', 'GO:0007048', ('96', '107'))	('mutations', 'Var', (14, 23))
65384	29774094	This effect was observed at a concentration of 1.2 mM DTIC in MP38, MP41, and MP46 cells, and at 2.5 mM DTIC in MM28 and MP65 cells, for all concentrations of selumetinib tested.	('MM28', 'Gene', '79148', (112, 116))	('MP46', 'Var', (78, 82))	('selumetinib', 'Chemical', 'MESH:C517975', (159, 170))	('MM28', 'Gene', (112, 116))	('DTIC', 'Chemical', 'MESH:D003606', (54, 58))	('DTIC', 'Chemical', 'MESH:D003606', (104, 108))
65387	29774094	We then assessed the efficacy of selumetinib as a single agent in three uveal melanoma PDXs: MP34, MP55, and MM26 (Figure 2).	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('MM26', 'CellLine', 'CVCL:L791', (109, 113))	('MM26', 'Disease', (109, 113))	('uveal melanoma PDXs', 'Disease', (72, 91))	('selumetinib', 'Chemical', 'MESH:C517975', (33, 44))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('MP55', 'Var', (99, 103))	('MP34', 'Var', (93, 97))	('uveal melanoma PDXs', 'Disease', 'MESH:C536494', (72, 91))
65409	29774094	The efficacy of three other combinations with selumetinib that have yet to be tested clinically was evaluated in five UM PDXs (MP34, MP46, MP55, MP77, and MM26).	('MM26', 'CellLine', 'CVCL:L791', (155, 159))	('MP55', 'Var', (139, 143))	('MP77', 'Var', (145, 149))	('MP34', 'Var', (127, 131))	('MP46', 'Var', (133, 137))	('selumetinib', 'Chemical', 'MESH:C517975', (46, 57))	('PD', 'Disease', 'MESH:D010300', (121, 123))	('MM26', 'Var', (155, 159))
65410	29774094	The drugs used in combination with selumetinib were docetaxel, the ERK inhibitor AZ6197, and the mTORC1/2 inhibitor AZD2014.	('AZ6197', 'Chemical', '-', (81, 87))	('ERK', 'Gene', '5594', (67, 70))	('ERK', 'molecular_function', 'GO:0004707', ('67', '70'))	('ERK', 'Gene', (67, 70))	('mTORC1/2', 'Gene', '74343;382056', (97, 105))	('docetaxel', 'Chemical', 'MESH:D000077143', (52, 61))	('selumetinib', 'Chemical', 'MESH:C517975', (35, 46))	('mTORC1', 'cellular_component', 'GO:0031931', ('97', '103'))	('AZ6197', 'Var', (81, 87))	('mTORC1/2', 'Gene', (97, 105))	('AZD2014', 'Chemical', 'MESH:C585537', (116, 123))
65414	29774094	Selumetinib, docetaxel and AZ6197 scored 16, 14, and 13, respectively, and the total score for AZD2014 was 7, highlighting the greater efficacy of this mTORC1/2 inhibitor than of the other compounds.	('docetaxel', 'Chemical', 'MESH:D000077143', (13, 22))	('mTORC1', 'cellular_component', 'GO:0031931', ('152', '158'))	('mTORC1/2', 'Gene', '74343;382056', (152, 160))	('AZ6197', 'Chemical', '-', (27, 33))	('AZ6197', 'Var', (27, 33))	('mTORC1/2', 'Gene', (152, 160))	('Selumetinib', 'Chemical', 'MESH:C517975', (0, 11))	('AZD2014', 'Chemical', 'MESH:C585537', (95, 102))
65419	29774094	Finally, the combination treatments resulted in a slight increase in ORR (< -0.5) for selumetinib + docetaxel relative to selumetinib or docetaxel alone, and a significant increase for both selumetinib + AZ6197 and selumetinib + AZD2014 relative to monotherapies (Supplementary Figure 2).	('increase', 'PosReg', (172, 180))	('selumetinib', 'Chemical', 'MESH:C517975', (86, 97))	('docetaxel', 'Chemical', 'MESH:D000077143', (100, 109))	('ORR', 'MPA', (69, 72))	('selumetinib', 'Chemical', 'MESH:C517975', (190, 201))	('selumetinib', 'Chemical', 'MESH:C517975', (215, 226))	('increase', 'PosReg', (57, 65))	('selumetinib', 'Var', (215, 226))	('AZ6197', 'Chemical', '-', (204, 210))	('AZD2014', 'Chemical', 'MESH:C585537', (229, 236))	('docetaxel', 'Chemical', 'MESH:D000077143', (137, 146))	('selumetinib', 'Var', (190, 201))	('selumetinib', 'Chemical', 'MESH:C517975', (122, 133))
65420	29774094	A PD study was performed on tumors collected at the end of in vivo experiments on the five treated UM PDXs, MP34, MP46, MP55, MP77, and MM26 (Figure 6).	('MP46', 'Var', (114, 118))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('PD', 'Disease', 'MESH:D010300', (102, 104))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('MM26', 'CellLine', 'CVCL:L791', (136, 140))	('MP55', 'Var', (120, 124))	('MP77', 'Var', (126, 130))	('MP34', 'Var', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('PD', 'Disease', 'MESH:D010300', (2, 4))
65421	29774094	The principal modifications to the MAPK pathway (Figure 6A) observed concerned p-ERK expression, which was increased by the administration of AZ6197 and decreased by the administration of AZD2014, either alone or in combination with selumetinib.	('AZD2014', 'Chemical', 'MESH:C585537', (188, 195))	('modifications', 'Reg', (14, 27))	('AZ6197', 'Var', (142, 148))	('expression', 'MPA', (85, 95))	('MAPK pathway', 'Pathway', (35, 47))	('increased', 'PosReg', (107, 116))	('ERK', 'Gene', '5594', (81, 84))	('ERK', 'Gene', (81, 84))	('MAPK', 'molecular_function', 'GO:0004707', ('35', '39'))	('decreased', 'NegReg', (153, 162))	('AZ6197', 'Chemical', '-', (142, 148))	('AZD2014', 'Var', (188, 195))	('selumetinib', 'Chemical', 'MESH:C517975', (233, 244))	('ERK', 'molecular_function', 'GO:0004707', ('81', '84'))
65435	29774094	Indeed, all the PDXs tested had GNAQ/11 mutations, but only one had a BAP1 mutation and two had SF3B1mutations.	('GNAQ', 'Gene', (32, 36))	('BAP1', 'Gene', '8314', (70, 74))	('SF3B1', 'Gene', (96, 101))	('GNAQ', 'Gene', '2776', (32, 36))	('mutations', 'Var', (40, 49))	('BAP1', 'Gene', (70, 74))	('SF3B1', 'Gene', '23451', (96, 101))	('PD', 'Disease', 'MESH:D010300', (16, 18))
65436	29774094	Thus, all the preclinical and clinical results suggest that, despite the presence of GNAQ or GNA11 mutations, targeting MEK activity is not sufficient for the effective treatment of metastatic UM.	('MEK', 'Gene', (120, 123))	('MEK', 'Gene', '5609', (120, 123))	('GNAQ', 'Gene', (85, 89))	('mutations', 'Var', (99, 108))	('GNAQ', 'Gene', '2776', (85, 89))	('MEK activity', 'molecular_function', 'GO:0004708', ('120', '132'))	('metastatic UM', 'Disease', (182, 195))	('GNA11', 'Gene', '2767', (93, 98))	('GNA11', 'Gene', (93, 98))
65443	29774094	In our preclinical studies, AZ6197 and AZD2014 displayed significant efficacy in two PDXs.	('PD', 'Disease', 'MESH:D010300', (85, 87))	('AZ6197', 'Chemical', '-', (28, 34))	('AZD2014', 'Chemical', 'MESH:C585537', (39, 46))	('AZ6197', 'Var', (28, 34))	('AZD2014', 'Var', (39, 46))
65444	29774094	These results provide the first evidence for the efficacy of ERK inhibition for treating uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('ERK', 'Gene', '5594', (61, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (89, 103))	('uveal melanoma', 'Disease', (89, 103))	('uveal melanoma', 'Disease', 'MESH:C536494', (89, 103))	('inhibition', 'Var', (65, 75))	('ERK', 'Gene', (61, 64))	('ERK', 'molecular_function', 'GO:0004707', ('61', '64'))
65461	29774094	They were obtained from primary tumors (MP38, MP41, MP46, and MP65), or from metastases from patients (MM66 and MM28).	('MM28', 'Gene', '79148', (112, 116))	('MP38', 'Var', (40, 44))	('metastases', 'Disease', 'MESH:D009362', (77, 87))	('MM28', 'Gene', (112, 116))	('metastases', 'Disease', (77, 87))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('MP46', 'Var', (52, 56))	('MP41', 'Var', (46, 50))	('tumors', 'Disease', (32, 38))	('MP65', 'Var', (62, 66))	('patients', 'Species', '9606', (93, 101))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
65465	29774094	Five UM PDXs were used in this study: MP34, MP46, MP55, MP77, and MM26.	('MP46', 'Var', (44, 48))	('MP55', 'Var', (50, 54))	('MP34', 'Var', (38, 42))	('MM26', 'Var', (66, 70))	('MM26', 'CellLine', 'CVCL:L791', (66, 70))	('MP77', 'Var', (56, 60))	('PD', 'Disease', 'MESH:D010300', (8, 10))
65492	29774094	Lysates were resolved by electrophoresis in 4-12% TGX gels (Bio-Rad ), and the resulting bands were transferred onto nitrocellulose membranes (Bio-Rad ) and probed with rabbit antibodies against GAPDH (Cell Signaling Technology, #2118), P-p44/42 MAPK (Thr202/Tyr204) (Cell Signaling Technology, #4370), p44/42 MAPK (Cell Signaling Technology, #9102), S6 (Cell Signaling Technology, #2117), P-S6 (Ser235/236) (Cell Signaling Technology, #2211), MEK1/2 (Cell Signaling Technology, #9126), p-MEK1/2 ser217/221) (Cell Signaling Technology, #9154), AKT (Cell Signaling Technology, #9272) and P-AKT (ser473) (Cell Signaling Technology, #4058).	('Rad', 'biological_process', 'GO:1990116', ('147', '150'))	('AKT', 'Gene', '207', (544, 547))	('GAPDH', 'Gene', (195, 200))	('Signaling', 'biological_process', 'GO:0023052', ('554', '563'))	('Signaling', 'biological_process', 'GO:0023052', ('457', '466'))	('ser', 'cellular_component', 'GO:0005790', ('496', '499'))	('P-S6', 'Gene', '338413', (390, 394))	('Ser', 'cellular_component', 'GO:0005790', ('396', '399'))	('Signaling', 'biological_process', 'GO:0023052', ('321', '330'))	('MEK1', 'molecular_function', 'GO:0004708', ('444', '448'))	('MEK1', 'molecular_function', 'GO:0004708', ('489', '493'))	('AKT', 'Gene', '207', (589, 592))	('Rad', 'biological_process', 'GO:1990116', ('64', '67'))	('ser', 'cellular_component', 'GO:0005790', ('594', '597'))	('rabbit', 'Species', '9986', (169, 175))	('Rad', 'Gene', '6236', (64, 67))	('Rad', 'Gene', (64, 67))	('p44', 'Gene', (303, 306))	('P-S6', 'Gene', (390, 394))	('p44', 'Gene', '10561', (303, 306))	('p44', 'Gene', (239, 242))	('Signaling', 'biological_process', 'GO:0023052', ('273', '282'))	('Signaling', 'biological_process', 'GO:0023052', ('414', '423'))	('AKT', 'Gene', (544, 547))	('MAPK', 'molecular_function', 'GO:0004707', ('246', '250'))	('p44', 'Gene', '10561', (239, 242))	('p-MEK1/2 ser217/221', 'Var', (487, 506))	('GAPDH', 'Gene', '2597', (195, 200))	('MAPK', 'molecular_function', 'GO:0004707', ('310', '314'))	('Signaling', 'biological_process', 'GO:0023052', ('360', '369'))	('Signaling', 'biological_process', 'GO:0023052', ('514', '523'))	('AKT', 'Gene', (589, 592))	('Rad', 'Gene', '6236', (147, 150))	('Signaling', 'biological_process', 'GO:0023052', ('207', '216'))	('Signaling', 'biological_process', 'GO:0023052', ('608', '617'))	('Rad', 'Gene', (147, 150))
65496	29774094	The same method was used to quantify P-S6/S6, P-p44/42MAPK/p44/42MAPK and P-AKT/AKT.	('MAPK', 'molecular_function', 'GO:0004707', ('54', '58'))	('P-S6', 'Gene', (37, 41))	('AKT', 'Gene', '207', (76, 79))	('AKT', 'Gene', '207', (80, 83))	('AKT', 'Gene', (76, 79))	('AKT', 'Gene', (80, 83))	('P-S6', 'Gene', '338413', (37, 41))	('MAPK', 'molecular_function', 'GO:0004707', ('65', '69'))	('P-p44/42MAPK/p44/42MAPK', 'Var', (46, 69))
65521	27110415	The case patient was of protooncogene braf mutation wild type and went on to receive four cycles of the immunotherapy, ipilimumab in early 2014, which were tolerated well.	('braf', 'Gene', (38, 42))	('mutation', 'Var', (43, 51))	('braf', 'Gene', '673', (38, 42))	('patient', 'Species', '9606', (9, 16))	('ipilimumab', 'Chemical', 'MESH:D000074324', (119, 129))
65536	27110415	Factors predictive of metastasis from uveal melanoma include tumour thickness and genetic aberrations.	('uveal melanoma', 'Disease', (38, 52))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('metastasis', 'CPA', (22, 32))	('tumour thickness', 'Disease', (61, 77))	('tumour thickness', 'Disease', 'MESH:D009369', (61, 77))	('genetic aberrations', 'Var', (82, 101))	('uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('uveal melanoma', 'Disease', 'MESH:C536494', (38, 52))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
65537	27110415	found for each millimeter increase in tumour thickness that there was a resultant increased risk of metastasis of 1.06.	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour thickness', 'Disease', (38, 54))	('millimeter', 'Var', (15, 25))	('tumour thickness', 'Disease', 'MESH:D009369', (38, 54))	('metastasis', 'CPA', (100, 110))
65539	27110415	Uveal melanomas also differ from cutaneous lesions in their expression of genetic abnormalities, in particular, anomalies of chromosomes 1, 3, 6, and 8.	('genetic abnormalities', 'Disease', (74, 95))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanomas', 'Disease', (6, 15))	('anomalies', 'Var', (112, 121))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('genetic abnormalities', 'Disease', 'MESH:D030342', (74, 95))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))
65542	27110415	A further difference between uveal melanoma and cutaneous melanoma is that the latter frequently carries oncogenic driver mutations in the proteins Raf and Ras, which results in constitutively activated mitogen associated protein kinase (MAPK) pathway signalling and leads to tumorigenesis, cellular proliferation, and dissemination.	('cutaneous melanoma', 'Disease', (48, 66))	('tumorigenesis', 'CPA', (276, 289))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (48, 66))	('dissemination', 'CPA', (319, 332))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 66))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('Raf', 'Gene', '22882', (148, 151))	('cellular proliferation', 'CPA', (291, 313))	('protein', 'cellular_component', 'GO:0003675', ('222', '229'))	('activated', 'PosReg', (193, 202))	('leads to', 'Reg', (267, 275))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('Raf', 'Gene', (148, 151))	('Ras', 'Gene', (156, 159))	('uveal melanoma', 'Disease', (29, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('signalling', 'biological_process', 'GO:0023052', ('252', '262'))	('mutations', 'Var', (122, 131))	('MAPK', 'molecular_function', 'GO:0004707', ('238', '242'))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
65544	27110415	Other genetic oncogenic drivers include GNAQ, GNA11, BAP1 mutations, and PTEN (phosphatase and tensin homolog) loss.	('mutations', 'Var', (58, 67))	('PTEN', 'Gene', (73, 77))	('GNAQ', 'Gene', (40, 44))	('loss', 'NegReg', (111, 115))	('PTEN', 'Gene', '5728', (73, 77))	('GNA11', 'Gene', '2767', (46, 51))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('79', '109'))	('GNAQ', 'Gene', '2776', (40, 44))	('BAP1', 'Gene', '8314', (53, 57))	('phosphatase', 'molecular_function', 'GO:0016791', ('79', '90'))	('GNA11', 'Gene', (46, 51))	('BAP1', 'Gene', (53, 57))
65545	27110415	Whether these mutations actually correlate with overall patient outcome is unconfirmed.	('patient', 'Species', '9606', (56, 63))	('correlate', 'Reg', (33, 42))	('mutations', 'Var', (14, 23))
65562	23694694	Lack of SF3B1 R625 mutations in cutaneous melanoma Melanoma is a deadly disease affecting people worldwide.	('melanoma', 'Disease', (42, 50))	('Lack', 'NegReg', (0, 4))	('SF3B1', 'Gene', '23451', (8, 13))	('people', 'Species', '9606', (90, 96))	('Melanoma', 'Disease', 'MESH:D008545', (51, 59))	('Melanoma', 'Disease', (51, 59))	('deadly disease', 'Disease', (65, 79))	('deadly disease', 'Disease', 'MESH:D004194', (65, 79))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (32, 50))	('R625', 'Var', (14, 18))	('SF3B1', 'Gene', (8, 13))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
65564	23694694	Hotspot mutations in SF3B1 were recently reported in uveal melanoma.	('reported', 'Reg', (41, 49))	('mutations', 'Var', (8, 17))	('SF3B1', 'Gene', (21, 26))	('uveal melanoma', 'Disease', (53, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (53, 67))	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('SF3B1', 'Gene', '23451', (21, 26))
65569	23694694	High numbers of BRAF and NRAS mutations were identified with frequencies varying according to melanoma subtype.	('BRAF', 'Gene', '673', (16, 20))	('BRAF', 'Gene', (16, 20))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma subtype', 'Disease', (94, 110))	('melanoma subtype', 'Disease', 'MESH:D008545', (94, 110))	('mutations', 'Var', (30, 39))	('NRAS', 'Gene', (25, 29))	('NRAS', 'Gene', '4893', (25, 29))
65571	23694694	We conclude that recurrent mutations in codon 625 of SF3B1 as reported in uveal melanoma are not present in most types of cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('mutations in codon 625', 'Var', (27, 49))	('SF3B1', 'Gene', '23451', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (122, 140))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('cutaneous melanoma', 'Disease', (122, 140))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (122, 140))	('uveal melanoma', 'Disease', (74, 88))	('SF3B1', 'Gene', (53, 58))
65577	23694694	Activating driver mutations in genes such as NRAS and BRAF were identified in cutaneous melanoma.	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('NRAS', 'Gene', (45, 49))	('cutaneous melanoma', 'Disease', (78, 96))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (78, 96))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (78, 96))	('NRAS', 'Gene', '4893', (45, 49))	('mutations', 'Var', (18, 27))
65581	23694694	However there is some overlap in tumor biology as ~80% of blue nevi, which are benign melanocytic tumors of the skin, also harbor GNAQ or GNA11 mutations, and BAP1 mutations can be found in both cutaneous nevi and cutaneous melanoma.	('nevi', 'Phenotype', 'HP:0003764', (63, 67))	('BAP1', 'Gene', '8314', (159, 163))	('nevi', 'Phenotype', 'HP:0003764', (205, 209))	('cutaneous melanoma', 'Disease', (214, 232))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (214, 232))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (214, 232))	('tumor', 'Disease', (98, 103))	('mutations', 'Var', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('blue nevi', 'Disease', (58, 67))	('GNA11', 'Gene', (138, 143))	('tumor', 'Disease', (33, 38))	('BAP1', 'Gene', (159, 163))	('GNAQ', 'Gene', '2776', (130, 134))	('blue nevi', 'Phenotype', 'HP:0100814', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('GNAQ', 'Gene', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('harbor', 'Reg', (123, 129))	('cutaneous nevi', 'Disease', (195, 209))	('benign melanocytic tumors of the skin', 'Disease', (79, 116))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors of the skin', 'Phenotype', 'HP:0008069', (98, 116))	('benign melanocytic tumors of the skin', 'Disease', 'MESH:D012878', (79, 116))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('GNA11', 'Gene', '2767', (138, 143))	('melanocytic tumors of the skin', 'Phenotype', 'HP:0002861', (86, 116))
65584	23694694	SF3B1 mutations had been previously detected in myeloid malignancies such as CLL (chronic lymphoid leukemia) and MDS (myelodysplastic syndrome) and also reported in breast cancer.	('myeloid malignancies', 'Disease', (48, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('detected', 'Reg', (36, 44))	('MDS', 'Disease', 'MESH:D009190', (113, 116))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('SF3B1', 'Gene', (0, 5))	('chronic lymphoid leukemia', 'Disease', 'MESH:D007945', (82, 107))	('breast cancer', 'Disease', (165, 178))	('lymphoid leukemia', 'Phenotype', 'HP:0005526', (90, 107))	('myelodysplastic syndrome', 'Disease', (118, 142))	('MDS', 'Disease', (113, 116))	('CLL', 'Disease', (77, 80))	('reported', 'Reg', (153, 161))	('mutations', 'Var', (6, 15))	('SF3B1', 'Gene', '23451', (0, 5))	('chronic lymphoid leukemia', 'Disease', (82, 107))	('leukemia', 'Phenotype', 'HP:0001909', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (118, 142))	('CLL', 'Disease', 'MESH:D015451', (77, 80))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (118, 142))	('chronic lymphoid leukemia', 'Phenotype', 'HP:0005550', (82, 107))	('myeloid malignancies', 'Disease', 'MESH:D009369', (48, 68))
65585	23694694	SF3B1 is a splice factor, with mutations expected to result in altered pre mRNA splicing.	('mutations', 'Var', (31, 40))	('SF3B1', 'Gene', (0, 5))	('altered', 'Reg', (63, 70))	('pre mRNA splicing', 'MPA', (71, 88))	('SF3B1', 'Gene', '23451', (0, 5))	('pre mRNA splicing', 'biological_process', 'GO:0000398', ('71', '88'))	('pre', 'molecular_function', 'GO:0003904', ('71', '74'))
65586	23694694	The goal of our study was to analyze if SF3B1 mutations not only play a role in uveal, but also in cutaneous melanoma.	('SF3B1', 'Gene', (40, 45))	('mutations', 'Var', (46, 55))	('role', 'Reg', (72, 76))	('SF3B1', 'Gene', '23451', (40, 45))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('uveal', 'Disease', (80, 85))	('cutaneous melanoma', 'Disease', (99, 117))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (99, 117))	('play', 'Reg', (65, 69))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (99, 117))
65595	23694694	BRAF Exon 15 and NRAS Exon 1 and 2 were analyzed for presence of mutations by Sanger sequencing (Table 1).	('NRAS', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (0, 4))	('NRAS', 'Gene', '4893', (17, 21))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (65, 74))
65596	23694694	We identified 36 BRAF mutations (35 p.V600E, 1 p.V600K) and 19 NRAS mutations (11 p.Q61K, 3 p.Q61L, 5 p.Q61R).	('NRAS', 'Gene', '4893', (63, 67))	('p.V600K', 'Mutation', 'rs121913227', (47, 54))	('p.V600E', 'Mutation', 'rs113488022', (36, 43))	('p.Q61R', 'Mutation', 'rs11554290', (102, 108))	('p.Q61L', 'Mutation', 'rs11554290', (92, 98))	('BRAF', 'Gene', '673', (17, 21))	('p.Q61R', 'Var', (102, 108))	('p.V600E', 'Var', (36, 43))	('p.Q61K', 'Var', (82, 88))	('BRAF', 'Gene', (17, 21))	('p.Q61L', 'Var', (92, 98))	('p.Q61K', 'Mutation', 'rs121913254', (82, 88))	('p.V600K', 'Var', (47, 54))	('NRAS', 'Gene', (63, 67))
65598	23694694	Prevalence of BRAF and NRAS mutations varied by histologic subtype; ALM - 33% BRAF, 13% NRAS, NM - 42% BRAF, 25% NRAS, and SSM - 60% BRAF, 23% NRAS mutations.	('NRAS', 'Gene', (113, 117))	('BRAF', 'Gene', '673', (103, 107))	('NRAS', 'Gene', '4893', (23, 27))	('BRAF', 'Gene', (103, 107))	('BRAF', 'Gene', '673', (78, 82))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (78, 82))	('NRAS', 'Gene', (88, 92))	('BRAF', 'Gene', (133, 137))	('NRAS', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (14, 18))	('BRAF', 'Gene', (14, 18))	('NRAS', 'Gene', (23, 27))	('SSM', 'cellular_component', 'GO:1990843', ('123', '126'))	('ALM', 'Phenotype', 'HP:0012060', (68, 71))	('NRAS', 'Gene', '4893', (113, 117))	('SSM', 'Phenotype', 'HP:0012057', (123, 126))	('mutations', 'Var', (28, 37))	('NRAS', 'Gene', '4893', (88, 92))	('NRAS', 'Gene', '4893', (143, 147))	('NM', 'Phenotype', 'HP:0012058', (94, 96))
65603	23694694	The distribution of activating oncogene mutations in BRAF and NRAS in our cohort is comparable to those reported elsewhere.	('NRAS', 'Gene', '4893', (62, 66))	('activating', 'PosReg', (20, 30))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('mutations', 'Var', (40, 49))	('NRAS', 'Gene', (62, 66))
65604	23694694	Overall 65% of melanoma had a BRAF or NRAS mutation in a mutually exclusive pattern.	('NRAS', 'Gene', '4893', (38, 42))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('mutation', 'Var', (43, 51))	('melanoma', 'Disease', (15, 23))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('NRAS', 'Gene', (38, 42))
65605	23694694	Of the three melanoma subtypes analyzed in considerable numbers (SSM, NM, ALM), percentages of BRAF and NRAS mutations combined were highest in SSM reaching 82%, lower in NM with 67% and lowest in ALM with 46%.	('NRAS', 'Gene', '4893', (104, 108))	('highest', 'Reg', (133, 140))	('SSM', 'Phenotype', 'HP:0012057', (144, 147))	('ALM', 'Phenotype', 'HP:0012060', (74, 77))	('SSM', 'Phenotype', 'HP:0012057', (65, 68))	('ALM', 'Phenotype', 'HP:0012060', (197, 200))	('BRAF', 'Gene', '673', (95, 99))	('SSM', 'cellular_component', 'GO:1990843', ('144', '147'))	('NM', 'Phenotype', 'HP:0012058', (171, 173))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('BRAF', 'Gene', (95, 99))	('SSM', 'Disease', (144, 147))	('SSM', 'cellular_component', 'GO:1990843', ('65', '68'))	('mutations', 'Var', (109, 118))	('NRAS', 'Gene', (104, 108))	('melanoma subtype', 'Disease', (13, 29))	('NM', 'Phenotype', 'HP:0012058', (70, 72))	('melanoma subtype', 'Disease', 'MESH:D008545', (13, 29))
65608	23694694	However p.N505H (c.1513A > C) is listed as a "variant of unknown origin" in a gastrointestinal stromal tumor in the COSMIC database.	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (78, 108))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('p.N505H (c.1513A > C', 'Var', (8, 28))	('gastrointestinal stromal tumor', 'Disease', (78, 108))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (78, 108))	('p.N505H', 'Mutation', 'p.N505H', (8, 15))	('c.1513A > C', 'Mutation', 'c.1513A>C', (17, 28))
65609	23694694	The cutaneous ALM sample lacked mutations in BRAF or NRAS which could support a potential relevance, as typically KIT mutations are found to be mutually exclusive with BRAF and NRAS mutations.	('mutations', 'Var', (118, 127))	('NRAS', 'Gene', (177, 181))	('NRAS', 'Gene', (53, 57))	('mutations', 'Var', (32, 41))	('BRAF', 'Gene', (45, 49))	('NRAS', 'Gene', '4893', (177, 181))	('BRAF', 'Gene', '673', (45, 49))	('NRAS', 'Gene', '4893', (53, 57))	('BRAF', 'Gene', '673', (168, 172))	('BRAF', 'Gene', (168, 172))	('KIT', 'molecular_function', 'GO:0005020', ('114', '117'))	('ALM', 'Phenotype', 'HP:0012060', (14, 17))
65611	23694694	We obtained high quality sequencing results allowing analysis of exon 14 and in particular codon 625 of SF3B1 in 81 samples and found no mutations.	('SF3B1', 'Gene', (104, 109))	('SF3B1', 'Gene', '23451', (104, 109))	('codon 625', 'Var', (91, 100))
65613	23694694	In uveal melanomas, mutations were primarily found in tumors with a favorable prognosis.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanomas', 'Phenotype', 'HP:0002861', (9, 18))	('uveal melanomas', 'Disease', (3, 18))	('uveal melanomas', 'Phenotype', 'HP:0007716', (3, 18))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('uveal melanomas', 'Disease', 'MESH:C536494', (3, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('found', 'Reg', (45, 50))	('mutations', 'Var', (20, 29))	('tumors', 'Disease', (54, 60))
65614	23694694	Future studies could analyze if SF3B1 mutations occur in benign cutaneous melanocytic tumors (nevi) or potentially in sites other than in codon 603-641 of exon 14 of SF3B1.	('SF3B1', 'Gene', '23451', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('occur', 'Reg', (48, 53))	('benign cutaneous melanocytic tumors', 'Disease', 'MESH:D009508', (57, 92))	('SF3B1', 'Gene', '23451', (32, 37))	('benign cutaneous melanocytic tumors', 'Disease', (57, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('nevi', 'Phenotype', 'HP:0003764', (94, 98))	('SF3B1', 'Gene', (166, 171))	('mutations', 'Var', (38, 47))	('SF3B1', 'Gene', (32, 37))
65617	23694694	In contrast, genetic alterations in uveal melanoma such as GNAQ and GNA11 mutations were also found in selected cases of cutaneous melanoma and are frequently found in blue nevi (benign cutaneous melanocytic tumors).	('uveal melanoma', 'Disease', 'MESH:C536494', (36, 50))	('GNA11', 'Gene', '2767', (68, 73))	('uveal melanoma', 'Disease', (36, 50))	('GNAQ', 'Gene', '2776', (59, 63))	('uveal melanoma', 'Phenotype', 'HP:0007716', (36, 50))	('GNAQ', 'Gene', (59, 63))	('nevi', 'Phenotype', 'HP:0003764', (173, 177))	('found', 'Reg', (159, 164))	('blue nevi', 'Disease', (168, 177))	('GNA11', 'Gene', (68, 73))	('benign cutaneous melanocytic tumors', 'Disease', (179, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('found', 'Reg', (94, 99))	('blue nevi', 'Phenotype', 'HP:0100814', (168, 177))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('cutaneous melanoma', 'Disease', (121, 139))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (121, 139))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (121, 139))	('mutations', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('benign cutaneous melanocytic tumors', 'Disease', 'MESH:D009508', (179, 214))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
65618	23694694	BAP1 inactivating mutations are found in cutaneous nevi and melanoma, although considerably less frequently than in uveal melanoma.	('cutaneous nevi', 'Disease', (41, 55))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('nevi', 'Phenotype', 'HP:0003764', (51, 55))	('BAP1', 'Gene', (0, 4))	('found', 'Reg', (32, 37))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (116, 130))	('uveal melanoma', 'Disease', (116, 130))	('uveal melanoma', 'Disease', 'MESH:C536494', (116, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('BAP1', 'Gene', '8314', (0, 4))	('inactivating mutations', 'Var', (5, 27))
65619	23694694	Our current study would signify that SF3B1 mutations, occurring in almost 20% of uveal melanoma, do not play a major role in cutaneous melanoma.	('cutaneous melanoma', 'Disease', (125, 143))	('SF3B1', 'Gene', '23451', (37, 42))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (125, 143))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (125, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('uveal melanoma', 'Disease', (81, 95))	('mutations', 'Var', (43, 52))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('uveal melanoma', 'Disease', 'MESH:C536494', (81, 95))	('SF3B1', 'Gene', (37, 42))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
65707	23467474	Following PPV, adverse effects such as intraocular tumor dissemination, endophthalmitis, and hypotony have been described.	('intraocular tumor dissemination', 'Disease', 'MESH:D064090', (39, 70))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('hypotony', 'Disease', (93, 101))	('PPV', 'Var', (10, 13))	('endophthalmitis', 'Disease', 'MESH:D009877', (72, 87))	('endophthalmitis', 'Disease', (72, 87))	('hypotony', 'Disease', 'MESH:D015814', (93, 101))	('intraocular tumor dissemination', 'Disease', (39, 70))
65714	23467474	Additionally, in the present study we obtained a statistically significant improvement of VA after microincisional vitrectomy, indicating that visual function can be enhanced in these patients.	('patients', 'Species', '9606', (184, 192))	('visual function', 'CPA', (143, 158))	('improvement', 'PosReg', (75, 86))	('enhanced', 'PosReg', (166, 174))	('microincisional', 'Var', (99, 114))
65723	22834783	In uveal melanoma, monosomy 3 is the most common genetic alteration and somatic mutations of BAP1, a tumor suppressor gene, have been reported in nearly 50% of primary uveal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanomas', 'Phenotype', 'HP:0002861', (174, 183))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('101', '117'))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('uveal melanoma', 'Disease', (3, 17))	('BAP1', 'Gene', '8314', (93, 97))	('mutations', 'Var', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor suppressor', 'biological_process', 'GO:0051726', ('101', '117'))	('uveal melanomas', 'Disease', 'MESH:C536494', (168, 183))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (168, 182))	('BAP1', 'Gene', (93, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('reported', 'Reg', (134, 142))	('monosomy 3', 'Var', (19, 29))	('uveal melanomas', 'Disease', (168, 183))	('uveal melanomas', 'Phenotype', 'HP:0007716', (168, 183))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
65724	22834783	The retinoblastoma gene RB1 is the prototype tumor suppressor gene:mutations in RB1 alleles lead to inactivated RB protein and the development of retinoblastoma.	('RB1', 'Gene', (24, 27))	('retinoblastoma', 'Gene', (4, 18))	('tumor', 'Disease', (45, 50))	('RB1', 'Gene', (80, 83))	('retinoblastoma', 'Gene', (146, 160))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('RB1', 'Gene', '5925', (24, 27))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('45', '61'))	('RB1', 'Gene', '5925', (80, 83))	('RB', 'Chemical', 'MESH:D012413', (112, 114))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor suppressor', 'biological_process', 'GO:0051726', ('45', '61'))	('retinoblastoma', 'Gene', '5925', (4, 18))	('inactivated RB protein', 'Protein', (100, 122))	('retinoblastoma', 'Gene', '5925', (146, 160))	('retinoblastoma', 'Phenotype', 'HP:0009919', (4, 18))	('retinoblastoma', 'Phenotype', 'HP:0009919', (146, 160))	('RB', 'Chemical', 'MESH:D012413', (80, 82))	('mutations', 'Var', (67, 76))	('RB', 'Chemical', 'MESH:D012413', (24, 26))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))
65725	22834783	Immunoglobulin heavy chain (IgH) or T-cell receptor (TCR) gene rearrangement is observed in B-cell or T-cell primary vitreoretinal lymphoma, respectively.	('vitreoretinal lymphoma', 'Disease', (117, 139))	('TCR', 'Gene', '6962', (53, 56))	('TCR', 'cellular_component', 'GO:0042101', ('53', '56'))	('observed', 'Reg', (80, 88))	('rearrangement', 'Var', (63, 76))	('T-cell receptor', 'Gene', '6962', (36, 51))	('vitreoretinal lymphoma', 'Disease', 'MESH:D008223', (117, 139))	('B-cell', 'Disease', (92, 98))	('IgH', 'Gene', '3492', (28, 31))	('IgH', 'Gene', (28, 31))	('Immunoglobulin', 'molecular_function', 'GO:0003823', ('0', '14'))	('TCR', 'Gene', (53, 56))	('primary vitreoretinal lymphoma', 'Phenotype', 'HP:0030069', (109, 139))	('TCR', 'biological_process', 'GO:0006283', ('53', '56'))	('T-cell receptor', 'Gene', (36, 51))	('lymphoma', 'Phenotype', 'HP:0002665', (131, 139))
65738	22834783	Finally, genetic profiling of UM has led to the discovery of several somatic mutations in genes such as BAP1 and chromosomal anomalies that play a role in pathogenesis and prognosis.	('BAP1', 'Gene', '8314', (104, 108))	('chromosomal anomalies', 'Disease', 'MESH:D002869', (113, 134))	('chromosomal anomalies', 'Disease', (113, 134))	('BAP1', 'Gene', (104, 108))	('mutations', 'Var', (77, 86))	('pathogenesis', 'biological_process', 'GO:0009405', ('155', '167'))
65745	22834783	Certain mutations in MC1R have been shown to affect the risk of CM and were also studied in UM.	('affect', 'Reg', (45, 51))	('CM', 'Phenotype', 'HP:0012056', (64, 66))	('MC1R', 'Gene', '4157', (21, 25))	('MC1R', 'Gene', (21, 25))	('mutations', 'Var', (8, 17))	('CM', 'Disease', 'MESH:D009202', (64, 66))
65746	22834783	One large study consisting of 350 UM patients and 133 controls detected eight MC1R variants (V60L, D84E, V92M, R151C, I155T, R160H, R163Q, and D294H), but found no significant difference in the frequencies of these variants between those with or without UM.	('V92M', 'Var', (105, 109))	('D84E', 'Var', (99, 103))	('R160H', 'Var', (125, 130))	('MC1R', 'Gene', '4157', (78, 82))	('I155T', 'Mutation', 'rs1110400', (118, 123))	('MC1R', 'Gene', (78, 82))	('patients', 'Species', '9606', (37, 45))	('D294H', 'Mutation', 'rs1805009', (143, 148))	('I155T', 'Var', (118, 123))	('V60L', 'Mutation', 'rs1805005', (93, 97))	('R151C', 'Mutation', 'rs1805007', (111, 116))	('V92M', 'Mutation', 'rs2228479', (105, 109))	('R163Q', 'Var', (132, 137))	('D84E', 'Mutation', 'rs1805006', (99, 103))	('D294H', 'Var', (143, 148))	('R160H', 'Mutation', 'p.R160H', (125, 130))	('R163Q', 'Mutation', 'rs885479', (132, 137))	('V60L', 'Var', (93, 97))	('R151C', 'Var', (111, 116))
65747	22834783	These results have been confirmed in other studies, which demonstrate that MC1R variants do not play a significant role in susceptibility to develop UM.	('MC1R', 'Gene', '4157', (75, 79))	('MC1R', 'Gene', (75, 79))	('variants', 'Var', (80, 88))
65751	22834783	Therefore, current studies suggest that the MC1R variants are not primarily responsible for UM susceptibility; however, heritable phenotypic features dictated by melanin appear to affect the development of this condition.	('affect', 'Reg', (180, 186))	('variants', 'Var', (49, 57))	('development', 'CPA', (191, 202))	('MC1R', 'Gene', '4157', (44, 48))	('MC1R', 'Gene', (44, 48))	('melanin', 'Chemical', 'MESH:D008543', (162, 169))
65756	22834783	Of note, 20-40% of familial cases of CM are related to CDKN2A mutations disrupting p16, while ARF and CDK4 germline mutations are far less common.	('CDKN2A', 'Gene', '1029', (55, 61))	('p16', 'Gene', '1029', (83, 86))	('ARF', 'Gene', '1029', (94, 97))	('CDK4', 'Gene', '1019', (102, 106))	('CDK4', 'Gene', (102, 106))	('CM', 'Disease', 'MESH:D009202', (37, 39))	('p16', 'Gene', (83, 86))	('disrupting', 'NegReg', (72, 82))	('CDK', 'molecular_function', 'GO:0004693', ('102', '105'))	('ARF', 'Gene', (94, 97))	('CDKN2A', 'Gene', (55, 61))	('mutations', 'Var', (62, 71))	('CM', 'Phenotype', 'HP:0012056', (37, 39))
65757	22834783	Somatic changes and allelic imbalance at this locus have been demonstrated in sporadic cases of UM, and in 30% of UM, expression of p16 is reduced via promoter hypermethylation, which only strengthens the hypothesis that germline mutations may also exist in CDKN2A.	('imbalance', 'Phenotype', 'HP:0002172', (28, 37))	('p16', 'Gene', '1029', (132, 135))	('promoter hypermethylation', 'Var', (151, 176))	('CDKN2A', 'Gene', (258, 264))	('reduced', 'NegReg', (139, 146))	('p16', 'Gene', (132, 135))	('CDKN2A', 'Gene', '1029', (258, 264))	('expression', 'MPA', (118, 128))
65758	22834783	A CDKN2A germline mutation at exon 2 (199 GA) leading to CDKN2A Gly67Ser and ARF Arg81Gln was identified in one family wherein the proband was diagnosed with UM at the age of 47 and the proband's sister and daughter had CM.	('ARF', 'Gene', (77, 80))	('CDKN2A', 'Gene', (57, 63))	('CDKN2A', 'Gene', (2, 8))	('CDKN2A', 'Gene', '1029', (2, 8))	('CM', 'Disease', 'MESH:D009202', (220, 222))	('CDKN2A', 'Gene', '1029', (57, 63))	('Arg81Gln', 'SUBSTITUTION', 'None', (81, 89))	('CM', 'Phenotype', 'HP:0012056', (220, 222))	('Gly67Ser', 'Var', (64, 72))	('ARF', 'Gene', '1029', (77, 80))	('Ser', 'cellular_component', 'GO:0005790', ('69', '72'))	('Arg81Gln', 'Var', (81, 89))	('Gly67Ser', 'SUBSTITUTION', 'None', (64, 72))
65759	22834783	Another germline mutation in exon 1 of CDKN2A has also been reported in an individual originally diagnosed with UM at the age of 59 but with no family history of UM or CM.	('CDKN2A', 'Gene', (39, 45))	('CM', 'Disease', 'MESH:D009202', (168, 170))	('CDKN2A', 'Gene', '1029', (39, 45))	('CM', 'Phenotype', 'HP:0012056', (168, 170))	('germline mutation in', 'Var', (8, 28))	('reported', 'Reg', (60, 68))
65765	22834783	BAP1 is hypothesized to be a tumor suppressor gene and somatic mutations in this gene have been associated not only with UM but also with breast and lung cancers.	('mutations', 'Var', (63, 72))	('lung cancers', 'Phenotype', 'HP:0100526', (149, 161))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('BAP1', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('associated', 'Reg', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('breast and lung cancers', 'Disease', 'MESH:D001943', (138, 161))	('tumor suppressor', 'biological_process', 'GO:0051726', ('29', '45'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('29', '45'))	('tumor', 'Disease', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('BAP1', 'Gene', '8314', (0, 4))
65766	22834783	In UM, monosomy 3 is both the most common genetic alteration and is associated with tumor aggressiveness.	('associated', 'Reg', (68, 78))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (84, 104))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('monosomy 3', 'Var', (7, 17))	('tumor aggressiveness', 'Disease', (84, 104))	('aggressiveness', 'Phenotype', 'HP:0000718', (90, 104))
65768	22834783	Thus, recent studies have focused on investigating whether germline mutations in the BAP1 gene occur in patients with UM, especially in those with a strong hereditary risk of cancer.	('BAP1', 'Gene', (85, 89))	('occur', 'Reg', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('BAP1', 'Gene', '8314', (85, 89))	('patients', 'Species', '9606', (104, 112))	('germline mutations', 'Var', (59, 77))
65769	22834783	One study identified a single patient with a germline BAP1 mutation; however, no family history was available.	('BAP1', 'Gene', '8314', (54, 58))	('patient', 'Species', '9606', (30, 37))	('BAP1', 'Gene', (54, 58))	('germline', 'Var', (45, 53))
65771	22834783	Several family members of this patient were identified as having this mutation and had developed tumors, including UM, lung adenocarcinoma, and meningioma.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('meningioma', 'Disease', (144, 154))	('patient', 'Species', '9606', (31, 38))	('tumors', 'Disease', (97, 103))	('lung adenocarcinoma', 'Disease', (119, 138))	('meningioma', 'Phenotype', 'HP:0002858', (144, 154))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (119, 138))	('mutation', 'Var', (70, 78))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('meningioma', 'Disease', 'MESH:D008577', (144, 154))
65773	22834783	Currently, it appears that germline mutations in BAP1 are responsible for only a small subset of hereditary UM; thus, the search for other contributory genes continues.	('hereditary UM', 'Disease', (97, 110))	('BAP1', 'Gene', (49, 53))	('responsible', 'Reg', (58, 69))	('germline mutations', 'Var', (27, 45))	('BAP1', 'Gene', '8314', (49, 53))
65774	22834783	It was established in the 1990s that germline mutations of BRCA1/BRCA2 genes correlate with an increased risk of breast and ovarian cancer.	('BRCA1', 'Gene', '672', (59, 64))	('BRCA2', 'Gene', '675', (65, 70))	('germline mutations', 'Var', (37, 55))	('BRCA1', 'Gene', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('ovarian cancer', 'Phenotype', 'HP:0100615', (124, 138))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (113, 138))	('BRCA2', 'Gene', (65, 70))
65775	22834783	The protein products of these genes are often involved in processes such as DNA repair; thus, mutations may lead to increased risk of other cancers as well.	('mutations', 'Var', (94, 103))	('N', 'Chemical', 'MESH:D009584', (77, 78))	('DNA repair', 'biological_process', 'GO:0006281', ('76', '86'))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('lead to', 'Reg', (108, 115))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
65777	22834783	This observation strengthens the hypothesis that germline mutations in BRCA genes may be associated with UM.	('associated', 'Reg', (89, 99))	('germline mutations', 'Var', (49, 67))	('BRCA', 'Gene', (71, 75))	('BRCA', 'Gene', '672', (71, 75))
65779	22834783	One study found 2 cases of UM from 468 BRCA germline mutation carriers; interestingly, one case was a BRCA1 mutation and the other was a BRCA2 mutation.	('BRCA', 'Gene', (39, 43))	('BRCA1', 'Gene', (102, 107))	('BRCA', 'Gene', (137, 141))	('BRCA2', 'Gene', '675', (137, 142))	('BRCA', 'Gene', (102, 106))	('BRCA1', 'Gene', '672', (102, 107))	('BRCA2', 'Gene', (137, 142))	('mutation', 'Var', (108, 116))	('BRCA', 'Gene', '672', (39, 43))	('BRCA', 'Gene', '672', (137, 141))	('BRCA', 'Gene', '672', (102, 106))
65780	22834783	report that in a cohort of 490 families with germline BRCA1/BRCA2 mutations, 2 carriers of pathogenic BRCA2 mutations had confirmed cases of UM.	('mutations', 'Var', (66, 75))	('BRCA2', 'Gene', (60, 65))	('BRCA2', 'Gene', (102, 107))	('BRCA1', 'Gene', '672', (54, 59))	('BRCA2', 'Gene', '675', (60, 65))	('BRCA2', 'Gene', '675', (102, 107))	('BRCA1', 'Gene', (54, 59))
65781	22834783	Both of these studies suggest that increased risk of UM may be associated with germline BRCA mutations, particularly in BRCA2.	('BRCA', 'Gene', (120, 124))	('mutations', 'Var', (93, 102))	('germline', 'Var', (79, 87))	('BRCA2', 'Gene', (120, 125))	('BRCA', 'Gene', '672', (88, 92))	('BRCA', 'Gene', '672', (120, 124))	('BRCA2', 'Gene', '675', (120, 125))	('BRCA', 'Gene', (88, 92))
65783	22834783	Neurofibromatosis (NF1; von Recklinghausen syndrome) is an autosomal dominant condition associated with a mutation in NF1.	('NF1', 'Gene', '4763', (118, 121))	('NF1', 'Gene', (19, 22))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (0, 17))	('mutation', 'Var', (106, 114))	('NF1', 'Gene', '4763', (19, 22))	('Neurofibromatosis', 'Disease', 'MESH:C537392', (0, 17))	('associated', 'Reg', (88, 98))	('von Recklinghausen syndrome', 'Disease', (24, 51))	('Neurofibromatosis', 'Disease', (0, 17))	('von Recklinghausen syndrome', 'Disease', 'MESH:C537392', (24, 51))	('NF1', 'Gene', (118, 121))
65788	22834783	One study examined the status of the NF1 tumor suppressor locus in UM and demonstrated NF1 deletions and decreased expression of neurofibromin in 38 samples of UM.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('NF1', 'Gene', '4763', (87, 90))	('tumor', 'Disease', (41, 46))	('deletions', 'Var', (91, 100))	('NF1', 'Gene', (37, 40))	('NF1', 'Gene', '4763', (37, 40))	('neurofibromin', 'Gene', '4763', (129, 142))	('expression', 'MPA', (115, 125))	('tumor suppressor', 'biological_process', 'GO:0051726', ('41', '57'))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('41', '57'))	('decreased', 'NegReg', (105, 114))	('NF1', 'Gene', (87, 90))	('neurofibromin', 'Gene', (129, 142))
65789	22834783	This study demonstrated a role for the NF1 gene in the pathogenesis of UM; however, whether or not germline NF1 mutations predispose to UM remains unclear.	('NF1', 'Gene', '4763', (108, 111))	('pathogenesis', 'biological_process', 'GO:0009405', ('55', '67'))	('UM', 'Disease', (71, 73))	('NF1', 'Gene', (39, 42))	('NF1', 'Gene', '4763', (39, 42))	('mutations', 'Var', (112, 121))	('NF1', 'Gene', (108, 111))
65816	22834783	Retinoblastoma is caused by the bi-allelic inactivation of the retinoblastoma susceptibility gene RB1.	('RB1', 'Gene', '5925', (98, 101))	('Retinoblastoma', 'Gene', '5925', (0, 14))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (0, 14))	('Retinoblastoma', 'Gene', (0, 14))	('retinoblastoma', 'Gene', (63, 77))	('bi-allelic inactivation', 'Var', (32, 55))	('retinoblastoma', 'Gene', '5925', (63, 77))	('RB1', 'Gene', (98, 101))	('retinoblastoma', 'Phenotype', 'HP:0009919', (63, 77))	('caused by', 'Reg', (18, 27))
65817	22834783	Cytogenetic deletions noted in retinoblastoma have assigned the genetic locus of the disease to q14 of chromosome 13 linked with polymorphic marker gene enzyme esterase D. More than 900 mutations have been reported in the RB1 gene, thus reflecting its mutational heterogeneity.	('chromosome', 'cellular_component', 'GO:0005694', ('103', '113'))	('retinoblastoma', 'Gene', '5925', (31, 45))	('mutations', 'Var', (186, 195))	('retinoblastoma', 'Gene', (31, 45))	('esterase D', 'Gene', '2098', (160, 170))	('retinoblastoma', 'Phenotype', 'HP:0009919', (31, 45))	('esterase D', 'Gene', (160, 170))	('RB1', 'Gene', (222, 225))	('RB1', 'Gene', '5925', (222, 225))
65819	22834783	RB1 mutations are found in the second malignant neoplasms seen in retinoblastoma as well as in the sporadic tumors of lungs, breast, and many others.	('RB1', 'Gene', '5925', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('breast', 'Disease', (125, 131))	('found', 'Reg', (18, 23))	('retinoblastoma', 'Gene', (66, 80))	('retinoblastoma', 'Gene', '5925', (66, 80))	('malignant neoplasms', 'Disease', 'MESH:D009369', (38, 57))	('neoplasm', 'Phenotype', 'HP:0002664', (48, 56))	('retinoblastoma', 'Phenotype', 'HP:0009919', (66, 80))	('malignant neoplasms', 'Disease', (38, 57))	('tumors of lungs', 'Phenotype', 'HP:0100526', (108, 123))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('lungs', 'Disease', (118, 123))	('mutations', 'Var', (4, 13))	('neoplasms', 'Phenotype', 'HP:0002664', (48, 57))	('RB1', 'Gene', (0, 3))
65822	22834783	Detection of the RB1 mutations has been an ongoing challenge for numerous reasons, which include the large size of the gene, mosaicims, mutational heterogeneity, and the presence of mutations in noncoding regions.	('RB1', 'Gene', '5925', (17, 20))	('RB1', 'Gene', (17, 20))	('mutations', 'Var', (21, 30))
65824	22834783	described a comprehensive and economical approach to detecting RB1 mutations in an effort to make this clinically more feasible.	('RB1', 'Gene', '5925', (63, 66))	('RB1', 'Gene', (63, 66))	('mutations', 'Var', (67, 76))
65826	22834783	attempted to correlate the mutations with the severity of the disease at presentation and found that the size of the RB1 gene deletion positively correlated with advanced stages at diagnosis, a higher chance of enucleation, and a higher incidence of aggressive histopathological features and metastasis as compared to splice or nonsense mutations.	('aggressive histopathological features', 'CPA', (250, 287))	('correlated', 'Reg', (146, 156))	('RB1', 'Gene', (117, 120))	('RB1', 'Gene', '5925', (117, 120))	('deletion', 'Var', (126, 134))	('enucleation', 'biological_process', 'GO:0090601', ('211', '222'))	('metastasis', 'CPA', (292, 302))
65827	22834783	showed that precise identification of the RB1 gene mutation helped in better management of subsequent siblings and relatives at risk.	('RB1', 'Gene', (42, 45))	('mutation', 'Var', (51, 59))	('RB1', 'Gene', '5925', (42, 45))
65828	22834783	showed how precise identification of the mutation helped in preimplantation diagnosis during in vitro fertilization (IVF), thereby successfully selecting against mutational carriers.	('mutation', 'Var', (41, 49))	('IVF', 'Disease', 'MESH:C537182', (117, 120))	('IVF', 'Disease', (117, 120))	('fertilization', 'biological_process', 'GO:0009566', ('102', '115'))
65839	22834783	Monoclonality is a hallmark of lymphomas, as evidenced by the expression of identical cellular surface markers and gene restriction observed in either immunoglobulin heavy/light chain (IgH/IgL) or T-cell receptor (TCR).	('T-cell receptor', 'Gene', (197, 212))	('TCR', 'Gene', '6962', (214, 217))	('IgL', 'Gene', (189, 192))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('151', '165'))	('IgL', 'molecular_function', 'GO:0033984', ('189', '192'))	('IgL', 'Gene', '3535', (189, 192))	('Monoclonality', 'Var', (0, 13))	('IgH', 'Gene', '3492', (185, 188))	('IgH', 'Gene', (185, 188))	('hallmark of lymphomas', 'Disease', 'MESH:D008223', (19, 40))	('T-cell receptor', 'Gene', '6962', (197, 212))	('lymphomas', 'Phenotype', 'HP:0002665', (31, 40))	('TCR', 'cellular_component', 'GO:0042101', ('214', '217'))	('TCR', 'Gene', (214, 217))	('lymphoma', 'Phenotype', 'HP:0002665', (31, 39))	('TCR', 'biological_process', 'GO:0006283', ('214', '217'))	('hallmark of lymphomas', 'Disease', (19, 40))
65842	22834783	These include cancer-related and relevant genes: B-cell lymphoma 2 (BCL2) ectopic expression, MYC (Myc, a regulator gene that codes for a transcription factor) dysregulation, phosphatase and tensin homolog (PTEN) deletion, human c-Rel proto-oncogene (REL) amplification, phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) mutation, and a number of mutated chromatin-modifying genes.	('PIK3CA', 'Gene', '5290', (328, 334))	('transcription factor', 'molecular_function', 'GO:0000981', ('138', '158'))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('175', '205'))	('BCL2', 'Gene', (68, 72))	('chromatin', 'cellular_component', 'GO:0000785', ('370', '379'))	('human', 'Species', '9606', (223, 228))	('mutation', 'Var', (336, 344))	('B-cell lymphoma 2', 'Gene', '596', (49, 66))	('deletion', 'Var', (213, 221))	('transcription', 'biological_process', 'GO:0006351', ('138', '151'))	('dysregulation', 'Var', (160, 173))	('lymphoma', 'Phenotype', 'HP:0002665', (56, 64))	('Myc', 'Gene', (99, 102))	('PIK3CA', 'Gene', (328, 334))	('PTEN', 'Gene', (207, 211))	('phosphatase', 'molecular_function', 'GO:0016791', ('175', '186'))	('MYC', 'Gene', (94, 97))	('c-Rel proto-oncogene', 'Gene', '5966', (229, 249))	('cell lymphoma', 'Phenotype', 'HP:0012191', (51, 64))	('amplification', 'Var', (256, 269))	('BCL2', 'molecular_function', 'GO:0015283', ('68', '72'))	('B-cell lymphoma 2', 'Gene', (49, 66))	('c-Rel proto-oncogene', 'Gene', (229, 249))	('cancer', 'Disease', (14, 20))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (49, 64))	('PTEN', 'Gene', '5728', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('BCL2', 'Gene', '596', (68, 72))	('phosphoinositide-3-kinase, catalytic, alpha polypeptide', 'Gene', '5290', (271, 326))	('MYC', 'Gene', '4609', (94, 97))	('Myc', 'Gene', '4609', (99, 102))
65843	22834783	The ABC subtype is characterized by constitutive nuclear factor (NF)-kappaB pathway activation due to mutations in tumor necrosis factor alpha-induced protein 3 (TNFAIP3), caspase recruitment domain family, member 11 (CARD11), and myeloid differentiation factor 88 (MYD88) genes.	('myeloid differentiation factor 88', 'Gene', (231, 264))	('TNFAIP3', 'Gene', '7128', (162, 169))	('CARD11', 'Gene', '84433', (218, 224))	('TNFAIP3', 'Gene', (162, 169))	('necrosis', 'biological_process', 'GO:0008219', ('121', '129'))	('myeloid differentiation factor 88', 'Gene', '4615', (231, 264))	('N', 'Chemical', 'MESH:D009584', (163, 164))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('115', '136'))	('mutations', 'Var', (102, 111))	('ABC', 'Disease', (4, 7))	('necrosis', 'biological_process', 'GO:0008220', ('121', '129'))	('tumor necrosis factor alpha-induced protein 3', 'Gene', (115, 160))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('necrosis', 'biological_process', 'GO:0070265', ('121', '129'))	('MYD88', 'Gene', '4615', (266, 271))	('necrosis', 'biological_process', 'GO:0019835', ('121', '129'))	('necrosis', 'biological_process', 'GO:0001906', ('121', '129'))	('N', 'Chemical', 'MESH:D009584', (65, 66))	('activation', 'PosReg', (84, 94))	('CARD11', 'Gene', (218, 224))	('tumor necrosis factor alpha-induced protein 3', 'Gene', '7128', (115, 160))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('MYD88', 'Gene', (266, 271))
65849	22834783	In this study, patients who are positive for BCL2 t(14;18) translocation are significantly younger than those who lack the translocation.	('BCL2', 'Gene', '596', (45, 49))	('patients', 'Species', '9606', (15, 23))	('translocation', 'Var', (59, 72))	('BCL2', 'Gene', (45, 49))	('BCL2', 'molecular_function', 'GO:0015283', ('45', '49'))
65851	22834783	Analysis of IgH variable region (VH) gene mutation reveals the cell origin and stage of tumor transformation.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('mutation', 'Var', (42, 50))	('VH', 'Gene', (33, 35))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('IgH', 'Gene', '3492', (12, 15))	('IgH', 'Gene', (12, 15))	('tumor', 'Disease', (88, 93))
65856	22834783	BCL6 is also considered a proto-oncogene; BCL6 mutations are the most frequently detected genetic alterations in both GCB and ABC DLBCL and high expression of BCL6 transcripts is detected in PVRL.	('BCL6', 'Gene', '604', (159, 163))	('BCL6', 'Gene', (42, 46))	('BCL6', 'Gene', (159, 163))	('mutations', 'Var', (47, 56))	('BCL6', 'Gene', '604', (0, 4))	('BCL6', 'Gene', '604', (42, 46))	('BCL6', 'Gene', (0, 4))
65857	22834783	Chromosomal translocation of BCL6 at 3q27 is the most characteristic genetic abnormality seen in DLBCL.	('BCL6', 'Gene', (29, 33))	('BCL6', 'Gene', '604', (29, 33))	('Chromosomal translocation', 'Var', (0, 25))	('DLBCL', 'Disease', (97, 102))
65859	22834783	Deregulated BCL6 expression suppresses p53 transcription, which prevents tumor cell apoptosis and permits lymphoma development.	('BCL6', 'Gene', '604', (12, 16))	('prevents', 'NegReg', (64, 72))	('Deregulated', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('permits lymphoma', 'Disease', (98, 114))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('permits lymphoma', 'Disease', 'MESH:D008223', (98, 114))	('suppresses', 'NegReg', (28, 38))	('tumor', 'Disease', (73, 78))	('BCL6', 'Gene', (12, 16))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('lymphoma', 'Phenotype', 'HP:0002665', (106, 114))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('transcription', 'biological_process', 'GO:0006351', ('43', '56'))	('transcription', 'MPA', (43, 56))
65860	22834783	Since NF-kappaB promotes proliferation and survival of lymphocytes, aberrant NF-kappaB activation drives lymphoma pathogenesis, particularly in ABC DLBCL and MALT lymphoma.	('lymphoma', 'Disease', 'MESH:D008223', (105, 113))	('activation', 'PosReg', (87, 97))	('lymphoma', 'Phenotype', 'HP:0002665', (163, 171))	('lymphoma', 'Phenotype', 'HP:0002665', (105, 113))	('MALT lymphoma', 'Disease', (158, 171))	('NF-kappaB', 'Gene', (77, 86))	('N', 'Chemical', 'MESH:D009584', (77, 78))	('ABC DLBCL', 'Disease', (144, 153))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('77', '97'))	('N', 'Chemical', 'MESH:D009584', (6, 7))	('pathogenesis', 'biological_process', 'GO:0009405', ('114', '126'))	('lymphoma', 'Disease', (163, 171))	('lymphoma', 'Disease', (105, 113))	('MALT lymphoma', 'Disease', 'MESH:D018442', (158, 171))	('aberrant', 'Var', (68, 76))	('lymphoma', 'Disease', 'MESH:D008223', (163, 171))
65862	22834783	In contrast, genetic rearrangement of NF-kappaB2 is responsible for alternative NF-kappaB pathway activation in DLBCL.	('NF-kappaB pathway', 'Pathway', (80, 97))	('DLBCL', 'Disease', (112, 117))	('NF-kappaB2', 'Gene', (38, 48))	('activation', 'PosReg', (98, 108))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('genetic rearrangement', 'Var', (13, 34))	('N', 'Chemical', 'MESH:D009584', (80, 81))
65878	22834783	TNF-alpha (rs1799724) CC genotype has been found to be associated with NHL and DLBCL in both population-based and case-control studies.	('TNF-alpha', 'Gene', (0, 9))	('NHL', 'Phenotype', 'HP:0012539', (71, 74))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('associated', 'Reg', (55, 65))	('rs1799724', 'Mutation', 'rs1799724', (11, 20))	('rs1799724) CC', 'Var', (11, 24))	('DLBCL', 'Disease', (79, 84))	('NHL', 'Disease', (71, 74))	('TNF-alpha', 'Gene', '7124', (0, 9))	('N', 'Chemical', 'MESH:D009584', (1, 2))
65899	33126538	Trametinib Induces the Stabilization of a Dual GNAQ p.Gly48Leu- and FGFR4 p.Cys172Gly-Mutated Uveal Melanoma.	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('p.Gly48Leu', 'Mutation', 'p.G48L', (52, 62))	('Melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('p.Gly48Leu-', 'Var', (52, 63))	('Melanoma', 'Disease', 'MESH:D008545', (100, 108))	('Melanoma', 'Disease', (100, 108))	('FGFR', 'molecular_function', 'GO:0005007', ('68', '72'))	('GNAQ', 'Gene', (47, 51))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('p.Cys172Gly-Mutated', 'Var', (74, 93))	('GNAQ', 'Gene', '2776', (47, 51))	('FGFR4', 'Gene', '2264', (68, 73))	('FGFR4', 'Gene', (68, 73))	('p.Cys172Gly', 'Mutation', 'p.C172G', (74, 85))
65901	33126538	Our molecular modelling study predicted that GNAQ p.Gly48Leu introduces new favorable interactions in its active conformation, whereas little or no impact is expected in its inactive form.	('favorable', 'PosReg', (76, 85))	('p.Gly48Leu', 'Mutation', 'p.G48L', (50, 60))	('p.Gly48Leu', 'Var', (50, 60))	('active conformation', 'MPA', (106, 125))	('interactions', 'Interaction', (86, 98))	('GNAQ', 'Gene', (45, 49))	('GNAQ', 'Gene', '2776', (45, 49))
65902	33126538	This strongly suggests that GNAQ p.Gly48Leu is a possible tumor-activating driver mutation, consequently triggering the MEK pathway.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('MEK', 'Gene', (120, 123))	('p.Gly48Leu', 'Var', (33, 43))	('triggering', 'Reg', (105, 115))	('GNAQ', 'Gene', '2776', (28, 32))	('p.Gly48Leu', 'Mutation', 'p.G48L', (33, 43))	('MEK', 'Gene', '5609', (120, 123))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('GNAQ', 'Gene', (28, 32))
65903	33126538	In addition, we also found an FGFR4 p.Cys172Gly mutation, which was predicted by molecular modelling analysis to lead to a gain of function by impacting the Ig-like domain 2 folding, which is involved in FGF binding and increases the stability of the homodimer.	('impacting', 'NegReg', (143, 152))	('FGF binding', 'molecular_function', 'GO:0017134', ('204', '215'))	('FGF', 'Gene', (204, 207))	('Ig-like domain 2 folding', 'MPA', (157, 181))	('FGF', 'Gene', (30, 33))	('stability of', 'MPA', (234, 246))	('increases', 'PosReg', (220, 229))	('FGF', 'Gene', '2246', (204, 207))	('FGF', 'Gene', '2246', (30, 33))	('p.Cys172Gly', 'Var', (36, 47))	('FGFR4', 'Gene', '2264', (30, 35))	('FGFR4', 'Gene', (30, 35))	('gain', 'PosReg', (123, 127))	('p.Cys172Gly', 'Mutation', 'p.C172G', (36, 47))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('binding', 'Interaction', (208, 215))
65908	33126538	Most pathologic mutants involve hotspots of Arg183 and Gln209 in Galphaq switch I and II regions, respectively.	('pathologic', 'Reg', (5, 15))	('Gln209', 'Chemical', '-', (55, 61))	('Galphaq', 'Gene', (65, 72))	('Arg183', 'Var', (44, 50))	('Arg183', 'Chemical', '-', (44, 50))	('Gln209', 'Var', (55, 61))
65910	33126538	GNAQ or GNA11 mutations are found in >90% of uveal melanomas, mutually exclusive of one another, most commonly affecting the Gln209 hotspot.	('Gln209', 'Var', (125, 131))	('uveal melanomas', 'Disease', 'MESH:C536494', (45, 60))	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('GNA11', 'Gene', (8, 13))	('GNAQ', 'Gene', '2776', (0, 4))	('GNA11', 'Gene', '2767', (8, 13))	('uveal melanomas', 'Disease', (45, 60))	('uveal melanomas', 'Phenotype', 'HP:0007716', (45, 60))	('GNAQ', 'Gene', (0, 4))	('affecting', 'Reg', (111, 120))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('mutations', 'Var', (14, 23))	('Gln209', 'Chemical', '-', (125, 131))
65914	33126538	FGFR members are quite often implicated in various types of cancers and FGFR4 mutations are present in 6% of melanoma.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR4', 'Gene', '2264', (72, 77))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('FGFR4', 'Gene', (72, 77))	('FGFR', 'Gene', (0, 4))	('implicated', 'Reg', (29, 39))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Disease', (109, 117))	('FGFR', 'Gene', '2260;2263;2261;2264', (0, 4))	('mutations', 'Var', (78, 87))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('FGFR', 'molecular_function', 'GO:0005007', ('72', '76'))	('FGFR', 'Gene', (72, 76))	('FGFR', 'Gene', '2260;2263;2261;2264', (72, 76))	('present', 'Reg', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
65915	33126538	GNAQ c.142_143delinsTT (p. Gly48Leu) and FGFR4 c.514T > G (p.Cys172Gly) were detected by next-generation sequencing (NGS) in a subcutaneous metastasis of a patient known to have a uveal melanoma, and presented in the weekly molecular tumor board (MTB) at Lausanne University Hospital (CHUV), Switzerland.	('tumor', 'Disease', (234, 239))	('uveal melanoma', 'Phenotype', 'HP:0007716', (180, 194))	('p.Cys172Gly', 'Mutation', 'p.C172G', (59, 70))	('c.142_143delinsTT', 'Mutation', 'c.142_143delinsTT', (5, 22))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('FGFR4', 'Gene', '2264', (41, 46))	('Gly48Leu', 'SUBSTITUTION', 'None', (27, 35))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('Gly48Leu', 'Var', (27, 35))	('c.514T > G', 'Var', (47, 57))	('MTB', 'cellular_component', 'GO:0015627', ('247', '250'))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('FGFR4', 'Gene', (41, 46))	('c.142_143delinsTT', 'Var', (5, 22))	('patient', 'Species', '9606', (156, 163))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('GNAQ', 'Gene', '2776', (0, 4))	('uveal melanoma', 'Disease', (180, 194))	('uveal melanoma', 'Disease', 'MESH:C536494', (180, 194))	('GNAQ', 'Gene', (0, 4))	('c.514T > G', 'Mutation', 'c.514T>G', (47, 57))
65919	33126538	Three switch regions (SW-I, SW-II, SW-III) in the RAS-like domain play crucial roles in the protein activity (Figure 1).	('SW-II', 'Chemical', '-', (35, 40))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('SW-II', 'Chemical', '-', (28, 33))	('SW-II', 'Var', (28, 33))	('protein', 'Protein', (92, 99))	('activity', 'MPA', (100, 108))
65920	33126538	Interestingly, GNAQ p.Gly48 corresponds to H/K/NRAS p.Gly12, a famous mutation hotspot in RAS (Figure S3).	('GNAQ', 'Gene', (15, 19))	('p.Gly48', 'Var', (20, 27))	('NRAS', 'Gene', (47, 51))	('Gly12', 'Chemical', '-', (54, 59))	('GNAQ', 'Gene', '2776', (15, 19))	('NRAS', 'Gene', '4893', (47, 51))	('Gly48', 'Chemical', '-', (22, 27))
65924	33126538	p.Gly48Val was found in cherry hemangiomas in the presence of a hotspot mutation in position Gln209, and no effect was attributed to it.	('cherry hemangiomas', 'Disease', (24, 42))	('Gln209', 'Chemical', '-', (93, 99))	('found', 'Reg', (15, 20))	('p.Gly48Val', 'Mutation', 'p.G48V', (0, 10))	('p.Gly48Val', 'Var', (0, 10))	('cherry hemangiomas', 'Disease', 'MESH:D006391', (24, 42))	('hemangiomas', 'Phenotype', 'HP:0001028', (31, 42))
65927	33126538	The third one is the nonsense mutation Gly48*, which means that no other residue is expressed after position 48, leading to a loss of function as essential domains are deleted.	('function', 'MPA', (134, 142))	('essential domains', 'MPA', (146, 163))	('Gly48', 'Chemical', '-', (39, 44))	('loss', 'NegReg', (126, 130))	('Gly48*', 'Var', (39, 45))
65935	33126538	In the inactive conformation, Gly48 is surrounded within 5 A by Gly46, Thr47, Glu49, Ser50, Lys52, the GDP phosphate tail, Glu234 and Arg247 (Figure 2a and Figure S10).	('Thr47', 'Chemical', '-', (71, 76))	('Gly48', 'Var', (30, 35))	('Ser50', 'Chemical', '-', (85, 90))	('Ser50', 'Var', (85, 90))	('Glu49', 'Var', (78, 83))	('Gly46', 'Var', (64, 69))	('Gly48', 'Chemical', '-', (30, 35))	('Thr47', 'Var', (71, 76))	('Glu49', 'Chemical', '-', (78, 83))	('Arg247', 'Var', (134, 140))	('Glu234', 'Var', (123, 129))	('Lys52', 'Var', (92, 97))	('Glu234', 'Chemical', '-', (123, 129))	('Gly46', 'Chemical', '-', (64, 69))	('GDP phosphate', 'Chemical', '-', (103, 116))	('Ser', 'cellular_component', 'GO:0005790', ('85', '88'))	('Arg247', 'Chemical', '-', (134, 140))	('Lys52', 'Chemical', '-', (92, 97))
65936	33126538	In the active conformation, the same residues are found in the vicinity of Gly48, together with other residues from SW-II: Gly208, Gln209 and Arg213 (Figure 2b and Figure S10).	('Gln209', 'Var', (131, 137))	('Gly208', 'Var', (123, 129))	('Gly48', 'Var', (75, 80))	('Gln209', 'Chemical', '-', (131, 137))	('Gly208', 'Chemical', '-', (123, 129))	('SW-II', 'Chemical', '-', (116, 121))	('Arg213', 'Var', (142, 148))	('Arg213', 'Chemical', '-', (142, 148))	('Gly48', 'Chemical', '-', (75, 80))
65939	33126538	Hence, we estimated the impact of the p.Gly48Leu mutation on the folding free energy of the Galphaq and Galphai/Galphaq structures with the FoldX software, a well-known and efficient program for predicting changes in free energy of folding upon mutations, whose predictive efficiency has been trained on a large set of mutants covering most of the existing structural environment.	('mutations', 'Var', (245, 254))	('p.Gly48Leu', 'Mutation', 'p.G48L', (38, 48))	('p.Gly48Leu', 'Var', (38, 48))
65940	33126538	These results indicate that mutation p.Gly48Leu is favorable to the structural stability of Galphaq both in the active and inactive conformations.	('structural stability', 'MPA', (68, 88))	('p.Gly48Leu', 'Mutation', 'p.G48L', (37, 47))	('Galphaq', 'Gene', (92, 99))	('p.Gly48Leu', 'Var', (37, 47))
65941	33126538	Analyses of the mutant structures generated by FoldX suggest that p.Gly48Leu active conformation is surrounded by the same residues as Gly48, plus Glu34 and Arg247 as well as Leu239, Val240 and Glu241 from SW-III.	('plus Glu34', 'Var', (142, 152))	('Gly48', 'Chemical', '-', (68, 73))	('SW-II', 'Chemical', '-', (206, 211))	('Leu239', 'Chemical', '-', (175, 181))	('Glu34', 'Chemical', '-', (147, 152))	('Gly48', 'Chemical', '-', (135, 140))	('Glu241', 'Var', (194, 200))	('Val240', 'Chemical', '-', (183, 189))	('Glu241', 'Chemical', '-', (194, 200))	('Arg247', 'Chemical', '-', (157, 163))	('Arg247', 'Var', (157, 163))	('Leu239', 'Var', (175, 181))	('Gly48', 'Var', (135, 140))	('p.Gly48Leu', 'Var', (66, 76))	('Val240', 'Var', (183, 189))	('p.Gly48Leu', 'Mutation', 'p.G48L', (66, 76))
65942	33126538	For each active conformation, the best conformer of the p.Gly48Leu mutant is oriented toward the SW-III region, which allows hydrophobic interactions with Leu239 and Val240 and thus contributes to stabilizing SW-III close to the active site, which favors the active conformation.	('interactions', 'Interaction', (137, 149))	('p.Gly48Leu', 'Var', (56, 66))	('Val240', 'Chemical', '-', (166, 172))	('Val240', 'Var', (166, 172))	('SW-II', 'Chemical', '-', (97, 102))	('stabilizing', 'MPA', (197, 208))	('Leu239', 'Var', (155, 161))	('SW-II', 'Chemical', '-', (209, 214))	('hydrophobic', 'MPA', (125, 136))	('Leu239', 'Chemical', '-', (155, 161))	('p.Gly48Leu', 'Mutation', 'p.G48L', (56, 66))
65944	33126538	In the active conformation, the median distances between Leu48 and Leu239, or Leu48 and Leu249 are 6.3 and 5.3 A, respectively (Figure 3, Figures S11 and S12).	('Leu239', 'Chemical', '-', (67, 73))	('Leu249', 'Var', (88, 94))	('Leu249', 'Chemical', '-', (88, 94))	('Leu48', 'Var', (78, 83))	('Leu48', 'Chemical', '-', (78, 83))	('Leu48', 'Var', (57, 62))	('Leu48', 'Chemical', '-', (57, 62))	('Leu239', 'Var', (67, 73))
65945	33126538	All these findings argue in favor of a possible activation of Galphaq as a result of the GNAQ p.Gly48Leu mutation.	('p.Gly48Leu', 'Mutation', 'p.G48L', (94, 104))	('Galphaq', 'Disease', (62, 69))	('p.Gly48Leu mutation', 'Var', (94, 113))	('GNAQ', 'Gene', '2776', (89, 93))	('GNAQ', 'Gene', (89, 93))	('activation', 'PosReg', (48, 58))
65947	33126538	Structural analysis shows that FGFR4 p.Cys172 is buried in Ig-like D2 in the ECD, and participates in a disulfide bridge with Cys224 from the same domain.	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('participates in', 'Reg', (86, 101))	('FGFR4', 'Gene', '2264', (31, 36))	('Cys224', 'Chemical', '-', (126, 132))	('FGFR4', 'Gene', (31, 36))	('disulfide bridge', 'MPA', (104, 120))	('disulfide', 'Chemical', 'MESH:D004220', (104, 113))	('p.Cys172', 'Var', (37, 45))	('Cys172', 'Chemical', '-', (39, 45))
65949	33126538	Due to glycine being unable to reproduce Cys172 interactions, mutation FGFR4 p.Cys172Gly is predicted to have a severe structural impact on Ig-like D2.	('glycine', 'Chemical', 'MESH:D005998', (7, 14))	('impact', 'Reg', (130, 136))	('FGFR', 'molecular_function', 'GO:0005007', ('71', '75'))	('Ig-like', 'MPA', (140, 147))	('Cys172', 'Chemical', '-', (41, 47))	('Cys172', 'Chemical', '-', (79, 85))	('mutation', 'Var', (62, 70))	('FGFR4', 'Gene', '2264', (71, 76))	('FGFR4', 'Gene', (71, 76))	('p.Cys172Gly', 'Var', (77, 88))	('p.Cys172Gly', 'Mutation', 'p.C172G', (77, 88))
65951	33126538	FGFR4 p.Cys172 is also conserved in the whole FGFR family and corresponds to Cys178, -179 and -176 in FGFR1-2 and -3, respectively (Figure 4c).	('FGFR', 'Gene', '2260;2263;2261;2264', (102, 106))	('Cys178', 'Chemical', '-', (77, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('FGFR', 'Gene', (102, 106))	('FGFR', 'Gene', (0, 4))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('FGFR', 'Gene', '2260;2263;2261;2264', (0, 4))	('FGFR4', 'Gene', (0, 5))	('FGFR1-2 and -3', 'Gene', '2260;2263;2261', (102, 116))	('FGFR', 'Gene', '2260;2263;2261;2264', (46, 50))	('Cys172', 'Chemical', '-', (8, 14))	('FGFR4', 'Gene', '2264', (0, 5))	('FGFR', 'Gene', (46, 50))	('p.Cys172', 'Var', (6, 14))	('Cys178', 'Var', (77, 83))
65952	33126538	FGFR1 p.Cys178Ser is already reported in the literature and predicted to lead to a gain of function as it demonstrates a constitutive activation of the FGFR1 dimer state in vitro.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('p.Cys178Ser', 'Var', (6, 17))	('p.Cys178Ser', 'Mutation', 'p.C178S', (6, 17))	('FGFR', 'molecular_function', 'GO:0005007', ('152', '156'))	('FGFR1', 'Gene', (0, 5))	('activation', 'PosReg', (134, 144))	('FGFR1', 'Gene', '2260', (0, 5))	('Ser', 'cellular_component', 'GO:0005790', ('14', '17'))	('dimer', 'MPA', (158, 163))	('FGFR1', 'Gene', (152, 157))	('function', 'MPA', (91, 99))	('FGFR1', 'Gene', '2260', (152, 157))
65953	33126538	There is no mutation reported for FGFR4 p.Cys179 and FGFR3 p.Cys176 positions.	('Cys179', 'Chemical', '-', (42, 48))	('FGFR4', 'Gene', (34, 39))	('FGFR3 p', 'Gene', '2261', (53, 60))	('FGFR', 'molecular_function', 'GO:0005007', ('53', '57'))	('p.Cys179', 'Var', (40, 48))	('Cys176', 'Chemical', '-', (61, 67))	('FGFR3 p', 'Gene', (53, 60))	('FGFR', 'molecular_function', 'GO:0005007', ('34', '38'))	('FGFR4', 'Gene', '2264', (34, 39))
65954	33126538	However, the recently reported mutation FGFR2 p.His167_Asn173del demonstrated oncogenic transformation in cells and was therefore predicted to lead to a gain of function.	('gain of function', 'PosReg', (153, 169))	('oncogenic transformation in', 'CPA', (78, 105))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('p.His167_Asn173del', 'Mutation', 'p.167_,173delN', (46, 64))	('FGFR2', 'Gene', '2263', (40, 45))	('FGFR2', 'Gene', (40, 45))	('p.His167_Asn173del', 'Var', (46, 64))
65955	33126538	Based on our analysis and by analogy with mutations FGFR1 p.Cys178Ser and FGFR2 p.His167_Asn173del, mutation FGFR4 p.Cys172Gly is predicted to be an activating mutation that triggers the MEK pathway, similarly to GNAQ p.G48L.	('GNAQ', 'Gene', '2776', (213, 217))	('FGFR2', 'Gene', (74, 79))	('GNAQ', 'Gene', (213, 217))	('MEK', 'Gene', '5609', (187, 190))	('FGFR1', 'Gene', '2260', (52, 57))	('p.Cys172Gly', 'Mutation', 'p.C172G', (115, 126))	('FGFR', 'molecular_function', 'GO:0005007', ('109', '113'))	('FGFR2', 'Gene', '2263', (74, 79))	('MEK', 'Gene', (187, 190))	('triggers', 'Reg', (174, 182))	('FGFR4', 'Gene', '2264', (109, 114))	('FGFR1', 'Gene', (52, 57))	('Ser', 'cellular_component', 'GO:0005790', ('66', '69'))	('p.Cys178Ser', 'Mutation', 'p.C178S', (58, 69))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('p.Cys172Gly', 'Var', (115, 126))	('p.G48L', 'Mutation', 'p.G48L', (218, 224))	('FGFR4', 'Gene', (109, 114))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))	('p.His167_Asn173del', 'Mutation', 'p.167_,173delN', (80, 98))
65971	33126538	Three potentially pathological mutations were detected: BAP1 c.68-4_84delinsGA (p.?	('c.68-4_84delinsGA', 'Mutation', 'c.68-4_84delinsGA', (61, 78))	('c.68-4_84delinsGA', 'Var', (61, 78))	('BAP1', 'Gene', '8314', (56, 60))	('BAP1', 'Gene', (56, 60))	('pathological', 'Reg', (18, 30))
65972	33126538	), FGFR4 c.514T > G (p.Cys172Gly) and GNAQ c.142_143delinsTT (p. Gly48Leu), with allelic frequencies of 82%, 47% and 41%, respectively (Table S4).	('FGFR4', 'Gene', (3, 8))	('GNAQ', 'Gene', '2776', (38, 42))	('c.514T > G', 'Var', (9, 19))	('Gly48Leu', 'SUBSTITUTION', 'None', (65, 73))	('p.Cys172Gly', 'Mutation', 'p.C172G', (21, 32))	('c.514T > G', 'Mutation', 'c.514T>G', (9, 19))	('c.142_143delinsTT', 'Var', (43, 60))	('Gly48Leu', 'Var', (65, 73))	('GNAQ', 'Gene', (38, 42))	('FGFR', 'molecular_function', 'GO:0005007', ('3', '7'))	('c.142_143delinsTT', 'Mutation', 'c.142_143delinsTT', (43, 60))	('FGFR4', 'Gene', '2264', (3, 8))
65975	33126538	The functional significance of the GNAQ mutation was described as uncertain in publicly available variant databases.	('mutation', 'Var', (40, 48))	('GNAQ', 'Gene', (35, 39))	('GNAQ', 'Gene', '2776', (35, 39))
65976	33126538	Consequently, molecular modelling was requested, which predicted a potential activating role of the GNAQ mutation.	('GNAQ', 'Gene', (100, 104))	('activating', 'PosReg', (77, 87))	('GNAQ', 'Gene', '2776', (100, 104))	('mutation', 'Var', (105, 113))
65981	33126538	So far, only a limited efficacy of MEK inhibitors was detected, in immune therapy naive patients with classical GNAQ mutations.	('mutations', 'Var', (117, 126))	('GNAQ', 'Gene', (112, 116))	('patients', 'Species', '9606', (88, 96))	('MEK', 'Gene', (35, 38))	('MEK', 'Gene', '5609', (35, 38))	('GNAQ', 'Gene', '2776', (112, 116))
65983	33126538	An additional reason for proposing a MEK inhibitor in our immune therapy exposed patient is that in patients with NRAS mutant melanoma, MEK inhibitors showed a better response rate and progression-free survival (PFS) in immune therapy-exposed patients than in immune therapy-naive patients in the NRAS-mutant melanoma (NEMO) trial.	('patient', 'Species', '9606', (81, 88))	('MEK', 'Gene', (136, 139))	('patient', 'Species', '9606', (281, 288))	('NRAS', 'Gene', (297, 301))	('NEMO', 'Gene', '8517', (319, 323))	('patients', 'Species', '9606', (100, 108))	('melanoma', 'Phenotype', 'HP:0002861', (309, 317))	('melanoma', 'Disease', (309, 317))	('MEK', 'Gene', '5609', (37, 40))	('NRAS', 'Gene', (114, 118))	('patients', 'Species', '9606', (243, 251))	('response rate', 'CPA', (167, 180))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('mutant', 'Var', (119, 125))	('melanoma', 'Disease', (126, 134))	('MEK', 'Gene', (37, 40))	('progression-free survival', 'CPA', (185, 210))	('patients', 'Species', '9606', (281, 289))	('NEMO', 'Gene', (319, 323))	('patient', 'Species', '9606', (100, 107))	('NRAS', 'Gene', '4893', (297, 301))	('better', 'PosReg', (160, 166))	('melanoma', 'Disease', 'MESH:D008545', (309, 317))	('patient', 'Species', '9606', (243, 250))	('MEK', 'Gene', '5609', (136, 139))	('NRAS', 'Gene', '4893', (114, 118))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))
65990	33126538	Using molecular modelling, we predicted that mutation GNAQ p.Gly48Leu in protein Galphaq introduces new favorable hydrophobic interactions with SW-III that can maintain SW-III close to the active site and contributes to maintaining the active conformation of Galphaq.	('p.Gly48Leu', 'Var', (59, 69))	('GNAQ', 'Gene', (54, 58))	('SW-II', 'Chemical', '-', (169, 174))	('maintain', 'Reg', (160, 168))	('hydrophobic interactions', 'MPA', (114, 138))	('SW-III', 'MPA', (169, 175))	('GNAQ', 'Gene', '2776', (54, 58))	('maintaining', 'Reg', (220, 231))	('SW-II', 'Chemical', '-', (144, 149))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('p.Gly48Leu', 'Mutation', 'p.G48L', (59, 69))	('active conformation', 'MPA', (236, 255))	('Galphaq', 'Gene', (81, 88))
65993	33126538	hypothesized that mutation p.Gly48Leu could increase Galphaq activity.	('increase', 'PosReg', (44, 52))	('Galphaq', 'Enzyme', (53, 60))	('p.Gly48Leu', 'Var', (27, 37))	('p.Gly48Leu', 'Mutation', 'p.G48L', (27, 37))
65994	33126538	Our analysis strongly suggests that GNAQ p.Gly48Leu is a tumor-driver mutation possibly activating Galphaq.	('p.Gly48Leu', 'Mutation', 'p.G48L', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('GNAQ', 'Gene', '2776', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('activating', 'PosReg', (88, 98))	('p.Gly48Leu', 'Var', (41, 51))	('Galphaq', 'Disease', (99, 106))	('tumor', 'Disease', (57, 62))	('GNAQ', 'Gene', (36, 40))
65996	33126538	In addition, we also predicted that mutated FGFR4 p.Cys172Gly likely leads to a gain of function by stabilizing the homodimer conformation, analogous with what was observed in FGFR1 p.Cys178Ser and FGFR2 p.His167_Asn173del.	('homodimer conformation', 'MPA', (116, 138))	('FGFR4', 'Gene', (44, 49))	('p.Cys172Gly', 'Mutation', 'p.C172G', (50, 61))	('function', 'MPA', (88, 96))	('stabilizing', 'MPA', (100, 111))	('p.His167_Asn173del', 'Mutation', 'p.167_,173delN', (204, 222))	('p.Cys178Ser', 'Mutation', 'p.C178S', (182, 193))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('mutated', 'Var', (36, 43))	('FGFR', 'molecular_function', 'GO:0005007', ('198', '202'))	('FGFR1', 'Gene', '2260', (176, 181))	('FGFR', 'molecular_function', 'GO:0005007', ('176', '180'))	('gain', 'PosReg', (80, 84))	('FGFR2', 'Gene', (198, 203))	('p.Cys178Ser', 'Var', (182, 193))	('p.Cys172Gly', 'Var', (50, 61))	('FGFR1', 'Gene', (176, 181))	('FGFR2', 'Gene', '2263', (198, 203))	('FGFR4', 'Gene', '2264', (44, 49))	('Ser', 'cellular_component', 'GO:0005790', ('190', '193'))	('p.His167_Asn173del', 'Var', (204, 222))
65997	33126538	Similarly to GNAQ p.Gly48Leu, this mutation-driven activation of FGFR4 could trigger the MEK pathway.	('FGFR4', 'Gene', '2264', (65, 70))	('MEK', 'Gene', (89, 92))	('FGFR4', 'Gene', (65, 70))	('MEK', 'Gene', '5609', (89, 92))	('mutation-driven', 'Var', (35, 50))	('trigger', 'Reg', (77, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('GNAQ', 'Gene', (13, 17))	('GNAQ', 'Gene', '2776', (13, 17))	('activation', 'PosReg', (51, 61))	('p.Gly48Leu', 'Mutation', 'p.G48L', (18, 28))
66000	33126538	Although the analysis of the GNAQ p.Gly48Leu mutation predicted the activation of the protein function and consequently of the MEK pathway, strongly supporting the use of trametinib, we cannot exclude another mechanism by which trametinib might have contributed to stabilize the patient's situation, including for instance a possible impact on the tumor microenvironment in melanoma, as mentioned by Kuske et al..	('GNAQ', 'Gene', (29, 33))	('MEK', 'Gene', (127, 130))	('protein', 'Protein', (86, 93))	('MEK', 'Gene', '5609', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('trametinib', 'Chemical', 'MESH:C560077', (171, 181))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('activation', 'PosReg', (68, 78))	('p.Gly48Leu', 'Mutation', 'p.G48L', (34, 44))	('patient', 'Species', '9606', (279, 286))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('GNAQ', 'Gene', '2776', (29, 33))	('tumor', 'Disease', (348, 353))	('melanoma', 'Phenotype', 'HP:0002861', (374, 382))	('p.Gly48Leu mutation', 'Var', (34, 53))	('melanoma', 'Disease', (374, 382))	('trametinib', 'Chemical', 'MESH:C560077', (228, 238))	('melanoma', 'Disease', 'MESH:D008545', (374, 382))
66001	33126538	Depending on data and resources, it can lead:within the timeframe of the clinical evaluation of the case:to a valuable prediction of the possible impact of unknown mutations on the structure and activity of the modified protein, and by extension on the biological pathway involved, helping clinicians to propose the best treatment for their patients.	('patients', 'Species', '9606', (341, 349))	('mutations', 'Var', (164, 173))	('protein', 'cellular_component', 'GO:0003675', ('220', '227'))	('activity', 'MPA', (195, 203))
66024	32158967	Patients with positive BAP-1 expression showed significantly shorter disease-free survival (p=0.013).	('shorter', 'NegReg', (61, 68))	('expression', 'Var', (29, 39))	('BAP-1', 'Gene', (23, 28))	('disease-free survival', 'CPA', (69, 90))	('Patients', 'Species', '9606', (0, 8))	('positive', 'Var', (14, 22))	('BAP-1', 'Gene', '8314', (23, 28))
66037	32158967	In recent years, a BAP-1 loss-of-function mutation has been described for several cancers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('BAP-1', 'Gene', '8314', (19, 24))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('loss-of-function', 'NegReg', (25, 41))	('BAP-1', 'Gene', (19, 24))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('mutation', 'Var', (42, 50))
66038	32158967	According to earlier reports, a germline BAP-1 mutation is associated with several hereditary cancer syndromes, including uveal melanoma, malignant pleural mesothelioma, clear cell renal cell carcinoma, and cholangiocarcinoma.	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (170, 201))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (138, 168))	('clear cell renal cell carcinoma', 'Disease', (170, 201))	('hereditary cancer syndromes', 'Disease', (83, 110))	('uveal melanoma', 'Disease', (122, 136))	('uveal melanoma', 'Disease', 'MESH:C536494', (122, 136))	('germline', 'Var', (32, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('hereditary cancer syndromes', 'Disease', 'MESH:D009386', (83, 110))	('uveal melanoma', 'Phenotype', 'HP:0007716', (122, 136))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (170, 201))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (148, 168))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (207, 225))	('malignant pleural mesothelioma', 'Disease', (138, 168))	('cholangiocarcinoma', 'Disease', (207, 225))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('BAP-1', 'Gene', '8314', (41, 46))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (207, 225))	('BAP-1', 'Gene', (41, 46))	('mutation', 'Var', (47, 55))	('associated', 'Reg', (59, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (181, 201))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))
66039	32158967	Additional studies identified somatic BAP-1 mutations that were also associated with corresponding cases.	('BAP-1', 'Gene', (38, 43))	('associated', 'Reg', (69, 79))	('mutations', 'Var', (44, 53))	('BAP-1', 'Gene', '8314', (38, 43))
66041	32158967	Patients with BAP-1 loss-of-function mutations have shorter overall survival in clear cell renal cell carcinoma and uveal melanoma.	('clear cell renal cell carcinoma', 'Disease', (80, 111))	('shorter', 'NegReg', (52, 59))	('loss-of-function', 'NegReg', (20, 36))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (91, 111))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (80, 111))	('mutations', 'Var', (37, 46))	('Patients', 'Species', '9606', (0, 8))	('BAP-1', 'Gene', '8314', (14, 19))	('overall survival', 'MPA', (60, 76))	('uveal melanoma', 'Disease', (116, 130))	('uveal melanoma', 'Disease', 'MESH:C536494', (116, 130))	('uveal melanoma', 'Phenotype', 'HP:0007716', (116, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (80, 111))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('BAP-1', 'Gene', (14, 19))
66042	32158967	In contrast, malignant pleural mesothelioma patients with high BAP-1 expression have shorter overall survival.	('shorter', 'NegReg', (85, 92))	('patients', 'Species', '9606', (44, 52))	('overall survival', 'MPA', (93, 109))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (13, 43))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (23, 43))	('malignant pleural mesothelioma', 'Disease', (13, 43))	('BAP-1', 'Gene', '8314', (63, 68))	('high', 'Var', (58, 62))	('BAP-1', 'Gene', (63, 68))
66044	32158967	A previous study showed that immunohistochemical staining for BAP-1 protein was a good surrogate marker for locating BAP-1 mutations.	('BAP-1', 'Gene', (117, 122))	('locating', 'NegReg', (108, 116))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('BAP-1', 'Gene', '8314', (117, 122))	('BAP-1', 'Gene', '8314', (62, 67))	('mutations', 'Var', (123, 132))	('BAP-1', 'Gene', (62, 67))
66081	32158967	When tumor suppressors are deubiquitinated, their expression is preserved, preventing uncontrolled cellular proliferation.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('preventing', 'NegReg', (75, 85))	('tumor', 'Disease', (5, 10))	('deubiquitinated', 'Var', (27, 42))	('expression', 'MPA', (50, 60))
66087	32158967	BAP-1 depletion by RNAi inhibits proliferation of breast cancer cells (MCF-7 and T-47D).	('inhibits', 'NegReg', (24, 32))	('BAP-1', 'Gene', '8314', (0, 5))	('RNAi', 'biological_process', 'GO:0016246', ('19', '23'))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('depletion', 'Var', (6, 15))	('proliferation', 'CPA', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('BAP-1', 'Gene', (0, 5))	('breast cancer', 'Disease', (50, 63))	('T-47D', 'CellLine', 'CVCL:0553', (81, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('MCF-7', 'CellLine', 'CVCL:0031', (71, 76))
66094	32158967	First, genomic hybridization can inspect for deletions in the BAP-1 gene locus at 3p21.	('BAP-1', 'Gene', '8314', (62, 67))	('deletions', 'Var', (45, 54))	('BAP-1', 'Gene', (62, 67))
66098	32158967	Moreover, because most BAP-1 mutations cause rapid degradation of proteins or reduce nuclear localization, BAP-1 mutations are highly associated with negative immunohistochemical staining.	('reduce', 'NegReg', (78, 84))	('BAP-1', 'Gene', '8314', (23, 28))	('BAP-1', 'Gene', (23, 28))	('mutations', 'Var', (29, 38))	('degradation of proteins', 'MPA', (51, 74))	('degradation', 'biological_process', 'GO:0009056', ('51', '62'))	('mutations', 'Var', (113, 122))	('BAP-1', 'Gene', '8314', (107, 112))	('localization', 'biological_process', 'GO:0051179', ('93', '105'))	('nuclear localization', 'MPA', (85, 105))	('BAP-1', 'Gene', (107, 112))
66100	32158967	In our study, PCa cases with positive BAP-1 expression had significantly higher T-stage and higher PSA level.	('T-stage', 'CPA', (80, 87))	('higher', 'PosReg', (92, 98))	('PSA', 'Gene', '354', (99, 102))	('BAP-1', 'Gene', '8314', (38, 43))	('PCa', 'Disease', (14, 17))	('PCa', 'Disease', 'MESH:D011471', (14, 17))	('PSA', 'Gene', (99, 102))	('BAP-1', 'Gene', (38, 43))	('positive', 'Var', (29, 37))	('higher', 'PosReg', (73, 79))
66101	32158967	Consistently, PCa patients with positive BAP-1 expression had shorter disease-free survival than did patients with negative BAP-1 expression.	('BAP-1', 'Gene', (41, 46))	('patients', 'Species', '9606', (101, 109))	('shorter', 'NegReg', (62, 69))	('BAP-1', 'Gene', (124, 129))	('expression', 'Var', (47, 57))	('disease-free survival', 'CPA', (70, 91))	('PCa', 'Disease', (14, 17))	('PCa', 'Disease', 'MESH:D011471', (14, 17))	('BAP-1', 'Gene', '8314', (41, 46))	('patients', 'Species', '9606', (18, 26))	('BAP-1', 'Gene', '8314', (124, 129))	('positive', 'Var', (32, 40))
66102	32158967	Also, high preoperative PSA level, high grade group, and lymphovascular invasion were significantly associated with shorter disease-free survival.	('shorter', 'NegReg', (116, 123))	('PSA', 'Gene', (24, 27))	('PSA', 'Gene', '354', (24, 27))	('lymphovascular invasion', 'CPA', (57, 80))	('disease-free survival', 'CPA', (124, 145))	('high grade group', 'Var', (35, 51))
66115	32158967	The poor prognosis among patients with positive BAP-1 expression might be explained by BRCA1 gene gain affecting dedifferentiation.	('dedifferentiation', 'biological_process', 'GO:0043696', ('113', '130'))	('BRCA1', 'Gene', '672', (87, 92))	('dedifferentiation', 'CPA', (113, 130))	('BRCA1', 'Gene', (87, 92))	('patients', 'Species', '9606', (25, 33))	('BAP-1', 'Gene', '8314', (48, 53))	('gain', 'PosReg', (98, 102))	('BAP-1', 'Gene', (48, 53))	('positive', 'Var', (39, 47))
66144	27265506	ARF6 is an actionable node that orchestrates oncogenic GNAQ signaling in uveal melanoma Activating mutations in Galphaq proteins, which form the a subunit of certain heterotrimeric G proteins, drive uveal melanoma oncogenesis by triggering multiple downstream signaling pathways, including PLC/PKC, Rho/Rac, and YAP.	('Rac', 'Gene', (303, 306))	('YAP', 'Gene', '10413', (312, 315))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('PLC', 'cellular_component', 'GO:0042824', ('290', '293'))	('Galphaq', 'Gene', (112, 119))	('drive', 'PosReg', (193, 198))	('signaling', 'biological_process', 'GO:0023052', ('60', '69'))	('triggering', 'Reg', (229, 239))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('oncogenesis', 'biological_process', 'GO:0007048', ('214', '225'))	('uveal melanoma', 'Disease', 'MESH:C536494', (199, 213))	('uveal melanoma', 'Disease', (199, 213))	('PKC', 'Gene', '112476', (294, 297))	('Galphaq', 'Gene', '2776', (112, 119))	('uveal melanoma', 'Disease', 'MESH:C536494', (73, 87))	('PKC', 'molecular_function', 'GO:0004697', ('294', '297'))	('uveal melanoma', 'Disease', (73, 87))	('ARF6', 'Gene', '382', (0, 4))	('PKC', 'Gene', (294, 297))	('uveal melanoma', 'Phenotype', 'HP:0007716', (199, 213))	('YAP', 'Gene', (312, 315))	('PLC', 'Gene', '3339', (290, 293))	('Rac', 'Gene', '207', (303, 306))	('signaling', 'biological_process', 'GO:0023052', ('260', '269'))	('GNAQ', 'Gene', '2776', (55, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (73, 87))	('ARF6', 'Gene', (0, 4))	('mutations', 'Var', (99, 108))	('GNAQ', 'Gene', (55, 59))	('PLC', 'Gene', (290, 293))
66150	27265506	Mutations that confer constitutive activity to G protein-coupled receptors (GPCRs) or Galpha proteins have been identified in numerous diseases, including human cancers, McCune-Albright syndrome, and Sturge-Weber syndrome.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('numerous diseases', 'Disease', 'MESH:D004194', (126, 143))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('Sturge-Weber syndrome', 'Disease', (200, 221))	('human', 'Species', '9606', (155, 160))	('Galpha', 'Gene', '8802', (86, 92))	('Weber syndrome', 'Phenotype', 'HP:0002277', (207, 221))	('Galpha', 'Gene', (86, 92))	('McCune-Albright syndrome', 'Disease', (170, 194))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (112, 122))	('G protein-coupled receptors', 'Protein', (47, 74))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (200, 221))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Disease', (161, 168))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (170, 194))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('numerous diseases', 'Disease', (126, 143))
66151	27265506	One such disease is uveal melanoma in which over 80% of tumors harbor an oncogenic activating mutation in either of two Galphaq class (Galphaq) proteins: GNAQ and GNA11.	('GNAQ', 'Gene', '2776', (154, 158))	('GNA11', 'Gene', '2767', (163, 168))	('GNA11', 'Gene', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Galphaq', 'Gene', (120, 127))	('Galphaq', 'Gene', '2776', (120, 127))	('GNAQ', 'Gene', (154, 158))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('Galphaq', 'Gene', (135, 142))	('Galphaq', 'Gene', '2776', (135, 142))	('uveal melanoma', 'Disease', 'MESH:C536494', (20, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (20, 34))	('oncogenic', 'Reg', (73, 82))	('mutation', 'Var', (94, 102))	('uveal melanoma', 'Disease', (20, 34))
66153	27265506	The discovery of oncogenic GNAQ and GNA11 mutations in uveal melanoma has led to the identification of multiple downstream signaling pathways that could be targeted for therapeutic purposes.	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('GNAQ', 'Gene', '2776', (27, 31))	('uveal melanoma', 'Phenotype', 'HP:0007716', (55, 69))	('uveal melanoma', 'Disease', (55, 69))	('uveal melanoma', 'Disease', 'MESH:C536494', (55, 69))	('GNA11', 'Gene', '2767', (36, 41))	('GNA11', 'Gene', (36, 41))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('GNAQ', 'Gene', (27, 31))	('mutations', 'Var', (42, 51))
66155	27265506	However, it has been unclear how activating mutations in Galphaq proteins exert their control over these divergent downstream pathways and whether activated Galphaq proteins govern additional oncogenic pathways.	('Galphaq', 'Gene', (157, 164))	('Galphaq', 'Gene', (57, 64))	('Galphaq', 'Gene', '2776', (157, 164))	('Galphaq', 'Gene', '2776', (57, 64))	('govern', 'Reg', (174, 180))	('oncogenic pathways', 'Pathway', (192, 210))	('mutations', 'Var', (44, 53))	('activating', 'PosReg', (33, 43))
66160	27265506	In this study, we investigate the role of ARF6 as a mediator of all known oncogenic signaling pathways that are controlled by activating GNAQ mutations.	('mutations', 'Var', (142, 151))	('GNAQ', 'Gene', (137, 141))	('GNAQ', 'Gene', '2776', (137, 141))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('activating', 'PosReg', (126, 136))
66163	27265506	Finally, we seek to provide a mechanistic framework for studying other cancers harboring activating Galpha mutations and an alternative approach for identifying therapeutic targets for these cancers.	('activating', 'PosReg', (89, 99))	('mutations', 'Var', (107, 116))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancers', 'Disease', (71, 78))	('cancers', 'Disease', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('Galpha', 'Gene', '8802', (100, 106))	('Galpha', 'Gene', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
66164	27265506	We investigated whether ARF6 might also be important in cancers harboring somatic activating mutations of Galphaq based on the reported role of ARF6 in several cancers and studies showing that Galphaq proteins can activate or signal through ARF6.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('mutations', 'Var', (93, 102))	('Galphaq', 'Gene', (106, 113))	('activating', 'PosReg', (82, 92))	('Galphaq', 'Gene', '2776', (106, 113))	('cancers', 'Disease', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('signal', 'MPA', (226, 232))	('Galphaq', 'Gene', (193, 200))	('Galphaq', 'Gene', '2776', (193, 200))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('activate', 'PosReg', (214, 222))
66165	27265506	We first examined ARF6 protein levels in human uveal melanomas that carried activating mutations in either GNAQ or GNA11.	('GNA11', 'Gene', '2767', (115, 120))	('uveal melanomas', 'Disease', (47, 62))	('uveal melanomas', 'Phenotype', 'HP:0007716', (47, 62))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('human', 'Species', '9606', (41, 46))	('GNAQ', 'Gene', '2776', (107, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('ARF6 protein levels', 'MPA', (18, 37))	('uveal melanomas', 'Disease', 'MESH:C536494', (47, 62))	('GNA11', 'Gene', (115, 120))	('GNAQ', 'Gene', (107, 111))	('mutations', 'Var', (87, 96))
66170	27265506	Each knockdown reduced ARF-GTP levels by greater than 50% compared to a negative control siRNA that lacks homology to any known mammalian gene (Figure 1A).	('knockdown', 'Var', (5, 14))	('-GTP', 'Chemical', 'MESH:D006160', (26, 30))	('mammalian', 'Species', '9606', (128, 137))	('reduced', 'NegReg', (15, 22))	('ARF-GTP levels', 'MPA', (23, 37))
66172	27265506	Knockdown of GNAQ in cultured uveal melanoma cells has been shown to inhibit cell growth.	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('Knockdown', 'Var', (0, 9))	('GNAQ', 'Gene', (13, 17))	('cell growth', 'CPA', (77, 88))	('GNAQ', 'Gene', '2776', (13, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (30, 44))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('uveal melanoma', 'Disease', (30, 44))	('cell growth', 'biological_process', 'GO:0016049', ('77', '88'))	('inhibit', 'NegReg', (69, 76))
66173	27265506	To determine if this inhibition is ARF6 dependent, we compared growth parameters between uveal melanoma cells transfected with siRNAs directed against ARF6 or GNAQ.	('GNAQ', 'Gene', (159, 163))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('GNAQ', 'Gene', '2776', (159, 163))	('ARF6', 'Gene', (151, 155))	('uveal melanoma', 'Phenotype', 'HP:0007716', (89, 103))	('uveal melanoma', 'Disease', 'MESH:C536494', (89, 103))	('uveal melanoma', 'Disease', (89, 103))	('directed against', 'Var', (134, 150))
66177	27265506	Both cell proliferation and anchorage-independent colony growth were partially rescued by constitutively active ARF6 when GNAQ expression was knocked down (Figure S1C-S1E), suggesting that the activation of ARF6 may serve to enhance oncogenic GNAQ signaling, not replace it.	('ARF6', 'Gene', (207, 211))	('cell proliferation', 'biological_process', 'GO:0008283', ('5', '23'))	('signaling', 'biological_process', 'GO:0023052', ('248', '257'))	('GNAQ', 'Gene', (243, 247))	('activation', 'PosReg', (193, 203))	('GNAQ', 'Gene', (122, 126))	('anchorage-independent colony growth', 'CPA', (28, 63))	('ARF6', 'Gene', (112, 116))	('enhance', 'PosReg', (225, 232))	('GNAQ', 'Gene', '2776', (243, 247))	('knocked', 'Var', (142, 149))	('GNAQ', 'Gene', '2776', (122, 126))	('cell proliferation', 'CPA', (5, 23))
66178	27265506	Constitutively active ARF6 may act through the residual GNAQ present following GNAQ knockdown to partially rescue the function of GNAQ.	('rescue', 'PosReg', (107, 113))	('GNAQ', 'Gene', '2776', (79, 83))	('GNAQ', 'Gene', (130, 134))	('knockdown', 'Var', (84, 93))	('GNAQ', 'Gene', '2776', (56, 60))	('ARF6', 'Protein', (22, 26))	('function', 'MPA', (118, 126))	('GNAQ', 'Gene', (79, 83))	('GNAQ', 'Gene', (56, 60))	('GNAQ', 'Gene', '2776', (130, 134))
66181	27265506	Consistent with this reduction in PLC activity, the level of phosphorylated myristoylated alanine-rich C kinase substrate (p-MARCKS), a substrate of PKC, was decreased by ARF6 knockdown (Figures 2B and S2A).	('activity', 'MPA', (38, 46))	('decreased', 'NegReg', (158, 167))	('PLC', 'Gene', '3339', (34, 37))	('MARCKS', 'Gene', '4082', (125, 131))	('myristoylated alanine-rich C kinase substrate', 'Gene', (76, 121))	('PLC', 'Gene', (34, 37))	('PLC', 'cellular_component', 'GO:0042824', ('34', '37'))	('PKC', 'Gene', (149, 152))	('PKC', 'Gene', '112476', (149, 152))	('ARF6', 'Gene', (171, 175))	('myristoylated alanine-rich C kinase substrate', 'Gene', '4082', (76, 121))	('PKC', 'molecular_function', 'GO:0004697', ('149', '152'))	('reduction', 'NegReg', (21, 30))	('MARCKS', 'Gene', (125, 131))	('knockdown', 'Var', (176, 185))
66185	27265506	Silencing ARF6 or GNAQ inhibited by 60% the nuclear localization of YAP in uveal melanoma cells, as detected by immunocytofluorescence and subcellular fractionation/immunoblotting (Figures 2G, 2H, and S2H).	('localization', 'biological_process', 'GO:0051179', ('52', '64'))	('inhibited', 'NegReg', (23, 32))	('GNAQ', 'Gene', '2776', (18, 22))	('uveal melanoma', 'Phenotype', 'HP:0007716', (75, 89))	('uveal melanoma', 'Disease', 'MESH:C536494', (75, 89))	('YAP', 'Gene', '10413', (68, 71))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('ARF6', 'Gene', (10, 14))	('nuclear localization', 'MPA', (44, 64))	('GNAQ', 'Gene', (18, 22))	('uveal melanoma', 'Disease', (75, 89))	('YAP', 'Gene', (68, 71))	('Silencing', 'Var', (0, 9))
66194	27265506	Knocking down GNAQ or ARF6 in uveal melanoma cells resulted in an increase in the membrane pool of beta-catenin and a corresponding decrease in the cytosolic and nuclear pools, as shown by both immunocytofluorescence and subcellular fractionation analyses (Figure 3A and 3B).	('increase', 'PosReg', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('Knocking down', 'Var', (0, 13))	('GNAQ', 'Gene', '2776', (14, 18))	('membrane', 'cellular_component', 'GO:0016020', ('82', '90'))	('ARF6', 'Gene', (22, 26))	('uveal melanoma', 'Disease', 'MESH:C536494', (30, 44))	('GNAQ', 'Gene', (14, 18))	('beta-catenin', 'Gene', (99, 111))	('uveal melanoma', 'Disease', (30, 44))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('decrease', 'NegReg', (132, 140))	('beta-catenin', 'Gene', '1499', (99, 111))
66201	27265506	To determine whether a similar mechanism drives beta-catenin release in uveal melanoma cells, we knocked down CK2alpha (the catalytic subunit) and determined the intracellular location of beta-catenin by subcellular fractionation.	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('uveal melanoma', 'Disease', (72, 86))	('knocked', 'Var', (97, 104))	('beta-catenin', 'Gene', (48, 60))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('beta-catenin', 'Gene', '1499', (48, 60))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('intracellular', 'cellular_component', 'GO:0005622', ('162', '175'))	('beta-catenin', 'Gene', (188, 200))	('CK2alpha', 'Gene', '1459', (110, 118))	('beta-catenin', 'Gene', '1499', (188, 200))	('CK2alpha', 'Gene', (110, 118))
66202	27265506	CK2alpha knockdown simultaneously increased beta-catenin in the membrane fraction and decreased its localization to the cytoplasm and nucleus (Figure S3D), suggesting that a similar ERK-CK2-alpha-catenin mechanism may control beta-catenin release from cadherins in uveal melanoma cells.	('ERK', 'molecular_function', 'GO:0004707', ('182', '185'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('120', '129'))	('CK2alpha', 'Gene', '1459', (0, 8))	('uveal melanoma', 'Disease', (265, 279))	('uveal melanoma', 'Disease', 'MESH:C536494', (265, 279))	('membrane fraction', 'cellular_component', 'GO:0005624', ('64', '81'))	('alpha', 'Chemical', 'MESH:C002017', (3, 8))	('ERK', 'Gene', '5594', (182, 185))	('increased', 'PosReg', (34, 43))	('uveal melanoma', 'Phenotype', 'HP:0007716', (265, 279))	('knockdown', 'Var', (9, 18))	('beta-catenin', 'Gene', (44, 56))	('localization', 'biological_process', 'GO:0051179', ('100', '112'))	('decreased', 'NegReg', (86, 95))	('ERK', 'Gene', (182, 185))	('alpha', 'Chemical', 'MESH:C002017', (190, 195))	('beta-catenin', 'Gene', '1499', (44, 56))	('beta-catenin', 'Gene', (226, 238))	('beta-catenin', 'Gene', '1499', (226, 238))	('melanoma', 'Phenotype', 'HP:0002861', (271, 279))	('CK2alpha', 'Gene', (0, 8))	('nucleus', 'cellular_component', 'GO:0005634', ('134', '141'))	('localization to the cytoplasm', 'MPA', (100, 129))
66205	27265506	After 72 hours of treatment, both XAV939 and IWR-1-endo inhibited cell proliferation in a concentration-dependent manner with a GI50 (50% growth inhibition) of around 3 microM and 10 microM, respectively, in both cell lines (Figure S3E).	('cell proliferation', 'CPA', (66, 84))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('inhibited', 'NegReg', (56, 65))	('XAV939', 'Var', (34, 40))	('XAV', 'Chemical', '-', (34, 37))	('IWR-1-endo', 'Var', (45, 55))
66211	27265506	Similar to the silencing of ARF6 and GNAQ, knockdown of GEP100 also inhibited PLC-PKC, Rac1/RhoA, YAP, and beta-catenin signaling, as evidenced by decreased activation of the downstream effectors and reduced nuclear localization and transcriptional activity of YAP and beta-catenin (Figures S4C-S4L).	('PKC', 'molecular_function', 'GO:0004697', ('82', '85'))	('YAP', 'Gene', (261, 264))	('decreased', 'NegReg', (147, 156))	('YAP', 'Gene', '10413', (98, 101))	('GNAQ', 'Gene', '2776', (37, 41))	('PLC', 'cellular_component', 'GO:0042824', ('78', '81'))	('PKC', 'Gene', '112476', (82, 85))	('transcriptional activity', 'MPA', (233, 257))	('beta-catenin', 'Gene', (269, 281))	('GNAQ', 'Gene', (37, 41))	('beta-catenin', 'Gene', '1499', (269, 281))	('knockdown', 'Var', (43, 52))	('reduced', 'NegReg', (200, 207))	('RhoA', 'Gene', (92, 96))	('inhibited', 'NegReg', (68, 77))	('Rac1', 'Gene', '5879', (87, 91))	('YAP', 'Gene', '10413', (261, 264))	('PLC', 'Gene', '3339', (78, 81))	('PKC', 'Gene', (82, 85))	('GEP100', 'Gene', (56, 62))	('GEP100', 'Gene', '9922', (56, 62))	('localization', 'biological_process', 'GO:0051179', ('216', '228'))	('RhoA', 'Gene', '387', (92, 96))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('YAP', 'Gene', (98, 101))	('PLC', 'Gene', (78, 81))	('beta-catenin', 'Gene', (107, 119))	('nuclear localization', 'MPA', (208, 228))	('beta-catenin', 'Gene', '1499', (107, 119))	('activation', 'PosReg', (157, 167))	('Rac1', 'Gene', (87, 91))
66213	27265506	Immunoprecipitation of GNAQ from uveal melanoma cells harboring the activating mutation co-precipitated GEP100 (Figure 4D), suggesting the existence of a GNAQQ209L-GEP100 complex.	('GNAQ', 'Gene', '2776', (154, 158))	('GEP100', 'Gene', (104, 110))	('GEP100', 'Gene', '9922', (104, 110))	('GNAQ', 'Gene', (23, 27))	('uveal melanoma', 'Disease', 'MESH:C536494', (33, 47))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('GNAQ', 'Gene', (154, 158))	('uveal melanoma', 'Disease', (33, 47))	('uveal melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('GNAQ', 'Gene', '2776', (23, 27))	('mutation', 'Var', (79, 87))	('GEP100', 'Gene', (164, 170))	('GEP100', 'Gene', '9922', (164, 170))
66215	27265506	To examine whether ARF6 might control activated GNAQ signaling through a similar protein trafficking mechanism, we knocked down ARF6 in Mel92.1 and Mel202 cells and assessed intracellular localization of GNAQ using both immunocytofluorescence and cell fractionation analysis.	('GNAQ', 'Gene', (204, 208))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('knocked', 'Var', (115, 122))	('GNAQ', 'Gene', '2776', (48, 52))	('intracellular localization', 'biological_process', 'GO:0051641', ('174', '200'))	('GNAQ', 'Gene', '2776', (204, 208))	('GNAQ', 'Gene', (48, 52))	('ARF6', 'Gene', (128, 132))	('intracellular', 'cellular_component', 'GO:0005622', ('174', '187'))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))
66216	27265506	Upon ARF6 silencing, there was an increase in GNAQ localized to the plasma membrane with a concomitant reduction of GNAQ in the cytosol and cytoplasmic vesicles (Figure 5).	('ARF6', 'Gene', (5, 9))	('GNAQ', 'Gene', (46, 50))	('GNAQ', 'Gene', (116, 120))	('plasma membrane', 'cellular_component', 'GO:0005886', ('68', '83'))	('cytosol', 'cellular_component', 'GO:0005829', ('128', '135'))	('GNAQ', 'Gene', '2776', (46, 50))	('increase', 'PosReg', (34, 42))	('reduction', 'NegReg', (103, 112))	('GNAQ', 'Gene', '2776', (116, 120))	('silencing', 'Var', (10, 19))
66217	27265506	GEP100 knockdown likewise exhibited a shift of GNAQ localization from the cytosol and cytoplasmic vesicles to the plasma membrane (Figure S5A and S5B).	('GEP100', 'Gene', (0, 6))	('GEP100', 'Gene', '9922', (0, 6))	('localization', 'biological_process', 'GO:0051179', ('52', '64'))	('cytosol', 'cellular_component', 'GO:0005829', ('74', '81'))	('GNAQ', 'Gene', (47, 51))	('shift', 'Reg', (38, 43))	('GNAQ', 'Gene', '2776', (47, 51))	('plasma membrane', 'cellular_component', 'GO:0005886', ('114', '129'))	('knockdown', 'Var', (7, 16))
66218	27265506	Silencing of other human ARF family members did not cause appreciable intracellular relocalization of GNAQ (Figure S5C), thus suggesting that this function is specific to ARF6.	('intracellular', 'cellular_component', 'GO:0005622', ('70', '83'))	('GNAQ', 'Gene', (102, 106))	('Silencing', 'Var', (0, 9))	('human', 'Species', '9606', (19, 24))	('GNAQ', 'Gene', '2776', (102, 106))
66219	27265506	Cumulatively, these results suggest that activated ARF6 directs GNAQ to the cytoplasmic vesicles, leading to an increase in signaling of downstream oncogenic pathways.	('GNAQ', 'Gene', (64, 68))	('activated', 'Var', (41, 50))	('signaling', 'biological_process', 'GO:0023052', ('124', '133'))	('increase', 'PosReg', (112, 120))	('ARF6', 'Gene', (51, 55))	('signaling', 'MPA', (124, 133))	('GNAQ', 'Gene', '2776', (64, 68))	('oncogenic pathways', 'Pathway', (148, 166))
66230	27265506	Most importantly, NAV-2729 exhibited a spectrum of biological activities in uveal melanoma cells that are predicted for an ARF6 inhibitor.	('uveal melanoma', 'Phenotype', 'HP:0007716', (76, 90))	('uveal melanoma', 'Disease', 'MESH:C536494', (76, 90))	('uveal melanoma', 'Disease', (76, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('NAV-2729', 'Var', (18, 26))	('NAV-2729', 'Chemical', 'MESH:C000623233', (18, 26))	('biological activities', 'MPA', (51, 72))
66231	27265506	Treatment of Mel92.1 and Mel202 cells with NAV-2729 inhibited ARF6 activation (Figure 6H) and mimicked ARF6 and GEP100 knockdown by driving GNAQ from the cytoplasmic vesicles to the plasma membrane (Figure 6I and 6J) and reducing anchorage-independent colony growth (Figure 6K).	('GNAQ', 'Gene', '2776', (140, 144))	('plasma membrane', 'cellular_component', 'GO:0005886', ('182', '197'))	('activation', 'PosReg', (67, 77))	('GNAQ', 'Gene', (140, 144))	('NAV-2729', 'Var', (43, 51))	('anchorage-independent colony growth', 'CPA', (230, 265))	('GEP100', 'Gene', '9922', (112, 118))	('NAV-2729', 'Chemical', 'MESH:C000623233', (43, 51))	('knockdown', 'Var', (119, 128))	('inhibited', 'NegReg', (52, 61))	('ARF6', 'Gene', (103, 107))	('GEP100', 'Gene', (112, 118))	('ARF6', 'Gene', (62, 66))	('reducing', 'NegReg', (221, 229))	('driving', 'PosReg', (132, 139))
66232	27265506	NAV-2729 also blocked all of the known downstream signaling pathways of oncogenic GNAQ, including PLC/PKC, Rho/Rac, YAP, and beta-catenin (Figure 7).	('PKC', 'Gene', '112476', (102, 105))	('PLC', 'Gene', (98, 101))	('YAP', 'Gene', (116, 119))	('Rac', 'Gene', '207', (111, 114))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('beta-catenin', 'Gene', (125, 137))	('GNAQ', 'Gene', (82, 86))	('NAV-2729', 'Var', (0, 8))	('Rac', 'Gene', (111, 114))	('YAP', 'Gene', '10413', (116, 119))	('beta-catenin', 'Gene', '1499', (125, 137))	('PLC', 'cellular_component', 'GO:0042824', ('98', '101'))	('PKC', 'molecular_function', 'GO:0004697', ('102', '105'))	('blocked', 'NegReg', (14, 21))	('PKC', 'Gene', (102, 105))	('NAV-2729', 'Chemical', 'MESH:C000623233', (0, 8))	('GNAQ', 'Gene', '2776', (82, 86))	('PLC', 'Gene', '3339', (98, 101))
66237	27265506	Tumor incidence and size were markedly decreased in mice injected with Mel202 cells expressing ARF6 shRNA compared to mice injected with cells expressing control shRNA (Figure 8A and 8B).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ARF6 shRNA', 'Var', (95, 105))	('mice', 'Species', '10090', (52, 56))	('decreased', 'NegReg', (39, 48))	('mice', 'Species', '10090', (118, 122))
66240	27265506	Collectively, these results suggest that the pharmacological inhibition of ARF6 may represent an effective therapeutic approach to the treatment of uveal melanoma and possibly other cancers driven by activating Galpha mutations.	('Galpha', 'Gene', '8802', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('uveal melanoma', 'Phenotype', 'HP:0007716', (148, 162))	('mutations', 'Var', (218, 227))	('ARF6', 'Gene', (75, 79))	('uveal melanoma', 'Disease', 'MESH:C536494', (148, 162))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('uveal melanoma', 'Disease', (148, 162))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('cancers', 'Disease', (182, 189))	('activating', 'PosReg', (200, 210))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('Galpha', 'Gene', (211, 217))
66242	27265506	Previous studies have shown that activating mutations in either GNAQ or GNA11 promote PLC/PCK and Rac/Rho signaling, leading to both the activation of ERK, p38, JNK, and YAP and subsequent AP-1- and YAP/TEAD-mediated transcription.	('YAP', 'Gene', (199, 202))	('YAP', 'Gene', '10413', (170, 173))	('transcription', 'biological_process', 'GO:0006351', ('217', '230'))	('p38', 'Gene', (156, 159))	('ERK', 'molecular_function', 'GO:0004707', ('151', '154'))	('AP-1', 'cellular_component', 'GO:0005907', ('189', '193'))	('Rac', 'Gene', (98, 101))	('GNA11', 'Gene', (72, 77))	('PLC', 'Gene', '3339', (86, 89))	('ERK', 'Gene', '5594', (151, 154))	('activation', 'PosReg', (137, 147))	('YAP', 'Gene', '10413', (199, 202))	('p38', 'Gene', '5594', (156, 159))	('GNA11', 'Gene', '2767', (72, 77))	('JNK', 'molecular_function', 'GO:0004705', ('161', '164'))	('promote', 'PosReg', (78, 85))	('PLC', 'Gene', (86, 89))	('Rac', 'Gene', '207', (98, 101))	('PLC', 'cellular_component', 'GO:0042824', ('86', '89'))	('YAP', 'Gene', (170, 173))	('GNAQ', 'Gene', '2776', (64, 68))	('ERK', 'Gene', (151, 154))	('GNAQ', 'Gene', (64, 68))	('mutations', 'Var', (44, 53))	('AP-1- and YAP', 'Gene', '3725;10413', (189, 202))	('JNK', 'Gene', (161, 164))	('JNK', 'Gene', '5599', (161, 164))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))
66243	27265506	In the present study, we have expanded the number of signaling pathways that are known to be regulated by an activated Galphaq protein to include an ARF6-beta-catenin pathway in which activated ARF6 promotes the release and subsequent translocation of membrane-bound beta-catenin to the nucleus where it induces transcription.	('nucleus', 'cellular_component', 'GO:0005634', ('287', '294'))	('beta-catenin', 'Gene', '1499', (267, 279))	('ARF6', 'Gene', (194, 198))	('beta-catenin', 'Gene', (154, 166))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('beta-catenin', 'Gene', '1499', (154, 166))	('promotes', 'PosReg', (199, 207))	('activated', 'Var', (184, 193))	('Galphaq', 'Gene', '2776', (119, 126))	('translocation', 'MPA', (235, 248))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('release', 'MPA', (212, 219))	('membrane', 'cellular_component', 'GO:0016020', ('252', '260'))	('beta-catenin', 'Gene', (267, 279))	('transcription', 'biological_process', 'GO:0006351', ('312', '325'))	('Galphaq', 'Gene', (119, 126))	('transcription', 'MPA', (312, 325))	('induces', 'Reg', (304, 311))
66244	27265506	By employing biochemical and cellular assays and a newly identified small molecule inhibitor, we also show that a GNAQQ209L-GEP100 complex activates ARF6, which functions as an immediate downstream effector to induce the PLC/PKC and Rho/Rac signaling pathways that lead to AP-1 and YAP/TEAD-mediated transcription (Figure 8E).	('YAP', 'Gene', '10413', (282, 285))	('PKC', 'molecular_function', 'GO:0004697', ('225', '228'))	('GEP100', 'Gene', '9922', (124, 130))	('GEP100', 'Gene', (124, 130))	('induce', 'PosReg', (210, 216))	('PKC', 'Gene', '112476', (225, 228))	('PLC', 'cellular_component', 'GO:0042824', ('221', '224'))	('signaling', 'biological_process', 'GO:0023052', ('241', '250'))	('Rac', 'Gene', (237, 240))	('ARF6', 'Gene', (149, 153))	('lead to', 'Reg', (265, 272))	('PKC', 'Gene', (225, 228))	('PLC', 'Gene', '3339', (221, 224))	('activates', 'PosReg', (139, 148))	('YAP', 'Gene', (282, 285))	('GNAQ', 'Gene', '2776', (114, 118))	('PLC', 'Gene', (221, 224))	('GNAQ', 'Gene', (114, 118))	('transcription', 'biological_process', 'GO:0006351', ('300', '313'))	('complex', 'Var', (131, 138))	('AP-1', 'Disease', (273, 277))	('AP-1', 'cellular_component', 'GO:0005907', ('273', '277'))	('Rac', 'Gene', '207', (237, 240))
66245	27265506	Thus, the activation of ARF6 controls all of the currently known oncogenic pathways mediated by Galphaq activating mutations.	('mutations', 'Var', (115, 124))	('Galphaq', 'Gene', (96, 103))	('Galphaq', 'Gene', '2776', (96, 103))	('ARF6', 'Gene', (24, 28))	('oncogenic pathways', 'Pathway', (65, 83))	('activation', 'PosReg', (10, 20))
66248	27265506	GNAQ signaling appears to primarily occur in these vesicles, because knockdown of ARF6 or GEP100 or chemical inhibition of ARF6 induces the relocalization of GNAQ from the cytoplasm to the plasma membrane with a concomitant decrease in signaling of all GNAQ-mediated pathways.	('signaling', 'MPA', (236, 245))	('GEP100', 'Gene', (90, 96))	('GNAQ', 'Gene', '2776', (158, 162))	('GNAQ', 'Gene', (253, 257))	('GNAQ', 'Gene', '2776', (0, 4))	('GEP100', 'Gene', '9922', (90, 96))	('signaling', 'biological_process', 'GO:0023052', ('236', '245'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('189', '204'))	('ARF6', 'Gene', (123, 127))	('ARF6', 'Gene', (82, 86))	('decrease', 'NegReg', (224, 232))	('signaling', 'biological_process', 'GO:0023052', ('5', '14'))	('GNAQ', 'Gene', (158, 162))	('GNAQ', 'Gene', (0, 4))	('GNAQ', 'Gene', '2776', (253, 257))	('cytoplasm', 'cellular_component', 'GO:0005737', ('172', '181'))	('knockdown', 'Var', (69, 78))	('relocalization', 'MPA', (140, 154))
66256	27265506	Our discovery that ARF6 is an immediate downstream effector of the GNAQQ209L-GEP100 complex suggests that targeting ARF6 with a single small molecule may inhibit all of the currently known Galphaq-mediated oncogenic signaling pathways.	('oncogenic signaling pathways', 'Pathway', (206, 234))	('GNAQ', 'Gene', (67, 71))	('Galphaq', 'Gene', (189, 196))	('targeting', 'Var', (106, 115))	('inhibit', 'NegReg', (154, 161))	('Galphaq', 'Gene', '2776', (189, 196))	('ARF6', 'Gene', (116, 120))	('GEP100', 'Gene', (77, 83))	('GEP100', 'Gene', '9922', (77, 83))	('signaling', 'biological_process', 'GO:0023052', ('216', '225'))	('GNAQ', 'Gene', '2776', (67, 71))
66258	27265506	We provide evidence that ARF6 is an actionable node suitable for further development as a therapeutic target by identifying a direct inhibitor of ARF6 that reduces tumor establishment and growth in a xenograft model of uveal melanoma.	('inhibitor', 'Var', (133, 142))	('uveal melanoma', 'Disease', (219, 233))	('uveal melanoma', 'Disease', 'MESH:C536494', (219, 233))	('tumor', 'Disease', (164, 169))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('reduces', 'NegReg', (156, 163))	('uveal melanoma', 'Phenotype', 'HP:0007716', (219, 233))	('ARF6', 'Gene', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('growth', 'CPA', (188, 194))
66287	27265506	ARF6 is an immediate downstream effector of an activated GNAQ/GEP100 complex ARF6 acts as a node for all downstream signaling pathways induced by oncogenic GNAQ Maximal signaling occurs when GNAQ is shuttled to cytoplasmic vesicles Targeting nodes such as ARF6 provide an approach for treating recalcitrant cancers Activating mutations in G proteins, such as Galphaq and RAS, drive oncogenesis in many cancers by triggering multiple downstream signaling pathways.	('signaling', 'biological_process', 'GO:0023052', ('444', '453'))	('mutations', 'Var', (326, 335))	('GNAQ', 'Gene', '2776', (156, 160))	('cancers', 'Disease', 'MESH:D009369', (402, 409))	('Galphaq', 'Gene', (359, 366))	('GNAQ', 'Gene', (156, 160))	('cancers', 'Disease', 'MESH:D009369', (307, 314))	('oncogenesis', 'biological_process', 'GO:0007048', ('382', '393'))	('Galphaq', 'Gene', '2776', (359, 366))	('G proteins', 'Protein', (339, 349))	('GNAQ', 'Gene', '2776', (191, 195))	('cancers', 'Phenotype', 'HP:0002664', (402, 409))	('cancers', 'Disease', (402, 409))	('GNAQ', 'Gene', '2776', (57, 61))	('GEP100', 'Gene', (62, 68))	('GEP100', 'Gene', '9922', (62, 68))	('GNAQ', 'Gene', (191, 195))	('cancers', 'Phenotype', 'HP:0002664', (307, 314))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))	('cancer', 'Phenotype', 'HP:0002664', (402, 408))	('cancers', 'Disease', (307, 314))	('GNAQ', 'Gene', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('signaling', 'biological_process', 'GO:0023052', ('169', '178'))	('drive', 'Reg', (376, 381))	('RAS', 'Disease', (371, 374))	('triggering', 'Reg', (413, 423))
66288	27265506	We found that oncogenic GNAQ, a Galphaq protein, induces its multiple signaling pathways through a single node:the small GTPase ARF6.	('GNAQ', 'Gene', '2776', (24, 28))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('induces', 'Reg', (49, 56))	('GNAQ', 'Gene', (24, 28))	('oncogenic', 'Var', (14, 23))	('GTP', 'Chemical', 'MESH:D006160', (121, 124))	('Galphaq', 'Gene', (32, 39))	('Galphaq', 'Gene', '2776', (32, 39))	('signaling', 'biological_process', 'GO:0023052', ('70', '79'))
66297	25506912	Depletion of BAP1, a known suppressor of metastasis in patients, increased the amount of transmigration of uveal melanoma cells in transwell assays; but BAP1 depletion did not affect the rate of intercalation, based on movies of living cells.	('increased', 'PosReg', (65, 74))	('BAP1', 'Gene', (13, 17))	('transmigration', 'CPA', (89, 103))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('uveal melanoma', 'Disease', (107, 121))	('BAP1', 'Gene', '8314', (153, 157))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('Depletion', 'Var', (0, 9))	('patients', 'Species', '9606', (55, 63))	('BAP1', 'Gene', '8314', (13, 17))	('BAP1', 'Gene', (153, 157))	('uveal melanoma', 'Disease', 'MESH:C536494', (107, 121))
66298	25506912	Our results reveal a novel route of transendothelial migration for uveal melanoma cells, and they provide insight into the mechanism by which loss of BAP1 promotes metastasis.	('BAP1', 'Gene', (150, 154))	('loss', 'Var', (142, 146))	('uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('uveal melanoma', 'Disease', (67, 81))	('uveal melanoma', 'Disease', 'MESH:C536494', (67, 81))	('promotes', 'PosReg', (155, 163))	('metastasis', 'CPA', (164, 174))	('BAP1', 'Gene', '8314', (150, 154))	('transendothelial migration', 'CPA', (36, 62))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
66313	25506912	We find that this process requires VCAM-mediated adhesion between UM cells and ECs and that loss of the metastasis suppressor BAP1 enhances TEM.	('enhances', 'PosReg', (131, 139))	('BAP1', 'Gene', (126, 130))	('TEM', 'cellular_component', 'GO:0097197', ('140', '143'))	('TEM', 'MPA', (140, 143))	('loss', 'Var', (92, 96))	('BAP1', 'Gene', '8314', (126, 130))
66338	25506912	OCM-1A cells were faster, with 67% initiating TEM by 1 hr after addition, compared with 29% of 92.1 cells (Fig.	('TEM', 'cellular_component', 'GO:0097197', ('46', '49'))	('initiating TEM', 'MPA', (35, 49))	('OCM-1', 'Species', '83984', (0, 5))	('OCM-1A', 'Var', (0, 6))
66351	25506912	BAP1 loss-of-function mutations promote the metastatic spread of UM cancers in patients, and TEM should be a rate-limiting step of metastasis.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('BAP1', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('metastatic spread', 'CPA', (44, 61))	('mutations', 'Var', (22, 31))	('patients', 'Species', '9606', (79, 87))	('TEM', 'cellular_component', 'GO:0097197', ('93', '96'))	('BAP1', 'Gene', '8314', (0, 4))	('promote', 'PosReg', (32, 39))	('loss-of-function', 'NegReg', (5, 21))
66352	25506912	Therefore, we asked whether loss of BAP1 affected transmigration of UM cells in our model of TEM.	('loss', 'Var', (28, 32))	('BAP1', 'Gene', '8314', (36, 40))	('affected', 'Reg', (41, 49))	('BAP1', 'Gene', (36, 40))	('TEM', 'cellular_component', 'GO:0097197', ('93', '96'))	('transmigration', 'CPA', (50, 64))
66354	25506912	Depletion of BAP1 doubled the number of transmigration events by UM cells in these assays (Fig.ure 6A).	('BAP1', 'Gene', (13, 17))	('ure', 'Chemical', 'MESH:D014508', (95, 98))	('Depletion', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (13, 17))	('transmigration', 'CPA', (40, 54))
66368	25506912	Antibody crosslinking of ICAM1 can activate the ICAM1 pathway in ECs, and this may be affecting EC activity in our movies.	('ICAM1', 'Gene', '3383', (48, 53))	('ICAM1', 'Gene', '3383', (25, 30))	('activate', 'PosReg', (35, 43))	('Antibody crosslinking', 'Var', (0, 21))	('affecting', 'Reg', (86, 95))	('ICAM1', 'Gene', (25, 30))	('ICAM1', 'Gene', (48, 53))
66370	25506912	However, anti-VCAM increased the overall level of transmigration in transwell assays, while anti-ICAM1 had no effect in this assay.	('ICAM1', 'Gene', (97, 102))	('anti-VCAM', 'Var', (9, 18))	('increased', 'PosReg', (19, 28))	('ICAM1', 'Gene', '3383', (97, 102))	('transmigration', 'MPA', (50, 64))
66372	25506912	Human uveal melanoma tumors with loss-of-function mutations in BAP1 are more likely to metastasize.	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (6, 27))	('Human', 'Species', '9606', (0, 5))	('uveal melanoma tumors', 'Disease', (6, 27))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('metastasize', 'CPA', (87, 98))	('mutations', 'Var', (50, 59))	('BAP1', 'Gene', (63, 67))	('BAP1', 'Gene', '8314', (63, 67))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('uveal melanoma', 'Phenotype', 'HP:0007716', (6, 20))	('loss-of-function', 'NegReg', (33, 49))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
66375	25506912	As predicted, shRNA-mediated depletion of BAP1 increased the overall rate of TEM by UM cells in transwell assays.	('depletion', 'Var', (29, 38))	('BAP1', 'Gene', '8314', (42, 46))	('BAP1', 'Gene', (42, 46))	('increased', 'PosReg', (47, 56))	('TEM', 'cellular_component', 'GO:0097197', ('77', '80'))	('TEM', 'CPA', (77, 80))
66376	25506912	However, movies of UM cells undergoing transmigration revealed no effect of BAP1 depletion on the rate of UM cell intercalation into the monolayer.	('BAP1', 'Gene', '8314', (76, 80))	('depletion', 'Var', (81, 90))	('BAP1', 'Gene', (76, 80))
66377	25506912	Thus, BAP1 depletion appears to affect later steps in transmigration of UM cells, such as disengagement from and invasion underneath the monolayer.	('disengagement from', 'CPA', (90, 108))	('BAP1', 'Gene', (6, 10))	('affect', 'Reg', (32, 38))	('invasion underneath the monolayer', 'CPA', (113, 146))	('depletion', 'Var', (11, 20))	('transmigration', 'CPA', (54, 68))	('BAP1', 'Gene', '8314', (6, 10))
66380	25506912	Depletion of BAP1 from these cell lines makes them less spindle-like in culture.	('spindle', 'cellular_component', 'GO:0005819', ('56', '63'))	('BAP1', 'Gene', (13, 17))	('ure', 'Chemical', 'MESH:D014508', (76, 79))	('less spindle-like in culture', 'CPA', (51, 79))	('Depletion', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (13, 17))
66386	25506912	BAP1 depletion appears to promote UM cell migration underneath the monolayer.	('promote', 'PosReg', (26, 33))	('depletion', 'Var', (5, 14))	('BAP1', 'Gene', (0, 4))	('cell migration', 'biological_process', 'GO:0016477', ('37', '51'))	('UM cell migration underneath the monolayer', 'CPA', (34, 76))	('BAP1', 'Gene', '8314', (0, 4))
66397	23867514	We discovered that PBRM1 mutations tend to anti-correlate with BAP1 mutations in ccRCC, and that PBRM1- and BAP1-mutated tumors exhibit different biology and are associated with markedly different outcomes.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('mutations', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('BAP1', 'Gene', (63, 67))	('tumors', 'Disease', (121, 127))	('anti-correlate', 'NegReg', (43, 57))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('associated', 'Reg', (162, 172))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('mutations', 'Var', (68, 77))	('PBRM1', 'Gene', (19, 24))
66401	23867514	The following year, the same group reported frequent VHL mutations in sporadic ccRCC.	('VHL', 'Disease', (53, 56))	('VHL', 'Disease', 'MESH:D006623', (53, 56))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('mutations', 'Var', (57, 66))
66412	23867514	Thus, with a single deletion, renal cells lose one copy of 4 tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('deletion', 'Var', (20, 28))	('tumor suppressor', 'biological_process', 'GO:0051726', ('61', '77'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('61', '77'))	('tumor', 'Disease', (61, 66))	('lose', 'NegReg', (42, 46))
66415	23867514	Meta-analyses show that the frequency of SETD2 mutations in ccRCC is twice as high in tumors with PBRM1 mutations.	('PBRM1', 'Gene', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutations', 'Var', (104, 113))	('mutations', 'Var', (47, 56))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('SETD2', 'Gene', '29072', (41, 46))	('RCC', 'Disease', (62, 65))	('SETD2', 'Gene', (41, 46))
66417	23867514	Mutations acquired early during the process of tumorigenesis are ubiquitous, whereas those acquired at very late stages are private, with shared mutations in between.	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
66418	23867514	VHL and PBRM1 mutations may be acquired early, whereas BAP1 and SETD2 mutations may occur later.	('VHL', 'Disease', 'MESH:D006623', (0, 3))	('BAP1', 'Gene', (55, 59))	('SETD2', 'Gene', '29072', (64, 69))	('VHL', 'Disease', (0, 3))	('SETD2', 'Gene', (64, 69))	('mutations', 'Var', (14, 23))	('PBRM1', 'Gene', (8, 13))
66419	23867514	In some ccRCC, there are different mutations in SETD2 and this convergence may be explained by cooperation between PBRM1 and SETD2.	('RCC', 'Disease', (10, 13))	('SETD2', 'Gene', '29072', (48, 53))	('RCC', 'Disease', 'MESH:C538614', (10, 13))	('SETD2', 'Gene', '29072', (125, 130))	('SETD2', 'Gene', (48, 53))	('SETD2', 'Gene', (125, 130))	('mutations', 'Var', (35, 44))
66420	23867514	The finding that PBRM1 and BAP1 mutations are largely exclusive and that tumors with these mutations exhibit different biology and are associated with markedly different overall survival (OS) set the foundation for the first molecular genetic classification of sporadic ccRCC.	('RCC', 'Disease', (272, 275))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('BAP1', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('PBRM1', 'Gene', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('associated', 'Reg', (135, 145))	('mutations', 'Var', (32, 41))	('tumors', 'Disease', (73, 79))	('RCC', 'Disease', 'MESH:C538614', (272, 275))
66422	23867514	Exome sequencing of 7 ccRCC and matched normal tissues by the Sanger Institute identified truncating mutations in PBRM1 (Polybromo 1) in 4 tumors.	('RCC', 'Disease', (24, 27))	('Polybromo 1', 'Gene', '55193', (121, 132))	('Polybromo 1', 'Gene', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('truncating mutations', 'Var', (90, 110))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('PBRM1', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
66424	23867514	The PBRM1 gene is located on chromosome 3p21 and in 38 tumors examined, PBRM1 mutations were uniformly associated with loss of heterozygosity (LOH).	('p21', 'Gene', (41, 44))	('p21', 'Gene', '644914', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('chromosome', 'cellular_component', 'GO:0005694', ('29', '39'))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (78, 87))	('PBRM1', 'Gene', (72, 77))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('loss', 'NegReg', (119, 123))
66425	23867514	PBRM1 mutations occurred most often together with VHL mutations and nearly all of the PBRM1-mutant tumors that Varela et al., examined (36/38) exhibited a hypoxia signature, including some cases without a detectable VHL mutation.	('VHL', 'Disease', (50, 53))	('PBRM1-mutant', 'Var', (86, 98))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('VHL', 'Disease', (216, 219))	('PBRM1', 'Gene', (0, 5))	('VHL', 'Disease', 'MESH:D006623', (216, 219))	('PBRM1-mutant', 'Gene', (86, 98))	('hypoxia', 'Disease', 'MESH:D000860', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))	('hypoxia', 'Disease', (155, 162))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('VHL', 'Disease', 'MESH:D006623', (50, 53))	('mutations', 'Var', (6, 15))	('exhibited', 'Reg', (143, 152))
66426	23867514	These data suggest that PBRM1 mutations are often associated with loss of VHL.	('loss', 'NegReg', (66, 70))	('PBRM1', 'Gene', (24, 29))	('mutations', 'Var', (30, 39))	('associated', 'Reg', (50, 60))	('VHL', 'Disease', (74, 77))	('VHL', 'Disease', 'MESH:D006623', (74, 77))
66429	23867514	PBRM1 mutation in ccRCC was initially reported to portend aggressiveness.	('aggressiveness', 'Disease', 'MESH:D001523', (58, 72))	('aggressiveness', 'Disease', (58, 72))	('PBRM1', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('aggressiveness', 'Phenotype', 'HP:0000718', (58, 72))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('portend', 'PosReg', (50, 57))	('RCC', 'Disease', (20, 23))
66430	23867514	However, more recent reports suggest that PBRM1 mutations are found in tumors at similar rates regardless of stage, and PBRM1 mutations appear not to adversely impact patient survival.	('impact', 'Reg', (160, 166))	('PBRM1', 'Gene', (120, 125))	('patient', 'Species', '9606', (167, 174))	('PBRM1', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('mutations', 'Var', (48, 57))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
66442	23867514	The importance of bromodomains and BAH domains for BAF180 tumor suppressor function is highlighted by their being frequent targets of missense mutations in renal cancer.	('BAF180', 'Gene', (51, 57))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('BAF180', 'Gene', '55193', (51, 57))	('missense mutations', 'Var', (134, 152))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('renal cancer', 'Disease', (156, 168))	('tumor suppressor', 'biological_process', 'GO:0051726', ('58', '74'))	('renal cancer', 'Disease', 'MESH:D007680', (156, 168))	('renal cancer', 'Phenotype', 'HP:0009726', (156, 168))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('58', '74'))
66443	23867514	While these domains are highly structured and missense mutations may inactivate BAF180 by disrupting folding and protein stability, there is precedent for a missense mutation in a bromodomain not affecting BAF180 levels.	('missense mutations', 'Var', (46, 64))	('BAF180', 'Gene', '55193', (80, 86))	('BAF180', 'Gene', '55193', (206, 212))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('folding', 'MPA', (101, 108))	('protein stability', 'CPA', (113, 130))	('inactivate', 'NegReg', (69, 79))	('disrupting', 'NegReg', (90, 100))	('missense mutation', 'Var', (157, 174))	('BAF180', 'Gene', (80, 86))	('BAF180', 'Gene', (206, 212))
66444	23867514	Should other such mutations be found, the data would suggest that each bromodomain may be required for BAF180 tumor suppressor function.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('BAF180', 'Gene', '55193', (103, 109))	('mutations', 'Var', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('BAF180', 'Gene', (103, 109))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
66447	23867514	In addition, ARID1A and ARID1B, which encode the putative targeting subunits of the BAF complex, are also mutated in renal cancer (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/ and http://cancergenome.nih.gov/).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (138, 144))	('ARID1A', 'Gene', '8289', (13, 19))	('ARID1B', 'Gene', '57492', (24, 30))	('renal cancer', 'Disease', (117, 129))	('renal cancer', 'Phenotype', 'HP:0009726', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (158, 164))	('renal cancer', 'Disease', 'MESH:D007680', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('mutated', 'Var', (106, 113))	('ARID1A', 'Gene', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (123, 129))	('ARID1B', 'Gene', (24, 30))
66448	23867514	These mutations are not exclusive with PBRM1 mutations, suggesting that mutations in these genes may cooperate in tumorigenesis.	('mutations', 'Var', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('mutations', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('cooperate', 'Reg', (101, 110))	('PBRM1', 'Gene', (39, 44))
66450	23867514	In addition, the catalytic subunits, and in particular BRG1, which forms part of both the BAF and PBAF complexes, are targeted by mutation in ccRCC (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/ and http://cancergenome.nih.gov/).	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('BRG1', 'Gene', '6597', (55, 59))	('mutation', 'Var', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (176, 182))	('RCC', 'Disease', (144, 147))	('BRG1', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
66451	23867514	Other subunits mutated in ccRCC include BAF170, BAF60A and BAF47.	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('BAF170', 'Gene', '6601', (40, 46))	('BAF47', 'Gene', '6598', (59, 64))	('BAF47', 'Gene', (59, 64))	('BAF60A', 'Gene', '6602', (48, 54))	('mutated', 'Var', (15, 22))	('BAF170', 'Gene', (40, 46))	('BAF60A', 'Gene', (48, 54))	('RCC', 'Disease', (28, 31))
66453	23867514	The mutation of other subunits suggests that SWI/SNF function is important, but it is conceivable that BAF180 may be implicated in other processes.	('implicated', 'Reg', (117, 127))	('BAF180', 'Gene', '55193', (103, 109))	('mutation', 'Var', (4, 12))	('BAF180', 'Gene', (103, 109))
66461	23867514	Conversely, mutations in PBRM1 and SETD2 co-occur in tumors at a frequency higher than expected by chance alone.	('mutations', 'Var', (12, 21))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PBRM1', 'Gene', (25, 30))	('SETD2', 'Gene', '29072', (35, 40))	('SETD2', 'Gene', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', (53, 59))
66463	23867514	Interestingly, mutations in SETD2 in tumors are associated with loss of DNA methylation at non-promoter regions.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('mutations', 'Var', (15, 24))	('DNA methylation at non-promoter regions', 'MPA', (72, 111))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('loss', 'NegReg', (64, 68))	('SETD2', 'Gene', '29072', (28, 33))	('DNA methylation', 'biological_process', 'GO:0006306', ('72', '87'))	('tumors', 'Disease', (37, 43))	('SETD2', 'Gene', (28, 33))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
66464	23867514	A greater understanding of the cooperativity between PBRM1 and SETD2 mutations may identify opportunities for therapeutic intervention.	('SETD2', 'Gene', '29072', (63, 68))	('mutations', 'Var', (69, 78))	('SETD2', 'Gene', (63, 68))	('PBRM1', 'Gene', (53, 58))
66470	23867514	Smarca4+/- mice develop mammary tumors, albeit at low penetrance.	('mammary', 'Disease', (24, 31))	('mice', 'Species', '10090', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('Smarca4+/-', 'Var', (0, 10))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
66473	23867514	In addition, conditional biallelic inactivation of Smarcb1 in lymphocytes causes lymphoma with 100% penetrance and a short latency.	('lymphoma', 'Disease', (81, 89))	('causes', 'Reg', (74, 80))	('biallelic inactivation', 'Var', (25, 47))	('lymphoma', 'Disease', 'MESH:D008223', (81, 89))	('lymphoma', 'Phenotype', 'HP:0002665', (81, 89))	('Smarcb1', 'Gene', (51, 58))
66475	23867514	PBRM1 knockdown in 4/5 RCC cell lines increased proliferation and the cell line with discrepant results was PBRM1-deficient.	('PBRM1-deficient', 'Disease', (108, 123))	('proliferation', 'CPA', (48, 61))	('PBRM1', 'Gene', (0, 5))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('knockdown', 'Var', (6, 15))	('increased', 'PosReg', (38, 47))	('PBRM1-deficient', 'Disease', 'MESH:D007153', (108, 123))
66476	23867514	The development of therapies exploiting the loss of PBRM1 in renal cancer will be facilitated by a greater understanding of the molecular mechanism of BAF180 tumor suppressor action.	('renal cancer', 'Phenotype', 'HP:0009726', (61, 73))	('tumor', 'Disease', (158, 163))	('tumor suppressor', 'biological_process', 'GO:0051726', ('158', '174'))	('renal cancer', 'Disease', 'MESH:D007680', (61, 73))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('158', '174'))	('PBRM1', 'Gene', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('loss', 'Var', (44, 48))	('BAF180', 'Gene', (151, 157))	('renal cancer', 'Disease', (61, 73))	('BAF180', 'Gene', '55193', (151, 157))
66482	23867514	A screen in Drosophila for suppressors of a PcG mutant identified the orthologue of BRM/BRG1 in flies, brm.	('PcG', 'Gene', (44, 47))	('PcG', 'Gene', '40358', (44, 47))	('mutant', 'Var', (48, 54))	('Drosophila', 'Species', '7227', (12, 22))	('BRG1', 'Gene', (88, 92))	('BRG1', 'Gene', '6597', (88, 92))
66483	23867514	Heterozygous mutations (or deficiencies) in brm suppressed homeotic transformations (alterations in body patterning) induced by a polycomb loss-of-function mutation.	('brm', 'Gene', (44, 47))	('polycomb', 'Gene', (130, 138))	('body patterning', 'CPA', (100, 115))	('polycomb', 'Gene', '40358', (130, 138))	('suppressed', 'NegReg', (48, 58))	('homeotic transformations', 'CPA', (59, 83))	('loss-of-function', 'NegReg', (139, 155))	('mutation', 'Var', (156, 164))
66484	23867514	These data suggest that the derepression of gene expression induced by a polycomb gene mutation involves BRM/BRG1 and nucleosome remodeling.	('gene expression', 'MPA', (44, 59))	('BRG1', 'Gene', (109, 113))	('gene expression', 'biological_process', 'GO:0010467', ('44', '59'))	('polycomb', 'Gene', (73, 81))	('nucleosome', 'cellular_component', 'GO:0000786', ('118', '128'))	('derepression', 'PosReg', (28, 40))	('BRG1', 'Gene', '6597', (109, 113))	('polycomb', 'Gene', '40358', (73, 81))	('mutation', 'Var', (87, 95))
66485	23867514	Loss of SMARCB1, frequently observed in malignant rhabdoid tumors, results in PRC2-dependent repression of p16.	('SMARCB1', 'Gene', '6598', (8, 15))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (40, 65))	('SMARCB1', 'Gene', (8, 15))	('p16', 'Gene', '1029', (107, 110))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('PRC2-dependent repression', 'MPA', (78, 103))	('p16', 'Gene', (107, 110))	('malignant rhabdoid tumors', 'Disease', (40, 65))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
66487	23867514	Furthermore, PRC2 appears to play a critical role in tumorigenesis following Smarcb1 inactivation.	('inactivation', 'Var', (85, 97))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('Smarcb1', 'Gene', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
66488	23867514	Lymphoma development in mice with conditional biallelic inactivation of Smarcb1 is suppressed by simultaneous inactivation of Ezh2, which encodes the catalytic subunit of PRC2.	('mice', 'Species', '10090', (24, 28))	('suppressed', 'NegReg', (83, 93))	('Ezh2', 'Gene', (126, 130))	('inactivation', 'Var', (110, 122))	('Ezh2', 'Gene', '14056', (126, 130))	('Lymphoma', 'Disease', 'MESH:D008223', (0, 8))	('biallelic inactivation', 'Var', (46, 68))	('Lymphoma', 'Phenotype', 'HP:0002665', (0, 8))	('Smarcb1', 'Gene', (72, 79))	('Lymphoma', 'Disease', (0, 8))
66492	23867514	Whether loss of PBRM1 would similarly activate EZH2 and sensitize RCC to EZH2 inhibitors remains to be determined.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('EZH2', 'Gene', '2146', (47, 51))	('EZH2', 'Gene', (47, 51))	('EZH2', 'Gene', '2146', (73, 77))	('activate', 'PosReg', (38, 46))	('EZH2', 'Gene', (73, 77))	('loss', 'Var', (8, 12))	('RCC', 'Disease', (66, 69))	('PBRM1', 'Gene', (16, 21))
66494	23867514	In addition, the preferential mutation of PBRM1 over SMARCB1 in ccRCC further suggests that they are not equivalent.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('SMARCB1', 'Gene', '6598', (53, 60))	('mutation', 'Var', (30, 38))	('PBRM1', 'Gene', (42, 47))	('SMARCB1', 'Gene', (53, 60))	('RCC', 'Disease', (66, 69))
66497	23867514	Knock-down of EZH2 reduces cell proliferation, and causes apoptosis in a subset of RCC cell lines.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('EZH2', 'Gene', (14, 18))	('cell proliferation', 'CPA', (27, 45))	('Knock-down', 'Var', (0, 10))	('EZH2', 'Gene', '2146', (14, 18))	('apoptosis', 'biological_process', 'GO:0097194', ('58', '67'))	('apoptosis', 'biological_process', 'GO:0006915', ('58', '67'))	('causes', 'Reg', (51, 57))	('apoptosis', 'CPA', (58, 67))	('reduces', 'NegReg', (19, 26))	('cell proliferation', 'biological_process', 'GO:0008283', ('27', '45'))
66499	23867514	Of note, the one cell line that did not undergo apoptosis in response to EZH2 knock-down, 769-P, is BAP1 mutant.	('knock-down', 'Var', (78, 88))	('apoptosis', 'biological_process', 'GO:0006915', ('48', '57'))	('BAP1', 'Gene', (100, 104))	('EZH2', 'Gene', '2146', (73, 77))	('EZH2', 'Gene', (73, 77))	('mutant', 'Var', (105, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('48', '57'))
66506	23867514	However, SMARCC1 mutations in ccRCC are exceedingly rare (0 mutations in 459 ccRCC sequenced; http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/).	('SMARCC1', 'Gene', (9, 16))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('SMARCC1', 'Gene', '6599', (9, 16))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (12, 15))	('RCC', 'Disease', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
66507	23867514	These data suggest that mutations in SMARCC1 and PBRM1 are non-equivalent, and raise the possibility that SMARCC1 mutations would be detrimental for ccRCC.	('mutations', 'Var', (114, 123))	('SMARCC1', 'Gene', (37, 44))	('detrimental', 'NegReg', (133, 144))	('RCC', 'Disease', (40, 43))	('SMARCC1', 'Gene', '6599', (37, 44))	('SMARCC1', 'Gene', (106, 113))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('SMARCC1', 'Gene', '6599', (106, 113))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('PBRM1', 'Gene', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (151, 154))	('mutations', 'Var', (24, 33))
66510	23867514	The lack of mutations in SMARCC1 raise the possibility that SMARCC1 may be required for ccRCC survival.	('RCC', 'Disease', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('SMARCC1', 'Gene', (60, 67))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('mutations', 'Var', (12, 21))	('RCC', 'Disease', 'MESH:C538614', (63, 66))	('SMARCC1', 'Gene', '6599', (60, 67))	('SMARCC1', 'Gene', (25, 32))	('SMARCC1', 'Gene', '6599', (25, 32))	('RCC', 'Disease', (28, 31))	('RCC', 'Disease', (90, 93))
66511	23867514	Interestingly, inactivation of another SWI/SNF gene, Smarca4 (encoding Brg1) abrogates lymphomas arising from biallelic loss of Smarcb1.	('Smarcb1', 'Gene', (128, 135))	('lymphomas', 'Disease', 'MESH:D008223', (87, 96))	('Smarca4', 'Gene', (53, 60))	('abrogates', 'NegReg', (77, 86))	('lymphomas', 'Disease', (87, 96))	('lymphoma', 'Phenotype', 'HP:0002665', (87, 95))	('inactivation', 'Var', (15, 27))
66512	23867514	Thus, inactivation of SWI/SNF complexes may be a viable approach for cancer therapy.	('inactivation', 'Var', (6, 18))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('SWI/SNF complexes', 'Protein', (22, 39))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
66513	23867514	SWI/SNF complexes may be broadly required for cell survival, but in the case of ccRCC with 3p deletions, the loss of one SMARCC1 allele may sensitize tumor cells to this approach.	('RCC', 'Disease', (124, 127))	('SMARCC1', 'Gene', '6599', (121, 128))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('loss', 'Var', (109, 113))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('sensitize', 'Reg', (140, 149))	('tumor', 'Disease', (150, 155))	('SMARCC1', 'Gene', (121, 128))
66515	23867514	While the function of BAF180 at the kinetochore is not well understood, mutations in kinetochore components may sensitize cells to microtubule-destabilizing drugs.	('mutations', 'Var', (72, 81))	('BAF180', 'Gene', (22, 28))	('BAF180', 'Gene', '55193', (22, 28))	('sensitize', 'Reg', (112, 121))	('microtubule', 'cellular_component', 'GO:0005874', ('131', '142'))	('kinetochore', 'cellular_component', 'GO:0000776', ('85', '96'))	('kinetochore', 'cellular_component', 'GO:0000776', ('36', '47'))
66516	23867514	BRCA1 associated protein-1 (BAP1) was identified in a yeast two-hybrid screen for proteins that interacted with the RING finger of BRCA1.	('BRCA1', 'Gene', (0, 5))	('yeast', 'Species', '4932', (54, 59))	('BRCA1', 'Gene', '672', (131, 136))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('RING finger', 'Var', (116, 127))	('BRCA1', 'Gene', (131, 136))	('BRCA1', 'Gene', '672', (0, 5))
66521	23867514	An analysis of multiple lung cancer cell lines identified a cell line with biallelic inactivation suggesting that BAP1 may be a two-hit tumor suppressor gene.	('multiple lung cancer', 'Disease', (15, 35))	('tumor suppressor', 'biological_process', 'GO:0051726', ('136', '152'))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('multiple lung cancer', 'Disease', 'MESH:D008175', (15, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('136', '152'))	('BAP1', 'Gene', (114, 118))	('biallelic inactivation', 'Var', (75, 97))	('tumor', 'Disease', (136, 141))
66522	23867514	In NCI-H226, where BAP1 suppresses cell proliferation, ectopic BAP1 expression also inhibited tumor formation in xenografts.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('BAP1', 'Gene', (63, 67))	('tumor', 'Disease', (94, 99))	('cell proliferation', 'CPA', (35, 53))	('suppresses', 'NegReg', (24, 34))	('formation', 'biological_process', 'GO:0009058', ('100', '109'))	('cell proliferation', 'biological_process', 'GO:0008283', ('35', '53'))	('ectopic', 'Var', (55, 62))	('NCI-H226', 'CellLine', 'CVCL:1544', (3, 11))	('inhibited', 'NegReg', (84, 93))
66523	23867514	BAP1 mutations in tumors were first identified in a search for metastasis-related genes in uveal melanoma (UM).	('UM', 'Phenotype', 'HP:0007716', (107, 109))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('BAP1', 'Gene', (0, 4))	('uveal melanoma', 'Disease', 'MESH:C536494', (91, 105))	('mutations', 'Var', (5, 14))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('uveal melanoma', 'Disease', (91, 105))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('uveal melanoma', 'Phenotype', 'HP:0007716', (91, 105))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
66524	23867514	Loss of chromosome 3 is the most important cytogenetic predictor of UM metastases, and Harbour et al., embarked on exome sequencing of two metastatic UM with chromosome 3 loss.	('chromosome', 'cellular_component', 'GO:0005694', ('158', '168'))	('metastases', 'Disease', (71, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('loss', 'NegReg', (171, 175))	('metastases', 'Disease', 'MESH:D009362', (71, 81))	('UM', 'Phenotype', 'HP:0007716', (68, 70))	('UM', 'Phenotype', 'HP:0007716', (150, 152))	('Loss', 'Var', (0, 4))
66525	23867514	BAP1 sequencing of a larger UM cohort showed BAP1 mutations in 84% of metastasizing UM, but in 4% of non-metastasizing tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('UM', 'Phenotype', 'HP:0007716', (28, 30))	('BAP1', 'Gene', (45, 49))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('mutations', 'Var', (50, 59))	('tumors', 'Disease', (119, 125))	('metastasizing UM', 'Disease', (70, 86))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
66526	23867514	In non-metastasizing tumors, BAP1 localized to the nucleus and BAP1 knockdown in a UM cell line caused epithelioid changes and cell rounding, reproducing features observed in metastasizing UM.	('caused', 'Reg', (96, 102))	('UM', 'Phenotype', 'HP:0007716', (189, 191))	('BAP1', 'Gene', (63, 67))	('UM', 'Phenotype', 'HP:0007716', (83, 85))	('nucleus', 'cellular_component', 'GO:0005634', ('51', '58'))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('knockdown', 'Var', (68, 77))	('epithelioid changes', 'CPA', (103, 122))	('BAP1', 'Gene', (29, 33))	('cell rounding', 'CPA', (127, 140))
66527	23867514	A year later, BAP1 mutations were reported in 23% of malignant pleural mesotheliomas (MPMs).	('malignant pleural mesotheliomas', 'Disease', (53, 84))	('BAP1', 'Gene', (14, 18))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (63, 84))	('malignant pleural mesotheliomas', 'Disease', 'MESH:C562839', (53, 84))	('mutations', 'Var', (19, 28))
66529	23867514	However, other investigators have postulated an inverse relationship between BAP1 and NF2 mutations.	('NF2', 'Gene', (86, 89))	('mutations', 'Var', (90, 99))	('NF2', 'Gene', '4771', (86, 89))	('inverse', 'NegReg', (48, 55))	('BAP1', 'Gene', (77, 81))
66534	23867514	In addition, BAP1 was found to be mutated in 1/10 ccRCC cell lines examined.	('RCC', 'Disease', (52, 55))	('BAP1', 'Gene', (13, 17))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('mutated', 'Var', (34, 41))
66536	23867514	Two tumors had mutations in BAP1 and subsequent analyses of BAP1 in 168 matched ccRCC/normal pairs identified 22 tumors with additional mutations.	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('mutations', 'Var', (15, 24))	('tumors', 'Disease', (4, 10))	('BAP1', 'Gene', (28, 32))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
66538	23867514	Overall, BAP1 loss (either by mutation or IHC) was observed in 15% of ccRCC (25/168).	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('mutation', 'Var', (30, 38))	('BAP1', 'Gene', (9, 13))	('loss', 'NegReg', (14, 18))
66540	23867514	BAP1 mutation rates increase as a function of stage suggesting that BAP1 may be implicated in ccRCC progression.	('RCC', 'Disease', (96, 99))	('BAP1', 'Gene', (0, 4))	('implicated', 'Reg', (80, 90))	('mutation', 'Var', (5, 13))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
66542	23867514	Interestingly, mutations in BAP1 and PBRM1 in ccRCC tend to be mutually exclusive.	('PBRM1', 'Gene', (37, 42))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('mutations', 'Var', (15, 24))	('BAP1', 'Gene', (28, 32))	('RCC', 'Disease', (48, 51))
66543	23867514	First, whereas BAP1 mutations in tumors are associated with high Fuhrman grade and mTORC1 activation, PBRM1 mutations are associated with low grade and a lack of mTORC1 activation.	('BAP1', 'Gene', (15, 19))	('activation', 'PosReg', (90, 100))	('mutations', 'Var', (108, 117))	('mTORC1', 'Gene', (162, 168))	('PBRM1', 'Gene', (102, 107))	('mTORC1', 'Gene', (83, 89))	('mTORC1', 'Gene', '382056', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('mTORC1', 'cellular_component', 'GO:0031931', ('83', '89'))	('mTORC1', 'Gene', '382056', (162, 168))	('tumors', 'Disease', (33, 39))	('mTORC1', 'cellular_component', 'GO:0031931', ('162', '168'))	('mutations', 'Var', (20, 29))	('high Fuhrman grade', 'MPA', (60, 78))
66544	23867514	In addition, BAP1 and PBRM1 mutations in ccRCC are associated with characteristic and non-overlapping gene expression signatures.	('gene expression', 'biological_process', 'GO:0010467', ('102', '117'))	('BAP1', 'Gene', (13, 17))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('mutations', 'Var', (28, 37))	('PBRM1', 'Gene', (22, 27))
66545	23867514	Finally, the outcomes of patients with ccRCCs mutated for BAP1 and PBRM1 is quite different.	('BAP1', 'Gene', (58, 62))	('mutated', 'Var', (46, 53))	('patients', 'Species', '9606', (25, 33))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))	('PBRM1', 'Gene', (67, 72))
66546	23867514	Thus, these data suggest that BAP1 and PBRM1 mutations define two different molecular subtypes of ccRCC, with different biology and outcomes.	('mutations', 'Var', (45, 54))	('BAP1', 'Gene', (30, 34))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('PBRM1', 'Gene', (39, 44))
66547	23867514	Kaplan-Meier analyses of patients with BAP1- and PBRM1-mutated tumors showed that BAP1 mutation was associated with a significantly worse OS than that PBRM1 mutation (median OS of 4.6 years; 95% CI 2.1-7.2 vs. 10.6 years; 95% CI 9.8-11.5) corresponding to a hazard ratio (HR) of 2.7 (95% CI 0.99-7.6, p=0.044).	('BAP1', 'Gene', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('patients', 'Species', '9606', (25, 33))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mutation', 'Var', (87, 95))
66552	23867514	Somatically-acquired mutations in BAP1 have been identified at low frequencies (<2%) in tumors from other sites including breast, lung, uterus, large bowel, ovary and prostate (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/).	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('BAP1', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('prostate', 'Disease', (167, 175))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('bowel', 'Disease', 'MESH:D015212', (150, 155))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('breast', 'Disease', (122, 128))	('ovary', 'Disease', (157, 162))	('cancer', 'Disease', (204, 210))	('uterus', 'Disease', (136, 142))	('ovary', 'Disease', 'MESH:D010051', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('large bowel', 'Phenotype', 'HP:0002037', (144, 155))	('mutations', 'Var', (21, 30))	('bowel', 'Disease', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('lung', 'Disease', (130, 134))
66553	23867514	During their studies, Harbour et al., discovered a BAP1 frameshift mutation in the germline of a patient with UM suggesting that BAP1 mutations may also predispose to familial UM.. BAP1 was subsequently found to be mutated in affected individuals of two families with a syndrome of autosomal dominant inheritance characterized by uveal and cutaneous melanomas.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (340, 359))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (340, 359))	('BAP1', 'Gene', (181, 185))	('UM', 'Phenotype', 'HP:0007716', (110, 112))	('cutaneous melanomas', 'Disease', (340, 359))	('melanomas', 'Phenotype', 'HP:0002861', (350, 359))	('mutated', 'Var', (215, 222))	('melanoma', 'Phenotype', 'HP:0002861', (350, 358))	('patient', 'Species', '9606', (97, 104))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (340, 358))	('UM', 'Phenotype', 'HP:0007716', (176, 178))
66554	23867514	The estimated frequency of germline BAP1 mutations in patients with familial cutaneous melanoma is <1%, but this percentage is higher for families with both cutaneous and uveal melanoma.	('mutations', 'Var', (41, 50))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (77, 95))	('patients', 'Species', '9606', (54, 62))	('familial cutaneous melanoma', 'Disease', (68, 95))	('cutaneous', 'Disease', (157, 166))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('uveal melanoma', 'Phenotype', 'HP:0007716', (171, 185))	('uveal melanoma', 'Disease', (171, 185))	('uveal melanoma', 'Disease', 'MESH:C536494', (171, 185))	('BAP1', 'Gene', (36, 40))	('familial cutaneous melanoma', 'Disease', 'MESH:C562393', (68, 95))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
66558	23867514	Germline BAP1 mutations were also discovered in families with a high incidence of mesothelioma.	('mesothelioma', 'Disease', (82, 94))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('discovered', 'Reg', (34, 44))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
66559	23867514	Families with germline BAP1 mutations exhibit a variety of other tumors including lung and breast cancers.	('lung', 'Disease', (82, 86))	('BAP1', 'Gene', (23, 27))	('breast cancers', 'Disease', (91, 105))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('exhibit', 'Reg', (38, 45))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('germline', 'Var', (14, 22))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancers', 'Phenotype', 'HP:0003002', (91, 105))	('breast cancers', 'Disease', 'MESH:D001943', (91, 105))	('mutations', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
66563	23867514	During our search for somatically-acquired BAP1 mutations in ccRCC, a germline BAP1 missense variant was discovered in one patient who was found to have familial RCC suggesting that BAP1 mutations may predispose to renal cancer as well.	('RCC', 'Disease', (63, 66))	('BAP1', 'Gene', (43, 47))	('renal cancer', 'Disease', 'MESH:D007680', (215, 227))	('RCC', 'Disease', (162, 165))	('patient', 'Species', '9606', (123, 130))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('BAP1', 'Gene', (182, 186))	('mutations', 'Var', (187, 196))	('familial RCC', 'Disease', 'MESH:C538614', (153, 165))	('renal cancer', 'Phenotype', 'HP:0009726', (215, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('renal cancer', 'Disease', (215, 227))	('predispose to', 'Reg', (201, 214))	('mutations', 'Var', (48, 57))	('familial RCC', 'Disease', (153, 165))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
66564	23867514	A study of 83 families with an unexplained predisposition to renal cancer revealed a novel missense mutation in BAP1 that cosegregated with the ccRCC phenotype in one family.	('BAP1', 'Gene', (112, 116))	('renal cancer', 'Phenotype', 'HP:0009726', (61, 73))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('renal cancer', 'Disease', 'MESH:D007680', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cosegregated', 'Reg', (122, 134))	('renal cancer', 'Disease', (61, 73))	('missense mutation', 'Var', (91, 108))
66569	23867514	In additional studies of 32 unrelated individuals with familial RCC, no more BAP1 mutations were found.	('familial RCC', 'Disease', (55, 67))	('mutations', 'Var', (82, 91))	('BAP1', 'Gene', (77, 81))	('familial RCC', 'Disease', 'MESH:C538614', (55, 67))
66572	23867514	The risk of RCC was markedly increased compared to the general population suggesting that BAP1 was a RCC-predisposing gene and that RCC should be added to the list of tumors associated with germline mutations in BAP1.	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('germline mutations', 'Var', (190, 208))	('BAP1', 'Gene', (212, 216))	('RCC', 'Disease', (132, 135))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', (12, 15))	('RCC', 'Disease', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
66580	23867514	BAP1 mutations target residues across the protein, although the UCH domain appears to be targeted particularly frequently (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/).	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('UCH', 'Gene', (64, 67))	('BAP1', 'Gene', (0, 4))	('target', 'Reg', (15, 21))	('cancer', 'Disease', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('mutations', 'Var', (5, 14))	('cancer', 'Disease', (150, 156))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('UCH', 'Gene', '7345', (64, 67))
66581	23867514	Mapping of missense mutations not affecting protein levels to a BAP1 structure model suggests that BAP1 tumor suppressor function requires not only ubiquitin binding, but also an intramolecular interaction between the UCH and ULD domains.	('ULD', 'Disease', (226, 229))	('UCH', 'Gene', '7345', (218, 221))	('BAP1', 'Gene', (99, 103))	('ubiquitin binding', 'molecular_function', 'GO:0043130', ('148', '165'))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor suppressor', 'biological_process', 'GO:0051726', ('104', '120'))	('UCH', 'Gene', (218, 221))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('104', '120'))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('missense', 'Var', (11, 19))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('interaction', 'Interaction', (194, 205))	('ubiquitin', 'MPA', (148, 157))	('binding', 'Interaction', (158, 165))	('ULD', 'Disease', 'MESH:D020194', (226, 229))
66588	23867514	PR-DUB deubiquitylates H2AK119ub1 (K118 in Drosophila), and despite that, at face value, this would antagonize PRC1, PR-DUB seemingly synergizes with PRC1.	('antagonize', 'NegReg', (100, 110))	('H2AK119ub1', 'Var', (23, 33))	('K118', 'Chemical', '-', (35, 39))	('Drosophila', 'Species', '7227', (43, 53))
66591	23867514	Calypso mutant fly embryos failed to suppress HOX genes leading to homeotic transformations characteristic of mutations in PcG genes.	('PcG', 'Gene', (123, 126))	('mutations', 'Var', (110, 119))	('PcG', 'Gene', '40358', (123, 126))	('HOX', 'Gene', (46, 49))	('HOX', 'Gene', '42536', (46, 49))	('homeotic transformations', 'CPA', (67, 91))
66592	23867514	As expected, Calypso/ASX complexes bound to HOX genes by ChIP and calypso and Asx mutant embryos exhibited global increases in H2Aub1 levels.	('ASX', 'Gene', '36612', (21, 24))	('Asx', 'Gene', '36612', (78, 81))	('HOX', 'Gene', '42536', (44, 47))	('H2Aub1 levels', 'MPA', (127, 140))	('bound', 'Interaction', (35, 40))	('increases', 'PosReg', (114, 123))	('ASX', 'Gene', (21, 24))	('HOX', 'Gene', (44, 47))	('Asx', 'Gene', (78, 81))	('calypso', 'Gene', (66, 73))	('mutant', 'Var', (82, 88))
66594	23867514	As Drosophila Calypso, human BAP1 deubiquitylates H2AK119ub1.	('Drosophila Calypso', 'Disease', (3, 21))	('Drosophila Calypso', 'Disease', 'None', (3, 21))	('human', 'Species', '9606', (23, 28))	('deubiquitylates', 'MPA', (34, 49))	('H2AK119ub1', 'Var', (50, 60))
66595	23867514	Furthermore, depletion of BAP1 in uveal melanoma cells increases global H2AK119ub1 levels.	('BAP1', 'Gene', (26, 30))	('global H2AK119ub1 levels', 'MPA', (65, 89))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('depletion', 'Var', (13, 22))	('increases', 'PosReg', (55, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (34, 48))	('uveal melanoma', 'Disease', 'MESH:C536494', (34, 48))	('uveal melanoma', 'Disease', (34, 48))
66604	23867514	Mutation in the Kelch domain of HCF-1 (P134S) disrupts binding to HBM-containing proteins, and also markedly impairs BAP1 binding.	('binding', 'Interaction', (122, 129))	('binding', 'molecular_function', 'GO:0005488', ('122', '129'))	('impairs', 'NegReg', (109, 116))	('BAP1', 'Protein', (117, 121))	('Mutation', 'Var', (0, 8))	('HBM-containing proteins', 'Protein', (66, 89))	('binding', 'Interaction', (55, 62))	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))	('disrupts', 'NegReg', (46, 54))	('HCF-1', 'Gene', (32, 37))	('P134S', 'Mutation', 'p.P134S', (39, 44))	('P134S', 'Var', (39, 44))
66613	23867514	Postnatal systemic Bap1 inactivation (using an inducible Cre from a ubiquitously expressed locus) led to the development of myelodysplasia with thrombocytopenia and anemia.	('anemia', 'Phenotype', 'HP:0001903', (165, 171))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (144, 160))	('systemic Bap1', 'Gene', (10, 23))	('inactivation', 'Var', (24, 36))	('thrombocytopenia', 'Disease', (144, 160))	('myelodysplasia', 'Phenotype', 'HP:0002863', (124, 138))	('anemia', 'Disease', (165, 171))	('anemia', 'Disease', 'MESH:D000740', (165, 171))	('myelodysplasia', 'Disease', 'MESH:D009190', (124, 138))	('thrombocytopenia', 'Disease', 'MESH:D013921', (144, 160))	('myelodysplasia', 'Disease', (124, 138))
66614	23867514	Thrombocytopenia developed as early as one week after Bap1 inactivation.	('inactivation', 'Var', (59, 71))	('Thrombocytopenia', 'Disease', (0, 16))	('Thrombocytopenia', 'Phenotype', 'HP:0001873', (0, 16))	('Bap1', 'Gene', (54, 58))	('Thrombocytopenia', 'Disease', 'MESH:D013921', (0, 16))
66620	23867514	In atypical Spitz tumors, which uncommonly have mutations in BRAF, BRAFV600E mutations tend to co-occur with BAP1 mutations.	('BRAF', 'Gene', '673', (67, 71))	('BRAF', 'Gene', '673', (61, 65))	('BRAF', 'Gene', (67, 71))	('BRAF', 'Gene', (61, 65))	('Spitz tumors', 'Disease', 'MESH:D018332', (12, 24))	('mutations', 'Var', (77, 86))	('BRAFV600E', 'Mutation', 'rs113488022', (67, 76))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('BAP1', 'Gene', (109, 113))	('Spitz tumors', 'Disease', (12, 24))	('mutations', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
66621	23867514	Among 32 tumors examined, 9 had lost BAP1 expression and 8 of them had mutations in BRAF.	('BRAF', 'Gene', '673', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('expression', 'MPA', (42, 52))	('BRAF', 'Gene', (84, 88))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (71, 80))	('BAP1', 'Protein', (37, 41))	('tumors', 'Disease', (9, 15))	('lost', 'NegReg', (32, 36))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
66622	23867514	In contrast, only one tumor out of 23 without BAP1 expression had a BRAF mutation (p<0.0001).	('BRAF', 'Gene', '673', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('BRAF', 'Gene', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('mutation', 'Var', (73, 81))
66625	23867514	BAP1 reintroduction into two different BAP1-deficient ccRCC cell lines reduced cell growth.	('RCC', 'Disease', (56, 59))	('BAP1', 'Gene', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('BAP1-deficient', 'Gene', (39, 53))	('cell growth', 'biological_process', 'GO:0016049', ('79', '90'))	('reintroduction', 'Var', (5, 19))	('reduced', 'NegReg', (71, 78))	('cell growth', 'CPA', (79, 90))
66627	23867514	Mammalian BAP1 deubiquitylates H2AK119ub1, and BAP1 reintroduction into BAP1-deficient ccRCC cell lines affected global levels of H2AK119ub1.	('Mammalian', 'Species', '9606', (0, 9))	('RCC', 'Disease', (89, 92))	('H2AK119ub1', 'MPA', (130, 140))	('affected', 'Reg', (104, 112))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('global levels', 'MPA', (113, 126))	('reintroduction', 'Var', (52, 66))	('BAP1', 'Gene', (47, 51))
66642	23867514	In experiments performed with BAP1-deficient and reconstituted ccRCC cell lines, BAP1 reintroduction reduced the sensitivity of two different cell lines to radiation and the PARP inhibitor olaparib.	('PARP', 'Gene', '1302', (174, 178))	('reintroduction', 'Var', (86, 100))	('BAP1', 'Gene', (81, 85))	('PARP', 'Gene', (174, 178))	('olaparib', 'Chemical', 'MESH:C531550', (189, 197))	('reduced', 'NegReg', (101, 108))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('sensitivity', 'MPA', (113, 124))	('RCC', 'Disease', (65, 68))
66644	23867514	Interestingly, atypical Spitz tumors with BAP1 mutations commonly exhibit a lymphocytic infiltrate.	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('Spitz tumors', 'Disease', 'MESH:D018332', (24, 36))	('BAP1', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('Spitz tumors', 'Disease', (24, 36))	('lymphocytic infiltrate', 'CPA', (76, 98))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
66647	23867514	Valproic acid seemingly counteracted the effects of BAP1 knockdown on H2AK119ub1.	('BAP1', 'Gene', (52, 56))	('Valproic acid', 'Chemical', 'MESH:D014635', (0, 13))	('knockdown', 'Var', (57, 66))
66648	23867514	As determined by the development of dendrites, valproic acid also induced differentiation of tumor cells with BAP1 mutations and shifted the gene expression signature to a more differentiated type.	('valproic acid', 'Chemical', 'MESH:D014635', (47, 60))	('mutations', 'Var', (115, 124))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('BAP1', 'Gene', (110, 114))	('induced', 'Reg', (66, 73))	('differentiation', 'CPA', (74, 89))	('gene expression', 'biological_process', 'GO:0010467', ('141', '156'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
66653	23867514	The development and evaluation of candidate compounds may be facilitated by the availability of tumorgraft models of renal cancer that reproduce the treatment responsiveness of human RCC, and the availability of mice bearing tumors with BAP1 and PBRM1 mutations.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('PBRM1', 'Gene', (246, 251))	('mice', 'Species', '10090', (212, 216))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('RCC', 'Disease', (183, 186))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('BAP1', 'Gene', (237, 241))	('renal cancer', 'Phenotype', 'HP:0009726', (117, 129))	('mutations', 'Var', (252, 261))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('human', 'Species', '9606', (177, 182))	('tumors', 'Disease', (225, 231))	('tumorgraft models of renal cancer', 'Disease', 'MESH:D007680', (96, 129))	('tumorgraft models of renal cancer', 'Disease', (96, 129))
66659	24169649	Patients were divided into disomy 3 and normal chromosome 8 (D3/8nl), disomy 3 and 8q gain (D3/8g), monosomy 3 and normal chromosome 8 (M3/8nl) and monosomy 3 and 8 or 8q gain (M3/8g).	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('disomy 3', 'Var', (70, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('122', '132'))	('gain', 'PosReg', (86, 90))	('Patients', 'Species', '9606', (0, 8))
66662	24169649	Multivariate Cox modelling analysis showed that the status of chromosomes 3 and 8 were the only two variables that independently contributed to prognosis: monosomy 3 alone p=0.001 and monosomy 3 and 8q gain p<0.0001.	('Cox', 'Gene', '1351', (13, 16))	('monosomy 3', 'Var', (155, 165))	('Cox', 'Gene', (13, 16))
66669	24169649	Many anatomical, histological and, more recently, genomic prognostic features have been used to identify patients with a higher risk of recurrence: large basal diameter, ciliary body involvement, extrascleral extension, epithelioid cell histology, high mitotic rate, chromosome imbalances (monosomy 3, 8q gain) and class 2 gene expression profile (GEP).	('patients', 'Species', '9606', (105, 113))	('chromosome', 'cellular_component', 'GO:0005694', ('267', '277'))	('chromosome imbalances', 'CPA', (267, 288))	('ciliary body involvement', 'CPA', (170, 194))	('high mitotic rate', 'CPA', (248, 265))	('monosomy', 'Var', (290, 298))	('imbalances', 'Phenotype', 'HP:0002172', (278, 288))	('extrascleral extension', 'CPA', (196, 218))	('epithelioid cell histology', 'CPA', (220, 246))	('gene expression', 'biological_process', 'GO:0010467', ('323', '338'))	('imbalance', 'Phenotype', 'HP:0002172', (278, 287))
66688	24169649	Four genomic types were subsequently defined taking into account the status of chromosomes 3 and 8: tumours with disomy 3 and normal dosage of chromosome 8 (named as 'D3/8nl'), monosomy 3 and normal dosage of chromosome 8 ('M3/8nl'), disomy 3 and any type of gain of chromosome 8 ('D3/8g') and monosomy 3 with any type of gain of chromosome 8 ('M3/8g').	('tumours', 'Disease', (100, 107))	("'M3/8g'", 'Var', (344, 351))	('chromosome', 'cellular_component', 'GO:0005694', ('267', '277'))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('chromosome', 'cellular_component', 'GO:0005694', ('209', '219'))	('gain', 'PosReg', (259, 263))	('chromosome', 'cellular_component', 'GO:0005694', ('143', '153'))	('chromosome', 'cellular_component', 'GO:0005694', ('330', '340'))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('tumours', 'Disease', 'MESH:D009369', (100, 107))	("'D3/8g'", 'Var', (281, 288))
66700	24169649	Ninety-one patients were classified in the D3/8nl group, 47 in the D3/8g group, 41 in the M3/8nl group and 159 in the M3/8g group (table 2).	('patients', 'Species', '9606', (11, 19))	('M3/8nl', 'Var', (90, 96))	('D3/8g', 'Var', (67, 72))
66704	24169649	Compared with the D3/8nl group, the HR of developing a metastasis was similar for patients with monosomy 3 alone (HR=7.3; p=0.01) and for those with gain of chromosome 8 alone (HR=10.6; p=0.002).	('patients', 'Species', '9606', (82, 90))	('monosomy 3', 'Var', (96, 106))	('metastasis', 'CPA', (55, 65))	('chromosome', 'cellular_component', 'GO:0005694', ('157', '167'))
66705	24169649	HR was 42.6 for patients with monosomy 3 and gain of chromosome 8 (p<0.0001).	('monosomy 3', 'Var', (30, 40))	('chromosome', 'cellular_component', 'GO:0005694', ('53', '63'))	('patients', 'Species', '9606', (16, 24))	('gain', 'PosReg', (45, 49))
66707	24169649	Three genomic prognostic groups were able to be identified on the basis of these data: a low-risk group corresponding to patients in the D3/8nl genomic group, an intermediate-risk group corresponding to patients with a tumour presenting either monosomy 3 (M3/8nl) or gain of chromosome 8 (D3/8g) and a high-risk group corresponding to patients in the M3/8g group.	('chromosome', 'cellular_component', 'GO:0005694', ('275', '285'))	('tumour', 'Phenotype', 'HP:0002664', (219, 225))	('tumour', 'Disease', 'MESH:D009369', (219, 225))	('tumour', 'Disease', (219, 225))	('patients', 'Species', '9606', (203, 211))	('patients', 'Species', '9606', (335, 343))	('gain', 'PosReg', (267, 271))	('monosomy', 'Var', (244, 252))	('patients', 'Species', '9606', (121, 129))	('D3/8nl', 'Var', (137, 143))
66715	24169649	The 2-year MFI was 100% for patients with a tumour presenting no imbalances of chromosomes 3 or 8, about 82.1-85.0% for tumours presenting an imbalance of one of these two chromosomes (either one of the two classes of imbalances) and 37.1% for tumours with monosomy 3 and any type of gain of chromosome 8.	('imbalance', 'Phenotype', 'HP:0002172', (65, 74))	('tumour', 'Phenotype', 'HP:0002664', (244, 250))	('tumour', 'Disease', 'MESH:D009369', (244, 250))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('tumour', 'Disease', (244, 250))	('imbalance', 'Phenotype', 'HP:0002172', (142, 151))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Disease', (44, 50))	('tumours', 'Disease', (120, 127))	('imbalances', 'Phenotype', 'HP:0002172', (218, 228))	('patients', 'Species', '9606', (28, 36))	('imbalance', 'Var', (142, 151))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('tumour', 'Disease', (120, 126))	('chromosome', 'cellular_component', 'GO:0005694', ('292', '302'))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumours', 'Disease', (244, 251))	('imbalance', 'Phenotype', 'HP:0002172', (218, 227))	('tumours', 'Phenotype', 'HP:0002664', (244, 251))	('imbalances', 'Phenotype', 'HP:0002172', (65, 75))	('tumours', 'Disease', 'MESH:D009369', (244, 251))
66725	24169649	Damato et al, based on a study of 356 patients, showed that monosomy 3 evaluated by FISH was strongly associated with metastatic deaths.	('metastatic deaths', 'CPA', (118, 135))	('associated with', 'Reg', (102, 117))	('monosomy 3', 'Var', (60, 70))	('patients', 'Species', '9606', (38, 46))
66728	24169649	They have recently published a large series of 452 patients showing an increased mortality when loss of chromosome 3 is associated with gain of 8q versus loss of chromosome 3 alone.	('loss', 'Var', (96, 100))	('patients', 'Species', '9606', (51, 59))	('chromosome', 'cellular_component', 'GO:0005694', ('162', '172'))	('gain', 'PosReg', (136, 140))	('chromosome', 'cellular_component', 'GO:0005694', ('104', '114'))
66739	24169649	For example, a recent randomised trial, initiated in 2009, is comparing adjuvant fotemustine versus close follow-up only in high-risk patients as defined on clinical and genomic criteria (ie, diameter >15 mm with retinal detachment or diameter >18 mm or monosomy 3 with or without gain of 8q; EudraCT No.	('retinal detachment', 'Phenotype', 'HP:0000541', (213, 231))	('monosomy 3', 'Var', (254, 264))	('patients', 'Species', '9606', (134, 142))	('retinal detachment', 'Disease', (213, 231))	('retinal detachment', 'Disease', 'MESH:D012163', (213, 231))	('fotemustine', 'Chemical', 'MESH:C054368', (81, 92))
66740	24169649	In future, the prognosis of patients with uveal melanoma will probably use new genomic technologies such as next-generation sequencing not only to refine prognosis by looking for additional mutations in BAP1, GNAQ, GNA11, SF3B1 or loss of heterozygosity in the primary tumour but also to follow circulating tumour DNA.	('GNA11', 'Gene', (215, 220))	('tumour', 'Phenotype', 'HP:0002664', (307, 313))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('tumour', 'Disease', 'MESH:D009369', (307, 313))	('uveal melanoma', 'Disease', (42, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('tumour', 'Disease', (307, 313))	('mutations', 'Var', (190, 199))	('patients', 'Species', '9606', (28, 36))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('SF3B1', 'Gene', (222, 227))	('GNAQ', 'Gene', '2776', (209, 213))	('BAP1', 'Gene', '8314', (203, 207))	('GNAQ', 'Gene', (209, 213))	('GNA11', 'Gene', '2767', (215, 220))	('SF3B1', 'Gene', '23451', (222, 227))	('BAP1', 'Gene', (203, 207))	('loss', 'Var', (231, 235))	('tumour', 'Phenotype', 'HP:0002664', (269, 275))	('tumour', 'Disease', 'MESH:D009369', (269, 275))	('DNA', 'cellular_component', 'GO:0005574', ('314', '317'))	('tumour', 'Disease', (269, 275))
66820	33837821	Anti-TNF-alpha antibodies induce a decrease of IL-1beta, IL-6, IL-8 (Nesbitt et al.	('IL-1beta', 'Gene', '3552', (47, 55))	('IL-6', 'Gene', (57, 61))	('IL-1', 'molecular_function', 'GO:0005149', ('47', '51'))	('IL-1beta', 'Gene', (47, 55))	('TNF-alpha', 'Gene', '7124', (5, 14))	('decrease', 'NegReg', (35, 43))	('IL-6', 'Gene', '3569', (57, 61))	('TNF-alpha', 'Gene', (5, 14))	('IL-8', 'Gene', '3576', (63, 67))	('IL-8', 'Gene', (63, 67))	('antibodies', 'Var', (15, 25))	('IL-6', 'molecular_function', 'GO:0005138', ('57', '61'))	('IL-8', 'molecular_function', 'GO:0005153', ('63', '67'))
66872	33765045	Internal tumor reflectivity was assessed qualitatively using B-scan and quantitatively using A-scan and graduated in five categories according to Type I quantitative ultrasonography classification by Ossoinig: low, medium-low, medium, medium-high, and high.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('medium', 'Var', (227, 233))	('tumor', 'Disease', (9, 14))	('medium-low', 'Var', (215, 225))
66968	31777292	Studies with anti-PD-1, anti-PD-L1, or anti-CTLA-4 monotherapy or a combination of any two of these therapies that enrolled at least ten patients who had no PD-L1 tumor expression were included in our analysis.	('anti-PD-1', 'Var', (13, 22))	('PD-L1 tumor', 'Disease', 'MESH:D010300', (157, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('patients', 'Species', '9606', (137, 145))	('PD-L1 tumor', 'Disease', (157, 168))	('anti-PD-L1', 'Var', (24, 34))
66970	31777292	Databases including MEDLINE and Google Scholar, as well as abstracts presented at the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), and the American Association for Cancer Research (AACR) were also used to identify clinical data for anti-PD1 or anti-PD-L1 therapy in each of these cancer types or subtypes.	('anti-PD1', 'Var', (283, 291))	('Cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('Cancer', 'Phenotype', 'HP:0002664', (215, 221))	('Oncology', 'Phenotype', 'HP:0002664', (165, 173))	('anti-PD-L1', 'Gene', (295, 305))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('Oncology', 'Phenotype', 'HP:0002664', (115, 123))	('Cancer', 'Disease', (215, 221))
66971	31777292	We searched for clinical trials using the following specific search terms: nivolumab, BMS-936558, pembrolizumab, MK-3475, atezolizumab, MPDL3280A, durvalumab, MEDI4736, avelumab, MSB0010718C, BMS-936559, cemiplimab, and REGN2810.	('MPDL3280A', 'Var', (136, 145))	('MSB', 'cellular_component', 'GO:0150086', ('179', '182'))	('atezolizumab', 'Chemical', 'MESH:C000594389', (122, 134))	('nivolumab', 'Chemical', 'MESH:D000077594', (75, 84))	('cemiplimab', 'Chemical', 'MESH:C000627974', (204, 214))	('BMS-936558', 'Gene', (86, 96))	('durvalumab', 'Chemical', 'MESH:C000613593', (147, 157))	('pembrolizumab', 'Chemical', 'MESH:C582435', (98, 111))	('REGN2810', 'Chemical', 'MESH:C000627974', (220, 228))	('MK-3475', 'Var', (113, 120))
66974	31777292	We plotted the ORR for anti-PD-1, anti-PD-L1, anti-CTLA-4, or combination therapy against the corresponding all-grade and G3/4 TRAEs across a variety of cancer types.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('anti-PD-L1', 'Var', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (153, 159))
66984	31777292	The precise mechanism of ICI-induced AEs remains unclear and current understanding includes increasing T-cell activity against antigens that are present in tumors and healthy tissue, increasing levels of preexisting autoantibodies, increasing level of inflammatory cytokines, and enhanced complement-mediated inflammation resulting from direct binding of an antibody against CTLA-4, which is expressed on normal tissue.	('inflammation', 'Disease', (309, 321))	('increasing level of inflammatory cytokines', 'Phenotype', 'HP:0012649', (232, 274))	('antibody', 'molecular_function', 'GO:0003823', ('358', '366'))	('antibody', 'Var', (358, 366))	('increasing', 'PosReg', (92, 102))	('level', 'MPA', (243, 248))	('CTLA-4', 'Gene', (375, 381))	('antibody', 'cellular_component', 'GO:0042571', ('358', '366'))	('binding', 'Interaction', (344, 351))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('levels', 'MPA', (194, 200))	('T-cell activity', 'CPA', (103, 118))	('inflammatory cytokines', 'MPA', (252, 274))	('binding', 'molecular_function', 'GO:0005488', ('344', '351'))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('inflammation', 'Disease', 'MESH:D007249', (309, 321))	('antibody', 'cellular_component', 'GO:0019815', ('358', '366'))	('tumors', 'Disease', (156, 162))	('increasing', 'PosReg', (232, 242))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('antibody', 'cellular_component', 'GO:0019814', ('358', '366'))	('enhanced', 'PosReg', (280, 288))	('increasing', 'PosReg', (183, 193))	('inflammation', 'biological_process', 'GO:0006954', ('309', '321'))
66987	31777292	However, CTLA-4 blockade entails a more global immune modulation than PD-1/PD-L1 blockade.	('blockade', 'Var', (16, 24))	('PD-1/PD-L1 blockade', 'Disease', (70, 89))	('CTLA-4', 'Gene', (9, 15))	('PD-1/PD-L1 blockade', 'Disease', 'MESH:D010300', (70, 89))
66998	31777292	There is agreement with the predictive effect between all-grade and G3/4 TREAs in most cancer types.	('cancer', 'Disease', (87, 93))	('G3/4', 'Var', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))
67114	32299493	In cutaneous melanoma most of the mutations concern the mitogen-activated protein kinase pathway (MAPK).	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('mitogen-activated protein kinase pathway', 'Pathway', (56, 96))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('MAPK', 'molecular_function', 'GO:0004707', ('98', '102'))	('concern', 'Reg', (44, 51))	('mutations', 'Var', (34, 43))	('cutaneous melanoma', 'Disease', (3, 21))
67115	32299493	The mutations altering this pathway most commonly are found in the serine/threonine-protein kinase B-Raf (BRAF) kinase; 40-50% of cutaneous melanoma have BRAF mutations.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (130, 148))	('mutations', 'Var', (159, 168))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('BRAF', 'Gene', '673', (106, 110))	('BRAF', 'Gene', '673', (154, 158))	('BRAF', 'Gene', (106, 110))	('BRAF', 'Gene', (154, 158))	('serine/threonine-protein kinase B-Raf', 'Gene', (67, 104))	('serine/threonine-protein kinase B-Raf', 'Gene', '673', (67, 104))	('cutaneous melanoma', 'Disease', (130, 148))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('mutations', 'Var', (4, 13))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (130, 148))
67117	32299493	The tumour suppressor BAP1 gene shows inactivating mutations in 85% of aggressive tumours and is considered to be a marker of metastatic disease.	('inactivating mutations', 'Var', (38, 60))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))	('aggressive tumours', 'Disease', 'MESH:D009369', (71, 89))	('BAP1', 'Gene', '8314', (22, 26))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('aggressive tumours', 'Disease', (71, 89))	('BAP1', 'Gene', (22, 26))
67132	32299493	The following seven cell lines were tested: Mel-202, MP41, MP38, MP65, MP46, MM28 and 92-1.	('MP65', 'Var', (65, 69))	('MM28', 'Gene', '79148', (77, 81))	('MP46', 'Var', (71, 75))	('MM28', 'Gene', (77, 81))
67154	32299493	MP41 cells treated with MOI of 70 Rigvir had earlier cytotoxic response than the MOI of 7 group.	('earlier', 'PosReg', (45, 52))	('MOI of 70', 'Var', (24, 33))	('Rigvir', 'Chemical', '-', (34, 40))
67156	32299493	92-1 cells treated with MOI of 70 Rigvir particles also showed earlier cytotoxic response than for the MOI of 7 treatment group.	('Rigvir', 'Chemical', '-', (34, 40))	('MOI of 70', 'Var', (24, 33))	('earlier', 'PosReg', (63, 70))	('cytotoxic response', 'CPA', (71, 89))
67158	32299493	Mel-202 cell treatment with MOI of 70 Rigvir also had earlier cytotoxic response than the MOI of 7 treatment group.	('earlier', 'PosReg', (54, 61))	('Rigvir', 'Chemical', '-', (38, 44))	('cytotoxic response', 'CPA', (62, 80))	('MOI of 70 Rigvir', 'Var', (28, 44))
67164	32299493	The MP41 cell line has a mutation in GNA11 (c.626 A > A/T), the 92-1 cell line has mutations in GNAQ (c.626 A > T) and EIF1AX (c.17 G/A).	('c.626 A > A/T', 'Var', (44, 57))	('c.17 G/A', 'Var', (127, 135))	('GNAQ', 'Gene', '2776', (96, 100))	('GNA11', 'Gene', '2767', (37, 42))	('GNA11', 'Gene', (37, 42))	('c.626 A > T', 'Mutation', 'rs121913492', (102, 113))	('c.17 G/A', 'Mutation', 'c.17G>A', (127, 135))	('EIF1AX', 'Gene', '1964', (119, 125))	('GNAQ', 'Gene', (96, 100))	('EIF1AX', 'Gene', (119, 125))	('c.626 A > A/T', 'Mutation', 'rs1057519742', (44, 57))	('c.626 A > T', 'Var', (102, 113))
67165	32299493	The Mel-202 cell line has mutations in GNAQ (c. 629 G > A) and SF3B1 (c.1793 C > T).	('c.1793 C > T', 'Mutation', 'c.1793C>T', (70, 82))	('629 G > A', 'SUBSTITUTION', 'None', (48, 57))	('GNAQ', 'Gene', (39, 43))	('SF3B1', 'Gene', (63, 68))	('c.1793 C > T', 'Var', (70, 82))	('SF3B1', 'Gene', '23451', (63, 68))	('629 G > A', 'Var', (48, 57))	('GNAQ', 'Gene', '2776', (39, 43))
67166	32299493	These mutations are specific to uveal melanoma as is BAP1 protein, which is considered to be a marker of metastatic disease.	('uveal melanoma', 'Phenotype', 'HP:0007716', (32, 46))	('uveal melanoma', 'Disease', 'MESH:C536494', (32, 46))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('uveal melanoma', 'Disease', (32, 46))	('BAP1', 'Gene', '8314', (53, 57))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('mutations', 'Var', (6, 15))	('BAP1', 'Gene', (53, 57))
67167	32299493	It has also been mentioned that the combination of loss of heterozygosity of chromosome 3 and BAP1 gene mutation cause metastases.	('cause', 'Reg', (113, 118))	('BAP1', 'Gene', '8314', (94, 98))	('chromosome', 'cellular_component', 'GO:0005694', ('77', '87'))	('loss of heterozygosity', 'Var', (51, 73))	('metastases', 'Disease', (119, 129))	('mutation', 'Var', (104, 112))	('BAP1', 'Gene', (94, 98))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
67169	32299493	Although GNA11 and GNAQ mutations are said to occur in an equal manner in both metastatic and nonmetastatic disease and not to be of prognostic value.	('GNA11', 'Gene', (9, 14))	('nonmetastatic disease', 'Disease', 'MESH:D003141', (94, 115))	('GNAQ', 'Gene', (19, 23))	('metastatic', 'Disease', (79, 89))	('nonmetastatic disease', 'Disease', (94, 115))	('GNAQ', 'Gene', '2776', (19, 23))	('mutations', 'Var', (24, 33))	('GNA11', 'Gene', '2767', (9, 14))
67170	32299493	GNA11 mutations are assumed to affect melanocytes more strongly than mutations in GNAQ, despite the proteins Galphaq (encoded by GNAQ) and Galpha11 (encoded by GNA11) having 90% homologous amino acid sequences.	('affect', 'Reg', (31, 37))	('Galpha11', 'Gene', (139, 147))	('GNA11', 'Gene', (160, 165))	('GNAQ', 'Gene', (82, 86))	('GNAQ', 'Gene', (129, 133))	('GNA11', 'Gene', (0, 5))	('GNA11', 'Gene', '2767', (160, 165))	('GNA11', 'Gene', '2767', (0, 5))	('Galpha11', 'Gene', '2767', (139, 147))	('GNAQ', 'Gene', '2776', (129, 133))	('Galphaq', 'Gene', (109, 116))	('Galphaq', 'Gene', '2776', (109, 116))	('GNAQ', 'Gene', '2776', (82, 86))	('mutations', 'Var', (6, 15))
67205	31936623	DHICA, 5H6MI2C, 6H5MI2C and 5SCD are also known to be excreted into the urine by the sulfate or ester glucuronide conjugates.	('glucuronide', 'Chemical', 'MESH:D020719', (102, 113))	('sulfate', 'Chemical', 'MESH:D013431', (85, 92))	('ester', 'Chemical', 'MESH:D004952', (96, 101))	('6H5MI2C', 'Var', (16, 23))	('5H6MI2C', 'Var', (7, 14))	('6H5MI2C', 'Chemical', 'MESH:C017408', (16, 23))	('5H6MI2C', 'Chemical', 'MESH:C017407', (7, 14))	('5SCD', 'Chemical', 'MESH:D003548', (28, 32))	('DHICA', 'Chemical', 'MESH:C030692', (0, 5))
67206	31936623	showed the urinary excretion and serum concentration levels of 5SCD and 6H5MI2C in 33 healthy Japanese subjects (average age 39 years).	('5SCD', 'Var', (63, 67))	('6H5MI2C', 'Var', (72, 79))	('serum concentration levels', 'MPA', (33, 59))	('6H5MI2C', 'Chemical', 'MESH:C017408', (72, 79))	('5SCD', 'Chemical', 'MESH:D003548', (63, 67))	('urinary excretion', 'MPA', (11, 28))	('excretion', 'biological_process', 'GO:0007588', ('19', '28'))
67207	31936623	The urinary excretion levels of 5SCD and 6H5MI2C were 0.45 +- 0.29 micromol/day and 0.39 +- 0.32 micromol/day, respectively, and their serum concentrations were 4.3 +- 1.8 nmol/L and 3.6 +- 1.8 nmol/L, respectively.	('6H5MI2C', 'Var', (41, 48))	('5SCD', 'Chemical', 'MESH:D003548', (32, 36))	('6H5MI2C', 'Chemical', 'MESH:C017408', (41, 48))	('5SCD', 'Var', (32, 36))	('serum concentrations', 'MPA', (135, 155))	('urinary excretion levels', 'MPA', (4, 28))	('excretion', 'biological_process', 'GO:0007588', ('12', '21'))
67245	31936623	However, the indole derivatives 6H5MI2C and 5H6MI2C are considered to be less effective than 5SCD because they are very unstable, and the analytical method needed to detect them is complicated.	('5H6MI2C', 'Var', (44, 51))	('5H6MI2C', 'Chemical', 'MESH:C017407', (44, 51))	('6H5MI2C', 'Var', (32, 39))	('indole', 'Chemical', 'MESH:C030374', (13, 19))	('6H5MI2C', 'Chemical', 'MESH:C017408', (32, 39))	('5SCD', 'Chemical', 'MESH:D003548', (93, 97))
67261	31936623	It is also known that the urinary excretion of 5SCD and 6H5MI2C increases several-fold during PUVA therapy and they change in parallel.	('urinary excretion', 'MPA', (26, 43))	('6H5MI2C', 'Var', (56, 63))	('5SCD', 'Chemical', 'MESH:D003548', (47, 51))	('6H5MI2C', 'Chemical', 'MESH:C017408', (56, 63))	('excretion', 'biological_process', 'GO:0007588', ('34', '43'))	('increases', 'PosReg', (64, 73))
67262	31936623	Therefore, 6H5MI2C and 5H6MI2C appear to be good markers for melanogenesis in normal melanocytes.	('5H6MI2C', 'Chemical', 'MESH:C017407', (23, 30))	('5H6MI2C', 'Var', (23, 30))	('6H5MI2C', 'Var', (11, 18))	('6H5MI2C', 'Chemical', 'MESH:C017408', (11, 18))
67357	31936623	In addition, HGF also controls the growth, invasion and metastasis of cancer cells and activating mutations of the receptor for HGF (c-Met) predisposes humans to cancer.	('metastasis of cancer', 'Disease', (56, 76))	('cancer', 'Disease', (162, 168))	('humans', 'Species', '9606', (152, 158))	('growth', 'CPA', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('HGF', 'Gene', '3082', (128, 131))	('invasion', 'CPA', (43, 51))	('metastasis of cancer', 'Disease', 'MESH:D009362', (56, 76))	('HGF', 'Gene', (128, 131))	('c-Met', 'Gene', '4233', (133, 138))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('HGF', 'Gene', '3082', (13, 16))	('predisposes', 'Reg', (140, 151))	('HGF', 'Gene', (13, 16))	('mutations', 'Var', (98, 107))	('c-Met', 'Gene', (133, 138))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
67423	31936623	Their results suggest that miR-16-5p, miR-17-5p, and miR-20a-5p are useful indicators of successful anti-PD-1 antibody therapy.	('miR-17-5p', 'Gene', '406952', (38, 47))	('miR-16-5p', 'Var', (27, 36))	('antibody', 'cellular_component', 'GO:0019815', ('110', '118'))	('miR-17-5p', 'Gene', (38, 47))	('antibody', 'cellular_component', 'GO:0019814', ('110', '118'))	('antibody', 'molecular_function', 'GO:0003823', ('110', '118'))	('miR-20a-5p', 'Chemical', '-', (53, 63))	('miR-20a-5p', 'Var', (53, 63))	('miR-16-5p', 'Chemical', '-', (27, 36))	('antibody', 'cellular_component', 'GO:0042571', ('110', '118'))
67427	31936623	In BRAF mutated patients with normal LDH, first-line immunotherapy seems to be a more effective approach.	('mutated', 'Var', (8, 15))	('patients', 'Species', '9606', (16, 24))	('BRAF', 'Gene', '673', (3, 7))	('LDH', 'MPA', (37, 40))	('BRAF', 'Gene', (3, 7))
67428	31936623	has demonstrated that the use of two different systemic treatment modalities allows the achievement of comparable survival in BRAF mutated and BRAF wild-type patients although BRAF mutation is a negative prognostic factor in stage IV melanoma.	('mutated', 'Var', (131, 138))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('BRAF', 'Gene', '673', (176, 180))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('patients', 'Species', '9606', (158, 166))	('melanoma', 'Disease', (234, 242))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))	('BRAF', 'Gene', (176, 180))
67454	31039142	High expression of BTNL9 was significantly associated with favorable prognosis of UM.	('BTNL9', 'Gene', (19, 24))	('High', 'Var', (0, 4))	('associated', 'Reg', (43, 53))	('BTNL9', 'Gene', '153579', (19, 24))	('UM', 'Phenotype', 'HP:0007716', (82, 84))
67462	31039142	Activating mutations in genes encoding the G-protein-alpha subunits GNAQ or GNA11 and ectopic stimulation of downstream signaling, including MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways, were observed in about 85-95% UM patients.	('GNA11', 'Gene', '2767', (76, 81))	('GNA11', 'Gene', (76, 81))	('mutations', 'Var', (11, 20))	('Activating', 'PosReg', (0, 10))	('MAPK', 'Pathway', (141, 145))	('Akt', 'Gene', (187, 190))	('GNAQ', 'Gene', (68, 72))	('MAPK', 'molecular_function', 'GO:0004707', ('141', '145'))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('PI3K', 'molecular_function', 'GO:0016303', ('181', '185'))	('UM', 'Phenotype', 'HP:0007716', (231, 233))	('patients', 'Species', '9606', (234, 242))	('phosphatidylinositol 3-kinase', 'Gene', (150, 179))	('downstream signaling', 'MPA', (109, 129))	('Akt', 'Gene', '207', (187, 190))	('GNAQ', 'Gene', '2776', (68, 72))	('phosphatidylinositol 3-kinase', 'Gene', '5294', (150, 179))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))
67470	31039142	Although it has been generally accepted that the ectopic function of T cells was associated with proliferative disorders especially cancer, the role of most BTN and BTNL family members in tumorigenesis and cancer progression is little understood.	('tumor', 'Disease', (188, 193))	('cancer', 'Disease', (132, 138))	('BTN', 'Gene', (165, 168))	('BTN', 'Gene', (157, 160))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('BTN', 'Gene', '696', (165, 168))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('BTN', 'Gene', '696', (157, 160))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('proliferative disorders especially cancer', 'Disease', 'MESH:D009369', (97, 138))	('ectopic', 'Var', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('associated', 'Reg', (81, 91))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('proliferative disorders especially cancer', 'Disease', (97, 138))
67478	31039142	orb2153) was from Biorbyt Company (Cambridge, UK) and antibody of beta-actin was from Santa Cruz Biotechnology (Santa Cruz, CA, USA).	('antibody', 'cellular_component', 'GO:0019815', ('54', '62'))	('beta-actin', 'Gene', (66, 76))	('antibody', 'cellular_component', 'GO:0019814', ('54', '62'))	('antibody', 'molecular_function', 'GO:0003823', ('54', '62'))	('orb2153', 'Var', (0, 7))	('beta-actin', 'Gene', '728378', (66, 76))	('antibody', 'cellular_component', 'GO:0042571', ('54', '62'))
67514	31039142	The 5-year overall survival rates of patients with low or high BTNL9 expression were 45.5% and 85.7%, respectively (Figure 2A).	('patients', 'Species', '9606', (37, 45))	('BTNL9', 'Gene', '153579', (63, 68))	('low', 'NegReg', (51, 54))	('high', 'Var', (58, 62))	('BTNL9', 'Gene', (63, 68))
67517	31039142	In our study, the high expression of BTNL9 was identified as an independent favorable prognostic factor in our study (P=0.033).	('high expression', 'Var', (18, 33))	('BTNL9', 'Gene', (37, 42))	('BTNL9', 'Gene', '153579', (37, 42))
67518	31039142	Post-operational risk of UM-related death of patients with high expression of BTNL9 was 0.33-fold ratio compared with those with low expression of BTNL9 (95% CI=0.06-0.89).	('BTNL9', 'Gene', '153579', (78, 83))	('BTNL9', 'Gene', '153579', (147, 152))	('BTNL9', 'Gene', (78, 83))	('patients', 'Species', '9606', (45, 53))	('UM', 'Phenotype', 'HP:0007716', (25, 27))	('high expression', 'Var', (59, 74))	('BTNL9', 'Gene', (147, 152))	('UM-related', 'Disease', (25, 35))
67522	31039142	After knocking down BTNL9 expression, we detected the influence of BTNL9 on melanoma proliferation and invasion, with MTT assay and Transwell assay.	('BTNL9', 'Gene', '153579', (67, 72))	('BTNL9', 'Gene', '153579', (20, 25))	('melanoma proliferation', 'Disease', (76, 98))	('melanoma proliferation', 'Disease', 'MESH:D008545', (76, 98))	('BTNL9', 'Gene', (67, 72))	('BTNL9', 'Gene', (20, 25))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('MTT', 'Chemical', 'MESH:C070243', (118, 121))	('influence', 'Reg', (54, 63))	('invasion', 'CPA', (103, 111))	('detected', 'Reg', (41, 49))	('knocking down', 'Var', (6, 19))
67523	31039142	As a result, there was no significant difference of proliferation between BTNL9 knockdown and control group (Figure 3C), whereas silencing BTNL9 substantially promoted the invasion of MeWo cells (Figure 3D).	('BTNL9', 'Gene', (139, 144))	('invasion of MeWo cells', 'CPA', (172, 194))	('BTNL9', 'Gene', (74, 79))	('silencing', 'Var', (129, 138))	('BTNL9', 'Gene', '153579', (74, 79))	('promoted', 'PosReg', (159, 167))	('BTNL9', 'Gene', '153579', (139, 144))
67525	31039142	One biological feature of UM is the mutations in guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) and guanine nucleotide-binding protein subunit alpha-11 (GNA11), which constitutively stimulates downstream signaling pathway including MAPK and PI3K/AKT signaling pathway.	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('AKT signaling', 'biological_process', 'GO:0043491', ('260', '273'))	('AKT', 'Gene', (260, 263))	('signaling pathway', 'biological_process', 'GO:0007165', ('264', '281'))	('GNA11', 'Gene', '2767', (167, 172))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('UM', 'Phenotype', 'HP:0007716', (26, 28))	('PI3K', 'molecular_function', 'GO:0016303', ('255', '259'))	('guanine nucleotide-binding protein subunit alpha-11', 'Gene', '2767', (114, 165))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('57', '75'))	('GNAQ', 'Gene', '2776', (104, 108))	('AKT', 'Gene', '207', (260, 263))	('downstream signaling pathway', 'Pathway', (207, 235))	('signaling pathway', 'biological_process', 'GO:0007165', ('218', '235'))	('MAPK', 'molecular_function', 'GO:0004707', ('246', '250'))	('GNAQ', 'Gene', (104, 108))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('122', '140'))	('GNA11', 'Gene', (167, 172))	('mutations', 'Var', (36, 45))	('stimulates', 'PosReg', (196, 206))
67530	31039142	The gammadeltaT cells are involved in the infiltration of several types of tumors including melanoma, breast, ovarian, colon, lung, pancreatic and prostate, and are considered to have potent antitumor activity.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('pancreatic', 'Disease', 'MESH:D010195', (132, 142))	('involved', 'Reg', (26, 34))	('lung', 'Disease', (126, 130))	('tumor', 'Disease', (195, 200))	('pancreatic', 'Disease', (132, 142))	('prostate', 'Disease', (147, 155))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma, breast, ovarian, colon', 'Disease', 'MESH:D008545', (92, 124))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('gammadeltaT', 'Var', (4, 15))	('tumors', 'Disease', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (75, 80))
67556	29593251	Depletion of MDMX, like the pharmacological activation of p53, inhibits the survival of UM cells, which is enhanced in combination with PKC inhibition.	('PKC', 'Gene', (136, 139))	('PKC', 'Gene', '112476', (136, 139))	('inhibits', 'NegReg', (63, 71))	('enhanced', 'PosReg', (107, 115))	('PKC', 'molecular_function', 'GO:0004697', ('136', '139'))	('survival of UM cells', 'CPA', (76, 96))	('UM', 'Phenotype', 'HP:0007716', (88, 90))	('Depletion', 'MPA', (0, 9))	('MDMX', 'Var', (13, 17))
67559	29593251	Here we show that specifically depleting PKCdelta inhibits UM cell growth, which can be further enhanced by p53 reactivation.	('UM cell growth', 'CPA', (59, 73))	('PKCdelta', 'molecular_function', 'GO:0004697', ('41', '49'))	('PKCdelta', 'Gene', (41, 49))	('depleting', 'Var', (31, 40))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))	('inhibits', 'NegReg', (50, 58))	('PKCdelta', 'Gene', '5580', (41, 49))	('UM', 'Phenotype', 'HP:0007716', (59, 61))
67560	29593251	In conclusion, our data show that the synergistic effects of p53 activation by MDM2 inhibition and broad spectrum PKC inhibition on survival of UM cells can also largely be achieved by the presumably less toxic combination of depletion of MDMX and targeting a specific PKC isoform, PKCdelta.	('PKC', 'Gene', (269, 272))	('PKC', 'Gene', (114, 117))	('PKCdelta', 'Gene', '5580', (282, 290))	('PKC', 'Gene', (282, 285))	('PKCdelta', 'Gene', (282, 290))	('PKC', 'molecular_function', 'GO:0004697', ('269', '272'))	('PKC', 'Gene', '112476', (269, 272))	('PKC', 'Gene', '112476', (114, 117))	('PKC', 'Gene', '112476', (282, 285))	('PKC', 'molecular_function', 'GO:0004697', ('114', '117'))	('MDM2', 'Gene', '4193', (79, 83))	('PKCdelta', 'molecular_function', 'GO:0004697', ('282', '290'))	('MDM2', 'Gene', (79, 83))	('p53', 'Gene', (61, 64))	('inhibition', 'Var', (84, 94))	('activation', 'PosReg', (65, 75))	('UM', 'Phenotype', 'HP:0007716', (144, 146))
67564	29593251	UM is most frequently driven by activating mutations in the G-proteins GNAQ (50%) or GNA11 (43%).	('activating mutations', 'Var', (32, 52))	('GNAQ', 'Gene', (71, 75))	('driven', 'Reg', (22, 28))	('GNA11', 'Gene', '2767', (85, 90))	('GNA11', 'Gene', (85, 90))	('GNAQ', 'Gene', '2776', (71, 75))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
67569	29593251	UM cells containing a GNAQ or GNA11 mutation are indeed dependent on MAPK signaling and were shown to be sensitive to both MEK and PKC inhibition.	('MAPK signaling', 'MPA', (69, 83))	('sensitive', 'Reg', (105, 114))	('MEK', 'Gene', (123, 126))	('MEK', 'Gene', '5609', (123, 126))	('PKC', 'molecular_function', 'GO:0004697', ('131', '134'))	('GNA11', 'Gene', (30, 35))	('GNAQ', 'Gene', (22, 26))	('PKC', 'Gene', (131, 134))	('GNA11', 'Gene', '2767', (30, 35))	('dependent', 'Reg', (56, 65))	('MAPK', 'molecular_function', 'GO:0004707', ('69', '73'))	('PKC', 'Gene', '112476', (131, 134))	('GNAQ', 'Gene', '2776', (22, 26))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('MAPK signaling', 'biological_process', 'GO:0000165', ('69', '83'))	('mutation', 'Var', (36, 44))
67580	29593251	Detailed genetic studies showed that depletion of MDMX from UM cells enhances the efficacy of pan-PKC inhibition and, vice versa, PKCdelta depletion sensitizes UM cells for p53 activation.	('PKC', 'Gene', '112476', (130, 133))	('depletion', 'Var', (37, 46))	('PKC', 'Gene', '112476', (98, 101))	('PKC', 'molecular_function', 'GO:0004697', ('98', '101'))	('PKCdelta', 'molecular_function', 'GO:0004697', ('130', '138'))	('activation', 'PosReg', (177, 187))	('UM', 'Phenotype', 'HP:0007716', (160, 162))	('efficacy', 'MPA', (82, 90))	('enhances', 'PosReg', (69, 77))	('PKCdelta', 'Gene', '5580', (130, 138))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('PKCdelta', 'Gene', (130, 138))	('PKC', 'Gene', (98, 101))	('depletion', 'Var', (139, 148))	('PKC', 'Gene', (130, 133))
67585	29593251	As expected, and shown before, MEL290 cells, lacking a GNAQ/11 mutation, are not responsive to Sotrastaurin and the combination of Nutlin-3 and Sotrastaurin is even antagonistic.	('Nutlin-3', 'Chemical', 'MESH:C482205', (131, 139))	('Sotrastaurin', 'Chemical', 'MESH:C543528', (95, 107))	('GNAQ', 'Gene', '2776', (55, 59))	('mutation', 'Var', (63, 71))	('Sotrastaurin', 'Chemical', 'MESH:C543528', (144, 156))	('GNAQ', 'Gene', (55, 59))	('MEL290', 'CellLine', 'CVCL:C304', (31, 37))
67597	29593251	However, in MM66 and MM28 the full-length PARP levels in the combined treated cells decreased, indicating that the percentage of cleaved PARP compared with full-length still increased in the Nutlin-3/Sotrastaurin-treated cells.	('Sotrastaurin', 'Chemical', 'MESH:C543528', (200, 212))	('PARP', 'Gene', (137, 141))	('PARP', 'Gene', (42, 46))	('PARP', 'Gene', '142', (137, 141))	('decreased', 'NegReg', (84, 93))	('PARP', 'Gene', '142', (42, 46))	('MM66', 'Var', (12, 16))	('Nutlin-3', 'Chemical', 'MESH:C482205', (191, 199))
67605	29593251	Importantly, simultaneous p53 reactivation and PKC inhibition significantly increased the fraction of subG1 cells in all cell lines, most strikingly in MM28, MM66 and OMM2.5 cells.	('inhibition', 'NegReg', (51, 61))	('PKC', 'Gene', '112476', (47, 50))	('increased', 'PosReg', (76, 85))	('p53', 'Protein', (26, 29))	('reactivation', 'Var', (30, 42))	('PKC', 'molecular_function', 'GO:0004697', ('47', '50'))	('PKC', 'Gene', (47, 50))
67614	29593251	Combining MDMX depletion with PKC inhibition resulted in a further reduction of survival of ~30%, an reduction of ~20% compared with Sotrastaurin (Fig.	('depletion', 'Var', (15, 24))	('Sotrastaurin', 'Chemical', 'MESH:C543528', (133, 145))	('PKC', 'Gene', '112476', (30, 33))	('reduction', 'NegReg', (67, 76))	('PKC', 'Gene', (30, 33))	('PKC', 'molecular_function', 'GO:0004697', ('30', '33'))	('survival', 'CPA', (80, 88))	('MDMX', 'MPA', (10, 14))
67615	29593251	These results suggest that targeting MDMX could be further explored as an alternative for p53 activation by MDM2 inhibitors in obtaining enhanced UM growth inhibition by PKC inhibition with Sotrastaurin.	('enhanced', 'PosReg', (137, 145))	('p53', 'Gene', (90, 93))	('UM', 'Phenotype', 'HP:0007716', (146, 148))	('inhibitors', 'Var', (113, 123))	('PKC', 'Gene', (170, 173))	('PKC', 'Gene', '112476', (170, 173))	('UM growth inhibition', 'CPA', (146, 166))	('MDM2', 'Gene', '4193', (108, 112))	('PKC', 'molecular_function', 'GO:0004697', ('170', '173'))	('MDM2', 'Gene', (108, 112))	('Sotrastaurin', 'Chemical', 'MESH:C543528', (190, 202))	('activation', 'PosReg', (94, 104))
67622	29593251	OMM2.5 cells expressing i-shCtrl or i-shPKCdelta shRNAs showed similar sensitivity to Nutlin-3 treatment with a survival of 29-38%.	('i-shCtrl', 'Var', (24, 32))	('PKCdelta', 'Gene', '5580', (40, 48))	('PKCdelta', 'Gene', (40, 48))	('Nutlin-3', 'Chemical', 'MESH:C482205', (86, 94))	('sensitivity to Nutlin-3 treatment', 'MPA', (71, 104))
67629	29593251	Melanomas originating from the uvea are most commonly driven by activating mutations in G-proteins GNAQ (50%) or GNA11 (43%).	('uvea', 'Disease', (31, 35))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('Melanomas', 'Disease', (0, 9))	('GNA11', 'Gene', '2767', (113, 118))	('GNA11', 'Gene', (113, 118))	('GNAQ', 'Gene', (99, 103))	('activating mutations', 'Var', (64, 84))	('uvea', 'Disease', 'MESH:C536494', (31, 35))	('driven by', 'Reg', (54, 63))	('GNAQ', 'Gene', '2776', (99, 103))
67630	29593251	These distinct mutations, among additional effects, hyper-activate PKC isoforms, which in turn feed into the MAPK pathway.	('PKC', 'molecular_function', 'GO:0004697', ('67', '70'))	('mutations', 'Var', (15, 24))	('PKC', 'Gene', (67, 70))	('hyper-activate', 'PosReg', (52, 66))	('PKC', 'Gene', '112476', (67, 70))	('MAPK pathway', 'Pathway', (109, 121))	('MAPK', 'molecular_function', 'GO:0004707', ('109', '113'))	('feed', 'Reg', (95, 99))
67637	29593251	Previous studies have already shown that MDM2/X inhibitors have the potential to be used as therapeutic intervention for UM.	('MDM2', 'Gene', '4193', (41, 45))	('UM', 'Phenotype', 'HP:0007716', (121, 123))	('MDM2', 'Gene', (41, 45))	('inhibitors', 'Var', (48, 58))
67638	29593251	During the course of our studies, it has been reported that inhibition of p53 regulation by MDM2 using CGM097 further constrained in vivo tumor growth in UM PDX models when combined with PKC inhibition, although this combination did not result in synergistic growth inhibition in vitro.	('PKC', 'molecular_function', 'GO:0004697', ('187', '190'))	('regulation', 'biological_process', 'GO:0065007', ('78', '88'))	('CGM097', 'Chemical', 'MESH:C000602644', (103, 109))	('MDM2', 'Gene', '4193', (92, 96))	('tumor', 'Disease', (138, 143))	('MDM2', 'Gene', (92, 96))	('constrained', 'NegReg', (118, 129))	('PKC', 'Gene', (187, 190))	('CGM097', 'Var', (103, 109))	('p53', 'Gene', (74, 77))	('inhibition', 'NegReg', (60, 70))	('PKC', 'Gene', '112476', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('UM', 'Phenotype', 'HP:0007716', (154, 156))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
67639	29593251	In contrast, our results clearly show synergistic effects when p53 reactivation is combined with PKC inhibition with the same PKC inhibitor and also with an alternative inhibitor GF109203X (data not shown).	('PKC', 'Gene', (126, 129))	('PKC', 'Gene', '112476', (126, 129))	('p53', 'Gene', (63, 66))	('PKC', 'molecular_function', 'GO:0004697', ('126', '129'))	('PKC', 'Gene', (97, 100))	('PKC', 'Gene', '112476', (97, 100))	('GF109203X', 'Var', (179, 188))	('GF109203X', 'Chemical', 'MESH:C070515', (179, 188))	('PKC', 'molecular_function', 'GO:0004697', ('97', '100'))
67647	29593251	Much more promising, Dewaele and colleagues recently showed the potential of stimulating the naturally occurring alternative splicing of MDMX by antisense oligonucleotides, thereby decreasing the amount of full-length MDMX protein.	('amount', 'MPA', (196, 202))	('stimulating', 'Reg', (77, 88))	('protein', 'cellular_component', 'GO:0003675', ('223', '230'))	('antisense oligonucleotides', 'Var', (145, 171))	('decreasing', 'NegReg', (181, 191))	('full-length', 'MPA', (206, 217))	('alternative splicing', 'MPA', (113, 133))	('splicing', 'biological_process', 'GO:0045292', ('125', '133'))	('oligonucleotides', 'Chemical', 'MESH:D009841', (155, 171))	('MDMX', 'Gene', (137, 141))
67650	29593251	We sought to determine whether an inhibition or depletion of a single PKC isoform could also be capable of enhancing MDM2/MDMX inhibition.	('PKC', 'Gene', (70, 73))	('PKC', 'Gene', '112476', (70, 73))	('enhancing', 'PosReg', (107, 116))	('MDM2', 'Gene', '4193', (117, 121))	('depletion', 'Var', (48, 57))	('PKC', 'molecular_function', 'GO:0004697', ('70', '73'))	('MDM2', 'Gene', (117, 121))
67676	29593251	EoB was used to determine the extent of synergism between MDMX depletion and Sotrastaurin and PKCdelta depletion and Nutlin-3.	('Sotrastaurin', 'Chemical', 'MESH:C543528', (77, 89))	('PKCdelta', 'Gene', '5580', (94, 102))	('PKCdelta', 'Gene', (94, 102))	('Sotrastaurin', 'MPA', (77, 89))	('PKCdelta', 'molecular_function', 'GO:0004697', ('94', '102'))	('depletion', 'Var', (63, 72))	('Nutlin-3', 'Chemical', 'MESH:C482205', (117, 125))
67677	27348266	Ric-8A gene deletion or phorbol ester suppresses tumorigenesis in a mouse model of GNAQQ209L-driven melanoma The heterotrimeric G protein alpha subunit oncogenes GNAQ or GNA11 carry Q209X or R183X activating mutations and are present with ~90% frequency in human uveal melanomas.	('uveal melanomas', 'Disease', (263, 278))	('uveal melanomas', 'Phenotype', 'HP:0007716', (263, 278))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('melanoma', 'Disease', 'MESH:D008545', (269, 277))	('human', 'Species', '9606', (257, 262))	('R183X', 'Mutation', 'p.R183X', (191, 196))	('Ric-8A', 'Gene', (0, 6))	('melanomas', 'Phenotype', 'HP:0002861', (269, 278))	('Q209X', 'Mutation', 'p.Q209X', (182, 187))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('113', '137'))	('GNA11', 'Gene', (170, 175))	('deletion', 'Var', (12, 20))	('Q209X', 'Var', (182, 187))	('melanoma', 'Disease', (269, 277))	('melanoma', 'Phenotype', 'HP:0002861', (269, 277))	('uveal melanoma', 'Phenotype', 'HP:0007716', (263, 277))	('uveal melanomas', 'Disease', 'MESH:C536494', (263, 278))	('R183X', 'Var', (191, 196))	('Ric-8A', 'Gene', '101489', (0, 6))	('suppresses', 'NegReg', (38, 48))	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('mouse', 'Species', '10090', (68, 73))	('phorbol ester', 'Chemical', 'MESH:D010703', (24, 37))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('tumorigenesis', 'CPA', (49, 62))
67678	27348266	Forced expression of GNAQ/11Q209L in melanocytes is sufficient to drive metastatic melanoma in immune-compromised mice.	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('GNAQ/11Q209L', 'Var', (21, 33))	('expression', 'Species', '29278', (7, 17))	('drive', 'PosReg', (66, 71))	('mice', 'Species', '10090', (114, 118))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('Q209L', 'Mutation', 'rs121913492', (28, 33))	('melanoma', 'Disease', (83, 91))
67681	27348266	Here, using mouse melanocyte cell graft tumorigenesis models, we determined that Ric-8A genetic ablation attenuated the abundance and melanoma-driving potential of Galphaq-Q209L.	('Q209L', 'Mutation', 'rs121913492', (172, 177))	('Ric-8A', 'Gene', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Galphaq', 'Gene', '14682', (164, 171))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('abundance', 'MPA', (120, 129))	('attenuated', 'NegReg', (105, 115))	('mouse', 'Species', '10090', (12, 17))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('Galphaq', 'Gene', (164, 171))	('genetic ablation', 'Var', (88, 104))
67684	27348266	Stable expression of human GNAQQ209L, but not GNAQWT in the cell line promoted TPA-independent cell proliferation, and upon cell grafting in mice, the initiation and robust growth of darkly-pigmented melanoma tumors.	('TPA', 'molecular_function', 'GO:0031299', ('79', '82'))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('cell proliferation', 'biological_process', 'GO:0008283', ('95', '113'))	('expression', 'Species', '29278', (7, 17))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('pigmented melanoma tumors', 'Disease', 'MESH:D008545', (190, 215))	('human', 'Species', '9606', (21, 26))	('TPA-independent cell proliferation', 'CPA', (79, 113))	('growth', 'CPA', (173, 179))	('TPA', 'Chemical', 'MESH:D013755', (79, 82))	('mice', 'Species', '10090', (141, 145))	('GNAQQ209L', 'Var', (27, 36))	('pigmented melanoma tumors', 'Disease', (190, 215))	('promoted', 'PosReg', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
67685	27348266	Deletion of Ric-8A in GNAQQ209L cells restored TPA-dependent growth, reduced Galphaq-Q209L below detectable levels and completely mitigated tumorigenesis from primary or secondary cell line grafts.	('TPA', 'molecular_function', 'GO:0031299', ('47', '50'))	('TPA', 'Chemical', 'MESH:D013755', (47, 50))	('reduced', 'NegReg', (69, 76))	('Galphaq', 'Gene', '14682', (77, 84))	('restored', 'PosReg', (38, 46))	('Deletion', 'Var', (0, 8))	('Q209L', 'Mutation', 'rs121913492', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('Galphaq', 'Gene', (77, 84))	('mitigated', 'NegReg', (130, 139))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('Q209L', 'Mutation', 'rs121913492', (26, 31))	('Ric-8A', 'Gene', (12, 18))	('TPA-dependent growth', 'MPA', (47, 67))	('tumor', 'Disease', (140, 145))
67686	27348266	Interestingly, TPA treatment of cultured GNAQQ209L cells or host animals grafted with GNAQQ209L cells also sharply reduced Galphaq-Q209L abundance and tumorigenic capacity.	('Q209L', 'Mutation', 'rs121913492', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('Q209L', 'Mutation', 'rs121913492', (131, 136))	('reduced', 'NegReg', (115, 122))	('tumor', 'Disease', (151, 156))	('Q209L', 'Mutation', 'rs121913492', (90, 95))	('TPA', 'molecular_function', 'GO:0031299', ('15', '18'))	('Galphaq', 'Gene', '14682', (123, 130))	('abundance', 'MPA', (137, 146))	('GNAQQ209L', 'Var', (86, 95))	('TPA', 'Chemical', 'MESH:D013755', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('Galphaq', 'Gene', (123, 130))
67687	27348266	Finally, tumorigenesis initiated from GNAQQ209L cell grafts, followed by host mouse systemic tamoxifen treatment to delete Ric-8A in the grafted cells completely abrogated GNAQQ209L-driven tumor progression unless a stable human RIC-8A transgene was used to rescue the floxed Ric-8A alleles.	('abrogated', 'NegReg', (162, 171))	('tumor', 'Disease', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('Ric-8A', 'Gene', (123, 129))	('Q209L', 'Mutation', 'rs121913492', (176, 181))	('human', 'Species', '9606', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('delete', 'Var', (116, 122))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tamoxifen', 'Chemical', 'MESH:D013629', (93, 102))	('mouse', 'Species', '10090', (78, 83))	('Q209L', 'Mutation', 'rs121913492', (42, 47))	('GNAQQ209L-driven', 'Var', (172, 188))
67692	27348266	The genetic alterations in uveal melanoma are distinct from cutaneous melanoma, which commonly carry driver mutations in BRAF or NRAS.	('uveal melanoma', 'Phenotype', 'HP:0007716', (27, 41))	('uveal melanoma', 'Disease', (27, 41))	('BRAF', 'Gene', (121, 125))	('uveal melanoma', 'Disease', 'MESH:C536494', (27, 41))	('NRAS', 'Gene', '18176', (129, 133))	('mutations', 'Var', (108, 117))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('NRAS', 'Gene', (129, 133))	('cutaneous melanoma', 'Disease', (60, 78))	('BRAF', 'Gene', '109880', (121, 125))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (60, 78))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (60, 78))
67693	27348266	Uveal melanomas are predominantly (>=85%) driven by mutations in GNAQ or GNA11, genes that encode the partially redundant heterotrimeric G protein alpha subunits, Galphaq and Galpha11.	('GNA11', 'Gene', (73, 78))	('mutations', 'Var', (52, 61))	('Galphaq', 'Gene', '14682', (163, 170))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('122', '146'))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanomas', 'Disease', (6, 15))	('Galphaq', 'Gene', (163, 170))	('driven by', 'Reg', (42, 51))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('Galpha11', 'Gene', (175, 183))	('GNAQ', 'Gene', (65, 69))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('Galpha11', 'Gene', '14672', (175, 183))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))
67694	27348266	The point mutations are restricted to residues Q209 and R183, which are critical for intrinsic GTP hydrolysis (GTPase) activity of the G proteins, resulting in persistently active GTP-bound Galpha subunits, and therefore constitutively-active signaling.	('active GTP-bound', 'MPA', (173, 189))	('Galpha subunits', 'Protein', (190, 205))	('signaling', 'biological_process', 'GO:0023052', ('243', '252'))	('GTP', 'Chemical', 'MESH:D006160', (180, 183))	('GTPase) activity', 'molecular_function', 'GO:0003924', ('111', '127'))	('GTP', 'Chemical', 'MESH:D006160', (111, 114))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('95', '109'))	('R183', 'Var', (56, 60))	('GTP', 'Chemical', 'MESH:D006160', (95, 98))	('signaling', 'MPA', (243, 252))
67695	27348266	Q209 mutations are more prevalent than R183 mutations in uveal melanoma because Galphaq/11-Q209X proteins are stronger activators of downstream signaling.	('activators', 'MPA', (119, 129))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('Galphaq', 'Gene', '14682', (80, 87))	('proteins', 'Protein', (97, 105))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('Q209 mutations', 'Var', (0, 14))	('stronger', 'PosReg', (110, 118))	('uveal melanoma', 'Disease', (57, 71))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('Galphaq', 'Gene', (80, 87))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('Q209X', 'Mutation', 'p.Q209X', (91, 96))
67697	27348266	Interestingly, GNAQ or GNA11 activating mutations induce dermal hyperpigmentation, and are frequently found in cutaneous benign blue nevi and a small subset of melanomas, indicating that overactive Galphaq/11 signaling may also be important during priming events of dermal melanocyte neoplasms.	('GNAQ', 'Gene', (15, 19))	('GNA11', 'Gene', (23, 28))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('Galphaq', 'Gene', '14682', (198, 205))	('nevi', 'Phenotype', 'HP:0003764', (133, 137))	('induce', 'Reg', (50, 56))	('melanomas', 'Disease', 'MESH:D008545', (160, 169))	('dermal melanocyte neoplasms', 'Disease', (266, 293))	('melanocyte neoplasms', 'Phenotype', 'HP:0002861', (273, 293))	('mutations', 'Var', (40, 49))	('melanomas', 'Disease', (160, 169))	('Galphaq', 'Gene', (198, 205))	('cutaneous benign blue nevi', 'Disease', (111, 137))	('dermal hyperpigmentation', 'Phenotype', 'HP:0000953', (57, 81))	('dermal hyperpigmentation', 'Disease', (57, 81))	('dermal hyperpigmentation', 'Disease', 'MESH:D017495', (57, 81))	('signaling', 'biological_process', 'GO:0023052', ('209', '218'))	('dermal melanocyte neoplasms', 'Disease', 'MESH:D009508', (266, 293))	('neoplasms', 'Phenotype', 'HP:0002664', (284, 293))	('melanomas', 'Phenotype', 'HP:0002861', (160, 169))	('blue nevi', 'Phenotype', 'HP:0100814', (128, 137))
67698	27348266	Studies using genetic or xenograft mouse models demonstrated that melanocyte-specific GNAQ or 11 Q209L expression promoted invasive and metastatic melanoma.	('11 Q209L expression', 'Var', (94, 113))	('expression', 'Species', '29278', (103, 113))	('Q209L', 'Mutation', 'rs121913492', (97, 102))	('mouse', 'Species', '10090', (35, 40))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('promoted', 'PosReg', (114, 122))	('melanoma', 'Disease', (147, 155))
67701	27348266	The emerging evidence is quite convincing that aberrant stimulation of Galphaq/11 signaling pathways by hyperactive GPCRs or oncogenic GNAQ/11 mutations, contributes to the development of various melanocyte neoplasms including cellular transformation and uveal melanoma.	('uveal melanoma', 'Disease', (255, 269))	('uveal melanoma', 'Disease', 'MESH:C536494', (255, 269))	('contributes', 'Reg', (154, 165))	('signaling', 'biological_process', 'GO:0023052', ('82', '91'))	('neoplasms', 'Phenotype', 'HP:0002664', (207, 216))	('Galphaq', 'Gene', '14682', (71, 78))	('hyperactive GPCRs', 'Disease', 'MESH:D006948', (104, 121))	('melanocyte neoplasms', 'Phenotype', 'HP:0002861', (196, 216))	('GNAQ/11', 'Gene', (135, 142))	('cellular transformation', 'CPA', (227, 250))	('Galphaq', 'Gene', (71, 78))	('neoplasms', 'Disease', (207, 216))	('stimulation', 'PosReg', (56, 67))	('hyperactive GPCRs', 'Disease', (104, 121))	('neoplasms', 'Disease', 'MESH:D009369', (207, 216))	('melanoma', 'Phenotype', 'HP:0002861', (261, 269))	('mutations', 'Var', (143, 152))	('uveal melanoma', 'Phenotype', 'HP:0007716', (255, 269))
67707	27348266	A new C57Bl6J mouse with floxed Ric-8A alleles was derived for the work that permitted conditional Ric-8A deletion.	('Ric-8A', 'Gene', (99, 105))	('deletion', 'Var', (106, 114))	('mouse', 'Species', '10090', (14, 19))
67709	27348266	The GNAQQ209L but not the GNAQWT melanocyte cell line exhibited phorbol ester-independent proliferation in culture; a feature associated with melanocyte transformation, and one that was abolished by Ric-8A deletion.	('associated', 'Reg', (126, 136))	('phorbol ester-independent', 'MPA', (64, 89))	('GNAQQ209L', 'Var', (4, 13))	('phorbol ester', 'Chemical', 'MESH:D010703', (64, 77))	('melanocyte transformation', 'CPA', (142, 167))
67712	27348266	Deletion of Ric-8A in culture before GNAQQ209L cell grafting completely abrogated tumor growth.	('abrogated', 'NegReg', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Ric-8A', 'Gene', (12, 18))	('tumor', 'Disease', (82, 87))	('Deletion', 'Var', (0, 8))
67713	27348266	Ric-8AFlox/Flox; GNAQQ209L murine melanoma cell lines were cultured ex vivo from primary tumor explants and secondary tumor formation from these cells was also blocked by in vitro Ric-8A deletion.	('deletion', 'Var', (187, 195))	('Q209L', 'Mutation', 'rs121913492', (21, 26))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('Flox', 'Chemical', '-', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('formation', 'biological_process', 'GO:0009058', ('124', '133'))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Ric-8AFlox', 'Chemical', '-', (0, 10))	('Ric-8A', 'Gene', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', (118, 123))	('Flox', 'Chemical', '-', (6, 10))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('murine', 'Species', '10090', (27, 33))	('melanoma', 'Disease', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
67714	27348266	GNAQQ209L melanocyte cell grafts were then permitted to initiate tumorigenesis, followed by host mouse tamoxifen treatment to delete floxed Ric-8A in the grafted melanocytes.	('tumor', 'Disease', (65, 70))	('delete floxed', 'Var', (126, 139))	('mouse', 'Species', '10090', (97, 102))	('tamoxifen', 'Chemical', 'MESH:D013629', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('floxed', 'Var', (133, 139))
67715	27348266	Systemic tamoxifen treatment specifically abrogated GNAQQ209L-driven tumorigenesis from Ric-8AFlox/Flox melanocytes.	('tamoxifen', 'Chemical', 'MESH:D013629', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('abrogated', 'NegReg', (42, 51))	('GNAQQ209L-driven', 'Var', (52, 68))	('Q209L', 'Mutation', 'rs121913492', (56, 61))	('tumor', 'Disease', (69, 74))	('Flox', 'Chemical', '-', (99, 103))	('Ric-8AFlox', 'Chemical', '-', (88, 98))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('Flox', 'Chemical', '-', (94, 98))
67716	27348266	We also made an unexpected observation that culture of GNAQQ209L melanocytes in the presence of phorbol ester led to a dramatic decrease in Galphaq-Q209L oncoprotein levels.	('Galphaq', 'Gene', (140, 147))	('phorbol ester', 'Chemical', 'MESH:D010703', (96, 109))	('Q209L', 'Mutation', 'rs121913492', (148, 153))	('Galphaq', 'Gene', '14682', (140, 147))	('decrease', 'NegReg', (128, 136))	('GNAQQ209L', 'Var', (55, 64))	('Q209L', 'Mutation', 'rs121913492', (59, 64))
67717	27348266	Accordingly, phorbol ester-pre-cultured GNAQQ209L melanocytes completely failed to form melanoma tumors when grafted into mice, and systemic phorbol ester treatment of host mice grafted with GNAQQ209L melanoma cells suppressed tumor initiation and progression.	('GNAQQ209L', 'Var', (191, 200))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('suppressed', 'NegReg', (216, 226))	('melanoma tumors', 'Disease', 'MESH:D008545', (88, 103))	('mice', 'Species', '10090', (173, 177))	('tumor initiation', 'Disease', 'MESH:D009369', (227, 243))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('phorbol ester', 'Chemical', 'MESH:D010703', (141, 154))	('tumor initiation', 'Disease', (227, 243))	('melanoma tumors', 'Disease', (88, 103))	('pre', 'molecular_function', 'GO:0003904', ('27', '30'))	('phorbol ester', 'Chemical', 'MESH:D010703', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('mice', 'Species', '10090', (122, 126))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('melanoma', 'Disease', (201, 209))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))
67724	27348266	PCR analysis of MEF genomic DNA revealed efficient Cre-mediated deletion of Ric-8A exon 5 (Supplementary Figure S2).	('MEF', 'Gene', '56501', (16, 19))	('deletion', 'Var', (64, 72))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('Ric-8A', 'Gene', (76, 82))	('MEF', 'Gene', (16, 19))
67726	27348266	To investigate the effect of Ric-8A deletion on Galpha subunit abundances in melanocytes and melanocyte transformation induced by oncogenic Galphaq-Q209L, we first created and characterized an immortalized melanocyte cell line with inducible Ric-8A knockout potential.	('deletion', 'Var', (36, 44))	('Galphaq', 'Gene', (140, 147))	('Q209L', 'Mutation', 'rs121913492', (148, 153))	('Galphaq', 'Gene', '14682', (140, 147))	('Ric-8A', 'Gene', (29, 35))	('Galpha', 'Protein', (48, 54))
67728	27348266	The Ric-8AFlox/Flox; Rosa-CreER+/- melanocyte cell line exhibited TPA- and CTX-dependent growth, a shared characteristic with the non-tumorigenic mouse melanocyte cell line, Melan-a (Figure 1a).	('Flox', 'Chemical', '-', (15, 19))	('Ric-8AFlox', 'Chemical', '-', (4, 14))	('TPA', 'Chemical', 'MESH:D013755', (66, 69))	('mouse', 'Species', '10090', (146, 151))	('TPA', 'molecular_function', 'GO:0031299', ('66', '69'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('Flox', 'Chemical', '-', (10, 14))	('CTX', 'Disease', (75, 78))	('CTX', 'Disease', 'MESH:D019294', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Ric-8AFlox/Flox', 'Var', (4, 19))	('tumor', 'Disease', (134, 139))
67730	27348266	Ric-8A deletion in the melanocyte cell line mediated by Cre-NLS lentiviral infection or by 4-hydroxytamoxifen (4OHT) activation of Cre recombinase, decreased Ric-8A abundance and caused concomitant decreases in the levels of G protein subunits folded by Ric-8A (Figure 1b).	('4-hydroxytamoxifen', 'Chemical', '-', (91, 109))	('G protein', 'Protein', (225, 234))	('Ric-8A', 'Gene', (158, 164))	('levels of', 'MPA', (215, 224))	('protein', 'cellular_component', 'GO:0003675', ('227', '234'))	('NLS lentiviral infection', 'Disease', (60, 84))	('Ric-8A', 'Gene', (0, 6))	('decreased', 'NegReg', (148, 157))	('abundance', 'MPA', (165, 174))	('decreases', 'NegReg', (198, 207))	('4OHT', 'Chemical', 'MESH:C032278', (111, 115))	('NLS lentiviral infection', 'Disease', 'MESH:C536405', (60, 84))	('deletion', 'Var', (7, 15))
67732	27348266	Ric-8A deletion had no effect on the requirements of TPA or CTX for melanocyte cell line growth, but did modestly enhance the cell proliferation rate (Figures 1a and c).	('TPA', 'Chemical', 'MESH:D013755', (53, 56))	('cell proliferation rate', 'CPA', (126, 149))	('Ric-8A', 'Gene', (0, 6))	('cell proliferation', 'biological_process', 'GO:0008283', ('126', '144'))	('CTX', 'Disease', 'MESH:D019294', (60, 63))	('enhance', 'PosReg', (114, 121))	('TPA', 'molecular_function', 'GO:0031299', ('53', '56'))	('CTX', 'Disease', (60, 63))	('deletion', 'Var', (7, 15))
67733	27348266	We hypothesize that Ric-8A deletion and the consequent decreases in G protein alpha subunit abundances (Galphaq/i/13 classes) release a modest cell proliferation damper conferred normally by homeostatic G protein signaling.	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('signaling', 'biological_process', 'GO:0023052', ('213', '222'))	('Ric-8A', 'Gene', (20, 26))	('cell proliferation', 'CPA', (143, 161))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('decreases', 'NegReg', (55, 64))	('G protein alpha subunit abundances (Galphaq/i/13', 'Gene', '14682', (68, 116))	('deletion', 'Var', (27, 35))	('damper', 'NegReg', (162, 168))	('cell proliferation', 'biological_process', 'GO:0008283', ('143', '161'))
67737	27348266	The GNAQQ209L oncogene conferred sustained cell proliferation in the absence of TPA, whereas the GNAQWT and GFP cell lines failed to grow unless TPA was provided (Figures 2a and b).	('TPA', 'molecular_function', 'GO:0031299', ('145', '148'))	('cell proliferation', 'biological_process', 'GO:0008283', ('43', '61'))	('TPA', 'molecular_function', 'GO:0031299', ('80', '83'))	('TPA', 'Chemical', 'MESH:D013755', (145, 148))	('GNAQQ209L', 'Var', (4, 13))	('TPA', 'Chemical', 'MESH:D013755', (80, 83))	('cell proliferation', 'CPA', (43, 61))
67738	27348266	We next determined that 4OHT-induced Ric-8A deletion had no significant effect on GNAQQ209L, GNAQWT or GFP melanocyte cell line proliferation when the cells were grown in the presence of TPA (Figure 2b).	('deletion', 'Var', (44, 52))	('TPA', 'molecular_function', 'GO:0031299', ('187', '190'))	('4OHT', 'Chemical', 'MESH:C032278', (24, 28))	('TPA', 'Chemical', 'MESH:D013755', (187, 190))	('Ric-8A', 'Gene', (37, 43))
67740	27348266	Ric-8A deletion dramatically attenuated TPA-independent growth of the GNAQQ209L melanocyte cell line (Figures 2a and b).	('TPA', 'Chemical', 'MESH:D013755', (40, 43))	('TPA-independent growth', 'CPA', (40, 62))	('Ric-8A', 'Gene', (0, 6))	('TPA', 'molecular_function', 'GO:0031299', ('40', '43'))	('attenuated', 'NegReg', (29, 39))	('deletion', 'Var', (7, 15))
67742	27348266	Ric-8A deletion in the melanocyte cell line sharply reduced Galphaq-Q209L levels, thereby reversing the TPA-independent growth conferred by this constitutively-active oncoprotein.	('Q209L', 'Mutation', 'rs121913492', (68, 73))	('reduced', 'NegReg', (52, 59))	('Galphaq', 'Gene', '14682', (60, 67))	('Ric-8A', 'Gene', (0, 6))	('TPA-independent growth', 'MPA', (104, 126))	('TPA', 'Chemical', 'MESH:D013755', (104, 107))	('TPA', 'molecular_function', 'GO:0031299', ('104', '107'))	('reversing', 'NegReg', (90, 99))	('Galphaq', 'Gene', (60, 67))	('deletion', 'Var', (7, 15))
67749	27348266	A striking recovery of Galphaq-Q209L oncoprotein was observed upon MG132 treatment, whereas wild-type Galphaq/11 and Ric-8A levels hardly fluctuated (Figure 2g).	('Galphaq', 'Gene', (102, 109))	('Q209L', 'Mutation', 'rs121913492', (31, 36))	('recovery', 'PosReg', (11, 19))	('Galphaq', 'Gene', '14682', (23, 30))	('Galphaq', 'Gene', '14682', (102, 109))	('Galphaq', 'Gene', (23, 30))	('MG132', 'Var', (67, 72))	('MG132', 'Chemical', 'MESH:C072553', (67, 72))
67750	27348266	Importantly, the degree of MG132-mediated recovery of Galphaq-Q209L levels in the chronically-treated TPA cell line was substantially less than that in the TPA-untreated cell line.	('TPA', 'molecular_function', 'GO:0031299', ('102', '105'))	('TPA', 'Chemical', 'MESH:D013755', (102, 105))	('Q209L', 'Mutation', 'rs121913492', (62, 67))	('Galphaq', 'Gene', '14682', (54, 61))	('MG132', 'Chemical', 'MESH:C072553', (27, 32))	('TPA', 'molecular_function', 'GO:0031299', ('156', '159'))	('MG132-mediated', 'Var', (27, 41))	('TPA', 'Chemical', 'MESH:D013755', (156, 159))	('less', 'NegReg', (134, 138))	('Galphaq', 'Gene', (54, 61))
67757	27348266	The GNAQQ209L tumors were roughly 0.6-2.0 cm in diameter and often oblong and/or multi-lobed.	('GNAQQ209L', 'Var', (4, 13))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
67759	27348266	The GNAQQ209L and control GFP melanocyte cell lines were then treated with or without 4OHT in culture to delete Ric-8A before grafting into NSG mice (left flanks, solvent-treated cells and right flanks, 4OHT-treated cells).	('Ric-8A', 'Gene', (112, 118))	('4OHT', 'Chemical', 'MESH:C032278', (86, 90))	('mice', 'Species', '10090', (144, 148))	('delete', 'Var', (105, 111))	('4OHT', 'Chemical', 'MESH:C032278', (203, 207))
67760	27348266	The GFP-only melanocyte cell line had no tumorigenic capacity regardless of Ric-8A expression or deletion (Figures 3a and d, bottom panel).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('Ric-8A', 'Gene', (76, 82))	('expression', 'Species', '29278', (83, 93))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('deletion', 'Var', (97, 105))
67761	27348266	Ric-8A deletion substantially attenuated GNAQQ209L-driven tumor progression (Figure 3b) and measured tumor weights at the completion of the experiments (Figures 3c and d).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('Ric-8A', 'Gene', (0, 6))	('tumor', 'Disease', (101, 106))	('GNAQQ209L-driven', 'MPA', (41, 57))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('measured', 'PosReg', (92, 100))	('deletion', 'Var', (7, 15))	('attenuated', 'NegReg', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
67762	27348266	This indicates that the modest in vitro melanocyte proliferation advantage conferred by Ric-8A knockout (Figure 1c) was negated by loss of Galphaq-Q209L oncoprotein folding capacity during in vivo tumor growth.	('Q209L', 'Mutation', 'rs121913492', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('oncoprotein folding capacity', 'MPA', (153, 181))	('knockout', 'Var', (95, 103))	('Galphaq', 'Gene', '14682', (139, 146))	('melanocyte proliferation', 'biological_process', 'GO:0097325', ('40', '64'))	('loss', 'NegReg', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('Ric-8A', 'Gene', (88, 94))	('Galphaq', 'Gene', (139, 146))	('negated', 'NegReg', (120, 127))	('tumor', 'Disease', (197, 202))
67766	27348266	Excised Ric-8AFlox/Flox; Rosa-CreER+/-; Tg (GNAQQ209L) tumors from Figure 3a were cultured ex vivo in standard melanocyte culture medium lacking TPA to derive two independent GNAQQ209L melanoma cell lines, with which to determine the effect of Ric-8A deletion on secondary tumor progression.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('Flox', 'Chemical', '-', (19, 23))	('TPA', 'molecular_function', 'GO:0031299', ('145', '148'))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', (273, 278))	('Q209L', 'Mutation', 'rs121913492', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('TPA', 'Chemical', 'MESH:D013755', (145, 148))	('Ric-8A', 'Gene', (244, 250))	('Ric-8AFlox', 'Chemical', '-', (8, 18))	('deletion', 'Var', (251, 259))	('tumors', 'Disease', (55, 61))	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('Flox', 'Chemical', '-', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('Q209L', 'Mutation', 'rs121913492', (48, 53))	('tumor', 'Disease', (55, 60))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))
67767	27348266	The melanoma cell lines exhibited TPA-independent growth and acquired TPA dependence after Ric-8A deletion, both characteristics of the parental GNAQQ209L melanocyte cell line used to generate the primary tumors (Figures 4a and b).	('acquired', 'PosReg', (61, 69))	('exhibited', 'Reg', (24, 33))	('TPA-independent growth', 'MPA', (34, 56))	('TPA', 'molecular_function', 'GO:0031299', ('70', '73'))	('TPA dependence', 'MPA', (70, 84))	('TPA', 'Chemical', 'MESH:D013755', (34, 37))	('melanoma', 'Disease', (4, 12))	('deletion', 'Var', (98, 106))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('TPA', 'Chemical', 'MESH:D013755', (70, 73))	('TPA', 'molecular_function', 'GO:0031299', ('34', '37'))	('primary tumors', 'Disease', (197, 211))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('Ric-8A', 'Gene', (91, 97))	('primary tumors', 'Disease', 'MESH:D009369', (197, 211))
67768	27348266	The GNAQQ209L melanoma cell lines retained melanin pigmentation but had adopted a morphology that was more spindle-shaped or epithelial-like in comparison with the parental melanocyte cell line (Figure 4b).	('melanoma', 'Disease', (14, 22))	('melanin pigmentation', 'MPA', (43, 63))	('spindle', 'cellular_component', 'GO:0005819', ('107', '114'))	('melanin', 'Chemical', 'MESH:D008543', (43, 50))	('GNAQQ209L', 'Var', (4, 13))	('adopted', 'Reg', (72, 79))	('pigmentation', 'biological_process', 'GO:0043473', ('51', '63'))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
67769	27348266	Both tumor cell lines retained the capacity to induce Ric-8A deletion and deplete endogenous G proteins and Galphaq-Q209L (Figure 4c).	('Ric-8A', 'Gene', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('Galphaq', 'Gene', (108, 115))	('deletion', 'Var', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('deplete endogenous G proteins', 'MPA', (74, 103))	('tumor', 'Disease', (5, 10))	('induce', 'Reg', (47, 53))	('Q209L', 'Mutation', 'rs121913492', (116, 121))	('Galphaq', 'Gene', '14682', (108, 115))
67771	27348266	Ric-8A knockout dramatically blunted Galphaq-Q209L-driven secondary melanoma tumor progression.	('Galphaq', 'Gene', (37, 44))	('Q209L', 'Mutation', 'rs121913492', (45, 50))	('blunted', 'NegReg', (29, 36))	('Ric-8A', 'Gene', (0, 6))	('Galphaq', 'Gene', '14682', (37, 44))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma tumor', 'Disease', (68, 82))	('secondary', 'CPA', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('melanoma tumor', 'Disease', 'MESH:D008545', (68, 82))	('knockout', 'Var', (7, 15))
67774	27348266	4OHT treatment of both melanocyte cell lines in culture induced deletion of the floxed, mouse Ric-8A alleles, which resulted in greatly reduced Galphaq-Q209L and Galphaq/11 levels in the cell line lacking the RIC-8A transgene.	('Galphaq', 'Gene', '14682', (162, 169))	('Q209L', 'Mutation', 'rs121913492', (152, 157))	('Galphaq', 'Gene', (144, 151))	('deletion', 'Var', (64, 72))	('Galphaq', 'Gene', (162, 169))	('4OHT', 'Chemical', 'MESH:C032278', (0, 4))	('reduced', 'NegReg', (136, 143))	('mouse', 'Species', '10090', (88, 93))	('Ric-8A', 'Gene', (94, 100))	('Galphaq', 'Gene', '14682', (144, 151))
67780	27348266	In vivo tamoxifen treatment effectively ablated tumorigenesis driven by GNAQQ209L in the Ric-8AFlox/Flox background, but not in the background in which the floxed Ric-8A alleles were rescued by expression of the RIC-8A cDNA transgene (Figures 5b and c).	('tumor', 'Disease', (48, 53))	('Flox', 'Chemical', '-', (95, 99))	('expression', 'Species', '29278', (194, 204))	('Flox', 'Chemical', '-', (100, 104))	('GNAQQ209L', 'Var', (72, 81))	('ablated', 'NegReg', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tamoxifen', 'Chemical', 'MESH:D013629', (8, 17))	('Ric-8AFlox', 'Chemical', '-', (89, 99))
67781	27348266	These results clearly show that loss of tumor cell Ric-8A expression and not whole animal tamoxifen treatment per se accounts for the block of GNAQQ209L-driven melanoma tumorigenesis.	('expression', 'Species', '29278', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('loss', 'NegReg', (32, 36))	('melanoma tumor', 'Disease', (160, 174))	('melanoma tumor', 'Disease', 'MESH:D008545', (160, 174))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('GNAQQ209L-driven', 'Var', (143, 159))	('Ric-8A', 'Gene', (51, 57))	('tumor', 'Disease', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tamoxifen', 'Chemical', 'MESH:D013629', (90, 99))
67784	27348266	MG132 treatment provided a substantial boost in Galphaq-209L abundance, as shown for the parental GNAQQ209L melanocyte cell line in Figure 2g.	('MG132', 'Var', (0, 5))	('MG132', 'Chemical', 'MESH:C072553', (0, 5))	('Galphaq', 'Gene', (48, 55))	('boost', 'PosReg', (39, 44))	('Q209L', 'Mutation', 'rs121913492', (102, 107))	('Galphaq', 'Gene', '14682', (48, 55))
67789	27348266	The present study provides a genetic demonstration that melanocyte deletion of the molecular chaperone Ric-8A suppressed tumorigenesis mediated by the uveal melanoma oncogenic driver G protein, Galphaq-Q209L.	('Q209L', 'Mutation', 'rs121913492', (202, 207))	('uveal melanoma', 'Disease', (151, 165))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Ric-8A', 'Gene', (103, 109))	('deletion', 'Var', (67, 75))	('tumor', 'Disease', (121, 126))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('Galphaq', 'Gene', '14682', (194, 201))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('suppressed', 'NegReg', (110, 120))	('Galphaq', 'Gene', (194, 201))	('uveal melanoma', 'Phenotype', 'HP:0007716', (151, 165))	('uveal melanoma', 'Disease', 'MESH:C536494', (151, 165))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
67797	27348266	Induced Ric-8A deletion in the cultured melanocyte cell lines effectively reduced Galphaq-Q209L protein levels and had no obvious cytotoxic effects.	('Galphaq', 'Gene', (82, 89))	('deletion', 'Var', (15, 23))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('Q209L', 'Mutation', 'rs121913492', (90, 95))	('Galphaq', 'Gene', '14682', (82, 89))	('Ric-8A', 'Gene', (8, 14))	('reduced', 'NegReg', (74, 81))
67798	27348266	In fact, Ric-8A deletion imparted a modest in vitro growth advantage to cultured melanocytes and melanoma cell lines.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('deletion', 'Var', (16, 24))	('Ric-8A', 'Gene', (9, 15))
67800	27348266	Ric-8A deletion completely blocked melanoma tumorigenesis of the grafted GNAQQ209L melanocyte cell line and secondarily-derived GNAQQ209L melanoma cell lines.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('Ric-8A', 'Gene', (0, 6))	('deletion', 'Var', (7, 15))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('blocked', 'NegReg', (27, 34))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma tumor', 'Disease', (35, 49))	('melanoma', 'Disease', (35, 43))	('melanoma tumor', 'Disease', 'MESH:D008545', (35, 49))
67807	27348266	Ric-8A was initially characterized as a GEF that stimulates Galpha subunit guanine nucleotide exchange in vitro.	('Ric-8A', 'Var', (0, 6))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (75, 93))	('Galpha subunit guanine nucleotide exchange', 'MPA', (60, 102))	('GEF', 'molecular_function', 'GO:0005085', ('40', '43'))	('GEF', 'Gene', (40, 43))	('GEF', 'Gene', '16800', (40, 43))	('stimulates', 'PosReg', (49, 59))
67812	27348266	The fact that Ric-8A deletion suppresses the oncogenic action of Galphaq-Q209L indicates that the chaperoning activity is either the authentic cellular activity or is more penetrant than GEF activity.	('GEF', 'molecular_function', 'GO:0005085', ('187', '190'))	('Galphaq', 'Gene', (65, 72))	('suppresses', 'NegReg', (30, 40))	('GEF', 'Gene', (187, 190))	('Q209L', 'Mutation', 'rs121913492', (73, 78))	('GEF', 'Gene', '16800', (187, 190))	('deletion', 'Var', (21, 29))	('Ric-8A', 'Gene', (14, 20))	('Galphaq', 'Gene', '14682', (65, 72))	('chaperoning', 'MPA', (98, 109))	('oncogenic action', 'MPA', (45, 61))
67814	27348266	A key remaining question is to understand why GNAQ/11Q209L drives the majority of uveal melanomas, yet the oncogene is far less prevalent in cutaneous melanomas.	('uveal melanomas', 'Disease', (82, 97))	('uveal melanomas', 'Phenotype', 'HP:0007716', (82, 97))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (141, 160))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (141, 160))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (141, 159))	('cutaneous melanomas', 'Disease', (141, 160))	('Q209L', 'Mutation', 'rs121913492', (53, 58))	('drives', 'PosReg', (59, 65))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('uveal melanomas', 'Disease', 'MESH:C536494', (82, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('melanomas', 'Phenotype', 'HP:0002861', (151, 160))	('GNAQ/11Q209L', 'Var', (46, 58))
67818	27348266	Constitutively-active GNAQ/11 mutations are in fact highly prevalent in benign melanocytic neoplasms and can cause skin hyperpigmentation.	('skin hyperpigmentation', 'Phenotype', 'HP:0000953', (115, 137))	('cause', 'Reg', (109, 114))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (79, 100))	('neoplasms', 'Phenotype', 'HP:0002664', (91, 100))	('mutations', 'Var', (30, 39))	('GNAQ/11', 'Gene', (22, 29))	('skin hyperpigmentation', 'Disease', (115, 137))	('skin hyperpigmentation', 'Disease', 'MESH:D017495', (115, 137))	('prevalent', 'Reg', (59, 68))	('benign melanocytic neoplasms', 'Disease', 'MESH:D009369', (72, 100))	('benign melanocytic neoplasms', 'Disease', (72, 100))
67821	27348266	In accordance with this hypothesis, when our GNAQQ209L cutaneous murine melanocyte or melanoma cell lines were treated in culture with a phorbol ester, Galphaq-Q209L protein abundance, but not wild-type Galphaq/11 abundance was reduced dramatically, an effect on the order of that which occurred when Ric-8A is deleted.	('Galphaq', 'Gene', '14682', (152, 159))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('melanoma', 'Disease', (86, 94))	('Q209L', 'Mutation', 'rs121913492', (49, 54))	('Galphaq', 'Gene', (203, 210))	('reduced', 'NegReg', (228, 235))	('phorbol ester', 'Chemical', 'MESH:D010703', (137, 150))	('Q209L', 'Mutation', 'rs121913492', (160, 165))	('Galphaq', 'Gene', (152, 159))	('GNAQQ209L', 'Var', (45, 54))	('murine', 'Species', '10090', (65, 71))	('Galphaq', 'Gene', '14682', (203, 210))	('protein abundance', 'MPA', (166, 183))
67822	27348266	The TPA-treated GNAQQ209L cell line did not form tumors when grafted, despite efficient production of the GNAQQ209L-IRES-GFP transcript as visualized via the efficient GFP fluorescent signal (Supplementary Figure S3) and by RT-PCR analyses (Figure 2e).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('TPA', 'Chemical', 'MESH:D013755', (4, 7))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('Q209L', 'Mutation', 'rs121913492', (110, 115))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('GFP', 'MPA', (168, 171))	('TPA', 'molecular_function', 'GO:0031299', ('4', '7'))	('GNAQQ209L-IRES-GFP', 'Var', (106, 124))	('Q209L', 'Mutation', 'rs121913492', (20, 25))
67827	27348266	We are actively investigating the potentially distinct signaling properties of ocular and cutaneous melanocytes to cipher out an explanation of why GNAQ/11Q209L-induced oncogenesis is highly biased toward uveal melanocytes.	('GNAQ/11Q209L-induced', 'Var', (148, 168))	('Q209L', 'Mutation', 'rs121913492', (155, 160))	('signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('oncogenesis', 'CPA', (169, 180))	('oncogenesis', 'biological_process', 'GO:0007048', ('169', '180'))
67830	27348266	Yet for GNAQ/11Q209L-driven uveal melanoma, super-activation of the Galphaq/11-Q209L-stimulated PKC pathway could provide two distinct mechanisms of therapy: (1) PKC-activated feedback reduction of Galphaq/11 oncoprotein abundance or (2) inducement of cancer cell apoptosis.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('Galphaq', 'Gene', '14682', (198, 205))	('inducement', 'Reg', (238, 248))	('uveal melanoma', 'Phenotype', 'HP:0007716', (28, 42))	('PKC', 'molecular_function', 'GO:0004697', ('162', '165'))	('apoptosis', 'biological_process', 'GO:0097194', ('264', '273'))	('PKC', 'molecular_function', 'GO:0004697', ('96', '99'))	('Galphaq', 'Gene', '14682', (68, 75))	('apoptosis', 'biological_process', 'GO:0006915', ('264', '273'))	('reduction', 'NegReg', (185, 194))	('Galphaq', 'Gene', (198, 205))	('cancer', 'Disease', (252, 258))	('uveal melanoma', 'Disease', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('Q209L', 'Mutation', 'rs121913492', (79, 84))	('Galphaq', 'Gene', (68, 75))	('abundance', 'MPA', (221, 230))	('Q209L', 'Mutation', 'rs121913492', (15, 20))	('GNAQ/11Q209L-driven', 'Var', (8, 27))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('uveal melanoma', 'Disease', 'MESH:C536494', (28, 42))
67832	27348266	Wild-type PKC rescue of loss-of-function PKC alleles in human tumor cells inhibited tumorigenesis, showing that PKC is a tumor suppressor.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('PKC', 'molecular_function', 'GO:0004697', ('41', '44'))	('inhibited', 'NegReg', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('121', '137'))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('PKC', 'Enzyme', (41, 44))	('tumor', 'Disease', (121, 126))	('human', 'Species', '9606', (56, 61))	('tumor suppressor', 'biological_process', 'GO:0051726', ('121', '137'))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('PKC', 'molecular_function', 'GO:0004697', ('10', '13'))	('loss-of-function', 'NegReg', (24, 40))	('alleles', 'Var', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (84, 89))	('PKC', 'molecular_function', 'GO:0004697', ('112', '115'))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
67834	27348266	Our ongoing and future work involves active trials to reduce Galphaq/11-Q209L oncoproteins through Ric-8A inhibition or phorbol ester inhibitory feedback as two new potential strategies to treat GNAQ/11Q209L melanoma.	('Q209L', 'Mutation', 'rs121913492', (202, 207))	('Ric-8A', 'Gene', (99, 105))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('reduce', 'NegReg', (54, 60))	('melanoma', 'Disease', (208, 216))	('GNAQ/11Q209L', 'Var', (195, 207))	('Q209L', 'Mutation', 'rs121913492', (72, 77))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('Galphaq', 'Gene', '14682', (61, 68))	('phorbol ester', 'Chemical', 'MESH:D010703', (120, 133))	('Galphaq', 'Gene', (61, 68))	('oncoproteins', 'Protein', (78, 90))
67842	27348266	In detail, cell explants were co-cultured in melanocyte medium (RPMI-1640, 10% FBS, 2 mm l-Glutamine, 100 U/ml penicillin, 100 mug/ml streptomycin, 200 nm TPA, 200 pm CTX and 200 mum phenylthiourea) with XB2 keratinocyte feeder cells (ATCCCL-177, ATCC, Manassas, VA, USA) that had been mitotically-inactivated with mitomycin C. Growth of melanocytes was selectively promoted by TPA and CTX supplementation.	('TPA', 'molecular_function', 'GO:0031299', ('378', '381'))	('CTX', 'Disease', (167, 170))	('TPA', 'molecular_function', 'GO:0031299', ('155', '158'))	('supplementation', 'Var', (390, 405))	('melanocyte medium', 'Chemical', '-', (45, 62))	('TPA', 'Chemical', 'MESH:D013755', (378, 381))	('promoted', 'PosReg', (366, 374))	('CTX', 'Disease', 'MESH:D019294', (386, 389))	('Growth', 'CPA', (328, 334))	('TPA', 'Chemical', 'MESH:D013755', (155, 158))	('CTX', 'Disease', (386, 389))	('mug', 'molecular_function', 'GO:0043739', ('127', '130'))	('CTX', 'Disease', 'MESH:D019294', (167, 170))
67862	27348266	Deletion of Ric-8A in cultured Ric-8AFlox/Flox; Rosa-CreER+/- melanocyte cell lines was achieved by treating the cells in culture with 500 nm 4OHT (Sigma-Aldrich) for 5 days or by infection with Cre-NLS-lentivirus for 48 h followed by selection with 2 mug/ml puromycin (Sigma-Aldrich).	('mug', 'molecular_function', 'GO:0043739', ('252', '255'))	('Flox', 'Chemical', '-', (37, 41))	('Ric-8AFlox', 'Chemical', '-', (31, 41))	('puromycin', 'Chemical', 'MESH:D011691', (259, 268))	('Flox', 'Chemical', '-', (42, 46))	('infection', 'Disease', (180, 189))	('infection', 'Disease', 'MESH:D007239', (180, 189))	('Ric-8A', 'Gene', (12, 18))	('4OHT', 'Chemical', 'MESH:C032278', (142, 146))	('Deletion', 'Var', (0, 8))
67866	27348266	In vivo deletion of Ric-8A in melanocyte cell lines grafted into NSG mice was achieved by treating host animals with 10-15 i.p.	('Ric-8A', 'Gene', (20, 26))	('deletion', 'Var', (8, 16))	('mice', 'Species', '10090', (69, 73))
67880	22236444	Genetic and Molecular Characterization of Uveal Melanoma Cell Lines The recent identification of frequent activating mutations in GNAQ or GNA11 in uveal melanoma provides an opportunity to better understand the pathogenesis of this melanoma subtype, and to develop rational therapeutics to target the cellular effects mediated by these mutations.	('mutations', 'Var', (117, 126))	('uveal melanoma', 'Disease', (147, 161))	('Melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('Uveal Melanoma Cell', 'Disease', (42, 61))	('GNAQ', 'Gene', (130, 134))	('activating', 'PosReg', (106, 116))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('GNAQ', 'Gene', '2776', (130, 134))	('pathogenesis', 'biological_process', 'GO:0009405', ('211', '223'))	('GNA11', 'Gene', (138, 143))	('melanoma subtype', 'Disease', (232, 248))	('melanoma subtype', 'Disease', 'MESH:D008545', (232, 248))	('uveal melanoma', 'Phenotype', 'HP:0007716', (147, 161))	('GNA11', 'Gene', '2767', (138, 143))	('uveal melanoma', 'Disease', 'MESH:C536494', (147, 161))	('Uveal Melanoma Cell', 'Disease', 'MESH:C536494', (42, 61))
67884	22236444	The data confirms the mutually exclusive nature of GNAQ and GNA11 mutations in vitro.	('GNAQ', 'Gene', '2776', (51, 55))	('mutations', 'Var', (66, 75))	('GNA11', 'Gene', (60, 65))	('GNA11', 'Gene', '2767', (60, 65))	('GNAQ', 'Gene', (51, 55))
67885	22236444	The lack of BRAF, NRAS, KIT, PI3K, and AKT mutations reveal GNAQ and GNA11 uveal melanoma cells to be distinct among melanoma types.	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('KIT', 'molecular_function', 'GO:0005020', ('24', '27'))	('uveal melanoma', 'Disease', 'MESH:C536494', (75, 89))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('GNAQ', 'Gene', '2776', (60, 64))	('uveal melanoma', 'Disease', (75, 89))	('GNA11', 'Gene', (69, 74))	('AKT', 'Gene', (39, 42))	('NRAS', 'Gene', (18, 22))	('GNAQ', 'Gene', (60, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (75, 89))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))	('AKT', 'Gene', '207', (39, 42))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('GNA11', 'Gene', '2767', (69, 74))	('PI3K', 'Gene', (29, 33))	('PI3K', 'molecular_function', 'GO:0016303', ('29', '33'))	('BRAF', 'Gene', (12, 16))	('NRAS', 'Gene', '4893', (18, 22))	('BRAF', 'Gene', '673', (12, 16))	('mutations', 'Var', (43, 52))
67893	22236444	The most common site of mutation occurs in the Q209 position in either GNAQ (45%) or GNA11 (32%).	('GNAQ', 'Gene', (71, 75))	('Q209', 'Var', (47, 51))	('GNA11', 'Gene', '2767', (85, 90))	('GNA11', 'Gene', (85, 90))	('mutation', 'Var', (24, 32))	('GNAQ', 'Gene', '2776', (71, 75))
67894	22236444	Less frequently mutations affect the R183 position in either GNAQ (3%) or GNA11 (2%).	('GNA11', 'Gene', (74, 79))	('GNA11', 'Gene', '2767', (74, 79))	('R183', 'Var', (37, 41))	('GNAQ', 'Gene', (61, 65))	('mutations', 'Var', (16, 25))	('GNAQ', 'Gene', '2776', (61, 65))
67896	22236444	Folberg, et al., have reported karyotype and short tandem repeat analysis on seven commonly used uveal melanoma cell lines (OCM1, OCM3, OCM8, MUM2B, MUM2C, C918, M619), most obtained from original stock sources.	('short tandem', 'MPA', (45, 57))	('M619', 'Var', (162, 166))	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('C918', 'Var', (156, 160))	('uveal melanoma', 'Disease', (97, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('OCM1', 'Species', '83984', (124, 128))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
67897	22236444	The analysis indicated that many of these cell lines previously believed to be distinct were actually derived from the same patients (OCM1 = MUM2C, OCM3 = OCM8, and M619 = C918 = MUM2B).	('M619 = C918 = MUM2B', 'Var', (165, 184))	('OCM1', 'Var', (134, 138))	('OCM1', 'Species', '83984', (134, 138))	('patients', 'Species', '9606', (124, 132))
67901	22236444	In this study we analyzed a panel of 19 cell lines reported to be derived from uveal melanoma for mutation of relevant genes.	('mutation', 'Var', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Disease', (79, 93))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))
67904	22236444	Cell lines were analyzed for the presence of hotspot mutations in exons 4 (R183) or 5 (Q209) of GNAQ or GNA11 by Sanger sequencing of genomic DNA.	('GNA11', 'Gene', '2767', (104, 109))	('GNAQ', 'Gene', '2776', (96, 100))	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('R183', 'Var', (75, 79))	('GNAQ', 'Gene', (96, 100))	('GNA11', 'Gene', (104, 109))
67905	22236444	We observed GNAQ or GNA11 mutations in 11 of 19 cell lines examined.	('GNAQ', 'Gene', (12, 16))	('GNA11', 'Gene', (20, 25))	('mutations', 'Var', (26, 35))	('GNA11', 'Gene', '2767', (20, 25))	('GNAQ', 'Gene', '2776', (12, 16))
67906	22236444	Mutations in GNAQ were either Q209L (92.1, MEL202, UPMM2) or Q209P (MEL270, OMM2.3, OMM2.5, UPMM3), whereas mutations in GNA11 were only Q209L (UPMD1, UPMD2, OMM1).	('GNA11', 'Gene', '2767', (121, 126))	('Q209P', 'Var', (61, 66))	('Q209L', 'Var', (30, 35))	('GNAQ', 'Gene', (13, 17))	('Q209P', 'Mutation', 'rs121913492', (61, 66))	('Q209L', 'Mutation', 'rs121913492', (30, 35))	('GNA11', 'Gene', (121, 126))	('GNAQ', 'Gene', '2776', (13, 17))	('Q209L', 'Mutation', 'rs121913492', (137, 142))
67907	22236444	One line (MEL202) harbored a Q209L and a R210K mutation in GNAQ.	('R210K', 'Var', (41, 46))	('Q209L', 'Var', (29, 34))	('R210K', 'Mutation', 'p.R210K', (41, 46))	('Q209L', 'Mutation', 'rs121913492', (29, 34))	('GNAQ', 'Gene', (59, 63))	('GNAQ', 'Gene', '2776', (59, 63))
67908	22236444	Mutations at codon 183 (R183Q) were found in GNAQ in one cell line (UPMM1), whereas no GNA11 R183 mutations were observed in any of the cell lines tested.	('GNAQ', 'Gene', (45, 49))	('R183Q', 'Var', (24, 29))	('GNA11', 'Gene', '2767', (87, 92))	('GNA11', 'Gene', (87, 92))	('R183Q', 'Mutation', 'rs397514698', (24, 29))	('GNAQ', 'Gene', '2776', (45, 49))
67909	22236444	All mutations in GNAQ and GNA11 occurred in a mutually exclusive pattern.	('occurred', 'Reg', (32, 40))	('GNAQ', 'Gene', (17, 21))	('GNA11', 'Gene', (26, 31))	('GNA11', 'Gene', '2767', (26, 31))	('mutations', 'Var', (4, 13))	('GNAQ', 'Gene', '2776', (17, 21))
67912	22236444	We used Sequenom-based genotyping to interrogate mutations in a larger set of genes known to be mutated in other melanoma subtypes and cancer in general.	('cancer', 'Disease', (135, 141))	('melanoma subtypes', 'Disease', 'MESH:D008545', (113, 130))	('mutations', 'Var', (49, 58))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('melanoma subtypes', 'Disease', (113, 130))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
67914	22236444	GNAQ, GNA11, and BRAF mutations observed by Sanger sequencing in the uveal melanoma cell lines noted were also detected using the Sequenom-based platform.	('GNAQ', 'Gene', '2776', (0, 4))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('uveal melanoma', 'Disease', (69, 83))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('BRAF', 'Gene', '673', (17, 21))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('BRAF', 'Gene', (17, 21))	('GNAQ', 'Gene', (0, 4))	('GNA11', 'Gene', (6, 11))	('mutations', 'Var', (22, 31))	('GNA11', 'Gene', '2767', (6, 11))
67919	22236444	The three cell lines MEL270, OMM2.3, and OMM2.5, which were derived from primary and metastatic tumors from the same patient also showed similar fingerprints (Mel270 to OMM2.3, 35/38 p-value 3.2057E-10; Mel270 to OMM2.5, 34/36 p-value 1.0051E-10).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('Mel270', 'Var', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('Mel270', 'Var', (159, 165))	('patient', 'Species', '9606', (117, 124))
67921	22236444	Our data show that at least some GNAQ and GNA11 mutant uveal melanoma cells are capable of growth in culture using standard cell culture conditions.	('mutant', 'Var', (48, 54))	('GNAQ', 'Gene', (33, 37))	('uveal melanoma', 'Phenotype', 'HP:0007716', (55, 69))	('uveal melanoma', 'Disease', (55, 69))	('uveal melanoma', 'Disease', 'MESH:C536494', (55, 69))	('GNAQ', 'Gene', '2776', (33, 37))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('GNA11', 'Gene', (42, 47))	('GNA11', 'Gene', '2767', (42, 47))
67922	22236444	The cell lines highlighted in this study have mutually exclusive GNAQ or GNA11 mutations and lack mutations in BRAF, NRAS, and KIT, consistent with the genotype observed in tissues.	('GNA11', 'Gene', (73, 78))	('NRAS', 'Gene', (117, 121))	('KIT', 'molecular_function', 'GO:0005020', ('127', '130'))	('GNA11', 'Gene', '2767', (73, 78))	('GNAQ', 'Gene', '2776', (65, 69))	('NRAS', 'Gene', '4893', (117, 121))	('GNAQ', 'Gene', (65, 69))	('BRAF', 'Gene', '673', (111, 115))	('KIT', 'Gene', (127, 130))	('BRAF', 'Gene', (111, 115))	('mutations', 'Var', (79, 88))
67923	22236444	Prior studies have shown that both GNAQ and GNA11 mutant cells activate the MEK/MAPK pathway in vitro.	('activate', 'PosReg', (63, 71))	('GNA11', 'Gene', (44, 49))	('MAPK', 'molecular_function', 'GO:0004707', ('80', '84'))	('GNAQ', 'Gene', '2776', (35, 39))	('MEK', 'Gene', (76, 79))	('GNA11', 'Gene', '2767', (44, 49))	('mutant', 'Var', (50, 56))	('MEK', 'Gene', '5609', (76, 79))	('GNAQ', 'Gene', (35, 39))
67924	22236444	The lack of common BRAF, NRAS, or KIT mutations in GNAQ and GNA11 mutant cells is thus consistent with the notion that redundant mutant proteins within the RAS/MEK/MAPK are not necessary for adequate activation of this signaling pathway.	('GNAQ', 'Gene', '2776', (51, 55))	('BRAF', 'Gene', '673', (19, 23))	('KIT', 'molecular_function', 'GO:0005020', ('34', '37'))	('mutant', 'Var', (66, 72))	('GNA11', 'Gene', (60, 65))	('BRAF', 'Gene', (19, 23))	('MAPK', 'molecular_function', 'GO:0004707', ('164', '168'))	('GNA11', 'Gene', '2767', (60, 65))	('NRAS', 'Gene', '4893', (25, 29))	('signaling pathway', 'biological_process', 'GO:0007165', ('219', '236'))	('GNAQ', 'Gene', (51, 55))	('NRAS', 'Gene', (25, 29))	('MEK', 'Gene', (160, 163))	('mutations', 'Var', (38, 47))	('MEK', 'Gene', '5609', (160, 163))	('KIT', 'Gene', (34, 37))
67928	22236444	Tumors with BRAF mutations, that activate the MEK/MAPK, usually have concurrent loss of PTEN activation, or other aberrations that result in PI3K/AKT pathway signaling.	('MEK', 'Gene', '5609', (46, 49))	('AKT', 'Gene', '207', (146, 149))	('signaling', 'biological_process', 'GO:0023052', ('158', '167'))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('MEK', 'Gene', (46, 49))	('mutations', 'Var', (17, 26))	('result in', 'Reg', (131, 140))	('Tumors', 'Disease', (0, 6))	('activation', 'MPA', (93, 103))	('AKT', 'Gene', (146, 149))	('PTEN', 'Gene', (88, 92))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('MAPK', 'molecular_function', 'GO:0004707', ('50', '54'))	('activate', 'PosReg', (33, 41))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('loss', 'NegReg', (80, 84))	('PTEN', 'Gene', '5728', (88, 92))	('PI3K', 'molecular_function', 'GO:0016303', ('141', '145'))
67929	22236444	As mutant NRAS is able to activate both the MEK/MAPK and PI3K/AKT pathways, cutaneous melanomas with NRAS mutations tend not to demonstrate PTEN loss or mutations in PI3K or AKT (Ko et al.).	('AKT', 'Gene', (62, 65))	('mutant', 'Var', (3, 9))	('NRAS', 'Gene', (10, 14))	('MEK', 'Gene', '5609', (44, 47))	('MAPK', 'molecular_function', 'GO:0004707', ('48', '52'))	('PI3K', 'Pathway', (166, 170))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('PTEN loss', 'Disease', (140, 149))	('mutations', 'Reg', (153, 162))	('NRAS', 'Gene', '4893', (101, 105))	('AKT', 'Gene', '207', (174, 177))	('AKT', 'Gene', '207', (62, 65))	('MEK', 'Gene', (44, 47))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (76, 95))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (76, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (76, 94))	('PI3K', 'molecular_function', 'GO:0016303', ('166', '170'))	('PI3K', 'molecular_function', 'GO:0016303', ('57', '61'))	('NRAS', 'Gene', '4893', (10, 14))	('NRAS', 'Gene', (101, 105))	('activate', 'PosReg', (26, 34))	('cutaneous melanomas', 'Disease', (76, 95))	('mutations', 'Var', (106, 115))	('PTEN loss', 'Disease', 'MESH:D006223', (140, 149))	('AKT', 'Gene', (174, 177))
67930	22236444	The observation that GNAQ and GNA11 mutant uveal melanoma cells have intact PTEN expression (unpublished data) and lack PI3K or AKT mutations is intriguing.	('GNAQ', 'Gene', '2776', (21, 25))	('PTEN', 'Gene', (76, 80))	('GNA11', 'Gene', (30, 35))	('PI3K', 'molecular_function', 'GO:0016303', ('120', '124'))	('uveal melanoma', 'Disease', 'MESH:C536494', (43, 57))	('AKT', 'Gene', (128, 131))	('PTEN', 'Gene', '5728', (76, 80))	('GNAQ', 'Gene', (21, 25))	('GNA11', 'Gene', '2767', (30, 35))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('uveal melanoma', 'Disease', (43, 57))	('mutant', 'Var', (36, 42))	('AKT', 'Gene', '207', (128, 131))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('expression', 'MPA', (81, 91))
67934	22236444	Multiple studies using standard PCR-based techniques have failed to identify BRAF mutations in uveal melanoma tumors.	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('BRAF', 'Gene', '673', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('BRAF', 'Gene', (77, 81))	('mutations', 'Var', (82, 91))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (95, 109))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (95, 116))	('uveal melanoma tumors', 'Disease', (95, 116))
67935	22236444	However, using highly sensitive techniques, BRAF mutations have been identified in a subset of uveal melanoma, but appear to be present only in small populations of cells within a tumor.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('BRAF', 'Gene', '673', (44, 48))	('mutations', 'Var', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('BRAF', 'Gene', (44, 48))	('identified', 'Reg', (69, 79))	('tumor', 'Disease', (180, 185))	('uveal melanoma', 'Disease', 'MESH:C536494', (95, 109))	('uveal melanoma', 'Phenotype', 'HP:0007716', (95, 109))	('uveal melanoma', 'Disease', (95, 109))
67937	22236444	To date, mutations in GNAQ, GNA11 or BRAF have been found in a consistently mutually exclusive pattern.	('found', 'Reg', (52, 57))	('BRAF', 'Gene', '673', (37, 41))	('mutations', 'Var', (9, 18))	('GNAQ', 'Gene', (22, 26))	('BRAF', 'Gene', (37, 41))	('GNA11', 'Gene', (28, 33))	('GNAQ', 'Gene', '2776', (22, 26))	('GNA11', 'Gene', '2767', (28, 33))
67938	22236444	If a small proportion of uveal melanomas indeed harbor BRAF mutations, it is conceivable that this proportion could be skewed under culture conditions.	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('uveal melanomas', 'Disease', (25, 40))	('uveal melanomas', 'Phenotype', 'HP:0007716', (25, 40))	('BRAF', 'Gene', '673', (55, 59))	('uveal melanomas', 'Disease', 'MESH:C536494', (25, 40))	('mutations', 'Var', (60, 69))	('BRAF', 'Gene', (55, 59))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))
67939	22236444	We have observed that cell lines derived from cutaneous melanoma with BRAF mutations generally tend to grow well in culture, relative to cell lines derived from cutaneous melanoma without BRAF mutations (Woodman, unpublished).	('cutaneous melanoma', 'Disease', (161, 179))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (161, 179))	('BRAF', 'Gene', '673', (188, 192))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (161, 179))	('BRAF', 'Gene', (188, 192))	('grow', 'CPA', (103, 107))	('BRAF', 'Gene', '673', (70, 74))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('cutaneous melanoma', 'Disease', (46, 64))	('mutations', 'Var', (75, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (46, 64))	('BRAF', 'Gene', (70, 74))
67941	22236444	Uveal melanomas, of which more than 80% carry GNAQ or GNA11 mutations, are likewise difficult to establish in culture.	('GNAQ', 'Gene', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('GNA11', 'Gene', (54, 59))	('GNA11', 'Gene', '2767', (54, 59))	('melanomas', 'Disease', (6, 15))	('GNAQ', 'Gene', '2776', (46, 50))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('mutations', 'Var', (60, 69))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))
67944	22236444	In summary, considering the predominance of GNAQ and GNA11 mutations in human uveal melanoma tumor samples as well as the fact, that a number of studies have failed to identify GNAQ mutations in large panels of other malignancies we believe the origin and validity of cell lines harboring GNAQ or GNA11 mutations as derived from uveal melanoma is near certain.	('mutations', 'Var', (303, 312))	('GNA11', 'Gene', '2767', (297, 302))	('malignancies', 'Disease', 'MESH:D009369', (217, 229))	('uveal melanoma', 'Disease', 'MESH:C536494', (329, 343))	('uveal melanoma', 'Phenotype', 'HP:0007716', (78, 92))	('GNAQ', 'Gene', '2776', (44, 48))	('uveal melanoma', 'Disease', (329, 343))	('malignancies', 'Disease', (217, 229))	('melanoma', 'Phenotype', 'HP:0002861', (335, 343))	('GNA11', 'Gene', (53, 58))	('GNAQ', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('GNAQ', 'Gene', '2776', (289, 293))	('human', 'Species', '9606', (72, 77))	('uveal melanoma tumor', 'Disease', 'MESH:C536494', (78, 98))	('uveal melanoma', 'Phenotype', 'HP:0007716', (329, 343))	('GNAQ', 'Gene', (289, 293))	('GNA11', 'Gene', (297, 302))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('GNAQ', 'Gene', '2776', (177, 181))	('mutations', 'Var', (59, 68))	('GNAQ', 'Gene', (177, 181))	('GNA11', 'Gene', '2767', (53, 58))	('uveal melanoma tumor', 'Disease', (78, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (78, 92))
67945	22236444	On the other hand, taking into account the questionable presence of BRAF mutations in uveal melanomas, and the high similarity of some of the here described BRAF mutant cell lines, both to each other, and for OCM3/OCM8 to SK-Mel28, a well known cutaneous melanoma cell line, the origin and representatively of these cell lines is less clear.	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('BRAF', 'Gene', '673', (68, 72))	('cutaneous melanoma', 'Disease', (245, 263))	('melanomas', 'Phenotype', 'HP:0002861', (92, 101))	('BRAF', 'Gene', '673', (157, 161))	('BRAF', 'Gene', (68, 72))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (245, 263))	('mutant', 'Var', (162, 168))	('uveal melanomas', 'Phenotype', 'HP:0007716', (86, 101))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (245, 263))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('uveal melanomas', 'Disease', (86, 101))	('BRAF', 'Gene', (157, 161))	('melanoma', 'Phenotype', 'HP:0002861', (255, 263))	('mutations', 'Var', (73, 82))	('uveal melanomas', 'Disease', 'MESH:C536494', (86, 101))
67946	22236444	Considering these findings, we believe future studies on uveal melanoma should always include cell lines shown here to harbor GNAQ or GNA11 mutations Multiple studies analyzing expression of melanoma markers have shown that the uveal melanoma cell lines highlighted in this study express similar markers to those observed in cutaneous melanoma cell lines.	('GNAQ', 'Gene', '2776', (126, 130))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('melanoma', 'Disease', (191, 199))	('GNA11', 'Gene', (134, 139))	('GNAQ', 'Gene', (126, 130))	('uveal melanoma', 'Phenotype', 'HP:0007716', (228, 242))	('cutaneous melanoma', 'Disease', (325, 343))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (325, 343))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (325, 343))	('melanoma', 'Phenotype', 'HP:0002861', (335, 343))	('melanoma', 'Disease', (335, 343))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))	('melanoma', 'Disease', (63, 71))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('uveal melanoma', 'Disease', (57, 71))	('melanoma', 'Disease', 'MESH:D008545', (191, 199))	('GNA11', 'Gene', '2767', (134, 139))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('mutations', 'Var', (140, 149))	('melanoma', 'Disease', 'MESH:D008545', (335, 343))	('melanoma', 'Disease', (234, 242))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('uveal melanoma', 'Disease', 'MESH:C536494', (228, 242))	('uveal melanoma', 'Disease', (228, 242))
67948	22236444	It is unclear whether the absence of these melanoma-associated antigens is a product of the expansion of these cells in culture or represents the antigenic nature of the tumors from which they were derived; however, it is of interest that this phenotype was observed in uveal melanoma cell lines lacking mutations in GNAQ or GNA11.	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('melanoma', 'Disease', (276, 284))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('GNAQ', 'Gene', '2776', (317, 321))	('melanoma', 'Disease', 'MESH:D008545', (276, 284))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('uveal melanoma', 'Phenotype', 'HP:0007716', (270, 284))	('melanoma', 'Disease', (43, 51))	('GNA11', 'Gene', (325, 330))	('mutations', 'Var', (304, 313))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('uveal melanoma', 'Disease', 'MESH:C536494', (270, 284))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('GNA11', 'Gene', '2767', (325, 330))	('uveal melanoma', 'Disease', (270, 284))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('GNAQ', 'Gene', (317, 321))	('tumors', 'Disease', (170, 176))
67949	22236444	Since the cell line we analyzed was obtained directly from the laboratory which in which it was generated, had a GNAQ Q209L mutation and expressed MCSP-1 by FACS, we believe this supports the authenticity of our cell line as derived from uveal melanoma.	('GNAQ', 'Gene', (113, 117))	('Q209L mutation', 'Var', (118, 132))	('MCSP', 'Gene', '1464', (147, 151))	('uveal melanoma', 'Phenotype', 'HP:0007716', (238, 252))	('uveal melanoma', 'Disease', (238, 252))	('uveal melanoma', 'Disease', 'MESH:C536494', (238, 252))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('Q209L', 'Mutation', 'rs121913492', (118, 123))	('GNAQ', 'Gene', '2776', (113, 117))	('MCSP', 'Gene', (147, 151))
67950	22236444	Functional analysis of GNAQ or GNA11 mutations within uveal melanoma will be greatly enhanced by the use of cell lines that harbor these mutations.	('GNAQ', 'Gene', (23, 27))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('mutations', 'Var', (37, 46))	('uveal melanoma', 'Disease', (54, 68))	('uveal melanoma', 'Disease', 'MESH:C536494', (54, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('GNA11', 'Gene', (31, 36))	('GNAQ', 'Gene', '2776', (23, 27))	('GNA11', 'Gene', '2767', (31, 36))
67951	22236444	This study aimed to identify and more fully characterize uveal melanoma cell lines with GNAQ or GNA11 mutations.	('GNAQ', 'Gene', (88, 92))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('mutations', 'Var', (102, 111))	('uveal melanoma', 'Disease', (57, 71))	('GNAQ', 'Gene', '2776', (88, 92))	('GNA11', 'Gene', '2767', (96, 101))	('GNA11', 'Gene', (96, 101))
67952	22236444	We determined that GNAQ or GNA11 mutant cell lines retain the mutually exclusive pattern of GNAQ or GNA11 mutations observed in uveal melanoma tumors, and do not harbor other recurrent mutations (e.g., BRAF, NRAS, KIT, PI3K, or AKT) found in other types of melanoma.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (128, 149))	('uveal melanoma tumors', 'Disease', (128, 149))	('AKT', 'Gene', (228, 231))	('mutant', 'Var', (33, 39))	('melanoma', 'Disease', 'MESH:D008545', (257, 265))	('GNAQ', 'Gene', '2776', (92, 96))	('GNA11', 'Gene', '2767', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('GNAQ', 'Gene', (92, 96))	('NRAS', 'Gene', (208, 212))	('KIT', 'molecular_function', 'GO:0005020', ('214', '217'))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('GNAQ', 'Gene', '2776', (19, 23))	('GNA11', 'Gene', (100, 105))	('GNAQ', 'Gene', (19, 23))	('AKT', 'Gene', '207', (228, 231))	('BRAF', 'Gene', '673', (202, 206))	('BRAF', 'Gene', (202, 206))	('GNA11', 'Gene', (27, 32))	('melanoma', 'Phenotype', 'HP:0002861', (257, 265))	('melanoma', 'Disease', (257, 265))	('uveal melanoma', 'Phenotype', 'HP:0007716', (128, 142))	('NRAS', 'Gene', '4893', (208, 212))	('mutations', 'Var', (106, 115))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('PI3K', 'molecular_function', 'GO:0016303', ('219', '223'))	('GNA11', 'Gene', '2767', (100, 105))
67953	22236444	We observed that mutation spectrum in cell lines (Q209L, Q209P, and R183Q) does not significantly diverge from what we have found in human tumor tissues.	('Q209L', 'Var', (50, 55))	('Q209P', 'Var', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('Q209P', 'Mutation', 'rs121913492', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('Q209L', 'Mutation', 'rs121913492', (50, 55))	('R183Q', 'Var', (68, 73))	('human', 'Species', '9606', (133, 138))	('R183Q', 'Mutation', 'rs397514698', (68, 73))
67955	22236444	The following cell lines were generously provided by the respective contributors: 92.1, MEL202, MEL270, MEL285, MEL290, OMM1, OMM2.3, OMM2.5, OCM1, OCM3, and OCM8 (Drs.	('OCM1', 'Species', '83984', (142, 146))	('MEL285', 'Var', (104, 110))	('MEL290', 'Var', (112, 118))	('OCM3', 'Var', (148, 152))
68083	33288675	Direct evidence that the GPCR CysLTR2 mutant causative of uveal melanoma is constitutively active with highly biased signaling Uveal melanoma is the most common eye cancer in adults and is clinically and genetically distinct from skin cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('CysLTR2', 'Gene', '57105', (30, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (58, 72))	('uveal melanoma', 'Disease', (58, 72))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (230, 253))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('melanoma', 'Disease', (245, 253))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('skin cutaneous melanoma', 'Disease', (230, 253))	('melanoma', 'Disease', (133, 141))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('CysLTR2', 'Gene', (30, 37))	('mutant', 'Var', (38, 44))	('eye cancer', 'Disease', (161, 171))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('GPCR', 'Gene', (25, 29))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (127, 141))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (235, 253))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('eye cancer', 'Disease', 'MESH:D009369', (161, 171))	('melanoma', 'Disease', 'MESH:D008545', (245, 253))	('eye cancer', 'Phenotype', 'HP:0100012', (161, 171))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('GPCR', 'Gene', '441931', (25, 29))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))
68084	33288675	In a subset of cases, the oncogenic driver is an activating mutation in CYSLTR2, the gene encoding the G protein-coupled receptor cysteinyl-leukotriene receptor 2 (CysLTR2).	('mutation', 'Var', (60, 68))	('CYSLTR2', 'Gene', '57105', (72, 79))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('CysLTR2', 'Gene', (164, 171))	('cysteinyl-leukotriene receptor 2', 'Gene', (130, 162))	('CYSLTR2', 'Gene', (72, 79))	('activating', 'PosReg', (49, 59))	('cysteinyl-leukotriene receptor 2', 'Gene', '57105', (130, 162))	('CysLTR2', 'Gene', '57105', (164, 171))
68085	33288675	The mutant CYSLTR2 encodes for the CysLTR2-L129Q receptor, with the substitution of Leu to Gln at position 129 (3.43).	('Leu to Gln at position 129', 'Mutation', 'p.L129Q', (84, 110))	('CysLTR2', 'Gene', '57105', (35, 42))	('CYSLTR2', 'Gene', '57105', (11, 18))	('mutant', 'Var', (4, 10))	('CysLTR2', 'Gene', (35, 42))	('CYSLTR2', 'Gene', (11, 18))	('L129Q', 'Var', (43, 48))	('L129Q', 'SUBSTITUTION', 'None', (43, 48))
68086	33288675	The ability of CysLTR2-L129Q to cause malignant transformation has been hypothesized to result from constitutive activity, but how the receptor could escape desensitization is unknown.	('constitutive', 'MPA', (100, 112))	('malignant transformation', 'CPA', (38, 62))	('L129Q', 'SUBSTITUTION', 'None', (23, 28))	('CysLTR2', 'Gene', '57105', (15, 22))	('L129Q', 'Var', (23, 28))	('CysLTR2', 'Gene', (15, 22))	('cause', 'Reg', (32, 37))
68087	33288675	Here, we characterize the functional properties of CysLTR2-L129Q.	('L129Q', 'SUBSTITUTION', 'None', (59, 64))	('L129Q', 'Var', (59, 64))	('CysLTR2', 'Gene', (51, 58))	('CysLTR2', 'Gene', '57105', (51, 58))
68088	33288675	We show that CysLTR2-L129Q is a constitutively active mutant that strongly drives Gq/11 signaling pathways.	('drives', 'PosReg', (75, 81))	('CysLTR2', 'Gene', (13, 20))	('L129Q', 'Var', (21, 26))	('signaling', 'biological_process', 'GO:0023052', ('88', '97'))	('L129Q', 'SUBSTITUTION', 'None', (21, 26))	('CysLTR2', 'Gene', '57105', (13, 20))	('Gq/11 signaling pathways', 'Pathway', (82, 106))
68089	33288675	However, CysLTR2-L129Q only poorly recruits beta-arrestin.	('L129Q', 'Var', (17, 22))	('L129Q', 'SUBSTITUTION', 'None', (17, 22))	('CysLTR2', 'Gene', (9, 16))	('CysLTR2', 'Gene', '57105', (9, 16))	('beta-arrestin', 'Protein', (44, 57))
68090	33288675	Using a modified Slack-Hall operational model, we quantified the constitutive activity for both pathways and conclude that CysLTR2-L129Q displays profound signaling bias for Gq/11 signaling pathways while escaping beta-arrestin-mediated downregulation.	('CysLTR2', 'Gene', (123, 130))	('CysLTR2', 'Gene', '57105', (123, 130))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('L129Q', 'Var', (131, 136))	('signaling', 'MPA', (155, 164))	('L129Q', 'SUBSTITUTION', 'None', (131, 136))	('signaling', 'biological_process', 'GO:0023052', ('180', '189'))	('Gq/11 signaling pathways', 'Pathway', (174, 198))
68092	33288675	These results provide new insights into the mechanism of CysLTR2-L129Q oncoprotein signaling and suggest CYSLTR2 as a promising potential therapeutic target in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('CysLTR2', 'Gene', (57, 64))	('L129Q', 'Var', (65, 70))	('oncoprotein signaling', 'MPA', (71, 92))	('L129Q', 'SUBSTITUTION', 'None', (65, 70))	('uveal melanoma', 'Disease', 'MESH:C536494', (160, 174))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (160, 174))	('uveal melanoma', 'Disease', (160, 174))	('CYSLTR2', 'Gene', '57105', (105, 112))	('CysLTR2', 'Gene', '57105', (57, 64))	('CYSLTR2', 'Gene', (105, 112))
68094	33288675	Large-scale genomic analysis has revealed that one in five individuals carries a missense variant (MV) in a clinically relevant GPCR gene.	('GPCR', 'Gene', (128, 132))	('missense variant', 'Var', (81, 97))	('GPCR', 'Gene', '441931', (128, 132))
68095	33288675	The rate of de novo germline MVs in a GPCR gene is one in every 300 newborns, and one in 7 MVs is observed at a potential functionally relevant site.	('GPCR', 'Gene', '441931', (38, 42))	('MVs', 'Var', (29, 32))	('GPCR', 'Gene', (38, 42))
68097	33288675	Somatic mutations are found in 20% of tumor samples, but the lack of specific "hotspot" variants makes it difficult to identify and validate individual receptors as driver oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('variants', 'Var', (88, 96))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
68099	33288675	The mutant CYSLTR2 encodes cysteinyl-leukotriene receptor 2 (CysLTR2)-L129Q that carries a single amino acid substitution at a highly conserved residue in helix 3 (Ballesteros-Weinstein generic position 3.43) and serves as a driver oncogene in patients with uveal melanoma (UVM).	('CysLTR2', 'Gene', '57105', (61, 68))	('uveal melanoma', 'Disease', (258, 272))	('CYSLTR2', 'Gene', '57105', (11, 18))	('mutant', 'Var', (4, 10))	('uveal melanoma', 'Disease', 'MESH:C536494', (258, 272))	('L129Q', 'Var', (70, 75))	('substitution', 'Var', (109, 121))	('CYSLTR2', 'Gene', (11, 18))	('UVM', 'Phenotype', 'HP:0007716', (274, 277))	('L129Q', 'SUBSTITUTION', 'None', (70, 75))	('patients', 'Species', '9606', (244, 252))	('uveal melanoma', 'Phenotype', 'HP:0007716', (258, 272))	('cysteinyl-leukotriene receptor 2', 'Gene', (27, 59))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))	('cysteinyl-leukotriene receptor 2', 'Gene', '57105', (27, 59))	('CysLTR2', 'Gene', (61, 68))
68102	33288675	The same CysLTR2-L129Q mutation has also been identified as an oncogenic driver mutation in several other melanocytic tumors.	('melanocytic tumors', 'Disease', (106, 124))	('L129Q', 'Var', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('L129Q', 'SUBSTITUTION', 'None', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('CysLTR2', 'Gene', '57105', (9, 16))	('CysLTR2', 'Gene', (9, 16))	('melanocytic tumors', 'Disease', 'MESH:D009508', (106, 124))
68104	33288675	Here, we report that the UVM oncogene product CysLTR2-L129Q has a unique gain-of-function phenotype and report its precise signaling mechanism.	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('L129Q', 'SUBSTITUTION', 'None', (54, 59))	('UVM', 'Phenotype', 'HP:0007716', (25, 28))	('CysLTR2', 'Gene', '57105', (46, 53))	('gain-of-function', 'PosReg', (73, 89))	('L129Q', 'Var', (54, 59))	('CysLTR2', 'Gene', (46, 53))
68105	33288675	We show that CysLTR2-L129Q is a constitutively active mutant (CAM) receptor that strongly couples to Gq/11 cellular signaling pathways.	('CysLTR2', 'Gene', (13, 20))	('L129Q', 'Var', (21, 26))	('L129Q', 'SUBSTITUTION', 'None', (21, 26))	('Gq/11 cellular signaling pathways', 'Pathway', (101, 134))	('couples', 'Reg', (90, 97))	('CysLTR2', 'Gene', '57105', (13, 20))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))
68106	33288675	We quantified the signaling bias of the mutant receptor by comparing the constitutive activity (CA) for the WT and L129Q mutant using values calculated from the modified Slack-Hall operational model.	('L129Q', 'Var', (115, 120))	('signaling', 'biological_process', 'GO:0023052', ('18', '27'))	('constitutive activity', 'MPA', (73, 94))	('L129Q', 'SUBSTITUTION', 'None', (115, 120))
68108	33288675	To characterize the functional phenotype of CysLTR2-L129Q, we first determined the agonist-dependent signaling for CysLTR2-L129Q and CysLTR2 WT.	('L129Q', 'Var', (123, 128))	('CysLTR2', 'Gene', (133, 140))	('L129Q', 'Var', (52, 57))	('L129Q', 'SUBSTITUTION', 'None', (123, 128))	('CysLTR2', 'Gene', '57105', (115, 122))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('L129Q', 'SUBSTITUTION', 'None', (52, 57))	('CysLTR2', 'Gene', (115, 122))	('CysLTR2', 'Gene', '57105', (44, 51))	('CysLTR2', 'Gene', '57105', (133, 140))	('CysLTR2', 'Gene', (44, 51))
68111	33288675	We first obtained a time course of basal and LTD4-dependent IP1 accumulation in HEK293T cells transiently transfected with plasmids for CysLTR2 WT, CysLTR2-L129Q, and mock controls.	('IP1', 'Gene', '8517', (60, 63))	('L129Q', 'SUBSTITUTION', 'None', (156, 161))	('CysLTR2', 'Gene', '57105', (148, 155))	('LTD4', 'Chemical', 'MESH:D017998', (45, 49))	('CysLTR2', 'Gene', (136, 143))	('CysLTR2', 'Gene', (148, 155))	('L129Q', 'Var', (156, 161))	('CysLTR2', 'Gene', '57105', (136, 143))	('HEK293T', 'CellLine', 'CVCL:0063', (80, 87))	('LTD', 'biological_process', 'GO:0060292', ('45', '48'))	('IP1', 'Gene', (60, 63))	('accumulation', 'PosReg', (64, 76))
68114	33288675	The samples transfected with the same amount of DNA encoding for the CysLTR2-L129Q mutant showed ligand-independent IP1 accumulation of comparable magnitude as LTD4-treated CysLTR2 WT.	('IP1', 'Gene', (116, 119))	('IP1', 'Gene', '8517', (116, 119))	('CysLTR2', 'Gene', '57105', (69, 76))	('CysLTR2', 'Gene', '57105', (173, 180))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('CysLTR2', 'Gene', (69, 76))	('LTD', 'biological_process', 'GO:0060292', ('160', '163'))	('CysLTR2', 'Gene', (173, 180))	('L129Q', 'Var', (77, 82))	('ligand', 'molecular_function', 'GO:0005488', ('97', '103'))	('LTD4', 'Chemical', 'MESH:D017998', (160, 164))	('L129Q', 'SUBSTITUTION', 'None', (77, 82))
68115	33288675	After 100 min, the basal IP1 accumulation of CysLTR2-L129Q kept increasing, whereas the ligand-dependent signaling of the WT receptor reached a plateau (Fig.	('ligand', 'molecular_function', 'GO:0005488', ('88', '94'))	('CysLTR2', 'Gene', '57105', (45, 52))	('IP1', 'Gene', (25, 28))	('IP1', 'Gene', '8517', (25, 28))	('CysLTR2', 'Gene', (45, 52))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('L129Q', 'Var', (53, 58))	('L129Q', 'SUBSTITUTION', 'None', (53, 58))
68116	33288675	We generated fusion constructs of CysLTR2 WT and CysLTR2-L129Q, with a version of GFP (GFP10) at the C-terminus.	('CysLTR2', 'Gene', '57105', (49, 56))	('CysLTR2', 'Gene', '57105', (34, 41))	('CysLTR2', 'Gene', (49, 56))	('CysLTR2', 'Gene', (34, 41))	('L129Q', 'Var', (57, 62))	('L129Q', 'SUBSTITUTION', 'None', (57, 62))
68117	33288675	The agonist LTD4 induces a dose-dependent increase in IP1 accumulation for CysLTR2 WT (Fig.	('IP1', 'Gene', '8517', (54, 57))	('LTD4', 'Chemical', 'MESH:D017998', (12, 16))	('LTD', 'biological_process', 'GO:0060292', ('12', '15'))	('LTD4', 'Var', (12, 16))	('CysLTR2', 'Gene', '57105', (75, 82))	('CysLTR2', 'Gene', (75, 82))	('IP1', 'Gene', (54, 57))	('increase', 'PosReg', (42, 50))
68118	33288675	In contrast, the CysLTR2-L129Q mutant shows little or no response to treatment with LTD4, but the ligand-independent basal IP1 accumulation dramatically increases with increasing gene dosage (Fig.	('LTD4', 'Chemical', 'MESH:D017998', (84, 88))	('IP1', 'Gene', (123, 126))	('IP1', 'Gene', '8517', (123, 126))	('gene dosage', 'Var', (179, 190))	('CysLTR2', 'Gene', (17, 24))	('LTD', 'biological_process', 'GO:0060292', ('84', '87'))	('L129Q', 'Var', (25, 30))	('L129Q', 'SUBSTITUTION', 'None', (25, 30))	('increases', 'PosReg', (153, 162))	('ligand', 'molecular_function', 'GO:0005488', ('98', '104'))	('CysLTR2', 'Gene', '57105', (17, 24))
68119	33288675	The results also show that under the experimental conditions, the Gq signaling pathway is not saturated, which suggests that the high basal receptor activation of Gq for CysLTR2-L129Q is not due to a high amplification of the Gq signaling pathway.	('L129Q', 'Var', (178, 183))	('signaling pathway', 'biological_process', 'GO:0007165', ('229', '246'))	('L129Q', 'SUBSTITUTION', 'None', (178, 183))	('CysLTR2', 'Gene', '57105', (170, 177))	('signaling pathway', 'biological_process', 'GO:0007165', ('69', '86'))	('CysLTR2', 'Gene', (170, 177))	('activation', 'PosReg', (149, 159))
68121	33288675	We next asked the question, how is CysLTR2-L129Q capable of sustained strong signaling at a level comparable with the fully agonist-stimulated WT receptor?	('CysLTR2', 'Gene', '57105', (35, 42))	('CysLTR2', 'Gene', (35, 42))	('L129Q', 'Var', (43, 48))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))	('L129Q', 'SUBSTITUTION', 'None', (43, 48))
68123	33288675	However, little is known about the beta-arrestin-dependent desensitization, trafficking, and downregulation of CysLTR2 and CysLTR2-L129Q.	('CysLTR2', 'Gene', (123, 130))	('CysLTR2', 'Gene', '57105', (123, 130))	('beta-arrestin-dependent', 'Protein', (35, 58))	('L129Q', 'Var', (131, 136))	('CysLTR2', 'Gene', (111, 118))	('CysLTR2', 'Gene', '57105', (111, 118))	('desensitization', 'MPA', (59, 74))	('L129Q', 'SUBSTITUTION', 'None', (131, 136))	('downregulation', 'NegReg', (93, 107))	('trafficking', 'MPA', (76, 87))
68124	33288675	We designed a bioluminescence resonance energy transfer 2 (BRET2) experiment to quantify the basal and agonist-dependent binding of beta-arrestins to CysLTR2 variants.	('variants', 'Var', (158, 166))	('bioluminescence', 'biological_process', 'GO:0008218', ('14', '29'))	('beta-arrestins', 'Protein', (132, 146))	('binding', 'Interaction', (121, 128))	('CysLTR2', 'Gene', '57105', (150, 157))	('binding', 'molecular_function', 'GO:0005488', ('121', '128'))	('CysLTR2', 'Gene', (150, 157))
68132	33288675	To characterize the effect of the L129Q mutation on beta-arrestin recruitment, we included a set of samples expressing CysLTR2-L129Q in the BRET2 experiments.	('L129Q', 'Var', (34, 39))	('L129Q', 'Var', (127, 132))	('L129Q', 'SUBSTITUTION', 'None', (34, 39))	('L129Q', 'SUBSTITUTION', 'None', (127, 132))	('CysLTR2', 'Gene', '57105', (119, 126))	('CysLTR2', 'Gene', (119, 126))
68135	33288675	We next quantified the CA for both Gq/11 signaling and beta-arrestin recruitment using the modified Slack-Hall operational model to enable the calculation of receptor bias between Gq/11 and beta-arrestin pathways for L129Q relative to WT.	('L129Q', 'SUBSTITUTION', 'None', (217, 222))	('L129Q', 'Var', (217, 222))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('beta-arrestin', 'Pathway', (190, 203))
68141	33288675	We plotted the BRET2 ratios against normalized F(GFP10) readings for each CysLTR2 variant and fit the data to a one-site saturation-binding isotherm accordingly (Fig.	('binding', 'molecular_function', 'GO:0005488', ('132', '139'))	('variant', 'Var', (82, 89))	('CysLTR2', 'Gene', (74, 81))	('CysLTR2', 'Gene', '57105', (74, 81))
68143	33288675	The ligand-independent CA of CysLTR2-L129Q corresponds to 84.5% (95% confidence interval [CI]: 46.9%-152%) of the maximally LTD4-stimulated CysLTR2 WT at a comparable total receptor concentration.	('CysLTR2', 'Gene', '57105', (140, 147))	('CysLTR2', 'Gene', (140, 147))	('LTD', 'biological_process', 'GO:0060292', ('124', '127'))	('ligand', 'molecular_function', 'GO:0005488', ('4', '10'))	('L129Q', 'Var', (37, 42))	('CysLTR2', 'Gene', '57105', (29, 36))	('LTD4', 'Chemical', 'MESH:D017998', (124, 128))	('CysLTR2', 'Gene', (29, 36))	('L129Q', 'SUBSTITUTION', 'None', (37, 42))
68144	33288675	Therefore, the L129Q mutation results in a 26-fold increase of the CA in the Gq pathway.	('increase', 'PosReg', (51, 59))	('L129Q', 'Var', (15, 20))	('L129Q', 'SUBSTITUTION', 'None', (15, 20))	('Gq pathway', 'Pathway', (77, 87))
68145	33288675	The ligand-dependent increase in IP1 signaling of CysLTR2-L129Q is statistically insignificant as reflected by the efficacy parameter epsilon of 1.11 (95% CI: 1.03-1.19) close to unity (Table S1B).	('L129Q', 'Var', (58, 63))	('L129Q', 'SUBSTITUTION', 'None', (58, 63))	('ligand', 'molecular_function', 'GO:0005488', ('4', '10'))	('CysLTR2', 'Gene', '57105', (50, 57))	('signaling', 'biological_process', 'GO:0023052', ('37', '46'))	('CysLTR2', 'Gene', (50, 57))	('IP1', 'Gene', (33, 36))	('increase', 'PosReg', (21, 29))	('IP1', 'Gene', '8517', (33, 36))
68146	33288675	Overall, the results suggest that CysLTR2-L129Q displays a gain-of-function phenotype for ligand-independent basal signaling and a loss-of-function phenotype for agonist-dependent signaling in the Gq/11 signaling pathway.	('Gq/11 signaling pathway', 'Pathway', (197, 220))	('L129Q', 'Var', (42, 47))	('signaling pathway', 'biological_process', 'GO:0007165', ('203', '220'))	('CysLTR2', 'Gene', '57105', (34, 41))	('ligand', 'molecular_function', 'GO:0005488', ('90', '96'))	('CysLTR2', 'Gene', (34, 41))	('gain-of-function', 'PosReg', (59, 75))	('L129Q', 'SUBSTITUTION', 'None', (42, 47))	('loss-of-function', 'NegReg', (131, 147))	('basal signaling', 'biological_process', 'GO:0038034', ('109', '124'))	('signaling', 'biological_process', 'GO:0023052', ('180', '189'))	('ligand-independent basal signaling', 'MPA', (90, 124))	('agonist-dependent signaling', 'MPA', (162, 189))
68148	33288675	Therefore, the effect of the L129Q mutation on the CA in the beta-arrestin pathway is a 2-fold increase, which is much smaller than the 26-fold increase in the Gq pathway.	('increase', 'PosReg', (95, 103))	('beta-arrestin pathway', 'Pathway', (61, 82))	('L129Q', 'Var', (29, 34))	('Gq pathway', 'Pathway', (160, 170))	('L129Q', 'SUBSTITUTION', 'None', (29, 34))
68149	33288675	Therefore, the L129Q mutation introduces a strong bias of the constitutive signaling ("receptor bias") toward Gq and away from beta-arrestins.	('constitutive signaling', 'MPA', (62, 84))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('L129Q', 'Var', (15, 20))	('bias', 'PosReg', (50, 54))	('L129Q', 'SUBSTITUTION', 'None', (15, 20))
68151	33288675	The method described here is generalizable and can be used to study mutations that might cause receptor bias in any GPCR.	('GPCR', 'Gene', (116, 120))	('mutations', 'Var', (68, 77))	('GPCR', 'Gene', '441931', (116, 120))
68156	33288675	To explore the strong bias of CysLTR2-L129Q toward Gq, we must investigate the relationship between beta-arrestin and Gq binding to CysLTR2.	('L129Q', 'Var', (38, 43))	('L129Q', 'SUBSTITUTION', 'None', (38, 43))	('CysLTR2', 'Gene', '57105', (132, 139))	('CysLTR2', 'Gene', (132, 139))	('binding', 'molecular_function', 'GO:0005488', ('121', '128'))	('CysLTR2', 'Gene', '57105', (30, 37))	('CysLTR2', 'Gene', (30, 37))
68158	33288675	By enhancing the beta-arrestin binding to CysLTR2-L129Q, is it possible to observe a shift in the bias?	('beta-arrestin', 'Protein', (17, 30))	('L129Q', 'SUBSTITUTION', 'None', (50, 55))	('CysLTR2', 'Gene', '57105', (42, 49))	('binding', 'Interaction', (31, 38))	('CysLTR2', 'Gene', (42, 49))	('enhancing', 'PosReg', (3, 12))	('binding', 'molecular_function', 'GO:0005488', ('31', '38'))	('L129Q', 'Var', (50, 55))
68159	33288675	The results from IP1 and BRET2 assays of the V2 and V2(A)6 tail variants for CysLTR2 WT and L129Q are shown in Figure 6.	('L129Q', 'SUBSTITUTION', 'None', (92, 97))	('IP1', 'Gene', (17, 20))	('IP1', 'Gene', '8517', (17, 20))	('CysLTR2', 'Gene', '57105', (77, 84))	('CysLTR2', 'Gene', (77, 84))	('L129Q', 'Var', (92, 97))
68160	33288675	Similarly, the basal signaling of the L129Q mutant is reduced for V2 as compared with V2(A)6 (Fig.	('L129Q', 'Var', (38, 43))	('L129Q', 'SUBSTITUTION', 'None', (38, 43))	('basal signaling', 'MPA', (15, 30))	('reduced', 'NegReg', (54, 61))	('basal signaling', 'biological_process', 'GO:0038034', ('15', '30'))
68162	33288675	Surprisingly, the V2 tail restores some of the agonist-dependent signaling of L129Q as indicated by an efficacy parameter epsilon of 1.84 (95% CI: 1.70-1.99) different from unity (Table S1B).	('L129Q', 'SUBSTITUTION', 'None', (78, 83))	('agonist-dependent signaling', 'MPA', (47, 74))	('restores', 'PosReg', (26, 34))	('L129Q', 'Var', (78, 83))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))
68164	33288675	Interestingly, the enhancement of basal, agonist-independent beta-arrestin recruitment to CysLTR2-L129Q was much more pronounced for the V2 tail variant than with the V2(A)6 control, which showed only weak beta-arrestin recruitment similar to that of CysLTR2-L129Q without the added sequences.	('L129Q', 'SUBSTITUTION', 'None', (98, 103))	('CysLTR2', 'Gene', (251, 258))	('CysLTR2', 'Gene', '57105', (90, 97))	('CysLTR2', 'Gene', (90, 97))	('enhancement', 'PosReg', (19, 30))	('L129Q', 'Var', (259, 264))	('L129Q', 'Var', (98, 103))	('L129Q', 'SUBSTITUTION', 'None', (259, 264))	('CysLTR2', 'Gene', '57105', (251, 258))
68166	33288675	The CA significantly increases from 18.0% for WT to 31.5% for L129Q in the -V2 tail variant, whereas the V2(A)6 variants have comparable CA values or 17.5% (WT) and 17.8% (L129Q).	('increases', 'PosReg', (21, 30))	('L129Q', 'Var', (172, 177))	('L129Q', 'Var', (62, 67))	('L129Q', 'SUBSTITUTION', 'None', (172, 177))	('L129Q', 'SUBSTITUTION', 'None', (62, 67))	('-V2', 'Gene', (75, 78))
68167	33288675	Therefore, the V2 tail reduces the receptor bias of L129Q away from beta-arrestins.	('beta-arrestins', 'Protein', (68, 82))	('L129Q', 'Var', (52, 57))	('receptor bias', 'MPA', (35, 48))	('L129Q', 'SUBSTITUTION', 'None', (52, 57))	('reduces', 'NegReg', (23, 30))
68172	33288675	Based upon the available structural and biochemical data, we conclude that with CysLTR2-L129Q, the beta-arrestin is unable to compete strongly with the G protein for the core binding site.	('core', 'cellular_component', 'GO:0019013', ('170', '174'))	('CysLTR2', 'Gene', '57105', (80, 87))	('L129Q', 'Var', (88, 93))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('binding', 'molecular_function', 'GO:0005488', ('175', '182'))	('CysLTR2', 'Gene', (80, 87))	('G protein', 'Protein', (152, 161))	('beta-arrestin', 'Protein', (99, 112))	('L129Q', 'SUBSTITUTION', 'None', (88, 93))
68173	33288675	We speculate that the strong receptor bias of CysLTR2-L129Q toward Gq signaling is due to a selective stabilization of an intermediate state that is partially activated, perhaps facilitated by the L129Q mutation.	('activated', 'PosReg', (159, 168))	('L129Q', 'SUBSTITUTION', 'None', (197, 202))	('L129Q', 'SUBSTITUTION', 'None', (54, 59))	('stabilization', 'MPA', (102, 115))	('CysLTR2', 'Gene', '57105', (46, 53))	('signaling', 'biological_process', 'GO:0023052', ('70', '79'))	('L129Q', 'Var', (54, 59))	('L129Q', 'Var', (197, 202))	('CysLTR2', 'Gene', (46, 53))	('Gq signaling', 'MPA', (67, 79))
68174	33288675	We plan to investigate further the mechanisms behind the receptor bias in CysLTR2-L129Q.	('L129Q', 'Var', (82, 87))	('CysLTR2', 'Gene', (74, 81))	('L129Q', 'SUBSTITUTION', 'None', (82, 87))	('CysLTR2', 'Gene', '57105', (74, 81))
68175	33288675	In conclusion, we characterized a CYSLTR2 oncogene in UVM and established that CysLTR2-L129Q drives Gq/11 signaling activity in malignant UVM and serves as a driver oncogene.	('CYSLTR2', 'Gene', '57105', (34, 41))	('CysLTR2', 'Gene', '57105', (79, 86))	('UVM', 'Phenotype', 'HP:0007716', (54, 57))	('L129Q', 'Var', (87, 92))	('CYSLTR2', 'Gene', (34, 41))	('CysLTR2', 'Gene', (79, 86))	('L129Q', 'SUBSTITUTION', 'None', (87, 92))	('Gq/11 signaling activity', 'MPA', (100, 124))	('drives', 'PosReg', (93, 99))	('UVM', 'Phenotype', 'HP:0007716', (138, 141))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))
68176	33288675	We established that the CysLTR2-L129Q CAM is highly biased toward Gq/11 cellular signaling pathways and fails to recruit significantly beta-arrestins.	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('Gq/11 cellular signaling pathways', 'Pathway', (66, 99))	('CysLTR2', 'Gene', (24, 31))	('CysLTR2', 'Gene', '57105', (24, 31))	('biased', 'Reg', (52, 58))	('L129Q', 'Var', (32, 37))	('L129Q', 'SUBSTITUTION', 'None', (32, 37))
68177	33288675	The biased constitutive signaling pattern of CysLTR2-L129Q explains why it can persistently activate Gq and avoid beta-arrestin-dependent cellular downregulation mechanisms.	('CysLTR2', 'Gene', '57105', (45, 52))	('CysLTR2', 'Gene', (45, 52))	('L129Q', 'Var', (53, 58))	('L129Q', 'SUBSTITUTION', 'None', (53, 58))	('activate', 'PosReg', (92, 100))	('signaling', 'biological_process', 'GO:0023052', ('24', '33'))
68220	33288675	For the DNA titration assay with the CysLTR2-V2 tail variants, cells were similarly transfected in FluoroBrite DMEM and plated in 0.01% poly-d-lysine-coated, black, clear-bottom, tissue culture-treated low volume 384-well plates.	('FluoroBrite', 'Chemical', '-', (99, 110))	('CysLTR2', 'Gene', (37, 44))	('poly-d-lysine', 'Chemical', '-', (136, 149))	('DMEM', 'Chemical', '-', (111, 115))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('CysLTR2', 'Gene', '57105', (37, 44))	('variants', 'Var', (53, 61))
68229	33288675	HEK293T cells were transiently transfected with a serial dilution of 11, 3.6, 1.2, 0.4, and 0.1 ng of WT and mutants of CysLTR2-GFP10 per well as described above.	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('CysLTR2', 'Gene', '57105', (120, 127))	('CysLTR2', 'Gene', (120, 127))	('mutants', 'Var', (109, 116))
68230	33288675	For the DNA titration assay of CysLTR2 WT and L129Q, either WT or L129Q assays were performed in individual plates with mock-transfected cells as controls.	('CysLTR2', 'Gene', '57105', (31, 38))	('L129Q', 'Var', (66, 71))	('L129Q', 'Var', (46, 51))	('CysLTR2', 'Gene', (31, 38))	('L129Q', 'SUBSTITUTION', 'None', (66, 71))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('L129Q', 'SUBSTITUTION', 'None', (46, 51))
68231	33288675	For the DNA titration assay of CysLTR2-V2 variants, each experiment was performed in three individual plates, with three sets of two technical replicates each, with WT and mock-transfected cells as controls.	('variants', 'Var', (42, 50))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('CysLTR2', 'Gene', (31, 38))	('CysLTR2', 'Gene', '57105', (31, 38))
68236	33288675	We obtained a time-course of basal and LTD4-dependent IP1 accumulation in HEK293T cells transiently transfected with plasmids for CysLTR2 WT, CysLTR2-L129Q, and mock-transfected control.	('IP1', 'Gene', '8517', (54, 57))	('LTD4', 'Chemical', 'MESH:D017998', (39, 43))	('L129Q', 'SUBSTITUTION', 'None', (150, 155))	('LTD', 'biological_process', 'GO:0060292', ('39', '42'))	('accumulation', 'PosReg', (58, 70))	('CysLTR2', 'Gene', '57105', (142, 149))	('HEK293T', 'CellLine', 'CVCL:0063', (74, 81))	('CysLTR2', 'Gene', (142, 149))	('CysLTR2', 'Gene', '57105', (130, 137))	('CysLTR2', 'Gene', (130, 137))	('L129Q', 'Var', (150, 155))	('IP1', 'Gene', (54, 57))
68237	33288675	HEK293T cells were transiently transfected with 11 ng of CysLTR2-1D4 (WT and L129Q) per well.	('CysLTR2', 'Gene', (57, 64))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('L129Q', 'Var', (77, 82))	('CysLTR2', 'Gene', '57105', (57, 64))	('L129Q', 'SUBSTITUTION', 'None', (77, 82))
68241	33288675	HEK293T cells were transiently cotransfected with beta-arrestin2-RLuc3 and CysLTR2-GFP10 WT or the L129Q mutant directly 'in-plate' in 96-well plates using Lipofectamine 2000 as described above with slight modifications to account for the larger well volume.	('L129Q', 'Var', (99, 104))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (156, 174))	('L129Q', 'SUBSTITUTION', 'None', (99, 104))	('CysLTR2', 'Gene', '57105', (75, 82))	('beta-arrestin2', 'Gene', '409', (50, 64))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('CysLTR2', 'Gene', (75, 82))	('beta-arrestin2', 'Gene', (50, 64))
68248	33288675	HEK293T cells were transiently transfected with 5 ng of beta-arrestin2-RLuc3 and 0, 12.8, 32, 80, or 200 ng of CysLTR2-GFP10 WT/-L129Q, CysLTR2-V2 WT/-L129Q, or CysLTR2-V2(A)6 WT/-L129Q per well.	('beta-arrestin2', 'Gene', '409', (56, 70))	('CysLTR2', 'Gene', (161, 168))	('CysLTR2', 'Gene', '57105', (161, 168))	('L129Q', 'Var', (151, 156))	('L129Q', 'Var', (180, 185))	('beta-arrestin2', 'Gene', (56, 70))	('L129Q', 'SUBSTITUTION', 'None', (151, 156))	('CysLTR2', 'Gene', (111, 118))	('CysLTR2', 'Gene', '57105', (111, 118))	('L129Q', 'SUBSTITUTION', 'None', (180, 185))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('CysLTR2', 'Gene', '57105', (136, 143))	('L129Q', 'Var', (129, 134))	('L129Q', 'SUBSTITUTION', 'None', (129, 134))	('CysLTR2', 'Gene', (136, 143))
68256	33288675	HEK293T cells were transiently transfected with 5 ng of beta-arrestin2-RLuc3 and 80 ng of CysLTR2-GFP10 WT/-L129Q, CysLTR2-V2 WT/-L129Q, or CysLTR2-V2(A)6 WT/-L129Q per well.	('CysLTR2', 'Gene', '57105', (140, 147))	('beta-arrestin2', 'Gene', '409', (56, 70))	('L129Q', 'SUBSTITUTION', 'None', (130, 135))	('CysLTR2', 'Gene', (140, 147))	('CysLTR2', 'Gene', '57105', (90, 97))	('L129Q', 'Var', (159, 164))	('CysLTR2', 'Gene', '57105', (115, 122))	('beta-arrestin2', 'Gene', (56, 70))	('L129Q', 'Var', (108, 113))	('CysLTR2', 'Gene', (90, 97))	('L129Q', 'SUBSTITUTION', 'None', (108, 113))	('CysLTR2', 'Gene', (115, 122))	('L129Q', 'SUBSTITUTION', 'None', (159, 164))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('L129Q', 'Var', (130, 135))
68279	33288675	We quantified the CA using a modified Slack-Hall operational model to enable the calculation of the receptor bias between Gq/11 and beta-arrestin pathways for L129Q relative to WT and to characterize the effect of the V2 tail variants.	('beta-arrestin pathways', 'Pathway', (132, 154))	('L129Q', 'Var', (159, 164))	('L129Q', 'SUBSTITUTION', 'None', (159, 164))
68282	33288675	We then plotted the BRET2 ratios against normalized F(GFP10) readings of each CysLTR2 variant (Fig.	('CysLTR2', 'Gene', '57105', (78, 85))	('variant', 'Var', (86, 93))	('CysLTR2', 'Gene', (78, 85))
68285	33364785	Knockdown of Long Non-Coding RNA LOC100132707 Inhibits the Migration of Uveal Melanoma Cells via Silencing JAK2 Although lots of long non-coding RNAs (lncRNAs) have been demonstrated to be involved in carcinogenesis, the functions of numerous of lncRNAs remain unknown.	('Inhibits', 'NegReg', (46, 54))	('Melanoma', 'Disease', (78, 86))	('JAK', 'molecular_function', 'GO:0004713', ('107', '110'))	('carcinogenesis', 'Disease', (201, 215))	('involved', 'Reg', (189, 197))	('LOC100132707', 'Var', (33, 45))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('Melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('RNA', 'cellular_component', 'GO:0005562', ('29', '32'))	('carcinogenesis', 'Disease', 'MESH:D063646', (201, 215))	('JAK2', 'Gene', (107, 111))	('Melanoma', 'Disease', 'MESH:D008545', (78, 86))	('Silencing', 'NegReg', (97, 106))
68286	33364785	Bioinformatics online database showed that lncRNA LOC100132707 was highly expressed in metastatic melanoma tissues, and its expression predicted a lower overall survival rate in melanoma patients.	('patients', 'Species', '9606', (187, 195))	('lower', 'NegReg', (147, 152))	('lncRNA', 'Var', (43, 49))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Disease', (178, 186))	('LOC100132707', 'Var', (50, 62))	('melanoma', 'Disease', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('overall survival rate', 'CPA', (153, 174))
68287	33364785	However, LOC100132707 function in uveal melanoma (UM) progression still remains unclear.	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('LOC100132707', 'Var', (9, 21))	('melanoma', 'Disease', (40, 48))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('uveal melanoma', 'Phenotype', 'HP:0007716', (34, 48))
68289	33364785	LOC100132707 expression in metastatic UM cell line MM28 was significantly higher than that of the non-metastatic UM cell lines, MP38, MP46 and MP65, as well as the expressions of LOC100132707-related genes, including XRN1, PARP14, JAK2, DDX60, BUB1 and SAMD9L.	('BUB1', 'Gene', (244, 248))	('SAMD9L', 'Gene', '219285', (253, 259))	('XRN1', 'Gene', '54464', (217, 221))	('DDX60', 'Gene', '55601', (237, 242))	('PARP14', 'Gene', (223, 229))	('MM28', 'CellLine', 'CVCL:4D15', (51, 55))	('expressions', 'MPA', (164, 175))	('JAK2', 'Gene', (231, 235))	('LOC100132707-related', 'Var', (179, 199))	('JAK', 'molecular_function', 'GO:0004713', ('231', '234'))	('UM', 'Phenotype', 'HP:0007716', (113, 115))	('XRN1', 'Gene', (217, 221))	('UM', 'Phenotype', 'HP:0007716', (38, 40))	('DDX60', 'Gene', (237, 242))	('SAMD9L', 'Gene', (253, 259))	('PARP14', 'Gene', '54625', (223, 229))	('higher', 'PosReg', (74, 80))	('expression', 'MPA', (13, 23))	('BUB1', 'Gene', '699', (244, 248))	('JAK2', 'Gene', '3717', (231, 235))	('LOC100132707', 'Gene', (0, 12))
68290	33364785	LOC100132707 downregulation significantly repressed cell migration and invasion abilities, whereas overexpressing JAK2 rescued these effects.	('LOC100132707', 'Var', (0, 12))	('JAK2', 'Gene', '3717', (114, 118))	('JAK2', 'Gene', (114, 118))	('JAK', 'molecular_function', 'GO:0004713', ('114', '117'))	('cell migration', 'CPA', (52, 66))	('downregulation', 'NegReg', (13, 27))	('cell migration', 'biological_process', 'GO:0016477', ('52', '66'))	('invasion abilities', 'CPA', (71, 89))	('repressed', 'NegReg', (42, 51))
68291	33364785	Consistently, upregulation of LOC100132707 induced significant increases in cell migration and invasion abilities via upregulating JAK2.	('increases', 'PosReg', (63, 72))	('JAK', 'molecular_function', 'GO:0004713', ('131', '134'))	('JAK2', 'Gene', (131, 135))	('cell migration', 'CPA', (76, 90))	('cell migration', 'biological_process', 'GO:0016477', ('76', '90'))	('upregulating', 'PosReg', (118, 130))	('JAK2', 'Gene', '3717', (131, 135))	('invasion abilities', 'CPA', (95, 113))	('upregulation', 'PosReg', (14, 26))	('LOC100132707', 'Var', (30, 42))
68292	33364785	In addition, silencing of LOC100132707 significantly repressed the in vivo tumor formation ability in UM cells.	('formation', 'biological_process', 'GO:0009058', ('81', '90'))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('repressed', 'NegReg', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('LOC100132707', 'Gene', (26, 38))	('UM', 'Phenotype', 'HP:0007716', (102, 104))	('tumor', 'Disease', (75, 80))	('silencing', 'Var', (13, 22))
68293	33364785	This study reveals that silence of LOC100132707 represses the migration of UM via downregulating JAK2.	('silence', 'Var', (24, 31))	('LOC100132707', 'Var', (35, 47))	('represses', 'NegReg', (48, 57))	('JAK', 'molecular_function', 'GO:0004713', ('97', '100'))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('downregulating', 'NegReg', (82, 96))	('JAK2', 'Gene', '3717', (97, 101))	('migration of UM via', 'CPA', (62, 81))	('JAK2', 'Gene', (97, 101))
68301	33364785	For instance, lncRNA loc285194 was identified to be a p53-regulated tumor suppressor, that partially inhibited tumor growth via inhibiting microRNA-211.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor suppressor', 'biological_process', 'GO:0051726', ('68', '84'))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('68', '84'))	('p53', 'Gene', (54, 57))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('inhibiting', 'NegReg', (128, 138))	('p53', 'Gene', '7157', (54, 57))	('lncRNA loc285194', 'Var', (14, 30))	('inhibited', 'NegReg', (101, 110))	('microRNA-211', 'MPA', (139, 151))
68305	33364785	For example, lncRNA LINC01234 acted as a ceRNA in osteosarcoma, and regulated CBFB expression via mutagenizing miR-204-5p.	('miR-204-5p', 'MPA', (111, 121))	('LINC01234', 'Gene', '100506465', (20, 29))	('CBFB', 'Gene', '865', (78, 82))	('LINC01234', 'Gene', (20, 29))	('osteosarcoma', 'Disease', (50, 62))	('regulated', 'Reg', (68, 77))	('expression', 'MPA', (83, 93))	('osteosarcoma', 'Phenotype', 'HP:0002669', (50, 62))	('mutagenizing', 'Var', (98, 110))	('CBFB', 'Gene', (78, 82))	('osteosarcoma', 'Disease', 'MESH:D012516', (50, 62))
68310	33364785	The expression patterns of lncRNA LOC100132707 were evaluated using The Cancer Genome Atlas (TCGA) data portal.	('LOC100132707', 'Var', (34, 46))	('Cancer', 'Disease', 'MESH:D009369', (72, 78))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Cancer', 'Disease', (72, 78))
68311	33364785	GEPIA database (http://gepia.cancer-pku.cn/) was used to find genes which are related to lncRNA LOC100132707 in melanoma.	('LOC100132707', 'Var', (96, 108))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('gepia.cancer-pku', 'Disease', (23, 39))	('gepia.cancer-pku', 'Disease', 'MESH:D009369', (23, 39))	('lncRNA', 'Gene', (89, 95))
68312	33364785	Four UM cell lines, MP38, MP46, MP65 and MM28 were purchased from American Type Culture Collection (ATCC, Manassas, VA, USA) and were grown in RPMI-1640 medium, supplemented with 20% fetal bovine serum (FBS, Gibco, MA, USA).	('MP65', 'Var', (32, 36))	('MP46', 'Var', (26, 30))	('MM28', 'CellLine', 'CVCL:4D15', (41, 45))	('RPMI-1640 medium', 'Chemical', '-', (143, 159))	('MP38', 'Var', (20, 24))	('UM', 'Phenotype', 'HP:0007716', (5, 7))
68328	33364785	Briefly, MM28 cells (5x 106 cells in 200 muL PBS/mouse) with sh-NC or sh-LOC100132707 stable transfection were subcutaneously injected into the flanks of male (6-week-old) NOD/SCID mice (Vitalriver, Beijing, China).	('sh-LOC100132707', 'Var', (70, 85))	('MM28', 'CellLine', 'CVCL:4D15', (9, 13))	('SCID', 'Disease', (176, 180))	('mice', 'Species', '10090', (181, 185))	('mouse', 'Species', '10090', (49, 54))	('PBS', 'Chemical', 'MESH:D007854', (45, 48))	('SCID', 'Disease', 'MESH:D053632', (176, 180))
68330	33364785	The results showed that several lncRNAs were upregulated in the metastatic melanoma, such as LOC100132707, LOC339524, FLJ41200, LOC100505812, LOC153684, OIP5-AS1, LOC100506585, etc.	('LOC100506585', 'Gene', (163, 175))	('FLJ41200', 'Chemical', '-', (118, 126))	('LOC100506585', 'Gene', '100506585', (163, 175))	('OIP5-AS1', 'Gene', (153, 161))	('LOC100132707', 'Var', (93, 105))	('upregulated', 'PosReg', (45, 56))	('lncRNAs', 'MPA', (32, 39))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('FLJ41200', 'Var', (118, 126))	('LOC153684', 'Gene', (142, 151))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('LOC153684', 'Gene', '153684', (142, 151))	('LOC339524', 'Var', (107, 116))	('OIP5-AS1', 'Gene', '729082', (153, 161))	('LOC100505812', 'Var', (128, 140))
68331	33364785	The high expression pattern of LOC100132707 in the metastatic melanoma was also confirmed by the data uploaded from the TCGA database (Figure 1B).	('melanoma', 'Disease', (62, 70))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('LOC100132707', 'Var', (31, 43))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
68332	33364785	Moreover, the high expression profile of LOC100132707 predicted a shorter overall survival in patients with melanoma (Figure 1C).	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('LOC100132707', 'Var', (41, 53))	('patients', 'Species', '9606', (94, 102))	('shorter', 'NegReg', (66, 73))	('overall survival', 'MPA', (74, 90))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))
68333	33364785	Similarly to LOC100132707 expression pattern in metastatic melanoma and primary melanoma samples, its expression was significantly higher in the metastatic human UM cell strain MM28 than that in the non-metastatic UM cell lines, such as MP38, MP46 and MP65 (Figure 1D).	('expression', 'MPA', (26, 36))	('MM28', 'CellLine', 'CVCL:4D15', (177, 181))	('expression', 'MPA', (102, 112))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('UM', 'Phenotype', 'HP:0007716', (162, 164))	('UM', 'Phenotype', 'HP:0007716', (214, 216))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('human', 'Species', '9606', (156, 161))	('higher', 'PosReg', (131, 137))	('LOC100132707', 'Var', (13, 25))
68335	33364785	The mRNA expressions of XRN1, PARP14, JAK2, DDX60, BUB1 and SAMD9L were significantly higher in MM28 cells than that in MP38, MP46 and MP65 cells (Figure 2A-F).	('SAMD9L', 'Gene', (60, 66))	('JAK', 'molecular_function', 'GO:0004713', ('38', '41'))	('BUB1', 'Gene', (51, 55))	('JAK2', 'Gene', (38, 42))	('DDX60', 'Gene', '55601', (44, 49))	('XRN1', 'Gene', '54464', (24, 28))	('mRNA expressions', 'MPA', (4, 20))	('PARP14', 'Gene', (30, 36))	('XRN1', 'Gene', (24, 28))	('SAMD9L', 'Gene', '219285', (60, 66))	('JAK2', 'Gene', '3717', (38, 42))	('MM28', 'Var', (96, 100))	('higher', 'PosReg', (86, 92))	('DDX60', 'Gene', (44, 49))	('MM28', 'CellLine', 'CVCL:4D15', (96, 100))	('PARP14', 'Gene', '54625', (30, 36))	('BUB1', 'Gene', '699', (51, 55))
68336	33364785	We then using Pearson correlation test to evaluate the correlations between LOC100132707 expression and XRN1, PARP14, JAK2, DDX60, BUB1 and SAMD9L expressions.	('DDX60', 'Gene', (124, 129))	('JAK2', 'Gene', (118, 122))	('XRN1', 'Gene', (104, 108))	('SAMD9L', 'Gene', '219285', (140, 146))	('PARP14', 'Gene', '54625', (110, 116))	('BUB1', 'Gene', (131, 135))	('XRN1', 'Gene', '54464', (104, 108))	('LOC100132707', 'Var', (76, 88))	('BUB1', 'Gene', '699', (131, 135))	('JAK', 'molecular_function', 'GO:0004713', ('118', '121'))	('DDX60', 'Gene', '55601', (124, 129))	('PARP14', 'Gene', (110, 116))	('JAK2', 'Gene', '3717', (118, 122))	('SAMD9L', 'Gene', (140, 146))
68337	33364785	The results showed that LOC100132707 expression showed positive association with XRN1, PARP14, JAK2, DDX60, BUB1 and SAMD9L levels (Figure 3A-F).	('BUB1', 'Gene', '699', (108, 112))	('XRN1', 'Gene', '54464', (81, 85))	('LOC100132707', 'Var', (24, 36))	('BUB1', 'Gene', (108, 112))	('JAK2', 'Gene', '3717', (95, 99))	('DDX60', 'Gene', (101, 106))	('XRN1', 'Gene', (81, 85))	('SAMD9L', 'Gene', (117, 123))	('PARP14', 'Gene', '54625', (87, 93))	('JAK2', 'Gene', (95, 99))	('DDX60', 'Gene', '55601', (101, 106))	('SAMD9L', 'Gene', '219285', (117, 123))	('PARP14', 'Gene', (87, 93))	('positive', 'PosReg', (55, 63))	('JAK', 'molecular_function', 'GO:0004713', ('95', '98'))
68338	33364785	Next, we performed gain- and loss-of-function assays in MP65 and MM28 cells to explore LOC100132707 effects on cell migration and invasion, respectively.	('cell migration', 'biological_process', 'GO:0016477', ('111', '125'))	('LOC100132707', 'Var', (87, 99))	('cell migration', 'CPA', (111, 125))	('invasion', 'CPA', (130, 138))	('MM28', 'CellLine', 'CVCL:4D15', (65, 69))	('gain-', 'PosReg', (19, 24))	('loss-of-function', 'NegReg', (29, 45))
68339	33364785	The expression of LOC100132707 was significantly reduced when MM28 cells were transfected with sh-LOC100132707-1 and sh- LOC100132707-2 (Figure 4A), while LOC100132707 expression was increased when MP65 cells were transfected with OE-LOC100132707 (Figure 4D).	('LOC100132707', 'Var', (18, 30))	('reduced', 'NegReg', (49, 56))	('expression', 'MPA', (4, 14))	('MM28', 'CellLine', 'CVCL:4D15', (62, 66))	('sh-LOC100132707-1', 'Var', (95, 112))	('sh- LOC100132707-2', 'Var', (117, 135))
68340	33364785	Knockdown of LOC100132707 significantly repressed cell invasion and migration in MM28 cells (Figure 4B and C), whereas overexpression of LOC100132707 induced significant promotions in cell invasion and migration abilities in MP65 cells (Figure 4E and F).	('MM28', 'CellLine', 'CVCL:4D15', (81, 85))	('cell invasion', 'CPA', (50, 63))	('cell invasion', 'CPA', (184, 197))	('repressed', 'NegReg', (40, 49))	('migration abilities', 'CPA', (202, 221))	('promotions', 'PosReg', (170, 180))	('LOC100132707', 'Var', (137, 149))	('LOC100132707', 'Var', (13, 25))
68341	33364785	OE-JAK2 transfection induced a 3-fold increase in JAK2 protein expression level in MM28 cells (Figure 5A).	('increase', 'PosReg', (38, 46))	('JAK2', 'Gene', (50, 54))	('JAK', 'molecular_function', 'GO:0004713', ('3', '6'))	('JAK2', 'Gene', '3717', (3, 7))	('JAK', 'molecular_function', 'GO:0004713', ('50', '53'))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('JAK2', 'Gene', '3717', (50, 54))	('MM28', 'CellLine', 'CVCL:4D15', (83, 87))	('JAK2', 'Gene', (3, 7))	('transfection', 'Var', (8, 20))
68343	33364785	In addition, JAK2 was silenced and LOC100132707 was upregulated in MP65 cells to revel the role of LOC100132707/JAK2 axis in cell invasion and migration.	('JAK2', 'Gene', '3717', (13, 17))	('LOC100132707', 'Var', (35, 47))	('JAK2', 'Gene', '3717', (112, 116))	('JAK', 'molecular_function', 'GO:0004713', ('112', '115'))	('JAK', 'molecular_function', 'GO:0004713', ('13', '16'))	('JAK2', 'Gene', (112, 116))	('cell invasion', 'CPA', (125, 138))	('JAK2', 'Gene', (13, 17))	('upregulated', 'PosReg', (52, 63))	('migration', 'CPA', (143, 152))
68346	33364785	The transwell chambers results showed that knockdown of JAK2 obviously blunted OE-LOC100132707 effects on the promotions of cell invasion and migration in MP65 cells (Figure 5F-H).	('JAK2', 'Gene', (56, 60))	('blunted', 'NegReg', (71, 78))	('knockdown', 'Var', (43, 52))	('cell invasion', 'CPA', (124, 137))	('JAK', 'molecular_function', 'GO:0004713', ('56', '59'))	('JAK2', 'Gene', '3717', (56, 60))
68347	33364785	These findings suggested that LOC100132707 facilitated UM cell migration and invasion via upregulating JAK2.	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('UM cell migration', 'CPA', (55, 72))	('invasion', 'CPA', (77, 85))	('facilitated', 'PosReg', (43, 54))	('JAK2', 'Gene', '3717', (103, 107))	('cell migration', 'biological_process', 'GO:0016477', ('58', '72'))	('upregulating', 'PosReg', (90, 102))	('JAK2', 'Gene', (103, 107))	('JAK', 'molecular_function', 'GO:0004713', ('103', '106'))	('LOC100132707', 'Var', (30, 42))
68348	33364785	Compared with the control group, downregulation of LOC100132707 significantly decreased the in vivo tumor formation ability of MM28 cells (Figure 6A-C), with decreased expression levels of JAK2, and the metastasis markers MMP2 and MMP9 (Figure 6D).	('expression levels', 'MPA', (168, 185))	('MMP2', 'molecular_function', 'GO:0004228', ('222', '226'))	('tumor', 'Disease', (100, 105))	('MMP2', 'Gene', '4313', (222, 226))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('MMP9', 'molecular_function', 'GO:0004229', ('231', '235'))	('JAK2', 'Gene', '3717', (189, 193))	('decreased', 'NegReg', (78, 87))	('metastasis', 'CPA', (203, 213))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('LOC100132707', 'Var', (51, 63))	('decreased', 'NegReg', (158, 167))	('MM28', 'CellLine', 'CVCL:4D15', (127, 131))	('JAK', 'molecular_function', 'GO:0004713', ('189', '192'))	('JAK2', 'Gene', (189, 193))	('MMP2', 'Gene', (222, 226))	('downregulation', 'NegReg', (33, 47))	('MMP9', 'Gene', '4318', (231, 235))	('MMP9', 'Gene', (231, 235))	('formation', 'biological_process', 'GO:0009058', ('106', '115'))
68351	33364785	For instance, Lu et al reported that the expression of lncRNA RHPN1 antisense RNA 1 was significantly increased in UM cell lines, and knockdown of it obviously inhibited UM cell proliferation and migration in vitro and in vivo.	('expression', 'MPA', (41, 51))	('antisense RNA', 'molecular_function', 'GO:0009388', ('68', '81'))	('cell proliferation', 'biological_process', 'GO:0008283', ('173', '191'))	('UM', 'Phenotype', 'HP:0007716', (115, 117))	('RNA', 'cellular_component', 'GO:0005562', ('78', '81'))	('knockdown', 'Var', (134, 143))	('RHPN1', 'Gene', (62, 67))	('UM', 'Phenotype', 'HP:0007716', (170, 172))	('increased', 'PosReg', (102, 111))	('RHPN1', 'Gene', '114822', (62, 67))	('inhibited', 'NegReg', (160, 169))
68354	33364785	Ding et al revealed that lncRNA PAUPAR expressed in UM tissues and cells at low levels; ectopic expression of it repressed the tumourigenesis of UM in vitro and in vivo.	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('ectopic expression', 'Var', (88, 106))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('PAUPAR', 'Gene', (32, 38))	('PAUPAR', 'Gene', '103157000', (32, 38))	('tumourigenesis', 'CPA', (127, 141))
68357	33364785	In the present study, we explored the expression pattern and function of lncRNA LOC100132707 (Genecards ID: PAXIP1-AS2) in UM for first time.	('PAXIP1-AS2', 'Gene', (108, 118))	('PAXIP1-AS2', 'Gene', '100132707', (108, 118))	('LOC100132707', 'Var', (80, 92))	('lncRNA', 'Gene', (73, 79))	('UM', 'Phenotype', 'HP:0007716', (123, 125))
68358	33364785	From the NCBI database (https://www.ncbi.nlm.nih.gov/gene/100132707), we find that LOC100132707 is widely expressed in human tissues, such as colon, endometrium, esophagus, spleen, ovary, etc.	('colon', 'Disease', 'MESH:D003110', (142, 147))	('LOC100132707', 'Var', (83, 95))	('esophagus', 'Disease', (162, 171))	('colon', 'Disease', (142, 147))	('human', 'Species', '9606', (119, 124))
68359	33364785	It has been demonstrated that LOC100132707 level was increased in glioblastoma samples when compared to normal brain tissues, which was associated with the malignancy grades of glioma.	('glioma', 'Disease', (177, 183))	('malignancy', 'Disease', 'MESH:D009369', (156, 166))	('increased', 'PosReg', (53, 62))	('glioblastoma', 'Disease', (66, 78))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('malignancy', 'Disease', (156, 166))	('glioblastoma', 'Disease', 'MESH:D005909', (66, 78))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('glioblastoma', 'Phenotype', 'HP:0012174', (66, 78))	('LOC100132707', 'Var', (30, 42))
68360	33364785	In the present study, we found that LOC100132707 expression was apparently increased in the metastatic melanoma using bioinformatics analysis, as well as its expression level in the metastatic UM cell line MM28, suggesting that the deregulation of LOC100132707 might be involved in the metastasis of UM.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('UM', 'Phenotype', 'HP:0007716', (300, 302))	('LOC100132707', 'Var', (248, 260))	('UM', 'Phenotype', 'HP:0007716', (193, 195))	('expression', 'MPA', (49, 59))	('LOC100132707', 'Gene', (36, 48))	('MM28', 'CellLine', 'CVCL:4D15', (206, 210))	('increased', 'PosReg', (75, 84))	('involved', 'Reg', (270, 278))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
68361	33364785	Further experiments also showed that knockdown of LOC100132707 also induced asignificant repression in the tumorigenesis in vivo, together with apparent decreases in the expression levels of metastasis markers (MMP2 and MMP9).	('MMP9', 'Gene', (220, 224))	('MMP2', 'Gene', '4313', (211, 215))	('tumor', 'Disease', (107, 112))	('MMP9', 'Gene', '4318', (220, 224))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('MMP9', 'molecular_function', 'GO:0004229', ('220', '224'))	('repression', 'NegReg', (89, 99))	('decreases', 'NegReg', (153, 162))	('expression levels', 'MPA', (170, 187))	('LOC100132707', 'Var', (50, 62))	('MMP2', 'Gene', (211, 215))	('MMP2', 'molecular_function', 'GO:0004228', ('211', '215'))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
68362	33364785	In mechanism, we found that the expression levels of XRN1, PARP14, JAK2, DDX60, BUB1 and SAMD9L showed positive correlation to LOC100132707 expression pattern in melanoma, suggesting that they might be implicated in LOC100132707-mediated metastasis in UM.	('JAK2', 'Gene', (67, 71))	('XRN1', 'Gene', (53, 57))	('SAMD9L', 'Gene', (89, 95))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('expression', 'MPA', (32, 42))	('JAK', 'molecular_function', 'GO:0004713', ('67', '70'))	('PARP14', 'Gene', '54625', (59, 65))	('DDX60', 'Gene', (73, 78))	('SAMD9L', 'Gene', '219285', (89, 95))	('XRN1', 'Gene', '54464', (53, 57))	('JAK2', 'Gene', '3717', (67, 71))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('expression', 'MPA', (140, 150))	('melanoma', 'Disease', (162, 170))	('BUB1', 'Gene', '699', (80, 84))	('BUB1', 'Gene', (80, 84))	('UM', 'Phenotype', 'HP:0007716', (252, 254))	('PARP14', 'Gene', (59, 65))	('DDX60', 'Gene', '55601', (73, 78))	('LOC100132707', 'Var', (127, 139))
68364	33364785	Activated JAK2 triggers STAT3 activation and nucleus translocation by inducing tyrosine phosphorylation, which then leads to transcription and translation of downstream genes.	('phosphorylation', 'biological_process', 'GO:0016310', ('88', '103'))	('nucleus translocation', 'CPA', (45, 66))	('tyrosine', 'Chemical', 'MESH:D014443', (79, 87))	('tyrosine phosphorylation', 'MPA', (79, 103))	('translation', 'biological_process', 'GO:0006412', ('143', '154'))	('translation', 'MPA', (143, 154))	('JAK2', 'Gene', '3717', (10, 14))	('transcription', 'MPA', (125, 138))	('Activated', 'Var', (0, 9))	('inducing', 'Reg', (70, 78))	('transcription', 'biological_process', 'GO:0006351', ('125', '138'))	('STAT3', 'Gene', '6774', (24, 29))	('JAK2', 'Gene', (10, 14))	('JAK', 'molecular_function', 'GO:0004713', ('10', '13'))	('nucleus', 'cellular_component', 'GO:0005634', ('45', '52'))	('STAT3', 'Gene', (24, 29))	('leads to', 'Reg', (116, 124))
68366	33364785	Herein, we explored JAK2 function in LOC100132707-mediated UM progression.	('LOC100132707-mediated', 'Var', (37, 58))	('JAK', 'molecular_function', 'GO:0004713', ('20', '23'))	('JAK2', 'Gene', '3717', (20, 24))	('JAK2', 'Gene', (20, 24))	('UM progression', 'CPA', (59, 73))	('UM', 'Phenotype', 'HP:0007716', (59, 61))
68367	33364785	We observed that JAK2 downregulation weakened LOC100132707 roles in promoting UM cell migration and invasion, indicating that JAK2 played an indispensable role in LOC100132707-mediated enhancements in UM cell migration and invasion.	('cell migration', 'biological_process', 'GO:0016477', ('81', '95'))	('JAK2', 'Gene', (17, 21))	('LOC100132707', 'Gene', (46, 58))	('cell migration', 'biological_process', 'GO:0016477', ('204', '218'))	('downregulation', 'NegReg', (22, 36))	('JAK2', 'Gene', '3717', (126, 130))	('UM', 'Phenotype', 'HP:0007716', (201, 203))	('UM cell migration', 'CPA', (78, 95))	('LOC100132707-mediated', 'Var', (163, 184))	('promoting', 'PosReg', (68, 77))	('JAK', 'molecular_function', 'GO:0004713', ('17', '20'))	('JAK2', 'Gene', (126, 130))	('invasion', 'CPA', (223, 231))	('JAK2', 'Gene', '3717', (17, 21))	('UM cell migration', 'CPA', (201, 218))	('enhancements', 'PosReg', (185, 197))	('invasion', 'CPA', (100, 108))	('UM', 'Phenotype', 'HP:0007716', (78, 80))	('JAK', 'molecular_function', 'GO:0004713', ('126', '129'))
68369	33364785	In summary, this study reveals that silence of LOC100132707 can repress the migration and invasion of UM via downregulating JAK2.	('repress', 'NegReg', (64, 71))	('silence', 'Var', (36, 43))	('JAK2', 'Gene', '3717', (124, 128))	('UM', 'Phenotype', 'HP:0007716', (102, 104))	('JAK', 'molecular_function', 'GO:0004713', ('124', '127'))	('LOC100132707', 'Var', (47, 59))	('downregulating', 'NegReg', (109, 123))	('JAK2', 'Gene', (124, 128))
68371	33053887	The Role of Non-Coding RNAs in Uveal Melanoma The development of uveal melanoma is a multifactorial and multi-step process, in which abnormal gene expression plays a key role.	('Melanoma', 'Disease', (37, 45))	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('uveal melanoma', 'Disease', (65, 79))	('gene expression', 'biological_process', 'GO:0010467', ('142', '157'))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('Non-Coding', 'Var', (12, 22))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (31, 45))	('Melanoma', 'Disease', 'MESH:D008545', (37, 45))	('Melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('uveal melanoma', 'Disease', 'MESH:C536494', (65, 79))
68372	33053887	Recently, several studies have highlighted the role of non-coding RNAs in the progression of uveal melanoma by affecting different signaling pathways.	('non-coding RNAs', 'Var', (55, 70))	('uveal melanoma', 'Phenotype', 'HP:0007716', (93, 107))	('uveal melanoma', 'Disease', 'MESH:C536494', (93, 107))	('uveal melanoma', 'Disease', (93, 107))	('signaling pathways', 'Pathway', (131, 149))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('affecting', 'Reg', (111, 120))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))
68373	33053887	As important agents in the regulation of genes, non-coding RNAs have enormous potential to open up therapeutic pathways, predict response to treatment, and anticipate patient outcome for uveal melanoma.	('non-coding RNAs', 'Var', (48, 63))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('patient', 'Species', '9606', (167, 174))	('uveal melanoma', 'Disease', 'MESH:C536494', (187, 201))	('therapeutic pathways', 'Pathway', (99, 119))	('uveal melanoma', 'Phenotype', 'HP:0007716', (187, 201))	('uveal melanoma', 'Disease', (187, 201))	('regulation', 'biological_process', 'GO:0065007', ('27', '37'))	('open up', 'Reg', (91, 98))
68378	33053887	In the last decade, chromosomal abnormalities and the aberrant expression of several signaling pathways and oncogenes in uveal melanomas have been described.	('signaling pathways', 'Pathway', (85, 103))	('uveal melanoma', 'Phenotype', 'HP:0007716', (121, 135))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('chromosomal abnormalities', 'Disease', (20, 45))	('expression', 'MPA', (63, 73))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (20, 45))	('uveal melanomas', 'Disease', (121, 136))	('uveal melanomas', 'Phenotype', 'HP:0007716', (121, 136))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('uveal melanomas', 'Disease', 'MESH:C536494', (121, 136))	('oncogenes', 'Gene', (108, 117))	('aberrant', 'Var', (54, 62))
68387	33053887	This poor prognosis is associated with clinical and molecular factors of primary UM, such as tumor height, presence of monosomy 3, and chromosome 8 gain, while 6p gain provides a protective effect.	('chromosome 8', 'Var', (135, 147))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('gain', 'PosReg', (148, 152))	('tumor', 'Disease', (93, 98))	('chromosome', 'cellular_component', 'GO:0005694', ('135', '145'))	('primary UM', 'Disease', (73, 83))	('UM', 'Phenotype', 'HP:0007716', (81, 83))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
68390	33053887	Likewise, tumor-specific mutations have been found in the genes GNAQ, GNA11, EIF1AX, SF3B1, and BAP1.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mutations', 'Var', (25, 34))	('GNAQ', 'Gene', (64, 68))	('BAP1', 'Gene', (96, 100))	('tumor', 'Disease', (10, 15))	('SF3B1', 'Gene', (85, 90))	('EIF1AX', 'Gene', '1964', (77, 83))	('EIF1AX', 'Gene', (77, 83))	('SF3B1', 'Gene', '23451', (85, 90))	('GNAQ', 'Gene', '2776', (64, 68))	('GNA11', 'Gene', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('BAP1', 'Gene', '8314', (96, 100))	('GNA11', 'Gene', '2767', (70, 75))
68405	33053887	LGR4 is overexpressed in UM cells, and transfection of miR-34a has been reported to decrease its expression.	('decrease', 'NegReg', (84, 92))	('transfection', 'Var', (39, 51))	('miR-34a', 'Gene', (55, 62))	('UM', 'Phenotype', 'HP:0007716', (25, 27))	('LGR4', 'Gene', (0, 4))	('LGR4', 'Gene', '55366', (0, 4))	('expression', 'MPA', (97, 107))	('miR-34a', 'Gene', '407040', (55, 62))
68413	33053887	miR-137 transfection also led to decreased levels of MITF, c-Met, and other cell cycle-related proteins such as CDK2 and CDK6.	('miR-137', 'Gene', (0, 7))	('c-Met', 'Gene', '4233', (59, 64))	('CDK', 'molecular_function', 'GO:0004693', ('121', '124'))	('MITF', 'Gene', '4286', (53, 57))	('MITF', 'Gene', (53, 57))	('miR-137', 'Gene', '406928', (0, 7))	('CDK2', 'Gene', '1017', (112, 116))	('levels', 'MPA', (43, 49))	('CDK', 'molecular_function', 'GO:0004693', ('112', '115'))	('CDK6', 'Gene', (121, 125))	('cell cycle', 'biological_process', 'GO:0007049', ('76', '86'))	('decreased', 'NegReg', (33, 42))	('CDK6', 'Gene', '1021', (121, 125))	('transfection', 'Var', (8, 20))	('CDK2', 'Gene', (112, 116))	('c-Met', 'Gene', (59, 64))
68427	33053887	demonstrated the tumor-suppressive action of miR-216a-5p in UM cell lines by inhibiting HK2 (hexokinase 2), an aerobic glycolysis-limiting enzyme that is overexpressed in numerous human cancers.	('inhibiting', 'NegReg', (77, 87))	('tumor', 'Disease', (17, 22))	('miR-216a-5p', 'Var', (45, 56))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('hexokinase 2', 'Gene', '3099', (93, 105))	('HK2', 'Gene', (88, 91))	('HK2', 'Gene', '3099', (88, 91))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancers', 'Disease', (186, 193))	('human', 'Species', '9606', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('glycolysis', 'biological_process', 'GO:0006096', ('119', '129'))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('HK2', 'molecular_function', 'GO:0008256', ('88', '91'))	('hexokinase 2', 'Gene', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('miR-216a-5p', 'Chemical', '-', (45, 56))
68448	33053887	Finally, the transfection of miR-20a into UM cell lines contributed to increased cell invasion and migration, although, in this case, its cellular target has not yet been elucidated.	('transfection', 'Var', (13, 25))	('miR-20a', 'Gene', '406982', (29, 36))	('increased', 'PosReg', (71, 80))	('migration', 'CPA', (99, 108))	('UM', 'Phenotype', 'HP:0007716', (42, 44))	('miR-20a', 'Gene', (29, 36))	('cell invasion', 'CPA', (81, 94))
68456	33053887	An extensive TCGA (The Cancer Genome Atlas) UM study analyzing 80 primary UM samples was conducted by Robertson et al., in which they identified four clusters of miRNAs that were associated with chromosome 3 status, risk of metastasis, and DNA methylation profile.	('metastasis', 'CPA', (224, 234))	('associated', 'Reg', (179, 189))	('Cancer', 'Disease', (23, 29))	('chromosome 3 status', 'Var', (195, 214))	('Cancer', 'Disease', 'MESH:D009369', (23, 29))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('DNA methylation', 'biological_process', 'GO:0006306', ('240', '255'))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('195', '205'))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('DNA', 'cellular_component', 'GO:0005574', ('240', '243'))	('miR', 'Gene', '220972', (162, 165))	('miR', 'Gene', (162, 165))
68458	33053887	classified 26 UM tissue samples into three groups based on previously described genetic mutations linked to oncological progression (GNAQ, GNA11, EIF1AX, SF3B1, BAP1, chromosome 3 monosomy).	('BAP1', 'Gene', (161, 165))	('GNA11', 'Gene', (139, 144))	('SF3B1', 'Gene', (154, 159))	('EIF1AX', 'Gene', (146, 152))	('oncological progression', 'Disease', (108, 131))	('GNA11', 'Gene', '2767', (139, 144))	('EIF1AX', 'Gene', '1964', (146, 152))	('GNAQ', 'Gene', (133, 137))	('mutations', 'Var', (88, 97))	('UM', 'Phenotype', 'HP:0007716', (14, 16))	('SF3B1', 'Gene', '23451', (154, 159))	('chromosome', 'cellular_component', 'GO:0005694', ('167', '177'))	('BAP1', 'Gene', '8314', (161, 165))	('GNAQ', 'Gene', '2776', (133, 137))	('linked', 'Reg', (98, 104))
68489	33053887	The levels of miR-21, miR-34a, and miR-146a were increased in vitreous humor, vitreous exosomes, and histological samples.	('miR-21', 'Gene', '406991', (14, 20))	('miR-146a', 'Var', (35, 43))	('vitreous humor', 'Phenotype', 'HP:0100832', (62, 76))	('increased', 'PosReg', (49, 58))	('miR-21', 'Gene', (14, 20))	('miR-34a', 'Gene', '407040', (22, 29))	('miR-34a', 'Gene', (22, 29))
68495	33053887	Although uveal melanoma is barely studied, miR-146a has been described to increase proliferation of skin melanoma cells in culture and able to form tumors in mice.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('proliferation', 'CPA', (83, 96))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('mice', 'Species', '10090', (158, 162))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('uveal melanoma', 'Phenotype', 'HP:0007716', (9, 23))	('uveal melanoma', 'Disease', (9, 23))	('skin melanoma', 'Disease', 'MESH:D008545', (100, 113))	('uveal melanoma', 'Disease', 'MESH:C536494', (9, 23))	('increase', 'PosReg', (74, 82))	('skin melanoma', 'Disease', (100, 113))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('miR-146a', 'Var', (43, 51))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
68502	33053887	The transfer of antimiR-155 to MUM2B cells (a highly invasive metastatic UM cell line) increased the sensitivity of NK cells.	('increased', 'PosReg', (87, 96))	('miR-155', 'Gene', '406947', (20, 27))	('UM', 'Phenotype', 'HP:0007716', (73, 75))	('MUM2B', 'CellLine', 'CVCL:3447', (31, 36))	('UM', 'Phenotype', 'HP:0007716', (32, 34))	('miR-155', 'Gene', (20, 27))	('transfer', 'Var', (4, 12))	('sensitivity', 'MPA', (101, 112))
68511	33053887	The silencing of PVT1 impedes the biological functions of UM cells, resulting in the inhibition of proliferation, S-phase sequestration, and migration in addition to inducing apoptosis.	('biological functions of UM cells', 'CPA', (34, 66))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))	('impedes', 'NegReg', (22, 29))	('migration', 'CPA', (141, 150))	('UM', 'Phenotype', 'HP:0007716', (58, 60))	('apoptosis', 'CPA', (175, 184))	('PVT1', 'Gene', (17, 21))	('inhibition', 'NegReg', (85, 95))	('S-phase sequestration', 'CPA', (114, 135))	('PVT1', 'Gene', '5820', (17, 21))	('inducing', 'Reg', (166, 174))	('S-phase', 'biological_process', 'GO:0051320', ('114', '121'))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('proliferation', 'CPA', (99, 112))	('silencing', 'Var', (4, 13))
68517	33053887	demonstrated the association between a high expression of PVT1 and a number of clinicopathological parameters of poor prognosis in UM, such as advanced age, histological epithelioid-type, presence of extra-scleral extension, and distant metastasis.	('expression', 'MPA', (44, 54))	('high', 'Var', (39, 43))	('UM', 'Phenotype', 'HP:0007716', (131, 133))	('extra-scleral extension', 'CPA', (200, 223))	('distant metastasis', 'CPA', (229, 247))	('PVT1', 'Gene', (58, 62))	('PVT1', 'Gene', '5820', (58, 62))
68524	33053887	Inhibition of JPX/FTX transmits the signal to XIST, decreasing its expression levels and completing the sequence that ultimately leads to both activation of tumor growth and stimulation of metastatic capacity.	('tumor', 'Disease', (157, 162))	('decreasing', 'NegReg', (52, 62))	('XIST', 'Gene', (46, 50))	('stimulation', 'PosReg', (174, 185))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('metastatic capacity', 'CPA', (189, 208))	('Inhibition', 'Var', (0, 10))	('activation', 'PosReg', (143, 153))	('expression levels', 'MPA', (67, 84))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('FTX', 'Gene', (18, 21))	('FTX', 'Gene', '100302692', (18, 21))	('XIST', 'Gene', '7503', (46, 50))
68534	33053887	Thus, low levels of SNHG7 expression are associated with worse prognosis in UM as well as a higher proportion of epithelioid cells, poor clinical staging, lower tumor-free survival, and a higher mortality rate.	('mortality', 'Disease', 'MESH:D003643', (195, 204))	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('low levels', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('mortality', 'Disease', (195, 204))	('lower', 'NegReg', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('SNHG7', 'Gene', '84973', (20, 25))	('SNHG7', 'Gene', (20, 25))	('tumor', 'Disease', (161, 166))
68539	33053887	P2RX7-V3 (Chr 12q24.31) is specifically expressed in UM and functions as an oncogene, present at high levels and promoting proliferation, migratory capacity, cell invasion, tumor growth, and metastasis.	('cell invasion', 'CPA', (158, 171))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('metastasis', 'CPA', (191, 201))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('UM', 'Phenotype', 'HP:0007716', (53, 55))	('P2RX7-V3', 'Var', (0, 8))	('promoting', 'PosReg', (113, 122))	('migratory capacity', 'CPA', (138, 156))
68540	33053887	Furthermore, by silencing P2RX7-V3, it was demonstrated that a wide variety of genes are deregulated and that the main target signaling pathway by which it performs its carcinogenic functions is the PI3K/AKT pathway.	('carcinogenic', 'Disease', (169, 181))	('signaling pathway', 'biological_process', 'GO:0007165', ('126', '143'))	('AKT', 'Gene', '207', (204, 207))	('PI3K', 'molecular_function', 'GO:0016303', ('199', '203'))	('deregulated', 'PosReg', (89, 100))	('silencing', 'Var', (16, 25))	('P2RX7-V3', 'Gene', (26, 34))	('AKT', 'Gene', (204, 207))	('carcinogenic', 'Disease', 'MESH:D063646', (169, 181))
68544	33053887	PAUPAR induces silencing of HES1, a mediator of the Notch signaling pathway which plays a key role in the survival of immature melanoblasts and melanocytic stem cells by inhibiting the onset of apoptotic phenomena.	('HES1', 'Gene', '3280', (28, 32))	('PAUPAR', 'Gene', (0, 6))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('52', '75'))	('PAUPAR', 'Gene', '103157000', (0, 6))	('silencing', 'Var', (15, 24))	('HES1', 'Gene', (28, 32))	('inhibiting', 'NegReg', (170, 180))
68558	33053887	described how BAP1 mutations can change the expression of a tumor-specific miRNA network, resulting in alterations to UM behavior.	('UM behavior', 'MPA', (118, 129))	('miR', 'Gene', '220972', (75, 78))	('expression', 'MPA', (44, 54))	('miR', 'Gene', (75, 78))	('BAP1', 'Gene', '8314', (14, 18))	('alterations', 'Reg', (103, 114))	('BAP1', 'Gene', (14, 18))	('change', 'Reg', (33, 39))	('mutations', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('UM', 'Phenotype', 'HP:0007716', (118, 120))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
68559	33053887	BAP1 is, conceptually, a driver gene in UM and its alteration has been linked to an increased risk of metastasis.	('BAP1', 'Gene', (0, 4))	('linked to', 'Reg', (71, 80))	('UM', 'Phenotype', 'HP:0007716', (40, 42))	('alteration', 'Var', (51, 61))	('metastasis', 'CPA', (102, 112))	('BAP1', 'Gene', '8314', (0, 4))
68613	31755471	reported a case of multifocal melanoma where the patient was detected to have BAP-1 mutation and the authors suggested that BAP-1 mutation could result in multifocal choroidal melanoma.	('multifocal choroidal melanoma', 'Disease', (155, 184))	('result in', 'Reg', (145, 154))	('BAP-1', 'Gene', '8314', (78, 83))	('BAP-1', 'Gene', (124, 129))	('multifocal choroidal melanoma', 'Disease', 'None', (155, 184))	('multifocal melanoma', 'Disease', 'None', (19, 38))	('mutation', 'Var', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (166, 184))	('patient', 'Species', '9606', (49, 56))	('BAP-1', 'Gene', (78, 83))	('multifocal melanoma', 'Disease', (19, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('BAP-1', 'Gene', '8314', (124, 129))	('mutation', 'Var', (84, 92))
68624	31722709	m6A modification suppresses ocular melanoma through modulating HINT2 mRNA translation Dynamic N6-methyladenosine (m6A) RNA modification generated and erased by N6-methyltransferases and demethylases regulates gene expression, alternative splicing and cell fate.	('RNA modification', 'biological_process', 'GO:0009451', ('119', '135'))	('m6A', 'Gene', '56339', (0, 3))	('ocular melanoma', 'Disease', (28, 43))	('HINT2', 'Gene', '84681', (63, 68))	('modification', 'Var', (4, 16))	('translation', 'biological_process', 'GO:0006412', ('74', '85'))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (94, 112))	('m6A', 'Gene', (0, 3))	('splicing', 'biological_process', 'GO:0045292', ('238', '246'))	('suppresses', 'NegReg', (17, 27))	('ocular melanoma', 'Phenotype', 'HP:0007716', (28, 43))	('ocular melanoma', 'Disease', 'MESH:D008545', (28, 43))	('gene expression', 'MPA', (209, 224))	('m6A', 'Gene', '56339', (114, 117))	('regulates', 'Reg', (199, 208))	('alternative splicing', 'MPA', (226, 246))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('m6A', 'Gene', (114, 117))	('modulating', 'Reg', (52, 62))	('HINT2', 'Gene', (63, 68))	('RNA', 'cellular_component', 'GO:0005562', ('119', '122'))	('gene expression', 'biological_process', 'GO:0010467', ('209', '224'))
68631	31722709	Here, we show that RNA methylation significantly inhibits the progression of UM and CM.	('CM', 'Phenotype', 'HP:0007716', (84, 86))	('methylation', 'Var', (23, 34))	('inhibits', 'NegReg', (49, 57))	('progression', 'CPA', (62, 73))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('CM', 'Disease', 'MESH:D009202', (84, 86))	('RNA', 'cellular_component', 'GO:0005562', ('19', '22'))	('RNA methylation', 'biological_process', 'GO:0001510', ('19', '34'))
68633	31722709	Changes in global m6A modification were highly associated with tumor progression in vitro and in vivo.	('tumor', 'Disease', (63, 68))	('m6A', 'Gene', '56339', (18, 21))	('modification', 'Var', (22, 34))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('associated', 'Reg', (47, 57))	('m6A', 'Gene', (18, 21))
68634	31722709	Mechanistically, YTHDF1 promoted the translation of methylated HINT2 mRNA, a tumor suppressor in ocular melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('77', '93'))	('translation', 'biological_process', 'GO:0006412', ('37', '48'))	('methylated', 'Var', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('translation', 'MPA', (37, 48))	('ocular melanoma', 'Disease', (97, 112))	('HINT2', 'Gene', '84681', (63, 68))	('HINT2', 'Gene', (63, 68))	('YTHDF1', 'Gene', '54915', (17, 23))	('ocular melanoma', 'Disease', 'MESH:D008545', (97, 112))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('promoted', 'PosReg', (24, 32))	('ocular melanoma', 'Phenotype', 'HP:0007716', (97, 112))	('YTHDF1', 'Gene', (17, 23))	('tumor', 'Disease', (77, 82))	('tumor suppressor', 'biological_process', 'GO:0051726', ('77', '93'))
68635	31722709	Our work uncovers a critical function for m6A methylation in ocular melanoma and provides additional insight into the understanding of m6A modification.	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('methylation', 'Var', (46, 57))	('m6A', 'Gene', '56339', (42, 45))	('m6A', 'Gene', (135, 138))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('function', 'Reg', (29, 37))	('m6A', 'Gene', '56339', (135, 138))	('ocular melanoma', 'Disease', (61, 76))	('ocular melanoma', 'Disease', 'MESH:D008545', (61, 76))	('m6A', 'Gene', (42, 45))	('ocular melanoma', 'Phenotype', 'HP:0007716', (61, 76))
68637	31722709	Dynamic m6A modification affects a variety of cellular processes, such as RNA stability, export, splicing or translation.	('m6A', 'Gene', (8, 11))	('translation', 'MPA', (109, 120))	('RNA stability', 'MPA', (74, 87))	('splicing', 'biological_process', 'GO:0045292', ('97', '105'))	('export', 'MPA', (89, 95))	('translation', 'biological_process', 'GO:0006412', ('109', '120'))	('RNA', 'cellular_component', 'GO:0005562', ('74', '77'))	('m6A', 'Gene', '56339', (8, 11))	('affects', 'Reg', (25, 32))	('splicing', 'MPA', (97, 105))	('cellular', 'MPA', (46, 54))	('modification', 'Var', (12, 24))
68638	31722709	For instance, m6A modification promotes the degradation of Notch1a mRNA in the earliest hematopoietic progenitor cells while promoting the translation of immediate-early genes in long-term memory.	('m6A', 'Gene', (14, 17))	('translation', 'MPA', (139, 150))	('long-term memory', 'biological_process', 'GO:0007616', ('179', '195'))	('translation', 'biological_process', 'GO:0006412', ('139', '150'))	('promoting', 'PosReg', (125, 134))	('m6A', 'Gene', '56339', (14, 17))	('Notch1a', 'Gene', (59, 66))	('modification', 'Var', (18, 30))	('degradation', 'MPA', (44, 55))	('degradation', 'biological_process', 'GO:0009056', ('44', '55'))
68640	31722709	As m6A modifications play a key role in the maintenance of homeostasis, aberrant m6A modifications may be an important inducer of tumorigenesis.	('m6A', 'Gene', '56339', (3, 6))	('homeostasis', 'biological_process', 'GO:0042592', ('59', '70'))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('m6A', 'Gene', (81, 84))	('homeostasis', 'MPA', (59, 70))	('aberrant', 'Var', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('m6A', 'Gene', (3, 6))	('modifications', 'Var', (85, 98))	('m6A', 'Gene', '56339', (81, 84))	('tumor', 'Disease', (130, 135))	('inducer', 'Reg', (119, 126))
68641	31722709	Disturbance of m6A modifications was reported to contribute to the tumorigenesis of glioblastoma, breast cancer and hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (116, 140))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('glioblastoma', 'Disease', 'MESH:D005909', (84, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('breast cancer', 'Disease', (98, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (84, 96))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('m6A', 'Gene', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('modifications', 'Var', (19, 32))	('m6A', 'Gene', '56339', (15, 18))	('contribute', 'Reg', (49, 59))	('tumor', 'Disease', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (116, 140))	('glioblastoma', 'Disease', (84, 96))	('hepatocellular carcinoma', 'Disease', (116, 140))
68642	31722709	For example, decreased METTL3 expression or METTL14 mutation in endometrial cancer reduces the m6A modification of AKT pathway-related genes, resulting in the activation of the AKT signaling pathway and contributing to tumorigenesis.	('AKT', 'Gene', '207', (115, 118))	('AKT', 'Gene', '207', (177, 180))	('tumor', 'Disease', (219, 224))	('reduces', 'NegReg', (83, 90))	('m6A', 'Gene', (95, 98))	('mutation', 'Var', (52, 60))	('METTL14', 'Gene', (44, 51))	('endometrial cancer', 'Disease', (64, 82))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('endometrial cancer', 'Disease', 'MESH:D016889', (64, 82))	('METTL3', 'Gene', (23, 29))	('METTL3', 'Gene', '56339', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('activation', 'PosReg', (159, 169))	('signaling pathway', 'biological_process', 'GO:0007165', ('181', '198'))	('AKT', 'Gene', (115, 118))	('AKT', 'Gene', (177, 180))	('AKT signaling', 'biological_process', 'GO:0043491', ('177', '190'))	('METTL14', 'Gene', '57721', (44, 51))	('expression', 'MPA', (30, 40))	('decreased', 'NegReg', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('contributing to', 'Reg', (203, 218))	('m6A', 'Gene', '56339', (95, 98))	('endometrial cancer', 'Phenotype', 'HP:0012114', (64, 82))
68644	31722709	Therapeutically, R-2-hydroxyglutarate inhibits the activity of FTO, thereby suppressing leukemia progression.	('activity', 'MPA', (51, 59))	('FTO', 'Gene', (63, 66))	('inhibits', 'NegReg', (38, 46))	('FTO', 'Gene', '79068', (63, 66))	('leukemia', 'Phenotype', 'HP:0001909', (88, 96))	('R-2-hydroxyglutarate', 'Var', (17, 37))	('suppressing', 'NegReg', (76, 87))	('R-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (17, 37))	('leukemia', 'Disease', (88, 96))	('leukemia', 'Disease', 'MESH:D007938', (88, 96))
68647	31722709	The loss of one copy of chromosome 3 has been frequently identified in ocular melanoma.	('chromosome', 'cellular_component', 'GO:0005694', ('24', '34'))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('ocular melanoma', 'Disease', (71, 86))	('ocular melanoma', 'Disease', 'MESH:D008545', (71, 86))	('ocular melanoma', 'Phenotype', 'HP:0007716', (71, 86))	('loss of', 'Var', (4, 11))
68648	31722709	Previous studies have revealed that mutations in G protein subunit alpha Q (GNAQ) or G protein subunit alpha 11 (GNA11) result in the promotion of cell proliferation and sensitize cells to mitogen-activated protein kinase (MAPK) inhibitors.	('G protein subunit alpha 11', 'Gene', (85, 111))	('protein', 'cellular_component', 'GO:0003675', ('207', '214'))	('sensitize', 'Reg', (170, 179))	('MAPK', 'molecular_function', 'GO:0004707', ('223', '227'))	('cell proliferation', 'biological_process', 'GO:0008283', ('147', '165'))	('cell proliferation', 'CPA', (147, 165))	('G protein subunit alpha Q', 'Gene', '2776', (49, 74))	('GNAQ', 'Gene', '2776', (76, 80))	('mutations', 'Var', (36, 45))	('GNA11', 'Gene', (113, 118))	('G protein subunit alpha 11', 'Gene', '2767', (85, 111))	('GNA11', 'Gene', '2767', (113, 118))	('promotion', 'PosReg', (134, 143))	('G protein subunit alpha Q', 'Gene', (49, 74))	('GNAQ', 'Gene', (76, 80))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
68649	31722709	Furthermore, epigenetic drivers, such as DNA methylation, histone modifications, microRNAs and lncRNAs, also participate in tumorigenesis of ocular melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('ocular melanoma', 'Disease', (141, 156))	('DNA methylation', 'biological_process', 'GO:0006306', ('41', '56'))	('ocular melanoma', 'Disease', 'MESH:D008545', (141, 156))	('tumor', 'Disease', (124, 129))	('participate', 'Reg', (109, 120))	('ocular melanoma', 'Phenotype', 'HP:0007716', (141, 156))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('histone', 'Protein', (58, 65))	('DNA methylation', 'Var', (41, 56))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
68652	31722709	We thus aimed to identify the functional role of m6A methylation in malignant ocular melanoma and reveal its potential mechanism in tumorigenesis.	('m6A', 'Gene', (49, 52))	('malignant ocular melanoma', 'Disease', (68, 93))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('ocular melanoma', 'Phenotype', 'HP:0007716', (78, 93))	('m6A', 'Gene', '56339', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('malignant ocular melanoma', 'Disease', 'MESH:D008545', (68, 93))	('tumor', 'Disease', (132, 137))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('malignant ocular melanoma', 'Phenotype', 'HP:0007716', (68, 93))	('methylation', 'biological_process', 'GO:0032259', ('53', '64'))	('methylation', 'Var', (53, 64))
68653	31722709	We show that m6A methylation significantly inhibits the progression of ocular melanoma cells.	('ocular melanoma', 'Phenotype', 'HP:0007716', (71, 86))	('methylation', 'Var', (17, 28))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('m6A', 'Gene', (13, 16))	('ocular melanoma', 'Disease', (71, 86))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('ocular melanoma', 'Disease', 'MESH:D008545', (71, 86))	('m6A', 'Gene', '56339', (13, 16))	('inhibits', 'NegReg', (43, 51))
68745	31722709	The METTL3 expression level decreased to ~ 30% of the original level in normal control cells, PIG1 (Additional file 4: Figure S1A-B), and the global m6A level decreased when METTL3 was knocked down (Additional file 4: Figure S1C), as expected.	('expression level', 'MPA', (11, 27))	('decreased', 'NegReg', (28, 37))	('METTL3', 'Gene', (174, 180))	('m6A', 'Gene', '56339', (149, 152))	('METTL3', 'Gene', '56339', (4, 10))	('METTL3', 'Gene', (4, 10))	('knocked down', 'Var', (185, 197))	('decreased', 'NegReg', (159, 168))	('PIG1', 'Gene', '57532', (94, 98))	('PIG1', 'Gene', (94, 98))	('METTL3', 'Gene', '56339', (174, 180))	('m6A', 'Gene', (149, 152))
68746	31722709	After silencing METTL3, normal melanocyte cells formed an enlarged colony (Fig.	('METTL3', 'Gene', '56339', (16, 22))	('silencing', 'Var', (6, 15))	('METTL3', 'Gene', (16, 22))
68751	31722709	Melanoma cells with METTL3 knockdown also displayed significantly greater migratory ability (Additional file 5: Figure S2E-F) and slightly accelerated cell growth (Additional file 5: Figure S2G-H).	('knockdown', 'Var', (27, 36))	('migratory ability', 'CPA', (74, 91))	('accelerated', 'PosReg', (139, 150))	('METTL3', 'Gene', (20, 26))	('METTL3', 'Gene', '56339', (20, 26))	('greater', 'PosReg', (66, 73))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanoma', 'Disease', (0, 8))	('cell growth', 'biological_process', 'GO:0016049', ('151', '162'))	('cell growth', 'CPA', (151, 162))
68753	31722709	CRISPR/Cas9 is utilized to delete ALKBH5 in OCM1 and CRMM1 cells (Additional file 6: Figure S3A), and m6A methylation increases significantly when ALKBH5 is knocked down (Additional file 6: Figure S3B).	('methylation', 'MPA', (106, 117))	('OCM1', 'Species', '83984', (44, 48))	('CM', 'Phenotype', 'HP:0007716', (45, 47))	('knocked down', 'Var', (157, 169))	('Cas', 'cellular_component', 'GO:0005650', ('7', '10'))	('ALKBH5', 'Gene', '54890', (34, 40))	('m6A', 'Gene', (102, 105))	('increases', 'PosReg', (118, 127))	('ALKBH5', 'Gene', (34, 40))	('ALKBH5', 'Gene', '54890', (147, 153))	('CRMM1', 'CellLine', 'CVCL:M593', (53, 58))	('ALKBH5', 'Gene', (147, 153))	('m6A', 'Gene', '56339', (102, 105))	('delete', 'Var', (27, 33))	('methylation', 'biological_process', 'GO:0032259', ('106', '117'))
68754	31722709	Moreover, the rate of colony formation decreased to 20% in melanoma cells with higher m6A methylation (Fig.	('m6A', 'Gene', '56339', (86, 89))	('colony formation', 'CPA', (22, 38))	('decreased', 'NegReg', (39, 48))	('methylation', 'biological_process', 'GO:0032259', ('90', '101'))	('methylation', 'Var', (90, 101))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('higher', 'PosReg', (79, 85))	('melanoma', 'Disease', (59, 67))	('m6A', 'Gene', (86, 89))	('formation', 'biological_process', 'GO:0009058', ('29', '38'))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
68755	31722709	Compared with control cells, ocular melanoma cells with higher m6A methylation exhibited significantly decreased tumor growth (Additional file 6: Figure S3C) as more cells underwent apoptosis (Additional file 6: Figure S3D) and fewer cells underwent cell division (Additional file 6: Figure S3E).	('cell division', 'biological_process', 'GO:0051301', ('250', '263'))	('m6A', 'Gene', '56339', (63, 66))	('cell division', 'CPA', (250, 263))	('apoptosis', 'CPA', (182, 191))	('ocular melanoma', 'Phenotype', 'HP:0007716', (29, 44))	('m6A', 'Gene', (63, 66))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('decreased', 'NegReg', (103, 112))	('ocular melanoma', 'Disease', 'MESH:D008545', (29, 44))	('methylation', 'Var', (67, 78))	('underwent', 'Reg', (172, 181))	('tumor', 'Disease', (113, 118))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('apoptosis', 'biological_process', 'GO:0097194', ('182', '191'))	('apoptosis', 'biological_process', 'GO:0006915', ('182', '191'))	('underwent', 'Reg', (240, 249))	('ocular melanoma', 'Disease', (29, 44))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('S3C', 'Chemical', 'MESH:D013455', (153, 156))
68761	31722709	Although the motif and the pattern of m6A distribution were observed similarly in all cells, we found that the m6A modifications were reduced globally in tumor cells compared to normal control cells (Additional file 7: Figure S4G) and that there were more genes with only one m6A site in normal cells among the detected m6A peaks (Fig.	('m6A', 'Gene', (38, 41))	('m6A', 'Gene', (320, 323))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('modifications', 'Var', (115, 128))	('m6A', 'Gene', (276, 279))	('m6A', 'Gene', (111, 114))	('m6A', 'Gene', '56339', (38, 41))	('m6A', 'Gene', '56339', (320, 323))	('m6A', 'Gene', '56339', (111, 114))	('m6A', 'Gene', '56339', (276, 279))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('reduced', 'NegReg', (134, 141))	('tumor', 'Disease', (154, 159))
68765	31722709	In detail, the number of transcripts with greater enriched m6A modifications in normal cells was more than 5 times higher than that in tumor cells (Fig.	('m6A', 'Gene', (59, 62))	('transcripts', 'MPA', (25, 36))	('m6A', 'Gene', '56339', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('modifications', 'Var', (63, 76))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
68769	31722709	4c, third panel; Additional file 12: Table S4), suggesting a potential posttranscriptional modulation of translation of m6A modifications.	('translation', 'biological_process', 'GO:0006412', ('105', '116'))	('modifications', 'Var', (124, 137))	('m6A', 'Gene', '56339', (120, 123))	('m6A', 'Gene', (120, 123))
68770	31722709	HINT2, one of the genes with most significant evaluated protein expression and m6A enrichment in normal cells, was chosen as a typical example for analyzing the mechanism of m6A modifications acting as translation modulators in tumorigenesis (Fig.	('m6A', 'Gene', '56339', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('HINT2', 'Gene', '84681', (0, 5))	('HINT2', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('m6A', 'Gene', (174, 177))	('tumor', 'Disease', (228, 233))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('m6A', 'Gene', '56339', (174, 177))	('translation', 'biological_process', 'GO:0006412', ('202', '213'))	('m6A', 'Gene', (79, 82))	('modifications', 'Var', (178, 191))
68785	31722709	The m6A status of HINT2 mRNA was further measured by MeRIP of fragmented RNA, and the m6A peak on the 3'UTR was specifically methylated by METTL3 and demethylated by ALKBH5, suggesting functional relevance (Fig.	('m6A', 'Gene', '56339', (4, 7))	('m6A', 'Gene', '56339', (86, 89))	('ALKBH5', 'Gene', '54890', (166, 172))	('demethylated', 'Var', (150, 162))	('ALKBH5', 'Gene', (166, 172))	('RNA', 'cellular_component', 'GO:0005562', ('73', '76'))	('METTL3', 'Gene', '56339', (139, 145))	('HINT2', 'Gene', (18, 23))	('MeRIP', 'Chemical', 'MESH:C528646', (53, 58))	('methylated', 'Var', (125, 135))	('HINT2', 'Gene', '84681', (18, 23))	('METTL3', 'Gene', (139, 145))	('m6A', 'Gene', (4, 7))	('m6A', 'Gene', (86, 89))
68787	31722709	6c, d, Right; Additional file 11 Figure S7A), was decreased when METTL3 was knocked down, while it was upregulated when ALKBH5 was knocked down, indicating that HINT2 translation is positively regulated by its m6A modifications.	('m6A', 'Gene', '56339', (210, 213))	('translation', 'biological_process', 'GO:0006412', ('167', '178'))	('METTL3', 'Gene', '56339', (65, 71))	('HINT2', 'Gene', '84681', (161, 166))	('HINT2', 'Gene', (161, 166))	('ALKBH5', 'Gene', '54890', (120, 126))	('decreased', 'NegReg', (50, 59))	('METTL3', 'Gene', (65, 71))	('ALKBH5', 'Gene', (120, 126))	('knocked down', 'Var', (131, 143))	('knocked down', 'Var', (76, 88))	('upregulated', 'PosReg', (103, 114))	('m6A', 'Gene', (210, 213))
68789	31722709	HINT2 knockdown in ALKBH5 knockdown cells promoted cell proliferation (Fig.	('cell proliferation', 'biological_process', 'GO:0008283', ('51', '69'))	('HINT2', 'Gene', '84681', (0, 5))	('HINT2', 'Gene', (0, 5))	('ALKBH5', 'Gene', '54890', (19, 25))	('ALKBH5', 'Gene', (19, 25))	('knockdown', 'Var', (6, 15))	('cell proliferation', 'CPA', (51, 69))	('promoted', 'PosReg', (42, 50))
68790	31722709	Importantly, the cell proliferation rates of ALKBH5 knockdown cells after HINT2 knockdown were only partially comparable to those of the control cells with normal ALKBH5 expression (Fig.	('knockdown', 'Var', (80, 89))	('HINT2', 'Gene', '84681', (74, 79))	('ALKBH5', 'Gene', (163, 169))	('cell proliferation', 'biological_process', 'GO:0008283', ('17', '35'))	('ALKBH5', 'Gene', '54890', (45, 51))	('cell proliferation rates', 'CPA', (17, 41))	('ALKBH5', 'Gene', (45, 51))	('HINT2', 'Gene', (74, 79))	('ALKBH5', 'Gene', '54890', (163, 169))
68791	31722709	6f, lanes 1,4, 6G-H), suggesting that there are more tumor-related genes regulated by their m6A modifications.	('modifications', 'Var', (96, 109))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('m6A', 'Gene', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('more', 'PosReg', (48, 52))	('tumor', 'Disease', (53, 58))	('m6A', 'Gene', '56339', (92, 95))
68793	31722709	Because m6A methylation appears to promote the translation of HINT2, we hypothesized that HINT2 transcripts are targets of the YTH family, the m6A reader that regulates translation of m6A modified transcripts.	('m6A', 'Gene', '56339', (143, 146))	('m6A', 'Gene', (8, 11))	('methylation', 'biological_process', 'GO:0032259', ('12', '23'))	('m6A', 'Gene', (184, 187))	('translation', 'MPA', (47, 58))	('translation', 'biological_process', 'GO:0006412', ('47', '58'))	('m6A', 'Gene', '56339', (8, 11))	('m6A', 'Gene', '56339', (184, 187))	('HINT2', 'Gene', '84681', (62, 67))	('HINT2', 'Gene', (62, 67))	('promote', 'PosReg', (35, 42))	('translation', 'biological_process', 'GO:0006412', ('169', '180'))	('m6A', 'Gene', (143, 146))	('methylation', 'Var', (12, 23))	('HINT2', 'Gene', '84681', (90, 95))	('HINT2', 'Gene', (90, 95))
68796	31722709	Consistently, YTHDF1 knockdown (Fig.	('knockdown', 'Var', (21, 30))	('YTHDF1', 'Gene', '54915', (14, 20))	('YTHDF1', 'Gene', (14, 20))
68801	31722709	We created reporter constructs with HINT2 3' UTR (WT) or m6A locus mutated (MT) sequences (Additional file 15: Table S5), and dual luciferase assays showed that ALKBH5 significantly decreased the luciferase activity of reporters carrying the wild-type fragment instead of the corresponding mutant fragment (Fig.	('luciferase activity', 'molecular_function', 'GO:0047077', ('196', '215'))	('HINT2', 'Gene', (36, 41))	('activity', 'MPA', (207, 215))	('decreased', 'NegReg', (182, 191))	('HINT2', 'Gene', '84681', (36, 41))	('luciferase activity', 'molecular_function', 'GO:0045289', ('196', '215'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('196', '215'))	('m6A', 'Gene', (57, 60))	('ALKBH5', 'Gene', '54890', (161, 167))	('luciferase', 'Enzyme', (196, 206))	('luciferase activity', 'molecular_function', 'GO:0050248', ('196', '215'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('196', '215'))	('ALKBH5', 'Gene', (161, 167))	('m6A', 'Gene', '56339', (57, 60))	('mutant', 'Var', (290, 296))
68802	31722709	In detail, the association of the HINT2 transcript with actively transcribing ribosomes was improved by its m6A modifications (Fig.	('m6A', 'Gene', (108, 111))	('m6A', 'Gene', '56339', (108, 111))	('HINT2', 'Gene', (34, 39))	('modifications', 'Var', (112, 125))	('HINT2', 'Gene', '84681', (34, 39))	('improved', 'PosReg', (92, 100))	('association', 'Interaction', (15, 26))	('actively transcribing ribosomes', 'MPA', (56, 87))
68806	31722709	A previous study discovered that the "writers" of m6A methylation, METTL3 and METTL14, could play both oncogenic and tumor suppressor roles in numerous cancers, while oncogenic roles have been reported for "erasers" such as FTO and ALKBH5.	('ALKBH5', 'Gene', (232, 238))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('cancers', 'Disease', (152, 159))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('115', '131'))	('methylation', 'Var', (54, 65))	('FTO', 'Gene', '79068', (224, 227))	('ALKBH5', 'Gene', '54890', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('FTO', 'Gene', (224, 227))	('play', 'Reg', (93, 97))	('METTL14', 'Gene', '57721', (78, 85))	('METTL3', 'Gene', (67, 73))	('tumor suppressor', 'biological_process', 'GO:0051726', ('115', '131'))	('METTL3', 'Gene', '56339', (67, 73))	('m6A', 'Gene', '56339', (50, 53))	('METTL14', 'Gene', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('tumor', 'Disease', (117, 122))	('m6A', 'Gene', (50, 53))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
68807	31722709	Here, we found that the decreased global m6A modification in ocular melanoma promoted tumorigenesis, which resulted from decreased "writers" and upregulated "erasers".	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('m6A', 'Gene', '56339', (41, 44))	('decreased', 'NegReg', (24, 33))	('promoted', 'PosReg', (77, 85))	('tumor', 'Disease', (86, 91))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('decreased', 'NegReg', (121, 130))	('modification', 'Var', (45, 57))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('erasers', 'CPA', (158, 165))	('ocular melanoma', 'Disease', (61, 76))	('upregulated', 'PosReg', (145, 156))	('m6A', 'Gene', (41, 44))	('ocular melanoma', 'Disease', 'MESH:D008545', (61, 76))	('ocular melanoma', 'Phenotype', 'HP:0007716', (61, 76))
68809	31722709	Notably, the balance of "writers" and "erasers" regulates clusters of gene function, and the AKT pathway is one of the most important targets regulated by m6A modifications.	('m6A', 'Gene', (155, 158))	('clusters of gene function', 'MPA', (58, 83))	('m6A', 'Gene', '56339', (155, 158))	('AKT', 'Gene', (93, 96))	('modifications', 'Var', (159, 172))	('regulates', 'Reg', (48, 57))	('AKT', 'Gene', '207', (93, 96))
68812	31722709	Although we did not find a significant regulation of the AKT pathway by m6A modifications in ocular melanoma, genes in other biological processes, such as mRNA processing, translation, Hippo-YAP signaling and MAPK signaling, were differentially expressed (Fig.	('MAPK', 'molecular_function', 'GO:0004707', ('209', '213'))	('m6A', 'Gene', (72, 75))	('modifications', 'Var', (76, 89))	('ocular melanoma', 'Disease', (93, 108))	('signaling', 'biological_process', 'GO:0023052', ('195', '204'))	('m6A', 'Gene', '56339', (72, 75))	('mRNA processing', 'MPA', (155, 170))	('Hippo-YAP signaling', 'MPA', (185, 204))	('ocular melanoma', 'Disease', 'MESH:D008545', (93, 108))	('AKT', 'Gene', '207', (57, 60))	('ocular melanoma', 'Phenotype', 'HP:0007716', (93, 108))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('regulation', 'biological_process', 'GO:0065007', ('39', '49'))	('translation', 'biological_process', 'GO:0006412', ('172', '183'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('209', '223'))	('mRNA processing', 'biological_process', 'GO:0006397', ('155', '170'))	('AKT', 'Gene', (57, 60))
68815	31722709	Other tumor-related genes, such as ACAT2, PIR and CTBP1, were potentially regulated by m6A modifications in ocular melanoma.	('CTBP1', 'Gene', (50, 55))	('m6A', 'Gene', (87, 90))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('ocular melanoma', 'Disease', (108, 123))	('regulated', 'Reg', (74, 83))	('PIR', 'Gene', (42, 45))	('m6A', 'Gene', '56339', (87, 90))	('PIR', 'Gene', '8544', (42, 45))	('ACAT2', 'Gene', '39', (35, 40))	('ocular melanoma', 'Disease', 'MESH:D008545', (108, 123))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('ocular melanoma', 'Phenotype', 'HP:0007716', (108, 123))	('CTBP1', 'Gene', '1487', (50, 55))	('modifications', 'Var', (91, 104))	('ACAT2', 'Gene', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
68817	31722709	Notably, the regulation mechanisms of m6A modifications are complicated, reflected not only in multitudinous targets but also in different regulations in various cells.	('modifications', 'Var', (42, 55))	('regulation', 'biological_process', 'GO:0065007', ('13', '23'))	('m6A', 'Gene', '56339', (38, 41))	('m6A', 'Gene', (38, 41))
68818	31722709	It should be noted that the key enzyme of m6A modification may have opposite effects on tumorigenesis in different systems, even within one specific type of tumor.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('m6A', 'Gene', '56339', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('effects', 'Reg', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (88, 93))	('m6A', 'Gene', (42, 45))	('modification', 'Var', (46, 58))
68833	31722709	Here, we revealed for the first time that HINT2 is regulated by m6A modification, indicating that disturbances in RNA methylation homeostasis result in dysregulation of proliferation and mitochondrial apoptosis, which contributes to the progression of ocular melanoma.	('RNA', 'cellular_component', 'GO:0005562', ('114', '117'))	('m6A', 'Gene', (64, 67))	('homeostasis', 'biological_process', 'GO:0042592', ('130', '141'))	('ocular melanoma', 'Disease', 'MESH:D008545', (252, 267))	('dysregulation', 'MPA', (152, 165))	('contributes', 'Reg', (218, 229))	('disturbances', 'Var', (98, 110))	('melanoma', 'Phenotype', 'HP:0002861', (259, 267))	('ocular melanoma', 'Disease', (252, 267))	('HINT2', 'Gene', (42, 47))	('mitochondrial apoptosis', 'CPA', (187, 210))	('result in', 'Reg', (142, 151))	('RNA methylation', 'MPA', (114, 129))	('proliferation', 'CPA', (169, 182))	('HINT2', 'Gene', '84681', (42, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('201', '210'))	('RNA methylation', 'biological_process', 'GO:0001510', ('114', '129'))	('apoptosis', 'biological_process', 'GO:0006915', ('201', '210'))	('ocular melanoma', 'Phenotype', 'HP:0007716', (252, 267))	('m6A', 'Gene', '56339', (64, 67))
68834	31722709	Notably, we found that knockdown of HINT2 only partially rescued the effect of knockdown of ALKBH5 on ocular melanoma cells, which indicates that there are other cofactors involved in tumorigenesis that are regulated by m6A modifications.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('m6A', 'Gene', '56339', (220, 223))	('HINT2', 'Gene', (36, 41))	('ALKBH5', 'Gene', '54890', (92, 98))	('ocular melanoma', 'Phenotype', 'HP:0007716', (102, 117))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('HINT2', 'Gene', '84681', (36, 41))	('ALKBH5', 'Gene', (92, 98))	('tumor', 'Disease', (184, 189))	('knockdown', 'Var', (79, 88))	('ocular melanoma', 'Disease', (102, 117))	('m6A', 'Gene', (220, 223))	('ocular melanoma', 'Disease', 'MESH:D008545', (102, 117))
68838	31722709	Although B-raf mutations are rare in UM, activation changes in other MAPK pathway components, such as GNAQ or GNA11, are found in 85-95% of patients and are partly responsible for tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('GNA11', 'Gene', '2767', (110, 115))	('MAPK pathway', 'Pathway', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('activation changes', 'PosReg', (41, 59))	('GNAQ', 'Gene', (102, 106))	('mutations', 'Var', (15, 24))	('UM', 'Phenotype', 'HP:0007716', (37, 39))	('tumor', 'Disease', (180, 185))	('MAPK', 'molecular_function', 'GO:0004707', ('69', '73'))	('patients', 'Species', '9606', (140, 148))	('B-raf', 'Gene', (9, 14))	('B-raf', 'Gene', '673', (9, 14))	('GNA11', 'Gene', (110, 115))	('GNAQ', 'Gene', '2776', (102, 106))
68844	31722709	In general, we revealed the critical role of m6A modification in ocular melanoma tumorigenesis.	('ocular melanoma tumorigenesis', 'Disease', (65, 94))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('m6A', 'Gene', '56339', (45, 48))	('ocular melanoma tumorigenesis', 'Disease', 'MESH:D063646', (65, 94))	('modification', 'Var', (49, 61))	('ocular melanoma', 'Phenotype', 'HP:0007716', (65, 80))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('m6A', 'Gene', (45, 48))
68845	31722709	Decreased m6A levels are identified in ocular melanoma samples, indicating poor prognosis, and changes in global m6A modification are highly associated with tumor progression.	('tumor', 'Disease', (157, 162))	('m6A', 'Gene', '56339', (10, 13))	('ocular melanoma', 'Phenotype', 'HP:0007716', (39, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('changes', 'Var', (95, 102))	('Decreased', 'NegReg', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('associated', 'Reg', (141, 151))	('m6A', 'Gene', (113, 116))	('ocular melanoma', 'Disease', (39, 54))	('ocular melanoma', 'Disease', 'MESH:D008545', (39, 54))	('m6A', 'Gene', (10, 13))	('m6A', 'Gene', '56339', (113, 116))
68846	31722709	Mechanistically, YTHDF1 promotes the translation of methylated mRNA of HINT2, a tumor suppressor in ocular melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('HINT2', 'Gene', (71, 76))	('ocular melanoma', 'Disease', 'MESH:D008545', (100, 115))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ocular melanoma', 'Disease', (100, 115))	('HINT2', 'Gene', '84681', (71, 76))	('methylated', 'Var', (52, 62))	('translation', 'MPA', (37, 48))	('tumor', 'Disease', (80, 85))	('YTHDF1', 'Gene', '54915', (17, 23))	('ocular melanoma', 'Phenotype', 'HP:0007716', (100, 115))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('promotes', 'PosReg', (24, 32))	('YTHDF1', 'Gene', (17, 23))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))	('translation', 'biological_process', 'GO:0006412', ('37', '48'))
68847	31722709	Our work uncovers a critical function of m6A methylation in ocular melanoma and provides insight into the understanding of m6A modification.	('m6A', 'Gene', (41, 44))	('m6A', 'Gene', '56339', (41, 44))	('ocular melanoma', 'Phenotype', 'HP:0007716', (60, 75))	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('m6A', 'Gene', (123, 126))	('function', 'Reg', (29, 37))	('methylation', 'Var', (45, 56))	('ocular melanoma', 'Disease', 'MESH:D008545', (60, 75))	('m6A', 'Gene', '56339', (123, 126))	('ocular melanoma', 'Disease', (60, 75))
68850	31722709	81772875, 81570884, 81770961, 91753000, U1932135), the Research Grant of the Shanghai Science and Technology Committee (17DZ2260100), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01) and the CAS Key Research Projects of Frontier Science (QYZDY-SSW-SMC027).	('2017SHZDZX01', 'CellLine', 'CVCL:K779', (191, 203))	('CAS', 'cellular_component', 'GO:0005650', ('213', '216'))	('U1932135', 'Var', (40, 48))	('91753000', 'Var', (30, 38))	('U1932135', 'Chemical', 'MESH:D014501', (40, 48))	('SMC', 'cellular_component', 'GO:0016029', ('270', '273'))	('81770961', 'Var', (20, 28))	('81570884', 'Var', (10, 18))	('CAS', 'Gene', (213, 216))	('CAS', 'Gene', '9564', (213, 216))	('81772875', 'Var', (0, 8))
68866	31623293	Mutational inactivation of this tumor suppressor is a key event in the acquisition of metastatic competence in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (111, 125))	('uveal melanoma', 'Disease', 'MESH:C536494', (111, 125))	('tumor suppressor', 'biological_process', 'GO:0051726', ('32', '48'))	('uveal melanoma', 'Disease', (111, 125))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('Mutational inactivation', 'Var', (0, 23))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('32', '48'))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('metastatic competence', 'CPA', (86, 107))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
68867	31623293	Earlier studies have shown somatic BAP1 mutations in 45% to 47% of primary tumors and in 81% to 84% of metastatic tumors.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('primary tumors', 'Disease', 'MESH:D001932', (67, 81))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('BAP1', 'Gene', '8314', (35, 39))	('mutations', 'Var', (40, 49))	('tumors', 'Disease', (114, 120))	('BAP1', 'Gene', (35, 39))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('primary tumors', 'Disease', (67, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Disease', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))
68868	31623293	Low nuclear immunohistochemical positivity for BAP1 has been shown to provide significant prognostic information in uveal melanoma and gain equal-level reliability with gene mutation assays.	('BAP1', 'Gene', '8314', (47, 51))	('uveal melanoma', 'Disease', 'MESH:C536494', (116, 130))	('uveal melanoma', 'Disease', (116, 130))	('gain', 'PosReg', (135, 139))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('uveal melanoma', 'Phenotype', 'HP:0007716', (116, 130))	('BAP1', 'Gene', (47, 51))	('Low nuclear', 'Var', (0, 11))
68958	31623293	Fourth, as shown by Farquhar et al., loss of BAP1 expression may be seen in a relevant proportion of cases without a BAP1 mutation, and vice versa: there is a possibility that a mutated and non-functional BAP1 is expressed in the nuclei of tumor cells, leading to a false impression of normal protein levels.	('protein', 'cellular_component', 'GO:0003675', ('293', '300'))	('tumor', 'Disease', (240, 245))	('BAP1', 'Gene', (45, 49))	('normal protein levels', 'MPA', (286, 307))	('BAP1', 'Gene', '8314', (117, 121))	('false', 'biological_process', 'GO:0071878', ('266', '271'))	('BAP1', 'Gene', '8314', (205, 209))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('non-functional', 'NegReg', (190, 204))	('false', 'biological_process', 'GO:0071877', ('266', '271'))	('BAP1', 'Gene', (117, 121))	('BAP1', 'Gene', (205, 209))	('mutated', 'Var', (178, 185))	('BAP1', 'Gene', '8314', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
68969	31394860	An abnormal expression of HLA Class I may influence cytotoxic T lymphocyte (CTL) as well as Natural Killer (NK) cell responses.	('abnormal', 'Var', (3, 11))	('HLA', 'Gene', '3123', (26, 29))	('HLA', 'Gene', (26, 29))	('influence', 'Reg', (42, 51))	('expression', 'MPA', (12, 22))
69052	31394860	Later, van Essen not only analyzed peptide-loading components but also some other regulators of expression, and (similarly) found significant associations between the presence of TAP1 and TAP2 and expression of HLA Class I, HLA Class II and B2M.	('TAP1', 'Gene', (179, 183))	('HLA', 'Gene', (211, 214))	('associations', 'Interaction', (142, 154))	('B2M', 'Gene', (241, 244))	('TAP1', 'Gene', '6890', (179, 183))	('TAP2', 'Gene', (188, 192))	('TAP2', 'Gene', '6891', (188, 192))	('B2M', 'Gene', '567', (241, 244))	('presence', 'Var', (167, 175))	('HLA', 'Gene', '3123', (224, 227))	('HLA', 'Gene', (224, 227))	('expression', 'MPA', (197, 207))	('HLA', 'Gene', '3123', (211, 214))
69083	31394860	While the first study on the relation between HLA type and prognosis showed an association between the presence of HLA-B40 and the development of metastases, the later study by Maat in 2006 did not reproduce this, but rather found an association between B44 and a worse survival.	('presence', 'Var', (103, 111))	('HLA', 'Gene', (115, 118))	('HLA', 'Gene', (46, 49))	('worse survival', 'CPA', (264, 278))	('metastases', 'Disease', (146, 156))	('HLA-B', 'Gene', (115, 120))	('association', 'Interaction', (79, 90))	('HLA-B', 'Gene', '3106', (115, 120))	('metastases', 'Disease', 'MESH:D009362', (146, 156))	('HLA', 'Gene', '3123', (115, 118))	('HLA', 'Gene', '3123', (46, 49))
69086	31394860	Almost all M3 tumors also show gain in chromosome 8q, while this aberration can also be present in Disomy 3 (D3) tumors.	('M3 tumors', 'Disease', 'MESH:D015473', (11, 20))	('tumors', 'Disease', (113, 119))	('chromosome', 'Var', (39, 49))	('M3 tumors', 'Disease', (11, 20))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('gain', 'PosReg', (31, 35))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Disomy 3', 'Disease', (99, 107))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
69091	31394860	investigated putative associations between copy numbers of multiple chromosomes and HLA expression.	('HLA', 'Gene', (84, 87))	('copy numbers', 'Var', (43, 55))	('expression', 'MPA', (88, 98))	('HLA', 'Gene', '3123', (84, 87))
69092	31394860	Half of the studied UM showed M3 according to Single Nucleotide Polymorphism (SNP) analysis, which was associated with death due to metastasis (Kaplan-Meier, p < 0.001).	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('associated with', 'Reg', (103, 118))	('Single Nucleotide Polymorphism', 'Var', (46, 76))	('UM', 'Phenotype', 'HP:0007716', (20, 22))
69147	31394860	Jumonji domain containing protein 2 (JARID2) knockdown resulted in elevated levels of CIITA mRNA upon IFNgamma stimulation, suggesting that JARID2 is an inhibitor of HLA Class II activation.	('JARID2', 'Gene', (140, 146))	('HLA', 'Gene', '3123', (166, 169))	('HLA', 'Gene', (166, 169))	('elevated', 'PosReg', (67, 75))	('JARID2', 'Gene', '3720', (37, 43))	('JARID2', 'Gene', '3720', (140, 146))	('CIITA', 'Gene', (86, 91))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('CIITA', 'Gene', '4261', (86, 91))	('JARID2', 'Gene', (37, 43))	('knockdown', 'Var', (45, 54))
69178	31394860	It would be interesting to see whether induction of IDO could serve as a potential mechanism to downregulate HLA Class I and lower the tumor cell's metastatic potential in UM.	('IDO', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('metastatic potential', 'CPA', (148, 168))	('HLA', 'Gene', '3123', (109, 112))	('IDO', 'molecular_function', 'GO:0033754', ('52', '55'))	('tumor', 'Disease', (135, 140))	('HLA', 'Gene', (109, 112))	('IDO', 'molecular_function', 'GO:0047719', ('52', '55'))	('downregulate', 'NegReg', (96, 108))	('IDO', 'Gene', '3620', (52, 55))	('lower', 'NegReg', (125, 130))	('induction', 'Var', (39, 48))	('UM', 'Phenotype', 'HP:0007716', (172, 174))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
69192	31394860	Several studies have been performed on the role of HLA in UM and all confirm that a high HLA Class I expression is associated with a bad prognosis, in contrast to the situation in many other malignancies.	('UM', 'Phenotype', 'HP:0007716', (58, 60))	('high', 'Var', (84, 88))	('HLA', 'Gene', '3123', (89, 92))	('HLA', 'Gene', (89, 92))	('malignancies', 'Disease', 'MESH:D009369', (191, 203))	('HLA', 'Gene', '3123', (51, 54))	('expression', 'MPA', (101, 111))	('malignancies', 'Disease', (191, 203))	('HLA', 'Gene', (51, 54))
69195	31394860	Epigenetic modifications influence expression, and loss of expression of the ubiquitin protease BAP1 is associated with an increased expression of HLA Class I antigens.	('increased', 'PosReg', (123, 132))	('expression', 'MPA', (133, 143))	('loss of', 'NegReg', (51, 58))	('BAP1', 'Gene', (96, 100))	('HLA', 'Gene', '3123', (147, 150))	('expression', 'MPA', (35, 45))	('expression', 'MPA', (59, 69))	('HLA', 'Gene', (147, 150))	('influence', 'Reg', (25, 34))	('Epigenetic modifications', 'Var', (0, 24))	('ubiquitin', 'molecular_function', 'GO:0031386', ('77', '86'))	('BAP1', 'Gene', '8314', (96, 100))
69212	30513872	Met- or Hgf-null mutations in mice resulted in a lethal phenotype in utero, which was caused by the impaired development of placenta and liver.	('resulted in', 'Reg', (35, 46))	('mice', 'Species', '10090', (30, 34))	('Hgf', 'Gene', (8, 11))	('Met-', 'Gene', (0, 4))	('Hgf', 'Gene', '15234', (8, 11))	('impaired', 'NegReg', (100, 108))	('mutations', 'Var', (17, 26))
69223	30513872	It has been demonstrated that HGF can accelerate wound healing by promoting the dedifferentiation of epidermal cells, whereas the inactivation of HGF in mice with anti-HGF IgG leads to retarded cutaneous wound healing, which is associated with decreased neovascularization, and the formation of tissue granulation.	('dedifferentiation of epidermal cells', 'CPA', (80, 116))	('promoting', 'PosReg', (66, 75))	('inactivation', 'Var', (130, 142))	('accelerate wound healing', 'Phenotype', 'HP:0001058', (38, 62))	('accelerate', 'PosReg', (38, 48))	('dedifferentiation', 'biological_process', 'GO:0043696', ('80', '97'))	('wound healing', 'CPA', (49, 62))	('formation', 'biological_process', 'GO:0009058', ('282', '291'))	('wound healing', 'biological_process', 'GO:0042060', ('204', '217'))	('mice', 'Species', '10090', (153, 157))	('wound healing', 'biological_process', 'GO:0042060', ('49', '62'))	('HGF', 'Gene', (146, 149))	('retarded cutaneous', 'Disease', (185, 203))	('retarded cutaneous', 'Disease', 'MESH:D008607', (185, 203))
69237	30513872	Interestingly, mutations in SHP2, blocking its activity, have been identified in LEOPARD syndrome, a disorder characterized by multiple lentigines.	('SHP2', 'Gene', '5781', (28, 32))	('SHP2', 'Gene', (28, 32))	('multiple lentigines', 'Phenotype', 'HP:0001003', (127, 146))	('mutations', 'Var', (15, 24))	('a disorder', 'Disease', (99, 109))	('a disorder', 'Disease', 'MESH:D030342', (99, 109))	('identified', 'Reg', (67, 77))	('LEOPARD syndrome', 'Disease', 'MESH:D044542', (81, 97))	('activity', 'MPA', (47, 55))	('LEOPARD syndrome', 'Disease', (81, 97))
69247	30513872	MITF silencing reduced MET expression in those cell lines that expressed both MITF and MET.	('MITF', 'Gene', '4286', (78, 82))	('MITF', 'Gene', (78, 82))	('silencing', 'Var', (5, 14))	('MET expression', 'MPA', (23, 37))	('reduced', 'NegReg', (15, 22))	('MITF', 'Gene', '4286', (0, 4))	('MITF', 'Gene', (0, 4))
69249	30513872	Overexpression of HGF and c-MET in melanoma cells enhances cell protection from cell death, which was shown to be mediated by the activation of the MAPK/ERK and PI3K/AKT pathways, frequently modified in melanomas.	('enhances', 'PosReg', (50, 58))	('activation', 'PosReg', (130, 140))	('melanomas', 'Disease', (203, 212))	('c-MET', 'Var', (26, 31))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('cell death', 'biological_process', 'GO:0008219', ('80', '90'))	('ERK', 'Gene', '5594', (153, 156))	('ERK', 'molecular_function', 'GO:0004707', ('153', '156'))	('HGF', 'Gene', (18, 21))	('melanomas', 'Phenotype', 'HP:0002861', (203, 212))	('ERK', 'Gene', (153, 156))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('cell protection from cell death', 'CPA', (59, 90))	('melanoma', 'Disease', (203, 211))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))	('MAPK', 'molecular_function', 'GO:0004707', ('148', '152'))	('PI3K', 'molecular_function', 'GO:0016303', ('161', '165'))	('melanomas', 'Disease', 'MESH:D008545', (203, 212))
69250	30513872	Apoptosis induced by the knockdown of BRAFV600E in melanoma cells can be prevented by growth factors, including HGF.	('BRAFV600E', 'Var', (38, 47))	('BRAFV600E', 'Mutation', 'rs113488022', (38, 47))	('Apoptosis', 'CPA', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('knockdown', 'Var', (25, 34))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
69251	30513872	HGF/c-MET-dependent activation of the MAPK/ERK cascade can be decreased by the membrane receptor NOTCH and intracellular protein SPROUTY, and c-MET can contribute to the upregulation of both proteins, thus inducing negative regulators of their own activity.	('intracellular', 'cellular_component', 'GO:0005622', ('107', '120'))	('membrane', 'cellular_component', 'GO:0016020', ('79', '87'))	('inducing', 'Reg', (206, 214))	('HGF/c-MET-dependent', 'Gene', (0, 19))	('c-MET', 'Var', (142, 147))	('negative regulators', 'MPA', (215, 234))	('decreased', 'NegReg', (62, 71))	('intracellular protein SPROUTY', 'MPA', (107, 136))	('upregulation', 'PosReg', (170, 182))	('ERK', 'molecular_function', 'GO:0004707', ('43', '46'))	('ERK', 'Gene', '5594', (43, 46))	('ERK', 'Gene', (43, 46))	('proteins', 'Protein', (191, 199))	('ERK cascade', 'biological_process', 'GO:0070371', ('43', '54'))	('activation', 'PosReg', (20, 30))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('MAPK', 'molecular_function', 'GO:0004707', ('38', '42'))
69263	30513872	It has been shown that the c-MET oncoprotein can be transported via melanoma-derived exosomes.	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('c-MET', 'Var', (27, 32))	('melanoma', 'Disease', (68, 76))
69265	30513872	It has been shown that exosomes derived from Met-high B16-F10 melanoma cells containing a higher level of Met than those from Met-low cells.	('melanoma', 'Disease', (62, 70))	('B16-F10', 'CellLine', 'CVCL:0159', (54, 61))	('Met', 'MPA', (106, 109))	('Met-high', 'Var', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
69271	30513872	It has been earlier shown that melanoma patients with a high stromal HGF level had a poorer response to treatment with vemurafenib, an inhibitor of BRAFV600E, used alone or in combination with trametinib, an inhibitor of MEK1/2, than those lacking HGF.	('BRAFV600E', 'Mutation', 'rs113488022', (148, 157))	('MEK1', 'molecular_function', 'GO:0004708', ('221', '225'))	('patients', 'Species', '9606', (40, 48))	('MEK1/2', 'Gene', '5604;5605', (221, 227))	('MEK1/2', 'Gene', (221, 227))	('BRAFV600E', 'Gene', (148, 157))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('vemurafenib', 'Chemical', 'MESH:D000077484', (119, 130))	('trametinib', 'Chemical', 'MESH:C560077', (193, 203))	('high', 'Var', (56, 60))
69274	30513872	As their expression is downregulated in melanoma, mainly by epigenetic silencing, the c-MET level is increased, leading to the enhancement of HGF/c-MET signaling.	('downregulated', 'NegReg', (23, 36))	('HGF/c-MET signaling', 'MPA', (142, 161))	('increased', 'PosReg', (101, 110))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Disease', (40, 48))	('expression', 'MPA', (9, 19))	('signaling', 'biological_process', 'GO:0023052', ('152', '161'))	('enhancement', 'PosReg', (127, 138))	('c-MET level', 'MPA', (86, 97))	('epigenetic silencing', 'Var', (60, 80))
69277	30513872	There are two FDA-approved drugs targeting BRAFV600E/K, vemurafenib (PLX4032) and dabrafenib, but their efficacy against melanoma is not fully satisfactory, even if they are used in combination with inhibitors of the downstream kinases MEK1/2, trametinib, and cobimetinib.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', (121, 129))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('MEK1', 'molecular_function', 'GO:0004708', ('236', '240'))	('MEK1/2', 'Gene', '5604;5605', (236, 242))	('dabrafenib', 'Chemical', 'MESH:C561627', (82, 92))	('MEK1/2', 'Gene', (236, 242))	('vemurafenib', 'Chemical', 'MESH:D000077484', (56, 67))	('BRAFV600E', 'Mutation', 'rs113488022', (43, 52))	('cobimetinib', 'Chemical', 'MESH:C574276', (260, 271))	('PLX4032', 'Chemical', 'MESH:D000077484', (69, 76))	('trametinib', 'Chemical', 'MESH:C560077', (244, 254))	('BRAFV600E/K', 'Var', (43, 54))
69285	30513872	A combination of vemurafenib and SU-11274 inhibited HGF-mediated invasion into Matrigel, preventing wound closure and inhibiting the expression of integrin beta1.	('expression', 'MPA', (133, 143))	('SU-11274', 'Var', (33, 41))	('integrin beta1', 'Gene', '3688', (147, 161))	('HGF-mediated', 'Protein', (52, 64))	('integrin beta1', 'Gene', (147, 161))	('inhibited', 'NegReg', (42, 51))	('preventing', 'NegReg', (89, 99))	('wound closure', 'CPA', (100, 113))	('SU-11274', 'Chemical', 'MESH:C478479', (33, 41))	('inhibiting', 'NegReg', (118, 128))	('vemurafenib', 'Chemical', 'MESH:D000077484', (17, 28))
69291	30513872	The proliferation of melanoma cells was less inhibited by PLX-4720 in the medium from HGF-secreting fibroblast cultures than in the fresh medium.	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))	('PLX-4720', 'Var', (58, 66))	('melanoma', 'Disease', (21, 29))
69304	30513872	This suggests that growth factors, including HGF, are not necessary for BRAFV600E melanoma cell growth in vitro.	('BRAFV600E', 'Var', (72, 81))	('BRAFV600E', 'Mutation', 'rs113488022', (72, 81))	('cell growth', 'biological_process', 'GO:0016049', ('91', '102'))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))
69318	30513872	SU11274 was shown to induce the apoptosis and differentiation of melanoma cells in vitro.	('apoptosis', 'biological_process', 'GO:0097194', ('32', '41'))	('apoptosis', 'CPA', (32, 41))	('apoptosis', 'biological_process', 'GO:0006915', ('32', '41'))	('induce', 'PosReg', (21, 27))	('SU11274', 'Var', (0, 7))	('SU11274', 'Chemical', 'MESH:C478479', (0, 7))	('differentiation', 'CPA', (46, 61))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
69319	30513872	The antitumor activity of SU11274 was also observed in a melanoma xenograft model.	('SU11274', 'Var', (26, 33))	('SU11274', 'Chemical', 'MESH:C478479', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('melanoma', 'Disease', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('tumor', 'Disease', (8, 13))
69320	30513872	SU11274, used for intraperitoneal administration achieved a significant inhibitory effect on liver metastasis induced by the intrasplenic injection of metastatic melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('SU11274', 'Var', (0, 7))	('SU11274', 'Chemical', 'MESH:C478479', (0, 7))	('liver metastasis', 'Disease', 'MESH:D009362', (93, 109))	('liver metastasis', 'Disease', (93, 109))	('inhibitory effect', 'NegReg', (72, 89))
69321	30513872	On the contrary, SU11274 was shown to increase the tumorigenicity and alter the bioenergetic state of melanoma cells.	('increase', 'PosReg', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('SU11274', 'Var', (17, 24))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('SU11274', 'Chemical', 'MESH:C478479', (17, 24))	('bioenergetic state', 'MPA', (80, 98))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('alter', 'Reg', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
69322	30513872	Interestingly, it has been demonstrated that combination of SU11274 and vemurafenib inhibited the growth of melanoma cells with constitutively activated c-MET more efficiently than SU11274 alone.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('SU11274', 'Var', (60, 67))	('SU11274', 'Chemical', 'MESH:C478479', (60, 67))	('vemurafenib', 'Chemical', 'MESH:D000077484', (72, 83))	('c-MET', 'Protein', (153, 158))	('SU11274', 'Chemical', 'MESH:C478479', (181, 188))	('growth', 'CPA', (98, 104))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))	('inhibited', 'NegReg', (84, 93))
69324	30513872	PHA-665752, another c-MET inhibitor, inhibited the migration of NRAS-mutated melanoma cells toward HGF.	('inhibited', 'NegReg', (37, 46))	('migration', 'CPA', (51, 60))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('NRAS', 'Gene', (64, 68))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('NRAS', 'Gene', '4893', (64, 68))	('PHA-665752', 'Var', (0, 10))
69325	30513872	PHA-665752, while suppressing the phosphorylation of c-MET, significantly inhibited the PI3K/AKT pathway activity and motility of uveal melanoma cells in vitro, and tumor growth in nude mice.	('inhibited', 'NegReg', (74, 83))	('tumor', 'Disease', (165, 170))	('phosphorylation', 'MPA', (34, 49))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('activity', 'MPA', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('uveal melanoma', 'Phenotype', 'HP:0007716', (130, 144))	('uveal melanoma', 'Disease', (130, 144))	('c-MET', 'Protein', (53, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (130, 144))	('PI3K/AKT pathway', 'Pathway', (88, 104))	('nude mice', 'Species', '10090', (181, 190))	('suppressing', 'NegReg', (18, 29))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('PI3K', 'molecular_function', 'GO:0016303', ('88', '92'))	('PHA-665752', 'Var', (0, 10))
69328	30513872	The synergistic effect of vemurafenib and tivantinib on cell viability was observed in c-MET-expressing melanoma cells that harbored a mutation leading to BRAFV600E.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('BRAFV600E', 'Var', (155, 164))	('BRAFV600E', 'Mutation', 'rs113488022', (155, 164))	('tivantinib', 'Chemical', 'MESH:C551661', (42, 52))	('vemurafenib', 'Chemical', 'MESH:D000077484', (26, 37))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
69345	30060843	BAP1 loss of function mutations often lead to loss of nuclear BAP1 (nBAP1) expression in humans; this is associated with a poorer prognosis in uveal and mucosal melanoma.	('mucosal melanoma', 'Disease', 'MESH:D008545', (153, 169))	('uveal and mucosal melanoma', 'Phenotype', 'HP:0007716', (143, 169))	('BAP1', 'Gene', (0, 4))	('loss', 'NegReg', (46, 50))	('humans', 'Species', '9606', (89, 95))	('mutations', 'Var', (22, 31))	('mucosal melanoma', 'Disease', (153, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('nBAP1', 'Gene', (68, 73))	('expression', 'MPA', (75, 85))	('loss of function', 'NegReg', (5, 21))
69361	30060843	BAP1 has been shown to undergo both somatic and germline mutation, the latter underpinning a familial cancer predisposition syndrome.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('BAP1', 'Gene', (0, 4))	('familial cancer', 'Disease', (93, 108))	('germline mutation', 'Var', (48, 65))	('underpinning', 'Reg', (78, 90))	('familial cancer', 'Disease', 'MESH:D009369', (93, 108))
69363	30060843	In humans, loss of nuclear BAP1 (nBAP1) is common in oral mucosal and uveal melanoma, but uncommon in cutaneous melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('uveal melanoma', 'Disease', (70, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('nBAP1', 'Gene', (33, 38))	('loss', 'Var', (11, 15))	('oral mucosal', 'Disease', (53, 65))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('humans', 'Species', '9606', (3, 9))	('cutaneous melanoma', 'Disease', (102, 120))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
69364	30060843	In uveal melanoma, mutation of the BAP1 gene is associated with loss of nBAP1 expression, which has been proposed as a surrogate clinical marker.	('nBAP1', 'Gene', (72, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('expression', 'MPA', (78, 88))	('mutation', 'Var', (19, 27))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('loss', 'NegReg', (64, 68))	('BAP1', 'Gene', (35, 39))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
69372	30060843	Specifically, we hypothesized that loss of nBAP1 in canine oral and uveal melanoma would be associated with a poorer prognosis.	('loss', 'Var', (35, 39))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('nBAP1', 'Gene', (43, 48))	('uveal melanoma', 'Disease', 'MESH:C536494', (68, 82))	('uveal melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('uveal melanoma', 'Disease', (68, 82))	('canine', 'Species', '9615', (52, 58))
69377	30060843	UCDK9M3 and UCDK9M4 are from primary oral mucosal melanomas, UCDK9M2 and UCDK9M5 are from lymph node metastases of oral mucosal melanoma and UCDK9M1 was derived from a skin metastasis of an oral mucosal melanoma.	('UCDK9M5', 'Var', (73, 80))	('M4', 'CellLine', 'CVCL:U812', (17, 19))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('oral mucosal melanoma', 'Disease', 'MESH:D013280', (37, 58))	('metastases of oral mucosal melanoma', 'Disease', 'MESH:D009362', (101, 136))	('oral mucosal melanomas', 'Disease', 'MESH:D013280', (37, 59))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('oral mucosal melanoma', 'Disease', (190, 211))	('oral mucosal melanoma', 'Disease', 'MESH:D013280', (190, 211))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('UCDK9M2', 'Var', (61, 68))	('oral mucosal melanoma', 'Disease', 'MESH:D013280', (115, 136))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('oral mucosal melanomas', 'Disease', (37, 59))	('metastases of oral mucosal melanoma', 'Disease', (101, 136))
69436	30060843	Lack of nBAP1 protein expression is associated with loss of function mutations of BAP1 and is common in several human cancers such as uveal and oral mucosal melanoma and malignant mesothelioma.	('mutations', 'Var', (69, 78))	('cancers', 'Disease', (118, 125))	('BAP1', 'Gene', (82, 86))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (170, 192))	('nBAP1', 'Gene', (8, 13))	('malignant mesothelioma', 'Disease', (170, 192))	('Lack', 'NegReg', (0, 4))	('protein', 'Protein', (14, 21))	('uveal and oral mucosal melanoma', 'Disease', 'MESH:C536494', (134, 165))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('loss of function', 'NegReg', (52, 68))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (170, 192))	('human', 'Species', '9606', (112, 117))	('expression', 'MPA', (22, 32))
69440	30060843	This study was performed in the same laboratory using the same technique as a previous study that reported that loss of nBAP1 is associated with a poorer outcome in human uveal melanoma.	('human', 'Species', '9606', (165, 170))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('nBAP1', 'Gene', (120, 125))	('uveal melanoma', 'Phenotype', 'HP:0007716', (171, 185))	('uveal melanoma', 'Disease', 'MESH:C536494', (171, 185))	('uveal melanoma', 'Disease', (171, 185))	('loss', 'Var', (112, 116))
69441	30060843	Moreover, the work presented here was performed contemporaneously with, and with the same methodology as, a follow-up study (to) in this laboratory, which confirmed the prognostic significance of loss of nBAP-1 in human uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (220, 234))	('uveal melanoma', 'Disease', (220, 234))	('uveal melanoma', 'Disease', 'MESH:C536494', (220, 234))	('nBAP-1', 'Gene', (204, 210))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('human', 'Species', '9606', (214, 219))	('loss', 'Var', (196, 200))
69443	30060843	Furthermore, the absence of nBAP1 protein expression is indicative of the presence of a BAP1 mutation in human cancers such as malignant mesothelioma and uveal melanoma, as well as Spitz melanoma.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('protein', 'Protein', (34, 41))	('expression', 'MPA', (42, 52))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (127, 149))	('human', 'Species', '9606', (105, 110))	('uveal melanoma', 'Disease', (154, 168))	('uveal melanoma', 'Disease', 'MESH:C536494', (154, 168))	('nBAP1', 'Gene', (28, 33))	('BAP1', 'Gene', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('uveal melanoma', 'Phenotype', 'HP:0007716', (154, 168))	('malignant mesothelioma', 'Disease', (127, 149))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('cancers', 'Disease', (111, 118))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (127, 149))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('absence', 'NegReg', (17, 24))	('mutation', 'Var', (93, 101))	('presence', 'Reg', (74, 82))
69447	30060843	demonstrated that missense mutations within the catalytic domain of BAP1 reduced tumour suppressor activity, but not protein expression, in a human NSCLC cell line.	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('NSCLC', 'Disease', (148, 153))	('reduced', 'NegReg', (73, 80))	('missense mutations', 'Var', (18, 36))	('human', 'Species', '9606', (142, 147))	('tumour', 'Disease', (81, 87))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('BAP1', 'Gene', (68, 72))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
69448	30060843	Of note, although BAP1 knockout mice develop a myelodysplastic disorder with features of chronic myelomonocytic leukaemia (CMML), in human CMML, mutation of BAP1 is rare but that of the BAP1 interacting protein ASXL1 is very common.	('chronic myelomonocytic leukaemia', 'Disease', (89, 121))	('myelodysplastic disorder', 'Phenotype', 'HP:0002863', (47, 71))	('chronic myelomonocytic leukaemia', 'Disease', 'MESH:D015477', (89, 121))	('myelodysplastic disorder', 'Disease', 'MESH:D009190', (47, 71))	('chronic myelomonocytic leukaemia', 'Phenotype', 'HP:0012325', (89, 121))	('ASXL1', 'Gene', '171023', (211, 216))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('human', 'Species', '9606', (133, 138))	('mutation', 'Var', (145, 153))	('BAP1', 'Gene', (157, 161))	('CMML', 'Disease', 'MESH:D054429', (123, 127))	('ASXL1', 'Gene', (211, 216))	('mice', 'Species', '10090', (32, 36))	('CMML', 'Disease', (123, 127))	('CMML', 'Phenotype', 'HP:0012325', (123, 127))	('CMML', 'Disease', 'MESH:D054429', (139, 143))	('CMML', 'Disease', (139, 143))	('CMML', 'Phenotype', 'HP:0012325', (139, 143))	('myelodysplastic disorder', 'Disease', (47, 71))
69461	29433557	Three weeks later, maintainence nivolumab 3mg/kg was initiated but two weeks later, he developed grade 4 liver toxicity with ALT 1565 unit/L (0-55 unit/L).	('nivolumab', 'Chemical', 'MESH:D000077594', (32, 41))	('ALT', 'Var', (125, 128))	('ALT', 'molecular_function', 'GO:0004021', ('125', '128'))	('liver toxicity', 'Disease', 'MESH:D056486', (105, 119))	('liver toxicity', 'Disease', (105, 119))
69473	29433557	Unlike cutaneous melanoma, which has benefited from therapies targeting mutated Braf, uveal melanoma does not harbor these mutations.	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('cutaneous melanoma', 'Disease', (7, 25))	('mutated', 'Var', (72, 79))	('uveal melanoma', 'Disease', 'MESH:C536494', (86, 100))	('Braf', 'Gene', (80, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (7, 25))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (7, 25))	('Braf', 'Gene', '673', (80, 84))	('uveal melanoma', 'Disease', (86, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))
69500	29433557	Molecular profiling did not reveal actionable mutations in c-kit, Braf, or Ras, but did show a mutation in GNA11 (codon 626 A > T).	('Braf', 'Gene', '673', (66, 70))	('626 A > T', 'Var', (120, 129))	('c-kit', 'Gene', '3815', (59, 64))	('c-kit', 'Gene', (59, 64))	('GNA11', 'Gene', '2767', (107, 112))	('GNA11', 'Gene', (107, 112))	('626 A > T', 'SUBSTITUTION', 'None', (120, 129))	('Braf', 'Gene', (66, 70))
69518	29433557	Monosomy 3, 1p loss, 1 q gain, 6 p gain, 8 p loss and 8 q gain are the most common chromosomal abnormalities seen in uveal melanoma.	('uveal melanoma', 'Disease', (117, 131))	('1p loss', 'Var', (12, 19))	('chromosomal abnormalities', 'Disease', (83, 108))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (83, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (117, 131))	('uveal melanoma', 'Disease', 'MESH:C536494', (117, 131))	('Monosomy 3', 'Var', (0, 10))
69519	29433557	Furthermore, greater than 80% of uveal melanomas possess oncogenic mutations in G-protein-alpha subunits associated genes GNAQ or GNA11 as found in our case.	('uveal melanomas', 'Disease', (33, 48))	('uveal melanomas', 'Phenotype', 'HP:0007716', (33, 48))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('GNA11', 'Gene', (130, 135))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('GNAQ', 'Gene', (122, 126))	('melanomas', 'Phenotype', 'HP:0002861', (39, 48))	('uveal melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('mutations', 'Var', (67, 76))	('GNA11', 'Gene', '2767', (130, 135))	('uveal melanomas', 'Disease', 'MESH:C536494', (33, 48))	('G-protein-alpha', 'Protein', (80, 95))	('GNAQ', 'Gene', '2776', (122, 126))
69526	29433557	Unlike some of the cutaneous melanomas, uveal melanoma does not harbor BRAF mutations that are the targets of currently available therapies such as vemurafenib or dabrafenib.	('mutations', 'Var', (76, 85))	('cutaneous melanomas', 'Disease', (19, 38))	('dabrafenib', 'Chemical', 'MESH:C561627', (163, 173))	('BRAF', 'Gene', '673', (71, 75))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanomas', 'Phenotype', 'HP:0002861', (29, 38))	('BRAF', 'Gene', (71, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))	('uveal melanoma', 'Disease', (40, 54))	('uveal melanoma', 'Disease', 'MESH:C536494', (40, 54))	('vemurafenib', 'Chemical', 'MESH:D000077484', (148, 159))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (19, 37))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (19, 38))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (19, 38))
69584	29433557	This is the unique report of a case of a MUM patient treated with combination anti-PD-1/anti-CTLA-4 therapy showing a durable response despite possessing worse prognostic features (GNA11 mutation, older age at presentation, male gender, short metastasis free interval and extraocular extension ciliary body involvement).	('CTLA-4', 'Gene', '1493', (93, 99))	('PD-1', 'Gene', '6139', (83, 87))	('PD-1', 'Gene', (83, 87))	('CTLA-4', 'Gene', (93, 99))	('short metastasis free interval', 'Disease', (237, 267))	('GNA11', 'Gene', '2767', (181, 186))	('GNA11', 'Gene', (181, 186))	('patient', 'Species', '9606', (45, 52))	('mutation', 'Var', (187, 195))	('short metastasis free interval', 'Disease', 'MESH:D009362', (237, 267))
69610	28137308	have shown the existence of stem cell-like subpopulation in CD20+ and CD133+ melanoma cells.	('stem cell-like subpopulation', 'CPA', (28, 56))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('CD133+', 'Var', (70, 76))	('CD20', 'Gene', '54474', (60, 64))	('CD20', 'Gene', (60, 64))
69627	28137308	reported that CD133+ keratinocytes exhibit high mitochondrial potential that may have clinical implications in non-melanoma skin cancer.	('high mitochondrial potential', 'MPA', (43, 71))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('skin cancer', 'Phenotype', 'HP:0008069', (124, 135))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (111, 135))	('CD133+', 'Var', (14, 20))	('implications', 'Reg', (95, 107))	('non-melanoma skin cancer', 'Disease', (111, 135))
69629	28137308	These data indicate that CD133+ D10 cells are highly resistant and aggressive in melanoma model.	('CD133+ D10', 'Var', (25, 35))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('aggressive', 'CPA', (67, 77))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))
69630	28137308	have shown that CD133+ melanoma specific CSCs maintain long term tumorigenic potential under in vivo condition.	('CD133+', 'Var', (16, 22))	('tumor', 'Disease', (65, 70))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
69634	28137308	Moreover, it has also been reported that the amplification of ABCB5 is a predisposing factor for melanoma development which further emphasize the specific role of stem cells in melanoma growth.	('melanoma growth', 'Disease', 'MESH:D008545', (177, 192))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('ABCB5', 'Gene', (62, 67))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('melanoma', 'Disease', (177, 185))	('predisposing factor', 'Reg', (73, 92))	('melanoma growth', 'Disease', (177, 192))	('amplification', 'Var', (45, 58))
69635	28137308	In addition, ABCB5+ melanoma cells showed tumor initiation at the level of 1x105 cells, whereas 100-fold more ABCB5- cells are required to develop tumor under in vivo condition indicating the importance of CSCs in melanoma progression.	('tumor initiation', 'Disease', 'MESH:D009369', (42, 58))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', (42, 47))	('ABCB5+', 'Var', (13, 19))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('melanoma', 'Disease', (214, 222))	('tumor initiation', 'Disease', (42, 58))	('melanoma', 'Disease', 'MESH:D008545', (214, 222))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanoma', 'Disease', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))
69636	28137308	In addition, PD-1+ and B7.2+ cells in human melanoma are responsible for higher tumorigenicity compared with PD-1- and B7.2- cells respectively.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('PD-1+', 'Var', (13, 18))	('human', 'Species', '9606', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('tumor', 'Disease', (80, 85))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('higher', 'PosReg', (73, 79))	('B7.2+', 'Var', (23, 28))
69654	28137308	However, AhR knockdown increased ALDH1A1 activity and enhances B16F10 melanoma growth through maintaining cancer stem-like phenotypes.	('B16F10', 'CellLine', 'CVCL:0159', (63, 69))	('ALDH1A1', 'Gene', '216', (33, 40))	('ALDH', 'molecular_function', 'GO:0004030', ('33', '37'))	('enhances', 'PosReg', (54, 62))	('melanoma growth', 'Disease', (70, 85))	('AhR', 'Gene', '196', (9, 12))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('AhR', 'Gene', (9, 12))	('melanoma growth', 'Disease', 'MESH:D008545', (70, 85))	('cancer', 'Disease', (106, 112))	('increased', 'PosReg', (23, 32))	('ALDH1A1', 'Gene', (33, 40))	('knockdown', 'Var', (13, 22))	('activity', 'MPA', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
69655	28137308	Further, knockdown of ALDH1A1 reduced the levels of CD133+/CD29+/CD44+ cells, melanosphere size and expression of Sox2, a pluripotency factor in AhR knockdown cells.	('AhR', 'Gene', (145, 148))	('ALDH1A1', 'Gene', '216', (22, 29))	('knockdown', 'Var', (9, 18))	('AhR', 'Gene', '196', (145, 148))	('Sox2', 'Gene', '6657', (114, 118))	('CD29', 'Gene', '3688', (59, 63))	('ALDH1A1', 'Gene', (22, 29))	('expression', 'MPA', (100, 110))	('CD29', 'Gene', (59, 63))	('Sox2', 'Gene', (114, 118))	('reduced', 'NegReg', (30, 37))	('pluripotency', 'Disease', (122, 134))	('ALDH', 'molecular_function', 'GO:0004030', ('22', '26'))	('melanosphere size', 'CPA', (78, 95))	('pluripotency', 'Disease', 'None', (122, 134))
69667	28137308	CD133+ melanoma specific CSCs exhibit the functional tube formation and maintain the endothelial cell alignment through secretory factors present in their conditioned medium as shown in Fig.	('melanoma', 'Disease', 'MESH:D008545', (7, 15))	('functional tube formation', 'CPA', (42, 67))	('tube formation', 'biological_process', 'GO:0035148', ('53', '67'))	('endothelial cell alignment', 'CPA', (85, 111))	('CD133+', 'Var', (0, 6))	('melanoma', 'Phenotype', 'HP:0002861', (7, 15))	('melanoma', 'Disease', (7, 15))
69668	28137308	In addition, ABCB5+ and CD133+ melanoma specific CSCs preferentially express VEGFR1 and VEGF that are essential for VM in human melanoma cells.	('VEGFR1', 'Gene', (77, 83))	('human', 'Species', '9606', (122, 127))	('VEGF', 'Gene', '7422', (77, 81))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('ABCB5+', 'Var', (13, 19))	('VEGF', 'Gene', (88, 92))	('preferentially', 'PosReg', (54, 68))	('VEGF', 'Gene', (77, 81))	('VEGFR1', 'Gene', '2321', (77, 83))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('VEGF', 'Gene', '7422', (88, 92))	('melanoma', 'Disease', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
69669	28137308	have identified that CD133+ and ABCB5+ subpopulations are colocalized in the perivascular niche of melanoma.	('ABCB5+', 'Gene', (32, 38))	('perivascular niche', 'Phenotype', 'HP:0012520', (77, 95))	('CD133+', 'Var', (21, 27))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))
69672	28137308	They have observed that vascular niches containing mosaic vessels that are partially lined up by both CD144+/GFP+ channels-forming melanoma cells and CD144+/GFP- mouse endothelial cells.	('CD144+/GFP-', 'Var', (150, 161))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('CD144+/GFP+', 'Var', (102, 113))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('mouse', 'Species', '10090', (162, 167))
69673	28137308	have also demonstrated that perivascular niches exhibit higher accumulation of CD133+ and CD271+ melanoma stem cells.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('perivascular niches', 'Phenotype', 'HP:0012520', (28, 47))	('perivascular niche', 'Phenotype', 'HP:0012520', (28, 46))	('perivascular niches', 'CPA', (28, 47))	('CD271', 'Gene', '4804', (90, 95))	('CD133+', 'Var', (79, 85))	('higher accumulation', 'PosReg', (56, 75))	('CD271', 'Gene', (90, 95))
69676	28137308	Furthermore, a recent study shows that CD133+ D10 melanoma cells exhibit a significant induction of early angiogenesis under in vivo condition compared with CD133- D10 cells.	('angiogenesis', 'biological_process', 'GO:0001525', ('106', '118'))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('CD133+ D10', 'Var', (39, 49))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('early angiogenesis', 'CPA', (100, 118))
69688	28137308	have shown the existence of CD133+ CSCs in development of malignant melanoma and their potential to metastasize in lymph nodes, lung and/or other visceral organs.	('malignant melanoma', 'Phenotype', 'HP:0002861', (58, 76))	('malignant melanoma', 'Disease', 'MESH:D008545', (58, 76))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('malignant melanoma', 'Disease', (58, 76))	('CD133+ CSCs', 'Var', (28, 39))	('metastasize', 'CPA', (100, 111))
69698	28137308	have recently showed that CD133+CD44+ melanoma CSCs are highly metastatic towards lung.	('melanoma CSCs', 'Disease', 'MESH:D008545', (38, 51))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('CD133+CD44+', 'Var', (26, 37))	('melanoma CSCs', 'Disease', (38, 51))
69699	28137308	During invasion, tumor cells exhibit different phenotypic changes through epigenetic modifications.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('epigenetic modifications', 'Var', (74, 98))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (17, 22))
69700	28137308	Studies revealed that combined expression of EZH2, H3K4me2 and H3K27me3 might correlate with potential CSCs properties.	('correlate', 'Reg', (78, 87))	('EZH2', 'Gene', '2146', (45, 49))	('EZH2', 'Gene', (45, 49))	('H3K27me3', 'Var', (63, 71))	('CSCs', 'Disease', (103, 107))	('H3K4me2', 'Var', (51, 58))
69701	28137308	Moreover, the expressions of EZH2, H3K4me2 and H3K27me3 were enhanced significantly at the invasive site of tumor.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('enhanced', 'PosReg', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('H3K27me3', 'Var', (47, 55))	('tumor', 'Disease', (108, 113))	('expressions', 'MPA', (14, 25))	('H3K4me2', 'Var', (35, 42))	('EZH2', 'Gene', (29, 33))	('EZH2', 'Gene', '2146', (29, 33))
69716	28137308	Recent studies also showed that silencing of CD133 downregulates Slug and Snail expression.	('CD133', 'Gene', (45, 50))	('Slug', 'Gene', '6591', (65, 69))	('Slug', 'Gene', (65, 69))	('silencing', 'Var', (32, 41))	('Snail', 'Gene', '6615', (74, 79))	('Snail', 'Gene', (74, 79))	('downregulates', 'NegReg', (51, 64))
69718	28137308	It has been shown that the expressions of epithelial markers were higher in tumors with full-length ESRP1.	('ESRP1', 'Gene', '54845', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('ESRP1', 'Gene', (100, 105))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('higher', 'PosReg', (66, 72))	('expressions of epithelial markers', 'MPA', (27, 60))	('full-length', 'Var', (88, 99))
69719	28137308	In contrast, the expression of mesenchymal markers is higher in tumors with low level of ESRP1.	('ESRP1', 'Gene', (89, 94))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('higher', 'PosReg', (54, 60))	('expression', 'MPA', (17, 27))	('low level', 'Var', (76, 85))	('ESRP1', 'Gene', '54845', (89, 94))
69729	28137308	Zeb1 expression is closely associated with maintenance of CD133+CD44+ CSCs-like properties in B16F10 cells that include colony formation, drug resistance, migration and invasion.	('colon', 'Disease', (120, 125))	('migration', 'CPA', (155, 164))	('CD133+CD44+', 'Var', (58, 69))	('Zeb1', 'Gene', (0, 4))	('invasion', 'CPA', (169, 177))	('B16F10', 'CellLine', 'CVCL:0159', (94, 100))	('associated', 'Reg', (27, 37))	('drug resistance', 'CPA', (138, 153))	('drug resistance', 'Phenotype', 'HP:0020174', (138, 153))	('colon', 'Disease', 'MESH:D015179', (120, 125))	('drug resistance', 'biological_process', 'GO:0009315', ('138', '153'))	('formation', 'biological_process', 'GO:0009058', ('127', '136'))	('drug resistance', 'biological_process', 'GO:0042493', ('138', '153'))
69737	28137308	Knocking down of Zeb2 leads to significant downregulation of MITF and concomitant upregulation of Zeb1, Vimentin and Fibronectin resulted in enhanced melanoma progression.	('Zeb1', 'Gene', (98, 102))	('Vimentin', 'Gene', (104, 112))	('Vimentin', 'cellular_component', 'GO:0045099', ('104', '112'))	('Knocking down', 'Var', (0, 13))	('Vimentin', 'cellular_component', 'GO:0045098', ('104', '112'))	('downregulation', 'NegReg', (43, 57))	('Vimentin', 'Gene', '7431', (104, 112))	('MITF', 'Gene', '4286', (61, 65))	('MITF', 'Gene', (61, 65))	('Fibronectin', 'Gene', '2335', (117, 128))	('Zeb2', 'Gene', '9839', (17, 21))	('Zeb2', 'Gene', (17, 21))	('Fibronectin', 'Gene', (117, 128))	('upregulation', 'PosReg', (82, 94))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('enhanced', 'PosReg', (141, 149))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))
69761	28137308	Moreover, NK cells preferentially eliminate CD24+/CD44+, CD133+ and ALDHbright CSCs in variety of human cancer cell lines through upregulation of NKG2D ligands.	('ALDH', 'Gene', '11670', (68, 72))	('CD24', 'Gene', '100133941', (44, 48))	('NKG2D', 'Gene', '22914', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ALDH', 'Gene', (68, 72))	('CD24', 'Gene', (44, 48))	('NKG2D', 'Gene', (146, 151))	('upregulation', 'PosReg', (130, 142))	('human', 'Species', '9606', (98, 103))	('eliminate', 'NegReg', (34, 43))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('CD133+', 'Var', (57, 63))
69768	28137308	In contrast, CD133+ melanoma CSCs express high level of cancer/testis (CT) antigens which make them more susceptible against CD8+ T lymphocytes.	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('melanoma CSCs', 'Disease', 'MESH:D008545', (20, 33))	('melanoma CSCs', 'Disease', (20, 33))	('CD133+', 'Var', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('more', 'PosReg', (100, 104))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('cancer', 'Disease', (56, 62))	('CD8', 'Gene', (125, 128))	('CD8', 'Gene', '925', (125, 128))	('susceptible', 'MPA', (105, 116))
69782	28137308	Moreover, abolishment of HH-GLI signaling pathway drastically attenuates the self-renewal and tumor initiating potential of ALDHbright melanoma CSCs.	('abolishment', 'Var', (10, 21))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('signaling pathway', 'biological_process', 'GO:0007165', ('32', '49'))	('GLI', 'Gene', '2735', (28, 31))	('self-renewal', 'CPA', (77, 89))	('attenuates', 'NegReg', (62, 72))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('ALDH', 'Gene', '11670', (124, 128))	('melanoma CSCs', 'Disease', 'MESH:D008545', (135, 148))	('melanoma CSCs', 'Disease', (135, 148))	('ALDH', 'Gene', (124, 128))	('GLI', 'Gene', (28, 31))
69784	28137308	Further, E2F1 modulates iASPP (inhibitor of apoptosis-stimulating protein of p53) by directly binding to the promoter region of iASPP and enhance the proliferation indicating that HH-GLI-E2F1-iASPP axis is essential for melanoma progression.	('iASPP', 'Gene', (128, 133))	('GLI', 'Gene', (183, 186))	('proliferation', 'CPA', (150, 163))	('E2F1', 'Var', (9, 13))	('modulates', 'Reg', (14, 23))	('binding', 'molecular_function', 'GO:0005488', ('94', '101'))	('inhibitor of apoptosis-stimulating protein of p53', 'Gene', (31, 80))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('melanoma', 'Disease', (220, 228))	('inhibitor of apoptosis-stimulating protein of p53', 'Gene', '10848', (31, 80))	('iASPP', 'Gene', '10848', (24, 29))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('iASPP', 'Gene', '10848', (192, 197))	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('GLI', 'Gene', '2735', (183, 186))	('enhance', 'PosReg', (138, 145))	('iASPP', 'Gene', '10848', (128, 133))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('binding', 'Interaction', (94, 101))	('iASPP', 'Gene', (24, 29))	('iASPP', 'Gene', (192, 197))	('melanoma', 'Disease', 'MESH:D008545', (220, 228))
69787	28137308	Knocking down of FZD7 suppressed JNK activation and metastatic growth in melanoma.	('melanoma', 'Disease', (73, 81))	('suppressed', 'NegReg', (22, 32))	('Knocking down', 'Var', (0, 13))	('FZD7', 'Gene', (17, 21))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('metastatic growth', 'CPA', (52, 69))	('JNK', 'Gene', (33, 36))	('JNK', 'molecular_function', 'GO:0004705', ('33', '36'))	('JNK', 'Gene', '5599', (33, 36))	('FZD7', 'Gene', '8324', (17, 21))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
69789	28137308	Notch receptors cleaved by gamma-secretase and TACE (Tumor Necrosis Factor-alpha-Converting Enzyme) resulted in release of NICD (Notch Intracellular Domain) that translocate into nucleus and regulate the promoter activity of various genes.	('promoter activity', 'MPA', (204, 221))	('Notch', 'Gene', (129, 134))	('Necrosis', 'biological_process', 'GO:0019835', ('59', '67'))	('Notch', 'Gene', '4851;4853;4855', (0, 5))	('Tumor Necrosis Factor', 'molecular_function', 'GO:0005164', ('53', '74'))	('genes', 'Gene', (233, 238))	('cleaved', 'Var', (16, 23))	('Necrosis', 'biological_process', 'GO:0008220', ('59', '67'))	('Tumor Necrosis Factor-alpha-Converting Enzyme', 'Gene', (53, 98))	('Tumor', 'Phenotype', 'HP:0002664', (53, 58))	('TACE', 'Gene', '6868', (47, 51))	('Intracellular', 'cellular_component', 'GO:0005622', ('135', '148'))	('Tumor Necrosis Factor-alpha-Converting Enzyme', 'Gene', '6868', (53, 98))	('Notch', 'Gene', (0, 5))	('Necrosis', 'biological_process', 'GO:0001906', ('59', '67'))	('Necrosis', 'biological_process', 'GO:0070265', ('59', '67'))	('regulate', 'Reg', (191, 199))	('nucleus', 'cellular_component', 'GO:0005634', ('179', '186'))	('translocate', 'MPA', (162, 173))	('Necrosis', 'biological_process', 'GO:0008219', ('59', '67'))	('Notch', 'Gene', '4851;4853;4855', (129, 134))	('TACE', 'Gene', (47, 51))
69790	28137308	Attenuation of gamma-secretase and TACE leads to downregulation of NICD2 and Hes1 which preferentially inhibit melanosphere formation indicating that Notch2 regulates melanoma progression in CSCs.	('NICD2', 'Gene', (67, 72))	('Notch2', 'Gene', (150, 156))	('TACE', 'Gene', '6868', (35, 39))	('formation', 'biological_process', 'GO:0009058', ('124', '133'))	('regulates', 'Reg', (157, 166))	('Hes1', 'Gene', (77, 81))	('gamma-secretase', 'Protein', (15, 30))	('melanosphere formation', 'CPA', (111, 133))	('Attenuation', 'Var', (0, 11))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('Hes1', 'Gene', '3280', (77, 81))	('melanoma', 'Disease', (167, 175))	('downregulation', 'NegReg', (49, 63))	('Notch2', 'Gene', '4853', (150, 156))	('TACE', 'Gene', (35, 39))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('inhibit', 'NegReg', (103, 110))
69793	28137308	In addition, activated Notch1 increases the stability of beta-catenin that play important role in melanoma cell migration and proliferation.	('proliferation', 'CPA', (126, 139))	('activated', 'Var', (13, 22))	('Notch1', 'Gene', '4851', (23, 29))	('stability', 'MPA', (44, 53))	('melanoma cell migration', 'Disease', 'MESH:D008545', (98, 121))	('Notch1', 'Gene', (23, 29))	('melanoma cell migration', 'Disease', (98, 121))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('cell migration', 'biological_process', 'GO:0016477', ('107', '121'))	('beta-catenin', 'Gene', (57, 69))	('increases', 'PosReg', (30, 39))	('beta-catenin', 'Gene', '1499', (57, 69))
69794	28137308	Recent data showed that Notch1 signaling is highly augmented in CD133+ CSCs in melanoma.	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('Notch1', 'Gene', '4851', (24, 30))	('CD133+', 'Var', (64, 70))	('augmented', 'PosReg', (51, 60))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('Notch1', 'Gene', (24, 30))
69807	28137308	Rh123low (Low Rhodamine 123) cells exhibit stem-like phenotype correlate with enhanced levels of HIF1alpha, Oct4 and ABCB5 and reduced level of Cyclin D1 and CDK4 which define the quiescent and chemoresistance properties of CSCs in melanoma.	('ABCB5', 'Gene', (117, 122))	('Cyclin', 'molecular_function', 'GO:0016538', ('144', '150'))	('Rhodamine', 'Chemical', 'MESH:D012235', (14, 23))	('CDK', 'molecular_function', 'GO:0004693', ('158', '161'))	('Rh123low', 'Var', (0, 8))	('HIF1alpha', 'Gene', '3091', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('melanoma', 'Disease', (232, 240))	('Oct4', 'Gene', (108, 112))	('Cyclin D1', 'Gene', '595', (144, 153))	('melanoma', 'Disease', 'MESH:D008545', (232, 240))	('CDK4', 'Gene', (158, 162))	('HIF1alpha', 'Gene', (97, 106))	('Cyclin D1', 'Gene', (144, 153))	('CDK4', 'Gene', '1019', (158, 162))	('reduced', 'NegReg', (127, 134))	('Oct4', 'Gene', '5460', (108, 112))	('enhanced', 'PosReg', (78, 86))
69808	28137308	It has been also reported that PI3K/Akt pathway is involved in the maintenance of Rh123low in melanoma stem cell compartment.	('Rh123low', 'Var', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('Akt', 'Gene', (36, 39))	('PI3K', 'molecular_function', 'GO:0016303', ('31', '35'))	('Akt', 'Gene', '207', (36, 39))
69812	28137308	Inhibition of VEGFR2 kinase activity with PTKi-II (protein tyrosine kinase inhibitor II) does not affect VM in melanoma cells however, attenuation of VEGFR1 significantly disrupts this process.	('VEGFR1', 'Gene', (150, 156))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('disrupts', 'NegReg', (171, 179))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('activity', 'MPA', (28, 36))	('attenuation', 'Var', (135, 146))	('kinase activity', 'molecular_function', 'GO:0016301', ('21', '36'))	('VEGFR2', 'Gene', '3791', (14, 20))	('VEGFR2', 'Gene', (14, 20))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('68', '84'))	('VEGFR1', 'Gene', '2321', (150, 156))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
69815	28137308	In addition, deficiency of p63, a p53 homolog suppresses tumor growth.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('p63', 'Gene', (27, 30))	('suppresses', 'NegReg', (46, 56))	('deficiency', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('p63', 'Gene', '8626', (27, 30))	('tumor', 'Disease', (57, 62))
69835	28137308	Therefore, deregulation in miRNA expression and function appears to be a pervasive feature of human cancers (Table 2).	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancers', 'Disease', (100, 107))	('deregulation', 'Var', (11, 23))	('function', 'MPA', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('human', 'Species', '9606', (94, 99))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('miRNA', 'Protein', (27, 32))
69836	28137308	Several studies have shown that cluster of miRNA such as miR-1908, miR-199a-3p and miR-199a-5p drive metastatic invasion, endothelial recruitment and angiogenesis.	('miR-199a-3p', 'Gene', '406977', (67, 78))	('metastatic invasion', 'CPA', (101, 120))	('drive', 'PosReg', (95, 100))	('angiogenesis', 'CPA', (150, 162))	('miR-1908', 'Var', (57, 65))	('endothelial recruitment', 'CPA', (122, 145))	('miR-199a-5p', 'Var', (83, 94))	('miR-199a-3p', 'Gene', (67, 78))	('angiogenesis', 'biological_process', 'GO:0001525', ('150', '162'))
69838	28137308	miRNA profiling revealed that miR-125a-5p suppresses melanoma growth through down regulation of TGFbeta signaling by direct targeting Lin28B, a well known inhibitor of Let-7 miRNA biogenesis.	('miR-125a-5p', 'Var', (30, 41))	('Lin28B', 'Gene', (134, 140))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('miRNA biogenesis', 'biological_process', 'GO:0035196', ('174', '190'))	('miR-125a-5p', 'Chemical', '-', (30, 41))	('TGFbeta', 'Gene', (96, 103))	('down regulation', 'NegReg', (77, 92))	('suppresses', 'NegReg', (42, 52))	('melanoma growth', 'Disease', (53, 68))	('Lin28B', 'Gene', '389421', (134, 140))	('regulation', 'biological_process', 'GO:0065007', ('82', '92'))	('TGFbeta', 'Gene', '7040', (96, 103))	('melanoma growth', 'Disease', 'MESH:D008545', (53, 68))
69842	28137308	Tumor derived exosomes also contain miRNAs including miR-105 which help in destroying the vascular endothelial barrier.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('miR-105', 'Var', (53, 60))	('miR-105', 'Chemical', '-', (53, 60))	('destroying the vascular endothelial barrier', 'CPA', (75, 118))
69853	28137308	Most of the melanoma develops due to BRAF and NRAS mutation.	('NRAS', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (37, 41))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('due', 'Reg', (30, 33))	('melanoma', 'Disease', (12, 20))	('NRAS', 'Gene', '4893', (46, 50))	('BRAF', 'Gene', (37, 41))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('mutation', 'Var', (51, 59))
69857	28137308	A single nucleotide C to G somatic mutation in miR-146a causes enhanced Notch signaling and promotes oncogenesis.	('oncogenesis', 'biological_process', 'GO:0007048', ('101', '112'))	('promotes', 'PosReg', (92, 100))	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('miR-146a', 'Gene', (47, 55))	('enhanced', 'PosReg', (63, 71))	('Notch', 'Gene', (72, 77))	('Notch', 'Gene', '4851;4853;4855', (72, 77))	('single nucleotide C to G', 'Var', (2, 26))	('miR-146a', 'Gene', '406938', (47, 55))	('oncogenesis', 'CPA', (101, 112))
69859	28137308	Augmentation of miR-9 significantly decreases melanoma cell proliferation and migration.	('melanoma cell proliferation', 'Disease', (46, 73))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('cell proliferation', 'biological_process', 'GO:0008283', ('55', '73'))	('miR-9', 'Gene', (16, 21))	('melanoma cell proliferation', 'Disease', 'MESH:D008545', (46, 73))	('migration', 'CPA', (78, 87))	('Augmentation', 'Var', (0, 12))	('decreases', 'NegReg', (36, 45))
69865	28137308	Melanoma specific CSCs carry specific marker (CD133, CD20, ABCB5, CD271 and ALDH1) or antigens, so targeting these cells using monoclonal antibodies could help to combat melanoma growth.	('CD20', 'Gene', (53, 57))	('ABCB5', 'Gene', (59, 64))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('ALDH1', 'Gene', (76, 81))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('ALDH', 'molecular_function', 'GO:0004030', ('76', '80'))	('CD271', 'Gene', '4804', (66, 71))	('Melanoma', 'Disease', (0, 8))	('ALDH1', 'Gene', '216', (76, 81))	('melanoma growth', 'Disease', (170, 185))	('CD271', 'Gene', (66, 71))	('CD133', 'Var', (46, 51))	('melanoma growth', 'Disease', 'MESH:D008545', (170, 185))	('CD20', 'Gene', '54474', (53, 57))
69881	28137308	In addition, Andro also impairs the EMT, angiogenesis and metastasis properties of these CD133+ cells.	('EMT', 'CPA', (36, 39))	('impairs', 'NegReg', (24, 31))	('Andro', 'Var', (13, 18))	('angiogenesis', 'biological_process', 'GO:0001525', ('41', '53'))	('EMT', 'biological_process', 'GO:0001837', ('36', '39'))	('Andro', 'Chemical', 'MESH:C030419', (13, 18))	('metastasis properties', 'CPA', (58, 79))
69891	28137308	Interestingly, the data shown that combination of ABT-737 and 4-HPR significantly eliminate ALDH+ CSCs in multiple melanoma cell lines including BRAF and NRAS mutant cells.	('BRAF', 'Gene', (145, 149))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('mutant', 'Var', (159, 165))	('ALDH', 'Gene', (92, 96))	('NRAS', 'Gene', '4893', (154, 158))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('eliminate', 'NegReg', (82, 91))	('HPR', 'Gene', '3250', (64, 67))	('ABT-737', 'Chemical', 'MESH:C501332', (50, 57))	('ALDH', 'Gene', '11670', (92, 96))	('ABT-737', 'Gene', (50, 57))	('NRAS', 'Gene', (154, 158))	('BRAF', 'Gene', '673', (145, 149))	('ALDH', 'molecular_function', 'GO:0004030', ('92', '96'))	('HPR', 'Gene', (64, 67))
69893	28137308	The results revealed that caffeic acid phenethyl ester (CAPE), a bioactive molecule induces apoptosis in ABCB5 knocked down CD133+ chemoresistant melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('knocked', 'Var', (111, 118))	('melanoma', 'Disease', (146, 154))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('CAPE', 'Chemical', 'MESH:C055494', (56, 60))	('ABCB5', 'Gene', (105, 110))	('caffeic acid phenethyl ester', 'Chemical', 'MESH:C055494', (26, 54))
69896	28137308	Recent study also demonstrates that inhibition of deacytylase activity of Sirtuin 1 and 2 (SIRT1/2) by Tenovin-6 induces apoptosis in uveal melanoma by upregulating the expression of tumor suppressor gene, p53 and elevation of ROS.	('inhibition', 'Var', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('Tenovin-6', 'Gene', (103, 112))	('expression', 'MPA', (169, 179))	('p53', 'Gene', '7157', (206, 209))	('SIRT1/2', 'Gene', '23411;22933', (91, 98))	('upregulating', 'PosReg', (152, 164))	('p53', 'Gene', (206, 209))	('ROS', 'Chemical', '-', (227, 230))	('uveal melanoma', 'Disease', 'MESH:C536494', (134, 148))	('deacytylase activity', 'MPA', (50, 70))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('ROS', 'Protein', (227, 230))	('tumor', 'Disease', (183, 188))	('uveal melanoma', 'Disease', (134, 148))	('apoptosis', 'CPA', (121, 130))	('SIRT1/2', 'Gene', (91, 98))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('183', '199'))	('elevation', 'PosReg', (214, 223))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('Sirtuin 1 and 2', 'Gene', '23411;22933', (74, 89))	('uveal melanoma', 'Phenotype', 'HP:0007716', (134, 148))	('induces', 'PosReg', (113, 120))	('tumor suppressor', 'biological_process', 'GO:0051726', ('183', '199'))	('apoptosis', 'biological_process', 'GO:0097194', ('121', '130'))	('apoptosis', 'biological_process', 'GO:0006915', ('121', '130'))
69913	28137308	Furthermore, HNK also significantly attenuates CSC properties through inhibition of Notch signaling.	('inhibition', 'NegReg', (70, 80))	('Notch', 'Gene', (84, 89))	('HNK', 'Var', (13, 16))	('CSC properties', 'CPA', (47, 61))	('signaling', 'biological_process', 'GO:0023052', ('90', '99'))	('attenuates', 'NegReg', (36, 46))	('Notch', 'Gene', '4851;4853;4855', (84, 89))
69945	28137308	In this review, we have discussed that there are several small molecule inhibitors (HNK, ABT-737, ABT-263), nanoparticles conjugated drugs (HA-SLNs-PTX), signaling antagonist (Cyclopamine, Gant61), monoclonal receptor antibodies (anti-CD20, anti-CD133, anti-ABCB5) and microRNAs (miR-200c, miR-33b) those could be used as novel therapeutic strategies for management of melanoma.	('anti-CD133', 'Var', (241, 251))	('PTX', 'Chemical', 'MESH:D017239', (148, 151))	('melanoma', 'Phenotype', 'HP:0002861', (369, 377))	('melanoma', 'Disease', (369, 377))	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('miR-200c', 'Gene', (280, 288))	('miR-33b', 'Gene', (290, 297))	('melanoma', 'Disease', 'MESH:D008545', (369, 377))	('miR-200c', 'Gene', '406985', (280, 288))	('ABT', 'Chemical', 'MESH:C002502', (89, 92))	('ABT', 'Chemical', 'MESH:C002502', (98, 101))	('Cyclopamine', 'Chemical', 'MESH:C000541', (176, 187))	('ABT-737', 'Chemical', 'MESH:C501332', (89, 96))	('anti-ABCB5', 'Var', (253, 263))	('miR-33b', 'Gene', '693120', (290, 297))	('CD20', 'Gene', '54474', (235, 239))	('CD20', 'Gene', (235, 239))
69955	27239574	The low rate of monosomy chromosome 3 and the consequent low rate of mortality may be indicative of good prognosis in Iranian patients with uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('chromosome', 'cellular_component', 'GO:0005694', ('25', '35'))	('monosomy chromosome 3', 'Var', (16, 37))	('patients', 'Species', '9606', (126, 134))	('uveal melanoma', 'Phenotype', 'HP:0007716', (140, 154))	('uveal melanoma', 'Disease', (140, 154))	('uveal melanoma', 'Disease', 'MESH:C536494', (140, 154))
69957	27239574	Since the noteworthy report of Prescher et al in 1996, several publications investigating the association between the chromosomal abnormalities and UM survival have revealed that the monosomy chromosome 3 is the most frequent karyotypic abnormality in this malignant intraocular tumor, predicting the worse prognosis.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('UM', 'Phenotype', 'HP:0007716', (148, 150))	('intraocular tumor', 'Disease', (267, 284))	('intraocular tumor', 'Disease', 'MESH:D064090', (267, 284))	('monosomy chromosome 3', 'Var', (183, 204))	('chromosomal abnormalities', 'Disease', (118, 143))	('chromosome', 'cellular_component', 'GO:0005694', ('192', '202'))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (118, 143))
69959	27239574	A recent article on molecular classification of UM according to transcriptomic and chromosomal features divided the uveal melanomas into four subgroups based on gene-expression profile and status of chromosomes 3, 6p, and 8p to precisely predict metastatic death: class 1A with minimal aneuploidy, class 1B with 6p gain, class 2A with monosomy 3, and class 2B with monosomy 3 and 8p loss.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('monosomy 3', 'Var', (335, 345))	('aneuploidy', 'Disease', (286, 296))	('uveal melanomas', 'Disease', (116, 131))	('uveal melanomas', 'Phenotype', 'HP:0007716', (116, 131))	('gene-expression', 'biological_process', 'GO:0010467', ('161', '176'))	('predict', 'Reg', (238, 245))	('death', 'Disease', 'MESH:D003643', (257, 262))	('death', 'Disease', (257, 262))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('uveal melanoma', 'Phenotype', 'HP:0007716', (116, 130))	('aneuploidy', 'Disease', 'MESH:D000782', (286, 296))	('uveal melanomas', 'Disease', 'MESH:C536494', (116, 131))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('gain', 'PosReg', (315, 319))
69985	27239574	Possible prognostic factors were age at time of diagnosis, cell type (mixed/epithelioid cell), tumor location (ciliary body/choroid), largest tumor diameter, tumor thickness, and monosomy of chromosome 3.	('chromosome', 'cellular_component', 'GO:0005694', ('191', '201'))	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('monosomy of chromosome', 'Var', (179, 201))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', (95, 100))
69989	27239574	Only one (2%) patient with monosomy of chromosome 3 died of liver metastasis, and three other patients were alive at the end of the study.	('liver metastasis', 'Disease', (60, 76))	('patients', 'Species', '9606', (94, 102))	('patient', 'Species', '9606', (14, 21))	('monosomy', 'Var', (27, 35))	('patient', 'Species', '9606', (94, 101))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))	('liver metastasis', 'Disease', 'MESH:D009362', (60, 76))
69992	27239574	Univariate analysis of the single possible prognostic factors did not show a statistically significantly higher metastasis incidence rate in patients with potential prognostic factors such as gender, age at time of diagnosis, mixed/epithelioid cell type in the tumor, tumor location, and monosomy of chromosome 3 tumors compared with patients without this chromosomal alteration.	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('monosomy', 'Var', (288, 296))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', (313, 318))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('tumor', 'Disease', (268, 273))	('metastasis', 'CPA', (112, 122))	('tumors', 'Disease', (313, 319))	('tumors', 'Disease', 'MESH:D009369', (313, 319))	('tumors', 'Phenotype', 'HP:0002664', (313, 319))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('patients', 'Species', '9606', (334, 342))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('chromosome', 'cellular_component', 'GO:0005694', ('300', '310'))	('patients', 'Species', '9606', (141, 149))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
70002	27239574	As proposed by Sandinha et al, we reported a tumor as monosomic for chromosome 3 if the percentage of nuclei with one hybridization site was greater than 60% of the nuclei counted.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('monosomic', 'Var', (54, 63))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
70006	27239574	The lower rate of monosomy 3, might be due to sampling error and tumor heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('monosomy 3', 'Var', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))
70007	27239574	In conclusion, our results demonstrated the less frequent events of monosomy chromosome 3, epithelioid cellularity, and lower rate of UM-related death in Iranian patients, which is different from previously published reports in Caucasian populations harboring this tumor.	('patients', 'Species', '9606', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('chromosome', 'cellular_component', 'GO:0005694', ('77', '87'))	('tumor', 'Disease', (265, 270))	('UM', 'Phenotype', 'HP:0007716', (134, 136))	('epithelioid cellularity', 'CPA', (91, 114))	('death', 'Disease', 'MESH:D003643', (145, 150))	('monosomy chromosome 3', 'Var', (68, 89))	('death', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (265, 270))
70086	21978383	Additionally, a multi-center study (n = 171) showed that correction of the melphalan dose for IBW was associated with a lower risk of severe toxicity after ILI.	('lower', 'NegReg', (120, 125))	('melphalan', 'Chemical', 'MESH:D008558', (75, 84))	('toxicity', 'Disease', 'MESH:D064420', (141, 149))	('toxicity', 'Disease', (141, 149))	('correction', 'Var', (57, 67))
70098	21978383	In addition to hyperthermia, cytotoxicity may be enhanced by manipulation of blood flow to tumor ultimately impacting PK.	('cytotoxicity', 'Disease', (29, 41))	('hyperthermia', 'Disease', 'MESH:D005334', (15, 27))	('enhanced', 'PosReg', (49, 57))	('manipulation', 'Var', (61, 73))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('hyperthermia', 'Phenotype', 'HP:0001945', (15, 27))	('cytotoxicity', 'Disease', 'MESH:D064420', (29, 41))	('hyperthermia', 'Disease', (15, 27))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
70101	21978383	We have studied the novel pentapeptide ADH-1 and demonstrated that ADH-1-induced disruption of N-cadherin adhesion complexes induces alterations in vascular permeability leading to increased melphalan drug delivery to tumors.	('ADH', 'molecular_function', 'GO:0004022', ('39', '42'))	('N-cadherin', 'Gene', (95, 105))	('melphalan drug delivery to tumors', 'Disease', (191, 224))	('rat', 'Species', '10116', (56, 59))	('N-cadherin', 'Gene', '1000', (95, 105))	('melphalan drug delivery to tumors', 'Disease', 'MESH:D009369', (191, 224))	('disruption', 'Var', (81, 91))	('cadherin', 'molecular_function', 'GO:0008014', ('97', '105'))	('ADH', 'molecular_function', 'GO:0047636', ('67', '70'))	('rat', 'Species', '10116', (137, 140))	('alterations', 'Reg', (133, 144))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('ADH', 'molecular_function', 'GO:0004022', ('67', '70'))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('increased', 'PosReg', (181, 190))	('ADH', 'molecular_function', 'GO:0047636', ('39', '42'))	('vascular permeability', 'MPA', (148, 169))	('ADH-1-induced', 'Gene', (67, 80))
70152	21978383	Significant improvements in both PFS and overall response rates were seen in patients treated with PHP compared with patients treated in the BAC arm.	('PFS', 'CPA', (33, 36))	('improvements', 'PosReg', (12, 24))	('patients', 'Species', '9606', (77, 85))	('rat', 'Species', '10116', (58, 61))	('patients', 'Species', '9606', (117, 125))	('PHP', 'Var', (99, 102))
70213	22581085	Management of Radiation-induced Severe Anophthalmic Socket Contracture in Patients with Uveal Melanoma High-dose radiotherapy can cause contracture of the anophthalmic socket, but the incidence of this complication in patients with enucleation for uveal melanoma has not previously been reported.	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('Patients', 'Species', '9606', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (254, 262))	('contracture', 'Phenotype', 'HP:0001371', (136, 147))	('contracture of the anophthalmic', 'Disease', 'MESH:D003286', (136, 167))	('uveal melanoma', 'Disease', 'MESH:C536494', (248, 262))	('patients', 'Species', '9606', (218, 226))	('uveal melanoma', 'Disease', (248, 262))	('enucleation', 'biological_process', 'GO:0090601', ('232', '243'))	('contracture of the anophthalmic', 'Disease', (136, 167))	('Uveal Melanoma', 'Disease', (88, 102))	('High-dose radiotherapy', 'Var', (103, 125))	('Uveal Melanoma', 'Disease', 'MESH:C536494', (88, 102))	('Contracture', 'Phenotype', 'HP:0001371', (59, 70))	('Severe Anophthalmic Socket Contracture', 'Disease', (32, 70))	('cause', 'Reg', (130, 135))	('uveal melanoma', 'Phenotype', 'HP:0007716', (248, 262))	('Severe Anophthalmic Socket Contracture', 'Disease', 'MESH:D003286', (32, 70))	('Melanoma', 'Phenotype', 'HP:0002861', (94, 102))
70298	21051595	Frequent Mutation of BAP1 in Metastasizing Uveal Melanomas Metastasis is a defining feature of malignant tumors and is the most common cause of cancer-related death, yet the genetics of metastasis are poorly understood.	('Metastasizing Uveal Melanomas', 'Disease', (29, 58))	('Mutation', 'Var', (9, 17))	('malignant tumors', 'Disease', (95, 111))	('Uveal Melanomas', 'Phenotype', 'HP:0007716', (43, 58))	('BAP1', 'Gene', (21, 25))	('malignant tumors', 'Disease', 'MESH:D018198', (95, 111))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('Melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('cancer', 'Disease', (144, 150))	('Metastasizing Uveal Melanomas', 'Disease', 'MESH:D009362', (29, 58))	('death', 'Disease', 'MESH:D003643', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('death', 'Disease', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('BAP1', 'Gene', '8314', (21, 25))
70300	21051595	Inactivating somatic mutations were identified in the gene encoding BRCA1-associated protein 1 (BAP1) on chromosome 3p21.1 in 26 of 31 (84%) metastasizing tumors, including 15 mutations causing premature protein termination, and six affecting its ubiquitin carboxy-terminal hydrolase (UCH) domains.	('mutations', 'Var', (176, 185))	('BRCA1-associated protein 1', 'Gene', (68, 94))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('BAP1', 'Gene', (96, 100))	('chromosome', 'cellular_component', 'GO:0005694', ('105', '115'))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('affecting', 'Reg', (233, 242))	('premature protein termination', 'MPA', (194, 223))	('protein', 'cellular_component', 'GO:0003675', ('204', '211'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('247', '256'))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('causing', 'Reg', (186, 193))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))	('BAP1', 'Gene', '8314', (96, 100))	('ubiquitin carboxy-terminal', 'MPA', (247, 273))	('BRCA1-associated protein 1', 'Gene', '8314', (68, 94))
70301	21051595	One tumor harbored a frameshift mutation that was germline in origin, thus representing a susceptibility allele.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('frameshift mutation', 'Var', (21, 40))
70304	21051595	Oncogenic mutations in the Galphaq stimulatory subunit GNAQ are common in UM, but these mutations occur early in tumorigenesis and are not correlated with molecular class or metastasis.	('tumor', 'Disease', (113, 118))	('Galphaq', 'Gene', (27, 34))	('GNAQ', 'Gene', '2776', (55, 59))	('Galphaq', 'Gene', '2776', (27, 34))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('GNAQ', 'Gene', (55, 59))	('mutations', 'Var', (10, 19))
70305	21051595	On the other hand, class 2 tumors are strongly associated with monosomy 3, suggesting that loss of one copy of chromosome 3 may unmask a mutant gene on the remaining copy which promotes metastasis.	('promotes', 'PosReg', (177, 185))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('metastasis', 'CPA', (186, 196))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('111', '121'))	('loss', 'Var', (91, 95))	('mutant', 'Var', (137, 143))
70306	21051595	Using exome capture followed by massively parallel sequencing, we analyzed two class 2 tumors that were monosomic for chromosome 3 (MM56 and MM70) and matching normal DNA from peripheral blood lymphocytes.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('118', '128'))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('MM70', 'Var', (141, 145))	('tumors', 'Disease', (87, 93))	('DNA', 'cellular_component', 'GO:0005574', ('167', '170'))	('MM56', 'CellLine', 'CVCL:L794', (132, 136))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('MM56', 'Var', (132, 136))
70307	21051595	Both tumors contained inactivating mutations in BAP1, located at chromosome 3p21.1 (Fig.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('BAP1', 'Gene', '8314', (48, 52))	('BAP1', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('inactivating mutations', 'Var', (22, 44))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('chromosome', 'cellular_component', 'GO:0005694', ('65', '75'))	('contained', 'Reg', (12, 21))
70308	21051595	MM56 contained a C/G to T/A transition that created a premature termination codon (p.W196X).	('p.W196X', 'Var', (83, 90))	('p.W196X', 'Mutation', 'p.W196X', (83, 90))	('premature termination codon', 'MPA', (54, 81))	('MM56', 'CellLine', 'CVCL:L794', (0, 4))
70309	21051595	MM70 contained a deletion of 11bp in exon 11, leading to a frameshift and premature termination of the BAP1 protein (p.Q322fsX100).	('BAP1', 'Gene', '8314', (103, 107))	('frameshift', 'Var', (59, 69))	('BAP1', 'Gene', (103, 107))	('protein', 'Protein', (108, 115))	('p.Q322fsX100', 'Mutation', 'p.Q322fsX100', (117, 129))	('p.Q322fsX100', 'Var', (117, 129))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
70314	21051595	BAP1 exhibits tumor suppressor activity in cancer cells, and BAP1 mutations have been reported in a small number of breast and lung cancer samples.	('mutations', 'Var', (66, 75))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('BAP1', 'Gene', (0, 4))	('BAP1', 'Gene', '8314', (61, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('breast and lung cancer', 'Disease', 'MESH:D001943', (116, 138))	('cancer', 'Disease', (132, 138))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('14', '30'))	('tumor', 'Disease', (14, 19))	('BAP1', 'Gene', (61, 65))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('reported', 'Reg', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('BAP1', 'Gene', '8314', (0, 4))	('tumor suppressor', 'biological_process', 'GO:0051726', ('14', '30'))
70316	21051595	Altogether, BAP1 mutations were identified in 26 of 31 (84%) class 2 tumors, including 13 out-of-frame deletions and two nonsense mutation leading to premature protein termination, six missense mutations, four in-frame deletions, and one mutation predicted to produce an abnormally extended BAP1 polypeptide (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('BAP1', 'Gene', (291, 295))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('missense mutations', 'Var', (185, 203))	('BAP1', 'Gene', '8314', (12, 16))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('BAP1', 'Gene', '8314', (291, 295))	('BAP1', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
70317	21051595	Three of the missense mutations affected catalytic residues of the UCH active site (C91 and H169), two occurred elsewhere in the UCH domain, and one affected the ULD (Fig.	('ULD', 'Disease', 'MESH:D020194', (162, 165))	('ULD', 'Disease', (162, 165))	('missense mutations', 'Var', (13, 31))	('affected', 'Reg', (32, 40))	('affected', 'Reg', (149, 157))	('catalytic residues', 'MPA', (41, 59))
70318	21051595	All BAP1 missense mutations and in-frame deletions affected phylogenetically conserved amino acids (fig.	('BAP1', 'Gene', (4, 8))	('phylogenetically conserved amino acids', 'MPA', (60, 98))	('affected', 'Reg', (51, 59))	('missense mutations', 'Var', (9, 27))	('BAP1', 'Gene', '8314', (4, 8))
70320	21051595	This case may represent a transition state in which the tumor has sustained a BAP1 mutation but has not yet converted to class 2, suggesting that BAP1 mutations may precede the emergence of the class 2 signature.	('BAP1', 'Gene', '8314', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('BAP1', 'Gene', (146, 150))	('mutation', 'Var', (83, 91))	('BAP1', 'Gene', '8314', (78, 82))	('mutations', 'Var', (151, 160))	('BAP1', 'Gene', (78, 82))
70321	21051595	Somatic BAP1 mutations were also detected in two of three metastatic tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('BAP1', 'Gene', '8314', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('detected', 'Reg', (33, 41))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('BAP1', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))
70322	21051595	One copy of chromosome 3 was missing in all 17 BAP1-mutant class 2 tumors for which cytogenetic data were available, consistent with chromosome 3 loss uncovering recessive BAP1 mutations.	('loss', 'NegReg', (146, 150))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('BAP1', 'Gene', (172, 176))	('mutations', 'Var', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('BAP1', 'Gene', '8314', (47, 51))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('chromosome', 'cellular_component', 'GO:0005694', ('133', '143'))	('tumors', 'Disease', (67, 73))	('BAP1', 'Gene', (47, 51))	('BAP1', 'Gene', '8314', (172, 176))
70324	21051595	However, we detected one germline mutation (p.E402fsX2; c.1318-1319insA) in the patient with tumor MM 087 (table S2) suggesting that germline alterations in BAP1 can predispose to UM.	('c.1318-1319insA', 'Mutation', 'c.1318_1319insA', (56, 71))	('p.E402fsX2', 'Mutation', 'p.E402fsX2', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('p.E402fsX2; c.1318-1319insA', 'Var', (44, 71))	('BAP1', 'Gene', (157, 161))	('UM', 'Phenotype', 'HP:0007716', (180, 182))	('tumor', 'Disease', (93, 98))	('predispose', 'Reg', (166, 176))	('BAP1', 'Gene', '8314', (157, 161))	('c.1318-1319insA', 'Var', (56, 71))	('patient', 'Species', '9606', (80, 87))	('germline alterations', 'Var', (133, 153))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
70326	21051595	GNAQ mutations were present in 4/9 BAP1 mutant tumors and 3/6 BAP1 wildtype tumors, indicating that there was no correlation between GNAQ and BAP1 mutation status.	('BAP1', 'Gene', '8314', (142, 146))	('GNAQ', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('BAP1', 'Gene', (35, 39))	('tumors', 'Disease', (47, 53))	('BAP1', 'Gene', '8314', (62, 66))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('BAP1', 'Gene', (142, 146))	('mutant', 'Var', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('BAP1', 'Gene', (62, 66))	('tumors', 'Disease', (76, 82))	('GNAQ', 'Gene', '2776', (0, 4))	('BAP1', 'Gene', '8314', (35, 39))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('GNAQ', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('GNAQ', 'Gene', '2776', (133, 137))
70329	21051595	To determine whether the low BAP1 mRNA levels in class 2 tumors without detectable BAP1 mutations may be explained by DNA methyation, we performed a preliminary analysis of DNA methylation of BAP1.	('BAP1', 'Gene', '8314', (83, 87))	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('BAP1', 'Gene', (192, 196))	('BAP1', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('low', 'NegReg', (25, 28))	('BAP1', 'Gene', '8314', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('DNA methylation', 'biological_process', 'GO:0006306', ('173', '188'))	('DNA', 'cellular_component', 'GO:0005574', ('173', '176'))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('BAP1', 'Gene', '8314', (192, 196))	('BAP1', 'Gene', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
70333	21051595	However, with almost 85% of class 2 tumors harboring mutations, we do not expect that methylation will be a major mechanism of BAP1 inactivation.	('BAP1', 'Gene', (127, 131))	('mutations', 'Var', (53, 62))	('methylation', 'biological_process', 'GO:0032259', ('86', '97'))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('BAP1', 'Gene', '8314', (127, 131))	('tumors', 'Disease', (36, 42))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
70334	21051595	An alternative explanation is that these tumors may contain very large deletions of the BAP1 locus not detectable by our sequencing method.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('deletions', 'Var', (71, 80))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('BAP1', 'Gene', '8314', (88, 92))	('BAP1', 'Gene', (88, 92))
70336	21051595	This was expected for the two tumors with mutations expected to cause premature protein terminations (MM 091 and MM 100), but it was surprising for the two tumors with missense mutations (MM 071 and MM 135) and suggests that these mutations lead to protein instability.	('tumors', 'Disease', (30, 36))	('MM 135', 'Var', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('protein', 'cellular_component', 'GO:0003675', ('249', '256'))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('mutations', 'Var', (231, 240))	('protein instability', 'MPA', (249, 268))	('missense', 'Var', (168, 176))	('MM 091', 'Var', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('lead to', 'Reg', (241, 248))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('MM 071', 'Var', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Disease', (156, 162))
70337	21051595	RNAi-mediated knock down of BAP1 in 92.1 UM cells, which did not harbor a detectable BAP1 mutation, recapitulated many characteristics of the de-differentiated class 2 UM phenotype.	('BAP1', 'Gene', '8314', (28, 32))	('BAP1', 'Gene', (85, 89))	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('UM', 'Phenotype', 'HP:0007716', (168, 170))	('92.1 UM', 'CellLine', 'CVCL:7796', (36, 43))	('knock down', 'Var', (14, 24))	('BAP1', 'Gene', (28, 32))	('RNAi', 'biological_process', 'GO:0016246', ('0', '4'))	('de-differentiated class 2 UM phenotype', 'CPA', (142, 180))	('BAP1', 'Gene', '8314', (85, 89))	('mutation', 'Var', (90, 98))
70340	21051595	Similarly, depletion of BAP1 shifted the gene expression profile of the multi- gene clinical prognostic assay towards the class 2 signature (Fig.	('gene expression', 'biological_process', 'GO:0010467', ('41', '56'))	('BAP1', 'Gene', (24, 28))	('gene expression', 'MPA', (41, 56))	('depletion', 'Var', (11, 20))	('BAP1', 'Gene', '8314', (24, 28))
70341	21051595	BAP1 depletion caused a reduction in mRNA levels of neural crest migration genes (ROBO1), melanocyte differentiation genes (CTNNB1, EDNRB and SOX10) and other genes that are down-regulated in class 2 tumors (LMCD1 and LTA4H).	('depletion', 'Var', (5, 14))	('LTA4H', 'Gene', (218, 223))	('ROBO1', 'Gene', '6091', (82, 87))	('melanocyte differentiation', 'biological_process', 'GO:0030318', ('90', '116'))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('LMCD1', 'Gene', '29995', (208, 213))	('CTNNB1', 'Gene', (124, 130))	('BAP1', 'Gene', (0, 4))	('LMCD1', 'Gene', (208, 213))	('SOX10', 'Gene', '6663', (142, 147))	('EDNRB', 'Gene', '1910', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('LTA4H', 'Gene', '4048', (218, 223))	('reduction', 'NegReg', (24, 33))	('SOX10', 'Gene', (142, 147))	('EDNRB', 'Gene', (132, 137))	('LTA4H', 'molecular_function', 'GO:0004463', ('218', '223'))	('ROBO1', 'Gene', (82, 87))	('CTNNB1', 'Gene', '1499', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Disease', (200, 206))	('mRNA levels', 'MPA', (37, 48))	('BAP1', 'Gene', '8314', (0, 4))
70342	21051595	In contrast, BAP1 depletion caused an increase in mRNA levels of CDH1 and the proto-oncogene KIT, which are highly expressed in class 2 tumors.	('tumors', 'Disease', (136, 142))	('increase', 'PosReg', (38, 46))	('BAP1', 'Gene', (13, 17))	('KIT', 'Gene', (93, 96))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('CDH1', 'Gene', (65, 69))	('KIT', 'molecular_function', 'GO:0005020', ('93', '96'))	('mRNA levels', 'MPA', (50, 61))	('CDH1', 'Gene', '999', (65, 69))	('depletion', 'Var', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('BAP1', 'Gene', '8314', (13, 17))
70344	21051595	GNAQ mutations occur early in UM and are not sufficient for malignant transformation, but they may create a dependency of the tumor cells on constitutive GNAQ activity.	('GNAQ', 'Gene', '2776', (154, 158))	('GNAQ', 'Gene', '2776', (0, 4))	('dependency', 'MPA', (108, 118))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (5, 14))	('GNAQ', 'Gene', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('GNAQ', 'Gene', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (30, 32))	('create', 'Reg', (99, 105))	('tumor', 'Disease', (126, 131))
70345	21051595	In contrast, BAP1 mutations occur later in UM progression and coincide with the onset of metastatic behavior.	('BAP1', 'Gene', (13, 17))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('BAP1', 'Gene', '8314', (13, 17))	('metastatic behavior', 'CPA', (89, 108))	('mutations', 'Var', (18, 27))
70346	21051595	One potential strategy to counteract the effects of BAP1 mutation would be to inhibit the RING1 ubiquinating activity that normally opposes the deubiquinating activity BAP1.	('mutation', 'Var', (57, 65))	('BAP1', 'Gene', '8314', (168, 172))	('BAP1', 'Gene', '8314', (52, 56))	('RING1', 'Gene', '6015', (90, 95))	('BAP1', 'Gene', (168, 172))	('BAP1', 'Gene', (52, 56))	('inhibit', 'NegReg', (78, 85))	('RING1', 'Gene', (90, 95))
70347	21051595	Our findings strongly implicate mutational inactivation of BAP1 as a key event in the acquisition of metastatic competence in UM, and they dramatically expand the role of BAP1 and other deubiquitinating enzymes as potential therapeutic targets in cancer.	('BAP1', 'Gene', (171, 175))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('mutational inactivation', 'Var', (32, 55))	('BAP1', 'Gene', (59, 63))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('UM', 'Phenotype', 'HP:0007716', (126, 128))	('BAP1', 'Gene', '8314', (171, 175))	('metastatic competence', 'CPA', (101, 122))	('BAP1', 'Gene', '8314', (59, 63))
70415	19351402	A recent meta-analysis by Shah et al identified welding, which is a significant source of blue-light, as a risk-factor for uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('uveal melanoma', 'Disease', 'MESH:C536494', (123, 137))	('welding', 'Var', (48, 55))	('uveal melanoma', 'Phenotype', 'HP:0007716', (123, 137))	('uveal melanoma', 'Disease', (123, 137))
70484	33595243	Twelve (6%) patients participated in four treatment trials (NCT02599402, NCT01974752, NCT00154388 and NCT00308607).	('patients', 'Species', '9606', (12, 20))	('NCT00308607', 'Var', (102, 113))	('NCT02599402', 'Var', (60, 71))	('NCT01974752', 'Var', (73, 84))	('NCT00154388', 'Var', (86, 97))
70495	33595243	In stage IVa, only three patients had performance status >1 and only two an alkaline phosphatase level >2.0 x UNL, but 29% had an LDLM >M1a with shorter OS (P = 0.018, log-rank test).	('phosphatase', 'molecular_function', 'GO:0016791', ('85', '96'))	('alkaline phosphatase level', 'MPA', (76, 102))	('patients', 'Species', '9606', (25, 33))	('LDLM >M1a', 'Var', (130, 139))	('alkaline phosphatase level', 'Phenotype', 'HP:0003155', (76, 102))
70498	33595243	Analyzed by working formulation stage (Supplementary Figure S9, Supplemental digital content 1, http://links.lww.com/MR/A258), lactate dehydrogenase (LDH) >2.0 x UNL was associated with shorter OS in stage IVa (P = 0.002; log-rank test for trend), whereas gender, age, presence of symptoms and sites of metastases were unassociated with OS in any stage.	('stage', 'Disease', (200, 205))	('metastases', 'Disease', (303, 313))	('metastases', 'Disease', 'MESH:D009362', (303, 313))	('shorter', 'NegReg', (186, 193))	('>2.0', 'Var', (155, 159))
70523	33595243	We advocate systematic collection of biopsies from metastases to promote the discovery of any other subcategories amenable to specific treatments such as CPI for patients who carry a pathogenic variant in MBD4 though such subcategories may be small.	('patients', 'Species', '9606', (162, 170))	('pathogenic', 'Reg', (183, 193))	('metastases', 'Disease', 'MESH:D009362', (51, 61))	('variant', 'Var', (194, 201))	('CPI', 'Chemical', '-', (154, 157))	('MBD4', 'Gene', '8930', (205, 209))	('MBD4', 'Gene', (205, 209))	('metastases', 'Disease', (51, 61))
70531	33595243	TYH2017218 and TYH2020315); all in Finland.	('TYH2020315)', 'Var', (15, 26))	('TYH2017218', 'Chemical', '-', (0, 10))	('TYH2017218', 'Var', (0, 10))	('TYH2020315', 'Chemical', '-', (15, 25))
70532	33208912	BAP1 mutant uveal melanoma is stratified by metabolic phenotypes with distinct vulnerability to metabolic inhibitors Cancer cell metabolism is a targetable vulnerability; however, a precise understanding of metabolic heterogeneity is required.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('BAP1', 'Gene', (0, 4))	('metabolism', 'biological_process', 'GO:0008152', ('129', '139'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (12, 26))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('Cancer', 'Disease', (117, 123))	('mutant', 'Var', (5, 11))	('Cancer', 'Disease', 'MESH:D009369', (117, 123))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))	('BAP1', 'Gene', '8314', (0, 4))	('melanoma', 'Disease', (18, 26))
70533	33208912	Inactivating mutations in BRCA1-associated protein 1 (BAP1) are associated with metastasis in uveal melanoma (UM), the deadliest adult eye cancer.	('associated with', 'Reg', (64, 79))	('metastasis', 'CPA', (80, 90))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('UM', 'Phenotype', 'HP:0007716', (110, 112))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('BRCA1-associated protein 1', 'Gene', '8314', (26, 52))	('Inactivating mutations', 'Var', (0, 22))	('eye cancer', 'Disease', 'MESH:D009369', (135, 145))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('eye cancer', 'Disease', (135, 145))	('melanoma', 'Disease', (100, 108))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('BAP1', 'Gene', (54, 58))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('BRCA1-associated protein 1', 'Gene', (26, 52))	('eye cancer', 'Phenotype', 'HP:0100012', (135, 145))
70534	33208912	UM patient sample analysis divided BAP1 mutant UM tumors into two subgroups based on oxidative phosphorylation (OXPHOS) gene expression suggesting metabolic heterogeneity.	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('85', '110'))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('patient', 'Species', '9606', (3, 10))	('OXPHOS', 'biological_process', 'GO:0002082', ('112', '118'))	('oxidative phosphorylation', 'MPA', (85, 110))	('BAP1', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mutant', 'Var', (40, 46))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('gene expression', 'biological_process', 'GO:0010467', ('120', '135'))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
70535	33208912	Consistent with patient data, transcriptomic analysis of BAP1 mutant UM cell lines also showed OXPHOShigh or OXPHOSlow subgroups.	('OXPHOShigh', 'CPA', (95, 105))	('mutant', 'Var', (62, 68))	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('OXPHOSlow subgroups', 'CPA', (109, 128))	('BAP1', 'Gene', (57, 61))	('patient', 'Species', '9606', (16, 23))
70536	33208912	Integrated RNA sequencing, metabolomics and molecular analyses showed that OXPHOShigh BAP1 mutant UM cells utilize glycolytic and nucleotide biosynthesis pathways, whereas OXPHOSlow BAP1 mutant UM cells employ fatty acid oxidation.	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('210', '230'))	('glycolytic', 'Pathway', (115, 125))	('nucleotide biosynthesis', 'biological_process', 'GO:0009165', ('130', '153'))	('UM', 'Phenotype', 'HP:0007716', (194, 196))	('RNA', 'cellular_component', 'GO:0005562', ('11', '14'))	('UM', 'Phenotype', 'HP:0007716', (98, 100))	('mutant', 'Var', (91, 97))	('OXPHOShigh BAP1', 'Gene', (75, 90))	('fatty acid', 'Chemical', 'MESH:D005227', (210, 220))
70537	33208912	Our findings indicate that targeting cancer metabolism is a promising therapeutic option for BAP1 mutant UM; however, tailored approaches may be required to due metabolic heterogeneities.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('metabolism', 'biological_process', 'GO:0008152', ('44', '54'))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('BAP1', 'Gene', (93, 97))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('mutant', 'Var', (98, 104))
70539	33208912	Transformation induced by oncogene and/or tumor suppressor mutations often involves changes in nutrient signaling pathways and metabolic enzyme expression.	('nutrient', 'MPA', (95, 103))	('tumor', 'Disease', (42, 47))	('changes', 'Reg', (84, 91))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('42', '58'))	('Transformation', 'CPA', (0, 14))	('oncogene', 'Gene', (26, 34))	('mutations', 'Var', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('42', '58'))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('metabolic enzyme', 'Enzyme', (127, 143))
70540	33208912	For example, Myc gain-of-function mutations alter mitochondrial metabolism and increase glucose and fatty acid (FA) utilization.	('increase', 'PosReg', (79, 87))	('fatty acid', 'Chemical', 'MESH:D005227', (100, 110))	('Myc', 'Gene', (13, 16))	('increase glucose', 'Phenotype', 'HP:0003074', (79, 95))	('gain-of-function', 'PosReg', (17, 33))	('mitochondrial metabolism', 'MPA', (50, 74))	('FA', 'Gene', '84027', (112, 114))	('glucose', 'Chemical', 'MESH:D005947', (88, 95))	('metabolism', 'biological_process', 'GO:0008152', ('64', '74'))	('mutations', 'Var', (34, 43))	('Myc', 'Gene', '4609', (13, 16))
70544	33208912	For example, variation in lipid metabolism due to MITF expression in cutaneous melanoma is associated with an invasive phenotype and differential response to drugs targeting lipid metabolism.	('MITF', 'Gene', '4286', (50, 54))	('MITF', 'Gene', (50, 54))	('lipid metabolism', 'MPA', (26, 42))	('lipid', 'Chemical', 'MESH:D008055', (26, 31))	('lipid metabolism', 'biological_process', 'GO:0006629', ('26', '42'))	('variation', 'Var', (13, 22))	('lipid', 'Chemical', 'MESH:D008055', (174, 179))	('cutaneous melanoma', 'Disease', (69, 87))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (69, 87))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (69, 87))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('lipid metabolism', 'biological_process', 'GO:0006629', ('174', '190'))	('associated', 'Reg', (91, 101))
70549	33208912	BAP1 inactivating mutations are found in > 80% of class 2 UM tumors, suggesting that BAP1 mutations are strongly correlated with metastasis and poor prognosis in UM.	('BAP1', 'Gene', (85, 89))	('correlated with', 'Reg', (113, 128))	('mutations', 'Var', (90, 99))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('UM', 'Phenotype', 'HP:0007716', (162, 164))	('metastasis', 'CPA', (129, 139))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('UM', 'Phenotype', 'HP:0007716', (58, 60))
70551	33208912	Deletion of chromosome 3 and BAP1 inactivating mutations cause loss of BAP1 expression and function in cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))	('loss', 'NegReg', (63, 67))	('BAP1', 'Gene', (71, 75))	('expression', 'MPA', (76, 86))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('BAP1', 'Gene', (29, 33))	('function', 'MPA', (91, 99))	('inactivating mutations', 'Var', (34, 56))	('Deletion', 'Var', (0, 8))
70552	33208912	Germline BAP1 mutations are associated with an elevated risk of developing UM, mesothelioma and renal cell carcinoma, a disorder named "BAP1 cancer predisposition syndrome".	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('mesothelioma and renal cell carcinoma', 'Disease', 'MESH:C538614', (79, 116))	('elevate', 'Disease', (47, 54))	('associated', 'Reg', (28, 38))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('elevate', 'Disease', 'MESH:D006973', (47, 54))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (96, 116))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('cancer', 'Disease', (141, 147))	('developing UM', 'Disease', (64, 77))
70554	33208912	Here, we show BAP1 mutant UM exhibits an upregulated gene set of OXPHOS, a major parameter of cancer cell metabolism, compared to BAP1 wild-type UM tumors.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('BAP1', 'Gene', (14, 18))	('upregulated', 'PosReg', (41, 52))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('gene set of OXPHOS', 'MPA', (53, 71))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('metabolism', 'biological_process', 'GO:0008152', ('106', '116'))	('OXPHOS', 'biological_process', 'GO:0002082', ('65', '71'))	('mutant', 'Var', (19, 25))	('UM', 'Phenotype', 'HP:0007716', (26, 28))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
70555	33208912	By integrating multiple approaches, two metabolic phenotypes in BAP1 mutant UM were characterized with either increased glycolysis and nucleotide biosynthesis (OXPHOShigh) or high dependency on FA oxidation (FAO, OXPHOSlow).	('nucleotide biosynthesis', 'MPA', (135, 158))	('mutant', 'Var', (69, 75))	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('increased', 'PosReg', (110, 119))	('glycolysis', 'biological_process', 'GO:0006096', ('120', '130'))	('nucleotide biosynthesis', 'biological_process', 'GO:0009165', ('135', '158'))	('glycolysis', 'MPA', (120, 130))	('FA', 'Gene', '84027', (208, 210))	('FA', 'Gene', '84027', (194, 196))	('BAP1', 'Gene', (64, 68))
70557	33208912	We analyzed UM cases in The Cancer Genome Atlas (TCGA) to investigate whether BAP1 alterations influence OXPHOS.	('alterations', 'Var', (83, 94))	('influence', 'Reg', (95, 104))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('Cancer', 'Disease', 'MESH:D009369', (28, 34))	('Cancer', 'Disease', (28, 34))	('Cancer', 'Phenotype', 'HP:0002664', (28, 34))	('OXPHOS', 'biological_process', 'GO:0002082', ('105', '111'))	('OXPHOS', 'MPA', (105, 111))	('BAP1', 'Gene', (78, 82))
70558	33208912	Gene set enrichment analysis (GSEA) was performed using the OXPHOS gene set, which was found to be positively enriched in the BAP1 mutant group compared to the wild-type group (Fig.	('mutant', 'Var', (131, 137))	('GSEA', 'Chemical', '-', (30, 34))	('OXPHOS', 'biological_process', 'GO:0002082', ('60', '66'))	('BAP1', 'Gene', (126, 130))
70562	33208912	Bulk RNA-seq and GSEA in these cell lines showed that MP65 have a significant OXPHOS gene sets upregulation compared to MP46 and MM66, while MP46 display significant downregulation compared to MM66 (Fig.	('MP65', 'Var', (54, 58))	('RNA', 'cellular_component', 'GO:0005562', ('5', '8'))	('upregulation', 'PosReg', (95, 107))	('OXPHOS gene sets', 'MPA', (78, 94))	('OXPHOS', 'biological_process', 'GO:0002082', ('78', '84'))	('GSEA', 'Chemical', '-', (17, 21))	('downregulation', 'NegReg', (166, 180))
70563	33208912	This indicates that MP65 and MP46 have different phenotypes that appear to resemble the two distinct subtypes observed in BAP1 mutant patient tumors using TCGA data.	('mutant', 'Var', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('BAP1', 'Gene', (122, 126))	('MP65', 'Var', (20, 24))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('patient', 'Species', '9606', (134, 141))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('MP46', 'Var', (29, 33))
70566	33208912	We found that metabolites upregulated in MP65 and MP46 were predominantly associated with nucleotide biosynthesis pathways (22 out of 34 identified metabolites or 65%) and FA metabolism (11 out of 32 identified metabolites or 34%), respectively (Supplementary Fig 2a, 2b, and Table 1).	('upregulated', 'PosReg', (26, 37))	('metabolites', 'MPA', (14, 25))	('metabolism', 'biological_process', 'GO:0008152', ('175', '185'))	('FA', 'Gene', '84027', (172, 174))	('MP65', 'Var', (41, 45))	('nucleotide biosynthesis', 'biological_process', 'GO:0009165', ('90', '113'))	('MP46', 'Var', (50, 54))	('nucleotide biosynthesis', 'Enzyme', (90, 113))
70567	33208912	1e), which showed that two distinct gene expression profiles exist among BAP1 mutant tumors and cell lines.	('tumors', 'Disease', (85, 91))	('BAP1', 'Gene', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mutant', 'Var', (78, 84))	('gene expression', 'biological_process', 'GO:0010467', ('36', '51'))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
70568	33208912	Metabolomics analysis indicates that OXPHOS gene expression patterns within BAP1 mutant UM are associated with distinguishable metabolic phenotypes: OXPHOShigh cells, which have increased nucleotide biosynthesis; and OXPHOSlow cells, which show elevated FA metabolism.	('elevate', 'Disease', (245, 252))	('metabolism', 'biological_process', 'GO:0008152', ('257', '267'))	('gene expression', 'biological_process', 'GO:0010467', ('44', '59'))	('FA', 'Gene', '84027', (254, 256))	('OXPHOS', 'biological_process', 'GO:0002082', ('37', '43'))	('nucleotide biosynthesis', 'biological_process', 'GO:0009165', ('188', '211'))	('BAP1', 'Gene', (76, 80))	('nucleotide biosynthesis', 'MPA', (188, 211))	('mutant', 'Var', (81, 87))	('elevate', 'Disease', 'MESH:D006973', (245, 252))	('UM', 'Phenotype', 'HP:0007716', (88, 90))	('increased', 'PosReg', (178, 187))
70571	33208912	Since MP65 have increased metabolites associated with nucleotide biosynthesis, we examined key enzymes involved in glucose utilization and the PPP in OXPHOShigh BAP1 mutant cells.	('glucose', 'Chemical', 'MESH:D005947', (115, 122))	('increased', 'PosReg', (16, 25))	('nucleotide biosynthesis', 'biological_process', 'GO:0009165', ('54', '77'))	('MP65', 'Var', (6, 10))	('metabolites', 'MPA', (26, 37))
70572	33208912	We observed that both MP65 and MP38 display up-regulation of glucose transporter 3 (GLUT3) and hexokinase 1 (HK1) compared to MM66 (Fig.	('HK1', 'Gene', '3098', (109, 112))	('regulation', 'biological_process', 'GO:0065007', ('47', '57'))	('glucose transporter 3', 'Gene', '6515', (61, 82))	('HK1', 'Gene', (109, 112))	('hexokinase 1', 'Gene', (95, 107))	('glucose transporter 3', 'Gene', (61, 82))	('MP65', 'Var', (22, 26))	('GLUT3', 'Gene', '6515', (84, 89))	('up-regulation', 'PosReg', (44, 57))	('hexokinase 1', 'Gene', '3098', (95, 107))	('MP38', 'Var', (31, 35))	('GLUT3', 'Gene', (84, 89))	('HK1', 'molecular_function', 'GO:0004673', ('109', '112'))
70574	33208912	Additionally, we observed that MP65 and MP38 express a markedly elevated level of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, and transketolase (TKT), the major enzyme involved in nucleotide synthesis (Fig.	('MP65', 'Var', (31, 35))	('MP38', 'Var', (40, 44))	('glucose-6-phosphate dehydrogenase', 'Gene', '2539', (82, 115))	('elevate', 'Disease', (64, 71))	('TKT', 'Gene', '7086', (180, 183))	('nucleotide synthesis', 'biological_process', 'GO:0009165', ('215', '235'))	('transketolase', 'Gene', '7086', (165, 178))	('TKT', 'Gene', (180, 183))	('G6PD', 'Gene', '2539', (117, 121))	('elevate', 'Disease', 'MESH:D006973', (64, 71))	('transketolase', 'Gene', (165, 178))	('G6PD', 'Gene', (117, 121))	('glucose-6-phosphate dehydrogenase', 'Gene', (82, 115))
70575	33208912	To test whether the increase in glycolysis and nucleotide biosynthesis enzymes represents a potential therapeutic vulnerability in OXPHOShigh BAP1 mutant cells, we treated MM66, MP65 and MP38 with WZB117 (a GLUT1, 3, 4 inhibitor) and 6-aminonicotinamide (6-AN, a G6PD inhibitor).	('G6PD', 'Gene', (263, 267))	('mutant', 'Var', (147, 153))	('WZB117', 'Chemical', 'MESH:C576807', (197, 203))	('GLUT1', 'Gene', '6513', (207, 212))	('6-aminonicotinamide', 'Chemical', 'MESH:D015120', (234, 253))	('glycolysis', 'MPA', (32, 42))	('increase', 'PosReg', (20, 28))	('glycolysis', 'biological_process', 'GO:0006096', ('32', '42'))	('6-AN', 'Chemical', 'MESH:D015120', (255, 259))	('nucleotide biosynthesis', 'biological_process', 'GO:0009165', ('47', '70'))	('G6PD', 'Gene', '2539', (263, 267))	('GLUT1', 'Gene', (207, 212))
70577	33208912	MP46) exhibit FA metabolites over other metabolites, we hypothesized that OXPHOSlow BAP1 mutant cells would exhibit poor responses to WZB117 and 6-AN.	('6-AN', 'Chemical', 'MESH:D015120', (145, 149))	('FA', 'Gene', '84027', (14, 16))	('responses', 'MPA', (121, 130))	('WZB117', 'Chemical', 'MESH:C576807', (134, 140))	('BAP1', 'Gene', (84, 88))	('mutant', 'Var', (89, 95))
70586	33208912	Since MP46 have elevated FA metabolism, we probed key metabolic enzymes involved in FAO in OXPHOSlow BAP1 mutant cells.	('mutant', 'Var', (106, 112))	('FA', 'Gene', '84027', (25, 27))	('elevate', 'Disease', 'MESH:D006973', (16, 23))	('FA', 'Gene', '84027', (84, 86))	('MP46', 'Var', (6, 10))	('elevate', 'Disease', (16, 23))	('metabolism', 'biological_process', 'GO:0008152', ('28', '38'))
70588	33208912	To investigate whether increased CPT1A expression represents a potential therapeutic vulnerability in OXPHOSlow BAP1 mutant cells, we targeted FAO with IACS (a selective inhibitor of mitochondrial ETC complex I,) or etomoxir (ETO, a CPT1 inhibitor) and determined changes in cell growth.	('BAP1', 'Gene', (112, 116))	('complex I', 'cellular_component', 'GO:0030964', ('201', '210'))	('CPT1', 'Gene', '1374', (33, 37))	('mutant', 'Var', (117, 123))	('CPT1', 'Gene', (33, 37))	('CPT', 'molecular_function', 'GO:0004142', ('33', '36'))	('cell growth', 'biological_process', 'GO:0016049', ('275', '286'))	('CPT1', 'Gene', '1374', (233, 237))	('ETO', 'Chemical', 'MESH:C054207', (226, 229))	('CPT1A', 'Gene', (33, 38))	('increased', 'PosReg', (23, 32))	('CPT', 'molecular_function', 'GO:0004095', ('33', '36'))	('expression', 'MPA', (39, 49))	('CPT', 'molecular_function', 'GO:0004095', ('233', '236'))	('CPT', 'molecular_function', 'GO:0004142', ('233', '236'))	('FA', 'Gene', '84027', (143, 145))	('CPT1', 'Gene', (233, 237))	('CPT1A', 'Gene', '1374', (33, 38))
70590	33208912	Since OXPHOShigh BAP1 mutant cells have a metabolic dependency on glucose utilization and nucleotide biosynthesis over FA metabolism, we predicted that these cells would respond poorly to FAO inhibitors.	('metabolic', 'MPA', (42, 51))	('glucose utilization', 'MPA', (66, 85))	('metabolism', 'biological_process', 'GO:0008152', ('122', '132'))	('mutant', 'Var', (22, 28))	('nucleotide biosynthesis', 'biological_process', 'GO:0009165', ('90', '113'))	('glucose', 'Chemical', 'MESH:D005947', (66, 73))	('FA', 'Gene', '84027', (188, 190))	('FA', 'Gene', '84027', (119, 121))
70591	33208912	As hypothesized, neither IACS nor ETO elicited a significant effect on the survival of MP65 and MP38 (Supplementary Fig 4a).	('MP65', 'Var', (87, 91))	('ETO', 'Chemical', 'MESH:C054207', (34, 37))	('MP38', 'Var', (96, 100))
70592	33208912	In comparison to MP46-BAP1, the predominant (56%) metabolites increased in MP46 were related to nucleotide biosynthesis pathways, while most metabolite decreases were associated with amino acid and FA metabolism (Fig.	('increased', 'PosReg', (62, 71))	('nucleotide biosynthesis', 'biological_process', 'GO:0009165', ('96', '119'))	('MP46', 'Var', (75, 79))	('nucleotide biosynthesis pathways', 'MPA', (96, 128))	('amino acid', 'MPA', (183, 193))	('decreases', 'NegReg', (152, 161))	('metabolite', 'MPA', (141, 151))	('metabolites', 'MPA', (50, 61))	('FA', 'Gene', '84027', (198, 200))	('metabolism', 'biological_process', 'GO:0008152', ('201', '211'))
70593	33208912	We further investigated the metabolite levels related to FA metabolism and observed MP46 had significantly lower levels of FAs and palmitoylcarnitine, which is involved in FA transport into mitochondria for oxidation compared to MP46-BAP1, but higher acetyl-carnitine levels, a byproduct of FAO (Supplementary Fig 4c).	('palmitoylcarnitine', 'MPA', (131, 149))	('acetyl-carnitine levels', 'MPA', (251, 274))	('MP46', 'Var', (84, 88))	('mitochondria', 'cellular_component', 'GO:0005739', ('190', '202'))	('metabolism', 'biological_process', 'GO:0008152', ('60', '70'))	('lower', 'NegReg', (107, 112))	('transport', 'biological_process', 'GO:0006810', ('175', '184'))	('acetyl-carnitine', 'Chemical', 'MESH:D000108', (251, 267))	('FA', 'Gene', '84027', (57, 59))	('palmitoylcarnitine', 'Chemical', 'MESH:D010172', (131, 149))	('FA', 'Gene', '84027', (291, 293))	('levels', 'MPA', (113, 119))	('FA', 'Gene', '84027', (123, 125))	('higher', 'PosReg', (244, 250))	('FA', 'Gene', '84027', (172, 174))
70594	33208912	We also found that BAP1 re-expression in MP46 reduced enzyme levels related to FAO, CPT1A and CPT1C (Fig.	('CPT1A', 'Gene', '1374', (84, 89))	('FA', 'Gene', '84027', (79, 81))	('MP46', 'Gene', (41, 45))	('CPT', 'molecular_function', 'GO:0004142', ('94', '97'))	('reduced', 'NegReg', (46, 53))	('CPT', 'molecular_function', 'GO:0004095', ('94', '97'))	('CPT', 'molecular_function', 'GO:0004142', ('84', '87'))	('CPT1A', 'Gene', (84, 89))	('re-expression', 'Var', (24, 37))	('enzyme levels', 'MPA', (54, 67))	('CPT', 'molecular_function', 'GO:0004095', ('84', '87'))	('CPT1C', 'Gene', '126129', (94, 99))	('CPT1C', 'Gene', (94, 99))
70595	33208912	Together, these results imply that FAO is enhanced in MP46 and this effect is reversed following BAP1 re-expression.	('FA', 'Gene', '84027', (35, 37))	('enhanced', 'PosReg', (42, 50))	('MP46', 'Var', (54, 58))
70597	33208912	First, we measured FA utilization levels between MP46 and MP46-BAP1 by incubating cells with palmitate (PAL) as the only oxidizable energy substrate.	('MP46-BAP1', 'Var', (58, 67))	('PAL', 'Chemical', 'MESH:D010168', (104, 107))	('palmitate', 'Chemical', 'MESH:D010168', (93, 102))	('MP46', 'Var', (49, 53))	('FA', 'Gene', '84027', (19, 21))	('PAL', 'molecular_function', 'GO:0004598', ('104', '107'))
70598	33208912	Following PAL treatment, OCR levels increased significantly in MP46, but were unchanged in MP46-BAP1 (Supplementary Fig 4d), suggesting that MP46 utilized or metabolized FA more efficiently than MP46-BAP1.	('PAL', 'Chemical', 'MESH:D010168', (10, 13))	('PAL', 'molecular_function', 'GO:0004598', ('10', '13'))	('increased', 'PosReg', (36, 45))	('FA', 'Gene', '84027', (170, 172))	('MP46', 'Var', (141, 145))	('OCR levels', 'MPA', (25, 35))	('metabolized', 'MPA', (158, 169))
70603	33208912	Overall, we observed that cell lines, which metabolically represent OXPHOSlow BAP1 mutant UM preferentially utilize FAO-dependent metabolic pathways.	('UM', 'Phenotype', 'HP:0007716', (90, 92))	('mutant', 'Var', (83, 89))	('preferentially', 'PosReg', (93, 107))	('FA', 'Gene', '84027', (116, 118))	('BAP1', 'Gene', (78, 82))
70605	33208912	These findings suggest that FAO inhibitors may be used to treat OXPHOSlow BAP1 mutant UM.	('UM', 'Phenotype', 'HP:0007716', (86, 88))	('mutant', 'Var', (79, 85))	('BAP1', 'Gene', (74, 78))	('FA', 'Gene', '84027', (28, 30))
70610	33208912	Of note, BAP1 expression was increased in hypoxic conditions in MP46-BAP1 (Fig 5b), implying the association between hypoxic-induced HIF1alpha and exogenous BAP1 expression.	('HIF1alpha', 'Gene', (133, 142))	('MP46-BAP1', 'Var', (64, 73))	('HIF1alpha', 'Gene', '3091', (133, 142))	('increased', 'PosReg', (29, 38))	('association', 'Interaction', (97, 108))	('expression', 'MPA', (14, 24))	('BAP1', 'Gene', (9, 13))
70611	33208912	This suggests that the distinct metabolic profiles (OXPHOShigh and OXPHOSlow) within BAP1 mutant UM is related to different patient survival outcomes.	('BAP1', 'Gene', (85, 89))	('UM', 'Phenotype', 'HP:0007716', (97, 99))	('mutant', 'Var', (90, 96))	('patient', 'Species', '9606', (124, 131))	('metabolic', 'MPA', (32, 41))	('related', 'Reg', (103, 110))
70613	33208912	Our results thus far have shown that distinct metabolic phenotypes in BAP1 mutant UM, OXPHOShigh or OXPHOSlow, have increased glycolysis and nucleotide synthesis or increased FA metabolism, respectively.	('metabolism', 'biological_process', 'GO:0008152', ('178', '188'))	('glycolysis', 'biological_process', 'GO:0006096', ('126', '136'))	('nucleotide synthesis', 'biological_process', 'GO:0009165', ('141', '161'))	('glycolysis', 'MPA', (126, 136))	('nucleotide synthesis', 'MPA', (141, 161))	('UM', 'Phenotype', 'HP:0007716', (82, 84))	('BAP1', 'Gene', (70, 74))	('mutant', 'Var', (75, 81))	('increased', 'PosReg', (116, 125))	('increased', 'PosReg', (165, 174))	('FA', 'Gene', '84027', (175, 177))
70615	33208912	We determined differences in gene expression and metabolite levels between MP65 and MP46 in pyrimidine and purine metabolism pathways, further supporting that the two BAP1 mutant cell lines have different profiles (Supplementary Fig 6a and 6b).	('purine metabolism', 'biological_process', 'GO:0042278', ('107', '124'))	('mutant', 'Var', (172, 178))	('purine metabolism', 'biological_process', 'GO:0006163', ('107', '124'))	('MP46', 'Var', (84, 88))	('purine metabolism', 'biological_process', 'GO:0006144', ('107', '124'))	('differences', 'Reg', (14, 25))	('metabolite levels', 'MPA', (49, 66))	('MP65', 'Var', (75, 79))	('gene expression', 'biological_process', 'GO:0010467', ('29', '44'))	('purine', 'Chemical', 'MESH:C030985', (107, 113))	('pyrimidine', 'Chemical', 'MESH:C030986', (92, 102))	('BAP1', 'Gene', (167, 171))	('gene expression', 'MPA', (29, 44))
70617	33208912	1b, we observed that patient samples separated BAP1 mutant (group 1 and 2) and BAP1 wild-type samples (Fig.	('patient', 'Species', '9606', (21, 28))	('BAP1', 'Gene', (47, 51))	('mutant', 'Var', (52, 58))
70618	33208912	Comparing the two subgroups within BAP1 mutant UM patient tumors and cell lines, GSEA plots showed that the OXPHOShigh subtype has upregulated gene expression of nucleotide and FA metabolism compared to OXPHOSlow subtype (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('FA', 'Gene', '84027', (177, 179))	('metabolism', 'biological_process', 'GO:0008152', ('180', '190'))	('gene expression', 'biological_process', 'GO:0010467', ('143', '158'))	('GSEA', 'Chemical', '-', (81, 85))	('BAP1', 'Gene', (35, 39))	('mutant', 'Var', (40, 46))	('upregulated', 'PosReg', (131, 142))	('patient', 'Species', '9606', (50, 57))
70619	33208912	Under metabolic stress, OXPHOShigh BAP1 mutant UM may increase utilization of nucleotide and FA metabolic pathways that allows them to be more resistant to metabolic stress than OXPHOSlow BAP1 mutant UM.	('resistant', 'MPA', (143, 152))	('UM', 'Phenotype', 'HP:0007716', (200, 202))	('increase', 'PosReg', (54, 62))	('utilization', 'MPA', (63, 74))	('FA', 'Gene', '84027', (93, 95))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('mutant', 'Var', (40, 46))	('nucleotide', 'Pathway', (78, 88))
70621	33208912	Here, we observed that BAP1 mutant UM exhibits metabolic heterogeneity based on OXPHOS gene expression profiles using both cell line and patient data.	('BAP1', 'Gene', (23, 27))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('mutant', 'Var', (28, 34))	('gene expression', 'biological_process', 'GO:0010467', ('87', '102'))	('patient', 'Species', '9606', (137, 144))	('OXPHOS', 'biological_process', 'GO:0002082', ('80', '86'))
70623	33208912	Our studies demonstrate that metabolism can be a new therapeutic target for BAP1 mutant UM and that the two subtypes of tumor cells respond differently to selective inhibitors according to their metabolic profiles.	('mutant UM', 'Var', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('metabolism', 'biological_process', 'GO:0008152', ('29', '39'))	('BAP1', 'Gene', (76, 80))	('UM', 'Phenotype', 'HP:0007716', (88, 90))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
70625	33208912	BAP1 mutations are highly correlated with advanced UM and poor patient survival; moreover, loss of BAP1 shapes transcriptional features of metastatic UM.	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('BAP1', 'Gene', (99, 103))	('BAP1', 'Gene', (0, 4))	('transcriptional', 'MPA', (111, 126))	('metastatic UM', 'Disease', (139, 152))	('mutations', 'Var', (5, 14))	('patient', 'Species', '9606', (63, 70))	('UM', 'Phenotype', 'HP:0007716', (150, 152))	('loss', 'Var', (91, 95))
70628	33208912	Cells that carry germline BAP1 mutations exhibit the Warburg effect, which renders these cells susceptible to malignancy.	('BAP1', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('malignancy', 'Disease', 'MESH:D009369', (110, 120))	('malignancy', 'Disease', (110, 120))	('Warburg effect', 'Disease', (53, 67))
70629	33208912	Similar to our observations with patient data, we found that the BAP1 mutant cell lines have different OXPHOS gene expression and metabolic characteristics, thereby confirming that BAP1 mutations result in metabolic heterogeneity in UM.	('metabolic characteristics', 'MPA', (130, 155))	('patient', 'Species', '9606', (33, 40))	('BAP1', 'Gene', (181, 185))	('mutations', 'Var', (186, 195))	('metabolic heterogeneity', 'MPA', (206, 229))	('mutant', 'Var', (70, 76))	('OXPHOS gene expression', 'MPA', (103, 125))	('BAP1', 'Gene', (65, 69))	('different', 'Reg', (93, 102))	('OXPHOS', 'biological_process', 'GO:0002082', ('103', '109'))	('result in', 'Reg', (196, 205))	('UM', 'Phenotype', 'HP:0007716', (233, 235))	('gene expression', 'biological_process', 'GO:0010467', ('110', '125'))
70633	33208912	We identified two distinct metabolic phenotypes in BAP1 mutant UM cells, which have either increased glycolysis-nucleotide biosynthesis or FAO.	('BAP1', 'Gene', (51, 55))	('UM', 'Phenotype', 'HP:0007716', (63, 65))	('mutant', 'Var', (56, 62))	('FA', 'Gene', '84027', (139, 141))	('glycolysis', 'biological_process', 'GO:0006096', ('101', '111'))	('nucleotide biosynthesis', 'biological_process', 'GO:0009165', ('112', '135'))	('increased', 'PosReg', (91, 100))	('glycolysis-nucleotide biosynthesis', 'MPA', (101, 135))
70638	33208912	Our data showed that inhibitors of nucleotide biosynthesis and FAO selectively suppressed BAP1 mutant cell growth according to their metabolic profiles with modest or no effect on cells that re-express BAP1 or wild-type UM cells.	('nucleotide biosynthesis', 'biological_process', 'GO:0009165', ('35', '58'))	('UM', 'Phenotype', 'HP:0007716', (220, 222))	('FA', 'Gene', '84027', (63, 65))	('suppressed', 'NegReg', (79, 89))	('BAP1', 'Gene', (90, 94))	('cell growth', 'biological_process', 'GO:0016049', ('102', '113'))	('metabolic', 'MPA', (133, 142))	('mutant', 'Var', (95, 101))
70639	33208912	Remodeling metabolism allows cancer cells to meet increased bioenergetic and biosynthetic needs for high growth rate; thus, it is possible that the different metabolic dependencies between BAP1 wild-type and BAP1 mutant UM cells are correlated to their different growth rates, requiring the further investigations in the future studies.	('UM', 'Phenotype', 'HP:0007716', (220, 222))	('BAP1', 'Gene', (189, 193))	('Remodeling metabolism allows cancer', 'Disease', (0, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('metabolism', 'biological_process', 'GO:0008152', ('11', '21'))	('Remodeling metabolism allows cancer', 'Disease', 'MESH:D009369', (0, 35))	('BAP1', 'Gene', (208, 212))	('mutant', 'Var', (213, 219))
70642	33208912	We found that OXPHOShigh BAP1 mutant cells survive better under metabolic stress than OXPHOSlow BAP1 mutant cells, which might come from transcriptional upregulation of both nucleotide and FA metabolic pathways.	('upregulation', 'PosReg', (153, 165))	('mutant', 'Var', (30, 36))	('nucleotide', 'Pathway', (174, 184))	('FA', 'Gene', '84027', (189, 191))
70645	33208912	In contrast with our in vitro results, there was no significant difference in overall patient survival between OXPHOShigh and OXPHOSlow phenotypes within BAP1 mutant UM.	('patient', 'Species', '9606', (86, 93))	('UM', 'Phenotype', 'HP:0007716', (166, 168))	('mutant UM', 'Var', (159, 168))	('BAP1', 'Gene', (154, 158))
70646	33208912	These findings can likely be explained by the fact that the BAP1 mutation itself, through its role in metastasis, is a strong influencer of patient survival in UM.	('patient', 'Species', '9606', (140, 147))	('UM', 'Phenotype', 'HP:0007716', (160, 162))	('influencer', 'Reg', (126, 136))	('mutation', 'Var', (65, 73))	('BAP1', 'Gene', (60, 64))
70647	33208912	We found two metabolically distinct subgroups in BAP1 mutant UM: OXPHOShigh, a glycolytic phenotype and OXPHOSlow, an FAO-dependent phenotype (Fig.	('mutant', 'Var', (54, 60))	('BAP1', 'Gene', (49, 53))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('FA', 'Gene', '84027', (118, 120))
70648	33208912	The OXPHOShigh phenotype have enhanced glucose utilization and nucleotide biosynthesis, making them more sensitive to glycolysis and nucleotide biosynthesis inhibitors.	('nucleotide biosynthesis', 'MPA', (63, 86))	('enhanced', 'PosReg', (30, 38))	('nucleotide biosynthesis', 'biological_process', 'GO:0009165', ('133', '156'))	('OXPHOShigh', 'Var', (4, 14))	('glucose', 'Chemical', 'MESH:D005947', (39, 46))	('more', 'PosReg', (100, 104))	('nucleotide biosynthesis', 'biological_process', 'GO:0009165', ('63', '86'))	('glucose utilization', 'MPA', (39, 58))	('glycolysis', 'biological_process', 'GO:0006096', ('118', '128'))	('sensitive to glycolysis', 'MPA', (105, 128))
70650	33208912	Our findings indicate that targeting cancer cell metabolism can be a promising therapeutic option for BAP1 mutant UM, especially when tailored to the metabolic heterogeneity present in BAP1 mutant UM.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('BAP1', 'Gene', (102, 106))	('mutant', 'Var', (107, 113))	('cancer', 'Disease', (37, 43))	('BAP1', 'Gene', (185, 189))	('UM', 'Phenotype', 'HP:0007716', (114, 116))	('UM', 'Phenotype', 'HP:0007716', (197, 199))	('metabolism', 'biological_process', 'GO:0008152', ('49', '59'))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
70652	33208912	MM66, MP46, MP65, and MP38 cell lines were obtained from Dr. Sergio Roman-Roman (Paris, France) and confirmed to harbor GNAQ, GNA11, or BAP1 mutation by Sanger DNA sequencing.	('BAP1', 'Gene', (136, 140))	('GNAQ', 'Gene', (120, 124))	('GNA11', 'Gene', (126, 131))	('DNA', 'cellular_component', 'GO:0005574', ('160', '163'))	('GNA11', 'Gene', '2767', (126, 131))	('mutation', 'Var', (141, 149))	('GNAQ', 'Gene', '2776', (120, 124))
70653	33208912	PDX4 was from Thomas Jefferson University and confirmed GNA11 or BAP1 mutation by Sanger sequencing.	('BAP1', 'Gene', (65, 69))	('PDX4', 'Gene', (0, 4))	('mutation', 'Var', (70, 78))	('GNA11', 'Gene', (56, 61))	('GNA11', 'Gene', '2767', (56, 61))
70656	33208912	Primary antibodies were: BAP1 (#13271), HK 1 (#2024), GLUT1 (#12939), GLUT4 (#2213), and CPT1A (#12252) from Cell Signaling Technology (Danvers, MA); CPT1C (ab123794) Abcam (Cambridge, UK); GLUT3 (sc-30107), G6PD (sc-373886), and TKT (sc-390179) from Santa Cruz Biotechnology (Santa Cruz, CA) and beta-actin from Sigma-Aldrich (St. Louis, MO).	('CPT1A', 'Gene', (89, 94))	('TKT', 'Gene', (230, 233))	('GLUT1', 'Gene', (54, 59))	('#12939', 'Var', (61, 67))	('HK 1', 'Gene', (40, 44))	('CPT', 'molecular_function', 'GO:0004095', ('89', '92'))	('ab123794', 'Var', (157, 165))	('Signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('#2213', 'Var', (77, 82))	('GLUT3', 'Gene', '6515', (190, 195))	('CPT', 'molecular_function', 'GO:0004142', ('150', '153'))	('#13271', 'Var', (31, 37))	('sc-390179', 'Var', (235, 244))	('CPT', 'molecular_function', 'GO:0004142', ('89', '92'))	('HK 1', 'molecular_function', 'GO:0004673', ('40', '44'))	('CPT1C', 'Gene', '126129', (150, 155))	('CPT1C', 'Gene', (150, 155))	('HK 1', 'Gene', '3098', (40, 44))	('GLUT1', 'Gene', '6513', (54, 59))	('GLUT3', 'Gene', (190, 195))	('G6PD', 'Gene', '2539', (208, 212))	('GLUT4', 'Gene', (70, 75))	('CPT', 'molecular_function', 'GO:0004095', ('150', '153'))	('CPT1A', 'Gene', '1374', (89, 94))	('sc-373886', 'Var', (214, 223))	('#12252', 'Var', (96, 102))	('G6PD', 'Gene', (208, 212))	('TKT', 'Gene', '7086', (230, 233))	('GLUT4', 'Gene', '6517', (70, 75))
70665	28059929	Multivariate analysis showed improved HPFS for PHP versus Y90 (P = 0.004), PHP versus CE (P = 0.02) but not for CE versus Y90.	('Y90', 'Chemical', 'MESH:C000615496', (122, 125))	('Y90', 'Chemical', 'MESH:C000615496', (58, 61))	('PHP', 'Var', (47, 50))	('HPFS', 'MPA', (38, 42))	('improved', 'PosReg', (29, 37))	('PHP', 'Var', (75, 78))
70669	28059929	Only PHP treatment versus Y90 and lower tumor burden had improved OS on multivariate analysis (P = 0.03, 0.03, respectively).	('PHP', 'Var', (5, 8))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('improved', 'PosReg', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('Y90', 'Chemical', 'MESH:C000615496', (26, 29))
70670	28059929	HPFS and PFS were significantly prolonged in patients treated with PHP versus CE or Y90.	('prolonged', 'PosReg', (32, 41))	('HPFS', 'CPA', (0, 4))	('patients', 'Species', '9606', (45, 53))	('PHP', 'Var', (67, 70))	('Y90', 'Chemical', 'MESH:C000615496', (84, 87))	('PFS', 'CPA', (9, 12))
70688	28059929	We performed a retrospective study to evaluate the outcomes of hepatic progression-free survival (HPFS), progression-free survival (PFS), and overall survival (OS) in highly selected patients with hepatic recurrence treated with Y90, PHP, or CE.	('hepatic', 'Disease', (197, 204))	('PHP', 'Gene', (234, 237))	('hepatic', 'MPA', (63, 70))	('Y90', 'Chemical', 'MESH:C000615496', (229, 232))	('Y90', 'Var', (229, 232))	('patients', 'Species', '9606', (183, 191))
70689	28059929	After obtaining Institutional Review Board approval, a single institution retrospective review of all patients treated with Y90, PHP, or CE for unresectable hepatic metastases secondary to uveal or cutaneous melanoma from 2008 to 2014 was conducted.	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('patients', 'Species', '9606', (102, 110))	('cutaneous melanoma', 'Disease', (198, 216))	('Y90', 'Chemical', 'MESH:C000615496', (124, 127))	('hepatic metastases', 'Disease', (157, 175))	('Y90', 'Var', (124, 127))	('uveal or cutaneous melanoma', 'Phenotype', 'HP:0007716', (189, 216))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (198, 216))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (198, 216))	('hepatic metastases', 'Disease', 'MESH:D009362', (157, 175))
70701	28059929	Y90 radioembolization of hepatic tumors has been proven to be a safe method of radiation delivery which minimizes the risk of systemic toxicity.	('Y90', 'Chemical', 'MESH:C000615496', (0, 3))	('hepatic tumors', 'Disease', 'MESH:D056486', (25, 39))	('Y90', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('hepatic tumors', 'Disease', (25, 39))	('toxicity', 'Disease', 'MESH:D064420', (135, 143))	('toxicity', 'Disease', (135, 143))
70723	28059929	There was a difference in the location of the primary tumor, with a majority of patients undergoing Y90 having uveal melanoma, whereas cutaneous melanoma was more common in the other treatment groups (Fisher's exact test; P = 0.002) (Table 1).	('uveal melanoma', 'Phenotype', 'HP:0007716', (111, 125))	('uveal melanoma', 'Disease', 'MESH:C536494', (111, 125))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('patients', 'Species', '9606', (80, 88))	('cutaneous melanoma', 'Disease', (135, 153))	('uveal melanoma', 'Disease', (111, 125))	('Y90', 'Chemical', 'MESH:C000615496', (100, 103))	('Y90', 'Var', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (135, 153))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (135, 153))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
70725	28059929	MVA showed significantly improved HPFS for PHP versus Y90 (hazard ratio [HR], 0.11, 95% confidence interval [CI], 0.03, 0.49; P = 0.004), PHP versus CE (HR, 0.31, 95% CI, 0.12, 0.81; P = 0.02) but not for CE versus Y90 (HR, 0.36, 95% CI, 0.089, 1.51; P = 0.17).	('improved', 'PosReg', (25, 33))	('HPFS', 'MPA', (34, 38))	('PHP', 'Var', (138, 141))	('Y90', 'Chemical', 'MESH:C000615496', (215, 218))	('Y90', 'Chemical', 'MESH:C000615496', (54, 57))	('PHP', 'Var', (43, 46))
70728	28059929	There was a significant difference in median PFS: Y90 54 days; PHP 245 days, and CE 52 days; Log-rank test, P = 0.03 (Fig.	('PHP 245', 'Var', (63, 70))	('Y90', 'Chemical', 'MESH:C000615496', (50, 53))	('CE 52', 'Var', (81, 86))	('Y90 54 days', 'Var', (50, 61))
70729	28059929	MVA showed improved PFS for PHP versus Y90 (HR, 0.17, 95% CI, 0.04, 0.63; P = 0.008), PHP versus CE (HR, 0.37, 95% CI, 0.14, 0.94; P = 0.04) but not for CE versus Y90 (HR, 0.46, 95% CI, 0.13, 1.65; P = 0.23).	('PFS', 'MPA', (20, 23))	('improved', 'PosReg', (11, 19))	('PHP', 'Var', (86, 89))	('PHP', 'Var', (28, 31))	('Y90', 'Chemical', 'MESH:C000615496', (163, 166))	('Y90', 'Chemical', 'MESH:C000615496', (39, 42))
70731	28059929	Median OS from time of treatment was longest for PHP at 608 days versus Y90 295 days or CE 265 days.	('Y90', 'Var', (72, 75))	('PHP', 'Var', (49, 52))	('Y90', 'Chemical', 'MESH:C000615496', (72, 75))
70738	28059929	The application of Y90 in the treatment of metastatic melanoma, although less well studied than its use for colorectal cancer and hepatocellular carcinoma, has been reported in the literature as safe and efficacious.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (130, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('melanoma', 'Disease', (54, 62))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('colorectal cancer', 'Disease', (108, 125))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (130, 154))	('Y90', 'Chemical', 'MESH:C000615496', (19, 22))	('Y90', 'Var', (19, 22))	('hepatocellular carcinoma', 'Disease', (130, 154))
70758	28059929	There was a difference, however, seen in HPFS and PFS and in OS for patients undergoing PHP compared with Y90 and these findings are important for discussing treatment options with patients and prompting additional studies to confirm these results.	('PFS', 'CPA', (50, 53))	('Y90', 'Chemical', 'MESH:C000615496', (106, 109))	('patients', 'Species', '9606', (68, 76))	('patients', 'Species', '9606', (181, 189))	('HPFS', 'Disease', (41, 45))	('PHP', 'Var', (88, 91))
70763	31285370	BAP1 loss is associated with DNA methylomic repatterning in highly aggressive Class 2 uveal melanomas The strong association between BAP1 mutations and metastasizing Class 2 uveal melanoma (UM) suggests that epigenetic alterations may play a significant role in tumor progression.	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('uveal melanomas', 'Phenotype', 'HP:0007716', (86, 101))	('loss', 'NegReg', (5, 9))	('BAP1', 'Gene', '8314', (133, 137))	('uveal melanomas', 'Disease', (86, 101))	('BAP1', 'Gene', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (92, 101))	('BAP1', 'Gene', (133, 137))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('tumor', 'Disease', (262, 267))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('uveal melanoma', 'Disease', 'MESH:C536494', (174, 188))	('uveal melanoma', 'Disease', (174, 188))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('uveal melanomas', 'Disease', 'MESH:C536494', (86, 101))	('mutations', 'Var', (138, 147))	('uveal melanoma', 'Disease', 'MESH:C536494', (86, 100))	('UM', 'Disease', 'MESH:C536494', (190, 192))	('uveal melanoma', 'Phenotype', 'HP:0007716', (174, 188))	('BAP1', 'Gene', '8314', (0, 4))
70767	31285370	Hypermethylation on chromosome 3 correlated with downregulated gene expression at several loci, including 3p21 where BAP1 is located.	('gene expression', 'biological_process', 'GO:0010467', ('63', '78'))	('BAP1', 'Gene', '8314', (117, 121))	('Hypermethylation', 'Var', (0, 16))	('p21', 'Gene', (107, 110))	('p21', 'Gene', '644914', (107, 110))	('BAP1', 'Gene', (117, 121))	('gene expression', 'MPA', (63, 78))	('downregulated', 'NegReg', (49, 62))	('chromosome', 'cellular_component', 'GO:0005694', ('20', '30'))
70770	31285370	In functional validation experiments, BAP1 knockdown in UM cells induced methylomic repatterning similar to UM tumors, enriched for genes involved in axon guidance, melanogenesis, and development.	('UM', 'Disease', 'MESH:C536494', (56, 58))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('BAP1', 'Gene', (38, 42))	('UM', 'Disease', 'MESH:C536494', (108, 110))	('axon', 'cellular_component', 'GO:0030424', ('150', '154'))	('knockdown', 'Var', (43, 52))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('axon guidance', 'biological_process', 'GO:0007411', ('150', '163'))	('methylomic repatterning', 'MPA', (73, 96))	('induced', 'Reg', (65, 72))	('BAP1', 'Gene', '8314', (38, 42))
70771	31285370	This study, coupled with previous work, suggests that the initial event in the divergence of Class 2 UM from Class 1 UM is loss of one copy of chromosome 3, followed by mutation of BAP1 on the remaining copy of chromosome 3, leading to the methylomic repatterning profile characteristic of Class 2 UMs.	('mutation', 'Var', (169, 177))	('UM', 'Disease', 'MESH:C536494', (117, 119))	('UMs', 'Disease', (298, 301))	('BAP1', 'Gene', (181, 185))	('UMs', 'Disease', 'MESH:C536494', (298, 301))	('chromosome', 'cellular_component', 'GO:0005694', ('143', '153'))	('loss', 'NegReg', (123, 127))	('UM', 'Disease', 'MESH:C536494', (101, 103))	('methylomic repatterning profile', 'MPA', (240, 271))	('chromosome', 'cellular_component', 'GO:0005694', ('211', '221'))	('BAP1', 'Gene', '8314', (181, 185))	('UM', 'Disease', 'MESH:C536494', (298, 300))
70772	31285370	We provide evidence that bi-allelic loss of BAP1 leads to extensive methylomic repatterning that results in the highly aggressive Class 2 phenotype, thereby providing a more complete picture of UM genomic evolution and potentially explaining the loss of melanocytic differentiation and gain of neural crest-like migratory behavior in Class 2 UM.	('loss of melanocytic differentiation', 'Disease', (246, 281))	('results in', 'Reg', (97, 107))	('highly aggressive Class 2 phenotype', 'MPA', (112, 147))	('loss', 'Var', (36, 40))	('gain', 'PosReg', (286, 290))	('loss of melanocytic differentiation', 'Disease', 'MESH:D009508', (246, 281))	('BAP1', 'Gene', '8314', (44, 48))	('UM', 'Disease', 'MESH:C536494', (342, 344))	('neural crest-like migratory behavior', 'CPA', (294, 330))	('UM', 'Disease', 'MESH:C536494', (194, 196))	('BAP1', 'Gene', (44, 48))
70780	31285370	We previously found that Class 2 UMs harbor loss-of-function mutations in BAP1, located on chromosome 3p21, and that the other copy of BAP1 is lost as a result of monosomy 3 or isodisomy 3, thereby fulfilling Knudson's "two hit" hypothesis for tumor suppressors.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('UMs', 'Disease', 'MESH:C536494', (33, 36))	('tumor', 'Disease', (244, 249))	('p21', 'Gene', (103, 106))	('BAP1', 'Gene', '8314', (135, 139))	('mutations', 'Var', (61, 70))	('BAP1', 'Gene', '8314', (74, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('91', '101'))	('BAP1', 'Gene', (135, 139))	('p21', 'Gene', '644914', (103, 106))	('monosomy 3', 'Var', (163, 173))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('BAP1', 'Gene', (74, 78))	('UMs', 'Disease', (33, 36))	('loss-of-function', 'NegReg', (44, 60))
70781	31285370	The discovery of BAP1 mutations finally explained the association between monosomy 3 and poor prognosis in UM that had been known for almost three decades with no mechanistic explanation.	('poor', 'Disease', (89, 93))	('UM', 'Disease', 'MESH:C536494', (107, 109))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('monosomy 3', 'Var', (74, 84))	('BAP1', 'Gene', (17, 21))
70782	31285370	However, in contrast to other BAP1-associated cancers such as renal cell carcinoma and mesothelioma, where BAP1 is frequently eliminated by regional deletions around the gene locus, Class 2 UMs demonstrate complete loss of an entire copy of chromosome 3.	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('chromosome', 'cellular_component', 'GO:0005694', ('241', '251'))	('BAP1', 'Gene', '8314', (30, 34))	('UMs', 'Disease', (190, 193))	('BAP1', 'Gene', '8314', (107, 111))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (62, 82))	('cancers', 'Disease', (46, 53))	('mesothelioma', 'Disease', (87, 99))	('loss', 'NegReg', (215, 219))	('deletions', 'Var', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mesothelioma', 'Disease', 'MESH:D008654', (87, 99))	('UMs', 'Disease', 'MESH:C536494', (190, 193))	('BAP1', 'Gene', (30, 34))	('BAP1', 'Gene', (107, 111))	('renal cell carcinoma', 'Disease', (62, 82))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (62, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
70783	31285370	Indeed, partial deletion of chromosome 3 is associated with low risk Class 1 UMs.	('chromosome', 'cellular_component', 'GO:0005694', ('28', '38'))	('UMs', 'Disease', (77, 80))	('UMs', 'Disease', 'MESH:C536494', (77, 80))	('partial deletion', 'Var', (8, 24))
70785	31285370	One possibility is that haploinsufficiency for multiple genes across the chromosome may be required for malignant progression, but this is unlikely since isodisomy 3 (loss of one copy of chromosome 3 and duplication of the remaining BAP1 mutation-bearing copy of chromosome 3) confers the same Class 2 GEP and metastatic risk as monosomy 3.	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('chromosome', 'cellular_component', 'GO:0005694', ('263', '273'))	('BAP1', 'Gene', (233, 237))	('metastatic', 'CPA', (310, 320))	('haploinsufficiency', 'Disease', 'MESH:D058495', (24, 42))	('chromosome', 'cellular_component', 'GO:0005694', ('187', '197'))	('loss', 'NegReg', (167, 171))	('haploinsufficiency', 'Disease', (24, 42))	('Class 2 GEP', 'Disease', (294, 305))	('BAP1', 'Gene', '8314', (233, 237))	('duplication', 'Var', (204, 215))
70786	31285370	A second possibility is that other tumor suppressor genes on chromosome 3 are also mutated in Class 2 tumors, and that these must also be reduced to homozygosity in order for the Class 2 phenotype to emerge.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('mutated', 'Var', (83, 90))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (35, 40))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('chromosome', 'cellular_component', 'GO:0005694', ('61', '71'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
70788	31285370	A third possibility is that the retained copy of chromosome 3 in Class 2 tumors contains not only a mutant copy of BAP1, but also epigenetic alterations that are required for the Class 2 phenotype.	('mutant', 'Var', (100, 106))	('BAP1', 'Gene', '8314', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('49', '59'))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('epigenetic alterations', 'Var', (130, 152))	('BAP1', 'Gene', (115, 119))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
70790	31285370	BAP1-mutant Class 2 UMs exhibit extensive non-random alterations in DNA methylation, many of which are located on chromosome 3 and some of which may be specifically triggered by loss of BAP1.	('triggered', 'Reg', (165, 174))	('loss', 'Var', (178, 182))	('DNA methylation', 'biological_process', 'GO:0006306', ('68', '83'))	('BAP1', 'Gene', (0, 4))	('chromosome', 'cellular_component', 'GO:0005694', ('114', '124'))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('UMs', 'Disease', (20, 23))	('DNA methylation', 'MPA', (68, 83))	('alterations', 'Reg', (53, 64))	('UMs', 'Disease', 'MESH:C536494', (20, 23))	('BAP1', 'Gene', '8314', (186, 190))	('BAP1', 'Gene', (186, 190))	('BAP1', 'Gene', '8314', (0, 4))
70807	31285370	Short hairpin RNA (shRNA) vectors targeting CGTCCGTGATTGATGATGATA, CCCTGTATATGGATTTATCTT, and CCACAACTACGATGAGTTCAT of human BAP1 cDNA (shBAP1) were individually cloned into a pLKO-TET-puro vector (Addgene #21915) and packaged into lentiviral particles by transient transfection into H293T cells, as previously described.	('H293T', 'SUBSTITUTION', 'None', (284, 289))	('BAP1', 'Gene', '8314', (138, 142))	('BAP1', 'Gene', '8314', (125, 129))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('H293T', 'Var', (284, 289))	('BAP1', 'Gene', (138, 142))	('BAP1', 'Gene', (125, 129))	('human', 'Species', '9606', (119, 124))
70810	31285370	Cells were clonally selected for optimal doxycycline-inducible BAP1 knockdown (>85% knockdown) and expanded for use in this study.	('BAP1', 'Gene', (63, 67))	('BAP1', 'Gene', '8314', (63, 67))	('knockdown', 'Var', (68, 77))	('doxycycline', 'Chemical', 'MESH:D004318', (41, 52))
70818	31285370	Genes with significant hypermethylation/downregulation or hypomethylation/upregulation from the BAP1KD cells (p < 0.05) were compared with hypermethylated/downregulated and hypomethylated/upregulated genes from the TCGA dataset (FDR < 0.05).	('hypomethylation/upregulation', 'Var', (58, 86))	('BAP1', 'Gene', (96, 100))	('hypermethylation/downregulation', 'NegReg', (23, 54))	('hypomethylation/upregulation', 'PosReg', (58, 86))	('BAP1', 'Gene', '8314', (96, 100))
70820	31285370	Primary UMs can be divided based on DNA methylomic profiling into two groups that correspond to BAP1 mutation status and clinical GEP classification (Class 1 versus Class 2).	('BAP1', 'Gene', (96, 100))	('UMs', 'Disease', (8, 11))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('UMs', 'Disease', 'MESH:C536494', (8, 11))	('mutation', 'Var', (101, 109))	('BAP1', 'Gene', '8314', (96, 100))
70821	31285370	To elucidate methylation changes associated with BAP1 mutations, we performed unsupervised principal component analysis (PCA) of the top 20% most differentially methylated probes on two datasets, including the 80 TCGA samples and 12 independent samples from our center, both analyzed on the Infinium Human Methylation 450K BeadChip array (Supplementary Table S2).	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('BAP1', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('Human', 'Species', '9606', (300, 305))	('Methylation', 'biological_process', 'GO:0032259', ('306', '317'))	('BAP1', 'Gene', '8314', (49, 53))
70824	31285370	Hypermethylated probes in Class 2 UMs relative to Class 1 UMs (FDR < 0.05) were most enriched within "shore" regions 1000-1500 bp upstream of transcription start sites (TSS-1500), followed by "shore" regions in the 5'UTR and "shelf" regions within the TSS-1500 (Fig.	('transcription', 'biological_process', 'GO:0006351', ('140', '153'))	('UMs', 'Disease', (58, 61))	('Hypermethylated', 'Var', (0, 15))	('UMs', 'Disease', 'MESH:C536494', (58, 61))	('UMs', 'Disease', (34, 37))	('UMs', 'Disease', 'MESH:C536494', (34, 37))
70825	31285370	Hypomethylated probes in Class 2 UMs relative to Class 1 UMs (FDR < 0.05) were most enriched in open sea regions.	('UMs', 'Disease', (57, 60))	('Hypomethylated', 'Var', (0, 14))	('UMs', 'Disease', 'MESH:C536494', (33, 36))	('UMs', 'Disease', 'MESH:C536494', (57, 60))	('UMs', 'Disease', (33, 36))
70829	31285370	As hypermethylation in promoter regions is usually associated with gene silencing, we identified genes with hypermethylation associated with decreased gene expression (hypermethylated/downregulated) or hypomethylation associated with increased gene expression (hypomethylated/upregulated) in Class 2 UMs relative to Class 1 UMs (Fig.	('increased', 'PosReg', (234, 243))	('gene expression', 'biological_process', 'GO:0010467', ('151', '166'))	('hypomethylation', 'Var', (202, 217))	('hypermethylation', 'Var', (108, 124))	('gene expression', 'biological_process', 'GO:0010467', ('244', '259'))	('gene silencing', 'biological_process', 'GO:0016458', ('67', '81'))	('gene expression', 'MPA', (151, 166))	('decreased', 'NegReg', (141, 150))	('hypermethylated/downregulated', 'NegReg', (168, 197))	('UMs', 'Disease', (324, 327))	('gene expression', 'MPA', (244, 259))	('UMs', 'Disease', (300, 303))	('UMs', 'Disease', 'MESH:C536494', (324, 327))	('UMs', 'Disease', 'MESH:C536494', (300, 303))
70830	31285370	Out of the twelve genes in the GEP test, six of the eight downregulated genes were hypermethylated (FXR1, ID2, ROBO1, LMCD1, SATB1, and MTUS1) and all four of the upregulated genes were hypomethylated (HTR2B, ECM1, RAB31, CDH1).	('CDH1', 'Gene', '999', (222, 226))	('HTR2B', 'Gene', (202, 207))	('downregulated', 'NegReg', (58, 71))	('CDH1', 'Gene', (222, 226))	('ROBO1', 'Gene', (111, 116))	('upregulated', 'PosReg', (163, 174))	('hypermethylated', 'Var', (83, 98))	('RAB31', 'Gene', (215, 220))	('ECM1', 'Gene', (209, 213))	('RAB31', 'Gene', '11031', (215, 220))	('ID2', 'Gene', '3398', (106, 109))	('ID2', 'Gene', (106, 109))	('ECM1', 'Gene', '1893', (209, 213))	('FXR1', 'Gene', '8087', (100, 104))	('ROBO1', 'Gene', '6091', (111, 116))	('MTUS1', 'Gene', (136, 141))	('hypomethylated', 'Var', (186, 200))	('MTUS1', 'Gene', '57509', (136, 141))	('FXR1', 'Gene', (100, 104))	('LMCD1', 'Gene', '29995', (118, 123))	('SATB1', 'Gene', (125, 130))	('LMCD1', 'Gene', (118, 123))	('HTR2B', 'Gene', '3357', (202, 207))	('SATB1', 'Gene', '6304', (125, 130))
70831	31285370	Similar to our global analysis, hypermethylated/downregulated genes in Class 2 tumors were enriched within the promoter and 5'UTR "shore" and "shelf" regions (Fig.	('hypermethylated/downregulated', 'Var', (32, 61))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
70832	31285370	2B), and hypomethylated/upregulated genes in Class 2 tumors occurred mostly in open sea regions.	('hypomethylated/upregulated', 'Var', (9, 35))	('hypomethylated/upregulated', 'PosReg', (9, 35))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
70835	31285370	Interestingly, 6p21 contains regions of both hypomethylated/upregulated and hypermethylated/downregulated genes in Class 2 tumors, but only the former is enriched for HLA genes, which are known to be expressed as part of the altered immune microenvironment in Class 2 tumors.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('hypomethylated/upregulated', 'PosReg', (45, 71))	('p21', 'Gene', (16, 19))	('tumors', 'Disease', (268, 274))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('tumors', 'Disease', 'MESH:D009369', (268, 274))	('p21', 'Gene', '644914', (16, 19))	('hypomethylated/upregulated', 'Var', (45, 71))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
70844	31285370	Interestingly, however, BAP1 is located within one of the hypermethylated/downregulated loci on chromosome 3 (3p21) and contained two significantly hypermethylated CpG probe sites (FDR < 0.05), one of which was located within the gene body (cg16871520) and the other in the 3'UTR (cg21746711)(Fig.	('BAP1', 'Gene', (24, 28))	('cg21746711', 'Var', (281, 291))	('p21', 'Gene', (111, 114))	('cg16871520', 'Var', (241, 251))	('p21', 'Gene', '644914', (111, 114))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('BAP1', 'Gene', '8314', (24, 28))
70845	31285370	The cg16871520 probe demonstrated the most significant inverse Spearman correlation coefficient between BAP1 gene expression and methylation (R=-0.79, p < 0.001).	('gene expression', 'biological_process', 'GO:0010467', ('109', '124'))	('BAP1', 'Gene', '8314', (104, 108))	('BAP1', 'Gene', (104, 108))	('expression', 'MPA', (114, 124))	('inverse', 'NegReg', (55, 62))	('cg16871520', 'Var', (4, 14))	('methylation', 'biological_process', 'GO:0032259', ('129', '140'))	('methylation', 'MPA', (129, 140))
70853	31285370	Consistent with findings in Class 2 UMs, development, axon guidance, and melanogenesis pathways were significantly enriched (FDR < 0.05) for genes with hypermethylated probes (FDR < 0.05) in the BAP1KD UM cell lines, which also showed the most significant hypermethylated loci enrichment for chromosomal band 3p21, where BAP1 is located, as well as another locus on chromosome 3 at 3q21 (FDR < 0.05, Supplementary Table S5).	('BAP1', 'Gene', (321, 325))	('UMs', 'Disease', 'MESH:C536494', (36, 39))	('UM', 'Disease', 'MESH:C536494', (202, 204))	('melanogenesis', 'CPA', (73, 86))	('BAP1', 'Gene', (195, 199))	('axon', 'cellular_component', 'GO:0030424', ('54', '58'))	('hypermethylated', 'Var', (256, 271))	('UM', 'Disease', 'MESH:C536494', (36, 38))	('axon guidance', 'biological_process', 'GO:0007411', ('54', '67'))	('development', 'CPA', (41, 52))	('p21', 'Gene', (310, 313))	('BAP1', 'Gene', '8314', (321, 325))	('axon guidance', 'CPA', (54, 67))	('UMs', 'Disease', (36, 39))	('chromosome', 'cellular_component', 'GO:0005694', ('366', '376'))	('p21', 'Gene', '644914', (310, 313))	('BAP1', 'Gene', '8314', (195, 199))	('enriched', 'Reg', (115, 123))
70854	31285370	Similarly to the Class 2 UMs, immune function, focal adhesion, and axon guidance pathways were significantly enriched for hypomethylated genes (FDR < 0.05).	('UMs', 'Disease', (25, 28))	('hypomethylated genes', 'Var', (122, 142))	('UMs', 'Disease', 'MESH:C536494', (25, 28))	('focal', 'CPA', (47, 52))	('focal adhesion', 'cellular_component', 'GO:0005925', ('47', '61'))	('axon', 'cellular_component', 'GO:0030424', ('67', '71'))	('immune function', 'CPA', (30, 45))	('axon guidance', 'CPA', (67, 80))	('axon guidance', 'biological_process', 'GO:0007411', ('67', '80'))
70856	31285370	Again, development, axon guidance, and melanogenesis were among the pathways most significantly enriched for hypermethylated/downregulated genes in BAP1KD UM cell lines (FDR < 0.05), whereas loci on chromosome 3 were no longer significantly enriched (Supplementary Table S6).	('hypermethylated/downregulated', 'NegReg', (109, 138))	('axon guidance', 'CPA', (20, 33))	('BAP1', 'Gene', '8314', (148, 152))	('UM', 'Disease', 'MESH:C536494', (155, 157))	('hypermethylated/downregulated', 'Var', (109, 138))	('development', 'CPA', (7, 18))	('melanogenesis', 'CPA', (39, 52))	('axon', 'cellular_component', 'GO:0030424', ('20', '24'))	('enriched', 'Reg', (96, 104))	('BAP1', 'Gene', (148, 152))	('axon guidance', 'biological_process', 'GO:0007411', ('20', '33'))	('chromosome', 'cellular_component', 'GO:0005694', ('199', '209'))
70857	31285370	Hypomethylated/upregulated genes from the BAP1KD cells were significantly enriched for pathways involved in apoptosis and cell death (FDR < 0.05).	('BAP1', 'Gene', '8314', (42, 46))	('Hypomethylated/upregulated', 'PosReg', (0, 26))	('BAP1', 'Gene', (42, 46))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('cell death', 'biological_process', 'GO:0008219', ('122', '132'))	('Hypomethylated/upregulated', 'Var', (0, 26))
70859	31285370	Next, we compared BAP1KD cells to Class 2 UMs from the TCGA dataset, and we found 31 hypermethylated/downregulated and 9 hypomethylated/upregulated genes shared in common.	('BAP1', 'Gene', '8314', (18, 22))	('UMs', 'Disease', (42, 45))	('hypermethylated/downregulated', 'NegReg', (85, 114))	('BAP1', 'Gene', (18, 22))	('hypomethylated/upregulated', 'PosReg', (121, 147))	('hypermethylated/downregulated', 'Var', (85, 114))	('UMs', 'Disease', 'MESH:C536494', (42, 45))
70861	31285370	For individual probes, only two exact probe sites (one on PC and one on PALMD) were shared for the hypermethylated/downregulated genes and one (ZEB1) for the hypomethylated/upregulated genes.	('PALMD', 'Gene', (72, 77))	('PALMD', 'Gene', '54873', (72, 77))	('hypermethylated/downregulated', 'Var', (99, 128))	('ZEB1', 'Gene', '6935', (144, 148))	('ZEB1', 'Gene', (144, 148))
70863	31285370	Overall, these findings confirm that loss of BAP1 leads to DNA methylomic repatterning, as recently described in liver cancer, with the most extensive changes in UM occurring in the axon guidance and melanogenesis pathways.	('axon', 'cellular_component', 'GO:0030424', ('182', '186'))	('axon guidance', 'biological_process', 'GO:0007411', ('182', '195'))	('liver cancer', 'Disease', (113, 125))	('BAP1', 'Gene', (45, 49))	('BAP1', 'Gene', '8314', (45, 49))	('DNA methylomic repatterning', 'MPA', (59, 86))	('changes', 'Reg', (151, 158))	('UM', 'Disease', 'MESH:C536494', (162, 164))	('liver cancer', 'Phenotype', 'HP:0002896', (113, 125))	('loss', 'Var', (37, 41))	('liver cancer', 'Disease', 'MESH:D006528', (113, 125))	('leads to', 'Reg', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))
70864	31285370	Here, we found that Class 2/BAP1 mutant UMs share a common DNA methylation profile reflecting extensive methylomic repatterning compared to Class 1/BAP1 wildtype UMs.	('BAP1', 'Gene', '8314', (28, 32))	('DNA methylation', 'biological_process', 'GO:0006306', ('59', '74'))	('UMs', 'Disease', 'MESH:C536494', (40, 43))	('BAP1', 'Gene', '8314', (148, 152))	('DNA methylation profile', 'MPA', (59, 82))	('BAP1', 'Gene', (28, 32))	('UMs', 'Disease', (162, 165))	('BAP1', 'Gene', (148, 152))	('mutant', 'Var', (33, 39))	('UMs', 'Disease', (40, 43))	('UMs', 'Disease', 'MESH:C536494', (162, 165))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))
70868	31285370	For example, the hypermethylated/downregulated axon guidance genes ROBO1, PLXNB1, SEMA3B, and CHL1 are involved in neuronal/neural crest migration but have been implicated as tumor suppressors, whereas the hypomethylated/upregulated SEMA3E is an axonal path finding gene that increases tumor invasiveness and metastatic spread.	('SEMA3E', 'Gene', (233, 239))	('ROBO1', 'Gene', '6091', (67, 72))	('SEMA3B', 'Gene', '7869', (82, 88))	('axon guidance', 'biological_process', 'GO:0007411', ('47', '60'))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('metastatic spread', 'CPA', (309, 326))	('CHL1', 'Gene', (94, 98))	('increases tumor invasiveness', 'Disease', (276, 304))	('SEMA3B', 'Gene', (82, 88))	('increases tumor invasiveness', 'Disease', 'MESH:D009369', (276, 304))	('tumor', 'Disease', (175, 180))	('SEMA3E', 'Gene', '9723', (233, 239))	('tumor', 'Disease', (286, 291))	('PLXNB1', 'Gene', (74, 80))	('axon', 'cellular_component', 'GO:0030424', ('47', '51'))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('CHL1', 'Gene', '10752', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('PLXNB1', 'Gene', '5364', (74, 80))	('ROBO1', 'Gene', (67, 72))	('hypermethylated/downregulated', 'Var', (17, 46))	('axon guidance', 'Gene', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
70873	31285370	Since all but three Class 2 tumors in this analysis had detectable inactivating BAP1 mutations, it is not clear how hypermethylation of the gene would be functionally relevant to conversion to Class 2.	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('BAP1', 'Gene', '8314', (80, 84))	('mutations', 'Var', (85, 94))	('BAP1', 'Gene', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('inactivating', 'MPA', (67, 79))
70874	31285370	BAP1 may negatively regulate its own methylation, as it does with the neural crest and melanogenesis genes described above, such that loss of BAP1 could lead to hypermethylation of the remaining allele as a "passenger event" in the absence of selective pressure, though this was not seen in the BAP1KD cells.	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('BAP1', 'Gene', (0, 4))	('BAP1', 'Gene', (295, 299))	('BAP1', 'Gene', '8314', (142, 146))	('BAP1', 'Gene', '8314', (0, 4))	('BAP1', 'Gene', (142, 146))	('hypermethylation', 'MPA', (161, 177))	('BAP1', 'Gene', '8314', (295, 299))	('loss', 'Var', (134, 138))	('lead to', 'Reg', (153, 160))	('methylation', 'MPA', (37, 48))
70876	31285370	This is consistent with a recent large study that identified BAP1 as one of several genes in which mutations were associated with global methylomic alterations.	('BAP1', 'Gene', (61, 65))	('global methylomic', 'MPA', (130, 147))	('mutations', 'Var', (99, 108))	('associated', 'Reg', (114, 124))	('BAP1', 'Gene', '8314', (61, 65))
70877	31285370	When pairing methylation and RNA-Seq datasets, the hypermethylated/downregulated genes in the BAP1KD cells maintained enrichment for axon guidance and melanogenesis pathways, however, enrichment for loci on chromosome 3 was not maintained.	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('BAP1', 'Gene', '8314', (94, 98))	('axon', 'cellular_component', 'GO:0030424', ('133', '137'))	('axon guidance', 'biological_process', 'GO:0007411', ('133', '146'))	('hypermethylated/downregulated', 'NegReg', (51, 80))	('BAP1', 'Gene', (94, 98))	('RNA', 'cellular_component', 'GO:0005562', ('29', '32'))	('hypermethylated/downregulated', 'Var', (51, 80))	('chromosome', 'cellular_component', 'GO:0005694', ('207', '217'))	('melanogenesis pathways', 'Pathway', (151, 173))	('axon guidance', 'CPA', (133, 146))
70879	31285370	Of note, we would not expect the depletion of BAP1 in 92.1 or Mel202 cells to precisely recapitulate the methylation or GEP findings in actual human Class 2 UMs.	('human', 'Species', '9606', (143, 148))	('depletion', 'Var', (33, 42))	('UMs', 'Disease', (157, 160))	('BAP1', 'Gene', '8314', (46, 50))	('UMs', 'Disease', 'MESH:C536494', (157, 160))	('methylation', 'biological_process', 'GO:0032259', ('105', '116'))	('BAP1', 'Gene', (46, 50))
70883	31285370	Finally, knocking down BAP1 is not equivalent to knocking down expression of the entire chromosome 3, which occurs in Class 2 UMs and is required for the Class 2 GEP.	('BAP1', 'Gene', (23, 27))	('knocking', 'Var', (49, 57))	('UMs', 'Disease', (126, 129))	('knocking down', 'Var', (9, 22))	('BAP1', 'Gene', '8314', (23, 27))	('UMs', 'Disease', 'MESH:C536494', (126, 129))	('chromosome', 'cellular_component', 'GO:0005694', ('88', '98'))
70888	31285370	Therefore, taken in context with previous work showing the evolution of genomic aberrations in UM, we hypothesize that the initial event presaging the divergence of Class 2 UM from Class 1 UM is loss of one copy of chromosome 3, which is followed by mutation of BAP1 on the other copy of chromosome 3, which then leads to the methylomic repatterning characteristic of Class 2 UMs.	('BAP1', 'Gene', '8314', (262, 266))	('chromosome', 'cellular_component', 'GO:0005694', ('288', '298'))	('mutation', 'Var', (250, 258))	('chromosome', 'cellular_component', 'GO:0005694', ('215', '225'))	('UM', 'Disease', 'MESH:C536494', (189, 191))	('BAP1', 'Gene', (262, 266))	('UM', 'Disease', 'MESH:C536494', (95, 97))	('UM', 'Disease', 'MESH:C536494', (376, 378))	('UM', 'Disease', 'MESH:C536494', (173, 175))	('loss', 'NegReg', (195, 199))	('UMs', 'Disease', 'MESH:C536494', (376, 379))	('UMs', 'Disease', (376, 379))
70890	29641532	Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers While a number of autosomal dominant and autosomal recessive cancer syndromes have an associated spectrum of cancers, the prevalence and variety of cancer predisposition mutations in patients with multiple primary cancers have not been extensively investigated.	('Germline mutations', 'Var', (0, 18))	('cutaneous melanoma', 'Disease', (73, 91))	('cancer syndromes', 'Disease', (209, 225))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (73, 91))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('autosomal recessive cancer syndrome', 'Disease', 'MESH:D009386', (189, 224))	('autosomal recessive cancer syndrome', 'Disease', (189, 224))	('patients', 'Species', '9606', (331, 339))	('cancer syndromes', 'Disease', 'MESH:D009369', (209, 225))	('cancers', 'Disease', 'MESH:D009369', (362, 369))	('cancer', 'Disease', 'MESH:D009369', (362, 368))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('primary cancers', 'Disease', 'MESH:D009369', (354, 369))	('primary cancers', 'Disease', 'MESH:D009369', (132, 147))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (257, 264))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancer', 'Disease', (140, 146))	('cancers', 'Disease', (257, 264))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('cancers', 'Phenotype', 'HP:0002664', (362, 369))	('cancer', 'Disease', (362, 368))	('cancers', 'Disease', (362, 369))	('primary cancers', 'Disease', (354, 369))	('cancer', 'Disease', (257, 263))	('primary cancers', 'Disease', (132, 147))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('cancer', 'Disease', (209, 215))	('cancers', 'Disease', (140, 147))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('cancer', 'Disease', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
70891	29641532	An understanding of the variants predisposing to more than one cancer type could improve patient care, including screening and genetic counselling, as well as advancing the understanding of tumour development.	('tumour', 'Disease', (190, 196))	('improve', 'PosReg', (81, 88))	('patient', 'Species', '9606', (89, 96))	('variants', 'Var', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))	('tumour', 'Disease', 'MESH:D009369', (190, 196))
70894	29641532	We focussed on variants in 525 pre-selected genes, including 65 autosomal dominant and 31 autosomal recessive cancer predisposition genes, 116 genes involved in the DNA repair pathway, and 313 commonly somatically mutated in cancer.	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('DNA repair', 'biological_process', 'GO:0006281', ('165', '175'))	('autosomal recessive cancer', 'Disease', (90, 116))	('cancer', 'Disease', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('pre', 'molecular_function', 'GO:0003904', ('31', '34'))	('autosomal recessive cancer', 'Disease', 'MESH:D009369', (90, 116))	('variants', 'Var', (15, 23))	('DNA', 'cellular_component', 'GO:0005574', ('165', '168'))	('autosomal dominant', 'Disease', (64, 82))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
70896	29641532	No known pathogenic autosomal dominant or previously described compound heterozygous mutations in autosomal recessive genes were observed in the multiple cancer cohort.	('autosomal recessive genes', 'Gene', (98, 123))	('multiple cancer', 'Disease', 'MESH:D009369', (145, 160))	('compound heterozygous mutations', 'Var', (63, 94))	('multiple cancer', 'Disease', (145, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
70897	29641532	Variants typically found somatically in haematological malignancies (in JAK1, JAK2, SF3B1, SRSF2, TET2 and TYK2) were present in lymphocyte DNA of patients with multiple primary cancers, all of whom had a history of haematological malignancy and cutaneous melanoma, as well as colorectal cancer and/or prostate cancer.	('Variants', 'Var', (0, 8))	('SF3B1', 'Gene', '23451', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('JAK', 'molecular_function', 'GO:0004713', ('78', '81'))	('TYK2', 'Gene', (107, 111))	('primary cancers', 'Disease', (170, 185))	('melanoma', 'Phenotype', 'HP:0002861', (256, 264))	('JAK', 'molecular_function', 'GO:0004713', ('72', '75'))	('cutaneous melanoma', 'Disease', (246, 264))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (246, 264))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (246, 264))	('haematological malignancy', 'Disease', 'MESH:D019337', (216, 241))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('JAK2', 'Gene', '3717', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('JAK1', 'Gene', (72, 76))	('prostate cancer', 'Disease', 'MESH:D011471', (302, 317))	('TYK2', 'Gene', '7297', (107, 111))	('prostate cancer', 'Phenotype', 'HP:0012125', (302, 317))	('colorectal cancer', 'Disease', 'MESH:D015179', (277, 294))	('patients', 'Species', '9606', (147, 155))	('TET2', 'Gene', (98, 102))	('SRSF2', 'Gene', '6427', (91, 96))	('prostate cancer', 'Disease', (302, 317))	('haematological malignancies', 'Disease', (40, 67))	('colorectal cancer', 'Disease', (277, 294))	('SRSF2', 'Gene', (91, 96))	('JAK2', 'Gene', (78, 82))	('primary cancers', 'Disease', 'MESH:D009369', (170, 185))	('SF3B1', 'Gene', (84, 89))	('JAK1', 'Gene', '3716', (72, 76))	('TET2', 'Gene', '54790', (98, 102))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('haematological malignancy', 'Disease', (216, 241))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('haematological malignancies', 'Disease', 'MESH:D019337', (40, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (277, 294))
70898	29641532	Other potentially pathogenic variants were discovered in BUB1B, POLE2, ROS1 and DNMT3A.	('BUB1B', 'Gene', (57, 62))	('ROS1', 'Gene', '6098', (71, 75))	('pathogenic', 'Reg', (18, 28))	('variants', 'Var', (29, 37))	('BUB1B', 'Gene', '701', (57, 62))	('POLE2', 'Gene', (64, 69))	('DNMT3A', 'Gene', (80, 86))	('DNMT3A', 'Gene', '1788', (80, 86))	('ROS1', 'Gene', (71, 75))	('POLE2', 'Gene', '5427', (64, 69))
70899	29641532	Compared to controls, multiple cancer cases had significantly more likely damaging mutations (nonsense, frameshift ins/del) in tumour suppressor and tyrosine kinase genes and higher overall burden of mutations in all cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('frameshift ins/del', 'Var', (104, 122))	('higher', 'PosReg', (175, 181))	('multiple cancer', 'Disease', 'MESH:D009369', (22, 37))	('tyrosine kinase', 'Gene', '7294', (149, 164))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('tyrosine kinase', 'Gene', (149, 164))	('tumour', 'Disease', (127, 133))	('cancer', 'Disease', (31, 37))	('multiple cancer', 'Disease', (22, 37))
70900	29641532	We identified several pathogenic variants that likely predispose to at least one of the tumours in patients with multiple cancers.	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('pathogenic', 'Reg', (22, 32))	('patients', 'Species', '9606', (99, 107))	('multiple cancers', 'Disease', (113, 129))	('tumours', 'Disease', (88, 95))	('predispose', 'Reg', (54, 64))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('multiple cancers', 'Disease', 'MESH:D009369', (113, 129))	('variants', 'Var', (33, 41))
70901	29641532	We additionally present evidence that there may be a higher burden of variants of unknown significance in 'cancer genes' in patients with multiple cancer types.	('multiple cancer', 'Disease', 'MESH:D009369', (138, 153))	("'cancer", 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('variants', 'Var', (70, 78))	("'cancer", 'Disease', (106, 113))	('multiple cancer', 'Disease', (138, 153))	('patients', 'Species', '9606', (124, 132))
70902	29641532	Further screens of this nature need to be carried out to build evidence to show if the cancers observed in these patients form part of a cancer spectrum associated with single germline variants in these genes, whether multiple layers of susceptibility exist (oligogenic or polygenic), or if the occurrence of multiple different cancers is due to random chance.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (87, 93))	('cancers', 'Disease', (87, 94))	('variants', 'Var', (185, 193))	('patients', 'Species', '9606', (113, 121))	('cancers', 'Disease', 'MESH:D009369', (328, 335))	('cancers', 'Phenotype', 'HP:0002664', (328, 335))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (328, 334))	('cancers', 'Disease', (328, 335))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('cancer', 'Disease', (137, 143))	('associated', 'Reg', (153, 163))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))
70904	29641532	CM risk is heritable and high penetrance germline mutations in CDKN2A, CDK4, BAP1, MITF, TERT, POT1, ACD, TERF2IP and POLE have been reported to contribute to CM development in some high density melanoma families.	('ACD', 'Gene', '65057', (101, 104))	('CDKN2A', 'Gene', '1029', (63, 69))	('TERF2IP', 'Gene', '54386', (106, 113))	('germline', 'Var', (41, 49))	('POT1', 'Gene', '25913', (95, 99))	('CDK4', 'Gene', '1019', (71, 75))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('POT1', 'Gene', (95, 99))	('BAP1', 'Gene', '8314', (77, 81))	('ACD', 'Gene', (101, 104))	('contribute', 'Reg', (145, 155))	('CDK', 'molecular_function', 'GO:0004693', ('71', '74'))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('MITF', 'Gene', '4286', (83, 87))	('CDKN2A', 'Gene', (63, 69))	('BAP1', 'Gene', (77, 81))	('CDK4', 'Gene', (71, 75))	('TERT', 'Gene', (89, 93))	('TERT', 'Gene', '7015', (89, 93))	('MITF', 'Gene', (83, 87))	('TERF2IP', 'Gene', (106, 113))
70906	29641532	Notably, GWAS hits have been proximal to three genes involved in DNA repair, ATM, also an autosomal recessive cancer gene, (11q22-q23; rs73008229, genome-wide significance = 1.4x10-12), PARP1 (1q42.12; rs3219090, genome-wide significance = 7.1x10-12) and RAD23B (9q31.2; rs10739221, genome-wide significance = 9.6x10-9); however the exact mechanisms behind risks associated with these GWAS hits have yet to be ascertained.	('11q22-q23; rs73008229', 'Var', (124, 145))	('RAD', 'biological_process', 'GO:1990116', ('255', '258'))	('autosomal recessive cancer', 'Disease', (90, 116))	('ATM', 'Gene', (77, 80))	('PARP1', 'Gene', '142', (186, 191))	('PARP1', 'Gene', (186, 191))	('ATM', 'Gene', '472', (77, 80))	('rs73008229', 'Var', (135, 145))	('rs3219090', 'Mutation', 'rs3219090', (202, 211))	('rs3219090', 'Var', (202, 211))	('RAD23B', 'Gene', '5887', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('rs73008229', 'Mutation', 'rs73008229', (135, 145))	('DNA repair', 'biological_process', 'GO:0006281', ('65', '75'))	('autosomal recessive cancer', 'Disease', 'MESH:D009369', (90, 116))	('RAD23B', 'Gene', (255, 261))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('rs10739221', 'Mutation', 'rs10739221', (271, 281))
70907	29641532	Additionally, pathogenic variants in BRCA1 and BRCA2, autosomal dominant cancer risk genes, both crucial in the process of homologous recombination DNA repair, increase risks to CM and uveal melanoma (UM), as well as several other cancer types including breast and ovarian cancer).	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('uveal melanoma', 'Disease', (185, 199))	('uveal melanoma', 'Disease', 'MESH:C536494', (185, 199))	('homologous recombination', 'biological_process', 'GO:0035825', ('123', '147'))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (254, 279))	('cancer', 'Disease', (73, 79))	('variants', 'Var', (25, 33))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('cancer', 'Disease', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('BRCA2', 'Gene', (47, 52))	('DNA repair', 'biological_process', 'GO:0006281', ('148', '158'))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('uveal melanoma', 'Phenotype', 'HP:0007716', (185, 199))	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (265, 279))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (54, 79))	('autosomal dominant cancer', 'Disease', (54, 79))	('BRCA2', 'Gene', '675', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('BRCA1', 'Gene', '672', (37, 42))	('BRCA1', 'Gene', (37, 42))
70909	29641532	Together, these data suggest a potential role for aberrations in DNA repair genes in the susceptibility to CM, UM and other cancers.	('aberrations', 'Var', (50, 61))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('DNA repair genes', 'Gene', (65, 81))	('DNA repair', 'biological_process', 'GO:0006281', ('65', '75'))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
70910	29641532	Recent evidence has shown an increased burden in pathogenic/probably pathogenic mutations in previously described 'cancer' genes (associated with autosomal dominant, autosomal recessive, cancer predisposition GWAS hits, or somatic driver events) in patients with paediatric cancer, compared to two control populations.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (115, 121))	('autosomal recessive', 'Disease', (166, 185))	('pathogenic/probably', 'CPA', (49, 68))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', (187, 193))	('patients', 'Species', '9606', (249, 257))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (274, 280))	("'cancer", 'Disease', 'MESH:D009369', (114, 121))	('autosomal dominant', 'Disease', (146, 164))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	("'cancer", 'Disease', (114, 121))
70912	29641532	This study found that 3% of all variants identified were classified as deleterious and that 85% of all variants identified were of unknown significance; importantly, every individual carried multiple rare nonsynonymous variants in these genes, with an average of 68 variants/person (range:49-97).	('variants', 'Var', (32, 40))	('person', 'Species', '9606', (275, 281))	('variants', 'Var', (219, 227))
70916	29641532	Here, we hypothesise that mutations in a curated 'cancer gene' list and/or DNA repair genes are key elements to the cancer susceptibility in individuals with three or more primary cancers.	('primary cancers', 'Disease', (172, 187))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	("'cancer", 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('primary cancers', 'Disease', 'MESH:D009369', (172, 187))	('DNA repair genes', 'Gene', (75, 91))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('mutations', 'Var', (26, 35))	("'cancer", 'Disease', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('DNA repair', 'biological_process', 'GO:0006281', ('75', '85'))	('cancer', 'Disease', (180, 186))
70917	29641532	We have therefore undertaken an investigation of 525 'cancer' or DNA repair genes and describe the prevalence and spectrum of germline variants in this cohort of multiple cancer patients, compared to a control (non-cancer) cohort.	("'cancer", 'Disease', (53, 60))	('multiple cancer', 'Disease', 'MESH:D009369', (162, 177))	('non-cancer', 'Disease', (211, 221))	('non-cancer', 'Disease', 'MESH:D009369', (211, 221))	('patients', 'Species', '9606', (178, 186))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('DNA repair genes', 'Gene', (65, 81))	('variants', 'Var', (135, 143))	('DNA repair', 'biological_process', 'GO:0006281', ('65', '75'))	("'cancer", 'Disease', 'MESH:D009369', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('multiple cancer', 'Disease', (162, 177))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
70930	29641532	Sanger validation was performed on frameshift mutations in the multiple cancer cohort to ensure the correct base pairs were called for the in/del.	('multiple cancer', 'Disease', 'MESH:D009369', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('frameshift mutations', 'Var', (35, 55))	('multiple cancer', 'Disease', (63, 78))
70931	29641532	Variants were assessed using four in silico tools that predict whether an amino acid alteration affects protein function: SIFT, PolyPhen-2, likelihood ratio test and Mutation Taster.	('SIFT', 'Disease', 'None', (122, 126))	('protein function', 'MPA', (104, 120))	('SIFT', 'Disease', (122, 126))	('affects', 'Reg', (96, 103))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('amino acid alteration', 'Var', (74, 95))
70938	29641532	Of the 57 individuals with three or more distinct primary tumours, 53 instances of non-silent mutation were identified from the 63 autosomal dominant cancer predisposition genes at a Kaviar aggregate population frequency of less than 1:100 (47 missense, 1 splicing, 1 nonsense, and 4 non-frameshift ins/dels).	('primary tumours', 'Disease', (50, 65))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('missense', 'Var', (244, 252))	('non-frameshift ins/dels', 'Var', (284, 307))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (131, 156))	('splicing', 'biological_process', 'GO:0045292', ('256', '264'))	('autosomal dominant cancer', 'Disease', (131, 156))	('splicing', 'Var', (256, 264))	('nonsense', 'Var', (268, 276))	('primary tumours', 'Disease', 'MESH:D009369', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
70939	29641532	The nonsense mutation (CBL p.E658X) results in the termination of the protein product 249 amino acids prematurely and the removal of the vital tyrosinases at p. 700, 731 and 774, which are the key phosphorylation sites.	('protein', 'Protein', (70, 77))	('tyrosinases', 'Enzyme', (143, 154))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('phosphorylation', 'biological_process', 'GO:0016310', ('197', '212'))	('termination', 'MPA', (51, 62))	('p.E658X', 'Var', (27, 34))	('p.E658X', 'Mutation', 'p.E658X', (27, 34))	('removal', 'NegReg', (122, 129))	('CBL', 'Gene', (23, 26))	('CBL', 'Gene', '867', (23, 26))
70941	29641532	Pathogenic mutations described to date require a functional tyrosine kinase binding domain (TKB, from p.51 - 349) and disruption of the alpha-helix formed between the TKB and RING domains; the truncating mutation in our cohort (p.Glu658X) does not disrupt this interaction.	('mutations', 'Var', (11, 20))	('tyrosine kinase', 'Gene', (60, 75))	('alpha-helix formed', 'MPA', (136, 154))	('p.Glu658X', 'Var', (228, 237))	('tyrosine kinase binding', 'molecular_function', 'GO:1990782', ('60', '83'))	('tyrosine kinase', 'Gene', '7294', (60, 75))	('p.Glu658X', 'Mutation', 'p.E658X', (228, 237))
70942	29641532	Additionally, the RASopathy associated mutations cluster around the RING domain, with described mutations occurring from p.Q367-R420, which is before the protein disruption described in our patient.	('p.Q367-R420', 'Var', (121, 132))	('RASopathy', 'Disease', 'None', (18, 27))	('mutations', 'Var', (39, 48))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('RASopathy', 'Disease', (18, 27))	('mutations', 'Var', (96, 105))	('patient', 'Species', '9606', (190, 197))
70944	29641532	Of the 47 missense mutations observed, 1 was present in <1:2000 in the Kaviar population and predicted as damaging by all four in silico prediction algorithms (BRCA2 p.A75P rs28897701).	('rs28897701', 'DBSNP_MENTION', 'None', (173, 183))	('BRCA2', 'Gene', (160, 165))	('missense mutations', 'Var', (10, 28))	('p.A75P', 'Var', (166, 172))	('BRCA2', 'Gene', '675', (160, 165))	('p.A75P', 'SUBSTITUTION', 'None', (166, 172))	('rs28897701', 'Var', (173, 183))
70945	29641532	The BRCA2 p.A75P mutation is, however, not classified as predisposing to breast/ovarian cancer by LOVD, or ClinVar.	('p.A75P', 'Var', (10, 16))	('breast/ovarian cancer', 'Disease', 'MESH:D010051', (73, 94))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('p.A75P', 'SUBSTITUTION', 'None', (10, 16))	('breast/ovarian cancer', 'Disease', (73, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('BRCA2', 'Gene', (4, 9))	('BRCA2', 'Gene', '675', (4, 9))
70946	29641532	Additionally, a variant in APC (p.E2445D rs587782127) was predicted as damaging by the three algorithms able to assess it; this variant is classified as being of unknown significance by three submitters in ClinVar and the individual carrying the variant has not had colorectal cancer, commonly associated with APC germline mutations, to date.	('APC', 'Disease', (310, 313))	('colorectal cancer', 'Disease', (266, 283))	('p.E2445D', 'Var', (32, 40))	('APC', 'Disease', 'MESH:D011125', (27, 30))	('rs587782127', 'Var', (41, 52))	('rs587782127', 'DBSNP_MENTION', 'None', (41, 52))	('variant', 'Var', (246, 253))	('APC', 'cellular_component', 'GO:0005680', ('310', '313'))	('APC', 'Disease', (27, 30))	('colorectal cancer', 'Disease', 'MESH:D015179', (266, 283))	('APC', 'cellular_component', 'GO:0005680', ('27', '30'))	('p.E2445D', 'SUBSTITUTION', 'None', (32, 40))	('colorectal cancer', 'Phenotype', 'HP:0003003', (266, 283))	('APC', 'Disease', 'MESH:D011125', (310, 313))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))
70947	29641532	The type and frequency of rare germline mutations in AD genes were then assessed in a control cohort (n = 1358); 1201 occurrences of non-silent mutation were identified from the 65 autosomal dominant cancer predisposition genes at a Kaviar aggregate population frequency of less than 1:100 (1132 missense mutations, 12 splicing, 5 nonsense, 18 frameshift and 34 non-frameshift ins/dels).	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (181, 206))	('non-frameshift ins/dels', 'Var', (362, 385))	('autosomal dominant cancer', 'Disease', (181, 206))	('nonsense', 'Var', (331, 339))	('frameshift', 'Var', (344, 354))	('AD', 'Disease', 'MESH:D000544', (53, 55))	('AD', 'Disease', (53, 55))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('1132', 'Var', (291, 295))	('missense mutations', 'Var', (296, 314))	('splicing', 'biological_process', 'GO:0045292', ('319', '327'))
70948	29641532	Two of the nonsense mutations (p.C675X and p.E1013X) in BRCA1, 7 of the frameshift (p.N1626*11, p.N3024*16, p.Q1429*8, p.L2092*6, p.K1057*7 (x2), and p.F1546*21) in BRCA2 and a single frameshift (p.Q60*6) in PALB2 would predispose the carrier to breast/ovarian cancer.	('p.N1626*', 'Var', (84, 92))	('p.F1546*', 'Var', (150, 158))	('predispose', 'Reg', (220, 230))	('PALB2', 'Gene', '79728', (208, 213))	('p.L2092*', 'SUBSTITUTION', 'None', (119, 127))	('p.E1013X', 'Var', (43, 51))	('p.C675X', 'Mutation', 'rs80356920', (31, 38))	('breast/ovarian cancer', 'Disease', (246, 267))	('p.L2092*', 'Var', (119, 127))	('p.N3024*', 'SUBSTITUTION', 'None', (96, 104))	('p.N3024*', 'Var', (96, 104))	('p.E1013X', 'Mutation', 'rs80357424', (43, 51))	('p.F1546*', 'SUBSTITUTION', 'None', (150, 158))	('p.N1626*', 'SUBSTITUTION', 'None', (84, 92))	('p.C675X', 'Var', (31, 38))	('p.K1057*', 'Var', (130, 138))	('BRCA2', 'Gene', (165, 170))	('BRCA1', 'Gene', '672', (56, 61))	('p.Q60*', 'SUBSTITUTION', 'None', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('carrier', 'molecular_function', 'GO:0005215', ('235', '242'))	('BRCA1', 'Gene', (56, 61))	('p.Q1429*', 'SUBSTITUTION', 'None', (108, 116))	('BRCA2', 'Gene', '675', (165, 170))	('p.Q60*', 'Var', (196, 202))	('p.K1057*', 'SUBSTITUTION', 'None', (130, 138))	('PALB2', 'Gene', (208, 213))	('p.Q1429*', 'Var', (108, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (253, 267))	('breast/ovarian cancer', 'Disease', 'MESH:D010051', (246, 267))
70949	29641532	Finally of note, a p.Q12X variant in TP53 results in early protein truncation (full length protein is 394 amino acids long) and would result in Li-Fraumeni syndrome in the carrier.	('Li-Fraumeni syndrome', 'Disease', (144, 164))	('protein', 'Protein', (59, 66))	('p.Q12X', 'Var', (19, 25))	('result in', 'Reg', (134, 143))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('results in', 'Reg', (42, 52))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (144, 164))	('carrier', 'molecular_function', 'GO:0005215', ('172', '179'))	('p.Q12X', 'Mutation', 'rs757274881', (19, 25))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
70950	29641532	A total of 109 instances of missense variants of a frequency <1:2000 in the Kaviar population were predicted as damaging by all four prediction algorithms; of these, only one of which has been reported as pathogenic in ClinVar (RET p.I852M rs377767426).	('rs377767426', 'DBSNP_MENTION', 'None', (240, 251))	('p.I852M', 'Var', (232, 239))	('RET', 'Gene', '5979', (228, 231))	('missense variants', 'Var', (28, 45))	('RET', 'Gene', (228, 231))	('p.I852M', 'SUBSTITUTION', 'None', (232, 239))	('rs377767426', 'Var', (240, 251))
70951	29641532	Examination of the autosomal recessive (AR) cancer predisposition gene variants from WES/WGS in all cohorts can only reveal where an individual has more than one variant in the same gene, but not whether they are on the same chromosome.	('variants', 'Var', (71, 79))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('225', '235'))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
70952	29641532	In the multiple cancer case cohort, one individual had two missense variants in the same gene (BRIP1; S3 Table, highlighted yellow); neither of these variants were classified as damaging by all four prediction tools.	('multiple cancer', 'Disease', (7, 22))	('missense variants', 'Var', (59, 76))	('BRIP1', 'Gene', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('multiple cancer', 'Disease', 'MESH:D009369', (7, 22))	('BRIP1', 'Gene', '83990', (95, 100))
70954	29641532	It is plausible that heterozygous variant(s) in AR genes could cause a more subtle effect, such as inducing haploinsufficiency that increases susceptibility to cancer without causing an overt cancer syndrome.	('inducing', 'Reg', (99, 107))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('haploinsufficiency', 'Disease', (108, 126))	('cancer', 'Disease', (160, 166))	('susceptibility', 'MPA', (142, 156))	('heterozygous variant', 'Var', (21, 41))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer syndrome', 'Disease', 'MESH:D009369', (192, 207))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('AR genes', 'Gene', (48, 56))	('haploinsufficiency', 'Disease', 'MESH:D058495', (108, 126))	('cancer syndrome', 'Disease', (192, 207))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
70955	29641532	In the multiple cancer cases, truncating variants were seen in FANCC (p.R484X) and in FANCF (c.484/485 AG deletion).	('FANCF', 'Gene', '2188', (86, 91))	('multiple cancer', 'Disease', 'MESH:D009369', (7, 22))	('truncating', 'MPA', (30, 40))	('c.484/485 AG deletion', 'Var', (93, 114))	('multiple cancer', 'Disease', (7, 22))	('FANCC', 'Gene', '2176', (63, 68))	('FANCC', 'Gene', (63, 68))	('FANCF', 'Gene', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('p.R484X', 'Mutation', 'rs768988593', (70, 77))	('p.R484X', 'Var', (70, 77))
70956	29641532	In the UK10K population, there are truncating mutations in 61 individuals, in 21 genes, including: ATM, BRIP1, MUTYH, NBN, NTHL1, RAD51C, RECQL4, WRN, XPC, members of the ERCC gene family (ERCC1, ERCC3, ERCC5) and members of the FANC gene family (FANCA, FANCC, FANCD2, FANCF, FANCG, FANCI, FANCM).	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (269, 273))	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (261, 265))	('NBN', 'Gene', '4683', (118, 121))	('RECQL4', 'Gene', (138, 144))	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (290, 294))	('NTHL1', 'Gene', '4913', (123, 128))	('BRIP1', 'Gene', '83990', (104, 109))	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (283, 287))	('FANCC', 'Gene', (254, 259))	('ERCC3', 'Gene', (196, 201))	('MUTYH', 'Gene', (111, 116))	('truncating mutations', 'Var', (35, 55))	('FANCF', 'Gene', (269, 274))	('FANC', 'Gene', (247, 251))	('mutations', 'Var', (46, 55))	('FANCG', 'Gene', (276, 281))	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (247, 251))	('NBN', 'Gene', (118, 121))	('ATM', 'Gene', '472', (99, 102))	('MUTYH', 'Gene', '4595', (111, 116))	('ERCC5', 'Gene', '2073', (203, 208))	('FANC', 'Gene', (254, 258))	('ERCC1', 'Gene', '2067', (189, 194))	('WRN', 'Gene', (146, 149))	('WRN', 'Gene', '7486', (146, 149))	('BRIP1', 'Gene', (104, 109))	('ERCC3', 'Gene', '2071', (196, 201))	('FANCI', 'Gene', (283, 288))	('RAD51C', 'Gene', '5889', (130, 136))	('FANC', 'Gene', (276, 280))	('FANC', 'Gene', (229, 233))	('FANCM', 'Gene', '57697', (290, 295))	('RAD', 'biological_process', 'GO:1990116', ('130', '133'))	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (254, 258))	('FANCM', 'Gene', (290, 295))	('ERCC5', 'Gene', (203, 208))	('ERCC1', 'Gene', (189, 194))	('FANCD2', 'Gene', (261, 267))	('XPC', 'Gene', '7508', (151, 154))	('FANCI', 'Gene', '55215', (283, 288))	('FANCG', 'Gene', '2189', (276, 281))	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (276, 280))	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (229, 233))	('ATM', 'Gene', (99, 102))	('NTHL1', 'Gene', (123, 128))	('FANCF', 'Gene', '2188', (269, 274))	('FANCC', 'Gene', '2176', (254, 259))	('FANC', 'Gene', (269, 273))	('FANC', 'Gene', (261, 265))	('RAD51C', 'Gene', (130, 136))	('XPC', 'Gene', (151, 154))	('RECQL4', 'Gene', '9401', (138, 144))	('FANC', 'Gene', (290, 294))	('FANC', 'Gene', (283, 287))	('FANCD2', 'Gene', '2177', (261, 267))
70958	29641532	Examination of the TSG that are not otherwise classified as AD or AR cancer syndrome genes (n = 49) in the multiple cancer cohort revealed 50 missense, 1 nonsense, 2 frameshift and 6 non-frameshift in/del variants at a frequency of <1:100 in the Kaviar control population.	('multiple cancer', 'Disease', 'MESH:D009369', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('AD', 'Disease', 'MESH:D000544', (60, 62))	('frameshift', 'Var', (166, 176))	('AD', 'Disease', (60, 62))	('missense', 'Var', (142, 150))	('multiple cancer', 'Disease', (107, 122))	('nonsense', 'Var', (154, 162))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('non-frameshift in/del', 'Var', (183, 204))	('cancer syndrome', 'Disease', 'MESH:D009369', (69, 84))	('cancer syndrome', 'Disease', (69, 84))
70959	29641532	Of all the missense mutations, two variants were predicted as damaging by all tools (PMS1 p.T75I rs61756360 and TNFAIP3 p.R761H rs368859219) and another variant was predicted as damaging by the 3 tools that could assess it (TET2 p.I1873T rs116519313).	('p.I1873T', 'Var', (229, 237))	('p.I1873T', 'SUBSTITUTION', 'None', (229, 237))	('TNFAIP3', 'Gene', '7128', (112, 119))	('rs116519313', 'Var', (238, 249))	('missense', 'Var', (11, 19))	('rs61756360', 'DBSNP_MENTION', 'None', (97, 107))	('p.T75I', 'Var', (90, 96))	('rs61756360', 'Var', (97, 107))	('TNFAIP3', 'Gene', (112, 119))	('p.R761H', 'Var', (120, 127))	('rs368859219', 'DBSNP_MENTION', 'None', (128, 139))	('rs368859219', 'Var', (128, 139))	('rs116519313', 'DBSNP_MENTION', 'None', (238, 249))	('p.R761H', 'SUBSTITUTION', 'None', (120, 127))	('TET2', 'Gene', (224, 228))	('TET2', 'Gene', '54790', (224, 228))	('p.T75I', 'SUBSTITUTION', 'None', (90, 96))
70961	29641532	The nonsense variant (p.L737X; rs759242053) occurred in BUB1B.	('p.L737X', 'Mutation', 'rs759242053', (22, 29))	('BUB1B', 'Gene', '701', (56, 61))	('occurred', 'Reg', (44, 52))	('rs759242053', 'Mutation', 'rs759242053', (31, 42))	('p.L737X; rs759242053', 'Var', (22, 42))	('BUB1B', 'Gene', (56, 61))
70962	29641532	Variants in this gene can cause the AR disorder mosaic variegated aneuploidy, however, when a single deleterious mutation is present, this can result in a premature chromatid separation trait (OMIM entry 176430), which can lead to an increased susceptibility to tumour development.	('premature chromatid separation', 'Phenotype', 'HP:0200024', (155, 185))	('tumour', 'Disease', (262, 268))	('cause', 'Reg', (26, 31))	('aneuploidy', 'Disease', (66, 76))	('Variants', 'Var', (0, 8))	('mutation', 'Var', (113, 121))	('chromatid', 'cellular_component', 'GO:0005694', ('165', '174'))	('aneuploidy', 'Disease', 'MESH:D000782', (66, 76))	('premature chromatid separation trait', 'CPA', (155, 191))	('tumour', 'Phenotype', 'HP:0002664', (262, 268))	('tumour', 'Disease', 'MESH:D009369', (262, 268))	('result in', 'Reg', (143, 152))	('chromatid', 'cellular_component', 'GO:0005695', ('165', '174'))
70963	29641532	Two variants in TET2 are of note; the first, p.I1873T (rs116519313), is commonly reported as a somatic mutation (COSMIC ID = COSM41741 in haematopoietic/lymphocyte cancer x18); this patient had CM, colorectal cancer and mast cell leukaemia as distinct primary tumours and the second, an AT deletion at c.4874/4875, causing a frameshift at p.T1626, is in a patient with myeloproliferative disorder at age 65 years.	('tumour', 'Phenotype', 'HP:0002664', (260, 266))	('myeloproliferative disorder', 'Disease', (369, 396))	('mast cell leukaemia', 'Phenotype', 'HP:0100495', (220, 239))	('p.I1873T', 'Var', (45, 53))	('mast cell leukaemia', 'Disease', 'MESH:D007946', (220, 239))	('rs116519313', 'Mutation', 'rs116519313', (55, 66))	('mast cell leukaemia', 'Disease', (220, 239))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('p.T1626', 'Var', (339, 346))	('p.I1873T', 'SUBSTITUTION', 'None', (45, 53))	('TET2', 'Gene', '54790', (16, 20))	('patient', 'Species', '9606', (182, 189))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('colorectal cancer', 'Disease', 'MESH:D015179', (198, 215))	('primary tumours', 'Disease', 'MESH:D009369', (252, 267))	('primary tumours', 'Disease', (252, 267))	('colorectal cancer', 'Disease', (198, 215))	('frameshift at p.T1626', 'Var', (325, 346))	('myeloproliferative disorder', 'Disease', 'MESH:D009196', (369, 396))	('patient', 'Species', '9606', (356, 363))	('cancer', 'Disease', (164, 170))	('myeloproliferative disorder', 'Phenotype', 'HP:0005547', (369, 396))	('tumours', 'Phenotype', 'HP:0002664', (260, 267))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (209, 215))	('colorectal cancer', 'Phenotype', 'HP:0003003', (198, 215))	('TET2', 'Gene', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
70965	29641532	One of the nonsense mutations observed was in BUB1B (p.R770X; rs750364303), which as previously described could cause premature chromatid separation trait.	('cause', 'Reg', (112, 117))	('rs750364303', 'Var', (62, 73))	('BUB1B', 'Gene', '701', (46, 51))	('premature chromatid separation', 'Phenotype', 'HP:0200024', (118, 148))	('rs750364303', 'Mutation', 'rs750364303', (62, 73))	('chromatid', 'cellular_component', 'GO:0005695', ('128', '137'))	('p.R770X; rs750364303', 'Var', (53, 73))	('p.R770X', 'Mutation', 'rs750364303', (53, 60))	('chromatid', 'cellular_component', 'GO:0005694', ('128', '137'))	('BUB1B', 'Gene', (46, 51))	('premature chromatid separation trait', 'CPA', (118, 154))
70966	29641532	A variant in ASXL1 (p.R693X rs373221034) has been reported to be somatically mutated 38 times in haematopoietic/lymphoid tissue/28 times in pancreatic cancer (ID = COSM51388) in the COSMIC database.	('p.R693X', 'SUBSTITUTION', 'None', (20, 27))	('pancreatic cancer', 'Disease', 'MESH:D010190', (140, 157))	('rs373221034', 'Var', (28, 39))	('pancreatic cancer', 'Disease', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('ASXL1', 'Gene', '171023', (13, 18))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (140, 157))	('rs373221034', 'DBSNP_MENTION', 'None', (28, 39))	('ASXL1', 'Gene', (13, 18))	('p.R693X', 'Var', (20, 27))
70968	29641532	Of particular note in the multiple cancer case patients is the variant in JAK2 (p.V617F rs77375493), which is very highly somatically mutated in haematopoietic and lymphoid tissues (reported over 40,000 times in COSMIC, ID = COSM12600) and has been reported as a gain of function variant in myeloproliferative disorders, as well as acting as a predisposition variant in the germline.	('p.V617F', 'Var', (80, 87))	('multiple cancer', 'Disease', (26, 41))	('gain of function', 'PosReg', (263, 279))	('myeloproliferative disorders', 'Disease', (291, 319))	('rs77375493', 'Var', (88, 98))	('JAK2', 'Gene', '3717', (74, 78))	('myeloproliferative disorders', 'Phenotype', 'HP:0005547', (291, 319))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('JAK2', 'Gene', (74, 78))	('patients', 'Species', '9606', (47, 55))	('JAK', 'molecular_function', 'GO:0004713', ('74', '77'))	('myeloproliferative disorders', 'Disease', 'MESH:D009196', (291, 319))	('multiple cancer', 'Disease', 'MESH:D009369', (26, 41))	('rs77375493', 'DBSNP_MENTION', 'None', (88, 98))	('p.V617F', 'SUBSTITUTION', 'None', (80, 87))	('myeloproliferative disorder', 'Phenotype', 'HP:0005547', (291, 318))
70969	29641532	The individual with this variant had myeloproliferative disorder at age 44.	('myeloproliferative disorder', 'Phenotype', 'HP:0005547', (37, 64))	('myeloproliferative disorder', 'Disease', (37, 64))	('variant', 'Var', (25, 32))	('myeloproliferative disorder', 'Disease', 'MESH:D009196', (37, 64))
70970	29641532	Additionally of potential functional impact: a frameshift variant in JAK1 (c.3031insC) in an individual who had a history of CM (n = 2), lymphoma (at 75 years of age) and prostate cancer (at 83 years of age); a frameshift variant in TYK2 (c.1725-1728delinsTT), in an individual with a history of CM (at 42 years of age), lymphoma and clear cell renal carcinoma (both at 58 years of age), colorectal cancer (at 63 years of age) and prostate cancer (at 64 years of age); and a nonsense variant in ROS1 (p.L1209X) in an individual who had CM (at 63 years of age), stomach cancer (at 67 years of age), colorectal cancer (at 68 years of age), Merkel cell carcinoma (at 78 years of age) and thyroid cancer (at 79 years of age).	('prostate cancer', 'Disease', 'MESH:D011471', (171, 186))	('prostate cancer', 'Phenotype', 'HP:0012125', (171, 186))	('frameshift variant', 'Var', (211, 229))	('cancer', 'Phenotype', 'HP:0002664', (440, 446))	('colorectal cancer', 'Phenotype', 'HP:0003003', (388, 405))	('carcinoma', 'Phenotype', 'HP:0030731', (351, 360))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (334, 360))	('JAK', 'molecular_function', 'GO:0004713', ('69', '72'))	('colorectal cancer', 'Disease', 'MESH:D015179', (598, 615))	('lymphoma', 'Phenotype', 'HP:0002665', (137, 145))	('prostate cancer', 'Disease', (171, 186))	('cancer', 'Phenotype', 'HP:0002664', (399, 405))	('Merkel cell carcinoma', 'Disease', (638, 659))	('prostate cancer', 'Disease', 'MESH:D011471', (431, 446))	('stomach cancer', 'Disease', (561, 575))	('prostate cancer', 'Phenotype', 'HP:0012125', (431, 446))	('lymphoma', 'Disease', (321, 329))	('colorectal cancer', 'Disease', (598, 615))	('prostate cancer', 'Disease', (431, 446))	('TYK2', 'Gene', (233, 237))	('lymphoma', 'Disease', 'MESH:D008223', (321, 329))	('carcinoma', 'Phenotype', 'HP:0030731', (650, 659))	('thyroid cancer', 'Disease', (685, 699))	('colorectal cancer', 'Disease', 'MESH:D015179', (388, 405))	('JAK1', 'Gene', (69, 73))	('TYK2', 'Gene', '7297', (233, 237))	('ROS1', 'Gene', '6098', (495, 499))	('frameshift variant', 'Var', (47, 65))	('lymphoma', 'Disease', (137, 145))	('p.L1209X', 'Var', (501, 509))	('stomach cancer', 'Disease', 'MESH:D013274', (561, 575))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('p.L1209X', 'Mutation', 'rs35302901', (501, 509))	('lymphoma', 'Disease', 'MESH:D008223', (137, 145))	('renal carcinoma', 'Phenotype', 'HP:0005584', (345, 360))	('colorectal cancer', 'Disease', (388, 405))	('stomach cancer', 'Phenotype', 'HP:0012126', (561, 575))	('cancer', 'Phenotype', 'HP:0002664', (609, 615))	('colorectal cancer', 'Phenotype', 'HP:0003003', (598, 615))	('c.3031insC', 'Mutation', 'c.3031insC', (75, 85))	('thyroid cancer', 'Disease', 'MESH:D013964', (685, 699))	('cancer', 'Phenotype', 'HP:0002664', (569, 575))	('c.1725-1728del', 'Var', (239, 253))	('lymphoma', 'Phenotype', 'HP:0002665', (321, 329))	('thyroid cancer', 'Phenotype', 'HP:0002890', (685, 699))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (638, 659))	('c.1725-1728del', 'DELETION', 'None', (239, 253))	('clear cell renal carcinoma', 'Disease', (334, 360))	('ROS1', 'Gene', (495, 499))	('JAK1', 'Gene', '3716', (69, 73))
70971	29641532	As shown in S3 Table, none of the variants in these kinase genes found in the UK10K control data have been reported as significantly mutated somatically in any cancer type.	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('variants', 'Var', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
70974	29641532	In the multiple cancer cases, several interesting variants are revealed, including in DNMT3A (p.R693H rs147001633 reported 121 times in haematopoietic/lymphoid tissue in COSMIC, ID = COSM442676), SF3B1 (p.K666N rs377023736 reported 31 times in haematopoietic/lymphoid tissue in COSMIC, ID = COSM132937) and SRSF2 p.P95L r751713049 reported 134 times in haematopoietic/lymphoid tissue in COSMIC, ID = COSM146288).	('p.P95L', 'Mutation', 'rs751713049', (313, 319))	('rs147001633', 'DBSNP_MENTION', 'None', (102, 113))	('p.R693H', 'SUBSTITUTION', 'None', (94, 101))	('COSM146288', 'Chemical', '-', (400, 410))	('SF3B1', 'Gene', '23451', (196, 201))	('p.K666N', 'SUBSTITUTION', 'None', (203, 210))	('multiple cancer', 'Disease', 'MESH:D009369', (7, 22))	('SRSF2', 'Gene', '6427', (307, 312))	('DNMT3A', 'Gene', '1788', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('p.R693H', 'Var', (94, 101))	('SRSF2', 'Gene', (307, 312))	('rs377023736', 'DBSNP_MENTION', 'None', (211, 222))	('multiple cancer', 'Disease', (7, 22))	('p.K666N', 'Var', (203, 210))	('p.P95L', 'Var', (313, 319))	('SF3B1', 'Gene', (196, 201))	('rs147001633', 'Var', (102, 113))	('rs377023736', 'Var', (211, 222))	('DNMT3A', 'Gene', (86, 92))
70975	29641532	The individual with the DNMT3A p.R693H variant had not had any haematological malignancy prior to death (at age 89 years), while the individual with the SF3B1 p.K666N variant had chronic myeloid leukaemia.	('chronic myeloid leukaemia', 'Disease', (179, 204))	('SF3B1', 'Gene', '23451', (153, 158))	('p.R693H', 'SUBSTITUTION', 'None', (31, 38))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (187, 204))	('chronic myeloid leukaemia', 'Disease', 'MESH:D015464', (179, 204))	('DNMT3A', 'Gene', (24, 30))	('DNMT3A', 'Gene', '1788', (24, 30))	('haematological malignancy', 'Disease', (63, 88))	('chronic myeloid leukaemia', 'Phenotype', 'HP:0005506', (179, 204))	('p.R693H', 'Var', (31, 38))	('SF3B1', 'Gene', (153, 158))	('haematological malignancy', 'Disease', 'MESH:D019337', (63, 88))	('p.K666N', 'SUBSTITUTION', 'None', (159, 166))	('p.K666N', 'Var', (159, 166))
70976	29641532	A second individual, who had CM (at age 76 years), prostate cancer (at 86 years) and chronic myeloid leukaemia (at age 88 years), had a novel splice variant, 2bp into the intron after exon 18 of DNMT3A; this variant is of unknown functional consequence.	('chronic myeloid leukaemia', 'Disease', 'MESH:D015464', (85, 110))	('2bp into', 'Var', (158, 166))	('DNMT3A', 'Gene', (195, 201))	('prostate cancer', 'Disease', 'MESH:D011471', (51, 66))	('DNMT3A', 'Gene', '1788', (195, 201))	('prostate cancer', 'Phenotype', 'HP:0012125', (51, 66))	('chronic myeloid leukaemia', 'Phenotype', 'HP:0005506', (85, 110))	('prostate cancer', 'Disease', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('chronic myeloid leukaemia', 'Disease', (85, 110))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (93, 110))
70977	29641532	The individual with the SRSF2 p.P95L variant is the same patient with the TET2 p.I1873T variant and mast cell leukaemia/colorectal cancer.	('SRSF2', 'Gene', '6427', (24, 29))	('leukaemia/colorectal cancer', 'Disease', (110, 137))	('patient', 'Species', '9606', (57, 64))	('TET2', 'Gene', '54790', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('p.I1873T', 'Var', (79, 87))	('mast cell leukaemia', 'Phenotype', 'HP:0100495', (100, 119))	('TET2', 'Gene', (74, 78))	('p.P95L', 'Mutation', 'rs751713049', (30, 36))	('mast cell leukaemia', 'Disease', 'MESH:D007946', (100, 119))	('SRSF2', 'Gene', (24, 29))	('p.P95L', 'Var', (30, 36))	('leukaemia/colorectal cancer', 'Disease', 'MESH:D015179', (110, 137))	('mast cell leukaemia', 'Disease', (100, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))	('p.I1873T', 'SUBSTITUTION', 'None', (79, 87))
70978	29641532	None of the variants in the multiple cancer cases have been classified as pathogenic by ClinVar.	('variants', 'Var', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('multiple cancer', 'Disease', 'MESH:D009369', (28, 43))	('multiple cancer', 'Disease', (28, 43))
70979	29641532	In the UK10K cohort, several variants are classified as pathogenic in ClinVar (S3 Table); however, none of these are associated with cancer predisposition by germline mutation.	('associated', 'Reg', (117, 127))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('variants', 'Var', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
70980	29641532	Two individuals in the UK10K control cohort had the same variant in DNMT3A (p.R693H) and two individuals had the same variant in SF3B1 (p.K666N) described in the multiple cancer cases.	('SF3B1', 'Gene', (129, 134))	('multiple cancer', 'Disease', 'MESH:D009369', (162, 177))	('p.K666N', 'Mutation', 'rs377023736', (136, 143))	('DNMT3A', 'Gene', (68, 74))	('SF3B1', 'Gene', '23451', (129, 134))	('DNMT3A', 'Gene', '1788', (68, 74))	('p.R693H', 'Mutation', 'rs147001633', (76, 83))	('variant', 'Var', (57, 64))	('multiple cancer', 'Disease', (162, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
70981	29641532	Additionally, an individual had the PIK3CA p.H1047L rs121913279 variant, which has been reported at high frequency in breast (n = 183), large intestine (n = 64) and endometrial (n = 43) cancers in COSMIC, ID = COSM776 and COSM94987.	('rs121913279', 'Var', (52, 63))	('PIK3CA', 'Gene', '5290', (36, 42))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('large intestine', 'Disease', (136, 151))	('cancers', 'Disease', (186, 193))	('p.H1047L', 'Var', (43, 51))	('breast', 'Disease', (118, 124))	('rs121913279', 'DBSNP_MENTION', 'None', (52, 63))	('p.H1047L', 'SUBSTITUTION', 'None', (43, 51))	('endometrial', 'Disease', (165, 176))	('PIK3CA', 'Gene', (36, 42))
70982	29641532	Many identified cancer predisposition genes encode DNA damage repair molecules; we have therefore additionally examined variants in genes not previously described as cancer genes, but which have a direct role in DNA damage repair.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('DNA', 'cellular_component', 'GO:0005574', ('212', '215'))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('variants', 'Var', (120, 128))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('cancer', 'Disease', (16, 22))	('Man', 'Species', '9606', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
70983	29641532	In the multiple cancer cases, there were 55 missense, 4 splicing, 6 nonsense, and 3 non-frameshift ins/del variants with a frequency of <1:100 in the Kaviar control population; of these, 31 missense, 2 splicing, 3 nonsense, and 1 non-frameshift ins/del variants had a frequency of <1:2000.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('splicing', 'biological_process', 'GO:0045292', ('202', '210'))	('missense', 'Var', (44, 52))	('splicing', 'biological_process', 'GO:0045292', ('56', '64'))	('multiple cancer', 'Disease', (7, 22))	('missense', 'Var', (190, 198))	('splicing', 'Var', (202, 210))	('multiple cancer', 'Disease', 'MESH:D009369', (7, 22))
70984	29641532	A total of 6 missense variants at a frequency <1:2000 were predicted as damaging by all four algorithms, of which a single individual had two rare variants in WRNIP1 and another had a missense variant in POLE2 (p.L249I).	('missense', 'Var', (13, 21))	('variants', 'Var', (147, 155))	('POLE2', 'Gene', (204, 209))	('POLE2', 'Gene', '5427', (204, 209))	('WRNIP1', 'Gene', (159, 165))	('p.L249I', 'Mutation', 'rs141483427', (211, 218))	('WRNIP1', 'Gene', '56897', (159, 165))	('missense', 'Var', (184, 192))
70985	29641532	The individual with two WRNIP missense variants (p.R537W rs145167237 and p.P615L rs372821009) had early onset cancers (Thyroid cancer at 31, CM at 42 and multifocal clear cell renal cancer at 58 years of age).	('WRN', 'Gene', (24, 27))	('Thyroid cancer', 'Disease', 'MESH:D013964', (119, 133))	('WRN', 'Gene', '7486', (24, 27))	('rs145167237', 'DBSNP_MENTION', 'None', (57, 68))	('rs372821009', 'Var', (81, 92))	('Thyroid cancer', 'Phenotype', 'HP:0002890', (119, 133))	('clear cell renal cancer', 'Disease', (165, 188))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('rs372821009', 'DBSNP_MENTION', 'None', (81, 92))	('cancers', 'Disease', (110, 117))	('rs145167237', 'Var', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('clear cell renal cancer', 'Disease', 'MESH:C538614', (165, 188))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('p.R537W', 'SUBSTITUTION', 'None', (49, 56))	('renal cancer', 'Phenotype', 'HP:0009726', (176, 188))	('p.R537W', 'Var', (49, 56))	('p.P615L', 'SUBSTITUTION', 'None', (73, 80))	('p.P615L', 'Var', (73, 80))	('Thyroid cancer', 'Disease', (119, 133))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
70987	29641532	The missense variant in POLE2 occurred in an individual who had colorectal cancer at age 59 years.	('POLE2', 'Gene', '5427', (24, 29))	('colorectal cancer', 'Disease', (64, 81))	('missense variant', 'Var', (4, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('occurred', 'Reg', (30, 38))	('POLE2', 'Gene', (24, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))
70989	29641532	Exploration of the proportion of individuals from each cohort with variants previously observed in the Kaviar control population was carried out to assess whether there were a greater proportion of variants never/rarely previously observed in the Kaviar control cohort (n = 77,301) in the multiple cancer cases, compared to the UK10K population control cohort.	('multiple cancer', 'Disease', (289, 304))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('multiple cancer', 'Disease', 'MESH:D009369', (289, 304))	('variants', 'Var', (198, 206))
70991	29641532	there was not an over-representation of very rare/novel mutations in cancer/DNA repair genes in multiple cancer patients compared to an unselected cohort of individuals.	('multiple cancer', 'Disease', 'MESH:D009369', (96, 111))	('mutations', 'Var', (56, 65))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('DNA repair', 'biological_process', 'GO:0006281', ('76', '86'))	('multiple cancer', 'Disease', (96, 111))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
70994	29641532	This revealed that a greater number of multiple cancer cases carried multiple variants in cancer genes (Mann-Whitney P = 0.0012; Fig 2A) and in all genes combined (Mann-Whitney P = 0.0014), but not the DNA repair genes alone (Mann-Whitney P = 0.092; Fig 2B), compared to those in the UK10K control population.	('multiple cancer', 'Disease', (39, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('DNA', 'cellular_component', 'GO:0005574', ('202', '205'))	('DNA repair', 'biological_process', 'GO:0006281', ('202', '212'))	('Man', 'Species', '9606', (164, 167))	('Man', 'Species', '9606', (226, 229))	('multiple cancer', 'Disease', 'MESH:D009369', (39, 54))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('Man', 'Species', '9606', (104, 107))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('variants', 'Var', (78, 86))
70996	29641532	The low frequency of germline mutations in TP53 or BRCA1/2, respectively means that statistical evidence supporting these associations is rather weak.	('BRCA1/2', 'Gene', '672;675', (51, 58))	('germline mutations', 'Var', (21, 39))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('BRCA1/2', 'Gene', (51, 58))
71003	29641532	It is of interest that in the UK10K data, 2 deleterious variants were identified in BRCA1 and 7 in BRCA2 (a frequency of 0.15% and 0.52%, respectively); the estimated population frequency of pathogenic BRCA1/2 mutations is 1:800 (0.125%) to 1:1000 (0.1%) per gene, although the prevalence varies between ethnic groups and geographical areas.	('BRCA1', 'Gene', '672', (202, 207))	('mutations', 'Var', (210, 219))	('BRCA1/2', 'Gene', '672;675', (202, 209))	('pathogenic', 'Reg', (191, 201))	('BRCA1', 'Gene', (202, 207))	('BRCA1', 'Gene', '672', (84, 89))	('BRCA2', 'Gene', (99, 104))	('BRCA1', 'Gene', (84, 89))	('BRCA1/2', 'Gene', (202, 209))	('BRCA2', 'Gene', '675', (99, 104))
71004	29641532	A frequency of pathogenic variants in approximately 1:200 individuals for BRCA2 is therefore higher than might be expected from a population of individuals selected for non-cancer studies.	('non-cancer', 'Disease', (169, 179))	('non-cancer', 'Disease', 'MESH:D009369', (169, 179))	('pathogenic', 'Reg', (15, 25))	('BRCA2', 'Gene', (74, 79))	('BRCA2', 'Gene', '675', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('variants', 'Var', (26, 34))
71006	29641532	In the UK10K cohort, 4 individuals had truncating mutations in MSH6 (0.29%, approximately 1:350), which would cause an increase in colorectal cancer risk (by 8 times) and in endometrial cancer risk (26 times) more than the general population in these individuals.	('MSH6', 'Gene', (63, 67))	('endometrial cancer', 'Phenotype', 'HP:0012114', (174, 192))	('truncating mutations', 'Var', (39, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('endometrial cancer', 'Disease', 'MESH:D016889', (174, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('MSH6', 'Gene', '2956', (63, 67))	('endometrial cancer', 'Disease', (174, 192))	('increase', 'PosReg', (119, 127))	('colorectal cancer', 'Disease', (131, 148))
71007	29641532	Finally, truncating or previously functionally described deleterious missense mutations were observed in CBL (predisposing to Noonan syndrome, OMIM ID: 613563), EPCAM (Lynch syndrome/hereditary nonpolyposis colorectal cancer, OMIM ID: 613244), NF1 (Neurofibromatosis, OMIM ID: 162200), PALB2 (breast cancer, OMIM ID: 114480), TP53 (Li Fraumeni Syndrome, OMIM ID: 151623) and TSC2 (Tuberous sclerosis type 2, OMIM ID: 613254) in the UK10K control cohort.	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (249, 266))	('Lynch syndrome', 'Disease', 'MESH:D003123', (168, 182))	('Neurofibromatosis', 'Disease', (249, 266))	('EPCAM', 'Gene', '4072', (161, 166))	('TP53', 'Gene', '7157', (326, 330))	('PALB2', 'Gene', '79728', (286, 291))	('CBL', 'Gene', '867', (105, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (293, 306))	('NF1', 'Gene', '4763', (244, 247))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (183, 224))	('Neurofibromatosis', 'Disease', 'MESH:C537392', (249, 266))	('Li Fraumeni Syndrome', 'Disease', 'MESH:D016864', (332, 352))	('breast cancer', 'Disease', (293, 306))	('NF1', 'Gene', (244, 247))	('breast cancer', 'Disease', 'MESH:D001943', (293, 306))	('Li Fraumeni Syndrome', 'Disease', (332, 352))	('Tuberous sclerosis type 2', 'Disease', (381, 406))	('EPCAM', 'Gene', (161, 166))	('Noonan syndrome', 'Disease', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('TSC2', 'Gene', '7249', (375, 379))	('colorectal cancer', 'Phenotype', 'HP:0003003', (207, 224))	('missense mutations', 'Var', (69, 87))	('Lynch syndrome', 'Disease', (168, 182))	('TP53', 'Gene', (326, 330))	('nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (194, 224))	('Tuberous sclerosis type 2', 'Disease', 'MESH:C566021', (381, 406))	('hereditary nonpolyposis colorectal cancer', 'Disease', (183, 224))	('TSC2', 'Gene', (375, 379))	('Noonan syndrome', 'Disease', 'MESH:D009634', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('CBL', 'Gene', (105, 108))	('PALB2', 'Gene', (286, 291))
71008	29641532	If we take these data as indicative of the types of deleterious genetic mutations present in a collection of individuals collated from non-cancer focused cohorts, it is clear that the multiple cancer cohort has a significant under-representation of such variants, and therefore no unidentified underlying cancer syndrome predisposition.	('non-cancer', 'Disease', (135, 145))	('mutations', 'Var', (72, 81))	('non-cancer', 'Disease', 'MESH:D009369', (135, 145))	('cancer syndrome', 'Disease', 'MESH:D009369', (305, 320))	('variants', 'Var', (254, 262))	('multiple cancer', 'Disease', 'MESH:D009369', (184, 199))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('under-representation', 'NegReg', (225, 245))	('cancer syndrome', 'Disease', (305, 320))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('multiple cancer', 'Disease', (184, 199))
71010	29641532	These cancer syndromes require homozygous or compound heterozygous mutations and often have a severe phenotype.	('cancer syndromes', 'Disease', (6, 22))	('compound heterozygous mutations', 'Var', (45, 76))	('cancer syndromes', 'Disease', 'MESH:D009369', (6, 22))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))
71013	29641532	In the multiple cancer patients, a nonsense variant in FANCC and a frameshift in FANCF were observed; three frameshifts were observed in these genes in the UK10 data.	('FANCC', 'Gene', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('patients', 'Species', '9606', (23, 31))	('frameshift', 'Var', (67, 77))	('FANCF', 'Gene', (81, 86))	('multiple cancer', 'Disease', (7, 22))	('FANCF', 'Gene', '2188', (81, 86))	('FANCC', 'Gene', '2176', (55, 60))	('multiple cancer', 'Disease', 'MESH:D009369', (7, 22))
71015	29641532	In the tumour suppressor, tyrosine kinase and 'other' categories of genes, several variants robustly described as somatic events in haematological malignancies were observed.	('variants', 'Var', (83, 91))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('tyrosine kinase', 'Gene', (26, 41))	('haematological malignancies', 'Disease', (132, 159))	('haematological malignancies', 'Disease', 'MESH:D019337', (132, 159))	('tumour', 'Disease', 'MESH:D009369', (7, 13))	('tyrosine kinase', 'Gene', '7294', (26, 41))	('tumour', 'Disease', (7, 13))
71016	29641532	As the JAK2 p.V617F, TET2 p.I1873T, SF3B1 p.K666N, SRSF2 p.P95L and DNMT3A p.R693H variants are frequent somatically mutated hotpots in haematological malignancy and have not been previously reported in the germline, it is plausible that our screen of buffy coat derived DNA detected somatic mutations.	('JAK', 'molecular_function', 'GO:0004713', ('7', '10'))	('SF3B1', 'Gene', (36, 41))	('p.I1873T', 'Mutation', 'rs116519313', (26, 34))	('p.P95L', 'Mutation', 'rs751713049', (57, 63))	('haematological malignancy', 'Disease', (136, 161))	('DNMT3A', 'Gene', (68, 74))	('JAK2', 'Gene', '3717', (7, 11))	('TET2', 'Gene', '54790', (21, 25))	('SF3B1', 'Gene', '23451', (36, 41))	('haematological malignancy', 'Disease', 'MESH:D019337', (136, 161))	('p.R693H', 'SUBSTITUTION', 'None', (75, 82))	('p.V617F', 'Var', (12, 19))	('SRSF2', 'Gene', '6427', (51, 56))	('JAK2', 'Gene', (7, 11))	('SRSF2', 'Gene', (51, 56))	('p.K666N', 'Mutation', 'rs377023736', (42, 49))	('DNA', 'cellular_component', 'GO:0005574', ('271', '274'))	('p.R693H', 'Var', (75, 82))	('p.V617F', 'Mutation', 'rs77375493', (12, 19))	('p.I1873T', 'Var', (26, 34))	('DNMT3A', 'Gene', '1788', (68, 74))	('p.P95L', 'Var', (57, 63))	('TET2', 'Gene', (21, 25))	('p.K666N', 'Var', (42, 49))
71017	29641532	The participant with the JAK2 p.V617F variant previously had myeloproliferative disorder at age 44, and had their blood drawn for DNA extraction approximately 20 years later; at their death aged 85 years, had no reported diagnosis of recurrent haematological malignancy.	('haematological malignancy', 'Disease', 'MESH:D019337', (244, 269))	('JAK', 'molecular_function', 'GO:0004713', ('25', '28'))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('p.V617F', 'Var', (30, 37))	('JAK2', 'Gene', '3717', (25, 29))	('myeloproliferative disorder', 'Disease', (61, 88))	('myeloproliferative disorder', 'Disease', 'MESH:D009196', (61, 88))	('haematological malignancy', 'Disease', (244, 269))	('JAK2', 'Gene', (25, 29))	('p.V617F', 'SUBSTITUTION', 'None', (30, 37))	('myeloproliferative disorder', 'Phenotype', 'HP:0005547', (61, 88))	('participant', 'Species', '9606', (4, 15))
71018	29641532	The participants with a) the SF3B1 p.K666N and b) SRSF2 p.P95L/TET2 p.I1873T variants, respectively, both had haematological malignancies diagnosed in a closer timeframe after blood draw (exact date unknown) and therefore, tumour cells may have been detected.	('p.I1873T', 'Var', (68, 76))	('TET2', 'Gene', (63, 67))	('SF3B1', 'Gene', '23451', (29, 34))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('SRSF2', 'Gene', (50, 55))	('haematological malignancies', 'Disease', 'MESH:D019337', (110, 137))	('haematological malignancies', 'Disease', (110, 137))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('participants', 'Species', '9606', (4, 16))	('tumour', 'Disease', (223, 229))	('SRSF2', 'Gene', '6427', (50, 55))	('p.K666N', 'SUBSTITUTION', 'None', (35, 42))	('p.I1873T', 'SUBSTITUTION', 'None', (68, 76))	('TET2', 'Gene', '54790', (63, 67))	('SF3B1', 'Gene', (29, 34))	('p.K666N', 'Var', (35, 42))	('p.P95L', 'Mutation', 'rs751713049', (56, 62))
71019	29641532	The variant in DNMT3A observed in haematological malignancies (p.R693H, as reported in COSMIC), was detected in an individual who had not developed such a tumour type prior to their death aged 89 years (previous cancers are: CM, prostate cancer and mesothelioma).	('DNMT3A', 'Gene', (15, 21))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('mesothelioma', 'Disease', (249, 261))	('tumour', 'Disease', (155, 161))	('mesothelioma', 'Disease', 'MESH:D008654', (249, 261))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('haematological malignancies', 'Disease', 'MESH:D019337', (34, 61))	('DNMT3A', 'Gene', '1788', (15, 21))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('prostate cancer', 'Disease', 'MESH:D011471', (229, 244))	('prostate cancer', 'Phenotype', 'HP:0012125', (229, 244))	('cancers', 'Disease', (212, 219))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('prostate cancer', 'Disease', (229, 244))	('p.R693H', 'Mutation', 'rs147001633', (63, 70))	('variant', 'Var', (4, 11))	('haematological malignancies', 'Disease', (34, 61))
71021	29641532	Frameshift or splice variants in JAK1, DNMT3A, TET2 and TYK2 all occurred in individuals with a history of CM and lymphoma/leukaemia and are not previously described as haematological malignancy hotspots; each of these individuals additionally had prostate and/or colorectal cancer, suggesting a potential phenotype associated with these variants.	('colorectal cancer', 'Disease', 'MESH:D015179', (264, 281))	('JAK1', 'Gene', (33, 37))	('colorectal cancer', 'Disease', (264, 281))	('occurred', 'Reg', (65, 73))	('lymphoma/leukaemia', 'Disease', 'MESH:D007938', (114, 132))	('DNMT3A', 'Gene', '1788', (39, 45))	('haematological malignancy', 'Disease', 'MESH:D019337', (169, 194))	('TET2', 'Gene', '54790', (47, 51))	('lymphoma/leukaemia', 'Disease', (114, 132))	('colorectal cancer', 'Phenotype', 'HP:0003003', (264, 281))	('JAK1', 'Gene', '3716', (33, 37))	('TYK2', 'Gene', (56, 60))	('JAK', 'molecular_function', 'GO:0004713', ('33', '36'))	('Frameshift', 'Var', (0, 10))	('DNMT3A', 'Gene', (39, 45))	('TYK2', 'Gene', '7297', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('TET2', 'Gene', (47, 51))	('prostate', 'Disease', (248, 256))	('lymphoma', 'Phenotype', 'HP:0002665', (114, 122))	('haematological malignancy', 'Disease', (169, 194))
71023	29641532	A variant in BUB1B (p.L373X) occurred in an individual with CM, breast cancer and mesothelioma.	('mesothelioma', 'Disease', (82, 94))	('p.L373X', 'Mutation', 'p.L373X', (20, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('BUB1B', 'Gene', (13, 18))	('occurred', 'Reg', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('BUB1B', 'Gene', '701', (13, 18))	('breast cancer', 'Disease', (64, 77))	('p.L373X', 'Var', (20, 27))
71026	29641532	Whether these variants additionally confer increased risk to the other malignancies in these individuals (which include cutaneous melanoma, colorectal cancer, clear cell renal carcinoma and prostate cancer), or there are further genetic predispositions in these individuals leading to the development of these independent primary tumours is an intriguing question.	('risk', 'Reg', (53, 57))	('tumour', 'Phenotype', 'HP:0002664', (330, 336))	('clear cell renal carcinoma and prostate cancer', 'Disease', 'MESH:C538614', (159, 205))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('malignancies', 'Disease', 'MESH:D009369', (71, 83))	('renal carcinoma', 'Phenotype', 'HP:0005584', (170, 185))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('malignancies', 'Disease', (71, 83))	('colorectal cancer', 'Disease', 'MESH:D015179', (140, 157))	('prostate cancer', 'Phenotype', 'HP:0012125', (190, 205))	('primary tumours', 'Disease', (322, 337))	('colorectal cancer', 'Disease', (140, 157))	('primary tumours', 'Disease', 'MESH:D009369', (322, 337))	('variants', 'Var', (14, 22))	('tumours', 'Phenotype', 'HP:0002664', (330, 337))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('cutaneous melanoma', 'Disease', (120, 138))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (120, 138))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (120, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
71027	29641532	Also in these two classifications of genes, the frequency of damaging variants (frameshift in/dels and nonsense) were higher in the multiple cancer cases at frequencies of <1:100 and <1:2000 compared to the UK10K cohort.	('higher', 'PosReg', (118, 124))	('multiple cancer', 'Disease', 'MESH:D009369', (132, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('multiple cancer', 'Disease', (132, 147))	('nonsense', 'Var', (103, 111))
71028	29641532	It is interesting that while these genes were previously associated with a specific type of cancer susceptibility, they could also confer risk of other primary tumour development and form part of a tumour spectrum; our observations therefore add further support to the previously observed similar results in prostate cancer and in paediatric cancers cohorts.	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', (342, 348))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('cancers', 'Phenotype', 'HP:0002664', (342, 349))	('cancers', 'Disease', (342, 349))	('genes', 'Var', (35, 40))	('cancer', 'Disease', (317, 323))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('cancer', 'Disease', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('prostate cancer', 'Disease', 'MESH:D011471', (308, 323))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('tumour', 'Disease', 'MESH:D009369', (198, 204))	('prostate cancer', 'Phenotype', 'HP:0012125', (308, 323))	('tumour', 'Disease', 'MESH:D009369', (160, 166))	('tumour', 'Disease', (198, 204))	('tumour', 'Disease', (160, 166))	('prostate cancer', 'Disease', (308, 323))	('cancers', 'Disease', 'MESH:D009369', (342, 349))	('associated', 'Reg', (57, 67))	('cancer', 'Disease', 'MESH:D009369', (317, 323))
71029	29641532	We observed a variant in POLE2, which was predicted as damaging by all in silico tools, in a patient who had colorectal cancer at age 59 years old.	('colorectal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('POLE2', 'Gene', (25, 30))	('POLE2', 'Gene', '5427', (25, 30))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('patient', 'Species', '9606', (93, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('variant', 'Var', (14, 21))
71030	29641532	Variants in this gene have recently been associated with the development of colorectal cancer and polyposis.	('Variants', 'Var', (0, 8))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('associated with', 'Reg', (41, 56))	('polyposis', 'Disease', 'MESH:D011125', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colorectal cancer', 'Disease', (76, 93))	('polyposis', 'Disease', (98, 107))
71031	29641532	POLE2 is a subunit of the polymerase epsilon enzyme complex; we have previously demonstrated that a deleterious variant in another member of this complex, POLE, was associated with cutaneous melanoma development.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (181, 199))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('POLE', 'Gene', (155, 159))	('associated with', 'Reg', (165, 180))	('variant', 'Var', (112, 119))	('POLE2', 'Gene', (0, 5))	('enzyme complex', 'cellular_component', 'GO:1902494', ('45', '59'))	('cutaneous melanoma', 'Disease', (181, 199))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (181, 199))	('POLE2', 'Gene', '5427', (0, 5))
71032	29641532	There is therefore an indication that variants in POLE and POLE2 might be associated with susceptibility to multiple cancer types.	('POLE2', 'Gene', '5427', (59, 64))	('multiple cancer', 'Disease', 'MESH:D009369', (108, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('variants', 'Var', (38, 46))	('multiple cancer', 'Disease', (108, 123))	('POLE', 'Gene', (50, 54))	('susceptibility', 'Reg', (90, 104))	('POLE2', 'Gene', (59, 64))	('associated', 'Reg', (74, 84))
71033	29641532	Also of interest were two variants in WRNIP1 that were predicted as damaging by all in silico tools, which occurred in the same individual, who had early onset cancers (thyroid cancer at 31, CM at 42 and multifocal clear cell renal cancer at 58 years of age.	('clear cell renal cancer', 'Disease', (215, 238))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('WRNIP1', 'Gene', (38, 44))	('thyroid cancer', 'Disease', (169, 183))	('cancers', 'Disease', (160, 167))	('renal cancer', 'Phenotype', 'HP:0009726', (226, 238))	('thyroid cancer', 'Phenotype', 'HP:0002890', (169, 183))	('WRNIP1', 'Gene', '56897', (38, 44))	('thyroid cancer', 'Disease', 'MESH:D013964', (169, 183))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('clear cell renal cancer', 'Disease', 'MESH:C538614', (215, 238))	('variants', 'Var', (26, 34))
71035	29641532	There are a large number of missense (n = 22) and frameshift (n = 4) variants in WRNIP1 in the UK10K cohort, which could be suggestive of a degree of plasticity in the ability of the protein to withstand mutation.	('WRNIP1', 'Gene', '56897', (81, 87))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('variants', 'Var', (69, 77))	('missense', 'Var', (28, 36))	('frameshift', 'Var', (50, 60))	('WRNIP1', 'Gene', (81, 87))
71036	29641532	The most intriguing implication from our observations is that there is a higher burden of variants in 'cancer' genes in patients with multiple primary cancers than in the control population.	("'cancer", 'Disease', 'MESH:D009369', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('primary cancers', 'Disease', 'MESH:D009369', (143, 158))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	("'cancer", 'Disease', (102, 109))	('variants', 'Var', (90, 98))	('patients', 'Species', '9606', (120, 128))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('primary cancers', 'Disease', (143, 158))
71037	29641532	It is plausible that a number of rare mutations in different genes can act synergistically or additively together to increase susceptibility to cancer development.	('susceptibility', 'Reg', (126, 140))	('increase', 'PosReg', (117, 125))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('act', 'Reg', (71, 74))	('mutations', 'Var', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
71038	29641532	This potential mechanism by which the combination of variants leads to an increased susceptibility to cancer development is intriguing and would require very careful dissection and functional assessment, and perhaps with the advent of Cas9/CRISPR technology, this type of complex genetic manipulation might be more feasible in the future.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Cas', 'cellular_component', 'GO:0005650', ('235', '238'))	('variants', 'Var', (53, 61))
71044	29641532	Another possibility is that the increased burden in missense variants detected in the DNA of individuals with multiple primary cancers is as a somatic event as a consequence to the treatment of their previous tumour(s).	('primary cancers', 'Disease', 'MESH:D009369', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('primary cancers', 'Disease', (119, 134))	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('tumour', 'Disease', 'MESH:D009369', (209, 215))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('tumour', 'Disease', (209, 215))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('missense variants', 'Var', (52, 69))
71048	29641532	It is clear from the genetic data that there are individuals present in the UK10K cohort who have cancer syndromes caused by deleterious mutations (such as BRCA1 nonsense, BRCA2 frameshift and APC frameshift variants).	('nonsense', 'Var', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer syndromes', 'Disease', (98, 114))	('BRCA2', 'Gene', '675', (172, 177))	('APC', 'cellular_component', 'GO:0005680', ('193', '196'))	('BRCA1', 'Gene', '672', (156, 161))	('cancer syndromes', 'Disease', 'MESH:D009369', (98, 114))	('APC', 'Disease', 'MESH:D011125', (193, 196))	('BRCA2', 'Gene', (172, 177))	('APC', 'Disease', (193, 196))	('frameshift', 'Var', (178, 188))	('BRCA1', 'Gene', (156, 161))	('caused by', 'Reg', (115, 124))
71049	29641532	This does, however, also indicate that the UK10K cohort is a representative cross-section of the general population and therefore any difference between this cohort and the multiple cancer cohort are potentially important.	('multiple cancer', 'Disease', (173, 188))	('UK10K', 'Var', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('multiple cancer', 'Disease', 'MESH:D009369', (173, 188))
71050	29641532	An example of this is at chr2:47637479, rs63749984, in MSH2.	('rs63749984', 'Mutation', 'rs63749984', (40, 50))	('MSH2', 'Gene', (55, 59))	('rs63749984', 'Var', (40, 50))	('MSH2', 'Gene', '4436', (55, 59))
71052	29641532	This variant (rs63749984) and chromosomal location are therefore both currently classified as 'pathogenic' by ClinVar and without further scrutiny, the incorrect conclusion would be reached.	("'pathogenic'", 'PosReg', (94, 106))	('rs63749984', 'Mutation', 'rs63749984', (14, 24))	('rs63749984', 'Var', (14, 24))
71053	29641532	For example, while the truncation observed in CBL (p.E658X) in the multiple cancer cohort and the frameshift in the UK10K cohort (a 7bp deletion at p.M222) could be automatically designated as damaging, there is no evidence in the literature of pathogenicity being conferred by truncation of CBL protein.	('truncation', 'MPA', (23, 33))	('CBL', 'Gene', (292, 295))	('CBL', 'Gene', '867', (292, 295))	('protein', 'cellular_component', 'GO:0003675', ('296', '303'))	('multiple cancer', 'Disease', 'MESH:D009369', (67, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('p.E658X', 'Var', (51, 58))	('multiple cancer', 'Disease', (67, 82))	('CBL', 'Gene', (46, 49))	('CBL', 'Gene', '867', (46, 49))	('p.E658X', 'Mutation', 'p.E658X', (51, 58))
71054	29641532	Given the observations of single pathogenic variants predisposing to multiple tumour types arising in distinct tissues, such as with BAP1 (uveal melanoma, mesothelioma, meningioma, clear cell renal cell carcinoma and cholangiocarcinoma), BRCA1 or BRCA2 (breast, ovarian, uveal melanoma), it is plausible that other examples exist that have diverse effects that have yet to be described.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('uveal melanoma', 'Disease', 'MESH:C536494', (139, 153))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (181, 212))	('tumour', 'Disease', (78, 84))	('uveal melanoma', 'Disease', (139, 153))	('BAP1', 'Gene', '8314', (133, 137))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (217, 235))	('BRCA2', 'Gene', (247, 252))	('meningioma', 'Disease', (169, 179))	('cholangiocarcinoma', 'Disease', (217, 235))	('meningioma', 'Phenotype', 'HP:0002858', (169, 179))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (217, 235))	('breast, ovarian, uveal melanoma', 'Disease', 'MESH:C536494', (254, 285))	('melanoma', 'Phenotype', 'HP:0002861', (277, 285))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (192, 212))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (181, 212))	('BAP1', 'Gene', (133, 137))	('uveal melanoma', 'Disease', 'MESH:C536494', (271, 285))	('BRCA2', 'Gene', '675', (247, 252))	('uveal melanoma', 'Disease', (271, 285))	('meningioma', 'Disease', 'MESH:D008577', (169, 179))	('BRCA1', 'Gene', '672', (238, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('BRCA1', 'Gene', (238, 243))	('clear cell renal cell carcinoma', 'Disease', (181, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('uveal melanoma', 'Phenotype', 'HP:0007716', (271, 285))	('mesothelioma', 'Disease', (155, 167))	('mesothelioma', 'Disease', 'MESH:D008654', (155, 167))	('variants', 'Var', (44, 52))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
71056	29641532	We identified a number of variants likely to have caused increased susceptibility to at least one of the primary tumours observed and have additionally shown an increased burden of mutation in affected individuals.	('primary tumours', 'Disease', (105, 120))	('primary tumours', 'Disease', 'MESH:D009369', (105, 120))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('variants', 'Var', (26, 34))
71057	29641532	Given the later age of onset of many of these tumours, it is plausible that these variants, either alone or in combination, do not have high impact on protein function and instead have more subtle cellular effects.	('variants', 'Var', (82, 90))	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('protein function', 'MPA', (151, 167))	('tumours', 'Disease', (46, 53))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('have', 'Reg', (180, 184))
71060	29641532	The implication from this and other recent studies is that there are a significant number of germline genetic variations in genes known to be associated with cancer processes in individuals with a wide variety of tumour types.	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumour', 'Disease', 'MESH:D009369', (213, 219))	('genetic variations', 'Var', (102, 120))	('cancer', 'Disease', (158, 164))	('tumour', 'Disease', (213, 219))	('associated', 'Reg', (142, 152))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
71061	28296713	Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma Mucosal melanomas are a rare subtype of melanoma, arising in mucosal tissues, which have a very poor prognosis due to the lack of effective targeted therapies.	('R625 mutation', 'Var', (50, 63))	('SF3B1', 'Gene', (44, 49))	('Mucosal melanomas', 'Disease', 'MESH:D008545', (114, 131))	('mucosal melanoma', 'Disease', 'MESH:D008545', (97, 113))	('mucosal melanoma', 'Disease', (97, 113))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('SF3B1', 'Gene', '23451', (44, 49))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('NF1', 'Gene', '4763', (82, 85))	('mutation', 'Var', (55, 63))	('Mucosal melanomas', 'Disease', (114, 131))	('KIT', 'molecular_function', 'GO:0005020', ('90', '93'))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('NF1', 'Gene', (82, 85))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))
71066	28296713	KIT and NF1 were frequently comutated (32%) in the mucosal subgroup, with a significantly higher incidence than that in cutaneous melanoma (4%).	('NF1', 'Gene', (8, 11))	('comutated', 'Var', (28, 37))	('NF1', 'Gene', '4763', (8, 11))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (120, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('cutaneous melanoma', 'Disease', (120, 138))	('KIT', 'Gene', (0, 3))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (120, 138))
71067	28296713	Recurrent SF3B1 R625H/S/C mutations were identified and validated in 7 of 19 (37%) mucosal melanoma patients.	('R625H', 'SUBSTITUTION', 'None', (16, 21))	('mucosal melanoma', 'Disease', (83, 99))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('R625H', 'Var', (16, 21))	('SF3B1', 'Gene', (10, 15))	('patients', 'Species', '9606', (100, 108))	('mucosal melanoma', 'Disease', 'MESH:D008545', (83, 99))	('SF3B1', 'Gene', '23451', (10, 15))
71068	28296713	Mutations in the spliceosome pathway were found to be enriched in mucosal melanomas when compared with cutaneous melanomas.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (103, 121))	('melanomas', 'Phenotype', 'HP:0002861', (74, 83))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (103, 122))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (103, 122))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('Mutations', 'Var', (0, 9))	('mucosal melanomas', 'Disease', (66, 83))	('cutaneous melanomas', 'Disease', (103, 122))	('mucosal melanomas', 'Disease', 'MESH:D008545', (66, 83))	('spliceosome pathway', 'Pathway', (17, 36))	('spliceosome', 'cellular_component', 'GO:0005681', ('17', '28'))
71070	28296713	This study identified potential new therapeutic targets for mucosal melanoma, including comutation of NF1 and KIT, and recurrent R625 mutations in SF3B1.	('mucosal melanoma', 'Disease', 'MESH:D008545', (60, 76))	('KIT', 'Gene', (110, 113))	('SF3B1', 'Gene', (147, 152))	('NF1', 'Gene', (102, 105))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('NF1', 'Gene', '4763', (102, 105))	('comutation', 'Var', (88, 98))	('SF3B1', 'Gene', '23451', (147, 152))	('mucosal melanoma', 'Disease', (60, 76))	('R625 mutations', 'Var', (129, 143))	('KIT', 'molecular_function', 'GO:0005020', ('110', '113'))
71071	28296713	This is the first report of SF3B1 R625 mutations in vulvovaginal mucosal melanoma, with the largest whole-exome sequencing project of mucosal melanomas to date.	('R625 mutations', 'Var', (34, 48))	('mucosal melanomas', 'Disease', (134, 151))	('SF3B1', 'Gene', (28, 33))	('vulvovaginal mucosal melanoma', 'Phenotype', 'HP:0030418', (52, 81))	('mutations', 'Var', (39, 48))	('mucosal melanomas', 'Disease', 'MESH:D008545', (134, 151))	('vulvovaginal mucosal melanoma', 'Disease', 'MESH:D014848', (52, 81))	('vulvovaginal mucosal melanoma', 'Disease', (52, 81))	('SF3B1', 'Gene', '23451', (28, 33))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanomas', 'Phenotype', 'HP:0002861', (142, 151))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
71072	28296713	The results here also indicated that the mutations in SF3B1 lead to alternative splicing in multiple genes.	('SF3B1', 'Gene', (54, 59))	('mutations', 'Var', (41, 50))	('lead to', 'Reg', (60, 67))	('SF3B1', 'Gene', '23451', (54, 59))	('splicing', 'biological_process', 'GO:0045292', ('80', '88'))	('alternative splicing in multiple genes', 'MPA', (68, 106))
71076	28296713	Common molecular drivers identified in cutaneous melanoma, such as mutated BRAF V600E, have not been identified in mucosal melanoma.	('BRAF', 'Gene', '673', (75, 79))	('V600E', 'Var', (80, 85))	('BRAF', 'Gene', (75, 79))	('cutaneous melanoma', 'Disease', (39, 57))	('mutated', 'Var', (67, 74))	('mucosal melanoma', 'Disease', (115, 131))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (39, 57))	('mucosal melanoma', 'Disease', 'MESH:D008545', (115, 131))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (39, 57))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('V600E', 'Mutation', 'rs113488022', (80, 85))
71082	28296713	Our study expands this knowledge by contributing the largest whole-exome sequenced cohort of mucosal melanoma known to date with validated mutations and differentially spliced genes as a result of these mutations.	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('mucosal melanoma', 'Disease', (93, 109))	('mutations', 'Var', (203, 212))	('mucosal melanoma', 'Disease', 'MESH:D008545', (93, 109))
71086	28296713	We identified comutations in NF1 and KIT in 32% of our patient samples.	('comutations', 'Var', (14, 25))	('KIT', 'molecular_function', 'GO:0005020', ('37', '40'))	('NF1', 'Gene', (29, 32))	('KIT', 'Gene', (37, 40))	('NF1', 'Gene', '4763', (29, 32))	('patient', 'Species', '9606', (55, 62))
71088	28296713	Importantly, we discovered a recurrent R625 mutation in SF3B1, in vulvovaginal melanomas that was previously only described in anorectal and ocular melanomas.	('ocular melanomas', 'Phenotype', 'HP:0025534', (141, 157))	('vulvovaginal melanomas', 'Phenotype', 'HP:0030418', (66, 88))	('vulvovaginal melanomas', 'Disease', 'MESH:D014848', (66, 88))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('SF3B1', 'Gene', '23451', (56, 61))	('R625', 'Var', (39, 43))	('ocular melanomas', 'Disease', 'MESH:D008545', (141, 157))	('SF3B1', 'Gene', (56, 61))	('ocular melanomas', 'Disease', (141, 157))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))	('anorectal', 'Disease', (127, 136))	('vulvovaginal melanomas', 'Disease', (66, 88))	('melanomas', 'Phenotype', 'HP:0002861', (148, 157))
71105	28296713	All samples from both cutaneous and mucosal patients were analyzed for variants and copy number alterations using IMPACT, our recently published WES analysis pipeline.	('variants', 'Var', (71, 79))	('patients', 'Species', '9606', (44, 52))	('copy number alterations', 'Var', (84, 107))
71106	28296713	To eliminate potential false positives, IMPACT performs a stringent filtering step, keeping only nonsynonymous somatic variants that are predicted to be deleterious by SIFT and PolyPhen2 or were present in the COSMIC database.	('false', 'biological_process', 'GO:0071878', ('23', '28'))	('SIFT', 'Disease', 'None', (168, 172))	('false', 'biological_process', 'GO:0071877', ('23', '28'))	('variants', 'Var', (119, 127))	('SIFT', 'Disease', (168, 172))
71118	28296713	For each splicing event, a two-tailed unpaired t-test (using GraphPad Prism software; GraphPad Software Inc., La Jolla, California, USA) was applied between SF3B1 mutated (n=3) and wild-type (n=4) cases.	('SF3B1', 'Gene', (157, 162))	('SF3B1', 'Gene', '23451', (157, 162))	('splicing', 'biological_process', 'GO:0045292', ('9', '17'))	('mutated', 'Var', (163, 170))
71131	28296713	Figure 1 summarizes the genes significantly enriched for mutations in mucosal versus cutaneous melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('mutations', 'Var', (57, 66))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (85, 104))	('mucosal versus cutaneous melanomas', 'Disease', (70, 104))	('mucosal versus cutaneous melanomas', 'Disease', 'MESH:C562393', (70, 104))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))
71133	28296713	Notably, the recurrent SF3B1 mutation was only found to be mutated in anorectal and vulvovaginal patients but not in nasopharyngeal melanoma samples.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('mutation', 'Var', (29, 37))	('melanoma', 'Disease', (132, 140))	('anorectal', 'Disease', (70, 79))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('SF3B1', 'Gene', '23451', (23, 28))	('vulvovaginal', 'Disease', 'MESH:D014848', (84, 96))	('SF3B1', 'Gene', (23, 28))	('vulvovaginal', 'Disease', (84, 96))	('patients', 'Species', '9606', (97, 105))
71134	28296713	There was one nasopharyngeal patient with a previously undescribed SF3B1 E1105G mutation.	('patient', 'Species', '9606', (29, 36))	('E1105G', 'Var', (73, 79))	('SF3B1', 'Gene', '23451', (67, 72))	('SF3B1', 'Gene', (67, 72))	('E1105G', 'Mutation', 'p.E1105G', (73, 79))
71136	28296713	In contrast, oncogenic driver mutations in BRAF were not detected in mucosal melanomas, and the mutations found were not commonly identified in cutaneous melanoma (Fig.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (144, 162))	('BRAF', 'Gene', '673', (43, 47))	('BRAF', 'Gene', (43, 47))	('mucosal melanomas', 'Disease', (69, 86))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('mucosal melanomas', 'Disease', 'MESH:D008545', (69, 86))	('mutations', 'Var', (30, 39))	('cutaneous melanoma', 'Disease', (144, 162))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (144, 162))
71138	28296713	Figure 2 molecularly classifies the patient samples with the common mutations of BRAF (V600), NRAS (G12, G13, Q61), NF1, and KIT mutations in our mucosal and cutaneous cohorts, as well as those samples that lacked these gene mutations (pan negative).	('NRAS', 'Gene', (94, 98))	('KIT', 'Gene', (125, 128))	('mutations', 'Var', (129, 138))	('BRAF', 'Gene', '673', (81, 85))	('NRAS', 'Gene', '4893', (94, 98))	('BRAF', 'Gene', (81, 85))	('NF1', 'Gene', (116, 119))	('NF1', 'Gene', '4763', (116, 119))	('Q61', 'Var', (110, 113))	('KIT', 'molecular_function', 'GO:0005020', ('125', '128'))	('patient', 'Species', '9606', (36, 43))
71146	28296713	We found that 68% of mucosal melanoma patients had one or more of the spliceosome genes mutated (Fig.	('mucosal melanoma', 'Disease', (21, 37))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('mucosal melanoma', 'Disease', 'MESH:D008545', (21, 37))	('spliceosome', 'cellular_component', 'GO:0005681', ('70', '81'))	('spliceosome genes', 'Gene', (70, 87))	('mutated', 'Var', (88, 95))	('patients', 'Species', '9606', (38, 46))
71148	28296713	From the WES analysis, we identified a total of seven vulvovaginal and anorectal mucosal melanomas harboring the SF3B1 recurrent mutations (R625H/S/C) and one nasopharyngeal mucosal melanoma mutated at E1105G.	('mucosal melanoma', 'Disease', 'MESH:D008545', (174, 190))	('mucosal melanoma', 'Disease', 'MESH:D008545', (81, 97))	('SF3B1', 'Gene', (113, 118))	('R625H', 'SUBSTITUTION', 'None', (140, 145))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('SF3B1', 'Gene', '23451', (113, 118))	('anorectal mucosal melanomas', 'Disease', (71, 98))	('R625H', 'Var', (140, 145))	('E1105G', 'Mutation', 'p.E1105G', (202, 208))	('E1105G', 'Var', (202, 208))	('anorectal mucosal melanomas', 'Disease', 'MESH:D008545', (71, 98))	('vulvovaginal', 'Disease', 'MESH:D014848', (54, 66))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('vulvovaginal', 'Disease', (54, 66))	('mucosal melanoma', 'Disease', (174, 190))
71149	28296713	Within anorectal and vulvovaginal melanomas, SF3B1 R625 mutations occurred in 50% (7/14) of all samples.	('anorectal', 'Disease', (7, 16))	('vulvovaginal melanomas', 'Phenotype', 'HP:0030418', (21, 43))	('mutations', 'Var', (56, 65))	('occurred', 'Reg', (66, 74))	('R625 mutations', 'Var', (51, 65))	('SF3B1', 'Gene', (45, 50))	('vulvovaginal melanomas', 'Disease', (21, 43))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('vulvovaginal melanomas', 'Disease', 'MESH:D014848', (21, 43))	('SF3B1', 'Gene', '23451', (45, 50))
71152	28296713	The Sanger sequencing results validated the WES findings of SF3B1 R625 mutations in these samples (Supplementary Fig.	('SF3B1', 'Gene', (60, 65))	('R625 mutations', 'Var', (66, 80))	('SF3B1', 'Gene', '23451', (60, 65))	('San', 'Gene', (4, 7))	('San', 'Gene', '80218', (4, 7))
71155	28296713	Mutations in SF3B1 are rare in cutaneous melanomas, and none of our in-house 135 cutaneous melanomas had an SF3B1 mutation.	('SF3B1', 'Gene', '23451', (108, 113))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (31, 50))	('SF3B1', 'Gene', (13, 18))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (31, 50))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (31, 49))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('Mutations', 'Var', (0, 9))	('cutaneous melanomas', 'Disease', (31, 50))	('SF3B1', 'Gene', '23451', (13, 18))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (81, 100))	('SF3B1', 'Gene', (108, 113))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (81, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (81, 99))	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))	('cutaneous melanomas', 'Disease', (81, 100))
71157	28296713	Figure 4a illustrates the known SF3B1 mutations found in this study and other published cancer studies from cBioPortal.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('SF3B1', 'Gene', '23451', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (38, 47))	('SF3B1', 'Gene', (32, 37))
71158	28296713	Both uveal melanoma and breast cancer harbor mutations in the HEAT domain of SF3B1, with a majority of samples having mutations at positions R625 and K700, respectively (Fig.	('K700', 'Var', (150, 154))	('SF3B1', 'Gene', (77, 82))	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('SF3B1', 'Gene', '23451', (77, 82))	('breast cancer', 'Disease', (24, 37))	('uveal melanoma', 'Phenotype', 'HP:0007716', (5, 19))	('uveal melanoma', 'Disease', (5, 19))	('uveal melanoma', 'Disease', 'MESH:C536494', (5, 19))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))
71159	28296713	Mutations in the HEAT (Huntingtin, Elongation factor 3, protein phosphatase 2A, Targets of rapamycin 1) domain of SF3B1, such as R625 and K700, have been associated with alternative splicing events, primarily through the induction of aberrant 3' splice site selection.	('Huntingtin', 'Gene', '3064', (23, 33))	('SF3B1', 'Gene', '23451', (114, 119))	('R625', 'Var', (129, 133))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('Huntingtin', 'Gene', (23, 33))	('protein phosphatase 2A', 'molecular_function', 'GO:0050115', ('56', '78'))	('K700', 'Var', (138, 142))	('splice site selection', 'biological_process', 'GO:0000381', ('246', '267'))	('splice site selection', 'biological_process', 'GO:0000380', ('246', '267'))	('splicing', 'biological_process', 'GO:0045292', ('182', '190'))	('SF3B1', 'Gene', (114, 119))	('alternative splicing events', 'MPA', (170, 197))	("3' splice site selection", 'MPA', (243, 267))	('associated', 'Reg', (154, 164))
71161	28296713	Considering the functional role of mutant SF3B1 in inducing differential splicing, we hypothesized that SF3B1 R625H/S/C mutations in mucosal melanoma would also lead to differential splicing of genes as compared with SF3B1 wild-type tumors.	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('SF3B1', 'Gene', (217, 222))	('SF3B1', 'Gene', (42, 47))	('mutant', 'Var', (35, 41))	('R625H', 'SUBSTITUTION', 'None', (110, 115))	('SF3B1', 'Gene', (104, 109))	('SF3B1', 'Gene', '23451', (217, 222))	('SF3B1', 'Gene', '23451', (42, 47))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('mucosal melanoma', 'Disease', 'MESH:D008545', (133, 149))	('differential splicing', 'MPA', (60, 81))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('lead to', 'Reg', (161, 168))	('differential splicing of genes', 'MPA', (169, 199))	('splicing', 'biological_process', 'GO:0045292', ('182', '190'))	('mucosal melanoma', 'Disease', (133, 149))	('SF3B1', 'Gene', '23451', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('R625H', 'Var', (110, 115))	('splicing', 'biological_process', 'GO:0045292', ('73', '81'))	('tumors', 'Disease', (233, 239))
71163	28296713	We selected seven genes (ABCC5, ANKHD1, CRNDE, GUSPB11, RPL31, TMEM14C, and UQCC) that have been previously identified by means of RNA sequencing and validated using qRT-PCR to be differentially spliced in SF3B1 R625 and K700E mutants compared with wild-type uveal melanomas and breast cancer.	('ANKHD1', 'Gene', '54882', (32, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (259, 273))	('uveal melanomas', 'Disease', 'MESH:C536494', (259, 274))	('breast cancer', 'Disease', 'MESH:D001943', (279, 292))	('R625', 'Var', (212, 216))	('TMEM14C', 'Gene', (63, 70))	('breast cancer', 'Disease', (279, 292))	('K700E', 'Mutation', 'rs559063155', (221, 226))	('ANKHD1', 'Gene', (32, 38))	('RPL31', 'Gene', '6160', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('ABCC5', 'Gene', '10057', (25, 30))	('RPL31', 'Gene', (56, 61))	('uveal melanomas', 'Disease', (259, 274))	('ABCC5', 'Gene', (25, 30))	('uveal melanomas', 'Phenotype', 'HP:0007716', (259, 274))	('CRNDE', 'Gene', (40, 45))	('TMEM14C', 'Gene', '51522', (63, 70))	('CRNDE', 'Gene', '643911', (40, 45))	('SF3B1', 'Gene', (206, 211))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('UQCC', 'Gene', '55245', (76, 80))	('K700E mutants', 'Var', (221, 234))	('melanomas', 'Phenotype', 'HP:0002861', (265, 274))	('UQCC', 'Gene', (76, 80))	('RNA', 'cellular_component', 'GO:0005562', ('131', '134'))	('breast cancer', 'Phenotype', 'HP:0003002', (279, 292))	('SF3B1', 'Gene', '23451', (206, 211))
71164	28296713	To validate these alternatively spliced genes in mucosal melanomas, we tested SF3B1 R625H-mutant (n=2) and wild-type (n=3) patient-derived xenografts established from our mucosal melanoma primary samples.	('tested', 'Reg', (71, 77))	('mucosal melanoma', 'Disease', (171, 187))	('patient', 'Species', '9606', (123, 130))	('R625H-mutant', 'Var', (84, 96))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('mucosal melanoma', 'Disease', 'MESH:D008545', (171, 187))	('SF3B1', 'Gene', '23451', (78, 83))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('mucosal melanomas', 'Disease', (49, 66))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('mucosal melanoma', 'Disease', 'MESH:D008545', (49, 65))	('mucosal melanomas', 'Disease', 'MESH:D008545', (49, 66))	('R625H', 'Mutation', 'rs1057519961', (84, 89))	('SF3B1', 'Gene', (78, 83))
71165	28296713	Uveal melanoma cell lines Mel202 (SF3B1 R625G) and MP41 (SF3B1 wild-type) were utilized as positive and negative controls, respectively, for differential splicing analysis.	('SF3B1', 'Gene', (57, 62))	('R625G', 'Mutation', 'rs775623976', (40, 45))	('SF3B1', 'Gene', (34, 39))	('SF3B1', 'Gene', '23451', (57, 62))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('splicing', 'biological_process', 'GO:0045292', ('154', '162'))	('R625G', 'Var', (40, 45))	('SF3B1', 'Gene', '23451', (34, 39))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
71166	28296713	This analysis identified all seven genes to be differentially spliced in mucosal melanomas with SF3B1 mutant as compared with wild-type samples (Fig.	('mutant', 'Var', (102, 108))	('SF3B1', 'Gene', (96, 101))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('mucosal melanomas', 'Disease', (73, 90))	('melanomas', 'Phenotype', 'HP:0002861', (81, 90))	('SF3B1', 'Gene', '23451', (96, 101))	('mucosal melanomas', 'Disease', 'MESH:D008545', (73, 90))
71168	28296713	This demonstrates that SF3B1 R625-mutant mucosal melanomas are functionally involved in alternative splicing of genes, similar to SF3B1 R625 and K700E mutants found in uveal melanoma and breast cancer.	('K700E', 'Mutation', 'rs559063155', (145, 150))	('SF3B1', 'Gene', (130, 135))	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('alternative splicing', 'MPA', (88, 108))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('splicing', 'biological_process', 'GO:0045292', ('100', '108'))	('SF3B1', 'Gene', '23451', (130, 135))	('mucosal melanomas', 'Disease', 'MESH:D008545', (41, 58))	('SF3B1', 'Gene', (23, 28))	('uveal melanoma', 'Disease', 'MESH:C536494', (168, 182))	('uveal melanoma', 'Disease', (168, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('K700E', 'Var', (145, 150))	('mucosal melanomas', 'Disease', (41, 58))	('R625-mutant', 'Var', (29, 40))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('breast cancer', 'Disease', (187, 200))	('SF3B1', 'Gene', '23451', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('R625', 'Var', (136, 140))	('involved', 'Reg', (76, 84))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
71169	28296713	The clinical data for patients harboring all SF3B1 mutations is summarized in Table 1.	('clinical', 'Species', '191496', (4, 12))	('mutations', 'Var', (51, 60))	('patients', 'Species', '9606', (22, 30))	('SF3B1', 'Gene', (45, 50))	('SF3B1', 'Gene', '23451', (45, 50))
71170	28296713	Of the eight patients with SF3B1 mutations, five had developed metastatic disease and had relatively longer survival times compared with those patients with wild-type SF3B1.	('longer', 'PosReg', (101, 107))	('SF3B1', 'Gene', (167, 172))	('patients', 'Species', '9606', (13, 21))	('survival times', 'CPA', (108, 122))	('mutations', 'Var', (33, 42))	('SF3B1', 'Gene', (27, 32))	('patients', 'Species', '9606', (143, 151))	('SF3B1', 'Gene', '23451', (167, 172))	('metastatic disease', 'CPA', (63, 81))	('developed', 'PosReg', (53, 62))	('SF3B1', 'Gene', '23451', (27, 32))
71175	28296713	Mutations in BRAF were seen but these were not the driver V600 mutations described in cutaneous melanoma (Table 1).	('cutaneous melanoma', 'Disease', (86, 104))	('BRAF', 'Gene', '673', (13, 17))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (86, 104))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (86, 104))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))
71176	28296713	Similar to other studies, frequent mutations in KIT were found, especially in the vulvovaginal and anorectal subtypes.	('vulvovaginal', 'Disease', 'MESH:D014848', (82, 94))	('KIT', 'Gene', (48, 51))	('vulvovaginal', 'Disease', (82, 94))	('found', 'Reg', (57, 62))	('KIT', 'molecular_function', 'GO:0005020', ('48', '51'))	('anorectal', 'Disease', (99, 108))	('mutations', 'Var', (35, 44))
71177	28296713	In these two groups of patients, the KIT mutations were comutated with NF1 in 32% of the samples.	('mutations', 'Var', (41, 50))	('NF1', 'Gene', (71, 74))	('KIT', 'molecular_function', 'GO:0005020', ('37', '40'))	('patients', 'Species', '9606', (23, 31))	('NF1', 'Gene', '4763', (71, 74))	('KIT', 'Gene', (37, 40))
71181	28296713	In the present study, KIT mutations, particularly in the vulvovaginal and anorectal subtypes, were often comutated with NF1, 22 and 60%, respectively.	('vulvovaginal', 'Disease', 'MESH:D014848', (57, 69))	('vulvovaginal', 'Disease', (57, 69))	('KIT', 'Gene', (22, 25))	('anorectal', 'Disease', (74, 83))	('NF1', 'Gene', (120, 123))	('mutations', 'Var', (26, 35))	('NF1', 'Gene', '4763', (120, 123))	('KIT', 'molecular_function', 'GO:0005020', ('22', '25'))
71183	28296713	Mutations in NF1 also activate RAS signaling, similar to some of the KIT mutations.	('KIT', 'molecular_function', 'GO:0005020', ('69', '72'))	('signaling', 'biological_process', 'GO:0023052', ('35', '44'))	('NF1', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('NF1', 'Gene', '4763', (13, 16))	('RAS', 'Pathway', (31, 34))	('activate', 'PosReg', (22, 30))
71184	28296713	Interestingly, mutations in either NF1 or KIT have been implicated as pivotal for the development of gastrointestinal stromal tumors.	('KIT', 'Gene', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('KIT', 'molecular_function', 'GO:0005020', ('42', '45'))	('mutations', 'Var', (15, 24))	('gastrointestinal stromal tumors', 'Disease', (101, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (101, 132))	('NF1', 'Gene', (35, 38))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (101, 132))	('NF1', 'Gene', '4763', (35, 38))
71185	28296713	Comutations of KIT and NF1 have also been reported in gastrointestinal stromal tumors, although they are rare.	('Comutations', 'Var', (0, 11))	('KIT', 'Gene', (15, 18))	('NF1', 'Gene', (23, 26))	('reported', 'Reg', (42, 50))	('NF1', 'Gene', '4763', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('KIT', 'molecular_function', 'GO:0005020', ('15', '18'))	('gastrointestinal stromal tumors', 'Disease', (54, 85))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (54, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (54, 85))
71186	28296713	We reason that mutations in either gene may only weakly activate the downstream signaling, and not be sufficient for tumorigenesis, whereas comutations in both genes lead to stronger and sufficient activation for tumor development.	('tumor', 'Disease', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('activation', 'PosReg', (198, 208))	('downstream signaling', 'MPA', (69, 89))	('tumor', 'Disease', (117, 122))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('activate', 'PosReg', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('comutations', 'Var', (140, 151))	('signaling', 'biological_process', 'GO:0023052', ('80', '89'))
71188	28296713	NF1 mutations have also been found concurrent with BRAF mutations in melanoma, and loss of NF1 can contribute to melanoma resistance to BRAF inhibitors (ref).	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('mutations', 'Var', (56, 65))	('NF1', 'Gene', (91, 94))	('loss', 'Var', (83, 87))	('contribute', 'Reg', (99, 109))	('BRAF', 'Gene', '673', (136, 140))	('NF1', 'Gene', '4763', (91, 94))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('BRAF', 'Gene', (136, 140))	('melanoma', 'Disease', (113, 121))	('BRAF', 'Gene', '673', (51, 55))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('BRAF', 'Gene', (51, 55))	('NF1', 'Gene', '4763', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
71189	28296713	In addition, loss of NF1 can cooperate with mutated BRAF to promote melanocyte proliferation and tumorigenesis.	('promote', 'PosReg', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('melanocyte proliferation', 'CPA', (68, 92))	('tumor', 'Disease', (97, 102))	('mutated', 'Var', (44, 51))	('melanocyte proliferation', 'biological_process', 'GO:0097325', ('68', '92'))	('NF1', 'Gene', (21, 24))	('BRAF', 'Gene', '673', (52, 56))	('NF1', 'Gene', '4763', (21, 24))	('loss', 'Var', (13, 17))	('BRAF', 'Gene', (52, 56))
71190	28296713	We conjecture that mutations in NF1 may also contribute to the resistance to imatinib in some KIT-mutated mucosal melanoma.	('KIT', 'molecular_function', 'GO:0005020', ('94', '97'))	('mucosal melanoma', 'Disease', (106, 122))	('NF1', 'Gene', (32, 35))	('resistance to imatinib', 'MPA', (63, 85))	('mucosal melanoma', 'Disease', 'MESH:D008545', (106, 122))	('NF1', 'Gene', '4763', (32, 35))	('mutations', 'Var', (19, 28))	('imatinib', 'Chemical', 'MESH:D000068877', (77, 85))	('contribute', 'Reg', (45, 55))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
71191	28296713	Further investigation is needed to determine whether there is cooperation between KIT and NF1 mutations in mucosal melanoma to uncover new areas for therapy.	('NF1', 'Gene', '4763', (90, 93))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('mutations', 'Var', (94, 103))	('mucosal melanoma', 'Disease', (107, 123))	('KIT', 'molecular_function', 'GO:0005020', ('82', '85'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (107, 123))	('KIT', 'Gene', (82, 85))	('NF1', 'Gene', (90, 93))
71194	28296713	SF3B1 mutations have previously been described in myelodysplastic syndrome, chronic lymphocytic leukemia (CLL), breast cancer, and uveal melanomas, within exons 12-15, which correspond to the C-terminal HEAT domain of SF3B1 (Fig.	('SF3B1', 'Gene', (218, 223))	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Disease', (112, 125))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (76, 104))	('described', 'Reg', (37, 46))	('uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))	('SF3B1', 'Gene', (0, 5))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (50, 74))	('SF3B1', 'Gene', '23451', (218, 223))	('uveal melanomas', 'Disease', (131, 146))	('uveal melanomas', 'Phenotype', 'HP:0007716', (131, 146))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (50, 74))	('mutations', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('CLL', 'Phenotype', 'HP:0005550', (106, 109))	('melanomas', 'Phenotype', 'HP:0002861', (137, 146))	('SF3B1', 'Gene', '23451', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (76, 104))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('myelodysplastic syndrome', 'Disease', (50, 74))	('chronic lymphocytic leukemia', 'Disease', (76, 104))	('uveal melanomas', 'Disease', 'MESH:C536494', (131, 146))
71195	28296713	SF3B1 is the most frequently mutated spliceosome gene in cancer and is mutated in 20% of hematological malignancies (myelodysplastic syndrome and CLL), 18% of uveal melanomas, 5% of pancreatic cancers, 1.8% of breast cancers, and less than 1% in cutaneous melanoma.	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (117, 141))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('hematological malignancies', 'Disease', (89, 115))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (182, 200))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (57, 63))	('spliceosome', 'cellular_component', 'GO:0005681', ('37', '48'))	('melanoma', 'Phenotype', 'HP:0002861', (256, 264))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (117, 141))	('melanomas', 'Phenotype', 'HP:0002861', (165, 174))	('cutaneous melanoma', 'Disease', (246, 264))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('pancreatic cancers', 'Disease', (182, 200))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (246, 264))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (246, 264))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('SF3B1', 'Gene', (0, 5))	('CLL', 'Phenotype', 'HP:0005550', (146, 149))	('breast cancers', 'Disease', 'MESH:D001943', (210, 224))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('breast cancers', 'Disease', (210, 224))	('pancreatic cancers', 'Disease', 'MESH:D010190', (182, 200))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('uveal melanomas', 'Disease', 'MESH:C536494', (159, 174))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('hematological malignancies', 'Disease', 'MESH:D019337', (89, 115))	('breast cancers', 'Phenotype', 'HP:0003002', (210, 224))	('myelodysplastic syndrome', 'Disease', (117, 141))	('SF3B1', 'Gene', '23451', (0, 5))	('hematological malignancies', 'Phenotype', 'HP:0004377', (89, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (210, 223))	('uveal melanoma', 'Phenotype', 'HP:0007716', (159, 173))	('mutated', 'Var', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('cancer', 'Disease', (217, 223))	('uveal melanomas', 'Disease', (159, 174))	('uveal melanomas', 'Phenotype', 'HP:0007716', (159, 174))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
71196	28296713	The frequency of mutations in SF3B1 in this study (8/19, 42%) is higher than that reported in any other cancer type (Fig.	('SF3B1', 'Gene', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('SF3B1', 'Gene', '23451', (30, 35))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
71197	28296713	Furthermore, we identified that mutations in other spliceosome pathway genes occurred at a higher frequency in mucosal melanoma as compared with our 135 sun-exposed cutaneous melanomas (Fig.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (165, 184))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (165, 184))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (165, 183))	('cutaneous melanomas', 'Disease', (165, 184))	('mucosal melanoma', 'Disease', (111, 127))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanomas', 'Phenotype', 'HP:0002861', (175, 184))	('mutations', 'Var', (32, 41))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('spliceosome', 'cellular_component', 'GO:0005681', ('51', '62'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (111, 127))	('spliceosome pathway genes', 'Gene', (51, 76))
71198	28296713	We observed that patient 1 harbored the most mutations in our cohort; this may explain the higher comutation rate of SF3B1 with other spliceosomal component genes.	('mutations', 'Var', (45, 54))	('patient', 'Species', '9606', (17, 24))	('SF3B1', 'Gene', (117, 122))	('comutation', 'MPA', (98, 108))	('SF3B1', 'Gene', '23451', (117, 122))
71201	28296713	In our study, seven (37%) of the mucosal melanoma patients carried the recurrent SF3B1 mutation at codon 625 (Fig.	('SF3B1', 'Gene', (81, 86))	('patients', 'Species', '9606', (50, 58))	('SF3B1', 'Gene', '23451', (81, 86))	('mutation at codon', 'Var', (87, 104))	('mucosal melanoma', 'Disease', (33, 49))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('mucosal melanoma', 'Disease', 'MESH:D008545', (33, 49))
71202	28296713	Five of the mucosal melanoma patients harbored the mutation R625H, which is also a common mutation found in uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (108, 122))	('patients', 'Species', '9606', (29, 37))	('R625H', 'Mutation', 'rs1057519961', (60, 65))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('uveal melanoma', 'Disease', (108, 122))	('R625H', 'Var', (60, 65))	('mucosal melanoma', 'Disease', (12, 28))	('mucosal melanoma', 'Disease', 'MESH:D008545', (12, 28))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
71203	28296713	The other two patients carried mutation R625C in SF3B1, and one variant R625S.	('SF3B1', 'Gene', '23451', (49, 54))	('R625S', 'Var', (72, 77))	('R625C', 'Mutation', 'rs775623976', (40, 45))	('SF3B1', 'Gene', (49, 54))	('R625S', 'Mutation', 'p.R625S', (72, 77))	('patients', 'Species', '9606', (14, 22))
71204	28296713	A recent targeted sequencing of 15 anorectal mucosal melanoma patients described five patients with the identical SF3B1 R625 mutation, confirming our findings.	('15 anorectal mucosal melanoma', 'Disease', (32, 61))	('SF3B1', 'Gene', '23451', (114, 119))	('15 anorectal mucosal melanoma', 'Disease', 'MESH:D008545', (32, 61))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('R625', 'Var', (120, 124))	('SF3B1', 'Gene', (114, 119))	('patients', 'Species', '9606', (62, 70))	('patients', 'Species', '9606', (86, 94))
71205	28296713	WES in cutaneous melanoma found only a very low frequency of SF3B1 R625H/C mutations, 2/231 cutaneous patient samples.	('cutaneous melanoma', 'Disease', (7, 25))	('R625H', 'Mutation', 'rs1057519961', (67, 72))	('SF3B1', 'Gene', (61, 66))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (7, 25))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (7, 25))	('patient', 'Species', '9606', (102, 109))	('R625H/C', 'Var', (67, 74))	('SF3B1', 'Gene', '23451', (61, 66))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))
71207	28296713	A previous study found four patients with SF3B1 mutation in 20 desmoplastic melanoma patient; none of these mutations was at codon 625.	('desmoplastic melanoma', 'Disease', (63, 84))	('patient', 'Species', '9606', (85, 92))	('SF3B1', 'Gene', (42, 47))	('patient', 'Species', '9606', (28, 35))	('mutation', 'Var', (48, 56))	('SF3B1', 'Gene', '23451', (42, 47))	('patients', 'Species', '9606', (28, 36))	('desmoplastic melanoma', 'Disease', 'MESH:D008545', (63, 84))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
71208	28296713	Recent studies have elucidated a functional role for recurrent hotspot mutations found in the C-terminal HEAT domains in SF3B1, indicating that these mutations result in alternative splicing, primarily by inducing aberrant 3' splice site selection.	("3' splice site selection", 'MPA', (223, 247))	('result in', 'Reg', (160, 169))	('alternative splicing', 'MPA', (170, 190))	('splice site selection', 'biological_process', 'GO:0000380', ('226', '247'))	('splice site selection', 'biological_process', 'GO:0000381', ('226', '247'))	('inducing', 'Reg', (205, 213))	('SF3B1', 'Gene', (121, 126))	('mutations', 'Var', (150, 159))	('splicing', 'biological_process', 'GO:0045292', ('182', '190'))	('SF3B1', 'Gene', '23451', (121, 126))
71209	28296713	Thus, it was hypothesized that the SF3B1 R625 mutation results in differential interaction with the pre-mRNA or other splicing factors of the U2 snRNP complex, such as p14 or U2AF65, resulting in binding to a noncanonical branch point, thus facilitating alternative 3' splice site selection.	('binding', 'Interaction', (196, 203))	('binding', 'molecular_function', 'GO:0005488', ('196', '203'))	('U2AF65', 'Gene', (175, 181))	('U2AF', 'cellular_component', 'GO:0089701', ('175', '179'))	('interaction', 'Interaction', (79, 90))	('noncanonical branch point', 'MPA', (209, 234))	('SF3B1', 'Gene', (35, 40))	("alternative 3' splice site selection", 'MPA', (254, 290))	('splice site selection', 'biological_process', 'GO:0000380', ('269', '290'))	('snRNP', 'molecular_function', 'GO:0003734', ('145', '150'))	('facilitating', 'Reg', (241, 253))	('U2AF65', 'Gene', '11338', (175, 181))	('splicing', 'biological_process', 'GO:0045292', ('118', '126'))	('SF3B1', 'Gene', '23451', (35, 40))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('142', '150'))	('p14', 'Gene', (168, 171))	('pre', 'molecular_function', 'GO:0003904', ('100', '103'))	('p14', 'Gene', '11102', (168, 171))	('R625', 'Var', (41, 45))	('splice site selection', 'biological_process', 'GO:0000381', ('269', '290'))
71210	28296713	In our current study, we show for the first time that SF3B1 mutations in mucosal melanoma are associated with alternative splicing (Fig.	('SF3B1', 'Gene', (54, 59))	('alternative splicing', 'MPA', (110, 130))	('mucosal melanoma', 'Disease', (73, 89))	('SF3B1', 'Gene', '23451', (54, 59))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('associated', 'Reg', (94, 104))	('mucosal melanoma', 'Disease', 'MESH:D008545', (73, 89))	('splicing', 'biological_process', 'GO:0045292', ('122', '130'))	('mutations', 'Var', (60, 69))
71212	28296713	We validated all these genes to be differentially spliced in mucosal melanoma, highlighting a functional role for mutations in SF3B1.	('mucosal melanoma', 'Disease', 'MESH:D008545', (61, 77))	('SF3B1', 'Gene', (127, 132))	('mutations', 'Var', (114, 123))	('SF3B1', 'Gene', '23451', (127, 132))	('mucosal melanoma', 'Disease', (61, 77))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))
71213	28296713	Specifically, we found ABCC5, CRNDE, RPL31, and TMEM14C, in which the alternatively spliced variants were highly expressed in SF3B1 mutant as compared with wild-type mucosal melanoma samples.	('highly expressed', 'PosReg', (106, 122))	('RPL31', 'Gene', (37, 42))	('SF3B1', 'Gene', (126, 131))	('mutant', 'Var', (132, 138))	('CRNDE', 'Gene', '643911', (30, 35))	('CRNDE', 'Gene', (30, 35))	('TMEM14C', 'Gene', '51522', (48, 55))	('ABCC5', 'Gene', (23, 28))	('SF3B1', 'Gene', '23451', (126, 131))	('mucosal melanoma', 'Disease', (166, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('RPL31', 'Gene', '6160', (37, 42))	('TMEM14C', 'Gene', (48, 55))	('ABCC5', 'Gene', '10057', (23, 28))	('mucosal melanoma', 'Disease', 'MESH:D008545', (166, 182))
71222	28296713	Interestingly, SF3B1 wild-type overexpression in cell lines does not recapitulate the alternative splicing events induced by SF3B1 mutant, indicating that mutations in SF3B1 are neomorphic.	('SF3B1', 'Gene', '23451', (125, 130))	('SF3B1', 'Gene', '23451', (15, 20))	('mutant', 'Var', (131, 137))	('splicing', 'biological_process', 'GO:0045292', ('98', '106'))	('SF3B1', 'Gene', (168, 173))	('SF3B1', 'Gene', (125, 130))	('SF3B1', 'Gene', '23451', (168, 173))	('SF3B1', 'Gene', (15, 20))
71223	28296713	identified that selective inhibition of SF3B1 mutant, but not wild-type alleles, resulted in differential splicing without effecting cell growth.	('SF3B1', 'Gene', (40, 45))	('SF3B1', 'Gene', '23451', (40, 45))	('splicing', 'MPA', (106, 114))	('inhibition', 'NegReg', (26, 36))	('mutant', 'Var', (46, 52))	('splicing', 'biological_process', 'GO:0045292', ('106', '114'))	('cell growth', 'biological_process', 'GO:0016049', ('133', '144'))
71224	28296713	However, inhibition of SF3B1 wild-type resulted in growth inhibition in vitro, indicating that cells are reliant on SF3B1 wild-type for growth.	('SF3B1', 'Gene', (116, 121))	('SF3B1', 'Gene', '23451', (23, 28))	('SF3B1', 'Gene', '23451', (116, 121))	('SF3B1', 'Gene', (23, 28))	('growth', 'MPA', (51, 57))	('inhibition', 'Var', (9, 19))
71227	28296713	Recently, a phase I study of E7101, a novel spliceosome inhibitor, whose main target is SF3B1, has begun in solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (108, 120))	('spliceosome', 'cellular_component', 'GO:0005681', ('44', '55'))	('SF3B1', 'Gene', '23451', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('E7101', 'Chemical', '-', (29, 34))	('solid tumors', 'Disease', (108, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('SF3B1', 'Gene', (88, 93))	('E7101', 'Var', (29, 34))
71229	28296713	Identifying the effects of SF3B1 inhibition in mucosal melanoma may open new avenues for the treatment of mucosal melanomas with an SF3B1 mutation.	('SF3B1', 'Gene', '23451', (27, 32))	('mucosal melanomas', 'Disease', (106, 123))	('SF3B1', 'Gene', '23451', (132, 137))	('mucosal melanoma', 'Disease', 'MESH:D008545', (47, 63))	('mucosal melanoma', 'Disease', 'MESH:D008545', (106, 122))	('melanomas', 'Phenotype', 'HP:0002861', (114, 123))	('inhibition', 'NegReg', (33, 43))	('SF3B1', 'Gene', (27, 32))	('mucosal melanomas', 'Disease', 'MESH:D008545', (106, 123))	('mutation', 'Var', (138, 146))	('SF3B1', 'Gene', (132, 137))	('mucosal melanoma', 'Disease', (47, 63))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
71230	28296713	There were too few patients in our study to make significant survival correlations between patients with SF3B1 mutations and those with wild-type SF3B1.	('mutations', 'Var', (111, 120))	('SF3B1', 'Gene', (105, 110))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (19, 27))	('SF3B1', 'Gene', '23451', (105, 110))	('SF3B1', 'Gene', (146, 151))	('SF3B1', 'Gene', '23451', (146, 151))
71231	28296713	The presence of SF3B1 mutations in CLL correlates to a worse prognosis, whereas SF3B1 hotspot mutations appear to correlate with better prognosis in uveal melanomas.	('SF3B1', 'Gene', '23451', (80, 85))	('uveal melanomas', 'Disease', 'MESH:C536494', (149, 164))	('melanomas', 'Phenotype', 'HP:0002861', (155, 164))	('CLL', 'Phenotype', 'HP:0005550', (35, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (149, 163))	('SF3B1', 'Gene', '23451', (16, 21))	('uveal melanomas', 'Disease', (149, 164))	('uveal melanomas', 'Phenotype', 'HP:0007716', (149, 164))	('mutations', 'Var', (22, 31))	('SF3B1', 'Gene', (80, 85))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('SF3B1', 'Gene', (16, 21))
71232	28296713	More patient samples are needed to establish the correlation between SF3B1 mutation and overall survival in mucosal melanomas.	('mucosal melanomas', 'Disease', 'MESH:D008545', (108, 125))	('patient', 'Species', '9606', (5, 12))	('mutation', 'Var', (75, 83))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('SF3B1', 'Gene', (69, 74))	('mucosal melanomas', 'Disease', (108, 125))	('SF3B1', 'Gene', '23451', (69, 74))
71233	28296713	For future work, we plan to perform RNA sequencing in the mucosal melanoma samples to compare the alternatively spliced transcripts in SF3B1 mutant as compared with wild-type as previously described.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('mutant', 'Var', (141, 147))	('mucosal melanoma', 'Disease', (58, 74))	('RNA', 'cellular_component', 'GO:0005562', ('36', '39'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (58, 74))	('SF3B1', 'Gene', (135, 140))	('SF3B1', 'Gene', '23451', (135, 140))
71237	28296713	We identified comutations of KIT and NF1 (32%), as well as recurrent SF3B1 mutations (42%).	('KIT', 'molecular_function', 'GO:0005020', ('29', '32'))	('comutations', 'Var', (14, 25))	('NF1', 'Gene', (37, 40))	('SF3B1', 'Gene', (69, 74))	('KIT', 'Gene', (29, 32))	('NF1', 'Gene', '4763', (37, 40))	('mutations', 'Var', (75, 84))	('SF3B1', 'Gene', '23451', (69, 74))
71238	28296713	SF3B1 mutations have not been previously reported in vulvovaginal or nasopharyngeal mucosal melanoma, and only once previous study found mutations in anorectal mucosal melanoma using targeted sequencing.	('vulvovaginal', 'Disease', (53, 65))	('mucosal melanoma', 'Disease', 'MESH:D008545', (84, 100))	('SF3B1', 'Gene', (0, 5))	('anorectal mucosal melanoma', 'Disease', 'MESH:D008545', (150, 176))	('SF3B1', 'Gene', '23451', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('anorectal mucosal melanoma', 'Disease', (150, 176))	('vulvovaginal', 'Disease', 'MESH:D014848', (53, 65))	('mucosal melanoma', 'Disease', (84, 100))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('mutations', 'Var', (6, 15))	('mucosal melanoma', 'Disease', 'MESH:D008545', (160, 176))
71239	28296713	In addition, our report is the first study in demonstrating the functional role of SF3B1 R625 mutations inducing alternative splicing in mucosal melanoma.	('R625 mutations', 'Var', (89, 103))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('mutations', 'Var', (94, 103))	('mucosal melanoma', 'Disease', 'MESH:D008545', (137, 153))	('alternative splicing', 'MPA', (113, 133))	('SF3B1', 'Gene', (83, 88))	('splicing', 'biological_process', 'GO:0045292', ('125', '133'))	('SF3B1', 'Gene', '23451', (83, 88))	('mucosal melanoma', 'Disease', (137, 153))
71240	28296713	Future studies will focus on the wide spread effects of SF3B1 mutations on aberrant mRNA isoforms, and the effect of alternate splicing on tumor progression in mucosal melanoma.	('effects', 'Reg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('aberrant mRNA isoforms', 'MPA', (75, 97))	('SF3B1', 'Gene', '23451', (56, 61))	('splicing', 'biological_process', 'GO:0045292', ('127', '135'))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('mucosal melanoma', 'Disease', (160, 176))	('SF3B1', 'Gene', (56, 61))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('mutations', 'Var', (62, 71))	('mucosal melanoma', 'Disease', 'MESH:D008545', (160, 176))
71241	28296713	These findings advance our understanding of mucosal melanoma and offer potential targetable mutations that could improve treatment for these rare forms of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('mutations', 'Var', (92, 101))	('mucosal melanoma', 'Disease', (44, 60))	('melanoma', 'Disease', (155, 163))	('mucosal melanoma', 'Disease', 'MESH:D008545', (44, 60))
71280	26575174	The primary uveal tumors are often multi-nodular and the individual tumor nodules isolated 4 or 21 weeks post-operation were significantly larger in CLND-resected animals than the controls at both time-points (Figure 2B).	('tumor', 'Disease', (68, 73))	('CLND', 'Chemical', '-', (149, 153))	('tumor', 'Disease', (18, 23))	('multi-nodular', 'Disease', (35, 48))	('rat', 'Species', '10116', (113, 116))	('uveal tumors', 'Disease', 'MESH:D014604', (12, 24))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('CLND-resected', 'Var', (149, 162))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('uveal tumors', 'Disease', (12, 24))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('multi-nodular', 'Disease', 'MESH:D020518', (35, 48))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
71283	26575174	The size of body metastases was also significantly larger in the CLND-resected group than the controls (Figure 2E).	('metastases', 'Disease', 'MESH:D009362', (17, 27))	('larger', 'PosReg', (51, 57))	('CLND-resected', 'Var', (65, 78))	('metastases', 'Disease', (17, 27))	('CLND', 'Chemical', '-', (65, 69))
71293	26575174	Furthermore, LN removal is expected to promote and/or sustain inflammation at the upstream peripheral site by disrupting lymphatic drainage (Supplementary Figure S3).	('inflammation', 'Disease', 'MESH:D007249', (62, 74))	('inflammation', 'Disease', (62, 74))	('promote', 'PosReg', (39, 46))	('lymphatic drainage', 'MPA', (121, 139))	('inflammation', 'biological_process', 'GO:0006954', ('62', '74'))	('removal', 'Var', (16, 23))	('disrupting lymphatic drainage', 'Phenotype', 'HP:0001004', (110, 139))	('disrupting', 'NegReg', (110, 120))
71321	26575174	Immunoblotting using phospho-specific antibodies revealed a significantly higher expression of pAKT while pERK1/2 expression remained unchanged in the tumor-bearing eyes of the CLND group as compared to control group (Figure 5A-5B and data not shown).	('CLND', 'Var', (177, 181))	('ERK1/2', 'Gene', (107, 113))	('AKT', 'Gene', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('higher', 'PosReg', (74, 80))	('CLND', 'Chemical', '-', (177, 181))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('AKT', 'Gene', '11651', (96, 99))	('ERK1/2', 'Gene', '26417;26413', (107, 113))	('expression', 'MPA', (81, 91))
71342	26575174	Therefore, we propose that the removal of LN may promote the growth of primary tumor and cancer cell dissemination by stimulating a pro-tumoral environment.	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', (79, 84))	('removal', 'Var', (31, 38))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cancer', 'Disease', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('promote', 'PosReg', (49, 56))	('primary tumor', 'Disease', (71, 84))	('stimulating', 'PosReg', (118, 129))	('growth', 'CPA', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('primary tumor', 'Disease', 'MESH:D009369', (71, 84))
71350	26575174	In addition to its analgesic property, Celecoxib has anti-tumor effects by blocking angiogenesis and inducing cell cycle arrest and apoptosis.	('apoptosis', 'CPA', (132, 141))	('arrest', 'Disease', 'MESH:D006323', (121, 127))	('tumor', 'Disease', (58, 63))	('angiogenesis', 'CPA', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (110, 127))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('110', '127'))	('Celecoxib', 'Chemical', 'MESH:D000068579', (39, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('132', '141'))	('arrest', 'Disease', (121, 127))	('Celecoxib', 'Var', (39, 48))	('apoptosis', 'biological_process', 'GO:0006915', ('132', '141'))	('inducing', 'PosReg', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('blocking', 'NegReg', (75, 83))	('angiogenesis', 'biological_process', 'GO:0001525', ('84', '96'))
71366	26575174	Similarly, in the transplanted tumor models using Lewis lung carcinoma, T241 sarcoma and B16F10 melanoma, removal of the primary tumor led to large and highly neovascularized growing metastases and reduced apoptosis in metastatic tumor cells.	('sarcoma', 'Disease', 'MESH:D012509', (77, 84))	('primary tumor', 'Disease', 'MESH:D009369', (121, 134))	('sarcoma', 'Disease', (77, 84))	('apoptosis', 'CPA', (206, 215))	('tumor', 'Disease', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('primary tumor', 'Disease', (121, 134))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('metastases', 'Disease', 'MESH:D009362', (183, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (77, 84))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('tumor', 'Disease', (230, 235))	('removal', 'Var', (106, 113))	('metastases', 'Disease', (183, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('Lewis lung carcinoma', 'Disease', (50, 70))	('apoptosis', 'biological_process', 'GO:0097194', ('206', '215'))	('reduced', 'NegReg', (198, 205))	('apoptosis', 'biological_process', 'GO:0006915', ('206', '215'))	('tumor', 'Disease', (31, 36))	('Lewis lung carcinoma', 'Disease', 'MESH:D018827', (50, 70))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
71370	26575174	Notably, perioperative administration of NSAID ketorolac, a common surgical anti-inflammatory analgesic, in breast cancer patients, is associated with superior disease-free survival in the first few years after surgery and the absence of early cancer recurrence.	('breast cancer', 'Disease', (108, 121))	('cancer', 'Disease', (115, 121))	('rat', 'Species', '10116', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('patients', 'Species', '9606', (122, 130))	('superior', 'PosReg', (151, 159))	('rat', 'Species', '10116', (31, 34))	('ketorolac', 'Chemical', 'MESH:D020910', (47, 56))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('disease-free survival', 'CPA', (160, 181))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', (244, 250))	('NSAID ketorolac', 'Var', (41, 56))
71373	26575174	Finally, although this point will need further investigations, we cannot exclude that a reduction in anti-tumor immunity as a result of the removal of LN, a central site for T cell priming, may account for the enhanced tumor growth and cancer cell dissemination observed in RET mice after lymphadenectomy.	('tumor growth', 'Disease', (219, 231))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('removal', 'Var', (140, 147))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('enhanced', 'PosReg', (210, 218))	('tumor', 'Disease', (219, 224))	('tumor growth', 'Disease', 'MESH:D006130', (219, 231))	('cancer', 'Disease', (236, 242))	('reduction', 'NegReg', (88, 97))	('mice', 'Species', '10090', (278, 282))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Disease', (106, 111))
71374	26575174	Here, we show that CLND enhances primary tumor growth and metastasis in a mouse model of melanoma in part by promoting a pro-tumoral inflammatory environment.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('promoting', 'PosReg', (109, 118))	('primary tumor', 'Disease', 'MESH:D009369', (33, 46))	('tumor growth', 'Disease', (41, 53))	('CLND', 'Var', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('primary tumor', 'Disease', (33, 46))	('enhances', 'PosReg', (24, 32))	('tumor', 'Disease', (41, 46))	('mouse', 'Species', '10090', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('metastasis', 'CPA', (58, 68))	('tumor growth', 'Disease', 'MESH:D006130', (41, 53))	('CLND', 'Chemical', '-', (19, 23))	('tumor', 'Disease', (125, 130))
71425	26934137	Type II, or variant NKT cells, express variable TCR gene rearrangements; and while a subset react to sulfatide, an activating ligand that identifies and activates the whole cell population has not yet been identified.	('sulfatide', 'Chemical', 'MESH:D013433', (101, 110))	('TCR', 'Gene', (48, 51))	('TCR', 'biological_process', 'GO:0006283', ('48', '51'))	('variant', 'Var', (12, 19))	('NKT', 'Gene', (20, 23))	('ligand', 'molecular_function', 'GO:0005488', ('126', '132'))	('TCR', 'Gene', '328483', (48, 51))	('react to sulfatide', 'MPA', (92, 110))	('TCR', 'cellular_component', 'GO:0042101', ('48', '51'))
71436	26934137	The role of type II NKT cells on the resulting immunopathology of bystander ocular tissue destruction normally seen in this model of intraocular tumor rejection was assessed by utilizing three genotypes of mice: C57BL/6J wild-type (WT), Jalpha18 KO, and CD1d KO mice.	('CD1d', 'Gene', '12479', (254, 258))	('C57BL/6J', 'Var', (212, 220))	('ocular tumor', 'Phenotype', 'HP:0100012', (138, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mice', 'Species', '10090', (206, 210))	('mice', 'Species', '10090', (262, 266))	('intraocular tumor', 'Disease', (133, 150))	('intraocular tumor', 'Disease', 'MESH:D064090', (133, 150))	('CD1d', 'Gene', (254, 258))
71461	26934137	Mice were euthanized 14 days after AC injection with Ad5E1 tumor, and their tumor-bearing eyes were harvested and single cell suspensions generated.	('tumor', 'Disease', (59, 64))	('Ad5E1', 'Var', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('rat', 'Species', '10116', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
71463	26934137	Mice were euthanized 14 days after AC injection with Ad5E1 tumor, and their tumor-bearing eyes were processed for immunohistochemistry as previously described.	('tumor', 'Disease', (59, 64))	('Ad5E1', 'Var', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
71468	26934137	We have previously shown that the Ad5E1 intraocular tumor undergoes a necrotizing form of immune rejection in the eyes of WT mice.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('undergoes', 'Reg', (58, 67))	('ocular tumor', 'Phenotype', 'HP:0100012', (45, 57))	('mice', 'Species', '10090', (125, 129))	('intraocular tumor', 'Disease', (40, 57))	('immune rejection', 'CPA', (90, 106))	('Ad5E1', 'Var', (34, 39))	('intraocular tumor', 'Disease', 'MESH:D064090', (40, 57))
71474	26934137	Intraocular tumors grew transiently and underwent rejection in all the Jalpha18 KO mice, with a similar incidence of phthisis (72%) found in WT mice (Fig.	('Jalpha18', 'Var', (71, 79))	('mice', 'Species', '10090', (144, 148))	('Intraocular tumors', 'Disease', (0, 18))	('mice', 'Species', '10090', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('Intraocular tumors', 'Disease', 'MESH:D064090', (0, 18))	('ocular tumor', 'Phenotype', 'HP:0100012', (5, 17))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))
71478	26934137	Thus, the absence of an intact type II NKT cell repertoire profoundly affects the immunopathological phenotype of intraocular tumor rejection and as a result, preserves the integrity of the eye.	('preserves', 'Reg', (159, 168))	('intraocular tumor', 'Disease', (114, 131))	('intraocular tumor', 'Disease', 'MESH:D064090', (114, 131))	('affects', 'Reg', (70, 77))	('integrity', 'MPA', (173, 182))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('absence', 'Var', (10, 17))	('ocular tumor', 'Phenotype', 'HP:0100012', (119, 131))
71479	26934137	Due to the different intraocular rejection phenotypes in WT mice compared to CD1d KO mice, we tested if the loss of NKT cells would lead to reduced inflammatory responses after AC tumor injection.	('tested', 'Reg', (94, 100))	('mice', 'Species', '10090', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('reduced inflammatory response', 'Phenotype', 'HP:0012648', (140, 169))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('loss', 'Var', (108, 112))	('inflammatory responses', 'CPA', (148, 170))	('tumor', 'Disease', (180, 185))	('CD1d', 'Gene', (77, 81))	('CD1d', 'Gene', '12479', (77, 81))	('NKT cells', 'Gene', (116, 125))	('mice', 'Species', '10090', (60, 64))	('reduced', 'NegReg', (140, 147))
71499	26934137	This bears noting as neutrophils are known to cause bystander tissue damage in other tissues such as the heart, peritoneal toxic shock, pancreas, kidney, and liver, as well as in ocular infections.	('neutrophils', 'Var', (21, 32))	('peritoneal toxic shock', 'Disease', (112, 134))	('pancreas', 'Disease', (136, 144))	('shock', 'Phenotype', 'HP:0031273', (129, 134))	('peritoneal toxic shock', 'Disease', 'MESH:D012772', (112, 134))	('pancreas', 'Disease', 'MESH:D010190', (136, 144))	('cause', 'Reg', (46, 51))	('ocular infections', 'Disease', (179, 196))	('ocular infections', 'Disease', 'MESH:D015817', (179, 196))
71515	26934137	We hypothesized that removal of neutrophils would lead to a reduced rate of phthisis that would resemble the low rate of phthisis seen in CD1d KO mice.	('CD1d', 'Gene', '12479', (138, 142))	('rat', 'Species', '10116', (113, 116))	('phthisis', 'Disease', (76, 84))	('reduced', 'NegReg', (60, 67))	('neutrophils', 'Var', (32, 43))	('mice', 'Species', '10090', (146, 150))	('rat', 'Species', '10116', (68, 71))	('removal', 'Var', (21, 28))	('CD1d', 'Gene', (138, 142))
71534	26934137	We found a distinctly different outcome in our intraocular tumor model, where the loss of type II NKT cells in CD1d KO mice, compared to only the loss of type I NKT cells in Jalpha18 KO mice, led to a more efficient antitumor response that also spared bystander ocular tissue from destruction.	('CD1d', 'Gene', (111, 115))	('intraocular tumor', 'Disease', 'MESH:D064090', (47, 64))	('mice', 'Species', '10090', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (59, 64))	('ocular tumor', 'Phenotype', 'HP:0100012', (52, 64))	('tumor', 'Disease', (220, 225))	('CD1d', 'Gene', '12479', (111, 115))	('more', 'PosReg', (201, 205))	('intraocular tumor', 'Disease', (47, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('mice', 'Species', '10090', (186, 190))	('loss', 'Var', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
71536	26934137	This is reminiscent of the results reported for a model of ischemia-reperfusion injury of the kidney in which inhibition of both neutrophil infiltration mitigated kidney damage in CD1d-depleted mice compared to Jalpha18 KO mice.	('ischemia-reperfusion injury of the kidney', 'Disease', 'MESH:D015427', (59, 100))	('CD1d', 'Gene', (180, 184))	('mice', 'Species', '10090', (223, 227))	('infiltration mitigated kidney damage', 'Disease', (140, 176))	('infiltration mitigated kidney damage', 'Disease', 'MESH:D007674', (140, 176))	('CD1d', 'Gene', '12479', (180, 184))	('ischemia-reperfusion injury of the kidney', 'Disease', (59, 100))	('inhibition', 'Var', (110, 120))	('mice', 'Species', '10090', (194, 198))	('kidney damage', 'Phenotype', 'HP:0000112', (163, 176))
71543	26934137	In the present study, the absence of type II NKT cells in the CD1d KO mice leads to reduced CXCL3 levels and thus reduces neutrophil recruitment that dampens the full development of a DTH response in these mice.	('CXCL3', 'Gene', '330122', (92, 97))	('CD1d', 'Gene', '12479', (62, 66))	('CXCL3', 'Gene', (92, 97))	('absence', 'Var', (26, 33))	('mice', 'Species', '10090', (206, 210))	('neutrophil recruitment', 'MPA', (122, 144))	('reduces', 'NegReg', (114, 121))	('reduced', 'NegReg', (84, 91))	('mice', 'Species', '10090', (70, 74))	('reduced CXCL3 levels', 'Phenotype', 'HP:0031037', (84, 104))	('dampens', 'NegReg', (150, 157))	('DTH response', 'MPA', (184, 196))	('DTH', 'Phenotype', 'HP:0002972', (184, 187))	('CD1d', 'Gene', (62, 66))
71545	26934137	The absence of NKT cells has been shown to contribute to a decreased neutrophil infiltration in other peripheral tissues.	('absence', 'Var', (4, 11))	('rat', 'Species', '10116', (86, 89))	('NKT', 'Protein', (15, 18))	('decreased', 'NegReg', (59, 68))
71549	26934137	Mice with induced corneal human IL-8 expression developed corneal ulcers, angiogenesis, and significant endothelial cell disruption permitting increased immune cell infiltration.	('endothelial cell disruption', 'CPA', (104, 131))	('expression', 'Var', (37, 47))	('human IL-8', 'Gene', (26, 36))	('immune cell infiltration', 'CPA', (153, 177))	('corneal ulcers', 'Disease', 'MESH:D003320', (58, 72))	('angiogenesis', 'CPA', (74, 86))	('angiogenesis', 'biological_process', 'GO:0001525', ('74', '86'))	('corneal ulcers', 'Disease', (58, 72))	('rat', 'Species', '10116', (171, 174))	('corneal ulcers', 'Phenotype', 'HP:0012804', (58, 72))	('Mice', 'Species', '10090', (0, 4))	('IL-8', 'molecular_function', 'GO:0005153', ('32', '36'))	('human', 'Species', '9606', (26, 31))
71563	26934137	Dampening the initial proinflammatory innate immune responses generated by type II NKT cells, which then promote the activity and recruitment of neutrophils, generates a productive antitumor response with minimal ischemia and necrosis.	('tumor', 'Disease', (185, 190))	('necrosis', 'Disease', (226, 234))	('necrosis', 'biological_process', 'GO:0001906', ('226', '234'))	('promote', 'PosReg', (105, 112))	('rat', 'Species', '10116', (162, 165))	('activity', 'MPA', (117, 125))	('necrosis', 'biological_process', 'GO:0019835', ('226', '234'))	('necrosis', 'Disease', 'MESH:D009336', (226, 234))	('rat', 'Species', '10116', (66, 69))	('necrosis', 'biological_process', 'GO:0008220', ('226', '234'))	('ischemia', 'Disease', (213, 221))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('necrosis', 'biological_process', 'GO:0070265', ('226', '234'))	('necrosis', 'biological_process', 'GO:0008219', ('226', '234'))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('ischemia', 'Disease', 'MESH:D007511', (213, 221))	('Dampening', 'Var', (0, 9))
71566	26934137	That is, deletion of NKT cells results in enhanced NK cell-mediated cytolysis of murine melanoma cells and a steep reduction in the development of liver metastases arising from intraocular melanomas in mice.	('NKT cells', 'Gene', (21, 30))	('liver metastases', 'Disease', (147, 163))	('deletion', 'Var', (9, 17))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('NK cell-mediated cytolysis', 'biological_process', 'GO:0042267', ('51', '77'))	('enhanced', 'PosReg', (42, 50))	('melanomas', 'Phenotype', 'HP:0002861', (189, 198))	('reduction', 'NegReg', (115, 124))	('mice', 'Species', '10090', (202, 206))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', (189, 197))	('intraocular melanomas', 'Disease', 'MESH:C563596', (177, 198))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('liver metastases', 'Disease', 'MESH:D009362', (147, 163))	('development', 'CPA', (132, 143))	('intraocular melanomas', 'Phenotype', 'HP:0007716', (177, 198))	('murine', 'Species', '10090', (81, 87))	('intraocular melanomas', 'Disease', (177, 198))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))	('NK cell-mediated cytolysis', 'MPA', (51, 77))
71569	26934137	who reported that patients expressing high levels of MHC class I on their primary uveal melanomas experienced a poorer prognosis than patients expressing lower levels of MHC class I molecules on their uveal melanomas.	('uveal melanomas', 'Disease', (82, 97))	('uveal melanomas', 'Phenotype', 'HP:0007716', (82, 97))	('uveal melanomas', 'Disease', 'MESH:C536494', (201, 216))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (201, 215))	('patients', 'Species', '9606', (134, 142))	('melanomas', 'Phenotype', 'HP:0002861', (207, 216))	('uveal melanomas', 'Disease', 'MESH:C536494', (82, 97))	('patients', 'Species', '9606', (18, 26))	('uveal melanomas', 'Phenotype', 'HP:0007716', (201, 216))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('MHC class I', 'Var', (53, 64))	('uveal melanomas', 'Disease', (201, 216))
71584	25684974	There is convincing evidence that monosomy 3 and polysomy 8q are strongly associated with a poor survival prognosis in CM.	('CM', 'Disease', 'MESH:D009202', (119, 121))	('monosomy 3', 'Var', (34, 44))	('polysomy 8q', 'Var', (49, 60))
71636	25536104	IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group.	('alterations', 'Var', (25, 36))	('DNA repair', 'biological_process', 'GO:0006281', ('9', '19'))	('IDH1', 'Gene', '3417', (0, 4))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (65, 81))	('ERBB2', 'Gene', (89, 94))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('ERBB2', 'Gene', '2064', (89, 94))	('intrahepatic CCA', 'Disease', (65, 81))	('IDH1', 'Gene', (0, 4))	('DNA repair gene', 'Gene', (9, 24))
71644	25536104	The overall survival of this disease remains dismal due to delayed detection, suboptimal response to standard therapy and underlying liver disease such as non-alcoholic steatohepatitis (NASH), which can limit liver-directed therapies.	('liver disease', 'Disease', 'MESH:D008107', (133, 146))	('non-alcoholic steatohepatitis', 'Disease', 'MESH:D005234', (155, 184))	('liver disease', 'Phenotype', 'HP:0001392', (133, 146))	('suboptimal', 'Var', (78, 88))	('liver disease', 'Disease', (133, 146))	('non-alcoholic steatohepatitis', 'Disease', (155, 184))
71651	25536104	Using Sanger sequencing, they noted activating mutations in P53, KRAS, SMAD4 and 10 other newly implicated genes including MLL3, ROBO2, RNF3 and PEG3 .	('P53', 'Gene', (60, 63))	('ROBO2', 'Gene', '6092', (129, 134))	('PEG3', 'Gene', (145, 149))	('KRAS', 'Gene', '3845', (65, 69))	('ROBO2', 'Gene', (129, 134))	('MLL3', 'Gene', (123, 127))	('SMAD4', 'Gene', (71, 76))	('PEG3', 'Gene', '5178', (145, 149))	('P53', 'Gene', '7157', (60, 63))	('mutations', 'Var', (47, 56))	('KRAS', 'Gene', (65, 69))	('RNF3', 'Gene', (136, 140))	('MLL3', 'Gene', '58508', (123, 127))	('SMAD4', 'Gene', '4089', (71, 76))	('RNF3', 'Gene', '6046', (136, 140))	('activating', 'PosReg', (36, 46))
71667	25536104	The 46 genes in the panel for detection of targetable mutations included: AKT1, BRAF, FGFR1, GNAS, IDH1, FGFR2, KRAS, NRAS, PIK3CA, MET, RET, EGFR, JAK2, MPL, PDGFRA, PTEN, TP53, FGFR3, FLT3, KIT, ERBB2, ABL1, HNF1A, HRAS, ATM, RB1, CDH1, SMAD4, STK11, ALK, SRC, SMARCB1, VHL, MLH1, CTNNB1, KDR, FBXW7, APC, CSF1R, NPM1, SMO, ERBB4, CDKN2A, NOTCH1, JAK3, and PTPN11.	('STK11', 'Gene', '6794', (246, 251))	('TP53', 'Gene', (173, 177))	('NOTCH1', 'Gene', '4851', (341, 347))	('FGFR', 'molecular_function', 'GO:0005007', ('86', '90'))	('IDH1', 'Gene', '3417', (99, 103))	('FGFR3', 'Gene', (179, 184))	('NRAS', 'Gene', '4893', (118, 122))	('EGFR', 'molecular_function', 'GO:0005006', ('142', '146'))	('AKT1', 'Gene', '207', (74, 78))	('FGFR', 'molecular_function', 'GO:0005007', ('105', '109'))	('CTNNB1', 'Gene', '1499', (283, 289))	('EGFR', 'Gene', (142, 146))	('SMARCB1', 'Gene', (263, 270))	('MPL', 'Gene', '4352', (154, 157))	('AKT1', 'Gene', (74, 78))	('CDH1', 'Gene', (233, 237))	('ALK', 'Gene', '238', (253, 256))	('STK11', 'molecular_function', 'GO:0033868', ('246', '251'))	('SRC', 'Gene', (258, 261))	('APC', 'Disease', (303, 306))	('NOTCH1', 'Gene', (341, 347))	('ERBB4', 'Gene', '2066', (326, 331))	('ATM', 'Gene', '472', (223, 226))	('MLH1', 'Gene', (277, 281))	('EGFR', 'Gene', '1956', (142, 146))	('RB1', 'Gene', (228, 231))	('KDR', 'Gene', (291, 294))	('MLH1', 'Gene', '4292', (277, 281))	('FBXW7', 'Gene', '55294', (296, 301))	('mutations', 'Var', (54, 63))	('JAK2', 'Gene', '3717', (148, 152))	('FGFR1', 'Gene', (86, 91))	('FGFR2', 'Gene', (105, 110))	('ATM', 'Gene', (223, 226))	('RB1', 'Gene', '5925', (228, 231))	('ERBB2', 'Gene', (197, 202))	('KIT', 'molecular_function', 'GO:0005020', ('192', '195'))	('GNAS', 'Gene', '2778', (93, 97))	('SMARCB1', 'Gene', '6598', (263, 270))	('CDH1', 'Gene', '999', (233, 237))	('NPM1', 'Gene', (315, 319))	('CDKN2A', 'Gene', (333, 339))	('TP53', 'Gene', '7157', (173, 177))	('PIK3CA', 'Gene', '5290', (124, 130))	('STK11', 'Gene', (246, 251))	('ABL1', 'Gene', '25', (204, 208))	('PDGFRA', 'Gene', (159, 165))	('NRAS', 'Gene', (118, 122))	('CSF1', 'molecular_function', 'GO:0005011', ('308', '312'))	('CDKN2A', 'Gene', '1029', (333, 339))	('ALK', 'Gene', (253, 256))	('ERBB4', 'Gene', (326, 331))	('PIK3CA', 'Gene', (124, 130))	('SMAD4', 'Gene', '4089', (239, 244))	('BRAF', 'Gene', '673', (80, 84))	('APC', 'cellular_component', 'GO:0005680', ('303', '306'))	('HNF1A', 'Gene', '6927', (210, 215))	('JAK3', 'Gene', '3718', (349, 353))	('GNAS', 'Gene', (93, 97))	('HNF1A', 'Gene', (210, 215))	('HRAS', 'Gene', (217, 221))	('ABL1', 'Gene', (204, 208))	('KRAS', 'Gene', (112, 116))	('VHL', 'Gene', (272, 275))	('SRC', 'Gene', '6714', (258, 261))	('FGFR2', 'Gene', '2263', (105, 110))	('CSF1R', 'Gene', '1436', (308, 313))	('SMAD4', 'Gene', (239, 244))	('PTPN11', 'Gene', '5781', (359, 365))	('PDGFRA', 'Gene', '5156', (159, 165))	('FGFR', 'molecular_function', 'GO:0005007', ('179', '183'))	('IDH1', 'Gene', (99, 103))	('FBXW7', 'Gene', (296, 301))	('PTEN', 'Gene', '5728', (167, 171))	('APC', 'Disease', 'MESH:D011125', (303, 306))	('VHL', 'Gene', '7428', (272, 275))	('RET', 'Gene', '5979', (137, 140))	('MPL', 'Gene', (154, 157))	('JAK3', 'Gene', (349, 353))	('SMO', 'Gene', '6608', (321, 324))	('NPM1', 'Gene', '4869', (315, 319))	('BRAF', 'Gene', (80, 84))	('RET', 'Gene', (137, 140))	('JAK', 'molecular_function', 'GO:0004713', ('148', '151'))	('FLT3', 'Gene', (186, 190))	('SMO', 'Gene', (321, 324))	('KRAS', 'Gene', '3845', (112, 116))	('HRAS', 'Gene', '3265', (217, 221))	('FLT3', 'Gene', '2322', (186, 190))	('FGFR3', 'Gene', '2261', (179, 184))	('JAK', 'molecular_function', 'GO:0004713', ('349', '352'))	('KDR', 'Gene', '3791', (291, 294))	('PTEN', 'Gene', (167, 171))	('PTPN11', 'Gene', (359, 365))	('JAK2', 'Gene', (148, 152))	('ERBB2', 'Gene', '2064', (197, 202))	('CSF1R', 'Gene', (308, 313))	('FGFR1', 'Gene', '2260', (86, 91))	('CTNNB1', 'Gene', (283, 289))
71686	25536104	IDH1 mutations occurred exclusively in intrahepatic CCA while ERBB2 mutations were seen in extrahepatic CCA.	('intrahepatic CCA', 'Disease', (39, 55))	('occurred', 'Reg', (15, 23))	('mutations', 'Var', (5, 14))	('ERBB2', 'Gene', (62, 67))	('ERBB2', 'Gene', '2064', (62, 67))	('IDH1', 'Gene', (0, 4))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (39, 55))	('IDH1', 'Gene', '3417', (0, 4))
71698	25536104	MAPK, chromatin modification and mTOR pathway aberrations were relatively common (35%, 33% and 25%, respectively) followed by DNA repair (16%) and FGF signaling (13%).	('chromatin modification', 'Var', (6, 28))	('chromatin modification', 'biological_process', 'GO:0016569', ('6', '28'))	('mTOR', 'Gene', '2475', (33, 37))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('mTOR', 'Gene', (33, 37))	('aberrations', 'Var', (46, 57))	('MAPK', 'molecular_function', 'GO:0004707', ('0', '4'))	('DNA repair', 'biological_process', 'GO:0006281', ('126', '136'))	('MAPK', 'Disease', (0, 4))	('signaling', 'biological_process', 'GO:0023052', ('151', '160'))	('chromatin modification', 'biological_process', 'GO:0006325', ('6', '28'))	('chromatin', 'cellular_component', 'GO:0000785', ('6', '15'))
71699	25536104	Potential associations between the mutations with PFS and overall survival OS were explored in this study.	('OS', 'Chemical', '-', (75, 77))	('PFS', 'Gene', (50, 53))	('mutations', 'Var', (35, 44))
71701	25536104	In intrahepatic CCA, PFS was significantly associated with the clinical stage, KRAS mutations, and aberrations in the MAP/ERK pathway.	('intrahepatic CCA', 'Disease', 'MESH:C536211', (3, 19))	('intrahepatic CCA', 'Disease', (3, 19))	('KRAS', 'Gene', '3845', (79, 83))	('ERK', 'molecular_function', 'GO:0004707', ('122', '125'))	('aberrations', 'Var', (99, 110))	('mutations', 'Var', (84, 93))	('MAP', 'molecular_function', 'GO:0004239', ('118', '121'))	('ERK', 'Gene', '5594', (122, 125))	('associated', 'Reg', (43, 53))	('ERK', 'Gene', (122, 125))	('PFS', 'Disease', (21, 24))	('KRAS', 'Gene', (79, 83))
71702	25536104	The median PFS for patients with and without KRAS mutations was 3.4 and 10 months (p = 0.01).	('mutations', 'Var', (50, 59))	('KRAS', 'Gene', (45, 49))	('patients', 'Species', '9606', (19, 27))	('KRAS', 'Gene', '3845', (45, 49))
71703	25536104	Median PFS for patients with and without aberrant MAP/ERK pathway genes was 3.9 and 10 months (p = 0.004).	('patients', 'Species', '9606', (15, 23))	('ERK', 'Gene', '5594', (54, 57))	('aberrant', 'Var', (41, 49))	('ERK', 'molecular_function', 'GO:0004707', ('54', '57'))	('ERK', 'Gene', (54, 57))	('MAP', 'molecular_function', 'GO:0004239', ('50', '53'))
71706	25536104	OS was significantly associated with clinical stage, surgery, gender, TP53 mutations, KRAS mutations, MAP/ERK, mTOR and FGF pathway GAs (Table 6).	('OS', 'Chemical', '-', (0, 2))	('mTOR', 'Gene', '2475', (111, 115))	('KRAS', 'Gene', (86, 90))	('TP53', 'Gene', '7157', (70, 74))	('mTOR', 'Gene', (111, 115))	('associated', 'Reg', (21, 31))	('KRAS', 'Gene', '3845', (86, 90))	('MAP', 'molecular_function', 'GO:0004239', ('102', '105'))	('ERK', 'Gene', '5594', (106, 109))	('TP53', 'Gene', (70, 74))	('mutations', 'Var', (91, 100))	('ERK', 'molecular_function', 'GO:0004707', ('106', '109'))	('ERK', 'Gene', (106, 109))	('FGF pathway', 'Pathway', (120, 131))
71709	25536104	However, male gender (HR 3.25, p = 0.01) and TP53 mutations (HR 4.92, p = 0.0006) were found to be associated with reduced OS.	('TP53', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('reduced', 'NegReg', (115, 122))	('TP53', 'Gene', '7157', (45, 49))	('OS', 'Chemical', '-', (123, 125))
71717	25536104	One of the ERBB2 mutations was in the kinase domain (V777L) while 3 involved the extracellular domain (S310F).	('S310F', 'Var', (103, 108))	('ERBB2', 'Gene', (11, 16))	('V777L', 'Var', (53, 58))	('ERBB2', 'Gene', '2064', (11, 16))	('extracellular', 'cellular_component', 'GO:0005576', ('81', '94'))	('S310F', 'Mutation', 'rs1057519816', (103, 108))	('V777L', 'Mutation', 'rs121913471', (53, 58))
71718	25536104	IHC for ERBB2 was negative in all cases with ERBB2 mutations.	('ERBB2', 'Gene', '2064', (8, 13))	('mutations', 'Var', (51, 60))	('ERBB2', 'Gene', (8, 13))	('ERBB2', 'Gene', '2064', (45, 50))	('ERBB2', 'Gene', (45, 50))
71719	25536104	MAPK, mTOR and DNA repair pathway aberrations were relatively common (55%, 40% and 45%, respectively) followed by chromatin modification (15%) and FGF signaling (5%).	('chromatin modification', 'MPA', (114, 136))	('DNA repair', 'biological_process', 'GO:0006281', ('15', '25'))	('chromatin modification', 'biological_process', 'GO:0016569', ('114', '136'))	('DNA repair pathway', 'Pathway', (15, 33))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('FGF signaling', 'MPA', (147, 160))	('MAPK', 'molecular_function', 'GO:0004707', ('0', '4'))	('chromatin', 'cellular_component', 'GO:0000785', ('114', '123'))	('signaling', 'biological_process', 'GO:0023052', ('151', '160'))	('chromatin modification', 'biological_process', 'GO:0006325', ('114', '136'))	('mTOR', 'Gene', '2475', (6, 10))	('MAPK', 'Pathway', (0, 4))	('aberrations', 'Var', (34, 45))	('mTOR', 'Gene', (6, 10))
71720	25536104	Survival analysis of extrahepatic CCA cases noted significant correlation of PFS with surgery, radiation, BAP1 mutation, and FGF pathway aberrations.	('BAP1', 'Gene', (106, 110))	('FGF pathway', 'Pathway', (125, 136))	('correlation', 'Interaction', (62, 73))	('PFS', 'Disease', (77, 80))	('BAP1', 'Gene', '8314', (106, 110))	('mutation', 'Var', (111, 119))	('aberrations', 'Var', (137, 148))
71721	25536104	OS was found to be associated with clinical stage, surgery, radiation therapy, and mutations in PBRM1 and BAP1 genes (Table 7).	('associated', 'Reg', (19, 29))	('mutations', 'Var', (83, 92))	('OS', 'Chemical', '-', (0, 2))	('BAP1', 'Gene', (106, 110))	('BAP1', 'Gene', '8314', (106, 110))	('PBRM1', 'Gene', (96, 101))	('PBRM1', 'Gene', '55193', (96, 101))
71722	25536104	A Kaplan-Meier curve demonstrating the relationship between BAP1 mutations and overall survival are shown in Fig.	('BAP1', 'Gene', '8314', (60, 64))	('BAP1', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
71723	25536104	The presence of BAP1 mutations was significantly associated with reduced PFS (median: 3 vs. 8.8 months, p = 0.02) and reduced OS (median: 8.9 vs. 19.9 months, p = 0.007).	('reduced', 'NegReg', (65, 72))	('reduced', 'NegReg', (118, 125))	('BAP1', 'Gene', '8314', (16, 20))	('OS', 'Chemical', '-', (126, 128))	('PFS', 'CPA', (73, 76))	('BAP1', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
71724	25536104	In our series, 6 cases had BAP1 mutations; 3 of these experienced early recurrence (less than six months) after potentially curative surgical resection.	('BAP1', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('BAP1', 'Gene', '8314', (27, 31))
71727	25536104	In addition, all cases with BAP1 mutation were treated with systemic chemotherapy consisting of gemcitabine and cisplatin.	('BAP1', 'Gene', '8314', (28, 32))	('mutation', 'Var', (33, 41))	('BAP1', 'Gene', (28, 32))	('gemcitabine', 'Chemical', 'MESH:C056507', (96, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))
71730	25536104	These patients had FGFR2 mutation, FGFR2-PARK2 fusion and FGF19 amplification, respectively.	('fusion', 'Var', (47, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('35', '39'))	('FGF19', 'Gene', '9965', (58, 63))	('PARK2', 'Gene', '5071', (41, 46))	('FGFR2', 'Gene', (35, 40))	('amplification', 'Var', (64, 77))	('mutation', 'Var', (25, 33))	('FGFR2', 'Gene', '2263', (35, 40))	('PARK2', 'Gene', (41, 46))	('FGF19', 'Gene', (58, 63))	('FGFR2', 'Gene', (19, 24))	('FGFR2', 'Gene', '2263', (19, 24))	('patients', 'Species', '9606', (6, 14))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))
71732	25536104	In contrast, one patient with concomitant FGFR2-NOL4 fusion had a rapidly progressive course; this patient also had co-existing BAP1 mutation.	('FGFR2', 'Gene', (42, 47))	('FGFR2', 'Gene', '2263', (42, 47))	('NOL4', 'Gene', (48, 52))	('mutation', 'Var', (133, 141))	('patient', 'Species', '9606', (99, 106))	('BAP1', 'Gene', '8314', (128, 132))	('patient', 'Species', '9606', (17, 24))	('NOL4', 'Gene', '8715', (48, 52))	('BAP1', 'Gene', (128, 132))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))
71736	25536104	One patient with KRAS mutation was enrolled on a clinical trial with pazopanib + trametinib and experienced stable disease after prior progression on first-line chemotherapy as illustrated in Fig.	('mutation', 'Var', (22, 30))	('trametinib', 'Chemical', 'MESH:C560077', (81, 91))	('pazopanib', 'Chemical', 'MESH:C516667', (69, 78))	('patient', 'Species', '9606', (4, 11))	('KRAS', 'Gene', (17, 21))	('KRAS', 'Gene', '3845', (17, 21))
71737	25536104	Two patients with BRAF mutation were referred for a trial with BRAF inhibitor; both experienced partial responses.	('mutation', 'Var', (23, 31))	('BRAF', 'Gene', '673', (18, 22))	('BRAF', 'Gene', '673', (63, 67))	('patients', 'Species', '9606', (4, 12))	('BRAF', 'Gene', (18, 22))	('BRAF', 'Gene', (63, 67))
71739	25536104	Another patient with c-met mutation was enrolled on an expansion cohort with a c-met inhibitor and experienced a metabolic response as illustrated in Fig.	('c-met', 'Gene', '4233', (79, 84))	('c-met', 'Gene', '4233', (21, 26))	('mutation', 'Var', (27, 35))	('patient', 'Species', '9606', (8, 15))	('metabolic', 'MPA', (113, 122))	('c-met', 'Gene', (79, 84))	('c-met', 'Gene', (21, 26))
71740	25536104	In case of her2/neu mutations, no response was observed in two cases treated with trastuzumab and lapatinib, respectively.	('trastuzumab', 'Chemical', 'MESH:D000068878', (82, 93))	('her2', 'Gene', '2064', (11, 15))	('her2', 'Gene', (11, 15))	('neu', 'Gene', '2064', (16, 19))	('neu', 'Gene', (16, 19))	('lapatinib', 'Chemical', 'MESH:D000077341', (98, 107))	('mutations', 'Var', (20, 29))
71746	25536104	Higher frequency of KRAS, P16 and SMAD4 mutations in extrahepatic CCA suggest a molecular phenotype that resembles pancreatic cancer rather than intrahepatic CCA.	('P16', 'Gene', (26, 29))	('KRAS', 'Gene', '3845', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (115, 132))	('SMAD4', 'Gene', '4089', (34, 39))	('P16', 'Gene', '1029', (26, 29))	('pancreatic cancer', 'Disease', (115, 132))	('extrahepatic CCA', 'Disease', (53, 69))	('mutations', 'Var', (40, 49))	('pancreatic cancer', 'Disease', 'MESH:D010190', (115, 132))	('SMAD4', 'Gene', (34, 39))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (145, 161))	('intrahepatic CCA', 'Disease', (145, 161))	('KRAS', 'Gene', (20, 24))
71749	25536104	The prognostic importance of these GAs is highlighted by the association between survival and BAP1 mutation.	('association', 'Interaction', (61, 72))	('BAP1', 'Gene', (94, 98))	('BAP1', 'Gene', '8314', (94, 98))	('mutation', 'Var', (99, 107))
71750	25536104	Jiao et al., noted frequent mutations of chromatin-modulation genes including BAP1, PBRM1 and ARID1A and an adverse prognosis was noted in the BAP1 mutated cases.	('BAP1', 'Gene', (143, 147))	('PBRM1', 'Gene', '55193', (84, 89))	('chromatin', 'cellular_component', 'GO:0000785', ('41', '50'))	('mutated', 'Var', (148, 155))	('ARID1A', 'Gene', '8289', (94, 100))	('BAP1', 'Gene', '8314', (78, 82))	('BAP1', 'Gene', '8314', (143, 147))	('ARID1A', 'Gene', (94, 100))	('PBRM1', 'Gene', (84, 89))	('mutations', 'Var', (28, 37))	('BAP1', 'Gene', (78, 82))
71753	25536104	Germline BAP1 mutations confer susceptibility to uveal melanoma, epithelioid atypical Spitz tumors, cutaneous melanoma, and mesothelioma.	('uveal melanoma', 'Disease', 'MESH:C536494', (49, 63))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('cutaneous melanoma', 'Disease', (100, 118))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (100, 118))	('uveal melanoma', 'Disease', (49, 63))	('mesothelioma', 'Disease', (124, 136))	('mesothelioma', 'Disease', 'MESH:D008654', (124, 136))	('BAP1', 'Gene', '8314', (9, 13))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (100, 118))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('epithelioid atypical Spitz tumors', 'Disease', (65, 98))	('susceptibility', 'Reg', (31, 45))	('epithelioid atypical Spitz tumors', 'Disease', 'MESH:D018332', (65, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (49, 63))
71754	25536104	Somatic BAP1 mutations are infrequent but have been reported in prostate, ovarian, colon, breast, lung cancers and in mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (118, 130))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('prostate', 'Disease', (64, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('BAP1', 'Gene', '8314', (8, 12))	('lung cancers', 'Phenotype', 'HP:0100526', (98, 110))	('reported', 'Reg', (52, 60))	('mesothelioma', 'Disease', (118, 130))	('BAP1', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('ovarian, colon, breast, lung cancers', 'Disease', 'MESH:D010051', (74, 110))
71757	25536104	Interestingly, our study also noted early recurrence after surgery in the presence of BAP1 mutation.	('BAP1', 'Gene', (86, 90))	('mutation', 'Var', (91, 99))	('BAP1', 'Gene', '8314', (86, 90))
71758	25536104	We propose that surgically resected CCA cases with BAP1 mutation be considered for neoadjuvant approaches, so that their disease biology can be identified before considered major hepatic resection.	('mutation', 'Var', (56, 64))	('CCA', 'Disease', (36, 39))	('BAP1', 'Gene', '8314', (51, 55))	('BAP1', 'Gene', (51, 55))
71761	25536104	Chen et al., had previously reported a poor prognosis and presence of peri-neural invasion in the presence of KRAS mutation in CCA.	('neu', 'Gene', '2064', (75, 78))	('KRAS', 'Gene', '3845', (110, 114))	('neu', 'Gene', (75, 78))	('CCA', 'Disease', (127, 130))	('mutation', 'Var', (115, 123))	('KRAS', 'Gene', (110, 114))
71762	25536104	One case in our series with mutated KRAS experienced disease stability after prior progression on chemotherapy with trametinib + pazopanib.	('mutated', 'Var', (28, 35))	('trametinib', 'Chemical', 'MESH:C560077', (116, 126))	('KRAS', 'Gene', (36, 40))	('KRAS', 'Gene', '3845', (36, 40))	('pazopanib', 'Chemical', 'MESH:C516667', (129, 138))	('disease', 'MPA', (53, 60))
71763	25536104	Response to MEK inhibitors in this setting has also been reported by other studies and this option may be worth investigating further for KRAS mutated CCA.	('KRAS', 'Gene', (138, 142))	('KRAS', 'Gene', '3845', (138, 142))	('CCA', 'Disease', (151, 154))	('MEK', 'Gene', '5609', (12, 15))	('MEK', 'Gene', (12, 15))	('mutated', 'Var', (143, 150))
71764	25536104	The presence of ERBB2 mutations also contrasts with the GAs reported in gallbladder cancer, wherein ERBB2 amplifications have been reported.	('gallbladder cancer', 'Disease', (72, 90))	('ERBB2', 'Gene', (16, 21))	('gallbladder cancer', 'Disease', 'MESH:D005706', (72, 90))	('ERBB2', 'Gene', '2064', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mutations', 'Var', (22, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('ERBB2', 'Gene', (100, 105))	('ERBB2', 'Gene', '2064', (16, 21))
71765	25536104	ERBB2 GAs occurred in 6 cases, which included 2 amplifications and 4 somatic mutations.	('amplifications', 'Var', (48, 62))	('ERBB2', 'Gene', (0, 5))	('occurred', 'Reg', (10, 18))	('ERBB2', 'Gene', '2064', (0, 5))
71766	25536104	ERBB2 mutations have been described in non-small cell lung cancer, breast cancer, gastric cancer and colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (43, 65))	('ERBB2', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (39, 65))	('ERBB2', 'Gene', '2064', (0, 5))	('mutations', 'Var', (6, 15))	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('non-small cell lung cancer', 'Disease', (39, 65))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('described', 'Reg', (26, 35))	('colorectal cancer', 'Disease', (101, 118))	('breast cancer', 'Disease', (67, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('gastric cancer', 'Disease', (82, 96))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (39, 65))
71770	25536104	In our cases with ERBB2 mutation, IHC expression of ERBB2 was not detectable in our study; one of the ERBB2 mutations was in the kinase domain (V777L) while 3 involved the extracellular domain (S310F).	('ERBB2', 'Gene', '2064', (102, 107))	('S310F', 'Mutation', 'rs1057519816', (194, 199))	('ERBB2', 'Gene', (52, 57))	('ERBB2', 'Gene', (102, 107))	('extracellular', 'cellular_component', 'GO:0005576', ('172', '185'))	('involved', 'Reg', (159, 167))	('V777L', 'Mutation', 'rs121913471', (144, 149))	('ERBB2', 'Gene', '2064', (18, 23))	('ERBB2', 'Gene', '2064', (52, 57))	('ERBB2', 'Gene', (18, 23))	('mutation', 'Var', (24, 32))	('S310F', 'Var', (194, 199))	('V777L', 'Var', (144, 149))
71772	25536104	Bose et al., noted that V777L mutation was associated with negative ERBB2 protein expression and resistance to lapatinib.	('expression', 'MPA', (82, 92))	('resistance to lapatinib', 'MPA', (97, 120))	('negative', 'NegReg', (59, 67))	('lapatinib', 'Chemical', 'MESH:D000077341', (111, 120))	('ERBB2', 'Gene', '2064', (68, 73))	('ERBB2', 'Gene', (68, 73))	('V777L', 'Mutation', 'rs121913471', (24, 29))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('protein', 'Protein', (74, 81))	('V777L', 'Var', (24, 29))
71775	25536104	Three cases had FGFR2 fusion genes; these have been described before in CCA and are oncogenic in vitro .	('CCA', 'Disease', (72, 75))	('FGFR', 'molecular_function', 'GO:0005007', ('16', '20'))	('FGFR2', 'Gene', (16, 21))	('FGFR2', 'Gene', '2263', (16, 21))	('fusion genes', 'Var', (22, 34))
71776	25536104	Preclinical data indicate that these fusion proteins may indicate tumor susceptibility to targeted FGFR inhibitors, BGJ398 and PD173074.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('FGFR', 'Gene', (99, 103))	('PD173074', 'Var', (127, 135))	('tumor', 'Disease', (66, 71))	('indicate', 'Reg', (57, 65))	('PD173074', 'Chemical', 'MESH:C115711', (127, 135))	('FGFR', 'molecular_function', 'GO:0005007', ('99', '103'))	('BGJ398', 'Chemical', 'MESH:C568950', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('BGJ398', 'Gene', (116, 122))
71777	25536104	Recent data from Arai et al., indicate that FGFR2 fusion genes occur in 13.6% of intrahepatic CCA cases; Borad et al.	('intrahepatic CCA', 'Disease', 'MESH:C536211', (81, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('44', '48'))	('intrahepatic CCA', 'Disease', (81, 97))	('FGFR2', 'Gene', '2263', (44, 49))	('FGFR2', 'Gene', (44, 49))	('fusion genes', 'Var', (50, 62))
71782	25536104	The p53-subtype was resistant to chemotherapy while cases with FGFR mutation constituted a luminal subtype with good prognosis.	('p53', 'Gene', '7157', (4, 7))	('mutation', 'Var', (68, 76))	('FGFR', 'Gene', (63, 67))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('p53', 'Gene', (4, 7))
71784	25536104	The incidence of these mutations in CCA is low (estimated at 3% for BRAF V600E in intrahepatic CCA) but the sustained responses seen with BRAF inhibitor deserve further exploration.	('V600E', 'Mutation', 'rs113488022', (73, 78))	('BRAF', 'Gene', '673', (68, 72))	('CCA', 'Disease', (36, 39))	('intrahepatic CCA', 'Disease', (82, 98))	('V600E', 'Var', (73, 78))	('BRAF', 'Gene', '673', (138, 142))	('BRAF', 'Gene', (68, 72))	('BRAF', 'Gene', (138, 142))	('intrahepatic CCA', 'Disease', 'MESH:C536211', (82, 98))
71785	25536104	IDH1 (R132C) mutations represented a significant number of cases that may be potentially targetable, given the advent of potent IDH inhibitors.	('IDH', 'Gene', (0, 3))	('R132C', 'Mutation', 'rs121913499', (6, 11))	('R132C) mutations', 'Var', (6, 22))	('IDH', 'Gene', (128, 131))	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', '3417', (128, 131))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
71787	24928783	Germline Mutation of Bap1 Accelerates Development of Asbestos-Induced Malignant Mesothelioma Malignant mesotheliomas are highly aggressive tumors usually caused by exposure to asbestos.	('Germline Mutation', 'Var', (0, 17))	('Asbestos-Induced Malignant Mesothelioma', 'Disease', (53, 92))	('Accelerates', 'PosReg', (26, 37))	('Malignant mesotheliomas', 'Disease', (93, 116))	('Bap1', 'Gene', (21, 25))	('asbestos', 'Chemical', 'MESH:D001194', (176, 184))	('Malignant mesotheliomas', 'Disease', 'MESH:C562839', (93, 116))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('Malignant Mesothelioma', 'Phenotype', 'HP:0100001', (70, 92))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('Asbestos-Induced Malignant Mesothelioma', 'Disease', 'MESH:C562839', (53, 92))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (93, 115))	('Bap1', 'Gene', '104416', (21, 25))
71788	24928783	Germline inactivating mutations of BAP1 predispose to mesothelioma and certain other cancers.	('mesothelioma', 'Disease', 'MESH:D008654', (54, 66))	('Germline inactivating mutations', 'Var', (0, 31))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('predispose', 'Reg', (40, 50))	('BAP1', 'Gene', (35, 39))	('mesothelioma', 'Disease', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
71789	24928783	However, why mesothelioma is the predominate malignancy in some BAP1 families and not others, and whether exposure to asbestos is required for development of mesothelioma in BAP1 mutation carriers, are not known.	('mesothelioma', 'Disease', (13, 25))	('malignancy', 'Disease', 'MESH:D009369', (45, 55))	('BAP1', 'Gene', (174, 178))	('mesothelioma', 'Disease', (158, 170))	('asbestos', 'Chemical', 'MESH:D001194', (118, 126))	('mutation', 'Var', (179, 187))	('mesothelioma', 'Disease', 'MESH:D008654', (13, 25))	('malignancy', 'Disease', (45, 55))	('mesothelioma', 'Disease', 'MESH:D008654', (158, 170))	('BAP1', 'Gene', (64, 68))
71791	24928783	Bap1+/- mice exhibited a significantly higher incidence of asbestos-induced mesothelioma than WT littermates(73% vs. 32%, respectively).	('asbestos-induced mesothelioma', 'Disease', 'MESH:D008654', (59, 88))	('mice', 'Species', '10090', (8, 12))	('Bap1+/-', 'Var', (0, 7))	('asbestos-induced mesothelioma', 'Disease', (59, 88))
71792	24928783	Furthermore, mesotheliomas arose at an accelerated rate in Bap1+/- mice compared to WT animals(median survival, 43 weeks versus 55 weeks after initial exposure, respectively) and showed increased invasiveness and proliferation.	('proliferation', 'CPA', (213, 226))	('mesotheliomas', 'Disease', 'MESH:D008654', (13, 26))	('mesotheliomas', 'Disease', (13, 26))	('accelerated', 'PosReg', (39, 50))	('increased', 'PosReg', (186, 195))	('Bap1+/-', 'Var', (59, 66))	('invasiveness', 'CPA', (196, 208))	('mice', 'Species', '10090', (67, 71))
71794	24928783	Mesothelioma cells from Bap1+/- mice showed biallelic inactivation of Bap1, consistent with its proposed role as a recessive cancer susceptibility gene.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('Bap1', 'Gene', (70, 74))	('mice', 'Species', '10090', (32, 36))	('cancer', 'Disease', (125, 131))	('biallelic inactivation', 'Var', (44, 66))	('Mesothelioma', 'Disease', (0, 12))	('Mesothelioma', 'Disease', 'MESH:D008654', (0, 12))
71796	24928783	However, normal mesothelial cells and mesothelioma cells from Bap1+/- mice showed downregulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of Bap1+/- mice to mesothelioma may be facilitated, in part, by cooperation between Bap1 and Rb.	('mesothelioma', 'Disease', 'MESH:D008654', (197, 209))	('mesothelioma', 'Disease', (38, 50))	('mice', 'Species', '10090', (189, 193))	('Ink4a', 'Gene', '12578', (117, 122))	('downregulation', 'NegReg', (82, 96))	('Rb', 'Chemical', 'MESH:D012413', (100, 102))	('mice', 'Species', '10090', (70, 74))	('Rb', 'Chemical', 'MESH:D012413', (271, 273))	('Bap1+/-', 'Var', (62, 69))	('mesothelioma', 'Disease', (197, 209))	('Ink4a', 'Gene', (117, 122))	('mesothelioma', 'Disease', 'MESH:D008654', (38, 50))
71797	24928783	Drawing parallels to human disease, these unbiased genetic findings indicate that BAP1 mutation carriers are predisposed to the tumorigenic effects of asbestos and suggest that high penetrance of mesothelioma requires such environmental exposure.	('BAP1', 'Gene', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mesothelioma', 'Disease', (196, 208))	('human', 'Species', '9606', (21, 26))	('mesothelioma', 'Disease', 'MESH:D008654', (196, 208))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('mutation', 'Var', (87, 95))	('asbestos', 'Chemical', 'MESH:D001194', (151, 159))
71802	24928783	identified a novel protein, BAP1 (BRCA1-associated protein 1), a nuclear-localized deubiquitylase, and intragenic homozygous rearrangements and deletions of BAP1 were found in several lung carcinoma cell lines(8).	('lung carcinoma', 'Disease', 'MESH:D008175', (184, 198))	('lung carcinoma', 'Disease', (184, 198))	('BAP1', 'Gene', (157, 161))	('BRCA1-associated protein 1', 'Gene', (34, 60))	('deletions', 'Var', (144, 153))	('deubiquitylase', 'molecular_function', 'GO:0004843', ('83', '97'))	('BAP1', 'Gene', (28, 32))	('found', 'Reg', (167, 172))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('BRCA1-associated protein 1', 'Gene', '104416', (34, 60))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
71804	24928783	Indeed, the high incidence(~25-60%) of somatic BAP1 mutations reported in MM implicates defects of this putative tumor suppressor gene along with frequent alterations of CDKN2A(13, 14), which encodes the tumor suppressors p16(INK4A) and p14(ARF), as well as NF2(15, 16) as the main drivers of MM tumorigenesis identified to date.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('defects', 'NegReg', (88, 95))	('NF2', 'Gene', '18016', (258, 261))	('ARF', 'Disease', 'MESH:D058186', (241, 244))	('CDKN2A', 'Gene', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (296, 301))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('BAP1', 'Gene', (47, 51))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('ARF', 'Disease', (241, 244))	('mutations', 'Var', (52, 61))	('p14', 'Gene', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('113', '129'))	('NF2', 'Gene', (258, 261))	('p14', 'Gene', '18542', (237, 240))	('tumor', 'Disease', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor suppressor', 'biological_process', 'GO:0051726', ('113', '129'))
71805	24928783	Importantly, in 2011 germline BAP1 mutations were found in two families with multiple MMs (one also having two UMs) as well as in two sporadic cases affected by both MM and UM(11), the first demonstration that a hereditary defect can affect risk of MM.	('affect', 'Reg', (234, 240))	('BAP1', 'Gene', (30, 34))	('MMs', 'Chemical', 'MESH:D008741', (86, 89))	('UM', 'Phenotype', 'HP:0007716', (111, 113))	('UM', 'Phenotype', 'HP:0007716', (173, 175))	('found', 'Reg', (50, 55))	('mutations', 'Var', (35, 44))
71806	24928783	described germline BAP1 mutations in two families with atypical melanocytic tumors, UM and cutaneous melanoma (CM)(17), and similar findings were reported by others (18).	('melanocytic tumors', 'Disease', (64, 82))	('melanocytic tumors', 'Disease', 'MESH:D009508', (64, 82))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (91, 109))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('CM', 'Disease', 'MESH:D009202', (111, 113))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('cutaneous melanoma', 'Disease', (91, 109))	('BAP1', 'Gene', (19, 23))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (91, 109))	('mutations', 'Var', (24, 33))	('CM', 'Phenotype', 'HP:0012056', (111, 113))
71807	24928783	Collectively, the observations in these high-risk cancer families have led investigators to propose that germline BAP1 mutations cause a novel cancer susceptibility syndrome characterized by a high incidence of MM, UM, CM and probably additional cancers(19, 20).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cause', 'Reg', (129, 134))	('CM', 'Disease', 'MESH:D009202', (219, 221))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('cancer', 'Disease', (246, 252))	('cancers', 'Disease', (246, 253))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('CM', 'Phenotype', 'HP:0012056', (219, 221))	('UM', 'Phenotype', 'HP:0007716', (215, 217))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('BAP1', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))
71809	24928783	We have hypothesized that when families with germline BAP1 mutations are exposed to asbestos, MM may represent the predominant cancer observed(11).	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('germline', 'Var', (45, 53))	('asbestos', 'Chemical', 'MESH:D001194', (84, 92))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('mutations', 'Var', (59, 68))	('cancer', 'Disease', (127, 133))	('BAP1', 'Gene', (54, 58))
71811	24928783	(2012) reported a germline BAP1 mutation in a European family with four MMs, none with any known exposure to asbestos(26).	('asbestos', 'Chemical', 'MESH:D001194', (109, 117))	('BAP1', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))	('MMs', 'Chemical', 'MESH:D008741', (72, 75))
71812	24928783	Thus, it is possible that exposure to carcinogenic mineral fibers may not be required for development of MM in BAP1 mutation carriers.	('carcinogenic mineral fibers', 'Disease', 'MESH:C537337', (38, 65))	('carriers', 'Reg', (125, 133))	('mutation', 'Var', (116, 124))	('carcinogenic mineral fibers', 'Disease', (38, 65))	('BAP1', 'Gene', (111, 115))
71814	24928783	While conditional, whole-body (except brain) homozygous deletion of Bap1 in adult mice recapitulates features of human myelodysplastic syndrome (MDS)(27), studies of germline heterozygous mutation of Bap1 have not been described to date.	('Bap1', 'Gene', (68, 72))	('deletion', 'Var', (56, 64))	('mice', 'Species', '10090', (82, 86))	('MDS', 'Disease', (145, 148))	('MDS', 'Disease', 'MESH:D009190', (145, 148))	('MDS', 'Phenotype', 'HP:0002863', (145, 148))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (119, 143))	('myelodysplastic syndrome', 'Disease', (119, 143))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (119, 143))	('human', 'Species', '9606', (113, 118))
71816	24928783	While no spontaneous MMs or MDS were seen in unexposed Bap1+/- mice followed for up to 20 months of age, such haploinsufficient mutant mice exhibited a markedly higher incidence and accelerated onset of asbestos-induced MM when compared to wild-type (WT) littermates.	('MMs', 'Chemical', 'MESH:D008741', (21, 24))	('asbestos', 'Chemical', 'MESH:D001194', (203, 211))	('MDS', 'Disease', (28, 31))	('MDS', 'Disease', 'MESH:D009190', (28, 31))	('MDS', 'Phenotype', 'HP:0002863', (28, 31))	('haploinsufficient', 'Disease', (110, 127))	('asbestos-induced', 'Disease', (203, 219))	('mice', 'Species', '10090', (63, 67))	('mutant', 'Var', (128, 134))	('mice', 'Species', '10090', (135, 139))	('accelerated', 'PosReg', (182, 193))	('higher', 'PosReg', (161, 167))	('haploinsufficient', 'Disease', 'MESH:D058495', (110, 127))
71817	24928783	Mechanistically, we also demonstrate that predisposition of Bap1+/- mice to MM may be facilitated, in part, by cooperation between Bap1 and p16(Ink4a)-independent epigenetic inactivation of Rb.	('mice', 'Species', '10090', (68, 72))	('Ink4a', 'Gene', '12578', (144, 149))	('Ink4a', 'Gene', (144, 149))	('epigenetic inactivation', 'Var', (163, 186))	('Rb', 'Chemical', 'MESH:D012413', (190, 192))
71834	24928783	To assess cell proliferation and apoptosis, IHC staining of tumors was performed with antibodies for Ki-67 (Dako)and cleaved caspase 3(Cell Signaling), respectively.	('apoptosis', 'biological_process', 'GO:0097194', ('33', '42'))	('Signaling', 'biological_process', 'GO:0023052', ('140', '149'))	('apoptosis', 'biological_process', 'GO:0006915', ('33', '42'))	('cleaved', 'Var', (117, 124))	('Ki-67', 'Gene', '17345', (101, 106))	('Ki-67', 'Gene', (101, 106))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('10', '28'))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
71840	24928783	Primary MM cells were isolated from ascitic fluid and/or peritoneal lavage from Bap1+/- and WT mice as described (30).	('ascitic', 'Disease', 'MESH:D001201', (36, 43))	('mice', 'Species', '10090', (95, 99))	('ascitic', 'Disease', (36, 43))	('Bap1+/-', 'Var', (80, 87))
71857	24928783	Bone marrow smears from the three 18-month-old Bap1+/- mice showed no evidence of MDS or other hematological disease, and no macroscopic and microscopic abnormalities of the uvea, skin, mesothelial tissues, or other organs were observed except for the single SCC.	('hematological disease', 'Disease', (95, 116))	('abnormalities of the uvea', 'Phenotype', 'HP:0000553', (153, 178))	('Bap1+/-', 'Var', (47, 54))	('mice', 'Species', '10090', (55, 59))	('hematological disease', 'Disease', 'MESH:D006402', (95, 116))	('abnormalities of the uvea', 'Disease', 'MESH:C536494', (153, 178))	('abnormalities of the uvea', 'Disease', (153, 178))	('hematological disease', 'Phenotype', 'HP:0001871', (95, 116))	('MDS', 'Phenotype', 'HP:0002863', (82, 85))	('SCC', 'Phenotype', 'HP:0002860', (259, 262))	('MDS', 'Disease', (82, 85))	('MDS', 'Disease', 'MESH:D009190', (82, 85))
71861	24928783	Abdominal swelling was observed in Bap1+/- mice as early as 20 weeks after the first injection of asbestos, whereas WT animals did not begin showing this effect until 27 weeks after the initial injection.	('mice', 'Species', '10090', (43, 47))	('Abdominal swelling', 'Disease', 'MESH:D015746', (0, 18))	('asbestos', 'Chemical', 'MESH:D001194', (98, 106))	('Abdominal swelling', 'Phenotype', 'HP:0003270', (0, 18))	('observed', 'Reg', (23, 31))	('Bap1+/-', 'Var', (35, 42))	('Abdominal swelling', 'Disease', (0, 18))
71862	24928783	Eventually, 90% of the asbestos-exposed Bap1+/- mice showed abdominal distention, and ~60% of these were found to have as cites when sacrificed.	('abdominal distention', 'Phenotype', 'HP:0003270', (60, 80))	('Bap1+/-', 'Var', (40, 47))	('mice', 'Species', '10090', (48, 52))	('abdominal distention', 'CPA', (60, 80))	('asbestos', 'Chemical', 'MESH:D001194', (23, 31))
71865	24928783	The Bap1+/- mice were found to succumb to disease earlier than their WT littermates, with a median survival of 43 weeks from the time of the first asbestos injection in Bap1+/- mice versus 55 weeks in WT mice (Fig.	('mice', 'Species', '10090', (12, 16))	('Bap1+/-', 'Var', (4, 11))	('mice', 'Species', '10090', (204, 208))	('mice', 'Species', '10090', (177, 181))	('asbestos', 'Chemical', 'MESH:D001194', (147, 155))	('Bap1+/-', 'Var', (169, 176))
71867	24928783	Other deaths in WT and Bap1+/- mice occurred mainly due to plaque-related organ failure or intestinal obstructions related to fibrosis.	('plaque-related', 'Disease', (59, 73))	('deaths', 'Disease', 'MESH:D003643', (6, 12))	('Bap1+/-', 'Var', (23, 30))	('intestinal obstructions', 'Phenotype', 'HP:0005214', (91, 114))	('fibrosis', 'Disease', 'MESH:D005355', (126, 134))	('fibrosis', 'Disease', (126, 134))	('mice', 'Species', '10090', (31, 35))	('organ failure', 'Disease', (74, 87))	('organ failure', 'Disease', 'MESH:D009102', (74, 87))	('intestinal obstructions', 'Disease', (91, 114))	('deaths', 'Disease', (6, 12))
71870	24928783	Notably, asbestos-induced MMs seen in Bap1+/- mice were consistently larger and more aggressive than those found in WT littermates, often with invasion to the pancreas, liver, and/or intestinal smooth muscle (Suppl.	('pancreas', 'Disease', 'MESH:D010190', (159, 167))	('asbestos', 'Chemical', 'MESH:D001194', (9, 17))	('pancreas', 'Disease', (159, 167))	('mice', 'Species', '10090', (46, 50))	('Bap1+/-', 'Var', (38, 45))	('MMs', 'Chemical', 'MESH:D008741', (26, 29))	('aggressive', 'CPA', (85, 95))	('more', 'PosReg', (80, 84))
71871	24928783	3); occasional metastasis to the lungs was also observed in the Bap1+/- mice.	('metastasis to the lungs', 'CPA', (15, 38))	('Bap1+/-', 'Var', (64, 71))	('mice', 'Species', '10090', (72, 76))
71872	24928783	Moreover, tumors in Bap1+/- mice were more proliferative based on Ki-67 staining (Suppl.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mice', 'Species', '10090', (28, 32))	('Ki-67', 'Gene', (66, 71))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('proliferative', 'CPA', (43, 56))	('more', 'PosReg', (38, 42))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('Bap1+/-', 'Var', (20, 27))	('Ki-67', 'Gene', '17345', (66, 71))
71881	24928783	Intriguingly, aCGH analysis revealed that all three MM cell cultures derived from WT mice had homozygous deletions of the Cdkn2a/Cdkn2b loci, whereas MM cells from two Bap1+/- mice did not (Fig.	('Cdkn2b', 'Gene', (129, 135))	('mice', 'Species', '10090', (85, 89))	('deletions', 'Var', (105, 114))	('Cdkn2a', 'Gene', '12578', (122, 128))	('Cdkn2a', 'Gene', (122, 128))	('Cdkn2b', 'Gene', '12579', (129, 135))	('mice', 'Species', '10090', (176, 180))
71884	24928783	Interestingly, expression of Rb was strikingly decreased in MM cells from Bap1+/- mice, which showed no expression of Bap1 protein, when compared toBap1-expressing MM cells from WT tumors that lacked expression of p16Ink4a(Fig.	('mice', 'Species', '10090', (82, 86))	('WT tumors', 'Disease', 'MESH:C536751', (178, 187))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('p16Ink4a', 'Gene', '12578', (214, 222))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('Bap1+/-', 'Var', (74, 81))	('p16Ink4a', 'Gene', (214, 222))	('WT tumors', 'Disease', (178, 187))	('expression', 'MPA', (15, 25))	('Rb', 'Chemical', 'MESH:D012413', (29, 31))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('decreased', 'NegReg', (47, 56))
71886	24928783	Surprisingly, expression of total Rb protein was markedly decreased in tumor cells from Bap1+/- mice.	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('Rb protein', 'Protein', (34, 44))	('mice', 'Species', '10090', (96, 100))	('Bap1+/-', 'Var', (88, 95))	('decreased', 'NegReg', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Rb', 'Chemical', 'MESH:D012413', (34, 36))	('expression', 'MPA', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
71887	24928783	Quantitative RT-PCR revealed that the mRNA expression levels of Rb1 in MM cells from the Bap1+/- mice were less than half that of tumor cells from WT mice (Fig.	('less', 'NegReg', (107, 111))	('mice', 'Species', '10090', (150, 154))	('Bap1+/-', 'Var', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('mice', 'Species', '10090', (97, 101))	('Rb1', 'Gene', (64, 67))	('mRNA expression levels', 'MPA', (38, 60))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Rb1', 'Gene', '19645', (64, 67))	('tumor', 'Disease', (130, 135))
71888	24928783	Intriguingly, expression of Rb1 mRNA and Rb protein was also found to be down regulated in early passage (<=3) normal mesothelial cells isolated from Bap1+/- mice compared to those from WT mice (Fig.	('Bap1+/-', 'Var', (150, 157))	('Rb protein', 'Protein', (41, 51))	('mice', 'Species', '10090', (158, 162))	('mice', 'Species', '10090', (189, 193))	('Rb', 'Chemical', 'MESH:D012413', (41, 43))	('expression', 'MPA', (14, 24))	('down regulated', 'NegReg', (73, 87))	('Rb', 'Chemical', 'MESH:D012413', (28, 30))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('protein', 'Protein', (44, 51))	('Rb1', 'Gene', (28, 31))	('Rb1', 'Gene', '19645', (28, 31))
71890	24928783	Since aCGH analysis did not uncover any DNA copy number changes at theRb1 locus in any of the MM cell cultures tested, we hypothesized that the decreased Rb1 expression was due to aberrant epigenetic modification of the Rb1 gene in MM cells from Bap1+/- mice.	('decreased', 'NegReg', (144, 153))	('Rb1', 'Gene', (70, 73))	('Rb1', 'Gene', '19645', (70, 73))	('expression', 'MPA', (158, 168))	('mice', 'Species', '10090', (254, 258))	('Rb1', 'Gene', (154, 157))	('Rb1', 'Gene', '19645', (154, 157))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('epigenetic modification', 'Var', (189, 212))	('Rb1', 'Gene', (220, 223))	('Rb1', 'Gene', '19645', (220, 223))
71893	24928783	Indeed, we found that treatment of Bap1-null MM cells with 5-Aza-CdRsignificantly increased the expression of Rb (Fig.	('5-Aza', 'Chemical', 'MESH:D001374', (59, 64))	('5-Aza-CdRsignificantly', 'Var', (59, 81))	('expression', 'MPA', (96, 106))	('Rb', 'Chemical', 'MESH:D012413', (110, 112))	('increased', 'PosReg', (82, 91))
71895	24928783	Collectively, these findings suggest that the lower expression of Rb1 in Bap1-null MM cells is due to hypermethylation of theRb1 promoter.	('Rb1', 'Gene', (125, 128))	('Rb1', 'Gene', '19645', (125, 128))	('expression', 'MPA', (52, 62))	('lower', 'NegReg', (46, 51))	('hypermethylation', 'Var', (102, 118))	('Rb1', 'Gene', (66, 69))	('Rb1', 'Gene', '19645', (66, 69))
71897	24928783	Interestingly, we found MM cell cultures from both WT and Bap1+/- mice were sensitive to the E2f inhibitor, but only the cells derived from WT mice were highly sensitive to the Cdk4/6 inhibitor.	('Cdk4/6', 'Gene', (177, 183))	('E2f inhibitor', 'MPA', (93, 106))	('Bap1+/-', 'Var', (58, 65))	('mice', 'Species', '10090', (66, 70))	('Cdk', 'molecular_function', 'GO:0004693', ('177', '180'))	('Cdk4/6', 'Gene', '12567;12571', (177, 183))	('sensitive', 'MPA', (76, 85))	('mice', 'Species', '10090', (143, 147))
71898	24928783	p16(Ink4a)is known to inhibit the activity of a complex composed by cyclin D, Cdk4 and Cdk6, leading to inactivation of Rb by phosphorylation, thereby abolishing binding between Rb and E2f, leading to activation of E2f target genes.	('activity', 'MPA', (34, 42))	('Cdk4', 'Gene', (78, 82))	('Ink4a', 'Gene', '12578', (4, 9))	('cyclin', 'molecular_function', 'GO:0016538', ('68', '74'))	('Ink4a', 'Gene', (4, 9))	('E2f', 'Protein', (185, 188))	('Cdk6', 'Gene', '12571', (87, 91))	('activation', 'PosReg', (201, 211))	('Cdk', 'molecular_function', 'GO:0004693', ('87', '90'))	('inactivation', 'NegReg', (104, 116))	('inhibit', 'NegReg', (22, 29))	('Cdk4', 'Gene', '12567', (78, 82))	('binding', 'Interaction', (162, 169))	('phosphorylation', 'MPA', (126, 141))	('Rb', 'Chemical', 'MESH:D012413', (178, 180))	('phosphorylation', 'biological_process', 'GO:0016310', ('126', '141'))	('abolishing', 'NegReg', (151, 161))	('Cdk6', 'Gene', (87, 91))	('p16', 'Var', (0, 3))	('Rb', 'Chemical', 'MESH:D012413', (120, 122))	('binding', 'molecular_function', 'GO:0005488', ('162', '169'))	('Cdk', 'molecular_function', 'GO:0004693', ('78', '81'))
71907	24928783	Importantly, MM development was significantly accelerated and more aggressive in the Bap1+/- mice, providing unbiased genetic evidence supporting a fundamental role of Bap1 loss in MM pathogenesis.	('accelerated', 'PosReg', (46, 57))	('Bap1+/-', 'Var', (85, 92))	('Bap1', 'Gene', (168, 172))	('aggressive', 'CPA', (67, 77))	('loss', 'NegReg', (173, 177))	('MM development', 'CPA', (13, 27))	('more', 'PosReg', (62, 66))	('mice', 'Species', '10090', (93, 97))	('pathogenesis', 'biological_process', 'GO:0009405', ('184', '196'))
71911	24928783	In our report of human BAP1 families(11), all of the available MM specimens seen in BAP1 mutation carriers were of the epithelial type, although the significance of this finding could not be established due to the relatively small number of cases evaluated.	('human', 'Species', '9606', (17, 22))	('BAP1', 'Gene', (84, 88))	('mutation', 'Var', (89, 97))
71913	24928783	could find no obvious difference in tumor histology among MMs with and without somatic BAP1 mutations (39).	('MMs', 'Chemical', 'MESH:D008741', (58, 61))	('BAP1', 'Gene', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
71914	24928783	Collectively, the experimental findings summarized here indicate that germline Bap1 mutation predisposes to the tumorigenic effects of asbestos.	('predisposes', 'Reg', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('Bap1', 'Gene', (79, 83))	('asbestos', 'Chemical', 'MESH:D001194', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('germline', 'Var', (70, 78))	('tumor', 'Disease', (112, 117))	('mutation', 'Var', (84, 92))
71915	24928783	By using an unbiased genetic model system and chronic exposure to asbestos, we have been able to demonstrate that germline haploinsufficiency for Bap1 causes increased susceptibility to asbestos-induced MM formation, which may be facilitated, at least in part, by a p16(Ink4a)-independent mechanism involving epigenetic dysregulation of Rb.	('Ink4a', 'Gene', '12578', (270, 275))	('formation', 'biological_process', 'GO:0009058', ('206', '215'))	('haploinsufficiency', 'Disease', 'MESH:D058495', (123, 141))	('asbestos', 'Chemical', 'MESH:D001194', (66, 74))	('Ink4a', 'Gene', (270, 275))	('MM formation', 'CPA', (203, 215))	('asbestos', 'Chemical', 'MESH:D001194', (186, 194))	('susceptibility', 'Reg', (168, 182))	('epigenetic dysregulation', 'Var', (309, 333))	('Rb', 'Chemical', 'MESH:D012413', (337, 339))	('Bap1', 'Gene', (146, 150))	('haploinsufficiency', 'Disease', (123, 141))
71916	24928783	Although loss of p16(INK4A) expression, via homozygous deletion of CDKN2A, has long been known to be a frequent finding in human MM(13, 14), a recent integrated genomic analysis of 53 sporadic pleural MMs revealed that 6 of 12 tumors with BAP1 mutations did not exhibit allelic losses of CDKN2A; moreover, 17 of 20 tumors with homozygous losses of CDKN2A did not show point mutations in BAP1(10).	('tumors', 'Disease', (315, 321))	('CDKN2A', 'Gene', (67, 73))	('BAP1', 'Gene', (387, 391))	('tumors', 'Disease', 'MESH:D009369', (315, 321))	('human', 'Species', '9606', (123, 128))	('pleural MMs', 'Disease', (193, 204))	('tumors', 'Disease', (227, 233))	('loss', 'NegReg', (9, 13))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('pleural MMs', 'Disease', 'MESH:D010995', (193, 204))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('deletion', 'Var', (55, 63))	('mutations', 'Var', (244, 253))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('BAP1', 'Gene', (239, 243))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
71917	24928783	It is also noteworthy that our earlier aCGH analysis of MMs from two unrelated BAP1 mutation carriers revealed no homozygous losses of CDKN2A, although one of the tumors did exhibit monosomy 9, resulting in heterozygous loss of CDKN2A(11).	('CDKN2A', 'Gene', (135, 141))	('losses', 'NegReg', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CDKN2A', 'MPA', (228, 234))	('BAP1', 'Gene', (79, 83))	('loss', 'NegReg', (220, 224))	('MMs', 'Chemical', 'MESH:D008741', (56, 59))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('mutation', 'Var', (84, 92))
71920	24928783	Relevant to this possibility, germline heterozygous mutations of other cancer susceptibility genes, such as the tumor suppressor gene VHL connected with hereditary renal cancer, have been shown to alter the mRNA expression profiles of primary cultures of phenotypically normal epithelial cells in a gene-specific manner, and in some instances the expression data confirmed what is known about key tumorigenic pathways affected by biallelic mutations of such tumor suppressor genes (40).	('tumor', 'Disease', 'MESH:D009369', (458, 463))	('cancer', 'Disease', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('458', '474'))	('cancer', 'Disease', (71, 77))	('VHL', 'Disease', 'MESH:D006623', (134, 137))	('renal cancer', 'Phenotype', 'HP:0009726', (164, 176))	('tumor', 'Phenotype', 'HP:0002664', (458, 463))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', (112, 117))	('tumor suppressor', 'biological_process', 'GO:0051726', ('458', '474'))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('112', '128'))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('biallelic mutations', 'Var', (430, 449))	('tumor', 'Disease', (397, 402))	('tumor suppressor', 'biological_process', 'GO:0051726', ('112', '128'))	('mutations', 'Var', (52, 61))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('hereditary renal cancer', 'Disease', 'MESH:D007680', (153, 176))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('VHL', 'Disease', (134, 137))	('alter', 'Reg', (197, 202))	('hereditary renal cancer', 'Disease', (153, 176))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mRNA expression profiles', 'MPA', (207, 231))	('tumor', 'Disease', (458, 463))
71921	24928783	In Bap1+/- mice, heterozygous ("one hit") mutation is associated with alteration in the expression of a central node (Rb) in a cellular corridor - the p16(Ink4a)-Rb pathway - that is strongly implicated in MM pathogenesis generally.	('Rb', 'Gene', (118, 120))	('Ink4a', 'Gene', (155, 160))	('Rb', 'Chemical', 'MESH:D012413', (118, 120))	('mice', 'Species', '10090', (11, 15))	('Ink4a', 'Gene', '12578', (155, 160))	('mutation', 'Var', (42, 50))	('Rb', 'Chemical', 'MESH:D012413', (162, 164))	('expression', 'MPA', (88, 98))	('alteration', 'Reg', (70, 80))
71924	24928783	Germane to this possibility, the initial two reports of families with germline BAP1 mutations were paradoxical, with our group reporting two families with multiple (5 and 7) MMs(11), and a second group describing two families with atypical melanocytic neoplasms but no MMs (17), although a follow up study uncovered a single MM in one of the latter families(26).	('MMs', 'Chemical', 'MESH:D008741', (174, 177))	('MMs', 'Chemical', 'MESH:D008741', (269, 272))	('neoplasms', 'Phenotype', 'HP:0002664', (252, 261))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (240, 261))	('BAP1', 'Gene', (79, 83))	('melanocytic neoplasms', 'Disease', (240, 261))	('mutations', 'Var', (84, 93))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (240, 261))
71925	24928783	Rather than representing two dissimilar cancer-related syndromes, it became apparent that germline BAP1 mutations are associated with a spectrum of neoplasms, suggesting that BAP1 has acritical tumor suppressor function in a variety of tissues (41, 42).	('BAP1', 'Gene', (99, 103))	('mutations', 'Var', (104, 113))	('neoplasms', 'Disease', (148, 157))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('neoplasms', 'Disease', 'MESH:D009369', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Disease', (40, 46))	('acritical tumor', 'Disease', (184, 199))	('tumor suppressor', 'biological_process', 'GO:0051726', ('194', '210'))	('associated', 'Reg', (118, 128))	('neoplasms', 'Phenotype', 'HP:0002664', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('acritical tumor', 'Disease', 'MESH:D009369', (184, 199))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('194', '210'))
71928	24928783	Based on our earlier work on two BAP1 families with multiple MMs(11),it appears that the level of asbestos exposure need not be high in BAP1 mutation carriers, as occupational histories on those families did not suggest any obvious exposure, and only modest or trace levels of asbestos were found in their homes.	('BAP1', 'Gene', (136, 140))	('asbestos', 'Chemical', 'MESH:D001194', (98, 106))	('asbestos', 'Chemical', 'MESH:D001194', (277, 285))	('mutation', 'Var', (141, 149))	('MMs', 'Chemical', 'MESH:D008741', (61, 64))
71930	24928783	Drawing parallels to humans, our findings provide experimental support for the idea that BAP1 mutation carriers may be highly susceptible to MM even at modest levels of asbestos exposure that would be considerably less tumorigenic in the general population and, thus, would require close clinical monitoring with the goal of early detection and intervention.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('BAP1', 'Gene', (89, 93))	('tumor', 'Disease', (219, 224))	('susceptible', 'Reg', (126, 137))	('asbestos', 'Chemical', 'MESH:D001194', (169, 177))	('humans', 'Species', '9606', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('mutation', 'Var', (94, 102))
71990	24890689	Uveal melanoma might display similar behaviour: some factors may result from the tumour originating cell (e.g., gene profile or chromosomal anomalies such as chromosome 3 deletion), or by tumour traits (e.g., location or size) while others may result from host traits (e.g., sex, age).	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('chromosomal anomalies', 'Disease', (128, 149))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('chromosome', 'cellular_component', 'GO:0005694', ('158', '168'))	('behaviour', 'biological_process', 'GO:0007610', ('37', '46'))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('tumour', 'Disease', (81, 87))	('chromosome 3 deletion', 'Var', (158, 179))	('tumour', 'Disease', (188, 194))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('result', 'Reg', (65, 71))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('chromosomal anomalies', 'Disease', 'MESH:D002869', (128, 149))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
71999	22733540	Combination Small Molecule MEK and PI3K Inhibition Enhances Uveal Melanoma Cell Death in a Mutant GNAQ and GNA11 Dependent Manner Activating Q209L/P mutations in GNAQ or GNA11 (GNAQ/11) are present in ~ 80% of uveal melanomas (UM).	('Mutant', 'Var', (91, 97))	('Melanoma Cell Death', 'Disease', 'MESH:D008545', (66, 85))	('uveal melanomas', 'Disease', 'MESH:C536494', (210, 225))	('Cell Death', 'biological_process', 'GO:0008219', ('75', '85'))	('GNA11', 'Chemical', '-', (107, 112))	('MEK', 'Gene', '5609', (27, 30))	('GNA11', 'Chemical', '-', (170, 175))	('Melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('GNAQ', 'Gene', '2776', (162, 166))	('GNAQ', 'Gene', '2776', (98, 102))	('Q209L', 'Var', (141, 146))	('GNAQ', 'Gene', (162, 166))	('GNA11', 'Gene', (170, 175))	('Enhances', 'PosReg', (51, 59))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (210, 224))	('MEK', 'Gene', (27, 30))	('GNAQ', 'Gene', (98, 102))	('Melanoma Cell Death', 'Disease', (66, 85))	('uveal melanomas', 'Disease', (210, 225))	('uveal melanomas', 'Phenotype', 'HP:0007716', (210, 225))	('GNAQ', 'Gene', '2776', (177, 181))	('melanomas', 'Phenotype', 'HP:0002861', (216, 225))	('Q209L', 'SUBSTITUTION', 'None', (141, 146))	('GNAQ', 'Gene', (177, 181))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))
72001	22733540	In this study, we test the effect of the clinically relevant small molecule inhibitors GSK1120212 (MEK inhibitor) and GSK2126458 (pan class I PI3K inhibitor) on UM cells with different GNAQ/11 mutation backgrounds.	('MEK', 'Gene', '5609', (99, 102))	('PI3', 'Gene', (142, 145))	('PI3K', 'molecular_function', 'GO:0016303', ('142', '146'))	('GSK1120212', 'Var', (87, 97))	('GSK2126458', 'Chemical', 'MESH:C561454', (118, 128))	('PI3', 'Gene', '5266', (142, 145))	('GSK', 'molecular_function', 'GO:0050321', ('118', '121'))	('GSK2126458', 'Var', (118, 128))	('GSK', 'molecular_function', 'GO:0050321', ('87', '90'))	('GSK1120212', 'Chemical', 'MESH:C560077', (87, 97))	('MEK', 'Gene', (99, 102))
72003	22733540	RNA interference and small molecule MEK and/or PI3K inhibitor treatment were employed to determine the dependency of uveal melanoma cells with different GNAQ/11 mutation backgrounds on MEK/MAPK and/or PI3K/AKT signaling.	('AKT', 'Gene', (206, 209))	('MEK', 'Gene', '5609', (36, 39))	('PI3', 'Gene', (201, 204))	('mutation', 'Var', (161, 169))	('MEK', 'Gene', (36, 39))	('AKT', 'Gene', '207', (206, 209))	('PI3K', 'molecular_function', 'GO:0016303', ('201', '205'))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))	('RNA interference', 'biological_process', 'GO:0016246', ('0', '16'))	('PI3', 'Gene', '5266', (47, 50))	('GNAQ/11', 'Gene', (153, 160))	('MEK', 'Gene', '5609', (185, 188))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('AKT signaling', 'biological_process', 'GO:0043491', ('206', '219'))	('uveal melanoma', 'Disease', 'MESH:C536494', (117, 131))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('uveal melanoma', 'Disease', (117, 131))	('MEK', 'Gene', (185, 188))	('MAPK', 'molecular_function', 'GO:0004707', ('189', '193'))	('PI3', 'Gene', (47, 50))	('PI3', 'Gene', '5266', (201, 204))	('uveal melanoma', 'Phenotype', 'HP:0007716', (117, 131))
72004	22733540	Proteomic network analysis was performed to unveil signaling alterations in response to MEK and/or PI3K small molecule inhibition.	('MEK', 'Gene', '5609', (88, 91))	('PI3', 'Gene', '5266', (99, 102))	('PI3K', 'molecular_function', 'GO:0016303', ('99', '103'))	('small molecule inhibition', 'Var', (104, 129))	('PI3', 'Gene', (99, 102))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('MEK', 'Gene', (88, 91))
72012	22733540	Activating-Q209L/P mutations in GNAQ and GNA11 have been identified in approximately 80% of uveal melanoma tumors.	('GNA11', 'Chemical', '-', (41, 46))	('GNAQ', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('Q209L', 'Var', (11, 16))	('uveal melanoma', 'Phenotype', 'HP:0007716', (92, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (92, 113))	('Q209L', 'SUBSTITUTION', 'None', (11, 16))	('GNA11', 'Gene', (41, 46))	('uveal melanoma tumors', 'Disease', (92, 113))	('identified', 'Reg', (57, 67))
72017	22733540	The presence of activating-Q209L/P mutations in GNAQ or GNA11 in approximately 80% of uveal melanoma tumors suggests a potential mechanism for the activation of the MEK/MAPK and PI3K/AKT pathways in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('MEK', 'Gene', '5609', (165, 168))	('Q209L', 'SUBSTITUTION', 'None', (27, 32))	('PI3', 'Gene', (178, 181))	('activation', 'PosReg', (147, 157))	('AKT', 'Gene', '207', (183, 186))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('MEK', 'Gene', (165, 168))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('uveal melanoma', 'Disease', 'MESH:C536494', (199, 213))	('uveal melanoma', 'Disease', (199, 213))	('uveal melanoma tumors', 'Disease', (86, 107))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (86, 107))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('178', '182'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (199, 213))	('uveal melanoma', 'Disease', 'MESH:C536494', (86, 100))	('GNA11', 'Chemical', '-', (56, 61))	('PI3', 'Gene', '5266', (178, 181))	('AKT', 'Gene', (183, 186))	('MAPK', 'molecular_function', 'GO:0004707', ('169', '173'))	('GNAQ', 'Gene', (48, 52))	('Q209L', 'Var', (27, 32))	('GNA11', 'Gene', (56, 61))
72019	22733540	GSK1120212 is an orally available selective allosteric inhibitor of the MEK1 and MEK2 (MEK1/2) enzymes.	('MEK1', 'Gene', (72, 76))	('MEK1/2', 'Gene', '5605;5604', (87, 93))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('MEK2', 'molecular_function', 'GO:0004708', ('81', '85'))	('MEK2', 'Gene', '5605', (81, 85))	('MEK2', 'Gene', (81, 85))	('MEK1/2', 'Gene', (87, 93))	('GSK1120212', 'Var', (0, 10))	('MEK1', 'Gene', '5604', (87, 91))	('GSK1120212', 'Chemical', 'MESH:C560077', (0, 10))	('MEK1', 'Gene', '5604', (72, 76))	('MEK1', 'Gene', (87, 91))	('MEK1', 'molecular_function', 'GO:0004708', ('72', '76'))	('MEK1', 'molecular_function', 'GO:0004708', ('87', '91'))
72020	22733540	GSK1120212 has potent in vitro and in vivo growth inhibitory effects in cells harboring RAS or BRAF mutations for which MEK1/2 is a downstream effector.	('mutations', 'Var', (100, 109))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('BRAF', 'Gene', '673', (95, 99))	('MEK1/2', 'Gene', '5605;5604', (120, 126))	('BRAF', 'Gene', (95, 99))	('GSK1120212', 'Var', (0, 10))	('growth inhibitory', 'CPA', (43, 60))	('GSK1120212', 'Chemical', 'MESH:C560077', (0, 10))	('MEK1', 'molecular_function', 'GO:0004708', ('120', '124'))	('RAS', 'Gene', (88, 91))	('MEK1/2', 'Gene', (120, 126))
72021	22733540	GSK1120212 has a low Cmax to Ctrough ratio and a long half-life, and early phase trials show clinical activity.	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('low', 'NegReg', (17, 20))	('GSK1120212', 'Var', (0, 10))	('Cmax to Ctrough ratio', 'MPA', (21, 42))	('GSK1120212', 'Chemical', 'MESH:C560077', (0, 10))
72022	22733540	GSK2126458 is an orally available selective inhibitor of the class I phosphoinositide 3-kinase (PI3K) enzymes and the mammalian target of rapamycin (MTOR1/2) complexes.	('mammalian target of rapamycin', 'Gene', '2475', (118, 147))	('GSK2126458', 'Chemical', 'MESH:C561454', (0, 10))	('mammalian target of rapamycin', 'Gene', (118, 147))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('phosphoinositide 3-kinase', 'Gene', '5295', (69, 94))	('phosphoinositide 3-kinase', 'Gene', (69, 94))	('PI3', 'Gene', '5266', (96, 99))	('GSK2126458', 'Var', (0, 10))	('PI3', 'Gene', (96, 99))	('PI3K', 'molecular_function', 'GO:0016303', ('96', '100'))
72023	22733540	Biochemical studies show GSK2126458 to have Ki values in the picomolar range for each of the class I PI3K isoforms and MTOR1/2 complexes.	('GSK2126458', 'Var', (25, 35))	('PI3', 'Gene', (101, 104))	('GSK', 'molecular_function', 'GO:0050321', ('25', '28'))	('PI3K', 'molecular_function', 'GO:0016303', ('101', '105'))	('PI3', 'Gene', '5266', (101, 104))	('GSK2126458', 'Chemical', 'MESH:C561454', (25, 35))
72024	22733540	GSK2126458 has potent in vitro and in vivo growth inhibitory effects on cancer cells.	('GSK2126458', 'Chemical', 'MESH:C561454', (0, 10))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('growth inhibitory effects', 'CPA', (43, 68))	('GSK2126458', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
72027	22733540	A previous report has shown that exogenous expression of either mutant GNAQ or GNA11 Q209L in immortalized melanocytes injected into the flank of immunodeficient mice results in highly pigmented xenograft lesions.	('immunodeficient', 'Disease', (146, 161))	('GNAQ', 'Gene', (71, 75))	('Q209L', 'Var', (85, 90))	('pigmented xenograft lesions', 'Disease', 'MESH:D010859', (185, 212))	('results in', 'Reg', (167, 177))	('mice', 'Species', '10090', (162, 166))	('GNA11', 'Gene', (79, 84))	('pigmented xenograft lesions', 'Disease', (185, 212))	('Q209L', 'Mutation', 'rs121913492', (85, 90))	('mutant', 'Var', (64, 70))	('immunodeficient', 'Disease', 'MESH:D007153', (146, 161))	('GNA11', 'Chemical', '-', (79, 84))
72028	22733540	In addition, transfection of GNAQ or GNA11 Q209L into melanocytes results in the elevation of MAPK phosphorylation, consistent with the notion that mutant GNAQ or GNA11 activate the MEK/MAPK pathway in uveal melanoma tumors.	('MEK', 'Gene', (182, 185))	('MAPK', 'molecular_function', 'GO:0004707', ('186', '190'))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('GNA11', 'Chemical', '-', (37, 42))	('GNAQ', 'Gene', (29, 33))	('GNA11', 'Gene', (37, 42))	('GNA11', 'Chemical', '-', (163, 168))	('Q209L', 'Mutation', 'rs121913492', (43, 48))	('GNAQ', 'Gene', (155, 159))	('uveal melanoma', 'Phenotype', 'HP:0007716', (202, 216))	('MAPK', 'molecular_function', 'GO:0004707', ('94', '98'))	('GNA11', 'Gene', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('elevation', 'PosReg', (81, 90))	('MAPK phosphorylation', 'MPA', (94, 114))	('activate', 'PosReg', (169, 177))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (202, 223))	('phosphorylation', 'biological_process', 'GO:0016310', ('99', '114'))	('uveal melanoma tumors', 'Disease', (202, 223))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('Q209L', 'Var', (43, 48))	('MEK', 'Gene', '5609', (182, 185))	('mutant', 'Var', (148, 154))
72031	22733540	In this study, we use very selective small molecule inhibitors of MEK1/2 and/or PI3K that are currently in multiple clinical trials to inhibit the MEK/MAPK and/or PI3K/AKT pathways in uveal melanoma cell lines with a GNAQ/11 mutation or wild-type background.	('PI3', 'Gene', (163, 166))	('AKT', 'Gene', '207', (168, 171))	('mutation', 'Var', (225, 233))	('uveal melanoma', 'Disease', 'MESH:C536494', (184, 198))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('inhibit', 'NegReg', (135, 142))	('MEK', 'Gene', '5609', (147, 150))	('uveal melanoma', 'Disease', (184, 198))	('MEK', 'Gene', '5609', (66, 69))	('MAPK', 'molecular_function', 'GO:0004707', ('151', '155'))	('GNAQ/11', 'Gene', (217, 224))	('PI3', 'Gene', '5266', (80, 83))	('PI3K', 'molecular_function', 'GO:0016303', ('80', '84'))	('MEK1/2', 'Gene', (66, 72))	('MEK', 'Gene', (147, 150))	('uveal melanoma', 'Phenotype', 'HP:0007716', (184, 198))	('MEK', 'Gene', (66, 69))	('PI3', 'Gene', '5266', (163, 166))	('MEK1', 'molecular_function', 'GO:0004708', ('66', '70'))	('AKT', 'Gene', (168, 171))	('PI3K', 'molecular_function', 'GO:0016303', ('163', '167'))	('PI3', 'Gene', (80, 83))	('MEK1/2', 'Gene', '5605;5604', (66, 72))
72034	22733540	Figure 1A shows the growth inhibitory effect of GNAQ knockdown in uveal melanoma cells with an activating GNAQ (Q209L/P) or GNA11 (Q209L) mutation (hereafter referred to as either GNAQ or GNA11 mutant) or without either a GNAQ or GNA11 mutation (hereafter referred to as 'wild-type').	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('uveal melanoma', 'Disease', (66, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('Q209L', 'SUBSTITUTION', 'None', (112, 117))	('Q209L', 'Var', (112, 117))	('GNA11', 'Chemical', '-', (124, 129))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('Q209L', 'Mutation', 'rs121913492', (131, 136))	('GNA11', 'Chemical', '-', (230, 235))	('GNAQ', 'Gene', (106, 110))	('Q209L', 'Mutation', 'rs121913492', (112, 117))	('Q209L', 'Var', (131, 136))	('GNA11', 'Chemical', '-', (188, 193))	('growth inhibitory', 'MPA', (20, 37))	('GNA11', 'Gene', (124, 129))	('Q209L', 'SUBSTITUTION', 'None', (131, 136))	('activating', 'PosReg', (95, 105))
72035	22733540	siRNA knockdown of GNAQ or GNA11 resulted in a marked inhibition of growth (on par with the siRNA positive control) in GNAQ or GNA11 mutant uveal melanoma cells, respectively, relative to untreated or control (lipid transfectant alone or non-targeting siRNA) treated cells.	('GNA11', 'Chemical', '-', (27, 32))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('GNAQ', 'Gene', (19, 23))	('GNAQ', 'Gene', (119, 123))	('uveal melanoma', 'Phenotype', 'HP:0007716', (140, 154))	('growth', 'MPA', (68, 74))	('inhibition', 'NegReg', (54, 64))	('lipid', 'Chemical', 'MESH:D008055', (210, 215))	('GNA11', 'Gene', (27, 32))	('GNA11', 'Gene', (127, 132))	('uveal melanoma', 'Disease', (140, 154))	('GNA11', 'Chemical', '-', (127, 132))	('mutant', 'Var', (133, 139))	('inhibition of growth', 'biological_process', 'GO:0045926', ('54', '74'))	('uveal melanoma', 'Disease', 'MESH:C536494', (140, 154))
72036	22733540	Neither GNAQ nor GNA11 knock-down in wild-type uveal melanoma cells resulted in a growth inhibitory effect similar to the siRNA positive control.	('knock-down', 'Var', (23, 33))	('GNAQ', 'Gene', (8, 12))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('GNA11', 'Gene', (17, 22))	('growth inhibitory effect', 'MPA', (82, 106))	('uveal melanoma', 'Disease', (47, 61))	('GNA11', 'Chemical', '-', (17, 22))
72037	22733540	In order to determine the effect of mutant GNAQ or GNA11 on the MEK/MAPK and PI3K/AKT signaling pathways, western blot analysis of phosphorylated MAPK (threonine 202, tyrosine 204) and phosphorylated AKT (serine 473) was performed following the siRNA knockdown of GNAQ or GNA11 in GNAQ or GNA11 mutant uveal melanoma cells, respectively.	('MEK', 'Gene', (64, 67))	('AKT signaling', 'biological_process', 'GO:0043491', ('82', '95'))	('AKT', 'Gene', '207', (82, 85))	('mutant', 'Var', (295, 301))	('PI3K', 'molecular_function', 'GO:0016303', ('77', '81'))	('AKT', 'Gene', '207', (200, 203))	('melanoma', 'Phenotype', 'HP:0002861', (308, 316))	('MAPK', 'molecular_function', 'GO:0004707', ('146', '150'))	('GNA11', 'Chemical', '-', (272, 277))	('PI3', 'Gene', '5266', (77, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (302, 316))	('GNA11', 'Chemical', '-', (51, 56))	('uveal melanoma', 'Disease', (302, 316))	('GNA11', 'Chemical', '-', (289, 294))	('MAPK', 'molecular_function', 'GO:0004707', ('68', '72'))	('GNA11', 'Gene', (289, 294))	('AKT', 'Gene', (82, 85))	('uveal melanoma', 'Phenotype', 'HP:0007716', (302, 316))	('MEK', 'Gene', '5609', (64, 67))	('threonine', 'Chemical', 'MESH:D013912', (152, 161))	('PI3', 'Gene', (77, 80))	('AKT', 'Gene', (200, 203))	('mutant', 'Var', (36, 42))	('tyrosine', 'Chemical', 'MESH:D014443', (167, 175))	('serine', 'Chemical', 'MESH:D012694', (205, 211))
72038	22733540	Figure 1B shows that siRNA knock-down of GNAQ or GNA11 using two unique siRNAs in GNAQ or GNA11 mutant uveal melanoma cells, respectively, results in the loss of MAPK phosphorylation, with no significant change in the phosphorylation of AKT.	('AKT', 'Gene', (237, 240))	('GNA11', 'Gene', (90, 95))	('uveal melanoma', 'Disease', (103, 117))	('GNA11', 'Chemical', '-', (90, 95))	('mutant', 'Var', (96, 102))	('GNA11', 'Chemical', '-', (49, 54))	('uveal melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('MAPK', 'molecular_function', 'GO:0004707', ('162', '166'))	('phosphorylation', 'MPA', (167, 182))	('GNAQ', 'Gene', (82, 86))	('knock-down', 'Var', (27, 37))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('phosphorylation', 'biological_process', 'GO:0016310', ('218', '233'))	('AKT', 'Gene', '207', (237, 240))	('phosphorylation', 'biological_process', 'GO:0016310', ('167', '182'))	('MAPK', 'Protein', (162, 166))	('loss', 'NegReg', (154, 158))	('uveal melanoma', 'Disease', 'MESH:C536494', (103, 117))
72040	22733540	Total levels of MAPK, AKT, or PTEN (a negative regulator of PI3K/AKT signaling) were unchanged after GNAQ or GNA11 knockdown in either GNAQ mutant, GNA11 mutant or wild-type cells.	('GNAQ', 'Gene', (135, 139))	('GNA11', 'Chemical', '-', (148, 153))	('PI3', 'Gene', (60, 63))	('MAPK', 'molecular_function', 'GO:0004707', ('16', '20'))	('AKT', 'Gene', (22, 25))	('AKT', 'Gene', '207', (65, 68))	('GNA11', 'Chemical', '-', (109, 114))	('PTEN', 'Gene', (30, 34))	('GNAQ', 'Gene', (101, 105))	('knockdown', 'Var', (115, 124))	('AKT signaling', 'biological_process', 'GO:0043491', ('65', '78'))	('GNA11', 'Gene', (109, 114))	('PTEN', 'Gene', '5728', (30, 34))	('AKT', 'Gene', '207', (22, 25))	('mutant', 'Var', (140, 146))	('PI3', 'Gene', '5266', (60, 63))	('AKT', 'Gene', (65, 68))	('PI3K', 'molecular_function', 'GO:0016303', ('60', '64'))	('mutant', 'Var', (154, 160))
72043	22733540	In addition, phospho-AKT levels were moderately less in all the GNA11 mutant cell lines Western blot analysis was used to assess the concentration dependent effect of MEKi (0-1 uM) or PI3Ki (0-1uM) treatment on the phosphorylation status of their respective downstream effectors, MAPK or AKT.	('PI3', 'Gene', '5266', (184, 187))	('MEK', 'Gene', (167, 170))	('MEK', 'Gene', '5609', (167, 170))	('PI3', 'Gene', (184, 187))	('mutant', 'Var', (70, 76))	('AKT', 'Gene', '207', (288, 291))	('phosphorylation', 'biological_process', 'GO:0016310', ('215', '230'))	('AKT', 'Gene', '207', (21, 24))	('GNA11', 'Gene', (64, 69))	('GNA11', 'Chemical', '-', (64, 69))	('AKT', 'Gene', (288, 291))	('less', 'NegReg', (48, 52))	('AKT', 'Gene', (21, 24))	('MAPK', 'molecular_function', 'GO:0004707', ('280', '284'))
72044	22733540	Figure 2A shows that MEKi or PI3Ki treatment of either GNAQ mutant, GNA11 mutant or wild-type cells results in the loss of phosphorylation of their respective downstream targets at low nanomolar concentrations (also see Supplementary Fig.	('PI3', 'Gene', '5266', (29, 32))	('phosphorylation', 'MPA', (123, 138))	('MEK', 'Gene', (21, 24))	('loss', 'NegReg', (115, 119))	('MEK', 'Gene', '5609', (21, 24))	('GNA11', 'Chemical', '-', (68, 73))	('PI3', 'Gene', (29, 32))	('mutant', 'Var', (60, 66))	('GNA11', 'Gene', (68, 73))	('GNAQ', 'Gene', (55, 59))	('mutant', 'Var', (74, 80))	('phosphorylation', 'biological_process', 'GO:0016310', ('123', '138'))
72046	22733540	To determine the growth dependency of GNAQ or GNA11 mutant or wild-type uveal melanoma cells on activation of the MEK/MAPK or PI3K/AKT pathways, cells were treated with increasing concentrations of either MEKi or PI3Ki.	('AKT', 'Gene', '207', (131, 134))	('GNAQ', 'Gene', (38, 42))	('PI3K', 'molecular_function', 'GO:0016303', ('126', '130'))	('MEK', 'Gene', (205, 208))	('PI3', 'Gene', '5266', (213, 216))	('MEK', 'Gene', '5609', (114, 117))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('GNA11', 'Gene', (46, 51))	('uveal melanoma', 'Disease', (72, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('growth dependency', 'Phenotype', 'HP:0001510', (17, 34))	('MAPK', 'molecular_function', 'GO:0004707', ('118', '122'))	('AKT', 'Gene', (131, 134))	('MEK', 'Gene', (114, 117))	('PI3', 'Gene', '5266', (126, 129))	('PI3', 'Gene', (213, 216))	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('GNA11', 'Chemical', '-', (46, 51))	('mutant', 'Var', (52, 58))	('PI3', 'Gene', (126, 129))	('MEK', 'Gene', '5609', (205, 208))
72047	22733540	Figure 2B shows GNAQ and GNA11 mutant cell growth to be more sensitive to MEKi treatment than wild-type cells, reaching 50% of half-maximal growth inhibition at ~1 log less nanomolar concentration.	('MEK', 'Gene', '5609', (74, 77))	('GNA11', 'Chemical', '-', (25, 30))	('mutant', 'Var', (31, 37))	('growth', 'MPA', (140, 146))	('cell growth', 'biological_process', 'GO:0016049', ('38', '49'))	('GNA11', 'Gene', (25, 30))	('MEK', 'Gene', (74, 77))
72049	22733540	Impedance measurements were taken over time in GNAQ mutant and wild-type cells with increasing concentrations of MEKi (0-500 nM) or PI3Ki (0-1000 nM) compared to no treatment (Supplementary Fig.	('MEK', 'Gene', '5609', (113, 116))	('PI3', 'Gene', (132, 135))	('mutant', 'Var', (52, 58))	('0-500 nM', 'Var', (119, 127))	('0-1000 nM', 'Var', (139, 148))	('PI3', 'Gene', '5266', (132, 135))	('MEK', 'Gene', (113, 116))
72051	22733540	PI3Ki treatment resulted in a similar reduction in impedance in both GNAQ mutant and wild-type cells.	('impedance', 'MPA', (51, 60))	('PI3', 'Gene', '5266', (0, 3))	('reduction', 'NegReg', (38, 47))	('mutant', 'Var', (74, 80))	('PI3', 'Gene', (0, 3))
72053	22733540	Figure 3A shows that both mutant and wild-type uveal melanoma cells demonstrate a marked reduction in MAPK phosphorylation after MEKi treatment.	('MAPK', 'Protein', (102, 106))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('MAPK', 'molecular_function', 'GO:0004707', ('102', '106'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('reduction', 'NegReg', (89, 98))	('uveal melanoma', 'Disease', (47, 61))	('phosphorylation', 'biological_process', 'GO:0016310', ('107', '122'))	('mutant', 'Var', (26, 32))	('phosphorylation', 'MPA', (107, 122))	('MEK', 'Gene', (129, 132))	('MEK', 'Gene', '5609', (129, 132))
72058	22733540	Combination MEKi + PI3Ki treatment resulted in a decrease in phosphorylation in both MAPK and AKT in both GNAQ mutant and wild-type cells without a reciprocal increase in AKT or MAPK phosphorylation, respectively.	('AKT', 'Gene', '207', (94, 97))	('MAPK', 'molecular_function', 'GO:0004707', ('178', '182'))	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))	('phosphorylation', 'MPA', (61, 76))	('phosphorylation', 'biological_process', 'GO:0016310', ('183', '198'))	('PI3', 'Gene', '5266', (19, 22))	('mutant', 'Var', (111, 117))	('MAPK', 'molecular_function', 'GO:0004707', ('85', '89'))	('AKT', 'Gene', (94, 97))	('PI3', 'Gene', (19, 22))	('MAPK', 'Protein', (85, 89))	('decrease', 'NegReg', (49, 57))	('AKT', 'Gene', '207', (171, 174))	('MEK', 'Gene', (12, 15))	('MEK', 'Gene', '5609', (12, 15))	('AKT', 'Gene', (171, 174))
72059	22733540	MEKi alone treatment resulted in the relative decrease in phosphorylation of p70S6K (threonine 389), with little change in 4EBP1 (serine 65, threonine 37) or S6 phosphorylation (serine 236/244) in GNAQ mutant and wild-type cells.	('4EBP1', 'Gene', (123, 128))	('threonine', 'Chemical', 'MESH:D013912', (141, 150))	('p70S6K', 'Gene', '6198', (77, 83))	('S6 phosphorylation', 'MPA', (158, 176))	('p70S6K', 'Gene', (77, 83))	('MEK', 'Gene', (0, 3))	('phosphorylation', 'MPA', (58, 73))	('MEK', 'Gene', '5609', (0, 3))	('serine', 'Chemical', 'MESH:D012694', (178, 184))	('threonine', 'Chemical', 'MESH:D013912', (85, 94))	('phosphorylation', 'biological_process', 'GO:0016310', ('58', '73'))	('4EBP1', 'Gene', '1978', (123, 128))	('phosphorylation', 'biological_process', 'GO:0016310', ('161', '176'))	('decrease', 'NegReg', (46, 54))	('serine', 'Chemical', 'MESH:D012694', (130, 136))	('mutant', 'Var', (202, 208))
72060	22733540	PI3Ki alone treatment resulted in decreased phosphorylation of 4EBP1, S6, and p70S6K in GNAQ mutant and wild-type cells, although the complete extinguishment of S6 phosphorylation required combination MEKi + PI3Ki treatment in mutant cells.	('phosphorylation', 'MPA', (44, 59))	('phosphorylation', 'biological_process', 'GO:0016310', ('44', '59'))	('decreased', 'NegReg', (34, 43))	('p70S6K', 'Gene', '6198', (78, 84))	('p70S6K', 'Gene', (78, 84))	('PI3', 'Gene', '5266', (0, 3))	('PI3', 'Gene', (208, 211))	('MEK', 'Gene', (201, 204))	('mutant', 'Var', (93, 99))	('phosphorylation', 'biological_process', 'GO:0016310', ('164', '179'))	('MEK', 'Gene', '5609', (201, 204))	('4EBP1', 'Gene', '1978', (63, 68))	('PI3', 'Gene', (0, 3))	('PI3', 'Gene', '5266', (208, 211))	('4EBP1', 'Gene', (63, 68))
72061	22733540	MEKi alone treatment resulted in a stark reduction in myc transcription factor levels after 12 hours with a corresponding reduction in the phosphorylation of Rb (serine 807/811) in GNAQ mutant cells.	('transcription factor', 'molecular_function', 'GO:0000981', ('58', '78'))	('phosphorylation', 'MPA', (139, 154))	('transcription', 'biological_process', 'GO:0006351', ('58', '71'))	('MEK', 'Gene', (0, 3))	('myc transcription factor levels', 'MPA', (54, 85))	('MEK', 'Gene', '5609', (0, 3))	('Rb', 'Chemical', 'MESH:D012413', (158, 160))	('mutant', 'Var', (186, 192))	('reduction', 'NegReg', (122, 131))	('phosphorylation', 'biological_process', 'GO:0016310', ('139', '154'))	('serine', 'Chemical', 'MESH:D012694', (162, 168))	('reduction', 'NegReg', (41, 50))
72062	22733540	PI3Ki alone treatment resulted in decreased Rb phosphorylation in both GNAQ mutant and wild-type cells, but failed to have any effect on myc levels.	('decreased', 'NegReg', (34, 43))	('GNAQ', 'Gene', (71, 75))	('mutant', 'Var', (76, 82))	('PI3', 'Gene', '5266', (0, 3))	('Rb phosphorylation', 'MPA', (44, 62))	('Rb', 'Chemical', 'MESH:D012413', (44, 46))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('PI3', 'Gene', (0, 3))
72065	22733540	Neither MEKi nor PI3Ki treatment alone resulted in significant elevation in cleaved caspase 3 or 7 in mutant or wild-type cells.	('mutant', 'Var', (102, 108))	('cleaved', 'MPA', (76, 83))	('PI3', 'Gene', '5266', (17, 20))	('caspase 3', 'Gene', (84, 93))	('MEK', 'Gene', (8, 11))	('elevation', 'PosReg', (63, 72))	('PI3', 'Gene', (17, 20))	('MEK', 'Gene', '5609', (8, 11))	('caspase 3', 'Gene', '836', (84, 93))
72066	22733540	However, combination MEKi + PI3Ki treatment resulted in a marked increase in cleaved caspase 3 and 7 levels in GNAQ mutant cells, not observed in wild-type cells.	('increase', 'PosReg', (65, 73))	('MEK', 'Gene', (21, 24))	('MEK', 'Gene', '5609', (21, 24))	('caspase 3', 'Gene', '836', (85, 94))	('PI3', 'Gene', '5266', (28, 31))	('caspase 3', 'Gene', (85, 94))	('mutant', 'Var', (116, 122))	('PI3', 'Gene', (28, 31))
72067	22733540	No clear trend in Bcl-2 family member protein expression was observed after MEKi and/or PI3Ki treatment in any of the cell lines, with the exception of BIM, which was elevated after MEKi alone and combination MEKi + PI3Ki treatment in both mutant and wild-type cells.	('MEK', 'Gene', (209, 212))	('Bcl-2', 'Gene', (18, 23))	('MEK', 'Gene', (182, 185))	('PI3', 'Gene', '5266', (88, 91))	('MEK', 'Gene', '5609', (209, 212))	('MEK', 'Gene', '5609', (182, 185))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('PI3', 'Gene', '5266', (216, 219))	('mutant', 'Var', (240, 246))	('PI3', 'Gene', (88, 91))	('elevated', 'PosReg', (167, 175))	('MEK', 'Gene', (76, 79))	('Bcl-2', 'molecular_function', 'GO:0015283', ('18', '23'))	('PI3', 'Gene', (216, 219))	('Bcl-2', 'Gene', '596', (18, 23))	('MEK', 'Gene', '5609', (76, 79))
72068	22733540	To determine whether elevated levels of BIM following MEKi + PI3Ki treatment mediated cleavage of caspase 3 and 7 in GNAQ mutant cells, two distinct siRNAs targeting BIM were employed.	('MEK', 'Gene', '5609', (54, 57))	('PI3', 'Gene', '5266', (61, 64))	('caspase 3', 'Gene', (98, 107))	('PI3', 'Gene', (61, 64))	('caspase 3', 'Gene', '836', (98, 107))	('cleavage', 'MPA', (86, 94))	('mutant', 'Var', (122, 128))	('MEK', 'Gene', (54, 57))
72074	22733540	Conversely, network analysis following PI3Ki alone treatment demonstrated phosphorylated MAPK (threonine 202, tyrosine 204) to be among the highest scoring interactants within the signaling network.	('tyrosine', 'Chemical', 'MESH:D014443', (110, 118))	('MAPK', 'Gene', (89, 93))	('threonine 202', 'Var', (95, 108))	('tyrosine 204', 'Var', (110, 122))	('PI3', 'Gene', (39, 42))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('threonine', 'Chemical', 'MESH:D013912', (95, 104))	('signaling', 'biological_process', 'GO:0023052', ('180', '189'))	('PI3', 'Gene', '5266', (39, 42))
72078	22733540	Figure 4B shows a marked loss of c-jun and p-cjun expression following siRNA knockdown of c-jun.	('p-cjun expression', 'MPA', (43, 60))	('knockdown', 'Var', (77, 86))	('c-jun', 'Gene', '3725', (90, 95))	('loss', 'NegReg', (25, 29))	('c-jun', 'Gene', (90, 95))	('c-jun', 'Gene', '3725', (33, 38))	('c-jun', 'Gene', (33, 38))
72079	22733540	A growth assay demonstrates knock-down of c-jun to have a modest effect on uveal melanoma cell growth at baseline, however, knockdown of c-jun significantly enhanced the growth inhibitory effect of MEKi + PI3Ki treatment (Fig.	('knockdown', 'Var', (124, 133))	('PI3', 'Gene', (205, 208))	('cell growth', 'biological_process', 'GO:0016049', ('90', '101'))	('enhanced', 'PosReg', (157, 165))	('c-jun', 'Gene', '3725', (137, 142))	('c-jun', 'Gene', (137, 142))	('uveal melanoma', 'Phenotype', 'HP:0007716', (75, 89))	('uveal melanoma', 'Disease', 'MESH:C536494', (75, 89))	('c-jun', 'Gene', '3725', (42, 47))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('c-jun', 'Gene', (42, 47))	('uveal melanoma', 'Disease', (75, 89))	('growth inhibitory effect', 'CPA', (170, 194))	('MEK', 'Gene', (198, 201))	('PI3', 'Gene', '5266', (205, 208))	('MEK', 'Gene', '5609', (198, 201))
72080	22733540	To determine the effect of MEKi and/or PI3Ki treatment on cell cycle regulation in uveal melanoma cells at the single cell level, we performed flow cytometric analysis of DNA content in GNAQ mutant, GNA11 mutant, or wild-type cells treated with MEKi alone, PI3Ki alone, or the combination.	('uveal melanoma', 'Disease', (83, 97))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('58', '79'))	('DNA', 'cellular_component', 'GO:0005574', ('171', '174'))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('PI3', 'Gene', (257, 260))	('MEK', 'Gene', (245, 248))	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('MEK', 'Gene', '5609', (27, 30))	('mutant', 'Var', (191, 197))	('GNAQ', 'Gene', (186, 190))	('PI3', 'Gene', '5266', (39, 42))	('MEK', 'Gene', (27, 30))	('mutant', 'Var', (205, 211))	('GNA11', 'Chemical', '-', (199, 204))	('GNA11', 'Gene', (199, 204))	('PI3', 'Gene', (39, 42))	('PI3', 'Gene', '5266', (257, 260))	('uveal melanoma', 'Disease', 'MESH:C536494', (83, 97))	('MEK', 'Gene', '5609', (245, 248))
72082	22733540	MEKi treatment resulted in a significant decrease in cycling cells in the majority of uveal melanoma cell lines (3 of 3 GNAQ mutant, 2 of 3 GNA11 mutant, 0 of 2 wild-type).	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('uveal melanoma', 'Disease', 'MESH:C536494', (86, 100))	('cycling cells', 'CPA', (53, 66))	('mutant', 'Var', (125, 131))	('uveal melanoma', 'Disease', (86, 100))	('decrease', 'NegReg', (41, 49))	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('GNA11', 'Chemical', '-', (140, 145))
72083	22733540	Similarly, uveal melanoma cell lines showed a significant decrease in cycling cells after PI3Ki treatment alone (2 of 3 GNAQ mutant, 2 of 3 GNA11 mutant, 1 of 2 wild-type).	('cycling cells', 'CPA', (70, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (11, 25))	('uveal melanoma', 'Disease', (11, 25))	('uveal melanoma', 'Disease', 'MESH:C536494', (11, 25))	('mutant', 'Var', (125, 131))	('decrease', 'NegReg', (58, 66))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('PI3', 'Gene', '5266', (90, 93))	('GNA11', 'Chemical', '-', (140, 145))	('PI3', 'Gene', (90, 93))
72088	22733540	GNAQ mutant, GNA11 mutant, or wild-type cells were treated with MEKi alone, PI3Ki alone, or the combination of MEKi + PI3Ki.	('MEK', 'Gene', (64, 67))	('PI3', 'Gene', (76, 79))	('PI3', 'Gene', (118, 121))	('MEK', 'Gene', '5609', (64, 67))	('GNA11', 'Gene', (13, 18))	('mutant', 'Var', (19, 25))	('mutant', 'Var', (5, 11))	('MEK', 'Gene', (111, 114))	('MEK', 'Gene', '5609', (111, 114))	('GNA11', 'Chemical', '-', (13, 18))	('PI3', 'Gene', '5266', (76, 79))	('PI3', 'Gene', '5266', (118, 121))
72089	22733540	Figure 6B shows MEKi treatment alone resulted in little to no induction of early apoptosis in all the uveal melanoma cell lines tested, with the exception of the GNAQ mutant MEL270 cell lines in which 55% of cells (relative to baseline) were observed to have an early apoptotic response.	('apoptosis', 'biological_process', 'GO:0006915', ('81', '90'))	('MEK', 'Gene', (16, 19))	('uveal melanoma', 'Disease', (102, 116))	('mutant', 'Var', (167, 173))	('uveal melanoma', 'Disease', 'MESH:C536494', (102, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('apoptosis', 'biological_process', 'GO:0097194', ('81', '90'))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('MEK', 'Gene', '5609', (16, 19))
72090	22733540	PI3Ki alone treatment also resulted in a modest induction of early apoptosis in all the uveal melanoma cell lines tested with the exception of the GNAQ mutant MEL 270 cell line (38%, relative to baseline).	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('PI3', 'Gene', '5266', (0, 3))	('uveal melanoma', 'Disease', 'MESH:C536494', (88, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('mutant', 'Var', (152, 158))	('uveal melanoma', 'Disease', (88, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('67', '76'))	('apoptosis', 'biological_process', 'GO:0006915', ('67', '76'))	('PI3', 'Gene', (0, 3))
72093	22733540	GNA11 mutant and wild-type cells displayed a variable apoptotic response to MEKi + PI3Ki combination treatment (GNA11 = 20% in UPMD2, 20% in OMM1, 4% in UPMD1; wild-type = 5% in MEL285 and 7% in MEL290).	('PI3', 'Gene', (83, 86))	('mutant', 'Var', (6, 12))	('MEK', 'Gene', (76, 79))	('PI3', 'Gene', '5266', (83, 86))	('GNA11', 'Chemical', '-', (112, 117))	('GNA11', 'Chemical', '-', (0, 5))	('apoptotic', 'CPA', (54, 63))	('MEK', 'Gene', '5609', (76, 79))
72102	22733540	Of cell lines noted to be of uveal origin, many have been identified to have an activating V600E mutation in BRAF despite BRAF mutations not being identified in uveal melanoma tissues using standard techniques.	('uveal melanoma', 'Phenotype', 'HP:0007716', (161, 175))	('uveal melanoma', 'Disease', (161, 175))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('BRAF', 'Gene', '673', (122, 126))	('V600E', 'Mutation', 'rs113488022', (91, 96))	('BRAF', 'Gene', (122, 126))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('V600E', 'Var', (91, 96))	('activating', 'PosReg', (80, 90))	('uveal melanoma', 'Disease', 'MESH:C536494', (161, 175))
72103	22733540	Given that approximately 80% of uveal melanoma tumors harbor mutually exclusive Q209 mutations in GNAQ or GNA11, use of uveal melanoma cell lines with these mutations are a powerful tool to assess the efficacy of targeted therapeutic approaches.	('Q209 mutations', 'Var', (80, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (32, 46))	('GNA11', 'Gene', (106, 111))	('uveal melanoma', 'Disease', 'MESH:C536494', (32, 46))	('GNAQ', 'Gene', (98, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (120, 134))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (32, 53))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('uveal melanoma tumors', 'Disease', (32, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('GNA11', 'Chemical', '-', (106, 111))	('uveal melanoma', 'Disease', (120, 134))	('uveal melanoma', 'Phenotype', 'HP:0007716', (120, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))
72104	22733540	This study uses the largest number of GNAQ mutant, GNA11 mutant, or wild-type uveal melanoma cell lines to-date in order to determine the relative efficacy of employing very selective MEK and/or PI3K inhibitors in uveal melanoma.	('GNA11', 'Chemical', '-', (51, 56))	('uveal melanoma', 'Disease', 'MESH:C536494', (214, 228))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('PI3', 'Gene', '5266', (195, 198))	('uveal melanoma', 'Phenotype', 'HP:0007716', (214, 228))	('uveal melanoma', 'Disease', (214, 228))	('PI3K', 'molecular_function', 'GO:0016303', ('195', '199'))	('mutant', 'Var', (57, 63))	('mutant', 'Var', (43, 49))	('MEK', 'Gene', (184, 187))	('uveal melanoma', 'Disease', 'MESH:C536494', (78, 92))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('uveal melanoma', 'Phenotype', 'HP:0007716', (78, 92))	('PI3', 'Gene', (195, 198))	('uveal melanoma', 'Disease', (78, 92))	('MEK', 'Gene', '5609', (184, 187))
72106	22733540	Activating mutations in BRAF, NRAS, KIT, AKT, PI3K and loss of PTEN are mechanisms by which the MEK/MAPK and PI3K/AKT pathways are activated in cutaneous melanoma.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (144, 162))	('PTEN', 'Gene', '5728', (63, 67))	('mutations', 'Var', (11, 20))	('AKT', 'Gene', '207', (114, 117))	('PI3K', 'molecular_function', 'GO:0016303', ('109', '113'))	('KIT', 'Gene', (36, 39))	('AKT', 'Gene', '207', (41, 44))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('activated', 'PosReg', (131, 140))	('MAPK', 'molecular_function', 'GO:0004707', ('100', '104'))	('NRAS', 'Gene', '4893', (30, 34))	('PI3', 'Gene', '5266', (46, 49))	('PI3', 'Gene', '5266', (109, 112))	('PI3K', 'molecular_function', 'GO:0016303', ('46', '50'))	('AKT', 'Gene', (114, 117))	('MEK', 'Gene', '5609', (96, 99))	('PTEN', 'Gene', (63, 67))	('AKT', 'Gene', (41, 44))	('loss', 'NegReg', (55, 59))	('PI3', 'Gene', (46, 49))	('MEK', 'Gene', (96, 99))	('PI3', 'Gene', (109, 112))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('NRAS', 'Gene', (30, 34))	('KIT', 'molecular_function', 'GO:0005020', ('36', '39'))	('cutaneous melanoma', 'Disease', (144, 162))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (144, 162))
72107	22733540	We have previously determined that the uveal melanoma cell lines examined in this study lack common mutations in BRAF, NRAS, KIT, AKT, PI3K or loss of PTEN, and consistent with their uveal melanoma tissue counterparts, harbor mutually exclusive activating Q209L/P mutations in GNAQ or GNA11.	('GNA11', 'Chemical', '-', (285, 290))	('KIT', 'Gene', (125, 128))	('GNAQ', 'Gene', (277, 281))	('Q209L', 'Var', (256, 261))	('AKT', 'Gene', '207', (130, 133))	('activating', 'PosReg', (245, 255))	('GNA11', 'Gene', (285, 290))	('Q209L', 'SUBSTITUTION', 'None', (256, 261))	('NRAS', 'Gene', (119, 123))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('lack', 'NegReg', (88, 92))	('PI3', 'Gene', '5266', (135, 138))	('uveal melanoma', 'Disease', 'MESH:C536494', (183, 197))	('uveal melanoma', 'Disease', 'MESH:C536494', (39, 53))	('uveal melanoma', 'Disease', (183, 197))	('uveal melanoma', 'Disease', (39, 53))	('PI3K', 'molecular_function', 'GO:0016303', ('135', '139'))	('PTEN', 'Gene', (151, 155))	('KIT', 'molecular_function', 'GO:0005020', ('125', '128'))	('AKT', 'Gene', (130, 133))	('mutations', 'Var', (100, 109))	('BRAF', 'Gene', '673', (113, 117))	('uveal melanoma', 'Phenotype', 'HP:0007716', (183, 197))	('BRAF', 'Gene', (113, 117))	('PI3', 'Gene', (135, 138))	('uveal melanoma', 'Phenotype', 'HP:0007716', (39, 53))	('NRAS', 'Gene', '4893', (119, 123))	('loss', 'Var', (143, 147))	('PTEN', 'Gene', '5728', (151, 155))
72109	22733540	Thus we investigated the relative contribution of mutation activated GNAQ or GNA11 on MEK/MAPK and/or PI3K/AKT signaling in uveal melanoma cells.	('PI3', 'Gene', '5266', (102, 105))	('uveal melanoma', 'Phenotype', 'HP:0007716', (124, 138))	('uveal melanoma', 'Disease', (124, 138))	('MEK', 'Gene', (86, 89))	('uveal melanoma', 'Disease', 'MESH:C536494', (124, 138))	('GNA11', 'Gene', (77, 82))	('AKT', 'Gene', (107, 110))	('AKT signaling', 'biological_process', 'GO:0043491', ('107', '120'))	('PI3K', 'molecular_function', 'GO:0016303', ('102', '106'))	('MAPK', 'molecular_function', 'GO:0004707', ('90', '94'))	('investigated', 'Reg', (8, 20))	('MEK', 'Gene', '5609', (86, 89))	('PI3', 'Gene', (102, 105))	('GNA11', 'Chemical', '-', (77, 82))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('GNAQ', 'Gene', (69, 73))	('AKT', 'Gene', '207', (107, 110))	('mutation', 'Var', (50, 58))
72110	22733540	Knockdown of GNAQ or GNA11 resulted in diminished MAPK phosphorylation in uveal melanoma cell lines with GNAQ or GNA11 mutations, respectively, but not in wild-type cells, confirming that activated GNAQ or GNA11 signal through the MEK/MAPK pathway in GNAQ or GNA11 mutant uveal melanoma, respectively.	('GNA11', 'Chemical', '-', (206, 211))	('GNA11', 'Chemical', '-', (259, 264))	('mutant', 'Var', (265, 271))	('GNAQ', 'Gene', (251, 255))	('uveal melanoma', 'Disease', 'MESH:C536494', (272, 286))	('melanoma', 'Phenotype', 'HP:0002861', (278, 286))	('GNA11', 'Chemical', '-', (21, 26))	('uveal melanoma', 'Disease', (272, 286))	('GNA11', 'Gene', (259, 264))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('uveal melanoma', 'Disease', (74, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (272, 286))	('phosphorylation', 'biological_process', 'GO:0016310', ('55', '70'))	('diminished', 'NegReg', (39, 49))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('GNA11', 'Chemical', '-', (113, 118))	('MAPK', 'molecular_function', 'GO:0004707', ('50', '54'))	('MEK', 'Gene', '5609', (231, 234))	('MAPK', 'Protein', (50, 54))	('MAPK', 'molecular_function', 'GO:0004707', ('235', '239'))	('MEK', 'Gene', (231, 234))
72111	22733540	However, loss of mutant GNAQ or GNA11 had no significant effect on AKT phosphorylation in either GNAQ or GNA11 mutant or wild-type uveal melanoma cell lines.	('AKT', 'Gene', '207', (67, 70))	('uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))	('uveal melanoma', 'Disease', 'MESH:C536494', (131, 145))	('mutant', 'Var', (111, 117))	('GNA11', 'Gene', (105, 110))	('uveal melanoma', 'Disease', (131, 145))	('GNA11', 'Gene', (32, 37))	('GNA11', 'Chemical', '-', (32, 37))	('loss', 'NegReg', (9, 13))	('AKT', 'Gene', (67, 70))	('GNAQ', 'Gene', (24, 28))	('phosphorylation', 'biological_process', 'GO:0016310', ('71', '86'))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('GNA11', 'Chemical', '-', (105, 110))	('mutant', 'Var', (17, 23))	('GNAQ', 'Gene', (97, 101))
72113	22733540	It has been proposed that tumors with activating mutations in the RAS/RAF axis depend more on MAPK signaling whereas activating mutations in receptor tyrosine kinases depend more on PI3K signaling.	('MAPK', 'molecular_function', 'GO:0004707', ('94', '98'))	('MAPK signaling', 'MPA', (94, 108))	('mutations', 'Var', (49, 58))	('activating', 'PosReg', (38, 48))	('RAF', 'Gene', '22882', (70, 73))	('PI3', 'Gene', '5266', (182, 185))	('PI3K', 'molecular_function', 'GO:0016303', ('182', '186'))	('RAF', 'Gene', (70, 73))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('PI3K signaling', 'biological_process', 'GO:0014065', ('182', '196'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('94', '108'))	('depend', 'Reg', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tyrosine', 'Chemical', 'MESH:D014443', (150, 158))	('PI3', 'Gene', (182, 185))	('tumors', 'Disease', (26, 32))
72114	22733540	Data presented in this paper suggest that the activating mutations in GNAQ and GNA11 are akin to mutations in the RAS/RAF axis given their greater sensitivity to growth inhibition following treatment with a selective MEKi and loss of MAPK phosphorylation with GNAQ or GNA11 loss, respectively.	('GNA11', 'Chemical', '-', (268, 273))	('sensitivity', 'MPA', (147, 158))	('loss', 'NegReg', (274, 278))	('mutations', 'Var', (57, 66))	('loss', 'NegReg', (226, 230))	('GNA11', 'Gene', (268, 273))	('GNAQ', 'Gene', (70, 74))	('phosphorylation', 'biological_process', 'GO:0016310', ('239', '254'))	('phosphorylation', 'MPA', (239, 254))	('RAF', 'Gene', '22882', (118, 121))	('activating', 'PosReg', (46, 56))	('RAF', 'Gene', (118, 121))	('MEK', 'Gene', '5609', (217, 220))	('MAPK', 'Protein', (234, 238))	('greater', 'PosReg', (139, 146))	('GNA11', 'Chemical', '-', (79, 84))	('MAPK', 'molecular_function', 'GO:0004707', ('234', '238'))	('MEK', 'Gene', (217, 220))	('GNA11', 'Gene', (79, 84))
72115	22733540	This conclusion is further supported by previous data that shows 4EBP1 to be a redundant downstream mediator in tumors with coexistent mutational activation of the MEK/MAPK and PI3K/AKT pathways (e.g., colon carcinomas with both KRAS and PI3KCA mutations).	('colon carcinomas', 'Disease', 'MESH:D015179', (202, 218))	('MEK', 'Gene', '5609', (164, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('carcinomas', 'Phenotype', 'HP:0030731', (208, 218))	('PI3', 'Gene', '5266', (238, 241))	('PI3K', 'molecular_function', 'GO:0016303', ('177', '181'))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('MEK', 'Gene', (164, 167))	('activation', 'PosReg', (146, 156))	('PI3', 'Gene', (177, 180))	('AKT', 'Gene', '207', (182, 185))	('mutational', 'Var', (135, 145))	('4EBP1', 'Gene', (65, 70))	('PI3', 'Gene', (238, 241))	('KRAS', 'Gene', '3845', (229, 233))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('MAPK', 'molecular_function', 'GO:0004707', ('168', '172'))	('KRAS', 'Gene', (229, 233))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('colon carcinomas', 'Disease', (202, 218))	('PI3', 'Gene', '5266', (177, 180))	('4EBP1', 'Gene', '1978', (65, 70))	('AKT', 'Gene', (182, 185))	('tumors', 'Disease', (112, 118))
72118	22733540	Given the clear activation of the MEK/MAPK pathway by mutant GNAQ or GNA11, inhibition of MEK would appear to be a rational therapeutic approach in patients with GNAQ or GNA11 mutant tumors.	('GNA11', 'Chemical', '-', (69, 74))	('patients', 'Species', '9606', (148, 156))	('activation', 'PosReg', (16, 26))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('MEK', 'Gene', (34, 37))	('GNA11', 'Chemical', '-', (170, 175))	('MEK', 'Gene', '5609', (34, 37))	('GNAQ', 'Gene', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('MEK', 'Gene', (90, 93))	('MEK', 'Gene', '5609', (90, 93))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('GNA11', 'Gene', (69, 74))	('mutant', 'Var', (54, 60))	('tumors', 'Disease', (183, 189))	('MAPK', 'molecular_function', 'GO:0004707', ('38', '42'))
72120	22733540	A review of three completed trials in which 20 patients with metastatic uveal melanoma were treated either upfront with AZD6244 or following progression on temozolomide suggested an improvement in progression free survival in favor of MEK inhibitor treatment, although too few patients were treated to definitively make this conclusion.	('MEK', 'Gene', '5609', (235, 238))	('AZD6244', 'Chemical', 'MESH:C517975', (120, 127))	('uveal melanoma', 'Disease', (72, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('patients', 'Species', '9606', (47, 55))	('progression free survival', 'MPA', (197, 222))	('patients', 'Species', '9606', (277, 285))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('AZD6244', 'Var', (120, 127))	('improvement', 'PosReg', (182, 193))	('temozolomide', 'Chemical', 'MESH:D000077204', (156, 168))	('MEK', 'Gene', (235, 238))
72121	22733540	Finally, a phase I clinical trial has recently been completed which used the GSK1120212 MEK inhibitor.	('MEK', 'Gene', '5609', (88, 91))	('GSK1120212', 'Var', (77, 87))	('GSK1120212', 'Chemical', 'MESH:C560077', (77, 87))	('MEK', 'Gene', (88, 91))	('GSK', 'molecular_function', 'GO:0050321', ('77', '80'))
72123	22733540	None of the aforementioned studies systematically evaluated the GNAQ or GNA11 mutation status of tumors to determine if efficacy correlated with GNAQ mutation, GNA11 mutation or wild-type status.	('GNA11', 'Chemical', '-', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutation', 'Var', (150, 158))	('GNA11', 'Chemical', '-', (160, 165))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
72124	22733540	A clinical trial powered to determine the efficacy of MEK inhibition in GNAQ/11 mutant uveal melanoma is ongoing.	('MEK', 'Gene', '5609', (54, 57))	('GNAQ/11', 'Gene', (72, 79))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('uveal melanoma', 'Disease', (87, 101))	('mutant', 'Var', (80, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (87, 101))	('uveal melanoma', 'Phenotype', 'HP:0007716', (87, 101))	('MEK', 'Gene', (54, 57))
72125	22733540	Data presented in this paper suggests that MEK inhibition alone is able to achieve cell cycle arrest and reduced growth in most uveal melanoma cells, but only results in modest apoptotic cell death in the majority of uveal melanoma cells.	('MEK', 'Gene', '5609', (43, 46))	('inhibition', 'Var', (47, 57))	('growth', 'MPA', (113, 119))	('uveal melanoma', 'Disease', 'MESH:C536494', (128, 142))	('arrest', 'Disease', 'MESH:D006323', (94, 100))	('uveal melanoma', 'Phenotype', 'HP:0007716', (128, 142))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('177', '197'))	('uveal melanoma', 'Disease', (128, 142))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('arrest', 'Disease', (94, 100))	('reduced', 'NegReg', (105, 112))	('uveal melanoma', 'Disease', 'MESH:C536494', (217, 231))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (83, 100))	('uveal melanoma', 'Phenotype', 'HP:0007716', (217, 231))	('uveal melanoma', 'Disease', (217, 231))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('83', '100'))	('MEK', 'Gene', (43, 46))
72127	22733540	However, the combination of MEK + PI3K inhibition results in a strong induction of apoptotic death, most pronounced in GNAQ mutant cells, but also evident in the majority of GNA11 mutant cells.	('GNAQ', 'Gene', (119, 123))	('mutant', 'Var', (124, 130))	('PI3', 'Gene', '5266', (34, 37))	('MEK', 'Gene', (28, 31))	('apoptotic death', 'CPA', (83, 98))	('MEK', 'Gene', '5609', (28, 31))	('PI3K', 'molecular_function', 'GO:0016303', ('34', '38'))	('GNA11', 'Chemical', '-', (174, 179))	('PI3', 'Gene', (34, 37))
72128	22733540	Proteomic network analysis reveals a homeostatic relationship between the MEK/MAPK and PI3K/AKT pathways in uveal melanoma cells -- inhibition of MEK resulted in a relative increase in AKT phosphorylation, whereas, an increase in the phosphorylation of MAPK was elicited after inhibition of PI3K.	('uveal melanoma', 'Disease', 'MESH:C536494', (108, 122))	('uveal melanoma', 'Disease', (108, 122))	('PI3', 'Gene', (291, 294))	('AKT', 'Gene', '207', (185, 188))	('phosphorylation', 'biological_process', 'GO:0016310', ('234', '249'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('MAPK', 'molecular_function', 'GO:0004707', ('78', '82'))	('increase', 'PosReg', (173, 181))	('MEK', 'Gene', '5609', (146, 149))	('PI3', 'Gene', '5266', (87, 90))	('AKT', 'Gene', (92, 95))	('MAPK', 'molecular_function', 'GO:0004707', ('253', '257'))	('MEK', 'Gene', '5609', (74, 77))	('MEK', 'Gene', (146, 149))	('phosphorylation', 'biological_process', 'GO:0016310', ('189', '204'))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('MEK', 'Gene', (74, 77))	('AKT', 'Gene', (185, 188))	('PI3', 'Gene', (87, 90))	('PI3', 'Gene', '5266', (291, 294))	('AKT', 'Gene', '207', (92, 95))	('PI3K', 'molecular_function', 'GO:0016303', ('291', '295'))	('PI3K', 'molecular_function', 'GO:0016303', ('87', '91'))	('inhibition', 'Var', (132, 142))
72129	22733540	Similar feedback regulatory mechanisms have been observed in cancers driven by activating RAS or RAF mutations in lung, breast and cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('mutations', 'Var', (101, 110))	('activating', 'PosReg', (79, 89))	('RAF', 'Gene', (97, 100))	('cutaneous melanoma', 'Disease', (131, 149))	('RAF', 'Gene', '22882', (97, 100))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('RAS', 'Protein', (90, 93))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (131, 149))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (131, 149))	('cancers', 'Disease', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('lung', 'Disease', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast', 'Disease', (120, 126))
72130	22733540	In addition, signaling network analysis of proteomic data revealed that inhibition of both the MEK/MAPK and PI3K/AKT pathways increases the activation of the transcription factor c-jun.	('increases', 'PosReg', (126, 135))	('PI3', 'Gene', (108, 111))	('signaling', 'biological_process', 'GO:0023052', ('13', '22'))	('c-jun', 'Gene', '3725', (179, 184))	('AKT', 'Gene', '207', (113, 116))	('c-jun', 'Gene', (179, 184))	('PI3K', 'molecular_function', 'GO:0016303', ('108', '112'))	('activation', 'PosReg', (140, 150))	('PI3', 'Gene', '5266', (108, 111))	('transcription', 'biological_process', 'GO:0006351', ('158', '171'))	('inhibition', 'Var', (72, 82))	('MAPK', 'molecular_function', 'GO:0004707', ('99', '103'))	('AKT', 'Gene', (113, 116))	('transcription factor', 'molecular_function', 'GO:0000981', ('158', '178'))	('MEK', 'Gene', (95, 98))	('MEK', 'Gene', '5609', (95, 98))
72133	22733540	Combinatorial targeted therapies, such as the one employed in this study, using MEK inhibitors as a "back-bone" may offer greater therapeutic effect by enhancing uveal melanoma cell death.	('inhibitors', 'Var', (84, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (162, 176))	('enhancing', 'PosReg', (152, 161))	('uveal melanoma cell death', 'Disease', 'MESH:C536494', (162, 187))	('uveal melanoma cell death', 'Disease', (162, 187))	('cell death', 'biological_process', 'GO:0008219', ('175', '185'))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('MEK', 'Gene', (80, 83))	('MEK', 'Gene', '5609', (80, 83))
72136	22733540	siRNAs were purchased from Life Technologies (Grand Island, NY) for GNAQ#1 (s5886:UUGUGCAUGAGCCUUAUUGtg), GNAQ#2 (s5887:UCGUCUAUCAUAGCA UUCCtg), GNA11#1 (s5862: AAAGGGUACUCGAUGAUGCcg, GNA11#2 (s5864: UUCUGGUAGACGAGCUUGGtg), BIM#1 (s19474), BIM#2 (s223065), c-JUN#1(s7658), c-JUN#2 (s7659), PLK1 (positive control) (s450), and Silencer  Select Negative Control No.	('GNA11', 'Chemical', '-', (145, 150))	('s223065', 'Var', (247, 254))	('c-JUN', 'Gene', (273, 278))	('c-JUN', 'Gene', '3725', (273, 278))	('GNA11', 'Chemical', '-', (184, 189))	('PLK1', 'Gene', (290, 294))	('c-JUN', 'Gene', '3725', (257, 262))	('s19474', 'Var', (231, 237))	('PLK1', 'Gene', '5347', (290, 294))	('c-JUN', 'Gene', (257, 262))	('s7659', 'Var', (282, 287))
72157	22733540	Importantly, this effect was most pronounced in GNAQ/11 mutant cells, and not significant in GNAQ/11 wild-type uveal melanoma cells.	('uveal melanoma', 'Phenotype', 'HP:0007716', (111, 125))	('uveal melanoma', 'Disease', 'MESH:C536494', (111, 125))	('uveal melanoma', 'Disease', (111, 125))	('mutant', 'Var', (56, 62))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
72158	22733540	These results offer pre-clinical evidence for the use of combination MEK + PI3K inhibition in metastatic uveal melanoma and suggest that tumors with specific mutations may show variable response to this combination therapy.	('tumors', 'Disease', (137, 143))	('inhibition', 'NegReg', (80, 90))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('MEK', 'Gene', (69, 72))	('PI3', 'Gene', (75, 78))	('MEK', 'Gene', '5609', (69, 72))	('uveal melanoma', 'Phenotype', 'HP:0007716', (105, 119))	('uveal melanoma', 'Disease', (105, 119))	('uveal melanoma', 'Disease', 'MESH:C536494', (105, 119))	('mutations', 'Var', (158, 167))	('pre', 'molecular_function', 'GO:0003904', ('20', '23'))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('PI3K', 'molecular_function', 'GO:0016303', ('75', '79'))	('PI3', 'Gene', '5266', (75, 78))
72174	20819828	Inhibition of VEGF may prevent or slow the metastatic potential of a recently diagnosed and treated uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('VEGF', 'Protein', (14, 18))	('uveal melanoma', 'Disease', (100, 114))	('slow', 'NegReg', (34, 38))	('metastatic potential', 'CPA', (43, 63))	('Inhibition', 'Var', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
72256	32050636	In TCGA database, higher TDO2 expression in primary UM significantly correlated to BAP1 mutation and monosomy 3.	('TDO', 'molecular_function', 'GO:0004833', ('25', '28'))	('correlated', 'Reg', (69, 79))	('expression', 'MPA', (30, 40))	('mutation', 'Var', (88, 96))	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('TDO2', 'Gene', '6999', (25, 29))	('UM', 'Disease', 'MESH:C536494', (52, 54))	('BAP1', 'Gene', (83, 87))	('monosomy 3', 'Disease', (101, 111))	('higher', 'PosReg', (18, 24))	('TDO2', 'Gene', (25, 29))
72263	32050636	Loss of one copy of chromosome 3 (monosomy 3) and BAP1 mutation in primary UM is associated with an increased risk of metastasis and a poor prognosis.	('metastasis', 'CPA', (118, 128))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('UM', 'Disease', 'MESH:C536494', (75, 77))	('BAP1', 'Gene', (50, 54))	('mutation', 'Var', (55, 63))	('chromosome', 'cellular_component', 'GO:0005694', ('20', '30'))
72328	32050636	We found that patients with BAP1 mutations have increased expression of TDO2 (p = 0.007) compared to BAP1 wild-type.	('increased', 'PosReg', (48, 57))	('TDO', 'molecular_function', 'GO:0004833', ('72', '75'))	('TDO2', 'Gene', (72, 76))	('expression', 'MPA', (58, 68))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('TDO2', 'Gene', '6999', (72, 76))	('patients', 'Species', '9606', (14, 22))
72332	32050636	Interestingly, when we focused on only patients whose tumor expresses TDO2 (n = 34), the survival of patients with high TDO2 RNA expression (those above the median) showed shorter survival compared to patients with low TDO2 RNA expression (those below the median) (p = 0.007) (Figure 7).	('TDO2', 'Gene', (70, 74))	('patients', 'Species', '9606', (39, 47))	('shorter', 'NegReg', (172, 179))	('RNA', 'cellular_component', 'GO:0005562', ('125', '128'))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('TDO2', 'Gene', (219, 223))	('TDO2', 'Gene', '6999', (120, 124))	('patients', 'Species', '9606', (101, 109))	('TDO', 'molecular_function', 'GO:0004833', ('219', '222'))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('survival', 'MPA', (89, 97))	('RNA', 'cellular_component', 'GO:0005562', ('224', '227'))	('patients', 'Species', '9606', (201, 209))	('TDO2', 'Gene', (120, 124))	('TDO2', 'Gene', '6999', (70, 74))	('TDO', 'molecular_function', 'GO:0004833', ('120', '123'))	('high', 'Var', (115, 119))	('survival', 'MPA', (180, 188))	('TDO2', 'Gene', '6999', (219, 223))	('TDO', 'molecular_function', 'GO:0004833', ('70', '73'))	('tumor', 'Disease', (54, 59))
72344	32050636	Conversion of Trp into Kyn (in presence of TDO) causes Trp starvation in the microenvironment which suppresses immune cell functions.	('Kyn', 'Chemical', 'MESH:D007737', (23, 26))	('Trp starvation', 'MPA', (55, 69))	('TDO', 'molecular_function', 'GO:0004833', ('43', '46'))	('immune cell functions', 'MPA', (111, 132))	('Trp', 'Chemical', 'MESH:D014364', (14, 17))	('suppresses', 'NegReg', (100, 110))	('Trp', 'Chemical', 'MESH:D014364', (55, 58))	('Conversion', 'Var', (0, 10))
72345	32050636	Apart from having immune suppression induced by Trp catabolism, Kyn binds to the aryl hydrocarbon receptor (AHR), a cytoplasmic transcription factor.	('AHR', 'Gene', '196', (108, 111))	('AHR', 'Gene', (108, 111))	('transcription', 'biological_process', 'GO:0006351', ('128', '141'))	('aryl hydrocarbon receptor', 'Gene', (81, 106))	('Kyn', 'Chemical', 'MESH:D007737', (64, 67))	('catabolism', 'biological_process', 'GO:0009056', ('52', '62'))	('transcription factor', 'molecular_function', 'GO:0000981', ('128', '148'))	('Kyn', 'Var', (64, 67))	('Trp', 'Chemical', 'MESH:D014364', (48, 51))	('immune', 'MPA', (18, 24))	('binds', 'Interaction', (68, 73))	('aryl hydrocarbon receptor', 'Gene', '196', (81, 106))
72350	32050636	This is the first demonstration of TDO2 mRNA as well as functional TDO protein in MUM tumors.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('MUM', 'Disease', 'MESH:C536494', (82, 85))	('TDO2', 'Gene', (35, 39))	('mRNA', 'Var', (40, 44))	('MUM', 'Disease', (82, 85))	('UM', 'Phenotype', 'HP:0007716', (83, 85))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('TDO', 'molecular_function', 'GO:0004833', ('35', '38'))	('TDO2', 'Gene', '6999', (35, 39))	('TDO protein', 'Protein', (67, 78))	('TDO', 'molecular_function', 'GO:0004833', ('67', '70'))
72355	32050636	On the other hand, a clear survival difference is indicated between patients with TDO2 high and TDO2 low primary UM.	('TDO2', 'Gene', '6999', (82, 86))	('TDO2', 'Gene', '6999', (96, 100))	('patients', 'Species', '9606', (68, 76))	('TDO2', 'Gene', (82, 86))	('high', 'Var', (87, 91))	('TDO', 'molecular_function', 'GO:0004833', ('82', '85'))	('UM', 'Phenotype', 'HP:0007716', (113, 115))	('TDO', 'molecular_function', 'GO:0004833', ('96', '99'))	('UM', 'Disease', 'MESH:C536494', (113, 115))	('TDO2', 'Gene', (96, 100))	('low', 'NegReg', (101, 104))
72368	32050636	The expression of TDO2 RNA from the TCGA database also shows a correlation between TDO2 mRNA expression and poor prognostic markers (BAP1 mutation and Monosomy 3 (M3)) in UM.	('TDO2', 'Gene', (83, 87))	('UM', 'Disease', 'MESH:C536494', (171, 173))	('Monosomy 3', 'Disease', (151, 161))	('TDO', 'molecular_function', 'GO:0004833', ('18', '21'))	('mRNA expression', 'MPA', (88, 103))	('TDO2', 'Gene', '6999', (83, 87))	('TDO2', 'Gene', '6999', (18, 22))	('RNA', 'cellular_component', 'GO:0005562', ('23', '26'))	('mutation', 'Var', (138, 146))	('TDO', 'molecular_function', 'GO:0004833', ('83', '86'))	('UM', 'Phenotype', 'HP:0007716', (171, 173))	('correlation', 'Reg', (63, 74))	('BAP1', 'Gene', (133, 137))	('TDO2', 'Gene', (18, 22))
72393	32050636	UMp005 was newly established from a PDX mouse model and it was confirmed to have BAP1 mutation at c.828dupT and GNA11 Q209L mutation by Sanger sequencing (Figure S3A).	('UM', 'Disease', 'MESH:C536494', (0, 2))	('c.828dupT', 'Var', (98, 107))	('BAP1', 'Gene', (81, 85))	('mutation at c.828dupT', 'Var', (86, 107))	('Q209L', 'Mutation', 'rs1057519742', (118, 123))	('c.828dupT', 'Mutation', 'c.828dupT', (98, 107))	('mouse', 'Species', '10090', (40, 45))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('Q209L', 'Var', (118, 123))
72405	32050636	To determine an association between TDO2 expression and BAP1 mutations, we first stratified patients as being BAP1 wild-type versus having a BAP1 alteration.	('TDO2', 'Gene', (36, 40))	('patients', 'Species', '9606', (92, 100))	('mutations', 'Var', (61, 70))	('BAP1', 'Gene', (56, 60))	('TDO', 'molecular_function', 'GO:0004833', ('36', '39'))	('TDO2', 'Gene', '6999', (36, 40))	('alteration', 'Var', (146, 156))
72430	32050636	The membrane was incubated with primary antibodies at 4  C overnight: mouse anti-human TDO antibody purchased from Abnova (#H00006999-B01P; dilution 1:500, San Jose, CA, USA), anti-human IDO antibody (#D5J4ETM; dilution 1:1000) and anti-human beta-actin antibody (#D6A8; dilution 1:10,000) purchased from Cell Signaling Technology (Beverly, MA, USA).	('IDO', 'molecular_function', 'GO:0033754', ('187', '190'))	('antibody', 'cellular_component', 'GO:0019814', ('191', '199'))	('antibody', 'cellular_component', 'GO:0019814', ('254', '262'))	('antibody', 'cellular_component', 'GO:0019815', ('91', '99'))	('IDO', 'Gene', '3620', (187, 190))	('human', 'Species', '9606', (81, 86))	('antibody', 'molecular_function', 'GO:0003823', ('191', '199'))	('antibody', 'molecular_function', 'GO:0003823', ('254', '262'))	('mouse', 'Species', '10090', (70, 75))	('Signaling', 'biological_process', 'GO:0023052', ('310', '319'))	('IDO', 'molecular_function', 'GO:0047719', ('187', '190'))	('antibody', 'cellular_component', 'GO:0042571', ('191', '199'))	('antibody', 'cellular_component', 'GO:0042571', ('254', '262'))	('membrane', 'cellular_component', 'GO:0016020', ('4', '12'))	('antibody', 'cellular_component', 'GO:0019814', ('91', '99'))	('human', 'Species', '9606', (181, 186))	('human', 'Species', '9606', (237, 242))	('antibody', 'molecular_function', 'GO:0003823', ('91', '99'))	('IDO', 'Gene', (187, 190))	('antibody', 'cellular_component', 'GO:0019815', ('191', '199'))	('antibody', 'cellular_component', 'GO:0019815', ('254', '262'))	('antibody', 'cellular_component', 'GO:0042571', ('91', '99'))	('#D5J4ETM', 'Var', (201, 209))	('TDO', 'molecular_function', 'GO:0004833', ('87', '90'))
72501	31906411	Of the 141 patients who had available chromosomal analysis in Cohorts 2 and 3, 82% had monosomy-3, 6% had 6q loss, 57% had 8q amplification.	('patients', 'Species', '9606', (11, 19))	('loss', 'NegReg', (109, 113))	('8q amplification', 'Var', (123, 139))	('monosomy-3', 'Var', (87, 97))
72505	31906411	In other words, for patients who received liver-directed and systemic treatments in consecutive order or in combination, the hazard of death was 65% and 72% lower than for patients who received liver-directed therapy only or systemic therapy only, respectively.	('liver-directed', 'Var', (42, 56))	('patients', 'Species', '9606', (172, 180))	('patients', 'Species', '9606', (20, 28))	('lower', 'NegReg', (157, 162))
72615	32021081	Under the above, it is important to note that although progression of UM cannot be excluded in those patients with normal serum MIA levels, abnormal levels of MIA may indicate a probable presence of metastatic disease.	('MIA', 'Gene', (128, 131))	('patients', 'Species', '9606', (101, 109))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('MIA', 'Gene', '8190', (128, 131))	('MIA', 'Gene', '8190', (159, 162))	('UM', 'Disease', 'MESH:C536494', (70, 72))	('metastatic disease', 'Disease', (199, 217))	('indicate', 'Reg', (167, 175))	('MIA', 'Gene', (159, 162))	('abnormal', 'Var', (140, 148))
72702	32021081	Although a positive correlation was found between the presence of CTCs and the probability of metastasis at 5 years, there was no correlation between the positivity of CTCs and clinical risk factors, such as tumor size, histology, or treatment method.	('metastasis', 'CPA', (94, 104))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('presence', 'Var', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('clinical', 'Species', '191496', (177, 185))	('tumor', 'Disease', (208, 213))
72727	32021081	Therefore, expression of certain miRNAs (let-7b, miR-199a, miR-199a, miR-143, miR-193b, and miR-652) was associated with chromosome 3 status, gene expression profile classes, and prognosis.	('chromosome', 'cellular_component', 'GO:0005694', ('121', '131'))	('miR-652', 'Gene', (92, 99))	('expression', 'MPA', (11, 21))	('let-7b', 'Gene', '406884', (41, 47))	('gene expression', 'biological_process', 'GO:0010467', ('142', '157'))	('miR-193b', 'Gene', '574455', (78, 86))	('miR-143', 'Gene', '406935', (69, 76))	('let-7b', 'Gene', (41, 47))	('miR-199a', 'Var', (59, 67))	('miR-193b', 'Gene', (78, 86))	('miR-199a', 'Var', (49, 57))	('miR-143', 'Gene', (69, 76))	('miR-652', 'Gene', '724022', (92, 99))	('associated', 'Reg', (105, 115))
72736	32021081	Plasma levels of miR-20a, 125b, 146a, 155, 181a, and 223 were all higher in the patients at the time of diagnosis compared with that of controls.	('patients', 'Species', '9606', (80, 88))	('miR-20a', 'Gene', (17, 24))	('146a', 'Var', (32, 36))	('155', 'Var', (38, 41))	('miR-20a', 'Gene', '406982', (17, 24))	('higher', 'PosReg', (66, 72))	('Plasma levels', 'MPA', (0, 13))
72744	32021081	More than 80% of the UMs present with mutations in the proto-oncogenes GNAQ and GNA11.	('UM', 'Disease', 'MESH:C536494', (21, 23))	('GNA11', 'Gene', '2767', (80, 85))	('present', 'Reg', (25, 32))	('GNAQ', 'Gene', (71, 75))	('UM', 'Phenotype', 'HP:0007716', (21, 23))	('mutations', 'Var', (38, 47))	('GNAQ', 'Gene', '2776', (71, 75))	('GNA11', 'Gene', (80, 85))
72745	32021081	For that reason, PCR techniques for ctDNA of UM patients include screening for GNAQ c.626A>T, GNAQ c.626A>C, and GNA11 c.626A>T.	('UM', 'Disease', 'MESH:C536494', (45, 47))	('GNAQ', 'Gene', '2776', (79, 83))	('c.626A>C', 'Mutation', 'rs121913492', (99, 107))	('GNA11', 'Gene', '2767', (113, 118))	('GNA11', 'Gene', (113, 118))	('GNAQ', 'Gene', '2776', (94, 98))	('c.626A>T', 'Var', (84, 92))	('GNAQ', 'Gene', (79, 83))	('c.626A>T', 'Mutation', 'rs121913492', (84, 92))	('c.626A>C', 'Var', (99, 107))	('c.626A>T', 'Mutation', 'rs121913492', (119, 127))	('patients', 'Species', '9606', (48, 56))	('GNAQ', 'Gene', (94, 98))	('UM', 'Phenotype', 'HP:0007716', (45, 47))
72748	32021081	In patients with detectable mutations, ctDNA is detected more frequently than CTCs and therefore appears to have a higher prognostic value.	('patients', 'Species', '9606', (3, 11))	('ctDNA', 'Disease', (39, 44))	('mutations', 'Var', (28, 37))
72758	32021081	Detection of the gene mutation in ctDNA could also be very useful for prognostic classification of UMs as it is in other types of cancer.	('mutation', 'Var', (22, 30))	('UM', 'Disease', 'MESH:C536494', (99, 101))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('ctDNA', 'Gene', (34, 39))
72760	31939615	PET/CT and PET/MRI in ophthalmic oncology (Review) Orbital and ocular anatomy is quite complex, consisting of several tissues, which can give rise to both benign and malignant tumors, while several primary neoplasms can metastasize to the orbital and ocular space.	('malignant tumors', 'Disease', (166, 182))	('malignant tumors', 'Disease', 'MESH:D009369', (166, 182))	('give rise to', 'Reg', (137, 149))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('neoplasm', 'Phenotype', 'HP:0002664', (206, 214))	('oncology', 'Phenotype', 'HP:0002664', (33, 41))	('ophthalmic oncology', 'Phenotype', 'HP:0100012', (22, 41))	('neoplasms', 'Disease', 'MESH:D009369', (206, 215))	('neoplasms', 'Disease', (206, 215))	('PET/MRI', 'Var', (11, 18))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('neoplasms', 'Phenotype', 'HP:0002664', (206, 215))	('metastasize', 'CPA', (220, 231))
72788	31939615	However, even for low-grade OLs and OALs, 18F-FDG PET/CT has been proven to be highly sensitive for accurate disease staging by detecting distant metastases, missed on conventional imaging.	('detecting', 'Reg', (128, 137))	('18F-FDG', 'Var', (42, 49))	('OL', 'Disease', 'MESH:C537131', (28, 30))	('metastases', 'Disease', (146, 156))	('OAL', 'Disease', (36, 39))	('OAL', 'Disease', 'MESH:D000292', (36, 39))	('metastases', 'Disease', 'MESH:D009362', (146, 156))	('18F-FDG', 'Chemical', 'MESH:D019788', (42, 49))
72810	31939615	18F-FDG PET/CT detected the primary tumor in 5 out of 7 patients, concluding that large nodular choroidal melanomas can be effectively identified by 18F-FDG PET/CT, in contrast to diffusely infiltrating choroidal melanomas without nodular formation, which proved to be 18F-FDG-negative.	('patients', 'Species', '9606', (56, 64))	('18F-FDG PET/CT', 'Var', (149, 163))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (96, 114))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (96, 115))	('melanomas', 'Phenotype', 'HP:0002861', (213, 222))	('tumor', 'Disease', (36, 41))	('nodular choroidal melanomas', 'Disease', (88, 115))	('choroidal melanomas', 'Disease', 'MESH:D008545', (203, 222))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (203, 221))	('choroidal melanomas', 'Disease', 'MESH:D008545', (96, 115))	('18F-FDG', 'Chemical', 'MESH:D019788', (0, 7))	('formation', 'biological_process', 'GO:0009058', ('239', '248'))	('melanomas', 'Phenotype', 'HP:0002861', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('18F-FDG', 'Chemical', 'MESH:D019788', (149, 156))	('18F-FDG', 'Chemical', 'MESH:D019788', (269, 276))	('choroidal melanomas', 'Disease', (203, 222))	('nodular choroidal melanomas', 'Disease', 'MESH:D008545', (88, 115))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (203, 222))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
72813	31939615	McCannelet al, in a retrospective study including 37 patients with primary choroidal melanomas, reported significant association between 18F-FDG positivity of the tumors (SUVmax >2.5) with larger tumor size and with chromosome 3 loss, which is a known risk factor related with increased metastatic potential of choroidal melanomas.	('primary choroidal melanomas', 'Disease', 'MESH:D008545', (67, 94))	('tumor', 'Disease', (196, 201))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (311, 330))	('primary choroidal melanomas', 'Disease', (67, 94))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('choroidal melanomas', 'Disease', 'MESH:D008545', (75, 94))	('18F-FDG', 'Gene', (137, 144))	('patients', 'Species', '9606', (53, 61))	('18F-FDG', 'Chemical', 'MESH:D019788', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('chromosome', 'cellular_component', 'GO:0005694', ('216', '226'))	('choroidal melanomas', 'Disease', 'MESH:D008545', (311, 330))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('melanoma', 'Phenotype', 'HP:0002861', (321, 329))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('positivity', 'Var', (145, 155))	('tumors', 'Disease', (163, 169))	('melanomas', 'Phenotype', 'HP:0002861', (321, 330))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('chromosome', 'Gene', (216, 226))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (75, 93))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (75, 94))	('loss', 'NegReg', (229, 233))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('choroidal melanomas', 'Disease', (311, 330))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (311, 329))
72814	31939615	This data indicated that apart from tumor size, 18F-FDG positivity may be associated with molecular features of UMs and that 18F-FDG avidity holds promise to serve as an independent prognostic biomarker for patients with UM.	('patients', 'Species', '9606', (207, 215))	('positivity', 'Var', (56, 66))	('UM', 'Phenotype', 'HP:0007716', (221, 223))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('UM', 'Disease', 'MESH:C536494', (221, 223))	('18F-FDG', 'Chemical', 'MESH:D019788', (48, 55))	('UM', 'Phenotype', 'HP:0007716', (112, 114))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('18F-FDG', 'Chemical', 'MESH:D019788', (125, 132))	('18F-FDG', 'Protein', (48, 55))	('UM', 'Disease', 'MESH:C536494', (112, 114))	('tumor', 'Disease', (36, 41))	('associated', 'Reg', (74, 84))
72816	31939615	In addition, 94% of patients with chromosome 3 monosomy exhibited 18F-FDG avidity (SUVmax >2.5), whereas patients with abnormalities (gains) in chromosome 8, which is also associated with a poor prognosis in UM did not exhibit significantly higher 18F-FDG activity.	('exhibited', 'Reg', (56, 65))	('patients', 'Species', '9606', (105, 113))	('chromosome', 'cellular_component', 'GO:0005694', ('34', '44'))	('UM', 'Phenotype', 'HP:0007716', (208, 210))	('chromosome', 'cellular_component', 'GO:0005694', ('144', '154'))	('monosomy', 'Var', (47, 55))	('18F-FDG', 'Protein', (66, 73))	('UM', 'Disease', 'MESH:C536494', (208, 210))	('18F-FDG', 'Chemical', 'MESH:D019788', (66, 73))	('18F-FDG', 'Chemical', 'MESH:D019788', (248, 255))	('patients', 'Species', '9606', (20, 28))	('abnormalities', 'Var', (119, 132))
72820	31939615	Furthermore, 18F-FDG PET/CT significantly contributed to the detection of osseous extra-hepatic metastatic lesions, implying the application of this technique for disease staging at the time of initial diagnosis as well as for follow-up purposes.	('18F-FDG', 'Var', (13, 20))	('18F-FDG', 'Chemical', 'MESH:D019788', (13, 20))	('osseous', 'Disease', (74, 81))
72831	31939615	RB can be encountered either in a hereditary (40%) or in a sporadic form (60%), with patients with hereditary RB presenting with an increased risk of developing intracranial primitive neuroecto-dermal tumor (PNET), most frequently pineoblastomas.	('RB', 'Disease', 'MESH:D012175', (0, 2))	('pineoblastomas', 'Disease', (231, 245))	('pineoblastomas', 'Disease', 'MESH:D010871', (231, 245))	('hereditary', 'Var', (99, 109))	('primitive neuroecto-dermal tumor', 'Phenotype', 'HP:0030065', (174, 206))	('neuroecto-dermal tumor', 'Phenotype', 'HP:0030061', (184, 206))	('RB', 'Disease', 'MESH:D012175', (110, 112))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('RB', 'Phenotype', 'HP:0009919', (0, 2))	('dermal tumor', 'Phenotype', 'HP:0008069', (194, 206))	('PNET', 'Phenotype', 'HP:0030065', (208, 212))	('RB', 'Phenotype', 'HP:0009919', (110, 112))	('neuroecto-dermal tumor', 'Disease', 'MESH:D016136', (184, 206))	('neuroecto-dermal tumor', 'Disease', (184, 206))
72836	31939615	However, the detection of 18F-FDG uptake by the optic nerve at the baseline PET/CT study was strongly associated with poor event-free survival (EFS) and overall survival (OS), indicating a strong prognostic value, in comparison to patients with no 18F-FDG uptake by the optic nerve.	('uptake', 'biological_process', 'GO:0098739', ('34', '40'))	('18F-FDG', 'Chemical', 'MESH:D019788', (26, 33))	('18F-FDG uptake', 'Var', (26, 40))	('patients', 'Species', '9606', (231, 239))	('poor', 'NegReg', (118, 122))	('event-free survival', 'CPA', (123, 142))	('uptake', 'biological_process', 'GO:0098657', ('256', '262'))	('overall survival', 'CPA', (153, 169))	('uptake', 'biological_process', 'GO:0098739', ('256', '262'))	('18F-FDG', 'Chemical', 'MESH:D019788', (248, 255))	('uptake', 'biological_process', 'GO:0098657', ('34', '40'))
72876	31939615	Normanet al, in a systematic review including 272 patients with RMS, with orbits being the primary tumor site in at least 13 cases (not all included studies provided information on the location of the primary tumor), investigated the role of 18F-FDG PET and 18F-FDG PET/CT in the management of childhood RMS.	('18F-FDG', 'Chemical', 'MESH:D019788', (258, 265))	('18F-FDG PET/CT', 'Var', (258, 272))	('RMS', 'Disease', (64, 67))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', (209, 214))	('RMS', 'Disease', 'MESH:D012208', (304, 307))	('child', 'Species', '9606', (294, 299))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('RMS', 'Phenotype', 'HP:0002859', (304, 307))	('patients', 'Species', '9606', (50, 58))	('RMS', 'Disease', 'MESH:D012208', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('RMS', 'Phenotype', 'HP:0002859', (64, 67))	('investigated', 'Reg', (217, 229))	('RMS', 'Disease', (304, 307))	('18F-FDG', 'Chemical', 'MESH:D019788', (242, 249))	('18F-FDG PET', 'Var', (242, 253))
72885	31939615	ONGs in pediatric patients usually present with painless proptosis, decreased visual acuity, visual fields, or color vision, while compression effects can cause hypothalamic symptoms or obstructive hydrocephalus due to the compression of the third ventricle and central retinal vein occlusion (CRVO) because of the compression of the central retinal vein.	('obstructive hydrocephalus', 'Disease', 'MESH:D006849', (186, 211))	('vision', 'biological_process', 'GO:0007601', ('117', '123'))	('hypothalamic symptoms', 'Phenotype', 'HP:0025058', (161, 182))	('CRVO', 'Phenotype', 'HP:0020166', (294, 298))	('painless proptosis', 'Disease', 'MESH:D005094', (48, 66))	('color vision', 'CPA', (111, 123))	('vein occlusion', 'Phenotype', 'HP:0025322', (278, 292))	('painless proptosis', 'Disease', (48, 66))	('obstructive hydrocephalus', 'Disease', (186, 211))	('central retinal vein occlusion', 'Phenotype', 'HP:0020166', (262, 292))	('visual fields', 'CPA', (93, 106))	('ONG', 'Disease', 'MESH:D020339', (0, 3))	('pain', 'Phenotype', 'HP:0012531', (48, 52))	('ONG', 'Disease', (0, 3))	('decreased visual acuity', 'Disease', (68, 91))	('hydrocephalus', 'Phenotype', 'HP:0000238', (198, 211))	('decreased visual acuity', 'Phenotype', 'HP:0007663', (68, 91))	('compression of the third ventricle', 'Phenotype', 'HP:0007082', (223, 257))	('patients', 'Species', '9606', (18, 26))	('cause', 'Reg', (155, 160))	('retinal vein occlusion', 'Disease', (270, 292))	('ONG', 'Phenotype', 'HP:0009734', (0, 3))	('hypothalamic symptoms', 'Disease', (161, 182))	('hypothalamic symptoms', 'Disease', 'MESH:D051271', (161, 182))	('proptosis', 'Phenotype', 'HP:0000520', (57, 66))	('retinal vein occlusion', 'Disease', 'MESH:D012170', (270, 292))	('decreased visual acuity', 'Disease', 'MESH:D014786', (68, 91))	('compression effects', 'Var', (131, 150))	('retinal vein occlusion', 'Phenotype', 'HP:0012636', (270, 292))
72934	31939615	However, 18F-FDG PET/CT has an established role for patients with OL and OAL both at initial staging and post-treatment assessment.	('18F-FDG', 'Var', (9, 16))	('18F-FDG', 'Chemical', 'MESH:D019788', (9, 16))	('OAL', 'Disease', (73, 76))	('OL', 'Disease', 'MESH:C537131', (66, 68))	('OAL', 'Disease', 'MESH:D000292', (73, 76))	('patients', 'Species', '9606', (52, 60))
73011	31179240	MiRNAs microarray analyses on circPCMTD1 silencing models in U251 and U118MG cells were performed, and the results suggested that circPCMTD1 knockdown could upregulate the expression of miR-224-5p and downregulate the expression of mTOR, one of miR-224-5p targets, in both cell lines.	('PCMTD1', 'Gene', '115294', (34, 40))	('knockdown', 'Var', (141, 150))	('PCMTD1', 'Gene', '115294', (134, 140))	('PCMTD1', 'Gene', (134, 140))	('miR-224', 'Gene', (186, 193))	('miR-224', 'Gene', '407009', (186, 193))	('PCMTD1', 'Gene', (34, 40))	('miR-224', 'Gene', '407009', (245, 252))	('miR-224', 'Gene', (245, 252))	('expression', 'MPA', (172, 182))	('upregulate', 'PosReg', (157, 167))	('U118MG', 'CellLine', 'CVCL:0633', (70, 76))	('mTOR', 'Gene', (232, 236))	('mTOR', 'Gene', '2475', (232, 236))	('expression', 'MPA', (218, 228))	('-224-5p', 'Chemical', '-', (189, 196))	('-224-5p', 'Chemical', '-', (248, 255))	('downregulate', 'NegReg', (201, 213))
73021	31179240	In addition, dysregulated miRNAs can act as oncogenes or tumor suppressor genes that play important roles in tumorigenesis and progression of malignancies.	('miR', 'Gene', '220972', (26, 29))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('57', '73'))	('miR', 'Gene', (26, 29))	('tumor suppressor', 'biological_process', 'GO:0051726', ('57', '73'))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('malignancies', 'Disease', 'MESH:D009369', (142, 154))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('malignancies', 'Disease', (142, 154))	('tumor', 'Disease', (57, 62))	('dysregulated', 'Var', (13, 25))	('tumor', 'Disease', (109, 114))
73046	31179240	The fragments of circPCMTD1-WT and CircPCMTD1 mutant were cloned into the psiCHECK-2 luciferase vector (Promega, USA) with NotI and XholI endonuclease.	('PCMTD1', 'Gene', '115294', (21, 27))	('PCMTD1', 'Gene', (21, 27))	('mutant', 'Var', (46, 52))	('PCMTD1', 'Gene', '115294', (39, 45))	('PCMTD1', 'Gene', (39, 45))
73072	31179240	In addition, the cell cycle was accelerated to S/G2/M phase when the expression of circPCMTD1 was upregulated (Figures 1G,H) in both U251 and U118MG cells, while massive G1 phase arrest was observed when the expression of circPCMTD1 was stably silenced (Figures 1G,H).	('arrest', 'Disease', 'MESH:D006323', (179, 185))	('G1 phase', 'biological_process', 'GO:0051318', ('170', '178'))	('cell cycle', 'CPA', (17, 27))	('PCMTD1', 'Gene', '115294', (226, 232))	('accelerated', 'PosReg', (32, 43))	('arrest', 'Disease', (179, 185))	('PCMTD1', 'Gene', (226, 232))	('upregulated', 'PosReg', (98, 109))	('cell cycle', 'biological_process', 'GO:0007049', ('17', '27'))	('PCMTD1', 'Gene', '115294', (87, 93))	('U118MG', 'Var', (142, 148))	('S/G2', 'Var', (47, 51))	('expression', 'MPA', (69, 79))	('S/G2', 'SUBSTITUTION', 'None', (47, 51))	('M phase', 'biological_process', 'GO:0000279', ('52', '59'))	('U118MG', 'CellLine', 'CVCL:0633', (142, 148))	('PCMTD1', 'Gene', (87, 93))
73074	31179240	It indicated that silencing circPCMTD1 could induce cell cycle arrest and reduce proliferation in glioma cells.	('PCMTD1', 'Gene', (32, 38))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (52, 69))	('arrest', 'Disease', 'MESH:D006323', (63, 69))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('52', '69'))	('silencing', 'Var', (18, 27))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('reduce', 'NegReg', (74, 80))	('induce', 'PosReg', (45, 51))	('arrest', 'Disease', (63, 69))	('glioma cell', 'Disease', 'MESH:D005910', (98, 109))	('PCMTD1', 'Gene', '115294', (32, 38))	('glioma cell', 'Disease', (98, 109))	('proliferation', 'CPA', (81, 94))
73076	31179240	When circPCMTD1 was downregulated, the migration ability was suppressed significantly, especially by the si-circ-2 siRNA in U118MG cells (Figures 2A,B).	('suppressed', 'NegReg', (61, 71))	('si-circ-2', 'Var', (105, 114))	('PCMTD1', 'Gene', '115294', (9, 15))	('PCMTD1', 'Gene', (9, 15))	('U118MG', 'CellLine', 'CVCL:0633', (124, 130))	('migration ability', 'CPA', (39, 56))
73080	31179240	It is a significantly higher level of circPCMTD1 in U118MG cells (Figure 3A).	('higher', 'PosReg', (22, 28))	('PCMTD1', 'Gene', '115294', (42, 48))	('U118MG', 'Var', (52, 58))	('U118MG', 'CellLine', 'CVCL:0633', (52, 58))	('PCMTD1', 'Gene', (42, 48))
73087	31179240	Results from the bioinformatics analysis found that circPCMTD1 knockdown could, respectively, affect miRNAs in both cell models (Figures 4C,D).	('affect', 'Reg', (94, 100))	('PCMTD1', 'Gene', '115294', (56, 62))	('PCMTD1', 'Gene', (56, 62))	('knockdown', 'Var', (63, 72))	('miR', 'Gene', '220972', (101, 104))	('miR', 'Gene', (101, 104))
73092	31179240	All raw data can be found at the NCBI SRA with accession numbers SRR8934915, SRR8934916, SRR8934917, SRR8934918.	('SRR8934918', 'Var', (101, 111))	('SRR8934915', 'Var', (65, 75))	('SRR8934916', 'Var', (77, 87))	('SRR8934917', 'Var', (89, 99))	('SRA', 'Gene', '10011', (38, 41))	('SRA', 'Gene', (38, 41))
73103	31179240	In addition, overexpression of circPCMTD1 in U251 and U118MG can reduce the expression levels of miR-224-5p (Figure 5H), while upregulation of miR-224-5p was observed when circPCMTD1 was silenced in glioma cells (Figure 5I).	('overexpression', 'PosReg', (13, 27))	('PCMTD1', 'Gene', (35, 41))	('PCMTD1', 'Gene', (176, 182))	('glioma cell', 'Disease', 'MESH:D005910', (199, 210))	('-224-5p', 'Chemical', '-', (100, 107))	('glioma cell', 'Disease', (199, 210))	('U118MG', 'CellLine', 'CVCL:0633', (54, 60))	('PCMTD1', 'Gene', '115294', (35, 41))	('expression levels', 'MPA', (76, 93))	('PCMTD1', 'Gene', '115294', (176, 182))	('-224-5p', 'Chemical', '-', (146, 153))	('glioma', 'Phenotype', 'HP:0009733', (199, 205))	('miR-224', 'Gene', '407009', (97, 104))	('miR-224', 'Gene', (97, 104))	('miR-224', 'Gene', '407009', (143, 150))	('U251', 'Var', (45, 49))	('miR-224', 'Gene', (143, 150))	('reduce', 'NegReg', (65, 71))	('U118MG', 'Var', (54, 60))
73106	31179240	Dysregulation of mTOR was found in different types of tumors including glioblastoma.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('glioblastoma', 'Disease', (71, 83))	('Dysregulation', 'Var', (0, 13))	('glioblastoma', 'Disease', 'MESH:D005909', (71, 83))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('found', 'Reg', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mTOR', 'Gene', (17, 21))	('mTOR', 'Gene', '2475', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
73108	31179240	Overexpression or silencing of miR-224-5p was performed to further understand their role in the progression of glioma.	('glioma', 'Disease', (111, 117))	('silencing', 'Var', (18, 27))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('-224-5p', 'Chemical', '-', (34, 41))	('miR-224', 'Gene', '407009', (31, 38))	('miR-224', 'Gene', (31, 38))
73110	31179240	The cell cycle was accelerated to S/G2/M phase when inhibited the expression of miR-224-5p (Figures 6G,H), conversely, miR-224-5p stably overexpressing in U251 and U118MG cells exhibited a massive G1 phase arrest compared with their control cells (Figures 6G,H).	('S/G2', 'SUBSTITUTION', 'None', (34, 38))	('G1 phase', 'biological_process', 'GO:0051318', ('197', '205'))	('miR-224', 'Gene', (80, 87))	('cell cycle', 'CPA', (4, 14))	('U118MG', 'Var', (164, 170))	('miR-224', 'Gene', '407009', (80, 87))	('arrest', 'Disease', (206, 212))	('expression', 'MPA', (66, 76))	('inhibited', 'NegReg', (52, 61))	('M phase', 'biological_process', 'GO:0000279', ('39', '46'))	('U251', 'Var', (155, 159))	('cell cycle', 'biological_process', 'GO:0007049', ('4', '14'))	('arrest', 'Disease', 'MESH:D006323', (206, 212))	('U118MG', 'CellLine', 'CVCL:0633', (164, 170))	('accelerated', 'PosReg', (19, 30))	('miR-224', 'Gene', '407009', (119, 126))	('miR-224', 'Gene', (119, 126))	('S/G2', 'Var', (34, 38))	('overexpressing', 'PosReg', (137, 151))
73113	31179240	In the wound-healing assays, we found that the migration ability of U118MG and U251 was inhibited by overexpression of miR-224-5p (Figure 7).	('inhibited', 'NegReg', (88, 97))	('overexpression', 'PosReg', (101, 115))	('migration ability', 'CPA', (47, 64))	('U118MG', 'Var', (68, 74))	('U118MG', 'CellLine', 'CVCL:0633', (68, 74))	('miR-224', 'Gene', '407009', (119, 126))	('miR-224', 'Gene', (119, 126))	('-224-5p', 'Chemical', '-', (122, 129))	('wound-healing', 'biological_process', 'GO:0042060', ('7', '20'))
73115	31179240	Both silencing of circPCMTD1 or upregulation of miR-224-5p significantly reduced the cell migration and invasion.	('miR-224', 'Gene', '407009', (48, 55))	('miR-224', 'Gene', (48, 55))	('PCMTD1', 'Gene', (22, 28))	('upregulation', 'PosReg', (32, 44))	('reduced', 'NegReg', (73, 80))	('silencing', 'Var', (5, 14))	('cell migration', 'biological_process', 'GO:0016477', ('85', '99'))	('PCMTD1', 'Gene', '115294', (22, 28))
73118	31179240	Silencing of mTOR, as a target of miR-224-5p, could inhibit the viability, proliferation, migration, and invasion in U251 and U118MG cells, which has similar effects with silencing of circPCMTD1 and overexpression of miR-224-5p (Figure S1).	('invasion', 'CPA', (105, 113))	('inhibit', 'NegReg', (52, 59))	('PCMTD1', 'Gene', '115294', (188, 194))	('viability', 'CPA', (64, 73))	('U118MG', 'CellLine', 'CVCL:0633', (126, 132))	('migration', 'CPA', (90, 99))	('miR-224', 'Gene', '407009', (34, 41))	('PCMTD1', 'Gene', (188, 194))	('miR-224', 'Gene', (217, 224))	('mTOR', 'Gene', (13, 17))	('silencing', 'Var', (171, 180))	('mTOR', 'Gene', '2475', (13, 17))	('miR-224', 'Gene', '407009', (217, 224))	('proliferation', 'CPA', (75, 88))	('Silencing', 'Var', (0, 9))	('miR-224', 'Gene', (34, 41))
73124	31179240	For instance, hsa_circ_0007534 promoted the progression of glioma through the miR-761/ZIC5 regulatory loop.	('glioma', 'Disease', (59, 65))	('progression', 'CPA', (44, 55))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('ZIC5', 'Gene', (86, 90))	('miR-761', 'Gene', '100313892', (78, 85))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('promoted', 'PosReg', (31, 39))	('miR-761', 'Gene', (78, 85))	('hsa_circ_0007534', 'Var', (14, 30))	('ZIC5', 'Gene', '85416', (86, 90))
73133	31179240	U118MG, a WHO grade IV human GBM cell line, derived from highly malignant GBM tumors.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('U118MG', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('U118MG', 'CellLine', 'CVCL:0633', (0, 6))	('human', 'Species', '9606', (23, 28))	('GBM tumors', 'Disease', (74, 84))	('GBM tumors', 'Disease', 'MESH:D005910', (74, 84))
73149	31179240	In addition, inhibition of mTOR could suppress glioma cells progression, and mTOR has an interaction with miR-224-5p.	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('interaction', 'Interaction', (89, 100))	('-224-5p', 'Chemical', '-', (109, 116))	('inhibition', 'Var', (13, 23))	('glioma cell', 'Disease', 'MESH:D005910', (47, 58))	('mTOR', 'Gene', '2475', (77, 81))	('miR-224', 'Gene', (106, 113))	('mTOR', 'Gene', (77, 81))	('glioma cell', 'Disease', (47, 58))	('miR-224', 'Gene', '407009', (106, 113))	('mTOR', 'Gene', (27, 31))	('suppress', 'NegReg', (38, 46))	('mTOR', 'Gene', '2475', (27, 31))
73157	30400891	We found a strong correlation between multiple calling-card transposon insertions targeted by BAP1-PBase and BAP1-responsive expression of adjacent genes.	('BAP1', 'Gene', '8314', (94, 98))	('BAP1', 'Gene', '8314', (109, 113))	('BAP1', 'Gene', (94, 98))	('BAP1', 'Gene', (109, 113))	('insertions', 'Var', (71, 81))
73158	30400891	BAP1-bound genomic loci showed narrow distributions of insertions and were near transcription start sites, consistent with recruitment of BAP1 to these sites by specific DNA-binding proteins.	('BAP1', 'Gene', '8314', (138, 142))	('BAP1', 'Gene', (0, 4))	('DNA-binding', 'molecular_function', 'GO:0003677', ('170', '181'))	('BAP1', 'Gene', (138, 142))	('insertions', 'Var', (55, 65))	('transcription', 'biological_process', 'GO:0006351', ('80', '93'))	('BAP1', 'Gene', '8314', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))
73169	30400891	Over 95% of class 2 UMs show complete loss of expression of BAP1 protein, with inactivating somatic mutations in the BAP1 gene in 80% of these tumors.	('mutations', 'Var', (100, 109))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('class 2 UMs', 'Disease', (12, 23))	('BAP1', 'Gene', '8314', (117, 121))	('protein', 'Protein', (65, 72))	('tumors', 'Disease', (143, 149))	('loss', 'NegReg', (38, 42))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('BAP1', 'Gene', '8314', (60, 64))	('BAP1', 'Gene', (117, 121))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('UM', 'Phenotype', 'HP:0007716', (20, 22))	('expression', 'MPA', (46, 56))	('BAP1', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
73170	30400891	Loss of BAP1 causes UM cells to assume a rounded, epithelioid morphology, to deposit distinctive extracellular matrix materials, and to grow well under clonogenic conditions, and BAP1-depleted UM cells display increased diapedesis through endothelial monolayers in a cell-culture model of transendothelial migration, which may reflect their ability to metastasize.	('BAP1', 'Gene', (179, 183))	('increased', 'PosReg', (210, 219))	('diapedesis', 'biological_process', 'GO:0050904', ('220', '230'))	('BAP1', 'Gene', '8314', (8, 12))	('UM', 'Phenotype', 'HP:0007716', (193, 195))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('97', '117'))	('BAP1', 'Gene', (8, 12))	('UM', 'Phenotype', 'HP:0007716', (20, 22))	('Loss', 'Var', (0, 4))	('BAP1', 'Gene', '8314', (179, 183))	('diapedesis', 'MPA', (220, 230))
73171	30400891	BAP1 mutations have been found in other aggressive cancers, including skin-derived melanomas, mesotheliomas, and renal cell carcinomas, suggesting a general role for BAP1 as a suppressor of metastasis in cancer.	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('BAP1', 'Gene', '8314', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('melanomas', 'Disease', (83, 92))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (113, 134))	('BAP1', 'Gene', (0, 4))	('renal cell carcinomas', 'Disease', (113, 134))	('BAP1', 'Gene', (166, 170))	('found', 'Reg', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('cancer', 'Disease', (204, 210))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (113, 134))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('mutations', 'Var', (5, 14))	('mesotheliomas', 'Disease', (94, 107))	('aggressive cancers', 'Disease', (40, 58))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('mesotheliomas', 'Disease', 'MESH:D008654', (94, 107))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('aggressive cancers', 'Disease', 'MESH:D009369', (40, 58))	('BAP1', 'Gene', '8314', (0, 4))	('cancer', 'Disease', (51, 57))	('melanomas', 'Disease', 'MESH:D008545', (83, 92))
73190	30400891	Three biological replicates for BAP1 and control (GFP) knockdowns were sequenced.	('knockdowns', 'Var', (55, 65))	('BAP1', 'Gene', '8314', (32, 36))	('BAP1', 'Gene', (32, 36))
73198	30400891	The BAP1-PBase and PBase-BAP1 fusion constructs produced 199,209 and 179,244 genomic transposon insertions, respectively, and these insertion sites clustered into 7,810 (see Additional file 1) and 7,634 (see Additional file 2) genomic peaks.	('fusion', 'Var', (30, 36))	('BAP1', 'Gene', (25, 29))	('BAP1', 'Gene', (4, 8))	('BAP1', 'Gene', '8314', (25, 29))	('BAP1', 'Gene', '8314', (4, 8))
73204	30400891	Comparing BAP1-fusion insertions with all background insertions, we found distances to transcription start sites as highly enriched for both fusions (p < 0.0001, Mann-Whitney U tests).	('transcription', 'biological_process', 'GO:0006351', ('87', '100'))	('BAP1', 'Gene', (10, 14))	('BAP1', 'Gene', '8314', (10, 14))	('insertions', 'Var', (22, 32))
73211	30400891	We performed pathway and gene ontology analyses on the 784 genes identified by the combination of > 2-fold BAP1-sensitive RNA expression changes and calling-card transposon targeting.	('BAP1', 'Gene', '8314', (107, 111))	('RNA', 'cellular_component', 'GO:0005562', ('122', '125'))	('gene ontology', 'biological_process', 'GO:0003673', ('25', '38'))	('BAP1', 'Gene', (107, 111))	('changes', 'Var', (137, 144))
73214	30400891	Two highly significant (p < 0.001) molecular signatures were identified by Gene Set Enrichment Analysis of BAP1 calling-card target genes associated with gene expression response to BAP1 depletion (see Additional file 7): an Epithelial-to-Mesenchymal Transition (EMT) signature was associated with up-regulated genes; and a polycomb-mediated lysine27-trimethylation of histone H3 in Embryonic Stem Cells was associated with down-regulated genes (Fig.	('Epithelial-to-Mesenchymal Transition', 'biological_process', 'GO:0001837', ('225', '261'))	('BAP1', 'Gene', '8314', (107, 111))	('BAP1', 'Gene', '8314', (182, 186))	('gene expression', 'biological_process', 'GO:0010467', ('154', '169'))	('genes', 'Gene', (311, 316))	('BAP1', 'Gene', (107, 111))	('BAP1', 'Gene', (182, 186))	('polycomb-mediated lysine27-trimethylation', 'Var', (324, 365))	('up-regulated', 'PosReg', (298, 310))	('lysine27', 'Chemical', '-', (342, 350))	('down-regulated', 'NegReg', (424, 438))	('histone H3', 'Protein', (369, 379))	('EMT', 'biological_process', 'GO:0001837', ('263', '266'))
73229	30400891	We found that fusions of BAP1 with transposase at either the N-terminus and C-terminus did not impair transposase function, and that while a substantial number (32%) of the genes were identified by both the N-terminal and C-terminal fusion constructs, the majority were identified by only one (Fig.	('BAP1', 'Gene', (25, 29))	('function', 'MPA', (114, 122))	('BAP1', 'Gene', '8314', (25, 29))	('fusions', 'Var', (14, 21))	('impair', 'NegReg', (95, 101))
73234	30400891	We found pathways related to Epithelial-to-Mesenchymal Transition (EMT) and embryonic stem cell differentiation affected by depletion of BAP1 in UM cells.	('embryonic stem cell differentiation', 'CPA', (76, 111))	('BAP1', 'Gene', (137, 141))	('stem cell differentiation', 'biological_process', 'GO:0048863', ('86', '111'))	('affected', 'Reg', (112, 120))	('Epithelial-to-Mesenchymal Transition', 'CPA', (29, 65))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('EMT', 'biological_process', 'GO:0001837', ('67', '70'))	('BAP1', 'Gene', '8314', (137, 141))	('depletion', 'Var', (124, 133))	('Epithelial-to-Mesenchymal Transition', 'biological_process', 'GO:0001837', ('29', '65'))
73237	30400891	In contrast, in hematopoietic cells, loss of BAP1 affected pathways related to hematopoietic differentiation.	('BAP1', 'Gene', (45, 49))	('pathways', 'Pathway', (59, 67))	('loss', 'Var', (37, 41))	('BAP1', 'Gene', '8314', (45, 49))	('affected', 'Reg', (50, 58))
73262	29917326	Analysis of UM by array comparative genomic hybridisation revealed: 25 (64%) patients with high risk (monosomy3/8q gain); 13 (33%) intermediate risk (M3/8normal or disomy3/8q gain); and 1 low risk (disomy3/8normal).	('8q', 'Chemical', '-', (172, 174))	('monosomy3/8q gain', 'Var', (102, 119))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('patients', 'Species', '9606', (77, 85))	('M3/8normal', 'Var', (150, 160))	('disomy3/8q gain', 'Var', (164, 179))	('8q', 'Chemical', '-', (112, 114))
73268	29917326	array CGH array comparative genomic hybridisation D3 Disomy 3, no loss of chromosome 3 EVMM Extravascular migratory metastasis HGP histopathological growth pattern LTD largest tumour diameter (primary uveal melanoma) MD Missing Data MRI Magnetic resonance imaging M3 monosomy 3, loss of chromosome 3 UM uveal melanoma 8g gain in chromosome 8q 8nl 8 chromosome normal, absence of 8q gain 8q long arm of chromosome 8 Up to 50% of uveal melanomas (UM) metastasise to the liver within 10 years of diagnosis, and these almost always prove rapidly fatal 1.	('8q', 'Chemical', '-', (387, 389))	('8q', 'Chemical', '-', (340, 342))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('primary uveal melanoma', 'Disease', (193, 215))	('chromosome', 'cellular_component', 'GO:0005694', ('74', '84'))	('metastasise', 'CPA', (449, 460))	('melanoma', 'Phenotype', 'HP:0002861', (309, 317))	('uveal melanomas', 'Disease', (428, 443))	('uveal melanomas', 'Phenotype', 'HP:0007716', (428, 443))	('uveal melanoma', 'Disease', 'MESH:C536494', (201, 215))	('melanomas', 'Phenotype', 'HP:0002861', (434, 443))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('growth pattern', 'biological_process', 'GO:0007150', ('149', '163'))	('tumour', 'Disease', 'MESH:D009369', (176, 182))	('LTD', 'biological_process', 'GO:0060292', ('164', '167'))	('chromosome', 'cellular_component', 'GO:0005694', ('287', '297'))	('tumour', 'Disease', (176, 182))	('chromosome', 'cellular_component', 'GO:0005694', ('349', '359'))	('uveal melanoma', 'Disease', (303, 317))	('uveal melanoma', 'Disease', 'MESH:C536494', (303, 317))	('melanoma', 'Phenotype', 'HP:0002861', (434, 442))	('uveal melanoma', 'Phenotype', 'HP:0007716', (201, 215))	('uveal melanoma', 'Disease', 'MESH:C536494', (428, 442))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (193, 215))	('UM', 'Phenotype', 'HP:0007716', (445, 447))	('growth pattern', 'biological_process', 'GO:0040007', ('149', '163'))	('chromosome', 'cellular_component', 'GO:0005694', ('329', '339'))	('UM', 'Phenotype', 'HP:0007716', (300, 302))	('EVMM', 'Chemical', '-', (87, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (303, 317))	('uveal melanoma', 'Phenotype', 'HP:0007716', (428, 442))	('uveal melanomas', 'Disease', 'MESH:C536494', (428, 443))	('8q', 'Chemical', '-', (379, 381))	('chromosome', 'cellular_component', 'GO:0005694', ('402', '412'))	('absence', 'Var', (368, 375))
73273	29917326	In another autopsy study of 10 patients 15, UM liver metastases were categorised into three stages: stage I, deposits <=50 mum in diameter, and stage II, deposits 51-500 mum, both within sinusoidal spaces; and stage III, deposits >=500 mum.	('liver metastases', 'Disease', (47, 63))	('liver metastases', 'Disease', 'MESH:D009362', (47, 63))	('patients', 'Species', '9606', (31, 39))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('deposits 51-500 mum', 'Var', (154, 173))	('deposits <=50 mum', 'Var', (109, 126))
73308	29917326	These Cassoux risk groups 36 were defined by the presence or absence of chromosome 3 loss (monosomy 3) and the presence or absence of chromosome 8 gain (including gain of the entire 8 chromosome, gain of the entire 8q, and distal gain of 8q), as follows: Cassoux risk group 1, Low risk for metastasis: normal status of chromosomes 3 (disomy 3) and 8 (8nl): D3/8nl; Group 2, Intermediate risk: monosomy 3 and normal status of 8: M3/8nl; Group 3, Intermediate risk: disomy 3 and gain of 8q (8g): D3/8g; and Group 4, High risk: M3/8g (Tables 1 and 3) 36.	('disomy 3', 'Var', (464, 472))	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('D3/8g', 'Var', (494, 499))	('8q', 'Chemical', '-', (485, 487))	('chromosome', 'cellular_component', 'GO:0005694', ('184', '194'))	('metastasis', 'CPA', (290, 300))	('M3/8g', 'Var', (525, 530))	('8q', 'Chemical', '-', (238, 240))	('chromosome', 'cellular_component', 'GO:0005694', ('134', '144'))	('8q', 'Chemical', '-', (215, 217))
73319	29917326	Genetic analysis revealed: D3/8nl: 1 patient (2.6%), D3/8g: 8 (20.5%), M3/8nl: 5 (13%), M3/8g: 25 (64%).	('M3/8nl', 'Var', (71, 77))	('patient', 'Species', '9606', (37, 44))	('M3/8g', 'Var', (88, 93))	('D3/8nl', 'Disease', (27, 33))	('D3/8g', 'Var', (53, 58))
73352	29917326	Univariate analysis with the Log Rank test showed that HGP had a striking effect on OS metastasis (p = 0.041) (Figure 5I).	('HGP', 'Var', (55, 58))	('OS', 'Chemical', '-', (84, 86))	('OS metastasis', 'CPA', (84, 97))
73354	29917326	None of the other variables including age, gender, laterality, monosomy 3, 8q gain, the high-risk genomic variable M3/8q gain, melanoma cell type, size of metastasis, and the various treatments for metastatic disease had any significant effect on survival.	('monosomy 3', 'Var', (63, 73))	('M3/8q gain', 'Var', (115, 125))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('8q', 'Chemical', '-', (118, 120))	('melanoma', 'Disease', (127, 135))	('8q', 'Chemical', '-', (75, 77))
73356	29917326	On univariate analysis, other conventional prognostic factors such as patient age, the high risk genomic variable M3/8q gain (Figure 5II), LTD (Figure 5II), and time to metastasis had important predictive value.	('8q', 'Chemical', '-', (117, 119))	('M3/8q', 'Var', (114, 119))	('patient', 'Species', '9606', (70, 77))	('LTD', 'biological_process', 'GO:0060292', ('139', '142'))	('gain', 'PosReg', (120, 124))
73358	29917326	On univariate analysis, the following prognostic factors were significant: age, monosomy 3, 8q gain, M3/8q gain (p = 0.008), and LTD (p = 0.03).	('8q', 'Chemical', '-', (92, 94))	('M3/8q', 'Var', (101, 106))	('LTD', 'biological_process', 'GO:0060292', ('129', '132'))	('gain', 'PosReg', (107, 111))	('8q', 'Chemical', '-', (104, 106))	('monosomy 3', 'Var', (80, 90))	('gain', 'PosReg', (95, 99))
73370	29917326	With respect to metastasis-free survival, the genetic variables (monosomy 3, 8q gain, and M3/8q gain) and LTD had important predictive value in the univariate model but were not significant on multivariate analysis.	('LTD', 'biological_process', 'GO:0060292', ('106', '109'))	('8q gain', 'Var', (77, 84))	('monosomy 3', 'Var', (65, 75))	('M3/8q gain', 'Var', (90, 100))	('8q', 'Chemical', '-', (93, 95))	('8q', 'Chemical', '-', (77, 79))
73391	29917326	The lack of correlation between monosomy 3 and 8q gain and liver HGP in UM and the lack of prognostic significance of these genetic factors in the context of UM liver metastases prompts some discussion.	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('liver metastases', 'Disease', (161, 177))	('liver metastases', 'Disease', 'MESH:D009362', (161, 177))	('liver HGP', 'Gene', (59, 68))	('UM', 'Phenotype', 'HP:0007716', (158, 160))	('monosomy 3', 'Var', (32, 42))	('8q', 'Chemical', '-', (47, 49))
73527	29988983	The patient with MUP harbored a v-Raf murine sarcoma viral oncogene homolog (BRAF) V600E mutation and was assigned to the group of cutaneous melanomas.	('murine', 'Species', '10090', (38, 44))	('sarcoma viral', 'Disease', 'MESH:D001102', (45, 58))	('V600E', 'Var', (83, 88))	('v-Raf', 'Gene', (32, 37))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanomas', 'Phenotype', 'HP:0002861', (141, 150))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (131, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (131, 150))	('patient', 'Species', '9606', (4, 11))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (131, 149))	('BRAF', 'Gene', (77, 81))	('v-Raf', 'Gene', '110157', (32, 37))	('sarcoma viral', 'Disease', (45, 58))	('cutaneous melanomas', 'Disease', (131, 150))	('V600E', 'Mutation', 'rs113488022', (83, 88))
73528	29988983	In 17% (N = 4) of the patients with cutaneous melanoma, prior treatment was recorded and consisted of targeted therapy with BRAF and MEK inhibitors (33% of BRAF mutant patients; N = 4).	('MEK', 'Gene', (133, 136))	('mutant', 'Var', (161, 167))	('MEK', 'Gene', '5609', (133, 136))	('BRAF', 'Gene', (156, 160))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('patients', 'Species', '9606', (22, 30))	('cutaneous melanoma', 'Disease', (36, 54))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (36, 54))	('patients', 'Species', '9606', (168, 176))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (36, 54))
73553	29988983	Vitiligo as treatment-related AE is typically observed in melanoma patients treated with anti-PD-1 antibodies and indicated positive response to therapy in 4 of our patients (Figure 1, Patient 2, 9, 25, 30).	('anti-PD-1', 'Var', (89, 98))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('Vitiligo', 'Phenotype', 'HP:0001045', (0, 8))	('patients', 'Species', '9606', (67, 75))	('Vitiligo', 'Gene', (0, 8))	('Vitiligo', 'Gene', '246319', (0, 8))	('patients', 'Species', '9606', (165, 173))	('Patient', 'Species', '9606', (185, 192))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
73566	26154183	Multiple Cutaneous Melanomas and Clinically Atypical Moles in a Patient With a Novel Germline BAP1 Mutation Several kindreds having germline BAP1 mutations with a propensity for uveal and cutaneous melanomas and other internal malignancies have been described in an autosomal dominant tumor predisposition syndrome.	('autosomal dominant tumor', 'Disease', (266, 290))	('melanomas', 'Phenotype', 'HP:0002861', (198, 207))	('Multiple Cutaneous Melanomas', 'Disease', (0, 28))	('Melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('autosomal dominant tumor', 'Disease', 'MESH:D030342', (266, 290))	('BAP1', 'Gene', '8314', (141, 145))	('BAP1', 'Gene', '8314', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (188, 207))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (188, 206))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (188, 207))	('Multiple Cutaneous Melanomas', 'Disease', 'MESH:C562393', (0, 28))	('Atypical Moles', 'Phenotype', 'HP:0001062', (44, 58))	('BAP1', 'Gene', (141, 145))	('Mutation', 'Var', (99, 107))	('Cutaneous Melanomas', 'Phenotype', 'HP:0012056', (9, 28))	('BAP1', 'Gene', (94, 98))	('Moles', 'Phenotype', 'HP:0003764', (53, 58))	('mutations', 'Var', (146, 155))	('cutaneous melanomas', 'Disease', (188, 207))	('malignancies', 'Disease', 'MESH:D009369', (227, 239))	('Patient', 'Species', '9606', (64, 71))	('malignancies', 'Disease', (227, 239))
73567	26154183	We describe the first kindred to date with a germline mutation in BAP1 associated with multiple cutaneous melanomas and classic dysplastic nevus syndrome.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (96, 115))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (96, 115))	('dysplastic nevus syndrome', 'Disease', (128, 153))	('BAP1', 'Gene', '8314', (66, 70))	('nevus', 'Phenotype', 'HP:0003764', (139, 144))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (96, 114))	('cutaneous melanomas', 'Disease', (96, 115))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (128, 144))	('BAP1', 'Gene', (66, 70))	('dysplastic nevus syndrome', 'Disease', 'MESH:D004416', (128, 153))	('germline mutation', 'Var', (45, 62))	('melanomas', 'Phenotype', 'HP:0002861', (106, 115))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('associated', 'Reg', (71, 81))
73569	26154183	Germline testing was performed in the proband, his 16-year-old son, and his 13-year-old daughter, revealing a germline mutation in the BAP1 gene (c.592G>T, p.Glu198X) in the proband and in his 16-year-old son.	('BAP1', 'Gene', '8314', (135, 139))	('p.Glu198X', 'Mutation', 'p.E198X', (156, 165))	('c.592G>T', 'Var', (146, 154))	('c.592G>T', 'Mutation', 'c.592G>T', (146, 154))	('p.Glu198X', 'Var', (156, 165))	('BAP1', 'Gene', (135, 139))
73572	26154183	To our knowledge, this is the first report of a patient with multiple melanomas, dysplastic nevus syndrome, and an inactivating germline BAP1 mutation.	('BAP1', 'Gene', (137, 141))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (81, 97))	('dysplastic nevus syndrome', 'Disease', 'MESH:D004416', (81, 106))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))	('nevus', 'Phenotype', 'HP:0003764', (92, 97))	('germline', 'Var', (128, 136))	('patient', 'Species', '9606', (48, 55))	('BAP1', 'Gene', '8314', (137, 141))	('mutation', 'Var', (142, 150))	('dysplastic nevus syndrome', 'Disease', (81, 106))	('inactivating germline', 'Var', (115, 136))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('multiple melanomas', 'Disease', 'MESH:D008545', (61, 79))	('multiple melanomas', 'Disease', (61, 79))
73573	26154183	The coexistence of dysplastic nevus syndrome and a BAP1 germline mutation extends the spectrum of the BAP1 tumor predisposition syndrome and may confer a greater risk for cutaneous melanomas.	('BAP1', 'Gene', (102, 106))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (171, 190))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (171, 189))	('tumor', 'Disease', (107, 112))	('cutaneous melanomas', 'Disease', (171, 190))	('BAP1', 'Gene', (51, 55))	('BAP1', 'Gene', '8314', (51, 55))	('dysplastic nevus syndrome', 'Disease', (19, 44))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('melanomas', 'Phenotype', 'HP:0002861', (181, 190))	('mutation', 'Var', (65, 73))	('nevus', 'Phenotype', 'HP:0003764', (30, 35))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (19, 35))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (171, 190))	('dysplastic nevus syndrome', 'Disease', 'MESH:D004416', (19, 44))	('BAP1', 'Gene', '8314', (102, 106))
73574	26154183	Several kindreds with germline mutations in the BRCA1-associated protein 1 gene (BAP1 [OMIM 603089]) and a propensity for uveal and cutaneous melanomas have been described.	('BRCA1-associated protein 1', 'Gene', '8314', (48, 74))	('BAP1', 'Gene', '8314', (81, 85))	('BAP1', 'Gene', (81, 85))	('germline mutations', 'Var', (22, 40))	('BRCA1-associated protein 1', 'Gene', (48, 74))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (132, 151))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (132, 151))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (132, 150))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('cutaneous melanomas', 'Disease', (132, 151))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanomas', 'Phenotype', 'HP:0002861', (142, 151))
73575	26154183	BAP1 mutation carriers often develop crops of small (<10 mm) orange-red translucent papules, plaques, or nodules, typically located on the torso or the scalp.	('scalp', 'Disease', (152, 157))	('BAP1', 'Gene', (0, 4))	('papules', 'Phenotype', 'HP:0200034', (84, 91))	('orange-red translucent', 'MPA', (61, 83))	('develop', 'PosReg', (29, 36))	('BAP1', 'Gene', '8314', (0, 4))	('red translucent papules', 'Phenotype', 'HP:0030350', (68, 91))	('mutation', 'Var', (5, 13))	('scalp', 'Disease', 'MESH:C538225', (152, 157))
73579	26154183	Cytogenetically, BDTs in these patients often exhibit allelic loss on chromosome 3p21 at the BAP1 locus.	('BAP1', 'Gene', '8314', (93, 97))	('BDTs', 'Gene', (17, 21))	('BDTs', 'Chemical', '-', (17, 21))	('chromosome', 'cellular_component', 'GO:0005694', ('70', '80'))	('patients', 'Species', '9606', (31, 39))	('BAP1', 'Gene', (93, 97))	('allelic loss', 'Var', (54, 66))
73581	26154183	Patients with germline mutations in BAP1 have an increased risk for internal cancers such as mesothelioma, lung adenocarcinoma, meningiomas, and renal cell carcinoma, indicating that BAP1 inactivation leads to a mixed cancer phenotype.	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('BAP1', 'Gene', (183, 187))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (145, 165))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('lung adenocarcinoma', 'Disease', (107, 126))	('internal cancers', 'Disease', (68, 84))	('BAP1', 'Gene', '8314', (36, 40))	('Patients', 'Species', '9606', (0, 8))	('germline mutations', 'Var', (14, 32))	('meningiomas', 'Disease', 'MESH:D008577', (128, 139))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('renal cell carcinoma', 'Disease', (145, 165))	('internal cancers', 'Disease', 'MESH:D009369', (68, 84))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (107, 126))	('cancer', 'Disease', (77, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (145, 165))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('meningiomas', 'Phenotype', 'HP:0002858', (128, 139))	('BAP1', 'Gene', (36, 40))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (107, 126))	('BAP1', 'Gene', '8314', (183, 187))	('meningiomas', 'Disease', (128, 139))	('cancer', 'Disease', (218, 224))	('mesothelioma', 'Disease', (93, 105))	('leads to', 'Reg', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('mesothelioma', 'Disease', 'MESH:D008654', (93, 105))	('inactivation', 'Var', (188, 200))
73586	26154183	We describe a new kindred with a novel germline mutation in BAP1 in which the proband phenotypically has dysplastic nevi, BDTs, and multiple conventional superficial spreading melanomas (SSMs).	('superficial spreading melanomas', 'Phenotype', 'HP:0012057', (154, 185))	('melanomas', 'Disease', 'MESH:D008545', (176, 185))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('dysplastic nevi', 'Disease', (105, 120))	('germline mutation', 'Var', (39, 56))	('BDTs', 'Disease', (122, 126))	('BDTs', 'Chemical', '-', (122, 126))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (105, 120))	('dysplastic nevi', 'Disease', 'MESH:D004416', (105, 120))	('BAP1', 'Gene', '8314', (60, 64))	('SSMs', 'Phenotype', 'HP:0012057', (187, 191))	('melanomas', 'Disease', (176, 185))	('nevi', 'Phenotype', 'HP:0003764', (116, 120))	('BAP1', 'Gene', (60, 64))	('melanomas', 'Phenotype', 'HP:0002861', (176, 185))
73595	26154183	Two SSMs were also evaluated for BRAF (OMIM 164757) mutation using a test (cobas 4800 BRAF V600; Roche), and were both negative.	('BRAF', 'Gene', '673', (33, 37))	('SSMs', 'Phenotype', 'HP:0012057', (4, 8))	('BRAF', 'Gene', (33, 37))	('BRAF', 'Gene', '673', (86, 90))	('mutation', 'Var', (52, 60))	('BRAF', 'Gene', (86, 90))
73607	26154183	Sanger sequencing was performed to analyze the germline DNA for BAP1, CDKN2A, and CDK4 mutations.	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('CDK', 'molecular_function', 'GO:0004693', ('82', '85'))	('CDK4', 'Gene', '1019', (82, 86))	('CDK4', 'Gene', (82, 86))	('BAP1', 'Gene', '8314', (64, 68))	('CDKN2A', 'Gene', (70, 76))	('CDKN2A', 'Gene', '1029', (70, 76))	('mutations', 'Var', (87, 96))	('BAP1', 'Gene', (64, 68))
73608	26154183	The proband and his son had identical germline nonsense mutations in BAP1 (c.592G>T, p.Glu198X) (Figure 4C and D).	('p.Glu198X', 'Mutation', 'p.E198X', (85, 94))	('p.Glu198X', 'Var', (85, 94))	('BAP1', 'Gene', (69, 73))	('c.592G>T', 'Var', (75, 83))	('c.592G>T', 'Mutation', 'c.592G>T', (75, 83))	('BAP1', 'Gene', '8314', (69, 73))
73610	26154183	Analysis of a melanoma from the same patient demonstrated the presence of the germline mutation, while the other allele was wild type (Figure 4B).	('melanoma', 'Disease', (14, 22))	('patient', 'Species', '9606', (37, 44))	('germline mutation', 'Var', (78, 95))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
73611	26154183	There were no germline CDKN2A or CDK4 mutations.	('CDK', 'molecular_function', 'GO:0004693', ('33', '36'))	('CDK4', 'Gene', (33, 37))	('CDKN2A', 'Gene', (23, 29))	('CDK4', 'Gene', '1019', (33, 37))	('CDKN2A', 'Gene', '1029', (23, 29))	('mutations', 'Var', (38, 47))
73615	26154183	The BRAF mutation was detected using DNA extracted from formalin-fixed paraffin-embedded tissue with the mutation test (cobas 4800 BRAF V600), performed according to the manufacturer's protocol.	('mutation', 'Var', (9, 17))	('BRAF', 'Gene', '673', (131, 135))	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('BRAF', 'Gene', (131, 135))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('paraffin', 'Chemical', 'MESH:D010232', (71, 79))	('formalin', 'Chemical', 'MESH:D005557', (56, 64))	('man', 'Species', '9606', (170, 173))
73616	26154183	Multiple cutaneous melanomas have been associated with mutations in different genes (eg, CDKN2A or CDK4).	('mutations', 'Var', (55, 64))	('Multiple cutaneous melanomas', 'Disease', (0, 28))	('Multiple cutaneous melanomas', 'Disease', 'MESH:C562393', (0, 28))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (9, 27))	('CDKN2A', 'Gene', (89, 95))	('CDK4', 'Gene', (99, 103))	('associated', 'Reg', (39, 49))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (9, 28))	('CDK', 'molecular_function', 'GO:0004693', ('99', '102'))	('CDKN2A', 'Gene', '1029', (89, 95))	('CDK4', 'Gene', '1019', (99, 103))
73617	26154183	Germline variants in BAP1 have an increased susceptibility for different malignancies, with cancers appearing earlier than sporadic cases.	('susceptibility', 'Reg', (44, 58))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('BAP1', 'Gene', (21, 25))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('malignancies', 'Disease', 'MESH:D009369', (73, 85))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('malignancies', 'Disease', (73, 85))	('Germline variants', 'Var', (0, 17))	('BAP1', 'Gene', '8314', (21, 25))
73619	26154183	To our knowledge, this is the first report of a patient with dysplastic nevus syndrome and an inactivating germline BAP1 mutation.	('nevus', 'Phenotype', 'HP:0003764', (72, 77))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (61, 77))	('BAP1', 'Gene', (116, 120))	('dysplastic nevus syndrome', 'Disease', 'MESH:D004416', (61, 86))	('patient', 'Species', '9606', (48, 55))	('mutation', 'Var', (121, 129))	('germline', 'Var', (107, 115))	('inactivating germline', 'Var', (94, 115))	('dysplastic nevus syndrome', 'Disease', (61, 86))	('BAP1', 'Gene', '8314', (116, 120))
73621	26154183	Conversely, 3 of the 6 BDTs that were evaluated for a BRAFV600E mutation were positive.	('positive', 'Reg', (78, 86))	('BDTs', 'Chemical', '-', (23, 27))	('BRAFV600E', 'Var', (54, 63))	('BRAFV600E', 'Mutation', 'rs113488022', (54, 63))
73622	26154183	Hence, there may be distinct tumorigenic pathways in patients with constitutive BAP1 inactivation.	('inactivation', 'Var', (85, 97))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('patients', 'Species', '9606', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('BAP1', 'Gene', '8314', (80, 84))	('tumor', 'Disease', (29, 34))	('BAP1', 'Gene', (80, 84))
73623	26154183	If the cooperating driver mutation is BRAFV600E, the melanocytic proliferation may more likely evolve into a characteristic BDT.	('BRAFV600E', 'Var', (38, 47))	('BRAFV600E', 'Mutation', 'rs113488022', (38, 47))	('evolve', 'Reg', (95, 101))	('BDT', 'Chemical', '-', (124, 127))	('melanocytic proliferation', 'Disease', (53, 78))	('melanocytic proliferation', 'Disease', 'MESH:D059545', (53, 78))
73625	26154183	On the other hand, if a cooperating driver mutation is an oncogenic hit other than BRAFV600E, there may be a higher likelihood of melanoma considering that none of our patient's SSMs had a BRAF mutation, although this model is speculative.	('BRAF', 'Gene', (189, 193))	('BRAF', 'Gene', '673', (189, 193))	('BRAFV600E', 'Mutation', 'rs113488022', (83, 92))	('mutation', 'Var', (43, 51))	('SSMs', 'Phenotype', 'HP:0012057', (178, 182))	('patient', 'Species', '9606', (168, 175))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('BRAF', 'Gene', '673', (83, 87))	('melanoma', 'Disease', (130, 138))	('BRAF', 'Gene', (83, 87))
73626	26154183	Nevertheless, 3 of our 6 BDTs tested did not have a BRAF mutation.	('mutation', 'Var', (57, 65))	('BRAF', 'Gene', (52, 56))	('BRAF', 'Gene', '673', (52, 56))	('BDTs', 'Chemical', '-', (25, 29))
73628	26154183	To our knowledge, the p.Glu198X is a novel germline BAP1 mutation, although this mutation has been observed in an unrelated tumor specimen.	('p.Glu198X', 'Var', (22, 31))	('BAP1', 'Gene', '8314', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('BAP1', 'Gene', (52, 56))	('p.Glu198X', 'Mutation', 'p.E198X', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
73632	26154183	Therefore, mutations in BAP1 could increase the susceptibility to UV radiation and the risk for melanomas.	('melanomas', 'Disease', 'MESH:D008545', (96, 105))	('mutations', 'Var', (11, 20))	('increase', 'PosReg', (35, 43))	('susceptibility', 'MPA', (48, 62))	('BAP1', 'Gene', (24, 28))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('melanomas', 'Disease', (96, 105))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('BAP1', 'Gene', '8314', (24, 28))
73633	26154183	BRAF mutations have been identified in melanomas resulting from intense intermittent bouts of UV exposure.	('melanomas', 'Disease', (39, 48))	('identified', 'Reg', (25, 35))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanomas', 'Phenotype', 'HP:0002861', (39, 48))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('melanomas', 'Disease', 'MESH:D008545', (39, 48))	('BRAF', 'Gene', (0, 4))
73638	26154183	Identification of this germline BAP1 mutation in a patient with a constellation of multiple cancers and multiple atypical melanocytic tumors expands the cutaneous phenotype of the BAP1 tumor predisposition syndrome.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('mutation', 'Var', (37, 45))	('BAP1', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (185, 190))	('BAP1', 'Gene', '8314', (180, 184))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('BAP1', 'Gene', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (134, 139))	('constellation of multiple cancers', 'Disease', 'MESH:D009369', (66, 99))	('melanocytic tumors', 'Disease', (122, 140))	('melanocytic tumors', 'Disease', 'MESH:D009508', (122, 140))	('constellation of multiple cancers', 'Disease', (66, 99))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('BAP1', 'Gene', '8314', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('patient', 'Species', '9606', (51, 58))
73640	26154183	We speculate that the presence of a BAP1 germline mutation in a patient who phenotypically has dysplastic nevus syndrome may result in a considerable increased risk for cutaneous melanomas.	('dysplastic nevus syndrome', 'Disease', 'MESH:D004416', (95, 120))	('patient', 'Species', '9606', (64, 71))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (169, 188))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (169, 188))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (169, 187))	('BAP1', 'Gene', '8314', (36, 40))	('dysplastic nevus syndrome', 'Disease', (95, 120))	('result', 'Reg', (125, 131))	('melanomas', 'Phenotype', 'HP:0002861', (179, 188))	('presence', 'Var', (22, 30))	('cutaneous melanomas', 'Disease', (169, 188))	('BAP1', 'Gene', (36, 40))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('nevus', 'Phenotype', 'HP:0003764', (106, 111))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (95, 111))
73641	26154183	However, further research is needed to determine if the BAP1 germline mutation increases the risk of cutaneous melanoma beyond the dysplastic nevus phenotype alone.	('nevus', 'Phenotype', 'HP:0003764', (142, 147))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('increases', 'PosReg', (79, 88))	('BAP1', 'Gene', '8314', (56, 60))	('germline mutation', 'Var', (61, 78))	('cutaneous melanoma', 'Disease', (101, 119))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (101, 119))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (101, 119))	('BAP1', 'Gene', (56, 60))	('dysplastic nevus', 'Disease', 'MESH:D004416', (131, 147))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (131, 147))	('dysplastic nevus', 'Disease', (131, 147))
73642	26154183	Although no formal guidelines exist for patients with germline BAP1 alterations, strict sun protection and regular dermatologic and ophthalmologic evaluations are advisable.	('BAP1', 'Gene', (63, 67))	('patients', 'Species', '9606', (40, 48))	('alterations', 'Var', (68, 79))	('sun protection', 'Phenotype', 'HP:0000992', (88, 102))	('BAP1', 'Gene', '8314', (63, 67))
73645	29100322	The high levels of mitoses count and Ki67 labeling index had significant correlation with overexpression EZH2 (R = 0.408, P Our critical finding is that overexpression EZH2 in UM can be served as predictive marker and is associated with adverse clinical outcomes.	('EZH2', 'Gene', (168, 172))	('EZH2', 'Gene', '2146', (168, 172))	('overexpression', 'Var', (153, 167))	('EZH2', 'Gene', '2146', (105, 109))	('EZH2', 'Gene', (105, 109))	('associated with', 'Reg', (221, 236))
73666	29100322	Additionally, Ki67 LI and mitoses count were represented significantly higher in high EZH2 expression group than low expression group (P = 0.034,<0.0001) (Figure 2A, 2B).	('higher', 'PosReg', (71, 77))	('high', 'Var', (81, 85))	('EZH2', 'Gene', (86, 90))	('EZH2', 'Gene', '2146', (86, 90))
73669	29100322	Figure 3A shows Kaplan-Meier curves for the impact of high EZH2 expression was significantly associated with high trend of distant metastases during disease-free survival period (log rank P = 0.018).	('metastases', 'Disease', (131, 141))	('expression', 'MPA', (64, 74))	('EZH2', 'Gene', '2146', (59, 63))	('high', 'Var', (54, 58))	('EZH2', 'Gene', (59, 63))	('metastases', 'Disease', 'MESH:D009362', (131, 141))	('associated', 'Reg', (93, 103))
73670	29100322	Moreover, significant associations were found between presence of epithelioid cell pattern (hazard ratio (HR), 3.90; P = 0.021), high mitoses count (HR, 1.40; P = 0.0001), high level of Ki67 LI (HR, 1.23; P = 0.012), overexpression of EZH2 (HR, 3.64; P = 0.035) and higher risk of metastases by univariate Cox regression (Table 2).	('high mitoses count', 'CPA', (129, 147))	('Ki67 LI', 'Var', (186, 193))	('metastases', 'Disease', (281, 291))	('metastases', 'Disease', 'MESH:D009362', (281, 291))	('overexpression', 'PosReg', (217, 231))	('Cox', 'Gene', (306, 309))	('high', 'Var', (172, 176))	('Cox', 'Gene', '1351', (306, 309))	('EZH2', 'Gene', (235, 239))	('EZH2', 'Gene', '2146', (235, 239))
73674	29100322	And by multivariate Cox regression, we found high mitoses count (HR, 1.39; P = 0.0001), Ki67 LI (HR, 1.45; P = 0.041) and EZH2 expression (HR, 3.92; P = 0.036) were significantly associated with worse prognosis (Table 2).	('EZH2', 'Gene', (122, 126))	('EZH2', 'Gene', '2146', (122, 126))	('expression', 'MPA', (127, 137))	('Cox', 'Gene', '1351', (20, 23))	('Cox', 'Gene', (20, 23))	('mitoses count', 'CPA', (50, 63))	('Ki67 LI', 'Var', (88, 95))
73682	29100322	Recently, three EZH2 inhibitors have been observed in clinical trials including CPI-1205 in B-Cell Lymphomas, E7438 in Advanced Solid Tumors/B Cell Lymphomas and GSK2816126 in Relapsed/ Refractory Diffuse Large B Cell and Transformed Follicular Lymphomas.	('Tumors', 'Phenotype', 'HP:0002664', (134, 140))	('Lymphomas', 'Phenotype', 'HP:0002665', (99, 108))	('Tumor', 'Phenotype', 'HP:0002664', (134, 139))	('B-Cell Lymphomas', 'Phenotype', 'HP:0012191', (92, 108))	('Follicular Lymphomas', 'Disease', (234, 254))	('B-Cell Lymphomas', 'Disease', (92, 108))	('E7438', 'Var', (110, 115))	('GSK2816126', 'Var', (162, 172))	('EZH2', 'Gene', '2146', (16, 20))	('EZH2', 'Gene', (16, 20))	('Follicular Lymphomas', 'Disease', 'MESH:D008224', (234, 254))	('Lymphomas', 'Phenotype', 'HP:0002665', (245, 254))	('Tumors/B Cell Lymphomas', 'Disease', (134, 157))	('Lymphomas', 'Phenotype', 'HP:0002665', (148, 157))	('Large B Cell', 'Phenotype', 'HP:0005404', (205, 217))	('GSK', 'molecular_function', 'GO:0050321', ('162', '165'))	('Tumors/B Cell Lymphomas', 'Disease', 'MESH:D016393', (134, 157))	('B Cell Lymphomas', 'Phenotype', 'HP:0012191', (141, 157))	('CPI-1205', 'Chemical', 'MESH:C000619999', (80, 88))	('CPI-1205', 'Gene', (80, 88))	('B-Cell Lymphomas', 'Disease', 'MESH:D016393', (92, 108))	('GSK2816126', 'Chemical', '-', (162, 172))
73684	29100322	In addition, high EZH2 expression and metastatic mortality were associated with other UM parameters such as presence of epithelioid cell pattern, high mitoses count and Ki67 LI.	('associated', 'Reg', (64, 74))	('high', 'Var', (13, 17))	('EZH2', 'Gene', '2146', (18, 22))	('EZH2', 'Gene', (18, 22))	('high mitoses count', 'CPA', (146, 164))	('metastatic mortality', 'CPA', (38, 58))	('expression', 'MPA', (23, 33))
73704	29100322	The Ki67 labeling index (LI) was determined by counting the number of positive cells in a total of 800-1000 tumor cells observed in regions of highest staining (hot spot) at several HPF(x400).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('x400', 'Var', (186, 190))	('tumor', 'Disease', (108, 113))
73709	28486107	RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma Constitutive activation of Galphaq signaling by mutations in GNAQ or GNA11 occurs in over 80% of uveal melanomas (UMs) and activates MAPK.	('MAPK Pathway', 'Pathway', (17, 29))	('GNAQ', 'Gene', '2776', (132, 136))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanomas', 'Phenotype', 'HP:0002861', (174, 183))	('GNAQ', 'Gene', '2776', (44, 48))	('GNAQ', 'Gene', (132, 136))	('GNAQ', 'Gene', (44, 48))	('Melanoma', 'Disease', 'MESH:D008545', (62, 70))	('GNA11', 'Gene', (140, 145))	('RasGRP3', 'Gene', '25780', (0, 7))	('uveal melanomas', 'Disease', 'MESH:C536494', (168, 183))	('mutations', 'Var', (119, 128))	('Mutant', 'Var', (49, 55))	('MAPK', 'molecular_function', 'GO:0004707', ('204', '208'))	('UM', 'Phenotype', 'HP:0007716', (185, 187))	('UMs', 'Phenotype', 'HP:0007716', (185, 188))	('RasGRP3', 'Gene', (0, 7))	('Galphaq signaling', 'MPA', (98, 115))	('activates', 'PosReg', (194, 203))	('Melanoma', 'Disease', (62, 70))	('MAPK', 'Enzyme', (204, 208))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('Melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('activation', 'PosReg', (84, 94))	('MAPK', 'molecular_function', 'GO:0004707', ('17', '21'))	('uveal melanomas', 'Disease', (168, 183))	('uveal melanomas', 'Phenotype', 'HP:0007716', (168, 183))	('Activation', 'PosReg', (30, 40))	('GNA11', 'Gene', '2767', (140, 145))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))
73711	28486107	We identified PKC delta and epsilon as required and sufficient to activate MAPK in GNAQ mutant melanomas.	('PKC delta', 'Gene', (14, 23))	('MAPK', 'Gene', (75, 79))	('melanomas', 'Disease', (95, 104))	('PKC delta', 'Gene', '5580', (14, 23))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('MAPK', 'molecular_function', 'GO:0004707', ('75', '79'))	('activate', 'PosReg', (66, 74))	('melanomas', 'Disease', 'MESH:D008545', (95, 104))	('PKC', 'molecular_function', 'GO:0004697', ('14', '17'))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('mutant', 'Var', (88, 94))	('GNAQ', 'Gene', (83, 87))
73712	28486107	MAPK activation depends on Ras and is caused by RasGRP3, which is significantly and selectively overexpressed in response to GNAQ/11 mutation in UM.	('mutation', 'Var', (133, 141))	('Ras', 'Chemical', 'MESH:D011883', (27, 30))	('MAPK', 'Gene', (0, 4))	('Ras', 'Chemical', 'MESH:D011883', (48, 51))	('activation', 'PosReg', (5, 15))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('GNAQ/11', 'Gene', (125, 132))	('MAPK', 'molecular_function', 'GO:0004707', ('0', '4'))	('MAPK activation', 'biological_process', 'GO:0000187', ('0', '15'))
73715	28486107	find that Ras is required for GNAQ-mediated MAPK activation and identify PKC delta, epsilon and RasGRP3 as components of a signaling module necessary and sufficient to activate the Ras/MAPK pathway in GNAQ mutant uveal melanoma (UM).	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('MAPK', 'molecular_function', 'GO:0004707', ('44', '48'))	('Ras', 'Chemical', 'MESH:D011883', (181, 184))	('PKC delta', 'Gene', '5580', (73, 82))	('MAPK activation', 'biological_process', 'GO:0000187', ('44', '59'))	('GNAQ', 'Gene', (201, 205))	('Ras/MAPK pathway', 'Pathway', (181, 197))	('PKC delta', 'Gene', (73, 82))	('mutant', 'Var', (206, 212))	('PKC', 'molecular_function', 'GO:0004697', ('73', '76'))	('MAPK', 'molecular_function', 'GO:0004707', ('185', '189'))	('uveal melanoma', 'Disease', 'MESH:C536494', (213, 227))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('uveal melanoma', 'Disease', (213, 227))	('Ras', 'Chemical', 'MESH:D011883', (96, 99))	('Ras', 'Chemical', 'MESH:D011883', (10, 13))	('activate', 'PosReg', (168, 176))	('UM', 'Phenotype', 'HP:0007716', (229, 231))	('uveal melanoma', 'Phenotype', 'HP:0007716', (213, 227))
73719	28486107	Instead, UM harbors mutually exclusive mutations in GNAQ, GNA11, PLCB4, or cysteinyl leukotriene receptor 2 (CYSLTR2).	('CYSLTR2', 'Gene', (109, 116))	('cysteinyl leukotriene receptor 2', 'Gene', (75, 107))	('PLCB4', 'Gene', '5332', (65, 70))	('CYSLTR2', 'Gene', '57105', (109, 116))	('mutations', 'Var', (39, 48))	('GNA11', 'Gene', (58, 63))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('PLCB4', 'Gene', (65, 70))	('GNAQ', 'Gene', (52, 56))	('GNA11', 'Gene', '2767', (58, 63))	('cysteinyl leukotriene receptor 2', 'Gene', '57105', (75, 107))
73722	28486107	Approximately 95% of GNAQ and GNA11 mutations in melanoma affect codons 209 (Q209) of the G proteins with only 5% affecting codon 183 (R183) in the Ras-like domain.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('GNA11', 'Gene', (30, 35))	('G proteins', 'Protein', (90, 100))	('mutations', 'Var', (36, 45))	('GNAQ', 'Gene', (21, 25))	('Ras', 'Chemical', 'MESH:D011883', (148, 151))	('GNA11', 'Gene', '2767', (30, 35))	('codons', 'MPA', (65, 71))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))	('affect', 'Reg', (58, 64))
73723	28486107	The respective mutations result in complete or partial loss of GTPase activity, thereby locking GNAQ/11 into its active protein, GTP-bound conformation, resulting in a dominant acting oncogene that transforms melanocytes.	('loss', 'NegReg', (55, 59))	('activity', 'MPA', (70, 78))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('GTPase', 'Enzyme', (63, 69))	('mutations', 'Var', (15, 24))	('oncogene', 'CPA', (184, 192))	('GTP', 'Chemical', 'MESH:D006160', (63, 66))	('GTPase activity', 'molecular_function', 'GO:0003924', ('63', '78'))	('GTP', 'Chemical', 'MESH:D006160', (129, 132))
73725	28486107	Recently, mutations in the CYSLTR2, a Gq-coupled GPCR, and the downstream effector of Galphaq PLCB4, encoding a phospholipase C beta(PLC beta) isoform, have been reported in the small percentage of UMs without GNAQ or GNA11 mutations.	('PLC', 'cellular_component', 'GO:0042824', ('133', '136'))	('CYSLTR2', 'Gene', '57105', (27, 34))	('PLCB4', 'Gene', (94, 99))	('GNA11', 'Gene', '2767', (218, 223))	('GNA11', 'Gene', (218, 223))	('CYSLTR2', 'Gene', (27, 34))	('eta', 'Gene', '1909', (138, 141))	('eta', 'Gene', (138, 141))	('PLCB4', 'Gene', '5332', (94, 99))	('reported', 'Reg', (162, 170))	('UM', 'Phenotype', 'HP:0007716', (198, 200))	('UMs', 'Phenotype', 'HP:0007716', (198, 201))	('eta', 'Gene', '1909', (129, 132))	('mutations', 'Var', (10, 19))	('eta', 'Gene', (129, 132))
73726	28486107	In the TCGA, 78 out of 80 human UMs have mutations in either GNAQ, GNA11, PLCB4, or CYSLTR2, indicating that UM is defined by activating mutations in the GNAQ/11 pathway.	('mutations', 'Var', (41, 50))	('PLCB4', 'Gene', (74, 79))	('GNA11', 'Gene', (67, 72))	('UMs', 'Phenotype', 'HP:0007716', (32, 35))	('GNA11', 'Gene', '2767', (67, 72))	('GNAQ', 'Gene', (61, 65))	('UM', 'Phenotype', 'HP:0007716', (32, 34))	('CYSLTR2', 'Gene', '57105', (84, 91))	('UM', 'Phenotype', 'HP:0007716', (109, 111))	('PLCB4', 'Gene', '5332', (74, 79))	('CYSLTR2', 'Gene', (84, 91))	('human', 'Species', '9606', (26, 31))	('activating', 'PosReg', (126, 136))
73728	28486107	PLC beta, a direct downstream effector of mutant GNAQ/11, hydrolyzes the membrane phospholipid phosphatidylinositol 4,5-bisphosphate to release two potent second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).	('mutant', 'Var', (42, 48))	('phospholipid phosphatidylinositol 4,5-bisphosphate', 'Chemical', '-', (82, 132))	('GNAQ/11', 'Gene', (49, 56))	('membrane', 'cellular_component', 'GO:0016020', ('73', '81'))	('release two potent second messengers', 'MPA', (136, 172))	('inositol 1,4,5-trisphosphate', 'Chemical', 'MESH:D015544', (174, 202))	('PLC', 'cellular_component', 'GO:0042824', ('0', '3'))	('eta', 'Gene', '1909', (5, 8))	('IP3', 'Chemical', 'MESH:D015544', (204, 207))	('DAG', 'Chemical', 'MESH:D004075', (229, 232))	('diacylglycerol', 'MPA', (213, 227))	('diacylglycerol', 'Chemical', 'MESH:D004075', (213, 227))	('eta', 'Gene', (5, 8))
73734	28486107	The specific PKC isoforms that mediate the activating effect on the MAPK pathway in the context of GNAQ or GNA11 mutations remain unclear.	('PKC', 'Gene', '112476', (13, 16))	('GNAQ', 'Gene', (99, 103))	('PKC', 'molecular_function', 'GO:0004697', ('13', '16'))	('mutations', 'Var', (113, 122))	('MAPK pathway', 'Pathway', (68, 80))	('MAPK', 'molecular_function', 'GO:0004707', ('68', '72'))	('PKC', 'Gene', (13, 16))	('GNA11', 'Gene', '2767', (107, 112))	('GNA11', 'Gene', (107, 112))
73735	28486107	Recent studies have also demonstrated that mutant GNAQ/11 promote UM tumorigenesis by activating YAP independent of PLC beta.	('YAP', 'Gene', '10413', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('tumor', 'Disease', (69, 74))	('promote', 'PosReg', (58, 65))	('eta', 'Gene', '1909', (121, 124))	('activating', 'Reg', (86, 96))	('PLC', 'cellular_component', 'GO:0042824', ('116', '119'))	('YAP', 'Gene', (97, 100))	('mutant', 'Var', (43, 49))	('eta', 'Gene', (121, 124))	('GNAQ/11', 'Gene', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
73736	28486107	Furthermore, prior studies have shown that PKC inhibition alone in UM cell lines is not sufficient to completely suppress MAPK signaling, suggesting that PKC-independent effectors may be involved that mediate MAPK signaling in GNAQ/11 mutant cells.	('MAPK', 'molecular_function', 'GO:0004707', ('209', '213'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('122', '136'))	('MAPK', 'molecular_function', 'GO:0004707', ('122', '126'))	('PKC', 'molecular_function', 'GO:0004697', ('43', '46'))	('PKC', 'Gene', '112476', (43, 46))	('MAPK signaling', 'MPA', (122, 136))	('suppress', 'NegReg', (113, 121))	('PKC', 'molecular_function', 'GO:0004697', ('154', '157'))	('UM', 'Phenotype', 'HP:0007716', (67, 69))	('MAPK signaling', 'biological_process', 'GO:0000165', ('209', '223'))	('PKC', 'Gene', (154, 157))	('PKC', 'Gene', (43, 46))	('mutant', 'Var', (235, 241))	('PKC', 'Gene', '112476', (154, 157))
73738	28486107	Studies in BRAFV600E melanomas suggest that therapeutically meaningful responses in patients can only be expected if marked suppression of the MAPK pathway is achieved.	('BRAFV600E', 'Var', (11, 20))	('BRAFV600E', 'Mutation', 'rs113488022', (11, 20))	('MAPK', 'molecular_function', 'GO:0004707', ('143', '147'))	('patients', 'Species', '9606', (84, 92))	('melanomas', 'Disease', (21, 30))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('MAPK pathway', 'Pathway', (143, 155))
73739	28486107	To achieve this goal in UM, a more refined understanding of the connection between MAPK signaling and GNAQ/11 mutant in uveal melanoma is required to develop more effective targeting strategies.	('GNAQ/11', 'Gene', (102, 109))	('UM', 'Phenotype', 'HP:0007716', (24, 26))	('MAPK signaling', 'biological_process', 'GO:0000165', ('83', '97'))	('mutant', 'Var', (110, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (120, 134))	('MAPK', 'molecular_function', 'GO:0004707', ('83', '87'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (120, 134))	('uveal melanoma', 'Disease', (120, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))
73740	28486107	Here, the goal of the current study is to investigate which PKC isoforms activate MAPK signaling and how PKC signaling relays to the MAPK pathway in GNAQ/11 mutant melanoma, thus identifying specific therapeutic targets for cancers driven by oncogenic GNAQ/11.	('PKC', 'molecular_function', 'GO:0004697', ('105', '108'))	('signaling', 'biological_process', 'GO:0023052', ('109', '118'))	('MAPK', 'molecular_function', 'GO:0004707', ('133', '137'))	('GNAQ/11', 'Gene', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('MAPK signaling', 'biological_process', 'GO:0000165', ('82', '96'))	('PKC', 'Gene', (60, 63))	('PKC', 'Gene', '112476', (105, 108))	('melanoma', 'Disease', 'MESH:D008545', (164, 172))	('cancers', 'Disease', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('PKC', 'Gene', (105, 108))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))	('activate', 'PosReg', (73, 81))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('melanoma', 'Disease', (164, 172))	('mutant', 'Var', (157, 163))	('PKC', 'molecular_function', 'GO:0004697', ('60', '63'))	('PKC', 'Gene', '112476', (60, 63))	('MAPK signaling', 'Pathway', (82, 96))
73743	28486107	To overcome this limitation we tested the specificity of commercially available PKC antibodies by transfecting HA-tagged full-length PKC isoforms or their catalytic subunits (Figures S1A and S1B) into 293FT cells and identified a panel of specific antibodies that was used to screen a panel of melanoma cells with or without GNAQ/11 mutations.	('PKC', 'molecular_function', 'GO:0004697', ('80', '83'))	('mutations', 'Var', (333, 342))	('melanoma', 'Disease', 'MESH:D008545', (294, 302))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('melanoma', 'Disease', (294, 302))	('PKC', 'molecular_function', 'GO:0004697', ('133', '136'))	('PKC', 'Gene', (80, 83))	('PKC', 'Gene', '112476', (80, 83))	('tested', 'Reg', (31, 37))	('293FT', 'CellLine', 'CVCL:6911', (201, 206))	('PKC', 'Gene', (133, 136))	('GNAQ/11', 'Gene', (325, 332))	('PKC', 'Gene', '112476', (133, 136))
73744	28486107	As shown in Figure 1A, five PKC isoforms (PKC alpha, delta, epsilon, zeta, and iota) were consistently expressed throughout all six UM cells with GNAQ/11 mutations tested (MEL202, 92-1, OMM1.3, and MEL270 with GNAQ mutations, and OMM-GN11 and UPMD-1 with GNA11 mutations).	('mutations', 'Var', (261, 270))	('PKC alpha, delta, epsilon, zeta, and iota', 'Gene', '5578;5580;5581;5590', (42, 83))	('MEL270', 'Var', (198, 204))	('PKC', 'Gene', (42, 45))	('PKC', 'Gene', (28, 31))	('PKC', 'Gene', '112476', (42, 45))	('GNAQ/11', 'Gene', (146, 153))	('PKC', 'Gene', '112476', (28, 31))	('UM', 'Phenotype', 'HP:0007716', (132, 134))	('GNAQ', 'Gene', (210, 214))	('mutations', 'Var', (154, 163))	('PKC', 'molecular_function', 'GO:0004697', ('42', '45'))	('GNA11', 'Gene', '2767', (255, 260))	('GNA11', 'Gene', (255, 260))	('PKC', 'molecular_function', 'GO:0004697', ('28', '31'))
73749	28486107	While PKC beta II showed differential expression between melanoma cell lines with and without GNAQ/11 mutations, it was not expressed in all GNAQ/11 mutant cell lines, ruling it out as a universal effector downstream of mutant GNAQ/11.	('PKC', 'molecular_function', 'GO:0004697', ('6', '9'))	('PKC beta', 'Gene', '5579', (6, 14))	('GNAQ/11', 'Gene', (94, 101))	('expression', 'MPA', (38, 48))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('mutations', 'Var', (102, 111))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('PKC beta', 'Gene', (6, 14))
73750	28486107	While PKC zeta and iota, where found to be expressed in GNAQ/11 mutant cell lines, are classified as atypical PKCs as they are not activated by either calcium or DAG, making them unlikely candidate effectors of mutant Galphaq.	('PKC', 'Gene', (6, 9))	('PKC zeta', 'Gene', (6, 14))	('PKC', 'Gene', '112476', (6, 9))	('PKC', 'molecular_function', 'GO:0004697', ('6', '9'))	('GNAQ/11', 'Gene', (56, 63))	('PKC', 'Gene', (110, 113))	('PKC', 'Gene', '112476', (110, 113))	('PKC zeta', 'Gene', '5590', (6, 14))	('iota', 'Chemical', '-', (19, 23))	('calcium', 'Chemical', 'MESH:D002118', (151, 158))	('DAG', 'Chemical', 'MESH:D004075', (162, 165))	('mutant', 'Var', (64, 70))
73751	28486107	By contrast, PKC alpha, delta, and epsilon, which were consistently expressed in all UM cell lines with GNAQ or GNA11 mutations, are candidates to mediate MAPK signaling in GNAQ mutant melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('GNA11', 'Gene', (112, 117))	('melanomas', 'Disease', (185, 194))	('MAPK signaling', 'biological_process', 'GO:0000165', ('155', '169'))	('mediate', 'Reg', (147, 154))	('mutations', 'Var', (118, 127))	('GNA11', 'Gene', '2767', (112, 117))	('MAPK', 'molecular_function', 'GO:0004707', ('155', '159'))	('PKC alpha, delta, and epsilon', 'Gene', '5578;5580;5581', (13, 42))	('melanomas', 'Phenotype', 'HP:0002861', (185, 194))	('GNAQ', 'Gene', (104, 108))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('PKC', 'molecular_function', 'GO:0004697', ('13', '16'))	('melanomas', 'Disease', 'MESH:D008545', (185, 194))
73752	28486107	To determine which of these PKC isoforms mediate MAPK signaling in GNAQ/11 mutant cells, we performed small interfering RNAs (siRNA)-mediated knockdown of PKC isoforms (PKC alpha, delta, epsilon as well as zeta used as control) alone or in combination in three GNAQ mutant cell lines (92-1, OMM1.3, and MEL202) and examined MAPK signaling at the level of pMEK and pERK.	('PKC', 'Gene', (155, 158))	('MEK', 'Gene', '5609', (356, 359))	('PKC', 'Gene', '112476', (28, 31))	('PKC', 'Gene', '112476', (169, 172))	('MAPK signaling', 'biological_process', 'GO:0000165', ('49', '63'))	('MAPK', 'molecular_function', 'GO:0004707', ('324', '328'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('324', '338'))	('PKC', 'molecular_function', 'GO:0004697', ('155', '158'))	('PKC alpha, delta, epsilon as well as zeta', 'Gene', '5578;5580', (169, 210))	('MAPK', 'molecular_function', 'GO:0004707', ('49', '53'))	('MEK', 'Gene', (356, 359))	('PKC', 'Gene', (28, 31))	('PKC', 'Gene', (169, 172))	('PKC', 'molecular_function', 'GO:0004697', ('28', '31'))	('pERK', 'Gene', (364, 368))	('PKC', 'molecular_function', 'GO:0004697', ('169', '172'))	('pERK', 'Gene', '9451', (364, 368))	('PKC', 'Gene', '112476', (155, 158))	('mutant', 'Var', (75, 81))
73753	28486107	As shown in Figures 1B and S1C, knockdown of either PKC delta or epsilon alone resulted in partial inhibition of pMEK and pERK, whereas knockdown of PKC alpha and PKC zeta had no significant effect.	('pERK', 'Gene', (122, 126))	('PKC alpha', 'Gene', (149, 158))	('PKC', 'molecular_function', 'GO:0004697', ('52', '55'))	('PKC delta', 'Gene', (52, 61))	('pERK', 'Gene', '9451', (122, 126))	('PKC', 'molecular_function', 'GO:0004697', ('149', '152'))	('knockdown', 'Var', (32, 41))	('MEK', 'Gene', (114, 117))	('inhibition', 'NegReg', (99, 109))	('PKC delta', 'Gene', '5580', (52, 61))	('PKC zeta', 'Gene', (163, 171))	('PKC alpha', 'Gene', '5578', (149, 158))	('MEK', 'Gene', '5609', (114, 117))	('PKC', 'molecular_function', 'GO:0004697', ('163', '166'))	('PKC zeta', 'Gene', '5590', (163, 171))
73754	28486107	Combined knockdown of PKC delta and epsilon inhibited pMEK and pERK levels similar to knockdown of GNAQ itself.	('PKC delta', 'Gene', '5580', (22, 31))	('knockdown', 'Var', (9, 18))	('epsilon', 'Enzyme', (36, 43))	('PKC', 'molecular_function', 'GO:0004697', ('22', '25'))	('inhibited', 'NegReg', (44, 53))	('pERK', 'Gene', '9451', (63, 67))	('MEK', 'Gene', (55, 58))	('pERK', 'Gene', (63, 67))	('MEK', 'Gene', '5609', (55, 58))	('PKC delta', 'Gene', (22, 31))
73757	28486107	By contrast, knockdown of PKC betaII in 92-1 with GNAQ mutation (Figure 1B) and OMM-GN11 and UPMD-2 cell lines with GNA11 mutation (Figure S1E) had no effect on pMEK and pERK.	('PKC beta', 'Gene', '5579', (26, 34))	('GNA11', 'Gene', (116, 121))	('UPMD-2', 'CellLine', 'CVCL:C298', (93, 99))	('GNA11', 'Gene', '2767', (116, 121))	('PKC beta', 'Gene', (26, 34))	('pERK', 'Gene', '9451', (170, 174))	('pERK', 'Gene', (170, 174))	('MEK', 'Gene', (162, 165))	('MEK', 'Gene', '5609', (162, 165))	('mutation', 'Var', (55, 63))	('PKC', 'molecular_function', 'GO:0004697', ('26', '29'))	('GNAQ', 'Gene', (50, 54))
73758	28486107	To establish an initial connection between specific PKC isoforms and mutant GNAQ, we co-transfected PKC isoforms (alpha, delta, epsilon, zeta, iota) together with GNAQQ209L into the 293FT model cell line.	('PKC', 'molecular_function', 'GO:0004697', ('52', '55'))	('PKC isoforms (alpha, delta, epsilon, zeta, iota', 'Gene', '5578;5580;5581;5590', (100, 147))	('293FT', 'CellLine', 'CVCL:6911', (182, 187))	('mutant', 'Var', (69, 75))	('PKC', 'Gene', '112476', (100, 103))	('PKC', 'Gene', (100, 103))	('PKC', 'Gene', (52, 55))	('PKC', 'Gene', '112476', (52, 55))	('GNAQQ209L', 'Chemical', '-', (163, 172))	('PKC', 'molecular_function', 'GO:0004697', ('100', '103'))
73760	28486107	We confirmed that the synergistic effect was dependent on the kinase activity of PKC delta and epsilon, by using kinase-dead mutants of PKC delta and epsilon (Figure S2A).	('PKC delta', 'Gene', '5580', (136, 145))	('PKC', 'molecular_function', 'GO:0004697', ('81', '84'))	('PKC delta', 'Gene', '5580', (81, 90))	('kinase activity', 'molecular_function', 'GO:0016301', ('62', '77'))	('mutants', 'Var', (125, 132))	('PKC', 'molecular_function', 'GO:0004697', ('136', '139'))	('dependent', 'Reg', (45, 54))	('PKC delta', 'Gene', (136, 145))	('PKC delta', 'Gene', (81, 90))
73761	28486107	Furthermore, only GNAQQ209L, but not wild-type GNAQ, synergized with PKC delta and epsilon, indicating that the synergy depended on active GNAQ (Figure S2B).	('PKC delta', 'Gene', (69, 78))	('PKC delta', 'Gene', '5580', (69, 78))	('GNAQQ209L', 'Chemical', '-', (18, 27))	('GNAQQ209L', 'Var', (18, 27))	('PKC', 'molecular_function', 'GO:0004697', ('69', '72'))
73765	28486107	In UM cell lines with GNAQ/11 mutations, PKC alpha and zeta were localized in the cytosolic fraction, while a considerable portion of the PKC delta and epsilon signal was localized at the membrane (Figure S2E).	('PKC delta', 'Gene', (138, 147))	('PKC', 'molecular_function', 'GO:0004697', ('41', '44'))	('PKC alpha', 'Gene', '5578', (41, 50))	('PKC delta', 'Gene', '5580', (138, 147))	('eta', 'Gene', '1909', (56, 59))	('eta', 'Gene', (56, 59))	('mutations', 'Var', (30, 39))	('GNAQ/11', 'Gene', (22, 29))	('PKC', 'molecular_function', 'GO:0004697', ('138', '141'))	('PKC alpha', 'Gene', (41, 50))	('membrane', 'cellular_component', 'GO:0016020', ('188', '196'))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
73766	28486107	These data further support the notion that the main active isoforms in the context of GNAQ/11 mutations are PKC delta and epsilon.	('GNAQ/11', 'Gene', (86, 93))	('mutations', 'Var', (94, 103))	('PKC delta', 'Gene', (108, 117))	('epsilon', 'Enzyme', (122, 129))	('PKC delta', 'Gene', '5580', (108, 117))	('PKC', 'molecular_function', 'GO:0004697', ('108', '111'))
73767	28486107	As previously shown, cell proliferation of GNAQ mutant UM cells depends on GNAQ and PKC as knockdown of GNAQ or PKC inhibition suppress cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('21', '39'))	('mutant', 'Var', (48, 54))	('cell proliferation', 'CPA', (21, 39))	('GNAQ', 'Gene', (43, 47))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('PKC', 'molecular_function', 'GO:0004697', ('84', '87'))	('PKC', 'molecular_function', 'GO:0004697', ('112', '115'))	('PKC', 'Gene', (84, 87))	('PKC', 'Gene', '112476', (84, 87))	('suppress', 'NegReg', (127, 135))	('cell proliferation', 'biological_process', 'GO:0008283', ('136', '154'))	('PKC', 'Gene', (112, 115))	('PKC', 'Gene', '112476', (112, 115))	('cell proliferation', 'CPA', (136, 154))
73769	28486107	Combined knockdown of PKC delta and epsilon, but not alpha, reduced cell proliferation similar to knockdown of GNAQ in GNAQ mutant cell lines (92-1 and OMM1.3), while the knockdown had no effect in cell lines without GNAQ mutations (Figure 1E).	('PKC delta', 'Gene', '5580', (22, 31))	('PKC', 'molecular_function', 'GO:0004697', ('22', '25'))	('cell proliferation', 'CPA', (68, 86))	('GNAQ', 'Gene', (119, 123))	('mutant', 'Var', (124, 130))	('reduced', 'NegReg', (60, 67))	('PKC delta', 'Gene', (22, 31))	('cell proliferation', 'biological_process', 'GO:0008283', ('68', '86'))
73771	28486107	Taken together, these experiments indicate that PKC delta and epsilon are essential for MAPK signaling and proliferation of UM cell lines with GNAQ mutations, but not in related cell lines without GNAQ mutations.	('PKC delta', 'Gene', (48, 57))	('mutations', 'Var', (148, 157))	('MAPK', 'molecular_function', 'GO:0004707', ('88', '92'))	('PKC', 'molecular_function', 'GO:0004697', ('48', '51'))	('GNAQ', 'Gene', (143, 147))	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('PKC delta', 'Gene', '5580', (48, 57))	('MAPK signaling', 'biological_process', 'GO:0000165', ('88', '102'))
73772	28486107	To determine at which level mutant GNAQ activates the MAP-kinase pathway, we investigated whether the activation depended on Ras.	('mutant', 'Var', (28, 34))	('MAP', 'molecular_function', 'GO:0004239', ('54', '57'))	('activates', 'PosReg', (40, 49))	('Ras', 'Chemical', 'MESH:D011883', (125, 128))	('MAP-kinase pathway', 'Pathway', (54, 72))	('GNAQ', 'Gene', (35, 39))
73773	28486107	We found that 293FT cells transfected with GNAQQ209L had increased levels of Ras-GTP compared with controls, which could be further increased by co-transfection of PKC delta and epsilon compared with co-transfection of GFP (Figure 2A), while PKC alpha or zeta together with GNAQQ209L also increased Ras-GTP level, albeit to a lesser extent (Figure S2H).	('PKC delta', 'Gene', '5580', (164, 173))	('Ras-GTP level', 'MPA', (299, 312))	('PKC', 'molecular_function', 'GO:0004697', ('242', '245'))	('eta', 'Gene', (256, 259))	('PKC delta', 'Gene', (164, 173))	('increased', 'PosReg', (132, 141))	('Ras-GTP', 'Chemical', '-', (77, 84))	('GNAQQ209L', 'Var', (43, 52))	('Ras-GTP', 'Chemical', '-', (299, 306))	('PKC alpha', 'Gene', (242, 251))	('increased', 'PosReg', (289, 298))	('levels', 'MPA', (67, 73))	('increased', 'PosReg', (57, 66))	('Ras-GTP', 'MPA', (77, 84))	('293FT', 'CellLine', 'CVCL:6911', (14, 19))	('GNAQQ209L', 'Chemical', '-', (43, 52))	('PKC', 'molecular_function', 'GO:0004697', ('164', '167'))	('GNAQQ209L', 'Chemical', '-', (274, 283))	('PKC alpha', 'Gene', '5578', (242, 251))	('eta', 'Gene', '1909', (256, 259))
73777	28486107	These results indicate that activation of MAPK signaling in GNAQ mutant cells requires the presence of Ras, with little or no specific preference of any specific Ras family member.	('GNAQ', 'Gene', (60, 64))	('mutant', 'Var', (65, 71))	('MAPK', 'molecular_function', 'GO:0004707', ('42', '46'))	('Ras', 'Chemical', 'MESH:D011883', (103, 106))	('Ras', 'Chemical', 'MESH:D011883', (162, 165))	('activation', 'PosReg', (28, 38))	('Ras', 'Protein', (103, 106))	('MAPK signaling', 'biological_process', 'GO:0000165', ('42', '56'))	('MAPK signaling', 'MPA', (42, 56))
73778	28486107	To determine how mutant GNAQ activates Ras/MAPK signaling, we compared gene expression profiles between five GNAQ or GNA11 mutant melanoma cells (GNAQmt: 92-1, MEL202, OMM1.3; GNA11mt: UPMD-1, OMM-GN11) and five GNAQ/11 wild-type melanoma cells with either NRAS (SK-MEL-2, MM415, and MM485, all from cutaneous origins) or BRAF mutations (SK-MEL-5 from cutaneous origin and MUM2C from uveal origin).	('mutations', 'Var', (327, 336))	('GNAQ', 'Gene', (109, 113))	('gene expression', 'biological_process', 'GO:0010467', ('71', '86'))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('melanoma', 'Disease', (230, 238))	('GNA11', 'Gene', (117, 122))	('Ras', 'Chemical', 'MESH:D011883', (39, 42))	('mutant', 'Var', (17, 23))	('GNA11', 'Gene', '2767', (176, 181))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('UM', 'Phenotype', 'HP:0007716', (374, 376))	('melanoma', 'Disease', (130, 138))	('MAPK', 'molecular_function', 'GO:0004707', ('43', '47'))	('NRAS', 'Gene', '4893', (257, 261))	('BRAF', 'Gene', (322, 326))	('BRAF', 'Gene', '673', (322, 326))	('MAPK signaling', 'biological_process', 'GO:0000165', ('43', '57'))	('GNA11', 'Gene', '2767', (117, 122))	('GNA11', 'Gene', (176, 181))	('melanoma', 'Disease', 'MESH:D008545', (230, 238))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('NRAS', 'Gene', (257, 261))	('mutant', 'Var', (123, 129))
73781	28486107	qRT-PCR experiments confirmed that RasGRP3 mRNA is markedly upregulated (>100-fold) in melanoma cell lines with GNAQ or GNA11 mutations, compared with normal melanocytes or melanoma cell lines with other mutations.	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('upregulated', 'PosReg', (60, 71))	('GNAQ', 'Gene', (112, 116))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('GNA11', 'Gene', (120, 125))	('melanoma', 'Disease', (173, 181))	('mRNA', 'MPA', (43, 47))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('GNA11', 'Gene', '2767', (120, 125))	('RasGRP3', 'Gene', (35, 42))	('mutations', 'Var', (126, 135))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
73782	28486107	Other RasGRP family members, as well as the RasGEF SOS1, did not show any increased expression levels in melanoma cell lines with GNAQ or GNA11 mutations or showed differential expression differences in these cells (Figure S3A).	('SOS1', 'Gene', '6654', (51, 55))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('GNAQ', 'Gene', (130, 134))	('melanoma', 'Disease', (105, 113))	('Ras', 'Chemical', 'MESH:D011883', (6, 9))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('GNA11', 'Gene', (138, 143))	('Ras', 'Chemical', 'MESH:D011883', (44, 47))	('SOS1', 'Gene', (51, 55))	('RasGRP', 'Gene', '10125', (6, 12))	('mutations', 'Var', (144, 153))	('GNA11', 'Gene', '2767', (138, 143))	('RasGRP', 'Gene', (6, 12))
73784	28486107	Interestingly, the four samples in the 478 samples of cutaneous melanoma samples that harbor GNAQ or GNA11 hotspot mutations, also had elevated RasGRP3 mRNA with levels comparable with those present in UM (Figure 3D).	('GNA11', 'Gene', '2767', (101, 106))	('GNA11', 'Gene', (101, 106))	('UM', 'Phenotype', 'HP:0007716', (202, 204))	('mutations', 'Var', (115, 124))	('elevated', 'PosReg', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('cutaneous melanoma', 'Disease', (54, 72))	('RasGRP3', 'Protein', (144, 151))	('GNAQ', 'Gene', (93, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (54, 72))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (54, 72))
73786	28486107	We found that both RasGRP3 and p-RasGRP3 (T133) protein levels in melanoma cell lines with GNAQ mutations were significantly higher than in cell lines without GNAQ mutations, including SK-MEL-5 and UACC257 (Figure S3D).	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('T133', 'Chemical', '-', (42, 46))	('GNAQ', 'Gene', (91, 95))	('higher', 'PosReg', (125, 131))	('protein levels', 'MPA', (48, 62))	('mutations', 'Var', (96, 105))
73788	28486107	As shown in Figure S3E, two conjunctival melanoma cell lines that had no GNAQ/11 mutations (CRMM1 and CRMM2) had no detectable expression of RasGRP3 protein by western blot and immunohistochemistry (Figure 3F), while UM cell lines with GNAQ mutation (92-1, MEL270) or GNA11 mutation (OMM1) showed strong RasGRP3 immunoreactivity (Figures 3F and S3F).	('GNA11', 'Gene', '2767', (268, 273))	('mutation', 'Var', (274, 282))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('GNAQ/11', 'Gene', (73, 80))	('conjunctival melanoma', 'Disease', (28, 49))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (28, 49))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (28, 49))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('mutations', 'Var', (81, 90))	('RasGRP3 immunoreactivity', 'MPA', (304, 328))	('GNA11', 'Gene', (268, 273))	('UM', 'Phenotype', 'HP:0007716', (217, 219))
73789	28486107	RasGRP3 protein expression was also detected by immunohistochemistry in UM tissues with GNAQ and GNA11 mutations (Figure 3G).	('mutations', 'Var', (103, 112))	('GNAQ', 'Gene', (88, 92))	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('GNA11', 'Gene', '2767', (97, 102))	('GNA11', 'Gene', (97, 102))
73790	28486107	Conversely, expression of GNAQQ209L or GNA11Q209L, but not BRAFV600E, in human melanocytes significantly increased total RasGRP3 and p-RasGRP3 levels (Figure 4B).	('BRAFV600E', 'Mutation', 'rs113488022', (59, 68))	('GNA11', 'Gene', (39, 44))	('GNAQQ209L', 'Chemical', '-', (26, 35))	('GNAQQ209L', 'Var', (26, 35))	('p-RasGRP3 levels', 'MPA', (133, 149))	('GNA11', 'Gene', '2767', (39, 44))	('human', 'Species', '9606', (73, 78))	('RasGRP3', 'MPA', (121, 128))	('increased', 'PosReg', (105, 114))
73794	28486107	The effect of PKC inhibition on RasGRP3 expression levels and p-RasGRP3 levels was dose dependent in three different GNAQ mutant cell lines incubated with two different PKC inhibitors, AEB071 and AHT956 for 24 hr (Figures 4D and S4B), but had no effects on RasGRP3 expression while inhibiting p-RasGRP3 in melanoma cell lines with BrafV600E or NRAS mutations (Figure S4C), which have very weak expression of RasGRP3 compared with GNAQ mutant cells.	('BrafV600E', 'Mutation', 'rs113488022', (331, 340))	('melanoma', 'Phenotype', 'HP:0002861', (306, 314))	('melanoma', 'Disease', (306, 314))	('NRAS', 'Gene', (344, 348))	('PKC', 'Gene', (14, 17))	('PKC', 'Gene', '112476', (14, 17))	('melanoma', 'Disease', 'MESH:D008545', (306, 314))	('PKC', 'molecular_function', 'GO:0004697', ('169', '172'))	('PKC', 'Gene', (169, 172))	('PKC', 'Gene', '112476', (169, 172))	('NRAS', 'Gene', '4893', (344, 348))	('PKC', 'molecular_function', 'GO:0004697', ('14', '17'))	('inhibiting', 'NegReg', (282, 292))	('mutant', 'Var', (122, 128))	('BrafV600E', 'Var', (331, 340))
73796	28486107	TPA also increased RasGRP3 expression in human melanoma cells with BRAF mutations (Figure S4D).	('mutations', 'Var', (72, 81))	('BRAF', 'Gene', '673', (67, 71))	('TPA', 'Gene', '5327', (0, 3))	('TPA', 'molecular_function', 'GO:0031299', ('0', '3'))	('BRAF', 'Gene', (67, 71))	('RasGRP3', 'Protein', (19, 26))	('human', 'Species', '9606', (41, 46))	('increased', 'PosReg', (9, 18))	('expression', 'MPA', (27, 37))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('TPA', 'Gene', (0, 3))
73797	28486107	These data indicate that activation of PKC in melanocytic cells results in upregulation of RasGRP3 expression as well as T133 phosphorylation of RasGRP3, and that the markedly elevated protein and phosphorylation levels found in GNAQ mutant melanoma cells are a consequence of Galphaq-mediated upregulation of PKC activity.	('expression', 'MPA', (99, 109))	('mutant', 'Var', (234, 240))	('melanoma', 'Disease', (241, 249))	('GNAQ', 'Gene', (229, 233))	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('T133', 'Chemical', '-', (121, 125))	('PKC activity', 'molecular_function', 'GO:0004697', ('310', '322'))	('phosphorylation', 'biological_process', 'GO:0016310', ('197', '212'))	('upregulation', 'PosReg', (294, 306))	('T133 phosphorylation', 'MPA', (121, 141))	('melanoma', 'Disease', 'MESH:D008545', (241, 249))	('elevated', 'PosReg', (176, 184))	('phosphorylation', 'biological_process', 'GO:0016310', ('126', '141'))	('PKC', 'Gene', '112476', (310, 313))	('RasGRP3', 'Enzyme', (91, 98))	('PKC', 'Gene', '112476', (39, 42))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('upregulation', 'PosReg', (75, 87))	('PKC', 'Gene', (310, 313))	('PKC', 'Gene', (39, 42))	('PKC', 'molecular_function', 'GO:0004697', ('39', '42'))
73798	28486107	Among the four PKC isoforms, PKC alpha, delta, epsilon, and zeta, which we found to be invariably expressed in GNAQ or GNA11 mutant UM cell lines, only PKC delta and epsilon robustly phosphorylated T133 of RasGRP3, whereas PKC alpha and zeta had weaker effects with no significant consequences on MAPK signaling (Figures 4F and S4F).	('eta', 'Gene', (61, 64))	('PKC alpha, delta, epsilon, and zeta', 'Gene', '5578;5580;5581;5590', (29, 64))	('PKC', 'molecular_function', 'GO:0004697', ('152', '155'))	('eta', 'Gene', '1909', (238, 241))	('UM', 'Phenotype', 'HP:0007716', (132, 134))	('GNA11', 'Gene', (119, 124))	('PKC', 'Gene', '112476', (29, 32))	('PKC', 'Gene', (29, 32))	('RasGRP3', 'Enzyme', (206, 213))	('PKC alpha', 'Gene', '5578', (223, 232))	('PKC alpha', 'Gene', (29, 38))	('PKC', 'molecular_function', 'GO:0004697', ('223', '226'))	('phosphorylated', 'MPA', (183, 197))	('T133', 'Chemical', '-', (198, 202))	('eta', 'Gene', (238, 241))	('PKC delta', 'Gene', '5580', (152, 161))	('PKC', 'Gene', '112476', (152, 155))	('T133', 'Var', (198, 202))	('MAPK', 'molecular_function', 'GO:0004707', ('297', '301'))	('mutant', 'Var', (125, 131))	('PKC', 'Gene', '112476', (223, 226))	('PKC delta', 'Gene', (152, 161))	('GNA11', 'Gene', '2767', (119, 124))	('PKC', 'Gene', (152, 155))	('PKC alpha', 'Gene', '5578', (29, 38))	('PKC', 'Gene', '112476', (15, 18))	('eta', 'Gene', '1909', (61, 64))	('PKC', 'molecular_function', 'GO:0004697', ('29', '32'))	('PKC', 'molecular_function', 'GO:0004697', ('15', '18'))	('MAPK signaling', 'MPA', (297, 311))	('PKC', 'Gene', (223, 226))	('PKC', 'Gene', (15, 18))	('MAPK signaling', 'biological_process', 'GO:0000165', ('297', '311'))	('PKC alpha', 'Gene', (223, 232))
73800	28486107	We ruled out a positive feedback loop involving MAPK activation and RasGRP3 regulation by suppressing MAP-kinase signaling using the two different MEK inhibitors PD0325901 and Trametinib (Figures 4H and S4G).	('MAPK', 'molecular_function', 'GO:0004707', ('48', '52'))	('Trametinib', 'Chemical', 'MESH:C560077', (176, 186))	('signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('MAP-kinase signaling', 'MPA', (102, 122))	('MEK', 'Gene', (147, 150))	('MEK', 'Gene', '5609', (147, 150))	('MAP', 'molecular_function', 'GO:0004239', ('102', '105'))	('MAPK activation', 'biological_process', 'GO:0000187', ('48', '63'))	('regulation', 'biological_process', 'GO:0065007', ('76', '86'))	('suppressing', 'NegReg', (90, 101))	('PD0325901', 'Var', (162, 171))	('PD0325901', 'Chemical', 'MESH:C506614', (162, 171))
73801	28486107	The YAP1 pathway has been shown to play an important role in GNAQ mutant melanoma development.	('melanoma', 'Disease', (73, 81))	('YAP1', 'Gene', (4, 8))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('mutant', 'Var', (66, 72))	('YAP1', 'Gene', '10413', (4, 8))	('GNAQ', 'Gene', (61, 65))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
73803	28486107	Combined inhibition of the YAP1 and PKC/MAPK pathways neither synergistically suppressed MAPK signaling nor increased cleaved PARP levels, compared with combined inhibition of PKC and MEK (Figures S5B and S5C).	('MAPK signaling', 'biological_process', 'GO:0000165', ('89', '103'))	('PARP', 'Gene', (126, 130))	('MAPK', 'molecular_function', 'GO:0004707', ('40', '44'))	('MAPK signaling', 'MPA', (89, 103))	('PKC', 'Gene', (36, 39))	('inhibition', 'Var', (9, 19))	('increased', 'PosReg', (108, 117))	('PKC', 'molecular_function', 'GO:0004697', ('36', '39'))	('PKC', 'Gene', '112476', (176, 179))	('S5B', 'Gene', (197, 200))	('YAP1', 'Gene', '10413', (27, 31))	('suppressed', 'NegReg', (78, 88))	('PKC', 'Gene', (176, 179))	('MEK', 'Gene', '5609', (184, 187))	('PARP', 'Gene', '1302', (126, 130))	('YAP1', 'Gene', (27, 31))	('PKC', 'molecular_function', 'GO:0004697', ('176', '179'))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('MEK', 'Gene', (184, 187))	('PKC', 'Gene', '112476', (36, 39))	('S5B', 'Gene', '5711', (197, 200))
73805	28486107	However, knockdown of MET or inhibition with the MET inhibitor INC280 had no effect on RasGRP3 and p-RasGRP3 levels or pERK in UM cell lines (Figures S5D and S5E).	('pERK', 'Gene', (119, 123))	('knockdown', 'Var', (9, 18))	('p-RasGRP3 levels', 'MPA', (99, 115))	('RasGRP3', 'MPA', (87, 94))	('INC280', 'Gene', (63, 69))	('INC280', 'Chemical', 'MESH:C000613976', (63, 69))	('UM', 'Phenotype', 'HP:0007716', (127, 129))	('pERK', 'Gene', '9451', (119, 123))
73808	28486107	By contrast, the knockdown had no effect on the RASGEF SOS1.	('SOS1', 'Gene', (55, 59))	('SOS1', 'Gene', '6654', (55, 59))	('knockdown', 'Var', (17, 26))
73809	28486107	The PKC inhibitors AEB071 and AHT956 also both decreased RasGRP3 mRNA, also with no effect on SOS1 mRNAs (Figure S6G).	('SOS1', 'Gene', (94, 98))	('PKC', 'Gene', (4, 7))	('PKC', 'Gene', '112476', (4, 7))	('SOS1', 'Gene', '6654', (94, 98))	('AEB071', 'Var', (19, 25))	('RasGRP3', 'Protein', (57, 64))	('PKC', 'molecular_function', 'GO:0004697', ('4', '7'))	('AHT956', 'Var', (30, 36))	('decreased', 'NegReg', (47, 56))
73810	28486107	Conversely, overexpression of GNAQQ209L or GNA11Q209L in melanocytes increased RasGRP3 mRNA (Figure S6F).	('increased', 'PosReg', (69, 78))	('GNA11', 'Gene', (43, 48))	('GNAQQ209L', 'Chemical', '-', (30, 39))	('GNAQQ209L', 'Var', (30, 39))	('GNA11', 'Gene', '2767', (43, 48))	('RasGRP3 mRNA', 'MPA', (79, 91))
73812	28486107	Together, these data suggest that RasGRP3 regulation in the context of GNAQ mutations occurs transcriptionally and involves PKC signaling.	('signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('mutations', 'Var', (76, 85))	('GNAQ', 'Gene', (71, 75))	('PKC', 'Gene', (124, 127))	('PKC', 'Gene', '112476', (124, 127))	('RasGRP3', 'Gene', (34, 41))	('regulation', 'biological_process', 'GO:0065007', ('42', '52'))	('PKC', 'molecular_function', 'GO:0004697', ('124', '127'))
73813	28486107	The consistently elevated expression levels implicated RasGRP3 as a candidate protein involved in activation of Ras signaling downstream of mutant GNAQ/11.	('GNAQ/11', 'Gene', (147, 154))	('Ras signaling', 'Pathway', (112, 125))	('activation', 'PosReg', (98, 108))	('Ras', 'Chemical', 'MESH:D011883', (55, 58))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('RasGRP3', 'Gene', (55, 62))	('elevated', 'PosReg', (17, 25))	('expression levels', 'MPA', (26, 43))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))	('Ras', 'Chemical', 'MESH:D011883', (112, 115))	('mutant', 'Var', (140, 146))
73814	28486107	Knockdown of RasGRP3 in GNAQ mutant melanoma cell lines significantly reduced levels of pMEK and pERK, but not pAKT (Figures 5A and S7A), but had no effect in other melanoma cell lines (Figure 5B).	('MEK', 'Gene', (89, 92))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('reduced', 'NegReg', (70, 77))	('melanoma', 'Disease', (36, 44))	('MEK', 'Gene', '5609', (89, 92))	('RasGRP3', 'Gene', (13, 20))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('mutant', 'Var', (29, 35))	('GNAQ', 'Gene', (24, 28))	('pERK', 'Gene', '9451', (97, 101))	('pERK', 'Gene', (97, 101))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
73816	28486107	Knockdown of SOS1 only slightly reduced pMEK and pERK levels (Figure S7D).	('MEK', 'Gene', (41, 44))	('Knockdown', 'Var', (0, 9))	('MEK', 'Gene', '5609', (41, 44))	('pERK', 'Gene', '9451', (49, 53))	('SOS1', 'Gene', (13, 17))	('reduced', 'NegReg', (32, 39))	('pERK', 'Gene', (49, 53))	('SOS1', 'Gene', '6654', (13, 17))
73817	28486107	Knockdown of either GNAQ or RasGRP3 also decreased Ras-GTP levels in GNAQ mutant UM cell lines (Figure S7E).	('Ras-GTP levels', 'MPA', (51, 65))	('Ras-GTP', 'Chemical', '-', (51, 58))	('decreased', 'NegReg', (41, 50))	('UM', 'Phenotype', 'HP:0007716', (81, 83))	('GNAQ', 'Gene', (69, 73))	('mutant', 'Var', (74, 80))
73818	28486107	siRNA-mediated knockdown of RasGRP3 also significantly decreased proliferation of GNAQ mutant cells during a 5-day proliferation assay, whereas it had no significant effect on other melanoma cell lines (Figure 5C).	('proliferation', 'CPA', (65, 78))	('GNAQ', 'Gene', (82, 86))	('RasGRP3', 'Gene', (28, 35))	('decreased', 'NegReg', (55, 64))	('mutant', 'Var', (87, 93))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('melanoma', 'Disease', (182, 190))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))
73820	28486107	To further confirm that RasGRP3 modulates MAPK signaling in the setting of GNAQ mutation, we co-transfected 293FT cells with GNAQQ209L combined with individual RasGRP isoforms and examined their effects on MAPK signaling.	('RasGRP', 'Gene', '10125', (160, 166))	('RasGRP', 'Gene', (160, 166))	('GNAQ', 'Gene', (75, 79))	('MAPK', 'molecular_function', 'GO:0004707', ('42', '46'))	('293FT', 'CellLine', 'CVCL:6911', (108, 113))	('GNAQQ209L', 'Var', (125, 134))	('RasGRP', 'Gene', '10125', (24, 30))	('RasGRP', 'Gene', (24, 30))	('MAPK signaling', 'biological_process', 'GO:0000165', ('206', '220'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('42', '56'))	('examined', 'Reg', (180, 188))	('MAPK signaling', 'MPA', (42, 56))	('GNAQQ209L', 'Chemical', '-', (125, 134))	('modulates', 'Reg', (32, 41))	('mutation', 'Var', (80, 88))	('MAPK', 'molecular_function', 'GO:0004707', ('206', '210'))
73821	28486107	As shown in Figure 5G, RasGRP1, RasGRP3, and RasGRP4 alone, but not RasGRP2, induced pERK, while only co-transfection GNAQQ209L with RasGRP1 or RasGRP3 potentiated MAPK signaling as demonstrated by markedly increased pMEK and pERK levels.	('pERK', 'Gene', (226, 230))	('pERK', 'Gene', '9451', (85, 89))	('pERK', 'Gene', (85, 89))	('pERK', 'Gene', '9451', (226, 230))	('RasGRP1', 'Gene', (23, 30))	('RasGRP1', 'Gene', (133, 140))	('GNAQQ209L', 'Var', (118, 127))	('RasGRP1', 'Gene', '10125', (23, 30))	('RasGRP1', 'Gene', '10125', (133, 140))	('MEK', 'Gene', '5609', (218, 221))	('GNAQQ209L', 'Chemical', '-', (118, 127))	('induced', 'Reg', (77, 84))	('potentiated', 'PosReg', (152, 163))	('RasGRP4', 'Gene', (45, 52))	('MAPK signaling', 'MPA', (164, 178))	('MAPK', 'molecular_function', 'GO:0004707', ('164', '168'))	('MEK', 'Gene', (218, 221))	('increased', 'PosReg', (207, 216))	('RasGRP4', 'Gene', '115727', (45, 52))	('MAPK signaling', 'biological_process', 'GO:0000165', ('164', '178'))
73822	28486107	In contrast, co-transfection GNAQQ209L with RasGRP2 had no synergistic effect on MAPK signaling, consistent with the notion that RasGRP2 activates Rap, but not Ras.	('GNAQQ209L', 'Chemical', '-', (29, 38))	('GNAQQ209L', 'Var', (29, 38))	('Rap', 'Gene', '4043', (147, 150))	('RasGRP2', 'Var', (129, 136))	('activates', 'PosReg', (137, 146))	('MAPK', 'molecular_function', 'GO:0004707', ('81', '85'))	('MAPK signaling', 'MPA', (81, 95))	('Rap', 'Gene', (147, 150))	('Ras', 'Chemical', 'MESH:D011883', (160, 163))	('MAPK signaling', 'biological_process', 'GO:0000165', ('81', '95'))	('Ras', 'Chemical', 'MESH:D011883', (44, 47))	('Ras', 'Chemical', 'MESH:D011883', (129, 132))
73824	28486107	GNAQQ209L increased p-RasGRP1 (T184) and p-RasGRP3 (T133) levels in RasGRP1-and RasGRP3-expressing cells, respectively, indicating that oncogenic GNAQ can in principle activate both RasGRP1 and RasGRP3.	('T133', 'Chemical', '-', (52, 56))	('GNAQQ209L', 'Chemical', '-', (0, 9))	('GNAQQ209L', 'Var', (0, 9))	('activate', 'PosReg', (168, 176))	('RasGRP1', 'Gene', '10125', (22, 29))	('RasGRP1', 'Gene', (22, 29))	('RasGRP1', 'Gene', '10125', (68, 75))	('RasGRP1', 'Gene', (68, 75))	('RasGRP1', 'Gene', '10125', (182, 189))	('increased', 'PosReg', (10, 19))	('RasGRP1', 'Gene', (182, 189))
73826	28486107	In B cells, it has been shown that PKC can phosphorylate RasGRP3 at T133, located near the amino terminal region of CDC25 Ras activator domain.	('Ras', 'Chemical', 'MESH:D011883', (122, 125))	('PKC', 'molecular_function', 'GO:0004697', ('35', '38'))	('T133', 'Var', (68, 72))	('PKC', 'Gene', (35, 38))	('PKC', 'Gene', '112476', (35, 38))	('CDC25', 'Gene', (116, 121))	('CDC25', 'Gene', '995', (116, 121))	('T133', 'Chemical', '-', (68, 72))	('Ras', 'Chemical', 'MESH:D011883', (57, 60))
73827	28486107	A phosphorylation site mutant RasGRP3T133A substantially reduces but does not abrogate all RasGRP3 activity in B cells.	('RasGRP3T133A', 'Gene', (30, 42))	('T133A', 'Mutation', 'rs760130608', (37, 42))	('activity', 'MPA', (99, 107))	('mutant', 'Var', (23, 29))	('phosphorylation', 'biological_process', 'GO:0016310', ('2', '17'))
73828	28486107	To determine the role of T133 phosphorylation in the context of mutant GNAQ/11, we introduced RasGRP3T133A into 293FT cells.	('phosphorylation', 'biological_process', 'GO:0016310', ('30', '45'))	('T133', 'Chemical', '-', (101, 105))	('GNAQ/11', 'Gene', (71, 78))	('293FT', 'CellLine', 'CVCL:6911', (112, 117))	('mutant', 'Var', (64, 70))	('T133', 'Chemical', '-', (25, 29))
73829	28486107	RasGRP3 T133A also was less effective in synergizing with GNAQQ209L in activating the MAP-kinase pathway (Figure 6A) and Ras (Figures S7G) than wild-type RasGRP3.	('Ras', 'MPA', (121, 124))	('Ras', 'Chemical', 'MESH:D011883', (0, 3))	('T133A', 'Var', (8, 13))	('MAP', 'molecular_function', 'GO:0004239', ('86', '89'))	('MAP-kinase pathway', 'Pathway', (86, 104))	('Ras', 'Chemical', 'MESH:D011883', (121, 124))	('T133A', 'Mutation', 'rs760130608', (8, 13))	('GNAQQ209L', 'Chemical', '-', (58, 67))	('activating', 'MPA', (71, 81))	('Ras', 'Chemical', 'MESH:D011883', (154, 157))
73831	28486107	These data indicate that PKC phosphorylation at T133 also contributes to RasGRP3-mediated Ras/MAPK signaling in the context of mutant GNAQ.	('mutant', 'Var', (127, 133))	('PKC', 'Gene', (25, 28))	('PKC', 'Gene', '112476', (25, 28))	('MAPK', 'molecular_function', 'GO:0004707', ('94', '98'))	('T133', 'Chemical', '-', (48, 52))	('Ras', 'Chemical', 'MESH:D011883', (90, 93))	('contributes', 'Reg', (58, 69))	('MAPK signaling', 'biological_process', 'GO:0000165', ('94', '108'))	('PKC', 'molecular_function', 'GO:0004697', ('25', '28'))	('phosphorylation', 'biological_process', 'GO:0016310', ('29', '44'))	('Ras', 'Chemical', 'MESH:D011883', (73, 76))	('RasGRP3-mediated Ras/MAPK signaling', 'MPA', (73, 108))
73832	28486107	However, the phosphorylation site mutant of RasGRP3 had a residual activating effect on the MAP-kinase pathway, indicating that some RasGRP3 activity may be PKC independent.	('RasGRP3', 'Gene', (44, 51))	('PKC', 'molecular_function', 'GO:0004697', ('157', '160'))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('activating effect', 'MPA', (67, 84))	('MAP-kinase pathway', 'Pathway', (92, 110))	('phosphorylation', 'Var', (13, 28))	('PKC', 'Gene', (157, 160))	('MAP', 'molecular_function', 'GO:0004239', ('92', '95'))	('mutant', 'Var', (34, 40))	('PKC', 'Gene', '112476', (157, 160))
73833	28486107	To resolve this, we inhibited PKC activity using the pan-PKC inhibitor AEB071 in 293FT cells transfected with combinations of mutant or wild-type RasGRP3 with mutant GNAQ (Figure 6B).	('combinations', 'Interaction', (110, 122))	('mutant', 'Var', (159, 165))	('PKC activity', 'molecular_function', 'GO:0004697', ('30', '42'))	('PKC', 'molecular_function', 'GO:0004697', ('57', '60'))	('inhibited', 'NegReg', (20, 29))	('PKC', 'Gene', (30, 33))	('PKC', 'Gene', (57, 60))	('RasGRP3', 'Gene', (146, 153))	('PKC', 'Gene', '112476', (30, 33))	('293FT', 'CellLine', 'CVCL:6911', (81, 86))	('mutant', 'Var', (126, 132))	('PKC', 'Gene', '112476', (57, 60))
73834	28486107	At a concentration of 1 muM AEB071 was able to completely abrogate T133 phosphorylation of RasGRP3, consistent with prior studies showing complete extinction of PKC activity at this concentration.	('PKC', 'Gene', (161, 164))	('RasGRP3', 'Gene', (91, 98))	('PKC', 'Gene', '112476', (161, 164))	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('PKC activity', 'molecular_function', 'GO:0004697', ('161', '173'))	('T133', 'Chemical', '-', (67, 71))	('AEB071', 'Var', (28, 34))	('abrogate', 'NegReg', (58, 66))	('T133 phosphorylation', 'MPA', (67, 87))
73835	28486107	By contrast, AEB071 had no significant effect on MAP-kinase pathway activation of wild-type RasGRP3 or RasGRP3T133A in the absence of mutant GNAQ, indicating that this residual activity was PKC independent.	('MAP-kinase pathway', 'Pathway', (49, 67))	('activation', 'PosReg', (68, 78))	('AEB071', 'Var', (13, 19))	('T133A', 'Mutation', 'rs760130608', (110, 115))	('PKC', 'molecular_function', 'GO:0004697', ('190', '193'))	('PKC', 'Gene', (190, 193))	('PKC', 'Gene', '112476', (190, 193))	('MAP', 'molecular_function', 'GO:0004239', ('49', '52'))
73836	28486107	As a control, addition of a MEK inhibitor, PD0325901, in this experiment blocked all MAPK activation (Figure 6C).	('PD0325901', 'Var', (43, 52))	('activation', 'PosReg', (90, 100))	('MAPK activation', 'biological_process', 'GO:0000187', ('85', '100'))	('MAPK', 'molecular_function', 'GO:0004707', ('85', '89'))	('PD0325901', 'Chemical', 'MESH:C506614', (43, 52))	('MEK', 'Gene', (28, 31))	('MAPK', 'Protein', (85, 89))	('MEK', 'Gene', '5609', (28, 31))	('blocked', 'NegReg', (73, 80))
73839	28486107	As shown in Figure 6D, deletion of the C1 domain of RasGRP3 significantly reduces the ability of mutant GNAQ to activate the MAP-kinase pathway, and the RasGRP3 activity could be further reduced by mutating the T133 phosphorylation site.	('phosphorylation', 'biological_process', 'GO:0016310', ('216', '231'))	('MAP-kinase pathway', 'Pathway', (125, 143))	('deletion', 'Var', (23, 31))	('MAP', 'molecular_function', 'GO:0004239', ('125', '128'))	('T133', 'Chemical', '-', (211, 215))	('mutating', 'Var', (198, 206))	('RasGRP3', 'Gene', (52, 59))	('ability', 'MPA', (86, 93))	('reduces', 'NegReg', (74, 81))	('activate', 'PosReg', (112, 120))
73840	28486107	The effect of C1 deletion could be completely rescued by adding Fyn or Src membrane binding motifs to the RasGRP3 C1 deletion mutants (Figure 6E), indicating that C1-mediated membrane binding is essential for GNAQ-mediated activation of MAP-kinase signaling.	('Fyn', 'Gene', (64, 67))	('RasGRP3 C1', 'Gene', (106, 116))	('binding', 'molecular_function', 'GO:0005488', ('184', '191'))	('signaling', 'biological_process', 'GO:0023052', ('248', '257'))	('membrane', 'cellular_component', 'GO:0016020', ('175', '183'))	('binding', 'molecular_function', 'GO:0005488', ('84', '91'))	('mutants', 'Var', (126, 133))	('deletion', 'Var', (17, 25))	('membrane', 'cellular_component', 'GO:0016020', ('75', '83'))	('Fyn', 'Gene', '2534', (64, 67))	('activation of MAP-kinase', 'biological_process', 'GO:0000187', ('223', '247'))	('deletion mutants', 'Var', (117, 133))	('MAP', 'molecular_function', 'GO:0004239', ('237', '240'))
73841	28486107	Together, these data demonstrate that membrane binding via the C1 domain and T133 phosphorylation cooperate in RasGRP3-mediated activation of MAPK signaling in the setting of GNAQ mutations.	('activation', 'PosReg', (128, 138))	('MAPK signaling', 'MPA', (142, 156))	('mutations', 'Var', (180, 189))	('MAPK signaling', 'biological_process', 'GO:0000165', ('142', '156'))	('GNAQ', 'Gene', (175, 179))	('binding', 'molecular_function', 'GO:0005488', ('47', '54'))	('MAPK', 'molecular_function', 'GO:0004707', ('142', '146'))	('T133', 'Chemical', '-', (77, 81))	('membrane', 'cellular_component', 'GO:0016020', ('38', '46'))	('RasGRP3-mediated', 'Protein', (111, 127))	('phosphorylation', 'biological_process', 'GO:0016310', ('82', '97'))
73842	28486107	Constitutive activation of the MAPK pathway (RAS/RAF/MEK/ERK) is common in cutaneous melanoma and typically occurs through mutations and/or amplification of signaling modules such as BRAF or NRAS.	('RAF', 'Gene', '22882', (49, 52))	('ERK', 'molecular_function', 'GO:0004707', ('57', '60'))	('RAF', 'Gene', '22882', (184, 187))	('amplification', 'Var', (140, 153))	('MEK', 'Gene', '5609', (53, 56))	('NRAS', 'Gene', (191, 195))	('RAF', 'Gene', (49, 52))	('ERK', 'Gene', '5594', (57, 60))	('RAF', 'Gene', (184, 187))	('MEK', 'Gene', (53, 56))	('signaling', 'biological_process', 'GO:0023052', ('157', '166'))	('MAPK pathway', 'Pathway', (31, 43))	('MAPK', 'molecular_function', 'GO:0004707', ('31', '35'))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('ERK', 'Gene', (57, 60))	('cutaneous melanoma', 'Disease', (75, 93))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (75, 93))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (75, 93))	('NRAS', 'Gene', '4893', (191, 195))	('activation', 'PosReg', (13, 23))	('BRAF', 'Gene', '673', (183, 187))	('BRAF', 'Gene', (183, 187))	('mutations', 'Var', (123, 132))
73847	28486107	Among the more than ten different PKC isoforms we found that, irrespective of GNAQ or GNA11 mutation status, PKC alpha, delta, epsilon, or zeta were ubiquitously expressed in melanoma cells, while PKC iota was only weakly expressed, mostly consistent with published reports.	('PKC', 'Gene', (34, 37))	('PKC', 'Gene', '112476', (34, 37))	('mutation', 'Var', (92, 100))	('GNAQ', 'Gene', (78, 82))	('PKC', 'molecular_function', 'GO:0004697', ('34', '37'))	('PKC alpha, delta, epsilon, or zeta', 'Gene', '5578;5580;5581;5590', (109, 143))	('PKC', 'Gene', '112476', (109, 112))	('iota', 'Chemical', '-', (201, 205))	('PKC', 'Gene', (197, 200))	('PKC', 'Gene', '112476', (197, 200))	('PKC', 'Gene', (109, 112))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('GNA11', 'Gene', (86, 91))	('melanoma', 'Disease', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('PKC', 'molecular_function', 'GO:0004697', ('109', '112'))	('GNA11', 'Gene', '2767', (86, 91))	('PKC', 'molecular_function', 'GO:0004697', ('197', '200'))
73849	28486107	Only knockdown of PKC delta or epsilon, but not other PKC isoforms significantly reduced MAPK signaling in GNAQ mutant melanoma cells.	('PKC delta', 'Gene', (18, 27))	('MAPK signaling', 'biological_process', 'GO:0000165', ('89', '103'))	('PKC', 'Gene', (18, 21))	('reduced', 'NegReg', (81, 88))	('PKC', 'Gene', (54, 57))	('PKC', 'Gene', '112476', (18, 21))	('PKC delta', 'Gene', '5580', (18, 27))	('MAPK signaling', 'MPA', (89, 103))	('melanoma', 'Disease', (119, 127))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('epsilon', 'Enzyme', (31, 38))	('PKC', 'molecular_function', 'GO:0004697', ('54', '57'))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('PKC', 'molecular_function', 'GO:0004697', ('18', '21'))	('mutant', 'Var', (112, 118))	('PKC', 'Gene', '112476', (54, 57))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))
73850	28486107	Only combined depletion of PKC delta and epsilon, but not combined knockdown of either PKC zeta with delta or epsilon, or PKC alpha with delta or epsilon extinguished MAP-kinase pathway signaling and inhibited proliferation of GNAQ mutant melanoma cell lines but had no such effect on melanoma cell lines with other mutations.	('PKC', 'molecular_function', 'GO:0004697', ('27', '30'))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('melanoma', 'Disease', (239, 247))	('MAP-kinase pathway', 'Pathway', (167, 185))	('PKC', 'molecular_function', 'GO:0004697', ('87', '90'))	('mutant', 'Var', (232, 238))	('melanoma', 'Phenotype', 'HP:0002861', (285, 293))	('melanoma', 'Disease', (285, 293))	('MAP', 'molecular_function', 'GO:0004239', ('167', '170'))	('PKC zeta', 'Gene', (87, 95))	('PKC delta', 'Gene', '5580', (27, 36))	('GNAQ', 'Gene', (227, 231))	('inhibited', 'NegReg', (200, 209))	('PKC delta', 'Gene', (27, 36))	('extinguished', 'NegReg', (154, 166))	('depletion', 'NegReg', (14, 23))	('melanoma', 'Disease', 'MESH:D008545', (239, 247))	('PKC alpha', 'Gene', (122, 131))	('melanoma', 'Disease', 'MESH:D008545', (285, 293))	('proliferation', 'CPA', (210, 223))	('signaling', 'biological_process', 'GO:0023052', ('186', '195'))	('PKC', 'molecular_function', 'GO:0004697', ('122', '125'))	('PKC zeta', 'Gene', '5590', (87, 95))	('PKC alpha', 'Gene', '5578', (122, 131))
73851	28486107	Concordantly, co-transfection of GNAQQ209L with PKC delta or epsilon, but not PKC alpha, zeta, and iota potentiated MAPK signaling in 293FT cells.	('PKC delta', 'Gene', (48, 57))	('GNAQQ209L', 'Chemical', '-', (33, 42))	('PKC', 'molecular_function', 'GO:0004697', ('48', '51'))	('PKC delta', 'Gene', '5580', (48, 57))	('epsilon', 'Enzyme', (61, 68))	('PKC', 'molecular_function', 'GO:0004697', ('78', '81'))	('MAPK', 'molecular_function', 'GO:0004707', ('116', '120'))	('MAPK signaling', 'MPA', (116, 130))	('PKC alpha, zeta, and iota', 'Gene', '5578;5590', (78, 103))	('MAPK signaling', 'biological_process', 'GO:0000165', ('116', '130'))	('potentiated', 'PosReg', (104, 115))	('GNAQQ209L', 'Var', (33, 42))	('293FT', 'CellLine', 'CVCL:6911', (134, 139))
73858	28486107	We show that the significantly increased expression level of RasGRP3 in UM is a direct consequence of Galphaq signaling, and that Galphaq signaling not only increases RasGRP3 transcription in a PKC-dependent manner but activates RasGRP3 by two independent mechanisms: membrane recruitment and phosphorylation by PKC delta and epsilon.	('transcription', 'MPA', (175, 188))	('increased', 'PosReg', (31, 40))	('PKC', 'Gene', '112476', (194, 197))	('PKC', 'Gene', '112476', (312, 315))	('PKC', 'molecular_function', 'GO:0004697', ('312', '315'))	('PKC delta', 'Gene', '5580', (312, 321))	('PKC', 'Gene', (194, 197))	('transcription', 'biological_process', 'GO:0006351', ('175', '188'))	('phosphorylation', 'MPA', (293, 308))	('PKC delta', 'Gene', (312, 321))	('PKC', 'Gene', (312, 315))	('activates', 'PosReg', (219, 228))	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('RasGRP3', 'Gene', (167, 174))	('increases', 'PosReg', (157, 166))	('phosphorylation', 'biological_process', 'GO:0016310', ('293', '308'))	('PKC', 'molecular_function', 'GO:0004697', ('194', '197'))	('RasGRP3', 'Gene', (229, 236))	('Galphaq', 'Var', (130, 137))	('membrane', 'cellular_component', 'GO:0016020', ('268', '276'))	('signaling', 'biological_process', 'GO:0023052', ('110', '119'))	('membrane recruitment', 'MPA', (268, 288))	('signaling', 'biological_process', 'GO:0023052', ('138', '147'))	('expression level', 'MPA', (41, 57))
73860	28486107	Here we show that the expression level of RasGRP3 in GNAQ or GNA11 mutant melanoma cell lines and human UM tissues by far exceeds the expression levels of the previously reported tissue types, indicating a specific role of this protein in UM.	('expression', 'MPA', (134, 144))	('GNAQ', 'Gene', (53, 57))	('UM', 'Phenotype', 'HP:0007716', (104, 106))	('protein', 'cellular_component', 'GO:0003675', ('228', '235'))	('GNA11', 'Gene', '2767', (61, 66))	('GNA11', 'Gene', (61, 66))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('expression level', 'MPA', (22, 38))	('RasGRP3', 'Gene', (42, 49))	('melanoma', 'Disease', (74, 82))	('mutant', 'Var', (67, 73))	('UM', 'Phenotype', 'HP:0007716', (239, 241))	('human', 'Species', '9606', (98, 103))
73861	28486107	Our results indicate that GNAQ signaling and PKC delta and epsilon are involved in upregulating RasGRP3 expression, and that this effect is restricted to melanocytes, as mutant GNAQ did not increase RasGRP3 expression levels in 293FT (data not shown).	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('GNAQ', 'Gene', (177, 181))	('PKC', 'molecular_function', 'GO:0004697', ('45', '48'))	('PKC delta', 'Gene', (45, 54))	('PKC delta', 'Gene', '5580', (45, 54))	('upregulating', 'PosReg', (83, 95))	('expression', 'MPA', (104, 114))	('RasGRP3', 'Protein', (96, 103))	('mutant', 'Var', (170, 176))	('293FT', 'CellLine', 'CVCL:6911', (228, 233))
73864	28486107	Phosphorylation of RasGRP3 at threonine 133 by PKC enhances the ability of RasGRP3 to maximally activate Ras signaling in antigen receptor-stimulated B cells, and in that context is suggested to be mediated by PKC theta and PKC beta.	('signaling', 'biological_process', 'GO:0023052', ('109', '118'))	('PKC', 'Gene', '112476', (210, 213))	('PKC beta', 'Gene', '5579', (224, 232))	('threonine 133', 'Var', (30, 43))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('PKC', 'molecular_function', 'GO:0004697', ('210', '213'))	('PKC', 'molecular_function', 'GO:0004697', ('47', '50'))	('RasGRP3', 'Gene', (19, 26))	('PKC', 'Gene', (210, 213))	('eta', 'Gene', (216, 219))	('PKC', 'Gene', '112476', (224, 227))	('eta', 'Gene', '1909', (229, 232))	('PKC beta', 'Gene', (224, 232))	('Ras', 'Chemical', 'MESH:D011883', (75, 78))	('threonine', 'Chemical', 'MESH:D013912', (30, 39))	('PKC', 'molecular_function', 'GO:0004697', ('224', '227'))	('PKC', 'Gene', (224, 227))	('activate', 'PosReg', (96, 104))	('ability', 'MPA', (64, 71))	('eta', 'Gene', (229, 232))	('Ras signaling', 'MPA', (105, 118))	('Ras', 'Chemical', 'MESH:D011883', (105, 108))	('Ras', 'Chemical', 'MESH:D011883', (19, 22))	('PKC', 'Gene', '112476', (47, 50))	('Phosphorylation', 'MPA', (0, 15))	('enhances', 'PosReg', (51, 59))	('PKC', 'Gene', (47, 50))	('eta', 'Gene', '1909', (216, 219))
73865	28486107	We confirm the critical role of RasGRP3 phosphorylation at T133 in the setting of GNAQ mutations with PKC delta and epsilon as the relevant PKC isoforms for this modification in UM.	('PKC delta', 'Gene', '5580', (102, 111))	('PKC', 'Gene', '112476', (102, 105))	('PKC', 'Gene', (140, 143))	('PKC', 'Gene', '112476', (140, 143))	('UM', 'Phenotype', 'HP:0007716', (178, 180))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('GNAQ', 'Gene', (82, 86))	('PKC', 'molecular_function', 'GO:0004697', ('140', '143'))	('PKC', 'molecular_function', 'GO:0004697', ('102', '105'))	('PKC delta', 'Gene', (102, 111))	('PKC', 'Gene', (102, 105))	('mutations', 'Var', (87, 96))	('T133', 'Chemical', '-', (59, 63))	('phosphorylation', 'MPA', (40, 55))
73866	28486107	We show that mutating the PKC phosphorylation site of RasGRP3 (T133A) partially, but not completely, attenuated RasGRP3-mediated MAPK signaling.	('phosphorylation', 'biological_process', 'GO:0016310', ('30', '45'))	('T133A', 'Mutation', 'rs760130608', (63, 68))	('MAPK signaling', 'biological_process', 'GO:0000165', ('129', '143'))	('attenuated', 'NegReg', (101, 111))	('mutating', 'Var', (13, 21))	('PKC', 'Gene', (26, 29))	('PKC', 'Gene', '112476', (26, 29))	('PKC', 'molecular_function', 'GO:0004697', ('26', '29'))	('RasGRP3-mediated MAPK signaling', 'MPA', (112, 143))	('MAPK', 'molecular_function', 'GO:0004707', ('129', '133'))
73870	28486107	This PKC-independent activity may explain why PKC inhibition fails to induce sustained suppression of MAPK signaling in GNAQ mutant melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanomas', 'Phenotype', 'HP:0002861', (132, 141))	('mutant', 'Var', (125, 131))	('MAPK', 'molecular_function', 'GO:0004707', ('102', '106'))	('GNAQ', 'Gene', (120, 124))	('MAPK signaling', 'MPA', (102, 116))	('melanomas', 'Disease', 'MESH:D008545', (132, 141))	('MAPK signaling', 'biological_process', 'GO:0000165', ('102', '116'))	('PKC', 'Gene', (46, 49))	('PKC', 'Gene', '112476', (46, 49))	('PKC', 'molecular_function', 'GO:0004697', ('5', '8'))	('PKC', 'molecular_function', 'GO:0004697', ('46', '49'))	('PKC', 'Gene', (5, 8))	('PKC', 'Gene', '112476', (5, 8))	('melanomas', 'Disease', (132, 141))
73895	28486107	PD0325901 and Trametinib were obtained from Chemie TEK(Indianapolis, IN).	('Trametinib', 'Chemical', 'MESH:C560077', (14, 24))	('TEK', 'Gene', '7010', (51, 54))	('PD0325901', 'Var', (0, 9))	('TEK', 'Gene', (51, 54))	('PD0325901', 'Chemical', 'MESH:C506614', (0, 9))
73901	28486107	After 48 hr transfection, cells were counted using TC10 automated cell counter (Bio-Rad, Hercules, CA) and plated in triplicate into 6-well plates at 5x104 cells/well and cultured for the indicated times.	('Rad', 'biological_process', 'GO:1990116', ('84', '87'))	('Rad', 'Gene', '6236', (84, 87))	('TC10', 'Gene', (51, 55))	('Rad', 'Gene', (84, 87))	('TC10', 'Gene', '23433', (51, 55))	('transfection', 'Var', (12, 24))
73911	28486107	SOS1 (Hs00362308_m1), RasGRP2 (Hs00183378_m1), 3 (Hs00209808_m1) and 4 (Hs01073182_m1) probes and primers were obtained at Applied Bio System.	('Hs00183378_m1', 'Var', (31, 44))	('Hs00362308_m1', 'Var', (6, 19))	('SOS1', 'Gene', (0, 4))	('Hs00209808_m1', 'Var', (50, 63))	('SOS1', 'Gene', '6654', (0, 4))
73914	28486107	Gene level differential expression was compared between 5 GNAQ/11 mutant melanoma cells and 5 BRAF/Nras mutant melanoma cells by using Affymetrix transcriptome Analysis Console (TAC) software.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('BRAF', 'Gene', (94, 98))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('mutant', 'Var', (66, 72))	('Nras', 'Gene', (99, 103))	('TAC', 'cellular_component', 'GO:0120121', ('178', '181'))	('Nras', 'Gene', '4893', (99, 103))	('BRAF', 'Gene', '673', (94, 98))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
73930	28486107	The cohort of patients included in this paper were as follows: GNAQ mutant: male 78 years, male 78 years, male 77 years, male 51 years; GNA11 mutant: female 73 years, female 73 years, female 53 years, female 43 years.	('GNA11', 'Gene', (136, 141))	('mutant', 'Var', (142, 148))	('GNA11', 'Gene', '2767', (136, 141))	('GNAQ', 'Gene', (63, 67))	('patients', 'Species', '9606', (14, 22))	('mutant', 'Var', (68, 74))
73939	28486107	PKC delta/epsilon mediate ERK activation in uveal melanoma with Galphaq pathway mutations The RAS exchange factor RasGRP3 is a critical module for ERK activation PKC delta, PKC epsilon, and RasGRP3 are novel therapeutic targets for uveal melanoma Uveal melanoma (UM) is the most lethal form of melanoma with a 10-year survival rate of approximately 50%.	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('PKC epsilon', 'Gene', '5581', (173, 184))	('melanoma', 'Disease', (238, 246))	('ERK', 'Gene', '5594', (26, 29))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('melanoma', 'Disease', (294, 302))	('PKC delta', 'Gene', '5580', (162, 171))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('ERK', 'Gene', (147, 150))	('ERK', 'molecular_function', 'GO:0004707', ('147', '150'))	('ERK', 'molecular_function', 'GO:0004707', ('26', '29'))	('uveal melanoma', 'Disease', (44, 58))	('PKC', 'molecular_function', 'GO:0004697', ('162', '165'))	('mutations', 'Var', (80, 89))	('PKC delta', 'Gene', (162, 171))	('melanoma', 'Phenotype', 'HP:0002861', (253, 261))	('melanoma', 'Disease', (253, 261))	('uveal melanoma', 'Disease', 'MESH:C536494', (232, 246))	('UM', 'Phenotype', 'HP:0007716', (263, 265))	('ERK', 'Gene', (26, 29))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('uveal melanoma', 'Disease', (232, 246))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (247, 261))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('PKC epsilon', 'Gene', (173, 184))	('PKC delta', 'Gene', '5580', (0, 9))	('melanoma', 'Disease', 'MESH:D008545', (238, 246))	('uveal melanoma', 'Phenotype', 'HP:0007716', (232, 246))	('melanoma', 'Disease', 'MESH:D008545', (294, 302))	('PKC', 'molecular_function', 'GO:0004697', ('173', '176'))	('PKC delta', 'Gene', (0, 9))	('PKC', 'molecular_function', 'GO:0004697', ('0', '3'))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('ERK', 'Gene', '5594', (147, 150))	('melanoma', 'Disease', 'MESH:D008545', (253, 261))
73945	28203054	New insights into the molecular biology of UM have found frequent activating mutations in genes encoding for the G-protein alpha-subunit, GNAQ and GNA11, and improved understanding of the downstream signaling pathways MAPK, PI3K/Akt, and Hippo have afforded an array of new targets for treatment of this disease.	('Akt', 'Gene', '207', (229, 232))	('GNAQ', 'Gene', '2776', (138, 142))	('MAPK', 'molecular_function', 'GO:0004707', ('218', '222'))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('activating', 'PosReg', (66, 76))	('Akt', 'Gene', (229, 232))	('MAPK', 'Pathway', (218, 222))	('PI3', 'Gene', '5266', (224, 227))	('mutations', 'Var', (77, 86))	('Hippo', 'Disease', (238, 243))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('GNAQ', 'Gene', (138, 142))	('GNA11', 'Gene', (147, 152))	('GNA11', 'Gene', '2767', (147, 152))	('PI3K', 'molecular_function', 'GO:0016303', ('224', '228'))	('signaling', 'biological_process', 'GO:0023052', ('199', '208'))	('PI3', 'Gene', (224, 227))
73949	28203054	A variety of risk factors have been identified, including the presence of light eyes, fair skin, an inability to tan, ocular melanocytosis, dysplastic nevus syndrome, and BAP1 mutations.	('BAP1', 'Gene', (171, 175))	('mutations', 'Var', (176, 185))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (140, 156))	('dysplastic nevus syndrome', 'Disease', 'MESH:D004416', (140, 165))	('fair', 'Disease', (86, 90))	('ocular melanocytosis', 'Disease', (118, 138))	('nevus', 'Phenotype', 'HP:0003764', (151, 156))	('fair skin', 'Phenotype', 'HP:0007513', (86, 95))	('BAP1', 'Gene', '8314', (171, 175))	('dysplastic nevus syndrome', 'Disease', (140, 165))	('ocular melanocytosis', 'Disease', 'MESH:C535835', (118, 138))	('ocular melanocytosis', 'Phenotype', 'HP:0025534', (118, 138))
73951	28203054	UM in BAP1 germ-line mutants is usually diagnosed between the ages of 30 and 59 years, and is driven by inactivating mutations in the lone functional BAP1 gene, analogous to the frequent loss of chromosome 3 observed in high-risk sporadic disease.	('mutants', 'Var', (21, 28))	('BAP1', 'Gene', (150, 154))	('BAP1', 'Gene', (6, 10))	('inactivating mutations', 'Var', (104, 126))	('chromosome', 'cellular_component', 'GO:0005694', ('195', '205'))	('BAP1', 'Gene', '8314', (150, 154))	('BAP1', 'Gene', '8314', (6, 10))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
73952	28203054	Interestingly, patients with UM have an 11% higher risk of second malignancies, such as cutaneous melanoma and renal cell carcinoma, than the general population, which may be driven by the presence of germ-line BAP1 mutations.	('patients', 'Species', '9606', (15, 23))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (111, 131))	('second', 'Disease', (59, 65))	('BAP1', 'Gene', '8314', (211, 215))	('UM', 'Phenotype', 'HP:0007716', (29, 31))	('cutaneous melanoma', 'Disease', (88, 106))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (111, 131))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (88, 106))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (88, 106))	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('BAP1', 'Gene', (211, 215))	('malignancies', 'Disease', (66, 78))	('mutations', 'Var', (216, 225))	('renal cell carcinoma', 'Disease', (111, 131))
73966	28203054	Recently, PRAME has been reported to be an independent biomarker for UM, and when combined with a 12-gene expression panel, PRAME messenger-RNA expression predicted a 5-year metastatic rate of 0 in class 1/PRAME-, 38% in class 1/PRAME+, and 71% in class 2.	('PRAME', 'Gene', '23532', (206, 211))	('RNA', 'cellular_component', 'GO:0005562', ('140', '143'))	('PRAME', 'Gene', (10, 15))	('PRAME', 'Gene', '23532', (124, 129))	('PRAME', 'Gene', (206, 211))	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('PRAME', 'Gene', (124, 129))	('PRAME', 'Gene', '23532', (229, 234))	('PRAME', 'Gene', (229, 234))	('messenger-RNA', 'Var', (130, 143))	('gene expression', 'biological_process', 'GO:0010467', ('101', '116'))	('PRAME', 'Gene', '23532', (10, 15))	('metastatic', 'CPA', (174, 184))
73968	28203054	Unlike cutaneous melanoma, UM is genetically characterized by a small number of alterations; however, several of these alterations have been well characterized and been found to alter intracellular signaling, surface-receptor expression, and ligand production.	('surface-receptor expression', 'MPA', (209, 236))	('cutaneous melanoma', 'Disease', (7, 25))	('UM', 'Phenotype', 'HP:0007716', (27, 29))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (7, 25))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (7, 25))	('signaling', 'biological_process', 'GO:0023052', ('198', '207'))	('alter', 'Reg', (178, 183))	('ligand', 'molecular_function', 'GO:0005488', ('242', '248'))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('ligand production', 'MPA', (242, 259))	('intracellular', 'cellular_component', 'GO:0005622', ('184', '197'))	('alterations', 'Var', (119, 130))	('intracellular signaling', 'MPA', (184, 207))
73969	28203054	While cutaneous melanomas are driven by MAPK activation through mutations in BRAF (~50% of cases), NRAS (10%-25% of cases), or loss of function in NF1 (14% of cases), UM rarely harbors such alterations and rather is characterized by point mutations in the G-protein alpha-subunit.	('MAPK', 'molecular_function', 'GO:0004707', ('40', '44'))	('melanomas', 'Phenotype', 'HP:0002861', (16, 25))	('NRAS', 'Gene', (99, 103))	('cutaneous melanoma', 'Disease', (6, 24))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (6, 24))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (6, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('UM', 'Phenotype', 'HP:0007716', (167, 169))	('mutations', 'Var', (64, 73))	('MAPK', 'Gene', (40, 44))	('NF1', 'Gene', '4763', (147, 150))	('protein', 'cellular_component', 'GO:0003675', ('258', '265'))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (6, 25))	('loss of function', 'NegReg', (127, 143))	('point', 'Var', (233, 238))	('BRAF', 'Gene', '673', (77, 81))	('MAPK activation', 'biological_process', 'GO:0000187', ('40', '55'))	('BRAF', 'Gene', (77, 81))	('melanomas', 'Disease', 'MESH:D008545', (16, 25))	('NF1', 'Gene', (147, 150))	('NRAS', 'Gene', '4893', (99, 103))	('melanomas', 'Disease', (16, 25))	('activation', 'PosReg', (45, 55))
73973	28203054	It has been demonstrated that glutamine at the 209 position is required for GTPase activity, and mutations that disrupt this activity cause a constitutively active GTP-bound state.	('mutations', 'Var', (97, 106))	('GTP', 'Chemical', 'MESH:D006160', (164, 167))	('cause', 'Reg', (134, 139))	('constitutively active GTP-bound state', 'MPA', (142, 179))	('GTP', 'Chemical', 'MESH:D006160', (76, 79))	('glutamine', 'Chemical', 'MESH:D005973', (30, 39))	('GTPase activity', 'molecular_function', 'GO:0003924', ('76', '91'))	('GTPase', 'Protein', (76, 82))
73978	28203054	Recently, additional mutations that are mutually exclusive to GNAQ/GNA11 but work along similar pathways have been identified.	('GNA11', 'Gene', (67, 72))	('GNAQ', 'Gene', '2776', (62, 66))	('GNA11', 'Gene', '2767', (67, 72))	('GNAQ', 'Gene', (62, 66))	('mutations', 'Var', (21, 30))
73979	28203054	PLCB4 is a downstream effector of GNAQ/GNA11 that has been found to be mutated in three of 28 UM samples without GNAQ/GNA11 mutations.	('GNA11', 'Gene', (118, 123))	('GNAQ', 'Gene', (113, 117))	('UM', 'Phenotype', 'HP:0007716', (94, 96))	('GNA11', 'Gene', (39, 44))	('PLCB4', 'Gene', '5332', (0, 5))	('GNA11', 'Gene', '2767', (118, 123))	('GNA11', 'Gene', '2767', (39, 44))	('mutated', 'Var', (71, 78))	('GNAQ', 'Gene', (34, 38))	('PLCB4', 'Gene', (0, 5))	('GNAQ', 'Gene', '2776', (113, 117))	('GNAQ', 'Gene', '2776', (34, 38))
73980	28203054	Furthermore, recurrent activating mutations in the G-protein-coupled receptor CYSLTR2 have been found in UM without GNAQ/GNA11 or PCLB4 mutations.	('GNA11', 'Gene', '2767', (121, 126))	('GNAQ', 'Gene', (116, 120))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('CYSLTR2', 'Gene', (78, 85))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('CYSLTR2', 'Gene', '57105', (78, 85))	('GNA11', 'Gene', (121, 126))	('GNAQ', 'Gene', '2776', (116, 120))	('mutations', 'Var', (34, 43))	('activating', 'PosReg', (23, 33))
73981	28203054	These less frequent mutations reaffirm the importance of the Galpha-signaling pathway in this disease.	('Galpha', 'Gene', (61, 67))	('Galpha', 'Gene', '8802', (61, 67))	('signaling pathway', 'biological_process', 'GO:0007165', ('68', '85'))	('mutations', 'Var', (20, 29))
73983	28203054	Mutant GNAQ/GNA11 activates phospholipase C, which cleaves phosphatidylinositol bisphosphate into inositol trisphosphate and diacylglycerol that subsequently activates PKC.	('diacylglycerol', 'Chemical', 'MESH:D004075', (125, 139))	('PKC', 'molecular_function', 'GO:0004697', ('168', '171'))	('GNA11', 'Gene', '2767', (12, 17))	('GNA11', 'Gene', (12, 17))	('GNAQ', 'Gene', '2776', (7, 11))	('PKC', 'Enzyme', (168, 171))	('inositol trisphosphate', 'Chemical', '-', (98, 120))	('phosphatidylinositol bisphosphate', 'Chemical', '-', (59, 92))	('GNAQ', 'Gene', (7, 11))	('phospholipase C', 'Enzyme', (28, 43))	('Mutant', 'Var', (0, 6))	('activates', 'Reg', (158, 167))	('activates', 'PosReg', (18, 27))
73991	28203054	Alternatively, GNAQ/GNA11 mutations have been shown to increase YAP and TAZ activation through an alternative pathway utilizing Trio, a guanine nucleotide-exchange factor, and the downstream GTPases Rho and Rac.	('GNAQ', 'Gene', (15, 19))	('increase', 'PosReg', (55, 63))	('downstream GTPases Rho and Rac', 'Gene', '207', (180, 210))	('GNA11', 'Gene', (20, 25))	('YAP', 'Gene', '10413', (64, 67))	('mutations', 'Var', (26, 35))	('GNA11', 'Gene', '2767', (20, 25))	('TAZ', 'Gene', '6901', (72, 75))	('Trio', 'Gene', '7204', (128, 132))	('GNAQ', 'Gene', '2776', (15, 19))	('Trio', 'Gene', (128, 132))	('TAZ', 'Gene', (72, 75))	('YAP', 'Gene', (64, 67))
73996	28203054	BAP1 has inactivating mutations in approximately 47% of primary UMs and 84% of metastatic UMs, consistent with the association of BAP1 mutations with inferior outcomes.	('BAP1', 'Gene', (130, 134))	('BAP1', 'Gene', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (64, 66))	('UM', 'Phenotype', 'HP:0007716', (90, 92))	('inactivating mutations', 'Var', (9, 31))	('mutations', 'Var', (135, 144))	('BAP1', 'Gene', '8314', (0, 4))	('BAP1', 'Gene', '8314', (130, 134))	('primary UMs', 'Disease', (56, 67))	('metastatic', 'CPA', (79, 89))
73998	28203054	SF3B1 alterations are associated with more favorable prognostic features, including younger age at diagnosis, fewer undifferentiated epithelioid cells, and disomy 3, as well as an inverse correlation with BAP1 mutations; however, SF3B1 mutations appear to be associated with the development of delayed metastasis, with a median of 8.2 years.	('associated with', 'Reg', (259, 274))	('alterations', 'Var', (6, 17))	('SF3B1', 'Gene', (0, 5))	('SF3B1', 'Gene', (230, 235))	('BAP1', 'Gene', '8314', (205, 209))	('SF3B1', 'Gene', '23451', (0, 5))	('delayed metastasis', 'CPA', (294, 312))	('mutations', 'Var', (236, 245))	('SF3B1', 'Gene', '23451', (230, 235))	('BAP1', 'Gene', (205, 209))
74000	28203054	As with SF3B1, EIF1AX mutations are associated with disomy 3, but are less frequently associated with metastases.	('disomy 3', 'Disease', (52, 60))	('SF3B1', 'Gene', '23451', (8, 13))	('EIF1AX', 'Gene', '1964', (15, 21))	('EIF1AX', 'Gene', (15, 21))	('metastases', 'Disease', (102, 112))	('mutations', 'Var', (22, 31))	('associated', 'Reg', (36, 46))	('SF3B1', 'Gene', (8, 13))	('metastases', 'Disease', 'MESH:D009362', (102, 112))
74001	28203054	Of note, given the mutual exclusivity from BAP1 and SF3B1, it is not clear if the presence of EIF1AX mutations is protective or whether the association is due to a lack of negative effects of the other mutations.	('BAP1', 'Gene', (43, 47))	('EIF1AX', 'Gene', (94, 100))	('mutations', 'Var', (101, 110))	('EIF1AX', 'Gene', '1964', (94, 100))	('SF3B1', 'Gene', (52, 57))	('BAP1', 'Gene', '8314', (43, 47))	('SF3B1', 'Gene', '23451', (52, 57))
74002	28203054	Tumor suppressors, such as RASSF1A, and other molecules, such as the adhesion protein E-cadherin, are hypermethylated in 50%-70% of UM, correlate with metastatic disease, and may provide potential novel therapeutic strategies.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('RASSF1A', 'Gene', (27, 34))	('UM', 'Phenotype', 'HP:0007716', (132, 134))	('cadherin', 'molecular_function', 'GO:0008014', ('88', '96'))	('hypermethylated', 'Var', (102, 117))	('metastatic disease', 'CPA', (151, 169))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('RASSF1A', 'Gene', '11186', (27, 34))	('E-cadherin', 'Gene', (86, 96))	('E-cadherin', 'Gene', '999', (86, 96))	('correlate with', 'Reg', (136, 150))
74004	28203054	miR-124, miR-137, and miR-34b/c act as tumor suppressors by inhibiting oncogenes and are downregulated in UM, whereas many miRNAs, like miR-20a, -25b, -146a, and 199a, are overexpressed and may promote metastatic progression, in these examples likely through immunosuppression.	('miR-20a', 'Gene', (136, 143))	('oncogenes', 'MPA', (71, 80))	('inhibiting', 'NegReg', (60, 70))	('promote', 'PosReg', (194, 201))	('miR-20a', 'Gene', '406982', (136, 143))	('miR-34b', 'Gene', (22, 29))	('miR-34b', 'Gene', '407041', (22, 29))	('miR-124', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('metastatic progression', 'CPA', (202, 224))	('downregulated', 'NegReg', (89, 102))	('miR-137', 'Gene', '406928', (9, 16))	('miR-137', 'Gene', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('UM', 'Phenotype', 'HP:0007716', (106, 108))
74008	28203054	125I emits gamma-radiation, which penetrates more deeply into tissues than the beta-emitting 106Ru (<6 mm tumor thickness).	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('125I', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
74010	28203054	Although associated with good local control, brachytherapy is associated with complications, including radiation-induced retinopathy (45%-67%), cataracts (44%), neovascular glaucoma (28.3%), and macular edema (24.5%).	('retinopathy', 'Disease', (121, 132))	('brachytherapy', 'Var', (45, 58))	('retinopathy', 'Phenotype', 'HP:0000488', (121, 132))	('neovascular glaucoma', 'Disease', (161, 181))	('cataracts', 'Phenotype', 'HP:0000518', (144, 153))	('macular edema', 'Disease', 'MESH:D008269', (195, 208))	('glaucoma', 'Phenotype', 'HP:0000501', (173, 181))	('neovascular glaucoma', 'Disease', 'MESH:D015355', (161, 181))	('macular edema', 'Phenotype', 'HP:0040049', (195, 208))	('macular edema', 'Disease', (195, 208))	('cataracts', 'Disease', 'MESH:D002386', (144, 153))	('retinopathy', 'Disease', 'MESH:D012164', (121, 132))	('cataracts', 'Disease', (144, 153))	('edema', 'Phenotype', 'HP:0000969', (203, 208))
74018	28203054	Interestingly, the COMS quality-of-life report found that patients undergoing enucleation were less likely to have anxiety than patients treated with brachytherapy.	('anxiety', 'Disease', 'MESH:D001008', (115, 122))	('enucleation', 'Var', (78, 89))	('anxiety', 'Disease', (115, 122))	('anxiety', 'Phenotype', 'HP:0000739', (115, 122))	('enucleation', 'biological_process', 'GO:0090601', ('78', '89'))	('less', 'NegReg', (95, 99))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (128, 136))
74055	28203054	Crizotinib is an inhibitor of c-Met, ALK, and ROS1, and has been shown to inhibit phosphorylation of c-Met but not ALK or ROS1 in UM.	('ALK', 'Gene', (115, 118))	('ROS1', 'Gene', (122, 126))	('ALK', 'Gene', (37, 40))	('phosphorylation', 'MPA', (82, 97))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('ROS1', 'Gene', '6098', (122, 126))	('c-Met', 'Gene', (101, 106))	('inhibit', 'NegReg', (74, 81))	('Crizotinib', 'Var', (0, 10))	('ALK', 'Gene', '238', (115, 118))	('c-Met', 'Gene', '4233', (101, 106))	('ALK', 'Gene', '238', (37, 40))	('c-Met', 'Gene', (30, 35))	('ROS1', 'Gene', (46, 50))	('UM', 'Phenotype', 'HP:0007716', (130, 132))	('c-Met', 'Gene', '4233', (30, 35))	('phosphorylation', 'biological_process', 'GO:0016310', ('82', '97'))	('ROS1', 'Gene', '6098', (46, 50))
74064	28203054	Some areas of ongoing investigation include therapies targeting the MAPK and/or PI3K pathway, and epigenetic modification with an HDAC inhibitor.	('MAPK and/or', 'Pathway', (68, 79))	('PI3', 'Gene', (80, 83))	('epigenetic modification', 'Var', (98, 121))	('PI3K', 'molecular_function', 'GO:0016303', ('80', '84'))	('MAPK', 'molecular_function', 'GO:0004707', ('68', '72'))	('HDAC', 'Gene', (130, 134))	('HDAC', 'Gene', '9734', (130, 134))	('PI3', 'Gene', '5266', (80, 83))
74084	26988753	More than 80% of UM have mutations in the G proteins GNAQ/GNA11, which activate the protein kinase C (PKC), MAPK and Hippo/YAP signaling pathways.	('PKC', 'Gene', '112476', (102, 105))	('activate', 'PosReg', (71, 79))	('mutations', 'Var', (25, 34))	('protein kinase C', 'Gene', (84, 100))	('GNAQ', 'Gene', (53, 57))	('signaling', 'biological_process', 'GO:0023052', ('127', '136'))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('YAP', 'Gene', '10413', (123, 126))	('protein kinase C', 'Gene', '112476', (84, 100))	('PKC', 'molecular_function', 'GO:0004697', ('102', '105'))	('GNA11', 'Gene', '2767', (58, 63))	('GNA11', 'Gene', (58, 63))	('PKC', 'Gene', (102, 105))	('GNAQ', 'Gene', '2776', (53, 57))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('YAP', 'Gene', (123, 126))	('UM', 'Phenotype', 'HP:0007716', (17, 19))
74086	26988753	However, inhibition of PKC or MEK alone is not sufficient to completely eliminate tumor cells or to reduce tumor burden in animals.	('eliminate', 'NegReg', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('MEK', 'Gene', '5609', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('PKC', 'Gene', (23, 26))	('PKC', 'molecular_function', 'GO:0004697', ('23', '26'))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('reduce', 'NegReg', (100, 106))	('tumor', 'Disease', (82, 87))	('MEK', 'Gene', (30, 33))	('inhibition', 'Var', (9, 19))	('PKC', 'Gene', '112476', (23, 26))
74098	26988753	We selected GDC0941, RAD001 and AZD6244 as tool compounds to inhibit respectively PI3K, mTORC1 and MEK activities.	('MEK', 'Gene', '5609', (99, 102))	('mTORC1', 'Gene', (88, 94))	('RAD', 'biological_process', 'GO:1990116', ('21', '24'))	('AZD6244', 'Var', (32, 39))	('AZD6244', 'Chemical', 'MESH:C517975', (32, 39))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('inhibit', 'NegReg', (61, 68))	('PI3K', 'Pathway', (82, 86))	('GDC0941', 'Chemical', 'MESH:C532162', (12, 19))	('mTORC1', 'cellular_component', 'GO:0031931', ('88', '94'))	('mTORC1', 'Gene', '382056', (88, 94))	('MEK', 'Gene', (99, 102))
74100	26988753	Importantly, the PI3Ki + mTORi combination showed higher scores in most of our panel of cell lines compared to PI3Ki + MEKi, with the exception of the MP41 and MP65 models.	('MEK', 'Gene', (119, 122))	('PI3Ki', 'Var', (17, 22))	('MEK', 'Gene', '5609', (119, 122))	('higher', 'PosReg', (50, 56))	('scores', 'MPA', (57, 63))	('mTOR', 'Gene', '2475', (25, 29))	('mTOR', 'Gene', (25, 29))
74103	26988753	All molecular analyses were done at a drug concentration for which most cell lines had their highest Excess over Bliss value: 2.5muM for both GDC0941 and RAD001 (Supplementary Figure S1).	('Excess', 'MPA', (101, 107))	('GDC0941', 'Var', (142, 149))	('RAD', 'biological_process', 'GO:1990116', ('154', '157'))	('GDC0941', 'Chemical', 'MESH:C532162', (142, 149))	('RAD001', 'Var', (154, 160))
74112	26988753	Importantly, our data further highlight that the PI3Ki + mTORi treatment induces apoptosis on contrary to the PI3Ki + MEKi combination, in at least one synergistic model.	('apoptosis', 'biological_process', 'GO:0006915', ('81', '90'))	('PI3Ki +', 'Var', (49, 56))	('apoptosis', 'CPA', (81, 90))	('MEK', 'Gene', (118, 121))	('induces', 'Reg', (73, 80))	('mTOR', 'Gene', (57, 61))	('mTOR', 'Gene', '2475', (57, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('81', '90'))	('MEK', 'Gene', '5609', (118, 121))
74113	26988753	Having observed a strong synergy and apoptosis between PI3Ki and mTORi, we next asked what would be its mechanism of action and performed molecular analyses in the synergistic model Mel202 (Figure 4).	('mTOR', 'Gene', (65, 69))	('mTOR', 'Gene', '2475', (65, 69))	('PI3Ki', 'Var', (55, 60))	('apoptosis', 'CPA', (37, 46))	('apoptosis', 'biological_process', 'GO:0097194', ('37', '46'))	('apoptosis', 'biological_process', 'GO:0006915', ('37', '46'))	('synergy', 'MPA', (25, 32))
74116	26988753	To verify that the PI3Ki and mTORi were indeed able to block activity of the PI3K/AKT/mTOR pathway, expression levels of phosphorylated AKT (pAKT), phosphorylated S6 (pS6) and phosphorylated 4EBP1 (p4EBP1) were analyzed.	('PI3K', 'molecular_function', 'GO:0016303', ('77', '81'))	('mTOR', 'Gene', '2475', (86, 90))	('mTOR', 'Gene', (86, 90))	('PI3Ki', 'Var', (19, 24))	('AKT', 'Gene', (142, 145))	('mTOR', 'Gene', (29, 33))	('mTOR', 'Gene', '2475', (29, 33))	('4EBP1', 'Gene', '1978', (191, 196))	('4EBP1', 'Gene', (191, 196))	('AKT', 'Gene', '207', (82, 85))	('AKT', 'Gene', '207', (136, 139))	('4EBP1', 'Gene', (199, 204))	('4EBP1', 'Gene', '1978', (199, 204))	('activity', 'MPA', (61, 69))	('AKT', 'Gene', '207', (142, 145))	('AKT', 'Gene', (82, 85))	('AKT', 'Gene', (136, 139))
74117	26988753	As soon as 6h after treatment, PI3Ki reduced pAKT, pS6 and p4EBP1 levels, while mTORi decreased pS6 levels only.	('AKT', 'Gene', '207', (46, 49))	('PI3Ki', 'Var', (31, 36))	('mTOR', 'Gene', (80, 84))	('mTOR', 'Gene', '2475', (80, 84))	('AKT', 'Gene', (46, 49))	('4EBP1', 'Gene', '1978', (60, 65))	('4EBP1', 'Gene', (60, 65))	('reduced', 'NegReg', (37, 44))	('pS6', 'MPA', (51, 54))
74119	26988753	Notably, a complete loss of phosphorylation on AKT, S6 and 4EBP1 was observed only after co-inhibition of PI3K and mTORC1, indicating that inhibition of both proteins was necessary to fully block the PI3K/AKT/mTOR pathway activity as previously shown.	('mTORC1', 'Gene', (115, 121))	('mTOR', 'Gene', (115, 119))	('AKT', 'Gene', (205, 208))	('mTORC1', 'Gene', '382056', (115, 121))	('mTOR', 'Gene', (209, 213))	('loss', 'NegReg', (20, 24))	('PI3K', 'molecular_function', 'GO:0016303', ('200', '204'))	('phosphorylation', 'biological_process', 'GO:0016310', ('28', '43'))	('AKT', 'Gene', (47, 50))	('PI3K', 'Var', (106, 110))	('mTOR', 'Gene', '2475', (115, 119))	('mTORC1', 'cellular_component', 'GO:0031931', ('115', '121'))	('activity', 'MPA', (222, 230))	('mTOR', 'Gene', '2475', (209, 213))	('AKT', 'Gene', '207', (205, 208))	('AKT', 'Gene', '207', (47, 50))	('PI3K', 'molecular_function', 'GO:0016303', ('106', '110'))	('phosphorylation', 'MPA', (28, 43))	('S6 and 4EBP1', 'Gene', '6194', (52, 64))
74120	26988753	The particularly strong synergy observed between PI3Ki and mTORi led us think that additional mechanisms may explain the combination activity and enhance the anti-proliferative effect of PI3K/AKT/mTOR pathway inhibition.	('AKT', 'Gene', (192, 195))	('PI3Ki', 'Var', (49, 54))	('mTOR', 'Gene', '2475', (59, 63))	('AKT', 'Gene', '207', (192, 195))	('PI3K', 'molecular_function', 'GO:0016303', ('187', '191'))	('enhance', 'PosReg', (146, 153))	('anti-proliferative effect', 'CPA', (158, 183))	('mTOR', 'Gene', '2475', (196, 200))	('mTOR', 'Gene', (196, 200))	('mTOR', 'Gene', (59, 63))
74122	26988753	No significant change in pERK levels was observed after treatment with PI3Ki or mTORi.	('ERK', 'Gene', '5594', (26, 29))	('mTOR', 'Gene', (80, 84))	('mTOR', 'Gene', '2475', (80, 84))	('ERK', 'Gene', (26, 29))	('PI3Ki', 'Var', (71, 76))
74123	26988753	While PI3Ki treatment slightly increased pYAP levels from 24h of treatment, no further variation was detected in the combination setting.	('YAP', 'Gene', '10413', (42, 45))	('YAP', 'Gene', (42, 45))	('PI3Ki', 'Var', (6, 11))	('increased', 'PosReg', (31, 40))
74129	26988753	In particular, treatment with inhibitors of mTORC1 such as RAD001 has been shown to induce a feedback loop on AKT through activation of IRS1 and mTORC2 or receptor tyrosine kinases (RTKs).	('mTORC2', 'Gene', '74343', (145, 151))	('mTORC1', 'Gene', '382056', (44, 50))	('RAD001', 'Gene', (59, 65))	('mTORC1', 'cellular_component', 'GO:0031931', ('44', '50'))	('mTORC2', 'cellular_component', 'GO:0031932', ('145', '151'))	('AKT', 'Gene', (110, 113))	('mTORC1', 'Gene', (44, 50))	('inhibitors', 'Var', (30, 40))	('feedback loop', 'MPA', (93, 106))	('activation', 'PosReg', (122, 132))	('induce', 'Reg', (84, 90))	('IRS1', 'Gene', '3667', (136, 140))	('RAD', 'biological_process', 'GO:1990116', ('59', '62'))	('receptor tyrosine kinases', 'MPA', (155, 180))	('mTORC2', 'Gene', (145, 151))	('IRS1', 'Gene', (136, 140))	('AKT', 'Gene', '207', (110, 113))
74131	26988753	Following these findings, combinations of PI3K and mTORC1 inhibitors were proved to enhance the anti-proliferative effect of the single agents.	('combinations', 'Interaction', (26, 38))	('mTORC1', 'cellular_component', 'GO:0031931', ('51', '57'))	('anti-proliferative effect', 'CPA', (96, 121))	('inhibitors', 'Var', (58, 68))	('mTORC1', 'Gene', '382056', (51, 57))	('PI3K', 'Gene', (42, 46))	('mTORC1', 'Gene', (51, 57))	('enhance', 'PosReg', (84, 91))	('PI3K', 'molecular_function', 'GO:0016303', ('42', '46'))
74134	26988753	Western blot analyses were performed after 72h of treatment with PI3Ki, mTORi alone or in combination (Figure 5).	('mTOR', 'Gene', (72, 76))	('PI3Ki', 'Var', (65, 70))	('mTOR', 'Gene', '2475', (72, 76))
74135	26988753	In all cells, abolition of pAKT and reduction of p4EBP1 and pS6 levels were observed after PI3Ki treatment.	('AKT', 'Gene', (28, 31))	('reduction', 'NegReg', (36, 45))	('4EBP1', 'Gene', '1978', (50, 55))	('PI3Ki', 'Var', (91, 96))	('4EBP1', 'Gene', (50, 55))	('AKT', 'Gene', '207', (28, 31))	('pS6 levels', 'MPA', (60, 70))
74139	26988753	In OMM1 cells, the PI3Ki + mTORi combination did not result in an increase of the apoptosis already induced by each single agent (Figure 5B).	('mTOR', 'Gene', (27, 31))	('PI3Ki', 'Var', (19, 24))	('apoptosis', 'biological_process', 'GO:0097194', ('82', '91'))	('apoptosis', 'biological_process', 'GO:0006915', ('82', '91'))	('mTOR', 'Gene', '2475', (27, 31))
74141	26988753	In conclusion, these results show that co-inhibition of PI3K and mTORC1 induced or increased apoptosis in most UM cell lines (70%; 7 out of 10) compared to single treatments.	('increased', 'PosReg', (83, 92))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('co-inhibition', 'Var', (39, 52))	('UM', 'Phenotype', 'HP:0007716', (111, 113))	('PI3K', 'Var', (56, 60))	('mTORC1', 'Gene', '382056', (65, 71))	('mTORC1', 'cellular_component', 'GO:0031931', ('65', '71'))	('apoptosis', 'CPA', (93, 102))	('mTORC1', 'Gene', (65, 71))	('PI3K', 'molecular_function', 'GO:0016303', ('56', '60'))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))
74145	26988753	Interestingly, addition of PI3Ki led to complete reduction of pPRAS40 levels and thus AKT activity (Figure 5A).	('reduction', 'NegReg', (49, 58))	('AKT', 'Gene', (86, 89))	('PRAS40', 'Gene', '84335', (63, 69))	('PRAS40', 'Gene', (63, 69))	('AKT', 'Gene', '207', (86, 89))	('PI3Ki', 'Var', (27, 32))
74150	26988753	Drug tolerability and toxicity assessment were performed as preliminary experiments and doses for each compound were chosen accordingly: the PI3Ki GDC0941 and mTORi RAD001 were administrated per os once daily at 100mg/kg/day and 2mg/kg/day respectively.	('GDC0941', 'Chemical', 'MESH:C532162', (147, 154))	('toxicity', 'Disease', 'MESH:D064420', (22, 30))	('toxicity', 'Disease', (22, 30))	('PI3Ki', 'Var', (141, 146))	('mTOR', 'Gene', (159, 163))	('mTOR', 'Gene', '2475', (159, 163))	('RAD', 'biological_process', 'GO:1990116', ('165', '168'))
74165	26988753	Our data demonstrate that the PI3K inhibitor GDC0941/Pictilisib and the mTORC1 inhibitor RAD001/Everolimus synergistically induce a strong apoptotic effect in vitro in most UM cells and enhance tumor growth inhibition in vivo in two UM PDXs.	('Everolimus', 'Chemical', 'MESH:D000068338', (96, 106))	('induce', 'Reg', (123, 129))	('mTORC1', 'cellular_component', 'GO:0031931', ('72', '78'))	('GDC0941', 'Chemical', 'MESH:C532162', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('UM', 'Phenotype', 'HP:0007716', (173, 175))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('RAD', 'biological_process', 'GO:1990116', ('89', '92'))	('mTORC1', 'Gene', '382056', (72, 78))	('Pictilisib', 'Chemical', 'MESH:C532162', (53, 63))	('apoptotic effect', 'CPA', (139, 155))	('tumor', 'Disease', (194, 199))	('PI3K', 'molecular_function', 'GO:0016303', ('30', '34'))	('enhance', 'PosReg', (186, 193))	('UM', 'Phenotype', 'HP:0007716', (233, 235))	('GDC0941/Pictilisib', 'Var', (45, 63))	('mTORC1', 'Gene', (72, 78))
74167	26988753	Especially, combinations between PI3Ki and MEKi as well as the monotherapy using mTORi are therapeutic approaches that could be worthwhile testing in clinical trials.	('MEK', 'Gene', '5609', (43, 46))	('PI3Ki', 'Var', (33, 38))	('combinations', 'Interaction', (12, 24))	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (81, 85))	('MEK', 'Gene', (43, 46))
74169	26988753	Markedly, our immunoblot analyses have confirmed the reactivation of AKT induced by inhibition of the mTORC1 complex as previously described in other cancers and in the UM cell line 92.1.	('AKT', 'Gene', (69, 72))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('mTORC1', 'Gene', '382056', (102, 108))	('mTORC1', 'cellular_component', 'GO:0031931', ('102', '108'))	('UM', 'Phenotype', 'HP:0007716', (169, 171))	('cancers', 'Disease', (150, 157))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('mTORC1', 'Gene', (102, 108))	('reactivation', 'MPA', (53, 65))	('AKT', 'Gene', '207', (69, 72))	('inhibition', 'Var', (84, 94))
74171	26988753	In our screen, combinations of GDC0941 + RAD001 and BEZ235 + RAD001 resulted in the highest average Excess over Bliss values.	('GDC0941', 'Chemical', 'MESH:C532162', (31, 38))	('Excess', 'PosReg', (100, 106))	('RAD', 'biological_process', 'GO:1990116', ('41', '44'))	('BEZ235', 'Chemical', 'MESH:C531198', (52, 58))	('GDC0941 + RAD001', 'Var', (31, 47))	('BEZ235 + RAD001', 'Var', (52, 67))	('RAD', 'biological_process', 'GO:1990116', ('61', '64'))
74173	26988753	BEZ235 is a dual ATP-competitive PI3K and mTOR targeting p110 alpha/gamma/delta/beta subunits and mTOR; it can therefore inhibit both mTORC1 and mTORC2 complexes.	('inhibit', 'NegReg', (121, 128))	('mTOR', 'Gene', (98, 102))	('p110 alpha', 'Gene', (57, 67))	('mTORC2', 'Gene', '74343', (145, 151))	('mTOR', 'Gene', (42, 46))	('mTOR', 'Gene', (145, 149))	('BEZ235', 'Chemical', 'MESH:C531198', (0, 6))	('mTOR', 'Gene', '2475', (98, 102))	('mTORC2', 'Gene', (145, 151))	('mTOR', 'Gene', '2475', (42, 46))	('p110 alpha', 'Gene', '5290', (57, 67))	('mTORC2', 'cellular_component', 'GO:0031932', ('145', '151'))	('ATP', 'Chemical', 'MESH:D000255', (17, 20))	('mTORC1', 'Gene', (134, 140))	('mTOR', 'Gene', '2475', (145, 149))	('mTOR', 'Gene', (134, 138))	('mTORC1', 'Gene', '382056', (134, 140))	('mTORC1', 'cellular_component', 'GO:0031931', ('134', '140'))	('BEZ235', 'Var', (0, 6))	('mTOR', 'Gene', '2475', (134, 138))	('PI3K', 'molecular_function', 'GO:0016303', ('33', '37'))
74174	26988753	The fact that BEZ235 and GDC0941 had similar synergistic effects when combined with RAD001 suggests that the synergy derives from the outcome of either GDC0941 or BEZ235 on PI3K alpha/delta subunits and that mTORC2 inhibition does not contribute to the synergy.	('PI3K', 'molecular_function', 'GO:0016303', ('173', '177'))	('GDC0941', 'Chemical', 'MESH:C532162', (25, 32))	('mTORC2', 'Gene', '74343', (208, 214))	('PI3K alpha', 'Gene', '5290', (173, 183))	('GDC0941', 'Var', (152, 159))	('BEZ235', 'Var', (163, 169))	('mTORC2', 'cellular_component', 'GO:0031932', ('208', '214'))	('BEZ235', 'Chemical', 'MESH:C531198', (163, 169))	('PI3K alpha', 'Gene', (173, 183))	('GDC0941', 'Chemical', 'MESH:C532162', (152, 159))	('BEZ235', 'Chemical', 'MESH:C531198', (14, 20))	('RAD', 'biological_process', 'GO:1990116', ('84', '87'))	('mTORC2', 'Gene', (208, 214))
74176	26988753	Interestingly, we observed a correlation between the removal of the mTORi-induced AKT reactivation and the induction of apoptosis by PI3Ki + mTORi treatment.	('induction of apoptosis', 'biological_process', 'GO:0006915', ('107', '129'))	('mTOR', 'Gene', '2475', (141, 145))	('PI3Ki +', 'Var', (133, 140))	('mTOR', 'Gene', (141, 145))	('apoptosis', 'CPA', (120, 129))	('mTOR', 'Gene', '2475', (68, 72))	('AKT', 'Gene', '207', (82, 85))	('mTOR', 'Gene', (68, 72))	('AKT', 'Gene', (82, 85))
74178	26988753	Recently, it has been shown that resistance to PI3K inhibition correlates with high levels of pS6 and thus, a high activity of the mTORC1 complex.	('pS6', 'MPA', (94, 97))	('mTORC1', 'Gene', (131, 137))	('activity', 'MPA', (115, 123))	('mTORC1', 'Gene', '382056', (131, 137))	('mTORC1', 'cellular_component', 'GO:0031931', ('131', '137'))	('PI3K', 'Var', (47, 51))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))
74179	26988753	Association of PI3K with mTOR or AKT inhibitors could alleviate this resistance by enhancing PI3K/AKT/mTOR pathway inhibition.	('PI3K', 'Var', (15, 19))	('inhibition', 'NegReg', (115, 125))	('PI3K', 'molecular_function', 'GO:0016303', ('15', '19'))	('AKT', 'Gene', (33, 36))	('enhancing', 'PosReg', (83, 92))	('PI3K', 'molecular_function', 'GO:0016303', ('93', '97'))	('AKT', 'Gene', '207', (33, 36))	('AKT', 'Gene', '207', (98, 101))	('mTOR', 'Gene', '2475', (25, 29))	('mTOR', 'Gene', (102, 106))	('mTOR', 'Gene', '2475', (102, 106))	('Association', 'Interaction', (0, 11))	('AKT', 'Gene', (98, 101))	('mTOR', 'Gene', (25, 29))	('alleviate', 'NegReg', (54, 63))
74184	26988753	Interestingly, the PI3Ki + mTORi combination showed antagonism in the MM28 model.	('PI3Ki', 'Var', (19, 24))	('MM28', 'Gene', '79148', (70, 74))	('mTOR', 'Gene', (27, 31))	('mTOR', 'Gene', '2475', (27, 31))	('MM28', 'Gene', (70, 74))
74186	26988753	In a similar note, we confirmed the effectiveness of PI3K and mTORC1 co-inhibition in vivo in two PDX models.	('mTORC1', 'cellular_component', 'GO:0031931', ('62', '68'))	('mTORC1', 'Gene', '382056', (62, 68))	('mTORC1', 'Gene', (62, 68))	('co-inhibition', 'Var', (69, 82))	('PI3K', 'molecular_function', 'GO:0016303', ('53', '57'))	('PI3K', 'Var', (53, 57))
74190	26988753	In conclusion, our work has identified the association of PI3Ki + mTORi as an effective combination in a broad spectrum of UM models and provide evidence that it could be a valuable therapeutic approach to test in clinical trials for GNAQ/11 mutated UM patients.	('mTOR', 'Gene', (66, 70))	('mTOR', 'Gene', '2475', (66, 70))	('GNAQ', 'Gene', '2776', (234, 238))	('PI3Ki +', 'Var', (58, 65))	('patients', 'Species', '9606', (253, 261))	('UM', 'Phenotype', 'HP:0007716', (250, 252))	('GNAQ', 'Gene', (234, 238))	('UM', 'Phenotype', 'HP:0007716', (123, 125))
74193	26988753	Cells were cultured in RPMI-1640 supplemented with 10% FBS (92.1, Mel202, OMM1, OMM2.5, Mel285, MRC5, RPE1) or 20% FBS (MP38, MP41, MP46, MP65, MM28, MM66), complemented with Penicillin at 100U/ml and Streptomycin 100mug/ml (Life Technologies).	('FBS', 'Disease', (55, 58))	('Penicillin', 'Chemical', 'MESH:D010406', (175, 185))	('MP41', 'Var', (126, 130))	('MM66', 'Var', (150, 154))	('RPMI-1640', 'Chemical', '-', (23, 32))	('MM28', 'Gene', '79148', (144, 148))	('FBS', 'Disease', (115, 118))	('MP38', 'Var', (120, 124))	('Streptomycin', 'Chemical', 'MESH:D013307', (201, 213))	('MRC5', 'CellLine', 'CVCL:0440', (96, 100))	('FBS', 'Disease', 'MESH:D005198', (115, 118))	('FBS', 'Disease', 'MESH:D005198', (55, 58))	('mug', 'molecular_function', 'GO:0043739', ('217', '220'))	('MM28', 'Gene', (144, 148))	('92.1', 'Var', (60, 64))	('MP46', 'Var', (132, 136))	('MP65', 'Var', (138, 142))
74196	26988753	Melanocytic origin and absence of GNAQ/11 mutation in Melan3 were validated by sequencing.	('Melan3', 'Gene', (54, 60))	('mutation', 'Var', (42, 50))	('GNAQ', 'Gene', (34, 38))	('GNAQ', 'Gene', '2776', (34, 38))
74204	26988753	The percentages of living cells (low AnnexinV and low PI), apoptotic cells (high AnnexinV and low PI) and necrotic cells (high AnnexinV and high PI) were evaluated.	('necrotic', 'Disease', (106, 114))	('high AnnexinV', 'Var', (76, 89))	('necrotic', 'Disease', 'MESH:D009336', (106, 114))	('low', 'Var', (33, 36))
74326	24370793	Epigenetic mechanisms mediated by specific microRNAs (miRs) regulate immune responses.	('miR', 'Gene', '220972', (54, 57))	('miR', 'Gene', (54, 57))	('regulate', 'Reg', (60, 68))	('immune responses', 'CPA', (69, 85))	('microRNAs', 'Var', (43, 52))
74332	24370793	Plasma levels of miR-20a, 125b, 146a, 155, 181a, and 223 were higher in the study patients at diagnosis compared to controls.	('miR-20a', 'Gene', (17, 24))	('146a', 'Var', (32, 36))	('155', 'Var', (38, 41))	('patients', 'Species', '9606', (82, 90))	('miR-20a', 'Gene', '406982', (17, 24))	('higher', 'PosReg', (62, 68))	('Plasma levels', 'MPA', (0, 13))
28162	24370793	Plasma levels of miR-20a, 125b, 146a, 155, and 223 increased, and miR-181a decreased when metastasis manifested.	('miR-20a', 'Gene', (17, 24))	('increased', 'PosReg', (51, 60))	('155', 'Var', (38, 41))	('miR', 'Gene', (17, 20))	('146a', 'Var', (32, 36))	('miR-20a', 'Gene', '406982', (17, 24))	('miR', 'Gene', (66, 69))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', '220972', (66, 69))
74349	24370793	Predominant among these are miR-125b, 146a, 155, 181a, 223, and miRs of the 17-92 complex.	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))	('155', 'Var', (44, 47))
74402	24370793	We observed increases in plasma levels of several miRs implicated in immune regulation as metastasis manifested, including miRs-125b, 146a, 155, 20a, and 223.	('plasma levels', 'MPA', (25, 38))	('155', 'Var', (140, 143))	('miR', 'Gene', (50, 53))	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', '220972', (123, 126))	('miR', 'Gene', (123, 126))	('regulation', 'biological_process', 'GO:0065007', ('76', '86'))	('increases', 'PosReg', (12, 21))	('146a', 'Var', (134, 138))
74405	24370793	miR-125b, 155, 181a, and miRs of the 17-92 complex have been shown to play central roles in T-cell development and function.	('155', 'Var', (10, 13))	('T-cell development', 'CPA', (92, 110))	('miR', 'Gene', '220972', (25, 28))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('miR', 'Gene', (25, 28))	('T-cell development', 'biological_process', 'GO:0030217', ('92', '110'))
74427	23313955	Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma Uveal melanoma is the most common primary cancer of the eye and often results in fatal metastasis.	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('SF3B1', 'Gene', (56, 61))	('fatal metastasis', 'CPA', (161, 177))	('uveal melanoma', 'Disease', 'MESH:C536494', (65, 79))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('uveal melanoma', 'Disease', (65, 79))	('melanoma', 'Disease', (86, 94))	('cancer of the eye', 'Phenotype', 'HP:0100012', (122, 139))	('results in', 'Reg', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('SF3B1', 'Gene', '23451', (56, 61))	('splicing', 'biological_process', 'GO:0045292', ('40', '48'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('cancer', 'Disease', (122, 128))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('mutations at', 'Var', (10, 22))
74429	23313955	Thus, uveal melanoma is among a small group of cancers associated with SF3B1 mutation, and these mutations denote a distinct molecular subset of uveal melanomas.	('SF3B1', 'Gene', (71, 76))	('uveal melanoma', 'Phenotype', 'HP:0007716', (145, 159))	('uveal melanoma', 'Disease', 'MESH:C536494', (145, 159))	('uveal melanoma', 'Disease', (6, 20))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('mutation', 'Var', (77, 85))	('associated', 'Reg', (55, 65))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('uveal melanomas', 'Disease', (145, 160))	('uveal melanomas', 'Phenotype', 'HP:0007716', (145, 160))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('melanomas', 'Phenotype', 'HP:0002861', (151, 160))	('uveal melanoma', 'Phenotype', 'HP:0007716', (6, 20))	('uveal melanoma', 'Disease', 'MESH:C536494', (6, 20))	('uveal melanomas', 'Disease', 'MESH:C536494', (145, 160))
74433	23313955	We recently described loss of function mutations in BAP1 (BRCA1-associated protein 1), located at chromosome 3p21.1, in ~40% of uveal melanomas, virtually all of which were the aggressive class 2 tumors.	('BRCA1-associated protein 1', 'Gene', '8314', (58, 84))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('BAP1', 'Gene', '8314', (52, 56))	('BRCA1-associated protein 1', 'Gene', (58, 84))	('uveal melanomas', 'Disease', 'MESH:C536494', (128, 143))	('uveal melanoma', 'Phenotype', 'HP:0007716', (128, 142))	('chromosome', 'cellular_component', 'GO:0005694', ('98', '108'))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('mutations', 'Var', (39, 48))	('BAP1', 'Gene', (52, 56))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanomas', 'Phenotype', 'HP:0002861', (134, 143))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('uveal melanomas', 'Disease', (128, 143))	('uveal melanomas', 'Phenotype', 'HP:0007716', (128, 143))	('loss of function', 'NegReg', (22, 38))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
74435	23313955	Only two genes were found to harbor deleterious somatic variants in at least three tumor samples: guanine nucleotide-binding protein G(q) subunit alpha (GNAQ), which is already known to undergo mutation in uveal melanoma, and splicing factor 3B subunit 1 (SF3B1).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (206, 220))	('uveal melanoma', 'Disease', (206, 220))	('SF3B1', 'Gene', (256, 261))	('tumor', 'Disease', (83, 88))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('106', '124'))	('splicing factor 3B subunit 1', 'Gene', (226, 254))	('splicing', 'biological_process', 'GO:0045292', ('226', '234'))	('variants', 'Var', (56, 64))	('splicing factor 3B subunit 1', 'Gene', '23451', (226, 254))	('GNAQ', 'Gene', '2776', (153, 157))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('uveal melanoma', 'Disease', 'MESH:C536494', (206, 220))	('GNAQ', 'Gene', (153, 157))
74436	23313955	In the case of SF3B1, the mutation in all three tumors led to a p.R625C alteration (hg19 chr2:198267484G>A) which was confirmed by Sanger sequencing.	('p.R625C', 'Var', (64, 71))	('chr2:198267484G>A', 'Var', (89, 106))	('chr2:198267484G>A', 'SUBSTITUTION', 'None', (89, 106))	('led to', 'Reg', (55, 61))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('p.R625C', 'Mutation', 'rs775623976', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
74437	23313955	SF3B1 mutations were recently described in myelodysplastic syndrome (MDS) and chronic lymphocytic leukemia (CLL), clustering within exons 12 to 15.	('MDS', 'Disease', (69, 72))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (43, 67))	('MDS', 'Disease', 'MESH:D009190', (69, 72))	('SF3B1', 'Gene', (0, 5))	('MDS', 'Phenotype', 'HP:0002863', (69, 72))	('chronic lymphocytic leukemia', 'Disease', (78, 106))	('leukemia', 'Phenotype', 'HP:0001909', (98, 106))	('CLL', 'Phenotype', 'HP:0005550', (108, 111))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (43, 67))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (78, 106))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (78, 106))	('mutations', 'Var', (6, 15))	('myelodysplastic syndrome', 'Disease', (43, 67))
74438	23313955	Thus, we re-sequenced these exons in a total of 102 primary uveal melanomas and matching blood DNA samples and identified SF3B1 mutations in 19 (18.6%) tumors (Supplementary Table 1).	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('SF3B1', 'Gene', (122, 127))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('uveal melanomas', 'Disease', (60, 75))	('uveal melanomas', 'Phenotype', 'HP:0007716', (60, 75))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('mutations', 'Var', (128, 137))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('uveal melanomas', 'Disease', 'MESH:C536494', (60, 75))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('tumors', 'Disease', (152, 158))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
74440	23313955	Strikingly, all of the mutations in uveal melanoma occurred atarginine-625, including twelve R625H, five R625C, one R625G and one R625L substitutions (Supplementary Fig.	('R625G', 'Mutation', 'rs775623976', (116, 121))	('R625L', 'Var', (130, 135))	('R625C', 'Mutation', 'rs775623976', (105, 110))	('uveal melanoma', 'Phenotype', 'HP:0007716', (36, 50))	('R625C', 'Var', (105, 110))	('uveal melanoma', 'Disease', 'MESH:C536494', (36, 50))	('mutations', 'Var', (23, 32))	('atarginine', 'Chemical', '-', (60, 70))	('R625L', 'Mutation', 'p.R625L', (130, 135))	('R625G', 'Var', (116, 121))	('uveal melanoma', 'Disease', (36, 50))	('R625H', 'Mutation', 'rs1057519961', (93, 98))	('R625H', 'Var', (93, 98))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
74441	23313955	Interestingly, R625 is one of many sites in SF3B1 that are mutated in MDS, but it is the only site that was identified as deleterious by the SIFT algorithm, which predicts the effect an amino acid substitution has on protein function.	('protein', 'Protein', (217, 224))	('SF3B1', 'Gene', (44, 49))	('MDS', 'Phenotype', 'HP:0002863', (70, 73))	('amino acid substitution', 'Var', (186, 209))	('R625', 'Var', (15, 19))	('MDS', 'Disease', (70, 73))	('MDS', 'Disease', 'MESH:D009190', (70, 73))	('SIFT algorithm', 'Disease', (141, 155))	('protein', 'cellular_component', 'GO:0003675', ('217', '224'))	('SIFT algorithm', 'Disease', 'None', (141, 155))
74442	23313955	In each of the tumors with SF3B1 mutations, wildtype and mutant alleles were present in roughly equal proportions (Supplementary Fig.	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mutations', 'Var', (33, 42))	('SF3B1', 'Gene', (27, 32))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
74443	23313955	An evaluation of DNA copy number in 30 of the uveal melanomas, including seven with SF3B1 mutations, revealed no loss of chromosome 2q33.1 where SF3B1 resides (Supplementary Fig.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('mutations', 'Var', (90, 99))	('uveal melanomas', 'Disease', 'MESH:C536494', (46, 61))	('chromosome', 'cellular_component', 'GO:0005694', ('121', '131'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (46, 60))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('SF3B1', 'Gene', (84, 89))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))	('uveal melanomas', 'Disease', (46, 61))	('uveal melanomas', 'Phenotype', 'HP:0007716', (46, 61))
74445	23313955	Rather, these findings are more consistent with SF3B1 mutations functioning as dominant-negative, gain-of-function or haploinsufficient alteration.	('haploinsufficient', 'Disease', (118, 135))	('gain-of-function', 'PosReg', (98, 114))	('mutations', 'Var', (54, 63))	('SF3B1', 'Gene', (48, 53))	('haploinsufficient', 'Disease', 'MESH:D058495', (118, 135))
74446	23313955	SF3B1 mutations were associated with favorable prognostic features such as younger patient age (P=0.03) and fewer undifferentiated epithelioid cells (P=0.003), and they were inversely associated with poor prognostic features such as the class 2 transcriptomic signature (P = 0.02), loss of chromosome 3 (P = 0.001) and mutation of BAP1 (P=0.002) (Table 1).	('SF3B1', 'Gene', (0, 5))	('BAP1', 'Gene', '8314', (331, 335))	('chromosome', 'cellular_component', 'GO:0005694', ('290', '300'))	('mutation', 'Var', (319, 327))	('BAP1', 'Gene', (331, 335))	('patient', 'Species', '9606', (83, 90))	('mutations', 'Var', (6, 15))
74448	23313955	Five uveal melanoma samples from distant metastases were available for testing, and none harbored SF3B1 mutations, further supporting the notion that these mutations might be associated with less aggressive tumors.	('associated', 'Reg', (175, 185))	('mutations', 'Var', (104, 113))	('aggressive tumors', 'Disease', (196, 213))	('metastases', 'Disease', 'MESH:D009362', (41, 51))	('mutations', 'Var', (156, 165))	('aggressive tumors', 'Disease', 'MESH:D001523', (196, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('uveal melanoma', 'Phenotype', 'HP:0007716', (5, 19))	('uveal melanoma', 'Disease', (5, 19))	('uveal melanoma', 'Disease', 'MESH:C536494', (5, 19))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('metastases', 'Disease', (41, 51))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('SF3B1', 'Gene', (98, 103))
74449	23313955	Taken together, these findings indicate that SF3B1 mutations are associated with better prognosis in uveal melanoma, which is similar to findings in MDS.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('better', 'PosReg', (81, 87))	('mutations', 'Var', (51, 60))	('MDS', 'Disease', (149, 152))	('MDS', 'Disease', 'MESH:D009190', (149, 152))	('uveal melanoma', 'Phenotype', 'HP:0007716', (101, 115))	('uveal melanoma', 'Disease', 'MESH:C536494', (101, 115))	('uveal melanoma', 'Disease', (101, 115))	('SF3B1', 'Gene', (45, 50))	('MDS', 'Phenotype', 'HP:0002863', (149, 152))
74451	23313955	Activating oncogenic mutations in GNAQ or GNA11 occur in about 85% of primary uveal melanomas and are thought to represent early events because they are found in uveal melanomas of all stages, including pre-malignant nevi, and they are not associated with prognosis.	('Activating', 'PosReg', (0, 10))	('uveal melanoma', 'Phenotype', 'HP:0007716', (78, 92))	('GNA11', 'Gene', '2767', (42, 47))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('pre', 'molecular_function', 'GO:0003904', ('203', '206'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (162, 176))	('uveal melanomas', 'Disease', 'MESH:C536494', (162, 177))	('uveal melanomas', 'Disease', (78, 93))	('uveal melanomas', 'Phenotype', 'HP:0007716', (78, 93))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('GNAQ', 'Gene', '2776', (34, 38))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('GNA11', 'Gene', (42, 47))	('GNAQ', 'Gene', (34, 38))	('uveal melanomas', 'Disease', (162, 177))	('uveal melanomas', 'Phenotype', 'HP:0007716', (162, 177))	('nevi', 'Phenotype', 'HP:0003764', (217, 221))	('mutations', 'Var', (21, 30))	('uveal melanomas', 'Disease', 'MESH:C536494', (78, 93))	('melanomas', 'Phenotype', 'HP:0002861', (168, 177))
74453	23313955	In contrast, SF3B1 and BAP1 mutations were almost mutually exclusive, suggesting that they may represent alternative pathways in tumor progression.	('BAP1', 'Gene', (23, 27))	('SF3B1', 'Gene', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('BAP1', 'Gene', '8314', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('mutations', 'Var', (28, 37))
74454	23313955	To explore the effects of mutant SF3B1 on global RNA expression, we analyzed five SF3B1-mutant and six SF3B1-wildtype class 1 tumors for differentially expressed transcripts using the Illumina Bead Array platform.	('SF3B1-mutant', 'Var', (82, 94))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('SF3B1-mutant', 'Gene', (82, 94))	('RNA', 'cellular_component', 'GO:0005562', ('49', '52'))
74455	23313955	This analysis was limited to class 1 tumors because most SF3B1 mutations occurred in this subset.	('mutations', 'Var', (63, 72))	('SF3B1', 'Gene', (57, 62))	('occurred', 'Reg', (73, 81))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
74457	23313955	Three SF3B1-mutant and five SF3B1-wildtype class 1 tumors were analyzed for alterations in splice donor and splice acceptor retention using RNA-Seq (Supplementary Methods).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('SF3B1-mutant', 'Var', (6, 18))	('RNA', 'cellular_component', 'GO:0005562', ('140', '143'))	('donor', 'Species', '9606', (98, 103))	('retention', 'biological_process', 'GO:0051235', ('124', '133'))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))
74460	23313955	Despite the known role of SF3B1 in RNA splicing, there have not been consistent results linking SF3B1 mutations to specific splicing errors in MDS or CLL, and the functional consequences of SF3B1 mutations remain elusive despite intensive investigation.	('MDS', 'Phenotype', 'HP:0002863', (143, 146))	('CLL', 'Phenotype', 'HP:0005550', (150, 153))	('splicing', 'biological_process', 'GO:0045292', ('124', '132'))	('RNA splicing', 'biological_process', 'GO:0008380', ('35', '47'))	('SF3B1', 'Gene', (96, 101))	('mutations', 'Var', (102, 111))	('MDS', 'Disease', (143, 146))	('MDS', 'Disease', 'MESH:D009190', (143, 146))	('RNA', 'cellular_component', 'GO:0005562', ('35', '38'))
74461	23313955	Recent links between SF3B1 and chromatin remodelling complexes raise the question of whether the primary effect of SF3B1 mutations on tumor progression involve RNA processing at all.	('mutations', 'Var', (121, 130))	('RNA', 'cellular_component', 'GO:0005562', ('160', '163'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('chromatin', 'cellular_component', 'GO:0000785', ('31', '40'))	('SF3B1', 'Gene', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('31', '52'))	('RNA processing', 'biological_process', 'GO:0006396', ('160', '174'))	('tumor', 'Disease', (134, 139))
74462	23313955	Further investigations are under way to elucidate the effects of SF3B1 mutations on uveal melanoma progression in order to therapeutically target these effects.	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('uveal melanoma', 'Disease', (84, 98))	('SF3B1', 'Gene', (65, 70))	('effects', 'Reg', (54, 61))	('mutations', 'Var', (71, 80))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
74494	23440248	In case #2, the chronic overlying RPE alterations and localized subretinal fluid could have lead to direct CME or remote CME from vitreoretinal biochemical factors.	('vitreoretinal', 'Disease', (130, 143))	('lead', 'Reg', (92, 96))	('CME', 'biological_process', 'GO:0072583', ('107', '110'))	('vitreoretinal', 'Disease', 'MESH:D012173', (130, 143))	('CME', 'biological_process', 'GO:0072583', ('121', '124'))	('CME', 'Phenotype', 'HP:0011505', (107, 110))	('localized subretinal fluid', 'Phenotype', 'HP:0031529', (54, 80))	('alterations', 'Var', (38, 49))	('CME', 'Phenotype', 'HP:0011505', (121, 124))	('subretinal fluid', 'Phenotype', 'HP:0031526', (64, 80))
74516	21773036	These mutations appear to involve the RAF/MEK/ERK pathway.	('ERK', 'Gene', '5594', (46, 49))	('RAF', 'Gene', '22882', (38, 41))	('RAF', 'Gene', (38, 41))	('ERK', 'Gene', (46, 49))	('involve', 'Reg', (26, 33))	('MEK', 'Gene', (42, 45))	('MEK', 'Gene', '5609', (42, 45))	('ERK', 'molecular_function', 'GO:0004707', ('46', '49'))	('mutations', 'Var', (6, 15))
74518	21773036	An oncogene mutation affecting this pathway is a mutation of the genes GNAQ and GNA11 in codon 29.	('GNA11', 'Gene', '2767', (80, 85))	('GNAQ', 'Gene', (71, 75))	('mutation', 'Var', (49, 57))	('GNAQ', 'Gene', '2776', (71, 75))	('GNA11', 'Gene', (80, 85))
74523	21773036	GNA11 mutations have been noted at 31.9% of uveal melanoma samples.	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('GNA11', 'Gene', (0, 5))	('GNA11', 'Gene', '2767', (0, 5))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('uveal melanoma', 'Disease', (44, 58))	('mutations', 'Var', (6, 15))
74524	21773036	Another molecular event associated with dysfunction of the retinoblastoma protein is the inactivation of the INK4A gene.	('mole', 'Phenotype', 'HP:0003764', (8, 12))	('inactivation', 'Var', (89, 101))	('dysfunction of the retinoblastoma', 'Disease', (40, 73))	('dysfunction of the retinoblastoma', 'Disease', 'MESH:D012175', (40, 73))	('INK4A', 'Gene', '1029', (109, 114))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (59, 73))	('INK4A', 'Gene', (109, 114))
74626	21773036	In a recent study, the coexpression of IGF-1 and c-met in uveal melanoma samples was highly predictive of metastasis.	('coexpression', 'Var', (23, 35))	('c-met', 'Gene', (49, 54))	('predictive of', 'Reg', (92, 105))	('IGF-1', 'Gene', '3479', (39, 44))	('IGF-1', 'Gene', (39, 44))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('uveal melanoma', 'Disease', 'MESH:C536494', (58, 72))	('c-met', 'Gene', '4233', (49, 54))	('metastasis', 'CPA', (106, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('uveal melanoma', 'Disease', (58, 72))
74629	21773036	In short, monosomy 3 (loss of whole of chromosome 3) tends to be found in large uveal tract melanoma in the ciliary body location.	('uveal tract melanoma', 'Disease', (80, 100))	('uveal tract melanoma', 'Phenotype', 'HP:0007716', (80, 100))	('large uveal tract', 'Phenotype', 'HP:0001090', (74, 91))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('monosomy 3', 'Var', (10, 20))	('uveal tract melanoma', 'Disease', 'MESH:C536494', (80, 100))	('found', 'Reg', (65, 70))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))
74631	21773036	In a recent large series of 500 patients with uveal melanoma, those with monosomy 3 had a significantly worse 3-year prognosis in relation to patients with partial monosomy 3 or disomy 3.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('patients', 'Species', '9606', (32, 40))	('uveal melanoma', 'Disease', 'MESH:C536494', (46, 60))	('worse', 'NegReg', (104, 109))	('uveal melanoma', 'Phenotype', 'HP:0007716', (46, 60))	('uveal melanoma', 'Disease', (46, 60))	('monosomy 3', 'Var', (73, 83))	('patients', 'Species', '9606', (142, 150))
74635	21773036	Class II denoted tumours with only one copy of chromosome 3 (monosomy 3) and other deleterious chromosome changes including gain of chromosome 8p and/ or isochromosome 8p.	('Class II denoted tumours', 'Disease', 'MESH:D008312', (0, 24))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('isochromosome', 'Var', (154, 167))	('gain', 'PosReg', (124, 128))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('chromosome', 'cellular_component', 'GO:0005694', ('95', '105'))	('Class II denoted tumours', 'Disease', (0, 24))	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('chromosome', 'cellular_component', 'GO:0005694', ('132', '142'))
74641	21773036	Mutations in genes GNAQ and GNA11 have been associated with the development of uveal melanoma (see Pathogenesis).	('GNAQ', 'Gene', (19, 23))	('Pathogenesis', 'biological_process', 'GO:0009405', ('99', '111'))	('GNA11', 'Gene', (28, 33))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Disease', (79, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('GNAQ', 'Gene', '2776', (19, 23))	('GNA11', 'Gene', '2767', (28, 33))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('associated with', 'Reg', (44, 59))
74642	21773036	GNAQ and GNA11 mutations at codon 209 were encountered in 21.7% and 56.5% of metastatic uveal melanoma samples, respectively.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations at', 'Var', (15, 27))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (88, 102))	('GNAQ', 'Gene', (0, 4))	('encountered', 'Reg', (43, 54))	('uveal melanoma', 'Disease', (88, 102))	('GNA11', 'Gene', '2767', (9, 14))
74643	21773036	In the same series, GNA11 mutations were more common in locally advanced tumours and in tumours of the ciliochoroidal region.	('tumours', 'Disease', (73, 80))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('GNA11', 'Gene', (20, 25))	('common', 'Reg', (46, 52))	('mutations', 'Var', (26, 35))	('tumours', 'Disease', (88, 95))	('GNA11', 'Gene', '2767', (20, 25))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('tumours', 'Disease', 'MESH:D009369', (73, 80))
74644	21773036	In a recent series of 75 patients, GNAQ mutations were not associated with disease-free survival despite an occurrence of 53.3%.	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (25, 33))	('GNAQ', 'Gene', (35, 39))	('GNAQ', 'Gene', '2776', (35, 39))
74674	21773036	AZD6244 is currently evaluated in a Phase II randomized trial with temozolomide in patients stratified with GNAQ/11 status.	('temozolomide', 'Chemical', 'MESH:D000077204', (67, 79))	('patients', 'Species', '9606', (83, 91))	('GNAQ', 'Gene', '2776', (108, 112))	('AZD6244', 'Var', (0, 7))	('GNAQ', 'Gene', (108, 112))	('AZD6244', 'Chemical', 'MESH:C517975', (0, 7))
74753	21406065	The combination of 0.5% Triton X-100, 0.5% Tween-20 and 0.1% Genapol C-100 was shown to increase protein extraction from the sclera.	('0.1', 'Var', (56, 59))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('0.5% Tween-20', 'Var', (38, 51))	('Genapol C-100', 'Chemical', '-', (61, 74))	('Triton X-100', 'Chemical', 'MESH:D017830', (24, 36))	('increase', 'PosReg', (88, 96))	('Tween-20', 'Chemical', 'MESH:D011136', (43, 51))	('Tween-20', 'Var', (43, 51))	('protein extraction', 'MPA', (97, 115))	('Genapol C-100', 'Var', (61, 74))
74795	21406065	This research group has recently performed 2D-PAGE LC-ESI-MS/MS analysis upon human uveal melanoma tissue with monosomy and disomy 3.	('disomy 3', 'Var', (124, 132))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('uveal melanoma', 'Disease', (84, 98))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('monosomy', 'Var', (111, 119))	('human', 'Species', '9606', (78, 83))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
74921	21406065	The authors obtained healthy age-matched donor RPE cells with the wild-type complement factor H (CFH) genotype, and AMD donor RPE cells with the homozygous and heterozygous CFH genotype for culture in isotopically unlabelled and heavy amino acids respectively (13C6-Arg and 13C6, 15N2-Lys).	('donor', 'Species', '9606', (41, 46))	('Lys', 'Chemical', 'MESH:D008239', (285, 288))	('CFH', 'Gene', '3075', (97, 100))	('CFH', 'Gene', '3075', (173, 176))	('AMD', 'Disease', (116, 119))	('13C6-Arg', 'Chemical', '-', (261, 269))	('13C6-Arg', 'Var', (261, 269))	('13C6, 15N2-Lys', 'Var', (274, 288))	('AMD', 'Disease', 'MESH:D006009', (116, 119))	('donor', 'Species', '9606', (120, 125))	('13C6', 'Chemical', '-', (261, 265))	('13C6', 'Chemical', '-', (274, 278))	('CFH', 'Gene', (97, 100))	('CFH', 'Gene', (173, 176))
74978	31671564	Secondary Somatic Mutations in G-Protein-Related Pathways and Mutation Signatures in Uveal Melanoma Background: Uveal melanoma (UM), a rare cancer of the eye, is characterized by initiating mutations in the genes G-protein subunit alpha Q (GNAQ), G-protein subunit alpha 11 (GNA11), cysteinyl leukotriene receptor 2 (CYSLTR2), and phospholipase C beta 4 (PLCB4) and by metastasis-promoting mutations in the genes splicing factor 3B1 (SF3B1), serine and arginine rich splicing factor 2 (SRSF2), and BRCA1-associated protein 1 (BAP1).	('SF3B1', 'Gene', '23451', (434, 439))	('mutations', 'Var', (390, 399))	('BRCA1-associated protein 1', 'Gene', (498, 524))	('BAP1', 'Gene', (526, 530))	('phospholipase C beta 4', 'Gene', (331, 353))	('splicing factor 3B1', 'Gene', '23451', (413, 432))	('PLCB4', 'Gene', (355, 360))	('cancer of the eye', 'Disease', 'MESH:D009369', (140, 157))	('cancer of the eye', 'Disease', (140, 157))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (112, 126))	('serine and arginine rich splicing factor 2', 'Gene', '6427', (442, 484))	('mutations', 'Var', (190, 199))	('metastasis-promoting', 'CPA', (369, 389))	('cysteinyl leukotriene receptor 2', 'Gene', '57105', (283, 315))	('cancer of the eye', 'Phenotype', 'HP:0100012', (140, 157))	('phospholipase C beta 4', 'Gene', '5332', (331, 353))	('Melanoma', 'Disease', 'MESH:D008545', (91, 99))	('GNA11', 'Gene', (275, 280))	('splicing factor 3B1', 'Gene', (413, 432))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (85, 99))	('G-protein subunit alpha Q', 'Gene', (213, 238))	('protein', 'cellular_component', 'GO:0003675', ('515', '522'))	('PLCB4', 'Gene', '5332', (355, 360))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('SRSF2', 'Gene', '6427', (486, 491))	('G-protein subunit alpha 11', 'Gene', '2767', (247, 273))	('SF3B1', 'Gene', (434, 439))	('cysteinyl leukotriene receptor 2', 'Gene', (283, 315))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Melanoma', 'Disease', (91, 99))	('protein', 'cellular_component', 'GO:0003675', ('249', '256'))	('splicing', 'biological_process', 'GO:0045292', ('467', '475'))	('SRSF2', 'Gene', (486, 491))	('BAP1', 'Gene', '8314', (526, 530))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('BRCA1-associated protein 1', 'Gene', '8314', (498, 524))	('G-protein subunit alpha 11', 'Gene', (247, 273))	('G-protein subunit alpha Q', 'Gene', '2776', (213, 238))	('Melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('splicing', 'biological_process', 'GO:0045292', ('413', '421'))
74979	31671564	Here, we tested the hypothesis that additional mutations, though occurring in only a few cases ("secondary drivers"), might influence tumor development.	('mutations', 'Var', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('influence', 'Reg', (124, 133))	('tumor', 'Disease', (134, 139))
74983	31671564	We identified additional mutations in PTK2B.	('mutations', 'Var', (25, 34))	('PTK2B', 'Gene', '2185', (38, 43))	('PTK2B', 'Gene', (38, 43))
74984	31671564	Conclusions: A considerable part of rare mutations that occur in addition to known driver mutations are likely to affect tumor development and progression.	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('progression', 'CPA', (143, 154))	('affect', 'Reg', (114, 120))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
74991	31671564	PLCB4 carries activating mutations in 4% of UM and catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate using calcium as a cofactor.	('mutations', 'Var', (25, 34))	('diacylglycerol', 'MPA', (111, 125))	('phosphatidylinositol 4,5-bisphosphate', 'Chemical', 'MESH:D019269', (131, 168))	('PLCB4', 'Gene', '5332', (0, 5))	('diacylglycerol', 'Chemical', 'MESH:D004075', (111, 125))	('inositol 1,4,5-trisphosphate', 'Chemical', 'MESH:D015544', (78, 106))	('activating', 'PosReg', (14, 24))	('PLCB4', 'Gene', (0, 5))	('calcium', 'Chemical', 'MESH:D002118', (175, 182))	('formation', 'biological_process', 'GO:0009058', ('65', '74'))
74994	31671564	BAP1, SF3B1, and SRSF2 mutations are linked to tumor progression and usually occur in concomitance to the initiating mutations.	('BAP1', 'Gene', (0, 4))	('SF3B1', 'Gene', (6, 11))	('SRSF2', 'Gene', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mutations', 'Var', (23, 32))	('SF3B1', 'Gene', '23451', (6, 11))	('linked', 'Reg', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('BAP1', 'Gene', '8314', (0, 4))	('SRSF2', 'Gene', '6427', (17, 22))	('tumor', 'Disease', (47, 52))
74997	31671564	In UM, C>T transitions prevalently occur in the context of CCN.	('CCN', 'Chemical', '-', (59, 62))	('occur', 'Reg', (35, 40))	('CCN', 'Disease', (59, 62))	('C>T', 'Var', (7, 10))
74998	31671564	Following this interpretation, UM mutations (including the metastasis-associated BAP1 mutation) occur early during UM tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('BAP1', 'Gene', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('mutation', 'Var', (86, 94))	('BAP1', 'Gene', '8314', (81, 85))
75000	31671564	We address here the question of whether other somatic mutations that occur concomitantly with the four putative initiating mutations or during tumor growth show some enrichment for specific pathways, indicative of a co-driver function, or whether they occur completely at random as simple bystander mutations.	('tumor', 'Disease', (143, 148))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mutations', 'Var', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
75001	31671564	This question, that might be relevant for all tumor types, can be easily addressed for UM because an enrichment in a specific pathway can more easily be documented among the few mutations typical of UM.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('mutations', 'Var', (178, 187))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
75002	31671564	We also apply a novel approach to the identification of mutational signatures on UM and CM to dissect possible differences in the profiles of the two tumors.	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('mutational', 'Var', (56, 66))	('tumors', 'Disease', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))
75003	31671564	We furthermore describe additional mutations in the protein tyrosine kinase 2 beta (PTK2B) gene, suggesting its function as a putative co-driver gene.	('PTK2B', 'Gene', '2185', (84, 89))	('protein tyrosine kinase 2 beta', 'Gene', '2185', (52, 82))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))	('protein tyrosine kinase 2 beta', 'Gene', (52, 82))	('PTK2B', 'Gene', (84, 89))	('mutations', 'Var', (35, 44))
75005	31671564	Two unusual cases from the TCGA dataset were included in the analysis: one case with the unusually high number of 222 non-synonymous mutations having R183S mutations in both GNAQ and GNA11, whereas another has a stop gain mutation in GNAQ.	('GNA11', 'Gene', (183, 188))	('R183S', 'Var', (150, 155))	('R183S', 'Mutation', 'p.R183S', (150, 155))	('GNAQ', 'Gene', (174, 178))
75006	31671564	The known UM driver mutations were recurrent (GNAQ n = 67, GNA11 n = 64, CYSLTR2 n = 7, PLCB4 n = 3, BAP1 n = 58, SF3B1 n = 31, EIF1AX n = 18, SRSF2 n = 3).	('SF3B1', 'Gene', '23451', (114, 119))	('EIF1AX', 'Gene', '1964', (128, 134))	('EIF1AX', 'Gene', (128, 134))	('BAP1', 'Gene', '8314', (101, 105))	('PLCB4', 'Gene', (88, 93))	('SRSF2', 'Gene', (143, 148))	('BAP1', 'Gene', (101, 105))	('SF3B1', 'Gene', (114, 119))	('PLCB4', 'Gene', '5332', (88, 93))	('mutations', 'Var', (20, 29))	('SRSF2', 'Gene', '6427', (143, 148))
75007	31671564	Mutations in GNAQ, GNA11, CYSLTR2, and PLCB4 are considered as potential initiating mutations because they are present in most if not all the cells of the tumors, as the mutations lead to constitutive activation of G-protein/calcium signaling and because they are already present in nevi.	('activation', 'PosReg', (201, 211))	('GNA11', 'Gene', (19, 24))	('calcium', 'Chemical', 'MESH:D002118', (225, 232))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('PLCB4', 'Gene', (39, 44))	('mutations', 'Var', (170, 179))	('GNAQ', 'Gene', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('protein', 'cellular_component', 'GO:0003675', ('217', '224'))	('nevi', 'Phenotype', 'HP:0003764', (283, 287))	('G-protein/calcium signaling', 'MPA', (215, 242))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('calcium signaling', 'biological_process', 'GO:0019722', ('225', '242'))	('PLCB4', 'Gene', '5332', (39, 44))	('CYSLTR2', 'Gene', (26, 33))
75008	31671564	In addition to these initiating mutations, there are frequent mutations in BAP1, SF3B1, and SRSF2 that promote metastasis, and in EIF1AX that does not affect progression.	('SRSF2', 'Gene', (92, 97))	('metastasis', 'CPA', (111, 121))	('SF3B1', 'Gene', (81, 86))	('BAP1', 'Gene', (75, 79))	('EIF1AX', 'Gene', '1964', (130, 136))	('EIF1AX', 'Gene', (130, 136))	('SRSF2', 'Gene', '6427', (92, 97))	('SF3B1', 'Gene', '23451', (81, 86))	('promote', 'PosReg', (103, 110))	('BAP1', 'Gene', '8314', (75, 79))	('mutations', 'Var', (62, 71))
75012	31671564	Of the 4117 genes carrying non-synonymous mutations (in the following termed "secondary mutations", in contrast with the known driver mutations), 66 were annotated to belong to the calcium signaling pathway that contains 188 genes of the approximately 22,000 of the whole genome.	('non-synonymous mutations', 'Var', (27, 51))	('calcium', 'Chemical', 'MESH:D002118', (181, 188))	('belong', 'Reg', (167, 173))
75015	31671564	We then analyzed whether the secondary mutations can be considered driver mutations following the 20/20 rule, established by Vogelstein et al., that requires that at least 20% of all mutations encountered in cancers are hotspot mutations to classify the gene as an oncogene and truncating mutations to establish tumor suppressor function.	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('mutations', 'Var', (183, 192))	('tumor suppressor', 'biological_process', 'GO:0051726', ('312', '328'))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('cancers', 'Disease', (208, 215))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('312', '328'))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Disease', (312, 317))
75016	31671564	A total of 28 mutations could be classified as oncogenic and 31 as tumor suppressor mutations, 7 of which possessed both potential activities (Table S1).	('tumor suppressor', 'biological_process', 'GO:0051726', ('67', '83'))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('67', '83'))	('tumor', 'Disease', (67, 72))	('mutations', 'Var', (14, 23))
75017	31671564	Because known oncogenes and tumor suppressor genes are also exposed to bystander mutations, only known hotspot mutations can be taken as evidence for potential oncogenic effects and protein truncating mutations as evidence for tumor suppressor function in the case of biallelic mutation (except for breast cancer associated 1 and 2 (BRCA1, BRACA2) for which gene dosage effects have been shown).	('BRACA2', 'Gene', (340, 346))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', (227, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (299, 312))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('breast cancer', 'Disease', 'MESH:D001943', (299, 312))	('breast cancer', 'Disease', (299, 312))	('protein', 'cellular_component', 'GO:0003675', ('182', '189'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('28', '44'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('227', '243'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('28', '44'))	('biallelic mutation', 'Var', (268, 286))	('BRCA1', 'Gene', '672', (333, 338))	('BRCA1', 'Gene', (333, 338))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('tumor suppressor', 'biological_process', 'GO:0051726', ('227', '243'))
75018	31671564	The oncogene isocitrate dehydrogenase (nicotinamide adenine diphosphate, NADP(+)) 1 (IDH1) carried the mutation R132C that has been observed in 1290 samples registered in the COSMIC database and a total of 9829 samples showed an amino acid substitution in this position.	('NADP', 'Chemical', 'MESH:D009249', (73, 77))	('IDH1', 'Gene', (85, 89))	('nicotinamide adenine diphosphate', 'Chemical', '-', (39, 71))	('R132C', 'Var', (112, 117))	('IDH1', 'Gene', '3417', (85, 89))	('R132C', 'Mutation', 'rs121913499', (112, 117))
75019	31671564	The most frequent mutation affecting this amino acid (395G>A, R132H) was most frequent in tumors of the central nervous system, whereas the mutation that we observed in UM (394C>T, R132C) has been identified in several cancers, among which are skin cancers.	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('cancers', 'Disease', (249, 256))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('R132C', 'Mutation', 'rs121913499', (181, 186))	('skin cancers', 'Phenotype', 'HP:0008069', (244, 256))	('395G>A', 'Var', (54, 60))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (90, 126))	('frequent', 'Reg', (78, 86))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('R132H', 'Mutation', 'rs121913500', (62, 67))	('skin cancers', 'Disease', (244, 256))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('cancers', 'Disease', (219, 226))	('394C>T', 'Mutation', 'rs121913499', (173, 179))	('identified', 'Reg', (197, 207))	('skin cancers', 'Disease', 'MESH:D012878', (244, 256))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors of the central nervous system', 'Disease', 'MESH:D016543', (90, 126))	('tumors of the central nervous system', 'Disease', (90, 126))	('395G>A', 'Mutation', 'rs121913500', (54, 60))
75020	31671564	R132 is the only hotspot observed in IDH1.	('R132', 'Var', (0, 4))	('IDH1', 'Gene', '3417', (37, 41))	('IDH1', 'Gene', (37, 41))
75021	31671564	The F-box and wing domain repeat domain containing 7 gene (FBXW7), which has already been implied in UM carcinogenesis, carried the mutation R479Q in one UM sample.	('FBXW7', 'Gene', '55294', (59, 64))	('R479Q', 'Mutation', 'rs866987936', (141, 146))	('FBXW7', 'Gene', (59, 64))	('R479Q', 'Var', (141, 146))	('carcinogenesis', 'Disease', 'MESH:D063646', (104, 118))	('carcinogenesis', 'Disease', (104, 118))
75022	31671564	R479 was one of three mutation hotspots in this gene that was mutated in 184 COSMIC cases, 136 of which were R479Q, a mutation found in several cancers but not melanoma.	('R479Q', 'Var', (109, 114))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('R479Q', 'Mutation', 'rs866987936', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
75023	31671564	Mutations affecting R183 constituted the major hotspot in the protein phosphatase 2 scaffold subunit A alpha gene (PPP2R1A) found in 120 cases, 38 of which corresponded to the R183Q mutation found in one case of UM.	('R183Q', 'Var', (176, 181))	('R183Q', 'Mutation', 'rs1057519947', (176, 181))	('PPP2R1A', 'Gene', (115, 122))	('Mutations', 'Var', (0, 9))	('PPP2R1A', 'Gene', '5518', (115, 122))	('R183', 'Gene', (20, 24))	('phosphatase', 'molecular_function', 'GO:0016791', ('70', '81'))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
75024	31671564	The SWItch/Sucrose Non-Fermentable (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 gene (SMARCA4) carried an unusual high number of hotspots, with T910 being the amino acid most frequently affected (38 cases).	('chromatin', 'cellular_component', 'GO:0000785', ('102', '111'))	('SMARCA4', 'Gene', (141, 148))	('SMARCA4', 'Gene', '6597', (141, 148))	('Sucrose', 'Chemical', 'MESH:D013395', (11, 18))	('T910', 'Var', (199, 203))
75026	31671564	It was found that 10 of the 31 potential tumor suppressor genes that were mutated in a single or few UM cases carried protein truncating (frameshift or stop gain) mutations compatible with a putative functional consequence.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutations', 'Var', (163, 172))	('tumor', 'Disease', (41, 46))	('tumor suppressor', 'biological_process', 'GO:0051726', ('41', '57'))	('protein truncating', 'MPA', (118, 136))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('41', '57'))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))
75032	31671564	In the dataset of Martin et al., we identified a G941D mutation in the PTK2B gene.	('G941D', 'Var', (49, 54))	('PTK2B', 'Gene', '2185', (71, 76))	('G941D', 'Mutation', 'p.G941D', (49, 54))	('PTK2B', 'Gene', (71, 76))
75033	31671564	there was an R572Q substitution in the tyrosine protein kinase domain of PTK2B in the absence of a GNAQ or GNA11 mutation.	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('R572Q', 'Var', (13, 18))	('PTK2B', 'Gene', '2185', (73, 78))	('R572Q', 'Mutation', 'rs757800100', (13, 18))	('PTK2B', 'Gene', (73, 78))
75034	31671564	We found two mutations in two cases, one, R936Q, in the FAT domain and the other, S542I, in the kinase domain (Figure 3).	('R936Q', 'Var', (42, 47))	('R936Q', 'Mutation', 'rs758581673', (42, 47))	('S542I', 'Mutation', 'p.S542I', (82, 87))	('S542I', 'Var', (82, 87))
75035	31671564	In silico prediction of the effects of these mutations using the algorithms polyphen, Sorting Intolerant From Tolerant (SIFT), Protein Variation Effect Analyzer (PROVEAN), and Functional Analysis through Hidden Markov Models (FATHMM) showed high likelihood of functional consequences predicted for the R572Q mutation by all four algorithms, for the S542I by PROVEAN and FATHMM and for the G941D and R936Q mutations by polyphen and SIFT.	('R572Q', 'Var', (302, 307))	('R936Q', 'Var', (399, 404))	('predicted', 'Reg', (284, 293))	('S542I', 'Mutation', 'p.S542I', (349, 354))	('G941D', 'Var', (389, 394))	('R936Q', 'Mutation', 'rs758581673', (399, 404))	('G941D', 'Mutation', 'p.G941D', (389, 394))	('S542I', 'Var', (349, 354))	('R572Q', 'Mutation', 'rs757800100', (302, 307))
75039	31671564	These two signatures have also been identified by Robertson et al.. Signature 1A is associated with age and signature 3A with BRCA1/2 mutations.	('BRCA1/2', 'Gene', '672;675', (126, 133))	('BRCA1/2', 'Gene', (126, 133))	('mutations', 'Var', (134, 143))
75042	31671564	UM signature 1B showed a prevalence of C>T mutations again in the context of NCG, yet now also including the triplets CCN (Figure 5a).	('C>T mutations', 'Var', (39, 52))	('CCN', 'Chemical', '-', (118, 121))	('NCG', 'Disease', (77, 80))	('NCG', 'Chemical', '-', (77, 80))
75045	31671564	Tumor evolution is a Darwinian selection process where cells that carry somatic mutations are positively selected because they determine a net growth advantage (more proliferation and/or less cell death).	('Tumor', 'Disease', 'MESH:D009369', (0, 5))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (80, 89))	('Tumor', 'Disease', (0, 5))	('cell death', 'CPA', (192, 202))	('cell death', 'biological_process', 'GO:0008219', ('192', '202'))
75048	31671564	In both cases, in addition to few positively selected mutations that drive tumorigenesis, there are many other mutations that do not affect the viability of tumor cells, the so-called passenger mutations.	('tumor', 'Disease', (157, 162))	('mutations', 'Var', (111, 120))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (75, 80))
75049	31671564	Mutations that negatively affect tumor growth are negatively selected.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (33, 38))
75050	31671564	Net tumor growth results from the balance between growth promoting (driver) mutations and growth limiting negative mutations.	('tumor', 'Disease', (4, 9))	('growth', 'MPA', (50, 56))	('mutations', 'Var', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
75051	31671564	Driver and passenger mutations are identified operatively:driver mutations occur early during carcinogenesis and are therefore present in most if not all cells forming a tumor, and they occur in many tumors of the same type.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', (170, 175))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('carcinogenesis', 'Disease', 'MESH:D063646', (94, 108))	('mutations', 'Var', (65, 74))	('carcinogenesis', 'Disease', (94, 108))
75052	31671564	Driver mutations normally are hotspot missense mutations in oncogenes or truncating or frameshift mutations in tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('frameshift mutations', 'Var', (87, 107))	('oncogenes', 'Gene', (60, 69))	('tumor', 'Disease', (111, 116))	('tumor suppressor', 'biological_process', 'GO:0051726', ('111', '127'))	('truncating', 'Var', (73, 83))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('111', '127'))	('Driver', 'Disease', (0, 6))
75053	31671564	Passenger mutations are thought of as neutral bystanders that do not affect the fitness of the tumor cell, are infrequent, and often occur in a subclonal manner.	('mutations', 'Var', (10, 19))	('fitness of the tumor', 'Disease', 'MESH:D012640', (80, 100))	('fitness of the tumor', 'Disease', (80, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))
75054	31671564	Most likely, there is a grey zone of somatic mutations that slightly affect tumor fitness, and the cumulative effect of these mutations is linked to the vastly heterogeneous development paths observed for natural human tumors.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('mutations', 'Var', (45, 54))	('tumor fitness', 'Disease', (76, 89))	('affect', 'Reg', (69, 75))	('tumors', 'Disease', (219, 225))	('human', 'Species', '9606', (213, 218))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor fitness', 'Disease', 'MESH:D012640', (76, 89))
75055	31671564	Since the formulation of the two hits hypothesis by Knudson, one assumes that transformation of a normal cell into a cancer cell needs at least two irreversible steps, usually mutations in oncogenes and tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('mutations', 'Var', (176, 185))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor suppressor', 'biological_process', 'GO:0051726', ('203', '219'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('203', '219'))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('oncogenes', 'Gene', (189, 198))	('cancer', 'Disease', (117, 123))
75060	31671564	UM has a very low mutational burden, and we showed that the KEGG pathway annotations of mutations other than the few known drivers were significantly enriched in the same pathways that involve GNAQ and GNA11, especially the calcium-signaling pathway.	('calcium-signaling', 'biological_process', 'GO:0019722', ('224', '241'))	('mutations', 'Var', (88, 97))	('enriched', 'Reg', (150, 158))	('signaling pathway', 'biological_process', 'GO:0007165', ('232', '249'))	('calcium-signaling pathway', 'Pathway', (224, 249))	('KEGG', 'Gene', (60, 64))	('calcium', 'Chemical', 'MESH:D002118', (224, 231))
75062	31671564	We therefore postulate that a second mutation that further destabilizes the control of the pathway is apparently needed, or at least one that accelerates tumorigenesis.	('mutation', 'Var', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('destabilizes', 'NegReg', (59, 71))	('accelerates', 'PosReg', (142, 153))	('tumor', 'Disease', (154, 159))
75063	31671564	According to this hypothesis, mutations in GNAQ, GNA11, CYSLTR2, and PLCB4 (and the frequently mutated genes SF3B1/SRSF2 and EIF1AX) are not sufficient to yield a UM.	('SF3B1', 'Gene', (109, 114))	('SRSF2', 'Gene', '6427', (115, 120))	('GNAQ', 'Gene', (43, 47))	('PLCB4', 'Gene', '5332', (69, 74))	('SF3B1', 'Gene', '23451', (109, 114))	('CYSLTR2', 'Gene', (56, 63))	('yield', 'Reg', (155, 160))	('mutations', 'Var', (30, 39))	('EIF1AX', 'Gene', '1964', (125, 131))	('PLCB4', 'Gene', (69, 74))	('GNA11', 'Gene', (49, 54))	('EIF1AX', 'Gene', (125, 131))	('SRSF2', 'Gene', (115, 120))
75064	31671564	This is in apparent contrast with data showing that GNAQ and GNA11 mutations, as well as mutations in CYSLTR2, when overexpressed from transgenic overexpression constructs in spontaneously immortalized melan-A cells, induce tumorigenesis in syngeneic mice.	('CYSLTR2', 'Gene', (102, 109))	('mice', 'Species', '10090', (251, 255))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('induce', 'Reg', (217, 223))	('tumor', 'Disease', (224, 229))	('mutations', 'Var', (67, 76))	('mutations', 'Var', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
75065	31671564	In CM, mutation of BRAF is not sufficient for full transformation and it is highly likely that experimental tumorigenesis using xenografts with transgene overexpression in mice does not underlie the same restrictions as natural cancer evolution in humans.	('humans', 'Species', '9606', (248, 254))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('cancer', 'Disease', (228, 234))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('BRAF', 'Gene', (19, 23))	('mice', 'Species', '10090', (172, 176))	('tumor', 'Disease', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('mutation', 'Var', (7, 15))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
75066	31671564	Indeed, despite the fact that two hits are sufficient for transformation in experimental melanomagenesis, human tumors generally show many more mutations that might affect carcinogenesis driven by mutations in strong driver genes.	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('affect', 'Reg', (165, 171))	('human', 'Species', '9606', (106, 111))	('carcinogenesis', 'Disease', (172, 186))	('mutations', 'Var', (197, 206))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('carcinogenesis', 'Disease', 'MESH:D063646', (172, 186))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('mutations', 'Var', (144, 153))	('tumors', 'Disease', (112, 118))
75067	31671564	There are, however, mosaic cases of GNAQ R183 mutations that give rise to port wine stains and Sturge-Weber syndrome, characterized by vascular malformations that, in the latter case, are associated with cerebral symptoms and glaucoma but apparently not with an increased risk of UM.	('GNAQ R183', 'Gene', (36, 45))	('associated', 'Reg', (188, 198))	('mutations', 'Var', (46, 55))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (95, 116))	('glaucoma', 'Disease', 'MESH:D005901', (226, 234))	('give rise', 'Reg', (61, 70))	('vascular malformations', 'Disease', 'MESH:D000014', (135, 157))	('port wine stains', 'Disease', (74, 90))	('port wine stains', 'Phenotype', 'HP:0001052', (74, 90))	('Weber syndrome', 'Phenotype', 'HP:0002277', (102, 116))	('cerebral symptoms', 'Disease', (204, 221))	('glaucoma', 'Phenotype', 'HP:0000501', (226, 234))	('Sturge-Weber syndrome', 'Disease', (95, 116))	('glaucoma', 'Disease', (226, 234))	('vascular malformations', 'Disease', (135, 157))
75069	31671564	In addition to the three mutations in PLCB4, there were three mutations in PLCB1 and five in PLCB2, which was more consistent with our concept of secondary rather than primary driver mutations.	('PLCB2', 'Gene', (93, 98))	('PLCB1', 'Gene', (75, 80))	('PLCB4', 'Gene', '5332', (38, 43))	('PLCB2', 'Gene', '5330', (93, 98))	('PLCB4', 'Gene', (38, 43))	('PLCB1', 'Gene', '23236', (75, 80))	('mutations', 'Var', (62, 71))
75070	31671564	A recent report showed, however, the presence of PLCB4 mutations in melanocytosis that apparently drove the development of UM.	('PLCB4', 'Gene', '5332', (49, 54))	('melanocytosis', 'MPA', (68, 81))	('PLCB4', 'Gene', (49, 54))	('mutations', 'Var', (55, 64))
75073	31671564	The relatively rare mutations in PTK2B and their distribution are consistent with its activity as a secondary driver with tumor suppressor activity, as described for breast cancer, or as an oncogene, as described for hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (217, 241))	('PTK2B', 'Gene', (33, 38))	('hepatocellular carcinoma', 'Disease', (217, 241))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (217, 241))	('tumor suppressor', 'biological_process', 'GO:0051726', ('122', '138'))	('PTK2B', 'Gene', '2185', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('122', '138'))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('breast cancer', 'Disease', (166, 179))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('tumor', 'Disease', (122, 127))	('mutations', 'Var', (20, 29))
75074	31671564	It was unclear whether these mutations contributed to tumor development.	('contributed', 'Reg', (39, 50))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mutations', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
75089	31671564	In conclusion, it is highly likely that secondary mutations affect tumor development and progression.	('progression', 'CPA', (89, 100))	('mutations', 'Var', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('affect', 'Reg', (60, 66))	('tumor', 'Disease', (67, 72))
75177	31588689	Chromatin staining with DAPI revealed that vehicle-treated MP46 nuclei displayed evidence of chromosome arrangement suggesting cells transitioning into mitosis, while most of the cells showed relaxed chromatin (Figure S2B).	('chromatin', 'cellular_component', 'GO:0000785', ('200', '209'))	('mitosis', 'Disease', (152, 159))	('Chromatin', 'cellular_component', 'GO:0000785', ('0', '9'))	('mitosis', 'biological_process', 'GO:0000278', ('152', '159'))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('MP46', 'Var', (59, 63))	('mitosis', 'Disease', 'OMIM:604588', (152, 159))	('chromosome arrangement', 'CPA', (93, 115))
75183	31588689	To assess whether increased cell death due to propranolol would result in increased secretion of cfDNA into the cell culture media supernatant, we quantified cfDNA from cell lines after treatment using ddPCR for mutations in GNAQ (Q209P) and GNA11 (Q209L) in UM cells and BRAF (V600D) in CM cells.	('Q209P', 'Mutation', 'rs121913492', (231, 236))	('GNA11', 'Gene', (242, 247))	('V600D', 'Mutation', 'rs121913377', (278, 283))	('GNA11', 'Gene', '2767', (242, 247))	('UM', 'Phenotype', 'HP:0007716', (259, 261))	('cell death', 'biological_process', 'GO:0008219', ('28', '38'))	('propranolol', 'Chemical', 'MESH:D011433', (46, 57))	('GNAQ', 'Gene', '2776', (225, 229))	('UM', 'Disease', 'MESH:C536494', (259, 261))	('Q209L', 'Mutation', 'rs1057519742', (249, 254))	('BRAF', 'Gene', '673', (272, 276))	('mutations', 'Var', (212, 221))	('secretion', 'biological_process', 'GO:0046903', ('84', '93'))	('CM', 'Disease', 'MESH:C562393', (288, 290))	('CM', 'Phenotype', 'HP:0012056', (288, 290))	('BRAF', 'Gene', (272, 276))	('GNAQ', 'Gene', (225, 229))
75221	31683701	CjM is commonly characterized by mutations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF), neurofibromin 1 (NF1) and telomerase reverse transcriptase (TERT), high expression of mammalian target of rapamycin (mTOR) and heat shock protein 90 (HSP90), frequent phosphatase and tensin homolog (PTEN) loss and upregulation of specific miRNAs.	('PTEN', 'Gene', (300, 304))	('CjM', 'Phenotype', 'HP:0007716', (0, 3))	('mutations', 'Var', (33, 42))	('CjM', 'Disease', (0, 3))	('transcriptase', 'molecular_function', 'GO:0003899', ('146', '159'))	('mTOR', 'Gene', (218, 222))	('mammalian target of rapamycin', 'Gene', '2475', (187, 216))	('neurofibromin 1', 'Gene', '4763', (101, 116))	('loss', 'NegReg', (306, 310))	('PTEN', 'Gene', '5728', (300, 304))	('mTOR', 'Gene', '2475', (218, 222))	('heat shock protein 90', 'Gene', '3320', (228, 249))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('268', '298'))	('phosphatase', 'Enzyme', (268, 279))	('neurofibromin 1', 'Gene', (101, 116))	('high', 'PosReg', (168, 172))	('mammalian target of rapamycin', 'Gene', (187, 216))	('telomerase reverse transcriptase', 'Gene', (127, 159))	('phosphatase', 'molecular_function', 'GO:0016791', ('268', '279'))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (46, 92))	('HSP90', 'Gene', (251, 256))	('telomerase reverse transcriptase', 'Gene', '21752', (127, 159))	('transcriptase', 'molecular_function', 'GO:0003968', ('146', '159'))	('upregulation', 'PosReg', (315, 327))	('transcriptase', 'molecular_function', 'GO:0034062', ('146', '159'))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('protein', 'cellular_component', 'GO:0003675', ('239', '246'))	('CjM', 'Disease', 'MESH:D003229', (0, 3))	('HSP90', 'Gene', '3320', (251, 256))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', (46, 92))	('heat shock protein 90', 'Gene', (228, 249))	('shock', 'Phenotype', 'HP:0031273', (233, 238))
75240	31683701	V-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E mutation characterizes up to 50% of conjunctival melanomas as an early event in tumor development.	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (96, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('V600E', 'Mutation', 'rs113488022', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (96, 118))	('V-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (0, 46))	('conjunctival melanomas', 'Disease', (96, 118))	('V600E', 'Var', (54, 59))	('V-raf murine sarcoma viral oncogene homolog B1', 'Gene', (0, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('BRAF', 'Gene', (48, 52))	('tumor', 'Disease', (140, 145))
75241	31683701	NF1 mutations can be detected in about 30% of conjunctival melanomas.	('conjunctival melanomas', 'Disease', 'MESH:D003229', (46, 68))	('conjunctival melanomas', 'Disease', (46, 68))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('melanomas', 'Phenotype', 'HP:0002861', (59, 68))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (46, 67))
75242	31683701	Neuroblastoma RAS viral [v-ras] oncogene homolog (NRAS) mutations occur in about 20% of the cases and are mutually exclusive with BRAF mutations.	('mutations', 'Var', (56, 65))	('NRAS', 'Gene', (50, 54))	('Neuroblastoma', 'Phenotype', 'HP:0003006', (0, 13))	('NRAS', 'Gene', '4893', (50, 54))	('Neuroblastoma', 'Disease', 'MESH:D009447', (0, 13))	('Neuroblastoma', 'Disease', (0, 13))
75243	31683701	KIT mutations are more seldomly detected (lower than 7%) and are mutually exclusive with NRAS and BRAF mutations.	('NRAS', 'Gene', '4893', (89, 93))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('KIT', 'Gene', '3815', (0, 3))	('NRAS', 'Gene', (89, 93))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))
75247	31683701	In addition, molecular features of this tumor may also include the overexpression of HSP90 and Bcl-2, the inactivation of p16, other minor chromosome abnormalities and miRNAs upregulation.	('inactivation', 'Var', (106, 118))	('HSP90', 'Gene', (85, 90))	('overexpression', 'PosReg', (67, 81))	('p16', 'Gene', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('HSP90', 'Gene', '3320', (85, 90))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (139, 163))	('chromosome abnormalities', 'Disease', 'MESH:D002869', (139, 163))	('chromosome abnormalities', 'Disease', (139, 163))	('upregulation', 'PosReg', (175, 187))	('chromosome', 'cellular_component', 'GO:0005694', ('139', '149'))	('p16', 'Gene', '1029', (122, 125))	('tumor', 'Disease', (40, 45))	('Bcl-2', 'Gene', (95, 100))	('miRNAs', 'CPA', (168, 174))	('Bcl-2', 'Gene', '596', (95, 100))	('Bcl-2', 'molecular_function', 'GO:0015283', ('95', '100'))
75248	31683701	However, none of these genetic or epigenetic alterations seems to have a prognostic role in CjM.	('CjM', 'Disease', (92, 95))	('CjM', 'Phenotype', 'HP:0007716', (92, 95))	('epigenetic alterations', 'Var', (34, 56))	('CjM', 'Disease', 'MESH:D003229', (92, 95))
75257	31683701	The frequency of BRAF, NRAS and KIT mutations in CjM is more similar to cutaneous melanoma than uveal/mucosal melanoma.	('cutaneous melanoma than uveal/mucosal melanoma', 'Disease', (72, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('KIT', 'Gene', '3815', (32, 35))	('CjM', 'Phenotype', 'HP:0007716', (49, 52))	('NRAS', 'Gene', (23, 27))	('KIT', 'Gene', (32, 35))	('cutaneous melanoma than uveal/mucosal melanoma', 'Disease', 'MESH:C536494', (72, 118))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (72, 90))	('mutations', 'Var', (36, 45))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('KIT', 'molecular_function', 'GO:0005020', ('32', '35'))	('CjM', 'Disease', 'MESH:D003229', (49, 52))	('BRAF', 'Gene', (17, 21))	('CjM', 'Disease', (49, 52))	('uveal/mucosal melanoma', 'Phenotype', 'HP:0007716', (96, 118))	('NRAS', 'Gene', '4893', (23, 27))
75258	31683701	BRAF mutations have been detected in up to 50% of primary and metastatic conjunctival melanomas as in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('metastatic conjunctival melanomas', 'Phenotype', 'HP:0007716', (62, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('cutaneous melanoma', 'Disease', (102, 120))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (73, 94))	('BRAF', 'Gene', (0, 4))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (73, 95))	('conjunctival melanomas', 'Disease', (73, 95))	('detected', 'Reg', (25, 33))
75261	31683701	Other uncommon BRAF mutations are detectable in <6% of conjunctival melanomas.	('BRAF', 'Gene', (15, 19))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (55, 76))	('melanomas', 'Phenotype', 'HP:0002861', (68, 77))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (55, 77))	('conjunctival melanomas', 'Disease', (55, 77))	('mutations', 'Var', (20, 29))
75262	31683701	These BRAF mutations found in CjM are similar to cutaneous melanoma, in which V600E represents the most typical mutation (almost 70% of cases), followed by V600K (about 20% of cases) and less frequent mutations, such as V600D and V600R.	('V600D', 'Var', (220, 225))	('CjM', 'Disease', 'MESH:D003229', (30, 33))	('CjM', 'Disease', (30, 33))	('cutaneous melanoma', 'Disease', (49, 67))	('V600D', 'Mutation', 'rs121913377', (220, 225))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (49, 67))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (49, 67))	('V600E', 'Mutation', 'rs113488022', (78, 83))	('V600R', 'Mutation', 'rs121913227', (230, 235))	('V600K', 'Var', (156, 161))	('CjM', 'Phenotype', 'HP:0007716', (30, 33))	('V600E', 'Var', (78, 83))	('V600K', 'Mutation', 'rs121913227', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('V600R', 'Var', (230, 235))
75263	31683701	Acral and mucosal melanomas more rarely harbor BRAF mutations (respectively, 10-15% and 5% of cases), which, on the contrary, have never been reported in uveal melanoma.	('mutations', 'Var', (52, 61))	('mucosal melanomas', 'Disease', 'MESH:D008545', (10, 27))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('BRAF', 'Gene', (47, 51))	('mucosal melanomas', 'Disease', (10, 27))	('uveal melanoma', 'Phenotype', 'HP:0007716', (154, 168))	('uveal melanoma', 'Disease', (154, 168))	('uveal melanoma', 'Disease', 'MESH:C536494', (154, 168))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))
75264	31683701	BRAF mutations are frequently associated with melanocytic nevi (up to 67%) and probably occur in early stages of CjM development from nevi.	('associated', 'Reg', (30, 40))	('CjM', 'Disease', 'MESH:D003229', (113, 116))	('nevi', 'Phenotype', 'HP:0003764', (58, 62))	('CjM', 'Disease', (113, 116))	('melanocytic nevi', 'Disease', (46, 62))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (46, 62))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', (0, 4))	('nevi', 'Phenotype', 'HP:0003764', (134, 138))	('CjM', 'Phenotype', 'HP:0007716', (113, 116))
75265	31683701	Indeed, up to 50% of conjunctival nevi harbor BRAF mutations, which are less common in PAM.	('BRAF', 'Gene', (46, 50))	('mutations', 'Var', (51, 60))	('PAM', 'Gene', '5066', (87, 90))	('conjunctival nevi', 'Disease', (21, 38))	('PAM', 'Gene', (87, 90))	('nevi', 'Phenotype', 'HP:0003764', (34, 38))
75267	31683701	Similarly, in cutaneous melanoma BRAF mutations are more predominant among younger patients.	('cutaneous melanoma BRAF', 'Disease', 'MESH:C562393', (14, 37))	('cutaneous melanoma BRAF', 'Disease', (14, 37))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (14, 32))	('patients', 'Species', '9606', (83, 91))	('mutations', 'Var', (38, 47))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))
75269	31683701	BRAF mutations are not significantly associated with increased recurrence, regional metastases or mortality from CjM, but they are correlated with reduced distant metastases free-survival.	('CjM', 'Disease', 'MESH:D003229', (113, 116))	('metastases', 'Disease', (163, 173))	('CjM', 'Disease', (113, 116))	('metastases', 'Disease', (84, 94))	('mutations', 'Var', (5, 14))	('metastases', 'Disease', 'MESH:D009362', (84, 94))	('metastases', 'Disease', 'MESH:D009362', (163, 173))	('BRAF', 'Gene', (0, 4))	('reduced', 'NegReg', (147, 154))	('CjM', 'Phenotype', 'HP:0007716', (113, 116))
75270	31683701	In vitro, Vemurafenib and Dabrafenib inhibit BRAF-mutant CjM cell lines, similarly to cutaneous melanoma cells.	('CjM', 'Phenotype', 'HP:0007716', (57, 60))	('cutaneous melanoma', 'Disease', (86, 104))	('Vemurafenib', 'Chemical', 'MESH:C551177', (10, 21))	('CjM', 'Disease', 'MESH:D003229', (57, 60))	('CjM', 'Disease', (57, 60))	('inhibit', 'NegReg', (37, 44))	('Dabrafenib', 'Chemical', 'MESH:C561627', (26, 36))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (86, 104))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (86, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('BRAF-mutant', 'Var', (45, 56))
75271	31683701	In vivo, several BRAF mutated conjunctival melanomas were effectively treated with BRAF inhibitors in monotherapy or in combination with MEK inhibitors.	('MEK', 'Gene', (137, 140))	('inhibitors', 'Var', (88, 98))	('MEK', 'Gene', '5609', (137, 140))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (30, 51))	('conjunctival melanomas', 'Disease', (30, 52))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (30, 52))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanomas', 'Phenotype', 'HP:0002861', (43, 52))	('mutated', 'Var', (22, 29))	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', (83, 87))
75273	31683701	In conclusion, we believe that tests for BRAF mutations should be included in the management of CjM and that clinical studies with BRAF and MEK inhibitors are required in this setting.	('MEK', 'Gene', (140, 143))	('mutations', 'Var', (46, 55))	('CjM', 'Phenotype', 'HP:0007716', (96, 99))	('MEK', 'Gene', '5609', (140, 143))	('CjM', 'Disease', 'MESH:D003229', (96, 99))	('CjM', 'Disease', (96, 99))	('BRAF', 'Gene', (41, 45))
75275	31683701	NRAS mutations have been found in almost 20% of conjunctival melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('conjunctival melanomas', 'Disease', (48, 70))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (48, 70))	('NRAS', 'Gene', (0, 4))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (48, 69))	('found', 'Reg', (25, 30))	('NRAS', 'Gene', '4893', (0, 4))
75276	31683701	Regarding the other types of melanoma, NRAS mutations have been found in about 20% of cutaneous melanomas, 5-13% of mucosal melanomas and 10% of acral melanomas.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('acral melanomas', 'Phenotype', 'HP:0012060', (145, 160))	('mucosal melanomas', 'Disease', 'MESH:D008545', (116, 133))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('NRAS', 'Gene', '4893', (39, 43))	('melanomas', 'Phenotype', 'HP:0002861', (151, 160))	('acral melanomas', 'Disease', (145, 160))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (86, 105))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (86, 105))	('mucosal melanomas', 'Disease', (116, 133))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (86, 104))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanomas', 'Phenotype', 'HP:0002861', (124, 133))	('melanoma', 'Disease', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('NRAS', 'Gene', (39, 43))	('cutaneous melanomas', 'Disease', (86, 105))	('found', 'Reg', (64, 69))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('mutations', 'Var', (44, 53))	('acral melanomas', 'Disease', 'MESH:D008545', (145, 160))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))
75278	31683701	It is worth noting that benign cutaneous nevi can harbor NRAS mutations.	('harbor', 'Reg', (50, 56))	('NRAS', 'Gene', (57, 61))	('NRAS', 'Gene', '4893', (57, 61))	('mutations', 'Var', (62, 71))	('nevi', 'Phenotype', 'HP:0003764', (41, 45))
75279	31683701	In CjM, NRAS mutations are mutually exclusive with BRAF mutations, similarly to cutaneous melanoma, in which concomitant BRAF and NRAS mutations occur in less than 0.6% of cases.	('mutations', 'Var', (56, 65))	('CjM', 'Phenotype', 'HP:0007716', (3, 6))	('NRAS', 'Gene', (8, 12))	('cutaneous melanoma', 'Disease', (80, 98))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (80, 98))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (80, 98))	('NRAS', 'Gene', '4893', (8, 12))	('CjM', 'Disease', 'MESH:D003229', (3, 6))	('CjM', 'Disease', (3, 6))	('NRAS', 'Gene', (130, 134))	('mutations', 'Var', (13, 22))	('NRAS', 'Gene', '4893', (130, 134))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
75280	31683701	c-KIT mutations have been detected in almost 2-7% of conjunctival melanomas and they are mutually exclusive with NRAS and BRAF mutations, as in cutaneous melanoma.	('c-KIT', 'Gene', (0, 5))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (144, 162))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (53, 75))	('conjunctival melanomas', 'Disease', (53, 75))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (53, 74))	('c-KIT', 'Gene', '3815', (0, 5))	('NRAS', 'Gene', (113, 117))	('cutaneous melanoma', 'Disease', (144, 162))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('NRAS', 'Gene', '4893', (113, 117))	('KIT', 'molecular_function', 'GO:0005020', ('2', '5'))	('detected', 'Reg', (26, 34))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('mutations', 'Var', (6, 15))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (144, 162))
75281	31683701	Similarly, in cutaneous melanomas, the incidence of KIT mutations ranges from 5.1% for non 'sun-exposed' patients to 9.8% for chronically 'sun-exposed' patients.	('mutations', 'Var', (56, 65))	('patients', 'Species', '9606', (105, 113))	('to 9', 'Species', '1214577', (114, 118))	('KIT', 'Gene', (52, 55))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (14, 33))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (14, 32))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (14, 33))	('KIT', 'Gene', '3815', (52, 55))	('cutaneous melanomas', 'Disease', (14, 33))	('KIT', 'molecular_function', 'GO:0005020', ('52', '55'))	('melanomas', 'Phenotype', 'HP:0002861', (24, 33))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('patients', 'Species', '9606', (152, 160))
75282	31683701	KIT mutations are more frequently detected in mucosal (about 11.5% of cases) and acral (10.8% of cases) melanomas while they have not been reported in uveal melanoma.	('detected', 'Reg', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanomas', 'Phenotype', 'HP:0002861', (104, 113))	('acral', 'Disease', (81, 86))	('uveal melanoma', 'Disease', (151, 165))	('melanomas', 'Disease', 'MESH:D008545', (104, 113))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('mucosal', 'Disease', (46, 53))	('KIT', 'Gene', '3815', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanomas', 'Disease', (104, 113))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))	('uveal melanoma', 'Phenotype', 'HP:0007716', (151, 165))	('uveal melanoma', 'Disease', 'MESH:C536494', (151, 165))
75285	31683701	It is noteworthy that KIT mutations are not directly correlated with KIT gene copy number or CD117, the KIT gene product, expression.	('KIT', 'Gene', (69, 72))	('KIT', 'molecular_function', 'GO:0005020', ('69', '72'))	('KIT', 'Gene', (104, 107))	('KIT', 'Gene', '3815', (22, 25))	('CD117', 'Gene', '3815', (93, 98))	('KIT', 'Gene', (22, 25))	('CD117', 'Gene', (93, 98))	('mutations', 'Var', (26, 35))	('KIT', 'molecular_function', 'GO:0005020', ('22', '25'))	('KIT', 'Gene', '3815', (69, 72))	('KIT', 'molecular_function', 'GO:0005020', ('104', '107'))	('KIT', 'Gene', '3815', (104, 107))
75287	31683701	Consequently, we can assume that not all KIT mutations are drivers in melanomas and are not principal therapeutic targets.	('mutations', 'Var', (45, 54))	('melanomas', 'Disease', 'MESH:D008545', (70, 79))	('KIT', 'Gene', '3815', (41, 44))	('melanomas', 'Disease', (70, 79))	('KIT', 'molecular_function', 'GO:0005020', ('41', '44'))	('KIT', 'Gene', (41, 44))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))
75290	31683701	NF1 mutations, leading to neurofibromin 1 dysfunction, occur in up to 30% of CjM and can be found simultaneously with BRAF and RAS mutations.	('CjM', 'Disease', (77, 80))	('CjM', 'Disease', 'MESH:D003229', (77, 80))	('neurofibromin 1', 'Gene', '4763', (26, 41))	('NF1', 'Gene', (0, 3))	('CjM', 'Phenotype', 'HP:0007716', (77, 80))	('mutations', 'Var', (4, 13))	('neurofibromin 1', 'Gene', (26, 41))
75293	31683701	NF1 mutations are particularly frequent in CjM that have been exposed to UVs, highlighting the possible pathogenetic role of sunlight exposure.	('CjM', 'Disease', 'MESH:D003229', (43, 46))	('CjM', 'Disease', (43, 46))	('frequent', 'Reg', (31, 39))	('NF1', 'Gene', (0, 3))	('sunlight exposure', 'Phenotype', 'HP:0000992', (125, 142))	('mutations', 'Var', (4, 13))	('CjM', 'Phenotype', 'HP:0007716', (43, 46))
75294	31683701	NF1 mutations are associated with sunlight exposure also in cutaneous melanoma and are more frequent in the desmoplastic subtype.	('frequent', 'Reg', (92, 100))	('sunlight exposure', 'Phenotype', 'HP:0000992', (34, 51))	('associated', 'Reg', (18, 28))	('cutaneous melanoma', 'Disease', (60, 78))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (60, 78))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (60, 78))
75295	31683701	It has been demonstrated that cutaneous melanomas with NF1 mutations harbor a higher mutational load.	('cutaneous melanomas', 'Disease', (30, 49))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('mutational load', 'MPA', (85, 100))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('mutations', 'Var', (59, 68))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (30, 49))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (30, 49))	('NF1', 'Gene', (55, 58))
75300	31683701	These kinases activate AKT through the phosphorylation of its residues Threonine-308 (Thr308) and Serine-473 (Ser473).	('phosphorylation', 'MPA', (39, 54))	('Ser', 'Chemical', 'MESH:C530429', (98, 101))	('AKT', 'Gene', '207', (23, 26))	('activate', 'PosReg', (14, 22))	('phosphorylation', 'biological_process', 'GO:0016310', ('39', '54'))	('Ser', 'cellular_component', 'GO:0005790', ('110', '113'))	('kinases', 'Disease', 'MESH:D058495', (6, 13))	('kinases', 'Disease', (6, 13))	('Ser', 'Chemical', 'MESH:C530429', (110, 113))	('AKT', 'Gene', (23, 26))	('Threonine', 'Chemical', 'MESH:C061951', (71, 80))	('Serine-473', 'MPA', (98, 108))	('Serine', 'Chemical', 'MESH:C047902', (98, 104))	('Thr308', 'Var', (86, 92))
75308	31683701	S6 and its phosphorylated form (Ser235/236) are expressed in 100% and 75% of CjM cells, respectively.	('CjM', 'Disease', (77, 80))	('CjM', 'Disease', 'MESH:D003229', (77, 80))	('CjM', 'Phenotype', 'HP:0007716', (77, 80))	('Ser235', 'Chemical', 'MESH:C530429', (32, 38))	('Ser', 'cellular_component', 'GO:0005790', ('32', '35'))	('Ser235/236', 'Var', (32, 42))
75312	31683701	The association between mTOR nonsynonymous mutations and a short survival has been reported in cutaneous and mucosal melanoma patients.	('mucosal melanoma', 'Disease', 'MESH:D008545', (109, 125))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('association', 'Interaction', (4, 15))	('nonsynonymous mutations', 'Var', (29, 52))	('patients', 'Species', '9606', (126, 134))	('mucosal melanoma', 'Disease', (109, 125))	('mTOR', 'Gene', (24, 28))	('mTOR', 'Gene', '2475', (24, 28))
75313	31683701	In mTOR mutant cell lines, high levels of phosphorylated S6, AKT and 4E-BP1 have been found.	('mTOR', 'Gene', '2475', (3, 7))	('found', 'Reg', (86, 91))	('mutant', 'Var', (8, 14))	('AKT and 4E-BP1', 'Gene', '207;1978', (61, 75))	('mTOR', 'Gene', (3, 7))
75337	31683701	TERT promoter mutations, which cause an increased TERT expression, are detectable in 32-41% of conjunctival melanomas and in 8% of PAM cases.	('melanomas', 'Phenotype', 'HP:0002861', (108, 117))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (95, 117))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (95, 116))	('TERT promoter', 'Gene', (0, 13))	('conjunctival melanomas', 'Disease', (95, 117))	('PAM', 'Gene', '5066', (131, 134))	('TERT expression', 'MPA', (50, 65))	('mutations', 'Var', (14, 23))	('PAM', 'Gene', (131, 134))
75338	31683701	Indeed, while several conjunctival melanocytic nevi harbor BRAF mutations, TERT promoter mutations are detectable only in melanomas and premalignant lesions (such as PAM with atypia), playing a role in tumor progression.	('PAM', 'Gene', '5066', (166, 169))	('nevi', 'Phenotype', 'HP:0003764', (47, 51))	('mutations', 'Var', (89, 98))	('melanomas', 'Disease', 'MESH:D008545', (122, 131))	('melanomas', 'Disease', (122, 131))	('tumor', 'Disease', (202, 207))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('PAM', 'Gene', (166, 169))	('premalignant lesions', 'Disease', (136, 156))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('BRAF', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (35, 51))	('several conjunctival melanocytic nevi', 'Phenotype', 'HP:0005603', (14, 51))	('TERT promoter', 'Gene', (75, 88))	('premalignant lesions', 'Disease', 'MESH:D051437', (136, 156))	('conjunctival melanocytic nevi', 'Disease', (22, 51))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))
75339	31683701	TERT promoter mutations detected in CjM consist of C>T or CC>TT nucleotide changes.	('CjM', 'Disease', 'MESH:D003229', (36, 39))	('CjM', 'Disease', (36, 39))	('C>T', 'Var', (51, 54))	('CjM', 'Phenotype', 'HP:0007716', (36, 39))
75341	31683701	The occurrence of TERT promoter mutations in CjM is similar to cutaneous melanoma in which TERT mutations can be found in 64-68% of lesions, both in primary and metastases, and are associated with a shorter survival.	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('shorter', 'NegReg', (199, 206))	('CjM', 'Phenotype', 'HP:0007716', (45, 48))	('cutaneous melanoma', 'Disease', (63, 81))	('survival', 'MPA', (207, 215))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (63, 81))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (63, 81))	('CjM', 'Disease', (45, 48))	('mutations', 'Var', (32, 41))	('CjM', 'Disease', 'MESH:D003229', (45, 48))	('metastases', 'Disease', (161, 171))	('metastases', 'Disease', 'MESH:D009362', (161, 171))
75344	31683701	The detection of TERT promoter mutations reveals future therapeutic options for CjM.	('CjM', 'Disease', (80, 83))	('mutations', 'Var', (31, 40))	('TERT promoter', 'Gene', (17, 30))	('CjM', 'Phenotype', 'HP:0007716', (80, 83))	('CjM', 'Disease', 'MESH:D003229', (80, 83))
75345	31683701	Thus, reverse transcriptase inhibitors, such as azidothymidine (AZT), may become possible candidates for therapies directed against TERT-promoter mutant conjunctival melanomas (Figure 4A).	('conjunctival melanomas', 'Disease', 'MESH:D003229', (153, 175))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanomas', 'Phenotype', 'HP:0002861', (166, 175))	('conjunctival melanomas', 'Disease', (153, 175))	('TERT-promoter mutant', 'Var', (132, 152))	('AZT', 'Chemical', 'MESH:D015215', (64, 67))	('transcriptase', 'molecular_function', 'GO:0034062', ('14', '27'))	('transcriptase', 'molecular_function', 'GO:0003899', ('14', '27'))	('transcriptase', 'molecular_function', 'GO:0003968', ('14', '27'))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (153, 174))	('azidothymidine', 'Chemical', 'MESH:D015215', (48, 62))
75348	31683701	CDKN2A mutations can be found both in cutaneous and in CjM.	('CjM', 'Phenotype', 'HP:0007716', (55, 58))	('CjM', 'Disease', 'MESH:D003229', (55, 58))	('CjM', 'Disease', (55, 58))	('cutaneous', 'Disease', (38, 47))	('CDKN2A', 'Gene', (0, 6))	('found', 'Reg', (24, 29))	('CDKN2A', 'Gene', '1029', (0, 6))	('mutations', 'Var', (7, 16))
75349	31683701	Furthermore, CDKN2A germline mutations are associated with familiar melanomas.	('melanomas', 'Disease', (68, 77))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('CDKN2A', 'Gene', (13, 19))	('germline mutations', 'Var', (20, 38))	('melanomas', 'Phenotype', 'HP:0002861', (68, 77))	('CDKN2A', 'Gene', '1029', (13, 19))	('associated', 'Reg', (43, 53))	('melanomas', 'Disease', 'MESH:D008545', (68, 77))
75350	31683701	Acral melanoma expresses mutations of the CDK4/6 pathway in about 82.7% of the cases.	('mutations', 'Var', (25, 34))	('Acral melanoma', 'Disease', (0, 14))	('CDK', 'molecular_function', 'GO:0004693', ('42', '45'))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('CDK4/6', 'Gene', '1019;1021', (42, 48))	('Acral melanoma', 'Disease', 'MESH:D008545', (0, 14))	('CDK4/6', 'Gene', (42, 48))	('Acral melanoma', 'Phenotype', 'HP:0012060', (0, 14))
75351	31683701	CDKN2A alterations have been also found in mucosal melanoma of the oral cavity, but they are not related to specific clinicopathological subsets.	('mucosal melanoma', 'Disease', 'MESH:D008545', (43, 59))	('found', 'Reg', (34, 39))	('CDKN2A', 'Gene', (0, 6))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('alterations', 'Var', (7, 18))	('CDKN2A', 'Gene', '1029', (0, 6))	('mucosal melanoma', 'Disease', (43, 59))
75352	31683701	To date, CDKN2A mutations have never been reported in uveal melanoma.	('CDKN2A', 'Gene', '1029', (9, 15))	('mutations', 'Var', (16, 25))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('uveal melanoma', 'Disease', 'MESH:C536494', (54, 68))	('uveal melanoma', 'Disease', (54, 68))	('CDKN2A', 'Gene', (9, 15))
75355	31683701	In conclusion, we believe that CDKN2A mutations can be of interest as a potential therapeutic target for CjM and can also be useful for the differential diagnosis between CjM and benign atypical conjunctival nevi.	('CjM', 'Disease', (105, 108))	('CjM', 'Phenotype', 'HP:0007716', (171, 174))	('CjM', 'Disease', 'MESH:D003229', (171, 174))	('CjM', 'Disease', (171, 174))	('nevi', 'Phenotype', 'HP:0003764', (208, 212))	('CjM', 'Phenotype', 'HP:0007716', (105, 108))	('CDKN2A', 'Gene', (31, 37))	('mutations', 'Var', (38, 47))	('CjM', 'Disease', 'MESH:D003229', (105, 108))	('CDKN2A', 'Gene', '1029', (31, 37))
75360	31683701	Furthermore, metastatic CjM conjunctival melanoma shows the amplification of MLH1 (3p22.1) and TIMP2 (17q25.3) and the deletion of MGMT (20q26.3) and ECHS1 (10q26.3).	('TIMP2', 'Gene', (95, 100))	('MGMT', 'molecular_function', 'GO:0003908', ('131', '135'))	('MLH1', 'Gene', '4292', (77, 81))	('ECHS1', 'Gene', '1892', (150, 155))	('MLH1', 'Gene', (77, 81))	('CjM', 'Phenotype', 'HP:0007716', (24, 27))	('deletion', 'Var', (119, 127))	('MGMT', 'Gene', '4255', (131, 135))	('MGMT', 'Gene', (131, 135))	('conjunctival melanoma', 'Disease', (28, 49))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (28, 49))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (28, 49))	('CjM', 'Disease', 'MESH:D003229', (24, 27))	('ECHS1', 'Gene', (150, 155))	('CjM', 'Disease', (24, 27))	('TIMP2', 'Gene', '7077', (95, 100))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))
75363	31683701	Deletion of MGMT, which is involved in genome stability, has been detected in many cancer types, including cutaneous melanoma.	('cutaneous melanoma', 'Disease', (107, 125))	('detected', 'Reg', (66, 74))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (107, 125))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (107, 125))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('MGMT', 'Gene', (12, 16))	('MGMT', 'Gene', '4255', (12, 16))	('MGMT', 'molecular_function', 'GO:0003908', ('12', '16'))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('cancer', 'Disease', (83, 89))	('Deletion', 'Var', (0, 8))
75366	31683701	The deletion of 10q only was correlated with shorter metastases-free survival, lymphatic invasion and major tumor thickness in 59 CjM patients.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('CjM', 'Phenotype', 'HP:0007716', (130, 133))	('deletion of', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('metastases', 'Disease', (53, 63))	('shorter', 'NegReg', (45, 52))	('CjM', 'Disease', 'MESH:D003229', (130, 133))	('CjM', 'Disease', (130, 133))	('patients', 'Species', '9606', (134, 142))	('tumor', 'Disease', (108, 113))	('metastases', 'Disease', 'MESH:D009362', (53, 63))	('lymphatic invasion', 'CPA', (79, 97))
75368	31683701	Moreover, there is a higher frequency of 10q loss in BRAF mutant CjM.	('mutant', 'Var', (58, 64))	('10q', 'CPA', (41, 44))	('CjM', 'Phenotype', 'HP:0007716', (65, 68))	('BRAF', 'Gene', (53, 57))	('CjM', 'Disease', (65, 68))	('CjM', 'Disease', 'MESH:D003229', (65, 68))
75369	31683701	In uveal melanoma, typically BRAF-wild type, the most frequent chromosome abnormalities, such as chromosome 3 monosomy and gain of chromosome 8q, demonstrated a prognostic value for relapse, but they did not predict response to treatment.	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('chromosome abnormalities', 'Disease', (63, 87))	('chromosome', 'cellular_component', 'GO:0005694', ('131', '141'))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('chromosome 3 monosomy', 'Var', (97, 118))	('chromosome abnormalities', 'Disease', 'MESH:D002869', (63, 87))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('chromosome', 'cellular_component', 'GO:0005694', ('97', '107'))	('monosomy', 'Var', (110, 118))	('gain', 'PosReg', (123, 127))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (63, 87))
75375	31683701	We could assume that tumors with BRAF mutation need a further genetic event, which induces AKT pathway, for their development.	('AKT', 'Gene', '207', (91, 94))	('BRAF', 'Gene', (33, 37))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('induces', 'Reg', (83, 90))	('AKT', 'Gene', (91, 94))	('mutation', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
75380	31683701	High EZH2 is correlated with CjM thickness and poor prognosis.	('CjM', 'Disease', 'MESH:D003229', (29, 32))	('CjM', 'Disease', (29, 32))	('High', 'Var', (0, 4))	('CjM', 'Phenotype', 'HP:0007716', (29, 32))	('EZH2', 'Gene', (5, 9))
75382	31683701	In zebrafish xenografts, genetic and pharmacological knockdown of EZH2, through molecules such as GSK503 or UNC1999, reduces tumor growth and colony formation of CjM cells.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('zebrafish', 'Species', '7955', (3, 12))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('knockdown', 'Var', (53, 62))	('EZH2', 'Gene', (66, 70))	('reduces', 'NegReg', (117, 124))	('tumor', 'Disease', (125, 130))	('GSK', 'molecular_function', 'GO:0050321', ('98', '101'))	('CjM', 'Phenotype', 'HP:0007716', (162, 165))	('formation', 'biological_process', 'GO:0009058', ('149', '158'))	('CjM', 'Disease', 'MESH:D003229', (162, 165))	('CjM', 'Disease', (162, 165))
75383	31683701	Inactivation of EZH2 upregulates the oncogene p21/CDKN1A, that controls cellular transition from the G1 to S phase.	('EZH2', 'Gene', (16, 20))	('CDKN1A', 'Gene', (50, 56))	('S phase', 'biological_process', 'GO:0051320', ('107', '114'))	('p21', 'Gene', '1026', (46, 49))	('CDKN1A', 'Gene', '1026', (50, 56))	('p21', 'Gene', (46, 49))	('upregulates', 'PosReg', (21, 32))	('Inactivation', 'Var', (0, 12))
75385	31683701	Inhibition of EZH2 in CjM cells slows the cellular progression to the S-phase and determines cell death through apoptosis and autophagy.	('CjM', 'Disease', 'MESH:D003229', (22, 25))	('CjM', 'Disease', (22, 25))	('apoptosis', 'biological_process', 'GO:0097194', ('112', '121'))	('apoptosis', 'biological_process', 'GO:0006915', ('112', '121'))	('apoptosis', 'CPA', (112, 121))	('EZH2', 'Gene', (14, 18))	('determines', 'Reg', (82, 92))	('autophagy', 'biological_process', 'GO:0016236', ('126', '135'))	('autophagy', 'biological_process', 'GO:0006914', ('126', '135'))	('Inhibition', 'Var', (0, 10))	('slows', 'NegReg', (32, 37))	('cellular progression to the S-phase', 'CPA', (42, 77))	('CjM', 'Phenotype', 'HP:0007716', (22, 25))	('S-phase', 'biological_process', 'GO:0051320', ('70', '77'))	('autophagy', 'CPA', (126, 135))	('cell death', 'biological_process', 'GO:0008219', ('93', '103'))
75387	31683701	In conclusion, EZH2 knockdown in CjM cells leads to an S-phase depletion with G1 arrest and accumulation of cells in the G2/M phase.	('S-phase', 'biological_process', 'GO:0051320', ('55', '62'))	('CjM', 'Disease', 'MESH:D003229', (33, 36))	('CjM', 'Disease', (33, 36))	('M phase', 'biological_process', 'GO:0000279', ('124', '131'))	('CjM', 'Phenotype', 'HP:0007716', (33, 36))	('S-phase depletion', 'MPA', (55, 72))	('arrest', 'Disease', 'MESH:D006323', (81, 87))	('knockdown', 'Var', (20, 29))	('EZH2', 'Gene', (15, 19))	('arrest', 'Disease', (81, 87))	('leads to', 'Reg', (43, 51))	('accumulation', 'PosReg', (92, 104))
75403	31683701	The association between the upregulation of mir-3916 and an increased risk of local recurrence of CjM has been pointed out.	('CjM', 'Phenotype', 'HP:0007716', (98, 101))	('mir-3916', 'Var', (44, 52))	('CjM', 'Disease', 'MESH:D003229', (98, 101))	('CjM', 'Disease', (98, 101))	('local recurrence', 'Disease', (78, 94))	('upregulation', 'PosReg', (28, 40))
75406	31683701	Overall, CjM is commonly characterized by mutations of BRAF, NF1 and TERT, high expression of mTOR and HSP90, frequent PTEN loss and upregulation of specific miRNAs.	('loss', 'NegReg', (124, 128))	('CjM', 'Disease', 'MESH:D003229', (9, 12))	('mTOR', 'Gene', (94, 98))	('mTOR', 'Gene', '2475', (94, 98))	('HSP90', 'Gene', (103, 108))	('BRAF', 'Gene', (55, 59))	('upregulation', 'PosReg', (133, 145))	('NF1', 'Gene', (61, 64))	('PTEN', 'Gene', (119, 123))	('CjM', 'Phenotype', 'HP:0007716', (9, 12))	('HSP90', 'Gene', '3320', (103, 108))	('PTEN', 'Gene', '5728', (119, 123))	('expression', 'MPA', (80, 90))	('mutations', 'Var', (42, 51))	('CjM', 'Disease', (9, 12))
75407	31683701	The anti-BRAF and anti-MEK combination could be a therapeutic option in case of BRAF mutations.	('MEK', 'Gene', '5609', (23, 26))	('mutations', 'Var', (85, 94))	('MEK', 'Gene', (23, 26))	('BRAF', 'Disease', (80, 84))
75413	31683701	The challenge for the future is the identification of the driver molecular alterations to achieve a clinically relevant therapeutic effect in CjM patients.	('CjM', 'Phenotype', 'HP:0007716', (142, 145))	('alterations', 'Var', (75, 86))	('CjM', 'Disease', (142, 145))	('CjM', 'Disease', 'MESH:D003229', (142, 145))	('patients', 'Species', '9606', (146, 154))
75427	31596927	The loss of one copy of chromosome 3 (Chr3) in a primary UM tumor, referred to as monosomy 3 (M3), is associated with metastasis and poor prognosis.	('associated', 'Reg', (102, 112))	('chromosome', 'cellular_component', 'GO:0005694', ('24', '34'))	('metastasis', 'CPA', (118, 128))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('Chr3', 'Gene', (38, 42))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('UM', 'Disease', 'MESH:C536494', (57, 59))	('tumor', 'Disease', (60, 65))	('loss', 'Var', (4, 8))
75437	31596927	Loss-of-function mutations in SDHA, or other alterations in Complex II, result in elevated succinate, which serves as an oncometabolite.	('Loss-of-function', 'NegReg', (0, 16))	('Complex II', 'molecular_function', 'GO:0008177', ('60', '70'))	('succinate', 'MPA', (91, 100))	('elevated', 'PosReg', (82, 90))	('succinate', 'Chemical', 'MESH:D013386', (91, 100))	('SDHA', 'Gene', '6389', (30, 34))	('elevated succinate', 'Phenotype', 'HP:0020149', (82, 100))	('mutations', 'Var', (17, 26))	('SDHA', 'Gene', (30, 34))
75441	31596927	The SDHA antibody was obtained from ABCAM (#ab14715; Abcam, Cambridge, MA, USA).	('SDHA', 'Gene', (4, 8))	('antibody', 'cellular_component', 'GO:0019815', ('9', '17'))	('antibody', 'cellular_component', 'GO:0019814', ('9', '17'))	('antibody', 'molecular_function', 'GO:0003823', ('9', '17'))	('#ab14715;', 'Var', (43, 52))	('antibody', 'cellular_component', 'GO:0042571', ('9', '17'))	('SDHA', 'Gene', '6389', (4, 8))
75509	31596927	Kaplan-Meier analysis of both cohorts showed high SDHA expression to be strongly associated with a poor clinical outcome.	('SDHA', 'Gene', (50, 54))	('high', 'Var', (45, 49))	('associated', 'Reg', (81, 91))	('SDHA', 'Gene', '6389', (50, 54))
75525	31596927	Loss-of-function mutations in the SDH genes (SDHA, SDHB, SDHC and SDHD), which comprise Complex II of the ETC, increase the propensity for cellular transformation and the development of tumors.	('SDH', 'Gene', (66, 69))	('SDH', 'Gene', (51, 54))	('SDH', 'Gene', '6390', (57, 60))	('mutations', 'Var', (17, 26))	('SDHD', 'Gene', (66, 70))	('cellular transformation', 'CPA', (139, 162))	('SDHC', 'Gene', '6391', (57, 61))	('Complex II', 'molecular_function', 'GO:0008177', ('88', '98'))	('SDH', 'Gene', (34, 37))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('SDHB', 'Gene', '6390', (51, 55))	('SDH', 'Gene', '6390', (45, 48))	('SDH', 'Gene', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('SDHA', 'Gene', (45, 49))	('tumors', 'Disease', (186, 192))	('SDHA', 'Gene', '6389', (45, 49))	('SDHB', 'Gene', (51, 55))	('SDHC', 'Gene', (57, 61))	('SDH', 'Gene', '6390', (51, 54))	('Loss-of-function', 'NegReg', (0, 16))	('SDH', 'Gene', '6390', (66, 69))	('SDH', 'Gene', (45, 48))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('SDHD', 'Gene', '6392', (66, 70))	('SDH', 'Gene', '6390', (34, 37))
75526	31596927	Mutations in SDH genes and in fumarate hydratase (FH), which catalyzes in the TCA cycle, result in the accumulation of succinate or fumarate, respectively.	('fumarate', 'MPA', (132, 140))	('TCA', 'Chemical', 'MESH:D014233', (78, 81))	('SDH', 'Gene', (13, 16))	('fumarate', 'Chemical', 'MESH:D005650', (30, 38))	('fumarate hydratase', 'Gene', '2271', (30, 48))	('fumarate hydratase', 'Gene', (30, 48))	('TCA cycle', 'biological_process', 'GO:0006099', ('78', '87'))	('succinate', 'MPA', (119, 128))	('succinate', 'Chemical', 'MESH:D013386', (119, 128))	('Mutations', 'Var', (0, 9))	('accumulation', 'PosReg', (103, 115))	('FH', 'Gene', '2271', (50, 52))	('SDH', 'Gene', '6390', (13, 16))	('fumarate', 'Chemical', 'MESH:D005650', (132, 140))
75527	31596927	The build-up of these dicarboxylic acids is akin to the accumulation of D-2-hydroxyglutarate (D-2HG) that results from mutations in isocitrate dehydrogenase-1 or -2 (IDH-1 or -2).	('dicarboxylic acids', 'Chemical', 'MESH:D003998', (22, 40))	('D-2HG', 'Chemical', 'MESH:C019417', (94, 99))	('IDH-1', 'Gene', '3417', (166, 171))	('IDH-1', 'Gene', (166, 171))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (72, 92))	('mutations', 'Var', (119, 128))	('isocitrate', 'Chemical', 'MESH:D007523', (132, 142))
75528	31596927	The term "oncometabolites" has emerged to describe the products of these (SDH, FH, IDH1, and IDH2) metabolic genes when they are mutated.	('SDH', 'Gene', (74, 77))	('IDH1', 'Gene', '3417', (83, 87))	('IDH2', 'Gene', '3418', (93, 97))	('FH', 'Gene', '2271', (79, 81))	('mutated', 'Var', (129, 136))	('SDH', 'Gene', '6390', (74, 77))	('IDH1', 'Gene', (83, 87))	('IDH2', 'Gene', (93, 97))
75534	31596927	Notably, M3 UM tumors are highly associated with chromosome 8q copy number gain, and CYC1 localizes to Chr 8q24.3.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('CYC1', 'Gene', (85, 89))	('gain', 'PosReg', (75, 79))	('chromosome', 'cellular_component', 'GO:0005694', ('49', '59'))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('associated', 'Reg', (33, 43))	('UM', 'Disease', 'MESH:C536494', (12, 14))	('CYC1', 'Gene', '1537', (85, 89))	('chromosome', 'Var', (49, 59))	('tumors', 'Disease', (15, 21))
75542	31596927	Modulating particular members of specific ETC complexes appears to be a feasible approach, although cancer cell versus normal cell metabolic dependencies and context-dependent differences among ETC pathway members need to be taken into account.	('Modulating', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))
75544	31227497	Integrative copy number analysis of uveal melanoma reveals novel candidate genes involved in tumorigenesis including a tumor suppressor role for PHF10/ BAF45a Uveal melanoma (UM) is a primary malignancy of the eye with oncogenic mutations in GNAQ, GNA11, or CYSLTR2, and additional mutations in BAP1 (usually associated with LOH of Chr 3), SF3B1 or EIF1AX.	('UM', 'Disease', 'MESH:C536494', (175, 177))	('associated', 'Reg', (309, 319))	('Uveal melanoma', 'Disease', (159, 173))	('uveal melanoma', 'Disease', 'MESH:C536494', (36, 50))	('EIF1AX', 'Gene', (349, 355))	('uveal melanoma', 'Disease', (36, 50))	('GNA11', 'Gene', '2767', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Uveal melanoma', 'Disease', 'MESH:C536494', (159, 173))	('BAP1', 'Gene', (295, 299))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('CYSLTR2', 'Gene', '57105', (258, 265))	('mutations', 'Var', (229, 238))	('PHF10', 'Gene', '55274', (145, 150))	('uveal melanoma', 'Phenotype', 'HP:0007716', (36, 50))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('119', '135'))	('EIF1AX', 'Gene', '1964', (349, 355))	('GNAQ', 'Gene', '2776', (242, 246))	('malignancy of the eye', 'Phenotype', 'HP:0100012', (192, 213))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (159, 173))	('SF3B1', 'Gene', (340, 345))	('GNAQ', 'Gene', (242, 246))	('tumor suppressor', 'biological_process', 'GO:0051726', ('119', '135'))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('CYSLTR2', 'Gene', (258, 265))	('GNA11', 'Gene', (248, 253))	('PHF10', 'Gene', (145, 150))	('mutations', 'Var', (282, 291))	('malignancy of the eye', 'Disease', (192, 213))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', (93, 98))	('SF3B1', 'Gene', '23451', (340, 345))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('BAP1', 'Gene', '8314', (295, 299))	('malignancy of the eye', 'Disease', 'MESH:D000853', (192, 213))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
75553	31227497	UMs display characteristic genomic signatures including recurrent chromosomal aberrations, gene mutations and gene expression profiles (GEP), some of which are predictive of metastatic risk.	('UM', 'Disease', 'MESH:C536494', (0, 2))	('chromosomal aberrations', 'Var', (66, 89))	('recurrent chromosomal aberrations', 'Phenotype', 'HP:0040012', (56, 89))	('gene expression', 'biological_process', 'GO:0010467', ('110', '125'))	('gene expression profiles', 'MPA', (110, 134))	('predictive', 'Reg', (160, 170))
75554	31227497	Mutations in GNAQ, GNA11, CYSLTR2 and PLCB4 that constitutively activate Galphaq signaling are seen in almost all tumors in a mutually exclusive manner.	('GNA11', 'Gene', (19, 24))	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('PLCB4', 'Gene', '5332', (38, 43))	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (19, 24))	('Galphaq', 'Gene', (73, 80))	('Mutations', 'Var', (0, 9))	('CYSLTR2', 'Gene', '57105', (26, 33))	('tumors', 'Disease', (114, 120))	('Galphaq', 'Gene', '2776;2767', (73, 80))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('PLCB4', 'Gene', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('CYSLTR2', 'Gene', (26, 33))	('GNAQ', 'Gene', '2776', (13, 17))	('activate', 'PosReg', (64, 72))
75555	31227497	Inactivating mutations in BAP1 at Chromosome 3p21 are found in tumors with loss of heterozygosity for Chr 3 (LOH3) and a GEP predictive of metastatic risk (class 2 tumors), and mutations in SF3B1 or EIF1AX are found in tumors with disomy 3 and a GEP associated with an intermediate and low likelihood of metastasis respectively (class 1 tumors).	('mutations', 'Var', (177, 186))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('EIF1AX', 'Gene', '1964', (199, 205))	('BAP1', 'Gene', (26, 30))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('disomy 3', 'Disease', (231, 239))	('Inactivating mutations', 'Var', (0, 22))	('tumors', 'Phenotype', 'HP:0002664', (337, 343))	('tumors', 'Disease', (63, 69))	('p21', 'Gene', (46, 49))	('loss', 'NegReg', (75, 79))	('SF3B1', 'Gene', (190, 195))	('p21', 'Gene', '644914', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('tumors', 'Disease', (219, 225))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', (337, 343))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('Chromosome', 'cellular_component', 'GO:0005694', ('34', '44'))	('SF3B1', 'Gene', '23451', (190, 195))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (337, 343))	('EIF1AX', 'Gene', (199, 205))	('BAP1', 'Gene', '8314', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
75561	31227497	We describe candidate genes on chromosomes 1p, 8q and 6q and provide evidence for a tumor suppressor role for PHF10 mapping to Chr 6q27.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('mapping', 'Var', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor suppressor', 'biological_process', 'GO:0051726', ('84', '100'))	('PHF10', 'Gene', '55274', (110, 115))	('tumor', 'Disease', (84, 89))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('84', '100'))	('PHF10', 'Gene', (110, 115))
75565	31227497	Established cell lines derived from primary uveal melanomas (Mel202, 92-1 and Mel290 (described in Supplementary Table 1) were subjected to PHF10 knockdown with siRNA (Santa-cruz, sc-95343) or a siRNA control that consisted of scrambled sequence/non-silencing siRNA (Santa-cruz, sc-37007) (SiCtrl).	('knockdown', 'Var', (146, 155))	('uveal melanomas', 'Phenotype', 'HP:0007716', (44, 59))	('PHF10', 'Gene', '55274', (140, 145))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('PHF10', 'Gene', (140, 145))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('uveal melanoma', 'Disease', (44, 58))
75566	31227497	This was performed with standard approaches by querying a set of proteins identified following PHF10 knockdown in cell lines.	('PHF10', 'Gene', '55274', (95, 100))	('PHF10', 'Gene', (95, 100))	('knockdown', 'Var', (101, 110))
75568	31227497	Three replicates per cell line were used for PHF10 knock downs.	('PHF10', 'Gene', (45, 50))	('knock downs', 'Var', (51, 62))	('PHF10', 'Gene', '55274', (45, 50))
75571	31227497	Ploidy estimates revealed an average of 2.4n in 103 tumors from the WU and CC cohorts (Supplementary Figure 2C) due to a minority of tumors being tetraploid which was more common in class 2 versus class 1 tumors consistent with BAP1 deficiency being the prognostic predictor for patients with polyploid tumors.	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumors', 'Disease', (303, 309))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('common', 'Reg', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('BAP1', 'Gene', '8314', (228, 232))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', 'MESH:D009369', (303, 309))	('tumors', 'Disease', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Disease', (133, 139))	('deficiency', 'Var', (233, 243))	('tumors', 'Disease', (52, 58))	('patients', 'Species', '9606', (279, 287))	('polyploid tumors', 'Disease', (293, 309))	('BAP1', 'Gene', (228, 232))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('polyploid tumors', 'Disease', 'MESH:D011123', (293, 309))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))
75573	31227497	The monosomy 3 tumors from both groups C & D showed gain of the entire 8q arm in nearly all samples as reported previously in TCGA cohort.	('tumors', 'Disease', (15, 21))	('showed', 'PosReg', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('monosomy', 'Var', (4, 12))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
75574	31227497	Patients with monosomy 3, 8p loss, and 8q gain had lower overall survival (OS) as described elsewhere.	('8p loss', 'Var', (26, 33))	('8q gain', 'Var', (39, 46))	('monosomy 3', 'Var', (14, 24))	('lower', 'NegReg', (51, 56))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (57, 73))
75576	31227497	Loss of transcripts from the cytoband in which BAP1 is located (3p21) was significant in both TCGA and CC cohorts and BAP1 showed strong correlation between copy number change and expression in both cohorts (Corr.	('p21', 'Gene', (65, 68))	('copy number change', 'Var', (157, 175))	('p21', 'Gene', '644914', (65, 68))	('transcripts', 'MPA', (8, 19))	('expression', 'MPA', (180, 190))	('Loss', 'NegReg', (0, 4))	('BAP1', 'Gene', '8314', (118, 122))	('BAP1', 'Gene', '8314', (47, 51))	('BAP1', 'Gene', (118, 122))	('BAP1', 'Gene', (47, 51))
75580	31227497	To search for genes driving regions of gain or loss in UM we looked for regions of common focal amplification or deletion and then asked which of the genes whose expression was correlated with CNA, resided in these regions.	('deletion', 'Var', (113, 121))	('UM', 'Disease', 'MESH:C536494', (55, 57))	('loss', 'NegReg', (47, 51))
75581	31227497	We then asked if any of the genes in regions with focal alterations also harbored deleterious mutations in any UMs since this could be further evidence that the correct gene had been identified.	('UM', 'Disease', 'MESH:C536494', (111, 113))	('mutations', 'Var', (94, 103))	('harbored', 'Reg', (73, 81))	('alterations', 'Var', (56, 67))
75585	31227497	Six of these regions mapped to chromosomal regions with copy number change already implicated in UM: Chr 3, Chr 1p36, Chr 6q, and Chr 8q.	('copy', 'Var', (56, 60))	('UM', 'Disease', 'MESH:C536494', (97, 99))	('Chr', 'Var', (118, 121))
75586	31227497	An overlapping region of deletion at Chr 1p36.11 (chr1:26387424-26491354) deleted a segment of TRIM63, the entire PDIK1L gene and a segment of FAM110D.	('chr1:26387424-26491354', 'STRUCTURAL_ABNORMALITY', 'None', (50, 72))	('PDIK1L', 'Gene', '149420', (114, 120))	('deletion', 'Var', (25, 33))	('FAM110D', 'Gene', (143, 150))	('TRIM63', 'Gene', (95, 101))	('deleted', 'NegReg', (74, 81))	('TRIM63', 'Gene', '84676', (95, 101))	('FAM110D', 'Gene', '79927', (143, 150))	('PDIK1L', 'Gene', (114, 120))
75587	31227497	Of these genes, TRIM63 showed the strongest correlation between deletion and expression in TCGA cohort (correlation coeff.	('expression', 'MPA', (77, 87))	('deletion', 'Var', (64, 72))	('TRIM63', 'Gene', (16, 22))	('TRIM63', 'Gene', '84676', (16, 22))	('correlation', 'Interaction', (44, 55))
75592	31227497	At Chr 6q27 we identified an overlapping deletion of a region harboring WDR27, c6orf120, PHF10 and TCTE3 (chr6:169652569-170152990).	('PHF10', 'Gene', '55274', (89, 94))	('TCTE3', 'Gene', '6991', (99, 104))	('c6orf120', 'Gene', '387263', (79, 87))	('PHF10', 'Gene', (89, 94))	('WDR27', 'Gene', (72, 77))	('chr6:169652569-170152990', 'STRUCTURAL_ABNORMALITY', 'None', (106, 130))	('deletion', 'Var', (41, 49))	('TCTE3', 'Gene', (99, 104))	('WDR27', 'Gene', '253769', (72, 77))	('c6orf120', 'Gene', (79, 87))
75593	31227497	In the case of WDR27 and PHF10, expression was correlated with deletion in both TCGA and CC cohorts (Supplementary Table 3).	('TCGA', 'Gene', (80, 84))	('PHF10', 'Gene', '55274', (25, 30))	('correlated', 'Reg', (47, 57))	('WDR27', 'Gene', (15, 20))	('deletion', 'Var', (63, 71))	('PHF10', 'Gene', (25, 30))	('expression', 'MPA', (32, 42))	('WDR27', 'Gene', '253769', (15, 20))
75594	31227497	Further inspection of this region revealed that UM patient MM016 (WU cohort) harbored a homozygous deletion of this region that resulted from a complex deletion of one Chr 6q homolog and a second deletion that spanned 54kb at Chr6:170099399-170152990.	('deletion', 'Var', (152, 160))	('resulted from', 'Reg', (128, 141))	('UM', 'Disease', 'MESH:C536494', (48, 50))	('patient', 'Species', '9606', (51, 58))
75596	31227497	MM016 did not harbor a mutation in any previously identified prognostic driver (BAP1, EIF1AX, SF3B1) although it did harbor an oncogenic mutation in GNAQ and had upregulated PRAME (not shown) consistent with its metastatic features and its classification as a class IB tumor.	('PRAME', 'Gene', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('SF3B1', 'Gene', '23451', (94, 99))	('GNAQ', 'Gene', (149, 153))	('mutation', 'Var', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('BAP1', 'Gene', '8314', (80, 84))	('tumor', 'Disease', (269, 274))	('GNAQ', 'Gene', '2776', (149, 153))	('EIF1AX', 'Gene', '1964', (86, 92))	('upregulated', 'PosReg', (162, 173))	('BAP1', 'Gene', (80, 84))	('SF3B1', 'Gene', (94, 99))	('PRAME', 'Gene', '23532', (174, 179))	('EIF1AX', 'Gene', (86, 92))
75599	31227497	The overlapping regions of homozygous deletion in both of these tumors disrupted PHF10, C6orf120 and WDR27 (Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('PHF10', 'Gene', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('disrupted', 'NegReg', (71, 80))	('WDR27', 'Gene', (101, 106))	('deletion', 'Var', (38, 46))	('PHF10', 'Gene', '55274', (81, 86))	('WDR27', 'Gene', '253769', (101, 106))	('C6orf120', 'Gene', '387263', (88, 96))	('C6orf120', 'Gene', (88, 96))
75600	31227497	Analysis of exome data also revealed a somatic frameshift mutation in PHF10 in a class 2 tumor MM133 (c.678delT, p.F226fs) (Supplementary Table 5) that was validated with Sanger sequencing (Supplementary Figure 5).	('c.678delT', 'Mutation', 'c.678delT', (102, 111))	('c.678delT', 'Var', (102, 111))	('PHF10', 'Gene', '55274', (70, 75))	('frameshift', 'Var', (47, 57))	('p.F226fs', 'Var', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('PHF10', 'Gene', (70, 75))	('p.F226fs', 'Mutation', 'p.F226fsX', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
75604	31227497	We also identified a deleterious missense mutation (p.D453E, rs761295711) in PHF10 in TCGA tumor A8KM (Supplementary Table 5).	('PHF10', 'Gene', (77, 82))	('p.D453E', 'Var', (52, 59))	('rs761295711', 'Var', (61, 72))	('p.D453E', 'Mutation', 'rs761295711', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('PHF10', 'Gene', '55274', (77, 82))	('rs761295711', 'Mutation', 'rs761295711', (61, 72))
75606	31227497	The second region mapped to Chr 8q24.3 (chr8:144992452-144993067) but only harboured a segment of PLEC whose expression was only weakly correlated with copy number gain in TCGA (Supplementary Table 3).	('copy number gain', 'Var', (152, 168))	('expression', 'MPA', (109, 119))	('PLEC', 'Gene', '5339', (98, 102))	('chr8:144992452-144993067', 'STRUCTURAL_ABNORMALITY', 'None', (40, 64))	('PLEC', 'Gene', (98, 102))	('TCGA', 'Gene', (172, 176))
75607	31227497	There were 1984 transcripts with a significant correlation with hypo- or hyper methylated CpG sites.	('hypo-', 'Var', (64, 69))	('methyl', 'Chemical', 'MESH:C031105', (79, 85))	('hyper', 'Disease', 'MESH:D053306', (73, 78))	('CpG', 'Disease', (90, 93))	('hyper', 'Disease', (73, 78))
75609	31227497	Genes in deleted regions where there was also hypermethylation included EXTL1, RUNX3 and WASF2.	('RUNX3', 'Gene', '864', (79, 84))	('WASF2', 'Gene', (89, 94))	('RUNX3', 'Gene', (79, 84))	('EXTL1', 'Gene', '2134', (72, 77))	('EXTL1', 'Gene', (72, 77))	('WASF2', 'Gene', '10163', (89, 94))	('hypermethylation', 'Var', (46, 62))
75612	31227497	Upregulation of ENPP2, mapping to 8q24.3 and previously reported (as a gene expressed at high levels in class 2 tumors appears to have been driven exclusively by methylation (Supplementary Table 6).	('Upregulation', 'PosReg', (0, 12))	('ENPP2', 'Gene', (16, 21))	('methyl', 'Chemical', 'MESH:C031105', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('methylation', 'biological_process', 'GO:0032259', ('162', '173'))	('ENPP2', 'Gene', '5168', (16, 21))	('methylation', 'Var', (162, 173))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
75614	31227497	Its expression was correlated with both copy number and methylation in TCGA, however it was not significant in the CC cohort (Supplementary Table 3, Supplementary Table 6).	('methyl', 'Chemical', 'MESH:C031105', (56, 62))	('copy number', 'Var', (40, 51))	('expression', 'MPA', (4, 14))	('TCGA', 'Gene', (71, 75))	('correlated', 'Reg', (19, 29))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('methylation', 'Var', (56, 67))
75617	31227497	On Chr 1p36, two tumors harbored mutations in MTOR, and at Chr 1p34.1, one TCGA tumor (AA9A) harboured a mutation in KDM4A (exon13:c.C1942T:p.P648S) with loss of the wild type allele.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('MTOR', 'Gene', (46, 50))	('c.C1942T:p.P648S', 'Var', (131, 147))	('tumor', 'Disease', (17, 22))	('c.C1942T:p.P648S', 'SUBSTITUTION', 'None', (131, 147))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('AA9A', 'Mutation', 'c.9AA>A', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', (80, 85))	('MTOR', 'Gene', '2475', (46, 50))	('KDM4A', 'Gene', '9682', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('KDM4A', 'Gene', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
75618	31227497	Exon 32 of PTK2 mapping to Chr 8q24.3 was somatically mutated in MM127 (c.G3091T:p.A1031S), a class 2 tumor with an activating mutation in GNAQ, no identified mutation in BAP1, SF3B1 or EIF1AX and no apparent copy number change (Supplementary Table 2B).	('BAP1', 'Gene', (171, 175))	('activating', 'PosReg', (116, 126))	('EIF1AX', 'Gene', (186, 192))	('EIF1AX', 'Gene', '1964', (186, 192))	('tumor', 'Disease', (102, 107))	('PTK2', 'Gene', '5747', (11, 15))	('c.G3091T:p.A1031S', 'SUBSTITUTION', 'None', (72, 89))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('SF3B1', 'Gene', '23451', (177, 182))	('GNAQ', 'Gene', '2776', (139, 143))	('SF3B1', 'Gene', (177, 182))	('BAP1', 'Gene', '8314', (171, 175))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('PTK2', 'Gene', (11, 15))	('c.G3091T:p.A1031S', 'Var', (72, 89))	('GNAQ', 'Gene', (139, 143))
75619	31227497	CYC1 on Chr 8q24.3 was mutated in TCGA tumor A883 (p.D209delinsDYY).	('p.D209delinsDYY', 'Var', (51, 66))	('CYC1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('p.D209delinsDYY', 'Mutation', 'p.209delinsD,DYY', (51, 66))	('CYC1', 'Gene', '1537', (0, 4))	('tumor', 'Disease', (39, 44))	('TCGA', 'Gene', (34, 38))
75620	31227497	On Chr 16q23.1, MON1 homolog B (MON1B) showed the highest correlation with expression in TCGA cohort (Supplementary Table 3) and was mutated in TCGA tumor A87Y (c.C1390T:p.R464X).	('c.C1390T:p.R464X', 'Var', (161, 177))	('correlation', 'Interaction', (58, 69))	('MON1 homolog B', 'Gene', (16, 30))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('A87Y', 'Mutation', 'p.A87Y', (155, 159))	('MON1B', 'Gene', '22879', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('MON1B', 'Gene', (32, 37))	('MON1 homolog B', 'Gene', '22879', (16, 30))	('tumor', 'Disease', (149, 154))	('TCGA', 'Gene', (144, 148))	('c.C1390T:p.R464X', 'SUBSTITUTION', 'None', (161, 177))	('expression', 'MPA', (75, 85))
75621	31227497	A87Y was a primary tumor from an enucleated specimen that had metastasized.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('A87Y', 'Var', (0, 4))	('A87Y', 'Mutation', 'p.A87Y', (0, 4))
75622	31227497	The same mutation has been described in an aggressive cutaneous neuroendocrine tumor (Merkel cell) where Merkel cell polyomavirus has been implicated in a subset of tumors.	('mutation', 'Var', (9, 17))	('described', 'Reg', (27, 36))	('aggressive cutaneous neuroendocrine tumor', 'Disease', (43, 84))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('aggressive cutaneous neuroendocrine tumor', 'Disease', 'MESH:D018358', (43, 84))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('Merkel cell polyomavirus', 'Species', '493803', (105, 129))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (64, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
75624	31227497	Hence, it is possible that the UM in A87Y represents a metastasis from a different primary tumor or that in some instances loss of function of MON1B is associated with the development of UM.	('UM', 'Disease', 'MESH:C536494', (31, 33))	('loss of function', 'NegReg', (123, 139))	('MON1B', 'Gene', '22879', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('UM', 'Disease', 'MESH:C536494', (187, 189))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('A87Y', 'Mutation', 'p.A87Y', (37, 41))	('A87Y', 'Var', (37, 41))	('associated', 'Reg', (152, 162))	('tumor', 'Disease', (91, 96))	('MON1B', 'Gene', (143, 148))
75627	31227497	In the case of Chr 3, downregulation of BAP1 expression (HR=11.39, CI:3.36-38.54, P value=9.0e-05) was more significant than monosomy 3 (HR=14.5, CI:3.37-62.44, P value =3.3e-04) or the presence of BAP1 mutations (HR=6.58, CI:2.4-17.89, p-value=2.18e-04) (Figure 3A).	('downregulation', 'NegReg', (22, 36))	('BAP1', 'Gene', (40, 44))	('mutations', 'Var', (203, 212))	('BAP1', 'Gene', '8314', (198, 202))	('HR=14', 'Disease', 'MESH:C535488', (137, 142))	('BAP1', 'Gene', '8314', (40, 44))	('expression', 'MPA', (45, 55))	('BAP1', 'Gene', (198, 202))	('HR=14', 'Disease', (137, 142))
75629	31227497	MTUS1 on chromosome 8p was more strongly correlated with metastasis than Chr 8p gain (Supplementary Table 3, Table 2, Figure 3B), We used small interfering RNAs (siRNAs) to investigate the consequences of PHF10 knockdown in the established UM cell lines Mel202, 92.1 and Mel290 (Figure 3).	('PHF10', 'Gene', (205, 210))	('UM', 'Disease', 'MESH:C536494', (240, 242))	('chromosome', 'cellular_component', 'GO:0005694', ('9', '19'))	('MTUS1', 'Gene', '57509', (0, 5))	('metastasis', 'CPA', (57, 67))	('knockdown', 'Var', (211, 220))	('PHF10', 'Gene', '55274', (205, 210))	('correlated', 'Reg', (41, 51))	('MTUS1', 'Gene', (0, 5))
75631	31227497	Although there can be considerable differences in cell lines versus primary tumors, a number of transcripts altered by PHF10 knockdown exhibited the same trend in the PHF10 mutant tumors MM16 and A8KB (TCGA) (Supplementary Table 13).	('PHF10', 'Gene', (167, 172))	('transcripts', 'MPA', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('MM16', 'CellLine', 'CVCL:L789', (187, 191))	('PHF10', 'Gene', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('mutant', 'Var', (173, 179))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('PHF10', 'Gene', '55274', (167, 172))	('PHF10', 'Gene', '55274', (119, 124))
75633	31227497	Many of these were transcription factors/chromatin remodelers and western analysis of the PHF10 knockdowns with antibodies to some of the encoded peptides confirmed altered protein expression of JAZF1, PCGF5 and SMAD2 in the cell lines (Figure 4C).	('SMAD2', 'Gene', (212, 217))	('altered', 'Reg', (165, 172))	('chromatin', 'cellular_component', 'GO:0000785', ('41', '50'))	('JAZF1', 'Gene', (195, 200))	('protein', 'cellular_component', 'GO:0003675', ('173', '180'))	('PHF10', 'Gene', '55274', (90, 95))	('protein expression', 'MPA', (173, 191))	('transcription', 'biological_process', 'GO:0006351', ('19', '32'))	('PCGF5', 'Gene', '84333', (202, 207))	('knockdowns', 'Var', (96, 106))	('PHF10', 'Gene', (90, 95))	('JAZF1', 'Gene', '221895', (195, 200))	('PCGF5', 'Gene', (202, 207))
75634	31227497	We also asked if there were transcripts that were also upregulated or downregulated in correlation with PHF10 changes in the larger cohort of UMs.	('changes', 'Var', (110, 117))	('PHF10', 'Gene', '55274', (104, 109))	('UM', 'Disease', 'MESH:C536494', (142, 144))	('downregulated', 'NegReg', (70, 83))	('upregulated', 'PosReg', (55, 66))	('PHF10', 'Gene', (104, 109))
75639	31227497	No change in invasion was observed with PHF10 knockdown (Supplementary Figure 8).	('PHF10', 'Gene', '55274', (40, 45))	('PHF10', 'Gene', (40, 45))	('knockdown', 'Var', (46, 55))
75641	31227497	Knockdown of PHF10 resulted in significantly reduced migration in a chemotaxis assay in Mel202 and 92.1, but not in Mel290 (Figure 4G).	('PHF10', 'Gene', '55274', (13, 18))	('reduced', 'NegReg', (45, 52))	('Knockdown', 'Var', (0, 9))	('migration in a chemotaxis assay', 'CPA', (53, 84))	('PHF10', 'Gene', (13, 18))	('chemotaxis', 'biological_process', 'GO:0006935', ('68', '78'))
75643	31227497	Clustering of broad copy number changes revealed four tumor groups characterized primarily by alterations involving 1p loss, 1p gain, monosomy 3, 6p gain, 6q loss, 8p gain/loss 8q gain and 16q loss.	('monosomy', 'Disease', (134, 142))	('16q loss', 'Var', (189, 197))	('gain', 'PosReg', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('8p gain/loss 8q gain', 'Var', (164, 184))	('gain', 'PosReg', (149, 153))	('loss', 'NegReg', (119, 123))	('tumor', 'Disease', (54, 59))
75644	31227497	Although, there were no significant differences in the ploidy estimates between the class 1 and class 2 subgroups, class 2 tumors tended to exhibit higher ploidy states (tetraploidy), consistent with BAP1 deficiency being the prognostic predictor for patients with polyploid tumors  Integration of copy number with expression showed enrichment of genes in cytogenetic bands 1p36, 6p21, 8q22, 8q24 and 3p21 (the locale of BAP1), consistent with comparative genomic hybridization analysis.	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('BAP1', 'Gene', (421, 425))	('patients', 'Species', '9606', (251, 259))	('polyploid tumors', 'Disease', (265, 281))	('BAP1', 'Gene', (200, 204))	('deficiency', 'Var', (205, 215))	('polyploid tumors', 'Disease', 'MESH:D011123', (265, 281))	('p21', 'Gene', (381, 384))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('p21', 'Gene', '644914', (381, 384))	('tetraploidy', 'Disease', 'MESH:D057891', (170, 181))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('p21', 'Gene', (402, 405))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('p21', 'Gene', '644914', (402, 405))	('tumors', 'Disease', (275, 281))	('tetraploidy', 'Disease', (170, 181))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Disease', (123, 129))	('BAP1', 'Gene', '8314', (421, 425))	('BAP1', 'Gene', '8314', (200, 204))	('tumors', 'Disease', 'MESH:D009369', (275, 281))
75646	31227497	From our studies of clonality in UM, BAP1 mutations were found to be occasionally present in the subclones suggesting loss of one Chr 3 homolog precedes mutations in BAP1.	('mutations', 'Var', (153, 162))	('BAP1', 'Gene', '8314', (166, 170))	('loss', 'NegReg', (118, 122))	('BAP1', 'Gene', '8314', (37, 41))	('UM', 'Disease', 'MESH:C536494', (33, 35))	('BAP1', 'Gene', (166, 170))	('BAP1', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))
75647	31227497	Thus, it is unlikely that haplo-insufficienty of BAP1 is driving LOH3.	('BAP1', 'Gene', (49, 53))	('BAP1', 'Gene', '8314', (49, 53))	('haplo-insufficienty', 'Var', (26, 45))
75648	31227497	However, we identified an overlapping region of deletion at 3p11.1-q11.1 that contains PROS1 and ARL13B as well as pericentromeric sequence.	('PROS1', 'Gene', (87, 92))	('ARL13B', 'Gene', (97, 103))	('PROS1', 'Gene', '5627', (87, 92))	('deletion', 'Var', (48, 56))	('ARL13B', 'Gene', '200894', (97, 103))
75651	31227497	We also showed that in addition to Chr 8q24.3 gain, upregulation of PTK2 and PTP4A3 could be a consequence of de-methylation.	('upregulation', 'PosReg', (52, 64))	('methylation', 'biological_process', 'GO:0032259', ('113', '124'))	('PTP4A3', 'Gene', '11156', (77, 83))	('de-methylation', 'Var', (110, 124))	('PTK2', 'Gene', (68, 72))	('PTP4A3', 'Gene', (77, 83))	('PTK2', 'Gene', '5747', (68, 72))	('gain', 'PosReg', (46, 50))	('methyl', 'Chemical', 'MESH:C031105', (113, 119))
75653	31227497	PTK2/FAK is an established driver of some tumors and is a target for amplification at 8q in primary hepatocellular carcinoma (HCC) and breast cancer.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (100, 124))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('FAK', 'Gene', (5, 8))	('PTK2', 'Gene', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('breast cancer', 'Disease', (135, 148))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (100, 124))	('FAK', 'Gene', '5747', (5, 8))	('HCC', 'Disease', (126, 129))	('FAK', 'molecular_function', 'GO:0004717', ('5', '8'))	('PTK2', 'Gene', '5747', (0, 4))	('hepatocellular carcinoma', 'Disease', (100, 124))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('tumors', 'Disease', (42, 48))	('HCC', 'Disease', 'MESH:D006528', (126, 129))	('amplification', 'Var', (69, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
75655	31227497	Tumor MM127 harbored an A1031S alteration in PTK2 and no other detectable abnormalities.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('A1031S', 'Var', (24, 30))	('A1031S', 'Mutation', 'rs751168363', (24, 30))	('PTK2', 'Gene', (45, 49))	('PTK2', 'Gene', '5747', (45, 49))
75656	31227497	This alteration alters a highly conserved "DAKNL" motif in the C-terminal end of PTK2 that is conserved from humans to flies.	('alteration', 'Var', (5, 15))	('humans', 'Species', '9606', (109, 115))	('PTK2', 'Gene', (81, 85))	('highly conserved "DAKNL', 'MPA', (25, 48))	('PTK2', 'Gene', '5747', (81, 85))	('alters', 'Reg', (16, 22))
75658	31227497	We hypothesize that this p.A1031S alteration strengthens cellular adhesion mediated by FAK.	('p.A1031S', 'Mutation', 'rs751168363', (25, 33))	('FAK', 'Gene', '5747', (87, 90))	('strengthens', 'PosReg', (45, 56))	('cellular adhesion', 'CPA', (57, 74))	('FAK', 'Gene', (87, 90))	('p.A1031S', 'Var', (25, 33))	('FAK', 'molecular_function', 'GO:0004717', ('87', '90'))
75659	31227497	Inhibition of FAK has been implicated in improving local control in HPV-negative head and neck squamous cell carcinoma (HNSCC) and in castrate resistant prostate cancer and might also be a therapeutic target in UM.	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (90, 118))	('FAK', 'Gene', '5747', (14, 17))	('prostate cancer', 'Disease', 'MESH:D011471', (153, 168))	('neck squamous cell carcinoma', 'Disease', (90, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('neck', 'cellular_component', 'GO:0044326', ('90', '94'))	('Inhibition', 'Var', (0, 10))	('UM', 'Disease', 'MESH:C536494', (211, 213))	('prostate cancer', 'Phenotype', 'HP:0012125', (153, 168))	('FAK', 'Gene', (14, 17))	('FAK', 'molecular_function', 'GO:0004717', ('14', '17'))	('local control', 'MPA', (51, 64))	('improving', 'PosReg', (41, 50))	('prostate cancer', 'Disease', (153, 168))
75660	31227497	This is consistent with recent studies showing that oncogenic mutations found in GNAQ in UM activates YAP through FAK and that inhibition of FAK reduces UM growth.	('reduces', 'NegReg', (145, 152))	('FAK', 'Gene', '5747', (114, 117))	('GNAQ', 'Gene', (81, 85))	('activates', 'PosReg', (92, 101))	('UM', 'Disease', 'MESH:C536494', (153, 155))	('inhibition', 'Var', (127, 137))	('YAP', 'Gene', '10413', (102, 105))	('FAK', 'Gene', (141, 144))	('UM', 'Disease', 'MESH:C536494', (89, 91))	('FAK', 'Gene', '5747', (141, 144))	('FAK', 'molecular_function', 'GO:0004717', ('114', '117'))	('FAK', 'molecular_function', 'GO:0004717', ('141', '144'))	('YAP', 'Gene', (102, 105))	('mutations', 'Var', (62, 71))	('FAK', 'Gene', (114, 117))	('GNAQ', 'Gene', '2776', (81, 85))
75661	31227497	Chr 8q24 also harbors MYC which is amplified in about 30% of UMs, but its expression was not significantly upregulated as a consequence of 8q24 amplification.	('MYC', 'Gene', (22, 25))	('8q24', 'Var', (139, 143))	('UM', 'Disease', 'MESH:C536494', (61, 63))
75662	31227497	At Chr 6q27 we obtained evidence for PHF10/BAF45a as a novel tumor suppressor for UM on the basis of three tumors with definitive loss of function mutations: two tumors with overlapping homozygous deletion (HD) and one with a frameshift mutation and concomitant loss of the wild type allele (MM133).	('mutations', 'Var', (147, 156))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('BAF45a', 'Gene', '55274', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('PHF10', 'Gene', (37, 42))	('loss of function', 'NegReg', (130, 146))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('BAF45a', 'Gene', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('61', '77'))	('UM', 'Disease', 'MESH:C536494', (82, 84))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumor suppressor', 'biological_process', 'GO:0051726', ('61', '77'))	('PHF10', 'Gene', '55274', (37, 42))	('tumors', 'Disease', (162, 168))	('tumor', 'Disease', (61, 66))
75663	31227497	GEP had classified one MM016 as a class 1B tumor and MM133 as a class 2 tumor although they lacked SF3B1 and BAP1 mutations respectively.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('SF3B1', 'Gene', (99, 104))	('tumor', 'Disease', (72, 77))	('MM016', 'Var', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('BAP1', 'Gene', '8314', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('SF3B1', 'Gene', '23451', (99, 104))	('BAP1', 'Gene', (109, 113))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('lacked', 'NegReg', (92, 98))
75664	31227497	However, in addition to the PHF10 frameshift mutation, MM133 also harbored a mutation in SF3B1 leading to a R625C alteration and was disomic for Chr 3 despite being classified as a class 2 tumor (Supplementary Table 2).	('tumor', 'Disease', (189, 194))	('SF3B1', 'Gene', (89, 94))	('R625C alteration', 'MPA', (108, 124))	('R625C', 'Mutation', 'rs775623976', (108, 113))	('PHF10', 'Gene', '55274', (28, 33))	('mutation', 'Var', (77, 85))	('SF3B1', 'Gene', '23451', (89, 94))	('PHF10', 'Gene', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
75665	31227497	We also identified a mis-sense mutation in TCGA tumor A8KM (p.D453E, rs761295711).	('tumor', 'Disease', (48, 53))	('p.D453E', 'Var', (60, 67))	('p.D453E', 'Mutation', 'rs761295711', (60, 67))	('rs761295711', 'Mutation', 'rs761295711', (69, 80))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mis-sense', 'Var', (21, 30))	('rs761295711', 'Var', (69, 80))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
75666	31227497	This mutation was very rare (frequency in Exac is 8.3 X 10-6) and although tumorigenicity of mis-sense alterations is hard to predict, this alteration was predicted to be damaging.	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('alterations', 'Var', (103, 114))	('tumor', 'Disease', 'MESH:D009369', (75, 80))
75667	31227497	Tumor A8KM had also lost one copy of Chr 3 (Supplementary Table 1) and PRAME was upregulated but it lacked identified mutations in BAP1, SF3B1 or EIF1AX (Supplementary Table 2).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('EIF1AX', 'Gene', '1964', (146, 152))	('EIF1AX', 'Gene', (146, 152))	('mutations', 'Var', (118, 127))	('SF3B1', 'Gene', (137, 142))	('BAP1', 'Gene', '8314', (131, 135))	('PRAME', 'Gene', '23532', (71, 76))	('SF3B1', 'Gene', '23451', (137, 142))	('BAP1', 'Gene', (131, 135))	('PRAME', 'Gene', (71, 76))
75668	31227497	Hence, the presence of alterations in PHF10 and BAP1 were mutually exclusive in the small number of tumors sampled.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('BAP1', 'Gene', '8314', (48, 52))	('PHF10', 'Gene', '55274', (38, 43))	('BAP1', 'Gene', (48, 52))	('tumors', 'Disease', (100, 106))	('PHF10', 'Gene', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('alterations', 'Var', (23, 34))
75669	31227497	Loss of 6q where PHF10 resides was not correlated with worse overall survival in TCGA, nor were levels of PHF10.	('PHF10', 'Gene', '55274', (106, 111))	('PHF10', 'Gene', '55274', (17, 22))	('PHF10', 'Gene', (106, 111))	('PHF10', 'Gene', (17, 22))	('Loss', 'Var', (0, 4))
75671	31227497	During PHF10 silencing, other components of the PBAF complex (SMARCE1, SMARCC1 and SMARCA4) (Supplementary Figure 7) were upregulated, potentially as a compensation mechanism.	('SMARCC1', 'Gene', (71, 78))	('SMARCC1', 'Gene', '6599', (71, 78))	('PHF10', 'Gene', '55274', (7, 12))	('SMARCE1', 'Gene', (62, 69))	('upregulated', 'PosReg', (122, 133))	('SMARCA4', 'Gene', (83, 90))	('SMARCA4', 'Gene', '6597', (83, 90))	('PBAF complex', 'cellular_component', 'GO:0016586', ('48', '60'))	('PHF10', 'Gene', (7, 12))	('SMARCE1', 'Gene', '6605', (62, 69))	('silencing', 'Var', (13, 22))
75683	31227497	Mutations in PHF10 that drive tumor development have not been described before, although mutations in other PBAF components such as ARID2, PBRM1, SMARCA4 (BRG), SMARCB1 (BAF47) are implicated in other cancer types.	('PHF10', 'Gene', '55274', (13, 18))	('cancer', 'Disease', (201, 207))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('BAF47', 'Gene', '6598', (170, 175))	('ARID2', 'Gene', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('mutations', 'Var', (89, 98))	('PHF10', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('SMARCB1', 'Gene', '6598', (161, 168))	('SMARCA4', 'Gene', '6597', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('SMARCB1', 'Gene', (161, 168))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('implicated', 'Reg', (181, 191))	('BAF47', 'Gene', (170, 175))	('PBRM1', 'Gene', '55193', (139, 144))	('ARID2', 'Gene', '196528', (132, 137))	('SMARCA4', 'Gene', (146, 153))	('tumor', 'Disease', (30, 35))	('PBRM1', 'Gene', (139, 144))
75686	31227497	Although loss of one copy of Chromosome 3 is usually accompanied by loss of function mutations in BAP1, the significance of other chromosomal changes such as loss of Chr 1p, 6q and 8p, and gain of Chr 6p and 8q are not clear.	('BAP1', 'Gene', (98, 102))	('loss of function', 'NegReg', (68, 84))	('gain', 'PosReg', (189, 193))	('Chromosome', 'cellular_component', 'GO:0005694', ('29', '39'))	('mutations', 'Var', (85, 94))	('BAP1', 'Gene', '8314', (98, 102))	('loss', 'NegReg', (158, 162))
75691	26795274	A Phase 2 Trial of Everolimus and Pasireotide Long Acting Release in Patients with Metastatic Uveal Melanoma Test the hypothesis that inhibiting mammalian target of rapamycin (mTOR) and Insulin Growth Factor-1 Receptor would be efficacious in metastatic uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (254, 268))	('Insulin', 'Protein', (186, 193))	('Melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('Insulin', 'molecular_function', 'GO:0016088', ('186', '193'))	('mTOR', 'Gene', '2475', (176, 180))	('Metastatic Uveal Melanoma', 'Disease', 'MESH:C536494', (83, 108))	('mTOR', 'Gene', (176, 180))	('Metastatic Uveal Melanoma', 'Disease', (83, 108))	('Everolimus', 'Chemical', 'MESH:D000068338', (19, 29))	('melanoma', 'Phenotype', 'HP:0002861', (260, 268))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('uveal melanoma', 'Disease', 'MESH:C536494', (254, 268))	('inhibiting', 'Var', (134, 144))	('mammalian target of rapamycin', 'Gene', '2475', (145, 174))	('mammalian target of rapamycin', 'Gene', (145, 174))	('Patients', 'Species', '9606', (69, 77))	('uveal melanoma', 'Disease', (254, 268))
75703	26795274	Over the past several years, studies have identified activating mutations in the G alpha protein subunits GNAQ and GNA11 in the vast majority of uveal melanomas that lead to downstream activation of multiple signaling pathways, including mitogen-activated protein kinase (MAPK), Protein Kinase C (PKC), and Phosphoinositol-3-Kinase (PI3K)/Akt/mammalian target of Rapamycin (mTOR).	('GNA11', 'Gene', '2767', (115, 120))	('signaling', 'biological_process', 'GO:0023052', ('208', '217'))	('PKC', 'Gene', (297, 300))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('Akt', 'Gene', (339, 342))	('Phosphoinositol-3-Kinase', 'Gene', (307, 331))	('protein', 'cellular_component', 'GO:0003675', ('256', '263'))	('activation', 'PosReg', (185, 195))	('melanomas', 'Phenotype', 'HP:0002861', (151, 160))	('uveal melanomas', 'Disease', 'MESH:C536494', (145, 160))	('Phosphoinositol-3-Kinase', 'Gene', '5290', (307, 331))	('Akt', 'Gene', '207', (339, 342))	('Protein Kinase C', 'Gene', (279, 295))	('mutations', 'Var', (64, 73))	('activating', 'PosReg', (53, 63))	('PKC', 'molecular_function', 'GO:0004697', ('297', '300'))	('mTOR', 'Gene', (374, 378))	('GNA11', 'Gene', (115, 120))	('MAPK', 'molecular_function', 'GO:0004707', ('272', '276'))	('GNAQ', 'Gene', '2776', (106, 110))	('uveal melanoma', 'Phenotype', 'HP:0007716', (145, 159))	('GNAQ', 'Gene', (106, 110))	('Protein Kinase C', 'Gene', '112476', (279, 295))	('mammalian target of Rapamycin', 'Gene', (343, 372))	('uveal melanomas', 'Disease', (145, 160))	('uveal melanomas', 'Phenotype', 'HP:0007716', (145, 160))	('mammalian target of Rapamycin', 'Gene', '2475', (343, 372))	('mTOR', 'Gene', '2475', (374, 378))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('PI3K', 'molecular_function', 'GO:0016303', ('333', '337'))	('PKC', 'Gene', '112476', (297, 300))
75712	26795274	In uveal melanoma, tumor IGF1R expression has been associated with disease progression and in vitro inhibition of IGF1R causes uveal melanoma tumor regression.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('IGF1R', 'Gene', '3480', (114, 119))	('tumor', 'Disease', (19, 24))	('uveal melanoma tumor', 'Disease', 'MESH:C536494', (127, 147))	('IGF1R', 'Gene', (114, 119))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('uveal melanoma', 'Disease', (3, 17))	('IGF1R', 'Gene', '3480', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('IGF1R', 'Gene', (25, 30))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('uveal melanoma tumor', 'Disease', (127, 147))	('uveal melanoma', 'Disease', 'MESH:C536494', (127, 141))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('associated', 'Reg', (51, 61))	('inhibition', 'Var', (100, 110))	('uveal melanoma', 'Phenotype', 'HP:0007716', (127, 141))
75715	26795274	A recent report by Valsecchi and colleagues demonstrated In111 octreotide avidity in 14/30 patients (44%) with advanced uveal melanoma.	('patients', 'Species', '9606', (91, 99))	('uveal melanoma', 'Disease', 'MESH:C536494', (120, 134))	('uveal melanoma', 'Disease', (120, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('uveal melanoma', 'Phenotype', 'HP:0007716', (120, 134))	('octreotide', 'Chemical', 'MESH:D015282', (63, 73))	('In111', 'Var', (57, 62))
75720	26795274	We hypothesized that plasma IGF1 levels would decrease while receiving pasireotide LAR, consistent with IGF1R pathway inhibition, and patients with positive In111 octreotide uptake in their tumors would derive more benefit from the study combination than those whose tumors did not take up In111 octreotide.	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('patients', 'Species', '9606', (134, 142))	('IGF1', 'Gene', (104, 108))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('octreotide', 'Chemical', 'MESH:D015282', (163, 173))	('IGF1R', 'Gene', '3480', (104, 109))	('pasireotide LAR', 'Chemical', '-', (71, 86))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('benefit', 'PosReg', (215, 222))	('octreotide', 'Chemical', 'MESH:D015282', (296, 306))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Disease', (267, 273))	('IGF1R', 'Gene', (104, 109))	('IGF1', 'Gene', '3479', (28, 32))	('tumors', 'Disease', 'MESH:D009369', (267, 273))	('uptake', 'biological_process', 'GO:0098657', ('174', '180'))	('In111', 'Var', (157, 162))	('IGF1', 'Gene', '3479', (104, 108))	('IGF1', 'Gene', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('decrease', 'NegReg', (46, 54))	('uptake', 'biological_process', 'GO:0098739', ('174', '180'))
75736	26795274	The majority of patients had M1b or M1c disease (64 and 14%, respectively) by AJCC 7th edition staging guidelines for uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('patients', 'Species', '9606', (16, 24))	('uveal melanoma', 'Disease', (118, 132))	('uveal melanoma', 'Disease', 'MESH:C536494', (118, 132))	('M1b', 'Disease', (29, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (118, 132))	('M1c', 'Var', (36, 39))
75740	26795274	10 of these 12 patients had Q209 mutations (GNAQ n=5, GNA11 n=5).	('patients', 'Species', '9606', (15, 23))	('GNAQ', 'Gene', (44, 48))	('GNA11', 'Gene', (54, 59))	('GNA11', 'Gene', '2767', (54, 59))	('Q209 mutations', 'Var', (28, 42))	('GNAQ', 'Gene', '2776', (44, 48))
75741	26795274	Of the two Exon 5 wild-type samples, 1 had a GNA11 Exon 4 R183Q mutation and 1 was not tested further.	('GNA11', 'Gene', (45, 50))	('GNA11', 'Gene', '2767', (45, 50))	('R183Q', 'Var', (58, 63))	('R183Q', 'Mutation', 'rs397514698', (58, 63))
75748	26795274	Two patients had disease regression (-10% and -28%), both of which had tumors that were wild-type for GNAQ/11 Exon 5 mutations.	('mutations', 'Var', (117, 126))	('GNAQ', 'Gene', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('patients', 'Species', '9606', (4, 12))	('tumors', 'Disease', (71, 77))	('disease', 'CPA', (17, 24))	('GNAQ', 'Gene', '2776', (102, 106))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
75761	26795274	Five of 7 patients with >1 assessable lesion had both In111 octreotide avid and non-avid tumors.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('octreotide', 'Chemical', 'MESH:D015282', (60, 70))	('patients', 'Species', '9606', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('In111', 'Var', (54, 59))
75777	26795274	In this small sample size, there was a trend between In111 octreotide avidity and stability of disease with combined anti-IGF1R plus mTOR therapy that did not reach statistical significance.	('avidity', 'MPA', (70, 77))	('IGF1R', 'Gene', (122, 127))	('mTOR', 'Gene', '2475', (133, 137))	('mTOR', 'Gene', (133, 137))	('stability', 'Disease', (82, 91))	('In111', 'Var', (53, 58))	('IGF1R', 'Gene', '3480', (122, 127))	('octreotide', 'Chemical', 'MESH:D015282', (59, 69))
75778	26795274	This suggests that, while the routine use of In111-octreotide scans in this disease cannot be recommended to document extent of metastatic disease, there may be a biologically relevant relationship between In111 octreotide avidity and cytostatic effect of somatostatin analogues in uveal melanoma.	('uveal melanoma', 'Disease', (282, 296))	('cytostatic', 'MPA', (235, 245))	('In111', 'Var', (206, 211))	('melanoma', 'Phenotype', 'HP:0002861', (288, 296))	('octreotide', 'Chemical', 'MESH:D015282', (212, 222))	('octreotide', 'Chemical', 'MESH:D015282', (51, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (282, 296))	('uveal melanoma', 'Disease', 'MESH:C536494', (282, 296))
75782	26795274	Combination therapy with mTOR and IGF1-R inhibitors led to a relatively high rate of AEs, most commonly metabolic, GI, and hematologic in nature.	('metabolic', 'Disease', (104, 113))	('hematologic', 'Disease', (123, 134))	('IGF1-R', 'Gene', '3480', (34, 40))	('AEs', 'Chemical', '-', (85, 88))	('AEs', 'Disease', (85, 88))	('inhibitors', 'Var', (41, 51))	('GI', 'Disease', 'MESH:D005767', (115, 117))	('mTOR', 'Gene', '2475', (25, 29))	('mTOR', 'Gene', (25, 29))	('IGF1-R', 'Gene', (34, 40))
75821	27847631	We highlight this uncommon occurrence to create awareness that BDUMP can lead to infiltration of the uveal tract including the iris and ciliary body, which may further lead to angle-closure glaucoma and cataracts.	('cataracts', 'Disease', 'MESH:D002386', (203, 212))	('-closure glaucoma', 'Phenotype', 'HP:0012109', (181, 198))	('glaucoma', 'Phenotype', 'HP:0000501', (190, 198))	('infiltration', 'CPA', (81, 93))	('cataracts', 'Phenotype', 'HP:0000518', (203, 212))	('glaucoma', 'Disease', (190, 198))	('BDUMP', 'Chemical', '-', (63, 68))	('lead to', 'Reg', (168, 175))	('lead to', 'Reg', (73, 80))	('BDUMP', 'Var', (63, 68))	('cataracts', 'Disease', (203, 212))	('glaucoma', 'Disease', 'MESH:D005901', (190, 198))
75845	26870807	Several histologic, genetic, and demographic factors have been associated with metastases in UM, including large tumor size in primary cancer of the eye, monosomy 3, and BAP1 mutation.	('tumor', 'Disease', (113, 118))	('cancer', 'Disease', (135, 141))	('metastases', 'Disease', 'MESH:D009362', (79, 89))	('BAP1', 'Gene', '8314', (170, 174))	('mutation', 'Var', (175, 183))	('associated', 'Reg', (63, 73))	('cancer of the eye', 'Phenotype', 'HP:0100012', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('BAP1', 'Gene', (170, 174))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('monosomy 3', 'Disease', (154, 164))	('metastases', 'Disease', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
75846	26870807	It has been reported that 80% of metastatic uveal melanoma have mutation in BAP1.	('mutation', 'Var', (64, 72))	('BAP1', 'Gene', '8314', (76, 80))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('BAP1', 'Gene', (76, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', (44, 58))
75898	26870807	The nonparametric Kruskal-Wallis rank sum test was used to compare numbers of CTC in arterial blood specimens of patients with three different levels of liver-only tumor involvement (< 20%, 20%-50%, > 50%).	('tumor', 'Disease', (164, 169))	('patients', 'Species', '9606', (113, 121))	('< 20', 'Var', (183, 187))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
75912	26870807	In this small pilot study, we detected CTCs in all arterial blood samples from UM patients who have multiple hepatic metastases.	('CTCs', 'Var', (39, 43))	('multiple hepatic metastases', 'Disease', 'MESH:D009362', (100, 127))	('patients', 'Species', '9606', (82, 90))	('multiple hepatic metastases', 'Disease', (100, 127))	('detected', 'Reg', (30, 38))
75944	26140217	Genetic testing confirmed a novel and unusual germline mutation in the ubiquitin hydrolase domain of the BAP1 gene (p.Tyr173Cys) and the patient was diagnosed with the BAP1 hereditary cancer predisposition syndrome.	('BAP1', 'Gene', '8314', (168, 172))	('patient', 'Species', '9606', (137, 144))	('BAP1', 'Gene', '8314', (105, 109))	('hereditary cancer', 'Disease', 'MESH:D009369', (173, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('BAP1', 'Gene', (168, 172))	('p.Tyr173Cys', 'Var', (116, 127))	('germline mutation in', 'Var', (46, 66))	('ubiquitin', 'molecular_function', 'GO:0031386', ('71', '80'))	('hereditary cancer', 'Disease', (173, 190))	('p.Tyr173Cys', 'Mutation', 'p.Y173C', (116, 127))	('BAP1', 'Gene', (105, 109))
75945	26140217	The diagnosis of a germline BAP1 mutation may have important implications for both the patient and their families with regards to further genetic testing and active surveillance programs.	('BAP1', 'Gene', '8314', (28, 32))	('patient', 'Species', '9606', (87, 94))	('mutation', 'Var', (33, 41))	('BAP1', 'Gene', (28, 32))
75949	26140217	Genetic studies of these families subsequently lead to the discovery of germline mutations in BAP1 and the recognition of a new cancer predisposition syndrome.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('BAP1', 'Gene', '8314', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('BAP1', 'Gene', (94, 98))	('germline mutations', 'Var', (72, 90))	('cancer', 'Disease', (128, 134))
75976	26140217	Testing for BAP1 mutations by immunohistochemistry showed loss of nuclear BAP1 labeling in the primary biliary tract adenocarcinoma, but nuclear labeling for BAP1 was retained in the malignant mesothelioma (Fig.	('labeling', 'MPA', (79, 87))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (183, 205))	('loss', 'NegReg', (58, 62))	('BAP1', 'Gene', '8314', (158, 162))	('BAP1', 'Gene', (158, 162))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (183, 205))	('malignant mesothelioma', 'Disease', (183, 205))	('nuclear', 'MPA', (66, 73))	('BAP1', 'Gene', '8314', (12, 16))	('BAP1', 'Gene', (74, 78))	('BAP1', 'Gene', '8314', (74, 78))	('primary biliary tract adenocarcinoma', 'Disease', (95, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('primary biliary tract adenocarcinoma', 'Disease', 'MESH:D001661', (95, 131))	('BAP1', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
75978	26140217	Germline DNA sequencing was performed and revealed the patient to carry a germline missense mutation in the catalytic domain (g.52441252A > G, p.Tyr173Cys) located in exon 7 of the BAP1 gene (Fig.	('BAP1', 'Gene', (181, 185))	('g.52441252A > G', 'Mutation', 'g.52441252A>G', (126, 141))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('patient', 'Species', '9606', (55, 62))	('BAP1', 'Gene', '8314', (181, 185))	('g.52441252A > G', 'Var', (126, 141))	('p.Tyr173Cys', 'Mutation', 'p.Y173C', (143, 154))
75984	26140217	Other cancers have been reported in families suffering germline mutations but no direct correlations have yet been established.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Disease', (6, 13))	('germline mutations', 'Var', (55, 73))
75985	26140217	In a review of 76 patients with a BAP1 germline mutation, 53 patients had developed at least one malignancy with 13 developing at least two.	('BAP1', 'Gene', (34, 38))	('germline mutation', 'Var', (39, 56))	('patients', 'Species', '9606', (61, 69))	('malignancy', 'Disease', 'MESH:D009369', (97, 107))	('patients', 'Species', '9606', (18, 26))	('BAP1', 'Gene', '8314', (34, 38))	('malignancy', 'Disease', (97, 107))
75987	26140217	This study highlights the strong link between germline BAP1 mutations and carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (74, 88))	('BAP1', 'Gene', (55, 59))	('carcinogenesis', 'Disease', (74, 88))	('mutations', 'Var', (60, 69))	('BAP1', 'Gene', '8314', (55, 59))
75988	26140217	Here, we reported a case involving an individual with a germline BAP1 mutation who was diagnosed with 3 distinct malignancies in short succession, an event that appears uncommon even for individuals carrying a germline BAP1 mutation.	('BAP1', 'Gene', '8314', (65, 69))	('BAP1', 'Gene', (219, 223))	('malignancies', 'Disease', (113, 125))	('BAP1', 'Gene', (65, 69))	('malignancies', 'Disease', 'MESH:D009369', (113, 125))	('germline', 'Var', (56, 64))	('mutation', 'Var', (70, 78))	('BAP1', 'Gene', '8314', (219, 223))
75992	26140217	BAP1 mutations may result in proteins that lack the nuclear localization sequence, or may affect its deubiquitinase activity.	('affect', 'Reg', (90, 96))	('BAP1', 'Gene', (0, 4))	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('101', '124'))	('deubiquitinase activity', 'MPA', (101, 124))	('result in', 'Reg', (19, 28))	('proteins', 'Protein', (29, 37))	('mutations', 'Var', (5, 14))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('101', '124'))	('localization', 'biological_process', 'GO:0051179', ('60', '72'))	('nuclear localization sequence', 'MPA', (52, 81))	('lack', 'NegReg', (43, 47))	('BAP1', 'Gene', '8314', (0, 4))
75993	26140217	It is not fully known why germline mutations may predispose to the development of certain cancers over others; most likely cell-type specific functions as well as gene-environment interactions play an important role.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('predispose', 'Reg', (49, 59))	('germline mutations', 'Var', (26, 44))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
75994	26140217	The BAP1 germline alteration identified in our patient was a missense mutation at the active site of its ubiquitin hydrolase domain.	('patient', 'Species', '9606', (47, 54))	('BAP1', 'Gene', (4, 8))	('ubiquitin', 'molecular_function', 'GO:0031386', ('105', '114'))	('missense mutation', 'Var', (61, 78))	('BAP1', 'Gene', '8314', (4, 8))
75995	26140217	Similar missense mutations were found in uveal melanoma (p.Ser172Arg) and pleural biphasic mesothelioma (p.Tyr173Ser) tissue.	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('uveal melanoma', 'Disease', (41, 55))	('p.Tyr173Ser', 'Mutation', 'p.Y173S', (105, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (41, 55))	('p.Ser172Arg', 'Var', (57, 68))	('p.Ser172Arg', 'Mutation', 'p.S172R', (57, 68))	('p.Tyr173Ser', 'Var', (105, 116))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('Ser', 'cellular_component', 'GO:0005790', ('113', '116'))	('Ser', 'cellular_component', 'GO:0005790', ('59', '62'))	('pleural biphasic mesothelioma', 'Disease', (74, 103))	('pleural biphasic mesothelioma', 'Disease', 'MESH:D008654', (74, 103))
75998	26140217	Both N-terminus BAP1 mutations and C-terminus mutations lead to lack of BAP1 nuclear labeling due to either lack of the nuclear localization signal, or to lack of deubiquitinase activity, as autodeubiquition is required for nuclear transport of BAP1 protein.	('deubiquitinase activity', 'MPA', (163, 186))	('localization', 'biological_process', 'GO:0051179', ('128', '140'))	('nuclear labeling', 'MPA', (77, 93))	('BAP1', 'Gene', '8314', (72, 76))	('nuclear localization signal', 'MPA', (120, 147))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('163', '186'))	('lack', 'NegReg', (155, 159))	('BAP1', 'Gene', '8314', (245, 249))	('lack', 'NegReg', (108, 112))	('nuclear transport', 'biological_process', 'GO:0051169', ('224', '241'))	('BAP1', 'Gene', (72, 76))	('BAP1', 'Gene', '8314', (16, 20))	('protein', 'cellular_component', 'GO:0003675', ('250', '257'))	('BAP1', 'Gene', (245, 249))	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('163', '186'))	('lack', 'NegReg', (64, 68))	('BAP1', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
75999	26140217	This has been confirmed in a comprehensive study showing that all BAP1 abnormalities found in mesothelioma to date are always associated with absence of BAP1 nuclear staining and/or presence of cytoplasmic BAP1 staining.	('BAP1', 'Gene', '8314', (206, 210))	('mesothelioma', 'Disease', 'MESH:D008654', (94, 106))	('BAP1', 'Gene', '8314', (66, 70))	('BAP1', 'Gene', (206, 210))	('BAP1', 'Gene', '8314', (153, 157))	('BAP1', 'Gene', (66, 70))	('abnormalities', 'Var', (71, 84))	('mesothelioma', 'Disease', (94, 106))	('absence', 'NegReg', (142, 149))	('BAP1', 'Gene', (153, 157))
76001	26140217	One could argue that the fact that mesothelioma developed even in absence of LOH further confirms the deleteriousness of the Tyr 173 mutation.	('mesothelioma', 'Disease', (35, 47))	('Tyr 173', 'Var', (125, 132))	('mesothelioma', 'Disease', 'MESH:D008654', (35, 47))	('Tyr', 'Chemical', 'MESH:D014443', (125, 128))
76003	26140217	Loss of nuclear BAP1 staining on immunohistochemistry was thought to be an accessible and reliable test of BAP1 mutations, including germline and has been used for prognostication in mesothelioma.	('BAP1', 'Gene', '8314', (107, 111))	('BAP1', 'Gene', (107, 111))	('mesothelioma', 'Disease', (183, 195))	('mutations', 'Var', (112, 121))	('BAP1', 'Gene', '8314', (16, 20))	('mesothelioma', 'Disease', 'MESH:D008654', (183, 195))	('BAP1', 'Gene', (16, 20))
76005	26140217	With regards to specific cancers, germline BAP1 mutations have been shown to play a role in a small number (3-4 %) of uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (118, 133))	('BAP1', 'Gene', (43, 47))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanomas', 'Phenotype', 'HP:0002861', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('uveal melanoma', 'Phenotype', 'HP:0007716', (118, 132))	('germline', 'Var', (34, 42))	('BAP1', 'Gene', '8314', (43, 47))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('uveal melanomas', 'Disease', (118, 133))	('uveal melanomas', 'Phenotype', 'HP:0007716', (118, 133))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))
76007	26140217	BAP1 mutations have been implicated in metastatic ability.	('BAP1', 'Gene', (0, 4))	('metastatic ability', 'CPA', (39, 57))	('mutations', 'Var', (5, 14))	('implicated', 'Reg', (25, 35))	('BAP1', 'Gene', '8314', (0, 4))
76008	26140217	A germline mutation was found in 4 out of 50 metastatic uveal melanomas and was not identified in a further 50 non-metastatic tumours.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('uveal melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('uveal melanomas', 'Disease', 'MESH:C536494', (56, 71))	('germline mutation', 'Var', (2, 19))	('tumours', 'Phenotype', 'HP:0002664', (126, 133))	('tumours', 'Disease', 'MESH:D009369', (126, 133))	('uveal melanomas', 'Phenotype', 'HP:0007716', (56, 71))	('tumours', 'Disease', (126, 133))	('found', 'Reg', (24, 29))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('uveal melanomas', 'Disease', (56, 71))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
76009	26140217	Sporadic BAP1 mutations have also been found in 84 % of metastasizing uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (70, 85))	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('found', 'Reg', (39, 44))	('BAP1', 'Gene', '8314', (9, 13))	('uveal melanomas', 'Disease', (70, 85))	('uveal melanomas', 'Phenotype', 'HP:0007716', (70, 85))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
76010	26140217	Loss of BAP1 both germline and sporadic appears to lead to a more aggressive tumour phenotype in uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('aggressive tumour', 'Disease', (66, 83))	('BAP1', 'Gene', '8314', (8, 12))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('uveal melanoma', 'Disease', (97, 111))	('lead to', 'Reg', (51, 58))	('aggressive tumour', 'Disease', 'MESH:D001523', (66, 83))	('BAP1', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
76013	26140217	Both germline and sporadic BAP1 mutations has been shown to play a role in malignant mesothelioma.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (75, 97))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (75, 97))	('BAP1', 'Gene', (27, 31))	('play', 'Reg', (60, 64))	('role', 'Reg', (67, 71))	('mutations', 'Var', (32, 41))	('malignant mesothelioma', 'Disease', (75, 97))	('BAP1', 'Gene', '8314', (27, 31))
76015	26140217	Germline mutations make up much smaller proportion of cancers.	('Germline mutations', 'Var', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
76016	26140217	A recent study compared the clinical characteristics of 23 mesotheliomas that occurred in carriers of germline BAP1 mutations to 10,556 sporadic mesotheliomas.	('mesotheliomas', 'Disease', 'MESH:D008654', (59, 72))	('mesotheliomas', 'Disease', (59, 72))	('BAP1', 'Gene', '8314', (111, 115))	('mesotheliomas', 'Disease', 'MESH:D008654', (145, 158))	('mesotheliomas', 'Disease', (145, 158))	('BAP1', 'Gene', (111, 115))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (136, 158))	('mutations', 'Var', (116, 125))
76018	26140217	Tumors that occur in a setting of germline BAP1 mutations are much less aggressive than their somatic counterparts and are associated with a significant improved mean survival of 5 years compared to 1 year with sporadic malignant mesothelioma.	('malignant mesothelioma', 'Disease', (220, 242))	('BAP1', 'Gene', (43, 47))	('aggressive', 'CPA', (72, 82))	('less', 'NegReg', (67, 71))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (220, 242))	('BAP1', 'Gene', '8314', (43, 47))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('improved', 'PosReg', (153, 161))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (220, 242))	('mutations', 'Var', (48, 57))
76021	26140217	Germline mutations also had a higher incidence of peritoneal disease (as in our patient) where in sporadic tumours pleural disease predominates.	('Germline mutations', 'Var', (0, 18))	('peritoneal disease', 'Disease', 'MESH:D010532', (50, 68))	('peritoneal disease', 'Disease', (50, 68))	('sporadic tumours pleural disease', 'Disease', 'MESH:D010997', (98, 130))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('sporadic tumours pleural disease', 'Disease', (98, 130))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('patient', 'Species', '9606', (80, 87))	('pleural disease', 'Phenotype', 'HP:0002103', (115, 130))
76023	26140217	Germline BAP1 mutations have cutaneous manifestations that include basal cell carcinomas, malignant melanoma and the recently described melanocytic-BAP1 mutated atypical intradermal tumour (MBAIT).	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (67, 88))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('BAP1', 'Gene', '8314', (148, 152))	('mutated', 'Var', (153, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('malignant melanoma', 'Phenotype', 'HP:0002861', (90, 108))	('intradermal tumour', 'Disease', 'MESH:D018330', (170, 188))	('basal cell carcinomas', 'Disease', (67, 88))	('BAP1', 'Gene', '8314', (9, 13))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (67, 88))	('BAP1', 'Gene', (148, 152))	('malignant melanoma', 'Disease', 'MESH:D008545', (90, 108))	('intradermal tumour', 'Disease', (170, 188))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('malignant melanoma', 'Disease', (90, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
76028	26140217	Bi-allelic loss of BAP1 in itself along with a BRAF mutation is not sufficient for melanoma formation.	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('formation', 'biological_process', 'GO:0009058', ('92', '101'))	('loss', 'NegReg', (11, 15))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('BAP1', 'Gene', '8314', (19, 23))	('mutation', 'Var', (52, 60))	('BAP1', 'Gene', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('Bi-allelic', 'Var', (0, 10))	('melanoma', 'Disease', (83, 91))
76029	26140217	It has been suggested that MBAITs may be used to screen individuals for germline BAP1 mutations; 19 out of 35 individuals with a BAP1 mutation were found to have one or more lesion.	('mutations', 'Var', (86, 95))	('BAP1', 'Gene', (81, 85))	('mutation', 'Var', (134, 142))	('BAP1', 'Gene', '8314', (129, 133))	('BAP1', 'Gene', (129, 133))	('BAP1', 'Gene', '8314', (81, 85))
76033	26140217	A much smaller component can be attributed to germline BAP1 mutations.	('BAP1', 'Gene', (55, 59))	('germline', 'Var', (46, 54))	('BAP1', 'Gene', '8314', (55, 59))
76035	26140217	Sporadic BAP1 mutations have also been associated with a more aggressive form of cancer however it appears germline mutations may have different consequences.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('BAP1', 'Gene', '8314', (9, 13))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
76037	26140217	Other cancers including meningioma, lung, ovarian, pancreatic and breast cancers have been found in families that harbor BAP1 germline mutations.	('cancers', 'Disease', (73, 80))	('BAP1', 'Gene', '8314', (121, 125))	('breast cancers', 'Phenotype', 'HP:0003002', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('germline', 'Var', (126, 134))	('found', 'Reg', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('BAP1', 'Gene', (121, 125))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('meningioma', 'Phenotype', 'HP:0002858', (24, 34))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('meningioma, lung, ovarian, pancreatic and breast cancers', 'Disease', 'MESH:D001943', (24, 80))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
76038	26140217	However it is unclear whether germline BAP1 mutations directly predispose to the development of these tumours.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('predispose', 'Reg', (63, 73))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('tumours', 'Disease', 'MESH:D009369', (102, 109))	('mutations', 'Var', (44, 53))	('BAP1', 'Gene', '8314', (39, 43))	('tumours', 'Disease', (102, 109))	('BAP1', 'Gene', (39, 43))
76040	26140217	There are reports of individuals with BAP1 mutations developing primary biliary tract cancers but no definitive predisposition has been attributed.	('developing', 'Reg', (53, 63))	('BAP1', 'Gene', (38, 42))	('primary biliary tract cancer', 'Disease', (64, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (72, 92))	('biliary tract cancers', 'Disease', 'MESH:D001661', (72, 93))	('mutations', 'Var', (43, 52))	('biliary tract cancers', 'Disease', (72, 93))	('primary biliary tract cancer', 'Disease', 'MESH:D001661', (64, 92))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('BAP1', 'Gene', '8314', (38, 42))
76041	26140217	Somatic BAP1 mutations are relatively frequent in cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (50, 68))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (50, 68))	('BAP1', 'Gene', '8314', (8, 12))	('cholangiocarcinoma', 'Disease', (50, 68))	('BAP1', 'Gene', (8, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('mutations', 'Var', (13, 22))	('frequent', 'Reg', (38, 46))
76043	26140217	This indicates that secondary sporadic mutations had occurred in the adenocarcinoma, resulting in loss of protein translocation (Fig.	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('protein translocation', 'MPA', (106, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('mutations', 'Var', (39, 48))	('loss', 'NegReg', (98, 102))	('adenocarcinoma', 'Disease', (69, 83))	('adenocarcinoma', 'Disease', 'MESH:D000230', (69, 83))
76049	26140217	Those who are confirmed to carry a BAP1 mutation will then need appropriate genetic counseling for themselves and their families.	('mutation', 'Var', (40, 48))	('BAP1', 'Gene', '8314', (35, 39))	('BAP1', 'Gene', (35, 39))
76051	26140217	BAP1 mutations have been described in some US and European families with a very high incidence of cancer and they are transmitted in a Mendelian fashion (i.e., about 50 % of offspring inherit the mutation).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('BAP1', 'Gene', (0, 4))	('mutation', 'Var', (196, 204))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('mutations', 'Var', (5, 14))	('cancer', 'Disease', (98, 104))	('BAP1', 'Gene', '8314', (0, 4))
76052	26140217	So far all of the family members that inherited this mutation have developed one and often several cancers by age 65 (18).	('mutation', 'Var', (53, 61))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('developed', 'Reg', (67, 76))
76053	26140217	Characteristically, when malignancies occur in a setting of germline BAP1 mutations they are less aggressive and patients live significantly longer compared to patients with the same types of tumors occurring in a sporadic setting.	('less', 'NegReg', (93, 97))	('patients', 'Species', '9606', (160, 168))	('malignancies', 'Disease', 'MESH:D009369', (25, 37))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('BAP1', 'Gene', (69, 73))	('patients', 'Species', '9606', (113, 121))	('mutations', 'Var', (74, 83))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('aggressive', 'CPA', (98, 108))	('malignancies', 'Disease', (25, 37))	('longer', 'PosReg', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('BAP1', 'Gene', '8314', (69, 73))
76071	23550303	Recent findings indicate that germline BAP1 mutations cause a novel cancer syndrome, characterized, at least in the affected families studied so far, by the onset at an early age of benign melanocytic skin tumours with mutated BAP1, and later in life by a high incidence of mesothelioma, uveal melanoma, cutaneous melanoma and possibly additional cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mesothelioma', 'Disease', 'MESH:D008654', (274, 286))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('mutated', 'Var', (219, 226))	('cancers', 'Disease', 'MESH:D009369', (347, 354))	('uveal melanoma', 'Disease', 'MESH:C536494', (288, 302))	('uveal melanoma', 'Disease', (288, 302))	('benign melanocytic skin tumours', 'Disease', (182, 213))	('BAP1', 'Gene', (39, 43))	('cause', 'Reg', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('cancer syndrome', 'Disease', 'MESH:D009369', (68, 83))	('tumours', 'Phenotype', 'HP:0002664', (206, 213))	('early age of benign melanocytic skin', 'Phenotype', 'HP:0007396', (169, 205))	('cancers', 'Phenotype', 'HP:0002664', (347, 354))	('uveal melanoma', 'Phenotype', 'HP:0007716', (288, 302))	('cancers', 'Disease', (347, 354))	('germline', 'Var', (30, 38))	('benign melanocytic skin tumours', 'Disease', 'MESH:D012878', (182, 213))	('melanoma', 'Phenotype', 'HP:0002861', (314, 322))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('BAP1', 'Gene', (227, 231))	('mutations', 'Var', (44, 53))	('cancer syndrome', 'Disease', (68, 83))	('cutaneous melanoma', 'Disease', (304, 322))	('mesothelioma', 'Disease', (274, 286))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (304, 322))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (304, 322))
76078	23550303	Chromosome microarray and genetic linkage analyses on the L and W families implicated chromosome region 3p21, a locus frequently altered in both UVM and mesotheliomas.	('UVM', 'Disease', (145, 148))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('chromosome region 3p21', 'Var', (86, 108))	('mesotheliomas', 'Disease', 'MESH:D008654', (153, 166))	('chromosome region', 'cellular_component', 'GO:0098687', ('86', '103'))	('mesotheliomas', 'Disease', (153, 166))
76079	23550303	Sequencing this region of chromosome 3 led to the identification of BAP1 as the gene mutated and associated with high rates of mesothelioma in the L and W families (experiments are in progress to address whether BAP1 also causes the high incidence of mesothelioma in Cappadocia).	('mesothelioma', 'Disease', (127, 139))	('mesothelioma in Cappadocia', 'Disease', (251, 277))	('mesothelioma', 'Disease', (251, 263))	('BAP1', 'Var', (212, 216))	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('mesothelioma', 'Disease', 'MESH:D008654', (127, 139))	('mesothelioma in Cappadocia', 'Disease', 'MESH:D008654', (251, 277))	('mesothelioma', 'Disease', 'MESH:D008654', (251, 263))	('associated', 'Reg', (97, 107))	('BAP1', 'Gene', (68, 72))	('causes', 'Reg', (222, 228))
76080	23550303	BAP1 is a member of the ubiquitin C-terminal hydrolases (UCH) subfamily of deubiquitylating enzymes (DUBs) and was mutated in each family member who had developed mesothelioma, UVM and other cancers.	('BAP1', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancers', 'Disease', (191, 198))	('mutated', 'Var', (115, 122))	('mesothelioma', 'Disease', (163, 175))	('UVM', 'Disease', (177, 180))	('developed', 'PosReg', (153, 162))	('ubiquitin C', 'Gene', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('mesothelioma', 'Disease', 'MESH:D008654', (163, 175))	('ubiquitin', 'molecular_function', 'GO:0031386', ('24', '33'))	('ubiquitin C', 'Gene', '7316', (24, 35))
76081	23550303	None of these tumour types was detected in family members who did not carry BAP1 mutations.	('tumour', 'Disease', (14, 20))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('BAP1', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('tumour', 'Disease', 'MESH:D009369', (14, 20))
76082	23550303	Moreover, among several cases of sporadic mesotheliomas, we found that 2/26 patients had germline BAP1 mutations and importantly we found that both of these patients had been previously diagnosed with UVM.	('BAP1', 'Gene', (98, 102))	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (76, 84))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (33, 55))	('sporadic mesotheliomas', 'Disease', (33, 55))	('patients', 'Species', '9606', (157, 165))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (33, 55))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (33, 54))
76084	23550303	On the basis of these findings, we have proposed that germline BAP1 mutations cause a new cancer syndrome characterized by mesothelioma and UVM.	('cause', 'Reg', (78, 83))	('cancer syndrome', 'Disease', (90, 105))	('UVM', 'Disease', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('BAP1', 'Gene', (63, 67))	('mesothelioma', 'Disease', 'MESH:D008654', (123, 135))	('mutations', 'Var', (68, 77))	('cancer syndrome', 'Disease', 'MESH:D009369', (90, 105))	('germline', 'Var', (54, 62))	('mesothelioma', 'Disease', (123, 135))
76085	23550303	In this Progress article, we discuss this potential inherited cancer syndrome, the possible mechanisms through which mutations in BAP1 might lead to tumour development and the clinical implications raised by detection of germline BAP1 mutations.	('mutations', 'Var', (117, 126))	('BAP1', 'Gene', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('lead to', 'Reg', (141, 148))	('cancer syndrome', 'Disease', 'MESH:D009369', (62, 77))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('cancer syndrome', 'Disease', (62, 77))	('tumour', 'Disease', (149, 155))
76086	23550303	reported that germline BAP1 mutations caused benign atypical melanocytic tumours.	('BAP1', 'Gene', (23, 27))	('melanocytic tumours', 'Disease', 'MESH:D009508', (61, 80))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('melanocytic tumours', 'Disease', (61, 80))	('mutations', 'Var', (28, 37))	('caused', 'Reg', (38, 44))
76089	23550303	They studied 32 sporadic ASTs and found that 9 had loss of BAP1 expression and 8 of these had concomitant BRAF mutations.	('mutations', 'Var', (111, 120))	('expression', 'MPA', (64, 74))	('BAP1', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (106, 110))	('BRAF', 'Gene', (106, 110))	('loss', 'NegReg', (51, 55))
76090	23550303	Only 1 of 23 ASTs that expressed BAP1 had a BRAF mutation (P< 0.0001) .	('BRAF', 'Gene', (44, 48))	('BRAF', 'Gene', '673', (44, 48))	('BAP1', 'Gene', (33, 37))	('mutation', 'Var', (49, 57))
76091	23550303	BRAF mutations are common in melanocytic nevi (80%) and in cutaneous melanoma (65%) but are rare in ASTs.	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('cutaneous melanoma', 'Disease', (59, 77))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (59, 77))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (59, 77))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (29, 45))	('common', 'Reg', (19, 25))	('BRAF', 'Gene', (0, 4))	('melanocytic', 'Disease', (29, 40))	('melanocytic', 'Disease', 'MESH:D009508', (29, 40))	('nevi', 'Phenotype', 'HP:0003764', (41, 45))
76092	23550303	noted the same type of skin tumours arising in families with germline BAP1 mutations and referred to them as nevoid melanoma-like melanocytic proliferations (NEMMPs).	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('skin tumours', 'Disease', 'MESH:D012878', (23, 35))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('skin tumours', 'Disease', (23, 35))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('BAP1', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('melanoma-like melanocytic proliferations', 'Disease', 'MESH:D059545', (116, 156))	('melanoma-like melanocytic proliferations', 'Disease', (116, 156))
76096	23550303	We found that all the melanocytic tumors in these BAP1 mutant patients had the same histological and molecular characteristics.	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('melanocytic tumors', 'Disease', 'MESH:D009508', (22, 40))	('mutant', 'Var', (55, 61))	('patients', 'Species', '9606', (62, 70))	('BAP1', 'Gene', (50, 54))	('melanocytic tumors', 'Disease', (22, 40))
76097	23550303	In our review of the skin tumours in patients with mutant BAP1 we found that these are nevus-like lesions usually formed by a conventional junctional, compound or dermal nevus composed of small melanocytes expressing BAP1.	('patients', 'Species', '9606', (37, 45))	('nevus', 'Phenotype', 'HP:0003764', (170, 175))	('BAP1', 'Gene', (58, 62))	('mutant', 'Var', (51, 57))	('skin tumours', 'Disease', 'MESH:D012878', (21, 33))	('skin tumours', 'Disease', (21, 33))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('nevus', 'Phenotype', 'HP:0003764', (87, 92))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))
76098	23550303	Next to these conventional nevus cells there is a dermal lesion formed by large epithelioid BAP1 negative and most frequently BRAF mutated melanocytes with virtually no mitotic activity.	('mutated', 'Var', (131, 138))	('dermal lesion', 'Disease', (50, 63))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('nevus', 'Phenotype', 'HP:0003764', (27, 32))	('dermal lesion', 'Disease', 'MESH:D016136', (50, 63))
76100	23550303	Acknowledging that these lesions are characteristic of, although possibly not unique to, BAP1 mutation carriers, we proposed naming them melanocytic BAP1-mutated atypical intradermal tumours (MBAITs).	('melanocytic', 'Disease', 'MESH:D009508', (137, 148))	('melanocytic', 'Disease', (137, 148))	('BAP1', 'Gene', (89, 93))	('intradermal tumours', 'Disease', 'MESH:D018330', (171, 190))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('intradermal tumours', 'Disease', (171, 190))	('tumours', 'Phenotype', 'HP:0002664', (183, 190))	('mutation', 'Var', (94, 102))
76104	23550303	reported inactivating mutations of BAP1 in 26 of 31 aggressive (class 2) UVMs, among which a germline mutation was found in 1 of 26 patients.	('inactivating mutations', 'Var', (9, 31))	('patients', 'Species', '9606', (132, 140))	('BAP1', 'Gene', (35, 39))
76107	23550303	In this family, there were 7 BAP1 mutation carriers (5 tested and two inferred) and only one was cancer free at age 55; the other six had developed UVM (2 cases), cutaneous melanoma, mesothelioma, meningioma, lung and other types of carcinoma.	('lung', 'Disease', (209, 213))	('carcinoma', 'Disease', (233, 242))	('meningioma', 'Disease', 'MESH:D008577', (197, 207))	('cancer', 'Disease', (97, 103))	('mutation', 'Var', (34, 42))	('mesothelioma', 'Disease', (183, 195))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('carcinoma', 'Disease', 'MESH:D002277', (233, 242))	('mesothelioma', 'Disease', 'MESH:D008654', (183, 195))	('cutaneous melanoma', 'Disease', (163, 181))	('developed', 'PosReg', (138, 147))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (163, 181))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (163, 181))	('BAP1', 'Gene', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('meningioma', 'Disease', (197, 207))	('meningioma', 'Phenotype', 'HP:0002858', (197, 207))	('UVM', 'Disease', (148, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
76111	23550303	Also, they found that 2 of 7 probands from families with UVM-cutaneous melanoma carried germline BAP1 mutations, compared to 1 of 193 probands from families with a history of cutaneous melanoma and no UVMs (p=0.003).	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('UVM-cutaneous melanoma', 'Disease', 'MESH:C562393', (57, 79))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('UVM-cutaneous melanoma', 'Disease', (57, 79))	('cutaneous melanoma', 'Disease', (175, 193))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (175, 193))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (175, 193))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (61, 79))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))
76112	23550303	reported that 2 of 66 (3%) patients with UVM unselected for family history carried germline BAP1 mutations.	('mutations', 'Var', (97, 106))	('patients', 'Species', '9606', (27, 35))	('BAP1', 'Gene', (92, 96))
76113	23550303	Additional tumour types, including renal, breast and lung carcinomas were also found among BAP1 mutation carriers.	('BAP1', 'Gene', (91, 95))	('carriers', 'Reg', (105, 113))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('mutation', 'Var', (96, 104))	('renal', 'Disease', (35, 40))	('tumour', 'Disease', 'MESH:D009369', (11, 17))	('found', 'Reg', (79, 84))	('breast and lung carcinomas', 'Disease', 'MESH:D001943', (42, 68))	('tumour', 'Disease', (11, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
76114	23550303	Very recently, BAP1 mutations have been reported in sporadic renal carcinoma.	('renal carcinoma', 'Phenotype', 'HP:0005584', (61, 76))	('sporadic renal carcinoma', 'Disease', (52, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('sporadic renal carcinoma', 'Disease', 'MESH:C538614', (52, 76))	('reported', 'Reg', (40, 48))	('BAP1', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))
76115	23550303	Moreover, a novel inactivating germline splice mutation was reported in a family with UVM and cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('cutaneous melanoma', 'Disease', (94, 112))	('UVM', 'Disease', (86, 89))	('inactivating germline splice mutation', 'Var', (18, 55))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (94, 112))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (94, 112))
76117	23550303	To date, 53 of 76 BAP1 germline mutation carriers have developed malignancies; 13 of these 53 developed two or more cancers.	('germline mutation', 'Var', (23, 40))	('malignancies', 'Disease', 'MESH:D009369', (65, 77))	('BAP1', 'Gene', (18, 22))	('developed', 'PosReg', (55, 64))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('malignancies', 'Disease', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))
76120	23550303	In the BAP1 mutation families, there is an exceptionally high incidence of malignancy overall (69.74% cancer incidence among 76 mutation carriers).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('BAP1', 'Gene', (7, 11))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('malignancy', 'Disease', 'MESH:D009369', (75, 85))	('mutation', 'Var', (12, 20))	('malignancy', 'Disease', (75, 85))
76122	23550303	All of the mutation carriers unaffected by cancer are younger than 55 years old and may develop malignancies later in life.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('cancer', 'Disease', (43, 49))	('malignancies', 'Disease', (96, 108))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('mutation', 'Var', (11, 19))	('develop', 'PosReg', (88, 95))
76123	23550303	However, the relatively high frequency in the general population of the carcinomas that develop in BAP1 mutation carriers does not allow us yet to distinguish with certainty if the association with carcinomas is causal.	('BAP1', 'Gene', (99, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('carcinomas', 'Disease', 'MESH:D002277', (72, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('carcinomas', 'Disease', (72, 82))	('mutation', 'Var', (104, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (198, 208))	('carcinomas', 'Disease', (198, 208))	('carcinomas', 'Disease', 'MESH:D002277', (198, 208))
76124	23550303	It should also be noted that population-based studies have shown that mutation carriers in the general population may have a lower risk than suggested by estimates obtained from families with multiple tumours, as for example observed for CDKN2A mutations.	('multiple tumours', 'Disease', (192, 208))	('CDKN2A', 'Gene', (238, 244))	('CDKN2A', 'Gene', '1029', (238, 244))	('mutations', 'Var', (245, 254))	('multiple tumours', 'Disease', 'MESH:D009369', (192, 208))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('mutation', 'Var', (70, 78))	('tumours', 'Phenotype', 'HP:0002664', (201, 208))
76125	23550303	Therefore, large population based studies will be required to validate the association of germline BAP1 mutations with the exceptionally high incidence of malignancies detected in the BAP1 mutant families.	('BAP1', 'Gene', (99, 103))	('mutations', 'Var', (104, 113))	('mutant', 'Var', (189, 195))	('malignancies', 'Disease', 'MESH:D009369', (155, 167))	('BAP1', 'Gene', (184, 188))	('malignancies', 'Disease', (155, 167))	('association', 'Interaction', (75, 86))
76127	23550303	However, the Li-Fraumeni syndrome, caused by inherited mutations of the TP53 tumour suppressor gene, is an autosomal dominant cancer syndrome characteristically associated with the development of multiple tumour types .	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('caused by', 'Reg', (35, 44))	('Li-Fraumeni syndrome', 'Disease', (13, 33))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumour', 'Disease', (205, 211))	('multiple tumour', 'Disease', (196, 211))	('mutations', 'Var', (55, 64))	('TP53', 'Gene', '7157', (72, 76))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('autosomal dominant cancer syndrome', 'Disease', 'MESH:D009386', (107, 141))	('tumour', 'Disease', (77, 83))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('TP53', 'Gene', (72, 76))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (13, 33))	('autosomal dominant cancer syndrome', 'Disease', (107, 141))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('multiple tumour', 'Disease', 'MESH:D009369', (196, 211))
76132	23550303	Protein ubiquitylation was initially seen as a mechanism to label proteins for degradation; however, this notion has evolved as we have come to understand that ubiquitylation and DUBs regulate various cellular processes, including DNA repair, gene transcription, cell membrane trafficking, cell cycle progression, stress response, cell communication, differentiation and apoptosis, and that they have a role in cancer development.	('transcription', 'biological_process', 'GO:0006351', ('248', '261'))	('apoptosis', 'CPA', (371, 380))	('cancer', 'Disease', 'MESH:D009369', (411, 417))	('stress response', 'CPA', (314, 329))	('cell membrane trafficking', 'CPA', (263, 288))	('cell communication', 'biological_process', 'GO:0007154', ('331', '349'))	('differentiation', 'CPA', (351, 366))	('role', 'Reg', (403, 407))	('cell cycle progression', 'CPA', (290, 312))	('DNA repair', 'MPA', (231, 241))	('cell cycle', 'biological_process', 'GO:0007049', ('290', '300'))	('DNA', 'cellular_component', 'GO:0005574', ('231', '234'))	('cell membrane', 'cellular_component', 'GO:0005886', ('263', '276'))	('apoptosis', 'biological_process', 'GO:0097194', ('371', '380'))	('Protein ubiquitylation', 'biological_process', 'GO:0016567', ('0', '22'))	('cancer', 'Disease', (411, 417))	('apoptosis', 'biological_process', 'GO:0006915', ('371', '380'))	('degradation', 'biological_process', 'GO:0009056', ('79', '90'))	('regulate', 'Reg', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (411, 417))	('ubiquitylation', 'Var', (160, 174))	('cell communication', 'CPA', (331, 349))	('cellular processes', 'CPA', (201, 219))	('DNA repair', 'biological_process', 'GO:0006281', ('231', '241'))	('gene transcription', 'CPA', (243, 261))
76139	23550303	Indeed, inhibition of BAP1 by short hairpin RNAs (shRNAs) impaired the DDR and caused HeLa cells to become hypersensitive to ionizing radiation resulting in S-phase retardation, a phenotype similar to BRCA1 deficiency.	('hypersensitive', 'Disease', (107, 121))	('HeLa', 'CellLine', 'CVCL:0030', (86, 90))	('hypersensitive to ionizing radiation', 'Phenotype', 'HP:0011133', (107, 143))	('hypersensitive', 'Disease', 'MESH:D004342', (107, 121))	('DDR', 'MPA', (71, 74))	('BRCA1 deficiency', 'Disease', 'OMIM:604370', (201, 217))	('S-phase', 'biological_process', 'GO:0051320', ('157', '164'))	('inhibition', 'Var', (8, 18))	('retardation', 'Disease', (165, 176))	('retardation', 'Disease', 'MESH:D008607', (165, 176))	('impaired', 'NegReg', (58, 66))	('BAP1', 'Gene', (22, 26))	('BRCA1 deficiency', 'Disease', (201, 217))
76143	23550303	Accordingly, NCI-H226 cells expressing exogenous wild-type BAP1 grew poorly in cell culture and when injected into athymic nude mice, they formed tumours that were about 10-15-fold smaller than those obtained with cells infected with vector alone or expressing BAP1 mutants lacking deubiquitylating activity (C91A substitution) or the second nuclear localization signal, NLS2, that is required for the nuclear compartmentalization of BAP1.	('lacking', 'NegReg', (274, 281))	('tumours', 'Disease', 'MESH:D009369', (146, 153))	('tumours', 'Disease', (146, 153))	('deubiquitylating activity', 'MPA', (282, 307))	('C91A', 'SUBSTITUTION', 'None', (309, 313))	('localization', 'biological_process', 'GO:0051179', ('350', '362'))	('BAP1', 'Gene', (261, 265))	('mutants', 'Var', (266, 273))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('NCI-H226', 'CellLine', 'CVCL:1544', (13, 21))	('nude mice', 'Species', '10090', (123, 132))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('C91A', 'Var', (309, 313))
76147	23550303	HCF1 is ubiquitylated on lysine residues, preferentially through K48-linked and K63-linked chains.	('HCF1', 'Gene', (0, 4))	('K63-linked chains', 'Var', (80, 97))	('preferentially', 'PosReg', (42, 56))	('K48-linked', 'Var', (65, 75))	('lysine', 'Chemical', 'MESH:D008239', (25, 31))
76158	23550303	PRC2 might also be important in tumours that have mutant BAP1.	('tumours', 'Disease', 'MESH:D009369', (32, 39))	('tumours', 'Disease', (32, 39))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('mutant', 'Var', (50, 56))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('BAP1', 'Gene', (57, 61))
76160	23550303	proposed inhibiting PRC2 as a possible therapeutic strategy for treating mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (73, 85))	('mesothelioma', 'Disease', (73, 85))	('inhibiting', 'Var', (9, 19))	('PRC2', 'Gene', (20, 24))
76170	23550303	In the tumours that develop in BAP1 mutant carriers, BAP1 expression is either absent because of loss of heterozygosity (LOH), resulting in biallelic inactivation, or the BAP1 protein is localized in the cytoplasm where it may retain DUB activity, with as yet unknown possible effects on the cellular 'ubiquitinome'.	('biallelic', 'MPA', (140, 149))	('heterozygosity', 'MPA', (105, 119))	('absent', 'NegReg', (79, 85))	('expression', 'MPA', (58, 68))	('activity', 'MPA', (238, 246))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('tumours', 'Phenotype', 'HP:0002664', (7, 14))	('tumours', 'Disease', 'MESH:D009369', (7, 14))	('BAP1', 'Gene', (31, 35))	('cytoplasm', 'cellular_component', 'GO:0005737', ('204', '213'))	('mutant', 'Var', (36, 42))	('tumours', 'Disease', (7, 14))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))	('BAP1', 'Gene', (53, 57))
76171	23550303	Because germline BAP1 mutations are associated with mesotheliomas, UVMs and cutaneous melanomas, there should be some common pathways controlled by BAP1 that are of particular importance to the development of these malignancies.	('UVMs', 'Disease', (67, 71))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('mesotheliomas', 'Disease', 'MESH:D008654', (52, 65))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('mesotheliomas', 'Disease', (52, 65))	('malignancies', 'Disease', (215, 227))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (76, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (76, 94))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (76, 95))	('cutaneous melanomas', 'Disease', (76, 95))	('mutations', 'Var', (22, 31))	('associated', 'Reg', (36, 46))	('malignancies', 'Disease', 'MESH:D009369', (215, 227))	('BAP1', 'Gene', (17, 21))
76172	23550303	The finding that somatic BAP1 mutations are common in these cancers supports this interpretation.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('BAP1', 'Gene', (25, 29))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('common', 'Reg', (44, 50))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
76173	23550303	Somatic BAP1 mutations were found in 84% of metastasizing UVM biopsies and in 22% and 23% of sporadic US mesothelioma biopsies.	('mesothelioma', 'Disease', 'MESH:D008654', (105, 117))	('found', 'Reg', (28, 33))	('mesothelioma', 'Disease', (105, 117))	('BAP1', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))	('metastasizing UVM', 'Disease', (44, 61))
76174	23550303	found somatic inactivating BAP1 mutations in 61% of Japanese mesothelioma biopsies.	('BAP1', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('mesothelioma', 'Disease', (61, 73))	('mesothelioma', 'Disease', 'MESH:D008654', (61, 73))
76175	23550303	Studies in mice revealed that Bap1 deletion is lethal during embryogenesis.	('embryogenesis', 'biological_process', 'GO:0009790', ('61', '74'))	('Bap1', 'Gene', (30, 34))	('embryogenesis', 'biological_process', 'GO:0009793', ('61', '74'))	('mice', 'Species', '10090', (11, 15))	('deletion', 'Var', (35, 43))	('embryogenesis', 'biological_process', 'GO:0009792', ('61', '74'))	('Bap1', 'Gene', '104416', (30, 34))
76179	23550303	We are presently testing the hypothesis that germline Bap1 mutations increase the susceptibility to mineral fibre-induced and UV light-induced carcinogenesis; this may explain the absence of mesothelioma and melanoma in mice that were not exposed to these carcinogens.	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('mice', 'Species', '10090', (220, 224))	('mesothelioma and melanoma', 'Disease', 'MESH:D008654', (191, 216))	('Bap1', 'Gene', '104416', (54, 58))	('carcinogenesis', 'Disease', (143, 157))	('mutations', 'Var', (59, 68))	('Bap1', 'Gene', (54, 58))	('susceptibility', 'MPA', (82, 96))
76183	23550303	In such an environment, an impaired DDR caused by BAP1 deletion, might be expected to favour the accumulation of genetic damage that eventually gives rise to a malignant clone.	('favour', 'PosReg', (86, 92))	('genetic damage', 'Disease', 'MESH:D030342', (113, 127))	('gives rise to', 'Reg', (144, 157))	('genetic damage', 'Disease', (113, 127))	('DDR', 'MPA', (36, 39))	('malignant clone', 'CPA', (160, 175))	('deletion', 'Var', (55, 63))	('BAP1', 'Gene', (50, 54))	('accumulation', 'MPA', (97, 109))
76185	23550303	Moreover, we found very minimal and Wiesner et al, found no evidence of exposure to asbestos or erionite among the patients who developed mesothelioma in the families with BAP1 mutations, findings that do not support gene-environment interaction in causing mesothelioma, at least in these families.	('patients', 'Species', '9606', (115, 123))	('mesothelioma', 'Disease', (257, 269))	('asbestos', 'Disease', (84, 92))	('BAP1', 'Gene', (172, 176))	('mutations', 'Var', (177, 186))	('mesothelioma', 'Disease', (138, 150))	('asbestos', 'Disease', 'MESH:D001195', (84, 92))	('mesothelioma', 'Disease', 'MESH:D008654', (257, 269))	('erionite', 'Chemical', 'MESH:C083174', (96, 104))	('mesothelioma', 'Disease', 'MESH:D008654', (138, 150))
76189	23550303	Because BAP1 mutation carriers represent only a fraction of patients who develop UVM (3-4%), the overall association of UVM with UV light exposure should be re-evaluated in BAP1 mutations positive versus BAP1 mutation negative patients.	('mutation', 'Var', (13, 21))	('patients', 'Species', '9606', (60, 68))	('BAP1', 'Gene', (8, 12))	('BAP1', 'Gene', (173, 177))	('patients', 'Species', '9606', (227, 235))
76192	23550303	We anticipate that as more studies uncover the precise mechanisms by which BAP1 mutations cause mesothelioma and melanomas, specific preventive and therapeutic approaches for these malignancies will be developed (Box 1).	('mesothelioma and melanoma', 'Disease', 'MESH:D008654', (96, 121))	('melanomas', 'Disease', (113, 122))	('BAP1', 'Gene', (75, 79))	('mutations', 'Var', (80, 89))	('malignancies', 'Disease', 'MESH:D009369', (181, 193))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('malignancies', 'Disease', (181, 193))	('melanomas', 'Disease', 'MESH:D008545', (113, 122))	('cause', 'Reg', (90, 95))
76193	23550303	It is worth noting that a recent paper showed that histone deacetylase inhibitors (HDACIs) impair the in vitro and in vivo growth of UVM metastatic tumours with BAP1 inactivating mutations.	('tumours', 'Disease', 'MESH:D009369', (148, 155))	('tumours', 'Disease', (148, 155))	('BAP1', 'Gene', (161, 165))	('inactivating mutations', 'Var', (166, 188))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))	('growth', 'CPA', (123, 129))	('impair', 'NegReg', (91, 97))	('UVM', 'Disease', (133, 136))
76194	23550303	The apparent ability of BAP1 mutations to cause multiple tumour types and the high tumour phenotype penetrance (Table 1) suggests that this gene has a major role in influencing cancer cell growth.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cell growth', 'biological_process', 'GO:0016049', ('184', '195'))	('BAP1', 'Gene', (24, 28))	('multiple tumour', 'Disease', 'MESH:D009369', (48, 63))	('mutations', 'Var', (29, 38))	('cause', 'Reg', (42, 47))	('high tumour', 'Disease', (78, 89))	('high tumour', 'Disease', 'MESH:D009369', (78, 89))	('multiple tumour', 'Disease', (48, 63))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))
76202	23550303	Wiesner et al noted that in BAP1 mutation carriers benign melanocytic tumors develop during the second decade of life and their number increases with age, a finding confirmed in the BAP1 mutant families we are studying.	('mutation', 'Var', (33, 41))	('melanocytic tumors', 'Disease', 'MESH:D009508', (58, 76))	('BAP1', 'Gene', (28, 32))	('increases', 'PosReg', (135, 144))	('melanocytic tumors', 'Disease', (58, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))
76203	23550303	The occurrence of cutaneous melanoma in some BAP1 mutation carriers, including one that appeared to originate from these melanoctytic tumors, suggests that occasionally these benign tumors may undergo malignant transformation.	('melanoctytic tumors', 'Disease', (121, 140))	('melanoctytic tumors', 'Disease', 'MESH:D009369', (121, 140))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('BAP1', 'Gene', (45, 49))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('cutaneous melanoma', 'Disease', (18, 36))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (18, 36))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (18, 36))	('mutation', 'Var', (50, 58))
76204	23550303	This finding may account, at least in part, for the overall high risk of cutaneous melanoma detected among BAP1 germline mutation carriers (Table 1).	('cutaneous melanoma', 'Disease', (73, 91))	('germline mutation', 'Var', (112, 129))	('BAP1', 'Gene', (107, 111))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (73, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
76207	23550303	Suspected MBAITs could be removed and tested to identify patients with BAP1 mutations.	('patients', 'Species', '9606', (57, 65))	('BAP1', 'Gene', (71, 75))	('mutations', 'Var', (76, 85))
76211	23550303	Thus, the detection of families with inherited mutations of BAP1 offers opportunities for early cancer detection and more effective therapeutic approaches.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('BAP1', 'Gene', (60, 64))
76224	23914254	Similarly, detectable phosphorylated VEGF-R2 was present in all cells, which was reduced significantly in all cell lines following bevacizumab treatment (107525.2 +- 8602.0 versus 1024.5 +- 98.2, 46587.3 +- 4192.9 versus 12821.1 +- 1666.7, and 60394.3 +- 4026.4 versus 6908.2 +- 607.2; 92.1, OCM-1, and UW-1, respectively; P< 0.05).	('VEGF-R2', 'Gene', (37, 44))	('46587.3 +- 4192.9', 'Var', (196, 213))	('107525.2 +- 8602.0', 'Var', (154, 172))	('12821.1 +- 1666.7', 'Var', (221, 238))	('bevacizumab', 'Chemical', 'MESH:D000068258', (131, 142))	('VEGF-R2', 'Gene', '3791', (37, 44))	('OCM-1', 'Species', '83984', (292, 297))	('reduced', 'NegReg', (81, 88))	('phosphorylated', 'MPA', (22, 36))	('60394.3 +- 4026.4', 'Var', (244, 261))
76249	23914254	Reports vary with regard to VEGF-A positivity in primary UM tumours, ranging from 22% to 84%, and there are conflicting reports regarding correlations between expression levels and tumour size, vascularisation, or metastasis.	('VEGF-A', 'Gene', '7422', (28, 34))	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('tumour', 'Disease', (60, 66))	('VEGF-A', 'Gene', (28, 34))	('positivity', 'Var', (35, 45))	('tumours', 'Disease', (60, 67))	('tumour', 'Disease', 'MESH:D009369', (181, 187))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('tumour', 'Disease', (181, 187))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
76259	23914254	Finally, we determined how inhibiting VEGF-A affects the ability of our cell lines to proliferate, migrate, and invade.	('VEGF-A', 'Gene', '7422', (38, 44))	('inhibiting', 'Var', (27, 37))	('proliferate', 'CPA', (86, 97))	('VEGF-A', 'Gene', (38, 44))	('migrate', 'CPA', (99, 106))	('invade', 'CPA', (112, 118))
76270	23914254	For this experiment, we used two different platforms, which provide quantitative data pertaining to ten pro-angiogenic cytokines (angiogenin, ANG-2, EGF, bFGF, HB-EGF, HGF, Leptin, PDGF-BB, P1GF, and VEGF) and 20 cytokines (IL-1a, IL-2, IL-5, IL-8, IL-12p70, GM-CSF, IFNy, CCL3, MMP-9, TNF-a, IL-1b, IL-4, IL-6, IL-10, IL-13, GRO, MCP-1, MIP-1b, RANTES, and VEGF).	('EGF', 'Gene', '1950', (163, 166))	('ANG-2', 'Gene', '285', (142, 147))	('CCL', 'molecular_function', 'GO:0044101', ('273', '276'))	('EGF', 'molecular_function', 'GO:0005154', ('149', '152'))	('IL-1', 'molecular_function', 'GO:0005149', ('293', '297'))	('IL-12p70', 'Var', (249, 257))	('TNF-a', 'Gene', (286, 291))	('MIP-1b', 'Gene', '6351', (338, 344))	('HGF', 'Gene', '3082', (168, 171))	('EGF', 'molecular_function', 'GO:0005154', ('163', '166'))	('EGF', 'Gene', (149, 152))	('CCL3', 'Gene', (273, 277))	('IL-13', 'molecular_function', 'GO:0005144', ('319', '324'))	('MCP-1', 'Gene', (331, 336))	('GM-CSF', 'Gene', (259, 265))	('HB-EGF', 'Gene', (160, 166))	('Leptin', 'Gene', (173, 179))	('MCP', 'molecular_function', 'GO:0004298', ('331', '334'))	('IL-5', 'molecular_function', 'GO:0005137', ('237', '241'))	('MIP', 'molecular_function', 'GO:0004243', ('338', '341'))	('bFGF', 'Gene', '2247', (154, 158))	('PDGF', 'molecular_function', 'GO:0005161', ('181', '185'))	('HGF', 'Gene', (168, 171))	('IL-8', 'Gene', '3576', (243, 247))	('EGF', 'Gene', '1950', (201, 204))	('IL-13', 'Gene', '3596', (319, 324))	('IL-6', 'Gene', '3569', (306, 310))	('IL-5', 'Gene', (237, 241))	('IL-1a', 'Gene', '3552', (224, 229))	('angiogenin', 'Gene', (130, 140))	('VEGF', 'Gene', '7422', (358, 362))	('VEGF', 'Gene', '7422', (200, 204))	('Leptin', 'Gene', '3952', (173, 179))	('IL-2', 'Gene', (231, 235))	('MMP-9', 'molecular_function', 'GO:0004229', ('279', '284'))	('GM-CSF', 'Gene', '1437', (259, 265))	('EGF', 'Gene', (163, 166))	('MIP-1b', 'Gene', (338, 344))	('IL-6', 'Gene', (306, 310))	('VEGF', 'Gene', (358, 362))	('IL-2', 'molecular_function', 'GO:0005134', ('231', '235'))	('IL-4', 'molecular_function', 'GO:0005136', ('300', '304'))	('VEGF', 'Gene', (200, 204))	('IL-8', 'molecular_function', 'GO:0005153', ('243', '247'))	('EGF', 'Gene', '1950', (359, 362))	('bFGF', 'Gene', (154, 158))	('IFNy', 'Gene', (267, 271))	('angiogenin', 'Gene', '283', (130, 140))	('IL-12', 'molecular_function', 'GO:0005143', ('249', '254'))	('EGF', 'Gene', (201, 204))	('IL-10', 'Gene', '3586', (312, 317))	('TNF-a', 'Gene', '7124', (286, 291))	('IL-10', 'molecular_function', 'GO:0005141', ('312', '317'))	('IL-1b', 'Gene', '3553', (293, 298))	('IFNy', 'Gene', '3458', (267, 271))	('IL-13', 'Gene', (319, 324))	('RANTES', 'Gene', (346, 352))	('EGF', 'Gene', '1950', (149, 152))	('IL-4', 'Gene', '3565', (300, 304))	('MCP-1', 'Gene', '6347', (331, 336))	('CCL3', 'Gene', '6348', (273, 277))	('MMP-9', 'Gene', '4318', (279, 284))	('RANTES', 'Gene', '6352', (346, 352))	('IL-10', 'Gene', (312, 317))	('IL-1', 'molecular_function', 'GO:0005149', ('224', '228'))	('IL-8', 'Gene', (243, 247))	('IL-5', 'Gene', '3567', (237, 241))	('MMP-9', 'Gene', (279, 284))	('IL-1b', 'Gene', (293, 298))	('HB-EGF', 'Gene', '1839', (160, 166))	('IL-2', 'Gene', '3558', (231, 235))	('IL-6', 'molecular_function', 'GO:0005138', ('306', '310'))	('ANG-2', 'Gene', (142, 147))	('IL-4', 'Gene', (300, 304))	('IL-1a', 'Gene', (224, 229))	('EGF', 'Gene', (359, 362))
76278	23914254	Next, 30 muL of control and experimental samples were subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis on 8% acrylamide separating gel before being transferred to nitrocellulose membranes (Invitrogen) and incubating overnight at 4 C with Phospho-VEGF-R2 (1:500; Cell Signalling Technology, Beverly, Massachusetts, United States) and beta-Actin (1:1000; Abcam plc, Cambridge, Massachusetts).	('polyacrylamide', 'Chemical', 'MESH:C016679', (90, 104))	('acrylamide', 'Chemical', 'MESH:D020106', (94, 104))	('beta-Actin', 'Gene', (355, 365))	('acrylamide', 'Chemical', 'MESH:D020106', (131, 141))	('beta-Actin', 'Gene', '728378', (355, 365))	('sodium dodecyl sulfate', 'Chemical', 'MESH:D012967', (67, 89))	('Signalling', 'biological_process', 'GO:0023052', ('289', '299'))	('VEGF-R2', 'Gene', '3791', (268, 275))	('VEGF-R2', 'Gene', (268, 275))	('muL', 'Gene', '4591', (9, 12))	('muL', 'Gene', (9, 12))	('1:1000', 'Var', (367, 373))
76365	23914254	For instance, it has been shown that OCM-1 (a cell line used in the present study) produces high levels of notch signalling intermediates, whereas Mel290 expresses low levels.Moreover, it has been demonstrated in bladder carcinoma and glioblastoma that high DII4/Notch signalling may confer resistance to anti-VEGF therapies, thus offering a potential explanation for the aforementioned discrepancy.	('OCM-1', 'Species', '83984', (37, 42))	('glioblastoma', 'Disease', 'MESH:D005909', (235, 247))	('high', 'Var', (253, 257))	('VEGF', 'Gene', (310, 314))	('signalling', 'biological_process', 'GO:0023052', ('269', '279'))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('bladder carcinoma', 'Disease', (213, 230))	('bladder carcinoma', 'Disease', 'MESH:D001749', (213, 230))	('glioblastoma', 'Phenotype', 'HP:0012174', (235, 247))	('signalling', 'biological_process', 'GO:0023052', ('113', '123'))	('DII4/Notch signalling', 'MPA', (258, 279))	('DII4', 'Chemical', '-', (258, 262))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (213, 230))	('VEGF', 'Gene', '7422', (310, 314))	('resistance', 'CPA', (291, 301))	('glioblastoma', 'Disease', (235, 247))
76368	23914254	Thus, in our study, we hypothesise that bevacizumab blocked this signalling cascade that subsequently reduced migration; however, bevacizumab also increased MMP-9 secretion, permitting easier digestion of the basement membrane, which is an inherent impediment to migration in invasion assays.	('secretion', 'biological_process', 'GO:0046903', ('163', '172'))	('basement membrane', 'cellular_component', 'GO:0005604', ('209', '226'))	('increased', 'PosReg', (147, 156))	('digestion', 'MPA', (192, 201))	('bevacizumab', 'Chemical', 'MESH:D000068258', (130, 141))	('migration', 'CPA', (110, 119))	('digestion', 'biological_process', 'GO:0007586', ('192', '201'))	('bevacizumab', 'Chemical', 'MESH:D000068258', (40, 51))	('bevacizumab', 'Var', (130, 141))	('MMP-9', 'Gene', '4318', (157, 162))	('reduced', 'NegReg', (102, 109))	('MMP-9', 'Gene', (157, 162))	('MMP-9', 'molecular_function', 'GO:0004229', ('157', '162'))	('signalling cascade', 'biological_process', 'GO:0007165', ('65', '83'))	('easier', 'PosReg', (185, 191))
76376	23914254	In addition, it has been demonstrated that high MMP-9 expression in UM tumours is associated with poor prognosis.	('expression', 'MPA', (54, 64))	('MMP-9', 'Gene', '4318', (48, 53))	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('high', 'Var', (43, 47))	('MMP-9', 'Gene', (48, 53))	('MMP-9', 'molecular_function', 'GO:0004229', ('48', '53'))	('tumours', 'Disease', (71, 78))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('UM', 'Phenotype', 'HP:0007716', (68, 70))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
76388	23914254	Amplification of MMP-9, in turn, allows UM cells to degrade the extracellular matrix and escape the VEGF-A inhibited environment as well as releasing any ECM-bound VEGF.	('Amplification', 'Var', (0, 13))	('ECM', 'Gene', (154, 157))	('releasing', 'PosReg', (140, 149))	('MMP-9', 'Gene', (17, 22))	('VEGF', 'Gene', (164, 168))	('VEGF', 'Gene', '7422', (100, 104))	('VEGF', 'Gene', '7422', (164, 168))	('VEGF-A', 'Gene', '7422', (100, 106))	('MMP-9', 'molecular_function', 'GO:0004229', ('17', '22'))	('VEGF-A', 'Gene', (100, 106))	('UM', 'Phenotype', 'HP:0007716', (40, 42))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('64', '84'))	('ECM', 'Gene', '22915', (154, 157))	('VEGF', 'Gene', (100, 104))	('degrade', 'NegReg', (52, 59))	('MMP-9', 'Gene', '4318', (17, 22))
76398	23914254	The ideology that inhibiting a tumour's blood supply undeniably conforms with the aforementioned declaration; however, in UM cell lines, abrogating VEGF-A induces secretory changes in factors that can promote the accumulation of macrophages, which are indicators of poor prognosis, and gelatinases that facilitate haematogenous spreading.	('promote', 'PosReg', (201, 208))	('abrogating', 'Var', (137, 147))	('secretory changes in factors', 'MPA', (163, 191))	("tumour's blood", 'Disease', (31, 45))	('accumulation', 'MPA', (213, 225))	("tumour's blood", 'Disease', 'MESH:D009369', (31, 45))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('induces', 'Reg', (155, 162))	('VEGF-A', 'Gene', '7422', (148, 154))	('UM', 'Phenotype', 'HP:0007716', (122, 124))	('VEGF-A', 'Gene', (148, 154))
76399	23071601	A Novel Anticancer Therapy That Simultaneously Targets Aberrant p53 and Notch Activities in Tumors Notch signaling pathway plays an important role in tumorigenesis by maintaining the activity of self-renewal of cancer stem cells, and therefore, it is hypothesized that interference of Notch signaling may inhibit tumor formation and progression.	('tumor', 'Disease', (313, 318))	('activity', 'MPA', (183, 191))	('signaling', 'biological_process', 'GO:0023052', ('291', '300'))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('p53', 'Gene', '7157', (64, 67))	('Tumors', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('Aberrant', 'Var', (55, 63))	('self-renewal', 'CPA', (195, 207))	('Tumor', 'Phenotype', 'HP:0002664', (92, 97))	('p53', 'Gene', (64, 67))	('Tumors', 'Disease', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('inhibit', 'NegReg', (305, 312))	('tumor', 'Disease', (150, 155))	('Tumors', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', (12, 18))	('cancer', 'Disease', (211, 217))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('maintaining', 'PosReg', (167, 178))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('formation', 'biological_process', 'GO:0009058', ('319', '328'))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('99', '122'))	('interference', 'Var', (269, 281))
76404	23071601	Moreover, Notch1-siRNA increased Hexon gene expression at both the transcriptional and the translational levels, and promoted H101 replication in tumors, thereby enhancing the oncolytic activity of H101.	('Hexon gene', 'Protein', (33, 43))	('replication', 'MPA', (131, 142))	('oncolytic activity', 'CPA', (176, 194))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('gene expression', 'biological_process', 'GO:0010467', ('39', '54'))	('Notch1-siRNA', 'Var', (10, 22))	('enhancing', 'PosReg', (162, 171))	('increased', 'PosReg', (23, 32))	('promoted', 'PosReg', (117, 125))	('tumors', 'Disease', (146, 152))	('H101', 'Gene', (126, 130))
76405	23071601	These data demonstrate the feasibility to combine H101 p53-targted oncolysis and anti-Notch siRNA activities as a novel anti-cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('H101 p53-targted', 'Var', (50, 66))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('oncolysis', 'MPA', (67, 76))
76408	23071601	A virus-based strategy takes advantage of the fact that the intracellular replication and production of adenoviral progeny requires the cell cycle gatekeeper p53 to be in an inactive status, and in many tumors, p53 is either mutated or epigenetically silenced.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('epigenetically silenced', 'Var', (236, 259))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('p53', 'Gene', (211, 214))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('mutated', 'Var', (225, 232))	('gatekeeper', 'Species', '111938', (147, 157))	('cell cycle', 'biological_process', 'GO:0007049', ('136', '146'))	('intracellular', 'cellular_component', 'GO:0005622', ('60', '73'))
76416	23071601	In addition, the deletion of a 78.3-85.8 microm gene segment in the E3 region, which encodes the adenovirus death protein, may enhance the safety of the product.	('enhance', 'PosReg', (127, 134))	('adenovirus', 'Species', '28285', (97, 107))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('safety', 'MPA', (139, 145))	('deletion', 'Var', (17, 25))
76420	23071601	While there is abundant evidence that Notch signaling can stimulate the growth of wide range of tumors, the precise molecular mechanisms underlying alterations of this pathway during carcinogenesis are yet to be identified.	('carcinogenesis', 'Disease', (183, 197))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('signaling', 'biological_process', 'GO:0023052', ('44', '53'))	('stimulate', 'PosReg', (58, 67))	('carcinogenesis', 'Disease', 'MESH:D063646', (183, 197))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('Notch signaling', 'Var', (38, 53))	('growth', 'MPA', (72, 78))
76426	23071601	We have previously shown that knockdown of the Notch 1 gene could inhibit the proliferation and growth of HeLa cells both in vitro and in vivo .	('Notch 1', 'Gene', '4851', (47, 54))	('growth', 'CPA', (96, 102))	('HeLa', 'CellLine', 'CVCL:0030', (106, 110))	('inhibit', 'NegReg', (66, 73))	('Notch 1', 'Gene', (47, 54))	('knockdown', 'Var', (30, 39))
76427	23071601	In this study, we test a dual therapeutic approach by simultaneously targeting p53 mutations and aberrant Notch signal activity in tumors.	('mutations', 'Var', (83, 92))	('p53', 'Gene', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('Notch signal activity', 'MPA', (106, 127))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('aberrant', 'Var', (97, 105))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))
76429	23071601	It is assumed that H101 replication specifically lyses the bulk of cancer cells that are p53-inactive.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('H101', 'Var', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
76430	23071601	At the same time, Notch1 siRNA targets both the Notch-pathway mutated tumors and the minority CSC population of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('Notch-pathway', 'Gene', (48, 61))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('mutated', 'Var', (62, 69))
76431	23071601	As a first step to prove this concept, in this communication we report the in vitro and in vivo therapeutic effects of H101/Notch1-siRNA combined therapy in HeLa-S3 tumor cells.	('H101/Notch1-siRNA', 'Var', (119, 136))	('HeLa-S3 tumor', 'Disease', 'MESH:D009369', (157, 170))	('HeLa-S3 tumor', 'Disease', (157, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))
76433	23071601	Our previous in vitro and in vivo studies demonstrated that knockdown of the Notch 1 gene inhibited the proliferation and growth of HeLa cells.	('HeLa', 'CellLine', 'CVCL:0030', (132, 136))	('Notch 1', 'Gene', (77, 84))	('knockdown', 'Var', (60, 69))	('inhibited', 'NegReg', (90, 99))	('Notch 1', 'Gene', '4851', (77, 84))
76435	23071601	Using RT-PCR, we found that Notch1 was expressed in HeLa-S3 cells, while other three family members Notch2, Notch3, and Notch4 were barely detectable (Fig.	('Notch2', 'Gene', '4853', (100, 106))	('Notch4', 'Gene', '4855', (120, 126))	('HeLa-S3', 'CellLine', 'CVCL:0058', (52, 59))	('Notch4', 'Gene', (120, 126))	('Notch3', 'Gene', '4854', (108, 114))	('Notch2', 'Gene', (100, 106))	('Notch3', 'Gene', (108, 114))	('Notch1', 'Var', (28, 34))
76442	23071601	At this stage, animals began to receive an intra-tumor injection of Notch1-siRNA, H101 or PBS every three days, for a total of four injections.	('Notch1-siRNA', 'Var', (68, 80))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('PBS', 'Gene', (90, 93))	('intra-tumor', 'Disease', 'MESH:D009369', (43, 54))	('H101', 'Gene', (82, 86))	('PBS', 'Chemical', 'MESH:D007854', (90, 93))	('intra-tumor', 'Disease', (43, 54))
76446	23071601	Tumors from the H101-Notch1-siRNA treated group were more differentiated than those from the PBS treated group ( Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('PBS', 'Chemical', 'MESH:D007854', (93, 96))	('H101-Notch1-siRNA', 'Var', (16, 33))
76448	23071601	These data suggest an augment effect of Notch1-siRNA and H101 in inducing tumor apoptosis.	('inducing', 'PosReg', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('tumor', 'Disease', (74, 79))	('H101', 'Gene', (57, 61))	('augment', 'PosReg', (22, 29))	('Notch1-siRNA', 'Var', (40, 52))
76462	23071601	Notch1 antisense RNA treatment may lead to growth inhibition and even cell death if stably transfected in cervical cancer cells.	('cell death', 'biological_process', 'GO:0008219', ('70', '80'))	('cancer', 'Disease', (115, 121))	('antisense RNA', 'Var', (7, 20))	('Notch1', 'Gene', (0, 6))	('RNA', 'cellular_component', 'GO:0005562', ('17', '20'))	('antisense RNA', 'molecular_function', 'GO:0009388', ('7', '20'))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('growth inhibition', 'CPA', (43, 60))	('cell death', 'CPA', (70, 80))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
76463	23071601	Notch signaling promotes cell survival, and the increment in Notch1 activity promotes tumor growth in lung adenocarcinoma when cultured under hypoxic conditions.	('promotes', 'PosReg', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('promotes', 'PosReg', (77, 85))	('cell survival', 'CPA', (25, 38))	('tumor', 'Disease', (86, 91))	('signaling', 'biological_process', 'GO:0023052', ('6', '15'))	('Notch1', 'Gene', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (102, 121))	('hypoxic conditions', 'Disease', (142, 160))	('activity', 'MPA', (68, 76))	('increment', 'Var', (48, 57))	('hypoxic conditions', 'Disease', 'MESH:D009135', (142, 160))	('lung adenocarcinoma', 'Disease', (102, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (102, 121))
76467	23071601	Studies have demonstrated the existence of a novel intracellular mechanism for Notch1 regulation mediated by DDR1, in which deregulated DDR1 activation results in persistent autonomous activation of a Notch signaling and subsequent induction of Notch-dependent pro-survival neoplastics.	('intracellular', 'cellular_component', 'GO:0005622', ('51', '64'))	('pro-survival', 'biological_process', 'GO:0043066', ('261', '273'))	('signaling', 'biological_process', 'GO:0023052', ('207', '216'))	('DDR1', 'Gene', '780', (109, 113))	('Notch', 'Pathway', (201, 206))	('DDR1', 'Gene', (109, 113))	('regulation', 'biological_process', 'GO:0065007', ('86', '96'))	('DDR1', 'Gene', '780', (136, 140))	('activation', 'PosReg', (185, 195))	('DDR1', 'Gene', (136, 140))	('deregulated', 'Var', (124, 135))	('activation', 'PosReg', (141, 151))
76475	23071601	In this communication, we tested combined therapy of Notch1 siRNA with a p53-targeted oncolytic adenovirus H101, in order to target two common abnormalities in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('Notch1', 'Var', (53, 59))	('cancer', 'Disease', (160, 166))	('tested', 'Reg', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('adenovirus', 'Species', '28285', (96, 106))
76478	23071601	However, H101 has limited potential to eradicate tumors when used as monotherapy.	('H101', 'Var', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))
76481	23071601	The combined action of Notch1 knockdown and H101 oncolysis significantly inhibited tumor growth in vitro, suggesting an additional effect of the combined tumor therapy.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('H101', 'Var', (44, 48))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('inhibited', 'NegReg', (73, 82))	('knockdown', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('Notch1', 'Gene', (23, 29))	('tumor', 'Disease', (154, 159))
76482	23071601	In the animal studies, we used direct intratumoral injections of high concentrations of Notch1-siRNA to increase the efficiency of intracellular transport of siRNA in the animal models.	('increase', 'PosReg', (104, 112))	('intracellular', 'cellular_component', 'GO:0005622', ('131', '144'))	('Notch1-siRNA', 'Var', (88, 100))	('intracellular transport', 'biological_process', 'GO:0046907', ('131', '154'))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('intracellular transport', 'MPA', (131, 154))	('tumor', 'Disease', (43, 48))
76485	23071601	We also tested this combined therapy in other three tumor cell lines that had different status of p53 mutations, including lung cancer cells (A549) and uveal melanoma cells (OCM1 and VUP).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('A549', 'CellLine', 'CVCL:0023', (142, 146))	('uveal melanoma', 'Phenotype', 'HP:0007716', (152, 166))	('uveal melanoma', 'Disease', (152, 166))	('uveal melanoma', 'Disease', 'MESH:C536494', (152, 166))	('OCM1', 'Species', '83984', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (102, 111))	('p53', 'Gene', (98, 101))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))
76486	23071601	Both OCM1 and VUP cell lines contain a common mutation (C. 797G>A, P. Gly133Glu) in the exon 7 of p53, thus serving as a ideal therapeutic target for H101.	('Gly133Glu', 'Var', (70, 79))	('Gly133Glu', 'SUBSTITUTION', 'None', (70, 79))	('797G>A', 'Mutation', 'c.797G>A', (59, 65))	('C. 797G>A', 'Var', (56, 65))	('p53', 'Gene', (98, 101))	('OCM1', 'Species', '83984', (5, 9))
76489	23071601	Theoretically, the mutant virus with the deleted E1B, like H101, is able to replicate only in p53-defifcient cells.	('deleted', 'Var', (41, 48))	('E1B', 'Gene', (49, 52))	('E1B', 'Gene', '6080', (49, 52))
76490	23071601	The molecular basis for such p53 status-independent effect of H101 in certain tumor cells, like A549, remains to be determined.	('A549', 'CellLine', 'CVCL:0023', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('H101', 'Var', (62, 66))
76495	23071601	In tumor cells treated by the combined Notch1-siRNA and H101, we found an enhanced induction of apoptosis in HeLa-S3 cells, but we did not detect significant alteration of caspase-3 or activated caspase-3 expression.	('caspase-3', 'Gene', '836', (195, 204))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', (3, 8))	('HeLa-S3', 'CellLine', 'CVCL:0058', (109, 116))	('caspase-3', 'Gene', '836', (172, 181))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('83', '105'))	('apoptosis', 'CPA', (96, 105))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('caspase-3', 'Gene', (195, 204))	('H101', 'Var', (56, 60))	('caspase-3', 'Gene', (172, 181))	('Notch1-siRNA', 'Var', (39, 51))
76496	23071601	Neither Notch1-siRNA nor H101 appears to induce apoptosis by a non-caspase-3 pathway, and neither agent alters p53 expression.	('apoptosis', 'biological_process', 'GO:0006915', ('48', '57'))	('caspase-3', 'Gene', (67, 76))	('p53', 'Gene', (111, 114))	('expression', 'MPA', (115, 125))	('H101', 'Var', (25, 29))	('apoptosis', 'CPA', (48, 57))	('caspase-3', 'Gene', '836', (67, 76))	('apoptosis', 'biological_process', 'GO:0097194', ('48', '57'))
76498	23071601	MDM2 ablation in mice results in early embryonic lethality due to elevated levels of p53-induced apoptosis, and this phenotype is reversed by the simultaneous deletion of p53, demonstrating the importance of MDM2 in suppressing p53.	('mice', 'Species', '10090', (17, 21))	('apoptosis', 'biological_process', 'GO:0097194', ('97', '106'))	('embryonic lethality', 'Disease', (39, 58))	('p53-induced apoptosis', 'MPA', (85, 106))	('ablation', 'Var', (5, 13))	('apoptosis', 'biological_process', 'GO:0006915', ('97', '106'))	('MDM2', 'Gene', (0, 4))	('deletion', 'Var', (159, 167))	('p53', 'Gene', (171, 174))	('embryonic lethality', 'Disease', 'MESH:D020964', (39, 58))	('elevated', 'PosReg', (66, 74))
76505	23071601	Interestingly, we found that Notch1 knock-down increased the amplification of the adenovirus as measured by late gene Hexon protein.	('knock-down', 'Var', (36, 46))	('amplification', 'MPA', (61, 74))	('Notch1', 'Gene', (29, 35))	('increased', 'PosReg', (47, 56))	('adenovirus', 'Species', '28285', (82, 92))	('adenovirus', 'Protein', (82, 92))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))
76506	23071601	Thus, promotion of viral replication by Notch1-siRNA may partially explain the increased antitumor efficacy in our combined therapeutic approach.	('increased', 'PosReg', (79, 88))	('viral replication', 'MPA', (19, 36))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('viral replication', 'biological_process', 'GO:0008166', ('19', '36'))	('tumor', 'Disease', (93, 98))	('viral replication', 'biological_process', 'GO:0019058', ('19', '36'))	('Notch1-siRNA', 'Var', (40, 52))	('viral replication', 'biological_process', 'GO:0019079', ('19', '36'))	('promotion', 'PosReg', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
76510	23071601	We hypothesized that interference of Notch signaling may inhibit tumor formation and progression by cutting off the source for cancer stem cells, therefore enhancing the therapeutic efficacy of oncolytic H101.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('progression', 'CPA', (85, 96))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('cutting off', 'NegReg', (100, 111))	('inhibit', 'NegReg', (57, 64))	('interference', 'Var', (21, 33))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('formation', 'biological_process', 'GO:0009058', ('71', '80'))	('cancer', 'Disease', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Notch', 'Gene', (37, 42))	('enhancing', 'PosReg', (156, 165))	('signaling', 'biological_process', 'GO:0023052', ('43', '52'))	('therapeutic efficacy', 'MPA', (170, 190))
76511	23071601	It would be interesting in future studies to examine whether these strategies can be combined to offer a "three punch" approach by targeting p53 deficiency, Bcl2 overexpression, and cancer stem cell.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('p53', 'Gene', (141, 144))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('Bcl2', 'Gene', '596', (157, 161))	('deficiency', 'Var', (145, 155))	('cancer', 'Disease', (182, 188))	('Bcl2', 'Gene', (157, 161))
76513	23071601	We demonstrated an anticancer augmentation of the combined therapy of Notch1-siRNA and H101.	('augmentation', 'PosReg', (30, 42))	('H101', 'Gene', (87, 91))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('Notch1-siRNA', 'Var', (70, 82))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
76516	23071601	Our previous in vitro and in vivo studies also demonstrated that knockdown of the Notch 1 gene inhibited the proliferation and growth of HeLa cells.	('Notch 1', 'Gene', '4851', (82, 89))	('inhibited', 'NegReg', (95, 104))	('HeLa', 'CellLine', 'CVCL:0030', (137, 141))	('Notch 1', 'Gene', (82, 89))	('knockdown', 'Var', (65, 74))
76535	23071601	The 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was performed to assess the effect of H101 in combination with RNA interference on cell proliferation.	('RNA interference', 'biological_process', 'GO:0016246', ('145', '161'))	('RNA interference', 'MPA', (145, 161))	('3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide', 'Chemical', '-', (4, 69))	('cell proliferation', 'biological_process', 'GO:0008283', ('165', '183'))	('H101', 'Var', (120, 124))	('RNA', 'cellular_component', 'GO:0005562', ('145', '148'))	('MTT', 'Chemical', 'MESH:C070243', (71, 74))
76542	23071601	The Notch1-siRNA plus H101 group received intratumoral injections of 10 microg Notch1-siRNA on day 1, 4, 8, 11, 15, and H101 adenovirus at 1x108 plague-forming units on day 2, 5, 9, 12, and 16.	('H101', 'Var', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('adenovirus', 'Species', '28285', (125, 135))	('tumor', 'Disease', (47, 52))
76554	21451571	The ability to engage in apoptosis is critical to the tumour-suppressor role of p53 that is strongly supported by the presence of p53 mutations in over half of human cancers and the compromised p53 activity by other mechanisms in the majority of other cancers.	('cancers', 'Disease', (166, 173))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('cancers', 'Disease', (252, 259))	('tumour', 'Disease', (54, 60))	('cancers', 'Disease', 'MESH:D009369', (252, 259))	('apoptosis', 'biological_process', 'GO:0097194', ('25', '34'))	('apoptosis', 'biological_process', 'GO:0006915', ('25', '34'))	('activity', 'MPA', (198, 206))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('mutations', 'Var', (134, 143))	('p53', 'Gene', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('human', 'Species', '9606', (160, 165))
76558	21451571	We have shown that PERP is an important molecular determinant of apoptosis in primary uveal melanoma (UM) tumours that is significantly downregulated in the aggressive monosomy-3 type, compared with less aggressive disomy-3 type of UM.	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('uveal melanoma', 'Disease', 'MESH:C536494', (86, 100))	('downregulated', 'NegReg', (136, 149))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('uveal melanoma', 'Disease', (86, 100))	('tumours', 'Phenotype', 'HP:0002664', (106, 113))	('UM', 'Phenotype', 'HP:0007716', (232, 234))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('monosomy-3 type', 'Var', (168, 183))	('apoptosis', 'CPA', (65, 74))	('tumours', 'Disease', 'MESH:D009369', (106, 113))	('tumours', 'Disease', (106, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('UM', 'Phenotype', 'HP:0007716', (102, 104))
76564	21451571	There was also evidence that endogenous PERP protein (21 kDa) was slightly elevated in MEL202 cells at 72 h following transfection with GFP-PERP (Figure 1c).	('GFP-PERP', 'Gene', (136, 144))	('MEL202', 'CellLine', 'CVCL:C301', (87, 93))	('elevated', 'PosReg', (75, 83))	('GFP-PERP', 'Gene', '64065', (136, 144))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('transfection', 'Var', (118, 130))
76566	21451571	An increase in endogenous PERP was apparent in U2OS cells at 48 and 72 h following transfection with GFP-PERP (Figure 1c).	('GFP-PERP', 'Gene', (101, 109))	('increase', 'PosReg', (3, 11))	('endogenous PERP', 'MPA', (15, 30))	('transfection', 'Var', (83, 95))	('U2OS', 'CellLine', 'CVCL:0042', (47, 51))	('GFP-PERP', 'Gene', '64065', (101, 109))
76570	21451571	The first striking observation was the almost exclusive nuclear localization of MDM2-YFP when co-expressed with GFP-PERP (in 96.8% of co-transfected cells; T-test, P=0.02 and 0.04 versus MDM2-YFP or MDM2-YFP and GFP-only; Figures 2a and b).	('GFP-PERP', 'Gene', (112, 120))	('GFP-PERP', 'Gene', '64065', (112, 120))	('localization', 'biological_process', 'GO:0051179', ('64', '76'))	('nuclear localization', 'MPA', (56, 76))	('MDM2-YFP', 'Var', (80, 88))
76572	21451571	To determine the effect of PERP on the expression of MDM2, YFP fluorescence was measured in cells co-expressing GFP-PERP and MDM2-YFP and compared with that in control cells (MDM2-YFP-transfected and GFP-only plus MDM2-YFP co-transfected cells).	('GFP-PERP', 'Gene', '64065', (112, 120))	('MDM2-YFP-transfected and GFP-only plus MDM2-YFP', 'Disease', 'MESH:D054331', (175, 222))	('GFP-PERP', 'Gene', (112, 120))	('MDM2-YFP', 'Var', (125, 133))
76585	21451571	We also observed cell death in approximately 31% of cells expressing GFP-PERP and MDM2-YFP over the time frame of imaging, which corresponded to approximately 30-48-h post-transfection (PT).	('MDM2-YFP', 'Var', (82, 90))	('cell death', 'CPA', (17, 27))	('GFP-PERP', 'Gene', '64065', (69, 77))	('GFP-PERP', 'Gene', (69, 77))	('cell death', 'biological_process', 'GO:0008219', ('17', '27'))
76594	21451571	In response to DNA damage, phosphorylation by ataxia telangiectasia mutated and ataxia telangiectasia and Rad3 related at Ser15 and Ser37 can impair the interaction between p53 and MDM2, promoting the accumulation and activation of p53.	('activation', 'PosReg', (218, 228))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('impair', 'NegReg', (142, 148))	('telangiectasia', 'Phenotype', 'HP:0001009', (87, 101))	('ataxia telangiectasia', 'Disease', (46, 67))	('ataxia telangiectasia', 'Disease', (80, 101))	('p53', 'Protein', (173, 176))	('Ser', 'cellular_component', 'GO:0005790', ('122', '125'))	('promoting', 'PosReg', (187, 196))	('mutated', 'Var', (68, 75))	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('Ser15', 'Var', (122, 127))	('Ser', 'cellular_component', 'GO:0005790', ('132', '135'))	('MDM2', 'Protein', (181, 185))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (80, 101))	('telangiectasia', 'Phenotype', 'HP:0001009', (53, 67))	('interaction', 'Interaction', (153, 164))	('ataxia', 'Phenotype', 'HP:0001251', (80, 86))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (46, 67))	('Ser37', 'Chemical', '-', (132, 137))	('accumulation', 'MPA', (201, 213))	('Ser37', 'Var', (132, 137))	('Ser15', 'Chemical', '-', (122, 127))	('p53', 'Protein', (232, 235))	('phosphorylation', 'MPA', (27, 42))	('ataxia', 'Phenotype', 'HP:0001251', (46, 52))	('Rad', 'biological_process', 'GO:1990116', ('106', '109'))
76597	21451571	As p53Ser20P is known to interfere with p53 binding to MDM2, it is possible that this modification may contribute to the PERP-related increased p53 accumulation.	('interfere', 'NegReg', (25, 34))	('Ser', 'cellular_component', 'GO:0005790', ('6', '9'))	('p53Ser20P', 'Var', (3, 12))	('p53', 'Protein', (40, 43))	('p53', 'MPA', (144, 147))	('PERP-related', 'Disease', (121, 133))	('Ser20', 'Chemical', '-', (6, 11))	('accumulation', 'PosReg', (148, 160))	('binding', 'Interaction', (44, 51))	('p53 binding', 'molecular_function', 'GO:0002039', ('40', '51'))	('increased', 'PosReg', (134, 143))
76598	21451571	Total p53 protein level, detected using anti-p53 antibody (clone 7F5) confirmed the upregulation of p53 protein in cells transfected with GFP-PERP detected previously with a different anti-p53 antibody (clone DO-1; Figure 1a), albeit with a slightly higher p53 level in NT cells (Figure 5a).The detection of p53Ser15P in cells in which total p53 was low/undetectable (NT and GFP-only-transfected) is likely due to differences in antibody specificity.	('p53Ser15P', 'Var', (308, 317))	('antibody', 'cellular_component', 'GO:0019815', ('193', '201'))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('NT', 'Chemical', '-', (368, 370))	('antibody', 'molecular_function', 'GO:0003823', ('49', '57'))	('antibody', 'cellular_component', 'GO:0019814', ('429', '437'))	('antibody', 'cellular_component', 'GO:0042571', ('49', '57'))	('antibody', 'cellular_component', 'GO:0019814', ('193', '201'))	('Ser', 'cellular_component', 'GO:0005790', ('311', '314'))	('antibody', 'molecular_function', 'GO:0003823', ('429', '437'))	('NT', 'Chemical', '-', (270, 272))	('antibody', 'cellular_component', 'GO:0042571', ('429', '437'))	('antibody', 'cellular_component', 'GO:0019815', ('429', '437'))	('GFP-PERP', 'Gene', (138, 146))	('antibody', 'cellular_component', 'GO:0019815', ('49', '57'))	('GFP-PERP', 'Gene', '64065', (138, 146))	('antibody', 'molecular_function', 'GO:0003823', ('193', '201'))	('antibody', 'cellular_component', 'GO:0042571', ('193', '201'))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('antibody', 'cellular_component', 'GO:0019814', ('49', '57'))
76599	21451571	Phosphorylation of p53 at Ser46 was characterized as a specific phosphorylation event that irreversibly commits cells to apoptosis.	('phosphorylation', 'biological_process', 'GO:0016310', ('64', '79'))	('Ser46', 'Chemical', '-', (26, 31))	('Phosphorylation', 'Var', (0, 15))	('Ser46', 'Var', (26, 31))	('p53', 'Gene', (19, 22))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('apoptosis', 'biological_process', 'GO:0097194', ('121', '130'))	('Ser', 'cellular_component', 'GO:0005790', ('26', '29'))	('apoptosis', 'biological_process', 'GO:0006915', ('121', '130'))
76600	21451571	We detected the presence of p53Ser46P in control MEL202 cells with significantly higher levels in GFP-PERP-expressing cells (T-test, P<=0.03 versus GFP-only-transfected cells; Figure 5b), indicating that the p53 protein elevated in response to PERP expression is likely to be active in apoptosis regulation.	('protein', 'Protein', (212, 219))	('apoptosis', 'biological_process', 'GO:0097194', ('286', '295'))	('GFP-PERP', 'Gene', (98, 106))	('regulation', 'biological_process', 'GO:0065007', ('296', '306'))	('apoptosis', 'biological_process', 'GO:0006915', ('286', '295'))	('MEL202', 'CellLine', 'CVCL:C301', (49, 55))	('GFP-PERP', 'Gene', '64065', (98, 106))	('higher', 'PosReg', (81, 87))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('Ser', 'cellular_component', 'GO:0005790', ('31', '34'))	('p53', 'Gene', (208, 211))	('elevated', 'PosReg', (220, 228))	('Ser46', 'Chemical', '-', (31, 36))	('p53Ser46P', 'Var', (28, 37))
76603	21451571	Q-PCR analysis of p53 target genes revealed a statistically significant upregulation of death receptor 4 (DR4) and leucine-rich repeats and death domain containing (LRDD), both pro-apoptotic genes in MEL202 cells expressing GFP-PERP compared with GFP-only-expressing cells (Figure 5c).	('death receptor 4', 'Gene', (88, 104))	('leucine-rich repeats', 'Var', (115, 135))	('upregulation', 'PosReg', (72, 84))	('LRDD', 'Gene', (165, 169))	('death receptor 4', 'Gene', '8797', (88, 104))	('MEL202', 'CellLine', 'CVCL:C301', (200, 206))	('GFP-PERP', 'Gene', (224, 232))	('DR4', 'Gene', '8797', (106, 109))	('LRDD', 'Gene', '55367', (165, 169))	('DR4', 'Gene', (106, 109))	('GFP-PERP', 'Gene', '64065', (224, 232))
76611	21451571	Furthermore, time-lapse analysis of individual cells co-expressing GFP-PERP and MDM2-YFP provided evidence of the oscillatory nature of p53 regulation, manifested in regular pulses in MDM2 at 5-6-h intervals, analogous with previously reported oscillatory behaviour of p53 in DNA-damaged cells.	('GFP-PERP', 'Gene', (67, 75))	('GFP-PERP', 'Gene', '64065', (67, 75))	('behaviour', 'biological_process', 'GO:0007610', ('256', '265'))	('regulation', 'biological_process', 'GO:0065007', ('140', '150'))	('DNA', 'cellular_component', 'GO:0005574', ('276', '279'))	('MDM2', 'Var', (184, 188))	('oscillatory', 'MPA', (114, 125))	('oscillatory behaviour', 'Phenotype', 'HP:0032104', (244, 265))	('MDM2-YFP', 'Var', (80, 88))	('p53', 'Gene', (136, 139))
76612	21451571	Cell death following co-expression of GFP-PERP with MDM2-YFP was consistent with the previously observed level of apoptosis in GFP-PERP-expressing MEL202 cells, substantiating the finding that elevated PERP is sufficient to induce apoptosis in MEL202 cells via the caspase-dependent pathway, downstream of the p53/MDM2 feedback loop junction.	('apoptosis', 'CPA', (231, 240))	('apoptosis', 'biological_process', 'GO:0097194', ('231', '240'))	('PERP', 'Var', (202, 206))	('apoptosis', 'biological_process', 'GO:0097194', ('114', '123'))	('Cell death', 'biological_process', 'GO:0008219', ('0', '10'))	('GFP-PERP', 'Gene', (127, 135))	('MEL202', 'CellLine', 'CVCL:C301', (244, 250))	('apoptosis', 'biological_process', 'GO:0006915', ('231', '240'))	('induce', 'PosReg', (224, 230))	('GFP-PERP', 'Gene', '64065', (127, 135))	('GFP-PERP', 'Gene', '64065', (38, 46))	('Cell death', 'Disease', 'MESH:D003643', (0, 10))	('GFP-PERP', 'Gene', (38, 46))	('Cell death', 'Disease', (0, 10))	('caspase-dependent pathway', 'Pathway', (265, 290))	('apoptosis', 'biological_process', 'GO:0006915', ('114', '123'))	('MEL202', 'CellLine', 'CVCL:C301', (147, 153))
76616	21451571	Phosphorylation at p53Ser15, Ser20 and Ser37 can lower the affinity between p53 and MDM2, resulting in their reduced interaction and the subsequent accumulation of p53.	('Ser20', 'Chemical', '-', (29, 34))	('p53', 'Protein', (76, 79))	('p53', 'MPA', (164, 167))	('p53Ser15', 'Var', (19, 27))	('Ser', 'cellular_component', 'GO:0005790', ('22', '25'))	('Ser20', 'Var', (29, 34))	('Ser37', 'Var', (39, 44))	('interaction', 'Interaction', (117, 128))	('Ser37', 'Chemical', '-', (39, 44))	('affinity', 'Interaction', (59, 67))	('lower', 'NegReg', (49, 54))	('accumulation', 'PosReg', (148, 160))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('reduced', 'NegReg', (109, 116))	('Ser', 'cellular_component', 'GO:0005790', ('29', '32'))	('MDM2', 'Protein', (84, 88))	('Ser', 'cellular_component', 'GO:0005790', ('39', '42'))
76617	21451571	Our results showed that p53Ser15 phosphorylation is reduced in cells expressing PERP, however, a slight but significant increase in the level of p53Ser20 phosphorylation was detected in the presence of elevated PERP.	('Ser', 'cellular_component', 'GO:0005790', ('148', '151'))	('reduced', 'NegReg', (52, 59))	('p53Ser15', 'Protein', (24, 32))	('phosphorylation', 'biological_process', 'GO:0016310', ('154', '169'))	('Ser15', 'Chemical', '-', (27, 32))	('Ser', 'cellular_component', 'GO:0005790', ('27', '30'))	('PERP', 'Var', (80, 84))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('increase', 'PosReg', (120, 128))	('Ser20', 'Chemical', '-', (148, 153))
76618	21451571	Phosphorylation at Ser20 enhances p53 tetramerization, nuclear accumulation, stability and transcriptional activity, and therefore it is likely that this modification contributes to the stability and increased levels of nuclear p53 seen in response to PERP expression.	('Ser20', 'Chemical', '-', (19, 24))	('Ser20', 'Var', (19, 24))	('Phosphorylation', 'Var', (0, 15))	('enhances', 'PosReg', (25, 33))	('nuclear', 'CPA', (55, 62))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('Ser', 'cellular_component', 'GO:0005790', ('19', '22'))	('transcriptional activity', 'CPA', (91, 115))	('p53', 'Protein', (34, 37))	('stability', 'MPA', (77, 86))
76620	21451571	The increase in p53Ser46P induced by PERP expression is likely insufficient to drive the switch of gene-promoter targets to the level seen in response to genotoxic stress.	('Ser46', 'Chemical', '-', (19, 24))	('insufficient', 'Disease', 'MESH:D000309', (63, 75))	('insufficient', 'Disease', (63, 75))	('response to genotoxic stress', 'biological_process', 'GO:0006974', ('142', '170'))	('p53Ser46P', 'Var', (16, 25))	('Ser', 'cellular_component', 'GO:0005790', ('19', '22'))	('increase', 'PosReg', (4, 12))	('PERP', 'Gene', (37, 41))
76623	21451571	PERP expression may enhance these signals or may render p53 more susceptible to Ser46 phosphorylation.	('Ser', 'cellular_component', 'GO:0005790', ('80', '83'))	('more', 'PosReg', (60, 64))	('phosphorylation', 'biological_process', 'GO:0016310', ('86', '101'))	('PERP expression', 'Var', (0, 15))	('p53', 'Gene', (56, 59))	('Ser46 phosphorylation', 'MPA', (80, 101))	('enhance', 'PosReg', (20, 27))	('susceptible', 'MPA', (65, 76))	('render', 'Reg', (49, 55))	('Ser46', 'Chemical', '-', (80, 85))
76624	21451571	Initial experiments suggest that p53Ser46 phosphorylation in response to PERP may occur by processes other than HIPK2 or p38 activation.	('Ser46', 'Chemical', '-', (36, 41))	('p53Ser46', 'Var', (33, 41))	('phosphorylation', 'MPA', (42, 57))	('Ser', 'cellular_component', 'GO:0005790', ('36', '39'))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))
76625	21451571	Many tumours express p53 mutants with a reduced ability to activate p53-target gene expression that normally respond to wild-type p53 activation.	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('mutants', 'Var', (25, 32))	('gene expression', 'biological_process', 'GO:0010467', ('79', '94'))	('tumours', 'Disease', 'MESH:D009369', (5, 12))	('activate', 'PosReg', (59, 67))	('tumours', 'Disease', (5, 12))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('p53', 'Gene', (21, 24))
76626	21451571	This study demonstrates the transcriptional activity of p53 in MEL202 cells and reflects the reported low frequency of p53 mutations in primary UMs.	('MEL202', 'CellLine', 'CVCL:C301', (63, 69))	('UM', 'Phenotype', 'HP:0007716', (144, 146))	('transcriptional activity', 'MPA', (28, 52))	('p53', 'Gene', (119, 122))	('mutations', 'Var', (123, 132))
76656	32239153	Germline MBD4 Mutations and Predisposition to Uveal Melanoma Uveal melanoma (UM) arises from malignant transformation of melanocytes in the uveal tract of the eye.	('MBD4', 'Gene', (9, 13))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (46, 60))	('Melanoma', 'Disease', 'MESH:D008545', (52, 60))	('Melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('Melanoma', 'Disease', (52, 60))	('malignant transformation of melanocytes', 'Phenotype', 'HP:0002861', (93, 132))	('Mutations', 'Var', (14, 23))	('MBD4', 'Gene', '8930', (9, 13))
76659	32239153	UMs are generally characterized by low tumor mutation burden, but some UMs display a high level of CpG>TpG mutations associated with MBD4 inactivation.	('low tumor', 'Disease', 'MESH:D009800', (35, 44))	('CpG', 'Var', (99, 102))	('MBD4', 'Gene', '8930', (133, 137))	('low tumor', 'Disease', (35, 44))	('MBD4', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))
76660	32239153	Here, we explored the incidence of germline MBD4 variants in a consecutive series of 1093 primary UM case patients and a series of 192 UM tumors with monosomy 3 (M3).	('MBD4', 'Gene', '8930', (44, 48))	('MBD4', 'Gene', (44, 48))	('variants', 'Var', (49, 57))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Disease', (138, 144))	('patients', 'Species', '9606', (106, 114))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
76662	32239153	MBD4 variants (n = 28) were validated by Sanger sequencing.	('MBD4', 'Gene', '8930', (0, 4))	('MBD4', 'Gene', (0, 4))	('variants', 'Var', (5, 13))
76663	32239153	We performed whole-exome sequencing on available tumor samples harboring MBD4 variants (n = 9).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('MBD4', 'Gene', '8930', (73, 77))	('MBD4', 'Gene', (73, 77))	('variants', 'Var', (78, 86))
76664	32239153	We identified 8 deleterious MBD4 mutations in the consecutive UM series, a 9.15-fold (95% confidence interval = 4.24-fold to 19.73-fold) increased incidence compared with the general population (Fisher exact test, P = 2.00 x 10-5, 2-sided), and 4 additional deleterious MBD4 mutations in the M3 cohort, including 3 germline and 1 somatic mutations.	('MBD4', 'Gene', '8930', (270, 274))	('MBD4', 'Gene', (270, 274))	('mutations', 'Var', (33, 42))	('MBD4', 'Gene', '8930', (28, 32))	('MBD4', 'Gene', (28, 32))
76665	32239153	Tumors carrying deleterious MBD4 mutations were all associated with high tumor mutation burden and a CpG>TpG hypermutator phenotype.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('associated', 'Reg', (52, 62))	('mutations', 'Var', (33, 42))	('Tumors', 'Disease', (0, 6))	('tumor', 'Disease', (73, 78))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('MBD4', 'Gene', '8930', (28, 32))	('MBD4', 'Gene', (28, 32))
76671	32239153	UMs with high risk of developing metastases are characterized by loss of chromosome 3 and by BAP1 (encoded in 3p21) inactivation resulting from loss-of-function (LoF) mutations and loss of the remaining wild-type copy on chromosome 3.	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('inactivation', 'NegReg', (116, 128))	('loss', 'NegReg', (65, 69))	('BAP1', 'Gene', '8314', (93, 97))	('metastases', 'Disease', (33, 43))	('loss-of-function', 'NegReg', (144, 160))	('chromosome', 'cellular_component', 'GO:0005694', ('221', '231'))	('mutations', 'Var', (167, 176))	('metastases', 'Disease', 'MESH:D009362', (33, 43))	('BAP1', 'Gene', (93, 97))	('loss', 'NegReg', (181, 185))
76672	32239153	Rare familial UMs are associated with germline mutations of BAP1 (Mendelian Inheritance in Man [MIM]: 614327), which is the only known highly penetrant UM predisposition gene.	('familial UMs', 'Disease', (5, 17))	('BAP1', 'Gene', '8314', (60, 64))	('germline mutations', 'Var', (38, 56))	('associated', 'Reg', (22, 32))	('BAP1', 'Gene', (60, 64))
76674	32239153	Recently, the characterization of a metastatic UM patient with an exceptional response to anti-Programmed cell death protein 1 (anti-PD-1) therapy led us to identify a CpG>TpG mutator phenotype linked to germline protein truncating variants (PTV) in MBD4 (Methyl-CpG Binding Domain Protein 4) and somatic loss of the wild-type allele in tumors in 2 patients with UM and 1 with glioma.	('protein', 'cellular_component', 'GO:0003675', ('213', '220'))	('Methyl-CpG Binding Domain Protein 4', 'Gene', '8930', (256, 291))	('glioma', 'Disease', (377, 383))	('patient', 'Species', '9606', (349, 356))	('glioma', 'Disease', 'MESH:D005910', (377, 383))	('Programmed cell death protein 1', 'Gene', '5133', (95, 126))	('MBD4', 'Gene', '8930', (250, 254))	('Methyl-CpG Binding Domain Protein 4', 'Gene', (256, 291))	('tumors', 'Phenotype', 'HP:0002664', (337, 343))	('PTV', 'cellular_component', 'GO:1990257', ('242', '245'))	('loss', 'NegReg', (305, 309))	('variants', 'Var', (232, 240))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('glioma', 'Phenotype', 'HP:0009733', (377, 383))	('MBD4', 'Gene', (250, 254))	('CpG', 'Var', (168, 171))	('tumors', 'Disease', (337, 343))	('Methyl-CpG Binding', 'molecular_function', 'GO:0008327', ('256', '274'))	('PD-1', 'Gene', (133, 137))	('PD-1', 'Gene', '5133', (133, 137))	('patients', 'Species', '9606', (349, 357))	('Programmed cell death protein 1', 'Gene', (95, 126))	('Programmed cell death', 'biological_process', 'GO:0012501', ('95', '116'))	('linked', 'Reg', (194, 200))	('tumors', 'Disease', 'MESH:D009369', (337, 343))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('patient', 'Species', '9606', (50, 57))
76678	32239153	Altogether, these germline deleterious MBD4 variants in UM prompted us to investigate the role of MBD4 as a predisposing gene for UM.	('MBD4', 'Gene', '8930', (39, 43))	('MBD4', 'Gene', (39, 43))	('MBD4', 'Gene', (98, 102))	('MBD4', 'Gene', '8930', (98, 102))	('variants', 'Var', (44, 52))
76679	32239153	Here, we performed MBD4 targeted-sequencing in germline DNA of a large consecutive series of 1093 UM patients and in tumor DNA of a second cohort of 192 UM patients with M3 and investigated the TMB and mutational signature in patients harboring MBD4 mutations.	('patients', 'Species', '9606', (156, 164))	('patients', 'Species', '9606', (101, 109))	('MBD4', 'Gene', '8930', (19, 23))	('MBD4', 'Gene', (19, 23))	('MBD4', 'Gene', (245, 249))	('MBD4', 'Gene', '8930', (245, 249))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('DNA', 'cellular_component', 'GO:0005574', ('123', '126'))	('tumor', 'Disease', (117, 122))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('mutations', 'Var', (250, 259))	('patients', 'Species', '9606', (226, 234))	('TMB', 'Chemical', '-', (194, 197))	('investigated', 'Reg', (177, 189))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
76686	32239153	Germline DNA of 1099 UM patients from the UM consecutive series (before removal of the 6 a forementioned patients) and DNA of a series of 192 M3 UM tumors were screened for MBD4 variants by pooled MBD4 targeted sequencing.	('variants', 'Var', (178, 186))	('patients', 'Species', '9606', (105, 113))	('MBD4', 'Gene', '8930', (173, 177))	('MBD4', 'Gene', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('MBD4', 'Gene', '8930', (197, 201))	('MBD4', 'Gene', (197, 201))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('patients', 'Species', '9606', (24, 32))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Disease', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))
76687	32239153	Deconvolution of the identified pooled DNA samples with an MBD4 variant was carried out by Sanger sequencing.	('MBD4', 'Gene', '8930', (59, 63))	('MBD4', 'Gene', (59, 63))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('variant', 'Var', (64, 71))
76688	32239153	Identified MBD4 variants (Supplementary Table 1, available online) were defined following the recommendations of the Human Genome Variation Society (http://varnomen.hgvs.org/) and numbered based on the MBD4 (MIM: 603574) cDNA and protein sequences (GenBank accession numbers NM_003925.2 and NP_003916.1, respectively).	('MBD4', 'Gene', '8930', (202, 206))	('MBD4', 'Gene', (202, 206))	('Human', 'Species', '9606', (117, 122))	('MBD4', 'Gene', '8930', (11, 15))	('MBD4', 'Gene', (11, 15))	('variants', 'Var', (16, 24))	('protein', 'cellular_component', 'GO:0003675', ('230', '237'))
76689	32239153	Wild-type and mutant MBD4 were expressed to assess their enzymatic activity by in vitro MBD4 glycosylase assay as previously described (Supplementary Methods, available online).	('MBD4', 'Gene', '8930', (88, 92))	('MBD4', 'Gene', (88, 92))	('mutant', 'Var', (14, 20))	('MBD4', 'Gene', '8930', (21, 25))	('MBD4', 'Gene', (21, 25))	('glycosylase', 'molecular_function', 'GO:0016798', ('93', '104'))
76690	32239153	WES was performed on tumor samples from MBD4 variant carriers who consented to germline studies (Supplementary Table 2, available online).	('MBD4', 'Gene', '8930', (40, 44))	('MBD4', 'Gene', (40, 44))	('tumor', 'Disease', (21, 26))	('variant', 'Var', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
76694	32239153	To evaluate the potential predisposing role of MBD4 in UM, we mined all available public UM cohorts for germline MBD4 variants.	('MBD4', 'Gene', '8930', (113, 117))	('MBD4', 'Gene', (113, 117))	('MBD4', 'Gene', '8930', (47, 51))	('MBD4', 'Gene', (47, 51))	('variants', 'Var', (118, 126))
76695	32239153	We identified 1 case harboring the germline deleterious MBD4 PTV c.1443delT (p.Leu482Trpfs*9) in a first cohort containing 37 UM patients (phs001421.v1.p1).	('MBD4', 'Gene', (56, 60))	('p.Leu482Trpfs*9', 'Var', (77, 92))	('patients', 'Species', '9606', (129, 137))	('p.Leu482Trpfs*9', 'FRAMESHIFT', 'None', (77, 92))	('p1', 'Gene', '1423', (152, 154))	('c.1443delT', 'Mutation', 'rs769076971', (65, 75))	('PTV', 'cellular_component', 'GO:1990257', ('61', '64'))	('MBD4', 'Gene', '8930', (56, 60))
76696	32239153	A second cohort of 98 UM patients (phs000823.v1.p1) included a second case with an MBD4 c.1020delA (p.Asp341Thrfs*13) PTV.	('p.Asp341Thrfs*13', 'FRAMESHIFT', 'None', (100, 116))	('p1', 'Gene', '1423', (48, 50))	('PTV', 'cellular_component', 'GO:1990257', ('118', '121'))	('c.1020delA', 'Mutation', 'c.1020delA', (88, 98))	('p.Asp341Thrfs*13', 'Var', (100, 116))	('patients', 'Species', '9606', (25, 33))	('MBD4', 'Gene', '8930', (83, 87))	('MBD4', 'Gene', (83, 87))
76698	32239153	In contrast, such variants are exceedingly rare in an unselected population (88 of approximately 125 000 individuals in GnomAD v2.1.1).	('v2.1.1', 'Gene', (127, 133))	('v2.1.1', 'Gene', '28799', (127, 133))	('variants', 'Var', (18, 26))
76699	32239153	Out of these 5 UM case patients with germline MBD4 variants, 4 had available tumor profiles that all showed M3 and somatic BAP1 inactivation, presumably because of the localization of both MBD4 and BAP1 on chromosome 3.	('BAP1', 'Gene', (123, 127))	('MBD4', 'Gene', '8930', (46, 50))	('MBD4', 'Gene', (46, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('206', '216'))	('patients', 'Species', '9606', (23, 31))	('variants', 'Var', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('BAP1', 'Gene', '8314', (198, 202))	('inactivation', 'NegReg', (128, 140))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('BAP1', 'Gene', '8314', (123, 127))	('localization', 'biological_process', 'GO:0051179', ('168', '180'))	('MBD4', 'Gene', '8930', (189, 193))	('MBD4', 'Gene', (189, 193))	('BAP1', 'Gene', (198, 202))	('tumor', 'Disease', (77, 82))
76701	32239153	Targeted next-generation sequencing in pooled patient DNA followed by Sanger sequencing revealed germline MBD4 PTVs in 7 patients (Table 1): 2 splice site variants (c.1562-1G>T [p.Asp521Profs*4] in 2 patients and a c.335 + 1G>A [p.Arg83Profs*5] variant), 2 frameshift deletion variants (c.1443delT [p.Leu482Trpfs*9] and c.1384delG [p.Ala462Leufs*29]), and 1 stop-gain near the end of the last exon of MBD4 (c.1706G>A [p.Trp569*] in 2 patients).	('c.1706G>A [', 'Var', (407, 418))	('c.1443delT', 'Mutation', 'rs769076971', (287, 297))	('MBD4', 'Gene', '8930', (401, 405))	('1G>A', 'SUBSTITUTION', 'None', (223, 227))	('c.1384delG', 'Mutation', 'c.1384delG', (320, 330))	('patient', 'Species', '9606', (121, 128))	('patient', 'Species', '9606', (200, 207))	('p.Ala462Leufs*29', 'FRAMESHIFT', 'None', (332, 348))	('p.Asp521Profs*4', 'FRAMESHIFT', 'None', (178, 193))	('patients', 'Species', '9606', (434, 442))	('c.1706G>A', 'Mutation', 'rs939751619', (407, 416))	('p.Trp569*', 'Mutation', 'rs939751619', (418, 427))	('MBD4', 'Gene', '8930', (106, 110))	('MBD4', 'Gene', (401, 405))	('p.Asp521Profs*4', 'Var', (178, 193))	('patient', 'Species', '9606', (46, 53))	('MBD4', 'Gene', (106, 110))	('1G>A', 'Var', (223, 227))	('c.1562-1G>T', 'Var', (165, 176))	('patients', 'Species', '9606', (121, 129))	('patient', 'Species', '9606', (434, 441))	('patients', 'Species', '9606', (200, 208))	('p.Arg83Profs*5', 'Var', (229, 243))	('c.1384delG', 'Var', (320, 330))	('p.Leu482Trpfs*9', 'FRAMESHIFT', 'None', (299, 314))	('c.1562-1G>T', 'Mutation', 'rs778697654', (165, 176))	('p.Ala462Leufs*29', 'Var', (332, 348))	('p.Arg83Profs*5', 'FRAMESHIFT', 'None', (229, 243))	('p.Leu482Trpfs*9', 'Var', (299, 314))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))
76702	32239153	We also identified and characterized 9 rare germline MBD4 variants (frequency <1% in the general population): 7 missense variants in 13 patients and 2 intronic variants in 2 patients (Figure 1A).	('MBD4', 'Gene', '8930', (53, 57))	('MBD4', 'Gene', (53, 57))	('variants', 'Var', (58, 66))	('missense variants', 'Var', (112, 129))	('patients', 'Species', '9606', (174, 182))	('patients', 'Species', '9606', (136, 144))
76703	32239153	Out of these, 3 were predicted with possible splicing consequences: 2 missense variants (c.1652A>G [p.Asn551Ser] and c.1400A>G [p.Asn467Ser]), and 1 intronic variant (c.1277-18T>A) (Supplementary Table 1, available online).	('p.Asn551Ser', 'Mutation', 'rs577234840', (100, 111))	('c.1277-18T>A', 'Var', (167, 179))	('c.1400A>G', 'Var', (117, 126))	('splicing', 'biological_process', 'GO:0045292', ('45', '53'))	('Ser', 'cellular_component', 'GO:0005790', ('136', '139'))	('c.1652A>G', 'Var', (89, 98))	('c.1277-18T>A', 'Mutation', 'rs1434697310', (167, 179))	('c.1400A>G', 'Mutation', 'rs78782061', (117, 126))	('p.Asn467Ser', 'Mutation', 'rs78782061', (128, 139))	('c.1652A>G', 'Mutation', 'rs577234840', (89, 98))	('Ser', 'cellular_component', 'GO:0005790', ('108', '111'))
76704	32239153	Exon-trapping assays performed on the 3 aforementioned variants demonstrated the use of an alternative acceptor site with c.1277-18T>A, albeit to a lesser extent than the canonical splice site, whereas c.1652A>G and c.1400A>G did not show any measurable effect (Supplementary Figure 2, available online).	('c.1400A>G', 'Var', (216, 225))	('c.1652A>G', 'Mutation', 'rs577234840', (202, 211))	('c.1277-18T>A', 'Var', (122, 134))	('c.1400A>G', 'Mutation', 'rs78782061', (216, 225))	('c.1277-18T>A', 'Mutation', 'rs1434697310', (122, 134))	('c.1652A>G', 'Var', (202, 211))
76705	32239153	All missense variants within the MBD4 glycosylase domain [aa425-580] were assessed by in vitro glycosylase assay together with p. Trp569* because of its localization near the end of the protein (Figure 1; Table 1).	('glycosylase', 'molecular_function', 'GO:0016798', ('95', '106'))	('MBD4', 'Gene', '8930', (33, 37))	('MBD4', 'Gene', (33, 37))	('glycosylase', 'molecular_function', 'GO:0016798', ('38', '49'))	('protein', 'cellular_component', 'GO:0003675', ('186', '193'))	('missense variants', 'Var', (4, 21))	('localization', 'MPA', (153, 165))	('Trp569', 'Chemical', '-', (130, 136))	('localization', 'biological_process', 'GO:0051179', ('153', '165'))
76706	32239153	The assay confirmed that p. Trp569* results in a catalytically inactive protein and further demonstrated p. Arg468Trp to be a LoF variant (Figure 1).	('Arg468Trp', 'Var', (108, 117))	('Trp569', 'Chemical', '-', (28, 34))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('catalytically inactive protein', 'MPA', (49, 79))	('Arg468Trp', 'SUBSTITUTION', 'None', (108, 117))	('p. Trp569*', 'Var', (25, 35))
76707	32239153	Consistent with this finding, the key role of Arg468 was previously established in binding at the G/T mismatch site, maintaining the T base in a position required for catalysis, and interacting with the orphan G base through hydrogen bonding.	('maintaining', 'PosReg', (117, 128))	('T base', 'MPA', (133, 139))	('Arg468', 'Var', (46, 52))	('Arg468', 'Chemical', '-', (46, 52))	('hydrogen bonding', 'Protein', (225, 241))	('binding', 'molecular_function', 'GO:0005488', ('83', '90'))	('interacting', 'Reg', (182, 193))	('hydrogen', 'Chemical', 'MESH:D006859', (225, 233))
76708	32239153	We next characterized by WES the 3 available tumors from patients carrying germline MBD4 LoF variants (UM75: p. Trp569*, UM605: p. Ala462Leufs*29, and UM656: p. Leu482Trpfs*9).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('MBD4', 'Gene', '8930', (84, 88))	('MBD4', 'Gene', (84, 88))	('tumors', 'Disease', (45, 51))	('patients', 'Species', '9606', (57, 65))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('Ala462Leufs', 'Chemical', '-', (131, 142))	('p. Ala462Leufs*29', 'Var', (128, 145))	('UM75: p. Trp569*', 'Var', (103, 119))	('p. Leu482Trpfs*9', 'Var', (158, 174))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('LoF', 'NegReg', (89, 92))	('Leu482Trpfs', 'Chemical', '-', (161, 172))	('Trp569', 'Chemical', '-', (112, 118))
76709	32239153	We confirmed that the 3 MBD4 germline LoF mutations were associated with somatic loss of the wild-type allele in the tumors by either M3 (UM75 and UM605) or isodisomy 3 (UM656) (Figure 1C;Supplementary Table 1, available online), consistent with the 3q21.3 location of MBD4.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('UM656', 'Var', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', (117, 123))	('mutations', 'Var', (42, 51))	('UM605', 'Var', (147, 152))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('MBD4', 'Gene', '8930', (24, 28))	('MBD4', 'Gene', (24, 28))	('loss', 'NegReg', (81, 85))	('MBD4', 'Gene', '8930', (269, 273))	('MBD4', 'Gene', (269, 273))
76710	32239153	To further evaluate the incidence of MBD4 alterations in UM, and assuming that MBD4def UMs are associated with M3, we accrued a series of 192 UM tumor samples with M3 (of which 120 case patients were independent from the present consecutive UM series) and screened for MBD4 mutations using the aforementioned strategy (Supplementary Figure 1B, available online).	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('MBD4', 'Gene', '8930', (37, 41))	('MBD4', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('MBD4', 'Gene', '8930', (79, 83))	('MBD4', 'Gene', (79, 83))	('mutations', 'Var', (274, 283))	('MBD4', 'Gene', '8930', (269, 273))	('MBD4', 'Gene', (269, 273))	('patients', 'Species', '9606', (186, 194))
76711	32239153	We identified 6 additional MBD4 variants, including 4 LoF mutations (UMT62: c.1688T>A [p.Leu563*], UMT45: c.1562-1G>T [p.Asp521Profs*4], UMT61: c.1002delTTTG [p.Lys335Phefs*18], UMT162: c.541C>T [p.Arg181*]) and 2 missense variants (UMT88: c.1402C>T [p.Arg468Trp] and UMT105: c.1073T>C [p.Ile358Thr]) (Table 1; Figure 1; Supplementary Table 1, available online).	('p.Asp521Profs*4', 'FRAMESHIFT', 'None', (119, 134))	('c.1688T>A', 'Mutation', 'rs200758755', (76, 85))	('p.Lys335Phefs*18', 'Var', (159, 175))	('p.Arg181*', 'Mutation', 'rs1270271346', (196, 205))	('p.Ile358Thr', 'Mutation', 'rs2307298', (287, 298))	('p.Lys335Phefs*18', 'FRAMESHIFT', 'None', (159, 175))	('LoF', 'NegReg', (54, 57))	('MBD4', 'Gene', '8930', (27, 31))	('MBD4', 'Gene', (27, 31))	('c.1562-1G>T', 'Mutation', 'rs778697654', (106, 117))	('c.1073T>C', 'Mutation', 'rs2307298', (276, 285))	('p.Asp521Profs*4', 'Var', (119, 134))	('p.Leu563*', 'Mutation', 'rs200758755', (87, 96))	('p.Arg468Trp', 'Mutation', 'rs1380952147', (251, 262))	('c.1402C>T', 'Mutation', 'rs1380952147', (240, 249))	('c.1002delTTTG', 'Mutation', 'c.1002delTTTG', (144, 157))	('c.541C>T', 'Mutation', 'rs1270271346', (186, 194))
76713	32239153	Characterization by WES of their tumor samples showed that the 3 tested LoF mutations were germline variants, the missense p. Arg468Trp was somatic, and all were associated with Loss Of Heterozygosity (LOH) of the wild-type allele in tumors (Figure 1, A and B; Supplementary Table 1, available online).	('LoF', 'NegReg', (72, 75))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('Arg468Trp', 'SUBSTITUTION', 'None', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', (234, 240))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('Loss', 'NegReg', (178, 182))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('Arg468Trp', 'Var', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
76714	32239153	MBD4 inactivation has been associated with a high TMB and a CpG>TpG mutational pattern.	('associated', 'Reg', (27, 37))	('MBD4', 'Gene', '8930', (0, 4))	('high TMB', 'MPA', (45, 53))	('MBD4', 'Gene', (0, 4))	('CpG', 'Disease', (60, 63))	('inactivation', 'Var', (5, 17))	('TMB', 'Chemical', '-', (50, 53))
76715	32239153	We confirmed the high TMB in all 3 available MBD4def UMs from the germline consecutive cohort with 275, 122, and 181 variants per exome in UM75, UM605, and UM656, respectively, compared with 16 +- 4.0 (median +- median absolute deviation) variants in MBD4-proficient UMs (Figure 1C;Supplementary Table 2, available online).	('UM75', 'Var', (139, 143))	('UM656', 'Var', (156, 161))	('variants', 'Var', (117, 125))	('MBD4', 'Gene', '8930', (45, 49))	('MBD4', 'Gene', (45, 49))	('MBD4', 'Gene', (251, 255))	('TMB', 'Chemical', '-', (22, 25))	('MBD4', 'Gene', '8930', (251, 255))	('UM605', 'Var', (145, 150))
76716	32239153	CpG>TpG transitions represented 96.4%, 85.7%, and 92.8% of all single nucleotide variants (SNVs), respectively, compared with 24.3 +- 7.6% in MBD4-proficient UMs (Figure 1, C and D; Supplementary Table 2, available online).	('MBD4', 'Gene', (142, 146))	('CpG>TpG', 'Var', (0, 7))	('single nucleotide variants', 'Var', (63, 89))	('MBD4', 'Gene', '8930', (142, 146))
76717	32239153	In line with the glycosylase assay, TMB results and somatic chromosome 3 LOH further confirmed the deleterious effect of p. Trp569* in UM75 (Figure 1).	('p. Trp569*', 'Var', (121, 131))	('UM75', 'Gene', (135, 139))	('TMB', 'Chemical', '-', (36, 39))	('Trp569', 'Chemical', '-', (124, 130))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))	('glycosylase', 'molecular_function', 'GO:0016798', ('17', '28'))
76718	32239153	Similarly, within the M3 UM tumor series, the 3 available UMs carrying a germline LoF MBD4 variant exhibited a high TMB (269, 288, and 86 variants per exome in UMT162, UMT45, and UMT61, respectively) and a predominance of CpG>TpG transitions (85.6%, 94.4%, and 63.9%, respectively) among all SNVs (Figure 1, C and D; Supplementary Table 2, available online).	('tumor', 'Disease', (28, 33))	('variant', 'Var', (91, 98))	('TMB', 'Chemical', '-', (116, 119))	('LoF', 'NegReg', (82, 85))	('TMB', 'MPA', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('CpG>TpG', 'Disease', (222, 229))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('MBD4', 'Gene', '8930', (86, 90))	('MBD4', 'Gene', (86, 90))
76719	32239153	The tumor sample of patient UMT88, carrying a somatic p. Arg468Trp variant identical to that found as a germline variant in UM293, also carried a high TMB (243 variants) and the CpG>TpG mutational pattern (92.5%) (Figure 1, C and D; Supplementary Table 2, available online), thereby confirming the deleterious effect of this missense variant previously demonstrated in the glycosylase assay (Figure 1).	('tumor', 'Disease', (4, 9))	('TMB', 'Chemical', '-', (151, 154))	('patient', 'Species', '9606', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('Arg468Trp', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CpG>TpG', 'Var', (178, 185))	('TMB', 'MPA', (151, 154))	('glycosylase', 'molecular_function', 'GO:0016798', ('373', '384'))	('UM293', 'CellLine', 'CVCL:0045', (124, 129))	('Arg468Trp', 'SUBSTITUTION', 'None', (57, 66))
76720	32239153	Taken together, these 7 patients with MBD4 deleterious mutations had a 15-fold increase in number of variants per exome (MBD4def: 243 +- 66.7 variants vs MBD4pro: 16 +- 4.0, Mann-Whitney P = 8.72 x 10-5) and a statistically significantly higher CpG>TpG median proportion among SNVs (MBD4def: 92.5 +- 5.7% vs MBD4pro: 24.3 +- 7.5%, P = 9.82 x 10-7).	('higher', 'PosReg', (238, 244))	('increase', 'PosReg', (79, 87))	('mutations', 'Var', (55, 64))	('MBD4', 'Gene', '8930', (308, 312))	('MBD4', 'Gene', (308, 312))	('MBD4', 'Gene', (283, 287))	('MBD4', 'Gene', '8930', (283, 287))	('MBD4', 'Gene', '8930', (154, 158))	('MBD4', 'Gene', '8930', (38, 42))	('variants', 'Var', (101, 109))	('MBD4', 'Gene', (154, 158))	('MBD4', 'Gene', (38, 42))	('patients', 'Species', '9606', (24, 32))	('MBD4', 'Gene', '8930', (121, 125))	('MBD4', 'Gene', (121, 125))
76721	32239153	In addition, we characterized the available tumor samples from 2 patients harboring missense variants that were not predicted to be deleterious (UM102: c.139G>A [p.Gly47Arg] and UM350: c.1652A>G [p.Asn551Ser]; Figure 1; Supplementary Table 1; Supplementary Figure 2, available online).	('p.Gly47Arg', 'Mutation', 'rs755035506', (162, 172))	('c.1652A>G', 'Mutation', 'rs577234840', (185, 194))	('UM102: c.139G>A', 'Var', (145, 160))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patients', 'Species', '9606', (65, 73))	('p.Asn551Ser', 'Mutation', 'rs577234840', (196, 207))	('c.139G>A', 'Mutation', 'rs755035506', (152, 160))	('c.139G>A', 'Var', (152, 160))	('tumor', 'Disease', (44, 49))	('Ser', 'cellular_component', 'GO:0005790', ('204', '207'))
76723	32239153	Taken together, we thus identified 8 LoF germline variants in MBD4 among the 1093 consecutive UM case patients, including p. Arg468Trp with deleterious effect on MBD4 glycosylase activity (Table 1).	('activity', 'MPA', (179, 187))	('Arg468Trp', 'Var', (125, 134))	('patients', 'Species', '9606', (102, 110))	('LoF', 'NegReg', (37, 40))	('MBD4', 'Gene', '8930', (62, 66))	('glycosylase', 'molecular_function', 'GO:0016798', ('167', '178'))	('Arg468Trp', 'SUBSTITUTION', 'None', (125, 134))	('MBD4', 'Gene', '8930', (162, 166))	('MBD4', 'Gene', (162, 166))	('MBD4', 'Gene', (62, 66))
76724	32239153	These account for a statistically significant 9.15-fold increase in deleterious variant frequency compared with the general population, even when restricting ourselves to truncating and splicing MBD4 LoFs as defined by GnomAD (7 LoFs of 2186 observed alleles in UM, representing a variant allele frequency [VAF] of 0.0032 vs 88 LoFs out of a median of 251 450 alleles in the GnomAD v2.1 general population; VAF = 3.50 x 10-4; Fisher exact test P = 2.00 x 10-5).	('increase', 'PosReg', (56, 64))	('variant', 'Var', (80, 87))	('MBD4', 'Gene', '8930', (195, 199))	('MBD4', 'Gene', (195, 199))	('splicing', 'biological_process', 'GO:0045292', ('186', '194'))
76725	32239153	Therefore, we demonstrate that the prevalence of MBD4 germline deleterious variants in UM is approximately 0.7%, close to that of BAP1 germline mutation in UM (1.6%), and that MBD4 mutations strongly predispose to UM with an RR of 9.15 (95% CI = 4.24 to 19.73).	('MBD4', 'Gene', (176, 180))	('BAP1', 'Gene', (130, 134))	('mutations', 'Var', (181, 190))	('MBD4', 'Gene', (49, 53))	('MBD4', 'Gene', '8930', (49, 53))	('BAP1', 'Gene', '8314', (130, 134))	('predispose to', 'Reg', (200, 213))	('variants', 'Var', (75, 83))	('MBD4', 'Gene', '8930', (176, 180))
76727	32239153	Within the UM tumor cohort with M3, we identified a total of 5 MBD4 LoF variants, including at least 3 of germline origin and 1 somatic, out of 192 UM patients.	('tumor', 'Disease', (14, 19))	('patients', 'Species', '9606', (151, 159))	('variants', 'Var', (72, 80))	('MBD4', 'Gene', '8930', (63, 67))	('LoF', 'NegReg', (68, 71))	('MBD4', 'Gene', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
76730	32239153	To further characterize this new cancer predisposition, we investigated the medical records of MBD4 mutation carriers.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('MBD4', 'Gene', '8930', (95, 99))	('MBD4', 'Gene', (95, 99))	('mutation', 'Var', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
76735	32239153	Although the size of the MBD4def series prevents any definitive conclusion, we observed no difference in metastatic-free survival or overall survival between MBD4def and M3 UM patients in contrast with the better outcome in D3 compared with M3 UMs (Figure 2, B and C).	('patients', 'Species', '9606', (176, 184))	('MBD4', 'Gene', '8930', (158, 162))	('MBD4', 'Gene', (158, 162))	('metastatic-free survival', 'CPA', (105, 129))	('MBD4', 'Gene', (25, 29))	('MBD4', 'Gene', '8930', (25, 29))	('M3 UM', 'Var', (170, 175))
76742	32239153	This first step, presumably the Galphaq-initiating event consisting of mutually exclusive activating mutations in GNAQ, GNA11, PLCB4, or CYSLTR2, would be the main determinant of age of onset (Figure 3).	('mutations', 'Var', (101, 110))	('CYSLTR2', 'Gene', (137, 144))	('PLCB4', 'Gene', '5332', (127, 132))	('GNA11', 'Gene', (120, 125))	('GNAQ', 'Gene', '2776', (114, 118))	('CYSLTR2', 'Gene', '57105', (137, 144))	('activating', 'PosReg', (90, 100))	('Galphaq', 'Gene', (32, 39))	('GNA11', 'Gene', '2767', (120, 125))	('Galphaq', 'Gene', '2776', (32, 39))	('PLCB4', 'Gene', (127, 132))	('GNAQ', 'Gene', (114, 118))
76743	32239153	The second step in the malignant transformation, composed of mutations in BAP1, SF3B1, or EIF1AX ("BSE" events), leads to a punctuated evolution of UM, which would marginally influence age of onset (Figure 3).	('EIF1AX', 'Gene', (90, 96))	('SF3B1', 'Gene', '23451', (80, 85))	('EIF1AX', 'Gene', '1964', (90, 96))	('mutations', 'Var', (61, 70))	('BAP1', 'Gene', '8314', (74, 78))	('SF3B1', 'Gene', (80, 85))	('BAP1', 'Gene', (74, 78))	('leads to', 'Reg', (113, 121))
76745	32239153	Importantly, germline MBD4 mutations were recently reported in other types of malignancy, including a polyposis-associated colorectal adenocarcinoma, a spiradenocarcinoma, a glioblastoma, a pilocytic astrocytoma, a gastric adenocarcinoma, a pancreatic adenocarcinoma, and a pancreatic endocrine tumor (Table 1).	('mutations', 'Var', (27, 36))	('reported', 'Reg', (51, 59))	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (190, 211))	('MBD4', 'Gene', '8930', (22, 26))	('pancreatic adenocarcinoma', 'Disease', (241, 266))	('astrocytoma', 'Phenotype', 'HP:0009592', (200, 211))	('pilocytic astrocytoma', 'Disease', (190, 211))	('malignancy', 'Disease', 'MESH:D009369', (78, 88))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (215, 237))	('spiradenocarcinoma', 'Disease', 'None', (152, 170))	('MBD4', 'Gene', (22, 26))	('spiradenocarcinoma', 'Disease', (152, 170))	('colorectal adenocarcinoma', 'Disease', (123, 148))	('polyposis', 'Disease', (102, 111))	('malignancy', 'Disease', (78, 88))	('glioblastoma', 'Disease', 'MESH:D005909', (174, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (241, 266))	('pancreatic endocrine tumor', 'Disease', (274, 300))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (241, 266))	('gastric adenocarcinoma', 'Disease', (215, 237))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (123, 148))	('glioblastoma', 'Disease', (174, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('endocrine tumor', 'Phenotype', 'HP:0100568', (285, 300))	('glioblastoma', 'Phenotype', 'HP:0012174', (174, 186))	('pancreatic endocrine tumor', 'Disease', 'MESH:D010190', (274, 300))	('pancreatic endocrine tumor', 'Phenotype', 'HP:0030405', (274, 300))	('polyposis', 'Disease', 'MESH:D044483', (102, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
76746	32239153	Furthermore, although the above case patients were all heterozygous in the germline, biallelic germline deleterious MBD4 mutations were reported in 3 individuals who developed acute myeloid leukemias, 2 of which had additional colonic polyposis.	('myeloid leukemias', 'Phenotype', 'HP:0012324', (182, 199))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (176, 199))	('colonic polyposis', 'Disease', 'MESH:D011125', (227, 244))	('mutations', 'Var', (121, 130))	('leukemias', 'Phenotype', 'HP:0001909', (190, 199))	('acute myeloid leukemias', 'Disease', (176, 199))	('MBD4', 'Gene', (116, 120))	('patients', 'Species', '9606', (37, 45))	('MBD4', 'Gene', '8930', (116, 120))	('colonic polyposis', 'Disease', (227, 244))	('acute myeloid leukemias', 'Disease', 'MESH:D015470', (176, 199))	('additional colonic polyposis', 'Phenotype', 'HP:0005227', (216, 244))
76749	32239153	To be noticed, both leukemias and UMs associated with MBD4 inactivation share a consistent inactivation of the BAP1-ASXL complex.	('BAP1', 'Gene', '8314', (111, 115))	('MBD4', 'Gene', '8930', (54, 58))	('inactivation', 'Var', (59, 71))	('MBD4', 'Gene', (54, 58))	('leukemias', 'Disease', 'MESH:D007938', (20, 29))	('UMs', 'Disease', (34, 37))	('inactivation', 'MPA', (91, 103))	('BAP1', 'Gene', (111, 115))	('leukemias', 'Phenotype', 'HP:0001909', (20, 29))	('leukemias', 'Disease', (20, 29))
76753	32239153	Interestingly, 5 recurrent MBD4 germline deleterious mutations were identified when taking together the LoF variants from our UM cohort and those found in public databases and reports of other cancer types: c.1706G>A [p.Trp569*] (2 patients), c.1562G>T [p.Asp521Profs*4] (4 patients), c.1443delT [p.Leu482Trpfs*9] (3 patients), c.335 + 1G>A [p.Arg83Profs*5] (2 patients), and c.939insA [p.Glu314Argfs*13] (2 patients) (Table 1), suggesting founder mutations.	('p.Leu482Trpfs*9', 'Var', (297, 312))	('p.Asp521Profs*4', 'Var', (254, 269))	('cancer', 'Disease', (193, 199))	('MBD4', 'Gene', '8930', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('p.Glu314Argfs*13', 'FRAMESHIFT', 'None', (387, 403))	('p.Arg83Profs*5', 'Var', (342, 356))	('1G>A', 'Var', (336, 340))	('patients', 'Species', '9606', (274, 282))	('MBD4', 'Gene', (27, 31))	('patients', 'Species', '9606', (408, 416))	('p.Arg83Profs*5', 'FRAMESHIFT', 'None', (342, 356))	('c.1443delT', 'Mutation', 'rs769076971', (285, 295))	('p.Trp569*', 'Mutation', 'rs939751619', (218, 227))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('patients', 'Species', '9606', (361, 369))	('c.939insA', 'Mutation', 'c.939insA', (376, 385))	('c.1706G>A', 'Mutation', 'rs939751619', (207, 216))	('1G>A', 'SUBSTITUTION', 'None', (336, 340))	('patients', 'Species', '9606', (232, 240))	('p.Asp521Profs*4', 'FRAMESHIFT', 'None', (254, 269))	('p.Glu314Argfs*13', 'Var', (387, 403))	('c.1706G>A [p.Trp569', 'Var', (207, 226))	('p.Leu482Trpfs*9', 'FRAMESHIFT', 'None', (297, 312))	('patients', 'Species', '9606', (317, 325))	('c.1562G>T', 'Mutation', 'c.1562G>T', (243, 252))
76756	32239153	In summary, we described here a novel autosomal-dominant syndrome that is caused by germline mutations of MBD4, characterized by a high RR of developing hypermutated UM and possibly other malignancies.	('autosomal-dominant syndrome', 'Disease', (38, 65))	('mutations', 'Var', (93, 102))	('caused by', 'Reg', (74, 83))	('malignancies', 'Disease', (188, 200))	('MBD4', 'Gene', '8930', (106, 110))	('MBD4', 'Gene', (106, 110))	('developing hypermutated UM', 'Disease', (142, 168))	('autosomal-dominant syndrome', 'Disease', 'MESH:D030342', (38, 65))	('malignancies', 'Disease', 'MESH:D009369', (188, 200))
76757	32239153	Tumors arising in such a context are associated with a CpG>TpG mutator phenotype and have clinical relevance because they may respond to immune-checkpoint inhibitors.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CpG>TpG', 'Var', (55, 62))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('respond', 'MPA', (126, 133))
76769	32555170	Most cancers emerge from epithelial cells that suffer oncogenic mutations in the coding sequence of proteins normally controlling cell proliferation and survival.	('cell proliferation', 'biological_process', 'GO:0008283', ('130', '148'))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('cancers', 'Disease', (5, 12))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('mutations in', 'Var', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('rat', 'Species', '10116', (142, 145))
76770	32555170	Driving genetic alterations that cause cancer occur associated to multiple external factors, including chemicals, toxins, radiation, and viral infection.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('genetic alterations', 'Var', (8, 27))	('viral infection', 'Disease', (137, 152))	('viral infection', 'biological_process', 'GO:0016032', ('137', '152'))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('rat', 'Species', '10116', (20, 23))	('viral infection', 'Disease', 'MESH:D001102', (137, 152))
76799	32555170	Therefore, translational research focuses on disrupting cellular communication as a strategy to fight tumor growth and dissemination.	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('disrupting', 'Var', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('rat', 'Species', '10116', (86, 89))
76800	32555170	In the next sections, we discuss how tumor cells communicate with the immune (Section "Evasion of the immune response: aberrant communication between cancer and immune cells") and nervous system (Sections "Reciprocal communication between cancer cells and the nervous system promotes tumor progression" and "Classical central nervous system neurotransmitters (dopamine, glutamate, and GABA) impact cancer progression").	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('promotes', 'PosReg', (275, 283))	('GABA', 'Chemical', 'MESH:D005680', (385, 389))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('cancer', 'Disease', (398, 404))	('aberrant', 'Var', (119, 127))	('dopamine', 'Chemical', 'MESH:D004298', (360, 368))	('cancer', 'Phenotype', 'HP:0002664', (398, 404))	('impact', 'Reg', (391, 397))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cancer', 'Disease', (239, 245))	('cancer', 'Disease', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('glutamate', 'Chemical', 'MESH:D018698', (370, 379))	('cancer', 'Disease', 'MESH:D009369', (398, 404))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', (284, 289))
76823	32555170	Galphaq/11-Q209L in uveal melanoma, Galphas-R201C in pancreatic cancer, and Gbeta1-K57E/N/T, Gbeta1-I80N/T or Gbeta1-K89E/T in leukemias), as well as changes in their expression and signaling properties.	('leukemia', 'Phenotype', 'HP:0001909', (127, 135))	('leukemias', 'Disease', 'MESH:D007938', (127, 136))	('changes', 'Reg', (150, 157))	('I80N', 'Var', (100, 104))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (26, 34))	('leukemias', 'Phenotype', 'HP:0001909', (127, 136))	('K57E', 'SUBSTITUTION', 'None', (83, 87))	('Galphas', 'Gene', (36, 43))	('pancreatic cancer', 'Disease', 'MESH:D010190', (53, 70))	('K57E', 'Var', (83, 87))	('expression', 'MPA', (167, 177))	('uveal melanoma', 'Phenotype', 'HP:0007716', (20, 34))	('Galphaq', 'Gene', (0, 7))	('I80N', 'SUBSTITUTION', 'None', (100, 104))	('pancreatic cancer', 'Disease', (53, 70))	('leukemias', 'Disease', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('Q209L', 'Mutation', 'rs121913492', (11, 16))	('Galphaq', 'Gene', '2776', (0, 7))	('K89E', 'Var', (117, 121))	('K89E', 'SUBSTITUTION', 'None', (117, 121))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))	('Galphas', 'Gene', '79447', (36, 43))	('signaling', 'biological_process', 'GO:0023052', ('182', '191'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (53, 70))	('signaling properties', 'MPA', (182, 202))
76842	32555170	However, cancer cells with altered Fas receptors evade the immune response.	('cancer', 'Disease', (9, 15))	('altered', 'Var', (27, 34))	('immune response', 'biological_process', 'GO:0006955', ('59', '74'))	('evade', 'NegReg', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('immune response', 'CPA', (59, 74))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('Fas receptors', 'Protein', (35, 48))
76846	32555170	The immune response is modulated by fatty acid-derived factors, including resolvins, pronectins, lipoxins, and endocannabinoids, among others, released by cells involved in inflammation resolution mechanisms; In addition, acetylcholine, known to be involved in the cholinergic reflex, activates alpha7 nicotinic receptor in immune cells, triggering immunosuppressive JAK2/STAT signaling.	('inflammation', 'Disease', 'MESH:D007249', (173, 185))	('JAK2', 'Gene', (367, 371))	('reflex', 'biological_process', 'GO:0060004', ('277', '283'))	('lipoxins', 'Chemical', 'MESH:D044045', (97, 105))	('fatty acid', 'Chemical', 'MESH:D005227', (36, 46))	('acetylcholine', 'Chemical', 'MESH:D000109', (222, 235))	('activates', 'PosReg', (285, 294))	('inflammation', 'Disease', (173, 185))	('immune response', 'biological_process', 'GO:0006955', ('4', '19'))	('triggering', 'Reg', (338, 348))	('STAT', 'Gene', '6774', (372, 376))	('STAT', 'Gene', (372, 376))	('signaling', 'biological_process', 'GO:0023052', ('377', '386'))	('alpha7 nicotinic receptor', 'Gene', '89832', (295, 320))	('alpha7 nicotinic receptor', 'Gene', (295, 320))	('JAK', 'molecular_function', 'GO:0004713', ('367', '370'))	('JAK2', 'Gene', '3717', (367, 371))	('inflammation', 'biological_process', 'GO:0006954', ('173', '185'))	('acetylcholine', 'Var', (222, 235))
76862	32555170	Overexpression of PD-L1 in cancer cells correlates with drug resistance and poor prognosis.	('drug resistance', 'biological_process', 'GO:0009315', ('56', '71'))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('drug resistance', 'biological_process', 'GO:0042493', ('56', '71'))	('drug resistance', 'CPA', (56, 71))	('drug resistance', 'Phenotype', 'HP:0020174', (56, 71))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('PD-L1', 'Gene', (18, 23))	('PD-L1', 'Gene', '29126', (18, 23))
76863	32555170	Immunotherapy with anti-PD-1 antibodies increases the infiltration of CD8+ cytotoxic T cells into soft tissue sarcomas, melanoma, and murine renal cancer.	('sarcomas', 'Disease', 'MESH:D012509', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('sarcomas', 'Phenotype', 'HP:0100242', (110, 118))	('renal cancer', 'Disease', (141, 153))	('murine', 'Species', '10090', (134, 140))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('sarcomas', 'Disease', (110, 118))	('melanoma', 'Disease', (120, 128))	('renal cancer', 'Phenotype', 'HP:0009726', (141, 153))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (98, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('renal cancer', 'Disease', 'MESH:D007680', (141, 153))	('CD8', 'Gene', '925', (70, 73))	('anti-PD-1 antibodies', 'Var', (19, 39))	('infiltration', 'CPA', (54, 66))	('rat', 'Species', '10116', (60, 63))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('increases', 'PosReg', (40, 49))	('antibodies', 'Var', (29, 39))	('CD8', 'Gene', (70, 73))
76877	32555170	The phosphatase PP2A mediates CTLA-4 signaling to inhibit the activation of T cells; in fact, PP2A is a target for immunotherapy, and the inhibition of the phosphatase activity increases the cytotoxicity of intratumor lymphocytes.	('phosphatase activity', 'molecular_function', 'GO:0016791', ('156', '176'))	('inhibit', 'NegReg', (50, 57))	('cytotoxicity', 'Disease', 'MESH:D064420', (191, 203))	('PP2A', 'Gene', (16, 20))	('PP2A', 'Gene', '5524', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('phosphatase', 'molecular_function', 'GO:0016791', ('4', '15'))	('increases', 'PosReg', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('inhibition', 'Var', (138, 148))	('signaling', 'biological_process', 'GO:0023052', ('37', '46'))	('rat', 'Species', '10116', (210, 213))	('PP2A', 'Gene', '5524', (16, 20))	('phosphatase', 'Enzyme', (156, 167))	('cytotoxicity', 'Disease', (191, 203))	('tumor', 'Disease', (212, 217))	('PP2A', 'Gene', (94, 98))
76879	32555170	Partial blockade of CTLA-4 shows therapeutic potential as it increases the antineoplastic effect of non-selective cytotoxic substances contributing to tumor regression in experimental cancer models, whereas non-immunogenic tumors are resistant.	('cancer', 'Disease', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Disease', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Partial blockade', 'Var', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('increases', 'PosReg', (61, 70))	('CTLA-4', 'Gene', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
76881	32555170	In clinical settings, anti-CTLA-4 monoclonal antibodies (ipilimumab and tremelimumab) are particularly effective in patients with melanoma.	('patients', 'Species', '9606', (116, 124))	('ipilimumab', 'Chemical', 'MESH:D000074324', (57, 67))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Disease', (130, 138))	('tremelimumab', 'Chemical', 'MESH:C520704', (72, 84))	('anti-CTLA-4', 'Var', (22, 33))
76884	32555170	As mentioned before, blocking the CTLA-4 receptor increases CD4+ T cells activities therefore stimulating effector cells.	('CTLA-4 receptor', 'Protein', (34, 49))	('blocking', 'Var', (21, 29))	('increases', 'PosReg', (50, 59))	('CD4', 'Gene', (60, 63))	('stimulating', 'Reg', (94, 105))	('CD4', 'Gene', '920', (60, 63))
76885	32555170	The antitumor effect of anti-CTLA-4 monoclonal antibodies is based on their ability to deplete CD4+/FOXP3+ T regulatory cell population.	('CD4', 'Gene', '920', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('FOXP3', 'Gene', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('anti-CTLA-4', 'Var', (24, 35))	('CD4', 'Gene', (95, 98))	('tumor', 'Disease', (8, 13))	('FOXP3', 'Gene', '50943', (100, 105))	('anti-CTLA-4', 'Gene', (24, 35))
76911	32555170	Other mechanisms of immune regulation by MDSCs have been described, they include alterations in antigen presentation, T cell signaling, immunosuppressive and pro-apoptotic factor production, induction of inhibitory signaling cascades and recruitment of regulatory T cells.	('inhibitory signaling cascades', 'MPA', (204, 233))	('signaling', 'biological_process', 'GO:0023052', ('215', '224'))	('T cell signaling', 'MPA', (118, 134))	('rat', 'Species', '10116', (85, 88))	('alterations', 'Reg', (81, 92))	('immune', 'MPA', (20, 26))	('antigen presentation', 'MPA', (96, 116))	('MDSCs', 'Var', (41, 46))	('regulatory T cells', 'CPA', (253, 271))	('immunosuppressive and', 'MPA', (136, 157))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('induction', 'Reg', (191, 200))	('recruitment', 'CPA', (238, 249))	('antigen presentation', 'biological_process', 'GO:0019882', ('96', '116'))	('regulation', 'biological_process', 'GO:0065007', ('27', '37'))
76920	32555170	Differentiation is blocked by antagonists of prostaglandin receptors: EP4 (AH23848), EP1/EP2 (AH6809); and cyclooxygenase-2 inhibitor (COX2 inhibitor SC58236).	('EP1', 'Gene', (85, 88))	('AH6809', 'Var', (94, 100))	('cyclooxygenase-2', 'Gene', '5743', (107, 123))	('AH6809', 'Chemical', 'MESH:C053876', (94, 100))	('AH23848', 'Var', (75, 82))	('cyclooxygenase-2', 'Gene', (107, 123))	('SC58236', 'Chemical', 'MESH:C119130', (150, 157))	('prostaglandin', 'Chemical', 'MESH:D011453', (45, 58))	('AH23848', 'Chemical', 'MESH:C046926', (75, 82))	('EP1', 'Gene', '5731', (85, 88))	('EP4', 'Gene', '5734', (70, 73))	('EP4', 'Gene', (70, 73))
76937	32555170	In p50 deficient mice or with restricted deficiency in bone marrow cell, it retards the growth of melanoma (B16) and fibrosarcoma (MN/MCA1) tumors.	('MCA1', 'Gene', '53308', (134, 138))	('retards', 'Disease', 'MESH:D008607', (76, 83))	('growth', 'CPA', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('restricted deficiency', 'Disease', 'MESH:D002313', (30, 51))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (117, 129))	('tumors', 'Disease', (140, 146))	('MCA1', 'Gene', (134, 138))	('mice', 'Species', '10090', (17, 21))	('MN', 'CellLine', 'CVCL:U508', (131, 133))	('p50', 'Var', (3, 6))	('fibrosarcoma', 'Disease', 'MESH:D005354', (117, 129))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('restricted deficiency', 'Disease', (30, 51))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('fibrosarcoma', 'Disease', (117, 129))	('retards', 'Disease', (76, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
76953	32555170	In fact, knocking out of Sema4D prevents tumor growth and metastasis in a breast cancer murine model (TSA cells).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('prevents', 'NegReg', (32, 40))	('breast cancer', 'Disease', (74, 87))	('murine', 'Species', '10090', (88, 94))	('tumor', 'Disease', (41, 46))	('knocking out', 'Var', (9, 21))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('TSA', 'molecular_function', 'GO:0033984', ('102', '105'))	('Sema4D', 'Gene', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
76957	32555170	The inhibition of adrenergic signaling increases the antitumor immune response via the impact on multiple leukocytes.	('signaling', 'biological_process', 'GO:0023052', ('29', '38'))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('inhibition', 'Var', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('adrenergic', 'Protein', (18, 28))	('increases', 'PosReg', (39, 48))	('tumor', 'Disease', (57, 62))	('immune response', 'biological_process', 'GO:0006955', ('63', '78'))
77014	32555170	However, in neuroblastoma patients, high expression of TrkA or TrkC correlates with a better prognosis.	('TrkC', 'Gene', (63, 67))	('neuroblastoma', 'Disease', 'MESH:D009447', (12, 25))	('TrkC', 'Gene', '4916', (63, 67))	('neuroblastoma', 'Disease', (12, 25))	('patients', 'Species', '9606', (26, 34))	('neuroblastoma', 'Phenotype', 'HP:0003006', (12, 25))	('TrkA', 'Gene', '4914', (55, 59))	('TrkA', 'Gene', (55, 59))	('high', 'Var', (36, 40))
77017	32555170	BDNF/TrkB promotes ovarian cancer cell migration and invasion and it is decreased in TrkB knockdown cells while enhanced apoptosis.	('enhanced', 'PosReg', (112, 120))	('TrkB', 'Gene', '4915', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('knockdown', 'Var', (90, 99))	('invasion', 'CPA', (53, 61))	('TrkB promotes ovarian cancer', 'Disease', (5, 33))	('decreased', 'NegReg', (72, 81))	('cell migration', 'biological_process', 'GO:0016477', ('34', '48'))	('TrkB', 'Gene', '4915', (85, 89))	('TrkB', 'Gene', (5, 9))	('TrkB promotes ovarian cancer', 'Disease', 'MESH:D010051', (5, 33))	('apoptosis', 'biological_process', 'GO:0097194', ('121', '130'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (19, 33))	('TrkB', 'Gene', (85, 89))	('rat', 'Species', '10116', (42, 45))	('apoptosis', 'biological_process', 'GO:0006915', ('121', '130'))
77028	32555170	Antagonism or inhibition of Trks could potentially prevent the communication induced by neurotrophins, avoiding relevant processes in cancer: neuroplasticity involved in neuropathic pain, cancer cell proliferation, tumor-axonogenesis, and tumor-angiogenesis.	('rat', 'Species', '10116', (207, 210))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('neuropathic pain', 'Disease', (170, 186))	('axonogenesis', 'biological_process', 'GO:0007409', ('221', '233'))	('Antagonism', 'Var', (0, 10))	('cancer', 'Disease', (134, 140))	('communication', 'MPA', (63, 76))	('tumor', 'Disease', (239, 244))	('Trks', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumor-axonogenesis', 'Disease', 'MESH:D009369', (215, 233))	('cell proliferation', 'biological_process', 'GO:0008283', ('195', '213'))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('angiogenesis', 'biological_process', 'GO:0001525', ('245', '257'))	('tumor-axonogenesis', 'Disease', (215, 233))	('prevent', 'NegReg', (51, 58))	('cancer', 'Disease', (188, 194))	('tumor', 'Disease', (215, 220))	('neuropathic pain', 'Disease', 'MESH:D009437', (170, 186))	('pain', 'Phenotype', 'HP:0012531', (182, 186))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('inhibition', 'Var', (14, 24))
77036	32555170	Ablation of sensory neurons (C fibers mainly) in a neonatal mouse model (induced by capsaicin) prevents PNI and improves survival.	('improves', 'PosReg', (112, 120))	('Ablation', 'Var', (0, 8))	('capsaicin', 'Chemical', 'MESH:D002211', (84, 93))	('survival', 'CPA', (121, 129))	('PNI', 'Disease', (104, 107))	('mouse', 'Species', '10090', (60, 65))
77043	32555170	Communication networks among afferent fibers, mast cells and vessels exacerbate the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('Communication', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('exacerbate', 'PosReg', (69, 79))	('tumor', 'Disease', (84, 89))
77049	32555170	Direct communication between sensorial afferent fibers and cancer cells stimulates proliferation and invasion of transformed cells.	('proliferation', 'CPA', (83, 96))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('invasion of transformed cells', 'CPA', (101, 130))	('stimulates', 'PosReg', (72, 82))	('Direct communication', 'Var', (0, 20))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('rat', 'Species', '10116', (90, 93))
77052	32555170	These findings suggest that NK1 antagonists could prevent growth factor receptor transactivation, restricting proliferation, but also preventing the effect of SP on mast cells and tumor peripheral vessels.	('effect', 'MPA', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('receptor transactivation', 'biological_process', 'GO:0035624', ('72', '96'))	('prevent', 'NegReg', (50, 57))	('rat', 'Species', '10116', (117, 120))	('NK1', 'Gene', '11126', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('NK1', 'Gene', (28, 31))	('antagonists', 'Var', (32, 43))	('proliferation', 'CPA', (110, 123))	('tumor', 'Disease', (180, 185))	('preventing', 'NegReg', (134, 144))	('restricting', 'NegReg', (98, 109))	('growth factor receptor', 'Protein', (58, 80))	('SP', 'Gene', '6863', (159, 161))
77056	32555170	Antibodies against G-CSFR or GM-CSFRalpha and JAK inhibitor (AG490) reduce tumor size, neurite outgrowth, and cancer pain.	('cancer pain', 'Disease', (110, 121))	('Antibodies', 'Var', (0, 10))	('pain', 'Phenotype', 'HP:0012531', (117, 121))	('G-CSFR', 'Gene', (19, 25))	('G-CSFR', 'Gene', '1441', (19, 25))	('JAK', 'molecular_function', 'GO:0004713', ('46', '49'))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('reduce', 'NegReg', (68, 74))	('GM-CSFRalpha', 'Gene', '1438', (29, 41))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('neurite outgrowth', 'CPA', (87, 104))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('neurite', 'cellular_component', 'GO:0043005', ('87', '94'))	('GM-CSFRalpha', 'Gene', (29, 41))	('cancer pain', 'Disease', 'MESH:D000072716', (110, 121))	('tumor', 'Disease', (75, 80))	('neurite outgrowth', 'biological_process', 'GO:0031175', ('87', '104'))
77061	32555170	Indeed, EphB1 knock out or the truncated extracellular domain partially prevents exosome-dependent axonogenesis.	('EphB1', 'Gene', '1947', (8, 13))	('extracellular', 'cellular_component', 'GO:0005576', ('41', '54'))	('exosome', 'cellular_component', 'GO:0070062', ('81', '88'))	('axonogenesis', 'biological_process', 'GO:0007409', ('99', '111'))	('knock out', 'Var', (14, 23))	('exosome-dependent axonogenesis', 'MPA', (81, 111))	('prevents', 'NegReg', (72, 80))	('EphB1', 'Gene', (8, 13))
77068	32555170	Loss of p53, either by knock out or p53 mutants (p53R273H, p53C238F, and p53G245D) promotes the release of pro-axonogenic extracellular vesicles increasing sensory nerves infiltration.	('p53', 'Gene', (8, 11))	('p53G245D', 'Var', (73, 81))	('rat', 'Species', '10116', (177, 180))	('p53', 'Gene', (36, 39))	('promotes', 'PosReg', (83, 91))	('p53R273H', 'Mutation', 'p.R53,273H', (49, 57))	('p53C238F', 'Var', (59, 67))	('Loss', 'NegReg', (0, 4))	('p53R273H', 'Var', (49, 57))	('sensory nerves infiltration', 'CPA', (156, 183))	('p53G245D', 'Mutation', 'p.G53,245D', (73, 81))	('increasing', 'PosReg', (145, 155))	('extracellular', 'cellular_component', 'GO:0005576', ('122', '135'))	('release of pro-axonogenic extracellular vesicles', 'MPA', (96, 144))
77069	32555170	Conditioned media derived from human OCSCC cell line (HN31 cells with p53C176F and p53A161S mutations) contain EV and promote DRG neuritogenesis in vitro, while knock out of GTPases Rab27A and 27B prevented the effect.	('HN31', 'CellLine', 'CVCL:5526', (54, 58))	('Rab27A', 'Gene', (182, 188))	('human', 'Species', '9606', (31, 36))	('p53A161S mutations', 'Var', (83, 101))	('Rab27A', 'Gene', '5873', (182, 188))	('DRG neuritogenesis', 'MPA', (126, 144))	('p53C176F', 'Var', (70, 78))	('promote', 'PosReg', (118, 125))
77072	32555170	In fact, miR-34a knock down or antagomiR-34a is enough to transform p53WT cell-derived to p53KO cell-derived EVs, promoting neuritogenesis.	('neuritogenesis', 'CPA', (124, 138))	('miR-34a', 'Gene', '407040', (9, 16))	('miR-34a', 'Gene', '407040', (37, 44))	('miR-34a', 'Gene', (9, 16))	('promoting', 'PosReg', (114, 123))	('miR-34a', 'Gene', (37, 44))	('knock down', 'Var', (17, 27))
77092	32555170	Consistent with the pro-oncogenic role of these Gs-coupled receptors, constitutively-active Galphas mutant exacerbates Ras-dependent pancreatic cancer.	('Galphas', 'Gene', (92, 99))	('exacerbates', 'PosReg', (107, 118))	('mutant', 'Var', (100, 106))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (133, 150))	('pancreatic cancer', 'Disease', (133, 150))	('pancreatic cancer', 'Disease', 'MESH:D010190', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('Galphas', 'Gene', '79447', (92, 99))
77093	32555170	In addition, stress increases MMP-2 and MMP-9 expression in tumor and stromal cells to invade adjacent tissues.	('MMP-2', 'Gene', (30, 35))	('stress', 'Var', (13, 19))	('MMP-9', 'molecular_function', 'GO:0004229', ('40', '45'))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('MMP-2', 'Gene', '4313', (30, 35))	('MMP-2', 'molecular_function', 'GO:0004228', ('30', '35'))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MMP-9', 'Gene', '4318', (40, 45))	('expression', 'MPA', (46, 56))	('MMP-9', 'Gene', (40, 45))	('increases', 'PosReg', (20, 29))
77099	32555170	In a model of chemically induced hepatocarcinogenesis, adrenaline promotes cancer cell proliferation and survival triggered by beta2-adrenergic signaling.	('adrenaline', 'Var', (55, 65))	('rat', 'Species', '10116', (94, 97))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cell proliferation', 'biological_process', 'GO:0008283', ('82', '100'))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('cancer', 'Disease', (75, 81))	('adrenaline', 'Chemical', 'MESH:D004837', (55, 65))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (33, 53))	('promotes', 'PosReg', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('survival', 'CPA', (105, 113))	('hepatocarcinogenesis', 'Disease', (33, 53))
77101	32555170	Adrenaline effect on tumor cells is inhibited by beta2 antagonists (ICI-118,551 and butoxamine) and by receptor knockdown.	('beta2', 'Protein', (49, 54))	('butoxamine', 'Chemical', 'MESH:D002078', (84, 94))	('inhibited', 'NegReg', (36, 45))	('tumor', 'Disease', (21, 26))	('Adrenaline', 'Chemical', 'MESH:D004837', (0, 10))	('knockdown', 'Var', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
77102	32555170	Moreover, inhibition of beta2-adrenergic signaling improved sorafenib effects, a small molecule inhibitor that targets VEGFRs, PDGFR, and RAF kinases.	('VEGF', 'Gene', '7422', (119, 123))	('RAF', 'Gene', '22882', (138, 141))	('sorafenib', 'Gene', (60, 69))	('RAF', 'Gene', (138, 141))	('improved', 'PosReg', (51, 59))	('effects', 'MPA', (70, 77))	('beta2-adrenergic signaling', 'MPA', (24, 50))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('VEGF', 'Gene', (119, 123))	('EGFR', 'Gene', '1956', (120, 124))	('PDGFR', 'Gene', (127, 132))	('inhibition', 'Var', (10, 20))	('PDGFR', 'Gene', '5159', (127, 132))	('sorafenib', 'Chemical', 'MESH:D000077157', (60, 69))	('EGFR', 'Gene', (120, 124))
77114	32555170	Therefore, inhibition of beta2 adrenergic signaling in the tumor decreases vascularization and tumor growth.	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('tumor decreases', 'Disease', (59, 74))	('tumor decreases', 'Disease', 'MESH:D002303', (59, 74))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('inhibition', 'Var', (11, 21))	('vascularization', 'CPA', (75, 90))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('beta2', 'Protein', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', (95, 100))
77121	32555170	This process correlates with poor prognosis as it correlates with cancer aggressiveness and lower survival, particularly, high M3 receptor expression correlates with poor prognostic and tumor budding.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('aggressiveness', 'Phenotype', 'HP:0000718', (73, 87))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('high', 'Var', (122, 126))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (66, 87))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('budding', 'biological_process', 'GO:0007114', ('192', '199'))	('cancer aggressiveness', 'Disease', (66, 87))	('tumor', 'Disease', (186, 191))	('poor prognostic', 'CPA', (166, 181))	('expression', 'MPA', (139, 149))	('lower', 'NegReg', (92, 97))	('M3 receptor', 'Protein', (127, 138))
77134	32555170	By knocking down MAP2 it has been revealed that these undifferentiated cells generate functional autonomic neurons that stimulate tumor growth.	('stimulate', 'PosReg', (120, 129))	('MAP', 'molecular_function', 'GO:0004239', ('17', '20'))	('rat', 'Species', '10116', (81, 84))	('MAP2', 'Gene', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('MAP2', 'Gene', '4133', (17, 21))	('knocking down', 'Var', (3, 16))
77135	32555170	The knocking down of MAP2 decreased the generation of neurons from human gastric and colorectal cancer stem cells and reduced the growth of tumor xenografts derived from human colorectal cancer stem cells.	('colorectal cancer', 'Disease', 'MESH:D015179', (176, 193))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('colorectal cancer', 'Disease', (176, 193))	('generation of neurons', 'CPA', (40, 61))	('decreased', 'NegReg', (26, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('MAP2', 'Gene', '4133', (21, 25))	('generation of neurons', 'biological_process', 'GO:0048699', ('40', '61'))	('MAP', 'molecular_function', 'GO:0004239', ('21', '24'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (176, 193))	('reduced', 'NegReg', (118, 125))	('rat', 'Species', '10116', (44, 47))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('knocking down', 'Var', (4, 17))	('colorectal cancer', 'Disease', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('human', 'Species', '9606', (170, 175))	('human', 'Species', '9606', (67, 72))	('MAP2', 'Gene', (21, 25))	('tumor', 'Disease', (140, 145))
77145	32555170	The migration of both cells requires PI3K/AKT and Cdc42 activation and the inhibition of small GTPases, and PI3K prevents the migration and invasive capacity.	('AKT', 'Gene', '207', (42, 45))	('invasive capacity', 'CPA', (140, 157))	('small GTPases', 'Protein', (89, 102))	('prevents', 'NegReg', (113, 121))	('AKT', 'Gene', (42, 45))	('Cdc42', 'Gene', '998', (50, 55))	('inhibition', 'NegReg', (75, 85))	('rat', 'Species', '10116', (129, 132))	('PI3K', 'molecular_function', 'GO:0016303', ('108', '112'))	('PI3K', 'Var', (108, 112))	('PI3K', 'molecular_function', 'GO:0016303', ('37', '41'))	('rat', 'Species', '10116', (7, 10))	('Cdc42', 'Gene', (50, 55))	('migration', 'CPA', (126, 135))	('migration', 'CPA', (4, 13))	('activation', 'PosReg', (56, 66))
77149	32555170	Prostate cancer cells overexpress semaphorin 4F (Sema4F) and its knock down inhibits the tumor axonogenesis and neurogenesis in vitro.	('Prostate cancer', 'Phenotype', 'HP:0012125', (0, 15))	('knock down', 'Var', (65, 75))	('Sema4F', 'Gene', '10505', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('Prostate cancer', 'Disease', (0, 15))	('axonogenesis', 'biological_process', 'GO:0007409', ('95', '107'))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('inhibits', 'NegReg', (76, 84))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('semaphorin 4F', 'Gene', '10505', (34, 47))	('Sema4F', 'Gene', (49, 55))	('semaphorin 4F', 'Gene', (34, 47))	('neurogenesis', 'biological_process', 'GO:0022008', ('112', '124'))	('overexpress', 'PosReg', (22, 33))	('Prostate cancer', 'Disease', 'MESH:D011471', (0, 15))	('tumor', 'Disease', (89, 94))
77152	32555170	Granulocyte colony-stimulating factor (G-CSF) has neurotropic functions; in prostate tumor mice (Hi-Myc) G-CSF increased nerve outgrowth, invasion, and metastases.	('mice', 'Species', '10090', (91, 95))	('prostate tumor', 'Phenotype', 'HP:0100787', (76, 90))	('G-CSF', 'Var', (105, 110))	('increased', 'PosReg', (111, 120))	('metastases', 'Disease', (152, 162))	('Myc', 'Gene', (100, 103))	('Granulocyte colony-stimulating factor', 'Gene', (0, 37))	('metastases', 'Disease', 'MESH:D009362', (152, 162))	('Myc', 'Gene', '17869', (100, 103))	('prostate tumor', 'Disease', 'MESH:D011471', (76, 90))	('Granulocyte colony-stimulating factor', 'Gene', '12985', (0, 37))	('CSF increased', 'Phenotype', 'HP:0002922', (107, 120))	('invasion', 'CPA', (138, 146))	('nerve outgrowth', 'CPA', (121, 136))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Granulocyte colony-stimulating factor', 'molecular_function', 'GO:0005130', ('0', '37'))	('prostate tumor', 'Disease', (76, 90))
77153	32555170	G-CSF induces new cholinergic parasympathetic nerve fibers in the orthotopic tumor for metastasized.	('G-CSF', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cholinergic parasympathetic nerve', 'MPA', (18, 51))	('tumor', 'Disease', (77, 82))
77161	32555170	Immune cells, including B lymphocytes, NK cells, monocytes, macrophages, dendritic cells, neutrophils, effector and regulatory T cells express dopamine receptors, which are either coupled to Gs (D1R and D5R) or Gi (D2R, D3R, and D4R).	('D4R', 'Var', (229, 232))	('D5R', 'Var', (203, 206))	('D3R', 'Var', (220, 223))	('dopamine receptors', 'Protein', (143, 161))	('D2R', 'Var', (215, 218))	('dopamine', 'Chemical', 'MESH:D004298', (143, 151))
77172	32555170	In murine lung cancer, D2R agonist inhibits angiogenesis, limiting tumor advance, although the mechanism remains to be clarified.	('limiting', 'NegReg', (58, 66))	('angiogenesis', 'CPA', (44, 56))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('inhibits', 'NegReg', (35, 43))	('angiogenesis', 'biological_process', 'GO:0001525', ('44', '56'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('lung cancer', 'Disease', (10, 21))	('D2R', 'Var', (23, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (10, 21))	('murine', 'Species', '10090', (3, 9))	('tumor', 'Disease', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('lung cancer', 'Disease', 'MESH:D008175', (10, 21))
77180	32555170	Accumulating evidence includes D4R, which has also been found overexpressed in breast cancer, and D5R which, according to preclinical studies, promotes autophagy leading to cell death via increased ROS production and inhibition of the mTOR pathway.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('breast cancer', 'Disease', (79, 92))	('mTOR', 'Gene', '2475', (235, 239))	('increased', 'PosReg', (188, 197))	('D4R', 'Var', (31, 34))	('increased ROS production', 'Phenotype', 'HP:0025464', (188, 212))	('ROS', 'Chemical', 'MESH:D017382', (198, 201))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('autophagy', 'biological_process', 'GO:0016236', ('152', '161'))	('cell death', 'biological_process', 'GO:0008219', ('173', '183'))	('inhibition', 'NegReg', (217, 227))	('D5R', 'Var', (98, 101))	('cell death', 'CPA', (173, 183))	('autophagy', 'CPA', (152, 161))	('promotes', 'PosReg', (143, 151))	('mTOR', 'Gene', (235, 239))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('autophagy', 'biological_process', 'GO:0006914', ('152', '161'))	('ROS production', 'MPA', (198, 212))
77185	32555170	Moreover, aberrant glutamatergic signaling in glioma has also been linked to decreased glutamate uptake due to poor glutamate transporter activity (EAAT, excitatory aminoacid transporter), or expression (GLT1, glutamate transporter-1 and GLAST, glutamate/aspartate transporter).	('decreased glutamate', 'Phenotype', 'HP:0500150', (77, 96))	('transporter activity', 'molecular_function', 'GO:0005215', ('126', '146'))	('poor glutamate', 'Phenotype', 'HP:0500150', (111, 125))	('aberrant', 'Var', (10, 18))	('glutamate', 'Chemical', 'MESH:D018698', (87, 96))	('uptake', 'biological_process', 'GO:0098657', ('97', '103'))	('glutamate', 'Chemical', 'MESH:D018698', (245, 254))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))	('expression', 'MPA', (192, 202))	('signaling', 'biological_process', 'GO:0023052', ('33', '42'))	('uptake', 'biological_process', 'GO:0098739', ('97', '103'))	('GLAST', 'Gene', (238, 243))	('glutamate', 'Chemical', 'MESH:D018698', (116, 125))	('GLAST', 'Gene', '6507', (238, 243))	('GLT1', 'Gene', '6506', (204, 208))	('glutamate transporter activity', 'MPA', (116, 146))	('glutamatergic signaling', 'MPA', (19, 42))	('GLT1', 'Gene', (204, 208))	('glutamate uptake', 'MPA', (87, 103))	('glutamate', 'Chemical', 'MESH:D018698', (19, 28))	('decreased', 'NegReg', (77, 86))	('poor', 'NegReg', (111, 115))	('glioma', 'Disease', (46, 52))	('glutamate', 'Chemical', 'MESH:D018698', (210, 219))	('glioma', 'Disease', 'MESH:D005910', (46, 52))
77190	32555170	In vitro, a mGlu3R agonist (LY379268, mGluR2/3 agonist) maintains glioma-initiating cells in the undifferentiated state, whereas a mGlu3R antagonist (LY341495) induces differentiation to astrocytes.	('glioma', 'Disease', (66, 72))	('LY379268', 'Var', (28, 36))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('Glu', 'Chemical', 'MESH:D018698', (132, 135))	('mGluR2/3', 'Gene', (38, 46))	('LY341495', 'Var', (150, 158))	('mGluR2/3', 'Gene', '108068;108069;14800;53623', (38, 46))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('LY379268', 'Chemical', 'MESH:C118218', (28, 36))	('Glu', 'Chemical', 'MESH:D018698', (39, 42))	('Glu', 'Chemical', 'MESH:D018698', (13, 16))	('induces', 'Reg', (160, 167))	('differentiation', 'CPA', (168, 183))	('LY341495', 'Chemical', 'MESH:C114624', (150, 158))
77191	32555170	In vivo mGlu3R antagonists limited brain tumor growth or infiltration in nude mice models.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('brain tumor', 'Phenotype', 'HP:0030692', (35, 46))	('rat', 'Species', '10116', (63, 66))	('limited', 'NegReg', (27, 34))	('antagonists', 'Var', (15, 26))	('Glu', 'Chemical', 'MESH:D018698', (9, 12))	('brain tumor', 'Disease', 'MESH:D001932', (35, 46))	('brain tumor', 'Disease', (35, 46))	('mGlu3R', 'Protein', (8, 14))	('nude mice', 'Species', '10090', (73, 82))
77192	32555170	In non-neuronal cancer cells, genomic and proteomic studies have revealed glutamate receptor mutations and aberrant glutamatergic signaling related to iGluRs, mGluRs, and their downstream effectors.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('mutations', 'Var', (93, 102))	('mGluRs', 'Gene', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('glutamatergic signaling', 'MPA', (116, 139))	('cancer', 'Disease', (16, 22))	('Glu', 'Chemical', 'MESH:D018698', (152, 155))	('aberrant', 'Var', (107, 115))	('Glu', 'Chemical', 'MESH:D018698', (160, 163))	('glutamate', 'Chemical', 'MESH:D018698', (116, 125))	('mGluRs', 'Gene', '2911;14816;108068;108069', (159, 165))	('glutamate receptor', 'Protein', (74, 92))	('glutamate', 'Chemical', 'MESH:D018698', (74, 83))	('signaling', 'biological_process', 'GO:0023052', ('130', '139'))
77200	32555170	Reminiscent of uveal melanoma driven by mutant Gq/11, which in preclinical studies is sensitive to FR900359, the mGluR1/Gq signaling pathway emerges as a potential target in melanoma.	('signaling pathway', 'biological_process', 'GO:0007165', ('123', '140'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (15, 29))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Disease', (174, 182))	('melanoma', 'Disease', (21, 29))	('mutant', 'Var', (40, 46))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))	('Gq/11', 'Gene', (47, 52))
77210	32555170	In fact, epigenetic control of the NR2B subunit promoter, by methylation, is being postulated as a biomarker in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('methylation', 'Var', (61, 72))	('gastric cancer', 'Disease', 'MESH:D013274', (112, 126))	('gastric cancer', 'Disease', (112, 126))	('NR2B', 'Gene', '2904', (35, 39))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('epigenetic control', 'Var', (9, 27))	('gastric cancer', 'Phenotype', 'HP:0012126', (112, 126))	('NR2B', 'Gene', (35, 39))
77265	32013269	These include the presence of choroidal or cutaneous nevi, fair skin, light eye color, oculodermal melanocytosis, inactivating mutations of the tumor-suppressor BRCA1-associated protein 1 (BAP1), and exposure to ultraviolet (UV) radiation.	('oculodermal melanocytosis', 'Disease', (87, 112))	('light eye color', 'Disease', (70, 85))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('144', '160'))	('BRCA1-associated protein 1', 'Gene', '8314', (161, 187))	('BAP1', 'Gene', '8314', (189, 193))	('fair skin', 'Phenotype', 'HP:0007513', (59, 68))	('choroidal', 'Disease', (30, 39))	('inactivating mutations', 'Var', (114, 136))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('144', '160'))	('nevi', 'Phenotype', 'HP:0003764', (53, 57))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('light eye color', 'Phenotype', 'HP:0007730', (70, 85))	('BRCA1-associated protein 1', 'Gene', (161, 187))	('tumor', 'Disease', (144, 149))	('BAP1', 'Gene', (189, 193))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('oculodermal melanocytosis', 'Phenotype', 'HP:0009920', (87, 112))	('oculodermal melanocytosis', 'Disease', 'MESH:C535835', (87, 112))	('choroidal', 'Disease', 'MESH:D002833', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
77267	32013269	Similar to other cancer entities that are associated with the exposure to environmental carcinogens such as nonsmall cell lung cancer (NSCLC), CM has an extremely high mutational burden with up to 100 mutations per megabase.	('mutations', 'Var', (201, 210))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('CM', 'Phenotype', 'HP:0012056', (143, 145))	('nonsmall cell lung cancer', 'Disease', (108, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (108, 133))	('NSCLC', 'Disease', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('cancer', 'Disease', (17, 23))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (108, 133))	('cancer', 'Disease', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('CM', 'Disease', 'MESH:C562393', (143, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (135, 140))
77268	32013269	Despite this huge number, a few typical driver mutations are found in the majority of CM tissue samples that affect members of the BRAF-MEK-ERK signaling cascade.	('signaling cascade', 'biological_process', 'GO:0007165', ('144', '161'))	('ERK', 'molecular_function', 'GO:0004707', ('140', '143'))	('MEK', 'Gene', (136, 139))	('CM', 'Disease', 'MESH:C562393', (86, 88))	('MEK', 'Gene', '5609', (136, 139))	('mutations', 'Var', (47, 56))	('CM', 'Phenotype', 'HP:0012056', (86, 88))	('ERK', 'Gene', '5594', (140, 143))	('affect', 'Reg', (109, 115))	('ERK', 'Gene', (140, 143))
77269	32013269	About 40% to 50% harbor mutations in the BRAF gene coding for v-Raf murine sarcoma viral oncogene homolog, and about 20% harbor mutations in the NRAS gene coding for neuroblastoma rat sarcoma viral oncogene homolog.	('neuroblastoma', 'Disease', 'MESH:D009447', (166, 179))	('NRAS', 'Gene', (145, 149))	('sarcoma', 'Disease', 'MESH:D012509', (184, 191))	('v-Raf', 'Gene', '110157', (62, 67))	('rat', 'Species', '10116', (180, 183))	('mutations', 'Var', (128, 137))	('neuroblastoma', 'Disease', (166, 179))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('neuroblastoma', 'Phenotype', 'HP:0003006', (166, 179))	('sarcoma', 'Disease', (75, 82))	('sarcoma', 'Disease', (184, 191))	('murine', 'Species', '10090', (68, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (184, 191))	('BRAF', 'Gene', (41, 45))	('v-Raf', 'Gene', (62, 67))	('mutations', 'Var', (24, 33))
77270	32013269	Both activating BRAF and NRAS mutations lead to a constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway that promotes proliferation and survival, and thereby contribute to cancer formation and progression.	('rat', 'Species', '10116', (160, 163))	('MAPK) signaling', 'biological_process', 'GO:0000165', ('115', '130'))	('NRAS', 'Gene', (25, 29))	('MAPK', 'Gene', (115, 119))	('cancer', 'Disease', (207, 213))	('BRAF', 'Gene', (16, 20))	('MAPK', 'Gene', '5594', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('signaling pathway', 'biological_process', 'GO:0007165', ('121', '138'))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('survival', 'CPA', (171, 179))	('contribute', 'Reg', (193, 203))	('MAPK', 'molecular_function', 'GO:0004707', ('115', '119'))	('mutations', 'Var', (30, 39))	('activation', 'PosReg', (63, 73))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('activating', 'PosReg', (5, 15))	('formation', 'biological_process', 'GO:0009058', ('214', '223'))	('promotes', 'PosReg', (144, 152))	('proliferation', 'CPA', (153, 166))
77272	32013269	Instead of BRAF and NRAS mutations, which are almost never observed in UM, more than 80% of all UM harbor mutations in the genes encoding the guanine nucleotide-binding proteins Q polypeptide (GNAQ) and alpha11 (GNA11).	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('150', '168'))	('UM', 'Disease', 'MESH:C536494', (96, 98))	('GNA11', 'Gene', (212, 217))	('UM', 'Phenotype', 'HP:0007716', (71, 73))	('GNA11', 'Gene', '2767', (212, 217))	('UM', 'Disease', 'MESH:C536494', (71, 73))	('mutations', 'Var', (106, 115))	('Q polypeptide (GNAQ) and alpha11', 'Gene', '2776', (178, 210))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (142, 160))
77274	32013269	In about 90% of all cases, codon 209 located in the Ras-like GTPase domain of the proteins is affected, and most commonly, glutamine is substituted by leucine (Q209L).	('codon 209', 'Var', (27, 36))	('GTP', 'Chemical', 'MESH:D006160', (61, 64))	('Q209L', 'Var', (160, 165))	('substituted', 'Reg', (136, 147))	('leucine', 'Chemical', 'MESH:D007930', (151, 158))	('Q209L', 'Mutation', 'rs1057519742', (160, 165))	('glutamine', 'Chemical', 'MESH:D005973', (123, 132))	('affected', 'Reg', (94, 102))
77276	32013269	Besides, other downstream pathways as Trio-Rho-Rac and YAP-Hippo get activated by mutated Galpha proteins.	('Trio-Rho-Rac', 'Disease', (38, 50))	('YAP', 'Gene', (55, 58))	('Galpha', 'Gene', '8802', (90, 96))	('mutated', 'Var', (82, 89))	('Galpha', 'Gene', (90, 96))	('activated', 'PosReg', (69, 78))	('YAP', 'Gene', '10413', (55, 58))
77278	32013269	Other driver mutations in UM are by far less frequently detected and involve CYSLTR2 encoding the G-protein-coupled cysteinyl leukotriene receptor 2 and PLCB4 coding for phospholipase C beta4, which act immediately upstream and downstream of GNAQ/11 in the signal transduction cascade.	('phospholipase C beta4', 'Gene', (170, 191))	('cysteinyl leukotriene receptor 2', 'Gene', '70086', (116, 148))	('signal transduction', 'biological_process', 'GO:0007165', ('257', '276'))	('cysteinyl leukotriene receptor 2', 'Gene', (116, 148))	('GNAQ', 'Gene', (242, 246))	('PLCB4', 'Gene', (153, 158))	('UM', 'Phenotype', 'HP:0007716', (26, 28))	('CYSLTR2', 'Gene', '57105', (77, 84))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('GNAQ', 'Gene', '2776', (242, 246))	('PLCB4', 'Gene', '5332', (153, 158))	('mutations', 'Var', (13, 22))	('UM', 'Disease', 'MESH:C536494', (26, 28))	('phospholipase C beta4', 'Gene', '5332', (170, 191))	('CYSLTR2', 'Gene', (77, 84))
77279	32013269	Inactivating mutations in BAP1 are present in about 40% to 47% of UM primary tumors and 80% of UM metastases.	('tumors', 'Disease', (77, 83))	('BAP1', 'Gene', (26, 30))	('UM', 'Disease', 'MESH:C536494', (66, 68))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('Inactivating mutations', 'Var', (0, 22))	('metastases', 'Disease', (98, 108))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('metastases', 'Disease', 'MESH:D009362', (98, 108))	('BAP1', 'Gene', '8314', (26, 30))	('UM', 'Disease', 'MESH:C536494', (95, 97))
77280	32013269	BAP1 is a tumor suppressor involved in the repair of DNA double strand breaks, and about 8% of UM patients carry BAP1 germline mutations leading to a loss of function.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('BAP1', 'Gene', (0, 4))	('tumor', 'Disease', (10, 15))	('patients', 'Species', '9606', (98, 106))	('tumor suppressor', 'biological_process', 'GO:0051726', ('10', '26'))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('BAP1', 'Gene', '8314', (113, 117))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('10', '26'))	('germline', 'Var', (118, 126))	('UM', 'Disease', 'MESH:C536494', (95, 97))	('BAP1', 'Gene', '8314', (0, 4))	('BAP1', 'Gene', (113, 117))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('loss of function', 'NegReg', (150, 166))
77281	32013269	Mutations in genes coding for splicing factor 3B, subunit 1 (SF3B1), which is required for RNA splicing, and the eukaryotic translation initiation factor 1A, x-linked (EIF1AX), are present in 29% and 48%, respectively.	('SF3B1', 'Gene', (61, 66))	('translation initiation', 'biological_process', 'GO:0006413', ('124', '146'))	('RNA splicing', 'biological_process', 'GO:0008380', ('91', '103'))	('SF3B1', 'Gene', '23451', (61, 66))	('Mutations', 'Var', (0, 9))	('splicing factor 3B, subunit 1', 'Gene', '23451', (30, 59))	('eukaryotic translation initiation factor 1A, x-linked', 'Gene', '1964', (113, 166))	('splicing', 'biological_process', 'GO:0045292', ('30', '38'))	('EIF1AX', 'Gene', '1964', (168, 174))	('EIF1AX', 'Gene', (168, 174))	('RNA', 'cellular_component', 'GO:0005562', ('91', '94'))
77282	32013269	Commonly observed chromosomal aberrations in primary UM include monosomy of chromosome 3 and loss of chromosome 1p, 6q, and 8p, as well as amplifications of chromosome 1q, 6p, and 8q.	('chromosome', 'cellular_component', 'GO:0005694', ('101', '111'))	('monosomy', 'Var', (64, 72))	('loss', 'NegReg', (93, 97))	('chromosome', 'cellular_component', 'GO:0005694', ('76', '86'))	('UM', 'Phenotype', 'HP:0007716', (53, 55))	('amplifications', 'Var', (139, 153))	('rat', 'Species', '10116', (34, 37))	('UM', 'Disease', 'MESH:C536494', (53, 55))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (18, 41))	('chromosome', 'cellular_component', 'GO:0005694', ('157', '167'))
77283	32013269	These alterations also decisively affect the patient's prognosis.	('alterations', 'Var', (6, 17))	('affect', 'Reg', (34, 40))	('patient', 'Species', '9606', (45, 52))	('rat', 'Species', '10116', (10, 13))
77294	32013269	The presence of certain genetic aberrations has an impact on the clinical outcome and prognosis of UM in general.	('rat', 'Species', '10116', (36, 39))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('presence', 'Var', (4, 12))	('UM', 'Disease', 'MESH:C536494', (99, 101))	('impact', 'Reg', (51, 57))
77295	32013269	A poor prognosis has been associated with monosomy 3, mutations in the BAP1 gene, which is also located on chromosome 3p21.3, and chromosome 8q amplifications.	('mutations', 'Var', (54, 63))	('BAP1', 'Gene', '8314', (71, 75))	('chromosome', 'cellular_component', 'GO:0005694', ('107', '117'))	('monosomy 3', 'Disease', (42, 52))	('chromosome', 'cellular_component', 'GO:0005694', ('130', '140'))	('BAP1', 'Gene', (71, 75))
77296	32013269	Metastatic spread of UM occurs more often in tumors harboring GNA11 than GNAQ mutations, and SF3B1 mutations are associated with an intermediate risk of metastases and the onset of late-occurring metastases.	('metastases', 'Disease', 'MESH:D009362', (153, 163))	('GNA11', 'Gene', (62, 67))	('UM', 'Disease', 'MESH:C536494', (21, 23))	('metastases', 'Disease', (153, 163))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('mutations', 'Var', (78, 87))	('Metastatic spread', 'CPA', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('GNAQ', 'Gene', '2776', (73, 77))	('tumors', 'Disease', (45, 51))	('SF3B1', 'Gene', (93, 98))	('GNAQ', 'Gene', (73, 77))	('GNA11', 'Gene', '2767', (62, 67))	('metastases', 'Disease', 'MESH:D009362', (196, 206))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('mutations', 'Var', (99, 108))	('UM', 'Phenotype', 'HP:0007716', (21, 23))	('metastases', 'Disease', (196, 206))	('SF3B1', 'Gene', '23451', (93, 98))
77301	32013269	The frequently occurring GNAQ and GNA11 mutations that lead to a constitutive activity of the MAPK signaling pathway provided the rationale for the use of small molecule inhibitors targeting the downstream kinases.	('MAPK', 'molecular_function', 'GO:0004707', ('94', '98'))	('constitutive', 'MPA', (65, 77))	('MAPK', 'Gene', '5594', (94, 98))	('MAPK signaling', 'biological_process', 'GO:0000165', ('94', '108'))	('mutations', 'Var', (40, 49))	('signaling pathway', 'biological_process', 'GO:0007165', ('99', '116'))	('GNAQ', 'Gene', (25, 29))	('MAPK', 'Gene', (94, 98))	('GNA11', 'Gene', (34, 39))	('rat', 'Species', '10116', (130, 133))	('GNA11', 'Gene', '2767', (34, 39))	('GNAQ', 'Gene', '2776', (25, 29))
77324	32013269	The inhibitory effect of CTLA-4 can be overcome either by upregulating CD80/86 on APCs:which occurs physiologically in response to inflammatory stimuli in vivo:or therapeutically by administering antibodies targeting CTLA-4.	('CD80', 'Gene', (71, 75))	('CD80', 'Gene', '941', (71, 75))	('upregulating', 'PosReg', (58, 70))	('APCs', 'Disease', (82, 86))	('antibodies', 'Var', (196, 206))	('CTLA-4', 'Gene', (217, 223))
77330	32013269	When the TCR is simultaneously bound, the interaction of PD-L1 and PD-1 leads to the transduction of an inhibitory signal that blocks TCR signaling by reducing PTEN phosphorylation, phosphoinositide 3-kinase (PI3K) inhibition, and MEK-ERK pathway activation.	('inhibition', 'NegReg', (215, 225))	('PD-L1', 'Var', (57, 62))	('ERK', 'Gene', (235, 238))	('transduction', 'biological_process', 'GO:0009293', ('85', '97'))	('phosphorylation', 'biological_process', 'GO:0016310', ('165', '180'))	('PD-1', 'Gene', (67, 71))	('PD-1', 'Gene', '5133', (67, 71))	('TCR', 'cellular_component', 'GO:0042101', ('134', '137'))	('TCR', 'Gene', (9, 12))	('reducing', 'NegReg', (151, 159))	('TCR', 'Gene', '6962', (134, 137))	('transduction of an inhibitory signal', 'MPA', (85, 121))	('TCR', 'biological_process', 'GO:0006283', ('134', '137'))	('activation', 'PosReg', (247, 257))	('PTEN', 'Gene', (160, 164))	('ERK', 'molecular_function', 'GO:0004707', ('235', '238'))	('TCR', 'Gene', (134, 137))	('TCR', 'cellular_component', 'GO:0042101', ('9', '12'))	('MEK', 'Gene', '5609', (231, 234))	('TCR', 'biological_process', 'GO:0006283', ('9', '12'))	('interaction', 'Interaction', (42, 53))	('ERK', 'Gene', '5594', (235, 238))	('PTEN', 'Gene', '5728', (160, 164))	('blocks', 'NegReg', (127, 133))	('PI3K', 'molecular_function', 'GO:0016303', ('209', '213'))	('signaling', 'biological_process', 'GO:0023052', ('138', '147'))	('MEK', 'Gene', (231, 234))	('TCR', 'Gene', '6962', (9, 12))
77339	32013269	Antibodies against PD-1 or its ligand PD-L1 are able to inhibit the PD-1-mediated transduction of inhibitory signals and prevent the inactivation of tumor-reactive immune cells.	('PD-1', 'Gene', '5133', (68, 72))	('PD-1', 'Gene', (19, 23))	('Antibodies', 'Var', (0, 10))	('ligand', 'molecular_function', 'GO:0005488', ('31', '37'))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('inactivation', 'MPA', (133, 145))	('tumor', 'Disease', (149, 154))	('transduction', 'biological_process', 'GO:0009293', ('82', '94'))	('prevent', 'NegReg', (121, 128))	('PD-1', 'Gene', '5133', (19, 23))	('PD-1', 'Gene', (68, 72))	('inhibit', 'NegReg', (56, 63))
77430	32013269	The exposure to environmental noxae, such as tobacco smoke, UV radiation, and other carcinogens facilitate the accumulation of dozens of mutations and result in the formation of tumors with a high mutational burden.	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('formation', 'biological_process', 'GO:0009058', ('165', '174'))	('mutations', 'Var', (137, 146))	('tobacco', 'Species', '4097', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('result in', 'Reg', (151, 160))
77438	32013269	The tumors of both patients were characterized by an extraordinary high mutational burden and the presence of germline mutations of methyl-CpG-binding domain protein 4 (MBD4) that are found in about 2% of UM patients.	('presence', 'Reg', (98, 106))	('MBD4', 'Gene', '8930', (169, 173))	('MBD4', 'Gene', (169, 173))	('patients', 'Species', '9606', (208, 216))	('patients', 'Species', '9606', (19, 27))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('methyl-CpG-binding', 'molecular_function', 'GO:0008327', ('132', '150'))	('methyl-CpG-binding domain protein 4', 'Gene', (132, 167))	('UM', 'Phenotype', 'HP:0007716', (205, 207))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('UM', 'Disease', 'MESH:C536494', (205, 207))	('mutational burden', 'MPA', (72, 89))	('mutations', 'Var', (119, 128))	('protein', 'cellular_component', 'GO:0003675', ('158', '165'))	('methyl-CpG-binding domain protein 4', 'Gene', '8930', (132, 167))
77440	32013269	MBD4 mutations are also present in up to 43% of colorectal, endometrial, gastric, and pancreatic cancer with microsatellite instability.	('microsatellite instability', 'Disease', 'MESH:D053842', (109, 135))	('pancreatic cancer', 'Disease', (86, 103))	('present', 'Reg', (24, 31))	('pancreatic cancer', 'Disease', 'MESH:D010190', (86, 103))	('mutations', 'Var', (5, 14))	('microsatellite instability', 'Disease', (109, 135))	('gastric', 'Disease', (73, 80))	('colorectal', 'Disease', 'MESH:D015179', (48, 58))	('MBD4', 'Gene', (0, 4))	('MBD4', 'Gene', '8930', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('endometrial', 'Disease', (60, 71))	('colorectal', 'Disease', (48, 58))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (86, 103))
77508	32013269	Currently, a randomized controlled trial comparing IMCgp100 vs. physician's choice chemotherapy or immunotherapy is recruiting patients with advanced UM (NCT03070392).	('NCT03070392', 'Var', (154, 165))	('gp100', 'Gene', (54, 59))	('patients', 'Species', '9606', (127, 135))	('UM', 'Disease', 'MESH:C536494', (150, 152))	('UM', 'Phenotype', 'HP:0007716', (150, 152))	('gp100', 'Gene', '6490', (54, 59))
77536	31568700	Meanwhile, the high level of MIR155HG was associated with poorer OS in glioblastoma multiforme (GBM), kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), and uveal melanoma (UVM).	('glioblastoma multiforme', 'Disease', (71, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (180, 194))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (71, 94))	('GBM', 'Disease', (96, 99))	('GBM', 'Disease', 'MESH:D005909', (96, 99))	('glioma', 'Disease', (162, 168))	('KIRC', 'Disease', (137, 141))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (102, 135))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('UVM', 'Disease', 'MESH:C536494', (196, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('KIRC', 'Disease', 'MESH:D002292', (137, 141))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('UVM', 'Disease', (196, 199))	('kidney renal clear cell carcinoma', 'Disease', (102, 135))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('uveal melanoma', 'Disease', (180, 194))	('uveal melanoma', 'Disease', 'MESH:C536494', (180, 194))	('MIR155HG', 'Var', (29, 37))
77537	31568700	(b) The expression of MIR155HG was significantly correlated with infiltrating levels of immune cells and immune molecules, especially with immune checkpoint molecules such as programmed cell death protein 1 (PD-1), PD-1 ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) in most kinds of cancers.	('CTLA4', 'Gene', (287, 292))	('MIR155HG', 'Var', (22, 30))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', (242, 285))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', '1493', (242, 285))	('PD-L1', 'Gene', (230, 235))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('cancers', 'Disease', (311, 318))	('PD-L1', 'Gene', '29126', (230, 235))	('protein', 'cellular_component', 'GO:0003675', ('197', '204'))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('PD-1', 'Gene', (215, 219))	('PD-1', 'Gene', '5133', (215, 219))	('PD-1', 'Gene', (208, 212))	('correlated', 'Reg', (49, 59))	('PD-1', 'Gene', '5133', (208, 212))	('PD-1 ligand 1', 'Gene', (215, 228))	('programmed cell death protein 1', 'Gene', (175, 206))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('infiltrating levels of immune cells', 'MPA', (65, 100))	('CTLA4', 'Gene', '1493', (287, 292))	('programmed cell death', 'biological_process', 'GO:0012501', ('175', '196'))	('PD-1 ligand 1', 'Gene', '29126', (215, 228))	('programmed cell death protein 1', 'Gene', '5133', (175, 206))	('ligand', 'molecular_function', 'GO:0005488', ('220', '226'))
77538	31568700	(c) Detection of clinical CHOL and liver hepatocellular carcinoma tissues confirmed that there was a strong positive correlation between MIR155HG expression and the levels of CTLA4 and PD-L1.	('CTLA4', 'Gene', '1493', (175, 180))	('MIR155HG', 'Var', (137, 145))	('CHOL', 'Disease', (26, 30))	('CTLA4', 'Gene', (175, 180))	('CHOL', 'Disease', 'MESH:D018281', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('PD-L1', 'Gene', '29126', (185, 190))	('liver hepatocellular carcinoma', 'Disease', (35, 65))	('PD-L1', 'Gene', (185, 190))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (35, 65))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (41, 65))	('clinical', 'Species', '191496', (17, 25))
77548	31568700	At the same time, MIR155HG is also thought to be involved in the human immune response.	('involved', 'Reg', (49, 57))	('human', 'Species', '9606', (65, 70))	('MIR155HG', 'Var', (18, 26))	('immune response', 'biological_process', 'GO:0006955', ('71', '86'))
77550	31568700	We also analyzed the association of MIR155HG with tumor-infiltrating immune cells and immune molecules in tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (50, 55))	('MIR155HG', 'Var', (36, 44))	('tumor', 'Disease', (106, 111))
77551	31568700	The results indicated that the expression of MIR155HG in these tumors is closely related to the immunological checkpoint molecules PD-1, PD-L1, CTLA4, LAG3, and TIM3.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('CTLA4', 'Gene', (144, 149))	('LAG3', 'Gene', (151, 155))	('MIR155HG', 'Var', (45, 53))	('tumors', 'Disease', (63, 69))	('PD-L1', 'Gene', (137, 142))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('LAG3', 'Gene', '3902', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('TIM3', 'Gene', (161, 165))	('PD-1', 'Gene', (131, 135))	('PD-L1', 'Gene', '29126', (137, 142))	('TIM3', 'Gene', '84868', (161, 165))	('PD-1', 'Gene', '5133', (131, 135))	('CTLA4', 'Gene', '1493', (144, 149))
77553	31568700	Therefore, we believe that MIR155HG can be used as a predictor for assessing the prognosis of cancer patients and the effectiveness of immunotherapy with checkpoint blockade.	('patients', 'Species', '9606', (101, 109))	('MIR155HG', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
77555	31568700	The gene pattern was used to analyze the correlation of MIR155HG with immune cell infiltration in various tumors, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells (DCs).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('MIR155HG', 'Var', (56, 64))
77557	31568700	The gene expression profiling interactive analysis (GEPIA) database integrates tens of thousands of tumor and non-tumor samples from TCGA and GTEx gene expression data to analyze gene expression, differential gene expression, survival, correlation, and co-expression of genes online.21 We analyzed the expression of MIR155HG in various tumors and corresponding normal tissues by GEPIA quick start tab.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('gene expression', 'biological_process', 'GO:0010467', ('4', '19'))	('tumors', 'Phenotype', 'HP:0002664', (336, 342))	('gene expression', 'biological_process', 'GO:0010467', ('179', '194'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumors', 'Disease', (336, 342))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('tumors', 'Disease', 'MESH:D009369', (336, 342))	('tumor', 'Disease', (114, 119))	('gene expression', 'biological_process', 'GO:0010467', ('147', '162'))	('MIR155HG', 'Var', (316, 324))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumor', 'Disease', (336, 341))	('gene expression', 'biological_process', 'GO:0010467', ('209', '224'))
77562	31568700	The TIMER online database was used to analyze the differential expression of MIR155HG in 17 types of tumors and adjacent tissues in TCGA, and the differential expression was evaluated by Wilcoxon test.	('MIR155HG', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
77563	31568700	The results showed that, compared to the paracancerous control, MIR155HG was highly expressed in breast invasive carcinoma, HNSC, KIRC, kidney renal papillary cell carcinoma, LUAD, stomach adenocarcinoma and uterine corpus endometrial carcinoma, lower expression in kidney chromophobe (KICH), rectum adenocarcinoma (P < .05) (Figure 1A).	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (97, 122))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (223, 244))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('stomach adenocarcinoma', 'Disease', (181, 203))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D002292', (136, 173))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (143, 173))	('KIRC', 'Disease', (130, 134))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (97, 122))	('kidney chromophobe', 'Disease', (266, 284))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (293, 314))	('LUAD', 'Disease', (175, 179))	('MIR155HG', 'Var', (64, 72))	('KIRC', 'Disease', 'MESH:D002292', (130, 134))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (181, 203))	('endometrial carcinoma', 'Disease', (223, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('kidney renal papillary cell carcinoma', 'Disease', (136, 173))	('cancer', 'Disease', (45, 51))	('expression', 'MPA', (252, 262))	('lower', 'NegReg', (246, 251))	('LUAD', 'Disease', 'MESH:C538231', (175, 179))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('breast invasive carcinoma', 'Disease', (97, 122))	('rectum adenocarcinoma', 'Disease', (293, 314))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (223, 244))
77564	31568700	The GEPIA database analyzes the expression of MIR155HG in various tumors and matched normal tissues (match TCGA normal and GTEx data), and the results showed that MIR155HG was higher than the matched normal tissue in the lymphoid neoplasm DLBC lymphoma, GBM, KIRC, acute myeloid leukemia, thymoma (cutoff criteria:  log2fold change  > 1.0 and P < .05) (Figure 1B).	('KIRC', 'Disease', (259, 263))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (265, 287))	('lymphoma', 'Disease', (244, 252))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('lymphoma', 'Disease', 'MESH:D008223', (244, 252))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (265, 287))	('thymoma', 'Disease', (289, 296))	('MIR155HG', 'Var', (163, 171))	('thymoma', 'Phenotype', 'HP:0100522', (289, 296))	('KIRC', 'Disease', 'MESH:D002292', (259, 263))	('GBM', 'Disease', (254, 257))	('lymphoid neoplasm', 'Phenotype', 'HP:0002665', (221, 238))	('GBM', 'Disease', 'MESH:D005909', (254, 257))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('lymphoma', 'Phenotype', 'HP:0002665', (244, 252))	('higher', 'PosReg', (176, 182))	('MIR155HG', 'Var', (46, 54))	('acute myeloid leukemia', 'Disease', (265, 287))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('neoplasm', 'Phenotype', 'HP:0002664', (230, 238))	('leukemia', 'Phenotype', 'HP:0001909', (279, 287))	('tumors', 'Disease', (66, 72))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (271, 287))	('thymoma', 'Disease', 'MESH:D013945', (289, 296))
77565	31568700	We used GEPIA to analyze the relation of MIR155HG and clinical features in 33 kinds of tumors and found that MIR155HG was correlated with OS, DFS, and staging in multiple tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('multiple tumors', 'Disease', (162, 177))	('DFS', 'Disease', (142, 145))	('clinical', 'Species', '191496', (54, 62))	('correlated', 'Reg', (122, 132))	('tumors', 'Disease', (87, 93))	('multiple tumors', 'Disease', 'MESH:D009369', (162, 177))	('tumors', 'Disease', (171, 177))	('MIR155HG', 'Var', (109, 117))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
77566	31568700	The MIR155HG higher expression has better OS and DFS in CHOL and prophase SKCM.	('SKCM', 'Disease', 'MESH:C562393', (74, 78))	('prophase', 'biological_process', 'GO:0051324', ('65', '73'))	('SKCM', 'Disease', (74, 78))	('DFS', 'MPA', (49, 52))	('MIR155HG higher expression', 'Var', (4, 30))	('better', 'PosReg', (35, 41))	('CHOL', 'Disease', (56, 60))	('CHOL', 'Disease', 'MESH:D018281', (56, 60))
77567	31568700	In LUAD and early stage of HNSC, patients with high levels of MIR155HG have better OS than patients with low expression of MIR155HG.	('LUAD', 'Disease', (3, 7))	('patients', 'Species', '9606', (91, 99))	('LUAD', 'Disease', 'MESH:C538231', (3, 7))	('patients', 'Species', '9606', (33, 41))	('MIR155HG', 'Var', (62, 70))	('better', 'PosReg', (76, 82))
77568	31568700	While high levels of MIR155HG was associated with poor OS in GBM, KIRC, LGG, and UVM, and poor DFS in LGG early stage and UVM MIR155HG was closely related to tumor stage in KICH, KIRC, LUAD, SKCM, Thyroid carcinoma (THCA) (Figure 2; Table S2).	('SKCM', 'Disease', (191, 195))	('GBM', 'Disease', 'MESH:D005909', (61, 64))	('KIRC', 'Disease', (179, 183))	('UVM', 'Disease', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('THCA', 'Disease', 'MESH:D013964', (216, 220))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (197, 214))	('UVM', 'Disease', (122, 125))	('LUAD', 'Disease', (185, 189))	('KIRC', 'Disease', 'MESH:D002292', (179, 183))	('related', 'Reg', (147, 154))	('THCA', 'Disease', (216, 220))	('SKCM', 'Disease', 'MESH:C562393', (191, 195))	('KIRC', 'Disease', (66, 70))	('LUAD', 'Disease', 'MESH:C538231', (185, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('KIRC', 'Disease', 'MESH:D002292', (66, 70))	('tumor', 'Disease', (158, 163))	('MIR155HG', 'Var', (21, 29))	('UVM', 'Disease', 'MESH:C536494', (81, 84))	('MIR155HG', 'Var', (126, 134))	('Thyroid carcinoma', 'Disease', (197, 214))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('UVM', 'Disease', 'MESH:C536494', (122, 125))	('Thyroid carcinoma', 'Disease', 'MESH:D013964', (197, 214))	('GBM', 'Disease', (61, 64))
77569	31568700	According to the correlation between MIR155HG and OS or DFS in eight types of tumors (CHOL, HNSC, GBM, KIRC, LGG, LUAD, SKCM, UVM), the gene pathway enrichment and functional enrichment were further analyzed.	('CHOL', 'Disease', 'MESH:D018281', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('SKCM', 'Disease', (120, 124))	('GBM', 'Disease', (98, 101))	('GBM', 'Disease', 'MESH:D005909', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('LUAD', 'Disease', (114, 118))	('LGG', 'Disease', (109, 112))	('UVM', 'Disease', 'MESH:C536494', (126, 129))	('tumors', 'Disease', (78, 84))	('SKCM', 'Disease', 'MESH:C562393', (120, 124))	('KIRC', 'Disease', (103, 107))	('CHOL', 'Disease', (86, 90))	('LUAD', 'Disease', 'MESH:C538231', (114, 118))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('UVM', 'Disease', (126, 129))	('HNSC', 'Disease', (92, 96))	('KIRC', 'Disease', 'MESH:D002292', (103, 107))	('MIR155HG', 'Var', (37, 45))
77570	31568700	The top 80 mRNAs co-expressed with MIR155HG in various tumors were obtained by GEPIA's similar genes model.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('MIR155HG', 'Var', (35, 43))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))
77574	31568700	To investigate the correlation between MIR155HG and tumor immune cells, we used the TIMER to analyze the correlation of MIR155HG with tumor purity, lymphocytes, macrophages, neutrophils, DCs, NK cells, Treg cells, mast cells, Th1, Th2, Th17, Tfh cells, MDSC in the above eight tumors.	('Th1', 'Gene', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Th1', 'Gene', '51497', (236, 239))	('tumor', 'Disease', (52, 57))	('MIR155HG', 'Var', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('Th1', 'Gene', (236, 239))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('Th1', 'Gene', '51497', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('tumor', 'Disease', (277, 282))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (134, 139))	('tumors', 'Disease', (277, 283))
77575	31568700	The results showed that the expression of MIR155HG in CHOL, HNSC, KIRC, LGG, LUAD, and SKCM was significantly correlated with tumor purity and the infiltration level of immune cells such as B lymphocytes, CD8+ T cells, CD4+ T cells and DCs.	('CHOL', 'Disease', (54, 58))	('SKCM', 'Disease', (87, 91))	('CHOL', 'Disease', 'MESH:D018281', (54, 58))	('correlated', 'Reg', (110, 120))	('infiltration level', 'MPA', (147, 165))	('MIR155HG', 'Var', (42, 50))	('SKCM', 'Disease', 'MESH:C562393', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('KIRC', 'Disease', 'MESH:D002292', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('KIRC', 'Disease', (66, 70))	('LUAD', 'Disease', (77, 81))	('LUAD', 'Disease', 'MESH:C538231', (77, 81))	('tumor', 'Disease', (126, 131))
77577	31568700	MIR155 host gene was highly correlated with NK cells, Treg cells, macrophages, Th1, Tfh cells and M-MDSC in CHOL, HNSC, KIRC, LUAD, and SKCM, and have a certain correlation with MDSC in GBM MIR155HG was related to the infiltration of macrophages, Th1 and DMSC in a certain degree in LGG, and has moderate correlated with Treg cells, Th1 and Tfh cells in UVM (Table S3).	('LUAD', 'Disease', 'MESH:C538231', (126, 130))	('Th1', 'Gene', (79, 82))	('Th1', 'Gene', '51497', (333, 336))	('SKCM', 'Disease', (136, 140))	('GBM', 'Disease', (186, 189))	('Th1', 'Gene', '51497', (79, 82))	('GBM', 'Disease', 'MESH:D005909', (186, 189))	('MIR155', 'Gene', (0, 6))	('UVM', 'Disease', 'MESH:C536494', (354, 357))	('SKCM', 'Disease', 'MESH:C562393', (136, 140))	('KIRC', 'Disease', (120, 124))	('CHOL', 'Disease', (108, 112))	('MIR155HG', 'Var', (190, 198))	('Th1', 'Gene', (247, 250))	('LUAD', 'Disease', (126, 130))	('KIRC', 'Disease', 'MESH:D002292', (120, 124))	('UVM', 'Disease', (354, 357))	('Th1', 'Gene', '51497', (247, 250))	('CHOL', 'Disease', 'MESH:D018281', (108, 112))	('Th1', 'Gene', (333, 336))
77579	31568700	To evaluate the efficacy of MIR155HG in predicting cancer patient response to checkpoint inhibitor, we used the TIMER database to analyze the relevance of MIR155HG and the currently available blocking molecules with superior therapeutic effects PD-1, PD-L1, CTLA4, LAG3, TIM3.	('TIM3', 'Gene', '84868', (271, 275))	('LAG3', 'Gene', '3902', (265, 269))	('PD-L1', 'Gene', '29126', (251, 256))	('CTLA4', 'Gene', '1493', (258, 263))	('PD-1', 'Gene', '5133', (245, 249))	('patient', 'Species', '9606', (58, 65))	('CTLA4', 'Gene', (258, 263))	('MIR155HG', 'Var', (155, 163))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('PD-L1', 'Gene', (251, 256))	('PD-1', 'Gene', (245, 249))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('LAG3', 'Gene', (265, 269))	('TIM3', 'Gene', (271, 275))
77580	31568700	A significant strong positive correlation (cor > 0.5) was found between MIR155HG with PD-1 (PDCD1), PD-L1 (CD274), CTLA4, LAG3, and TIM3 (HAVCR2) molecules in LUAD and SKCM, and with a median or higher correlation in CHOL and UVM patients (cor > 0.3), a significant correlation in HNSC, LGG (P < .0001).	('TIM3', 'Gene', (132, 136))	('UVM', 'Disease', (226, 229))	('HAVCR2', 'Gene', '84868', (138, 144))	('TIM3', 'Gene', '84868', (132, 136))	('CD274', 'Gene', '29126', (107, 112))	('CHOL', 'Disease', (217, 221))	('HNSC', 'Disease', (281, 285))	('SKCM', 'Disease', (168, 172))	('LGG', 'Disease', (287, 290))	('PDCD1', 'Gene', '5133', (92, 97))	('PDCD1', 'Gene', (92, 97))	('CTLA4', 'Gene', '1493', (115, 120))	('LAG3', 'Gene', '3902', (122, 126))	('CHOL', 'Disease', 'MESH:D018281', (217, 221))	('CD274', 'Gene', (107, 112))	('HAVCR2', 'Gene', (138, 144))	('SKCM', 'Disease', 'MESH:C562393', (168, 172))	('LAG3', 'Gene', (122, 126))	('LUAD', 'Disease', (159, 163))	('MIR155HG', 'Var', (72, 80))	('CTLA4', 'Gene', (115, 120))	('UVM', 'Disease', 'MESH:C536494', (226, 229))	('PD-L1', 'Gene', (100, 105))	('PD-L1', 'Gene', '29126', (100, 105))	('patients', 'Species', '9606', (230, 238))	('LUAD', 'Disease', 'MESH:C538231', (159, 163))	('PD-1', 'Gene', (86, 90))	('PD-1', 'Gene', '5133', (86, 90))
77582	31568700	The relationship between MIR155HG and immunity was relatively close in the eight types of prognostic-related tumor mentioned above, and what is the relationship with other types of tumors that unrelated to prognosis?	('tumor', 'Disease', (181, 186))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('MIR155HG', 'Var', (25, 33))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', (109, 114))
77584	31568700	The results showed that MIR155HG was significantly negative associated with tumor purity, positive correlated with B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and DCs.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('negative', 'NegReg', (51, 59))	('tumor', 'Disease', (76, 81))	('MIR155HG', 'Var', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
77585	31568700	In LIHC, MIR155HG has a high correlation with immunological checkpoint molecules PD-1, CTLA4, LAG3, and TIM3 (cor > 0.5), and also has a significant correlation with PD-L1.	('LAG3', 'Gene', (94, 98))	('LIHC', 'Disease', 'MESH:D006528', (3, 7))	('PD-L1', 'Gene', '29126', (166, 171))	('TIM3', 'Gene', (104, 108))	('PD-1', 'Gene', (81, 85))	('TIM3', 'Gene', '84868', (104, 108))	('CTLA4', 'Gene', '1493', (87, 92))	('PD-1', 'Gene', '5133', (81, 85))	('CTLA4', 'Gene', (87, 92))	('correlation', 'Interaction', (149, 160))	('LAG3', 'Gene', '3902', (94, 98))	('MIR155HG', 'Var', (9, 17))	('PD-L1', 'Gene', (166, 171))	('correlation', 'Interaction', (29, 40))	('LIHC', 'Disease', (3, 7))
77587	31568700	We also analyzed the relationship between MIR155HG and immune in other tumors, and found that MIR155HG is closely related to immune cells and molecules in most kind of tumors (Figures S2 and S3).	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('MIR155HG', 'Var', (94, 102))	('related', 'Reg', (114, 121))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
77588	31568700	Since the great value of MIR155HG predicting the immune checkpoint molecular expression level in tumor, we selected the prognostic-related tumor type CHOL and the prognostic-unrelated tumor type LIHC to detect the correlation.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CHOL', 'Disease', (150, 154))	('MIR155HG', 'Var', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('immune checkpoint molecular expression level', 'MPA', (49, 93))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (184, 189))	('CHOL', 'Disease', 'MESH:D018281', (150, 154))	('LIHC', 'Disease', (195, 199))	('LIHC', 'Disease', 'MESH:D006528', (195, 199))
77589	31568700	The relationship of MIR155HG and the immunological checkpoint molecules PD-L1 and CTLA4 were verified by qRT-PCR.	('PD-L1', 'Gene', '29126', (72, 77))	('MIR155HG', 'Var', (20, 28))	('CTLA4', 'Gene', '1493', (82, 87))	('PD-L1', 'Gene', (72, 77))	('CTLA4', 'Gene', (82, 87))
77590	31568700	The results showed that MIR155HG showed a striking positive correlation with both PD-L1 and CTLA4 in CHOL and LIHC (Figure 7).	('CTLA4', 'Gene', (92, 97))	('LIHC', 'Disease', 'MESH:D006528', (110, 114))	('PD-L1', 'Gene', (82, 87))	('MIR155HG', 'Var', (24, 32))	('PD-L1', 'Gene', '29126', (82, 87))	('positive', 'PosReg', (51, 59))	('LIHC', 'Disease', (110, 114))	('CHOL', 'Disease', (101, 105))	('CTLA4', 'Gene', '1493', (92, 97))	('CHOL', 'Disease', 'MESH:D018281', (101, 105))	('correlation', 'Interaction', (60, 71))
77591	31568700	In this report, we analyzed the expression of MIR155HG in various cancers and paracancer or normal tissues, and analyzed the relationship between MIR155HG expression and OS, DFS and staging, consistent with Wu's finding that MIR155HG was associated with poor tumor prognosis in glioma.10 As reported, the expression of MIR155HG was significantly higher in cancer than paracancer in KIRC,26 and MIR155HG was associated with poor OS.27 GO and KEGG analysis in these types of tumors showed that mRNAs co-expressed with MIR155HG were mostly enriched in immune-related functions and immune-related pathways, which indicated that MIR155HG may be related to immunity.	('tumors', 'Disease', 'MESH:D009369', (473, 479))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', (473, 478))	('cancers', 'Disease', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('immune-related functions', 'CPA', (549, 573))	('cancer', 'Disease', (356, 362))	('tumor', 'Disease', 'MESH:D009369', (473, 478))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('glioma', 'Disease', (278, 284))	('enriched', 'Reg', (537, 545))	('KIRC', 'Disease', (382, 386))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('tumors', 'Phenotype', 'HP:0002664', (473, 479))	('cancer', 'Disease', (372, 378))	('glioma', 'Disease', 'MESH:D005910', (278, 284))	('immune-related pathways', 'Pathway', (578, 601))	('cancer', 'Phenotype', 'HP:0002664', (372, 378))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('MIR155HG', 'Var', (516, 524))	('tumor', 'Phenotype', 'HP:0002664', (473, 478))	('KIRC', 'Disease', 'MESH:D002292', (382, 386))	('tumors', 'Disease', (473, 479))	('cancer', 'Disease', 'MESH:D009369', (356, 362))	('glioma', 'Phenotype', 'HP:0009733', (278, 284))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('tumor', 'Disease', (259, 264))	('cancer', 'Disease', 'MESH:D009369', (372, 378))	('cancer', 'Disease', (66, 72))
77594	31568700	In this study, we examined the association of MIR155HG with immune cells attempting to reveal the immune status in cancer patients by understanding the expression of MIR155HG.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('patients', 'Species', '9606', (122, 130))	('MIR155HG', 'Var', (166, 174))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
77595	31568700	The results showed that MIR155HG was significantly negatively correlated with tumor purity and significantly positively correlated with B cells, CD8+ T cells, CD4+ T cells, and DCs in most kinds of cancers.	('positively correlated', 'Reg', (109, 130))	('negatively', 'NegReg', (51, 61))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cancers', 'Disease', (198, 205))	('MIR155HG', 'Var', (24, 32))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', (78, 83))
77596	31568700	Moreover, to fully demonstrate the relationship between MIR155HG and immunity, we also analyzed the association of MIR155HG with immunosuppressive molecules and immunostimulatory molecules in the above described cancer types.	('association', 'Interaction', (100, 111))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('MIR155HG', 'Var', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
77600	31568700	We found that MIR155HG was significantly associated with immunological checkpoint blocking molecules PD-1, PD-L1, CTLA4, LAG3, and TIM3 in many tumors, and some of those types of tumor have better reactivity against immunological checkpoint blockade.	('tumors', 'Disease', (144, 150))	('associated', 'Reg', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('reactivity', 'MPA', (197, 207))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('TIM3', 'Gene', (131, 135))	('TIM3', 'Gene', '84868', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('LAG3', 'Gene', '3902', (121, 125))	('tumor', 'Disease', (144, 149))	('CTLA4', 'Gene', '1493', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('LAG3', 'Gene', (121, 125))	('PD-L1', 'Gene', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('PD-L1', 'Gene', '29126', (107, 112))	('MIR155HG', 'Var', (14, 22))	('PD-1', 'Gene', (101, 105))	('PD-1', 'Gene', '5133', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('CTLA4', 'Gene', (114, 119))	('tumor', 'Disease', (179, 184))
77604	31568700	They found that the expression of LAYN was associated with increased levels of immune permeation of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in colon and gastric cancer.41 Compared with the results of Pan et al, MIR155HG has a wider range of tumor applicability and was more closely related to immune cells and immune molecules.	('LAYN', 'Gene', '143903', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('MIR155HG', 'Var', (233, 241))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', (263, 268))	('LAYN', 'Gene', (34, 38))	('colon and gastric cancer', 'Disease', 'MESH:D013274', (165, 189))	('gastric cancer', 'Phenotype', 'HP:0012126', (175, 189))
77605	31568700	The previous research reported that MIR155HG participate the regulator of innate immunity17 and macrophage polarization,16 and associated with acute rejection, T-cell-mediated acute rejection and graft loss.42 MIR-155 regulates the expression of many immune-specific transcripts, such as regulate polarization of macrophages, DCs maturation, T-cell differentiation, controls B cell proliferation and antibody production.43, 44 Consider that MIR155 is derived from MIR155HG and that MIR155HG play a critical role by interaction with MIR155,9, 10 we speculated that MIR155HG may affect the immune process through its interaction with MIR155 or other mechanisms.	('affect', 'Reg', (577, 583))	('graft loss', 'Disease', 'MESH:D055589', (196, 206))	('B cell proliferation', 'biological_process', 'GO:0042100', ('375', '395'))	('interaction', 'Interaction', (615, 626))	('antibody', 'cellular_component', 'GO:0019815', ('400', '408'))	('graft loss', 'Disease', (196, 206))	('macrophage polarization', 'biological_process', 'GO:0042116', ('96', '119'))	('antibody', 'cellular_component', 'GO:0019814', ('400', '408'))	('MIR-155', 'Gene', '406947', (210, 217))	('MIR155HG', 'Var', (564, 572))	('innate immunity', 'biological_process', 'GO:0045087', ('74', '89'))	('antibody', 'molecular_function', 'GO:0003823', ('400', '408'))	('T-cell differentiation', 'biological_process', 'GO:0030217', ('342', '364'))	('MIR-155', 'Gene', (210, 217))	('antibody production', 'biological_process', 'GO:0002377', ('400', '419'))	('immune process', 'CPA', (588, 602))	('antibody', 'cellular_component', 'GO:0042571', ('400', '408'))
77606	31568700	To preliminarily verify the relationship between MIR155HG and immune infiltration in an individual patient, we verified the correlation between MIR155HG and immune checkpoint molecules PD-L1 and CTLA4 by realtime quantitative reverse transcription polymerase chain reaction (qRT-PCR) in frozen tissue specimens of patients with CHOL and LIHC.	('CTLA4', 'Gene', '1493', (195, 200))	('patient', 'Species', '9606', (99, 106))	('LIHC', 'Disease', (337, 341))	('patients', 'Species', '9606', (314, 322))	('LIHC', 'Disease', 'MESH:D006528', (337, 341))	('CTLA4', 'Gene', (195, 200))	('CHOL', 'Disease', (328, 332))	('MIR155HG', 'Var', (144, 152))	('CHOL', 'Disease', 'MESH:D018281', (328, 332))	('PD-L1', 'Gene', (185, 190))	('reverse transcription', 'biological_process', 'GO:0001171', ('226', '247'))	('patient', 'Species', '9606', (314, 321))	('PD-L1', 'Gene', '29126', (185, 190))
77607	31568700	There was a significant positive correlation between the expression of MIR155HG and PD-L1, CTLA4 in clinical specimens.	('expression', 'MPA', (57, 67))	('clinical', 'Species', '191496', (100, 108))	('PD-L1', 'Gene', (84, 89))	('MIR155HG', 'Var', (71, 79))	('PD-L1', 'Gene', '29126', (84, 89))	('CTLA4', 'Gene', '1493', (91, 96))	('CTLA4', 'Gene', (91, 96))
77609	31568700	In conclusion, the above results indicate that MIR155HG expression might help to predict the prognosis and understanding immune status in cancer.	('cancer', 'Disease', (138, 144))	('MIR155HG', 'Var', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('help', 'Reg', (73, 77))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
77610	31568700	In this study, we found that MIR155HG can be used as a biomarker of prognosis in CHOL, GBM, HNSC, KIRC, LGG, LUAD, SKCM, and UVM through bioinformatics analysis.	('UVM', 'Disease', 'MESH:C536494', (125, 128))	('GBM', 'Disease', (87, 90))	('SKCM', 'Disease', (115, 119))	('KIRC', 'Disease', (98, 102))	('CHOL', 'Disease', (81, 85))	('KIRC', 'Disease', 'MESH:D002292', (98, 102))	('CHOL', 'Disease', 'MESH:D018281', (81, 85))	('UVM', 'Disease', (125, 128))	('LUAD', 'Disease', 'MESH:C538231', (109, 113))	('GBM', 'Disease', 'MESH:D005909', (87, 90))	('HNSC', 'Disease', (92, 96))	('SKCM', 'Disease', 'MESH:C562393', (115, 119))	('LUAD', 'Disease', (109, 113))	('MIR155HG', 'Var', (29, 37))
77611	31568700	And the expression level of MIR155HG has a certain correlation with immune molecules in various types of tumors, especially in HNSC, LUAD, KIRC, SKCM, and LIHC, which are suitable for predicting the curative effect of immune checkpoint blockade therapy.	('tumors', 'Disease', (105, 111))	('correlation', 'Reg', (51, 62))	('KIRC', 'Disease', (139, 143))	('LIHC', 'Disease', (155, 159))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('SKCM', 'Disease', (145, 149))	('LUAD', 'Disease', 'MESH:C538231', (133, 137))	('LIHC', 'Disease', 'MESH:D006528', (155, 159))	('MIR155HG', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('expression', 'MPA', (8, 18))	('SKCM', 'Disease', 'MESH:C562393', (145, 149))	('HNSC', 'Disease', (127, 131))	('LUAD', 'Disease', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('KIRC', 'Disease', 'MESH:D002292', (139, 143))
77644	31311081	Moreover, PRAME expression has been associated with poor prognosis in solid cancers including breast cancer, sarcoma, head and neck cancer, medulloblastoma, uveal melanoma, and neuroblastoma.	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (157, 171))	('neuroblastoma', 'Disease', (177, 190))	('sarcoma', 'Disease', (109, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (157, 171))	('neuroblastoma', 'Phenotype', 'HP:0003006', (177, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('solid cancers', 'Disease', 'MESH:D009369', (70, 83))	('medulloblastoma', 'Disease', 'MESH:D008527', (140, 155))	('medulloblastoma', 'Phenotype', 'HP:0002885', (140, 155))	('neuroblastoma', 'Disease', 'MESH:D009447', (177, 190))	('PRAME expression', 'Var', (10, 26))	('medulloblastoma', 'Disease', (140, 155))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('solid cancers', 'Disease', (70, 83))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('breast cancer', 'Disease', (94, 107))	('neck', 'cellular_component', 'GO:0044326', ('127', '131'))	('associated', 'Reg', (36, 46))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('head and neck cancer', 'Phenotype', 'HP:0012288', (118, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('neck cancer', 'Disease', 'MESH:D006258', (127, 138))	('neck cancer', 'Disease', (127, 138))	('uveal melanoma', 'Disease', (157, 171))
77651	31311081	Of note, the silencing of PRAME could restore sensitivity to retinoic acid treatment in RA-resistant melanoma cell lines, thereby reducing cancer cell proliferation by de-repressing the expression of RAR target genes.	('PRAME', 'Gene', (26, 31))	('RAR', 'Gene', '5914', (200, 203))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('reducing', 'NegReg', (130, 138))	('retinoic acid', 'Chemical', 'MESH:D014212', (61, 74))	('de-repressing', 'NegReg', (168, 181))	('melanoma', 'Disease', (101, 109))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('restore', 'PosReg', (38, 45))	('sensitivity to retinoic acid treatment', 'MPA', (46, 84))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('RAR', 'Gene', (200, 203))	('expression', 'MPA', (186, 196))	('cell proliferation', 'biological_process', 'GO:0008283', ('146', '164'))	('silencing', 'Var', (13, 22))	('cancer', 'Disease', (139, 145))
77659	31311081	We demonstrated that PRAME increased the migratory and invasive behavior of triple negative breast cancer cells in vitro by promoting the epithelial-to-mesenchymal transition (EMT).	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('138', '174'))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('increased', 'PosReg', (27, 36))	('breast cancer', 'Disease', (92, 105))	('epithelial-to-mesenchymal transition', 'CPA', (138, 174))	('EMT', 'biological_process', 'GO:0001837', ('176', '179'))	('promoting', 'PosReg', (124, 133))	('PRAME', 'Var', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
77666	31311081	Moreover, given the association of PRAME expression with favorable outcomes in hematological diseases, directly targeting PRAME by small molecule inhibitors or gene silencing might not be as beneficial as compared with cytotoxic targeting of the tumor cells expressing PRAME.	('gene silencing', 'Var', (160, 174))	('hematological diseases', 'Disease', (79, 101))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', (246, 251))	('hematological diseases', 'Disease', 'MESH:D006402', (79, 101))	('gene silencing', 'biological_process', 'GO:0016458', ('160', '174'))
77683	31311081	Analysis of proteasome cleavage of PRAME polypeptides in conjunction with in silico epitope prediction identified four additional HLA-A*0201-restricted epitopes: PRA100-108 (VLDGLDVLL), PRA142-151 (SLYSFPEPEA), PRA300-309 (ALYVDSLFFL), and PRA425-433 (SLLQHLIGL).	('PRA', 'molecular_function', 'GO:0004196', ('211', '214'))	('PRA', 'molecular_function', 'GO:0004196', ('162', '165'))	('PRA300-309', 'Var', (211, 221))	('HLA-A', 'Gene', '3105', (130, 135))	('proteasome', 'molecular_function', 'GO:0004299', ('12', '22'))	('HLA-A', 'Gene', (130, 135))	('proteasome', 'cellular_component', 'GO:0000502', ('12', '22'))	('PRA', 'molecular_function', 'GO:0004196', ('186', '189'))	('PRA', 'molecular_function', 'GO:0004196', ('240', '243'))	('PRA100-108', 'Var', (162, 172))	('PRA142-151', 'Var', (186, 196))	('PRA425-433', 'Var', (240, 250))
77685	31311081	In vitro priming of isolated peripheral blood mononuclear cells with peptide-pulsed autologous antigen presenting cells demonstrated the presence of PRA100-108 and PRA300-309-specific T cells in 36% of melanoma and 70% of AML cancer patients, respectively.	('PRA300-309-specific', 'Var', (164, 183))	('AML cancer', 'Disease', (222, 232))	('PRA', 'molecular_function', 'GO:0004196', ('164', '167'))	('PRA', 'molecular_function', 'GO:0004196', ('149', '152'))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', (202, 210))	('patients', 'Species', '9606', (233, 241))	('PRA100-108', 'Var', (149, 159))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('AML cancer', 'Disease', 'MESH:D015470', (222, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
77686	31311081	Furthermore, the ex vivo expanded PRA100-108 and PRA300-309-specific T cells exhibited cytotoxic activity against autologous chronic myeloid leukemia (CML) blasts and cancer cell lines of various histologic origins.	('PRA', 'molecular_function', 'GO:0004196', ('49', '52'))	('CML', 'Disease', 'MESH:D015464', (151, 154))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (133, 149))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('PRA', 'molecular_function', 'GO:0004196', ('34', '37'))	('PRA100-108', 'Var', (34, 44))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('CML', 'Phenotype', 'HP:0005506', (151, 154))	('CML', 'Disease', (151, 154))	('leukemia', 'Phenotype', 'HP:0001909', (141, 149))	('cytotoxic activity', 'CPA', (87, 105))	('chronic myeloid leukemia', 'Disease', (125, 149))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (125, 149))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (125, 149))
77692	31311081	To date, numerous ongoing clinical trials are studying the safety and efficacy of targeting PRAME using ex vivo expanded multi-TAA-specific T cells in hematological malignancies (NCT02291848, NCT02475707, NCT02494167 and NCT02203903), neuro-oncologic disease (NCT03652545), rhabdomyosarcoma (NCT02239861), pancreatic cancer (NCT03192462), breast cancer (NCT03093350), and a range of high-risk solid tumors (NCT02789228).	('NCT03192462', 'Var', (325, 336))	('oncologic disease', 'Phenotype', 'HP:0002664', (241, 258))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (274, 290))	('solid tumors', 'Disease', (393, 405))	('neuro-oncologic disease', 'Disease', (235, 258))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (274, 290))	('NCT03652545', 'Var', (260, 271))	('breast cancer', 'Phenotype', 'HP:0003002', (339, 352))	('hematological malignancies', 'Disease', (151, 177))	('NCT02475707', 'Var', (192, 203))	('pancreatic cancer', 'Disease', 'MESH:D010190', (306, 323))	('sarcoma', 'Phenotype', 'HP:0100242', (283, 290))	('solid tumors', 'Disease', 'MESH:D009369', (393, 405))	('NCT02239861', 'Var', (292, 303))	('neuro-oncologic disease', 'Disease', 'MESH:C536203', (235, 258))	('NCT02494167', 'Var', (205, 216))	('NCT02203903', 'Disease', (221, 232))	('breast cancer', 'Disease', 'MESH:D001943', (339, 352))	('NCT02789228', 'Var', (407, 418))	('breast cancer', 'Disease', (339, 352))	('pancreatic cancer', 'Disease', (306, 323))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('tumors', 'Phenotype', 'HP:0002664', (399, 405))	('NCT03093350', 'Var', (354, 365))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('rhabdomyosarcoma', 'Disease', (274, 290))	('tumor', 'Phenotype', 'HP:0002664', (399, 404))	('hematological malignancies', 'Disease', 'MESH:D019337', (151, 177))	('hematological malignancies', 'Phenotype', 'HP:0004377', (151, 177))	('NCT02291848', 'Var', (179, 190))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (306, 323))
77695	31311081	A recent study reported that the transduction of T cells with a high affinity PRAME TCR and an inducible caspase-9 safety switch (BPX-701) eliminated the genetically modified T cells in case of detrimental toxicity.	('TCR', 'Gene', '6962', (84, 87))	('detrimental toxicity', 'Disease', (194, 214))	('transduction', 'biological_process', 'GO:0009293', ('33', '45'))	('caspase-9', 'Gene', '842', (105, 114))	('genetically', 'Var', (154, 165))	('TCR', 'Gene', (84, 87))	('caspase-9', 'Gene', (105, 114))	('BPX', 'Chemical', '-', (130, 133))	('detrimental toxicity', 'Disease', 'MESH:D064420', (194, 214))	('TCR', 'cellular_component', 'GO:0042101', ('84', '87'))	('TCR', 'biological_process', 'GO:0006283', ('84', '87'))
77697	31311081	Moreover, the transduced T cells induced tumor regression in an orthotopic medulloblastoma mouse model without excess neurological toxicity and were successfully eradicated by the suicide gene.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('neurological toxicity', 'Disease', (118, 139))	('medulloblastoma', 'Phenotype', 'HP:0002885', (75, 90))	('tumor', 'Disease', (41, 46))	('medulloblastoma', 'Disease', (75, 90))	('neurological toxicity', 'Disease', 'MESH:D020258', (118, 139))	('transduced', 'Var', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mouse', 'Species', '10090', (91, 96))	('medulloblastoma', 'Disease', 'MESH:D008527', (75, 90))
77703	31311081	These epigenetic modulators have been successfully used to upregulate tumor PRAME expression, resulting in an increase in cytolytic activity of ex vivo expanded autologous T cells.	('increase', 'PosReg', (110, 118))	('cytolytic activity', 'MPA', (122, 140))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('upregulate', 'PosReg', (59, 69))	('epigenetic modulators', 'Var', (6, 27))
77709	31311081	Countermeasures for these include demethylation agents and histone deacetylase inhibitors to increase target expression, and MEK inhibitors and NK cell therapy to induce HLA expression.	('target expression', 'MPA', (102, 119))	('increase', 'PosReg', (93, 101))	('inhibitors', 'Var', (129, 139))	('HLA', 'Protein', (170, 173))	('induce', 'PosReg', (163, 169))	('MEK', 'Gene', (125, 128))	('MEK', 'Gene', '5609', (125, 128))	('demethylation', 'biological_process', 'GO:0070988', ('34', '47'))
77714	31311081	This dose-dependent immune response has been demonstrated in the context of PRA100-108 specific T cell activation in HLA-A*0201+ acute lymphocytic leukemia (ALL) and melanoma cell lines.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (129, 155))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('PRA', 'molecular_function', 'GO:0004196', ('76', '79'))	('acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (129, 155))	('ALL', 'Phenotype', 'HP:0006721', (157, 160))	('HLA-A', 'Gene', '3105', (117, 122))	('T cell activation', 'biological_process', 'GO:0042110', ('96', '113'))	('T cell', 'CPA', (96, 102))	('PRA100-108', 'Var', (76, 86))	('HLA-A', 'Gene', (117, 122))	('activation', 'PosReg', (103, 113))	('immune response', 'biological_process', 'GO:0006955', ('20', '35'))	('acute lymphocytic leukemia', 'Disease', (129, 155))
77720	31311081	However, caution is warranted as the impact of re-expression of a tumor-associated antigen in normal tissues remains unknown and epigenetic agents may alter immune cell function.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('immune cell function', 'CPA', (157, 177))	('tumor', 'Disease', (66, 71))	('alter', 'Reg', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('epigenetic agents', 'Var', (129, 146))
77738	31311081	However, a research group from the Memorial Sloan Kettering Cancer Center developed a TCR mimic human antibody that can recognize the PRA300-309 peptide in a complex with HLA-A2.	('TCR', 'Gene', (86, 89))	('HLA-A', 'Gene', '3105', (171, 176))	('antibody', 'cellular_component', 'GO:0042571', ('102', '110'))	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('TCR', 'cellular_component', 'GO:0042101', ('86', '89'))	('HLA-A', 'Gene', (171, 176))	('complex', 'Interaction', (158, 165))	('human', 'Species', '9606', (96, 101))	('PRA300-309', 'Var', (134, 144))	('TCR', 'Gene', '6962', (86, 89))	('PRA', 'molecular_function', 'GO:0004196', ('134', '137'))	('TCR', 'biological_process', 'GO:0006283', ('86', '89'))	('antibody', 'cellular_component', 'GO:0019815', ('102', '110'))	('Memorial Sloan Kettering Cancer', 'Disease', (35, 66))	('antibody', 'cellular_component', 'GO:0019814', ('102', '110'))	('antibody', 'molecular_function', 'GO:0003823', ('102', '110'))	('Memorial Sloan Kettering Cancer', 'Disease', 'MESH:D008569', (35, 66))
77745	31311081	The authors demonstrated specific binding of MPA1 to PRAME+ liquid and solid cancer cell lines, with increased binding upon demethylation treatment.	('binding', 'molecular_function', 'GO:0005488', ('34', '41'))	('binding', 'Interaction', (34, 41))	('increased', 'PosReg', (101, 110))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('demethylation', 'biological_process', 'GO:0070988', ('124', '137'))	('binding', 'Interaction', (111, 118))	('binding', 'molecular_function', 'GO:0005488', ('111', '118'))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('demethylation', 'Var', (124, 137))	('MPA1', 'Protein', (45, 49))
77756	31277366	By stratifying patients based on the expression of CD47 in the tumor, we observed that patients with high levels of CD47 have a significant increase in immune score as compared to patients with low levels of CD47.	('CD4', 'Gene', '920', (208, 211))	('tumor', 'Disease', (63, 68))	('patients', 'Species', '9606', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('CD4', 'Gene', '920', (116, 119))	('CD4', 'Gene', (51, 54))	('CD4', 'Gene', '920', (51, 54))	('patients', 'Species', '9606', (180, 188))	('high levels', 'Var', (101, 112))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('CD4', 'Gene', (208, 211))	('increase', 'PosReg', (140, 148))	('patients', 'Species', '9606', (87, 95))	('CD4', 'Gene', (116, 119))	('immune score', 'MPA', (152, 164))
77763	31277366	The most frequent chromosomal aberrations found in UM patients are chromosome 3 monosomy (that occurs in 50% of the cases) and amplification of 8q and 6p.	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('chromosome', 'cellular_component', 'GO:0005694', ('67', '77'))	('patients', 'Species', '9606', (54, 62))	('frequent chromosomal aberrations', 'Phenotype', 'HP:0040012', (9, 41))	('chromosome 3 monosomy', 'CPA', (67, 88))	('amplification', 'Var', (127, 140))
77783	31277366	Although no differences were observed for overall survival (Figure 2A,B), patients with low levels of CD47 showed a trend of better progression-free survival (p = 0.064) (Figure 2C) that reached the statistical significance after correcting for the presence of BAP1, GNAQ, and GNA11 mutations (p = 0.0447) (Figure 2D).	('GNAQ', 'Gene', (267, 271))	('BAP1', 'Gene', '8314', (261, 265))	('GNA11', 'Gene', (277, 282))	('patients', 'Species', '9606', (74, 82))	('GNA11', 'Gene', '2767', (277, 282))	('better', 'PosReg', (125, 131))	('BAP1', 'Gene', (261, 265))	('progression-free survival', 'CPA', (132, 157))	('GNAQ', 'Gene', '2776', (267, 271))	('low levels', 'Var', (88, 98))	('CD4', 'Gene', (102, 105))	('CD4', 'Gene', '920', (102, 105))
77790	31277366	On the contrary, a significantly higher immune score was found in samples with high CD47 levels as compared to samples to low CD47 levels (p = 0.004) (Figure 4).	('CD4', 'Gene', (126, 129))	('immune score', 'MPA', (40, 52))	('higher', 'PosReg', (33, 39))	('CD4', 'Gene', '920', (126, 129))	('CD4', 'Gene', (84, 87))	('high', 'Var', (79, 83))	('CD4', 'Gene', '920', (84, 87))
77791	31277366	In particular, a significantly higher number of CD4+ and CD8+ T cells can be found in samples with high CD47 expression, with a significant increase in Th2, Treg, and CD8+ Tcm cells (Figure 4B,C).	('increase', 'PosReg', (140, 148))	('expression', 'MPA', (109, 119))	('CD8', 'Gene', (57, 60))	('CD4', 'Gene', (48, 51))	('CD4', 'Gene', (104, 107))	('CD8', 'Gene', (167, 170))	('CD8', 'Gene', '925', (57, 60))	('CD8', 'Gene', '925', (167, 170))	('high', 'Var', (99, 103))	('CD4', 'Gene', '920', (48, 51))	('CD4', 'Gene', '920', (104, 107))	('Th2', 'CPA', (152, 155))	('higher', 'PosReg', (31, 37))	('Treg', 'CPA', (157, 161))
77809	31277366	By stratifying patients based on the expression of CD47 in the tumor, we observed that samples with high CD47 levels have a significant increase in immune score as compared to samples with low CD47 expression.	('tumor', 'Disease', (63, 68))	('patients', 'Species', '9606', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('CD4', 'Gene', (51, 54))	('CD4', 'Gene', '920', (193, 196))	('CD4', 'Gene', '920', (51, 54))	('CD4', 'Gene', (193, 196))	('high', 'Var', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('increase', 'PosReg', (136, 144))	('CD4', 'Gene', (105, 108))	('CD4', 'Gene', '920', (105, 108))	('immune score', 'MPA', (148, 160))
77818	31277366	Several CD47 inhibitors are currently available, e.g., Hu5F9-G4, CC-90002, TTI-621, NI-1701, NI-1801, and SRF231, and some of them are already being tested in clinical trials on solid and hematological tumors.	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('NI-1701', 'Var', (84, 91))	('CD4', 'Gene', (8, 11))	('CD4', 'Gene', '920', (8, 11))	('hematological tumors', 'Disease', 'MESH:D006402', (188, 208))	('SRF231', 'Var', (106, 112))	('hematological tumors', 'Disease', (188, 208))	('NI-1801', 'Var', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
77819	31277366	Recently, a Phase 1b study involving patients with relapsed or refractory non-Hodgkin's lymphoma showed that the anti-CD47 antibody, Hu5F9-G4, combined with rituximab, exerted promising activity in patients with aggressive and indolent lymphoma, without showing clinically significant safety events.	("non-Hodgkin's lymphoma", 'Disease', (74, 96))	('antibody', 'cellular_component', 'GO:0019815', ('123', '131'))	('Hu5F9-G4', 'Var', (133, 141))	('patients', 'Species', '9606', (198, 206))	('CD4', 'Gene', (118, 121))	('aggressive', 'Disease', (212, 222))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (78, 96))	('lymphoma', 'Disease', (236, 244))	('lymphoma', 'Disease', 'MESH:D008223', (236, 244))	('patients', 'Species', '9606', (37, 45))	('lymphoma', 'Phenotype', 'HP:0002665', (88, 96))	('antibody', 'cellular_component', 'GO:0019814', ('123', '131'))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (74, 96))	('antibody', 'molecular_function', 'GO:0003823', ('123', '131'))	('lymphoma', 'Disease', (88, 96))	('lymphoma', 'Disease', 'MESH:D008223', (88, 96))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (74, 96))	('rituximab', 'Chemical', 'MESH:D000069283', (157, 166))	('antibody', 'cellular_component', 'GO:0042571', ('123', '131'))	('activity', 'MPA', (186, 194))	('lymphoma', 'Phenotype', 'HP:0002665', (236, 244))	('CD4', 'Gene', '920', (118, 121))
77825	31277366	Clinical data included TNM disease stage, progression-free survival time, overall survival time, presence of BAP1, GNAQ, and GNA11 mutations.	('mutations', 'Var', (131, 140))	('GNAQ', 'Gene', (115, 119))	('TNM disease', 'Disease', (23, 34))	('GNAQ', 'Gene', '2776', (115, 119))	('BAP1', 'Gene', '8314', (109, 113))	('TNM disease', 'Disease', 'MESH:D004194', (23, 34))	('presence', 'Reg', (97, 105))	('BAP1', 'Gene', (109, 113))	('GNA11', 'Gene', '2767', (125, 130))	('GNA11', 'Gene', (125, 130))
77840	31277366	Predicted values were obtained by Multivariate General Linear Model using BAP1, GNAQ, and GNA11 mutations as fixed factors.	('GNA11', 'Gene', '2767', (90, 95))	('GNA11', 'Gene', (90, 95))	('GNAQ', 'Gene', '2776', (80, 84))	('BAP1', 'Gene', '8314', (74, 78))	('mutations', 'Var', (96, 105))	('BAP1', 'Gene', (74, 78))	('GNAQ', 'Gene', (80, 84))
77857	30962963	Some tumours are characterised by genome-wide changes in the methylation status of their genomic DNA that includes demethylation of the promoter regions of genes encoding cancer testis antigens (CTAs) leading to aberrant expression of these CTAs in cancer cells.	('changes', 'Reg', (46, 53))	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('aberrant', 'Var', (212, 220))	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancer testis', 'Phenotype', 'HP:0010788', (171, 184))	('tumours', 'Disease', 'MESH:D009369', (5, 12))	('demethylation', 'biological_process', 'GO:0070988', ('115', '128'))	('tumours', 'Disease', (5, 12))	('cancer', 'Disease', (171, 177))	('cancer', 'Disease', (249, 255))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('expression', 'MPA', (221, 231))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('demethylation', 'Var', (115, 128))
77859	30962963	Inhibiting the programmed cell death-1 (PD-1)/(programmed death-ligand 1) PD-L1 axis or the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptor has resulted in a paradigm shift in the treatment of certain cancer types such as melanoma and non-small-cell lung cancer.	('programmed cell death', 'biological_process', 'GO:0012501', ('15', '36'))	('Inhibiting', 'Var', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (236, 244))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (92, 135))	('lung cancer', 'Disease', 'MESH:D008175', (264, 275))	('cancer', 'Disease', (215, 221))	('CTLA-4', 'Gene', '1493', (137, 143))	('ligand', 'molecular_function', 'GO:0005488', ('64', '70'))	('lung cancer', 'Phenotype', 'HP:0100526', (264, 275))	('CTLA-4', 'Gene', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', (269, 275))	('PD-1', 'Gene', (40, 44))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (92, 135))	('PD-L1 axis', 'Disease', 'MESH:D010300', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('melanoma', 'Disease', (236, 244))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('resulted in', 'Reg', (158, 169))	('PD-L1 axis', 'Disease', (74, 84))	('lung cancer', 'Disease', (264, 275))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
77934	30607140	Despite the fact that tremendous somatic mutations in a variety of cancer types can give chances for personalized treatment targeting at patients' specific mutations, these mutations can eventually translate into new antigens for possible anti-tumor immune response.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('translate', 'Reg', (198, 207))	('cancer', 'Disease', (67, 73))	('tumor', 'Disease', (244, 249))	('mutations', 'Var', (156, 165))	('patients', 'Species', '9606', (137, 145))	('mutations', 'Var', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('immune response', 'biological_process', 'GO:0006955', ('250', '265'))
77940	30607140	Thus, monoclonal antibodies blocking PD-1 have arisen as an impressive treatment strategy for cancer patients and have been approved by the U.S. Food and Drug Administration (FDA) for human use.	('patients', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (184, 189))	('monoclonal', 'Var', (6, 16))	('PD-1', 'Gene', (37, 41))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
78009	30607140	The combination of PD-1 and CTLA-4 blockade has demonstrated higher response rates in advanced melanoma, while combination with LAG3 blockade are still carrying on clinical trials (NCT03250832, NCT02658981, NCT01968109, NCT03005782).	('advanced melanoma', 'Disease', 'MESH:D008545', (86, 103))	('LAG3', 'Gene', '3902', (128, 132))	('higher', 'PosReg', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('advanced melanoma', 'Disease', (86, 103))	('NCT03250832', 'Var', (181, 192))	('CTLA-4', 'Gene', '1493', (28, 34))	('PD-1', 'Gene', (19, 23))	('LAG3', 'Gene', (128, 132))	('CTLA-4', 'Gene', (28, 34))
78013	30607140	Therefore, we can infer that the high expression of LFA-1 may improve the efficacy of T cells that have been released from the "brake" of PD-1 by PD-1 blockade.	('LFA-1', 'Gene', (52, 57))	('high expression', 'Var', (33, 48))	('improve', 'PosReg', (62, 69))	('efficacy', 'CPA', (74, 82))	('LFA-1', 'Gene', '3689', (52, 57))
78029	28372848	Splicing Factor Mutations in Myelodysplasias: Insights from Spliceosome Structures Somatic mutations of pre-mRNA splicing factors recur among patients with myelodysplastic syndromes (MDS) and related malignancies.	('MDS', 'Phenotype', 'HP:0002863', (183, 186))	('malignancies', 'Disease', 'MESH:D009369', (200, 212))	('pre', 'molecular_function', 'GO:0003904', ('104', '107'))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (156, 181))	('malignancies', 'Disease', (200, 212))	('myelodysplastic syndromes', 'Disease', (156, 181))	('splicing factor', 'Gene', '10569', (113, 128))	('MDS', 'Disease', 'MESH:D009190', (183, 186))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('104', '121'))	('Spliceosome', 'cellular_component', 'GO:0005681', ('60', '71'))	('Myelodysplasias', 'Disease', 'MESH:D009190', (29, 44))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (156, 181))	('Myelodysplasias', 'Disease', (29, 44))	('MDS', 'Disease', (183, 186))	('Splicing', 'biological_process', 'GO:0045292', ('0', '8'))	('mutations', 'Var', (91, 100))	('Splicing Factor', 'Gene', (0, 15))	('splicing factor', 'Gene', (113, 128))	('patients', 'Species', '9606', (142, 150))	('Splicing Factor', 'Gene', '10569', (0, 15))
78030	28372848	Although these MDS-relevant mutations alter splicing of a subset of transcripts, the mechanisms by which these single amino acid substitutions change gene expression remain controversial.	('gene expression', 'biological_process', 'GO:0010467', ('150', '165'))	('gene expression', 'MPA', (150, 165))	('change', 'Reg', (143, 149))	('MDS', 'Disease', (15, 18))	('MDS', 'Disease', 'MESH:D009190', (15, 18))	('MDS', 'Phenotype', 'HP:0002863', (15, 18))	('alter', 'Reg', (38, 43))	('splicing of', 'MPA', (44, 55))	('mutations', 'Var', (28, 37))	('splicing', 'biological_process', 'GO:0045292', ('44', '52'))
78032	28372848	The frequently mutated SF3B1 residues contact the pre-mRNA splice site.	('pre', 'molecular_function', 'GO:0003904', ('50', '53'))	('pre-mRNA splice site', 'MPA', (50, 70))	('SF3B1', 'Gene', '23451', (23, 28))	('mutated', 'Var', (15, 22))	('SF3B1', 'Gene', (23, 28))
78033	28372848	Altered pre-mRNA recognition emerges as a molecular theme among MDS-relevant mutations of pre-mRNA splicing factors.	('MDS', 'Disease', 'MESH:D009190', (64, 67))	('splicing factor', 'Gene', '10569', (99, 114))	('pre-mRNA', 'Protein', (8, 16))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('90', '107'))	('pre', 'molecular_function', 'GO:0003904', ('8', '11'))	('mutations', 'Var', (77, 86))	('splicing factor', 'Gene', (99, 114))	('MDS', 'Disease', (64, 67))	('Altered', 'Reg', (0, 7))	('MDS', 'Phenotype', 'HP:0002863', (64, 67))	('pre', 'molecular_function', 'GO:0003904', ('90', '93'))
78034	28372848	Prevalent, acquired mutations of pre-mRNA splicing factors in cancers were discovered initially from whole-exome sequencing of myelodysplastic syndromes (MDS), chronic lymphocytic leukemias (CLL), and related disorders (Box 1).	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (127, 152))	('splicing factor', 'Gene', '10569', (42, 57))	('MDS', 'Disease', (154, 157))	('chronic lymphocytic leukemias', 'Disease', 'MESH:D015451', (160, 189))	('chronic lymphocytic leukemias', 'Phenotype', 'HP:0005550', (160, 189))	('leukemias', 'Phenotype', 'HP:0001909', (180, 189))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('33', '50'))	('leukemia', 'Phenotype', 'HP:0001909', (180, 188))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('chronic lymphocytic leukemias', 'Disease', (160, 189))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('CLL', 'Phenotype', 'HP:0005550', (191, 194))	('MDS', 'Phenotype', 'HP:0002863', (154, 157))	('mutations', 'Var', (20, 29))	('splicing factor', 'Gene', (42, 57))	('pre', 'molecular_function', 'GO:0003904', ('33', '36'))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (127, 152))	('lymphocytic leukemias', 'Phenotype', 'HP:0005526', (168, 189))	('myelodysplastic syndromes', 'Disease', (127, 152))	('MDS', 'Disease', 'MESH:D009190', (154, 157))	('cancers', 'Disease', 'MESH:D009369', (62, 69))
78036	28372848	The recurrent SF3B1, U2AF1, and SRSF2 mutations alter amino acids at specific "hotspots" (mapped on SF3B1 and U2AF1 protein domains in Figure 1A; the SRSF2 hotspot is P95).	('U2AF1', 'Gene', (21, 26))	('SRSF2', 'Gene', (32, 37))	('SRSF2', 'Gene', (150, 155))	('U2AF', 'cellular_component', 'GO:0089701', ('21', '25'))	('U2AF', 'cellular_component', 'GO:0089701', ('108', '112'))	('amino acids', 'MPA', (54, 65))	('RS', 'Phenotype', 'HP:0004828', (151, 153))	('SF3B1', 'Gene', '23451', (100, 105))	('alter', 'Reg', (48, 53))	('mutations', 'Var', (38, 47))	('P95', 'Gene', (167, 170))	('SF3B1', 'Gene', (14, 19))	('P95', 'Gene', '4683', (167, 170))	('RS', 'Phenotype', 'HP:0004828', (33, 35))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('SF3B1', 'Gene', (100, 105))	('SRSF2', 'Gene', '6427', (32, 37))	('SRSF2', 'Gene', '6427', (150, 155))	('SF3B1', 'Gene', '23451', (14, 19))
78037	28372848	An exception is the null as well as missense mutations found distributed throughout ZRSR2 (also called URP), which is associated with the "minor" U12-type spliceosome rather than the "major" U2-type spliceosome (Box 2).	('spliceosome', 'cellular_component', 'GO:0005681', ('195', '206'))	('missense mutations', 'Var', (36, 54))	('spliceosome', 'cellular_component', 'GO:0005681', ('153', '164'))	('U12', 'Gene', '26823', (146, 149))	('URP', 'Gene', '8233', (103, 106))	('RS', 'Phenotype', 'HP:0004828', (85, 87))	('ZRSR2', 'Gene', (84, 89))	('ZRSR2', 'Gene', '8233', (84, 89))	('URP', 'Gene', (103, 106))	('U12', 'Gene', (146, 149))
78039	28372848	For example, as expanded below, SF3B1 mutations occur in the majority of refractory anemia with ringed sideroblasts (RARS).	('anemia', 'Disease', 'MESH:D000740', (84, 90))	('anemia', 'Disease', (84, 90))	('occur', 'Reg', (48, 53))	('ringed sideroblasts', 'Disease', (96, 115))	('SF3B1', 'Gene', '23451', (32, 37))	('refractory anemia with ringed sideroblasts', 'Phenotype', 'HP:0004828', (73, 115))	('anemia', 'Phenotype', 'HP:0001903', (84, 90))	('RS', 'Phenotype', 'HP:0004828', (119, 121))	('RARS', 'Phenotype', 'HP:0004828', (117, 121))	('RA', 'Disease', 'MESH:D001172', (117, 119))	('refractory anemia', 'Phenotype', 'HP:0005505', (73, 90))	('mutations', 'Var', (38, 47))	('SF3B1', 'Gene', (32, 37))	('RA', 'Phenotype', 'HP:0005505', (117, 119))
78040	28372848	On the other hand, SRSF2 mutations occur in more than a third of chronic myelomonocytic leukemias (CMML).	('CMML', 'Disease', (99, 103))	('SRSF2', 'Gene', (19, 24))	('mutations', 'Var', (25, 34))	('CMML', 'Phenotype', 'HP:0012325', (99, 103))	('leukemias', 'Phenotype', 'HP:0001909', (88, 97))	('occur', 'Reg', (35, 40))	('CMML', 'Disease', 'MESH:D054429', (99, 103))	('SRSF2', 'Gene', '6427', (19, 24))	('chronic myelomonocytic leukemias', 'Disease', (65, 97))	('chronic myelomonocytic leukemias', 'Phenotype', 'HP:0012325', (65, 97))	('RS', 'Phenotype', 'HP:0004828', (20, 22))	('leukemia', 'Phenotype', 'HP:0001909', (88, 96))	('chronic myelomonocytic leukemias', 'Disease', 'MESH:D015477', (65, 97))
78041	28372848	Somatic mutations of certain splicing factors also recur among a variety of solid tumors - primarily, SF3B1 mutations in uveal melanoma, pancreatic ductal adenocarcinoma, or breast cancer and U2AF1 mutations in pancreatic ductal adenocarcinoma or lung adenocarcinoma.	('pancreatic ductal adenocarcinoma', 'Disease', (211, 243))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (137, 169))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('uveal melanoma', 'Disease', 'MESH:C536494', (121, 135))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('uveal melanoma', 'Disease', (121, 135))	('breast cancer', 'Disease', (174, 187))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (211, 243))	('pancreatic ductal adenocarcinoma', 'Disease', (137, 169))	('mutations', 'Var', (8, 17))	('mutations', 'Var', (198, 207))	('solid tumors', 'Disease', (76, 88))	('U2AF1', 'Gene', (192, 197))	('SF3B1', 'Gene', (102, 107))	('uveal melanoma', 'Phenotype', 'HP:0007716', (121, 135))	('pancreatic ductal adenocarcinoma or lung adenocarcinoma', 'Disease', 'MESH:D000077192', (211, 266))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (137, 169))	('splicing factor', 'Gene', (29, 44))	('U2AF', 'cellular_component', 'GO:0089701', ('192', '196'))	('solid tumors', 'Disease', 'MESH:D009369', (76, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('mutations', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (211, 243))	('SF3B1', 'Gene', '23451', (102, 107))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (247, 266))	('splicing', 'biological_process', 'GO:0045292', ('29', '37'))	('splicing factor', 'Gene', '10569', (29, 44))
78051	28372848	Chronic lymphocytic leukemia (CLL), in which SF3B1 is frequently mutated, is classified as a lymphoid (rather than myeloid) neoplasm.	('Chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (0, 28))	('neoplasm', 'Disease', (124, 132))	('leukemia', 'Phenotype', 'HP:0001909', (20, 28))	('neoplasm', 'Disease', 'MESH:D009369', (124, 132))	('neoplasm', 'Phenotype', 'HP:0002664', (124, 132))	('SF3B1', 'Gene', (45, 50))	('CLL', 'Phenotype', 'HP:0005550', (30, 33))	('Chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (0, 28))	('SF3B1', 'Gene', '23451', (45, 50))	('Chronic lymphocytic leukemia', 'Disease', (0, 28))	('mutated', 'Var', (65, 72))
78056	28372848	As discussed herein, high-throughput DNA sequencing revealed pre-mRNA splicing as the most frequent target of acquired mutations in MDS.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('MDS', 'Phenotype', 'HP:0002863', (132, 135))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('61', '78'))	('MDS', 'Disease', (132, 135))	('MDS', 'Disease', 'MESH:D009190', (132, 135))	('pre', 'molecular_function', 'GO:0003904', ('61', '64'))	('pre-mRNA splicing', 'MPA', (61, 78))	('mutations', 'Var', (119, 128))
78062	28372848	The recurrently mutated SF3B1, U2AF1, and SRSF2 splicing factors assist assembly of the major spliceosome.	('splicing factor', 'Gene', (48, 63))	('U2AF1', 'Gene', (31, 36))	('splicing', 'biological_process', 'GO:0045292', ('48', '56'))	('SF3B1', 'Gene', (24, 29))	('spliceosome', 'cellular_component', 'GO:0005681', ('94', '105'))	('RS', 'Phenotype', 'HP:0004828', (43, 45))	('mutated', 'Var', (16, 23))	('SRSF2', 'Gene', (42, 47))	('assembly', 'MPA', (72, 80))	('assist', 'PosReg', (65, 71))	('splicing factor', 'Gene', '10569', (48, 63))	('SF3B1', 'Gene', '23451', (24, 29))	('SRSF2', 'Gene', '6427', (42, 47))	('U2AF', 'cellular_component', 'GO:0089701', ('31', '35'))
78064	28372848	SRSF2 is member of the arginine-serine-rich (RS) splicing factor family, which typically recognizes exonic splicing enhancer sequences with an RNA recognition motif (RRM) and promotes snRNA-pre-mRNA annealing and protein-protein interactions with an RS-domain.	('splicing factor', 'Gene', (49, 64))	('RS', 'Phenotype', 'HP:0004828', (1, 3))	('protein', 'cellular_component', 'GO:0003675', ('213', '220'))	('snRNA-pre-mRNA', 'Protein', (184, 198))	('protein-protein', 'Protein', (213, 228))	('protein', 'cellular_component', 'GO:0003675', ('221', '228'))	('splicing factor', 'Gene', '10569', (49, 64))	('RS', 'Phenotype', 'HP:0004828', (45, 47))	('splicing', 'biological_process', 'GO:0045292', ('49', '57'))	('RS', 'Phenotype', 'HP:0004828', (250, 252))	('RNA', 'cellular_component', 'GO:0005562', ('143', '146'))	('SRSF2', 'Gene', '6427', (0, 5))	('pre', 'molecular_function', 'GO:0003904', ('190', '193'))	('interactions', 'Interaction', (229, 241))	('serine', 'Chemical', 'MESH:D012694', (32, 38))	('arginine', 'Chemical', 'MESH:D001120', (23, 31))	('splicing', 'biological_process', 'GO:0045292', ('107', '115'))	('promotes', 'PosReg', (175, 183))	('SRSF2', 'Gene', (0, 5))	('exonic splicing', 'Var', (100, 115))
78068	28372848	Subsequently, the U4/U5/U6 snRNP joins the "B"-complex, which is activated following ATP-dependent loss of the U4 snRNP (BACT).	('ATP', 'Chemical', 'MESH:D000255', (85, 88))	('U6 snRNP', 'cellular_component', 'GO:0005688', ('24', '32'))	('snRNP', 'Gene', '57819', (114, 119))	('snRNP', 'molecular_function', 'GO:0003734', ('112', '117'))	('snRNP', 'Gene', (27, 32))	('activated', 'PosReg', (65, 74))	('loss', 'Var', (99, 103))	('U4 snRNP', 'cellular_component', 'GO:0005687', ('109', '117'))	('snRNP', 'Gene', (114, 119))	('snRNP', 'Gene', '57819', (27, 32))	('snRNP', 'molecular_function', 'GO:0003734', ('27', '32'))
78071	28372848	Several genetic attributes hint that the hotspot mutations of splicing factors confer new functions rather than inhibit existing ones.	('splicing', 'biological_process', 'GO:0045292', ('62', '70'))	('mutations', 'Var', (49, 58))	('functions', 'MPA', (90, 99))	('splicing factor', 'Gene', '10569', (62, 77))	('splicing factor', 'Gene', (62, 77))
78072	28372848	In all cases, the allelic burdens of the mutant splicing factor alleles (~50%) are consistent with heterozygous mutations (e.g.).	('splicing', 'biological_process', 'GO:0045292', ('48', '56'))	('splicing factor', 'Gene', (48, 63))	('splicing factor', 'Gene', '10569', (48, 63))	('mutant', 'Var', (41, 47))
78074	28372848	among others), although multiple single cells carrying only SF3B1 mutations have been detected in single-cell sequences from CLL patient samples.	('mutations', 'Var', (66, 75))	('SF3B1', 'Gene', (60, 65))	('SF3B1', 'Gene', '23451', (60, 65))	('CLL', 'Phenotype', 'HP:0005550', (125, 128))	('CLL', 'Disease', (125, 128))	('patient', 'Species', '9606', (129, 136))
78076	28372848	In support of new functional attributes conferred by the mutant splicing factors, most of the altered splice sites in the presence of the hotspot splicing factor mutations differ from affected splice sites following knockdown of that splicing factor.	('differ', 'Reg', (172, 178))	('splicing factor', 'Gene', '10569', (64, 79))	('mutations', 'Var', (162, 171))	('altered', 'Reg', (94, 101))	('splicing', 'biological_process', 'GO:0045292', ('64', '72'))	('splicing factor', 'Gene', (146, 161))	('splice sites', 'MPA', (102, 114))	('splicing factor', 'Gene', '10569', (234, 249))	('splicing', 'biological_process', 'GO:0045292', ('146', '154'))	('splicing factor', 'Gene', (64, 79))	('splicing factor', 'Gene', '10569', (146, 161))	('splicing', 'biological_process', 'GO:0045292', ('234', '242'))	('splicing factor', 'Gene', (234, 249))
78077	28372848	We refer the reader to several excellent reviews covering the potential means for progression from pre-mRNA splicing factor mutations to cancer development (e.g.).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (124, 133))	('splicing factor', 'Gene', (108, 123))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('99', '116'))	('splicing factor', 'Gene', '10569', (108, 123))	('cancer', 'Disease', (137, 143))	('pre', 'molecular_function', 'GO:0003904', ('99', '102'))
78078	28372848	Here, we focus on recent ribonucleoprotein structures and RNA interactions that increase our molecular-level understanding of the consequences of SF3B1 and U2AF1 mutations in myeloid neoplasms and cancers.	('RNA', 'cellular_component', 'GO:0005562', ('58', '61'))	('neoplasms', 'Phenotype', 'HP:0002664', (183, 192))	('mutations', 'Var', (162, 171))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (175, 192))	('myeloid neoplasms and cancers', 'Disease', 'MESH:D009369', (175, 204))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('ribonucleoprotein', 'molecular_function', 'GO:0003733', ('25', '42'))	('neoplasm', 'Phenotype', 'HP:0002664', (183, 191))	('U2AF1', 'Gene', (156, 161))	('SF3B1', 'Gene', (146, 151))	('U2AF', 'cellular_component', 'GO:0089701', ('156', '160'))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('SF3B1', 'Gene', '23451', (146, 151))
78092	28372848	Altogether, the spliceosome structures show that the MDS-relevant SF3B1 hotspots contact the pre-mRNA and also suggest that the mutated U2AF1 residues contact the 3' splice site.	('pre', 'molecular_function', 'GO:0003904', ('93', '96'))	('mutated', 'Var', (128, 135))	("3' splice site", 'MPA', (163, 177))	('MDS', 'Disease', (53, 56))	('SF3B1', 'Gene', (66, 71))	('MDS', 'Disease', 'MESH:D009190', (53, 56))	('MDS', 'Phenotype', 'HP:0002863', (53, 56))	('U2AF', 'cellular_component', 'GO:0089701', ('136', '140'))	('spliceosome', 'cellular_component', 'GO:0005681', ('16', '27'))	('U2AF1', 'Gene', (136, 141))	('SF3B1', 'Gene', '23451', (66, 71))
78094	28372848	Below, we discuss the molecular-mechanisms of MDS-relevant mutations and new insights gained from these SF3B1 and U2AF1 structures.	('U2AF', 'cellular_component', 'GO:0089701', ('114', '118'))	('MDS', 'Disease', (46, 49))	('MDS', 'Disease', 'MESH:D009190', (46, 49))	('MDS', 'Phenotype', 'HP:0002863', (46, 49))	('SF3B1', 'Gene', (104, 109))	('mutations', 'Var', (59, 68))	('SF3B1', 'Gene', '23451', (104, 109))
78097	28372848	SF3B1 mutations also recur among pancreatic or breast cancers (2-4% frequencies).	('pancreatic or breast cancers', 'Disease', 'MESH:D010190', (33, 61))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('SF3B1', 'Gene', (0, 5))	('breast cancers', 'Phenotype', 'HP:0003002', (47, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('SF3B1', 'Gene', '23451', (0, 5))	('pancreatic or breast cancers', 'Disease', (33, 61))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (6, 15))
78098	28372848	Major hotspots for cancer-relevant SF3B1 mutations are located on the fifth to eighth sequence repeats of the protein, which structures map to the fourth to seventh alpha-helical "HEAT" repeats (HR) (Figure 1A).	('mutations', 'Var', (41, 50))	('SF3B1', 'Gene', '23451', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('cancer', 'Disease', (19, 25))	('SF3B1', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
78099	28372848	A K700E substitution is the most frequent SF3B1 mutation among hematologic malignancies as well as pancreatic and breast cancers, whereas mutations of R625 (and in some cases K666) predominate in uveal melanomas.	('hematologic malignancies', 'Disease', (63, 87))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('SF3B1', 'Gene', (42, 47))	('K700E', 'Mutation', 'rs559063155', (2, 7))	('hematologic malignancies', 'Disease', 'MESH:D019337', (63, 87))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('uveal melanoma', 'Phenotype', 'HP:0007716', (196, 210))	('K666', 'Var', (175, 179))	('frequent', 'Reg', (33, 41))	('uveal melanomas', 'Disease', (196, 211))	('uveal melanomas', 'Phenotype', 'HP:0007716', (196, 211))	('pancreatic and breast cancers', 'Disease', 'MESH:D010190', (99, 128))	('SF3B1', 'Gene', '23451', (42, 47))	('K700E', 'Var', (2, 7))	('breast cancers', 'Phenotype', 'HP:0003002', (114, 128))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('melanomas', 'Phenotype', 'HP:0002861', (202, 211))	('uveal melanomas', 'Disease', 'MESH:C536494', (196, 211))
78100	28372848	Several groups have demonstrated that SF3B1 mutations in cancers and hematologic malignancies are associated with altered selection of 3' splice sites for a subset of transcripts, including splicing-induced down-regulation of an iron transporter that may increase iron accumulation in RARS.	('RA', 'Phenotype', 'HP:0005505', (285, 287))	('down-regulation', 'NegReg', (207, 222))	('RARS', 'Phenotype', 'HP:0004828', (285, 289))	('increase iron accumulation', 'Phenotype', 'HP:0012465', (255, 281))	('regulation', 'biological_process', 'GO:0065007', ('212', '222'))	('iron', 'Chemical', 'MESH:D007501', (229, 233))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('selection', 'MPA', (122, 131))	('splicing', 'biological_process', 'GO:0045292', ('190', '198'))	('hematologic malignancies', 'Disease', (69, 93))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('hematologic malignancies', 'Disease', 'MESH:D019337', (69, 93))	('RA', 'Disease', 'MESH:D001172', (285, 287))	('SF3B1', 'Gene', (38, 43))	('iron accumulation', 'MPA', (264, 281))	('increase', 'PosReg', (255, 263))	('iron transporter', 'MPA', (229, 245))	('RS', 'Phenotype', 'HP:0004828', (287, 289))	('iron', 'Chemical', 'MESH:D007501', (264, 268))	('altered', 'Reg', (114, 121))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('SF3B1', 'Gene', '23451', (38, 43))	('mutations', 'Var', (44, 53))
78101	28372848	Two recent studies further investigate the molecular mechanisms for altered 3' splice site choice in the presence of mutant SF3B1 (SF3B1MUT) (Figure 2A).	('SF3B1', 'Gene', '23451', (131, 136))	('SF3B1', 'Gene', '23451', (124, 129))	("3' splice site choice", 'MPA', (76, 97))	('mutant', 'Var', (117, 123))	('SF3B1', 'Gene', (124, 129))	('SF3B1MUT', 'Gene', '23451', (131, 139))	('SF3B1', 'Gene', (131, 136))	('altered', 'Reg', (68, 75))	('SF3B1MUT', 'Gene', (131, 139))
78102	28372848	The studies converge on a key set of common conclusions across a range of sample contexts and SF3B1 mutations, including K700E/R625/K666 and other mutations in CLL samples, a few solid tumors, and pancreatic cancer cell lines or K625/K666 mutations in uveal melanoma patient samples and minigene models in cell lines.	('SF3B1', 'Gene', '23451', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('uveal melanoma', 'Phenotype', 'HP:0007716', (252, 266))	('K625/K666 mutations', 'Var', (229, 248))	('pancreatic cancer', 'Disease', 'MESH:D010190', (197, 214))	('solid tumors', 'Disease', (179, 191))	('pancreatic cancer', 'Disease', (197, 214))	('K700E', 'Var', (121, 126))	('CLL', 'Phenotype', 'HP:0005550', (160, 163))	('SF3B1', 'Gene', (94, 99))	('solid tumors', 'Disease', 'MESH:D009369', (179, 191))	('melanoma', 'Phenotype', 'HP:0002861', (258, 266))	('mutations', 'Var', (100, 109))	('patient', 'Species', '9606', (267, 274))	('K700E', 'SUBSTITUTION', 'None', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (197, 214))	('uveal melanoma', 'Disease', (252, 266))	('uveal melanoma', 'Disease', 'MESH:C536494', (252, 266))
78105	28372848	Indeed, the predicted complementarity of this pre-mRNA region for annealing with the U2 snRNA, and hence "strength" was greater for BPS' than for a normal BPS (BPS0).	('greater', 'PosReg', (120, 127))	('BPS', 'Chemical', '-', (155, 158))	('strength', 'MPA', (106, 114))	('annealing', 'MPA', (66, 75))	('complementarity', 'MPA', (22, 37))	('BPS', 'Chemical', '-', (132, 135))	("BPS'", 'Var', (132, 136))	('BPS', 'Chemical', '-', (160, 163))	('pre', 'molecular_function', 'GO:0003904', ('46', '49'))
78107	28372848	Diverse proposals have been made to explain the switch to BPS' and AG' in the presence of mutant SF3B1, including that mutations could enhance SF3B1MUT interactions with pre-mRNA sequences flanking BPS', decrease SF3B1MUT interactions with BPS0, and/or trigger a conformational change in SF3B1MUT such that the "stronger" complementarity of U2 snRNA for BPS' in turn outweighs BPS0.	('BPS', 'Chemical', '-', (354, 357))	('trigger', 'Reg', (253, 260))	('SF3B1MUT', 'Gene', '23451', (213, 221))	('mutant', 'Var', (90, 96))	('SF3B1MUT', 'Gene', (213, 221))	('SF3B1', 'Gene', (97, 102))	('enhance', 'PosReg', (135, 142))	('BPS', 'Chemical', '-', (58, 61))	('BPS', 'Chemical', '-', (377, 380))	('decrease', 'NegReg', (204, 212))	('SF3B1', 'Gene', (288, 293))	('interactions', 'Interaction', (152, 164))	('mutations', 'Var', (119, 128))	('SF3B1MUT', 'Gene', '23451', (288, 296))	('SF3B1', 'Gene', '23451', (97, 102))	('BPS', 'Chemical', '-', (240, 243))	('SF3B1', 'Gene', (213, 218))	('SF3B1MUT', 'Gene', (288, 296))	('SF3B1', 'Gene', (143, 148))	('SF3B1', 'Gene', '23451', (288, 293))	('BPS', 'Chemical', '-', (198, 201))	('pre', 'molecular_function', 'GO:0003904', ('170', '173'))	('interactions', 'Interaction', (222, 234))	('SF3B1MUT', 'Gene', '23451', (143, 151))	('SF3B1MUT', 'Gene', (143, 151))	('SF3B1', 'Gene', '23451', (213, 218))	('SF3B1', 'Gene', '23451', (143, 148))	('conformational change', 'MPA', (263, 284))
78108	28372848	Recent structural information raises a striking variation of these hypotheses, namely that hotspot SF3B1 mutations could influence the conformation of the bound pre-mRNA splice site.	('conformation of the bound pre-mRNA splice site', 'MPA', (135, 181))	('SF3B1', 'Gene', (99, 104))	('pre', 'molecular_function', 'GO:0003904', ('161', '164'))	('SF3B1', 'Gene', '23451', (99, 104))	('mutations', 'Var', (105, 114))	('influence', 'Reg', (121, 130))
78113	28372848	Notably, a key residue for which mutation to histidine confers resistance to the cell-cycle inhibitor pladienolide and its derivatives (R1074 in HR15) contributes part of the binding pocket for an extrahelical branch site adenosine.	('mutation', 'Var', (33, 41))	('R1074', 'Var', (136, 141))	('binding', 'Interaction', (175, 182))	('HR15', 'Gene', (145, 149))	('extrahelical branch site adenosine', 'MPA', (197, 231))	('cell-cycle', 'biological_process', 'GO:0007049', ('81', '91'))	('adenosine', 'Chemical', 'MESH:D000241', (222, 231))	('pladienolide', 'Chemical', '-', (102, 114))	('binding', 'molecular_function', 'GO:0005488', ('175', '182'))	('histidine', 'Chemical', 'MESH:D006639', (45, 54))	('resistance', 'MPA', (63, 73))
78120	28372848	As such, the hotspot amino acid substitutions are expected to disrupt local RNA interactions and dissociate the 5' end of the pre-mRNA from the SF3B1MUT protein surface.	('disrupt', 'NegReg', (62, 69))	('SF3B1MUT', 'Gene', '23451', (144, 152))	('pre', 'molecular_function', 'GO:0003904', ('126', '129'))	('protein', 'cellular_component', 'GO:0003675', ('153', '160'))	('RNA', 'cellular_component', 'GO:0005562', ('76', '79'))	('SF3B1MUT', 'Gene', (144, 152))	('dissociate', 'NegReg', (97, 107))	('amino acid substitutions', 'Var', (21, 45))	('local RNA', 'Protein', (70, 79))
78122	28372848	As such, the RNA-bound SF3B1 structure in the BACT spliceosome suggests that hotspot mutations could alter the SF3B1MUT-bound conformation of the pre-mRNA, rather than RNA-sequence specificity or the protein conformation itself.	('SF3B1', 'Gene', '23451', (111, 116))	('spliceosome', 'cellular_component', 'GO:0005681', ('51', '62'))	('RNA', 'cellular_component', 'GO:0005562', ('168', '171'))	('SF3B1', 'Gene', '23451', (23, 28))	('pre', 'molecular_function', 'GO:0003904', ('146', '149'))	('mutations', 'Var', (85, 94))	('SF3B1MUT', 'Gene', '23451', (111, 119))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('protein', 'cellular_component', 'GO:0003675', ('200', '207'))	('SF3B1', 'Gene', (111, 116))	('alter', 'Reg', (101, 106))	('SF3B1', 'Gene', (23, 28))	('SF3B1MUT', 'Gene', (111, 119))
78123	28372848	Acquired mutations of the U2AF1 splicing factor are common among hematopoietic malignancies, particularly MDS without ring sideroblasts (~11%), secondary AML (~9%), or CMML (8-11%), as well as hairy-cell leukemia-variant (HCLv) (10%).	('mutations', 'Var', (9, 18))	('splicing factor', 'Gene', (32, 47))	('hairy-cell leukemia-variant', 'Disease', 'MESH:D007943', (193, 220))	('ring sideroblasts', 'Phenotype', 'HP:0004828', (118, 135))	('CMML', 'Disease', 'MESH:D054429', (168, 172))	('MDS', 'Disease', 'MESH:D009190', (106, 109))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (65, 91))	('CMML', 'Disease', (168, 172))	('CMML', 'Phenotype', 'HP:0012325', (168, 172))	('U2AF1', 'Gene', (26, 31))	('leukemia', 'Phenotype', 'HP:0001909', (204, 212))	('MDS', 'Disease', (106, 109))	('splicing factor', 'Gene', '10569', (32, 47))	('splicing', 'biological_process', 'GO:0045292', ('32', '40'))	('AML', 'Disease', 'MESH:D015470', (154, 157))	('U2AF', 'cellular_component', 'GO:0089701', ('26', '30'))	('AML', 'Disease', (154, 157))	('AML', 'Phenotype', 'HP:0004808', (154, 157))	('hairy-cell leukemia-variant', 'Disease', (193, 220))	('hematopoietic malignancies', 'Disease', (65, 91))	('MDS', 'Phenotype', 'HP:0002863', (106, 109))
78124	28372848	Among solid tumors, U2AF1 is mutated in pancreatic ductal adenocarcinomas at similar frequencies as SF3B1 (~2% frequency) and is the major mutated splicing factor gene found in lung adenocarcinomas (~3% frequency).	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (40, 73))	('splicing', 'biological_process', 'GO:0045292', ('147', '155'))	('lung adenocarcinomas', 'Disease', (177, 197))	('solid tumors', 'Disease', (6, 18))	('pancreatic ductal adenocarcinomas', 'Disease', (40, 73))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (177, 197))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (177, 197))	('splicing factor', 'Gene', '10569', (147, 162))	('SF3B1', 'Gene', (100, 105))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (40, 72))	('mutated', 'Var', (29, 36))	('solid tumors', 'Disease', 'MESH:D009369', (6, 18))	('U2AF1', 'Gene', (20, 25))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('U2AF', 'cellular_component', 'GO:0089701', ('20', '24'))	('SF3B1', 'Gene', '23451', (100, 105))	('splicing factor', 'Gene', (147, 162))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (177, 196))
78125	28372848	Indeed, S34F mutations account for 60-80% of U2AF1 mutations in MDS and nearly all documented U2AF1 mutations in HCLv, lung adenocarcinomas and pancreatic cancers.	('mutations', 'Var', (51, 60))	('U2AF1', 'Gene', (45, 50))	('S34F', 'Mutation', 'rs371769427', (8, 12))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('pancreatic cancers', 'Disease', 'MESH:D010190', (144, 162))	('MDS', 'Phenotype', 'HP:0002863', (64, 67))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (119, 139))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (144, 161))	('lung adenocarcinomas', 'Disease', (119, 139))	('MDS', 'Disease', 'MESH:D009190', (64, 67))	('U2AF', 'cellular_component', 'GO:0089701', ('45', '49'))	('U2AF', 'cellular_component', 'GO:0089701', ('94', '98'))	('MDS', 'Disease', (64, 67))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('mutations', 'Var', (100, 109))	('S34F mutations', 'Var', (8, 22))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (144, 162))	('U2AF1', 'Gene', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('pancreatic cancers', 'Disease', (144, 162))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (119, 139))
78126	28372848	Less frequently, the S34 residue changes to a tyrosine (10-15% of U2AF1 mutations in MDS), which shares similar aromatic properties with the phenylalanine, or the Q157 residue changes to either proline or arginine (up to 20% of U2AF1 mutations in MDS).	('changes', 'Reg', (33, 40))	('tyrosine', 'Chemical', 'MESH:D014443', (46, 54))	('U2AF', 'cellular_component', 'GO:0089701', ('66', '70'))	('MDS', 'Disease', 'MESH:D009190', (247, 250))	('Q157', 'Var', (163, 167))	('mutations', 'Var', (72, 81))	('U2AF1', 'Gene', (66, 71))	('U2AF', 'cellular_component', 'GO:0089701', ('228', '232'))	('MDS', 'Phenotype', 'HP:0002863', (85, 88))	('MDS', 'Disease', (247, 250))	('proline', 'Chemical', 'MESH:D011392', (194, 201))	('phenylalanine', 'Chemical', 'MESH:D010649', (141, 154))	('MDS', 'Disease', 'MESH:D009190', (85, 88))	('arginine', 'Chemical', 'MESH:D001120', (205, 213))	('mutations', 'Var', (234, 243))	('U2AF1', 'Gene', (228, 233))	('MDS', 'Disease', (85, 88))	('MDS', 'Phenotype', 'HP:0002863', (247, 250))	('changes', 'Reg', (176, 183))
78127	28372848	The U2AF1 mutations are associated with altered splicing of approximately 5% of gene transcripts in patient samples and cell lines, primarily due to cassette exon skipping/inclusion or to a lesser extent, alternative 3' splice site choice.	('skipping/inclusion', 'Var', (163, 181))	('splicing', 'biological_process', 'GO:0045292', ('48', '56'))	('cassette exon skipping/inclusion', 'Var', (149, 181))	('U2AF', 'cellular_component', 'GO:0089701', ('4', '8'))	('patient', 'Species', '9606', (100, 107))	('splicing', 'MPA', (48, 56))	('altered', 'Reg', (40, 47))	('mutations', 'Var', (10, 19))	('U2AF1', 'Gene', (4, 9))
78128	28372848	As for SF3B1 mutations, the splicing events that are affected by U2AF1 mutations have low overlap with those affected by U2AF1 knockdown, which suggested that these mutations subtly alter recognition of splice sites rather than completely disable the spliceosome.	('U2AF1', 'Gene', (65, 70))	('U2AF', 'cellular_component', 'GO:0089701', ('121', '125'))	('splicing', 'biological_process', 'GO:0045292', ('28', '36'))	('SF3B1', 'Gene', '23451', (7, 12))	('U2AF', 'cellular_component', 'GO:0089701', ('65', '69'))	('recognition of splice sites', 'MPA', (188, 215))	('SF3B1', 'Gene', (7, 12))	('mutations', 'Var', (71, 80))	('alter', 'Reg', (182, 187))	('splicing', 'MPA', (28, 36))	('disable', 'NegReg', (239, 246))	('spliceosome', 'MPA', (251, 262))	('spliceosome', 'cellular_component', 'GO:0005681', ('251', '262'))	('mutations', 'Var', (13, 22))
78130	28372848	Recently, the U2AF1 S34F mutation was discovered to increase use of distal cleavage and polyadenylation sites (~40% frequency among S34F-affected transcripts in a BaF3 cell line).	('U2AF', 'cellular_component', 'GO:0089701', ('14', '18'))	('S34F', 'Mutation', 'rs371769427', (132, 136))	('increase', 'PosReg', (52, 60))	('S34F mutation', 'Var', (20, 33))	('BaF3', 'CellLine', 'CVCL:0161', (163, 167))	('use', 'MPA', (61, 64))	('S34F-affected', 'Gene', (132, 145))	('S34F', 'Mutation', 'rs371769427', (20, 24))	('U2AF1', 'Gene', (14, 19))
78131	28372848	Each of these groups shares common sequence trends surrounding the conserved "AG" consensus: S34 mutants preferentially skip splice junctions preceded by a -3U and splice those preceded by -3C/A, whereas Q157 mutants preferentially skip splice junctions followed by a +1A and splice those followed by +1G.	('splice junctions', 'MPA', (237, 253))	('-3C/A', 'Mutation', 'c.-3C>A', (189, 194))	('mutants', 'Var', (97, 104))	('splice junctions', 'MPA', (125, 141))	('skip', 'NegReg', (120, 124))	('S34', 'Gene', (93, 96))	('Q157', 'Var', (204, 208))
78134	28372848	The S34F mutation reduced association of the SpU2AFMIN protein with a core 5-nucleotide RNA oligonucleotide (5'-CUAGG, AG consensus underlined, -3 and +1 nucleotides in bold), although the weak binding affinity was beyond the limit of the isothermal titration calorimetry (ITC) experiment (>3-fold penalties reduce the c-value = [macromolecule in sample cell]/KD to below the limit of ~10 for a reliable fit).	('mutation', 'Var', (9, 17))	('reduce', 'NegReg', (308, 314))	('c-value = [macromolecule in sample', 'MPA', (319, 353))	('protein', 'Protein', (55, 62))	('reduced', 'NegReg', (18, 25))	('S34F mutation', 'Var', (4, 17))	('oligonucleotide', 'Chemical', 'MESH:D009841', (92, 107))	('core', 'cellular_component', 'GO:0019013', ('70', '74'))	('binding', 'molecular_function', 'GO:0005488', ('194', '201'))	('RNA', 'cellular_component', 'GO:0005562', ('88', '91'))	('S34F', 'Mutation', 'rs371769427', (4, 8))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('association', 'Interaction', (26, 37))	('SpU2AFMIN', 'Gene', (45, 54))	('binding', 'Interaction', (194, 201))
78135	28372848	A subtle increase in RNA binding, rather than decrease, was observed for SpU2AFMIN carrying the counterpart of the Q157R mutation to this RNA (by ~2-fold).	('RNA', 'cellular_component', 'GO:0005562', ('21', '24'))	('Q157R', 'Var', (115, 120))	('RNA binding', 'Interaction', (21, 32))	('increase', 'PosReg', (9, 17))	('RNA', 'cellular_component', 'GO:0005562', ('138', '141'))	('SpU2AFMIN', 'Gene', (73, 82))	('Q157R', 'Mutation', 'rs371246226', (115, 120))	('RNA binding', 'molecular_function', 'GO:0003723', ('21', '32'))
78136	28372848	Although surprisingly different, these mutation-induced changes in SpU2AFMIN binding the CUAGG RNA matched the sequence trends among affected splice sites; namely, the S34F mutant suffers a penalty for binding a -3U RNA, which is typically skipped in affected splice sites, whereas mutation of the Q157R counterpart prefers to bind a +1G RNA, which is typically spliced in affected splice sites.	('binding', 'molecular_function', 'GO:0005488', ('77', '84'))	('RNA', 'cellular_component', 'GO:0005562', ('95', '98'))	('Q157R', 'Mutation', 'rs371246226', (298, 303))	('binding', 'Interaction', (202, 209))	('RNA', 'cellular_component', 'GO:0005562', ('338', '341'))	('binding', 'molecular_function', 'GO:0005488', ('202', '209'))	('S34F', 'Mutation', 'rs371769427', (168, 172))	('RNA', 'cellular_component', 'GO:0005562', ('216', '219'))	('S34F', 'Var', (168, 172))
78137	28372848	We used quantitative fluorescence anisotropy assays to compare a series of splice site RNAs with various -3 nucleotides binding to S34F or WT variants of human ternary U2AF1-U2AF2-SF1 complexes.	('human', 'Species', '9606', (154, 159))	('binding', 'molecular_function', 'GO:0005488', ('120', '127'))	('S34F', 'Mutation', 'rs371769427', (131, 135))	('S34F', 'Var', (131, 135))	('SF1', 'Gene', (180, 183))	('U2AF2', 'Gene', '11338', (174, 179))	('U2AF', 'cellular_component', 'GO:0089701', ('168', '172'))	('SF1', 'Gene', '7536', (180, 183))	('U2AF', 'cellular_component', 'GO:0089701', ('174', '178'))	('U2AF2', 'Gene', (174, 179))
78138	28372848	Although the changes in RNA binding due to the S34F mutation were mild (2- to 7-fold), in nearly all cases these binding trends matched the observed consequences for splicing: The S34F mutation typically decreased U2AF1 binding to sites preceded by -3U and in some cases increased affinity for -3C.	('increased', 'PosReg', (271, 280))	('to 7', 'Species', '1214577', (75, 79))	('S34F', 'Mutation', 'rs371769427', (180, 184))	('binding', 'molecular_function', 'GO:0005488', ('113', '120'))	('U2AF', 'cellular_component', 'GO:0089701', ('214', '218'))	('S34F', 'Var', (180, 184))	('U2AF1', 'Protein', (214, 219))	('splicing', 'biological_process', 'GO:0045292', ('166', '174'))	('binding', 'Interaction', (220, 227))	('affinity', 'MPA', (281, 289))	('RNA binding', 'molecular_function', 'GO:0003723', ('24', '35'))	('binding', 'molecular_function', 'GO:0005488', ('220', '227'))	('S34F', 'Mutation', 'rs371769427', (47, 51))	('decreased', 'NegReg', (204, 213))	('RNA', 'cellular_component', 'GO:0005562', ('24', '27'))
78139	28372848	The U2AF1 hotspots are located in two CCCH-type zinc knuckles that surround the U2AF2-heterodimerization motif (UHM,), namely S34 is in the N-terminal ZnK1 and Q157 in the C-terminal ZnK2 (Figure 1A).	('Q157', 'Var', (160, 164))	('U2AF', 'cellular_component', 'GO:0089701', ('80', '84'))	('S34', 'Var', (126, 129))	('U2AF2', 'Gene', (80, 85))	('U2AF', 'cellular_component', 'GO:0089701', ('4', '8'))	('U2AF2', 'Gene', '11338', (80, 85))
78151	28372848	Mutations of S34 or Q157 to phenylalanine or proline are expected to have little impact on the protein fold, considering their respective locations in either an unstructured loop or the N-terminal turn of an alpha-helix, which does not require backbone hydrogen bonds for proper folding.	('phenylalanine', 'Chemical', 'MESH:D010649', (28, 41))	('hydrogen', 'Chemical', 'MESH:D006859', (253, 261))	('impact', 'Reg', (81, 87))	('S34', 'Gene', (13, 16))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('proline', 'Chemical', 'MESH:D011392', (45, 52))	('Q157', 'Var', (20, 24))	('Mutations', 'Var', (0, 9))	('protein fold', 'MPA', (95, 107))	('phenylalanine', 'Var', (28, 41))
78153	28372848	For CWC24, this residue (K160) donates hydrogen bonds from the peptide backbone to a guanine base and from the side chain to the ribose oxygen (Figure 4C, left).	('CWC24', 'Gene', (4, 9))	('CWC24', 'Gene', '7737', (4, 9))	('donates', 'Reg', (31, 38))	('K160', 'Var', (25, 29))	('oxygen', 'Chemical', 'MESH:D010100', (136, 142))	('hydrogen', 'Chemical', 'MESH:D006859', (39, 47))	('hydrogen bonds', 'MPA', (39, 53))	('ribose', 'Chemical', 'MESH:D012266', (129, 135))	('K160', 'Chemical', '-', (25, 29))	('guanine', 'Chemical', 'MESH:D006147', (85, 92))
78154	28372848	Although the exact consequences of the hotspot phenylalanine substitution are unpredictable, introduction of a bulky aromatic side chain certainly would alter the nucleotide position and interactions at this site.	('alter', 'Reg', (153, 158))	('nucleotide position', 'MPA', (163, 182))	('phenylalanine substitution', 'Var', (47, 73))	('interactions', 'Interaction', (187, 199))	('phenylalanine', 'Chemical', 'MESH:D010649', (47, 60))
78155	28372848	The Q157 counterparts of MBNL1 ZnK1, MBNL1 ZnK2, or CWC24 ZnK primarily interact with the 3' terminal nucleotide of the bound dinucleotide.	('MBNL1', 'Gene', (25, 30))	("3' terminal nucleotide of the", 'MPA', (90, 119))	('MBNL1', 'Gene', '4154', (25, 30))	('dinucleotide', 'Chemical', 'MESH:D015226', (126, 138))	('CWC24', 'Gene', (52, 57))	('MBNL1', 'Gene', (37, 42))	('CWC24', 'Gene', '7737', (52, 57))	('Q157', 'Var', (4, 8))	('MBNL1', 'Gene', '4154', (37, 42))	('interact', 'Reg', (72, 80))
78156	28372848	By analogy, the hotspot mutation of Q157 to a proline residue, which lacks the peptide N-H group, would obliterate a peptide hydrogen bond to the nucleobase.	('peptide hydrogen bond to the nucleobase', 'MPA', (117, 156))	('obliterate', 'NegReg', (104, 114))	('hydrogen', 'Chemical', 'MESH:D006859', (125, 133))	('Q157', 'Var', (36, 40))	('proline', 'Chemical', 'MESH:D011392', (46, 53))
78159	28372848	The C-terminus of the heterodimeric SpU2AF2 is oriented towards the 5' of the RNA strand, consistent with the C-terminal U2AF2 RRMs binding the upstream Py tract signal.	('U2AF', 'cellular_component', 'GO:0089701', ('121', '125'))	('U2AF2', 'Gene', (121, 126))	('U2AF2', 'Gene', '11338', (38, 43))	('RNA', 'cellular_component', 'GO:0005562', ('78', '81'))	('binding', 'molecular_function', 'GO:0005488', ('132', '139'))	('C-terminal', 'Var', (110, 120))	('U2AF2', 'Gene', '11338', (121, 126))	('U2AF2', 'Gene', (38, 43))
78165	28372848	Yet, additional evidence is needed to fully understand the mechanistic underpinnings and downstream consequences of recurrent splicing factor mutations (Outstanding Questions).	('splicing factor', 'Gene', '10569', (126, 141))	('mutations', 'Var', (142, 151))	('splicing', 'biological_process', 'GO:0045292', ('126', '134'))	('splicing factor', 'Gene', (126, 141))
78167	28372848	Greater changes in the rate constants of RNA binding could underlie subtle apparent changes in the equilibrium RNA binding of mutant compared to WT splicing factors.	('RNA binding', 'molecular_function', 'GO:0003723', ('111', '122'))	('RNA', 'cellular_component', 'GO:0005562', ('111', '114'))	('splicing', 'biological_process', 'GO:0045292', ('148', '156'))	('changes', 'Reg', (84, 91))	('RNA', 'cellular_component', 'GO:0005562', ('41', '44'))	('RNA', 'Protein', (41, 44))	('splicing factor', 'Gene', (148, 163))	('RNA binding', 'molecular_function', 'GO:0003723', ('41', '52'))	('changes', 'Reg', (8, 15))	('splicing factor', 'Gene', '10569', (148, 163))	('mutant', 'Var', (126, 132))
78168	28372848	Accordingly, the U2AF1 S34F mutation appears to delay the rate of spliced transcript release, which in turn is expected to alter splice site choice (reviewed in).	('S34F mutation', 'Var', (23, 36))	('delay', 'NegReg', (48, 53))	('U2AF1', 'Gene', (17, 22))	('S34F', 'Mutation', 'rs371769427', (23, 27))	('rate of spliced transcript release', 'MPA', (58, 92))	('alter', 'Reg', (123, 128))	('U2AF', 'cellular_component', 'GO:0089701', ('17', '21'))	('splice site choice', 'MPA', (129, 147))
78170	28372848	Such roles for hotspot residues in contacting pre-mRNA splice sites may emerge as a common theme among MDS-relevant mutations of splicing factors.	('MDS', 'Phenotype', 'HP:0002863', (103, 106))	('MDS', 'Disease', 'MESH:D009190', (103, 106))	('splicing factor', 'Gene', '10569', (129, 144))	('MDS', 'Disease', (103, 106))	('splicing', 'biological_process', 'GO:0045292', ('129', '137'))	('mutations', 'Var', (116, 125))	('splicing factor', 'Gene', (129, 144))	('pre', 'molecular_function', 'GO:0003904', ('46', '49'))
78171	28372848	Do SF3B1 hotspot mutations alter the bound pre-mRNA conformation and does this structural mechanism underlie aberrant splice site choice?	('SF3B1', 'Gene', (3, 8))	('pre', 'molecular_function', 'GO:0003904', ('43', '46'))	('bound pre-mRNA conformation', 'MPA', (37, 64))	('alter', 'Reg', (27, 32))	('SF3B1', 'Gene', '23451', (3, 8))	('mutations', 'Var', (17, 26))
78172	28372848	Do SF3B1 hotspot mutations alter pre-mRNA binding?	('pre-mRNA binding', 'molecular_function', 'GO:0036002', ('33', '49'))	('SF3B1', 'Gene', (3, 8))	('pre-mRNA', 'Protein', (33, 41))	('alter', 'Reg', (27, 32))	('SF3B1', 'Gene', '23451', (3, 8))	('mutations', 'Var', (17, 26))
78173	28372848	Does altered RNA binding by SF3B1 hotspot mutations contribute to altered protein cofactor functions, for example of PRP5?	('protein cofactor functions', 'MPA', (74, 100))	('altered', 'Reg', (66, 73))	('PRP5', 'Protein', (117, 121))	('SF3B1', 'Gene', (28, 33))	('mutations', 'Var', (42, 51))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('RNA binding', 'molecular_function', 'GO:0003723', ('13', '24'))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('SF3B1', 'Gene', '23451', (28, 33))	('contribute', 'Reg', (52, 62))	('altered', 'Reg', (5, 12))	('RNA binding', 'MPA', (13, 24))
78174	28372848	Do SF3b1 hotspot mutations affect auxiliary SF3b1 functions, for example nucleosome association?	('SF3b1', 'Gene', (44, 49))	('nucleosome association', 'MPA', (73, 95))	('SF3b1', 'Gene', '23451', (44, 49))	('SF3b1', 'Gene', (3, 8))	('functions', 'MPA', (50, 59))	('nucleosome', 'cellular_component', 'GO:0000786', ('73', '83'))	('SF3b1', 'Gene', '23451', (3, 8))	('mutations', 'Var', (17, 26))	('affect', 'Reg', (27, 33))
78175	28372848	Do U2AF1 or SF3B1 hotspot mutations alter the rates of pre-mRNA binding and release?	('release', 'MPA', (76, 83))	('SF3B1', 'Gene', (12, 17))	('pre-mRNA', 'Protein', (55, 63))	('pre-mRNA binding', 'molecular_function', 'GO:0036002', ('55', '71'))	('alter', 'Reg', (36, 41))	('SF3B1', 'Gene', '23451', (12, 17))	('rates', 'MPA', (46, 51))	('mutations', 'Var', (26, 35))	('U2AF', 'cellular_component', 'GO:0089701', ('3', '7'))	('U2AF1', 'Gene', (3, 8))
78177	28372848	Yet, RNA interactions by splicing factor hotspots offer only a partial, albeit potentially complementary, explanation for multifaceted effects of hotspot mutations.	('RNA', 'cellular_component', 'GO:0005562', ('5', '8'))	('splicing factor', 'Gene', '10569', (25, 40))	('splicing', 'biological_process', 'GO:0045292', ('25', '33'))	('mutations', 'Var', (154, 163))	('splicing factor', 'Gene', (25, 40))
78178	28372848	Recently, the DEAD-box RNP-unwindase PRP5 (also called DDX46) was found to interact genetically and physically with the yeast SF3B1 homologue (called HSH155), and hotspot mutations altered this interaction.	('altered', 'Reg', (181, 188))	('RNP', 'Gene', (23, 26))	('SF3B1', 'Gene', (126, 131))	('HSH155', 'Gene', (150, 156))	('yeast', 'Species', '4932', (120, 125))	('RNP', 'cellular_component', 'GO:1990904', ('23', '26'))	('HSH155', 'Gene', '855332', (150, 156))	('RNP', 'Gene', '55599', (23, 26))	('SF3B1', 'Gene', '23451', (126, 131))	('mutations', 'Var', (171, 180))	('interact', 'Interaction', (75, 83))
78180	28372848	Auxiliary to pre-mRNA splicing, the impacts of SF3B1 mutations on its chromatin association with and nucleosome positioning have yet to be tested.	('SF3B1', 'Gene', (47, 52))	('nucleosome positioning', 'biological_process', 'GO:0016584', ('101', '123'))	('nucleosome', 'cellular_component', 'GO:0000786', ('101', '111'))	('chromatin', 'cellular_component', 'GO:0000785', ('70', '79'))	('SF3B1', 'Gene', '23451', (47, 52))	('mutations', 'Var', (53, 62))	('chromatin association', 'MPA', (70, 91))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('13', '30'))	('pre', 'molecular_function', 'GO:0003904', ('13', '16'))
78181	28372848	For U2AF1, the S34F mutation already has been found to alter the cleavage and polyadenylation sites of a subset of affected transcripts.	('S34F', 'Mutation', 'rs371769427', (15, 19))	('S34F', 'Var', (15, 19))	('U2AF', 'cellular_component', 'GO:0089701', ('4', '8'))	('U2AF1', 'Gene', (4, 9))	('alter', 'Reg', (55, 60))
78182	28372848	In particular, S34F-associated use of a distal polyadenylation site in the ATG7 transcript was sufficient to transform BaF3 or small airway cell lines, and also was observed in patient samples.	('S34F', 'Mutation', 'rs371769427', (15, 19))	('transform', 'Reg', (109, 118))	('ATG7', 'Gene', '74244', (75, 79))	('BaF3', 'CPA', (119, 123))	('BaF3', 'CellLine', 'CVCL:0161', (119, 123))	('ATG7', 'Gene', (75, 79))	('patient', 'Species', '9606', (177, 184))	('S34F-associated', 'Var', (15, 30))
78183	28372848	Although the coupling of pre-mRNA splicing to cleavage and polyadenylation and specific association of U2AF subunits with polyadenylation factors have been established (, reviewed in) how these processes crosstalk in the downstream progression of U2AF1 mutations to malignancies remains an outstanding question.	('U2AF1', 'Gene', (247, 252))	('malignancies', 'Disease', (266, 278))	('U2AF', 'cellular_component', 'GO:0089701', ('103', '107'))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('25', '42'))	('mutations', 'Var', (253, 262))	('crosstalk', 'Reg', (204, 213))	('pre', 'molecular_function', 'GO:0003904', ('25', '28'))	('malignancies', 'Disease', 'MESH:D009369', (266, 278))	('U2AF', 'cellular_component', 'GO:0089701', ('247', '251'))
78184	28372848	Altogether, current findings represent only a starting point for fully understanding the mechanistic effects of recurrent splicing factor mutations.	('splicing', 'biological_process', 'GO:0045292', ('122', '130'))	('splicing factor', 'Gene', (122, 137))	('splicing factor', 'Gene', '10569', (122, 137))	('mutations', 'Var', (138, 147))
78186	28372848	Mutations of pre-mRNA splicing factors are common acquired mutations among patients with MDS and related myeloid neoplasms, and also recur in certain solid tumors.	('splicing factor', 'Gene', '10569', (22, 37))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (105, 122))	('solid tumors', 'Disease', (150, 162))	('patients', 'Species', '9606', (75, 83))	('neoplasms', 'Phenotype', 'HP:0002664', (113, 122))	('splicing factor', 'Gene', (22, 37))	('myeloid neoplasms', 'Disease', (105, 122))	('Mutations', 'Var', (0, 9))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (105, 122))	('solid tumors', 'Disease', 'MESH:D009369', (150, 162))	('MDS', 'Disease', (89, 92))	('MDS', 'Disease', 'MESH:D009190', (89, 92))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('MDS', 'Phenotype', 'HP:0002863', (89, 92))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('13', '30'))	('neoplasm', 'Phenotype', 'HP:0002664', (113, 121))	('pre', 'molecular_function', 'GO:0003904', ('13', '16'))
78187	28372848	"Hotspot" mutations of pre-mRNA splicing factors alter splicing of a subset of transcripts.	('splicing', 'biological_process', 'GO:0045292', ('53', '61'))	('splicing of a subset of transcripts', 'MPA', (55, 90))	('pre', 'molecular_function', 'GO:0003904', ('21', '24'))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('21', '38'))	('splicing factor', 'Gene', (32, 47))	('mutations', 'Var', (10, 19))	('alter', 'Reg', (49, 54))	('splicing factor', 'Gene', '10569', (32, 47))
78193	27148356	A pattern has emerged whereby melanocytes whose activities are affected by gain-of-function mutations of the Endothelin 3 ligand and Galphaq/11 are the same subset that arise from Schwann cell precursors.	('activities', 'MPA', (48, 58))	('Galphaq', 'Gene', (133, 140))	('Endothelin 3', 'Gene', (109, 121))	('gain-of-function', 'PosReg', (75, 91))	('mutations', 'Var', (92, 101))	('Galphaq', 'Gene', '14682', (133, 140))	('melanocytes', 'CPA', (30, 41))	('Endothelin 3', 'Gene', '13616', (109, 121))	('ligand', 'molecular_function', 'GO:0005488', ('122', '128'))
78217	27148356	In general, there are four mechanisms by which G protein coupled pathways drive tumorigenesis: excess ligand availability, excess GPCR expression, activating mutations in GPCRs, and activating mutations in Galpha proteins.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('GPCR', 'Gene', (130, 134))	('excess', 'PosReg', (95, 101))	('GPCR', 'Gene', (171, 175))	('tumor', 'Disease', (80, 85))	('GPCR', 'Gene', '227289', (130, 134))	('GPCR', 'Gene', '227289', (171, 175))	('G protein coupled pathways', 'Pathway', (47, 73))	('excess', 'PosReg', (123, 129))	('Galpha proteins', 'Protein', (206, 221))	('expression', 'MPA', (135, 145))	('ligand', 'molecular_function', 'GO:0005488', ('102', '108'))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('mutations', 'Var', (158, 167))	('ligand availability', 'MPA', (102, 121))
78223	27148356	Activating mutations in GPCRs represent another tumorigenic route.	('tumor', 'Disease', (48, 53))	('Activating mutations', 'Var', (0, 20))	('GPCR', 'Gene', '227289', (24, 28))	('GPCR', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
78224	27148356	Mutations in the thyroid-stimulating hormone receptor are found in ~30% of thyroid adenomas.	('thyroid adenomas', 'Disease', 'MESH:D013964', (75, 91))	('thyroid-stimulating hormone receptor', 'Gene', (17, 53))	('thyroid adenomas', 'Phenotype', 'HP:0000854', (75, 91))	('Mutations', 'Var', (0, 9))	('thyroid adenomas', 'Disease', (75, 91))	('thyroid-stimulating hormone receptor', 'Gene', '22095', (17, 53))	('found', 'Reg', (58, 63))
78225	27148356	Mutations have also been reported in Smoothened (SMO), glutamate metabotropic receptors (GRMs), members of the adhesion family of GPCRs, and receptors for bioactive lipid mediators such as LPA and sphingosine-1-phosphate (S1P) which tend to accumulate in the tumor microenvironment.	('SMO', 'Gene', (49, 52))	('SMO', 'Gene', '319757', (49, 52))	('Smoothened', 'Gene', '319757', (37, 47))	('lipid', 'Chemical', 'MESH:D008055', (165, 170))	('GPCR', 'Gene', (130, 134))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('GPCR', 'Gene', '227289', (130, 134))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (259, 264))	('Smoothened', 'Gene', (37, 47))	('LPA', 'Chemical', 'MESH:C032881', (189, 192))	('sphingosine-1-phosphate', 'Chemical', 'MESH:C060506', (197, 220))
78227	27148356	It was estimated that 20% of all cancers bear somatic mutations in GPCRs.	('GPCR', 'Gene', (67, 71))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('GPCR', 'Gene', '227289', (67, 71))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('somatic mutations', 'Var', (46, 63))
78228	27148356	Because the Galpha subunit must inactivate itself through the hydrolysis of GTP to GDP, mutations that reduce the function of the Ras-like GTPase domain paradoxically lead to constitutive active signaling.	('GTP', 'Chemical', '-', (76, 79))	('GDP', 'Chemical', '-', (83, 86))	('GTP', 'Chemical', '-', (139, 142))	('constitutive active signaling', 'MPA', (175, 204))	('lead to', 'Reg', (167, 174))	('mutations', 'Var', (88, 97))	('signaling', 'biological_process', 'GO:0023052', ('195', '204'))	('function', 'MPA', (114, 122))	('reduce', 'NegReg', (103, 109))
78232	27148356	Common to all these lesions is that the mutations occur in the Ras-like GTPase domain of Galpha at the perfectly conserved glutamine and arginine residues that directly contact the gamma phosphate of GTP, stabilizing it for hydrolysis.	('GTP', 'Chemical', '-', (72, 75))	('arginine', 'Chemical', 'MESH:D001120', (137, 145))	('GTP', 'Chemical', '-', (200, 203))	('hydrolysis', 'MPA', (224, 234))	('phosphate', 'Chemical', 'MESH:D010710', (187, 196))	('mutations', 'Var', (40, 49))	('stabilizing', 'Reg', (205, 216))	('glutamine', 'Chemical', 'MESH:D005973', (123, 132))
78235	27148356	The rest arise from non-epithelial melanocytes, which as a group are characterized by frequent oncogenic mutations in the heterotrimeric G protein alpha subunits, GNAQ and GNA11, which encode Galphaq and Galpha11 The importance of these two proteins in melanocytes first became apparent during a study of a set of mouse mutants with a darker dermis (Dsk1, Dsk7, Dsk10), obtained during an ENU (N-ethyl-N-nitrosourea) mutagenesis screen of 30,000 mice.	('Galpha11', 'Gene', '14672', (204, 212))	('mutations', 'Var', (105, 114))	('Dsk10', 'Gene', '14682', (362, 367))	('darker dermis', 'Phenotype', 'HP:0000953', (335, 348))	('Dsk1', 'Gene', (362, 366))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('122', '146'))	('Dsk1', 'Gene', '14682', (350, 354))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('mutagenesis', 'biological_process', 'GO:0006280', ('417', '428'))	('mice', 'Species', '10090', (446, 450))	('Dsk7', 'Gene', (356, 360))	('Galphaq', 'Gene', '14682', (192, 199))	('mouse', 'Species', '10090', (314, 319))	('Dsk10', 'Gene', (362, 367))	('N-ethyl-N-nitrosourea', 'Chemical', 'MESH:D005038', (394, 415))	('Galpha11', 'Gene', (204, 212))	('Dsk1', 'Gene', '14682', (362, 366))	('Dsk7', 'Gene', '14672', (356, 360))	('Dsk1', 'Gene', (350, 354))	('Galphaq', 'Gene', (192, 199))
78236	27148356	These mice carried hyper-active, but not constitutively active, single amino acid substitution mutations in either Gnaq or Gna11 at isoleucine 63, valine 179, or phenylalanine 335.	('valine 179', 'Var', (147, 157))	('mice', 'Species', '10090', (6, 10))	('phenylalanine', 'Chemical', 'MESH:D010649', (162, 175))	('Gna11', 'Gene', '14672', (123, 128))	('isoleucine', 'Chemical', 'MESH:D007532', (132, 142))	('phenylalanine 335', 'Var', (162, 179))	('hyper-active', 'Phenotype', 'HP:0000752', (19, 31))	('hyper-active', 'MPA', (19, 31))	('Gnaq', 'Gene', '14682', (115, 119))	('valine', 'Chemical', 'MESH:D014633', (147, 153))	('Gnaq', 'Gene', (115, 119))	('isoleucine 63', 'Var', (132, 145))	('Gna11', 'Gene', (123, 128))
78238	27148356	The Gnaq and Gna11 dark dermis mutations acted additively, darkening the dermis in a quantitative and step-wise fashion as the number of mutant Gnaq and Gna11 alleles increased, indicating that the read-out of Galphaq/11 signaling can be quantitative.	('mutations', 'Var', (31, 40))	('signaling', 'biological_process', 'GO:0023052', ('221', '230'))	('Galphaq', 'Gene', (210, 217))	('Gna11', 'Gene', '14672', (13, 18))	('Gnaq', 'Gene', '14682', (4, 8))	('Gna11', 'Gene', (153, 158))	('Gnaq', 'Gene', (4, 8))	('Gnaq', 'Gene', (144, 148))	('Gnaq', 'Gene', '14682', (144, 148))	('dark dermis', 'Phenotype', 'HP:0000953', (19, 30))	('Gna11', 'Gene', (13, 18))	('Galphaq', 'Gene', '14682', (210, 217))	('darkening', 'NegReg', (59, 68))	('mutant', 'Var', (137, 143))	('Gna11', 'Gene', '14672', (153, 158))
78239	27148356	Strikingly, the inter-follicular epidermis of the tail, which is pigmented, was unaffected by the mutations, even when all four Gnaq and Gna11 alleles were replaced with gain-of-function Dsk versions.	('gain-of-function', 'PosReg', (170, 186))	('Gna11', 'Gene', '14672', (137, 142))	('mutations', 'Var', (98, 107))	('Gnaq', 'Gene', '14682', (128, 132))	('Gnaq', 'Gene', (128, 132))	('Gna11', 'Gene', (137, 142))
78240	27148356	The gain-of-function alleles partially rescued the reduction in melanoblast numbers caused by heterozygous loss of the c-Kit tyrosine kinase receptor, Pax3 transcription factor, and endothelin B receptor, Ednrb.	('reduction', 'NegReg', (51, 60))	('c-Kit tyrosine kinase receptor', 'MPA', (119, 149))	('endothelin B receptor', 'Gene', '13618', (182, 203))	('transcription factor', 'molecular_function', 'GO:0000981', ('156', '176'))	('melanoblast numbers', 'CPA', (64, 83))	('transcription', 'biological_process', 'GO:0006351', ('156', '169'))	('loss', 'Var', (107, 111))	('Pax3', 'Gene', '18505', (151, 155))	('endothelin B receptor', 'Gene', (182, 203))	('Pax3', 'Gene', (151, 155))	('Ednrb', 'Gene', (205, 210))
78241	27148356	However, homozygous loss of Ednrb prevented all Galphaq and Galpha11 generated skin darkening.	('skin darkening', 'CPA', (79, 93))	('loss', 'Var', (20, 24))	('prevented', 'NegReg', (34, 43))	('Ednrb', 'Gene', (28, 33))	('skin darkening', 'Phenotype', 'HP:0000953', (79, 93))	('Galpha11', 'Gene', (60, 68))	('Galphaq', 'Gene', (48, 55))	('Galpha11', 'Gene', '14672', (60, 68))	('Galphaq', 'Gene', '14682', (48, 55))
78243	27148356	The mutations in GNAQ and GNA11 in human melanocytic lesions are somatic, mutually exclusive, and occur at two hotspots, glutamine 209 and arginine 183, which causes constitutive activity.	('glutamine', 'Chemical', 'MESH:D005973', (121, 130))	('human', 'Species', '9606', (35, 40))	('GNAQ', 'Gene', (17, 21))	('GNA11', 'Gene', (26, 31))	('arginine', 'Var', (139, 147))	('melanocytic lesions', 'Disease', 'MESH:D009508', (41, 60))	('mutations', 'Var', (4, 13))	('melanocytic lesions', 'Disease', (41, 60))	('arginine', 'Chemical', 'MESH:D001120', (139, 147))
78244	27148356	50%-85% of non-epithelial melanocytic lesions are affected by these mutations, and include lesions in the dermis, called blue nevi, leptomeningeal melanocytomas, uveal nevi, and uveal melanomas.	('uveal nevi', 'Disease', (162, 172))	('leptomeningeal melanocytomas', 'Disease', (132, 160))	('nevi', 'Phenotype', 'HP:0003764', (168, 172))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanomas', 'Phenotype', 'HP:0002861', (184, 193))	('uveal melanomas', 'Disease', (178, 193))	('uveal melanomas', 'Phenotype', 'HP:0007716', (178, 193))	('blue nevi', 'Phenotype', 'HP:0100814', (121, 130))	('melanocytic lesions', 'Disease', (26, 45))	('uveal melanoma', 'Phenotype', 'HP:0007716', (178, 192))	('melanocytic lesions', 'Disease', 'MESH:D009508', (26, 45))	('blue nevi', 'Disease', (121, 130))	('uveal melanomas', 'Disease', 'MESH:C536494', (178, 193))	('mutations', 'Var', (68, 77))	('leptomeningeal melanocytomas', 'Disease', 'MESH:D008577', (132, 160))	('nevi', 'Phenotype', 'HP:0003764', (126, 130))	('affected', 'Reg', (50, 58))
78245	27148356	GNAQ mutations are 7.9 times more frequent in dermal lesions, 4.6 times more frequent in leptomeningeal melanocytomas, and 1.4 times more frequent in primary uveal melanomas, compared with GNA11 mutations.	('leptomeningeal melanocytomas', 'Disease', 'MESH:D008577', (89, 117))	('uveal melanomas', 'Disease', (158, 173))	('uveal melanomas', 'Phenotype', 'HP:0007716', (158, 173))	('melanomas', 'Phenotype', 'HP:0002861', (164, 173))	('frequent', 'Reg', (77, 85))	('mutations', 'Var', (5, 14))	('frequent', 'Reg', (34, 42))	('dermal lesions', 'Disease', (46, 60))	('leptomeningeal melanocytomas', 'Disease', (89, 117))	('GNAQ', 'Gene', (0, 4))	('uveal melanomas', 'Disease', 'MESH:C536494', (158, 173))	('uveal melanoma', 'Phenotype', 'HP:0007716', (158, 172))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))
78246	27148356	Conversely, GNA11 mutations are 2.6 times more frequent than GNAQ mutations in uveal melanoma metastases.	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (79, 104))	('GNA11', 'Gene', (12, 17))	('uveal melanoma metastases', 'Disease', (79, 104))	('frequent', 'Reg', (47, 55))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('mutations', 'Var', (18, 27))
78247	27148356	Given their presence in uveal nevi, GNAQ and GNA11 mutations are hypothesized to be early events in uveal melanomagenesis.	('uveal melanomagenesis', 'Phenotype', 'HP:0007716', (100, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('mutations', 'Var', (51, 60))	('GNAQ', 'Gene', (36, 40))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('GNA11', 'Gene', (45, 50))	('uveal melanomagenesis', 'Disease', (100, 121))	('nevi', 'Phenotype', 'HP:0003764', (30, 34))	('uveal melanomagenesis', 'Disease', 'MESH:D014603', (100, 121))
78248	27148356	Q209 mutations are much more frequent than R183 mutations, and are predicted to have a greater inhibitory effect on the GTPase activity of Galphaq/11 (Figure 1A).	('Galphaq', 'Gene', '14682', (139, 146))	('GTPase activity', 'molecular_function', 'GO:0003924', ('120', '135'))	('GTPase', 'Protein', (120, 126))	('Q209 mutations', 'Var', (0, 14))	('GTP', 'Chemical', '-', (120, 123))	('inhibitory effect', 'MPA', (95, 112))	('Galphaq', 'Gene', (139, 146))
78249	27148356	Mutations in either gene are extremely rare in human melanomas located in the epidermis.	('melanomas', 'Disease', (53, 62))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('melanomas', 'Disease', 'MESH:D008545', (53, 62))	('Mutations', 'Var', (0, 9))	('human', 'Species', '9606', (47, 52))
78250	27148356	The COSMIC database v72 reported four patients with GNAQ mutations among 1,696 entries (0.2%) for superficial spreading, lentigo maligna, nodular, and otherwise unspecified malignant melanomas of the skin.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanomas', 'Phenotype', 'HP:0002861', (183, 192))	('melanomas of the skin', 'Disease', (183, 204))	('unspecified', 'Species', '32644', (161, 172))	('nodular', 'Disease', (138, 145))	('malignant melanomas', 'Phenotype', 'HP:0002861', (173, 192))	('patients', 'Species', '9606', (38, 46))	('lentigo maligna', 'Phenotype', 'HP:0012059', (121, 136))	('mutations', 'Var', (57, 66))	('melanomas of the skin', 'Disease', 'MESH:D008545', (183, 204))	('lentigo maligna', 'Disease', (121, 136))	('lentigo maligna', 'Disease', 'MESH:D018327', (121, 136))	('GNAQ', 'Gene', (52, 56))	('superficial spreading', 'Disease', (98, 119))
78251	27148356	Consistent with this, the forced expression of GNAQQ209L in mouse melanocytes caused cell loss in the inter-follicular epidermis, in contrast to the hyper-proliferation observed in the dermis, hair follicles, leptomeninges, and uveal tract.	('cell', 'CPA', (85, 89))	('mouse', 'Species', '10090', (60, 65))	('GNAQQ209L', 'Var', (47, 56))	('loss', 'NegReg', (90, 94))
78260	27148356	PKC activity may have additional effects, because PKC inhibition decreased NFkB signaling and combined PKC and MEK inhibition is more efficacious at inhibiting MAP-kinase pathway activation, halting proliferation, and inducing apoptosis in vitro.	('proliferation', 'CPA', (199, 212))	('PKC activity', 'molecular_function', 'GO:0004697', ('0', '12'))	('apoptosis', 'biological_process', 'GO:0006915', ('227', '236'))	('decreased', 'NegReg', (65, 74))	('NFkB', 'Pathway', (75, 79))	('MEK', 'Gene', (111, 114))	('PKC', 'molecular_function', 'GO:0004697', ('50', '53'))	('MAP', 'molecular_function', 'GO:0004239', ('160', '163'))	('PKC', 'Enzyme', (50, 53))	('activation', 'MPA', (179, 189))	('halting', 'NegReg', (191, 198))	('PKC', 'molecular_function', 'GO:0004697', ('103', '106'))	('MAP-kinase pathway', 'Pathway', (160, 178))	('apoptosis', 'CPA', (227, 236))	('signaling', 'biological_process', 'GO:0023052', ('80', '89'))	('PKC', 'Enzyme', (103, 106))	('inhibition', 'Var', (54, 64))	('MEK', 'Gene', '17242', (111, 114))	('inhibiting', 'NegReg', (149, 159))	('inhibition', 'Var', (115, 125))	('apoptosis', 'biological_process', 'GO:0097194', ('227', '236'))	('inducing', 'Reg', (218, 226))
78271	27148356	The loss of Endothelin receptor B (Ednrb) in mice causes a severe reduction in melanoblast numbers, while Endothelin receptor A (Ednra) knockout does not produce a pigmentation phenotype.	('Endothelin receptor A', 'Gene', (106, 127))	('Endothelin receptor A', 'Gene', '13617', (106, 127))	('mice', 'Species', '10090', (45, 49))	('pigmentation', 'Disease', 'MESH:D010859', (164, 176))	('pigmentation', 'Disease', (164, 176))	('Ednra', 'Gene', (129, 134))	('Ednrb', 'Gene', (35, 40))	('melanoblast numbers', 'CPA', (79, 98))	('Endothelin receptor B', 'Gene', (12, 33))	('Endothelin receptor B', 'Gene', '13618', (12, 33))	('pigmentation', 'biological_process', 'GO:0043473', ('164', '176'))	('Ednra', 'Gene', '13617', (129, 134))	('loss', 'Var', (4, 8))	('reduction', 'NegReg', (66, 75))
78272	27148356	Edn3 and Ece-1 mutant mice have a very similar phenotype compared to Ednrb mutant mice, neatly linking the three proteins during development.	('mice', 'Species', '10090', (82, 86))	('Edn3', 'Gene', (0, 4))	('Ece-1', 'Gene', (9, 14))	('Ece-1', 'Gene', '230857', (9, 14))	('mutant', 'Var', (15, 21))	('mice', 'Species', '10090', (22, 26))
78282	27148356	In chick experiments, Ednrb2 was required for melanoblasts to enter the dorsal-lateral pathway and the ectopic expression of Ednrb2 in neuronal neural crest cell precursors caused them to switch from the ventral pathway to the dorsal-lateral pathway.	('dorsal-lateral pathway', 'Pathway', (227, 249))	('switch', 'Reg', (188, 194))	('Ednrb2', 'Gene', (125, 131))	('ventral pathway', 'Pathway', (204, 219))	('Ednrb2', 'Gene', '373909', (125, 131))	('chick', 'Species', '9031', (3, 8))	('ectopic expression', 'Var', (103, 121))	('Ednrb2', 'Gene', (22, 28))	('Ednrb2', 'Gene', '373909', (22, 28))
78286	27148356	Apoptotic melanoblasts were not found in the melanocyte staging area of Ednrb mutants, but these cells may have been difficult to detect and it is likely that endothelins do stimulate melanocyte survival/proliferation.	('endothelins', 'Gene', '1906;13614;13615;768509;1908;13616', (159, 170))	('endothelins', 'Gene', (159, 170))	('melanocyte survival/proliferation', 'CPA', (184, 217))	('stimulate', 'PosReg', (174, 183))	('Ednrb', 'Gene', (72, 77))	('mutants', 'Var', (78, 85))
78289	27148356	Because homozygous loss of Ednrb prevented all Galphaq and Galpha11 generated skin darkening in the Dsk mice, it was hypothesized that Ednrb signals through Galphaq/11 in melanocytes.	('Galphaq', 'Gene', (157, 164))	('skin darkening', 'Phenotype', 'HP:0000953', (78, 92))	('Galpha11', 'Gene', '14672', (59, 67))	('Ednrb', 'Gene', (27, 32))	('mice', 'Species', '10090', (104, 108))	('Galphaq', 'Gene', '14682', (47, 54))	('Galphaq', 'Gene', '14682', (157, 164))	('loss', 'Var', (19, 23))	('skin darkening', 'CPA', (78, 92))	('Galpha11', 'Gene', (59, 67))	('Galphaq', 'Gene', (47, 54))
78292	27148356	A deletion in the C terminus of Ednrb, and the EdnrbG57S and EdnrbR319W mutations, impair Galphai signaling, but not Galphaq.	('EdnrbG57S', 'Gene', (47, 56))	('Galphai signaling', 'MPA', (90, 107))	('Galphaq', 'Gene', (117, 124))	('impair', 'NegReg', (83, 89))	('EdnrbR319W', 'Gene', (61, 71))	('deletion in', 'Var', (2, 13))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('Galphaq', 'Gene', '14682', (117, 124))	('Ednrb', 'Gene', (32, 37))
78296	27148356	If all of the effects of Ednrb activation in melanocytes were generated through Galphaq/11, then the complete knockout of Gnaq and Gna11 would be expected to have the same phenotype as Ednrb null mice, i.e., severe hypo-pigmentation.	('pigmentation', 'biological_process', 'GO:0043473', ('220', '232'))	('mice', 'Species', '10090', (196, 200))	('hypo-pigmentation', 'Disease', (215, 232))	('Gna11', 'Gene', (131, 136))	('Galphaq', 'Gene', '14682', (80, 87))	('Gnaq', 'Gene', (122, 126))	('Gnaq', 'Gene', '14682', (122, 126))	('Ednrb', 'Gene', (25, 30))	('Galphaq', 'Gene', (80, 87))	('hypo-pigmentation', 'Disease', 'MESH:D010859', (215, 232))	('knockout', 'Var', (110, 118))	('Gna11', 'Gene', '14672', (131, 136))	('activation', 'PosReg', (31, 41))
78297	27148356	A double knockout of Gnaq and Gna11 is lethal in mid-gestation in mice, however, the knockout of a single allele of Gnaq is enough to reduce the pigmentation of the adult dermis.	('Gna11', 'Gene', '14672', (30, 35))	('reduce', 'NegReg', (134, 140))	('Gnaq', 'Gene', '14682', (116, 120))	('Gnaq', 'Gene', (116, 120))	('gestation', 'biological_process', 'GO:0007565', ('53', '62'))	('pigmentation', 'Disease', 'MESH:D010859', (145, 157))	('Gnaq', 'Gene', '14682', (21, 25))	('mice', 'Species', '10090', (66, 70))	('Gnaq', 'Gene', (21, 25))	('pigmentation', 'Disease', (145, 157))	('pigmentation', 'biological_process', 'GO:0043473', ('145', '157'))	('knockout', 'Var', (85, 93))	('Gna11', 'Gene', (30, 35))
78299	27148356	There are several possible explanations for why Gnaq and Gna11 conditional knockout in the neural crest lineage did not completely eliminate melanoblasts.	('melanoblasts', 'CPA', (141, 153))	('Gna11', 'Gene', '14672', (57, 62))	('eliminate', 'NegReg', (131, 140))	('Gna11', 'Gene', (57, 62))	('Gnaq', 'Gene', '14682', (48, 52))	('Gnaq', 'Gene', (48, 52))	('conditional knockout', 'Var', (63, 83))
78304	27148356	We point out that Schwann cell precursor derived melanocytes localize to the dermis and hair follicles, and these are both places where Edn3 and Galphaq/11 gain-of-function mutations generate developmental phenotypes.	('gain-of-function', 'PosReg', (156, 172))	('Galphaq', 'Gene', (145, 152))	('mutations', 'Var', (173, 182))	('Edn3', 'Gene', (136, 140))	('Galphaq', 'Gene', '14682', (145, 152))
78306	27148356	Thus, there is a correlation between melanocyte lineage, response to Edn3 and Galphaq/11 gain-of-function mutations, and melanocyte location during development (Figure 1B).	('Edn3', 'Gene', (69, 73))	('gain-of-function', 'PosReg', (89, 105))	('Galphaq', 'Gene', '14682', (78, 85))	('mutations', 'Var', (106, 115))	('melanocyte lineage', 'CPA', (37, 55))	('Galphaq', 'Gene', (78, 85))
78307	27148356	Galphaq/11 mutations play an obvious role in the development of non-epithelial associated melanocytic lesions.	('melanocytic lesions', 'Disease', 'MESH:D009508', (90, 109))	('mutations', 'Var', (11, 20))	('Galphaq', 'Gene', (0, 7))	('Galphaq', 'Gene', '14682', (0, 7))	('melanocytic lesions', 'Disease', (90, 109))
78308	27148356	There are specific hotspot oncogenic mutations that are very frequently found in a specific subset of melanocytic lesions, which do not involve the epidermis.	('mutations', 'Var', (37, 46))	('melanocytic lesions', 'Disease', (102, 121))	('oncogenic', 'Gene', (27, 36))	('melanocytic lesions', 'Disease', 'MESH:D009508', (102, 121))
78317	27148356	The EDNRB inhibitors, BQ788, A192621, and Bonsentan inhibit melanoma cell growth in vitro, in xenografts of human melanomas in nude mice, and in some human patients, and restore cell morphology to a more normal appearance.	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('BQ788', 'Var', (22, 27))	('patients', 'Species', '9606', (156, 164))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('BQ788', 'Chemical', 'MESH:C086539', (22, 27))	('melanomas', 'Disease', 'MESH:D008545', (114, 123))	('nude mice', 'Species', '10090', (127, 136))	('melanomas', 'Disease', (114, 123))	('cell growth', 'biological_process', 'GO:0016049', ('69', '80'))	('human', 'Species', '9606', (150, 155))	('EDNRB', 'Gene', (4, 9))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('restore', 'PosReg', (170, 177))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))	('inhibit', 'NegReg', (52, 59))	('melanomas', 'Phenotype', 'HP:0002861', (114, 123))	('cell morphology', 'CPA', (178, 193))	('A192621', 'Var', (29, 36))	('human', 'Species', '9606', (108, 113))
78318	27148356	One recent study found that using a combination of an antibody-drug conjugate targeting EDNRB, together with small-molecule inhibitors of the MAP kinase pathway, increased anti-tumor activity in BRAF/NRAS mutant cell lines and tumor models.	('NRAS', 'Gene', '18176', (200, 204))	('increased', 'PosReg', (162, 171))	('NRAS', 'Gene', (200, 204))	('tumor', 'Disease', (227, 232))	('BRAF', 'Gene', '109880', (195, 199))	('antibody', 'cellular_component', 'GO:0019815', ('54', '62'))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('antibody', 'cellular_component', 'GO:0019814', ('54', '62'))	('antibody', 'molecular_function', 'GO:0003823', ('54', '62'))	('BRAF', 'Gene', (195, 199))	('MAP', 'molecular_function', 'GO:0004239', ('142', '145'))	('mutant', 'Var', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('antibody', 'cellular_component', 'GO:0042571', ('54', '62'))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', (177, 182))	('EDNRB', 'Gene', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
78319	27148356	In contrast to these studies, putative loss-of-function germline variants in EDNRB were associated with cyclin-dependent kinase inhibitor 2A, CDKN2A, variants in familial melanoma cases in a French population, but not in an Italian population.	('variants', 'Var', (150, 158))	('EDNRB', 'Gene', (77, 82))	('familial melanoma', 'Disease', (162, 179))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('121', '137'))	('variants', 'Var', (65, 73))	('familial melanoma', 'Disease', 'OMIM:155600', (162, 179))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '12578', (104, 140))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('104', '137'))	('CDKN2A', 'Gene', '12578', (142, 148))	('CDKN2A', 'Gene', (142, 148))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (104, 140))
78320	27148356	EDNRB variants were not associated with sporadic melanoma in either the French or Italian populations.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('variants', 'Var', (6, 14))	('EDNRB', 'Gene', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
78324	27148356	Because oncogenic Galphaq/11 mutations increase signaling, this is seems unexpected and contradictory if one assumes that EDNRB signals through Galphaq/11 in uveal melanoma cells.	('Galphaq', 'Gene', '14682', (18, 25))	('Galphaq', 'Gene', (144, 151))	('mutations', 'Var', (29, 38))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('Galphaq', 'Gene', (18, 25))	('increase', 'PosReg', (39, 47))	('signaling', 'MPA', (48, 57))	('uveal melanoma', 'Disease', 'MESH:C536494', (158, 172))	('Galphaq', 'Gene', '14682', (144, 151))	('uveal melanoma', 'Phenotype', 'HP:0007716', (158, 172))	('uveal melanoma', 'Disease', (158, 172))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))
78325	27148356	One, it is not known yet whether Galphaq/11 proteins with constitutively active mutations require a receptor for activation or, in fact, will even couple to a receptor given that they are fixedly bound to GTP.	('GTP', 'Chemical', '-', (205, 208))	('mutations', 'Var', (80, 89))	('Galphaq', 'Gene', '14682', (33, 40))	('activation', 'PosReg', (113, 123))	('Galphaq', 'Gene', (33, 40))	('couple', 'Interaction', (147, 153))
78327	27148356	If this is true, then it is possible that a decrease in the expression of EDNRB may reduce activation of the wildtype Galphaq/11 proteins, which could somehow enhance the effect of the mutant Galphaq/11 proteins through a lack of competition for downstream effectors.	('Galphaq', 'Gene', '14682', (118, 125))	('expression', 'MPA', (60, 70))	('reduce', 'NegReg', (84, 90))	('decrease', 'NegReg', (44, 52))	('mutant', 'Var', (185, 191))	('effect', 'MPA', (171, 177))	('enhance', 'PosReg', (159, 166))	('Galphaq', 'Gene', '14682', (192, 199))	('Galphaq', 'Gene', (118, 125))	('EDNRB', 'Gene', (74, 79))	('Galphaq', 'Gene', (192, 199))	('activation', 'MPA', (91, 101))
78328	27148356	The second point is that uveal melanoma patients without GNAQ or GNA11 mutations tend to have a worse prognosis than those with GNAQ or GNA11 mutations.	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('uveal melanoma', 'Disease', (25, 39))	('GNAQ', 'Gene', (57, 61))	('patients', 'Species', '9606', (40, 48))	('mutations', 'Var', (71, 80))	('GNA11', 'Gene', (65, 70))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('uveal melanoma', 'Disease', 'MESH:C536494', (25, 39))
78329	27148356	In a completely different hypothesis, GNAQ and GNA11 mutations could be early events that boost melanocyte cell growth, but eventually it is necessary to down-regulate Galphaq/11 signaling to achieve metastasis.	('cell growth', 'biological_process', 'GO:0016049', ('107', '118'))	('signaling', 'biological_process', 'GO:0023052', ('179', '188'))	('Galphaq', 'Gene', (168, 175))	('boost', 'PosReg', (90, 95))	('down-regulate', 'NegReg', (154, 167))	('melanocyte cell growth', 'CPA', (96, 118))	('GNA11', 'Gene', (47, 52))	('achieve', 'PosReg', (192, 199))	('mutations', 'Var', (53, 62))	('GNAQ', 'Gene', (38, 42))	('Galphaq', 'Gene', '14682', (168, 175))
78330	27148356	In addition, it would be very interesting to correlate tumor progression with both EDNRB expression and the presence or absence of GNAQ and GNA11 mutations in uveal melanoma.	('GNAQ', 'Gene', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('uveal melanoma', 'Disease', 'MESH:C536494', (159, 173))	('mutations', 'Var', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (159, 173))	('uveal melanoma', 'Disease', (159, 173))	('absence', 'NegReg', (120, 127))	('GNA11', 'Gene', (140, 145))	('tumor', 'Disease', (55, 60))	('EDNRB', 'Gene', (83, 88))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))
78333	27148356	Gain-of-function mutations in Edn3 and Galphaq/11 increase melanocytes in the dermis and have little effect on those in the inter-follicular epidermis.	('melanocytes in the dermis', 'CPA', (59, 84))	('Galphaq', 'Gene', '14682', (39, 46))	('increase', 'PosReg', (50, 58))	('Gain-of-function', 'PosReg', (0, 16))	('mutations', 'Var', (17, 26))	('Edn3', 'Gene', (30, 34))	('Galphaq', 'Gene', (39, 46))
78334	27148356	In addition, gain-of-function mutations in Edn3 and Galphaq/11 darken coat color using a mechanism that is independent of cell number in hair follicles.	('Galphaq', 'Gene', '14682', (52, 59))	('coat color', 'MPA', (70, 80))	('gain-of-function', 'PosReg', (13, 29))	('Galphaq', 'Gene', (52, 59))	('darken', 'NegReg', (63, 69))	('mutations', 'Var', (30, 39))	('Edn3', 'Gene', (43, 47))
78335	27148356	Thus, a pattern has emerged whereby melanocytes whose activities are affected by gain-of-function mutations of the Endothelin 3 ligand and Galphaq/11 are the same subset that arise from Schwann cell precursors.	('Galphaq', 'Gene', '14682', (139, 146))	('gain-of-function', 'PosReg', (81, 97))	('Endothelin 3', 'Gene', '13616', (115, 127))	('mutations', 'Var', (98, 107))	('activities', 'MPA', (54, 64))	('Galphaq', 'Gene', (139, 146))	('Endothelin 3', 'Gene', (115, 127))	('ligand', 'molecular_function', 'GO:0005488', ('128', '134'))
78337	26327518	Analysis of SDHD promoter mutations in various types of melanoma Recently, recurrent mutations in regulatory DNA regions, such as promoter mutations in the TERT gene were identified in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('melanoma', 'Disease', (56, 64))	('SDHD', 'Gene', (12, 16))	('SDHD', 'Gene', '6392', (12, 16))	('mutations', 'Var', (26, 35))	('TERT', 'Gene', (156, 160))	('mutations', 'Var', (85, 94))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))	('TERT', 'Gene', '7015', (156, 160))
78338	26327518	reported SDHD promoter mutations occurring in 10% of melanomas and being associated with a lower overall survival rate.	('lower', 'NegReg', (91, 96))	('melanomas', 'Disease', (53, 62))	('SDHD', 'Gene', (9, 13))	('SDHD', 'Gene', '6392', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('overall', 'MPA', (97, 104))	('mutations', 'Var', (23, 32))	('melanomas', 'Disease', 'MESH:D008545', (53, 62))
78339	26327518	Our study analyzes the mutation rate and clinico-pathologic associations of SDHD promoter mutations in a large cohort of different melanoma subtypes.	('SDHD', 'Gene', (76, 80))	('SDHD', 'Gene', '6392', (76, 80))	('mutations', 'Var', (90, 99))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma subtypes', 'Disease', (131, 148))	('melanoma subtypes', 'Disease', 'MESH:D008545', (131, 148))
78341	26327518	223 non-acral cutaneous, 38 acral, 33 mucosal, 43 occult, 43 conjunctival and 51 uveal melanoma) were analyzed for the presence of SDHD promoter mutations by Sanger-sequencing.	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('SDHD', 'Gene', (131, 135))	('mutations', 'Var', (145, 154))	('uveal melanoma', 'Disease', (81, 95))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('uveal melanoma', 'Disease', 'MESH:C536494', (81, 95))	('SDHD', 'Gene', '6392', (131, 135))
78344	26327518	ETS binding site changing SDHD promoter mutations were identified in 16 (4%) samples, of which 5 mutations had not been described previously.	('ETS', 'Chemical', '-', (0, 3))	('SDHD', 'Gene', (26, 30))	('SDHD', 'Gene', '6392', (26, 30))	('mutations', 'Var', (40, 49))	('binding', 'molecular_function', 'GO:0005488', ('4', '11'))
78346	26327518	Mutations in UV-exposed tumors were frequently C>T.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Disease', (24, 30))	('Mutations', 'Var', (0, 9))
78348	26327518	No statistically significant associations between SDHD promoter mutation status and various clinico-pathologic variables or overall patient survival were observed.	('patient', 'Species', '9606', (132, 139))	('SDHD', 'Gene', '6392', (50, 54))	('mutation', 'Var', (64, 72))	('SDHD', 'Gene', (50, 54))
78349	26327518	Melanomas harbor recurrent SDHD promoter mutations, which occur primarily as C>T alterations in UV-exposed melanomas.	('mutations', 'Var', (41, 50))	('melanomas', 'Disease', 'MESH:D008545', (107, 116))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('Melanomas', 'Disease', (0, 9))	('C>T alterations', 'Var', (77, 92))	('SDHD', 'Gene', '6392', (27, 31))	('melanomas', 'Disease', (107, 116))	('SDHD', 'Gene', (27, 31))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))
78350	26327518	In contrast to the initial report and promoter mutations in the TERT gene, our analysis suggests that SDHD promoter mutations are a relatively rare event in melanoma (4% of tumors) of unclear clinical and prognostic relevance.	('TERT', 'Gene', (64, 68))	('TERT', 'Gene', '7015', (64, 68))	('SDHD', 'Gene', (102, 106))	('SDHD', 'Gene', '6392', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('mutations', 'Var', (116, 125))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))
78357	26327518	Potentially the most relevant such mutation identified to date was the finding of TERT promoter mutations in a large proportion of melanoma samples (30-70%).	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('TERT', 'Gene', (82, 86))	('melanoma', 'Disease', (131, 139))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('TERT', 'Gene', '7015', (82, 86))	('mutations', 'Var', (96, 105))
78358	26327518	recently reported recurrent mutations of the succinate dehydrogenase complex subunit D (SDHD) promoter in melanoma.	('succinate dehydrogenase complex', 'cellular_component', 'GO:0045281', ('45', '76'))	('SDHD', 'Gene', (88, 92))	('SDHD', 'Gene', '6392', (88, 92))	('succinate dehydrogenase complex', 'cellular_component', 'GO:0045282', ('45', '76'))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('succinate dehydrogenase complex subunit D', 'Gene', '6392', (45, 86))	('melanoma', 'Disease', (106, 114))	('mutations', 'Var', (28, 37))	('succinate dehydrogenase complex subunit D', 'Gene', (45, 86))
78365	26327518	Mutations in SDHD have been described in gastrointestinal stromal tumor (GIST), paraganglioma and pheochromocytoma.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (41, 71))	('paraganglioma', 'Disease', 'MESH:D010235', (80, 93))	('SDHD', 'Gene', (13, 17))	('pheochromocytoma', 'Disease', (98, 114))	('Mutations', 'Var', (0, 9))	('SDHD', 'Gene', '6392', (13, 17))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (41, 71))	('pheochromocytoma', 'Disease', 'MESH:D010673', (98, 114))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (98, 114))	('paraganglioma', 'Phenotype', 'HP:0002668', (80, 93))	('GIST', 'Phenotype', 'HP:0100723', (73, 77))	('gastrointestinal stromal tumor', 'Disease', (41, 71))	('described', 'Reg', (28, 37))	('paraganglioma', 'Disease', (80, 93))
78367	26327518	All three described recurrent hotspot mutations in the SDHD promoter region substitute a cytosine for a thymine nucleotide (C>T).	('cytosine', 'Chemical', 'MESH:D003596', (89, 97))	('substitute', 'Reg', (76, 86))	('thymine nucleotide', 'Chemical', 'MESH:D013942', (104, 122))	('SDHD', 'Gene', '6392', (55, 59))	('mutations', 'Var', (38, 47))	('SDHD', 'Gene', (55, 59))
78370	26327518	The mutations alter existing ETS binding motifs predicted to lead to a reduced expression of the SDHD gene.	('ETS', 'Chemical', '-', (29, 32))	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('SDHD', 'Gene', (97, 101))	('expression', 'MPA', (79, 89))	('ETS', 'Protein', (29, 32))	('reduced', 'NegReg', (71, 78))	('mutations', 'Var', (4, 13))	('SDHD', 'Gene', '6392', (97, 101))
78371	26327518	The aim of our study was to further evaluate the incidence of SDHD promoter mutations in a large cohort of melanoma samples of various subtypes and to investigate associations of SDHD mutation status with clinico-pathologic variables and other common oncogenic mutations in melanoma, such as BRAF, NRAS, KIT and TERT promoter mutations.	('melanoma', 'Disease', 'MESH:D008545', (274, 282))	('KIT', 'molecular_function', 'GO:0005020', ('304', '307'))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('KIT', 'Gene', (304, 307))	('BRAF', 'Gene', '673', (292, 296))	('NRAS', 'Gene', '4893', (298, 302))	('SDHD', 'Gene', '6392', (62, 66))	('BRAF', 'Gene', (292, 296))	('TERT', 'Gene', (312, 316))	('TERT', 'Gene', '7015', (312, 316))	('melanoma', 'Phenotype', 'HP:0002861', (274, 282))	('melanoma', 'Disease', (274, 282))	('SDHD', 'Gene', '6392', (179, 183))	('SDHD', 'Gene', (62, 66))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('mutations', 'Var', (76, 85))	('NRAS', 'Gene', (298, 302))	('SDHD', 'Gene', (179, 183))
78373	26327518	Based on lack of detected SDHD promoter mutations (addressed below), the 51 primary uveal melanoma samples were excluded from further statistical analyses.	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('uveal melanoma', 'Disease', (84, 98))	('SDHD', 'Gene', (26, 30))	('SDHD', 'Gene', '6392', (26, 30))	('mutations', 'Var', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
78376	26327518	BRAF mutations occurred in 38% (142/376) of the tumor samples, including 128 (90%) V600E and 8 (6%) V600K.	('V600K', 'Var', (100, 105))	('V600E', 'Var', (83, 88))	('tumor', 'Disease', (48, 53))	('V600K', 'Mutation', 'rs121913227', (100, 105))	('V600E', 'Mutation', 'rs113488022', (83, 88))	('BRAF', 'Gene', '673', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('BRAF', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
78377	26327518	Additionally, individual (1%) V600G, V600D, K601N, K601E, G469A and D594N mutations were identified.	('D594N', 'Var', (68, 73))	('V600D', 'Var', (37, 42))	('K601N', 'Var', (44, 49))	('K601E', 'Var', (51, 56))	('K601N', 'Mutation', 'rs121913365', (44, 49))	('V600G', 'Mutation', 'rs113488022', (30, 35))	('G469A', 'Var', (58, 63))	('V600D', 'Mutation', 'rs121913377', (37, 42))	('V600G', 'Var', (30, 35))	('G469A', 'Mutation', 'rs121913355', (58, 63))	('D594N', 'Mutation', 'rs397516896', (68, 73))	('K601E', 'Mutation', 'rs121913364', (51, 56))
78378	26327518	NRAS mutations were found in 82 (22%) tumor samples, including 37 (45%) Q61R, 25 (25%) Q61K, 14 (17%) Q61L, 4 (5%) Q61H and 2 (1%) G12D mutations.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('Q61H', 'Mutation', 'rs121913255', (115, 119))	('G12D', 'Mutation', 'rs121913237', (131, 135))	('Q61L', 'Mutation', 'rs11554290', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('NRAS', 'Gene', (0, 4))	('found', 'Reg', (20, 25))	('Q61K', 'Var', (87, 91))	('Q61R', 'Var', (72, 76))	('Q61H', 'Var', (115, 119))	('Q61L', 'Var', (102, 106))	('G12D mutations', 'Var', (131, 145))	('NRAS', 'Gene', '4893', (0, 4))	('Q61K', 'Mutation', 'rs121913254', (87, 91))	('Q61R', 'Mutation', 'rs11554290', (72, 76))
78379	26327518	TERT promoter mutations occurred in 95 of 210 analyzed cases (45%), including 52 (55%) chr.5:1,295,250C>T, 31 (33%) chr.5:1,295,228C>T, 11 (12%) chr.5:1,295,242_1,295,243CC>TT and 1 (1%) chr.5:1,295,228_1,295,229CC>TT mutations (Table 1).	('243CC>TT', 'Mutation', 'c.243CC>TT', (167, 175))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('228C>T', 'Mutation', 'c.228C>T', (128, 134))	('229CC>TT', 'Mutation', 'c.229CC>TT', (209, 217))	('250C>T', 'Mutation', 'c.250C>T', (99, 105))	('mutations', 'Var', (14, 23))
78380	26327518	ETS binding site affecting SDHD promoter mutations were identified in 16 of 400 tumors (4%), obtained from 7 female and 9 male patients.	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ETS', 'Chemical', '-', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('SDHD', 'Gene', '6392', (27, 31))	('patients', 'Species', '9606', (127, 135))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('SDHD', 'Gene', (27, 31))	('binding', 'molecular_function', 'GO:0005488', ('4', '11'))
78382	26327518	Furthermore, we found five mutations occurring at two hotspots (Figure 1) located at chr.11:111,957,542 (TTCC>TTCA) and chr.11:111,957, 547 (CTTCC>CTTTC or CTTCC>CCTAC), which were not yet described, but also result in sequence alterations of the ETS-binding element (Figure 1).	('mutations', 'Var', (27, 36))	('sequence', 'MPA', (219, 227))	('ETS', 'Chemical', '-', (247, 250))	('542 (TTCC>TTCA)', 'Mutation', 'c.542TTCC>TTCA', (100, 115))	('binding', 'molecular_function', 'GO:0005488', ('251', '258'))	('ETS-binding', 'Protein', (247, 258))
78384	26327518	The SDHD promoter mutations identified included 5 (1.3%) 523C>T cases, 3 (0.8%) 541C>T, 3 (0.8%) 542C>A, 3 (0.8%) 544C>T cases, 1 (0.3%) 547C>T and 1 (0.3%) 547C>A case (Table 2).	('544C>T', 'Var', (114, 120))	('541C>T', 'Var', (80, 86))	('542C>A', 'Var', (97, 103))	('547C>T', 'Mutation', 'c.547C>T', (137, 143))	('541C>T', 'Mutation', 'c.541C>T', (80, 86))	('542C>A', 'Mutation', 'c.542C>A', (97, 103))	('547C>A', 'Mutation', 'c.547C>A', (157, 163))	('544C>T', 'Mutation', 'c.544C>T', (114, 120))	('SDHD', 'Gene', (4, 8))	('523C>T', 'Mutation', 'c.523C>T', (57, 63))	('547C>T', 'Var', (137, 143))	('SDHD', 'Gene', '6392', (4, 8))	('523C>T', 'Var', (57, 63))
78385	26327518	In addition to the ETS binding site affecting mutations, SDHD promoter mutations not affecting the ETS binding elements were identified in 5 tumor samples.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('ETS', 'Chemical', '-', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('SDHD', 'Gene', '6392', (57, 61))	('ETS', 'Chemical', '-', (99, 102))	('binding', 'molecular_function', 'GO:0005488', ('23', '30'))	('tumor', 'Disease', (141, 146))	('SDHD', 'Gene', (57, 61))	('binding', 'molecular_function', 'GO:0005488', ('103', '110'))	('mutations', 'Var', (71, 80))
78387	26327518	None of the 51 uveal tumor samples analyzed harbored a SDHD promoter mutation.	('uveal tumor', 'Disease', (15, 26))	('mutation', 'Var', (69, 77))	('SDHD', 'Gene', '6392', (55, 59))	('uveal tumor', 'Disease', 'MESH:D014604', (15, 26))	('SDHD', 'Gene', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
78388	26327518	For tumors in which SDHD promoter mutations were identified, matching constitutional DNA from peripheral blood mononuclear cells was analyzed if available.	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('SDHD', 'Gene', '6392', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('SDHD', 'Gene', (20, 24))	('mutations', 'Var', (34, 43))
78389	26327518	This was the case in 12 of the 16 tumors with SDHD promoter mutations affecting ETS binding sites and 4 of 5 tumor samples with SDHD promoter mutations not affecting ETS binding sites.	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('binding', 'molecular_function', 'GO:0005488', ('170', '177'))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('affecting', 'Reg', (70, 79))	('SDHD', 'Gene', (128, 132))	('SDHD', 'Gene', '6392', (46, 50))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Disease', (109, 114))	('SDHD', 'Gene', (46, 50))	('binding', 'molecular_function', 'GO:0005488', ('84', '91'))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Disease', (34, 40))	('ETS', 'Protein', (80, 83))	('mutations', 'Var', (60, 69))	('ETS', 'Chemical', '-', (166, 169))	('ETS', 'Chemical', '-', (80, 83))	('SDHD', 'Gene', '6392', (128, 132))
78391	26327518	In all other cases, SDHD promoter mutations detected in the tumor were not present in the constitutional DNA, confirming they were acquired somatically (Table 2).	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('SDHD', 'Gene', '6392', (20, 24))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('SDHD', 'Gene', (20, 24))	('mutations', 'Var', (34, 43))
78392	26327518	For the analyses presented in the paper, only those SDHD promoter mutations affecting the ETS domains were deemed to be relevant (n = 16).	('mutations', 'Var', (66, 75))	('ETS', 'Chemical', '-', (90, 93))	('SDHD', 'Gene', '6392', (52, 56))	('SDHD', 'Gene', (52, 56))
78393	26327518	However, no significant differences were observed when the samples harboring SDHD promoter mutations not affecting ETS binding domains were also included in the analysis (data not shown).	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('SDHD', 'Gene', '6392', (77, 81))	('SDHD', 'Gene', (77, 81))	('mutations', 'Var', (91, 100))	('ETS', 'Chemical', '-', (115, 118))
78394	26327518	ETS binding site affecting SDHD promoter mutations were detected in 9 metastatic and 4 primary tumor samples (Table 1).	('mutations', 'Var', (41, 50))	('primary tumor', 'Disease', (87, 100))	('ETS', 'Chemical', '-', (0, 3))	('SDHD', 'Gene', '6392', (27, 31))	('primary tumor', 'Disease', 'MESH:D009369', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('SDHD', 'Gene', (27, 31))	('binding', 'molecular_function', 'GO:0005488', ('4', '11'))
78395	26327518	Non-acral cutaneous melanomas harbored 9 of the 16 mutations (56%).	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (10, 29))	('mutations', 'Var', (51, 60))	('acral cutaneous melanoma', 'Phenotype', 'HP:0012060', (4, 28))	('Non-acral cutaneous melanomas', 'Disease', 'MESH:C562393', (0, 29))	('acral cutaneous melanomas', 'Phenotype', 'HP:0012060', (4, 29))	('Non-acral cutaneous melanomas', 'Disease', (0, 29))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanomas', 'Phenotype', 'HP:0002861', (20, 29))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (10, 28))
78398	26327518	Of the 5 SDHD promoter mutations not affecting the ETS binding domains, 4 were in metastatic samples of non-acral cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('SDHD', 'Gene', '6392', (9, 13))	('SDHD', 'Gene', (9, 13))	('cutaneous melanoma', 'Disease', (114, 132))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (114, 132))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (114, 132))	('acral cutaneous melanoma', 'Phenotype', 'HP:0012060', (108, 132))	('mutations', 'Var', (23, 32))	('ETS', 'Chemical', '-', (51, 54))	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))
78399	26327518	No statistically significant associations of SDHD promoter mutation status with available clinical parameters including stage at diagnosis, Breslow thickness, Clark level, presence of ulceration, histologic type and mutation status (BRAF, NRAS, KIT, TERT promoter) were identified (Table 1, Supplemental Table 1 + 2).	('TERT', 'Gene', (250, 254))	('TERT', 'Gene', '7015', (250, 254))	('NRAS', 'Gene', (239, 243))	('mutation', 'Var', (59, 67))	('SDHD', 'Gene', '6392', (45, 49))	('BRAF', 'Gene', (233, 237))	('NRAS', 'Gene', '4893', (239, 243))	('BRAF', 'Gene', '673', (233, 237))	('SDHD', 'Gene', (45, 49))	('KIT', 'molecular_function', 'GO:0005020', ('245', '248'))
78400	26327518	This was the case regardless of whether selectively ETS binding site mutations (Table 1) or all identified mutations were considered (data not shown).	('mutations', 'Var', (69, 78))	('binding', 'molecular_function', 'GO:0005488', ('56', '63'))	('ETS', 'Chemical', '-', (52, 55))	('ETS binding', 'Interaction', (52, 63))
78402	26327518	Six patients with SDHD promoter mutation died during the follow-up period.	('SDHD', 'Gene', '6392', (18, 22))	('mutation', 'Var', (32, 40))	('SDHD', 'Gene', (18, 22))	('patients', 'Species', '9606', (4, 12))
78403	26327518	A statistically significant association between SDHD promoter mutation and overall survival was not found (Figure 4).	('SDHD', 'Gene', (48, 52))	('mutation', 'Var', (62, 70))	('SDHD', 'Gene', '6392', (48, 52))
78404	26327518	To explore the general frequency of SDHD promoter mutations and potential relevance for therapy resistance in melanoma, we re-analyzed exomes sequenced from 69 melanoma patients under MAPKi therapy.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('patients', 'Species', '9606', (169, 177))	('SDHD', 'Gene', (36, 40))	('SDHD', 'Gene', '6392', (36, 40))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('mutations', 'Var', (50, 59))	('melanoma', 'Disease', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))
78406	26327518	In the 92 tumor exomes with sufficient coverage we detected 4 SDHD promoter variants (4.3%, Supplemental Table 3).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('variants', 'Var', (76, 84))	('SDHD', 'Gene', '6392', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('SDHD', 'Gene', (62, 66))
78407	26327518	In our study of a large cohort of ocular, cutaneous, mucosal and occult melanomas, SDHD promoter mutations affecting recurrent ETS binding elements were identified in only 4% (16/400) of the samples.	('mutations', 'Var', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('ETS', 'Chemical', '-', (127, 130))	('occult melanomas', 'Disease', (65, 81))	('occult melanomas', 'Disease', 'MESH:D008545', (65, 81))	('binding', 'molecular_function', 'GO:0005488', ('131', '138'))	('SDHD', 'Gene', '6392', (83, 87))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('SDHD', 'Gene', (83, 87))
78408	26327518	Additionally, 10 other mutations were identified, five of which altered the sequence of ETS transcription factor binding elements.	('ETS', 'Chemical', '-', (88, 91))	('ETS', 'Protein', (88, 91))	('sequence', 'MPA', (76, 84))	('mutations', 'Var', (23, 32))	('transcription', 'biological_process', 'GO:0006351', ('92', '105'))	('altered', 'Reg', (64, 71))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('92', '120'))
78409	26327518	Our study validates the finding of recurrent mutations in the SDHD promoter; however these mutations were considerably rarer than previously reported and showed no association with prognosis or the clinico-pathologic variables that were analyzed.	('SDHD', 'Gene', (62, 66))	('mutations', 'Var', (45, 54))	('SDHD', 'Gene', '6392', (62, 66))
78410	26327518	Most of the identified SDHD promoter mutations altering the TTCC element of the ETS transcription binding sites were found in one of the three previously described mutation hotspots located at chr.11:111,957,523, chr.11:111,957,541 and chr.11:111,957,544 (Figure 1).	('altering', 'Reg', (47, 55))	('SDHD', 'Gene', '6392', (23, 27))	('SDHD', 'Gene', (23, 27))	('mutations', 'Var', (37, 46))	('binding', 'molecular_function', 'GO:0005488', ('98', '105'))	('transcription', 'biological_process', 'GO:0006351', ('84', '97'))	('ETS', 'Chemical', '-', (80, 83))	('TTCC element', 'MPA', (60, 72))
78412	26327518	All of these newly identified mutations alter the ETS binding site core element (TTCC).	('binding', 'molecular_function', 'GO:0005488', ('54', '61'))	('alter', 'Reg', (40, 45))	('core', 'cellular_component', 'GO:0019013', ('67', '71'))	('mutations', 'Var', (30, 39))	('ETS binding site core element', 'MPA', (50, 79))	('ETS', 'Chemical', '-', (50, 53))
78415	26327518	It would appear logical that the various mutations exert differing effects on SDHD gene transcription and protein translation.	('mutations', 'Var', (41, 50))	('protein translation', 'biological_process', 'GO:0006412', ('106', '125'))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('transcription', 'biological_process', 'GO:0006351', ('88', '101'))	('SDHD', 'Gene', (78, 82))	('SDHD', 'Gene', '6392', (78, 82))	('protein translation', 'MPA', (106, 125))	('effects', 'Reg', (67, 74))	('transcription', 'MPA', (88, 101))
78418	26327518	The majority of ETS binding site altering SDHD promoter mutations (9 of 16 = 56%) were identified in the non-acral cutaneous melanoma.	('mutations', 'Var', (56, 65))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('cutaneous melanoma', 'Disease', (115, 133))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (115, 133))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (115, 133))	('binding', 'molecular_function', 'GO:0005488', ('20', '27'))	('SDHD', 'Gene', (42, 46))	('altering', 'Reg', (33, 41))	('SDHD', 'Gene', '6392', (42, 46))	('ETS', 'Chemical', '-', (16, 19))	('acral cutaneous melanoma', 'Phenotype', 'HP:0012060', (109, 133))
78419	26327518	C>T mutations, which are a marker of UV-exposure, were observed only in these tumors.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('C>T mutations', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))
78420	26327518	A single mucosal melanoma (1 of 33, 3%) harbored a 542C>A alteration; no mutations in acral (n = 38) melanomas were identified (Table 2).	('melanomas', 'Phenotype', 'HP:0002861', (101, 110))	('542C>A', 'Var', (51, 57))	('542C>A', 'Mutation', 'c.542C>A', (51, 57))	('melanomas', 'Disease', 'MESH:D008545', (101, 110))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('melanomas', 'Disease', (101, 110))	('mucosal melanoma', 'Disease', (9, 25))	('mucosal melanoma', 'Disease', 'MESH:D008545', (9, 25))
78422	26327518	The type of mutations identified does support SDHD promoter mutations in UV-exposed tumors (i.e.	('SDHD', 'Gene', '6392', (46, 50))	('SDHD', 'Gene', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('mutations', 'Var', (60, 69))
78423	26327518	non-acral cutaneous) being primarily UV-induced, whereas the 542C>A mutation occurring in a mucosal, non UV-exposed melanoma probably developed in a UV-independent fashion.	('542C>A', 'Var', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('542C>A', 'Mutation', 'c.542C>A', (61, 67))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))
78424	26327518	The overall lack of mutations in uveal melanoma further supports their being genetically distinct from cutaneous, mucosal and conjunctival melanoma.	('conjunctival melanoma', 'Disease', (126, 147))	('uveal melanoma', 'Disease', 'MESH:C536494', (33, 47))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (126, 147))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (126, 147))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('uveal melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('uveal melanoma', 'Disease', (33, 47))	('mutations', 'Var', (20, 29))
78425	26327518	The significance of the 5 SDHD promoter mutations identified outside of the three existing ETS binding elements (Figure 2) is unclear.	('ETS', 'Chemical', '-', (91, 94))	('SDHD', 'Gene', (26, 30))	('SDHD', 'Gene', '6392', (26, 30))	('mutations', 'Var', (40, 49))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))
78426	26327518	Given that melanoma has a particularly high frequency of mutations, many of unclear functional relevance, it is possible that the identified alterations are simply passenger mutations.	('mutations', 'Var', (57, 66))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
78427	26327518	The only recurrent mutation, chr.11:111,957,538 (TTTCC>ATTCC), identified in two tumors, is located just outside of the ETS core element, similar to the previously described 544C>T mutation, however resulting in a different sequence (ATTCC versus TTTCC, respectively).	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('544C>T', 'Var', (174, 180))	('ETS', 'Chemical', '-', (120, 123))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('core', 'cellular_component', 'GO:0019013', ('124', '128'))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('544C>T', 'Mutation', 'c.544C>T', (174, 180))
78428	26327518	To exclude the possibility that these mutations might have (as yet unknown) functional importance, all statistical analyses were also performed including all 21 samples with SDHD promoter mutations (independent of their known effects on ETS binding sites).	('ETS', 'Chemical', '-', (237, 240))	('binding', 'molecular_function', 'GO:0005488', ('241', '248'))	('SDHD', 'Gene', '6392', (174, 178))	('SDHD', 'Gene', (174, 178))	('mutations', 'Var', (188, 197))
78429	26327518	The identification of a germline SDHD promoter mutation altering the ETS binding site is intriguing.	('SDHD', 'Gene', '6392', (33, 37))	('SDHD', 'Gene', (33, 37))	('mutation', 'Var', (47, 55))	('altering', 'Reg', (56, 64))	('ETS', 'Chemical', '-', (69, 72))	('ETS binding site', 'MPA', (69, 85))	('binding', 'molecular_function', 'GO:0005488', ('73', '80'))
78433	26327518	Although the age of the affected patient argues against the role of this mutation in increasing the risk of melanoma, larger numbers of patients will be needed to adequately address this question.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('patient', 'Species', '9606', (33, 40))	('patient', 'Species', '9606', (136, 143))	('patients', 'Species', '9606', (136, 144))	('mutation', 'Var', (73, 81))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))
78434	26327518	To compare our Sanger sequencing results to NGS data, we explored an existing exome dataset detecting SDHD promoter variants in ~4% of tumors.	('variants', 'Var', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('SDHD', 'Gene', (102, 106))	('SDHD', 'Gene', '6392', (102, 106))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))
78435	26327518	These variants were equally distributed in pre-treatment and recurrent tumors, showing no obvious association of SDHD variants with therapy resistance.	('SDHD', 'Gene', (113, 117))	('SDHD', 'Gene', '6392', (113, 117))	('variants', 'Var', (118, 126))	('pre', 'molecular_function', 'GO:0003904', ('43', '46'))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
78438	26327518	Repeating our analysis without requiring a minimum of 2 unique reads to support a SDHD variant, we detected 11 variants in 92 tumors (12%).	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('SDHD', 'Gene', '6392', (82, 86))	('SDHD', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('variant', 'Var', (87, 94))
78439	26327518	No association of SDHD promoter mutation status with overall survival was seen (Figure 4).	('SDHD', 'Gene', '6392', (18, 22))	('mutation', 'Var', (32, 40))	('SDHD', 'Gene', (18, 22))
78440	26327518	Admittedly, the number of mutated samples in our cohort is low (n = 16, or n = 21 if including SDHD promoter mutations not affecting ETS binding sites), meaning larger studies will be required to convincingly assess survival.	('ETS', 'Chemical', '-', (133, 136))	('SDHD', 'Gene', '6392', (95, 99))	('binding', 'molecular_function', 'GO:0005488', ('137', '144'))	('SDHD', 'Gene', (95, 99))	('mutations', 'Var', (109, 118))
78441	26327518	reported a statistically significant (p = 0.005) survival difference with poorer prognosis for SDHD promoter mutations analyzing less mutant cases (n = 12).	('SDHD', 'Gene', (95, 99))	('SDHD', 'Gene', '6392', (95, 99))	('mutations', 'Var', (109, 118))
78442	26327518	's relatively small sample size, we believe that the prognostic association of SDHD promoter mutations is yet to be unequivocally established and should be explored further in future studies.	('SDHD', 'Gene', '6392', (79, 83))	('SDHD', 'Gene', (79, 83))	('mutations', 'Var', (93, 102))
78443	26327518	It would be interesting to determine to which extent expression levels of SDHD protein are actually affected by SDHD promoter mutations.	('SDHD', 'Gene', (74, 78))	('SDHD', 'Gene', '6392', (74, 78))	('SDHD', 'Gene', (112, 116))	('SDHD', 'Gene', '6392', (112, 116))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('affected', 'Reg', (100, 108))	('mutations', 'Var', (126, 135))	('expression levels', 'MPA', (53, 70))
78446	26327518	Overall, our study validates the finding of recurrent mutations in the SDHD promoter, which are enriched for mutations inactivating ETS transcription binding sites.	('SDHD', 'Gene', '6392', (71, 75))	('mutations', 'Var', (54, 63))	('SDHD', 'Gene', (71, 75))	('transcription', 'biological_process', 'GO:0006351', ('136', '149'))	('ETS', 'Chemical', '-', (132, 135))	('binding', 'molecular_function', 'GO:0005488', ('150', '157'))
78448	26327518	Should these findings be validated in additional cohorts, they argue that compared to the much more frequent and prognostically relevant TERT promoter mutations, SDHD promoter mutations play a relatively minor role in melanoma.	('SDHD', 'Gene', (162, 166))	('mutations', 'Var', (176, 185))	('TERT', 'Gene', (137, 141))	('TERT', 'Gene', '7015', (137, 141))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('SDHD', 'Gene', '6392', (162, 166))
78458	26327518	Sequencing for BRAF, NRAS and KIT was generally performed sequentially; NRAS sequenced in BRAF wild-type samples, KIT in BRAF and NRAS wild-type samples.	('BRAF', 'Gene', (90, 94))	('BRAF', 'Gene', (121, 125))	('NRAS', 'Gene', (72, 76))	('NRAS', 'Gene', '4893', (21, 25))	('BRAF', 'Gene', '673', (15, 19))	('KIT', 'molecular_function', 'GO:0005020', ('30', '33'))	('BRAF', 'Gene', '673', (121, 125))	('BRAF', 'Gene', (15, 19))	('NRAS', 'Gene', '4893', (72, 76))	('NRAS', 'Gene', (21, 25))	('NRAS', 'Gene', (130, 134))	('sequenced', 'Var', (77, 86))	('BRAF', 'Gene', '673', (90, 94))	('NRAS', 'Gene', '4893', (130, 134))	('KIT', 'molecular_function', 'GO:0005020', ('114', '117'))
78460	26327518	Associations of SDHD promoter mutations and clinico-pathologic variables, such as age, sex, primary tumor location, TNM status, histologic type, mutation status (for BRAF, NRAS, KIT and TERT promoter mutations), Breslow thickness, Clark level, ulceration and sentinel lymph node status were explored using chi-square or Fisher exact tests as appropriate.	('TNM', 'Gene', '10178', (116, 119))	('BRAF', 'Gene', (166, 170))	('NRAS', 'Gene', '4893', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('KIT', 'molecular_function', 'GO:0005020', ('178', '181'))	('NRAS', 'Gene', (172, 176))	('SDHD', 'Gene', '6392', (16, 20))	('TNM', 'Gene', (116, 119))	('SDHD', 'Gene', (16, 20))	('mutations', 'Var', (30, 39))	('primary tumor', 'Disease', (92, 105))	('primary tumor', 'Disease', 'MESH:D009369', (92, 105))	('TERT', 'Gene', (186, 190))	('BRAF', 'Gene', '673', (166, 170))	('TERT', 'Gene', '7015', (186, 190))
78544	25834817	Interestingly, in a recent study, it has also been shown that while TRAIL-R1/DR4 and TRAIL-R2/DR5 methylation is not frequent in cutaneous melanoma, it was very frequent in uveal melanoma.	('TRAIL-R1', 'Gene', '8797', (68, 76))	('uveal melanoma', 'Phenotype', 'HP:0007716', (173, 187))	('DR4', 'Gene', (77, 80))	('TRAIL-R2', 'Gene', (85, 93))	('frequent', 'Reg', (161, 169))	('TRAIL-R2', 'Gene', '8795', (85, 93))	('TRAIL-R1', 'Gene', (68, 76))	('DR4', 'Gene', '8797', (77, 80))	('DR5', 'Gene', '8795', (94, 97))	('DR5', 'Gene', (94, 97))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('methylation', 'biological_process', 'GO:0032259', ('98', '109'))	('uveal melanoma', 'Disease', (173, 187))	('uveal melanoma', 'Disease', 'MESH:C536494', (173, 187))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('methylation', 'Var', (98, 109))	('cutaneous melanoma', 'Disease', (129, 147))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (129, 147))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (129, 147))
78565	25834817	Indeed, in a large cohort study consisting of 1826 subjects which included 300 cases with AMD, a significant association between TRAIL-R1 TNFRSF10-LOC389641 rs13278062 and increased risk of late macular age-related degeneration was observed.	('degeneration', 'Disease', 'MESH:D009410', (215, 227))	('rs13278062', 'Mutation', 'rs13278062', (157, 167))	('TRAIL-R1', 'Gene', '8797', (129, 137))	('rs13278062', 'Var', (157, 167))	('macular age-related degeneration', 'Phenotype', 'HP:0000608', (195, 227))	('AMD', 'Disease', 'MESH:D006009', (90, 93))	('TRAIL-R1', 'Gene', (129, 137))	('degeneration', 'Disease', (215, 227))	('AMD', 'Disease', (90, 93))
78567	25834817	Since TRAIL-R3 is believed to act as dominant-negative receptor, the authors suggest that the low levels of TRAIL-R3 in these patients may increase the amount of TRAIL interacting with the proapoptotic receptors (TRAIL-R1 and TRAIL-R2), thus resulting in enhanced TRAIL apoptosis of photoreceptors and retinal pigment epithelium cells, which are well known phenomena involved in the pathogenesis of AMD.	('TRAIL', 'MPA', (162, 167))	('enhanced', 'PosReg', (255, 263))	('TRAIL-R2', 'Gene', (226, 234))	('interacting', 'Interaction', (168, 179))	('patients', 'Species', '9606', (126, 134))	('TRAIL-R2', 'Gene', '8795', (226, 234))	('TRAIL-R3', 'Gene', (6, 14))	('amount', 'MPA', (152, 158))	('TRAIL-R3', 'Gene', (108, 116))	('AMD', 'Disease', 'MESH:D006009', (399, 402))	('increase', 'PosReg', (139, 147))	('TRAIL-R3', 'Gene', '8794', (6, 14))	('TRAIL-R3', 'Gene', '8794', (108, 116))	('low', 'Var', (94, 97))	('pathogenesis', 'biological_process', 'GO:0009405', ('383', '395'))	('AMD', 'Disease', (399, 402))	('TRAIL-R1', 'Gene', (213, 221))	('TRAIL apoptosis', 'CPA', (264, 279))	('TRAIL-R1', 'Gene', '8797', (213, 221))	('apoptosis', 'biological_process', 'GO:0097194', ('270', '279'))	('apoptosis', 'biological_process', 'GO:0006915', ('270', '279'))
78573	23177739	A genome-wide RNAi screen reveals a Trio-regulated Rho GTPase circuitry transducing GPCR-initiated mitogenic signals Activating mutations in GNAQ and GNA11, encoding members of the Galphaq family of G protein alpha subunits, are the driver uveal melanoma oncogenes, while mutations in Gq-linked G proteincoupled receptors (GPCRs) have been identified recently in numerous human malignancies.	('Activating', 'PosReg', (117, 127))	('GNA11', 'Gene', (150, 155))	('GNAQ', 'Gene', '2776', (141, 145))	('GNAQ', 'Gene', (141, 145))	('GPCR', 'Gene', (323, 327))	('GPCR', 'Gene', (84, 88))	('Trio', 'Gene', (36, 40))	('mutations', 'Var', (128, 137))	('human', 'Species', '9606', (372, 377))	('melanoma', 'Phenotype', 'HP:0002861', (246, 254))	('RNAi', 'biological_process', 'GO:0016246', ('14', '18'))	('GPCR', 'Gene', '441931', (323, 327))	('uveal melanoma', 'Disease', (240, 254))	('uveal melanoma', 'Disease', 'MESH:C536494', (240, 254))	('GPCR', 'Gene', '441931', (84, 88))	('GNA11', 'Gene', '2767', (150, 155))	('Gq', 'Gene', '36384', (285, 287))	('Trio', 'Gene', '7204', (36, 40))	('uveal melanoma', 'Phenotype', 'HP:0007716', (240, 254))	('malignancies', 'Disease', 'MESH:D009369', (378, 390))	('protein', 'cellular_component', 'GO:0003675', ('201', '208'))	('malignancies', 'Disease', (378, 390))
78580	23177739	In addition, two of the six known human cancerassociated viruses, Epstein-Barr virus and Kaposi's sarcoma-associated human Herpesvirus express constitutively active mutant GPCRs from their viral genome, while recent cancer sequencing initiatives have revealed a surprisingly high incidence of GPCR mutations (5-30%), in some of the most prevalent human malignancies.	('human', 'Species', '9606', (34, 39))	('Herpesvirus', 'Species', '39059', (123, 134))	('cancer', 'Disease', (216, 222))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (89, 105))	('GPCR', 'Gene', '441931', (293, 297))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Disease', (40, 46))	('GPCR', 'Gene', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('human', 'Species', '9606', (117, 122))	('human', 'Species', '9606', (347, 352))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))	('GPCR', 'Gene', '441931', (172, 176))	('malignancies', 'Disease', 'MESH:D009369', (353, 365))	('mutant', 'Var', (165, 171))	('Epstein-Barr virus', 'Species', '10376', (66, 84))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('malignancies', 'Disease', (353, 365))	('mutations', 'Var', (298, 307))	('GPCR', 'Gene', (293, 297))
78582	23177739	In line with this coupling selectivity, activated Galphaq mutants harbor transforming potential, and Gq-linked receptors can act as potent oncogenes in experimental model systems.	('Gq', 'Gene', '36384', (101, 103))	('mutants', 'Var', (58, 65))	('transforming potential', 'CPA', (73, 95))	('Galphaq', 'Protein', (50, 57))
78583	23177739	Mutations in Gq-coupled receptors (Gq-GPCRs) have been recently demonstrated in multiple human cancers, and activating mutations in the genes for Galphaq family members, Galphaq (GNAQ) and Galpha11 (GNA11), have been identified in approximately 80% of uveal melanomas, where they are now considered to represent the driver uveal melanoma oncogene.	('uveal melanoma', 'Disease', 'MESH:C536494', (323, 337))	('uveal melanoma', 'Disease', (323, 337))	('uveal melanoma', 'Phenotype', 'HP:0007716', (252, 266))	('GPCR', 'Gene', (38, 42))	('Gq', 'Gene', '36384', (35, 37))	('melanoma', 'Phenotype', 'HP:0002861', (329, 337))	('uveal melanomas', 'Disease', (252, 267))	('uveal melanomas', 'Phenotype', 'HP:0007716', (252, 267))	('GNAQ', 'Gene', '2776', (179, 183))	('human', 'Species', '9606', (89, 94))	('Galpha11', 'Gene', '2767', (189, 197))	('uveal melanoma', 'Phenotype', 'HP:0007716', (323, 337))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('GNAQ', 'Gene', (179, 183))	('Mutations', 'Var', (0, 9))	('GNA11', 'Gene', '2767', (199, 204))	('GPCR', 'Gene', '441931', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mutations', 'Var', (119, 128))	('melanomas', 'Phenotype', 'HP:0002861', (258, 267))	('Galpha11', 'Gene', (189, 197))	('melanoma', 'Phenotype', 'HP:0002861', (258, 266))	('uveal melanomas', 'Disease', 'MESH:C536494', (252, 267))	('Gq', 'Gene', '36384', (13, 15))	('GNA11', 'Gene', (199, 204))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (252, 266))	('Galphaq', 'Gene', (146, 153))	('Galphaq', 'Gene', (170, 177))
78595	23177739	NIH3T3-Sy-Gq were co-transfected with AP-1 luc and pRLNull and appropriate siRNAs and stimulated for 4h prior to the detection of the luciferase activity.	('luciferase activity', 'molecular_function', 'GO:0047077', ('134', '153'))	('AP-1', 'cellular_component', 'GO:0005907', ('38', '42'))	('luciferase', 'Enzyme', (134, 144))	('luciferase activity', 'molecular_function', 'GO:0045289', ('134', '153'))	('4h', 'Chemical', '-', (101, 103))	('luciferase activity', 'molecular_function', 'GO:0047712', ('134', '153'))	('NIH3T3-Sy-Gq', 'Var', (0, 12))	('luciferase activity', 'molecular_function', 'GO:0050248', ('134', '153'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('134', '153'))	('NIH3T3-Sy-Gq', 'CellLine', 'CVCL:0594', (0, 12))
78601	23177739	Furthermore, CNO stimulated phospholipase C (PLC) activation and a rapid raise in cytoplasmatic [Ca2+] only in cells expressing Sy-Rq (Fig.	('cytoplasmatic [Ca2+]', 'MPA', (82, 102))	('Sy-Rq', 'Chemical', '-', (128, 133))	('CNO', 'Gene', '55330', (13, 16))	('raise', 'PosReg', (73, 78))	('Ca2+', 'Chemical', 'MESH:D000069285', (97, 101))	('CNO', 'Gene', (13, 16))	('activation', 'PosReg', (50, 60))	('PLC', 'Gene', (45, 48))	('PLC', 'Gene', '31376', (45, 48))	('PLC', 'cellular_component', 'GO:0042824', ('45', '48'))	('phospholipase C', 'Enzyme', (28, 43))	('Sy-Rq', 'Var', (128, 133))
78603	23177739	Prolonged activation of Sy-Rq led to oncogenic transformation of NIH3T3 cells, with foci of transformed cells expressing Sy-Rq (Fig.	('Sy-Rq', 'Chemical', '-', (121, 126))	('NIH3T3', 'CellLine', 'CVCL:0594', (65, 71))	('Sy-Rq', 'Var', (121, 126))	('Sy-Rq', 'Chemical', '-', (24, 29))	('oncogenic transformation', 'CPA', (37, 61))
78604	23177739	Sy-Rq activation elicited a potent proliferative response, comparable to that induced by PDGF when used as control (Fig.	('Sy-Rq', 'Var', (0, 5))	('PDGF', 'molecular_function', 'GO:0005161', ('89', '93'))	('Sy-Rq', 'Chemical', '-', (0, 5))	('proliferative response', 'CPA', (35, 57))
78609	23177739	PLC inhibition reduced the stimulation of the ERK MAPK by Sy-Rq, albeit partially (Fig.	('ERK', 'Gene', '5594', (46, 49))	('stimulation', 'MPA', (27, 38))	('PLC', 'Gene', (0, 3))	('ERK', 'Gene', (46, 49))	('PLC', 'Gene', '31376', (0, 3))	('Sy-Rq', 'Var', (58, 63))	('MAPK', 'Gene', '5594', (50, 54))	('PLC', 'cellular_component', 'GO:0042824', ('0', '3'))	('MAPK', 'Gene', (50, 54))	('inhibition reduced', 'NegReg', (4, 22))	('ERK', 'molecular_function', 'GO:0004707', ('46', '49'))	('Sy-Rq', 'Chemical', '-', (58, 63))	('MAPK', 'molecular_function', 'GO:0004707', ('50', '54'))
78610	23177739	Surprisingly, inhibition of PLC had only a limited impact on DNA-synthesis in response to CNO, despite completely abolishing its ability to increase intracellular Ca2+ levels, a direct downstream consequence of PLC activation (Fig.	('intracellular Ca2+ levels', 'MPA', (149, 174))	('intracellular', 'cellular_component', 'GO:0005622', ('149', '162'))	('increase intracellular Ca2+', 'Phenotype', 'HP:0003575', (140, 167))	('PLC', 'cellular_component', 'GO:0042824', ('28', '31'))	('PLC', 'Gene', (28, 31))	('PLC', 'cellular_component', 'GO:0042824', ('211', '214'))	('Ca2+', 'Chemical', 'MESH:D000069285', (163, 167))	('PLC', 'Gene', '31376', (28, 31))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('DNA-synthesis', 'biological_process', 'GO:0071897', ('61', '74'))	('abolishing', 'NegReg', (114, 124))	('DNA-synthesis', 'MPA', (61, 74))	('PLC', 'Gene', (211, 214))	('increase', 'PosReg', (140, 148))	('CNO', 'Gene', '55330', (90, 93))	('inhibition', 'Var', (14, 24))	('PLC', 'Gene', '31376', (211, 214))	('CNO', 'Gene', (90, 93))
78611	23177739	Taken together, we can conclude that an engineered Gq-coupled receptor can activate cells to undergo normal and malignant cell growth.	('activate', 'PosReg', (75, 83))	('engineered', 'Var', (40, 50))	('cell growth', 'biological_process', 'GO:0016049', ('122', '133'))	('cells', 'CPA', (84, 89))	('Gq', 'Gene', '36384', (51, 53))
78624	23177739	As expected, knock down of Galphaq and NorpA, a PLC isoform acting downstream of Galphaq, but not dJun, impaired the activation of PI breakdown by M1 Gq- GPCR (Fig.	('dJun', 'Gene', (98, 102))	('impaired', 'NegReg', (104, 112))	('breakdown', 'biological_process', 'GO:0009056', ('134', '143'))	('Gq', 'Gene', '36384', (150, 152))	('M1', 'Gene', '1128', (147, 149))	('activation', 'MPA', (117, 127))	('PLC', 'Gene', (48, 51))	('dJun', 'Gene', '36057', (98, 102))	('NorpA', 'Gene', '31376', (39, 44))	('PLC', 'Gene', '31376', (48, 51))	('GPCR', 'Gene', '441931', (154, 158))	('GPCR', 'Gene', (154, 158))	('PLC', 'cellular_component', 'GO:0042824', ('48', '51'))	('NorpA', 'Gene', (39, 44))	('knock down', 'Var', (13, 23))	('PI breakdown', 'MPA', (131, 143))
78625	23177739	Surprisingly, however, AP-1 activation was dependent on Galphaq and dJun, but not on NorpA or another Drosophila PLC isoform under multiple experimental conditions (Fig.	('NorpA', 'Gene', (85, 90))	('PLC', 'Gene', '31376', (113, 116))	('AP-1', 'Gene', (23, 27))	('Galphaq', 'Var', (56, 63))	('dJun', 'Gene', '36057', (68, 72))	('PLC', 'cellular_component', 'GO:0042824', ('113', '116'))	('Drosophila', 'Species', '7227', (102, 112))	('AP-1', 'cellular_component', 'GO:0005907', ('23', '27'))	('activation', 'PosReg', (28, 38))	('NorpA', 'Gene', '31376', (85, 90))	('dJun', 'Gene', (68, 72))	('PLC', 'Gene', (113, 116))
78641	23177739	Effective knock down of dTrio (Fig.	('dTrio', 'Gene', '43974', (24, 29))	('knock down', 'Var', (10, 20))	('dTrio', 'Gene', (24, 29))
78645	23177739	Furthermore, dTrio knockdown inhibited AP-1 activation potently (Fig.	('inhibited', 'NegReg', (29, 38))	('AP-1', 'Protein', (39, 43))	('dTrio', 'Gene', '43974', (13, 18))	('knockdown', 'Var', (19, 28))	('dTrio', 'Gene', (13, 18))	('AP-1', 'cellular_component', 'GO:0005907', ('39', '43'))
78647	23177739	3J), whereas knockdown of dGq inhibited both.	('dGq', 'Gene', '36384', (26, 29))	('knockdown', 'Var', (13, 22))	('dGq', 'Gene', (26, 29))
78648	23177739	Defective AP-1 activation due to dTrio knockdown was rescued by re-expressing a truncated form of dTrio comprising the Cterminal region including the two DH-PH GEF domains and a C-terminal area of predicted interaction with Galphaq (see below), but not by its N-terminal spectrin region (Fig.	('dTrio', 'Gene', '43974', (98, 103))	('spectrin', 'cellular_component', 'GO:0008091', ('271', '279'))	('dTrio', 'Gene', (33, 38))	('activation', 'PosReg', (15, 25))	('dTrio', 'Gene', (98, 103))	('knockdown', 'Var', (39, 48))	('GEF', 'molecular_function', 'GO:0005085', ('160', '163'))	('interaction', 'Interaction', (207, 218))	('AP-1', 'cellular_component', 'GO:0005907', ('10', '14'))	('AP-1', 'Gene', (10, 14))	('Galphaq', 'Protein', (224, 231))	('dTrio', 'Gene', '43974', (33, 38))
78650	23177739	AP-1 activation required both of these GEFs domains, as activation of AP-1 was rescued only partially when expressing mutant forms of dTrio in which either of the two GEF domains were inactivated (Fig.	('dTrio', 'Gene', '43974', (134, 139))	('dTrio', 'Gene', (134, 139))	('GEF', 'molecular_function', 'GO:0005085', ('167', '170'))	('AP-1', 'cellular_component', 'GO:0005907', ('0', '4'))	('mutant', 'Var', (118, 124))	('AP-1', 'cellular_component', 'GO:0005907', ('70', '74'))
78654	23177739	4A, upper panel) impaired the ability to stimulate AP-1 by Sy-Rq, which was rescued by the co-transfection of expression vectors for the dTrio Cterminal region that includes its two GEF domains (Fig.	('expression vectors', 'Species', '29278', (110, 128))	('Sy-Rq', 'Var', (59, 64))	('dTrio', 'Gene', '43974', (137, 142))	('dTrio', 'Gene', (137, 142))	('impaired', 'NegReg', (17, 25))	('Sy-Rq', 'Chemical', '-', (59, 64))	('GEF', 'molecular_function', 'GO:0005085', ('182', '185'))	('AP-1', 'cellular_component', 'GO:0005907', ('51', '55'))	('stimulate', 'PosReg', (41, 50))	('AP-1', 'MPA', (51, 55))
78655	23177739	Cells in which Trio was knocked down retained their ability to activate PLC (Fig.	('Trio', 'Gene', (15, 19))	('PLC', 'cellular_component', 'GO:0042824', ('72', '75'))	('activate', 'PosReg', (63, 71))	('knocked down', 'Var', (24, 36))	('PLC', 'Gene', (72, 75))	('PLC', 'Gene', '31376', (72, 75))
78662	23177739	Furthermore, both Rac1 and RhoA knockdown impaired the ability to activate AP-1 in response to CNO, without affecting PLC activation (Fig.	('PLC', 'cellular_component', 'GO:0042824', ('118', '121'))	('PLC', 'Gene', '31376', (118, 121))	('CNO', 'Gene', '55330', (95, 98))	('AP-1', 'Gene', (75, 79))	('CNO', 'Gene', (95, 98))	('knockdown', 'Var', (32, 41))	('activate', 'MPA', (66, 74))	('AP-1', 'cellular_component', 'GO:0005907', ('75', '79'))	('PLC', 'Gene', (118, 121))	('ability', 'MPA', (55, 62))	('impaired', 'NegReg', (42, 50))
78664	23177739	Trio knock down did not affect the activation of JNK, p38, and ERK in response to serum (Fig.	('p38', 'Gene', '5594', (54, 57))	('ERK', 'molecular_function', 'GO:0004707', ('63', '66'))	('p38', 'Gene', (54, 57))	('knock down', 'Var', (5, 15))	('JNK', 'molecular_function', 'GO:0004705', ('49', '52'))	('ERK', 'Gene', '5594', (63, 66))	('ERK', 'Gene', (63, 66))
78667	23177739	This reduced JNK and p38 activation by Sy-Rq was reflected at the level of c-jun and c-fos mRNA expression (Fig.	('Sy-Rq', 'Chemical', '-', (39, 44))	('expression', 'Species', '29278', (96, 106))	('p38', 'Gene', '5594', (21, 24))	('c-jun', 'MPA', (75, 80))	('fos', 'Gene', (87, 90))	('JNK', 'molecular_function', 'GO:0004705', ('13', '16'))	('Sy-Rq', 'Var', (39, 44))	('fos', 'Gene', '2353', (87, 90))	('reduced', 'NegReg', (5, 12))	('activation', 'PosReg', (25, 35))	('JNK', 'MPA', (13, 16))	('p38', 'Gene', (21, 24))
78671	23177739	In this regard, we observed that active mutants of Galphaq can form stable molecular complexes with Trio (Fig S4C), and that the activation of Sy-Rq leads to a progressive accumulation of a GFP-tagged form of mammalian Trio at the level of the plasma membrane (Fig.	('Galphaq', 'Gene', (51, 58))	('Sy-Rq', 'Gene', (143, 148))	('GFP-tagged form', 'MPA', (190, 205))	('mutants', 'Var', (40, 47))	('accumulation', 'PosReg', (172, 184))	('Sy-Rq', 'Chemical', '-', (143, 148))	('mammalian', 'Species', '9606', (209, 218))	('plasma membrane', 'cellular_component', 'GO:0005886', ('244', '259'))
78677	23177739	S5A), and Trio knockdown diminished the ability of the cells to proliferate in response to GRP without affecting PLC (Fig.	('PLC', 'Gene', '31376', (113, 116))	('knockdown', 'Var', (15, 24))	('PLC', 'cellular_component', 'GO:0042824', ('113', '116'))	('diminished', 'NegReg', (25, 35))	('PLC', 'Gene', (113, 116))
78683	23177739	6B and S5G), respectively, both of which are able to generate tumors in animal models.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('S5G', 'Var', (7, 10))
78685	23177739	Both Trio Rho- and Rac-GEF regions are required for nuclear signaling through Gq, as a wild type human Trio but not Trio mutants harboring mutations in their individual GEF1 and GEF2 domains were able to rescue AP-1 activation after Trio knock down in HeLa-Sy-Rq cells (Fig.	('AP-1', 'Gene', (211, 215))	('activation', 'PosReg', (216, 226))	('GEF', 'molecular_function', 'GO:0005085', ('178', '181'))	('mutations', 'Var', (139, 148))	('Rac', 'Gene', '207', (19, 22))	('rescue', 'PosReg', (204, 210))	('Gq', 'Gene', '36384', (78, 80))	('mutants', 'Var', (121, 128))	('human', 'Species', '9606', (97, 102))	('knock down', 'Var', (238, 248))	('GEF1', 'Gene', '9138', (169, 173))	('HeLa-Sy-Rq', 'CellLine', 'CVCL:0030', (252, 262))	('GEF', 'molecular_function', 'GO:0005085', ('169', '172'))	('AP-1', 'cellular_component', 'GO:0005907', ('211', '215'))	('Rac', 'Gene', (19, 22))	('GEF1', 'Gene', (169, 173))	('GEF', 'molecular_function', 'GO:0005085', ('23', '26'))	('signaling', 'biological_process', 'GO:0023052', ('60', '69'))
78688	23177739	Furthermore, Trio deficiency resulted in the dramatic reduced growth of HeLa (Fig.	('HeLa', 'CellLine', 'CVCL:0030', (72, 76))	('HeLa', 'Protein', (72, 76))	('reduced', 'NegReg', (54, 61))	('growth', 'MPA', (62, 68))	('deficiency', 'Var', (18, 28))
78693	23177739	These mutated forms, collectively known as the GNAQ oncogene, result in the activation of ERK in the absence of mutations in the B-RAF or N-RAS oncogenes, which are frequently mutated in cutaneous melanomas.	('ERK', 'Gene', (90, 93))	('N-RAS', 'Gene', '4893', (138, 143))	('B-RAF', 'Gene', '673', (129, 134))	('B-RAF', 'Gene', (129, 134))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('melanomas', 'Phenotype', 'HP:0002861', (197, 206))	('GNAQ', 'Gene', (47, 51))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (187, 206))	('ERK', 'Gene', '5594', (90, 93))	('ERK', 'molecular_function', 'GO:0004707', ('90', '93'))	('activation', 'PosReg', (76, 86))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (187, 206))	('GNAQ', 'Gene', '2776', (47, 51))	('cutaneous melanomas', 'Disease', (187, 206))	('N-RAS', 'Gene', (138, 143))	('mutated', 'Var', (6, 13))
78694	23177739	Indeed, knock down of Galphaq in cell lines derived from primary or metastatic uveal melanomas resulted in decreased ERK activation and reduced DNA-synthesis (Fig.	('uveal melanomas', 'Disease', 'MESH:C536494', (79, 94))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))	('ERK', 'Gene', (117, 120))	('activation', 'MPA', (121, 131))	('decreased ERK', 'Phenotype', 'HP:0000654', (107, 120))	('knock down', 'Var', (8, 18))	('decreased', 'NegReg', (107, 116))	('uveal melanomas', 'Disease', (79, 94))	('uveal melanomas', 'Phenotype', 'HP:0007716', (79, 94))	('DNA-synthesis', 'biological_process', 'GO:0071897', ('144', '157'))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('reduced', 'NegReg', (136, 143))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('Galphaq', 'Gene', (22, 29))	('ERK', 'molecular_function', 'GO:0004707', ('117', '120'))	('DNA-synthesis', 'MPA', (144, 157))	('ERK', 'Gene', '5594', (117, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))
78696	23177739	6H and S5J) both of which harbor GNAQ mutations.	('GNAQ', 'Gene', '2776', (33, 37))	('mutations', 'Var', (38, 47))	('GNAQ', 'Gene', (33, 37))
78697	23177739	In both cases, however, knock down of active Galphaq decreased JNK and p38 activity, and these effects were phenocopied by Trio knock down (Fig.	('JNK', 'molecular_function', 'GO:0004705', ('63', '66'))	('JNK', 'MPA', (63, 66))	('p38', 'Gene', '5594', (71, 74))	('Galphaq', 'Protein', (45, 52))	('p38', 'Gene', (71, 74))	('activity', 'MPA', (75, 83))	('decreased', 'NegReg', (53, 62))	('knock down', 'Var', (24, 34))
78698	23177739	Furthermore, Trio knock down diminished AP-1 activation and the aberrant proliferation and tumorigenicity of uveal melanoma cells, without affecting PLC activation or p-ERK levels (Fig.	('ERK', 'Gene', '5594', (169, 172))	('knock down', 'Var', (18, 28))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('PLC', 'cellular_component', 'GO:0042824', ('149', '152'))	('tumor', 'Disease', (91, 96))	('ERK', 'Gene', (169, 172))	('ERK', 'molecular_function', 'GO:0004707', ('169', '172'))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('activation', 'MPA', (45, 55))	('AP-1', 'cellular_component', 'GO:0005907', ('40', '44'))	('PLC', 'Gene', '31376', (149, 152))	('PLC', 'Gene', (149, 152))	('aberrant', 'CPA', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('diminished', 'NegReg', (29, 39))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('uveal melanoma', 'Disease', 'MESH:C536494', (109, 123))	('uveal melanoma', 'Disease', (109, 123))	('AP-1', 'Protein', (40, 44))
78706	23177739	IP3 raises cytoplasmic Ca2+ levels, which stimulates multiple calcium-regulated pathways and together with DAG, activates classic PKC isoforms.	('cytoplasmic Ca2+ levels', 'MPA', (11, 34))	('classic PKC isoforms', 'Enzyme', (122, 142))	('stimulates', 'PosReg', (42, 52))	('activates', 'PosReg', (112, 121))	('calcium-regulated pathways', 'Pathway', (62, 88))	('IP3', 'Chemical', 'MESH:D015544', (0, 3))	('DAG', 'Chemical', 'MESH:D004075', (107, 110))	('Ca2+', 'Chemical', 'MESH:D000069285', (23, 27))	('raises', 'PosReg', (4, 10))	('calcium', 'Chemical', 'MESH:D002118', (62, 69))	('PKC', 'molecular_function', 'GO:0004697', ('130', '133'))	('IP3', 'Var', (0, 3))
78711	23177739	Activation of PLC by tyrosine kinase receptors that stimulate PLC-gamma potently, plays similarly only a partial role in cell growth promotion, while mutant tryrosine kinase receptors that specifically stimulate PLC but no other downstream targets are not effective in promoting cell growth.	('cell growth promotion', 'CPA', (121, 142))	('PLC', 'Gene', (212, 215))	('PLC', 'Gene', (62, 65))	('PLC', 'cellular_component', 'GO:0042824', ('212', '215'))	('PLC', 'cellular_component', 'GO:0042824', ('62', '65'))	('PLC', 'Gene', '31376', (212, 215))	('PLC', 'Gene', '31376', (62, 65))	('PLC', 'Gene', (14, 17))	('PLC', 'Gene', '31376', (14, 17))	('cell growth', 'biological_process', 'GO:0016049', ('121', '132'))	('stimulate', 'PosReg', (52, 61))	('cell growth', 'biological_process', 'GO:0016049', ('279', '290'))	('mutant', 'Var', (150, 156))	('PLC', 'cellular_component', 'GO:0042824', ('14', '17'))
78720	23177739	dTrio knockdown did not affect PLC activation, but it abolished the stimulation of AP-1 by Gq-GPCRs, which was fully rescued when re-expressing the C-terminal region of dTrio as long as both GEF1 and GEF2 domains of dTrio remained intact, each acting in an additive manner.	('GEF', 'molecular_function', 'GO:0005085', ('191', '194'))	('Gq', 'Gene', '36384', (91, 93))	('dTrio', 'Gene', '43974', (0, 5))	('dTrio', 'Gene', (216, 221))	('stimulation', 'MPA', (68, 79))	('AP-1', 'cellular_component', 'GO:0005907', ('83', '87'))	('GPCR', 'Gene', (94, 98))	('dTrio', 'Gene', (169, 174))	('dTrio', 'Gene', (0, 5))	('GEF1', 'Gene', '9138', (191, 195))	('PLC', 'Gene', '31376', (31, 34))	('abolished', 'NegReg', (54, 63))	('PLC', 'cellular_component', 'GO:0042824', ('31', '34'))	('GPCR', 'Gene', '441931', (94, 98))	('PLC', 'Gene', (31, 34))	('GEF1', 'Gene', (191, 195))	('AP-1', 'MPA', (83, 87))	('dTrio', 'Gene', '43974', (216, 221))	('GEF', 'molecular_function', 'GO:0005085', ('200', '203'))	('knockdown', 'Var', (6, 15))	('dTrio', 'Gene', '43974', (169, 174))
78726	23177739	Indeed, knock down of Trio abolished the ability of GPCRs acting on Galphaq to stimulate RhoA in fibroblasts and multiple cancer cells.	('abolished', 'NegReg', (27, 36))	('cancer', 'Disease', (122, 128))	('knock down', 'Var', (8, 18))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('RhoA in fibroblasts', 'CPA', (89, 108))	('stimulate', 'PosReg', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('GPCR', 'Gene', '441931', (52, 56))	('GPCR', 'Gene', (52, 56))
78732	23177739	Using cervical and oral squamous carcinoma cells as an example of Trio overexpressing cancers, we observed that Trio knock down prevents the proliferative response to mitogens acting on endogenous GPCRs.	('knock down', 'Var', (117, 127))	('squamous carcinoma', 'Disease', 'MESH:D002294', (24, 42))	('squamous carcinoma', 'Disease', (24, 42))	('GPCR', 'Gene', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('proliferative response to mitogens', 'MPA', (141, 175))	('GPCR', 'Gene', '441931', (197, 201))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (24, 42))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('prevents', 'NegReg', (128, 136))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
78733	23177739	In fact, Trio knock down converted the pro-proliferative effect of GRP and endothelin, both stimulating Gq-GPCRs, into growth inhibitory.	('GPCR', 'Gene', '441931', (107, 111))	('stimulating', 'PosReg', (92, 103))	('knock down', 'Var', (14, 24))	('pro-proliferative effect', 'MPA', (39, 63))	('endothelin', 'Protein', (75, 85))	('Gq', 'Gene', '36384', (104, 106))	('GPCR', 'Gene', (107, 111))	('GRP', 'Protein', (67, 70))
78734	23177739	Thus, de-regulated Trio may mediate the growth promoting function of GPCRs acting on Gq in cancer cells.	('growth', 'MPA', (40, 46))	('de-regulated', 'Var', (6, 18))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Gq', 'Gene', '36384', (85, 87))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('GPCR', 'Gene', (69, 73))	('GPCR', 'Gene', '441931', (69, 73))
78739	23177739	However, this effect is likely fast and transient due to structural features in PLC-beta limiting the duration of signal transmission through this PLC family.	('limiting', 'NegReg', (89, 97))	('PLC', 'Gene', (147, 150))	('structural features', 'Var', (57, 76))	('PLC', 'Gene', '31376', (147, 150))	('signal transmission', 'biological_process', 'GO:0023060', ('114', '133'))	('PLC', 'cellular_component', 'GO:0042824', ('147', '150'))	('PLC', 'cellular_component', 'GO:0042824', ('80', '83'))	('duration of signal transmission', 'MPA', (102, 133))	('PLC', 'Gene', (80, 83))	('PLC', 'Gene', '31376', (80, 83))
78743	23177739	These observations also raise the possibility that targeting the Galphaq-Trio interaction or the GEF activities of Trio may represent a suitable therapeutic strategy to halt cancer growth in patients harboring activating mutations in Gq-GPCRs, GNAQ or GNA11, or Trio gene amplification, and in human malignancies involving the persistent activation of Gq-GPCRs in an autocrine and paracrine fashion.	('GNAQ', 'Gene', '2776', (244, 248))	('GNAQ', 'Gene', (244, 248))	('Gq', 'Gene', '36384', (234, 236))	('GPCR', 'Gene', (237, 241))	('GPCR', 'Gene', (355, 359))	('Gq', 'Gene', '36384', (352, 354))	('mutations', 'Var', (221, 230))	('GNA11', 'Gene', (252, 257))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('GPCR', 'Gene', '441931', (237, 241))	('GPCR', 'Gene', '441931', (355, 359))	('human', 'Species', '9606', (294, 299))	('malignancies', 'Disease', 'MESH:D009369', (300, 312))	('malignancies', 'Disease', (300, 312))	('halt', 'NegReg', (169, 173))	('patients', 'Species', '9606', (191, 199))	('activating', 'PosReg', (210, 220))	('GNA11', 'Gene', '2767', (252, 257))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('GEF', 'molecular_function', 'GO:0005085', ('97', '100'))
78744	23177739	Human cancers harbor frequent mutations in Gq-linked GPCRs and Galphaq subunits A genome-wide RNAi screen revealed that Trio is essential to activate AP-1 by Galphaq A network of Trio-regulated Rho GTPases and MAPKs links Gq to the nucleus A hardwired Gq-Trio signaling axis promotes the growth of many human malignancies	('Human', 'Species', '9606', (0, 5))	('Gq', 'Gene', '36384', (43, 45))	('MAPK', 'Gene', (210, 214))	('promotes', 'PosReg', (275, 283))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('MAPK', 'Gene', '5594', (210, 214))	('malignancies', 'Disease', 'MESH:D009369', (309, 321))	('GPCR', 'Gene', (53, 57))	('malignancies', 'Disease', (309, 321))	('human', 'Species', '9606', (303, 308))	('nucleus', 'cellular_component', 'GO:0005634', ('232', '239'))	('growth', 'MPA', (288, 294))	('Gq', 'Gene', '36384', (222, 224))	('RNAi', 'biological_process', 'GO:0016246', ('94', '98'))	('GPCR', 'Gene', '441931', (53, 57))	('AP-1', 'Gene', (150, 154))	('mutations', 'Var', (30, 39))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('GTP', 'Chemical', 'MESH:D006160', (198, 201))	('signaling', 'biological_process', 'GO:0023052', ('260', '269'))	('Gq', 'Gene', '36384', (252, 254))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('AP-1', 'cellular_component', 'GO:0005907', ('150', '154'))
78820	23055575	PCR can determine monoclonality by immunoglobulin heavy chain (IGH) rearrangement and t(14; 18) translocation of the bcl-2 gene that promote cell survival and predict a more aggressive tumor course in B-cell lymphoma.	('immunoglobulin', 'molecular_function', 'GO:0003823', ('35', '49'))	('lymphoma', 'Phenotype', 'HP:0002665', (208, 216))	('cell lymphoma', 'Phenotype', 'HP:0012191', (203, 216))	('rearrangement', 'Var', (68, 81))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (201, 216))	('bcl-2', 'Gene', (117, 122))	('aggressive tumor', 'Disease', 'MESH:D001523', (174, 190))	('promote', 'PosReg', (133, 140))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (201, 216))	('bcl-2', 'molecular_function', 'GO:0015283', ('117', '122'))	('IGH', 'Gene', '3495', (63, 66))	('immunoglobulin heavy chain', 'Gene', '3495', (35, 61))	('bcl-2', 'Gene', '596', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('aggressive tumor', 'Disease', (174, 190))	('immunoglobulin heavy chain', 'Gene', (35, 61))	('B-cell lymphoma', 'Disease', (201, 216))	('cell survival', 'CPA', (141, 154))	('IGH', 'Gene', (63, 66))
78821	23055575	PCR has been found to be 64% sensitive for PVRL, and is being used to study the genotypic classification of PVRL with the goal of identifying prognostic factors; patients with a translocation in the bcl-2 gene are significantly younger than patients who lacked the translocation, suggesting that younger patients with the translocation may need to be treated aggressively.	('patients', 'Species', '9606', (162, 170))	('bcl-2', 'Gene', (199, 204))	('translocation', 'Var', (178, 191))	('patients', 'Species', '9606', (304, 312))	('PVRL', 'Phenotype', 'HP:0030069', (43, 47))	('bcl-2', 'molecular_function', 'GO:0015283', ('199', '204'))	('PVRL', 'Phenotype', 'HP:0030069', (108, 112))	('bcl-2', 'Gene', '596', (199, 204))	('patients', 'Species', '9606', (241, 249))
78908	14612910	Role of MC1R variants in uveal melanoma Uveal melanoma although rare is the most common primary intraocular malignancy in adults with an incidence of six per million per year (Parkin et al, 1992).	('variants', 'Var', (13, 21))	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('uveal melanoma', 'Disease', (25, 39))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('intraocular malignancy', 'Disease', 'MESH:C563596', (96, 118))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('MC1R', 'Gene', '4157', (8, 12))	('intraocular malignancy', 'Disease', (96, 118))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('uveal melanoma', 'Disease', 'MESH:C536494', (25, 39))	('MC1R', 'Gene', (8, 12))
78921	14612910	Several point mutations in MC1R affecting function have been identified, for example, V60L, R151C, R160W, D294H, some of which have been reported to be over-represented in individuals with fair hair and skin (Valverde et al, 1995; Flanagan et al, 2000; Box et al, 2001a,2001b).	('affecting', 'Reg', (32, 41))	('R160W', 'Mutation', 'rs1805008', (99, 104))	('R151C', 'Var', (92, 97))	('R160W', 'Var', (99, 104))	('D294H', 'Mutation', 'rs1805009', (106, 111))	('MC1R', 'Gene', (27, 31))	('MC1R', 'Gene', '4157', (27, 31))	('function', 'MPA', (42, 50))	('V60L', 'Var', (86, 90))	('fair hair', 'Phenotype', 'HP:0002286', (189, 198))	('R151C', 'Mutation', 'rs1805007', (92, 97))	('D294H', 'Var', (106, 111))	('V60L', 'Mutation', 'rs1805005', (86, 90))
78922	14612910	In addition to acting as determinates of pigmentation, some variants may confer an increased risk of cutaneous melanoma (Valverde et al, 1996; Healy et al, 1999; Palmer et al, 2000).	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('cutaneous melanoma', 'Disease', (101, 119))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (101, 119))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (101, 119))	('pigmentation', 'biological_process', 'GO:0043473', ('41', '53'))	('variants', 'Var', (60, 68))
78924	14612910	We have assessed the risk of uveal melanoma associated with germline MC1R variants through sequence analysis of 350 patients and a series of 133 population controls.	('MC1R', 'Gene', '4157', (69, 73))	('patients', 'Species', '9606', (116, 124))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('MC1R', 'Gene', (69, 73))	('variants', 'Var', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))
78945	14612910	Eight variants were detected - V60L, D84E, V92M, R151C, I155T, R160W, R163Q, D294H - among the patients and controls studied (Table 1  ).	('R163Q', 'Mutation', 'rs885479', (70, 75))	('D294H', 'Mutation', 'rs1805009', (77, 82))	('patients', 'Species', '9606', (95, 103))	('R160W', 'Mutation', 'rs1805008', (63, 68))	('D84E', 'Var', (37, 41))	('R151C', 'Mutation', 'rs1805007', (49, 54))	('I155T', 'Var', (56, 61))	('V60L', 'Var', (31, 35))	('R160W', 'Var', (63, 68))	('V92M', 'Var', (43, 47))	('R163Q', 'Var', (70, 75))	('I155T', 'Mutation', 'rs1110400', (56, 61))	('R151C', 'Var', (49, 54))	('D84E', 'Mutation', 'rs1805006', (37, 41))	('D294H -', 'Var', (77, 84))	('V92M', 'Mutation', 'rs2228479', (43, 47))	('V60L', 'Mutation', 'rs1805005', (31, 35))
78946	14612910	The frequencies of combinations of MC1R variants did not differ from expected observed allele frequencies (data not shown).	('variants', 'Var', (40, 48))	('MC1R', 'Gene', '4157', (35, 39))	('MC1R', 'Gene', (35, 39))
78947	14612910	Hence, the MC1R variants can be considered as independent variants and consequently were analysed as such.	('MC1R', 'Gene', (11, 15))	('variants', 'Var', (16, 24))	('MC1R', 'Gene', '4157', (11, 15))
78948	14612910	The frequencies of the MC1R variants that have been reported in 190 UK population controls - D84E (3.5%), V92M (17.3%) and D294H (6.8%) (Ichii-Jones et al, 1998) - are not statically different from that observed in the cases and controls in our study.	('MC1R', 'Gene', (23, 27))	('D294H', 'Var', (123, 128))	('D84E', 'Var', (93, 97))	('Ichii', 'Species', '99806', (137, 142))	('D84E', 'Mutation', 'rs1805006', (93, 97))	('D294H', 'Mutation', 'rs1805009', (123, 128))	('V92M', 'Var', (106, 110))	('MC1R', 'Gene', '4157', (23, 27))	('V92M', 'Mutation', 'rs2228479', (106, 110))
78949	14612910	In addition, the frequencies of the V60L, D84E, R151C, R160W and D294H variants are not statistically different from the frequencies previously documented in the 738 individuals of Northern European ancestry reported by Vajdic et al (2003) (23.2, 2.8, 20.6, 15.6 and 6.0%, respectively).	('R151C', 'Mutation', 'rs1805007', (48, 53))	('D294H', 'Var', (65, 70))	('V60L', 'Mutation', 'rs1805005', (36, 40))	('D84E', 'Mutation', 'rs1805006', (42, 46))	('D294H', 'Mutation', 'rs1805009', (65, 70))	('R160W', 'Mutation', 'rs1805008', (55, 60))	('V60L', 'Var', (36, 40))	('R151C', 'Var', (48, 53))	('R160W', 'Var', (55, 60))	('D84E', 'Var', (42, 46))
78951	14612910	The relationship between these three phenotypes and MC1R variation is detailed in Table 2  .	('variation', 'Var', (57, 66))	('MC1R', 'Gene', '4157', (52, 56))	('MC1R', 'Gene', (52, 56))
78952	14612910	No significant association was seen between possession of one or more MC1R variants and eye colour (P=0.46).	('MC1R', 'Gene', '4157', (70, 74))	('MC1R', 'Gene', (70, 74))	('variants', 'Var', (75, 83))	('eye colour', 'Disease', (88, 98))
78953	14612910	Similarly, no significant relationship was seen between skin type and possession of a MC1R variant (P=0.29) or naevus count (P=0.45).	('MC1R', 'Gene', (86, 90))	('naevus', 'Phenotype', 'HP:0003764', (111, 117))	('MC1R', 'Gene', '4157', (86, 90))	('variant', 'Var', (91, 98))
78954	14612910	There was, however, an association between MC1R status and hair colour with an over-representation of variants in individuals with light or red hair (P=0.03).	('MC1R', 'Gene', (43, 47))	('over-representation', 'PosReg', (79, 98))	('association', 'Interaction', (23, 34))	('variants', 'Var', (102, 110))	('red hair', 'Disease', (140, 148))	('MC1R', 'Gene', '4157', (43, 47))	('red hair', 'Phenotype', 'HP:0002297', (140, 148))	('red hair', 'Disease', 'MESH:C567091', (140, 148))
78955	14612910	The frequency of each of the MC1R variants in the 350 patients was not statistically different from that observed in the controls.	('patients', 'Species', '9606', (54, 62))	('MC1R', 'Gene', (29, 33))	('variants', 'Var', (34, 42))	('MC1R', 'Gene', '4157', (29, 33))
78956	14612910	Of the 350 patients studied, 129 (36.9%) had no MC1R variants, 154 (44.0%) had one MC1R variant and 67 (19.1%) possessed two or more variants.	('MC1R', 'Gene', '4157', (83, 87))	('MC1R', 'Gene', '4157', (48, 52))	('MC1R', 'Gene', (48, 52))	('MC1R', 'Gene', (83, 87))	('patients', 'Species', '9606', (11, 19))	('variants', 'Var', (53, 61))
78957	14612910	The mean ages at diagnosis in noncarriers and carriers of one and two or more of MC1R variants in our study were not significantly different - 57.9, s.d.	('MC1R', 'Gene', '4157', (81, 85))	('MC1R', 'Gene', (81, 85))	('variants', 'Var', (86, 94))
78958	14612910	Two research groups have previously reported on the relationship between MC1R variants and risk of uveal melanoma - Metzelaar-Blok et al (2001) based on analysis of 162 patients and Vajdic et al (2003) based on analysis of 62 patients.	('patients', 'Species', '9606', (169, 177))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('MC1R', 'Gene', '4157', (73, 77))	('MC1R', 'Gene', (73, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('uveal melanoma', 'Disease', 'MESH:C536494', (99, 113))	('patients', 'Species', '9606', (226, 234))	('uveal melanoma', 'Disease', (99, 113))	('variants', 'Var', (78, 86))
78959	14612910	Also shown are pooled estimates of the risk of uveal melanoma based on all studies for individual variants and one, two or more and any MC1R variant.	('MC1R', 'Gene', '4157', (136, 140))	('MC1R', 'Gene', (136, 140))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('uveal melanoma', 'Disease', (47, 61))	('variant', 'Var', (141, 148))	('variants', 'Var', (98, 106))
78961	14612910	We performed this study to determine whether germline MC1R variants confer an increased risk of uveal melanoma.	('uveal melanoma', 'Disease', (96, 110))	('variants', 'Var', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('MC1R', 'Gene', '4157', (54, 58))	('MC1R', 'Gene', (54, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('uveal melanoma', 'Disease', 'MESH:C536494', (96, 110))
78963	14612910	The frequency of MC1R variants detected in patients in our study was not significantly different from the frequencies in the general population, and were very similar to estimates obtained in unselected North-European populations.	('patients', 'Species', '9606', (43, 51))	('MC1R', 'Gene', '4157', (17, 21))	('variants', 'Var', (22, 30))	('MC1R', 'Gene', (17, 21))
78964	14612910	Furthermore, we found that the age at diagnosis of uveal melanoma in carriers of MC1R variants was not significantly different from noncarriers.	('uveal melanoma', 'Phenotype', 'HP:0007716', (51, 65))	('uveal melanoma', 'Disease', (51, 65))	('MC1R', 'Gene', (81, 85))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('variants', 'Var', (86, 94))	('MC1R', 'Gene', '4157', (81, 85))	('carriers', 'Reg', (69, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (51, 65))
78965	14612910	These findings imply that MC1R variants are unlikely to confer an increased risk of uveal melanoma.	('MC1R', 'Gene', (26, 30))	('variants', 'Var', (31, 39))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma', 'Disease', (84, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('MC1R', 'Gene', '4157', (26, 30))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
78966	14612910	The main strengths of our study are the large number of patients in our sample and correlation of MC1R variants with age at diagnosis, a factor that has not previously been investigated.	('patients', 'Species', '9606', (56, 64))	('variants', 'Var', (103, 111))	('correlation', 'Interaction', (83, 94))	('MC1R', 'Gene', '4157', (98, 102))	('MC1R', 'Gene', (98, 102))
78967	14612910	In our study, we detected eight MC1R variants: V60L, D84E V92M, R151C, I155T, R160H, R163Q and D294H.	('R151C', 'Mutation', 'rs1805007', (64, 69))	('R160H', 'Var', (78, 83))	('R163Q', 'Var', (85, 90))	('V92M', 'SUBSTITUTION', 'None', (58, 62))	('V60L', 'Mutation', 'rs1805005', (47, 51))	('D294H', 'Mutation', 'rs1805009', (95, 100))	('R151C', 'Var', (64, 69))	('D84E', 'Var', (53, 57))	('D84E', 'SUBSTITUTION', 'None', (53, 57))	('D294H', 'Var', (95, 100))	('MC1R', 'Gene', '4157', (32, 36))	('R160H', 'Mutation', 'p.R160H', (78, 83))	('R163Q', 'Mutation', 'rs885479', (85, 90))	('V60L', 'Var', (47, 51))	('MC1R', 'Gene', (32, 36))	('I155T', 'Var', (71, 76))	('I155T', 'Mutation', 'rs1110400', (71, 76))	('V92M', 'Var', (58, 62))
78968	14612910	Previous studies have demonstrated a relationship between MC1R variants and hair and skin type, notably a strong association between the R151C, R160Q and R294H variants, with fair skin and red hair (Valverde et al, 1995; Palmer et al, 2000; Bastiaens et al, 2001).	('red hair', 'Disease', (189, 197))	('red hair', 'Phenotype', 'HP:0002297', (189, 197))	('R151C', 'Mutation', 'rs1805007', (137, 142))	('red hair', 'Disease', 'MESH:C567091', (189, 197))	('MC1R', 'Gene', '4157', (58, 62))	('R160Q', 'Var', (144, 149))	('R160Q', 'Mutation', 'rs780813746', (144, 149))	('R294H', 'Var', (154, 159))	('MC1R', 'Gene', (58, 62))	('R151C', 'Var', (137, 142))	('fair skin', 'Phenotype', 'HP:0007513', (175, 184))	('fair skin', 'Disease', (175, 184))	('R294H', 'Mutation', 'p.R294H', (154, 159))
78969	14612910	Collectively, the MC1R variants we detected were over-represented in the patients with light skin and red or fair hair, in keeping with these previous observations.	('light skin', 'Phenotype', 'HP:0001010', (87, 97))	('fair hair', 'Phenotype', 'HP:0002286', (109, 118))	('over-represented', 'PosReg', (49, 65))	('MC1R', 'Gene', '4157', (18, 22))	('MC1R', 'Gene', (18, 22))	('variants', 'Var', (23, 31))	('patients', 'Species', '9606', (73, 81))
78971	14612910	Most, but not all, previous studies have shown that MC1R variants are associated with an increased risk of both cutaneous melanoma (Valverde et al, 1996; Palmer et al, 2000) and nonmelanoma skin cancers (Box et al, 2001a,2001b).	('nonmelanoma skin cancers', 'Disease', (178, 202))	('skin cancers', 'Phenotype', 'HP:0008069', (190, 202))	('nonmelanoma skin cancers', 'Disease', 'MESH:D012878', (178, 202))	('MC1R', 'Gene', '4157', (52, 56))	('MC1R', 'Gene', (52, 56))	('cutaneous melanoma', 'Disease', (112, 130))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('variants', 'Var', (57, 65))	('skin cancer', 'Phenotype', 'HP:0008069', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
78972	14612910	This suggests that certain MC1R variants can exert an effect on melanoma tumorigenesis in a dual manner, both as a determinant of fair skin and as a component in an independent additional pathway (Palmer et al, 2000; Van der Velden et al, 2001).	('MC1R', 'Gene', '4157', (27, 31))	('MC1R', 'Gene', (27, 31))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('variants', 'Var', (32, 40))	('effect', 'Reg', (54, 60))	('fair skin', 'Phenotype', 'HP:0007513', (130, 139))
78973	14612910	Our data support the findings of Metzelaar-Blok et al (2001) and the recent study reported by Vajdic et al (2003), who found no relationship between variation in MC1R and risk of uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (179, 193))	('MC1R', 'Gene', '4157', (162, 166))	('MC1R', 'Gene', (162, 166))	('variation', 'Var', (149, 158))	('uveal melanoma', 'Phenotype', 'HP:0007716', (179, 193))	('uveal melanoma', 'Disease', (179, 193))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))
78974	14612910	Moreover, pooling data from all three studies provide no evidence that variants confer an increased risk of uveal melanoma.	('variants', 'Var', (71, 79))	('uveal melanoma', 'Disease', 'MESH:C536494', (108, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('uveal melanoma', 'Disease', (108, 122))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
78981	14612910	Moreover, differences in the relative importance of aetiological factors between the two tumour types are reflected at the molecular level - activating mutations of BRAF are almost universal in cutaneous melanomas but not in uveal tumours (Davies et al, 2002; Cohen et al, 2003; Edmunds et al, 2003).	('mutations', 'Var', (152, 161))	('cutaneous melanomas', 'Disease', (194, 213))	('melanomas', 'Phenotype', 'HP:0002861', (204, 213))	('BRAF', 'Gene', '673', (165, 169))	('activating', 'PosReg', (141, 151))	('BRAF', 'Gene', (165, 169))	('tumours', 'Phenotype', 'HP:0002664', (231, 238))	('uveal tumours', 'Disease', 'MESH:D014604', (225, 238))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (194, 212))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))	('tumour', 'Disease', 'MESH:D009369', (231, 237))	('uveal tumours', 'Disease', (225, 238))	('tumour', 'Disease', (231, 237))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (194, 213))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (194, 213))
79091	33342197	This problem is overcome by excluding Tis from metastasis analyses, which made it possible to purely study the effects of thickness and ulceration, as Tis lesions are not expected to cause distant metastases or death.	('death', 'Disease', (211, 216))	('metastases', 'Disease', (197, 207))	('lesions', 'Var', (155, 162))	('cause', 'Reg', (183, 188))	('metastases', 'Disease', 'MESH:D009362', (197, 207))	('death', 'Disease', 'MESH:D003643', (211, 216))
79108	32085461	Among the main mechanisms used by mitochondria for the malignant transformation of cells, first, there is the production of ROS, which favors the accumulation of potential oncogenic defects in DNA, and the activation of probable oncogenic signaling pathways.	('mitochondria', 'cellular_component', 'GO:0005739', ('34', '46'))	('favors', 'PosReg', (135, 141))	('DNA', 'cellular_component', 'GO:0005574', ('193', '196'))	('ROS', 'Chemical', 'MESH:D017382', (124, 127))	('oncogenic signaling pathways', 'Pathway', (229, 257))	('signaling', 'biological_process', 'GO:0023052', ('239', '248'))	('accumulation', 'PosReg', (146, 158))	('ROS', 'Gene', (124, 127))	('activation', 'PosReg', (206, 216))	('defects', 'Var', (182, 189))
79115	32085461	HIG2A has a role in the respiratory supercomplexes assembly, a function that has been evidenced in the C2C12 mouse cell line, where the knockdown of Higd2a (nomenclature of mice gene) impaired supercomplex formation by the release of CIV.	('formation', 'biological_process', 'GO:0009058', ('206', '215'))	('supercomplex formation', 'MPA', (193, 215))	('impaired', 'NegReg', (184, 192))	('Higd2a', 'Gene', (149, 155))	('rat', 'Species', '10116', (29, 32))	('knockdown', 'Var', (136, 145))	('mice', 'Species', '10090', (173, 177))	('release', 'MPA', (223, 230))	('CIV', 'MPA', (234, 237))	('respiratory supercomplexes assembly', 'MPA', (24, 59))	('mouse', 'Species', '10090', (109, 114))
79116	32085461	Recently, we showed that the knockdown of HIGD2A (nomenclature of a human gene) decreases the activity of Complex I in the supercomplexes of HEK293 cells.	('human', 'Species', '9606', (68, 73))	('knockdown', 'Var', (29, 38))	('decreases', 'NegReg', (80, 89))	('activity', 'MPA', (94, 102))	('HIGD2A', 'Gene', (42, 48))	('Complex I', 'Enzyme', (106, 115))	('decreases the activity of Complex I', 'Phenotype', 'HP:0011923', (80, 115))	('supercomplexes', 'MPA', (123, 137))	('Complex I', 'cellular_component', 'GO:0030964', ('106', '115'))
79121	32085461	These studies evidenced several probable binding sites for different transcription factors related to cell cycle control, including E2F-1, E2F-2, E2F-3a, E2F-4, and E2F-5.	('E2F-4', 'Gene', '1874', (154, 159))	('binding', 'molecular_function', 'GO:0005488', ('41', '48'))	('E2F-4', 'Gene', (154, 159))	('transcription', 'biological_process', 'GO:0006351', ('69', '82'))	('E2F-5', 'Gene', (165, 170))	('binding', 'Interaction', (41, 48))	('E2F-3a', 'Var', (146, 152))	('cell cycle control', 'biological_process', 'GO:1901987', ('102', '120'))	('E2F-5', 'Gene', '1875', (165, 170))	('E2F-1, E2F-2', 'Gene', '1869;1870', (132, 144))
79129	32085461	Depletion of HIGD2A selectively impairs the viability of colon adenocarcinoma cells (DLD1), which are Ras mutant cells, suggesting a role of HIG2A in cell cycle regulation and a potential target in cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('viability', 'CPA', (44, 53))	('mutant', 'Var', (106, 112))	('cancer', 'Disease', (198, 204))	('colon adenocarcinoma', 'Disease', (57, 77))	('HIGD2A', 'Gene', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('Depletion', 'MPA', (0, 9))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (57, 77))	('impairs', 'NegReg', (32, 39))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('150', '171'))
79134	32085461	The microarray Illumina Human HT-12 V4.0 expression bead chips were used in the study; "Role of hypoxia in Diffuse Large B-cell Lymphoma: Metabolic repression and selective translation of HK2 facilitates development of DLBCL".	('facilitates', 'PosReg', (192, 203))	('B-cell Lymphoma', 'Disease', 'MESH:D016393', (121, 136))	('Lymphoma', 'Phenotype', 'HP:0002665', (128, 136))	('B-cell Lymphoma', 'Disease', (121, 136))	('Human', 'Species', '9606', (24, 29))	('selective translation', 'Var', (163, 184))	('HK2', 'Gene', (188, 191))	('HK2', 'Gene', '3099', (188, 191))	('hypoxia', 'Disease', (96, 103))	('hypoxia', 'Disease', 'MESH:D000860', (96, 103))	('DLBCL', 'Disease', (219, 224))	('development', 'CPA', (204, 215))	('B-cell Lymphoma', 'Phenotype', 'HP:0012191', (121, 136))
79164	32085461	The Catalogue of Somatic Mutations in Cancer (COSMIC) Cancer Gene Census (CGC) database indicates that the HIGD2A gene (COSG58129) has been reported as having mutations in 29 unique samples out of a total of 35183 samples; therefore, HIGD2A is not a known cancer-driving gene.	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('mutations', 'Var', (159, 168))	('cancer', 'Disease', (256, 262))	('Cancer', 'Disease', 'MESH:D009369', (54, 60))	('Cancer', 'Disease', (38, 44))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('HIGD2A', 'Gene', (107, 113))
79166	32085461	On the other hand, DNA methylation is a vital epigenetic mechanism that stabilizes gene expression and cellular states; their alteration has a role in tumor initiation and evolution.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor initiation', 'Disease', (151, 167))	('methylation', 'Var', (23, 34))	('alteration', 'Var', (126, 136))	('gene expression', 'biological_process', 'GO:0010467', ('83', '98'))	('role', 'Reg', (143, 147))	('rat', 'Species', '10116', (130, 133))	('DNA methylation', 'biological_process', 'GO:0006306', ('19', '34'))	('stabilizes gene expression', 'MPA', (72, 98))	('tumor initiation', 'Disease', 'MESH:D009369', (151, 167))	('cellular states', 'MPA', (103, 118))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
79191	32085461	The effect of HIGD2A high expression level on DLBCL patient survival illustrates a downward trend of survival probability in patients (n = 11) with high expression in relation with patients (n = 36) with low expression, p = 0.85 (Figure 8).	('HIGD2A', 'Gene', (14, 20))	('survival', 'MPA', (101, 109))	('patient', 'Species', '9606', (181, 188))	('rat', 'Species', '10116', (75, 78))	('downward', 'NegReg', (83, 91))	('patients', 'Species', '9606', (181, 189))	('patient', 'Species', '9606', (52, 59))	('patient', 'Species', '9606', (125, 132))	('high expression', 'Var', (148, 163))	('patients', 'Species', '9606', (125, 133))
79239	32085461	Roscovitine is an inhibitor of CDK that suppresses the proliferation of mammalian cells lines, and roscovitine induced a significant increase in HIGD2A gene expression in the human embryonic kidney HEK293 cell line.	('human', 'Species', '9606', (175, 180))	('embryonic kidney', 'Disease', (181, 197))	('mammalian', 'Species', '9606', (72, 81))	('expression', 'MPA', (157, 167))	('rat', 'Species', '10116', (62, 65))	('suppresses', 'NegReg', (40, 50))	('roscovitine', 'Var', (99, 110))	('embryonic kidney', 'Disease', 'MESH:D007674', (181, 197))	('CDK', 'molecular_function', 'GO:0004693', ('31', '34'))	('increase', 'PosReg', (133, 141))	('HIGD2A gene', 'Gene', (145, 156))	('Roscovitine', 'Chemical', 'MESH:D000077546', (0, 11))	('roscovitine', 'Chemical', 'MESH:D000077546', (99, 110))	('gene expression', 'biological_process', 'GO:0010467', ('152', '167'))
79284	30773789	Slope time: region size (P < 0.001) and TTP: region size ratios (P < 0.001) of ROI 1 and ROI 2 were significantly lower compared to ROI 3 and ROI 4, while both anterior uveal regions did not vary significantly to each other (P > 0.05).	('TTP', 'Gene', (40, 43))	('ROI', 'Var', (89, 92))	('lower', 'NegReg', (114, 119))	('ROI', 'Var', (79, 82))	('TTP', 'Gene', '7538', (40, 43))
79332	30262890	The emphasis has been on finding ligands that lead either to preferential activation of G proteins or to beta-arrestin binding by GPCRs.	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('arrestin', 'Gene', '20215', (110, 118))	('G proteins', 'Protein', (88, 98))	('activation', 'PosReg', (74, 84))	('arrestin', 'Gene', (110, 118))	('GPCRs', 'Var', (130, 135))	('preferential', 'PosReg', (61, 73))	('binding', 'Interaction', (119, 126))
79358	30262890	Ins(1,4,5)P3 causes the release of calcium into the cytoplasm and DAG activates protein kinase C (PKC); both of these pathways are ubiquitous regulators of cell physiology.	('activates', 'PosReg', (70, 79))	('cytoplasm', 'cellular_component', 'GO:0005737', ('52', '61'))	('cell physiology', 'biological_process', 'GO:0009987', ('156', '171'))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('PKC', 'molecular_function', 'GO:0004697', ('98', '101'))	('Ins(1,4,5)P3', 'Chemical', 'MESH:D015544', (0, 12))	('release of calcium into the cytoplasm', 'MPA', (24, 61))	('DAG', 'Chemical', 'MESH:D004075', (66, 69))	('Ins', 'Var', (0, 3))	('PKC', 'Gene', '5578;18754;18762', (98, 101))	('PKC', 'Gene', (98, 101))	('calcium', 'Chemical', 'MESH:D002118', (35, 42))
79359	30262890	Galphaq or Galpha11 regulation of PLCbeta and subsequent Ca2+ release are major drivers of cell function throughout the body.	('PLCbeta', 'Gene', '18795', (34, 41))	('Ca2+ release', 'MPA', (57, 69))	('PLCbeta', 'Gene', (34, 41))	('Galphaq', 'Var', (0, 7))	('regulation', 'biological_process', 'GO:0065007', ('20', '30'))	('Galpha11', 'Gene', (11, 19))	('Ca2+', 'Chemical', 'MESH:D000069285', (57, 61))
79399	30262890	QS3666 as an inhibitor of ADP-dependent platelet aggregation (FIG.	('platelet aggregation', 'biological_process', 'GO:0070527', ('40', '60'))	('QS3666', 'Chemical', '-', (0, 6))	('ADP', 'Chemical', 'MESH:D000244', (26, 29))	('QS3666', 'Var', (0, 6))	('platelet aggregation', 'Disease', 'MESH:D001791', (40, 60))	('platelet aggregation', 'Disease', (40, 60))	('platelet aggregation', 'Phenotype', 'HP:0003540', (40, 60))
79400	30262890	These and subsequent studies demonstrated that YM-254890 inhibits Galphaq/11 signalling downstream of multiple Galphaq-linked GPCRs in platelets and other native and heterologous systems without affecting other GPCR signalling pathways.	('signalling', 'biological_process', 'GO:0023052', ('77', '87'))	('YM-254890', 'Chemical', 'MESH:C475455', (47, 56))	('signalling', 'biological_process', 'GO:0023052', ('216', '226'))	('inhibits', 'NegReg', (57, 65))	('Galphaq/11', 'Pathway', (66, 76))	('YM-254890', 'Var', (47, 56))
79403	30262890	YM-254890 binds to a hinge between two independent domains of the Galpha subunit, the alpha-helical domain and the Ras-like domain, and GDP and GTP bind at the interface between the domains (FIG.	('GDP', 'Chemical', 'MESH:D006153', (136, 139))	('YM-254890', 'Var', (0, 9))	('GTP', 'Chemical', 'MESH:D006160', (144, 147))	('Galpha', 'Gene', '8802', (66, 72))	('Galpha', 'Gene', (66, 72))	('YM-254890', 'Chemical', 'MESH:C475455', (0, 9))
79405	30262890	Binding of YM-254890 at the hinge between these domains is predicted to prevent domain opening and thereby prevent GDP release and GTP binding, leading to G protein inhibition.	('GTP binding', 'molecular_function', 'GO:0005525', ('131', '142'))	('GTP binding', 'MPA', (131, 142))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('prevent', 'NegReg', (72, 79))	('G protein', 'Protein', (155, 164))	('YM-254890', 'Var', (11, 20))	('Binding', 'Var', (0, 7))	('GDP', 'Chemical', 'MESH:D006153', (115, 118))	('opening', 'Disease', 'MESH:D005597', (87, 94))	('GTP', 'Chemical', 'MESH:D006160', (131, 134))	('prevent', 'NegReg', (107, 114))	('inhibition', 'NegReg', (165, 175))	('opening', 'Disease', (87, 94))	('YM-254890', 'Chemical', 'MESH:C475455', (11, 20))	('GDP release', 'MPA', (115, 126))
79406	30262890	FR900359 is structurally very similar to YM-254890 and likely binds in a very similar mode.	('binds', 'Interaction', (62, 67))	('FR900359', 'Var', (0, 8))	('FR900359', 'Chemical', 'MESH:C000607068', (0, 8))	('YM-254890', 'Chemical', 'MESH:C475455', (41, 50))
79407	30262890	Indeed, FR900359 was demonstrated to be a potent inhibitor of GDP release in biochemical assays.	('GDP release', 'MPA', (62, 73))	('FR900359', 'Chemical', 'MESH:C000607068', (8, 16))	('GDP', 'Chemical', 'MESH:D006153', (62, 65))	('FR900359', 'Var', (8, 16))
79408	30262890	FR900359 has been extensively characterized in vitro to assess its specificity and efficacy for inhibition of Galphaq/11 -mediated signal transduction.	('Galphaq/11 -mediated signal transduction', 'MPA', (110, 150))	('FR900359', 'Var', (0, 8))	('FR900359', 'Chemical', 'MESH:C000607068', (0, 8))	('inhibition', 'NegReg', (96, 106))	('signal transduction', 'biological_process', 'GO:0007165', ('131', '150'))
79419	30262890	YM-254890 effectively and potently inhibited thrombus formation in a vascular carotid injury model in mice but also significantly increased bleeding time using the FeCl3 assay.	('FeCl3', 'Chemical', 'MESH:C024555', (164, 169))	('mice', 'Species', '10090', (102, 106))	('YM-254890', 'Var', (0, 9))	('vascular carotid injury', 'Disease', 'MESH:D057772', (69, 92))	('increased bleeding time', 'Phenotype', 'HP:0003010', (130, 153))	('thrombus', 'Disease', 'MESH:D013927', (45, 53))	('bleeding time', 'CPA', (140, 153))	('YM-254890', 'Chemical', 'MESH:C475455', (0, 9))	('inhibited', 'NegReg', (35, 44))	('formation', 'biological_process', 'GO:0009058', ('54', '63'))	('thrombus', 'Disease', (45, 53))	('vascular carotid injury', 'Disease', (69, 92))	('increased', 'PosReg', (130, 139))
79422	30262890	It is through these types of pathway that Galphaq/11 inhibitors have hypotensive effects in vascular smooth muscle.	('inhibitors', 'Var', (53, 63))	('vascular smooth muscle', 'CPA', (92, 114))	('hypotensive', 'Disease', (69, 80))	('hypotensive', 'Disease', 'MESH:D007022', (69, 80))	('Galphaq/11', 'Gene', (42, 52))
79425	30262890	In this study, FR900359 inhibited airway smooth muscle growth in vitro, which could prevent airway occlusion during airway remodelling in asthma.	('FR900359', 'Var', (15, 23))	('airway smooth muscle growth', 'CPA', (34, 61))	('FR900359', 'Chemical', 'MESH:C000607068', (15, 23))	('asthma', 'Disease', 'MESH:D001249', (138, 144))	('inhibited', 'NegReg', (24, 33))	('asthma', 'Disease', (138, 144))	('asthma', 'Phenotype', 'HP:0002099', (138, 144))	('airway occlusion', 'MPA', (92, 108))	('prevent', 'NegReg', (84, 91))
79426	30262890	FR900359 also blocked constriction of lung slices stimulated with a muscarinic agonist, carbachol, or with histamine.	('constriction', 'CPA', (22, 34))	('carbachol', 'Chemical', 'MESH:D002217', (88, 97))	('histamine', 'Chemical', 'MESH:D006632', (107, 116))	('FR900359', 'Var', (0, 8))	('blocked', 'NegReg', (14, 21))	('constriction', 'cellular_component', 'GO:0005702', ('22', '34'))	('FR900359', 'Chemical', 'MESH:C000607068', (0, 8))
79427	30262890	These data suggested that targeting Galphaq/11 could alleviate airway occlusion by blocking both smooth muscle remodelling and smooth muscle constriction mechanisms.	('blocking', 'NegReg', (83, 91))	('targeting', 'Var', (26, 35))	('alleviate', 'PosReg', (53, 62))	('constriction', 'cellular_component', 'GO:0005702', ('141', '153'))	('airway occlusion', 'Disease', (63, 79))	('Galphaq/11', 'Gene', (36, 46))	('smooth muscle constriction mechanisms', 'CPA', (127, 164))	('muscle remodelling', 'Disease', (104, 122))	('muscle remodelling', 'Disease', 'MESH:D020257', (104, 122))
79428	30262890	As suggested from previous work, Galphaq/11 inhibition with FR900359 completely reversed methacholine-induced murine tracheal and lung tissue constriction.	('Galphaq/11', 'Enzyme', (33, 43))	('FR900359', 'Var', (60, 68))	('constriction', 'cellular_component', 'GO:0005702', ('142', '154'))	('FR900359', 'Chemical', 'MESH:C000607068', (60, 68))	('methacholine', 'Chemical', 'MESH:D016210', (89, 101))	('inhibition', 'NegReg', (44, 54))	('methacholine-induced murine tracheal', 'MPA', (89, 125))	('murine', 'Species', '10090', (110, 116))
79431	30262890	Because of the blood pressure side effects with systemic administration of YM-254890 or FR900359, it was postulated that local delivery in the airways may be an ideal strategy to produce therapeutic efficacy.	('blood pressure', 'MPA', (15, 29))	('YM-254890', 'Var', (75, 84))	('FR900359', 'Chemical', 'MESH:C000607068', (88, 96))	('FR900359', 'Var', (88, 96))	('YM-254890', 'Chemical', 'MESH:C475455', (75, 84))
79433	30262890	A single dose of FR900359 blocked acute methacholine-induced increases in airway resistance without affecting basal tone.	('methacholine', 'Chemical', 'MESH:D016210', (40, 52))	('airway resistance', 'MPA', (74, 91))	('FR900359', 'Chemical', 'MESH:C000607068', (17, 25))	('FR900359', 'Var', (17, 25))	('increases', 'PosReg', (61, 70))
79434	30262890	This effect persisted for up to 24 hours, suggesting that FR900359 is stable in vivo and/or only slowly dissociates from Galphaq/11 after binding.	('binding', 'Interaction', (138, 145))	('binding', 'molecular_function', 'GO:0005488', ('138', '145'))	('FR900359', 'Chemical', 'MESH:C000607068', (58, 66))	('FR900359', 'Var', (58, 66))
79435	30262890	As postulated, aerosol delivery of FR900359 did not affect blood pressure or heart rate at doses that strongly inhibited airway constriction.	('airway constriction', 'CPA', (121, 140))	('constriction', 'cellular_component', 'GO:0005702', ('128', '140'))	('inhibited', 'NegReg', (111, 120))	('FR900359', 'Chemical', 'MESH:C000607068', (35, 43))	('FR900359', 'Var', (35, 43))
79438	30262890	FR900359 treatment completely blocked sensitized respiratory system resistance in response to methacholine.	('methacholine', 'Chemical', 'MESH:D016210', (94, 106))	('sensitized respiratory system resistance', 'MPA', (38, 78))	('blocked', 'NegReg', (30, 37))	('FR900359', 'Var', (0, 8))	('FR900359', 'Chemical', 'MESH:C000607068', (0, 8))
79440	30262890	This model also results in inflammatory cell infiltration and mucin production, which was not inhibited by FR900359, but, again, FR900359 was very effective at inhibition of hyperresponsiveness to methacholine.	('FR900359', 'Chemical', 'MESH:C000607068', (107, 115))	('methacholine', 'Chemical', 'MESH:D016210', (197, 209))	('inflammatory cell infiltration', 'CPA', (27, 57))	('FR900359', 'Var', (129, 137))	('FR900359', 'Chemical', 'MESH:C000607068', (129, 137))	('results', 'Reg', (16, 23))	('inhibition', 'NegReg', (160, 170))	('hyperresponsiveness', 'Disease', (174, 193))	('hyperresponsiveness', 'Disease', 'None', (174, 193))	('mucin', 'CPA', (62, 67))
79444	30262890	In melanoma, for example, metabotropic glutamate receptor 1 (mGluR1), which is a Galphaq-coupled receptor, is highly elevated, and as such, FR900359 was tested in a variety of melanoma cell lines for inhibition of ERK signalling and cell proliferation.	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))	('cell proliferation', 'CPA', (233, 251))	('ERK', 'molecular_function', 'GO:0004707', ('214', '217'))	('FR900359', 'Var', (140, 148))	('ERK', 'Gene', '26413', (214, 217))	('metabotropic glutamate receptor 1', 'Gene', (26, 59))	('mGluR1', 'Gene', '14816', (61, 67))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('cell proliferation', 'biological_process', 'GO:0008283', ('233', '251'))	('mGluR1', 'Gene', (61, 67))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('FR900359', 'Chemical', 'MESH:C000607068', (140, 148))	('signalling', 'biological_process', 'GO:0023052', ('218', '228'))	('metabotropic glutamate receptor 1', 'Gene', '14816', (26, 59))	('ERK', 'Gene', (214, 217))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('elevated', 'PosReg', (117, 125))
79445	30262890	In cell lines for which growth was sensitive to FR900359, a high basal level of inositol phosphates (IPs) was detected that was suppressed by FR900359, indicating high basal Galphaq/11 activation.	('inositol phosphates', 'Chemical', 'MESH:D007295', (80, 99))	('IPs', 'Chemical', 'MESH:D007295', (101, 104))	('FR900359', 'Var', (142, 150))	('FR900359', 'Var', (48, 56))	('FR900359', 'Chemical', 'MESH:C000607068', (142, 150))	('FR900359', 'Chemical', 'MESH:C000607068', (48, 56))
79446	30262890	FR900359 caused the sensitive cells to change from a proliferative migrating phenotype to a differentiated, non-dividing and non-migratory state.	('FR900359', 'Var', (0, 8))	('FR900359', 'Chemical', 'MESH:C000607068', (0, 8))	('proliferative migrating', 'CPA', (53, 76))	('change', 'Reg', (39, 45))
79447	30262890	This finding suggests that Galphaq/11 inhibition is useful for treating melanoma and inhibiting its metastatic progression.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('Galphaq/11', 'Protein', (27, 37))	('inhibiting', 'NegReg', (85, 95))	('metastatic progression', 'CPA', (100, 122))	('inhibition', 'Var', (38, 48))
79448	30262890	Constitutively active Galphaq/11 mutations Galphaq/11(Q209L) and Galphaq/11(R183C) are prevalent in patients with uveal melanoma.	('prevalent', 'Reg', (87, 96))	('Galphaq/11', 'Var', (65, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('Galphaq/11(Q209L', 'Var', (43, 59))	('uveal melanoma', 'Disease', (114, 128))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('patients', 'Species', '9606', (100, 108))	('Galphaq/11', 'Gene', (22, 32))	('Q209L', 'Mutation', 'rs121913492', (54, 59))	('R183C', 'Mutation', 'p.R183C', (76, 81))
79449	30262890	These mutations prevent hydrolysis of GTP, maintaining Galphaq/11 in the GTP-bound state, and therefore do not require GDP-GTP exchange to become active.	('GDP-GTP', 'Chemical', '-', (119, 126))	('hydrolysis', 'MPA', (24, 34))	('GTP', 'Chemical', 'MESH:D006160', (38, 41))	('GTP', 'Chemical', 'MESH:D006160', (123, 126))	('GTP', 'Chemical', 'MESH:D006160', (73, 76))	('GTP', 'MPA', (38, 41))	('prevent', 'NegReg', (16, 23))	('mutations', 'Var', (6, 15))	('Galphaq/11', 'MPA', (55, 65))
79450	30262890	Thus, FR900359 or YM-254890 would not be predicted to inhibit Galphaq/11(Q209L) activity in cells.	('YM-254890', 'Chemical', 'MESH:C475455', (18, 27))	('inhibit', 'NegReg', (54, 61))	('Q209L', 'Mutation', 'rs121913492', (73, 78))	('YM-254890', 'Var', (18, 27))	('FR900359', 'Var', (6, 14))	('FR900359', 'Chemical', 'MESH:C000607068', (6, 14))
79451	30262890	However, FR900359 has been shown to suppress IP production and proliferation in a human melanoma cell line that carries a Galphaq/11(Q209L) mutation.	('FR900359', 'Var', (9, 17))	('proliferation', 'CPA', (63, 76))	('FR900359', 'Chemical', 'MESH:C000607068', (9, 17))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('suppress', 'NegReg', (36, 44))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('IP production', 'MPA', (45, 58))	('Q209L', 'Mutation', 'rs121913492', (133, 138))	('Galphaq/11', 'Gene', (122, 132))	('human', 'Species', '9606', (82, 87))	('IP', 'Chemical', 'MESH:D007295', (45, 47))
79453	30262890	Indeed a recent study demonstrated that FR900359 drives constitutively active Galphaq (Q209L) into the inactive, GDP-bound state by suppressing nucleotide exchange, which results in inhibition of downstream signalling pathways.	('signalling', 'biological_process', 'GO:0023052', ('207', '217'))	('GDP', 'Chemical', 'MESH:D006153', (113, 116))	('Q209L', 'Mutation', 'rs121913492', (87, 92))	('FR900359', 'Var', (40, 48))	('FR900359', 'Chemical', 'MESH:C000607068', (40, 48))	('inhibition', 'NegReg', (182, 192))	('nucleotide exchange', 'MPA', (144, 163))	('downstream signalling pathways', 'Pathway', (196, 226))	('suppressing', 'NegReg', (132, 143))
79454	30262890	Additionally, treatment with FR900359 inhibited the proliferation and dedifferentiation of Galphaq (Q209L)-driven uveal melanoma cell lines, suggesting that FR900359 could be considered as a treatment for uveal melanoma.	('FR900359', 'Var', (29, 37))	('Q209L', 'Mutation', 'rs121913492', (100, 105))	('proliferation', 'CPA', (52, 65))	('FR900359', 'Chemical', 'MESH:C000607068', (29, 37))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('dedifferentiation', 'biological_process', 'GO:0043696', ('70', '87'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (205, 219))	('uveal melanoma', 'Disease', (205, 219))	('uveal melanoma', 'Disease', 'MESH:C536494', (205, 219))	('FR900359', 'Var', (157, 165))	('uveal melanoma', 'Disease', (114, 128))	('inhibited', 'NegReg', (38, 47))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('FR900359', 'Chemical', 'MESH:C000607068', (157, 165))	('dedifferentiation', 'CPA', (70, 87))
79455	30262890	For patients with activating Galphaq/11 mutations in uveal melanoma, local application of the compound could bypass systemic effects of FR900359 administration.	('Galphaq/11', 'Gene', (29, 39))	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('uveal melanoma', 'Disease', (53, 67))	('mutations', 'Var', (40, 49))	('uveal melanoma', 'Disease', 'MESH:C536494', (53, 67))	('activating', 'PosReg', (18, 28))	('FR900359', 'Chemical', 'MESH:C000607068', (136, 144))	('patients', 'Species', '9606', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))
79456	30262890	As discussed above, both YM-254890 and FR900359 are GDP dissociation inhibitors and would be predicted to inhibit GTP binding and activation of Galphaq.	('FR900359', 'Var', (39, 47))	('FR900359', 'Chemical', 'MESH:C000607068', (39, 47))	('activation', 'PosReg', (130, 140))	('GDP', 'Chemical', 'MESH:D006153', (52, 55))	('GTP', 'Chemical', 'MESH:D006160', (114, 117))	('inhibit', 'NegReg', (106, 113))	('YM-254890', 'Var', (25, 34))	('Galphaq', 'Protein', (144, 151))	('GTP binding', 'molecular_function', 'GO:0005525', ('114', '125'))	('GTP', 'Protein', (114, 117))	('YM-254890', 'Chemical', 'MESH:C475455', (25, 34))
79457	30262890	Thus, this strategy would be expected to be effective under conditions in which the upstream GPCR is overexpressed but not under conditions in which the G protein is constitutively active; Galphaq/11(Q209L) is predicted to have a negligible rate of GTP hydrolysis in vitro and is locked in the GTP-bound state.	('GTP', 'Chemical', 'MESH:D006160', (249, 252))	('GTP', 'Chemical', 'MESH:D006160', (294, 297))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('Q209L', 'Mutation', 'rs121913492', (200, 205))	('Galphaq/11(Q209L', 'Var', (189, 205))	('GTP hydrolysis', 'MPA', (249, 263))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('249', '263'))
79458	30262890	Nevertheless, the Kostenis group showed that FR900359 is able to inhibit IP accumulation driven by Galphaq/11(Q209L) and Galphaq/11(R183C) in HEK293 cells, although fairly high concentrations of FR900359 were used in these experiments.	('R183C', 'Mutation', 'p.R183C', (132, 137))	('IP', 'Chemical', 'MESH:D007295', (73, 75))	('Galphaq/11(Q209L', 'Var', (99, 115))	('Q209L', 'Mutation', 'rs121913492', (110, 115))	('FR900359', 'Var', (45, 53))	('IP accumulation', 'MPA', (73, 88))	('Galphaq/11(R183C', 'Var', (121, 137))	('FR900359', 'Chemical', 'MESH:C000607068', (195, 203))	('FR900359', 'Chemical', 'MESH:C000607068', (45, 53))	('inhibit', 'NegReg', (65, 72))	('HEK293', 'CellLine', 'CVCL:0045', (142, 148))
79460	30262890	Although the detailed characterization of FR900359 by the Kostenis group provided strong evidence for the specificity of FR900359 for Galphaq/11, subsequent analysis has revealed unexpected effects of FR900359 on Galphai-mediated signalling.	('FR900359', 'Chemical', 'MESH:C000607068', (121, 129))	('FR900359', 'Var', (201, 209))	('Galpha', 'Gene', '8802', (134, 140))	('Galpha', 'Gene', '8802', (213, 219))	('FR900359', 'Chemical', 'MESH:C000607068', (201, 209))	('Galpha', 'Gene', (134, 140))	('Galpha', 'Gene', (213, 219))	('effects', 'Reg', (190, 197))	('signalling', 'biological_process', 'GO:0023052', ('230', '240'))	('FR900359', 'Var', (121, 129))	('FR900359', 'Chemical', 'MESH:C000607068', (42, 50))
79463	30262890	In these studies, FR900359 inhibited PTX-sensitive IP mobilization and ERK1-ERK2 activation stimulated by adenosine A1, M2 muscarinic and P2Y12 purinergic receptors expressed in CHO cells.	('M2 muscarinic', 'Protein', (120, 133))	('CHO', 'molecular_function', 'GO:0043848', ('178', '181'))	('P2Y12', 'Gene', (138, 143))	('IP', 'Chemical', 'MESH:D007295', (51, 53))	('CHO', 'CellLine', 'CVCL:0213', (178, 181))	('ERK', 'Gene', (76, 79))	('activation', 'PosReg', (81, 91))	('inhibited', 'NegReg', (27, 36))	('ERK2', 'molecular_function', 'GO:0004707', ('76', '80'))	('ERK1', 'molecular_function', 'GO:0004707', ('71', '75'))	('FR900359', 'Var', (18, 26))	('ERK', 'Gene', '26413', (76, 79))	('ERK', 'Gene', (71, 74))	('PTX-sensitive IP mobilization', 'MPA', (37, 66))	('ERK', 'Gene', '26413', (71, 74))	('adenosine', 'Protein', (106, 115))	('FR900359', 'Chemical', 'MESH:C000607068', (18, 26))	('P2Y12', 'Gene', '70839', (138, 143))	('P2Y', 'molecular_function', 'GO:0045028', ('138', '141'))
79464	30262890	FR900359 did not inhibit Galphai-mediated inhibition of cAMP production.	('cAMP', 'Chemical', 'MESH:D000242', (56, 60))	('Galpha', 'Gene', (25, 31))	('Galpha', 'Gene', '8802', (25, 31))	('cAMP production', 'MPA', (56, 71))	('FR900359', 'Var', (0, 8))	('FR900359', 'Chemical', 'MESH:C000607068', (0, 8))
79465	30262890	One possible explanation is that FR900359 can bind directly to Gbetagamma and inhibit downstream signalling to PLC.	('FR900359', 'Var', (33, 41))	('downstream signalling', 'MPA', (86, 107))	('FR900359', 'Chemical', 'MESH:C000607068', (33, 41))	('PLC', 'cellular_component', 'GO:0042824', ('111', '114'))	('bind', 'Interaction', (46, 50))	('inhibit', 'NegReg', (78, 85))	('signalling', 'biological_process', 'GO:0023052', ('97', '107'))	('Gbetagamma', 'Chemical', '-', (63, 73))	('Gbetagamma', 'Protein', (63, 73))
79471	30262890	Perhaps a low basal level of Galphaq/11 signalling in these cells is required to observe Gbetagamma-dependent stimulation and FR900359 inhibits this low-level Galphaq/11 basal activity.	('low-level Galphaq/11 basal activity', 'MPA', (149, 184))	('Gbetagamma', 'Chemical', '-', (89, 99))	('FR900359', 'Chemical', 'MESH:C000607068', (126, 134))	('FR900359', 'Var', (126, 134))	('inhibits', 'NegReg', (135, 143))	('signalling', 'biological_process', 'GO:0023052', ('40', '50'))	('Gbetagamma-dependent stimulation', 'MPA', (89, 121))
79472	30262890	A related issue is that FR900359 and YM-254890 stabilize the Galphaq-GDP state, which has a high affinity for Gbetagamma.	('YM-254890', 'Var', (37, 46))	('Gbetagamma', 'Protein', (110, 120))	('YM-254890', 'Chemical', 'MESH:C475455', (37, 46))	('FR900359', 'Chemical', 'MESH:C000607068', (24, 32))	('GDP', 'Chemical', 'MESH:D006153', (69, 72))	('FR900359', 'Var', (24, 32))	('Gbetagamma', 'Chemical', '-', (110, 120))	('Galphaq-GDP', 'MPA', (61, 72))
79473	30262890	Thus, FR900359 and YM-254890 would inhibit signalling by both Galphaq and Gbetagamma released from Galphaq heterotrimers.	('Gbetagamma', 'Chemical', '-', (74, 84))	('Gbetagamma', 'Protein', (74, 84))	('YM-254890', 'Chemical', 'MESH:C475455', (19, 28))	('signalling', 'MPA', (43, 53))	('FR900359', 'Chemical', 'MESH:C000607068', (6, 14))	('signalling', 'biological_process', 'GO:0023052', ('43', '53'))	('Galphaq', 'Protein', (62, 69))	('FR900359', 'Var', (6, 14))	('YM-254890', 'Var', (19, 28))	('inhibit', 'NegReg', (35, 42))
79519	30262890	The strength of this response is likely because they express high levels of the Gbetagamma-responsive PI3Kgamma isoform, which consists of P110gamma and P101 subunits.	('PI3Kgamma', 'Gene', '30955', (102, 111))	('PI3Kgamma', 'Gene', (102, 111))	('P110gamma', 'Gene', '30955', (139, 148))	('P101', 'Var', (153, 157))	('P110gamma', 'Gene', (139, 148))	('Gbetagamma', 'Chemical', '-', (80, 90))
79522	30262890	As another source of specificity, small-molecule inhibitors of Gbetagamma that have been identified thus far inhibit a subset of protein-protein interactions without affecting interactions with Galpha subunits.	('Galpha', 'Gene', (194, 200))	('protein-protein', 'Protein', (129, 144))	('inhibit', 'NegReg', (109, 116))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('small-molecule', 'Var', (34, 48))	('Gbetagamma', 'Chemical', '-', (63, 73))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('inhibitors', 'Var', (49, 59))	('Galpha', 'Gene', '8802', (194, 200))	('Gbetagamma', 'Protein', (63, 73))
79529	30262890	Gbetagamma activates GIRK channels in neurons and in atria, leading to a hyperpolarization-induced decrease in action potential firing.	('Gbetagamma', 'Var', (0, 10))	('action potential firing', 'MPA', (111, 134))	('activates', 'PosReg', (11, 20))	('action potential firing', 'biological_process', 'GO:0099610', ('111', '134'))	('hyper', 'Disease', 'MESH:D053307', (73, 78))	('GIRK', 'Protein', (21, 25))	('decrease', 'NegReg', (99, 107))	('hyper', 'Disease', (73, 78))	('Gbetagamma', 'Chemical', '-', (0, 10))
79538	30262890	Gbetagamma activates GIRK channels to hyperpolarize presynaptic neurons and thus reduce excitability, and Gbetagamma inhibits the N-type calcium channels that are responsible for Ca2+ influx upon neuronal depolarization; both of these mechanisms inhibit neurotransmitter release.	('hyper', 'Disease', (38, 43))	('Gbetagamma', 'Var', (106, 116))	('excitability', 'MPA', (88, 100))	('Ca2+', 'Chemical', 'MESH:D000069285', (179, 183))	('inhibit', 'NegReg', (246, 253))	('reduce', 'NegReg', (81, 87))	('neurotransmitter release', 'biological_process', 'GO:0007269', ('254', '278'))	('neurotransmitter release', 'MPA', (254, 278))	('inhibits', 'NegReg', (117, 125))	('GIRK', 'Protein', (21, 25))	('presynaptic neurons', 'MPA', (52, 71))	('Gbetagamma', 'Chemical', '-', (0, 10))	('Gbetagamma', 'Chemical', '-', (106, 116))	('calcium', 'Chemical', 'MESH:D002118', (137, 144))	('N-type', 'Pathway', (130, 136))	('hyper', 'Disease', 'MESH:D053307', (38, 43))
79586	30262890	In a recent study, inhibition of Gbetagamma-regulated GRK2 activation, using adenoviruses to express GRK2ct, prevented alpha2-AR desensitization and reduced plasma adrenaline levels in a heart failure model.	('prevented', 'NegReg', (109, 118))	('alpha2-AR desensitization', 'MPA', (119, 144))	('GRK2', 'Gene', (101, 105))	('inhibition', 'Var', (19, 29))	('GRK2', 'Gene', (54, 58))	('adrenaline', 'Chemical', 'MESH:D004837', (164, 174))	('heart failure', 'Phenotype', 'HP:0001635', (187, 200))	('plasma adrenaline levels', 'MPA', (157, 181))	('reduced', 'NegReg', (149, 156))	('GRK2', 'Gene', '110355', (101, 105))	('heart failure', 'Disease', 'MESH:D006333', (187, 200))	('GRK2', 'Gene', '110355', (54, 58))	('GRK2', 'molecular_function', 'GO:0047696', ('54', '58'))	('heart failure', 'Disease', (187, 200))	('Gbetagamma', 'Chemical', '-', (33, 43))	('GRK2', 'molecular_function', 'GO:0047696', ('101', '105'))
79595	30262890	For example, it was recently shown that Gbetagamma can directly bind to and activate ERK, leading to its phosphorylation and trans-location to the nucleus in cardiac myocytes; ERK trans-location is associated with the development of cardiac hypertrophy.	('trans-location', 'Var', (180, 194))	('associated with', 'Reg', (198, 213))	('phosphorylation', 'MPA', (105, 120))	('nucleus', 'cellular_component', 'GO:0005634', ('147', '154'))	('Gbetagamma', 'Chemical', '-', (40, 50))	('ERK', 'Gene', (176, 179))	('ERK', 'Gene', '26413', (176, 179))	('bind', 'Interaction', (64, 68))	('ERK', 'Gene', (85, 88))	('cardiac hypertrophy', 'Disease', (233, 252))	('ERK', 'molecular_function', 'GO:0004707', ('176', '179'))	('trans-location', 'MPA', (125, 139))	('ERK', 'molecular_function', 'GO:0004707', ('85', '88'))	('ERK', 'Gene', '26413', (85, 88))	('cardiac hypertrophy', 'Disease', 'MESH:D006332', (233, 252))	('cardiac hypertrophy', 'Phenotype', 'HP:0001639', (233, 252))	('phosphorylation', 'biological_process', 'GO:0016310', ('105', '120'))
79687	29203441	Overexpression of oncogenes and inactivation of tumor suppressor genes are typically the initiating events in tumor development.	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('inactivation', 'Var', (32, 44))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor suppressor', 'biological_process', 'GO:0051726', ('48', '64'))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('48', '64'))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
79704	29203441	This inactivation of pRB releases E2F, which then promotes cell proliferation.	('RB', 'Phenotype', 'HP:0009919', (22, 24))	('pRB', 'Gene', (21, 24))	('cell proliferation', 'CPA', (59, 77))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('inactivation', 'Var', (5, 17))	('pRB', 'Gene', '5925', (21, 24))	('promotes', 'PosReg', (50, 58))	('E2F', 'MPA', (34, 37))
79713	29203441	In RB1+/+ cells, pRB was found to be phosphorylated at S608 and S795, which are key residues for its interaction with E2F, but the MYCN/SKP2/p27 pathway was shown to be inactive.	('RB1', 'Gene', '5925', (3, 6))	('p27', 'Gene', '3429', (141, 144))	('SKP2', 'Gene', '6502', (136, 140))	('pRB', 'Gene', (17, 20))	('RB', 'Phenotype', 'HP:0009919', (3, 5))	('interaction', 'Interaction', (101, 112))	('p27', 'Gene', (141, 144))	('pRB', 'Gene', '5925', (17, 20))	('SKP2', 'Gene', (136, 140))	('RB1', 'Gene', (3, 6))	('RB', 'Phenotype', 'HP:0009919', (18, 20))	('S795', 'Var', (64, 68))
79732	29203441	Inhibition of this pathway can slow RB cell proliferation, which shows its potential as a therapeutic target.	('RB', 'Phenotype', 'HP:0009919', (36, 38))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('Inhibition', 'Var', (0, 10))	('RB', 'Gene', '5925', (36, 38))	('slow', 'NegReg', (31, 35))
79748	29203441	Knockdown of HIF-1- alpha was shown to reduce proliferation, induce cell cycle arrest, and promote apoptosis in Weri-RB1 cells under hypoxic conditions.	('reduce', 'NegReg', (39, 45))	('promote', 'PosReg', (91, 98))	('Knockdown', 'Var', (0, 9))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('Weri-RB1', 'CellLine', 'CVCL:L985', (112, 120))	('HIF-1- alpha', 'Gene', (13, 25))	('apoptosis', 'CPA', (99, 108))	('HIF-1- alpha', 'Gene', '3091', (13, 25))	('proliferation', 'CPA', (46, 59))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (68, 85))	('RB', 'Phenotype', 'HP:0009919', (117, 119))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('68', '85'))	('induce', 'Reg', (61, 67))	('cell cycle arrest', 'CPA', (68, 85))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))
79757	29203441	TPT is a topoisomerase I inhibitor, but it can also decrease the rate of HIF-1-alpha translation in U251 human glioma cells.	('glioma', 'Disease', (111, 117))	('TPT', 'molecular_function', 'GO:0009670', ('0', '3'))	('U251', 'CellLine', 'CVCL:0021', (100, 104))	('TPT', 'Chemical', 'MESH:D019772', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('rate', 'MPA', (65, 69))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('topoisomerase', 'molecular_function', 'GO:0003917', ('9', '22'))	('HIF-1-alpha', 'Gene', (73, 84))	('topoisomerase', 'molecular_function', 'GO:0003918', ('9', '22'))	('TPT', 'Var', (0, 3))	('decrease', 'NegReg', (52, 60))	('human', 'Species', '9606', (105, 110))	('HIF-1-alpha', 'Gene', '3091', (73, 84))	('translation', 'biological_process', 'GO:0006412', ('85', '96'))
79800	29203441	YAP-inhibition by verteporfin was shown to block tumor growth of GNAQ/11 mutated UM cells.	('verteporfin', 'Chemical', 'MESH:D000077362', (18, 29))	('mutated', 'Var', (73, 80))	('block tumor', 'Disease', (43, 54))	('block tumor', 'Disease', 'MESH:D006327', (43, 54))	('GNAQ', 'Gene', '2776', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('YAP-inhibition', 'MPA', (0, 14))	('GNAQ', 'Gene', (65, 69))	('UM', 'Phenotype', 'HP:0007716', (81, 83))
79829	29203441	In SCC, 30% of the cases involve a mutation in a downstream target of Wnt signaling, LEF-1.	('LEF-1', 'Gene', (85, 90))	('SCC', 'Gene', '6317', (3, 6))	('LEF-1', 'Gene', '51176', (85, 90))	('mutation', 'Var', (35, 43))	('involve', 'Reg', (25, 32))	('signaling', 'biological_process', 'GO:0023052', ('74', '83'))	('SCC', 'Gene', (3, 6))
79832	29203441	A mutation in LEF-1 preventing its interactions with beta-catenin resulted in the disruption of skin differentiation, and the overexpression of this mutant resulted in the formation of tumors with sebaceous characteristics.	('resulted in', 'Reg', (156, 167))	('formation', 'biological_process', 'GO:0009058', ('172', '181'))	('mutation', 'Var', (2, 10))	('LEF-1', 'Gene', (14, 19))	('interactions', 'Interaction', (35, 47))	('overexpression', 'PosReg', (126, 140))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('beta-catenin', 'Gene', (53, 65))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('LEF-1', 'Gene', '51176', (14, 19))	('disruption', 'NegReg', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('skin differentiation', 'CPA', (96, 116))	('beta-catenin', 'Gene', '1499', (53, 65))
79892	28737763	Approximately two-thirds of these melanomas harbor BRAF mutations, and are most often classified histologically as superficial spreading and nodular melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('mutations', 'Var', (56, 65))	('melanomas', 'Disease', 'MESH:D008545', (149, 158))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanomas', 'Phenotype', 'HP:0002861', (149, 158))	('nodular melanomas', 'Disease', (141, 158))	('nodular melanomas', 'Phenotype', 'HP:0012058', (141, 158))	('melanomas', 'Disease', (34, 43))	('superficial spreading', 'Disease', (115, 136))	('BRAF', 'Gene', '673', (51, 55))	('melanomas', 'Disease', (149, 158))	('melanomas', 'Disease', 'MESH:D008545', (34, 43))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('BRAF', 'Gene', (51, 55))	('nodular melanomas', 'Disease', 'MESH:D020518', (141, 158))
79895	28737763	This subtype is also often associated with intratumoral lymphoid aggregates and is more likely to be associated with mutations in tumor-suppressor genes when compared to the mixed desmoplastic type, which is more likely to be associated with BRAF and NRAS activating oncogenic driver mutations.	('intratumoral lymphoid aggregates', 'Disease', (43, 75))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mutations', 'Var', (117, 126))	('BRAF', 'Gene', '673', (242, 246))	('tumor-suppressor', 'Gene', '7248', (130, 146))	('BRAF', 'Gene', (242, 246))	('associated', 'Reg', (27, 37))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('130', '146'))	('intratumoral lymphoid aggregates', 'Disease', 'MESH:D008223', (43, 75))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('130', '146'))	('NRAS', 'Gene', (251, 255))	('associated', 'Reg', (101, 111))	('tumor-suppressor', 'Gene', (130, 146))	('NRAS', 'Gene', '4893', (251, 255))
79943	28737763	Adaptive PD-L1 expression in the pretreatment melanoma microenvironment has been associated with an improved prognosis, and is also predictive of response to anti-PD-1/PD-L1 therapies in melanoma and other tumor types.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('expression', 'Var', (15, 25))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('improved', 'PosReg', (100, 108))	('melanoma', 'Disease', (187, 195))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Disease', (46, 54))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('PD-L1', 'Gene', '29126', (9, 14))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('PD-L1', 'Gene', (168, 173))	('PD-1', 'Gene', (163, 167))	('PD-1', 'Gene', '5133', (163, 167))	('prognosis', 'MPA', (109, 118))	('PD-L1', 'Gene', '29126', (168, 173))	('PD-L1', 'Gene', (9, 14))
79945	28737763	Many of the more recent studies reporting response rates to anti-PD-1/PD-L1 for patients with melanoma variants did not study PD-L1 expression.	('PD-L1', 'Gene', '29126', (70, 75))	('patients', 'Species', '9606', (80, 88))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('variants', 'Var', (103, 111))	('PD-1', 'Gene', (65, 69))	('PD-L1', 'Gene', (126, 131))	('PD-1', 'Gene', '5133', (65, 69))	('PD-L1', 'Gene', '29126', (126, 131))	('PD-L1', 'Gene', (70, 75))
79956	28737763	The association between PD-L1 expression and TILs is also in keeping with a prior observation that the presence of TILs is associated with improved outcomes in acral melanoma and a lower risk of metastasis in mucosal melanoma, and that patients with PD-L1(+) mucosal melanoma experience a significantly longer recurrence-free survival.	('mucosal melanoma', 'Disease', 'MESH:D008545', (209, 225))	('PD-L1', 'Gene', (24, 29))	('TILs', 'Gene', (115, 119))	('PD-L1', 'Gene', '29126', (24, 29))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('mucosal melanoma', 'Disease', (209, 225))	('presence', 'Var', (103, 111))	('patients', 'Species', '9606', (236, 244))	('acral melanoma', 'Disease', (160, 174))	('metastasis', 'CPA', (195, 205))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('longer', 'PosReg', (303, 309))	('acral melanoma', 'Disease', 'MESH:D008545', (160, 174))	('mucosal melanoma', 'Disease', 'MESH:D008545', (259, 275))	('PD-L1', 'Gene', (250, 255))	('lower', 'NegReg', (181, 186))	('acral melanoma', 'Phenotype', 'HP:0012060', (160, 174))	('improved', 'PosReg', (139, 147))	('PD-L1', 'Gene', '29126', (250, 255))	('mucosal melanoma', 'Disease', (259, 275))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('recurrence-free survival', 'CPA', (310, 334))
79963	28737763	PD-L1 expression has previously been associated with an epithelial to mesenchymal transition (EMT) in other tumor types, though the relationship between PD-L1, EMT, and the presence of a cytotoxic T-cell infiltrate was not assessed.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('associated with', 'Reg', (37, 52))	('PD-L1', 'Gene', (153, 158))	('EMT', 'biological_process', 'GO:0001837', ('94', '97'))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('56', '92'))	('PD-L1', 'Gene', '29126', (153, 158))	('tumor', 'Disease', (108, 113))	('PD-L1', 'Gene', (0, 5))	('EMT', 'biological_process', 'GO:0001837', ('160', '163'))	('PD-L1', 'Gene', '29126', (0, 5))	('expression', 'Var', (6, 16))	('epithelial to mesenchymal transition', 'CPA', (56, 92))
79965	28737763	Features beyond PD-L1 expression such as mutational burden have also been proposed as biomarkers of response to anti-PD-1.	('PD-L1', 'Gene', (16, 21))	('mutational burden', 'Var', (41, 58))	('PD-L1', 'Gene', '29126', (16, 21))	('PD-1', 'Gene', (117, 121))	('PD-1', 'Gene', '5133', (117, 121))
79969	28737763	Thus, mutational burden also generally parallels the reported ORRs for melanoma subtypes, though perhaps not as closely as PD-L1 expression.	('melanoma subtypes', 'Disease', 'MESH:D008545', (71, 88))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('mutational burden', 'Var', (6, 23))	('PD-L1', 'Gene', (123, 128))	('melanoma subtypes', 'Disease', (71, 88))	('PD-L1', 'Gene', '29126', (123, 128))
79971	28737763	A recent study showed that mutational burden was a contributing factor to general prognosis for patients with melanoma, but its relative contribution was less than PD-1/PD-L1 axis molecule expression.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('PD-L1', 'Gene', (169, 174))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('contributing', 'Reg', (51, 63))	('PD-L1', 'Gene', '29126', (169, 174))	('PD-1', 'Gene', (164, 168))	('PD-1', 'Gene', '5133', (164, 168))	('patients', 'Species', '9606', (96, 104))	('mutational burden', 'Var', (27, 44))
79973	28737763	The relationship of these alterations to PD-L1 expression or specific melanoma subtypes has yet to be defined.	('PD-L1', 'Gene', '29126', (41, 46))	('melanoma subtypes', 'Disease', (70, 87))	('alterations', 'Var', (26, 37))	('melanoma subtypes', 'Disease', 'MESH:D008545', (70, 87))	('PD-L1', 'Gene', (41, 46))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
79993	28737763	These features, when combined with other characteristics of the tumor microenvironment, such as high mutational load and the presence of lymphoid aggregates, provide a possible explanation for the observed high response rates to anti-PD-1 monotherapy in these patients.	('tumor', 'Disease', (64, 69))	('PD-1', 'Gene', (234, 238))	('PD-1', 'Gene', '5133', (234, 238))	('patients', 'Species', '9606', (260, 268))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mutational load', 'Var', (101, 116))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
80002	26835669	For example, deregulations in miRNAs expression have been identified to play a role not only in major cancers like lung, breast and prostate but also in rare cancers like waldenstrom macroglobulinemia and cholangiocarcinoma.	('role', 'Reg', (79, 83))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('macroglobulinemia', 'Disease', 'MESH:D008258', (183, 200))	('play', 'Reg', (72, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('prostate', 'Disease', (132, 140))	('deregulations', 'Var', (13, 26))	('breast', 'Disease', (121, 127))	('miRNAs', 'Protein', (30, 36))	('waldenstrom macroglobulinemia', 'Phenotype', 'HP:0005508', (171, 200))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('expression', 'MPA', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (205, 223))	('macroglobulinemia', 'Disease', (183, 200))	('lung', 'Disease', (115, 119))	('cholangiocarcinoma', 'Disease', (205, 223))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (205, 223))
80008	26835669	Furthermore, single nucleotide polymorphisms in the 3'UTR of mRNAs may affect miRNA-mediated regulation and have been associated with certain cancer risk.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('regulation', 'biological_process', 'GO:0065007', ('93', '103'))	('miRNA-mediated regulation', 'MPA', (78, 103))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('affect', 'Reg', (71, 77))	('associated with', 'Reg', (118, 133))	('mRNAs', 'Gene', (61, 66))	('single nucleotide polymorphisms', 'Var', (13, 44))	('cancer', 'Disease', (142, 148))
80009	26835669	showed the biological relevance of miRNAs in cancer development; miR-15 and miR-16 were significantly downregulated in chronic lymphoid leukemia (CLL) through deletions in chromosome 13q14 locus.	('downregulated', 'NegReg', (102, 115))	('leukemia', 'Phenotype', 'HP:0001909', (136, 144))	('lymphoid leukemia', 'Phenotype', 'HP:0005526', (127, 144))	('chronic lymphoid leukemia', 'Disease', 'MESH:D007945', (119, 144))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('CLL', 'Phenotype', 'HP:0005550', (146, 149))	('miR-16', 'Gene', (76, 82))	('chronic lymphoid leukemia', 'Disease', (119, 144))	('chromosome', 'cellular_component', 'GO:0005694', ('172', '182'))	('miR-16', 'Gene', '51573', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('deletions', 'Var', (159, 168))	('miR-15', 'Gene', (65, 71))	('cancer', 'Disease', (45, 51))	('chronic lymphoid leukemia', 'Phenotype', 'HP:0005550', (119, 144))
80028	26835669	on uveal melanoma, which is the most common primary form of the intra ocular tumor in adults, the transfection of uveal melanoma cells by miR-34b/c caused cell cycle arrest resulting in significant reduction of melanoma cell growth and migration.	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('ocular tumor', 'Phenotype', 'HP:0100012', (70, 82))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('reduction of melanoma cell growth', 'Disease', (198, 231))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('uveal melanoma', 'Disease', (3, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('155', '172'))	('uveal melanoma', 'Disease', (114, 128))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('miR-34b', 'Gene', '407041', (138, 145))	('reduction of melanoma cell growth', 'Disease', 'MESH:D008545', (198, 231))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('cell growth', 'biological_process', 'GO:0016049', ('220', '231'))	('cell cycle arrest', 'CPA', (155, 172))	('intra ocular tumor', 'Disease', 'MESH:D009369', (64, 82))	('miR-34b', 'Gene', (138, 145))	('transfection', 'Var', (98, 110))	('intra ocular tumor', 'Disease', (64, 82))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (155, 172))
80030	26835669	Interestingly, many studies have demonstrated miRNAs as oncogenes or tumor suppressors by involving multiple molecular mechanisms and different signaling pathways.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('miRNAs', 'Var', (46, 52))	('tumor', 'Disease', (69, 74))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('involving', 'Reg', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
80059	26835669	demonstrated the stability of miRNAs (miR-15b, miR-16, miR-19b and miR-24) occurring in normal human sera and their resistance to RNase digestion.	('miR-24', 'Var', (67, 73))	('human', 'Species', '9606', (95, 100))	('miR-16', 'Gene', '51573', (47, 53))	('miR-19b', 'Gene', (55, 62))	('digestion', 'biological_process', 'GO:0007586', ('136', '145'))	('sera', 'molecular_function', 'GO:0004617', ('101', '105'))	('miR-15b', 'Gene', '406949', (38, 45))	('miR-19b', 'Gene', '406980', (55, 62))	('miR-15b', 'Gene', (38, 45))	('miR-16', 'Gene', (47, 53))
80085	26835669	Even though, there is no exclusive method available for miRNA extraction, which is rapid, involving easy protocols with minimal requirement of starting material that is also cost effective, the above-mentioned approaches all have great potential in detecting miRNAs in tumor tissues/cells with good amount of sensitivity and specificity.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('detecting', 'Reg', (249, 258))	('miRNAs', 'Var', (259, 265))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumor', 'Disease', (269, 274))
80095	25653058	Detection of GNAQ mutations and reduction of cell viability in uveal melanoma cells with functionalized gold nanoparticles Uveal melanoma (UM) is the most common primary intraocular malignancy in adults.	('intraocular malignancy', 'Disease', (170, 192))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (63, 77))	('uveal melanoma', 'Disease', (63, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (63, 77))	('GNAQ', 'Gene', (13, 17))	('intraocular malignancy', 'Disease', 'MESH:C563596', (170, 192))	('cell viability', 'CPA', (45, 59))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('reduction', 'NegReg', (32, 41))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (123, 137))	('GNAQ', 'Gene', '2776', (13, 17))	('melanoma', 'Disease', (69, 77))	('mutations', 'Var', (18, 27))
80096	25653058	Up to 95 % of all UMs carry somatic mutations in the G-coupled proteins GNAQ and GNA11 promoting anchorage-independent growth and proliferation.	('promoting', 'PosReg', (87, 96))	('GNAQ', 'Gene', '2776', (72, 76))	('GNA11', 'Gene', '2767', (81, 86))	('GNA11', 'Gene', (81, 86))	('mutations', 'Var', (36, 45))	('anchorage-independent growth', 'CPA', (97, 125))	('GNAQ', 'Gene', (72, 76))
80098	25653058	We have developed functionalized gold nanoparticles (AuNPs) to visualize transcripts of mutant GNAQ mRNA in living cells.	('mutant', 'Var', (88, 94))	('GNAQ', 'Gene', (95, 99))	('GNAQ', 'Gene', '2776', (95, 99))
80100	25653058	Knockdown of GNAQ with siRNA-AuNPs effectively reduced downstream signals and decreased cell viability in GNAQ mutant uveal melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('mutant', 'Var', (111, 117))	('GNAQ', 'Gene', (13, 17))	('uveal melanoma', 'Phenotype', 'HP:0007716', (118, 132))	('uveal melanoma', 'Disease', (118, 132))	('GNAQ', 'Gene', (106, 110))	('uveal melanoma', 'Disease', 'MESH:C536494', (118, 132))	('GNAQ', 'Gene', '2776', (13, 17))	('cell viability', 'CPA', (88, 102))	('decreased', 'NegReg', (78, 87))	('reduced', 'NegReg', (47, 54))	('downstream signals', 'MPA', (55, 73))	('GNAQ', 'Gene', '2776', (106, 110))
80108	25653058	The management of patients with UM has recently been revolutionized by the discovery that metastasis almost exclusively occurs in patients with tumors that show chromosome 3 loss or a class 2 gene expression profile.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('gene expression', 'biological_process', 'GO:0010467', ('192', '207'))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('occurs', 'Reg', (120, 126))	('metastasis', 'CPA', (90, 100))	('patients', 'Species', '9606', (130, 138))	('class 2 gene expression profile', 'Var', (184, 215))	('patients', 'Species', '9606', (18, 26))	('chromosome', 'cellular_component', 'GO:0005694', ('161', '171'))	('chromosome', 'Var', (161, 171))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('loss', 'NegReg', (174, 178))
80110	25653058	Several studies have identified mutations in the alpha subunit of the G-coupled protein GNAQ/GNA11 which occur in approximately 90 % of UMs and which predominantly result in the substitution of glutamine by proline (Q209P) or leucine (Q209L).	('leucine', 'Chemical', 'MESH:D007930', (226, 233))	('GNAQ', 'Gene', (88, 92))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('Q209P', 'Var', (216, 221))	('glutamine', 'Protein', (194, 203))	('glutamine', 'Chemical', 'MESH:D005973', (194, 203))	('Q209P', 'Mutation', 'rs1057519742', (216, 221))	('mutations', 'Var', (32, 41))	('Q209L', 'Mutation', 'rs1057519742', (235, 240))	('result in', 'Reg', (164, 173))	('GNAQ', 'Gene', '2776', (88, 92))	('GNA11', 'Gene', '2767', (93, 98))	('GNA11', 'Gene', (93, 98))	('proline', 'Chemical', 'MESH:D011392', (207, 214))	('Q209L', 'Var', (235, 240))
80111	25653058	This region is critical for the intrinsic GTPase activity of the protein of which mutations cause constitutive activation, making GNAQ/GNA11 a bona fide oncogene.	('GNA11', 'Gene', '2767', (135, 140))	('GTPase activity', 'molecular_function', 'GO:0003924', ('42', '57'))	('GNAQ', 'Gene', (130, 134))	('mutations', 'Var', (82, 91))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('constitutive', 'MPA', (98, 110))	('GNA11', 'Gene', (135, 140))	('GNAQ', 'Gene', '2776', (130, 134))
80112	25653058	To date, to our knowledge, it has been impossible to synthetically restore the enzymatic activity of mutant GNAQ or target the permanently active protein.	('enzymatic', 'MPA', (79, 88))	('GNAQ', 'Gene', '2776', (108, 112))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('mutant', 'Var', (101, 107))	('GNAQ', 'Gene', (108, 112))
80114	25653058	The high prevalence of GNAQ mutations in UM make mutant GNAQ a possibly interesting candidate for new therapeutic approaches.	('mutant', 'Var', (49, 55))	('GNAQ', 'Gene', (23, 27))	('GNAQ', 'Gene', '2776', (56, 60))	('GNAQ', 'Gene', '2776', (23, 27))	('GNAQ', 'Gene', (56, 60))	('mutations', 'Var', (28, 37))
80115	25653058	In this study we sought to answer 2 questions: Can AuNPs be functionalized to detect specific GNAQ mutations?	('GNAQ', 'Gene', '2776', (94, 98))	('mutations', 'Var', (99, 108))	('GNAQ', 'Gene', (94, 98))
80117	25653058	First, we provide evidence that functionalized AuNPs can be used to visualize mutant GNAQ mRNA.	('GNAQ', 'Gene', (85, 89))	('GNAQ', 'Gene', '2776', (85, 89))	('mutant', 'Var', (78, 84))
80119	25653058	GNAQ and GNA11 mutations are frequent in UM.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('frequent', 'Reg', (29, 37))	('mutations', 'Var', (15, 24))	('GNAQ', 'Gene', (0, 4))	('GNA11', 'Gene', '2767', (9, 14))
80121	25653058	In addition, we also sequenced 4 indeterminate uveal melanocytic proliferations that were initially classified as benign or indeterminate, but progressed to UM over time; interestingly, all tumors harboured mutations in GNAQ orGNA11.	('GNAQ', 'Gene', '2776', (220, 224))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('uveal melanocytic proliferations', 'Disease', 'MESH:D059545', (47, 79))	('mutations', 'Var', (207, 216))	('uveal melanocytic proliferations', 'Phenotype', 'HP:0007716', (47, 79))	('GNAQ', 'Gene', (220, 224))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('GNA11', 'Gene', (227, 232))	('tumors', 'Disease', (190, 196))	('GNA11', 'Gene', '2767', (227, 232))	('uveal melanocytic proliferations', 'Disease', (47, 79))
80123	25653058	One out of 4 uveal nevi sequenced in this study carried a mutation in GNAQ, suggesting that these genetic aberrations are not limited to UM.	('mutation', 'Var', (58, 66))	('nevi', 'Phenotype', 'HP:0003764', (19, 23))	('GNAQ', 'Gene', (70, 74))	('GNAQ', 'Gene', '2776', (70, 74))
80124	25653058	Even though GNAQ mutations seem to be more prevalent in malignant melanocytic tumors sequenced in this study, they might also be present in benign uveal melanocytic proliferations and are therefore of limited value in distinguishing benign from malignant lesions (Table 1).	('GNAQ', 'Gene', (12, 16))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('malignant melanocytic tumors', 'Disease', (56, 84))	('malignant melanocytic tumors', 'Disease', 'MESH:D018198', (56, 84))	('prevalent', 'Reg', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('benign uveal melanocytic proliferations', 'Disease', (140, 179))	('GNAQ', 'Gene', '2776', (12, 16))	('benign uveal melanocytic proliferations', 'Disease', 'MESH:D059545', (140, 179))	('malignant melanocytic tumors', 'Phenotype', 'HP:0002861', (56, 84))	('uveal melanocytic proliferations', 'Phenotype', 'HP:0007716', (147, 179))	('mutations', 'Var', (17, 26))	('present', 'Reg', (129, 136))
80127	25653058	To test specificity of modified AuNPs to detect single nucleotide changes, we designed AuNPs recognizing the wild type and the mutant transcript of GNAQ.	('mutant', 'Var', (127, 133))	('GNAQ', 'Gene', (148, 152))	('GNAQ', 'Gene', '2776', (148, 152))
80129	25653058	AuNPs modified to recognize the mutant transcript (AuNPmut) gave a strong fluorescent signal when incubated with synthesised oligonucleotieds of the matching, mutant GNAQ transcript.	('mutant', 'Var', (159, 165))	('GNAQ', 'Gene', (166, 170))	('fluorescent signal', 'MPA', (74, 92))	('GNAQ', 'Gene', '2776', (166, 170))
80130	25653058	To demonstrate the capacity of modified AuNPs to detect target gene mutations in live cells, we incubated the human uveal melanoma cell lines OMM1.3, Mel202 and C918 and the cutaneous melanoma cell line Sk-Mel-2 with modified AuNPs.	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('human', 'Species', '9606', (110, 115))	('uveal melanoma', 'Phenotype', 'HP:0007716', (116, 130))	('uveal melanoma', 'Disease', (116, 130))	('uveal melanoma', 'Disease', 'MESH:C536494', (116, 130))	('C918', 'CellLine', 'CVCL:8471', (161, 165))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('mutations', 'Var', (68, 77))	('cutaneous melanoma', 'Disease', (174, 192))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (174, 192))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (174, 192))
80131	25653058	We found a near 4-fold increase in fluorescence measured by flow cytometric analysis when GNAQQ209P mutant OMM1.3 cells were incubated with AuNPs that specifically recognize the mutant transcript (Fig.	('mutant', 'Var', (178, 184))	('fluorescence', 'MPA', (35, 47))	('GNAQQ209P', 'Mutation', 'rs121913492', (90, 99))	('increase', 'PosReg', (23, 31))	('GNAQQ209P', 'Gene', (90, 99))
80145	25653058	Using siRNA-AuNPs targeting GNAQ, we sought to modulate GNAQ protein levels, downstream signaling and cell viability in GNAQ mutant cells.	('GNAQ', 'Gene', '2776', (28, 32))	('signaling', 'biological_process', 'GO:0023052', ('88', '97'))	('mutant', 'Var', (125, 131))	('GNAQ', 'Gene', '2776', (56, 60))	('GNAQ', 'Gene', (120, 124))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))	('modulate', 'Reg', (47, 55))	('GNAQ', 'Gene', (28, 32))	('GNAQ', 'Gene', (56, 60))	('GNAQ', 'Gene', '2776', (120, 124))
80146	25653058	Incubation of cells with siRNA-AuNPs for 3 days caused a significant reduction of cell viability in the GNAQ mutant UM cell line OMM1.3.	('cell viability', 'CPA', (82, 96))	('GNAQ', 'Gene', '2776', (104, 108))	('GNAQ', 'Gene', (104, 108))	('mutant', 'Var', (109, 115))	('reduction', 'NegReg', (69, 78))
80156	25653058	We have shown that our functionalized AuNPs selectively detect a specific mutant transcript in living human cells.	('mutant', 'Var', (74, 80))	('detect', 'Reg', (56, 62))	('human', 'Species', '9606', (102, 107))
80157	25653058	For this proof-of-principle study we chose GNAQ as our gene of interest and selectively detected mutations in live, GNAQ mutant cells.	('mutations', 'Var', (97, 106))	('mutant', 'Var', (121, 127))	('GNAQ', 'Gene', (43, 47))	('GNAQ', 'Gene', (116, 120))	('GNAQ', 'Gene', '2776', (43, 47))	('GNAQ', 'Gene', '2776', (116, 120))
80164	25653058	Despite the fact that siRNA mediated GNAQ knockdown has been shown to inhibit UM cell proliferation and to shrink tumors in animal models, significant challenges in the delivery of such GNAQ-targeting oligonucleotides in vitro and in vivo persist.	('UM cell proliferation', 'CPA', (78, 99))	('oligonucleotides', 'Chemical', 'MESH:D009841', (201, 217))	('shrink', 'NegReg', (107, 113))	('GNAQ', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cell proliferation', 'biological_process', 'GO:0008283', ('81', '99'))	('GNAQ', 'Gene', '2776', (186, 190))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('inhibit', 'NegReg', (70, 77))	('GNAQ', 'Gene', '2776', (37, 41))	('GNAQ', 'Gene', (186, 190))	('knockdown', 'Var', (42, 51))
80169	25653058	As expected, we also observed that knockdown of mutant GNAQ with siRNA-AuNPs results in a significant decrease of cell viability consistent with the established role of the MAPK pathway in maintaining cell viability.	('mutant', 'Var', (48, 54))	('decrease', 'NegReg', (102, 110))	('GNAQ', 'Gene', '2776', (55, 59))	('MAPK', 'molecular_function', 'GO:0004707', ('173', '177'))	('cell viability', 'CPA', (114, 128))	('GNAQ', 'Gene', (55, 59))
80192	23915344	BAP1 deficiency causes loss of melanocytic cell identity in uveal melanoma Uveal melanoma is a highly aggressive cancer with a strong propensity for metastasis, yet little is known about the biological mechanisms underlying this metastatic potential.	('loss of melanocytic', 'Disease', (23, 42))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('Uveal melanoma', 'Disease', 'MESH:C536494', (75, 89))	('BAP1', 'Gene', (0, 4))	('deficiency', 'Var', (5, 15))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (75, 89))	('aggressive cancer', 'Disease', 'MESH:D009369', (102, 119))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('Uveal melanoma', 'Disease', (75, 89))	('uveal melanoma', 'Disease', 'MESH:C536494', (60, 74))	('aggressive cancer', 'Disease', (102, 119))	('loss of melanocytic', 'Disease', 'MESH:D009508', (23, 42))	('uveal melanoma', 'Disease', (60, 74))	('BAP1', 'Gene', '104416', (0, 4))
80193	23915344	We recently showed that most metastasizing uveal melanomas, which exhibit a class 2 gene expression profile, contain inactivating mutations in the tumor suppressor BAP1.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('inactivating mutations', 'Var', (117, 139))	('uveal melanomas', 'Disease', (43, 58))	('uveal melanomas', 'Phenotype', 'HP:0007716', (43, 58))	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('BAP1', 'Gene', (164, 168))	('uveal melanomas', 'Disease', 'MESH:C536494', (43, 58))	('tumor suppressor', 'biological_process', 'GO:0051726', ('147', '163'))	('gene expression', 'biological_process', 'GO:0010467', ('84', '99'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('147', '163'))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
80195	23915344	Uveal melanoma cells were studied following RNAi-mediated depletion of BAP1 using proliferation, BrdU incorporation, flow cytometry, migration, invasion, differentiation and clonogenic assays, as well as in vivo tumorigenicity experiments in NOD-SCID-Gamma mice.	('SCID', 'Disease', 'MESH:D053632', (246, 250))	('mice', 'Species', '10090', (257, 261))	('SCID', 'Disease', (246, 250))	('Uveal melanoma', 'Disease', 'MESH:C536494', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('BrdU', 'Chemical', 'MESH:D001973', (97, 101))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('depletion', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('RNAi', 'biological_process', 'GO:0016246', ('44', '48'))	('Uveal melanoma', 'Disease', (0, 14))	('BAP1', 'Gene', (71, 75))	('tumor', 'Disease', (212, 217))
80196	23915344	Depletion of BAP1 in uveal melanoma cells resulted in a loss of differentiation and gain of stem-like properties, including expression of stem cell markers, increased capacity for self-replication, and enhanced ability to grow in stem cell conditions.	('uveal melanoma', 'Disease', (21, 35))	('BAP1', 'Gene', (13, 17))	('loss', 'NegReg', (56, 60))	('enhanced', 'PosReg', (202, 210))	('Depletion', 'Var', (0, 9))	('stem-like properties', 'CPA', (92, 112))	('expression', 'MPA', (124, 134))	('increased', 'PosReg', (157, 166))	('uveal melanoma', 'Disease', 'MESH:C536494', (21, 35))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('gain', 'PosReg', (84, 88))	('differentiation', 'CPA', (64, 79))	('self-replication', 'CPA', (180, 196))	('uveal melanoma', 'Phenotype', 'HP:0007716', (21, 35))
80197	23915344	BAP1 depletion did not result in increased proliferation, migration, invasion or tumorigenicity.	('depletion', 'Var', (5, 14))	('BAP1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('increased', 'PosReg', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
80201	23915344	We recently showed that inactivating mutations in the tumor suppressor BAP1 occur almost exclusively in class 2 tumors and are strongly associated with metastasis, suggesting that BAP1 may function as a metastasis suppressor in uveal melanoma.	('associated', 'Reg', (136, 146))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('54', '70'))	('metastasis', 'CPA', (152, 162))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (228, 242))	('tumor suppressor', 'biological_process', 'GO:0051726', ('54', '70'))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (112, 117))	('BAP1', 'Gene', (71, 75))	('inactivating mutations', 'Var', (24, 46))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('uveal melanoma', 'Disease', 'MESH:C536494', (228, 242))	('uveal melanoma', 'Disease', (228, 242))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (54, 59))	('tumors', 'Disease', (112, 118))
80202	23915344	One patient in this report carried a germline BAP1 mutation, indicating that BAP1 mutations can give rise to a familial cancer syndrome.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('give rise to', 'Reg', (96, 108))	('familial cancer syndrome', 'Disease', 'MESH:D009386', (111, 135))	('patient', 'Species', '9606', (4, 11))	('familial cancer syndrome', 'Disease', (111, 135))	('mutations', 'Var', (82, 91))	('mutation', 'Var', (51, 59))	('BAP1', 'Gene', (46, 50))	('BAP1', 'Gene', (77, 81))
80203	23915344	Since this report, somatic and germline BAP1 mutations have been identified in a variety of other tumors, including mesothelioma, cutaneous melanoma, atypical cutaneous melanocytic tumors, lung adenocarcinoma, meningioma and renal cell carcinoma.	('mesothelioma', 'Disease', (116, 128))	('lung adenocarcinoma', 'Disease', (189, 208))	('tumors', 'Disease', (98, 104))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('meningioma', 'Phenotype', 'HP:0002858', (210, 220))	('BAP1', 'Gene', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (189, 208))	('identified', 'Reg', (65, 75))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (225, 245))	('meningioma and renal cell carcinoma', 'Disease', 'MESH:C538614', (210, 245))	('cutaneous melanocytic tumors', 'Disease', 'MESH:D009508', (159, 187))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (189, 208))	('tumors', 'Disease', (181, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('cutaneous melanoma', 'Disease', (130, 148))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (130, 148))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (130, 148))	('cutaneous melanocytic tumors', 'Disease', (159, 187))	('mutations', 'Var', (45, 54))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (181, 187))
80217	23915344	Due to the low frequency of BRAF mutations in uveal melanoma, OCM1A cells may not be representative of the vast majority of primary uveal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('BRAF', 'Gene', '673', (28, 32))	('uveal melanomas', 'Disease', 'MESH:C536494', (132, 147))	('uveal melanoma', 'Phenotype', 'HP:0007716', (132, 146))	('uveal melanoma', 'Disease', 'MESH:C536494', (132, 146))	('uveal melanoma', 'Disease', 'MESH:C536494', (46, 60))	('mutations', 'Var', (33, 42))	('uveal melanomas', 'Phenotype', 'HP:0007716', (132, 147))	('uveal melanoma', 'Disease', (46, 60))	('OCM1', 'Species', '83984', (62, 66))	('uveal melanoma', 'Phenotype', 'HP:0007716', (46, 60))	('uveal melanomas', 'Disease', (132, 147))	('BRAF', 'Gene', (28, 32))	('melanomas', 'Phenotype', 'HP:0002861', (138, 147))
80248	23915344	Gene expression profiling (GEP) was performed on two independent sets of uveal melanoma cell lines (OCM1A, 92.1 and Mel290), each expressing either GFP or BAP1 shRNA for four weeks (12 samples total).	('BAP1 shRNA', 'Var', (155, 165))	('uveal melanoma', 'Disease', 'MESH:C536494', (73, 87))	('uveal melanoma', 'Phenotype', 'HP:0007716', (73, 87))	('uveal melanoma', 'Disease', (73, 87))	('OCM1', 'Species', '83984', (100, 104))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('GFP', 'Var', (148, 151))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))
80252	23915344	5-8 week old NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ JAX [non-obese diabetic severe-combined immunodeficient gamma (NSG)] males (Jackson Laboratory) were injected subcutaneously into the flank with 500 OCM1A or 1000 92.1 cells in 50 mul Cultrex (Trevigen, Gaithersburg MD, USA).	('obese diabetic', 'Disease', (55, 69))	('Gaithersburg MD', 'Disease', (249, 264))	('Il2', 'molecular_function', 'GO:0005134', ('30', '33'))	('immunodeficient gamma', 'Disease', 'OMIM:615607', (86, 107))	('OCM1', 'Species', '83984', (195, 199))	('obese diabetic', 'Disease', 'MESH:D009765', (55, 69))	('immunodeficient gamma', 'Disease', (86, 107))	('Il2rgtm1Wjl/SzJ', 'Var', (30, 45))
80265	23915344	The uveal melanoma cells stably expressing shRNA against BAP1 and control shRNA against GFP were compared using in vitro and in vivo assays of tumorigenicity.	('uveal melanoma', 'Phenotype', 'HP:0007716', (4, 18))	('tumor', 'Disease', (143, 148))	('uveal melanoma', 'Disease', (4, 18))	('BAP1', 'Gene', (57, 61))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('shRNA', 'Var', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('uveal melanoma', 'Disease', 'MESH:C536494', (4, 18))
80276	23915344	Since BRCA pathway deregulation and telomere dysfunction are both associated with amplifications and deletions in cancer cells, we wished to determine whether BAP1 depletion might result in such large-scale chromosomal gains and losses in uveal melanoma cells.	('telomere dysfunction', 'Disease', 'MESH:C536801', (36, 56))	('chromosomal', 'Var', (207, 218))	('amplifications', 'Var', (82, 96))	('depletion', 'Var', (164, 173))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('deregulation', 'NegReg', (19, 31))	('telomere', 'cellular_component', 'GO:0000781', ('36', '44'))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('telomere', 'cellular_component', 'GO:0005696', ('36', '44'))	('BAP1', 'Gene', (159, 163))	('gains', 'PosReg', (219, 224))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('uveal melanoma', 'Disease', (239, 253))	('uveal melanoma', 'Disease', 'MESH:C536494', (239, 253))	('telomere dysfunction', 'Disease', (36, 56))	('losses', 'NegReg', (229, 235))	('BRCA pathway', 'Pathway', (6, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (239, 253))	('deletions', 'Var', (101, 110))	('cancer', 'Disease', (114, 120))
80279	23915344	Consistent with this hypothesis, depletion of BAP1 caused a down-regulation of canonical genes of the melanocyte differentiation program (MITF, TRPM1, TYR and DCT) (Figure 6a).	('depletion', 'Var', (33, 42))	('down-regulation', 'NegReg', (60, 75))	('DCT', 'Gene', (159, 162))	('melanocyte differentiation', 'biological_process', 'GO:0030318', ('102', '128'))	('TRPM1', 'Gene', (144, 149))	('BAP1', 'Gene', (46, 50))	('TYR', 'Chemical', 'MESH:D014443', (151, 154))	('regulation', 'biological_process', 'GO:0065007', ('65', '75'))	('MITF', 'Gene', (138, 142))	('TYR', 'Gene', (151, 154))
80280	23915344	Similar changes were seen in cultures of primary uveal melanocyte samples from three independent patients stably expressing shRNA against BAP1 or control shRNA against GFP and also in two short-term cultures from fresh primary class 1 tumors (Figure 6a and data not shown).	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumors', 'Disease', (235, 241))	('BAP1', 'Gene', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('shRNA against', 'Var', (124, 137))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('patients', 'Species', '9606', (97, 105))
80286	23915344	As we showed previously, HDAC inhibition reverts primary class 2 uveal melanoma cells to a differentiated, less aggressive class 1 phenotype.	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('uveal melanoma', 'Disease', (65, 79))	('inhibition', 'Var', (30, 40))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('HDAC', 'Protein', (25, 29))	('reverts', 'NegReg', (41, 48))	('uveal melanoma', 'Disease', 'MESH:C536494', (65, 79))
80299	23915344	In summary, we demonstrate that BAP1 is necessary for maintenance of melanocyte identity in uveal melanoma cells, and that loss of BAP1 leads to a loss of cell identity and acquisition of a primitive, stem-like phenotype.	('loss', 'NegReg', (147, 151))	('cell identity', 'CPA', (155, 168))	('uveal melanoma', 'Phenotype', 'HP:0007716', (92, 106))	('uveal melanoma', 'Disease', (92, 106))	('uveal melanoma', 'Disease', 'MESH:C536494', (92, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('loss', 'Var', (123, 127))	('BAP1', 'Gene', (131, 135))	('acquisition', 'PosReg', (173, 184))
80312	15381927	Among these is the recent detection of mutations in the BRAF gene (Davies et al, 2002).	('BRAF', 'Gene', '673', (56, 60))	('mutations', 'Var', (39, 48))	('BRAF', 'Gene', (56, 60))
80431	18239976	Hepatic toxicity consisted mainly of a transient rise of liver enzymes during the first week after IHHP.	('IHHP', 'Chemical', '-', (99, 103))	('liver enzymes', 'MPA', (57, 70))	('rise', 'PosReg', (49, 53))	('IHHP', 'Var', (99, 103))	('Hepatic toxicity', 'Disease', 'MESH:D056486', (0, 16))	('Hepatic toxicity', 'Disease', (0, 16))
80443	18239976	Thus, intrahepatic melphalan concentrations during the IHHP are >9 fold higher than the post-IHHP systemic melphalan concentrations.	('melphalan', 'Chemical', 'MESH:D008558', (19, 28))	('intrahepatic melphalan', 'Disease', (6, 28))	('intrahepatic melphalan', 'Disease', 'MESH:D002780', (6, 28))	('IHHP', 'Chemical', '-', (55, 59))	('IHHP', 'Chemical', '-', (93, 97))	('higher', 'PosReg', (72, 78))	('melphalan', 'Chemical', 'MESH:D008558', (107, 116))	('IHHP', 'Var', (55, 59))
80542	32922550	The disruption of CA4 may be associated with the perturbation of pH homeostasis in retina and correlated with retinitis pigmentosa.	('retinitis pigmentosa', 'Disease', (110, 130))	('correlated', 'Reg', (94, 104))	('pH homeostasis', 'MPA', (65, 79))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (110, 130))	('perturbation', 'MPA', (49, 61))	('homeostasis', 'biological_process', 'GO:0042592', ('68', '79'))	('retinitis', 'Phenotype', 'HP:0032118', (110, 119))	('associated', 'Reg', (29, 39))	('retinitis pigmentosa', 'Disease', 'MESH:C538365', (110, 130))	('disruption', 'Var', (4, 14))	('CA4', 'Gene', (18, 21))	('CA4', 'Gene', '762', (18, 21))
80573	32922550	Formalin-fixed, paraffin-embedded KIRC tissues and human renal tissues were stained for anti-CA4 using ab236315 (Abcam, USA) at 1/3000 dilution in Fudan University Shanghai Cancer Center (FUSCC) cohort, and then independently evaluated by two experienced pathologists.	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('Cancer', 'Disease', 'MESH:D009369', (173, 179))	('Cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Cancer', 'Disease', (173, 179))	('human', 'Species', '9606', (51, 56))	('ab236315', 'Var', (103, 111))	('paraffin', 'Chemical', 'MESH:D010232', (16, 24))	('CA4', 'Gene', (93, 96))	('CA4', 'Gene', '762', (93, 96))
80592	32922550	Remarkably, CA4 amplification was obviously related to better PFS (KIRC: hazard ratio [HR] = 0.661, p < 0.001; LGG: HR = 0.552, p = 0.002; LUAD: HR = 0.922, p = 0.020; UVM: HR = 0.454, p = 0.001) and better OS (KIRC: HR = 0.847, p < 0.001; LGG: HR = 0.552, p < 0.001; LUAD: HR = 0.918, p = 0.007; UVM: HR = 0.454, p < 0.001) in all of these four cancers.	('CA4', 'Gene', (12, 15))	('CA4', 'Gene', '762', (12, 15))	('UVM', 'Phenotype', 'HP:0007716', (297, 300))	('LUAD', 'Phenotype', 'HP:0030078', (268, 272))	('PFS', 'MPA', (62, 65))	('amplification', 'Var', (16, 29))	('cancers', 'Disease', 'MESH:D009369', (346, 353))	('cancers', 'Phenotype', 'HP:0002664', (346, 353))	('LUAD', 'Phenotype', 'HP:0030078', (139, 143))	('cancers', 'Disease', (346, 353))	('better', 'PosReg', (55, 61))	('UVM', 'Phenotype', 'HP:0007716', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))
80599	32922550	Notably, CA4 amplification obviously correlated with better PFS in KIRC, LGG and LUAD (KIRC: HR = 0.749, p = 0.003; LGG: HR = 0.585, p = 0.005; LUAD: HR = 0.927, p = 0.029) and better OS in KIRC, LGG and UVM (KIRC: HR = 0.900, p = 0.022; LGG: HR = 0.655, p = 0.029; UVM: HR = 0.689, p = 0.005).	('PFS', 'MPA', (60, 63))	('LUAD', 'Phenotype', 'HP:0030078', (81, 85))	('LUAD', 'Phenotype', 'HP:0030078', (144, 148))	('CA4', 'Gene', (9, 12))	('CA4', 'Gene', '762', (9, 12))	('UVM', 'Phenotype', 'HP:0007716', (266, 269))	('UVM', 'Phenotype', 'HP:0007716', (204, 207))	('amplification', 'Var', (13, 26))	('better', 'PosReg', (53, 59))
80623	32922550	Compared with low or no protein expression, high expression of CA2 is related to better survival outcomes, suggesting that CA2 can be a potential marker for this interstitial tumor diagnosis.	('survival', 'CPA', (88, 96))	('high', 'Var', (44, 48))	('tumor', 'Disease', (175, 180))	('CA2', 'Gene', (123, 126))	('CA2', 'Gene', '760', (123, 126))	('CA2', 'Gene', (63, 66))	('CA2', 'Gene', '760', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
80656	32081490	Cohort of 154 UM patients with high risk of hereditary cancer defined as patients with one or more of the following: 1) familial UM; 2) young age (<35 years) at diagnosis; 3) personal history of other primary cancers; 4) family history of >=2 primary cancers with no detectable mutation or deletion in BAP1 gene.	('deletion', 'Var', (290, 298))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('BAP1', 'Gene', '8314', (302, 306))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('familial UM', 'Disease', (120, 131))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('cancers', 'Disease', (251, 258))	('cancers', 'Disease', (209, 216))	('BAP1', 'Gene', (302, 306))	('cancers', 'Disease', 'MESH:D009369', (251, 258))	('patients', 'Species', '9606', (17, 25))	('hereditary cancer', 'Disease', 'MESH:D009369', (44, 61))	('patients', 'Species', '9606', (73, 81))	('hereditary cancer', 'Disease', (44, 61))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
80659	32081490	Clinical characterization of UM patients with germline alterations in known cancer genes.	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('germline alterations', 'Var', (46, 66))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
80660	32081490	We identified actionable pathogenic variants in eight known hereditary cancer predisposition genes (PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1 and CTNNA1) in nine patients, including 3/27 (11%) with familial UM and 6/127 (4.7%) with high-risk for cancer.	('CTNNA1', 'Gene', '1495', (150, 156))	('BRCA1', 'Gene', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('ATM', 'Gene', '472', (135, 138))	('SMARCE1', 'Gene', '6605', (126, 133))	('hereditary cancer', 'Disease', (60, 77))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (71, 77))	('SMARCE1', 'Gene', (126, 133))	('hereditary cancer', 'Disease', 'MESH:D009369', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('MLH1', 'Gene', (107, 111))	('PALB2', 'Gene', (100, 105))	('ATM', 'Gene', (135, 138))	('MSH6', 'Gene', (113, 117))	('PALB2', 'Gene', '79728', (100, 105))	('pathogenic', 'Reg', (25, 35))	('MSH6', 'Gene', '2956', (113, 117))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('CHEK2', 'Gene', (119, 124))	('cancer', 'Disease', (250, 256))	('variants', 'Var', (36, 44))	('CTNNA1', 'Gene', (150, 156))	('BRCA1', 'Gene', '672', (140, 145))	('patients', 'Species', '9606', (166, 174))	('CHEK2', 'Gene', '11200', (119, 124))
80661	32081490	Two patients had pathogenic variants in CHEK2 and PALB2; while variants in the other genes each occurred in one patient.	('patient', 'Species', '9606', (112, 119))	('PALB2', 'Gene', (50, 55))	('variants', 'Var', (28, 36))	('PALB2', 'Gene', '79728', (50, 55))	('patient', 'Species', '9606', (4, 11))	('CHEK2', 'Gene', '11200', (40, 45))	('patients', 'Species', '9606', (4, 12))	('pathogenic', 'Reg', (17, 27))	('CHEK2', 'Gene', (40, 45))
80663	32081490	The frequencies of pathogenic variants in PALB2, MLH1 and SMARCE1 in UM patients were significantly higher than the observed frequencies in non-cancer controls [p=0.02, OR: 8.9 (1.5-30.6); p=0.04, OR: 25.4 (1.2-143); p= 0.001, OR: 2047 (52-4.5e15), respectively].	('variants', 'Var', (30, 38))	('SMARCE1', 'Gene', (58, 65))	('non-cancer', 'Disease', 'MESH:D009369', (140, 150))	('non-cancer', 'Disease', (140, 150))	('PALB2', 'Gene', '79728', (42, 47))	('MLH1', 'Gene', (49, 53))	('SMARCE1', 'Gene', '6605', (58, 65))	('higher', 'PosReg', (100, 106))	('pathogenic', 'CPA', (19, 29))	('PALB2', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('patients', 'Species', '9606', (72, 80))
80664	32081490	The study provides moderate evidence of gene/disease association of germline mutations in PALB2 and MLH1 with hereditary predisposition to UM.	('PALB2', 'Gene', (90, 95))	('germline mutations', 'Var', (68, 86))	('PALB2', 'Gene', '79728', (90, 95))	('MLH1', 'Gene', (100, 104))
80670	32081490	Germline pathogenic variants in BAP1 have been reported in at least 80 UM patients.	('patients', 'Species', '9606', (74, 82))	('variants', 'Var', (20, 28))	('BAP1', 'Gene', (32, 36))	('BAP1', 'Gene', '8314', (32, 36))
80671	32081490	The frequency of BAP1 pathogenic variants is 3-4% in UM with strong personal and family history of cancer  and about 20% in familial UM.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('pathogenic', 'Reg', (22, 32))	('cancer', 'Disease', (99, 105))	('BAP1', 'Gene', '8314', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('variants', 'Var', (33, 41))	('BAP1', 'Gene', (17, 21))
80672	32081490	Germline pathogenic variants in BRCA2 have been reported in a total of six UM patients , MBD4 in four, while only case reports of UM associated with several other genes, including BRCA1, MLH1, CDKN2A, FLCN and MSH6 are documented.	('variants', 'Var', (20, 28))	('CDKN2A', 'Gene', (193, 199))	('FLCN', 'Gene', (201, 205))	('BRCA2', 'Gene', (32, 37))	('reported', 'Reg', (48, 56))	('CDKN2A', 'Gene', '1029', (193, 199))	('patients', 'Species', '9606', (78, 86))	('MSH6', 'Gene', '2956', (210, 214))	('BRCA1', 'Gene', '672', (180, 185))	('MBD4', 'Gene', '8930', (89, 93))	('MBD4', 'Gene', (89, 93))	('BRCA1', 'Gene', (180, 185))	('BRCA2', 'Gene', '675', (32, 37))	('FLCN', 'Gene', '201163', (201, 205))	('MSH6', 'Gene', (210, 214))
80675	32081490	Patients were included if they met one of the following criteria: 1) familial UM defined as a UM with 1st, 2nd or 3rd degree family member with UM;; 2) young age (<35 years) at diagnosis; 3) personal history of other primary cancers; 4) family history of >=2 primary cancers with no detectable mutation or deletion in BAP1 gene.	('met', 'Gene', '79811', (31, 34))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('cancers', 'Disease', (225, 232))	('met', 'Gene', (31, 34))	('cancers', 'Disease', 'MESH:D009369', (267, 274))	('BAP1', 'Gene', '8314', (318, 322))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('Patients', 'Species', '9606', (0, 8))	('cancers', 'Disease', (267, 274))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('familial UM', 'Disease', (69, 80))	('BAP1', 'Gene', (318, 322))	('deletion', 'Var', (306, 314))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
80681	32081490	Variants with a maximum frequency >0.005 as observed in the ExAC (Exome Aggregation Consortium) without TCGA (The Cancer Genome Atlas), the 1000 Genome Project and the EVS (Exome Variant Server) were excluded.	('Cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Variants', 'Var', (0, 8))	('Cancer', 'Disease', 'MESH:D009369', (114, 120))	('Cancer', 'Disease', (114, 120))
80685	32081490	A custom panel of ten microsatellite markers, labeled with either FAM or HEX dyes, was used (BAT25, BAT26, BAT40, NR27, NR21, NR22, D2S123, D3S1260, D17S250 and D5S346).	('BAT25', 'Var', (93, 98))	('D2S123', 'Var', (132, 138))	('D3S1260', 'Var', (140, 147))	('HEX', 'Gene', (73, 76))	('BAT26', 'Var', (100, 105))	('NR22', 'Var', (126, 130))	('HEX', 'Gene', '3087', (73, 76))	('BAT40', 'Var', (107, 112))	('D5S346', 'Var', (161, 167))	('D17S250', 'Var', (149, 156))
80687	32081490	The metric is ratio of the observed number of loss-of-function variants in the gene in gnomAD to what would be expected if such variants were selectively neutral.	('met', 'Gene', '79811', (4, 7))	('met', 'Gene', (4, 7))	('variants', 'Var', (63, 71))	('gnomAD', 'Gene', (87, 93))	('loss-of-function', 'NegReg', (46, 62))
80693	32081490	We identified actionable pathogenic variants in eight known hereditary cancer predisposition genes (PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1 and CTNNA1) accross nine patients, including 3/27 (11.1%) patients with familial UM and 6/127 (4.7%) UM patients with strong personal and/or family history of cancer, (Table 2 and 3).	('CTNNA1', 'Gene', '1495', (150, 156))	('BRCA1', 'Gene', (140, 145))	('ATM', 'Gene', '472', (135, 138))	('SMARCE1', 'Gene', '6605', (126, 133))	('hereditary cancer', 'Disease', (60, 77))	('patients', 'Species', '9606', (204, 212))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('SMARCE1', 'Gene', (126, 133))	('hereditary cancer', 'Disease', 'MESH:D009369', (60, 77))	('patients', 'Species', '9606', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('MLH1', 'Gene', (107, 111))	('PALB2', 'Gene', (100, 105))	('ATM', 'Gene', (135, 138))	('familial UM', 'Disease', (218, 229))	('patients', 'Species', '9606', (250, 258))	('MSH6', 'Gene', (113, 117))	('PALB2', 'Gene', '79728', (100, 105))	('pathogenic', 'Reg', (25, 35))	('MSH6', 'Gene', '2956', (113, 117))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('CHEK2', 'Gene', (119, 124))	('cancer', 'Disease', (305, 311))	('variants', 'Var', (36, 44))	('CTNNA1', 'Gene', (150, 156))	('BRCA1', 'Gene', '672', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('CHEK2', 'Gene', '11200', (119, 124))
80694	32081490	Given the rarity of UM, for the 29 UM patients studied by WES we focused our analysis on rare variants (<= 0.005 minor allele frequency (MAF) in the general population) with strong evidence of pathogenesis (stop gain, start loss, frame shift, canonical splice site <=2 base pairs from exons) and missense variants reported as pathogenic in ClinVar.	('frame', 'Disease', (230, 235))	('pathogenesis', 'biological_process', 'GO:0009405', ('193', '205'))	('patients', 'Species', '9606', (38, 46))	('missense variants', 'Var', (296, 313))	('start', 'Disease', (218, 223))
80695	32081490	In addition to pathogenic variants in four known cancer predisposition genes, CHEK2, MLH1, PALB2 and SMARCE1 (Table 2), pathogenic variants in five other genes were detected, Table 4.	('SMARCE1', 'Gene', '6605', (101, 108))	('PALB2', 'Gene', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('PALB2', 'Gene', '79728', (91, 96))	('MLH1', 'Gene', (85, 89))	('CHEK2', 'Gene', '11200', (78, 83))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('CHEK2', 'Gene', (78, 83))	('SMARCE1', 'Gene', (101, 108))	('cancer', 'Disease', (49, 55))	('variants', 'Var', (26, 34))
80696	32081490	This included three (RECQL4, MMS19 and POLI) genes associated with DNA damage repair, one (DLEC1) reported as a tumor suppressor in UNIPROT (http://www.uniprot.org/keywords/KW-0043), and TP53AIP1, which has been suggested as a cutaneous melanoma (CM) susceptibility gene  In addition, a total of 1969 unique missense variants predicted as deleterious by multiple computational tools were identified by WES.	('melanoma', 'Disease', 'MESH:D008545', (237, 245))	('missense variants', 'Var', (308, 325))	('DLEC1', 'Gene', '9940', (91, 96))	('POLI', 'Gene', '11201', (39, 43))	('MMS19', 'Gene', (29, 34))	('tumor', 'Disease', (112, 117))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('melanoma', 'Disease', (237, 245))	('POLI', 'Gene', (39, 43))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('112', '128'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (227, 245))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('RECQL4', 'Gene', '9401', (21, 27))	('MMS19', 'Gene', '64210', (29, 34))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('112', '128'))	('DLEC1', 'Gene', (91, 96))	('TP53AIP1', 'Gene', (187, 195))	('RECQL4', 'Gene', (21, 27))	('associated', 'Reg', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('TP53AIP1', 'Gene', '63970', (187, 195))
80700	32081490	Variants in DAPK1 and MSH3 were each seen in two patients, variants in LZSTS1 in three patients, while variants in SRRM2 were seen in four patients, including one with two different variants.	('Variants', 'Var', (0, 8))	('LZSTS1', 'Gene', (71, 77))	('patients', 'Species', '9606', (139, 147))	('variants', 'Var', (59, 67))	('MSH3', 'Gene', (22, 26))	('DAPK1', 'Gene', (12, 17))	('MSH3', 'Gene', '4437', (22, 26))	('SRRM2', 'Gene', '23524', (115, 120))	('SRRM2', 'Gene', (115, 120))	('seen', 'Reg', (37, 41))	('patients', 'Species', '9606', (49, 57))	('patients', 'Species', '9606', (87, 95))	('DAPK1', 'Gene', '1612', (12, 17))
80701	32081490	A canonical splice site variant, c.3201+1G>C, in PALB2 was detected in a patient with a personal history of UM and RCC, both diagnosed at age 67 years.	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('patient', 'Species', '9606', (73, 80))	('c.3201+1G>C', 'Mutation', 'rs587776423', (33, 44))	('c.3201+1G>C', 'Var', (33, 44))	('PALB2', 'Gene', (49, 54))	('PALB2', 'Gene', '79728', (49, 54))
80702	32081490	WES of the tumor identified biallelic inactivation of PALB2, with a somatic truncating mutation, c.3279delT:p.Ile1093fs.	('biallelic inactivation', 'Var', (28, 50))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('p.Ile1093fs', 'Var', (108, 119))	('c.3279delT', 'Mutation', 'c.3279delT', (97, 107))	('PALB2', 'Gene', '79728', (54, 59))	('tumor', 'Disease', (11, 16))	('PALB2', 'Gene', (54, 59))	('p.Ile1093fs', 'Mutation', 'p.I1093fsX', (108, 119))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('c.3279delT:p.Ile1093fs', 'Var', (97, 119))
80703	32081490	A 75-80% decrease in the expression of PALB2 was detected in the UM compared to the non-tumor choroid of the same patient, confirming the biallelic inactivation of PALB2 (Figure 1).	('PALB2', 'Gene', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('PALB2', 'Gene', '79728', (39, 44))	('expression', 'MPA', (25, 35))	('patient', 'Species', '9606', (114, 121))	('PALB2', 'Gene', '79728', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('inactivation', 'Var', (148, 160))	('PALB2', 'Gene', (164, 169))	('decrease', 'NegReg', (9, 17))	('tumor', 'Disease', (88, 93))
80706	32081490	In addition to PALB2, this patient had a likely pathogenic non-synonymous variant, c.T470C:p.Ile157Thr (rs17879961) in CHEK2.	('PALB2', 'Gene', '79728', (15, 20))	('c.T470C:p.Ile157Thr', 'SUBSTITUTION', 'None', (83, 102))	('CHEK2', 'Gene', (119, 124))	('rs17879961', 'Var', (104, 114))	('PALB2', 'Gene', (15, 20))	('rs17879961', 'Mutation', 'rs17879961', (104, 114))	('patient', 'Species', '9606', (27, 34))	('c.T470C:p.Ile157Thr', 'Var', (83, 102))	('CHEK2', 'Gene', '11200', (119, 124))
80707	32081490	No tumor tissue was available for the assessment of biallelic inactivation.	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', (3, 8))	('biallelic inactivation', 'Var', (52, 74))	('tumor', 'Disease', 'MESH:D009369', (3, 8))
80708	32081490	One additional patient, a female presenting with UM at age 65 years, breast cancer at age 67 years and multiple non-melanoma skin cancers (ages 62-67 years), had a missense variant of uncertain significance (VUS), c.3418T>G :p.Trp1140Gly (rs62625283) in PALB2.	('c.3418T>G :p.Trp1140Gly (rs62625283', 'Var', (214, 249))	('melanoma skin cancers', 'Disease', (116, 137))	('skin cancer', 'Phenotype', 'HP:0008069', (125, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('PALB2', 'Gene', '79728', (254, 259))	('rs62625283', 'Var', (239, 249))	('c.3418T>G', 'Mutation', 'rs62625283', (214, 223))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('breast cancer', 'Disease', (69, 82))	('skin cancers', 'Phenotype', 'HP:0008069', (125, 137))	('melanoma skin cancers', 'Disease', 'MESH:D012878', (116, 137))	('rs62625283', 'Mutation', 'rs62625283', (239, 249))	('patient', 'Species', '9606', (15, 22))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('p.Trp1140Gly', 'Mutation', 'rs62625283', (225, 237))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('PALB2', 'Gene', (254, 259))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
80710	32081490	Recent, biochemical studies of this variant suggests that it has a deleterious effect on the DNA damage repair function of PALB2 and its interaction with BRCA2.	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('variant', 'Var', (36, 43))	('effect', 'Reg', (79, 85))	('DNA damage repair function', 'MPA', (93, 119))	('BRCA2', 'Gene', (154, 159))	('PALB2', 'Gene', (123, 128))	('PALB2', 'Gene', '79728', (123, 128))	('BRCA2', 'Gene', '675', (154, 159))	('interaction', 'Interaction', (137, 148))
80712	32081490	We further surveyed a database of patients with germline mutations in PALB2 for cases of UM.	('germline mutations', 'Var', (48, 66))	('PALB2', 'Gene', (70, 75))	('PALB2', 'Gene', '79728', (70, 75))	('patients', 'Species', '9606', (34, 42))
80715	32081490	Genetic testing identified a pathogenic germline PALB2 c.3113G>A variant, which results in the generation of a premature stop codon and has been previously reported on multiple occasions.	('c.3113G>A', 'Var', (55, 64))	('pathogenic', 'Reg', (29, 39))	('PALB2', 'Gene', (49, 54))	('c.3113G>A', 'Mutation', 'rs180177132', (55, 64))	('premature stop codon', 'MPA', (111, 131))	('PALB2', 'Gene', '79728', (49, 54))
80717	32081490	A missense pathogenic variant, c.200G>A, p.Gly67Glu (rs63749939), in MLH1 was detected in a female diagnosed with UM at age 49 years, breast cancer at age 39 and a sebaceous adenocarcinoma.	('breast cancer', 'Disease', (134, 147))	('p.Gly67Glu', 'Mutation', 'rs63749939', (41, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('adenocarcinoma', 'Disease', (174, 188))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('c.200G>A', 'Var', (31, 39))	('adenocarcinoma', 'Disease', 'MESH:D000230', (174, 188))	('rs63749939', 'Mutation', 'rs63749939', (53, 63))	('c.200G>A', 'Mutation', 'rs63749939', (31, 39))	('p.Gly67Glu', 'Var', (41, 51))	('MLH1', 'Gene', (69, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('detected', 'Reg', (78, 86))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
80722	32081490	Genotyping with markers in the vicinity of MLH1 (D3S3135) showed loss of heterozygosity, and immunostaining showed loss of MLH1 protein expression in the tumor (Figure 2) but no microsatellite instability was observed.	('expression', 'MPA', (136, 146))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('loss', 'NegReg', (115, 119))	('microsatellite instability', 'Disease', 'MESH:D053842', (178, 204))	('MLH1', 'Gene', (123, 127))	('protein', 'Protein', (128, 135))	('D3S3135', 'Var', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('microsatellite instability', 'Disease', (178, 204))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
80723	32081490	One, c.1039-8T>A (rs193922367) was reported benign in ClinVar, while the other one, c.277A>G:p.Ser93Gly (rs41295282) is rare in the general population (MAF 0.00003 in ExAC and 0.00008 in GO-ESP)but recently reported as likely benign by multiple clinical laboratories.	('rs193922367', 'Var', (18, 29))	('rs41295282', 'Var', (105, 115))	('c.277A>G', 'Mutation', 'rs41295282', (84, 92))	('p.Ser93Gly', 'Mutation', 'rs41295282', (93, 103))	('p.Ser93Gly', 'Var', (93, 103))	('ESP', 'Gene', (190, 193))	('Ser', 'cellular_component', 'GO:0005790', ('95', '98'))	('rs41295282', 'Mutation', 'rs41295282', (105, 115))	('ESP', 'Gene', '148713', (190, 193))	('c.1039-8T>A', 'Mutation', 'rs193922367', (5, 16))	('rs193922367', 'Mutation', 'rs193922367', (18, 29))
80726	32081490	A novel truncating pathogenic variant, c.373G>T:p.Glu125*, was detected in a female patient who was diagnosed with UM at age 46 and endometrial carcinoma at age 51.	('c.373G>T:p.Glu125*', 'Var', (39, 57))	('c.373G>T', 'Mutation', 'rs377072761', (39, 47))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (132, 153))	('p.Glu125*', 'Mutation', 'p.E125*', (48, 57))	('endometrial carcinoma', 'Disease', (132, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (132, 153))	('patient', 'Species', '9606', (84, 91))
80728	32081490	An unreported missense VUS in MSH6, c.2589C>G:p.Cys863Trp, was also identified in the proband.	('MSH6', 'Gene', '2956', (30, 34))	('c.2589C>G', 'Mutation', 'c.2589C>G', (36, 45))	('p.Cys863Trp', 'Var', (46, 57))	('p.Cys863Trp', 'SUBSTITUTION', 'None', (46, 57))	('MSH6', 'Gene', (30, 34))
80732	32081490	Using WES and a cancer gene panel we identified actionable pathogenic variants in eight known hereditary cancer predisposition genes: PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1 and CTNNA1 in nine UM patients, including three (11%) with familial UM and six with strong personal and/or family history of cancer (4.7%).	('SMARCE1', 'Gene', (160, 167))	('cancer', 'Disease', (105, 111))	('PALB2', 'Gene', (134, 139))	('hereditary cancer', 'Disease', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('MLH1', 'Gene', (141, 145))	('hereditary cancer', 'Disease', 'MESH:D009369', (94, 111))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('cancer', 'Disease', (16, 22))	('PALB2', 'Gene', '79728', (134, 139))	('patients', 'Species', '9606', (202, 210))	('CHEK2', 'Gene', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('MSH6', 'Gene', (147, 151))	('pathogenic', 'Reg', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('CTNNA1', 'Gene', (184, 190))	('ATM', 'Gene', '472', (169, 172))	('MSH6', 'Gene', '2956', (147, 151))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('CHEK2', 'Gene', '11200', (153, 158))	('CTNNA1', 'Gene', '1495', (184, 190))	('BRCA1', 'Gene', '672', (174, 179))	('SMARCE1', 'Gene', '6605', (160, 167))	('familial UM', 'Disease', (239, 250))	('BRCA1', 'Gene', (174, 179))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (305, 311))	('variants', 'Var', (70, 78))	('ATM', 'Gene', (169, 172))
80733	32081490	Combined with our previous study of germline mutation in BAP1 in the same cohort, pathogenic variants in established hereditary predisposition genes were detected in 9/33 (27.3%) familial UM patients and 8/129 (6.1%) of UM patients with strong personal and/or family history of cancer.	('patients', 'Species', '9606', (223, 231))	('patients', 'Species', '9606', (191, 199))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('variants', 'Var', (93, 101))	('familial UM', 'Disease', (179, 190))	('BAP1', 'Gene', '8314', (57, 61))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('cancer', 'Disease', (278, 284))	('detected', 'Reg', (154, 162))	('BAP1', 'Gene', (57, 61))
80736	32081490	Among the eight cancer predisposition genes with pathogenic variants observed in our cohort only two (PALB2 and MLH1) showed moderate evidence of an association with hereditary predisposition to UM.	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('PALB2', 'Gene', '79728', (102, 107))	('MLH1', 'Gene', (112, 116))	('cancer', 'Disease', (16, 22))	('association', 'Interaction', (149, 160))	('PALB2', 'Gene', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('variants', 'Var', (60, 68))
80737	32081490	The evidence included the higher frequency of pathogenic variants in the UM cohort compared to the general population, the biallelic inactivation of the gene product in tumors and the observation of pathogenic variants in more than one unrelated UM patient.	('patient', 'Species', '9606', (249, 256))	('pathogenic', 'Reg', (46, 56))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('variants', 'Var', (57, 65))	('tumors', 'Disease', (169, 175))	('biallelic inactivation', 'Var', (123, 145))
80738	32081490	For PALB2 three unrelated cases were identified with pathogenic variants, two identified by screening a UM cohort and the third by screening a PALB2 cohort.	('pathogenic', 'Reg', (53, 63))	('PALB2', 'Gene', '79728', (4, 9))	('PALB2', 'Gene', (143, 148))	('PALB2', 'Gene', (4, 9))	('PALB2', 'Gene', '79728', (143, 148))	('variants', 'Var', (64, 72))
80739	32081490	The personal and family history of the patient with a pathogenic variant in MLH1 was consistent with Lynch syndrome and the personal and/or family histories of the three patients with PALB2 were consistent with the reported cancer phenotype for the gene.	('PALB2', 'Gene', '79728', (184, 189))	('patients', 'Species', '9606', (170, 178))	('patient', 'Species', '9606', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('Lynch syndrome', 'Disease', 'MESH:D003123', (101, 115))	('patient', 'Species', '9606', (170, 177))	('pathogenic', 'Reg', (54, 64))	('Lynch syndrome', 'Disease', (101, 115))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('variant', 'Var', (65, 72))	('cancer', 'Disease', (224, 230))	('PALB2', 'Gene', (184, 189))	('MLH1', 'Gene', (76, 80))
80740	32081490	It is not clear whether UM hereditary risk is unique to MLH1 or could be associated with other mismatch repair genes especially that germline pathogenic variant in MSH6 was observed in one UM patient in our cohort and has been reported in another patient.	('variant', 'Var', (153, 160))	('patient', 'Species', '9606', (192, 199))	('patient', 'Species', '9606', (247, 254))	('mismatch repair', 'biological_process', 'GO:0006298', ('95', '110'))	('MSH6', 'Gene', '2956', (164, 168))	('MSH6', 'Gene', (164, 168))
80741	32081490	One potential explanation of the rarity of UM in subjects with germline pathogenic variant in MLH1 and PALB2 is the 4-6/million general population prevalence of UM so even a 100-fold increase in the odds ratio would still be observed as a rare phenotype.	('variant', 'Var', (83, 90))	('MLH1', 'Gene', (94, 98))	('PALB2', 'Gene', '79728', (103, 108))	('PALB2', 'Gene', (103, 108))
80744	32081490	So far seven probands/families have been reported with germline mutations in SMARCE1: six with meningiomas and one with Coffin-Siris Syndrome and anaplastic astrocytoma.	('Coffin-Siris Syndrome', 'Disease', (120, 141))	('SMARCE1', 'Gene', (77, 84))	('SMARCE1', 'Gene', '6605', (77, 84))	('meningiomas', 'Phenotype', 'HP:0002858', (95, 106))	('Coffin-Siris Syndrome', 'Disease', 'MESH:C536436', (120, 141))	('astrocytoma', 'Phenotype', 'HP:0009592', (157, 168))	('anaplastic astrocytoma', 'Disease', (146, 168))	('meningiomas', 'Disease', (95, 106))	('meningiomas', 'Disease', 'MESH:D008577', (95, 106))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (146, 168))	('germline mutations', 'Var', (55, 73))
80745	32081490	It is noteworthy that evidence of biallelic inactivation of SMARCE1 was observed in some but not all of these patients.	('SMARCE1', 'Gene', (60, 67))	('biallelic inactivation', 'Var', (34, 56))	('SMARCE1', 'Gene', '6605', (60, 67))	('patients', 'Species', '9606', (110, 118))
80749	32081490	Although a significant difference was observed between cases and controls in that study, the high frequency (2%), of TP53AIP1 truncating variants in the non-cancer general population largely preclude it as a predisposition gene to UM or CM.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('non-cancer', 'Disease', (153, 163))	('truncating variants', 'Var', (126, 145))	('non-cancer', 'Disease', 'MESH:D009369', (153, 163))	('TP53AIP1', 'Gene', '63970', (117, 125))	('UM or CM', 'Disease', (231, 239))	('TP53AIP1', 'Gene', (117, 125))
80751	32081490	Pathogenic and likely pathogenic variants in more than one cancer associated gene were observed in several patients most notably PALB2/CHEK2 in one and SMARCE1/MSH6 in another, supplement Table 1.	('SMARCE1', 'Gene', (152, 159))	('patients', 'Species', '9606', (107, 115))	('PALB2', 'Gene', (129, 134))	('PALB2', 'Gene', '79728', (129, 134))	('CHEK2', 'Gene', '11200', (135, 140))	('Pathogenic', 'Reg', (0, 10))	('MSH6', 'Gene', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('CHEK2', 'Gene', (135, 140))	('MSH6', 'Gene', '2956', (160, 164))	('pathogenic', 'CPA', (22, 32))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('variants', 'Var', (33, 41))	('SMARCE1', 'Gene', '6605', (152, 159))
80753	32081490	Combined with previous reports of germline pathogenic variants of several known cancer genes such as BRCA2 , BRCA1, MLH1 CDKN2A, FLCN and MSH6, our study suggests that in UM patients with strong personal and/or family history of cancer a panel testing of at least the known-cancer genes is warranted.	('BRCA1', 'Gene', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('CDKN2A', 'Gene', (121, 127))	('cancer', 'Disease', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('FLCN', 'Gene', '201163', (129, 133))	('CDKN2A', 'Gene', '1029', (121, 127))	('BRCA2', 'Gene', (101, 106))	('MSH6', 'Gene', (138, 142))	('cancer', 'Disease', (229, 235))	('MSH6', 'Gene', '2956', (138, 142))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('FLCN', 'Gene', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('variants', 'Var', (54, 62))	('cancer', 'Disease', (274, 280))	('patients', 'Species', '9606', (174, 182))	('BRCA2', 'Gene', '675', (101, 106))	('BRCA1', 'Gene', '672', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
80754	32081490	Given the high frequency of somatic BAP1 pathogenic alterations in UM, IHC screening of the tumors for BAP1 has very limited role in predicting patients with germline mutation.	('BAP1', 'Gene', '8314', (103, 107))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('alterations', 'Var', (52, 63))	('BAP1', 'Gene', (103, 107))	('BAP1', 'Gene', '8314', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('patients', 'Species', '9606', (144, 152))	('BAP1', 'Gene', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))
80756	32081490	The median age of onset of patients with pathogenic variants in this study, 51 years (range 39-89), was slightly lower than the median age of patients with no pathogenic variants, median 58 years (range 3 months-87 years), but the difference was not statistically significant.	('patients', 'Species', '9606', (142, 150))	('patients', 'Species', '9606', (27, 35))	('lower', 'NegReg', (113, 118))	('variants', 'Var', (52, 60))
80757	32081490	Younger age of onset has been observed in patients with germline BAP1 pathogenic variants  and the frequency of pathogenic variants is much higher (19%) in subjects with young age of onset <= 30 of their tumors compared to general UM population (1-2%).	('pathogenic', 'Reg', (70, 80))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('BAP1', 'Gene', '8314', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('higher', 'PosReg', (140, 146))	('BAP1', 'Gene', (65, 69))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('patients', 'Species', '9606', (42, 50))	('variants', 'Var', (81, 89))
80758	32081490	We recommend screening UM patients developing their tumors at young age for at least germline pathogenic variants in BAP1.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('BAP1', 'Gene', '8314', (117, 121))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('patients', 'Species', '9606', (26, 34))	('BAP1', 'Gene', (117, 121))	('variants', 'Var', (105, 113))
80759	32081490	Actionable pathogenic variants in established cancer genes, other than BAP1, were identified in 3/27 (11%) familial UM and 6/129 (4.7%) of UM with high-risk for hereditary cancer.	('identified', 'Reg', (82, 92))	('hereditary cancer', 'Disease', (161, 178))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (46, 52))	('variants', 'Var', (22, 30))	('BAP1', 'Gene', '8314', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('hereditary cancer', 'Disease', 'MESH:D009369', (161, 178))	('cancer', 'Disease', (172, 178))	('pathogenic', 'Reg', (11, 21))	('BAP1', 'Gene', (71, 75))	('familial UM', 'Disease', (107, 118))
80825	31990743	Disruption of the retinal capillary endothelium leads to downstream activation of the clotting cascade, resulting in nonperfusion and ultimate retinal and optic disc ischemia.	('clotting', 'biological_process', 'GO:0050817', ('86', '94'))	('clotting cascade', 'Pathway', (86, 102))	('optic disc ischemia', 'Disease', 'MESH:D018917', (155, 174))	('activation', 'PosReg', (68, 78))	('optic disc ischemia', 'Disease', (155, 174))	('nonperfusion', 'MPA', (117, 129))	('Disruption', 'Var', (0, 10))
80865	31980621	UMs with the class 1 GEP typically harbor mutations in EIF1AX (class 1A, low metastatic risk), SF3B1, or other splicing factors (class 1B, intermediate metastatic risk), and exhibit chromosomal gains of 6p and 8q.	('EIF1AX', 'Gene', '1964', (55, 61))	('EIF1AX', 'Gene', (55, 61))	('UM', 'Disease', 'MESH:C536494', (0, 2))	('SF3B1', 'Gene', (95, 100))	('SF3B1', 'Gene', '23451', (95, 100))	('chromosomal gains', 'CPA', (182, 199))	('splicing', 'biological_process', 'GO:0045292', ('111', '119'))	('mutations', 'Var', (42, 51))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
80866	31980621	Those with class 2 GEP (high metastatic risk) are associated with inactivating mutations in BAP1, loss of chromosome 1p, 3, 6q and 8p, and gain of 8q.	('GEP', 'Disease', (19, 22))	('inactivating mutations', 'Var', (66, 88))	('chromosome', 'cellular_component', 'GO:0005694', ('106', '116'))	('gain', 'PosReg', (139, 143))	('BAP1', 'Gene', '8314', (92, 96))	('loss', 'Var', (98, 102))	('BAP1', 'Gene', (92, 96))
80870	31980621	As expected, tumor cells cluster most strongly according to the GEP-based clinical prognostic classifier, with the primary division occurring between class 1 (BAP1 wild-type) and class 2 (BAP1 mutant) tumors (Fig.	('tumor', 'Disease', (13, 18))	('BAP1', 'Gene', (188, 192))	('BAP1', 'Gene', '8314', (159, 163))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('BAP1', 'Gene', '8314', (188, 192))	('mutant', 'Var', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('clinical', 'Species', '191496', (74, 82))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumor', 'Disease', (201, 206))	('BAP1', 'Gene', (159, 163))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
80876	31980621	For example, five cases (BSSR0022, UMM062, UMM063, UMM065, and UMM067L) show evidence for initial gain of 8q followed later by gain of 8p.	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('UM', 'Disease', 'MESH:C536494', (51, 53))	('UM', 'Disease', 'MESH:C536494', (35, 37))	('UM', 'Disease', 'MESH:C536494', (63, 65))	('UM', 'Phenotype', 'HP:0007716', (63, 65))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('UM', 'Disease', 'MESH:C536494', (43, 45))	('BSSR0022', 'Var', (25, 33))	('gain', 'PosReg', (98, 102))	('gain', 'PosReg', (127, 131))
80879	31980621	Previous studies showed that canonical genomic aberrations arise early in UM and give rise to one of three principal evolutionary trajectories associated with signature driver mutations:EIF1AX in class 1 A, SF3B1 and other splicing mutations in class 1B, and BAP1 in class 2 tumors, yet the single-cell resolution of our current findings reveal that these tumors continue to evolve with the development of heretofore unrecognized non-canonical CNV subclones that may contribute to tumor progression, as suggested by recent work.	('tumors', 'Phenotype', 'HP:0002664', (356, 362))	('mutations', 'Var', (176, 185))	('tumor', 'Disease', (275, 280))	('tumor', 'Disease', (481, 486))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (356, 361))	('tumors', 'Disease', (356, 362))	('tumor', 'Disease', 'MESH:D009369', (481, 486))	('BAP1', 'Gene', '8314', (259, 263))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('splicing', 'biological_process', 'GO:0045292', ('223', '231'))	('SF3B1', 'Gene', (207, 212))	('tumors', 'Disease', 'MESH:D009369', (356, 362))	('EIF1AX', 'Gene', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (481, 486))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumors', 'Disease', (275, 281))	('BAP1', 'Gene', (259, 263))	('UM', 'Disease', 'MESH:C536494', (74, 76))	('tumor', 'Disease', (356, 361))	('EIF1AX', 'Gene', '1964', (186, 192))	('SF3B1', 'Gene', '23451', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (356, 361))	('tumors', 'Disease', 'MESH:D009369', (275, 281))
80901	31980621	It is interesting to speculate that the long latency and low metastatic rate of class 1 UMs may be due, at least in part, to immune surveillance, which could result from neoantigens generated by EIF1AX and SF3B1 mutations.	('result', 'Reg', (158, 164))	('low', 'NegReg', (57, 60))	('EIF1AX', 'Gene', '1964', (195, 201))	('EIF1AX', 'Gene', (195, 201))	('SF3B1', 'Gene', (206, 211))	('immune', 'MPA', (125, 131))	('UM', 'Phenotype', 'HP:0007716', (88, 90))	('mutations', 'Var', (212, 221))	('SF3B1', 'Gene', '23451', (206, 211))	('UM', 'Disease', 'MESH:C536494', (88, 90))	('metastatic rate', 'CPA', (61, 76))
80937	31980621	Immune cell subpopulations were identified using genes previously reported to identify the following populations: T regulatory cells (FOXP3, TNFRSF4, IKZF2, IL2RA), Follicular T cells (CD200, GNG4, CHN1, IGFL2, ITM2A, CPM, NR3C1), Naive T cells (IL7R), CD8+ T effector memory cells (CD8A, ZNF683), CD8+ resident memory cells (KLRK1, ITGAE [CD103]), Cytotoxic CD8+ T cells (PRF1, GZMA, GZMK, NKG7 with varying levels of expression of the exhaustion markers LAG3, PD1, CTLA4, TIGIT, HAVCR2 [TIM3], and TNFRSF9 [4-1BB]), CD8+ gamma delta T cells (TRDC, TRDG2), Mitotic CD8+ T cells (MKI67, STMN1, HMGB2, TUBB, TUBA1B), Dendritic cells (CD1C and lack of expression of C1QA, C1QB, and C1QC), Monocytes (S100A12, CLEC10A), M2 macrophages (CD163, C1QA, C1QB, C1QC, IL10), M1 macrophages (C1QA, C1QB, C1QC, lack of M2 macrophage markers).	('IL7R', 'molecular_function', 'GO:0004917', ('246', '250'))	('C1QB', 'Gene', '12260', (787, 791))	('CD8', 'Gene', (566, 569))	('TUBB', 'Gene', (601, 605))	('ITM2A', 'Gene', '16431', (211, 216))	('TUBA1B', 'Gene', '22143', (607, 613))	('KLRK1', 'Gene', (326, 331))	('HMGB2', 'Gene', '97165', (594, 599))	('IL2', 'molecular_function', 'GO:0005134', ('157', '160'))	('GNG4', 'Gene', '14706', (192, 196))	('CD8', 'Gene', (253, 256))	('IL7R', 'Gene', (246, 250))	('CPM', 'Gene', (218, 221))	('CPM', 'Gene', '70574', (218, 221))	('IL10', 'molecular_function', 'GO:0005141', ('758', '762'))	('CD8', 'Gene', '925', (566, 569))	('C1QC', 'Gene', '12262', (793, 797))	('CD8', 'Gene', (283, 286))	('PRF1', 'Gene', (373, 377))	('STMN1', 'Gene', (587, 592))	('IL2RA', 'Gene', (157, 162))	('C1QB', 'Gene', (670, 674))	('CD8', 'Gene', (298, 301))	('CD200', 'Gene', '17470', (185, 190))	('CD8', 'Gene', '925', (253, 256))	('IL7R', 'Gene', '16197', (246, 250))	('TRDC', 'Gene', (544, 548))	('C1QB', 'Gene', (787, 791))	('GZMA', 'Gene', '14938', (379, 383))	('C1QB', 'Gene', '12260', (746, 750))	('CD8', 'Gene', (359, 362))	('CD8', 'Gene', '925', (298, 301))	('GNG4', 'Gene', (192, 196))	('memory', 'biological_process', 'GO:0007613', ('269', '275'))	('CD163', 'Var', (733, 738))	('TRDC', 'Gene', '100123473', (544, 548))	('C1QC', 'Gene', (793, 797))	('IKZF2', 'Gene', (150, 155))	('NKG7', 'Gene', '72310', (391, 395))	('CD8', 'Gene', '925', (359, 362))	('MKI67', 'Gene', '17345', (580, 585))	('GZMA', 'Gene', (379, 383))	('HMGB2', 'Gene', (594, 599))	('CHN1', 'Gene', (198, 202))	('NR3C1', 'Gene', '14815', (223, 228))	('ITM2A', 'Gene', (211, 216))	('CD8', 'Gene', (518, 521))	('CD103', 'Gene', '16407', (340, 345))	('IL10', 'Gene', '16153', (758, 762))	('GZMK', 'Gene', (385, 389))	('CD103', 'Gene', (340, 345))	('NKG7', 'Gene', (391, 395))	('CD8', 'Gene', '925', (283, 286))	('CD200', 'Gene', (185, 190))	('C1QA', 'Var', (781, 785))	('C1QB', 'Gene', (746, 750))	('CLEC10A', 'Gene', (707, 714))	('MKI67', 'Gene', (580, 585))	('C1QC', 'Gene', (680, 684))	('CD8', 'Gene', '925', (518, 521))	('C1QC', 'Gene', (752, 756))	('TNFRSF4', 'Gene', '22163', (141, 148))	('memory', 'biological_process', 'GO:0007613', ('312', '318'))	('C1QC', 'Gene', '12262', (680, 684))	('IL2RA', 'Gene', '16184', (157, 162))	('C1QC', 'Gene', '12262', (752, 756))	('NR3C1', 'Gene', (223, 228))	('PRF1', 'Gene', '18646', (373, 377))	('ITGAE', 'Gene', '16407', (333, 338))	('KLRK1', 'Gene', '27007', (326, 331))	('IKZF2', 'Gene', '22779', (150, 155))	('TUBA1B', 'Gene', (607, 613))	('IL10', 'Gene', (758, 762))	('TNFRSF4', 'Gene', (141, 148))	('TUBB', 'Gene', '22153', (601, 605))	('CHN1', 'Gene', '108699', (198, 202))	('CLEC10A', 'Gene', '17312', (707, 714))	('C1QB', 'Gene', '12260', (670, 674))	('ITGAE', 'Gene', (333, 338))	('STMN1', 'Gene', '16765', (587, 592))	('GZMK', 'Gene', '14945', (385, 389))
80952	31980621	UM-specific cells were identified from the annotated Louvain clusters as determined above and filtered for cells expressing any of the following immune cell markers (IGHG1, CD3E, CD68, CD163, LYZ, MS4A1, CD79A, CD14, C1QA).	('CD14', 'Gene', '929', (211, 215))	('CD163', 'Var', (185, 190))	('UM', 'Disease', 'MESH:C536494', (0, 2))	('MS4A1', 'Gene', (197, 202))	('LYZ', 'Gene', '4069', (192, 195))	('CD79A', 'Gene', '973', (204, 209))	('CD3E', 'Gene', '916', (173, 177))	('CD79A', 'Gene', (204, 209))	('CD68', 'Gene', '968', (179, 183))	('CD3E', 'Gene', (173, 177))	('CD68', 'Gene', (179, 183))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('IGHG1', 'Gene', '3500', (166, 171))	('CD14', 'Gene', (211, 215))	('IGHG1', 'Gene', (166, 171))	('MS4A1', 'Gene', '931', (197, 202))	('LYZ', 'Gene', (192, 195))
80961	31980621	The detection cocktail comprised anti-CH014-CL550, anti-CH015-CL490, anti-CH016-CL750 and anti-CH021-CL650.	('anti-CH014-CL550', 'Var', (33, 49))	('anti-CH015-CL490', 'Var', (51, 67))	('CH014', 'Chemical', 'MESH:C574644', (38, 43))	('anti-CH021-CL650', 'Var', (90, 106))	('CH015', 'Chemical', 'MESH:C087338', (56, 61))	('anti-CH016-CL750', 'Var', (69, 85))	('CH021', 'Chemical', 'MESH:C079280', (95, 100))	('CH016', 'Chemical', 'MESH:C060112', (74, 79))
81045	29023197	We identified 281 RBPs to be enriched for mutations (GEMs) in at least one cancer type.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('GEMs', 'cellular_component', 'GO:0015030', ('53', '57'))	('cancer', 'Disease', (75, 81))	('RBP', 'Gene', (18, 21))	('RBP', 'Gene', '57794', (18, 21))	('GEMs', 'cellular_component', 'GO:0097504', ('53', '57'))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (42, 51))
81046	29023197	GEM RBPs were found to undergo frequent frameshift and inframe deletions as well as missense, nonsense and silent mutations when compared to those that are not enriched for mutations.	('nonsense', 'Var', (94, 102))	('RBP', 'Gene', (4, 7))	('RBP', 'Gene', '57794', (4, 7))	('frameshift', 'Var', (40, 50))	('missense', 'Var', (84, 92))
81048	29023197	Using the OncodriveFM framework, we also identified more than 200 candidate driver RBPs that were found to accumulate functionally impactful mutations in at least one cancer.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('mutations', 'Var', (141, 150))	('cancer', 'Disease', (167, 173))	('RBP', 'Gene', (83, 86))	('RBP', 'Gene', '57794', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
81057	29023197	Given the importance of regulatory molecules like RBPs in controlling gene expression, it is evident that any deviation from normal function of these proteins can lead to various disorders including cancer.	('RBP', 'Gene', '57794', (50, 53))	('deviation', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('various disorders', 'Disease', (171, 188))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('gene expression', 'biological_process', 'GO:0010467', ('70', '85'))	('cancer', 'Disease', (199, 205))	('RBP', 'Gene', (50, 53))	('lead to', 'Reg', (163, 170))	('various disorders', 'Disease', 'MESH:C566351', (171, 188))
81062	29023197	An increased expression of this protein facilitates the inclusion of exon5 in the pre-mRNA of CD44 - a cell surface protein involved in cancer proliferation.	('CD44', 'Gene', (94, 98))	('increased', 'PosReg', (3, 12))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('expression', 'MPA', (13, 23))	('exon5', 'Protein', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cell surface', 'cellular_component', 'GO:0009986', ('103', '115'))	('pre', 'molecular_function', 'GO:0003904', ('82', '85'))	('cancer', 'Disease', (136, 142))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('CD44', 'Gene', '960', (94, 98))	('facilitates', 'PosReg', (40, 51))	('inclusion', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
81069	29023197	Mutational analysis of all the genes in the human genome across 12 cancer types identified SF3B1, U2AF1 and PCBP1 - RBPs involved in splicing to be significantly mutated in multiple cancers suggesting their role in causing cancer phenotypes.	('human', 'Species', '9606', (44, 49))	('SF3B1', 'Gene', (91, 96))	('PCBP1', 'Gene', (108, 113))	('splicing', 'biological_process', 'GO:0045292', ('133', '141'))	('U2AF1', 'Gene', (98, 103))	('cancer', 'Disease', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('RBP', 'Gene', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('SF3B1', 'Gene', '23451', (91, 96))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('U2AF1', 'Gene', '7307', (98, 103))	('multiple cancers', 'Disease', 'MESH:D009369', (173, 189))	('cancer', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('mutated', 'Var', (162, 169))	('PCBP1', 'Gene', '5093', (108, 113))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (67, 73))	('multiple cancers', 'Disease', (173, 189))	('U2AF', 'cellular_component', 'GO:0089701', ('98', '102'))	('RBP', 'Gene', '57794', (116, 119))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
81070	29023197	Furthermore, APOBEC3B - an important protein in the RNA editing mechanism was found to be upregulated and frequently mutated in cancers of bladder, cervix, lung, head and neck and breast.	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('mutated', 'Var', (117, 124))	('cancers of bladder', 'Disease', (128, 146))	('cervix', 'Disease', (148, 154))	('cancers of bladder', 'Disease', 'MESH:D001749', (128, 146))	('neck', 'cellular_component', 'GO:0044326', ('171', '175'))	('APOBEC3B', 'Gene', (13, 21))	('APOBEC3B', 'Gene', '9582', (13, 21))	('breast', 'Disease', (180, 186))	('lung', 'Disease', (156, 160))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('APOBEC', 'cellular_component', 'GO:0030895', ('13', '19'))	('upregulated', 'PosReg', (90, 101))	('RNA editing', 'biological_process', 'GO:0009451', ('52', '63'))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))
81071	29023197	Also notable are the mutations in the gene coding for RBM10 in lung cancer which was found to misregulate the alternative splicing of NUMB protein- a critical regulator of the Notch pathway and hence leading to irregular cell proliferation in lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (243, 254))	('lung cancers', 'Phenotype', 'HP:0100526', (243, 255))	('lung cancer', 'Disease', (63, 74))	('RBM10', 'Gene', '8241', (54, 59))	('splicing', 'biological_process', 'GO:0045292', ('122', '130'))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('alternative splicing', 'MPA', (110, 130))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('NUMB', 'Gene', (134, 138))	('irregular cell proliferation', 'CPA', (211, 239))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('misregulate', 'Var', (94, 105))	('mutations', 'Var', (21, 30))	('irregular cell proliferation', 'Phenotype', 'HP:0031377', (211, 239))	('NUMB', 'Gene', '8650', (134, 138))	('lung cancers', 'Disease', 'MESH:D008175', (243, 255))	('cell proliferation', 'biological_process', 'GO:0008283', ('221', '239'))	('lung cancer', 'Disease', 'MESH:D008175', (243, 254))	('RBM10', 'Gene', (54, 59))	('lung cancers', 'Disease', (243, 255))	('leading to', 'Reg', (200, 210))
81073	29023197	Hence, to expand the current understanding of mutations in these genes, we performed a systematic analyses of somatic mutations occurring in ~1300 RBPs in ~6000 tumor samples across 26 cancer types.	('tumor', 'Disease', (161, 166))	('RBP', 'Gene', (147, 150))	('RBP', 'Gene', '57794', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mutations', 'Var', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
81075	29023197	We then analyzed the exome sequencing data of 26 cancer types to identify candidate drivers and integrated their transcriptome profiles to assess alterations in their expression due to mutation.	('expression', 'MPA', (167, 177))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('mutation', 'Var', (185, 193))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
81079	29023197	Secondly, we identify Genes Enriched for Mutations (GEMs) in a given cancer using a Fisher's exact test that calculates the probability of observing mutations in a given gene against a genomic background (Fig.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('GEMs', 'cellular_component', 'GO:0015030', ('52', '56'))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('GEMs', 'cellular_component', 'GO:0097504', ('52', '56'))	('Mutations', 'Var', (41, 50))	('cancer', 'Disease', (69, 75))
81080	29023197	Finally, we identify RBPs that accumulate high functionally-impactful mutations using OncodriveFM approach (Fig.	('RBP', 'Gene', (21, 24))	('mutations', 'Var', (70, 79))	('RBP', 'Gene', '57794', (21, 24))
81081	29023197	1C) (See Materials and Methods) that relies on SIFT, PPH2 and Mutation Assessor to estimate the functional impact of individual mutations.	('SIFT', 'Disease', 'None', (47, 51))	('mutations', 'Var', (128, 137))	('PPH', 'molecular_function', 'GO:0033978', ('53', '56'))	('SIFT', 'Disease', (47, 51))	('PPH', 'molecular_function', 'GO:0004238', ('53', '56'))
81082	29023197	It does so by computing the bias towards the accumulation of high-impact mutations across the cancer in the cohort as a signal of their involvement in tumorogenesis.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('mutations', 'Var', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
81086	29023197	Overall, we find the mutational frequency of Non-RBPs to be significantly higher than that of RBPs in ~70% of the cancer types studied (Fig.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('higher', 'PosReg', (74, 80))	('RBP', 'Gene', (49, 52))	('RBP', 'Gene', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('RBP', 'Gene', '57794', (49, 52))	('RBP', 'Gene', '57794', (94, 97))	('mutational', 'Var', (21, 31))	('cancer', 'Disease', (114, 120))
81102	29023197	S1D), suggesting that these observations could reveal common mechanisms of dysregulation at post-transcriptional level with in members of these cancer type clusters due to mutations in RBPs.	('mutations', 'Var', (172, 181))	('cancer type clusters', 'Disease', (144, 164))	('RBP', 'Gene', (185, 188))	('RBP', 'Gene', '57794', (185, 188))	('cancer type clusters', 'Disease', 'MESH:D003027', (144, 164))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
81104	29023197	1B to identify Genes Enriched for Mutations (GEMs) in a given cancer type (see Materials and Methods).	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Mutations', 'Var', (34, 43))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('GEMs', 'cellular_component', 'GO:0015030', ('45', '49'))	('GEMs', 'cellular_component', 'GO:0097504', ('45', '49'))
81105	29023197	This identified 281 genes encoding for RBPs to be significantly enriched for mutations in at least one cancer (see Fig.	('RBP', 'Gene', '57794', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('RBP', 'Gene', (39, 42))
81106	29023197	3A for RBPs enriched for mutations in at least 4 cancers and Fig.	('mutations', 'Var', (25, 34))	('RBP', 'Gene', (7, 10))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('RBP', 'Gene', '57794', (7, 10))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))
81108	29023197	Comparison of GEM and non-GEM RBPs with corresponding gene sets for non-RBPs, for differences in the GC content and exome length, revealed that while GC content does not contribute to the extent of mutations in RBPs (p = 0.496, Wilcoxon test), it was found to be significantly different (p = 4.21e-08, Wilcoxon test) between GEM and non-GEM groups for non-RBPs (Fig.	('RBP', 'Gene', '57794', (30, 33))	('RBP', 'Gene', (356, 359))	('RBP', 'Gene', '57794', (72, 75))	('RBP', 'Gene', '57794', (356, 359))	('mutations', 'Var', (198, 207))	('RBP', 'Gene', (72, 75))	('RBP', 'Gene', (211, 214))	('RBP', 'Gene', '57794', (211, 214))	('different', 'Reg', (277, 286))	('RBP', 'Gene', (30, 33))
81110	29023197	These observations suggest that while GC content has no significant influence on the extent of mutations in RBPs, exome length might be higher for GEM RBPs, however it does not necessarily determine whether a gene is a GEM since non-RBPs GEMs exhibited significantly lower exome lengths.	('RBP', 'Gene', (233, 236))	('RBP', 'Gene', (151, 154))	('exome lengths', 'MPA', (273, 286))	('exome length', 'MPA', (114, 126))	('higher', 'PosReg', (136, 142))	('RBP', 'Gene', '57794', (151, 154))	('RBP', 'Gene', '57794', (233, 236))	('RBP', 'Gene', (108, 111))	('RBP', 'Gene', '57794', (108, 111))	('GEMs', 'cellular_component', 'GO:0015030', ('238', '242'))	('mutations', 'Var', (95, 104))	('lower', 'NegReg', (267, 272))	('GEMs', 'cellular_component', 'GO:0097504', ('238', '242'))
81111	29023197	Among the GEM RBPs, we identified KMT2C (MLL3), a histone 3- lysine 4 methyltransferase with tumor-suppressor properties that belongs to a family of chromatin regulator genes, to be enriched for mutations in 40% of the cancer types (Fig.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('93', '109'))	('RBP', 'Gene', (14, 17))	('tumor', 'Disease', (93, 98))	('MLL3', 'Gene', (41, 45))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('93', '109'))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('chromatin', 'cellular_component', 'GO:0000785', ('149', '158'))	('mutations', 'Var', (195, 204))	('KMT2C', 'Gene', '58508', (34, 39))	('cancer', 'Disease', (219, 225))	('KMT2C', 'Gene', (34, 39))	('RBP', 'Gene', '57794', (14, 17))	('MLL3', 'Gene', '58508', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
81113	29023197	Furthermore, PLEC (plectin) - an abundantly expressed versatile protein that links different elements of the cytoskeleton was also seen to be enriched for mutations in 11 cancer types including lung, head and neck, bladder and pancreas.	('plectin', 'Gene', '5339', (19, 26))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('109', '121'))	('mutations', 'Var', (155, 164))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('neck', 'cellular_component', 'GO:0044326', ('209', '213'))	('cancer', 'Disease', (171, 177))	('PLEC', 'Gene', '5339', (13, 17))	('lung', 'Disease', (194, 198))	('PLEC', 'Gene', (13, 17))	('plectin', 'Gene', (19, 26))	('bladder and pancreas', 'Disease', 'MESH:D001749', (215, 235))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
81116	29023197	Also notable is the gene encoding for EPPK1 which was seen to be mutated in ~40% of the cancers including cancers of cervix, colon, head and neck, pancreas etc.	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('pancreas', 'Disease', (147, 155))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (88, 95))	('EPPK1', 'Gene', '83481', (38, 43))	('neck', 'cellular_component', 'GO:0044326', ('141', '145'))	('cancers', 'Disease', (106, 113))	('EPPK1', 'Gene', (38, 43))	('colon', 'Disease', (125, 130))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutated', 'Var', (65, 72))
81118	29023197	Further, functional analysis of RBPs enriched for mutations identified diverse pathways including translation, mRNA splicing and apoptosis to be over-represented (p < 0.01, Fig.	('mRNA splicing', 'biological_process', 'GO:0000373', ('111', '124'))	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('mRNA splicing', 'biological_process', 'GO:0006371', ('111', '124'))	('mRNA splicing', 'biological_process', 'GO:0000398', ('111', '124'))	('translation', 'biological_process', 'GO:0006412', ('98', '109'))	('apoptosis', 'CPA', (129, 138))	('mRNA splicing', 'biological_process', 'GO:0000394', ('111', '124'))	('mutations', 'Var', (50, 59))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('mRNA splicing', 'biological_process', 'GO:0000372', ('111', '124'))	('translation', 'MPA', (98, 109))	('over-represented', 'PosReg', (145, 161))	('RBP', 'Gene', (32, 35))	('mRNA splicing', 'biological_process', 'GO:0000374', ('111', '124'))	('mRNA splicing', 'MPA', (111, 124))	('RBP', 'Gene', '57794', (32, 35))
81120	29023197	As different genes are susceptible to undergo different kinds of mutations at varied frequency, we aimed to identify mutation types that RBPs enriched for mutations (GEM-RBPs) frequently undergo when compared to RBPs that are not enriched for mutations (NonGEM-RBPs) (See Materials and Methods).	('mutations', 'Var', (155, 164))	('RBP', 'Gene', (212, 215))	('RBP', 'Gene', (137, 140))	('RBP', 'Gene', '57794', (212, 215))	('RBP', 'Gene', (261, 264))	('RBP', 'Gene', '57794', (137, 140))	('RBP', 'Gene', '57794', (261, 264))	('RBP', 'Gene', (170, 173))	('RBP', 'Gene', '57794', (170, 173))
81121	29023197	In particular, we quantified the mutation frequencies of nine different classes of mutations namely Frameshift mutations - Deletion and Insertion, Inframe Deletion, Inframe Insertion, Missense, Nonsense, Nonstop, Silent and Splice Site for all the RBPs across cancer samples (Materials and Methods, Table S2).	('Inframe Deletion', 'Var', (147, 163))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('RBP', 'Gene', (248, 251))	('cancer', 'Disease', (260, 266))	('Nonstop', 'Var', (204, 211))	('Missense', 'Var', (184, 192))	('RBP', 'Gene', '57794', (248, 251))	('Insertion', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('Nonsense', 'Var', (194, 202))	('Frameshift mutations - Deletion', 'Var', (100, 131))
81122	29023197	Our analysis clearly revealed that RBPs frequently and significantly undergo Frameshift deletion, Inframe deletion, Missense, Nonsense and Silent mutations (Fig.	('Frameshift deletion', 'Var', (77, 96))	('Silent mutations', 'Var', (139, 155))	('Inframe deletion', 'Var', (98, 114))	('RBP', 'Gene', (35, 38))	('RBP', 'Gene', '57794', (35, 38))	('Missense', 'Var', (116, 124))	('undergo', 'Reg', (69, 76))
81124	29023197	Abundance of Frameshift deletions in GEM-RBPs clearly indicates that deletion mutations causing change in reading frame thereby resulting in different translation than the original polypeptide, could be a frequent mechanism of dysregulation.	('deletion mutations', 'Var', (69, 87))	('RBP', 'Gene', (41, 44))	('RBP', 'Gene', '57794', (41, 44))	('resulting in different', 'Reg', (128, 150))	('translation', 'MPA', (151, 162))	('Frameshift deletions', 'Var', (13, 33))	('translation', 'biological_process', 'GO:0006412', ('151', '162'))	('reading frame', 'MPA', (106, 119))
81125	29023197	Also, a significant difference in the frequency of nonsense mutations - which introduce a premature termination codon (PTC) in the gene; between the two groups indicate the importance of these mutations in triggering the mechanism of nonsense mediate decay (NMD) of RBPs enriched for mutations in several cancers.	('cancers', 'Disease', 'MESH:D009369', (305, 312))	('cancers', 'Phenotype', 'HP:0002664', (305, 312))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('cancers', 'Disease', (305, 312))	('mutations', 'Var', (193, 202))	('RBP', 'Gene', (266, 269))	('RBP', 'Gene', '57794', (266, 269))
81127	29023197	This study showed that mutations that change the reading frame and introduce a premature termination codon cause a severe form of the disease as the whole transcript is eliminated by NMD, whereas mutations that did not give rise to a PTC resulted in a milder form of muscular dystrophy.	('muscular dystrophy', 'Disease', (267, 285))	('muscular dystrophy', 'Disease', 'MESH:D009136', (267, 285))	('cause', 'Reg', (107, 112))	('premature termination codon', 'MPA', (79, 106))	('mutations', 'Var', (23, 32))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (267, 285))	('eliminated', 'NegReg', (169, 179))
81128	29023197	A similar mechanism could be leading to the dysregulation of RBPs that are enriched for mutations in several cancer phenotypes, due to the higher mutational rate of nonsense mutations in GEM-RBPs (Fig.	('nonsense mutations', 'Var', (165, 183))	('RBP', 'Gene', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('RBP', 'Gene', '57794', (61, 64))	('mutational rate', 'MPA', (146, 161))	('cancer', 'Disease', (109, 115))	('dysregulation', 'MPA', (44, 57))	('RBP', 'Gene', (191, 194))	('RBP', 'Gene', '57794', (191, 194))	('higher', 'PosReg', (139, 145))
81129	29023197	Likewise, missense mutations that result in a change in the amino acid composition and inframe deletions which although do not change the frame of transcription but can result in a dysfunctional protein form could contribute to the loss of function phenotypes in RBPs enriched for mutations.	('dysfunctional', 'Disease', (181, 194))	('dysfunctional', 'Disease', 'MESH:D006331', (181, 194))	('amino acid composition', 'MPA', (60, 82))	('protein form', 'MPA', (195, 207))	('transcription', 'biological_process', 'GO:0006351', ('147', '160'))	('result', 'Reg', (169, 175))	('missense mutations', 'Var', (10, 28))	('RBP', 'Gene', '57794', (263, 266))	('RBP', 'Gene', (263, 266))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))	('change', 'Reg', (46, 52))
81130	29023197	In addition to identifying Genes Enriched for Mutations (GEMs), which can comprise of both synonymous and nonsynonymous somatic mutations in a cancer genome, we aimed to uncover RBPs that exhibit a bias towards the accumulation of nonsynonymous mutations with high functional impact during tumorigenesis, as a means to uncover likely driver RBPs.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('GEMs', 'cellular_component', 'GO:0015030', ('57', '61'))	('RBP', 'Gene', (178, 181))	('RBP', 'Gene', '57794', (178, 181))	('GEMs', 'cellular_component', 'GO:0097504', ('57', '61'))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('RBP', 'Gene', (341, 344))	('cancer', 'Disease', (143, 149))	('nonsynonymous mutations', 'Var', (231, 254))	('RBP', 'Gene', '57794', (341, 344))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('accumulation', 'PosReg', (215, 227))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumor', 'Disease', (290, 295))
81131	29023197	Driver genes are known to provide a significant growth advantage to cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('genes', 'Var', (7, 12))	('cancer', 'Disease', (68, 74))	('growth advantage', 'CPA', (48, 64))
81133	29023197	A significant trend towards the accumulation of such functional mutations is calculated as FM bias - signal of positive selection during cancer development (See Materials and Methods).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (137, 143))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (137, 143))
81140	29023197	We predict AHNAK to be a candidate driver in 12 cancers including head and neck squamous carcinoma, lung adenocarcinoma, lung squamous carcinoma, breast cancers (See Table S3) suggesting the impact of nonsynonymous mutations on protein function and thus misregulating pathways responsible for cellular growth and hence leading to a cancer phenotype.	('lung squamous carcinoma', 'Disease', (121, 144))	('lung adenocarcinoma', 'Disease', (100, 119))	('neck squamous carcinoma', 'Disease', 'MESH:D000077195', (75, 98))	('cancer', 'Disease', (153, 159))	('cancers', 'Disease', (153, 160))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('leading to', 'Reg', (319, 329))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (100, 119))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('protein', 'cellular_component', 'GO:0003675', ('228', '235'))	('pathways', 'Pathway', (268, 276))	('nonsynonymous mutations', 'Var', (201, 224))	('protein', 'Protein', (228, 235))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('breast cancers', 'Disease', 'MESH:D001943', (146, 160))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (100, 119))	('breast cancers', 'Disease', (146, 160))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancers', 'Disease', (48, 55))	('misregulating', 'Reg', (254, 267))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('impact', 'Reg', (191, 197))	('AHNAK', 'Gene', '79026', (11, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('breast cancers', 'Phenotype', 'HP:0003002', (146, 160))	('cancer', 'Disease', (332, 338))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('AHNAK', 'Gene', (11, 16))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (80, 98))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('cellular growth', 'biological_process', 'GO:0016049', ('293', '308'))	('neck squamous carcinoma', 'Disease', (75, 98))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (126, 144))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('neck', 'cellular_component', 'GO:0044326', ('75', '79'))
81141	29023197	Another striking example is AGO2 which was found to accumulate functional mutations in cancers of breast, skin, lung and stomach.	('AGO2', 'Gene', '27161', (28, 32))	('cancers of breast', 'Disease', 'MESH:D001943', (87, 104))	('stomach', 'Disease', (121, 128))	('mutations', 'Var', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('skin', 'Disease', (106, 110))	('AGO2', 'Gene', (28, 32))	('cancers of breast', 'Disease', (87, 104))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('lung', 'Disease', (112, 116))
81148	29023197	Interestingly, we find the gene encoding SF3B1 - an important splicing factor to be frequently mutated and accumulating functional mutations in uveal melanoma (UVM) which is in accordance with a study that showed the impact of SF3B1 mutations on alternative splicing in uveal melanomas.	('uveal melanomas', 'Disease', (270, 285))	('uveal melanomas', 'Phenotype', 'HP:0007716', (270, 285))	('melanomas', 'Phenotype', 'HP:0002861', (276, 285))	('splicing', 'biological_process', 'GO:0045292', ('258', '266'))	('SF3B1', 'Gene', '23451', (227, 232))	('splicing factor', 'Gene', (62, 77))	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('SF3B1', 'Gene', (41, 46))	('uveal melanoma', 'Disease', 'MESH:C536494', (144, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('uveal melanoma', 'Disease', (144, 158))	('splicing factor', 'Gene', '10569', (62, 77))	('uveal melanomas', 'Disease', 'MESH:C536494', (270, 285))	('uveal melanoma', 'Disease', 'MESH:C536494', (270, 284))	('uveal melanoma', 'Phenotype', 'HP:0007716', (144, 158))	('SF3B1', 'Gene', '23451', (41, 46))	('mutations', 'Var', (131, 140))	('splicing', 'biological_process', 'GO:0045292', ('62', '70'))	('SF3B1', 'Gene', (227, 232))	('uveal melanoma', 'Phenotype', 'HP:0007716', (270, 284))	('mutations', 'Var', (233, 242))
81149	29023197	Furthermore, recurrent missense mutation at R625 in patients with uveal melanoma was observed suggesting an oncogenic role of this mutation (Fig.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('uveal melanoma', 'Disease', (66, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('missense mutation at R625', 'Var', (23, 48))	('patients', 'Species', '9606', (52, 60))
81152	29023197	Also, recurrent missense mutations at S34 in the zf-CCCH domain was observed to be highly recurrent in patients with LAML (Fig.	('LAML', 'Disease', (117, 121))	('patients', 'Species', '9606', (103, 111))	('missense mutations at S34', 'Var', (16, 41))
81153	29023197	To identify if mutations in an RBP gene affects its RNA levels, we performed pan-cancer expression analysis for all the candidate RBP drivers between patient cohorts containing these mutations and cohorts that don't carry such mutations (See Materials and Methods).	('RBP', 'Gene', (130, 133))	('patient', 'Species', '9606', (150, 157))	('affects', 'Reg', (40, 47))	('mutations', 'Var', (183, 192))	('RBP', 'Gene', '57794', (130, 133))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('mutations', 'Var', (15, 24))	('cancer', 'Disease', (81, 87))	('RBP', 'Gene', (31, 34))	('RBP', 'Gene', '57794', (31, 34))	('RNA levels', 'MPA', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))
81155	29023197	Of these, CDKN2A, a cyclin-dependent kinase inhibitor 2A known to stabilize the tumor suppressor protein p53 was observed to have higher levels of RNA in mutated samples when compared to the non-mutated samples (Fold change = 3.9, p = 1.26E-11, Wilcox test).	('kinase inhibitor', 'biological_process', 'GO:0033673', ('37', '53'))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('p53', 'Gene', (105, 108))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (20, 56))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('mutated', 'Var', (154, 161))	('CDKN2A', 'Gene', (10, 16))	('RNA', 'MPA', (147, 150))	('higher', 'PosReg', (130, 136))	('tumor', 'Disease', (80, 85))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('20', '53'))	('RNA', 'cellular_component', 'GO:0005562', ('147', '150'))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('CDKN2A', 'Gene', '1029', (10, 16))	('p53', 'Gene', '7157', (105, 108))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (20, 56))	('levels', 'MPA', (137, 143))
81156	29023197	Additionally, two distinct RNA helicases - DDX5 and DHX9 were found to have significantly different expression profiles between mutated and non-mutated cohorts.	('RNA helicases', 'Protein', (27, 40))	('expression profiles', 'MPA', (100, 119))	('mutated', 'Var', (128, 135))	('RNA', 'cellular_component', 'GO:0005562', ('27', '30'))	('different', 'Reg', (90, 99))	('DDX5', 'Gene', (43, 47))	('DHX9', 'Gene', (52, 56))	('DDX5', 'Gene', '1655', (43, 47))	('DHX9', 'Gene', '1660', (52, 56))
81158	29023197	RBM10 was seen to be 2 fold down regulated in mutated samples when compared to the non-mutated samples.	('RBM10', 'Gene', (0, 5))	('down regulated', 'NegReg', (28, 42))	('mutated', 'Var', (46, 53))	('RBM10', 'Gene', '8241', (0, 5))
81159	29023197	We hypothesize that the lower expression in the mutated samples could be a result of the presence of truncated transcripts due to several non-sense mutations in the gene encoding for RBM10 (Fig.	('mutations', 'Var', (148, 157))	('expression', 'MPA', (30, 40))	('lower', 'NegReg', (24, 29))	('RBM10', 'Gene', '8241', (183, 188))	('RBM10', 'Gene', (183, 188))
81160	29023197	Hence, mutations in the RBP gene might not only lead to abnormal subcellular localization, defective binding to RNA but also lead to altered protein-protein interactions and thus conferring a cancer phenotype.	('conferring', 'Reg', (179, 189))	('defective', 'NegReg', (91, 100))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('protein-protein interactions', 'MPA', (141, 169))	('cancer', 'Disease', (192, 198))	('binding', 'Interaction', (101, 108))	('abnormal', 'Reg', (56, 64))	('lead', 'Reg', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('subcellular localization', 'MPA', (65, 89))	('RBP', 'Gene', '57794', (24, 27))	('altered', 'Reg', (133, 140))	('mutations', 'Var', (7, 16))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))	('localization', 'biological_process', 'GO:0051179', ('77', '89'))	('RNA', 'Protein', (112, 115))	('RNA', 'cellular_component', 'GO:0005562', ('112', '115'))	('RBP', 'Gene', (24, 27))	('lead', 'Reg', (48, 52))
81170	29023197	Higher degree, betweenness and closeness of drivers when compared to the non-drivers indicates that they form an integral part of the protein-protein interaction network of RBPs and thus mutations in them could significantly contribute to causing lethal phenotypes by potentially disrupting the formation of RNP complexes.	('disrupting', 'NegReg', (280, 290))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('contribute', 'Reg', (225, 235))	('formation', 'MPA', (295, 304))	('RNP', 'Gene', (308, 311))	('mutations', 'Var', (187, 196))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('RNP', 'Gene', '55599', (308, 311))	('RBP', 'Gene', (173, 176))	('causing', 'Reg', (239, 246))	('RBP', 'Gene', '57794', (173, 176))	('RNP', 'cellular_component', 'GO:1990904', ('308', '311'))	('formation', 'biological_process', 'GO:0009058', ('295', '304'))
81173	29023197	Hence, mutations in them may not only affect the expression, defective binding to RNA but can also lead to altered protein-protein interactions and thus conferring a cancer phenotype.	('RNA', 'cellular_component', 'GO:0005562', ('82', '85'))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('cancer', 'Disease', (166, 172))	('defective', 'NegReg', (61, 70))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('RNA', 'Protein', (82, 85))	('lead to altered', 'Reg', (99, 114))	('expression', 'MPA', (49, 59))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('conferring', 'Reg', (153, 163))	('protein-protein interactions', 'MPA', (115, 143))	('binding', 'Interaction', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('affect', 'Reg', (38, 44))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))	('mutations', 'Var', (7, 16))
81181	29023197	This RBP interacts with CDC5L and SF3A1 in LUAD whereas it interacts with SNRNP300 and SF3B3 in COAD suggesting that different combinations of RBP mutated complexes could be contributing to disruption in different post-transcriptional sub-networks leading to varying cancer phenotypes.	('COAD', 'Disease', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('disruption', 'Reg', (190, 200))	('LUAD', 'Disease', (43, 47))	('RBP', 'Gene', (5, 8))	('leading to', 'Reg', (248, 258))	('RBP', 'Gene', '57794', (143, 146))	('CDC5L', 'Gene', (24, 29))	('post-transcriptional sub-networks', 'Pathway', (214, 247))	('SNRNP', 'cellular_component', 'GO:0030532', ('74', '79'))	('SF3B3', 'Gene', (87, 92))	('mutated', 'Var', (147, 154))	('contributing', 'Reg', (174, 186))	('CDC5L', 'Gene', '988', (24, 29))	('interacts', 'Reg', (9, 18))	('cancer', 'Disease', (267, 273))	('SF3B3', 'Gene', '23450', (87, 92))	('SF3A1', 'Gene', '10291', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('COAD', 'Disease', 'MESH:D029424', (96, 100))	('RBP', 'Gene', '57794', (5, 8))	('RNP', 'Gene', '55599', (76, 79))	('RBP', 'Gene', (143, 146))	('SNRNP', 'molecular_function', 'GO:0003734', ('74', '79'))	('SF3A1', 'Gene', (34, 39))	('RNP', 'Gene', (76, 79))
81185	29023197	Hence, to understand if the mutations in these proteins are truly deleterious and/or can have a phenotypic impact in breast cancer, we choose SF3B1 and PRPF8 to study their effect on breast cancer cell lines.	('PRPF8', 'Gene', (152, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))	('SF3B1', 'Gene', '23451', (142, 147))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('SF3B1', 'Gene', (142, 147))	('breast cancer', 'Disease', (117, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('PRPF8', 'Gene', '10594', (152, 157))	('breast cancer', 'Disease', (183, 196))	('mutations', 'Var', (28, 37))
81189	29023197	Despite inefficient knockdown of SF3B1 (Fig.	('knockdown', 'Var', (20, 29))	('SF3B1', 'Gene', (33, 38))	('SF3B1', 'Gene', '23451', (33, 38))
81190	29023197	8A), CD44+/CD24+ cells were reproducibly reduced upon SF3B1 knockdown (Fig.	('CD24', 'Gene', (11, 15))	('reduced', 'NegReg', (41, 48))	('SF3B1', 'Gene', (54, 59))	('CD44', 'Gene', (5, 9))	('SF3B1', 'Gene', '23451', (54, 59))	('knockdown', 'Var', (60, 69))	('CD24', 'Gene', '100133941', (11, 15))	('CD44', 'Gene', '960', (5, 9))
81191	29023197	By contrast, SF3B1 knockdown cells displayed elevated levels of CD24 compared with control luciferase siRNA transfected cells (Fig.	('CD24', 'Gene', '100133941', (64, 68))	('SF3B1', 'Gene', (13, 18))	('knockdown', 'Var', (19, 28))	('CD24', 'Gene', (64, 68))	('SF3B1', 'Gene', '23451', (13, 18))	('elevated', 'PosReg', (45, 53))	('levels', 'MPA', (54, 60))
81192	29023197	Similar results were obtained upon knockdown of PRPF8 in these cells (Fig.	('knockdown', 'Var', (35, 44))	('PRPF8', 'Gene', '10594', (48, 53))	('PRPF8', 'Gene', (48, 53))
81193	29023197	Interestingly, SF3B1 or PRPF8 knockdown in MDA-MB-231 cell line, which represents mesenchymal stem like triple negative breast cancer, had no effect on CD44+/CD24- status (Fig.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('CD44', 'Gene', (152, 156))	('SF3B1', 'Gene', '23451', (15, 20))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('CD24', 'Gene', '100133941', (158, 162))	('CD24', 'Gene', (158, 162))	('PRPF8', 'Gene', '10594', (24, 29))	('PRPF8', 'Gene', (24, 29))	('knockdown', 'Var', (30, 39))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (43, 53))	('SF3B1', 'Gene', (15, 20))	('CD44', 'Gene', '960', (152, 156))
81197	29023197	Consistent with this possibility, recent studies have demonstrated SF3B1 mutation (K700E) in breast cancer, preferentially in estrogen receptor positive breast cancer, to be a driver mutation.	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('SF3B1', 'Gene', '23451', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('K700E', 'Mutation', 'rs559063155', (83, 88))	('breast cancer', 'Disease', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('SF3B1', 'Gene', (67, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('K700E', 'Var', (83, 88))	('breast cancer', 'Disease', (153, 166))
81201	29023197	Dysregulation of these proteins has been implicated in several disorders including cancer although the causes of such dysregulation is poorly understood.	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('implicated', 'Reg', (41, 51))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
81203	29023197	Our computational analysis revealed that RBPs have an average of ~3 mutations per Mb across 26 cancers and enabled the identification of 281 RBPs to be enriched for mutations in at least one cancer type.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('RBP', 'Gene', (41, 44))	('cancer', 'Disease', (95, 101))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('RBP', 'Gene', (141, 144))	('RBP', 'Gene', '57794', (41, 44))	('RBP', 'Gene', '57794', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('mutations', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
81204	29023197	Among these, genes encoding for EPPK1, KMT2C, AHNAK and PLEC were found to be enriched for mutations in at least 10 cancers suggesting common players in mediating cancer phenotypes in different tissues.	('PLEC', 'Gene', '5339', (56, 60))	('EPPK1', 'Gene', '83481', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('PLEC', 'Gene', (56, 60))	('EPPK1', 'Gene', (32, 37))	('AHNAK', 'Gene', '79026', (46, 51))	('KMT2C', 'Gene', '58508', (39, 44))	('KMT2C', 'Gene', (39, 44))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('mutations', 'Var', (91, 100))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('cancer', 'Disease', (163, 169))	('AHNAK', 'Gene', (46, 51))
81205	29023197	GC content and exome length were not found to play a major role in contributing to the mutational frequency of RBPs in majority of the studied cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mutational', 'Var', (87, 97))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('RBP', 'Gene', (111, 114))	('RBP', 'Gene', '57794', (111, 114))
81208	29023197	Our analyses also revealed that RBPs enriched for mutations in atleast one cancer type were seen to be undergoing frequent Frameshift and Inframe deletions, missense, nonsense and silent mutations when compared to those that are not enriched, revealing the abundance of these variant types in mutated RBPs as significant contributor for malfunction in cancer genomes.	('cancer', 'Disease', 'MESH:D009369', (352, 358))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (352, 358))	('cancer', 'Disease', (75, 81))	('atleast', 'Gene', (63, 70))	('RBP', 'Gene', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('RBP', 'Gene', (301, 304))	('RBP', 'Gene', '57794', (301, 304))	('missense', 'Var', (157, 165))	('RBP', 'Gene', '57794', (32, 35))
81212	29023197	We show that the presence of non-synonymous mutations correlate with change in the RNA levels of a significant fraction of driver RBPs (15% of the drivers), when cancer samples are grouped by the presence of mutations in an RBP irrespective of the cancer type.	('cancer', 'Disease', (248, 254))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('RBP', 'Gene', (130, 133))	('RNA', 'cellular_component', 'GO:0005562', ('83', '86'))	('RBP', 'Gene', '57794', (130, 133))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('RBP', 'Gene', (224, 227))	('RBP', 'Gene', '57794', (224, 227))	('change', 'Reg', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('presence', 'Var', (17, 25))	('non-synonymous mutations', 'Var', (29, 53))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('RNA levels', 'MPA', (83, 93))
81215	29023197	Our knock down experiments indicated that deletion of either of these RBPs resulted in MCF7 cells, which are estrogen receptor positive, to exhibit reduced stem cell features.	('MCF7', 'CellLine', 'CVCL:0031', (87, 91))	('stem cell features', 'CPA', (156, 174))	('reduced', 'NegReg', (148, 155))	('RBP', 'Gene', (70, 73))	('RBP', 'Gene', '57794', (70, 73))	('MCF7', 'Gene', (87, 91))	('deletion', 'Var', (42, 50))
81223	29023197	This analysis should form a foundation to help us uncover the mutational spectrum of RBPs and their wiring dynamics in different cancer types thereby leading to dysregulation of post-transcriptional regulatory networks and also emphasizes the potential of various proteins of the splicesomal machinery as possible drug targets in cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutational', 'Var', (62, 72))	('RBP', 'Gene', (85, 88))	('RBP', 'Gene', '57794', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('leading to', 'Reg', (150, 160))	('cancer', 'Disease', (129, 135))	('dysregulation', 'MPA', (161, 174))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('post-transcriptional', 'Pathway', (178, 198))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('cancer', 'Disease', (330, 336))
81232	29023197	Genes with corrected p < 0.01 and odds ratio < 1 were classified as Genes Enriched in Mutations (GEMs) in a given cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('GEMs', 'cellular_component', 'GO:0015030', ('97', '101'))	('Mutations', 'Var', (86, 95))	('GEMs', 'cellular_component', 'GO:0097504', ('97', '101'))
81234	29023197	We then obtained the mutation frequency of these genes in each cancer type for nine different variant classes viz - Inframe deletion, Inframe insertion, Frameshift deletion, Frameshift Insertion, Missense mutation, Nonsense mutation, Nonstop mutation, Silent and Splice Site mutations.	('Inframe insertion', 'Var', (134, 151))	('Frameshift deletion', 'Var', (153, 172))	('Nonsense mutation', 'Var', (215, 232))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('Nonstop mutation', 'Var', (234, 250))	('Frameshift Insertion', 'Var', (174, 194))	('cancer', 'Disease', (63, 69))	('Missense mutation', 'Var', (196, 213))
81235	29023197	Variants were classified into the above mentioned categories based on the annotations provided in the downloaded MAF files.	('MAF', 'Gene', '4094', (113, 116))	('MAF', 'Gene', (113, 116))	('Variants', 'Var', (0, 8))
81237	29023197	Upon obtaining the mutation frequencies in each cancer type for all the variant classes, we pooled the mutational frequencies of RBPs enriched for mutations across the cancers into one bin named as GEM-RBPs (Fig.	('mutations', 'Var', (147, 156))	('RBP', 'Gene', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('RBP', 'Gene', '57794', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('RBP', 'Gene', (202, 205))	('RBP', 'Gene', '57794', (202, 205))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancer', 'Disease', (48, 54))	('cancers', 'Disease', (168, 175))	('cancer', 'Disease', (168, 174))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
81253	29023197	Further, genes were categorized as drivers - if they are predicted to be candidate drivers in at least two cancer types and the remaining RBPs are termed nondrivers.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('RBP', 'Gene', (138, 141))	('RBP', 'Gene', '57794', (138, 141))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('genes', 'Var', (9, 14))	('cancer', 'Disease', (107, 113))
81264	29023197	Antibodies against SF3B1 (cat# 14434S, Cell Signaling), PRPF8 (Cat#Ab190347, Abcam), CD24 (Cat#555428, BD Biosciences) and CD44 (Cat#559942, BD Biosciences) were used as per instructions from manufacturers.	('Cat', 'molecular_function', 'GO:0004096', ('91', '94'))	('Signaling', 'biological_process', 'GO:0023052', ('44', '53'))	('Cat#Ab190347', 'Var', (63, 75))	('Cat', 'molecular_function', 'GO:0004096', ('129', '132'))	('CD44', 'Gene', '960', (123, 127))	('SF3B1', 'Gene', '23451', (19, 24))	('cat# 14434S', 'Var', (26, 37))	('Cat', 'molecular_function', 'GO:0004096', ('63', '66'))	('CD24', 'Gene', '100133941', (85, 89))	('CD44', 'Gene', (123, 127))	('CD24', 'Gene', (85, 89))	('PRPF8', 'Gene', (56, 61))	('PRPF8', 'Gene', '10594', (56, 61))	('SF3B1', 'Gene', (19, 24))	('cat', 'molecular_function', 'GO:0004096', ('26', '29'))
81378	22268848	Mutations in oncogenes and tumor suppressors that are common in other cancers are conspicuously absent in uveal melanoma.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', (27, 32))	('absent', 'NegReg', (96, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('uveal melanoma', 'Disease', (106, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('cancers', 'Disease', (70, 77))	('oncogenes', 'Protein', (13, 22))
81380	22268848	Mutations in the Gq alpha subunits, encoded by GNAQ and GNA11, appear to be early or perhaps initiating events that require further mutations for malignant transformation.	('GNAQ', 'Gene', (47, 51))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', '2776', (47, 51))	('GNA11', 'Gene', (56, 61))	('GNA11', 'Gene', '2767', (56, 61))
81381	22268848	On the other hand, mutations in the BRCA1-associated protein-1 (BAP1) appear to occur later and demarcate a molecular brink beyond which metastasis becomes highly likely.	('BRCA1-associated protein-1', 'Gene', (36, 62))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('mutations', 'Var', (19, 28))	('BRCA1-associated protein-1', 'Gene', '8314', (36, 62))	('metastasis', 'CPA', (137, 147))	('BAP1', 'Gene', (64, 68))
81382	22268848	BAP1 mutations can also occur in the germline, leading to a distinctive cancer predisposition syndrome.	('BAP1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('leading to', 'Reg', (47, 57))	('mutations', 'Var', (5, 14))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
81397	22268848	1p loss is one of the few chromosomal abnormalities that provides prognostic information that is independent of chromosome 3 status, with its presence portending decreased disease-free survival.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (26, 51))	('decreased', 'NegReg', (162, 171))	('disease-free survival', 'CPA', (172, 193))	('1p loss', 'Var', (0, 7))	('chromosomal abnormalities', 'Disease', (26, 51))	('chromosome', 'cellular_component', 'GO:0005694', ('112', '122'))
81400	22268848	This relative mutual exclusivity of 6p gain and monosomy 3 may represent alternative evolutionary pathways that are available during tumor progression, the former being less likely to eventuate in metastasis than the latter.	('monosomy 3', 'Var', (48, 58))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (133, 138))
81407	22268848	These findings suggest that inactivation of CDKN2A may play a role in UM progression.	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('CDKN2A', 'Gene', (44, 50))	('inactivation', 'Var', (28, 40))	('CDKN2A', 'Gene', '1029', (44, 50))	('play', 'Reg', (55, 59))
81408	22268848	However, germline CDKN2A mutations are very rare in patients with UM.	('CDKN2A', 'Gene', '1029', (18, 24))	('mutations', 'Var', (25, 34))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('CDKN2A', 'Gene', (18, 24))	('patients', 'Species', '9606', (52, 60))
81412	22268848	These mutations occurred almost exclusively in metastasizing tumors that had also lost the other copy of chromosome 3, consistent with the 'two-hit' model for recessive cancer genes.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('chromosome', 'cellular_component', 'GO:0005694', ('105', '115'))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('occurred', 'Reg', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('recessive cancer', 'Disease', 'MESH:D009369', (159, 175))	('recessive cancer', 'Disease', (159, 175))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (6, 15))
81413	22268848	BAP1 mutations had previously been identified in a small number of breast and lung cancer cell lines and more recently in malignant pleural mesotheliomas, cutaneous melanoma, and possibly other cancers such as meningioma.	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('identified', 'Reg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancers', 'Disease', (194, 201))	('meningioma', 'Disease', (210, 220))	('meningioma', 'Phenotype', 'HP:0002858', (210, 220))	('BAP1', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('meningioma', 'Disease', 'MESH:D008577', (210, 220))	('cutaneous melanoma', 'Disease', (155, 173))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (155, 173))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (155, 173))	('mutations', 'Var', (5, 14))	('malignant pleural mesotheliomas', 'Disease', 'MESH:C562839', (122, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('malignant pleural mesotheliomas', 'Disease', (122, 153))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (132, 153))	('breast and lung cancer', 'Disease', 'MESH:D001943', (67, 89))
81417	22268848	While the relative importance of these various interactions remains unclear, a crucial role for BAP1's deubiquinating activity is strongly suggested by several lines of evidence: (i) the requirement for this activity for tumor suppression in cell culture experiments and (ii) most missense mutations directly target the deubiquitinating catalytic domain.	('deubiquinating activity', 'MPA', (103, 126))	('missense mutations', 'Var', (281, 299))	('deubiquitinating catalytic domain', 'MPA', (320, 353))	('BAP1', 'Gene', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('target', 'Reg', (309, 315))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
81430	22268848	However, in a much larger study of 75 primary UMs, LOH of the PTEN locus was found in 76% of tumors, and actual mutations within the PTEN coding region were found in 11% of tumors.	('PTEN', 'Gene', (62, 66))	('PTEN', 'Gene', '5728', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('LOH', 'Var', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('PTEN', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('PTEN', 'Gene', '5728', (133, 137))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Disease', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))
18191	22268848	PTEN inactivation was also found to be associated with increased aneuploidy and decreased survival in UM.	('aneuploidy', 'Disease', (65, 75))	('increased', 'PosReg', (55, 64))	('decreased', 'NegReg', (80, 89))	('aneuploidy', 'Disease', 'MESH:D000782', (65, 75))	('survival in UM', 'CPA', (90, 104))	('inactivation', 'Var', (5, 17))	('PTEN', 'Gene', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (102, 104))	('PTEN', 'Gene', '5728', (0, 4))
81433	22268848	Interestingly, however, BRAF mutations may occur in up to 47% of iris melanomas, which are more anterior and more strongly linked to ultraviolet light exposure than the more common posterior UMs of the ciliary body and choroid.	('iris melanomas', 'Disease', 'MESH:D007499', (65, 79))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))	('mutations', 'Var', (29, 38))	('UM', 'Phenotype', 'HP:0007716', (191, 193))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('iris melanomas', 'Disease', (65, 79))	('iris melanomas', 'Phenotype', 'HP:0011524', (65, 79))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('linked', 'Reg', (123, 129))
81435	22268848	This curious absence of MAPK pathway mutations persisted until the recent discovery of mutations in GNAQ, which encodes the Galphaq subunit, in almost half of UMs.	('MAPK', 'molecular_function', 'GO:0004707', ('24', '28'))	('GNAQ', 'Gene', '2776', (100, 104))	('UM', 'Phenotype', 'HP:0007716', (159, 161))	('Galphaq', 'Gene', (124, 131))	('Galphaq', 'Gene', '2776', (124, 131))	('GNAQ', 'Gene', (100, 104))	('mutations', 'Var', (87, 96))	('MAPK', 'Pathway', (24, 28))
81436	22268848	Mutant GNAQ was shown to activate the MAPK pathway, although it may have also important effects on other pathways such as the phosphatidylinositol-calcium second messenger system.	('activate', 'PosReg', (25, 33))	('phosphatidylinositol-calcium', 'Chemical', '-', (126, 154))	('GNAQ', 'Gene', '2776', (7, 11))	('Mutant', 'Var', (0, 6))	('GNAQ', 'Gene', (7, 11))	('effects', 'Reg', (88, 95))	('MAPK pathway', 'Pathway', (38, 50))	('MAPK', 'molecular_function', 'GO:0004707', ('38', '42'))
81437	22268848	Attention was drawn to this gene as a result of a forward genetic screen in mice that identified hypermorphic mutations in Gnaq or its paralog Gna11, which act through the melanocyte lineage factor Ednrb, as a cause of increased numbers of intradermal melanocytes.	('Gnaq', 'Gene', '14682', (123, 127))	('mutations', 'Var', (110, 119))	('Gnaq', 'Gene', (123, 127))	('Gna11', 'Gene', '14672', (143, 148))	('mice', 'Species', '10090', (76, 80))	('Gna11', 'Gene', (143, 148))	('increased', 'PosReg', (219, 228))
81438	22268848	A subsequent study found that 83% of UMs contained mutations in either GNAQ or GNA11 affecting either Q209 or R183 in a mutually exclusive pattern.	('mutations', 'Var', (51, 60))	('GNAQ', 'Gene', (71, 75))	('UM', 'Phenotype', 'HP:0007716', (37, 39))	('Q209', 'MPA', (102, 106))	('GNA11', 'Gene', '2767', (79, 84))	('GNA11', 'Gene', (79, 84))	('R183', 'Var', (110, 114))	('GNAQ', 'Gene', '2776', (71, 75))
81439	22268848	These mutations lead to constitutive activation of the Galphaq and Galpha11 subunits by abrogating their intrinsic GTPase activity required to return them to an inactive state.	('GTPase activity', 'molecular_function', 'GO:0003924', ('115', '130'))	('abrogating', 'NegReg', (88, 98))	('activation', 'PosReg', (37, 47))	('Galpha11', 'Gene', (67, 75))	('Galphaq', 'Gene', (55, 62))	('intrinsic', 'MPA', (105, 114))	('Galphaq', 'Gene', '2776', (55, 62))	('Galpha11', 'Gene', '2767', (67, 75))	('GTPase', 'Protein', (115, 121))	('mutations', 'Var', (6, 15))
81440	22268848	GNAQ/11 mutations are found in benign uveal nevi and in the vast majority of UMs regardless of cytogenetic status, GEP class, or BAP1 status.	('GNAQ', 'Gene', '2776', (0, 4))	('benign uveal', 'Disease', 'MESH:D014603', (31, 43))	('found', 'Reg', (22, 27))	('mutations', 'Var', (8, 17))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('nevi', 'Phenotype', 'HP:0003764', (44, 48))	('GNAQ', 'Gene', (0, 4))	('benign uveal', 'Disease', (31, 43))
81441	22268848	Further, these mutations are not sufficient for full malignant transformation to melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('mutations', 'Var', (15, 24))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))
81442	22268848	This would seem to place GNAQ/11 mutations as early or perhaps initiating events in UM progression.	('GNAQ', 'Gene', '2776', (25, 29))	('GNAQ', 'Gene', (25, 29))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('mutations', 'Var', (33, 42))
81443	22268848	On the other hand, BAP1 mutations are seen almost exclusively in metastasizing class 2 tumors with monosomy 3, suggesting that this mutation occurs relatively late in the primary tumor and may represent a rate-limiting step in metastasis.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('primary tumor', 'Disease', 'MESH:D009369', (171, 184))	('primary tumor', 'Disease', (171, 184))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('mutations', 'Var', (24, 33))	('BAP1', 'Gene', (19, 23))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
81444	22268848	Either BAP1 mutation or loss of chromosome 3 can occur first, but both events appear to be necessary for the tumor to acquire the metastasizing class 2 phenotype.	('BAP1', 'Gene', (7, 11))	('chromosome', 'cellular_component', 'GO:0005694', ('32', '42'))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mutation', 'Var', (12, 20))	('tumor', 'Disease', (109, 114))
81447	22268848	Monosomy 3, the most common change in UM, is also seen in cutaneous melanoma, although at a lower frequency.	('cutaneous melanoma', 'Disease', (58, 76))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (58, 76))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (58, 76))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('UM', 'Phenotype', 'HP:0007716', (38, 40))	('Monosomy 3', 'Var', (0, 10))
81448	22268848	Likewise, loss on 9p and 10, which are very common in cutaneous melanoma, are also seen in UM, albeit not as often.	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('loss on 9p', 'Var', (10, 20))	('UM', 'Phenotype', 'HP:0007716', (91, 93))	('cutaneous melanoma', 'Disease', (54, 72))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (54, 72))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (54, 72))
81449	22268848	Activating mutations in BRAF and NRAS are common in some types of cutaneous melanoma, but are distinctively rare in UM.	('cutaneous melanoma', 'Disease', (66, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (66, 84))	('NRAS', 'Gene', (33, 37))	('Activating mutations', 'Var', (0, 20))	('NRAS', 'Gene', '4893', (33, 37))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('UM', 'Phenotype', 'HP:0007716', (116, 118))	('common', 'Reg', (42, 48))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
81451	22268848	BAP1 mutations, which are strongly linked to metastasis in UM, also occur in cutaneous melanoma, but it is unclear whether these mutations play the same role in the latter as they do in the former.	('occur', 'Reg', (68, 73))	('BAP1', 'Gene', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (59, 61))	('mutations', 'Var', (5, 14))	('cutaneous melanoma', 'Disease', (77, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (77, 95))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (77, 95))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
81453	22268848	A few studies have suggested a link between UM and breast cancer, possibly as a consequence of germline BRCA2 mutations.	('BRCA2', 'Gene', (104, 109))	('mutations', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('BRCA2', 'Gene', '675', (104, 109))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('breast cancer', 'Disease', (51, 64))
81454	22268848	In one study, constitutional DNA samples were analyzed for BRCA2 mutations in 62 patients with UM who were selected primarily on the basis of a family history of breast cancer or UM harbored; three (4.8%) patients harbored BRCA2 sequence variants that were judged to be potentially deleterious.	('UM', 'Phenotype', 'HP:0007716', (179, 181))	('BRCA2', 'Gene', '675', (59, 64))	('patients', 'Species', '9606', (205, 213))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('BRCA2', 'Gene', '675', (223, 228))	('variants', 'Var', (238, 246))	('patients', 'Species', '9606', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('BRCA2', 'Gene', (59, 64))	('breast cancer', 'Disease', (162, 175))	('BRCA2', 'Gene', (223, 228))	('mutations', 'Var', (65, 74))
81455	22268848	An Israeli study identified 4/143 (2.8%) patients with UM who carried a germline 6174delT BRCA2 mutation.	('BRCA2', 'Gene', (90, 95))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('BRCA2', 'Gene', '675', (90, 95))	('6174delT', 'Var', (81, 89))	('patients', 'Species', '9606', (41, 49))	('6174delT', 'Mutation', 'rs786204278', (81, 89))
81456	22268848	An Australian study found germline BRCA2 mutations in 2/71 (2.8%) patients with UM, but neither of these patients had a positive family history, thus leaving open the possibility that these were silent polymorphisms.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (105, 113))	('BRCA2', 'Gene', '675', (35, 40))	('UM', 'Phenotype', 'HP:0007716', (80, 82))	('patients', 'Species', '9606', (66, 74))	('BRCA2', 'Gene', (35, 40))
81457	22268848	Given the rarity of familial UM in the literature, we were surprised to find that one of the patients with UM in our original study carried a germline BAP1 mutation that was reduced to homozygosity in the tumor by loss of the other copy of chromosome 3.	('UM', 'Phenotype', 'HP:0007716', (107, 109))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('BAP1', 'Gene', (151, 155))	('UM', 'Phenotype', 'HP:0007716', (29, 31))	('loss', 'NegReg', (214, 218))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('chromosome', 'cellular_component', 'GO:0005694', ('240', '250'))	('patients', 'Species', '9606', (93, 101))	('mutation', 'Var', (156, 164))
81458	22268848	We have identified another family from our ocular oncology center in which UM and cutaneous melanoma occurred in multiple family member in association with a germline BAP1 mutation (author's unpublished data).	('cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 100))	('occurred', 'Reg', (101, 109))	('germline', 'Var', (158, 166))	('mutation', 'Var', (172, 180))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('ocular oncology', 'Phenotype', 'HP:0100012', (43, 58))	('oncology', 'Phenotype', 'HP:0002664', (50, 58))	('cutaneous melanoma', 'Disease', (82, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (82, 100))	('BAP1', 'Gene', (167, 171))
81462	22268848	In support of this idea, a cutaneous melanocytic tumor associated with germline BAP1 mutation also harbored mutant BRAF, and only the portion of the tumor that had lost the other copy of BAP1 progressed to melanoma.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('BRAF', 'Gene', '673', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('BRAF', 'Gene', (115, 119))	('harbored', 'Reg', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('associated', 'Reg', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mutant', 'Var', (108, 114))	('mutation', 'Var', (85, 93))	('tumor', 'Disease', (49, 54))	('cutaneous melanocytic tumor', 'Disease', (27, 54))	('cutaneous melanocytic tumor', 'Disease', 'MESH:D009508', (27, 54))	('tumor', 'Disease', (149, 154))	('BAP1', 'Gene', (80, 84))	('melanoma', 'Disease', (206, 214))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('melanoma', 'Disease', 'MESH:D008545', (206, 214))
81463	22268848	Similarly, our reported case of UM associated with a germline BAP1 mutation harbored a GNAQ mutation and had lost the other copy of chromosome 3.	('mutation', 'Var', (67, 75))	('GNAQ', 'Gene', '2776', (87, 91))	('BAP1', 'Gene', (62, 66))	('other copy of chromosome 3', 'MPA', (118, 144))	('UM', 'Phenotype', 'HP:0007716', (32, 34))	('harbored', 'Reg', (76, 84))	('GNAQ', 'Gene', (87, 91))	('chromosome', 'cellular_component', 'GO:0005694', ('132', '142'))	('lost', 'NegReg', (109, 113))
81465	22268848	The discovery of GNAQ/11 and BAP1 mutations in UM provides an unprecedented opportunity for targeted therapy of metastatic disease.	('metastatic disease', 'Disease', (112, 130))	('GNAQ', 'Gene', (17, 21))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('BAP1', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))	('GNAQ', 'Gene', '2776', (17, 21))
81466	22268848	For GNAQ/11 mutations, the therapeutic goal is to inhibit oncogenic downstream signaling resulting from these mutations.	('GNAQ', 'Gene', '2776', (4, 8))	('mutations', 'Var', (110, 119))	('mutations', 'Var', (12, 21))	('inhibit', 'NegReg', (50, 57))	('GNAQ', 'Gene', (4, 8))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('oncogenic downstream signaling', 'MPA', (58, 88))
81467	22268848	Direct inhibition of mutant Galphaq or Galpha11 may prove difficult, however, because these mutations abrogate the intrinsic GTPase activity that would normally allow these proteins to return to their GDP-bound, inactive state.	('mutant', 'Var', (21, 27))	('GTPase activity', 'molecular_function', 'GO:0003924', ('125', '140'))	('activity', 'MPA', (132, 140))	('Galphaq', 'Gene', (28, 35))	('Galphaq', 'Gene', '2776', (28, 35))	('Galpha11', 'Gene', (39, 47))	('mutations', 'Var', (92, 101))	('GDP', 'Chemical', 'MESH:D006153', (201, 204))	('abrogate', 'NegReg', (102, 110))	('Galpha11', 'Gene', '2767', (39, 47))	('GTPase', 'Protein', (125, 131))
81468	22268848	An alternative strategy is to inhibit downstream signaling molecules that are activated by GNAQ/11 mutations.	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('inhibit', 'NegReg', (30, 37))	('GNAQ', 'Gene', (91, 95))	('mutations', 'Var', (99, 108))	('GNAQ', 'Gene', '2776', (91, 95))
81469	22268848	One such target is MEK, a key component of the MAPK mitogenic pathway that is activated by GNAQ/11 mutations.	('MEK', 'Gene', '5609', (19, 22))	('activated', 'PosReg', (78, 87))	('GNAQ', 'Gene', (91, 95))	('MAPK', 'molecular_function', 'GO:0004707', ('47', '51'))	('mutations', 'Var', (99, 108))	('MEK', 'Gene', (19, 22))	('GNAQ', 'Gene', '2776', (91, 95))
81477	22268848	Activating mutations in GNAQ/11 appear to represent a very early or initiating event, whereas inactivating mutations in BAP1 appear to demarcate a threshold in tumor progression beyond which metastasis and death await.	('GNAQ', 'Gene', '2776', (24, 28))	('demarcate', 'Reg', (135, 144))	('Activating mutations', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('inactivating mutations', 'Var', (94, 116))	('GNAQ', 'Gene', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))	('BAP1', 'Gene', (120, 124))
81478	22268848	The opportunities for targeted therapy afforded by the discovery of GNAQ/11 and BAP1 mutations are being explored.	('GNAQ', 'Gene', (68, 72))	('mutations', 'Var', (85, 94))	('GNAQ', 'Gene', '2776', (68, 72))	('BAP1', 'Gene', (80, 84))
81487	25113308	Uveal melanoma belongs to a clade of melanocytic neoplasms that are thought to arise from melanocytes not associated with epithelial structures, and are genetically characterized by frequent, mutually exclusive mutations in guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) and guanine nucleotide-binding protein subunit alpha-11 (GNA11), two closely related large GTPases of the Galphaq family.	('Galphaq', 'Gene', (391, 398))	('Uveal melanoma', 'Disease', 'MESH:C536494', (0, 14))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('297', '315'))	('protein', 'cellular_component', 'GO:0003675', ('251', '258'))	('guanine nucleotide-binding protein G(q) subunit alpha', 'Gene', '2776', (224, 277))	('Galphaq', 'Gene', '2776', (391, 398))	('GNA11', 'Gene', '2767', (342, 347))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('232', '250'))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('guanine nucleotide-binding protein subunit alpha-11', 'Gene', '2767', (289, 340))	('GNAQ', 'Gene', '2776', (279, 283))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (37, 58))	('GNAQ', 'Gene', (279, 283))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (37, 58))	('neoplasms', 'Phenotype', 'HP:0002664', (49, 58))	('protein', 'cellular_component', 'GO:0003675', ('316', '323'))	('melanocytic neoplasms', 'Disease', (37, 58))	('GNA11', 'Gene', (342, 347))	('mutations', 'Var', (211, 220))	('Uveal melanoma', 'Disease', (0, 14))
81488	25113308	These mutations render the heterotrimeric G protein alpha subunits Galphaq and Galpha11 GTPase defective, and hence constitutively active.	('Galpha11', 'Gene', '2767', (79, 87))	('defective', 'NegReg', (95, 104))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('heterotrimeric G protein alpha subunits', 'Protein', (27, 66))	('GTPase', 'Enzyme', (88, 94))	('Galphaq', 'Gene', (67, 74))	('Galpha11', 'Gene', (79, 87))	('Galphaq', 'Gene', '2776', (67, 74))	('mutations', 'Var', (6, 15))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('27', '51'))
81491	25113308	IP3 induces the rapid increase in cytoplasmic Ca2+ levels, thereby controlling a variety of calcium-regulated pathways, and together with DAG, stimulates the classical isoforms of protein kinase C (PKC).	('cytoplasmic Ca2+ levels', 'MPA', (34, 57))	('PKC', 'molecular_function', 'GO:0004697', ('198', '201'))	('IP3', 'Var', (0, 3))	('protein kinase C', 'Gene', '112476', (180, 196))	('calcium', 'Chemical', 'MESH:D002118', (92, 99))	('protein', 'cellular_component', 'GO:0003675', ('180', '187'))	('increase', 'PosReg', (22, 30))	('stimulates', 'PosReg', (143, 153))	('Ca2+', 'Chemical', 'MESH:D000069285', (46, 50))	('IP3', 'Chemical', 'MESH:D015544', (0, 3))	('DAG', 'Chemical', 'MESH:D004075', (138, 141))	('PKC', 'Gene', (198, 201))	('protein kinase C', 'Gene', (180, 196))	('calcium-regulated pathways', 'Pathway', (92, 118))	('PKC', 'Gene', '112476', (198, 201))	('controlling', 'Reg', (67, 78))
81493	25113308	This is similar to the consequence of mutations in the B-RAF or N-RAS oncogenes in cutaneous melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (83, 101))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (83, 102))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (83, 102))	('N-RAS', 'Gene', '4893', (64, 69))	('N-RAS', 'Gene', (64, 69))	('B-RAF', 'Gene', '673', (55, 60))	('cutaneous melanomas', 'Disease', (83, 102))	('mutations', 'Var', (38, 47))	('B-RAF', 'Gene', (55, 60))
81496	25113308	The presence of a BAP1 mutation in UM is associated with a high likelihood of metastasis.	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('BAP1', 'Gene', '8314', (18, 22))	('mutation', 'Var', (23, 31))	('BAP1', 'Gene', (18, 22))	('presence', 'Var', (4, 12))	('metastasis', 'CPA', (78, 88))
81498	25113308	The BAP1 gene maps to chromosome 3p21 and BAP1 mutations in UMs are accompanied by primarily somatic complete or partial loss of chromosome 3.	('BAP1', 'Gene', '8314', (42, 46))	('chromosome', 'cellular_component', 'GO:0005694', ('22', '32'))	('BAP1', 'Gene', (4, 8))	('loss', 'NegReg', (121, 125))	('BAP1', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('BAP1', 'Gene', '8314', (4, 8))	('chromosome', 'cellular_component', 'GO:0005694', ('129', '139'))
81500	25113308	Approximately 1-3% of patients with UM are likely to harbor a predisposing germline mutation in BAP1, although tumor development will also depend on loss of wild type BAP1.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('BAP1', 'Gene', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('germline mutation', 'Var', (75, 92))	('patients', 'Species', '9606', (22, 30))	('tumor', 'Disease', (111, 116))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('BAP1', 'Gene', '8314', (167, 171))	('BAP1', 'Gene', '8314', (96, 100))	('BAP1', 'Gene', (167, 171))
81502	25113308	Most BAP1 alterations are likely to lead to loss of the BAP1 peptide in tumors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('alterations', 'Var', (10, 21))	('BAP1', 'Gene', '8314', (56, 60))	('BAP1', 'Gene', '8314', (5, 9))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('loss', 'NegReg', (44, 48))	('BAP1', 'Gene', (56, 60))	('BAP1', 'Gene', (5, 9))
81503	25113308	However, some tumors harbor missense alterations that affect BAP1 function.	('missense alterations', 'Var', (28, 48))	('BAP1', 'Gene', (61, 65))	('tumors', 'Disease', (14, 20))	('function', 'MPA', (66, 74))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('affect', 'Reg', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('BAP1', 'Gene', '8314', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
81504	25113308	Critical domains of BAP1 that are altered in such tumors are the ubiquitin carboxy-terminal hydrolase (UCH) domains, suggesting that loss of UCH activity in UM predisposes to metastasis.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('BAP1', 'Gene', '8314', (20, 24))	('BAP1', 'Gene', (20, 24))	('UM', 'Phenotype', 'HP:0007716', (157, 159))	('activity', 'MPA', (145, 153))	('metastasis', 'CPA', (175, 185))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('loss', 'Var', (133, 137))	('ubiquitin', 'molecular_function', 'GO:0031386', ('65', '74'))	('UCH', 'Enzyme', (141, 144))
81508	25113308	Cells where BAP1 has been knocked down also have fewer dendritic aborizations and less differentiated spindle morphology.	('fewer', 'NegReg', (49, 54))	('knocked down', 'Var', (26, 38))	('spindle', 'cellular_component', 'GO:0005819', ('102', '109'))	('less differentiated spindle morphology', 'CPA', (82, 120))	('BAP1', 'Gene', '8314', (12, 16))	('dendritic aborizations', 'CPA', (55, 77))	('BAP1', 'Gene', (12, 16))
81509	25113308	Depletion of BAP1 does not lead to increased proliferation, migration, invasion or tumorigenicity.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('BAP1', 'Gene', (13, 17))	('tumor', 'Disease', (83, 88))	('invasion', 'CPA', (71, 79))	('Depletion', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
81512	25113308	Mutations in SF3B1 and EIF1AX have been associated with low-grade UM and a good prognosis.	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('SF3B1', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('EIF1AX', 'Gene', (23, 29))	('SF3B1', 'Gene', '23451', (13, 18))	('EIF1AX', 'Gene', '1964', (23, 29))	('low-grade UM', 'Disease', (56, 68))	('associated', 'Reg', (40, 50))
81513	25113308	These mutations rarely co-exist with BAP1 mutations and seem to confer a phenotype associated with a lower risk of systemic recurrence.	('BAP1', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('BAP1', 'Gene', '8314', (37, 41))
81514	25113308	Expression of mutant SF3B1 has been associated with alternative RNA splicing in multiple tumor types including UM.	('SF3B1', 'Gene', '23451', (21, 26))	('RNA', 'cellular_component', 'GO:0005562', ('64', '67'))	('mutant', 'Var', (14, 20))	('UM', 'Phenotype', 'HP:0007716', (111, 113))	('SF3B1', 'Gene', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('RNA splicing', 'biological_process', 'GO:0008380', ('64', '76'))	('alternative RNA splicing', 'MPA', (52, 76))	('associated', 'Reg', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
81516	25113308	However, the precise role of SF3B1 alterations in UM tumorigenesis is not yet defined.	('alterations', 'Var', (35, 46))	('SF3B1', 'Gene', '23451', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('tumor', 'Disease', (53, 58))	('SF3B1', 'Gene', (29, 34))
81539	25113308	Elimination of CD8 Treg in a mouse intraocular tumor model caused spontaneous tumor rejection suggesting a potential therapeutic target.	('CD8', 'Gene', '925', (15, 18))	('intraocular tumor', 'Disease', (35, 52))	('intraocular tumor', 'Disease', 'MESH:D064090', (35, 52))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('Elimination', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('ocular tumor', 'Phenotype', 'HP:0100012', (40, 52))	('mouse', 'Species', '10090', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', (47, 52))	('CD8', 'Gene', (15, 18))
81544	25113308	Changes within the tumor may be epigenetic as well as genetic.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('epigenetic', 'Var', (32, 42))	('tumor', 'Disease', (19, 24))
81549	25113308	Plasma levels of miR-20a, 125b, 146a, 155, and 223 increase, and miR181a decrease in patients with UM followed from diagnosis to the development of metastasis.	('increase', 'PosReg', (51, 59))	('miR-20a', 'Gene', (17, 24))	('146a', 'Var', (32, 36))	('miR', 'Gene', (17, 20))	('miR-20a', 'Gene', '406982', (17, 24))	('miR', 'Gene', '220972', (17, 20))	('patients', 'Species', '9606', (85, 93))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('decrease', 'NegReg', (73, 81))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('Plasma levels', 'MPA', (0, 13))
81556	25113308	These findings are aligned with the recent report of MEK inhibition conferring a progression-free survival (PFS) benefit in patients with metastatic UM (2013).	('progression-free survival', 'CPA', (81, 106))	('metastatic UM', 'Disease', (138, 151))	('inhibition', 'Var', (57, 67))	('patients', 'Species', '9606', (124, 132))	('UM', 'Phenotype', 'HP:0007716', (149, 151))	('benefit', 'PosReg', (113, 120))	('MEK', 'Gene', (53, 56))	('MEK', 'Gene', '5609', (53, 56))
81588	25113308	Kaplan-Meier survival curves of murine treatment studies revealed that KCN1 extended survival; immunostaining demonstrated a reduction in phosphorylation of MET, MAPK and STAT3 as well as Ki67, and VEGF.	('reduction', 'NegReg', (125, 134))	('extended', 'PosReg', (76, 84))	('MET', 'Protein', (157, 160))	('Ki67', 'Var', (188, 192))	('KCN1', 'Gene', '3744', (71, 75))	('MAPK', 'molecular_function', 'GO:0004707', ('162', '166'))	('murine', 'Species', '10090', (32, 38))	('survival', 'CPA', (85, 93))	('phosphorylation', 'MPA', (138, 153))	('phosphorylation', 'biological_process', 'GO:0016310', ('138', '153'))	('MAPK', 'Protein', (162, 166))	('KCN1', 'Gene', (71, 75))	('STAT3', 'MPA', (171, 176))
81592	25113308	As described earlier the presence of BAP1 mutations is also strongly correlated with likelihood of metastasis.	('correlated', 'Reg', (69, 79))	('BAP1', 'Gene', '8314', (37, 41))	('metastasis', 'CPA', (99, 109))	('BAP1', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))
81593	25113308	BAP1 mutations are usually sporadic and are found in approximately 85% of class 2 (metastatic) tumors and less than 5% of class 1 tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('BAP1', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('BAP1', 'Gene', '8314', (0, 4))	('tumors', 'Disease', (95, 101))
81594	25113308	Loss of BAP1 in uveal melanocytes recapitulates the class 2 phenotype.	('Loss', 'Var', (0, 4))	('BAP1', 'Gene', '8314', (8, 12))	('BAP1', 'Gene', (8, 12))
81598	25113308	Loss of BAP1 in mammalian cells results in abnormal ubiquitination of histone H2A and that this can be reversed with histone deacetylase (HDAC) inhibitors.	('HDAC', 'Gene', (138, 142))	('HDAC', 'Gene', '9734', (138, 142))	('ubiquitination', 'MPA', (52, 66))	('histone deacetylase', 'Gene', '9734', (117, 136))	('BAP1', 'Gene', '8314', (8, 12))	('histone deacetylase', 'Gene', (117, 136))	('mammalian', 'Species', '9606', (16, 25))	('histone H2A', 'Protein', (70, 81))	('BAP1', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))
81599	25113308	Further, HDAC inhibitors revert primary class 2 UM cells to a differentiated class 1 phenotype, and restore to normal levels the expression of melanocyte differentiation genes that are down-regulated by BAP1 depletion.	('BAP1', 'Gene', '8314', (203, 207))	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('expression', 'MPA', (129, 139))	('primary class 2 UM cells', 'CPA', (32, 56))	('BAP1', 'Gene', (203, 207))	('restore', 'PosReg', (100, 107))	('HDAC', 'Gene', (9, 13))	('melanocyte differentiation genes', 'Gene', (143, 175))	('melanocyte differentiation', 'biological_process', 'GO:0030318', ('143', '169'))	('HDAC', 'Gene', '9734', (9, 13))	('revert', 'NegReg', (25, 31))	('inhibitors', 'Var', (14, 24))
81600	25113308	Inhibitors of HDACs also induce morphological changes that are consistent with melanocyte differentiation.	('HDAC', 'Gene', (14, 18))	('morphological changes', 'CPA', (32, 53))	('HDAC', 'Gene', '9734', (14, 18))	('induce', 'Reg', (25, 31))	('melanocyte differentiation', 'CPA', (79, 105))	('Inhibitors', 'Var', (0, 10))	('melanocyte differentiation', 'biological_process', 'GO:0030318', ('79', '105'))
81619	25113308	Such interest may be tempered somewhat however based on the described preclinical effects of MEK inhibitors in dampening T cell activation.	('T cell activation', 'MPA', (121, 138))	('dampening T cell', 'Phenotype', 'HP:0005403', (111, 127))	('T cell activation', 'biological_process', 'GO:0042110', ('121', '138'))	('MEK', 'Gene', (93, 96))	('dampening T cell activation', 'Phenotype', 'HP:0005419', (111, 138))	('MEK', 'Gene', '5609', (93, 96))	('dampening', 'NegReg', (111, 120))	('inhibitors', 'Var', (97, 107))
81645	25113308	Based upon the finding that UM is characterized by functionally active mutations in GNAQ or GNA11, as well as preclinical findings demonstrating antitumor effects of MEK inhibition in UM in a genotype-specific fashion, a randomized trial of selumetinib, a selective, orally-available, non-ATP competitive small molecule inhibitor of MEK 1/2, versus temozolomide in patients with metastatic UM was performed (Table 1).	('patients', 'Species', '9606', (365, 373))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('MEK', 'Gene', (166, 169))	('GNAQ', 'Gene', '2776', (84, 88))	('MEK 1/2', 'Gene', '5604;5605', (333, 340))	('selumetinib', 'Chemical', 'MESH:C517975', (241, 252))	('temozolomide', 'Chemical', 'MESH:D000077204', (349, 361))	('GNA11', 'Gene', (92, 97))	('UM', 'Phenotype', 'HP:0007716', (28, 30))	('GNAQ', 'Gene', (84, 88))	('UM', 'Phenotype', 'HP:0007716', (184, 186))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mutations', 'Var', (71, 80))	('ATP', 'Chemical', 'MESH:D000255', (289, 292))	('MEK 1/2', 'Gene', (333, 340))	('UM', 'Phenotype', 'HP:0007716', (390, 392))	('MEK', 'Gene', '5609', (333, 336))	('GNA11', 'Gene', '2767', (92, 97))	('MEK 1', 'molecular_function', 'GO:0004708', ('333', '338'))	('tumor', 'Disease', (149, 154))	('MEK', 'Gene', '5609', (166, 169))	('MEK', 'Gene', (333, 336))
81652	25113308	Using gain and loss of function mutants in human and mouse melanocytes, as well as human UM cell lines, it has been demonstrated that the MAPK pathway activation requires signaling through Protein Kinase C isoforms, and that the oncogenic effects of GNAQ or GNA11 can be partially blocked by PKC inhibition (Xu Chen and Boris Bastian, unpublished data, Figure 1).	('MAPK pathway', 'Pathway', (138, 150))	('MAPK', 'molecular_function', 'GO:0004707', ('138', '142'))	('Protein Kinase C', 'Gene', '112476', (189, 205))	('PKC', 'molecular_function', 'GO:0004697', ('292', '295'))	('GNA11', 'Gene', (258, 263))	('GNAQ', 'Gene', '2776', (250, 254))	('UM', 'Phenotype', 'HP:0007716', (89, 91))	('mouse', 'Species', '10090', (53, 58))	('PKC', 'Gene', '112476', (292, 295))	('GNAQ', 'Gene', (250, 254))	('mutants', 'Var', (32, 39))	('activation', 'PosReg', (151, 161))	('PKC', 'Gene', (292, 295))	('signaling', 'MPA', (171, 180))	('signaling', 'biological_process', 'GO:0023052', ('171', '180'))	('human', 'Species', '9606', (83, 88))	('Protein Kinase C', 'Gene', (189, 205))	('GNA11', 'Gene', '2767', (258, 263))	('human', 'Species', '9606', (43, 48))
81653	25113308	Inhibitors of PKC, including sotrastaurin (AEB071) and related compounds, selectively block the proliferation of melanoma cell lines with mutations in GNAQ or GNA11, without any effects in cell lines with mutations in other oncogenes.	('GNAQ', 'Gene', '2776', (151, 155))	('sotrastaurin', 'Chemical', 'MESH:C543528', (29, 41))	('melanoma cell', 'Disease', 'MESH:D008545', (113, 126))	('block', 'NegReg', (86, 91))	('PKC', 'Gene', (14, 17))	('proliferation', 'CPA', (96, 109))	('PKC', 'Gene', '112476', (14, 17))	('GNAQ', 'Gene', (151, 155))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('PKC', 'molecular_function', 'GO:0004697', ('14', '17'))	('mutations', 'Var', (138, 147))	('melanoma cell', 'Disease', (113, 126))	('GNA11', 'Gene', '2767', (159, 164))	('GNA11', 'Gene', (159, 164))
81654	25113308	In in vivo studies with an allograft model of melanocytes stably transduced with mutant GNAQ, sotrastaurin slows tumor growth, but fails to induce tumor shrinkage.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (147, 152))	('GNAQ', 'Gene', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('slows', 'NegReg', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('GNAQ', 'Gene', '2776', (88, 92))	('mutant', 'Var', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('sotrastaurin', 'Chemical', 'MESH:C543528', (94, 106))
81655	25113308	Similar results are observed with human melanoma cell lines with GNAQ or GNA11 mutations.	('GNA11', 'Gene', (73, 78))	('human', 'Species', '9606', (34, 39))	('melanoma cell', 'Disease', 'MESH:D008545', (40, 53))	('GNA11', 'Gene', '2767', (73, 78))	('GNAQ', 'Gene', '2776', (65, 69))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('GNAQ', 'Gene', (65, 69))	('melanoma cell', 'Disease', (40, 53))	('mutations', 'Var', (79, 88))
81659	25113308	While MEK inhibitors suppress the growth of UM cell lines, they show no selectivity compared to melanoma cell lines with mutations in other oncogenes.	('melanoma cell', 'Disease', (96, 109))	('MEK', 'Gene', (6, 9))	('growth of UM cell lines', 'CPA', (34, 57))	('MEK', 'Gene', '5609', (6, 9))	('melanoma cell', 'Disease', 'MESH:D008545', (96, 109))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('suppress', 'NegReg', (21, 29))	('inhibitors', 'Var', (10, 20))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))
81660	25113308	By contrast, in UM with GNAQ or GNA11 mutations, a combination of PKC inhibition with sotrastaurin and MEK inhibitors leads to a highly synergistic effect, resulting in sustained MAPK pathway extinction and apoptosis in vitro.	('apoptosis', 'CPA', (207, 216))	('PKC', 'Gene', '112476', (66, 69))	('GNA11', 'Gene', (32, 37))	('MEK', 'Gene', (103, 106))	('inhibition', 'NegReg', (70, 80))	('PKC', 'molecular_function', 'GO:0004697', ('66', '69'))	('PKC', 'Gene', (66, 69))	('mutations', 'Var', (38, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('207', '216'))	('apoptosis', 'biological_process', 'GO:0006915', ('207', '216'))	('GNA11', 'Gene', '2767', (32, 37))	('extinction', 'MPA', (192, 202))	('UM', 'Phenotype', 'HP:0007716', (16, 18))	('MAPK', 'molecular_function', 'GO:0004707', ('179', '183'))	('sotrastaurin', 'Chemical', 'MESH:C543528', (86, 98))	('GNAQ', 'Gene', '2776', (24, 28))	('GNAQ', 'Gene', (24, 28))	('MEK', 'Gene', '5609', (103, 106))	('MAPK pathway', 'Pathway', (179, 191))
81661	25113308	In melanoma cell lines with mutations in other oncogenes such as BRAF or NRAS, this combination does not have a synergistic effect.	('NRAS', 'Gene', '4893', (73, 77))	('melanoma cell', 'Disease', 'MESH:D008545', (3, 16))	('BRAF', 'Gene', '673', (65, 69))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('BRAF', 'Gene', (65, 69))	('mutations', 'Var', (28, 37))	('NRAS', 'Gene', (73, 77))	('melanoma cell', 'Disease', (3, 16))
81662	25113308	The combination of sotrastaurin with a MEK inhibitor, but neither compound as monotherapy, led to tumor shrinkage in a xenograft model of GNAQ mutant UM.	('mutant', 'Var', (143, 149))	('sotrastaurin', 'Chemical', 'MESH:C543528', (19, 31))	('GNAQ', 'Gene', '2776', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('GNAQ', 'Gene', (138, 142))	('UM', 'Phenotype', 'HP:0007716', (150, 152))	('tumor', 'Disease', (98, 103))	('combination', 'Interaction', (4, 15))	('MEK', 'Gene', (39, 42))	('MEK', 'Gene', '5609', (39, 42))
81680	22569040	Monosomy 3 status of uveal melanoma metastases is associated with rapidly progressive tumors and short survival The aim of the study was to investigate the molecular genetics of uveal melanoma (UM) metastases and correlate it with disease progression.	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('metastases', 'Disease', (36, 46))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('uveal melanoma', 'Disease', 'MESH:C536494', (178, 192))	('uveal melanoma', 'Disease', (178, 192))	('uveal melanoma', 'Phenotype', 'HP:0007716', (21, 35))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', (86, 92))	('metastases', 'Disease', 'MESH:D009362', (198, 208))	('UM', 'Phenotype', 'HP:0007716', (194, 196))	('uveal melanoma', 'Phenotype', 'HP:0007716', (178, 192))	('Monosomy 3', 'Var', (0, 10))	('metastases', 'Disease', (198, 208))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('uveal melanoma metastases', 'Disease', (21, 46))	('associated', 'Reg', (50, 60))	('uveal melanoma', 'Disease', 'MESH:C536494', (21, 35))	('metastases', 'Disease', 'MESH:D009362', (36, 46))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (21, 46))
81684	22569040	We identified monosomy of chromosome 3 in tumors from four patients with an average survival of 5 months (range 1-8 months) from time of diagnosis of metastatic disease.	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('monosomy', 'Var', (14, 22))	('patients', 'Species', '9606', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
81685	22569040	In contrast, tumors with either disomy or partial chromosome 3 alterations showed significantly slower metastatic disease progression with an average survival of 69 months (range 40-123 months, p = 0.003).	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('metastatic disease progression', 'CPA', (103, 133))	('slower', 'NegReg', (96, 102))	('chromosome', 'cellular_component', 'GO:0005694', ('50', '60'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('disomy', 'Var', (32, 38))	('partial chromosome', 'Var', (42, 60))
81686	22569040	Alterations in chromosomal arms 1p, 6p, and 8q and mutations in either GNAQ or GNA11 showed no association with disease progression.	('mutations', 'Var', (51, 60))	('GNAQ', 'Gene', (71, 75))	('Alterations', 'Var', (0, 11))	('GNA11', 'Gene', '2767', (79, 84))	('GNA11', 'Gene', (79, 84))	('GNAQ', 'Gene', '2776', (71, 75))
81688	22569040	In conclusion, in UM metastases, monosomy 3 is associated with highly aggressive, rapidly progressive disease while disomy or partial change of 3 and prominent mononuclear inflammatory infiltrate in the tumor is associated with better prognosis.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('metastases', 'Disease', 'MESH:D009362', (21, 31))	('associated with', 'Reg', (47, 62))	('UM', 'Phenotype', 'HP:0007716', (18, 20))	('partial change of', 'Var', (126, 143))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('metastases', 'Disease', (21, 31))	('monosomy 3', 'Var', (33, 43))	('disomy', 'Var', (116, 122))
81692	22569040	Monosomy 3 is noted in 50-60% of primary tumors and confers a poor clinical prognosis.	('noted', 'Reg', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('primary tumors', 'Disease', (33, 47))	('primary tumors', 'Disease', 'MESH:D009369', (33, 47))	('Monosomy 3', 'Var', (0, 10))
81693	22569040	Mutation in the BRCA-1 associated protein-1 (BAP1) gene, located on chromosome 3, has been identified recently with a high frequency in UM primary tumors that metastasize.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('BRCA-1 associated protein-1', 'Gene', (16, 43))	('BAP1', 'Gene', (45, 49))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('Mutation', 'Var', (0, 8))	('BAP1', 'Gene', '8314', (45, 49))	('primary tumors', 'Disease', (139, 153))	('UM', 'Phenotype', 'HP:0007716', (136, 138))	('primary tumors', 'Disease', 'MESH:D009369', (139, 153))	('BRCA-1 associated protein-1', 'Gene', '8314', (16, 43))
81694	22569040	Other chromosomal abnormalities portending a poor prognosis include gain in chromosomal arm 8q and loss of chromosomal arm 1p, while alteration in chromosomal arm 6p is associated with better prognosis.	('chromosomal abnormalities', 'Disease', (6, 31))	('arm 1p', 'Gene', (119, 125))	('alteration', 'Var', (133, 143))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (6, 31))	('loss', 'NegReg', (99, 103))	('chromosomal', 'MPA', (107, 118))	('arm 1p', 'Gene', '11047', (119, 125))	('gain', 'PosReg', (68, 72))	('chromosomal arm', 'Var', (76, 91))
81696	22569040	Finally, mutations in two G-proteins, GNAQ and GNA11, have also recently been identified in the majority of UM primary tumors and are being considered potential targets for novel therapies.	('identified', 'Reg', (78, 88))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('GNAQ', 'Gene', '2776', (38, 42))	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('mutations', 'Var', (9, 18))	('GNA11', 'Gene', (47, 52))	('primary tumors', 'Disease', (111, 125))	('GNA11', 'Gene', '2767', (47, 52))	('GNAQ', 'Gene', (38, 42))	('primary tumors', 'Disease', 'MESH:D009369', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
81698	22569040	The two studies reporting on the molecular genetics of UM metastases revealed monosomy 3 in the majority of tumors However, a small subset, 25.6%, showed either disomy of chromosome 3 or partial chromosome 3 alterations.	('chromosome', 'cellular_component', 'GO:0005694', ('171', '181'))	('monosomy 3', 'Var', (78, 88))	('disomy', 'Var', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('tumors However', 'Disease', (108, 122))	('partial chromosome', 'Var', (187, 205))	('revealed', 'Reg', (69, 77))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('chromosome', 'cellular_component', 'GO:0005694', ('195', '205'))	('tumors However', 'Disease', 'MESH:D009369', (108, 122))	('metastases', 'Disease', (58, 68))	('metastases', 'Disease', 'MESH:D009362', (58, 68))
81718	22569040	Deletion of BAP1 was assessed by evaluation of loss of heterozygosity (LOH) using microsatellite markers flanking the BAP1 region on 3p21.	('BAP1', 'Gene', '8314', (12, 16))	('BAP1', 'Gene', '8314', (118, 122))	('loss', 'NegReg', (47, 51))	('BAP1', 'Gene', (12, 16))	('BAP1', 'Gene', (118, 122))	('Deletion', 'Var', (0, 8))
81737	22569040	Mutations in codon 209 (Q209L) in either GNAQ or GNA11 were observed in tumors from 8/11 patients.	('Q209L', 'Mutation', 'rs121913492', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('GNAQ', 'Gene', '2776', (41, 45))	('Q209L', 'Var', (24, 29))	('observed', 'Reg', (60, 68))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('GNAQ', 'Gene', (41, 45))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('patients', 'Species', '9606', (89, 97))	('GNA11', 'Gene', '2767', (49, 54))	('GNA11', 'Gene', (49, 54))
81738	22569040	Primary tumors from four patients, UM6001, UM8008, UM8002 and UM4033 were available and showed identical genetic changes to the metastatic tumors.	('UM6001', 'Var', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('tumors', 'Disease', (8, 14))	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('UM8002', 'Var', (51, 57))	('Primary tumors', 'Disease', (0, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('patients', 'Species', '9606', (25, 33))	('tumors', 'Disease', (139, 145))	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('UM4033', 'Var', (62, 68))	('Primary tumors', 'Disease', 'MESH:D009369', (0, 14))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('UM8008', 'Var', (43, 49))
81740	22569040	In all except two patients, MM0001 and MM0004, the Tmet were within two weeks of the time of obtaining of tissue samples.	('MM0004', 'Var', (39, 45))	('Tmet', 'Chemical', '-', (51, 55))	('MM0001', 'Var', (28, 34))	('patients', 'Species', '9606', (18, 26))
81748	22569040	In contrast, metastases with partial 3 and disomy 3 status were present in patients with long survival.	('disomy 3 status', 'Var', (43, 58))	('partial 3', 'Var', (29, 38))	('patients', 'Species', '9606', (75, 83))	('metastases', 'Disease', (13, 23))	('metastases', 'Disease', 'MESH:D009362', (13, 23))
81750	22569040	Such information may also be crucial for designing therapeutic clinical trials because the relatively long survival of patients with partial change of chromosome 3 or disomy 3 could bias the outcome of any clinical trial that includes a significant number of these patients.	('patients', 'Species', '9606', (119, 127))	('chromosome 3', 'Gene', (151, 163))	('patients', 'Species', '9606', (265, 273))	('disomy', 'Var', (167, 173))	('chromosome', 'cellular_component', 'GO:0005694', ('151', '161'))
81756	22569040	The association between monosomy 3, but not disomy or partial chromosome 3 alteration, with aggressive UM, lack of inflammatory cellular infiltration and rapidly progressive metastatic tumors suggests that combined disruption of more than one gene in different locations on chromosome 3 is important for tumor aggressiveness.	('monosomy 3', 'Var', (24, 34))	('chromosome', 'cellular_component', 'GO:0005694', ('62', '72'))	('association', 'Interaction', (4, 15))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (304, 324))	('chromosome', 'cellular_component', 'GO:0005694', ('274', '284'))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('aggressive UM', 'CPA', (92, 105))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor aggressiveness', 'Disease', (304, 324))	('aggressiveness', 'Phenotype', 'HP:0000718', (310, 324))	('UM', 'Phenotype', 'HP:0007716', (103, 105))
81766	22569040	In addition, the association between monosomy 3 and increased HLA class I expression on tumor cells could explain the immune escape mechanism of monosomy 3 tumors which would be more resistant to NK cell lysis in extra-ocular locations.	('expression', 'MPA', (74, 84))	('increased', 'PosReg', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('HLA class I', 'Protein', (62, 73))	('lysis', 'biological_process', 'GO:0019835', ('204', '209'))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('monosomy 3', 'Disease', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('monosomy 3', 'Var', (145, 155))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', (88, 93))	('tumors', 'Disease', (156, 162))
81772	22569040	A recent report has indicated high frequency of somatic BAP1 mutation in primary UM tumors that metastasize.	('BAP1', 'Gene', '8314', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('mutation', 'Var', (61, 69))	('BAP1', 'Gene', (56, 60))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('UM', 'Phenotype', 'HP:0007716', (81, 83))
81773	22569040	We tested for somatic deletions in BAP1 using genotyping of markers spanning the gene and identified LOH of markers in close proximity to BAP1 in 8/11 patients, including four with long survival.	('deletions', 'Var', (22, 31))	('BAP1', 'Gene', '8314', (138, 142))	('BAP1', 'Gene', '8314', (35, 39))	('tested', 'Reg', (3, 9))	('BAP1', 'Gene', (138, 142))	('patients', 'Species', '9606', (151, 159))	('BAP1', 'Gene', (35, 39))
81775	22569040	However, our data don't exclude the possibility of a biallelic inactivation of BAP1, through mutation and deletion, being associated with rapidly progressive tumors.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('BAP1', 'Gene', '8314', (79, 83))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('associated with', 'Reg', (122, 137))	('BAP1', 'Gene', (79, 83))	('deletion', 'Var', (106, 114))	('biallelic inactivation', 'Var', (53, 75))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutation', 'Var', (93, 101))
81784	22569040	In support of the dormancy/slow growth of a subset of metastatic UM, two patients with multiple liver metastasis (UM4033 and UM0004) showed very slow growth of their metastatic lesions during follow up.	('UM', 'Phenotype', 'HP:0007716', (65, 67))	('slow growth', 'Phenotype', 'HP:0001510', (27, 38))	('UM', 'Phenotype', 'HP:0007716', (125, 127))	('dormancy', 'biological_process', 'GO:0030431', ('18', '26'))	('multiple liver metastasis', 'Disease', (87, 112))	('slow growth', 'Phenotype', 'HP:0001510', (145, 156))	('UM', 'Phenotype', 'HP:0007716', (114, 116))	('UM0004', 'Var', (125, 131))	('multiple liver metastasis', 'Disease', 'MESH:D009362', (87, 112))	('UM4033', 'Var', (114, 120))	('patients', 'Species', '9606', (73, 81))
81785	22569040	Somatic GNAQ and GNA11 mutations are unique for UM, and have not been reported in other types of melanomas.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('melanomas', 'Disease', 'MESH:D008545', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('GNAQ', 'Gene', (8, 12))	('melanomas', 'Phenotype', 'HP:0002861', (97, 106))	('mutations', 'Var', (23, 32))	('GNA11', 'Gene', (17, 22))	('melanomas', 'Disease', (97, 106))	('GNAQ', 'Gene', '2776', (8, 12))	('GNA11', 'Gene', '2767', (17, 22))
81786	22569040	GNAQ or GNA11 mutations were present in the majority of the metastatic tumors in our study, including the three tumors with a disease free interval greater than 10 years between primary and metastatic disease.	('GNA11', 'Gene', (8, 13))	('GNAQ', 'Gene', '2776', (0, 4))	('GNA11', 'Gene', '2767', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('GNAQ', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('present', 'Reg', (29, 36))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('mutations', 'Var', (14, 23))	('tumors', 'Disease', (112, 118))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
81792	22569040	It also suggests that in metastatic UM monosomy 3 is associated with highly aggressive, rapidly progressive disease while prominent mononuclear inflammatory infiltrate in the tumor is associated with better prognosis.	('tumor', 'Disease', (175, 180))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('associated with', 'Reg', (53, 68))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('monosomy 3', 'Var', (39, 49))
81794	22180178	NRAS Mutation Status is an Independent Prognostic Factor in Metastatic Melanoma There is a need for improved prognostic markers in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('Metastatic Melanoma', 'Disease', 'MESH:D008545', (60, 79))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('Metastatic Melanoma', 'Disease', (60, 79))	('NRAS', 'Gene', (0, 4))	('Melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('NRAS', 'Gene', '4893', (0, 4))	('Mutation', 'Var', (5, 13))
81795	22180178	This study tested the prognostic significance and clinicopathologic correlations of BRAF and NRAS mutations in patients with metastatic melanoma.	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('NRAS', 'Gene', '4893', (93, 97))	('mutations', 'Var', (98, 107))	('tested', 'Reg', (11, 17))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))	('NRAS', 'Gene', (93, 97))	('patients', 'Species', '9606', (111, 119))
81796	22180178	Clinical and pathologic data were collected retrospectively on melanoma patients clinically tested for BRAF (exon 15) and NRAS (exons 1, 2) mutations at the M. D. Anderson Cancer Center.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('BRAF', 'Gene', '673', (103, 107))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('Cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Cancer', 'Disease', (172, 178))	('NRAS', 'Gene', (122, 126))	('Cancer', 'Disease', 'MESH:D009369', (172, 178))	('mutations', 'Var', (140, 149))	('NRAS', 'Gene', '4893', (122, 126))	('melanoma', 'Disease', (63, 71))	('BRAF', 'Gene', (103, 107))	('patients', 'Species', '9606', (72, 80))
81797	22180178	Analyses were performed to identify significant associations of mutations with tumor and patient characteristics, and with survival from the diagnosis of stage IV disease.	('patient', 'Species', '9606', (89, 96))	('tumor', 'Disease', (79, 84))	('associations', 'Interaction', (48, 60))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
81798	22180178	The genotypes of the full cohort (n=677) were 47% BRAF mutation, 20% NRAS mutation, and 32% wild-type for BRAF and NRAS ("WT").	('NRAS', 'Gene', '4893', (69, 73))	('BRAF', 'Gene', (50, 54))	('NRAS', 'Gene', (115, 119))	('NRAS', 'Gene', '4893', (115, 119))	('BRAF', 'Gene', '673', (106, 110))	('BRAF', 'Gene', (106, 110))	('mutation', 'Var', (55, 63))	('NRAS', 'Gene', (69, 73))	('BRAF', 'Gene', '673', (50, 54))
81800	22180178	Among non-uveal melanoma patients with mutation testing within 6 months of stage IV diagnosis (n=313), patients with NRAS mutations had a median survival of 8.2 months from stage IV diagnosis, which was shorter than WT patients (15.1 months, p=0.004).	('uveal melanoma', 'Disease', 'MESH:C536494', (10, 24))	('NRAS', 'Gene', (117, 121))	('mutation', 'Var', (39, 47))	('uveal melanoma', 'Phenotype', 'HP:0007716', (10, 24))	('uveal melanoma', 'Disease', (10, 24))	('NRAS', 'Gene', '4893', (117, 121))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('patients', 'Species', '9606', (25, 33))	('mutations', 'Var', (122, 131))	('patients', 'Species', '9606', (219, 227))	('patients', 'Species', '9606', (103, 111))
81801	22180178	Multivariate analysis of this population incorporating age, gender, M1 category, serum LDH, and mutation status confirmed NRAS mutations are independently associated with decreased OS (vs WT, p=0.005, HR= 2.05).	('mutations', 'Var', (127, 136))	('decreased', 'NegReg', (171, 180))	('NRAS', 'Gene', '4893', (122, 126))	('NRAS', 'Gene', (122, 126))
81802	22180178	Patients with BRAF or NRAS mutations are more likely than WT patients to have CNS involvement at the diagnosis of distant metastatic disease.	('mutations', 'Var', (27, 36))	('patients', 'Species', '9606', (61, 69))	('NRAS', 'Gene', (22, 26))	('CNS', 'Disease', (78, 81))	('Patients', 'Species', '9606', (0, 8))	('BRAF', 'Gene', '673', (14, 18))	('NRAS', 'Gene', '4893', (22, 26))	('BRAF', 'Gene', (14, 18))
81803	22180178	NRAS mutation status is an independent predictor of shorter survival from the diagnosis of stage IV melanoma.	('shorter', 'NegReg', (52, 59))	('IV melanoma', 'Disease', (97, 108))	('NRAS', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('IV melanoma', 'Disease', 'MESH:D008545', (97, 108))	('NRAS', 'Gene', '4893', (0, 4))	('mutation', 'Var', (5, 13))
81806	22180178	The most common somatic event in melanoma is mutation of the serine-threonine kinase BRAF, which is a component of the RAS-RAF-MEK-MAPK signaling pathway.	('RAF', 'Gene', '22882', (86, 89))	('RAF', 'Gene', (86, 89))	('MEK', 'Gene', (127, 130))	('MEK', 'Gene', '5609', (127, 130))	('common', 'Reg', (9, 15))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('MAPK signaling', 'biological_process', 'GO:0000165', ('131', '145'))	('mutation', 'Var', (45, 53))	('RAF', 'Gene', '22882', (123, 126))	('MAPK', 'molecular_function', 'GO:0004707', ('131', '135'))	('signaling pathway', 'biological_process', 'GO:0007165', ('136', '153'))	('RAF', 'Gene', (123, 126))
81807	22180178	Overall, point mutations in the BRAF gene occur in 40-50% of melanomas.	('BRAF', 'Gene', '673', (32, 36))	('BRAF', 'Gene', (32, 36))	('occur', 'Reg', (42, 47))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('melanomas', 'Disease', 'MESH:D008545', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('point mutations', 'Var', (9, 24))	('melanomas', 'Disease', (61, 70))
81808	22180178	Over 90% of the mutations in BRAF result in substitution of the valine at position 600, resulting in activation of the downstream effectors of the RAS-RAF-MEK-MAPK pathway.	('RAF', 'Gene', (151, 154))	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('substitution', 'Var', (44, 56))	('activation', 'PosReg', (101, 111))	('MAPK', 'molecular_function', 'GO:0004707', ('159', '163'))	('MEK', 'Gene', (155, 158))	('mutations', 'Var', (16, 25))	('MEK', 'Gene', '5609', (155, 158))	('RAF', 'Gene', '22882', (30, 33))	('valine', 'Chemical', 'MESH:D014633', (64, 70))	('RAF', 'Gene', (30, 33))	('RAF', 'Gene', '22882', (151, 154))
81809	22180178	This pathway may also be activated by point mutations in NRAS, which codes for a small GTP-binding protein.	('GTP-binding', 'molecular_function', 'GO:0005525', ('87', '98'))	('activated', 'Reg', (25, 34))	('NRAS', 'Gene', (57, 61))	('point mutations', 'Var', (38, 53))	('GTP', 'Chemical', 'MESH:D006160', (87, 90))	('NRAS', 'Gene', '4893', (57, 61))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))
81811	22180178	The overwhelming majority of activating BRAF and NRAS mutations in melanomas have been mutually exclusive.	('melanomas', 'Disease', (67, 76))	('BRAF', 'Gene', '673', (40, 44))	('NRAS', 'Gene', '4893', (49, 53))	('BRAF', 'Gene', (40, 44))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('mutations', 'Var', (54, 63))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('melanomas', 'Disease', 'MESH:D008545', (67, 76))	('NRAS', 'Gene', (49, 53))	('activating', 'PosReg', (29, 39))
81812	22180178	Previous studies have examined associations of BRAF and NRAS mutations with primary tumor characteristics and prognosis in earlier stage disease.	('associations', 'Interaction', (31, 43))	('NRAS', 'Gene', (56, 60))	('earlier stage disease', 'Disease', (123, 144))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('BRAF', 'Gene', (47, 51))	('primary tumor', 'Disease', (76, 89))	('NRAS', 'Gene', '4893', (56, 60))	('BRAF', 'Gene', '673', (47, 51))	('mutations', 'Var', (61, 70))	('primary tumor', 'Disease', 'MESH:D009369', (76, 89))
81814	22180178	An improved understanding of the prognostic significance of mutation status in these patients may help in the appropriate design and interpretation of clinical trials, and add to the understanding of the biology of this disease.	('patients', 'Species', '9606', (85, 93))	('mutation', 'Var', (60, 68))	('help', 'Reg', (98, 102))
81815	22180178	We have performed a retrospective analysis of a large cohort of advanced melanoma patients who underwent testing for both BRAF (exon 15) and NRAS (exons 1 and 2) mutations.	('melanoma', 'Disease', (73, 81))	('mutations', 'Var', (162, 171))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('NRAS', 'Gene', '4893', (141, 145))	('patients', 'Species', '9606', (82, 90))	('BRAF', 'Gene', '673', (122, 126))	('BRAF', 'Gene', (122, 126))	('NRAS', 'Gene', (141, 145))
81816	22180178	The results of this analysis provide the first evidence that melanoma patients with an activating mutation in the NRAS gene have significantly shorter survival from stage IV diagnosis than patients without a mutation in either the BRAF or NRAS gene, and the prognostic value of this marker is independent of current validated prognostic markers.	('patients', 'Species', '9606', (70, 78))	('BRAF', 'Gene', (231, 235))	('shorter', 'NegReg', (143, 150))	('mutation', 'Var', (98, 106))	('BRAF', 'Gene', '673', (231, 235))	('NRAS', 'Gene', (114, 118))	('NRAS', 'Gene', (239, 243))	('NRAS', 'Gene', '4893', (114, 118))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('activating', 'PosReg', (87, 97))	('melanoma', 'Disease', (61, 69))	('NRAS', 'Gene', '4893', (239, 243))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('patients', 'Species', '9606', (189, 197))	('survival', 'MPA', (151, 159))
81817	22180178	The results of CLIA-certified testing for BRAF and NRAS mutations performed by the University of Texas MD Anderson Cancer Center Molecular Diagnostics lab for melanoma patients from February 1, 2007, to September, 13, 2010, were reviewed under an Institutional Review Board approved protocol.	('melanoma', 'Disease', (159, 167))	('BRAF', 'Gene', '673', (42, 46))	('mutations', 'Var', (56, 65))	('Texas MD Anderson Cancer', 'Disease', 'MESH:C535460', (97, 121))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))	('Texas MD Anderson Cancer', 'Disease', (97, 121))	('patients', 'Species', '9606', (168, 176))	('NRAS', 'Gene', (51, 55))	('BRAF', 'Gene', (42, 46))	('Cancer', 'Phenotype', 'HP:0002664', (115, 121))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('NRAS', 'Gene', '4893', (51, 55))
81820	22180178	Treatments with the selective BRAF inhibitors vemurafenib (Roche) or GSK2118436 (GlaxoSmithKline) or the selective MEK inhibitors selumitinib (AstraZeneca) or GSK1120212 (GlaxoSmithKline) were also recorded.	('selumitinib', 'Chemical', '-', (130, 141))	('MEK', 'Gene', '5609', (115, 118))	('GSK2118436', 'Var', (69, 79))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('GSK', 'molecular_function', 'GO:0050321', ('69', '72'))	('vemurafenib', 'Chemical', 'MESH:D000077484', (46, 57))	('MEK', 'Gene', (115, 118))	('GSK1120212', 'Var', (159, 169))	('GSK1120212', 'Chemical', 'MESH:C560077', (159, 169))	('GSK', 'molecular_function', 'GO:0050321', ('159', '162'))	('GSK2118436', 'Chemical', 'MESH:C561627', (69, 79))
81824	22180178	Mutations in exon 15 of BRAF (only) were found in 320 (47.3%), and NRAS mutations (only) in 136 (20.1%).	('mutations', 'Var', (72, 81))	('NRAS', 'Gene', (67, 71))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('Mutations in', 'Var', (0, 12))	('NRAS', 'Gene', '4893', (67, 71))
81825	22180178	The majority of the BRAF mutations were represented by the V600E (71.9% of BRAF mutations) and V600K (22.5%) substitutions.	('V600K', 'Mutation', 'rs121913227', (95, 100))	('BRAF', 'Gene', '673', (75, 79))	('BRAF', 'Gene', (75, 79))	('BRAF', 'Gene', '673', (20, 24))	('V600E', 'Mutation', 'rs113488022', (59, 64))	('V600K', 'Var', (95, 100))	('BRAF', 'Gene', (20, 24))	('V600E', 'Var', (59, 64))
81826	22180178	Substitutions at position 60-61 accounted for 82.4% of NRAS mutations, most frequently Q61R/K/L.	('NRAS', 'Gene', '4893', (55, 59))	('NRAS', 'Gene', (55, 59))	('Q61R', 'SUBSTITUTION', 'None', (87, 91))	('Q61R', 'Var', (87, 91))
81828	22180178	Due to the rarity and uncertain functional significance of non-V600 BRAF exon 15 mutations (n=6) and dual BRAF/NRAS mutations (n=4), patients with these genotypes were excluded from further analyses.	('NRAS', 'Gene', (111, 115))	('BRAF', 'Gene', '673', (68, 72))	('NRAS', 'Gene', '4893', (111, 115))	('non-V600', 'Var', (59, 67))	('patients', 'Species', '9606', (133, 141))	('BRAF', 'Gene', '673', (106, 110))	('BRAF', 'Gene', (68, 72))	('BRAF', 'Gene', (106, 110))
81829	22180178	At the time of initial diagnosis of melanoma, patients with a BRAF mutation ("BRAF") were significantly younger (median age, 49.8 years) than the NRAS-mutant ("NRAS") (55.7 years, p=0.0008) or the WT (59.5 years, p<0.0001) patients (Table 2).	('patients', 'Species', '9606', (46, 54))	('BRAF', 'Gene', '673', (78, 82))	('NRAS', 'Gene', (160, 164))	('melanoma', 'Disease', (36, 44))	('mutation', 'Var', (67, 75))	('BRAF"', 'Gene', '673', (78, 83))	('NRAS', 'Gene', '4893', (146, 150))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('BRAF', 'Gene', (78, 82))	('NRAS', 'Gene', '4893', (160, 164))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('NRAS"', 'Gene', (160, 165))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('patients', 'Species', '9606', (223, 231))	('BRAF"', 'Gene', (78, 83))	('NRAS"', 'Gene', '4893', (160, 165))	('NRAS', 'Gene', (146, 150))
81831	22180178	NRAS mutations were less common in Hispanic patients (8.8%) compared to the Caucasians (21.1 %) while Asian/Black/Unknown patients had an increased frequency of being WT (61.1% versus 31.1% of Caucasians).	('patients', 'Species', '9606', (44, 52))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (122, 130))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))
81832	22180178	Mutation status was strongly associated with the anatomic type of melanoma (p<0.0001) (Table 2).	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('Mutation', 'Var', (0, 8))	('associated', 'Reg', (29, 39))
81835	22180178	None of the uveal melanoma patients (n=11) had a mutation in either BRAF or NRAS.	('NRAS', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (68, 72))	('uveal melanoma', 'Phenotype', 'HP:0007716', (12, 26))	('NRAS', 'Gene', '4893', (76, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (12, 26))	('BRAF', 'Gene', (68, 72))	('mutation', 'Var', (49, 57))	('patients', 'Species', '9606', (27, 35))	('uveal melanoma', 'Disease', (12, 26))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))
81837	22180178	Among the patients with documented cutaneous primary tumor characteristics, there was no significant association observed between mutation status and Breslow thickness (n=424, p=0.40), mitotic rate (n=311, p=0.16), or ulceration status (n=344, p=0.44) (Table 3).	('mutation', 'Var', (130, 138))	('primary tumor', 'Disease', (45, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('primary tumor', 'Disease', 'MESH:D009369', (45, 58))	('mitotic rate', 'CPA', (185, 197))	('Breslow thickness', 'CPA', (150, 167))	('patients', 'Species', '9606', (10, 18))
81838	22180178	Mutation status was significantly associated with primary tumor site and histology.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('associated', 'Reg', (34, 44))	('Mutation', 'Var', (0, 8))	('primary tumor', 'Disease', (50, 63))	('primary tumor', 'Disease', 'MESH:D009369', (50, 63))
81839	22180178	BRAF mutations were most prevalent in truncal melanomas (63.9%) and with superficial spreading morphology (63.2%); NRAS mutations were most prevalent in melanomas arising from the arm/leg (34.7%) and with nodular histology (28.3%) (Table 3).	('prevalent', 'Reg', (25, 34))	('NRAS', 'Gene', (115, 119))	('melanomas', 'Phenotype', 'HP:0002861', (153, 162))	('melanomas', 'Disease', 'MESH:D008545', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('melanomas', 'Disease', 'MESH:D008545', (153, 162))	('NRAS', 'Gene', '4893', (115, 119))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('mutations', 'Var', (5, 14))	('truncal melanomas', 'Disease', 'MESH:D001259', (38, 55))	('BRAF', 'Gene', '673', (0, 4))	('truncal melanomas', 'Disease', (38, 55))	('prevalent', 'Reg', (140, 149))	('melanomas', 'Disease', (46, 55))	('mutations', 'Var', (120, 129))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Disease', (153, 162))
81840	22180178	After excluding non-V600 BRAF (n=6) mutants, patients with concurrent BRAF and NRAS mutations (n=4), and one patient with incomplete data, a total of 519 patients in the cohort that developed stage IV melanoma (48.6% BRAF, 20.0% NRAS, 31.4% WT) were further analyzed.	('NRAS', 'Gene', '4893', (79, 83))	('NRAS', 'Gene', '4893', (229, 233))	('patients', 'Species', '9606', (45, 53))	('mutants', 'Var', (36, 43))	('BRAF', 'Gene', '673', (70, 74))	('NRAS', 'Gene', (79, 83))	('BRAF', 'Gene', (70, 74))	('patient', 'Species', '9606', (109, 116))	('IV melanoma', 'Disease', 'MESH:D008545', (198, 209))	('NRAS', 'Gene', (229, 233))	('patients', 'Species', '9606', (154, 162))	('mutations', 'Var', (84, 93))	('patient', 'Species', '9606', (45, 52))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('patient', 'Species', '9606', (154, 161))	('BRAF', 'Gene', '673', (217, 221))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (217, 221))	('BRAF', 'Gene', (25, 29))	('IV melanoma', 'Disease', (198, 209))
81847	22180178	Analysis of anatomic sites that characterize M1c disease (i.e., non-pulmonary visceral) identified a significant association of mutation status with the rate of CNS involvement at the time of the diagnosis of stage IV disease (p=0.0076).	('mutation status', 'Var', (128, 143))	('non-pulmonary visceral', 'Disease', (64, 86))	('M1c', 'Disease', (45, 48))	('CNS', 'Disease', (161, 164))	('non-pulmonary visceral', 'Disease', 'MESH:D007418', (64, 86))
81855	22180178	As recent reports support that targeted therapies against the RAS-RAF-MEK-MAPK may have marked clinical activity in patients with activating BRAF mutations, the BRAF patients who had enrolled on non-randomized clinical trials of selective BRAF or MEK inhibitors (n=41) were analyzed separately from BRAF patients who had not (n=112).	('RAF', 'Gene', '22882', (240, 243))	('RAF', 'Gene', (66, 69))	('BRAF', 'Gene', (239, 243))	('BRAF', 'Gene', '673', (239, 243))	('RAF', 'Gene', (162, 165))	('MEK', 'Gene', '5609', (70, 73))	('RAF', 'Gene', (240, 243))	('RAF', 'Gene', '22882', (142, 145))	('patients', 'Species', '9606', (116, 124))	('MEK', 'Gene', (70, 73))	('BRAF', 'Gene', '673', (299, 303))	('BRAF', 'Gene', (299, 303))	('BRAF', 'Gene', '673', (141, 145))	('BRAF', 'Gene', (141, 145))	('patients', 'Species', '9606', (304, 312))	('MEK', 'Gene', '5609', (247, 250))	('RAF', 'Gene', (142, 145))	('RAF', 'Gene', '22882', (300, 303))	('RAF', 'Gene', '22882', (66, 69))	('activating', 'PosReg', (130, 140))	('mutations', 'Var', (146, 155))	('MEK', 'Gene', (247, 250))	('MAPK', 'molecular_function', 'GO:0004707', ('74', '78'))	('RAF', 'Gene', '22882', (162, 165))	('RAF', 'Gene', (300, 303))	('BRAF', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (161, 165))	('patients', 'Species', '9606', (166, 174))
81857	22180178	Patients with uveal melanoma (n=11) were also excluded due to the lack of BRAF or NRAS mutations in these patients and the distinctive clinical course of this disease.	('uveal melanoma', 'Phenotype', 'HP:0007716', (14, 28))	('uveal melanoma', 'Disease', 'MESH:C536494', (14, 28))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('uveal melanoma', 'Disease', (14, 28))	('Patients', 'Species', '9606', (0, 8))	('NRAS', 'Gene', (82, 86))	('patients', 'Species', '9606', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('NRAS', 'Gene', '4893', (82, 86))	('mutations', 'Var', (87, 96))
81866	22180178	This study represents one of the largest single-institution cohorts of melanoma patients characterized for activating BRAF and NRAS mutations to date, and to our knowledge the largest cohort of stage IV patients.	('BRAF', 'Gene', '673', (118, 122))	('patients', 'Species', '9606', (80, 88))	('BRAF', 'Gene', (118, 122))	('mutations', 'Var', (132, 141))	('activating', 'PosReg', (107, 117))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('patients', 'Species', '9606', (203, 211))	('NRAS', 'Gene', (127, 131))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('NRAS', 'Gene', '4893', (127, 131))
81867	22180178	The study is strengthened by the use of a clinically certified mutation detection method for all patients, and by the inclusion of testing for mutations in exon 1 (as well as exon 2) of NRAS, which was not performed in some previous studies in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (244, 252))	('NRAS', 'Gene', (186, 190))	('NRAS', 'Gene', '4893', (186, 190))	('mutations in', 'Var', (143, 155))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('melanoma', 'Disease', (244, 252))	('patients', 'Species', '9606', (97, 105))
81868	22180178	We report here the novel findings that the presence of an NRAS mutation correlates with shorter survival from the diagnosis of stage IV melanoma, and that the presence of either a BRAF or NRAS mutation is associated with an increased risk of CNS involvement at initial stage IV diagnosis.	('shorter', 'NegReg', (88, 95))	('IV melanoma', 'Disease', (133, 144))	('BRAF', 'Gene', (180, 184))	('NRAS', 'Gene', '4893', (58, 62))	('presence', 'Var', (159, 167))	('NRAS', 'Gene', (188, 192))	('IV melanoma', 'Disease', 'MESH:D008545', (133, 144))	('mutation', 'Var', (63, 71))	('presence', 'Var', (43, 51))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('NRAS', 'Gene', (58, 62))	('NRAS', 'Gene', '4893', (188, 192))	('mutation', 'Var', (193, 201))	('BRAF', 'Gene', '673', (180, 184))	('survival', 'MPA', (96, 104))	('CNS involvement', 'Disease', (242, 257))
81869	22180178	Our study has also confirmed several previously reported associations with BRAF mutations, including age, primary tumor site, and improved survival with targeted therapies against the RAS-RAF-MEK-MAPK pathway.	('MEK', 'Gene', (192, 195))	('primary tumor', 'Disease', 'MESH:D009369', (106, 119))	('MEK', 'Gene', '5609', (192, 195))	('MAPK', 'molecular_function', 'GO:0004707', ('196', '200'))	('mutations', 'Var', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('RAF', 'Gene', '22882', (76, 79))	('BRAF', 'Gene', '673', (75, 79))	('RAF', 'Gene', (76, 79))	('BRAF', 'Gene', (75, 79))	('RAF', 'Gene', '22882', (188, 191))	('RAF', 'Gene', (188, 191))	('survival', 'CPA', (139, 147))	('primary tumor', 'Disease', (106, 119))	('improved', 'PosReg', (130, 138))
81871	22180178	Two recent consecutive series of >200 primary melanomas both reported that primary tumors with NRAS mutations were associated with increased Breslow thickness.	('mutations', 'Var', (100, 109))	('primary tumor', 'Disease', 'MESH:D009369', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('increased', 'PosReg', (131, 140))	('melanomas', 'Disease', 'MESH:D008545', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('Breslow', 'Disease', (141, 148))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('NRAS', 'Gene', (95, 99))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('melanomas', 'Disease', (46, 55))	('primary melanoma', 'Disease', 'MESH:D008545', (38, 54))	('primary tumor', 'Disease', (75, 88))	('NRAS', 'Gene', '4893', (95, 99))	('primary melanoma', 'Disease', (38, 54))
81872	22180178	These studies, however, had conflicting findings regarding the relationship for NRAS mutation status with mitotic rate and ulceration.	('NRAS', 'Gene', (80, 84))	('NRAS', 'Gene', '4893', (80, 84))	('mutation', 'Var', (85, 93))
81874	22180178	However, as our patient population was selected by retrospectively identifying patients who had undergone clinically indicated mutation testing and thus overwhelmingly consisted of patients who developed distant metastases, it is possible that these results are not representative of all patients with primary melanoma.	('patient', 'Species', '9606', (288, 295))	('metastases', 'Disease', 'MESH:D009362', (212, 222))	('primary melanoma', 'Disease', (302, 318))	('primary melanoma', 'Disease', 'MESH:D008545', (302, 318))	('melanoma', 'Phenotype', 'HP:0002861', (310, 318))	('patients', 'Species', '9606', (288, 296))	('patient', 'Species', '9606', (181, 188))	('mutation testing', 'Var', (127, 143))	('patients', 'Species', '9606', (181, 189))	('patient', 'Species', '9606', (79, 86))	('patients', 'Species', '9606', (79, 87))	('patient', 'Species', '9606', (16, 23))	('metastases', 'Disease', (212, 222))
81876	22180178	Previous analyses comparing NRAS mutations to patient survival have also reported discordant results.	('patient', 'Species', '9606', (46, 53))	('NRAS', 'Gene', '4893', (28, 32))	('NRAS', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
81880	22180178	The study that identified shorter RFS did not detect a significant difference in survival by NRAS mutation status after the diagnosis of metastatic disease, but its power was limited by a low prevalence of patients with distant metastases and few relevant events for analysis.	('mutation', 'Var', (98, 106))	('metastases', 'Disease', (228, 238))	('NRAS', 'Gene', '4893', (93, 97))	('patients', 'Species', '9606', (206, 214))	('metastases', 'Disease', 'MESH:D009362', (228, 238))	('NRAS', 'Gene', (93, 97))
81884	22180178	In our study, compared to WT patients, NRAS mutation was associated with shorter survival from stage IV diagnosis, in both the full cohort of all metastatic melanoma patients (n=519), as well as in the cohort who underwent molecular testing within 6 months of the diagnosis of stage IV (n=313).	('stage IV', 'Disease', (95, 103))	('patients', 'Species', '9606', (29, 37))	('mutation', 'Var', (44, 52))	('NRAS', 'Gene', (39, 43))	('shorter', 'NegReg', (73, 80))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('survival', 'MPA', (81, 89))	('melanoma', 'Disease', (157, 165))	('NRAS', 'Gene', '4893', (39, 43))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('patients', 'Species', '9606', (166, 174))
81886	22180178	The presence of an NRAS mutation did not correlate with established stage IV prognostic factors such as elevated LDH or advanced M1 category.	('NRAS', 'Gene', (19, 23))	('NRAS', 'Gene', '4893', (19, 23))	('mutation', 'Var', (24, 32))	('LDH', 'MPA', (113, 116))	('elevated', 'PosReg', (104, 112))
81890	22180178	The trend for shorter survival from stage IV diagnosis for BRAF mutant patients who did not receive BRAF or MEK inhibitors compared to BRAF patients treated with these agents is similar to the findings recently reported by Long et al of 197 consecutive advanced melanoma patients.	('melanoma', 'Disease', (262, 270))	('BRAF', 'Gene', '673', (135, 139))	('BRAF', 'Gene', (135, 139))	('shorter', 'NegReg', (14, 21))	('patients', 'Species', '9606', (71, 79))	('MEK', 'Gene', (108, 111))	('MEK', 'Gene', '5609', (108, 111))	('BRAF', 'Gene', '673', (100, 104))	('BRAF', 'Gene', (59, 63))	('survival', 'MPA', (22, 30))	('BRAF', 'Gene', '673', (59, 63))	('patients', 'Species', '9606', (271, 279))	('patients', 'Species', '9606', (140, 148))	('BRAF', 'Gene', (100, 104))	('mutant', 'Var', (64, 70))	('melanoma', 'Disease', 'MESH:D008545', (262, 270))	('melanoma', 'Phenotype', 'HP:0002861', (262, 270))
81893	22180178	However, our population appears very typical genetically, as the prevalence of BRAF and NRAS mutations in this cohort is nearly identical that that reported in two different meta-analyses of >2,000 patients each.	('mutations', 'Var', (93, 102))	('patients', 'Species', '9606', (198, 206))	('NRAS', 'Gene', (88, 92))	('NRAS', 'Gene', '4893', (88, 92))	('BRAF', 'Gene', '673', (79, 83))	('BRAF', 'Gene', (79, 83))
81894	22180178	In addition, we note the frequencies of V600E and V600K mutations in our cohort are similar to that of the Australian study of 197 advanced melanoma patients.	('V600K', 'Mutation', 'rs121913227', (50, 55))	('patients', 'Species', '9606', (149, 157))	('V600K', 'Var', (50, 55))	('V600E', 'Mutation', 'rs113488022', (40, 45))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('V600E', 'Var', (40, 45))
81896	22180178	Finally, additional genetic aberrations may characterize each of the mutation-defined cohorts here, such as PTEN loss or activating c-KIT mutations.	('PTEN loss', 'Disease', 'MESH:D006223', (108, 117))	('activating', 'PosReg', (121, 131))	('PTEN loss', 'Disease', (108, 117))	('c-KIT', 'Gene', (132, 137))	('c-KIT', 'Gene', '3815', (132, 137))	('KIT', 'molecular_function', 'GO:0005020', ('134', '137'))	('mutations', 'Var', (138, 147))
81897	22180178	The emergence of BRAF targeted therapies that benefit only patients with activating BRAF mutations will almost certainly lead to clinical trials designed specifically for BRAF wild-type patients in the near future.	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', '673', (17, 21))	('BRAF', 'Gene', (84, 88))	('BRAF', 'Gene', '673', (171, 175))	('activating', 'PosReg', (73, 83))	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', (171, 175))	('mutations', 'Var', (89, 98))	('patients', 'Species', '9606', (59, 67))	('patients', 'Species', '9606', (186, 194))
81899	22180178	Our data support that melanoma patients with an NRAS mutation represent a distinct cohort, with a highly aggressive disease and shorter survival with stage IV disease.	('NRAS', 'Gene', '4893', (48, 52))	('mutation', 'Var', (53, 61))	('aggressive disease', 'Disease', 'MESH:D001523', (105, 123))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('aggressive disease', 'Disease', (105, 123))	('melanoma', 'Disease', (22, 30))	('patients', 'Species', '9606', (31, 39))	('NRAS', 'Gene', (48, 52))
81902	22180178	In addition, these results highlight the critical need for more effective therapies for melanoma patients with activating NRAS mutations.	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('activating', 'PosReg', (111, 121))	('NRAS', 'Gene', (122, 126))	('mutations', 'Var', (127, 136))	('NRAS', 'Gene', '4893', (122, 126))	('patients', 'Species', '9606', (97, 105))
82003	22346112	The purpose of this step is to denature any residual protein that might otherwise incite inflammation, that is, sympathetic ophthalmia.	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('denature', 'Var', (31, 39))	('sympathetic ophthalmia', 'Disease', 'MESH:D009879', (112, 134))	('inflammation', 'Disease', 'MESH:D007249', (89, 101))	('incite', 'Reg', (82, 88))	('inflammation', 'Disease', (89, 101))	('protein', 'Protein', (53, 60))	('sympathetic ophthalmia', 'Disease', (112, 134))	('inflammation', 'biological_process', 'GO:0006954', ('89', '101'))
82014	22346112	Also, in the few studies that assessed motility, dismantling the sclera did not adversely affect implant excursion or patients' overall satisfaction.	('patients', 'Species', '9606', (118, 126))	('dismantling', 'Var', (49, 60))	('man', 'Species', '9606', (52, 55))	('implant excursion', 'CPA', (97, 114))
82060	21305041	Subsequent researchers found that loss of chromosome 3 (monosomy 3) and gain of chromosome 8q were associated significantly with high death rates of UM and the loss of 6p was a specific character of primary UM metastases.	('loss', 'Var', (34, 38))	('UM', 'Phenotype', 'HP:0007716', (149, 151))	('metastases', 'Disease', 'MESH:D009362', (210, 220))	('UM', 'Phenotype', 'HP:0007716', (207, 209))	('chromosome', 'cellular_component', 'GO:0005694', ('80', '90'))	('gain', 'PosReg', (72, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('42', '52'))	('metastases', 'Disease', (210, 220))
82062	21305041	Recently, it has been reported that mutation of GNAQ gene (gene encodes heterotrimetric G protein alpha-subunit) occurred in approximate 50% of UM patients, but not in cutaneous melanoma.	('cutaneous melanoma', 'Disease', (168, 186))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (168, 186))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (168, 186))	('GNAQ', 'Gene', '2776', (48, 52))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('occurred', 'Reg', (113, 121))	('patients', 'Species', '9606', (147, 155))	('GNAQ', 'Gene', (48, 52))	('UM', 'Phenotype', 'HP:0007716', (144, 146))	('mutation', 'Var', (36, 44))
82097	21305041	Chromosome 3 deletion is found in several cancers, monosomy 3 is the most common abnormality of chromosomes in the pathogenesis of UM, which has been found to be associated with UM metastasis.	('cancers', 'Disease', (42, 49))	('UM', 'Phenotype', 'HP:0007716', (131, 133))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('pathogenesis', 'biological_process', 'GO:0009405', ('115', '127'))	('associated', 'Reg', (162, 172))	('monosomy 3', 'Var', (51, 61))	('UM metastasis', 'Disease', (178, 191))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('UM', 'Phenotype', 'HP:0007716', (178, 180))	('cancers', 'Disease', 'MESH:D009369', (42, 49))
82103	21305041	This mutation induces activation of one of the MAPK signal pathways (ERK1/2) and upregulation of PKA.	('MAPK', 'Gene', (47, 51))	('PKA', 'cellular_component', 'GO:0005952', ('97', '100'))	('ERK1/2', 'Gene', (69, 75))	('ERK1/2', 'Gene', '5595;5594', (69, 75))	('activation', 'PosReg', (22, 32))	('MAPK', 'molecular_function', 'GO:0004707', ('47', '51'))	('upregulation', 'PosReg', (81, 93))	('PKA', 'Pathway', (97, 100))	('PKA', 'molecular_function', 'GO:0004691', ('97', '100'))	('mutation', 'Var', (5, 13))	('MAPK', 'Gene', '5595;5594;5595', (47, 51))	('ERK1', 'molecular_function', 'GO:0004707', ('69', '73'))
82105	21305041	The lack of BRAF mutations in posterior UM predicates that missense mutations of BRAF is not related to the unlimited cell proliferation in UM, which is differnt from the pathogenesis of cutaneous melanoma.	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', (12, 16))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('BRAF', 'Gene', '673', (81, 85))	('cutaneous melanoma', 'Disease', (187, 205))	('pathogenesis', 'biological_process', 'GO:0009405', ('171', '183'))	('BRAF', 'Gene', (81, 85))	('missense mutations', 'Var', (59, 77))	('UM', 'Phenotype', 'HP:0007716', (40, 42))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (187, 205))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (187, 205))	('cell proliferation', 'biological_process', 'GO:0008283', ('118', '136'))	('UM', 'Phenotype', 'HP:0007716', (140, 142))
82114	21305041	However, cancer cells can become resistant to apoptosis by activating proteins that protect the cell from apoptosis, by mutating proteins that cause apoptosis or by developing the ability to ignore apoptotic signals.	('cancer', 'Disease', (9, 15))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))	('activating', 'PosReg', (59, 69))	('proteins', 'Protein', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('apoptosis', 'biological_process', 'GO:0097194', ('149', '158'))	('apoptosis', 'biological_process', 'GO:0006915', ('149', '158'))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('mutating', 'Var', (120, 128))	('proteins', 'Protein', (129, 137))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('ability', 'MPA', (180, 187))
82121	21305041	According to our analysis in cell cycle pathway, the inactivation of P53 leads to the continual process of DNA damage cell from G1 to S without proper repair.	('cell cycle', 'biological_process', 'GO:0007049', ('29', '39'))	('leads to', 'Reg', (73, 81))	('P53', 'Gene', (69, 72))	('inactivation', 'Var', (53, 65))	('P53', 'Gene', '7157', (69, 72))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))	('DNA', 'Disease', (107, 110))
82217	20169050	Any vertical movement of the blade may cause perforation of the retina or nonpigmented ciliary epithelium and vitreous loss.	('cause', 'Reg', (39, 44))	('vertical movement', 'Var', (4, 21))	('vitreous loss', 'Phenotype', 'HP:0100832', (110, 123))	('perforation of the retina', 'Phenotype', 'HP:0011958', (45, 70))	('vitreous loss', 'Disease', 'MESH:D014823', (110, 123))	('nonpigmented ciliary epithelium', 'CPA', (74, 105))	('vitreous loss', 'Disease', (110, 123))	('perforation of the retina', 'CPA', (45, 70))
82252	33588787	Involvement of mutant and wild-type CYSLTR2 in the development and progression of uveal nevi and melanoma Activating Galphaq signalling mutations are considered an early event in the development of uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('melanoma', 'Disease', 'MESH:D008545', (204, 212))	('mutations', 'Var', (136, 145))	('CYSLTR2', 'Gene', '57105', (36, 43))	('Involvement', 'Reg', (0, 11))	('CYSLTR2', 'Gene', (36, 43))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('signalling', 'biological_process', 'GO:0023052', ('125', '135'))	('melanoma', 'Disease', (204, 212))	('Galphaq', 'Gene', (117, 124))	('uveal melanoma', 'Disease', 'MESH:C536494', (198, 212))	('uveal melanoma', 'Disease', (198, 212))	('mutant', 'Var', (15, 21))	('uveal melanoma', 'Phenotype', 'HP:0007716', (198, 212))	('Galphaq', 'Gene', '2776', (117, 124))	('nevi', 'Phenotype', 'HP:0003764', (88, 92))	('uveal nevi', 'Disease', (82, 92))
82253	33588787	Whereas most tumours harbour a mutation in GNAQ or GNA11, CYSLTR2 (encoding G-protein coupled receptor CysLT2R) forms a rare alternative.	('GNA11', 'Gene', '2767', (51, 56))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('CYSLTR2', 'Gene', (58, 65))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('GNAQ', 'Gene', (43, 47))	('mutation', 'Var', (31, 39))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('tumours', 'Disease', (13, 20))	('CysLT2R', 'Gene', (103, 110))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('GNA11', 'Gene', (51, 56))	('GNAQ', 'Gene', '2776', (43, 47))	('CYSLTR2', 'Gene', '57105', (58, 65))	('CysLT2R', 'Gene', '57105', (103, 110))
82256	33588787	Publicly available bulk and single cell sequencing data were mined to further study mutant and wild-type CYSLTR2 in primary and metastatic uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('uveal melanoma', 'Disease', 'MESH:C536494', (139, 153))	('uveal melanoma', 'Disease', (139, 153))	('mutant', 'Var', (84, 90))	('primary', 'Disease', (116, 123))	('CYSLTR2', 'Gene', '57105', (105, 112))	('CYSLTR2', 'Gene', (105, 112))
82259	33588787	In the melanomas, secondary, subclonal CYSLTR2 alterations shifted the allelic balance towards the mutant.	('melanoma', 'Phenotype', 'HP:0002861', (7, 15))	('shifted', 'Reg', (59, 66))	('melanomas', 'Disease', (7, 16))	('CYSLTR2', 'Gene', '57105', (39, 46))	('alterations', 'Var', (47, 58))	('melanomas', 'Disease', 'MESH:D008545', (7, 16))	('melanomas', 'Phenotype', 'HP:0002861', (7, 16))	('CYSLTR2', 'Gene', (39, 46))
82261	33588787	At the RNA level, further silencing of wild-type and preferential expression of mutant CYSLTR2 was identified, which was also observed in two CYSLTR2 mutant primary melanomas and one metastatic lesion from other cohorts.	('mutant', 'Var', (80, 86))	('melanomas', 'Disease', (165, 174))	('RNA', 'cellular_component', 'GO:0005562', ('7', '10'))	('CYSLTR2', 'Gene', '57105', (142, 149))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('CYSLTR2', 'Gene', '57105', (87, 94))	('expression', 'MPA', (66, 76))	('CYSLTR2', 'Gene', (142, 149))	('silencing', 'NegReg', (26, 35))	('CYSLTR2', 'Gene', (87, 94))	('melanomas', 'Phenotype', 'HP:0002861', (165, 174))	('preferential', 'PosReg', (53, 65))	('melanomas', 'Disease', 'MESH:D008545', (165, 174))	('mutant', 'Var', (150, 156))
82264	33588787	Whereas the CYSLTR2 p.L129Q mutation is likely to be the initiating oncogenic event, various mechanisms further increase the mutant allele abundance during tumour progression.	('tumour', 'Disease', (156, 162))	('CYSLTR2', 'Gene', '57105', (12, 19))	('increase', 'PosReg', (112, 120))	('CYSLTR2', 'Gene', (12, 19))	('p.L129Q', 'Var', (20, 27))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('p.L129Q', 'Mutation', 'p.L129Q', (20, 27))	('tumour', 'Disease', 'MESH:D009369', (156, 162))
82265	33588787	This makes mutant CysLT2R an attractive therapeutic target in uveal melanoma.	('CysLT2R', 'Gene', '57105', (18, 25))	('mutant', 'Var', (11, 17))	('uveal melanoma', 'Disease', (62, 76))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('CysLT2R', 'Gene', (18, 25))	('uveal melanoma', 'Phenotype', 'HP:0007716', (62, 76))	('uveal melanoma', 'Disease', 'MESH:C536494', (62, 76))
82272	33588787	Activating Galphaq signalling mutations at mutually-exclusive hotspots in GNAQ and GNA11 (p.Q209 and p.R183) are found in a large majority of uveal melanomas.	('Activating', 'PosReg', (0, 10))	('GNAQ', 'Gene', (74, 78))	('uveal melanomas', 'Disease', 'MESH:C536494', (142, 157))	('Galphaq', 'Gene', '2776', (11, 18))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('uveal melanoma', 'Phenotype', 'HP:0007716', (142, 156))	('Galphaq', 'Gene', (11, 18))	('p.R183', 'Var', (101, 107))	('mutations', 'Var', (30, 39))	('uveal melanomas', 'Disease', (142, 157))	('p.Q209', 'Var', (90, 96))	('GNA11', 'Gene', (83, 88))	('GNAQ', 'Gene', '2776', (74, 78))	('uveal melanomas', 'Phenotype', 'HP:0007716', (142, 157))	('signalling', 'biological_process', 'GO:0023052', ('19', '29'))	('GNA11', 'Gene', '2767', (83, 88))	('melanomas', 'Phenotype', 'HP:0002861', (148, 157))
82274	33588787	The essential role of Galphaq signalling in uveal melanoma tumorigenesis has been further supported by the discovery of rare but recurrent mutations in PLCB4 (p.D630) and CYSLTR2 (p.L129Q) .	('CYSLTR2', 'Gene', '57105', (171, 178))	('melanoma tumorigenesis', 'Disease', 'MESH:D063646', (50, 72))	('p.D630', 'Var', (159, 165))	('CYSLTR2', 'Gene', (171, 178))	('p.L129Q', 'Mutation', 'p.L129Q', (180, 187))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('signalling', 'biological_process', 'GO:0023052', ('30', '40'))	('PLCB4', 'Gene', '5332', (152, 157))	('Galphaq', 'Gene', '2776', (22, 29))	('p.L129Q', 'Var', (180, 187))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('Galphaq', 'Gene', (22, 29))	('melanoma tumorigenesis', 'Disease', (50, 72))	('uveal melanoma', 'Disease', (44, 58))	('PLCB4', 'Gene', (152, 157))
82275	33588787	These genes, encoding phospholipase C beta4 and a Galphaq-coupled receptor respectively, are typically mutated in GNAQ and GNA11 wild-type tumours, providing an alternative way of activating the Galphaq signalling pathway.	('tumours', 'Phenotype', 'HP:0002664', (139, 146))	('mutated', 'Var', (103, 110))	('Galphaq', 'Gene', (195, 202))	('phospholipase C beta4', 'Gene', (22, 43))	('Galphaq', 'Gene', '2776', (195, 202))	('tumours', 'Disease', 'MESH:D009369', (139, 146))	('phospholipase C beta4', 'Gene', '5332', (22, 43))	('signalling pathway', 'biological_process', 'GO:0007165', ('203', '221'))	('activating', 'PosReg', (180, 190))	('tumours', 'Disease', (139, 146))	('GNAQ', 'Gene', '2776', (114, 118))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('GNA11', 'Gene', (123, 128))	('Galphaq', 'Gene', '2776', (50, 57))	('Galphaq', 'Gene', (50, 57))	('GNA11', 'Gene', '2767', (123, 128))	('GNAQ', 'Gene', (114, 118))
82280	33588787	Mutant CYSLTR2 however leads to constitutive activation of endogenous Galphaq signalling, thereby stimulating the same pathways as oncogenic mutations in GNAQ and GNA11.	('GNAQ', 'Gene', '2776', (154, 158))	('CYSLTR2', 'Gene', '57105', (7, 14))	('GNA11', 'Gene', (163, 168))	('GNA11', 'Gene', '2767', (163, 168))	('Galphaq', 'Gene', (70, 77))	('stimulating', 'PosReg', (98, 109))	('Galphaq', 'Gene', '2776', (70, 77))	('CYSLTR2', 'Gene', (7, 14))	('GNAQ', 'Gene', (154, 158))	('signalling', 'biological_process', 'GO:0023052', ('78', '88'))	('Mutant', 'Var', (0, 6))	('activation', 'PosReg', (45, 55))
82281	33588787	In this study, we examined the presence of CYSLTR2 mutations in non-malignant choroidal nevi and primary uveal melanomas.	('uveal melanomas', 'Phenotype', 'HP:0007716', (105, 120))	('non-malignant choroidal nevi', 'Disease', (64, 92))	('CYSLTR2', 'Gene', (43, 50))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('mutations', 'Var', (51, 60))	('choroidal nevi', 'Phenotype', 'HP:0025314', (78, 92))	('uveal melanomas', 'Disease', 'MESH:C536494', (105, 120))	('nevi', 'Phenotype', 'HP:0003764', (88, 92))	('uveal melanoma', 'Phenotype', 'HP:0007716', (105, 119))	('CYSLTR2', 'Gene', '57105', (43, 50))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))	('uveal melanomas', 'Disease', (105, 120))
82282	33588787	By targeted analysis using digital PCR, an accurate quantification of both CYSLTR2 mutant and wild-type alleles could be achieved even in DNA samples of lower quality and quantity.	('mutant', 'Var', (83, 89))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('quantification', 'MPA', (52, 66))	('CYSLTR2', 'Gene', '57105', (75, 82))	('CYSLTR2', 'Gene', (75, 82))
82283	33588787	In the CYSLTR2 mutant melanomas, we further assessed the genetic heterogeneity within tumours and investigated the allelic balance of CYSLTR2 at the RNA level.	('CYSLTR2', 'Gene', (134, 141))	('CYSLTR2', 'Gene', '57105', (7, 14))	('melanomas', 'Disease', (22, 31))	('CYSLTR2', 'Gene', (7, 14))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('RNA', 'cellular_component', 'GO:0005562', ('149', '152'))	('melanomas', 'Disease', 'MESH:D008545', (22, 31))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('CYSLTR2', 'Gene', '57105', (134, 141))	('mutant', 'Var', (15, 21))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumours', 'Disease', (86, 93))
82284	33588787	Expansion into publicly available bulk and single cell uveal melanoma sequencing data allowed to evaluate our findings in independent cohorts of primary and metastatic tumours and to study the role of wild-type CYSLTR2 in melanomas with a mutation in GNAQ, GNA11 or PLCB4.	('uveal melanoma', 'Phenotype', 'HP:0007716', (55, 69))	('GNAQ', 'Gene', (251, 255))	('CYSLTR2', 'Gene', '57105', (211, 218))	('melanomas', 'Phenotype', 'HP:0002861', (222, 231))	('tumours', 'Disease', (168, 175))	('GNA11', 'Gene', '2767', (257, 262))	('tumours', 'Phenotype', 'HP:0002664', (168, 175))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('tumours', 'Disease', 'MESH:D009369', (168, 175))	('CYSLTR2', 'Gene', (211, 218))	('mutation', 'Var', (239, 247))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('PLCB4', 'Gene', (266, 271))	('melanomas', 'Disease', 'MESH:D008545', (222, 231))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('GNA11', 'Gene', (257, 262))	('melanomas', 'Disease', (222, 231))	('uveal melanoma', 'Disease', (55, 69))	('uveal melanoma', 'Disease', 'MESH:C536494', (55, 69))	('PLCB4', 'Gene', '5332', (266, 271))	('GNAQ', 'Gene', '2776', (251, 255))
82292	33588787	B14.003/DH/sh and B20.026.	('B14', 'Gene', '4700', (0, 3))	('B14', 'Gene', (0, 3))	('DH', 'Disease', 'MESH:D065630', (8, 10))	('B20.026', 'Var', (18, 25))
82299	33588787	Allele-specific RNA expression was determined based on the balance between the CYSLTR2 mutation versus wild-type and the balance between variants from common SNP's in the transcribed CYSLTR2 gene.	('CYSLTR2', 'Gene', '57105', (79, 86))	('CYSLTR2', 'Gene', (79, 86))	('CYSLTR2', 'Gene', '57105', (183, 190))	('CYSLTR2', 'Gene', (183, 190))	('mutation', 'Var', (87, 95))	('RNA', 'cellular_component', 'GO:0005562', ('16', '19'))
82300	33588787	For both, the number of reads mapping to the specific variants were determined using samtools (v1.7) and freebayes (v1.3.1).	('v1.3', 'Gene', '28816', (116, 120))	('v1.7', 'Gene', '28813', (95, 99))	('v1.7', 'Gene', (95, 99))	('v1.3', 'Gene', (116, 120))	('variants', 'Var', (54, 62))
82301	33588787	DNA and RNA levels of the CYSLTR2 mutation in metastatic uveal melanoma CheckMate-03820,035 were available from the recent study performed by Anagnostou et al..	('RNA', 'cellular_component', 'GO:0005562', ('8', '11'))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('mutation', 'Var', (34, 42))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('CYSLTR2', 'Gene', '57105', (26, 33))	('uveal melanoma', 'Disease', (57, 71))	('CYSLTR2', 'Gene', (26, 33))
82305	33588787	Previously, 16 choroidal nevi from 13 post-mortem collected eyes were analysed for GNAQ and GNA11 hotspot mutations.	('nevi', 'Phenotype', 'HP:0003764', (25, 29))	('GNAQ', 'Gene', '2776', (83, 87))	('GNA11', 'Gene', (92, 97))	('GNA11', 'Gene', '2767', (92, 97))	('choroidal nevi', 'Phenotype', 'HP:0025314', (15, 29))	('mutations', 'Var', (106, 115))	('GNAQ', 'Gene', (83, 87))
82306	33588787	In the same cohort we applied a custom digital PCR assay, which targets the CYSLTR2 p.L129Q wild-type and mutant allele specifically.	('p.L129Q', 'Var', (84, 91))	('CYSLTR2', 'Gene', (76, 83))	('p.L129Q', 'Mutation', 'p.L129Q', (84, 91))	('CYSLTR2', 'Gene', '57105', (76, 83))
82307	33588787	In nevus 12B, the only one being GNAQ and GNA11 wild-type, we now identified this CYSLTR2 mutation, while only CYSLTR2 wild-type alleles were detected in other nevi (Fig.	('CYSLTR2', 'Gene', (82, 89))	('GNAQ', 'Gene', (33, 37))	('nevi', 'Phenotype', 'HP:0003764', (160, 164))	('CYSLTR2', 'Gene', '57105', (82, 89))	('GNAQ', 'Gene', '2776', (33, 37))	('GNA11', 'Gene', '2767', (42, 47))	('GNA11', 'Gene', (42, 47))	('CYSLTR2', 'Gene', '57105', (111, 118))	('CYSLTR2', 'Gene', (111, 118))	('mutation', 'Var', (90, 98))	('nevus', 'Phenotype', 'HP:0003764', (3, 8))
82309	33588787	As an earlier Melan-A staining indicated a > 95% nevus cell purity of the macrodissected tissue, it turns out that a subpopulation of the nevus cells was mutated (Fig.	('nevus', 'Phenotype', 'HP:0003764', (138, 143))	('mutated', 'Var', (154, 161))	('Melan-A', 'Gene', (14, 21))	('Melan-A', 'Gene', '2315', (14, 21))	('nevus', 'Phenotype', 'HP:0003764', (49, 54))
82310	33588787	A cohort of 120 archival primary uveal melanomas, treated by enucleation at the LUMC, was screened for the CYSLTR2 p.L129Q mutation.	('uveal melanomas', 'Disease', (33, 48))	('uveal melanomas', 'Phenotype', 'HP:0007716', (33, 48))	('p.L129Q', 'Mutation', 'p.L129Q', (115, 122))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanomas', 'Phenotype', 'HP:0002861', (39, 48))	('enucleation', 'biological_process', 'GO:0090601', ('61', '72'))	('CYSLTR2', 'Gene', '57105', (107, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('uveal melanomas', 'Disease', 'MESH:C536494', (33, 48))	('CYSLTR2', 'Gene', (107, 114))	('p.L129Q', 'Var', (115, 122))	('LUMC', 'Chemical', '-', (80, 84))
82315	33588787	Digital PCR for the CYSLTR2 p.L129Q mutation in PUM-1A revealed a mutant allele fraction of 55% (Fig.	('CYSLTR2', 'Gene', '57105', (20, 27))	('CYSLTR2', 'Gene', (20, 27))	('p.L129Q', 'Var', (28, 35))	('PUM-1', 'Gene', (48, 53))	('PUM-1', 'Gene', '9698', (48, 53))	('p.L129Q', 'Mutation', 'p.L129Q', (28, 35))
82317	33588787	This was confirmed by the allelic imbalance of heterozygous common single nucleotide polymorphism (SNP) rs2057413 in SETDB2, located ~ 776 kb telomeric from CYSLTR2 (Supplementary Data 1).	('SETDB2', 'Gene', (117, 123))	('CYSLTR2', 'Gene', '57105', (157, 164))	('rs2057413', 'Mutation', 'rs2057413', (104, 113))	('SETDB2', 'Gene', '83852', (117, 123))	('CYSLTR2', 'Gene', (157, 164))	('single nucleotide', 'Var', (67, 84))	('rs2057413', 'Var', (104, 113))	('imbalance', 'Phenotype', 'HP:0002172', (34, 43))
82318	33588787	The comparable abundances (~ 74% of total tumour) of the CYSLTR2 mutation, gain of 8q and losses of 1p and 16q suggest that these alterations are clonally present in this sample and occurred during an early developmental phase.	('CYSLTR2', 'Gene', (57, 64))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('mutation', 'Var', (65, 73))	('tumour', 'Disease', (42, 48))	('CYSLTR2', 'Gene', '57105', (57, 64))	('losses', 'NegReg', (90, 96))	('gain', 'PosReg', (75, 79))
82322	33588787	Again, two different clones were identified: in 99% of the cells the CYSLTR2 mutation was present, with chromosome 3p and 13q lost in ~ 93% of the cells, giving clonal sizes of 6 and 93%, and a healthy cell fraction of 1% (Fig.	('mutation', 'Var', (77, 85))	('CYSLTR2', 'Gene', '57105', (69, 76))	('lost', 'NegReg', (126, 130))	('CYSLTR2', 'Gene', (69, 76))	('cell fraction', 'cellular_component', 'GO:0000267', ('202', '215'))	('chromosome', 'cellular_component', 'GO:0005694', ('104', '114'))
82323	33588787	The genetic alterations of PUM-1 are typically associated with a poor prognosis, which is highlighted by the observed negative BAP1 nuclear staining (Table 1).	('genetic alterations', 'Var', (4, 23))	('BAP1', 'Gene', (127, 131))	('BAP1', 'Gene', '8314', (127, 131))	('PUM-1', 'Gene', (27, 32))	('associated', 'Reg', (47, 57))	('PUM-1', 'Gene', '9698', (27, 32))
82327	33588787	In PUM-2A a CYSLTR2 p.L129Q mutant allele fraction of 57% was observed (Fig.	('CYSLTR2', 'Gene', '57105', (12, 19))	('CYSLTR2', 'Gene', (12, 19))	('p.L129Q', 'Var', (20, 27))	('PUM-2', 'Gene', '23369', (3, 8))	('p.L129Q', 'Mutation', 'p.L129Q', (20, 27))	('PUM-2', 'Gene', (3, 8))
82328	33588787	In this tumour, a gain of chromosome 13q caused the relative excess of the mutant alleles (Fig.	('tumour', 'Disease', (8, 14))	('gain', 'PosReg', (18, 22))	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('excess', 'PosReg', (61, 67))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('mutant', 'Var', (75, 81))	('tumour', 'Disease', 'MESH:D009369', (8, 14))
82329	33588787	While the corrected mutant cell fraction was calculated to be 85%, the gain of the mutant CYSLTR2 allele was quantified to be present in 68% of the cells, giving clonal sizes of 17 and 68%, and a healthy cell fraction of 15% (Fig.	('cell fraction', 'cellular_component', 'GO:0000267', ('204', '217'))	('CYSLTR2', 'Gene', '57105', (90, 97))	('mutant', 'Var', (83, 89))	('CYSLTR2', 'Gene', (90, 97))	('gain', 'PosReg', (71, 75))	('cell fraction', 'cellular_component', 'GO:0000267', ('27', '40'))
82330	33588787	In PUM-2B, we also observed two clones: in 83% of all cells the CYSLTR2 p.L129Q mutation was identified, while 45% of the cells carried an extra copy of chromosome 13q.	('chromosome', 'cellular_component', 'GO:0005694', ('153', '163'))	('p.L129Q', 'Var', (72, 79))	('CYSLTR2', 'Gene', '57105', (64, 71))	('PUM-2', 'Gene', '23369', (3, 8))	('PUM-2', 'Gene', (3, 8))	('p.L129Q', 'Mutation', 'p.L129Q', (72, 79))	('CYSLTR2', 'Gene', (64, 71))
82331	33588787	The copy number profile (normal chromosomes 3p and 8) of this tumour is correlated to a relatively good prognosis, which is supported by the positive BAP1 nuclear staining (Table 1).	('BAP1', 'Gene', (150, 154))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('copy number', 'Var', (4, 15))	('tumour', 'Disease', (62, 68))	('BAP1', 'Gene', '8314', (150, 154))
82333	33588787	Since both CYSLTR2 mutant tumours presented with chromosome 13q aberrations, we questioned whether such copy number alterations are common in CYSLTR2 mutant and wild-type uveal melanomas.	('tumours', 'Disease', (26, 33))	('presented', 'Reg', (34, 43))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('uveal melanoma', 'Phenotype', 'HP:0007716', (171, 185))	('CYSLTR2', 'Gene', (142, 149))	('mutant', 'Var', (19, 25))	('uveal melanomas', 'Disease', 'MESH:C536494', (171, 186))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))	('CYSLTR2', 'Gene', '57105', (11, 18))	('chromosome', 'cellular_component', 'GO:0005694', ('49', '59'))	('tumours', 'Disease', 'MESH:D009369', (26, 33))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('mutant', 'Var', (150, 156))	('uveal melanomas', 'Disease', (171, 186))	('uveal melanomas', 'Phenotype', 'HP:0007716', (171, 186))	('CYSLTR2', 'Gene', (11, 18))	('chromosome', 'Var', (49, 59))	('melanomas', 'Phenotype', 'HP:0002861', (177, 186))	('CYSLTR2', 'Gene', '57105', (142, 149))
82335	33588787	3/80 cases presented with a CYSLTR2 p.L129Q mutation (V4-A9ED, VD-AA8O and YZ-A982), of which the clinical details are summarised in Table 1.	('p.L129Q', 'Var', (36, 43))	('CYSLTR2', 'Gene', '57105', (28, 35))	('p.L129Q', 'Mutation', 'p.L129Q', (36, 43))	('CYSLTR2', 'Gene', (28, 35))	('presented', 'Reg', (11, 20))
82337	33588787	In the 77 CYSLTR2 wild-type tumours, eight cases presented with a copy number alteration involving the CYSLTR2 locus at chromosome 13q, making it an uncommon event in uveal melanoma (Supplementary Figure 3).	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('copy number alteration', 'Var', (66, 88))	('CYSLTR2', 'Gene', '57105', (10, 17))	('CYSLTR2', 'Gene', '57105', (103, 110))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('uveal melanoma', 'Phenotype', 'HP:0007716', (167, 181))	('uveal melanoma', 'Disease', 'MESH:C536494', (167, 181))	('CYSLTR2', 'Gene', (10, 17))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('CYSLTR2', 'Gene', (103, 110))	('presented', 'Reg', (49, 58))	('uveal melanoma', 'Disease', (167, 181))	('tumours', 'Disease', 'MESH:D009369', (28, 35))	('tumours', 'Disease', (28, 35))	('chromosome', 'cellular_component', 'GO:0005694', ('120', '130'))
82338	33588787	In the two CYSLTR2 mutant uveal melanomas from our Leiden cohort, we also evaluated the gene expression of both wild-type and mutant allele by digital PCR.	('gene expression', 'biological_process', 'GO:0010467', ('88', '103'))	('uveal melanomas', 'Disease', (26, 41))	('CYSLTR2', 'Gene', '57105', (11, 18))	('uveal melanomas', 'Phenotype', 'HP:0007716', (26, 41))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('CYSLTR2', 'Gene', (11, 18))	('uveal melanomas', 'Disease', 'MESH:C536494', (26, 41))	('melanomas', 'Phenotype', 'HP:0002861', (32, 41))	('uveal melanoma', 'Phenotype', 'HP:0007716', (26, 40))	('mutant', 'Var', (19, 25))
82339	33588787	Despite a lower level of significance, preferential expression of the mutant allele was also observed in two of the three CYSLTR2 mutant primary uveal melanomas from the TCGA cohort (Fig.	('uveal melanoma', 'Phenotype', 'HP:0007716', (145, 159))	('CYSLTR2', 'Gene', '57105', (122, 129))	('CYSLTR2', 'Gene', (122, 129))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('uveal melanomas', 'Disease', (145, 160))	('uveal melanomas', 'Phenotype', 'HP:0007716', (145, 160))	('melanomas', 'Phenotype', 'HP:0002861', (151, 160))	('mutant', 'Var', (130, 136))	('uveal melanomas', 'Disease', 'MESH:C536494', (145, 160))
82340	33588787	described the mutations and their expression in various types of metastatic melanomas studied in the CheckMate-038 (https://clinicaltrials.gov/ct2/show/results/NCT01621490) clinical trial.	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('melanomas', 'Disease', 'MESH:D008545', (76, 85))	('melanomas', 'Disease', (76, 85))	('mutations', 'Var', (14, 23))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
82341	33588787	One uveal melanoma metastasis (case MUM-20035) carried a copy number stable heterozygous CYSLTR2 mutation which was also hemizygously expressed at the RNA level (Fig.	('uveal melanoma', 'Phenotype', 'HP:0007716', (4, 18))	('uveal melanoma', 'Disease', (4, 18))	('melanoma metastasis', 'Disease', (10, 29))	('RNA', 'cellular_component', 'GO:0005562', ('151', '154'))	('melanoma metastasis', 'Disease', 'MESH:D009362', (10, 29))	('CYSLTR2', 'Gene', '57105', (89, 96))	('mutation', 'Var', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('uveal melanoma', 'Disease', 'MESH:C536494', (4, 18))	('CYSLTR2', 'Gene', (89, 96))
82345	33588787	To investigate this variable CYSLTR2 expression, we further analysed the 77 primary melanomas from the TCGA cohort and extended the analysis with the eight primary and three metastatic melanomas studied using single cell RNA sequencing as described by Durante et al.. All these melanomas were wild-type for CYSLTR2 and the majority carried mutations in GNAQ, GNA11 or PLCB4.	('melanomas', 'Disease', (84, 93))	('CYSLTR2', 'Gene', '57105', (307, 314))	('CYSLTR2', 'Gene', '57105', (29, 36))	('melanomas', 'Disease', 'MESH:D008545', (185, 194))	('melanoma', 'Phenotype', 'HP:0002861', (278, 286))	('GNA11', 'Gene', '2767', (359, 364))	('GNAQ', 'Gene', '2776', (353, 357))	('melanomas', 'Disease', (185, 194))	('GNAQ', 'Gene', (353, 357))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('CYSLTR2', 'Gene', (307, 314))	('mutations', 'Var', (340, 349))	('PLCB4', 'Gene', (368, 373))	('CYSLTR2', 'Gene', (29, 36))	('melanomas', 'Disease', 'MESH:D008545', (278, 287))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanomas', 'Disease', (278, 287))	('melanomas', 'Phenotype', 'HP:0002861', (185, 194))	('carried', 'Reg', (332, 339))	('GNA11', 'Gene', (359, 364))	('RNA', 'cellular_component', 'GO:0005562', ('221', '224'))	('melanomas', 'Disease', 'MESH:D008545', (84, 93))	('PLCB4', 'Gene', '5332', (368, 373))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanomas', 'Phenotype', 'HP:0002861', (278, 287))
82346	33588787	Based on bulk RNA data from the TCGA cohort, the highest levels of wild-type CYSLTR2 expression were observed in tumours with an inflammatory phenotype as shown by their immune gene expression signature (high expression of CD14, CD163 [monocytes/macrophages] and CD3D, CD8A [T cells]) (Fig.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('CD163', 'Gene', (229, 234))	('gene expression', 'biological_process', 'GO:0010467', ('177', '192'))	('CD3D', 'Gene', '915', (263, 267))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('CD8A', 'Gene', '925', (269, 273))	('tumours', 'Disease', 'MESH:D009369', (113, 120))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('CD3D', 'Gene', (263, 267))	('CD8A', 'Gene', (269, 273))	('CD14', 'Var', (223, 227))	('tumours', 'Disease', (113, 120))	('CYSLTR2', 'Gene', '57105', (77, 84))	('CD163', 'Gene', '9332', (229, 234))	('CYSLTR2', 'Gene', (77, 84))
82354	33588787	The majority of uveal melanomas are characterised by an activating Galphaq signalling mutation.	('uveal melanomas', 'Disease', (16, 31))	('signalling', 'biological_process', 'GO:0023052', ('75', '85'))	('uveal melanomas', 'Disease', 'MESH:C536494', (16, 31))	('activating', 'PosReg', (56, 66))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('uveal melanomas', 'Phenotype', 'HP:0007716', (16, 31))	('mutation', 'Var', (86, 94))	('Galphaq', 'Gene', (67, 74))	('Galphaq', 'Gene', '2776', (67, 74))
82355	33588787	Whereas most tumours harbour a hotspot mutation in GNAQ or GNA11, the CYSLTR2 p.L129Q mutation forms a rare alternative.	('GNAQ', 'Gene', '2776', (51, 55))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('CYSLTR2', 'Gene', '57105', (70, 77))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('p.L129Q', 'Var', (78, 85))	('CYSLTR2', 'Gene', (70, 77))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('p.L129Q', 'Mutation', 'p.L129Q', (78, 85))	('GNA11', 'Gene', (59, 64))	('tumours', 'Disease', (13, 20))	('GNAQ', 'Gene', (51, 55))	('GNA11', 'Gene', '2767', (59, 64))
82357	33588787	The potential role of wild-type CYSLTR2 in GNAQ, GNA11 or PLCB4 mutant uveal melanomas was studied in publicly available bulk and single cell sequencing data.	('GNAQ', 'Gene', (43, 47))	('PLCB4', 'Gene', '5332', (58, 63))	('GNAQ', 'Gene', '2776', (43, 47))	('CYSLTR2', 'Gene', '57105', (32, 39))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('uveal melanomas', 'Disease', 'MESH:C536494', (71, 86))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (71, 85))	('CYSLTR2', 'Gene', (32, 39))	('PLCB4', 'Gene', (58, 63))	('GNA11', 'Gene', '2767', (49, 54))	('mutant', 'Var', (64, 70))	('GNA11', 'Gene', (49, 54))	('uveal melanomas', 'Disease', (71, 86))	('uveal melanomas', 'Phenotype', 'HP:0007716', (71, 86))
82358	33588787	Previously, mutually-exclusive mutations in GNAQ and GNA11 (p.Q209L and p.Q209P) were found in 15/16 choroidal nevi.	('p.Q209P', 'Var', (72, 79))	('found', 'Reg', (86, 91))	('GNA11', 'Gene', (53, 58))	('GNAQ', 'Gene', (44, 48))	('nevi', 'Phenotype', 'HP:0003764', (111, 115))	('p.Q209L', 'Var', (60, 67))	('choroidal nevi', 'Disease', (101, 115))	('GNA11', 'Gene', '2767', (53, 58))	('p.Q209L', 'Mutation', 'rs1057519742', (60, 67))	('GNAQ', 'Gene', '2776', (44, 48))	('choroidal nevi', 'Phenotype', 'HP:0025314', (101, 115))	('p.Q209P', 'Mutation', 'rs1057519742', (72, 79))
82359	33588787	12B), we now identified CYSLTR2 to be mutated (p.L129Q) (Fig.	('CYSLTR2', 'Gene', (24, 31))	('p.L129Q', 'Mutation', 'p.L129Q', (47, 54))	('p.L129Q', 'Var', (47, 54))	('CYSLTR2', 'Gene', '57105', (24, 31))
82360	33588787	12A) showed a GNA11 p.Q209L mutation.	('GNA11', 'Gene', '2767', (14, 19))	('p.Q209L', 'Var', (20, 27))	('GNA11', 'Gene', (14, 19))	('p.Q209L', 'Mutation', 'rs1057519742', (20, 27))
82361	33588787	Taken together, these findings indicate that mutations in GNAQ, GNA11 and CYSLTR2 - all recurrently found in uveal melanomas - can also present as an independent somatic event in benign uveal nevi.	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('uveal melanomas', 'Disease', (109, 124))	('mutations', 'Var', (45, 54))	('CYSLTR2', 'Gene', (74, 81))	('uveal melanomas', 'Phenotype', 'HP:0007716', (109, 124))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('GNAQ', 'Gene', '2776', (58, 62))	('benign uveal nevi', 'Disease', (179, 196))	('uveal melanomas', 'Disease', 'MESH:C536494', (109, 124))	('GNA11', 'Gene', '2767', (64, 69))	('GNA11', 'Gene', (64, 69))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('GNAQ', 'Gene', (58, 62))	('nevi', 'Phenotype', 'HP:0003764', (192, 196))	('CYSLTR2', 'Gene', '57105', (74, 81))
82362	33588787	In cutaneous epidermal melanocytes, the BRAF p.V600E mutation - an established oncogenic driver of cutaneous melanoma - is considered sufficient to initiate nevus formation.	('BRAF', 'Gene', '673', (40, 44))	('formation', 'biological_process', 'GO:0009058', ('163', '172'))	('BRAF', 'Gene', (40, 44))	('initiate', 'Reg', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('p.V600E', 'Mutation', 'rs113488022', (45, 52))	('nevus', 'Phenotype', 'HP:0003764', (157, 162))	('cutaneous melanoma', 'Disease', (99, 117))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (99, 117))	('p.V600E', 'Var', (45, 52))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (99, 117))
82364	33588787	Likewise, it may now be hypothesised that Galphaq signalling mutations in GNAQ, GNA11 and CYSLTR2 represent a first step in uveal melanomagenesis.	('GNAQ', 'Gene', (74, 78))	('GNA11', 'Gene', '2767', (80, 85))	('uveal melanoma', 'Phenotype', 'HP:0007716', (124, 138))	('CYSLTR2', 'Gene', '57105', (90, 97))	('uveal melanomagenesis', 'Disease', 'MESH:D014603', (124, 145))	('Galphaq', 'Gene', (42, 49))	('Galphaq', 'Gene', '2776', (42, 49))	('CYSLTR2', 'Gene', (90, 97))	('mutations', 'Var', (61, 70))	('uveal melanomagenesis', 'Disease', (124, 145))	('GNAQ', 'Gene', '2776', (74, 78))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('uveal melanomagenesis', 'Phenotype', 'HP:0007716', (124, 145))	('signalling', 'biological_process', 'GO:0023052', ('50', '60'))	('GNA11', 'Gene', (80, 85))
82365	33588787	We detected the CYSLTR2 mutation in 2/120 (~ 2%) screened primary uveal melanomas.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('uveal melanomas', 'Phenotype', 'HP:0007716', (66, 81))	('CYSLTR2', 'Gene', '57105', (16, 23))	('uveal melanomas', 'Disease', (66, 81))	('mutation', 'Var', (24, 32))	('CYSLTR2', 'Gene', (16, 23))	('uveal melanomas', 'Disease', 'MESH:C536494', (66, 81))	('detected', 'Reg', (3, 11))
82366	33588787	Both tumours in our study did not have a mutation in any of the hotspots of GNAQ or GNA11, confirming the mutual-exclusivity of these mutations.	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('GNA11', 'Gene', '2767', (84, 89))	('tumours', 'Disease', 'MESH:D009369', (5, 12))	('GNAQ', 'Gene', '2776', (76, 80))	('tumours', 'Disease', (5, 12))	('mutation', 'Var', (41, 49))	('GNAQ', 'Gene', (76, 80))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('GNA11', 'Gene', (84, 89))
82367	33588787	Further analysis showed that the CYSLTR2 p.L129Q was clonal in both of these uveal melanomas, supporting an acquisition of this mutation early during tumour development.	('uveal melanomas', 'Phenotype', 'HP:0007716', (77, 92))	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('tumour', 'Disease', (150, 156))	('uveal melanomas', 'Disease', 'MESH:C536494', (77, 92))	('p.L129Q', 'Var', (41, 48))	('uveal melanoma', 'Phenotype', 'HP:0007716', (77, 91))	('CYSLTR2', 'Gene', '57105', (33, 40))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('p.L129Q', 'Mutation', 'p.L129Q', (41, 48))	('CYSLTR2', 'Gene', (33, 40))	('uveal melanomas', 'Disease', (77, 92))
82372	33588787	Similarly, in two of the three CYSLTR2 mutant primary uveal melanomas from the TCGA cohort preferential expression of the mutant allele was observed, while in all cases the wild-type allele was still present (Fig.	('uveal melanomas', 'Disease', (54, 69))	('CYSLTR2', 'Gene', '57105', (31, 38))	('uveal melanomas', 'Phenotype', 'HP:0007716', (54, 69))	('CYSLTR2', 'Gene', (31, 38))	('uveal melanomas', 'Disease', 'MESH:C536494', (54, 69))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('expression', 'MPA', (104, 114))	('preferential', 'PosReg', (91, 103))	('mutant', 'Var', (39, 45))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('mutant', 'Var', (122, 128))
82373	33588787	This suggests that besides genetic mechanisms epigenetic mechanisms might also lead to an increased relative abundance of mutant CYSLTR2.	('CYSLTR2', 'Gene', (129, 136))	('mutant', 'Var', (122, 128))	('CYSLTR2', 'Gene', '57105', (129, 136))
82375	33588787	This supports that the CYSLTR2 allelic imbalances at DNA and RNA levels are indeed associated with the p.L129Q mutation specifically.	('RNA', 'cellular_component', 'GO:0005562', ('61', '64'))	('CYSLTR2', 'Gene', (23, 30))	('associated', 'Reg', (83, 93))	('imbalance', 'Phenotype', 'HP:0002172', (39, 48))	('CYSLTR2', 'Gene', '57105', (23, 30))	('p.L129Q', 'Var', (103, 110))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('p.L129Q', 'Mutation', 'p.L129Q', (103, 110))	('imbalances', 'Phenotype', 'HP:0002172', (39, 49))
82376	33588787	However, the observation has been made that the mutation and secondary alterations involving CYSLTR2 are found in all different molecular subtypes of uveal melanoma (Table 1).	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('found', 'Reg', (105, 110))	('CYSLTR2', 'Gene', '57105', (93, 100))	('alterations', 'Var', (71, 82))	('mutation', 'Var', (48, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (150, 164))	('uveal melanoma', 'Disease', (150, 164))	('CYSLTR2', 'Gene', (93, 100))	('uveal melanoma', 'Disease', 'MESH:C536494', (150, 164))
82377	33588787	Recently, the CYSLTR2 mutation was also detected in metastasising uveal melanomas.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('mutation', 'Var', (22, 30))	('CYSLTR2', 'Gene', '57105', (14, 21))	('CYSLTR2', 'Gene', (14, 21))	('uveal melanomas', 'Phenotype', 'HP:0007716', (66, 81))	('detected', 'Reg', (40, 48))	('metastasising uveal melanomas', 'Disease', (52, 81))	('metastasising uveal melanomas', 'Disease', 'MESH:C536494', (52, 81))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))
82379	33588787	While the mutation was heterozygous at DNA level, the RNA expression was skewed towards the mutant allele, in line with our observations in the primary tumours.	('skewed', 'Reg', (73, 79))	('tumours', 'Disease', 'MESH:D009369', (152, 159))	('tumours', 'Disease', (152, 159))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('RNA expression', 'MPA', (54, 68))	('RNA', 'cellular_component', 'GO:0005562', ('54', '57'))	('primary tumour', 'Disease', (144, 158))	('mutant', 'Var', (92, 98))	('primary tumour', 'Disease', 'MESH:D009369', (144, 158))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('tumours', 'Phenotype', 'HP:0002664', (152, 159))
82380	33588787	Again, our findings regarding CYSLTR2 p.L129Q show similarities to BRAF p.V600E in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('BRAF', 'Gene', '673', (67, 71))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (83, 101))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (83, 101))	('BRAF', 'Gene', (67, 71))	('p.V600E', 'Mutation', 'rs113488022', (72, 79))	('p.L129Q', 'Var', (38, 45))	('CYSLTR2', 'Gene', '57105', (30, 37))	('p.V600E', 'Var', (72, 79))	('p.L129Q', 'Mutation', 'p.L129Q', (38, 45))	('cutaneous melanoma', 'Disease', (83, 101))	('CYSLTR2', 'Gene', (30, 37))
82382	33588787	Along with the progression from nevus to (metastatic) melanoma, absolute and relative copy-number increases and proportionally higher expression levels of the mutant allele are observed, enhancing oncogenic signalling.	('signalling', 'biological_process', 'GO:0023052', ('207', '217'))	('mutant', 'Var', (159, 165))	('nevus', 'Phenotype', 'HP:0003764', (32, 37))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('oncogenic signalling', 'CPA', (197, 217))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('copy-number', 'MPA', (86, 97))	('higher', 'PosReg', (127, 133))	('increases', 'PosReg', (98, 107))	('enhancing', 'PosReg', (187, 196))	('expression levels', 'MPA', (134, 151))
82383	33588787	This possibly explains why therapies targeting mutant BRAF (a driver mutation already present in the pre-malignant cutaneous nevus) have been so successful in the treatment of metastatic melanoma.	('nevus', 'Phenotype', 'HP:0003764', (125, 130))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('melanoma', 'Disease', (187, 195))	('pre', 'molecular_function', 'GO:0003904', ('101', '104'))	('mutant', 'Var', (47, 53))
82384	33588787	In analogy, mutant CysLT2R could be an attractive drug target for metastatic uveal melanoma.	('CysLT2R', 'Gene', (19, 26))	('CysLT2R', 'Gene', '57105', (19, 26))	('uveal melanoma', 'Disease', 'MESH:C536494', (77, 91))	('mutant', 'Var', (12, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (77, 91))	('uveal melanoma', 'Disease', (77, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
82393	33588787	Constitutive activation of the receptor (as seen with the p.L129Q mutation) leads to oncogenic signalling, cell proliferation and enforcement of a melanocyte-lineage-specific transcriptional program in vitro and in vivo.	('cell proliferation', 'biological_process', 'GO:0008283', ('107', '125'))	('p.L129Q', 'Var', (58, 65))	('enforcement', 'CPA', (130, 141))	('oncogenic', 'MPA', (85, 94))	('cell proliferation', 'CPA', (107, 125))	('leads to', 'Reg', (76, 84))	('activation', 'PosReg', (13, 23))	('signalling', 'biological_process', 'GO:0023052', ('95', '105'))	('p.L129Q', 'Mutation', 'p.L129Q', (58, 65))
82394	33588787	Similarly, associations with a heavily pigmented phenotype have been reported in other melanocytic neoplasms carrying the p.L129Q mutation.	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (87, 108))	('pigmented', 'Disease', (39, 48))	('p.L129Q', 'Var', (122, 129))	('associations', 'Reg', (11, 23))	('neoplasms', 'Phenotype', 'HP:0002664', (99, 108))	('pigmented', 'Disease', 'MESH:D010859', (39, 48))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (87, 108))	('melanocytic neoplasms', 'Disease', (87, 108))	('p.L129Q', 'Mutation', 'p.L129Q', (122, 129))
82397	33588787	Further research should evaluate whether such activation indeed has an extra oncogenic effect in these uveal melanoma cells which do not have a CYSLTR2 mutation, but carry an activating Galphaq signalling mutation downstream in GNAQ, GNA11 or PLCB4.	('CYSLTR2', 'Gene', '57105', (144, 151))	('activating', 'PosReg', (175, 185))	('uveal melanoma', 'Disease', (103, 117))	('GNAQ', 'Gene', (228, 232))	('uveal melanoma', 'Disease', 'MESH:C536494', (103, 117))	('PLCB4', 'Gene', '5332', (243, 248))	('uveal melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('signalling', 'biological_process', 'GO:0023052', ('194', '204'))	('CYSLTR2', 'Gene', (144, 151))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('Galphaq', 'Gene', '2776', (186, 193))	('GNA11', 'Gene', (234, 239))	('GNAQ', 'Gene', '2776', (228, 232))	('PLCB4', 'Gene', (243, 248))	('Galphaq', 'Gene', (186, 193))	('GNA11', 'Gene', '2767', (234, 239))	('mutation', 'Var', (205, 213))
82399	33588787	In contrast, mutant CysLT2R appeared unresponsive to leukotriene stimulation and we observed that expression of the wild-type allele was downregulated in mutant tumours.	('downregulated', 'NegReg', (137, 150))	('mutant', 'Var', (13, 19))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('leukotriene', 'Chemical', 'MESH:D015289', (53, 64))	('tumours', 'Phenotype', 'HP:0002664', (161, 168))	('CysLT2R', 'Gene', (20, 27))	('tumours', 'Disease', 'MESH:D009369', (161, 168))	('CysLT2R', 'Gene', '57105', (20, 27))	('tumours', 'Disease', (161, 168))	('mutant', 'Var', (154, 160))	('expression', 'MPA', (98, 108))
82400	33588787	This argues against a similar effect of the microenvironment in CYSLTR2 mutant melanomas.	('melanomas', 'Disease', 'MESH:D008545', (79, 88))	('mutant', 'Var', (72, 78))	('melanomas', 'Disease', (79, 88))	('CYSLTR2', 'Gene', '57105', (64, 71))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))	('CYSLTR2', 'Gene', (64, 71))
82403	33588787	Importantly, the oncogenic alterations in uveal melanoma are not restricted to the CYSLTR2 mutation.	('mutation', 'Var', (91, 99))	('CYSLTR2', 'Gene', '57105', (83, 90))	('CYSLTR2', 'Gene', (83, 90))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('uveal melanoma', 'Disease', (42, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
82405	33588787	In PUM-1 we found that the loss of wild-type CYSLTR2 - together with the loss of chromosome 3p - was subclonally present and occurred after the CYSLTR2 mutation, losses of chromosome 1p and 16q and gain of chromosome 8q.	('CYSLTR2', 'Gene', '57105', (144, 151))	('PUM-1', 'Gene', '9698', (3, 8))	('chromosome', 'cellular_component', 'GO:0005694', ('206', '216'))	('CYSLTR2', 'Gene', '57105', (45, 52))	('losses', 'NegReg', (162, 168))	('CYSLTR2', 'Gene', (144, 151))	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('CYSLTR2', 'Gene', (45, 52))	('chromosome', 'cellular_component', 'GO:0005694', ('172', '182'))	('PUM-1', 'Gene', (3, 8))	('gain', 'PosReg', (198, 202))	('mutation', 'Var', (152, 160))
82406	33588787	PUM-2 presented as a relatively stable tumour, but with a chromosome 13q alteration (leading to gain of mutant CYSLTR2) which also existed in a tumour subclone.	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('tumour', 'Disease', (39, 45))	('gain', 'PosReg', (96, 100))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('mutant', 'Var', (104, 110))	('CYSLTR2', 'Gene', '57105', (111, 118))	('PUM-2', 'Gene', '23369', (0, 5))	('tumour', 'Disease', (144, 150))	('PUM-2', 'Gene', (0, 5))	('CYSLTR2', 'Gene', (111, 118))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))
82412	33588787	In conclusion, our findings strongly nominate the rare CYSLTR2 p.L129Q mutation as an early oncogenic event in GNAQ and GNA11 wild-type uveal nevi and melanomas.	('nevi', 'Phenotype', 'HP:0003764', (142, 146))	('CYSLTR2', 'Gene', '57105', (55, 62))	('GNAQ', 'Gene', '2776', (111, 115))	('GNAQ', 'Gene', (111, 115))	('GNA11', 'Gene', (120, 125))	('melanomas', 'Disease', (151, 160))	('CYSLTR2', 'Gene', (55, 62))	('uveal nevi', 'Disease', (136, 146))	('GNA11', 'Gene', '2767', (120, 125))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('p.L129Q', 'Var', (63, 70))	('melanomas', 'Phenotype', 'HP:0002861', (151, 160))	('p.L129Q', 'Mutation', 'p.L129Q', (63, 70))	('melanomas', 'Disease', 'MESH:D008545', (151, 160))
82414	33588787	This makes these tumours promising candidates for mutant CysLT2R-targeted therapy.	('CysLT2R', 'Gene', (57, 64))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('CysLT2R', 'Gene', '57105', (57, 64))	('tumours', 'Disease', 'MESH:D009369', (17, 24))	('mutant', 'Var', (50, 56))	('tumours', 'Disease', (17, 24))
82415	33588787	Moreover, we identified elevated expression of wild-type CYSLTR2 in inflamed tumours carrying a mutation in GNAQ, GNA11 or PLCB4.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('CYSLTR2', 'Gene', (57, 64))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('GNA11', 'Gene', '2767', (114, 119))	('PLCB4', 'Gene', '5332', (123, 128))	('GNAQ', 'Gene', '2776', (108, 112))	('tumours', 'Disease', (77, 84))	('mutation', 'Var', (96, 104))	('PLCB4', 'Gene', (123, 128))	('expression', 'MPA', (33, 43))	('GNAQ', 'Gene', (108, 112))	('CYSLTR2', 'Gene', '57105', (57, 64))	('elevated', 'PosReg', (24, 32))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('GNA11', 'Gene', (114, 119))
82417	33588787	FFPE Formalin-Fixed Paraffin-Embedded H&E Haematoxylin and Eosin LUMC Leiden University Medical Center MAPK Mitogen-Activated Protein Kinase PCR Polymerase Chain Reaction PUM Primary Uveal Melanoma SNP Single Nucleotide Polymorphism TCGA The Cancer Genome Atlas RJN and PAvV conceptualised this study and wrote the manuscript.	('Cancer', 'Disease', 'MESH:D009369', (242, 248))	('Haematoxylin', 'Chemical', 'MESH:D006416', (42, 54))	('Melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('Paraffin', 'Chemical', 'MESH:D010232', (20, 28))	('Cancer', 'Phenotype', 'HP:0002664', (242, 248))	('Melanoma', 'Disease', 'MESH:D008545', (189, 197))	('Melanoma', 'Disease', (189, 197))	('MAPK', 'molecular_function', 'GO:0004707', ('103', '107'))	('Eosin', 'Chemical', 'MESH:D004801', (59, 64))	('LUMC', 'Chemical', '-', (65, 69))	('H&E', 'Chemical', '-', (38, 41))	('SNP Single Nucleotide', 'Var', (198, 219))	('Formalin', 'Chemical', 'MESH:D005557', (5, 13))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (183, 197))	('Cancer', 'Disease', (242, 248))
82493	31832407	Current treatment options for metastatic disease included immunotherapy, such as antibodies targeting the cytotoxic T-lymphocyte antigen-4, antibodies targeting the programmed cell death 1, and MEK inhibitor.	('programmed cell death', 'biological_process', 'GO:0012501', ('165', '186'))	('antibodies', 'Var', (81, 91))	('metastatic disease', 'Disease', (30, 48))	('lymphocyte antigen', 'molecular_function', 'GO:0005557', ('118', '136'))	('MEK', 'Gene', (194, 197))	('MEK', 'Gene', '5609', (194, 197))
82503	31417644	Furthermore, inhibition of RHPN1-AS1 suppressed the expression of epithelial-mesenchymal transition (EMT)-related genes (beta-Catenin, Claudin-1 and Vimentin) in HNSCC cells.	('beta-Catenin', 'Gene', (121, 133))	('Vimentin', 'cellular_component', 'GO:0045098', ('149', '157'))	('beta-Catenin', 'Gene', '1499', (121, 133))	('Vimentin', 'Gene', (149, 157))	('Claudin-1', 'Gene', '9076', (135, 144))	('HNSCC', 'Phenotype', 'HP:0012288', (162, 167))	('inhibition', 'Var', (13, 23))	('Vimentin', 'cellular_component', 'GO:0045099', ('149', '157'))	('RHPN1-AS1', 'Gene', (27, 36))	('Claudin-1', 'Gene', (135, 144))	('expression', 'MPA', (52, 62))	('Vimentin', 'Gene', '7431', (149, 157))	('EMT', 'biological_process', 'GO:0001837', ('101', '104'))	('RHPN1-AS1', 'Gene', '78998;114822;5729', (27, 36))	('suppressed', 'NegReg', (37, 47))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('66', '99'))
82512	31417644	The lncRNAs CCAT1 and CCAT2, located in the 8q24.21 locus, were highly overexpressed in colorectal cancer and were significantly associated with recurrence-free survival (RFS) and overall survival (OS), which serve as important prognostic biomarkers in colorectal cancer.	('recurrence-free survival', 'CPA', (145, 169))	('associated with', 'Reg', (129, 144))	('colorectal cancer', 'Disease', (88, 105))	('CCAT1', 'Gene', '100507056', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('CCAT2', 'Gene', '101805488', (22, 27))	('colorectal cancer', 'Disease', 'MESH:D015179', (253, 270))	('overall survival', 'CPA', (180, 196))	('CCAT1', 'Gene', (12, 17))	('overexpressed', 'PosReg', (71, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (253, 270))	('CCAT2', 'Gene', (22, 27))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('lncRNAs', 'Var', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colorectal cancer', 'Disease', (253, 270))
82513	31417644	The lncRNA DANCR increased cancer stem cell function by upregulating AXL/PI3K-Akt via competitive binding to miR-33a-5p in osteosarcoma.	('increased', 'PosReg', (17, 26))	('binding', 'Interaction', (98, 105))	('osteosarcoma', 'Phenotype', 'HP:0002669', (123, 135))	('osteosarcoma', 'Disease', (123, 135))	('DANCR', 'Gene', (11, 16))	('osteosarcoma', 'Disease', 'MESH:D012516', (123, 135))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('DANCR', 'Gene', '57291', (11, 16))	('PI3K', 'molecular_function', 'GO:0016303', ('73', '77'))	('binding', 'molecular_function', 'GO:0005488', ('98', '105'))	('upregulating', 'PosReg', (56, 68))	('AXL', 'Gene', '558', (69, 72))	('miR-33a-5p', 'Var', (109, 119))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('AXL', 'Gene', (69, 72))
82548	31417644	In addition, patients with high RHPN1-AS1 expression had poor survival compared to patients with low RHPN1-AS1 expression; however, the P value was greater than 0.05 (P = 0.086, data not shown).	('survival', 'MPA', (62, 70))	('poor', 'NegReg', (57, 61))	('patients', 'Species', '9606', (13, 21))	('RHPN1-AS1', 'Gene', '78998;114822;5729', (32, 41))	('high', 'Var', (27, 31))	('RHPN1-AS1', 'Gene', (101, 110))	('RHPN1-AS1', 'Gene', '78998;114822;5729', (101, 110))	('patients', 'Species', '9606', (83, 91))	('RHPN1-AS1', 'Gene', (32, 41))
82552	31417644	2B, RHPN1-AS1 knockdown significantly inhibited migration by approximately 50% in Cal-27 cells and by nearly 60% in Tca8113 cells (P < 0.01).	('migration', 'CPA', (48, 57))	('RHPN1-AS1', 'Gene', (4, 13))	('inhibited', 'NegReg', (38, 47))	('RHPN1-AS1', 'Gene', '78998;114822;5729', (4, 13))	('knockdown', 'Var', (14, 23))
82557	31417644	However, the percentage of apoptotic cells was significantly increased after silencing RHPN1-AS1 in both Cal-27 and Tca8113 cells (Fig.	('apoptotic cells', 'CPA', (27, 42))	('silencing', 'Var', (77, 86))	('increased', 'PosReg', (61, 70))	('RHPN1-AS1', 'Gene', (87, 96))	('RHPN1-AS1', 'Gene', '78998;114822;5729', (87, 96))
82561	31417644	The results showed that RHPN1-AS1 knockdown significantly downregulated the expression of beta-catenin, claudin-1 and vimentin in Cal-27 and Tca8113 cells (Fig.	('vimentin', 'Gene', '7431', (118, 126))	('claudin-1', 'Gene', (104, 113))	('vimentin', 'cellular_component', 'GO:0045099', ('118', '126'))	('vimentin', 'Gene', (118, 126))	('beta-catenin', 'Gene', (90, 102))	('vimentin', 'cellular_component', 'GO:0045098', ('118', '126'))	('RHPN1-AS1', 'Gene', (24, 33))	('claudin-1', 'Gene', '9076', (104, 113))	('downregulated', 'NegReg', (58, 71))	('expression', 'MPA', (76, 86))	('RHPN1-AS1', 'Gene', '78998;114822;5729', (24, 33))	('beta-catenin', 'Gene', '1499', (90, 102))	('knockdown', 'Var', (34, 43))
82566	31417644	To date, the dysregulated expression and involvement of lncRNAs have been reported in diverse cancers, including HNSCC.	('expression', 'MPA', (26, 36))	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('lncRNAs', 'Gene', (56, 63))	('HNSCC', 'Disease', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('HNSCC', 'Phenotype', 'HP:0012288', (113, 118))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('reported', 'Reg', (74, 82))	('dysregulated', 'Var', (13, 25))	('cancers', 'Disease', (94, 101))
82572	31417644	A previous study reported that RHPN1-AS1 was upregulated in the UM and that knockdown of RHPN1-AS1 significantly inhibited UM cell proliferation, migration and invasion.	('RHPN1-AS1', 'Gene', (89, 98))	('knockdown', 'Var', (76, 85))	('UM cell proliferation', 'CPA', (123, 144))	('inhibited', 'NegReg', (113, 122))	('RHPN1-AS1', 'Gene', (31, 40))	('upregulated', 'PosReg', (45, 56))	('RHPN1-AS1', 'Gene', '78998;114822;5729', (89, 98))	('cell proliferation', 'biological_process', 'GO:0008283', ('126', '144'))	('UM', 'Phenotype', 'HP:0007716', (64, 66))	('UM', 'Phenotype', 'HP:0007716', (123, 125))	('RHPN1-AS1', 'Gene', '78998;114822;5729', (31, 40))
82576	31417644	Inhibition of RHPN1-AS1 in Cal-27 and Tca8113 cells suppressed migration, invasion and cell viability, which is consistent with the findings of a previous study of UM.	('cell viability', 'CPA', (87, 101))	('UM', 'Phenotype', 'HP:0007716', (164, 166))	('RHPN1-AS1', 'Gene', (14, 23))	('suppressed', 'NegReg', (52, 62))	('Inhibition', 'Var', (0, 10))	('RHPN1-AS1', 'Gene', '78998;114822;5729', (14, 23))	('migration', 'CPA', (63, 72))
82577	31417644	In addition, knockdown of RHPN1-AS1 promoted HNSCC cell apoptosis, but it had no effect on the cell cycle.	('HNSCC', 'Phenotype', 'HP:0012288', (45, 50))	('RHPN1-AS1', 'Gene', '78998;114822;5729', (26, 35))	('cell cycle', 'biological_process', 'GO:0007049', ('95', '105'))	('RHPN1-AS1', 'Gene', (26, 35))	('apoptosis', 'biological_process', 'GO:0097194', ('56', '65'))	('apoptosis', 'biological_process', 'GO:0006915', ('56', '65'))	('knockdown', 'Var', (13, 22))	('promoted', 'PosReg', (36, 44))	('HNSCC cell apoptosis', 'CPA', (45, 65))
82591	31417644	For instance, the lncRNA SNHG15 acts as a ceRNA to regulate the YAP1-Hippo signaling pathway by sponging miR-200a-3p in papillary thyroid carcinoma.	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (120, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('sponging', 'Var', (96, 104))	('SNHG15', 'Gene', (25, 31))	('miR-200a-3p', 'Gene', (105, 116))	('YAP1', 'Gene', '10413', (64, 68))	('papillary thyroid carcinoma', 'Disease', (120, 147))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('69', '92'))	('regulate', 'Reg', (51, 59))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (120, 147))	('SNHG15', 'Gene', '285958', (25, 31))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (130, 147))	('YAP1', 'Gene', (64, 68))
82621	29788760	Since that time, multiple comparative dosimetry studies (including those of the AAPM TG-129) have demonstrated that in comparison to iodine-125 (125I), 103Pd photons are more rapidly absorbed within uveal melanomas, while less radiation reaches most normal ocular structures.	('iodine', 'Chemical', 'MESH:D007455', (133, 139))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('melanomas', 'Phenotype', 'HP:0002861', (205, 214))	('103Pd photons', 'Var', (152, 165))	('uveal melanomas', 'Disease', (199, 214))	('uveal melanomas', 'Phenotype', 'HP:0007716', (199, 214))	('uveal melanoma', 'Phenotype', 'HP:0007716', (199, 213))	('uveal melanomas', 'Disease', 'MESH:C536494', (199, 214))
82626	29788760	Most recently, our group described regression patterns of iris melanoma following 103Pd plaque.	('iris melanoma', 'Disease', 'MESH:D007499', (58, 71))	('iris melanoma', 'Disease', (58, 71))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('iris melanoma', 'Phenotype', 'HP:0011524', (58, 71))	('103Pd plaque', 'Var', (82, 94))
82654	29788760	According to the 8th edition of the American Joint Committee on Cancer staging system for uveal melanoma, there were 86-T1, 59-T2, 21-T3, and 4-T4 sized tumors (Table 2).	('59-T2', 'Var', (124, 129))	('Cancer', 'Disease', (64, 70))	('uveal melanoma', 'Disease', 'MESH:C536494', (90, 104))	('uveal melanoma', 'Disease', (90, 104))	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
82717	29788760	reported 43% decrease in thickness and 42% decrease in cross-sectional area of tumor after 106Ru and 125I plaque brachytherapy.	('decrease', 'NegReg', (43, 51))	('106Ru', 'Var', (91, 96))	('tumor', 'Disease', (79, 84))	('decrease', 'NegReg', (13, 21))	('cross-sectional area of', 'MPA', (55, 78))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('125I plaque', 'Var', (101, 112))	('thickness', 'MPA', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
82719	29788760	also reported that the amount of reduction in tumor thickness after 60Co and 125I therapy was the same, irrespective of location of tumor.	('125I', 'Var', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('reduction', 'NegReg', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
82728	29788760	noted that after 106Ru plaque brachytherapy, 56% of patients had visual acuity of 20/25 initially, out of which more than half stayed with 20/40.	('patients', 'Species', '9606', (52, 60))	('visual acuity', 'MPA', (65, 78))	('106Ru', 'Var', (17, 22))
82749	29732441	There was an inverse linear correlation between D50 and the PPCD (Pearson's; r= -0.528, P=0.043) and between visual acuity and the PPCD (Pearson's; r= -0.564, P=0.028).	('PPCD', 'Chemical', '-', (131, 135))	('visual acuity', 'CPA', (109, 122))	('PPCD', 'Chemical', '-', (60, 64))	('D50', 'Var', (48, 51))
82796	29732441	When the PPCD was "normalized" by comparing it to the fellow eye (PPCD fellow eye - PPCD treated eye= Delta PPCD), an even stronger correlation was seen between the Delta PPCD and the D50 (Pearson r=0.664, P=0.013) (Figure 5C).	('PPCD', 'Chemical', '-', (84, 88))	('stronger', 'PosReg', (123, 131))	('D50', 'MPA', (184, 187))	('Delta PPCD', 'Chemical', '-', (102, 112))	('PPCD', 'Chemical', '-', (171, 175))	('Delta PPCD', 'Chemical', '-', (165, 175))	('PPCD', 'Chemical', '-', (66, 70))	('Delta PPCD', 'Var', (165, 175))	('PPCD', 'Chemical', '-', (108, 112))	('PPCD', 'Chemical', '-', (9, 13))
82839	29109715	In kidney transplant patients, BKPyV may cause haemorrhagic cystitis and allograft rejection (Hashida et al.,; Mininberg et al.,).	('allograft rejection', 'CPA', (73, 92))	('haemorrhagic cystitis', 'Disease', (47, 68))	('patients', 'Species', '9606', (21, 29))	('cause', 'Reg', (41, 46))	('BKPyV', 'Var', (31, 36))	('haemorrhagic cystitis', 'Disease', 'MESH:D006470', (47, 68))	('BKPyV', 'Species', '1891762', (31, 36))
82840	29109715	BKPyV has transforming and oncogenic properties, which are due to the activities of two viral oncogenes, named large T antigen (Tag) and small t antigen (tag).	('small t', 'Var', (137, 144))	('oncogenic properties', 'CPA', (27, 47))	('BKPyV', 'Species', '1891762', (0, 5))	('BKPyV', 'Gene', (0, 5))	('transforming', 'CPA', (10, 22))	('large T antigen', 'Var', (111, 126))
82841	29109715	In this context, it is worth recalling that Tag induces chromosomal aberrations and stimulates cellular gene expression.	('recalling', 'Disease', 'MESH:D008569', (29, 38))	('Tag', 'Var', (44, 47))	('gene expression', 'biological_process', 'GO:0010467', ('104', '119'))	('induces', 'Reg', (48, 55))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (56, 79))	('cellular gene expression', 'MPA', (95, 119))	('recalling', 'Disease', (29, 38))	('chromosomal', 'MPA', (56, 67))	('stimulates', 'PosReg', (84, 94))
82842	29109715	BKPyV transforms different animal and human cell types in vitro, whereas, it induces tumors of different histotypes in experimental animals.	('human', 'Species', '9606', (38, 43))	('BKPyV', 'Var', (0, 5))	('BKPyV', 'Species', '1891762', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('induces', 'Reg', (77, 84))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
82865	29109715	The positive BKPyV control was represented by immune rabbit serum containing anti-BKPyV antibodies; negative controls were represented by immune sera anti-SV40 and anti-JCPyV and three human serum samples which were found to be BKPyV-negative in our previous investigation both by indirect E.L.I.S.A.s and Haemagglutination Inhibition Assay (H.I.A.	('human', 'Species', '9606', (185, 190))	('BKPyV', 'Species', '1891762', (228, 233))	('rabbit', 'Species', '9986', (53, 59))	('BKPyV', 'Species', '1891762', (82, 87))	('SV', 'Disease', 'None', (155, 157))	('JCPyV', 'Species', '10632', (169, 174))	('BKPyV', 'Species', '1891762', (13, 18))	('sera', 'molecular_function', 'GO:0004617', ('145', '149'))	('anti-BKPyV', 'Var', (77, 87))	('antibodies', 'Var', (88, 98))
82868	29109715	Sera with antibodies against BKPyV were considered VP1-positive upon reacting to both peptides of the late region and when sera that had been analyzed three times by indirect E.L.I.S.A.	('VP1', 'Gene', (51, 54))	('BKPyV', 'Gene', (29, 34))	('BKPyV', 'Species', '1891762', (29, 34))	('reacting', 'Reg', (69, 77))	('VP1', 'Gene', '29031008', (51, 54))	('peptides', 'Chemical', 'MESH:D010455', (86, 94))	('Sera', 'molecular_function', 'GO:0004617', ('0', '4'))	('antibodies', 'Var', (10, 20))	('sera', 'molecular_function', 'GO:0004617', ('123', '127'))
82892	29109715	It is interesting to note that the prevalence of antibodies against BKPyV obtained with the two VP1 peptides L and M did not differ statistically within each group, which was 93.0% for peptide L vs. 88.7% for peptide M in CN group and 64.4% for peptide L vs. 74.7% for peptide M in HS1 group (Table 1).	('VP1', 'Gene', (96, 99))	('HS1', 'Gene', (282, 285))	('peptides', 'Chemical', 'MESH:D010455', (100, 108))	('VP1', 'Gene', '29031008', (96, 99))	('CN', 'Phenotype', 'HP:0025314', (222, 224))	('HS1', 'Gene', '10971', (282, 285))	('BKPyV', 'Gene', (68, 73))	('BKPyV', 'Species', '1891762', (68, 73))	('peptide L', 'Var', (185, 194))
82901	29109715	The two indirect ELISAs, with two distinct VP1 mimotopes gave overlapping results, thus confirming the higher prevalence of anti-BKPyV VP1 antibodies in human sera from patients affected by CN compared to controls (Table 1).	('patients', 'Species', '9606', (169, 177))	('CN', 'Phenotype', 'HP:0025314', (190, 192))	('BKPyV', 'Species', '1891762', (129, 134))	('sera', 'molecular_function', 'GO:0004617', ('159', '163'))	('VP1', 'Gene', (135, 138))	('anti-BKPyV', 'Var', (124, 134))	('human', 'Species', '9606', (153, 158))	('VP1', 'Gene', (43, 46))	('higher', 'PosReg', (103, 109))	('VP1', 'Gene', '29031008', (135, 138))	('VP1', 'Gene', '29031008', (43, 46))
82922	29109715	Two indirect E.L.I.S.A.s, with two distinct VP1 mimotopes gave overlapping results, thus confirming the higher prevalence of anti-BKPyV VP1 antibodies in human sera from patients affected by choroidal nevi compared to controls (Table 1).	('patients', 'Species', '9606', (170, 178))	('human', 'Species', '9606', (154, 159))	('choroidal nevi', 'Disease', (191, 205))	('antibodies', 'Var', (140, 150))	('VP1', 'Gene', '29031008', (136, 139))	('nevi', 'Phenotype', 'HP:0003764', (201, 205))	('anti-BKPyV', 'Var', (125, 135))	('BKPyV', 'Species', '1891762', (130, 135))	('choroidal nevi', 'Phenotype', 'HP:0025314', (191, 205))	('VP1', 'Gene', (44, 47))	('sera', 'molecular_function', 'GO:0004617', ('160', '164'))	('higher', 'PosReg', (104, 110))	('VP1', 'Gene', '29031008', (44, 47))	('VP1', 'Gene', (136, 139))
82976	27822007	A total of 7,516 patients with a primary diagnosis of UM were identified to form the final study cohort, using the SEER International Classification of Disease for Oncology (ICD-O-3) codes C69.3 (choroid) and C69.4 (ciliary body and iris).	('C69.3', 'Var', (189, 194))	('C69.4', 'Var', (209, 214))	('patients', 'Species', '9606', (17, 25))	('Oncology', 'Phenotype', 'HP:0002664', (164, 172))	('UM', 'Phenotype', 'HP:0007716', (54, 56))
83020	27822007	Similarly, the COM study demonstrated improved survival rates for iodine-125 brachytherapy compared to enucleation for medium sized melanomas, with comparable 5-year all-cause mortality (19% vs 18%) and 5-year tumor-related mortality (11% vs 9%).	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('improved', 'PosReg', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('melanomas', 'Phenotype', 'HP:0002861', (132, 141))	('iodine-125 brachytherapy', 'Var', (66, 90))	('tumor', 'Disease', (210, 215))	('melanomas', 'Disease', 'MESH:D008545', (132, 141))	('survival', 'MPA', (47, 55))	('enucleation', 'biological_process', 'GO:0090601', ('103', '114'))	('melanomas', 'Disease', (132, 141))	('iodine-125', 'Chemical', 'MESH:C000614960', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
83031	27822007	In addition, targeted therapies such as histone deacetylase inhibitors and ipilimumab, as well as genetic counseling to identify BAP1 mutations for patients at high risk for developing UM, are currently under investigation.	('patients', 'Species', '9606', (148, 156))	('UM', 'Phenotype', 'HP:0007716', (185, 187))	('BAP1', 'Gene', '8314', (129, 133))	('ipilimumab', 'Chemical', 'MESH:D000074324', (75, 85))	('mutations', 'Var', (134, 143))	('BAP1', 'Gene', (129, 133))
83075	23591547	Intratumoral heterogeneity for monosomy 3 is estimated to occur in 14-18% of uveal melanomas  ; however, heterogeneity for gene expression profiling appears to be significantly lower.	('uveal melanomas', 'Phenotype', 'HP:0007716', (77, 92))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('monosomy 3', 'Var', (31, 41))	('uveal melanomas', 'Disease', 'MESH:C536494', (77, 92))	('uveal melanoma', 'Phenotype', 'HP:0007716', (77, 91))	('tumor', 'Disease', (5, 10))	('gene expression', 'biological_process', 'GO:0010467', ('123', '138'))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('uveal melanomas', 'Disease', (77, 92))
83128	18655191	Our findings suggest that plasticity of aggressive melanoma can enable autopoiesis of critical vascular-mimicking elements within the tumor infrastructure, and may reflect in part the implications of current anti-angiogenic treatments.	('aggressive melanoma', 'Disease', 'MESH:D008545', (40, 59))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('enable', 'PosReg', (64, 70))	('aggressive melanoma', 'Disease', (40, 59))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('plasticity', 'Var', (26, 36))	('autopoiesis of', 'CPA', (71, 85))	('tumor', 'Disease', (134, 139))
83151	18655191	After fixation with -10 C methanol for 5 min, air drying, and washing (3x) with PBS, the specimens were incubated for 20 min with 10% blocking serum-PBS, washed with PBS, and then incubated for 60 min with one of the following rabbit-derived primary antibodies at 4mug/ml in 1.5% blocking serum-PBS: anti-ephrin-A1 (sc-911), -A3 (sc-1012), -B2 (sc-1010) (Santa Cruz); or 12 mug/ml anti-ephrin-A3 (ZMD.322; Invitrogen); or 12 mug/ml goat-derived anti-ephrin-B2 (AF496; R&D).	('ephrin', 'molecular_function', 'GO:0005106', ('450', '456'))	('ephrin', 'molecular_function', 'GO:0005106', ('386', '392'))	('ephrin', 'molecular_function', 'GO:0005106', ('305', '311'))	('mug', 'molecular_function', 'GO:0043739', ('374', '377'))	('ephrin-A3', 'Gene', (386, 395))	('AF', 'Disease', 'MESH:D001281', (461, 463))	('ephrin-A3', 'Gene', '100358959', (386, 395))	('anti-ephrin-A1', 'Var', (300, 314))	('PBS', 'Chemical', 'MESH:D007854', (295, 298))	('ephrin', 'molecular_function', 'GO:0046875', ('450', '456'))	('PBS', 'Chemical', 'MESH:D007854', (149, 152))	('ethanol', 'Chemical', 'MESH:D000431', (27, 34))	('PBS', 'Chemical', 'MESH:D007854', (166, 169))	('PBS', 'Chemical', 'MESH:D007854', (80, 83))	('ephrin', 'molecular_function', 'GO:0046875', ('386', '392'))	('ephrin', 'molecular_function', 'GO:0046875', ('305', '311'))	('goat', 'Species', '9925', (432, 436))	('mug', 'molecular_function', 'GO:0043739', ('265', '268'))	('mug', 'molecular_function', 'GO:0043739', ('425', '428'))	('rabbit', 'Species', '9986', (227, 233))
83227	18655191	It is documented that AUM-2 (or MUM2B) disseminates hematogenously while C8161 metastasizes hematogenously and/or via the lymphatics.	('AUM-2', 'Gene', (22, 27))	('disseminates', 'CPA', (39, 51))	('AUM', 'cellular_component', 'GO:0120001', ('22', '25'))	('metastasizes', 'CPA', (79, 91))	('MUM2B', 'CellLine', 'CVCL:3447', (32, 37))	('C8161', 'Var', (73, 78))
83245	17261188	Migratory stimulation of uveal melanoma cell lines (SOM196B, SOM157d, SOM267, SOM269) with CXCL1 has been previously shown.	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('Migratory', 'CPA', (0, 9))	('uveal melanoma', 'Disease', (25, 39))	('CXCL1', 'Gene', (91, 96))	('SOM196B', 'Var', (52, 59))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('uveal melanoma', 'Disease', 'MESH:C536494', (25, 39))	('CXCL1', 'Gene', '2919', (91, 96))
83252	17261188	Hepatocyte growth factor (HGF) has been previously shown to promote the migration of uveal melanoma cell lines in vitro (SOM196B, SOM157d, SOM267, SOM269).	('promote', 'PosReg', (60, 67))	('migration', 'CPA', (72, 81))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('Hepatocyte growth factor (HGF)', 'Gene', '3082', (0, 30))	('SOM196B', 'Var', (121, 128))	('uveal melanoma', 'Phenotype', 'HP:0007716', (85, 99))	('uveal melanoma', 'Disease', 'MESH:C536494', (85, 99))	('Hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('0', '24'))	('Hepatocyte growth factor (HGF', 'Gene', (0, 29))	('uveal melanoma', 'Disease', (85, 99))
83290	17261188	It is possible that the expression of HGF by these 5 cell lines does induce the motility of these c-met positive cells, which can also be homed to the liver via HGF secretion.	('HGF', 'Gene', (161, 164))	('secretion', 'biological_process', 'GO:0046903', ('165', '174'))	('induce', 'Reg', (69, 75))	('HGF', 'Gene', (38, 41))	('HGF', 'Gene', '3082', (161, 164))	('motility', 'CPA', (80, 88))	('expression', 'Var', (24, 34))	('HGF', 'Gene', '3082', (38, 41))
83294	33348918	ddPCR was employed to assess UM-specific GNA11, GNAQ, PLCbeta4, and CYSLTR2 mutations in plasma DNA.	('CYSLTR2', 'Gene', (68, 75))	('mutations', 'Var', (76, 85))	('PLCbeta4', 'Gene', (54, 62))	('GNAQ', 'Gene', '2776', (48, 52))	('PLCbeta4', 'Gene', '5332', (54, 62))	('UM', 'Phenotype', 'HP:0007716', (29, 31))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('GNAQ', 'Gene', (48, 52))	('GNA11', 'Gene', (41, 46))	('CYSLTR2', 'Gene', '57105', (68, 75))	('GNA11', 'Gene', '2767', (41, 46))
83298	33348918	Tumor-specific mutations were detected in the plasma of 21.4% patients, merely, in 9.4% of primary UM, while 54.5% in metastatic patients.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('patients', 'Species', '9606', (129, 137))	('mutations', 'Var', (15, 24))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('patients', 'Species', '9606', (62, 70))	('primary UM', 'Disease', (91, 101))
83305	33348918	The loss of function mutations in the BRCA1 associated protein (BAP1) gene, located on 3p21, were predominantly determined in M3 tumors, implying that BAP1 abnormalities are significantly correlated with the development of metastases in UM patients.	('BAP1', 'Gene', (64, 68))	('metastases', 'Disease', 'MESH:D009362', (223, 233))	('BRCA1 associated protein', 'Gene', '8315', (38, 62))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('BAP1', 'Gene', (151, 155))	('loss of function', 'NegReg', (4, 20))	('UM', 'Phenotype', 'HP:0007716', (237, 239))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('patients', 'Species', '9606', (240, 248))	('BAP1', 'Gene', '8314', (64, 68))	('BRCA1 associated protein', 'Gene', (38, 62))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('correlated', 'Reg', (188, 198))	('BAP1', 'Gene', '8314', (151, 155))	('metastases', 'Disease', (223, 233))	('mutations', 'Var', (21, 30))
83317	33348918	Various techniques are available to assess ctDNA; among them, the most specific method is the detection of the specific gene mutations harbored by the tumor.	('mutations', 'Var', (125, 134))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))
83318	33348918	About 95% of UM-specific mutations occur in G protein subunit alfa q (GNAQ), G protein subunit alfa 11 (GNA11), cysteinyl leukotriene receptor 2 (CYSTLR2), and phospholipase C beta 4 (PLCB4) genes.	('phospholipase C beta 4', 'Gene', (160, 182))	('G protein subunit alfa 11', 'Gene', '2767', (77, 102))	('GNAQ', 'Gene', '2776', (70, 74))	('PLCB4', 'Gene', '5332', (184, 189))	('cysteinyl leukotriene receptor 2', 'Gene', '57105', (112, 144))	('GNAQ', 'Gene', (70, 74))	('mutations', 'Var', (25, 34))	('phospholipase C beta 4', 'Gene', '5332', (160, 182))	('GNA11', 'Gene', '2767', (104, 109))	('cysteinyl leukotriene receptor 2', 'Gene', (112, 144))	('G protein subunit alfa q', 'Gene', (44, 68))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('G protein subunit alfa q', 'Gene', '2776', (44, 68))	('G protein subunit alfa 11', 'Gene', (77, 102))	('CYSTLR2', 'Gene', (146, 153))	('PLCB4', 'Gene', (184, 189))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('CYSTLR2', 'Gene', '57105', (146, 153))	('GNA11', 'Gene', (104, 109))	('UM', 'Phenotype', 'HP:0007716', (13, 15))
83320	33348918	Moreover, we assessed the presence of CTCs and ctDNA in the peripheral blood of primary and metastatic UM patients, focusing on the detection of traditional EMT-associated transcription factors (TFs) and driver mutations, previously associated with UM development and progression.	('associated', 'Reg', (233, 243))	('transcription', 'biological_process', 'GO:0006351', ('172', '185'))	('mutations', 'Var', (211, 220))	('EMT', 'biological_process', 'GO:0001837', ('157', '160'))	('UM', 'Phenotype', 'HP:0007716', (249, 251))	('patients', 'Species', '9606', (106, 114))	('UM', 'Phenotype', 'HP:0007716', (103, 105))
83331	33348918	As chromosome 3 monosomy strongly correlates with metastatic death, while chromosome 8 gains occur later in UM tumorigenesis, we focus herein on monosomy 3 (M3) only.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('monosomy', 'Var', (16, 24))	('death', 'Disease', 'MESH:D003643', (61, 66))	('correlates', 'Reg', (34, 44))	('death', 'Disease', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('chromosome', 'cellular_component', 'GO:0005694', ('3', '13'))	('chromosome', 'cellular_component', 'GO:0005694', ('74', '84'))	('tumor', 'Disease', (111, 116))
83332	33348918	M3 was detected in 51.6% (n = 16), disomy 3 (D3) in 48.4% (n = 15) of analyzed tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('disomy 3', 'Var', (35, 43))	('tumor', 'Disease', (79, 84))
83342	33348918	Eight ddPCR assays were used (their numbers are listed in the material and methods paragraph) to detect nine mutations in four genes, namely, GNA11 p.Q209L, p.Q209P, and p.R183C; GNAQ p.Q209L, p.Q209P, p.Q209R, and p.R183Q; PLCbeta4 p.D630Y, and CYSLTR2 p.L129Q.	('p.Q209R', 'Mutation', 'rs121913492', (202, 209))	('PLCbeta4', 'Gene', '5332', (224, 232))	('p.Q209L', 'Mutation', 'rs1057519742', (148, 155))	('p.Q209P', 'Mutation', 'rs1057519742', (193, 200))	('p.R183Q', 'Mutation', 'rs397514698', (215, 222))	('p.R183Q', 'Var', (215, 222))	('GNAQ', 'Gene', '2776', (179, 183))	('p.Q209L', 'Var', (184, 191))	('p.Q209R', 'Var', (202, 209))	('GNAQ', 'Gene', (179, 183))	('p.Q209P', 'Var', (193, 200))	('PLCbeta4', 'Gene', (224, 232))	('p.D630Y', 'Mutation', 'p.D630Y', (233, 240))	('GNA11', 'Gene', '2767', (142, 147))	('p.L129Q', 'Mutation', 'rs764805904', (254, 261))	('p.R183C', 'Var', (170, 177))	('p.Q209P', 'Mutation', 'rs1057519742', (157, 164))	('CYSLTR2', 'Gene', '57105', (246, 253))	('p.L129Q', 'Var', (254, 261))	('p.Q209L', 'Mutation', 'rs1057519742', (184, 191))	('p.Q209L', 'Var', (148, 155))	('p.R183C', 'Mutation', 'rs748346103', (170, 177))	('p.D630Y', 'Var', (233, 240))	('p.Q209P', 'Var', (157, 164))	('GNA11', 'Gene', (142, 147))	('CYSLTR2', 'Gene', (246, 253))
83346	33348918	GNA11 p.Q209L and GNAQ p.Q209P were the two most frequent mutations.	('p.Q209L', 'Mutation', 'rs1057519742', (6, 13))	('GNAQ', 'Gene', '2776', (18, 22))	('GNA11', 'Gene', (0, 5))	('p.Q209P', 'Mutation', 'rs1057519742', (23, 30))	('GNA11', 'Gene', '2767', (0, 5))	('p.Q209L', 'Var', (6, 13))	('GNAQ', 'Gene', (18, 22))	('p.Q209P', 'Var', (23, 30))
83347	33348918	GNA11 p.Q209L was present in 54.8% (n = 17), while GNAQ p.Q209P in 32.3% (n = 10) tumors.	('GNAQ', 'Gene', '2776', (51, 55))	('p.Q209L', 'Mutation', 'rs1057519742', (6, 13))	('tumors', 'Disease', (82, 88))	('p.Q209P', 'Mutation', 'rs1057519742', (56, 63))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('p.Q209P', 'Var', (56, 63))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('GNA11', 'Gene', (0, 5))	('GNA11', 'Gene', '2767', (0, 5))	('p.Q209L', 'Var', (6, 13))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('GNAQ', 'Gene', (51, 55))
83348	33348918	GNA11 p.Q209P, GNA11 p.R183C, GNAQ p.Q209L, and GNAQ p.Q209R mutations were identified each in one tumor sample (Table 2).	('GNA11', 'Gene', (15, 20))	('GNAQ', 'Gene', '2776', (30, 34))	('p.R183C', 'Var', (21, 28))	('tumor', 'Disease', (99, 104))	('p.Q209L', 'Mutation', 'rs1057519742', (35, 42))	('GNAQ', 'Gene', (30, 34))	('GNA11', 'Gene', '2767', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('p.R183C', 'Mutation', 'rs748346103', (21, 28))	('GNA11', 'Gene', '2767', (15, 20))	('p.Q209R', 'Mutation', 'rs121913492', (53, 60))	('p.Q209P', 'Mutation', 'rs1057519742', (6, 13))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('GNAQ', 'Gene', '2776', (48, 52))	('GNA11', 'Gene', (0, 5))	('GNAQ', 'Gene', (48, 52))	('p.Q209L', 'Var', (35, 42))	('p.Q209R', 'Var', (53, 60))	('p.Q209P', 'Var', (6, 13))
83349	33348918	In plasma samples, tumor-specific mutations were identified in 21.4% (n = 9) of patients, only in 9.4% (n = 3) primary UMs, while in 54.5% (n = 6) of metastatic patients.	('UM', 'Phenotype', 'HP:0007716', (119, 121))	('patients', 'Species', '9606', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('patients', 'Species', '9606', (161, 169))	('tumor', 'Disease', (19, 24))	('mutations', 'Var', (34, 43))
83385	33348918	A high number of tumor-specific recurrent hot spot mutations allows for tumor-specific ctDNA detection.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mutations', 'Var', (51, 60))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('ctDNA', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
83387	33348918	GNA11 p.Q209L and GNAQ p.Q209P were the most frequent tumor-specific mutations, with four more in the same genes identified each in one patient.	('p.Q209L', 'Mutation', 'rs1057519742', (6, 13))	('patient', 'Species', '9606', (136, 143))	('GNAQ', 'Gene', '2776', (18, 22))	('GNA11', 'Gene', (0, 5))	('p.Q209P', 'Mutation', 'rs1057519742', (23, 30))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('GNA11', 'Gene', '2767', (0, 5))	('p.Q209L', 'Var', (6, 13))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('p.Q209P', 'Var', (23, 30))	('GNAQ', 'Gene', (18, 22))	('tumor', 'Disease', (54, 59))
83400	33348918	The authors demonstrated in vitro and in vivo, that spindle UM cells were able to convert to epithelioid cells and that higher ZEB1 expression drives UM progression by inducing cell dedifferentiation, proliferation, invasion, and dissemination without a change in the cell morphology.	('expression', 'Var', (132, 142))	('cell dedifferentiation', 'CPA', (177, 199))	('higher', 'Var', (120, 126))	('cell dedifferentiation', 'biological_process', 'GO:0043697', ('177', '199'))	('dissemination', 'CPA', (230, 243))	('inducing', 'Reg', (168, 176))	('ZEB1', 'Gene', '6935', (127, 131))	('spindle', 'cellular_component', 'GO:0005819', ('52', '59'))	('ZEB1', 'Gene', (127, 131))	('invasion', 'CPA', (216, 224))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('UM', 'Phenotype', 'HP:0007716', (150, 152))
83410	33348918	Chromosomal rearrangements and altered expression of this gene have been implicated in tumor metastasis formation.	('implicated', 'Reg', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('altered', 'Var', (31, 38))	('tumor metastasis', 'Disease', 'MESH:D009362', (87, 103))	('tumor metastasis', 'Disease', (87, 103))	('expression', 'MPA', (39, 49))	('Chromosomal rearrangements', 'Var', (0, 26))	('formation', 'biological_process', 'GO:0009058', ('104', '113'))
83420	33348918	The down-regulation of Jag-1 expression was facilitated by GNAQ knockdown.	('regulation', 'biological_process', 'GO:0065007', ('9', '19'))	('Jag-1', 'Gene', (23, 28))	('GNAQ', 'Gene', (59, 63))	('knockdown', 'Var', (64, 73))	('expression', 'MPA', (29, 39))	('down-regulation', 'NegReg', (4, 19))	('Jag-1', 'Gene', '182', (23, 28))	('GNAQ', 'Gene', '2776', (59, 63))
83431	33348918	Unlike other EMT-associated TFs, the loss of Prrx1 is required for cancer cells to metastasize in vivo in carcinomas.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('carcinomas', 'Disease', (106, 116))	('EMT', 'biological_process', 'GO:0001837', ('13', '16'))	('cancer', 'Disease', (67, 73))	('Prrx1', 'Gene', '5396', (45, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('loss', 'Var', (37, 41))	('carcinomas', 'Disease', 'MESH:D009369', (106, 116))	('Prrx1', 'Gene', (45, 50))
83446	33348918	Therefore, combination therapies and novel experimental approaches such as gene therapy or targeting epigenetic modifications may offer possible clues for more effective patient management options in UM.	('epigenetic modifications', 'Var', (101, 125))	('UM', 'Phenotype', 'HP:0007716', (200, 202))	('gene', 'Var', (75, 79))	('patient', 'Species', '9606', (170, 177))
83461	33348918	The following TaqMan assays from Life Technologies (Carlsbad, CA, USA) were used: TWIST1: Hs00361186_m1; SNAI1: Hs00195591_m1; SNAI2: Hs00161904_m1; ZEB1: Hs01566408_m1; GAPDH Hs99999905_m1; and KRT19: Hs00761767_s1.	('Hs99999905_m1', 'Var', (176, 189))	('Hs00161904_m1', 'Var', (134, 147))	('TWIST1', 'Gene', (82, 88))	('TWIST1', 'Gene', '7291', (82, 88))	('ZEB1', 'Gene', (149, 153))	('KRT19', 'Gene', (195, 200))	('KRT19', 'Gene', '3880', (195, 200))	('SNAI1', 'Gene', (105, 110))	('ZEB1', 'Gene', '6935', (149, 153))	('SNAI2', 'Gene', '6591', (127, 132))	('SNAI2', 'Gene', (127, 132))	('SNAI1', 'Gene', '6615', (105, 110))	('Hs00761767_s1', 'Var', (202, 215))	('GAPDH', 'Gene', '2597', (170, 175))	('GAPDH', 'Gene', (170, 175))	('Hs01566408_m1', 'Var', (155, 168))
83471	33348918	We used 8 assays, namely dHsaMVD2010049 for GNA11 p.Q209L, dHsaMDS961917975 for GNA11 p.Q209P, dHsaMDS314447910 for GNA11 p.R183C, dHsaP2010051 for GNAQ p.Q209L, as well as for the GNAQ Q209R mutation detection, dHsaMDV2516794 for GNAQ p.Q209P, dHsaMDS533896396 for GNAQ p.R183Q,, dHsaMDS848188535 for PLCB4 p.D630Y and dHsaMDS821441396 for CYSLTR2 p.L129Q mutations.	('p.R183Q', 'Mutation', 'rs397514698', (271, 278))	('p.R183Q', 'Var', (271, 278))	('GNAQ', 'Gene', (181, 185))	('GNAQ', 'Gene', '2776', (148, 152))	('dHsaMDS848188535', 'Var', (281, 297))	('GNA11', 'Gene', '2767', (44, 49))	('p.D630Y', 'Mutation', 'p.D630Y', (308, 315))	('CYSLTR2', 'Gene', (341, 348))	('GNAQ', 'Gene', '2776', (266, 270))	('GNAQ', 'Gene', (148, 152))	('Q209R', 'Mutation', 'rs121913492', (186, 191))	('GNAQ', 'Gene', (266, 270))	('GNA11', 'Gene', (116, 121))	('p.Q209L', 'Mutation', 'rs1057519742', (153, 160))	('PLCB4', 'Gene', '5332', (302, 307))	('dHsaP2010051', 'Chemical', '-', (131, 143))	('p.Q209L', 'Mutation', 'rs1057519742', (50, 57))	('p.L129Q', 'Mutation', 'rs764805904', (349, 356))	('p.Q209P', 'Mutation', 'rs1057519742', (86, 93))	('p.R183C', 'Mutation', 'rs748346103', (122, 129))	('GNA11', 'Gene', '2767', (80, 85))	('p.L129Q', 'Var', (349, 356))	('GNA11', 'Gene', (44, 49))	('dHsaMDS533896396', 'Var', (245, 261))	('p.D630Y', 'Var', (308, 315))	('dHsaMDS821441396', 'Var', (320, 336))	('GNAQ', 'Gene', '2776', (231, 235))	('p.Q209P', 'Mutation', 'rs1057519742', (236, 243))	('GNAQ', 'Gene', (231, 235))	('CYSLTR2', 'Gene', '57105', (341, 348))	('GNA11', 'Gene', '2767', (116, 121))	('GNA11', 'Gene', (80, 85))	('dHsaMDV2516794', 'Var', (212, 226))	('PLCB4', 'Gene', (302, 307))	('GNAQ', 'Gene', '2776', (181, 185))
83477	33348918	A total of 100 ng of DNA was used to identify chromosomal rearrangements in tumor tissues by SALSA MLPA Probemix P027 Uveal melanoma (MRC Holland, Amsterdam, Netherlands).	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('P027', 'Var', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (118, 132))
83492	32127003	Although GNAQ/GNA11 mutations are believed to confer pathogenesis of UM, the underlying mechanism of liver metastasis remains poorly understood.	('pathogenesis', 'biological_process', 'GO:0009405', ('53', '65'))	('GNAQ', 'Gene', (9, 13))	('UM', 'Disease', 'MESH:C536494', (69, 71))	('GNA11', 'Gene', (14, 19))	('GNAQ', 'Gene', '2776', (9, 13))	('GNA11', 'Gene', '2767', (14, 19))	('mutations', 'Var', (20, 29))
83508	32127003	Mutually exclusive gain-of-function mutations in GNAQ/GNA11 found in 80% of UM, which activate multiple pathways, resulting in activation of MAPK and YAP to promote the growth of UM, presumably drive the pathogenesis of UM.	('growth', 'MPA', (169, 175))	('UM', 'Disease', 'MESH:C536494', (220, 222))	('MAPK', 'Pathway', (141, 145))	('gain-of-function', 'PosReg', (19, 35))	('GNA11', 'Gene', (54, 59))	('UM', 'Disease', 'MESH:C536494', (179, 181))	('GNAQ', 'Gene', '2776', (49, 53))	('MAPK', 'molecular_function', 'GO:0004707', ('141', '145'))	('YAP', 'Gene', '10413', (150, 153))	('mutations', 'Var', (36, 45))	('promote', 'PosReg', (157, 164))	('GNA11', 'Gene', '2767', (54, 59))	('UM', 'Disease', 'MESH:C536494', (76, 78))	('YAP', 'Gene', (150, 153))	('pathogenesis', 'biological_process', 'GO:0009405', ('204', '216'))	('GNAQ', 'Gene', (49, 53))	('activation', 'PosReg', (127, 137))
83509	32127003	Genetic analysis revealed that inactivating somatic mutation in BAP1 is a significant predictor for metastatic UM.	('UM', 'Disease', 'MESH:C536494', (111, 113))	('inactivating somatic mutation', 'Var', (31, 60))	('metastatic', 'Disease', (100, 110))	('BAP1', 'Gene', (64, 68))
83551	32127003	GSK126 caused to reduced clonogenecity (Supplementary Fig.	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('clonogenecity', 'CPA', (25, 38))	('GSK126', 'Chemical', 'MESH:C577920', (0, 6))	('GSK126', 'Var', (0, 6))	('reduced', 'NegReg', (17, 24))
83552	32127003	Moreover, GSK126 diminished the levels of H3K27me3 and increased the protein levels of p53 and p16 (Supplementary Fig.	('H3K27me3', 'MPA', (42, 50))	('protein levels', 'MPA', (69, 83))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('GSK', 'molecular_function', 'GO:0050321', ('10', '13'))	('increased', 'PosReg', (55, 64))	('GSK126', 'Chemical', 'MESH:C577920', (10, 16))	('p16', 'Gene', '1029', (95, 98))	('diminished', 'NegReg', (17, 27))	('levels', 'MPA', (32, 38))	('GSK126', 'Var', (10, 16))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('p16', 'Gene', (95, 98))
83554	32127003	These results suggest that GSK126 leads to declined H3K27me3 and activation of p53.	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('declined', 'NegReg', (43, 51))	('GSK126', 'Chemical', 'MESH:C577920', (27, 33))	('GSK126', 'Var', (27, 33))	('GSK', 'molecular_function', 'GO:0050321', ('27', '30'))	('H3K27me3', 'Protein', (52, 60))	('activation', 'PosReg', (65, 75))
83564	32127003	Our findings indicate that Survivin plays a vital role in GSK126-induced apoptosis in UM cells.	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('GSK126', 'Chemical', 'MESH:C577920', (58, 64))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('GSK', 'molecular_function', 'GO:0050321', ('58', '61'))	('UM', 'Disease', 'MESH:C536494', (86, 88))	('GSK126-induced', 'Var', (58, 72))	('apoptosis', 'CPA', (73, 82))	('Survivin', 'Protein', (27, 35))
83568	32127003	Meanwhile, GSK126 induced apoptosis in vivo as indicated by TUNEL assay (Supplementary Fig.	('apoptosis', 'CPA', (26, 35))	('GSK', 'molecular_function', 'GO:0050321', ('11', '14'))	('GSK126', 'Chemical', 'MESH:C577920', (11, 17))	('apoptosis', 'biological_process', 'GO:0097194', ('26', '35'))	('apoptosis', 'biological_process', 'GO:0006915', ('26', '35'))	('GSK126', 'Var', (11, 17))
83577	32127003	Obviously, the ALDH+ Omm1 subpopulation formed more xenografted tumors than either ALDH- Omm1 subpopulation or unsorted Omm1 cells (Fig.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors', 'Disease', (64, 70))	('more', 'PosReg', (47, 51))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('ALDH', 'molecular_function', 'GO:0004030', ('15', '19'))	('ALDH', 'molecular_function', 'GO:0004030', ('83', '87'))	('ALDH+ Omm1', 'Var', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
83582	32127003	Moreover, the in vivo limiting dilution assay showed that inhibition of EZH2 eradicates CSCs in UM (Supplementary Table S4).	('UM', 'Disease', 'MESH:C536494', (96, 98))	('CSCs', 'Disease', (88, 92))	('inhibition', 'Var', (58, 68))	('eradicates', 'NegReg', (77, 87))	('EZH2', 'Gene', (72, 76))
83587	32127003	In another approach, treatment with GSK3beta inhibitors (e.g., LiCl and SB216763) gave rise to the accumulation of beta-catenin and promoted serially-replating ability of melanosphere (Fig.	('SB216763', 'Chemical', 'MESH:C417521', (72, 80))	('GSK3beta', 'Gene', (36, 44))	('GSK3beta', 'Gene', '2931', (36, 44))	('GSK', 'molecular_function', 'GO:0050321', ('36', '39'))	('beta-catenin', 'Gene', (115, 127))	('LiCl', 'Chemical', 'MESH:D018021', (63, 67))	('serially-replating ability of melanosphere', 'CPA', (141, 183))	('beta-catenin', 'Gene', '1499', (115, 127))	('promoted', 'PosReg', (132, 140))	('accumulation', 'PosReg', (99, 111))	('SB216763', 'Var', (72, 80))
83590	32127003	Notably, GSK126 blocked the in vivo Wnt/beta-catenin signaling as shown by Western blotting analysis of Omm1 xenografted and MP41 PDX tumors (Fig.	('blocked', 'NegReg', (16, 23))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('GSK', 'molecular_function', 'GO:0050321', ('9', '12'))	('MP41', 'Gene', '26930', (125, 129))	('GSK126', 'Chemical', 'MESH:C577920', (9, 15))	('beta-catenin', 'Gene', (40, 52))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('beta-catenin', 'Gene', '1499', (40, 52))	('GSK126', 'Var', (9, 15))	('MP41', 'Gene', (125, 129))
83591	32127003	Collectively, these data indicate that EZH2 strengths the stemness of CSCs in UM through Wnt/beta-catenin pathway.	('strengths', 'PosReg', (44, 53))	('beta-catenin', 'Gene', (93, 105))	('EZH2', 'Var', (39, 43))	('beta-catenin', 'Gene', '1499', (93, 105))	('stemness of CSCs', 'CPA', (58, 74))	('UM', 'Disease', 'MESH:C536494', (78, 80))
83601	32127003	Inhibition of EZH2 markedly augmented the expression of mature miR-29c-3p (Supplementary Fig.	('augmented', 'PosReg', (28, 37))	('EZH2', 'Gene', (14, 18))	('expression', 'MPA', (42, 52))	('Inhibition', 'Var', (0, 10))	('miR-29c', 'Gene', (63, 70))	('miR-29c', 'Gene', '407026', (63, 70))
83609	32127003	The expression of matrix metalloproteinase 9 (MMP9) and MMP2, critical metastasis-associated proteins, was reduced in the GSK126-treated UM cells (Fig.	('MMP2', 'Gene', '4313', (56, 60))	('GSK126-treated', 'Var', (122, 136))	('matrix metalloproteinase 9', 'Gene', '4318', (18, 44))	('reduced', 'NegReg', (107, 114))	('expression', 'MPA', (4, 14))	('MMP2', 'Gene', (56, 60))	('MMP9', 'Gene', '4318', (46, 50))	('MMP9', 'Gene', (46, 50))	('GSK', 'molecular_function', 'GO:0050321', ('122', '125'))	('MMP9', 'molecular_function', 'GO:0004229', ('46', '50'))	('MMP2', 'molecular_function', 'GO:0004228', ('56', '60'))	('matrix metalloproteinase 9', 'Gene', (18, 44))	('GSK126', 'Chemical', 'MESH:C577920', (122, 128))	('UM', 'Disease', 'MESH:C536494', (137, 139))
83612	32127003	These results indicate that EZH2 facilitates the UM cell motility through inducing F-actin polymerization.	('EZH2', 'Var', (28, 32))	('UM', 'Disease', 'MESH:C536494', (49, 51))	('F-actin', 'cellular_component', 'GO:0031941', ('83', '90'))	('cell motility', 'biological_process', 'GO:0048870', ('52', '65'))	('actin polymerization', 'biological_process', 'GO:0030041', ('85', '105'))	('F-actin polymerization', 'MPA', (83, 105))	('inducing', 'Reg', (74, 82))	('facilitates', 'PosReg', (33, 44))
83621	32127003	Silence of EZH2 abrogated such EZH2 recruitment, however, the reconstitution of EZH2 in EZH2-silenced UM cells reconducted EZH2 recruitment (Supplementary Fig.	('UM', 'Disease', 'MESH:C536494', (102, 104))	('abrogated', 'NegReg', (16, 25))	('Silence', 'Var', (0, 7))
83623	32127003	The binding of H3K27me3 to the promoter of ARHGDIG was abolished with EZH2 depletion, which was rescued when EZH2 was reconstituted (Supplementary Fig.	('ARHGDIG', 'Gene', (43, 50))	('binding', 'Interaction', (4, 11))	('depletion', 'Var', (75, 84))	('abolished', 'NegReg', (55, 64))	('ARHGDIG', 'Gene', '398', (43, 50))	('H3K27me3', 'Protein', (15, 23))	('binding', 'molecular_function', 'GO:0005488', ('4', '11'))
83636	32127003	Additionally, IHC staining revealed that the expression of RhoGDIgamma in the metastatic liver sections with GSK126 was expanded comparing with those with placebo, while levels of H3K27me3 were declined in those sections from GSK126-treated mice (Fig.	('expanded', 'PosReg', (120, 128))	('GSK', 'molecular_function', 'GO:0050321', ('109', '112'))	('GSK126', 'Chemical', 'MESH:C577920', (226, 232))	('GSK126', 'Var', (109, 115))	('RhoGDIgamma', 'Gene', (59, 70))	('levels', 'MPA', (170, 176))	('mice', 'Species', '10090', (241, 245))	('GSK', 'molecular_function', 'GO:0050321', ('226', '229'))	('expression', 'MPA', (45, 55))	('GSK126', 'Chemical', 'MESH:C577920', (109, 115))
83639	32127003	The expression of EZH2 and its HMT indicator H3K27me3 was not altered in UM cells transfected with BAP1-WT or its kinase dead mutation BAP1-C91S, comparing with that in vector-transfected-UM cells (Supplementary Fig.	('HMT', 'Gene', '56979', (31, 34))	('UM', 'Disease', 'MESH:C536494', (73, 75))	('BAP1-C91S', 'Var', (135, 144))	('C91S', 'Mutation', 'p.C91S', (140, 144))	('UM', 'Disease', 'MESH:C536494', (188, 190))	('HMT', 'Gene', (31, 34))
83653	32127003	We found that EZH2 accelerates the migration and invasion which are motivated by F-actin polymerization, in the metastatic cascade of UM cells.	('migration', 'CPA', (35, 44))	('accelerates', 'PosReg', (19, 30))	('actin polymerization', 'biological_process', 'GO:0030041', ('83', '103'))	('invasion', 'CPA', (49, 57))	('F-actin', 'cellular_component', 'GO:0031941', ('81', '88'))	('UM', 'Disease', 'MESH:C536494', (134, 136))	('EZH2', 'Var', (14, 18))
83673	32127003	Based on cytogenetic and genetic analysis in UM patient samples, several predictors for metastatic risk were identified: monosomy 3, BAP1 and Class1 vs 2 GEP prognostic factors.	('monosomy 3', 'Var', (121, 131))	('UM', 'Disease', 'MESH:C536494', (45, 47))	('patient', 'Species', '9606', (48, 55))	('BAP1', 'Gene', (133, 137))
83677	32127003	Loss-of-function mutations of the BAP1 gene are found in ~ 80% of metastatic UM patients, rendering BAP1 an independent indicator for UM metastasis.	('Loss-of-function', 'NegReg', (0, 16))	('patients', 'Species', '9606', (80, 88))	('BAP1', 'Gene', (34, 38))	('UM', 'Disease', 'MESH:C536494', (77, 79))	('UM', 'Disease', 'MESH:C536494', (134, 136))	('mutations', 'Var', (17, 26))
83679	32127003	reported that knockout of BAP1 results in elevated transcription of EZH2 gene in acute myeloid leukemia mouse bone marrow cells and human mesothelioma cells.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (81, 103))	('BAP1', 'Gene', (26, 30))	('acute myeloid leukemia', 'Disease', (81, 103))	('EZH2 gene', 'Gene', (68, 77))	('mouse', 'Species', '10090', (104, 109))	('mesothelioma', 'Disease', (138, 150))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (81, 103))	('transcription', 'MPA', (51, 64))	('transcription', 'biological_process', 'GO:0006351', ('51', '64'))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (87, 103))	('human', 'Species', '9606', (132, 137))	('mesothelioma', 'Disease', 'MESH:D008654', (138, 150))	('elevated', 'PosReg', (42, 50))	('knockout', 'Var', (14, 22))	('leukemia', 'Phenotype', 'HP:0001909', (95, 103))
83686	32127003	Comparing to the other 5 HMT inhibitors, EPZ6438 manifested the least inhibitory potency against both EZH2 enzyme activity and cell viability with relatively higher IC50 values (77.83-92.75 mumol/L).	('cell viability', 'CPA', (127, 141))	('HMT', 'Gene', '56979', (25, 28))	('activity', 'MPA', (114, 122))	('enzyme activity', 'molecular_function', 'GO:0003824', ('107', '122'))	('IC50 values', 'MPA', (165, 176))	('higher', 'PosReg', (158, 164))	('inhibitory potency', 'MPA', (70, 88))	('EZH2 enzyme', 'Enzyme', (102, 113))	('EPZ6438', 'Var', (41, 48))	('EPZ6438', 'Chemical', 'MESH:C000593333', (41, 48))	('least', 'NegReg', (64, 69))	('HMT', 'Gene', (25, 28))
83688	32127003	Our in vitro and in vivo data consistently revealed that the capacities of clonogenicity, stemness, and metastasis were significantly reduced in UM after treatment with EZH2 shRNAs or GSK126, suggesting that EZH2 is an effective druggable target.	('metastasis', 'CPA', (104, 114))	('UM', 'Disease', 'MESH:C536494', (145, 147))	('GSK126', 'Chemical', 'MESH:C577920', (184, 190))	('GSK', 'molecular_function', 'GO:0050321', ('184', '187'))	('EZH2 shRNAs', 'Var', (169, 180))	('reduced', 'NegReg', (134, 141))	('GSK126', 'Var', (184, 190))	('stemness', 'CPA', (90, 98))	('clonogenicity', 'CPA', (75, 88))
83697	30885979	Inhibition of NF-kappaB-Dependent Signaling Enhances Sensitivity and Overcomes Resistance to BET Inhibition in Uveal Melanoma Bromodomain and extraterminal protein inhibitors (BETi) are epigenetic therapies aimed to target dysregulated gene expression in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('gene expression', 'biological_process', 'GO:0010467', ('236', '251'))	('Melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('NF-kappaB', 'Gene', '4790', (14, 23))	('BETi', 'Chemical', '-', (176, 180))	('Enhances', 'PosReg', (44, 52))	('Melanoma', 'Disease', (117, 125))	('NF-kappaB', 'Gene', (14, 23))	('Melanoma', 'Disease', 'MESH:D008545', (117, 125))	('Signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (111, 125))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('Sensitivity', 'MPA', (53, 64))
83701	30885979	These findings suggest that inhibitors of NF-kappaB signaling may improve the efficacy of BET inhibition in patients with advanced uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))	('uveal melanoma', 'Disease', 'MESH:C536494', (131, 145))	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('patients', 'Species', '9606', (108, 116))	('uveal melanoma', 'Disease', (131, 145))	('efficacy', 'MPA', (78, 86))	('improve', 'PosReg', (66, 73))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('inhibitors', 'Var', (28, 38))	('BET inhibition', 'MPA', (90, 104))	('NF-kappaB', 'Protein', (42, 51))
83704	30885979	Nearly 90% of uveal melanoma is characterized by oncogenic mutations in the G-protein alpha subunits q (GNAQ) and 11 (GNA11; refs.).	('GNA11', 'Gene', (118, 123))	('uveal melanoma', 'Phenotype', 'HP:0007716', (14, 28))	('uveal melanoma', 'Disease', 'MESH:C536494', (14, 28))	('GNA11', 'Gene', '2767', (118, 123))	('GNAQ', 'Gene', '2776', (104, 108))	('uveal melanoma', 'Disease', (14, 28))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('GNAQ', 'Gene', (104, 108))	('mutations', 'Var', (59, 68))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))
83705	30885979	Gain of chromosome 8 and monosomy of chromosome 3 are poor prognostic markers, and amplification of Myc is present in about 40% of cases of uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('chromosome', 'cellular_component', 'GO:0005694', ('37', '47'))	('Myc', 'Gene', '4609', (100, 103))	('uveal melanoma', 'Disease', 'MESH:C536494', (140, 154))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('monosomy', 'Var', (25, 33))	('Myc', 'Gene', (100, 103))	('uveal melanoma', 'Phenotype', 'HP:0007716', (140, 154))	('uveal melanoma', 'Disease', (140, 154))	('amplification', 'Var', (83, 96))
83706	30885979	Recent findings have highlighted the importance of epigenetic dysregulation, including CpG hypermethylation of candidate tumor suppressor genes and altered histone modifications in uveal melanoma tumorigenesis, progression, and metastasis.	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('tumor', 'Disease', (196, 201))	('histone modifications', 'MPA', (156, 177))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('121', '137'))	('tumor', 'Disease', (121, 126))	('tumor suppressor', 'biological_process', 'GO:0051726', ('121', '137'))	('epigenetic dysregulation', 'Var', (51, 75))	('melanoma tumorigenesis', 'Disease', (187, 209))	('hypermethylation', 'Var', (91, 107))	('uveal melanoma', 'Disease', 'MESH:C536494', (181, 195))	('uveal melanoma', 'Phenotype', 'HP:0007716', (181, 195))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('melanoma tumorigenesis', 'Disease', 'MESH:D063646', (187, 209))	('uveal melanoma', 'Disease', (181, 195))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
83711	30885979	We previously reported that JQ1, a BRD4 inhibitor, induced cell-cycle arrest in uveal melanoma cell lines, and it had proapoptotic effects in cells with GNAQ/11 mutations, irrespective of MYC status.	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('proapoptotic effects', 'MPA', (118, 138))	('uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('uveal melanoma', 'Disease', (80, 94))	('JQ1', 'Gene', (28, 31))	('arrest', 'Disease', 'MESH:D006323', (70, 76))	('uveal melanoma', 'Disease', 'MESH:C536494', (80, 94))	('MYC', 'Gene', '4609', (188, 191))	('BRD4', 'Gene', '23476', (35, 39))	('arrest', 'Disease', (70, 76))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('59', '76'))	('GNAQ', 'Gene', '2776', (153, 157))	('mutations', 'Var', (161, 170))	('MYC', 'Gene', (188, 191))	('BRD4', 'Gene', (35, 39))	('GNAQ', 'Gene', (153, 157))
83712	30885979	Transcriptional microarray analysis revealed that GNAQ/11 mutant cells are highly dependent on BRD4 activity compared with cells without the mutations, and we identified two genes, Bcl-xL and Rad51, as important targets of JQ1 in GNAQ/11-mutant cells.	('mutant', 'Var', (58, 64))	('dependent', 'Reg', (82, 91))	('Bcl-xL', 'Gene', '598', (181, 187))	('GNAQ', 'Gene', '2776', (230, 234))	('Rad', 'biological_process', 'GO:1990116', ('192', '195'))	('Bcl-xL', 'Gene', (181, 187))	('BRD4', 'Gene', (95, 99))	('GNAQ', 'Gene', (230, 234))	('GNAQ', 'Gene', '2776', (50, 54))	('BRD4', 'Gene', '23476', (95, 99))	('Rad51', 'Gene', '5888', (192, 197))	('Rad51', 'Gene', (192, 197))	('GNAQ', 'Gene', (50, 54))
83723	30885979	PLX51107 and PLX8573 were from Plexxikon, Inc. JQ1 and QNZ (EVP4593) were from Selleck Chemicals.	('EVP4593', 'Chemical', 'MESH:C562064', (60, 67))	('PLX8573', 'Var', (13, 20))	('PLX51107', 'Chemical', '-', (0, 8))	('QNZ', 'Chemical', '-', (55, 58))	('PLX51107', 'Var', (0, 8))
83738	30885979	PVDF membranes were blocked with 5% nonfat dried milk in TBS buffer and probed with antibody for p65, p-p65, p50, IkBalpha, c-Myc, PARP, REL, RELB, tubulin (Cell Signaling Technology), CEBPD, and SOD2 (Santa Cruz Biotechnology).	('c-Myc', 'Gene', '4609', (124, 129))	('antibody', 'molecular_function', 'GO:0003823', ('84', '92'))	('PARP', 'Gene', '1302', (131, 135))	('SOD2', 'molecular_function', 'GO:0004784', ('196', '200'))	('antibody', 'cellular_component', 'GO:0042571', ('84', '92'))	('p-p65', 'Var', (102, 107))	('p50', 'Var', (109, 112))	('Signaling', 'biological_process', 'GO:0023052', ('162', '171'))	('TBS', 'Chemical', 'MESH:D013725', (57, 60))	('SOD2', 'Gene', (196, 200))	('PARP', 'Gene', (131, 135))	('RELB', 'Gene', (142, 146))	('antibody', 'cellular_component', 'GO:0019815', ('84', '92'))	('IkBalpha', 'Gene', (114, 122))	('PVDF', 'Chemical', 'MESH:C024865', (0, 4))	('p65', 'Var', (97, 100))	('SOD2', 'Gene', '6648', (196, 200))	('antibody', 'cellular_component', 'GO:0019814', ('84', '92'))	('c-Myc', 'Gene', (124, 129))	('RELB', 'Gene', '5971', (142, 146))	('IkBalpha', 'Gene', '4792', (114, 122))
83739	30885979	Two nontargeting and specific siRNA sets against p65, IkBalpha, REL, RELB, CEBPD, and SOD2 were purchased from Santa Cruz Biotechnology, Dharmacon, or Thermo Fisher Scientific.	('SOD2', 'Gene', '6648', (86, 90))	('IkBalpha', 'Gene', '4792', (54, 62))	('IkBalpha', 'Gene', (54, 62))	('SOD2', 'Gene', (86, 90))	('p65', 'Var', (49, 52))	('RELB', 'Gene', '5971', (69, 73))	('SOD2', 'molecular_function', 'GO:0004784', ('86', '90'))	('RELB', 'Gene', (69, 73))
83746	30885979	When these tumors reached an average of 270 mm3 diameter, the mice were administered (7/group) with vehicle or PLX51107 20 mg/kg orally PTL 10 mg/kg i.p.	('PLX51107', 'Var', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('mice', 'Species', '10090', (62, 66))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('PLX51107', 'Chemical', '-', (111, 119))	('PTL', 'Chemical', 'MESH:C002669', (136, 139))
83751	30885979	The tissue samples were fixed in buffered formalin (1:10) for 24 hours, then embedded in paraffin, and sections were stained with p-p65 and CEBPD antibodies by IHC.	('CEBPD', 'Gene', (140, 145))	('paraffin', 'Chemical', 'MESH:D010232', (89, 97))	('p-p65', 'Var', (130, 135))	('formalin', 'Chemical', 'MESH:D005557', (42, 50))
83760	30885979	Furthermore, the combination PLX51107+ PTL suppressed the expression of the subunit p50, inducedththe NF-kappaB inhibitor IkBalpha, and increased PARP cleavage in both cell lines.	('NF-kappaB inhibitor', 'biological_process', 'GO:0032088', ('102', '121'))	('expression', 'MPA', (58, 68))	('PLX51107', 'Chemical', '-', (29, 37))	('PARP', 'Gene', '1302', (146, 150))	('PTL', 'Gene', (39, 42))	('PARP', 'Gene', (146, 150))	('IkBalpha', 'Gene', '4792', (122, 130))	('PLX51107+', 'Var', (29, 38))	('subunit p50', 'Protein', (76, 87))	('increased', 'PosReg', (136, 145))	('PTL', 'Chemical', 'MESH:C002669', (39, 42))	('IkBalpha', 'Gene', (122, 130))	('inducedththe', 'PosReg', (89, 101))	('suppressed', 'NegReg', (43, 53))
83763	30885979	In contrast, the silencing of IkBalpha increased NF-kappaB activity (Fig.	('activity', 'MPA', (59, 67))	('NF-kappaB', 'Protein', (49, 58))	('IkBalpha', 'Gene', '4792', (30, 38))	('increased', 'PosReg', (39, 48))	('IkBalpha', 'Gene', (30, 38))	('silencing', 'Var', (17, 26))
83774	30885979	Moreover, PLX51107 induced PARP cleavage in the parental cells only (Fig.	('PARP', 'Gene', '1302', (27, 31))	('induced', 'Reg', (19, 26))	('PARP', 'Gene', (27, 31))	('PLX51107', 'Chemical', '-', (10, 18))	('PLX51107', 'Var', (10, 18))
83775	30885979	Interestingly, the BRD4 target c-Myc was downregulated by PLX51107 in both parental and resistant cells (Fig.	('PLX51107', 'Var', (58, 66))	('BRD4', 'Gene', (19, 23))	('downregulated', 'NegReg', (41, 54))	('c-Myc', 'Gene', (31, 36))	('BRD4', 'Gene', '23476', (19, 23))	('PLX51107', 'Chemical', '-', (58, 66))	('c-Myc', 'Gene', '4609', (31, 36))
83780	30885979	In a first analysis, we found that many genes regulated by acute drug exposure in the sensitive uveal melanoma cells were no longer induced or repressed after drug resistance had developed, suggesting the acquisition of stable epigenetic changes in BETi target genes.	('uveal melanoma', 'Disease', (96, 110))	('drug resistance', 'biological_process', 'GO:0009315', ('159', '174'))	('drug resistance', 'biological_process', 'GO:0042493', ('159', '174'))	('drug resistance', 'Phenotype', 'HP:0020174', (159, 174))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('BETi', 'Chemical', '-', (249, 253))	('epigenetic changes', 'Var', (227, 245))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('uveal melanoma', 'Disease', 'MESH:C536494', (96, 110))
83790	30885979	On the basis of the GSEA analysis, we first sought to confirm the induction of several genes involved in the NF-kappaB signaling (REL, RELB, CEBPD, SOD2) in all the resistant cell lines by qPCR (Fig.	('qPCR', 'Var', (189, 193))	('SOD2', 'Gene', '6648', (148, 152))	('SOD2', 'Gene', (148, 152))	('SOD2', 'molecular_function', 'GO:0004784', ('148', '152'))	('RELB', 'Gene', (135, 139))	('RELB', 'Gene', '5971', (135, 139))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))	('GSEA', 'Chemical', '-', (20, 24))
83793	30885979	The combination PLX51107+PTL decreased p-p65 and p50, while it induced IkBalpha and PARP cleavage in both parental and resistant cells (Fig.	('PLX51107+PTL', 'Gene', (16, 28))	('p-p65', 'MPA', (39, 44))	('PLX51107', 'Chemical', '-', (16, 24))	('p50', 'MPA', (49, 52))	('IkBalpha', 'Gene', '4792', (71, 79))	('IkBalpha', 'Gene', (71, 79))	('decreased', 'NegReg', (29, 38))	('PARP', 'Gene', '1302', (84, 88))	('induced', 'Reg', (63, 70))	('PLX51107+PTL', 'Var', (16, 28))	('PARP', 'Gene', (84, 88))	('PTL', 'Chemical', 'MESH:C002669', (25, 28))
83794	30885979	In addition, CEBPD was downregulated by the combination in the resistant cell lines, while PLX51107 alone was sufficient to suppress it in the parental cells.	('downregulated', 'NegReg', (23, 36))	('combination', 'Var', (44, 55))	('CEBPD', 'Gene', (13, 18))	('PLX51107', 'Chemical', '-', (91, 99))
83797	30885979	We next utilized a mouse xenograft model of BETi-resistant uveal melanoma cells to test the effects of the combination PLX51107+PTL in vivo.	('PLX51107+PTL', 'Var', (119, 131))	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('uveal melanoma', 'Disease', (59, 73))	('PTL', 'Chemical', 'MESH:C002669', (128, 131))	('PLX51107', 'Chemical', '-', (119, 127))	('BETi', 'Chemical', '-', (44, 48))	('mouse', 'Species', '10090', (19, 24))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('uveal melanoma', 'Disease', 'MESH:C536494', (59, 73))
83801	30885979	The combination of PLX51107 + PTL could significantly inhibit tumor growth in a dose-dependent manner compared with vehicle or PLX51107 single agent (Fig.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('inhibit', 'NegReg', (54, 61))	('PLX51107', 'Chemical', '-', (19, 27))	('tumor', 'Disease', (62, 67))	('PLX51107', 'Var', (19, 27))	('PLX51107', 'Chemical', '-', (127, 135))	('PTL', 'Gene', (30, 33))	('PTL', 'Chemical', 'MESH:C002669', (30, 33))	('combination', 'Interaction', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
83804	30885979	Western blot analysis of tumor specimens from two mice in each group showed downregulation of target genes (i.e., p-p65, p50, CEBPD) especially with the combination therapy (Fig.	('CEBPD', 'Gene', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('p50', 'Var', (121, 124))	('tumor', 'Disease', (25, 30))	('p-p65', 'Var', (114, 119))	('mice', 'Species', '10090', (50, 54))	('downregulation', 'NegReg', (76, 90))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
83806	30885979	Furthermore, the depletion of each gene in the resistant cells slightly decreased cell viability after treatment with PLX51107 (Fig.	('cell viability', 'CPA', (82, 96))	('PLX51107', 'Var', (118, 126))	('decreased', 'NegReg', (72, 81))	('PLX51107', 'Chemical', '-', (118, 126))	('depletion', 'MPA', (17, 26))
83807	30885979	Finally, we sought to determine the expression levels of p-p65 and CEBPD in tumor biopsy samples from patients enrolled in the PLX51107 clinical trial.	('patients', 'Species', '9606', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('PLX51107', 'Chemical', '-', (127, 135))	('CEBPD', 'Gene', (67, 72))	('p-p65', 'Var', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
83822	30885979	Thus, both strategies revealed that inhibition of NF-kappaB signaling enhances sensitivity to BET inhibition and can reverse resistance to PLX51107 in uveal melanoma cells.	('resistance', 'MPA', (125, 135))	('PLX51107', 'Chemical', '-', (139, 147))	('uveal melanoma', 'Disease', (151, 165))	('NF-kappaB', 'Protein', (50, 59))	('inhibition', 'Var', (36, 46))	('sensitivity to BET inhibition', 'MPA', (79, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (151, 165))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('uveal melanoma', 'Disease', 'MESH:C536494', (151, 165))	('enhances', 'PosReg', (70, 78))	('signaling', 'biological_process', 'GO:0023052', ('60', '69'))
83825	30885979	In fact, this pathway was reported to be downregulated in BETi-resistant leukemia cells, and it was also suppressed by BRD4 inhibitors in melanoma and lung carcinoma.	('suppressed', 'NegReg', (105, 115))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('BETi', 'Chemical', '-', (58, 62))	('downregulated', 'NegReg', (41, 54))	('BRD4', 'Gene', (119, 123))	('melanoma and lung carcinoma', 'Disease', 'MESH:D008175', (138, 165))	('leukemia', 'Phenotype', 'HP:0001909', (73, 81))	('leukemia', 'Disease', 'MESH:D007938', (73, 81))	('leukemia', 'Disease', (73, 81))	('BRD4', 'Gene', '23476', (119, 123))	('inhibitors', 'Var', (124, 134))
83830	30885979	CEBPD can amplify NF-kappaB-mediated transcription, resulting in the synergistic stimulation of promoters with C/EBP-binding sites, including promoters of immune or acute-phase responding genes, such as IL8.	('stimulation', 'PosReg', (81, 92))	('IL8', 'molecular_function', 'GO:0005153', ('203', '206'))	('synergistic', 'MPA', (69, 80))	('transcription', 'biological_process', 'GO:0006351', ('37', '50'))	('promoters', 'MPA', (96, 105))	('C/EBP', 'Gene', (111, 116))	('binding', 'molecular_function', 'GO:0005488', ('117', '124'))	('IL8', 'Gene', (203, 206))	('CEBPD', 'Var', (0, 5))	('C/EBP', 'Gene', '1050', (111, 116))	('IL8', 'Gene', '3576', (203, 206))
83841	30885979	Significance: These findings provide evidence that inhibitors of NF-kappaB signaling synergize with BET inhibition in in vitro and in vivo models, suggesting a clinical utility of these targeted therapies in patients with uveal melanoma.	('patients', 'Species', '9606', (208, 216))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('uveal melanoma', 'Disease', 'MESH:C536494', (222, 236))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('uveal melanoma', 'Phenotype', 'HP:0007716', (222, 236))	('uveal melanoma', 'Disease', (222, 236))	('inhibitors', 'Var', (51, 61))	('NF-kappaB', 'Protein', (65, 74))
83850	31019223	DNA double strand breakage triggers the DNA damage response network and two Fanconi anaemia DNA repair pathway members showed elevated expression in the metastasising OMMs.	('double strand breakage', 'Var', (4, 26))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('anaemia', 'Phenotype', 'HP:0001903', (84, 91))	('Fanconi anaemia', 'Disease', (76, 91))	('Fanconi anaemia', 'Phenotype', 'HP:0001994', (76, 91))	('DNA repair', 'biological_process', 'GO:0006281', ('92', '102'))	('DNA damage response', 'biological_process', 'GO:0006974', ('40', '59'))	('Fanconi anaemia', 'Disease', 'MESH:D005199', (76, 91))	('triggers', 'Reg', (27, 35))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('metastasising OMMs', 'Disease', (153, 171))	('expression', 'MPA', (135, 145))	('elevated', 'PosReg', (126, 134))	('OMM', 'Chemical', '-', (167, 170))	('DNA damage response network', 'Pathway', (40, 67))
83868	31019223	Putative activating mutations in Kit have been described in 7-16% of human mucosal melanomas and in 12% of canine OMM, and mutations in NRAS have been reported in 3.9% of canine OMMs and in 10-22% of human mucosal melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (214, 223))	('mucosal melanomas', 'Disease', (206, 223))	('Kit', 'Gene', (33, 36))	('human', 'Species', '9606', (200, 205))	('OMM', 'Chemical', '-', (178, 181))	('OMM', 'Chemical', '-', (114, 117))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('mucosal melanomas', 'Disease', 'MESH:D008545', (75, 92))	('NRAS', 'Gene', (136, 140))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('mucosal melanomas', 'Disease', (75, 92))	('human', 'Species', '9606', (69, 74))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('mutations', 'Var', (20, 29))	('NRAS', 'Gene', '403872', (136, 140))	('canine', 'Species', '9615', (171, 177))	('activating', 'PosReg', (9, 19))	('mucosal melanomas', 'Disease', 'MESH:D008545', (206, 223))	('canine', 'Species', '9615', (107, 113))	('mutations', 'Var', (123, 132))
83869	31019223	Around 50% of human cutaneous melanomas have an activating BRAF mutation, but BRAF mutations occur in only 4-9.5% of human mucosal melanomas, and have not been found in canine OMMs.	('cutaneous melanomas', 'Disease', (20, 39))	('BRAF', 'Gene', '673', (78, 82))	('activating', 'MPA', (48, 58))	('BRAF', 'Gene', (78, 82))	('canine', 'Species', '9615', (169, 175))	('melanomas', 'Phenotype', 'HP:0002861', (30, 39))	('mucosal melanomas', 'Disease', 'MESH:D008545', (123, 140))	('melanomas', 'Phenotype', 'HP:0002861', (131, 140))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (20, 38))	('mutation', 'Var', (64, 72))	('human', 'Species', '9606', (117, 122))	('human', 'Species', '9606', (14, 19))	('mucosal melanomas', 'Disease', (123, 140))	('OMM', 'Chemical', '-', (176, 179))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (20, 39))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (20, 39))
83870	31019223	The metastatic cascade comprises a series of steps, which are believed to be at least partially mediated by the acquisition of metastasis-associated genetic and/or epigenetic alterations additional to those that drive tumour development.	('tumour', 'Disease', (218, 224))	('metastasis-associated', 'Disease', (127, 148))	('epigenetic alterations', 'Var', (164, 186))	('genetic', 'Var', (149, 156))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('tumour', 'Disease', 'MESH:D009369', (218, 224))
83871	31019223	These somatic changes may affect gene expression, and metastasis-associated gene expression signatures have been identified for many human tumours.	('gene expression', 'MPA', (33, 48))	('tumours', 'Phenotype', 'HP:0002664', (139, 146))	('tumours', 'Disease', 'MESH:D009369', (139, 146))	('gene expression', 'biological_process', 'GO:0010467', ('76', '91'))	('affect', 'Reg', (26, 32))	('tumours', 'Disease', (139, 146))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('changes', 'Var', (14, 21))	('gene expression', 'biological_process', 'GO:0010467', ('33', '48'))	('human', 'Species', '9606', (133, 138))
83909	31019223	For SLC25A51 and SNORA76 there was a negative correlation between the gene expression values measured by microarray and RT-qPCR, and for SLC25A51 there was a difference between the 'direction' of NM: M differential expression as assessed by microarray and RT-qPCR, respectively (Table 4).	('difference', 'Reg', (158, 168))	('SNORA76', 'Var', (17, 24))	('SLC25A51', 'Gene', (4, 12))	('gene expression', 'MPA', (70, 85))	('SLC25A51', 'Gene', '100686420', (137, 145))	('gene expression', 'biological_process', 'GO:0010467', ('70', '85'))	('SLC25A51', 'Gene', (137, 145))	('SLC25A51', 'Gene', '100686420', (4, 12))	('negative', 'NegReg', (37, 45))
83920	31019223	Molecular genetic and epigenetic 'events' that promote canine OMM metastasis may be both predictive indicators of canine OMM metastasis and the focus for therapeutics intended to prevent metastasis.	('canine', 'Species', '9615', (55, 61))	('canine', 'Species', '9615', (114, 120))	('OMM', 'Chemical', '-', (121, 124))	('promote', 'PosReg', (47, 54))	('canine OMM', 'Disease', (55, 65))	("epigenetic 'events", 'Var', (22, 40))	('OMM', 'Chemical', '-', (62, 65))
83924	31019223	An understanding of the mechanisms by which changes in gene expression mediate OMM metastasis is afforded by functional annotation enrichment analysis.	('OMM', 'Chemical', '-', (79, 82))	('gene expression', 'biological_process', 'GO:0010467', ('55', '70'))	('changes', 'Var', (44, 51))	('OMM', 'Disease', (79, 82))	('mediate', 'Reg', (71, 78))
83925	31019223	Disruption of the balance between phosphorylation and dephosphorylation is associated with carcinogenesis, and protein phosphatases have been recognised as tumour suppressors.	('phosphorylation', 'MPA', (34, 49))	('balance', 'MPA', (18, 25))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('tumour', 'Disease', (156, 162))	('carcinogenesis', 'Disease', (91, 105))	('dephosphorylation', 'biological_process', 'GO:0016311', ('54', '71'))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('dephosphorylation', 'MPA', (54, 71))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('associated', 'Reg', (75, 85))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('carcinogenesis', 'Disease', 'MESH:D063646', (91, 105))	('Disruption', 'Var', (0, 10))
83926	31019223	Aberrant expression of protein phosphatase inhibitors has been reported in a wide variety of human cancers.	('protein phosphatase inhibitors', 'Protein', (23, 53))	('Aberrant', 'Var', (0, 8))	('reported', 'Reg', (63, 71))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('human', 'Species', '9606', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('phosphatase', 'molecular_function', 'GO:0016791', ('31', '42'))	('cancers', 'Disease', (99, 106))	('expression', 'MPA', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
83928	31019223	PPP1R37, GPATCH2 (also known as PPP1R30), CASC5 (or PPP1R55) and CSRNP2 (or PPP1R72) encode proteins recognised as inhibitory regulatory subunits of phosphoprotein phosphatase 1 (PPP1), a protein serine-threonine phosphatase that regulates several members of the Transforming growth factor beta signalling pathway, which promotes invasion and metastasis in advanced stages of cancer.	('signalling pathway', 'biological_process', 'GO:0007165', ('295', '313'))	('cancer', 'Disease', (376, 382))	('Transforming growth factor beta', 'molecular_function', 'GO:0005160', ('263', '294'))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('promotes', 'PosReg', (321, 329))	('GPATCH2', 'Gene', (9, 16))	('cancer', 'Disease', 'MESH:D009369', (376, 382))	('Transforming growth factor beta signalling pathway', 'Pathway', (263, 313))	('PPP1R37', 'Gene', '484452', (0, 7))	('CSRNP2', 'Gene', '486541', (65, 71))	('regulates', 'Reg', (230, 239))	('PPP1R37', 'Gene', (0, 7))	('phosphatase', 'molecular_function', 'GO:0016791', ('213', '224'))	('phosphatase', 'molecular_function', 'GO:0016791', ('164', '175'))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('PPP1R55', 'Var', (52, 59))	('CSRNP2', 'Gene', (65, 71))	('invasion', 'CPA', (330, 338))	('CASC5', 'Gene', (42, 47))	('GPATCH2', 'Gene', '488594', (9, 16))
83929	31019223	Inhibition of PPP1 by the regulatory subunit PPP1R1A in Ewing sarcoma has been shown to promote tumour growth and metastasis.	('PPP1', 'Gene', (14, 18))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (56, 69))	('PPP1R1A', 'Gene', (45, 52))	('promote', 'PosReg', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour growth', 'Disease', (96, 109))	('Ewing sarcoma', 'Disease', (56, 69))	('Inhibition', 'Var', (0, 10))	('tumour growth', 'Disease', 'MESH:D006130', (96, 109))	('PPP1R1A', 'Gene', '100855706', (45, 52))
83946	31019223	Deregulation of the expression of genes involved in cholesterol homeostasis pathways has been associated with cancer development and progression.	('cancer', 'Disease', (110, 116))	('expression', 'MPA', (20, 30))	('Deregulation', 'Var', (0, 12))	('progression', 'CPA', (133, 144))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('associated', 'Reg', (94, 104))	('cholesterol', 'Chemical', 'MESH:D002784', (52, 63))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cholesterol homeostasis', 'biological_process', 'GO:0042632', ('52', '75'))
83967	31019223	Deregulated APOBEC3A expression in cancer is believed to induce double strand breaks in genomic DNA activating DNA damage response pathways.	('double', 'MPA', (64, 70))	('DNA damage response pathways', 'Pathway', (111, 139))	('Deregulated', 'Var', (0, 11))	('APOBEC3A', 'Gene', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('APOBEC', 'cellular_component', 'GO:0030895', ('12', '18'))	('induce', 'Reg', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('DNA damage response', 'biological_process', 'GO:0006974', ('111', '130'))	('cancer', 'Disease', (35, 41))
83968	31019223	The repair of such breaks triggers the formation of single stranded DNAs which are substrates for APOBEC3A-mediated hypermutation, such that 5'-(C/T)TTA APOBEC3A mutation signatures occur in clusters (on one DNA strand) in multiple human cancers.	('APOBEC', 'cellular_component', 'GO:0030895', ('98', '104'))	('cancers', 'Disease', (238, 245))	('cancers', 'Disease', 'MESH:D009369', (238, 245))	("5'-(C/T)TTA", 'Var', (141, 152))	('APOBEC3A', 'Gene', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('APOBEC', 'cellular_component', 'GO:0030895', ('153', '159'))	('formation', 'biological_process', 'GO:0009058', ('39', '48'))	('human', 'Species', '9606', (232, 237))	('DNA', 'cellular_component', 'GO:0005574', ('208', '211'))	('mutation', 'Var', (162, 170))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))
83969	31019223	APOBEC3A-mediated mutagenesis occurs at different stages in different cancers, and is thought to drive tumour evolution, including promoting metastasis.	('metastasis', 'CPA', (141, 151))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))	('mutagenesis', 'biological_process', 'GO:0006280', ('18', '29'))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutagenesis', 'Var', (18, 29))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('promoting', 'PosReg', (131, 140))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('APOBEC3A-mediated', 'Gene', (0, 17))	('drive', 'Reg', (97, 102))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))	('tumour', 'Disease', (103, 109))
83973	31019223	Silencing of RPL29 suppressed the proliferation of human pancreatic tumour cells and enhanced apoptosis suggesting an involvement in cell proliferation.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('involvement', 'Reg', (118, 129))	('cell proliferation', 'biological_process', 'GO:0008283', ('133', '151'))	('suppressed', 'NegReg', (19, 29))	('enhanced', 'PosReg', (85, 93))	('RPL29', 'Gene', (13, 18))	('pancreatic tumour', 'Disease', 'MESH:D010190', (57, 74))	('pancreatic tumour', 'Disease', (57, 74))	('human', 'Species', '9606', (51, 56))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))	('Silencing', 'Var', (0, 9))	('apoptosis', 'CPA', (94, 103))	('pancreatic tumour', 'Phenotype', 'HP:0002894', (57, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))
83974	31019223	However, RPL29 silencing had no effect on the viability of human metastatic melanoma cells.	('melanoma', 'Disease', (76, 84))	('human', 'Species', '9606', (59, 64))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('silencing', 'Var', (15, 24))	('RPL29', 'Gene', (9, 14))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
83979	31019223	Small molecule inhibitors of CXCR4 were shown to be effective at disrupting the liver metastasis of uveal melanoma cells in mice, and migration of human cutaneous melanoma cells in vitro.	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('CXCR4', 'molecular_function', 'GO:0038147', ('29', '34'))	('human', 'Species', '9606', (147, 152))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('uveal melanoma', 'Disease', (100, 114))	('cutaneous melanoma', 'Disease', (153, 171))	('mice', 'Species', '10090', (124, 128))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (153, 171))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (153, 171))	('liver metastasis', 'Disease', 'MESH:D009362', (80, 96))	('disrupting', 'NegReg', (65, 75))	('liver metastasis', 'Disease', (80, 96))	('migration', 'CPA', (134, 143))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('inhibitors', 'Var', (15, 25))
83981	31019223	Intriguingly, it has been postulated that APOBEC3A-mediated hypermutation could generate new tumour-specific antigens thereby enhancing the efficacy of immune stimulation therapies.	('tumour', 'Disease', (93, 99))	('enhancing', 'PosReg', (126, 135))	('hypermutation', 'Var', (60, 73))	('APOBEC3A-mediated', 'Gene', (42, 59))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('APOBEC', 'cellular_component', 'GO:0030895', ('42', '48'))	('immune stimulation therapies', 'CPA', (152, 180))
83992	31019223	Several of the differences in gene expression observed between primary canine OMMs that metastasised and OMMs that did not metastasise in this study have previously been associated with human cutaneous melanoma metastasis.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (192, 210))	('gene expression', 'MPA', (30, 45))	('cutaneous melanoma metastasis', 'Disease', (192, 221))	('canine', 'Species', '9615', (71, 77))	('cutaneous melanoma metastasis', 'Disease', 'MESH:D009362', (192, 221))	('OMM', 'Chemical', '-', (105, 108))	('human', 'Species', '9606', (186, 191))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('differences', 'Var', (15, 26))	('OMM', 'Chemical', '-', (78, 81))	('associated', 'Reg', (170, 180))	('gene expression', 'biological_process', 'GO:0010467', ('30', '45'))
84023	27934878	Activating cysteinyl leukotriene receptor 2 (CYSLTR2) mutations in blue nevi Blue nevi are common melanocytic tumors arising in the dermal layer of the skin.	('Activating', 'PosReg', (0, 10))	('cysteinyl leukotriene receptor 2', 'Gene', '57105', (11, 43))	('CYSLTR2', 'Gene', '57105', (45, 52))	('mutations', 'Var', (54, 63))	('nevi', 'Phenotype', 'HP:0003764', (72, 76))	('cysteinyl leukotriene receptor 2', 'Gene', (11, 43))	('CYSLTR2', 'Gene', (45, 52))	('Blue nevi', 'Phenotype', 'HP:0100814', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('blue nevi', 'Phenotype', 'HP:0100814', (67, 76))	('nevi', 'Phenotype', 'HP:0003764', (82, 86))	('melanocytic tumors', 'Disease', 'MESH:D009508', (98, 116))	('melanocytic tumors', 'Disease', (98, 116))	('blue nevi Blue nevi', 'Disease', (67, 86))
84024	27934878	Similar to uveal melanomas, blue nevi frequently harbor GNAQ and GNA11 mutations.	('blue nevi', 'Phenotype', 'HP:0100814', (28, 37))	('harbor', 'Reg', (49, 55))	('uveal melanoma', 'Phenotype', 'HP:0007716', (11, 25))	('blue nevi', 'Disease', (28, 37))	('melanomas', 'Phenotype', 'HP:0002861', (17, 26))	('GNAQ', 'Gene', '2776', (56, 60))	('uveal melanomas', 'Disease', (11, 26))	('uveal melanomas', 'Phenotype', 'HP:0007716', (11, 26))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('mutations', 'Var', (71, 80))	('GNA11', 'Gene', '2767', (65, 70))	('GNA11', 'Gene', (65, 70))	('nevi', 'Phenotype', 'HP:0003764', (33, 37))	('uveal melanomas', 'Disease', 'MESH:C536494', (11, 26))	('GNAQ', 'Gene', (56, 60))
84025	27934878	Recently, recurrent CYSLTR2 and PLCB4 mutations were identified in uveal melanomas not harboring GNAQ or GNA11 mutations.	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('uveal melanomas', 'Disease', 'MESH:C536494', (67, 82))	('CYSLTR2', 'Gene', '57105', (20, 27))	('GNA11', 'Gene', (105, 110))	('PLCB4', 'Gene', (32, 37))	('GNAQ', 'Gene', '2776', (97, 101))	('CYSLTR2', 'Gene', (20, 27))	('GNA11', 'Gene', '2767', (105, 110))	('uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('mutations', 'Var', (38, 47))	('uveal melanomas', 'Disease', (67, 82))	('uveal melanomas', 'Phenotype', 'HP:0007716', (67, 82))	('PLCB4', 'Gene', '5332', (32, 37))	('GNAQ', 'Gene', (97, 101))
84026	27934878	All four genes (GNAQ, GNA11, CYSLTR2, and PLCB4) code for proteins involved in the same signaling pathway, which is activated by mutations in these genes.	('GNA11', 'Gene', (22, 27))	('PLCB4', 'Gene', '5332', (42, 47))	('signaling pathway', 'biological_process', 'GO:0007165', ('88', '105'))	('mutations', 'Var', (129, 138))	('GNAQ', 'Gene', (16, 20))	('activated', 'PosReg', (116, 125))	('GNA11', 'Gene', '2767', (22, 27))	('CYSLTR2', 'Gene', '57105', (29, 36))	('PLCB4', 'Gene', (42, 47))	('GNAQ', 'Gene', '2776', (16, 20))	('CYSLTR2', 'Gene', (29, 36))
84027	27934878	Given the related functional consequences of these mutations and the known genetic similarities between uveal melanoma and blue nevi, we analyzed a cohort of blue nevi to investigate whether CYSLTR2 and PLCB4 mutations occur in tumors lacking GNAQ or GNA11 mutations (as in uveal melanoma).	('mutations', 'Var', (51, 60))	('uveal melanoma', 'Disease', 'MESH:C536494', (274, 288))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('uveal melanoma', 'Disease', (274, 288))	('GNAQ', 'Gene', '2776', (243, 247))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('GNAQ', 'Gene', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('GNA11', 'Gene', (251, 256))	('tumors', 'Disease', (228, 234))	('uveal melanoma', 'Phenotype', 'HP:0007716', (274, 288))	('PLCB4', 'Gene', (203, 208))	('blue nevi', 'Phenotype', 'HP:0100814', (123, 132))	('uveal melanoma', 'Disease', (104, 118))	('uveal melanoma', 'Disease', 'MESH:C536494', (104, 118))	('nevi', 'Phenotype', 'HP:0003764', (163, 167))	('CYSLTR2', 'Gene', '57105', (191, 198))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('occur', 'Reg', (219, 224))	('melanoma', 'Phenotype', 'HP:0002861', (280, 288))	('nevi', 'Phenotype', 'HP:0003764', (128, 132))	('PLCB4', 'Gene', '5332', (203, 208))	('mutations', 'Var', (209, 218))	('CYSLTR2', 'Gene', (191, 198))	('GNA11', 'Gene', '2767', (251, 256))	('blue nevi', 'Phenotype', 'HP:0100814', (158, 167))
84028	27934878	A targeted next-generation sequencing assay covering known activating mutations in GNAQ, GNA11, CYSLTR2, PLCB4, KIT, NRAS, and BRAF was applied to 103 blue nevi.	('CYSLTR2', 'Gene', '57105', (96, 103))	('NRAS', 'Gene', (117, 121))	('mutations', 'Var', (70, 79))	('GNAQ', 'Gene', '2776', (83, 87))	('CYSLTR2', 'Gene', (96, 103))	('BRAF', 'Gene', '673', (127, 131))	('NRAS', 'Gene', '4893', (117, 121))	('PLCB4', 'Gene', (105, 110))	('blue nevi', 'Phenotype', 'HP:0100814', (151, 160))	('nevi', 'Phenotype', 'HP:0003764', (156, 160))	('BRAF', 'Gene', (127, 131))	('GNA11', 'Gene', '2767', (89, 94))	('GNA11', 'Gene', (89, 94))	('KIT', 'Gene', (112, 115))	('GNAQ', 'Gene', (83, 87))	('KIT', 'molecular_function', 'GO:0005020', ('112', '115'))	('PLCB4', 'Gene', '5332', (105, 110))
84031	27934878	In three tumors (3%) harboring none of the aforementioned gene alterations, CYSLTR2 mutations were identified.	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('mutations', 'Var', (84, 93))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('CYSLTR2', 'Gene', '57105', (76, 83))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('CYSLTR2', 'Gene', (76, 83))
84032	27934878	All three CYSLTR2 mutations were the same c.386T > A, L129Q mutation previously identified in uveal melanoma that has been shown to lead to increased receptor activation and signaling.	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('signaling', 'MPA', (174, 183))	('L129Q', 'Mutation', 'p.L129Q', (54, 59))	('uveal melanoma', 'Disease', (94, 108))	('CYSLTR2', 'Gene', '57105', (10, 17))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('c.386T > A', 'Mutation', 'rs776734905', (42, 52))	('signaling', 'biological_process', 'GO:0023052', ('174', '183'))	('c.386T > A', 'Var', (42, 52))	('CYSLTR2', 'Gene', (10, 17))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('L129Q', 'Var', (54, 59))	('receptor activation', 'MPA', (150, 169))	('increased', 'PosReg', (140, 149))	('mutations', 'Var', (18, 27))
84034	27934878	Similar to GNAQ and GNA11 mutations, CYSLTR2 mutations, when present, are likely defining pathogenetic events in blue nevi.	('CYSLTR2', 'Gene', (37, 44))	('mutations', 'Var', (45, 54))	('blue nevi', 'Disease', (113, 122))	('GNAQ', 'Gene', '2776', (11, 15))	('GNA11', 'Gene', (20, 25))	('nevi', 'Phenotype', 'HP:0003764', (118, 122))	('GNA11', 'Gene', '2767', (20, 25))	('GNAQ', 'Gene', (11, 15))	('CYSLTR2', 'Gene', '57105', (37, 44))	('blue nevi', 'Phenotype', 'HP:0100814', (113, 122))
84042	27934878	Blue nevi show a distinct genetic profile from that of epidermal-derived common acquired nevi; the majority of the latter (80-90%) harbor activating BRAF V600E mutations, which are not commonly found in blue nevi.	('nevi', 'Phenotype', 'HP:0003764', (89, 93))	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('V600E', 'Mutation', 'rs113488022', (154, 159))	('Blue nevi', 'Phenotype', 'HP:0100814', (0, 9))	('nevi', 'Phenotype', 'HP:0003764', (5, 9))	('nevi', 'Phenotype', 'HP:0003764', (208, 212))	('activating', 'PosReg', (138, 148))	('V600E', 'Var', (154, 159))	('blue nevi', 'Phenotype', 'HP:0100814', (203, 212))
84043	27934878	Blue nevi harbor highly recurrent activating GNAQ and GNA11 mutations, which are also found in uveal melanoma.	('activating', 'PosReg', (34, 44))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('GNA11', 'Gene', (54, 59))	('GNA11', 'Gene', '2767', (54, 59))	('Blue nevi', 'Disease', (0, 9))	('uveal melanoma', 'Disease', 'MESH:C536494', (95, 109))	('Blue nevi', 'Phenotype', 'HP:0100814', (0, 9))	('nevi', 'Phenotype', 'HP:0003764', (5, 9))	('GNAQ', 'Gene', (45, 49))	('uveal melanoma', 'Phenotype', 'HP:0007716', (95, 109))	('uveal melanoma', 'Disease', (95, 109))	('mutations', 'Var', (60, 69))	('GNAQ', 'Gene', '2776', (45, 49))
84044	27934878	The two activating mutations reported recurrently in blue nevi to date are GNAQ mutations (~55%) and GNA11 mutations (~7%).	('GNA11', 'Gene', '2767', (101, 106))	('GNA11', 'Gene', (101, 106))	('mutations', 'Var', (107, 116))	('nevi', 'Phenotype', 'HP:0003764', (58, 62))	('mutations', 'Var', (80, 89))	('GNAQ', 'Gene', (75, 79))	('blue nevi', 'Phenotype', 'HP:0100814', (53, 62))	('GNAQ', 'Gene', '2776', (75, 79))
84045	27934878	A number of studies have further demonstrated mutations or protein loss of the tumor suppressor BAP1 occurring in malignant blue nevi.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('79', '95'))	('mutations', 'Var', (46, 55))	('tumor', 'Disease', (79, 84))	('BAP1', 'Gene', (96, 100))	('protein', 'Protein', (59, 66))	('blue nevi', 'Phenotype', 'HP:0100814', (124, 133))	('nevi', 'Phenotype', 'HP:0003764', (129, 133))	('loss', 'NegReg', (67, 71))	('malignant blue nevi', 'Disease', (114, 133))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor suppressor', 'biological_process', 'GO:0051726', ('79', '95'))	('BAP1', 'Gene', '8314', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
84046	27934878	In all studies to date, there remain tumors (eg, 35-40% of blue nevi) lacking GNAQ or GNA11 mutations, implying that they harbor other unrecognized activating oncogene mutations.	('GNA11', 'Gene', '2767', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('blue nevi', 'Phenotype', 'HP:0100814', (59, 68))	('GNAQ', 'Gene', (78, 82))	('lacking', 'NegReg', (70, 77))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('nevi', 'Phenotype', 'HP:0003764', (64, 68))	('GNA11', 'Gene', (86, 91))	('GNAQ', 'Gene', '2776', (78, 82))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
84047	27934878	All known gene alterations reported in blue nevus variants to date (GNAQ, GNA11, and BAP1) are also frequently found present in uveal melanomas.	('BAP1', 'Gene', (85, 89))	('GNA11', 'Gene', (74, 79))	('uveal melanomas', 'Disease', 'MESH:C536494', (128, 143))	('GNA11', 'Gene', '2767', (74, 79))	('GNAQ', 'Gene', (68, 72))	('uveal melanoma', 'Phenotype', 'HP:0007716', (128, 142))	('blue nevus', 'Phenotype', 'HP:0100814', (39, 49))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanomas', 'Phenotype', 'HP:0002861', (134, 143))	('uveal melanomas', 'Disease', (128, 143))	('uveal melanomas', 'Phenotype', 'HP:0007716', (128, 143))	('variants', 'Var', (50, 58))	('BAP1', 'Gene', '8314', (85, 89))	('nevus', 'Phenotype', 'HP:0003764', (44, 49))	('GNAQ', 'Gene', '2776', (68, 72))
84048	27934878	Recently, two studies demonstrated rarer mutations in PLCB4 and CYSLTR2 occurring in uveal melanomas lacking GNAQ or GNA11 mutations.	('mutations', 'Var', (41, 50))	('uveal melanomas', 'Disease', (85, 100))	('uveal melanomas', 'Phenotype', 'HP:0007716', (85, 100))	('GNAQ', 'Gene', (109, 113))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('PLCB4', 'Gene', (54, 59))	('CYSLTR2', 'Gene', '57105', (64, 71))	('uveal melanomas', 'Disease', 'MESH:C536494', (85, 100))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('GNAQ', 'Gene', '2776', (109, 113))	('uveal melanoma', 'Phenotype', 'HP:0007716', (85, 99))	('GNA11', 'Gene', '2767', (117, 122))	('GNA11', 'Gene', (117, 122))	('PLCB4', 'Gene', '5332', (54, 59))	('CYSLTR2', 'Gene', (64, 71))
84050	27934878	CYSLTR2 codes for a seven transmembrane receptor (also termed G protein-coupled receptor), which demonstrates increased activation by the L129Q mutation.	('transmembrane', 'cellular_component', 'GO:0016021', ('26', '39'))	('CYSLTR2', 'Gene', '57105', (0, 7))	('CYSLTR2', 'Gene', (0, 7))	('L129Q', 'Var', (138, 143))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('L129Q', 'Mutation', 'p.L129Q', (138, 143))	('increased activation', 'PosReg', (110, 130))	('transmembrane', 'cellular_component', 'GO:0044214', ('26', '39'))
84053	27934878	As mutations in one of the four genes (GNA11, GNAQ, PLCB4, and CYSLTR2) were identified in 96% of tumor samples (131 of 136) it appears likely the majority of relevant activating mutations has been identified.	('PLCB4', 'Gene', (52, 57))	('GNAQ', 'Gene', (46, 50))	('GNA11', 'Gene', (39, 44))	('CYSLTR2', 'Gene', '57105', (63, 70))	('PLCB4', 'Gene', '5332', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('GNA11', 'Gene', '2767', (39, 44))	('GNAQ', 'Gene', '2776', (46, 50))	('CYSLTR2', 'Gene', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('identified', 'Reg', (77, 87))	('tumor', 'Disease', (98, 103))	('mutations', 'Var', (3, 12))
84054	27934878	The goal of our study was to investigate the frequency of activating CYSLTR2 or PLCB4 mutations in blue nevi.	('mutations', 'Var', (86, 95))	('nevi', 'Phenotype', 'HP:0003764', (104, 108))	('blue nevi', 'Disease', (99, 108))	('activating', 'PosReg', (58, 68))	('CYSLTR2', 'Gene', '57105', (69, 76))	('PLCB4', 'Gene', '5332', (80, 85))	('CYSLTR2', 'Gene', (69, 76))	('blue nevi', 'Phenotype', 'HP:0100814', (99, 108))	('PLCB4', 'Gene', (80, 85))
84064	27934878	In line with previous results, the most frequent activating mutations identified were in GNAQ, 59% (54c.626A > T Q209L, 6c.626A > C Q209P, and 1c.548G > A R183Q) and GNA11, 16% (17c.626A > T Q209L) (Figures 1 and 2).	('54c.626A > T Q209L', 'Var', (100, 118))	('GNA11', 'Gene', '2767', (166, 171))	('Q209P', 'Mutation', 'rs1057519742', (132, 137))	('R183Q', 'Mutation', 'rs397514698', (155, 160))	('6c.626A > C Q209P', 'Var', (120, 137))	('GNAQ', 'Gene', '2776', (89, 93))	('1c.548G > A R183Q', 'Var', (143, 160))	('activating', 'PosReg', (49, 59))	('GNAQ', 'Gene', (89, 93))	('Q209L', 'Mutation', 'rs121913492', (191, 196))	('Q209L', 'Mutation', 'rs121913492', (113, 118))	('GNA11', 'Gene', (166, 171))
84065	27934878	One (1%) BRAF (c.1799A > T, V600E) and 3 (3%) NRAS mutations (1c.182A > G Q61R, 1c.181C > A Q61K, and 1c.34G > C G12R) were detected.	('1c.34G > C G12R', 'Var', (102, 117))	('V600E', 'Var', (28, 33))	('1c.181C > A Q61K', 'Var', (80, 96))	('NRAS', 'Gene', (46, 50))	('BRAF', 'Gene', (9, 13))	('Q61K', 'Mutation', 'rs121913254', (92, 96))	('Q61R', 'Mutation', 'rs11554290', (74, 78))	('c.1799A > T', 'Mutation', 'rs113488022', (15, 26))	('NRAS', 'Gene', '4893', (46, 50))	('G12R', 'Mutation', 'rs121913250', (113, 117))	('c.1799A > T', 'Var', (15, 26))	('1c.182A > G Q61R', 'Var', (62, 78))	('V600E', 'Mutation', 'rs113488022', (28, 33))	('BRAF', 'Gene', '673', (9, 13))
84067	27934878	Three tumors (3%) harbored activating CYSLTR2 c.386T > A L129Q mutations (Figure 3, Supplementary Figures 1 and 2).	('activating', 'PosReg', (27, 37))	('CYSLTR2', 'Gene', '57105', (38, 45))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('CYSLTR2', 'Gene', (38, 45))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('L129Q', 'Var', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('L129Q', 'SUBSTITUTION', 'None', (57, 62))
84068	27934878	We analyzed a cohort of blue nevi and found that in addition to previously recognized recurrent activating mutations in GNAQ and GNA11, mutually exclusive activating hotspot mutations in the CYSLTR2 gene occur.	('mutations', 'Var', (107, 116))	('GNA11', 'Gene', '2767', (129, 134))	('GNA11', 'Gene', (129, 134))	('GNAQ', 'Gene', (120, 124))	('CYSLTR2', 'Gene', '57105', (191, 198))	('nevi', 'Phenotype', 'HP:0003764', (29, 33))	('CYSLTR2', 'Gene', (191, 198))	('mutations', 'Var', (174, 183))	('blue nevi', 'Phenotype', 'HP:0100814', (24, 33))	('GNAQ', 'Gene', '2776', (120, 124))
84069	27934878	The mutation type and frequency are essentially identical to the initial report of CYSLTR2 mutations in uveal melanoma, once again underlying the genetic similarities between these two melanocytic tumor entities, affecting different organ systems.	('melanocytic tumor', 'Disease', (185, 202))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('uveal melanoma', 'Disease', (104, 118))	('uveal melanoma', 'Disease', 'MESH:C536494', (104, 118))	('CYSLTR2', 'Gene', '57105', (83, 90))	('CYSLTR2', 'Gene', (83, 90))	('mutations', 'Var', (91, 100))	('melanocytic tumor', 'Disease', 'MESH:D009508', (185, 202))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))
84071	27934878	Frequent Q209L or Q209P mutations with only a rare occurrence of one R183Q mutation is in line with previous data.	('R183Q', 'Mutation', 'rs397514698', (69, 74))	('Q209L', 'Mutation', 'rs121913492', (9, 14))	('Q209P', 'Var', (18, 23))	('Q209P', 'Mutation', 'rs1057519742', (18, 23))	('Q209L', 'Var', (9, 14))
84072	27934878	The frequency of GNA11 mutations with 16% is somewhat higher than the 7.5% frequency (exon 4 and 5 mutations) initially reported in blue nevi.	('blue nevi', 'Phenotype', 'HP:0100814', (132, 141))	('mutations', 'Var', (23, 32))	('GNA11', 'Gene', (17, 22))	('nevi', 'Phenotype', 'HP:0003764', (137, 141))	('GNA11', 'Gene', '2767', (17, 22))
84074	27934878	The ratio of GNAQ to GNA11 mutations in our cohort is 3.7, which is lower than the initial report of 8.4; however, the clear predominance of GNAQ mutations remains well documented.	('mutations', 'Var', (27, 36))	('GNAQ', 'Gene', (13, 17))	('GNAQ', 'Gene', '2776', (141, 145))	('GNA11', 'Gene', (21, 26))	('GNA11', 'Gene', '2767', (21, 26))	('GNAQ', 'Gene', '2776', (13, 17))	('GNAQ', 'Gene', (141, 145))
84075	27934878	Our study identified one BRAF (V600E) and three NRAS (one Q61R, one Q61K, and one G12V) mutations.	('NRAS', 'Gene', '4893', (48, 52))	('Q61K', 'Mutation', 'rs121913254', (68, 72))	('G12V', 'Var', (82, 86))	('V600E', 'Var', (31, 36))	('Q61K', 'Var', (68, 72))	('BRAF', 'Gene', '673', (25, 29))	('G12V', 'Mutation', 'rs121913237', (82, 86))	('Q61R', 'Var', (58, 62))	('V600E', 'Mutation', 'rs113488022', (31, 36))	('BRAF', 'Gene', (25, 29))	('NRAS', 'Gene', (48, 52))	('Q61R', 'Mutation', 'rs11554290', (58, 62))
84076	27934878	BRAF mutations are frequent in acquired nevi, and NRAS mutations in congenital nevi.	('nevi', 'Phenotype', 'HP:0003764', (79, 83))	('mutations', 'Var', (55, 64))	('frequent', 'Reg', (19, 27))	('NRAS', 'Gene', (50, 54))	('mutations', 'Var', (5, 14))	('NRAS', 'Gene', '4893', (50, 54))	('nevi', 'Phenotype', 'HP:0003764', (40, 44))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('acquired nevi', 'Disease', (31, 44))
84079	27934878	Potentially, future studies will be able to further clarify if presence of BRAF or NRAS mutations is clearly associated with an epidermal-derived (acquired or combined type) nevus component, leaving GNAQ, GNA11, and CYSLTR2 mutations as genetic markers of truly dermal-derived blue nevi.	('NRAS', 'Gene', '4893', (83, 87))	('associated', 'Reg', (109, 119))	('CYSLTR2', 'Gene', '57105', (216, 223))	('GNAQ', 'Gene', '2776', (199, 203))	('nevi', 'Phenotype', 'HP:0003764', (282, 286))	('GNA11', 'Gene', '2767', (205, 210))	('CYSLTR2', 'Gene', (216, 223))	('GNA11', 'Gene', (205, 210))	('BRAF', 'Gene', '673', (75, 79))	('mutations', 'Var', (88, 97))	('BRAF', 'Gene', (75, 79))	('GNAQ', 'Gene', (199, 203))	('blue nevi', 'Phenotype', 'HP:0100814', (277, 286))	('nevus', 'Phenotype', 'HP:0003764', (174, 179))	('NRAS', 'Gene', (83, 87))
84080	27934878	The frequency of CYSLTR2 mutations (3%) in our study is identical to that reported in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('mutations', 'Var', (25, 34))	('uveal melanoma', 'Disease', 'MESH:C536494', (86, 100))	('CYSLTR2', 'Gene', (17, 24))	('uveal melanoma', 'Disease', (86, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('CYSLTR2', 'Gene', '57105', (17, 24))
84081	27934878	Additionally, all mutations identified were c.386T > A alterations resulting in a L129Q amino acid change, which has been shown to lead to increased receptor activation and signaling output.	('L129Q', 'Mutation', 'p.L129Q', (82, 87))	('c.386T > A', 'Var', (44, 54))	('signaling output', 'MPA', (173, 189))	('increased', 'PosReg', (139, 148))	('signaling', 'biological_process', 'GO:0023052', ('173', '182'))	('activation', 'PosReg', (158, 168))	('L129Q', 'Var', (82, 87))	('receptor', 'MPA', (149, 157))	('c.386T > A', 'Mutation', 'rs776734905', (44, 54))
84082	27934878	In conjunction with the genetic evidence of CYSLTR2 mutations occurring in a mutually exclusive fashion to other known activating mutations (GNAQ and GNA11) activating the same pathway, this makes a strong case for CYSLTR2 L129Q mutations being bona-fide driver mutations in the pathogenesis of blue nevi as well as uveal melanoma.	('CYSLTR2', 'Gene', (215, 222))	('L129Q', 'Var', (223, 228))	('uveal melanoma', 'Phenotype', 'HP:0007716', (316, 330))	('GNA11', 'Gene', (150, 155))	('GNAQ', 'Gene', '2776', (141, 145))	('CYSLTR2', 'Gene', '57105', (44, 51))	('GNAQ', 'Gene', (141, 145))	('nevi', 'Phenotype', 'HP:0003764', (300, 304))	('L129Q', 'Mutation', 'p.L129Q', (223, 228))	('CYSLTR2', 'Gene', (44, 51))	('blue nevi', 'Disease', (295, 304))	('activating', 'Reg', (157, 167))	('melanoma', 'Phenotype', 'HP:0002861', (322, 330))	('GNA11', 'Gene', '2767', (150, 155))	('blue nevi', 'Phenotype', 'HP:0100814', (295, 304))	('CYSLTR2', 'Gene', '57105', (215, 222))	('mutations', 'Var', (52, 61))	('uveal melanoma', 'Disease', (316, 330))	('uveal melanoma', 'Disease', 'MESH:C536494', (316, 330))	('pathogenesis', 'biological_process', 'GO:0009405', ('279', '291'))
84083	27934878	We identified one PLCB4 D630 mutation using our assay in a cutaneous metastasis of a uveal melanoma (data not shown), but failed to find a PLCB4 D630 mutation in our cohort of blue nevi.	('mutation', 'Var', (29, 37))	('PLCB4', 'Gene', (139, 144))	('PLCB4', 'Gene', '5332', (18, 23))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('blue nevi', 'Phenotype', 'HP:0100814', (176, 185))	('cutaneous metastasis', 'CPA', (59, 79))	('PLCB4', 'Gene', '5332', (139, 144))	('uveal melanoma', 'Phenotype', 'HP:0007716', (85, 99))	('uveal melanoma', 'Disease', 'MESH:C536494', (85, 99))	('PLCB4', 'Gene', (18, 23))	('D630 mutation', 'Var', (24, 37))	('nevi', 'Phenotype', 'HP:0003764', (181, 185))	('uveal melanoma', 'Disease', (85, 99))
84084	27934878	Considering in uveal melanoma, PLCB4 mutations are rare with a frequency of ~ 4%, selection bias may be a factor.	('uveal melanoma', 'Phenotype', 'HP:0007716', (15, 29))	('uveal melanoma', 'Disease', 'MESH:C536494', (15, 29))	('uveal melanoma', 'Disease', (15, 29))	('PLCB4', 'Gene', '5332', (31, 36))	('mutations', 'Var', (37, 46))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('PLCB4', 'Gene', (31, 36))
84085	27934878	Additional studies analyzing considerably larger numbers of tumors will be required before a potential role of activating PLCB4 D630 mutations in blue nevi can be excluded.	('blue nevi', 'Phenotype', 'HP:0100814', (146, 155))	('PLCB4', 'Gene', (122, 127))	('blue nevi', 'Disease', (146, 155))	('D630 mutations', 'Var', (128, 142))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('nevi', 'Phenotype', 'HP:0003764', (151, 155))	('PLCB4', 'Gene', '5332', (122, 127))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
84086	27934878	The frequency of wild-type tumors (harboring neither a mutation in GNAQ, GNA11, PLCB4, or CYSLTR2) in uveal melanoma is ~ 5%.	('GNA11', 'Gene', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('GNAQ', 'Gene', (67, 71))	('GNA11', 'Gene', '2767', (73, 78))	('CYSLTR2', 'Gene', '57105', (90, 97))	('tumors', 'Disease', (27, 33))	('CYSLTR2', 'Gene', (90, 97))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('PLCB4', 'Gene', '5332', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('uveal melanoma', 'Disease', (102, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (102, 116))	('mutation', 'Var', (55, 63))	('GNAQ', 'Gene', '2776', (67, 71))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('PLCB4', 'Gene', (80, 85))
84091	27934878	The three CYSLTR2 mutations we identified in our study occurred in morphologically benign common blue nevi (Figure 3, Supplementary Figures 1 and 2).	('mutations', 'Var', (18, 27))	('CYSLTR2', 'Gene', '57105', (10, 17))	('blue nevi', 'Phenotype', 'HP:0100814', (97, 106))	('CYSLTR2', 'Gene', (10, 17))	('nevi', 'Phenotype', 'HP:0003764', (102, 106))	('common blue nevi', 'Disease', (90, 106))	('common blue', 'Species', '42299', (90, 101))	('occurred', 'Reg', (55, 63))
84096	27934878	Considering the low mutation frequency determined in blue nevi and uveal melanoma, higher numbers of these tumors will need to be analyzed to definitively ascertain the presence of CYLSTR2 mutations in these tumors.	('nevi', 'Phenotype', 'HP:0003764', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('uveal melanoma', 'Disease', (67, 81))	('uveal melanoma', 'Disease', 'MESH:C536494', (67, 81))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumors', 'Disease', (208, 214))	('CYLSTR2', 'Gene', (181, 188))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('blue nevi', 'Phenotype', 'HP:0100814', (53, 62))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('mutations', 'Var', (189, 198))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
84098	27934878	Should CYSLTR2 mutations prove to be of therapeutic value, identifying such a mutation could potentially be of immediate benefit to affected patients.	('CYSLTR2', 'Gene', (7, 14))	('patients', 'Species', '9606', (141, 149))	('mutations', 'Var', (15, 24))	('CYSLTR2', 'Gene', '57105', (7, 14))
84099	27934878	Considering five different oncogene mutations were identified, some of them being rare, a considerably larger tumor cohort will be necessary to allow meaningful statistical analyses.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('mutations', 'Var', (36, 45))	('oncogene', 'Gene', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
84100	27934878	In summary, our findings identify blue nevi as a second tumor type harboring activating mutations in the newly identified CYLSTR2 oncogene.	('blue nevi', 'Phenotype', 'HP:0100814', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('blue nevi', 'Disease', (34, 43))	('tumor', 'Disease', (56, 61))	('mutations', 'Var', (88, 97))	('CYLSTR2', 'Gene', (122, 129))	('nevi', 'Phenotype', 'HP:0003764', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
84102	27934878	CYSLTR2 mutations being mutually exclusive of oncogenic driver GNAQ and GNA11 mutations in blue nevi is additional supportive evidence of this mutation being a bona-fide driver mutation with clear oncogenic potential.	('CYSLTR2', 'Gene', '57105', (0, 7))	('CYSLTR2', 'Gene', (0, 7))	('GNAQ', 'Gene', (63, 67))	('GNAQ', 'Gene', '2776', (63, 67))	('mutations', 'Var', (8, 17))	('mutations', 'Var', (78, 87))	('blue nevi', 'Phenotype', 'HP:0100814', (91, 100))	('GNA11', 'Gene', (72, 77))	('nevi', 'Phenotype', 'HP:0003764', (96, 100))	('GNA11', 'Gene', '2767', (72, 77))
84103	27934878	The genetic evidence suggests that similar to activating GNAQ and GNA11 mutations, CYSLTR2 L129Q mutations may be the only driver mutation present in these tumors and fully sufficient to induce a blue nevus.	('L129Q', 'Mutation', 'p.L129Q', (91, 96))	('blue nevus', 'Disease', (196, 206))	('GNAQ', 'Gene', (57, 61))	('CYSLTR2', 'Gene', '57105', (83, 90))	('GNA11', 'Gene', '2767', (66, 71))	('nevus', 'Phenotype', 'HP:0003764', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('CYSLTR2', 'Gene', (83, 90))	('L129Q mutations', 'Var', (91, 106))	('induce', 'Reg', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('GNA11', 'Gene', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('blue nevus', 'Phenotype', 'HP:0100814', (196, 206))	('GNAQ', 'Gene', '2776', (57, 61))	('tumors', 'Disease', (156, 162))
84188	27128153	Racial and ethnic disparities in uveal melanoma incidence, as well as those intra-racial differences in incidence associated with differences in iris coloration, suggest a possible protective role of increased pigmentation.	('pigmentation', 'biological_process', 'GO:0043473', ('210', '222'))	('uveal melanoma', 'Disease', 'MESH:C536494', (33, 47))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('uveal melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('uveal melanoma', 'Disease', (33, 47))	('differences', 'Var', (130, 141))	('men', 'Species', '9606', (213, 216))	('increased pigmentation', 'Phenotype', 'HP:0000953', (200, 222))
84242	27128153	This syndrome is the result of germline mutations in the BAP1 gene, a tumor suppressor gene found on chromosome 3.	('chromosome', 'cellular_component', 'GO:0005694', ('101', '111'))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', (70, 75))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('result', 'Reg', (21, 27))	('BAP1', 'Gene', '8314', (57, 61))	('germline mutations', 'Var', (31, 49))	('BAP1', 'Gene', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
84246	27128153	Notably, BAP1 mutations can be either germline mutations, resulting in the familial cancer predisposition, or sporadic in the uveal melanoma tumor cells alone.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('familial cancer', 'Disease', 'MESH:D009369', (75, 90))	('resulting in', 'Reg', (58, 70))	('BAP1', 'Gene', '8314', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('uveal melanoma tumor', 'Disease', (126, 146))	('uveal melanoma', 'Phenotype', 'HP:0007716', (126, 140))	('uveal melanoma tumor', 'Disease', 'MESH:C536494', (126, 146))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('familial cancer', 'Disease', (75, 90))
36576	27128153	Either type of recessive BAP1 mutation is unmasked by a loss of chromosome 3.	('BAP1', 'Gene', '8314', (25, 29))	('mutation', 'Var', (30, 38))	('BAP1', 'Gene', (25, 29))	('chromosome', 'cellular_component', 'GO:0005694', ('64', '74'))
84247	27128153	BAP1 mutations have been shown to relate to uveal melanoma metastatic potential and the classification of tumors as higher-risk, class 2 tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('BAP1', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('relate', 'Reg', (34, 40))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('mutations', 'Var', (5, 14))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('BAP1', 'Gene', '8314', (0, 4))	('uveal melanoma', 'Disease', (44, 58))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
84363	22453011	Molecular Testing in Melanoma Melanoma is the deadliest form of skin cancer and is increasing in incidence.	('Melanoma', 'Disease', 'MESH:D008545', (21, 29))	('Melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('Melanoma', 'Disease', 'MESH:D008545', (30, 38))	('Molecular Testing', 'Var', (0, 17))	('skin cancer', 'Disease', (64, 75))	('Melanoma', 'Disease', (21, 29))	('skin cancer', 'Disease', 'MESH:D012878', (64, 75))	('Melanoma', 'Disease', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('skin cancer', 'Phenotype', 'HP:0008069', (64, 75))
84374	22453011	Through genetic and molecular studies, a number of somatic mutations have been identified which play key roles in melanoma pathogenesis, either in the early stages of tumor development, during metastasis, or both.	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('roles', 'Reg', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('pathogenesis', 'biological_process', 'GO:0009405', ('123', '135'))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mutations', 'Var', (59, 68))	('tumor', 'Disease', (167, 172))	('melanoma', 'Disease', (114, 122))
84376	22453011	The identification of mutant BRAF as a factor in melanoma pathogenesis was integral in the development of targeted BRAF inhibition, which has led to improved overall survival for patients with advanced melanoma .	('BRAF', 'Gene', '673', (29, 33))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('BRAF', 'Gene', '673', (115, 119))	('pathogenesis', 'biological_process', 'GO:0009405', ('58', '70'))	('BRAF', 'Gene', (115, 119))	('BRAF', 'Gene', (29, 33))	('improved', 'PosReg', (149, 157))	('inhibition', 'NegReg', (120, 130))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('mutant', 'Var', (22, 28))	('melanoma', 'Disease', (202, 210))	('patients', 'Species', '9606', (179, 187))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
84377	22453011	Continued discovery of genetic mutations in melanoma will allow for the development of specific therapies directed towards individual mutations and for the development of personalized medicine.	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('mutations', 'Var', (31, 40))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))
84382	22453011	Understanding of these genetic underpinnings of melanoma has enabled the development of targeted therapy directed against KIT, MEK 1/2, and mutant BRAF led to a number of mutation driven clinical trials, and most recently, the FDA approval of vemurafenib .	('vemurafenib', 'Chemical', 'MESH:D000077484', (243, 254))	('melanoma', 'Disease', (48, 56))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('MEK 1', 'molecular_function', 'GO:0004708', ('127', '132'))	('MEK 1/2', 'Gene', (127, 134))	('MEK 1/2', 'Gene', '5604;5605', (127, 134))	('KIT', 'molecular_function', 'GO:0005020', ('122', '125'))	('mutant', 'Var', (140, 146))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
84383	22453011	Other genes have both inherited mutations in familial melanoma and somatic changes in sporadic melanoma, such as MITF, CDKN2A and CDK4.	('familial melanoma', 'Disease', 'OMIM:155600', (45, 62))	('MITF', 'Gene', '4286', (113, 117))	('MITF', 'Gene', (113, 117))	('CDK', 'molecular_function', 'GO:0004693', ('130', '133'))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('CDK4', 'Gene', (130, 134))	('melanoma', 'Disease', (95, 103))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Disease', (54, 62))	('CDKN2A', 'Gene', (119, 125))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('mutations', 'Var', (32, 41))	('CDK4', 'Gene', '1019', (130, 134))	('CDKN2A', 'Gene', '1029', (119, 125))	('familial melanoma', 'Disease', (45, 62))
84384	22453011	The roles of some of these mutations have been well defined in melanoma, while others continue to be under study.	('mutations', 'Var', (27, 36))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
84385	22453011	Identification of the array of mutations in patients with melanoma will be useful in determining a genetic profile of the tumor with potential implications for treatment decisions.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('mutations', 'Var', (31, 40))	('patients', 'Species', '9606', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('tumor', 'Disease', (122, 127))	('melanoma', 'Disease', (58, 66))
84386	22453011	Integral to the development of therapies directed against genetic mutations in any cancer, and particularly melanoma, is the reliable identification of these genetic aberrations in tumor samples, both fresh and formalin-fixed paraffin embedded.	('mutations', 'Var', (66, 75))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('formalin', 'Chemical', 'MESH:D005557', (211, 219))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('melanoma', 'Disease', (108, 116))	('genetic mutations', 'Var', (58, 75))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('paraffin', 'Chemical', 'MESH:D010232', (226, 234))	('cancer', 'Disease', (83, 89))
84387	22453011	Moreover, the presence or absence of specific mutations may determine the use of a particular therapy and inclusion and exclusion in a clinical trial specific for patients carrying a known mutation in their melanoma.	('determine', 'Reg', (60, 69))	('patients', 'Species', '9606', (163, 171))	('melanoma', 'Disease', 'MESH:D008545', (207, 215))	('mutations', 'Var', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanoma', 'Disease', (207, 215))	('mutation', 'Var', (189, 197))
84389	22453011	Direct sequencing of DNA from tumor samples can identify all point mutations in a given stretch of DNA.	('point mutations', 'Var', (61, 76))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('tumor', 'Disease', (30, 35))
84390	22453011	Mutations can be detected when the mutant DNA comprises 5% of the total DNA sample, which has been demonstrated to occur even in DNA samples from FFPE tumors .	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('FFPE tumors', 'Disease', 'MESH:D009369', (146, 157))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('mutant', 'Var', (35, 41))	('DNA', 'cellular_component', 'GO:0005574', ('129', '132'))	('Mutations', 'Var', (0, 9))	('FFPE tumors', 'Disease', (146, 157))
84396	22453011	FISH allows for the detection of larger amplifications, deletions, and rearrangements in tumors spanning approximately 100,000 base pairs.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('deletions', 'Var', (56, 65))	('rearrangements', 'Var', (71, 85))
84398	22453011	FISH also is used in solid malignancies as well , mostly recently with clinical identification of ALK rearrangement in lung cancers for determining treatment with the ALK inhibitor crizotinib  and genomic analysis of malignant mesothelioma .	('malignant mesothelioma', 'Disease', (217, 239))	('rearrangement', 'Var', (102, 115))	('malignancies', 'Disease', 'MESH:D009369', (27, 39))	('ALK', 'Gene', (98, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('lung cancers', 'Disease', 'MESH:D008175', (119, 131))	('lung cancers', 'Phenotype', 'HP:0100526', (119, 131))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (217, 239))	('crizotinib', 'Chemical', 'MESH:D000077547', (181, 191))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('malignancies', 'Disease', (27, 39))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (217, 239))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('lung cancers', 'Disease', (119, 131))
84405	22453011	DNA copy number alterations have been shown to be involved in the pathogenesis of a number of human cancers  and may play a role in prediction of progression or clinical outcome of several tumor types .	('play', 'Reg', (117, 121))	('role', 'Reg', (124, 128))	('tumor', 'Disease', (189, 194))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('DNA', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('copy number alterations', 'Var', (4, 27))	('human', 'Species', '9606', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('pathogenesis', 'biological_process', 'GO:0009405', ('66', '78'))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('involved', 'Reg', (50, 58))	('cancers', 'Disease', (100, 107))
84406	22453011	Copy number profiling in melanoma can be performed in order to analyze multiple genomic aberrations in melanoma tumor samples and evaluate distinct genomic changes, including high copy gains and losses of chromosomes or parts of chromosomes, as well as minute gains or losses.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('high copy gains', 'Var', (175, 190))	('losses', 'NegReg', (269, 275))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('losses', 'NegReg', (195, 201))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma tumor', 'Disease', (103, 117))	('melanoma', 'Disease', (25, 33))	('melanoma tumor', 'Disease', 'MESH:D008545', (103, 117))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
84407	22453011	Previous studies have evaluated melanoma cell lines looking for genomic alterations involved in the pathogenesis of melanoma; amplifications have been identified in a number of genes including BRAF, NRAS, MITF, CCND1, MDM2, CCNE1, and NOTCH2, and homozygous deletions were identified in CDKN2A and PTEN .	('NOTCH2', 'Gene', '4853', (235, 241))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('CCND1', 'Gene', (211, 216))	('deletions', 'Var', (258, 267))	('PTEN', 'Gene', (298, 302))	('CCNE1', 'Gene', '898', (224, 229))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('MITF', 'Gene', '4286', (205, 209))	('MDM2', 'Gene', (218, 222))	('CDKN2A', 'Gene', (287, 293))	('amplifications', 'Var', (126, 140))	('NOTCH2', 'Gene', (235, 241))	('PTEN', 'Gene', '5728', (298, 302))	('NRAS', 'Gene', (199, 203))	('MITF', 'Gene', (205, 209))	('MDM2', 'Gene', '4193', (218, 222))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('CDKN2A', 'Gene', '1029', (287, 293))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('pathogenesis', 'biological_process', 'GO:0009405', ('100', '112'))	('BRAF', 'Gene', (193, 197))	('BRAF', 'Gene', '673', (193, 197))	('CCNE1', 'Gene', (224, 229))	('CCND1', 'Gene', '595', (211, 216))	('NRAS', 'Gene', '4893', (199, 203))
84424	22453011	An analysis of 14 metastatic melanoma tumors revealed a number of genes that contained somatic mutations at an elevated frequency, beyond those previously identified.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma tumors', 'Disease', (29, 44))	('melanoma tumors', 'Disease', 'MESH:D008545', (29, 44))	('mutations', 'Var', (95, 104))
84425	22453011	identified a recurrent mutation in TRRAP at position p.S722F, found to be mutated in ~4% (6/167) of the samples, with subsequent functional analysis suggestive of TRRAP functioning as an oncogene.	('p.S722F', 'Var', (53, 60))	('p.S722F', 'Mutation', 'rs147405090', (53, 60))	('TRRAP', 'Gene', '8295', (35, 40))	('TRRAP', 'Gene', (35, 40))	('TRRAP', 'Gene', '8295', (163, 168))	('TRRAP', 'Gene', (163, 168))
84426	22453011	GRIN2A was also found to be mutated in 33% (17/52) of melanoma samples.	('GRIN2A', 'Gene', '2903', (0, 6))	('mutated', 'Var', (28, 35))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('GRIN2A', 'Gene', (0, 6))
84427	22453011	Similar to what had been previously observed, BRAF was found to be mutated in ~50% of tumor samples.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('mutated', 'Var', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
84428	22453011	NRAS mutations were not identified in this set sequencing, but are known to be present in approximately 15%-20% of melanomas .	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('melanomas', 'Disease', 'MESH:D008545', (115, 124))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('mutations', 'Var', (5, 14))	('NRAS', 'Gene', (0, 4))	('melanomas', 'Disease', (115, 124))	('NRAS', 'Gene', '4893', (0, 4))
84429	22453011	Recently, additional exome sequencing of melanoma identified recurrent somatic mutations in MAP2K1 and MAP2K2 .	('MAP2K1', 'Gene', '5604', (92, 98))	('MAP2K', 'molecular_function', 'GO:0004708', ('92', '97'))	('MAP2K2', 'Gene', (103, 109))	('MAP2K1', 'Gene', (92, 98))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('MAP2K', 'molecular_function', 'GO:0004708', ('103', '108'))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('MAP2K2', 'Gene', '5605', (103, 109))	('mutations', 'Var', (79, 88))
84431	22453011	The seven samples analyzed contained either BRAF or NRAS mutations; mutations in homologous codons in MAP2K1 and MAP2K2 were identified in two melanoma samples.	('NRAS', 'Gene', (52, 56))	('BRAF', 'Gene', '673', (44, 48))	('NRAS', 'Gene', '4893', (52, 56))	('BRAF', 'Gene', (44, 48))	('identified', 'Reg', (125, 135))	('MAP2K1', 'Gene', '5604', (102, 108))	('MAP2K', 'molecular_function', 'GO:0004708', ('102', '107'))	('MAP2K', 'molecular_function', 'GO:0004708', ('113', '118'))	('mutations', 'Var', (57, 66))	('MAP2K2', 'Gene', '5605', (113, 119))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('mutations', 'Var', (68, 77))	('MAP2K1', 'Gene', (102, 108))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('MAP2K2', 'Gene', (113, 119))
84432	22453011	Further evaluation revealed mutations in either MAP2K1 or MAP2K2 in 8% of melanoma samples (10/127 samples) .	('MAP2K', 'molecular_function', 'GO:0004708', ('48', '53'))	('MAP2K2', 'Gene', (58, 64))	('MAP2K', 'molecular_function', 'GO:0004708', ('58', '63'))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('MAP2K1', 'Gene', '5604', (48, 54))	('MAP2K2', 'Gene', '5605', (58, 64))	('mutations', 'Var', (28, 37))	('MAP2K1', 'Gene', (48, 54))
84433	22453011	Additional genes, FAT4, DSC1, and LRP1B, were also identified as mutated, but their significance in melanoma is unknown at this time.	('FAT4', 'Gene', (18, 22))	('FAT4', 'Gene', '79633', (18, 22))	('DSC1', 'Gene', '1823', (24, 28))	('DSC1', 'Gene', (24, 28))	('LRP1B', 'Gene', (34, 39))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('LRP1B', 'Gene', '53353', (34, 39))	('mutated', 'Var', (65, 72))
84434	22453011	Genetic information generated identified known mutated genes involved in melanoma pathogenesis and has led to the identification of additional candidate genes which may be involved in melanoma.	('melanoma', 'Disease', (73, 81))	('pathogenesis', 'biological_process', 'GO:0009405', ('82', '94'))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('melanoma', 'Disease', (184, 192))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('mutated', 'Var', (47, 54))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
84447	22453011	It is also quite possible that given the heterogeneous nature of melanoma samples, and in cancer in general, next generation sequencing will identify mutations specific to each patient's melanoma and therefore directly affect therapeutic interventions with small molecules.	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('patient', 'Species', '9606', (177, 184))	('cancer', 'Disease', (90, 96))	('mutations', 'Var', (150, 159))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('affect', 'Reg', (219, 225))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
84449	22453011	Activation of the MAP kinase pathway has been identified as a key player in a number of cancers and is identified to be important in melanoma; a number of activating mutations in the MAP kinase pathway have been found .	('mutations', 'Var', (166, 175))	('MAP', 'molecular_function', 'GO:0004239', ('18', '21'))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('MAP', 'molecular_function', 'GO:0004239', ('183', '186'))	('activating', 'PosReg', (155, 165))	('MAP kinase pathway', 'Pathway', (18, 36))	('cancers', 'Disease', (88, 95))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('MAP kinase pathway', 'Pathway', (183, 201))
84450	22453011	Activating mutations in NRAS have been identified in approximately 15% - 20% of melanoma tumors .	('NRAS', 'Gene', '4893', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('melanoma tumors', 'Disease', (80, 95))	('Activating mutations', 'Var', (0, 20))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma tumors', 'Disease', 'MESH:D008545', (80, 95))	('identified', 'Reg', (39, 49))	('NRAS', 'Gene', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
84451	22453011	The most common NRAS mutations are in exon 2 at codon 61, specifically Q61L (leucine substitution for glutamine) , although other amino acid changes also are observed (ie, Q61R, Q61H) .	('Q61R', 'Mutation', 'rs11554290', (172, 176))	('Q61H', 'Var', (178, 182))	('NRAS', 'Gene', (16, 20))	('Q61L', 'Mutation', 'rs11554290', (71, 75))	('Q61L', 'Var', (71, 75))	('glutamine', 'Chemical', 'MESH:D005973', (102, 111))	('NRAS', 'Gene', '4893', (16, 20))	('Q61H', 'Mutation', 'rs121913255', (178, 182))	('Q61R', 'Var', (172, 176))	('leucine', 'Chemical', 'MESH:D007930', (77, 84))
84452	22453011	NRAS mutations also are observed in exon 1 at codons 12 and 13 .	('NRAS', 'Gene', '4893', (0, 4))	('NRAS', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
84453	22453011	A recent meta-analysis was performed looking at the presence of NRAS mutations in melanoma tumor samples and found it to be associated with nodular melanomas and melanomas at sites of chronic sun-damaged skin .	('melanomas', 'Disease', 'MESH:D008545', (162, 171))	('sun-damage', 'Phenotype', 'HP:0000992', (192, 202))	('melanomas', 'Disease', (162, 171))	('melanoma tumor', 'Disease', 'MESH:D008545', (82, 96))	('nodular melanomas', 'Disease', (140, 157))	('melanomas', 'Phenotype', 'HP:0002861', (148, 157))	('NRAS', 'Gene', (64, 68))	('nodular melanomas', 'Phenotype', 'HP:0012058', (140, 157))	('melanomas', 'Phenotype', 'HP:0002861', (162, 171))	('mutations', 'Var', (69, 78))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma tumor', 'Disease', (82, 96))	('associated', 'Reg', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('melanomas', 'Disease', 'MESH:D008545', (148, 157))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('nodular melanomas', 'Disease', 'MESH:D020518', (140, 157))	('melanomas', 'Disease', (148, 157))	('sun-damaged', 'Phenotype', 'HP:0000992', (192, 203))	('NRAS', 'Gene', '4893', (64, 68))
84454	22453011	Moreover, NRAS mutations were associated with thicker tumor samples, increased mitotic rate, and demonstrated a worse clinical outcome compared to patients with BRAF V600E mutations or without NRAS or BRAF mutations .	('NRAS', 'Gene', '4893', (10, 14))	('NRAS', 'Gene', (193, 197))	('increased', 'PosReg', (69, 78))	('BRAF', 'Gene', '673', (201, 205))	('mutations', 'Var', (15, 24))	('NRAS', 'Gene', '4893', (193, 197))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('BRAF', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (161, 165))	('mitotic rate', 'CPA', (79, 91))	('patients', 'Species', '9606', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('NRAS', 'Gene', (10, 14))	('V600E', 'Mutation', 'rs113488022', (166, 171))	('BRAF', 'Gene', (201, 205))
84456	22453011	BRAF has been found to be mutated in 40% to 60% of melanoma samples, with the most common BRAF mutation at codon 600, resulting in the substitution of glutamic acid for valine (V600E mutation) .	('BRAF', 'Gene', (90, 94))	('glutamic acid', 'MPA', (151, 164))	('valine', 'Chemical', 'MESH:D014633', (169, 175))	('V600E', 'Mutation', 'rs113488022', (177, 182))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (90, 94))	('melanoma', 'Disease', (51, 59))	('glutamic acid', 'Chemical', 'MESH:D018698', (151, 164))	('mutation', 'Var', (95, 103))
84459	22453011	Occasionally, mutations have been identified in BRAF in the loop domain (exon 11) .	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('mutations', 'Var', (14, 23))
84460	22453011	Interestingly, BRAF has also been shown to be mutated in a significant percentage of benign nevi .	('BRAF', 'Gene', '673', (15, 19))	('BRAF', 'Gene', (15, 19))	('benign nevi', 'Disease', (85, 96))	('mutated', 'Var', (46, 53))	('nevi', 'Phenotype', 'HP:0003764', (92, 96))
84461	22453011	Out of 77 benign nevi that were evaluated, 63 (82%) contained BRAF mutations, suggesting they are an early event in the progression to melanoma .	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('mutations', 'Var', (67, 76))	('contained', 'Reg', (52, 61))	('BRAF', 'Gene', (62, 66))	('BRAF', 'Gene', '673', (62, 66))	('nevi', 'Phenotype', 'HP:0003764', (17, 21))
84462	22453011	While BRAF and NRAS mutations are the most common mutations in melanoma and both result in activation of the MAPK signaling pathway, these two mutations are generally mutually exclusive.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('activation', 'PosReg', (91, 101))	('NRAS', 'Gene', (15, 19))	('MAPK', 'Gene', (109, 113))	('MAPK signaling', 'biological_process', 'GO:0000165', ('109', '123'))	('NRAS', 'Gene', '4893', (15, 19))	('BRAF', 'Gene', '673', (6, 10))	('signaling pathway', 'biological_process', 'GO:0007165', ('114', '131'))	('BRAF', 'Gene', (6, 10))	('MAPK', 'molecular_function', 'GO:0004707', ('109', '113'))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('mutations', 'Var', (20, 29))	('melanoma', 'Disease', (63, 71))	('MAPK', 'Gene', '26413', (109, 113))
84463	22453011	Vemurafenib, a targeted therapy directed against V600-mutant BRAF, was recently approved by the FDA to treat advanced stage melanoma with a known V600E mutation , providing a specific example of how identifying a specific somatic mutation in melanoma tumors has led to direct targeted therapy that has also demonstrated a significant clinical benefit.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('stage melanoma', 'Disease', (118, 132))	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('V600E', 'Var', (146, 151))	('V600-mutant', 'Var', (49, 60))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('melanoma tumors', 'Disease', (242, 257))	('BRAF', 'Gene', '673', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('BRAF', 'Gene', (61, 65))	('stage melanoma', 'Disease', 'MESH:D008545', (118, 132))	('melanoma tumors', 'Disease', 'MESH:D008545', (242, 257))	('V600E', 'Mutation', 'rs113488022', (146, 151))
84464	22453011	As this therapy is directed against this specific mutation, molecular testing of tumor samples is required in order to determine the presence or absence of this mutation.	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('mutation', 'Var', (50, 58))
84466	22453011	The cobas  test is a real-time PCR assay which uses TaqMan probes that are labeled with different fluorescent tags which bind to wild-type and V600E mutant BRAF sequences, and are detected when they match to the correct sequence, and a second set of primers for DNA amplification.	('V600E', 'Var', (143, 148))	('BRAF', 'Gene', (156, 160))	('bind', 'Interaction', (121, 125))	('DNA amplification', 'biological_process', 'GO:0006277', ('262', '279'))	('DNA', 'cellular_component', 'GO:0005574', ('262', '265'))	('V600E', 'Mutation', 'rs113488022', (143, 148))	('mers', 'Species', '1335626', (253, 257))	('BRAF', 'Gene', '673', (156, 160))
84467	22453011	This test is also limited in its detection of non-V600E BRAF mutations (package insert).	('BRAF', 'Gene', '673', (56, 60))	('non-V600E', 'Var', (46, 55))	('V600E', 'Mutation', 'rs113488022', (50, 55))	('BRAF', 'Gene', (56, 60))
84468	22453011	It demonstrates a 66% cross-sensitivity for BRAF V600K mutations.	('V600K', 'Var', (49, 54))	('V600K', 'Mutation', 'rs121913227', (49, 54))	('BRAF', 'Gene', (44, 48))	('BRAF', 'Gene', '673', (44, 48))
84473	22453011	Analysis of 102 primary melanomas from mucosa, acral skin, chronic sun-damaged skin and skin without chronic sun-damage by aCGH demonstrated somatic mutations and/or increased copy number of KIT in close to 30% of each melanoma tumor type (except those arising from areas of skin without chronic sun-damage) and this corresponded with increased KIT expression .	('KIT expression', 'MPA', (345, 359))	('melanoma tumor', 'Disease', (219, 233))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('copy', 'MPA', (176, 180))	('melanomas', 'Disease', 'MESH:D008545', (24, 33))	('KIT', 'molecular_function', 'GO:0005020', ('345', '348'))	('mutations', 'Var', (149, 158))	('KIT', 'molecular_function', 'GO:0005020', ('191', '194'))	('sun-damaged', 'Phenotype', 'HP:0000992', (67, 78))	('melanomas', 'Disease', (24, 33))	('sun-damage', 'Phenotype', 'HP:0000992', (109, 119))	('KIT', 'Gene', (191, 194))	('melanoma tumor', 'Disease', 'MESH:D008545', (219, 233))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('increased', 'PosReg', (335, 344))	('sun-damage', 'Phenotype', 'HP:0000992', (67, 77))	('increased', 'PosReg', (166, 175))	('melanomas', 'Phenotype', 'HP:0002861', (24, 33))	('sun-damage', 'Phenotype', 'HP:0000992', (296, 306))
84474	22453011	Imatinib, which inhibits the tyrosine kinase activity of c-KIT and PDGFR, has been shown to be effective in the treatment of other tumors, including gastrointestinal stromal tumors, where KIT has been amplified or mutated , so it is not unreasonable to expect a response in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (274, 282))	('tyrosine kinase activity', 'MPA', (29, 53))	('mutated', 'Var', (214, 221))	('inhibits', 'NegReg', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Disease', (174, 180))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (149, 180))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (149, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('KIT', 'molecular_function', 'GO:0005020', ('59', '62'))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('melanoma', 'Phenotype', 'HP:0002861', (274, 282))	('melanoma', 'Disease', (274, 282))	('tumors', 'Disease', (131, 137))	('c-KIT', 'Gene', (57, 62))	('kinase activity', 'molecular_function', 'GO:0016301', ('38', '53'))	('c-KIT', 'Gene', '3815', (57, 62))	('gastrointestinal stromal tumors', 'Disease', (149, 180))	('KIT', 'molecular_function', 'GO:0005020', ('188', '191'))	('PDGFR', 'Gene', (67, 72))	('PDGFR', 'Gene', '5159', (67, 72))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
84476	22453011	Emerging data, however, indicates that not all mutations may result in functional dependence upon c-KIT, or at least correspond with sensitivity to KIT inhibitors  PTEN is a tumor suppressor gene found on chromosome 10q23 and functions as a lipid phosphatase, regulating the PI3K pathway.	('tumor', 'Disease', (174, 179))	('c-KIT', 'Gene', '3815', (98, 103))	('KIT', 'molecular_function', 'GO:0005020', ('148', '151'))	('regulating', 'Reg', (260, 270))	('tumor suppressor', 'biological_process', 'GO:0051726', ('174', '190'))	('phosphatase', 'molecular_function', 'GO:0016791', ('247', '258'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('174', '190'))	('mutations', 'Var', (47, 56))	('KIT', 'molecular_function', 'GO:0005020', ('100', '103'))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('PI3K', 'molecular_function', 'GO:0016303', ('275', '279'))	('chromosome', 'cellular_component', 'GO:0005694', ('205', '215'))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('PTEN', 'Gene', (164, 168))	('PI3K pathway', 'Pathway', (275, 287))	('c-KIT', 'Gene', (98, 103))	('PTEN', 'Gene', '5728', (164, 168))
84479	22453011	PTEN mutations have been identified in a number of tumors in addition to melanoma, such as breast and prostate cancer , and when involved mutated in the germline, is associated with autosomal dominant inherited PTEN hamartomatous syndrome (formerly known as Cowden disease and Bannayan-Riley-Ruvalcaba ).	('melanoma', 'Disease', (73, 81))	('PTEN hamartomatous syndrome', 'Phenotype', 'HP:0004390', (211, 238))	('PTEN', 'Gene', (211, 215))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (91, 117))	('identified', 'Reg', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('PTEN', 'Gene', '5728', (211, 215))	('associated', 'Reg', (166, 176))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('Cowden disease', 'Disease', (258, 272))	('mutations', 'Var', (5, 14))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('PTEN', 'Gene', (0, 4))	('prostate cancer', 'Phenotype', 'HP:0012125', (102, 117))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Cowden disease', 'Disease', 'MESH:D006223', (258, 272))	('tumors', 'Disease', (51, 57))	('autosomal dominant inherited PTEN hamartomatous syndrome', 'Disease', 'MESH:D006223', (182, 238))	('PTEN', 'Gene', '5728', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
84480	22453011	PTEN mutations and loss have been observed to principally co-exist with BRAF mutations .	('BRAF', 'Gene', (72, 76))	('loss', 'NegReg', (19, 23))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (72, 76))	('mutations', 'Var', (77, 86))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
84482	22453011	In melanoma, PTEN mutations include missense mutations, deletions, and insertions , as well as LOH and epigenetic silencing making interrogation for mutations and genomic rearrangements in PTEN necessary .	('PTEN', 'Gene', (189, 193))	('PTEN', 'Gene', '5728', (189, 193))	('missense mutations', 'Var', (36, 54))	('insertions', 'Var', (71, 81))	('epigenetic silencing', 'Var', (103, 123))	('PTEN', 'Gene', '5728', (13, 17))	('deletions', 'Var', (56, 65))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('PTEN', 'Gene', (13, 17))	('melanoma', 'Disease', (3, 11))	('LOH', 'Var', (95, 98))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('mutations', 'Var', (18, 27))
84484	22453011	While BRAF and NRAS mutations have been shown to play an integral role in cutaneous melanomas, they are not involved in the pathogenesis of uveal melanoma .	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('cutaneous melanomas', 'Disease', (74, 93))	('pathogenesis', 'biological_process', 'GO:0009405', ('124', '136'))	('NRAS', 'Gene', (15, 19))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('uveal melanoma', 'Phenotype', 'HP:0007716', (140, 154))	('NRAS', 'Gene', '4893', (15, 19))	('BRAF', 'Gene', '673', (6, 10))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (74, 92))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (74, 93))	('uveal melanoma', 'Disease', (140, 154))	('BRAF', 'Gene', (6, 10))	('uveal melanoma', 'Disease', 'MESH:C536494', (140, 154))	('mutations', 'Var', (20, 29))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (74, 93))
84485	22453011	Mutations affecting the pathogenesis of uveal melanomas have been identified in GNAQ and GNA11.	('uveal melanomas', 'Disease', (40, 55))	('uveal melanomas', 'Phenotype', 'HP:0007716', (40, 55))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('pathogenesis', 'biological_process', 'GO:0009405', ('24', '36'))	('uveal melanomas', 'Disease', 'MESH:C536494', (40, 55))	('GNAQ', 'Gene', '2776', (80, 84))	('uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))	('Mutations', 'Var', (0, 9))	('GNA11', 'Gene', (89, 94))	('GNAQ', 'Gene', (80, 84))
84488	22453011	The most frequent observed mutation was in exon 5 (Q209) in both genes and was observed in blue nevi, primary uveal melanoma, and uveal melanoma metastases .	('uveal melanoma', 'Phenotype', 'HP:0007716', (110, 124))	('uveal melanoma', 'Disease', (110, 124))	('uveal melanoma', 'Disease', 'MESH:C536494', (110, 124))	('uveal melanoma metastases', 'Disease', (130, 155))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('Q209', 'Var', (51, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (130, 144))	('uveal melanoma', 'Phenotype', 'HP:0007716', (130, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('blue nevi', 'Phenotype', 'HP:0100814', (91, 100))	('observed', 'Reg', (79, 87))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (130, 155))	('nevi', 'Phenotype', 'HP:0003764', (96, 100))	('blue nevi', 'Disease', (91, 100))
84489	22453011	Additional mutations in GNAQ and GNA11 were also identified in blue nevi and uveal melanoma, but not to the extent as the Q209 mutation.	('mutations', 'Var', (11, 20))	('GNAQ', 'Gene', '2776', (24, 28))	('GNA11', 'Gene', (33, 38))	('blue nevi', 'Phenotype', 'HP:0100814', (63, 72))	('identified', 'Reg', (49, 59))	('blue nevi', 'Disease', (63, 72))	('uveal melanoma', 'Disease', 'MESH:C536494', (77, 91))	('GNAQ', 'Gene', (24, 28))	('uveal melanoma', 'Phenotype', 'HP:0007716', (77, 91))	('uveal melanoma', 'Disease', (77, 91))	('nevi', 'Phenotype', 'HP:0003764', (68, 72))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
84490	22453011	GNAQ Q209 transfection into melanocytes resulted in increased anchorage independent growth and when injected into mice, increased tumorigenicty was observed .	('increased', 'PosReg', (52, 61))	('GNAQ', 'Gene', '2776', (0, 4))	('Q209 transfection', 'Var', (5, 22))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('anchorage independent growth', 'CPA', (62, 90))	('GNAQ', 'Gene', (0, 4))	('transfection', 'Var', (10, 22))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mice', 'Species', '10090', (114, 118))	('tumor', 'Disease', (130, 135))
84491	22453011	The GNA11 Q209 mutation increased oncogenic potential when injected into mice and cells transduced with this variant demonstrated increased MAP kinase activation, evident through increased ERK phosphorylation .	('ERK', 'molecular_function', 'GO:0004707', ('189', '192'))	('MAP', 'molecular_function', 'GO:0004239', ('140', '143'))	('oncogenic potential', 'CPA', (34, 53))	('ERK', 'Gene', '26413', (189, 192))	('mice', 'Species', '10090', (73, 77))	('phosphorylation', 'biological_process', 'GO:0016310', ('193', '208'))	('GNA11', 'Gene', (4, 9))	('MAP kinase', 'Enzyme', (140, 150))	('Q209', 'Var', (10, 14))	('increased', 'PosReg', (130, 139))	('increased', 'PosReg', (179, 188))	('activation', 'PosReg', (151, 161))	('increased', 'PosReg', (24, 33))	('ERK', 'Gene', (189, 192))
84493	22453011	A number of genetic mutations have been identified to play a role in both familial and spontaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('familial', 'Disease', (74, 82))	('mutations', 'Var', (20, 29))
84497	23125934	Diagnostic Role of Chromosomal Instability in Melanoma Early diagnosis gives melanoma patients the best chance for long term survival.	('Melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('Chromosomal Instability', 'Var', (19, 42))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('Melanoma', 'Disease', 'MESH:D008545', (46, 54))	('Chromosomal Instability', 'Phenotype', 'HP:0040012', (19, 42))	('Melanoma', 'Disease', (46, 54))	('patients', 'Species', '9606', (86, 94))
84505	23125934	Just as overdiagnosis causes problems, underdiagnosis creates the obvious issue of leaving an aggressive cancer untreated.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('underdiagnosis', 'Var', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
84516	23125934	While some chromosomal rearrangements are detrimental to cells, leading to their death, others can be advantageous due to deregulation of gene expression, amplification of oncogenes, and deletion of tumor suppressor genes.	('oncogenes', 'Protein', (172, 181))	('deletion', 'Var', (187, 195))	('tumor', 'Disease', (199, 204))	('amplification', 'Var', (155, 168))	('death', 'Disease', 'MESH:D003643', (81, 86))	('tumor suppressor', 'biological_process', 'GO:0051726', ('199', '215'))	('death', 'Disease', (81, 86))	('leading', 'Reg', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('gene expression', 'biological_process', 'GO:0010467', ('138', '153'))	('deregulation', 'MPA', (122, 134))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('gene expression', 'MPA', (138, 153))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('199', '215'))
84521	23125934	CGH uses DNA extracted from the tumor and hybridizes it to a DNA array allowing for detection and fine mapping of amplifications/deletions of genomic DNA segments.	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('amplifications/deletions', 'Var', (114, 138))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('DNA', 'cellular_component', 'GO:0005574', ('150', '153'))	('tumor', 'Disease', (32, 37))
84522	23125934	CGH revealed that 96% of melanomas exhibited chromosomal aberrations.	('melanomas', 'Disease', 'MESH:D008545', (25, 34))	('exhibited', 'Reg', (35, 44))	('chromosomal aberrations', 'Var', (45, 68))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (45, 68))	('melanomas', 'Disease', (25, 34))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanomas', 'Phenotype', 'HP:0002861', (25, 34))
84531	23125934	The 11p changes amplify DNA that includes the HRAS gene, which has also been found to be specifically mutated in Spitz nevi.	('changes', 'Var', (8, 15))	('Spitz nevi', 'Disease', (113, 123))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('HRAS', 'Disease', 'None', (46, 50))	('amplify', 'Reg', (16, 23))	('HRAS', 'Disease', (46, 50))	('nevi', 'Phenotype', 'HP:0003764', (119, 123))
84532	23125934	The aberrations noted on 11p in Spitz nevi may represent an initiating event that is propagated as the tumor grows.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('aberrations', 'Var', (4, 15))	('tumor', 'Disease', (103, 108))	('Spitz nevi', 'Disease', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('nevi', 'Phenotype', 'HP:0003764', (38, 42))
84541	23125934	Examination of this region revealed amplifications and mutations of KIT, a gene critically involved in the homeostatic pathways of human cutaneous melanocytes.	('KIT', 'Gene', (68, 71))	('KIT', 'molecular_function', 'GO:0005020', ('68', '71'))	('human', 'Species', '9606', (131, 136))	('mutations', 'Var', (55, 64))
84543	23125934	At this point it is not entirely clear if the state of cellular differentiation, the type of underlying mutations or the local environment in which the tumor develops has the greatest impact on the differences seen in the chromosomal changes.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutations', 'Var', (104, 113))	('tumor', 'Disease', (152, 157))
84547	23125934	This suggests that loss of 9p21 may be a cytogenetic marker for nevi with high potential to progress to melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('nevi', 'Disease', (64, 68))	('loss of', 'Var', (19, 26))	('nevi', 'Phenotype', 'HP:0003764', (64, 68))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
84548	23125934	Thus these findings suggest that the patterns of chromosomal aberrations in melanocytic lesions have potential diagnostic and prognostic value.	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (49, 72))	('melanocytic lesions', 'Disease', 'MESH:D009508', (76, 95))	('melanocytic lesions', 'Disease', (76, 95))	('chromosomal aberrations', 'Var', (49, 72))
84558	23125934	However, CGH did reveal significantly more chromosomal aberrations in the melanocytic lesions that developed metastasis.	('melanocytic lesions', 'Disease', 'MESH:D009508', (74, 93))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (43, 66))	('melanocytic lesions', 'Disease', (74, 93))	('chromosomal aberrations', 'Var', (43, 66))
84559	23125934	Using alpha-satellite DNA probes, D18Z1, DXZ1, and DYZ3, they were able to detect tetraploidy in all of their melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('D18Z1', 'Var', (34, 39))	('melanomas', 'Disease', 'MESH:D008545', (110, 119))	('detect', 'Reg', (75, 81))	('tetraploidy', 'Var', (82, 93))	('melanomas', 'Disease', (110, 119))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))
84565	23125934	Sixteen (48%) of those tumors were found to have genetic imbalances and 14 (88%) of those patients had died by the end of the study.	('imbalances', 'Phenotype', 'HP:0002172', (57, 67))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('genetic imbalances', 'Var', (49, 67))	('patients', 'Species', '9606', (90, 98))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
84574	23125934	Nevertheless, current technologies detecting differences in CIN have diagnostic value and as the technologies continue to improve, they have the potential to eventually surpass the accuracy of standard histopathologic diagnosis.	('CIN', 'Phenotype', 'HP:0040012', (60, 63))	('differences', 'Var', (45, 56))	('CIN', 'Disease', 'MESH:D007674', (60, 63))	('CIN', 'Disease', (60, 63))
84592	22207316	For example, the mutated BRAF, which is detected in up to 62% of cutaneous melanoma and represents a novel target molecule, is rarely found in ocular melanoma.	('ocular melanoma', 'Disease', 'MESH:D008545', (143, 158))	('cutaneous melanoma', 'Disease', (65, 83))	('ocular melanoma', 'Phenotype', 'HP:0007716', (143, 158))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (65, 83))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (65, 83))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('BRAF', 'Gene', '673', (25, 29))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('BRAF', 'Gene', (25, 29))	('mutated', 'Var', (17, 24))	('ocular melanoma', 'Disease', (143, 158))
84614	22207316	Melanoma cell lines were established in vitro from surgically resectable tumor lesions from both cutaneous (#1061, 1067, 2710, 4478D, 49318, 0342, 25368 and 7 mel) and ocular (#2130, 4330, 4022, 1141, 37165, 48409 and 15765) melanoma patients.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('49318', 'Var', (134, 139))	('melanoma', 'Disease', 'MESH:D008545', (225, 233))	('2710', 'Var', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Melanoma', 'Disease', (0, 8))	('melanoma', 'Disease', (225, 233))	('4478D', 'Var', (127, 132))	('#2130', 'Var', (176, 181))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('#1061', 'Var', (108, 113))	('tumor', 'Disease', (73, 78))	('patients', 'Species', '9606', (234, 242))	('37165', 'Var', (201, 206))
84624	22207316	The monoclonal antibodies (mAbs) used were directed against the following antigens: anti-CD3, anti-CD4, anti-CD25 and anti-CD163 (Novocastra), anti-CD8 (DB Biotech), anti-FOXP3 (CNIO Madrid), anti-GATA3 (Becton-Dickinson; BD Biosciences, San Jose, CA, USA) and anti-T-Bet (Santa Cruz Biotechnology, Inc.).	('CD8', 'Gene', '925', (148, 151))	('CD25', 'Gene', (109, 113))	('FOXP3', 'Gene', '50943', (171, 176))	('CD163', 'Gene', '9332', (123, 128))	('CD25', 'Gene', '3559', (109, 113))	('GATA3', 'Gene', (197, 202))	('CD163', 'Gene', (123, 128))	('anti-CD3', 'Var', (84, 92))	('CD8', 'Gene', (148, 151))	('CD4', 'Gene', (99, 102))	('GATA3', 'Gene', '2625', (197, 202))	('FOXP3', 'Gene', (171, 176))	('CD4', 'Gene', '920', (99, 102))
84638	22207316	The specificity of T-cell recognition was determined by the inhibition of the IFN-gamma release after pre-incubation of target cells with the W6/32 (anti-HLA class I) or L243 (anti-HLA class II DR molecules) mAbs (ATCC).	('inhibition', 'NegReg', (60, 70))	('L243', 'Var', (170, 174))	('IFN-gamma', 'Gene', '3458', (78, 87))	('IFN-gamma', 'Gene', (78, 87))	('pre', 'molecular_function', 'GO:0003904', ('102', '105'))	('cell recognition', 'biological_process', 'GO:0008037', ('21', '37'))
84661	22207316	2, T lymphocytes maintained in culture with IL-2 and IL-15 released the highest amount of IFN-gamma (n. 337 spots/5,000 cells) after the incubation with the autologous tumor cells (#2710 mel) (Fig.	('IL-2', 'molecular_function', 'GO:0005134', ('44', '48'))	('tumor', 'Disease', (168, 173))	('IL-15', 'Gene', '3600', (53, 58))	('IFN-gamma', 'Gene', '3458', (90, 99))	('IFN-gamma', 'Gene', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('IL-15', 'molecular_function', 'GO:0016170', ('53', '58'))	('#2710 mel', 'Var', (181, 190))	('IL-2', 'Gene', '3558', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('IL-2', 'Gene', (44, 48))	('IL-15', 'Gene', (53, 58))
84663	22207316	Specific inhibition of IFN-gamma release was observed after pre-incubation of the autologous tumor cells with the anti-HLA class I mAb (W6/32), not with the anti-HLA class II (L243) mAb (Fig.	('inhibition', 'NegReg', (9, 19))	('anti-HLA', 'Var', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('IFN-gamma', 'Gene', '3458', (23, 32))	('IFN-gamma', 'Gene', (23, 32))	('pre', 'molecular_function', 'GO:0003904', ('60', '63'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
84673	22207316	Independent MLTC cultures were set up from PBMCs isolated from 6 metastatic cutaneous melanoma patients (#2710, 4478D, JOFR-IA, DAJU, 0342 and 7).	('MLTC', 'Chemical', '-', (12, 16))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('patients', 'Species', '9606', (95, 103))	('cutaneous melanoma', 'Disease', (76, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (76, 94))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (76, 94))	('#2710', 'Var', (105, 110))
84678	22207316	These T lymphocytes exhibit specific recognition of the autologous tumor lines (285 spots/5,000 cells for #2710 Fig.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('285', 'Var', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
84679	22207316	Instead, low inhibition (26% for #2710) of IFN-gamma release was found in the presence of the anti-MHC class II (L243) mAb (Fig.	('IFN-gamma', 'Gene', '3458', (43, 52))	('IFN-gamma', 'Gene', (43, 52))	('MHC', 'Gene', (99, 102))	('L243', 'Var', (113, 117))	('MHC', 'Gene', '3107', (99, 102))
84694	22207316	We could also isolate CD4+ T cells specifically directed against the autologous tumor (#15765) as shown by the inhibition of IFN-gamma release by L243 mAb in MLTC1 (Figure 1S Panel B of supplementary results).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('IFN-gamma', 'Gene', '3458', (125, 134))	('IFN-gamma', 'Gene', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('L243 mAb', 'Var', (146, 154))	('tumor', 'Disease', (80, 85))	('MLTC', 'Chemical', '-', (158, 162))	('CD4', 'Gene', (22, 25))	('MLTC1', 'Gene', (158, 163))	('CD4', 'Gene', '920', (22, 25))	('inhibition', 'NegReg', (111, 121))
84703	22207316	These T-cell cultures expressed, though to a variable extent (20-40% of positive cells), some co-stimulatory receptors such as CD28, NKG2D, OX40 (CD134), 4-1BB (CD137), while CD27 was found positive only in 3/6 patients (4478D, JOFR-IA and DAJU; representative data are shown in Fig.	('JOFR-IA', 'Disease', (228, 235))	('OX40', 'Gene', '7293', (140, 144))	('4-1BB', 'Gene', (154, 159))	('patients', 'Species', '9606', (211, 219))	('OX40', 'Gene', (140, 144))	('CD28', 'Gene', (127, 131))	('CD27', 'Gene', '939', (175, 179))	('CD27', 'Gene', (175, 179))	('NKG2D', 'Gene', '22914', (133, 138))	('CD28', 'Gene', '940', (127, 131))	('CD137', 'Gene', (161, 166))	('4-1BB', 'Gene', '3604', (154, 159))	('CD134', 'Gene', (146, 151))	('4478D', 'Var', (221, 226))	('CD137', 'Gene', '3604', (161, 166))	('CD134', 'Gene', '7293', (146, 151))	('NKG2D', 'Gene', (133, 138))
84712	22207316	Initially, we isolated TILs from 5 metastatic cutaneous melanoma (3 subcutaneous lesions #4478D, 9476, 25368 and 2 lymph node lesions #3681 and 4931, respectively) and from 4 ocular melanoma (3 primary #3470, 1141, 4022 and one metastatic #15765) patients.	('ocular melanoma', 'Disease', 'MESH:D008545', (175, 190))	('ocular melanoma', 'Disease', (175, 190))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('ocular melanoma', 'Phenotype', 'HP:0007716', (175, 190))	('subcutaneous lesions', 'Phenotype', 'HP:0001482', (68, 88))	('patients', 'Species', '9606', (247, 255))	('cutaneous melanoma', 'Disease', (46, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('9476', 'Var', (97, 101))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (46, 64))
84713	22207316	6 (cutaneous melanoma patients # 3681, 4931, 9476 and 25368, panels A, B and C and primary ocular melanoma patients #3470, 1141 and 4022, panels D, E and F).	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('4931', 'Var', (39, 43))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('ocular melanoma', 'Phenotype', 'HP:0007716', (91, 106))	('cutaneous melanoma', 'Disease', (3, 21))	('patients', 'Species', '9606', (22, 30))	('9476', 'Var', (45, 49))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('ocular melanoma', 'Disease', (91, 106))	('ocular melanoma', 'Disease', 'MESH:D008545', (91, 106))	('patients', 'Species', '9606', (107, 115))	('#3470', 'Var', (116, 121))
84719	22207316	All T cells expressed homogeneously CD45RO (data not shown) and high levels of CD28 (40-94% of positive cells; Panels B and E), while CD27 was detected only in TILs from two cutaneous melanoma patients (#25368 and #9476, 39 and 46% of CD8+ T cells, respectively; panel B) and in CD8+ lymphocytes from one ocular melanoma patient (# 3470, 24% of CD8+ T cells; panel E).	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('CD8', 'Gene', (235, 238))	('cutaneous melanoma', 'Disease', (174, 192))	('CD8', 'Gene', (345, 348))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (174, 192))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (174, 192))	('ocular melanoma', 'Phenotype', 'HP:0007716', (305, 320))	('#25368', 'Var', (203, 209))	('CD8', 'Gene', (279, 282))	('CD28', 'Gene', (79, 83))	('ocular melanoma', 'Disease', 'MESH:D008545', (305, 320))	('patients', 'Species', '9606', (193, 201))	('CD8', 'Gene', '925', (235, 238))	('CD27', 'Gene', (134, 138))	('CD28', 'Gene', '940', (79, 83))	('CD8', 'Gene', '925', (345, 348))	('patient', 'Species', '9606', (321, 328))	('#9476', 'Var', (214, 219))	('CD45', 'Gene', (36, 40))	('CD27', 'Gene', '939', (134, 138))	('melanoma', 'Phenotype', 'HP:0002861', (312, 320))	('ocular melanoma', 'Disease', (305, 320))	('CD8', 'Gene', '925', (279, 282))	('CD45', 'Gene', '5788', (36, 40))	('patient', 'Species', '9606', (193, 200))
84723	22207316	CD134 was homogeneously associated with both CD4+ and CD8+ T cells from TILs of #9476 and #1141 cutaneous and ocular melanoma patients, respectively (Fig.	('#1141', 'Var', (90, 95))	('CD8', 'Gene', '925', (54, 57))	('CD134', 'Gene', (0, 5))	('associated', 'Reg', (24, 34))	('CD4', 'Gene', (45, 48))	('CD4', 'Gene', '920', (45, 48))	('ocular melanoma', 'Disease', 'MESH:D008545', (110, 125))	('ocular melanoma', 'Disease', (110, 125))	('CD134', 'Gene', '7293', (0, 5))	('patients', 'Species', '9606', (126, 134))	('ocular melanoma', 'Phenotype', 'HP:0007716', (110, 125))	('cutaneous', 'Disease', (96, 105))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('CD8', 'Gene', (54, 57))
84728	22207316	Notably, an immune infiltrate was detected also by IHC analysis in 10 primary ocular melanoma lesions (representative results of patients #50306324 and 50316250 are shown in the Fig.	('ocular melanoma', 'Phenotype', 'HP:0007716', (78, 93))	('patients', 'Species', '9606', (129, 137))	('ocular melanoma lesions', 'Disease', (78, 101))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('50316250', 'Var', (152, 160))	('ocular melanoma lesions', 'Disease', 'MESH:D008545', (78, 101))
84738	22207316	High levels of IFN-gamma release (355 and 334 spots/5,000 cells for patients #4478D and #15765, respectively) were observed following incubation of TILs from both patients with the autologous tumor cell lines.	('tumor', 'Disease', (192, 197))	('patients', 'Species', '9606', (163, 171))	('#15765', 'Var', (88, 94))	('patients', 'Species', '9606', (68, 76))	('IFN-gamma', 'Gene', '3458', (15, 24))	('IFN-gamma', 'Gene', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
84739	22207316	Moreover, the tumor recognition was HLA-restricted as the cytokine secretion was inhibited (65 and 58% for patients #4478D and #15765, respectively) by the incubation of tumor cells with the anti-HLA-class I (W6/32) mAb, but not by the anti-HLA class II mAb (L243).	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', (14, 19))	('cytokine secretion', 'biological_process', 'GO:0050663', ('58', '76'))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('inhibited', 'NegReg', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('cytokine secretion', 'MPA', (58, 76))	('tumor', 'Disease', (170, 175))	('anti-HLA-class', 'Var', (191, 205))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('#15765', 'Var', (127, 133))	('patients', 'Species', '9606', (107, 115))
84744	22207316	8 indicate that efficient expansion (68-148 x 106 T cells) of TILs (#15765 and #4478D) and MLTCs (#4478D, #2710 and #0342) could be achieved with an increase value of 240-592 times (Fig.	('#4478D', 'Var', (98, 104))	('#0342', 'Var', (116, 121))	('#4478D', 'Var', (79, 85))	('MLTCs', 'Chemical', '-', (91, 96))	('#2710', 'Var', (106, 111))	('#15765', 'Var', (68, 74))
84747	22207316	The specific anti-tumor reactivity by MLTC-derived T lymphocytes expanded in vitro in large scale with the use of the REP protocol was obtained for all of the 7 cutaneous or ocular melanoma patients (# 7, 2710, 0342, 4478D, DAJU-1A, JOFR and 15765).	('ocular melanoma', 'Disease', (174, 189))	('obtained', 'Reg', (135, 143))	('REP', 'molecular_function', 'GO:0017137', ('118', '121'))	('tumor', 'Disease', (18, 23))	('patients', 'Species', '9606', (190, 198))	('ocular melanoma', 'Phenotype', 'HP:0007716', (174, 189))	('4478D', 'Var', (217, 222))	('MLTC', 'Chemical', '-', (38, 42))	('# 7', 'Var', (200, 203))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('ocular melanoma', 'Disease', 'MESH:D008545', (174, 189))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
84775	22207316	However, higher levels of co-stimulatory molecules were found in MLTC lymphocytes, suggesting that efficient anti-tumor activity and persistence in vivo can be associated with MLTCs rather than with TILs.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('MLTCs', 'Chemical', '-', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('MLTC', 'Chemical', '-', (65, 69))	('persistence', 'CPA', (133, 144))	('MLTC', 'Chemical', '-', (176, 180))	('MLTCs', 'Var', (176, 181))
84809	22419847	In addition, the effect of miR-34b/c on c-Met, cell cycle-related proteins, v-akt murine thymoma viral oncogene homolog (Akt) and extracellular signal-regulated kinase (ERK) pathway was determined by western blotting.	('extracellular signal-regulated kinase', 'Gene', (130, 167))	('ERK', 'Gene', (169, 172))	('ERK', 'molecular_function', 'GO:0004707', ('169', '172'))	('akt', 'Gene', (78, 81))	('akt', 'Gene', '207', (78, 81))	('extracellular', 'cellular_component', 'GO:0005576', ('130', '143'))	('miR-34b/c', 'Var', (27, 36))	('c-Met', 'MPA', (40, 45))	('ERK', 'Gene', '26413', (169, 172))	('thymoma', 'Phenotype', 'HP:0100522', (89, 96))	('thymoma viral', 'Disease', (89, 102))	('murine', 'Species', '10090', (82, 88))	('cell cycle', 'biological_process', 'GO:0007049', ('47', '57'))	('thymoma viral', 'Disease', 'MESH:D013945', (89, 102))	('extracellular signal-regulated kinase', 'Gene', '26413', (130, 167))
84810	22419847	miR-34b/c expression, which was dramatically decreased in uveal melanoma cells and clinical samples, can be upregulated by doxorubicin and epigenetic drugs.	('clinical samples', 'Species', '191496', (83, 99))	('epigenetic drugs', 'Var', (139, 155))	('doxorubicin', 'Chemical', 'MESH:D004317', (123, 134))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('uveal melanoma cell', 'Disease', (58, 77))	('decreased', 'NegReg', (45, 54))	('expression', 'MPA', (10, 20))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('upregulated', 'PosReg', (108, 119))	('uveal melanoma cell', 'Disease', 'MESH:C536494', (58, 77))	('miR-34b/c', 'Gene', (0, 9))
84811	22419847	The transfection of miR-34b/c into uveal melanoma cells leads to a significant reduction in cell growth and migration.	('miR-34b/c', 'Gene', (20, 29))	('cell growth', 'biological_process', 'GO:0016049', ('92', '103'))	('uveal melanoma cell', 'Disease', 'MESH:C536494', (35, 54))	('transfection', 'Var', (4, 16))	('uveal melanoma cell', 'Disease', (35, 54))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('reduction', 'NegReg', (79, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))
84812	22419847	Our results demonstrate that both miR-34b and miR-34c act as tumor suppressors in uveal melanoma cell proliferation and migration through the downregulation of multiple targets.	('miR-34c', 'Gene', '407042', (46, 53))	('cell proliferation', 'biological_process', 'GO:0008283', ('97', '115'))	('miR-34b', 'Var', (34, 41))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('miR-34c', 'Gene', (46, 53))	('uveal melanoma cell', 'Disease', (82, 101))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('migration', 'CPA', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('uveal melanoma cell', 'Disease', 'MESH:C536494', (82, 101))	('tumor', 'Disease', (61, 66))	('downregulation', 'NegReg', (142, 156))
84815	22419847	Aberrant expression of miRNAs can lead to oncogenesis with the enhancement of cell proliferation and metastatic potential.	('cell proliferation', 'biological_process', 'GO:0008283', ('78', '96'))	('Aberrant expression', 'Var', (0, 19))	('enhancement', 'PosReg', (63, 74))	('oncogenesis', 'Disease', (42, 53))	('metastatic potential', 'CPA', (101, 121))	('As c', 'Gene', '29108', (27, 31))	('lead to', 'Reg', (34, 41))	('As c', 'Gene', (27, 31))	('oncogenesis', 'biological_process', 'GO:0007048', ('42', '53'))	('cell proliferation', 'CPA', (78, 96))
84827	22419847	In the present study, we aimed to investigate the role of miR-34b/c in uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (71, 85))	('miR-34b/c', 'Var', (58, 67))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('uveal melanoma', 'Phenotype', 'HP:0007716', (71, 85))	('uveal melanoma', 'Disease', (71, 85))
84829	22419847	The expression of miR-34b/c was upregulated by doxorubicin (DOX) and epigenetic drugs.	('epigenetic drugs', 'Var', (69, 85))	('doxorubicin', 'Chemical', 'MESH:D004317', (47, 58))	('miR-34b/c', 'Gene', (18, 27))	('expression', 'MPA', (4, 14))	('DOX', 'Chemical', 'MESH:D004317', (60, 63))	('upregulated', 'PosReg', (32, 43))
84830	22419847	Furthermore, the introduction of miR-34b/c into tumor cells led to the inhibition of growth through cell cycle G1 arrest, instead of the induction of apoptosis.	('tumor', 'Disease', (48, 53))	('cell cycle', 'biological_process', 'GO:0007049', ('100', '110'))	('apoptosis', 'CPA', (150, 159))	('inhibition of growth', 'biological_process', 'GO:0045926', ('71', '91'))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('137', '159'))	('inhibition', 'NegReg', (71, 81))	('growth through cell cycle G1 arrest', 'CPA', (85, 120))	('miR-34b/c', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
84831	22419847	We also provide evidence that c-Met was a target of miR-34b/c, and miR-34b/c decreased endogenous c-Met, phosphorylated v-akt murine thymoma viral oncogene homolog (p-Akt), cyclin-dependent kinase (CDK) 4, and CDK6 protein levels in uveal melanoma cells.	('CDK6 protein levels', 'MPA', (210, 229))	('murine', 'Species', '10090', (126, 132))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('phosphorylated', 'MPA', (105, 119))	('cyclin-dependent kinase (CDK) 4', 'Gene', '12567', (173, 204))	('miR-34b/c', 'Var', (52, 61))	('akt', 'Gene', '207', (122, 125))	('cyclin', 'molecular_function', 'GO:0016538', ('173', '179'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (233, 247))	('miR-34b/c', 'Var', (67, 76))	('endogenous c-Met', 'MPA', (87, 103))	('CDK', 'molecular_function', 'GO:0004693', ('210', '213'))	('CDK', 'molecular_function', 'GO:0004693', ('198', '201'))	('akt', 'Gene', (122, 125))	('uveal melanoma cell', 'Disease', (233, 252))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('uveal melanoma cell', 'Disease', 'MESH:C536494', (233, 252))	('decreased', 'NegReg', (77, 86))	('thymoma viral', 'Disease', (133, 146))	('thymoma viral', 'Disease', 'MESH:D013945', (133, 146))	('thymoma', 'Phenotype', 'HP:0100522', (133, 140))
84832	22419847	In summary, our study demonstrates that miR-34b/c can function as a tumor suppressor in uveal melanoma cell proliferation and migration.	('tumor', 'Disease', (68, 73))	('migration', 'CPA', (126, 135))	('uveal melanoma cell', 'Disease', (88, 107))	('tumor suppressor', 'biological_process', 'GO:0051726', ('68', '84'))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('68', '84'))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cell proliferation', 'biological_process', 'GO:0008283', ('103', '121'))	('uveal melanoma cell', 'Disease', 'MESH:C536494', (88, 107))	('miR-34b/c', 'Var', (40, 49))
84841	22419847	SP6.5 cells were transfected with 50 nM of miR-34b/c mimic or a negative control.	('miR-34b/c mimic', 'Var', (43, 58))	('SP6', 'Gene', '80320', (0, 3))	('SP6', 'Gene', (0, 3))
84853	22419847	For each well, 50 nM of miR-34b, miR-34c mimic, or a negative control was cotransfected with the reporter constructs.	('miR-34b', 'Var', (24, 31))	('miR-34c', 'Gene', (33, 40))	('miR-34c', 'Gene', '407042', (33, 40))
84862	22419847	Consistent with the results from primary samples, miR-34b/c was expressed in uveal melanocytes, but was dramatically decreased in the SP6.5 cell line (Figure 1B).	('SP6', 'Gene', (134, 137))	('miR-34b/c', 'Var', (50, 59))	('decreased', 'NegReg', (117, 126))	('SP6', 'Gene', '80320', (134, 137))
84864	22419847	Treatment of tumor cells with DOX (doxorubicin) or inhibitors of DNA methyltransferases and/or histone deacetylase suppresses cell growth by activating multiple tumor suppressor genes.	('suppresses', 'NegReg', (115, 125))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', (13, 18))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('161', '177'))	('DOX', 'Chemical', 'MESH:D004317', (30, 33))	('activating', 'Reg', (141, 151))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cell growth', 'CPA', (126, 137))	('cell growth', 'biological_process', 'GO:0016049', ('126', '137'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('doxorubicin', 'Chemical', 'MESH:D004317', (35, 46))	('inhibitors', 'Var', (51, 61))	('tumor suppressor', 'biological_process', 'GO:0051726', ('161', '177'))
84865	22419847	We detected the expression levels of miR-34b/c in SP6.5 cells treated with either DOX, 5-aza-dC (a DNA hypomethylating agent), and/or TSA (a histone deacetylase inhibitor).	('DOX', 'Chemical', 'MESH:D004317', (82, 85))	('SP6', 'Gene', (50, 53))	('TSA', 'Chemical', 'MESH:C012589', (134, 137))	('SP6', 'Gene', '80320', (50, 53))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (87, 95))	('TSA', 'molecular_function', 'GO:0033984', ('134', '137'))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('miR-34b/c', 'Var', (37, 46))
84867	22419847	Similarly, miR-34b/c was also upregulated by 5-aza-dC or TSA (Figure 2B).	('TSA', 'Chemical', 'MESH:C012589', (57, 60))	('upregulated', 'PosReg', (30, 41))	('5-aza-dC', 'Var', (45, 53))	('miR-34b/c', 'Gene', (11, 20))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (45, 53))	('TSA', 'molecular_function', 'GO:0033984', ('57', '60'))	('TSA', 'Var', (57, 60))
84868	22419847	Overall, these results demonstrated that the expression of miR-34b/c in uveal melanoma cells can be affected by DOX and epigenetic drugs.	('miR-34b/c', 'Gene', (59, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('uveal melanoma cell', 'Disease', 'MESH:C536494', (72, 91))	('affected', 'Reg', (100, 108))	('expression', 'MPA', (45, 55))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('uveal melanoma cell', 'Disease', (72, 91))	('epigenetic drugs', 'Var', (120, 136))	('DOX', 'Chemical', 'MESH:D004317', (112, 115))
84871	22419847	We detected a decrease of cell numbers in the SP6.5 cell line by day 2 following transfection, and the growth of cells transfected with the miR-34b/c mimic was statistically significantly retarded, as compared with the negative control.	('growth', 'CPA', (103, 109))	('SP6', 'Gene', (46, 49))	('retarded', 'Disease', 'MESH:D008607', (188, 196))	('SP6', 'Gene', '80320', (46, 49))	('decrease', 'NegReg', (14, 22))	('miR-34b/c mimic', 'Var', (140, 155))	('retarded', 'Disease', (188, 196))
84872	22419847	A significant reduction in cell number persisted through day 5 (48.85+-5.39% decrease for miR-34b and 61.72+-3.6% for miR-34c, p<0.01, Figure 3A).	('miR-34c', 'Gene', (118, 125))	('decrease', 'NegReg', (77, 85))	('miR-34b', 'Var', (90, 97))	('cell number', 'CPA', (27, 38))	('reduction', 'NegReg', (14, 23))	('miR-34c', 'Gene', '407042', (118, 125))
84876	22419847	These results indicate that miR-34b/c inhibits cell proliferation and plays an important role in regulating uveal melanoma cell cycle G1 phase.	('miR-34b/c', 'Var', (28, 37))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('uveal melanoma cell', 'Disease', 'MESH:C536494', (108, 127))	('inhibits', 'NegReg', (38, 46))	('uveal melanoma cell', 'Disease', (108, 127))	('cell cycle', 'biological_process', 'GO:0007049', ('123', '133'))	('cell proliferation', 'biological_process', 'GO:0008283', ('47', '65'))	('G1 phase', 'biological_process', 'GO:0051318', ('134', '142'))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('cell proliferation', 'CPA', (47, 65))
84877	22419847	No significant difference in caspase 3/7 activity was observed between miR-34b/c transfected cells and negative control transfected cells (Figure 4A).	('miR-34b/c transfected', 'Var', (71, 92))	('caspase 3', 'Gene', (29, 38))	('caspase 3', 'Gene', '836', (29, 38))
84878	22419847	Thus, these analyses indicate that miR-34b/c inhibited uveal melanoma cell growth by cell cycle G1 arrest rather than by inducing apoptosis.	('uveal melanoma', 'Phenotype', 'HP:0007716', (55, 69))	('uveal melanoma cell', 'Disease', 'MESH:C536494', (55, 74))	('miR-34b/c', 'Var', (35, 44))	('cell cycle', 'biological_process', 'GO:0007049', ('85', '95'))	('inducing', 'Reg', (121, 129))	('cell cycle G1 arrest', 'CPA', (85, 105))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('inhibited', 'NegReg', (45, 54))	('uveal melanoma cell', 'Disease', (55, 74))	('cell growth', 'biological_process', 'GO:0016049', ('70', '81'))
84879	22419847	After 48 h, caspase 3/7 activity was significantly increased in miR-34b/c-transfected cells in comparison to negative control after DOX treatment (Figure 4B), which suggested that miR-34b/c enhanced cell sensitivity to DOX.	('miR-34b/c-transfected', 'Var', (64, 85))	('activity', 'MPA', (24, 32))	('DOX', 'Chemical', 'MESH:D004317', (219, 222))	('increased', 'PosReg', (51, 60))	('caspase 3', 'Gene', (12, 21))	('cell sensitivity to DOX', 'MPA', (199, 222))	('miR-34b/c', 'Var', (180, 189))	('DOX', 'Chemical', 'MESH:D004317', (132, 135))	('caspase 3', 'Gene', '836', (12, 21))	('enhanced', 'PosReg', (190, 198))
84881	22419847	Following transfection with either miR-34b/c mimic or a negative control, SP6.5 cells were seeded on cultured inserts and the ability of cells to migrate to the underside of the inserts was assessed in the presence of HGF.	('HGF', 'Gene', (218, 221))	('miR-34b/c mimic', 'Var', (35, 50))	('HGF', 'Gene', '3082', (218, 221))	('SP6', 'Gene', (74, 77))	('SP6', 'Gene', '80320', (74, 77))
84882	22419847	As shown in Figure 5, the migration of cells transfected with miR-34b/c was significantly inhibited, as compared with negative control (208+-15 for NC, 122+-10 for miR-34b, 116+-9 for miR-34c, n=3 each, p<0.01).	('miR-34c', 'Gene', '407042', (184, 191))	('miR-34c', 'Gene', (184, 191))	('miR-34b/c', 'Var', (62, 71))	('migration', 'CPA', (26, 35))	('inhibited', 'NegReg', (90, 99))	('miR-34b, 116+-9', 'Gene', '407041', (164, 179))
84883	22419847	Therefore, the introduction of miR-34b/c caused reduced cell migration in response to HGF.	('reduced', 'NegReg', (48, 55))	('cell migration', 'CPA', (56, 70))	('HGF', 'Gene', (86, 89))	('miR-34b/c', 'Var', (31, 40))	('HGF', 'Gene', '3082', (86, 89))	('cell migration', 'biological_process', 'GO:0016477', ('56', '70'))
84884	22419847	As expected, the luciferase activity of the wild-type pLuc-MET 3' UTR construct was significantly suppressed following the transfection of miR-34b/c into SP6.5 cells, in contrast to the negative control (Figure 4C).	('luciferase activity', 'molecular_function', 'GO:0045289', ('17', '36'))	('suppressed', 'NegReg', (98, 108))	('luciferase activity', 'molecular_function', 'GO:0050397', ('17', '36'))	('activity', 'MPA', (28, 36))	('luciferase activity', 'molecular_function', 'GO:0050248', ('17', '36'))	('SP6', 'Gene', '80320', (154, 157))	('luciferase', 'Enzyme', (17, 27))	('SP6', 'Gene', (154, 157))	('miR-34b/c', 'Var', (139, 148))	('luciferase activity', 'molecular_function', 'GO:0047077', ('17', '36'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('17', '36'))
84885	22419847	To confirm that miR-34b/c was indeed responsible for the downregulation of c-Met in uveal melanoma cells, SP6.5 cells were transfected with the miR-34b/c or a negative control.	('c-Met', 'Protein', (75, 80))	('downregulation', 'NegReg', (57, 71))	('uveal melanoma cell', 'Disease', (84, 103))	('miR-34b/c', 'Var', (144, 153))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma cell', 'Disease', 'MESH:C536494', (84, 103))	('SP6', 'Gene', (106, 109))	('SP6', 'Gene', '80320', (106, 109))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
84886	22419847	Next, we examined the expression patterns of ERK1/2 and Akt after downregulation of c-Met by miR-34b/c.	('ERK1/2', 'Gene', (45, 51))	('ERK1', 'molecular_function', 'GO:0004707', ('45', '49'))	('ERK1/2', 'Gene', '5595;5594', (45, 51))	('Akt', 'Pathway', (56, 59))	('miR-34b/c', 'Var', (93, 102))	('c-Met', 'Protein', (84, 89))	('downregulation', 'NegReg', (66, 80))
84887	22419847	As shown in Figure 7A, miR-34b/c caused a significant reduction of phosphorylated Akt in SP6.5 cells, but had no obvious effect on ERK1/2 phosphorylation.	('ERK1', 'molecular_function', 'GO:0004707', ('131', '135'))	('reduction', 'NegReg', (54, 63))	('ERK1/2', 'Gene', (131, 137))	('ERK1/2', 'Gene', '5595;5594', (131, 137))	('SP6', 'Gene', (89, 92))	('phosphorylated', 'MPA', (67, 81))	('SP6', 'Gene', '80320', (89, 92))	('phosphorylation', 'biological_process', 'GO:0016310', ('138', '153'))	('miR-34b/c', 'Var', (23, 32))
84889	22419847	In addition to the effects on c-Met and p-Akt, we also examined the expression of cell cycle-related proteins after transfection with miR-34b/c into SP6.5 cells.	('SP6', 'Gene', (149, 152))	('cell cycle', 'biological_process', 'GO:0007049', ('82', '92'))	('SP6', 'Gene', '80320', (149, 152))	('expression', 'MPA', (68, 78))	('examined', 'Reg', (55, 63))	('miR-34b/c', 'Var', (134, 143))
84890	22419847	As indicated, CDK4, CDK6, and phosphorylated retinoblastoma protein (p-Rb) were dramatically decreased in miR-34b/c-transfected cells (Figure 7B).	('retinoblastoma', 'Disease', 'MESH:D012175', (45, 59))	('retinoblastoma', 'Disease', (45, 59))	('p-Rb', 'Gene', (69, 73))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('CDK6', 'Protein', (20, 24))	('miR-34b/c-transfected', 'Var', (106, 127))	('p-Rb', 'Gene', '5925', (69, 73))	('decreased', 'NegReg', (93, 102))	('retinoblastoma', 'Phenotype', 'HP:0009919', (45, 59))	('CDK4', 'Gene', (14, 18))	('phosphorylated', 'MPA', (30, 44))	('CDK', 'molecular_function', 'GO:0004693', ('14', '17'))	('CDK4', 'Gene', '1019', (14, 18))	('CDK', 'molecular_function', 'GO:0004693', ('20', '23'))
84891	22419847	Thus, miR-34b/c also downregulated cell cycle regulatory proteins in SP6.5 cells (Figure 7B).	('SP6', 'Gene', '80320', (69, 72))	('miR-34b/c', 'Var', (6, 15))	('cell cycle', 'Protein', (35, 45))	('downregulated', 'NegReg', (21, 34))	('cell cycle', 'biological_process', 'GO:0007049', ('35', '45'))	('SP6', 'Gene', (69, 72))
84897	22419847	miR-34b/c is also important in various types of cancer.	('miR-34b/c', 'Var', (0, 9))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))
84898	22419847	So far, however, little is known about the function of miR-34b/c in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('miR-34b/c', 'Var', (55, 64))	('uveal melanoma', 'Disease', 'MESH:C536494', (68, 82))	('uveal melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('uveal melanoma', 'Disease', (68, 82))
84905	22419847	In contrast to other reports, our results indicated that miR-34b/c did not induce uveal melanoma cell apoptosis directly, but rather enhanced the cell sensitivity to DOX.	('enhanced', 'PosReg', (133, 141))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('apoptosis', 'biological_process', 'GO:0097194', ('102', '111'))	('apoptosis', 'biological_process', 'GO:0006915', ('102', '111'))	('uveal melanoma cell', 'Disease', (82, 101))	('DOX', 'Chemical', 'MESH:D004317', (166, 169))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('uveal melanoma cell', 'Disease', 'MESH:C536494', (82, 101))	('miR-34b/c', 'Var', (57, 66))	('cell sensitivity to DOX', 'MPA', (146, 169))
84906	22419847	In addition to cell proliferation and migration, aberrant miRNAs have also been shown to affect tumor cell migration.	('aberrant miRNAs', 'Var', (49, 64))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cell proliferation', 'biological_process', 'GO:0008283', ('15', '33'))	('tumor', 'Disease', (96, 101))	('cell proliferation', 'CPA', (15, 33))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('affect', 'Reg', (89, 95))	('migration', 'CPA', (38, 47))	('cell migration', 'biological_process', 'GO:0016477', ('102', '116'))
84908	22419847	Here, we demonstrated that miR-34b/c can inhibit uveal melanoma cell migration dramatically in an hepatocyte growth factor (HGF)-dependent fashion.	('uveal melanoma cell', 'Disease', 'MESH:C536494', (49, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (49, 63))	('miR-34b/c', 'Var', (27, 36))	('hepatocyte growth factor', 'Gene', '3082', (98, 122))	('HGF', 'Gene', (124, 127))	('uveal melanoma cell', 'Disease', (49, 68))	('cell migration', 'biological_process', 'GO:0016477', ('64', '78'))	('inhibit', 'NegReg', (41, 48))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('98', '122'))	('HGF', 'Gene', '3082', (124, 127))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('hepatocyte growth factor', 'Gene', (98, 122))
84911	22419847	Therefore, we examined the effect of miR-34b/c on c-Met expression and its pathway in uveal melanoma cells.	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('uveal melanoma cell', 'Disease', 'MESH:C536494', (86, 105))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('uveal melanoma cell', 'Disease', (86, 105))	('miR-34b/c', 'Var', (37, 46))
84915	22419847	As c-Met expression is directly regulated by miR-34b/c, its downstream effects are similarly altered in uveal melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('uveal melanoma cell', 'Disease', 'MESH:C536494', (104, 123))	('regulated', 'Reg', (32, 41))	('altered', 'Reg', (93, 100))	('As c', 'Gene', '29108', (0, 4))	('miR-34b/c', 'Var', (45, 54))	('expression', 'MPA', (9, 19))	('uveal melanoma cell', 'Disease', (104, 123))	('As c', 'Gene', (0, 4))
84916	22419847	In addition to regulation of c-Met activity, introduction of miR-34b/c downregulated cell cycle-related proteins, including p-Rb, CDK4, and CDK6.	('regulation', 'biological_process', 'GO:0065007', ('15', '25'))	('downregulated', 'NegReg', (71, 84))	('p-Rb', 'Gene', (124, 128))	('c-Met activity', 'MPA', (29, 43))	('CDK', 'molecular_function', 'GO:0004693', ('130', '133'))	('CDK6', 'Protein', (140, 144))	('cell', 'CPA', (85, 89))	('cell cycle', 'biological_process', 'GO:0007049', ('85', '95'))	('CDK4', 'Gene', (130, 134))	('CDK', 'molecular_function', 'GO:0004693', ('140', '143'))	('p-Rb', 'Gene', '5925', (124, 128))	('CDK4', 'Gene', '1019', (130, 134))	('miR-34b/c', 'Var', (61, 70))
84920	22419847	The downregulation of CDK4 and CDK6 (Figure 7B), which downregulates Rb in turn, supports the notion that miR-34b/c can also inhibit cell proliferation through cell cycle protein regulation.	('miR-34b/c', 'Var', (106, 115))	('cell proliferation', 'biological_process', 'GO:0008283', ('133', '151'))	('inhibit', 'NegReg', (125, 132))	('cell proliferation', 'CPA', (133, 151))	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('regulation', 'biological_process', 'GO:0065007', ('179', '189'))	('CDK4', 'Gene', (22, 26))	('CDK', 'molecular_function', 'GO:0004693', ('22', '25'))	('cell cycle', 'biological_process', 'GO:0007049', ('160', '170'))	('CDK6', 'Gene', (31, 35))	('downregulation', 'NegReg', (4, 18))	('CDK4', 'Gene', '1019', (22, 26))	('downregulates', 'NegReg', (55, 68))	('CDK', 'molecular_function', 'GO:0004693', ('31', '34'))	('cell', 'MPA', (160, 164))	('Rb', 'Gene', '5925', (69, 71))
84923	22419847	In this study, we also demonstrated that downregulation of miR-34b/c in uveal melanoma, miR-34b/c suppressed cell proliferation and migration by targeting c-Met.	('cell proliferation', 'CPA', (109, 127))	('miR-34b/c', 'Gene', (59, 68))	('uveal melanoma', 'Disease', (72, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('suppressed', 'NegReg', (98, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('c-Met', 'Protein', (155, 160))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('downregulation', 'NegReg', (41, 55))	('miR-34b/c', 'Var', (88, 97))	('cell proliferation', 'biological_process', 'GO:0008283', ('109', '127'))	('targeting', 'Reg', (145, 154))
84925	22419847	To sum up, our results showed a low level of miR-34b/c expression in uveal melanoma, and provided the approaches to activate miR-34b/c.	('miR-34b/c', 'Protein', (45, 54))	('activate', 'PosReg', (116, 124))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('uveal melanoma', 'Disease', (69, 83))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('miR-34b/c', 'Var', (125, 134))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))
84926	22419847	Specifically, we demonstrated the molecular mechanism of miR-34b/c in the modulation of uveal melanoma cell proliferation and migration.	('uveal melanoma cell', 'Disease', 'MESH:C536494', (88, 107))	('uveal melanoma cell', 'Disease', (88, 107))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('cell proliferation', 'biological_process', 'GO:0008283', ('103', '121'))	('migration', 'CPA', (126, 135))	('miR-34b/c', 'Var', (57, 66))
84927	22419847	In addition, miR-34b/c suppressed cell proliferation via cell cycle proteins CDK4, CDK6, and Rb.	('Rb', 'Gene', '5925', (93, 95))	('miR-34b/c', 'Var', (13, 22))	('suppressed', 'NegReg', (23, 33))	('cell proliferation', 'CPA', (34, 52))	('CDK4', 'Gene', (77, 81))	('CDK6', 'Protein', (83, 87))	('CDK4', 'Gene', '1019', (77, 81))	('CDK', 'molecular_function', 'GO:0004693', ('83', '86'))	('cell cycle', 'biological_process', 'GO:0007049', ('57', '67'))	('cell proliferation', 'biological_process', 'GO:0008283', ('34', '52'))	('cell cycle', 'CPA', (57, 67))	('CDK', 'molecular_function', 'GO:0004693', ('77', '80'))
84928	22419847	Taken together, our findings suggest that miR-34b/c may play an important role in controlling the carcinogenesis of uveal melanoma.	('miR-34b/c', 'Var', (42, 51))	('carcinogenesis of uveal melanoma', 'Disease', (98, 130))	('carcinogenesis of uveal melanoma', 'Disease', 'MESH:C536494', (98, 130))	('uveal melanoma', 'Phenotype', 'HP:0007716', (116, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))
85066	21811667	There is a familial tendency from mutation of the cerebral cavernous malformation gene located in chromosome 7 in which cerebral or cutaneous cavernous hemangiomas may also be present.	('cerebral', 'Disease', (120, 128))	('hemangioma', 'Phenotype', 'HP:0001028', (152, 162))	('chromosome', 'cellular_component', 'GO:0005694', ('98', '108'))	('hemangiomas', 'Disease', 'MESH:D006391', (152, 163))	('cavernous hemangiomas', 'Phenotype', 'HP:0001048', (142, 163))	('mutation', 'Var', (34, 42))	('hemangiomas', 'Disease', (152, 163))	('hemangiomas', 'Phenotype', 'HP:0001028', (152, 163))	('cavernous hemangioma', 'Phenotype', 'HP:0001048', (142, 162))	('cerebral cavernous malformation', 'Phenotype', 'HP:0002408', (50, 81))
85089	19568237	Whereas mutant BRAF and NRAS are responsible for the activation of the RAS/RAF/MEK/ERK pathway in most cutaneous melanoma, mutations in these genes are usually absent in UM.	('NRAS', 'Gene', '4893', (24, 28))	('cutaneous melanoma', 'Disease', (103, 121))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (103, 121))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (103, 121))	('MEK', 'Gene', (79, 82))	('RAF', 'Gene', '22882', (16, 19))	('BRAF', 'Gene', '673', (15, 19))	('ERK', 'Gene', (83, 86))	('ERK', 'molecular_function', 'GO:0004707', ('83', '86'))	('BRAF', 'Gene', (15, 19))	('mutant', 'Var', (8, 14))	('RAF', 'Gene', (16, 19))	('UM', 'Phenotype', 'HP:0007716', (170, 172))	('NRAS', 'Gene', (24, 28))	('RAF', 'Gene', '22882', (75, 78))	('activation', 'PosReg', (53, 63))	('MEK', 'Gene', '5609', (79, 82))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('RAF', 'Gene', (75, 78))	('ERK', 'Gene', '5594', (83, 86))
85099	19568237	Cutaneous melanoma and UM share the same embryonic origin and similar histological features, but mutations that regulate proliferation and cause a loss of cell-cycle control in CM can hardly be found in UM.	('mutations', 'Var', (97, 106))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('cell-cycle control', 'biological_process', 'GO:1901987', ('155', '173'))	('CM', 'Phenotype', 'HP:0012056', (177, 179))	('cell-cycle control', 'MPA', (155, 173))	('UM', 'Phenotype', 'HP:0007716', (203, 205))	('loss', 'NegReg', (147, 151))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('UM', 'Phenotype', 'HP:0007716', (23, 25))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('Cutaneous melanoma', 'Disease', (0, 18))
85100	19568237	Whereas p16-regulated cell cycle control is targeted by the deletion of chromosome 9p or by the mutation of CDKN2A in CM, most of the UM cell lines posses a wild-type p16-encoding gene that is, however, not expressed because of the epigenetic modification of the CDKN2A gene (van der Velden et al, 2001).	('CDKN2A', 'Gene', (263, 269))	('cell cycle control', 'biological_process', 'GO:1901987', ('22', '40'))	('CDKN2A', 'Gene', '1029', (108, 114))	('p16', 'Gene', '1029', (8, 11))	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('CDKN2A', 'Gene', '1029', (263, 269))	('deletion', 'Var', (60, 68))	('p16', 'Gene', (167, 170))	('mutation', 'Var', (96, 104))	('UM', 'Phenotype', 'HP:0007716', (134, 136))	('p16', 'Gene', (8, 11))	('CM', 'Phenotype', 'HP:0012056', (118, 120))	('p16', 'Gene', '1029', (167, 170))	('CDKN2A', 'Gene', (108, 114))
85103	19568237	In CM, the activation of the MAPK pathway has been shown to occur by a variety of mechanisms, including autocrine growth factor stimulation and mutation of the NRAS (20% of cases) and BRAF (60% of cases) genes (van Elsas et al, 1995; Davies et al, 2002; Satyamoorthy et al, 2003).	('BRAF', 'Gene', (184, 188))	('NRAS', 'Gene', (160, 164))	('autocrine growth factor stimulation', 'MPA', (104, 139))	('CM', 'Phenotype', 'HP:0012056', (3, 5))	('NRAS', 'Gene', '4893', (160, 164))	('MAPK pathway', 'Pathway', (29, 41))	('mutation', 'Var', (144, 152))	('MAPK', 'molecular_function', 'GO:0004707', ('29', '33'))	('BRAF', 'Gene', '673', (184, 188))
85104	19568237	The BRAF mutations have only rarely been reported in UM and activating mutations in NRAS, which are found in 25% of all cancers, have never been reported (Mooy et al, 1991; Soparker et al, 1993; Cohen et al, 2003; Cruz III et al, 2003; Edmunds et al, 2003; Rimoldi et al, 2003).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('NRAS', 'Gene', (84, 88))	('mutations', 'Var', (9, 18))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('NRAS', 'Gene', '4893', (84, 88))	('UM', 'Phenotype', 'HP:0007716', (53, 55))	('cancers', 'Disease', (120, 127))	('BRAF', 'Gene', (4, 8))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('BRAF', 'Gene', '673', (4, 8))
85105	19568237	However, we and others have found that UM is heterogeneous and that, with more sensitive techniques, the percentage of mutant BRAF-positive UM may be higher (Janssen et al, 2008; Maat et al, 2008).	('UM', 'Phenotype', 'HP:0007716', (39, 41))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('UM', 'Phenotype', 'HP:0007716', (140, 142))	('mutant', 'Var', (119, 125))
85107	19568237	Nevertheless, the pharmacological inhibition of MAPK/ERK kinases 1 and 2 (MEK1/2) and the genetic targeting of BRAF with siRNA resulted in a reduced proliferation of UM cell lines (Lefevre et al, 2004; Calipel et al, 2006).	('MAPK', 'molecular_function', 'GO:0004707', ('48', '52'))	('reduced', 'NegReg', (141, 148))	('ERK', 'Gene', '5594', (53, 56))	('ERK', 'molecular_function', 'GO:0004707', ('53', '56'))	('genetic targeting', 'Var', (90, 107))	('proliferation', 'CPA', (149, 162))	('UM', 'Phenotype', 'HP:0007716', (166, 168))	('ERK', 'Gene', (53, 56))	('MEK1/2', 'Gene', '5604;5605', (74, 80))	('BRAF', 'Gene', '673', (111, 115))	('MEK1/2', 'Gene', (74, 80))	('BRAF', 'Gene', (111, 115))	('MEK1', 'molecular_function', 'GO:0004708', ('74', '78'))
85128	19568237	Blocking experiments were carried out with Src family-selective tyrosine kinase inhibitors, PP1, PP2 (Biomol International, LP, of Plymouth Meeting, PA, USA) and PP3 (the inactive analogue, Calbiochem), at an end concentration of 10 muM in line with a large body of literature.	('PP3', 'Var', (162, 165))	('Src', 'Gene', (43, 46))	('Src', 'Gene', '6714', (43, 46))	('tyrosine kinase', 'Gene', (64, 79))	('muM', 'Gene', (233, 236))	('muM', 'Gene', '56925', (233, 236))	('PP2', 'Gene', (97, 100))	('PP2', 'Gene', '4888', (97, 100))	('PP1', 'Gene', (92, 95))	('tyrosine kinase', 'Gene', '7294', (64, 79))	('PP1', 'Gene', '5540', (92, 95))
85130	19568237	The membranes were blocked with 5% skim milk in a PBS-Tween 0.1% solution and probed at room temperature for 1 h with antibodies specific to each antigen: phospho-Src (Tyr527; dilution 1 : 1000), phospho-Src family (Tyr416; dilution 1 : 1000) and Src (36D10; dilution 1 : 1000) antibody (all from Cell Signaling Technology, Hertfordshire, UK).	('Tween', 'Chemical', 'MESH:D011136', (54, 59))	('Src', 'Gene', (204, 207))	('Tyr416;', 'Var', (216, 223))	('Src', 'Gene', '6714', (163, 166))	('Tyr416', 'Chemical', '-', (216, 222))	('Tyr527', 'Chemical', '-', (168, 174))	('antibody', 'cellular_component', 'GO:0042571', ('278', '286'))	('Src', 'Gene', (247, 250))	('Src', 'Gene', '6714', (247, 250))	('antibody', 'cellular_component', 'GO:0019815', ('278', '286'))	('antibody', 'cellular_component', 'GO:0019814', ('278', '286'))	('Src', 'Gene', (163, 166))	('Signaling', 'biological_process', 'GO:0023052', ('302', '311'))	('antibody', 'molecular_function', 'GO:0003823', ('278', '286'))	('Src', 'Gene', '6714', (204, 207))	('PBS', 'Chemical', 'MESH:D007854', (50, 53))
85144	19568237	Reduction of ERK1/2 activation in metastatic cell lines compared with that in primary UM cell lines provides a model to identify the underlying mechanism of ERK1/2 activation in the absence of BRAF and NRAS mutations.	('BRAF', 'Gene', (193, 197))	('BRAF', 'Gene', '673', (193, 197))	('ERK1/2', 'Gene', (157, 163))	('ERK1/2', 'Gene', '5595;5594', (157, 163))	('ERK1/2', 'Gene', '5595;5594', (13, 19))	('UM', 'Phenotype', 'HP:0007716', (86, 88))	('mutations', 'Var', (207, 216))	('NRAS', 'Gene', (202, 206))	('Reduction', 'NegReg', (0, 9))	('ERK1', 'molecular_function', 'GO:0004707', ('157', '161'))	('NRAS', 'Gene', '4893', (202, 206))	('ERK1', 'molecular_function', 'GO:0004707', ('13', '17'))	('ERK1/2', 'Gene', (13, 19))
85152	19568237	The peptide representing FAK1 Y576/Y577 is a genuine substrate for Src, which was not detected in the UM cell line comparison, but phosphorylation was significantly downregulated by PP1 and PP2 treatments.	('PP1', 'Gene', (182, 185))	('Y576/Y577', 'Var', (30, 39))	('downregulated', 'NegReg', (165, 178))	('phosphorylation', 'biological_process', 'GO:0016310', ('131', '146'))	('FAK1', 'Gene', (25, 29))	('Src', 'Gene', (67, 70))	('FAK', 'molecular_function', 'GO:0004717', ('25', '28'))	('phosphorylation', 'MPA', (131, 146))	('Src', 'Gene', '6714', (67, 70))	('PP2', 'Gene', (190, 193))	('UM', 'Phenotype', 'HP:0007716', (102, 104))	('PP2', 'Gene', '4888', (190, 193))	('FAK1', 'Gene', '5747', (25, 29))	('PP1', 'Gene', '5540', (182, 185))
85163	19568237	Src is regulated by the phosphorylation of tyrosine residues at position 416 (Y416) and 527 (Y527).	('Y416', 'Chemical', '-', (78, 82))	('Src', 'Gene', '6714', (0, 3))	('Src', 'Gene', (0, 3))	('tyrosine', 'Chemical', 'MESH:D014443', (43, 51))	('Y416', 'Var', (78, 82))	('phosphorylation', 'biological_process', 'GO:0016310', ('24', '39'))
85165	19568237	Surprisingly, the phosphorylation of Y527, which is associated with an inactive conformation, was also low, and a subsequent analysis indicated that Src expression is low in metastatic UM cell lines.	('UM', 'Phenotype', 'HP:0007716', (185, 187))	('Y527', 'Var', (37, 41))	('low', 'NegReg', (167, 170))	('Src', 'Gene', (149, 152))	('Src', 'Gene', '6714', (149, 152))	('phosphorylation', 'MPA', (18, 33))	('low', 'NegReg', (103, 106))	('expression', 'MPA', (153, 163))	('phosphorylation', 'biological_process', 'GO:0016310', ('18', '33'))
85176	19568237	Loss of activated ERK1/2 may not only relieve the associated inhibitory mechanisms in a direct manner but may also require alternative mitogenic signals to take over in UM metastasis.	('relieve', 'PosReg', (38, 45))	('ERK1/2', 'Gene', (18, 24))	('UM', 'Phenotype', 'HP:0007716', (169, 171))	('ERK1/2', 'Gene', '5595;5594', (18, 24))	('ERK1', 'molecular_function', 'GO:0004707', ('18', '22'))	('inhibitory mechanisms', 'MPA', (61, 82))	('Loss', 'Var', (0, 4))
85201	33262460	Here, we systematically examined the oncogenic signaling output of various mutations recurrently identified in human tumors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('human', 'Species', '9606', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))	('mutations', 'Var', (75, 84))
85206	33262460	Our findings highlight the GNAQ/11->PLCbeta->PKC->MAPK pathway as the central signaling axis to be suppressed pharmacologically to treat for neoplastic disorders with Galphaq pathway mutations.	('PKC', 'Gene', (45, 48))	('GNAQ', 'Gene', '2776', (27, 31))	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('mutations', 'Var', (183, 192))	('PKC', 'molecular_function', 'GO:0004697', ('45', '48'))	('PKC', 'Gene', '112476', (45, 48))	('neoplastic disorders', 'Disease', (141, 161))	('GNAQ', 'Gene', (27, 31))	('MAPK', 'molecular_function', 'GO:0004707', ('50', '54'))	('Galphaq', 'Gene', (167, 174))	('neoplastic disorders', 'Disease', 'MESH:D009369', (141, 161))	('Galphaq', 'Gene', '2776', (167, 174))
85211	33262460	UMs do not have mutations in BRAF, NRAS and NF1 that are common in other melanoma types.	('BRAF', 'Gene', '673', (29, 33))	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('NRAS', 'Gene', (35, 39))	('BRAF', 'Gene', (29, 33))	('NF1', 'Gene', (44, 47))	('mutations', 'Var', (16, 25))	('NRAS', 'Gene', '4893', (35, 39))	('NF1', 'Gene', '4763', (44, 47))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
85212	33262460	Instead, more than 90% of uveal melanomas harbor constitutively active mutations in GNAQ and GNA11, which encode the closely related alpha subunits Gq and G11.	('uveal melanomas', 'Disease', (26, 41))	('uveal melanomas', 'Phenotype', 'HP:0007716', (26, 41))	('GNAQ', 'Gene', (84, 88))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('uveal melanomas', 'Disease', 'MESH:C536494', (26, 41))	('melanomas', 'Phenotype', 'HP:0002861', (32, 41))	('uveal melanoma', 'Phenotype', 'HP:0007716', (26, 40))	('mutations', 'Var', (71, 80))	('GNAQ', 'Gene', '2776', (84, 88))	('GNA11', 'Gene', '2767', (93, 98))	('GNA11', 'Gene', (93, 98))
85215	33262460	The mutations in UM mainly affect codons Q209 and less frequently codons R183 of either GNAQ or GNA11 and functionally compromise their GTPase catalytic activity.	('GNAQ', 'Gene', (88, 92))	('GTP', 'Chemical', 'MESH:D006160', (136, 139))	('compromise', 'NegReg', (119, 129))	('catalytic activity', 'molecular_function', 'GO:0003824', ('143', '161'))	('catalytic activity', 'MPA', (143, 161))	('GNAQ', 'Gene', '2776', (88, 92))	('GTPase', 'Enzyme', (136, 142))	('UM', 'Phenotype', 'HP:0007716', (17, 19))	('mutations', 'Var', (4, 13))	('GNA11', 'Gene', '2767', (96, 101))	('GNA11', 'Gene', (96, 101))	('affect', 'Reg', (27, 33))	('codons R183', 'Var', (66, 77))
85217	33262460	The 10% of UMs that do not have GNAQ or GNA11 mutations harbor recurrent mutations at codon Leu129 in CYSLTR2, a Galphaq-coupled GPCR, or at Asp630 in PLCB4, encoding phospholipase C beta4, the immediate downstream of Galphaq.	('Leu129', 'Chemical', '-', (92, 98))	('CYSLTR2', 'Gene', (102, 109))	('GNAQ', 'Gene', (32, 36))	('at Asp630', 'Var', (138, 147))	('phospholipase C beta4', 'Gene', (167, 188))	('GNA11', 'Gene', (40, 45))	('Galphaq', 'Gene', '2776', (218, 225))	('CYSLTR2', 'Gene', '57105', (102, 109))	('phospholipase C beta4', 'Gene', '5332', (167, 188))	('UM', 'Phenotype', 'HP:0007716', (11, 13))	('PLCB4', 'Gene', '5332', (151, 156))	('GNAQ', 'Gene', '2776', (32, 36))	('GNA11', 'Gene', '2767', (40, 45))	('Asp630', 'Chemical', '-', (141, 147))	('Galphaq', 'Gene', (218, 225))	('Galphaq', 'Gene', (113, 120))	('PLCB4', 'Gene', (151, 156))	('Galphaq', 'Gene', '2776', (113, 120))
85219	33262460	Mutations in the Galphaq pathway are also found in additional neoplastic disorders, including blue nevus, and blue nevus-like melanoma, and mucosal melanoma, melanocytomas of the central nervous system, phakomatosis pigmentovascularis, and a range of vascular proliferations including congenital, and anastomosing hemangiomas, capillary malformations, hepatic small vessel neoplasms, Sturge-Weber syndrome and port-wine stains.	('mucosal melanoma', 'Disease', (140, 156))	('Galphaq', 'Gene', (17, 24))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('hemangiomas', 'Disease', (314, 325))	('hemangiomas', 'Phenotype', 'HP:0001028', (314, 325))	('capillary malformations', 'Phenotype', 'HP:0025104', (327, 350))	('found', 'Reg', (42, 47))	('Weber syndrome', 'Phenotype', 'HP:0002277', (391, 405))	('capillary malformations', 'Disease', 'MESH:D000014', (327, 350))	('vessel neoplasms', 'Phenotype', 'HP:0100742', (366, 382))	('port-wine stains', 'Phenotype', 'HP:0001052', (410, 426))	('blue nevus', 'Phenotype', 'HP:0100814', (94, 104))	('melanocytomas of the central nervous system', 'Disease', 'MESH:D002493', (158, 201))	('Galphaq', 'Gene', '2776', (17, 24))	('blue nevus', 'Phenotype', 'HP:0100814', (110, 120))	('blue nevus', 'Disease', (94, 104))	('hemangiomas', 'Disease', 'MESH:D006391', (314, 325))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))	('capillary malformations', 'Disease', (327, 350))	('neoplastic disorders', 'Disease', (62, 82))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('phakomatosis pigmentovascularis', 'Disease', (203, 234))	('melanoma', 'Disease', (148, 156))	('hepatic small vessel neoplasms', 'Disease', 'MESH:D056486', (352, 382))	('hepatic small vessel neoplasms', 'Disease', (352, 382))	('phakomatosis pigmentovascularis', 'Disease', 'MESH:D020752', (203, 234))	('neoplastic disorders', 'Disease', 'MESH:D009369', (62, 82))	('nevus', 'Phenotype', 'HP:0003764', (115, 120))	('congenital', 'Disease', (285, 295))	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (115, 134))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (384, 405))	('port-wine stains', 'Disease', (410, 426))	('mucosal melanoma', 'Disease', 'MESH:D008545', (140, 156))	('neoplasms', 'Phenotype', 'HP:0002664', (373, 382))	('nevus', 'Phenotype', 'HP:0003764', (99, 104))	('Sturge-Weber syndrome', 'Disease', (384, 405))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanocytomas of the central nervous system', 'Disease', (158, 201))
85220	33262460	Similar to BRAF mutations in cutaneous melanomas, Galphaq pathway mutations arise early during tumor evolution of melanocytic neoplasms and can already be found in benign lesions.	('mutations', 'Var', (66, 75))	('melanocytic neoplasms', 'Disease', (114, 135))	('tumor', 'Disease', (95, 100))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanomas', 'Phenotype', 'HP:0002861', (39, 48))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (29, 48))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (29, 48))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (114, 135))	('neoplasms', 'Phenotype', 'HP:0002664', (126, 135))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (29, 47))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (114, 135))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('Galphaq', 'Gene', (50, 57))	('Galphaq', 'Gene', '2776', (50, 57))	('cutaneous melanomas', 'Disease', (29, 48))	('BRAF', 'Gene', (11, 15))	('BRAF', 'Gene', '673', (11, 15))
85221	33262460	Additional mutations in genes including BAP1, SF3B1, or EIF1AX are required for full malignant transformation of UM.	('mutations', 'Var', (11, 20))	('SF3B1', 'Gene', '23451', (46, 51))	('BAP1', 'Gene', '8314', (40, 44))	('SF3B1', 'Gene', (46, 51))	('UM', 'Phenotype', 'HP:0007716', (113, 115))	('BAP1', 'Gene', (40, 44))	('EIF1AX', 'Gene', '1964', (56, 62))	('EIF1AX', 'Gene', (56, 62))
85226	33262460	IP3 plays an important role in raising intracellular Ca2+ levels, which activates a plethora of signaling pathways including classic protein kinase C (PKC) isoforms.	('PKC', 'Gene', (151, 154))	('PKC', 'Gene', '112476', (151, 154))	('intracellular Ca2+ levels', 'MPA', (39, 64))	('plethora', 'Phenotype', 'HP:0001050', (84, 92))	('raising intracellular Ca2+ levels', 'Phenotype', 'HP:0003575', (31, 64))	('protein kinase C', 'Gene', (133, 149))	('signaling', 'biological_process', 'GO:0023052', ('96', '105'))	('raising', 'PosReg', (31, 38))	('activates', 'Reg', (72, 81))	('IP3', 'Chemical', 'MESH:D015544', (0, 3))	('intracellular', 'cellular_component', 'GO:0005622', ('39', '52'))	('PKC', 'molecular_function', 'GO:0004697', ('151', '154'))	('protein kinase C', 'Gene', '112476', (133, 149))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('Ca2+', 'Chemical', 'MESH:D000069285', (53, 57))	('IP3', 'Var', (0, 3))
85229	33262460	Additional oncogenic effector pathways downstream implicated in UM include activation of the Hippo/YAP pathway via TRIO-RhoA-FAK, downstream of mutant Galphaq independent of PLC beta.	('Galphaq', 'Gene', (151, 158))	('RhoA', 'Gene', '387', (120, 124))	('Galphaq', 'Gene', '2776', (151, 158))	('FAK', 'Gene', '5747', (125, 128))	('activation', 'PosReg', (75, 85))	('oncogenic effector pathways', 'Pathway', (11, 38))	('FAK', 'molecular_function', 'GO:0004717', ('125', '128'))	('Hippo/YAP pathway', 'Pathway', (93, 110))	('RhoA', 'Gene', (120, 124))	('TRIO', 'Gene', (115, 119))	('UM', 'Phenotype', 'HP:0007716', (64, 66))	('mutant', 'Var', (144, 150))	('FAK', 'Gene', (125, 128))	('PLC', 'cellular_component', 'GO:0042824', ('174', '177'))	('TRIO', 'Gene', '7204', (115, 119))
85231	33262460	Specifically, it is not clear whether the different mutations in GNAQ/11 or mutations in CYSLTR2 and PLCB4 are functionally equivalent as some studies indicate that mutant Galphaq may activate the MAP-kinase independent of PLCbeta.	('Galphaq', 'Gene', (172, 179))	('mutant', 'Var', (165, 171))	('PLCB4', 'Gene', (101, 106))	('Galphaq', 'Gene', '2776', (172, 179))	('GNAQ', 'Gene', '2776', (65, 69))	('MAP-kinase', 'Enzyme', (197, 207))	('PLCB4', 'Gene', '5332', (101, 106))	('GNAQ', 'Gene', (65, 69))	('CYSLTR2', 'Gene', '57105', (89, 96))	('activate', 'PosReg', (184, 192))	('MAP', 'molecular_function', 'GO:0004239', ('197', '200'))	('CYSLTR2', 'Gene', (89, 96))
85232	33262460	A detailed understanding of the oncogenic signaling pathways and their branches is critical to meet the desperate need of rationally based therapies for UM and other neoplasms driven by aberrant Galphaq signaling.	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('neoplasms', 'Phenotype', 'HP:0002664', (166, 175))	('Galphaq', 'Gene', (195, 202))	('Galphaq', 'Gene', '2776', (195, 202))	('UM', 'Phenotype', 'HP:0007716', (153, 155))	('signaling', 'biological_process', 'GO:0023052', ('203', '212'))	('neoplasms', 'Disease', 'MESH:D009369', (166, 175))	('neoplasms', 'Disease', (166, 175))	('aberrant', 'Var', (186, 194))
85233	33262460	The goal of the current study was to characterize signaling pathways induced by mutations found in human tumors to determine paradigms for targeted therapy of neoplasms driven by mutations in the Galphaq signaling pathway.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('Galphaq', 'Gene', '2776', (196, 203))	('neoplasms', 'Phenotype', 'HP:0002664', (159, 168))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('Galphaq', 'Gene', (196, 203))	('mutations', 'Var', (80, 89))	('neoplasms', 'Disease', 'MESH:D009369', (159, 168))	('signaling pathway', 'biological_process', 'GO:0007165', ('204', '221'))	('neoplasms', 'Disease', (159, 168))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mutations', 'Var', (179, 188))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('human', 'Species', '9606', (99, 104))
85234	33262460	78 out of 80 (97.5%) of human UMs in The Cancer Genome Atlas (TCGA) have mutually exclusive mutations in either GNAQ (n=40, 56%), GNA11(n=36, 46%), CYSLTR2 (n=3, 4%) or PLCbeta4 (n=2, 2.5%) (Figure 1A).	('human', 'Species', '9606', (24, 29))	('GNAQ', 'Gene', (112, 116))	('PLCbeta4', 'Gene', (169, 177))	('GNA11', 'Gene', (130, 135))	('CYSLTR2', 'Gene', '57105', (148, 155))	('Cancer', 'Disease', (41, 47))	('mutations', 'Var', (92, 101))	('GNA11', 'Gene', '2767', (130, 135))	('CYSLTR2', 'Gene', (148, 155))	('Cancer', 'Disease', 'MESH:D009369', (41, 47))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('UM', 'Phenotype', 'HP:0007716', (30, 32))	('GNAQ', 'Gene', '2776', (112, 116))	('PLCbeta4', 'Gene', '5332', (169, 177))
85235	33262460	The main hotspot in GNAQ and GNA11 is at codon 209, with Q209L and Q209P mutations accounting for 54.9% and 34.4% of all GNAQ mutations, respectively (sources TCGA and COSMIC), whereas for GNA11 92.1% are Q209L mutations (Figure 1B).	('Q209L', 'Var', (205, 210))	('GNA11', 'Gene', (29, 34))	('Q209L', 'Var', (57, 62))	('GNAQ', 'Gene', '2776', (20, 24))	('GNA11', 'Gene', '2767', (29, 34))	('Q209P', 'Mutation', 'rs1057519742', (67, 72))	('GNAQ', 'Gene', '2776', (121, 125))	('GNA11', 'Gene', (189, 194))	('GNA11', 'Gene', '2767', (189, 194))	('Q209L', 'Mutation', 'rs1057519742', (205, 210))	('GNAQ', 'Gene', (20, 24))	('Q209P mutations', 'Var', (67, 82))	('mutations', 'Var', (126, 135))	('Q209L', 'Mutation', 'rs1057519742', (57, 62))	('GNAQ', 'Gene', (121, 125))	('mutations', 'Var', (73, 82))
85236	33262460	A second minor hotspot affects the arginine at codon 183, with R183Q accounting for 4.3% of GNAQ mutations and R183C for 4.4% of GNA11 mutations.	('affects', 'Reg', (23, 30))	('GNAQ', 'Gene', (92, 96))	('GNA11', 'Gene', (129, 134))	('GNA11', 'Gene', '2767', (129, 134))	('R183C', 'Var', (111, 116))	('R183C', 'Mutation', 'p.R183C', (111, 116))	('arginine', 'Chemical', 'MESH:D001120', (35, 43))	('R183Q', 'Var', (63, 68))	('arginine', 'MPA', (35, 43))	('GNAQ', 'Gene', '2776', (92, 96))	('R183Q', 'Mutation', 'rs397514698', (63, 68))
85241	33262460	We monitored MAP-kinase pathway activation downstream using pERK and pp90RSK levels.	('pp90RSK', 'Var', (69, 76))	('activation', 'PosReg', (32, 42))	('MAP', 'molecular_function', 'GO:0004239', ('13', '16'))	('pERK', 'Gene', (60, 64))	('pERK', 'Gene', '9451', (60, 64))	('MAP-kinase pathway', 'Pathway', (13, 31))
85242	33262460	As shown in Figure 1C, there was considerable variation in the accumulation of IP1 induced by different GNAQ/11 variants.	('GNAQ', 'Gene', '2776', (104, 108))	('IP1', 'Gene', (79, 82))	('IP1', 'Gene', '8517', (79, 82))	('accumulation', 'MPA', (63, 75))	('GNAQ', 'Gene', (104, 108))	('variants', 'Var', (112, 120))
85243	33262460	GNAQQ209L and GNAQQ209P transfected cells had more than 12-fold increases in IP1, while the increase induced by GNAQR183Q and GNA11Q209L was lower.	('GNAQQ209P', 'Mutation', 'rs121913492', (14, 23))	('GNA11Q209L', 'Var', (126, 136))	('GNAQQ209L', 'Var', (0, 9))	('GNAQQ209P transfected', 'Var', (14, 35))	('IP1', 'Gene', (77, 80))	('IP1', 'Gene', '8517', (77, 80))	('increases', 'PosReg', (64, 73))
85244	33262460	By contrast, the Galphaq variants of unknown significance had no effect, rendering it unlikely that they are bona fide driver mutations.	('variants', 'Var', (25, 33))	('Galphaq', 'Gene', (17, 24))	('Galphaq', 'Gene', '2776', (17, 24))
85246	33262460	All IP1 inducing mutations - in GNAQ/11, CYSLTR2 or PLCbeta4 - also increased pERK, pp90RSK and pPKD, supporting the notion that they all activate the PLCbeta, PKC and MAPK signaling pathway (Figure 1C, bottom panel).	('inducing', 'Reg', (8, 16))	('MAPK signaling', 'biological_process', 'GO:0000165', ('168', '182'))	('PLCbeta4', 'Gene', (52, 60))	('mutations', 'Var', (17, 26))	('pp90RSK', 'MPA', (84, 91))	('PKD', 'Gene', (97, 100))	('PKC', 'molecular_function', 'GO:0004697', ('160', '163'))	('IP1', 'Gene', (4, 7))	('IP1', 'Gene', '8517', (4, 7))	('activate', 'PosReg', (138, 146))	('PKC', 'Gene', '112476', (160, 163))	('increased', 'PosReg', (68, 77))	('CYSLTR2', 'Gene', '57105', (41, 48))	('PKD', 'Gene', '5587', (97, 100))	('GNAQ', 'Gene', '2776', (32, 36))	('PKC', 'Gene', (160, 163))	('pERK', 'Gene', (78, 82))	('MAPK signaling pathway', 'Pathway', (168, 190))	('pERK', 'Gene', '9451', (78, 82))	('GNAQ', 'Gene', (32, 36))	('PLCbeta', 'Pathway', (151, 158))	('CYSLTR2', 'Gene', (41, 48))	('PLCbeta4', 'Gene', '5332', (52, 60))	('signaling pathway', 'biological_process', 'GO:0007165', ('173', '190'))	('MAPK', 'molecular_function', 'GO:0004707', ('168', '172'))
85248	33262460	As shown in Figure 2A, The YM-254890 compound inhibited IP1 accumulation induced by GNAQQ209L, GNAQQ209P, GNAQR183Q and GNA11Q209L in a dose dependent manner.	('YM-254890', 'Chemical', 'MESH:C475455', (27, 36))	('GNAQQ209P', 'Mutation', 'rs121913492', (95, 104))	('GNAQQ209P', 'Var', (95, 104))	('GNA11Q209L', 'Var', (120, 130))	('GNAQR183Q', 'Var', (106, 115))	('IP1', 'Gene', (56, 59))	('IP1', 'Gene', '8517', (56, 59))	('inhibited', 'NegReg', (46, 55))	('GNAQQ209L', 'Var', (84, 93))
85250	33262460	By contrast, it had no effect on PLCbeta4D630Y, which confirms that YM-254890 acts directly on GNAQ/11, upstream of PLCbeta.	('YM-254890', 'Var', (68, 77))	('PLCbeta4', 'Gene', (33, 41))	('GNAQ', 'Gene', (95, 99))	('YM-254890', 'Chemical', 'MESH:C475455', (68, 77))	('PLCbeta4', 'Gene', '5332', (33, 41))	('GNAQ', 'Gene', '2776', (95, 99))
85251	33262460	Notably, YM-254890 was less effective on GNAQQ209L compared to the other Galphaq variants.	('YM-254890', 'Chemical', 'MESH:C475455', (9, 18))	('Galphaq', 'Gene', (73, 80))	('less', 'NegReg', (23, 27))	('Galphaq', 'Gene', '2776', (73, 80))	('GNAQQ209L', 'Var', (41, 50))	('YM-254890', 'Var', (9, 18))
85252	33262460	As the Galphaq family has additional members, GNA14 and GNA15/16, we tested the selectivity of YM-254890 acts on Galphaq family members, using GNA14Q205L and GNA15Q212L, constitutively active mutants corresponding to GNAQ/11Q209L.	('YM-254890', 'Var', (95, 104))	('GNA15/16', 'Gene', (56, 64))	('GNA14', 'Gene', '9630', (143, 148))	('YM-254890', 'Chemical', 'MESH:C475455', (95, 104))	('Galphaq', 'Gene', '2776', (113, 120))	('Galphaq', 'Gene', (7, 14))	('GNA15', 'Gene', (56, 61))	('GNA15', 'Gene', '2769', (56, 61))	('tested', 'Reg', (69, 75))	('Galphaq', 'Gene', '2776', (7, 14))	('GNAQ', 'Gene', '2776', (217, 221))	('GNA15', 'Gene', '2769', (158, 163))	('GNA14Q205L', 'Chemical', '-', (143, 153))	('GNA15', 'Gene', (158, 163))	('GNA14', 'Gene', (46, 51))	('GNAQ', 'Gene', (217, 221))	('GNA14', 'Gene', (143, 148))	('Q209L', 'Mutation', 'rs1057519742', (224, 229))	('GNA15/16', 'Gene', '2769', (56, 64))	('GNA14', 'Gene', '9630', (46, 51))	('Galphaq', 'Gene', (113, 120))
85254	33262460	As shown in Figure S1A, all three variants increased pERK, pp90RSK, but only GNA14Q205L and GNA15Q227L increased IP1 accumulation and pPKD.	('pERK', 'Gene', '9451', (53, 57))	('GNA14Q205L', 'Chemical', '-', (77, 87))	('GNA15', 'Gene', (92, 97))	('GNA15', 'Gene', '2769', (92, 97))	('IP1', 'Gene', '8517', (113, 116))	('GNA14Q205L', 'Var', (77, 87))	('increased', 'PosReg', (103, 112))	('PKD', 'Gene', (135, 138))	('pp90RSK', 'MPA', (59, 66))	('PKD', 'Gene', '5587', (135, 138))	('increased', 'PosReg', (43, 52))	('pERK', 'Gene', (53, 57))	('IP1', 'Gene', (113, 116))
85256	33262460	YM-254890 had no effect on GNA14Q205L and GNA15Q227L nor GNASQ227L (Figure 2A).	('GNAS', 'Gene', (57, 61))	('YM-254890', 'Var', (0, 9))	('GNA15', 'Gene', '2769', (42, 47))	('GNA14Q205L', 'Chemical', '-', (27, 37))	('GNA15', 'Gene', (42, 47))	('YM-254890', 'Chemical', 'MESH:C475455', (0, 9))	('GNA14Q205L', 'Var', (27, 37))	('GNAS', 'Gene', '2778', (57, 61))
85258	33262460	YM-254890 strongly inhibited PKC and MAPK in cells transfected with GNAQQ209L, GNAQQ209P, GNAQR183Q, GNA11Q209L, CYSLTR2L129Q as evidenced by a reduction of pERK, pp90RSK, and pPKD (Figure 2B) confirming that CYSLTR2 acts upstream of Galphaq.	('PKD', 'Gene', (177, 180))	('Galphaq', 'Gene', '2776', (234, 241))	('PKC', 'Gene', '112476', (29, 32))	('GNAQQ209P', 'Var', (79, 88))	('PKC', 'Gene', (29, 32))	('CYSLTR2', 'Gene', '57105', (209, 216))	('pp90RSK', 'MPA', (163, 170))	('inhibited', 'NegReg', (19, 28))	('PKD', 'Gene', '5587', (177, 180))	('CYSLTR2', 'Gene', '57105', (113, 120))	('CYSLTR2', 'Gene', (209, 216))	('MAPK', 'molecular_function', 'GO:0004707', ('37', '41'))	('GNAQR183Q', 'Var', (90, 99))	('GNAQQ209L', 'Var', (68, 77))	('MAPK', 'Enzyme', (37, 41))	('reduction', 'NegReg', (144, 153))	('PKC', 'molecular_function', 'GO:0004697', ('29', '32'))	('CYSLTR2', 'Gene', (113, 120))	('GNAQQ209P', 'Mutation', 'rs121913492', (79, 88))	('pERK', 'Gene', (157, 161))	('YM-254890', 'Var', (0, 9))	('pERK', 'Gene', '9451', (157, 161))	('Galphaq', 'Gene', (234, 241))	('YM-254890', 'Chemical', 'MESH:C475455', (0, 9))	('GNA11Q209L', 'Var', (101, 111))
85259	33262460	By contrast, YM-254890 had no effect on cells transfected with PLCbeta4D630Y, consistent with its position downstream of Galphaq (Figure 2B and Figure S1B).	('PLCbeta4', 'Gene', '5332', (63, 71))	('YM-254890', 'Var', (13, 22))	('Galphaq', 'Gene', '2776', (121, 128))	('Galphaq', 'Gene', (121, 128))	('PLCbeta4', 'Gene', (63, 71))	('YM-254890', 'Chemical', 'MESH:C475455', (13, 22))
85260	33262460	By contrast, the PKC inhibitor LXS196 that is currently under clinical investigation strongly inhibited pERK, pp90RSK and pPKD in all UM oncogenes.	('pp90RSK', 'Var', (110, 117))	('PKC', 'Gene', (17, 20))	('PKC', 'Gene', '112476', (17, 20))	('pERK', 'Gene', '9451', (104, 108))	('pERK', 'Gene', (104, 108))	('PKC', 'molecular_function', 'GO:0004697', ('17', '20'))	('LXS196', 'Var', (31, 37))	('UM', 'Phenotype', 'HP:0007716', (134, 136))	('LXS196', 'Chemical', '-', (31, 37))	('PKD', 'Gene', (123, 126))	('PKD', 'Gene', '5587', (123, 126))	('inhibited', 'NegReg', (94, 103))
85265	33262460	As shown in Figure 3B, mutant but not wild type PLCbeta4 activated FAK as evidenced by increased phosphorylation at Y397, putting PLCbeta4 upstream of FAK.	('increased', 'PosReg', (87, 96))	('PLCbeta4', 'Gene', '5332', (130, 138))	('FAK', 'Gene', (67, 70))	('activated', 'PosReg', (57, 66))	('PLCbeta4', 'Gene', '5332', (48, 56))	('FAK', 'Gene', '5747', (151, 154))	('PLCbeta4', 'Gene', (130, 138))	('FAK', 'molecular_function', 'GO:0004717', ('67', '70'))	('phosphorylation', 'biological_process', 'GO:0016310', ('97', '112'))	('Y397', 'Var', (116, 120))	('FAK', 'Gene', (151, 154))	('phosphorylation', 'MPA', (97, 112))	('PLCbeta4', 'Gene', (48, 56))	('FAK', 'molecular_function', 'GO:0004717', ('151', '154'))	('mutant', 'Var', (23, 29))	('FAK', 'Gene', '5747', (67, 70))
85266	33262460	This activation could be suppressed by the PKC inhibitor LXS196, in a dose-dependent manner (Figure 3C) and LXS196 also suppressed FAK phosphorylation in UM cells with GNAQ or GNA11 mutations, with no effect on BRAF mutant cells (Figure 3D).	('suppressed', 'NegReg', (120, 130))	('PKC', 'molecular_function', 'GO:0004697', ('43', '46'))	('PKC', 'Gene', '112476', (43, 46))	('UM', 'Phenotype', 'HP:0007716', (154, 156))	('FAK', 'Gene', (131, 134))	('GNA11', 'Gene', '2767', (176, 181))	('FAK', 'molecular_function', 'GO:0004717', ('131', '134'))	('PKC', 'Gene', (43, 46))	('LXS196', 'Chemical', '-', (108, 114))	('FAK', 'Gene', '5747', (131, 134))	('mutations', 'Var', (182, 191))	('BRAF', 'Gene', (211, 215))	('BRAF', 'Gene', '673', (211, 215))	('phosphorylation', 'biological_process', 'GO:0016310', ('135', '150'))	('GNA11', 'Gene', (176, 181))	('LXS196', 'Chemical', '-', (57, 63))	('GNAQ', 'Gene', '2776', (168, 172))	('LXS196', 'Var', (108, 114))	('GNAQ', 'Gene', (168, 172))
85268	33262460	These data indicate that in the context of Galphaq pathway mutations FAK activation occurs via PLCbeta and involves PKC.	('PKC', 'Gene', '112476', (116, 119))	('Galphaq', 'Gene', (43, 50))	('activation', 'PosReg', (73, 83))	('Galphaq', 'Gene', '2776', (43, 50))	('PKC', 'molecular_function', 'GO:0004697', ('116', '119'))	('PLCbeta', 'Enzyme', (95, 102))	('mutations', 'Var', (59, 68))	('FAK', 'Gene', (69, 72))	('FAK', 'Gene', '5747', (69, 72))	('FAK', 'molecular_function', 'GO:0004717', ('69', '72'))	('PKC', 'Gene', (116, 119))
85270	33262460	We examined the relationship between these two pathways by using the FAK inhibitor VS-4718 and the MEK inhibitor trametinib.	('VS-4718', 'Var', (83, 90))	('MEK', 'Gene', '5609', (99, 102))	('trametinib', 'Chemical', 'MESH:C560077', (113, 123))	('examined', 'Reg', (3, 11))	('FAK', 'Gene', (69, 72))	('FAK', 'Gene', '5747', (69, 72))	('FAK', 'molecular_function', 'GO:0004717', ('69', '72'))	('MEK', 'Gene', (99, 102))
85271	33262460	VS-4718 suppressed FAK phosphorylation in a dose-dependent manner, but had no effect on p-ERK levels, even at higher concentrations in GNAQ (MEL202), GNA11 (MP41), BRAF mutant (MUM2C) cell lines (Figure 3E).	('phosphorylation', 'biological_process', 'GO:0016310', ('23', '38'))	('ERK', 'Gene', (90, 93))	('GNAQ', 'Gene', (135, 139))	('FAK', 'Gene', '5747', (19, 22))	('UM', 'Phenotype', 'HP:0007716', (178, 180))	('GNA11', 'Gene', (150, 155))	('FAK', 'Gene', (19, 22))	('GNAQ', 'Gene', '2776', (135, 139))	('BRAF', 'Gene', '673', (164, 168))	('GNA11', 'Gene', '2767', (150, 155))	('ERK', 'molecular_function', 'GO:0004707', ('90', '93'))	('VS-4718', 'Var', (0, 7))	('mutant', 'Var', (169, 175))	('BRAF', 'Gene', (164, 168))	('ERK', 'Gene', '5594', (90, 93))	('suppressed', 'NegReg', (8, 18))	('FAK', 'molecular_function', 'GO:0004717', ('19', '22'))
85273	33262460	These findings indicate that mutations in the Galphaq pathway at the level of Galphaq or PLC beta activate PKC, after which the signal flux branches into the MAPK and FAK pathways.	('Galphaq', 'Gene', '2776', (78, 85))	('FAK', 'molecular_function', 'GO:0004717', ('167', '170'))	('PKC', 'Gene', (107, 110))	('mutations', 'Var', (29, 38))	('PKC', 'Gene', '112476', (107, 110))	('FAK', 'Gene', '5747', (167, 170))	('FAK', 'Gene', (167, 170))	('PKC', 'molecular_function', 'GO:0004697', ('107', '110'))	('Galphaq', 'Gene', (46, 53))	('Galphaq', 'Gene', '2776', (46, 53))	('PLC', 'cellular_component', 'GO:0042824', ('89', '92'))	('MAPK', 'Pathway', (158, 162))	('MAPK', 'molecular_function', 'GO:0004707', ('158', '162'))	('Galphaq', 'Gene', (78, 85))	('activate', 'PosReg', (98, 106))
85274	33262460	Nearly all UM cell lines that are available to the research community harbor mutations in GNAQ or GNA11.	('UM', 'Phenotype', 'HP:0007716', (11, 13))	('GNA11', 'Gene', (98, 103))	('GNA11', 'Gene', '2767', (98, 103))	('GNAQ', 'Gene', '2776', (90, 94))	('mutations', 'Var', (77, 86))	('GNAQ', 'Gene', (90, 94))
85275	33262460	We determined the intrinsic PLCbeta activity in 12 UM cell lines, 11 with different Galphaq mutations (GNAQ: Q209L, Q209P, R183Q; GNA11: Q209L) and MEL290.	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('Q209L', 'Mutation', 'rs1057519742', (137, 142))	('GNAQ', 'Gene', '2776', (103, 107))	('GNA11', 'Gene', (130, 135))	('Q209P', 'Var', (116, 121))	('activity', 'MPA', (36, 44))	('GNA11', 'Gene', '2767', (130, 135))	('Q209P', 'Mutation', 'rs1057519742', (116, 121))	('R183Q', 'Var', (123, 128))	('Galphaq', 'Gene', (84, 91))	('GNAQ', 'Gene', (103, 107))	('Galphaq', 'Gene', '2776', (84, 91))	('R183Q', 'Mutation', 'rs397514698', (123, 128))	('Q209L', 'Mutation', 'rs1057519742', (109, 114))	('PLCbeta', 'Enzyme', (28, 35))
85276	33262460	These cell lines also harbor a range of secondary driver mutations including those in SF3B1, EIF1AX or BAP1, representative of the genetic landscape of human UM (mutation details in supplemental table 1).	('BAP1', 'Gene', '8314', (103, 107))	('EIF1AX', 'Gene', '1964', (93, 99))	('EIF1AX', 'Gene', (93, 99))	('BAP1', 'Gene', (103, 107))	('SF3B1', 'Gene', (86, 91))	('mutations', 'Var', (57, 66))	('human', 'Species', '9606', (152, 157))	('UM', 'Phenotype', 'HP:0007716', (158, 160))	('SF3B1', 'Gene', '23451', (86, 91))
85278	33262460	Cutaneous melanoma (CM) cell lines have no mutations in the Galphaq pathway and instead have MAP-kinase pathway mutations, mainly in BRAF or NRAS.	('CM', 'Phenotype', 'HP:0012056', (20, 22))	('MAP-kinase pathway', 'Pathway', (93, 111))	('NRAS', 'Gene', '4893', (141, 145))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (133, 137))	('mutations', 'Var', (112, 121))	('mutations', 'Var', (43, 52))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('MAP', 'molecular_function', 'GO:0004239', ('93', '96'))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('Galphaq', 'Gene', (60, 67))	('Galphaq', 'Gene', '2776', (60, 67))	('Cutaneous melanoma', 'Disease', (0, 18))	('NRAS', 'Gene', (141, 145))
85284	33262460	This pattern is independent of mutation of secondary driver mutations in BAP1, SF3B1, and EIF1AX.	('EIF1AX', 'Gene', (90, 96))	('BAP1', 'Gene', '8314', (73, 77))	('BAP1', 'Gene', (73, 77))	('SF3B1', 'Gene', (79, 84))	('SF3B1', 'Gene', '23451', (79, 84))	('mutations', 'Var', (60, 69))	('EIF1AX', 'Gene', '1964', (90, 96))
85287	33262460	As shown in Figure 4B, all 10 melanoma cell lines with GNAQ/GNA11 mutations expressed RasGRP3, p-RasGRP3T133, and p-PKDS744/748, whereas CM cell lines did not.	('mutations', 'Var', (66, 75))	('RasGRP3', 'Gene', '25780', (97, 104))	('CM', 'Phenotype', 'HP:0012056', (137, 139))	('GNA11', 'Gene', (60, 65))	('GNAQ', 'Gene', '2776', (55, 59))	('GNA11', 'Gene', '2767', (60, 65))	('RasGRP3', 'Gene', (86, 93))	('RasGRP3', 'Gene', '25780', (86, 93))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('GNAQ', 'Gene', (55, 59))	('PKD', 'Gene', (116, 119))	('melanoma', 'Disease', (30, 38))	('RasGRP3', 'Gene', (97, 104))	('PKD', 'Gene', '5587', (116, 119))
85289	33262460	These data indicate that across the board of UM cells with diverse secondary mutations but not in melanoma cell lines with other mutations, PKC is invariably activated.	('PKC', 'Gene', (140, 143))	('PKC', 'Gene', '112476', (140, 143))	('PKC', 'molecular_function', 'GO:0004697', ('140', '143'))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('mutations', 'Var', (77, 86))	('melanoma', 'Disease', (98, 106))	('UM', 'Phenotype', 'HP:0007716', (45, 47))
85291	33262460	Interestingly, FAK signaling also showed no difference across melanoma cell lines and had no specific associations with mutations in the Galphaq pathway.	('associations', 'Interaction', (102, 114))	('melanoma', 'Disease', (62, 70))	('FAK', 'Gene', '5747', (15, 18))	('Galphaq', 'Gene', '2776', (137, 144))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('FAK', 'Gene', (15, 18))	('FAK', 'molecular_function', 'GO:0004717', ('15', '18'))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('mutations', 'Var', (120, 129))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('Galphaq', 'Gene', (137, 144))
85293	33262460	As shown in Figure 4B, the expression levels of p-YAPS127, p-YAPY357 and total YAP1 were similar in melanoma cell lines regardless of their genetic status.	('YAP1', 'Gene', (79, 83))	('YAP1', 'Gene', '10413', (79, 83))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('p-YAPS127', 'Var', (48, 57))	('melanoma', 'Disease', (100, 108))	('p-YAPY357', 'Var', (59, 68))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))
85294	33262460	In the immortalized mouse melanocyte line melan-a YAP remained cytoplasmic in the setting of GNAQQ209L mutation (Figure 4C).	('GNAQQ209L', 'Gene', (93, 102))	('melan-a', 'Gene', '77836', (42, 49))	('mutation', 'Var', (103, 111))	('melan-a', 'Gene', (42, 49))	('mouse', 'Species', '10090', (20, 25))
85295	33262460	Similar results were observed in a panel of melanoma cells and no increased nuclear localization was seen in cells with Galphaq pathway mutations.	('localization', 'biological_process', 'GO:0051179', ('84', '96'))	('Galphaq', 'Gene', (120, 127))	('Galphaq', 'Gene', '2776', (120, 127))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('mutations', 'Var', (136, 145))
85297	33262460	In aggregate, these data affirm the selective activation of PLCbeta and PKC in melanomas with Galphaq pathway mutations, and do not specifically implicate FAK/YAP signaling in this context.	('melanomas', 'Disease', 'MESH:D008545', (79, 88))	('FAK', 'molecular_function', 'GO:0004717', ('155', '158'))	('mutations', 'Var', (110, 119))	('signaling', 'biological_process', 'GO:0023052', ('163', '172'))	('Galphaq', 'Gene', (94, 101))	('activation', 'PosReg', (46, 56))	('Galphaq', 'Gene', '2776', (94, 101))	('PKC', 'Gene', (72, 75))	('PKC', 'Gene', '112476', (72, 75))	('melanomas', 'Disease', (79, 88))	('PLCbeta', 'Enzyme', (60, 67))	('FAK', 'Gene', (155, 158))	('FAK', 'Gene', '5747', (155, 158))	('PKC', 'molecular_function', 'GO:0004697', ('72', '75'))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))
85300	33262460	PKC delta and epsilon mediate MAPK activation in UM, and their simultaneous knock-down reduced cell survival by 50-75% at 6 days in UM cells with GNAQ or GNA11 mutations (Figure 5A, top panel).	('PKC delta', 'Gene', '5580', (0, 9))	('mutations', 'Var', (160, 169))	('MAPK', 'molecular_function', 'GO:0004707', ('30', '34'))	('GNAQ', 'Gene', '2776', (146, 150))	('UM', 'Phenotype', 'HP:0007716', (49, 51))	('MAPK activation', 'biological_process', 'GO:0000187', ('30', '45'))	('reduced', 'NegReg', (87, 94))	('GNA11', 'Gene', (154, 159))	('UM', 'Phenotype', 'HP:0007716', (132, 134))	('knock-down', 'Var', (76, 86))	('GNA11', 'Gene', '2767', (154, 159))	('PKC delta', 'Gene', (0, 9))	('cell survival', 'CPA', (95, 108))	('GNAQ', 'Gene', (146, 150))	('MAPK', 'Enzyme', (30, 34))	('activation', 'PosReg', (35, 45))	('PKC', 'molecular_function', 'GO:0004697', ('0', '3'))
85301	33262460	Comparable effects were obtained after ERK1/2 knock-down.	('ERK1/2', 'Gene', '5595;5594', (39, 45))	('ERK1/2', 'Gene', (39, 45))	('knock-down', 'Var', (46, 56))	('ERK1', 'molecular_function', 'GO:0004707', ('39', '43'))
85302	33262460	In contrast, FAK knock-down reduced cell viability by no more than 25% and YAP1 knock-down had no effect.	('reduced', 'NegReg', (28, 35))	('FAK', 'molecular_function', 'GO:0004717', ('13', '16'))	('FAK', 'Gene', '5747', (13, 16))	('YAP1', 'Gene', '10413', (75, 79))	('knock-down', 'Var', (17, 27))	('FAK', 'Gene', (13, 16))	('cell viability', 'CPA', (36, 50))	('YAP1', 'Gene', (75, 79))
85306	33262460	Knock-out of YAP1 has no effect on long term cell proliferation, whereas genetic depletion of RasGRP3 and GNAQ significantly inhibited cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('135', '153'))	('GNAQ', 'Gene', (106, 110))	('cell proliferation', 'biological_process', 'GO:0008283', ('45', '63'))	('genetic depletion', 'Var', (73, 90))	('YAP1', 'Gene', '10413', (13, 17))	('RasGRP3', 'Gene', (94, 101))	('cell proliferation', 'CPA', (135, 153))	('inhibited', 'NegReg', (125, 134))	('RasGRP3', 'Gene', '25780', (94, 101))	('YAP1', 'Gene', (13, 17))	('GNAQ', 'Gene', '2776', (106, 110))
85309	33262460	By contrast, there was no difference in the drug response curves between UM and CM cells for VS-4718, Verteporfin, and CM cell lines were more sensitive to MEK inhibitor Trametinib.	('UM', 'Phenotype', 'HP:0007716', (73, 75))	('CM', 'Phenotype', 'HP:0012056', (119, 121))	('Trametinib', 'Chemical', 'MESH:C560077', (170, 180))	('sensitive', 'MPA', (143, 152))	('CM', 'Phenotype', 'HP:0012056', (80, 82))	('MEK', 'Gene', (156, 159))	('MEK', 'Gene', '5609', (156, 159))	('VS-4718', 'Var', (93, 100))	('Verteporfin', 'Chemical', 'MESH:D000077362', (102, 113))
85312	33262460	We exposed one GNAQ mutant (OMM1.3) and one GNA11 mutant cell line (MP41) to pair-wise combinations of three inhibitors (VS-471 for FAK, Trametinib for MEK, and LXS196 for PKC) across different concentration ranges and determined the effect on cell viability after four days.	('PKC', 'Gene', (172, 175))	('FAK', 'Gene', (132, 135))	('GNAQ', 'Gene', (15, 19))	('PKC', 'Gene', '112476', (172, 175))	('PKC', 'molecular_function', 'GO:0004697', ('172', '175'))	('GNA11', 'Gene', (44, 49))	('LXS196', 'Var', (161, 167))	('FAK', 'molecular_function', 'GO:0004717', ('132', '135'))	('combinations', 'Interaction', (87, 99))	('GNA11', 'Gene', '2767', (44, 49))	('MEK', 'Gene', (152, 155))	('LXS196', 'Chemical', '-', (161, 167))	('GNAQ', 'Gene', '2776', (15, 19))	('FAK', 'Gene', '5747', (132, 135))	('MEK', 'Gene', '5609', (152, 155))	('Trametinib', 'Chemical', 'MESH:C560077', (137, 147))
85316	33262460	We investigated whether the GNAQ/11 specific inhibitor YM-254890, can suppress growth in a broad range of UM cells with different secondary driver mutations and primary and metastatic origin.	('YM-254890', 'Chemical', 'MESH:C475455', (55, 64))	('GNAQ', 'Gene', '2776', (28, 32))	('suppress', 'NegReg', (70, 78))	('growth', 'MPA', (79, 85))	('YM-254890', 'Var', (55, 64))	('GNAQ', 'Gene', (28, 32))	('UM', 'Phenotype', 'HP:0007716', (106, 108))
85317	33262460	We found that YM-254890 selectively inhibited IP1 production in a dose-dependent manner in all 10 UM cell lines with GNAQ/11 mutations, irrespective of their pattern of additional mutations (Figure 7A, Figure S6A, supplemental table 1) and had no effect on CM cell lines and on the MEL290 cell line.	('mutations', 'Var', (125, 134))	('inhibited', 'NegReg', (36, 45))	('CM', 'Phenotype', 'HP:0012056', (257, 259))	('GNAQ', 'Gene', '2776', (117, 121))	('YM-254890', 'Chemical', 'MESH:C475455', (14, 23))	('IP1', 'Gene', (46, 49))	('GNAQ', 'Gene', (117, 121))	('IP1', 'Gene', '8517', (46, 49))	('UM', 'Phenotype', 'HP:0007716', (98, 100))
85318	33262460	Similarly, YM-254890 dose-dependently extinguished RasGRP3/MAPK signaling (Figure 7B and Figure S6B) in all UM cell lines irrespective of mutations in EIF1AX, SF3B1 or BAP1, but had no effect on CM cell lines.	('CM', 'Phenotype', 'HP:0012056', (195, 197))	('BAP1', 'Gene', '8314', (168, 172))	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('MAPK signaling', 'biological_process', 'GO:0000165', ('59', '73'))	('BAP1', 'Gene', (168, 172))	('MAPK', 'molecular_function', 'GO:0004707', ('59', '63'))	('SF3B1', 'Gene', (159, 164))	('RasGRP3', 'Gene', (51, 58))	('extinguished', 'NegReg', (38, 50))	('RasGRP3', 'Gene', '25780', (51, 58))	('EIF1AX', 'Gene', '1964', (151, 157))	('EIF1AX', 'Gene', (151, 157))	('SF3B1', 'Gene', '23451', (159, 164))	('YM-254890', 'Chemical', 'MESH:C475455', (11, 20))	('mutations', 'Var', (138, 147))
85319	33262460	FAK signaling was also suppressed by YM-254890 (Figure 7B and Figure S6B).	('YM-254890', 'Var', (37, 46))	('suppressed', 'NegReg', (23, 33))	('FAK', 'molecular_function', 'GO:0004717', ('0', '3'))	('YM-254890', 'Chemical', 'MESH:C475455', (37, 46))	('FAK', 'Gene', (0, 3))	('FAK', 'Gene', '5747', (0, 3))	('signaling', 'biological_process', 'GO:0023052', ('4', '13'))
85320	33262460	At concentration above 10nM, YM-254890 induced apoptosis in GNAQ/11 mutant cells, as evidenced by PARP cleavage (Figure 7B and Figure S6B).	('PARP', 'Gene', '1302', (98, 102))	('GNAQ', 'Gene', (60, 64))	('PARP', 'Gene', (98, 102))	('YM-254890', 'Chemical', 'MESH:C475455', (29, 38))	('apoptosis', 'biological_process', 'GO:0097194', ('47', '56'))	('apoptosis', 'biological_process', 'GO:0006915', ('47', '56'))	('apoptosis', 'CPA', (47, 56))	('GNAQ', 'Gene', '2776', (60, 64))	('YM-254890', 'Var', (29, 38))	('mutant', 'Var', (68, 74))
85321	33262460	Growth assays showed a similar pattern in that all UM cell lines were highly sensitive to YM-254890 (IC50 0.5nM - 84nM), whereas the compound had no effect on CM cell lines (Figure 8A).	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('YM-254890', 'Var', (90, 99))	('CM', 'Phenotype', 'HP:0012056', (159, 161))	('sensitive', 'Reg', (77, 86))	('YM-254890', 'Chemical', 'MESH:C475455', (90, 99))
85322	33262460	Interestingly, GNA11 mutant cells were more sensitive (IC50: 0.5-2.7nM) than GNAQ mutant cells (IC50: 8.2 to 84.7nM) (p-value <0.05) (Figure 8 A,B).	('GNA11', 'Gene', (15, 20))	('mutant', 'Var', (21, 27))	('GNA11', 'Gene', '2767', (15, 20))	('GNAQ', 'Gene', (77, 81))	('sensitive', 'MPA', (44, 53))	('GNAQ', 'Gene', '2776', (77, 81))
85323	33262460	YM-254890 also markedly inhibited colony formation of UM cells with GNAQ (92-1, MEL270) or GNA11 mutations (MP41, UPMD1), with no effect on CM cells (Figure 8C).	('mutations', 'Var', (97, 106))	('CM', 'Phenotype', 'HP:0012056', (140, 142))	('formation', 'biological_process', 'GO:0009058', ('41', '50'))	('GNA11', 'Gene', (91, 96))	('GNAQ', 'Gene', (68, 72))	('colony formation of UM cells', 'CPA', (34, 62))	('inhibited', 'NegReg', (24, 33))	('GNA11', 'Gene', '2767', (91, 96))	('YM-254890', 'Chemical', 'MESH:C475455', (0, 9))	('UM', 'Phenotype', 'HP:0007716', (54, 56))	('GNAQ', 'Gene', '2776', (68, 72))
85324	33262460	In sum, YM-254890 effectively suppressed signaling downstream of Galphaq and cell proliferation across a broad range of UM cells with different genetic backgrounds and irrespective of primary or metastatic provenance.	('cell proliferation', 'biological_process', 'GO:0008283', ('77', '95'))	('Galphaq', 'Gene', (65, 72))	('suppressed', 'NegReg', (30, 40))	('Galphaq', 'Gene', '2776', (65, 72))	('YM-254890', 'Chemical', 'MESH:C475455', (8, 17))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('UM', 'Phenotype', 'HP:0007716', (120, 122))	('signaling downstream', 'MPA', (41, 61))	('YM-254890', 'Var', (8, 17))	('cell proliferation', 'CPA', (77, 95))
85325	33262460	Targeted therapy has become a mainstay of therapy in melanomas with BRAF mutations.	('melanomas', 'Disease', (53, 62))	('BRAF', 'Gene', '673', (68, 72))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('BRAF', 'Gene', (68, 72))	('melanomas', 'Disease', 'MESH:D008545', (53, 62))	('mutations', 'Var', (73, 82))
85329	33262460	Over 90% of uveal melanomas have mutations at the level of the the Galphaq family members GNAQ and GNA11 and the remainder mostly have mutations in CYSLTR2, a GPCR known to be Galphaq-coupled, or PLCB4, encoding the Galphaq effector PLCbeta4.	('uveal melanomas', 'Disease', 'MESH:C536494', (12, 27))	('Galphaq', 'Gene', (216, 223))	('PLCbeta4', 'Gene', '5332', (233, 241))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('CYSLTR2', 'Gene', '57105', (148, 155))	('mutations', 'Var', (33, 42))	('GNA11', 'Gene', '2767', (99, 104))	('Galphaq', 'Gene', (176, 183))	('Galphaq', 'Gene', '2776', (216, 223))	('uveal melanoma', 'Phenotype', 'HP:0007716', (12, 26))	('mutations', 'Var', (135, 144))	('CYSLTR2', 'Gene', (148, 155))	('PLCbeta4', 'Gene', (233, 241))	('Galphaq', 'Gene', '2776', (176, 183))	('PLCB4', 'Gene', (196, 201))	('uveal melanomas', 'Disease', (12, 27))	('uveal melanomas', 'Phenotype', 'HP:0007716', (12, 27))	('GNAQ', 'Gene', '2776', (90, 94))	('GNA11', 'Gene', (99, 104))	('Galphaq', 'Gene', (67, 74))	('GNAQ', 'Gene', (90, 94))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))	('PLCB4', 'Gene', '5332', (196, 201))	('Galphaq', 'Gene', '2776', (67, 74))
85330	33262460	This distribution of mutations on its own implicates the CYSLTR2->Galphaq->PLCbeta4 module as critical for oncogenic signaling in UM.	('CYSLTR2', 'Gene', (57, 64))	('Galphaq', 'Gene', (66, 73))	('Galphaq', 'Gene', '2776', (66, 73))	('PLCbeta4', 'Gene', (75, 83))	('UM', 'Phenotype', 'HP:0007716', (130, 132))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))	('CYSLTR2', 'Gene', '57105', (57, 64))	('PLCbeta4', 'Gene', '5332', (75, 83))	('mutations', 'Var', (21, 30))
85331	33262460	We show that mutant CYSLTR2 indeed activates GNAQ/11 and activates PLCbeta.	('mutant', 'Var', (13, 19))	('activates', 'PosReg', (35, 44))	('CYSLTR2', 'Gene', '57105', (20, 27))	('PLCbeta', 'Enzyme', (67, 74))	('CYSLTR2', 'Gene', (20, 27))	('activates', 'PosReg', (57, 66))	('GNAQ', 'Gene', (45, 49))	('GNAQ', 'Gene', '2776', (45, 49))
85332	33262460	This and the finding of activating mutations in PLCB4 in the few UMs without GPCR or Galphaq mutations points to PLC beta activation as the central signaling node in UM.	('UM', 'Phenotype', 'HP:0007716', (65, 67))	('PLCB4', 'Gene', '5332', (48, 53))	('activating', 'PosReg', (24, 34))	('PLC', 'cellular_component', 'GO:0042824', ('113', '116'))	('signaling', 'biological_process', 'GO:0023052', ('148', '157'))	('UM', 'Phenotype', 'HP:0007716', (166, 168))	('PLCB4', 'Gene', (48, 53))	('Galphaq', 'Gene', (85, 92))	('Galphaq', 'Gene', '2776', (85, 92))	('mutations', 'Var', (35, 44))
85334	33262460	We note that the MEL290 line included in our panel is attributed to a uveal melanoma arising within a nevus of Ota but does not show any of the common genetic attributes of UM, such as mutations in the Galphaq pathway or affecting BAP1, SF3B1, or EIF1AX.	('melanoma', 'Disease', (76, 84))	('Galphaq', 'Gene', '2776', (202, 209))	('nevus of Ota', 'Phenotype', 'HP:0009920', (102, 114))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('Galphaq', 'Gene', (202, 209))	('SF3B1', 'Gene', (237, 242))	('UM', 'Phenotype', 'HP:0007716', (173, 175))	('BAP1', 'Gene', '8314', (231, 235))	('mutations', 'Var', (185, 194))	('nevus', 'Phenotype', 'HP:0003764', (102, 107))	('EIF1AX', 'Gene', '1964', (247, 253))	('EIF1AX', 'Gene', (247, 253))	('SF3B1', 'Gene', '23451', (237, 242))	('BAP1', 'Gene', (231, 235))	('affecting', 'Reg', (221, 230))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
85335	33262460	It also does not express melanocyte lineage markers such as HMB45 or Melan-A/MART1, or RasGRP3 or MITF that is detected in all Galphaq mutant UM cells.	('Galphaq', 'Gene', (127, 134))	('Melan-A', 'Gene', (69, 76))	('Galphaq', 'Gene', '2776', (127, 134))	('Melan-A', 'Gene', '2315', (69, 76))	('MITF', 'Gene', '4286', (98, 102))	('MITF', 'Gene', (98, 102))	('UM', 'Phenotype', 'HP:0007716', (142, 144))	('mutant', 'Var', (135, 141))	('MART1', 'Gene', (77, 82))	('RasGRP3', 'Gene', '25780', (87, 94))	('RasGRP3', 'Gene', (87, 94))	('MART1', 'Gene', '2315', (77, 82))
85338	33262460	GNAQQ209L and GNAQQ209P increased IP1 levels 12-fold compared to a merely 3-fold increase by GNA11Q209L.	('GNAQQ209P', 'Mutation', 'rs121913492', (14, 23))	('IP1', 'Gene', (34, 37))	('GNAQQ209L', 'Var', (0, 9))	('IP1', 'Gene', '8517', (34, 37))	('GNAQQ209P', 'Var', (14, 23))	('increased', 'PosReg', (24, 33))
85339	33262460	R183 mutants of GNA11 also resulted in lower IP1 accumulation than corresponding mutations in GNAQ.	('GNA11', 'Gene', (16, 21))	('IP1', 'Gene', (45, 48))	('GNA11', 'Gene', '2767', (16, 21))	('IP1', 'Gene', '8517', (45, 48))	('GNAQ', 'Gene', '2776', (94, 98))	('R183 mutants', 'Var', (0, 12))	('lower', 'NegReg', (39, 44))	('GNAQ', 'Gene', (94, 98))
85340	33262460	The finding that R183 mutants had an overall weaker signaling output than Q209 mutants was expected, as the mutations at R183 are known to only partially impede GTPase activity.	('activity', 'MPA', (168, 176))	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('GTP', 'Chemical', 'MESH:D006160', (161, 164))	('GTPase activity', 'molecular_function', 'GO:0003924', ('161', '176'))	('GTPase', 'Protein', (161, 167))	('weaker', 'NegReg', (45, 51))	('impede', 'NegReg', (154, 160))	('R183 mutants', 'Var', (17, 29))	('signaling output', 'MPA', (52, 68))
85341	33262460	The difference between PLC beta induction of mutant GNAQ and GNA11 might be attributable to variation in their effector spectrum resulting from subtle changes in their molecular conformations.	('mutant', 'Var', (45, 51))	('PLC', 'cellular_component', 'GO:0042824', ('23', '26'))	('GNAQ', 'Gene', '2776', (52, 56))	('GNA11', 'Gene', '2767', (61, 66))	('GNA11', 'Gene', (61, 66))	('changes', 'Reg', (151, 158))	('GNAQ', 'Gene', (52, 56))
85344	33262460	This contrasted with markedly reduced variation in IP1 levels among UM cell lines despite similar variations in GNAQ and GNA11 mutations and therefore indicates additional complexity in how cancer cells with driver mutations that vary in their ability to activate PLC beta regulate optimal second messenger production.	('optimal second messenger production', 'MPA', (282, 317))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('GNA11', 'Gene', '2767', (121, 126))	('PLC', 'Enzyme', (264, 267))	('GNAQ', 'Gene', (112, 116))	('IP1', 'Gene', (51, 54))	('activate', 'PosReg', (255, 263))	('GNAQ', 'Gene', '2776', (112, 116))	('IP1', 'Gene', '8517', (51, 54))	('PLC', 'cellular_component', 'GO:0042824', ('264', '267'))	('mutations', 'Var', (215, 224))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('reduced', 'NegReg', (30, 37))	('UM', 'Phenotype', 'HP:0007716', (68, 70))	('mutations', 'Var', (127, 136))	('GNA11', 'Gene', (121, 126))	('variations', 'Var', (98, 108))
85345	33262460	The variation among the biologic effects of the various mutations in the CYSLTR2->Galphaq->PLC beta pathway was also reflected in their response to YM-254890.	('Galphaq', 'Gene', (82, 89))	('mutations', 'Var', (56, 65))	('CYSLTR2', 'Gene', '57105', (73, 80))	('PLC', 'cellular_component', 'GO:0042824', ('91', '94'))	('CYSLTR2', 'Gene', (73, 80))	('Galphaq', 'Gene', '2776', (82, 89))	('YM-254890', 'Chemical', 'MESH:C475455', (148, 157))
85346	33262460	The compound was less effective on GNAQQ209L compared to the other Galphaq variants including GNAQQ209P.	('GNAQQ209P', 'Mutation', 'rs121913492', (94, 103))	('less', 'NegReg', (17, 21))	('GNAQQ209L', 'Var', (35, 44))	('Galphaq', 'Gene', (67, 74))	('Galphaq', 'Gene', '2776', (67, 74))
85347	33262460	The variation is possibly due to the unique conformation of GNAQQ209L resulting in lower affinity for YM-254890 compared to GNAQQ209P.	('YM-254890', 'Var', (102, 111))	('GNAQQ209L', 'Var', (60, 69))	('GNAQQ209P', 'Mutation', 'rs121913492', (124, 133))	('lower', 'NegReg', (83, 88))	('YM-254890', 'Chemical', 'MESH:C475455', (102, 111))	('affinity', 'Interaction', (89, 97))
85358	33262460	Targeted cancer therapy has been most successful in situations, in which a proliferation-driving gain of function mutation can be targeted directly.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('mutation', 'Var', (114, 122))	('proliferation-driving gain of function', 'PosReg', (75, 113))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
85360	33262460	The mechanism of mutational activation of GNAQ/11 is essentially similar to that of RAS oncogenes but the prospect of their direct pharmacological inhibition has moved within reach with the recent identification of direct inhibitors.	('mutational', 'Var', (17, 27))	('GNAQ', 'Gene', (42, 46))	('GNAQ', 'Gene', '2776', (42, 46))
85361	33262460	In this study, we provide evidence that YM-254890 is effective in blocking signaling and proliferation across the board in a broad panel of UM cells carrying different activating mutation in Galphaq pathway, independent of secondary mutations and tumor cell origin (primary or metastasis).	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('YM-254890', 'Var', (40, 49))	('signaling', 'MPA', (75, 84))	('proliferation across', 'CPA', (89, 109))	('tumor', 'Disease', (247, 252))	('blocking', 'NegReg', (66, 74))	('YM-254890', 'Chemical', 'MESH:C475455', (40, 49))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('Galphaq', 'Gene', (191, 198))	('Galphaq', 'Gene', '2776', (191, 198))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('UM', 'Phenotype', 'HP:0007716', (140, 142))
85363	33262460	Although YM-254890 and FR900359 have similar structures, differing only by one amino acid and acyl group, we demonstrate that YM-254890 is GNAQ/11 specific.	('YM-254890', 'Chemical', 'MESH:C475455', (9, 18))	('FR900359', 'Var', (23, 31))	('YM-254890', 'Var', (126, 135))	('FR900359', 'Chemical', 'MESH:C000607068', (23, 31))	('GNAQ', 'Gene', '2776', (139, 143))	('YM-254890', 'Chemical', 'MESH:C475455', (126, 135))	('YM-254890', 'Var', (9, 18))	('GNAQ', 'Gene', (139, 143))
85366	33262460	Therefore, YM-254890 as a GNAQ/11 specific inhibitor would be expected to have less toxicity due to specific G protein inhibition than FR900359.	('FR900359', 'Chemical', 'MESH:C000607068', (135, 143))	('GNAQ', 'Gene', (26, 30))	('inhibition', 'NegReg', (119, 129))	('YM-254890', 'Chemical', 'MESH:C475455', (11, 20))	('YM-254890', 'Var', (11, 20))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('GNAQ', 'Gene', '2776', (26, 30))	('toxicity', 'Disease', 'MESH:D064420', (84, 92))	('specific G protein', 'Protein', (100, 118))	('toxicity', 'Disease', (84, 92))
85383	33262460	The human gene ON-TARGET plus SMARTpool siRNAs were used: Non targeting siRNAs pool (D-001810-10-05), GNAQ (L-008562-00-0005), YAP1 (L-012200-00-0005), PKC delta (L-003524-00-0005), PKC epsilon (L-004653-00-0005), FAK1 (L-003164-00-0005), ERK1 (L-003592-00-0005), ERK2 (L-003555-00-0005) were all from Dharmacon, Inc. (Chicago, IL).	('ERK1', 'Gene', '5595', (239, 243))	('L-003524-00-0005', 'Var', (163, 179))	('GNAQ', 'Gene', (102, 106))	('PKC', 'molecular_function', 'GO:0004697', ('152', '155'))	('PKC epsilon', 'Disease', (182, 193))	('FAK', 'molecular_function', 'GO:0004717', ('214', '217'))	('YAP1', 'Gene', (127, 131))	('ERK2', 'Gene', '5594', (264, 268))	('L-003592-00-0005', 'Var', (245, 261))	('L-004653-00-0005', 'Var', (195, 211))	('ERK2', 'Gene', (264, 268))	('PKC delta', 'Gene', '5580', (152, 161))	('ERK2', 'molecular_function', 'GO:0004707', ('264', '268'))	('ERK1', 'molecular_function', 'GO:0004707', ('239', '243'))	('FAK1', 'Gene', (214, 218))	('L-012200-00-0005', 'Var', (133, 149))	('PKC delta', 'Gene', (152, 161))	('PKC', 'molecular_function', 'GO:0004697', ('182', '185'))	('L-003164-00-0005', 'Var', (220, 236))	('FAK1', 'Gene', '5747', (214, 218))	('PKC epsilon', 'Disease', 'MESH:C537180', (182, 193))	('human', 'Species', '9606', (4, 9))	('L-003555-00-0005', 'Var', (270, 286))	('ERK1', 'Gene', (239, 243))	('GNAQ', 'Gene', '2776', (102, 106))	('YAP1', 'Gene', '10413', (127, 131))
85406	33435389	In 2020, the first triple-therapy combining BRAF/MEK targeted and anti-PD-1 immunotherapy with atezolizumab, vemurafenib and cobimetinib was approved for unresectable or metastatic BRAF V600-mutated melanoma (IMspire150 study), while another trial investigating triple therapy missed its endpoint.	('BRAF', 'Gene', '673', (44, 48))	('BRAF', 'Gene', (44, 48))	('MEK', 'Gene', (49, 52))	('cobimetinib', 'Chemical', 'MESH:C574276', (125, 136))	('MEK', 'Gene', '5609', (49, 52))	('V600-mutated', 'Var', (186, 198))	('BRAF', 'Gene', (181, 185))	('BRAF', 'Gene', '673', (181, 185))	('vemurafenib', 'Chemical', 'MESH:D000077484', (109, 120))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('melanoma', 'Disease', (199, 207))	('atezolizumab', 'Chemical', 'MESH:C000594389', (95, 107))
85407	33435389	In the adjuvant setting, updated data continue to support the use of either anti-PD-1 antibodies and BRAF/MEK inhibitors.	('BRAF', 'Gene', (101, 105))	('MEK', 'Gene', (106, 109))	('MEK', 'Gene', '5609', (106, 109))	('anti-PD-1', 'Var', (76, 85))	('BRAF', 'Gene', '673', (101, 105))
85430	33435389	The IMspire150 study randomized 514 treatment-naive patients with V600 BRAF mutated unresectable stage III/IV melanoma to treatment with vemurafenib and cobimetinib (V/C) plus or minus the PD-L1 inhibitor atezolizumab.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('PD-L1', 'Gene', '29126', (189, 194))	('cobimetinib', 'Chemical', 'MESH:C574276', (153, 164))	('BRAF', 'Gene', '673', (71, 75))	('mutated', 'Var', (76, 83))	('BRAF', 'Gene', (71, 75))	('atezolizumab', 'Chemical', 'MESH:C000594389', (205, 217))	('PD-L1', 'Gene', (189, 194))	('V600', 'Var', (66, 70))	('patients', 'Species', '9606', (52, 60))	('vemurafenib', 'Chemical', 'MESH:D000077484', (137, 148))
85437	33435389	This trial also reported other endpoints, such as incidence and time to development of brain metastases with first-line combination treatment with V/C combined with atezolizumab or placebo.	('brain metastases', 'Disease', (87, 103))	('atezolizumab', 'Chemical', 'MESH:C000594389', (165, 177))	('V/C', 'Var', (147, 150))	('brain metastases', 'Disease', 'MESH:D009362', (87, 103))
85440	33435389	After six weeks of pembrolizumab treatment, patients with advanced melanoma expressing BRAF V600E/K were randomized, as part of the phase 2 IMPemBra trial, to continue pembrolizumab alone or added dabrafenib plus trametinib (two cohorts of intermittent dosing and a cohort of continuous dosing for six weeks).	('V600E', 'SUBSTITUTION', 'None', (92, 97))	('patients', 'Species', '9606', (44, 52))	('trametinib', 'Chemical', 'MESH:C560077', (213, 223))	('dabrafenib', 'Chemical', 'MESH:C561627', (197, 207))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('pembrolizumab', 'Chemical', 'MESH:C582435', (19, 32))	('V600E', 'Var', (92, 97))	('BRAF', 'Gene', (87, 91))	('pembrolizumab', 'Chemical', 'MESH:C582435', (168, 181))	('BRAF', 'Gene', '673', (87, 91))
85456	33435389	For patients who received systemic treatment after acquired resistance, anti-PD-1 was the most common choice (51% of the patients; 41% continuation, 59% reinduction) compared to dual checkpoint inhibition with anti-PD-1 and anti-CTLA-4 in 12%; anti-CTLA-4 monotherapy in 6%; targeted therapy in 19%; and investigational drugs in 11%.	('CTLA-4', 'Gene', '1493', (229, 235))	('CTLA-4', 'Gene', '1493', (249, 255))	('anti-PD-1', 'Var', (72, 81))	('CTLA-4', 'Gene', (229, 235))	('CTLA-4', 'Gene', (249, 255))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (121, 129))
85480	33435389	Neurotrophic tropomyosin receptor kinase (NTRK) fusions can be found in melanoma, and tropomyosin receptor kinase (TRK) inhibitors larotrectinib and entrectinib are approved to treat solid tumors with this key genetic driver, therefore there are clinical trials to investigate these drugs in melanoma patients (NCT02465060, NCT02576431, NCT02568267).	('solid tumors', 'Disease', 'MESH:D009369', (183, 195))	('melanoma', 'Disease', 'MESH:D008545', (292, 300))	('patients', 'Species', '9606', (301, 309))	('tropomyosin receptor kinase', 'Gene', (86, 113))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('NCT02576431', 'Var', (324, 335))	('TRK', 'Gene', (115, 118))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('TRK', 'Gene', (43, 46))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tropomyosin receptor kinase', 'Gene', (13, 40))	('larotrectinib', 'Chemical', 'MESH:C000609083', (131, 144))	('melanoma', 'Phenotype', 'HP:0002861', (292, 300))	('melanoma', 'Disease', (292, 300))	('TRK', 'Gene', '4914', (115, 118))	('tropomyosin receptor kinase', 'Gene', '4914', (86, 113))	('TRK', 'Gene', '4914', (43, 46))	('solid tumors', 'Disease', (183, 195))	('tropomyosin receptor kinase', 'Gene', '4914', (13, 40))	('entrectinib', 'Chemical', 'MESH:C000607349', (149, 160))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('NCT02465060', 'Var', (311, 322))
85483	33435389	A retrospective multicenter study with 101 patients, including, but not limited to, melanoma patients, has suggested better outcomes to immune checkpoint blockade for patients with alterations in the tumor suppressor gene LRP1b (low-density lipoprotein receptor-related protein 1b).	('LRP1b', 'Gene', (222, 227))	('alterations', 'Var', (181, 192))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('patients', 'Species', '9606', (43, 51))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('low-density lipoprotein receptor-related protein 1b', 'Gene', '53353', (229, 280))	('patients', 'Species', '9606', (167, 175))	('melanoma', 'Disease', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('tumor', 'Disease', (200, 205))	('low-density lipoprotein', 'molecular_function', 'GO:0005322', ('229', '252'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('200', '216'))	('protein', 'cellular_component', 'GO:0003675', ('270', '277'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('200', '216'))	('LRP1b', 'Gene', '53353', (222, 227))	('patients', 'Species', '9606', (93, 101))
85484	33435389	Patients with pathogenic LRP1b alterations had better ORRs and PFS:even after excluding microsatellite instability (MSI)-high or tumor mutational burden (TMB) tumors:compared to patients with variants of undetermined significance alterations.	('alterations', 'Var', (31, 42))	('better', 'PosReg', (47, 53))	('ORRs', 'MPA', (54, 58))	('LRP1b', 'Gene', '53353', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('patients', 'Species', '9606', (178, 186))	('PFS', 'MPA', (63, 66))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('microsatellite instability', 'MPA', (88, 114))	('tumor', 'Disease', (159, 164))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('LRP1b', 'Gene', (25, 30))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
85485	33435389	Other upcoming treatment modalities in clinical trials include quadruple therapy with BRAK/MEK inhibitors in combination or sequential regimens with anti-CTLA-4 and anti-PD1/PD-L1 antibodies (NCT01940809, NCT02968303, NCT02224781); intratumoral RNA-based TLR-7/-8 and RIG-I agonists as monotherapy or in combination with anti-PD-1 drugs (NCT03291002); subcutaneous and intratumoral DNA TLR-9 agonists in monotherapy (NCT04126876) or combination with checkpoint inhibitors (NCT03445533, NCT04401995, NCT03618641); T cell redirection with tebentafusp (formerly known as IMCgp100) as monotherapy or combined with anti-CTLA-4 antibody tremelimumab, or anti-PD-L1 antibody durvalumab, or both (NCT02535078); histone deacetylase (HDAC) inhibitors (e.g., entinostat, panobinostat, abexinostat) in combination with ipilimumab (NCT02032810) or anti-PD-1 (NCT02697630, NCT03765229, NCT03590054); and intratumorally administered stimulator of interferon genes (STING) agonist (NCT04144140).	('tumor', 'Disease', (895, 900))	('DNA', 'cellular_component', 'GO:0005574', ('382', '385'))	('CTLA-4', 'Gene', '1493', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (374, 379))	('tumor', 'Disease', 'MESH:D009369', (895, 900))	('TLR-9', 'Gene', (386, 391))	('CTLA-4', 'Gene', '1493', (615, 621))	('NCT02032810', 'Var', (819, 830))	('CTLA-4', 'Gene', (154, 160))	('MEK', 'Gene', '5609', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('RIG-I', 'Gene', '23586', (268, 273))	('antibody', 'cellular_component', 'GO:0019814', ('659', '667'))	('RIG-I', 'Gene', (268, 273))	('CTLA-4', 'Gene', (615, 621))	('antibody', 'cellular_component', 'GO:0019815', ('622', '630'))	('PD-L1', 'Gene', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (895, 900))	('MEK', 'Gene', (91, 94))	('PD-L1', 'Gene', '29126', (174, 179))	('NCT03590054', 'Var', (872, 883))	('antibody', 'molecular_function', 'GO:0003823', ('659', '667'))	('tumor', 'Disease', (374, 379))	('NCT02697630', 'Var', (846, 857))	('BRAK', 'Gene', '9547', (86, 90))	('antibody', 'cellular_component', 'GO:0019814', ('622', '630'))	('antibody', 'cellular_component', 'GO:0042571', ('659', '667'))	('tumor', 'Disease', 'MESH:D009369', (374, 379))	('TLR-7/-8', 'Gene', (255, 263))	('ipilimumab', 'Chemical', 'MESH:D000074324', (807, 817))	('tumor', 'Disease', (237, 242))	('TLR-7/-8', 'Gene', '51284;51311', (255, 263))	('TLR-9', 'Gene', '54106', (386, 391))	('NCT04144140', 'Var', (966, 977))	('antibody', 'molecular_function', 'GO:0003823', ('622', '630'))	('RNA', 'cellular_component', 'GO:0005562', ('245', '248'))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('BRAK', 'Gene', (86, 90))	('PD-L1', 'Gene', (653, 658))	('antibody', 'cellular_component', 'GO:0019815', ('659', '667'))	('antibody', 'cellular_component', 'GO:0042571', ('622', '630'))	('PD-L1', 'Gene', '29126', (653, 658))
85486	33435389	The three-year follow-up of pembrolizumab's adjuvant trial Keynote 054 displayed improved recurrence-free survival (RFS) across all subgroups (stages IIIA, IIIB and IIIC; PD-L1 positive and negative; BRAF-mutated and wildtype).	('improved', 'PosReg', (81, 89))	('pembrolizumab', 'Chemical', 'MESH:C582435', (28, 41))	('BRAF', 'Gene', (200, 204))	('PD-L1', 'Gene', (171, 176))	('BRAF', 'Gene', '673', (200, 204))	('PD-L1', 'Gene', '29126', (171, 176))	('recurrence-free survival', 'CPA', (90, 114))	('positive', 'Var', (177, 185))
85516	33435389	Ongoing clinical trials that address this question include combinations of immunoembolization with checkpoint inhibitors (NCT03472586), hepatic perfusion as monotherapy (NCT01785316) or combined with checkpoint blockade (NCT04283890), transarterial radioembolisation and transarterial chemoembolisation (NCT02936388), and PV-10 chemoablation (NCT00986661).	('NCT02936388', 'Var', (304, 315))	('NCT04283890', 'Var', (221, 232))	('NCT01785316', 'Var', (170, 181))	('PV-10', 'Chemical', '-', (322, 327))	('NCT03472586', 'Var', (122, 133))	('NCT00986661', 'Var', (343, 354))
85517	33435389	Promising clinical approaches for uveal melanoma in the adjuvant setting include adjuvant dendritic cell (DC) vaccination with autologous tumor RNA (NCT01983748), and sunitinib or valproic acid (NCT02068586).	('tumor', 'Disease', (138, 143))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('RNA', 'cellular_component', 'GO:0005562', ('144', '147'))	('valproic acid', 'Chemical', 'MESH:D014635', (180, 193))	('NCT01983748', 'Var', (149, 160))	('uveal melanoma', 'Phenotype', 'HP:0007716', (34, 48))	('uveal melanoma', 'Disease', 'MESH:C536494', (34, 48))	('sunitinib', 'Chemical', 'MESH:D000077210', (167, 176))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('uveal melanoma', 'Disease', (34, 48))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
85518	33435389	In patients with metastatic disease, currently recruiting clinical trials include novel immunotherapies such as tebentafusp (a first-in-class bispecific fusion protein that targets the melanoma-associated antigen gp100, NCT03070392), adoptive cell therapy (NCT03467516, NCT03467516, NCT03068624), combinations of radiation therapy and immunotherapy agents (NCT02913417), combinations of checkpoint inhibitors with novel molecules such as relatlimab (NCT04552223), MEK inhibitor with the FAK inhibitor IN10018 (NCT04109456), RO7293583 (a putative CD3 T-Cell engager targeting TYRP1, + tocilizumab +/- obinutuzumab, NCT04551352), intermittent therapy with selumetinib (NCT02768766), and DC vaccination in combination with a dual checkpoint blockade in metastatic patients (NCT04335890).	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('TYRP1', 'Gene', (575, 580))	('MEK', 'Gene', (464, 467))	('TYRP1', 'Gene', '7306', (575, 580))	('MEK', 'Gene', '5609', (464, 467))	('NCT02768766', 'Var', (667, 678))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('FAK', 'Gene', (487, 490))	('FAK', 'Gene', '5747', (487, 490))	('patients', 'Species', '9606', (3, 11))	('melanoma', 'Disease', (185, 193))	('patients', 'Species', '9606', (761, 769))	('selumetinib', 'Chemical', 'MESH:C517975', (654, 665))	('FAK', 'molecular_function', 'GO:0004717', ('487', '490'))	('obinutuzumab', 'Chemical', 'MESH:C543332', (600, 612))	('NCT04109456', 'Var', (510, 521))	('RO7293583', 'Var', (524, 533))
85530	33196849	In addition, a disruption in this chromosomal interaction prevented the histone acetyltransferase EP300 from embedding in the promoter of NTS and resulted in NTS silencing.	('NTS', 'Gene', (158, 161))	('embedding', 'MPA', (109, 118))	('prevented', 'NegReg', (58, 67))	('NTS', 'Gene', (138, 141))	('NTS', 'Gene', '4922', (158, 161))	('disruption', 'Var', (15, 25))	('NTS', 'Gene', '4922', (138, 141))	('silencing', 'NegReg', (162, 171))	('histone acetyltransferase EP300', 'Enzyme', (72, 103))
85531	33196849	Most importantly, in vitro and in vivo experiments showed that the ability of tumor formation was significantly suppressed via deletion of the enhancer by CRISPR-Cas9.	('Cas', 'cellular_component', 'GO:0005650', ('162', '165'))	('suppressed', 'NegReg', (112, 122))	('formation', 'biological_process', 'GO:0009058', ('84', '93'))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('deletion', 'Var', (127, 135))	('tumor', 'Disease', (78, 83))
85533	33196849	In a genomic analysis of over 9000 tumor cases, it was found that CTCF/cohesin-binding sites are frequently mutated in cancers.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('mutated', 'Var', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('CTCF/cohesin-binding', 'Protein', (66, 86))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('tumor', 'Disease', (35, 40))	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('cancers', 'Disease', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
85534	33196849	For example, in medulloblastoma, somatic structural variants juxtapose GFI1- or GFI1B-coding sequences proximal to active enhancer elements, including super enhancers, instigating oncogenic activity.	('GFI1-', 'Gene', (71, 76))	('oncogenic activity', 'CPA', (180, 198))	('GFI1B-coding', 'Gene', (80, 92))	('medulloblastoma', 'Disease', (16, 31))	('variants', 'Var', (52, 60))	('instigating', 'Reg', (168, 179))	('medulloblastoma', 'Disease', 'MESH:D008527', (16, 31))	('medulloblastoma', 'Phenotype', 'HP:0002885', (16, 31))
85572	33196849	The following antibodies were used in this study: anti-NTS (Abcam, ab233107, USA), anti-EP300 (Abcam, ab10485, USA), anti-CTCF (Abcam, ab70303, USA), anti-SMC1 (Abcam, ab9262, USA) and GAPDH (Sigma-Aldrich).	('SMC', 'cellular_component', 'GO:0016029', ('155', '158'))	('NTS', 'Gene', (55, 58))	('NTS', 'Gene', '4922', (55, 58))	('anti-EP300', 'Var', (83, 93))
85581	33196849	Bioluminescence was detected after 40 days by in vivo small animal imaging systems, the numbers of nude mice presented with stronger luminescence signal in sgRNA groups have been calculated as compared with NC group.	('Bioluminescence', 'biological_process', 'GO:0008218', ('0', '15'))	('stronger', 'PosReg', (124, 132))	('nude mice', 'Species', '10090', (99, 108))	('luminescence signal', 'MPA', (133, 152))	('sgRNA', 'Var', (156, 161))
85595	33196849	Next, we tested the chromatin status of the NTS promoter through formaldehyde-assisted isolation of regulatory elements (FAIRE) assays and found that the CTCF-bound NTS promoter presented an open chromatin status in tumor cells, while the non-CTCF-bound NTS promoter showed a closed chromatin status in normal cells (Figure 1F).	('tumor', 'Disease', (216, 221))	('open chromatin status', 'MPA', (191, 212))	('CTCF-bound', 'Var', (154, 164))	('NTS', 'Gene', '4922', (44, 47))	('NTS', 'Gene', (254, 257))	('NTS', 'Gene', (165, 168))	('formaldehyde', 'Chemical', 'MESH:D005557', (65, 77))	('chromatin', 'cellular_component', 'GO:0000785', ('20', '29'))	('NTS', 'Gene', '4922', (165, 168))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('chromatin', 'cellular_component', 'GO:0000785', ('283', '292'))	('NTS', 'Gene', '4922', (254, 257))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('chromatin', 'cellular_component', 'GO:0000785', ('196', '205'))	('NTS', 'Gene', (44, 47))
85601	33196849	Real-time PCR and Western blot assays both demonstrated that NTS expression was significantly decreased after small interfering RNA (siRNA) interference (Supplementary Figure S2).	('NTS', 'Gene', (61, 64))	('NTS', 'Gene', '4922', (61, 64))	('decreased', 'NegReg', (94, 103))	('expression', 'MPA', (65, 75))	('RNA', 'cellular_component', 'GO:0005562', ('128', '131'))	('small interfering', 'Var', (110, 127))
85603	33196849	The wound healing assay demonstrated a similar inhibition of cell migration after NTS silencing, which could also be rescued by the exogenous addition of recombinant NTS (100 ng/mul, Supplementary Figure S4A-C).	('NTS', 'Gene', '4922', (166, 169))	('NTS', 'Gene', (82, 85))	('silencing', 'Var', (86, 95))	('inhibition', 'NegReg', (47, 57))	('NTS', 'Gene', '4922', (82, 85))	('inhibition of cell migration', 'biological_process', 'GO:0030336', ('47', '75'))	('NTS', 'Gene', (166, 169))	('cell migration', 'CPA', (61, 75))	('wound healing', 'biological_process', 'GO:0042060', ('4', '17'))
85606	33196849	Next, by exploring The Cancer Genome Atlas (TCGA) database, we investigated the overall survival probability in the NTS high expression group and the low expression group in patients with UM.	('Cancer', 'Disease', (23, 29))	('NTS', 'Gene', (116, 119))	('Cancer', 'Disease', 'MESH:D009369', (23, 29))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('NTS', 'Gene', '4922', (116, 119))	('high expression', 'Var', (120, 135))	('patients', 'Species', '9606', (174, 182))	('UM', 'Phenotype', 'HP:0007716', (188, 190))
85607	33196849	As expected, Gene Expression Profiling Interactive Analysis (GEPIA, http://gepia.cancer-pku.cn) showed that high NTS levels positively correlated with a poor prognosis (P = 0.000047) (Figure 2E).	('NTS', 'Gene', (113, 116))	('NTS', 'Gene', '4922', (113, 116))	('high', 'Var', (108, 112))	('gepia.cancer-pku', 'Disease', (75, 91))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gepia.cancer-pku', 'Disease', 'MESH:D009369', (75, 91))	('Gene Expression', 'biological_process', 'GO:0010467', ('13', '28'))
85613	33196849	As expected, we observed NTS-LRRIQ1 interactions using L2a-N4 and L2b-N5 primer sets in tumors (Figure 3C).	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('L2b-N5', 'Var', (66, 72))	('LRRIQ1', 'Gene', (29, 35))	('NTS', 'Gene', (25, 28))	('NTS', 'Gene', '4922', (25, 28))	('LRRIQ1', 'Gene', '84125', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('L2a-N4', 'Var', (55, 61))	('interactions', 'Interaction', (36, 48))	('tumors', 'Disease', (88, 94))
85615	33196849	These NTS-LRRIQ1 interactions were then confirmed by DNA sequencing (Figure 3C, Supplementary Figure S9-S10).	('LRRIQ1', 'Gene', (10, 16))	('interactions', 'Var', (17, 29))	('LRRIQ1', 'Gene', '84125', (10, 16))	('NTS', 'Gene', (6, 9))	('NTS', 'Gene', '4922', (6, 9))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))
85626	33196849	To determine whether the deletion could control the transcription of NTS, we tested the expression of NTS through RNA-seq.	('NTS', 'Gene', (102, 105))	('control', 'Reg', (40, 47))	('tested', 'Reg', (77, 83))	('NTS', 'Gene', '4922', (102, 105))	('transcription', 'MPA', (52, 65))	('RNA', 'cellular_component', 'GO:0005562', ('114', '117'))	('NTS', 'Gene', (69, 72))	('deletion', 'Var', (25, 33))	('transcription', 'biological_process', 'GO:0006351', ('52', '65'))	('NTS', 'Gene', '4922', (69, 72))
85632	33196849	We next tested whether the interrupted chromosomal looping induced by enhancer deletion could inhibit tumorigenesis.	('enhancer', 'Gene', (70, 78))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('deletion', 'Var', (79, 87))	('inhibit', 'NegReg', (94, 101))
85637	33196849	As expected, the tumor volume in the enhancer-deleted group was significantly reduced compared with the empty vector group (Figure 5C, Supplementary Figure S13A).	('S13A', 'Var', (156, 160))	('tumor', 'Disease', (17, 22))	('enhancer-deleted', 'PosReg', (37, 53))	('S13A', 'SUBSTITUTION', 'None', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('reduced', 'NegReg', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
85641	33196849	Most importantly, after deleting the enhancer, the survival rate of the mice was significantly extended (Figure 5G).	('survival rate', 'CPA', (51, 64))	('mice', 'Species', '10090', (72, 76))	('extended', 'PosReg', (95, 103))	('deleting', 'Var', (24, 32))
85642	33196849	In the metastatic tumor model, there were fewer metastatic loci in the lungs of nude mice at 15 weeks in the enhancer-deleted group compared with the control group (Figure 5H, Supplementary Figure S13B).	('fewer', 'NegReg', (42, 47))	('S13B', 'SUBSTITUTION', 'None', (197, 201))	('nude mice', 'Species', '10090', (80, 89))	('tumor', 'Disease', (18, 23))	('metastatic loci in the lungs', 'CPA', (48, 76))	('enhancer-deleted', 'PosReg', (109, 125))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('S13B', 'Var', (197, 201))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
85649	33196849	As expected, the mRNA (Supplementary Figure S14A) and protein (Supplementary Figure S14B) expression levels of EP300 were diminished after interference with two esiRNAs.	('esiRNAs', 'Disease', (161, 168))	('esiRNAs', 'Disease', 'None', (161, 168))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('diminished', 'NegReg', (122, 132))	('EP300', 'Var', (111, 116))	('mRNA', 'MPA', (17, 21))	('interference', 'Interaction', (139, 151))	('S14B', 'SUBSTITUTION', 'None', (84, 88))	('S14A', 'Mutation', 'p.S14A', (44, 48))	('S14B', 'Var', (84, 88))
85650	33196849	Next, we found that EP300 interacted with the NTS promoter (Supplementary Figure S14C, f site, esiNC groups) and its upstream enhancer fragment (~ -800 kb) (Supplementary Figure S14C, b site, esiNC groups).	('NTS', 'Gene', '4922', (46, 49))	('S14C', 'Mutation', 'p.S14C', (178, 182))	('esiNC', 'Disease', 'None', (95, 100))	('esiNC', 'Disease', 'None', (192, 197))	('esiNC', 'Disease', (192, 197))	('esiNC', 'Disease', (95, 100))	('~ -800 kb', 'Var', (145, 154))	('NTS', 'Gene', (46, 49))	('S14C', 'Mutation', 'p.S14C', (81, 85))
85652	33196849	However, after knocking down EP300, both EP300 binding and the H3K27Ac signal were significantly decreased at the NTS promoter and enhancer (Figure 7A, esiEP300-1 groups).	('EP300', 'Protein', (41, 46))	('binding', 'molecular_function', 'GO:0005488', ('47', '54'))	('EP300', 'Var', (29, 34))	('NTS', 'Gene', (114, 117))	('decreased', 'NegReg', (97, 106))	('knocking down EP300', 'Var', (15, 34))	('H3K27Ac', 'Protein', (63, 70))	('NTS', 'Gene', '4922', (114, 117))
85654	33196849	We also found that the NTS-LRRIQ1 intrachromosomal loop remained after EP300 silencing (Supplementary Figure S15).	('NTS', 'Gene', (23, 26))	('LRRIQ1', 'Gene', '84125', (27, 33))	('NTS', 'Gene', '4922', (23, 26))	('EP300', 'Var', (71, 76))	('LRRIQ1', 'Gene', (27, 33))
85655	33196849	These data indicate that EP300 is not involved in loop formation and might play a key histone acetyltransferase to control NTS expression.	('NTS', 'Gene', (123, 126))	('EP300', 'Var', (25, 30))	('expression', 'MPA', (127, 137))	('NTS', 'Gene', '4922', (123, 126))	('formation', 'biological_process', 'GO:0009058', ('55', '64'))
85656	33196849	During tumor formation, numerous oncogenes are activated by hijacking a distal enhancer, which has been identified as an essential oncogenic driver required for the maintenance of cancer cell identity.	('oncogenes', 'Gene', (33, 42))	('tumor', 'Disease', (7, 12))	('formation', 'biological_process', 'GO:0009058', ('13', '22'))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('activated', 'PosReg', (47, 56))	('hijacking', 'Var', (60, 69))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('cancer', 'Disease', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
85660	33196849	The targeted correction of abnormal NTS-LRRIQ1 chromosomal interactions significantly inhibited tumorigenesis by deleting an oncogenic enhancer or inactivating a histone acetyltransferase, thereby leading to a novel mechanism for responding to the critical role of novel onco-enhancer in chromatin remodeling and tumorigenesis (Figure 7D).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('correction', 'Var', (13, 23))	('tumor', 'Disease', (313, 318))	('interactions', 'Var', (59, 71))	('LRRIQ1', 'Gene', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('chromatin', 'cellular_component', 'GO:0000785', ('288', '297'))	('oncogenic', 'Enzyme', (125, 134))	('deleting', 'NegReg', (113, 121))	('NTS', 'Gene', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('abnormal', 'Var', (27, 35))	('NTS', 'Gene', '4922', (36, 39))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('288', '308'))	('tumor', 'Disease', (96, 101))	('inactivating', 'NegReg', (147, 159))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('histone acetyltransferase', 'Enzyme', (162, 187))	('inhibited', 'NegReg', (86, 95))	('LRRIQ1', 'Gene', '84125', (40, 46))
85662	33196849	For example, the CTCF-mediated KCNQ1 and CDKN1C intrachromosomal conformation could significantly inhibit tumor formation, while aberrant chromosomal looping may lead to imprinting abnormalities and activation of the oncogenic long noncoding RNA (lncRNA) KCNQ1OT1, thereby accelerating tumorigenesis.	('formation', 'biological_process', 'GO:0009058', ('112', '121'))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('accelerating', 'PosReg', (273, 285))	('aberrant chromosomal looping', 'Var', (129, 157))	('imprinting', 'MPA', (170, 180))	('tumor', 'Disease', (286, 291))	('activation', 'PosReg', (199, 209))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('inhibit', 'NegReg', (98, 105))	('KCNQ1OT1', 'Gene', (255, 263))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('RNA', 'cellular_component', 'GO:0005562', ('242', '245'))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('lead to', 'Reg', (162, 169))	('CDKN1C', 'Gene', (41, 47))	('tumor', 'Disease', (106, 111))
85666	33196849	An alternative explanation is that enhancer deletion-caused NTS silencing plays a critical role in regulation of other gene expression.	('deletion-caused', 'Var', (44, 59))	('enhancer', 'PosReg', (35, 43))	('NTS', 'Gene', '4922', (60, 63))	('gene expression', 'biological_process', 'GO:0010467', ('119', '134'))	('silencing', 'NegReg', (64, 73))	('NTS', 'Gene', (60, 63))	('regulation', 'biological_process', 'GO:0065007', ('99', '109'))
85667	33196849	NTS has been proven to involve in numerous signal pathways, including Wnt/beta-Catenin pathway, IL-8 pathways, and epithelial-mesenchymal transition pathways, NTS silencing can lead to alteration of a series of cascade effect and subsequently induce dramatic gene changes.	('lead to', 'Reg', (177, 184))	('induce', 'Reg', (243, 249))	('series of cascade', 'MPA', (201, 218))	('Wnt/beta-Catenin pathway', 'Pathway', (70, 94))	('silencing', 'Var', (163, 172))	('NTS', 'Gene', (0, 3))	('alteration', 'MPA', (185, 195))	('NTS', 'Gene', '4922', (0, 3))	('NTS', 'Gene', (159, 162))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('115', '148'))	('NTS', 'Gene', '4922', (159, 162))	('gene changes', 'MPA', (259, 271))	('IL-8', 'molecular_function', 'GO:0005153', ('96', '100'))
85674	33196849	In this study, we noticed that the knockdown of EP300 did not appear to cause as severe a reduction in NTS expression as loss of the enhancer.	('EP300', 'Var', (48, 53))	('reduction', 'NegReg', (90, 99))	('NTS', 'Gene', '4922', (103, 106))	('NTS', 'Gene', (103, 106))
85675	33196849	Thus, it provides a possibility that CTCF dimer firstly orchestrates an enhancer-promoter looping and secondly recruits the EP300, subsequently, looping-based enhancer activity and EP300-based epigenetic modification co-regulate the NTS expression.	('NTS', 'Gene', (233, 236))	('expression', 'MPA', (237, 247))	('EP300-based epigenetic modification', 'Var', (181, 216))	('NTS', 'Gene', '4922', (233, 236))	('co-regulate', 'Reg', (217, 228))
85676	33196849	These two separated phenomena is likely to provide an alternative explanation for the role of enhancer activity in mediating enhancer-promoter looping, at least in this case, further studies should focus on the identification of the co-regulated mechanism between enhancer activity and epigenetic factor modification in NTS expression of tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('tumor', 'Disease', (338, 343))	('epigenetic factor modification', 'Var', (286, 316))	('NTS', 'Gene', (320, 323))	('NTS', 'Gene', '4922', (320, 323))	('tumor', 'Disease', 'MESH:D009369', (338, 343))
85701	26699318	9 ,  10 ,  11   Several isotopes, including 125I and 103Pd are used in the brachytherapy of choroidal melanoma.	('103Pd', 'Var', (53, 58))	('choroidal melanoma', 'Disease', 'MESH:D008545', (92, 110))	('125I', 'Var', (44, 48))	('choroidal melanoma', 'Disease', (92, 110))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (92, 110))
85709	26699318	29 ,  30 ,  31  DEF is defined as the ratio of the absorbed dose by the tumor containing GNPs to the absorbed dose by the tumor without these nanoparticles.	('GNP', 'Chemical', '-', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('DEF', 'Gene', (16, 19))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('GNPs', 'Var', (89, 93))	('DEF', 'Gene', '27042', (16, 19))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (122, 127))
85711	26699318	(32)  demonstrated that the presence of GNPs in the tumor will cause more absorbed dose by the cancerous cells than that of the normal tissues.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cancerous', 'Disease', 'MESH:D009369', (95, 104))	('presence', 'Var', (28, 36))	('GNPs', 'Var', (40, 44))	('tumor', 'Disease', (52, 57))	('absorbed dose', 'MPA', (74, 87))	('cancerous', 'Disease', (95, 104))	('more', 'PosReg', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('GNP', 'Chemical', '-', (40, 43))
85782	26699318	Table 5 shows that defining the nanoparticles in the tumor area led to the dose increase inside the tumor with no significant changes in the absorbed dose by other parts of the eye in both phantom types.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('increase', 'PosReg', (80, 88))	('tumor', 'Disease', (100, 105))	('nanoparticles', 'Var', (32, 45))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('dose', 'MPA', (75, 79))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
85783	26699318	The calculated doses to the tumor apex in the presence of GNPs inside the tumor with the concentrations of 7 mg/g, 10 mg/g, 18 mg/g, and 30 mg/g was found to be increased by a factor of about 1.9, 2.2, 3.2, and 4.6, respectively, in the eye model and about 1.9, 2.3, 3.3, and 4.8 orders of magnitude, respectively, in the water phantom.	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('water', 'Chemical', 'MESH:D014867', (322, 327))	('GNP', 'Chemical', '-', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('increased', 'PosReg', (161, 170))	('apex', 'cellular_component', 'GO:0097683', ('34', '38'))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('doses', 'MPA', (15, 20))	('GNPs', 'Var', (58, 62))
85789	26699318	For example, in the presence of 18 mg/g GNPs, there is an increase of 20% in the eye model and 4% in the water phantom in the dose absorbed to sclera relative to that of the eye and water phantom with no nanoparticles present.	('increase', 'PosReg', (58, 66))	('GNPs', 'Var', (40, 44))	('water', 'Chemical', 'MESH:D014867', (105, 110))	('water', 'Chemical', 'MESH:D014867', (182, 187))	('GNP', 'Chemical', '-', (40, 43))
85791	26699318	For instance, the dose to the sclera and tumor apex in the water phantom in the presence of the plaque is about 14% less than that of the absence of the plaque, but with the same arrangement.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('dose', 'MPA', (18, 22))	('plaque', 'Var', (96, 102))	('tumor', 'Disease', (41, 46))	('less', 'NegReg', (116, 120))	('water', 'Chemical', 'MESH:D014867', (59, 64))	('apex', 'cellular_component', 'GO:0097683', ('47', '51'))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
85801	26699318	The results show that a significant tumor dose enhancement could be achieved, using GNPs inside the tumor during the irradiation by low energy source.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('GNPs', 'Var', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('enhancement', 'PosReg', (47, 58))	('GNP', 'Chemical', '-', (84, 87))	('tumor', 'Disease', (36, 41))
85803	26699318	The presence of GNPs inside the tumor made no significant changes in the radiation-absorbing sensitivity of other normal tissue of the eye.	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('GNPs', 'Var', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('radiation-absorbing sensitivity', 'MPA', (73, 104))	('GNP', 'Chemical', '-', (16, 19))	('tumor', 'Disease', (32, 37))
85827	28639409	Unlike cutaneous melanomas, about 80% of UMs show mutations in G-protein alpha-subunits q (GNAQ) and 11 (GNA11) 2.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (7, 26))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (7, 26))	('mutations', 'Var', (50, 59))	('UMs', 'Disease', (41, 44))	('GNA11', 'Gene', (105, 110))	('GNAQ', 'Gene', (91, 95))	('cutaneous melanomas', 'Disease', (7, 26))	('GNA11', 'Gene', '2767', (105, 110))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('melanomas', 'Phenotype', 'HP:0002861', (17, 26))	('G-protein', 'Protein', (63, 72))	('GNAQ', 'Gene', '2776', (91, 95))	('UMs', 'Phenotype', 'HP:0007716', (41, 44))
85901	26719535	Germline BAP1 mutational landscape of asbestos-exposed malignant mesothelioma patients with family history of cancer Heritable mutations in the BAP1 tumor suppressor gene predispose individuals to mesothelioma and other cancers.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('asbestos', 'Chemical', 'MESH:D001194', (38, 46))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('BAP1', 'Gene', (9, 13))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (55, 77))	('mesothelioma', 'Disease', (65, 77))	('BAP1', 'Gene', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('mutations', 'Var', (127, 136))	('cancer', 'Disease', (110, 116))	('malignant mesothelioma', 'Disease', (55, 77))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (55, 77))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('mesothelioma', 'Disease', (197, 209))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('149', '165'))	('cancer', 'Disease', (220, 226))	('cancers', 'Disease', (220, 227))	('mesothelioma', 'Disease', 'MESH:D008654', (197, 209))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('BAP1', 'Gene', '8314', (9, 13))	('tumor suppressor', 'biological_process', 'GO:0051726', ('149', '165'))	('predispose', 'Reg', (171, 181))	('tumor', 'Disease', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('BAP1', 'Gene', '8314', (144, 148))
85902	26719535	However, a large-scale assessment of germline BAP1 mutation incidence and associated clinical features in mesothelioma patients with a family history of cancer has not been reported.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('mesothelioma', 'Disease', (106, 118))	('cancer', 'Disease', (153, 159))	('BAP1', 'Gene', '8314', (46, 50))	('patients', 'Species', '9606', (119, 127))	('mesothelioma', 'Disease', 'MESH:D008654', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('mutation', 'Var', (51, 59))	('BAP1', 'Gene', (46, 50))
85905	26719535	Alterations among these cases were characterized by both missense and frameshift mutations, and enzymatic activity of BAP1 missense mutants was decreased compared to wild-type BAP1.	('decreased', 'NegReg', (144, 153))	('frameshift mutations', 'Var', (70, 90))	('enzymatic activity', 'MPA', (96, 114))	('BAP1', 'Gene', '8314', (176, 180))	('BAP1', 'Gene', '8314', (118, 122))	('BAP1', 'Gene', (176, 180))	('missense mutants', 'Var', (123, 139))	('missense', 'Var', (57, 65))	('BAP1', 'Gene', (118, 122))
85906	26719535	Furthermore, BAP1 mutation carriers developed mesothelioma at an earlier age that was more often peritoneal than pleural (5 of 9), and exhibited improved long-term survival compared to mesothelioma patients without BAP1 mutations.	('mesothelioma', 'Disease', 'MESH:D008654', (46, 58))	('pleural', 'Disease', (113, 120))	('BAP1', 'Gene', (13, 17))	('mesothelioma', 'Disease', (185, 197))	('patients', 'Species', '9606', (198, 206))	('BAP1', 'Gene', '8314', (215, 219))	('BAP1', 'Gene', '8314', (13, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (185, 197))	('improved', 'PosReg', (145, 153))	('mutation', 'Var', (18, 26))	('mesothelioma', 'Disease', (46, 58))	('pleural', 'Disease', 'MESH:D010995', (113, 120))	('developed', 'PosReg', (36, 45))	('BAP1', 'Gene', (215, 219))
85907	26719535	Moreover, many tumors harboring BAP1 germline mutations were associated with BAP1 syndrome, including mesothelioma and ocular/cutaneous melanomas, as well as renal, breast, lung, gastric, and basal cell carcinomas.	('gastric', 'Disease', (179, 186))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('BAP1', 'Gene', (32, 36))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (192, 213))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (126, 144))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('breast', 'Disease', (165, 171))	('germline mutations', 'Var', (37, 55))	('BAP1', 'Gene', '8314', (77, 81))	('basal cell carcinomas', 'Disease', (192, 213))	('associated', 'Reg', (61, 71))	('tumors', 'Disease', (15, 21))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (126, 145))	('renal', 'Disease', (158, 163))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (192, 213))	('lung', 'Disease', (173, 177))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (192, 212))	('BAP1', 'Gene', (77, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (203, 213))	('BAP1', 'Gene', '8314', (32, 36))	('melanomas', 'Phenotype', 'HP:0002861', (136, 145))	('mesothelioma and ocular/cutaneous melanomas', 'Disease', 'MESH:C562393', (102, 145))
85908	26719535	Collectively, these findings suggest that mesothelioma patients presenting with a family history of cancer should be considered for BAP1 genetic testing to identify those individuals who might benefit from further screening and routine monitoring for the purpose of early detection and intervention.	('BAP1', 'Gene', '8314', (132, 136))	('genetic', 'Var', (137, 144))	('mesothelioma', 'Disease', (42, 54))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('BAP1', 'Gene', (132, 136))	('patients', 'Species', '9606', (55, 63))	('mesothelioma', 'Disease', 'MESH:D008654', (42, 54))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
85915	26719535	In 2011, germline mutations of the BAP1 tumor suppressor gene were reported in two families with multiple MMs and/or uveal melanomas (UMs) as well as other tumors such as kidney cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('kidney cancer', 'Disease', (171, 184))	('uveal melanomas', 'Disease', (117, 132))	('uveal melanomas', 'Phenotype', 'HP:0007716', (117, 132))	('BAP1', 'Gene', (35, 39))	('tumor', 'Disease', (156, 161))	('reported', 'Reg', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('uveal melanomas', 'Disease', 'MESH:C536494', (117, 132))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('tumor', 'Disease', (40, 45))	('kidney cancer', 'Disease', 'MESH:D007680', (171, 184))	('tumors', 'Disease', (156, 162))	('germline mutations', 'Var', (9, 27))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('BAP1', 'Gene', '8314', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))	('kidney cancer', 'Phenotype', 'HP:0009726', (171, 184))
85916	26719535	In addition, germline BAP1 mutations were identified in 2 of 26 sporadic MMs, and both individuals with mutant BAP1 were previously diagnosed with UM.	('MMs', 'Disease', (73, 76))	('mutations', 'Var', (27, 36))	('BAP1', 'Gene', '8314', (111, 115))	('mutant', 'Var', (104, 110))	('BAP1', 'Gene', (111, 115))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', (22, 26))
85917	26719535	described germline BAP1 mutations in two families with atypical melanocytic tumors as well as cutaneous melanoma (CM) and UM.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanocytic tumors', 'Disease', (64, 82))	('melanocytic tumors', 'Disease', 'MESH:D009508', (64, 82))	('cutaneous melanoma', 'Disease', (94, 112))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('BAP1', 'Gene', '8314', (19, 23))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (94, 112))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (94, 112))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('CM', 'Disease', 'MESH:D009202', (114, 116))	('BAP1', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))
85918	26719535	To investigate the potential contribution of germline BAP1 mutations in UM patients with possible predisposition to hereditary cancer, Abdel-Rahman et al.	('hereditary cancer', 'Disease', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('patients', 'Species', '9606', (75, 83))	('BAP1', 'Gene', '8314', (54, 58))	('hereditary cancer', 'Disease', 'MESH:D009369', (116, 133))	('mutations', 'Var', (59, 68))	('BAP1', 'Gene', (54, 58))
85919	26719535	identified a patient with a germline truncating mutation of BAP1, which segregated in several family members with UM, lung adenocarcinoma, and meningioma.	('patient', 'Species', '9606', (13, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('lung adenocarcinoma', 'Disease', (118, 137))	('germline truncating mutation', 'Var', (28, 56))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (118, 137))	('BAP1', 'Gene', '8314', (60, 64))	('meningioma', 'Disease', 'MESH:D008577', (143, 153))	('meningioma', 'Disease', (143, 153))	('meningioma', 'Phenotype', 'HP:0002858', (143, 153))	('BAP1', 'Gene', (60, 64))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))	('segregated', 'Reg', (72, 82))
85921	26719535	Collectively, these findings have led to the identification of a BAP1 tumor predisposition syndrome characterized by MM, CM, UM, RCC and potentially other tumors due to heterozygous germline mutations of BAP1.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('BAP1', 'Gene', '8314', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('CM', 'Disease', 'MESH:D009202', (121, 123))	('tumor', 'Disease', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('BAP1', 'Gene', (65, 69))	('tumor', 'Disease', (155, 160))	('BAP1', 'Gene', '8314', (204, 208))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('RCC', 'Disease', (129, 132))	('tumors', 'Disease', (155, 161))	('germline mutations', 'Var', (182, 200))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('BAP1', 'Gene', (204, 208))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
85922	26719535	Based on these studies, we hypothesized that germline mutations in BAP1 may contribute to susceptibility to MM in asbestos-exposed individuals through a mechanism that involves a gene-environment interaction.	('asbestos', 'Chemical', 'MESH:D001194', (114, 122))	('BAP1', 'Gene', '8314', (67, 71))	('susceptibility', 'Reg', (90, 104))	('germline mutations', 'Var', (45, 63))	('contribute', 'Reg', (76, 86))	('BAP1', 'Gene', (67, 71))
85923	26719535	We further postulated that germline BAP1 mutations would more likely occur if an MM index case had a family history of various cancers, consistent with a genetic predisposition to cancer.	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('germline', 'Var', (27, 35))	('cancer', 'Disease', (127, 133))	('occur', 'Reg', (69, 74))	('BAP1', 'Gene', '8314', (36, 40))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('BAP1', 'Gene', (36, 40))	('cancer', 'Disease', (180, 186))
85924	26719535	We recently reported in vivo genetic evidence that germline heterozygous mutation of Bap1 accelerates development of asbestos-induced MM.	('Bap1', 'Gene', (85, 89))	('asbestos', 'Chemical', 'MESH:D001194', (117, 125))	('germline heterozygous mutation', 'Var', (51, 81))	('accelerates', 'PosReg', (90, 101))
85926	26719535	To further investigate its role in asbestos-induced MM, we determined the prevalence of germline BAP1 mutations in a population of asbestos-exposed MM cases and controls.	('BAP1', 'Gene', '8314', (97, 101))	('asbestos', 'Chemical', 'MESH:D001194', (35, 43))	('asbestos', 'Chemical', 'MESH:D001194', (131, 139))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))
85928	26719535	While no alterations of BAP1 were found in controls, BAP1 mutations were identified in a 9 of 150 MM cases with a personal or family history of cancer.	('mutations', 'Var', (58, 67))	('BAP1', 'Gene', (24, 28))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('identified', 'Reg', (73, 83))	('cancer', 'Disease', (144, 150))	('BAP1', 'Gene', '8314', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('BAP1', 'Gene', '8314', (24, 28))	('BAP1', 'Gene', (53, 57))
85949	26719535	BAP1 mutations were described using cDNA and protein mutation nomenclature standardized by the Human Genome Variation Society (HGVS, http://www.hgvs.org/mutnomen) and cDNA accession # NM_004656 and protein accession # NP_004647 as references.	('Human', 'Species', '9606', (95, 100))	('BAP1', 'Gene', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('mutations', 'Var', (5, 14))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))	('BAP1', 'Gene', '8314', (0, 4))
85950	26719535	293T cells were transfected with Myc-tagged wild-type (WT) or mutant BAP constructs.	('BAP', 'Gene', (69, 72))	('Myc', 'Gene', (33, 36))	('293T', 'CellLine', 'CVCL:0063', (0, 4))	('mutant', 'Var', (62, 68))	('BAP', 'Chemical', '-', (69, 72))	('Myc', 'Gene', '4609', (33, 36))
85963	26719535	Among the 150 MM cases with a family history of cancer, germline mutations of BAP1 were identified in 9 index cases, of which 8 tumors (88.9%) were of the epithelioid subtype, and 1 was sarcomatous.	('sarcomatous', 'Disease', 'MESH:D018316', (186, 197))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('identified', 'Reg', (88, 98))	('sarcomatous', 'Disease', (186, 197))	('cancer', 'Disease', (48, 54))	('tumors', 'Disease', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('BAP1', 'Gene', '8314', (78, 82))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('germline mutations', 'Var', (56, 74))	('BAP1', 'Gene', (78, 82))
85964	26719535	Of the 141 MM cases without BAP1 mutations, the histopathological subtype was available in 126 cases, of which 94 (74.6%) were epithelioid, 13 (10.3%) were biphasic, and 19 (15.1%) were sarcomatous.	('BAP1', 'Gene', '8314', (28, 32))	('sarcomatous', 'Disease', 'MESH:D018316', (186, 197))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('sarcomatous', 'Disease', (186, 197))	('epithelioid', 'Disease', (127, 138))
85965	26719535	Of the 9 index cases with a germline BAP1 mutation, 5 MMs (55.6%) were peritoneal and the 4 (44.4%) were thoracic.	('mutation', 'Var', (42, 50))	('BAP1', 'Gene', (37, 41))	('BAP1', 'Gene', '8314', (37, 41))	('MMs', 'Disease', (54, 57))
85968	26719535	Of the 9 cases found to harbor germline mutations affecting the coding sequence of the BAP1 protein, 3 were missense mutations, 2 were splice site mutations, and 4 were insertions/deletions (in/dels) (Table 2).	('BAP1', 'Gene', '8314', (87, 91))	('BAP1', 'Gene', (87, 91))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('insertions/deletions', 'Var', (169, 189))	('affecting', 'Reg', (50, 59))
85969	26719535	Analysis of the missense mutations was done using three tools: Protein Variation Effect Analyzer (PROVEAN), Sorting Intolerant from Tolerant (SIFT), and PolyPhen-2 (Fig.	('SIFT', 'Disease', 'None', (142, 146))	('SIFT', 'Disease', (142, 146))	('missense mutations', 'Var', (16, 34))
85971	26719535	In addition, the Arg383Cys mutation is not a conservative change, as a basic, positively-charged arginine is changed to a non-basic, uncharged cysteine and, thus, could potentially affect BAP1 protein structure or function.	('Arg383Cys', 'Var', (17, 26))	('BAP1', 'Gene', (188, 192))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('Arg383Cys', 'SUBSTITUTION', 'None', (17, 26))	('protein', 'Protein', (193, 200))	('changed', 'Reg', (109, 116))	('BAP1', 'Gene', '8314', (188, 192))	('structure', 'MPA', (201, 210))	('arginine', 'Chemical', 'MESH:D001120', (97, 105))	('cysteine', 'Chemical', 'MESH:D003545', (143, 151))	('function', 'MPA', (214, 222))	('affect', 'Reg', (181, 187))
85972	26719535	In addition, the introduction of a cysteine residue could alter disulfide bonds within the protein.	('cysteine', 'Chemical', 'MESH:D003545', (35, 43))	('disulfide bonds within the protein', 'MPA', (64, 98))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('alter', 'Reg', (58, 63))	('introduction', 'Var', (17, 29))	('disulfide', 'Chemical', 'MESH:D004220', (64, 73))
85974	26719535	However, several studies have shown that BAP1 Ser583 is phosphorylated in human cells after UV light exposure, providing functional significance of the serine at position 583.	('BAP1', 'Gene', (41, 45))	('Ser583', 'Chemical', '-', (46, 52))	('Ser', 'cellular_component', 'GO:0005790', ('46', '49'))	('Ser583', 'Var', (46, 52))	('serine', 'Chemical', 'MESH:D012694', (152, 158))	('human', 'Species', '9606', (74, 79))	('BAP1', 'Gene', '8314', (41, 45))
85975	26719535	The Ub-AMC assay revealed that the enzymatic activity of each of the three BAP1 missense mutants was reproducibly decreased compared to that of WT BAP1 protein (Fig.	('AMC', 'Chemical', '-', (7, 10))	('BAP1', 'Gene', (147, 151))	('BAP1', 'Gene', (75, 79))	('enzymatic activity', 'MPA', (35, 53))	('missense mutants', 'Var', (80, 96))	('Ub', 'Chemical', '-', (4, 6))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('decreased', 'NegReg', (114, 123))	('BAP1', 'Gene', '8314', (147, 151))	('BAP1', 'Gene', '8314', (75, 79))
85976	26719535	However, as expected, these BAP1 mutant proteins could still bind ASXL2 substrate, which was expected given that the missense mutations do not affect the carboxy-terminal ASXL1/2 binding domain of BAP1.	('BAP1', 'Gene', '8314', (28, 32))	('binding', 'molecular_function', 'GO:0005488', ('179', '186'))	('ASXL2', 'Gene', '55252', (66, 71))	('BAP1', 'Gene', (28, 32))	('ASXL2', 'Gene', (66, 71))	('missense mutations', 'Var', (117, 135))	('BAP1', 'Gene', '8314', (197, 201))	('proteins', 'Protein', (40, 48))	('bind', 'Interaction', (61, 65))	('mutant', 'Var', (33, 39))	('BAP1', 'Gene', (197, 201))
85977	26719535	As a control, we used a BAP1 mutant construct corresponding to the S628fs*8 mutation seen in family ABS3428.	('BAP1', 'Gene', '8314', (24, 28))	('BAP1', 'Gene', (24, 28))	('S628fs', 'Mutation', 'p.S628fsX', (67, 73))	('S628fs*8', 'Var', (67, 75))
85980	26719535	Location of missense mutations and the S628fs*8 mutation are shown in Fig.	('missense mutations', 'Var', (12, 30))	('S628fs*8', 'Var', (39, 47))	('S628fs', 'Mutation', 'p.S628fsX', (39, 45))
85981	26719535	2A, and representative Ub-AMC experiment of exogenously expressed wild-type and mutant BAP1 proteins are depicted in Fig.	('BAP1', 'Gene', '8314', (87, 91))	('mutant', 'Var', (80, 86))	('BAP1', 'Gene', (87, 91))	('AMC', 'Chemical', '-', (26, 29))	('proteins', 'Protein', (92, 100))	('Ub', 'Chemical', '-', (23, 25))
85982	26719535	Two cases had germline BAP1 mutations at consensus splice sites: cases MC7039 and MC7058.	('BAP1', 'Gene', (23, 27))	('MC7039', 'Var', (71, 77))	('MC7058', 'Var', (82, 88))	('BAP1', 'Gene', '8314', (23, 27))
85983	26719535	In both of these MM cases, the loss of an exon and the retention of part of an intron were each predicted to lead to a frameshift and premature truncation of the translated BAP1 protein.	('protein', 'Protein', (178, 185))	('lead to', 'Reg', (109, 116))	('loss', 'NegReg', (31, 35))	('exon', 'MPA', (42, 46))	('BAP1', 'Gene', '8314', (173, 177))	('frameshift', 'Var', (119, 129))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('retention', 'biological_process', 'GO:0051235', ('55', '64'))	('BAP1', 'Gene', (173, 177))	('premature truncation', 'MPA', (134, 154))
85984	26719535	Interestingly, two cases (ABS2778 and ABS3554) had the same germline mutation, c.1717delC, and the pedigrees of these two cases did not indicate any known relationship, although they may have a common ancestor.	('c.1717delC', 'Mutation', 'rs869025212', (79, 89))	('c.1717delC', 'Var', (79, 89))	('ABS2778', 'Var', (26, 33))	('ABS3554', 'Var', (38, 45))
85986	26719535	Four intronic SNPs in BAP1 (rs116234404, rs141765555, rs187797012 and rs190356708), were found in <= 4 cases and in <= 1 control.	('rs190356708', 'Mutation', 'rs190356708', (70, 81))	('rs141765555', 'Mutation', 'rs141765555', (41, 52))	('rs116234404', 'Var', (28, 39))	('rs190356708', 'Var', (70, 81))	('rs187797012', 'Mutation', 'rs187797012', (54, 65))	('BAP1', 'Gene', '8314', (22, 26))	('rs116234404', 'Mutation', 'rs116234404', (28, 39))	('rs141765555', 'Var', (41, 52))	('BAP1', 'Gene', (22, 26))	('rs187797012', 'Var', (54, 65))
85988	26719535	Compared with MM cases without a BAP1 mutation, the cases harboring germline mutations that could affect BAP1 protein coding sequence were diagnosed at an earlier age and were more likely to have peritoneal rather than pleural MM (Table 1).	('pleural MM', 'Disease', (219, 229))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('BAP1', 'Gene', '8314', (105, 109))	('BAP1', 'Gene', '8314', (33, 37))	('peritoneal', 'Disease', (196, 206))	('mutations', 'Var', (77, 86))	('pleural MM', 'Disease', 'MESH:D010995', (219, 229))	('BAP1', 'Gene', (33, 37))	('affect', 'Reg', (98, 104))	('BAP1', 'Gene', (105, 109))
85989	26719535	There was no significant difference in cancer signal score, gender or latency between cases with and without a BAP1 mutation.	('BAP1', 'Gene', '8314', (111, 115))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Disease', (39, 45))	('mutation', 'Var', (116, 124))	('BAP1', 'Gene', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
85990	26719535	Both families with and without mutations of BAP1 exhibited a significant number of malignancies that have been repeatedly associated with the BAP1 syndrome, i.e., MM, CM, UM and RCC, although the relative proportion of these neoplasms appeared to be greater in families of MM cases with a BAP1 mutation.	('associated', 'Reg', (122, 132))	('mutation', 'Var', (294, 302))	('mutations', 'Var', (31, 40))	('neoplasms', 'Phenotype', 'HP:0002664', (225, 234))	('BAP1', 'Gene', '8314', (142, 146))	('CM', 'Disease', 'MESH:D009202', (167, 169))	('malignancies', 'Disease', 'MESH:D009369', (83, 95))	('BAP1', 'Gene', (289, 293))	('BAP1', 'Gene', (142, 146))	('neoplasms', 'Disease', (225, 234))	('BAP1', 'Gene', '8314', (44, 48))	('neoplasms', 'Disease', 'MESH:D009369', (225, 234))	('RCC', 'Disease', (178, 181))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('malignancies', 'Disease', (83, 95))	('BAP1', 'Gene', (44, 48))	('BAP1', 'Gene', '8314', (289, 293))
85991	26719535	A total of 11 such tumors (4 RCC, 3 MMs, 2 CMS, and 2 UMs) were identified in the 9 families in which the MM proband has a germline BAP1 mutation.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('BAP1', 'Gene', '8314', (132, 136))	('mutation', 'Var', (137, 145))	('RCC', 'Disease', (29, 32))	('BAP1', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('CM', 'Disease', 'MESH:D009202', (43, 45))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
85992	26719535	Among the 141 MM cases without a BAP1 mutation, 27 such tumors (7 RCCs, 9 MMs, 10 CMs, and 1 ocular tumor) were documented.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CM', 'Disease', 'MESH:D009202', (82, 84))	('ocular tumor', 'Disease', 'MESH:D009369', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('ocular tumor', 'Disease', (93, 105))	('MMs', 'Disease', (74, 77))	('BAP1', 'Gene', '8314', (33, 37))	('ocular tumor', 'Phenotype', 'HP:0100012', (93, 105))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('mutation', 'Var', (38, 46))	('BAP1', 'Gene', (33, 37))	('RCC', 'Disease', (66, 69))
85993	26719535	Atypical cutaneous melanocytic tumors are also associated with the BAP1 syndrome, and we cannot rule out the existence of such lesions in some members of the 9 families with a germline BAP1 mutation, but detailed dermatological assessments of these families were not available.	('mutation', 'Var', (190, 198))	('Atypical cutaneous melanocytic tumors', 'Disease', (0, 37))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('BAP1', 'Gene', (185, 189))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('BAP1', 'Gene', '8314', (67, 71))	('Atypical cutaneous melanocytic tumors', 'Disease', 'MESH:D009508', (0, 37))	('associated', 'Reg', (47, 57))	('BAP1', 'Gene', '8314', (185, 189))	('BAP1', 'Gene', (67, 71))
85994	26719535	Among the families of cases with BAP1 mutations, 4 MM index cases had a second primary tumor, including 3 with RCC and 1 with UM.	('primary tumor', 'Disease', (79, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('primary tumor', 'Disease', 'MESH:D009369', (79, 92))	('BAP1', 'Gene', '8314', (33, 37))	('BAP1', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))
85995	26719535	Of the cases without a BAP1 mutation, 5 MM index cases had a second primary tumor (2 with RCC and 3 with CM).	('BAP1', 'Gene', (23, 27))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('primary tumor', 'Disease', 'MESH:D009369', (68, 81))	('BAP1', 'Gene', '8314', (23, 27))	('mutation', 'Var', (28, 36))	('CM', 'Disease', 'MESH:D009202', (105, 107))	('primary tumor', 'Disease', (68, 81))	('RCC', 'Disease', (90, 93))
85996	26719535	One MM case with a BAP1 mutation (ABS3554) had two siblings who also developed MM; similarly, two MM cases without a BAP1 mutation each had two siblings who developed MM.	('BAP1', 'Gene', '8314', (117, 121))	('mutation (ABS3554', 'Var', (24, 41))	('BAP1', 'Gene', '8314', (19, 23))	('BAP1', 'Gene', (117, 121))	('ABS3554', 'Var', (34, 41))	('MM', 'Disease', (79, 81))	('BAP1', 'Gene', (19, 23))
85997	26719535	Thus, the existence of multiple MMs in a given family need not be due to inheritance of a BAP1 mutation.	('BAP1', 'Gene', '8314', (90, 94))	('BAP1', 'Gene', (90, 94))	('mutation', 'Var', (95, 103))
85998	26719535	Among the three cases (ABS2570, ABS3023, ABS3313) with missense mutations, multiple malignancies were observed in their past personal and family histories.	('malignancies', 'Disease', (84, 96))	('malignancies', 'Disease', 'MESH:D009369', (84, 96))	('ABS2570', 'Var', (23, 30))	('missense mutations', 'Var', (55, 73))	('ABS3313', 'Var', (41, 48))	('ABS3023', 'Var', (32, 39))
85999	26719535	The cancers observed in families of these cases were similar to those identified in the six families with frameshift or splice site mutations, suggesting that families with missense BAP1 mutations also belong to the BAP1 syndrome.	('BAP1', 'Gene', (216, 220))	('BAP1', 'Gene', '8314', (182, 186))	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('BAP1', 'Gene', (182, 186))	('mutations', 'Var', (187, 196))	('belong', 'Reg', (202, 208))	('missense', 'Var', (173, 181))	('BAP1', 'Gene', '8314', (216, 220))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('cancers', 'Disease', (4, 11))
86000	26719535	For example, case ABS3023 had a daughter with breast cancer, and case ABS3313 had a daughter with cutaneous melanoma (Fig.	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cutaneous melanoma', 'Disease', (98, 116))	('ABS3023', 'Var', (18, 25))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (98, 116))	('breast cancer', 'Disease', (46, 59))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (98, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))
86002	26719535	Of the two splice site mutations, the father of MM case MC7058 had a non-Hodgkin's lymphoma and his sister had thyroid cancer.	('thyroid cancer', 'Phenotype', 'HP:0002890', (111, 125))	('thyroid cancer', 'Disease', (111, 125))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (73, 91))	('thyroid cancer', 'Disease', 'MESH:D013964', (111, 125))	("non-Hodgkin's lymphoma", 'Disease', (69, 91))	('lymphoma', 'Phenotype', 'HP:0002665', (83, 91))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (69, 91))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('MC7058', 'Var', (56, 62))
86004	26719535	The family history of case MC7039 is replete with malignancy (Fig.	('MC7039', 'Var', (27, 33))	('malignancy', 'Disease', (50, 60))	('malignancy', 'Disease', 'MESH:D009369', (50, 60))
86007	26719535	As noted above, both ABS2778 and ABS3554 exhibited the same mutation c.1717delC, which is identical to that described in a sporadic MM (SP-002) we reported earlier.	('ABS2778', 'Var', (21, 28))	('c.1717delC', 'Var', (69, 79))	('ABS3554', 'Var', (33, 40))	('SP', 'Chemical', 'MESH:C000604007', (136, 138))	('c.1717delC', 'Mutation', 'rs869025212', (69, 79))
86008	26719535	Notably, both ABS2778 and ABS3554 had MM simultaneously affecting both the pleura and peritoneum.	('pleura', 'Disease', (75, 81))	('ABS3554', 'Var', (26, 33))	('pleura', 'Disease', 'MESH:D054363', (75, 81))	('ABS2778', 'Var', (14, 21))	('affecting', 'Reg', (56, 65))
86009	26719535	Case ABS3554 had two sisters with MM, one with peritoneal and the other with pleural disease.	('pleural disease', 'Phenotype', 'HP:0002103', (77, 92))	('pleural disease', 'Disease', (77, 92))	('pleural disease', 'Disease', 'MESH:D010995', (77, 92))	('ABS3554', 'Var', (5, 12))
86013	26719535	No family history of melanoma was evoked from either case ABS2778 or ABS3554.	('melanoma', 'Disease', 'MESH:D008545', (21, 29))	('ABS2778', 'Var', (58, 65))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Disease', (21, 29))	('ABS3554', 'Var', (69, 76))
86014	26719535	The c.1882_1885delTCAC germline mutation observed in case ABS3428 was also previously described by us in a sporadic case (SP-008).	('SP-008', 'Chemical', 'MESH:C505413', (122, 128))	('c.1882_1885delTCAC', 'Mutation', 'c.1882_1885delTCAC', (4, 22))	('c.1882_1885delTCAC', 'Var', (4, 22))	('ABS3428', 'Gene', (58, 65))
86016	26719535	The fourth MM case with an in/del, ABS2573, had a past medical history of breast cancer and kidney cancer; thus, ABS2573 had three separate primary tumors.	('primary tumors', 'Disease', (140, 154))	('breast cancer', 'Disease', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('kidney cancer', 'Disease', (92, 105))	('primary tumors', 'Disease', 'MESH:D009369', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('kidney cancer', 'Phenotype', 'HP:0009726', (92, 105))	('kidney cancer', 'Disease', 'MESH:D007680', (92, 105))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('ABS2573', 'Var', (113, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
86020	26719535	Altogether, we found germline mutations of BAP1 in 9 of 150 (6%) cases with a personal or family history of cancer based on a high cancer signal, as defined above.	('cancer', 'Disease', (131, 137))	('BAP1', 'Gene', (43, 47))	('found', 'Reg', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('high cancer', 'Disease', 'MESH:D009369', (126, 137))	('high cancer', 'Disease', (126, 137))	('BAP1', 'Gene', '8314', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('germline mutations', 'Var', (21, 39))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
86021	26719535	Among the 9 families with BAP1 mutations, a total of 11 MMs were identified.	('BAP1', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('BAP1', 'Gene', '8314', (26, 30))
86023	26719535	Among the 141 cases without a BAP1 mutation, the mean age of MM diagnosis was 68.2 years (Table 1).	('BAP1', 'Gene', '8314', (30, 34))	('BAP1', 'Gene', (30, 34))	('mutation', 'Var', (35, 43))
86024	26719535	Since MM is generally regarded as a disease of the 60s and 70s, the age of onset in our BAP1 mutation carriers is younger than among the general population of sporadic MM cases.	('BAP1', 'Gene', '8314', (88, 92))	('mutation', 'Var', (93, 101))	('BAP1', 'Gene', (88, 92))
86026	26719535	However, it is noteworthy that while BAP1 mutation carriers tend to develop MM prior to the age of 60, two probands were diagnosed at 67 and 81 years of age (ABS3313 and ABS3023, respectively), and another (a sister of ABS3554) developed peritoneal MM at age 68.	('mutation', 'Var', (42, 50))	('BAP1', 'Gene', (37, 41))	('BAP1', 'Gene', '8314', (37, 41))	('develop', 'PosReg', (68, 75))
86027	26719535	Thus, not all MM cases with BAP1 mutations develop the disease at an early age.	('BAP1', 'Gene', '8314', (28, 32))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
86028	26719535	Among the 11 MM cases identified from the 9 families with germline BAP1 mutations, the 7 deceased patients had a median survival of 60 months after the initial diagnosis.	('mutations', 'Var', (72, 81))	('patients', 'Species', '9606', (98, 106))	('germline', 'Var', (58, 66))	('BAP1', 'Gene', '8314', (67, 71))	('BAP1', 'Gene', (67, 71))
86030	26719535	This 3.5-fold increased median survival rate among mutation carriers is similar to the improved long-term survival reported in a recent study in which a 60-month median survival was observed in MM patients with germline BAP1 mutations compared to a 9-month median survival among all MM cases recorded in the U.S. Surveillance, Epidemiology, and End Results (SEER) data from 1973 to 2010.	('patients', 'Species', '9606', (197, 205))	('mutations', 'Var', (225, 234))	('BAP1', 'Gene', (220, 224))	('mutation', 'Var', (51, 59))	('BAP1', 'Gene', '8314', (220, 224))
86031	26719535	In contrast, somatic BAP1 mutations in uveal melanomas are strongly associated with a more metastatic phenotype.	('uveal melanomas', 'Disease', (39, 54))	('uveal melanomas', 'Phenotype', 'HP:0007716', (39, 54))	('associated with', 'Reg', (68, 83))	('BAP1', 'Gene', (21, 25))	('mutations', 'Var', (26, 35))	('uveal melanomas', 'Disease', 'MESH:C536494', (39, 54))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('BAP1', 'Gene', '8314', (21, 25))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))
86032	26719535	Some factors that may contribute to the prolonged survival observed in BAP1 mutation carriers include the high proportion of peritoneal and epithelioid tumors in this subgroup as well as the younger age of diagnosis compared to non-carriers.	('prolonged', 'PosReg', (40, 49))	('epithelioid tumors', 'Disease', 'MESH:D012509', (140, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('BAP1', 'Gene', '8314', (71, 75))	('epithelioid tumors', 'Disease', (140, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('mutation', 'Var', (76, 84))	('BAP1', 'Gene', (71, 75))
86034	26719535	Among the nine families corresponding to cases with germline BAP1 mutations, two had a single case of cutaneous melanoma (father of MC7039; daughter of ABS3313), and one family had two UMs (case ABS3428 and his mother).	('mutations', 'Var', (66, 75))	('BAP1', 'Gene', (61, 65))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('cutaneous melanoma', 'Disease', (102, 120))	('germline', 'Var', (52, 60))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))	('BAP1', 'Gene', '8314', (61, 65))
86035	26719535	Three of the families with germline BAP1 mutations exhibited RCCs: ABS2573 and her daughter, ABS2570 (who also had MM), and ABS2778 (who also had MM).	('mutations', 'Var', (41, 50))	('ABS2570', 'Var', (93, 100))	('BAP1', 'Gene', '8314', (36, 40))	('ABS2778', 'Var', (124, 131))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('BAP1', 'Gene', (36, 40))
86038	26719535	In our series, breast cancer was observed in three individuals (ABS2573 and her sister; daughter of MM case ABS3023).	('ABS2573', 'Var', (64, 71))	('observed', 'Reg', (33, 41))	('ABS3023', 'Var', (108, 115))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Disease', (15, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
86044	26719535	To date, at least one stomach cancer has been previously reported in a BAP1 mutation carrier.	('carrier', 'molecular_function', 'GO:0005215', ('85', '92'))	('BAP1', 'Gene', '8314', (71, 75))	('stomach cancer', 'Disease', 'MESH:D013274', (22, 36))	('stomach cancer', 'Phenotype', 'HP:0012126', (22, 36))	('stomach cancer', 'Disease', (22, 36))	('mutation', 'Var', (76, 84))	('BAP1', 'Gene', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
86048	26719535	Our finding of two basal cell carcinomas in MM index cases is of interest in relation to recent work showing that germline BAP1 mutations can predispose to multiple basal cell carcinomas.	('BAP1', 'Gene', (123, 127))	('multiple basal cell carcinomas', 'Disease', (156, 186))	('basal cell carcinomas', 'Disease', (19, 40))	('mutations', 'Var', (128, 137))	('multiple basal cell carcinomas', 'Disease', 'MESH:C537656', (156, 186))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (19, 40))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (165, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (30, 40))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (19, 39))	('predispose to', 'Reg', (142, 155))	('BAP1', 'Gene', '8314', (123, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (165, 186))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (19, 40))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (165, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
86053	26719535	In fact, even among the families of the 141 MM cases without BAP1 mutations, 11 family members were diagnosed with basal cell carcinoma, including 10 that were found in MM index cases, i.e., non-BAP1 associated individuals who developed two primary cancers.	('mutations', 'Var', (66, 75))	('BAP1', 'Gene', '8314', (195, 199))	('BAP1', 'Gene', (195, 199))	('BAP1', 'Gene', (61, 65))	('primary cancer', 'Disease', (241, 255))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('primary cancer', 'Disease', 'MESH:D009369', (241, 255))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (115, 135))	('cancers', 'Disease', (249, 256))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (115, 135))	('basal cell carcinoma', 'Disease', (115, 135))	('diagnosed', 'Reg', (100, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('BAP1', 'Gene', '8314', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
86054	26719535	The BAP1 mutation sites observed in this study were spread widely within the gene, although most mutations occurred in the 3' end of the BAP1 coding region, with 7 of 9 mutations distributed between c.1695 and c.1891 (exons 13-14), corresponding to the ASXL1/2 binding domain of BAP1).	('BAP1', 'Gene', (137, 141))	('mutations', 'Var', (97, 106))	('BAP1', 'Gene', '8314', (279, 283))	('BAP1', 'Gene', (4, 8))	('BAP1', 'Gene', (279, 283))	('c.1695', 'Var', (199, 205))	('c.1891', 'Var', (210, 216))	('BAP1', 'Gene', '8314', (137, 141))	('binding', 'molecular_function', 'GO:0005488', ('261', '268'))	('BAP1', 'Gene', '8314', (4, 8))
86055	26719535	Although no BAP1 mutation hotspot has been identified to date, it was remarkable that two unrelated families (ABS2778 and ABS3554) had an identical mutation: c.1717delC, p.Leu573fs*3.	('p.Leu573fs*3', 'FRAMESHIFT', 'None', (170, 182))	('p.Leu573fs*3', 'Var', (170, 182))	('BAP1', 'Gene', '8314', (12, 16))	('c.1717delC', 'Mutation', 'rs869025212', (158, 168))	('BAP1', 'Gene', (12, 16))	('c.1717delC', 'Var', (158, 168))
86056	26719535	Upon review of reported germline hereditary and sporadic cases, we found the very same in/del mutation in a previously reported sporadic case of MM (SP-002) that was obtained through MARF.	('MARF', 'Gene', (183, 187))	('in/del mutation', 'Var', (87, 102))	('SP', 'Chemical', 'MESH:C000604007', (149, 151))	('MARF', 'Gene', '9927', (183, 187))
86057	26719535	In addition, the germline BAP1 mutation found in family ABS3428, i.e., c.1882_1885delTCAC, is identical to that seen in a previously reported "sporadic" MM case, SP-008, obtained through MARF.	('BAP1', 'Gene', (26, 30))	('MARF', 'Gene', '9927', (187, 191))	('c.1882_1885delTCAC', 'Mutation', 'c.1882_1885delTCAC', (71, 89))	('SP-008', 'Chemical', 'MESH:C505413', (162, 168))	('BAP1', 'Gene', '8314', (26, 30))	('MARF', 'Gene', (187, 191))	('c.1882_1885delTCAC', 'Var', (71, 89))
86059	26719535	The six BAP1 changes that involve frameshift or splice site mutations are predicted to result in loss of the carboxy-terminal region of the protein, which contains the nuclear localization signal.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('loss', 'NegReg', (97, 101))	('BAP1', 'Gene', '8314', (8, 12))	('changes', 'Var', (13, 20))	('BAP1', 'Gene', (8, 12))	('frameshift', 'Var', (34, 44))	('carboxy-terminal region of the protein', 'MPA', (109, 147))	('localization', 'biological_process', 'GO:0051179', ('176', '188'))
86060	26719535	In contrast, the carboxy terminus is retained in the three BAP1 missense mutants, although they appeared to have decreased activity (Fig.	('BAP1', 'Gene', (59, 63))	('missense mutants', 'Var', (64, 80))	('activity', 'MPA', (123, 131))	('BAP1', 'Gene', '8314', (59, 63))	('decreased', 'NegReg', (113, 122))
86061	26719535	The Ub-AMC assay demonstrated that the missense mutations still permit the BAP1 enzyme to be activated, but to a lesser extent than the WT protein.	('AMC', 'Chemical', '-', (7, 10))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('BAP1', 'Gene', (75, 79))	('Ub', 'Chemical', '-', (4, 6))	('activated', 'MPA', (93, 102))	('BAP1', 'Gene', '8314', (75, 79))	('missense mutations', 'Var', (39, 57))
86062	26719535	We had hypothesized that germline mutations of BAP1 contribute to susceptibility to MM in asbestos-exposed individuals through a mechanism that involves gene x environment interaction.	('asbestos', 'Chemical', 'MESH:D001194', (90, 98))	('susceptibility', 'Reg', (66, 80))	('BAP1', 'Gene', '8314', (47, 51))	('germline mutations', 'Var', (25, 43))	('BAP1', 'Gene', (47, 51))
86063	26719535	Our finding of an increased prevalence of inherited BAP1 mutations in asbestos-exposed MM cases versus asbestos-exposed controls appears to be consistent with this notion.	('BAP1', 'Gene', '8314', (52, 56))	('asbestos', 'Chemical', 'MESH:D001194', (103, 111))	('asbestos', 'Chemical', 'MESH:D001194', (70, 78))	('BAP1', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))
86064	26719535	The results from the cohort of 153 individuals with a significant exposure to asbestos but without MM or a familial cancer history did not, as expected, show any germline BAP1 mutations.	('BAP1', 'Gene', (171, 175))	('mutations', 'Var', (176, 185))	('familial cancer', 'Disease', (107, 122))	('BAP1', 'Gene', '8314', (171, 175))	('asbestos', 'Chemical', 'MESH:D001194', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('familial cancer', 'Disease', 'MESH:D009369', (107, 122))
86065	26719535	The other control cohort, consisting of 50 asbestos-exposed individuals from non-MM families with a high cancer signal similar to that of the 150 MM case cohort, also did not show any germline BAP1 mutations.	('BAP1', 'Gene', '8314', (193, 197))	('mutations', 'Var', (198, 207))	('high cancer', 'Disease', 'MESH:D009369', (100, 111))	('high cancer', 'Disease', (100, 111))	('BAP1', 'Gene', (193, 197))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('asbestos', 'Chemical', 'MESH:D001194', (43, 51))
86068	26719535	In their single family with a germline BAP1 mutation, three individuals who had potential exposure to asbestos developed MM, whereas another family member who was not exposed developed a different tumor type, i.e., a mucoepidermoid carcinoma.	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (217, 241))	('germline', 'Var', (30, 38))	('mutation', 'Var', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('mucoepidermoid carcinoma', 'Disease', (217, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('BAP1', 'Gene', '8314', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('asbestos', 'Chemical', 'MESH:D001194', (102, 110))	('tumor', 'Disease', (197, 202))	('BAP1', 'Gene', (39, 43))
86070	26719535	Instead, the significantly higher incidence of BAP1 mutations observed in MM cases versus controls suggests that asbestos and genetic factors cooperate to enhance the onset of MM.	('mutations', 'Var', (52, 61))	('enhance', 'PosReg', (155, 162))	('asbestos', 'Chemical', 'MESH:D001194', (113, 121))	('BAP1', 'Gene', '8314', (47, 51))	('BAP1', 'Gene', (47, 51))
86072	26719535	Taken together, the findings presented here indicate that patients presenting with MM and a personal or family history of other cancers should be considered for genetic testing, with the goal of identifying those families that might benefit from BAP1 mutation screening and regular clinical monitoring of family members for the purpose of early detection of cancers and clinical intervention.	('BAP1', 'Gene', (246, 250))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Disease', (358, 365))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (358, 365))	('mutation', 'Var', (251, 259))	('cancer', 'Phenotype', 'HP:0002664', (358, 364))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('BAP1', 'Gene', '8314', (246, 250))	('patients', 'Species', '9606', (58, 66))	('cancers', 'Disease', 'MESH:D009369', (358, 365))
86149	25118602	Bortezomib (a proteasome inhibitor) induces quiescence in surviving multiple myeloma cells, which have dephosphorylated eIF2alpha (eukaryotic translation initiation factor 2alpha) and reduced endoplasmic reticulum (ER) stress-related apoptotic gene induction (BOX 3).	('eIF2', 'cellular_component', 'GO:0005850', ('120', '124'))	('myeloma', 'Disease', (77, 84))	('quiescence', 'biological_process', 'GO:0044838', ('44', '54'))	('translation initiation', 'biological_process', 'GO:0006413', ('142', '164'))	('eIF2alpha', 'Gene', '83939', (120, 129))	('proteasome', 'molecular_function', 'GO:0004299', ('14', '24'))	('dephosphorylated', 'Var', (103, 119))	('Bortezomib', 'Chemical', 'MESH:D000069286', (0, 10))	('quiescence', 'MPA', (44, 54))	('reduced', 'NegReg', (184, 191))	('multiple myeloma', 'Phenotype', 'HP:0006775', (68, 84))	('eukaryotic translation initiation factor 2alpha', 'Gene', '83939', (131, 178))	('proteasome', 'cellular_component', 'GO:0000502', ('14', '24'))	('myeloma', 'Disease', 'MESH:D009101', (77, 84))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('192', '213'))	('eIF2alpha', 'Gene', (120, 129))	('eukaryotic translation initiation factor 2alpha', 'Gene', (131, 178))
86151	25118602	Similarly, in non-small-cell lung cancer (NSCLC) xenografts treated with an EGFR inhibitor (erlotinib), tumour cells entered a quiescence-like state, and cells that survived this treatment eventually grew after a prolonged arrest (BOX 3) but were eliminated when erlotinib was combined with the BH3-mimetic ABT-737 (a BCL-2 and BCL-XL inhibitor).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('inhibitor', 'Var', (81, 90))	('BCL-XL', 'Gene', (328, 334))	('EGFR', 'Gene', (76, 80))	('BCL-2', 'Gene', '596', (318, 323))	('BCL-2', 'Gene', (318, 323))	('erlotinib', 'Chemical', 'MESH:D000069347', (263, 272))	('ABT-737', 'Chemical', 'MESH:C501332', (307, 314))	('BCL-XL', 'Gene', '598', (328, 334))	('BCL-2', 'molecular_function', 'GO:0015283', ('318', '323'))	('non-small-cell lung cancer', 'Disease', (14, 40))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('BH3', 'Chemical', 'MESH:C006008', (295, 298))	('EGFR', 'Gene', '1956', (76, 80))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (14, 40))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('EGFR', 'molecular_function', 'GO:0005006', ('76', '80'))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('quiescence', 'biological_process', 'GO:0044838', ('127', '137'))	('tumour', 'Disease', (104, 110))	('NSCLC', 'Disease', (42, 47))	('erlotinib', 'Chemical', 'MESH:D000069347', (92, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
86157	25118602	Interestingly, DYRK1B also coordinates survival via an antioxidant response, and inhibition of this kinase, through unknown mechanisms, seems to specifically kill quiescent pancreatic cancer cells but not normal quiescent cells.	('antioxidant response', 'MPA', (55, 75))	('DYRK1B', 'Gene', (15, 21))	('DYRK1B', 'Gene', '9149', (15, 21))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (173, 190))	('inhibition', 'Var', (81, 91))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('pancreatic cancer', 'Disease', (173, 190))	('pancreatic cancer', 'Disease', 'MESH:D010190', (173, 190))	('kill', 'PosReg', (158, 162))
86168	25118602	Activation of p38 and/or the unfolded protein response (UPR), an adaptive ER stress tolerance mechanism, might promote the survival of dormant tumour cells.	('survival', 'CPA', (123, 131))	('unfolded', 'MPA', (29, 37))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('tumour', 'Disease', (143, 149))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('p38', 'Var', (14, 17))	('promote', 'PosReg', (111, 118))
86186	25118602	Leukaemia cells with the E2A-PBX1 fusion protein express high levels of MER, and when these cells are in contact with human osteoblasts, which produce GAS6 (FIG.	('E2A-PBX1 fusion', 'Var', (25, 40))	('MER', 'MPA', (72, 75))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('Leukaemia', 'Disease', (0, 9))	('Leukaemia', 'Disease', 'MESH:D007938', (0, 9))	('GAS6', 'Gene', '2621', (151, 155))	('GAS6', 'Gene', (151, 155))	('GAS', 'molecular_function', 'GO:0034005', ('151', '154'))	('human', 'Species', '9606', (118, 123))
86192	25118602	Similarly to BMP7, BMP4 is another BMPR2 ligand, and inhibition of BMP4 by the secreted antagonist COCO (also known as DAND5) induces the proliferation of dormant mouse mammary 4T07 DTCs in the lungs, a tissue with abundant BMP4 (REF.).	('inhibition', 'Var', (53, 63))	('BMP4', 'Gene', (67, 71))	('induces', 'Reg', (126, 133))	('proliferation', 'CPA', (138, 151))	('DTCs', 'Chemical', '-', (182, 186))	('DAND5', 'Gene', (119, 124))	('ligand', 'molecular_function', 'GO:0005488', ('41', '47'))	('DAND5', 'Gene', '23863', (119, 124))	('mouse', 'Species', '10090', (163, 168))
86197	25118602	Importantly, inhibition of p38 or TGFbetaR1 (a TGFbeta2 receptor) induced HNSCC multi-organ (liver, spleen, bone marrow and lung) proliferation of DTCs in mice.	('TGFbeta', 'Gene', '7040;7042;21808;7043', (34, 41))	('DTCs', 'Chemical', '-', (147, 151))	('TGFbetaR', 'molecular_function', 'GO:0005024', ('34', '42'))	('inhibition', 'Var', (13, 23))	('TGFbeta', 'Gene', (47, 54))	('TGFbeta', 'Gene', (34, 41))	('mice', 'Species', '10090', (155, 159))	('HNSCC multi-organ', 'Disease', 'MESH:D000077195', (74, 91))	('HNSCC multi-organ', 'Disease', (74, 91))	('TGFbeta', 'Gene', '7040;7042;21808;7043', (47, 54))	('p38', 'Gene', (27, 30))
86206	25118602	showed that the inhibition of myosin light chain kinase (MLCK) induced the dormancy of solitary DTCs in the lung, thus reducing the number of breast cancer lung macro-metastases (FIGS 2,3).	('MLCK', 'Gene', (57, 61))	('breast cancer lung macro-metastases', 'Disease', 'MESH:D009362', (142, 177))	('MLCK', 'molecular_function', 'GO:0004687', ('57', '61'))	('myosin light chain kinase', 'Gene', (30, 55))	('DTCs', 'Chemical', '-', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('dormancy', 'CPA', (75, 83))	('lung macro', 'Phenotype', 'HP:0002088', (156, 166))	('dormancy', 'biological_process', 'GO:0030431', ('75', '83'))	('myosin light chain kinase', 'molecular_function', 'GO:0004687', ('30', '55'))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('inhibition', 'Var', (16, 26))	('myosin light chain kinase', 'Gene', '4638', (30, 55))	('breast cancer lung macro-metastases', 'Disease', (142, 177))	('induced', 'Reg', (63, 70))	('MLCK', 'Gene', '4638', (57, 61))	('reducing', 'NegReg', (119, 127))
86210	25118602	Importantly, pharmacological inhibition of SRC alone induced the dormancy or slow cycling of breast cancer cells, while inhibition of both MEK1 and SRC caused apoptosis of DTCs, suggesting that this pathway can be specifically targeted in DTCs in different niches (FIG.	('SRC', 'Gene', (43, 46))	('slow cycling', 'CPA', (77, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('MEK1', 'Gene', '5604', (139, 143))	('apoptosis', 'biological_process', 'GO:0097194', ('159', '168'))	('inhibition', 'Var', (120, 130))	('dormancy', 'CPA', (65, 73))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('DTCs', 'Chemical', '-', (172, 176))	('apoptosis', 'biological_process', 'GO:0006915', ('159', '168'))	('breast cancer', 'Disease', (93, 106))	('dormancy', 'biological_process', 'GO:0030431', ('65', '73'))	('MEK1', 'molecular_function', 'GO:0004708', ('139', '143'))	('SRC', 'Gene', '6714', (148, 151))	('induced', 'Reg', (53, 60))	('inhibition', 'Var', (29, 39))	('MEK1', 'Gene', (139, 143))	('SRC', 'Gene', (148, 151))	('DTCs', 'Chemical', '-', (239, 243))	('SRC', 'Gene', '6714', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('slow cycling', 'Phenotype', 'HP:0002067', (77, 89))
86226	25118602	This is important because there is no direct clinical proof that the immune system is involved in the growth arrest of non-proliferative solitary DTCs or in controlling their numbers via immune editing.	('non-proliferative solitary DTCs', 'Disease', (119, 150))	('growth arrest', 'Disease', 'MESH:D006323', (102, 115))	('growth arrest', 'Disease', (102, 115))	('immune editing', 'Var', (187, 201))	('DTCs', 'Chemical', '-', (146, 150))	('growth arrest', 'Phenotype', 'HP:0001510', (102, 115))
86229	25118602	However, the small tumours resumed growth after CD8+ and CD4+ T cell depletion (FIG.	('small tumours', 'Disease', (13, 26))	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('resumed', 'PosReg', (27, 34))	('CD8', 'Gene', (48, 51))	('small tumours', 'Disease', 'MESH:D055752', (13, 26))	('CD4+ T', 'Var', (57, 63))	('CD8', 'Gene', '925', (48, 51))	('growth', 'MPA', (35, 41))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
86234	25118602	A similar function for CD4+ T cells but not CD8+ T cells was observed with a vaccination protocol that targeted tumour blood vessels.	('CD4+', 'Var', (23, 27))	('CD8', 'Gene', (44, 47))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('CD8', 'Gene', '925', (44, 47))	('tumour', 'Disease', (112, 118))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))
86239	25118602	The above data suggest that further work is necessary to conclusively determine whether the effects of CD4+ and CD8+ T cells on DTC behaviour require active cytotoxicity or whether they are the result of the immune system creating a microenvironment non-permissive for tumour expansion.	('DTC', 'MPA', (128, 131))	('CD8', 'Gene', (112, 115))	('cytotoxicity', 'Disease', (157, 169))	('CD8', 'Gene', '925', (112, 115))	('behaviour', 'biological_process', 'GO:0007610', ('132', '141'))	('tumour', 'Phenotype', 'HP:0002664', (269, 275))	('CD4+', 'Var', (103, 107))	('tumour', 'Disease', 'MESH:D009369', (269, 275))	('cytotoxicity', 'Disease', 'MESH:D064420', (157, 169))	('DTC', 'Chemical', '-', (128, 131))	('tumour', 'Disease', (269, 275))
86266	25118602	One study showed that, in both primary cells and breast cancer and leukaemia cell lines, the DNA methylation inhibitor 5-azacytidine alone caused decreased expression of G0 to G1 exit genes : such as DNMT1 and FOXM1 : that are also downregulated in haematological and epithelial tumour dormancy models.	('FOXM1', 'Gene', '2305', (210, 215))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('leukaemia', 'Disease', (67, 76))	('breast cancer', 'Disease', (49, 62))	('epithelial tumour', 'Disease', (268, 285))	('DNA methylation', 'biological_process', 'GO:0006306', ('93', '108'))	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('DNMT1', 'Gene', '1786', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('dormancy', 'biological_process', 'GO:0030431', ('286', '294'))	('epithelial tumour', 'Phenotype', 'HP:0031492', (268, 285))	('FOXM1', 'Gene', (210, 215))	('leukaemia', 'Disease', 'MESH:D007938', (67, 76))	('G0 to G1 exit genes ', 'Gene', (170, 190))	('5-azacytidine', 'Var', (119, 132))	('tumour', 'Phenotype', 'HP:0002664', (279, 285))	('DNMT1', 'Gene', (200, 205))	('5-azacytidine', 'Chemical', 'MESH:D001374', (119, 132))	('decreased', 'NegReg', (146, 155))	('epithelial tumour', 'Disease', 'MESH:D000077216', (268, 285))	('expression', 'MPA', (156, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))
86267	25118602	Remarkably, expression of other key genes upregulated in the p38-induced dormancy signature, such as RARB and CDKN1A, were induced by 5-azacytidine.	('CDKN1A', 'Gene', '1026', (110, 116))	('dormancy', 'biological_process', 'GO:0030431', ('73', '81'))	('induced', 'PosReg', (123, 130))	('5-azacytidine', 'Chemical', 'MESH:D001374', (134, 147))	('RARB', 'Gene', (101, 105))	('5-azacytidine', 'Var', (134, 147))	('RARB', 'Gene', '5915', (101, 105))	('dormancy', 'CPA', (73, 81))	('upregulated', 'PosReg', (42, 53))	('expression', 'MPA', (12, 22))	('CDKN1A', 'Gene', (110, 116))
86272	25118602	In this group, DTCs from different types of cancer (see the table) could be profiled for markers that indicate whether DTCs are proliferating (such as increased expression of COCO, fibronectin, periostin (POSTN), transforming growth factor-beta1 (TGFbeta1) or phosphorylated ERK (P-ERK) and low expression of phosphorylated p38 (P-p38)) or dormant (such as low expression of P-ERK, high expression of P-p38, TGFBR3, bone morphogenetic protein receptor type 2 (BMPR2), TGFbeta2 or BMPs).	('increased', 'PosReg', (151, 160))	('POSTN', 'Gene', '10631', (205, 210))	('ERK', 'Gene', '5594', (282, 285))	('bone morphogenetic protein receptor type 2', 'Gene', '659', (416, 458))	('transforming growth factor-beta', 'molecular_function', 'GO:0005160', ('213', '244'))	('BMPR2', 'Gene', (460, 465))	('ERK', 'Gene', (377, 380))	('expression', 'MPA', (295, 305))	('transforming growth factor-beta1', 'Gene', '7040', (213, 245))	('periostin', 'Gene', (194, 203))	('ERK', 'Gene', (282, 285))	('expression', 'MPA', (161, 171))	('TGFbeta1', 'Gene', '7040', (247, 255))	('low', 'NegReg', (357, 360))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('protein', 'cellular_component', 'GO:0003675', ('435', '442'))	('transforming growth factor-beta1', 'Gene', (213, 245))	('fibronectin', 'Gene', (181, 192))	('TGFbeta2', 'Gene', (468, 476))	('periostin', 'Gene', '10631', (194, 203))	('TGFBR3', 'Gene', '7049', (408, 414))	('TGFbeta1', 'Gene', (247, 255))	('ERK', 'molecular_function', 'GO:0004707', ('377', '380'))	('ERK', 'Gene', '5594', (275, 278))	('bone morphogenetic protein receptor type 2', 'Gene', (416, 458))	('DTCs', 'Chemical', '-', (119, 123))	('TGFBR3', 'Gene', (408, 414))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('ERK', 'molecular_function', 'GO:0004707', ('275', '278'))	('cancer', 'Disease', (44, 50))	('POSTN', 'Gene', (205, 210))	('fibronectin', 'Gene', '2335', (181, 192))	('ERK', 'Gene', '5594', (377, 380))	('ERK', 'molecular_function', 'GO:0004707', ('282', '285'))	('expression', 'MPA', (361, 371))	('DTCs', 'Chemical', '-', (15, 19))	('ERK', 'Gene', (275, 278))	('P-p38', 'Var', (401, 406))
86281	25118602	For example, inactivating mutations in BAP1 (REF.)	('inactivating mutations', 'Var', (13, 35))	('BAP1', 'Gene', '8314', (39, 43))	('BAP1', 'Gene', (39, 43))
86282	25118602	promote epigenetic deregulation, leading to poorly differentiated metastatic tumours that resemble primitive neuroectoderm.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('static tumours', 'Disease', (70, 84))	('leading to', 'Reg', (33, 43))	('primitive neuroectoderm', 'Phenotype', 'HP:0030065', (99, 122))	('static tumours', 'Disease', 'MESH:D014202', (70, 84))	('primitive neuroectoderm', 'Disease', (99, 122))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('epigenetic deregulation', 'Var', (8, 31))
86291	25118602	For example, p38 limits self-renewal, which is a property of stem cells, and a p38-regulated dormancy gene signature was associated with longer metastasis-free periods in patients with oestrogen receptor-positive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('associated with', 'Reg', (121, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('p38', 'Var', (13, 16))	('longer', 'PosReg', (137, 143))	('breast cancer', 'Disease', (213, 226))	('patients', 'Species', '9606', (171, 179))	('self-renewal', 'CPA', (24, 36))	('dormancy', 'biological_process', 'GO:0030431', ('93', '101'))	('p38-regulated dormancy gene', 'Gene', (79, 106))	('limits', 'NegReg', (17, 23))	('metastasis-free periods', 'CPA', (144, 167))
86294	25118602	1), is whether the genetic alterations that are present in early DTCs might predispose these cells to dormancy.	('predispose', 'Reg', (76, 86))	('DTCs', 'Chemical', '-', (65, 69))	('genetic alterations', 'Var', (19, 38))	('dormancy', 'CPA', (102, 110))	('alterations', 'Var', (27, 38))	('dormancy', 'biological_process', 'GO:0030431', ('102', '110'))
86296	25118602	DTCs in patients with breast cancer without distant metastasis carry specific chromosomal gains such as 5cen-5q23.3 or 18q.	('breast cancer', 'Disease', (22, 35))	('18q', 'Var', (119, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('DTCs', 'Chemical', '-', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('5cen-5q23.3', 'Var', (104, 115))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))	('patients', 'Species', '9606', (8, 16))
86299	25118602	Perhaps DTCs overexpressing NR2F1 may remain dormant until additional genetic and/or epigenetic changes override this signal.	('epigenetic changes', 'Var', (85, 103))	('override', 'PosReg', (104, 112))	('NR2F1', 'Gene', '7025', (28, 33))	('DTCs', 'Chemical', '-', (8, 12))	('NR2F1', 'Gene', (28, 33))
86306	25118602	The detection of DTCs in patients has been strongly suggested to be a risk factor for metastasis.	('patients', 'Species', '9606', (25, 33))	('DTCs', 'Chemical', '-', (17, 21))	('DTCs', 'Var', (17, 21))	('metastasis', 'CPA', (86, 96))
86389	25025426	It has been previously reported that successful melanin depigmentation methods using dilute H2O2, with particular interest on pathologic ocular tissues, usually take a minimum of 18 hours up to 2 or 3 weeks for thorough bleaching to occur at room temperature or at lower temperature i.e.	('melanin', 'Chemical', 'MESH:D008543', (48, 55))	('dilute', 'Var', (85, 91))	('H2O2', 'Chemical', 'MESH:D006861', (92, 96))	('H2O2', 'Var', (92, 96))
86393	25025426	Effective bleaching was also achieved using 10% H2O2 that was diluted in PBS, compared to the use of deionized water as a diluent.	('H2O2', 'Chemical', 'MESH:D006861', (48, 52))	('H2O2', 'Var', (48, 52))	('bleaching', 'CPA', (10, 19))	('water', 'Chemical', 'MESH:D014867', (111, 116))	('PBS', 'Chemical', '-', (73, 76))
86403	25025426	However, numerous studies reported that bleaching with H2O2 did not interfere with the antigenicity of the tissues for a wide range of antibodies in both human and animal tissue samples.	('H2O2', 'Chemical', 'MESH:D006861', (55, 59))	('H2O2', 'Var', (55, 59))	('human', 'Species', '9606', (154, 159))	('antigenicity', 'MPA', (87, 99))
86416	23832661	Cooperation and antagonism among cancer genes: the renal cancer paradigm It is poorly understood how driver mutations in cancer genes work together to promote tumor development.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('renal cancer', 'Disease', (51, 63))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('mutations', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (57, 63))	('renal cancer', 'Phenotype', 'HP:0009726', (51, 63))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('renal cancer', 'Disease', 'MESH:D007680', (51, 63))	('tumor', 'Disease', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('promote', 'PosReg', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('cancer', 'Disease', (121, 127))
86418	23832661	The four most commonly mutated genes in RCC of clear-cell type (the most common type) are two-hit tumor suppressor genes and they cluster in a 43 Mb region on chromosome 3p that is deleted in ~90% of tumors: VHL (mutated in ~80%), PBRM1 (~50%), BAP1 (~15%) and SETD2 (~15%).	('PBRM1', 'Gene', '55193', (231, 236))	('tumor suppressor', 'biological_process', 'GO:0051726', ('98', '114'))	('mutated', 'Var', (23, 30))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('PBRM1', 'Gene', (231, 236))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', (200, 205))	('BAP1', 'Gene', (245, 249))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('RCC', 'Disease', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('chromosome', 'cellular_component', 'GO:0005694', ('159', '169'))	('SETD2', 'Gene', (261, 266))	('VHL', 'Gene', (208, 211))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('tumors', 'Disease', (200, 206))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('98', '114'))	('SETD2', 'Gene', '29072', (261, 266))
86419	23832661	Meta-analyses that we conducted show that mutations in PBRM1 and SETD2 co-occur in tumors at a frequency higher than expected by chance alone, indicating that these mutations may cooperate in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('cooperate', 'Reg', (179, 188))	('tumor', 'Disease', (83, 88))	('tumors', 'Disease', (83, 89))	('SETD2', 'Gene', '29072', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('SETD2', 'Gene', (65, 70))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('PBRM1', 'Gene', (55, 60))	('PBRM1', 'Gene', '55193', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('mutations', 'Var', (42, 51))
86420	23832661	In contrast, consistent with our previous results, mutations in PBRM1 and BAP1 tend to be mutually exclusive.	('PBRM1', 'Gene', (64, 69))	('BAP1', 'Gene', (74, 78))	('mutations', 'Var', (51, 60))	('PBRM1', 'Gene', '55193', (64, 69))
86421	23832661	However, mutation exclusivity may indicate negative genetic interactions, as proposed herein for PBRM1 and BAP1, and mutations in these genes define RCC with different pathologic features, gene expression profiles, and outcomes.	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('mutations', 'Var', (117, 126))	('BAP1', 'Gene', (107, 111))	('PBRM1', 'Gene', (97, 102))	('define', 'Reg', (142, 148))	('PBRM1', 'Gene', '55193', (97, 102))	('gene expression', 'biological_process', 'GO:0010467', ('189', '204'))	('interactions', 'Interaction', (60, 72))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
86428	23832661	However, multiple residues may be targeted by mutations that disrupt autoinhibitory domains (as in mTOR).	('disrupt', 'NegReg', (61, 68))	('mutations', 'Var', (46, 55))	('autoinhibitory domains', 'MPA', (69, 91))	('mTOR', 'Gene', '2475', (99, 103))	('mTOR', 'Gene', (99, 103))
86429	23832661	In contrast, tumor suppressor genes, which are inactivated by mutation and are typically recessive, may be disrupted by a variety of alterations including insertions, deletions, nonsense, missense and splice-site mutations.	('tumor', 'Disease', (13, 18))	('deletions', 'Var', (167, 176))	('insertions', 'Var', (155, 165))	('tumor suppressor', 'biological_process', 'GO:0051726', ('13', '29'))	('nonsense', 'Var', (178, 186))	('mutation', 'Var', (62, 70))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('alterations', 'Var', (133, 144))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('disrupted', 'NegReg', (107, 116))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('13', '29'))
86430	23832661	Missense mutations in tumor suppressor genes are often used to identify domains important for function, but these analyses are confounded by mutations disrupting secondary or tertiary structure and causing protein instability.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('22', '38'))	('mutations', 'Var', (141, 150))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('protein', 'cellular_component', 'GO:0003675', ('206', '213'))	('secondary or tertiary structure', 'MPA', (162, 193))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('disrupting', 'NegReg', (151, 161))	('protein instability', 'MPA', (206, 225))	('tumor', 'Disease', (22, 27))	('causing', 'Reg', (198, 205))	('tumor suppressor', 'biological_process', 'GO:0051726', ('22', '38'))	('Missense mutations', 'Var', (0, 18))
86431	23832661	Typically one allele of a tumor suppressor gene is disrupted by an intragenic mutation and the other is lost as part of a large deletion, which results in loss of heterozygosity (LOH).	('loss', 'NegReg', (155, 159))	('mutation', 'Var', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor suppressor', 'biological_process', 'GO:0051726', ('26', '42'))	('disrupted', 'NegReg', (51, 60))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('26', '42'))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
86445	23832661	A comprehensive list of mutations in a tumor, together with an understanding of their prevalence and functional significance should pave the way for better analyses of genetic interactions among cancer genes.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('mutations', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
86448	23832661	This is illustrated, for instance, by mutations in p16, D-type cyclins, CDK4, and retinoblastoma, which tend to be exclusive and disrupt the same cell cycle regulatory pathway.	('CDK4', 'Gene', (72, 76))	('p16', 'Gene', '1029', (51, 54))	('CDK', 'molecular_function', 'GO:0004693', ('72', '75'))	('CDK4', 'Gene', '1019', (72, 76))	('retinoblastoma', 'Phenotype', 'HP:0009919', (82, 96))	('cell cycle', 'biological_process', 'GO:0007049', ('146', '156'))	('cell cycle regulatory pathway', 'Pathway', (146, 175))	('p16', 'Gene', (51, 54))	('disrupt', 'Reg', (129, 136))	('retinoblastoma', 'Disease', 'MESH:D012175', (82, 96))	('retinoblastoma', 'Disease', (82, 96))	('mutations', 'Var', (38, 47))
86450	23832661	As an example, when two genes are mutated at a frequency of 5%, the number of tumors required to show that a lack of mutation co-occurrence is due to a genetic interaction (as opposed to chance alone - after all, each gene is mutated in only 5% of the tumors) is 1,330.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumors', 'Disease', (252, 258))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('mutated', 'Var', (34, 41))	('tumors', 'Disease', 'MESH:D009369', (252, 258))
86452	23832661	In fact, the architecture of amplifications and deletions in tumors may be far more informative that previously appreciated.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('deletions', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
86453	23832661	This has important methodologically implications as the hunt for cancer genes may need to be redirected towards genes flanking a common region of amplification or deletion, rather than those at the center.	('deletion', 'Var', (163, 171))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))
86456	23832661	Subsequently, VHL was found to be frequently mutated in sporadic ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('VHL', 'Gene', (14, 17))	('mutated', 'Var', (45, 52))
86457	23832661	VHL is mutated in ~80% of sporadic ccRCC and is inactivated by methylation in an additional 10%.	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('methylation', 'biological_process', 'GO:0032259', ('63', '74'))	('VHL', 'Gene', (0, 3))	('RCC', 'Disease', (37, 40))	('mutated', 'Var', (7, 14))
86465	23832661	Both SETD2 and BAP1 are mutated in ~15% of ccRCC.	('mutated', 'Var', (24, 31))	('SETD2', 'Gene', (5, 10))	('BAP1', 'Gene', (15, 19))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('SETD2', 'Gene', '29072', (5, 10))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
86470	23832661	We identified studies (or datasets) reporting mutations in PBRM1 together with either SETD2 or BAP1.	('mutations', 'Var', (46, 55))	('PBRM1', 'Gene', (59, 64))	('PBRM1', 'Gene', '55193', (59, 64))	('SETD2', 'Gene', '29072', (86, 91))	('SETD2', 'Gene', (86, 91))
86472	23832661	One hundred and eleven tumors were found to be solely mutated for PBRM1 and seven were found solely mutant for SETD2.	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('PBRM1', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutated', 'Var', (54, 61))	('SETD2', 'Gene', '29072', (111, 116))	('PBRM1', 'Gene', '55193', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('SETD2', 'Gene', (111, 116))
86473	23832661	Given the individual mutation rates for PBRM1 and SETD2, five tumors were expected to have mutations in both genes, but eight were found (p=0.16; Table 1).	('SETD2', 'Gene', '29072', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('PBRM1', 'Gene', (40, 45))	('tumors', 'Disease', (62, 68))	('SETD2', 'Gene', (50, 55))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('PBRM1', 'Gene', '55193', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('mutation', 'Var', (21, 29))	('mutations', 'Var', (91, 100))
86475	23832661	Again, given the mutation rates for PBRM1 and SETD2, one tumor may have been expected to have mutations in both genes, but three were found (p=0.030; Table 1).	('SETD2', 'Gene', (46, 51))	('PBRM1', 'Gene', (36, 41))	('mutations', 'Var', (94, 103))	('PBRM1', 'Gene', '55193', (36, 41))	('mutation', 'Var', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('SETD2', 'Gene', '29072', (46, 51))
86478	23832661	Finally, The Cancer Genome Atlas consortium released results of 293 tumors and ninety tumors were found with mutations in PBRM1 and seventeen with mutations in SETD2.	('SETD2', 'Gene', '29072', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('293 tumors', 'CellLine', 'CVCL:0045', (64, 74))	('PBRM1', 'Gene', (122, 127))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('Cancer', 'Disease', (13, 19))	('SETD2', 'Gene', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('Cancer', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (86, 92))	('PBRM1', 'Gene', '55193', (122, 127))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
86479	23832661	Twelve tumors were expected to have mutations in both PBRM1 and SETD2, but sixteen were found (p=0.13; Table 1).	('PBRM1', 'Gene', (54, 59))	('PBRM1', 'Gene', '55193', (54, 59))	('SETD2', 'Gene', '29072', (64, 69))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('mutations', 'Var', (36, 45))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('SETD2', 'Gene', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
86480	23832661	Across all the studies, the number of tumors with mutations in both PBRM1 and SETD2 exceeded the number expected by chance alone.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('SETD2', 'Gene', '29072', (78, 83))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('PBRM1', 'Gene', (68, 73))	('mutations', 'Var', (50, 59))	('SETD2', 'Gene', (78, 83))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('PBRM1', 'Gene', '55193', (68, 73))
86481	23832661	Nonetheless, when considered together, among 924 ccRCC, there were 267 tumors with mutations only in PBRM1, 33 with mutations only in SETD2, and 33 with mutations in both SETD2 and PBRM1 (Table 1).	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('mutations', 'Var', (83, 92))	('SETD2', 'Gene', '29072', (134, 139))	('SETD2', 'Gene', '29072', (171, 176))	('SETD2', 'Gene', (134, 139))	('PBRM1', 'Gene', (181, 186))	('SETD2', 'Gene', (171, 176))	('PBRM1', 'Gene', '55193', (181, 186))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mutations', 'Var', (116, 125))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('PBRM1', 'Gene', (101, 106))	('PBRM1', 'Gene', '55193', (101, 106))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('RCC', 'Disease', (51, 54))
86482	23832661	The number of tumors expected to have mutations in both genes by chance alone was 21, and 33 were found.	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('mutations', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
86483	23832661	Overall, the frequency of mutations in SETD2 was two-fold higher for PBRM1-mutant tumors than wild-type tumors (Odds ratio [OR] = 2.1; 95% confidence interval [CI] 1.3 - 3.5).	('PBRM1', 'Gene', '55193', (69, 74))	('SETD2', 'Gene', (39, 44))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('PBRM1', 'Gene', (69, 74))	('tumors', 'Disease', (104, 110))	('mutations', 'Var', (26, 35))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('higher', 'Reg', (58, 64))	('SETD2', 'Gene', '29072', (39, 44))
86484	23832661	These results suggest that mutations in PBRM1 and SETD2 cooperate in renal tumorigenesis.	('mutations', 'Var', (27, 36))	('SETD2', 'Gene', '29072', (50, 55))	('PBRM1', 'Gene', (40, 45))	('PBRM1', 'Gene', '55193', (40, 45))	('SETD2', 'Gene', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cooperate', 'Reg', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
86488	23832661	We reported previously that mutations in PBRM1 and BAP1 are largely mutually exclusive, which stands in contrast to the findings from meta-analyses reported herein of PBRM1 and SETD2.	('SETD2', 'Gene', '29072', (177, 182))	('PBRM1', 'Gene', (167, 172))	('BAP1', 'Gene', (51, 55))	('PBRM1', 'Gene', '55193', (167, 172))	('SETD2', 'Gene', (177, 182))	('PBRM1', 'Gene', (41, 46))	('PBRM1', 'Gene', '55193', (41, 46))	('mutations', 'Var', (28, 37))
86489	23832661	Among 176 ccRCC we analyzed, we found 89 tumors with mutations solely in PBRM1 and 21 with mutations solely in BAP1.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('RCC', 'Phenotype', 'HP:0005584', (12, 15))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('RCC', 'Disease', (12, 15))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('mutations', 'Var', (53, 62))	('PBRM1', 'Gene', (73, 78))	('PBRM1', 'Gene', '55193', (73, 78))
86490	23832661	By chance, 13 tumors would have been expected to have mutations in both genes, but only 3 tumors were found.	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
86491	23832661	have also reported BAP1 and PBRM1 mutations in ccRCC.	('RCC', 'Disease', (49, 52))	('reported', 'Reg', (10, 18))	('PBRM1', 'Gene', (28, 33))	('PBRM1', 'Gene', '55193', (28, 33))	('BAP1', 'Gene', (19, 23))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('mutations', 'Var', (34, 43))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
86492	23832661	In both studies, the sensitivity for mutation detection was seemingly low, and consequently statistical power was insufficient.	('insufficient', 'Disease', (114, 126))	('insufficient', 'Disease', 'MESH:D000309', (114, 126))	('low', 'NegReg', (70, 73))	('mutation', 'Var', (37, 45))
86493	23832661	However, in both instances, fewer tumors were found with simultaneous mutations in both genes than were expected by chance alone (Table 2).	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumors', 'Disease', (34, 40))	('mutations', 'Var', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
86494	23832661	Similarly, in data from the TCGA, there was an under-representation of tumors with mutations in both BAP1 and PBRM1 (Table 2).	('mutations', 'Var', (83, 92))	('PBRM1', 'Gene', '55193', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('BAP1', 'Gene', (101, 105))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('PBRM1', 'Gene', (110, 115))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
86495	23832661	In the TCGA study, which is the largest, among 293 tumors, there were 101 with mutations solely in PBRM1 (independently of SETD2) and 22 with mutations solely in BAP1.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('PBRM1', 'Gene', (99, 104))	('PBRM1', 'Gene', '55193', (99, 104))	('SETD2', 'Gene', '29072', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('SETD2', 'Gene', (123, 128))	('293 tumors', 'CellLine', 'CVCL:0045', (47, 57))	('mutations', 'Var', (79, 88))
86496	23832661	Given the relative frequencies of tumors individually mutated for BAP1 and PBRM1, 10 tumors would have been expected to have mutations in both genes, but only 5 were found (p=0.058; Table 2).	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('PBRM1', 'Gene', (75, 80))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('PBRM1', 'Gene', '55193', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('BAP1', 'Gene', (66, 70))	('mutated', 'Var', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumors', 'Disease', (85, 91))
86497	23832661	When combined, these 3 studies evaluated 576 tumors and among them there were 175 tumors with mutations solely in PBRM1 and 40 with mutations solely in BAP1.	('PBRM1', 'Gene', '55193', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('mutations', 'Var', (94, 103))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('PBRM1', 'Gene', (114, 119))
86498	23832661	Considered together, 14 tumors would have been expected with mutations in both BAP1 and PBRM1, but only 6 were found, and the p value was significant (p=0.004).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('PBRM1', 'Gene', (88, 93))	('PBRM1', 'Gene', '55193', (88, 93))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (61, 70))	('BAP1', 'Gene', (79, 83))
86499	23832661	Thus, the odds of having a BAP1 mutation in PBRM1-mutant tumors are one third of those for wild-type tumors (OR=0.29; 95% CI, 0.12 - 0.70).	('PBRM1', 'Gene', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('BAP1', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('PBRM1', 'Gene', '55193', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('mutation', 'Var', (32, 40))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
86500	23832661	While we cannot exclude that mutation co-occurrence rates may be affected by epigenetic changes (or other factors), these data suggest that simultaneous mutations in BAP1 and PBRM1 are negatively selected for in ccRCC.	('mutations', 'Var', (153, 162))	('PBRM1', 'Gene', (175, 180))	('PBRM1', 'Gene', '55193', (175, 180))	('RCC', 'Disease', (214, 217))	('RCC', 'Phenotype', 'HP:0005584', (214, 217))	('RCC', 'Disease', 'MESH:C538614', (214, 217))	('BAP1', 'Gene', (166, 170))	('negatively', 'NegReg', (185, 195))
86501	23832661	However, differences in pathological features, gene expression and outcomes between tumors with BAP1 and PBRM1 mutations suggest that BAP1 and PBRM1 are not functionally redundant.	('differences', 'Reg', (9, 20))	('mutations', 'Var', (111, 120))	('PBRM1', 'Gene', (105, 110))	('PBRM1', 'Gene', '55193', (105, 110))	('BAP1', 'Gene', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('PBRM1', 'Gene', (143, 148))	('gene expression', 'biological_process', 'GO:0010467', ('47', '62'))	('PBRM1', 'Gene', '55193', (143, 148))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
86510	23832661	Whereas the median overall survival for patients with BAP1-mutant tumors is 4.6 years (95% CI, 2.1-7.2), for patients with PBRM1-mutant tumors, median survival is 10.6 years (95% CI, 9.8-11.5; hazard ratio, 2.7 [95%CI, 0.99-7.6]; p=0.044).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('patients', 'Species', '9606', (109, 117))	('BAP1-mutant', 'Var', (54, 65))	('patients', 'Species', '9606', (40, 48))	('PBRM1', 'Gene', (123, 128))	('tumors', 'Disease', (66, 72))	('PBRM1', 'Gene', '55193', (123, 128))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('BAP1-mutant', 'Gene', (54, 65))
86512	23832661	Thus, the observation that BAP1 and PBRM1 mutations co-occur in tumors at a frequency lower than expected suggests that even within a tumor type, a context-dependency of tumor suppressor function may exist.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', (64, 69))	('PBRM1', 'Gene', (36, 41))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('PBRM1', 'Gene', '55193', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('BAP1', 'Gene', (27, 31))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('170', '186'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('170', '186'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', (134, 139))
86514	23832661	This is illustrated in familial cancer syndromes, in which a germline mutation (typically in a tumor suppressor gene), predisposes to a limited spectrum of tumors.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('95', '111'))	('familial cancer syndromes', 'Disease', 'MESH:D009386', (23, 48))	('familial cancer syndromes', 'Disease', (23, 48))	('germline mutation', 'Var', (61, 78))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('predisposes', 'Reg', (119, 130))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Disease', (156, 162))	('tumor', 'Disease', (95, 100))	('tumor suppressor', 'biological_process', 'GO:0051726', ('95', '111'))
86515	23832661	Thus, despite the presence of the mutation in all diploid cells, tumors arise in a limited number of tissues.	('mutation', 'Var', (34, 42))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
86516	23832661	Nevertheless, a limited tumor spectrum is also observed in familial cancer syndromes resulting from germline mutations in oncogenes, such as RET, which are not associated with a mutation of the second allele.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('familial cancer syndromes', 'Disease', (59, 84))	('RET', 'Gene', '5979', (141, 144))	('tumor', 'Disease', (24, 29))	('resulting', 'Reg', (85, 94))	('familial cancer syndromes', 'Disease', 'MESH:D009386', (59, 84))	('RET', 'Gene', (141, 144))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('germline mutations', 'Var', (100, 118))
86520	23832661	1), mutations in the remaining PBRM1 or BAP1 allele may lead to tumors of different characteristics.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('PBRM1', 'Gene', (31, 36))	('mutations', 'Var', (4, 13))	('BAP1', 'Gene', (40, 44))	('PBRM1', 'Gene', '55193', (31, 36))	('lead to', 'Reg', (56, 63))
86527	23832661	Thus, in some species, a deletion may eliminate a combination of tumor suppressor genes conducive to tumor development, but if the genes are not collinear in another species, the species may be protected from the corresponding tumor type.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor suppressor', 'biological_process', 'GO:0051726', ('65', '81'))	('deletion', 'Var', (25, 33))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('65', '81'))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('eliminate', 'NegReg', (38, 47))	('combination', 'MPA', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
86529	23832661	For example, the type of second hit mutation observed may depend on whether there are neighboring tumor suppressor genes that function as such in the specific tissue.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor suppressor', 'biological_process', 'GO:0051726', ('98', '114'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('98', '114'))	('tumor', 'Disease', (98, 103))	('mutation', 'Var', (36, 44))
86530	23832661	For instance, BAP1 is mutated in mesothelioma, ccRCC, and uveal melanoma.	('RCC', 'Disease', (49, 52))	('mesothelioma', 'Disease', 'MESH:D008654', (33, 45))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('BAP1', 'Gene', (14, 18))	('mutated', 'Var', (22, 29))	('uveal melanoma', 'Disease', 'MESH:C536494', (58, 72))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('uveal melanoma', 'Disease', (58, 72))	('mesothelioma', 'Disease', (33, 45))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
86531	23832661	In mesothelioma, focal mutations may inactivate the second allele, whereas in ccRCC, the second allele is typically inactivated by loss of 3p (Fig.	('inactivate', 'NegReg', (37, 47))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('mesothelioma', 'Disease', (3, 15))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('loss', 'Var', (131, 135))	('mutations', 'Var', (23, 32))	('mesothelioma', 'Disease', 'MESH:D008654', (3, 15))
86535	23832661	We speculate that differences in the type of second hit mutations across tissues illustrate tissue-specific differences in tumor suppressor gene activities and tumor suppressor gene cooperativity.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('160', '176'))	('mutations', 'Var', (56, 65))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('activities', 'MPA', (145, 155))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor suppressor', 'biological_process', 'GO:0051726', ('123', '139'))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', (160, 165))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('123', '139'))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor suppressor', 'biological_process', 'GO:0051726', ('160', '176'))
86538	23832661	Thus, a large deletion may be poorly tolerated in some tumor types as it may uncover tissue-specific haploinsufficient genes, diminishing thereby the fitness of the tumor cell.	('fitness of the tumor', 'Disease', 'MESH:D012640', (150, 170))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('haploinsufficient', 'Disease', (101, 118))	('fitness of the tumor', 'Disease', (150, 170))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('deletion', 'Var', (14, 22))	('haploinsufficient', 'Disease', 'MESH:D058495', (101, 118))	('diminishing', 'NegReg', (126, 137))	('tumor', 'Disease', (165, 170))
86539	23832661	Improved functional annotation of mutations in cancer genes and an understanding of mutant allele ratios and mutation prevalence in tumors should facilitate the development of genetic interaction maps.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cancer', 'Disease', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('mutations', 'Var', (34, 43))
86541	23832661	Large deletions in tumors may be driven by the loss of more than one tumor suppressor gene, and syntenic differences may explain differential tumor predisposition across species.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('69', '85'))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor suppressor', 'biological_process', 'GO:0051726', ('69', '85'))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('loss', 'NegReg', (47, 51))	('tumor', 'Disease', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('Large deletions', 'Var', (0, 15))
86546	23877836	In the present study, the UM cell line SP6.5, which showed a high level of MART-1 expression, was subjected to small interfering RNA-mediated silencing of MART-1.	('RNA', 'cellular_component', 'GO:0005562', ('129', '132'))	('MART-1', 'Gene', '2315', (155, 161))	('MART-1', 'Gene', (155, 161))	('small', 'Var', (111, 116))	('SP6', 'Gene', (39, 42))	('MART-1', 'Gene', (75, 81))	('MART-1', 'Gene', '2315', (75, 81))	('UM', 'Phenotype', 'HP:0007716', (26, 28))	('SP6', 'Gene', '80320', (39, 42))	('silencing', 'NegReg', (142, 151))
86547	23877836	Silencing of MART-1 expression increased the migration ability of SP6.5 cells and down-regulated the expression of the metastasis suppressor NM23.	('SP6', 'Gene', '80320', (66, 69))	('down-regulated', 'NegReg', (82, 96))	('increased', 'PosReg', (31, 40))	('NM23', 'Gene', (141, 145))	('migration ability', 'CPA', (45, 62))	('MART-1', 'Gene', '2315', (13, 19))	('MART-1', 'Gene', (13, 19))	('NM23', 'Gene', '4830', (141, 145))	('expression', 'MPA', (101, 111))	('Silencing', 'Var', (0, 9))	('SP6', 'Gene', (66, 69))
86565	23877836	In agreement with the flow cytometry results, assessment of cell proliferation by MTT assay showed similar cell viability in siMart-1 transfected cells and in the controls at 1, 2, 3 and 4 days (Figure 2B).	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('MTT', 'Chemical', 'MESH:C070243', (82, 85))	('siMart-1', 'Chemical', '-', (125, 133))	('transfected', 'Var', (134, 145))	('siMart-1', 'Gene', (125, 133))
86566	23877836	Next, we determined whether silencing of MART-1 expression had an effect on the migration of SP6.5 cells.	('SP6', 'Gene', '80320', (93, 96))	('SP6', 'Gene', (93, 96))	('silencing', 'Var', (28, 37))	('MART-1', 'Gene', '2315', (41, 47))	('MART-1', 'Gene', (41, 47))
86569	23877836	These results indicated that silencing MART-1 expression increased the migration ability of SP6.5 cells.	('silencing', 'Var', (29, 38))	('MART-1', 'Gene', '2315', (39, 45))	('MART-1', 'Gene', (39, 45))	('SP6', 'Gene', (92, 95))	('increased', 'PosReg', (57, 66))	('SP6', 'Gene', '80320', (92, 95))
86571	23877836	Changes in cell migration induced by MART-1 gene silencing led us to examine the NM23 gene.	('silencing', 'NegReg', (49, 58))	('NM23', 'Gene', (81, 85))	('NM23', 'Gene', '4830', (81, 85))	('cell migration', 'biological_process', 'GO:0016477', ('11', '25'))	('cell migration', 'CPA', (11, 25))	('MART-1', 'Gene', '2315', (37, 43))	('MART-1', 'Gene', (37, 43))	('gene', 'Var', (44, 48))	('gene silencing', 'biological_process', 'GO:0016458', ('44', '58'))
86573	23877836	The results showed significant differences in NM23 mRNA (p < 0.01) and protein (p < 0.01) levels between siMart-1 and control cells, and indicated that silencing of MART-1 expression significantly down-regulated NM23 expression.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('MART-1', 'Gene', (165, 171))	('NM23', 'Gene', (212, 216))	('silencing', 'Var', (152, 161))	('NM23', 'Gene', '4830', (212, 216))	('expression', 'MPA', (217, 227))	('NM23', 'Gene', (46, 50))	('differences', 'Reg', (31, 42))	('NM23', 'Gene', '4830', (46, 50))	('siMart-1', 'Chemical', '-', (105, 113))	('MART-1', 'Gene', '2315', (165, 171))	('down-regulated', 'NegReg', (197, 211))
86585	23877836	To further investigate the biological functions of MART-1, we performed different experiments to examine the effects of MART-1 silencing on cell cycle progression and cell proliferation (Figure 2).	('MART-1', 'Gene', '2315', (51, 57))	('cell cycle', 'biological_process', 'GO:0007049', ('140', '150'))	('MART-1', 'Gene', (51, 57))	('cell proliferation', 'biological_process', 'GO:0008283', ('167', '185'))	('MART-1', 'Gene', '2315', (120, 126))	('MART-1', 'Gene', (120, 126))	('cell cycle progression', 'CPA', (140, 162))	('silencing', 'Var', (127, 136))	('cell proliferation', 'CPA', (167, 185))
86590	23877836	Our results showed that silencing MART-1 expression significantly increased the migration ability of SP6.5 cells (Figure 3A,B).	('increased', 'PosReg', (66, 75))	('SP6', 'Gene', (101, 104))	('SP6', 'Gene', '80320', (101, 104))	('MART-1', 'Gene', '2315', (34, 40))	('MART-1', 'Gene', (34, 40))	('silencing', 'Var', (24, 33))
86595	23877836	The pharmacological NF-kappaB inhibitor, BAY11-7082, has been reported to induce cell apoptosis and inhibit the migration of human uveal melanoma cells.	('induce', 'PosReg', (74, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))	('uveal melanoma', 'Disease', 'MESH:C536494', (131, 145))	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('uveal melanoma', 'Disease', (131, 145))	('inhibit', 'NegReg', (100, 107))	('cell apoptosis', 'CPA', (81, 95))	('human', 'Species', '9606', (125, 130))	('BAY11-7082', 'Chemical', 'MESH:C434003', (41, 51))	('NF-kappaB inhibitor', 'biological_process', 'GO:0032088', ('20', '39'))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('NF-kappaB', 'Protein', (20, 29))	('BAY11-7082', 'Var', (41, 51))
86596	23877836	High PTP4A3 phosphatase expression correlates with metastatic risk in uveal melanoma patients.	('phosphatase', 'molecular_function', 'GO:0016791', ('12', '23'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('uveal melanoma', 'Disease', (70, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('High', 'Var', (0, 4))	('expression', 'MPA', (24, 34))	('PTP4A3', 'Gene', '11156', (5, 11))	('metastatic risk', 'Disease', (51, 66))	('patients', 'Species', '9606', (85, 93))	('PTP4A3', 'Gene', (5, 11))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
86603	23877836	found that the lung cancer cell lines with stable NM23-H1 gene silencing were successfully established and their invasiveness was greatly increased after NM23-H1 gene knockdown.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('NM23-H1', 'Gene', (50, 57))	('increased', 'PosReg', (138, 147))	('NM23-H1', 'Gene', (154, 161))	('NM23-H1', 'Gene', '4830', (50, 57))	('gene', 'Var', (58, 62))	('NM23-H1', 'Gene', '4830', (154, 161))	('lung cancer', 'Disease', 'MESH:D008175', (15, 26))	('knockdown', 'Var', (167, 176))	('invasiveness', 'CPA', (113, 125))	('gene silencing', 'biological_process', 'GO:0016458', ('58', '72'))	('lung cancer', 'Disease', (15, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))
86612	23877836	We used full genome sequencing of the SP6.5 cell line to examine BAP1; the results showed that the SP6.5 cell line did not contain a BAP1 gene mutation (data not shown).	('SP6', 'Gene', '80320', (38, 41))	('BAP1', 'Gene', '8314', (65, 69))	('mutation', 'Var', (143, 151))	('SP6', 'Gene', (99, 102))	('BAP1', 'Gene', (65, 69))	('BAP1', 'Gene', '8314', (133, 137))	('SP6', 'Gene', '80320', (99, 102))	('SP6', 'Gene', (38, 41))	('BAP1', 'Gene', (133, 137))
86613	23877836	In the present study, silencing of MART-1 expression increased the levels of the BAP1 protein to a certain extent (Figure 5), suggesting that BAP1 may be associated with a transitory increase in a short-term stress.	('MART-1', 'Gene', '2315', (35, 41))	('MART-1', 'Gene', (35, 41))	('BAP1', 'Gene', (81, 85))	('BAP1', 'Gene', '8314', (142, 146))	('BAP1', 'Gene', (142, 146))	('silencing', 'Var', (22, 31))	('increased', 'PosReg', (53, 62))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('BAP1', 'Gene', '8314', (81, 85))
86614	23877836	In summary, targeted silencing of MART-1 expression increased the migration of UM cells and decreased NM23 gene expression.	('MART-1', 'Gene', '2315', (34, 40))	('increased', 'PosReg', (52, 61))	('NM23', 'Gene', '4830', (102, 106))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('gene expression', 'biological_process', 'GO:0010467', ('107', '122'))	('migration of UM cells', 'CPA', (66, 87))	('decreased', 'NegReg', (92, 101))	('MART-1', 'Gene', (34, 40))	('silencing', 'Var', (21, 30))	('NM23', 'Gene', (102, 106))	('expression', 'MPA', (112, 122))
86646	22307269	GNAQ and GNA11 mutations in melanocytomas of the central nervous system Melanocytic tumors in the central nervous system (CNS) include metastatic melanoma and less commonly primary melanocytic tumors, which usually arise from melanocytes of the leptomeninges.	('melanocytomas of the central nervous', 'Disease', (28, 64))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumors in the central nervous system', 'Phenotype', 'HP:0100006', (84, 120))	('GNA11', 'Gene', '2767', (9, 14))	('Melanocytic tumors', 'Disease', (72, 90))	('melanocytic tumors', 'Disease', (181, 199))	('melanocytic tumors', 'Disease', 'MESH:D009508', (181, 199))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Melanocytic tumors', 'Disease', 'MESH:D009508', (72, 90))	('mutations', 'Var', (15, 24))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('GNA11', 'Gene', (9, 14))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('GNAQ', 'Gene', '2776', (0, 4))	('melanocytomas of the central nervous', 'Disease', 'MESH:D002493', (28, 64))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('GNAQ', 'Gene', (0, 4))
86650	22307269	Neoplasms in this group share morphologic features such as predominance of spindled and epithelioid cells, conspicuous pigmentation and absence of epithelial involvement, along with frequent mutations of GNAQ or GNA11, two closely related G-proteins of the Gq family that encode critical amino acids required for the GTPase function of the proteins.	('GNAQ', 'Gene', (204, 208))	('pigmentation', 'Disease', 'MESH:D010859', (119, 131))	('GNA11', 'Gene', (212, 217))	('mutations', 'Var', (191, 200))	('GTP', 'Chemical', 'MESH:D006160', (317, 320))	('Neoplasms', 'Disease', 'MESH:D009369', (0, 9))	('GNA11', 'Gene', '2767', (212, 217))	('GNAQ', 'Gene', '2776', (204, 208))	('epithelia', 'Disease', 'None', (147, 156))	('pigmentation', 'biological_process', 'GO:0043473', ('119', '131'))	('spindled', 'CPA', (75, 83))	('pigmentation', 'Disease', (119, 131))	('epithelia', 'Disease', (147, 156))	('Neoplasms', 'Disease', (0, 9))
86651	22307269	GNAQ or GNA11 mutations occur in a mutually exclusive pattern and affect codon 183 in exon 4 or codon 209 in exon 5 of either gene.	('affect', 'Reg', (66, 72))	('GNA11', 'Gene', (8, 13))	('GNAQ', 'Gene', '2776', (0, 4))	('GNA11', 'Gene', '2767', (8, 13))	('GNAQ', 'Gene', (0, 4))	('codon', 'MPA', (73, 78))	('mutations', 'Var', (14, 23))	('codon 209', 'Var', (96, 105))
86652	22307269	Mutations at these sites cripple enzymatic function and lead to a constitutively activated GTP-bound state.	('constitutively activated GTP-bound state', 'MPA', (66, 106))	('enzymatic function', 'MPA', (33, 51))	('cripple', 'NegReg', (25, 32))	('Mutations', 'Var', (0, 9))	('GTP', 'Chemical', 'MESH:D006160', (91, 94))	('lead to', 'Reg', (56, 63))
86654	22307269	A recent study reported mutations in exon 5 of GNAQ in 6/12 (50%) melanocytomas, 5 of which were in paraspinal locations.	('melanocytomas', 'Disease', 'None', (66, 79))	('GNAQ', 'Gene', (47, 51))	('mutations in exon', 'Var', (24, 41))	('melanocytomas', 'Disease', (66, 79))	('GNAQ', 'Gene', '2776', (47, 51))
86663	22307269	Mutations were identified in exon 4 of GNAQ (1 case, Fig.	('GNAQ', 'Gene', '2776', (39, 43))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', (39, 43))
86665	22307269	The mutations [GNAQ:(c.548G>A, p.(Arg183Gln) and GNA11:c.626A>C, p.(Gln209Pro)] are identical to those seen in uveal melanoma and intradermal melanocytic proliferations.	('c.548G>A', 'Mutation', 'rs397514698', (21, 29))	('uveal melanoma', 'Phenotype', 'HP:0007716', (111, 125))	('GNAQ', 'Gene', (15, 19))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('p.(Gln209Pro)', 'Mutation', 'rs1057519742', (65, 78))	('GNA11:c.626A>C', 'SUBSTITUTION', 'None', (49, 63))	('c.548G>A', 'Var', (21, 29))	('GNAQ', 'Gene', '2776', (15, 19))	('p.(Arg183Gln)', 'Mutation', 'rs397514698', (31, 44))	('GNA11:c.626A>C', 'Var', (49, 63))	('intradermal melanocytic proliferations', 'Disease', (130, 168))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
86666	22307269	Our results expand the spectrum of GNAQ and GNA11 mutations that may occur in melanocytomas.	('melanocytomas', 'Disease', (78, 91))	('mutations', 'Var', (50, 59))	('GNA11', 'Gene', (44, 49))	('melanocytomas', 'Disease', 'None', (78, 91))	('occur', 'Reg', (69, 74))	('GNAQ', 'Gene', '2776', (35, 39))	('GNA11', 'Gene', '2767', (44, 49))	('GNAQ', 'Gene', (35, 39))
86667	22307269	To our knowledge, this is the first description of mutations in GNA11 and in exon 4 of GNAQ in melanocytomas.	('mutations', 'Var', (51, 60))	('GNAQ', 'Gene', '2776', (87, 91))	('melanocytomas', 'Disease', (95, 108))	('GNA11', 'Gene', '2767', (64, 69))	('GNA11', 'Gene', (64, 69))	('melanocytomas', 'Disease', 'None', (95, 108))	('GNAQ', 'Gene', (87, 91))
86668	22307269	The occurrence of GNAQ and GNA11 mutations in melanocytomas, dermal melanocytic tumors and uveal melanomas suggests the possibility of a developmental link between the cells of origin of these tumors.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mutations', 'Var', (33, 42))	('uveal melanomas', 'Disease', 'MESH:C536494', (91, 106))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('GNA11', 'Gene', '2767', (27, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (91, 105))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('melanocytomas, dermal melanocytic tumors', 'Disease', 'MESH:D057091', (46, 86))	('uveal melanomas', 'Disease', (91, 106))	('uveal melanomas', 'Phenotype', 'HP:0007716', (91, 106))	('GNAQ', 'Gene', '2776', (18, 22))	('occurrence', 'Reg', (4, 14))	('GNAQ', 'Gene', (18, 22))	('GNA11', 'Gene', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('melanomas', 'Phenotype', 'HP:0002861', (97, 106))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (193, 199))
86669	22307269	Although we identified a GNAQ exon 4 mutation in 1 of 5 cases of melanocytoma, exon 4 mutations in either GNAQ or GNA11 are rare in uveal melanomas (7/145, 4.8%) and blue nevi (2/96, 2.1%).	('mutation', 'Var', (37, 45))	('uveal melanomas', 'Disease', 'MESH:C536494', (132, 147))	('GNA11', 'Gene', '2767', (114, 119))	('melanocytoma', 'Disease', (65, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (132, 146))	('uveal melanomas', 'Disease', (132, 147))	('uveal melanomas', 'Phenotype', 'HP:0007716', (132, 147))	('melanomas', 'Phenotype', 'HP:0002861', (138, 147))	('nevi', 'Phenotype', 'HP:0003764', (171, 175))	('GNAQ', 'Gene', '2776', (25, 29))	('GNAQ', 'Gene', '2776', (106, 110))	('mutations', 'Var', (86, 95))	('GNAQ', 'Gene', (106, 110))	('blue nevi', 'Disease', (166, 175))	('GNAQ', 'Gene', (25, 29))	('melanocytoma', 'Disease', 'None', (65, 77))	('GNA11', 'Gene', (114, 119))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('blue nevi', 'Phenotype', 'HP:0100814', (166, 175))
86670	22307269	Mutational analysis of larger numbers of tumors is required to determine the true incidence of the different mutations in GNAQ and GNA11, and to investigate associations of specific mutations with clinical features, pathologic characteristics, and biologic behavior of melanocytomas.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('GNAQ', 'Gene', (122, 126))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('behavior of melanocytomas', 'Disease', 'MESH:D001523', (257, 282))	('GNA11', 'Gene', '2767', (131, 136))	('mutations', 'Var', (109, 118))	('behavior of melanocytomas', 'Disease', (257, 282))	('GNAQ', 'Gene', '2776', (122, 126))	('associations', 'Interaction', (157, 169))	('GNA11', 'Gene', (131, 136))
86677	21573095	The mean standard deviation of the difference in tumor height measurements between the examiners was +-0.24 mm for the 8 mHz A scan, +-0.46 mm for the 10 mHz B scan, and +-0.42 mm for the 20 mHz B scan.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('+-0.46', 'Var', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('+-0.42', 'Var', (170, 176))	('tumor', 'Disease', (49, 54))
86718	21573095	The mean standard deviation of the difference in tumor height measurements between examiners was +-0.24 mm for the 8 mHz A scan, +-0.46 mm for 10 mHz B scan, and +-0.42 mm for 20 mHz B scan.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('+-0.46', 'Var', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('+-0.42', 'Var', (162, 168))	('tumor', 'Disease', (49, 54))
86721	21573095	Height measurements for tumors in Group C were found to be significantly larger in the 8 mHz A scan as compared with the 20 mHz B scan (P = 0.003, Wilcoxon test), but not compared with the 10 mHz B scan (P = 0.209, Wilcoxon test).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('larger', 'PosReg', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('8 mHz A scan', 'Var', (87, 99))
86745	15928660	Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS In contrast to cutaneous melanoma, there is no evidence that BRAF mutations are involved in the activation of the mitogen-activated protein kinase (MAPK) pathway in uveal melanoma, although there is increasing evidence that this pathway is activated frequently in the latter tumours.	('uveal melanoma', 'Disease', 'MESH:C536494', (52, 66))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('tumours', 'Phenotype', 'HP:0002664', (401, 408))	('uveal melanoma', 'Phenotype', 'HP:0007716', (291, 305))	('latter tumours', 'Disease', 'MESH:D009369', (394, 408))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('mutations', 'Var', (192, 201))	('uveal melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('MAPK pathway', 'Pathway', (18, 30))	('uveal melanomas', 'Disease', 'MESH:C536494', (52, 67))	('cutaneous melanoma', 'Disease', (141, 159))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (141, 159))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (141, 159))	('MAPK', 'molecular_function', 'GO:0004707', ('274', '278'))	('protein', 'cellular_component', 'GO:0003675', ('258', '265'))	('BRAF', 'Gene', '673', (187, 191))	('BRAF', 'Gene', (187, 191))	('latter tumours', 'Disease', (394, 408))	('uveal melanomas', 'Disease', (52, 67))	('uveal melanomas', 'Phenotype', 'HP:0007716', (52, 67))	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (291, 305))	('melanoma', 'Phenotype', 'HP:0002861', (297, 305))	('uveal melanoma', 'Disease', (291, 305))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('tumour', 'Phenotype', 'HP:0002664', (401, 407))	('MAPK', 'molecular_function', 'GO:0004707', ('18', '22'))
86753	15928660	Notable exceptions are hypermethylation of CDKN2A, which is more common in tumours from patients who develop metastatic disease (van der Velden et al, 2001), and germline BRCA2 gene mutations, which occur in 3% of patients younger than 50 years of age (Scott et al, 2002).	('common', 'Reg', (65, 71))	('patients', 'Species', '9606', (214, 222))	('tumours', 'Disease', 'MESH:D009369', (75, 82))	('CDKN2A', 'Gene', (43, 49))	('tumours', 'Disease', (75, 82))	('patients', 'Species', '9606', (88, 96))	('metastatic disease', 'Disease', (109, 127))	('CDKN2A', 'Gene', '1029', (43, 49))	('BRCA2', 'Gene', (171, 176))	('van der Velden', 'Disease', 'MESH:C536528', (129, 143))	('hypermethylation', 'Var', (23, 39))	('van der Velden', 'Disease', (129, 143))	('germline', 'Var', (162, 170))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('BRCA2', 'Gene', '675', (171, 176))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
86758	15928660	Of three RAS genes found to be activated by mutation in human tumours, NRAS (neuroblastoma RAS viral (v-ras) oncogene homologue) is most commonly mutated in cutaneous melanomas (van Elsas et al, 1996).	('cutaneous melanomas', 'Disease', 'MESH:C562393', (157, 176))	('mutation', 'Var', (44, 52))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (157, 175))	('mutated', 'Var', (146, 153))	('cutaneous melanomas', 'Disease', (157, 176))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('neuroblastoma RAS viral', 'Disease', (77, 100))	('NRAS', 'Gene', (71, 75))	('human', 'Species', '9606', (56, 61))	('neuroblastoma RAS viral', 'Disease', 'MESH:D009447', (77, 100))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('NRAS', 'Gene', '4893', (71, 75))	('melanomas', 'Phenotype', 'HP:0002861', (167, 176))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('neuroblastoma', 'Phenotype', 'HP:0003006', (77, 90))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (157, 176))	('tumours', 'Disease', (62, 69))
86762	15928660	It has emerged that BRAF (v-raf murine sarcoma viral oncogene homologue B1) is very frequently activated by mutation in cutaneous melanomas (Brose et al, 2002; Davies et al, 2002; Alsina et al, 2003; Dong et al, 2003; Gorden et al, 2003; Kumar et al, 2003a, 2003b; Maldonado et al, 2003; Omholt et al, 2003; Pollock et al, 2003; Rimoldi et al, 2003; Satyamoorthy et al, 2003; Weber et al, 2003; Cohen et al, 2004; Reifenberger et al, 2004; Shinozaki et al, 2004; Tsao et al, 2004).	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (120, 139))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (120, 139))	('v-raf', 'Gene', (26, 31))	('sarcoma viral', 'Disease', (39, 52))	('Pollock', 'Species', '8060', (308, 315))	('murine', 'Species', '10090', (32, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('cutaneous melanomas', 'Disease', (120, 139))	('activated', 'PosReg', (95, 104))	('melanomas', 'Phenotype', 'HP:0002861', (130, 139))	('v-raf', 'Gene', '110157', (26, 31))	('sarcoma viral', 'Disease', 'MESH:D001102', (39, 52))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('mutation', 'Var', (108, 116))	('BRAF', 'Gene', (20, 24))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (120, 138))
86763	15928660	Notably, the frequency of BRAF mutations is also high in benign melanocytic naevi (Dong et al, 2003; Pollock et al, 2003; Uribe et al, 2003; Yazdi et al, 2003), indicating that constitutive activation of the MAPK pathway is an early event in melanomagenesis.	('benign melanocytic naevi', 'Disease', (57, 81))	('mutations', 'Var', (31, 40))	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('melanoma', 'Disease', (242, 250))	('melanoma', 'Disease', 'MESH:D008545', (242, 250))	('melanocytic naevi', 'Phenotype', 'HP:0000995', (64, 81))	('BRAF', 'Gene', (26, 30))	('naevi', 'Phenotype', 'HP:0003764', (76, 81))	('MAPK', 'molecular_function', 'GO:0004707', ('208', '212'))	('Pollock', 'Species', '8060', (101, 108))
86764	15928660	All BRAF mutations in cutaneous pigmented neoplasms occur within the kinase domain.	('mutations', 'Var', (9, 18))	('occur', 'Reg', (52, 57))	('cutaneous pigmented neoplasms', 'Disease', 'MESH:D010859', (22, 51))	('BRAF', 'Gene', (4, 8))	('neoplasms', 'Phenotype', 'HP:0002664', (42, 51))	('cutaneous pigmented neoplasms', 'Disease', (22, 51))
86765	15928660	The most frequently found mutation in BRAF (V599E) consists of a 1796T   A transversion in exon 15 (Davies et al, 2002).	('V599E', 'Mutation', 'p.V599E', (44, 49))	('1796T   A transversion', 'Var', (65, 87))	('BRAF', 'Gene', (38, 42))
86766	15928660	Various other mutations have been described in this exon in melanocytic tumours (V599D (Brose et al, 2002; Davies et al, 2002; Pollock et al, 2003); V599K (Pollock et al, 2003, Uribe et al, 2003); V599R (Pollock et al, 2003); K600E (Brose et al, 2002, Satyamoorthy et al, 2003)).	('Pollock', 'Species', '8060', (156, 163))	('Pollock', 'Species', '8060', (204, 211))	('V599R', 'Mutation', 'p.V599R', (197, 202))	('V599K', 'Mutation', 'p.V599K', (149, 154))	('V599K', 'Var', (149, 154))	('melanocytic tumours', 'Disease', 'MESH:D009508', (60, 79))	('K600E', 'Var', (226, 231))	('V599R', 'Var', (197, 202))	('Pollock', 'Species', '8060', (127, 134))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('K600E', 'Mutation', 'p.K600E', (226, 231))	('V599D', 'Mutation', 'p.V599D', (81, 86))	('melanocytic tumours', 'Disease', (60, 79))
86767	15928660	The latter consist of a 1352A   C transversion (K438Q) (Brose et al, 2002), a 1402G   A transition (G468R) and a 1402/1403GG   TC tandem transversion (Gorden et al, 2003), a 1394G   A transition (G465E) and a 1394G   C transversion (G465A) (Davies et al, 2002).	('G465A', 'Mutation', 'rs1379583365', (233, 238))	('K438Q', 'Mutation', 'p.K438Q', (48, 53))	('1402G', 'Var', (78, 83))	('G465E', 'Mutation', 'p.G465E', (196, 201))	('G468R', 'Mutation', 'p.G468R', (100, 105))	('G465E', 'Var', (196, 201))	('1402/1403GG   TC', 'Var', (113, 129))	('K438Q', 'Var', (48, 53))	('1394G', 'Var', (174, 179))	('1394G   C', 'Var', (209, 218))
86768	15928660	Furthermore, it is not surprising that since they activate the same pathway, mutations in NRAS and BRAF are almost mutually exclusive (Brose et al, 2002; Davies et al, 2002; Alsina et al, 2003; Dong et al, 2003; Gorden et al, 2003; Kumar et al, 2003a, 2003b; Omholt et al, 2003; Pollock et al, 2003; Satyamoorthy et al, 2003; Reifenberger et al, 2004; Tsao et al, 2004).	('NRAS', 'Gene', (90, 94))	('NRAS', 'Gene', '4893', (90, 94))	('BRAF', 'Gene', (99, 103))	('Pollock', 'Species', '8060', (279, 286))	('mutations', 'Var', (77, 86))	('activate', 'PosReg', (50, 58))
86788	15928660	After blocking with 5% skim milk in PBS-Tween solution, the membranes were probed overnight at 4 C with the following primary antibodies specific to each antigen: phospho-MEK1/2 (dilution 1 : 1000), phospho-ERK1/2 (p44/42) (#9106, dilution 1 : 5000), total ERK1/2 (#9102, dilution 1 : 1000) and phospho-ELK1 (dilution 1 : 1000) antibody (all from Cell Signaling Technology, Hertfordshire, UK).	('Tween', 'Chemical', 'MESH:D011136', (40, 45))	('ELK1', 'Gene', '2002', (303, 307))	('p44', 'Gene', (215, 218))	('antibody', 'cellular_component', 'GO:0019815', ('328', '336'))	('p44', 'Gene', '10561', (215, 218))	('antibody', 'cellular_component', 'GO:0019814', ('328', '336'))	('ERK1', 'molecular_function', 'GO:0004707', ('207', '211'))	('antibody', 'molecular_function', 'GO:0003823', ('328', '336'))	('Signaling', 'biological_process', 'GO:0023052', ('352', '361'))	('MEK1/2', 'Gene', '5604;5605', (171, 177))	('ERK1', 'molecular_function', 'GO:0004707', ('257', '261'))	('dilution 1 : 1000', 'Var', (309, 326))	('MEK1/2', 'Gene', (171, 177))	('MEK1', 'molecular_function', 'GO:0004708', ('171', '175'))	('PBS', 'Chemical', 'MESH:D007854', (36, 39))	('#9102', 'Var', (265, 270))	('antibody', 'cellular_component', 'GO:0042571', ('328', '336'))	('ELK1', 'Gene', (303, 307))
86798	15928660	Of the 11 uveal melanoma cell lines under study, only one cell line (Ocm 1) carried a BRAF mutation, the common V599E (also described by Calipel et al and Kilic et al).	('uveal melanoma', 'Disease', 'MESH:C536494', (10, 24))	('mutation', 'Var', (91, 99))	('V599E', 'Mutation', 'p.V599E', (112, 117))	('uveal melanoma', 'Phenotype', 'HP:0007716', (10, 24))	('uveal melanoma', 'Disease', (10, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('Ocm 1', 'Species', '83984', (69, 74))
86802	15928660	In response to the constitutively activating BRAF mutation in Ocm 1, downstream members of the MAPK pathway show activation (phosphorylated MEK, ERK and ELK).	('ERK', 'Gene', (145, 148))	('ELK', 'Gene', '2047', (153, 156))	('Ocm 1', 'Species', '83984', (62, 67))	('MEK', 'Gene', (140, 143))	('MEK', 'Gene', '5609', (140, 143))	('activating BRAF', 'PosReg', (34, 49))	('MAPK', 'molecular_function', 'GO:0004707', ('95', '99'))	('mutation', 'Var', (50, 58))	('activation', 'PosReg', (113, 123))	('MAPK pathway', 'Pathway', (95, 107))	('ERK', 'Gene', '5594', (145, 148))	('ERK', 'molecular_function', 'GO:0004707', ('145', '148'))	('ELK', 'Gene', (153, 156))	('Ocm 1', 'Gene', (62, 67))
86804	15928660	Interestingly, compared to the phosphorylation status of these members in Ocm 1, most cell lines show activation of MEK, ERK and ELK; however, these cell lines show this activation in the absence of mutations in the upstream RAS and BRAF genes.	('ERK', 'Gene', '5594', (121, 124))	('ERK', 'Gene', (121, 124))	('ELK', 'Gene', '2047', (129, 132))	('ELK', 'Gene', (129, 132))	('MEK', 'Gene', (116, 119))	('activation', 'PosReg', (170, 180))	('MEK', 'Gene', '5609', (116, 119))	('Ocm 1', 'Species', '83984', (74, 79))	('activation', 'PosReg', (102, 112))	('BRAF', 'Gene', (233, 237))	('ERK', 'molecular_function', 'GO:0004707', ('121', '124'))	('mutations', 'Var', (199, 208))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))
86811	15928660	In the uveal melanoma cell lines and primary uveal melanomas analysed in our study, only cell line Ocm 1 carried a mutation in BRAF (V599E), thus confirming the documentation of a mutation in this cell line by Calipel et al (2003) and Kilic et al (2004).	('uveal melanoma', 'Disease', (7, 21))	('V599E', 'Mutation', 'p.V599E', (133, 138))	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('uveal melanomas', 'Phenotype', 'HP:0007716', (45, 60))	('primary uveal melanomas', 'Disease', 'MESH:C536494', (37, 60))	('primary uveal melanomas', 'Disease', (37, 60))	('Ocm 1', 'Species', '83984', (99, 104))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('uveal melanoma', 'Disease', 'MESH:C536494', (7, 21))	('mutation', 'Var', (115, 123))	('uveal melanoma', 'Disease', 'MESH:C536494', (45, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (7, 21))
86812	15928660	Similarly, our observation of a complete lack of BRAF mutations in primary uveal tumours mirrors the findings of several recent reports (Cohen et al, 2003; Cruz et al, 2003; Edmunds et al, 2003; Rimoldi et al, 2003; Weber et al, 2003; Kilic et al, 2004).	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('uveal tumours', 'Disease', 'MESH:D014604', (75, 88))	('mutations', 'Var', (54, 63))	('uveal tumours', 'Disease', (75, 88))	('BRAF', 'Gene', (49, 53))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
86813	15928660	Table 3 contains a summary of published reports on RAS and BRAF mutations, as well as studies on other members of the MAPK pathway, in uveal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanomas', 'Phenotype', 'HP:0002861', (141, 150))	('RAS', 'Gene', (51, 54))	('uveal melanomas', 'Disease', 'MESH:C536494', (135, 150))	('uveal melanoma', 'Phenotype', 'HP:0007716', (135, 149))	('MAPK', 'molecular_function', 'GO:0004707', ('118', '122'))	('BRAF', 'Gene', (59, 63))	('mutations', 'Var', (64, 73))	('uveal melanomas', 'Disease', (135, 150))	('uveal melanomas', 'Phenotype', 'HP:0007716', (135, 150))
86815	15928660	It is somewhat surprising therefore that three out of three uveal melanoma cell lines studied by Calipel et al (2003) carried the V599E mutation in BRAF, especially since only one out of 11 cell lines in the panel we analysed was found to have this mutation.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('V599E', 'Mutation', 'p.V599E', (130, 135))	('uveal melanoma', 'Disease', 'MESH:C536494', (60, 74))	('V599E', 'Var', (130, 135))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('uveal melanoma', 'Disease', (60, 74))	('BRAF', 'Gene', (148, 152))
86816	15928660	Taken together, these data suggest that while a BRAF mutation is not required for uveal melanoma development in vivo, such mutations confer a cellular growth advantage and are hence selected if they occur in cell lines cultured in vitro.	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('cellular growth advantage', 'CPA', (142, 167))	('uveal melanoma', 'Disease', 'MESH:C536494', (82, 96))	('cellular growth', 'biological_process', 'GO:0016049', ('142', '157'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('uveal melanoma', 'Disease', (82, 96))	('mutations', 'Var', (123, 132))
86817	15928660	In our study, none of the cell lines or primary tumours carried mutations in any of the three RAS genes (N, H and K), a finding consistent with a previous report (Soparker et al, 1993).	('primary tumours', 'Disease', (40, 55))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('RAS', 'Gene', (94, 97))	('mutations', 'Var', (64, 73))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('primary tumours', 'Disease', 'MESH:D009369', (40, 55))
86822	15928660	It is tempting to speculate that MAPK activation in uveal melanoma may arise via crosstalk with the PI3K/PTEN/AKT pathway, possibly as a consequence of mutation of some of its components (other than PTEN, which is not mutated in this tumour type).	('PTEN', 'Gene', '5728', (199, 203))	('uveal melanoma', 'Disease', (52, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (52, 66))	('AKT', 'Gene', (110, 113))	('MAPK', 'molecular_function', 'GO:0004707', ('33', '37'))	('PI3K', 'molecular_function', 'GO:0016303', ('100', '104'))	('MAPK activation', 'biological_process', 'GO:0000187', ('33', '48'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('PTEN', 'Gene', (105, 109))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('tumour', 'Disease', 'MESH:D009369', (234, 240))	('tumour', 'Disease', (234, 240))	('MAPK', 'Gene', (33, 37))	('mutation', 'Var', (152, 160))	('AKT', 'Gene', '207', (110, 113))	('PTEN', 'Gene', '5728', (105, 109))	('activation', 'PosReg', (38, 48))	('PTEN', 'Gene', (199, 203))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
86826	15928660	Although many uveal melanoma samples have been studied for BRAF and NRAS mutations, few have been analysed for MAPK activation and there is the implicit assumption that this pathway is not involved in uveal melanoma genesis.	('uveal melanoma genesis', 'Disease', (201, 223))	('uveal melanoma', 'Phenotype', 'HP:0007716', (14, 28))	('uveal melanoma', 'Disease', 'MESH:C536494', (14, 28))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('uveal melanoma', 'Phenotype', 'HP:0007716', (201, 215))	('uveal melanoma', 'Disease', (14, 28))	('NRAS', 'Gene', (68, 72))	('uveal melanoma', 'Disease', 'MESH:C536494', (201, 215))	('MAPK activation', 'biological_process', 'GO:0000187', ('111', '126'))	('BRAF', 'Gene', (59, 63))	('NRAS', 'Gene', '4893', (68, 72))	('uveal melanoma genesis', 'Disease', 'MESH:C536494', (201, 223))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('MAPK', 'molecular_function', 'GO:0004707', ('111', '115'))	('mutations', 'Var', (73, 82))
86830	32690542	Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer Among more than 200 BAP1-mutant families affected by the "BAP1 cancer syndrome," nearly all individuals inheriting a BAP1 mutant allele developed one or more malignancies during their lifetime, mostly uveal and cutaneous melanoma, mesothelioma, and clear-cell renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (353, 362))	('cancer syndrome', 'Disease', (145, 160))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('malignancies', 'Disease', 'MESH:D009369', (240, 252))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('mesothelioma', 'Disease', (313, 325))	('malignancies', 'Disease', (240, 252))	('BAP1', 'Gene', '8314', (102, 106))	('mesothelioma', 'Disease', 'MESH:D008654', (313, 325))	('Cancer', 'Disease', (75, 81))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (331, 362))	('BAP1', 'Gene', (199, 203))	('cutaneous melanoma', 'Disease', (293, 311))	('Human', 'Species', '9606', (69, 74))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (293, 311))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (293, 311))	('Mutations', 'Var', (56, 65))	('BAP1', 'Gene', '8314', (51, 55))	('BAP1', 'Gene', '8314', (140, 144))	('developed', 'Reg', (218, 227))	('BAP1', 'Gene', (102, 106))	('clear-cell renal cell carcinoma', 'Disease', (331, 362))	('Cancer', 'Disease', 'MESH:D009369', (75, 81))	('mutant', 'Var', (204, 210))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (342, 362))	('cancer syndrome', 'Disease', 'MESH:D009369', (145, 160))	('BAP1', 'Gene', (140, 144))	('BAP1', 'Gene', (51, 55))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (331, 362))	('melanoma', 'Phenotype', 'HP:0002861', (303, 311))	('BAP1', 'Gene', '8314', (199, 203))
86831	32690542	These cancer types are also those that, when they occur sporadically, are more likely to carry somatic biallelic BAP1 mutations.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutations', 'Var', (118, 127))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('biallelic', 'Var', (103, 112))	('cancer', 'Disease', (6, 12))	('BAP1', 'Gene', (113, 117))
86834	32690542	BAP1 has emerged as a critical tumor suppressor across multiple cancer types, predisposing to tumor development when mutated in the germline as well as somatically.	('tumor suppressor', 'biological_process', 'GO:0051726', ('31', '47'))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mutated', 'Var', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('BAP1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (31, 36))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('31', '47'))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
86840	32690542	Because of the powerful tumor suppressor activity of BAP1 and of its role in modulating "gene-environment" (GxE) interactions in cancer, an increasing number of researchers are investigating the biological mechanisms and medical implications of inherited and acquired BAP1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumor suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('tumor', 'Disease', (24, 29))	('BAP1', 'Gene', (268, 272))	('cancer', 'Disease', (129, 135))	('mutations', 'Var', (273, 282))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('BAP1', 'Gene', (53, 57))
86842	32690542	It is an important component of the pathologic diagnosis of mesothelioma and early-detection clinical trials have been established at the NCI and elsewhere for carriers of germline BAP1 mutations (NCT03830229), including trials targeting BAP1 (NCT03207347, NCT03531840).	('NCT03830229', 'Var', (197, 208))	('BAP1', 'Gene', (181, 185))	('mesothelioma', 'Disease', 'MESH:D008654', (60, 72))	('mutations (NCT03830229', 'Var', (186, 208))	('NCT03207347', 'Var', (244, 255))	('NCT03531840', 'Var', (257, 268))	('mesothelioma', 'Disease', (60, 72))
86843	32690542	Here we review current understanding of how BAP1 suppresses tumorigenesis and how BAP1 status can inform diagnosis, prognosis, targeted therapy, and cancer prevention in patients with cancer with hereditary and acquired BAP1 mutations.	('cancer', 'Disease', (184, 190))	('patients', 'Species', '9606', (170, 178))	('cancer', 'Disease', (149, 155))	('mutations', 'Var', (225, 234))	('BAP1', 'Gene', (220, 224))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('suppresses', 'NegReg', (49, 59))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
86844	32690542	Moreover, we discuss some puzzling questions, such as why germline BAP1 mutations are associated with mesothelioma of low aggressiveness, but very aggressive uveal melanoma.	('mutations', 'Var', (72, 81))	('mesothelioma of low aggressiveness', 'Disease', 'MESH:D008654', (102, 136))	('aggressiveness', 'Phenotype', 'HP:0000718', (122, 136))	('associated', 'Reg', (86, 96))	('aggressive uveal melanoma', 'Disease', (147, 172))	('mesothelioma of low aggressiveness', 'Disease', (102, 136))	('uveal melanoma', 'Phenotype', 'HP:0007716', (158, 172))	('aggressive uveal melanoma', 'Disease', 'MESH:C536494', (147, 172))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('BAP1', 'Gene', (67, 71))
86848	32690542	The investigators proposed that GxE interactions caused the mesothelioma epidemic among genetically predisposed families, challenging the dogma that mesothelioma was an example of a malignancy caused exclusively by exposure to carcinogenic fibers.	('malignancy', 'Disease', 'MESH:D009369', (182, 192))	('interactions', 'Var', (36, 48))	('mesothelioma', 'Disease', 'MESH:D008654', (149, 161))	('malignancy', 'Disease', (182, 192))	('caused', 'Reg', (49, 55))	('mesothelioma', 'Disease', 'MESH:D008654', (60, 72))	('carcinogenic fibers', 'Disease', (227, 246))	('carcinogenic fibers', 'Disease', 'MESH:D000071075', (227, 246))	('mesothelioma', 'Disease', (149, 161))	('mesothelioma', 'Disease', (60, 72))
86854	32690542	Both tumors have a high frequency of 3p deletions, and, by sequencing 3p, Carbone and colleagues discovered that the individuals affected by mesothelioma, uveal melanoma, or breast cancer in both families carried truncating BAP1 mutations, a condition they named the "BAP1 cancer syndrome".	('uveal melanoma', 'Disease', 'MESH:C536494', (155, 169))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('uveal melanoma', 'Disease', (155, 169))	('BAP1', 'Gene', (224, 228))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('cancer syndrome', 'Disease', (273, 288))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('uveal melanoma', 'Phenotype', 'HP:0007716', (155, 169))	('breast cancer', 'Disease', (174, 187))	('mutations', 'Var', (229, 238))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('truncating', 'Var', (213, 223))	('carried', 'Reg', (205, 212))	('tumors', 'Disease', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer syndrome', 'Disease', 'MESH:D009369', (273, 288))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('mesothelioma', 'Disease', (141, 153))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))
86855	32690542	A parallel study by Weisner and colleagues reported that BAP1 germline mutations were causally linked to benign melanocytic tumors developing at a young age, which were initially identified as atypical Spitz tumors.	('Spitz tumors', 'Disease', 'MESH:D018332', (202, 214))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('germline', 'Var', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('Spitz tumors', 'Disease', (202, 214))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('linked to', 'Reg', (95, 104))	('BAP1', 'Gene', (57, 61))	('benign melanocytic tumors', 'Disease', 'MESH:D009369', (105, 130))	('benign melanocytic tumors', 'Disease', (105, 130))
86873	32690542	Studying primary fibroblast cell cultures derived from skin-punch biopsies of individuals from two separate families carrying heterozygous BAP1 mutations (BAP1+/-), and wild-type BAP1 (BAP1+/+) control fibroblasts (matched for sex and age from individuals from the same families), it was found that BAP1 localizes to the endoplasmic reticulum (ER), where it deubiquitylates and thus stabilizes the type 3 inositol-1,4,5-trisphosphate receptor (IP3R3; ref.).	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('321', '342'))	('IP3R3', 'Gene', '3710', (444, 449))	('deubiquitylates', 'MPA', (358, 373))	('IP3R3', 'Gene', (444, 449))	('BAP1', 'Gene', (299, 303))	('stabilizes', 'MPA', (383, 393))	('BAP1', 'Gene', (139, 143))	('mutations', 'Var', (144, 153))
86885	32690542	The transcriptional repression of ATF3 and CHOP is dependent upon the deubiquitinylation of H2A (at K119) by BAP1.	('transcriptional', 'MPA', (4, 19))	('H2A', 'Protein', (92, 95))	('CHOP', 'Gene', (43, 47))	('at K119', 'Var', (97, 104))	('K119', 'Chemical', 'MESH:C118156', (100, 104))	('deubiquitinylation', 'MPA', (70, 88))	('ATF3', 'Gene', '467', (34, 38))	('dependent', 'Reg', (51, 60))	('BAP1', 'Gene', (109, 113))	('ATF3', 'Gene', (34, 38))	('CHOP', 'Gene', '1649', (43, 47))
86886	32690542	By engineering a knock-in mouse model expressing the catalytically inactive C91A Bap1 mutant, He and colleagues showed that the loss of function of BAP1 has a proapoptotic effect in mouse embryonic stem cells, fibroblasts, liver, and pancreas, but not in melanocytes and mesothelial cells, the cells that give rise to the cancer types most commonly associated with BAP1 mutations in humans.	('proapoptotic effect', 'MPA', (159, 178))	('Bap1', 'Gene', (81, 85))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('humans', 'Species', '9606', (383, 389))	('mouse', 'Species', '10090', (182, 187))	('C91A', 'Var', (76, 80))	('mutant', 'Var', (86, 92))	('cancer', 'Disease', (322, 328))	('loss', 'Var', (128, 132))	('BAP1', 'Gene', (148, 152))	('C91A', 'SUBSTITUTION', 'None', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('BAP1', 'Gene', (365, 369))	('mouse', 'Species', '10090', (26, 31))	('mutations', 'Var', (370, 379))	('Bap1', 'Gene', '104416', (81, 85))
86893	32690542	Moreover, using a genetically engineered inducible Bap1 knockout murine model, it has been demonstrated that the deletion of Bap1 altered several metabolic pathways.	('Bap1', 'Gene', '104416', (125, 129))	('deletion', 'Var', (113, 121))	('Bap1', 'Gene', (51, 55))	('Bap1', 'Gene', (125, 129))	('metabolic pathways', 'Pathway', (146, 164))	('altered', 'Reg', (130, 137))	('murine', 'Species', '10090', (65, 71))	('Bap1', 'Gene', '104416', (51, 55))
86897	32690542	In 2010, Harbour and colleagues reported that 26 of 31 metastasizing uveal melanomas carried inactivating somatic BAP1 mutations, and one of the patients also carried a germline BAP1 mutation.	('patients', 'Species', '9606', (145, 153))	('inactivating', 'MPA', (93, 105))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('metastasizing uveal melanomas', 'Disease', 'MESH:D009362', (55, 84))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('uveal melanomas', 'Phenotype', 'HP:0007716', (69, 84))	('metastasizing uveal melanomas', 'Disease', (55, 84))	('BAP1', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))
86898	32690542	In 2011, Carbone's team reported that germline BAP1 mutations predisposed to mesothelioma and uveal melanoma, the BAP1 cancer syndrome.	('mutations', 'Var', (52, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('predisposed', 'Reg', (62, 73))	('mesothelioma', 'Disease', (77, 89))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('uveal melanoma', 'Disease', (94, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('germline', 'Var', (38, 46))	('cancer syndrome', 'Disease', 'MESH:D009369', (119, 134))	('cancer syndrome', 'Disease', (119, 134))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('BAP1', 'Gene', (47, 51))
86899	32690542	In 2012, Brugarolas and colleagues reported that 15% of ccRCCs carried somatic BAP1 mutations, and subsequently found that some patients also had inactivating germline mutations.	('carried', 'Reg', (63, 70))	('BAP1', 'Gene', (79, 83))	('mutations', 'Var', (84, 93))	('RCC', 'Disease', (58, 61))	('patients', 'Species', '9606', (128, 136))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
86901	32690542	Numerous studies have now confirmed and expanded on the direct link of BAP1 germline mutations to a cancer syndrome characterized by a predisposition to mesothelioma, uveal melanoma, and less frequently cutaneous melanoma, as well as ccRCC, which are the core cancer types in the BAP1 cancer syndrome.	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('RCC', 'Disease', 'MESH:C538614', (236, 239))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer syndrome', 'Disease', 'MESH:D009369', (285, 300))	('uveal melanoma', 'Disease', 'MESH:C536494', (167, 181))	('uveal melanoma', 'Disease', (167, 181))	('mesothelioma', 'Disease', (153, 165))	('cancer syndrome', 'Disease', 'MESH:D009369', (100, 115))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('BAP1', 'Gene', (71, 75))	('cancer', 'Disease', (285, 291))	('cutaneous melanoma', 'Disease', (203, 221))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (203, 221))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (203, 221))	('cancer syndrome', 'Disease', (285, 300))	('mesothelioma', 'Disease', 'MESH:D008654', (153, 165))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (260, 266))	('uveal melanoma', 'Phenotype', 'HP:0007716', (167, 181))	('mutations', 'Var', (85, 94))	('link', 'Reg', (63, 67))	('cancer', 'Disease', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancer syndrome', 'Disease', (100, 115))	('RCC', 'Disease', (236, 239))	('core', 'cellular_component', 'GO:0019013', ('255', '259'))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
86902	32690542	Although the term "mutations" has been widely used to encompass different types of genetic damage, most BAP1-mutant families carry truncating BAP1 mutations.	('mutations', 'Var', (147, 156))	('BAP1-mutant', 'Gene', (104, 115))	('truncating', 'MPA', (131, 141))	('BAP1', 'Gene', (142, 146))	('genetic damage', 'Disease', 'MESH:D030342', (83, 97))	('genetic damage', 'Disease', (83, 97))
86909	32690542	Recently, Badhai and colleagues reported that the combined deletion in the mesothelial cell lineage of Bap1, Nf2, and Cdkn2ab caused mesothelioma in 100% of mice.	('Bap1', 'Gene', '104416', (103, 107))	('Nf2', 'Gene', (109, 112))	('mice', 'Species', '10090', (157, 161))	('mesothelioma', 'Disease', 'MESH:D008654', (133, 145))	('Nf2', 'Gene', '18016', (109, 112))	('Cdkn2ab', 'Gene', (118, 125))	('Bap1', 'Gene', (103, 107))	('deletion', 'Var', (59, 67))	('mesothelioma', 'Disease', (133, 145))	('caused', 'Reg', (126, 132))
86910	32690542	Bap1 deletion alone caused mesothelioma in 5% of unexposed mice, and combined Nf2 and Cdkn2ab deletion alone did not.	('mesothelioma', 'Disease', (27, 39))	('Bap1', 'Gene', '104416', (0, 4))	('deletion', 'Var', (5, 13))	('mice', 'Species', '10090', (59, 63))	('Bap1', 'Gene', (0, 4))	('Nf2', 'Gene', (78, 81))	('mesothelioma', 'Disease', 'MESH:D008654', (27, 39))	('Nf2', 'Gene', '18016', (78, 81))	('caused', 'Reg', (20, 26))
86911	32690542	In summary, inherited BAP1 mutations cause cancer in mice and in humans, and cancer incidence increases upon exposure to asbestos or other carcinogenic fibers and when other mutations are present.	('mutations', 'Var', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('carcinogenic fibers', 'Disease', (139, 158))	('asbestos', 'Chemical', 'MESH:D001194', (121, 129))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('carcinogenic fibers', 'Disease', 'MESH:D000071075', (139, 158))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('humans', 'Species', '9606', (65, 71))	('cause', 'Reg', (37, 42))	('mice', 'Species', '10090', (53, 57))	('BAP1', 'Gene', (22, 26))
86912	32690542	However, the spontaneous development of mesotheliomas in Bap1+/- mice not exposed to asbestos, and the development of multiple cancer types in carriers of BAP1 mutations (Fig.	('Bap1', 'Gene', (57, 61))	('asbestos', 'Chemical', 'MESH:D001194', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (160, 169))	('mice', 'Species', '10090', (65, 69))	('BAP1', 'Gene', (155, 159))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('carriers', 'Reg', (143, 151))	('cancer', 'Disease', (127, 133))	('Bap1', 'Gene', '104416', (57, 61))	('mesotheliomas', 'Disease', 'MESH:D008654', (40, 53))	('mesotheliomas', 'Disease', (40, 53))
86913	32690542	2B), including tumor types that have not been associated with known carcinogens, suggests that BAP1 mutations also drive tumor growth independently of genotoxic stress, perhaps by favoring the accumulation of age-related DNA damage.	('mutations', 'Var', (100, 109))	('genotoxic stress', 'Disease', 'MESH:D000079225', (151, 167))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('BAP1', 'Gene', (95, 99))	('genotoxic stress', 'Disease', (151, 167))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('favoring', 'PosReg', (180, 188))	('DNA damage', 'MPA', (221, 231))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', (15, 20))	('DNA', 'cellular_component', 'GO:0005574', ('221', '224'))	('accumulation', 'MPA', (193, 205))	('drive', 'PosReg', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
86915	32690542	However, patients with uveal melanoma with germline BAP1 mutations always have an initiating mutation in the G-alpha-q (Gq) pathway, suggesting that additional genetic variants play a critical role in the development of uveal melanoma.	('patients', 'Species', '9606', (9, 17))	('uveal melanoma', 'Phenotype', 'HP:0007716', (220, 234))	('uveal melanoma', 'Disease', (220, 234))	('initiating', 'Reg', (82, 92))	('uveal melanoma', 'Disease', 'MESH:C536494', (220, 234))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('uveal melanoma', 'Phenotype', 'HP:0007716', (23, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (23, 37))	('G-alpha-q', 'Gene', (109, 118))	('BAP1', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))	('uveal melanoma', 'Disease', (23, 37))	('Gq', 'Chemical', '-', (120, 122))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('mutation', 'Var', (93, 101))	('G-alpha-q', 'Gene', '2776', (109, 118))
86918	32690542	Carriers of germline BAP1 mutations often develop multiple cancers during their lifetime.	('BAP1', 'Gene', (21, 25))	('develop', 'Reg', (42, 49))	('multiple cancers', 'Disease', (50, 66))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (26, 35))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('multiple cancers', 'Disease', 'MESH:D009369', (50, 66))
86920	32690542	The fact that most BAP1-associated cancers arise in middle-age and older individuals, and that the penetrance for any particular cancer type is less than 100%, suggests that genomic aberrations in addition to BAP1 loss are required for cancer formation, for example, mutations in the Gq signaling pathway.	('BAP1', 'Gene', (209, 213))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Gq', 'Chemical', '-', (284, 286))	('cancer', 'Disease', (129, 135))	('cancers', 'Disease', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Gq signaling pathway', 'Pathway', (284, 304))	('signaling pathway', 'biological_process', 'GO:0007165', ('287', '304'))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('formation', 'biological_process', 'GO:0009058', ('243', '252'))	('cancer', 'Disease', (236, 242))	('mutations', 'Var', (267, 276))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('BAP1-associated', 'Gene', (19, 34))	('loss', 'NegReg', (214, 218))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancer', 'Disease', (35, 41))
86921	32690542	The first cancer in which somatic (i.e., acquired) BAP1 mutations were found to be common was uveal melanoma, where these mutations are present in approximately 45% of primary tumors and are highly correlated with the poor prognosis class 2 transcriptional signature and metastatic phenotype (ref.	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('BAP1', 'Gene', (51, 55))	('uveal melanoma', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('correlated', 'Reg', (198, 208))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
86923	32690542	Other cancers in which acquired somatic BAP1 mutations are common include mesothelioma (60%-70% of them; ref.)	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mesothelioma', 'Disease', 'MESH:D008654', (74, 86))	('BAP1', 'Gene', (40, 44))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('mesothelioma', 'Disease', (74, 86))
86926	32690542	The parallel between the tumor types developing most frequently in carriers of germline BAP1 mutations and the tumor types that most frequently contain somatic BAP1 mutations underscores the increased susceptibility of uveal, mesothelial, and kidney cells to BAP1 loss.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mutations', 'Var', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (25, 30))	('germline', 'Var', (79, 87))	('tumor', 'Disease', (111, 116))	('BAP1', 'Gene', (160, 164))	('mutations', 'Var', (165, 174))	('BAP1', 'Gene', (88, 92))
86927	32690542	Somatic BAP1 mutations are also present in other malignancies, although at lower rates: thymic carcinoma (13%), cholangiocarcinoma (7%), cutaneous melanoma (5%), basal cell carcinoma (4%), and others (ref.	('carcinoma', 'Disease', 'MESH:D009369', (173, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (137, 155))	('malignancies', 'Disease', 'MESH:D009369', (49, 61))	('carcinoma', 'Disease', (121, 130))	('malignancies', 'Disease', (49, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (112, 130))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (162, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinoma', 'Disease', 'MESH:D009369', (121, 130))	('cholangiocarcinoma', 'Disease', (112, 130))	('BAP1', 'Gene', (8, 12))	('carcinoma', 'Disease', (95, 104))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (112, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (162, 182))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('mutations', 'Var', (13, 22))	('carcinoma', 'Disease', (173, 182))	('basal cell carcinoma', 'Disease', (162, 182))	('carcinoma', 'Disease', 'MESH:D009369', (95, 104))	('cutaneous melanoma', 'Disease', (137, 155))
86929	32690542	The role of BAP1 as a two-hit tumor suppressor gene is underscored by the fact that in humans they are accompanied by monoallelic loss of 3p, or by biallelic deletions of the BAP1 locus (LOH), including broad deletions of 3p21, narrow deletions of several exons, or loss of the entire BAP1 allele.	('humans', 'Species', '9606', (87, 93))	('BAP1', 'Gene', (175, 179))	('loss', 'NegReg', (266, 270))	('narrow deletions', 'Var', (228, 244))	('3p21', 'Protein', (222, 226))	('BAP1', 'Gene', (285, 289))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('loss', 'NegReg', (130, 134))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('tumor', 'Disease', (30, 35))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))
86930	32690542	Initial studies underestimated the frequency of BAP1 mutations in mesothelioma as 22% to 23%.	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))	('BAP1', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('mesothelioma', 'Disease', (66, 78))
86931	32690542	A subsequent study using a comprehensive integrated genomic approach that included Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), copy-number analysis, and cDNA sequencing, combined with IHC and DNA methylation analyses in mesothelioma biopsies, found that >60% carried biallelic somatic BAP1 mutations.	('mesothelioma', 'Disease', (252, 264))	('DNA methylation', 'biological_process', 'GO:0006306', ('224', '239'))	('mutations', 'Var', (322, 331))	('mesothelioma', 'Disease', 'MESH:D008654', (252, 264))	('DNA', 'cellular_component', 'GO:0005574', ('224', '227'))	('BAP1', 'Gene', (317, 321))
86932	32690542	This is because of the frequent occurrence of minute BAP1 deletions in the range of 250 to 3,000 kb, which are not reliably detected by targeted NGS (tNGS), by whole-exome sequencing (WES), or by Sanger sequencing, but are instead detected by MLPA.	('deletions', 'Var', (58, 67))	('tNGS', 'Chemical', '-', (150, 154))	('BAP1', 'Gene', (53, 57))
86933	32690542	These findings were supported by a study in which high-density aCGH to detect deletions larger than 250 bp, and tNGS to detect nucleotide level mutations, resulted in a much higher prevalence of BAP1 mutations in human mesothelioma biopsies than either technique alone (~50%).	('human', 'Species', '9606', (213, 218))	('BAP1', 'Gene', (195, 199))	('mutations', 'Var', (200, 209))	('mesothelioma', 'Disease', (219, 231))	('tNGS', 'Chemical', '-', (112, 116))	('mesothelioma', 'Disease', 'MESH:D008654', (219, 231))
86935	32690542	Additional studies confirmed that BAP1 is the most frequently mutated gene in mesothelioma; however, studies that relied only on tNGS or WES invariably underestimated the true incidence of BAP1 mutations.	('mesothelioma', 'Disease', 'MESH:D008654', (78, 90))	('tNGS', 'Chemical', '-', (129, 133))	('BAP1', 'Gene', (189, 193))	('mutations', 'Var', (194, 203))	('mesothelioma', 'Disease', (78, 90))
86936	32690542	Similarly, Harbour and colleagues used an integrated DNA/RNA-sequencing approach and a customized bioinformatics pipeline to improve the detection of BAP1 mutations in uveal melanoma, identifying BAP1 mutations in approximately 45% of uveal melanomas, twice the rate detected by previous NGS approaches.	('BAP1', 'Gene', (196, 200))	('uveal melanoma', 'Disease', 'MESH:C536494', (168, 182))	('mutations', 'Var', (201, 210))	('uveal melanomas', 'Disease', (235, 250))	('BAP1', 'Gene', (150, 154))	('uveal melanomas', 'Phenotype', 'HP:0007716', (235, 250))	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('uveal melanomas', 'Disease', 'MESH:C536494', (235, 250))	('RNA', 'cellular_component', 'GO:0005562', ('57', '60'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (235, 249))	('uveal melanoma', 'Disease', 'MESH:C536494', (235, 249))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanomas', 'Phenotype', 'HP:0002861', (241, 250))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('uveal melanoma', 'Disease', (168, 182))
86938	32690542	A detailed analysis of 3p deletions in sporadic mesotheliomas revealed that deletions are not contiguous but rather preferentially occur in BAP1 and in some nearby genes (SETD2, PBRM1, and SMARCC1), alternating with segments showing oscillating copy-number changes along the 3p21 chromosome, findings suggestive of chromothripsis.	('chromothripsis', 'Disease', 'MESH:D000072837', (315, 329))	('deletions', 'Var', (76, 85))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (39, 61))	('deletions', 'Var', (26, 35))	('BAP1', 'Gene', (140, 144))	('SETD2', 'Gene', '29072', (171, 176))	('sporadic mesotheliomas', 'Disease', (39, 61))	('PBRM1', 'Gene', (178, 183))	('SETD2', 'Gene', (171, 176))	('occur', 'Reg', (131, 136))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (39, 60))	('chromosome', 'cellular_component', 'GO:0005694', ('280', '290'))	('chromothripsis', 'Disease', (315, 329))	('SMARCC1', 'Gene', (189, 196))	('SMARCC1', 'Gene', '6599', (189, 196))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (39, 61))
86939	32690542	The occurrence of chromothripsis in mesothelioma may be favored by BAP1 inactivation, and it has been confirmed by mate-pair sequencing (MPseq) analyses and by WES.	('favored', 'PosReg', (56, 63))	('chromothripsis in mesothelioma', 'Disease', (18, 48))	('inactivation', 'Var', (72, 84))	('chromothripsis in mesothelioma', 'Disease', 'MESH:D000072837', (18, 48))	('BAP1', 'Gene', (67, 71))
86948	32690542	Negative BAP1 nuclear staining by IHC, regardless of cytoplasmic staining, is found in about 60% to 70% of mesotheliomas and is a reliable, rapid, and economical approach to identify biallelic BAP1 inactivating mutations.	('biallelic', 'Var', (183, 192))	('mesotheliomas', 'Disease', 'MESH:D008654', (107, 120))	('mesotheliomas', 'Disease', (107, 120))	('Negative', 'NegReg', (0, 8))	('inactivating mutations', 'Var', (198, 220))	('BAP1', 'Gene', (193, 197))
86949	32690542	In most tumor cells showing no nuclear staining (e.g., mutated BAP1), there is also no staining in the cytoplasm (Fig.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('mutated', 'Var', (55, 62))	('BAP1', 'Gene', (63, 67))	('cytoplasm', 'cellular_component', 'GO:0005737', ('103', '112'))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))
86956	32690542	The two discordant samples had missense mutations in the catalytic domain (p.Gly13Val and p.Phe170Leu).	('p.Phe170Leu', 'SUBSTITUTION', 'None', (90, 101))	('p.Phe170Leu', 'Var', (90, 101))	('p.Gly13Val', 'SUBSTITUTION', 'None', (75, 85))	('p.Gly13Val', 'Var', (75, 85))
86957	32690542	In addition, Western blot analyses of an IHC-negative sample with wild-type BAP1 failed to reveal detectable BAP1 protein, suggesting that BAP1 may have been inactivated through mutations eluding detection by conventional Sanger sequencing, as described in mesothelioma.	('mesothelioma', 'Disease', (257, 269))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('mesothelioma', 'Disease', 'MESH:D008654', (257, 269))	('BAP1', 'Gene', (139, 143))	('mutations', 'Var', (178, 187))
86960	32690542	Baumann and colleagues reported that the presence of germ line BAP1 mutations strikingly increased the 5-year survival rate of patients with mesothelioma by 7-fold [47% (95% confidence interval [CI], 24-67) vs. 6.7% (95% CI, 6.2-7.3)], indicating that mesothelioma is less aggressive when it occurs in the context of the BAP1 cancer syndrome.	('mesothelioma', 'Disease', (252, 264))	('BAP1', 'Gene', (63, 67))	('mesothelioma', 'Disease', 'MESH:D008654', (252, 264))	('patients', 'Species', '9606', (127, 135))	('cancer syndrome', 'Disease', 'MESH:D009369', (326, 341))	('cancer syndrome', 'Disease', (326, 341))	('mesothelioma', 'Disease', (141, 153))	('mutations', 'Var', (68, 77))	('increased', 'PosReg', (89, 98))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
86961	32690542	In these individuals, normal cells contain 50% of the BAP1 protein, whereas tumor cells show biallelic BAP1 mutations and thus do not contain a biologically functional BAP1 protein.	('mutations', 'Var', (108, 117))	('protein', 'Protein', (59, 66))	('BAP1', 'Gene', (103, 107))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('protein', 'cellular_component', 'GO:0003675', ('173', '180'))	('BAP1 protein', 'Protein', (54, 66))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
86965	32690542	Most subjects (43/79) carried germline BAP1 mutations; 12 of 79 carried germline mutations in other tumor suppressors; and 5 of 79 carried mutations in BAP1 and also in other cancer-related genes.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('mutations', 'Reg', (139, 148))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('mutations', 'Var', (44, 53))	('BAP1', 'Gene', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('BAP1', 'Gene', (39, 43))
86967	32690542	An analysis conducted at the University of Chicago on the germline DNA of 198 patients with mesothelioma using targeted capture and NGS of 85 cancer susceptibility genes revealed that 12% of patients within this cohort carried pathogenic germline mutations; BAP1 was the most commonly mutated gene.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('patients', 'Species', '9606', (191, 199))	('cancer', 'Disease', (142, 148))	('mesothelioma', 'Disease', 'MESH:D008654', (92, 104))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patients', 'Species', '9606', (78, 86))	('BAP1', 'Gene', (258, 262))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('pathogenic', 'Reg', (227, 237))	('mesothelioma', 'Disease', (92, 104))	('germline mutations', 'Var', (238, 256))
86968	32690542	A similar survey conducted at the NCI on a cohort of 385 patients using a panel of 73 genes involved in DNA repair and tumor suppression demonstrated that 12% of them carried germline mutations (mostly germline BAP1 mutations).	('tumor', 'Disease', (119, 124))	('patients', 'Species', '9606', (57, 65))	('germline BAP1 mutations', 'Var', (202, 225))	('germline mutations', 'Var', (175, 193))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('carried', 'Reg', (167, 174))	('DNA repair', 'biological_process', 'GO:0006281', ('104', '114'))
86969	32690542	The presence of inherited mutations significantly increased median overall survival compared with patients without these mutations (7.9 years vs. 2.4 years, P = 0.001; ref.).	('mutations', 'Var', (26, 35))	('overall survival', 'MPA', (67, 83))	('increased', 'PosReg', (50, 59))	('patients', 'Species', '9606', (98, 106))
86970	32690542	Together, these studies validate the prognostic significance of germline mutations that confer a significantly improved survival to patients with mesothelioma (Fig.	('improved', 'PosReg', (111, 119))	('germline mutations', 'Var', (64, 82))	('mesothelioma', 'Disease', (146, 158))	('mesothelioma', 'Disease', 'MESH:D008654', (146, 158))	('survival', 'MPA', (120, 128))	('patients', 'Species', '9606', (132, 140))
86971	32690542	The improved survival was also observed among patients who, in addition to mesothelioma, developed other aggressive malignancies, which, rather than an exception, is the norm among those carrying germline BAP1 mutations.	('patients', 'Species', '9606', (46, 54))	('improved', 'PosReg', (4, 12))	('mutations', 'Var', (210, 219))	('aggressive malignancies', 'Disease', (105, 128))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('aggressive malignancies', 'Disease', 'MESH:D009369', (105, 128))	('mesothelioma', 'Disease', (75, 87))
86973	32690542	Because almost all BAP1-mutated cancers contain biallelic BAP1 mutations, regardless of whether they are sporadic or occur in carriers of germline mutations, the markedly improved prognosis of mesotheliomas occurring in carriers of germline BAP1 mutations does not seem to be related only to the mutation in the tumor cells.	('mutations', 'Var', (63, 72))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Disease', (32, 39))	('BAP1', 'Gene', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('BAP1', 'Gene', (241, 245))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('mutations', 'Var', (246, 255))	('mesotheliomas', 'Disease', 'MESH:D008654', (193, 206))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', (312, 317))	('mesotheliomas', 'Disease', (193, 206))	('biallelic', 'Var', (48, 57))	('improved', 'PosReg', (171, 179))	('BAP1-mutated', 'Gene', (19, 31))
86974	32690542	Therefore, the improved prognosis of mesothelioma and other cancer types in carriers of germline BAP1 mutations may be influenced by the microenvironment and/or the immune system.	('mesothelioma', 'Disease', 'MESH:D008654', (37, 49))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('influenced', 'Reg', (119, 129))	('cancer', 'Disease', (60, 66))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('improved', 'PosReg', (15, 23))	('mesothelioma', 'Disease', (37, 49))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
86976	32690542	In contrast to mesothelioma, a study of 8 patients with uveal melanoma with germline BAP1 mutations found an increased risk of metastasis (p.003) compared with uveal melanoma patients with wild-type BAP1 in their germline, confirming that BAP1 mutations induce a metastatic phenotype.	('mutations', 'Var', (90, 99))	('p.0', 'SUBSTITUTION', 'None', (139, 142))	('metastasis', 'CPA', (127, 137))	('induce', 'Reg', (254, 260))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('mutations', 'Var', (244, 253))	('uveal melanoma', 'Disease', 'MESH:C536494', (56, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('uveal melanoma', 'Disease', (56, 70))	('uveal melanoma', 'Disease', 'MESH:C536494', (160, 174))	('p.0', 'Var', (139, 142))	('uveal melanoma', 'Disease', (160, 174))	('mesothelioma', 'Disease', (15, 27))	('patients', 'Species', '9606', (42, 50))	('BAP1', 'Gene', (85, 89))	('uveal melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('mesothelioma', 'Disease', 'MESH:D008654', (15, 27))	('patients', 'Species', '9606', (175, 183))	('uveal melanoma', 'Phenotype', 'HP:0007716', (160, 174))
86978	32690542	Somatic BAP1 mutations in the tumor biopsy are the strongest known risk factor for uveal melanoma metastatic death.	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('uveal melanoma metastatic death', 'Disease', (83, 114))	('uveal melanoma metastatic death', 'Disease', 'MESH:C536494', (83, 114))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('BAP1', 'Gene', (8, 12))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('mutations', 'Var', (13, 22))	('tumor', 'Disease', (30, 35))
86979	32690542	These phenotypic differences among cancer types associated with BAP1 mutations suggest that there are cell type- and context-dependent differences in the role of BAP1 in biology and cancer.	('mutations', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))	('BAP1', 'Gene', (64, 68))
86980	32690542	It is not yet clear whether germline BAP1 mutations are associated with improved survival in RCC.	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('improved', 'PosReg', (72, 80))	('germline', 'Var', (28, 36))	('BAP1', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))
86981	32690542	Mesotheliomas with acquired BAP1 mutations are mostly of the epithelial type and may have a slightly improved prognosis of a few months compared with mesotheliomas of similar histologic type with wild-type BAP1; however, some studies did not support this finding.	('mesotheliomas', 'Disease', (150, 163))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('improved', 'PosReg', (101, 109))	('Mesotheliomas', 'Disease', 'MESH:D008654', (0, 13))	('Mesotheliomas', 'Disease', (0, 13))	('mesotheliomas', 'Disease', 'MESH:D008654', (150, 163))
86982	32690542	Intriguingly, the opposite correlation with survival was observed in uveal melanoma, ccRCC, and cholangiocarcinoma, where somatic biallelic BAP1 mutations were associated with a metastatic phenotype and poor prognosis.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('BAP1', 'Gene', (140, 144))	('uveal melanoma', 'Disease', (69, 83))	('mutations', 'Var', (145, 154))	('biallelic', 'Var', (130, 139))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('cholangiocarcinoma', 'Disease', (96, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (96, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (96, 114))	('metastatic', 'CPA', (178, 188))	('associated', 'Reg', (160, 170))
86983	32690542	In uveal melanoma, detection of BAP1 mutations directly by sequencing, or indirectly via the class 2 transcriptional signature or other methods, is now a routine part of patient care, with high-risk patients stratified for increased surveillance and clinical trial entry.	('uveal melanoma', 'Disease', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('patient', 'Species', '9606', (199, 206))	('mutations', 'Var', (37, 46))	('BAP1', 'Gene', (32, 36))	('patients', 'Species', '9606', (199, 207))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('patient', 'Species', '9606', (170, 177))
86985	32690542	Brugarolas and colleagues found that ccRCCs with somatic BAP1 mutations were associated with high-grade tumors.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('BAP1', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('associated', 'Reg', (77, 87))
86988	32690542	To determine whether BAP1 and PBRM1 directly affect tumor grade, mice were generated with targeted inactivation of Bap1 or Pbrm1 in the kidney using the same Cre driver.	('affect', 'Reg', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('mice', 'Species', '10090', (65, 69))	('Bap1', 'Gene', '104416', (115, 119))	('Pbrm1', 'Gene', (123, 128))	('Pbrm1', 'Gene', '66923', (123, 128))	('Bap1', 'Gene', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('inactivation', 'Var', (99, 111))
86989	32690542	Inactivation of Bap1 or Pbrm1, along with Vhl, which is uniformly inactivated in ccRCC, led to the development of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('Bap1', 'Gene', (16, 20))	('led to', 'Reg', (88, 94))	('Pbrm1', 'Gene', (24, 29))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('Pbrm1', 'Gene', '66923', (24, 29))	('Vhl', 'Gene', '7428', (42, 45))	('Bap1', 'Gene', '104416', (16, 20))	('Inactivation', 'Var', (0, 12))	('RCC', 'Disease', (116, 119))	('Vhl', 'Gene', (42, 45))
86995	32690542	Following VHL inactivation, which is the signature and initiating event in ccRCC, a mutation of the second copy of BAP1 or PBRM1 likely leads to tumors of different grade and prognosis.	('leads to', 'Reg', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('PBRM1', 'Gene', (123, 128))	('RCC', 'Disease', (77, 80))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('BAP1', 'Gene', (115, 119))	('VHL', 'Gene', (10, 13))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('VHL', 'Gene', '7428', (10, 13))	('mutation', 'Var', (84, 92))
86996	32690542	A fourth tumor suppressor gene in the same 3p region, SETD2, is also mutated in ccRCC and is associated with poor prognosis.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('9', '25'))	('SETD2', 'Gene', '29072', (54, 59))	('mutated', 'Var', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('SETD2', 'Gene', (54, 59))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('tumor', 'Disease', (9, 14))	('RCC', 'Disease', (82, 85))	('tumor suppressor', 'biological_process', 'GO:0051726', ('9', '25'))
86997	32690542	Whereas mutations in BAP1 and PBRM1 tend to be mutually exclusive, mutations in PBRM1 and SETD2 appear to cooperate and are found at higher-than-expected frequencies.	('SETD2', 'Gene', (90, 95))	('PBRM1', 'Gene', (30, 35))	('BAP1', 'Gene', (21, 25))	('mutations', 'Var', (8, 17))	('mutations', 'Var', (67, 76))	('PBRM1', 'Gene', (80, 85))	('SETD2', 'Gene', '29072', (90, 95))
87002	32690542	The incorporation of the active metabolite of gemcitabine into DNA causes replication arrest and apoptosis, making this drug one of the most used chemotherapeutic agents against several cancers, including mesothelioma, for which it is approved as second-line treatment.	('incorporation', 'Var', (4, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (205, 217))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('97', '106'))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('arrest', 'Disease', (86, 92))	('apoptosis', 'biological_process', 'GO:0006915', ('97', '106'))	('mesothelioma', 'Disease', (205, 217))	('gemcitabine', 'Chemical', 'MESH:C056507', (46, 57))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('apoptosis', 'CPA', (97, 106))
87004	32690542	Upon treatment with this agent or with hydroxyurea, the viability of mesothelioma spheroids expressing nonfunctional C91A BAP1 was significantly higher compared with wild-type BAP1 counterparts.	('BAP1', 'Gene', (122, 126))	('C91A', 'Var', (117, 121))	('viability', 'CPA', (56, 65))	('hydroxyurea', 'Chemical', 'MESH:D006918', (39, 50))	('mesothelioma spheroids', 'Disease', 'MESH:D008654', (69, 91))	('C91A', 'SUBSTITUTION', 'None', (117, 121))	('mesothelioma spheroids', 'Phenotype', 'HP:0025014', (69, 91))	('mesothelioma spheroids', 'Disease', (69, 91))	('higher', 'PosReg', (145, 151))
87010	32690542	This combined therapy is the standard of care for BRAFV600E-mutant human melanoma.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('BRAFV600E-mutant', 'Var', (50, 66))	('human', 'Species', '9606', (67, 72))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
87012	32690542	In addition, a large study in more than 100 cases of metastatic RCC demonstrated that BAP1 mutational status did not correlate with clinical benefit upon rapalog therapy, despite the significantly higher aggressiveness of RCC in carriers of BAP1 mutations.	('aggressiveness of RCC', 'Disease', (204, 225))	('aggressiveness', 'Phenotype', 'HP:0000718', (204, 218))	('aggressiveness of RCC', 'Disease', 'MESH:C538614', (204, 225))	('higher', 'PosReg', (197, 203))	('rapalog', 'Chemical', '-', (154, 161))	('BAP1', 'Gene', (241, 245))	('BAP1', 'Gene', (86, 90))	('mutations', 'Var', (246, 255))	('RCC', 'Disease', 'MESH:C538614', (222, 225))	('RCC', 'Disease', (222, 225))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))
87018	32690542	The BAP1-deficient developmental phenotype could be rescued using SAHA or specific depletion of HDAC4.	('BAP1-deficient developmental', 'Disease', 'MESH:D007805', (4, 32))	('depletion', 'Var', (83, 92))	('HDAC4', 'Gene', '9759', (96, 101))	('BAP1-deficient developmental', 'Disease', (4, 32))	('HDAC4', 'Gene', (96, 101))
87021	32690542	In the context of mutations in BRCA1 or BRCA2 genes in patients with breast, ovary, prostate, or pancreatic cancers, PARP inhibitors have shown antitumor activity, and three agents are currently in the clinic.	('PARP', 'Gene', '142', (117, 121))	('pancreatic cancers', 'Disease', (97, 115))	('PARP', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('pancreatic cancers', 'Disease', 'MESH:D010190', (97, 115))	('breast', 'Disease', (69, 75))	('BRCA2', 'Gene', (40, 45))	('prostate', 'Disease', (84, 92))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('ovary', 'Disease', (77, 82))	('BRCA2', 'Gene', '675', (40, 45))	('BRCA1', 'Gene', '672', (31, 36))	('tumor', 'Disease', (148, 153))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (97, 115))	('BRCA1', 'Gene', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('mutations', 'Var', (18, 27))
87026	32690542	A BAP1 mutant by alternative splicing resulting in a 54-bp deletion increased sensitivity to the PARP inhibitor olaparib.	('PARP', 'Gene', '142', (97, 101))	('olaparib', 'Chemical', 'MESH:C531550', (112, 120))	('mutant', 'Var', (7, 13))	('splicing', 'biological_process', 'GO:0045292', ('29', '37'))	('PARP', 'Gene', (97, 101))	('deletion', 'Var', (59, 67))	('increased', 'PosReg', (68, 77))	('BAP1', 'Gene', (2, 6))
87027	32690542	A recent study on HR defects in a cohort of patients with mesothelioma showed both in vitro and by digital gene-expression analysis that loss of BAP1 increased sensitivity to PARP inhibitors.	('patients', 'Species', '9606', (44, 52))	('gene-expression', 'biological_process', 'GO:0010467', ('107', '122'))	('PARP', 'Gene', (175, 179))	('mesothelioma', 'Disease', (58, 70))	('HR defects', 'Disease', 'MESH:D000014', (18, 28))	('PARP', 'Gene', '142', (175, 179))	('mesothelioma', 'Disease', 'MESH:D008654', (58, 70))	('loss', 'Var', (137, 141))	('increased', 'PosReg', (150, 159))	('BAP1', 'Gene', (145, 149))	('HR defects', 'Disease', (18, 28))
87028	32690542	Presently, two ongoing clinical trials are testing the hypothesis that BAP1 mutations increase sensitivity to PARP inhibitors in mesothelioma (NCT03207347, NCT03531840).	('increase', 'PosReg', (86, 94))	('mutations', 'Var', (76, 85))	('mesothelioma', 'Disease', 'MESH:D008654', (129, 141))	('PARP', 'Gene', (110, 114))	('mesothelioma', 'Disease', (129, 141))	('BAP1', 'Gene', (71, 75))	('PARP', 'Gene', '142', (110, 114))
87030	32690542	We propose that these results may indicate that the increased resistance to cell death caused by BAP1 mutations in tumor cells over-come whatever increased DNA damage may be induced by PARP inhibitors in these same cells, making them resistant to this therapy.	('increased', 'PosReg', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('DNA damage', 'MPA', (156, 166))	('PARP', 'Gene', (185, 189))	('tumor', 'Disease', (115, 120))	('cell death', 'biological_process', 'GO:0008219', ('76', '86'))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('resistance', 'MPA', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('PARP', 'Gene', '142', (185, 189))
87044	32690542	Moreover, based on the structural rearrangements induced by chromothripsis, which may be favored by BAP1 mutations, Mansfield and colleagues predicted and validated in vitro the expression of altered peptides that may act as neoantigens and thus potentially increase mesothelioma immunogenicity and responsiveness to immunotherapy.	('chromothripsis', 'Disease', 'MESH:D000072837', (60, 74))	('BAP1', 'Gene', (100, 104))	('increase mesothelioma immunogenicity', 'Disease', (258, 294))	('mutations', 'Var', (105, 114))	('chromothripsis', 'Disease', (60, 74))	('increase mesothelioma immunogenicity', 'Disease', 'MESH:D008654', (258, 294))	('peptides', 'Protein', (200, 208))	('altered', 'Var', (192, 199))
87048	32690542	In addition, depletion or pharmacologic inhibition of EZH2 in BAP1-deficient Xenopus embryos did not rescue a neural crest developmental phenotype.	('EZH2', 'Gene', (54, 58))	('BAP1-deficient Xenopus embryos', 'Disease', (62, 92))	('neural crest developmental phenotype', 'CPA', (110, 146))	('depletion', 'Var', (13, 22))	('BAP1-deficient Xenopus embryos', 'Disease', 'MESH:D020964', (62, 92))
87050	32690542	Although the BAP1 cancer syndrome and the driving role of acquired BAP1 mutations in human cancer were discovered less than a decade ago, much progress has been made to elucidate critical mechanisms of BAP1 activities (Fig.	('mutations', 'Var', (72, 81))	('cancer syndrome', 'Disease', (18, 33))	('cancer syndrome', 'Disease', 'MESH:D009369', (18, 33))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('human', 'Species', '9606', (85, 90))	('BAP1', 'Gene', (67, 71))
87052	32690542	Therefore, reduced levels of BAP1, as observed in carriers of heterozygous BAP1 mutations, increase the amount of genetic damage that occurs spontaneously as cells divide, or that occurs in response to exposure to environmental carcinogens.	('genetic damage', 'Disease', (114, 128))	('BAP1', 'Gene', (75, 79))	('mutations', 'Var', (80, 89))	('increase', 'PosReg', (91, 99))	('genetic damage', 'Disease', 'MESH:D030342', (114, 128))
87053	32690542	Moreover, BAP1 loss favors tumor growth by inducing a Warburg effect (i.e., aerobic glycolysis) that provides the metabolic building blocks to support cell division and at the same time helps cancer cells to grow in a hypoxic environment.	('grow', 'CPA', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cell division', 'biological_process', 'GO:0051301', ('151', '164'))	('tumor', 'Disease', (27, 32))	('BAP1', 'Gene', (10, 14))	('Warburg', 'MPA', (54, 61))	('cancer', 'Disease', (192, 198))	('loss', 'Var', (15, 19))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('favors', 'PosReg', (20, 26))	('helps', 'PosReg', (186, 191))	('inducing', 'Reg', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('glycolysis', 'biological_process', 'GO:0006096', ('84', '94'))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
87055	32690542	Therefore, the combined nuclear and cytoplasmic BAP1 activities account for the very high incidence of cancer in carriers of germline BAP1 mutations (Fig.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BAP1', 'Gene', (134, 138))	('mutations', 'Var', (139, 148))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
87058	32690542	All published data support the notion that BAP1 is a potent tumor suppressor, as almost all carriers of pathogenic germline BAP1 mutations developed one or more cancers during their lifetime.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('mutations', 'Var', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('BAP1', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('developed', 'Reg', (139, 148))	('cancers', 'Disease', (161, 168))	('tumor', 'Disease', (60, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('60', '76'))
87059	32690542	LOH for BAP1 is observed in 100% of human tumors developing in carriers of germline BAP1 mutations, as well as in sporadic mesotheliomas with somatic BAP1 mutations, underscoring the potent tumor suppressor activity of BAP1.	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (114, 136))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('mutations', 'Var', (89, 98))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('190', '206'))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (114, 135))	('sporadic mesotheliomas', 'Disease', (114, 136))	('tumor', 'Disease', (42, 47))	('tumor suppressor', 'biological_process', 'GO:0051726', ('190', '206'))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('BAP1', 'Gene', (150, 154))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', (190, 195))	('BAP1', 'Gene', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('mutations', 'Var', (155, 164))	('tumors', 'Disease', (42, 48))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (114, 136))	('human', 'Species', '9606', (36, 41))
87060	32690542	Intriguingly, LOH for BAP1 is not always observed in tumors developing in mice carrying germline Bap1 mutations.	('Bap1', 'Gene', '104416', (97, 101))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('Bap1', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutations', 'Var', (102, 111))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('mice', 'Species', '10090', (74, 78))	('tumors', 'Disease', (53, 59))
87061	32690542	This critical question shall be addressed in the coming years to understand why germline BAP1 mutations cause or are present as somatic mutations more frequently in mesothelioma, uveal melanoma, and ccRCC, rather than in other cancer types.	('uveal melanoma', 'Disease', 'MESH:C536494', (179, 193))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('BAP1', 'Gene', (89, 93))	('mesothelioma', 'Disease', (165, 177))	('mutations', 'Var', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('uveal melanoma', 'Phenotype', 'HP:0007716', (179, 193))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('cancer', 'Disease', (227, 233))	('cause', 'Reg', (104, 109))	('uveal melanoma', 'Disease', (179, 193))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))
87062	32690542	This information will help to design more effective preventive and therapeutic strategies for patients carrying germline BAP1 mutations or cancers with somatic BAP1 mutations.	('germline', 'Var', (112, 120))	('patients', 'Species', '9606', (94, 102))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('BAP1', 'Gene', (121, 125))	('BAP1', 'Gene', (160, 164))	('mutations', 'Var', (126, 135))	('mutations', 'Var', (165, 174))
87063	32690542	An additional question that will be addressed in coming years is why BAP1 mutations have phenotypic and prognostic implications that are cell type- and context-dependent: Germline mutations confer a better prognosis in mesothelioma, whereas somatic mutations induce a worse prognosis in uveal melanoma and ccRCC.	('better', 'PosReg', (199, 205))	('mesothelioma', 'Disease', (219, 231))	('BAP1', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (287, 301))	('uveal melanoma', 'Disease', (287, 301))	('uveal melanoma', 'Disease', 'MESH:C536494', (287, 301))	('RCC', 'Disease', 'MESH:C538614', (308, 311))	('RCC', 'Disease', (308, 311))	('mesothelioma', 'Disease', 'MESH:D008654', (219, 231))	('melanoma', 'Phenotype', 'HP:0002861', (293, 301))
87064	32690542	The difference in survival is quite significant, with median survival of 5 to 7 years for mesothelioma developing in carriers of heterozygous BAP1 mutations compared with 1-year median survival in sporadic mesotheliomas, cancers characteristically resistant to therapy.	('mutations', 'Var', (147, 156))	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('mesothelioma', 'Disease', (206, 218))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (197, 218))	('cancers', 'Disease', (221, 228))	('sporadic mesotheliomas', 'Disease', (197, 219))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (197, 219))	('mesothelioma', 'Disease', 'MESH:D008654', (206, 218))	('BAP1', 'Gene', (142, 146))	('mesothelioma', 'Disease', (90, 102))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (197, 219))	('mesothelioma', 'Disease', 'MESH:D008654', (90, 102))
87067	32690542	Adding to this puzzle, in sporadic mesotheliomas acquired biallelic BAP1 mutations are frequent, yet these mesotheliomas are not associated with significantly improved survival.	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (26, 47))	('mesotheliomas', 'Disease', 'MESH:D008654', (107, 120))	('mesotheliomas', 'Disease', 'MESH:D008654', (35, 48))	('mesotheliomas', 'Disease', (107, 120))	('mesotheliomas', 'Disease', (35, 48))	('sporadic mesotheliomas', 'Disease', (26, 48))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (26, 48))	('biallelic', 'Var', (58, 67))	('BAP1', 'Gene', (68, 72))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (26, 48))	('mutations', 'Var', (73, 82))
87068	32690542	These findings in the same tumor type suggest that the improved survival in carriers of germline BAP1 mutations may be linked to the microenvironment, the immune system, and maybe in part to early diagnosis, as family members are being enrolled in early-detection screening programs.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('improved', 'PosReg', (55, 63))	('tumor', 'Disease', (27, 32))	('survival', 'MPA', (64, 72))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
87070	32690542	What if germline BAP1 mutations render the host capable to fight mesothelioma growth by affecting the tumor microenvironment?	('affecting', 'Reg', (88, 97))	('mesothelioma', 'Disease', (65, 77))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('mutations', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('fight', 'CPA', (59, 64))	('BAP1', 'Gene', (17, 21))
87071	32690542	BAP1 mutations may influence the response to immunotherapy by increasing the propensity to chromothripsis, by deregulating the expression of genes that modulate immune checkpoints, and by promoting a proinflammatory tumor microenvironment.	('tumor', 'Disease', (216, 221))	('influence', 'Reg', (19, 28))	('BAP1', 'Gene', (0, 4))	('response to immunotherapy', 'MPA', (33, 58))	('expression of', 'MPA', (127, 140))	('mutations', 'Var', (5, 14))	('chromothripsis', 'Disease', (91, 105))	('increasing', 'PosReg', (62, 72))	('proinflammatory', 'MPA', (200, 215))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('deregulating', 'PosReg', (110, 122))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('promoting', 'PosReg', (188, 197))	('chromothripsis', 'Disease', 'MESH:D000072837', (91, 105))
87072	32690542	By studying patients and mice with germline BAP1 mutations, we may learn how to treat mesotheliomas and maybe other cancers more effectively.	('patients', 'Species', '9606', (12, 20))	('mice', 'Species', '10090', (25, 29))	('mutations', 'Var', (49, 58))	('mesotheliomas', 'Disease', 'MESH:D008654', (86, 99))	('mesotheliomas', 'Disease', (86, 99))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('BAP1', 'Gene', (44, 48))
87073	32690542	For example, the role of metformin, a drug that reprograms cell metabolism by restraining aerobic glycolysis and promoting mitochondrial respiration, could be explored in the existing mouse models carrying heterozygous Bap1 mutations and in xenografts of BAP1-mutated tumors.	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('promoting', 'PosReg', (113, 122))	('Bap1', 'Gene', (219, 223))	('respiration', 'biological_process', 'GO:0045333', ('137', '148'))	('restraining', 'NegReg', (78, 89))	('tumors', 'Disease', (268, 274))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('mouse', 'Species', '10090', (184, 189))	('respiration', 'biological_process', 'GO:0007585', ('137', '148'))	('metabolism', 'biological_process', 'GO:0008152', ('64', '74'))	('tumors', 'Disease', 'MESH:D009369', (268, 274))	('mutations', 'Var', (224, 233))	('metformin', 'Chemical', 'MESH:D008687', (25, 34))	('aerobic glycolysis', 'MPA', (90, 108))	('mitochondrial respiration', 'MPA', (123, 148))	('glycolysis', 'biological_process', 'GO:0006096', ('98', '108'))	('Bap1', 'Gene', '104416', (219, 223))
87075	32690542	Family members of carriers of germline BAP1 mutations should be tested for BAP1 mutations, and those found to carry mutations should be enrolled in early-detection clinical trials (NCT03830229) that can help identify malignancies at an early stage, when they can be cured by surgery (uveal melanoma, RCC, cutaneous melanoma, etc.	('BAP1', 'Gene', (75, 79))	('RCC', 'Disease', 'MESH:C538614', (300, 303))	('RCC', 'Disease', (300, 303))	('melanoma', 'Phenotype', 'HP:0002861', (290, 298))	('malignancies', 'Disease', 'MESH:D009369', (217, 229))	('uveal melanoma', 'Phenotype', 'HP:0007716', (284, 298))	('uveal melanoma', 'Disease', 'MESH:C536494', (284, 298))	('melanoma', 'Phenotype', 'HP:0002861', (315, 323))	('mutations', 'Var', (44, 53))	('cutaneous melanoma', 'Disease', (305, 323))	('uveal melanoma', 'Disease', (284, 298))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (305, 323))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (305, 323))	('malignancies', 'Disease', (217, 229))	('BAP1', 'Gene', (39, 43))
87077	32690542	Moreover, BAP1 mutant carriers should limit exposure to diagnostic and therapeutic ionizing radiation that in these individuals may carry a higher cancer risk than in the population at large.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('BAP1', 'Gene', (10, 14))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('mutant', 'Var', (15, 21))
87157	32524777	Results of the studies reviewed here suggest that CIRT can significantly increase LC rates, which is particularly important regarding small tumors.	('small tumors', 'Disease', (134, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('increase', 'PosReg', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('small tumors', 'Disease', 'MESH:D058405', (134, 146))	('CIRT', 'Var', (50, 54))	('LC rates', 'CPA', (82, 90))
87178	32524777	38  Accordingly, although differences between the two particle beams for treating superficial tumors are minimal, eye retention rates after CIRT were substantially higher than those after proton RT (74.3%).	('CIRT', 'Var', (140, 144))	('retention', 'biological_process', 'GO:0051235', ('118', '127'))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('higher', 'PosReg', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('eye retention rates', 'CPA', (114, 133))
87180	32524777	In addition, small size of tumors, short tumor-disc distance, and V50 of the iris-ciliary body were also found to be associated with lower incidences of neovascular glaucoma.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', (27, 32))	('neovascular glaucoma', 'Disease', (153, 173))	('neovascular glaucoma', 'Disease', 'MESH:D015355', (153, 173))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('glaucoma', 'Phenotype', 'HP:0000501', (165, 173))	('lower', 'NegReg', (133, 138))	('V50', 'Var', (66, 69))
87221	32524777	G1/2 acute and late toxicity were observed in 17%-87.5% and in 10.8%-62.5%, respectively, of all CIRT-treated MMs, which were higher than those in patients treated with other conventional forms of RT.	('toxicity', 'Disease', 'MESH:D064420', (20, 28))	('patients', 'Species', '9606', (147, 155))	('toxicity', 'Disease', (20, 28))	('CIRT-treated', 'Var', (97, 109))
87234	32524777	63  Such mutations typically lead to aberrant activation of the RAS/RAF/MEK/ERK signaling cascades and of the phosphoinositol-3-kinase/AKT pathway, promoting tissue invasion and metastasis of MMs.	('AKT', 'Gene', '207', (135, 138))	('ERK', 'molecular_function', 'GO:0004707', ('76', '79'))	('promoting', 'PosReg', (148, 157))	('ERK', 'Gene', (76, 79))	('activation', 'PosReg', (46, 56))	('mutations', 'Var', (9, 18))	('tissue invasion', 'CPA', (158, 173))	('AKT', 'Gene', (135, 138))	('RAF', 'Gene', '673', (68, 71))	('MEK', 'Gene', (72, 75))	('MEK', 'Gene', '5609', (72, 75))	('metastasis', 'CPA', (178, 188))	('RAF', 'Gene', (68, 71))	('tissue invasion', 'biological_process', 'GO:0001404', ('158', '173'))	('signaling', 'biological_process', 'GO:0023052', ('80', '89'))	('ERK', 'Gene', '5594', (76, 79))
87244	32524777	This hypothesis is supported by the fact that almost all CIRT-treated patients included in the reviewed studies had suffered from inoperable or recurrent tumors, and CIRT substantially reduced local recurrence.	('patients', 'Species', '9606', (70, 78))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('CIRT', 'Var', (166, 170))	('local recurrence', 'CPA', (193, 209))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('reduced', 'NegReg', (185, 192))
87257	32186672	In patients surviving 5 years after enucleation, univariable analysis revealed that age (P = 0.03), tumor diameter (P < 0.001), monosomy 3 (P = 0.04), and 8q gain (P = 0.003) were associated with subsequent UM-related death.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('death', 'Disease', 'MESH:D003643', (218, 223))	('gain', 'PosReg', (158, 162))	('death', 'Disease', (218, 223))	('tumor', 'Disease', (100, 105))	('UM', 'Phenotype', 'HP:0007716', (207, 209))	('enucleation', 'biological_process', 'GO:0090601', ('36', '47'))	('patients', 'Species', '9606', (3, 11))	('monosomy 3', 'Var', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
87259	32186672	Among UM patients who survived the initial 5 years following enucleation, male gender and chromosome 8q status were the remaining factors related to UM-related death later on.	('patients', 'Species', '9606', (9, 17))	('death', 'Disease', 'MESH:D003643', (160, 165))	('death', 'Disease', (160, 165))	('UM', 'Phenotype', 'HP:0007716', (6, 8))	('UM', 'Phenotype', 'HP:0007716', (149, 151))	('enucleation', 'biological_process', 'GO:0090601', ('61', '72'))	('chromosome 8q status', 'Var', (90, 110))	('chromosome', 'cellular_component', 'GO:0005694', ('90', '100'))	('related', 'Reg', (138, 145))
87266	32186672	Recently, mutations in specific genes such as BAP1, EIF1AX, and SF3B1 have been shown to have prognostic value in UM.	('SF3B1', 'Gene', (64, 69))	('BAP1', 'Gene', '8314', (46, 50))	('UM', 'Phenotype', 'HP:0007716', (114, 116))	('BAP1', 'Gene', (46, 50))	('SF3B1', 'Gene', '23451', (64, 69))	('mutations', 'Var', (10, 19))	('EIF1AX', 'Gene', '1964', (52, 58))	('EIF1AX', 'Gene', (52, 58))
87295	32186672	In case of discrepancy between the tests, the tumor was classified as having monosomy 3 or chromosome 8q gain when either of the tests showed the abnormality.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('monosomy 3', 'Disease', (77, 87))	('chromosome', 'cellular_component', 'GO:0005694', ('91', '101'))	('gain', 'PosReg', (105, 109))	('chromosome 8q', 'Var', (91, 104))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
87318	32186672	Univariable Cox regression demonstrated that in this group, age at enucleation (HR, 1.03; 95% CI, 1.0-1.05; P = 0.03), largest basal diameter (HR, 1.14; 95% CI, 1.07-1.22; P < 0.001), monosomy 3 (HR, 3.12; 95% CI, 1.08-9.04; P = 0.04), and gain of 8q (HR, 10.31; 95% CI, 2.23-47.74; P = 0.003) were related to UM-related death.	('death', 'Disease', 'MESH:D003643', (321, 326))	('death', 'Disease', (321, 326))	('gain', 'PosReg', (240, 244))	('UM', 'Phenotype', 'HP:0007716', (310, 312))	('enucleation', 'biological_process', 'GO:0090601', ('67', '78'))	('monosomy 3', 'Var', (184, 194))	('largest basal diameter', 'CPA', (119, 141))
87319	32186672	After correction in a multivariable competing risk regression, only male gender (HR, 6.87; 95% CI, 1.26-37.42; P = 0.03) and gain of 8q (HR, 14.75; 95% CI, 1.77-122.99; P = 0.01) were independently associated with UM-related death (Table 3B).	('gain', 'Var', (125, 129))	('UM', 'Phenotype', 'HP:0007716', (214, 216))	('associated', 'Reg', (198, 208))	('death', 'Disease', 'MESH:D003643', (225, 230))	('death', 'Disease', (225, 230))
87344	32186672	Gain of 8q was the parameter with the highest HR that showed an independent association with poor survival in the total cohort as well as specifically 5 years following treatment of the primary tumor.	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('Gain', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('men', 'Species', '9606', (174, 177))
87346	32186672	Other studies have shown that late-death cases may show disomy 3/gene-expression profile class 1 with overexpression of PRAME or SF3B1 mutation.	('SF3B1', 'Gene', (129, 134))	('gene-expression', 'biological_process', 'GO:0010467', ('65', '80'))	('SF3B1', 'Gene', '23451', (129, 134))	('overexpression', 'PosReg', (102, 116))	('death', 'Disease', 'MESH:D003643', (35, 40))	('disomy 3/gene-expression', 'Disease', (56, 80))	('death', 'Disease', (35, 40))	('PRAME', 'Gene', '23532', (120, 125))	('mutation', 'Var', (135, 143))	('PRAME', 'Gene', (120, 125))
87347	32186672	Recently, PRAME overexpression has been shown to be associated with metastatic risk in class 1 tumors, and the SF3B1 mutation is similarly associated with the development of metastases in disomy 3 tumors.	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('metastases in disomy 3 tumors', 'Disease', 'MESH:D009362', (174, 203))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('metastases in disomy 3 tumors', 'Disease', (174, 203))	('tumors', 'Disease', (95, 101))	('metastatic', 'CPA', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('SF3B1', 'Gene', (111, 116))	('tumors', 'Disease', (197, 203))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('associated', 'Reg', (52, 62))	('men', 'Species', '9606', (166, 169))	('associated', 'Reg', (139, 149))	('PRAME', 'Gene', '23532', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('SF3B1', 'Gene', '23451', (111, 116))	('overexpression', 'PosReg', (16, 30))	('PRAME', 'Gene', (10, 15))	('mutation', 'Var', (117, 125))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
87348	32186672	Interestingly, in a recent study by The Cancer Genome Atlas, SF3B1 mutations in disomy 3 tumors were found to occur in combination with (partial) 8q gain.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('SF3B1', 'Gene', (61, 66))	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Cancer', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('Cancer', 'Disease', 'MESH:D009369', (40, 46))	('mutations', 'Var', (67, 76))	('SF3B1', 'Gene', '23451', (61, 66))	('gain', 'PosReg', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
87350	32186672	We hypothesize that the effect of monosomy 3, which has been shown to be strongly correlated to histopathologic tumor features, on survival was decreased by the presence of anatomic and histologic tumor features that we have evaluated in our model.	('monosomy 3', 'Var', (34, 44))	('decreased', 'NegReg', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (197, 202))
87355	32186672	We believe that the true percentage of tumors having monosomy 3 or gain of 8q may be higher when determined by newer and more sensitive techniques such as SNP-based copy number determination.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('gain', 'PosReg', (67, 71))	('monosomy 3', 'Var', (53, 63))	('tumors', 'Disease', (39, 45))
87365	32185172	Multiple lines of evidence suggest that numerous risk elements, containing genetic and environmental factors, account for cancer initiation and development, among which the involvement of mis-regulation of non-coding RNAs (ncRNAs) in cancer has aroused extensive attention during the past few decades.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('mis-regulation', 'Var', (188, 202))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer initiation', 'Disease', 'MESH:D009369', (122, 139))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('ncRNA', 'Gene', (223, 228))	('cancer initiation', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('regulation', 'biological_process', 'GO:0065007', ('192', '202'))	('cancer', 'Disease', (234, 240))	('account', 'Reg', (110, 117))	('ncRNA', 'Gene', '220202', (223, 228))
87375	32185172	lncRNAs are divided into several categories according to genomic organization and relation to coding genes, such as long intergenic non-coding RNAs, antisense RNAs, sense overlapping RNAs, sense intronic RNAs, enhancer RNAs as well as pseudogene-expressed lncRNAs.	('ncRNA', 'Gene', '220202', (257, 262))	('sense overlapping RNAs', 'Var', (165, 187))	('antisense', 'Var', (149, 158))	('ncRNA', 'Gene', '220202', (1, 6))	('ncRNA', 'Gene', (257, 262))	('sense intronic RNAs', 'Var', (189, 208))	('ncRNA', 'Gene', (1, 6))
87380	32185172	Dysregulation of lncRNAs, pseudogenes and circRNAs leads to alteration of abundance of miRNAs, thus affecting their inhibition of downstream target expression.	('Dysregulation', 'Var', (0, 13))	('abundance', 'MPA', (74, 83))	('alteration', 'Reg', (60, 70))	('downstream target expression', 'MPA', (130, 158))	('affecting', 'Reg', (100, 109))	('ncRNA', 'Gene', (18, 23))	('miRNAs', 'Protein', (87, 93))	('ncRNA', 'Gene', '220202', (18, 23))	('inhibition', 'MPA', (116, 126))
87382	32185172	Based on ceRNA mechanism, researchers and scholars have discovered a variety of potential cancer-associated pseudogenes using in silico analysis.	('pseudogenes', 'Var', (108, 119))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))
87387	32185172	Dysregulation of pseudogenes and their transcripts has been implicated into initiation and/or progression of human disorders, including cancer.	('human', 'Species', '9606', (109, 114))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('implicated', 'Reg', (60, 70))	('cancer', 'Disease', (136, 142))	('pseudogenes', 'Protein', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
87388	32185172	Among pseudogene-derived lncRNAs, some act as tumor promotors, facilitating cancer development, whereas the other function as tumor suppressors, inhibiting cancer progression.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('ncRNA', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('ncRNA', 'Gene', '220202', (26, 31))	('inhibiting', 'NegReg', (145, 155))	('facilitating', 'PosReg', (63, 75))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('pseudogene-derived', 'Var', (6, 24))	('tumor', 'Disease', (126, 131))
87402	32185172	Dysregulation of pseudogenes and their transcripts accounts for the development of chemo-resistance and radio-resistance of HCC which greatly reduces the efficacy of chemotherapy and radiotherapy.	('HCC', 'Phenotype', 'HP:0001402', (124, 127))	('Dysregulation', 'Var', (0, 13))	('reduces', 'NegReg', (142, 149))	('HCC', 'Disease', 'MESH:D006528', (124, 127))	('pseudogenes', 'Protein', (17, 28))	('HCC', 'Disease', (124, 127))
87403	32185172	For example, suggested that PDIAP3 caused doxorubicin resistance of HCC by targeting miR-125/124-TRAF6/NF-KB signaling; found that knockdown of SUMO1P3 markedly enhanced radio-sensitivity in HCC.	('HCC', 'Disease', 'MESH:D006528', (191, 194))	('enhanced', 'PosReg', (161, 169))	('knockdown', 'Var', (131, 140))	('HCC', 'Disease', (191, 194))	('SUMO1P3', 'Gene', '474338', (144, 151))	('doxorubicin', 'MPA', (42, 53))	('HCC', 'Phenotype', 'HP:0001402', (191, 194))	('signaling', 'biological_process', 'GO:0023052', ('109', '118'))	('TRAF6', 'Gene', (97, 102))	('TRAF6', 'Gene', '7189', (97, 102))	('HCC', 'Disease', 'MESH:D006528', (68, 71))	('HCC', 'Disease', (68, 71))	('SUMO1P3', 'Gene', (144, 151))	('doxorubicin', 'Chemical', 'MESH:D004317', (42, 53))	('HCC', 'Phenotype', 'HP:0001402', (68, 71))	('radio-sensitivity', 'MPA', (170, 187))
87413	32185172	NANOGP8 expression was significantly elevated in gastric cancer and knockdown of NANOGP8 resulted in decreased proliferation and promoted apoptosis of gastric cancer cells.	('elevated', 'PosReg', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('NANOGP8', 'Gene', (81, 88))	('gastric cancer', 'Disease', (151, 165))	('NANOGP8', 'Gene', '388112', (81, 88))	('gastric cancer', 'Disease', 'MESH:D013274', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('knockdown', 'Var', (68, 77))	('apoptosis', 'CPA', (138, 147))	('expression', 'MPA', (8, 18))	('gastric cancer', 'Disease', 'MESH:D013274', (151, 165))	('NANOGP8', 'Gene', (0, 7))	('NANOGP8', 'Gene', '388112', (0, 7))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('decreased', 'NegReg', (101, 110))	('promoted', 'PosReg', (129, 137))	('gastric cancer', 'Phenotype', 'HP:0012126', (151, 165))	('apoptosis', 'biological_process', 'GO:0097194', ('138', '147'))	('apoptosis', 'biological_process', 'GO:0006915', ('138', '147'))	('gastric cancer', 'Disease', (49, 63))
87416	32185172	Overexpression of DUXAP8 promoted cell proliferation and migration of gastric cancer by epigenetically inhibiting PLEKHO1 expression.	('gastric cancer', 'Disease', 'MESH:D013274', (70, 84))	('expression', 'MPA', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('PLEKHO1', 'Gene', '51177', (114, 121))	('cell proliferation', 'CPA', (34, 52))	('epigenetically', 'Var', (88, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (70, 84))	('DUXAP8', 'Gene', (18, 24))	('migration', 'CPA', (57, 66))	('DUXAP8', 'Gene', '503637', (18, 24))	('promoted', 'PosReg', (25, 33))	('PLEKHO1', 'Gene', (114, 121))	('cell proliferation', 'biological_process', 'GO:0008283', ('34', '52'))	('gastric cancer', 'Disease', (70, 84))
87421	32185172	High expression PTTG3P linked to large tumor size, increased tumor invasiveness and served as an unfavorable prognostic biomarker.	('High expression', 'Var', (0, 15))	('increased', 'PosReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('PTTG3P', 'Gene', '26255', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor invasiveness', 'Disease', (61, 79))	('tumor invasiveness', 'Disease', 'MESH:D009361', (61, 79))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (39, 44))	('PTTG3P', 'Gene', (16, 22))	('tumor', 'Disease', (61, 66))
87422	32185172	Besides, the abilities of gastric cancer proliferation and invasion were enhanced after ectopic expression of PTTG3P.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('ectopic expression', 'Var', (88, 106))	('PTTG3P', 'Gene', '26255', (110, 116))	('gastric cancer proliferation', 'Disease', (26, 54))	('gastric cancer proliferation', 'Disease', 'MESH:D013274', (26, 54))	('PTTG3P', 'Gene', (110, 116))	('enhanced', 'PosReg', (73, 81))	('invasion', 'CPA', (59, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (26, 40))
87427	32185172	High SUMO1P3 level was reported to be associated with advanced histological stages, metastasis, angiogenesis and poor prognosis of colon cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('colon cancer', 'Disease', 'MESH:D015179', (131, 143))	('associated', 'Reg', (38, 48))	('High', 'Var', (0, 4))	('angiogenesis', 'biological_process', 'GO:0001525', ('96', '108'))	('SUMO1P3', 'Gene', (5, 12))	('colon cancer', 'Disease', (131, 143))	('metastasis', 'CPA', (84, 94))	('patients', 'Species', '9606', (144, 152))	('angiogenesis', 'CPA', (96, 108))	('colon cancer', 'Phenotype', 'HP:0003003', (131, 143))	('SUMO1P3', 'Gene', '474338', (5, 12))
87428	32185172	Inhibition of SUMO1P3 repressed proliferation, migration, invasion and pro-angiogenesis of colon cancer cells in vitro, and reduced growth, liver metastasis and vascularization of colon cancer in vivo by decreasing cyclin D1, vimentin and VEGFA but increasing E-cadherin expression.	('vimentin', 'Gene', (226, 234))	('colon cancer', 'Disease', 'MESH:D015179', (91, 103))	('E-cadherin', 'Gene', (260, 270))	('VEGFA', 'Gene', (239, 244))	('migration', 'CPA', (47, 56))	('E-cadherin', 'Gene', '999', (260, 270))	('angiogenesis', 'biological_process', 'GO:0001525', ('75', '87'))	('vascularization', 'CPA', (161, 176))	('cyclin', 'molecular_function', 'GO:0016538', ('215', '221'))	('colon cancer', 'Disease', (180, 192))	('liver metastasis', 'Disease', (140, 156))	('expression', 'MPA', (271, 281))	('colon cancer', 'Disease', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cyclin D1', 'Gene', (215, 224))	('invasion', 'CPA', (58, 66))	('vimentin', 'cellular_component', 'GO:0045099', ('226', '234'))	('cadherin', 'molecular_function', 'GO:0008014', ('262', '270'))	('SUMO1P3', 'Gene', (14, 21))	('VEGFA', 'Gene', '7422', (239, 244))	('SUMO1P3', 'Gene', '474338', (14, 21))	('cyclin D1', 'Gene', '595', (215, 224))	('Inhibition', 'Var', (0, 10))	('colon cancer', 'Phenotype', 'HP:0003003', (180, 192))	('colon cancer', 'Phenotype', 'HP:0003003', (91, 103))	('pro-angiogenesis', 'CPA', (71, 87))	('vimentin', 'cellular_component', 'GO:0045098', ('226', '234'))	('reduced', 'NegReg', (124, 131))	('increasing', 'PosReg', (249, 259))	('liver metastasis', 'Disease', 'MESH:D009362', (140, 156))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('growth', 'CPA', (132, 138))	('vimentin', 'Gene', '7431', (226, 234))	('decreasing', 'NegReg', (204, 214))	('colon cancer', 'Disease', 'MESH:D015179', (180, 192))
87431	32185172	The authors also indicated that silencing expression of TPTE2P1 resulted in cell cycle arrest at S phase and caused cell apoptosis in colorectal cancer.	('cell cycle arrest at S phase', 'CPA', (76, 104))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (76, 93))	('colorectal cancer', 'Disease', (134, 151))	('cell apoptosis', 'CPA', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('S phase', 'biological_process', 'GO:0051320', ('97', '104'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('76', '93'))	('silencing', 'Var', (32, 41))	('TPTE2P1', 'Gene', (56, 63))	('caused', 'Reg', (109, 115))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('apoptosis', 'biological_process', 'GO:0097194', ('121', '130'))	('TPTE2P1', 'Gene', '646405', (56, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))	('apoptosis', 'biological_process', 'GO:0006915', ('121', '130'))
87433	32185172	DUXAP8 was remarkably overexpressed in colorectal cancer and DUXAP8 knockdown led to inhibited proliferation, migration and invasion and enhanced apoptosis.	('enhanced', 'PosReg', (137, 145))	('DUXAP8', 'Gene', (0, 6))	('inhibited', 'NegReg', (85, 94))	('DUXAP8', 'Gene', '503637', (0, 6))	('colorectal cancer', 'Disease', 'MESH:D015179', (39, 56))	('apoptosis', 'biological_process', 'GO:0097194', ('146', '155'))	('knockdown', 'Var', (68, 77))	('apoptosis', 'biological_process', 'GO:0006915', ('146', '155'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (39, 56))	('DUXAP8', 'Gene', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('invasion', 'CPA', (124, 132))	('apoptosis', 'CPA', (146, 155))	('DUXAP8', 'Gene', '503637', (61, 67))	('colorectal cancer', 'Disease', (39, 56))
87435	32185172	DUXAP10 promoted cell proliferation and cell cycle progression and blocked cell apoptosis by epigenetically silencing expression of p21 and PTEN.	('cell apoptosis', 'CPA', (75, 89))	('blocked', 'NegReg', (67, 74))	('cell proliferation', 'CPA', (17, 35))	('p21', 'Gene', '1026', (132, 135))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('DUXAP10', 'Gene', (0, 7))	('p21', 'Gene', (132, 135))	('cell cycle', 'biological_process', 'GO:0007049', ('40', '50'))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('cell proliferation', 'biological_process', 'GO:0008283', ('17', '35'))	('epigenetically silencing', 'Var', (93, 117))	('DUXAP10', 'Gene', '503639', (0, 7))	('cell cycle progression', 'CPA', (40, 62))	('PTEN', 'Gene', (140, 144))	('promoted', 'PosReg', (8, 16))	('PTEN', 'Gene', '5728', (140, 144))
87439	32185172	reported that DUXAP8, upregulated in non-small cell lung cancer and an unfavorable prognostic biomarker, significantly facilitated cell growth, migration and invasion, and impaired apoptosis both in vitro and in vivo by epigenetically silencing EGR1 and RHOB.	('upregulated', 'PosReg', (22, 33))	('cell growth', 'CPA', (131, 142))	('epigenetically silencing', 'Var', (220, 244))	('EGR1', 'Gene', (245, 249))	('apoptosis', 'CPA', (181, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('EGR1', 'Gene', '1958', (245, 249))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (37, 63))	('impaired', 'NegReg', (172, 180))	('DUXAP8', 'Gene', (14, 20))	('DUXAP8', 'Gene', '503637', (14, 20))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (41, 63))	('RHOB', 'Gene', '388', (254, 258))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (37, 63))	('RHOB', 'Gene', (254, 258))	('facilitated', 'PosReg', (119, 130))	('apoptosis', 'biological_process', 'GO:0097194', ('181', '190'))	('cell growth', 'biological_process', 'GO:0016049', ('131', '142'))	('apoptosis', 'biological_process', 'GO:0006915', ('181', '190'))	('non-small cell lung cancer', 'Disease', (37, 63))	('invasion', 'CPA', (158, 166))	('migration', 'CPA', (144, 153))
87441	32185172	Functional and mechanistic experiments suggested that DUXAP10 exerted oncogenic roles in non-small cell lung cancer by binding to LSD1 and epigenetic silencing expression of LATS2 and RRAD.	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (93, 115))	('DUXAP10', 'Gene', (54, 61))	('RRAD', 'Gene', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('RRAD', 'Gene', '6236', (184, 188))	('DUXAP10', 'Gene', '503639', (54, 61))	('LATS2', 'Gene', (174, 179))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (89, 115))	('LATS2', 'Gene', '26524', (174, 179))	('LSD1', 'Gene', '23028', (130, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('non-small cell lung cancer', 'Disease', (89, 115))	('epigenetic silencing', 'Var', (139, 159))	('LSD1', 'Gene', (130, 134))	('binding', 'Interaction', (119, 126))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (89, 115))
87448	32185172	also experimentally confirmed that knockdown of OGFRP1 suppressed the malignant behaviors of endometrial cancer, including suppressed cell viability, enhanced cell apoptosis and inhibited cell migration and invasion.	('knockdown', 'Var', (35, 44))	('OGFRP1', 'Gene', (48, 54))	('enhanced', 'PosReg', (150, 158))	('malignant behaviors of endometrial cancer', 'Disease', (70, 111))	('suppressed', 'NegReg', (123, 133))	('cell viability', 'CPA', (134, 148))	('endometrial cancer', 'Phenotype', 'HP:0012114', (93, 111))	('cell migration', 'biological_process', 'GO:0016477', ('188', '202'))	('inhibited', 'NegReg', (178, 187))	('OGFRP1', 'Gene', '388906', (48, 54))	('suppressed', 'NegReg', (55, 65))	('malignant behaviors of endometrial cancer', 'Disease', 'MESH:D016889', (70, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('apoptosis', 'biological_process', 'GO:0006915', ('164', '173'))	('apoptosis', 'biological_process', 'GO:0097194', ('164', '173'))	('cell apoptosis', 'CPA', (159, 173))
87453	32185172	demonstrated that FTH1P3 was notably upregulated in esophageal squamous cell carcinoma and knockdown of FTH1P3 significantly inhibited proliferation, migration and invasion of esophageal squamous cell carcinoma cells by regulating SP1/NF-kB signaling.	('proliferation', 'CPA', (135, 148))	('invasion', 'CPA', (164, 172))	('esophageal squamous cell carcinoma', 'Disease', (176, 210))	('migration', 'CPA', (150, 159))	('signaling', 'biological_process', 'GO:0023052', ('241', '250'))	('upregulated', 'PosReg', (37, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('knockdown', 'Var', (91, 100))	('regulating', 'Reg', (220, 230))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (52, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (187, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (176, 210))	('SP1/NF-kB signaling', 'MPA', (231, 250))	('FTH1P3', 'Gene', (104, 110))	('FTH1P3', 'Gene', (18, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('FTH1P3', 'Gene', '2498', (104, 110))	('FTH1P3', 'Gene', '2498', (18, 24))	('esophageal squamous cell carcinoma', 'Disease', (52, 86))	('inhibited', 'NegReg', (125, 134))
87455	32185172	They also showed that DUXAP10 was positively correlated with poor prognosis and epigenetically silenced p21 by recruiting EZH2 to the promoter of p21, thereby promoting cell proliferation and metastasis.	('EZH2', 'Gene', (122, 126))	('p21', 'Gene', '1026', (104, 107))	('EZH2', 'Gene', '2146', (122, 126))	('cell proliferation', 'biological_process', 'GO:0008283', ('169', '187'))	('p21', 'Gene', '1026', (146, 149))	('promoting', 'PosReg', (159, 168))	('p21', 'Gene', (104, 107))	('p21', 'Gene', (146, 149))	('DUXAP10', 'Gene', '503639', (22, 29))	('recruiting', 'PosReg', (111, 121))	('cell proliferation', 'CPA', (169, 187))	('metastasis', 'CPA', (192, 202))	('epigenetically silenced', 'Var', (80, 103))	('DUXAP10', 'Gene', (22, 29))
87463	32185172	By epigenetically silencing CDKN1A an KLF2, DUXAP8, upregulated in pancreatic cancer, promoted growth of pancreatic cancer.	('KLF2', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (105, 122))	('growth', 'MPA', (95, 101))	('epigenetically silencing', 'Var', (3, 27))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (67, 84))	('DUXAP8', 'Gene', '503637', (44, 50))	('pancreatic cancer', 'Disease', (105, 122))	('CDKN1A', 'Gene', (28, 34))	('DUXAP8', 'Gene', (44, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (105, 122))	('pancreatic cancer', 'Disease', 'MESH:D010190', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('pancreatic cancer', 'Disease', (67, 84))	('CDKN1A', 'Gene', '1026', (28, 34))	('upregulated', 'PosReg', (52, 63))	('promoted', 'PosReg', (86, 94))	('KLF2', 'Gene', '10365', (38, 42))
87465	32185172	They also confirmed that knockdown of DUXAP10 could result in inhibited proliferation, migration, invasion and enhanced apoptosis in renal cell carcinoma through interacting with RNA-binding proteins, EZH2 and LSD1.	('migration', 'CPA', (87, 96))	('proliferation', 'CPA', (72, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('RNA-binding', 'molecular_function', 'GO:0003723', ('179', '190'))	('invasion', 'CPA', (98, 106))	('enhanced', 'PosReg', (111, 119))	('LSD1', 'Gene', (210, 214))	('LSD1', 'Gene', '23028', (210, 214))	('RNA-binding proteins', 'Protein', (179, 199))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (133, 153))	('apoptosis', 'biological_process', 'GO:0097194', ('120', '129'))	('apoptosis', 'biological_process', 'GO:0006915', ('120', '129'))	('DUXAP10', 'Gene', '503639', (38, 45))	('knockdown', 'Var', (25, 34))	('apoptosis', 'CPA', (120, 129))	('renal cell carcinoma', 'Disease', (133, 153))	('DUXAP10', 'Gene', (38, 45))	('EZH2', 'Gene', '2146', (201, 205))	('inhibited', 'NegReg', (62, 71))	('RNA', 'cellular_component', 'GO:0005562', ('179', '182'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (133, 153))	('EZH2', 'Gene', (201, 205))	('interacting', 'Interaction', (162, 173))
87468	32185172	Furthermore, after knockdown of SUMO1P3, bladder cancer exhibited cell proliferation and migration inhibition and apoptosis induction.	('SUMO1P3', 'Gene', (32, 39))	('knockdown', 'Var', (19, 28))	('cell proliferation', 'CPA', (66, 84))	('migration inhibition', 'CPA', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('bladder cancer', 'Phenotype', 'HP:0009725', (41, 55))	('SUMO1P3', 'Gene', '474338', (32, 39))	('apoptosis induction', 'CPA', (114, 133))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('apoptosis', 'biological_process', 'GO:0097194', ('114', '123'))	('apoptosis', 'biological_process', 'GO:0006915', ('114', '123'))	('bladder cancer', 'Disease', 'MESH:D001749', (41, 55))	('bladder cancer', 'Disease', (41, 55))
87474	32185172	Two pseudogene-derived lncRNAs, TPTE2P1 and Loc344887, have been documented to play oncogenic roles in development of gallbladder cancer.	('TPTE2P1', 'Gene', '646405', (32, 39))	('bladder cancer', 'Phenotype', 'HP:0009725', (122, 136))	('gallbladder cancer', 'Disease', (118, 136))	('gallbladder cancer', 'Disease', 'MESH:D005706', (118, 136))	('ncRNA', 'Gene', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Loc344887', 'Var', (44, 53))	('TPTE2P1', 'Gene', (32, 39))	('ncRNA', 'Gene', '220202', (24, 29))	('play', 'Reg', (79, 83))
87475	32185172	Depletion of TPTE2P1 significantly blocked epithelial-mesenchymal transition, migration and invasion of gallbladder cancer.	('epithelial-mesenchymal transition', 'CPA', (43, 76))	('TPTE2P1', 'Gene', (13, 20))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('43', '76'))	('invasion of gallbladder cancer', 'Disease', 'MESH:D005706', (92, 122))	('Depletion', 'Var', (0, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('TPTE2P1', 'Gene', '646405', (13, 20))	('migration', 'CPA', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('blocked', 'NegReg', (35, 42))	('invasion of gallbladder cancer', 'Disease', (92, 122))
87476	32185172	Loc344887 was elevated in gallbladder cancer, was positively associated with larger tumor size, and facilitated cell proliferation, cell cycle progression, migration and invasion.	('cell proliferation', 'CPA', (112, 130))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cell cycle', 'biological_process', 'GO:0007049', ('132', '142'))	('facilitated', 'PosReg', (100, 111))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('migration', 'CPA', (156, 165))	('tumor', 'Disease', (84, 89))	('gallbladder cancer', 'Disease', (26, 44))	('gallbladder cancer', 'Disease', 'MESH:D005706', (26, 44))	('cell cycle progression', 'CPA', (132, 154))	('cell proliferation', 'biological_process', 'GO:0008283', ('112', '130'))	('Loc344887', 'Var', (0, 9))	('associated', 'Reg', (61, 71))	('invasion', 'CPA', (170, 178))	('bladder cancer', 'Phenotype', 'HP:0009725', (30, 44))	('elevated', 'Reg', (14, 22))
87478	32185172	confirmed FTH1P3 was significantly upregulated in laryngeal squamous cell cancer and positively linked to the poor differentiation, high T classification, positive lymph node metastasis and advanced clinical stage.	('poor differentiation', 'CPA', (110, 130))	('FTH1P3', 'Gene', '2498', (10, 16))	('linked', 'Reg', (96, 102))	('laryngeal squamous cell cancer', 'Disease', 'MESH:D018307', (50, 80))	('positive lymph node metastasis', 'CPA', (155, 185))	('laryngeal squamous cell cancer', 'Disease', (50, 80))	('upregulated', 'PosReg', (35, 46))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (60, 80))	('high', 'Var', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('FTH1P3', 'Gene', (10, 16))
87496	32185172	Apart from PTENP1, some pseudogene-derived lncRNAs were also demonstrated to be downregulated in gastric cancer and play tumor suppressive roles in gastric cancer progression.	('gastric cancer', 'Disease', (97, 111))	('gastric cancer', 'Disease', (148, 162))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('gastric cancer', 'Disease', 'MESH:D013274', (148, 162))	('ncRNA', 'Gene', (44, 49))	('tumor', 'Disease', (121, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (148, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('downregulated', 'NegReg', (80, 93))	('PTENP1', 'Gene', (11, 17))	('ncRNA', 'Gene', '220202', (44, 49))	('PTENP1', 'Gene', '11191', (11, 17))	('pseudogene-derived', 'Var', (24, 42))
87507	32185172	The investigation performed by the group of Johnson G demonstrated that silencing of NMRAL2P could protect against sulforaphane-mediated inhibition of cell growth, colony formation and migration in colon cancer.	('sulforaphane-mediated inhibition', 'MPA', (115, 147))	('silencing', 'Var', (72, 81))	('colon cancer', 'Phenotype', 'HP:0003003', (198, 210))	('colon cancer', 'Disease', 'MESH:D015179', (198, 210))	('formation', 'biological_process', 'GO:0009058', ('171', '180'))	('inhibition of cell growth', 'biological_process', 'GO:0030308', ('137', '162'))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('NMRAL2P', 'Gene', (85, 92))	('sulforaphane', 'Chemical', 'MESH:C016766', (115, 127))	('colon cancer', 'Disease', (198, 210))	('NMRAL2P', 'Gene', '344887', (85, 92))	('colony formation', 'CPA', (164, 180))	('cell growth', 'CPA', (151, 162))	('migration', 'CPA', (185, 194))
87517	32185172	Subsequently, they also validated that HERC2P2 overexpression attenuated migration and colony formation abilities of glioma in vitro and inhibited glioma xenograft growth in vivo.	('formation', 'biological_process', 'GO:0009058', ('94', '103'))	('attenuated', 'NegReg', (62, 72))	('inhibited', 'NegReg', (137, 146))	('overexpression', 'Var', (47, 61))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('HERC2P2', 'Gene', (39, 46))	('HERC2P2', 'Gene', '400322', (39, 46))	('glioma', 'Disease', (147, 153))	('glioma', 'Disease', (117, 123))
87528	32185172	Over the past decades, pseudogenes have been documented to play crucial roles in diverse cancer types in DNA, RNA and protein levels.	('pseudogenes', 'Var', (23, 34))	('DNA', 'MPA', (105, 108))	('protein levels', 'MPA', (118, 132))	('RNA', 'cellular_component', 'GO:0005562', ('110', '113'))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('roles', 'Reg', (72, 77))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
87541	32185172	also suggested a FTH1 gene: pseudogene: microRNA modulated tumorigenesis in prostate cancer.	('modulated', 'Reg', (49, 58))	('tumor', 'Disease', (59, 64))	('microRNA', 'Var', (40, 48))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('FTH1', 'Gene', (17, 21))	('FTH1', 'Gene', '2495', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('prostate cancer', 'Disease', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
87544	32185172	confirmed that FLT1P1 antisense transcript suppressed VEGFA by interaction with miR-520a and inhibited tumor cell proliferation and xenograft tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('VEGFA', 'Gene', '7422', (54, 59))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (103, 108))	('interaction', 'Interaction', (63, 74))	('miR-520a', 'Gene', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('antisense', 'Var', (22, 31))	('miR-520a', 'Gene', '574467', (80, 88))	('cell proliferation', 'biological_process', 'GO:0008283', ('109', '127'))	('FLT1P1', 'Gene', (15, 21))	('VEGFA', 'Gene', (54, 59))	('FLT1P1', 'Gene', '391533', (15, 21))	('inhibited', 'NegReg', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('suppressed', 'NegReg', (43, 53))
87550	32185172	for the first time, reported HMGA1 pseudogenes as candidate proto-oncogenic ceRNAs, including HMGA1P6 and HMGA1P7.	('HMGA1', 'Gene', (29, 34))	('HMGA1', 'Gene', '3159', (29, 34))	('HMGA1P7', 'Gene', (106, 113))	('HMGA1', 'Gene', (106, 111))	('HMGA1P6', 'Gene', '100130029', (94, 101))	('HMGA1P6', 'Gene', (94, 101))	('HMGA1P7', 'Gene', '387065', (106, 113))	('HMGA1', 'Gene', '3159', (106, 111))	('pseudogenes', 'Var', (35, 46))	('HMGA1', 'Gene', (94, 99))	('HMGA1', 'Gene', '3159', (94, 99))
87551	32185172	HMGA1P7 was found to increase H19 and lgf2 expression by acting as decoy for miR-15, miR-16, miR-214, and miR-761.	('H19', 'Gene', (30, 33))	('miR-16', 'Gene', '51573', (85, 91))	('miR-214', 'Gene', (93, 100))	('HMGA1P7', 'Gene', '387065', (0, 7))	('miR-15', 'Var', (77, 83))	('HMGA1P7', 'Gene', (0, 7))	('miR-214', 'Gene', '406996', (93, 100))	('lgf2', 'Gene', (38, 42))	('miR-761', 'Gene', (106, 113))	('increase', 'PosReg', (21, 29))	('H19', 'Gene', '283120', (30, 33))	('miR-761', 'Gene', '100313892', (106, 113))	('expression', 'MPA', (43, 53))	('miR-16', 'Gene', (85, 91))
87555	32185172	OCT4-pg5 also upregulated OCT4 by sponging miR-145 and thus facilitated cell proliferation of endometrial carcinoma.	('sponging', 'Var', (34, 42))	('OCT4-pg5', 'Gene', (0, 8))	('OCT4-pg5', 'Gene', '100009667', (0, 8))	('facilitated', 'PosReg', (60, 71))	('cell proliferation', 'biological_process', 'GO:0008283', ('72', '90'))	('miR-145', 'Gene', (43, 50))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (94, 115))	('OCT4', 'Gene', '5460', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('cell proliferation', 'CPA', (72, 90))	('miR-145', 'Gene', '406937', (43, 50))	('endometrial carcinoma', 'Disease', (94, 115))	('upregulated', 'PosReg', (14, 25))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (94, 115))	('OCT4', 'Gene', (26, 30))	('OCT4', 'Gene', '5460', (0, 4))	('OCT4', 'Gene', (0, 4))
87557	32185172	suggested that PTTG3P expression positively associated with PTTG1 expression and may function by sponging miR-129-5p, miR-383-5p, and miR-376c-3p.	('associated', 'Reg', (44, 54))	('miR-376c-3p', 'Var', (134, 145))	('PTTG1', 'Gene', (60, 65))	('miR-383', 'Gene', '494332', (118, 125))	('PTTG1', 'Gene', '9232', (60, 65))	('expression', 'MPA', (66, 76))	('miR-129-5p', 'Gene', '100302178', (106, 116))	('PTTG3P', 'Gene', '26255', (15, 21))	('miR-383', 'Gene', (118, 125))	('miR-129-5p', 'Gene', (106, 116))	('PTTG3P', 'Gene', (15, 21))
87562	32185172	What's more, TUSC2P promotes those functions by binding miR-17, miR-93, miR-299-3p, miR-520a, miR-608, and miR-661 according to the research conducted by.	('miR-93', 'Gene', (64, 70))	('binding', 'molecular_function', 'GO:0005488', ('48', '55'))	('miR-661', 'Gene', (107, 114))	('miR-17', 'Gene', (56, 62))	('promotes', 'PosReg', (20, 28))	('miR-661', 'Gene', '724031', (107, 114))	('miR-17', 'Gene', '406952', (56, 62))	('binding', 'Interaction', (48, 55))	('miR-520a', 'Gene', (84, 92))	('miR-608', 'Gene', (94, 101))	('TUSC2P', 'Gene', (13, 19))	('miR-608', 'Gene', '693193', (94, 101))	('miR-520a', 'Gene', '574467', (84, 92))	('TUSC2P', 'Gene', '359794', (13, 19))	('miR-93', 'Gene', '407051', (64, 70))	('miR-299-3p', 'Var', (72, 82))
87563	32185172	ASS1P3, a pseudogene of ASS1, promoted cell proliferation by functioning as a miRNA decoy for miR-34a-5p in renal cell carcinoma reported by the team of.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (108, 128))	('ASS1', 'Gene', '445', (0, 4))	('ASS1P3', 'Gene', '158452', (0, 6))	('ASS1', 'Gene', '445', (24, 28))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('ASS1P3', 'Gene', (0, 6))	('promoted', 'PosReg', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('cell proliferation', 'CPA', (39, 57))	('ASS1', 'Gene', (24, 28))	('miR-34a-5p', 'Var', (94, 104))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (108, 128))	('ASS1', 'Gene', (0, 4))	('renal cell carcinoma', 'Disease', (108, 128))
87565	32185172	CYP2A7P was discovered to affect expression of its cognate gene CYP2A6 by functioning as a decoy for miR-126 in human liver.	('CYP2A6', 'Gene', '1548', (64, 70))	('affect', 'Reg', (26, 32))	('CYP2A6', 'Gene', (64, 70))	('miR-126', 'Gene', '406913', (101, 108))	('expression', 'MPA', (33, 43))	('human', 'Species', '9606', (112, 117))	('miR-126', 'Gene', (101, 108))	('CYP2A7P', 'Var', (0, 7))
87568	32185172	By luciferase reporter assay, the authors confirmed that FOXO3P exerted its roles through sponging several miRNAs, including miR-22, miR-136*, miR-138, miR-149*, miR-433, miR-762, miR-3614-5p, and miR-3622b-5p.	('miR-149', 'Gene', '406941', (152, 159))	('miR-136', 'Gene', '406927', (133, 140))	('miR-22', 'Gene', '407004', (125, 131))	('FOXO3', 'Gene', (57, 62))	('miR-3614', 'Gene', '100500827', (180, 188))	('miR-22', 'Gene', (125, 131))	('sponging', 'Reg', (90, 98))	('miR-138', 'Var', (143, 150))	('miR-3622b-5p', 'Var', (197, 209))	('miR-433', 'Gene', (162, 169))	('FOXO3', 'Gene', '2309', (57, 62))	('miR-433', 'Gene', '574034', (162, 169))	('miR-762', 'Gene', (171, 178))	('miR-762', 'Gene', '100313837', (171, 178))	('miR-149', 'Gene', (152, 159))	('miR-3614', 'Gene', (180, 188))	('miR-136', 'Gene', (133, 140))
87569	32185172	GBA encodes lysosomal glucocerebrosidase and its mutations are associated with Parkinson's disease.	('glucocerebrosidase', 'Disease', 'MESH:D005776', (22, 40))	("Parkinson's disease", 'Disease', 'MESH:D010300', (79, 98))	('mutations', 'Var', (49, 58))	('GBA', 'Gene', '2629', (0, 3))	('associated', 'Reg', (63, 73))	('GBA', 'Gene', (0, 3))	('glucocerebrosidase', 'Disease', (22, 40))	("Parkinson's disease", 'Disease', (79, 98))
87584	32185172	Furthermore, seven miRNAs binding with RP11-564D11.3 were predicted, including miR-200b-3p, miR-200a-3p, miR-429, miR-101-3p, miR-9-5p, miR-200c-3p, and miR-141-3p.	('miR-429', 'Gene', (105, 112))	('miR-141-3p', 'Var', (153, 163))	('miR-9-5p', 'Gene', (126, 134))	('miR-9-5p', 'Gene', '407052', (126, 134))	('miR-101-3p', 'Var', (114, 124))	('RP11', 'Gene', (39, 43))	('binding', 'molecular_function', 'GO:0005488', ('26', '33'))	('miR-200b-3p', 'Var', (79, 90))	('RP11', 'Gene', '26121', (39, 43))	('binding', 'Interaction', (26, 33))	('miR-200c-3p', 'Var', (136, 147))	('miR-200a-3p', 'Var', (92, 103))	('miR-429', 'Gene', '554210', (105, 112))
87604	32185172	Expression and/or function dysregulation of these RNA transcripts account for the occurrence of multiple human disorders, containing cancer.	('occurrence', 'Reg', (82, 92))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('function', 'MPA', (18, 26))	('cancer', 'Disease', (133, 139))	('dysregulation', 'Var', (27, 40))	('account', 'Reg', (66, 73))	('human', 'Species', '9606', (105, 110))	('RNA', 'cellular_component', 'GO:0005562', ('50', '53'))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
87615	32185172	Of course, the current findings about roles and mechanisms of known pseudogene-derived lncRNAs need to be further precisely validated by basic lab experiments and large clinical trials.	('ncRNA', 'Gene', (88, 93))	('pseudogene-derived', 'Var', (68, 86))	('ncRNA', 'Gene', '220202', (88, 93))
87651	31842516	As expected, point mutations in RAS are not common in breast and prostate cancer.	('breast and prostate cancer', 'Disease', 'MESH:D001943', (54, 80))	('point mutations', 'Var', (13, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('RAS', 'Gene', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
87652	31842516	Interestingly, genetic alterations in HDAC4 are more frequent in uterine and stomach cancers, with a conspicuous incidence of truncations and point mutations of still unknown impact on the activities of this deacetylase (Figure 1).	('activities', 'MPA', (189, 199))	('frequent', 'Reg', (53, 61))	('stomach cancers', 'Disease', 'MESH:D013274', (77, 92))	('stomach cancers', 'Disease', (77, 92))	('truncations', 'MPA', (126, 137))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('genetic alterations', 'Var', (15, 34))	('point mutations', 'Var', (142, 157))	('HDAC4', 'Gene', '9759', (38, 43))	('uterine', 'Disease', (65, 72))	('HDAC4', 'Gene', (38, 43))	('stomach cancers', 'Phenotype', 'HP:0012126', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
87656	31842516	To prove the above enounced concept, we interrogated the gene expression profiles of BJ-hTERT/ST/LT/MYC, BJ-hTERT/ST/LT/HRASG12V, and BJ-hTERT/ST/LT/HDAC4-S246A, S467A, S632A, relatively to the isogenic pre-transformed control cells, expressing the SV40 LT and ST or the entire early region.	('S246A', 'Mutation', 'p.S246A', (155, 160))	('HDAC4', 'Gene', (149, 154))	('MYC', 'Gene', (100, 103))	('HDAC4', 'Gene', '9759', (149, 154))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (134, 142))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (85, 93))	('S632A', 'Var', (169, 174))	('S632A', 'SUBSTITUTION', 'None', (169, 174))	('MYC', 'Gene', '4609', (100, 103))	('gene expression', 'biological_process', 'GO:0010467', ('57', '72'))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (105, 113))	('S467A', 'Var', (162, 167))	('S467A', 'SUBSTITUTION', 'None', (162, 167))	('pre', 'molecular_function', 'GO:0003904', ('203', '206'))
87688	31842516	Finally, SRPX (sushi repeat containing protein X-linked), known also as ETX1 or DRS, was initially isolated as deleted in patients with X-linked retinitis pigmentosa, as well as downregulated by v-src.	('X-linked retinitis pigmentosa', 'Disease', (136, 165))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('retinitis', 'Phenotype', 'HP:0032118', (145, 154))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (145, 165))	('ETX1', 'Gene', '8406', (72, 76))	('sushi repeat containing protein X-linked', 'Gene', '8406', (15, 55))	('SRPX', 'Gene', (9, 13))	('downregulated', 'NegReg', (178, 191))	('DRS', 'Gene', '8406', (80, 83))	('deleted', 'Var', (111, 118))	('patients', 'Species', '9606', (122, 130))	('SRPX', 'Gene', '8406', (9, 13))	('sushi repeat containing protein X-linked', 'Gene', (15, 55))	('DRS', 'Gene', (80, 83))	('ETX1', 'Gene', (72, 76))	('X-linked retinitis pigmentosa', 'Disease', 'MESH:D012174', (136, 165))
87697	31842516	In fact in ACC, which is a rare, aggressive malignancy, G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal disease, amenable to targeted assessment using routine molecular diagnostics.	('aggressive malignancy', 'Disease', 'MESH:D001523', (33, 54))	('ACC', 'Disease', 'MESH:D018268', (11, 14))	('hypermethylation', 'Var', (61, 77))	('G0S2', 'Gene', (56, 60))	('aggressive malignancy', 'Disease', (33, 54))	('ACC', 'Disease', (11, 14))
87698	31842516	Very low levels of G0S2 mRNA expression characterize tumors with G0S2 hypermethylation.	('hypermethylation', 'Var', (70, 86))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mRNA expression', 'MPA', (24, 39))	('G0S2', 'Gene', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', (53, 59))	('G0S2', 'Protein', (19, 23))
87733	31842516	G0S2 is abundantly expressed in adipose tissue and G0S2 transgenic mice experience difficulties in shifting from carbohydrate to FA oxidation during fasting.	('transgenic mice', 'Species', '10090', (56, 71))	('shifting from carbohydrate to FA oxidation', 'MPA', (99, 141))	('G0S2', 'Gene', (51, 55))	('carbohydrate', 'Chemical', 'MESH:D002241', (113, 125))	('transgenic', 'Var', (56, 66))
87741	31842516	The recent discovery that the targeting of MYC through an epigenetic therapy provides an important advantage for an efficient immunotherapy could represent an important clinical perspective of all these studies.	('advantage', 'PosReg', (99, 108))	('MYC', 'Gene', '4609', (43, 46))	('epigenetic therapy', 'Var', (58, 76))	('MYC', 'Gene', (43, 46))
87752	31842516	In each dataset, the transformation model represented by pre-transformed BJ cells expressing RAS G12V (GSE17941) or MYC (GSE72530) or HDAC4 (GSE120040) was compared to the pre-transformation model which is represented by BJ fibroblasts expressing hTERT, LT, and ST SV40 genes.	('G12V', 'Mutation', 'rs104894230', (97, 101))	('BJ', 'CellLine', 'CVCL:6573', (73, 75))	('BJ', 'CellLine', 'CVCL:6573', (221, 223))	('hTERT', 'Gene', (247, 252))	('MYC', 'Gene', '4609', (116, 119))	('HDAC4', 'Gene', '9759', (134, 139))	('pre', 'molecular_function', 'GO:0003904', ('172', '175'))	('GSE120040', 'Var', (141, 150))	('HDAC4', 'Gene', (134, 139))	('pre', 'molecular_function', 'GO:0003904', ('57', '60'))	('hTERT', 'Gene', '7015', (247, 252))	('GSE17941', 'Var', (103, 111))	('GSE72530', 'Var', (121, 129))	('MYC', 'Gene', (116, 119))
87763	31842516	To evaluate the contribution/disturbance of the inflammatory infiltrate to the prediction of survival based on the transformation signatures, patients were divided into four groups accordingly to the expression levels of genes belonging to the MCPcounter signatures and to the transformation signatures: High-high (high levels of both), high-low (high MCP/low transformation), low-low (low levels of both), or low-high (low MCP-high transformation).	('MCP', 'Gene', (352, 355))	('MCP', 'molecular_function', 'GO:0004298', ('424', '427'))	('MCP', 'Gene', (424, 427))	('MCP', 'Gene', '822', (244, 247))	('low-high', 'Var', (410, 418))	('MCP', 'Gene', '822', (352, 355))	('MCP', 'Gene', '822', (424, 427))	('MCP', 'molecular_function', 'GO:0004298', ('352', '355'))	('patients', 'Species', '9606', (142, 150))	('MCP', 'Gene', (244, 247))	('low MCP', 'Phenotype', 'HP:0025066', (420, 427))
87785	31650817	Magnetic resonance imaging (MRI) showed hyperintensity of the medial rectus on T1-weighted imaging and hypointensity on T2-weighted imaging (Figure 2) compatible with melanoma metastases.	('melanoma metastases', 'Disease', (167, 186))	('hyperintensity', 'MPA', (40, 54))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanoma metastases', 'Disease', 'MESH:D009362', (167, 186))	('hypointensity', 'Var', (103, 116))
87789	31650817	Next-generation sequencing identified a somatic mutation in the GNA11 gene.	('GNA11', 'Gene', '2767', (64, 69))	('GNA11', 'Gene', (64, 69))	('mutation', 'Var', (48, 56))
87790	31650817	A sensitizing BRAF mutation was not found in this tumor.	('mutation', 'Var', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('BRAF', 'Gene', '673', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('BRAF', 'Gene', (14, 18))	('tumor', 'Disease', (50, 55))
87850	30932943	Defective FasL expression is associated with increased resistance to melanoma liver metastases and enhanced natural kill cell activity.	('melanoma liver metastases', 'Disease', (69, 94))	('natural kill cell activity', 'CPA', (108, 134))	('increased', 'PosReg', (45, 54))	('FasL', 'Gene', (10, 14))	('enhanced', 'PosReg', (99, 107))	('enhanced natural kill cell activity', 'Phenotype', 'HP:0012178', (99, 134))	('melanoma liver metastases', 'Disease', 'MESH:D009362', (69, 94))	('Defective', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('FasL', 'Gene', '14103', (10, 14))
87851	30932943	The objective was to determine if the absence of FasL signaling would affect melanoma liver metastases by influencing the anti-melanoma properties of liver natural killer (NK) cells.	('influencing', 'Reg', (106, 117))	('affect', 'Reg', (70, 76))	('signaling', 'biological_process', 'GO:0023052', ('54', '63'))	('melanoma liver metastases', 'Disease', 'MESH:D009362', (77, 102))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('absence', 'Var', (38, 45))	('melanoma liver metastases', 'Disease', (77, 102))
87852	30932943	Melanoma liver metastases were induced in wild-type C57BL/6 mice and the gld/gld mutant C57BL/6 mouse strain that expresses a defective form of FasL (CD95L) that fails to engage and signal via the Fas receptor (CD95).	('gld', 'Gene', '14103', (77, 80))	('gld', 'Gene', (77, 80))	('mice', 'Species', '10090', (60, 64))	('Melanoma liver metastases', 'Disease', 'MESH:D009362', (0, 25))	('CD95L', 'Gene', '14103', (150, 155))	('mouse', 'Species', '10090', (96, 101))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('CD95L', 'Gene', (150, 155))	('mutant', 'Var', (81, 87))	('induced', 'Reg', (31, 38))	('gld', 'Gene', '14103', (73, 76))	('gld', 'Gene', (73, 76))	('Melanoma liver metastases', 'Disease', (0, 25))
87855	30932943	Mice expressing defective FasL displayed reduced, rather than enhanced, melanoma liver metastases that coincided with increased liver NK cell-mediated tumor cell cytotoxicity.	('FasL', 'Gene', (26, 30))	('reduced', 'NegReg', (41, 48))	('tumor cell cytotoxicity', 'Disease', (151, 174))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('melanoma liver metastases', 'Disease', (72, 97))	('increased liver', 'Phenotype', 'HP:0002240', (118, 133))	('enhanced', 'PosReg', (62, 70))	('increased', 'PosReg', (118, 127))	('tumor cell cytotoxicity', 'Disease', 'MESH:D064420', (151, 174))	('melanoma liver metastases', 'Disease', 'MESH:D009362', (72, 97))	('Mice', 'Species', '10090', (0, 4))	('defective', 'Var', (16, 25))
87878	30932943	Cells from mice with the gld/gld mutation fail to induce apoptosis of Fas-expressing target cells.	('mutation', 'Var', (33, 41))	('apoptosis', 'biological_process', 'GO:0006915', ('57', '66'))	('gld', 'Gene', (29, 32))	('gld', 'Gene', '14103', (25, 28))	('mice', 'Species', '10090', (11, 15))	('gld', 'Gene', (25, 28))	('apoptosis', 'biological_process', 'GO:0097194', ('57', '66'))	('gld', 'Gene', '14103', (29, 32))
87918	30932943	The purity of a typical liver NK cell preparation used in the in vitro assays was >90% NK1.1+CD3- as determined by flow cytometry (Figure 2J).Moreover, depletion of NK cells with anti-asialo GM1 antiserum eliminated the enhanced resistance to liver metastases in gld/gld mice.	('gld', 'Gene', '14103', (267, 270))	('asialo', 'Chemical', '-', (184, 190))	('enhanced', 'PosReg', (220, 228))	('mice', 'Species', '10090', (271, 275))	('liver metastases', 'Disease', 'MESH:D009362', (243, 259))	('gld', 'Gene', (263, 266))	('NK1.1', 'Gene', '17059', (87, 92))	('gld', 'Gene', (267, 270))	('resistance to', 'CPA', (229, 242))	('CD3', 'Gene', (93, 96))	('GM1', 'Gene', (191, 194))	('NK1.1', 'Gene', (87, 92))	('GM1', 'Gene', '210582', (191, 194))	('CD3', 'Gene', '12503', (93, 96))	('depletion', 'Var', (152, 161))	('liver metastases', 'Disease', (243, 259))	('eliminated', 'NegReg', (205, 215))	('gld', 'Gene', '14103', (263, 266))
87945	30932943	However, the present results indicate that instead of exacerbating melanoma metastases, the absence of functional FasL on liver NK cells was associated with an increased resistance to metastatic disease.	('FasL', 'Protein', (114, 118))	('melanoma metastases', 'Disease', 'MESH:D009362', (67, 86))	('absence', 'Var', (92, 99))	('increased', 'PosReg', (160, 169))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('resistance to metastatic disease', 'CPA', (170, 202))	('exacerbating', 'PosReg', (54, 66))	('melanoma metastases', 'Disease', (67, 86))
87946	30932943	The enhanced resistance to liver metastases in mice expressing defective FasL (i.e., gld/gld mice) was associated with a transient, albeit significant increase in the cytolytic activity of liver NK cells.	('gld', 'Gene', '14103', (89, 92))	('liver metastases', 'Disease', (27, 43))	('gld', 'Gene', '14103', (85, 88))	('enhanced', 'PosReg', (4, 12))	('gld', 'Gene', (85, 88))	('defective', 'Var', (63, 72))	('gld', 'Gene', (89, 92))	('FasL', 'Gene', (73, 77))	('liver metastases', 'Disease', 'MESH:D009362', (27, 43))	('mice', 'Species', '10090', (47, 51))	('mice', 'Species', '10090', (93, 97))	('increase', 'PosReg', (151, 159))	('cytolytic activity', 'MPA', (167, 185))
87970	30932943	Similarly, blockade of Fas signaling in 4T1 mammary breast cancer cells reduced tumor growth and inhibited tumor metastasis in a murine xenograft model.	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('reduced tumor growth', 'Disease', (72, 92))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('Fas', 'Protein', (23, 26))	('murine', 'Species', '10090', (129, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('inhibited', 'NegReg', (97, 106))	('tumor metastasis', 'Disease', 'MESH:D009362', (107, 123))	('blockade', 'Var', (11, 19))	('tumor metastasis', 'Disease', (107, 123))	('reduced tumor growth', 'Disease', 'MESH:D006130', (72, 92))
87972	30932943	There is evidence that blockade of Fas/FasL reduces malignancy by decreasing the recruitment of MDSC.	('blockade', 'Var', (23, 31))	('malignancy', 'Disease', 'MESH:D009369', (52, 62))	('malignancy', 'Disease', (52, 62))	('Fas/FasL', 'Protein', (35, 43))	('decreasing', 'NegReg', (66, 76))	('reduces', 'NegReg', (44, 51))	('recruitment of MDSC', 'MPA', (81, 100))
87974	30932943	An important property of MDSC is their capacity to impair NK cell-mediated cytotoxicity.	('MDSC', 'Var', (25, 29))	('cytotoxicity', 'Disease', (75, 87))	('cytotoxicity', 'Disease', 'MESH:D064420', (75, 87))	('impair', 'NegReg', (51, 57))	('NK cell-mediated cytotoxicity', 'biological_process', 'GO:0042267', ('58', '87'))
87976	30932943	However, our findings indicate that gld/gld mice had same numbers of MDSC as WT mice at all time points examined, which suggests that the presence of MDSC did not affect the expression of the NKG2D activation receptor nor did MDSC impair liver NK cell cytotoxicity.	('presence', 'Var', (138, 146))	('gld', 'Gene', (36, 39))	('gld', 'Gene', (40, 43))	('liver NK cell cytotoxicity', 'Disease', 'MESH:D064420', (238, 264))	('mice', 'Species', '10090', (80, 84))	('liver NK cell cytotoxicity', 'Disease', (238, 264))	('mice', 'Species', '10090', (44, 48))	('gld', 'Gene', '14103', (36, 39))	('impair', 'NegReg', (231, 237))	('gld', 'Gene', '14103', (40, 43))
87978	30932943	The sharp reduction in liver metastases that occurs in mice with defective FasL raises the question as to whether blocking Fas/FasL interactions might have application for the management of liver metastases in UM patients.	('liver metastases', 'Disease', 'MESH:D009362', (23, 39))	('defective', 'Var', (65, 74))	('mice', 'Species', '10090', (55, 59))	('interactions', 'Interaction', (132, 144))	('liver metastases', 'Disease', (190, 206))	('patients', 'Species', '9606', (213, 221))	('reduction', 'NegReg', (10, 19))	('liver metastases', 'Disease', (23, 39))	('liver metastases', 'Disease', 'MESH:D009362', (190, 206))
87980	26842708	Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage Hotspot mutations in the spliceosome gene SF3B1 are reported in ~20% of uveal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanomas', 'Phenotype', 'HP:0002861', (183, 192))	('splicing', 'biological_process', 'GO:0045292', ('53', '61'))	('SF3B1', 'Gene', (147, 152))	('SF3B1', 'Gene', (18, 23))	('spliceosome', 'cellular_component', 'GO:0005681', ('130', '141'))	('mutations', 'Var', (113, 122))	('mutations', 'Var', (24, 33))	('uveal melanomas', 'Disease', 'MESH:C536494', (177, 192))	('SF3B1', 'Gene', '23451', (147, 152))	('SF3B1', 'Gene', '23451', (18, 23))	('affect', 'Reg', (34, 40))	('promoting', 'PosReg', (65, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (177, 191))	('alternative branchpoint usage', 'MPA', (75, 104))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('uveal melanomas', 'Disease', (177, 192))	('uveal melanomas', 'Phenotype', 'HP:0007716', (177, 192))	('alternative splicing', 'MPA', (41, 61))
87986	26842708	Altogether, this study provides a better understanding of the mechanisms underlying splicing alterations induced by mutant SF3B1 in cancer, and reveals a role for alternative branchpoints in disease.	('splicing alterations', 'MPA', (84, 104))	('cancer', 'Disease', (132, 138))	('rat', 'Species', '10116', (97, 100))	('SF3B1', 'Gene', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('splicing', 'biological_process', 'GO:0045292', ('84', '92'))	('SF3B1', 'Gene', '23451', (123, 128))	('mutant', 'Var', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
87987	26842708	Mutations in the splicing factor SF3B1 are found in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('uveal melanoma', 'Disease', (52, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (52, 66))	('splicing', 'biological_process', 'GO:0045292', ('17', '25'))	('SF3B1', 'Gene', '23451', (33, 38))	('found', 'Reg', (43, 48))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('SF3B1', 'Gene', (33, 38))
87988	26842708	use RNA-sequencing data from these cancers and experimental models, and show that mutant SF3B1 promotes alternative branchpoints in a specific gene subset and that the mutant protein gains a new function.	('protein', 'Protein', (175, 182))	('SF3B1', 'Gene', (89, 94))	('mutant', 'Var', (168, 174))	('gains', 'PosReg', (183, 188))	('promotes', 'PosReg', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('function', 'MPA', (195, 203))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('SF3B1', 'Gene', '23451', (89, 94))	('alternative branchpoints in a specific gene subset', 'MPA', (104, 154))	('protein', 'cellular_component', 'GO:0003675', ('175', '182'))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))	('mutant', 'Var', (82, 88))
87989	26842708	Discovery of recurrent missense mutations in splicing factors in cancers revealed the importance of the spliceosome pathway as a direct actor in carcinogenesis and questioned functional roles and molecular mechanisms of these mutations.	('missense mutations', 'Var', (23, 41))	('spliceosome', 'cellular_component', 'GO:0005681', ('104', '115'))	('splicing factors', 'Gene', (45, 61))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('splicing', 'biological_process', 'GO:0045292', ('45', '53'))	('carcinogenesis', 'Disease', 'MESH:D063646', (145, 159))	('spliceosome', 'Pathway', (104, 115))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('carcinogenesis', 'Disease', (145, 159))	('cancers', 'Disease', (65, 72))
87991	26842708	Alterations in SF3B1 were initially discovered in myelodysplastic syndromes (MDSs) and chronic lymphocytic leukemia (CLL), together with other mutations of splicing factors, such as U2AF1, SRSF2 and ZRSR2 (refs).	('U2AF1', 'Gene', '7307', (182, 187))	('CLL', 'Phenotype', 'HP:0005550', (117, 120))	('Alterations', 'Var', (0, 11))	('SRSF2', 'Gene', (189, 194))	('ZRSR2', 'Gene', '8233', (199, 204))	('discovered', 'Reg', (36, 46))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (87, 115))	('U2AF', 'cellular_component', 'GO:0089701', ('182', '186'))	('chronic lymphocytic leukemia', 'Disease', (87, 115))	('MDSs', 'Phenotype', 'HP:0002863', (77, 81))	('SF3B1', 'Gene', (15, 20))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (50, 75))	('splicing', 'biological_process', 'GO:0045292', ('156', '164'))	('myelodysplastic syndromes', 'Disease', (50, 75))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (87, 115))	('MDS', 'Disease', 'MESH:D009190', (77, 80))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('rat', 'Species', '10116', (4, 7))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (50, 75))	('ZRSR2', 'Gene', (199, 204))	('U2AF1', 'Gene', (182, 187))	('SF3B1', 'Gene', '23451', (15, 20))	('MDS', 'Disease', (77, 80))	('SRSF2', 'Gene', '6427', (189, 194))
87992	26842708	It has been shown that SF3B1 is mutated in a significant proportion (~20%) of uveal melanoma (UM), a rare malignant entity deriving from melanocytes from the uveal tract, and in other solid tumours at lesser frequencies.	('solid tumours', 'Disease', 'MESH:D009369', (184, 197))	('UM', 'Phenotype', 'HP:0007716', (94, 96))	('solid tumours', 'Disease', (184, 197))	('SF3B1', 'Gene', '23451', (23, 28))	('mutated', 'Var', (32, 39))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumours', 'Phenotype', 'HP:0002664', (190, 197))	('uveal melanoma', 'Phenotype', 'HP:0007716', (78, 92))	('uveal melanoma', 'Disease', 'MESH:C536494', (78, 92))	('SF3B1', 'Gene', (23, 28))	('uveal melanoma', 'Disease', (78, 92))
87995	26842708	After binding to the 3'ss, U2AF facilitates replacement of SF1 by U2 snRNP at the BP.	('snRNP', 'molecular_function', 'GO:0003734', ('69', '74'))	('SF1', 'Gene', (59, 62))	('binding', 'molecular_function', 'GO:0005488', ('6', '13'))	('U2AF', 'cellular_component', 'GO:0089701', ('27', '31'))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('66', '74'))	('SF1', 'Gene', '7536', (59, 62))	('BP', 'Chemical', '-', (82, 84))	('replacement', 'Var', (44, 55))
87996	26842708	Interaction between U1 and U2 snRNPs then triggers transesterification joining the 5'-end of the intron to the BP, most generally an adenosine located in a loosely defined consensus ~25 nucleotides upstream of the 3'ss.	('triggers', 'Reg', (42, 50))	('BP', 'Chemical', '-', (111, 113))	('Interaction', 'Var', (0, 11))	('transesterification', 'MPA', (51, 70))
87999	26842708	Cancer-associated mutations in SF3B1 are missense mutations with three major hotspots targeting the fifth, sixth and seventh HEAT repeats at codon positions R625, K666 and K700, respectively.	('SF3B1', 'Gene', '23451', (31, 36))	('K700', 'Var', (172, 176))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('K666', 'Var', (163, 167))	('SF3B1', 'Gene', (31, 36))	('Cancer-associated', 'Disease', (0, 17))	('mutations', 'Var', (18, 27))
88000	26842708	Interestingly, K700 mutations are by far the most frequent in haematopoietic malignancies, whereas R625 mutations are prevailing in UM.	('K700 mutations', 'Var', (15, 29))	('frequent', 'Reg', (50, 58))	('malignancies', 'Disease', (77, 89))	('UM', 'Phenotype', 'HP:0007716', (132, 134))	('malignancies', 'Disease', 'MESH:D009369', (77, 89))
88001	26842708	These alterations affect residues that are predicted to be spatially close to one another and therefore might have a similar functional impact.	('affect', 'Reg', (18, 24))	('rat', 'Species', '10116', (10, 13))	('alterations', 'Var', (6, 17))	('residues', 'Protein', (25, 33))
88005	26842708	In the present study, RNA-Seq analysis of 74 primary UMs, mutated or not for SF3B1, confirmed the SF3B1MUT-promoted pattern identified by DeBoever et al., demonstrating the robustness of the deregulated pattern.	('SF3B1', 'Gene', (77, 82))	('RNA', 'cellular_component', 'GO:0005562', ('22', '25'))	('rat', 'Species', '10116', (162, 165))	('SF3B1', 'Gene', '23451', (98, 103))	('SF3B1', 'Gene', '23451', (77, 82))	('UM', 'Phenotype', 'HP:0007716', (53, 55))	('mutated', 'Var', (58, 65))	('SF3B1', 'Gene', (98, 103))
88007	26842708	Our experiments provided evidence that (i) mutant SF3B1 preferentially recognizes alternative BPs upstream of the canonical sites and (ii) the alternative 3'ss used in a SF3B1MUT context are less dependent on U2AF.	('preferentially', 'PosReg', (56, 70))	('SF3B1', 'Gene', '23451', (170, 175))	('SF3B1', 'Gene', (50, 55))	('BP', 'Chemical', '-', (94, 96))	('SF3B1', 'Gene', '23451', (50, 55))	('mutant', 'Var', (43, 49))	('U2AF', 'cellular_component', 'GO:0089701', ('209', '213'))	('BPs', 'Protein', (94, 97))	('SF3B1', 'Gene', (170, 175))
88008	26842708	We propose a model of the SF3B1MUT dysfunctions that sheds new light on the mechanism of splicing dysregulation in cancer.	('SF3B1', 'Gene', (26, 31))	('cancer', 'Disease', (115, 121))	('SF3B1', 'Gene', '23451', (26, 31))	('dysfunctions', 'Var', (35, 47))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('splicing', 'biological_process', 'GO:0045292', ('89', '97'))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
88009	26842708	Following initial finding of recurrent mutations of SF3B1 gene in UM, we set up an independent consecutive series of UM to analyse the effect of SF3B1 hotspot mutations.	('SF3B1', 'Gene', '23451', (145, 150))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('mutations', 'Var', (39, 48))	('SF3B1', 'Gene', (52, 57))	('SF3B1', 'Gene', (145, 150))	('SF3B1', 'Gene', '23451', (52, 57))	('UM', 'Phenotype', 'HP:0007716', (117, 119))
88012	26842708	SF3B1 mutations were found in 16 tumours affecting two hotspots p.R625 and p.K666 (Supplementary Table 1).	('tumours', 'Phenotype', 'HP:0002664', (33, 40))	('SF3B1', 'Gene', (0, 5))	('tumours', 'Disease', 'MESH:D009369', (33, 40))	('tumours', 'Disease', (33, 40))	('SF3B1', 'Gene', '23451', (0, 5))	('p.K666', 'Var', (75, 81))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('found', 'Reg', (21, 26))	('mutations', 'Var', (6, 15))	('p.R625', 'Var', (64, 70))
88014	26842708	The overall mutation rate of 22% (16/74) is comparable to the rate (19%) recently reported for SF3B1 mutations in UM.	('mutations', 'Var', (101, 110))	('SF3B1', 'Gene', (95, 100))	('UM', 'Phenotype', 'HP:0007716', (114, 116))	('SF3B1', 'Gene', '23451', (95, 100))	('rat', 'Species', '10116', (21, 24))	('rat', 'Species', '10116', (62, 65))
88015	26842708	To evaluate the effects of SF3B1 mutations on splicing, we performed transcriptome analysis of the UM cohort using RNA-Seq technique.	('mutations', 'Var', (33, 42))	('SF3B1', 'Gene', (27, 32))	('splicing', 'biological_process', 'GO:0045292', ('46', '54'))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('SF3B1', 'Gene', '23451', (27, 32))	('RNA', 'cellular_component', 'GO:0005562', ('115', '118'))
88020	26842708	Interestingly, 72% (1,060/1,469) of differential splice variants had no Ensembl Transcript identifiers (ENST) and these novel splice variants were found almost exclusively in SF3B1 mutants.	('SF3B1', 'Gene', (175, 180))	('mutants', 'Var', (181, 188))	('SF3B1', 'Gene', '23451', (175, 180))	('found', 'Reg', (147, 152))
88025	26842708	showed that 619 cryptic 3'ss clustering 10-30 nucleotides upstream of canonical 3'ss were used in cancers with SF3B1 mutations.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (117, 126))	('SF3B1', 'Gene', '23451', (111, 116))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('SF3B1', 'Gene', (111, 116))
88033	26842708	Probably due to its low level of SF3B1K666T expression, SF3B1K666T-HEK293T clusters together with HEK293T (WT) and SF3B1WT tumours (Supplementary Fig.	('HEK293T', 'CellLine', 'CVCL:0063', (67, 74))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('HEK293T', 'CellLine', 'CVCL:0063', (98, 105))	('SF3B1K666T-HEK293T', 'Var', (56, 74))	('SF3B1WT tumours', 'Disease', 'MESH:D009369', (115, 130))	('SF3B1WT tumours', 'Disease', (115, 130))	('expression', 'Species', '29278', (44, 54))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
88040	26842708	The mode of action of SF3B1 mutant was then addressed by analysing endogenous DPH5 and ARMC9 transcripts.	('ARMC9', 'Gene', '80210', (87, 92))	('mutant', 'Var', (28, 34))	('ARMC9', 'Gene', (87, 92))	('DPH5', 'Gene', (78, 82))	('SF3B1', 'Gene', '23451', (22, 27))	('DPH5', 'Gene', '51611', (78, 82))	('endogenous', 'MPA', (67, 77))	('SF3B1', 'Gene', (22, 27))
88044	26842708	The overexpression of SF3B1K700E increased by only three-fold the AG'/AG index in SF3B1K666T HEK293T (transcript mutation rate=14%) and did not modify it in Mel202 cell line (transcript mutation rate=30%), which may indicate a saturating effect of SF3B1MUT.	('HEK293T', 'Var', (93, 100))	('SF3B1', 'Gene', (82, 87))	('SF3B1', 'Gene', '23451', (22, 27))	('rat', 'Species', '10116', (231, 234))	('SF3B1', 'Gene', (248, 253))	('SF3B1', 'Gene', '23451', (82, 87))	('expression', 'Species', '29278', (8, 18))	('increased', 'PosReg', (33, 42))	('rat', 'Species', '10116', (122, 125))	('rat', 'Species', '10116', (195, 198))	('SF3B1', 'Gene', '23451', (248, 253))	("AG'/AG index", 'MPA', (66, 78))	('HEK293T', 'CellLine', 'CVCL:0063', (93, 100))	('SF3B1', 'Gene', (22, 27))
88046	26842708	We conclude that SF3B1 mutation does not lead to a hyper-activity of the protein, as its phenotype is not reproduced by SF3B1 overexpression.	('hyper-activity', 'MPA', (51, 65))	('SF3B1', 'Gene', (120, 125))	('mutation', 'Var', (23, 31))	('SF3B1', 'Gene', (17, 22))	('SF3B1', 'Gene', '23451', (120, 125))	('SF3B1', 'Gene', '23451', (17, 22))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('expression', 'Species', '29278', (130, 140))
88047	26842708	To determine whether SF3B1 mutations are loss-of-function mutations, we then assessed the effect of SF3B1 short interfering RNA (siRNA)-mediated knockdown on alternative splicing in SF3B1WT HEK293T and MP41 and in SF3B1MUT Mel202.	('mutations', 'Var', (27, 36))	('MP41', 'Var', (202, 206))	('HEK293T', 'CellLine', 'CVCL:0063', (190, 197))	('SF3B1', 'Gene', '23451', (214, 219))	('HEK293T', 'Var', (190, 197))	('SF3B1', 'Gene', (182, 187))	('SF3B1', 'Gene', (21, 26))	('SF3B1', 'Gene', (100, 105))	('RNA', 'cellular_component', 'GO:0005562', ('124', '127'))	('splicing', 'biological_process', 'GO:0045292', ('170', '178'))	('SF3B1', 'Gene', '23451', (182, 187))	('SF3B1', 'Gene', '23451', (21, 26))	('SF3B1', 'Gene', '23451', (100, 105))	('SF3B1', 'Gene', (214, 219))
88048	26842708	3b, SF3B1 siRNA-mediated knockdown did not have any significant effect on AG'/AG index despite up to 93% of SF3B1 protein level reduction.	('SF3B1', 'Gene', '23451', (108, 113))	('reduction', 'NegReg', (128, 137))	('SF3B1', 'Gene', (4, 9))	("AG'/AG index", 'MPA', (74, 86))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('protein level', 'MPA', (114, 127))	('SF3B1', 'Gene', '23451', (4, 9))	('SF3B1', 'Gene', (108, 113))	('knockdown', 'Var', (25, 34))
88050	26842708	Altogether, our results provide the first evidence that SF3B1 mutants are neither gain- (hyperactive) nor loss-of-function mutants, and suggest change-of-function consequences.	('SF3B1', 'Gene', '23451', (56, 61))	('SF3B1', 'Gene', (56, 61))	('mutants', 'Var', (62, 69))	('loss-of-function', 'NegReg', (106, 122))
88051	26842708	As sensitivity to SF3B1 mutants was conferred by sequences in the close vicinity of 3'ss (Fig.	('sensitivity', 'MPA', (3, 14))	('mutants', 'Var', (24, 31))	('sequences', 'Var', (49, 58))	('SF3B1', 'Gene', (18, 23))	('conferred', 'Reg', (36, 45))	('SF3B1', 'Gene', '23451', (18, 23))
88056	26842708	4c, both U2AF1 and U2AF2 knockdowns increased the AG'/AG index of DPH5 and ARMC9 in SF3B1WT cells, and had no significant effect in SF3B1R625/K666 cells (Fig.	("AG'/AG index", 'MPA', (50, 62))	('DPH5', 'Gene', '51611', (66, 70))	('U2AF2', 'Gene', '11338', (19, 24))	('SF3B1', 'Gene', '23451', (84, 89))	('SF3B1', 'Gene', '23451', (132, 137))	('U2AF1', 'Gene', (9, 14))	('U2AF1', 'Gene', '7307', (9, 14))	('U2AF', 'cellular_component', 'GO:0089701', ('19', '23'))	('U2AF', 'cellular_component', 'GO:0089701', ('9', '13'))	('increased', 'PosReg', (36, 45))	('U2AF2', 'Gene', (19, 24))	('knockdowns', 'Var', (25, 35))	('ARMC9', 'Gene', '80210', (75, 80))	('ARMC9', 'Gene', (75, 80))	('SF3B1', 'Gene', (84, 89))	('DPH5', 'Gene', (66, 70))	('SF3B1', 'Gene', (132, 137))
88057	26842708	One hypothesis to explain why U2AF knockdown partially mimicked the effect of SF3B1MUT was that the SF3B1-U2AF2 interaction might be decreased in the case of mutant SF3B1.	('SF3B1', 'Gene', (78, 83))	('U2AF', 'cellular_component', 'GO:0089701', ('106', '110'))	('SF3B1', 'Gene', (165, 170))	('SF3B1', 'Gene', '23451', (78, 83))	('U2AF2', 'Gene', '11338', (106, 111))	('SF3B1', 'Gene', '23451', (100, 105))	('SF3B1', 'Gene', (100, 105))	('SF3B1', 'Gene', '23451', (165, 170))	('mutant', 'Var', (158, 164))	('U2AF2', 'Gene', (106, 111))	('interaction', 'Interaction', (112, 123))	('U2AF', 'cellular_component', 'GO:0089701', ('30', '34'))	('decreased', 'NegReg', (133, 142))
88059	26842708	Considering that U2AF1 mutations are reported in ~10% of patients with MDS and associated with partial functional impairment in regulated splicing, we tested two MDS samples each harbouring one of the two U2AF1 hotspot mutations, S34F and Q157P.	('MDS', 'Disease', 'MESH:D009190', (162, 165))	('U2AF1', 'Gene', '7307', (205, 210))	('tested', 'Reg', (151, 157))	('S34F', 'Var', (230, 234))	('regulated splicing', 'MPA', (128, 146))	('U2AF', 'cellular_component', 'GO:0089701', ('205', '209'))	('MDS', 'Disease', (162, 165))	('MDS', 'Disease', 'MESH:D009190', (71, 74))	('mutations', 'Var', (23, 32))	('functional impairment', 'Disease', 'MESH:D003072', (103, 124))	('U2AF1', 'Gene', (17, 22))	('functional impairment', 'Disease', (103, 124))	('Q157P', 'Var', (239, 244))	('MDS', 'Disease', (71, 74))	('Q157P', 'Mutation', 'rs371246226', (239, 244))	('U2AF1', 'Gene', '7307', (17, 22))	('splicing', 'biological_process', 'GO:0045292', ('138', '146'))	('patients', 'Species', '9606', (57, 65))	('U2AF1', 'Gene', (205, 210))	('S34F', 'Mutation', 'rs371769427', (230, 234))	('U2AF', 'cellular_component', 'GO:0089701', ('17', '21'))
88060	26842708	Neither of these MDS samples presented any increase of the AG'/AG index of DPH5, demonstrating that U2AF1 and SF3B1 hotspot mutations do not lead to the same aberrant splicing phenotype (Fig.	('U2AF1', 'Gene', (100, 105))	('U2AF1', 'Gene', '7307', (100, 105))	('mutations', 'Var', (124, 133))	('rat', 'Species', '10116', (88, 91))	('DPH5', 'Gene', (75, 79))	('splicing', 'biological_process', 'GO:0045292', ('167', '175'))	('SF3B1', 'Gene', (110, 115))	('DPH5', 'Gene', '51611', (75, 79))	('U2AF', 'cellular_component', 'GO:0089701', ('100', '104'))	('MDS', 'Disease', (17, 20))	('MDS', 'Disease', 'MESH:D009190', (17, 20))	('SF3B1', 'Gene', '23451', (110, 115))
88073	26842708	To explore such hypothesis, we mutated all adenosines within a region of 30 nts preceding the canonical AG in two sensitive sequences, TMEM14C and ENOSF1.	('TMEM14C', 'Gene', (135, 142))	('ENOSF1', 'Gene', '55556', (147, 153))	('adenosines', 'Protein', (43, 53))	('ENOSF1', 'Gene', (147, 153))	('adenosines', 'Chemical', 'MESH:D000241', (43, 53))	('TMEM14C', 'Gene', '51522', (135, 142))	('mutated', 'Var', (31, 38))
88076	26842708	The observed consequences of TMEM14C mutants were the following: (i) the -17A>G_-16A>G-double mutation completely abolished the usage of the alternative AG' in both recipient cell lines; (ii) the -13A>G mutation had no consequence on 3'ss usage; (iii) the -6A>G mutation completely abolished the usage of the canonical AG; (iv) the -2A>G mutation completely abolished the usage of the alternative AG' as it destroyed the AG' site.	('-6A>G', 'Mutation', 'rs200829025', (256, 261))	('-2A>G', 'Mutation', 'c.-2A>G', (332, 337))	('destroyed', 'NegReg', (407, 416))	('TMEM14C', 'Gene', (29, 36))	('-17A>G', 'Mutation', 'rs370559430', (73, 79))	('abolished', 'NegReg', (282, 291))	('-13A>G', 'Mutation', 'c.-13A>G', (196, 202))	('usage', 'MPA', (296, 301))	('abolished', 'NegReg', (358, 367))	('usage', 'MPA', (372, 377))	('mutants', 'Var', (37, 44))	('TMEM14C', 'Gene', '51522', (29, 36))	("AG' site", 'MPA', (421, 429))
88077	26842708	We interpret these data as indicating that the A at 30 nts upstream of AG is the BP' for AG', as its mutation allowed only the use of the canonical AG regardless of SF3B1 status.	('SF3B1', 'Gene', '23451', (165, 170))	('mutation', 'Var', (101, 109))	("BP'", 'Chemical', '-', (81, 84))	('SF3B1', 'Gene', (165, 170))
88082	26842708	The -18A>G mutation disturbed the usage of both AG' and AG, whereas the -17A>G mutation disturbed AG usage and inhibited the usage of AG'.	("usage of AG'", 'MPA', (125, 137))	('-18A>G', 'Mutation', 'rs142476712', (4, 10))	('disturbed', 'Reg', (20, 29))	('AG usage', 'MPA', (98, 106))	('-17A>G', 'Mutation', 'rs370559430', (72, 78))	('usage of', 'MPA', (34, 42))	('disturbed', 'Reg', (88, 97))	('inhibited', 'NegReg', (111, 120))	('the -17A>G', 'Var', (68, 78))
88087	26842708	To determine whether the potential of BP sequences to form base-pairing interaction with U2 snRNA (small nuclear RNAs) can modulate the sensitivity to SF3B1 mutations, BP and BP' mutants of TMEM14C were generated (Supplementary Fig.	('BP', 'Chemical', '-', (38, 40))	('BP', 'Chemical', '-', (175, 177))	('rat', 'Species', '10116', (207, 210))	('TMEM14C', 'Gene', (190, 197))	('modulate', 'Reg', (123, 131))	('mutations', 'Var', (157, 166))	('SF3B1', 'Gene', (151, 156))	("BP'", 'Chemical', '-', (175, 178))	('TMEM14C', 'Gene', '51522', (190, 197))	('base-pairing', 'molecular_function', 'GO:0003676', ('59', '71'))	('SF3B1', 'Gene', '23451', (151, 156))	('BP', 'Chemical', '-', (168, 170))
88092	26842708	Interestingly, swapping the BP and BP' sequences (TMEM14Cswap) decreased AG' usage, which could be interpreted as a higher strength of BP' as compared with BP to form base-pairing interactions with U2 snRNA.	('swapping', 'Var', (15, 23))	("AG' usage", 'MPA', (73, 82))	('TMEM14C', 'Gene', (50, 57))	("BP'", 'Chemical', '-', (135, 138))	('BP', 'Chemical', '-', (35, 37))	('decreased', 'NegReg', (63, 72))	('BP', 'Chemical', '-', (28, 30))	('BP', 'Chemical', '-', (135, 137))	('TMEM14C', 'Gene', '51522', (50, 57))	('BP', 'Chemical', '-', (156, 158))	('base-pairing', 'molecular_function', 'GO:0003676', ('167', '179'))	("BP'", 'Chemical', '-', (35, 38))
88097	26842708	Collectively, in an SF3B1MUT context, the stronger affinity of BP' for U2 snRNA when compared with BP may allow the use BP' with suboptimal AG' (not followed by G, Fig.	('SF3B1', 'Gene', (20, 25))	('BP', 'Chemical', '-', (63, 65))	("BP'", 'Chemical', '-', (120, 123))	('stronger', 'PosReg', (42, 50))	('SF3B1', 'Gene', '23451', (20, 25))	("AG'", 'MPA', (140, 143))	('U2 snRNA', 'Protein', (71, 79))	('BP', 'Chemical', '-', (120, 122))	("BP'", 'Chemical', '-', (63, 66))	("BP'", 'Var', (120, 123))	('BP', 'Chemical', '-', (99, 101))	('affinity', 'Interaction', (51, 59))
88098	26842708	Here, we addressed the consequences of SF3B1 hotspot mutations on splicing in UM and its underlying mechanisms.	('UM', 'Phenotype', 'HP:0007716', (78, 80))	('SF3B1', 'Gene', '23451', (39, 44))	('mutations', 'Var', (53, 62))	('splicing', 'biological_process', 'GO:0045292', ('66', '74'))	('splicing', 'MPA', (66, 74))	('SF3B1', 'Gene', (39, 44))
88099	26842708	First, we observed that SF3B1 hotspot mutations in UM are associated with deregulation of a restricted subset (~0.5%) of splice junctions, mostly caused by the usage of alternative 3'ss (AG') upstream of the canonical 3'ss (AG).	('caused by', 'Reg', (146, 155))	('hotspot', 'PosReg', (30, 37))	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('SF3B1', 'Gene', (24, 29))	('deregulation', 'MPA', (74, 86))	('splice junctions', 'MPA', (121, 137))	('mutations', 'Var', (38, 47))	('SF3B1', 'Gene', '23451', (24, 29))
88102	26842708	Second, we show here that SF3B1MUT pattern was reproduced neither by knockdown nor by overexpressing wild-type SF3B1, indicating that SF3B1 mutants could be qualified as change-of-function mutants.	('SF3B1', 'Gene', (26, 31))	('SF3B1', 'Gene', '23451', (111, 116))	('SF3B1', 'Gene', (134, 139))	('SF3B1', 'Gene', '23451', (26, 31))	('SF3B1', 'Gene', '23451', (134, 139))	('SF3B1', 'Gene', (111, 116))	('mutants', 'Var', (140, 147))
88108	26842708	Strikingly, however, we showed here that mutagenesis of the predicted BP' and the predicted canonical BP abrogated usage of AG' and AG, respectively, confirming the existence of two BPs differentially used according to SF3B1 status.	('BP', 'Chemical', '-', (102, 104))	("usage of AG'", 'MPA', (115, 127))	("BP'", 'Chemical', '-', (70, 73))	('BP', 'Chemical', '-', (70, 72))	('SF3B1', 'Gene', (219, 224))	('abrogated', 'NegReg', (105, 114))	('mutagenesis', 'biological_process', 'GO:0006280', ('41', '52'))	('SF3B1', 'Gene', '23451', (219, 224))	('mutagenesis', 'Var', (41, 52))	('BP', 'Chemical', '-', (182, 184))
88109	26842708	They also showed the consequences of SF3B1 mutations on transcription through the generation of nonsense-mediated mRNA decay-sensitive aberrant spliced transcripts.	('SF3B1', 'Gene', '23451', (37, 42))	('mutations', 'Var', (43, 52))	('consequences', 'Reg', (21, 33))	('transcription', 'MPA', (56, 69))	('transcription', 'biological_process', 'GO:0006351', ('56', '69'))	('SF3B1', 'Gene', (37, 42))	('nonsense-mediated mRNA decay', 'biological_process', 'GO:0000184', ('96', '124'))	('rat', 'Species', '10116', (86, 89))
88112	26842708	Our findings provide the first evidence that misregulation of alternative BPs is involved in physiology or pathology.	('misregulation', 'Var', (45, 58))	('involved', 'Reg', (81, 89))	('BP', 'Chemical', '-', (74, 76))
88116	26842708	Consistently, the hotspot mutations of SF3B1 target the HEAT repeats of SF3B1, which form helical structures that occlude the binding surface for RNA recognition motif of p14, a component of U2 snRNP that binds the BP.	('RNA', 'cellular_component', 'GO:0005562', ('146', '149'))	('p14', 'Gene', (171, 174))	('binding', 'Interaction', (126, 133))	('SF3B1', 'Gene', '23451', (39, 44))	('snRNP', 'molecular_function', 'GO:0003734', ('194', '199'))	('SF3B1', 'Gene', (72, 77))	('mutations', 'Var', (26, 35))	('occlude', 'NegReg', (114, 121))	('p14', 'Gene', '51639', (171, 174))	('RNA recognition motif', 'MPA', (146, 167))	('BP', 'Chemical', '-', (215, 217))	('binding', 'molecular_function', 'GO:0005488', ('126', '133'))	('SF3B1', 'Gene', '23451', (72, 77))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('191', '199'))	('SF3B1', 'Gene', (39, 44))
88117	26842708	The hotspot mutations of SF3B1 in the HEAT repeats occur on the inner surface of the structure and may induce a conformational change in the U2 snRNP complex altering its selectivity for BPs.	('conformational change', 'MPA', (112, 133))	('altering', 'Reg', (158, 166))	('snRNP', 'molecular_function', 'GO:0003734', ('144', '149'))	('mutations', 'Var', (12, 21))	('induce', 'Reg', (103, 109))	('U2 snRNP complex', 'Protein', (141, 157))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('141', '149'))	('SF3B1', 'Gene', (25, 30))	('BP', 'Chemical', '-', (187, 189))	('selectivity for BPs', 'MPA', (171, 190))	('SF3B1', 'Gene', '23451', (25, 30))
88121	26842708	Further work is required to evaluate the molecular mechanism by which the mutations of the SF3B1 HEAT domains may influence the base-pairing potential of U2 snRNA.	('base-pairing', 'molecular_function', 'GO:0003676', ('128', '140'))	('SF3B1', 'Gene', (91, 96))	('influence', 'Reg', (114, 123))	('base-pairing potential of', 'MPA', (128, 153))	('mutations', 'Var', (74, 83))	('SF3B1', 'Gene', '23451', (91, 96))
88142	26842708	K700E mutation in SF3B1 was introduced using QuikChange II Site Directed Mutagenesis Kit (Stratagene).	('Mutagenesis', 'biological_process', 'GO:0006280', ('73', '84'))	('SF3B1', 'Gene', (18, 23))	('rat', 'Species', '10116', (92, 95))	('K700E', 'Mutation', 'rs559063155', (0, 5))	('K700E', 'Var', (0, 5))	('SF3B1', 'Gene', '23451', (18, 23))
88143	26842708	Primers used for generating the mutated SF3B1 are: (forward) 5'-CTGGTGGATGAGCAGCAGGAGGTCAGAACCATCTCTGC-3' and (reverse) 5'-GCAGAGATGGTTCTGACCTCCTGCTGCTCATCCACCAG-3'.	('SF3B1', 'Gene', (40, 45))	('rat', 'Species', '10116', (21, 24))	('SF3B1', 'Gene', '23451', (40, 45))	('mutated', 'Var', (32, 39))
88144	26842708	Mutations of potential BP in TMEM14C and ENOSF1 ExonTrap constructs were introduced using QuikChange II Site Directed Mutagenesis Kit (Stratagene) and verified by DNA sequencing.	('ENOSF1', 'Gene', '55556', (41, 47))	('TMEM14C', 'Gene', (29, 36))	('ENOSF1', 'Gene', (41, 47))	('Mutagenesis', 'biological_process', 'GO:0006280', ('118', '129'))	('rat', 'Species', '10116', (137, 140))	('Mutations', 'Var', (0, 9))	('TMEM14C', 'Gene', '51522', (29, 36))	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))	('BP', 'Chemical', '-', (23, 25))
88147	26842708	A point mutation in SF3B1 resulting in K666T amino-acid substitution was introduced using CRISPR/CAS9-stimulated homology-mediated repair to generate isogenic HEK293T cell lines and was verified by Sanger sequencing.	('SF3B1', 'Gene', (20, 25))	('K666T', 'Var', (39, 44))	('K666T', 'Mutation', 'rs374250186', (39, 44))	('CAS', 'cellular_component', 'GO:0005650', ('97', '100'))	('SF3B1', 'Gene', '23451', (20, 25))	('HEK293T', 'CellLine', 'CVCL:0063', (159, 166))	('rat', 'Species', '10116', (145, 148))
88157	26842708	Proteins were transferred to nitrocellulose membranes followed by immunoblotting with specific primary antibodies for SF3B1 (1:1,000; #170854; Abcam), Flag (1:1,000, #3165; Sigma), U2AF1 (1:500; #19961; Santa Cruz Biotechnology), U2AF2 (1:500; #53942; Santa Cruz Biotechnology) and beta-actin (1:2,000; #5313; Sigma).	('1:500; #', 'Var', (188, 196))	('SF3B1', 'Gene', '23451', (118, 123))	('U2AF1', 'Gene', '7307', (181, 186))	('U2AF2', 'Gene', '11338', (230, 235))	('U2AF1', 'Gene', (181, 186))	('U2AF', 'cellular_component', 'GO:0089701', ('230', '234'))	('U2AF', 'cellular_component', 'GO:0089701', ('181', '185'))	('beta-actin', 'Gene', '728378', (282, 292))	('beta-actin', 'Gene', (282, 292))	('SF3B1', 'Gene', (118, 123))	('U2AF2', 'Gene', (230, 235))
88164	26842708	Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage.	('promoting', 'PosReg', (65, 74))	('splicing', 'biological_process', 'GO:0045292', ('53', '61'))	('alternative branchpoint usage', 'MPA', (75, 104))	('SF3B1', 'Gene', (18, 23))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('SF3B1', 'Gene', '23451', (18, 23))	('alternative splicing', 'MPA', (41, 61))	('mutations', 'Var', (24, 33))	('affect', 'Reg', (34, 40))
88181	24258991	Cytogenetic alterations provided an important step towards the development of accurate prognostic markers for uveal melanoma, but they have a number of significant drawbacks that limit their value for routine clinical use.	('uveal melanoma', 'Phenotype', 'HP:0007716', (110, 124))	('uveal melanoma', 'Disease', (110, 124))	('uveal melanoma', 'Disease', 'MESH:C536494', (110, 124))	('alterations', 'Var', (12, 23))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))
88186	24258991	Analysis of uveal melanomas using high-density microarrays showed that tumors with disomy 3 exhibited a different GEP than those with monosomy 3.	('disomy 3', 'Var', (83, 91))	('uveal melanomas', 'Disease', 'MESH:C536494', (12, 27))	('uveal melanoma', 'Phenotype', 'HP:0007716', (12, 26))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))	('uveal melanomas', 'Phenotype', 'HP:0007716', (12, 27))	('uveal melanomas', 'Disease', (12, 27))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
88191	24258991	Our findings suggested that class 2 tumors have undergone mutations that lead to a loss of melanocyte cell identity and reversion to a stem-like phenotype.	('mutations', 'Var', (58, 67))	('reversion', 'CPA', (120, 129))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('loss', 'NegReg', (83, 87))
88192	24258991	We used exome capture followed by next-generation sequencing to search for mutations that may be specifically associated with class 2 tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('associated', 'Reg', (110, 120))	('mutations', 'Var', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
88193	24258991	We identified frequent inactivating mutations in the BRCA1-associated protein 1 (BAP1), located at chromosome 3p21.1, and loss of the other copy of chromosome 3, in the vast majority of class 2 tumors but in only one class 1 tumor which retained two copies of chromosome 3.	('chromosome', 'cellular_component', 'GO:0005694', ('99', '109'))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', (194, 199))	('BRCA1-associated protein 1', 'Gene', (53, 79))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('BAP1', 'Gene', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('loss', 'NegReg', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('chromosome', 'cellular_component', 'GO:0005694', ('260', '270'))	('inactivating mutations', 'Var', (23, 45))	('tumors', 'Disease', (194, 200))	('BRCA1-associated protein 1', 'Gene', '8314', (53, 79))	('chromosome', 'cellular_component', 'GO:0005694', ('148', '158'))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('BAP1', 'Gene', '8314', (81, 85))
88195	24258991	We reported one uveal melanoma patient carrying a germline BAP1 mutation, and we identified another family with a germline BAP1 mutation in which uveal and cutaneous melanoma occurred in multiple family members (unpublished data).	('BAP1', 'Gene', (123, 127))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('mutation', 'Var', (64, 72))	('BAP1', 'Gene', (59, 63))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('uveal melanoma', 'Disease', (16, 30))	('uveal melanoma', 'Disease', 'MESH:C536494', (16, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('cutaneous melanoma', 'Disease', (156, 174))	('patient', 'Species', '9606', (31, 38))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (156, 174))	('BAP1', 'Gene', '8314', (123, 127))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (156, 174))	('BAP1', 'Gene', '8314', (59, 63))
88196	24258991	Subsequent to our report, there have been a growing number of cancers associated with somatic and germline BAP1 mutations, including uveal and cutaneous melanoma, mesothelioma, meningioma, lung cancer, breast cancer, and renal carcinoma.	('renal carcinoma', 'Disease', (221, 236))	('renal carcinoma', 'Phenotype', 'HP:0005584', (221, 236))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('mutations', 'Var', (112, 121))	('cutaneous melanoma', 'Disease', (143, 161))	('meningioma', 'Disease', (177, 187))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (143, 161))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (143, 161))	('meningioma', 'Phenotype', 'HP:0002858', (177, 187))	('associated', 'Reg', (70, 80))	('lung cancer', 'Disease', (189, 200))	('uveal', 'Disease', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('BAP1', 'Gene', '8314', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('meningioma', 'Disease', 'MESH:D008577', (177, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('breast cancer', 'Disease', (202, 215))	('BAP1', 'Gene', (107, 111))	('mesothelioma', 'Disease', (163, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('renal carcinoma', 'Disease', 'MESH:C538614', (221, 236))	('mesothelioma', 'Disease', 'MESH:D008654', (163, 175))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
88197	24258991	Despite the strong correlation between BAP1 mutations and the class 2 signature, however, the latter continues to be much more accurate for clinical prognostic testing.	('BAP1', 'Gene', '8314', (39, 43))	('mutations', 'Var', (44, 53))	('class 2 signature', 'MPA', (62, 79))	('BAP1', 'Gene', (39, 43))
88198	24258991	As with chromosomal analysis, which suffers from intratumoral heterogeneity and consequent sampling error, BAP1 mutations can also be heterogeneously distributed within the tumor.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('BAP1', 'Gene', '8314', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('BAP1', 'Gene', (107, 111))	('mutations', 'Var', (112, 121))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
88232	24258991	Pipet the sample/ethanol mixture on the cartridge and centrifuge at 10,000 x g for 30 s. Discard the flow through, and wash the filter cartridge with 700 mul of wash 1 buffer followed by 500 mul of wash 2/3.	('wash 1', 'Gene', '100287171', (161, 167))	('flow through', 'MPA', (101, 113))	('wash 1', 'Gene', (161, 167))	('mix', 'Gene', '83881', (25, 28))	('Discard', 'Var', (89, 96))	('ethanol', 'Chemical', 'MESH:D000431', (17, 24))	('mix', 'Gene', (25, 28))
88271	24559320	the absence of TSP-1 inhibits migration of fibroblasts delaying wound healing , but also enhances DC migration to draining lymph nodes promoting antigen sensitization and subsequent immune response .	('sensitization', 'biological_process', 'GO:0046960', ('153', '166'))	('migration of fibroblasts', 'CPA', (30, 54))	('inhibits', 'NegReg', (21, 29))	('delaying wound healing', 'Phenotype', 'HP:0001058', (55, 77))	('TSP-1', 'Gene', (15, 20))	('rat', 'Species', '10116', (33, 36))	('delaying', 'NegReg', (55, 63))	('DC migration to draining lymph nodes', 'CPA', (98, 134))	('wound healing', 'biological_process', 'GO:0042060', ('64', '77'))	('TSP-1', 'molecular_function', 'GO:0004277', ('15', '20'))	('wound healing', 'CPA', (64, 77))	('enhances', 'PosReg', (89, 97))	('absence', 'Var', (4, 11))	('immune response', 'biological_process', 'GO:0006955', ('182', '197'))	('rat', 'Species', '10116', (104, 107))
88273	24559320	The lymphangiogenic effect of TSP-1 is mediated indirectly via ligation of CD36 on tissue macrophages and inhibiting their expression of the VEGF-c .	('lymphangiogenic effect', 'CPA', (4, 26))	('TSP-1', 'Gene', (30, 35))	('CD36', 'Species', '42374', (75, 79))	('expression', 'MPA', (123, 133))	('VEGF-c', 'Gene', '22341', (141, 147))	('TSP-1', 'molecular_function', 'GO:0004277', ('30', '35'))	('inhibiting', 'NegReg', (106, 116))	('CD36', 'Protein', (75, 79))	('VEGF-c', 'Gene', (141, 147))	('ligation', 'Var', (63, 71))
88274	24559320	These mechanisms contribute to the observed increase in both hem- and lymphangiogenesis in TSP-1 deficient mice .	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('70', '87'))	('increase', 'PosReg', (44, 52))	('mice', 'Species', '10090', (107, 111))	('TSP-1', 'molecular_function', 'GO:0004277', ('91', '96'))	('deficient', 'Var', (97, 106))	('TSP-1', 'Gene', (91, 96))
88278	24559320	This may explain the importance of TSP-1 as a major TGF-beta activator in the ocular tissues where TGF-beta2 expression predominates  further supporting the spontaneous development of ocular pathology in TSP-1 deficient mice .	('TSP-1', 'molecular_function', 'GO:0004277', ('204', '209'))	('TGF-beta', 'Gene', (52, 60))	('mice', 'Species', '10090', (220, 224))	('TSP-1', 'Gene', (204, 209))	('TGF-beta', 'Gene', '21803', (99, 107))	('deficient', 'Var', (210, 219))	('TSP-1', 'molecular_function', 'GO:0004277', ('35', '40'))	('TGF-beta', 'Gene', (99, 107))	('TGF-beta', 'Gene', '21803', (52, 60))
88282	24559320	These processes are regulated by a tightly balanced production of positive and negative factors, whose alterations under various pathological conditions may result in retinal neovascularization and growth of abnormal vessels as occurs in retinopathy of prematurity and diabetic retinopathy.	('retinal neovascularization', 'Phenotype', 'HP:0030666', (167, 193))	('alterations', 'Var', (103, 114))	('retinopathy of prematurity and diabetic retinopathy', 'Disease', 'MESH:D012164', (238, 289))	('result in', 'Reg', (157, 166))	('retinopathy', 'Phenotype', 'HP:0000488', (278, 289))	('growth', 'CPA', (198, 204))	('abnormal vessels', 'Phenotype', 'HP:0002597', (208, 224))	('retinal neovascularization', 'CPA', (167, 193))	('retinopathy', 'Phenotype', 'HP:0000488', (238, 249))	('retinopathy of prematurity', 'Phenotype', 'HP:0500049', (238, 264))	('rat', 'Species', '10116', (107, 110))
88285	24559320	Alterations in production of these factors are linked to ocular neovascularization in various eye diseases.	('eye diseases', 'Disease', 'MESH:D005128', (94, 106))	('ocular neovascularization', 'Phenotype', 'HP:0011496', (57, 82))	('ocular neovascularization', 'Disease', (57, 82))	('eye diseases', 'Disease', (94, 106))	('Alterations', 'Var', (0, 11))	('linked', 'Reg', (47, 53))	('rat', 'Species', '10116', (4, 7))	('eye diseases', 'Phenotype', 'HP:0000478', (94, 106))
88292	24559320	Mice deficient in TSP1 have been generated and are viable .	('rat', 'Species', '10116', (37, 40))	('TSP1', 'Gene', (18, 22))	('TSP1', 'molecular_function', 'GO:0004277', ('18', '22'))	('Mice', 'Species', '10090', (0, 4))	('deficient', 'Var', (5, 14))
88295	24559320	Using these mice we investigated how lack of TSP1 impact postnatal retinal vascular development and neovascularization during oxygen induced ischemic retinopathy (OIR).	('oxygen', 'Chemical', 'MESH:D010100', (126, 132))	('neovascularization', 'CPA', (100, 118))	('impact', 'Reg', (50, 56))	('TSP1', 'Gene', (45, 49))	('lack', 'Var', (37, 41))	('ischemic retinopathy', 'Disease', 'MESH:D007511', (141, 161))	('postnatal retinal vascular development', 'CPA', (57, 95))	('retinopathy', 'Phenotype', 'HP:0000488', (150, 161))	('TSP1', 'molecular_function', 'GO:0004277', ('45', '49'))	('mice', 'Species', '10090', (12, 16))	('ischemic retinopathy', 'Disease', (141, 161))
88298	24559320	Although, an increase in degree of neovascularization at postnatal day 17 (P17; when maximum neovascularization occurs in this model) was observed in TSP1 deficient mice compared with wild type mice, it was not significant.	('mice', 'Species', '10090', (165, 169))	('TSP1', 'Gene', (150, 154))	('neovascularization', 'CPA', (35, 53))	('increase', 'PosReg', (13, 21))	('deficient', 'Var', (155, 164))	('TSP1', 'molecular_function', 'GO:0004277', ('150', '154'))	('mice', 'Species', '10090', (194, 198))
88305	24559320	Furthermore, we showed that postnatal retinal vascularization and neovascularization during OIR were attenuated in mice with increased levels of TSP1 expression in their eye.	('neovascularization', 'CPA', (66, 84))	('increased', 'PosReg', (125, 134))	('retinal vascularization', 'Phenotype', 'HP:0030666', (38, 61))	('levels', 'Var', (135, 141))	('attenuated', 'NegReg', (101, 111))	('postnatal retinal vascularization', 'CPA', (28, 61))	('TSP1', 'Gene', (145, 149))	('mice', 'Species', '10090', (115, 119))	('TSP1', 'molecular_function', 'GO:0004277', ('145', '149'))
88311	24559320	To test this hypothesis we bred our TSP1 deficient mice with the Akita/+ mice, which develop diabetes at four weeks of age.	('mice', 'Species', '10090', (51, 55))	('diabetes', 'Disease', (93, 101))	('mice', 'Species', '10090', (73, 77))	('diabetes', 'Disease', 'MESH:D003920', (93, 101))	('deficient', 'Var', (41, 50))	('TSP1', 'Gene', (36, 40))	('TSP1', 'molecular_function', 'GO:0004277', ('36', '40'))
88313	24559320	In contrast, we recently showed that Akita/+ mice deficient in TSP1 develop more severe retinopathies with 7 months of diabetes.	('deficient', 'Var', (50, 59))	('retinopathies', 'Phenotype', 'HP:0000488', (88, 101))	('mice', 'Species', '10090', (45, 49))	('TSP1', 'molecular_function', 'GO:0004277', ('63', '67'))	('TSP1', 'Gene', (63, 67))	('retinopathies', 'Disease', (88, 101))	('retinopathies', 'Disease', 'MESH:D012164', (88, 101))	('diabetes', 'Disease', (119, 127))	('diabetes', 'Disease', 'MESH:D003920', (119, 127))
88319	24559320	We recently showed that lack of TSP1 exacerbates the laser-induced choroidal neovascularization in TSP1-deficient mice compared with wild type mice.	('TSP1', 'molecular_function', 'GO:0004277', ('99', '103'))	('laser-induced choroidal neovascularization', 'CPA', (53, 95))	('choroidal neovascularization', 'Phenotype', 'HP:0011506', (67, 95))	('lack', 'Var', (24, 28))	('TSP1-deficient', 'Disease', 'MESH:D007153', (99, 113))	('TSP1', 'molecular_function', 'GO:0004277', ('32', '36'))	('exacerbates', 'PosReg', (37, 48))	('mice', 'Species', '10090', (114, 118))	('TSP1', 'Gene', (32, 36))	('TSP1-deficient', 'Disease', (99, 113))	('mice', 'Species', '10090', (143, 147))
88326	24559320	We hypothesized that changes in the expression of TSP1 may contribute to the development and progression of uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (108, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('uveal melanoma', 'Disease', (108, 122))	('TSP1', 'Gene', (50, 54))	('TSP1', 'molecular_function', 'GO:0004277', ('50', '54'))	('changes', 'Var', (21, 28))	('contribute', 'Reg', (59, 69))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
88332	24559320	Thus, alterations in production of TSP1 may also make a significant contribution to the pathogenesis of uveal melanoma and provides a suitable target for detection and treatment of uveal melanoma.	('alterations', 'Var', (6, 17))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('TSP1', 'molecular_function', 'GO:0004277', ('35', '39'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('uveal melanoma', 'Disease', (104, 118))	('uveal melanoma', 'Disease', 'MESH:C536494', (104, 118))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('contribution', 'Reg', (68, 80))	('production', 'MPA', (21, 31))	('TSP1', 'Gene', (35, 39))	('pathogenesis', 'biological_process', 'GO:0009405', ('88', '100'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (181, 195))	('uveal melanoma', 'Disease', 'MESH:C536494', (181, 195))	('rat', 'Species', '10116', (10, 13))	('uveal melanoma', 'Disease', (181, 195))
88335	24559320	Mice deficient in TSP2 exhibit mainly connective tissue defects presented as collagen fibril formation defects.	('TSP2', 'Gene', '104266', (18, 22))	('formation', 'biological_process', 'GO:0009058', ('93', '102'))	('collagen', 'molecular_function', 'GO:0005202', ('77', '85'))	('connective tissue defects', 'CPA', (38, 63))	('fibril', 'cellular_component', 'GO:0099512', ('86', '92'))	('collagen fibril formation defects', 'CPA', (77, 110))	('TSP2', 'Gene', (18, 22))	('Mice', 'Species', '10090', (0, 4))	('deficient', 'Var', (5, 14))
88351	24559320	The absence of TSP 1 and TSP 2 or both in genetically altered mice does not cause spontaneous ingrowths of blood vessels into the cornea  This supports the concept of a redundantly organized angiogenic privilege.	('TSP 1', 'Gene', '108314', (15, 20))	('TSP 1', 'Gene', (15, 20))	('mice', 'Species', '10090', (62, 66))	('TSP 2', 'Gene', '104266', (25, 30))	('TSP 2', 'Gene', (25, 30))	('absence', 'Var', (4, 11))	('TSP 1', 'molecular_function', 'GO:0004277', ('15', '20'))
88352	24559320	In contrast, lack of TSP 1 does cause an increased vascular density in other intraocular tissues  The iris vascularity in TSP 1 deficient mice is significantly higher compared to wild-type animals.	('deficient', 'Var', (128, 137))	('increased', 'PosReg', (41, 50))	('increased vascular density', 'Phenotype', 'HP:0002634', (41, 67))	('higher', 'PosReg', (160, 166))	('lack', 'Var', (13, 17))	('TSP 1', 'molecular_function', 'GO:0004277', ('21', '26'))	('TSP 1', 'Gene', '108314', (122, 127))	('TSP 1', 'molecular_function', 'GO:0004277', ('122', '127'))	('iris vascularity', 'CPA', (102, 118))	('mice', 'Species', '10090', (138, 142))	('TSP 1', 'Gene', (122, 127))	('TSP 1', 'Gene', '108314', (21, 26))	('vascular density', 'CPA', (51, 67))	('TSP 1', 'Gene', (21, 26))
88353	24559320	Under inflammatory conditions, TSP1 deficient mice show a significantly increased angiogenic and lymphangiogenic response.	('increased', 'PosReg', (72, 81))	('deficient', 'Var', (36, 45))	('TSP1', 'Gene', (31, 35))	('mice', 'Species', '10090', (46, 50))	('TSP1', 'molecular_function', 'GO:0004277', ('31', '35'))
88355	24559320	Lack of TSP 1 in older mice causes spontaneous ingrowths of lymphatic vessels from the limbal vascular arcade into the normally avascular cornea.	('avascular cornea', 'Disease', 'MESH:D010020', (128, 144))	('TSP 1', 'molecular_function', 'GO:0004277', ('8', '13'))	('TSP 1', 'Gene', '108314', (8, 13))	('TSP 1', 'Gene', (8, 13))	('Lack', 'Var', (0, 4))	('avascular cornea', 'Disease', (128, 144))	('mice', 'Species', '10090', (23, 27))
88357	24559320	The increased spontaneous corneal lymphangiogenesis in TSP1 deficient mice goes along with an increased induced lymphangiogenesis under inflammatory conditions (figure 2), e.g.	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('34', '51'))	('deficient', 'Var', (60, 69))	('increased', 'PosReg', (94, 103))	('TSP1', 'Gene', (55, 59))	('TSP1', 'molecular_function', 'GO:0004277', ('55', '59'))	('mice', 'Species', '10090', (70, 74))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('112', '129'))	('spontaneous corneal lymphangiogenesis', 'CPA', (14, 51))	('increased', 'PosReg', (4, 13))
88360	24559320	Indeed, CD36 deficient mice do show a similar corneal vascular phenotype as TSP 1 deficient mice.	('TSP 1', 'Gene', (76, 81))	('corneal vascular', 'Disease', 'MESH:D003316', (46, 62))	('corneal vascular phenotype', 'Phenotype', 'HP:0011496', (46, 72))	('TSP 1', 'Gene', '108314', (76, 81))	('CD36', 'Gene', (8, 12))	('deficient', 'Var', (13, 22))	('corneal vascular', 'Disease', (46, 62))	('TSP 1', 'molecular_function', 'GO:0004277', ('76', '81'))	('CD36', 'Species', '42374', (8, 12))	('mice', 'Species', '10090', (92, 96))	('mice', 'Species', '10090', (23, 27))
88363	24559320	We therefore tested the hypothesis that TSP 1, via CD36 on macrophages, inhibits lymphangiogenesis.	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('81', '98'))	('TSP 1', 'Gene', '108314', (40, 45))	('CD36', 'Species', '42374', (51, 55))	('CD36', 'Var', (51, 55))	('TSP 1', 'Gene', (40, 45))	('inhibits', 'NegReg', (72, 80))	('TSP 1', 'molecular_function', 'GO:0004277', ('40', '45'))	('lymphangiogenesis', 'CPA', (81, 98))
88378	24559320	(2004) reported that in Vitamin A deficient mice, TSP-1 was not deposited after wounding, which correlated with slowed healing.	('slowed', 'NegReg', (112, 118))	('slowed healing', 'Phenotype', 'HP:0001058', (112, 126))	('Vitamin A deficient', 'Phenotype', 'HP:0004905', (24, 43))	('healing', 'CPA', (119, 126))	('Vitamin A', 'Chemical', 'MESH:D014801', (24, 33))	('deficient', 'Var', (34, 43))	('TSP-1', 'Gene', (50, 55))	('mice', 'Species', '10090', (44, 48))	('TSP-1', 'molecular_function', 'GO:0004277', ('50', '55'))
88411	24559320	Membrane bound TSP-1 in APCs can also help activate TGF-beta in the vicinity of responding T cells engaged during antigen presentation and by ligating CD47 on APCs, it inhibits expression of Th1-promoting inflammatory cytokine .	('CD47', 'Gene', (151, 155))	('activate', 'PosReg', (43, 51))	('antigen presentation', 'biological_process', 'GO:0019882', ('114', '134'))	('Th1', 'Gene', '57314', (191, 194))	('inhibits', 'NegReg', (168, 176))	('TGF-beta', 'Gene', (52, 60))	('TSP-1', 'molecular_function', 'GO:0004277', ('15', '20'))	('Th1', 'Gene', (191, 194))	('ligating', 'Var', (142, 150))	('expression', 'MPA', (177, 187))	('TGF-beta', 'Gene', '21803', (52, 60))
88418	24559320	Consistent with this possibility loss of immune privilege in TSP-1 deficient mice is evident from exacerbated uveitic inflammation of the retina that results in irreversible tissue damage .	('mice', 'Species', '10090', (77, 81))	('TSP-1', 'molecular_function', 'GO:0004277', ('61', '66'))	('deficient', 'Var', (67, 76))	('loss', 'NegReg', (33, 37))	('immune privilege', 'CPA', (41, 57))	('inflammation', 'biological_process', 'GO:0006954', ('118', '130'))	('uveitic inflammation', 'Disease', (110, 130))	('exacerbated', 'PosReg', (98, 109))	('uveitic inflammation', 'Disease', 'MESH:D007249', (110, 130))	('TSP-1', 'Gene', (61, 66))	('uveitic inflammation', 'Phenotype', 'HP:0000554', (110, 130))
88421	24559320	The absence of overt spontaneous inflammation in the anterior or posterior segment of TSP-1 deficient mice appears contrary to the significant role of this molecule in ocular immune privilege.	('deficient', 'Var', (92, 101))	('mice', 'Species', '10090', (102, 106))	('inflammation', 'Disease', 'MESH:D007249', (33, 45))	('inflammation', 'biological_process', 'GO:0006954', ('33', '45'))	('TSP-1', 'Gene', (86, 91))	('inflammation', 'Disease', (33, 45))	('TSP-1', 'molecular_function', 'GO:0004277', ('86', '91'))
88424	24559320	Further characterization revealed spontaneous development of an ocular phenotype in TSP-1 deficient mice that involves inflammation of the ocular surface tissue associated with autoimmune Sjogren's syndrome.	("autoimmune Sjogren's syndrome", 'Disease', 'MESH:D012859', (177, 206))	('mice', 'Species', '10090', (100, 104))	('inflammation', 'Disease', 'MESH:D007249', (119, 131))	("autoimmune Sjogren's syndrome", 'Disease', (177, 206))	('inflammation', 'Disease', (119, 131))	('TSP-1', 'Gene', (84, 89))	('TSP-1', 'molecular_function', 'GO:0004277', ('84', '89'))	('deficient', 'Var', (90, 99))	('inflammation', 'biological_process', 'GO:0006954', ('119', '131'))
88426	24559320	These changes in turn increase vulnerability of the ocular surface to commensal flora or pathogens that succeed in inducing inflammatory responses, presumably of the innate cells in the conjunctiva, leading to increased expression of inflammatory cytokines such as IL-17A, TNF-alpha, IFN-gamma as well as IL-6 .	('IFN-gamma', 'Gene', '15978', (284, 293))	('IL-17A', 'Gene', (265, 271))	('IL-17A', 'Gene', '16171', (265, 271))	('IL-6', 'molecular_function', 'GO:0005138', ('305', '309'))	('increased', 'PosReg', (210, 219))	('expression', 'MPA', (220, 230))	('TNF-alpha', 'Gene', '21926', (273, 282))	('IL-6', 'Gene', (305, 309))	('changes', 'Var', (6, 13))	('IFN-gamma', 'Gene', (284, 293))	('inflammatory', 'MPA', (124, 136))	('inducing', 'Reg', (115, 123))	('IL-6', 'Gene', '16193', (305, 309))	('IL-17', 'molecular_function', 'GO:0030367', ('265', '270'))	('TNF-alpha', 'Gene', (273, 282))	('vulnerability', 'MPA', (31, 44))
88428	24559320	The TSP-1 deficient DCs with their enhanced CCR7 expression successfully sensitize the host against ocular surface derived antigens thus initiating a systemic inflammatory immune response as represented by the elevated expression of transcription factors associated with inflammatory effectors such as Tbet (Th1) and RORgammat (Th17 or NKT or gammadelta T cells) in the draining lymph nodes.	('Tbet', 'Gene', '57765', (302, 306))	('CCR', 'molecular_function', 'GO:0043880', ('44', '47'))	('Th1', 'Gene', '57314', (308, 311))	('elevated', 'PosReg', (210, 218))	('Th1', 'Gene', (308, 311))	('sensitize', 'Reg', (73, 82))	('TSP-1', 'molecular_function', 'GO:0004277', ('4', '9'))	('expression', 'MPA', (49, 59))	('CCR7', 'Gene', (44, 48))	('CCR7', 'Gene', '12775', (44, 48))	('transcription', 'biological_process', 'GO:0006351', ('233', '246'))	('deficient', 'Var', (10, 19))	('Th1', 'Gene', '57314', (328, 331))	('Tbet', 'Gene', (302, 306))	('systemic inflammatory immune', 'MPA', (150, 178))	('Th1', 'Gene', (328, 331))	('TSP-1', 'Gene', (4, 9))	('transcription', 'MPA', (233, 246))	('expression', 'MPA', (219, 229))	('initiating', 'Reg', (137, 147))	('immune response', 'biological_process', 'GO:0006955', ('172', '187'))	('enhanced', 'PosReg', (35, 43))
88435	24559320	Dysregulated TGF-beta activation in clearance of apoptotic cells has been described in the immunopathogenesis of autoimmune diseases and is likely to be an underlying mechanism in the development of autoimmune Sjogren's syndrome in TSP-1 deficient mice.	('autoimmune diseases', 'Disease', (113, 132))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (113, 132))	('TGF-beta activation', 'biological_process', 'GO:0036363', ('13', '32'))	('TGF-beta', 'Gene', '21803', (13, 21))	('TSP-1', 'molecular_function', 'GO:0004277', ('232', '237'))	('activation', 'PosReg', (22, 32))	("autoimmune Sjogren's syndrome", 'Disease', 'MESH:D012859', (199, 228))	('mice', 'Species', '10090', (248, 252))	('Dysregulated', 'Var', (0, 12))	('TGF-beta', 'Gene', (13, 21))	("autoimmune Sjogren's syndrome", 'Disease', (199, 228))	('autoimmune disease', 'Phenotype', 'HP:0002960', (113, 131))	('autoimmune diseases', 'Disease', 'MESH:D001327', (113, 132))
88439	24559320	In a small targeted-gene association study, such individuals that developed post-refractive surgery chronic ocular surface inflammation were screened for selected 4 single nucleotide polymorphisms in their TSP-1 encoding gene THBS1 .	('THBS1', 'Gene', (226, 231))	('single nucleotide polymorphisms', 'Var', (165, 196))	('TSP-1', 'Gene', (206, 211))	('inflammation', 'biological_process', 'GO:0006954', ('123', '135'))	('TSP-1', 'molecular_function', 'GO:0004277', ('206', '211'))	('inflammation', 'Disease', 'MESH:D007249', (123, 135))	('inflammation', 'Disease', (123, 135))	('THBS1', 'Gene', '21825', (226, 231))
88440	24559320	Significant correlation was detectable in the THBS1 polymorphism and the development of chronic ocular surface consistent with the observations in TSP-1 deficient mice.	('THBS1', 'Gene', '21825', (46, 51))	('polymorphism', 'Var', (52, 64))	('THBS1', 'Gene', (46, 51))	('development of chronic ocular surface', 'CPA', (73, 110))	('mice', 'Species', '10090', (163, 167))	('TSP-1', 'molecular_function', 'GO:0004277', ('147', '152'))
88441	24559320	In particular, TSP-1 mutation in the promoter region correlated with a decreased expression of TSP-1 in the ocular surface epithelia and increased expression of inflammatory marker IL-1beta.	('TSP-1', 'Gene', (95, 100))	('IL-1beta', 'Gene', '16176', (181, 189))	('IL-1', 'molecular_function', 'GO:0005149', ('181', '185'))	('expression', 'MPA', (147, 157))	('epithelia', 'Disease', (123, 132))	('mutation', 'Var', (21, 29))	('epithelia', 'Disease', 'None', (123, 132))	('TSP-1', 'molecular_function', 'GO:0004277', ('15', '20'))	('IL-1beta', 'Gene', (181, 189))	('increased', 'PosReg', (137, 146))	('TSP-1', 'Gene', (15, 20))	('TSP-1', 'molecular_function', 'GO:0004277', ('95', '100'))	('decreased', 'NegReg', (71, 80))	('expression', 'MPA', (81, 91))
88445	24559320	Therefore THBS1 polymorphism may serve as a potential genetic biomarker for early identification of individuals that are likely to develop chronic ocular surface inflammation and allow determination of early treatment strategy to possibly avoid the chronic condition.	('inflammation', 'Disease', 'MESH:D007249', (162, 174))	('THBS1', 'Gene', (10, 15))	('inflammation', 'Disease', (162, 174))	('polymorphism', 'Var', (16, 28))	('develop', 'PosReg', (131, 138))	('rat', 'Species', '10116', (220, 223))	('THBS1', 'Gene', '21825', (10, 15))	('inflammation', 'biological_process', 'GO:0006954', ('162', '174'))
88448	24559320	Studies using TSP-1 deficient mice have made it possible to understand mechanisms underlying retinal vascular homeostasis and vascular abnormalities detected in pathologic conditions that involve retinal neovascularization.	('vascular abnormalities', 'Disease', (126, 148))	('mice', 'Species', '10090', (30, 34))	('TSP-1', 'molecular_function', 'GO:0004277', ('14', '19'))	('TSP-1', 'Gene', (14, 19))	('vascular abnormalities', 'Disease', 'MESH:D000783', (126, 148))	('deficient', 'Var', (20, 29))	('homeostasis', 'biological_process', 'GO:0042592', ('110', '121'))	('retinal vascular homeostasis', 'Disease', (93, 121))	('retinal neovascularization', 'Phenotype', 'HP:0030666', (196, 222))	('vascular abnormalities', 'Phenotype', 'HP:0002597', (126, 148))	('retinal vascular homeostasis', 'Disease', 'MESH:D012173', (93, 121))
88449	24559320	This observation is supported by the increased hem- and lymphangiogenic responses invoked by corneal perturbations in TSP-1 deficient mice.	('mice', 'Species', '10090', (134, 138))	('perturbations', 'Var', (101, 114))	('TSP-1', 'molecular_function', 'GO:0004277', ('118', '123'))	('increased', 'PosReg', (37, 46))	('TSP-1', 'Gene', (118, 123))	('deficient', 'Var', (124, 133))
88454	24559320	The secretory deficit related to ocular surface inflammation in TSP-1 deficient mice has brought to light its potential involvement in regulating function of secretory epithelial cells in tissues like conjunctiva and lacrimal gland.	('inflammation', 'Disease', 'MESH:D007249', (48, 60))	('TSP-1', 'Gene', (64, 69))	('inflammation', 'Disease', (48, 60))	('inflammation', 'biological_process', 'GO:0006954', ('48', '60'))	('TSP-1', 'molecular_function', 'GO:0004277', ('64', '69'))	('mice', 'Species', '10090', (80, 84))	('epithelia', 'Disease', 'None', (168, 177))	('epithelia', 'Disease', (168, 177))	('secretory deficit', 'MPA', (4, 21))	('deficient', 'Var', (70, 79))
88455	24559320	While there are many TSP-dependent ocular mechanisms remain to be revealed in normal and disease states, emerging reports are promising translational opportunities ranging from a potential use of THBS-1 polymorphism as a genetic biomarker to the modulation of ocular angiogenesis using TSP-1 derived peptides in the treatment of various ocular pathologies.	('polymorphism', 'Var', (203, 215))	('THBS-1', 'Gene', '21825', (196, 202))	('angiogenesis', 'biological_process', 'GO:0001525', ('267', '279'))	('THBS-1', 'Gene', (196, 202))	('TSP-1', 'molecular_function', 'GO:0004277', ('286', '291'))
88545	21673068	In MMTV-Neu (Neu) mice, in which p38 antagonizes tumor development, premalignant lesions contained microinvasive cells, and dissemination to lungs and BM occurred early.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('Neu', 'Gene', '2064', (8, 11))	('MMTV', 'Species', '11757', (3, 7))	('p38', 'Var', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Neu', 'Gene', (13, 16))	('Neu', 'Gene', '2064', (13, 16))	('mice', 'Species', '10090', (18, 22))	('tumor', 'Disease', (49, 54))	('antagonizes', 'NegReg', (37, 48))	('Neu', 'Gene', (8, 11))
88550	21673068	Consequently, prolonged growth arrest with interspersed division might explain the clinical dormancy, during which slow accumulation of genetic and/or epigenetic alterations gives rise to malignant DTCs and relapse.	('malignant', 'CPA', (188, 197))	('relapse', 'CPA', (207, 214))	('gives rise', 'Reg', (174, 184))	('growth arrest', 'Phenotype', 'HP:0001510', (24, 37))	('DTC', 'Chemical', '-', (198, 201))	('growth arrest', 'Disease', 'MESH:D006323', (24, 37))	('growth arrest', 'Disease', (24, 37))	('dormancy', 'biological_process', 'GO:0030431', ('92', '100'))	('epigenetic alterations', 'Var', (151, 173))
88553	21673068	These genes may inhibit metastasis by inducing DTC growth arrest, preventing the formation of overt metastases.	('metastases', 'Disease', (100, 110))	('inhibit', 'NegReg', (16, 23))	('formation', 'biological_process', 'GO:0009058', ('81', '90'))	('metastases', 'Disease', 'MESH:D009362', (100, 110))	('inducing', 'Reg', (38, 46))	('growth arrest', 'Phenotype', 'HP:0001510', (51, 64))	('genes', 'Var', (6, 11))	('DTC', 'Chemical', '-', (47, 50))	('metastasis', 'CPA', (24, 34))	('growth arrest', 'Disease', 'MESH:D006323', (51, 64))	('growth arrest', 'Disease', (51, 64))	('preventing', 'NegReg', (66, 76))
88560	21673068	In addition, p38alpha can promote growth arrest by downregulating cyclin D1 and by activating the p53 to p21 and/or p16 to Rb pathways, among others.	('promote', 'PosReg', (26, 33))	('p38alpha', 'Var', (13, 21))	('cyclin D1', 'Gene', (66, 75))	('cyclin', 'molecular_function', 'GO:0016538', ('66', '72'))	('p16', 'Gene', (116, 119))	('downregulating', 'NegReg', (51, 65))	('growth arrest', 'Disease', (34, 47))	('growth arrest', 'Disease', 'MESH:D006323', (34, 47))	('p53', 'Gene', (98, 101))	('p21', 'Gene', (105, 108))	('activating', 'PosReg', (83, 93))	('p16', 'Gene', '1029', (116, 119))	('p21', 'Gene', '644914', (105, 108))	('growth arrest', 'Phenotype', 'HP:0001510', (34, 47))	('p53', 'Gene', '7157', (98, 101))	('cyclin D1', 'Gene', '595', (66, 75))
88561	21673068	Further, p38alpha inhibits transformation by sensing oncogene-induced oxidative stress, inactivation of p38alpha facilitates ErbB2-induced mammary tumorigenesis in vivo, and 18% of human primary breast carcinomas display Wip1/PPM1D (a p38 phosphatase) amplification.	('carcinomas', 'Phenotype', 'HP:0030731', (202, 212))	('phosphatase', 'molecular_function', 'GO:0016791', ('239', '250'))	('breast carcinomas', 'Phenotype', 'HP:0003002', (195, 212))	('breast carcinomas display Wip1', 'Disease', 'MESH:D001943', (195, 225))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('PPM1D', 'Gene', '8493', (226, 231))	('oxidative stress', 'Phenotype', 'HP:0025464', (70, 86))	('facilitates', 'PosReg', (113, 124))	('human', 'Species', '9606', (181, 186))	('ErbB2', 'Gene', '2064', (125, 130))	('inactivation', 'Var', (88, 100))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('inhibits', 'NegReg', (18, 26))	('p38alpha', 'Gene', (104, 112))	('PPM1D', 'Gene', (226, 231))	('breast carcinomas display Wip1', 'Disease', (195, 225))	('ErbB2', 'Gene', (125, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))
88566	21673068	Activation of p38alpha/beta is a barrier to mammary tumor progression.	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('p38alpha/beta', 'Var', (14, 27))
88567	21673068	This work revealed that p38alpha inhibited ERK1/2, possibly by regulation of PP2A and MKP phosphatases, and activated ATF-2 to induce c-Jun.	('regulation', 'biological_process', 'GO:0065007', ('63', '73'))	('ATF-2', 'Gene', (118, 123))	('c-Jun', 'Gene', '3725', (134, 139))	('induce', 'PosReg', (127, 133))	('p38alpha', 'Var', (24, 32))	('ATF-2', 'Gene', '1386', (118, 123))	('PP2A', 'Gene', (77, 81))	('ERK1/2', 'Enzyme', (43, 49))	('ERK1', 'molecular_function', 'GO:0004707', ('43', '47'))	('PP2A', 'Gene', '5524', (77, 81))	('c-Jun', 'Gene', (134, 139))	('inhibited', 'NegReg', (33, 42))
88569	21673068	In MMTV-Neu mice, where dissemination occurs during premalignant stages, p38alpha/beta inhibition accelerated premalignant lesion development, lumen occupancy, and local migration of both epithelial and myoepithelial cells.	('p38alpha/beta', 'Protein', (73, 86))	('Neu', 'Gene', '2064', (8, 11))	('MMTV', 'Species', '11757', (3, 7))	('premalignant lesion development', 'CPA', (110, 141))	('lumen occupancy', 'CPA', (143, 158))	('accelerated', 'PosReg', (98, 109))	('local migration of', 'CPA', (164, 182))	('mice', 'Species', '10090', (12, 16))	('inhibition', 'Var', (87, 97))	('Neu', 'Gene', (8, 11))
88576	21673068	Further, specific TFs can prevent quiescent cells from entering differentiation or senescence (an irreversible growth arrest that can lead to cell death or clearing by phagocytic cells; ref.	('cell death', 'biological_process', 'GO:0008219', ('142', '152'))	('senescence', 'CPA', (83, 93))	('growth arrest', 'Phenotype', 'HP:0001510', (111, 124))	('TFs', 'Var', (18, 21))	('senescence', 'biological_process', 'GO:0010149', ('83', '93'))	('growth arrest', 'Disease', (111, 124))	('differentiation', 'CPA', (64, 79))	('growth arrest', 'Disease', 'MESH:D006323', (111, 124))	('prevent', 'NegReg', (26, 33))
88584	21673068	Other groups have corroborated these findings, showing that loss of beta1-integrin or FAK signaling in the mammary epithelium or in intravenously delivered mouse breast cancer cells can also induce dormancy, and that Src MLKC signaling can prevent the onset of dormancy.	('beta1-integrin', 'Protein', (68, 82))	('dormancy', 'biological_process', 'GO:0030431', ('198', '206'))	('signaling', 'biological_process', 'GO:0023052', ('90', '99'))	('signaling', 'biological_process', 'GO:0023052', ('226', '235'))	('FAK', 'molecular_function', 'GO:0004717', ('86', '89'))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('loss', 'Var', (60, 64))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('mouse', 'Species', '10090', (156, 161))	('induce', 'Reg', (191, 197))	('FAK signaling', 'MPA', (86, 99))	('breast cancer', 'Disease', (162, 175))	('dormancy', 'CPA', (198, 206))	('dormancy', 'biological_process', 'GO:0030431', ('261', '269'))
88586	21673068	Activation of p38alpha/beta induced at least 3 TFs, p53 (R213Qmut), BHLHB3/41/Sharp1, and NR2F1, and inhibited the expression of c-Jun and FOXM1, 2 G1-S transition TFs.	('c-Jun', 'Gene', '3725', (129, 134))	('NR2F1', 'Gene', (90, 95))	('BHLHB3', 'Gene', (68, 74))	('p38alpha/beta', 'Var', (14, 27))	('R213Q', 'Mutation', 'rs587778720', (57, 62))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('c-Jun', 'Gene', (129, 134))	('FOXM1, 2 G1', 'Gene', '2305', (139, 150))	('expression', 'MPA', (115, 125))	('Sharp1', 'Gene', '79365', (78, 84))	('BHLHB3', 'Gene', '79365', (68, 74))	('inhibited', 'NegReg', (101, 110))	('NR2F1', 'Gene', '7025', (90, 95))	('Sharp1', 'Gene', (78, 84))
88587	21673068	Of importance, the R213Q mutation in p53 does not affect its ability to induce G0-G1 arrest, but it prevents the induction of senescence or apoptosis (ref.	('R213Q', 'Mutation', 'rs587778720', (19, 24))	('apoptosis', 'CPA', (140, 149))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('senescence', 'CPA', (126, 136))	('p53', 'Gene', (37, 40))	('prevents', 'NegReg', (100, 108))	('p53', 'Gene', '7157', (37, 40))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('R213Q', 'Var', (19, 24))	('senescence', 'biological_process', 'GO:0010149', ('126', '136'))
88600	21673068	However, if the mice were irradiated, the DTCs expanded in the BM (but not in other sites), suggesting that loss or gain of specific signals only after BM remodeling activated the DTCs to proliferate.	('DTC', 'Chemical', '-', (180, 183))	('loss', 'Var', (108, 112))	('proliferate', 'CPA', (188, 199))	('mice', 'Species', '10090', (16, 20))	('gain', 'PosReg', (116, 120))	('activated', 'PosReg', (166, 175))	('DTC', 'Chemical', '-', (42, 45))
88603	21673068	However, if p38alpha/beta is systemically inhibited, DTCs are detected and metastasis proceeds even in these growth-restrictive sites (our unpublished results; Fig.	('proceeds', 'Reg', (86, 94))	('metastasis', 'CPA', (75, 85))	('p38alpha/beta', 'Var', (12, 25))	('DTC', 'Chemical', '-', (53, 56))
88607	21673068	BHLHB3 was also found to function as a metastasis suppressor in MDA-MB-231 breast cancer cells when mutant p53 function was eliminated.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('mutant', 'Var', (100, 106))	('p53', 'Gene', (107, 110))	('BHLHB3', 'Gene', (0, 6))	('p53', 'Gene', '7157', (107, 110))	('metastasis', 'CPA', (39, 49))	('BHLHB3', 'Gene', '79365', (0, 6))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
88616	21673068	Additional studies proposed that p38alpha/beta upregulates the ER chaperone BiP/Grp78, which inhibits Bax activation and renders dormant HEp3 cells highly resistant to chemotherapy.	('Grp78', 'Gene', '3309', (80, 85))	('activation', 'MPA', (106, 116))	('resistant', 'CPA', (155, 164))	('Grp78', 'Gene', (80, 85))	('inhibits', 'NegReg', (93, 101))	('Bax', 'Gene', (102, 105))	('upregulates', 'PosReg', (47, 58))	('HEp3', 'CellLine', 'CVCL:0326', (137, 141))	('renders', 'Reg', (121, 128))	('p38alpha/beta', 'Var', (33, 46))	('BiP', 'Gene', (76, 79))	('Bax', 'Gene', '581', (102, 105))	('BiP', 'Gene', '3309', (76, 79))
88632	21673068	For example, in ER+/PR+ breast cancer, recurrences continue to develop after the initial 5 years of conventional antiestrogen treatment.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('ER+/PR+', 'Var', (16, 23))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('breast cancer', 'Disease', (24, 37))
88650	21673068	Inhibitors of p38 (such as SCIO-469, RO4402257, PH-797804, SB681323, and BMS-582949) are currently in clinical trials for several neoplastic and nonneoplastic diseases (e.g., hematological malignancies, asthma, neuropathic pain, atherosclerosis, and rheumatoid arthritis; see http://www.clinicaltrials.gov and Table 1).	('asthma', 'Disease', 'MESH:D001249', (203, 209))	('atherosclerosis', 'Phenotype', 'HP:0002621', (229, 244))	('hematological malignancies', 'Disease', (175, 201))	('asthma', 'Phenotype', 'HP:0002099', (203, 209))	('nonneoplastic diseases', 'Disease', (145, 167))	('arthritis', 'Phenotype', 'HP:0001369', (261, 270))	('rheumatoid arthritis', 'Disease', (250, 270))	('asthma', 'Disease', (203, 209))	('RO4402257', 'Var', (37, 46))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (250, 270))	('PH-797804', 'Var', (48, 57))	('neuropathic pain', 'Disease', 'MESH:D009437', (211, 227))	('pain', 'Phenotype', 'HP:0012531', (223, 227))	('hematological malignancies', 'Disease', 'MESH:D019337', (175, 201))	('hematological malignancies', 'Phenotype', 'HP:0004377', (175, 201))	('nonneoplastic diseases', 'Disease', 'MESH:D004194', (145, 167))	('atherosclerosis', 'Disease', 'MESH:D050197', (229, 244))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (250, 270))	('SB681323', 'Var', (59, 67))	('atherosclerosis', 'Disease', (229, 244))	('neuropathic pain', 'Disease', (211, 227))	('BMS-582949', 'Var', (73, 83))
88651	21673068	Thus, understanding how p38 inhibitors might carry an inherent risk for a proportion of patients with cancer, with a predisposition to cancer, or with other diseases is of crucial importance because inhibition of this pathway may fuel cancer progression and metastasis in these patients.	('cancer', 'Disease', (135, 141))	('fuel', 'PosReg', (230, 234))	('p38', 'Gene', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('inhibition', 'Var', (199, 209))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('inhibitors', 'Var', (28, 38))	('patients', 'Species', '9606', (278, 286))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('metastasis', 'CPA', (258, 268))
88656	21673068	Patients with BM DTCs usually have a worse prognosis than those without DTCs, and their presence reports for metastasis development but not necessarily in the BM, suggesting that they can serve as a reporter population even for cancers that do not metastasize in bone.	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('DTC', 'Chemical', '-', (72, 75))	('cancers', 'Disease', (228, 235))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('DTC', 'Chemical', '-', (17, 20))	('Patients', 'Species', '9606', (0, 8))	('metastasis development', 'CPA', (109, 131))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('DTCs', 'Var', (17, 21))	('reports', 'Reg', (97, 104))
88683	32205655	In a landmark study by Leach et al, blockage of CTLA-4 was demonstrated to cause tumor rejection, as well as future immunologic memory.	('cause', 'Reg', (75, 80))	('CTLA-4', 'Gene', (48, 54))	('blockage', 'Var', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('CTLA-4', 'Gene', '1493', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('memory', 'biological_process', 'GO:0007613', ('128', '134'))	('tumor', 'Disease', (81, 86))
88692	32205655	In 2014, the FDA approved nivolumab based on a study in which patients with metastatic melanoma without BRAF mutations were treated with either nivolumab or dacarbazine, with results showing that nivolumab resulted in superior overall survival and progression-free survival.	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('overall survival', 'CPA', (227, 243))	('nivolumab', 'Chemical', 'MESH:D000077594', (26, 35))	('superior', 'PosReg', (218, 226))	('progression-free survival', 'CPA', (248, 273))	('dacarbazine', 'Chemical', 'MESH:D003606', (157, 168))	('nivolumab', 'Chemical', 'MESH:D000077594', (144, 153))	('BRAF', 'Gene', '673', (104, 108))	('nivolumab', 'Chemical', 'MESH:D000077594', (196, 205))	('mutations', 'Var', (109, 118))	('BRAF', 'Gene', (104, 108))	('patients', 'Species', '9606', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
88711	32205655	In addition, cutaneous and conjunctival melanomas share several significant mutational similarities including high expression of BRAF, NRAS, numerous copy number variations, and heat shock protein 90 expressions while having low rates of GNA11, p16, and KIT.	('GNA11', 'Gene', (238, 243))	('NRAS', 'Gene', '4893', (135, 139))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('KIT', 'Gene', '3815', (254, 257))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('KIT', 'molecular_function', 'GO:0005020', ('254', '257'))	('shock', 'Phenotype', 'HP:0031273', (183, 188))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (27, 49))	('high', 'PosReg', (110, 114))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (27, 48))	('NRAS', 'Gene', (135, 139))	('GNA11', 'Gene', '2767', (238, 243))	('conjunctival melanomas', 'Disease', (27, 49))	('p16', 'Gene', (245, 248))	('KIT', 'Gene', (254, 257))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('p16', 'Gene', '1029', (245, 248))	('expression', 'MPA', (115, 125))	('copy number variations', 'Var', (150, 172))	('cutaneous', 'Disease', (13, 22))
88712	32205655	In contrast, conjunctival melanoma differs from uveal melanoma, which instead has higher GNAQ/GNA11 mutations.	('mutations', 'Var', (100, 109))	('GNA11', 'Gene', '2767', (94, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('uveal melanoma', 'Disease', (48, 62))	('conjunctival melanoma', 'Disease', (13, 34))	('GNAQ', 'Gene', '2776', (89, 93))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (13, 34))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (13, 34))	('higher', 'PosReg', (82, 88))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('GNAQ', 'Gene', (89, 93))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('GNA11', 'Gene', (94, 99))	('uveal melanoma', 'Disease', 'MESH:C536494', (48, 62))
88795	32663057	About 56% of patients in ipilimumab + dacarbazine arm experienced grade 3/4 AEs versus 27.5% of patients receiving dacarbazine + placebo, but no death due to ipilimumab occurred.	('dacarbazine', 'Chemical', 'MESH:D003606', (115, 126))	('ipilimumab', 'Chemical', 'MESH:D000074324', (25, 35))	('dacarbazine', 'Chemical', 'MESH:D003606', (38, 49))	('patients', 'Species', '9606', (13, 21))	('death', 'Disease', 'MESH:D003643', (145, 150))	('patients', 'Species', '9606', (96, 104))	('ipilimumab', 'Var', (25, 35))	('ipilimumab', 'Chemical', 'MESH:D000074324', (158, 168))	('death', 'Disease', (145, 150))
88811	32663057	The study enrolled 405 patients previously treated with ipilimumab and an anti-BRAF agent in case of BRAF mutation.	('BRAF', 'Gene', (101, 105))	('ipilimumab', 'Chemical', 'MESH:D000074324', (56, 66))	('patients', 'Species', '9606', (23, 31))	('mutation', 'Var', (106, 114))	('BRAF', 'Gene', '673', (79, 83))	('BRAF', 'Gene', '673', (101, 105))	('BRAF', 'Gene', (79, 83))
88817	32663057	RR was 33.7% and 32.9% for pembrolizumab q2 w and q3 w, respectively, and 11.9% for ipilimumab.	('q2 w', 'Var', (41, 45))	('q3 w', 'Var', (50, 54))	('ipilimumab', 'Chemical', 'MESH:D000074324', (84, 94))	('pembrolizumab', 'Chemical', 'MESH:C582435', (27, 40))
88839	32663057	After the demonstration of a synergy of CTLA-4 and PD-1 blockage in melanoma preclinical models, this strategy was tested in clinical trials.	('blockage', 'Var', (56, 64))	('PD-1', 'Gene', (51, 55))	('CTLA-4', 'Gene', '1493', (40, 46))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('CTLA-4', 'Gene', (40, 46))
88842	32663057	BRAF mutation was detected in 31.1% of the patients.	('BRAF', 'Gene', (0, 4))	('patients', 'Species', '9606', (43, 51))	('mutation', 'Var', (5, 13))	('BRAF', 'Gene', '673', (0, 4))
88854	32663057	Although in this study a direct comparison between combined immunotherapy and nivolumab alone was not pre-specified, we can infer that anti-PD-1 plus anti-CTLA-4 therapy shows a more impressive efficacy than nivolumab with a less favorable toxicity profile.	('nivolumab', 'Chemical', 'MESH:D000077594', (208, 217))	('nivolumab', 'Chemical', 'MESH:D000077594', (78, 87))	('CTLA-4', 'Gene', (155, 161))	('toxicity', 'Disease', 'MESH:D064420', (240, 248))	('toxicity', 'Disease', (240, 248))	('anti-PD-1', 'Var', (135, 144))	('pre', 'molecular_function', 'GO:0003904', ('102', '105'))	('CTLA-4', 'Gene', '1493', (155, 161))
88861	32663057	In the CheckMate 204 study, patients with asymptomatic brain metastases from melanoma (among whom 55% BRAF mutant) were treated with nivolumab + ipilimumab, with an intracranial RR of 57%.	('nivolumab', 'Chemical', 'MESH:D000077594', (133, 142))	('mutant', 'Var', (107, 113))	('BRAF', 'Gene', '673', (102, 106))	('ipilimumab', 'Chemical', 'MESH:D000074324', (145, 155))	('brain metastases', 'Disease', 'MESH:D009362', (55, 71))	('brain metastases', 'Disease', (55, 71))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('BRAF', 'Gene', (102, 106))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('patients', 'Species', '9606', (28, 36))
88867	32663057	The median recurrence-free survival (RFS) for ipilimumab was 26.1 months versus 17.1 months for placebo.	('recurrence-free', 'Disease', (11, 26))	('ipilimumab', 'Chemical', 'MESH:D000074324', (46, 56))	('ipilimumab', 'Var', (46, 56))
88872	32663057	The study included 906 patients, among whom about 42% were BRAF mutant.	('patients', 'Species', '9606', (23, 31))	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (59, 63))	('mutant', 'Var', (64, 70))
88879	32663057	The trial included 1019 patients, among whom about 47% were BRAF mutant.	('BRAF', 'Gene', (60, 64))	('mutant', 'Var', (65, 71))	('BRAF', 'Gene', '673', (60, 64))	('patients', 'Species', '9606', (24, 32))
88880	32663057	Among PD-L1 positive patients, the 1-yr RFS rate was 77.1% vs 62.6% for pembrolizumab and placebo populations, respectively, but the treatment was effective regardless of the PD-L1 expression.	('pembrolizumab', 'Chemical', 'MESH:C582435', (72, 85))	('men', 'Species', '9606', (138, 141))	('PD-L1', 'Gene', (175, 180))	('patients', 'Species', '9606', (21, 29))	('PD-L1', 'Gene', (6, 11))	('PD-L1', 'Gene', '29126', (175, 180))	('positive', 'Var', (12, 20))	('PD-L1', 'Gene', '29126', (6, 11))
88881	32663057	AEs G3-G5 were recorded in 14.7% patients receiving pembrolizumab vs 3.4% of patients receiving placebo.	('pembrolizumab', 'Var', (52, 65))	('pembrolizumab', 'Chemical', 'MESH:C582435', (52, 65))	('patients', 'Species', '9606', (33, 41))	('patients', 'Species', '9606', (77, 85))	('AEs G3-G5', 'Var', (0, 9))
88884	32663057	BRAF/MEK inhibitors are able to modify the tumor microenvironment of melanoma exerting an immunogenic effect such as the increasing of T-cell infiltration, the upregulation of melanoma antigens and the expression of MHC class I/II, opening a new scenario for the combination of target therapy and immunotherapy.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('upregulation', 'PosReg', (160, 172))	('modify', 'Reg', (32, 38))	('melanoma', 'Disease', (176, 184))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('tumor', 'Disease', (43, 48))	('MEK', 'Gene', '5609', (5, 8))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('MEK', 'Gene', (5, 8))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('increasing', 'PosReg', (121, 131))	('T-cell infiltration', 'CPA', (135, 154))	('MHC class I/II', 'Protein', (216, 230))	('men', 'Species', '9606', (61, 64))	('inhibitors', 'Var', (9, 19))
88890	32663057	In the KEYNOTE-022 phase II trial, 120 patients with BRAF mutation received dabrafenib and trametinib + pembrolizumab or placebo.	('trametinib', 'Chemical', 'MESH:C560077', (91, 101))	('BRAF', 'Gene', '673', (53, 57))	('patients', 'Species', '9606', (39, 47))	('pembrolizumab', 'Chemical', 'MESH:C582435', (104, 117))	('BRAF', 'Gene', (53, 57))	('mutation', 'Var', (58, 66))	('dabrafenib', 'Chemical', 'MESH:C561627', (76, 86))
88906	32663057	About 10% of MM are BRAF mutated compared with a 50% BRAF mutation rate in cutaneous melanoma.	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('BRAF', 'Gene', '673', (20, 24))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('cutaneous melanoma', 'Disease', (75, 93))	('BRAF', 'Gene', (20, 24))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (75, 93))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (75, 93))	('mutated', 'Var', (25, 32))
88908	32663057	The total rate of mutations, including the ultraviolet-related mutations, is lower for MM than cutaneous melanoma.	('lower', 'NegReg', (77, 82))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('cutaneous melanoma', 'Disease', (95, 113))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (95, 113))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (95, 113))	('mutations', 'Var', (18, 27))
88972	32209601	It has not been definitively shown that CPI improves survival in metastatic sun-shielded melanoma.	('CPI', 'Chemical', '-', (40, 43))	('improves', 'PosReg', (44, 52))	('CPI', 'Var', (40, 43))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
88973	32209601	We reviewed a single institutional experience using antibodies against CTLA-4, PD-1 and/or PD-L1 to treat patients with metastatic melanoma.	('CTLA-4', 'Gene', '1493', (71, 77))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('PD-L1', 'Gene', (91, 96))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('CTLA-4', 'Gene', (71, 77))	('PD-1', 'Gene', (79, 83))	('PD-L1', 'Gene', '29126', (91, 96))	('patients', 'Species', '9606', (106, 114))	('antibodies', 'Var', (52, 62))	('PD-1', 'Gene', '9825', (79, 83))
88984	32209601	Checkpoint inhibitors (CPI), including antibodies against CTLA-4, PD-1 and PD-L1, are a highly effective treatment for metastatic cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (130, 148))	('PD-L1', 'Gene', (75, 80))	('CTLA-4', 'Gene', '1493', (58, 64))	('PD-1', 'Gene', (66, 70))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('PD-L1', 'Gene', '29126', (75, 80))	('cutaneous melanoma', 'Disease', (130, 148))	('CPI', 'Chemical', '-', (23, 26))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (130, 148))	('PD-1', 'Gene', '9825', (66, 70))	('CTLA-4', 'Gene', (58, 64))	('antibodies', 'Var', (39, 49))
88988	32209601	One consequence of mutagenesis by ultraviolet (UV) radiation is the accumulation of a large burden of somatic mutations (neoantigens) that are thought to contribute to the immunogenicity of cutaneous melanoma.	('mutations', 'Var', (110, 119))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('cutaneous melanoma', 'Disease', (190, 208))	('contribute', 'Reg', (154, 164))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (190, 208))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (190, 208))	('mutagenesis', 'Var', (19, 30))	('mutagenesis', 'biological_process', 'GO:0006280', ('19', '30'))
88989	32209601	Genomic studies have demonstrated that cutaneous melanomas have an average mutation rate of 16.8 mutations per megabase, one of the highest reported for any cancer type thus far analyzed by The Cancer Genome Atlas Program.	('mutations', 'Var', (97, 106))	('Cancer', 'Disease', 'MESH:D009369', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('cutaneous melanomas', 'Disease', (39, 58))	('Cancer', 'Phenotype', 'HP:0002664', (194, 200))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (39, 57))	('cancer', 'Disease', (157, 163))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (39, 58))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (39, 58))	('Cancer', 'Disease', (194, 200))
88990	32209601	The mutagenic role of UV radiation in cutaneous melanoma was confirmed by studies showing a high fraction of C>T transitions at dipyrimidines as well as tandem double CC>TT mutations.	('tandem double CC>TT mutations', 'Var', (153, 182))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('C>T transitions', 'Var', (109, 124))	('dipyrimidines', 'Chemical', '-', (128, 141))	('cutaneous melanoma', 'Disease', (38, 56))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (38, 56))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (38, 56))
88991	32209601	Furthermore, UV mutagenesis in melanoma has been linked to unique tumor biology, such as hot-spot mutations in BRAF or or RAS, as well as loss-of-function mutations in NF1.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutagenesis', 'biological_process', 'GO:0006280', ('16', '27'))	('mutations', 'Var', (155, 164))	('NF1', 'Gene', '4763', (168, 171))	('tumor', 'Disease', (66, 71))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('loss-of-function', 'NegReg', (138, 154))	('mutations', 'Var', (98, 107))	('mutagenesis', 'Var', (16, 27))	('NF1', 'Gene', (168, 171))	('BRAF', 'Gene', '673', (111, 115))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('melanoma', 'Disease', (31, 39))	('BRAF', 'Gene', (111, 115))	('or or RAS', 'Gene', (116, 125))
88998	32209601	Also, sun-shielded melanomas often lack mutations in BRAF, RAS or NF1 and thus display a 'triple wild-type' signature, which is associated with a high proportion of copy number changes and complex structural arrangements.	('BRAF', 'Gene', '673', (53, 57))	('RAS', 'Gene', (59, 62))	('melanomas', 'Disease', 'MESH:D008545', (19, 28))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('BRAF', 'Gene', (53, 57))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('mutations', 'Var', (40, 49))	('lack', 'NegReg', (35, 39))	('NF1', 'Gene', (66, 69))	('NF1', 'Gene', '4763', (66, 69))	('melanomas', 'Disease', (19, 28))
89011	32209601	These reports show that while there are promising data to support the use of CPI in sun-shielded melanoma, the literature in terms of efficacy has been limited.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('CPI', 'Chemical', '-', (77, 80))	('CPI', 'Var', (77, 80))
89012	32209601	The extent to which CPI impacts survival in these patients is unclear, and there are few data to guide treatment sequencing or the use of adjunctive therapies.	('CPI', 'Chemical', '-', (20, 23))	('patients', 'Species', '9606', (50, 58))	('survival', 'MPA', (32, 40))	('impacts', 'Reg', (24, 31))	('CPI', 'Var', (20, 23))
89066	32209601	Neoantigen-reactive T cell clones have also been reliably isolated from microsatellite-stable tumors of gastrointestinal origin, which have a paucity of neoantigenic mutations.	('tumors of gastrointestinal', 'Disease', (94, 120))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors of gastrointestinal', 'Disease', 'MESH:D004067', (94, 120))	('tumors of gastrointestinal', 'Phenotype', 'HP:0007378', (94, 120))	('microsatellite-stable', 'Var', (72, 93))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
89079	32209601	Survival in patients with metastatic acral, mucosal and uveal melanoma was highly associated with blockade of both CTLA-4 and PD-1/PD-L1, either sequentially or in combination.	('patients', 'Species', '9606', (12, 20))	('uveal melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('associated', 'Reg', (82, 92))	('blockade', 'Var', (98, 106))	('metastatic acral', 'Disease', (26, 42))	('CTLA-4', 'Gene', (115, 121))	('PD-L1', 'Gene', '29126', (131, 136))	('PD-1', 'Gene', (126, 130))	('mucosal and uveal melanoma', 'Disease', 'MESH:C536494', (44, 70))	('PD-1', 'Gene', '9825', (126, 130))	('CTLA-4', 'Gene', '1493', (115, 121))	('PD-L1', 'Gene', (131, 136))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
89266	31382694	Families with BAP1-Tumor Predisposition Syndrome in The Netherlands: Path to Identification and a Proposal for Genetic Screening Guidelines Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1-tumor predisposition syndrome (BAP1-TPDS, OMIM 614327).	('BAP1', 'Gene', '8314', (14, 18))	('cause', 'Reg', (215, 220))	('BAP1', 'Gene', '8314', (261, 265))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('BAP1-tumor', 'Disease', (225, 235))	('BRCA1-associated protein-1', 'Gene', '8314', (176, 202))	('BAP1', 'Gene', (14, 18))	('BAP1', 'Gene', (204, 208))	('BAP1', 'Gene', '8314', (225, 229))	('BAP1', 'Gene', '8314', (204, 208))	('BAP1', 'Gene', (261, 265))	('BAP1-tumor', 'Disease', 'MESH:D009369', (225, 235))	('Tumor', 'Phenotype', 'HP:0002664', (19, 24))	('BAP1', 'Gene', (225, 229))	('BRCA1-associated protein-1', 'Gene', (176, 202))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('variants', 'Var', (160, 168))
89267	31382694	BAP1-TPDS is associated with an increased risk of developing uveal melanoma (UM), cutaneous melanoma (CM), malignant mesothelioma (MMe), renal cell carcinoma (RCC), meningioma, cholangiocarcinoma, multiple non-melanoma skin cancers, and BAP1-inactivated nevi.	('nevi', 'Phenotype', 'HP:0003764', (254, 258))	('skin cancer', 'Phenotype', 'HP:0008069', (219, 230))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 100))	('uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('BAP1-TPDS', 'Var', (0, 9))	('non-melanoma skin cancers', 'Disease', (206, 231))	('meningioma', 'Disease', 'MESH:D008577', (165, 175))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (177, 195))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('renal cell carcinoma', 'Disease', (137, 157))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (137, 157))	('cholangiocarcinoma', 'Disease', (177, 195))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (107, 129))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (177, 195))	('CM', 'Phenotype', 'HP:0012056', (102, 104))	('skin cancers', 'Phenotype', 'HP:0008069', (219, 231))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('malignant mesothelioma', 'Disease', (107, 129))	('MMe', 'Phenotype', 'HP:0100001', (131, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('uveal melanoma', 'Disease', 'MESH:C536494', (61, 75))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (107, 129))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('meningioma', 'Disease', (165, 175))	('uveal melanoma', 'Disease', (61, 75))	('non-melanoma skin cancers', 'Disease', 'MESH:D012878', (206, 231))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (137, 157))	('meningioma', 'Phenotype', 'HP:0002858', (165, 175))	('cutaneous melanoma', 'Disease', (82, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (82, 100))
89273	31382694	Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene underlie the BAP1-tumor predisposition syndrome (BAP1-TPDS, OMIM 614327).	('variants', 'Var', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('BAP1-tumor', 'Disease', (88, 98))	('BRCA1-associated protein-1', 'Gene', (36, 62))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('BAP1-tumor', 'Disease', 'MESH:D009369', (88, 98))	('BRCA1-associated protein-1', 'Gene', '8314', (36, 62))	('BAP1', 'Gene', (64, 68))
89274	31382694	At first, somatic BAP1 mutations were identified in 84% of 31 analyzed metastasized uveal melanoma (UM) and these mutations were found to be associated with metastatic progression of UM.	('UM', 'Phenotype', 'HP:0007716', (100, 102))	('mutations', 'Var', (114, 123))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma', 'Disease', (84, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('UM', 'Phenotype', 'HP:0007716', (183, 185))	('BAP1', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('associated with', 'Reg', (141, 156))	('metastatic progression', 'CPA', (157, 179))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
89276	31382694	Between 2011 and 2013, germline BAP1 variants were also reported in association with cutaneous melanoma (CM), malignant mesothelioma (MMe), and renal cell carcinoma (RCC).	('CM', 'Phenotype', 'HP:0012056', (105, 107))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('BAP1', 'Gene', (32, 36))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (110, 132))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (144, 164))	('MMe', 'Phenotype', 'HP:0100001', (134, 137))	('cutaneous melanoma', 'Disease', (85, 103))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (85, 103))	('malignant mesothelioma', 'Disease', (110, 132))	('association', 'Reg', (68, 79))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (110, 132))	('renal cell carcinoma', 'Disease', (144, 164))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (144, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('RCC', 'Disease', (166, 169))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('variants', 'Var', (37, 45))
89277	31382694	Since then, several malignancies were found to be associated with BAP1 germline pathogenic variants, the syndrome has been termed BAP1-TPDS.	('malignancies', 'Disease', 'MESH:D009369', (20, 32))	('malignancies', 'Disease', (20, 32))	('BAP1', 'Gene', (66, 70))	('variants', 'Var', (91, 99))	('associated', 'Reg', (50, 60))
89283	31382694	The penetrance of pathogenic germline BAP1 variants is high, with 85% of BAP1-TPDS individuals being diagnosed with >=1 tumors.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('pathogenic', 'Reg', (18, 28))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('BAP1', 'Gene', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('variants', 'Var', (43, 51))
89284	31382694	Diagnostic testing of BAP1 is needed to notify individuals carrying a pathogenic variant of BAP1 and their families of their increased cancer risk.	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('variant', 'Var', (81, 88))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('BAP1', 'Gene', (92, 96))
89286	31382694	The low frequency of pathogenic BAP1 variants in unselected patients with BAP1-TPDS-associated malignancies implies that guidelines for the selection of patients with an increased risk of BAP1-TPDS are needed.	('patients', 'Species', '9606', (153, 161))	('malignancies', 'Disease', (95, 107))	('patients', 'Species', '9606', (60, 68))	('BAP1', 'Gene', (32, 36))	('variants', 'Var', (37, 45))	('malignancies', 'Disease', 'MESH:D009369', (95, 107))
89287	31382694	In this cohort study of BAP1-TPDS families in the Netherlands, we describe the various routes to identification of patients with germline BAP1 pathogenic variants, their clinical phenotype, and genotype.	('patients', 'Species', '9606', (115, 123))	('variants', 'Var', (154, 162))	('BAP1', 'Gene', (138, 142))
89297	31382694	The family with variant c.437+1G>T (NL-18) was initially referred by a surgeon based on familial hepatocellular carcinoma, and the occurrence of UM and MMe in this family led to genetic analysis of BAP1.	('MMe', 'Phenotype', 'HP:0100001', (152, 155))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (97, 121))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('variant c.437+1G>T', 'Var', (16, 34))	('c.437+1G>T', 'Mutation', 'c.437+1G>T', (24, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('NL-1', 'Gene', '22871', (36, 40))	('familial hepatocellular carcinoma', 'Disease', (88, 121))	('BAP1', 'Gene', (198, 202))	('NL-1', 'Gene', (36, 40))	('familial hepatocellular carcinoma', 'Disease', 'MESH:D006528', (88, 121))	('c.437+1G>T', 'Var', (24, 34))
89298	31382694	It is likely that the Dutch families, NL-10 and NL-11, with the identical BAP1 germline variant have a common ancestor, however, no overlap in the family trees has been found.	('NL-1', 'Gene', '22871', (38, 42))	('NL-1', 'Gene', '22871', (48, 52))	('variant', 'Var', (88, 95))	('NL-1', 'Gene', (38, 42))	('NL-1', 'Gene', (48, 52))	('BAP1', 'Gene', (74, 78))
89302	31382694	Variant c.200A>G, p.Asp67Gly (NL-21) is located in the protein domain Peptidase C12, ubiquitin carboxyl-terminal hydrolase 1.	('ubiquitin', 'molecular_function', 'GO:0031386', ('85', '94'))	('ubiquitin carboxyl-terminal hydrolase 1', 'Gene', '7398', (85, 124))	('NL-2', 'Gene', (30, 34))	('c.200A>G', 'Var', (8, 16))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('c.200A>G', 'Mutation', 'rs780803896', (8, 16))	('NL-2', 'Gene', '51129', (30, 34))	('ubiquitin carboxyl-terminal hydrolase 1', 'Gene', (85, 124))	('p.Asp67Gly', 'Mutation', 'rs863224605', (18, 28))
89306	31382694	A novel missense variant c.1387C>G, p.(Leu463Val) was found in family NL-22, that was affected by multiple cases of CM.	('CM', 'Phenotype', 'HP:0012056', (116, 118))	('affected by', 'Reg', (86, 97))	('NL-2', 'Gene', '51129', (70, 74))	('p.(Leu463Val)', 'Mutation', 'rs35600253', (36, 49))	('c.1387C>G', 'Mutation', 'rs35600253', (25, 34))	('NL-2', 'Gene', (70, 74))	('c.1387C>G', 'Var', (25, 34))
89307	31382694	The mutational changes c.1017_1048del (NL-7) and c.1819delA (NL-13) in the germline BAP1 were not found in parents and a sibling of both probands.	('c.1017_1048del', 'Var', (23, 37))	('NL-1', 'Gene', (61, 65))	('c.1819delA', 'Var', (49, 59))	('c.1017_1048del', 'Mutation', 'c.1017_1048del', (23, 37))	('BAP1', 'Gene', (84, 88))	('c.1819delA', 'Mutation', 'c.1819delA', (49, 59))	('NL-1', 'Gene', '22871', (61, 65))
89308	31382694	The pathogenic variant in ENG (c.1116-1117insT, p.(Lys373*)) was inherited through the paternal lineage.	('p.(Lys373*)', 'SUBSTITUTION', 'None', (48, 59))	('c.1116-1117insT', 'Mutation', 'c.1116_1117insT', (31, 46))	('ENG', 'Gene', (26, 29))	('pathogenic', 'Reg', (4, 14))	('p.(Lys373*', 'Var', (48, 58))	('c.1116-1117insT', 'Var', (31, 46))
89310	31382694	In the remaining three index patients, the germline BAP1 variant was found after they passed away.	('BAP1', 'Gene', (52, 56))	('variant', 'Var', (57, 64))	('patients', 'Species', '9606', (29, 37))	('passed away', 'Phenotype', 'HP:0007185', (86, 97))
89336	31382694	No case of cholangiocarcinoma was reported in our patient population and meningioma was present in one proven carrier of a pathogenic BAP1 gene (1/72, 1.4%), who developed a vestibular schwannoma as well as an UM later in life.	('UM', 'Phenotype', 'HP:0007716', (210, 212))	('meningioma', 'Phenotype', 'HP:0002858', (73, 83))	('BAP1', 'Gene', (134, 138))	('meningioma', 'Disease', 'MESH:D008577', (73, 83))	('cholangiocarcinoma', 'Disease', (11, 29))	('vestibular schwannoma', 'Disease', (174, 195))	('vestibular schwannoma', 'Disease', 'MESH:D009464', (174, 195))	('developed', 'Reg', (162, 171))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (11, 29))	('schwannoma', 'Phenotype', 'HP:0100008', (185, 195))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (11, 29))	('vestibular schwannoma', 'Phenotype', 'HP:0009588', (174, 195))	('gene', 'Var', (139, 143))	('carrier', 'molecular_function', 'GO:0005215', ('110', '117'))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('patient', 'Species', '9606', (50, 57))	('meningioma', 'Disease', (73, 83))
89341	31382694	The described cohort in this study is too small to draw conclusions about possible associations of other tumors types to pathogenic BAP1 variants.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('associations', 'Interaction', (83, 95))	('BAP1', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('variants', 'Var', (137, 145))
89348	31382694	De novo germline BAP1 variants were found in families NL-7 and NL-13 (2/21, 9.5%), in both cases, paternity was confirmed.	('NL-1', 'Gene', '22871', (63, 67))	('variants', 'Var', (22, 30))	('NL-1', 'Gene', (63, 67))	('BAP1', 'Gene', (17, 21))
89349	31382694	No additional immunohistochemistry or genetic analysis of tumors in the carriers of germline BAP1 variants has been performed.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('carriers', 'Reg', (72, 80))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('BAP1', 'Gene', (93, 97))	('variants', 'Var', (98, 106))
89350	31382694	Consequently, it is uncertain if the development of the found malignancies are correlated to the aberrant BAP1 allele.	('malignancies', 'Disease', (62, 74))	('aberrant', 'Var', (97, 105))	('BAP1', 'Gene', (106, 110))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))
89354	31382694	When a larger cohort of 30 iris melanomas was analyzed by Van Poppelen et al., these findings were confirmed, with additional mutations observed in SF3B1, but also in the CM-associated genes NRAS, BRAF, PTEN, c-KIT, and TP53.	('TP53', 'Gene', (220, 224))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanomas', 'Phenotype', 'HP:0002861', (32, 41))	('PTEN', 'Gene', (203, 207))	('NRAS', 'Gene', (191, 195))	('iris melanomas', 'Disease', (27, 41))	('mutations', 'Var', (126, 135))	('c-KIT', 'Gene', (209, 214))	('TP53', 'Gene', '7157', (220, 224))	('PTEN', 'Gene', '5728', (203, 207))	('BRAF', 'Gene', (197, 201))	('iris melanomas', 'Disease', 'MESH:D007499', (27, 41))	('BRAF', 'Gene', '673', (197, 201))	('KIT', 'molecular_function', 'GO:0005020', ('211', '214'))	('c-KIT', 'Gene', '3815', (209, 214))	('SF3B1', 'Gene', (148, 153))	('iris melanoma', 'Phenotype', 'HP:0011524', (27, 40))	('iris melanomas', 'Phenotype', 'HP:0011524', (27, 41))	('CM', 'Phenotype', 'HP:0012056', (171, 173))	('NRAS', 'Gene', '4893', (191, 195))	('SF3B1', 'Gene', '23451', (148, 153))
89358	31382694	Mutations in the CM driver genes BRAF and NRAS have been found in conjunctival melanoma.	('NRAS', 'Gene', '4893', (42, 46))	('BRAF', 'Gene', '673', (33, 37))	('CM', 'Phenotype', 'HP:0012056', (17, 19))	('BRAF', 'Gene', (33, 37))	('CM driver', 'Gene', (17, 26))	('found', 'Reg', (57, 62))	('conjunctival melanoma', 'Disease', (66, 87))	('Mutations', 'Var', (0, 9))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (66, 87))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (66, 87))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('NRAS', 'Gene', (42, 46))
89368	31382694	This could imply that there is a genotype-phenotype relation between the specific BAP1 aberration and the type of malignancy.	('malignancy', 'Disease', 'MESH:D009369', (114, 124))	('BAP1', 'Gene', (82, 86))	('malignancy', 'Disease', (114, 124))	('aberration', 'Var', (87, 97))
89371	31382694	However, mouse models have been established where mice harbor a heterozygous pathogenic variant in BAP1.	('BAP1', 'Gene', (99, 103))	('variant', 'Var', (88, 95))	('mouse', 'Species', '10090', (9, 14))	('pathogenic', 'Reg', (77, 87))	('mice', 'Species', '10090', (50, 54))
89374	31382694	Moreover, MMe arose in a shorter period of time in the BAP1+/- mice after initial exposure (43 weeks vs. 55 weeks, respectively).	('MMe', 'Disease', (10, 13))	('MMe', 'Phenotype', 'HP:0100001', (10, 13))	('mice', 'Species', '10090', (63, 67))	('BAP1+/-', 'Var', (55, 62))
89383	31382694	The mean age at BAP1 germline analysis of the proband (or age at last follow-up in obligate carriers) was 44 years in the 42 carriers of a BAP1 pathogenic variant without BAP1-TPDS core malignancies and 59 years in the remaining 27 BAP1-TPDS patients (age at BAP1 analysis is missing for three patients) that have been diagnosed with UM, CM, MMe and/or RCC (p < 0.001).	('core', 'cellular_component', 'GO:0019013', ('181', '185'))	('UM', 'Phenotype', 'HP:0007716', (334, 336))	('malignancies', 'Disease', 'MESH:D009369', (186, 198))	('patients', 'Species', '9606', (294, 302))	('MMe', 'Phenotype', 'HP:0100001', (342, 345))	('RCC', 'Disease', (353, 356))	('RCC', 'Phenotype', 'HP:0005584', (353, 356))	('CM', 'Phenotype', 'HP:0012056', (338, 340))	('BAP1', 'Gene', (139, 143))	('variant', 'Var', (155, 162))	('RCC', 'Disease', 'MESH:C538614', (353, 356))	('MMe', 'Disease', (342, 345))	('malignancies', 'Disease', (186, 198))	('patients', 'Species', '9606', (242, 250))
89387	31382694	Testing bias plays a role as well, as patients with a previous medical history of BAP1-TPDS-associated malignancies are more likely to undergo genetic testing.	('undergo', 'Reg', (135, 142))	('genetic testing', 'Var', (143, 158))	('malignancies', 'Disease', 'MESH:D009369', (103, 115))	('patients', 'Species', '9606', (38, 46))	('malignancies', 'Disease', (103, 115))	('BAP1-TPDS-associated', 'Gene', (82, 102))
89392	31382694	However, carriers of a germline BAP1 pathogenic variant tend to develop BAP1-TPDS-associated malignancies at a younger age.	('malignancies', 'Disease', (93, 105))	('malignancies', 'Disease', 'MESH:D009369', (93, 105))	('BAP1', 'Gene', (32, 36))	('develop', 'PosReg', (64, 71))	('variant', 'Var', (48, 55))
89399	31382694	found 12 probands harboring pathogenic germline variants in BAP1 in a group of 17 (71%) patients with >=1 BINs and a suspicious medical or family history.	('patients', 'Species', '9606', (88, 96))	('pathogenic', 'Reg', (28, 38))	('BAP1', 'Gene', (60, 64))	('germline variants', 'Var', (39, 56))
89401	31382694	showed a median age at diagnosis for UM in patients with germline null variants of 53 years (interquartile range: 44-60 years) and a median age of 58 years for missense variants, (interquartile range: 45-69 years), which are both under the reported median age of incidental UM of 66 years in the Netherlands.	('variants', 'Var', (71, 79))	('missense variants', 'Var', (160, 177))	('patients', 'Species', '9606', (43, 51))	('UM', 'Phenotype', 'HP:0007716', (37, 39))	('UM', 'Phenotype', 'HP:0007716', (274, 276))
89406	31382694	The family harboring VUS c.1387C>G, p.Leu463Val (NL-22) would not have been genetically analyzed based on the proposed guidelines.	('p.Leu463Val', 'Mutation', 'rs35600253', (36, 47))	('NL-2', 'Gene', (49, 53))	('c.1387C>G', 'Mutation', 'rs35600253', (25, 34))	('p.Leu463Val', 'Var', (36, 47))	('NL-2', 'Gene', '51129', (49, 53))	('c.1387C>G', 'Var', (25, 34))
89408	31382694	If we apply the proposed guidelines based on BAP1-TPDS-associated malignancies to these families, assuming reported family members are first- or second-degree relatives, 120/141 (85%) families carrying null variants and 18/40 (45%) families carrying missense variants would have been offered genetic analysis.	('missense variants', 'Var', (250, 267))	('BAP1-TPDS-associated', 'Gene', (45, 65))	('null variants', 'Var', (202, 215))	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('malignancies', 'Disease', (66, 78))
89432	31382694	The following table is available online at , Table S1: Malignancies found in proband, tested non-proband carriers and untested members from families with germline variants in BAP1.	('Malignancies', 'Disease', 'MESH:D009369', (55, 67))	('variants', 'Var', (163, 171))	('BAP1', 'Gene', (175, 179))	('Malignancies', 'Disease', (55, 67))
89433	31382694	Data S1: RNA analysis of BAP1 variant c.122+5G>C (NL-17).	('c.122+5G>C', 'Var', (38, 48))	('RNA', 'cellular_component', 'GO:0005562', ('9', '12'))	('BAP1', 'Gene', (25, 29))	('c.122+5G>C', 'Mutation', 'c.122+5G>C', (38, 48))	('NL-1', 'Gene', '22871', (50, 54))	('variant c.122+5G>C', 'Var', (30, 48))	('NL-1', 'Gene', (50, 54))
89442	28828481	Risk is also increased by the presence of chromosome 3 monosomy, loss of chromosome 1p or 8p, or gain of 8q, or decreased by the gain of 6p in the tumors.	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('loss', 'NegReg', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('gain', 'PosReg', (97, 101))	('monosomy', 'Var', (55, 63))	('gain', 'PosReg', (129, 133))	('decreased', 'NegReg', (112, 121))	('chromosome', 'Var', (42, 52))	('chromosome', 'cellular_component', 'GO:0005694', ('42', '52'))
89444	28828481	Somatic mutations in BAP1 and SF3B1, and PRAME expression have also been associated with increased metastatic risk, whereas mutations in EIF1AX have been shown to be protective.	('SF3B1', 'Gene', (30, 35))	('PRAME', 'Gene', '23532', (41, 46))	('PRAME', 'Gene', (41, 46))	('BAP1', 'Gene', (21, 25))	('mutations', 'Var', (8, 17))	('associated', 'Reg', (73, 83))	('SF3B1', 'Gene', '23451', (30, 35))	('EIF1AX', 'Gene', '1964', (137, 143))	('metastatic risk', 'CPA', (99, 114))	('EIF1AX', 'Gene', (137, 143))	('BAP1', 'Gene', '8314', (21, 25))
89465	28828481	Tumors having a pattern of mixed chromosome disomy and monosomy likely as a result of tumor heterogeneity were categorized as mosaic.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('chromosome', 'cellular_component', 'GO:0005694', ('33', '43'))	('tumor', 'Disease', (86, 91))	('Tumors', 'Disease', (0, 6))	('monosomy', 'Var', (55, 63))	('disomy', 'Disease', (44, 50))	('disomy', 'Disease', 'MESH:D024182', (44, 50))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
89468	28828481	Chromosome 3 status (disomy, monosomy, partial monosomy, or mosaic) was available for 1158 tumors.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('monosomy', 'Var', (29, 37))	('disomy', 'Disease', 'MESH:D024182', (21, 27))	('mosaic', 'Var', (60, 66))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('partial monosomy', 'Var', (39, 55))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('disomy', 'Disease', (21, 27))
89478	28828481	In line with previous studies, Cox univariate analysis showed that male sex (P = 0.007), older age (P < 0.001), tumor basal diameter and thickness (both P < 0.001), ciliochoroidal location (CB-CH, P < 0.001), and chromosome 3 monosomy or partial monosomy (P < 0.001) were all significantly associated with increased incidence of metastases (Tables 2 and 3).	('partial monosomy', 'Var', (238, 254))	('Cox', 'Gene', '1351', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('monosomy', 'Var', (226, 234))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Cox', 'Gene', (31, 34))	('chromosome 3', 'Gene', (213, 225))	('chromosome', 'cellular_component', 'GO:0005694', ('213', '223'))	('metastases', 'Disease', (329, 339))	('tumor', 'Disease', (112, 117))	('metastases', 'Disease', 'MESH:D009362', (329, 339))
89484	28828481	Male sex (P < 0.001), tumor diameter (P < 0.001), chromosome 3 monosomy (P = 0.027), 1p loss (P = 0.028), 8p loss (P = 0.001), 8q gain (P = 0.007), and 6p gain (protective, P = 0.006) remained significantly associated with metastasis after adjusting for the effects of all other features.	('metastasis', 'CPA', (223, 233))	('6p gain', 'Var', (152, 159))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('loss', 'NegReg', (109, 113))	('chromosome', 'Var', (50, 60))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('loss', 'NegReg', (88, 92))	('monosomy', 'Var', (63, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('50', '60'))	('tumor', 'Disease', (22, 27))	('gain', 'PosReg', (130, 134))
89508	28828481	An increasing number of studies are showing that mutations in genes such as BAP1, SF3B1, and EIF1AX and expression of PRAME are associated with increased or decreased risk of metastases.	('SF3B1', 'Gene', (82, 87))	('mutations', 'Var', (49, 58))	('EIF1AX', 'Gene', (93, 99))	('EIF1AX', 'Gene', '1964', (93, 99))	('BAP1', 'Gene', '8314', (76, 80))	('SF3B1', 'Gene', '23451', (82, 87))	('metastases', 'Disease', (175, 185))	('PRAME', 'Gene', '23532', (118, 123))	('PRAME', 'Gene', (118, 123))	('BAP1', 'Gene', (76, 80))	('metastases', 'Disease', 'MESH:D009362', (175, 185))	('decreased', 'NegReg', (157, 166))
89533	29382357	Recently, epigenetic events mediated by miRNAs have been implicated in UM development.	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('UM development', 'CPA', (71, 85))	('implicated', 'Reg', (57, 67))	('epigenetic events', 'Var', (10, 27))
89561	29382357	To determine the common target region of the miR-181 family in CTDSPL, a segment of wild-type and mutated 3'-UTR of the human CTDSPL cDNA was constructed.	('mutated', 'Var', (98, 105))	('miR', 'Gene', (45, 48))	('human', 'Species', '9606', (120, 125))	('miR', 'Gene', '220972', (45, 48))
89562	29382357	293 T cells were plated in 24-well flat-bottomed plates and co-transfected with the wild-type or mutated 3'-UTR of the CTDSPL reporter plasmid, pRL-TK, and miR-181 family members or miR-NC using Lipofectamine 2000 reagent.	('mutated', 'Var', (97, 104))	('miR', 'Gene', '220972', (182, 185))	('293 T', 'CellLine', 'CVCL:0063', (0, 5))	('miR', 'Gene', (182, 185))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (195, 213))	('miR', 'Gene', '220972', (156, 159))	('miR', 'Gene', (156, 159))
89566	29382357	DPN1 enzyme (Sangon Biotech, Shanghai, China) was used to delete the genomic DNA from the extracted RNA, which was used to amplify the miRNAs.	('miR', 'Gene', (135, 138))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('delete', 'Var', (58, 64))	('RNA', 'cellular_component', 'GO:0005562', ('100', '103'))	('miR', 'Gene', '220972', (135, 138))
89578	29382357	Evolutionary conservation analysis of the miR-181 family members indicated that the sequences of miR-181a, -181b, -181c, and -181d are partly conserved in Homo sapiens, Mus musculus, Rattus norvegicus, Bos taurus and Pan troglodytes (Fig.	('Homo sapiens', 'Species', '9606', (155, 167))	('Pan troglodytes', 'Species', '9598', (217, 232))	('Mus musculus', 'Species', '10090', (169, 181))	('Rattus norvegicus', 'Species', '10116', (183, 200))	('miR', 'Gene', '220972', (97, 100))	('Bos taurus', 'Species', '9913', (202, 212))	('miR', 'Gene', '220972', (42, 45))	('miR', 'Gene', (42, 45))	('and -181d', 'Var', (121, 130))	('miR', 'Gene', (97, 100))
89580	29382357	The results demonstrated that mimics of miR-181 family members promoted cell cycle progression, while inhibitors of miR-181 family members led to cell cycle arrest (Fig.	('mimics', 'Var', (30, 36))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('cell cycle', 'biological_process', 'GO:0007049', ('72', '82'))	('cell cycle progression', 'CPA', (72, 94))	('miR', 'Gene', '220972', (116, 119))	('cell cycle arrest', 'CPA', (146, 163))	('miR', 'Gene', (116, 119))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('146', '163'))	('promoted', 'PosReg', (63, 71))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (146, 163))
89585	29382357	Western blot assays further indicated that mimics of miR-181 family members led to the reduced expression of CTDSPL, while inhibitors led to the increased expression of CTDSPL in MUM2b cells (Fig.	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', (53, 56))	('CTDSPL', 'Gene', (109, 115))	('reduced', 'NegReg', (87, 94))	('increased', 'PosReg', (145, 154))	('expression', 'MPA', (155, 165))	('expression', 'MPA', (95, 105))	('mimics', 'Var', (43, 49))
89586	29382357	To examine whether miR-181 family members could directly regulate CTDSPL expression, 293 T cells were transfected with a luciferase reporter construct containing the putative wild-type and mutant 3'-UTR of CTDSPL binding sites, together with one of the following miRNAs: miR-181a, -181b, -181c, -181d, miR-NC, as-miR-181a, -181b, -181c, or -181d.	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', (302, 305))	('miR', 'Gene', (19, 22))	('miR', 'Gene', '220972', (263, 266))	('miR', 'Gene', (263, 266))	('293 T', 'CellLine', 'CVCL:0063', (85, 90))	('mutant', 'Var', (189, 195))	('miR', 'Gene', '220972', (271, 274))	('miR', 'Gene', (271, 274))	('binding', 'molecular_function', 'GO:0005488', ('213', '220'))	('miR', 'Gene', '220972', (313, 316))	('miR', 'Gene', (313, 316))	('miR', 'Gene', '220972', (302, 305))
89588	29382357	2d), whereas activity increased approximately 3-fold when miR-181a, -181b, -181c, or -181d inhibitors were used (Fig.	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('or -181d inhibitors', 'Var', (82, 101))	('increased', 'PosReg', (22, 31))	('activity', 'MPA', (13, 21))
89611	29382357	Results of qRT-PCR demonstrated that CTDSPL expression was inhibited in UM cells after transfection of si-CTDSPL-1 and si-CTDSPL-2, respectively, approximately 65% and 75% in MUM2b cells and approximately 40% and 35% in OCM1a cells (Fig.	('CTDSPL-2', 'Gene', '51496', (122, 130))	('si-CTDSPL-1', 'Var', (103, 114))	('inhibited', 'NegReg', (59, 68))	('CTDSPL-2', 'Gene', (122, 130))	('OCM1', 'Species', '83984', (220, 224))	('CTDSPL', 'MPA', (37, 43))
89612	29382357	Western blotting further confirmed that expression of CTDSPL decreased in MUM2b and OCM1a cells after transfection with si-CTDSPL-1 and si-CTDSPL-2 (Fig.	('expression', 'MPA', (40, 50))	('CTDSPL-2', 'Gene', (139, 147))	('decreased', 'NegReg', (61, 70))	('CTDSPL-2', 'Gene', '51496', (139, 147))	('si-CTDSPL-1', 'Var', (120, 131))	('OCM1', 'Species', '83984', (84, 88))
89613	29382357	In addition, the cell cycle G0/G1-phase proportion decreased significantly, approximately 43% and 36% for MUM2b cells and 35% and 32% for OCM1a cells after transfection with si-CTDSPL-1 and si-CTDSPL-2, compared with control group which is 65% in MUM2b cells and 64% in OCM1a cells.	('G1-phase', 'biological_process', 'GO:0051318', ('31', '39'))	('cell cycle', 'biological_process', 'GO:0007049', ('17', '27'))	('decreased', 'NegReg', (51, 60))	('OCM1', 'Species', '83984', (138, 142))	('CTDSPL-2', 'Gene', '51496', (193, 201))	('si-CTDSPL-1', 'Var', (174, 185))	('cell cycle G0/G1-phase proportion', 'CPA', (17, 50))	('CTDSPL-2', 'Gene', (193, 201))	('OCM1', 'Species', '83984', (270, 274))
89614	29382357	While the cell cycle S-phase proportion increased from 13% to 21% and 15% in MUM2b cells and from 10% to 22% and 15% in OCM1a cells after transfection with si-CTDSPL-1 and si-CTDSPL-2 seperately (Fig.	('OCM1', 'Species', '83984', (120, 124))	('CTDSPL-2', 'Gene', '51496', (175, 183))	('S-phase', 'biological_process', 'GO:0051320', ('21', '28'))	('CTDSPL-2', 'Gene', (175, 183))	('si-CTDSPL-1', 'Var', (156, 167))	('increased', 'PosReg', (40, 49))	('cell cycle', 'biological_process', 'GO:0007049', ('10', '20'))	('cell cycle S-phase proportion', 'CPA', (10, 39))
89615	29382357	Increased pRB and E2F1 expression was also confirmed after transfection with si-CTDSPL-1 and si-CTDSPL-2 (Fig.	('E2F1', 'Gene', (18, 22))	('CTDSPL-2', 'Gene', '51496', (96, 104))	('pRB', 'Gene', (10, 13))	('Increased', 'PosReg', (0, 9))	('si-CTDSPL-1', 'Var', (77, 88))	('CTDSPL-2', 'Gene', (96, 104))	('pRB', 'Gene', '5925', (10, 13))	('expression', 'MPA', (23, 33))
89637	29382357	There is another report that the loss of miR-181a-1/b-1 dampens the induction of experimental autoimmune encephalomyelitis and reduces basal TCR signaling in peripheral T cells and their migration from lymph nodes to pathogenic sites.	('reduces', 'NegReg', (127, 134))	('basal TCR signaling', 'MPA', (135, 154))	('dampens', 'NegReg', (56, 63))	('b-1', 'Gene', '931', (52, 55))	('TCR', 'cellular_component', 'GO:0042101', ('141', '144'))	('miR-181a-1', 'Gene', '406995', (41, 51))	('miR-181a-1', 'Gene', (41, 51))	('loss', 'Var', (33, 37))	('b-1', 'Gene', (52, 55))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))	('TCR', 'biological_process', 'GO:0006283', ('141', '144'))	('autoimmune encephalomyelitis', 'Disease', (94, 122))	('autoimmune encephalomyelitis', 'Disease', 'MESH:D004681', (94, 122))	('migration from', 'CPA', (187, 201))
89663	29382357	Previous studies have also reported that CTDSPL removes the phosphate group from serines 807 and 811 in its substrate, pRB, and thereby induces the formation of the RB/E2F1 complex.	('RB/E2F1', 'MPA', (165, 172))	('phosphate group', 'MPA', (60, 75))	('pRB', 'Gene', (119, 122))	('serines', 'Chemical', 'MESH:D012694', (81, 88))	('formation', 'biological_process', 'GO:0009058', ('148', '157'))	('CTDSPL', 'Var', (41, 47))	('pRB', 'Gene', '5925', (119, 122))	('removes', 'NegReg', (48, 55))	('formation', 'MPA', (148, 157))	('phosphate', 'Chemical', 'MESH:D010710', (60, 69))	('induces', 'Reg', (136, 143))
89700	22228632	Our findings suggest that Notch plays an important role in inducing proliferation and invasion in uveal melanoma and that inhibiting this pathway may be effective in preventing tumor growth and metastasis.	('inducing', 'PosReg', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('proliferation', 'CPA', (68, 81))	('invasion', 'CPA', (86, 94))	('preventing', 'NegReg', (166, 176))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('uveal melanoma', 'Phenotype', 'HP:0007716', (98, 112))	('uveal melanoma', 'Disease', (98, 112))	('uveal melanoma', 'Disease', 'MESH:C536494', (98, 112))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))	('inhibiting', 'Var', (122, 132))
89706	22228632	Mutations in the tumor suppressor BAP1 were recently reported to occur almost exclusively in metastasizing class 2 tumors.	('tumor suppressor', 'biological_process', 'GO:0051726', ('17', '33'))	('occur', 'Reg', (65, 70))	('tumor', 'Disease', (17, 22))	('BAP1', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('17', '33'))	('tumors', 'Disease', (115, 121))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
89709	22228632	We have also recently shown that Notch activation can induce formation of pigmented, invasive uveal tumors in mice.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('invasive uveal tumors', 'Disease', 'MESH:D014603', (85, 106))	('mice', 'Species', '10090', (110, 114))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('Notch activation', 'Var', (33, 49))	('formation', 'biological_process', 'GO:0009058', ('61', '70'))	('pigmented', 'CPA', (74, 83))	('invasive uveal tumors', 'Disease', (85, 106))
89713	22228632	Aberrant Notch signaling has been identified in numerous tumor types, but the effects of the pathway depend upon the tissue and cellular context.	('Aberrant', 'Var', (0, 8))	('numerous tumor', 'Disease', (48, 62))	('Notch', 'Gene', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('numerous tumor', 'Disease', 'MESH:D009369', (48, 62))	('signaling', 'biological_process', 'GO:0023052', ('15', '24'))
89716	22228632	In human cutaneous melanoma, activation of Notch1 promotes cell growth and tumor invasion in 3-dimensional spheroids; Notch1 activation also induces a transformed cellular phenotype in cutaneous melanocytes in vitro.	('human', 'Species', '9606', (3, 8))	('transformed cellular phenotype in', 'CPA', (151, 184))	('induces', 'Reg', (141, 148))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('promotes', 'PosReg', (50, 58))	('cell growth', 'biological_process', 'GO:0016049', ('59', '70'))	('Notch1', 'Gene', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('activation', 'Var', (29, 39))	('Notch1', 'Gene', '4851', (118, 124))	('activation', 'PosReg', (125, 135))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('cutaneous melanoma', 'Disease', (9, 27))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (9, 27))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (9, 27))	('Notch1', 'Gene', (43, 49))	('Notch1', 'Gene', '4851', (43, 49))	('cell growth', 'CPA', (59, 70))
89762	22228632	S2E), whereas no expression was detected in cells transfected with CBF-BM, which contains a point mutation that renders the CBF1 responsive element inactive.	('CBF1', 'Gene', (124, 128))	('CBF1', 'Gene', '3516', (124, 128))	('point mutation', 'Var', (92, 106))
89773	22228632	To confirm that Notch pathway blockade was inducing cell death, we infected OCM3 and OCM1 cells with shRNAs targeting CBF1, the DNA-binding mediator of canonical Notch signaling.	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('OCM1', 'Species', '83984', (85, 89))	('blockade', 'Var', (30, 38))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('128', '139'))	('cell death', 'biological_process', 'GO:0008219', ('52', '62'))	('CBF1', 'Gene', '3516', (118, 122))	('CBF1', 'Gene', (118, 122))
89778	22228632	2G) and CBF1 knockdown (Fig.	('knockdown', 'Var', (13, 22))	('CBF1', 'Gene', '3516', (8, 12))	('CBF1', 'Gene', (8, 12))
89798	22228632	S5A), suggesting that the phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and JAK/STAT pathways may be regulated by Notch in uveal melanoma.	('Notch', 'Var', (143, 148))	('MAPK', 'molecular_function', 'GO:0004707', ('94', '98'))	('phosphoinositide 3-kinase', 'Pathway', (26, 51))	('JAK/STAT pathways', 'Pathway', (105, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (152, 166))	('uveal melanoma', 'Disease', (152, 166))	('uveal melanoma', 'Disease', 'MESH:C536494', (152, 166))	('regulated', 'Reg', (130, 139))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('MAPK', 'Gene', (94, 98))	('MAPK', 'Gene', '5595;5594;5595', (94, 98))	('mitogen-activated', 'MPA', (60, 77))	('PI3K', 'molecular_function', 'GO:0016303', ('53', '57'))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('JAK', 'molecular_function', 'GO:0004713', ('105', '108'))
89823	22228632	Finally, our preliminary in vivo analysis suggests that Notch inhibition using MRK003 significantly slows tumor growth in orthotopic xenograft models and may block hematogeneous spread, although models which metastasize more efficiently will need to be tested to establish the statistical significance of the latter finding.	('block', 'NegReg', (158, 163))	('slows', 'NegReg', (100, 105))	('Notch', 'Var', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('MRK', 'Gene', (79, 82))	('MRK', 'Gene', '51776', (79, 82))	('hematogeneous spread', 'CPA', (164, 184))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
89826	22228632	Early reports described increased expression of Notch pathway members in melanoma cells as compared with normal melanocytes and revealed that a tripeptide GSI could induce apoptosis in melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('melanoma', 'Disease', (73, 81))	('expression', 'MPA', (34, 44))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('induce', 'PosReg', (165, 171))	('tripeptide', 'Chemical', '-', (144, 154))	('apoptosis', 'biological_process', 'GO:0097194', ('172', '181'))	('apoptosis', 'CPA', (172, 181))	('tripeptide', 'Var', (144, 154))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('GSI', 'Chemical', '-', (155, 158))	('melanoma', 'Disease', (185, 193))	('increased', 'PosReg', (24, 33))	('apoptosis', 'biological_process', 'GO:0006915', ('172', '181'))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
89832	22228632	The invasive behavior associated with Notch activity may be due in part to the induction of Akt, Erk, and JAK/STAT pathways.	('Notch activity', 'Var', (38, 52))	('invasive behavior', 'MPA', (4, 21))	('Erk', 'Gene', (97, 100))	('Erk', 'molecular_function', 'GO:0004707', ('97', '100'))	('induction', 'Reg', (79, 88))	('Akt', 'Gene', '207', (92, 95))	('Erk', 'Gene', '5594', (97, 100))	('JAK', 'molecular_function', 'GO:0004713', ('106', '109'))	('Akt', 'Gene', (92, 95))	('JAK/STAT pathways', 'Pathway', (106, 123))
89835	22228632	We show that the Notch cascade is active in uveal melanomas and that inhibition of the pathway using genetic manipulation or small molecules suitable for clinical translation can slow tumor growth and invasion.	('uveal melanomas', 'Disease', (44, 59))	('uveal melanomas', 'Phenotype', 'HP:0007716', (44, 59))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('translation', 'biological_process', 'GO:0006412', ('163', '174'))	('slow', 'NegReg', (179, 183))	('tumor', 'Disease', (184, 189))	('uveal melanomas', 'Disease', 'MESH:C536494', (44, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('genetic', 'Var', (101, 108))	('inhibition', 'Var', (69, 79))
89871	24223611	C918 is epithelioid in morphology and is a highly invasive, metastatic, and aggressive melanoma cell line.	('C918', 'Var', (0, 4))	('aggressive melanoma', 'Disease', (76, 95))	('C918', 'CellLine', 'CVCL:8471', (0, 4))	('aggressive melanoma', 'Disease', 'MESH:D008545', (76, 95))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
90062	23077404	As VEGF-A inhibitors are being used to treat many different types of cancer metastases, we wondered whether they can be used to inhibit intraocular tumor growth.	('cancer metastases', 'Disease', 'MESH:D009362', (69, 86))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('VEGF-A', 'Gene', (3, 9))	('cancer metastases', 'Disease', (69, 86))	('intraocular tumor', 'Disease', (136, 153))	('inhibitors', 'Var', (10, 20))	('intraocular tumor', 'Disease', 'MESH:D064090', (136, 153))
90095	23077404	Unexpectedly, an acceleration of intraocular tumor growth in response to anti-VEGF-A occurred.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('anti-VEGF-A', 'Var', (73, 84))	('intraocular tumor', 'Disease', (33, 50))	('intraocular tumor', 'Disease', 'MESH:D064090', (33, 50))	('acceleration', 'PosReg', (17, 29))
90124	23077404	Research in glioblastoma multiforme has demonstrated HIF-1alpha to promote angiogenesis by inducing recruitment of mature F4/80+ macrophages in mice treated with bevacizumab.	('glioblastoma multiforme', 'Disease', (12, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (12, 24))	('bevacizumab', 'Chemical', 'MESH:D000068258', (162, 173))	('mice', 'Species', '10090', (144, 148))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (12, 35))	('angiogenesis', 'CPA', (75, 87))	('inducing', 'Reg', (91, 99))	('HIF-1alpha', 'Var', (53, 63))	('F4/80', 'Gene', (122, 127))	('angiogenesis', 'biological_process', 'GO:0001525', ('75', '87'))	('F4/80', 'Gene', '13733', (122, 127))	('promote', 'PosReg', (67, 74))
90145	22745734	In addition, ALCAM-null mice on a mixed C57BL/6-129 background exhibit retinal dysplasias, including disrupted organization of the outer nuclear layer photoreceptor neurons and invagination of the adjacent retinal pigment epithelium (RPE) and choroid (choriocapillaris); these dysplasias are greatly reduced on a congenic C57BL/6 background, however (data not shown).	('organization', 'CPA', (111, 123))	('retinal dysplasias', 'Disease', (71, 89))	('retinal dysplasias', 'Disease', 'MESH:D015792', (71, 89))	('mice', 'Species', '10090', (24, 28))	('dysplasias', 'Disease', (277, 287))	('choriocapillaris', 'Disease', 'MESH:D008268', (252, 268))	('C57BL/6-129', 'Var', (40, 51))	('invagination', 'CPA', (177, 189))	('choriocapillaris', 'Disease', (252, 268))	('dysplasias', 'Disease', (79, 89))	('retinal dysplasias', 'Phenotype', 'HP:0007973', (71, 89))	('ALCAM-null', 'Gene', (13, 23))	('dysplasias', 'Disease', 'MESH:D004476', (277, 287))	('dysplasias', 'Disease', 'MESH:D004476', (79, 89))
90146	22745734	This previously undocumented expression, as well as the fact that choroidal melanocytes were found within ectopic retinal folds suggests that in the absence of ALCAM, the structure and/or function of melanocytes in the uvea, which includes the choroid, iris, and ciliary body, might be disrupted.	('ALCAM', 'Gene', (160, 165))	('structure', 'CPA', (171, 180))	('uvea', 'Disease', 'MESH:C536494', (219, 223))	('uvea', 'Disease', (219, 223))	('choroidal melanocytes', 'Phenotype', 'HP:0012054', (66, 87))	('retinal folds', 'Phenotype', 'HP:0008052', (114, 127))	('disrupted', 'NegReg', (286, 295))	('absence', 'Var', (149, 156))	('function', 'CPA', (188, 196))
90150	22745734	Unfortunately, these data are necessarily correlative in nature; therefore, an understanding of the contribution of ALCAM to cancer progression and, indeed, normal cell motility and adhesion, has been hampered by a lack of studies aimed at directly manipulating ALCAM levels within particular cell lines and determining the outcome of this manipulation.	('manipulating', 'Var', (249, 261))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cell motility', 'biological_process', 'GO:0048870', ('164', '177'))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
90155	22745734	Silencing of ALCAM using targeted shRNAs in MUM-2B results in both impaired cell motility and reduced invasive capacity in an in vitro assay, consistent with an observed reduction in matrix metalloproteinase activation.	('impaired cell motility', 'Disease', (67, 89))	('reduction', 'NegReg', (170, 179))	('MUM-2', 'Gene', '58485', (44, 49))	('ALCAM', 'Gene', (13, 18))	('reduced', 'NegReg', (94, 101))	('impaired cell motility', 'Disease', 'MESH:D015835', (67, 89))	('MUM-2', 'Gene', (44, 49))	('invasive capacity in an', 'CPA', (102, 125))	('cell motility', 'biological_process', 'GO:0048870', ('76', '89'))	('Silencing', 'Var', (0, 9))
90159	22745734	Conversely, silencing of ALCAM expression in MUM-2B disrupts the formation of adherens junctions.	('formation of adherens junctions', 'CPA', (65, 96))	('silencing', 'Var', (12, 21))	('ALCAM', 'Gene', (25, 30))	('disrupts', 'NegReg', (52, 60))	('MUM-2', 'Gene', '58485', (45, 50))	('formation', 'biological_process', 'GO:0009058', ('65', '74'))	('MUM-2', 'Gene', (45, 50))
90216	22745734	Subsequent analysis of short tandem repeats in the genomic DNA of these uveal melanoma lines indicates that MUM-2B and MUM-2C are, in fact, unlikely to have derived from the same metastasis.	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('uveal melanoma', 'Disease', (72, 86))	('MUM-2', 'Gene', (108, 113))	('short tandem repeats', 'Var', (23, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('MUM-2', 'Gene', '58485', (119, 124))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('MUM-2', 'Gene', '58485', (108, 113))	('MUM-2', 'Gene', (119, 124))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))
90217	22745734	Folberg and colleagues (2008) additionally present evidence that OCM-1A and MUM-2C share the same origin, as do MUM-2B, M619, and C918; our data below are consistent with this.	('MUM-2', 'Gene', (76, 81))	('MUM-2', 'Gene', (112, 117))	('OCM-1', 'Species', '83984', (65, 70))	('M619', 'Var', (120, 124))	('C918', 'Var', (130, 134))	('MUM-2', 'Gene', '58485', (76, 81))	('MUM-2', 'Gene', '58485', (112, 117))
90223	22745734	Gap closure analysis of the remaining cell lines revealed that M619 and C918 were fast-moving like MUM-2B, while OCM-1A was slow-moving like MUM-2C.	('MUM-2', 'Gene', (141, 146))	('MUM-2', 'Gene', '58485', (99, 104))	('OCM-1', 'Species', '83984', (113, 118))	('C918', 'Var', (72, 76))	('fast-moving', 'MPA', (82, 93))	('MUM-2', 'Gene', (99, 104))	('MUM-2', 'Gene', '58485', (141, 146))	('M619', 'Var', (63, 67))
90224	22745734	MUM-2B, C918, and M619 all moved at speeds 2-3 fold greater than OCM-1A and MUM-2C (Fig.	('MUM-2', 'Gene', (76, 81))	('MUM-2', 'Gene', '58485', (0, 5))	('greater', 'PosReg', (52, 59))	('OCM-1', 'Species', '83984', (65, 70))	('MUM-2', 'Gene', (0, 5))	('C918', 'Var', (8, 12))	('MUM-2', 'Gene', '58485', (76, 81))	('M619', 'Var', (18, 22))
90225	22745734	ALCAM protein expression was undetectable in OCM-1A and MUM-2C; in contrast, it was similarly high in MUM-2B, C918, and M619 (Fig.	('high', 'PosReg', (94, 98))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('undetectable', 'NegReg', (29, 41))	('C918', 'Var', (110, 114))	('MUM-2', 'Gene', '58485', (102, 107))	('MUM-2', 'Gene', (102, 107))	('M619', 'Var', (120, 124))	('MUM-2', 'Gene', '58485', (56, 61))	('OCM-1', 'Species', '83984', (45, 50))	('ALCAM protein', 'Protein', (0, 13))	('MUM-2', 'Gene', (56, 61))
90232	22745734	To determine whether ALCAM regulates uveal melanoma cell behavior, we began by knocking down ALCAM levels in MUM-2B cells, which normally express high levels of ALCAM.	('MUM-2', 'Gene', '58485', (109, 114))	('knocking', 'Var', (79, 87))	('uveal melanoma', 'Disease', 'MESH:C536494', (37, 51))	('ALCAM', 'Gene', (93, 98))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('uveal melanoma', 'Phenotype', 'HP:0007716', (37, 51))	('uveal melanoma', 'Disease', (37, 51))	('MUM-2', 'Gene', (109, 114))
90238	22745734	Silencing ALCAM results in a significant reduction in motility: sh5 cells exhibit a closure rate nearly 50% lower than that of parental MUM-2B or non-silenced sh6 cells (Fig.	('ALCAM', 'Gene', (10, 15))	('MUM-2', 'Gene', '58485', (136, 141))	('closure rate', 'CPA', (84, 96))	('MUM-2', 'Gene', (136, 141))	('lower', 'NegReg', (108, 113))	('motility', 'CPA', (54, 62))	('Silencing', 'Var', (0, 9))	('reduction', 'NegReg', (41, 50))
90240	22745734	We next sought to determine how silencing ALCAM impacts invasive capacity of MUM-2B uveal melanoma cells.	('impacts', 'Reg', (48, 55))	('MUM-2B uveal melanoma', 'Disease', 'MESH:C536494', (77, 98))	('invasive capacity', 'CPA', (56, 73))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('ALCAM', 'Gene', (42, 47))	('silencing', 'Var', (32, 41))	('MUM-2B uveal melanoma', 'Disease', (77, 98))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
90261	22745734	4) MMP-2 activity was not increased in 2C-ALC compared to parental MUM-2C (Fig.	('MUM-2', 'Gene', '58485', (67, 72))	('2C-ALC', 'Var', (39, 45))	('MMP-2', 'Gene', (3, 8))	('MUM-2', 'Gene', (67, 72))	('activity', 'MPA', (9, 17))	('MMP-2', 'molecular_function', 'GO:0004228', ('3', '8'))	('MMP-2', 'Gene', '4313', (3, 8))
90277	22745734	Neither silencing of ALCAM in sh5 nor its re-expression in sh5rxd appeared to affect levels of ss-catenin or N-cadherin expression (Fig.	('levels of ss-catenin', 'MPA', (85, 105))	('silencing', 'Var', (8, 17))	('ALCAM', 'Gene', (21, 26))	('ss-catenin', 'Chemical', '-', (95, 105))	('affect', 'Reg', (78, 84))	('cadherin', 'molecular_function', 'GO:0008014', ('111', '119'))	('N-cadherin expression', 'MPA', (109, 130))
90286	22745734	Together with our analysis of sh5 silenced cells, these data suggest that ALCAM expression is both necessary and sufficient to promote the recruitment of N-cadherin and ss-catenin to form adherens junctions in uveal melanoma cells.	('cadherin', 'molecular_function', 'GO:0008014', ('156', '164'))	('ss-catenin', 'Chemical', '-', (169, 179))	('uveal melanoma', 'Disease', (210, 224))	('uveal melanoma', 'Phenotype', 'HP:0007716', (210, 224))	('promote', 'PosReg', (127, 134))	('N-cadherin', 'Protein', (154, 164))	('uveal melanoma', 'Disease', 'MESH:C536494', (210, 224))	('recruitment', 'MPA', (139, 150))	('ss-catenin', 'Protein', (169, 179))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('ALCAM', 'Gene', (74, 79))	('expression', 'Var', (80, 90))
90294	22745734	It appeared that the disruption of homophilic ALCAM contacts thus resulted in increased metastatic potential in cutaneous melanoma cell lines; this was, however, in contrast to previous expression data that predicted ALCAM would promote invasion and metastasis.	('promote', 'PosReg', (229, 236))	('metastatic potential', 'CPA', (88, 108))	('disruption', 'Var', (21, 31))	('cutaneous melanoma', 'Disease', (112, 130))	('increased', 'PosReg', (78, 87))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))
90301	22745734	We further find that silencing of ALCAM in the invasive MUM-2B line results in decreased motility, invasiveness, and MMP-2 activation.	('motility', 'CPA', (89, 97))	('decreased', 'NegReg', (79, 88))	('MMP-2', 'molecular_function', 'GO:0004228', ('117', '122'))	('MMP-2', 'Gene', (117, 122))	('ALCAM', 'Gene', (34, 39))	('invasiveness', 'CPA', (99, 111))	('MUM-2', 'Gene', '58485', (56, 61))	('activation', 'PosReg', (123, 133))	('MMP-2', 'Gene', '4313', (117, 122))	('silencing', 'Var', (21, 30))	('MUM-2', 'Gene', (56, 61))
90308	22745734	Thus, changes in the expression and localization of cell adhesion molecules can influence tumor progression by both modulating the adhesion status of a cell and by altering cell signaling.	('adhesion status', 'MPA', (131, 146))	('altering', 'Reg', (164, 172))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('cell adhesion molecules', 'Protein', (52, 75))	('tumor', 'Disease', (90, 95))	('expression', 'MPA', (21, 31))	('signaling', 'biological_process', 'GO:0023052', ('178', '187'))	('changes', 'Var', (6, 13))	('cell adhesion', 'biological_process', 'GO:0007155', ('52', '65'))	('localization of cell', 'biological_process', 'GO:0051674', ('36', '56'))	('localization', 'MPA', (36, 48))	('cell signaling', 'MPA', (173, 187))	('influence', 'Reg', (80, 89))	('modulating', 'Reg', (116, 126))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
90325	22745734	The reduction in invasiveness we observe appears at odds with the finding that amino-truncated ALCAM expression served to disrupt ALCAM junctions and to reduce MMP-2 activation, but actually increased the invasive capacity of BLM cutaneous melanoma cells  .	('reduce', 'NegReg', (153, 159))	('MMP-2', 'Gene', (160, 165))	('amino-truncated', 'Var', (79, 94))	('ALCAM', 'Gene', (95, 100))	('MMP-2', 'Gene', '4313', (160, 165))	('increased', 'PosReg', (191, 200))	('invasiveness', 'MPA', (17, 29))	('ALCAM junctions', 'MPA', (130, 145))	('disrupt', 'Reg', (122, 129))	('MMP-2', 'molecular_function', 'GO:0004228', ('160', '165'))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('cutaneous melanoma', 'Disease', (230, 248))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (230, 248))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (230, 248))
90326	22745734	An attractive hypothesis that could account for the increased invasiveness caused by a dominant-negative ALCAM versus our own results in which silencing ALCAM results in decreased invasiveness, centers around the cadherin status of the cell lines used in each study.	('ALCAM', 'Gene', (105, 110))	('invasiveness', 'MPA', (62, 74))	('increased', 'PosReg', (52, 61))	('cadherin', 'molecular_function', 'GO:0008014', ('213', '221'))	('cadherin', 'Gene', '999;442858;1000;12558;1003', (213, 221))	('cadherin', 'Gene', (213, 221))	('ALCAM', 'Gene', (153, 158))	('decreased invasiveness', 'Disease', (170, 192))	('decreased invasiveness', 'Disease', 'MESH:D009362', (170, 192))	('silencing', 'Var', (143, 152))
90332	22745734	It will also be important to determine the specificity of the interaction between ALCAM and cadherins: can silencing of ALCAM remove a variety of classical cadherins from adherens junctions in different cell types?	('adherens junctions', 'MPA', (171, 189))	('cadherin', 'Gene', (156, 164))	('silencing', 'Var', (107, 116))	('ALCAM', 'Gene', (120, 125))	('cadherin', 'Gene', '999;442858;1000;12558;1003', (92, 100))	('remove', 'NegReg', (126, 132))	('cadherin', 'Gene', (92, 100))	('cadherin', 'Gene', '999;442858;1000;12558;1003', (156, 164))
90334	21871071	EFS shows biallelic methylation in uveal melanoma with poor prognosis as well as tissue-specific methylation Uveal melanoma (UM) is a rare eye tumor.	('eye tumor', 'Phenotype', 'HP:0100012', (139, 148))	('biallelic methylation', 'Var', (10, 31))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('uveal melanoma', 'Disease', 'MESH:C536494', (35, 49))	('uveal melanoma', 'Disease', (35, 49))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))	('eye tumor', 'Disease', (139, 148))	('methylation', 'biological_process', 'GO:0032259', ('97', '108'))	('eye tumor', 'Disease', 'MESH:D005134', (139, 148))	('EFS', 'Gene', '10278', (0, 3))	('EFS', 'Gene', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))
90340	21871071	Kaplan-Meier analysis revealed a higher risk of metastatic progression for tumors with EFS methylation (p = 0.02).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('methylation', 'Var', (91, 102))	('EFS', 'Gene', (87, 90))	('metastatic progression', 'CPA', (48, 70))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('tumors', 'Disease', (75, 81))
90342	21871071	Notably, only UM with EFS methylation gave rise to metastases.	('methylation', 'Var', (26, 37))	('metastases', 'Disease', 'MESH:D009362', (51, 61))	('EFS', 'Gene', (22, 25))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('metastases', 'Disease', (51, 61))
90343	21871071	EFS methylation always affects both alleles in normal and tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('affects', 'Reg', (23, 30))	('methylation', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('EFS', 'Gene', (0, 3))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))
90344	21871071	The EFS methylation of a UM may depend on which type of precursor cell the tumor originated from.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('methylation', 'biological_process', 'GO:0032259', ('8', '19'))	('tumor', 'Disease', (75, 80))	('methylation', 'Var', (8, 19))
90346	21871071	As tumors with monosomy 3 are tightly associated with metastatic progression, chromosome 3 testing is used to predict patients' prognosis.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('associated', 'Reg', (38, 48))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('chromosome', 'cellular_component', 'GO:0005694', ('78', '88'))	('patients', 'Species', '9606', (118, 126))	('monosomy 3', 'Var', (15, 25))	('metastatic progression', 'CPA', (54, 76))
90347	21871071	Recently, inactivating somatic mutations in the gene encoding BRCA1-associated protein 1 (BAP1) on chromosome 3p21.1 were found to be frequent only in those UM that showed expression profiles linked to high metastatic potential.	('BRCA1-associated protein 1', 'Gene', '8314', (62, 88))	('chromosome', 'cellular_component', 'GO:0005694', ('99', '109'))	('BRCA1-associated protein 1', 'Gene', (62, 88))	('BAP1', 'Gene', '8314', (90, 94))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('BAP1', 'Gene', (90, 94))	('inactivating', 'Var', (10, 22))
90351	21871071	It is commonly assumed that epimutations, like other genetic changes in cancer, develop in a random manner and are then selected for growth advantage to the mutant cell clone.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('epimutations', 'Var', (28, 40))	('cancer', 'Disease', (72, 78))
90352	21871071	For example, hypermethylation of promoter-associated CGIs can result in transcriptional silencing of tumor suppressor genes (TSG).	('transcriptional', 'MPA', (72, 87))	('CGIs', 'Protein', (53, 57))	('promoter-associated', 'Protein', (33, 52))	('tumor', 'Disease', (101, 106))	('silencing', 'NegReg', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor suppressor', 'biological_process', 'GO:0051726', ('101', '117'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('101', '117'))	('hypermethylation', 'Var', (13, 29))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
90353	21871071	In some regions, this kind of CpG methylation establishes long-term gene inactivation and is part of the process of cell differentiation from pluripotent embryonic stem cells to terminally differentiated somatic cells.	('methylation', 'Var', (34, 45))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('pluripotent embryonic', 'Disease', 'MESH:D009373', (142, 163))	('gene', 'MPA', (68, 72))	('pluripotent embryonic', 'Disease', (142, 163))	('cell differentiation', 'biological_process', 'GO:0030154', ('116', '136'))
90357	21871071	All tumors analyzed in this study were selected from a cohort of 262 tumors with either monosomy 3 or disomy 3.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('monosomy 3', 'Var', (88, 98))	('disomy 3', 'Var', (102, 110))
90358	21871071	The set of 16 tumors (set I) used to screen for and confirm altered methylation in UM was selected to equally represent tumors with monosomy 3 and disomy 3.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('altered methylation', 'Var', (60, 79))	('methylation', 'Var', (68, 79))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
90377	21871071	We used specific probes and primers for Human HPRT 1 (hypoxanthine phosphoribosyltransferase 1) as reference gene (Human HPRT1 Hs99999909_m1, ABI).	('Hs99999909_m1', 'Var', (127, 140))	('hypoxanthine phosphoribosyltransferase 1', 'Gene', (54, 94))	('Human', 'Species', '9606', (40, 45))	('HPRT', 'molecular_function', 'GO:0004422', ('46', '50'))	('Human', 'Species', '9606', (115, 120))	('HPRT1', 'Gene', '3251', (121, 126))	('HPRT 1', 'Gene', '3251', (46, 52))	('hypoxanthine phosphoribosyltransferase 1', 'Gene', '3251', (54, 94))	('HPRT', 'molecular_function', 'GO:0004422', ('121', '125'))	('HPRT1', 'Gene', (121, 126))	('HPRT 1', 'Gene', (46, 52))
90383	21871071	In contrast, full methylation was only found in one of eight tumors with disomy 3 (set I, Table 1).	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('disomy', 'Var', (73, 79))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
90384	21871071	We analyzed the EFS genome dosage in all 8 tumors from set I that showed complete EFS methylation by quantitative RT-PCR to test whether complete methylation signals might be the result of monoallelic methylation on the background of a heterozygous EFS deletion.	('methylation', 'biological_process', 'GO:0032259', ('146', '157'))	('deletion', 'Var', (253, 261))	('methylation', 'biological_process', 'GO:0032259', ('201', '212'))	('methylation', 'biological_process', 'GO:0032259', ('86', '97'))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
90387	21871071	However, as the number of patients in set I was rather small, we analyzed another set of 24 tumors randomly chosen from a cohort of 246 tumor samples showing either monosomy 3 or disomy 3.	('disomy 3', 'Var', (179, 187))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('patients', 'Species', '9606', (26, 34))	('monosomy 3', 'Var', (165, 175))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumors', 'Disease', (92, 98))	('tumor', 'Disease', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (136, 141))
90388	21871071	In this confirmatory group (set II), the significant correlation of EFS methylation and metastatic death of patients was confirmed (p = 0.02).	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('death', 'Disease', 'MESH:D003643', (99, 104))	('death', 'Disease', (99, 104))	('methylation', 'Var', (72, 83))	('patients', 'Species', '9606', (108, 116))	('EFS', 'Protein', (68, 71))
90389	21871071	Notably, only tumors with EFS methylation gave rise to metastases.	('metastases', 'Disease', (55, 65))	('methylation', 'Var', (30, 41))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('metastases', 'Disease', 'MESH:D009362', (55, 65))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('EFS', 'Gene', (26, 29))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
90393	21871071	EFS expression was strongly reduced in tumors that showed complete EFS methylation compared to unmethylated tumor samples (p = 0.008).	('tumors', 'Disease', (39, 45))	('methylation', 'Var', (71, 82))	('reduced', 'NegReg', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('EFS', 'Gene', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('expression', 'MPA', (4, 14))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Disease', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('tumor', 'Disease', (39, 44))	('EFS', 'Gene', (0, 3))
90397	21871071	Such frequent biallelic methylation is unlikely to occur through random epimutations and suggests the action of a site-directed de novo methylation mechanism, which is distinct from the two-step mutation-selection process that underlies allele-specific de novo hypermethylation of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor suppressor', 'biological_process', 'GO:0051726', ('281', '297'))	('biallelic', 'Var', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('281', '297'))	('methylation', 'biological_process', 'GO:0032259', ('136', '147'))	('tumor', 'Disease', (281, 286))
90399	21871071	Identification of these genes might provide further insight into the biological difference inherent to both uveal melanoma classes as methylation is strongly associated with metastatic progression.	('uveal melanoma', 'Disease', 'MESH:C536494', (108, 122))	('metastatic progression', 'CPA', (174, 196))	('associated with', 'Reg', (158, 173))	('methylation', 'Var', (134, 145))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('uveal melanoma', 'Disease', (108, 122))	('methylation', 'biological_process', 'GO:0032259', ('134', '145'))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
90401	21871071	Here we found that EFS methylation is significantly correlated with patients' survival and the chromosome 3 status of the tumors.	('tumors', 'Disease', (122, 128))	('correlated', 'Reg', (52, 62))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('methylation', 'Var', (23, 34))	('chromosome', 'cellular_component', 'GO:0005694', ('95', '105'))	('patients', 'Species', '9606', (68, 76))	('methylation', 'biological_process', 'GO:0032259', ('23', '34'))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('EFS', 'Gene', (19, 22))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
90402	21871071	In fact, all patients in our series who died of metastases showed EFS methylation in their primary tumors.	('metastases', 'Disease', 'MESH:D009362', (48, 58))	('methylation', 'biological_process', 'GO:0032259', ('70', '81'))	('patients', 'Species', '9606', (13, 21))	('EFS', 'Protein', (66, 69))	('methylation', 'Var', (70, 81))	('primary tumors', 'Disease', (91, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('metastases', 'Disease', (48, 58))	('primary tumors', 'Disease', 'MESH:D009369', (91, 105))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
90403	21871071	These parameters have previously been shown to correlate with monosomy 3 in UM suggesting that EFS methylation is a typical feature of the tumor class characterized by monosomy 3.	('methylation', 'Var', (99, 110))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('methylation', 'biological_process', 'GO:0032259', ('99', '110'))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))
90405	21871071	Taking the differentially methylated melanocyte precursors into account, we propose that tumors with EFS methylation might be direct descendants from methylated precursors.	('tumors', 'Disease', (89, 95))	('methylation', 'Var', (105, 116))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('EFS', 'Gene', (101, 104))	('methylation', 'biological_process', 'GO:0032259', ('105', '116'))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
90414	21871071	Therefore, EFS methylation of an UM may depend on which type of precursor cell the tumor originated from.	('methylation', 'Var', (15, 26))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
90415	21871071	It remains to be elucidated whether biallelic EFS methylation is established during progression of UM, or whether it mainly represents an early epigenetic flag that traces the two tumor classes back to their precursor cell.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('methylation', 'biological_process', 'GO:0032259', ('50', '61'))	('tumor', 'Disease', (180, 185))	('biallelic EFS methylation', 'Var', (36, 61))
90417	33316946	HDAC Inhibition Increases HLA Class I Expression in Uveal Melanoma Chemotherapy and immunotherapy are both used to treat malignancies.	('HDAC', 'Gene', (0, 4))	('Increases HLA Class I', 'Phenotype', 'HP:0002853', (16, 37))	('HDAC', 'Gene', '9734', (0, 4))	('Expression', 'MPA', (38, 48))	('HLA Class I', 'Protein', (26, 37))	('Melanoma', 'Disease', 'MESH:D008545', (58, 66))	('Increases', 'PosReg', (16, 25))	('Melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('Inhibition', 'Var', (5, 15))	('Melanoma', 'Disease', (58, 66))	('malignancies', 'Disease', 'MESH:D009369', (121, 133))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('malignancies', 'Disease', (121, 133))
90421	33316946	We observed that especially high-risk UM tumours (monosomy 3, gain of 8q, loss of BAP1) expressed several HDACs, and showed a high HLA Class I expression.	('monosomy 3', 'Var', (50, 60))	('UM tumours', 'Disease', (38, 48))	('BAP1', 'Gene', (82, 86))	('gain', 'PosReg', (62, 66))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('loss', 'Var', (74, 78))	('BAP1', 'Gene', '8314', (82, 86))	('HDAC', 'Gene', (106, 110))	('HLA', 'MPA', (131, 134))	('UM', 'Phenotype', 'HP:0007716', (38, 40))	('UM tumours', 'Disease', 'MESH:D009369', (38, 48))	('HDAC', 'Gene', '9734', (106, 110))
90430	33316946	Our findings indicate that epigenetic drugs (in this case an HDAC inhibitor) may influence the expression of immunologically relevant cell surface molecules in UM, demonstrating that these drugs potentially influence immunotherapy.	('expression of', 'MPA', (95, 108))	('cell surface', 'cellular_component', 'GO:0009986', ('134', '146'))	('influence', 'Reg', (207, 216))	('influence', 'Reg', (81, 90))	('UM', 'Phenotype', 'HP:0007716', (160, 162))	('immunotherapy', 'CPA', (217, 230))	('HDAC', 'Gene', (61, 65))	('epigenetic drugs', 'Var', (27, 43))	('HDAC', 'Gene', '9734', (61, 65))
90435	33316946	All of these are related to the loss of one chromosome 3, a well-known risk factor for the development of metastases in this malignancy.	('metastases', 'Disease', 'MESH:D009362', (106, 116))	('chromosome', 'cellular_component', 'GO:0005694', ('44', '54'))	('malignancy', 'Disease', 'MESH:D009369', (125, 135))	('malignancy', 'Disease', (125, 135))	('related', 'Reg', (17, 24))	('loss', 'Var', (32, 36))	('metastases', 'Disease', (106, 116))
90437	33316946	On the other hand, the loss of HLA Class I expression has been identified as a tumour-escape mechanism in for instance cutaneous melanoma.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (119, 137))	('tumour', 'Disease', (79, 85))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('expression', 'MPA', (43, 53))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('loss', 'Var', (23, 27))	('HLA Class I', 'Protein', (31, 42))	('cutaneous melanoma', 'Disease', (119, 137))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (119, 137))
90441	33316946	A trial for the treatment of UM metastases has been set up, in which an immune checkpoint inhibitor (Pembrolizumab) is combined with the HDAC inhibitor Entinostat, under the hypothesis that the inhibition of HDACs may lead to an enhanced expression of HLA and cancer antigens, and a decreased activity of myeloid-derived suppressor cells.	('Entinostat', 'Chemical', 'MESH:C118739', (152, 162))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (101, 114))	('activity', 'CPA', (293, 301))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('metastases', 'Disease', (32, 42))	('HLA', 'Protein', (252, 255))	('cancer', 'Disease', (260, 266))	('UM', 'Phenotype', 'HP:0007716', (29, 31))	('HDAC', 'Gene', (208, 212))	('expression', 'MPA', (238, 248))	('HDAC', 'Gene', (137, 141))	('HDAC', 'Gene', '9734', (208, 212))	('metastases', 'Disease', 'MESH:D009362', (32, 42))	('HDAC', 'Gene', '9734', (137, 141))	('enhanced', 'PosReg', (229, 237))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('decreased', 'NegReg', (283, 292))	('inhibition', 'Var', (194, 204))
90464	33316946	Recent studies have shown that HDAC inhibitors are able to reduce growth in UM cell lines, but to our knowledge, no one has reported on the effect of epigenetic enzyme inhibition on the expression of immune modulators, such as HLA Class I, in UMs.	('reduce growth', 'Phenotype', 'HP:0001510', (59, 72))	('inhibitors', 'Var', (36, 46))	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('HDAC', 'Gene', (31, 35))	('HDAC', 'Gene', '9734', (31, 35))	('UM', 'Phenotype', 'HP:0007716', (243, 245))
90469	33316946	Cells which were treated with a combination of the two drugs (40 nM Q + 5microM T) changed morphologically and resembled Quisinostat single treatment: plates with OMM2.5 and MP38 seemed to have fewer cells than when treated with Quisinostat alone.	('Q', 'Chemical', 'MESH:D005973', (229, 230))	('Quisinostat', 'Chemical', 'MESH:C541788', (229, 240))	('fewer', 'NegReg', (194, 199))	('MP38', 'Var', (174, 178))	('Q', 'Chemical', 'MESH:D005973', (68, 69))	('cells', 'CPA', (200, 205))	('Quisinostat', 'Chemical', 'MESH:C541788', (121, 132))	('Q', 'Chemical', 'MESH:D005973', (121, 122))
90496	33316946	However, our results are generally in agreement with studies in other malignancies describing that HDAC inhibition will upregulate HLA Class I and some HLA regulatory components.	('HDAC', 'Gene', '9734', (99, 103))	('HLA Class I', 'Protein', (131, 142))	('malignancies', 'Disease', 'MESH:D009369', (70, 82))	('upregulate', 'PosReg', (120, 130))	('upregulate HLA Class I', 'Phenotype', 'HP:0002853', (120, 142))	('inhibition', 'Var', (104, 114))	('HDAC', 'Gene', (99, 103))	('malignancies', 'Disease', (70, 82))
90501	33316946	However, it does not necessarily mean that low HDAC11 expression has no causal relationship with an increased risk of the development of metastases.	('expression', 'MPA', (54, 64))	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('HDAC11', 'Gene', '79885', (47, 53))	('low', 'Var', (43, 46))	('HDAC11', 'Gene', (47, 53))	('metastases', 'Disease', (137, 147))
90503	33316946	It is therefore possible that the low HDAC11 expression may help the hematogenous spread to the liver.	('hematogenous spread to the liver', 'CPA', (69, 101))	('help', 'PosReg', (60, 64))	('HDAC11', 'Gene', '79885', (38, 44))	('expression', 'MPA', (45, 55))	('low', 'Var', (34, 37))	('HDAC11', 'Gene', (38, 44))
90505	33316946	Although this enzyme represses CIITA transcription by the K27m3 of histone 3, thereby silencing HLA Class II expression, we observed a high expression of EZH2 in high-risk M3 tumours, without any association to HLA Class I expression.	('HLA', 'Protein', (96, 99))	('silencing', 'NegReg', (86, 95))	('EZH2', 'Gene', (154, 158))	('represses', 'NegReg', (21, 30))	('EZH2', 'Gene', '2146', (154, 158))	('tumours', 'Phenotype', 'HP:0002664', (175, 182))	('CIITA', 'Gene', (31, 36))	('transcription', 'biological_process', 'GO:0006351', ('37', '50'))	('tumours', 'Disease', 'MESH:D009369', (175, 182))	('CIITA', 'Gene', '4261', (31, 36))	('tumours', 'Disease', (175, 182))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('K27m3', 'Var', (58, 63))
90545	32005293	For tumors classified as Monosomy 3 (M3), a ten-year disease-specific mortality of 55% was found, while it dropped to 0% for Disomy 3 (D3).	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('Monosomy 3', 'Var', (25, 35))
90558	32005293	Moreover, it appears that psychological impact of genetic testing is not only the result of the communicated cancer risk, but can be mediated by the patients' interpretation and perception of this risk.	('patients', 'Species', '9606', (149, 157))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('genetic testing', 'Var', (50, 65))
90598	32005293	Before prognostication, patients opting for genetic testing (Test Group) displayed significantly higher perceived risk of metastases than patients declining (Observational Group) it (estimated coefficient [SE], 1.06 [.35], p = .003).	('genetic testing', 'Var', (44, 59))	('higher', 'PosReg', (97, 103))	('patients', 'Species', '9606', (138, 146))	('metastases', 'Disease', (122, 132))	('patients', 'Species', '9606', (24, 32))	('SE', 'Disease', 'None', (206, 208))	('metastases', 'Disease', 'MESH:D009362', (122, 132))
90599	32005293	After announcement of test results, patients diagnosed with Monosomy 3 showed a significant increase in their perceived risk of metastases than before (.55 [.28], p = .048).	('metastases', 'Disease', (128, 138))	('patients', 'Species', '9606', (36, 44))	('metastases', 'Disease', 'MESH:D009362', (128, 138))	('increase', 'PosReg', (92, 100))	('Monosomy 3', 'Var', (60, 70))
90636	32005293	In our study, genetic testing was associated with an immediate reduction in fear of progression and depressive symptoms, irrespective of whether patients were informed they had a good or a poor prognosis.	('patients', 'Species', '9606', (145, 153))	('depressive symptoms', 'Disease', 'MESH:D003866', (100, 119))	('fear of progression', 'MPA', (76, 95))	('genetic testing', 'Var', (14, 29))	('depressive symptoms', 'Disease', (100, 119))	('depressive symptoms', 'Phenotype', 'HP:0000716', (100, 119))	('reduction', 'NegReg', (63, 72))
90697	31755445	The best-corrected visual acuity was divided into three categories, including 20/20-20/40 (considered functionally good vision), 20/50-20/100 (considered functionally intermediate vision), and 20/200 or worse (considered legally blind).	('20/200', 'Var', (193, 199))	('vision', 'biological_process', 'GO:0007601', ('120', '126'))	('legally blind', 'Disease', 'MESH:D001766', (221, 234))	('20/50-20/100', 'Var', (129, 141))	('legally blind', 'Phenotype', 'HP:0000618', (221, 234))	('legally blind', 'Disease', (221, 234))	('vision', 'biological_process', 'GO:0007601', ('180', '186'))
90769	31226786	Risk factors include fair skin, blonde hair, and light eye color, presence of choroidal nevus and presence of germline breast cancer 1-associated protein 1 (BAP1) mutation.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('fair skin', 'Phenotype', 'HP:0007513', (21, 30))	('breast cancer 1-associated protein 1', 'Gene', '8314', (119, 155))	('BAP1', 'Gene', (157, 161))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('breast cancer 1-associated protein 1', 'Gene', (119, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('choroidal nevus', 'Phenotype', 'HP:0025314', (78, 93))	('nevus', 'Phenotype', 'HP:0003764', (88, 93))	('blonde hair', 'Phenotype', 'HP:0002286', (32, 43))	('BAP1', 'Gene', '8314', (157, 161))	('mutation', 'Var', (163, 171))	('light eye color', 'Phenotype', 'HP:0007730', (49, 64))
90777	31226786	CTCs have been shown to initiate metastasis in pre-clinical mouse xenograft models.	('pre', 'molecular_function', 'GO:0003904', ('47', '50'))	('metastasis', 'CPA', (33, 43))	('mouse', 'Species', '10090', (60, 65))	('CTCs', 'Var', (0, 4))	('initiate', 'PosReg', (24, 32))
90799	31226786	Mutational analysis data was present for 19 of 20 patients (49%) out of which 12 (63%) had a GNAQ mutation, 5 (26%) had a GNA11 mutation, one (5%) patient was wild-type for both genes and one (5%) had another mutation separate from GNAQ or GNA11.	('mutation', 'Var', (98, 106))	('patients', 'Species', '9606', (50, 58))	('GNAQ', 'Gene', (232, 236))	('patient', 'Species', '9606', (147, 154))	('GNA11', 'Gene', (122, 127))	('GNAQ', 'Gene', '2776', (93, 97))	('GNA11', 'Gene', '2767', (122, 127))	('GNA11', 'Gene', (240, 245))	('mutation', 'Var', (128, 136))	('GNA11', 'Gene', '2767', (240, 245))	('GNAQ', 'Gene', '2776', (232, 236))	('GNAQ', 'Gene', (93, 97))	('patient', 'Species', '9606', (50, 57))
90830	31226786	correlated the presence of monosomy 3 in CTCs with its presence in primary tumors.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('monosomy 3', 'Var', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Disease', (75, 81))
90843	31142627	Moreover, elevated expression of FTH1P3 was found to increase LSCC cell proliferation, migration and invasion, and to inhibit cell apoptosis, Conversely, knockdown of FTH1P3 suppressed LSCC cell proliferation, migration and invasion, and induced cell apoptosis.	('LSCC cell proliferation', 'CPA', (62, 85))	('induced', 'Reg', (238, 245))	('inhibit', 'NegReg', (118, 125))	('expression', 'MPA', (19, 29))	('suppressed', 'NegReg', (174, 184))	('increase', 'PosReg', (53, 61))	('invasion', 'CPA', (224, 232))	('knockdown', 'Var', (154, 163))	('elevated', 'PosReg', (10, 18))	('cell apoptosis', 'CPA', (246, 260))	('apoptosis', 'biological_process', 'GO:0097194', ('131', '140'))	('FTH1P3', 'Gene', (33, 39))	('FTH1P3', 'Gene', (167, 173))	('cell apoptosis', 'CPA', (126, 140))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('FTH1P3', 'Gene', '2498', (167, 173))	('FTH1P3', 'Gene', '2498', (33, 39))	('apoptosis', 'biological_process', 'GO:0006915', ('131', '140'))	('migration', 'CPA', (210, 219))	('cell proliferation', 'biological_process', 'GO:0008283', ('190', '208'))	('apoptosis', 'biological_process', 'GO:0097194', ('251', '260'))	('LSCC cell proliferation', 'CPA', (185, 208))	('apoptosis', 'biological_process', 'GO:0006915', ('251', '260'))	('invasion', 'CPA', (101, 109))
90903	31142627	As shown in Table 1, high FTH1P3 expression was positively correlated with the poor differentiation, high T classification, positive lymph node metastasis, and advanced clinical stage (P<0.05).	('high T classification', 'CPA', (101, 122))	('high', 'Var', (21, 25))	('FTH1P3', 'Gene', (26, 32))	('positive lymph node metastasis', 'CPA', (124, 154))	('expression', 'MPA', (33, 43))	('FTH1P3', 'Gene', '2498', (26, 32))	('poor differentiation', 'CPA', (79, 99))	('correlated', 'Reg', (59, 69))
90907	31142627	With Kaplan-Meier method and log-rank test, we found that patients with high FTH1P3 expression had significantly poorer overall survival rates than those patients with low FTH1P3 expression (Figure 1C, P<0.05).	('poorer', 'NegReg', (113, 119))	('expression', 'Var', (84, 94))	('FTH1P3', 'Gene', '2498', (77, 83))	('patients', 'Species', '9606', (154, 162))	('FTH1P3', 'Gene', (77, 83))	('overall survival', 'MPA', (120, 136))	('patients', 'Species', '9606', (58, 66))	('FTH1P3', 'Gene', (172, 178))	('high', 'Var', (72, 76))	('FTH1P3', 'Gene', '2498', (172, 178))
90912	31142627	Decreased cell proliferation by silencing FTH1P3 was observed in Hep-2 cells as expected (Figure 2C, P<0.05).	('FTH1P3', 'Gene', '2498', (42, 48))	('cell proliferation', 'CPA', (10, 28))	('Decreased', 'NegReg', (0, 9))	('silencing', 'Var', (32, 41))	('Hep-2', 'CellLine', 'CVCL:1906', (65, 70))	('cell proliferation', 'biological_process', 'GO:0008283', ('10', '28'))	('FTH1P3', 'Gene', (42, 48))
90922	31142627	Compared with the empty overexpressed vector group and blank group, cell migration was promoted in Hep-2 cells by transfecting the FTH1P3 overexpressed vector (Figure 5B, P<0.05).	('cell migration', 'CPA', (68, 82))	('FTH1P3', 'Gene', (131, 137))	('transfecting', 'Var', (114, 126))	('Hep-2', 'CellLine', 'CVCL:1906', (99, 104))	('FTH1P3', 'Gene', '2498', (131, 137))	('cell migration', 'biological_process', 'GO:0016477', ('68', '82'))	('promoted', 'PosReg', (87, 95))
90945	31142627	Moreover, patients with high FTH1P3 expression had significantly poorer overall survival rates compared with those patients with low FTH1P3 expression.	('patients', 'Species', '9606', (115, 123))	('FTH1P3', 'Gene', (29, 35))	('overall survival', 'MPA', (72, 88))	('poorer', 'NegReg', (65, 71))	('expression', 'Var', (36, 46))	('FTH1P3', 'Gene', '2498', (29, 35))	('FTH1P3', 'Gene', (133, 139))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (10, 18))	('FTH1P3', 'Gene', '2498', (133, 139))
90946	31142627	These results indicated that high level of FTH1P3 is associated with the malignant phenotypes of LSCC patients.	('FTH1P3', 'Gene', (43, 49))	('patients', 'Species', '9606', (102, 110))	('high level', 'Var', (29, 39))	('LSCC', 'Disease', (97, 101))	('associated', 'Reg', (53, 63))	('FTH1P3', 'Gene', '2498', (43, 49))
90948	31142627	In order to understand the biological functions of FTH1P3 in LSCC cells, we detected the cell proliferation, migration, invasion, apoptosis, and cell cycle by silencing and overexpressing FTH1P3 in Hep-2 and TU212 cells.	('cell cycle', 'biological_process', 'GO:0007049', ('145', '155'))	('TU212', 'CellLine', 'CVCL:Z025', (208, 213))	('FTH1P3', 'Gene', (51, 57))	('Hep-2', 'CellLine', 'CVCL:1906', (198, 203))	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('cell proliferation', 'CPA', (89, 107))	('silencing', 'Var', (159, 168))	('apoptosis', 'CPA', (130, 139))	('detected', 'Reg', (76, 84))	('overexpressing', 'PosReg', (173, 187))	('FTH1P3', 'Gene', '2498', (51, 57))	('cell cycle', 'CPA', (145, 155))	('invasion', 'CPA', (120, 128))	('migration', 'CPA', (109, 118))	('cell proliferation', 'biological_process', 'GO:0008283', ('89', '107'))	('FTH1P3', 'Gene', (188, 194))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('FTH1P3', 'Gene', '2498', (188, 194))
90949	31142627	Similarly, our study showed that FTH1P3 silencing exerted inhibitory effects on the proliferation, migration and invasion of Hep-2 and TU212 cells, and played promotive effect on cell apoptosis.	('promotive', 'PosReg', (159, 168))	('invasion', 'CPA', (113, 121))	('inhibitory effects', 'NegReg', (58, 76))	('FTH1P3', 'Gene', (33, 39))	('cell apoptosis', 'CPA', (179, 193))	('apoptosis', 'biological_process', 'GO:0097194', ('184', '193'))	('FTH1P3', 'Gene', '2498', (33, 39))	('proliferation', 'CPA', (84, 97))	('Hep-2', 'CellLine', 'CVCL:1906', (125, 130))	('silencing', 'Var', (40, 49))	('migration', 'CPA', (99, 108))	('apoptosis', 'biological_process', 'GO:0006915', ('184', '193'))	('TU212', 'CellLine', 'CVCL:Z025', (135, 140))
91049	30884881	Finally, in UM treated with proton-beam therapy, ADC variations precede volume changes and early change in ADC value 1 month after therapy significantly correlated with tumor regression.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('correlated', 'Reg', (153, 163))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('tumor', 'Disease', (169, 174))	('variations', 'Var', (53, 63))	('ADC', 'MPA', (49, 52))
91090	30154641	Following approval by the institutional review board at the University of Tennessee Health Sciences Center, a billing code inquiry was requested on all patients treated at our center from 2000 until 2017 with the following International Classification of Diseases, Ninth Revision (ICD-9) or International Classification of Diseases, 10th Revision (ICD-10) codes corresponding with a malignant neoplasm of the choroid, ciliary body, or iris: 190.6, 190.0, C69.3, C69.4, C69.9.	('C69.3', 'Var', (455, 460))	('C69.4', 'Var', (462, 467))	('malignant neoplasm of the choroid', 'Disease', 'MESH:D009369', (383, 416))	('C69.9', 'Var', (469, 474))	('neoplasm', 'Phenotype', 'HP:0002664', (393, 401))	('patients', 'Species', '9606', (152, 160))	('malignant neoplasm of the choroid', 'Disease', (383, 416))
91171	29118486	Class 1 includes tumors with disomy 3 and gain of 6p.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('gain', 'PosReg', (42, 46))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('disomy 3', 'Var', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
91172	29118486	Class 2 includes tumors with monosomy 3, 1, and 8p with a gain of 8q and is associated with a poorer prognosis.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('gain', 'PosReg', (58, 62))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('monosomy 3', 'Var', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
91179	29118486	The role of genes such as GNAQ and GNA11 is uncertain as mutations of the same genes are universally present in all the uveal melanomas and also in benign lesions such as choroidal nevi.	('GNAQ', 'Gene', (26, 30))	('uveal melanomas', 'Disease', (120, 135))	('choroidal nevi', 'Disease', (171, 185))	('uveal melanomas', 'Phenotype', 'HP:0007716', (120, 135))	('mutations', 'Var', (57, 66))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanomas', 'Phenotype', 'HP:0002861', (126, 135))	('nevi', 'Phenotype', 'HP:0003764', (181, 185))	('present', 'Reg', (101, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (120, 134))	('uveal melanomas', 'Disease', 'MESH:C536494', (120, 135))	('GNAQ', 'Gene', '2776', (26, 30))	('GNA11', 'Gene', '2767', (35, 40))	('GNA11', 'Gene', (35, 40))	('choroidal nevi', 'Phenotype', 'HP:0025314', (171, 185))
91286	29118486	Radioisotopes commonly used are iodine-125 (I125), ruthenium-106 (RU 106), and palladium-103 (Pd 103).	('RU 106', 'Var', (66, 72))	('ruthenium-106', 'Chemical', 'MESH:C000615522', (51, 64))	('iodine-125', 'Chemical', 'MESH:C000614960', (32, 42))	('I125', 'Var', (44, 48))	('palladium-103', 'Chemical', 'MESH:C000615531', (79, 92))	('I125', 'Chemical', 'MESH:C000614960', (44, 48))
91332	27650277	Dysregulation or hyperactivation of this cascade is common in many human cancers.	('cancers', 'Disease', (73, 80))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('hyperactivation', 'PosReg', (17, 32))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
91334	27650277	RAS activating mutations occur in 30 % of all cancers, including a high prevalence in melanoma (15-25 %), with KRAS mutations more common in adenocarcinomas and solid tumors and NRAS mutations more common in leukemia, thyroid carcinoma, and malignant melanoma.	('RAS', 'Gene', (0, 3))	('malignant melanoma', 'Phenotype', 'HP:0002861', (241, 259))	('malignant melanoma', 'Disease', 'MESH:D008545', (241, 259))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('leukemia', 'Disease', 'MESH:D007938', (208, 216))	('NRAS', 'Gene', (178, 182))	('leukemia', 'Disease', (208, 216))	('mutations', 'Var', (183, 192))	('common', 'Reg', (131, 137))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (218, 235))	('mutations', 'Var', (15, 24))	('thyroid carcinoma', 'Disease', (218, 235))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('melanoma', 'Disease', (86, 94))	('solid tumors', 'Disease', (161, 173))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (218, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('malignant melanoma', 'Disease', (241, 259))	('mutations', 'Var', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('KRAS', 'Gene', (111, 115))	('adenocarcinomas', 'Disease', 'MESH:D000230', (141, 156))	('common', 'Reg', (198, 204))	('adenocarcinomas', 'Disease', (141, 156))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('leukemia', 'Phenotype', 'HP:0001909', (208, 216))
91336	27650277	Furthermore, approximately 8 % of human tumors have mutations in BRAF (a member of the RAF family) : melanoma, thyroid cancer, and CRC have been associated with a high frequency of BRAF mutations.	('mutations', 'Var', (52, 61))	('thyroid cancer', 'Phenotype', 'HP:0002890', (111, 125))	('thyroid cancer', 'Disease', (111, 125))	('CRC', 'Disease', (131, 134))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('mutations', 'Var', (186, 195))	('melanoma', 'Disease', (101, 109))	('associated', 'Reg', (145, 155))	('thyroid cancer', 'Disease', 'MESH:D013964', (111, 125))	('CRC', 'Phenotype', 'HP:0003003', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('BRAF', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
91337	27650277	Specifically, the V600E point mutation accounts for more than 80 % of BRAF activating mutations.	('V600E', 'Var', (18, 23))	('activating', 'PosReg', (75, 85))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('BRAF', 'Gene', (70, 74))
91338	27650277	A number of MEK1/2 inhibitors are currently being investigated in the clinic across a range of cancers including gynecologic malignancies, melanoma, colorectal cancer, and acute myelogenous leukemia, with trametinib approved alone and in combination with the BRAF inhibitor dabrafenib for advanced metastatic melanoma with BRAF V600 mutations.	('acute myelogenous leukemia', 'Disease', (172, 198))	('colorectal cancer', 'Phenotype', 'HP:0003003', (149, 166))	('leukemia', 'Phenotype', 'HP:0001909', (190, 198))	('melanoma', 'Phenotype', 'HP:0002861', (309, 317))	('trametinib', 'Chemical', 'MESH:C560077', (205, 215))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (172, 198))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (178, 198))	('BRAF', 'Gene', (323, 327))	('MEK1', 'molecular_function', 'GO:0004708', ('12', '16'))	('V600 mutations', 'Var', (328, 342))	('malignancies', 'Disease', 'MESH:D009369', (125, 137))	('colorectal cancer', 'Disease', (149, 166))	('malignancies', 'Disease', (125, 137))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('dabrafenib', 'Chemical', 'MESH:C561627', (274, 284))	('melanoma', 'Disease', (139, 147))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (172, 198))
91340	27650277	For example, TAK-733 has demonstrated activity against multiple cutaneous melanoma cell lines, with a high proportion of BRAF V600E-mutant cell lines showing high sensitivity (IC50 < 0.1 muM) and with no statistically significant association between BRAF status and response, and against uveal melanoma cell lines.	('V600E', 'Var', (126, 131))	('BRAF', 'Gene', (121, 125))	('V600E', 'SUBSTITUTION', 'None', (126, 131))	('melanoma cell lines', 'Disease', 'MESH:D008545', (74, 93))	('melanoma cell lines', 'Disease', 'MESH:D008545', (294, 313))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('uveal melanoma', 'Phenotype', 'HP:0007716', (288, 302))	('melanoma cell lines', 'Disease', (74, 93))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (64, 82))	('melanoma cell lines', 'Disease', (294, 313))
91368	27650277	One patient (male, age 68 years) with BRAF L597R cutaneous melanoma, who received TAK-733 at 16 mg, had a partial response that was reported at cycle 4 and maintained until cycle 8 (approximate duration of 4 months).	('L597R', 'Var', (43, 48))	('cutaneous melanoma', 'Disease', (49, 67))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (49, 67))	('L597R', 'SUBSTITUTION', 'None', (43, 48))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))
91371	27650277	Also of note, we showed that two patients with cutaneous melanoma, including one with a BRAF L597R mutation, achieved partial responses that lasted approximately 4 months, suggesting evidence of preliminary antitumor activity with TAK-733.	('BRAF', 'Gene', (88, 92))	('L597R', 'SUBSTITUTION', 'None', (93, 98))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('cutaneous melanoma', 'Disease', (47, 65))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (47, 65))	('L597R', 'Var', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))
91372	27650277	Like the approved agent trametinib, as well as selumetinib and other investigational MEK1/2 inhibitors, TAK-733 is a non-ATP competitive allosteric inhibitor of the MEK1 and MEK2 BRAF substrates.	('MEK1', 'molecular_function', 'GO:0004708', ('85', '89'))	('MEK2', 'Gene', '5605', (174, 178))	('MEK1', 'molecular_function', 'GO:0004708', ('165', '169'))	('MEK2', 'Gene', (174, 178))	('TAK-733', 'Var', (104, 111))	('selumetinib', 'Chemical', 'MESH:C517975', (47, 58))	('MEK2', 'molecular_function', 'GO:0004708', ('174', '178'))
91373	27650277	These are similar to the common toxicities reported with other MEK1/2 inhibitors including trametinib, selumetinib, RO4987655, and PD-0325901; trametinib has been reported to be specifically associated with acneiform eruptions.	('PD-0325901', 'Chemical', 'MESH:C506614', (131, 141))	('acneiform eruptions', 'Disease', 'MESH:D017486', (207, 226))	('RO4987655', 'Chemical', 'MESH:C559138', (116, 125))	('trametinib', 'Var', (143, 153))	('MEK1', 'molecular_function', 'GO:0004708', ('63', '67'))	('associated', 'Reg', (191, 201))	('acneiform eruptions', 'Disease', (207, 226))
91374	27650277	Similarly, DLTs in other phase I studies of MEK1/2 inhibitors have included rash, diarrhea, increased blood CPK, and ocular toxicities with ARRY-424704, refametinib, cobimetinib, ARRY-438162, and pimasertib.	('rash', 'Disease', (76, 80))	('blood CPK', 'MPA', (102, 111))	('pimasertib', 'Chemical', 'MESH:C550600', (196, 206))	('diarrhea', 'Disease', (82, 90))	('rash', 'Phenotype', 'HP:0000988', (76, 80))	('ocular toxicities', 'Disease', (117, 134))	('cobimetinib', 'Chemical', 'MESH:C574276', (166, 177))	('MEK1', 'molecular_function', 'GO:0004708', ('44', '48'))	('refametinib', 'Chemical', 'MESH:C544830', (153, 164))	('ARRY-424704', 'Var', (140, 151))	('ocular toxicities', 'Disease', 'MESH:D005128', (117, 134))	('increased', 'PosReg', (92, 101))	('cobimetinib', 'Gene', (166, 177))	('MEK1/2', 'Gene', (44, 50))	('ARRY-438162', 'Var', (179, 190))	('diarrhea', 'Phenotype', 'HP:0002014', (82, 90))
91377	27650277	a decrease in pERK levels in peripheral blood mononuclear cells, malignant cells, and/or paired tumor biopsies, have been reported with other MEK1/2 inhibitors, including trametinib, selumetinib (79 % geometric mean pERK reduction in paired tumor biopsies), ARRY-424704, and RO4987655, and with the dual Raf/MEK inhibitor RO5126766, although no correlations with response have been reported.	('ARRY-424704', 'Var', (258, 269))	('reduction', 'NegReg', (221, 230))	('decrease', 'NegReg', (2, 10))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('pERK levels', 'MPA', (14, 25))	('MEK1', 'molecular_function', 'GO:0004708', ('142', '146'))	('MEK1/2', 'Gene', (142, 148))	('selumetinib', 'Var', (183, 194))	('RO4987655', 'Var', (275, 284))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('RO5126766', 'Chemical', 'MESH:C577924', (322, 331))
91378	27650277	Notably, the response in a patient with BRAF L597R mutant melanoma is consistent with observations with other MEK1/2 inhibitors, including trametinib, which have shown activity in BRAF-mutant melanoma.	('L597R', 'SUBSTITUTION', 'None', (45, 50))	('BRAF', 'Gene', (40, 44))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('MEK1', 'molecular_function', 'GO:0004708', ('110', '114'))	('L597R', 'Var', (45, 50))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
91379	27650277	Specifically, trametinib has been approved by the US FDA for the treatment of BRAF V600E/K-mutant melanoma, having demonstrated substantial response rates of approximately 20 % and improved progression-free survival and overall survival compared to chemotherapy with dacarbazine or paclitaxel in this patient population.	('V600E', 'Var', (83, 88))	('paclitaxel', 'Chemical', 'MESH:D017239', (282, 292))	('improved', 'PosReg', (181, 189))	('BRAF', 'Gene', (78, 82))	('V600E', 'SUBSTITUTION', 'None', (83, 88))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('progression-free survival', 'CPA', (190, 215))	('melanoma', 'Disease', (98, 106))	('overall survival', 'CPA', (220, 236))
91413	27899960	Carriage of two or more variants for MC1R was found to increase the risk for CMM.	('MC1R', 'Gene', (37, 41))	('variants', 'Var', (24, 32))	('CMM', 'Gene', '1243', (77, 80))	('CMM', 'Phenotype', 'HP:0012056', (77, 80))	('increase', 'Reg', (55, 63))	('CMM', 'Gene', (77, 80))	('MC1R', 'Gene', '4157', (37, 41))
91414	27899960	All the variants associated with the appearance of red or blond hair color were significantly associated with an increase in CMM risk.	('increase', 'Reg', (113, 121))	('CMM', 'Gene', '1243', (125, 128))	('CMM', 'Phenotype', 'HP:0012056', (125, 128))	('variants', 'Var', (8, 16))	('CMM', 'Gene', (125, 128))	('blond hair', 'Phenotype', 'HP:0002286', (58, 68))	('blond hair color', 'Disease', (58, 74))	('blond hair color', 'Disease', 'MESH:C567139', (58, 74))
91415	27899960	In addition, carriage of MC1R variants without the typical red hair/blond hair and fair skin color was shown to be associated with an increase in CMM risk.	('CMM', 'Gene', '1243', (146, 149))	('variants', 'Var', (30, 38))	('MC1R', 'Gene', '4157', (25, 29))	('fair skin', 'Phenotype', 'HP:0007513', (83, 92))	('increase', 'Reg', (134, 142))	('CMM', 'Phenotype', 'HP:0012056', (146, 149))	('blond hair', 'Phenotype', 'HP:0002286', (68, 78))	('MC1R', 'Gene', (25, 29))	('CMM', 'Gene', (146, 149))	('red hair/blond hair', 'Disease', (59, 78))	('red hair', 'Phenotype', 'HP:0002297', (59, 67))	('red hair/blond hair', 'Disease', 'MESH:C567139', (59, 78))
91418	27899960	These mutations are dominated by regionally distinct variants in CDKN2A.	('CDKN2A', 'Gene', '1029', (65, 71))	('CDKN2A', 'Gene', (65, 71))	('variants', 'Var', (53, 61))
91419	27899960	Rare germ-line mutations in CDK4 are found in addition to aberrations in MITF, TERF2IP, ACD, POT1 and BAP1 genes, albeit at a low frequency.	('POT1', 'Gene', (93, 97))	('CDK4', 'Gene', '1019', (28, 32))	('BAP1', 'Gene', (102, 106))	('CDK', 'molecular_function', 'GO:0004693', ('28', '31'))	('ACD', 'Gene', (88, 91))	('mutations', 'Var', (15, 24))	('TERF2IP', 'Gene', '54386', (79, 86))	('MITF', 'Gene', '4286', (73, 77))	('MITF', 'Gene', (73, 77))	('BAP1', 'Gene', '8314', (102, 106))	('POT1', 'Gene', '25913', (93, 97))	('CDK4', 'Gene', (28, 32))	('TERF2IP', 'Gene', (79, 86))
91421	27899960	In addition, as some of these genes increase the risk for development of other neoplasms [pancreatic cancer for CDKN2A and CDK4; uveal melanoma (UM) for BAP1], screening of the alterations is useful for the identification of subjects with an increased risk for cancer.	('neoplasms', 'Disease', 'MESH:D009369', (79, 88))	('genes', 'Var', (30, 35))	('CDK4', 'Gene', (123, 127))	('BAP1', 'Gene', (153, 157))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('neoplasms', 'Disease', (79, 88))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('CDKN2A', 'Gene', (112, 118))	('CDK', 'molecular_function', 'GO:0004693', ('123', '126'))	('men', 'Species', '9606', (65, 68))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('uveal melanoma', 'Disease', 'MESH:C536494', (129, 143))	('CDK4', 'Gene', '1019', (123, 127))	('cancer', 'Disease', (261, 267))	('increase', 'Reg', (36, 44))	('uveal melanoma', 'Disease', (129, 143))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('CDKN2A', 'Gene', '1029', (112, 118))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('cancer', 'Disease', (101, 107))	('pancreatic cancer', 'Disease', (90, 107))	('BAP1', 'Gene', '8314', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (261, 267))
91424	27899960	In addition, the MAPK pathway is activated by oncogenic mutations in RAS (predominantly NRAS in CMM) or BRAF leading to a constitutively active MAPK downstream signaling and unregulated expression of cyclin D1 protein as one of the high impact oncogenic events.	('cyclin D1', 'Gene', (200, 209))	('MAPK pathway', 'Pathway', (17, 29))	('mutations', 'Var', (56, 65))	('cyclin D1', 'Gene', '595', (200, 209))	('protein', 'cellular_component', 'GO:0003675', ('210', '217'))	('CMM', 'Gene', (96, 99))	('RAS', 'Gene', (69, 72))	('NRAS', 'Gene', (88, 92))	('MAPK downstream signaling', 'MPA', (144, 169))	('signaling', 'biological_process', 'GO:0023052', ('160', '169'))	('CMM', 'Phenotype', 'HP:0012056', (96, 99))	('cyclin', 'molecular_function', 'GO:0016538', ('200', '206'))	('CMM', 'Gene', '1243', (96, 99))	('constitutively', 'MPA', (122, 136))	('MAPK', 'molecular_function', 'GO:0004707', ('144', '148'))	('MAPK', 'molecular_function', 'GO:0004707', ('17', '21'))	('NRAS', 'Gene', '4893', (88, 92))	('BRAF', 'Gene', '673', (104, 108))	('BRAF', 'Gene', (104, 108))
91425	27899960	GRM3 mutations lead to increased ERK phosphorylation, although the exact downstream signaling details remain to be determined.	('GRM3', 'Gene', '2913', (0, 4))	('phosphorylation', 'MPA', (37, 52))	('GRM3', 'Gene', (0, 4))	('ERK', 'Gene', '5594', (33, 36))	('mutations', 'Var', (5, 14))	('ERK', 'Gene', (33, 36))	('increased', 'PosReg', (23, 32))	('phosphorylation', 'biological_process', 'GO:0016310', ('37', '52'))	('ERK', 'molecular_function', 'GO:0004707', ('33', '36'))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))
91430	27899960	Similarly, the association of germ-line mutations in CDKN2A and aggregation of CMM in families has been recognized.	('CDKN2A', 'Gene', (53, 59))	('CMM', 'Gene', (79, 82))	('CDKN2A', 'Gene', '1029', (53, 59))	('mutations', 'Var', (40, 49))	('CMM', 'Phenotype', 'HP:0012056', (79, 82))	('CMM', 'Gene', '1243', (79, 82))	('association', 'Interaction', (15, 26))
91431	27899960	Loss of this tumor suppressive protein inhibits p53-dependent functions in apoptosis and prevents G2/M cell-cycle checkpoint engagement.	('p53', 'Gene', (48, 51))	('tumor', 'Disease', (13, 18))	('cell-cycle checkpoint', 'biological_process', 'GO:0000075', ('103', '124'))	('apoptosis', 'biological_process', 'GO:0006915', ('75', '84'))	('p53', 'Gene', '7157', (48, 51))	('apoptosis', 'CPA', (75, 84))	('inhibits', 'NegReg', (39, 47))	('men', 'Species', '9606', (131, 134))	('prevents', 'NegReg', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('G2/M cell-cycle checkpoint', 'CPA', (98, 124))	('Loss', 'Var', (0, 4))	('apoptosis', 'biological_process', 'GO:0097194', ('75', '84'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
91432	27899960	CMM involves loss of the tumor suppressor gene, CDKN2A, and the derived proteins, as well as constitutive, oncogenic activation of the RAS-RAF-MEK-ERK (MAPK) pathway by oncogenic mutations, primarily in genes for BRAF and NRAS.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('25', '41'))	('MEK', 'Gene', (143, 146))	('NRAS', 'Gene', '4893', (222, 226))	('tumor suppressor', 'biological_process', 'GO:0051726', ('25', '41'))	('RAF', 'Gene', (139, 142))	('ERK', 'Gene', (147, 150))	('ERK', 'molecular_function', 'GO:0004707', ('147', '150'))	('MAPK', 'molecular_function', 'GO:0004707', ('152', '156'))	('CDKN2A', 'Gene', (48, 54))	('BRAF', 'Gene', (213, 217))	('BRAF', 'Gene', '673', (213, 217))	('RAF', 'Gene', '22882', (214, 217))	('CMM', 'Gene', (0, 3))	('tumor', 'Disease', (25, 30))	('NRAS', 'Gene', (222, 226))	('RAF', 'Gene', (214, 217))	('mutations', 'Var', (179, 188))	('CDKN2A', 'Gene', '1029', (48, 54))	('activation', 'PosReg', (117, 127))	('CMM', 'Phenotype', 'HP:0012056', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('MEK', 'Gene', '5609', (143, 146))	('ERK', 'Gene', '5594', (147, 150))	('CMM', 'Gene', '1243', (0, 3))	('RAF', 'Gene', '22882', (139, 142))	('loss', 'NegReg', (13, 17))
91433	27899960	In addition, CDKN2A is deactivated transcriptionally by promoter methylation in approximately 20% of melanoma metastases.	('melanoma metastases', 'Disease', 'MESH:D009362', (101, 120))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('promoter methylation', 'Var', (56, 76))	('CDKN2A', 'Gene', (13, 19))	('melanoma metastases', 'Disease', (101, 120))	('CDKN2A', 'Gene', '1029', (13, 19))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))	('deactivated', 'NegReg', (23, 34))
91436	27899960	The epigenetic alterations in DNA and histones have recently become a part of melanoma genetic aberrations.	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('epigenetic alterations', 'Var', (4, 26))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('DNA', 'Protein', (30, 33))	('melanoma genetic aberrations', 'Disease', 'MESH:D030342', (78, 106))	('histones', 'Protein', (38, 46))	('melanoma genetic aberrations', 'Disease', (78, 106))
91437	27899960	Epigenetic alterations are regarded as being related to transcriptional deregulation leading to loss of tumor suppressor gene expression (transcriptional silencing) and/or upregulation of genes and their proteins, with an enhanced expression in malignant cells compared to normal cells.	('Epigenetic alterations', 'Var', (0, 22))	('tumor suppressor', 'biological_process', 'GO:0051726', ('104', '120'))	('gene expression', 'biological_process', 'GO:0010467', ('121', '136'))	('upregulation', 'PosReg', (172, 184))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('104', '120'))	('tumor', 'Disease', (104, 109))	('enhanced', 'PosReg', (222, 230))	('proteins', 'Protein', (204, 212))	('genes', 'Protein', (188, 193))	('loss', 'NegReg', (96, 100))	('expression', 'MPA', (231, 241))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
91438	27899960	Epigenetic regulation of gene expression has been associated with silencing of tumor suppressor genes in melanoma, specifically CDKN2A, RASSF1A and PTEN.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('79', '95'))	('PTEN', 'Gene', (148, 152))	('RASSF1A', 'Gene', '11186', (136, 143))	('CDKN2A', 'Gene', '1029', (128, 134))	('PTEN', 'Gene', '5728', (148, 152))	('tumor', 'Disease', (79, 84))	('silencing', 'MPA', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('tumor suppressor', 'biological_process', 'GO:0051726', ('79', '95'))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('Epigenetic regulation', 'Var', (0, 21))	('regulation of gene expression', 'biological_process', 'GO:0010468', ('11', '40'))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('associated', 'Reg', (50, 60))	('RASSF1A', 'Gene', (136, 143))	('CDKN2A', 'Gene', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
91439	27899960	Transcriptional silencing by aberrant promoter methylation is associated with dimethylated lysine 9 in histone H3 (me2H3K9), resulting from the activity of H3K9 histone methyltransferases such as SETDB1 and EHMT2, and counteracted by H3K9 histone demethylase LSD1.	('promoter methylation', 'MPA', (38, 58))	('EHMT2', 'Gene', (207, 212))	('Transcriptional', 'MPA', (0, 15))	('SETDB1', 'Gene', (196, 202))	('LSD1', 'Gene', (259, 263))	('silencing', 'NegReg', (16, 25))	('lysine', 'Chemical', 'MESH:D008239', (91, 97))	('EHMT2', 'Gene', '10919', (207, 212))	('LSD1', 'Gene', '23028', (259, 263))	('methylation', 'biological_process', 'GO:0032259', ('47', '58'))	('aberrant', 'Var', (29, 37))	('H3K9 histone methyltransferases', 'Enzyme', (156, 187))	('SETDB1', 'Gene', '9869', (196, 202))	('dimethylated lysine 9', 'Var', (78, 99))	('activity', 'MPA', (144, 152))
91444	27899960	One example of this is miR-125b, a negative regulator of the MAPK downstream targeting c-Jun by altering translation or protein stability.	('protein stability', 'MPA', (120, 137))	('c-Jun', 'Gene', (87, 92))	('altering', 'Reg', (96, 104))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('translation', 'MPA', (105, 116))	('miR-125b', 'Chemical', '-', (23, 31))	('translation', 'biological_process', 'GO:0006412', ('105', '116'))	('c-Jun', 'Gene', '3725', (87, 92))	('MAPK', 'molecular_function', 'GO:0004707', ('61', '65'))	('miR-125b', 'Var', (23, 31))
91446	27899960	Loss of gene regulation in melanoma may be associated with epigenetic regulation and a result of mutations in gene coding for epigenetic regulators of gene expression.	('Loss of', 'NegReg', (0, 7))	('mutations', 'Var', (97, 106))	('gene expression', 'biological_process', 'GO:0010467', ('151', '166'))	('regulation', 'biological_process', 'GO:0065007', ('70', '80'))	('epigenetic regulation', 'MPA', (59, 80))	('gene regulation', 'MPA', (8, 23))	('regulation', 'biological_process', 'GO:0065007', ('13', '23'))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))
91447	27899960	Alterations in EZH2 or SETDB1 are found in 37% of CMM tumors, accounting for increased mRNA transcription, gene amplification and mutation (TCGA database, 20).	('SETDB1', 'Gene', (23, 29))	('mutation', 'Var', (130, 138))	('Alterations', 'Var', (0, 11))	('CMM', 'Phenotype', 'HP:0012056', (50, 53))	('CMM tumors', 'Disease', 'OMIM:155600', (50, 60))	('mRNA transcription', 'MPA', (87, 105))	('SETDB1', 'Gene', '9869', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mRNA transcription', 'biological_process', 'GO:0009299', ('87', '105'))	('increased', 'PosReg', (77, 86))	('CMM tumors', 'Disease', (50, 60))	('EZH2', 'Gene', (15, 19))	('EZH2', 'Gene', '2146', (15, 19))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('gene amplification', 'MPA', (107, 125))
91448	27899960	This high frequency together with the appearance of EZH2 mutations in the catalytic domain suggest that these and possibly other epigenetic regulators are associated with the oncogenic potential of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('associated', 'Reg', (155, 165))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('EZH2', 'Gene', (52, 56))	('EZH2', 'Gene', '2146', (52, 56))	('mutations', 'Var', (57, 66))
91458	27899960	Heterogeneity inducers other than diversity in genetic aberrations may include hypoxia, tumor microenvironment, selection by therapeutic agents and may be executed by reversible alterations of epigenetic changes in miRNA profiles or histone modifications and be regarded as adaptations.	('epigenetic changes', 'Var', (193, 211))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('miRNA profiles', 'MPA', (215, 229))	('genetic aberrations', 'Disease', (47, 66))	('histone', 'Protein', (233, 240))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('hypoxia', 'Disease', (79, 86))	('hypoxia', 'Disease', 'MESH:D000860', (79, 86))	('alterations', 'Reg', (178, 189))	('tumor', 'Disease', (88, 93))	('genetic aberrations', 'Disease', 'MESH:D030342', (47, 66))	('men', 'Species', '9606', (106, 109))
91459	27899960	CMM exhibits a relatively small number of tumors activated by mutated RTKs and non-RTKs, whereas the overexpression of the RTKs, often several in the same tumors (including IGF1R, MET, SRC, EPHA2, KIT, ERBB3 and EGRF), is a relatively common feature (TCGA database).	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('ERBB3', 'Gene', (202, 207))	('SRC', 'Gene', (185, 188))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('EPHA2', 'Gene', '1969', (190, 195))	('CMM', 'Gene', (0, 3))	('ERBB3', 'Gene', '2065', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('IGF1R', 'Gene', '3480', (173, 178))	('KIT', 'molecular_function', 'GO:0005020', ('197', '200'))	('tumors', 'Disease', (155, 161))	('CMM', 'Phenotype', 'HP:0012056', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('IGF1R', 'Gene', (173, 178))	('tumors', 'Disease', (42, 48))	('CMM', 'Gene', '1243', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('SRC', 'Gene', '6714', (185, 188))	('EPHA2', 'Gene', (190, 195))	('mutated', 'Var', (62, 69))
91465	27123562	Driver Mutations in Uveal Melanoma Frequent mutations have been described in the following 5 genes in uveal melanoma (UM): BAP1, EIF1AX, GNA11, GNAQ, and SF3B1.	('SF3B1', 'Gene', (154, 159))	('EIF1AX', 'Gene', '1964', (129, 135))	('Melanoma', 'Disease', (26, 34))	('SF3B1', 'Gene', '23451', (154, 159))	('BAP1', 'Gene', '8314', (123, 127))	('GNA11', 'Gene', '2767', (137, 142))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('Melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (20, 34))	('uveal melanoma', 'Disease', (102, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (102, 116))	('BAP1', 'Gene', (123, 127))	('UM', 'Phenotype', 'HP:0007716', (118, 120))	('GNAQ', 'Gene', (144, 148))	('EIF1AX', 'Gene', (129, 135))	('mutations', 'Var', (44, 53))	('GNA11', 'Gene', (137, 142))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('Melanoma', 'Disease', 'MESH:D008545', (26, 34))
91470	27123562	BAP1 mutations were identified in 29 of 64 (45%), GNAQ mutations in 36 of 81 (44%), GNA11 mutations in 36 of 81 (44%), SF3B1 mutations in 19 of 81 (24%), and EIF1AX mutations in 14 of 81 (17%).	('mutations', 'Var', (125, 134))	('mutations', 'Var', (90, 99))	('BAP1', 'Gene', (0, 4))	('GNA11', 'Gene', '2767', (84, 89))	('mutations', 'Var', (55, 64))	('GNA11', 'Gene', (84, 89))	('SF3B1', 'Gene', (119, 124))	('mutations', 'Var', (5, 14))	('EIF1AX', 'Gene', (158, 164))	('SF3B1', 'Gene', '23451', (119, 124))	('EIF1AX', 'Gene', '1964', (158, 164))	('mutations', 'Var', (165, 174))	('BAP1', 'Gene', '8314', (0, 4))	('GNAQ', 'Gene', (50, 54))
91471	27123562	Sixteen of the mutations in BAP1 and 6 of the mutations in EIF1AX were previously unreported in UM.	('BAP1', 'Gene', '8314', (28, 32))	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('mutations', 'Var', (15, 24))	('BAP1', 'Gene', (28, 32))	('EIF1AX', 'Gene', '1964', (59, 65))	('EIF1AX', 'Gene', (59, 65))
91473	27123562	BAP1, SF3B1, and EIF1AX mutations were almost mutually exclusive with each other.	('SF3B1', 'Gene', (6, 11))	('BAP1', 'Gene', (0, 4))	('SF3B1', 'Gene', '23451', (6, 11))	('EIF1AX', 'Gene', '1964', (17, 23))	('EIF1AX', 'Gene', (17, 23))	('mutations', 'Var', (24, 33))	('BAP1', 'Gene', '8314', (0, 4))
91474	27123562	Using multiple regression analysis, BAP1 mutations were associated with class 2 GEP and older patient.	('mutations', 'Var', (41, 50))	('class 2 GEP', 'Disease', (72, 83))	('BAP1', 'Gene', '8314', (36, 40))	('associated', 'Reg', (56, 66))	('patient', 'Species', '9606', (94, 101))	('BAP1', 'Gene', (36, 40))
91475	27123562	EIF1AX mutations were associated with class 1 GEP and the absence of ciliary body involvement.	('class 1 GEP', 'Disease', (38, 49))	('associated', 'Reg', (22, 32))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
91476	27123562	SF3B1 mutations were associated with younger patient age.	('patient', 'Species', '9606', (45, 52))	('SF3B1', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('SF3B1', 'Gene', '23451', (0, 5))
91477	27123562	GNA11 mutations were not associated with any of the analyzed features.	('GNA11', 'Gene', '2767', (0, 5))	('GNA11', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
91478	27123562	Using Cox proportional hazards modeling, class 2 GEP was the prognostic factor most strongly associated with metastasis (relative risk, 9.4; 95% CI, 3.1-28.5) and melanoma-specific mortality (relative risk, 15.7; 95% CI, 3.6-69.1) (P < .001 for both).	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('class 2 GEP', 'Var', (41, 52))	('Cox', 'Gene', (6, 9))	('Cox', 'Gene', '1351', (6, 9))	('associated', 'Reg', (93, 103))	('metastasis', 'CPA', (109, 119))	('GEP', 'Var', (49, 52))
91479	27123562	After excluding GEP class, the presence of BAP1 mutations was the factor most strongly associated with metastasis (relative risk, 10.6; 95% CI, 3.4-33.5) and melanoma-specific mortality (relative risk, 9.0; 95% CI, 2.8-29.2) (P < .001 for both).	('BAP1', 'Gene', (43, 47))	('presence', 'Var', (31, 39))	('associated', 'Reg', (87, 97))	('BAP1', 'Gene', '8314', (43, 47))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('mutations', 'Var', (48, 57))	('melanoma', 'Disease', (158, 166))	('metastasis', 'CPA', (103, 113))
91480	27123562	BAP1, SF3B1, and EIF1AX mutations occur during UM tumor progression in an almost mutually exclusive manner and are associated with different levels of metastatic risk.	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('BAP1', 'Gene', (0, 4))	('SF3B1', 'Gene', (6, 11))	('occur', 'Reg', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('SF3B1', 'Gene', '23451', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('EIF1AX', 'Gene', '1964', (17, 23))	('EIF1AX', 'Gene', (17, 23))	('mutations', 'Var', (24, 33))	('BAP1', 'Gene', '8314', (0, 4))	('associated with', 'Reg', (115, 130))	('tumor', 'Disease', (50, 55))
91485	27123562	The class 2 profile is strongly associated with inactivating mutations in the BAP1 (OMIM 603089) tumor suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('97', '113'))	('inactivating mutations', 'Var', (48, 70))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('BAP1', 'Gene', '8314', (78, 82))	('associated', 'Reg', (32, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('97', '113'))	('BAP1', 'Gene', (78, 82))
91486	27123562	Four other genes are frequently mutated in UM, including EIF1AX (OMIM 300186), GNA11 (OMIM 139313), GNAQ (OMIM 600998), and SF3B1 (OMIM 605590).	('EIF1AX', 'Gene', '1964', (57, 63))	('EIF1AX', 'Gene', (57, 63))	('OMIM 139313', 'Var', (86, 97))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('GNA11', 'Gene', '2767', (79, 84))	('SF3B1', 'Gene', (124, 129))	('GNA11', 'Gene', (79, 84))	('OMIM 600998', 'Var', (106, 117))	('SF3B1', 'Gene', '23451', (124, 129))
91487	27123562	Herein, we describe the associations between mutations in these 5 genes, GEP molecular class, clinicopathologic features, and patient outcomes in 81 primary UMs treated by enucleation.	('mutations', 'Var', (45, 54))	('associations', 'Interaction', (24, 36))	('patient', 'Species', '9606', (126, 133))	('GEP', 'Gene', (73, 76))	('enucleation', 'biological_process', 'GO:0090601', ('172', '183'))	('UM', 'Phenotype', 'HP:0007716', (157, 159))
91494	27123562	Mutations in BAP1 and SF3B1 were initially identified with exome sequencing in a subset of tumors, and then the mutation status of additional samples was determined by Sanger sequencing, as previously described.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('BAP1', 'Gene', (13, 17))	('SF3B1', 'Gene', '23451', (22, 27))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('BAP1', 'Gene', '8314', (13, 17))	('SF3B1', 'Gene', (22, 27))
91496	27123562	For GNAQ and GNA11, the 2 mutation hot spots at R183 and Q209 were sequenced.	('GNA11', 'Gene', '2767', (13, 18))	('Q209', 'Var', (57, 61))	('R183', 'Var', (48, 52))	('GNA11', 'Gene', (13, 18))
91497	27123562	For SF3B1, the mutation hot spot at R625 was sequenced.	('SF3B1', 'Gene', '23451', (4, 9))	('R625', 'Var', (36, 40))	('SF3B1', 'Gene', (4, 9))
91498	27123562	For EIF1AX, the hot spot regions containing reported mutations within exons 1 and 2 were sequenced.	('EIF1AX', 'Gene', '1964', (4, 10))	('EIF1AX', 'Gene', (4, 10))	('mutations', 'Var', (53, 62))
91502	27123562	Among those with DNA samples available for sequencing, BAP1 mutations were identified in 29 of 64 (45%), GNAQ mutations in 36 of 81 (44%), GNA11 mutations in 36 of 81 (44%), SF3B1 mutations in 19 of 81 (24%), and EIF1AX mutations in 14 of 81 (17%).	('GNAQ', 'Gene', (105, 109))	('mutations', 'Var', (110, 119))	('mutations', 'Var', (180, 189))	('GNA11', 'Gene', (139, 144))	('SF3B1', 'Gene', (174, 179))	('mutations', 'Var', (145, 154))	('BAP1', 'Gene', (55, 59))	('mutations', 'Var', (60, 69))	('GNA11', 'Gene', '2767', (139, 144))	('SF3B1', 'Gene', '23451', (174, 179))	('EIF1AX', 'Gene', '1964', (213, 219))	('EIF1AX', 'Gene', (213, 219))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('identified', 'Reg', (75, 85))	('BAP1', 'Gene', '8314', (55, 59))
91503	27123562	Sixteen of the mutations in BAP1 were previously unreported in UM or any other cancer (Table 2).	('BAP1', 'Gene', '8314', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('UM', 'Phenotype', 'HP:0007716', (63, 65))	('mutations', 'Var', (15, 24))	('BAP1', 'Gene', (28, 32))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
91504	27123562	Six of the mutations in EIF1AX, found in 10 tumors, were novel in UM, and 2 of the 6 mutations were not previously reported in any cancer (Table 3).	('cancer', 'Disease', (131, 137))	('tumors', 'Disease', (44, 50))	('mutations', 'Var', (11, 20))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('EIF1AX', 'Gene', '1964', (24, 30))	('EIF1AX', 'Gene', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
91506	27123562	Among primary tumors that metastasized, mutations were detected in BAP1 in 17 of 24 (71%), GNAQ in 13 of 28 (46%), GNA11 in 12 of 28 (43%), SF3B1 in 3 of 28 (11%), and EIF1AX in none.	('GNA11', 'Gene', '2767', (115, 120))	('detected', 'Reg', (55, 63))	('SF3B1', 'Gene', (140, 145))	('GNAQ', 'Gene', (91, 95))	('EIF1AX', 'Gene', (168, 174))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (40, 49))	('SF3B1', 'Gene', '23451', (140, 145))	('BAP1', 'Gene', '8314', (67, 71))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('EIF1AX', 'Gene', '1964', (168, 174))	('GNA11', 'Gene', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('BAP1', 'Gene', (67, 71))
91507	27123562	Mutations in GNAQ and GNA11 were mutually exclusive (P < .001).	('Mutations', 'Var', (0, 9))	('GNA11', 'Gene', (22, 27))	('GNA11', 'Gene', '2767', (22, 27))	('GNAQ', 'Gene', (13, 17))
91508	27123562	Mutations in BAP1 and SF3B1 were almost mutually exclusive (P = .007), as were mutations in BAP1 and EIF1AX (P = .03).	('BAP1', 'Gene', (13, 17))	('SF3B1', 'Gene', '23451', (22, 27))	('EIF1AX', 'Gene', '1964', (101, 107))	('EIF1AX', 'Gene', (101, 107))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (92, 96))	('BAP1', 'Gene', '8314', (13, 17))	('SF3B1', 'Gene', (22, 27))	('BAP1', 'Gene', (92, 96))
91509	27123562	Mutations in SF3B1 and EIF1AX were also almost mutually exclusive, with only one tumor having a mutation in both, but this association did not achieve statistical significance (P = .17).	('SF3B1', 'Gene', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('Mutations', 'Var', (0, 9))	('EIF1AX', 'Gene', (23, 29))	('SF3B1', 'Gene', '23451', (13, 18))	('EIF1AX', 'Gene', '1964', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
91510	27123562	BAP1 mutations were associated with class 2 GEP (P < .001) and older patient age (P = .007).	('associated', 'Reg', (20, 30))	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('class 2 GEP', 'Disease', (36, 47))	('patient', 'Species', '9606', (69, 76))	('BAP1', 'Gene', '8314', (0, 4))
91511	27123562	EIF1AX mutations were associated with class 1 GEP and the absence of ciliary body involvement (P = .03 for both).	('EIF1AX', 'Gene', '1964', (0, 6))	('mutations', 'Var', (7, 16))	('EIF1AX', 'Gene', (0, 6))	('class 1 GEP', 'Disease', (38, 49))
91512	27123562	SF3B1 mutations were associated with younger patient age (P = .006).	('patient', 'Species', '9606', (45, 52))	('SF3B1', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('SF3B1', 'Gene', '23451', (0, 5))
91513	27123562	Cox proportional hazards modeling was used to analyze the prognostic value of GEP class, gene mutations, and clinicopathologic features vis-a-vis time to metastasis and to melanoma-specific mortality (eTable in the Supplement).	('GEP', 'Gene', (78, 81))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('mutations', 'Var', (94, 103))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanoma', 'Disease', (172, 180))
91514	27123562	When all of these variables were considered together, class 2 GEP was the prognostic factor most strongly associated with metastasis (relative risk, 9.4; 95% CI, 3.1-28.5) and melanoma-specific mortality (relative risk, 15.7; 95% CI, 3.6-69.1) (P < .001 for both).	('class 2 GEP', 'Var', (54, 65))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))	('associated', 'Reg', (106, 116))	('metastasis', 'CPA', (122, 132))
91515	27123562	The identification of driver mutations has become a centerpiece of cancer precision medicine for diagnostic, prognostic, and therapeutic decision making in individual patients with cancer.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', (67, 73))	('mutations', 'Var', (29, 38))	('patients', 'Species', '9606', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))
91518	27123562	Sixteen mutations in BAP1 and 6 mutations in EIF1AX were previously unreported in UM.	('BAP1', 'Gene', (21, 25))	('mutations', 'Var', (8, 17))	('EIF1AX', 'Gene', (45, 51))	('UM', 'Phenotype', 'HP:0007716', (82, 84))	('EIF1AX', 'Gene', '1964', (45, 51))	('BAP1', 'Gene', '8314', (21, 25))
91519	27123562	GNAQ and GNA11 mutations were mutually exclusive with each other, they were present in similar proportions in class 1 and class 2 UMs, and they showed no association with tumor size or patient outcomes, suggesting that these mutations occur early in tumorigenesis.	('GNA11', 'Gene', (9, 14))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('patient', 'Species', '9606', (185, 192))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('GNAQ', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('UM', 'Phenotype', 'HP:0007716', (130, 132))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', (250, 255))	('GNA11', 'Gene', '2767', (9, 14))
91520	27123562	Mutations in BAP1, SF3B1, EIF1AX were almost mutually exclusive with each other, suggesting that they may represent alternative downstream molecular events during tumor progression.	('BAP1', 'Gene', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('SF3B1', 'Gene', '23451', (19, 24))	('EIF1AX', 'Gene', '1964', (26, 32))	('EIF1AX', 'Gene', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (163, 168))	('BAP1', 'Gene', '8314', (13, 17))	('SF3B1', 'Gene', (19, 24))
91521	27123562	Of particular interest, BAP1 mutations were associated with poor prognostic factors (class 2 GEP and older patient age) and high metastatic risk.	('BAP1', 'Gene', (24, 28))	('patient', 'Species', '9606', (107, 114))	('mutations', 'Var', (29, 38))	('BAP1', 'Gene', '8314', (24, 28))
91522	27123562	In contrast, EIF1AX and SF3B1 mutations were associated with good prognostic factors (EIF1AX mutations with class 1 GEP and the absence of ciliary body involvement and SF3B1 mutations with younger patient age).	('mutations', 'Var', (93, 102))	('SF3B1', 'Gene', (24, 29))	('SF3B1', 'Gene', (168, 173))	('EIF1AX', 'Gene', '1964', (86, 92))	('mutations', 'Var', (30, 39))	('EIF1AX', 'Gene', (13, 19))	('EIF1AX', 'Gene', '1964', (13, 19))	('SF3B1', 'Gene', '23451', (168, 173))	('SF3B1', 'Gene', '23451', (24, 29))	('patient', 'Species', '9606', (197, 204))	('EIF1AX', 'Gene', (86, 92))
91523	27123562	After excluding GEP class, the next most accurate prognostic factor was the presence of BAP1 mutations for both time to metastasis and to melanoma-specific mortality.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('mutations', 'Var', (93, 102))	('BAP1', 'Gene', '8314', (88, 92))	('BAP1', 'Gene', (88, 92))
91524	27123562	These findings suggest that mutational analysis of BAP1 may have value as a biomarker for poor prognosis, whereas EIF1AX and SF3B1 may be useful markers of good prognosis, as previously suggested.	('SF3B1', 'Gene', '23451', (125, 130))	('EIF1AX', 'Gene', '1964', (114, 120))	('EIF1AX', 'Gene', (114, 120))	('BAP1', 'Gene', (51, 55))	('poor', 'Disease', (90, 94))	('mutational analysis', 'Var', (28, 47))	('SF3B1', 'Gene', (125, 130))	('BAP1', 'Gene', '8314', (51, 55))
91525	27123562	Our group recently reported that expression of the oncogene PRAME identifies class 1 UMs with intermediate metastatic risk, and these class 1 PRAME-positive UMs often harbor SF3B1 mutations.	('mutations', 'Var', (180, 189))	('SF3B1', 'Gene', (174, 179))	('PRAME', 'Gene', '23532', (142, 147))	('harbor', 'Reg', (167, 173))	('PRAME', 'Gene', (142, 147))	('UM', 'Phenotype', 'HP:0007716', (157, 159))	('SF3B1', 'Gene', '23451', (174, 179))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('PRAME', 'Gene', '23532', (60, 65))	('PRAME', 'Gene', (60, 65))
91526	27123562	As such, we anticipate that SF3B1 mutations will be associated with a newly identified subclass of UM associated with metastatic risk that is intermediate between UMs with BAP1 mutations (high risk) and UMs with EIF1AX mutations (low risk).	('UM associated', 'Disease', (99, 112))	('UM', 'Phenotype', 'HP:0007716', (163, 165))	('BAP1', 'Gene', (172, 176))	('SF3B1', 'Gene', (28, 33))	('associated', 'Reg', (52, 62))	('EIF1AX', 'Gene', '1964', (212, 218))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('SF3B1', 'Gene', '23451', (28, 33))	('metastatic risk', 'Disease', (118, 133))	('EIF1AX', 'Gene', (212, 218))	('mutations', 'Var', (34, 43))	('UM', 'Phenotype', 'HP:0007716', (203, 205))	('BAP1', 'Gene', '8314', (172, 176))
91529	27123562	However, most other studies have relied on immunohistochemistry for the presence of the BAP1 protein as a surrogate marker for BAP1 mutations, which is associated with considerable false-positive and false-negative results, so our study provides important new insights based on validated mutations.	('BAP1', 'Gene', (127, 131))	('false', 'biological_process', 'GO:0071878', ('200', '205'))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('false', 'biological_process', 'GO:0071877', ('181', '186'))	('mutations', 'Var', (132, 141))	('false', 'biological_process', 'GO:0071878', ('181', '186'))	('false', 'biological_process', 'GO:0071877', ('200', '205'))	('BAP1', 'Gene', '8314', (88, 92))	('BAP1', 'Gene', '8314', (127, 131))	('BAP1', 'Gene', (88, 92))
91532	27123562	These findings suggest that the mutation status of BAP1, SF3B1, and EIF1AX is of clinical value in the application of precision medicine in UM.	('SF3B1', 'Gene', (57, 62))	('BAP1', 'Gene', (51, 55))	('SF3B1', 'Gene', '23451', (57, 62))	('EIF1AX', 'Gene', '1964', (68, 74))	('EIF1AX', 'Gene', (68, 74))	('UM', 'Phenotype', 'HP:0007716', (140, 142))	('mutation', 'Var', (32, 40))	('BAP1', 'Gene', '8314', (51, 55))
91533	27123562	While GEP remains the most accurate prognostic biomarker, it is possible that continued research will show that the inclusion of mutational information with GEP could increase the prognostic accuracy or suggest specific treatment choices, such as an MEK inhibitor for GNAQ and GNA11 mutations or an epigenetic modulator for BAP1 mutations.	('epigenetic modulator', 'Var', (299, 319))	('GEP', 'Gene', (157, 160))	('prognostic accuracy', 'CPA', (180, 199))	('GNA11', 'Gene', (277, 282))	('BAP1', 'Gene', '8314', (324, 328))	('mutations', 'Var', (283, 292))	('GNA11', 'Gene', '2767', (277, 282))	('BAP1', 'Gene', (324, 328))	('mutations', 'Var', (329, 338))	('increase', 'PosReg', (167, 175))	('MEK', 'Gene', (250, 253))	('MEK', 'Gene', '5609', (250, 253))
91535	27123562	This retrospective study of patients with uveal melanoma treated by enucleation found that BAP1, SF3B1, and EIF1AX mutations were almost mutually exclusive with each other.	('SF3B1', 'Gene', '23451', (97, 102))	('EIF1AX', 'Gene', (108, 114))	('mutations', 'Var', (115, 124))	('BAP1', 'Gene', (91, 95))	('EIF1AX', 'Gene', '1964', (108, 114))	('enucleation', 'biological_process', 'GO:0090601', ('68', '79'))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('SF3B1', 'Gene', (97, 102))	('BAP1', 'Gene', '8314', (91, 95))	('patients', 'Species', '9606', (28, 36))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('uveal melanoma', 'Disease', (42, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
91536	27123562	BAP1 mutations were associated with poor prognostic factors, and EIF1AX and SF3B1 mutations were associated with good prognostic factors.	('EIF1AX', 'Gene', (65, 71))	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('SF3B1', 'Gene', (76, 81))	('BAP1', 'Gene', '8314', (0, 4))	('SF3B1', 'Gene', '23451', (76, 81))	('EIF1AX', 'Gene', '1964', (65, 71))
91537	27123562	BAP1, SF3B1, and EIF1AX mutations may have value as prognostic markers in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('BAP1', 'Gene', (0, 4))	('SF3B1', 'Gene', (6, 11))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('BAP1', 'Gene', '8314', (0, 4))	('SF3B1', 'Gene', '23451', (6, 11))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('EIF1AX', 'Gene', '1964', (17, 23))	('EIF1AX', 'Gene', (17, 23))	('mutations', 'Var', (24, 33))	('uveal melanoma', 'Disease', (74, 88))
91612	22541662	Alternatively, it is possible that more aggressive mutations in genes such as BAP1 are more likely to occur in older patients.	('occur', 'Reg', (102, 107))	('mutations', 'Var', (51, 60))	('BAP1', 'Gene', '8314', (78, 82))	('patients', 'Species', '9606', (117, 125))	('BAP1', 'Gene', (78, 82))
91628	22541662	After brachytherapy several groups have shown that tumor thickness shrinkage may be greater in melanomas with monosomy 3 as compared to disomy 3, although the methods of measuring tumor response were suboptimal.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('melanomas', 'Disease', (95, 104))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', (180, 185))	('monosomy 3', 'Var', (110, 120))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('melanomas', 'Disease', 'MESH:D008545', (95, 104))	('shrinkage', 'NegReg', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
91629	22541662	It is uncertain why there is a discrepancy between our analysis of response to proton therapy using molecular class and these other reports of a relationship between rates of tumor shrinkage and the presence of monosomy 3.	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('monosomy 3', 'Var', (211, 221))	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (175, 180))
91633	26226841	Loss of expression of BAP1 is a useful adjunct, which strongly supports the diagnosis of mesothelioma in effusion cytology Although most mesotheliomas present with pleural effusions, it is controversial whether mesothelioma can be diagnosed with confidence in effusion cytology.	('mesothelioma', 'Disease', 'MESH:D008654', (211, 223))	('pleural effusion', 'Phenotype', 'HP:0002202', (164, 180))	('pleural effusions', 'Disease', (164, 181))	('mesotheliomas', 'Disease', 'MESH:D008654', (137, 150))	('effusion', 'Disease', 'MESH:D010996', (260, 268))	('mesothelioma', 'Disease', (137, 149))	('mesotheliomas', 'Disease', (137, 150))	('effusion', 'Disease', 'MESH:D010996', (172, 180))	('mesothelioma', 'Disease', 'MESH:D008654', (137, 149))	('effusion', 'Disease', 'MESH:D010996', (105, 113))	('pleural effusions', 'Disease', 'MESH:D010996', (164, 181))	('BAP1', 'Gene', '8314', (22, 26))	('Loss of expression', 'Var', (0, 18))	('mesothelioma', 'Disease', (89, 101))	('effusion', 'Disease', (260, 268))	('mesothelioma', 'Disease', 'MESH:D008654', (89, 101))	('effusion', 'Disease', (172, 180))	('pleural effusions', 'Phenotype', 'HP:0002202', (164, 181))	('effusion', 'Disease', (105, 113))	('BAP1', 'Gene', (22, 26))	('mesothelioma in effusion', 'Disease', (89, 113))	('mesothelioma', 'Disease', (211, 223))	('mesothelioma in effusion', 'Disease', 'MESH:D008654', (89, 113))
91645	26226841	We conclude that loss of BAP1 expression, while not definitive, can be used to support the diagnosis of mesothelioma in effusion cytology.	('mesothelioma in effusion', 'Disease', 'MESH:D008654', (104, 128))	('expression', 'MPA', (30, 40))	('BAP1', 'Gene', (25, 29))	('mesothelioma in effusion', 'Disease', (104, 128))	('BAP1', 'Gene', '8314', (25, 29))	('loss', 'Var', (17, 21))
91650	26226841	The discovery of germline BAP1 mutations in families with high incidences of mesothelioma and other neoplasms has led to the recent recognition of the BAP1 tumor predisposition syndrome (OMIM #614327), which is inherited in an autosomal dominant manner and is characterised by uveal melanoma, mesothelioma, cutaneous melanocytic lesions, renal cell carcinoma, basal cell carcinoma, and possibly intrahepatic cholangiocarcinoma.	('mesothelioma', 'Disease', (77, 89))	('neoplasm', 'Phenotype', 'HP:0002664', (100, 108))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (395, 426))	('intrahepatic cholangiocarcinoma', 'Disease', (395, 426))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (408, 426))	('tumor', 'Disease', (156, 161))	('neoplasms', 'Phenotype', 'HP:0002664', (100, 109))	('BAP1', 'Gene', (26, 30))	('BAP1', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (371, 380))	('carcinoma', 'Phenotype', 'HP:0030731', (349, 358))	('cutaneous melanocytic lesions', 'Disease', (307, 336))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (360, 380))	('BAP1', 'Gene', '8314', (151, 155))	('mutations', 'Var', (31, 40))	('neoplasms', 'Disease', 'MESH:D009369', (100, 109))	('mesothelioma', 'Disease', (293, 305))	('uveal melanoma', 'Disease', 'MESH:C536494', (277, 291))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (338, 358))	('melanoma', 'Phenotype', 'HP:0002861', (283, 291))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('uveal melanoma', 'Disease', (277, 291))	('mesothelioma', 'Disease', 'MESH:D008654', (293, 305))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (360, 380))	('cutaneous melanocytic lesions', 'Disease', 'MESH:D009508', (307, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (417, 426))	('neoplasms', 'Disease', (100, 109))	('uveal melanoma', 'Phenotype', 'HP:0007716', (277, 291))	('BAP1', 'Gene', '8314', (26, 30))	('renal cell carcinoma', 'Disease', (338, 358))	('basal cell carcinoma', 'Disease', (360, 380))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (338, 358))
91656	26226841	These observations suggest a genetic predisposition to developing mesothelioma, and have led to the discovery of the association between germline BAP1 mutation and mesothelioma.	('BAP1', 'Gene', '8314', (146, 150))	('mesothelioma', 'Disease', (164, 176))	('association', 'Interaction', (117, 128))	('mutation', 'Var', (151, 159))	('BAP1', 'Gene', (146, 150))	('mesothelioma', 'Disease', (66, 78))	('mesothelioma', 'Disease', 'MESH:D008654', (164, 176))	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))
91657	26226841	Furthermore recent studies have identified an association between somatic BAP1 inactivation and mesothelioma, with double-hit inactivation of BAP1 reported in approximately half of all mesotheliomas.	('mesotheliomas', 'Disease', 'MESH:D008654', (185, 198))	('mesotheliomas', 'Disease', (185, 198))	('mesothelioma', 'Disease', (185, 197))	('mesothelioma', 'Disease', (96, 108))	('inactivation', 'Var', (79, 91))	('BAP1', 'Gene', '8314', (142, 146))	('BAP1', 'Gene', '8314', (74, 78))	('BAP1', 'Gene', (142, 146))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('mesothelioma', 'Disease', 'MESH:D008654', (185, 197))	('BAP1', 'Gene', (74, 78))
91665	26226841	Given the high rate of BAP1 double-hit inactivation in mesothelioma and its correlation with loss of BAP1 expression as determined by immunohistochemistry in tissue specimens, we sought to investigate whether loss of expression of BAP1 as determined in cell-block preparations from pleural effusion specimens could be used to support a diagnosis of mesothelioma.	('mesothelioma', 'Disease', (349, 361))	('BAP1', 'Gene', (23, 27))	('mesothelioma', 'Disease', 'MESH:D008654', (349, 361))	('mesothelioma', 'Disease', (55, 67))	('BAP1', 'Gene', '8314', (101, 105))	('pleural effusion', 'Disease', 'MESH:D010996', (282, 298))	('BAP1', 'Gene', '8314', (231, 235))	('pleural effusion', 'Phenotype', 'HP:0002202', (282, 298))	('pleural effusion', 'Disease', (282, 298))	('BAP1', 'Gene', '8314', (23, 27))	('BAP1', 'Gene', (101, 105))	('mesothelioma', 'Disease', 'MESH:D008654', (55, 67))	('BAP1', 'Gene', (231, 235))	('double-hit', 'Var', (28, 38))
91697	26226841	Loss of immunohistochemical staining for BAP1 in the presence of an internal positive control in non-neoplastic cells has been proven to be a reliable marker of BAP1 double-hit inactivation in tissue samples from mesothelioma and uveal melanoma.	('BAP1', 'Gene', (161, 165))	('mesothelioma', 'Disease', (213, 225))	('BAP1', 'Gene', (41, 45))	('double-hit', 'Var', (166, 176))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('Loss', 'NegReg', (0, 4))	('uveal melanoma', 'Phenotype', 'HP:0007716', (230, 244))	('uveal melanoma', 'Disease', 'MESH:C536494', (230, 244))	('mesothelioma', 'Disease', 'MESH:D008654', (213, 225))	('BAP1', 'Gene', '8314', (161, 165))	('uveal melanoma', 'Disease', (230, 244))	('BAP1', 'Gene', '8314', (41, 45))
91698	26226841	Given that double-hit inactivation of BAP1 has been reported as a key driver event in approximately half of all mesotheliomas, loss of immunohistochemical staining for BAP1 is an attractive ancillary marker for mesothelioma with the potential to be highly specific, albeit not particularly sensitive.	('mesothelioma', 'Disease', 'MESH:D008654', (211, 223))	('BAP1', 'Gene', '8314', (168, 172))	('BAP1', 'Gene', (38, 42))	('mesothelioma', 'Disease', 'MESH:D008654', (112, 124))	('BAP1', 'Gene', (168, 172))	('BAP1', 'Gene', '8314', (38, 42))	('mesothelioma', 'Disease', (211, 223))	('loss', 'Var', (127, 131))	('mesotheliomas', 'Disease', 'MESH:D008654', (112, 125))	('mesotheliomas', 'Disease', (112, 125))	('mesothelioma', 'Disease', (112, 124))
91710	26226841	Therefore, because BAP1 immunohistochemistry may be difficult to interpret with certainty in pleural effusion specimens, loss of BAP1 expression even when interpreted by experienced observers, can only be used to support a diagnosis of mesothelioma in the appropriate clinical and morphological context and is not completely definitive when interpreted in isolation.	('mesothelioma', 'Disease', (236, 248))	('mesothelioma', 'Disease', 'MESH:D008654', (236, 248))	('loss', 'Var', (121, 125))	('pleural effusion', 'Disease', 'MESH:D010996', (93, 109))	('BAP1', 'Gene', '8314', (19, 23))	('BAP1', 'Gene', '8314', (129, 133))	('pleural effusion', 'Disease', (93, 109))	('pleural effusion', 'Phenotype', 'HP:0002202', (93, 109))	('BAP1', 'Gene', (19, 23))	('BAP1', 'Gene', (129, 133))
91713	26226841	Therefore, in addition to supporting a diagnosis of mesothelioma over reactive mesothelial change in the appropriate context, loss of expression of BAP1 can also be used to support a malignancy as being mesothelial rather than epithelial.	('loss of expression', 'Var', (126, 144))	('BAP1', 'Gene', '8314', (148, 152))	('malignancy', 'Disease', 'MESH:D009369', (183, 193))	('mesothelioma', 'Disease', (52, 64))	('BAP1', 'Gene', (148, 152))	('malignancy', 'Disease', (183, 193))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))
91729	26462151	Uveal melanoma (UM) is a rare ocular neoplasm characterized by GNAQ and GNA11 mutations.	('melanoma', 'Disease', 'MESH:D008545', (6, 14))	('ocular neoplasm', 'Disease', 'MESH:D005134', (30, 45))	('GNAQ', 'Gene', (63, 67))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('GNAQ', 'Gene', '2776', (63, 67))	('mutations', 'Var', (78, 87))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('UM', 'Phenotype', 'HP:0007716', (16, 18))	('GNA11', 'Gene', (72, 77))	('ocular neoplasm', 'Phenotype', 'HP:0100012', (30, 45))	('neoplasm', 'Phenotype', 'HP:0002664', (37, 45))	('melanoma', 'Disease', (6, 14))	('GNA11', 'Gene', '2767', (72, 77))	('ocular neoplasm', 'Disease', (30, 45))
91737	26462151	Loss of chromosome 3 was predominantly presented in class II (a/b) tumors and was only detected in 3 out 25 class I tumors (Supplementary Table S3).	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('I tumors', 'Disease', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('I tumors', 'Disease', 'MESH:D009369', (114, 122))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('Loss', 'Var', (0, 4))	('tumors', 'Disease', (67, 73))
91738	26462151	In contrast, gain of chromosomal part 6p was most prominent in class I tumors.	('I tumors', 'Disease', (69, 77))	('part 6p', 'Gene', (33, 40))	('part 6p', 'Gene', '80351', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('I tumors', 'Disease', 'MESH:D009369', (69, 77))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('chromosomal', 'Var', (21, 32))	('gain', 'PosReg', (13, 17))
91739	26462151	Monosomy 3 and 6p gain molecularly characterize class II and class I tumors, respectively, but do not differentiate class IIa from class IIb tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('I tumors', 'Disease', 'MESH:D009369', (67, 75))	('I tumors', 'Disease', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('gain', 'PosReg', (18, 22))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('Monosomy 3', 'Var', (0, 10))	('class II', 'Disease', (48, 56))
91746	26462151	Based on the assumption that every tumor cell within a mutant UM l either carries a GNAQ or GNA11 mutation we were able to calculate the fractional abundance (FA), which represents the ratio between cancer cells and non-cancer cells (e.g.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('fractional abundance', 'MPA', (137, 157))	('mutation', 'Var', (98, 106))	('GNAQ', 'Gene', (84, 88))	('GNA11', 'Gene', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('GNA11', 'Gene', '2767', (92, 97))	('tumor', 'Disease', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('GNAQ', 'Gene', '2776', (84, 88))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (199, 205))	('cancer', 'Disease', (220, 226))	('non-cancer', 'Disease', (216, 226))	('non-cancer', 'Disease', 'MESH:D009369', (216, 226))
91749	26462151	This was warranted by the positive correlation between tumor fraction calculated with GNAQ/GNA11 mutation and monosomy 3 (Supplementary Figure S2).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('GNA11', 'Gene', (91, 96))	('GNAQ', 'Gene', '2776', (86, 90))	('monosomy 3', 'Disease', (110, 120))	('tumor', 'Disease', (55, 60))	('GNA11', 'Gene', '2767', (91, 96))	('mutation', 'Var', (97, 105))	('GNAQ', 'Gene', (86, 90))
91755	26462151	In UM 20-042 for example, 71.8% of the cells contained the GNAQ Q209P mutation while a chromosome 3 copy number of 1,64 indicated that 36% of the cells contained monosomy 3 and thereby revealed that monosomy 3 occurred after GNAQ mutation (Table 1).	('UM', 'Phenotype', 'HP:0007716', (3, 5))	('chromosome', 'cellular_component', 'GO:0005694', ('87', '97'))	('Q209P mutation', 'Var', (64, 78))	('Q209P', 'Mutation', 'rs121913492', (64, 69))	('GNAQ', 'Gene', '2776', (225, 229))	('GNAQ', 'Gene', (59, 63))	('GNAQ', 'Gene', (225, 229))	('GNAQ', 'Gene', '2776', (59, 63))
91756	26462151	Among 39 UM with monosomy 3 and 8q gain, three tumors (20-173, 06-015 and 06-023) displayed 8q gain in all tumor cells, but some cells contained two copies of chromosome 3.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('monosomy 3', 'Var', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('chromosome', 'cellular_component', 'GO:0005694', ('159', '169'))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (47, 52))	('gain', 'PosReg', (95, 99))
91758	26462151	With dPCR calculated tumor fractions we furthermore deduced that loss of 16q seems to be more common as a quaternary event following monosomy 3.	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('loss of 16q', 'Var', (65, 76))	('tumor', 'Disease', (21, 26))
91759	26462151	For monosomy 3 and chromosome 16q loss, 14 tumors showed heterogeneity (DeltaX > 0.2) and all showed a larger monosomy 3 tumor fraction.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('monosomy 3', 'Var', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('chromosome', 'cellular_component', 'GO:0005694', ('19', '29'))	('monosomy 3', 'MPA', (110, 120))	('tumors', 'Disease', (43, 49))	('loss', 'NegReg', (34, 38))	('tumor', 'Disease', (43, 48))	('heterogeneity', 'MPA', (57, 70))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
91760	26462151	For the combination of loss of 16q and 1p, only six UM were informative and all showed a higher 16q tumor fraction compared to the 1p fraction.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('16q', 'MPA', (96, 99))	('tumor', 'Disease', (100, 105))	('higher', 'PosReg', (89, 95))	('loss', 'Var', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
91763	26462151	In our tumor set, monosomy 3 and 6p gain clearly divided the tumors into class I and class II (a/b) (Figure 3).	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('monosomy 3', 'Var', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
91764	26462151	Though, our observations suggest that tumor clones presenting both monosomy 3 and 6p gain are unsuccessful and remain small.	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('monosomy 3', 'Var', (67, 77))
91765	26462151	Class IIa more commonly yielded tumors with gain of a complete chromosome 8 while class IIb tumors almost exclusively displayed 8q copy gains due to isochromosome formation.	('formation', 'biological_process', 'GO:0009058', ('163', '172'))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('isochromosome formation', 'Var', (149, 172))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('8q copy gains', 'Var', (128, 141))	('gain', 'PosReg', (44, 48))	('tumors', 'Disease', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
91790	26462151	GNAQ and GNA11 mutations were detected using hydrolysis probes in a multiplex dPCR.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('GNAQ', 'Gene', (0, 4))	('GNA11', 'Gene', '2767', (9, 14))
91815	22117885	With a diagnosis of metastatic non-small cell lung cancer and the EGFR mutation identified, the patient began treatment with erlotinib.	('non-small cell lung cancer', 'Disease', (31, 57))	('erlotinib', 'Chemical', 'MESH:D000069347', (125, 134))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (35, 57))	('EGFR', 'Gene', '1956', (66, 70))	('mutation', 'Var', (71, 79))	('EGFR', 'Gene', (66, 70))	('patient', 'Species', '9606', (96, 103))	('men', 'Species', '9606', (115, 118))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (31, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (31, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
91837	22117885	Later advances led to the development of chimeric and humanized anti-mouse antibodies, which are partly constructed from human sources and confer improved efficacy and reduced immunogenicity.	('mouse', 'Species', '10090', (69, 74))	('human', 'Species', '9606', (121, 126))	('efficacy', 'MPA', (155, 163))	('chimeric', 'Var', (41, 49))	('men', 'Species', '9606', (33, 36))	('human', 'Species', '9606', (54, 59))
91844	22117885	A particular side effect of monoclonal antibodies relates to a hypersensitivity from the murine component, and is characterized as a flu-like syndrome in 40% of patients during the initial drug infusion.	('hypersensitivity', 'Disease', 'MESH:D004342', (63, 79))	('flu-like syndrome', 'Disease', 'MESH:D007251', (133, 150))	('hypersensitivity', 'Disease', (63, 79))	('murine', 'Species', '10090', (89, 95))	('patients', 'Species', '9606', (161, 169))	('monoclonal antibodies', 'Var', (28, 49))	('hypersensitivity', 'biological_process', 'GO:0002524', ('63', '79'))	('flu-like syndrome', 'Disease', (133, 150))
91849	22117885	Erlotinib is a tyrosine kinase inhibitor of EGFR that has led to favorable responses, as seen in our patient who has the somatic gain-of-function mutation around the ATP binding pocket of the EGFR protein kinase domain.	('gain-of-function', 'PosReg', (129, 145))	('EGFR', 'molecular_function', 'GO:0005006', ('192', '196'))	('ATP binding', 'molecular_function', 'GO:0005524', ('166', '177'))	('tyrosine', 'Chemical', 'MESH:D014443', (15, 23))	('protein', 'cellular_component', 'GO:0003675', ('197', '204'))	('EGFR', 'Gene', '1956', (44, 48))	('ATP', 'Chemical', 'MESH:D000255', (166, 169))	('EGFR', 'Gene', (44, 48))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('24', '40'))	('patient', 'Species', '9606', (101, 108))	('mutation', 'Var', (146, 154))	('EGFR', 'Gene', '1956', (192, 196))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))	('EGFR', 'Gene', (192, 196))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))
91940	22117885	One month after intravitreal injection of 1.25 mg bevacizumab, the angiogram showed a 50% reduction in lesion size and significantly less leakage in the late frames.	('reduction', 'NegReg', (90, 99))	('leakage', 'MPA', (138, 145))	('bevacizumab', 'Chemical', 'MESH:D000068258', (50, 61))	('1.25 mg', 'Var', (42, 49))	('less', 'NegReg', (133, 137))	('lesion', 'MPA', (103, 109))
91957	22117885	As our case report illustrates, new targeted therapies such as tyrosine kinase inhibitors can stabilize metastatic disease and induce choroidal regression without the additional need for local therapy.	('metastatic', 'Disease', (104, 114))	('tyrosine', 'Chemical', 'MESH:D014443', (63, 71))	('choroidal regression', 'CPA', (134, 154))	('tyrosine', 'Var', (63, 71))
92038	25510783	Cluster 2 consisted of seven miRNAs (miR-9*, miR125a-5p, miR-25, miR-125b, miR-335, miR-19a and miR-9) that were also expressed almost equally in patients and the five tested cell lines (Figure 4C).	('miR-9*', 'Var', (37, 43))	('miR-25', 'Gene', (57, 63))	('miR-19a', 'Gene', '406979', (84, 91))	('miR-335', 'Gene', (75, 82))	('miR125a-5p', 'Var', (45, 55))	('miR-9', 'Var', (96, 101))	('miR-125b', 'Var', (65, 73))	('miR-335', 'Gene', '442904', (75, 82))	('miR-19a', 'Gene', (84, 91))	('patients', 'Species', '9606', (146, 154))	('miR-25', 'Gene', '407014', (57, 63))
92040	25510783	Cluster 3 consisted of six miRNAs (miR-370, miR-210, miR-320a, miR-124, miR-107 and miR-486-5p) that were primarily present in patients, and were also measurable in the A375 melanoma cell line, but not present in the other four cell lines (Figure 4C).	('miR-107', 'Gene', (72, 79))	('miR-486-5p', 'Var', (84, 94))	('miR-210', 'Gene', (44, 51))	('patients', 'Species', '9606', (127, 135))	('miR-320a', 'Gene', (53, 61))	('miR-124', 'Var', (63, 70))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('miR-370', 'Gene', '442915', (35, 42))	('melanoma', 'Disease', (174, 182))	('miR-320a', 'Gene', '407037', (53, 61))	('A375', 'CellLine', 'CVCL:0132', (169, 173))	('miR-210', 'Gene', '406992', (44, 51))	('miR-107', 'Gene', '406901', (72, 79))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('miR-370', 'Gene', (35, 42))
92061	25510783	In cluster 3, a number of miRNAs (miR-370, miR-210, miR-320a, miR-124, miR-107 and miR-486-5p) were identified that could not be detected in exosomes from most of the cell lines.	('miR-370', 'Gene', (34, 41))	('miR-320a', 'Gene', (52, 60))	('miR-107', 'Gene', '406901', (71, 78))	('miR-320a', 'Gene', '407037', (52, 60))	('miR-124', 'Var', (62, 69))	('miR-107', 'Gene', (71, 78))	('miR-210', 'Gene', (43, 50))	('miR-370', 'Gene', '442915', (34, 41))	('miR-210', 'Gene', '406992', (43, 50))
92163	24618486	Several authors have reported that local tumor control rates and need for enucleation appear to be inferior with 106Ru compared to 125I, especially when apical tumor height is considered.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('106Ru', 'Var', (113, 118))	('tumor', 'Disease', (41, 46))	('enucleation', 'biological_process', 'GO:0090601', ('74', '85'))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('inferior', 'NegReg', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))	('apical tumor', 'Phenotype', 'HP:0032176', (153, 165))
92207	24288566	Both M17 and SP.6.5 cell lines were originated from nonmetastatic uveal melanoma, and C918 is a metastatic and aggressive melanoma cell line.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('uveal melanoma', 'Disease', (66, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('C918', 'CellLine', 'CVCL:8471', (86, 90))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('aggressive melanoma', 'Disease', (111, 130))	('C918', 'Var', (86, 90))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('aggressive melanoma', 'Disease', 'MESH:D008545', (111, 130))
92238	24288566	After 24 h incubation, the medium was changed, and various signal inhibitors were added to the medium separately, including 10 muM of LY294002 (PI3K/Akt inhibitor), UO1026 (ERK inhibitor), SP600125 (JNK inhibitor), and SB203580 (p38 MAPK inhibitor), all from Calbiochem, San Diego, CA, USA.	('Akt', 'Gene', (149, 152))	('MAPK', 'Gene', '5595;5594;5595', (233, 237))	('SB203580', 'Chemical', 'MESH:C093642', (219, 227))	('ERK', 'molecular_function', 'GO:0004707', ('173', '176'))	('LY294002', 'Chemical', 'MESH:C085911', (134, 142))	('UO1026', 'Var', (165, 171))	('Akt', 'Gene', '207', (149, 152))	('JNK', 'Gene', (199, 202))	('MAPK', 'molecular_function', 'GO:0004707', ('233', '237'))	('p38', 'Gene', '1432', (229, 232))	('JNK', 'Gene', '5599', (199, 202))	('MAPK', 'Gene', (233, 237))	('SB203580', 'Var', (219, 227))	('SP600125', 'Chemical', 'MESH:C432165', (189, 197))	('muM', 'Gene', '56925', (127, 130))	('ERK', 'Gene', '5594', (173, 176))	('muM', 'Gene', (127, 130))	('PI3K', 'molecular_function', 'GO:0016303', ('144', '148'))	('UO1026', 'Chemical', '-', (165, 171))	('LY294002', 'Var', (134, 142))	('ERK', 'Gene', (173, 176))	('p38', 'Gene', (229, 232))	('SP600125', 'Var', (189, 197))	('JNK', 'molecular_function', 'GO:0004705', ('199', '202'))
92262	24288566	Treatment of cells with LY294002 (PI3K/Akt inhibitor) and UO1026 (ERK inhibitor) significantly decreased VEGF levels in the conditioned media (P < 0.05) (Figure 6).	('decreased', 'NegReg', (95, 104))	('ERK', 'molecular_function', 'GO:0004707', ('66', '69'))	('LY294002', 'Var', (24, 32))	('Akt', 'Gene', '207', (39, 42))	('VEGF', 'Gene', (105, 109))	('UO1026', 'Var', (58, 64))	('PI3K', 'molecular_function', 'GO:0016303', ('34', '38'))	('Akt', 'Gene', (39, 42))	('ERK', 'Gene', '5594', (66, 69))	('LY294002', 'Chemical', 'MESH:C085911', (24, 32))	('VEGF', 'Gene', '7422', (105, 109))	('UO1026', 'Chemical', '-', (58, 64))	('ERK', 'Gene', (66, 69))
92263	24288566	VEGF levels in the conditioned media from SP600125 (JNK1/2 inhibitor) and SB203580 (p38 MAPK inhibitor) treated cells did not show significant changes as compared with the control (P > 0.05) (Figure 6).	('MAPK', 'Gene', '5595;5594;5595', (88, 92))	('p38', 'Gene', '1432', (84, 87))	('MAPK', 'molecular_function', 'GO:0004707', ('88', '92'))	('JNK', 'molecular_function', 'GO:0004705', ('52', '55'))	('VEGF', 'Gene', '7422', (0, 4))	('p38', 'Gene', (84, 87))	('SB203580', 'Gene', (74, 82))	('SP600125', 'Chemical', 'MESH:C432165', (42, 50))	('SB203580', 'Chemical', 'MESH:C093642', (74, 82))	('MAPK', 'Gene', (88, 92))	('VEGF', 'Gene', (0, 4))	('SP600125', 'Var', (42, 50))
92272	24288566	It has been reported that apigenin could inhibit the growth of cancers in experimental animal models In vitro studies suggested that apigenin induced apoptosis and inhibited the growth and invasion of various cultured cancer cells, including breast, cervical, colon, lung, ovarian, prostate, gastric, liver, and skin cancer cells.	('colon', 'Disease', (260, 265))	('liver', 'Disease', (301, 306))	('apoptosis', 'CPA', (150, 159))	('inhibited', 'NegReg', (164, 173))	('cervical', 'Disease', (250, 258))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('apigenin', 'Chemical', 'MESH:D047310', (26, 34))	('skin cancer', 'Disease', (312, 323))	('breast', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (317, 323))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('ovarian', 'Disease', (273, 280))	('cancers', 'Disease', (63, 70))	('cancer', 'Disease', (63, 69))	('cancer', 'Disease', (317, 323))	('skin cancer', 'Phenotype', 'HP:0008069', (312, 323))	('apigenin', 'Chemical', 'MESH:D047310', (133, 141))	('ovarian', 'Disease', 'MESH:D010051', (273, 280))	('gastric', 'Disease', (292, 299))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('lung', 'Disease', (267, 271))	('prostate', 'Disease', (282, 290))	('cancer', 'Disease', (218, 224))	('apigenin', 'Var', (133, 141))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('apoptosis', 'biological_process', 'GO:0097194', ('150', '159'))	('skin cancer', 'Disease', 'MESH:D012878', (312, 323))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('invasion', 'CPA', (189, 197))	('inhibit', 'NegReg', (41, 48))	('colon', 'Disease', 'MESH:D015179', (260, 265))	('apoptosis', 'biological_process', 'GO:0006915', ('150', '159'))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
92297	24288566	However, only ERK1/2 and PI3 K/Akt inhibitors significantly reduced the secretion of VEGF by uveal melanoma cells, whereas JNK1/2 and p38 inhibitors did not influence the secretion of VEGF by melanoma cells in the present study.	('Akt', 'Gene', (31, 34))	('uveal melanoma', 'Disease', 'MESH:C536494', (93, 107))	('VEGF', 'Gene', '7422', (85, 89))	('uveal melanoma', 'Disease', (93, 107))	('JNK', 'molecular_function', 'GO:0004705', ('123', '126'))	('Akt', 'Gene', '207', (31, 34))	('secretion', 'biological_process', 'GO:0046903', ('72', '81'))	('VEGF', 'Gene', (85, 89))	('uveal melanoma', 'Phenotype', 'HP:0007716', (93, 107))	('p38', 'Gene', '1432', (134, 137))	('VEGF', 'Gene', '7422', (184, 188))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('secretion', 'biological_process', 'GO:0046903', ('171', '180'))	('VEGF', 'Gene', (184, 188))	('ERK1/2', 'Gene', (14, 20))	('ERK1/2', 'Gene', '5595;5594', (14, 20))	('PI3 K', 'molecular_function', 'GO:0016303', ('25', '30'))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanoma', 'Disease', (192, 200))	('reduced', 'NegReg', (60, 67))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('inhibitors', 'Var', (35, 45))	('ERK1', 'molecular_function', 'GO:0004707', ('14', '18'))	('p38', 'Gene', (134, 137))
92379	20089875	VEGF was reduced in Mel270 and Mel290 to 1128.81 and 2512.66pg/ml, respectively, after treatment with 10 mug/ml of bevacizumab and 3008.76 and 2611.66 pg/ml after treatment with 100 mug/ml of bevacizumab in Mel270 and Mel290 cells co-cultured with HUVECs.	('bevacizumab', 'Chemical', 'MESH:D000068258', (115, 126))	('HUVEC', 'CellLine', 'CVCL:2959', (248, 253))	('mug', 'molecular_function', 'GO:0043739', ('105', '108'))	('reduced', 'NegReg', (9, 16))	('mug', 'molecular_function', 'GO:0043739', ('182', '185'))	('2611.66 pg/ml', 'Var', (143, 156))	('3008.76', 'Var', (131, 138))	('bevacizumab', 'Chemical', 'MESH:D000068258', (192, 203))
92388	20089875	The average total capillary tube length in HUVECs with IgG1, 10mug/ml bevacizumab or 100mug/ml bevacizumab, respectively, was 2076+-183 mum, 888.9+-77mum, and 633+-28mum.	('IgG1', 'cellular_component', 'GO:0071735', ('55', '59'))	('mug', 'molecular_function', 'GO:0043739', ('88', '91'))	('IgG1', 'Gene', (55, 59))	('bevacizumab', 'Chemical', 'MESH:D000068258', (95, 106))	('mug', 'molecular_function', 'GO:0043739', ('63', '66'))	('888.9+-77mum', 'Var', (141, 153))	('HUVEC', 'CellLine', 'CVCL:2959', (43, 48))	('IgG1', 'Gene', '16017', (55, 59))	('bevacizumab', 'Chemical', 'MESH:D000068258', (70, 81))
92391	20089875	The average total capillary tube lengths in HUVECs treated with IgG1 or 100mug/ml bevacizumab, were 5097.26+-386.52 mum and 1182.67+-70.61 mum, resepctively (p<0.01).	('5097.26+-386.52', 'Var', (100, 115))	('mug', 'molecular_function', 'GO:0043739', ('75', '78'))	('IgG1', 'Gene', '16017', (64, 68))	('HUVEC', 'CellLine', 'CVCL:2959', (44, 49))	('100mug/ml', 'Var', (72, 81))	('bevacizumab', 'Chemical', 'MESH:D000068258', (82, 93))	('IgG1', 'cellular_component', 'GO:0071735', ('64', '68'))	('IgG1', 'Gene', (64, 68))
92402	20089875	The in vitro invasion assay showed significantly less invasion of both Mel 290 cells and B16LS9 cells treated with bevacizumab, with 100mug/ml being more effective than 10mug/ml of bevacizumab.	('invasion', 'CPA', (54, 62))	('bevacizumab', 'Chemical', 'MESH:D000068258', (115, 126))	('mug', 'molecular_function', 'GO:0043739', ('171', '174'))	('mug', 'molecular_function', 'GO:0043739', ('136', '139'))	('bevacizumab', 'Chemical', 'MESH:D000068258', (181, 192))	('100mug/ml', 'Var', (133, 142))	('B16LS9', 'CellLine', 'CVCL:2105', (89, 95))	('less', 'NegReg', (49, 53))
92403	20089875	Invasion of Mel290 cells decreased by 56% and 91% optical density (OD) units after treatment with 10mug/ml and 100mug/ml of bevacizumab (0.1063+-0.0142 & 0.0877+-0.0053), respectively, compared with IgG treatment (0.2399+-0.0184, P<0.001).	('mug', 'molecular_function', 'GO:0043739', ('100', '103'))	('bevacizumab', 'Chemical', 'MESH:D000068258', (124, 135))	('0.1063+-0.0142', 'Var', (137, 151))	('decreased', 'NegReg', (25, 34))	('mug', 'molecular_function', 'GO:0043739', ('114', '117'))	('Invasion of Mel290 cells', 'CPA', (0, 24))
92408	20089875	There was a significant decrease in the number of micrometastases in the 250mug/ml compared with the 50mug/ml treated groups (p=0.002).	('metastases', 'Disease', (55, 65))	('mug', 'molecular_function', 'GO:0043739', ('103', '106'))	('metastases', 'Disease', 'MESH:D009362', (55, 65))	('mug', 'molecular_function', 'GO:0043739', ('76', '79'))	('decrease', 'NegReg', (24, 32))	('250mug/ml', 'Var', (73, 82))
92413	20089875	New blood vessels that grow within the tumor secondarily to VEGF expression are structurally and functionally irregular as they exhibit dead ends, disordered blood flow and increased permeability.	('disordered blood', 'Disease', (147, 163))	('disordered blood', 'Disease', 'MESH:D006402', (147, 163))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('VEGF', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('increased', 'PosReg', (173, 182))	('tumor', 'Disease', (39, 44))	('permeability', 'MPA', (183, 195))	('expression', 'Var', (65, 75))
92414	20089875	These irregularities in blood flow lead to further tumor hypoxia and subsequent increases in VEGF production.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('increases', 'PosReg', (80, 89))	('tumor hypoxia', 'Disease', 'MESH:D000860', (51, 64))	('tumor hypoxia', 'Disease', (51, 64))	('VEGF production', 'biological_process', 'GO:0010573', ('93', '108'))	('VEGF production', 'MPA', (93, 108))	('irregularities', 'Var', (6, 20))
92434	20089875	A previous study has shown that VEGF expression is associated with areas of necrosis in the primary intraocular melanoma and does not correlate with metastasis.	('expression', 'Var', (37, 47))	('intraocular melanoma', 'Disease', 'MESH:C563596', (100, 120))	('intraocular melanoma', 'Disease', (100, 120))	('necrosis', 'biological_process', 'GO:0070265', ('76', '84'))	('VEGF', 'Gene', (32, 36))	('intraocular melanoma', 'Phenotype', 'HP:0007716', (100, 120))	('necrosis', 'biological_process', 'GO:0008219', ('76', '84'))	('necrosis', 'Disease', (76, 84))	('associated', 'Reg', (51, 61))	('necrosis', 'biological_process', 'GO:0019835', ('76', '84'))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('necrosis', 'biological_process', 'GO:0008220', ('76', '84'))	('necrosis', 'Disease', 'MESH:D009336', (76, 84))	('ocular melanoma', 'Phenotype', 'HP:0007716', (105, 120))	('necrosis', 'biological_process', 'GO:0001906', ('76', '84'))
92448	20089875	Warren and co-workers showed that administration of an anti-VEGF antibody in a colorectal cancer xenograft model caused a 90% reduction in the mass of the primary tumor and a 10- to 18-fold reduction in the number of liver metastases compared with controls.	('metastases', 'Disease', 'MESH:D009362', (223, 233))	('reduction', 'NegReg', (190, 199))	('antibody', 'cellular_component', 'GO:0042571', ('65', '73'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('colorectal cancer', 'Disease', (79, 96))	('antibody', 'cellular_component', 'GO:0019815', ('65', '73'))	('tumor', 'Disease', (163, 168))	('anti-VEGF', 'Var', (55, 64))	('reduction', 'NegReg', (126, 135))	('antibody', 'molecular_function', 'GO:0003823', ('65', '73'))	('antibody', 'cellular_component', 'GO:0019814', ('65', '73'))	('metastases', 'Disease', (223, 233))	('rat', 'Species', '10116', (42, 45))
92449	20089875	In addition, those authors did not find the presence of blood vessels or expression of VEFR-2 in the liver metastases of the mice treated with the anti-VEGF antibody.	('antibody', 'cellular_component', 'GO:0019814', ('157', '165'))	('metastases', 'Disease', 'MESH:D009362', (107, 117))	('VEFR-2', 'Gene', (87, 93))	('antibody', 'molecular_function', 'GO:0003823', ('157', '165'))	('mice', 'Species', '10090', (125, 129))	('anti-VEGF', 'Var', (147, 156))	('antibody', 'cellular_component', 'GO:0042571', ('157', '165'))	('metastases', 'Disease', (107, 117))	('antibody', 'cellular_component', 'GO:0019815', ('157', '165'))
92450	20089875	A similar reduction in the number and size of tumor lung metastases was observer after anti-VEGF antibody treatment three days after implantation of human prostate cancer cells in mice.	('antibody', 'cellular_component', 'GO:0019814', ('97', '105'))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('prostate cancer', 'Disease', 'MESH:D011471', (155, 170))	('anti-VEGF', 'Var', (87, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (155, 170))	('antibody', 'molecular_function', 'GO:0003823', ('97', '105'))	('tumor lung metastases', 'Disease', 'MESH:D009362', (46, 67))	('human', 'Species', '9606', (149, 154))	('mice', 'Species', '10090', (180, 184))	('tumor lung', 'Phenotype', 'HP:0100526', (46, 56))	('antibody', 'cellular_component', 'GO:0042571', ('97', '105'))	('reduction', 'NegReg', (10, 19))	('antibody', 'cellular_component', 'GO:0019815', ('97', '105'))	('prostate cancer', 'Disease', (155, 170))	('tumor lung metastases', 'Disease', (46, 67))
92451	20089875	When treatment was delayed until the primary tumors were well established, primary tumor growth and metastases were still inhibited by the anti-VEGF antibody.	('metastases', 'Disease', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('antibody', 'cellular_component', 'GO:0019814', ('149', '157'))	('antibody', 'molecular_function', 'GO:0003823', ('149', '157'))	('metastases', 'Disease', 'MESH:D009362', (100, 110))	('tumor', 'Disease', (83, 88))	('inhibited', 'NegReg', (122, 131))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('antibody', 'cellular_component', 'GO:0042571', ('149', '157'))	('antibody', 'cellular_component', 'GO:0019815', ('149', '157'))	('anti-VEGF', 'Var', (139, 148))	('primary tumors', 'Disease', (37, 51))	('primary tumors', 'Disease', 'MESH:D009369', (37, 51))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
92454	20089875	In summary, our experimental findings show that VEGF inhibition causes the reduction of ocular melanoma proliferation, angiogenesis, and invasion, resulting in suppression of establishment of micrometastases.	('inhibition', 'Var', (53, 63))	('ocular melanoma', 'Phenotype', 'HP:0007716', (88, 103))	('VEGF', 'Protein', (48, 52))	('ocular melanoma proliferation', 'Disease', 'MESH:D008545', (88, 117))	('invasion', 'CPA', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('metastases', 'Disease', (197, 207))	('angiogenesis', 'CPA', (119, 131))	('angiogenesis', 'biological_process', 'GO:0001525', ('119', '131'))	('suppression', 'NegReg', (160, 171))	('reduction', 'NegReg', (75, 84))	('metastases', 'Disease', 'MESH:D009362', (197, 207))	('ocular melanoma proliferation', 'Disease', (88, 117))
92510	32998469	UMs most often have a GNAQ or GNA11 mutation, while cutaneous melanomas usually have a BRAF, NRAS, KIT or NF1 mutation.	('KIT', 'Gene', (99, 102))	('GNAQ', 'Gene', '2776', (22, 26))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('KIT', 'molecular_function', 'GO:0005020', ('99', '102'))	('GNA11', 'Gene', (30, 35))	('GNAQ', 'Gene', (22, 26))	('NRAS', 'Gene', '4893', (93, 97))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('cutaneous melanoma', 'Disease', (52, 70))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (52, 71))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (52, 70))	('KIT', 'Gene', '3815', (99, 102))	('NF1', 'Gene', '4763', (106, 109))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('NRAS', 'Gene', (93, 97))	('melanomas', 'Disease', 'MESH:D008545', (62, 71))	('melanomas', 'Disease', (62, 71))	('NF1', 'Gene', (106, 109))	('GNA11', 'Gene', '2767', (30, 35))	('mutation', 'Var', (36, 44))
92511	32998469	However, the same BRAF mutation as in cutaneous melanoma has been found in some iris melanomas and in a fraction of cells of some posterior UMs.	('found', 'Reg', (66, 71))	('iris melanomas', 'Disease', 'MESH:D008545', (80, 94))	('mutation', 'Var', (23, 31))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('iris melanomas', 'Phenotype', 'HP:0011524', (80, 94))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('iris melanoma', 'Phenotype', 'HP:0011524', (80, 93))	('UM', 'Phenotype', 'HP:0007716', (140, 142))	('BRAF', 'Gene', (18, 22))	('cutaneous melanoma', 'Disease', (38, 56))	('iris melanomas', 'Disease', (80, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (38, 56))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (38, 56))
92514	32998469	Rare UM with specific germline MBD4 mutations has been described to respond to anti-PD-1 therapy, probably because MBD4 mutations are associated with a high tumour mutation burden.	('MBD4', 'Gene', '8930', (115, 119))	('MBD4', 'Gene', (115, 119))	('respond', 'MPA', (68, 75))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('tumour', 'Disease', 'MESH:D009369', (157, 163))	('mutations', 'Var', (36, 45))	('UM', 'Phenotype', 'HP:0007716', (5, 7))	('tumour', 'Disease', (157, 163))	('MBD4', 'Gene', '8930', (31, 35))	('MBD4', 'Gene', (31, 35))	('PD-1', 'Gene', (84, 88))	('PD-1', 'Gene', '5133', (84, 88))
92521	32998469	A genetic risk factor is the presence of a germline mutation in the BAP1 gene, which is associated with the BAP1-tumor predisposition syndrome.	('BAP1-tumor', 'Disease', (108, 118))	('BAP1', 'Gene', '8314', (108, 112))	('BAP1-tumor', 'Disease', 'MESH:D009369', (108, 118))	('germline mutation', 'Var', (43, 60))	('BAP1', 'Gene', '8314', (68, 72))	('BAP1', 'Gene', (108, 112))	('associated', 'Reg', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('BAP1', 'Gene', (68, 72))
92522	32998469	Patients with a mutation in this gene have an increased chance of developing UM, melanocytic cutaneous tumours, mesothelioma and renal cell carcinoma.	('mutation', 'Var', (16, 24))	('developing', 'PosReg', (66, 76))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('Patients', 'Species', '9606', (0, 8))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (129, 149))	('mesothelioma and renal cell carcinoma', 'Disease', 'MESH:C538614', (112, 149))	('melanocytic cutaneous tumours', 'Disease', 'MESH:D009369', (81, 110))	('melanocytic cutaneous tumours', 'Disease', (81, 110))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
92530	32998469	It is known that posterior UMs carry specific mutations: in 94% of all tumours, a mutation in either the GNAQ or GNA11 gene has been found.	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('GNAQ', 'Gene', (105, 109))	('UM', 'Phenotype', 'HP:0007716', (27, 29))	('mutation', 'Var', (82, 90))	('tumours', 'Disease', (71, 78))	('GNA11', 'Gene', '2767', (113, 118))	('GNA11', 'Gene', (113, 118))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('GNAQ', 'Gene', '2776', (105, 109))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
92533	32998469	Among all UM, these are most associated with light-coloured eyes and they often have an A > T mutation in GNAQ Q209L or GNA11 Q209L.	('UM', 'Phenotype', 'HP:0007716', (10, 12))	('light-coloured eyes', 'Disease', (45, 64))	('Q209L', 'Mutation', 'rs121913492', (111, 116))	('GNA11', 'Gene', (120, 125))	('GNAQ', 'Gene', (106, 110))	('A > T', 'Var', (88, 93))	('light-coloured eyes', 'Phenotype', 'HP:0007730', (45, 64))	('GNA11', 'Gene', '2767', (120, 125))	('associated', 'Reg', (29, 39))	('Q209L', 'Mutation', 'rs121913492', (126, 131))	('GNAQ', 'Gene', '2776', (106, 110))
92534	32998469	Other common genetic aberrations in posterior UM are chromosomal changes, such as a loss of chromosome 3, loss of chromosome 8 p and a gain of chromosome 8 q, which are associated with a higher risk of developing metastases.	('chromosome', 'cellular_component', 'GO:0005694', ('114', '124'))	('loss', 'NegReg', (84, 88))	('loss', 'Var', (106, 110))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('chromosome', 'cellular_component', 'GO:0005694', ('92', '102'))	('chromosome', 'cellular_component', 'GO:0005694', ('143', '153'))	('gain', 'PosReg', (135, 139))	('metastases', 'Disease', (213, 223))	('metastases', 'Disease', 'MESH:D009362', (213, 223))
92535	32998469	Whereas GNAQ and GNA11 mutations occur early in tumour formation and are not associated with prognosis, EIF1AX, SF3B1 and BAP1 mutations occur later in the development of the tumour and are related to prognosis.	('EIF1AX', 'Gene', (104, 110))	('BAP1', 'Gene', (122, 126))	('GNAQ', 'Gene', (8, 12))	('EIF1AX', 'Gene', '1964', (104, 110))	('SF3B1', 'Gene', (112, 117))	('formation', 'biological_process', 'GO:0009058', ('55', '64'))	('mutations', 'Var', (23, 32))	('GNA11', 'Gene', '2767', (17, 22))	('mutations', 'Var', (127, 136))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Disease', 'MESH:D009369', (175, 181))	('SF3B1', 'Gene', '23451', (112, 117))	('tumour', 'Disease', (175, 181))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (48, 54))	('BAP1', 'Gene', '8314', (122, 126))	('men', 'Species', '9606', (163, 166))	('related to', 'Reg', (190, 200))	('GNA11', 'Gene', (17, 22))	('GNAQ', 'Gene', '2776', (8, 12))
92536	32998469	A mutation in EIF1AX is present in 17% of primary UM, a mutation in SF3B1 in 25% and a mutation in BAP1 in about 45% of primary UM.	('BAP1', 'Gene', (99, 103))	('EIF1AX', 'Gene', '1964', (14, 20))	('primary UM', 'Disease', (42, 52))	('SF3B1', 'Gene', (68, 73))	('UM', 'Phenotype', 'HP:0007716', (128, 130))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('SF3B1', 'Gene', '23451', (68, 73))	('BAP1', 'Gene', '8314', (99, 103))	('mutation', 'Var', (56, 64))	('EIF1AX', 'Gene', (14, 20))
92537	32998469	EIF1AX mutations are associated with a good prognostic outcome; tumours with an SF3B1 mutation lead to an intermediate prognosis, in contrast to UMs with a BAP1 mutation.	('SF3B1', 'Gene', '23451', (80, 85))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('BAP1', 'Gene', '8314', (156, 160))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('SF3B1', 'Gene', (80, 85))	('mutation', 'Var', (86, 94))	('BAP1', 'Gene', (156, 160))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))
92539	32998469	The EIF1AX mutation is responsible for unsuccessful protein translation, and the SF3B1 mutation affects gene splicing.	('SF3B1', 'Gene', (81, 86))	('gene splicing', 'MPA', (104, 117))	('splicing', 'biological_process', 'GO:0045292', ('109', '117'))	('SF3B1', 'Gene', '23451', (81, 86))	('protein translation', 'biological_process', 'GO:0006412', ('52', '71'))	('protein translation', 'MPA', (52, 71))	('affects', 'Reg', (96, 103))	('mutation', 'Var', (87, 95))	('EIF1AX', 'Gene', '1964', (4, 10))	('EIF1AX', 'Gene', (4, 10))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
92540	32998469	The lack of the BAP1 protein interferes with a wide range of normal cell processes such as DNA damage repair; 40% of UM metastases have a BAP1 mutation.	('BAP1', 'Gene', '8314', (138, 142))	('mutation', 'Var', (143, 151))	('BAP1', 'Gene', (138, 142))	('metastases', 'Disease', (120, 130))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('BAP1', 'Gene', '8314', (16, 20))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('metastases', 'Disease', 'MESH:D009362', (120, 130))	('BAP1', 'Gene', (16, 20))	('UM', 'Phenotype', 'HP:0007716', (117, 119))
92542	32998469	GNAQ and GNA11 mutations are detected in 77% to 84% of the iris tumours, which are not as frequent as in UM.	('GNA11', 'Gene', (9, 14))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('iris tumours', 'Disease', (59, 71))	('GNAQ', 'Gene', (0, 4))	('iris tumours', 'Disease', 'MESH:D015811', (59, 71))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('GNA11', 'Gene', '2767', (9, 14))
92544	32998469	More iris melanomas have a GNAQ mutation (47%) than a GNA11 mutation (30%).	('GNAQ', 'Gene', '2776', (27, 31))	('GNA11', 'Gene', (54, 59))	('iris melanomas', 'Disease', (5, 19))	('GNA11', 'Gene', '2767', (54, 59))	('iris melanomas', 'Disease', 'MESH:D008545', (5, 19))	('GNAQ', 'Gene', (27, 31))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('iris melanomas', 'Phenotype', 'HP:0011524', (5, 19))	('mutation', 'Var', (32, 40))	('iris melanoma', 'Phenotype', 'HP:0011524', (5, 18))
92545	32998469	As in UM, mutations in BAP1, EIF1AX and SF3B1 are frequently seen in iris tumours.	('SF3B1', 'Gene', (40, 45))	('BAP1', 'Gene', (23, 27))	('EIF1AX', 'Gene', '1964', (29, 35))	('EIF1AX', 'Gene', (29, 35))	('UM', 'Phenotype', 'HP:0007716', (6, 8))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('SF3B1', 'Gene', '23451', (40, 45))	('iris tumours', 'Disease', (69, 81))	('BAP1', 'Gene', '8314', (23, 27))	('iris tumours', 'Disease', 'MESH:D015811', (69, 81))	('seen', 'Reg', (61, 65))	('mutations', 'Var', (10, 19))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
92546	32998469	The frequency of BAP1 mutations seems comparable with UM.	('UM', 'Phenotype', 'HP:0007716', (54, 56))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('BAP1', 'Gene', (17, 21))
92548	32998469	Although not much data about these mutations are available, EIF1AX mutations seem to occur more often than in posterior UM.	('UM', 'Phenotype', 'HP:0007716', (120, 122))	('EIF1AX', 'Gene', '1964', (60, 66))	('EIF1AX', 'Gene', (60, 66))	('mutations', 'Var', (67, 76))
92549	32998469	As EIF1AX mutations are correlated with a good prognosis in UM, this could be one of the explanations for the relatively good survival of patients with an iris tumour in comparison to more posteriorly located UM.	('UM', 'Phenotype', 'HP:0007716', (209, 211))	('iris tumour', 'Disease', (155, 166))	('iris tumour', 'Disease', 'MESH:D015811', (155, 166))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('EIF1AX', 'Gene', '1964', (3, 9))	('EIF1AX', 'Gene', (3, 9))	('mutations', 'Var', (10, 19))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('patients', 'Species', '9606', (138, 146))
92550	32998469	SF3B1 mutations are less common in iris tumours.	('common', 'Reg', (25, 31))	('SF3B1', 'Gene', (0, 5))	('iris tumours', 'Disease', (35, 47))	('SF3B1', 'Gene', '23451', (0, 5))	('iris tumours', 'Disease', 'MESH:D015811', (35, 47))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('mutations', 'Var', (6, 15))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))
92551	32998469	In a study by Van Poppelen et al., 10 out of 30 iris tumours had mutations in NRAS, BRAF, PTEN, c-KIT and/or TP53.	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('PTEN', 'Gene', (90, 94))	('c-KIT', 'Gene', (96, 101))	('BRAF', 'Gene', (84, 88))	('PTEN', 'Gene', '5728', (90, 94))	('NRAS', 'Gene', (78, 82))	('TP53', 'Gene', '7157', (109, 113))	('iris tumours', 'Disease', (48, 60))	('c-KIT', 'Gene', '3815', (96, 101))	('NRAS', 'Gene', '4893', (78, 82))	('TP53', 'Gene', (109, 113))	('KIT', 'molecular_function', 'GO:0005020', ('98', '101'))	('iris tumours', 'Disease', 'MESH:D015811', (48, 60))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('mutations', 'Var', (65, 74))
92552	32998469	Another study on 19 cases showed a BRAF mutation in 47% of the iris tumours.	('mutation', 'Var', (40, 48))	('BRAF', 'Gene', (35, 39))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('iris tumours', 'Disease', (63, 75))	('iris tumours', 'Disease', 'MESH:D015811', (63, 75))
92553	32998469	As previously mentioned, mutations in BRAF and NRAS are common in cutaneous melanoma.	('mutations', 'Var', (25, 34))	('cutaneous melanoma', 'Disease', (66, 84))	('common', 'Reg', (56, 62))	('men', 'Species', '9606', (14, 17))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (66, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('NRAS', 'Gene', (47, 51))	('BRAF', 'Gene', (38, 42))	('NRAS', 'Gene', '4893', (47, 51))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
92556	32998469	Immunotherapy, which is helpful in UMs with a MBD4 mutation and a high mutation burden, is therefore probably also useful for iris melanomas, but luckily, these tumours do not often give rise to metastases.	('metastases', 'Disease', 'MESH:D009362', (195, 205))	('MBD4', 'Gene', (46, 50))	('MBD4', 'Gene', '8930', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('iris melanomas', 'Disease', 'MESH:D008545', (126, 140))	('iris melanomas', 'Disease', (126, 140))	('tumours', 'Phenotype', 'HP:0002664', (161, 168))	('iris melanoma', 'Phenotype', 'HP:0011524', (126, 139))	('tumours', 'Disease', 'MESH:D009369', (161, 168))	('iris melanomas', 'Phenotype', 'HP:0011524', (126, 140))	('mutation', 'Var', (51, 59))	('metastases', 'Disease', (195, 205))	('tumours', 'Disease', (161, 168))	('melanomas', 'Phenotype', 'HP:0002861', (131, 140))
92561	32998469	In a recent study, the C > T substitute in DNA (associated with UV light) was even higher in UM than in cutaneous melanoma.	('cutaneous melanoma', 'Disease', (104, 122))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (104, 122))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (104, 122))	('UM', 'Phenotype', 'HP:0007716', (93, 95))	('C > T substitute', 'Var', (23, 39))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('higher', 'PosReg', (83, 89))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
92576	32998469	Mutations of MC1R have been identified, of which the Arg151Cys, Arg160Trp and Asp294 variants have been reported to be over-represented in individuals with fair hair and skin, but they have not been associated with specific eye colours (see below).	('MC1R', 'Gene', (13, 17))	('associated', 'Reg', (199, 209))	('Arg151Cys', 'SUBSTITUTION', 'None', (53, 62))	('Arg160Trp', 'SUBSTITUTION', 'None', (64, 73))	('Arg151Cys', 'Var', (53, 62))	('Arg160Trp', 'Var', (64, 73))	('Asp294', 'Var', (78, 84))	('fair hair', 'Phenotype', 'HP:0002286', (156, 165))	('Asp294', 'Chemical', '-', (78, 84))	('MC1R', 'Gene', '4157', (13, 17))
92584	32998469	This suggests that specific MC1R gene variants do not play a major role in the susceptibility to develop UM.	('MC1R', 'Gene', '4157', (28, 32))	('MC1R', 'Gene', (28, 32))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('variants', 'Var', (38, 46))
92588	32998469	In the synthesis pathway of eumelanin, the addition of an amino group to DOPA quinone results in the formation of leucadopachrome.	('amino group', 'Var', (58, 69))	('leucadopachrome', 'MPA', (114, 129))	('synthesis', 'biological_process', 'GO:0009058', ('7', '16'))	('eumelanin', 'Chemical', 'MESH:C041877', (28, 37))	('addition', 'Var', (43, 51))	('DOPA quinone', 'Chemical', '-', (73, 85))	('formation', 'MPA', (101, 110))	('formation', 'biological_process', 'GO:0009058', ('101', '110'))
92590	32998469	The presence of Zn2+ and Cu2+ ions leads to relatively higher conversion into DHICA than into DHI.	('DHI', 'Chemical', 'MESH:C071764', (78, 81))	('Cu2+', 'Chemical', '-', (25, 29))	('Zn2+', 'Var', (16, 20))	('Zn2+', 'Chemical', '-', (16, 20))	('DHICA', 'Chemical', 'MESH:C030692', (78, 83))	('conversion into DHICA', 'MPA', (62, 83))	('DHI', 'Chemical', 'MESH:C071764', (94, 97))	('higher', 'PosReg', (55, 61))
92597	32998469	When the MC1R gene is mutated, less cAMP is produced and less tyrosinase is activated.	('less', 'NegReg', (31, 35))	('cAMP', 'Chemical', '-', (36, 40))	('tyrosinase', 'Gene', '7299', (62, 72))	('activated', 'MPA', (76, 85))	('less', 'NegReg', (57, 61))	('mutated', 'Var', (22, 29))	('tyrosinase', 'Gene', (62, 72))	('cAMP', 'MPA', (36, 40))	('MC1R', 'Gene', '4157', (9, 13))	('MC1R', 'Gene', (9, 13))
92599	32998469	The incorporation of cysteine results in the formation of 5-S-cysteinyldopa (5-SCD) and 2-S-cysteinyldopa (5-SCD) in a ratio of 5:1.	('incorporation', 'Var', (4, 17))	('5-SCD', 'Chemical', 'MESH:D003548', (107, 112))	('5-S-cysteinyldopa', 'Chemical', 'MESH:D003548', (58, 75))	('5-SCD', 'Chemical', 'MESH:D003548', (77, 82))	('2-S-cysteinyldopa', 'Chemical', 'MESH:C034513', (88, 105))	('formation', 'biological_process', 'GO:0009058', ('45', '54'))	('cysteine', 'Chemical', 'MESH:D003545', (21, 29))	('2-S-cysteinyldopa', 'MPA', (88, 105))
92603	32998469	BTZ is a stronger pro-oxidant and induces ROS production by reduction-oxidation (redox) cycling in the dark.	('ROS production', 'MPA', (42, 56))	('induces', 'Reg', (34, 41))	('ROS', 'Chemical', 'MESH:D017382', (42, 45))	('BTZ', 'Var', (0, 3))	('BTZ', 'Chemical', '-', (0, 3))
92615	32998469	In a study on the development of cutaneous melanoma, a BRAF mutation was introduced in three different types of mice: red mice with an abundance of pheomelanin, albino mice with no melanin and black mice with an abundance of eumelanin.	('melanin', 'Chemical', 'MESH:D008543', (152, 159))	('mutation', 'Var', (60, 68))	('mice', 'Species', '10090', (122, 126))	('mice', 'Species', '10090', (199, 203))	('pheomelanin', 'Chemical', 'MESH:C018362', (148, 159))	('mice', 'Species', '10090', (168, 172))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('cutaneous melanoma', 'Disease', (33, 51))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (33, 51))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (33, 51))	('mice', 'Species', '10090', (112, 116))	('melanin', 'Chemical', 'MESH:D008543', (181, 188))	('eumelanin', 'Chemical', 'MESH:C041877', (225, 234))	('melanin', 'Chemical', 'MESH:D008543', (227, 234))	('men', 'Species', '9606', (25, 28))
92624	32998469	People with blue eyes often have specific single nucleotide polymorphisms (SNPs) in HERC2 and OCA2.	('single nucleotide polymorphisms', 'Var', (42, 73))	('blue eye', 'Phenotype', 'HP:0000635', (12, 20))	('HERC2', 'Gene', (84, 89))	('HERC2', 'Gene', '8924', (84, 89))	('People', 'Species', '9606', (0, 6))	('blue eyes', 'Phenotype', 'HP:0000635', (12, 21))	('OCA2', 'Gene', '4948', (94, 98))	('blue eyes', 'Species', '160493', (12, 21))	('OCA2', 'Gene', (94, 98))
92626	32998469	The specific SNP in the OCA2 gene, which is associated with blue eyes, causes a reduction in OCA2 transcription of that allele compared to the normal other allele.	('associated', 'Reg', (44, 54))	('blue eyes', 'Phenotype', 'HP:0000635', (60, 69))	('OCA2', 'Gene', '4948', (24, 28))	('blue eye', 'Phenotype', 'HP:0000635', (60, 68))	('reduction', 'NegReg', (80, 89))	('transcription', 'biological_process', 'GO:0006351', ('98', '111'))	('OCA2', 'Gene', '4948', (93, 97))	('OCA2', 'Gene', (24, 28))	('blue eyes', 'Disease', (60, 69))	('OCA2', 'Gene', (93, 97))	('SNP', 'Var', (13, 16))	('blue eyes', 'Species', '160493', (60, 69))	('transcription', 'MPA', (98, 111))
92634	32998469	They found six SNPs that functioned as major genetic predictors of eye colour on six different genes: in addition to the already mentioned HERC2 rs12913832 and OCA2 rs1800407, these were SLC24A4 rs12896399, SLC45A2 rs16891982, TYR rs1393350 and IRF4 rs12203592.	('HERC2', 'Gene', '8924', (139, 144))	('SLC45A2', 'Gene', (207, 214))	('men', 'Species', '9606', (129, 132))	('rs1800407', 'Mutation', 'rs1800407', (165, 174))	('HERC2', 'Gene', (139, 144))	('rs16891982', 'Mutation', 'rs16891982', (215, 225))	('SLC24A4', 'Gene', (187, 194))	('rs12203592', 'Mutation', 'rs12203592', (250, 260))	('rs1393350', 'Mutation', 'rs1393350', (231, 240))	('rs12913832', 'Mutation', 'rs12913832', (145, 155))	('OCA2', 'Gene', (160, 164))	('rs16891982', 'Var', (215, 225))	('rs12896399', 'Mutation', 'rs12896399', (195, 205))	('rs12203592', 'Var', (250, 260))	('rs12896399', 'Var', (195, 205))	('OCA2', 'Gene', '4948', (160, 164))	('IRF4', 'Gene', '3662', (245, 249))	('rs1800407', 'Var', (165, 174))	('TYR', 'Chemical', 'MESH:D014443', (227, 230))	('SLC45A2', 'Gene', '51151', (207, 214))	('SLC24A4', 'Gene', '123041', (187, 194))	('rs12913832', 'Var', (145, 155))	('IRF4', 'Gene', (245, 249))
92638	32998469	Of the 28 SNPs that had already been identified as risk factors for cutaneous melanoma, three had already been linked to iris colour: SNPs rs12913832, rs1129038 and rs916977, located on the pigmentation genes HERC2, OCA2 and IRF4, respectively.	('rs1129038', 'Mutation', 'rs1129038', (151, 160))	('rs1129038', 'Var', (151, 160))	('IRF4', 'Gene', '3662', (225, 229))	('pigmentation', 'Disease', 'MESH:D010859', (190, 202))	('HERC2', 'Gene', '8924', (209, 214))	('rs12913832', 'Mutation', 'rs12913832', (139, 149))	('OCA2', 'Gene', (216, 220))	('HERC2', 'Gene', (209, 214))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('IRF4', 'Gene', (225, 229))	('rs916977', 'Var', (165, 173))	('OCA2', 'Gene', '4948', (216, 220))	('pigmentation', 'Disease', (190, 202))	('pigmentation', 'biological_process', 'GO:0043473', ('190', '202'))	('rs12913832', 'Var', (139, 149))	('cutaneous melanoma', 'Disease', (68, 86))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (68, 86))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (68, 86))	('rs916977', 'Mutation', 'rs916977', (165, 173))
92647	32998469	People with more pheomelanin compared to eumelanin have more efficient vitamin D synthesis.	('People', 'Species', '9606', (0, 6))	('eumelanin', 'Chemical', 'MESH:C041877', (41, 50))	('vitamin D', 'Chemical', 'MESH:D014807', (71, 80))	('vitamin D synthesis', 'biological_process', 'GO:0042368', ('71', '90'))	('pheomelanin', 'Chemical', 'MESH:C018362', (17, 28))	('vitamin D synthesis', 'MPA', (71, 90))	('pheomelanin', 'Var', (17, 28))
92666	32347651	In the present study, we found the migration and invasion of UM-1 cells were inhibited by Pristimerin which also caused a rapid increase of ROS, decreased mitochondrial membrane potential, induced the accumulation of cells in G0/G1 phase, ending with apoptotic cell death.	('cells', 'CPA', (217, 222))	('inhibited', 'NegReg', (77, 86))	('accumulation', 'PosReg', (201, 213))	('decreased', 'NegReg', (145, 154))	('death', 'Disease', 'MESH:D003643', (266, 271))	('invasion of UM-1 cells', 'CPA', (49, 71))	('UM-1', 'CellLine', 'CVCL:W392', (61, 65))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('155', '177'))	('mitochondrial membrane potential', 'MPA', (155, 187))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('251', '271'))	('Pristimerin', 'Chemical', 'MESH:C009043', (90, 101))	('G1 phase', 'biological_process', 'GO:0051318', ('229', '237'))	('ROS', 'MPA', (140, 143))	('migration', 'CPA', (35, 44))	('increase', 'PosReg', (128, 136))	('death', 'Disease', (266, 271))	('ROS', 'Chemical', 'MESH:D017382', (140, 143))	('Pristimerin', 'Var', (90, 101))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('decreased mitochondrial membrane potential', 'Phenotype', 'HP:0040013', (145, 187))	('G0/G1 phase', 'CPA', (226, 237))
92668	32347651	LY294002 or Akt-siRNA inhibited the PI3K/Akt/FoxO3a pathway and promoted the Pristimerin-induced apoptosis, while Pristimerin effects were partially abolished in FoxO3a knockdown UM-1 cell cultures.	('inhibited', 'NegReg', (22, 31))	('promoted', 'PosReg', (64, 72))	('FoxO3a', 'Gene', (45, 51))	('Pristimerin-induced', 'MPA', (77, 96))	('PI3K', 'molecular_function', 'GO:0016303', ('36', '40'))	('FoxO3a', 'Gene', '2309', (45, 51))	('Pristimerin', 'Chemical', 'MESH:C009043', (77, 88))	('UM', 'Phenotype', 'HP:0007716', (179, 181))	('Akt', 'Gene', (12, 15))	('FoxO3a', 'Gene', (162, 168))	('LY294002', 'Var', (0, 8))	('Akt', 'Gene', '207', (12, 15))	('UM-1', 'CellLine', 'CVCL:W392', (179, 183))	('FoxO3a', 'Gene', '2309', (162, 168))	('Pristimerin', 'Chemical', 'MESH:C009043', (114, 125))	('Akt', 'Gene', (41, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('97', '106'))	('apoptosis', 'biological_process', 'GO:0006915', ('97', '106'))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('Akt', 'Gene', '207', (41, 44))
92674	32347651	2 ,  3  Recent studies have shown that Pristimerin potently induced anti-proliferative and apoptosis activities in several human cancer cell lines, which originated from lung, breast, prostate, glioma, cervical, leukaemia and multiple myeloma tumours.	('tumours', 'Phenotype', 'HP:0002664', (243, 250))	('glioma', 'Disease', (194, 200))	('cervical', 'Disease', (202, 210))	('human', 'Species', '9606', (123, 128))	('cancer', 'Disease', (129, 135))	('glioma', 'Disease', 'MESH:D005910', (194, 200))	('multiple myeloma', 'Phenotype', 'HP:0006775', (226, 242))	('Pristimerin', 'Chemical', 'MESH:C009043', (39, 50))	('tumour', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('anti-proliferative', 'CPA', (68, 86))	('glioma', 'Phenotype', 'HP:0009733', (194, 200))	('leukaemia and multiple myeloma tumours', 'Disease', 'MESH:D009101', (212, 250))	('Pristimerin', 'Var', (39, 50))	('breast', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('apoptosis activities', 'CPA', (91, 111))	('lung', 'Disease', (170, 174))
92676	32347651	9 ,  10 ,  11  In addition, Pristimerin has been reported to activate the stress kinase, c-Jun N-terminal kinase(JNK) and the DNA damage sensor, poly (ADP-ribose) polymerase-1 (PARP-1) through the generation of reactive oxygen species (ROS).	('poly (ADP-ribose) polymerase-1', 'Gene', (145, 175))	('activate', 'PosReg', (61, 69))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (211, 234))	('Pristimerin', 'Chemical', 'MESH:C009043', (28, 39))	('Pristimerin', 'Var', (28, 39))	('PARP-1', 'Gene', (177, 183))	('JNK', 'Gene', (113, 116))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('PARP-1', 'Gene', '142', (177, 183))	('JNK', 'molecular_function', 'GO:0004705', ('113', '116'))	('c-Jun N-terminal kinase', 'MPA', (89, 112))	('ROS', 'Chemical', 'MESH:D017382', (236, 239))	('JNK', 'Gene', '5599', (113, 116))	('poly (ADP-ribose) polymerase-1', 'Gene', '142', (145, 175))
92677	32347651	12  Moreover, other studies indicated that Pristimerin inhibited cell cycle progression, tumour cell migration and angiogenesis.	('Pristimerin', 'Chemical', 'MESH:C009043', (43, 54))	('cell migration', 'biological_process', 'GO:0016477', ('96', '110'))	('Pristimerin', 'Var', (43, 54))	('angiogenesis', 'CPA', (115, 127))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('cell cycle progression', 'CPA', (65, 87))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('angiogenesis', 'biological_process', 'GO:0001525', ('115', '127'))	('inhibited', 'NegReg', (55, 64))	('cell cycle', 'biological_process', 'GO:0007049', ('65', '75'))
92678	32347651	5 ,  13 ,  14 ,  15  Unfortunately, the cytotoxic effects and the molecular mechanism by which Pristimerin affects UM-1 were poorly investigated and only one study reported that Pristimerin inhibited the malignant phenotypes of UM cells through inactivation of NF-kappaB pathway.	('inhibited', 'NegReg', (190, 199))	('Pristimerin', 'Chemical', 'MESH:C009043', (178, 189))	('Pristimerin', 'Var', (178, 189))	('UM', 'Phenotype', 'HP:0007716', (228, 230))	('UM', 'Phenotype', 'HP:0007716', (115, 117))	('malignant phenotypes of UM cells', 'CPA', (204, 236))	('NF-kappaB', 'Gene', '4790', (261, 270))	('inactivation', 'NegReg', (245, 257))	('UM-1', 'CellLine', 'CVCL:W392', (115, 119))	('Pristimerin', 'Chemical', 'MESH:C009043', (95, 106))	('NF-kappaB', 'Gene', (261, 270))
92682	32347651	Inhibition of this pathway has been shown to cause better regression of human tumours and has been evaluated in preclinical research and clinical trials.	('regression', 'CPA', (58, 68))	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('human', 'Species', '9606', (72, 77))	('tumours', 'Disease', (78, 85))	('Inhibition', 'Var', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
92684	32347651	19  PI3K/Akt pathway dysregulation has also been associated with resistance to conventional chemotherapy.	('Akt', 'Gene', (9, 12))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('dysregulation', 'Var', (21, 34))	('resistance to conventional chemotherapy', 'CPA', (65, 104))	('Akt', 'Gene', '207', (9, 12))
92690	32347651	30 ,  31 ,  32   In the present study, we investigated Pristimerin-induced pro-apoptotic effects in the UM-1 cells cultures in relation to PI3K/Akt/FOXO3a signalling pathway and found that Pristimerin induced apoptosis by inhibiting the PI3K/Akt/FoxO3a pathway.	('Akt', 'Gene', (144, 147))	('Pristimerin', 'Chemical', 'MESH:C009043', (55, 66))	('Akt', 'Gene', '207', (144, 147))	('Pristimerin', 'Chemical', 'MESH:C009043', (189, 200))	('Akt', 'Gene', (242, 245))	('signalling pathway', 'biological_process', 'GO:0007165', ('155', '173'))	('Akt', 'Gene', '207', (242, 245))	('UM', 'Phenotype', 'HP:0007716', (104, 106))	('apoptosis', 'CPA', (209, 218))	('Pristimerin', 'Var', (189, 200))	('apoptosis', 'biological_process', 'GO:0097194', ('209', '218'))	('PI3K', 'molecular_function', 'GO:0016303', ('237', '241'))	('FoxO3a', 'Gene', (246, 252))	('PI3K', 'molecular_function', 'GO:0016303', ('139', '143'))	('apoptosis', 'biological_process', 'GO:0006915', ('209', '218'))	('FOXO3a', 'Gene', (148, 154))	('inhibiting', 'NegReg', (222, 232))	('UM-1', 'CellLine', 'CVCL:W392', (104, 108))	('FoxO3a', 'Gene', '2309', (246, 252))	('FOXO3a', 'Gene', '2309', (148, 154))
92709	32347651	In brief, UM-1 cells were seeded on 6-well plates and treated with various concentrations of Pristimerin with/without LY294002 (30 microM) or Akt siRNA for 24 hours, and then, cells were collected after gentle trypsin treatment and fixed overnight in ice-cold 70% ethanol, after which cells were treated with RNase A and stained with propidium iodide (PI).	('Akt', 'Gene', (142, 145))	('UM', 'Phenotype', 'HP:0007716', (10, 12))	('ethanol', 'Chemical', 'MESH:D000431', (264, 271))	('LY294002', 'Var', (118, 126))	('RNase A', 'Gene', (309, 316))	('UM-1', 'CellLine', 'CVCL:W392', (10, 14))	('Akt', 'Gene', '207', (142, 145))	('RNase A', 'Gene', '6035', (309, 316))	('Pristimerin', 'Chemical', 'MESH:C009043', (93, 104))	('LY294002', 'Chemical', 'MESH:C085911', (118, 126))	('propidium iodide', 'Chemical', 'MESH:D011419', (334, 350))
92731	32347651	As shown in Figure 1I, Pristimerin induced a decline of mitochondrial membrane potential in a dose-dependent fashion.	('Pristimerin', 'Chemical', 'MESH:C009043', (23, 34))	('Pristimerin', 'Var', (23, 34))	('decline', 'NegReg', (45, 52))	('mitochondrial membrane potential', 'MPA', (56, 88))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('56', '78'))
92737	32347651	As shown in Figure 2, Pristimerin induced in a dose-dependent manner a significant accumulation of a cell population in G0/G1phase, in parallel to a reduction of the distribution of other cell population in S-G2/M phase of the cell cycle.	('reduction', 'NegReg', (149, 158))	('G1phase', 'biological_process', 'GO:0051318', ('123', '130'))	('distribution', 'MPA', (166, 178))	('cell cycle', 'biological_process', 'GO:0007049', ('227', '237'))	('accumulation', 'PosReg', (83, 95))	('M phase', 'biological_process', 'GO:0000279', ('212', '219'))	('Pristimerin', 'Chemical', 'MESH:C009043', (22, 33))	('Pristimerin', 'Var', (22, 33))
92741	32347651	In the cell migration assay (Figure 3A,C), we found that Pristimerin, in a dose-dependent way, significantly inhibited that cells' ability to migrate through a collagen matrix with an estimate EC50 of 25 microM.	('inhibited', 'NegReg', (109, 118))	('collagen', 'molecular_function', 'GO:0005202', ('160', '168'))	('cell migration', 'biological_process', 'GO:0016477', ('7', '21'))	('Pristimerin', 'Chemical', 'MESH:C009043', (57, 68))	('Pristimerin', 'Var', (57, 68))
92745	32347651	We have noted a significant reduction of phosphorylated-AKT at Ser473 upon treatment with concentrations of Pristimerin higher than 3 microM and after 6 hours of treatment, while the level of its total protein remained stable throughout all the time points of treatment with the different Pristimerin concentrations (Figure 4A,B,E,F).	('AKT', 'Gene', '207', (56, 59))	('Ser', 'cellular_component', 'GO:0005790', ('63', '66'))	('AKT', 'Gene', (56, 59))	('Pristimerin', 'Chemical', 'MESH:C009043', (289, 300))	('Pristimerin', 'Chemical', 'MESH:C009043', (108, 119))	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('reduction', 'NegReg', (28, 37))	('Ser473', 'Var', (63, 69))	('Ser473', 'Chemical', '-', (63, 69))
92746	32347651	Consequently, the phosphorylation level of transcriptional factor FoxO3a at Ser253 was also found to be significantly inhibited at 3-36 h from the start of treatment with different Pristimerin concentrations (Figure 4A,C,E,G).	('inhibited', 'NegReg', (118, 127))	('Pristimerin', 'Chemical', 'MESH:C009043', (181, 192))	('FoxO3a', 'Gene', (66, 72))	('phosphorylation', 'biological_process', 'GO:0016310', ('18', '33'))	('Ser', 'cellular_component', 'GO:0005790', ('76', '79'))	('Ser253', 'Chemical', '-', (76, 82))	('Ser253', 'Var', (76, 82))	('phosphorylation level', 'MPA', (18, 39))	('FoxO3a', 'Gene', '2309', (66, 72))
92748	32347651	Meanwhile, we also found that Pristimerin in a dose-dependent fashion increased cleaved caspase-3, PARP and Bax levels of expression, but reduced the level of expression of Bcl-2 and as a consequence the ratio of Bcl-2/Bax was also decreased (Figure 5).	('reduced', 'NegReg', (138, 145))	('increased', 'PosReg', (70, 79))	('Bax', 'Gene', '581', (219, 222))	('Bcl-2', 'Gene', (173, 178))	('caspase-3', 'Gene', (88, 97))	('level of expression', 'MPA', (150, 169))	('Bcl-2', 'molecular_function', 'GO:0015283', ('213', '218'))	('decreased', 'NegReg', (232, 241))	('Bcl-2', 'Gene', '596', (213, 218))	('Pristimerin', 'Chemical', 'MESH:C009043', (30, 41))	('Bcl-2', 'molecular_function', 'GO:0015283', ('173', '178'))	('Bcl-2', 'Gene', '596', (173, 178))	('PARP', 'Gene', '142', (99, 103))	('ratio', 'MPA', (204, 209))	('Pristimerin', 'Var', (30, 41))	('PARP', 'Gene', (99, 103))	('Bax', 'Gene', (108, 111))	('Bax', 'Gene', '581', (108, 111))	('Bax', 'Gene', (219, 222))	('caspase-3', 'Gene', '836', (88, 97))	('Bcl-2', 'Gene', (213, 218))
92750	32347651	To explore the contribution of PI3K/Akt inhibition to the cytotoxic effects of Pristimerin, UM-1 cells were either pretreated with LY294002, a potent, reversible, morpholine-containing inhibitor of phosphoinositide 3-kinases (PI3K) which phosphorylates and activates Akt, or transfected with Akt siRNA, before exposure to Pristimerin.	('Akt', 'Gene', (292, 295))	('LY294002', 'Chemical', 'MESH:C085911', (131, 139))	('activates', 'PosReg', (257, 266))	('Akt', 'Gene', '207', (267, 270))	('morpholine', 'Chemical', 'MESH:C037574', (163, 173))	('Pristimerin', 'Chemical', 'MESH:C009043', (322, 333))	('phosphoinositide 3-kinases', 'Gene', '5290', (198, 224))	('PI3K', 'molecular_function', 'GO:0016303', ('226', '230'))	('LY294002', 'Var', (131, 139))	('Akt', 'Gene', (36, 39))	('Pristimerin', 'Chemical', 'MESH:C009043', (79, 90))	('Akt', 'Gene', '207', (292, 295))	('Akt', 'Gene', (267, 270))	('phosphoinositide 3-kinases', 'Gene', (198, 224))	('UM', 'Phenotype', 'HP:0007716', (92, 94))	('UM-1', 'CellLine', 'CVCL:W392', (92, 96))	('PI3K', 'molecular_function', 'GO:0016303', ('31', '35'))	('Akt', 'Gene', '207', (36, 39))
92752	32347651	When used in combination with Pristimerin, the PI3K/Akt inhibitors potentiated by 30% the percentage of apoptotic cells, with similar efficacy of LY294002 and Akt siRNA (Figure 6A-D).	('Akt', 'Gene', (159, 162))	('potentiated', 'PosReg', (67, 78))	('Akt', 'Gene', (52, 55))	('LY294002', 'Var', (146, 154))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))	('LY294002', 'Chemical', 'MESH:C085911', (146, 154))	('Akt', 'Gene', '207', (159, 162))	('Akt', 'Gene', '207', (52, 55))	('Pristimerin', 'Chemical', 'MESH:C009043', (30, 41))
92756	32347651	35 ,  36  Figure 7A-D indicated that both LY294002 and Akt siRNA treatments strongly potentiated the inhibitory effect of 3 muM Pristimerin on Akt (Ser473) and FoxO3a (Ser253) phosphorylations, when compared to the respective control groups.	('Akt', 'Gene', (55, 58))	('inhibitory effect', 'MPA', (101, 118))	('Ser', 'cellular_component', 'GO:0005790', ('148', '151'))	('Ser', 'cellular_component', 'GO:0005790', ('168', '171'))	('LY294002', 'Var', (42, 50))	('muM', 'Gene', '56925', (124, 127))	('FoxO3a', 'Gene', '2309', (160, 166))	('Ser253', 'Chemical', '-', (168, 174))	('Ser473', 'Chemical', '-', (148, 154))	('Akt', 'Gene', '207', (143, 146))	('potentiated', 'PosReg', (85, 96))	('Pristimerin', 'Chemical', 'MESH:C009043', (128, 139))	('muM', 'Gene', (124, 127))	('FoxO3a', 'Gene', (160, 166))	('LY294002', 'Chemical', 'MESH:C085911', (42, 50))	('Akt', 'Gene', (143, 146))	('Akt', 'Gene', '207', (55, 58))
92758	32347651	Likewise, inhibition of FoxO3a phosphorylation was followed by up-regulation of mRNA and protein level of the pro-apoptotic molecules BIM and p27Kip1 and down-regulation of anti-apoptotic protein cyclin D1, effects potentiated by LY294002 and Akt siRNA pretreatment (Figure 7E-J).	('inhibition', 'NegReg', (10, 20))	('regulation', 'biological_process', 'GO:0065007', ('159', '169'))	('cyclin', 'molecular_function', 'GO:0016538', ('196', '202'))	('p27Kip1', 'Gene', (142, 149))	('up-regulation', 'PosReg', (63, 76))	('p27Kip1', 'Gene', '1027', (142, 149))	('Akt', 'Gene', (243, 246))	('FoxO3a', 'Gene', (24, 30))	('LY294002', 'Var', (230, 238))	('Akt', 'Gene', '207', (243, 246))	('down-regulation', 'NegReg', (154, 169))	('FoxO3a', 'Gene', '2309', (24, 30))	('BIM', 'Gene', (134, 137))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('regulation', 'biological_process', 'GO:0065007', ('66', '76'))	('cyclin D1', 'Gene', (196, 205))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('phosphorylation', 'CPA', (31, 46))	('LY294002', 'Chemical', 'MESH:C085911', (230, 238))	('cyclin D1', 'Gene', '595', (196, 205))	('BIM', 'Gene', '10018', (134, 137))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))
92760	32347651	Complementary to these results, FoxO3a knockdown experiments, using a selective siRNA approach, indicated that Pristimerin effect was partially abolished in FoxO3a knockdown UM-1 cell, which indicated that knockdown of FOXO3a partially attenuated the Pristimerin-induced apoptosis (Figure 7 K-M).	('FoxO3a', 'Gene', (157, 163))	('UM-1', 'CellLine', 'CVCL:W392', (174, 178))	('Pristimerin', 'Chemical', 'MESH:C009043', (251, 262))	('FOXO3a', 'Gene', '2309', (219, 225))	('FOXO3a', 'Gene', (219, 225))	('FoxO3a', 'Gene', '2309', (32, 38))	('Pristimerin', 'Chemical', 'MESH:C009043', (111, 122))	('FoxO3a', 'Gene', (32, 38))	('attenuated', 'NegReg', (236, 246))	('Pristimerin-induced apoptosis', 'CPA', (251, 280))	('FoxO3a', 'Gene', '2309', (157, 163))	('apoptosis', 'biological_process', 'GO:0097194', ('271', '280'))	('apoptosis', 'biological_process', 'GO:0006915', ('271', '280'))	('UM', 'Phenotype', 'HP:0007716', (174, 176))	('knockdown', 'Var', (206, 215))
92769	32347651	The immunofluorescence micrographs unambiguously indicated that Pristimerin significantly and progressively enhanced, with a time course of 12-24 hours and by 3.4-fold, nuclear level of FoxO3a protein in UM-1 cells, an effect potentiated by LY294002 (Figure 8A,G).	('FoxO3a', 'Gene', '2309', (186, 192))	('nuclear level', 'MPA', (169, 182))	('UM', 'Phenotype', 'HP:0007716', (204, 206))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('LY294002', 'Var', (241, 249))	('FoxO3a', 'Gene', (186, 192))	('protein', 'Protein', (193, 200))	('enhanced', 'PosReg', (108, 116))	('UM-1', 'CellLine', 'CVCL:W392', (204, 208))	('LY294002', 'Chemical', 'MESH:C085911', (241, 249))	('Pristimerin', 'Chemical', 'MESH:C009043', (64, 75))
92771	32347651	We found that Pristimerin increased the nuclear levels of FoxO3a protein but decreased its levels of phosphorylation in a time-dependent manner (Figure 8B,D), an effect potentiated by LY294002 (Figure 8H-K).	('LY294002', 'Chemical', 'MESH:C085911', (184, 192))	('FoxO3a', 'Gene', (58, 64))	('protein', 'Protein', (65, 72))	('Pristimerin', 'Chemical', 'MESH:C009043', (14, 25))	('LY294002', 'Var', (184, 192))	('increased', 'PosReg', (26, 35))	('levels of phosphorylation', 'MPA', (91, 116))	('phosphorylation', 'biological_process', 'GO:0016310', ('101', '116'))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('FoxO3a', 'Gene', '2309', (58, 64))	('nuclear levels', 'MPA', (40, 54))	('decreased', 'NegReg', (77, 86))
92779	32347651	In the present study, we found that Pristimerin induced a pro-apoptotic effect in the UM-1 cells through modulation of the PI3K/Akt/FoxO3a signalling pathway.	('FoxO3a', 'Gene', '2309', (132, 138))	('pro-apoptotic', 'MPA', (58, 71))	('UM', 'Phenotype', 'HP:0007716', (86, 88))	('modulation', 'Reg', (105, 115))	('Akt', 'Gene', (128, 131))	('FoxO3a', 'Gene', (132, 138))	('UM-1', 'CellLine', 'CVCL:W392', (86, 90))	('Akt', 'Gene', '207', (128, 131))	('Pristimerin', 'Chemical', 'MESH:C009043', (36, 47))	('PI3K', 'molecular_function', 'GO:0016303', ('123', '127'))	('Pristimerin', 'Var', (36, 47))	('signalling pathway', 'biological_process', 'GO:0007165', ('139', '157'))
92780	32347651	We found that Pristimerin increased ROS, decreased the mitochondrial membrane potential, promoted accumulation of cells in G0/G1 phase of the cell cycle and induced apoptotic cell death.	('cells in G0/G1 phase of the cell cycle', 'CPA', (114, 152))	('ROS', 'Chemical', 'MESH:D017382', (36, 39))	('G1 phase', 'biological_process', 'GO:0051318', ('126', '134'))	('mitochondrial membrane potential', 'MPA', (55, 87))	('decreased', 'NegReg', (41, 50))	('induced', 'Reg', (157, 164))	('ROS', 'MPA', (36, 39))	('Pristimerin', 'Chemical', 'MESH:C009043', (14, 25))	('Pristimerin', 'Var', (14, 25))	('cell cycle', 'biological_process', 'GO:0007049', ('142', '152'))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('165', '185'))	('increased', 'PosReg', (26, 35))	('death', 'Disease', 'MESH:D003643', (180, 185))	('promoted accumulation', 'PosReg', (89, 110))	('death', 'Disease', (180, 185))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('55', '77'))
92781	32347651	In recent years, it has reported that Pristimerin could affect many tumour-related processes, such as autophagy, apoptosis, vasculogenesis, migration and invasion, and drug resistance.	('drug resistance', 'CPA', (168, 183))	('affect', 'Reg', (56, 62))	('drug resistance', 'Phenotype', 'HP:0020174', (168, 183))	('Pristimerin', 'Chemical', 'MESH:C009043', (38, 49))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('Pristimerin', 'Var', (38, 49))	('drug resistance', 'biological_process', 'GO:0042493', ('168', '183'))	('apoptosis', 'CPA', (113, 122))	('vasculogenesis', 'biological_process', 'GO:0001570', ('124', '138'))	('drug resistance', 'biological_process', 'GO:0009315', ('168', '183'))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('tumour', 'Disease', (68, 74))	('autophagy', 'biological_process', 'GO:0016236', ('102', '111'))	('apoptosis', 'biological_process', 'GO:0097194', ('113', '122'))	('autophagy', 'CPA', (102, 111))	('vasculogenesis', 'CPA', (124, 138))	('autophagy', 'biological_process', 'GO:0006914', ('102', '111'))	('apoptosis', 'biological_process', 'GO:0006915', ('113', '122'))
92782	32347651	42  In human breast cancer cells, Pristimerin-triggered apoptosis through caspase activation, which could be completely prevented by benzyloxycarbonyl Val-Ala-Asp-fluoromethyl ketone, a pan-caspase inhibitor.	('Pristimerin', 'Chemical', 'MESH:C009043', (34, 45))	('caspase', 'Protein', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('benzyloxycarbonyl Val-Ala-Asp-fluoromethyl ketone', 'Chemical', '-', (133, 182))	('caspase activation', 'biological_process', 'GO:0006919', ('74', '92'))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('human', 'Species', '9606', (7, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('breast cancer', 'Disease', (13, 26))	('activation', 'PosReg', (82, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('56', '65'))	('apoptosis', 'CPA', (56, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('56', '65'))	('Pristimerin-triggered', 'Var', (34, 55))
92786	32347651	In the present study, we found that Pristimerin inhibited of UM-1 cells proliferation, accumulation of cells in the G0/G1 phase of the cell cycle and decreased survival.	('survival', 'CPA', (160, 168))	('UM-1', 'CellLine', 'CVCL:W392', (61, 65))	('G1 phase', 'biological_process', 'GO:0051318', ('119', '127'))	('accumulation', 'PosReg', (87, 99))	('cell cycle', 'biological_process', 'GO:0007049', ('135', '145'))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('inhibited', 'NegReg', (48, 57))	('Pristimerin', 'Chemical', 'MESH:C009043', (36, 47))	('Pristimerin', 'Var', (36, 47))	('decreased', 'NegReg', (150, 159))
92787	32347651	Moreover, Pristimerin stimulated UM-1 apoptotic cell death expressed by nuclear condensation and fragmentation and increased Annexin V staining, representing binding to phosphatidylserine, which is increased in the plasma membrane of apoptotic cells.	('death', 'Disease', 'MESH:D003643', (53, 58))	('binding', 'molecular_function', 'GO:0005488', ('158', '165'))	('death', 'Disease', (53, 58))	('plasma membrane', 'cellular_component', 'GO:0005886', ('215', '230'))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('38', '58'))	('increased', 'PosReg', (115, 124))	('Pristimerin', 'Chemical', 'MESH:C009043', (10, 21))	('UM', 'Phenotype', 'HP:0007716', (33, 35))	('Pristimerin', 'Var', (10, 21))	('fragmentation', 'CPA', (97, 110))	('Annexin V', 'Gene', '308', (125, 134))	('Annexin V', 'Gene', (125, 134))	('nuclear condensation', 'CPA', (72, 92))	('UM-1', 'CellLine', 'CVCL:W392', (33, 37))	('binding', 'Interaction', (158, 165))
92802	32347651	53 ,  54 ,  55  Our study indicated that Pristimerin inhibited Akt, and Akt inhibition resulted with FoxO3a dephosphorylation which led to FoxO3a accumulation in the nucleus of the UM-1 cells.	('FoxO3a', 'Gene', '2309', (139, 145))	('inhibition', 'NegReg', (76, 86))	('inhibited', 'NegReg', (53, 62))	('Akt', 'Gene', (72, 75))	('UM-1', 'CellLine', 'CVCL:W392', (181, 185))	('FoxO3a', 'Gene', '2309', (101, 107))	('Pristimerin', 'Chemical', 'MESH:C009043', (41, 52))	('FoxO3a', 'Gene', (139, 145))	('Pristimerin', 'Var', (41, 52))	('nucleus', 'cellular_component', 'GO:0005634', ('166', '173'))	('dephosphorylation', 'biological_process', 'GO:0016311', ('108', '125'))	('dephosphorylation', 'MPA', (108, 125))	('FoxO3a', 'Gene', (101, 107))	('accumulation', 'PosReg', (146, 158))	('Akt', 'Gene', '207', (63, 66))	('Akt', 'Gene', '207', (72, 75))	('UM', 'Phenotype', 'HP:0007716', (181, 183))	('Akt', 'Gene', (63, 66))
92805	32347651	Taken together, the following findings indicated that Pristimerin-induced apoptosis in UM-1 cells is in a direct correlation with inhibition of PI3K/Akt/FoxO3a pathway in UM-1 cells: (a) The Pristimerin in a dose-and time-dependent manner inhibited PI3K/Akt signalling, changed the mRNA levels of FOXO3a and activated FoxO3a protein; (b) Inhibition of Akt strongly potentiated the inhibitory effect of Pristimerin on Akt (Ser473) and FoxO3a (Ser253) phosphorylation; (c) Pristimerin-induced inhibition of UM-1 cells' migration and invasion was potentiated by PI3K/Akt inhibition; (d) Pristimerin induced up-regulation of the pro-apoptotic molecules BIM, p27Kip1, cleaved caspase-3, PARP and Bax and down-regulation of anti-apoptotic protein cyclin D1 and Bcl-2, effects potentiated by Akt inhibition; (e) Pristimerin-induced FoxO3a translocation into the nucleus by inhibition of its cytoplasmic-nuclear shuttling and phosphorylation activity.	('UM', 'Phenotype', 'HP:0007716', (505, 507))	('PARP', 'Gene', (682, 686))	('Akt', 'Gene', (254, 257))	('Akt', 'Gene', '207', (785, 788))	('Akt', 'Gene', (149, 152))	('FoxO3a', 'Gene', '2309', (434, 440))	('cytoplasmic-nuclear shuttling', 'MPA', (884, 913))	('down-regulation', 'NegReg', (699, 714))	('cyclin D1', 'Gene', '595', (741, 750))	('UM-1', 'CellLine', 'CVCL:W392', (87, 91))	('Akt', 'Gene', '207', (254, 257))	('Akt', 'Gene', '207', (149, 152))	('PI3K', 'molecular_function', 'GO:0016303', ('249', '253'))	('Ser253', 'Chemical', '-', (442, 448))	('Pristimerin', 'Chemical', 'MESH:C009043', (54, 65))	('UM', 'Phenotype', 'HP:0007716', (171, 173))	('Akt', 'Gene', (417, 420))	('Pristimerin', 'Chemical', 'MESH:C009043', (402, 413))	('UM-1', 'CellLine', 'CVCL:W392', (505, 509))	('cyclin', 'molecular_function', 'GO:0016538', ('741', '747'))	('protein', 'cellular_component', 'GO:0003675', ('733', '740'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('755', '760'))	('FoxO3a', 'Gene', (153, 159))	('FoxO3a', 'Gene', (318, 324))	('Ser473', 'Chemical', '-', (422, 428))	('PI3K', 'molecular_function', 'GO:0016303', ('559', '563'))	('Ser', 'cellular_component', 'GO:0005790', ('442', '445'))	('phosphorylation activity', 'MPA', (918, 942))	('Akt', 'Gene', '207', (417, 420))	('regulation', 'biological_process', 'GO:0065007', ('704', '714'))	('Bax', 'Gene', (691, 694))	('UM-1', 'CellLine', 'CVCL:W392', (171, 175))	('Pristimerin', 'Chemical', 'MESH:C009043', (584, 595))	('nucleus', 'cellular_component', 'GO:0005634', ('855', '862'))	('Pristimerin', 'Chemical', 'MESH:C009043', (471, 482))	('FoxO3a', 'Gene', '2309', (153, 159))	('FoxO3a', 'Gene', '2309', (318, 324))	('Akt', 'Gene', (352, 355))	('Bax', 'Gene', '581', (691, 694))	('FoxO3a', 'Gene', (825, 831))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('PI3K', 'molecular_function', 'GO:0016303', ('144', '148'))	('regulation', 'biological_process', 'GO:0065007', ('607', '617'))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('Pristimerin', 'Chemical', 'MESH:C009043', (805, 816))	('Bcl-2', 'Gene', (755, 760))	('caspase-3', 'Gene', '836', (671, 680))	('translocation into the', 'MPA', (832, 854))	('FOXO3a', 'Gene', (297, 303))	('Akt', 'Gene', '207', (352, 355))	('BIM', 'Gene', (649, 652))	('FoxO3a', 'Gene', '2309', (825, 831))	('phosphorylation', 'biological_process', 'GO:0016310', ('450', '465'))	('Akt', 'Gene', (564, 567))	('UM', 'Phenotype', 'HP:0007716', (87, 89))	('p27Kip1', 'Gene', (654, 661))	('protein', 'cellular_component', 'GO:0003675', ('325', '332'))	('Pristimerin-induced', 'Var', (805, 824))	('PARP', 'Gene', '142', (682, 686))	('caspase-3', 'Gene', (671, 680))	('FoxO3a', 'Gene', (434, 440))	('cyclin D1', 'Gene', (741, 750))	('phosphorylation', 'biological_process', 'GO:0016310', ('918', '933'))	('Akt', 'Gene', (785, 788))	('Akt', 'Gene', '207', (564, 567))	('Pristimerin', 'Chemical', 'MESH:C009043', (191, 202))	('BIM', 'Gene', '10018', (649, 652))	('inhibition', 'NegReg', (866, 876))	('p27Kip1', 'Gene', '1027', (654, 661))	('FOXO3a', 'Gene', '2309', (297, 303))	('Ser', 'cellular_component', 'GO:0005790', ('422', '425'))	('Bcl-2', 'Gene', '596', (755, 760))	('signalling', 'biological_process', 'GO:0023052', ('258', '268'))
92810	31227503	HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance.	('HDAC', 'Gene', (0, 4))	('uveal melanoma', 'Disease', (127, 141))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('HDAC', 'Gene', '9734', (0, 4))	('uveal melanoma', 'Disease', 'MESH:C536494', (127, 141))	('inhibition', 'Var', (5, 15))	('enhances', 'PosReg', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('MEK', 'Gene', (49, 52))	('MEK', 'Gene', '5609', (49, 52))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (127, 141))	('uveal melanoma', 'Disease', (74, 88))	('MEK', 'Gene', (109, 112))	('MEK', 'Gene', '5609', (109, 112))
92823	31227503	These mutations (most commonly at Q209L/P) disable the intrinsic GTPase activity, leading to constitutive activation.	('intrinsic', 'MPA', (55, 64))	('GTPase activity', 'molecular_function', 'GO:0003924', ('65', '80'))	('activity', 'MPA', (72, 80))	('GTP', 'Chemical', 'MESH:D006160', (65, 68))	('Q209L', 'SUBSTITUTION', 'None', (34, 39))	('Q209L', 'Var', (34, 39))	('constitutive activation', 'MPA', (93, 116))	('disable', 'NegReg', (43, 50))	('GTPase', 'Protein', (65, 71))
92825	31227503	Protein kinase C (PKC) is activated by these second messengers in GNAQ/GNA11 mutant melanomas.	('melanomas', 'Disease', (84, 93))	('PKC', 'Disease', 'MESH:C537180', (18, 21))	('GNA11', 'Gene', (71, 76))	('GNAQ', 'Gene', '2776', (66, 70))	('melanomas', 'Disease', 'MESH:D008545', (84, 93))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('GNA11', 'Gene', '2767', (71, 76))	('activated', 'PosReg', (26, 35))	('PKC', 'molecular_function', 'GO:0004697', ('18', '21'))	('PKC', 'Disease', (18, 21))	('GNAQ', 'Gene', (66, 70))	('mutant', 'Var', (77, 83))
92835	31227503	Silencing of GNAQ/GNA11 in uveal melanoma cells led to decreased nuclear accumulation of YAP, with further studies showing that the YAP inhibitor verteporfin abrogates GNAQ/GNA11 driven tumor growth in an orthotopic uveal melanoma ocular xenograft model.	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('GNAQ', 'Gene', (13, 17))	('YAP', 'Gene', '10413', (89, 92))	('tumor', 'Disease', (186, 191))	('Silencing', 'Var', (0, 9))	('GNA11', 'Gene', '2767', (18, 23))	('GNA11', 'Gene', (173, 178))	('uveal melanoma', 'Disease', (27, 41))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('uveal melanoma', 'Disease', 'MESH:C536494', (27, 41))	('uveal melanoma ocular xenograft', 'Disease', (216, 247))	('YAP', 'Gene', (132, 135))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('uveal melanoma', 'Disease', 'MESH:C536494', (216, 230))	('uveal melanoma', 'Phenotype', 'HP:0007716', (27, 41))	('nuclear accumulation', 'MPA', (65, 85))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('decreased', 'NegReg', (55, 64))	('uveal melanoma ocular xenograft', 'Disease', 'MESH:C536494', (216, 247))	('GNA11', 'Gene', (18, 23))	('YAP', 'Gene', (89, 92))	('uveal melanoma', 'Phenotype', 'HP:0007716', (216, 230))	('YAP', 'Gene', '10413', (132, 135))	('GNA11', 'Gene', '2767', (173, 178))	('GNAQ', 'Gene', '2776', (168, 172))	('GNAQ', 'Gene', (168, 172))	('abrogates', 'NegReg', (158, 167))	('GNAQ', 'Gene', '2776', (13, 17))	('verteporfin', 'Chemical', 'MESH:D000077362', (146, 157))
92869	31227503	Media was changed for another 12h prior to the drug(s) treatment with MEKi (10nM), HDACi (10nM) or both for 72h.	('10nM', 'Var', (90, 94))	('10nM', 'Var', (76, 80))	('HDAC', 'Gene', '9734', (83, 87))	('HDAC', 'Gene', (83, 87))
92879	31227503	Eight week old female CBySmn.CB17-Prdkc scid/j mice (Stock No: 001803 - Jax) were subcutaneously injected with 1.0 x106 92.1 or MP41 uveal melanoma cells per mouse.	('mouse', 'Species', '10090', (158, 163))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('MP41', 'Var', (128, 132))	('uveal melanoma', 'Phenotype', 'HP:0007716', (133, 147))	('uveal melanoma', 'Disease', (133, 147))	('mice', 'Species', '10090', (47, 51))	('uveal melanoma', 'Disease', 'MESH:C536494', (133, 147))
92881	31227503	Eight week old female NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (Stock No: 005557 - Jackson Laboratory) were injected with 2.0 x105 MP41 uveal melanoma cells per mouse into the tail vein i.	('Il2', 'molecular_function', 'GO:0005134', ('39', '42'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (128, 142))	('uveal melanoma', 'Disease', 'MESH:C536494', (128, 142))	('uveal melanoma', 'Disease', (128, 142))	('mouse', 'Species', '10090', (153, 158))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('Il2rgtm1Wjl/SzJ', 'Var', (39, 54))
92889	31227503	We began by characterizing the MEK inhibitor response of a panel of GNAQ/GNA11 mutant uveal melanoma cell lines that were derived from primary and metastatic lesions (92.1, Mel270, MP41: primary, OMM1 and MM28: metastatic).	('GNA11', 'Gene', (73, 78))	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('uveal melanoma', 'Disease', 'MESH:C536494', (86, 100))	('MP41', 'Var', (181, 185))	('GNA11', 'Gene', '2767', (73, 78))	('uveal melanoma', 'Disease', (86, 100))	('GNAQ', 'Gene', (68, 72))	('mutant', 'Var', (79, 85))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('GNAQ', 'Gene', '2776', (68, 72))
92894	31227503	The ABPP studies demonstrated that MEK inhibition increased the ATP uptake of 128 proteins and 98 proteins in the 92.1 and Mel270 cells, respectively (Figure 1F).	('inhibition', 'Var', (39, 49))	('uptake', 'biological_process', 'GO:0098657', ('68', '74'))	('ATP', 'Chemical', 'MESH:D000255', (64, 67))	('ABPP', 'Gene', (4, 8))	('increased', 'PosReg', (50, 59))	('ABPP', 'Gene', '351', (4, 8))	('ATP uptake of 128 proteins', 'MPA', (64, 90))	('MEK', 'Enzyme', (35, 38))	('uptake', 'biological_process', 'GO:0098739', ('68', '74'))
92901	31227503	Although there was some evidence that the PI3Ki also suppressed the outgrowth of MEK inhibitor treated uveal melanoma cells in colony formation assays, the effects were incomplete and tumor cells were still able to evade therapy (Figure 2E,F).	('PI3Ki', 'Var', (42, 47))	('colony formation assays', 'CPA', (127, 150))	('uveal melanoma', 'Disease', (103, 117))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('uveal melanoma', 'Disease', 'MESH:C536494', (103, 117))	('uveal melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('formation', 'biological_process', 'GO:0009058', ('134', '143'))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('tumor', 'Disease', (184, 189))	('outgrowth', 'CPA', (68, 77))	('MEK inhibitor', 'Gene', (81, 94))	('suppressed', 'NegReg', (53, 63))
92903	31227503	These findings were confirmed by RTK arrays, with MEKi being found to increase the phosphorylation of multiple RTKs including IGF-1R (in the 92.1 cells), as well as ROR1 and ROR2 (in both the 92.1 and Mel270 cell lines) (Figures 3B).	('RTK', 'Gene', '5979', (33, 36))	('increase', 'PosReg', (70, 78))	('RTK', 'Gene', (111, 114))	('ROR2', 'Gene', '4920', (174, 178))	('ROR2', 'Gene', (174, 178))	('ROR1', 'Gene', (165, 169))	('ROR1', 'Gene', '4919', (165, 169))	('phosphorylation', 'MPA', (83, 98))	('phosphorylation', 'biological_process', 'GO:0016310', ('83', '98'))	('IGF-1R', 'Gene', (126, 132))	('IGF-1R', 'Gene', '3480', (126, 132))	('RTK', 'Gene', (33, 36))	('RTK', 'Gene', '5979', (111, 114))	('MEKi', 'Var', (50, 54))
92904	31227503	q-RT-PCR and Western Blot analyses demonstrated increases in IGF-1R, ROR1 and ROR2 mRNA and protein expression following MEKi (Figure 3C,D).	('increases', 'PosReg', (48, 57))	('IGF-1R', 'Gene', '3480', (61, 67))	('ROR1', 'Gene', '4919', (69, 73))	('IGF-1R', 'Gene', (61, 67))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('MEKi', 'Var', (121, 125))	('ROR1', 'Gene', (69, 73))	('ROR2', 'Gene', (78, 82))	('ROR2', 'Gene', '4920', (78, 82))
92907	31227503	Silencing of ROR1/2 (Figure 3F) in the 92.1 cells inhibited the increases in AKT phosphorylation observed following MEKi treatment (Figure 3G).	('AKT', 'Gene', '207', (77, 80))	('ROR1/2', 'Gene', (13, 19))	('ROR1/2', 'Gene', '4919;4920', (13, 19))	('AKT', 'Gene', (77, 80))	('phosphorylation', 'biological_process', 'GO:0016310', ('81', '96'))	('Silencing', 'Var', (0, 9))	('inhibited', 'NegReg', (50, 59))
92908	31227503	Silencing of IGF-1R in combination with the MEKi was found to increase cell death and decrease the numbers of 92.1 cells, but not Mel270 cells, a result consistent with the increased IGF-1R signaling seen only in the 92.1 cell line (Figure 3F,H,I).	('IGF-1R', 'Gene', '3480', (183, 189))	('cell death', 'CPA', (71, 81))	('signaling', 'biological_process', 'GO:0023052', ('190', '199'))	('IGF-1R', 'Gene', (183, 189))	('increased IGF-1R', 'Phenotype', 'HP:0030269', (173, 189))	('cell death', 'biological_process', 'GO:0008219', ('71', '81'))	('IGF-1R', 'Gene', '3480', (13, 19))	('decrease', 'NegReg', (86, 94))	('IGF-1R', 'Gene', (13, 19))	('Silencing', 'Var', (0, 9))	('increase', 'PosReg', (62, 70))
92909	31227503	In contrast, silencing of ROR1/2 enhanced the effects of MEKi in terms of decreased cell survival and apoptosis induction in both of the cell lines evaluated (Figures 3F,H,I).	('apoptosis induction', 'CPA', (102, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('102', '111'))	('ROR1/2', 'Gene', '4919;4920', (26, 32))	('apoptosis', 'biological_process', 'GO:0006915', ('102', '111'))	('silencing', 'Var', (13, 22))	('cell survival', 'CPA', (84, 97))	('decreased', 'NegReg', (74, 83))	('enhanced', 'PosReg', (33, 41))	('ROR1/2', 'Gene', (26, 32))
92917	31227503	Additionally, siRNA knockdown of YAP (Figure 4I) increased the level of MEKi -induced apoptosis in multiple uveal melanoma cell lines (Figure 4J).	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('MEKi -induced apoptosis', 'MPA', (72, 95))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('multiple uveal melanoma', 'Disease', (99, 122))	('multiple uveal melanoma', 'Disease', 'MESH:C536494', (99, 122))	('increased', 'PosReg', (49, 58))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('YAP', 'Gene', '10413', (33, 36))	('YAP', 'Gene', (33, 36))	('knockdown', 'Var', (20, 29))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
92928	31227503	Among these, several drugs were identified with some activity against one or more uveal melanoma cell lines including PI3K inhibitors (GSK2126458, idelalisib), two kinesin inhibitors (Ispinesib, SB743921), CDK inhibitors (dinaciclib), H3K27 histone demethylase (GSK-J4), and mTOR (Sapanisertib) (Figure 6B).	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('dinaciclib', 'Chemical', 'MESH:C553669', (222, 232))	('CDK', 'Enzyme', (206, 209))	('H3K27 histone', 'Protein', (235, 248))	('GSK', 'molecular_function', 'GO:0050321', ('262', '265'))	('GSK2126458', 'Chemical', 'MESH:C561454', (135, 145))	('Sapanisertib', 'Chemical', 'MESH:C572449', (281, 293))	('GSK2126458', 'Var', (135, 145))	('uveal melanoma', 'Disease', 'MESH:C536494', (82, 96))	('uveal melanoma', 'Disease', (82, 96))	('GSK', 'molecular_function', 'GO:0050321', ('135', '138'))	('PI3K', 'molecular_function', 'GO:0016303', ('118', '122'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('mTOR', 'Gene', (275, 279))	('PI3K', 'Gene', (118, 122))	('CDK', 'molecular_function', 'GO:0004693', ('206', '209'))	('idelalisib', 'Chemical', 'MESH:C552946', (147, 157))	('kinesin', 'molecular_function', 'GO:0003777', ('164', '171'))	('mTOR', 'Gene', '2475', (275, 279))
92934	31227503	It was found that co-treatment of multiple uveal melanoma cell lines, including 92.1, MP41, Mel270 and MM28 with the MEKi-HDACi (trametinib-panobinostat) combination was associated with significantly (P<0.05) higher levels of apoptosis compared to either single agent (Figure 6F).	('panobinostat', 'Chemical', 'MESH:D000077767', (140, 152))	('trametinib', 'Chemical', 'MESH:C560077', (129, 139))	('apoptosis', 'biological_process', 'GO:0006915', ('226', '235'))	('multiple uveal melanoma', 'Disease', (34, 57))	('apoptosis', 'MPA', (226, 235))	('multiple uveal melanoma', 'Disease', 'MESH:C536494', (34, 57))	('MP41', 'Var', (86, 90))	('higher', 'PosReg', (209, 215))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('apoptosis', 'biological_process', 'GO:0097194', ('226', '235'))	('HDAC', 'Gene', (122, 126))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('HDAC', 'Gene', '9734', (122, 126))
92944	31227503	Although single-agent MEKi was more effective against MP41 uveal melanoma cells than 92.1 cells, its effects in both models were relatively short lived and the tumors re-initiated growth.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('uveal melanoma', 'Disease', (59, 73))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('MP41', 'Var', (54, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (59, 73))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
92957	31227503	Uveal melanomas typically harbor activating mutations in the small G-proteins GNAQ and GNA11 which are not kinases and therefore not easily tractable to drug development.	('GNAQ', 'Gene', '2776', (78, 82))	('GNA11', 'Gene', (87, 92))	('GNAQ', 'Gene', (78, 82))	('small G-protein', 'Gene', (61, 76))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('Uveal melanoma', 'Disease', 'MESH:C536494', (0, 14))	('melanomas', 'Disease', (6, 15))	('small G-protein', 'Gene', '5880', (61, 76))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('mutations', 'Var', (44, 53))	('activating', 'PosReg', (33, 43))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('GNA11', 'Gene', '2767', (87, 92))	('Uveal melanoma', 'Disease', (0, 14))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))
92968	31227503	Inhibition of RAF and MEK is known to trigger a rapid transcriptional reprogramming that is associated with increased RTK expression.	('expression', 'MPA', (122, 132))	('RAF', 'Gene', (14, 17))	('RAF', 'Gene', '22882', (14, 17))	('RTK', 'Gene', (118, 121))	('increased', 'PosReg', (108, 117))	('Inhibition', 'Var', (0, 10))	('RTK', 'Gene', '5979', (118, 121))	('MEK', 'Gene', (22, 25))
92970	31227503	Similar findings have been also reported in many other cancers including BRAF and NRAS-mutant melanoma; where BRAF and MEK inhibition frequently leads to a relief of feedback inhibition and increased signaling through multiple RTKs including IGF-1R, EGFR, ERBB3, EphA2 and c-MET.	('MEK', 'Gene', (119, 122))	('BRAF', 'Gene', '673', (73, 77))	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('RTK', 'Gene', (227, 230))	('inhibition', 'Var', (123, 133))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('NRAS', 'Gene', (82, 86))	('RTK', 'Gene', '5979', (227, 230))	('BRAF', 'Gene', '673', (110, 114))	('signaling', 'MPA', (200, 209))	('BRAF', 'Gene', (110, 114))	('EGFR', 'Gene', (250, 254))	('ERBB3', 'Gene', (256, 261))	('EGFR', 'molecular_function', 'GO:0005006', ('250', '254'))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancers', 'Disease', (55, 62))	('feedback inhibition', 'MPA', (166, 185))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('melanoma', 'Disease', (94, 102))	('EphA2', 'Gene', (263, 268))	('EGFR', 'Gene', '1956', (250, 254))	('EphA2', 'Gene', '1969', (263, 268))	('NRAS', 'Gene', '4893', (82, 86))	('ERBB3', 'Gene', '2065', (256, 261))	('c-MET', 'Gene', '4233', (273, 278))	('IGF-1R', 'Gene', (242, 248))	('IGF-1R', 'Gene', '3480', (242, 248))	('increased', 'PosReg', (190, 199))	('signaling', 'biological_process', 'GO:0023052', ('200', '209'))	('c-MET', 'Gene', (273, 278))	('BRAF', 'Gene', (73, 77))	('relief', 'PosReg', (156, 162))
92972	31227503	To investigate whether this also occurred in GNAQ-mutant uveal melanoma cell lines, we performed RTK arrays and identified increased IGF1-R and ROR1/2 activity following MEK inhibition.	('increased', 'PosReg', (123, 132))	('RTK', 'Gene', (97, 100))	('ROR1/2', 'Gene', (144, 150))	('ROR1/2', 'Gene', '4919;4920', (144, 150))	('inhibition', 'Var', (174, 184))	('increased IGF1', 'Phenotype', 'HP:0030269', (123, 137))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('IGF1-R', 'Gene', '3480', (133, 139))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('uveal melanoma', 'Disease', (57, 71))	('GNAQ', 'Gene', (45, 49))	('IGF1-R', 'Gene', (133, 139))	('RTK', 'Gene', '5979', (97, 100))	('activity', 'MPA', (151, 159))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('MEK', 'Gene', (170, 173))	('GNAQ', 'Gene', '2776', (45, 49))
92977	31227503	In GNAQ/GNA11 mutant uveal melanoma cells, YAP is activated by the guanine nucleotide exchange factor Trio leading to YAP activation via Rho and Rac.	('uveal melanoma', 'Disease', (21, 35))	('GNA11', 'Gene', (8, 13))	('Rho', 'Protein', (137, 140))	('YAP', 'Gene', '10413', (43, 46))	('Trio', 'Gene', (102, 106))	('activation', 'PosReg', (122, 132))	('YAP', 'Gene', (118, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (21, 35))	('Rac', 'Gene', '207', (145, 148))	('YAP', 'Gene', '10413', (118, 121))	('GNAQ', 'Gene', '2776', (3, 7))	('Trio', 'Gene', '7204', (102, 106))	('GNA11', 'Gene', '2767', (8, 13))	('GNAQ', 'Gene', (3, 7))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('YAP', 'Gene', (43, 46))	('Rac', 'Gene', (145, 148))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (67, 85))	('mutant', 'Var', (14, 20))	('uveal melanoma', 'Disease', 'MESH:C536494', (21, 35))
92982	31227503	YAP signaling is known to be activated through GPCRs, with our RNA-seq studies identifying a whole series of candidate receptors that were upregulated following MEK inhibition.	('upregulated', 'PosReg', (139, 150))	('YAP', 'Gene', (0, 3))	('MEK', 'Gene', (161, 164))	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))	('GPCR', 'Gene', (47, 51))	('YAP', 'Gene', '10413', (0, 3))	('inhibition', 'Var', (165, 175))	('signaling', 'biological_process', 'GO:0023052', ('4', '13'))	('GPCR', 'Gene', '1909', (47, 51))
92986	31227503	There is also evidence from cutaneous melanoma that EDNRB antagonists reduce melanoma growth in vitro and in in vivo xenograft models.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (28, 46))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('EDNRB', 'Gene', (52, 57))	('melanoma', 'Disease', (77, 85))	('reduce', 'NegReg', (70, 76))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))	('antagonists', 'Var', (58, 69))	('cutaneous melanoma', 'Disease', (28, 46))
92988	31227503	Further evidence suggests that autocrine Endothelin-1 might also regulate melanoma heterogeneity following BRAF inhibition and could mediate the switch to an Axl-high/MITF-low (drug resistant) phenotype.	('BRAF', 'Gene', (107, 111))	('inhibition', 'Var', (112, 122))	('MITF', 'Gene', (167, 171))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('MITF', 'Gene', '4286', (167, 171))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('regulate', 'Reg', (65, 73))	('Endothelin-1', 'Gene', (41, 53))	('BRAF', 'Gene', '673', (107, 111))	('Endothelin-1', 'Gene', '1906', (41, 53))
92989	31227503	We here demonstrate that uveal melanoma cells released ET-3 in response to MEK inhibition and that the resulting increase in EDNRB signaling activates YAP signaling, leading to increased cell survival.	('EDNRB signaling', 'MPA', (125, 140))	('uveal melanoma', 'Disease', (25, 39))	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('activates', 'PosReg', (141, 150))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('ET-3', 'Gene', (55, 59))	('inhibition', 'Var', (79, 89))	('increased', 'PosReg', (177, 186))	('ET-3', 'Gene', '1908', (55, 59))	('increase', 'PosReg', (113, 121))	('cell survival', 'CPA', (187, 200))	('YAP', 'Gene', '10413', (151, 154))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('MEK', 'Gene', (75, 78))	('uveal melanoma', 'Disease', 'MESH:C536494', (25, 39))	('YAP', 'Gene', (151, 154))
92990	31227503	Although it is likely that EDNRB plays a role in the increased YAP signaling observed following MEK inhibition, it is unlikely to be only GCPR involved, and it is possible that different uveal melanomas may have unique GPCR dependencies.	('uveal melanomas', 'Disease', 'MESH:C536494', (187, 202))	('YAP', 'Gene', (63, 66))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('GPCR', 'Gene', '1909', (219, 223))	('MEK', 'Gene', (96, 99))	('melanomas', 'Phenotype', 'HP:0002861', (193, 202))	('EDNRB', 'Gene', (27, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (187, 201))	('increased', 'PosReg', (53, 62))	('inhibition', 'Var', (100, 110))	('GPCR', 'Gene', (219, 223))	('YAP', 'Gene', '10413', (63, 66))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('uveal melanomas', 'Disease', (187, 202))	('uveal melanomas', 'Phenotype', 'HP:0007716', (187, 202))
92991	31227503	One potential strategy to target multiple G-proteins (and GPCRs) simultaneously could be through allosteric inhibitors of GDP/GTP exchange with recent studies demonstrating that GTP exchange inhibitors such as the depsipeptide FR900359 have activity against GNAQ-mutant uveal melanoma cell lines.	('activity', 'MPA', (241, 249))	('GDP', 'Chemical', 'MESH:D006153', (122, 125))	('GTP', 'Chemical', 'MESH:D006160', (178, 181))	('GTP', 'Chemical', 'MESH:D006160', (126, 129))	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('GNAQ', 'Gene', '2776', (258, 262))	('GPCR', 'Gene', '1909', (58, 62))	('GTP', 'MPA', (178, 181))	('GNAQ', 'Gene', (258, 262))	('uveal melanoma', 'Disease', 'MESH:C536494', (270, 284))	('uveal melanoma', 'Phenotype', 'HP:0007716', (270, 284))	('uveal melanoma', 'Disease', (270, 284))	('GPCR', 'Gene', (58, 62))	('FR900359', 'Var', (227, 235))
92992	31227503	The increased GPCR expression noted following MEK inhibition might be expected to increase the adhesion of uveal melanoma cells to the extracellular matrix, potentially decreasing their metastatic potential.	('expression', 'MPA', (19, 29))	('uveal melanoma', 'Disease', 'MESH:C536494', (107, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('uveal melanoma', 'Disease', (107, 121))	('inhibition', 'Var', (50, 60))	('GPCR', 'Gene', '1909', (14, 18))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('135', '155'))	('metastatic potential', 'CPA', (186, 206))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('adhesion', 'CPA', (95, 103))	('increase', 'PosReg', (82, 90))	('MEK', 'Gene', (46, 49))	('GPCR', 'Gene', (14, 18))	('increased', 'PosReg', (4, 13))	('decreasing', 'NegReg', (169, 179))
92997	31227503	In cutaneous melanoma there is also evidence that HDAC inhibition can restore sensitivity to BRAF inhibition following the onset of resistance.	('BRAF', 'Gene', (93, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('HDAC', 'Gene', (50, 54))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('restore', 'PosReg', (70, 77))	('HDAC', 'Gene', '9734', (50, 54))	('inhibition', 'Var', (55, 65))	('BRAF', 'Gene', '673', (93, 97))	('cutaneous melanoma', 'Disease', (3, 21))
93025	30993893	Survival in metastasized cutaneous melanoma (CM) has been greatly improved with the advent of kinase inhibitors for BRAF-mutant tumors and monoclonal antibodies against the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and Programmed cell death protein 1 (PD-1) immune checkpoints.2 Used as single agents, response rates of 10%-20% for anti CTLA4 and 40% for anti-PD-1 have been reported.	('protein', 'cellular_component', 'GO:0003675', ('207', '214'))	('cutaneous melanoma', 'Disease', (25, 43))	('PD-1', 'Gene', (370, 374))	('Programmed cell death protein 1', 'Gene', (229, 260))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (25, 43))	('PD-1', 'Gene', '5133', (370, 374))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (25, 43))	('CTLA4', 'Gene', '1493', (347, 352))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (173, 216))	('protein', 'cellular_component', 'GO:0003675', ('251', '258'))	('anti', 'Var', (342, 346))	('CTLA4', 'Gene', (347, 352))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('CTLA4', 'Gene', '1493', (218, 223))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (173, 216))	('BRAF', 'Gene', '673', (116, 120))	('Programmed cell death protein 1', 'Gene', '5133', (229, 260))	('PD-1', 'Gene', (262, 266))	('BRAF', 'Gene', (116, 120))	('CM', 'Phenotype', 'HP:0012056', (45, 47))	('PD-1', 'Gene', '5133', (262, 266))	('Programmed cell death', 'biological_process', 'GO:0012501', ('229', '250'))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('CTLA4', 'Gene', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
93027	30993893	CD8 positive T cell infiltrates have been identified in a third of primary UM with high risk for metastasis, based on monosomy 3 (M3), but not in tumors with disomy 3 (D3).7 In DNA methylation and RNA-sequencing analysis, tissue from the M3 tumors were found to overexpress the immune checkpoints Indoleamine 2,3-dioxygenase (IDO1) and T cell Ig and ITIM domain (TIGIT) genes.7 IDO1 encodes the heme-containing IDO protein, that contributes to metabolic immune regulation by catalyzing catabolism of tryptophan along the kynurenine pathway, which limits T-cell function and engage mechanisms of immune tolerance.10, 11 TIGIT encodes an immune receptor on T cells, regulatory T cells, and Natural Killer cells (NK) that decreases cell proliferation, cytokine production, and degranulation.12, 13 TIGIT shares ligands with the T cell and NK receptors CD96 and CD226, and together form a pathway that closely resembles CTLA4.14  Blockade of IDO and TIGIT with monoclonal antibodies increases the proportion of antitumoral T cells and delays tumor growth in vitro.	('Blockade', 'Var', (926, 934))	('tumor', 'Disease', 'MESH:D009369', (1038, 1043))	('tumor', 'Disease', (1011, 1016))	('IDO', 'Gene', '3620', (411, 414))	('tumor', 'Disease', (146, 151))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('CD8', 'Gene', '925', (0, 3))	('IDO', 'molecular_function', 'GO:0033754', ('938', '941'))	('IDO', 'molecular_function', 'GO:0047719', ('326', '329'))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('IDO', 'Gene', (938, 941))	('tumor', 'Disease', 'MESH:D009369', (1011, 1016))	('IDO', 'molecular_function', 'GO:0033754', ('378', '381'))	('CD96', 'Gene', '10225', (849, 853))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('CD96', 'Gene', (849, 853))	('IDO', 'molecular_function', 'GO:0047719', ('938', '941'))	('IDO', 'molecular_function', 'GO:0033754', ('411', '414'))	('tumor', 'Disease', (241, 246))	('IDO1', 'Gene', (378, 382))	('IDO', 'Gene', (326, 329))	('IDO', 'Gene', '3620', (378, 381))	('increases', 'PosReg', (979, 988))	('IDO1', 'Gene', '3620', (326, 330))	('tumor', 'Phenotype', 'HP:0002664', (1038, 1043))	('regulation', 'biological_process', 'GO:0065007', ('461', '471'))	('delays tumor', 'Disease', 'MESH:D009369', (1031, 1043))	('protein', 'cellular_component', 'GO:0003675', ('415', '422'))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('CTLA4', 'Gene', '1493', (916, 921))	('DNA methylation', 'biological_process', 'GO:0006306', ('177', '192'))	('tumor', 'Phenotype', 'HP:0002664', (1011, 1016))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('IDO', 'molecular_function', 'GO:0047719', ('378', '381'))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('cell proliferation', 'biological_process', 'GO:0008283', ('729', '747'))	('CD8', 'Gene', (0, 3))	('IDO', 'molecular_function', 'GO:0047719', ('411', '414'))	('IDO', 'Gene', (411, 414))	('IDO', 'Gene', '3620', (938, 941))	('metabolic immune regulation', 'Phenotype', 'HP:0002958', (444, 471))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('IDO1', 'Gene', (326, 330))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('CTLA4', 'Gene', (916, 921))	('IDO', 'Gene', '3620', (326, 329))	('tumors', 'Disease', (241, 247))	('IDO', 'molecular_function', 'GO:0033754', ('326', '329'))	('DNA', 'cellular_component', 'GO:0005574', ('177', '180'))	('cytokine production', 'biological_process', 'GO:0001816', ('749', '768'))	('IDO', 'Gene', (378, 381))	('tumor', 'Disease', (1038, 1043))	('tumors', 'Disease', (146, 152))	('catabolism', 'biological_process', 'GO:0009056', ('486', '496'))	('IDO1', 'Gene', '3620', (378, 382))	('RNA', 'cellular_component', 'GO:0005562', ('197', '200'))	('delays tumor', 'Disease', (1031, 1043))
93083	30993893	In Cox regression, the time dependent hazard for metastasis was significantly increased for patients with a number of TIGIT positive cells/mm2 in primary tumor hot spots above the median (Hazard ratio TIGIT positive cells/mm2 above median = 7.9, 95% CI 1.0-69.3, P = 0.03.	('mm2', 'Gene', (222, 225))	('metastasis', 'CPA', (49, 59))	('patients', 'Species', '9606', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('TIGIT', 'Var', (118, 123))	('increased', 'PosReg', (78, 87))	('mm2', 'Gene', '10687', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mm2', 'Gene', '10687', (222, 225))	('mm2', 'Gene', (139, 142))	('tumor', 'Disease', (154, 159))
93084	30993893	In metastases, the number of TIGIT positive cells/ mm2 was not associated with worse (Hazard ratio TIGIT positive cells/mm2 above median in hot spots and full sections = 0.9, 95% CI 0.1-9.2, P = 0.95).	('metastases', 'Disease', 'MESH:D009362', (3, 13))	('mm2', 'Gene', '10687', (51, 54))	('mm2', 'Gene', (120, 123))	('TIGIT', 'Var', (99, 104))	('mm2', 'Gene', (51, 54))	('metastases', 'Disease', (3, 13))	('mm2', 'Gene', '10687', (120, 123))
93104	29383138	SF3B1 mutation is a poor prognostic indicator in luminal B and progesterone receptor-negative breast cancer patients The purpose of this study was to explore the relationship between SF3B1 mutations and the prognoses of patients with breast cancer.	('progesterone receptor', 'Gene', (63, 84))	('SF3B1', 'Gene', (0, 5))	('progesterone receptor', 'Gene', '5241', (63, 84))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('SF3B1', 'Gene', '23451', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('breast cancer', 'Disease', (234, 247))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('SF3B1', 'Gene', '23451', (0, 5))	('patients', 'Species', '9606', (220, 228))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('patients', 'Species', '9606', (108, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('mutations', 'Var', (189, 198))	('SF3B1', 'Gene', (183, 188))	('breast cancer', 'Disease', (94, 107))
93105	29383138	SF3B1 mutations were evaluated as prognostic factors in all breast cancer patients and specific subgroups through Cox regression and Kaplan-Meier analyses.	('breast cancer', 'Disease', (60, 73))	('SF3B1', 'Gene', (0, 5))	('patients', 'Species', '9606', (74, 82))	('Cox', 'Gene', '1351', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Cox', 'Gene', (114, 117))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('mutations', 'Var', (6, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
93106	29383138	SF3B1 mutations were a poor prognostic factor in luminal B and progesterone receptor (PR)-negative breast cancer (P < 0.01).	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('progesterone receptor', 'Gene', (63, 84))	('SF3B1', 'Gene', (0, 5))	('progesterone receptor', 'Gene', '5241', (63, 84))	('PR', 'Gene', '5241', (86, 88))	('breast cancer', 'Disease', (99, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('luminal B', 'Disease', (49, 58))	('mutations', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
93107	29383138	Age at diagnosis and estrogen receptor (ER) status were associated with SF3B1 mutations in all breast cancers (P < 0.01) and in luminal B and PR-negative subgroups (P < 0.01).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancers', 'Disease', 'MESH:D001943', (95, 109))	('breast cancers', 'Disease', (95, 109))	('PR', 'Gene', '5241', (142, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('estrogen receptor', 'Gene', (21, 38))	('estrogen receptor', 'Gene', '2099', (21, 38))	('associated', 'Reg', (56, 66))	('SF3B1', 'Gene', (72, 77))	('mutations', 'Var', (78, 87))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('ER', 'Gene', '2099', (40, 42))	('breast cancers', 'Phenotype', 'HP:0003002', (95, 109))
93108	29383138	The age at diagnosis and ER status combined had a higher sensitivity and specificity for predicting SF3B1 mutations than each factor alone.	('SF3B1', 'Gene', (100, 105))	('ER', 'Gene', '2099', (25, 27))	('mutations', 'Var', (106, 115))
93109	29383138	SF3B1 mutations are a poor prognostic factor in luminal B and PR-negative breast cancer patients.	('breast cancer', 'Disease', (74, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('SF3B1', 'Gene', (0, 5))	('patients', 'Species', '9606', (88, 96))	('luminal B', 'Disease', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('PR', 'Gene', '5241', (62, 64))	('mutations', 'Var', (6, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
93110	29383138	These mutations are significantly associated with age at diagnosis and ER status.	('ER', 'Gene', '2099', (71, 73))	('associated', 'Reg', (34, 44))	('mutations', 'Var', (6, 15))
93111	29383138	SF3B1 mutations may therefore be a novel therapeutic target for breast cancer patients.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('SF3B1', 'Gene', (0, 5))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('mutations', 'Var', (6, 15))	('breast cancer', 'Disease', (64, 77))
93112	29383138	Mutations in the largest SF3b subunit, SF3B1/SF3B155, are linked to cancer and lead to alternative branch site selection.	('SF3B155', 'Gene', '23451', (45, 52))	('linked', 'Reg', (58, 64))	('SF3B155', 'Gene', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (68, 74))	('lead to', 'Reg', (79, 86))
93114	29383138	The frequency of SF3B1 mutations is particularly high among the unique subtypes of myelodysplastic syndrome that are characterized by increased ring sideroblasts, in which mutation frequencies of 66.7-79% have been reported.	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (83, 107))	('SF3B1', 'Gene', (17, 22))	('myelodysplastic syndrome', 'Disease', (83, 107))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (83, 107))	('mutations', 'Var', (23, 32))	('increased ring sideroblasts', 'Phenotype', 'HP:0004828', (134, 161))	('high', 'Reg', (49, 53))
93116	29383138	SF3B1 was found to be the second most frequently mutated gene in chronic lymphocytic leukemia (CLL) at 5-15%; SF3B1 mutations are less common in the early stages of CLL and become more prevalent in advanced disease where they tend to be associated with poor prognosis.	('CLL', 'Phenotype', 'HP:0005550', (165, 168))	('leukemia', 'Phenotype', 'HP:0001909', (85, 93))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (65, 93))	('CLL', 'Disease', (165, 168))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (65, 93))	('CLL', 'Disease', 'MESH:D015451', (95, 98))	('CLL', 'Disease', 'MESH:D015451', (165, 168))	('chronic lymphocytic leukemia', 'Disease', (65, 93))	('mutations', 'Var', (116, 125))	('SF3B1', 'Gene', (110, 115))	('CLL', 'Phenotype', 'HP:0005550', (95, 98))	('prevalent', 'Reg', (185, 194))	('CLL', 'Disease', (95, 98))
93118	29383138	In addition to hematological malignancies, lower frequencies of SF3B1 mutation are also found in solid tumors such as breast cancers (1.8%), pancreatic carcinoma (4%), uveal melanoma (9.7%), and endometrial cancers (percentages not reported).	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('solid tumors', 'Disease', 'MESH:D009369', (97, 109))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('breast cancers', 'Phenotype', 'HP:0003002', (118, 132))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('hematological malignancies', 'Disease', (15, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('lower', 'NegReg', (43, 48))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('uveal melanoma', 'Disease', (168, 182))	('uveal melanoma', 'Disease', 'MESH:C536494', (168, 182))	('SF3B1', 'Gene', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (141, 161))	('solid tumors', 'Disease', (97, 109))	('hematological malignancies', 'Disease', 'MESH:D019337', (15, 41))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('endometrial cancers', 'Disease', 'MESH:D016889', (195, 214))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('hematological malignancies', 'Phenotype', 'HP:0004377', (15, 41))	('endometrial cancers', 'Disease', (195, 214))	('pancreatic carcinoma', 'Disease', (141, 161))	('mutation', 'Var', (70, 78))	('breast cancers', 'Disease', 'MESH:D001943', (118, 132))	('breast cancers', 'Disease', (118, 132))
93119	29383138	Patients with uveal melanoma who harbor SF3B1 mutations are reported to have better prognoses.	('SF3B1', 'Gene', (40, 45))	('uveal melanoma', 'Phenotype', 'HP:0007716', (14, 28))	('uveal melanoma', 'Disease', 'MESH:C536494', (14, 28))	('mutations', 'Var', (46, 55))	('uveal melanoma', 'Disease', (14, 28))	('Patients', 'Species', '9606', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))
93124	29383138	revealed that mutations in spliceosomal component genes occur in 5.6% of breast cancers.	('spliceosomal component genes', 'Gene', (27, 55))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancers', 'Phenotype', 'HP:0003002', (73, 87))	('occur', 'Reg', (56, 61))	('breast cancers', 'Disease', 'MESH:D001943', (73, 87))	('breast cancers', 'Disease', (73, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('mutations', 'Var', (14, 23))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
93125	29383138	Mutation of SF3B1 in spliceosomal component genes was the most common in breast cancers, and was detected in approximately 1.8% of cases.	('SF3B1', 'Gene', (12, 17))	('common', 'Reg', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Mutation', 'Var', (0, 8))	('breast cancers', 'Phenotype', 'HP:0003002', (73, 87))	('breast cancers', 'Disease', 'MESH:D001943', (73, 87))	('breast cancers', 'Disease', (73, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
93126	29383138	SF3B1 hotspot mutation K700E was detected in 16% and 6% of papillary and mucinous breast cancers, respectively.	('mucinous breast cancers', 'Disease', (73, 96))	('SF3B1', 'Gene', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('K700E', 'Mutation', 'rs559063155', (23, 28))	('K700E', 'Var', (23, 28))	('detected', 'Reg', (33, 41))	('mucinous breast cancers', 'Disease', 'MESH:D001943', (73, 96))	('breast cancers', 'Phenotype', 'HP:0003002', (82, 96))	('papillary', 'Disease', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
93127	29383138	These SF3B1 K700E mutations could lead to differential splicing.	('SF3B1', 'Gene', (6, 11))	('K700E', 'Mutation', 'rs559063155', (12, 17))	('K700E', 'Var', (12, 17))	('lead to', 'Reg', (34, 41))	('differential splicing', 'MPA', (42, 63))	('splicing', 'biological_process', 'GO:0045292', ('55', '63'))
93128	29383138	Alternative splicing of genes has also been shown to be associated with SF3B1 mutations in breast cancer, such as TMEM14C, RPL31, CRNDE, DYNLL1, MZB1, ICA1, RPL24, MTERFD3, OBSL1, ABCC5, UQCC, GUSBP11, ANKHD1, ADAM12, F8, and GAS8.	('RPL31', 'Gene', '6160', (123, 128))	('GAS', 'molecular_function', 'GO:0034005', ('226', '229'))	('CRNDE', 'Gene', '643911', (130, 135))	('MZB1', 'Gene', (145, 149))	('CRNDE', 'Gene', (130, 135))	('MZB1', 'Gene', '51237', (145, 149))	('TMEM14C', 'Gene', '51522', (114, 121))	('associated', 'Reg', (56, 66))	('RPL31', 'Gene', (123, 128))	('Alternative splicing', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('GUSBP11', 'Gene', (193, 200))	('OBSL1', 'Gene', (173, 178))	('RPL24', 'Gene', (157, 162))	('ICA1', 'Gene', '3382', (151, 155))	('mutations', 'Var', (78, 87))	('SF3B1', 'Gene', (72, 77))	('ICA1', 'Gene', (151, 155))	('UQCC', 'Gene', '55245', (187, 191))	('splicing', 'biological_process', 'GO:0045292', ('12', '20'))	('ADAM12', 'Gene', '8038', (210, 216))	('UQCC', 'Gene', (187, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('ADAM12', 'Gene', (210, 216))	('GAS8', 'Gene', (226, 230))	('ABCC5', 'Gene', '10057', (180, 185))	('ANKHD1', 'Gene', '54882', (202, 208))	('MTERFD3', 'Gene', (164, 171))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('TMEM14C', 'Gene', (114, 121))	('GUSBP11', 'Gene', '91316', (193, 200))	('breast cancer', 'Disease', (91, 104))	('ABCC5', 'Gene', (180, 185))	('GAS8', 'Gene', '2622', (226, 230))	('RPL24', 'Gene', '6152', (157, 162))	('ANKHD1', 'Gene', (202, 208))	('MTERFD3', 'Gene', '80298', (164, 171))	('DYNLL1', 'Gene', (137, 143))	('DYNLL1', 'Gene', '8655', (137, 143))	('OBSL1', 'Gene', '23363', (173, 178))
93129	29383138	also showed that recurrent K700E mutations in SF3B1 are associated with differential splicing activity in breast cancer; they found that patients presenting with mutations in SF3B1 tended to be older.	('mutations', 'Var', (162, 171))	('splicing', 'biological_process', 'GO:0045292', ('85', '93'))	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('SF3B1', 'Gene', (175, 180))	('patients', 'Species', '9606', (137, 145))	('differential splicing activity', 'MPA', (72, 102))	('SF3B1', 'Gene', (46, 51))	('K700E', 'Mutation', 'rs559063155', (27, 32))	('K700E', 'Var', (27, 32))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
93130	29383138	We performed this study to comprehensively investigate the association between SF3B1 mutations and prognoses in breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('SF3B1', 'Gene', (79, 84))	('mutations', 'Var', (85, 94))	('patients', 'Species', '9606', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
93131	29383138	Analysis of the cBioPortal for Cancer Genomics (www.cbioportal.org/) revealed 114 SF3B1 K700E/R hotspot mutations across different types of carcinoma, 54 of which were in invasive breast carcinoma.	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (171, 196))	('SF3B1', 'Gene', (82, 87))	('carcinoma', 'Disease', (140, 149))	('breast carcinoma', 'Phenotype', 'HP:0003002', (180, 196))	('invasive breast carcinoma', 'Disease', (171, 196))	('carcinoma', 'Disease', 'MESH:D002277', (187, 196))	('hotspot', 'PosReg', (96, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('K700E', 'Var', (88, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('carcinoma', 'Disease', 'MESH:D002277', (140, 149))	('K700E', 'SUBSTITUTION', 'None', (88, 93))	('carcinoma', 'Disease', (187, 196))
93132	29383138	Four patients with invasive breast carcinoma among 27 with various carcinoma types carried the SF3B1 K666E/M/N/Q/T hotspot mutation (Figure 1A).	('carcinoma', 'Disease', 'MESH:D002277', (35, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('SF3B1', 'Gene', (95, 100))	('patients', 'Species', '9606', (5, 13))	('K666E', 'Var', (101, 106))	('carcinoma', 'Disease', 'MESH:D002277', (67, 76))	('K666E', 'SUBSTITUTION', 'None', (101, 106))	('carcinoma', 'Disease', (35, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (19, 44))	('carcinoma', 'Disease', (67, 76))	('breast carcinoma', 'Phenotype', 'HP:0003002', (28, 44))	('invasive breast carcinoma', 'Disease', (19, 44))
93133	29383138	In terms of mutation frequency among different carcinomas, we found that the SF3B1 mutation ranged between 5% and 10% in breast cancer (Figure 1B).	('SF3B1', 'Gene', (77, 82))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('mutation', 'Var', (83, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('breast cancer', 'Disease', (121, 134))	('carcinomas', 'Disease', 'MESH:D002277', (47, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('carcinomas', 'Disease', (47, 57))
93139	29383138	Eighty-one of 3817 patients (2.12%) carried SF3B1 mutations.	('mutations', 'Var', (50, 59))	('SF3B1', 'Gene', (44, 49))	('patients', 'Species', '9606', (19, 27))
93141	29383138	Cox univariate analysis showed that the prognostic factors significantly associated with overall survival (OS) were age, N-Index, ER status, PR status, HER2 status, menopausal status, PAM-50 and claudin-low subtype, neoplasm histologic grade, breast cancer type, and tumor stage.	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('Cox', 'Gene', (0, 3))	('HER2', 'Gene', '2064', (152, 156))	('neoplasm', 'Disease', 'MESH:D009369', (216, 224))	('associated', 'Reg', (73, 83))	('overall survival', 'MPA', (89, 105))	('neoplasm', 'Disease', (216, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('PR', 'Gene', '5241', (141, 143))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('PAM-50', 'Var', (184, 190))	('neoplasm', 'Phenotype', 'HP:0002664', (216, 224))	('HER2', 'Gene', (152, 156))	('menopausal status', 'Phenotype', 'HP:0008209', (165, 182))	('breast cancer type', 'Disease', (243, 261))	('ER', 'Gene', '2099', (130, 132))	('breast cancer type', 'Disease', 'MESH:D001943', (243, 261))	('OS', 'Chemical', '-', (107, 109))	('Cox', 'Gene', '1351', (0, 3))	('ER', 'Gene', '2099', (153, 155))	('tumor', 'Disease', (267, 272))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))
93142	29383138	However, SF3B1 mutations and breast cancer laterality were not associated with OS.	('OS', 'Chemical', '-', (79, 81))	('mutations', 'Var', (15, 24))	('associated', 'Reg', (63, 73))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('SF3B1', 'Gene', (9, 14))	('breast cancer', 'Disease', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
93144	29383138	In the luminal B patient group, SF3B1 mutation was significantly associated with the OS (hazard ratio [HR]: 2.188, 95% confidence interval [CI]: 1.225-3.907, P = 0.008).	('OS', 'Chemical', '-', (85, 87))	('patient', 'Species', '9606', (17, 24))	('associated with', 'Reg', (65, 80))	('mutation', 'Var', (38, 46))	('SF3B1', 'Gene', (32, 37))
93145	29383138	In the PR-negative group, the SF3B1 mutation was also significantly associated with OS (HR: 1.845, 95% CI: 1.123-3.034, P = 0.016).	('SF3B1', 'Gene', (30, 35))	('associated with', 'Reg', (68, 83))	('mutation', 'Var', (36, 44))	('OS', 'Chemical', '-', (84, 86))	('PR', 'Gene', '5241', (7, 9))
93146	29383138	Kaplan-Meier survival analysis showed that the SF3B1 mutation was not an independent predictor for OS in breast cancer patients overall (log-rank test: P = 0.385).	('SF3B1', 'Gene', (47, 52))	('mutation', 'Var', (53, 61))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('OS', 'Chemical', '-', (99, 101))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
93147	29383138	In the luminal B and PR-negative groups, however, the SF3B1 mutation was a significantly independent prognostic factor for OS (log-rank test: P = 0.007 and P = 0.014, respectively) (Figure 2) Among 11 common prognostic factors investigated, univariate analysis showed that age, ER status, PR status, menopausal state, PAM50 and claudin-low subtype, and breast cancer type were significantly associated with SF3B1 mutation in all breast cancer patients (P < 0.01) (Table 3).	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('associated', 'Reg', (391, 401))	('breast cancer', 'Disease', 'MESH:D001943', (353, 366))	('breast cancer', 'Disease', 'MESH:D001943', (429, 442))	('PR', 'Gene', '5241', (289, 291))	('ER', 'Gene', '2099', (278, 280))	('breast cancer type', 'Disease', 'MESH:D001943', (353, 371))	('cancer', 'Phenotype', 'HP:0002664', (436, 442))	('breast cancer', 'Disease', (429, 442))	('breast cancer', 'Phenotype', 'HP:0003002', (353, 366))	('breast cancer', 'Phenotype', 'HP:0003002', (429, 442))	('PR', 'Gene', '5241', (21, 23))	('menopausal state', 'Phenotype', 'HP:0008209', (300, 316))	('patients', 'Species', '9606', (443, 451))	('breast cancer type', 'Disease', (353, 371))	('mutation', 'Var', (413, 421))	('OS', 'Chemical', '-', (123, 125))	('SF3B1', 'Gene', (407, 412))
93148	29383138	Age and ER status were significantly associated with SF3B1 mutation on multivariate analysis (odds ratio: 1.037, 95% CI: 1.007-1.067, P = 0.015; and odds ratio: 6.055, 95% CI: 1.253-29.253, P = 0.025; respectively).	('mutation', 'Var', (59, 67))	('associated', 'Reg', (37, 47))	('ER', 'Gene', '2099', (8, 10))	('SF3B1', 'Gene', (53, 58))
93149	29383138	Age and ER status were significantly associated with SF3B1 mutation specifically in the luminal B and PR-negative subgroups as well (P < 0.02).	('ER', 'Gene', '2099', (8, 10))	('mutation', 'Var', (59, 67))	('associated', 'Reg', (37, 47))	('PR', 'Gene', '5241', (102, 104))	('SF3B1', 'Gene', (53, 58))
93150	29383138	Receiver operating characteristic (ROC) curves were generated for all patients with breast cancer to identify the sensitivity and specificity of age at diagnosis and ER status in predicting SF3B1 mutation.	('patients', 'Species', '9606', (70, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('mutation', 'Var', (196, 204))	('ER', 'Gene', '2099', (166, 168))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('SF3B1', 'Gene', (190, 195))	('breast cancer', 'Disease', (84, 97))
93152	29383138	When age at diagnosis and ER status were assessed for their combined ability to predict SF3B1 mutation, the ROC curve showed a higher sensitivity and specificity of 66.2% and 69.0%, respectively, with an AUC of 0.690 (95% CI: 0.639-0.740, P < 0.000).	('SF3B1', 'Gene', (88, 93))	('mutation', 'Var', (94, 102))	('higher', 'PosReg', (127, 133))	('ER', 'Gene', '2099', (26, 28))
93155	29383138	When age at diagnosis and ER status were used in combination to predict SF3B1 mutation, the ROC curve showed a higher sensitivity and specificity of 82.6% and 70.8%, respectively, with an AUC of 0.756 (95% CI: 0.664-0.848, P < 0.000) (Figure 3).	('SF3B1', 'Gene', (72, 77))	('mutation', 'Var', (78, 86))	('higher', 'PosReg', (111, 117))	('ER', 'Gene', '2099', (26, 28))
93156	29383138	SF3b is essential for pre-mRNA splicing, and mutations in its largest subunit (SF3B1/SF3b155) are linked to cancer.	('mutations', 'Var', (45, 54))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('22', '39'))	('SF3b155', 'Gene', '23451', (85, 92))	('pre', 'molecular_function', 'GO:0003904', ('22', '25'))	('linked to', 'Reg', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('SF3b155', 'Gene', (85, 92))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
93157	29383138	The impact of SF3B1 mutations on patient outcomes varies according to tumor type; for instance, it is associated with poor outcomes in CLL patients but with good prognoses in uveal melanoma patients.	('patient', 'Species', '9606', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CLL', 'Disease', 'MESH:D015451', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('patients', 'Species', '9606', (139, 147))	('patients', 'Species', '9606', (190, 198))	('tumor', 'Disease', (70, 75))	('SF3B1', 'Gene', (14, 19))	('patient', 'Species', '9606', (139, 146))	('CLL', 'Phenotype', 'HP:0005550', (135, 138))	('CLL', 'Disease', (135, 138))	('uveal melanoma', 'Phenotype', 'HP:0007716', (175, 189))	('uveal melanoma', 'Disease', 'MESH:C536494', (175, 189))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('uveal melanoma', 'Disease', (175, 189))	('mutations', 'Var', (20, 29))	('patient', 'Species', '9606', (190, 197))
93161	29383138	in which whole genomes from 560 breast cancers and non-neoplastic tissue were sequenced revealed 3479652 somatic base substitutions, 371993 small indels, and 77695 rearrangements.	('371993', 'Var', (133, 139))	('3479652', 'Var', (97, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (55, 72))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast cancers', 'Phenotype', 'HP:0003002', (32, 46))	('breast cancers', 'Disease', 'MESH:D001943', (32, 46))	('breast cancers', 'Disease', (32, 46))	('77695', 'Var', (158, 163))
93162	29383138	An SF3B1 mutation can cause abnormal pre-RNA splicing that can lead to tumorigenesis, tumor drug resistance, or others detrimental features.	('mutation', 'Var', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('pre', 'molecular_function', 'GO:0003904', ('37', '40'))	('RNA', 'cellular_component', 'GO:0005562', ('41', '44'))	('tumor', 'Disease', (86, 91))	('SF3B1', 'Gene', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('drug resistance', 'biological_process', 'GO:0009315', ('92', '107'))	('drug resistance', 'biological_process', 'GO:0042493', ('92', '107'))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('lead to', 'Reg', (63, 70))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('RNA splicing', 'biological_process', 'GO:0008380', ('41', '53'))	('drug resistance', 'Phenotype', 'HP:0020174', (92, 107))
93163	29383138	Therefore, SF3B1 mutation may be useful as a prognostic indicator in different tumors.	('mutation', 'Var', (17, 25))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('SF3B1', 'Gene', (11, 16))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
93164	29383138	showed that mutations in driver genes were associated with the prognosis of breast cancer patients.	('associated with', 'Reg', (43, 58))	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('patients', 'Species', '9606', (90, 98))
93165	29383138	For instance, MAP3K1 and GATA3 mutations were associated with longer survival, and TP53 mutations with shorter survival, in ER-positive patients but not in ER-negative patients.	('TP53', 'Gene', '7157', (83, 87))	('mutations', 'Var', (31, 40))	('GATA3', 'Gene', (25, 30))	('GATA3', 'Gene', '2625', (25, 30))	('TP53', 'Gene', (83, 87))	('ER', 'Gene', '2099', (124, 126))	('mutations', 'Var', (88, 97))	('shorter', 'NegReg', (103, 110))	('MAP3K', 'molecular_function', 'GO:0004709', ('14', '19'))	('patients', 'Species', '9606', (136, 144))	('ER', 'Gene', '2099', (156, 158))	('MAP3K1', 'Gene', (14, 20))	('patients', 'Species', '9606', (168, 176))	('MAP3K1', 'Gene', '4214', (14, 20))
93166	29383138	Conversely, PIK3CA mutations were associated with shorter survival in ER-negative patients, but not in ER-positive patients.	('ER', 'Gene', '2099', (103, 105))	('PIK3CA', 'Gene', '5290', (12, 18))	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (82, 90))	('ER', 'Gene', '2099', (70, 72))	('mutations', 'Var', (19, 28))	('shorter', 'NegReg', (50, 57))	('PIK3CA', 'Gene', (12, 18))	('survival', 'MPA', (58, 66))
93167	29383138	Their study also showed associations between mutations in driver genes and clinicopathological parameters; for example, mutations in PIK3CA, GATA3, KMT2C, and CBFB were associated with lower grade tumors in ER-positive patients, while TP53 mutations were associated with higher grade tumors.	('PIK3CA', 'Gene', (133, 139))	('associated', 'Reg', (255, 265))	('ER', 'Gene', '2099', (207, 209))	('mutations', 'Var', (120, 129))	('TP53', 'Gene', (235, 239))	('tumors', 'Phenotype', 'HP:0002664', (284, 290))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('CBFB', 'Gene', '865', (159, 163))	('GATA3', 'Gene', '2625', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('patients', 'Species', '9606', (219, 227))	('tumors', 'Disease', (197, 203))	('GATA3', 'Gene', (141, 146))	('tumors', 'Disease', (284, 290))	('PIK3CA', 'Gene', '5290', (133, 139))	('TP53', 'Gene', '7157', (235, 239))	('KMT2C', 'Gene', '58508', (148, 153))	('KMT2C', 'Gene', (148, 153))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumors', 'Disease', 'MESH:D009369', (284, 290))	('associated', 'Reg', (169, 179))	('CBFB', 'Gene', (159, 163))
93168	29383138	GATA3, CBFB, CDH1, KMT2C, and SF3B1 mutations were also associated with age at diagnosis.	('CDH1', 'Gene', '999', (13, 17))	('GATA3', 'Gene', '2625', (0, 5))	('SF3B1', 'Gene', (30, 35))	('KMT2C', 'Gene', '58508', (19, 24))	('KMT2C', 'Gene', (19, 24))	('CBFB', 'Gene', (7, 11))	('mutations', 'Var', (36, 45))	('associated', 'Reg', (56, 66))	('GATA3', 'Gene', (0, 5))	('CBFB', 'Gene', '865', (7, 11))	('CDH1', 'Gene', (13, 17))
93169	29383138	In our study, we further analyzed the clinic value of SF3B1 mutations in breast cancer patents.	('SF3B1', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('breast cancer', 'Disease', (73, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('mutations', 'Var', (60, 69))
93170	29383138	SF3B1 mutations were not significantly associated with survival outcome in breast cancer patients overall.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('SF3B1', 'Gene', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('patients', 'Species', '9606', (89, 97))	('associated', 'Reg', (39, 49))	('mutations', 'Var', (6, 15))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
93172	29383138	In the PR-negative patient subgroup, SF3B1 mutations were associated with age at diagnosis, ER status, and histologic grade; in the luminal B subgroup, SF3B1 mutations were associated only with the age at diagnosis.	('patient', 'Species', '9606', (19, 26))	('associated', 'Reg', (58, 68))	('mutations', 'Var', (43, 52))	('SF3B1', 'Gene', (152, 157))	('SF3B1', 'Gene', (37, 42))	('ER', 'Gene', '2099', (92, 94))	('PR', 'Gene', '5241', (7, 9))
93173	29383138	The multivariate logistic regression model revealed that SF3B1 mutations were associated with age at diagnosis and ER status in all patients as well as in the PR-negative subgroup.	('mutations', 'Var', (63, 72))	('associated', 'Reg', (78, 88))	('SF3B1', 'Gene', (57, 62))	('PR', 'Gene', '5241', (159, 161))	('ER', 'Gene', '2099', (115, 117))	('patients', 'Species', '9606', (132, 140))
93174	29383138	Because SF3B1 mutations were associated with worse outcomes in the PR-negative and luminal B subgroups, we analyzed whether these mutations were significantly associated with the age at diagnosis and ER status with the hypothesis that the age and ER status can predicting the existence of an SF3B1 mutation.	('ER', 'Gene', '2099', (200, 202))	('associated', 'Reg', (159, 169))	('PR', 'Gene', '5241', (67, 69))	('mutations', 'Var', (14, 23))	('SF3B1', 'Gene', (8, 13))	('ER', 'Gene', '2099', (247, 249))
93175	29383138	We found that, when age at diagnosis and ER status were assessed in combination, the prediction of SF3B1 mutations had a slightly higher sensitivity, specificity, and AUC than the age at diagnosis in all patients.	('patients', 'Species', '9606', (204, 212))	('ER', 'Gene', '2099', (41, 43))	('higher', 'PosReg', (130, 136))	('SF3B1', 'Gene', (99, 104))	('mutations', 'Var', (105, 114))
93176	29383138	In the PR-negative subgroup, age and ER combined had a higher sensitivity (82.6%), specificity (70.8%), and AUC (0.756) in terms of predicting SF3B1 mutations than age alone.	('SF3B1', 'Gene', (143, 148))	('mutations', 'Var', (149, 158))	('PR', 'Gene', '5241', (7, 9))	('ER', 'Gene', '2099', (37, 39))
93177	29383138	showed that SF3B1 K700E mutations are associated with differential gene splicing in breast cancer, including of TMEM14C, RPL31, CRNDE, DYNLL1, ICA1, RPL24, and MTERFD3.	('SF3B1', 'Gene', (12, 17))	('RPL24', 'Gene', '6152', (149, 154))	('DYNLL1', 'Gene', (135, 141))	('RPL31', 'Gene', '6160', (121, 126))	('DYNLL1', 'Gene', '8655', (135, 141))	('TMEM14C', 'Gene', (112, 119))	('splicing', 'biological_process', 'GO:0045292', ('72', '80'))	('RPL31', 'Gene', (121, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('differential gene splicing', 'MPA', (54, 80))	('ICA1', 'Gene', '3382', (143, 147))	('ICA1', 'Gene', (143, 147))	('MTERFD3', 'Gene', (160, 167))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('K700E', 'Var', (18, 23))	('RPL24', 'Gene', (149, 154))	('TMEM14C', 'Gene', '51522', (112, 119))	('breast cancer', 'Disease', (84, 97))	('CRNDE', 'Gene', (128, 133))	('CRNDE', 'Gene', '643911', (128, 133))	('MTERFD3', 'Gene', '80298', (160, 167))	('K700E', 'Mutation', 'rs559063155', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
93178	29383138	Cell lines carrying the SF3B1 mutation were sensitive to the SF3b complex inhibitor spliceostatin A, which suppressed tumor growth.	('spliceostatin A', 'Chemical', 'MESH:C553684', (84, 99))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('SF3B1', 'Gene', (24, 29))	('mutation', 'Var', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('suppressed', 'NegReg', (107, 117))	('tumor', 'Disease', (118, 123))
93179	29383138	In conclusion, our analysis of TCGA revealed that SF3B1 mutations are frequently found in breast cancer patients, and that they are poor prognostic indicators in PR-negative and luminal B breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('mutations', 'Var', (56, 65))	('SF3B1', 'Gene', (50, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('breast cancer', 'Disease', (188, 201))	('PR', 'Gene', '5241', (162, 164))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('found', 'Reg', (81, 86))	('patients', 'Species', '9606', (202, 210))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('patients', 'Species', '9606', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
93180	29383138	SF3B1 mutations were found to be significantly associated with the age at diagnosis and/or ER status in PR-negative and luminal B breast cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('PR', 'Gene', '5241', (104, 106))	('SF3B1', 'Gene', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('patients', 'Species', '9606', (144, 152))	('ER', 'Gene', '2099', (91, 93))	('associated', 'Reg', (47, 57))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('mutations', 'Var', (6, 15))
93181	29383138	Moreover, combining the age at diagnosis and ER status could better predict the existence of SF3B1 mutations.	('ER', 'Gene', '2099', (45, 47))	('mutations', 'Var', (99, 108))	('SF3B1', 'Gene', (93, 98))
93182	29383138	As demonstrated by spliceostatin A, the SF3b complex may be a novel therapeutic target for breast cancer patients with SF3B1 mutations.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (125, 134))	('breast cancer', 'Disease', (91, 104))	('patients', 'Species', '9606', (105, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('SF3B1', 'Gene', (119, 124))	('spliceostatin A', 'Chemical', 'MESH:C553684', (19, 34))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
93183	29383138	We analyzed SF3B1 mutation data and clinic data of breast cancer patients from TCGA database (www.cbioportal.org/).	('SF3B1', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('mutation', 'Var', (18, 26))	('patients', 'Species', '9606', (65, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))
93185	29383138	There were 81 patients with SF3B1 mutations among 3817 patients with invasive breast carcinoma.	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (69, 94))	('SF3B1', 'Gene', (28, 33))	('breast carcinoma', 'Phenotype', 'HP:0003002', (78, 94))	('invasive breast carcinoma', 'Disease', (69, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (34, 43))
93192	29383138	The Cox proportional hazards model was used to estimate the HRs and CIs of potential prognostic factors in all patients, including that of SF3B1 mutation in the aforementioned subgroups.	('mutation', 'Var', (145, 153))	('Cox', 'Gene', '1351', (4, 7))	('Cox', 'Gene', (4, 7))	('SF3B1', 'Gene', (139, 144))	('patients', 'Species', '9606', (111, 119))
93194	29383138	We also assessed the combined effects of age at diagnosis and ER status on the occurrence of SF3B1 mutations.	('mutations', 'Var', (99, 108))	('ER', 'Gene', '2099', (62, 64))	('SF3B1', 'Gene', (93, 98))
93210	28688464	This association is plausible because levodopa is an intermediary product involved in melanin synthesis, and it has been shown to increase melanin and melanoma cell growth in plant and human cell studies, respectively.	('human', 'Species', '9606', (185, 190))	('melanin', 'Chemical', 'MESH:D008543', (139, 146))	('levodopa', 'Var', (38, 46))	('levodopa', 'Chemical', 'MESH:D007980', (38, 46))	('melanin', 'CPA', (139, 146))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('increase', 'PosReg', (130, 138))	('melanin', 'Chemical', 'MESH:D008543', (86, 93))	('melanin synthesis', 'biological_process', 'GO:0042438', ('86', '103'))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('cell growth', 'biological_process', 'GO:0016049', ('160', '171'))
93345	28688464	Certain genetic variations, including alpha-synuclein, parkin, and LRRK2 mutations, are also associated with development of PD and PD-associated dementia.	('dementia', 'Disease', (145, 153))	('alpha-synuclein', 'Gene', '6622', (38, 53))	('dementia', 'Disease', 'MESH:D003704', (145, 153))	('alpha-synuclein', 'Gene', (38, 53))	('PD', 'Disease', 'MESH:D010300', (131, 133))	('associated with', 'Reg', (93, 108))	('PD', 'Disease', 'MESH:D010300', (124, 126))	('dementia', 'Phenotype', 'HP:0000726', (145, 153))	('LRRK2', 'Gene', (67, 72))	('mutations', 'Var', (73, 82))	('LRRK2', 'Gene', '120892', (67, 72))
93413	23873690	The EGFR (#4267, clone D38B1, rabbit monoclonal), AKT (#4691, clone C67E7, rabbit monoclonal), AKT-S473 (#4060, clone D9E, rabbit monoclonal), E-cadherin (#3195, clone 24E10, rabbit monoclonal) and CTNNB1 (#9582, clone 6B3, rabbit monoclonal) antibodies were obtained from Cell Signaling Inc. (dilution 1:200) and C-Src-Y418, (#44660G, rabbit polyclonal) (dilution 1:200) from Invitrogen.	('AKT', 'Gene', '207', (50, 53))	('EGFR', 'Gene', (4, 8))	('rabbit', 'Species', '9986', (75, 81))	('#44660G', 'Var', (327, 334))	('C-Src', 'Gene', '6714', (314, 319))	('rabbit', 'Species', '9986', (123, 129))	('CTNNB1', 'Gene', '1499', (198, 204))	('AKT', 'Gene', '207', (95, 98))	('rabbit', 'Species', '9986', (175, 181))	('rabbit', 'Species', '9986', (224, 230))	('rabbit', 'Species', '9986', (336, 342))	('EGFR', 'Gene', '1956', (4, 8))	('cadherin', 'molecular_function', 'GO:0008014', ('145', '153'))	('AKT', 'Gene', (50, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('4', '8'))	('CTNNB1', 'Gene', (198, 204))	('C-Src', 'Gene', (314, 319))	('Signaling', 'biological_process', 'GO:0023052', ('278', '287'))	('rabbit', 'Species', '9986', (30, 36))	('AKT', 'Gene', (95, 98))	('E-cadherin', 'Gene', (143, 153))	('E-cadherin', 'Gene', '999', (143, 153))
93470	23873690	As shown in Figure 3A, we observed pronounced upregulation of activated EGFR (Tyr845), AKT (Ser473), c-Src (Tyr418) and PI3K (p101) in the MDA-9/Syntenin-transfected cells compared to empty vector-transfected cells.	('c-Src', 'Gene', '6714', (101, 106))	('AKT', 'Gene', (87, 90))	('p101', 'Gene', '23533', (126, 130))	('EGFR', 'Gene', '1956', (72, 76))	('Tyr845', 'Chemical', '-', (78, 84))	('Ser', 'cellular_component', 'GO:0005790', ('92', '95'))	('upregulation', 'PosReg', (46, 58))	('AKT', 'Gene', '207', (87, 90))	('Tyr418', 'Var', (108, 114))	('EGFR', 'molecular_function', 'GO:0005006', ('72', '76'))	('PI3K', 'molecular_function', 'GO:0016303', ('120', '124'))	('Tyr845', 'Var', (78, 84))	('EGFR', 'Gene', (72, 76))	('MDA-9', 'Gene', '6386', (139, 144))	('Tyr418', 'Chemical', '-', (108, 114))	('c-Src', 'Gene', (101, 106))	('Ser473', 'Var', (92, 98))	('Syntenin', 'Gene', '6386', (145, 153))	('p101', 'Gene', (126, 130))	('Ser473', 'Chemical', '-', (92, 98))	('Syntenin', 'Gene', (145, 153))	('MDA-9', 'Gene', (139, 144))	('activated', 'PosReg', (62, 71))
93471	23873690	Among the various EMT molecules examined, we observed marked upregulation of beta-catenin (Tyr333), vimentin and TCF4 (Figure 3B).	('Tyr333', 'Var', (91, 97))	('TCF4', 'Gene', '6934', (113, 117))	('vimentin', 'cellular_component', 'GO:0045098', ('100', '108'))	('upregulation', 'PosReg', (61, 73))	('vimentin', 'cellular_component', 'GO:0045099', ('100', '108'))	('beta-catenin', 'Gene', '1499', (77, 89))	('TCF4', 'Gene', (113, 117))	('Tyr333', 'Chemical', '-', (91, 97))	('EMT', 'biological_process', 'GO:0001837', ('18', '21'))	('vimentin', 'Gene', '7431', (100, 108))	('beta-catenin', 'Gene', (77, 89))	('vimentin', 'Gene', (100, 108))
93478	23873690	Marked downregulation of activated EGFR (Tyr845) and its downstream and interacting signaling molecules AKT (Ser473), PI3K (p101) and c-Src (Tyr418) (Figure 4D) were also evident in these clones.	('AKT', 'Gene', (104, 107))	('EGFR', 'Gene', '1956', (35, 39))	('downregulation', 'NegReg', (7, 21))	('EGFR', 'Gene', (35, 39))	('Ser473', 'Var', (109, 115))	('p101', 'Gene', (124, 128))	('c-Src', 'Gene', (134, 139))	('Ser473', 'Chemical', '-', (109, 115))	('p101', 'Gene', '23533', (124, 128))	('c-Src', 'Gene', '6714', (134, 139))	('EGFR', 'molecular_function', 'GO:0005006', ('35', '39'))	('Tyr845', 'Var', (41, 47))	('Ser', 'cellular_component', 'GO:0005790', ('109', '112'))	('Tyr845', 'Chemical', '-', (41, 47))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('Tyr418', 'Chemical', '-', (141, 147))	('PI3K', 'molecular_function', 'GO:0016303', ('118', '122'))	('AKT', 'Gene', '207', (104, 107))
93482	23873690	Of the various EMT molecules analyzed, we observed pronounced downregulation of beta-catenin (CTNNB1) (Tyr333) in all 3 MDA-9/Syntenin-KD UCC cell lines (Figure 4E).	('Syntenin', 'Gene', (126, 134))	('CTNNB1', 'Gene', '1499', (94, 100))	('Tyr333', 'Chemical', '-', (103, 109))	('Tyr333', 'Var', (103, 109))	('beta-catenin', 'Gene', (80, 92))	('EMT', 'biological_process', 'GO:0001837', ('15', '18'))	('downregulation', 'NegReg', (62, 76))	('beta-catenin', 'Gene', '1499', (80, 92))	('Syntenin', 'Gene', '6386', (126, 134))	('CTNNB1', 'Gene', (94, 100))	('MDA-9', 'Gene', (120, 125))	('MDA-9', 'Gene', '6386', (120, 125))
93494	23873690	To identify the potential binding site(s) of MDA-9/Syntenin necessary to interact with EGFR, we utilized HA-tagged wild type MDA-9/Syntenin and a deletion mutation construct with intact PDZ1/PDZ2 domains but lacking both N and C terminal domains (Figure S4).	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'molecular_function', 'GO:0005006', ('87', '91'))	('Syntenin', 'Gene', (51, 59))	('MDA-9', 'Gene', (45, 50))	('Syntenin', 'Gene', '6386', (131, 139))	('MDA-9', 'Gene', '6386', (45, 50))	('EGFR', 'Gene', (87, 91))	('MDA-9', 'Gene', (125, 130))	('deletion mutation', 'Var', (146, 163))	('MDA-9', 'Gene', '6386', (125, 130))	('binding', 'molecular_function', 'GO:0005488', ('26', '33'))	('Syntenin', 'Gene', (131, 139))	('lacking', 'NegReg', (208, 215))	('Syntenin', 'Gene', '6386', (51, 59))
93499	23873690	To determine whether the molecular changes observed in the cell lines was recapitulated in human samples, we performed immunohistochemical analysis with EGFR, beta-catenin (CTNNB1) (Tyr333), AKT (Ser473), c-Src (Tyr418) and E-cadherin antibodies in the same cohort of 44 primary tumors, described above.	('beta-catenin', 'Gene', (159, 171))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('beta-catenin', 'Gene', '1499', (159, 171))	('c-Src', 'Gene', '6714', (205, 210))	('EGFR', 'molecular_function', 'GO:0005006', ('153', '157'))	('AKT', 'Gene', '207', (191, 194))	('primary tumors', 'Disease', (271, 285))	('EGFR', 'Gene', (153, 157))	('Tyr418', 'Var', (212, 218))	('Ser', 'cellular_component', 'GO:0005790', ('196', '199'))	('CTNNB1', 'Gene', '1499', (173, 179))	('primary tumors', 'Disease', 'MESH:D009369', (271, 285))	('Tyr418', 'Chemical', '-', (212, 218))	('E-cadherin', 'Gene', (224, 234))	('E-cadherin', 'Gene', '999', (224, 234))	('Tyr333', 'Chemical', '-', (182, 188))	('Tyr333', 'Var', (182, 188))	('c-Src', 'Gene', (205, 210))	('cadherin', 'molecular_function', 'GO:0008014', ('226', '234'))	('EGFR', 'Gene', '1956', (153, 157))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('AKT', 'Gene', (191, 194))	('Ser473', 'Chemical', '-', (196, 202))	('CTNNB1', 'Gene', (173, 179))	('human', 'Species', '9606', (91, 96))
93502	23873690	Significantly higher expression of beta-catenin (CTNNB1) (Tyr333, p=0.002), AKT ((Ser473, p=0.001), c-Src (Tyr418, p=0.002) and lower expression of E-cadherin (p=0.006) was also evident in 43%, (19/44), 48% (21/44), 48% (21/44) and 50% (22/44) of primary tumors, respectively, compared to their corresponding normal counterparts (Table S2 and S3, Figure S5).	('AKT', 'Gene', '207', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('c-Src', 'Gene', '6714', (100, 105))	('E-cadherin', 'Gene', (148, 158))	('primary tumors', 'Disease', (247, 261))	('CTNNB1', 'Gene', '1499', (49, 55))	('Tyr333', 'Chemical', '-', (58, 64))	('Tyr333', 'Var', (58, 64))	('E-cadherin', 'Gene', '999', (148, 158))	('Ser473', 'Chemical', '-', (82, 88))	('higher', 'PosReg', (14, 20))	('Ser', 'cellular_component', 'GO:0005790', ('82', '85'))	('expression', 'MPA', (134, 144))	('primary tumors', 'Disease', 'MESH:D009369', (247, 261))	('AKT', 'Gene', (76, 79))	('CTNNB1', 'Gene', (49, 55))	('lower', 'NegReg', (128, 133))	('Tyr418', 'Chemical', '-', (107, 113))	('beta-catenin', 'Gene', (35, 47))	('beta-catenin', 'Gene', '1499', (35, 47))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('expression', 'MPA', (21, 31))	('cadherin', 'molecular_function', 'GO:0008014', ('150', '158'))	('c-Src', 'Gene', (100, 105))
93504	23873690	We observed alterations of some key regulatory molecules, such as EGFR, beta-catenin (CTNNB1) (Tyr333), AKT (Ser473), c-Src (Tyr418) and E-cadherin, following GOF/LOF analysis in the UCC cell lines that was recapitulated in the primary tumors.	('primary tumors', 'Disease', 'MESH:D009369', (228, 242))	('c-Src', 'Gene', '6714', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('AKT', 'Gene', '207', (104, 107))	('Tyr418', 'Var', (125, 131))	('beta-catenin', 'Gene', (72, 84))	('alterations', 'Reg', (12, 23))	('EGFR', 'Gene', (66, 70))	('beta-catenin', 'Gene', '1499', (72, 84))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('Tyr418', 'Chemical', '-', (125, 131))	('CTNNB1', 'Gene', '1499', (86, 92))	('cadherin', 'molecular_function', 'GO:0008014', ('139', '147'))	('E-cadherin', 'Gene', (137, 147))	('E-cadherin', 'Gene', '999', (137, 147))	('primary tumors', 'Disease', (228, 242))	('Tyr333', 'Chemical', '-', (95, 101))	('Ser', 'cellular_component', 'GO:0005790', ('109', '112'))	('Tyr333', 'Var', (95, 101))	('c-Src', 'Gene', (118, 123))	('EGFR', 'Gene', '1956', (66, 70))	('AKT', 'Gene', (104, 107))	('Ser473', 'Chemical', '-', (109, 115))	('CTNNB1', 'Gene', (86, 92))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
93505	23873690	To determine whether their alteration in concert with MDA-9/Syntenin was associated with disease progression, we performed a logistic regression model analysis utilizing these alterations alone and in various combinations with MDA-9/Syntenin overexpression.	('Syntenin', 'Gene', (233, 241))	('MDA-9', 'Gene', (227, 232))	('MDA-9', 'Gene', '6386', (227, 232))	('Syntenin', 'Gene', '6386', (60, 68))	('associated', 'Reg', (73, 83))	('alteration', 'Var', (27, 37))	('Syntenin', 'Gene', (60, 68))	('Syntenin', 'Gene', '6386', (233, 241))	('MDA-9', 'Gene', '6386', (54, 59))	('MDA-9', 'Gene', (54, 59))
93506	23873690	We observed a significant correlation between MDA-9/Syntenin and EGFR co-expression with clinical stage (p=0.04), but not with grade (p=0.28) or invasion (p=0.05) (Table S2).	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('MDA-9', 'Gene', '6386', (46, 51))	('Syntenin', 'Gene', (52, 60))	('MDA-9', 'Gene', (46, 51))	('co-expression', 'Var', (70, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('65', '69'))	('clinical stage', 'CPA', (89, 103))	('Syntenin', 'Gene', '6386', (52, 60))
93509	23873690	No significant association of these gene alterations was evident at a single gene level (except for MDA-9/Syntenin alone) or in a combination of all of the gene changes with any clinical parameter (p=0.92-0.08).	('Syntenin', 'Gene', (106, 114))	('MDA-9', 'Gene', (100, 105))	('MDA-9', 'Gene', '6386', (100, 105))	('Syntenin', 'Gene', '6386', (106, 114))	('alterations', 'Var', (41, 52))
93528	23873690	We also performed promoter methylation analysis hypothesizing hypomethylation as another potential mechanism of MDA-9/Syntenin activation.	('methylation', 'biological_process', 'GO:0032259', ('27', '38'))	('Syntenin', 'Gene', '6386', (118, 126))	('hypomethylation', 'Var', (62, 77))	('Syntenin', 'Gene', (118, 126))	('MDA-9', 'Gene', (112, 117))	('MDA-9', 'Gene', '6386', (112, 117))
93532	23873690	When phosphorylated at Tyr418, c-Src can phosphorylate EGFR at Tyr845 and Tyr1101 and thereby regulate EGFR functions and tumor progression.	('EGFR', 'Gene', '1956', (55, 59))	('regulate', 'Reg', (94, 102))	('c-Src', 'Gene', '6714', (31, 36))	('Tyr845', 'Chemical', '-', (63, 69))	('EGFR', 'Gene', '1956', (103, 107))	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('EGFR', 'Gene', (55, 59))	('EGFR', 'Gene', (103, 107))	('Tyr418', 'Chemical', '-', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('Tyr1101', 'Chemical', '-', (74, 81))	('Tyr418', 'Var', (23, 29))	('Tyr1101', 'Var', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))	('tumor', 'Disease', (122, 127))	('Tyr845', 'Var', (63, 69))	('c-Src', 'Gene', (31, 36))
93534	23873690	Notably, MDA-9/Syntenin depletion altered localization of EGFR and activated C-Src in the UCC cells, which could be associated with their functional impairment.	('C-Src', 'Gene', '6714', (77, 82))	('altered', 'Reg', (34, 41))	('men', 'Species', '9606', (155, 158))	('EGFR', 'Gene', '1956', (58, 62))	('activated', 'PosReg', (67, 76))	('localization', 'MPA', (42, 54))	('EGFR', 'Gene', (58, 62))	('Syntenin', 'Gene', '6386', (15, 23))	('depletion', 'Var', (24, 33))	('MDA-9', 'Gene', (9, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))	('C-Src', 'Gene', (77, 82))	('MDA-9', 'Gene', '6386', (9, 14))	('Syntenin', 'Gene', (15, 23))	('localization', 'biological_process', 'GO:0051179', ('42', '54'))
93541	23873690	Recently, c-Src mediated phosphorylation of beta-catenin at Y333 upon EGFR activation was implicated in tumorigenesis.	('at Y333', 'Var', (57, 64))	('implicated', 'Reg', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('phosphorylation', 'biological_process', 'GO:0016310', ('25', '40'))	('EGFR', 'Gene', '1956', (70, 74))	('tumor', 'Disease', (104, 109))	('activation', 'PosReg', (75, 85))	('beta-catenin', 'Gene', (44, 56))	('EGFR', 'molecular_function', 'GO:0005006', ('70', '74'))	('EGFR', 'Gene', (70, 74))	('beta-catenin', 'Gene', '1499', (44, 56))	('c-Src', 'Gene', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('c-Src', 'Gene', '6714', (10, 15))
93560	23873690	Along this pathway, induction of aberrant N-cadherin expression and silencing of E-cadherin transcription and an E-cadherin to N- cadherin switch during metastatic progression are also evident in various cancers.	('aberrant', 'Var', (33, 41))	('cadherin', 'molecular_function', 'GO:0008014', ('44', '52'))	('cadherin', 'molecular_function', 'GO:0008014', ('115', '123'))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('N-cadherin', 'Gene', (42, 52))	('silencing', 'NegReg', (68, 77))	('N-cadherin', 'Gene', '1000', (42, 52))	('transcription', 'MPA', (92, 105))	('cadherin', 'molecular_function', 'GO:0008014', ('83', '91'))	('N- cadherin', 'Gene', '1000', (127, 138))	('E-cadherin', 'Gene', (81, 91))	('E-cadherin', 'Gene', (113, 123))	('N- cadherin', 'Gene', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('E-cadherin', 'Gene', '999', (81, 91))	('E-cadherin', 'Gene', '999', (113, 123))	('expression', 'MPA', (53, 63))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cadherin', 'molecular_function', 'GO:0008014', ('130', '138'))	('cancers', 'Disease', (204, 211))	('transcription', 'biological_process', 'GO:0006351', ('92', '105'))
93563	23873690	Conversely, alteration of CTNNB1 and other key EMT-associated molecules in concert with EGFR results in the disruption of the adherens junctions and leads to muscle invasive disease (Figure 7).	('adherens junctions', 'MPA', (126, 144))	('alteration', 'Var', (12, 22))	('disruption', 'NegReg', (108, 118))	('CTNNB1', 'Gene', (26, 32))	('results in', 'Reg', (93, 103))	('EMT', 'biological_process', 'GO:0001837', ('47', '50'))	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('CTNNB1', 'Gene', '1499', (26, 32))	('EGFR', 'Gene', '1956', (88, 92))	('muscle invasive disease', 'Disease', 'MESH:D009135', (158, 181))	('muscle invasive disease', 'Disease', (158, 181))	('leads to', 'Reg', (149, 157))	('EGFR', 'Gene', (88, 92))
93595	33255843	According to Tabernero and Ellis et al., the VEGF signaling pathway is upregulated by EGFR expression and conversely, VEGF upregulation independent of EGFR signaling seems to contribute to resistance to therapies applying EGFR inhibitors.	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('VEGF', 'Gene', (118, 122))	('EGFR', 'Gene', '1956', (222, 226))	('VEGF signaling', 'biological_process', 'GO:0038084', ('45', '59'))	('EGFR', 'Gene', '1956', (86, 90))	('expression', 'Var', (91, 101))	('EGFR', 'molecular_function', 'GO:0005006', ('151', '155'))	('EGFR', 'Gene', (151, 155))	('EGFR', 'molecular_function', 'GO:0005006', ('222', '226'))	('upregulation', 'PosReg', (123, 135))	('EGFR', 'Gene', (222, 226))	('upregulated', 'PosReg', (71, 82))	('signaling pathway', 'biological_process', 'GO:0007165', ('50', '67'))	('VEGF', 'Gene', '7422', (45, 49))	('EGFR', 'Gene', (86, 90))	('VEGF', 'Gene', '7422', (118, 122))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))	('VEGF', 'Gene', (45, 49))	('EGFR', 'Gene', '1956', (151, 155))
93598	33255843	Thus, these changes may promote tumorigenesis and metastatic dissemination in a long run.	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('promote', 'PosReg', (24, 31))	('metastatic dissemination', 'CPA', (50, 74))	('tumor', 'Disease', (32, 37))	('changes', 'Var', (12, 19))
93630	33255843	After rinsing 3 times in EnVision  FLEX Wash Buffer (pH:7.6, 5 min each, (DM831, Dako, Glostrup, Denmark), sections were incubated in monoclonal antibody specific for VEGF (A-20; sc-152) in 1:100 (Santa Cruz Biotechnology, Dallas, TX, USA); for frizzled-6 (FZD6 (E-19; sc-32148) in 1:100 (Santa Cruz Biotechnology, Dallas, TX, USA) and for HIF-1A (Pab50130, Covalab, Villeurbanne, France) in 1:3000 at room temperature in wet chamber at 4  C overnight.	('HIF-1A', 'Gene', '3091', (340, 346))	('antibody', 'cellular_component', 'GO:0042571', ('145', '153'))	('FZD6', 'Gene', '8323', (257, 261))	('A-20', 'Gene', (173, 177))	('frizzled-6', 'Gene', '8323', (245, 255))	('VEGF', 'Gene', '7422', (167, 171))	('FZD6', 'Gene', (257, 261))	('HIF-1A', 'Gene', (340, 346))	('antibody', 'cellular_component', 'GO:0019815', ('145', '153'))	('antibody', 'cellular_component', 'GO:0019814', ('145', '153'))	('antibody', 'molecular_function', 'GO:0003823', ('145', '153'))	('VEGF', 'Gene', (167, 171))	('A-20', 'Gene', '7128', (173, 177))	('frizzled-6', 'Gene', (245, 255))	('Pab50130', 'Var', (348, 356))
93712	32825510	Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients The detection of somatic driver mutations by next-generation sequencing (NGS) is becoming increasingly important in the care of advanced melanoma patients.	('Melanoma', 'Disease', 'MESH:D008545', (34, 42))	('Melanoma', 'Disease', (34, 42))	('Influence', 'Reg', (56, 65))	('melanoma', 'Phenotype', 'HP:0002861', (256, 264))	('melanoma', 'Disease', (256, 264))	('Melanoma', 'Disease', 'MESH:D008545', (101, 109))	('patients', 'Species', '9606', (265, 273))	('Melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (256, 264))	('Melanoma', 'Disease', (101, 109))	('Melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('mutations', 'Var', (151, 160))	('Reveal', 'Reg', (27, 33))
93714	32825510	Besides determining the tumor mutational burden (TMB) and annotation of all genetic driver alterations, we investigated their potential as a predictor for resistance to immune checkpoint inhibitors (ICI) and as a distinguishing feature between melanoma subtypes.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('melanoma', 'Disease', 'MESH:D008545', (244, 252))	('tumor', 'Disease', (24, 29))	('TMB', 'Chemical', '-', (49, 52))	('alterations', 'Var', (91, 102))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('melanoma', 'Disease', (244, 252))
93716	32825510	Besides the typical hotspot mutation in BRAF and NRAS, we frequently observed CDKN2A deletions.	('BRAF', 'Gene', '673', (40, 44))	('NRAS', 'Gene', '4893', (49, 53))	('BRAF', 'Gene', (40, 44))	('deletions', 'Var', (85, 94))	('CDKN2A', 'Gene', (78, 84))	('CDKN2A', 'Gene', '1029', (78, 84))	('NRAS', 'Gene', (49, 53))	('observed', 'Reg', (69, 77))
93717	32825510	Acral and mucosal melanomas were dominated by CNV alterations affecting PDGFRA, KIT, CDK4, RICTOR, CCND2 and CHEK2.	('CHEK2', 'Gene', (109, 114))	('RICTOR', 'Gene', (91, 97))	('CCND2', 'Gene', (99, 104))	('CDK4', 'Gene', (85, 89))	('CHEK2', 'Gene', '11200', (109, 114))	('CCND2', 'Gene', '894', (99, 104))	('CDK', 'molecular_function', 'GO:0004693', ('85', '88'))	('KIT', 'Gene', '3815', (80, 83))	('alterations', 'Var', (50, 61))	('CDK4', 'Gene', '1019', (85, 89))	('mucosal melanomas', 'Disease', 'MESH:D008545', (10, 27))	('KIT', 'molecular_function', 'GO:0005020', ('80', '83'))	('mucosal melanomas', 'Disease', (10, 27))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))	('PDGFRA', 'Gene', '5156', (72, 78))	('PDGFRA', 'Gene', (72, 78))	('KIT', 'Gene', (80, 83))	('RICTOR', 'Gene', '253260', (91, 97))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))
93718	32825510	Uveal melanoma often had somatic SNVs in GNA11/Q and amplification of MYC in all cases.	('SNVs in', 'Var', (33, 40))	('amplification', 'Var', (53, 66))	('MYC', 'Gene', (70, 73))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('GNA11', 'Gene', (41, 46))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('GNA11', 'Gene', '2767', (41, 46))	('MYC', 'Gene', '4609', (70, 73))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
93719	32825510	A significantly higher incidence of BRAF V600 mutations and EGFR amplifications, PTEN and TP53 deletions was found in patients with disease progression while on ICI.	('BRAF', 'Gene', (36, 40))	('deletions', 'Var', (95, 104))	('disease', 'Disease', (132, 139))	('EGFR', 'molecular_function', 'GO:0005006', ('60', '64'))	('TP53', 'Gene', '7157', (90, 94))	('patients', 'Species', '9606', (118, 126))	('TP53', 'Gene', (90, 94))	('PTEN', 'Gene', (81, 85))	('EGFR', 'Gene', '1956', (60, 64))	('PTEN', 'Gene', '5728', (81, 85))	('EGFR', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (36, 40))
93721	32825510	In the last decade, multiple large-scale sequencing studies have elucidated the genetic landscape of cutaneous melanoma and led to the classification of the genetic subtypes BRAF mutant, RAS mutant, NF1 mutant or triple wild-type melanoma.	('mutant', 'Var', (203, 209))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('mutant', 'Var', (179, 185))	('melanoma', 'Disease', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('cutaneous melanoma', 'Disease', (101, 119))	('BRAF', 'Gene', '673', (174, 178))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (101, 119))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (101, 119))	('RAS', 'Protein', (187, 190))	('BRAF', 'Gene', (174, 178))	('melanoma', 'Disease', (230, 238))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('NF1', 'Gene', (199, 202))	('melanoma', 'Disease', 'MESH:D008545', (230, 238))	('NF1', 'Gene', '4763', (199, 202))
93723	32825510	Additionally, these comprehensive sequencing studies have revealed the genetic landscape not only for cutaneous melanoma but also for acral and mucosal melanoma, resulting in the identification of further driver alterations and highlighting the impact of copy number changes in these subtypes.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('mucosal melanoma', 'Disease', (144, 160))	('mucosal melanoma', 'Disease', 'MESH:D008545', (144, 160))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('cutaneous melanoma', 'Disease', (102, 120))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))	('alterations', 'Var', (212, 223))
93724	32825510	Especially in the light of treatment failure in patients treated with immunotherapy, certain genes and signaling cascades, like an amplification of MDM2 and EGFR, PTEN deletions and loss of functions mutations in JAK2 or the interferon gamma signaling were identified as potential markers of primary or acquired resistance.	('signaling', 'biological_process', 'GO:0023052', ('242', '251'))	('mutations', 'Var', (200, 209))	('primary', 'Disease', (292, 299))	('acquired resistance', 'Disease', (303, 322))	('EGFR', 'Gene', '1956', (157, 161))	('MDM2', 'Gene', '4193', (148, 152))	('interferon gamma', 'Gene', (225, 241))	('JAK', 'molecular_function', 'GO:0004713', ('213', '216'))	('interferon gamma', 'molecular_function', 'GO:0005133', ('225', '241'))	('PTEN', 'Gene', (163, 167))	('JAK2', 'Gene', '3717', (213, 217))	('amplification', 'PosReg', (131, 144))	('interferon gamma', 'Gene', '3458', (225, 241))	('PTEN', 'Gene', '5728', (163, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('157', '161'))	('signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('deletions', 'Var', (168, 177))	('JAK2', 'Gene', (213, 217))	('EGFR', 'Gene', (157, 161))	('patients', 'Species', '9606', (48, 56))	('MDM2', 'Gene', (148, 152))	('loss of functions', 'NegReg', (182, 199))
93727	32825510	We display the diversity of genetic mutations and affected pathways among this clinical cohort, highlighting both genetic differences and similarities among the melanoma subtypes and show potential genetic resistance mechanisms to ICI.	('melanoma', 'Disease', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('mutations', 'Var', (36, 45))
93737	32825510	Variants were annotated using SnpEff / SnpSift and the publicly available Cancer Genome Interpreter for information about driver alterations.	('Variants', 'Var', (0, 8))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Cancer', 'Disease', (74, 80))
93739	32825510	Since all three panel versions are designed to detect driver mutations in known tumor suppressor and oncogenes, we had to adjust the calculation to avoid overrating the TMB.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mutations', 'Var', (61, 70))	('tumor', 'Disease', (80, 85))	('TMB', 'Chemical', '-', (169, 172))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))
93745	32825510	Comprehensive sequencing of the 82 tumor samples identified in total 1650 somatic variants (SNVs and INDELs) and 2.137 somatic copy number alterations, such as amplification or deletion of a complete gene (Tables S5 and S6).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('amplification', 'Var', (160, 173))	('deletion', 'Var', (177, 185))	('tumor', 'Disease', (35, 40))
93747	32825510	Furthermore, we referred to CancerGenomeInterpreter.org for the annotation of driver mutations and revealed a total number of 527 driver alterations, 283 SNVs and 244 CNVs, affecting 149 genes (supplement Tables S8 and S9).	('Cancer', 'Disease', 'MESH:D009369', (28, 34))	('Cancer', 'Disease', (28, 34))	('mutations', 'Var', (85, 94))	('Cancer', 'Phenotype', 'HP:0002664', (28, 34))	('alterations', 'Var', (137, 148))	('affecting', 'Reg', (173, 182))
93751	32825510	Also, one patient had the BRAF G466E driver mutation, and another had two simultaneous driver mutations at positions P367S and K601E.	('K601E', 'Var', (127, 132))	('BRAF', 'Gene', '673', (26, 30))	('BRAF', 'Gene', (26, 30))	('patient', 'Species', '9606', (10, 17))	('G466E', 'Mutation', 'rs121913351', (31, 36))	('P367S', 'Var', (117, 122))	('K601E', 'Mutation', 'rs121913364', (127, 132))	('P367S', 'Mutation', 'p.P367S', (117, 122))
93752	32825510	The second most frequent mutation was the GTPase NRAS (24%) with Q61K/L/R mutations.	('NRAS', 'Gene', '4893', (49, 53))	('GTPase', 'Enzyme', (42, 48))	('Q61K', 'SUBSTITUTION', 'None', (65, 69))	('Q61K', 'Var', (65, 69))	('NRAS', 'Gene', (49, 53))
93754	32825510	Moreover, hotspot mutations in HRAS (Q61R) and KRAS (G12D, D119H) were present in one, two patients, respectively (not shown in Figure 1).	('HRAS', 'Gene', '3265', (31, 35))	('patients', 'Species', '9606', (91, 99))	('D119H', 'Mutation', 'p.D119H', (59, 64))	('Q61R', 'Mutation', 'rs121913233', (37, 41))	('D119H', 'Var', (59, 64))	('HRAS', 'Gene', (31, 35))	('G12D', 'Mutation', 'rs121913529', (53, 57))	('KRAS', 'Gene', (47, 51))	('KRAS', 'Gene', '3845', (47, 51))
93757	32825510	Besides driver mutations in the genes BRAF, NRAS and NF1, we found frequent activating amplifications in the receptor tyrosine kinases ERBB3 and MET, as well as in the signal transducers KRAS and PTPRD (Figure 1c).	('MET', 'Gene', '79811', (145, 148))	('NF1', 'Gene', (53, 56))	('PTPRD', 'Gene', (196, 201))	('mutations', 'Var', (15, 24))	('KRAS', 'Gene', (187, 191))	('PTPRD', 'Gene', '5789', (196, 201))	('NRAS', 'Gene', (44, 48))	('NF1', 'Gene', '4763', (53, 56))	('BRAF', 'Gene', '673', (38, 42))	('KRAS', 'Gene', '3845', (187, 191))	('MET', 'Gene', (145, 148))	('ERBB3', 'Gene', (135, 140))	('BRAF', 'Gene', (38, 42))	('ERBB3', 'Gene', '2065', (135, 140))	('NRAS', 'Gene', '4893', (44, 48))	('activating amplifications', 'PosReg', (76, 101))
93758	32825510	Interestingly, the activating mutations in ERBB3, MET and KRAS were more abundant in the triple wild-type group.	('ERBB3', 'Gene', (43, 48))	('KRAS', 'Gene', (58, 62))	('activating', 'PosReg', (19, 29))	('KRAS', 'Gene', '3845', (58, 62))	('mutations', 'Var', (30, 39))	('MET', 'Gene', '79811', (50, 53))	('ERBB3', 'Gene', '2065', (43, 48))	('MET', 'Gene', (50, 53))
93759	32825510	The genes most frequently affected by copy number alterations (deletion or amplification) were CDKN2A (24%) and CCND3 (23%), both of which belong to the cell cycle control (Figure 1c).	('copy number alterations', 'Var', (38, 61))	('CCND3', 'Gene', '896', (112, 117))	('CDKN2A', 'Gene', (95, 101))	('CCND3', 'Gene', (112, 117))	('cell cycle control', 'biological_process', 'GO:1901987', ('153', '171'))	('CDKN2A', 'Gene', '1029', (95, 101))
93761	32825510	The PI3K signaling cascade was the third most frequent mutated signaling pathway (38%) with driver mutations in the genes PTEN (17%) and RICTOR (12%).	('signaling cascade', 'biological_process', 'GO:0007165', ('9', '26'))	('signaling pathway', 'biological_process', 'GO:0007165', ('63', '80'))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('PI3K signaling', 'biological_process', 'GO:0014065', ('4', '18'))	('RICTOR', 'Gene', '253260', (137, 143))	('mutations', 'Var', (99, 108))	('mutated', 'Reg', (55, 62))	('PTEN', 'Gene', '5728', (122, 126))	('RICTOR', 'Gene', (137, 143))	('PTEN', 'Gene', (122, 126))	('PI3K signaling cascade', 'Pathway', (4, 26))
93762	32825510	Furthermore, we found frequent driver mutations in the Wnt and SWI/SNF signaling pathway (CTNNB1, ARID2, and SMARCA4).	('CTNNB1', 'Gene', '1499', (90, 96))	('ARID2', 'Gene', '196528', (98, 103))	('signaling pathway', 'biological_process', 'GO:0007165', ('71', '88'))	('ARID2', 'Gene', (98, 103))	('CTNNB1', 'Gene', (90, 96))	('mutations', 'Var', (38, 47))	('SMARCA4', 'Gene', (109, 116))	('SMARCA4', 'Gene', '6597', (109, 116))
93765	32825510	Both subtypes were dominated by somatic SNVs, leading to the highest number of mutations (median = 7) and a significantly higher TMB (median = 9.4, range = 0-36.4; p < 0.003) in patients with cutaneous melanoma compared to the other subtypes (Figure 2a, Table 2).	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (192, 210))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (192, 210))	('higher', 'PosReg', (122, 128))	('mutations', 'Var', (79, 88))	('patients', 'Species', '9606', (178, 186))	('TMB', 'MPA', (129, 132))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('TMB', 'Chemical', '-', (129, 132))	('cutaneous melanoma', 'Disease', (192, 210))
93772	32825510	Compared to cutaneous, acral and mucosal melanoma, there was no enrichment of mutations in the RTK/RAS signaling pathway, but frequent mutually exclusive mutations in the genes of the guanine nucleotide-binding protein subunits GNA11 and GNAQ in combination with either the splicing factor SF3B1 or the deubiquitinating enzyme BAP1 (Figure 3a,b).	('GNAQ', 'Gene', (238, 242))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('192', '210'))	('GNA11', 'Gene', (228, 233))	('SF3B1', 'Gene', (290, 295))	('BAP1', 'Gene', '8314', (327, 331))	('GNA11', 'Gene', '2767', (228, 233))	('protein', 'cellular_component', 'GO:0003675', ('211', '218'))	('signaling pathway', 'biological_process', 'GO:0007165', ('103', '120'))	('SF3B1', 'Gene', '23451', (290, 295))	('mucosal melanoma', 'Disease', (33, 49))	('BAP1', 'Gene', (327, 331))	('GNAQ', 'Gene', '2776', (238, 242))	('mutations', 'Var', (154, 163))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('303', '326'))	('splicing', 'biological_process', 'GO:0045292', ('274', '282'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (33, 49))
93773	32825510	Of note, we found MYC amplifications in each of the eight uveal melanoma patients, which is a significant difference to the other melanoma subtypes (p < 0.05).	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('MYC', 'Gene', (18, 21))	('melanoma', 'Disease', (64, 72))	('patients', 'Species', '9606', (73, 81))	('uveal melanoma', 'Disease', 'MESH:C536494', (58, 72))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Disease', (130, 138))	('MYC', 'Gene', '4609', (18, 21))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('uveal melanoma', 'Disease', (58, 72))	('amplifications', 'Var', (22, 36))
93774	32825510	On the other hand, hotspot mutations in the genes BRAF and NRAS, in combination with homozygous deletions of the gene CDKN2A, were frequently found in cutaneous melanoma.	('mutations', 'Var', (27, 36))	('hotspot', 'PosReg', (19, 26))	('cutaneous melanoma', 'Disease', (151, 169))	('CDKN2A', 'Gene', (118, 124))	('BRAF', 'Gene', (50, 54))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (151, 169))	('CDKN2A', 'Gene', '1029', (118, 124))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (151, 169))	('NRAS', 'Gene', (59, 63))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('BRAF', 'Gene', '673', (50, 54))	('found', 'Reg', (142, 147))	('NRAS', 'Gene', '4893', (59, 63))
93775	32825510	In contrast, acral and mucosal melanoma were dominated by copy number changes affecting the RTK/RAS pathway and regulators of the cell cycle (Figure 3a).	('mucosal melanoma', 'Disease', 'MESH:D008545', (23, 39))	('cell cycle', 'biological_process', 'GO:0007049', ('130', '140'))	('affecting', 'Reg', (78, 87))	('mucosal melanoma', 'Disease', (23, 39))	('copy number changes', 'Var', (58, 77))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('RTK/RAS pathway', 'Pathway', (92, 107))
93776	32825510	The co-amplifications of the receptor tyrosine kinases KIT and PDGFRA on chromosome 4, as well as CDK4 on chromosome 12, are of particular interest for acral melanoma.	('KIT', 'Gene', (55, 58))	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('acral melanoma', 'Phenotype', 'HP:0012060', (152, 166))	('acral melanoma', 'Disease', (152, 166))	('PDGFRA', 'Gene', (63, 69))	('KIT', 'molecular_function', 'GO:0005020', ('55', '58'))	('chromosome', 'cellular_component', 'GO:0005694', ('106', '116'))	('PDGFRA', 'Gene', '5156', (63, 69))	('CDK4', 'Gene', (98, 102))	('acral melanoma', 'Disease', 'MESH:D008545', (152, 166))	('CDK', 'molecular_function', 'GO:0004693', ('98', '101'))	('CDK4', 'Gene', '1019', (98, 102))	('KIT', 'Gene', '3815', (55, 58))	('co-amplifications', 'Var', (4, 21))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))
93777	32825510	Mucosal melanoma had a significant accumulation of amplification in the regulator of the cell cycle control CCND2 (Figure 3b).	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('cell cycle control', 'biological_process', 'GO:1901987', ('89', '107'))	('accumulation', 'PosReg', (35, 47))	('CCND2', 'Gene', '894', (108, 113))	('Mucosal melanoma', 'Disease', 'MESH:D008545', (0, 16))	('Mucosal melanoma', 'Disease', (0, 16))	('CCND2', 'Gene', (108, 113))	('amplification', 'Var', (51, 64))
93778	32825510	Furthermore, a member of the Fanconi anemia pathway, CHEK2, was enriched for deletions in mucosal melanoma.	('deletions', 'Var', (77, 86))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (29, 43))	('Fanconi anemia', 'Disease', (29, 43))	('mucosal melanoma', 'Disease', (90, 106))	('Fanconi anemia', 'Disease', 'MESH:D005199', (29, 43))	('mucosal melanoma', 'Disease', 'MESH:D008545', (90, 106))	('anemia', 'Phenotype', 'HP:0001903', (37, 43))	('CHEK2', 'Gene', '11200', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('CHEK2', 'Gene', (53, 58))
93781	32825510	Interestingly, most of the patients with PD and a BRAF mutation (16 of 18) had received therapy with BRAF and MEK inhibition (BRAF/MEKi) before initiation of ICI compared to those with stable disease or partial response (2 of 4) (Figure 4).	('BRAF', 'Gene', (101, 105))	('MEK', 'Gene', '5609', (131, 134))	('BRAF', 'Gene', (50, 54))	('patients', 'Species', '9606', (27, 35))	('MEK', 'Gene', (110, 113))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('MEK', 'Gene', (131, 134))	('MEK', 'Gene', '5609', (110, 113))	('mutation', 'Var', (55, 63))	('PD', 'Disease', 'MESH:D010300', (41, 43))	('BRAF', 'Gene', '673', (101, 105))	('BRAF', 'Gene', '673', (50, 54))
93784	32825510	The comparison of the OS between the three groups of patients, i.e., (a) melanoma BRAF wild-type, (b) BRAF mutant (BRAFmut) treatment naive and (c) pretreated with BRAF/MEKi (before ICI) melanoma showed a significantly better OS for patients in the first two groups (p = 0.01) (Figure S1b, Table S13).	('melanoma', 'Disease', (73, 81))	('melanoma BRAF', 'Disease', 'MESH:D008545', (73, 86))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('better', 'PosReg', (219, 225))	('patients', 'Species', '9606', (53, 61))	('BRAF', 'Gene', '673', (102, 106))	('BRAF', 'Gene', (102, 106))	('MEK', 'Gene', '5609', (169, 172))	('melanoma BRAF', 'Disease', (73, 86))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('BRAF', 'Gene', '673', (164, 168))	('MEK', 'Gene', (169, 172))	('BRAF', 'Gene', (164, 168))	('patients', 'Species', '9606', (233, 241))	('BRAF', 'Gene', '673', (115, 119))	('mutant', 'Var', (107, 113))	('BRAF', 'Gene', (115, 119))	('BRAF', 'Gene', '673', (82, 86))	('BRAF', 'Gene', (82, 86))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
93786	32825510	For instance, mutations in PTEN and amplifications of EGFR have previously been linked to resistance to ICI.	('PTEN', 'Gene', '5728', (27, 31))	('mutations', 'Var', (14, 23))	('EGFR', 'molecular_function', 'GO:0005006', ('54', '58'))	('linked to', 'Reg', (80, 89))	('EGFR', 'Gene', '1956', (54, 58))	('PTEN', 'Gene', (27, 31))	('EGFR', 'Gene', (54, 58))	('amplifications', 'Var', (36, 50))	('resistance', 'Disease', (90, 100))
93787	32825510	Mutations in TP53 have been associated with prolonged progression-free survival in lung cancer after immunotherapy, but also to increased ICI resistance in melanoma.	('TP53', 'Gene', (13, 17))	('prolonged', 'PosReg', (44, 53))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('melanoma', 'Disease', (156, 164))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('associated', 'Reg', (28, 38))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('increased', 'PosReg', (128, 137))	('lung cancer', 'Disease', (83, 94))	('Mutations', 'Var', (0, 9))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('TP53', 'Gene', '7157', (13, 17))	('ICI resistance', 'MPA', (138, 152))
93788	32825510	Indeed, we observed in our cohort that mutations in PTEN and EGFR are enriched in the PD group (24.5% and 13.3%) compared to the SD+PR group (10% and 0%), although only the difference for EGFR is borderline significant.	('PTEN', 'Gene', (52, 56))	('PTEN', 'Gene', '5728', (52, 56))	('mutations', 'Var', (39, 48))	('EGFR', 'Gene', '1956', (188, 192))	('PD', 'Disease', 'MESH:D010300', (86, 88))	('EGFR', 'molecular_function', 'GO:0005006', ('188', '192'))	('EGFR', 'molecular_function', 'GO:0005006', ('61', '65'))	('SD+PR', 'Gene', '8436', (129, 134))	('SD+PR', 'Gene', (129, 134))	('EGFR', 'Gene', (188, 192))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
93789	32825510	As previously suggested for melanoma, we also found that TP53 mutations are enriched in the PD (13.3%) compared to the SD+PR group (3.3%).	('melanoma', 'Disease', (28, 36))	('SD+PR', 'Gene', '8436', (119, 124))	('SD+PR', 'Gene', (119, 124))	('PD', 'Disease', 'MESH:D010300', (92, 94))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
93791	32825510	Combining these features in a multi-gene predictor of resistance to ICI, we observed that patients who are either pretreated with BRAF/MEKi or have a mutation in at least one of the genes PTEN, EGFR or TP53 are highly likely to show PD (84.4%, p = 0.0002; Table S14).	('TP53', 'Gene', (202, 206))	('EGFR', 'molecular_function', 'GO:0005006', ('194', '198'))	('BRAF', 'Gene', '673', (130, 134))	('mutation', 'Var', (150, 158))	('PD', 'Disease', 'MESH:D010300', (233, 235))	('BRAF', 'Gene', (130, 134))	('PTEN', 'Gene', (188, 192))	('S14', 'Gene', (262, 265))	('PTEN', 'Gene', '5728', (188, 192))	('EGFR', 'Gene', '1956', (194, 198))	('EGFR', 'Gene', (194, 198))	('S14', 'Gene', '6208', (262, 265))	('MEK', 'Gene', (135, 138))	('MEK', 'Gene', '5609', (135, 138))	('patients', 'Species', '9606', (90, 98))	('TP53', 'Gene', '7157', (202, 206))
93792	32825510	Accordingly, the relative risk (RR) to show PD in the first staging after starting with ICI was 1.99 for cases in which the tumor harbors a mutation in EGFR, PTEN or TP53 or the patient was pretreated with BRAF/MEKi.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('PD', 'Disease', 'MESH:D010300', (44, 46))	('PTEN', 'Gene', (158, 162))	('patient', 'Species', '9606', (178, 185))	('TP53', 'Gene', '7157', (166, 170))	('tumor', 'Disease', (124, 129))	('mutation', 'Var', (140, 148))	('EGFR', 'Gene', '1956', (152, 156))	('BRAF', 'Gene', '673', (206, 210))	('TP53', 'Gene', (166, 170))	('EGFR', 'Gene', (152, 156))	('BRAF', 'Gene', (206, 210))	('MEK', 'Gene', (211, 214))	('PTEN', 'Gene', '5728', (158, 162))	('MEK', 'Gene', '5609', (211, 214))	('EGFR', 'molecular_function', 'GO:0005006', ('152', '156'))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
93794	32825510	We also tested if a mutation in at least one of the genes PTEN, EGFR or TP53 alone (excluding BRAF/MEKi pretreatment as a feature) is a predictor of PD, which indeed is the case (82% show PD, p = 0.007), although only 42% of the PD patients (19/45) are identified with this reduced combination (RR = 1.65).	('MEK', 'Gene', '5609', (99, 102))	('PD', 'Disease', 'MESH:D010300', (229, 231))	('BRAF', 'Gene', (94, 98))	('PTEN', 'Gene', '5728', (58, 62))	('TP53', 'Gene', '7157', (72, 76))	('patients', 'Species', '9606', (232, 240))	('PD', 'Disease', 'MESH:D010300', (188, 190))	('mutation', 'Var', (20, 28))	('TP53', 'Gene', (72, 76))	('MEK', 'Gene', (99, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('EGFR', 'Gene', '1956', (64, 68))	('PD', 'Disease', 'MESH:D010300', (149, 151))	('EGFR', 'Gene', (64, 68))	('BRAF', 'Gene', '673', (94, 98))	('PTEN', 'Gene', (58, 62))
93795	32825510	We have previously reported that deletions or loss of function mutations in CDKN2A increase the resistance to ICI.	('mutations', 'Var', (63, 72))	('CDKN2A', 'Gene', '1029', (76, 82))	('increase', 'PosReg', (83, 91))	('resistance to ICI', 'MPA', (96, 113))	('CDKN2A', 'Gene', (76, 82))	('loss of function', 'NegReg', (46, 62))	('deletions', 'Var', (33, 42))
93796	32825510	Similarly, we find that CDKN2A deletions or loss of heterozygosity are enriched in PD (p = 0.024).	('CDKN2A', 'Gene', (24, 30))	('PD', 'Disease', 'MESH:D010300', (83, 85))	('deletions', 'Var', (31, 40))	('CDKN2A', 'Gene', '1029', (24, 30))	('loss of', 'NegReg', (44, 51))
93797	32825510	However, mutations are mostly redundant to the already included genes, i.e., many patients with CDKN2A deletion also harbor a mutation in PTEN, EGFR or TP53.	('CDKN2A', 'Gene', '1029', (96, 102))	('EGFR', 'Gene', (144, 148))	('PTEN', 'Gene', (138, 142))	('EGFR', 'molecular_function', 'GO:0005006', ('144', '148'))	('PTEN', 'Gene', '5728', (138, 142))	('patients', 'Species', '9606', (82, 90))	('TP53', 'Gene', '7157', (152, 156))	('mutation', 'Var', (126, 134))	('EGFR', 'Gene', '1956', (144, 148))	('TP53', 'Gene', (152, 156))	('CDKN2A', 'Gene', (96, 102))	('deletion', 'Var', (103, 111))
93799	32825510	Another well-known resistance gene, JAK2, was only mutated in three patients, two of which additionally harbored a PTEN or an EGFR mutation.	('JAK2', 'Gene', (36, 40))	('EGFR', 'Gene', (126, 130))	('EGFR', 'molecular_function', 'GO:0005006', ('126', '130'))	('PTEN', 'Gene', (115, 119))	('PTEN', 'Gene', '5728', (115, 119))	('JAK', 'molecular_function', 'GO:0004713', ('36', '39'))	('patients', 'Species', '9606', (68, 76))	('JAK2', 'Gene', '3717', (36, 40))	('EGFR', 'Gene', '1956', (126, 130))	('mutation', 'Var', (131, 139))
93800	32825510	The highest specificity of 100% (30/30) is observed for any combination of the above changes in EGFR, PTEN, TP53 and CDKN2A.	('TP53', 'Gene', '7157', (108, 112))	('EGFR', 'Gene', (96, 100))	('TP53', 'Gene', (108, 112))	('changes', 'Var', (85, 92))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('CDKN2A', 'Gene', (117, 123))	('PTEN', 'Gene', (102, 106))	('PTEN', 'Gene', '5728', (102, 106))	('CDKN2A', 'Gene', '1029', (117, 123))	('EGFR', 'Gene', '1956', (96, 100))
93802	32825510	In this study, we aimed to evaluate TMB and driver mutations in a real-world cohort of patients with cutaneous, acral, mucosal and uveal melanoma and melanoma of unknown primary.	('cutaneous', 'Disease', (101, 110))	('uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))	('uveal melanoma', 'Disease', 'MESH:C536494', (131, 145))	('mutations', 'Var', (51, 60))	('uveal melanoma', 'Disease', (131, 145))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('TMB', 'Chemical', '-', (36, 39))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('patients', 'Species', '9606', (87, 95))
93804	32825510	All subtypes were characterized by driver mutations in the genes of the RTK/RAS signaling pathway as well as cell cycle control and the PI3K pathway, except for patients with uveal melanoma.	('cell cycle', 'CPA', (109, 119))	('signaling pathway', 'biological_process', 'GO:0007165', ('80', '97'))	('cell cycle control', 'biological_process', 'GO:1901987', ('109', '127'))	('uveal melanoma', 'Disease', (175, 189))	('RTK/RAS signaling pathway', 'Pathway', (72, 97))	('PI3K', 'molecular_function', 'GO:0016303', ('136', '140'))	('patients', 'Species', '9606', (161, 169))	('PI3K pathway', 'Pathway', (136, 148))	('uveal melanoma', 'Disease', 'MESH:C536494', (175, 189))	('uveal melanoma', 'Phenotype', 'HP:0007716', (175, 189))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('mutations', 'Var', (42, 51))
93805	32825510	This subtype was dominated by amplification of MYC and GNA11 or GNAQ mutations in combination with the genes BAP1 or SF3B1.	('mutations', 'Var', (69, 78))	('GNAQ', 'Gene', (64, 68))	('BAP1', 'Gene', '8314', (109, 113))	('amplification', 'Var', (30, 43))	('MYC', 'Gene', '4609', (47, 50))	('SF3B1', 'Gene', (117, 122))	('GNAQ', 'Gene', '2776', (64, 68))	('BAP1', 'Gene', (109, 113))	('MYC', 'Gene', (47, 50))	('SF3B1', 'Gene', '23451', (117, 122))	('GNA11', 'Gene', (55, 60))	('GNA11', 'Gene', '2767', (55, 60))
93806	32825510	The high frequency of MYC amplification has been described in previous works, and it is known that high expression of MYC in tumors is associated with an increased risk of developing metastases and a worse prognosis.	('MYC', 'Gene', '4609', (22, 25))	('high expression', 'Var', (99, 114))	('metastases', 'Disease', (183, 193))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('associated', 'Reg', (135, 145))	('MYC', 'Gene', (118, 121))	('metastases', 'Disease', 'MESH:D009362', (183, 193))	('MYC', 'Gene', (22, 25))	('MYC', 'Gene', '4609', (118, 121))
93807	32825510	Furthermore, we found mutual exclusivity of SF3B1 or BAP1 driver mutations in all patients with uveal melanoma.	('SF3B1', 'Gene', (44, 49))	('uveal melanoma', 'Disease', 'MESH:C536494', (96, 110))	('uveal melanoma', 'Disease', (96, 110))	('patients', 'Species', '9606', (82, 90))	('SF3B1', 'Gene', '23451', (44, 49))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('BAP1', 'Gene', '8314', (53, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('mutations', 'Var', (65, 74))	('BAP1', 'Gene', (53, 57))
93811	32825510	The other three subtypes, as well as melanoma of unknown primary, were, as mentioned above, dominated by driver mutations in the genes of the cell cycle control (CDKN2A) and the RTK/RAS signaling pathway (BRAF, NRAS, ERRB2).	('cell cycle control', 'biological_process', 'GO:1901987', ('142', '160'))	('BRAF', 'Gene', (205, 209))	('CDKN2A', 'Gene', (162, 168))	('signaling pathway', 'biological_process', 'GO:0007165', ('186', '203'))	('NRAS', 'Gene', (211, 215))	('CDKN2A', 'Gene', '1029', (162, 168))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('NRAS', 'Gene', '4893', (211, 215))	('mutations', 'Var', (112, 121))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('BRAF', 'Gene', '673', (205, 209))
93817	32825510	The driver mutations in the genes RICTOR, CDK4, PDGFRA, KIT were specific for acral melanoma, while the amplification or deletion of the genes CCND2 and CHEK2 are uniquely found in mucosal melanoma.	('mutations', 'Var', (11, 20))	('acral melanoma', 'Disease', 'MESH:D008545', (78, 92))	('KIT', 'molecular_function', 'GO:0005020', ('56', '59'))	('acral melanoma', 'Phenotype', 'HP:0012060', (78, 92))	('RICTOR', 'Gene', (34, 40))	('KIT', 'Gene', '3815', (56, 59))	('CHEK2', 'Gene', (153, 158))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('CDK4', 'Gene', (42, 46))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('CHEK2', 'Gene', '11200', (153, 158))	('mucosal melanoma', 'Disease', 'MESH:D008545', (181, 197))	('acral melanoma', 'Disease', (78, 92))	('CCND2', 'Gene', (143, 148))	('amplification', 'Var', (104, 117))	('mucosal melanoma', 'Disease', (181, 197))	('CCND2', 'Gene', '894', (143, 148))	('CDK4', 'Gene', '1019', (42, 46))	('PDGFRA', 'Gene', '5156', (48, 54))	('PDGFRA', 'Gene', (48, 54))	('CDK', 'molecular_function', 'GO:0004693', ('42', '45'))	('KIT', 'Gene', (56, 59))	('RICTOR', 'Gene', '253260', (34, 40))
93818	32825510	Furthermore, the comparison of driver gene mutations in patients with PD compared to patients with SD+PR under ICI treatment revealed enrichment of EGFR, PTEN and TP53 gene mutations together with BRAF V600 mutations, if pretreated with BRAF/MEKi.	('patients', 'Species', '9606', (56, 64))	('MEK', 'Gene', '5609', (242, 245))	('EGFR', 'Gene', '1956', (148, 152))	('patients', 'Species', '9606', (85, 93))	('MEK', 'Gene', (242, 245))	('TP53', 'Gene', (163, 167))	('PD', 'Disease', 'MESH:D010300', (70, 72))	('BRAF', 'Gene', '673', (237, 241))	('PTEN', 'Gene', (154, 158))	('BRAF', 'Gene', (237, 241))	('SD+PR', 'Gene', '8436', (99, 104))	('BRAF', 'Gene', (197, 201))	('BRAF', 'Gene', '673', (197, 201))	('mutations', 'Var', (173, 182))	('PTEN', 'Gene', '5728', (154, 158))	('SD+PR', 'Gene', (99, 104))	('TP53', 'Gene', '7157', (163, 167))	('EGFR', 'Gene', (148, 152))	('EGFR', 'molecular_function', 'GO:0005006', ('148', '152'))
93819	32825510	We observed an 84.4% chance of progressive disease under ICI (p = 0.0002) for cases where the tumor harbors a mutation in one of these genes, or the patient was pretreated with BRAF/MEKi.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('MEK', 'Gene', (182, 185))	('MEK', 'Gene', '5609', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('BRAF', 'Gene', (177, 181))	('BRAF', 'Gene', '673', (177, 181))	('tumor', 'Disease', (94, 99))	('progressive', 'Disease', (31, 42))	('patient', 'Species', '9606', (149, 156))	('mutation', 'Var', (110, 118))
93822	32825510	Several studies in non-small-cell lung cancer have already shown the ineffectiveness of ICI in the case of tumors with EGFR mutations and low TMB.	('EGFR', 'molecular_function', 'GO:0005006', ('119', '123'))	('mutations', 'Var', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('lung cancer', 'Disease', (34, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('TMB', 'Chemical', '-', (142, 145))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('EGFR', 'Gene', '1956', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (19, 45))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (23, 45))	('EGFR', 'Gene', (119, 123))
93824	32825510	Moreover, an increased risk of progressive disease at the first staging was associated with the presence of PTEN and TP53 driver mutations.	('presence', 'Var', (96, 104))	('PTEN', 'Gene', (108, 112))	('TP53', 'Gene', '7157', (117, 121))	('PTEN', 'Gene', '5728', (108, 112))	('mutations', 'Var', (129, 138))	('TP53', 'Gene', (117, 121))	('progressive', 'Disease', (31, 42))
93825	32825510	Besides, driver mutations in the cyclin-dependent kinases CDKN2A, CDK4, CCND1/2/3 and the genes MDM2/4 and TP53 were abundant, which presumably contribute to significant deregulation of cell cycle control.	('MDM2/4', 'Gene', '4193;4194', (96, 102))	('CCND1/2/3', 'Gene', (72, 81))	('MDM2/4', 'Gene', (96, 102))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('mutations', 'Var', (16, 25))	('cyclin', 'molecular_function', 'GO:0016538', ('33', '39'))	('CCND1/2/3', 'Gene', '595;894;896', (72, 81))	('CDK', 'molecular_function', 'GO:0004693', ('66', '69'))	('cell cycle control', 'CPA', (186, 204))	('CDKN2A', 'Gene', (58, 64))	('cell cycle control', 'biological_process', 'GO:1901987', ('186', '204'))	('CDK4', 'Gene', (66, 70))	('CDKN2A', 'Gene', '1029', (58, 64))	('CDK4', 'Gene', '1019', (66, 70))
93826	32825510	Deletions of gene CDKN2A appear to lead to resistance to immunotherapy and, in combination with the deregulation of CDK4, worsen prognosis in acral melanoma.	('CDKN2A', 'Gene', '1029', (18, 24))	('acral melanoma', 'Disease', (142, 156))	('worsen', 'PosReg', (122, 128))	('resistance to immunotherapy', 'CPA', (43, 70))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('acral melanoma', 'Phenotype', 'HP:0012060', (142, 156))	('CDK', 'molecular_function', 'GO:0004693', ('116', '119'))	('CDK4', 'Gene', '1019', (116, 120))	('CDK4', 'Gene', (116, 120))	('lead to', 'Reg', (35, 42))	('acral melanoma', 'Disease', 'MESH:D008545', (142, 156))	('CDKN2A', 'Gene', (18, 24))	('Deletions', 'Var', (0, 9))
93829	32825510	Another potential treatment targets are driver mutations in the genes ATM, CHEK2, FANCA, FANCC and BRCA2, which belong to the DNA repair signaling pathway.	('CHEK2', 'Gene', '11200', (75, 80))	('FANCA', 'Gene', '2175', (82, 87))	('FANCC', 'Gene', '2176', (89, 94))	('ATM', 'Gene', '472', (70, 73))	('FANCC', 'Gene', (89, 94))	('mutations', 'Var', (47, 56))	('FANCA', 'Gene', (82, 87))	('signaling pathway', 'biological_process', 'GO:0007165', ('137', '154'))	('BRCA2', 'Gene', (99, 104))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('DNA repair', 'biological_process', 'GO:0006281', ('126', '136'))	('CHEK2', 'Gene', (75, 80))	('BRCA2', 'Gene', '675', (99, 104))	('ATM', 'Gene', (70, 73))
93842	32825510	Furthermore, in patients with a progressive disease, we found a strong enrichment of cases with a mutation in at least one of the genes BRAF, EGFR, PTEN, TP53 or CDKN2A.	('PTEN', 'Gene', (148, 152))	('PTEN', 'Gene', '5728', (148, 152))	('CDKN2A', 'Gene', (162, 168))	('mutation', 'Var', (98, 106))	('TP53', 'Gene', (154, 158))	('BRAF', 'Gene', '673', (136, 140))	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('CDKN2A', 'Gene', '1029', (162, 168))	('patients', 'Species', '9606', (16, 24))	('BRAF', 'Gene', (136, 140))	('EGFR', 'molecular_function', 'GO:0005006', ('142', '146'))	('TP53', 'Gene', '7157', (154, 158))
93844	32825510	Figure S1: Shown is the survival of the 75 patients who received immunocheckpoint therapy depending on response group (a) and the influence of BRAF mutation status and previous treatments (b).	('patients', 'Species', '9606', (43, 51))	('mutation', 'Var', (148, 156))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))
93855	32825510	Table S13: Overall survival based on BRAF mutation status and pretreatment with BRAF/MEK inhibitors.	('MEK', 'Gene', '5609', (85, 88))	('BRAF', 'Gene', (80, 84))	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('BRAF', 'Gene', '673', (80, 84))	('MEK', 'Gene', (85, 88))
93862	31960425	Monosomy 3 (M3), polysomy 8q, and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses.	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('BAP1', 'Gene', (34, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (55, 69))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('loss', 'NegReg', (39, 43))	('polysomy 8q', 'Var', (17, 28))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (47, 69))	('primary uveal melanoma', 'Disease', (47, 69))	('BAP1', 'Gene', '8314', (34, 38))
93880	31960425	Monosomy 3 (M3) has long been known to be associated with increased risk of UM metastasis 9, 10, 11, and more recently, it has become apparent that this is primarily due to inactivating mutations of the BAP1 gene, which has been reported to be a stronger prognosticator than M3 12, 13.	('BAP1', 'Gene', '8314', (203, 207))	('Monosomy', 'Var', (0, 8))	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('BAP1', 'Gene', (203, 207))	('inactivating mutations', 'Var', (173, 195))	('UM metastasis', 'CPA', (76, 89))
93884	31960425	Interestingly, previous work showed that loss of BAP1 in turn affects the expression of genes that impact the immune response 16.	('loss', 'Var', (41, 45))	('BAP1', 'Gene', (49, 53))	('impact', 'Reg', (99, 105))	('BAP1', 'Gene', '8314', (49, 53))	('immune response', 'biological_process', 'GO:0006955', ('110', '125'))	('affects', 'Reg', (62, 69))	('immune response', 'CPA', (110, 125))	('expression of genes', 'MPA', (74, 93))
93891	31960425	Supervised clustering of immune genes of the TCGA RNA-seq dataset was performed among those with significant Spearman's correlation to BAP1 expression or chromosome 3 copy number variation and sorted from the lowest rank (negative correlation) to the highest rank (positive correlation).	('copy number variation', 'Var', (167, 188))	('chromosome', 'cellular_component', 'GO:0005694', ('154', '164'))	('BAP1', 'Gene', '8314', (135, 139))	('BAP1', 'Gene', (135, 139))	('RNA', 'cellular_component', 'GO:0005562', ('50', '53'))
93928	31960425	The correlation between different mRNA expressions and overall survivals (OS) of TCGA-UM patients was evaluated by non-parametric Spearman's correlation, two-tailed, where *0.01 < p < 0.05, **0.001 < p < 0.01; ***0.0001 < p < 0.001, and ****p < 0.0001 were considered to indicate significant differences.	('****p', 'Var', (237, 242))	('UM', 'Phenotype', 'HP:0007716', (86, 88))	('TCGA-UM', 'Gene', (81, 88))	('patients', 'Species', '9606', (89, 97))	('**0.001 < p < 0.01; ***0.0001 < p < 0.001', 'Var', (190, 231))
93932	31960425	In addition, only about 50% of these genes are significantly associated with patient survival, indicated by blue squares representative of Kaplan-Meier statistical test results (Figure 1B and supplementary material, Table S5).	('genes', 'Var', (37, 42))	('associated', 'Reg', (61, 71))	('patient', 'Species', '9606', (77, 84))	('patient survival', 'CPA', (77, 93))
93935	31960425	Among 181 immune genes that significantly correlated with both BAP1 expression and chromosome 3 copy number variation, 151 genes were negatively correlated and 30 genes were positively correlated, all with a higher correlation score to BAP1 expression than to chromosome 3 (r scores varying from -0.60 to 0.67) (supplementary material, Table S7).	('BAP1', 'Gene', (63, 67))	('expression', 'MPA', (241, 251))	('copy number variation', 'Var', (96, 117))	('chromosome', 'cellular_component', 'GO:0005694', ('83', '93'))	('chromosome', 'cellular_component', 'GO:0005694', ('260', '270'))	('BAP1', 'Gene', '8314', (236, 240))	('S7', 'Gene', '6264', (342, 344))	('negatively', 'NegReg', (134, 144))	('BAP1', 'Gene', (236, 240))	('BAP1', 'Gene', '8314', (63, 67))
94009	31960425	The genetic diversity of UM was recently described, including copy number variations (CNVs), somatic mutations, and BAP1 alterations 63.	('BAP1', 'Gene', '8314', (116, 120))	('BAP1', 'Gene', (116, 120))	('copy number variations', 'Var', (62, 84))	('UM', 'Phenotype', 'HP:0007716', (25, 27))
94022	31960425	Changes in BAP1 expression have also been associated with immune transformation in mesothelioma, and became a predictive tool for immunotherapy of peritoneal mesothelioma 76, 77.	('peritoneal mesothelioma', 'Phenotype', 'HP:0100003', (147, 170))	('associated with', 'Reg', (42, 57))	('BAP1', 'Gene', '8314', (11, 15))	('mesothelioma', 'Disease', (158, 170))	('mesothelioma', 'Disease', (83, 95))	('BAP1', 'Gene', (11, 15))	('immune transformation', 'CPA', (58, 79))	('Changes', 'Var', (0, 7))	('mesothelioma', 'Disease', 'MESH:D008654', (83, 95))	('mesothelioma', 'Disease', 'MESH:D008654', (158, 170))	('expression', 'MPA', (16, 26))
94023	31960425	The impaired ability of thymic development and the proliferative responses of T lymphocytes in the context of BAP1 inhibition are strong evidence that loss of BAP1 function is associated with immune suppression and systemic myeloid transformation 16, 78.	('immune suppression', 'CPA', (192, 210))	('BAP1', 'Gene', '8314', (110, 114))	('proliferative responses', 'CPA', (51, 74))	('BAP1', 'Gene', '8314', (159, 163))	('BAP1', 'Gene', (110, 114))	('associated', 'Reg', (176, 186))	('thymic development', 'CPA', (24, 42))	('impaired', 'NegReg', (4, 12))	('inhibition', 'Var', (115, 125))	('BAP1', 'Gene', (159, 163))	('systemic myeloid transformation', 'CPA', (215, 246))	('loss', 'Var', (151, 155))
94028	31960425	Indeed, IFN-gamma is upregulated in the context of BAP1 loss and is widely associated with several immune-suppressive network categories, which is in accordance with recent reports showing the immune-suppressive roles of IFN-gamma 79.Therefore, targeting CD38 in UM may be considered a suitable strategy to improve the efficacy of immunotherapy using ICI in metastatic UM.	('targeting', 'Var', (245, 254))	('loss', 'NegReg', (56, 60))	('BAP1', 'Gene', (51, 55))	('UM', 'Phenotype', 'HP:0007716', (369, 371))	('IFN-gamma', 'Gene', '3458', (221, 230))	('IFN-gamma', 'Gene', (221, 230))	('IFN-gamma', 'Gene', '3458', (8, 17))	('IFN-gamma', 'Gene', (8, 17))	('UM', 'Phenotype', 'HP:0007716', (263, 265))	('CD38', 'Gene', '952', (255, 259))	('BAP1', 'Gene', '8314', (51, 55))	('CD38', 'Gene', (255, 259))
94032	31960425	Moreover, higher expression of IDO1 in both pUM and mUM suggests this molecule as an important adjuvant target for immunotherapy using ICIs, since IDO1 blockade has been shown to synergise the therapeutic effector of both CTLA-4 and PD1/PD-L1 inhibitors 61.	('IDO', 'molecular_function', 'GO:0047719', ('147', '150'))	('IDO1', 'Gene', (31, 35))	('IDO', 'molecular_function', 'GO:0033754', ('31', '34'))	('IDO1', 'Gene', (147, 151))	('expression', 'MPA', (17, 27))	('PD-L1', 'Gene', (237, 242))	('blockade', 'Var', (152, 160))	('PD1', 'Gene', (233, 236))	('IDO', 'molecular_function', 'GO:0047719', ('31', '34'))	('PD-L1', 'Gene', '29126', (237, 242))	('CTLA-4', 'Gene', '1493', (222, 228))	('mUM', 'Gene', (52, 55))	('CTLA-4', 'Gene', (222, 228))	('IDO1', 'Gene', '3620', (31, 35))	('IDO', 'molecular_function', 'GO:0033754', ('147', '150'))	('mUM', 'Gene', '56925', (52, 55))	('UM', 'Phenotype', 'HP:0007716', (53, 55))	('IDO1', 'Gene', '3620', (147, 151))	('PD1', 'Gene', '5133', (233, 236))	('UM', 'Phenotype', 'HP:0007716', (45, 47))
94035	31960425	A recent study showed that hepatocellular carcinoma patients displaying an altered Wnt/beta-catenin pathway were refractory to immune-checkpoint blockade 86, which is aligned with evidence that melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity 87.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (27, 51))	('beta-catenin', 'Gene', (87, 99))	('beta-catenin', 'Gene', '1499', (213, 225))	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('signalling', 'biological_process', 'GO:0023052', ('226', '236'))	('melanoma', 'Disease', (194, 202))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('tumour', 'Disease', 'MESH:D009369', (251, 257))	('altered', 'Var', (75, 82))	('beta-catenin', 'Gene', '1499', (87, 99))	('tumour', 'Disease', (251, 257))	('prevents', 'NegReg', (237, 245))	('beta-catenin', 'Gene', (213, 225))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (27, 51))	('patients', 'Species', '9606', (52, 60))	('hepatocellular carcinoma', 'Disease', (27, 51))
94051	31758842	Our studies indicate that DNMTi may enhance the activity of MEKi in uveal melanoma.	('MEK', 'Gene', '5609', (60, 63))	('activity', 'MPA', (48, 56))	('DNMTi', 'Var', (26, 31))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('DNMTi', 'Chemical', '-', (26, 31))	('uveal melanoma', 'Disease', 'MESH:C536494', (68, 82))	('uveal melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('uveal melanoma', 'Disease', (68, 82))	('enhance', 'PosReg', (36, 43))	('MEK', 'Gene', (60, 63))
94053	31758842	In contrast to cutaneous melanoma, uveal melanoma is not strongly associated with exposure to ultraviolet (UV) radiation, exhibits a much lower mutational burden, and is instead characterized by a high prevalence of initiating mutations in the G-alpha-q subunits GNAQ and GNA11.	('uveal melanoma', 'Disease', 'MESH:C536494', (35, 49))	('G-alpha-q', 'Gene', '2776', (244, 253))	('uveal melanoma', 'Disease', (35, 49))	('GNAQ', 'Gene', (263, 267))	('lower', 'NegReg', (138, 143))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))	('cutaneous melanoma', 'Disease', (15, 33))	('G-alpha-q', 'Gene', (244, 253))	('mutational burden', 'MPA', (144, 161))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (15, 33))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (15, 33))	('GNAQ', 'Gene', '2776', (263, 267))	('GNA11', 'Gene', '2767', (272, 277))	('GNA11', 'Gene', (272, 277))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('mutations', 'Var', (227, 236))
94054	31758842	The most common GNAQ and GNA11 mutations occur at position Q209 and lead to their constitutive activation by abrogating GTP hydrolase activity.	('mutations', 'Var', (31, 40))	('constitutive activation', 'MPA', (82, 105))	('GTP', 'Chemical', 'MESH:D006160', (120, 123))	('hydrolase activity', 'molecular_function', 'GO:0016787', ('124', '142'))	('abrogating', 'NegReg', (109, 119))	('GNAQ', 'Gene', (16, 20))	('GNAQ', 'Gene', '2776', (16, 20))	('GTP hydrolase activity', 'MPA', (120, 142))	('GNA11', 'Gene', (25, 30))	('GNA11', 'Gene', '2767', (25, 30))
94055	31758842	GNAQ/11 mutations function in an analogous fashion to Ras mutations and activate multiple signaling pathways involved in oncogenic transformation, including the mitogen-activated protein kinase (MAPK) and YAP/Hippo pathways.	('MAPK', 'molecular_function', 'GO:0004707', ('195', '199'))	('mutations', 'Var', (58, 67))	('GNAQ', 'Gene', '2776', (0, 4))	('YAP', 'Gene', '10413', (205, 208))	('mutations', 'Var', (8, 17))	('activate', 'PosReg', (72, 80))	('GNAQ', 'Gene', (0, 4))	('YAP', 'Gene', (205, 208))	('signaling pathways', 'Pathway', (90, 108))	('signaling', 'biological_process', 'GO:0023052', ('90', '99'))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))
94061	31758842	Studies in multiple cancers have shown that tumor cells rapidly adapt to kinase inhibitors through the adoption of a drug-tolerant state, which is often epigenetically mediated.	('multiple cancers', 'Disease', (11, 27))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('multiple cancers', 'Disease', 'MESH:D009369', (11, 27))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('kinase inhibitors', 'Var', (73, 90))	('tumor', 'Disease', (44, 49))
94062	31758842	Indeed, epigenetic drugs such as pan-HDAC inhibitors increase the efficacy of drugs targeting EGFR, JAK, p38 MAPK and RAF.	('EGFR', 'molecular_function', 'GO:0005006', ('94', '98'))	('p38', 'Var', (105, 108))	('EGFR', 'Gene', '1956', (94, 98))	('RAF', 'Gene', '22882', (118, 121))	('RAF', 'Gene', (118, 121))	('EGFR', 'Gene', (94, 98))	('increase', 'PosReg', (53, 61))	('JAK', 'molecular_function', 'GO:0004713', ('100', '103'))	('HDAC', 'Gene', (37, 41))	('JAK', 'Gene', (100, 103))	('HDAC', 'Gene', '9734', (37, 41))	('MAPK', 'molecular_function', 'GO:0004707', ('109', '113'))	('efficacy', 'MPA', (66, 74))
94063	31758842	The goal of the present study was to evaluate a series of clinical-grade epigenetic inhibitors to identify candidates that may increase the activity of MEKi in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('uveal melanoma', 'Disease', 'MESH:C536494', (160, 174))	('epigenetic inhibitors', 'Var', (73, 94))	('MEK', 'Gene', (152, 155))	('uveal melanoma', 'Disease', (160, 174))	('uveal melanoma', 'Phenotype', 'HP:0007716', (160, 174))	('increase', 'PosReg', (127, 135))	('activity', 'MPA', (140, 148))	('MEK', 'Gene', '5609', (152, 155))
94064	31758842	We focused on epigenetic inhibitors as there is evidence from BRAF-mutant cutaneous melanoma that epigenetic inhibitors can limit adaptation to BRAF inhibition.	('adaptation', 'MPA', (130, 140))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('epigenetic', 'Var', (98, 108))	('BRAF', 'Gene', '673', (144, 148))	('limit', 'NegReg', (124, 129))	('cutaneous melanoma', 'Disease', (74, 92))	('BRAF', 'Gene', (144, 148))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (74, 92))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (74, 92))
94067	31758842	Consistent with the well-established delay for DNMTi to manifest their anti-proliferative effects, we found in long-term colony formation assays that DNMTi also had a significant single-agent activity in every cell line tested (Figure 1b).	('DNMTi', 'Var', (150, 155))	('DNMTi', 'Chemical', '-', (47, 52))	('DNMTi', 'Chemical', '-', (150, 155))	('formation', 'biological_process', 'GO:0009058', ('128', '137'))	('single-agent activity', 'MPA', (179, 200))
94069	31758842	Silencing of BAP1 increased the responses to single agent MEKi and DNMTi in 92.1 cells, but not the Mel202 cells (Figure S1a,b).	('BAP1', 'Gene', (13, 17))	('increased', 'PosReg', (18, 27))	('MEK', 'Gene', (58, 61))	('MEK', 'Gene', '5609', (58, 61))	('DNMTi', 'Chemical', '-', (67, 72))	('BAP1', 'Gene', '8314', (13, 17))	('Silencing', 'Var', (0, 9))
94074	31758842	Silencing of DNMT1 using siRNA also enhanced the response to MEKi in 92.1, Mel270, MP41, and Mel290 uveal melanoma cell lines in both apoptosis and colony formation assays (Figure 1f,g and Figure S4).	('MEK', 'Gene', (61, 64))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('MEK', 'Gene', '5609', (61, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('apoptosis', 'biological_process', 'GO:0006915', ('134', '143'))	('uveal melanoma', 'Disease', (100, 114))	('formation', 'biological_process', 'GO:0009058', ('155', '164'))	('apoptosis', 'CPA', (134, 143))	('DNMT1', 'Gene', '1786', (13, 18))	('DNMT1', 'Gene', (13, 18))	('colony formation assays', 'CPA', (148, 171))	('response', 'MPA', (49, 57))	('enhanced', 'PosReg', (36, 44))	('Silencing', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('apoptosis', 'biological_process', 'GO:0097194', ('134', '143'))
94076	31758842	While DNMTi increased the number of gammaH2AX foci in 92.1 cells, this was not seen in the MP41 cells, and no increase in foci was detected following treatment with trametinib (Figure S5).	('gammaH2AX', 'Protein', (36, 45))	('DNMTi', 'Var', (6, 11))	('increased', 'PosReg', (12, 21))	('trametinib', 'Chemical', 'MESH:C560077', (165, 175))	('DNMTi', 'Chemical', '-', (6, 11))
94079	31758842	In 3D organoid-like spheroids using 92.1 Mel270 and Mel290 cells, the MEKi demonstrated some single-agent cytotoxicity, which was enhanced by the addition of the DNMTi, as shown by increased levels of propidium iodide uptake (red staining) and reduced Calcein-AM staining (Figure 1f and Figure S6).	('DNMTi', 'Chemical', '-', (162, 167))	('enhanced', 'PosReg', (130, 138))	('reduced', 'NegReg', (244, 251))	('propidium iodide', 'Chemical', 'MESH:D011419', (201, 217))	('levels', 'MPA', (191, 197))	('Calcein-AM', 'Chemical', 'MESH:C085925', (252, 262))	('cytotoxicity', 'Disease', (106, 118))	('MEK', 'Gene', (70, 73))	('cytotoxicity', 'Disease', 'MESH:D064420', (106, 118))	('uptake', 'biological_process', 'GO:0098739', ('218', '224'))	('Calcein-AM staining', 'MPA', (252, 271))	('uptake', 'biological_process', 'GO:0098657', ('218', '224'))	('MEK', 'Gene', '5609', (70, 73))	('increased', 'PosReg', (181, 190))	('DNMTi', 'Var', (162, 167))
94081	31758842	Cancer cells frequently inactivate expression of tumor suppressor genes through promoter methylation.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('methylation', 'biological_process', 'GO:0032259', ('89', '100'))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('49', '65'))	('tumor', 'Disease', (49, 54))	('promoter methylation', 'Var', (80, 100))	('Cancer', 'Disease', (0, 6))	('inactivate', 'NegReg', (24, 34))	('expression', 'MPA', (35, 45))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor suppressor', 'biological_process', 'GO:0051726', ('49', '65'))
94084	31758842	In triple-negative breast cancer, DNMTi alters the expression of multiple genes implicated in cell cycle control, differentiation, transcription factor activity, cell adhesion, apoptosis, cytokine signaling, the stress response, and metabolism.	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('transcription factor activity', 'molecular_function', 'GO:0003700', ('131', '160'))	('alters', 'Reg', (40, 46))	('cell cycle control', 'biological_process', 'GO:1901987', ('94', '112'))	('cell adhesion', 'biological_process', 'GO:0007155', ('162', '175'))	('transcription factor activity', 'molecular_function', 'GO:0000988', ('131', '160'))	('transcription', 'biological_process', 'GO:0006351', ('131', '144'))	('signaling', 'biological_process', 'GO:0023052', ('197', '206'))	('expression', 'MPA', (51, 61))	('DNMTi', 'Var', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('metabolism', 'biological_process', 'GO:0008152', ('233', '243'))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('apoptosis', 'biological_process', 'GO:0006915', ('177', '186'))	('apoptosis', 'biological_process', 'GO:0097194', ('177', '186'))	('DNMTi', 'Chemical', '-', (34, 39))	('breast cancer', 'Disease', (19, 32))
94100	31758842	IHC analysis revealed strong p21 staining in tumors treated with either the DNMTi or the DNMTi-MEKi combination, but not with vehicle or MEKi alone (Figure 3c).	('MEK', 'Gene', (137, 140))	('DNMTi', 'Chemical', '-', (76, 81))	('MEK', 'Gene', '5609', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('p21', 'Gene', '1026', (29, 32))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('DNMTi', 'Chemical', '-', (89, 94))	('p21', 'Gene', (29, 32))	('DNMTi', 'Var', (76, 81))	('MEK', 'Gene', (95, 98))	('MEK', 'Gene', '5609', (95, 98))
94111	31758842	For Western blot analysis, antibodies against DNMT1 (ab19905, Abcam, Cambridge, UK), p21 (#2947, Cell Signaling Technology, Danvers, MA), BIM (#2933, CST), and GAPDH (Millipore Sigma, Burlington, MA) were used.	('CST', 'Gene', (150, 153))	('BIM', 'Gene', '10018', (138, 141))	('Signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('BIM', 'Gene', (138, 141))	('DNMT1', 'Gene', (46, 51))	('DNMT1', 'Gene', '1786', (46, 51))	('p21', 'Gene', '1026', (85, 88))	('CST', 'Gene', '106478911', (150, 153))	('GAPDH', 'Gene', '2597', (160, 165))	('#2933', 'Var', (143, 148))	('p21', 'Gene', (85, 88))	('GAPDH', 'Gene', (160, 165))
94129	31758842	Here, we evaluated a panel of epigenetic inhibitors as a strategy to limit escape from MEKi therapy.	('MEK', 'Gene', (87, 90))	('MEK', 'Gene', '5609', (87, 90))	('epigenetic inhibitors', 'Var', (30, 51))
94131	31758842	This work provides the preclinical rationale for exploring new combinations of epigenetic and MEK inhibitors in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('inhibitors', 'Var', (98, 108))	('uveal melanoma', 'Disease', 'MESH:C536494', (112, 126))	('MEK', 'Gene', (94, 97))	('MEK', 'Gene', '5609', (94, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (112, 126))	('uveal melanoma', 'Disease', (112, 126))	('epigenetic', 'Var', (79, 89))
94132	30414346	Multigene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non-CDKN2A/CDK4 melanoma families Germline mutations in the major melanoma susceptibility gene CDKN2A explain genetic predisposition in only 10-40% of melanoma-prone families.	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('CDKN2A', 'Gene', (208, 214))	('CDK4', 'Gene', '1019', (124, 128))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('melanoma', 'Disease', (264, 272))	('melanoma', 'Disease', 'MESH:D008545', (264, 272))	('CDKN2A', 'Gene', '1029', (208, 214))	('Germline', 'Var', (147, 155))	('CDKN2A', 'Gene', (117, 123))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanoma', 'Disease', (179, 187))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('CDK', 'molecular_function', 'GO:0004693', ('124', '127'))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))	('CDKN2A', 'Gene', '1029', (117, 123))	('CDK4', 'Gene', (124, 128))
94133	30414346	In our study we comprehensively characterized 488 melanoma cases from 451 non-CDKN2A/CDK4 families for mutations in 30 established and candidate melanoma susceptibility genes using a custom-designed targeted gene panel approach.	('mutations', 'Var', (103, 112))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('CDKN2A', 'Gene', (78, 84))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('melanoma', 'Disease', (50, 58))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('CDKN2A', 'Gene', '1029', (78, 84))	('CDK4', 'Gene', (85, 89))	('CDK4', 'Gene', '1019', (85, 89))	('CDK', 'molecular_function', 'GO:0004693', ('85', '88'))
94134	30414346	We identified (likely) pathogenic variants in established melanoma susceptibility genes in 18 families (n = 3 BAP1, n = 15 MITF p.E318K; diagnostic yield 4.0%).	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('variants', 'Var', (34, 42))	('BAP1', 'Gene', '8314', (110, 114))	('p.E318K', 'Mutation', 'rs149617956', (128, 135))	('MITF', 'Gene', '4286', (123, 127))	('MITF', 'Gene', (123, 127))	('melanoma', 'Disease', (58, 66))	('BAP1', 'Gene', (110, 114))	('pathogenic', 'Reg', (23, 33))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('p.E318K', 'Var', (128, 135))
94136	30414346	MC1R risk variants were strongly enriched in our familial melanoma cohort compared to healthy controls (R variants: OR 3.67, 95% CI 2.88-4.68, p <0.001).	('variants', 'Var', (10, 18))	('familial melanoma cohort', 'Disease', (49, 73))	('MC1R', 'Gene', (0, 4))	('familial melanoma cohort', 'Disease', 'OMIM:155600', (49, 73))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
94137	30414346	Several variants of interest were also identified in candidate melanoma susceptibility genes, in particular rare (pathogenic) variants in the albinism gene OCA2 were repeatedly found.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('albinism', 'Phenotype', 'HP:0001022', (142, 150))	('variants', 'Var', (126, 134))	('OCA2', 'Species', '1933259', (156, 160))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('OCA2', 'Gene', (156, 160))
94140	30414346	Germline mutations in CDKN2A are major contributors to familial melanoma.	('Germline mutations', 'Var', (0, 18))	('familial melanoma', 'Disease', (55, 72))	('CDKN2A', 'Gene', (22, 28))	('CDKN2A', 'Gene', '1029', (22, 28))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('familial melanoma', 'Disease', 'OMIM:155600', (55, 72))	('contributors', 'Reg', (39, 51))
94141	30414346	These mutations, however, are responsible for only 10 to 40 percent of genetic susceptibility in melanoma-prone families.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('mutations', 'Var', (6, 15))
94143	30414346	From the candidate gene panel, (likely) pathogenic variants in BAP1 and MITF were identified in several families, and potentially deleterious variants were identified in the shelterin complex genes ACD and TERF2IP.	('MITF', 'Gene', '4286', (72, 76))	('ACD', 'Gene', (198, 201))	('shelterin complex', 'cellular_component', 'GO:0070187', ('174', '191'))	('BAP1', 'Gene', (63, 67))	('variants', 'Var', (51, 59))	('pathogenic', 'Reg', (40, 50))	('MITF', 'Gene', (72, 76))	('TERF2IP', 'Gene', (206, 213))	('BAP1', 'Gene', '8314', (63, 67))
94146	30414346	This familial clustering occurs in approximately 5-10% of melanoma cases, and is referred to as familial melanoma.4  The major high-risk susceptibility gene for familial melanoma is CDKN2A and germline mutations are identified in 10-40% of familial cases.5, 6 In the Netherlands, a specific founder mutation in CDKN2A, known as p16-Leiden (c.225_243del, p.A76Cfs*64; RefSeq NM_000077.4), is the most frequent cause of familial melanoma (~80% of CDKNA mutations).	('familial melanoma', 'Disease', 'OMIM:155600', (161, 178))	('c.225_243del', 'Mutation', 'c.225_243del', (340, 352))	('familial melanoma', 'Disease', (96, 113))	('melanoma', 'Phenotype', 'HP:0002861', (427, 435))	('CDKN2A', 'Gene', (311, 317))	('melanoma', 'Disease', (427, 435))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('c.225_243del', 'Var', (340, 352))	('familial melanoma', 'Disease', 'OMIM:155600', (96, 113))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('familial melanoma', 'Disease', (418, 435))	('familial melanoma', 'Disease', 'OMIM:155600', (418, 435))	('p.A76Cfs*64', 'Mutation', 'rs730881674', (354, 365))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('p.A76Cfs*64', 'Var', (354, 365))	('cause', 'Reg', (409, 414))	('CDKN2A', 'Gene', '1029', (311, 317))	('CDKN2A', 'Gene', (182, 188))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Disease', 'MESH:D008545', (427, 435))	('familial melanoma', 'Disease', (161, 178))	('CDKN2A', 'Gene', '1029', (182, 188))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
94147	30414346	Carriers of this mutation show not only a markedly increased risk for (multiple) cutaneous melanomas, but also for other cancers, especially pancreatic cancer and cancers of the upper respiratory tract (larynx, pharynx, oral cavity).7, 8 CDKN2A is an unusual gene in that it encodes two distinct proteins, p16INK4a and the alternatively spliced p14ARF, both of which are tumor-suppressors that act in two distinct pathways.	('tumor', 'Disease', (371, 376))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('pancreatic cancer', 'Disease', 'MESH:D010190', (141, 158))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('cancers of the upper respiratory tract', 'Disease', 'MESH:D012141', (163, 201))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('cutaneous melanomas', 'Disease', (81, 100))	('pancreatic cancer', 'Disease', (141, 158))	('cancers of the upper respiratory tract', 'Disease', (163, 201))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('p14ARF', 'Gene', (345, 351))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('CDKN2A', 'Gene', (238, 244))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('p16INK4a', 'Var', (306, 314))	('other cancers', 'Disease', 'MESH:D009369', (115, 128))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (141, 158))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('other cancers', 'Disease', (115, 128))	('CDKN2A', 'Gene', '1029', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (81, 100))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (81, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (81, 99))
94148	30414346	The p16-retinoblastoma(Rb)-pathway controls cell-cycle G1-phase exit, while the p14ARF-p53 pathway induces cell cycle arrest or apoptosis.9 Despite the major role of these pathways in melanoma susceptibility, only one other gene in the p16-retinoblastoma(Rb)-pathway, the CDK4 gene, has been shown to be associated with familial melanoma, and only a small number of families with germline mutations in this gene have been identified to date.10  However, new melanoma susceptibility pathways have emerged in recent years.5, 6 Several high penetrance genes involved in telomere lengthening (TERT) or telomere maintenance (Shelterin complex: POT1, ACD, TERF2IP) have been identified, and mutations in these genes each account for approximately 1% of familial melanoma predisposition.11, 12, 13 Furthermore, germline mutations in the BRCA1-associated protein (BAP1) gene cause a specific cancer predisposition syndrome mainly characterized by an increased susceptibility for uveal melanoma and malignant mesothelioma, but also including cutaneous melanoma, renal cancer, basal cell carcinoma and characteristic skin lesions called atypical Spitz tumors (AST) or melanocytic BAP1-mutated atypical intradermal tumors (MBAIT).14 The MITF gene is a medium penetrance melanoma susceptibility gene and shows incomplete co-segregation with the phenotype.	('retinoblastoma', 'Disease', (240, 254))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('BAP1', 'Gene', '8314', (856, 860))	('familial melanoma', 'Disease', (320, 337))	('familial melanoma', 'Disease', (747, 764))	('melanoma', 'Disease', 'MESH:D008545', (1043, 1051))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (990, 1012))	('uveal melanoma', 'Disease', (971, 985))	('Spitz tumors', 'Disease', 'MESH:D018332', (1136, 1148))	('cancer', 'Disease', 'MESH:D009369', (1059, 1065))	('tumors', 'Phenotype', 'HP:0002664', (1204, 1210))	('uveal melanoma', 'Phenotype', 'HP:0007716', (971, 985))	('BAP1', 'Gene', (856, 860))	('carcinoma', 'Phenotype', 'HP:0030731', (1078, 1087))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (1067, 1087))	('melanoma', 'Disease', 'MESH:D008545', (756, 764))	('arrest', 'Disease', 'MESH:D006323', (118, 124))	('retinoblastoma', 'Disease', 'MESH:D012175', (8, 22))	('BAP1', 'Gene', '8314', (1170, 1174))	('cancer', 'Disease', (1059, 1065))	('telomere maintenance', 'biological_process', 'GO:0000723', ('598', '618'))	('cancer', 'Phenotype', 'HP:0002664', (884, 890))	('retinoblastoma', 'Phenotype', 'HP:0009919', (240, 254))	('melanoma', 'Phenotype', 'HP:0002861', (329, 337))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (107, 124))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (1033, 1051))	('melanoma', 'Phenotype', 'HP:0002861', (756, 764))	('BAP1', 'Gene', (1170, 1174))	('retinoblastoma', 'Disease', (8, 22))	('intradermal tumors', 'Disease', 'MESH:D018330', (1192, 1210))	('melanoma', 'Disease', (977, 985))	('melanoma', 'Disease', 'MESH:D008545', (458, 466))	('arrest', 'Disease', (118, 124))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('107', '124'))	('skin lesions', 'Disease', (1107, 1119))	('tumor', 'Phenotype', 'HP:0002664', (1204, 1209))	('CDK4', 'Gene', (272, 276))	('melanoma', 'Disease', (1259, 1267))	('melanoma', 'Phenotype', 'HP:0002861', (458, 466))	('MITF', 'Gene', '4286', (1226, 1230))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (990, 1012))	('basal cell carcinoma', 'Disease', (1067, 1087))	('Spitz tumors', 'Disease', (1136, 1148))	('protein', 'cellular_component', 'GO:0003675', ('847', '854'))	('G1-phase', 'biological_process', 'GO:0051318', ('55', '63'))	('MITF', 'Gene', (1226, 1230))	('retinoblastoma', 'Phenotype', 'HP:0009919', (8, 22))	('cause', 'Reg', (867, 872))	('melanoma', 'Disease', (184, 192))	('melanoma', 'Disease', 'MESH:D008545', (1259, 1267))	('familial melanoma', 'Disease', 'OMIM:155600', (320, 337))	('renal cancer', 'Disease', (1053, 1065))	('intradermal tumors', 'Disease', (1192, 1210))	('tumor', 'Phenotype', 'HP:0002664', (1142, 1147))	('telomere', 'cellular_component', 'GO:0000781', ('567', '575'))	('telomere', 'cellular_component', 'GO:0005696', ('567', '575'))	('apoptosis', 'biological_process', 'GO:0006915', ('128', '137'))	('melanoma', 'Disease', 'MESH:D008545', (977, 985))	('cancer', 'Phenotype', 'HP:0002664', (1059, 1065))	('melanoma', 'Disease', (329, 337))	('mutations', 'Var', (813, 822))	('tumors', 'Phenotype', 'HP:0002664', (1142, 1148))	('melanoma', 'Disease', (756, 764))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (1033, 1051))	('cell-cycle', 'biological_process', 'GO:0007049', ('44', '54'))	('skin lesions', 'Disease', 'MESH:D012871', (1107, 1119))	('melanoma', 'Phenotype', 'HP:0002861', (977, 985))	('uveal melanoma', 'Disease', 'MESH:C536494', (971, 985))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (1067, 1087))	('renal cancer', 'Phenotype', 'HP:0009726', (1053, 1065))	('familial melanoma', 'Disease', 'OMIM:155600', (747, 764))	('cancer', 'Disease', 'MESH:D009369', (884, 890))	('melanoma', 'Disease', 'MESH:D008545', (329, 337))	('renal cancer', 'Disease', 'MESH:D007680', (1053, 1065))	('telomere', 'cellular_component', 'GO:0000781', ('598', '606'))	('retinoblastoma', 'Disease', 'MESH:D012175', (240, 254))	('malignant mesothelioma', 'Disease', (990, 1012))	('CDK', 'molecular_function', 'GO:0004693', ('272', '275'))	('telomere', 'cellular_component', 'GO:0005696', ('598', '606'))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('Shelterin complex', 'cellular_component', 'GO:0070187', ('620', '637'))	('melanoma', 'Disease', (458, 466))	('apoptosis', 'biological_process', 'GO:0097194', ('128', '137'))	('melanoma', 'Disease', (1043, 1051))	('CDK4', 'Gene', '1019', (272, 276))	('cancer', 'Disease', (884, 890))	('cutaneous melanoma', 'Disease', (1033, 1051))
94150	30414346	Loss-of-function mutations in this gene cause auditory-pigmentary syndromes, such as Waardenburg syndrome type 2A (MIM #193510).	('auditory-pigmentary syndromes', 'Disease', 'MESH:C535508', (46, 75))	('Loss-of-function', 'NegReg', (0, 16))	('Waardenburg syndrome', 'Disease', 'MESH:D014849', (85, 105))	('auditory-pigmentary syndromes', 'Disease', (46, 75))	('Waardenburg syndrome', 'Disease', (85, 105))	('mutations', 'Var', (17, 26))
94151	30414346	However, a specific missense variant (c.952G>A, p.E318K; RefSeq NM_000248.3) located in a small-ubiquitin-like modifier (SUMO) consensus site impairs the SUMOylation of MITF, which results in a gain-of-function increase in MITF transcriptional activity.	('ubiquitin', 'molecular_function', 'GO:0031386', ('96', '105'))	('gain-of-function increase', 'PosReg', (194, 219))	('SUMOylation', 'biological_process', 'GO:0016925', ('154', '165'))	('p.E318K', 'Mutation', 'rs149617956', (48, 55))	('c.952G>A', 'Mutation', 'rs149617956', (38, 46))	('SUMOylation', 'MPA', (154, 165))	('MITF', 'Gene', '4286', (223, 227))	('MITF', 'Gene', (223, 227))	('c.952G>A', 'Var', (38, 46))	('transcriptional activity', 'MPA', (228, 252))	('impairs', 'NegReg', (142, 149))	('MITF', 'Gene', '4286', (169, 173))	('MITF', 'Gene', (169, 173))
94152	30414346	Carriers of this variant have an approximately three- to fourfold increased risk for melanoma and are more likely to develop multiple primary melanomas.15 Several other cancers (renal cancer, pancreatic cancer) have also been reported in carriers of this variant.16, 17 In addition to these known high- and medium penetrance melanoma susceptibility genes, there are several well-established (common) variants in the lower penetrance MC1R gene that are associated with an increased risk for melanoma in the general population.	('melanoma', 'Phenotype', 'HP:0002861', (325, 333))	('melanoma', 'Disease', (325, 333))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (192, 209))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('variants', 'Var', (400, 408))	('associated', 'Reg', (452, 462))	('melanoma', 'Disease', 'MESH:D008545', (490, 498))	('primary melanomas', 'Disease', (134, 151))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('renal cancer', 'Disease', (178, 190))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma', 'Disease', (142, 150))	('renal cancer', 'Phenotype', 'HP:0009726', (178, 190))	('pancreatic cancer', 'Disease', 'MESH:D010190', (192, 209))	('renal cancer', 'Disease', 'MESH:D007680', (178, 190))	('primary melanomas', 'Disease', 'MESH:D008545', (134, 151))	('MC1R', 'Gene', (433, 437))	('melanoma', 'Disease', 'MESH:D008545', (325, 333))	('melanoma', 'Phenotype', 'HP:0002861', (490, 498))	('melanoma', 'Disease', (490, 498))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('other cancers', 'Disease', 'MESH:D009369', (163, 176))	('other cancers', 'Disease', (163, 176))	('pancreatic cancer', 'Disease', (192, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('melanomas', 'Phenotype', 'HP:0002861', (142, 151))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
94155	30414346	Although Dutch melanoma families are well characterized for CDKN2A and CDK4 mutations,23 no large scale investigation has yet been performed to identify (potential) deleterious variants in other established or candidate melanoma susceptibility genes.	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('CDK4', 'Gene', (71, 75))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('CDKN2A', 'Gene', (60, 66))	('CDK4', 'Gene', '1019', (71, 75))	('CDKN2A', 'Gene', '1029', (60, 66))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('melanoma', 'Disease', (220, 228))	('variants', 'Var', (177, 185))	('melanoma', 'Disease', 'MESH:D008545', (220, 228))	('CDK', 'molecular_function', 'GO:0004693', ('71', '74'))
94157	30414346	Our goal was to determine the frequency of pathogenic variants in established melanoma susceptibility genes and to investigate the role of a broad range of candidate susceptibility genes in familial melanoma.	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('familial melanoma', 'Disease', (190, 207))	('familial melanoma', 'Disease', 'OMIM:155600', (190, 207))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('variants', 'Var', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('melanoma', 'Disease', (199, 207))
94163	30414346	In one of these samples, a pathogenic variant in the 5'UTR region of CDKN2A (c.-34G>T) was identified.	('CDKN2A', 'Gene', '1029', (69, 75))	('c.-34G>T', 'Var', (77, 85))	('CDKN2A', 'Gene', (69, 75))	('pathogenic', 'Reg', (27, 37))	('c.-34G>T', 'Mutation', 'rs1800586', (77, 85))
94169	30414346	The functional effect of missense variants was predicted by the in silico tools SIFT (http://sift.jcvi.org/), Align GVGD (http://agvgd.hci.utah.edu/), PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) and the CADD score (http://cadd.gs.washington.edu/).	('pph', 'molecular_function', 'GO:0033978', ('195', '198'))	('pph', 'molecular_function', 'GO:0004238', ('195', '198'))	('SIFT', 'Disease', (80, 84))	('SIFT', 'Disease', 'None', (80, 84))	('missense variants', 'Var', (25, 42))
94170	30414346	A further selection of variants of interest (secondary filtering) was based on the following criteria: 1) known pathogenic variants in literature, 2) truncating variants, 3) missense variants with a CADD score >15 and at least two out of three in silico protein prediction tools predicting a possible functional effect, 4) in-frame indels, and 5) variants that likely affect splicing (predicted by SpliceSiteFinder-like, MaXEntScan, NNSPLICE, GeneSplicer and Human Splicing Finder, incorporated in Alamut ).	('affect', 'Reg', (368, 374))	('variants', 'Var', (347, 355))	('Splicing', 'biological_process', 'GO:0045292', ('465', '473'))	('splicing', 'biological_process', 'GO:0045292', ('375', '383'))	('protein', 'cellular_component', 'GO:0003675', ('254', '261'))	('Human', 'Species', '9606', (459, 464))	('splicing', 'MPA', (375, 383))
94171	30414346	Analysis of the POLE gene was confined to variants in the exonuclease domain (exon 9-14),20 while analysis of CDK4, TERT, MITF and MC1R was restricted to specific variants known to be associated with an increased melanoma risk.	('variants', 'Var', (42, 50))	('MITF', 'Gene', '4286', (122, 126))	('MITF', 'Gene', (122, 126))	('CDK', 'molecular_function', 'GO:0004693', ('110', '113'))	('associated', 'Reg', (184, 194))	('CDK4', 'Gene', (110, 114))	('melanoma', 'Disease', 'MESH:D008545', (213, 221))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('melanoma', 'Disease', (213, 221))	('CDK4', 'Gene', '1019', (110, 114))
94172	30414346	This included the p.R24H and p.R24C variants in CDK4,10 the c.-57T>G promoter variant in TERT,13 the p.E318K variant in MITF,15 and the R and r variants in MC1R.18 Co-segregation analysis of the detected variants was possible for families in which more than one case was included in the study.	('p.E318K', 'Var', (101, 108))	('c.-57T>G', 'Var', (60, 68))	('CDK4', 'Gene', '1019', (48, 52))	('p.R24H', 'Mutation', 'rs104894340', (18, 24))	('p.R24C', 'Mutation', 'rs11547328', (29, 35))	('p.E318K', 'Mutation', 'rs149617956', (101, 108))	('CDK', 'molecular_function', 'GO:0004693', ('48', '51'))	('c.-57T>G', 'Mutation', 'rs951173847', (60, 68))	('MITF', 'Gene', '4286', (120, 124))	('MITF', 'Gene', (120, 124))	('p.R24C', 'Var', (29, 35))	('p.R24H', 'Var', (18, 24))	('CDK4', 'Gene', (48, 52))
94176	30414346	variants are both located in a canonical splice site and are predicted to inactivate the splice donor site of intron 3 and splice acceptor site of intron 13, respectively, likely resulting in a prematurely truncated protein.	('variants', 'Var', (0, 8))	('splice donor site', 'MPA', (89, 106))	('protein', 'Protein', (216, 223))	('resulting in', 'Reg', (179, 191))	('inactivate', 'NegReg', (74, 84))	('prematurely truncated', 'MPA', (194, 215))	('protein', 'cellular_component', 'GO:0003675', ('216', '223'))	('donor', 'Species', '9606', (96, 101))
94177	30414346	The c.1936_1937insTT, p.(Y646Ffs*10) frameshift variant is also predicted to cause a truncated protein due to a premature stop codon.	('p.(Y646Ffs*10)', 'Mutation', 'p.Y646FfsX10', (22, 36))	('p.(Y646Ffs*10', 'Var', (22, 35))	('c.1936_1937insTT', 'Var', (4, 20))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('truncated protein', 'MPA', (85, 102))	('c.1936_1937insTT', 'Mutation', 'c.1936_1937insTT', (4, 20))
94180	30414346	Interestingly, in the proband who carried the BAP1 c.122+1G>T, p.?	('c.122+1G>T', 'Mutation', 'c.122+1G>T', (51, 61))	('c.122+1G>T', 'Var', (51, 61))	('BAP1', 'Gene', '8314', (46, 50))	('BAP1', 'Gene', (46, 50))
94181	30414346	variant we also identified a novel nonsense variant in the BRIP1 gene (c.894C>A, p.(C298*)).	('p.(C298*)', 'SUBSTITUTION', 'None', (81, 90))	('c.894C>A', 'Mutation', 'c.894C>A', (71, 79))	('c.894C>A', 'Var', (71, 79))	('p.(C298*', 'Var', (81, 89))	('C298*', 'SUBSTITUTION', 'None', (84, 89))	('C298*', 'Var', (84, 89))	('BRIP1', 'Gene', (59, 64))
94183	30414346	The MITF p.E318K risk variant was detected in a total of fifteen probands (3.3%), a frequency more than twice that of the Dutch reference population (MAF 0.015; GoNL: 0.007) (Table 3).	('MITF', 'Gene', '4286', (4, 8))	('MITF', 'Gene', (4, 8))	('p.E318K', 'Mutation', 'rs149617956', (9, 16))	('p.E318K', 'Var', (9, 16))
94184	30414346	All MITF p.E318K families had at least two members with CM ('familial CM'; seven two-case families, six three-case families, and two families with four or more cases).	('MITF', 'Gene', '4286', (4, 8))	('MITF', 'Gene', (4, 8))	('p.E318K', 'Mutation', 'rs149617956', (9, 16))	('p.E318K', 'Var', (9, 16))
94188	30414346	In the three shelterin complex subunits that have been reported as high penetrance melanoma susceptibility genes (POT1, ACD, TERF2IP), we identified two potentially deleterious variants (Table 3).	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('shelterin complex', 'cellular_component', 'GO:0070187', ('13', '30'))	('variants', 'Var', (177, 185))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))
94189	30414346	A rare missense variant in the ACD gene (c.871A>G, p.(T291A)), detected in a proband from a two-case family, is located in the POT1 binding domain in which previously reported pathogenic variants seem to cluster.12 A very rare missense variant in the TERF2IP gene (c.398G>A, p.(R133Q)), located in the MyB DNA binding domain, was detected in a proband of another two-case family.	('DNA', 'cellular_component', 'GO:0005574', ('306', '309'))	('c.398G>A', 'Mutation', 'rs1349826807', (265, 273))	('p.(T291A)', 'Mutation', 'rs139438549', (51, 60))	('DNA binding', 'molecular_function', 'GO:0003677', ('306', '317'))	('p.(R133Q)', 'Mutation', 'rs1349826807', (275, 284))	('binding', 'molecular_function', 'GO:0005488', ('132', '139'))	('c.398G>A', 'Var', (265, 273))	('TERF2IP', 'Gene', (251, 258))	('c.871A>G', 'Mutation', 'rs139438549', (41, 49))
94190	30414346	These included a novel variant in the ACD/TERF2 binding motif domain of the TINF2 gene (c.38G>T, p.(R13L)) and two extremely rare variants in the TERF1 gene (c.1193A>G, p.(Y398C); MyB DNA binding domain) and the TERF2 gene (c.794G>A, p.(R265H)).	('c.1193A>G', 'Var', (158, 167))	('c.1193A>G', 'Mutation', 'rs760966818', (158, 167))	('c.794G>A', 'Mutation', 'rs763347805', (224, 232))	('binding', 'molecular_function', 'GO:0005488', ('48', '55'))	('c.38G>T', 'Mutation', 'c.38G>T', (88, 95))	('DNA binding', 'molecular_function', 'GO:0003677', ('184', '195'))	('p.(R13L)', 'Mutation', 'p.R13L', (97, 105))	('DNA', 'cellular_component', 'GO:0005574', ('184', '187'))	('TINF2', 'Gene', (76, 81))	('c.794G>A', 'Var', (224, 232))	('p.(Y398C)', 'Mutation', 'rs760966818', (169, 178))	('c.38G>T', 'Var', (88, 95))	('p.(R265H)', 'Mutation', 'rs763347805', (234, 243))
94192	30414346	None of the patients in our cohort carried the known melanoma susceptibly variant in the TERT promoter region (c.-57T>G).	('c.-57T>G', 'Mutation', 'rs951173847', (111, 119))	('patients', 'Species', '9606', (12, 20))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('c.-57T>G', 'Var', (111, 119))
94193	30414346	The frequency of p.D84E was most strikingly increased in our cohort (OR 5.66, 95% CI 1.88-17.06, p = 0.001), followed by p.R160W (OR 3.82, 95% CI 2.72-5.37, p <0.001) and p.R151C (OR 3.78, 95% CI 2.68-5.34, p <0.001).	('p.R160W', 'Mutation', 'rs1805008', (121, 128))	('p.R151C', 'Mutation', 'rs1805007', (171, 178))	('p.D84E', 'Var', (17, 23))	('p.R160W', 'Var', (121, 128))	('p.R151C', 'Var', (171, 178))	('increased', 'PosReg', (44, 53))	('p.D84E', 'Mutation', 'rs1805006', (17, 23))
94194	30414346	In addition to the novel, truncating variant in the BRIP1 gene (c.894C>A, p.(C298*)) found in one of the BAP1-families, an additional seven potentially deleterious missense variants were identified in BRIP1 (Table 4).	('p.(C298*)', 'SUBSTITUTION', 'None', (74, 83))	('c.894C>A', 'Mutation', 'c.894C>A', (64, 72))	('C298*', 'Var', (77, 82))	('BRIP1', 'Gene', (52, 57))	('c.894C>A', 'Var', (64, 72))	('BAP1', 'Gene', '8314', (105, 109))	('p.(C298*', 'Var', (74, 82))	('BRIP1', 'Gene', (201, 206))	('C298*', 'SUBSTITUTION', 'None', (77, 82))	('BAP1', 'Gene', (105, 109))
94195	30414346	This included one novel variant (c.2069G>A, p.(G690E)) and two extremely rare variants (c.2582C>G, p.(S861C) and c.2593C>T, p.(R865W)) located in the DNA helicase domain and predicted to be damaging by all in silico tools including UMD-predictor.	('p.(G690E)', 'Mutation', 'rs878855144', (44, 53))	('c.2593C>T', 'Mutation', 'rs578022079', (113, 122))	('c.2582C>G', 'Var', (88, 97))	('c.2069G>A', 'Var', (33, 42))	('p.(R865W)', 'Mutation', 'rs578022079', (124, 133))	('c.2582C>G', 'Mutation', 'rs774415723', (88, 97))	('DNA', 'cellular_component', 'GO:0005574', ('150', '153'))	('c.2593C>T', 'Var', (113, 122))	('c.2069G>A', 'Mutation', 'rs878855144', (33, 42))	('p.(S861C)', 'Mutation', 'rs774415723', (99, 108))
94196	30414346	In this same domain, a different missense variant was previously reported to co-segregate in a three-case melanoma family.22 The remaining four variants were located in the ATPase/helicase core domain, and included an extremely rare variant (c.1198G>T, p.(D400Y)) in two probands and a very rare variant (c.1255C>T, p.(R419W)) in one proband.	('p.(R419W)', 'Mutation', 'rs150624408', (316, 325))	('c.1198G>T', 'Mutation', 'rs764711572', (242, 251))	('core', 'cellular_component', 'GO:0019013', ('189', '193'))	('p.(D400Y)', 'Mutation', 'rs764711572', (253, 262))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('c.1198G>T', 'Var', (242, 251))	('melanoma', 'Disease', (106, 114))	('c.1255C>T', 'Mutation', 'rs150624408', (305, 314))
94197	30414346	We further identified two missense variants in the exonuclease domain of the POLE gene: one novel variant (c.893A>G, p.(Y298C)) in a single proband and a rare variant (c.861T>A, p.(D287E)) in nine other probands (Table 4).	('p.(Y298C)', 'Mutation', 'rs750585084', (117, 126))	('c.861T>A', 'Var', (168, 176))	('p.(D287E)', 'Mutation', 'rs137904015', (178, 187))	('c.893A>G', 'Var', (107, 115))	('c.861T>A', 'Mutation', 'rs137904015', (168, 176))	('c.893A>G', 'Mutation', 'rs201613708', (107, 115))
94198	30414346	In another proband, we identified a novel truncating variant in POLE (c.1230G>A, p.(W410*)), but this variant did not co-segregate with the phenotype in a two-case family.	('c.1230G>A', 'Var', (70, 79))	('W410*', 'Var', (84, 89))	('W410*', 'SUBSTITUTION', 'None', (84, 89))	('p.(W410*', 'Var', (81, 89))	('c.1230G>A', 'Mutation', 'rs781127629', (70, 79))	('p.(W410*)', 'SUBSTITUTION', 'None', (81, 90))
94199	30414346	In the OCA2 gene, we identified nine (potentially) deleterious variants, of which six were previously reported in patients with the recessively inherited condition oculocutaneous albinism type 2 (MIM #203200) (Table 4).	('OCA2', 'Species', '1933259', (7, 11))	('variants', 'Var', (63, 71))	('oculocutaneous albinism type 2', 'Disease', (164, 194))	('OCA2', 'Gene', (7, 11))	('albinism', 'Phenotype', 'HP:0001022', (179, 187))	('patients', 'Species', '9606', (114, 122))
94200	30414346	Two of these established pathogenic variants, c.1327G>A, p.(V443I) and c.1465A>G, p.(N489D), were detected in multiple individuals (n = 17 and 7, respectively) and the frequency of these variants was more than twice that found in the Dutch GoNL reference database (MAF: 0.018 and 0.0071; GoNL: 0.008 and 0.003, respectively).	('pathogenic', 'CPA', (25, 35))	('p.(N489D)', 'Mutation', 'rs121918170', (82, 91))	('p.(V443I)', 'Mutation', 'rs121918166', (57, 66))	('c.1465A>G', 'Mutation', 'rs121918170', (71, 80))	('c.1327G>A', 'Var', (46, 55))	('c.1465A>G', 'Var', (71, 80))	('c.1327G>A', 'Mutation', 'rs121918166', (46, 55))
94204	30414346	Another proband, with a medical history of three primary melanomas from age 48 and a first-degree relative (child) with melanoma at age 32, carried two pathogenic variants in the OCA2 gene (c.1327G>A, p.(V443I) and c.2037G>C, p.(W679C)).	('c.2037G>C', 'Mutation', 'rs121918169', (215, 224))	('primary melanomas', 'Disease', 'MESH:D008545', (49, 66))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('c.1327G>A', 'Var', (190, 199))	('OCA2', 'Gene', (179, 183))	('melanoma', 'Disease', (120, 128))	('p.(W679C)', 'SUBSTITUTION', 'None', (226, 235))	('OCA2', 'Species', '1933259', (179, 183))	('c.2037G>C', 'Var', (215, 224))	('p.(W679C', 'Var', (226, 234))	('p.(V443I)', 'Mutation', 'rs121918166', (201, 210))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('c.1327G>A', 'Mutation', 'rs121918166', (190, 199))	('primary melanomas', 'Disease', (49, 66))	('child', 'Species', '9606', (108, 113))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))
94207	30414346	We identified (likely) pathogenic variants in established high- and medium penetrance melanoma susceptibility genes in 4.0% of these families (18/451; n = 3 BAP1, n = 15 MITF).	('MITF', 'Gene', '4286', (170, 174))	('MITF', 'Gene', (170, 174))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('variants', 'Var', (34, 42))	('melanoma', 'Disease', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('BAP1', 'Gene', (157, 161))	('pathogenic', 'Reg', (23, 33))	('BAP1', 'Gene', '8314', (157, 161))
94210	30414346	Although CM itself is relatively common in BAP1 mutation carriers (13-18%),14, 26 BAP1 mutations are rarely reported in CM families without these other cancers: a study by Njauw et al.27 detected only one BAP1 mutation in 193 CM families (0.5%), and a study by Wadt et al.28 found no BAP1 mutations in 133 high-risk CM patients (of which 94 CM families).	('BAP1', 'Gene', (43, 47))	('BAP1', 'Gene', (82, 86))	('BAP1', 'Gene', '8314', (205, 209))	('BAP1', 'Gene', '8314', (284, 288))	('patients', 'Species', '9606', (319, 327))	('BAP1', 'Gene', '8314', (43, 47))	('other cancers', 'Disease', 'MESH:D009369', (146, 159))	('mutation', 'Var', (48, 56))	('BAP1', 'Gene', (205, 209))	('BAP1', 'Gene', '8314', (82, 86))	('BAP1', 'Gene', (284, 288))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('other cancers', 'Disease', (146, 159))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
94211	30414346	By contrast, Gerami et al.29 found a BAP1 mutation in a single case with multiple primary cutaneous melanomas and a dysplastic nevus phenotype, with no family history for either CM or UM or any other BAP1-associated cancers.	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cutaneous melanomas', 'Disease', (90, 109))	('cancers', 'Disease', (216, 223))	('BAP1', 'Gene', (200, 204))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('BAP1', 'Gene', '8314', (37, 41))	('mutation', 'Var', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('nevus', 'Phenotype', 'HP:0003764', (127, 132))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (116, 132))	('dysplastic nevus', 'Disease', 'MESH:D004416', (116, 132))	('dysplastic nevus', 'Disease', (116, 132))	('cancers', 'Disease', 'MESH:D009369', (216, 223))	('BAP1', 'Gene', (37, 41))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (90, 109))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (90, 109))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (90, 108))	('BAP1', 'Gene', '8314', (200, 204))
94212	30414346	A recent population-based study reported only three loss-of-function BAP1 mutations in CM cases (<0.2%), and all these cases had relatives with BAP1-associated cancers, although none had UM.30 Our study demonstrates that BAP1 mutations can indeed be detected in some CM families without UM or malignant mesothelioma and it is therefore important to incorporate the BAP1 gene in a diagnostic (cutaneous) melanoma gene panel test.	('BAP1', 'Gene', '8314', (221, 225))	('BAP1', 'Gene', '8314', (365, 369))	('melanoma', 'Disease', 'MESH:D008545', (403, 411))	('loss-of-function', 'NegReg', (52, 68))	('BAP1', 'Gene', '8314', (69, 73))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (293, 315))	('cancers', 'Disease', (160, 167))	('BAP1', 'Gene', (144, 148))	('BAP1', 'Gene', (221, 225))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('detected', 'Reg', (250, 258))	('BAP1', 'Gene', (365, 369))	('melanoma', 'Phenotype', 'HP:0002861', (403, 411))	('malignant mesothelioma', 'Disease', (293, 315))	('BAP1', 'Gene', (69, 73))	('melanoma', 'Disease', (403, 411))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (293, 315))	('mutations', 'Var', (226, 235))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('mutations', 'Var', (74, 83))	('BAP1', 'Gene', '8314', (144, 148))
94213	30414346	However, it should be noted that basal cell carcinoma and (atypical) Spitz nevi, features also associated with BAP1 mutations, were reported in two of the families.	('BAP1', 'Gene', '8314', (111, 115))	('Spitz nevi', 'Disease', (69, 79))	('BAP1', 'Gene', (111, 115))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (33, 53))	('mutations', 'Var', (116, 125))	('basal cell carcinoma', 'Disease', (33, 53))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (33, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('nevi', 'Phenotype', 'HP:0003764', (75, 79))
94214	30414346	Fifteen probands in our familial CM cohort (15/442; 3.4%) carried the MITF p.E318K risk variant, which is among the highest frequencies reported in familial non-CDKN2A cases.	('p.E318K', 'Var', (75, 82))	('p.E318K', 'Mutation', 'rs149617956', (75, 82))	('CDKN2A', 'Gene', (161, 167))	('MITF', 'Gene', '4286', (70, 74))	('MITF', 'Gene', (70, 74))	('CDKN2A', 'Gene', '1029', (161, 167))
94215	30414346	Only one small study from Switzerland reported a higher frequency, 7.7% (2/26), in melanoma-prone families.31 A similar frequency, 3.4% (19/558) in familial cases, was found in a study from the United States, although it is unclear if these patients were all pre-screened for CDKN2A mutations.32 Frequencies in various other cohorts range from 0 to 3%,16, 28, 33, 34, 35 with the lowest frequency (<1%) reported in familial cases from Italy.17, 36 In the Netherlands, diagnostic testing for the MITF p.E318K risk variant is now included in the default genetic work-up for familial CM and all carriers are offered regular dermatologic surveillance (regardless of the familial burden for CM).	('MITF', 'Gene', (495, 499))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('CDKN2A', 'Gene', (276, 282))	('familial CM', 'Disease', (572, 583))	('pre', 'molecular_function', 'GO:0003904', ('259', '262'))	('p.E318K', 'Var', (500, 507))	('CDKN2A', 'Gene', '1029', (276, 282))	('p.E318K', 'Mutation', 'rs149617956', (500, 507))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('patients', 'Species', '9606', (241, 249))	('melanoma', 'Disease', (83, 91))	('MITF', 'Gene', '4286', (495, 499))
94217	30414346	Hence, knowledge about MITF p.E318K mutation status can be relevant for both the patient and the dermatologist.	('p.E318K', 'Mutation', 'rs149617956', (28, 35))	('patient', 'Species', '9606', (81, 88))	('MITF', 'Gene', '4286', (23, 27))	('MITF', 'Gene', (23, 27))	('p.E318K', 'Var', (28, 35))
94219	30414346	Germline mutations in the telomere maintenance pathway genes in melanoma families have been described in several studies.11, 12, 13 The present study demonstrates that mutations in these genes are probably very rare in the Dutch familial melanoma population.	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('telomere', 'cellular_component', 'GO:0005696', ('26', '34'))	('melanoma', 'Disease', (238, 246))	('melanoma', 'Disease', 'MESH:D008545', (238, 246))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('telomere maintenance', 'biological_process', 'GO:0000723', ('26', '46'))	('melanoma', 'Disease', (64, 72))	('familial melanoma', 'Disease', (229, 246))	('telomere', 'cellular_component', 'GO:0000781', ('26', '34'))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('familial melanoma', 'Disease', 'OMIM:155600', (229, 246))	('mutations', 'Var', (168, 177))
94223	30414346	We identified several variants of interest in the known cancer susceptibility genes BRIP1 and POLE, including a nonsense variant in BRIP1.	('BRIP1', 'Gene', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('BRIP1', 'Gene', (84, 89))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('variants', 'Var', (22, 30))
94230	30414346	It appears that only missense variants in the exonuclease domain confer an increased susceptibility for cancer through impaired proofreading, which results in tumors with a high mutation burden.40 Therefore, we restricted our analysis of variants to this specific exonuclease domain and, consequently, all reported variants in POLE are located within this domain.	('variants', 'Var', (315, 323))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
94231	30414346	Recently, a novel missense variant in the exonuclease domain of POLE was reported in a seven-case melanoma family and showed near-complete co-segregation.20 Although we were not able to perform co-segregation analysis for the novel missense variant (c.893A>G, p.(Y298C)) detected in our cohort, functional analysis of melanoma tissue (mutation burden test) might provide more insight.	('melanoma', 'Phenotype', 'HP:0002861', (318, 326))	('melanoma', 'Disease', (318, 326))	('p.(Y298C)', 'Mutation', 'rs750585084', (260, 269))	('c.893A>G', 'Mutation', 'rs201613708', (250, 258))	('melanoma', 'Disease', 'MESH:D008545', (318, 326))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('c.893A>G', 'Var', (250, 258))
94233	30414346	Biallelic germline mutations in OCA2 cause oculocutaneous albinism type 2 (MIM #203200).	('OCA2', 'Gene', (32, 36))	('oculocutaneous albinism type 2', 'Disease', (43, 73))	('Biallelic germline mutations', 'Var', (0, 28))	('OCA2', 'Species', '1933259', (32, 36))	('albinism', 'Phenotype', 'HP:0001022', (58, 66))	('cause', 'Reg', (37, 42))
94235	30414346	Loss-of-function of the P-protein results in hypopigmentation of the skin, hair and iris and an increased risk for sun-induced skin cancers, in particular basal cell carcinoma and squamous cell carcinoma.41 Although melanoma is not known to be a common cancer type in patients with OCA2-related albinism, families with multiple members with albinism and melanoma have been reported.42 In our cohort, one proband with a possible subclinical phenotype of albinism carried a homozygous pathogenic OCA2 variant.	('melanoma', 'Disease', 'MESH:D008545', (354, 362))	('skin cancers', 'Phenotype', 'HP:0008069', (127, 139))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('patients', 'Species', '9606', (268, 276))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (155, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('skin cancers', 'Disease', (127, 139))	('P-protein', 'Gene', '4948', (24, 33))	('albinism', 'Phenotype', 'HP:0001022', (295, 303))	('skin cancers', 'Disease', 'MESH:D012878', (127, 139))	('hypopigmentation', 'Phenotype', 'HP:0001010', (45, 61))	('albinism', 'Phenotype', 'HP:0001022', (453, 461))	('melanoma', 'Disease', 'MESH:D008545', (216, 224))	('variant', 'Var', (499, 506))	('melanoma', 'Phenotype', 'HP:0002861', (354, 362))	('albinism', 'Phenotype', 'HP:0001022', (341, 349))	('melanoma', 'Disease', (354, 362))	('OCA2', 'Species', '1933259', (282, 286))	('particular basal cell carcinoma', 'Disease', (144, 175))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (180, 203))	('OCA2', 'Gene', (494, 498))	('cancer', 'Disease', (253, 259))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('cancer', 'Disease', (132, 138))	('P-protein', 'Gene', (24, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('squamous cell carcinoma', 'Disease', (180, 203))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('melanoma', 'Disease', (216, 224))	('P-protein', 'molecular_function', 'GO:0004375', ('24', '33'))	('hypopigmentation of the skin, hair and iris', 'Disease', 'MESH:D017496', (45, 88))	('particular basal cell carcinoma', 'Disease', 'MESH:D002280', (144, 175))	('OCA2', 'Species', '1933259', (494, 498))
94236	30414346	Additionally, we observed an increased frequency of rare heterozygous variants in the OCA2 gene, in particular the known pathogenic variants c.1327G>A, p.(V443I) and c.1465A>G, p.(N489D).43, 44 The association with melanoma predisposition of the c.1327G>A, p.(V443I) variant in combination with another OCA2 variant was also studied by Hawkes et al.45 in one albinism-melanoma family.	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('melanoma', 'Disease', (215, 223))	('c.1327G>A', 'Var', (246, 255))	('albinism', 'Phenotype', 'HP:0001022', (359, 367))	('melanoma', 'Disease', 'MESH:D008545', (368, 376))	('albinism-melanoma', 'Disease', (359, 376))	('OCA2', 'Species', '1933259', (86, 90))	('c.1327G>A', 'Var', (141, 150))	('variants c.1327G>A', 'Var', (132, 150))	('melanoma', 'Disease', 'MESH:D008545', (215, 223))	('p.(N489D)', 'Mutation', 'rs121918170', (177, 186))	('c.1465A>G', 'Mutation', 'rs121918170', (166, 175))	('c.1465A>G', 'Var', (166, 175))	('albinism-melanoma', 'Disease', 'MESH:D008545', (359, 376))	('melanoma', 'Phenotype', 'HP:0002861', (368, 376))	('melanoma', 'Disease', (368, 376))	('p.(V443I)', 'Mutation', 'rs121918166', (257, 266))	('c.1327G>A', 'Mutation', 'rs121918166', (246, 255))	('p.(V443I)', 'Mutation', 'rs121918166', (152, 161))	('OCA2', 'Species', '1933259', (303, 307))	('variants', 'Var', (70, 78))	('c.1327G>A', 'Mutation', 'rs121918166', (141, 150))	('OCA2', 'Gene', (86, 90))
94237	30414346	They concluded that these variants might be high penetrance loci for melanoma in this family (OR 6.5).	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))	('variants', 'Var', (26, 34))
94239	30414346	Comparable to our study, numerous rare variants in OCA2 were found.	('OCA2', 'Species', '1933259', (51, 55))	('OCA2', 'Gene', (51, 55))	('variants', 'Var', (39, 47))
94240	30414346	The frequency of rare variants in other albinism genes (TYR, TYRP1) was also significantly increased in the Goldstein study.	('TYR', 'Chemical', 'MESH:D014443', (56, 59))	('TYR', 'Var', (56, 59))	('albinism', 'Phenotype', 'HP:0001022', (40, 48))	('TYRP1', 'Var', (61, 66))	('TYR', 'Chemical', 'MESH:D014443', (61, 64))	('increased', 'PosReg', (91, 100))
94241	30414346	Interestingly, a nonsense variant in TYR showed near-complete co-segregation in a large family with six melanoma cases.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('TYR', 'Chemical', 'MESH:D014443', (37, 40))	('nonsense', 'Var', (17, 25))	('TYR', 'Gene', (37, 40))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
94244	30414346	Since some of the familial occurrence of melanoma might be explained by the aggregation of common risk variants in a family, we are currently incorporating all MC1R R and r variants in a polygenic risk score (PRS) model that also includes approximately 40 other common risk variants derived from large melanoma GWAS.	('melanoma', 'Phenotype', 'HP:0002861', (302, 310))	('melanoma', 'Disease', (302, 310))	('melanoma GWAS', 'Disease', (302, 315))	('melanoma', 'Disease', 'MESH:D008545', (302, 310))	('melanoma', 'Disease', (41, 49))	('MC1R', 'Gene', (160, 164))	('melanoma GWAS', 'Disease', 'MESH:D008545', (302, 315))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('variants', 'Var', (173, 181))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))
94246	30414346	With the inclusion of 451 families lacking a mutation in the CDKN2A or CDK4 genes, of which 442 families had at least two cases of CM, to our knowledge this is the largest melanoma gene panel study to date.	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('CDKN2A', 'Gene', (61, 67))	('CDK4', 'Gene', (71, 75))	('CDK4', 'Gene', '1019', (71, 75))	('CDKN2A', 'Gene', '1029', (61, 67))	('mutation', 'Var', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanoma', 'Disease', (172, 180))	('CDK', 'molecular_function', 'GO:0004693', ('71', '74'))
94250	30414346	However, co-segregation analysis of (likely) pathogenic variants in known cancer susceptibility genes (BAP1, MITF, BRIP1) is currently being initiated.	('BAP1', 'Gene', '8314', (103, 107))	('MITF', 'Gene', (109, 113))	('MITF', 'Gene', '4286', (109, 113))	('BRIP1', 'Gene', (115, 120))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('BAP1', 'Gene', (103, 107))	('cancer', 'Disease', (74, 80))	('variants', 'Var', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
94252	30414346	The identification of several families with pathogenic variants in the BAP1 and MITF genes suggests a significant role of these genes in melanoma predisposition and it is therefore important to include these in a diagnostic test.	('MITF', 'Gene', (80, 84))	('variants', 'Var', (55, 63))	('BAP1', 'Gene', '8314', (71, 75))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('pathogenic', 'Reg', (44, 54))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('BAP1', 'Gene', (71, 75))	('MITF', 'Gene', '4286', (80, 84))
94253	30414346	In view of the relatively high frequency of (potential) pathogenic variants in the OCA2 gene in both our own and in a recently published American familial melanoma cohort, further elucidation of the role of heterozygous OCA2 variants in melanoma predisposition appears to be of particular interest.	('melanoma', 'Disease', (237, 245))	('pathogenic', 'Reg', (56, 66))	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('OCA2', 'Species', '1933259', (220, 224))	('melanoma', 'Disease', 'MESH:D008545', (237, 245))	('OCA2', 'Species', '1933259', (83, 87))	('variants', 'Var', (67, 75))	('familial melanoma cohort', 'Disease', (146, 170))	('familial melanoma cohort', 'Disease', 'OMIM:155600', (146, 170))	('OCA2', 'Gene', (220, 224))	('variants', 'Var', (225, 233))	('OCA2', 'Gene', (83, 87))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('melanoma', 'Disease', (155, 163))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))
94310	30418387	When Stage IIIA Class 1a tumors were compared to Stage IIIA Class 1b tumors, it was found that Stage IIIA Class 1b tumors were significantly more likely to have associated subretinal fluid (p = 0.015) (Supplemental Table 4).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('subretinal fluid', 'Phenotype', 'HP:0031526', (172, 188))	('subretinal fluid', 'Disease', (172, 188))	('tumors', 'Disease', (115, 121))	('Stage IIIA Class 1b', 'Var', (95, 114))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))
94335	30418387	Field et al found this to be true among Class 1 UMs that metastasized and both Decatur et al and Yavuzyigitoglu et al have reported an association between late metastases and mutations in the SF3B1 (splicing factor 3 subunit B1) gene.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('splicing factor 3 subunit B1', 'Gene', '23451', (199, 227))	('SF3B1', 'Gene', (192, 197))	('metastases', 'Disease', (160, 170))	('splicing', 'biological_process', 'GO:0045292', ('199', '207'))	('mutations', 'Var', (175, 184))	('SF3B1', 'Gene', '23451', (192, 197))	('metastases', 'Disease', 'MESH:D009362', (160, 170))	('splicing factor 3 subunit B1', 'Gene', (199, 227))
94340	30418387	When AJCC Stage IIA tumors were compared by GEP subclass, we found that Class 1b tumors were significantly thicker than their Class 1a counterparts.	('Class 1b', 'Var', (72, 80))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', (81, 87))	('thicker', 'PosReg', (107, 114))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
94362	31179139	According to the TNM staging of metastatic disease in uveal melanoma (MUM), M0 is defined as the absence of distant metastasis, while M1a is a disease with distant metastasis with the largest diameter of 3 cm or less, M1b is metastatic disease with the largest diameter of 3.1 to 8 cm, and M1c is metastatic disease with the largest diameter of 8 cm or more.	('TNM', 'Gene', '10178', (17, 20))	('M1a', 'Var', (134, 137))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('UM', 'Phenotype', 'HP:0007716', (71, 73))	('TNM', 'Gene', (17, 20))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))
94365	31179139	Oncogenic mutations in G-protein subunits a (GNAQ) and 11 (GNA11) have been described in 80% of uveal melanomas.	('described', 'Reg', (76, 85))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('uveal melanomas', 'Disease', (96, 111))	('GNA11', 'Gene', '2767', (59, 64))	('GNA11', 'Gene', (59, 64))	('GNAQ', 'Gene', (45, 49))	('uveal melanomas', 'Phenotype', 'HP:0007716', (96, 111))	('mutations', 'Var', (10, 19))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('uveal melanomas', 'Disease', 'MESH:C536494', (96, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('GNAQ', 'Gene', '2776', (45, 49))
94397	31179139	Another large multicenter case series including 56 patients who received anti-PD1 (nivolumab, pembrolizumab) or anti-PDL1 (atezolizumab) agents showed median OS and PFS of 7.6 months and 2.6 months, respectively.	('anti-PD1', 'Var', (73, 81))	('PDL1', 'Gene', '29126', (117, 121))	('atezolizumab', 'Chemical', 'MESH:C000594389', (123, 135))	('PDL1', 'Gene', (117, 121))
94444	30464381	Moreover, AJCC T4 tumors have reported Kaplan-Meier mortality estimates of 30% at 5 years, 43% at 10 years, and 51% at 20 years among the general population, while similar tumors in young adults have Kaplan-Meier mortality estimates of 35.1% at 5 years, 45.6% at 10 years, and 59.4% at 15 years with a median survival time of 11.9 years.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Disease', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('AJCC T4', 'Var', (10, 17))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
94459	30464381	Preliminary data, recently published, has shown that monosomy 3 with 8q gain corresponds to the highest risk of tumor metastasis, and disomy 3 corresponds to the lowest risk of metastasis, as in the general uveal melanoma patient population.	('disomy 3', 'Var', (134, 142))	('tumor metastasis', 'Disease', 'MESH:D009362', (112, 128))	('tumor metastasis', 'Disease', (112, 128))	('patient', 'Species', '9606', (222, 229))	('uveal melanoma', 'Disease', 'MESH:C536494', (207, 221))	('uveal melanoma', 'Phenotype', 'HP:0007716', (207, 221))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('gain', 'PosReg', (72, 76))	('uveal melanoma', 'Disease', (207, 221))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('monosomy 3', 'Var', (53, 63))
94461	30464381	That is because studies have found that twice as many non-spindle tumors (mixed and epithelioid) also showed monosomy 3.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('monosomy 3', 'Var', (109, 119))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('spindle', 'cellular_component', 'GO:0005819', ('58', '65'))
94463	30464381	These results concur with others finding that monosomy 3 with 8q gain correspond with an older age at treatment as well as a poorer prognosis, which could explain why younger patients tend to have a better prognosis than the general PUM population.	('patients', 'Species', '9606', (175, 183))	('gain', 'PosReg', (65, 69))	('monosomy 3', 'Var', (46, 56))
94476	29899166	Abnormally expressed JunB transactivated by IL-6/STAT3 signaling promotes uveal melanoma aggressiveness via epithelial-mesenchymal transition Uveal melanoma (UM) is the most common primary intraocular tumor in adults, and it carries a high risk of metastasis and mortality.	('STAT3', 'Gene', (49, 54))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('JunB', 'Gene', '3726', (21, 25))	('IL-6', 'Gene', '3569', (44, 48))	('Abnormally', 'Var', (0, 10))	('STAT3', 'Gene', '6774', (49, 54))	('IL-6', 'molecular_function', 'GO:0005138', ('44', '48'))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('IL-6', 'Gene', (44, 48))	('aggressiveness', 'Phenotype', 'HP:0000718', (89, 103))	('signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('ocular tumor', 'Phenotype', 'HP:0100012', (194, 206))	('uveal melanoma aggressiveness', 'Disease', (74, 103))	('intraocular tumor', 'Disease', 'MESH:D064090', (189, 206))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('uveal melanoma aggressiveness', 'Disease', 'MESH:C536494', (74, 103))	('epithelial-mesenchymal', 'CPA', (108, 130))	('promotes', 'PosReg', (65, 73))	('UM', 'Phenotype', 'HP:0007716', (158, 160))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('intraocular tumor', 'Disease', (189, 206))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (142, 156))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('108', '141'))	('JunB', 'Gene', (21, 25))
94483	29899166	Importantly, the knockdown of STAT3 prevented the IL-6-induced EMT phenotype as well as cell migration and invasion, whereas JunB overexpression recovered the attenuated aggressiveness of UM cells.	('invasion', 'CPA', (107, 115))	('aggressiveness', 'Phenotype', 'HP:0000718', (170, 184))	('IL-6', 'Gene', (50, 54))	('IL-6', 'Gene', '3569', (50, 54))	('aggressiveness', 'Disease', 'MESH:D001523', (170, 184))	('STAT3', 'Gene', '6774', (30, 35))	('cell migration', 'biological_process', 'GO:0016477', ('88', '102'))	('cell migration', 'CPA', (88, 102))	('IL-6', 'molecular_function', 'GO:0005138', ('50', '54'))	('knockdown', 'Var', (17, 26))	('STAT3', 'Gene', (30, 35))	('aggressiveness', 'Disease', (170, 184))	('UM', 'Phenotype', 'HP:0007716', (188, 190))	('EMT', 'biological_process', 'GO:0001837', ('63', '66'))	('prevented', 'NegReg', (36, 45))
94497	29899166	As Jun family members, Jun and JunB share extensive homology within the leucine zipper and basic domains, and JunB can rescue the lethal phenotype in Jun-null mice.	('JunB', 'Var', (110, 114))	('rescue', 'PosReg', (119, 125))	('lethal phenotype', 'CPA', (130, 146))	('mice', 'Species', '10090', (159, 163))
94499	29899166	Growing evidence has shown that aberrantly expressed JunB promotes migration, invasion, and metastasis during cancer progression.	('cancer', 'Disease', (110, 116))	('aberrantly expressed', 'Var', (32, 52))	('invasion', 'CPA', (78, 86))	('metastasis', 'CPA', (92, 102))	('promotes', 'PosReg', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('migration', 'CPA', (67, 76))	('JunB', 'Protein', (53, 57))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
94516	29899166	The reads containing adapter or poly-N and reads of low quality were removed from raw data to generate clean reads for further analyses.	('adapter', 'Var', (21, 28))	('poly-N', 'Chemical', '-', (32, 38))	('poly-N', 'Var', (32, 38))
94526	29899166	The reporter constructs containing various lengths of JunB promoter or mutated STAT3 binding sites were generated by subsequent PCR-based cloning.	('STAT3', 'Gene', '6774', (79, 84))	('STAT3', 'Gene', (79, 84))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('mutated', 'Var', (71, 78))
94536	29899166	In contrast, the IL6/C918 and IL6/OCM1A cells displayed a lower proliferative ability than the parental cells (Figure 1C, relative absorptivity: 0.71 (IL6/C918 vs C918); 0.74 (IL6/OCM1A vs OCM1A)).	('IL6', 'Gene', (30, 33))	('IL6', 'molecular_function', 'GO:0005138', ('176', '179'))	('IL6', 'Gene', '3569', (17, 20))	('IL6', 'Gene', '3569', (151, 154))	('lower', 'NegReg', (58, 63))	('IL6', 'Gene', (17, 20))	('IL6', 'Gene', (151, 154))	('IL6', 'molecular_function', 'GO:0005138', ('30', '33'))	('IL6', 'molecular_function', 'GO:0005138', ('151', '154'))	('OCM1', 'Species', '83984', (34, 38))	('C918', 'Var', (163, 167))	('IL6', 'Gene', '3569', (176, 179))	('OCM1', 'Species', '83984', (189, 193))	('proliferative ability', 'CPA', (64, 85))	('IL6', 'Gene', (176, 179))	('OCM1', 'Species', '83984', (180, 184))	('IL6', 'Gene', '3569', (30, 33))	('IL6', 'molecular_function', 'GO:0005138', ('17', '20'))
94553	29899166	Similarly, the knockdown of STAT3 markedly undermined JunB expression in IL6/C918 cells, suggesting that IL-6/STAT3 signaling is critical for the up-regulation of JunB in IL-6-transformed UM cells (Figure 4B).	('IL6', 'Gene', '3569', (73, 76))	('IL-6', 'Gene', '3569', (171, 175))	('STAT3', 'Gene', (110, 115))	('IL-6', 'Gene', (171, 175))	('IL-6', 'Gene', '3569', (105, 109))	('undermined', 'NegReg', (43, 53))	('IL6', 'Gene', (73, 76))	('IL-6', 'molecular_function', 'GO:0005138', ('105', '109'))	('JunB expression', 'MPA', (54, 69))	('STAT3', 'Gene', (28, 33))	('STAT3', 'Gene', '6774', (110, 115))	('IL6', 'molecular_function', 'GO:0005138', ('73', '76'))	('IL-6', 'Gene', (105, 109))	('regulation', 'biological_process', 'GO:0065007', ('149', '159'))	('STAT3', 'Gene', '6774', (28, 33))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))	('up-regulation', 'PosReg', (146, 159))	('knockdown', 'Var', (15, 24))	('IL-6', 'molecular_function', 'GO:0005138', ('171', '175'))	('UM', 'Phenotype', 'HP:0007716', (188, 190))
94557	29899166	A mutation in SBE1 significantly reduced the reporter activity induced by IL-6, while SBE2 mutation completely abolished the effect of IL-6 (Figure 4E).	('SBE1', 'Gene', (14, 18))	('IL-6', 'Gene', (135, 139))	('mutation', 'Var', (91, 99))	('mutation', 'Var', (2, 10))	('SBE2', 'Gene', (86, 90))	('IL-6', 'Gene', (74, 78))	('IL-6', 'Gene', '3569', (74, 78))	('IL-6', 'Gene', '3569', (135, 139))	('IL-6', 'molecular_function', 'GO:0005138', ('135', '139'))	('reduced', 'NegReg', (33, 40))	('reporter activity', 'MPA', (45, 62))	('IL-6', 'molecular_function', 'GO:0005138', ('74', '78'))
94559	29899166	Consistent with the reporter assay, a stronger enrichment of STAT3 on SBE2 was observed than on SBE1.	('STAT3', 'Gene', '6774', (61, 66))	('STAT3', 'Gene', (61, 66))	('SBE2', 'Var', (70, 74))
94560	29899166	Altogether, these results indicate that IL-6/STAT3 signaling can transactivate JunB via a novel SBE in UM cells.	('SBE', 'MPA', (96, 99))	('JunB', 'Gene', (79, 83))	('IL-6', 'molecular_function', 'GO:0005138', ('40', '44'))	('transactivate', 'Var', (65, 78))	('STAT3', 'Gene', (45, 50))	('IL-6', 'Gene', (40, 44))	('IL-6', 'Gene', '3569', (40, 44))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('UM', 'Phenotype', 'HP:0007716', (103, 105))	('STAT3', 'Gene', '6774', (45, 50))
94573	29899166	More recently, in vivo assays showed that C918-derived tumors completely disrupted the eye structure, while the structure of OCM1-grafted eyes remained intact.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('eye structure', 'CPA', (87, 100))	('tumors', 'Disease', (55, 61))	('C918-derived', 'Var', (42, 54))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('OCM1', 'Species', '83984', (125, 129))	('disrupted', 'NegReg', (73, 82))
94635	28930163	Over the past several years, genetic profiling:including microarray analysis and genome sequencing:have helped with identifying multiple key cellular pathways that are frequently mutated in leukemias.	('leukemias', 'Phenotype', 'HP:0001909', (190, 199))	('leukemias', 'Disease', (190, 199))	('leukemias', 'Disease', 'MESH:D007938', (190, 199))	('leukemia', 'Phenotype', 'HP:0001909', (190, 198))	('mutated', 'Var', (179, 186))
94654	28930163	Interestingly, withdrawal of 4HT results in T-lymphocyte apoptosis and tumor regression.	('4HT', 'Chemical', '-', (29, 32))	('T-lymphocyte apoptosis', 'biological_process', 'GO:0070231', ('44', '66'))	('4HT', 'Gene', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('T-lymphocyte apoptosis', 'CPA', (44, 66))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('withdrawal', 'Var', (15, 25))	('tumor', 'Disease', (71, 76))
94655	28930163	Thanks to this transgenic model the authors discovered that loss-of-function mutations in the two zebrafish pten genes, or the expression of constitutively active AKT2, render tumors independent of the MYC oncogene.	('pten', 'Gene', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('MYC', 'Gene', (202, 205))	('pten', 'Gene', '368415', (108, 112))	('AKT2', 'Gene', (163, 167))	('MYC', 'Gene', '30686', (202, 205))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('mutations', 'Var', (77, 86))	('AKT2', 'Gene', '378972', (163, 167))	('zebrafish', 'Species', '7955', (98, 107))	('loss-of-function', 'NegReg', (60, 76))
94679	28930163	Moreover, the AKT inhibitor MK2206 can sensitize refractory T-ALL cells to dexamethasone-induced killing in vivo.	('dexamethasone', 'Chemical', 'MESH:D003907', (75, 88))	('MK2206', 'Chemical', 'MESH:C548887', (28, 34))	('AKT', 'Gene', (14, 17))	('ALL', 'Phenotype', 'HP:0006721', (62, 65))	('sensitize', 'Reg', (39, 48))	('MK2206', 'Var', (28, 34))	('AKT', 'Gene', '207', (14, 17))
94682	28930163	This fish was generated by zinc finger nuclease mutation of the plant homeodomain (PHD) domain of recombination activating gene 2 (rag2) gene.	('rat', 'Species', '10116', (18, 21))	('rag2', 'Gene', '30658', (131, 135))	('rag2', 'Gene', (131, 135))	('PHD', 'Disease', 'MESH:D011547', (83, 86))	('mutation', 'Var', (48, 56))	('PHD', 'molecular_function', 'GO:0050175', ('83', '86'))	('PHD', 'Disease', (83, 86))
94683	28930163	Mutations in this domain disrupt RAG2 functions; mutations in the same domain are found in patients with Omenn syndrome, an autosomal recessive severe combined immunodeficiency (SCID) characterized by impaired T and B cell receptor rearrangement and reduced number of functionally mature lymphocytes in human patients.	('RAG2', 'Gene', '5897', (33, 37))	('Omenn syndrome', 'Disease', 'MESH:C538564', (105, 119))	('disrupt', 'Reg', (25, 32))	('impaired', 'NegReg', (201, 209))	('RAG2', 'Gene', (33, 37))	('patients', 'Species', '9606', (91, 99))	('mutations', 'Var', (49, 58))	('immunodeficiency', 'Disease', (160, 176))	('Mutations', 'Var', (0, 9))	('human', 'Species', '9606', (303, 308))	('SCID', 'Disease', 'MESH:D053632', (178, 182))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (144, 176))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (151, 176))	('immunodeficiency', 'Disease', 'MESH:D007153', (160, 176))	('SCID', 'Disease', (178, 182))	('SCID', 'Phenotype', 'HP:0004430', (178, 182))	('functions', 'MPA', (38, 47))	('immunodeficiency', 'Phenotype', 'HP:0002721', (160, 176))	('reduced', 'NegReg', (250, 257))	('Omenn syndrome', 'Disease', (105, 119))	('patients', 'Species', '9606', (309, 317))
94688	28930163	Extensive characterization of these mutants showed that prkdc deficiency results in loss of mature T and B cells and jak3 mutants lack T and putative Natural Killer cells.	('lack', 'NegReg', (130, 134))	('mutants', 'Var', (122, 129))	('prkdc deficiency', 'Disease', 'MESH:D007153', (56, 72))	('loss', 'NegReg', (84, 88))	('jak', 'molecular_function', 'GO:0004713', ('117', '120'))	('jak3', 'Gene', (117, 121))	('jak3', 'Gene', '561370', (117, 121))	('prkdc deficiency', 'Disease', (56, 72))
94689	28930163	Although all mutant lines engraft fluorescently labeled normal and malignant cells, only the prkdc mutant fish can be bred as homozygotes and survive well after cell transplantation.	('mutant', 'Var', (99, 105))	('prkdc', 'Gene', (93, 98))	('prkdc', 'Gene', '562283', (93, 98))
94690	28930163	To study the stochastic events governing the emergence of underrepresented clones within primary leukemia, the authors transplanted equal numbers of T-ALL cells with similar growth kinetics, labeled with 3 different fluorophores, in prkdc mutant casper line.	('prkdc', 'Gene', '562283', (233, 238))	('prkdc', 'Gene', (233, 238))	('ALL', 'Phenotype', 'HP:0006721', (151, 154))	('leukemia', 'Disease', (97, 105))	('leukemia', 'Phenotype', 'HP:0001909', (97, 105))	('leukemia', 'Disease', 'MESH:D007938', (97, 105))	('mutant', 'Var', (239, 245))
94703	28930163	Starting from the assumption that immature T cells and leukemic T lymphoblasts share similar pathways or biological processes on which both depend, Trede and colleagues performed a chemical screen using the transgenic line Tg(lck:lck-EGFP), that expresses EGFP-fused lck under the control of the T-cell specific tyrosine kinase (lck) promoter.	('tyr', 'Chemical', 'MESH:D014443', (312, 315))	('leukemic T', 'Disease', 'MESH:D007938', (55, 65))	('lck', 'Gene', '414333', (267, 270))	('lck', 'Gene', '414333', (329, 332))	('EGFP-fused', 'Var', (256, 266))	('lck', 'Gene', (267, 270))	('lck', 'Gene', '414333', (226, 229))	('lck', 'Gene', (329, 332))	('lck', 'Gene', '414333', (230, 233))	('leukemic T', 'Disease', (55, 65))	('lck', 'Gene', (226, 229))	('lck', 'Gene', (230, 233))
94707	28930163	Moreover, LDK is active against primary human leukemia cells, including BCR-ABL(T315I) mutated cells, therapy-refractory B-ALL, and CML samples.	('human', 'Species', '9606', (40, 45))	('mutated', 'Var', (87, 94))	('ALL', 'Phenotype', 'HP:0006721', (123, 126))	('CML', 'Disease', 'MESH:D015464', (132, 135))	('BCR-ABL', 'Gene', (72, 79))	('leukemia', 'Disease', (46, 54))	('BCR-ABL', 'Gene', '25', (72, 79))	('leukemia', 'Disease', 'MESH:D007938', (46, 54))	('leukemia', 'Phenotype', 'HP:0001909', (46, 54))	('CML', 'Phenotype', 'HP:0005506', (132, 135))	('T315I', 'Mutation', 'rs121913459', (80, 85))	('CML', 'Disease', (132, 135))
94722	28930163	Beside chromosomal rearrangements, molecular changes have also been implicated in the development of AML, including mutations in Fl3, N/K-RAS, TP53, STAT3, NPMI and CEBPA.	('TP53', 'Gene', (143, 147))	('STAT3', 'Gene', '30767', (149, 154))	('AML', 'Disease', 'MESH:D015470', (101, 104))	('NPMI', 'Gene', (156, 160))	('Fl3', 'Gene', (129, 132))	('STAT3', 'Gene', (149, 154))	('AML', 'Phenotype', 'HP:0004808', (101, 104))	('AML', 'Disease', (101, 104))	('CEBPA', 'Gene', (165, 170))	('CEBPA', 'Gene', '140815', (165, 170))	('mutations', 'Var', (116, 125))	('N/K-RAS', 'Protein', (134, 141))	('implicated', 'Reg', (68, 78))	('TP53', 'Gene', '30590', (143, 147))
94723	28930163	Frequent mutations have been observed in genes involved in epigenetic regulation, encoding DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2), as well as tet oncogene family member 2 gene (TET2).	('rat', 'Species', '10116', (132, 135))	('TET2', 'Gene', '101887161', (245, 249))	('regulation', 'biological_process', 'GO:0065007', ('70', '80'))	('mutations', 'Var', (9, 18))	('rat', 'Species', '10116', (170, 173))	('TET2', 'Gene', (245, 249))	('IDH2', 'Gene', (192, 196))	('IDH2', 'Gene', '386951', (192, 196))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('IDH1', 'Gene', (154, 158))	('DNMT3A', 'Gene', (117, 123))	('IDH1', 'Gene', '100006589', (154, 158))
94724	28930163	The presence of DNMT3A, TET2, IDH1 or IDH2 mutations may confer sensitivity to novel therapeutic approaches, including the use of demethylating agents.	('DNMT3A', 'Gene', (16, 22))	('IDH1', 'Gene', (30, 34))	('IDH2', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('IDH2', 'Gene', '386951', (38, 42))	('TET2', 'Gene', '101887161', (24, 28))	('sensitivity', 'Reg', (64, 75))	('TET2', 'Gene', (24, 28))	('IDH1', 'Gene', '100006589', (30, 34))
94734	28930163	Transgenic embryos had defects in early hematopoiesis, with an abundance of myeloid cells marked by spi1, loss of red cells marked by gata1 and inhibition of terminal myeloid differentiation.	('red cells', 'MPA', (114, 123))	('hematopoiesis', 'Disease', (40, 53))	('Transgenic', 'Var', (0, 10))	('gata1', 'Gene', '30481', (134, 139))	('hematopoiesis', 'biological_process', 'GO:0030097', ('40', '53'))	('terminal myeloid differentiation', 'CPA', (158, 190))	('spi1', 'Gene', '30117', (100, 104))	('hematopoiesis', 'Disease', 'MESH:C536227', (40, 53))	('spi1', 'Gene', (100, 104))	('defects', 'NegReg', (23, 30))	('inhibition', 'NegReg', (144, 154))	('loss', 'NegReg', (106, 110))	('gata1', 'Gene', (134, 139))
94737	28930163	An increased number of immature hematopoietic cells and arrest of myeloid maturation in kidney marrow was observed in few surviving juvenile transgenic fish.	('rat', 'Species', '10116', (78, 81))	('transgenic', 'Var', (141, 151))	('kidney marrow', 'Disease', (88, 101))	('kidney marrow', 'Disease', 'MESH:D001855', (88, 101))
94744	28930163	The results were further confirmed by experiments in mice, where AML1-ETO expression also induced COX-2 and activates beta-catenin in bone marrow cells.	('AML', 'Phenotype', 'HP:0004808', (65, 68))	('activates', 'PosReg', (108, 117))	('induced', 'PosReg', (90, 97))	('AML1-ETO expression', 'Var', (65, 84))	('COX-2', 'Gene', (98, 103))	('beta-catenin', 'MPA', (118, 130))	('mice', 'Species', '10090', (53, 57))
94747	28930163	Several evidences, from transgenic fish and transplantation experiments, highlight the role of the AKT pathway in T-ALL: functional mutations in PTEN genes or expression of constitutively active AKT2 render tumors independent from the MYC oncogene.	('AKT', 'Gene', (195, 198))	('AKT2', 'Gene', '378972', (195, 199))	('PTEN', 'Gene', (145, 149))	('tumors', 'Disease', (207, 213))	('mutations', 'Var', (132, 141))	('AKT', 'Gene', '207', (99, 102))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('ALL', 'Phenotype', 'HP:0006721', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('AKT', 'Gene', '207', (195, 198))	('AKT', 'Gene', (99, 102))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('MYC', 'Gene', (235, 238))	('AKT2', 'Gene', (195, 199))	('MYC', 'Gene', '30686', (235, 238))
94752	28930163	In the future, the availability of immunocompromised mutant fish will lead to the use of zebrafish in personalized medicine, where leukemic cells from patients could be transplanted in fish in order to study clonal evolution.	('leukemic', 'Disease', (131, 139))	('patients', 'Species', '9606', (151, 159))	('leukemic', 'Disease', 'MESH:D007938', (131, 139))	('mutant', 'Var', (53, 59))	('zebrafish', 'Species', '7955', (89, 98))
94753	28930163	Genome sequencing on the clones having growth advantage could reveal combinations of mutations that favor clonal expansion in one particular patient; drug combinations able to block the expansion could be tested in xenotransplanted fish.	('clonal', 'MPA', (106, 112))	('mutations', 'Var', (85, 94))	('patient', 'Species', '9606', (141, 148))
94755	28930163	The mutations found in human samples are already being recapitulated in zebrafish HSCs using Crispr/Cas9 editing technology, as reported at recent zebrafish meetings, and their effects in leukemia progression and recurrence will be investigated.	('leukemia', 'Disease', (188, 196))	('leukemia', 'Phenotype', 'HP:0001909', (188, 196))	('leukemia', 'Disease', 'MESH:D007938', (188, 196))	('zebrafish', 'Species', '7955', (72, 81))	('zebrafish', 'Species', '7955', (147, 156))	('human', 'Species', '9606', (23, 28))	('mutations', 'Var', (4, 13))	('Cas', 'cellular_component', 'GO:0005650', ('100', '103'))
94760	28930163	Recent next generation sequencing studies have revealed that, with a median number of >10 mutations per megabase of DNA, melanomas have the highest mutational load of all human malignancies, represented by a large number of UV-signature mutations, predominantly C > T or G > T transitions, which are induced by UVB and UVA, respectively.	('melanomas', 'Disease', 'MESH:D008545', (121, 130))	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanomas', 'Phenotype', 'HP:0002861', (121, 130))	('G > T transitions', 'Var', (271, 288))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('rat', 'Species', '10116', (16, 19))	('malignancies', 'Disease', (177, 189))	('malignancies', 'Disease', 'MESH:D009369', (177, 189))	('UVB', 'Disease', (311, 314))	('UV-signature', 'Gene', (224, 236))	('melanomas', 'Disease', (121, 130))	('UVB', 'Disease', 'None', (311, 314))	('mutational load', 'MPA', (148, 163))	('human', 'Species', '9606', (171, 176))	('C > T', 'Var', (262, 267))
94764	28930163	Common mutations include BRAFV600E, NRASQ61L or NRASQ61R and HRAS and KRAS mutations for cutaneous melanoma, KITV559A for mucosal and acral melanoma and GNAQQ209L or GNA11Q209L in uveal melanomas.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (89, 107))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (89, 107))	('BRAFV600E', 'Mutation', 'rs113488022', (25, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (180, 194))	('KRAS', 'Gene', (70, 74))	('uveal melanomas', 'Disease', 'MESH:C536494', (180, 195))	('HRAS', 'Gene', '550286', (61, 65))	('mucosal and acral melanoma', 'Disease', 'MESH:D008545', (122, 148))	('HRAS', 'Gene', (61, 65))	('uveal melanomas', 'Disease', (180, 195))	('uveal melanomas', 'Phenotype', 'HP:0007716', (180, 195))	('KITV559A', 'Var', (109, 117))	('melanomas', 'Phenotype', 'HP:0002861', (186, 195))	('BRAFV600E', 'Var', (25, 34))	('KRAS', 'Gene', '445289', (70, 74))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('NRASQ61L', 'Var', (36, 44))	('GNA11Q209L', 'Var', (166, 176))	('GNAQQ209L', 'Var', (153, 162))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('NRASQ61R', 'Var', (48, 56))	('acral melanoma', 'Phenotype', 'HP:0012060', (134, 148))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('cutaneous melanoma', 'Disease', (89, 107))
94767	28930163	The first zebrafish model for human BRAFV600E under the melanocyte-specific promoter mitfa was generated in 2005 by Patton and Zon.	('human', 'Species', '9606', (30, 35))	('zebrafish', 'Species', '7955', (10, 19))	('mitfa', 'Gene', (85, 90))	('mitfa', 'Gene', '30080', (85, 90))	('rat', 'Species', '10116', (99, 102))	('BRAFV600E', 'Var', (36, 45))	('BRAFV600E', 'Mutation', 'rs113488022', (36, 45))
94768	28930163	Mosaic BRAFV600E expression generated large melanocytic spots on the adult zebrafish that were similar to nevi.	('Mosaic BRAFV600E expression', 'Var', (0, 27))	('BRAFV600E', 'Mutation', 'rs113488022', (7, 16))	('rat', 'Species', '10116', (32, 35))	('melanocytic', 'Disease', 'MESH:D009508', (44, 55))	('nevi', 'Phenotype', 'HP:0003764', (106, 110))	('melanocytic', 'Disease', (44, 55))	('zebrafish', 'Species', '7955', (75, 84))
94769	28930163	The transgenic zebrafish line, Tg(mitfa:BRAFV600E), developed melanoma at a more rapid rate in a p53zdf1/zdf1 mutant zebrafish background, showing genetic cooperation between the tumor suppressor p53 and B-Raf proto-oncogene (BRAF) pathways in melanoma development.	('melanoma', 'Disease', 'MESH:D008545', (244, 252))	('rat', 'Species', '10116', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('BRAFV600E', 'Mutation', 'rs113488022', (40, 49))	('rat', 'Species', '10116', (87, 90))	('zebrafish', 'Species', '7955', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('melanoma', 'Disease', (244, 252))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('melanoma', 'Disease', (62, 70))	('mutant', 'Var', (110, 116))	('zebrafish', 'Species', '7955', (117, 126))	('mitfa', 'Gene', (34, 39))	('mitfa', 'Gene', '30080', (34, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('179', '195'))	('B-Raf proto-oncogene', 'Gene', (204, 224))	('B-Raf proto-oncogene', 'Gene', '403065', (204, 224))	('tumor suppressor', 'biological_process', 'GO:0051726', ('179', '195'))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('tumor', 'Disease', (179, 184))
94770	28930163	Moreover, zebrafish with p53 mutant background developed invasive and transplantable melanomas by 4 months of age.	('p53', 'Gene', (25, 28))	('melanomas', 'Disease', (85, 94))	('zebrafish', 'Species', '7955', (10, 19))	('melanomas', 'Disease', 'MESH:D008545', (85, 94))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('developed', 'PosReg', (47, 56))	('mutant background', 'Var', (29, 46))
94772	28930163	Although p53 is rarely mutated in human melanoma, the p53 pathway is often downregulated due to overexpression of its negative regulators MDM4 and MDM2 or to inactivating mutations in p14ARF.	('inactivating mutations', 'Var', (158, 180))	('human', 'Species', '9606', (34, 39))	('p14ARF', 'Gene', '1029', (184, 190))	('downregulated', 'NegReg', (75, 88))	('MDM2', 'Gene', '4193', (147, 151))	('MDM4', 'Gene', '4194', (138, 142))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('MDM2', 'Gene', (147, 151))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Disease', (40, 48))	('MDM4', 'Gene', (138, 142))	('p14ARF', 'Gene', (184, 190))	('p53 pathway', 'Pathway', (54, 65))	('overexpression', 'PosReg', (96, 110))
94773	28930163	Although BRAF and NRAS mutations encompass 80% of the oncogenic drivers for human cutaneous melanoma, these are not sufficient to explain the aggressiveness of this tumor, suggesting cooperation with other somatic events during cancer development, including chromosomal aberrations.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 100))	('BRAF', 'Gene', (9, 13))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (258, 281))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('NRAS', 'Gene', (18, 22))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (258, 280))	('mutations', 'Var', (23, 32))	('rat', 'Species', '10116', (188, 191))	('chromosomal aberrations', 'Disease', 'MESH:D002869', (258, 281))	('cancer', 'Disease', (228, 234))	('rat', 'Species', '10116', (274, 277))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('aggressiveness', 'Disease', (142, 156))	('tumor', 'Disease', (165, 170))	('aggressiveness', 'Phenotype', 'HP:0000718', (142, 156))	('human', 'Species', '9606', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('aggressiveness', 'Disease', 'MESH:D001523', (142, 156))	('chromosomal aberrations', 'Disease', (258, 281))	('cutaneous melanoma', 'Disease', (82, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (82, 100))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
94777	28930163	Tg(mitfa:BRAFV600E;p53zdf1/zdf1) were bred with the nacre mutant, that carries an inactivating mutation of mitfa.	('inactivating mutation', 'Var', (82, 103))	('BRAFV600E', 'Mutation', 'rs113488022', (9, 18))	('mitfa', 'Gene', '30080', (3, 8))	('p53zdf1/zdf1', 'Var', (19, 31))	('mitfa', 'Gene', '30080', (107, 112))	('mitfa', 'Gene', (3, 8))	('mitfa', 'Gene', (107, 112))
94781	28930163	The results of the screen showed that a single gene, SET domain bifurcated 1 (SETDB1), a histone H3K9 methyltransferase, is able to cooperate with the BRAFV600E mutation and promote melanoma development.	('SETDB1', 'Gene', (78, 84))	('BRAFV600E', 'Var', (151, 160))	('BRAFV600E', 'Mutation', 'rs113488022', (151, 160))	('promote', 'PosReg', (174, 181))	('SET domain bifurcated 1', 'Gene', (53, 76))	('rat', 'Species', '10116', (137, 140))	('SET domain bifurcated 1', 'Gene', '553292', (53, 76))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('melanoma', 'Disease', (182, 190))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))
94782	28930163	Tumors co-expressing both BRAFV600E and SETDB1 showed increased aggressiveness in p53zdf1/zdf1 zebrafish.	('zebrafish', 'Species', '7955', (95, 104))	('aggressiveness', 'Disease', 'MESH:D001523', (64, 78))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('aggressiveness', 'Disease', (64, 78))	('aggressiveness', 'Phenotype', 'HP:0000718', (64, 78))	('increased', 'PosReg', (54, 63))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('BRAFV600E', 'Var', (26, 35))	('BRAFV600E', 'Mutation', 'rs113488022', (26, 35))	('SETDB1', 'Gene', (40, 46))
94794	28930163	Hurlstone's lab generated a transgenic line expressing mutant HRAS in melanocytes using the mitfa promoter.	('mitfa', 'Gene', '30080', (92, 97))	('mitfa', 'Gene', (92, 97))	('HRAS', 'Gene', (62, 66))	('mutant', 'Var', (55, 61))	('rat', 'Species', '10116', (20, 23))	('HRAS', 'Gene', '550286', (62, 66))
94795	28930163	Development of melanoma in these zebrafish is sporadic, but can be accelerated by activating mutations in the PI3K pathway, thus confirming the role of this pathway in malignant transformation downstream of HRAS.	('HRAS', 'Gene', '550286', (207, 211))	('accelerated', 'PosReg', (67, 78))	('mutations', 'Var', (93, 102))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('PI3K', 'molecular_function', 'GO:0016303', ('110', '114'))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('zebrafish', 'Species', '7955', (33, 42))	('HRAS', 'Gene', (207, 211))	('activating mutations', 'Var', (82, 102))	('Development', 'CPA', (0, 11))	('rat', 'Species', '10116', (73, 76))	('PI3K pathway', 'Pathway', (110, 122))
94799	28930163	The tumors had infiltrative behaviour, polyploid nuclei and expressed melanoma markers such as Tyrosinase, Melan-a, HMB45 and s100.	('melanoma', 'Disease', (70, 78))	('Melan-a', 'Gene', (107, 114))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('s100', 'Gene', (126, 130))	('polyploid', 'Var', (39, 48))	('HMB45', 'Gene', (116, 121))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('rat', 'Species', '10116', (21, 24))	('behaviour', 'biological_process', 'GO:0007610', ('28', '37'))	('Tyrosinase', 'Gene', (95, 105))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('Tyrosinase', 'Gene', '30207', (95, 105))	('expressed', 'Reg', (60, 69))
94805	28930163	To find initiating events in melanoma, they compared gene expression profiles of embryos and melanoma in Tg(mitfa:BRAFV600E;p53zdf1/zdf1) fish by GSEA.	('p53zdf1/zdf1', 'Var', (124, 136))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('gene expression', 'biological_process', 'GO:0010467', ('53', '68'))	('GSEA', 'Chemical', '-', (146, 150))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('BRAFV600E', 'Mutation', 'rs113488022', (114, 123))	('mitfa', 'Gene', '30080', (108, 113))	('mitfa', 'Gene', (108, 113))
94808	28930163	These observations suggested that melanocytes return to a neural crest progenitor state when they become melanoma, and that BRAFV600E could play a key role in this process.	('BRAFV600E', 'Var', (124, 133))	('BRAFV600E', 'Mutation', 'rs113488022', (124, 133))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))
94810	28930163	After screening 2000 compounds they found that one compound of unknown function, NSC210627, strongly reduced crestin expression.	('crestin', 'Gene', '30186', (109, 116))	('reduced', 'NegReg', (101, 108))	('NSC210627', 'Var', (81, 90))	('crestin', 'Gene', (109, 116))
94811	28930163	NSC210627 was then found to have a similar structure to brequinar, a known dihydroorotate dehydrogenase (DHODH) inhibitor, and inhibited DHODH activity in vitro.	('DHODH', 'Gene', (137, 142))	('DHODH', 'Gene', '494065', (137, 142))	('dihydroorotate dehydrogenase', 'Gene', '494065', (75, 103))	('NSC210627', 'Var', (0, 9))	('inhibited', 'NegReg', (127, 136))	('DHODH', 'Gene', '494065', (105, 110))	('dihydroorotate dehydrogenase', 'Gene', (75, 103))	('DHODH', 'Gene', (105, 110))	('activity', 'MPA', (143, 151))
94814	28930163	Moreover, treatment of a human melanoma cell line with the active metabolite of leflunomide A771726, decreased proliferation in a dose-dependent manner.	('rat', 'Species', '10116', (118, 121))	('leflunomide A771726', 'Chemical', '-', (80, 99))	('proliferation', 'CPA', (111, 124))	('decreased', 'NegReg', (101, 110))	('human', 'Species', '9606', (25, 30))	('A771726', 'Var', (92, 99))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))
94815	28930163	Co-treatment of melanoma cells with A771726 and a BRAFV600E inhibitor had a synergistic effect in suppressing proliferation.	('rat', 'Species', '10116', (117, 120))	('suppressing', 'NegReg', (98, 109))	('A771726', 'Var', (36, 43))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('proliferation', 'CPA', (110, 123))	('melanoma', 'Disease', (16, 24))	('BRAFV600E', 'Mutation', 'rs113488022', (50, 59))	('BRAFV600E', 'Gene', (50, 59))	('A771726', 'Chemical', 'MESH:C072876', (36, 43))
94832	28930163	Embryos were injected with C8161-GFP, an aggressive melanoma cell line, at the animal pole of the embryo or close to the blastoderm margin.	('C8161-GFP', 'Var', (27, 36))	('aggressive melanoma', 'Disease', (41, 60))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('aggressive melanoma', 'Disease', 'MESH:D008545', (41, 60))
94843	28930163	This mutant was used as recipient of xenografted tumor cells deriving from melanomas developing in Tg(mitfa:NRASQ61K:GFP);p53zdf1/zdf1 or Tg(mitfa:BRAFV600E);p53zdf1/zdf1 zebrafish adult.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('zebrafish', 'Species', '7955', (171, 180))	('mitfa', 'Gene', '30080', (102, 107))	('BRAFV600E', 'Mutation', 'rs113488022', (147, 156))	('melanomas', 'Disease', (75, 84))	('mitfa', 'Gene', '30080', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mitfa', 'Gene', (102, 107))	('tumor', 'Disease', (49, 54))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('melanomas', 'Disease', 'MESH:D008545', (75, 84))	('p53zdf1/zdf1', 'Var', (122, 134))	('mitfa', 'Gene', (141, 146))
94850	28930163	Moreover, to test whether this xenograft model was suitable for chemical screening three different anticancer drugs were used: quisinostat, MLN-4924 and dasatinib.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('MLN-4924', 'Var', (140, 148))	('quisinostat', 'Chemical', 'MESH:C541788', (127, 138))	('dasatinib', 'Chemical', 'MESH:D000069439', (153, 162))	('MLN-4924', 'Chemical', 'MESH:C539933', (140, 148))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
94851	28930163	Quisinostat is a pan-inhibitor of HDAC activity, MLN-4924 is an inhibitor of the neddylation pathway that leads to S-phase defects and apoptosis.	('apoptosis', 'CPA', (135, 144))	('leads to', 'Reg', (106, 114))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('S-phase', 'biological_process', 'GO:0051320', ('115', '122'))	('S-phase defects', 'MPA', (115, 130))	('MLN-4924', 'Var', (49, 57))	('Quisinostat', 'Chemical', 'MESH:C541788', (0, 11))	('MLN-4924', 'Chemical', 'MESH:C539933', (49, 57))	('neddylation', 'Pathway', (81, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))
94853	28930163	Embryos treated with dasatinib showed decreased growth only of primary UM transplanted cells, while the treatment of transplanted embryos with the broad-spectrum anticancer drugs MLN-4924 and quisinostat showed decreased growth and migration of both cell lines.	('growth only', 'CPA', (48, 59))	('decreased', 'NegReg', (38, 47))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('MLN-4924', 'Var', (179, 187))	('dasatinib', 'Chemical', 'MESH:D000069439', (21, 30))	('decreased growth', 'Phenotype', 'HP:0001510', (211, 227))	('rat', 'Species', '10116', (235, 238))	('growth', 'CPA', (221, 227))	('quisinostat', 'Chemical', 'MESH:C541788', (192, 203))	('MLN-4924', 'Chemical', 'MESH:C539933', (179, 187))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('decreased', 'NegReg', (211, 220))	('decreased growth', 'Phenotype', 'HP:0001510', (38, 54))
94860	28930163	Whole genome sequencing analysis revealed 3 new DNA mutations in BUB1B, PINK1 and COL16A1 genes and more than 800 genes differentially expressed between original ZMEL1 and ZMEL-R1 cells, especially those belonging to cyclic AMP (cAMP) and PKA signalling.	('mutations', 'Var', (52, 61))	('cyclic AMP', 'Chemical', 'MESH:D000242', (217, 227))	('COL16A1', 'Gene', (82, 89))	('BUB1B', 'Gene', (65, 70))	('COL16A1', 'Gene', '100535782', (82, 89))	('cAMP', 'Chemical', 'MESH:D000242', (229, 233))	('PKA', 'cellular_component', 'GO:0005952', ('239', '242'))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('PINK1', 'Gene', (72, 77))	('PKA', 'molecular_function', 'GO:0004691', ('239', '242'))	('ZMEL1', 'CellLine', 'CVCL:B526', (162, 167))	('signalling', 'biological_process', 'GO:0023052', ('243', '253'))	('PINK1', 'Gene', '494085', (72, 77))
94880	28930163	Besides frequent-occurring mutations in IDH1 and IDH2 and TERT, there are four pathways that are physiologically and pathologically relevant to current glioma/glioblastoma therapies: (1) The P13K-PTEN-AKT-mTOR signaling pathway: In brain cells, this pathway is regulated by the epidermal growth factor (EGF), and its receptor, EGFR, both frequently overexpressed in GBM.	('mutations', 'Var', (27, 36))	('AKT', 'Gene', '207', (201, 204))	('IDH1', 'Gene', (40, 44))	('IDH1', 'Gene', '100006589', (40, 44))	('EGFR', 'molecular_function', 'GO:0005006', ('327', '331'))	('EGFR', 'Gene', (327, 331))	('glioblastoma', 'Disease', 'MESH:D005909', (159, 171))	('TERT', 'Gene', '796551', (58, 62))	('IDH2', 'Gene', '386951', (49, 53))	('signaling pathway', 'biological_process', 'GO:0007165', ('210', '227'))	('EGF', 'molecular_function', 'GO:0005154', ('303', '306'))	('EGFR', 'Gene', '378478', (327, 331))	('glioma', 'Disease', (152, 158))	('AKT', 'Gene', (201, 204))	('glioblastoma', 'Disease', (159, 171))	('TERT', 'Gene', (58, 62))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('IDH2', 'Gene', (49, 53))	('glioblastoma', 'Phenotype', 'HP:0012174', (159, 171))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('278', '301'))	('overexpressed', 'PosReg', (349, 362))	('P13K', 'Mutation', 'p.P13K', (191, 195))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))
94882	28930163	(2) The p53 signaling pathway: Inactivating mutations in p53 can directly drive glioma formation through uncontrolled progression of cell cycle and by blocking apoptosis of cells with DNA damage.	('blocking', 'NegReg', (151, 159))	('apoptosis', 'CPA', (160, 169))	('drive', 'PosReg', (74, 79))	('glioma', 'Disease', (80, 86))	('cell cycle', 'biological_process', 'GO:0007049', ('133', '143'))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('DNA', 'cellular_component', 'GO:0005574', ('184', '187'))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('uncontrolled', 'MPA', (105, 117))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('p53 signaling pathway', 'biological_process', 'GO:0030330', ('8', '29'))	('p53', 'Gene', (57, 60))	('p53 signaling pathway', 'Pathway', (8, 29))	('Inactivating mutations', 'Var', (31, 53))	('formation', 'biological_process', 'GO:0009058', ('87', '96'))
94883	28930163	(3) The Ras sarcoma (RAS)/MAPK signaling pathway: Although human RAS genes, including H-RAS, N-RAS and K-RAS are rarely mutated in glioma, the RAS/MAPK signaling cascade is a prime target for chemotherapy:this is due to numerous alterations of this pathway (for example: inactivation of NF-1, constitutive activation of BRAF and RAF1, MEK hyperactivation, abnormal activation of RAS by mutated growth factor receptors such as PDGFR or RTKs) that affect proliferative signaling and gliomagenesis.	('glioma', 'Disease', (481, 487))	('NF-1', 'Gene', (287, 291))	('glioma', 'Disease', (131, 137))	('activation', 'PosReg', (306, 316))	('H-RAS', 'Gene', (86, 91))	('N-RAS', 'Gene', '4893', (93, 98))	('MAPK', 'molecular_function', 'GO:0004707', ('147', '151'))	('MAPK', 'Gene', (147, 151))	('MAPK signaling', 'biological_process', 'GO:0000165', ('147', '161'))	('RAS', 'Gene', (379, 382))	('glioma', 'Disease', 'MESH:D005910', (481, 487))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('Ras sarcoma', 'Disease', 'MESH:D012509', (8, 19))	('H-RAS', 'Gene', '3265', (86, 91))	('rat', 'Species', '10116', (460, 463))	('Ras sarcoma', 'Disease', (8, 19))	('MAPK', 'Gene', '5594', (147, 151))	('proliferative signaling', 'MPA', (453, 476))	('signaling cascade', 'biological_process', 'GO:0007165', ('152', '169'))	('mutated', 'Var', (386, 393))	('RAF1', 'Gene', '5894', (329, 333))	('glioma', 'Phenotype', 'HP:0009733', (481, 487))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('N-RAS', 'Gene', (93, 98))	('MAPK', 'Gene', (26, 30))	('activation', 'PosReg', (365, 375))	('MEK', 'Gene', '5609', (335, 338))	('inactivation', 'Var', (271, 283))	('signaling pathway', 'biological_process', 'GO:0007165', ('31', '48'))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('RAF1', 'Gene', (329, 333))	('rat', 'Species', '10116', (233, 236))	('MAPK', 'Gene', '5594', (26, 30))	('PDGFR', 'Gene', (426, 431))	('signaling', 'biological_process', 'GO:0023052', ('467', '476'))	('MAPK', 'molecular_function', 'GO:0004707', ('26', '30'))	('PDGFR', 'Gene', '5159', (426, 431))	('MEK', 'Gene', (335, 338))	('affect', 'Reg', (446, 452))	('RTKs', 'Gene', (435, 439))	('human', 'Species', '9606', (59, 64))	('NF-1', 'Gene', '4763', (287, 291))	('MAPK signaling', 'biological_process', 'GO:0000165', ('26', '40'))	('hyperactivation', 'PosReg', (339, 354))
94884	28930163	(4) The cell cycle progression machinery: Critical regulators of cell growth are frequently mutated in human gliomas, including the tumor suppressor retinoblastoma (pRB), CDK4 (activating mutations) and CDKN2A (inactivating mutations) with consequent overexpression of MDM2, an inhibitor of the tumor suppressor protein ARF (p14ARF).	('p14ARF', 'Gene', (325, 331))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('132', '148'))	('gliomas', 'Disease', 'MESH:D005910', (109, 116))	('CDK', 'molecular_function', 'GO:0004693', ('171', '174'))	('CDK4', 'Gene', (171, 175))	('tumor', 'Disease', (132, 137))	('overexpression', 'PosReg', (251, 265))	('CDKN2A', 'Gene', '1029', (203, 209))	('pRB', 'Gene', '5925', (165, 168))	('ARF', 'Disease', 'MESH:D058186', (320, 323))	('retinoblastoma', 'Phenotype', 'HP:0009919', (149, 163))	('MDM2', 'Gene', '4193', (269, 273))	('tumor suppressor', 'biological_process', 'GO:0051726', ('132', '148'))	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('human', 'Species', '9606', (103, 108))	('retinoblastoma', 'Disease', (149, 163))	('ARF', 'Disease', 'MESH:D058186', (328, 331))	('pRB', 'Gene', (165, 168))	('cell cycle', 'biological_process', 'GO:0007049', ('8', '18'))	('gliomas', 'Phenotype', 'HP:0009733', (109, 116))	('mutated', 'Var', (92, 99))	('CDK4', 'Gene', '1019', (171, 175))	('protein', 'cellular_component', 'GO:0003675', ('312', '319'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('295', '311'))	('tumor', 'Disease', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cell growth', 'biological_process', 'GO:0016049', ('65', '76'))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('p14ARF', 'Gene', '1029', (325, 331))	('tumor suppressor', 'biological_process', 'GO:0051726', ('295', '311'))	('ARF', 'Disease', (320, 323))	('retinoblastoma', 'Disease', 'MESH:D012175', (149, 163))	('CDKN2A', 'Gene', (203, 209))	('gliomas', 'Disease', (109, 116))	('ARF', 'Disease', (328, 331))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('MDM2', 'Gene', (269, 273))
94885	28930163	The homozygous deletion of locus p16INK4a/p14ARF/p14INK4b is one of the most frequent mutations in GBM.	('deletion', 'Var', (15, 23))	('p14ARF', 'Gene', (42, 48))	('p14ARF', 'Gene', '1029', (42, 48))
94891	28930163	The authors found two orthologues of NF1 in zebrafish, nf1a and nf1b with high sequence similarities to human NF1 and generated mutants of these genes by zinc finger nuclease (ZFN) and Target Induced Local Lesions in Genome (TILLING).	('nf1a', 'Gene', (55, 59))	('mutants', 'Var', (128, 135))	('Local Lesions', 'Disease', 'MESH:D012594', (200, 213))	('NF1', 'Gene', (37, 40))	('Local Lesions', 'Disease', (200, 213))	('nf1b', 'Gene', (64, 68))	('human', 'Species', '9606', (104, 109))	('rat', 'Species', '10116', (122, 125))	('zebrafish', 'Species', '7955', (44, 53))
94892	28930163	nf1a+/-/nf1b-/- mutants in the p53zdf1/zdf1 background developed brain tumors in 33 weeks, with characteristic markers (sox10/Olig2/Gfap) of diffuse high-grade gliomas and hyperactivation of ERK and mTOR pathways, similar to mouse models and human gliomas.	('hyperactivation', 'PosReg', (172, 187))	('gliomas', 'Phenotype', 'HP:0009733', (248, 255))	('gliomas', 'Phenotype', 'HP:0009733', (160, 167))	('brain tumors', 'Disease', 'MESH:D001932', (65, 77))	('Gfap', 'Gene', '2670', (132, 136))	('brain tumors', 'Phenotype', 'HP:0030692', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('brain tumor', 'Phenotype', 'HP:0030692', (65, 76))	('ERK', 'Gene', '5594', (191, 194))	('mTOR pathways', 'Pathway', (199, 212))	('nf1a+/-/nf1b-/- mutants', 'Var', (0, 23))	('Gfap', 'cellular_component', 'GO:0045101', ('132', '136'))	('developed', 'PosReg', (55, 64))	('Gfap', 'Gene', (132, 136))	('ERK', 'molecular_function', 'GO:0004707', ('191', '194'))	('brain tumors', 'Disease', (65, 77))	('Olig2', 'Gene', (126, 131))	('gliomas', 'Disease', (248, 255))	('ERK', 'Gene', (191, 194))	('mutants', 'Var', (16, 23))	('gliomas', 'Disease', (160, 167))	('mouse', 'Species', '10090', (225, 230))	('gliomas', 'Disease', 'MESH:D005910', (248, 255))	('Olig2', 'Gene', '10215', (126, 131))	('gliomas', 'Disease', 'MESH:D005910', (160, 167))	('glioma', 'Phenotype', 'HP:0009733', (248, 254))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('human', 'Species', '9606', (242, 247))	('glioma', 'Phenotype', 'HP:0009733', (160, 166))
94893	28930163	The penetrance of these tumors in the triple mutants was compared with the penetrance of malignant peripheral nerve sheath tumors in p53 mutants (28%) and showed to be higher (62%).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('malignant peripheral nerve sheath tumors', 'Disease', (89, 129))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (89, 129))	('p53', 'Gene', (133, 136))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (89, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('mutants', 'Var', (137, 144))
94895	28930163	The induction of tumorigenesis was accelerated by co-expression of a dominant active (DA) form of RAC1, a protein involved in the migration and invasion of glioma cells (62% and 73.3% at 6 and 9 months, respectively).	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('glioma', 'Disease', (156, 162))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('rat', 'Species', '10116', (133, 136))	('rat', 'Species', '10116', (41, 44))	('RAC1', 'Gene', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('glioma', 'Disease', 'MESH:D005910', (156, 162))	('RAC1', 'Gene', '327204', (98, 102))	('glioma', 'Phenotype', 'HP:0009733', (156, 162))	('co-expression', 'Var', (50, 63))	('accelerated', 'PosReg', (35, 46))
94900	28930163	The same group reported that the expression of human KRASG12V under two different neural promoter:krt5 and gfap:induced high-grade brain tumors.	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('brain tumors', 'Disease', (131, 143))	('induced', 'Reg', (112, 119))	('brain tumor', 'Phenotype', 'HP:0030692', (131, 142))	('brain tumors', 'Phenotype', 'HP:0030692', (131, 143))	('gfap', 'cellular_component', 'GO:0045101', ('107', '111'))	('KRASG12V', 'Var', (53, 61))	('human', 'Species', '9606', (47, 52))	('brain tumors', 'Disease', 'MESH:D001932', (131, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
94903	28930163	The results showed a suppression of mitotic-proliferative effects of oncogenic KRAS in zebrafish embryos.	('zebrafish', 'Species', '7955', (87, 96))	('mitotic-proliferative effects', 'CPA', (36, 65))	('oncogenic', 'Var', (69, 78))	('suppression', 'NegReg', (21, 32))	('KRAS', 'Gene', '445289', (79, 83))	('KRAS', 'Gene', (79, 83))	('rat', 'Species', '10116', (51, 54))
94904	28930163	Recently, a new model to study brain tumor development was established by the Mione's lab, through germline or somatic expression of HRASG12V or other oncogenes (YAPS5A, Xmrk, AKT, KRASG12V, BRAFV600E, EGFRvIII) under the control of the zic4 enhancer.	('HRASG12V', 'Gene', (133, 141))	('EGFR', 'Gene', (202, 206))	('zic4', 'Gene', '767673', (237, 241))	('KRASG12V', 'Var', (181, 189))	('AKT', 'Gene', '207', (176, 179))	('AKT', 'Gene', (176, 179))	('brain tumor', 'Disease', 'MESH:D001932', (31, 42))	('YAP', 'Gene', (162, 165))	('brain tumor', 'Disease', (31, 42))	('YAP', 'Gene', '561411', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('BRAFV600E', 'Var', (191, 200))	('zic4', 'Gene', (237, 241))	('BRAFV600E', 'Mutation', 'rs113488022', (191, 200))	('EGFR', 'Gene', '378478', (202, 206))	('brain tumor', 'Phenotype', 'HP:0030692', (31, 42))
94927	28930163	Irradiation in the presence of TMZ decreased the survival of U251 cells growing within zebrafish embryos; similarly, a small molecule identified after an in vitro chemical screen, NS123 (40-bromo-30-nitropropiophenone) enhanced the effect of ionizing radiation on these cells.	('zebrafish', 'Species', '7955', (87, 96))	('enhanced', 'PosReg', (219, 227))	('NS123', 'Var', (180, 185))	('40-bromo-30-nitropropiophenone', 'Chemical', '-', (187, 217))	('decreased', 'NegReg', (35, 44))	('NS123', 'Chemical', 'MESH:C524372', (180, 185))	('TMZ', 'Chemical', 'MESH:D000077204', (31, 34))	('U251', 'CellLine', 'CVCL:0021', (61, 65))
94945	28930163	Treatment with AZD6244 and U0126, two MEK inhibitors, induced significant shrinkage of tumor spreading after 5 days of treatment.	('shrinkage', 'NegReg', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('U0126', 'Chemical', 'MESH:C113580', (27, 32))	('AZD6244', 'Var', (15, 22))	('MEK', 'Gene', (38, 41))	('tumor', 'Disease', (87, 92))	('MEK', 'Gene', '5609', (38, 41))	('AZD6244', 'Chemical', 'MESH:C517975', (15, 22))	('U0126', 'Var', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
94946	28930163	To validate these promising results, the authors treated juvenile fish with primary tumors with AZD6244 for 8 weeks, showing higher post treatment survival, with only 21% of fish having tumors in contrast to 88% of fish treated with dimethyl sulfoxide (DMSO).	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('DMSO', 'Chemical', 'MESH:D004121', (253, 257))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('primary tumors', 'Disease', (76, 90))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('tumors', 'Disease', (84, 90))	('higher', 'PosReg', (125, 131))	('AZD6244', 'Var', (96, 103))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (233, 251))	('primary tumors', 'Disease', 'MESH:D009369', (76, 90))	('AZD6244', 'Chemical', 'MESH:C517975', (96, 103))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
94947	28930163	These results showed that MEK inhibitors were remarkably powerful to decrease tumor growth.	('MEK', 'Gene', '5609', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('inhibitors', 'Var', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('decrease', 'NegReg', (69, 77))	('tumor', 'Disease', (78, 83))	('MEK', 'Gene', (26, 29))
94953	28930163	In this respect, a primary brain cancer model developed after xenotransplantation was recently used to study how to safely deliver siRNA across the BBB, with the goal of knocking down a target gene with high specificity and low toxicity (Figure 1C).	('brain cancer', 'Disease', 'MESH:D001932', (27, 39))	('knocking', 'Var', (170, 178))	('brain cancer', 'Phenotype', 'HP:0030692', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('brain cancer', 'Disease', (27, 39))	('low toxicity', 'Disease', (224, 236))	('low toxicity', 'Disease', 'MESH:D009800', (224, 236))
94965	28930163	Based on the observations that Roscovitine suppresses pituitary corticotroph tumor and ACTH production in patients with Cushing disease, a phase II clinical trial is currently recruiting patients with Cushing disease (Identifier: NCT02160730), thus supporting the use of zebrafish in preclinical drug discovery also for these tumors.	('tumors', 'Phenotype', 'HP:0002664', (326, 332))	('suppresses', 'NegReg', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('patients', 'Species', '9606', (187, 195))	('tumors', 'Disease', (326, 332))	('zebrafish', 'Species', '7955', (271, 280))	('Cushing disease', 'Disease', (120, 135))	('Cushing disease', 'Disease', 'MESH:D047748', (120, 135))	('Roscovitine', 'Var', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (326, 331))	('Cushing disease', 'Phenotype', 'HP:0003118', (201, 216))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('tumors', 'Disease', 'MESH:D009369', (326, 332))	('pituitary corticotroph tumor', 'Phenotype', 'HP:0008291', (54, 82))	('patients', 'Species', '9606', (106, 114))	('ACTH production', 'MPA', (87, 102))	('Cushing disease', 'Phenotype', 'HP:0003118', (120, 135))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('Cushing disease', 'Disease', (201, 216))	('Cushing disease', 'Disease', 'MESH:D047748', (201, 216))	('tumor', 'Disease', (77, 82))	('Roscovitine', 'Chemical', 'MESH:D000077546', (31, 42))
94966	28930163	The first transgenic model of zebrafish PTC has been recently generated in Houvras' lab by co-expressing the human oncogene BRAFV600E and the fluorescent protein Td-Tomato in thyrocytes through a thyroid specific promoter, thyroglobulin.	('human', 'Species', '9606', (109, 114))	('BRAFV600E', 'Mutation', 'rs113488022', (124, 133))	('Td-Tomato', 'Var', (162, 171))	('BRAFV600E', 'Gene', (124, 133))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('Tomato', 'Species', '4081', (165, 171))	('rat', 'Species', '10116', (66, 69))	('zebrafish', 'Species', '7955', (30, 39))
94967	28930163	In particular, the expression of one transcription factor involved in EMT, twist3, was found upregulated in BRAFV600E-expressing thyrocytes.	('expression', 'MPA', (19, 29))	('twist3', 'Gene', (75, 81))	('transcription factor', 'molecular_function', 'GO:0000981', ('37', '57'))	('BRAFV600E', 'Mutation', 'rs113488022', (108, 117))	('twist3', 'Gene', '30176', (75, 81))	('EMT', 'biological_process', 'GO:0001837', ('70', '73'))	('transcription', 'biological_process', 'GO:0006351', ('37', '50'))	('upregulated', 'PosReg', (93, 104))	('BRAFV600E-expressing', 'Var', (108, 128))
94969	28930163	Moreover, treatment of BRAF-expressing embryos with a combination of BRAF and MEK inhibitors was able to restore follicular structure, demonstrating the suitability of this model to be used in chemical screens to investigate BRAF-mediated pathways.	('MEK', 'Gene', (78, 81))	('follicular structure', 'CPA', (113, 133))	('MEK', 'Gene', '5609', (78, 81))	('inhibitors', 'Var', (82, 92))	('rat', 'Species', '10116', (142, 145))	('BRAF', 'Gene', (69, 73))	('restore', 'PosReg', (105, 112))
94998	24480708	The recent discovery of major driver mutations in uveal melanoma provide a rational basis for development of new targeted therapies.	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('uveal melanoma', 'Disease', 'MESH:C536494', (50, 64))	('mutations', 'Var', (37, 46))	('uveal melanoma', 'Disease', (50, 64))
95017	24480708	Another major advance in recent years has been the discovery of key driver mutations that underlie tumor initiation, progression and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('mutations', 'Var', (75, 84))
95018	24480708	Oncogenic mutations that activate growth-stimulating signaling pathways, such as those in RAS (Retrovirus associated sequence) family members, BRAF (v-raf murine sarcoma viral oncogene homolog B1), and KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog), are common in cancer.	('activate', 'PosReg', (25, 33))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (149, 195))	('KIT', 'molecular_function', 'GO:0005020', ('202', '205'))	('sarcoma viral', 'Disease', 'MESH:D001102', (162, 175))	('BRAF', 'Gene', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', (149, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('sarcoma viral', 'Disease', 'MESH:D001102', (238, 251))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('mutations', 'Var', (10, 19))	('growth-stimulating signaling pathways', 'Pathway', (34, 71))	('sarcoma viral', 'Disease', (238, 251))	('cancer', 'Disease', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
95019	24480708	Yet, the discovery of such mutations in uveal melanoma remained elusive for many years despite intensive investigation.	('mutations', 'Var', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))	('uveal melanoma', 'Disease', 'MESH:C536494', (40, 54))	('uveal melanoma', 'Disease', (40, 54))
95020	24480708	The first breakthrough came with the discovery of mutations in the GNAQ (Guanine nucleotide-binding protein subunit alpha-Q) gene in about half of all uveal melanomas, followed shortly thereafter by the discovery of mutations in the closely related GNA11 (Guanine nucleotide-binding protein subunit alpha-11) gene in many other uveal melanomas (Figure 1A).	('melanomas', 'Phenotype', 'HP:0002861', (334, 343))	('GNA11', 'Gene', '2767', (249, 254))	('uveal melanomas', 'Disease', (151, 166))	('uveal melanomas', 'Phenotype', 'HP:0007716', (151, 166))	('melanomas', 'Phenotype', 'HP:0002861', (157, 166))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('melanoma', 'Phenotype', 'HP:0002861', (334, 342))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('264', '282'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (328, 342))	('uveal melanomas', 'Disease', 'MESH:C536494', (328, 343))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('GNAQ', 'Gene', '2776', (67, 71))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('81', '99'))	('GNA11', 'Gene', (249, 254))	('GNAQ', 'Gene', (67, 71))	('protein', 'cellular_component', 'GO:0003675', ('283', '290'))	('uveal melanomas', 'Disease', 'MESH:C536494', (151, 166))	('Guanine nucleotide-binding protein subunit alpha-11', 'Gene', '2767', (256, 307))	('uveal melanomas', 'Disease', (328, 343))	('uveal melanomas', 'Phenotype', 'HP:0007716', (328, 343))	('mutations', 'Var', (50, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (151, 165))
95021	24480708	It appears that GNAQ and GNA11 mutations are mutually exclusive and are present in about 85% of uveal melanomas.	('mutations', 'Var', (31, 40))	('present', 'Reg', (72, 79))	('GNAQ', 'Gene', (16, 20))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('uveal melanomas', 'Disease', (96, 111))	('uveal melanomas', 'Phenotype', 'HP:0007716', (96, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('GNAQ', 'Gene', '2776', (16, 20))	('GNA11', 'Gene', (25, 30))	('uveal melanomas', 'Disease', 'MESH:C536494', (96, 111))	('GNA11', 'Gene', '2767', (25, 30))
95023	24480708	However, the mutations that occur in uveal melanoma at amino acid residues glutamine-209 and arginine-183 disable the GTPase activity and prevent inactivation of the protein, leading to constitutive activation of the MAPK pathway and other growth pathways.	('GTPase', 'Protein', (118, 124))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('inactivation', 'MPA', (146, 158))	('MAPK', 'molecular_function', 'GO:0004707', ('217', '221'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (37, 51))	('glutamine', 'Chemical', 'MESH:D005973', (75, 84))	('MAPK pathway', 'Pathway', (217, 229))	('GTPase activity', 'molecular_function', 'GO:0003924', ('118', '133'))	('activation', 'PosReg', (199, 209))	('protein', 'Protein', (166, 173))	('disable', 'NegReg', (106, 113))	('activity', 'MPA', (125, 133))	('prevent', 'NegReg', (138, 145))	('mutations', 'Var', (13, 22))	('uveal melanoma', 'Disease', 'MESH:C536494', (37, 51))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('uveal melanoma', 'Disease', (37, 51))	('arginine', 'Chemical', 'MESH:D001120', (93, 101))	('arginine-183', 'Var', (93, 105))	('growth pathways', 'Pathway', (240, 255))
95024	24480708	Since GNAQ/11 mutations are found in uveal melanomas of all stages, including benign nevi, they are thought to be early or initiating events in tumorigenesis (Figure 3).	('tumor', 'Disease', (144, 149))	('uveal melanomas', 'Disease', (37, 52))	('uveal melanomas', 'Phenotype', 'HP:0007716', (37, 52))	('GNAQ', 'Gene', '2776', (6, 10))	('benign nevi', 'Disease', (78, 89))	('uveal melanomas', 'Disease', 'MESH:C536494', (37, 52))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanomas', 'Phenotype', 'HP:0002861', (43, 52))	('uveal melanoma', 'Phenotype', 'HP:0007716', (37, 51))	('GNAQ', 'Gene', (6, 10))	('found', 'Reg', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('nevi', 'Phenotype', 'HP:0003764', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('mutations', 'Var', (14, 23))
95025	24480708	Metastasis has been reported to be more common in tumors with mutations in GNA11, leading to the speculation that mutations in GNA11 may be more virulent than those in G\NAQ.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('mutations', 'Var', (114, 123))	('GNA11', 'Gene', '2767', (75, 80))	('GNA11', 'Gene', (75, 80))	('GNA11', 'Gene', '2767', (127, 132))	('GNA11', 'Gene', (127, 132))	('common', 'Reg', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('Metastasis', 'CPA', (0, 10))	('mutations', 'Var', (62, 71))
95026	24480708	However, GNA11 mutations are also more common in tumors involving the ciliary body, which is an independent risk factor for metastasis, and in tumors with mutations in the metastasis suppressor BAP1 (Breast cancer 1, early onset (BRCA1)-associated protein 1) (see below), so it remains possible or even likely that the association between GNA11 and metastasis is not causal.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('protein', 'cellular_component', 'GO:0003675', ('248', '255'))	('tumors', 'Disease', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('GNA11', 'Gene', '2767', (9, 14))	('BRCA1)-associated protein 1', 'Gene', '8314', (230, 257))	('tumors', 'Disease', (143, 149))	('mutations', 'Var', (15, 24))	('GNA11', 'Gene', (339, 344))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('BAP1', 'Gene', '8314', (194, 198))	('Breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('GNA11', 'Gene', (9, 14))	('Breast cancer', 'Disease', (200, 213))	('mutations', 'Var', (155, 164))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('common', 'Reg', (39, 45))	('Breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('GNA11', 'Gene', '2767', (339, 344))	('BAP1', 'Gene', (194, 198))
95027	24480708	Taken together, existing evidence suggests that mutations in GNAQ/GNA11 represent early events in uveal melanoma tumorigenesis, but they are not sufficient for development of a metastatic tumor.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', (113, 118))	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('GNAQ', 'Gene', (61, 65))	('uveal melanoma', 'Phenotype', 'HP:0007716', (98, 112))	('uveal melanoma', 'Disease', (98, 112))	('uveal melanoma', 'Disease', 'MESH:C536494', (98, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('GNA11', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('GNA11', 'Gene', '2767', (66, 71))	('mutations', 'Var', (48, 57))	('GNAQ', 'Gene', '2776', (61, 65))
95028	24480708	Since GNAQ/11 mutations do not correlate with patient outcome and do not account for the class 2 signature or metastasis, the search continued for gene mutations associated with metastasis in class 2 tumors.	('patient', 'Species', '9606', (46, 53))	('GNAQ', 'Gene', '2776', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', (200, 206))	('GNAQ', 'Gene', (6, 10))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('mutations', 'Var', (14, 23))
95029	24480708	Using next generation DNA sequencing techniques, we discovered mutations in BAP1 in the vast majority of class 2 metastasizing uveal melanomas but rarely in the less aggressive class 1 tumors (Figure 1B).	('mutations', 'Var', (63, 72))	('BAP1', 'Gene', '8314', (76, 80))	('tumors', 'Disease', (185, 191))	('uveal melanomas', 'Disease', (127, 142))	('uveal melanomas', 'Phenotype', 'HP:0007716', (127, 142))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('BAP1', 'Gene', (76, 80))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('uveal melanomas', 'Disease', 'MESH:C536494', (127, 142))	('class 2', 'Disease', (105, 112))	('uveal melanoma', 'Phenotype', 'HP:0007716', (127, 141))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
95030	24480708	Consistent with its presumed function as a tumor suppressor gene, BAP1 undergoes mutational inactivation of one copy and deletion of the other copy through loss of the entire chromosome.	('BAP1', 'Gene', '8314', (66, 70))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('43', '59'))	('chromosome', 'cellular_component', 'GO:0005694', ('175', '185'))	('loss', 'NegReg', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('BAP1', 'Gene', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutational', 'Var', (81, 91))	('tumor suppressor', 'biological_process', 'GO:0051726', ('43', '59'))	('tumor', 'Disease', (43, 48))	('deletion', 'Var', (121, 129))
95031	24480708	Interestingly, the BAP1 gene is located at chromosome 3p21, so this discovery likely explains, at least in part, the long known association between loss of chromosome 3 and metastasis in uveal melanoma.	('chromosome', 'cellular_component', 'GO:0005694', ('156', '166'))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('loss', 'Var', (148, 152))	('uveal melanoma', 'Disease', 'MESH:C536494', (187, 201))	('BAP1', 'Gene', '8314', (19, 23))	('metastasis', 'CPA', (173, 183))	('chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (187, 201))	('uveal melanoma', 'Disease', (187, 201))	('BAP1', 'Gene', (19, 23))
95035	24480708	The precise reason why loss of BAP1 promotes uveal melanoma progression and metastasis remains unclear and is the subject of intense investigation.	('metastasis', 'CPA', (76, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('uveal melanoma', 'Disease', (45, 59))	('BAP1', 'Gene', '8314', (31, 35))	('BAP1', 'Gene', (31, 35))	('loss', 'Var', (23, 27))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('promotes', 'PosReg', (36, 44))	('uveal melanoma', 'Disease', 'MESH:C536494', (45, 59))
95036	24480708	In our ongoing research using next generation DNA sequencing in uveal melanoma, we discovered frequent driver mutations in another gene called SF3B1 (Splicing factor 3B, subunit 1) (Figure 1C).	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('mutations', 'Var', (110, 119))	('SF3B1', 'Gene', (143, 148))	('uveal melanoma', 'Phenotype', 'HP:0007716', (64, 78))	('uveal melanoma', 'Disease', 'MESH:C536494', (64, 78))	('Splicing', 'biological_process', 'GO:0045292', ('150', '158'))	('SF3B1', 'Gene', '23451', (143, 148))	('uveal melanoma', 'Disease', (64, 78))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
95037	24480708	The SF3B1 mutations reported so far are quite distinct in several respects: (1) they are single nucleotide point mutations predominantly occurring at a single amino acid (arginine-625), (2) they involve only one allele (heterozygous), (3) they are almost mutually exclusive with BAP1 mutations but occur with equal frequency in GNAQ versus GNA11 mutations, and (4) they are associated with class 1 tumors and better prognosis.	('associated with', 'Reg', (374, 389))	('BAP1', 'Gene', '8314', (279, 283))	('arginine', 'Chemical', 'MESH:D001120', (171, 179))	('SF3B1', 'Gene', (4, 9))	('tumors', 'Disease', (398, 404))	('tumors', 'Disease', 'MESH:D009369', (398, 404))	('tumors', 'Phenotype', 'HP:0002664', (398, 404))	('GNAQ', 'Gene', (328, 332))	('GNA11', 'Gene', (340, 345))	('BAP1', 'Gene', (279, 283))	('mutations', 'Var', (284, 293))	('SF3B1', 'Gene', '23451', (4, 9))	('GNA11', 'Gene', '2767', (340, 345))	('mutations', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (398, 403))	('GNAQ', 'Gene', '2776', (328, 332))
95038	24480708	Mutations in SF3B1 alter the splicing of certain mRNA transcripts, but it remains unclear how this promotes tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('alter', 'Reg', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('SF3B1', 'Gene', (13, 18))	('promotes', 'PosReg', (99, 107))	('tumor', 'Disease', (108, 113))	('Mutations', 'Var', (0, 9))	('SF3B1', 'Gene', '23451', (13, 18))	('splicing of', 'MPA', (29, 40))	('splicing', 'biological_process', 'GO:0045292', ('29', '37'))	('mRNA transcripts', 'MPA', (49, 65))
95039	24480708	Powerful genomic sequencing technologies are becoming less expensive and more widely available, so it is likely that more mutations will be reported in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (152, 166))	('uveal melanoma', 'Disease', 'MESH:C536494', (152, 166))	('uveal melanoma', 'Disease', (152, 166))	('mutations', 'Var', (122, 131))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))
95040	24480708	Recently, mutations in EIF1AX (Eukaryotic translation initiation factor 1A, X-linked), located on the X chromosome, were described in a subset of uveal melanomas (Figure 1D).	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanomas', 'Phenotype', 'HP:0002861', (152, 161))	('described', 'Reg', (121, 130))	('uveal melanomas', 'Disease', 'MESH:C536494', (146, 161))	('X chromosome', 'cellular_component', 'GO:0000805', ('102', '114'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (146, 160))	('EIF1AX', 'Gene', '1964', (23, 29))	('EIF1AX', 'Gene', (23, 29))	('translation initiation', 'biological_process', 'GO:0006413', ('42', '64'))	('uveal melanomas', 'Disease', (146, 161))	('uveal melanomas', 'Phenotype', 'HP:0007716', (146, 161))	('mutations', 'Var', (10, 19))	('Eukaryotic translation initiation factor 1A, X-linked', 'Gene', (31, 84))	('Eukaryotic translation initiation factor 1A, X-linked)', 'Gene', '1964', (31, 85))
95041	24480708	EIF1AX mutations reported to date are non-truncating and heterozygous (present in only one copy of the gene), which are characteristics usually associated with dominantly acting oncogenes.	('non-truncating', 'MPA', (38, 52))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
95042	24480708	In uveal melanomas harboring EIF1AX mutations, however, only mutant mRNA transcripts were expressed, suggesting that the wildtype copy of EIF1AX is epigenetically inactivated, in which case EIF1AX mutations might behave in a recessive fashion.	('EIF1AX', 'Gene', '1964', (138, 144))	('EIF1AX', 'Gene', (138, 144))	('EIF1AX', 'Gene', '1964', (190, 196))	('EIF1AX', 'Gene', (190, 196))	('EIF1AX', 'Gene', (29, 35))	('uveal melanomas', 'Disease', (3, 18))	('EIF1AX', 'Gene', '1964', (29, 35))	('uveal melanomas', 'Phenotype', 'HP:0007716', (3, 18))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanomas', 'Phenotype', 'HP:0002861', (9, 18))	('mutations', 'Var', (36, 45))	('uveal melanomas', 'Disease', 'MESH:C536494', (3, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))
95043	24480708	Like SF3B1, EIF1AX mutations appear to be associated with class 1 uveal melanomas and with better prognosis.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('EIF1AX', 'Gene', (12, 18))	('associated', 'Reg', (42, 52))	('SF3B1', 'Gene', '23451', (5, 10))	('EIF1AX', 'Gene', '1964', (12, 18))	('uveal melanomas', 'Phenotype', 'HP:0007716', (66, 81))	('mutations', 'Var', (19, 28))	('uveal melanomas', 'Disease', (66, 81))	('uveal melanomas', 'Disease', 'MESH:C536494', (66, 81))	('SF3B1', 'Gene', (5, 10))
95044	24480708	Further, EIF1AX mutations appear to be mutually exclusive with SF3B1 mutations, which has important implications in the construction of a molecular landscape model (below).	('mutations', 'Var', (69, 78))	('EIF1AX', 'Gene', '1964', (9, 15))	('EIF1AX', 'Gene', (9, 15))	('SF3B1', 'Gene', (63, 68))	('mutations', 'Var', (16, 25))	('SF3B1', 'Gene', '23451', (63, 68))
95045	24480708	As increasingly rare mutations of unclear significance are identified, it will become challenging to distinguish truly pathogenic mutations from silent polymorphisms and "passenger" mutations that are swept along during tumor evolution without providing any selective advantage.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (220, 225))	('pathogenic', 'Reg', (119, 129))	('mutations', 'Var', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
95046	24480708	Our focus will remain on the common driver mutations that have a clear mechanistic role in tumor progression.	('mutations', 'Var', (43, 52))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
95048	24480708	Gene expression profiling not only offers a highly accurate molecular prognostic classification, it also provides a rational framework for understanding how the major driver mutations relate to one another with respect to tumor evolution and patient prognosis.	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('patient', 'Species', '9606', (242, 249))	('mutations', 'Var', (174, 183))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))
95052	24480708	Mutations in GNAQ and GNA11 are mutually exclusive and appear to represent early or initiating events because they are found in pre-malignant nevi and in uveal melanoma of all stages.	('GNA11', 'Gene', (22, 27))	('nevi', 'Phenotype', 'HP:0003764', (142, 146))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('pre', 'molecular_function', 'GO:0003904', ('128', '131'))	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (22, 27))	('Mutations', 'Var', (0, 9))	('found', 'Reg', (119, 124))	('pre-malignant nevi', 'Disease', (128, 146))	('uveal melanoma', 'Phenotype', 'HP:0007716', (154, 168))	('uveal melanoma', 'Disease', (154, 168))	('uveal melanoma', 'Disease', 'MESH:C536494', (154, 168))	('GNAQ', 'Gene', '2776', (13, 17))
95053	24480708	In contrast, BAP1 mutations occur almost exclusively in class 2 tumors and are strongly associated with metastasis, a phenotype that presumably arises later in tumor evolution.	('tumors', 'Disease', (64, 70))	('BAP1', 'Gene', (13, 17))	('tumor', 'Disease', (64, 69))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('metastasis', 'CPA', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('BAP1', 'Gene', '8314', (13, 17))	('tumor', 'Disease', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('associated with', 'Reg', (88, 103))	('mutations', 'Var', (18, 27))
95054	24480708	Thus, we can place GNAQ/11 mutations early and BAP1 mutations later in this schema based on gene expression profile.	('mutations', 'Var', (52, 61))	('mutations', 'Var', (27, 36))	('GNAQ', 'Gene', (19, 23))	('gene expression', 'biological_process', 'GO:0010467', ('92', '107'))	('BAP1', 'Gene', '8314', (47, 51))	('GNAQ', 'Gene', '2776', (19, 23))	('BAP1', 'Gene', (47, 51))
95055	24480708	SF3B1 mutations occur mostly in class 1 tumors and are largely mutually exclusive with BAP1 mutations.	('BAP1', 'Gene', '8314', (87, 91))	('SF3B1', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('BAP1', 'Gene', (87, 91))	('SF3B1', 'Gene', '23451', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('occur', 'Reg', (16, 21))	('mutations', 'Var', (6, 15))	('tumors', 'Disease', (40, 46))
95056	24480708	Similarly, EIF1AX mutations appear to occur primarily in class 1 tumors, in a mutually exclusive fashion with SF3B1 and BAP1 mutations.	('mutations', 'Var', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('occur', 'Reg', (38, 43))	('SF3B1', 'Gene', '23451', (110, 115))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('SF3B1', 'Gene', (110, 115))	('BAP1', 'Gene', '8314', (120, 124))	('EIF1AX', 'Gene', '1964', (11, 17))	('EIF1AX', 'Gene', (11, 17))	('BAP1', 'Gene', (120, 124))
95060	24480708	For example, small molecule inhibitors of a mutant form of the BRAF oncoprotein have shown efficacy in metastatic cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('cutaneous melanoma', 'Disease', (114, 132))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (114, 132))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (114, 132))	('efficacy', 'PosReg', (91, 99))	('mutant', 'Var', (44, 50))	('BRAF', 'Gene', (63, 67))
95062	24480708	Several clinical trials are underway using agents that specifically target these driver mutations in uveal melanoma (Table 1).	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('uveal melanoma', 'Phenotype', 'HP:0007716', (101, 115))	('uveal melanoma', 'Disease', 'MESH:C536494', (101, 115))	('mutations', 'Var', (88, 97))	('uveal melanoma', 'Disease', (101, 115))
95063	24480708	Direct inhibition of the mutant G-alpha-q and G-alpha-11 proteins has not been possible to date, owing to the molecular nature of these mutations, but several proteins that are activated downstream of GNAQ/11 mutations have been successfully targeted.	('G-alpha-q', 'Gene', (32, 41))	('GNAQ', 'Gene', '2776', (201, 205))	('G-alpha-11', 'Gene', '2767', (46, 56))	('G-alpha-11', 'Gene', (46, 56))	('mutations', 'Var', (209, 218))	('GNAQ', 'Gene', (201, 205))	('G-alpha-q', 'Gene', '2776', (32, 41))
95064	24480708	For example, the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) is activated in GNAQ/11-mutant tumors, and inhibition of MEK can slow the growth of uveal melanomas in vitro and in vivo.	('MEK', 'Gene', (158, 161))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('melanomas', 'Phenotype', 'HP:0002861', (191, 200))	('GNAQ', 'Gene', '2776', (117, 121))	('growth', 'CPA', (175, 181))	('GNAQ', 'Gene', (117, 121))	('inhibition', 'Var', (144, 154))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('uveal melanoma', 'Phenotype', 'HP:0007716', (185, 199))	('uveal melanomas', 'Disease', 'MESH:C536494', (185, 200))	('extracellular', 'cellular_component', 'GO:0005576', ('50', '63'))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('MEK', 'Gene', '5609', (96, 99))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('tumors', 'Disease', (132, 138))	('activated', 'PosReg', (104, 113))	('slow', 'NegReg', (166, 170))	('MEK', 'Gene', '5609', (158, 161))	('mitogen-activated protein kinase/extracellular signal-regulated kinase kinase', 'Gene', '5609', (17, 94))	('MEK', 'Gene', (96, 99))	('uveal melanomas', 'Disease', (185, 200))	('uveal melanomas', 'Phenotype', 'HP:0007716', (185, 200))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
95066	24480708	Other downstream effectors of GNAQ/11 mutations have also shown promise as therapeutic targets, including protein kinase C (PKC) and members of the AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathway.	('AKT', 'Gene', '207', (148, 151))	('mammalian target of rapamycin', 'Gene', '2475', (177, 206))	('mammalian target of rapamycin', 'Gene', (177, 206))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('protein kinase C', 'Gene', (106, 122))	('GNAQ', 'Gene', (30, 34))	('PKC', 'Gene', (124, 127))	('PKC', 'Gene', '112476', (124, 127))	('AKT', 'Gene', (148, 151))	('protein', 'cellular_component', 'GO:0003675', ('153', '160'))	('PKC', 'molecular_function', 'GO:0004697', ('124', '127'))	('protein kinase C', 'Gene', '112476', (106, 122))	('mutations', 'Var', (38, 47))	('mTOR', 'Gene', (171, 175))	('mTOR', 'Gene', '2475', (171, 175))	('GNAQ', 'Gene', '2776', (30, 34))
95067	24480708	The strong association between BAP1 mutations and metastasis suggests that pharmacologic targeting of BAP1 mutations may be of therapeutic value.	('BAP1', 'Gene', (102, 106))	('mutations', 'Var', (107, 116))	('BAP1', 'Gene', '8314', (31, 35))	('mutations', 'Var', (36, 45))	('metastasis', 'CPA', (50, 60))	('BAP1', 'Gene', (31, 35))	('BAP1', 'Gene', '8314', (102, 106))
95068	24480708	Because of the recessive nature of BAP1 mutations, they will be difficult to target directly, but it may be possible to indirectly counteract the effects of BAP1 mutations by understanding its biochemical and cellular functions.	('BAP1', 'Gene', (157, 161))	('BAP1', 'Gene', '8314', (35, 39))	('mutations', 'Var', (40, 49))	('BAP1', 'Gene', (35, 39))	('BAP1', 'Gene', '8314', (157, 161))
95070	24480708	Consequently, BAP1 inactivation leads to abnormally high histone H2A ubiquitination.	('BAP1', 'Gene', '8314', (14, 18))	('histone H2A ubiquitination', 'biological_process', 'GO:0033522', ('57', '83'))	('histone H2A', 'Protein', (57, 68))	('BAP1', 'Gene', (14, 18))	('inactivation', 'Var', (19, 31))	('high', 'PosReg', (52, 56))
95074	24480708	Although BAP1 mutations are strongly associated with the class 2 profile, BAP1 mutations can be heterogeneously distributed throughout the tumor and are thus prone to sampling error.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('BAP1', 'Gene', '8314', (9, 13))	('tumor', 'Disease', (139, 144))	('BAP1', 'Gene', (74, 78))	('BAP1', 'Gene', '8314', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('associated', 'Reg', (37, 47))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('class 2 profile', 'MPA', (57, 72))
95077	24480708	Therefore, we were surprised to find that one of the uveal melanoma patients in our original description of BAP1 mutations carried a germline BAP1 mutation.	('germline', 'Var', (133, 141))	('BAP1', 'Gene', '8314', (108, 112))	('BAP1', 'Gene', '8314', (142, 146))	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('uveal melanoma', 'Disease', (53, 67))	('BAP1', 'Gene', (108, 112))	('BAP1', 'Gene', (142, 146))	('mutations', 'Var', (113, 122))	('patients', 'Species', '9606', (68, 76))	('uveal melanoma', 'Disease', 'MESH:C536494', (53, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))
95078	24480708	Subsequently, we found germline BAP1 mutations in two additional unrelated uveal melanoma patients, both of whom had first degree relatives with uveal melanoma and other cancers (JWH, unpublished data).	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('uveal melanoma', 'Phenotype', 'HP:0007716', (145, 159))	('uveal melanoma', 'Disease', 'MESH:C536494', (145, 159))	('uveal melanoma', 'Disease', (145, 159))	('BAP1', 'Gene', '8314', (32, 36))	('uveal melanoma', 'Phenotype', 'HP:0007716', (75, 89))	('uveal melanoma', 'Disease', 'MESH:C536494', (75, 89))	('mutations', 'Var', (37, 46))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('BAP1', 'Gene', (32, 36))	('uveal melanoma', 'Disease', (75, 89))	('uveal melanoma and other cancers', 'Disease', 'MESH:C536494', (145, 177))	('patients', 'Species', '9606', (90, 98))
95079	24480708	Prompted by our report, investigators have discovered BAP1 mutations in a subset of other cancer types including mesothelioma, renal cell carcinoma, atypical intradermal nevi, cutaneous melanoma, leading to the discovery of a newly described BAP1 familial cancer syndrome.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', (256, 262))	('BAP1', 'Gene', '8314', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('mesothelioma', 'Disease', (113, 125))	('atypical intradermal nevi', 'Phenotype', 'HP:0001062', (149, 174))	('familial cancer syndrome', 'Disease', (247, 271))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (127, 147))	('mesothelioma', 'Disease', 'MESH:D008654', (113, 125))	('BAP1', 'Gene', (54, 58))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('BAP1', 'Gene', '8314', (242, 246))	('nevi', 'Phenotype', 'HP:0003764', (170, 174))	('renal cell carcinoma', 'Disease', (127, 147))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (127, 147))	('mutations', 'Var', (59, 68))	('familial cancer syndrome', 'Disease', 'MESH:D009386', (247, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('cutaneous melanoma', 'Disease', (176, 194))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (176, 194))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (176, 194))	('atypical intradermal nevi', 'Disease', (149, 174))	('BAP1', 'Gene', (242, 246))	('cancer', 'Disease', (90, 96))
95082	24480708	A germline BAP1 mutation should be suspected when a patient is diagnosed with uveal melanoma at an early age (less than 30) or when one of more of the following is present in the patient or a first degree relative: (1) multiple atypical cutaneous nevi, (2) cutaneous melanoma, (3) mesothelioma, (4) renal cell carcinoma, or (5) two or more primary cancers of any type.	('cancers', 'Disease', 'MESH:D009369', (348, 355))	('BAP1', 'Gene', (11, 15))	('multiple atypical cutaneous nevi', 'Disease', (219, 251))	('uveal melanoma', 'Phenotype', 'HP:0007716', (78, 92))	('mesothelioma', 'Disease', (281, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('mesothelioma', 'Disease', 'MESH:D008654', (281, 293))	('cancers', 'Phenotype', 'HP:0002664', (348, 355))	('cancers', 'Disease', (348, 355))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (299, 319))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('nevi', 'Phenotype', 'HP:0003764', (247, 251))	('cutaneous melanoma', 'Disease', (257, 275))	('mutation', 'Var', (16, 24))	('BAP1', 'Gene', '8314', (11, 15))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (257, 275))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (257, 275))	('patient', 'Species', '9606', (179, 186))	('patient', 'Species', '9606', (52, 59))	('uveal melanoma', 'Disease', 'MESH:C536494', (78, 92))	('renal cell carcinoma', 'Disease', (299, 319))	('uveal melanoma', 'Disease', (78, 92))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (299, 319))
95089	24480708	Based on the discovery of the driver mutations described herein, we now have rational agents to test in the adjuvant setting, including small molecule inhibitors of MEK, mTOR, PKC, and HDACs (Figure 3), as well as promising immune checkpoint inhibitors such as ipilimumab.	('HDAC', 'Gene', (185, 189))	('HDAC', 'Gene', '9734', (185, 189))	('ipilimumab', 'Chemical', 'MESH:D000074324', (261, 271))	('MEK', 'Gene', (165, 168))	('mTOR', 'Gene', (170, 174))	('MEK', 'Gene', '5609', (165, 168))	('mTOR', 'Gene', '2475', (170, 174))	('PKC', 'Gene', (176, 179))	('PKC', 'Gene', '112476', (176, 179))	('mutations', 'Var', (37, 46))	('PKC', 'molecular_function', 'GO:0004697', ('176', '179'))
95094	24480708	Patients at high risk for harboring a germline BAP1 mutation are offered BAP1 sequencing and genetic counseling.	('BAP1', 'Gene', '8314', (73, 77))	('BAP1', 'Gene', (73, 77))	('germline', 'Var', (38, 46))	('Patients', 'Species', '9606', (0, 8))	('BAP1', 'Gene', '8314', (47, 51))	('BAP1', 'Gene', (47, 51))
95098	24243779	In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1.	('germline mutation', 'Var', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('patients', 'Species', '9606', (64, 72))	('BAP1', 'Gene', '8314', (135, 139))	('hereditary cancer', 'Disease', 'MESH:D009369', (92, 109))	('BAP1', 'Gene', (135, 139))	('hereditary cancer', 'Disease', (92, 109))
95100	24243779	We identified three patients with germline pathogenic mutations (c.2050 C>T, pGln684*; c.1182C>G, p.Tyr394*, and c.1882_1885delTCAC, p. Ser628Profs*8) in BAP1.	('pGln684*; c.1182C>G', 'Var', (77, 96))	('c.2050 C>T', 'Mutation', 'rs387906848', (65, 75))	('BAP1', 'Gene', (154, 158))	('pathogenic', 'Reg', (43, 53))	('c.1882_1885delTCAC', 'Var', (113, 131))	('Ser628Profs', 'Chemical', '-', (136, 147))	('p.Tyr394*', 'Mutation', 'p.Y394*', (98, 107))	('Ser', 'cellular_component', 'GO:0005790', ('136', '139'))	('patients', 'Species', '9606', (20, 28))	('p. Ser628Profs*8', 'Var', (133, 149))	('c.2050 C>T', 'Var', (65, 75))	('c.1182C>G', 'Var', (87, 96))	('p.Tyr394*', 'Var', (98, 107))	('c.1882_1885delTCAC', 'Mutation', 'c.1882_1885delTCAC', (113, 131))	('BAP1', 'Gene', '8314', (154, 158))	('c.1182C>G', 'Mutation', 'c.1182C>G', (87, 96))
95103	24243779	The results of this study confirm the association between germline BAP1 mutation and predisposition to UM, mesothelioma, CM and RCC.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('CM', 'Disease', 'MESH:D009202', (121, 123))	('mesothelioma', 'Disease', (107, 119))	('germline', 'Var', (58, 66))	('BAP1', 'Gene', '8314', (67, 71))	('association', 'Reg', (38, 49))	('mutation', 'Var', (72, 80))	('mesothelioma', 'Disease', 'MESH:D008654', (107, 119))	('BAP1', 'Gene', (67, 71))
95106	24243779	Germline mutations in the BAP1 gene have been identified in a small number of families with hereditary cancers.	('Germline mutations', 'Var', (0, 18))	('BAP1', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('hereditary cancers', 'Disease', (92, 110))	('hereditary cancers', 'Disease', 'MESH:D009369', (92, 110))	('BAP1', 'Gene', '8314', (26, 30))	('identified', 'Reg', (46, 56))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))
95111	24243779	Proper characterization of the phenotype is crucial to define diagnostic criteria and design management and follow-up protocols for patients with germline BAP1 mutations.	('BAP1', 'Gene', '8314', (155, 159))	('mutations', 'Var', (160, 169))	('BAP1', 'Gene', (155, 159))	('men', 'Species', '9606', (99, 102))	('patients', 'Species', '9606', (132, 140))
95112	24243779	In the following study, we report three additional patients with germline BAP1 mutations, including one presenting with metastatic adenocarcinoma likely from a cholangiocarcinoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (160, 178))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (160, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('germline', 'Var', (65, 73))	('BAP1', 'Gene', '8314', (74, 78))	('adenocarcinoma', 'Disease', (131, 145))	('patients', 'Species', '9606', (51, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('cholangiocarcinoma', 'Disease', (160, 178))	('BAP1', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))	('adenocarcinoma', 'Disease', 'MESH:D000230', (131, 145))
95123	24243779	Immunohistochemistry was carried out on tumor tissues from FUM103 (III.1) and FUM064 (III-12).	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('FUM064', 'Var', (78, 84))
95128	24243779	Out of the 50 patients tested, we identified three with pathogenic mutations in BAP1 and 4 with variants of uncertain significance: c.2057-4G>T (rs149499021) in two different patients, both c.2057-22A>C (rs144083199) and c.*45C>G (rs56898787) in a third patient and c. 932-58_59delTG in a fourth patient (Table 1).	('rs56898787', 'Var', (231, 241))	('c. 932-58_59delTG', 'Mutation', 'c.932-58_59delTG', (266, 283))	('c.2057-22A>C (rs144083199', 'Var', (190, 215))	('BAP1', 'Gene', '8314', (80, 84))	('rs144083199', 'Var', (204, 215))	('c. 932-58_59delTG', 'Var', (266, 283))	('patients', 'Species', '9606', (14, 22))	('c.2057-22A>C', 'Mutation', 'rs144083199', (190, 202))	('rs149499021', 'Var', (145, 156))	('c.2057-4G>T', 'Mutation', 'rs149499021', (132, 143))	('c.2057-4G>T (rs149499021', 'Var', (132, 156))	('patient', 'Species', '9606', (175, 182))	('rs149499021', 'Mutation', 'rs149499021', (145, 156))	('patient', 'Species', '9606', (254, 261))	('BAP1', 'Gene', (80, 84))	('rs56898787', 'Mutation', 'rs56898787', (231, 241))	('patient', 'Species', '9606', (14, 21))	('pathogenic', 'Reg', (56, 66))	('c.*45C>G', 'Mutation', 'rs56898787', (221, 229))	('c.*45C>G (rs56898787', 'Var', (221, 241))	('patient', 'Species', '9606', (296, 303))	('patients', 'Species', '9606', (175, 183))	('rs144083199', 'Mutation', 'rs144083199', (204, 215))
95129	24243779	A germline truncating mutation (c.2050 C>T, p.Gln684*) of BAP1 was identified in the proband (IV.1), who presented with UM (age 41), an epithelial malignancy of unknown origin at the porta hepatis with distant metastasis (age 42) and an unclassified spindle cell proliferation in her thigh (age 42).	('malignancy', 'Disease', 'MESH:D009369', (147, 157))	('malignancy', 'Disease', (147, 157))	('p.Gln684*', 'Var', (44, 53))	('BAP1', 'Gene', (58, 62))	('c.2050 C>T', 'Mutation', 'rs387906848', (32, 42))	('p.Gln684*', 'Mutation', 'rs387906848', (44, 53))	('spindle', 'cellular_component', 'GO:0005819', ('250', '257'))	('cell proliferation', 'biological_process', 'GO:0008283', ('258', '276'))	('distant metastasis', 'CPA', (202, 220))	('epithelial malignancy', 'Phenotype', 'HP:0031492', (136, 157))	('c.2050 C>T', 'Var', (32, 42))	('unclassified spindle cell proliferation in', 'CPA', (237, 279))	('BAP1', 'Gene', '8314', (58, 62))
95132	24243779	A paternal cousin once-removed (III-12) presenting with peritoneal papillary tumor was also positive for the same mutation; thus, making their parents and the proband's paternal grandmother obligate carriers of the same mutation.	('mutation', 'Var', (114, 122))	('papillary tumor', 'Disease', (67, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('papillary tumor', 'Disease', 'MESH:D002291', (67, 82))
95138	24243779	2B) with strong expression in nontumor tissue suggesting biallelic inactivation of BAP1 in the tumor tissue.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('biallelic', 'Var', (57, 66))	('BAP1', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))	('BAP1', 'Gene', '8314', (83, 87))
95140	24243779	A germline truncating mutation c.1182C>G, p.Tyr394* was identified in the proband (III.1) who presented with a metastatic adenocarcinoma to the rib and a hepatic focal lesion.	('adenocarcinoma', 'Disease', (122, 136))	('hepatic focal lesion', 'Disease', 'MESH:D056486', (154, 174))	('adenocarcinoma', 'Disease', 'MESH:D000230', (122, 136))	('p.Tyr394*', 'Var', (42, 51))	('c.1182C>G', 'Var', (31, 40))	('p.Tyr394*', 'Mutation', 'p.Y394*', (42, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('c.1182C>G', 'Mutation', 'c.1182C>G', (31, 40))	('hepatic focal lesion', 'Disease', (154, 174))
95151	24243779	A germline frameshift mutation c.1882_1885delTCAC, p. Ser628Profs*8in BAP1 was identified in the index case, her son and a great maternal aunt, who presented with invasive breast cancer (Figs.	('Ser628Profs', 'Chemical', '-', (54, 65))	('c.1882_1885delTCAC', 'Mutation', 'c.1882_1885delTCAC', (31, 49))	('p. Ser628Profs*8in', 'Var', (51, 69))	('invasive breast cancer', 'Disease', 'MESH:D001943', (163, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('BAP1', 'Gene', '8314', (70, 74))	('c.1882_1885delTCAC', 'Var', (31, 49))	('invasive breast cancer', 'Disease', (163, 185))	('Ser', 'cellular_component', 'GO:0005790', ('54', '57'))	('BAP1', 'Gene', (70, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))
95155	24243779	The association of germline BAP1 mutation with increased risks for UM, mesothelioma, CM, RCC, and MBAITs is now fairly well established.	('mesothelioma', 'Disease', (71, 83))	('BAP1', 'Gene', '8314', (28, 32))	('mutation', 'Var', (33, 41))	('mesothelioma', 'Disease', 'MESH:D008654', (71, 83))	('MBAITs', 'Disease', (98, 104))	('BAP1', 'Gene', (28, 32))	('RCC', 'Disease', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('CM', 'Disease', 'MESH:D009202', (85, 87))	('germline', 'Var', (19, 27))
95157	24243779	In the present study, we report three new families with germline pathogenic mutations in BAP1.	('BAP1', 'Gene', '8314', (89, 93))	('mutations', 'Var', (76, 85))	('BAP1', 'Gene', (89, 93))
95158	24243779	One of the mutations (p.Q684*) has been previously reported in another hereditary mesothelioma/UM family.	('mesothelioma', 'Disease', (82, 94))	('p.Q684*', 'Mutation', 'rs387906848', (22, 29))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('reported', 'Reg', (51, 59))	('p.Q684*', 'Var', (22, 29))
95159	24243779	The two other mutations (p.Tyr394* and p. Ser628Profs*8) have not been previously reported.	('p.Tyr394*', 'Mutation', 'p.Y394*', (25, 34))	('p.Tyr394*', 'Var', (25, 34))	('Ser628Profs', 'Chemical', '-', (42, 53))	('Ser', 'cellular_component', 'GO:0005790', ('42', '45'))	('p. Ser628Profs*', 'Var', (39, 54))
95160	24243779	Cancers reported in patients with germline BAP1 mutation in our study included cancers associated with BAP1 hereditary cancer predisposition syndrome, such as UM, CM, RCC and mesothelioma, as well as, other cancers such as hepatic cholangiocarcinoma and breast carcinoma.	('BAP1', 'Gene', '8314', (103, 107))	('hepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (223, 249))	('BAP1', 'Gene', (43, 47))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('germline', 'Var', (34, 42))	('CM', 'Disease', 'MESH:D009202', (163, 165))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cancers', 'Disease', (207, 214))	('BAP1', 'Gene', (103, 107))	('hereditary cancer', 'Disease', (108, 125))	('breast carcinoma', 'Disease', 'MESH:D001943', (254, 270))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancers', 'Disease', (79, 86))	('mesothelioma', 'Disease', (175, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (231, 249))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('hereditary cancer', 'Disease', 'MESH:D009369', (108, 125))	('mesothelioma', 'Disease', 'MESH:D008654', (175, 187))	('BAP1', 'Gene', '8314', (43, 47))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('mutation', 'Var', (48, 56))	('RCC', 'Disease', (167, 170))	('breast carcinoma', 'Phenotype', 'HP:0003002', (254, 270))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('breast carcinoma', 'Disease', (254, 270))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('hepatic cholangiocarcinoma', 'Disease', (223, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
95170	24243779	WDPM has been recently reported by another group in two siblings with germline mutation in BAP1.	('BAP1', 'Gene', '8314', (91, 95))	('BAP1', 'Gene', (91, 95))	('WDPM', 'Disease', (0, 4))	('germline mutation', 'Var', (70, 87))
95173	24243779	An earlier study by our group suggested that the frequency of germline mutation in BAP1 is low (1/53) in patients with UM, even in those with strong personal or family histories of cancer.	('germline mutation', 'Var', (62, 79))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('BAP1', 'Gene', (83, 87))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('BAP1', 'Gene', '8314', (83, 87))
95175	24243779	Whether other cancers seen in other mutation carriers in these families are coincidental or due to the mutation has yet to be definitively established.	('cancers', 'Disease', (14, 21))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutation', 'Var', (103, 111))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))
95176	24243779	Germline mutation in BAP1 has been observed in one patient in our study as well as reported in a few high-risk breast cancer families suggesting that breast cancer could be part of the phenotype.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('BAP1', 'Gene', (21, 25))	('breast cancer', 'Disease', (150, 163))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Germline mutation', 'Var', (0, 17))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('patient', 'Species', '9606', (51, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('breast cancer', 'Disease', (111, 124))	('observed', 'Reg', (35, 43))	('BAP1', 'Gene', '8314', (21, 25))
95179	24243779	Nevertheless, it appears clear that carrying a BAP1 germline mutation puts an individual at significantly increased risk of cancer.	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('BAP1', 'Gene', '8314', (47, 51))	('germline mutation', 'Var', (52, 69))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('BAP1', 'Gene', (47, 51))
95184	24243779	The high frequency of germline BAP1 mutations in patients presenting with metastatic disease suggests that UM is more aggressive in these patients.	('metastatic disease', 'Disease', (74, 92))	('BAP1', 'Gene', '8314', (31, 35))	('mutations', 'Var', (36, 45))	('BAP1', 'Gene', (31, 35))	('patients', 'Species', '9606', (49, 57))	('patients', 'Species', '9606', (138, 146))
95186	24243779	In conclusion, germline BAP1 mutations appear to predispose patients to an increasing spectrum of cancers including UM, CM, mesothelioma, and RCC.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('predispose', 'Reg', (49, 59))	('BAP1', 'Gene', (24, 28))	('patients', 'Species', '9606', (60, 68))	('mutations', 'Var', (29, 38))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('mesothelioma', 'Disease', (124, 136))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('CM', 'Disease', 'MESH:D009202', (120, 122))	('mesothelioma', 'Disease', 'MESH:D008654', (124, 136))	('BAP1', 'Gene', '8314', (24, 28))
95189	24243779	Finally, the current evidence justifies establishment of surveillance protocols for early diagnosis of UM and CM in patients with germline mutation in BAP1.	('men', 'Species', '9606', (49, 52))	('BAP1', 'Gene', (151, 155))	('patients', 'Species', '9606', (116, 124))	('germline mutation', 'Var', (130, 147))	('CM', 'Disease', 'MESH:D009202', (110, 112))	('BAP1', 'Gene', '8314', (151, 155))
95205	24653816	Molecular classification was found to be correlated with tumor cytology, patient survival, and other prognostic cytogenetic features such as monosomy of chromosome 3 and duplication of chromosome 8q.	('duplication of chromosome 8q', 'Var', (170, 198))	('chromosome', 'cellular_component', 'GO:0005694', ('185', '195'))	('chromosome', 'cellular_component', 'GO:0005694', ('153', '163'))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('patient', 'Species', '9606', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('monosomy of chromosome', 'Var', (141, 163))	('tumor', 'Disease', (57, 62))
95241	24015299	Moreover, HER2Bi-armed ATC expressed higher level of activation marker CD69 and secreted significantly higher level of IFN-gamma than unarmed ATC counterpart at the E/T ratio of 20:1.	('IFN-gamma', 'Gene', '3458', (119, 128))	('IFN-gamma', 'Gene', (119, 128))	('activation marker CD69', 'MPA', (53, 75))	('HER2Bi-armed ATC', 'Var', (10, 26))	('higher', 'PosReg', (37, 43))	('secreted', 'MPA', (80, 88))	('higher', 'PosReg', (103, 109))	('HER2Bi', 'Chemical', '-', (10, 16))
95242	24015299	In addition, compared with anti-HER2 mAb (Herceptin ) or unarmed ATC, HER2Bi-armed ATC showed remarkable suppression effect on Malme-3M-luc tumor cells.	('HER2Bi-armed', 'Var', (70, 82))	('Herceptin', 'Chemical', 'MESH:D000068878', (42, 51))	('suppression', 'NegReg', (105, 116))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('HER2Bi', 'Chemical', '-', (70, 76))	('tumor', 'Disease', (140, 145))
95284	24015299	To detect the CD69 expression on ATC, the floating cells from Malme-3M and ATC co-culture were incubated with anti-CD69-PE and anti-CD3-FITC (UCHT1, eBioscience).	('anti-CD69-PE', 'Var', (110, 122))	('CD69', 'Gene', (14, 18))	('CD3-FITC', 'Chemical', '-', (132, 140))	('anti-CD3-FITC', 'Var', (127, 140))
95322	24015299	After 18 hour incubation with HER2Bi-armed ATC or unarmed ATC, bioluminescence image signal expressed in photons per second was converted into living cell number and the cytotoxicity assays was calculated at the indicated E/T ratios.	('cytotoxicity', 'Disease', (170, 182))	('HER2Bi', 'Chemical', '-', (30, 36))	('bioluminescence', 'biological_process', 'GO:0008218', ('63', '78'))	('cytotoxicity', 'Disease', 'MESH:D064420', (170, 182))	('HER2Bi-armed ATC', 'Var', (30, 46))
95326	24015299	On the contrary, there was no difference in the cytotoxicity against mouse melanoma cell line B16-luc between HER2Bi-armed ATC and unarmed ATC (Figure 5C).	('HER2Bi-armed ATC', 'Var', (110, 126))	('HER2Bi', 'Chemical', '-', (110, 116))	('cytotoxicity', 'Disease', 'MESH:D064420', (48, 60))	('mouse', 'Species', '10090', (69, 74))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('cytotoxicity', 'Disease', (48, 60))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))
95328	24015299	As shown in Figure 5D, the IFN-gamma production increased with the enhanced E/T ratio in both unarmed and HER2Bi-armed ATC as effectors, with the concentration ranging from 27 to 641 ng/ml.	('E/T ratio', 'MPA', (76, 85))	('increased', 'PosReg', (48, 57))	('IFN-gamma', 'Gene', '3458', (27, 36))	('IFN-gamma', 'Gene', (27, 36))	('HER2Bi', 'Chemical', '-', (106, 112))	('HER2Bi-armed', 'Var', (106, 118))	('enhanced', 'PosReg', (67, 75))
95329	24015299	Although no significant difference was found at E/T ratios 1: 1 and 5: 1, a remarkable increase was observed in IFN-gamma secretion in the supernatants from HER2Bi-armed ATC over their unarmed ATC counterpart when ATC were co-cultured with Malme-3M-luc cells at a E/T ratio 20:1(p<0.01).	('increase', 'PosReg', (87, 95))	('IFN-gamma secretion', 'biological_process', 'GO:0072643', ('112', '131'))	('HER2Bi', 'Chemical', '-', (157, 163))	('IFN-gamma', 'Gene', '3458', (112, 121))	('IFN-gamma', 'Gene', (112, 121))	('HER2Bi-armed', 'Var', (157, 169))
95344	24015299	Moreover, HER2Bi-armed ATC secreted significantly higher level of IFN-gamma than unarmed ATC counterpart against Malme-3M-luc cells.	('HER2Bi-armed', 'Var', (10, 22))	('secreted', 'MPA', (27, 35))	('higher', 'PosReg', (50, 56))	('IFN-gamma', 'Gene', '3458', (66, 75))	('IFN-gamma', 'Gene', (66, 75))	('HER2Bi', 'Chemical', '-', (10, 16))
95360	24015299	Moreover, HER2Bi-armed ATC expressed higher level of activation marker CD69 and secreted significantly higher level of IFN-gamma than unarmed ATC counterpart against Malme-3M-luc cells.	('HER2Bi-armed', 'Var', (10, 22))	('IFN-gamma', 'Gene', (119, 128))	('activation marker CD69', 'MPA', (53, 75))	('IFN-gamma', 'Gene', '3458', (119, 128))	('higher', 'PosReg', (37, 43))	('secreted', 'MPA', (80, 88))	('higher', 'PosReg', (103, 109))	('HER2Bi', 'Chemical', '-', (10, 16))
95363	24015299	Our data from in vitro cytotoxicity assays indicated HER2Bi-armed ATC mediated cell killing without the addition of IL-2 to the cultures.	('cytotoxicity', 'Disease', (23, 35))	('IL-2', 'Gene', (116, 120))	('IL-2', 'molecular_function', 'GO:0005134', ('116', '120'))	('HER2Bi', 'Chemical', '-', (53, 59))	('cell killing', 'CPA', (79, 91))	('cytotoxicity', 'Disease', 'MESH:D064420', (23, 35))	('HER2Bi-armed', 'Var', (53, 65))	('cell killing', 'biological_process', 'GO:0001906', ('79', '91'))	('IL-2', 'Gene', '3558', (116, 120))
95381	18385798	Semiquantitative RT-PCR analysis showed that the tested cells did not differ in mRNA levels of beta1-6 -N-acetylglucosaminyltransferase V. However, FACS analysis showed that 92-1, Mel202 and IGR-39 cells expressed significantly higher amounts of beta1-6 branched N-oligosaccharides on the cell surface than FM55P cells did.	('N-oligosaccharides', 'Chemical', '-', (263, 281))	('higher', 'PosReg', (228, 234))	('beta1-6', 'Protein', (246, 253))	('cell surface', 'cellular_component', 'GO:0009986', ('289', '301'))	('beta1-6 -N-acetylglucosaminyltransferase V', 'Gene', (95, 137))	('IGR-39', 'Var', (191, 197))	('beta1-6 -N-acetylglucosaminyltransferase V', 'Gene', '146664', (95, 137))
95392	18385798	Loss, overexpression or malfunctioning of adhesion molecules may contribute to the detachment of tumor cells from the primary tumor, local invasion and metastasis.	('adhesion molecules', 'Protein', (42, 60))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('metastasis', 'CPA', (152, 162))	('malfunctioning', 'Var', (24, 38))	('local invasion', 'CPA', (133, 147))	('Loss', 'NegReg', (0, 4))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('overexpression', 'PosReg', (6, 20))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('contribute', 'Reg', (65, 75))	('detachment', 'CPA', (83, 93))	('tumor', 'Disease', (126, 131))
95434	18385798	Among the various classes of cell adhesion molecules, integrins are particularly associated with cell adhesion to extracellular matrices, and altered levels of integrin expression are related to tissue invasion and metastasis in many types of cancer.	('cell adhesion to extracellular matrices', 'CPA', (97, 136))	('tissue invasion', 'biological_process', 'GO:0001404', ('195', '210'))	('extracellular', 'cellular_component', 'GO:0005576', ('114', '127'))	('related to', 'Reg', (184, 194))	('altered', 'Var', (142, 149))	('metastasis', 'CPA', (215, 225))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cell adhesion', 'biological_process', 'GO:0007155', ('97', '110'))	('integrins', 'Protein', (54, 63))	('tissue invasion', 'CPA', (195, 210))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('associated', 'Reg', (81, 91))	('cell adhesion', 'biological_process', 'GO:0007155', ('29', '42'))
95437	18385798	The results also showed that the high levels of alpha3beta1, alpha4beta1 and alpha5beta1 integrin expression on IGR-39 cells correlate with strong attachment to FN-coated surfaces, and the high expression of alpha4beta1 integrin on FM55P probably was enough to make them adhere weakly to FN.	('FN', 'Gene', '2335', (288, 290))	('beta1 integrin', 'Gene', (83, 97))	('attachment', 'CPA', (147, 157))	('beta1 integrin', 'Gene', '3688', (214, 228))	('FM55P', 'Var', (232, 237))	('FN', 'Gene', '2335', (161, 163))	('beta1 integrin', 'Gene', (214, 228))	('beta1 integrin', 'Gene', '3688', (83, 97))	('alpha3beta1', 'Protein', (48, 59))	('alpha4beta1', 'Protein', (61, 72))
95445	18385798	To identify the glycoproteins bearing beta1-6 GlcNAc branched N-glycans from four melanoma cell lines, we precipitated clarified lysates of 92-1, Mel202, FM55P, and IGR-39 with PHA-L lectin.	('N-glycans', 'Chemical', '-', (62, 71))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('GlcNAc', 'Chemical', 'MESH:D000117', (46, 52))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('FM55P', 'Var', (154, 159))	('lectin', 'molecular_function', 'GO:0005530', ('183', '189'))
95464	18385798	We recently showed that changes in the number of proteins acting as substrates for GnT-V were associated more with melanoma development and progression than with expression of cell adhesion molecules.	('proteins', 'Protein', (49, 57))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('number of', 'MPA', (39, 48))	('GnT-V', 'Gene', (83, 88))	('progression', 'CPA', (140, 151))	('melanoma', 'Disease', (115, 123))	('GnT-V', 'Gene', '4249', (83, 88))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('associated', 'Reg', (94, 104))	('changes', 'Var', (24, 31))	('cell adhesion', 'biological_process', 'GO:0007155', ('176', '189'))
95465	18385798	It is believed that expression of beta1-6 branched N-oligosaccharides on integrins and other adhesion receptors may facilitate the turnover of cell-cell and cell-ECM contacts to enhance cell motility.	('enhance', 'PosReg', (178, 185))	('expression', 'Var', (20, 30))	('beta1-6', 'Var', (34, 41))	('CM', 'Phenotype', 'HP:0012056', (163, 165))	('N-oligosaccharides', 'Chemical', '-', (51, 69))	('cell motility', 'CPA', (186, 199))	('cell motility', 'biological_process', 'GO:0048870', ('186', '199'))	('facilitate', 'PosReg', (116, 126))
95468	18385798	In 92-1, Mel202, and FM55P cells, altered surface glycosylation might induce functional changes in adhesion proteins and in this way decrease the binding capacity of integrins to FN, possibly by holding the conformation in the low-affinity form to the ligand.	('adhesion', 'MPA', (99, 107))	('decrease', 'NegReg', (133, 141))	('altered', 'Var', (34, 41))	('changes', 'Reg', (88, 95))	('binding', 'molecular_function', 'GO:0005488', ('146', '153'))	('integrins', 'Protein', (166, 175))	('induce', 'Reg', (70, 76))	('binding', 'Interaction', (146, 153))	('FN', 'Gene', '2335', (179, 181))	('glycosylation', 'biological_process', 'GO:0070085', ('50', '63'))	('ligand', 'molecular_function', 'GO:0005488', ('252', '258'))	('functional', 'MPA', (77, 87))	('surface glycosylation', 'MPA', (42, 63))
95476	18385798	As 92-1 and Mel202 cells did not adhere to FN and were twice as mobile as CM cells, and since the presence of beta1-6 branched N-oligosaccharides on their surface enhanced their motility, it is tempting to speculate that these cells may have also been more metastatic, but this requires confirmation.	('beta1-6 branched N-oligosaccharides', 'Protein', (110, 145))	('metastatic', 'CPA', (257, 267))	('CM', 'Phenotype', 'HP:0012056', (74, 76))	('N-oligosaccharides', 'Chemical', '-', (127, 145))	('enhanced', 'PosReg', (163, 171))	('presence', 'Var', (98, 106))	('motility', 'CPA', (178, 186))	('FN', 'Gene', '2335', (43, 45))
95478	18385798	Indeed, most of the cell lines expressing beta1-6 branched N-oligosaccharides have been shown to metastasize to either the liver or the lungs.	('beta1-6 branched', 'Var', (42, 58))	('N-oligosaccharides', 'Chemical', '-', (59, 77))	('metastasize', 'CPA', (97, 108))
95488	18385798	Substitution by GnT-III effectively reduces beta1-6 branching because GnT-V cannot act on such bisected precursor, resulting in lowering tumor cell metastasis.	('Substitution', 'Var', (0, 12))	('tumor', 'Disease', (137, 142))	('GnT-III', 'Gene', (16, 23))	('GnT-V', 'Gene', (70, 75))	('GnT-V', 'Gene', '4249', (70, 75))	('GnT-III', 'Gene', '4248', (16, 23))	('reduces', 'NegReg', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('beta1-6 branching', 'MPA', (44, 61))	('lowering', 'NegReg', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
95490	18385798	It has been shown that the modification of alpha5beta1 integrin by bisecting GlcNAc inhibited cell spreading and migration on FN, subsequently leading to the down-regulation of integrin-mediated signaling.	('FN', 'Gene', '2335', (126, 128))	('integrin-mediated signaling', 'MPA', (177, 204))	('beta1 integrin', 'Gene', (49, 63))	('signaling', 'biological_process', 'GO:0023052', ('195', '204'))	('modification', 'Var', (27, 39))	('down-regulation', 'NegReg', (158, 173))	('regulation', 'biological_process', 'GO:0065007', ('163', '173'))	('GlcNAc', 'Chemical', 'MESH:D000117', (77, 83))	('beta1 integrin', 'Gene', '3688', (49, 63))	('inhibited', 'NegReg', (84, 93))
95497	32966238	AHNAK2 expression was significantly high in patients with advanced stage, advanced T classification, lymph node metastasis, increased BRAF mutations and decreased RAS mutations.	('lymph node metastasis', 'CPA', (101, 122))	('high', 'PosReg', (36, 40))	('patients', 'Species', '9606', (44, 52))	('mutations', 'Var', (139, 148))	('increased', 'PosReg', (124, 133))	('BRAF', 'Gene', '673', (134, 138))	('expression', 'MPA', (7, 17))	('AHNAK2', 'Gene', (0, 6))	('BRAF', 'Gene', (134, 138))	('decreased', 'NegReg', (153, 162))	('AHNAK2', 'Gene', '113146', (0, 6))	('RAS mutations', 'MPA', (163, 176))	('advanced T classification', 'CPA', (74, 99))
95502	32966238	Methylation may act as an upstream regulator to inhibit the expression and biological function of AHNAK2.	('expression', 'MPA', (60, 70))	('biological function', 'MPA', (75, 94))	('Methylation', 'Var', (0, 11))	('AHNAK2', 'Gene', (98, 104))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('AHNAK2', 'Gene', '113146', (98, 104))	('inhibit', 'NegReg', (48, 55))
95524	32966238	Kaplan-Meier (K-M) survival analysis showed that the high AHNAK2 (H-AHNAK2) group was associated with worse progression-free survival (PFS) than the low AHNAK2 (L-AHNAK2) group (P=0.0005) (Figure 1D).	('worse', 'NegReg', (102, 107))	('high', 'Var', (53, 57))	('AHNAK2', 'Gene', '113146', (153, 159))	('AHNAK2', 'Gene', (68, 74))	('AHNAK2', 'Gene', (58, 64))	('AHNAK2', 'Gene', '113146', (68, 74))	('progression-free survival', 'CPA', (108, 133))	('AHNAK2', 'Gene', '113146', (58, 64))	('AHNAK2', 'Gene', (163, 169))	('AHNAK2', 'Gene', '113146', (163, 169))	('AHNAK2', 'Gene', (153, 159))
95527	32966238	We analyzed the relationships between AHNAK2 and clinical parameters, including age, gender, stage, metastasis, N classification, T classification, pathologic type, and mutations in BRAF and RAS (Table 2, Supplementary Figure 1).	('mutations', 'Var', (169, 178))	('AHNAK2', 'Gene', (38, 44))	('BRAF', 'Gene', '673', (182, 186))	('RAS', 'Gene', (191, 194))	('AHNAK2', 'Gene', '113146', (38, 44))	('BRAF', 'Gene', (182, 186))
95528	32966238	AHNAK2 expression was significantly high in patients with an advanced stage, an advanced T classification, lymph node metastasis, increased BRAF mutations, decreased RAS mutations, and lower follicular PTC and higher tall-cell PTC proportions.	('PTC', 'Gene', '5979', (227, 230))	('PTC', 'Phenotype', 'HP:0002895', (227, 230))	('mutations', 'Var', (145, 154))	('lower', 'NegReg', (185, 190))	('patients', 'Species', '9606', (44, 52))	('TC', 'Phenotype', 'HP:0002890', (228, 230))	('increased', 'PosReg', (130, 139))	('TC', 'Phenotype', 'HP:0002890', (203, 205))	('BRAF', 'Gene', '673', (140, 144))	('expression', 'MPA', (7, 17))	('BRAF', 'Gene', (140, 144))	('decreased', 'NegReg', (156, 165))	('RAS', 'Protein', (166, 169))	('AHNAK2', 'Gene', '113146', (0, 6))	('higher', 'PosReg', (210, 216))	('high', 'PosReg', (36, 40))	('lymph node metastasis', 'CPA', (107, 128))	('AHNAK2', 'Gene', (0, 6))	('PTC', 'Gene', (202, 205))	('PTC', 'Phenotype', 'HP:0002895', (202, 205))	('PTC', 'Gene', (227, 230))	('PTC', 'Gene', '5979', (202, 205))
95529	32966238	Interestingly, in the study of the relationship between AHNAK2 expression and gene mutations in PTC (Supplementary Figure 1A), we found that AHNAK2 expression was positively correlated with BRAF mutations (Supplementary Figure 1B) and negatively correlated with RAS (NRAS, HRAS and KRAS) mutations (Supplementary Figure 1C-1E).	('KRAS', 'Gene', '3845', (282, 286))	('PTC', 'Gene', (96, 99))	('TC', 'Phenotype', 'HP:0002890', (97, 99))	('PTC', 'Gene', '5979', (96, 99))	('negatively', 'NegReg', (235, 245))	('PTC', 'Phenotype', 'HP:0002895', (96, 99))	('BRAF', 'Gene', '673', (190, 194))	('KRAS', 'Gene', (282, 286))	('BRAF', 'Gene', (190, 194))	('HRAS', 'Gene', '3265', (273, 277))	('NRAS', 'Gene', '4893', (267, 271))	('AHNAK2', 'Gene', '113146', (56, 62))	('HRAS', 'Gene', (273, 277))	('AHNAK2', 'Gene', (56, 62))	('mutations', 'Var', (195, 204))	('correlated', 'Reg', (174, 184))	('AHNAK2', 'Gene', '113146', (141, 147))	('RAS', 'Disease', (262, 265))	('NRAS', 'Gene', (267, 271))	('AHNAK2', 'Gene', (141, 147))	('expression', 'MPA', (148, 158))
95545	32966238	Among the DNA methylation sites of AHNAK2, cg06799735, cg01513078, cg11138227 and cg23385208 had the most significant negative correlations with the AHNAK2 expression level (Table 3).	('cg11138227', 'Var', (67, 77))	('expression level', 'MPA', (156, 172))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('cg23385208', 'Var', (82, 92))	('cg06799735', 'Var', (43, 53))	('negative', 'NegReg', (118, 126))	('cg01513078', 'Var', (55, 65))	('AHNAK2', 'Gene', (35, 41))	('AHNAK2', 'Gene', (149, 155))	('AHNAK2', 'Gene', '113146', (149, 155))	('AHNAK2', 'Gene', '113146', (35, 41))	('DNA methylation', 'biological_process', 'GO:0006306', ('10', '25'))
95546	32966238	Moreover, we found significant connections between AHNAK2 methylation and clinical parameters such as tumor purity, stage, T classification, N classification and histological type (Figure 5C-5G).	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('AHNAK2', 'Gene', (51, 57))	('methylation', 'Var', (58, 69))	('connections', 'Reg', (31, 42))	('methylation', 'biological_process', 'GO:0032259', ('58', '69'))	('T classification', 'CPA', (123, 139))	('AHNAK2', 'Gene', '113146', (51, 57))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
95548	32966238	Based on RNAseq, we screened 9,944 genes related to AHNAK2 methylation (false discovery rate (FDR) <0.01) (Figure 5H).	('false', 'biological_process', 'GO:0071877', ('72', '77'))	('AHNAK2', 'Gene', (52, 58))	('false', 'biological_process', 'GO:0071878', ('72', '77'))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('methylation', 'Var', (59, 70))	('AHNAK2', 'Gene', '113146', (52, 58))
95549	32966238	The top 50 significant genes that were positively and negatively correlated with AHNAK2 methylation are presented as two heatmaps in Figure 5I.	('methylation', 'Var', (88, 99))	('AHNAK2', 'Gene', (81, 87))	('AHNAK2', 'Gene', '113146', (81, 87))	('negatively', 'NegReg', (54, 64))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))
95550	32966238	The GO (biological process) analysis results derived by GSEA were significant; the results indicated that AHNAK2 methylation coexpressed genes participate primarily in metabolism-related pathways, while genes related to activities such as the adaptive immune response, granulocyte activation, leukocyte migration, regulation of leukocyte activation, and positive regulation of the defense response were inhibited.	('granulocyte activation', 'CPA', (269, 291))	('methylation', 'biological_process', 'GO:0032259', ('113', '124'))	('regulation', 'biological_process', 'GO:0065007', ('363', '373'))	('granulocyte activation', 'biological_process', 'GO:0036230', ('269', '291'))	('methylation', 'Var', (113, 124))	('AHNAK2', 'Gene', (106, 112))	('GSEA', 'Chemical', '-', (56, 60))	('adaptive immune response', 'biological_process', 'GO:0002250', ('243', '267'))	('biological process', 'biological_process', 'GO:0008150', ('8', '26'))	('metabolism', 'biological_process', 'GO:0008152', ('168', '178'))	('participate', 'Reg', (143, 154))	('AHNAK2', 'Gene', '113146', (106, 112))	('leukocyte migration', 'biological_process', 'GO:0050900', ('293', '312'))	('leukocyte migration', 'CPA', (293, 312))	('regulation of leukocyte activation', 'biological_process', 'GO:0002694', ('314', '348'))	('metabolism-related pathways', 'Pathway', (168, 195))	('defense response', 'biological_process', 'GO:0006952', ('381', '397'))
95552	32966238	These results illustrate the extensive effects of AHNAK2 methylation on transcriptome and immune-related pathways.	('methylation', 'Var', (57, 68))	('AHNAK2', 'Gene', '113146', (50, 56))	('transcriptome', 'MPA', (72, 85))	('effects', 'Reg', (39, 46))	('immune-related', 'CPA', (90, 104))	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('AHNAK2', 'Gene', (50, 56))
95557	32966238	K-M survival analysis showed that the high AHNAK2 group had significant associations with short OS in bladder urothelial carcinoma (BLCA), glioblastoma multiforme (GBM), lung adenocarcinoma (LUAD), mesothelioma (MESO), pancreatic adenocarcinoma (PAAD), skin cutaneous melanoma (SKCM) and uveal melanoma (UVM) (Figure 7D-7J).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('AHNAK2', 'Gene', '113146', (43, 49))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('UVM', 'Phenotype', 'HP:0007716', (304, 307))	('LUAD', 'Phenotype', 'HP:0030078', (191, 195))	('AHNAK2', 'Gene', (43, 49))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (219, 244))	('high', 'Var', (38, 42))	('lung adenocarcinoma', 'Disease', (170, 189))	('uveal melanoma', 'Disease', 'MESH:C536494', (288, 302))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (219, 244))	('uveal melanoma', 'Disease', (288, 302))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (253, 276))	('glioblastoma multiforme', 'Disease', (139, 162))	('bladder urothelial carcinoma', 'Disease', (102, 130))	('melanoma', 'Phenotype', 'HP:0002861', (268, 276))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (258, 276))	('skin cutaneous melanoma', 'Disease', (253, 276))	('associations', 'Interaction', (72, 84))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (139, 162))	('PAAD', 'Phenotype', 'HP:0006725', (246, 250))	('glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (170, 189))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (102, 130))	('uveal melanoma', 'Phenotype', 'HP:0007716', (288, 302))	('mesothelioma', 'Disease', (198, 210))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (170, 189))	('mesothelioma', 'Disease', 'MESH:D008654', (198, 210))	('pancreatic adenocarcinoma', 'Disease', (219, 244))
95576	32966238	AHNAK2 expression is significantly high in patients with an advanced cancer stage, an advanced T classification, lymph node metastasis, and increased BRAF mutations, showing a positive correlation with PTC progression.	('high', 'PosReg', (35, 39))	('TC', 'Phenotype', 'HP:0002890', (203, 205))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('mutations', 'Var', (155, 164))	('patients', 'Species', '9606', (43, 51))	('lymph node metastasis', 'CPA', (113, 134))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('expression', 'MPA', (7, 17))	('AHNAK2', 'Gene', (0, 6))	('BRAF', 'Gene', (150, 154))	('BRAF', 'Gene', '673', (150, 154))	('PTC', 'Gene', (202, 205))	('PTC', 'Phenotype', 'HP:0002895', (202, 205))	('AHNAK2', 'Gene', '113146', (0, 6))	('PTC', 'Gene', '5979', (202, 205))	('increased', 'PosReg', (140, 149))	('cancer', 'Disease', (69, 75))
95578	32966238	Interestingly, the two genes with the highest mutation rates in PTC exhibited a notable trend: BRAF mutations were positively associated with AHNAK2 expression, while RAS mutations were negatively correlated with AHNAK2 expression.	('mutations', 'Var', (100, 109))	('associated', 'Interaction', (126, 136))	('PTC', 'Gene', (64, 67))	('BRAF', 'Gene', '673', (95, 99))	('AHNAK2', 'Gene', (213, 219))	('TC', 'Phenotype', 'HP:0002890', (65, 67))	('AHNAK2', 'Gene', '113146', (213, 219))	('PTC', 'Gene', '5979', (64, 67))	('BRAF', 'Gene', (95, 99))	('expression', 'MPA', (149, 159))	('AHNAK2', 'Gene', (142, 148))	('PTC', 'Phenotype', 'HP:0002895', (64, 67))	('AHNAK2', 'Gene', '113146', (142, 148))
95590	32966238	reported that the methylation of AHNAK2 is associated with chemotherapy resistance in Epstein-Barr virus (EBV)-associated gastric cancer.	('AHNAK2', 'Gene', '113146', (33, 39))	('EBV', 'Species', '10376', (106, 109))	('chemotherapy resistance', 'MPA', (59, 82))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))	('gastric cancer', 'Disease', (122, 136))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('methylation', 'Var', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('associated', 'Reg', (43, 53))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('AHNAK2', 'Gene', (33, 39))	('Epstein-Barr virus', 'Disease', (86, 104))
95591	32966238	Our research on PTC epigenetics has also shown that methylation may act as an upstream regulatory mechanism of AHNAK2 expression to inhibit its biological function.	('inhibit', 'NegReg', (132, 139))	('PTC', 'Gene', (16, 19))	('TC', 'Phenotype', 'HP:0002890', (17, 19))	('PTC', 'Phenotype', 'HP:0002895', (16, 19))	('PTC', 'Gene', '5979', (16, 19))	('biological function', 'MPA', (144, 163))	('AHNAK2', 'Gene', (111, 117))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('methylation', 'Var', (52, 63))	('AHNAK2', 'Gene', '113146', (111, 117))
95622	32966238	We downloaded and visualized the correlation results between AHNAK2 methylation and clinical parameters from LinkedOmics.	('methylation', 'Var', (68, 79))	('AHNAK2', 'Gene', (61, 67))	('AHNAK2', 'Gene', '113146', (61, 67))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))
95715	32832247	Because melanin absorbs light at a wide range of wavelengths, variations in melanin content may lead to an emission pattern that differs from the shape of the tumor.	('melanin', 'Chemical', 'MESH:D008543', (8, 15))	('melanin', 'Chemical', 'MESH:D008543', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('variations', 'Var', (62, 72))	('tumor', 'Disease', (159, 164))	('emission pattern', 'MPA', (107, 123))	('lead to', 'Reg', (96, 103))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
95733	31334570	Mutations in spliceosome genes and therapeutic opportunities in myeloid malignancies Since the discovery of RNA splicing more than 40 years ago, our comprehension of the molecular events orchestrating constitutive and alternative splicing has greatly improved.	('RNA splicing', 'biological_process', 'GO:0008380', ('108', '120'))	('myeloid malignancies', 'Disease', 'OMIM:601308', (64, 84))	('splicing', 'biological_process', 'GO:0045292', ('230', '238'))	('spliceosome', 'cellular_component', 'GO:0005681', ('13', '24'))	('Mutations', 'Var', (0, 9))	('RNA', 'cellular_component', 'GO:0005562', ('108', '111'))	('myeloid malignancies', 'Disease', (64, 84))
95734	31334570	Dysregulation of pre-mRNA splicing has been observed in many human diseases including neurodegenerative diseases and cancer.	('neurodegenerative diseases', 'Disease', (86, 112))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (86, 112))	('pre-mRNA splicing', 'MPA', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('observed', 'Reg', (44, 52))	('Dysregulation', 'Var', (0, 13))	('pre', 'molecular_function', 'GO:0003904', ('17', '20'))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (86, 112))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('17', '34'))	('cancer', 'Disease', (117, 123))	('human', 'Species', '9606', (61, 66))
95736	31334570	In this review, we summarize our current understanding on the mechanisms of how mutant splicing factors impact splicing and the resulting functional and pathophysiological consequences.	('mutant', 'Var', (80, 86))	('splicing factor', 'Gene', (87, 102))	('splicing', 'biological_process', 'GO:0045292', ('111', '119'))	('splicing', 'biological_process', 'GO:0045292', ('87', '95'))	('impact', 'Reg', (104, 110))	('splicing factor', 'Gene', '10569', (87, 102))	('splicing', 'MPA', (111, 119))
95737	31334570	In 1977, Sharp, Roberts and colleagues discovered that eukaryotic genes are not contiguous but rather "split" by intervening sequences known as introns that are later removed to produce mature messenger RNAs by a macromolecular structure called the spliceosome.1, 2 One reason introns may have evolved is to diversify the number of messenger RNA species, and subsequently proteins, that can be produced by a single gene through alternative splicing.3 As with many other essential cellular processes, cancer cells have co-opted alternative splicing to promote their survival and response to therapy.	('Sharp', 'Gene', '23013', (9, 14))	('cancer', 'Disease', 'MESH:D009369', (500, 506))	('cancer', 'Phenotype', 'HP:0002664', (500, 506))	('Sharp', 'Gene', (9, 14))	('alternative splicing', 'Var', (527, 547))	('cancer', 'Disease', (500, 506))	('splicing', 'biological_process', 'GO:0045292', ('438', '446'))	('spliceosome', 'cellular_component', 'GO:0005681', ('247', '258'))	('RNA', 'cellular_component', 'GO:0005562', ('340', '343'))	('splicing', 'biological_process', 'GO:0045292', ('537', '545'))	('survival', 'CPA', (565, 573))	('promote', 'PosReg', (551, 558))
95738	31334570	Many studies have revealed global dysregulation of splicing in cancer.4, 5, 6, 7 For example, synonymous mutations occurring in consensus splice sites can alter intron recognition leading to intron retention and tumor suppressor inactivation.8, 9 Additionally, genes that encode for regulators of pre-mRNA splicing are often overexpressed in cancer and may presumably enhance processing of transcripts that are important for cancer cell growth and survival.10, 11, 12 A more extensive review of this literature can be found here.13, 14  Within the last decade, somatic mutations in genes encoding splicing factors themselves have been discovered at high frequency in patients with hematologic malignancies as well as in epithelial tumors, albeit less commonly.15, 16, 17, 18, 19, 20, 21, 22, 23 Approximately 60% of patients with myelodysplastic syndromes (MDS)15, 16, 18 or chronic myelomonocytic leukemia (CMML), and ~55% of secondary acute myeloid leukemia (s-AML)24 have mutations in genes encoding components of the spliceosome.15, 25, 26 The most common mutations occur in SF3B1, SRSF2, U2AF1, and ZRSR2 and they tend to be mutually exclusive with one another.15 In chronic lymphocytic leukemia (CLL), mutations in SF3B1 occur in ~15% of patients.	('myelodysplastic syndromes (MDS)15', 'Disease', 'MESH:D009190', (830, 863))	('AML', 'Disease', (963, 966))	('AML', 'Disease', 'MESH:D015470', (963, 966))	('spliceosome', 'cellular_component', 'GO:0005681', ('1021', '1032'))	('leukemia', 'Phenotype', 'HP:0001909', (951, 959))	('cancer', 'Disease', (342, 348))	('hematologic malignancies', 'Disease', (681, 705))	('U2AF1', 'Gene', '7307', (1093, 1098))	('acute myeloid leukemia', 'Disease', (937, 959))	('cancer', 'Disease', 'MESH:D009369', (425, 431))	('patients', 'Species', '9606', (816, 824))	('ZRSR2', 'Gene', '8233', (1104, 1109))	('splicing', 'biological_process', 'GO:0045292', ('51', '59'))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('chronic myelomonocytic leukemia', 'Disease', (875, 906))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('mutations', 'Var', (1208, 1217))	('CLL', 'Disease', 'MESH:D015451', (1202, 1205))	('hematologic malignancies', 'Disease', 'MESH:D019337', (681, 705))	('patients', 'Species', '9606', (1244, 1252))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (943, 959))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('212', '228'))	('CLL', 'Phenotype', 'HP:0005550', (1202, 1205))	('splicing factor', 'Gene', '10569', (597, 612))	('epithelial tumors', 'Disease', (720, 737))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('297', '314'))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (830, 855))	('splicing', 'biological_process', 'GO:0045292', ('597', '605'))	('MDS', 'Phenotype', 'HP:0002863', (857, 860))	('epithelial tumors', 'Disease', 'MESH:D002277', (720, 737))	('tumor', 'Disease', (731, 736))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (937, 959))	('cancer', 'Disease', (63, 69))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (875, 906))	('tumor suppressor', 'biological_process', 'GO:0051726', ('212', '228'))	('U2AF', 'cellular_component', 'GO:0089701', ('1093', '1097'))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('SF3B1', 'Gene', (1221, 1226))	('retention', 'biological_process', 'GO:0051235', ('198', '207'))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (937, 959))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (731, 736))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (1172, 1200))	('cancer', 'Disease', (425, 431))	('ZRSR2', 'Gene', (1104, 1109))	('SF3B1', 'Gene', (1079, 1084))	('chronic lymphocytic leukemia', 'Disease', (1172, 1200))	('pre', 'molecular_function', 'GO:0003904', ('297', '300'))	('CMML', 'Disease', 'MESH:D015477', (908, 912))	('tumor', 'Disease', (212, 217))	('tumors', 'Phenotype', 'HP:0002664', (731, 737))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (875, 906))	('cancer', 'Phenotype', 'HP:0002664', (425, 431))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (1172, 1200))	('cell growth', 'biological_process', 'GO:0016049', ('432', '443'))	('CLL', 'Disease', (1202, 1205))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('SF3B1', 'Gene', '23451', (1221, 1226))	('leukemia', 'Phenotype', 'HP:0001909', (1192, 1200))	('U2AF1', 'Gene', (1093, 1098))	('tumor', 'Phenotype', 'HP:0002664', (731, 736))	('patients', 'Species', '9606', (667, 675))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('splicing factor', 'Gene', (597, 612))	('leukemia', 'Phenotype', 'HP:0001909', (898, 906))	('CMML', 'Disease', (908, 912))	('CMML', 'Phenotype', 'HP:0012325', (908, 912))	('SF3B1', 'Gene', '23451', (1079, 1084))
95739	31334570	Spliceosomal mutations have also been discovered in a number of solid tumors including breast cancer,27 pancreatic cancer,28 lung cancer,21, 29 and uveal melanoma.19, 22, 30 With the exception of ZRSR2 mutations, somatic mutations in SF3B1, SRSF2, and U2AF1 cause characteristic changes in pre-mRNA splicing that are distinct from loss-of-function, and will be discussed in greater detail in this article.	('uveal melanoma', 'Disease', 'MESH:C536494', (148, 162))	('pancreatic cancer', 'Disease', (104, 121))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('solid tumors', 'Disease', 'MESH:D009369', (64, 76))	('uveal melanoma', 'Disease', (148, 162))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', (87, 100))	('U2AF1', 'Gene', '7307', (252, 257))	('pre', 'molecular_function', 'GO:0003904', ('290', '293'))	('SF3B1', 'Gene', '23451', (234, 239))	('ZRSR2', 'Gene', (196, 201))	('mutations', 'Var', (221, 230))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (148, 162))	('lung cancer', 'Disease', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('SRSF2', 'Gene', (241, 246))	('pre-mRNA splicing', 'MPA', (290, 307))	('solid tumors', 'Disease', (64, 76))	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('ZRSR2', 'Gene', '8233', (196, 201))	('SF3B1', 'Gene', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (104, 121))	('changes', 'Reg', (279, 286))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('U2AF1', 'Gene', (252, 257))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('290', '307'))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('U2AF', 'cellular_component', 'GO:0089701', ('252', '256'))
95741	31334570	Last, given the widespread aberrant splicing observed in cancers without spliceosome factor mutations, there is optimism that modulating the activity of the spliceosome may have broader therapeutic applicability in a larger group of cancer patients.	('splicing', 'MPA', (36, 44))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('aberrant', 'Var', (27, 35))	('cancer', 'Disease', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('mutations', 'Var', (92, 101))	('cancer', 'Disease', (233, 239))	('cancers', 'Disease', (57, 64))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('patients', 'Species', '9606', (240, 248))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('splicing', 'biological_process', 'GO:0045292', ('36', '44'))	('spliceosome', 'cellular_component', 'GO:0005681', ('73', '84'))	('spliceosome', 'cellular_component', 'GO:0005681', ('157', '168'))
95742	31334570	In 2011, several groups reported high frequency of splicing factor mutations in MDS, most frequently in SF3B1, SRSF2, U2AF1, and ZRSR2.15, 16, 18 This striking finding was accompanied by the observation that these mutations were generally mutually exclusive from one another, suggesting they may share overlapping function, and/or are synthetically lethal when coexpressed.	('U2AF', 'cellular_component', 'GO:0089701', ('118', '122'))	('ZRSR2.15', 'Disease', 'MESH:C567193', (129, 137))	('splicing factor', 'Gene', (51, 66))	('MDS', 'Disease', 'MESH:D007951', (80, 83))	('U2AF1', 'Gene', (118, 123))	('MDS', 'Disease', (80, 83))	('mutations', 'Var', (67, 76))	('U2AF1', 'Gene', '7307', (118, 123))	('splicing factor', 'Gene', '10569', (51, 66))	('MDS', 'Phenotype', 'HP:0002863', (80, 83))	('SF3B1', 'Gene', (104, 109))	('splicing', 'biological_process', 'GO:0045292', ('51', '59'))	('ZRSR2.15', 'Disease', (129, 137))	('SF3B1', 'Gene', '23451', (104, 109))
95743	31334570	Taken together, spliceosomal mutations appears to occur predominantly in MDS patients.	('MDS', 'Disease', (73, 76))	('MDS', 'Phenotype', 'HP:0002863', (73, 76))	('patients', 'Species', '9606', (77, 85))	('spliceosomal mutations', 'Var', (16, 38))	('occur', 'Reg', (50, 55))	('MDS', 'Disease', 'MESH:D007951', (73, 76))
95746	31334570	Indeed, a more recent study including 1540 patients with AML performed targeted sequencing of 111 genes and cytogenetic analysis and classified 11 subgroups,34 including ~18% of AML patients with mutations in chromatin modifiers (ASXL1, STAG2, BCOR, MLL PTD, EZH2, and PHF6) and spliceosome genes (SF3B1, SRSF2, U2AF1, and ZRSR2).	('ZRSR2', 'Gene', (323, 328))	('SF3B1', 'Gene', (298, 303))	('U2AF1', 'Gene', (312, 317))	('PTD', 'molecular_function', 'GO:0044102', ('254', '257'))	('patients', 'Species', '9606', (182, 190))	('PHF6', 'Gene', (269, 273))	('STAG2', 'Gene', '10735', (237, 242))	('PHF6', 'Gene', '84295', (269, 273))	('AML', 'Disease', 'MESH:D015470', (57, 60))	('MLL', 'Gene', '214162', (250, 253))	('U2AF', 'cellular_component', 'GO:0089701', ('312', '316'))	('spliceosome', 'cellular_component', 'GO:0005681', ('279', '290'))	('chromatin', 'cellular_component', 'GO:0000785', ('209', '218'))	('U2AF1', 'Gene', '7307', (312, 317))	('AML', 'Disease', (57, 60))	('SF3B1', 'Gene', '23451', (298, 303))	('STAG2', 'Gene', (237, 242))	('ZRSR2', 'Gene', '8233', (323, 328))	('SRSF2', 'Gene', (305, 310))	('BCOR', 'Gene', '54880', (244, 248))	('patients', 'Species', '9606', (43, 51))	('ASXL1', 'Gene', '171023', (230, 235))	('EZH2', 'Gene', '2146', (259, 263))	('BCOR', 'Gene', (244, 248))	('EZH2', 'Gene', (259, 263))	('mutations', 'Var', (196, 205))	('MLL', 'Gene', (250, 253))	('AML', 'Disease', 'MESH:D015470', (178, 181))	('AML', 'Disease', (178, 181))	('ASXL1', 'Gene', (230, 235))
95748	31334570	The older patients with chromatin-spliceosome gene mutations appear to be genetically and biologically different from many other subclasses of AML and do not benefit from current treatment paradigms.	('mutations', 'Var', (51, 60))	('chromatin-spliceosome gene', 'Gene', (24, 50))	('AML', 'Disease', 'MESH:D015470', (143, 146))	('chromatin', 'cellular_component', 'GO:0000785', ('24', '33'))	('men', 'Species', '9606', (184, 187))	('spliceosome', 'cellular_component', 'GO:0005681', ('34', '45'))	('patients', 'Species', '9606', (10, 18))	('AML', 'Disease', (143, 146))
95750	31334570	It is possible that AML patients that have chromatin-spliceosome mutations may have had a prodromal MDS period even if they did not necessarily meet the formal criteria for AML with myelodysplasia-related changes (AML-MRC).35 In fact, a study of 194 patients with rigorously defined s-AML found that mutations in SF3B1, SRSF2, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML.24 When mutations in these genes were found in de novo AML, they conferred the same poor prognosis as seen in s-AML.	('MDS', 'Disease', (100, 103))	('ASXL1', 'Gene', (341, 346))	('spliceosome', 'cellular_component', 'GO:0005681', ('53', '64'))	('chromatin', 'cellular_component', 'GO:0000785', ('43', '52'))	('STAG2', 'Gene', '10735', (363, 368))	('SF3B1', 'Gene', '23451', (313, 318))	('mutations', 'Var', (422, 431))	('myelodysplasia', 'Phenotype', 'HP:0002863', (182, 196))	('U2AF1', 'Gene', (327, 332))	('AML', 'Disease', 'MESH:D015470', (469, 472))	('ZRSR2', 'Gene', '8233', (334, 339))	('patients', 'Species', '9606', (24, 32))	('STAG2', 'Gene', (363, 368))	('AML', 'Disease', (469, 472))	('myelodysplasia', 'Disease', 'MESH:D009190', (182, 196))	('AML', 'Disease', 'MESH:D015470', (285, 288))	('AML', 'Disease', 'MESH:D015470', (173, 176))	('MDS', 'Phenotype', 'HP:0002863', (100, 103))	('U2AF', 'cellular_component', 'GO:0089701', ('327', '331'))	('AML', 'Disease', (285, 288))	('AML', 'Disease', 'MESH:D015470', (214, 217))	('U2AF1', 'Gene', '7307', (327, 332))	('BCOR', 'Gene', '54880', (354, 358))	('patients', 'Species', '9606', (250, 258))	('AML', 'Disease', (173, 176))	('AML', 'Disease', (214, 217))	('EZH2', 'Gene', '2146', (348, 352))	('ASXL1', 'Gene', '171023', (341, 346))	('EZH2', 'Gene', (348, 352))	('AML', 'Disease', 'MESH:D015470', (410, 413))	('BCOR', 'Gene', (354, 358))	('ZRSR2', 'Gene', (334, 339))	('SF3B1', 'Gene', (313, 318))	('AML', 'Disease', (410, 413))	('AML', 'Disease', 'MESH:D015470', (526, 529))	('AML', 'Disease', 'MESH:D015470', (20, 23))	('myelodysplasia', 'Disease', (182, 196))	('MDS', 'Disease', 'MESH:D007951', (100, 103))	('AML', 'Disease', (526, 529))	('AML', 'Disease', (20, 23))
95751	31334570	Furthermore, mutations in these genes have also been detected in elderly individuals with clonal hematopoiesis.36, 37, 38 Thus, either as a response to a stressor (genetic or environmental) that accumulates with age or as a phenomenon of aging itself, acquisition of mutations in chromatin modifiers and splicing factors predispose individuals to further development of MDS and/or AML.	('clonal hematopoiesis', 'Disease', 'MESH:C536227', (90, 110))	('splicing factor', 'Gene', '10569', (304, 319))	('splicing', 'biological_process', 'GO:0045292', ('304', '312'))	('aging', 'biological_process', 'GO:0007568', ('238', '243'))	('men', 'Species', '9606', (362, 365))	('chromatin', 'cellular_component', 'GO:0000785', ('280', '289'))	('mutations', 'Var', (267, 276))	('MDS', 'Phenotype', 'HP:0002863', (370, 373))	('hematopoiesis', 'biological_process', 'GO:0030097', ('97', '110'))	('splicing factor', 'Gene', (304, 319))	('predispose', 'Reg', (321, 331))	('AML', 'Disease', 'MESH:D015470', (381, 384))	('men', 'Species', '9606', (229, 232))	('MDS', 'Disease', 'MESH:D007951', (370, 373))	('clonal hematopoiesis', 'Disease', (90, 110))	('MDS', 'Disease', (370, 373))	('men', 'Species', '9606', (182, 185))	('AML', 'Disease', (381, 384))
95754	31334570	This includes mutations in SF3B1, SRSF2, U2AF1, and ZRSR2.	('U2AF1', 'Gene', (41, 46))	('U2AF1', 'Gene', '7307', (41, 46))	('ZRSR2', 'Gene', (52, 57))	('U2AF', 'cellular_component', 'GO:0089701', ('41', '45'))	('ZRSR2', 'Gene', '8233', (52, 57))	('SF3B1', 'Gene', (27, 32))	('SRSF2', 'Gene', (34, 39))	('SF3B1', 'Gene', '23451', (27, 32))	('mutations', 'Var', (14, 23))
95755	31334570	The first three (SF3B1, SRSF2, and U2AF1) are all components of the major spliceosome and have the unique features of: (a) always occurring as heterozygous change-of-function mutations and (b) generally occurring in a mutually exclusive manner.	('U2AF', 'cellular_component', 'GO:0089701', ('35', '39'))	('spliceosome', 'cellular_component', 'GO:0005681', ('74', '85'))	('change-of-function', 'PosReg', (156, 174))	('U2AF1', 'Gene', (35, 40))	('U2AF1', 'Gene', '7307', (35, 40))	('SF3B1', 'Gene', (17, 22))	('SRSF2', 'Gene', (24, 29))	('mutations', 'Var', (175, 184))	('SF3B1', 'Gene', '23451', (17, 22))
95756	31334570	Mutations in ZRSR2 do not always follow the same pattern; likely because ZRSR2 is not required for major splicing and is primarily a component of the minor spliceosome.	('splicing', 'biological_process', 'GO:0045292', ('105', '113'))	('spliceosome', 'cellular_component', 'GO:0005681', ('156', '167'))	('ZRSR2', 'Gene', '8233', (73, 78))	('ZRSR2', 'Gene', (73, 78))	('Mutations', 'Var', (0, 9))	('ZRSR2', 'Gene', '8233', (13, 18))	('ZRSR2', 'Gene', (13, 18))
95757	31334570	These mutations are usually seen as loss-of-function and can, on rare occasions, co-occur with other splicing factor mutations.	('splicing', 'biological_process', 'GO:0045292', ('101', '109'))	('splicing factor', 'Gene', (101, 116))	('loss-of-function', 'NegReg', (36, 52))	('mutations', 'Var', (6, 15))	('splicing factor', 'Gene', '10569', (101, 116))
95758	31334570	In the following sections, we will review basic mechanisms of splicing, how mutations in splicing factors affect normal splicing and the potential functional role of these mutations in myeloid neoplasms.	('splicing', 'biological_process', 'GO:0045292', ('120', '128'))	('myeloid neoplasms', 'Disease', (185, 202))	('mutations', 'Var', (76, 85))	('neoplasms', 'Phenotype', 'HP:0002664', (193, 202))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (185, 202))	('splicing', 'biological_process', 'GO:0045292', ('62', '70'))	('splicing factor', 'Gene', '10569', (89, 104))	('normal splicing', 'MPA', (113, 128))	('splicing', 'biological_process', 'GO:0045292', ('89', '97'))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (185, 202))	('splicing factor', 'Gene', (89, 104))	('affect', 'Reg', (106, 112))
95759	31334570	We will then discuss the potential for targeting these mutations or reversing their effects with splicing modulators in cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('splicing', 'biological_process', 'GO:0045292', ('97', '105'))	('mutations', 'Var', (55, 64))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
95760	31334570	It is estimated that as many as 95% of human multiexon genes undergo alternative splicing, which can significantly increase the diversity and function of the human proteome.3 Splicing represents a critical posttranscriptional mechanism for regulating gene expression, and is orchestrated by a large, dynamic group of ribonucleoprotein complexes known as the major and minor spliceosome.	('gene expression', 'biological_process', 'GO:0010467', ('251', '266'))	('human', 'Species', '9606', (158, 163))	('regulating gene expression', 'MPA', (240, 266))	('Splicing', 'biological_process', 'GO:0045292', ('175', '183'))	('spliceosome', 'cellular_component', 'GO:0005681', ('374', '385'))	('proteome.3 Splicing', 'Var', (164, 183))	('splicing', 'biological_process', 'GO:0045292', ('81', '89'))	('human', 'Species', '9606', (39, 44))	('ribonucleoprotein', 'molecular_function', 'GO:0003733', ('317', '334'))
95766	31334570	The distinction of the 3' splice site is further reinforced by a stretch of pyrimidine sequences located between the 3' splice site and the BPS known as the polypyrimidine tract, which serves as an essential signal for recruiting splicing factors to the 3' splice site.	('splicing factor', 'Gene', (230, 245))	('splicing', 'biological_process', 'GO:0045292', ('230', '238'))	('pyrimidine sequences', 'Var', (76, 96))	('splicing factor', 'Gene', '10569', (230, 245))	('pyrimidine', 'Chemical', 'MESH:C030986', (161, 171))	('polypyrimidine', 'Chemical', 'None', (157, 171))	('pyrimidine', 'Chemical', 'MESH:C030986', (76, 86))
95769	31334570	For examples, members of the serine/arginine (SR) family of proteins generally possess the ability to promote splicing by sequence-specific recognition of cis-elements in the pre-mRNA known as exonic or intronic splicing enhancers (ESE and ISE).	('exonic', 'Var', (193, 199))	('men', 'Species', '9606', (162, 165))	('splicing', 'biological_process', 'GO:0045292', ('212', '220'))	('promote', 'PosReg', (102, 109))	('splicing', 'biological_process', 'GO:0045292', ('110', '118'))	('enhancers', 'PosReg', (221, 230))	('arginine', 'Chemical', 'MESH:D001127', (36, 44))	('pre', 'molecular_function', 'GO:0003904', ('175', '178'))	('splicing', 'MPA', (110, 118))	('serine', 'Chemical', 'MESH:C047902', (29, 35))
95770	31334570	These splicing modulators are critical in ultimately dictating the choice of splice site usage, and are extensively reviewed here.50  One of the most surprising findings from cancer genome sequencing efforts was the identification of recurrent somatic mutations in genes encoding pre-mRNA splicing factors in both hematologic malignancies including MDS, AML, and CLL,15, 16, 17, 18, 20, 51 and in epithelial cancers such as uveal melanoma, lung adenocarcinoma, breast cancer, and pancreatic ductal adenocarcinoma.19, 21, 22, 27, 30, 52 While mutations have been observed in a large number of spliceosomal genes, SF3B1, SRSF2, U2AF1, and ZRSR2 are the four most commonly mutated genes (Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (408, 414))	('pancreatic ductal adenocarcinoma', 'Disease', (480, 512))	('cancer', 'Disease', (175, 181))	('uveal melanoma', 'Disease', 'MESH:C536494', (424, 438))	('breast cancer', 'Disease', 'MESH:D001943', (461, 474))	('MDS', 'Phenotype', 'HP:0002863', (349, 352))	('uveal melanoma', 'Disease', (424, 438))	('breast cancer', 'Disease', (461, 474))	('SF3B1', 'Gene', (612, 617))	('epithelial cancers', 'Disease', 'MESH:D009369', (397, 415))	('ZRSR2', 'Gene', '8233', (637, 642))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (440, 459))	('splicing factor', 'Gene', '10569', (289, 304))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (480, 512))	('lung adenocarcinoma', 'Disease', (440, 459))	('epithelial cancers', 'Disease', (397, 415))	('uveal melanoma', 'Phenotype', 'HP:0007716', (424, 438))	('pre', 'molecular_function', 'GO:0003904', ('280', '283'))	('cancer', 'Disease', 'MESH:D009369', (408, 414))	('CLL', 'Disease', (363, 366))	('cancer', 'Disease', (468, 474))	('SF3B1', 'Gene', '23451', (612, 617))	('U2AF1', 'Gene', (626, 631))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (468, 474))	('hematologic malignancies', 'Disease', (314, 338))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('280', '297'))	('ZRSR2', 'Gene', (637, 642))	('MDS', 'Disease', 'MESH:D007951', (349, 352))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (440, 459))	('MDS', 'Disease', (349, 352))	('AML', 'Disease', 'MESH:D015470', (354, 357))	('U2AF1', 'Gene', '7307', (626, 631))	('AML', 'Disease', (354, 357))	('hematologic malignancies', 'Disease', 'MESH:D019337', (314, 338))	('splicing factor', 'Gene', (289, 304))	('CLL', 'Disease', 'MESH:D015451', (363, 366))	('cancers', 'Phenotype', 'HP:0002664', (408, 415))	('breast cancer', 'Phenotype', 'HP:0003002', (461, 474))	('U2AF', 'cellular_component', 'GO:0089701', ('626', '630'))	('mutations', 'Var', (542, 551))	('melanoma', 'Phenotype', 'HP:0002861', (430, 438))	('CLL', 'Phenotype', 'HP:0005550', (363, 366))	('cancer', 'Disease', (408, 414))	('cancer', 'Disease', 'MESH:D009369', (468, 474))	('SRSF2', 'Gene', (619, 624))	('splicing', 'biological_process', 'GO:0045292', ('6', '14'))
95771	31334570	Mutations in SF3B1, SRSF2, and U2AF1 occur exclusively as heterozygous missense mutations located to very restricted regions, whereas ZRSR2 mutations are scattered across the gene and are predicted to be loss-of-function mutations.	('U2AF1', 'Gene', (31, 36))	('U2AF1', 'Gene', '7307', (31, 36))	('SF3B1', 'Gene', (13, 18))	('SRSF2', 'Gene', (20, 25))	('Mutations', 'Var', (0, 9))	('SF3B1', 'Gene', '23451', (13, 18))	('ZRSR2', 'Gene', '8233', (134, 139))	('loss-of-function', 'NegReg', (204, 220))	('ZRSR2', 'Gene', (134, 139))	('U2AF', 'cellular_component', 'GO:0089701', ('31', '35'))
95773	31334570	In the past few years, a wealth of transcriptomic data and functional studies have shed light on the effects of mutant splicing factors on pre-mRNA splicing and gene expression, and how dysregulation of various target genes can drive disease mechanisms unique to different subtypes of myeloid neoplasms.	('myeloid neoplasms', 'Disease', 'MESH:D007951', (285, 302))	('neoplasms', 'Phenotype', 'HP:0002664', (293, 302))	('splicing factor', 'Gene', '10569', (119, 134))	('myeloid neoplasms', 'Disease', (285, 302))	('effects', 'Reg', (101, 108))	('pre-mRNA splicing', 'MPA', (139, 156))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (285, 302))	('splicing', 'biological_process', 'GO:0045292', ('119', '127'))	('pre', 'molecular_function', 'GO:0003904', ('139', '142'))	('splicing factor', 'Gene', (119, 134))	('mutant', 'Var', (112, 118))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('139', '156'))	('dysregulation', 'Var', (186, 199))	('drive', 'Reg', (228, 233))	('gene expression', 'biological_process', 'GO:0010467', ('161', '176'))	('disease', 'Disease', (234, 241))
95774	31334570	In hematologic malignancies, SF3B1 mutations are commonly found in MDS,16, 53 AML, myeloproliferative neoplasms (MPN) and in some MDS/MPN overlap syndromes,54 and in ~10%-15% of CLL patients.17, 20 Mutations in SF3B1 are specifically enriched in a subtype of MDS previously known as refractory anemia with ring sideroblasts (RARS), characterized by anemia and dysplastic erythroblasts with abnormal iron accumulation in the mitochondria55 causing a "ring" of blue granules to appear around the nucleus upon Prussian blue staining.	('MPN', 'Disease', (113, 116))	('MDS', 'Disease', 'MESH:D007951', (67, 70))	('MPN', 'Phenotype', 'HP:0005547', (113, 116))	('SF3B1', 'Gene', '23451', (29, 34))	('MDS', 'Disease', (67, 70))	('MDS', 'Disease', 'MESH:D007951', (259, 262))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (83, 111))	('CLL', 'Disease', 'MESH:D015451', (178, 181))	('MDS', 'Disease', (259, 262))	('patients', 'Species', '9606', (182, 190))	('CLL', 'Phenotype', 'HP:0005550', (178, 181))	('anemia', 'Phenotype', 'HP:0001903', (294, 300))	('dysplastic erythroblasts', 'Disease', 'MESH:D017086', (360, 384))	('abnormal iron accumulation in the mitochondria55', 'Phenotype', 'HP:0008306', (390, 438))	('anemia', 'Phenotype', 'HP:0001903', (349, 355))	('myeloproliferative neoplasms', 'Disease', (83, 111))	('RARS', 'Phenotype', 'HP:0004828', (325, 329))	('refractory anemia', 'Disease', (283, 300))	('SF3B1', 'Gene', '23451', (211, 216))	('ring sideroblasts', 'Phenotype', 'HP:0004828', (306, 323))	('MPN', 'Disease', 'MESH:D009196', (113, 116))	('anemia', 'Disease', (349, 355))	('refractory anemia', 'Disease', 'MESH:D000753', (283, 300))	('anemia', 'Disease', (294, 300))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (83, 111))	('MDS', 'Disease', 'MESH:D007951', (130, 133))	('dysplastic erythroblasts', 'Disease', (360, 384))	('MDS', 'Disease', (130, 133))	('refractory anemia with ring sideroblasts', 'Phenotype', 'HP:0004828', (283, 323))	('hematologic malignancies', 'Disease', (3, 27))	('ring sideroblasts', 'Disease', (306, 323))	('MPN', 'Disease', (134, 137))	('Mutations', 'Var', (198, 207))	('AML', 'Disease', 'MESH:D015470', (78, 81))	('MDS', 'Phenotype', 'HP:0002863', (67, 70))	('MPN', 'Phenotype', 'HP:0005547', (134, 137))	('MDS', 'Phenotype', 'HP:0002863', (259, 262))	('nucleus', 'cellular_component', 'GO:0005634', ('492', '499'))	('hematologic malignancies', 'Disease', 'MESH:D019337', (3, 27))	('AML', 'Disease', (78, 81))	('SF3B1', 'Gene', (29, 34))	('CLL', 'Disease', (178, 181))	('refractory anemia', 'Phenotype', 'HP:0005505', (283, 300))	('anemia', 'Disease', 'MESH:D000740', (294, 300))	('neoplasms', 'Phenotype', 'HP:0002664', (102, 111))	('anemia', 'Disease', 'MESH:D000740', (349, 355))	('iron', 'Chemical', 'MESH:D007501', (399, 403))	('MPN', 'Disease', 'MESH:D009196', (134, 137))	('MDS', 'Phenotype', 'HP:0002863', (130, 133))	('SF3B1', 'Gene', (211, 216))	('mitochondria', 'cellular_component', 'GO:0005739', ('424', '436'))
95775	31334570	RARS has been renamed MDS with ring sideroblasts (MDS-RS) and is generally associated with a favorable clinical course.16, 53 Interestingly, SF3B1 mutations are so common in MDS-RS that the WHO classification criteria have recently been revised to allow diagnosis of MDS-RS with as low as 5% ring sideroblasts in the presence of mutant SF3B1.35 Most of the mutations in SF3B1 are clustered near the HEAT repeat domains 4 to 7 (HR4-HR7), with the most frequently mutated residues being K700 and K666 in MDS and CLL; while mutations in the R625 position are the most commonly occurring allele in uveal melanoma.	('SF3B1', 'Gene', '23451', (141, 146))	('SF3B1', 'Gene', (336, 341))	('MDS', 'Phenotype', 'HP:0002863', (502, 505))	('ring sideroblasts', 'Phenotype', 'HP:0004828', (292, 309))	('RARS', 'Phenotype', 'HP:0004828', (0, 4))	('SF3B1', 'Gene', '23451', (370, 375))	('MDS', 'Disease', 'MESH:D007951', (267, 270))	('ring sideroblasts', 'Phenotype', 'HP:0004828', (31, 48))	('MDS', 'Disease', (267, 270))	('MDS', 'Phenotype', 'HP:0002863', (174, 177))	('K666', 'Var', (494, 498))	('occurring', 'Reg', (574, 583))	('CLL', 'Disease', (510, 513))	('CLL', 'Disease', 'MESH:D015451', (510, 513))	('MDS', 'Disease', 'MESH:D007951', (50, 53))	('SF3B1', 'Gene', '23451', (336, 341))	('MDS', 'Disease', (50, 53))	('MDS', 'Phenotype', 'HP:0002863', (22, 25))	('CLL', 'Phenotype', 'HP:0005550', (510, 513))	('mutations', 'Var', (357, 366))	('MDS', 'Disease', 'MESH:D007951', (502, 505))	('MDS', 'Disease', (502, 505))	('MDS', 'Phenotype', 'HP:0002863', (267, 270))	('MDS', 'Disease', 'MESH:D007951', (174, 177))	('melanoma', 'Phenotype', 'HP:0002861', (600, 608))	('SF3B1', 'Gene', (141, 146))	('uveal melanoma', 'Disease', 'MESH:C536494', (594, 608))	('MDS', 'Disease', (174, 177))	('uveal melanoma', 'Disease', (594, 608))	('K700', 'Var', (485, 489))	('SF3B1', 'Gene', (370, 375))	('uveal melanoma', 'Phenotype', 'HP:0007716', (594, 608))	('MDS', 'Disease', 'MESH:D007951', (22, 25))	('MDS', 'Disease', (22, 25))	('MDS', 'Phenotype', 'HP:0002863', (50, 53))	('to 7', 'Species', '1214577', (421, 425))
95776	31334570	SF3B1 is a component of the U2 snRNP that binds to the branchpoint during the formation of Complex A, and is predicted to be ubiquitous in recognizing the majority of 3' splice sites.56 Transcriptomic analyses have revealed that the major splicing defect associated with SF3B1 mutations, regardless of cellular or disease origin, is the preferential usage of cryptic 3' splice sites approximately 10-30 nucleotides upstream of the canonical 3' splice site (Figure 2).	('formation', 'biological_process', 'GO:0009058', ('78', '87'))	('SF3B1', 'Gene', (0, 5))	('cryptic', 'Gene', '55997', (359, 366))	('splicing', 'MPA', (239, 247))	('cryptic', 'Gene', (359, 366))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('28', '36'))	('SF3B1', 'Gene', '23451', (0, 5))	('preferential', 'PosReg', (337, 349))	('mutations', 'Var', (277, 286))	('SF3B1', 'Gene', (271, 276))	('splicing', 'biological_process', 'GO:0045292', ('239', '247'))	('snRNP', 'molecular_function', 'GO:0003734', ('31', '36'))	('SF3B1', 'Gene', '23451', (271, 276))
95778	31334570	Structural analyses of the human and yeast spliceosome in the RNA-bound B-activated Complex suggest that cancer-associated mutations in SF3B1 change the charge and shape of the corresponding amino acid residues that results in direct disruption of the local interaction with pre-mRNA.46, 60, 61, 62 This results in a spatial shift in the pre-mRNA by approximately 10 nucleotides, consistent with bioinformatic predictions.	('SF3B1', 'Gene', (136, 141))	('yeast', 'Species', '4932', (37, 42))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('human', 'Species', '9606', (27, 32))	('SF3B1', 'Gene', '23451', (136, 141))	('spliceosome', 'cellular_component', 'GO:0005681', ('43', '54'))	('charge', 'MPA', (153, 159))	('pre-mRNA by', 'MPA', (338, 349))	('change', 'Reg', (142, 148))	('spatial shift', 'MPA', (317, 330))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('pre', 'molecular_function', 'GO:0003904', ('275', '278'))	('pre', 'molecular_function', 'GO:0003904', ('338', '341'))	('local interaction', 'MPA', (252, 269))	('mutations', 'Var', (123, 132))	('RNA', 'cellular_component', 'GO:0005562', ('62', '65'))	('disruption', 'NegReg', (234, 244))
95779	31334570	A study from Darman et al predicted that mutant SF3B1-induced cryptic 3' splice site usage can introduce premature termination codons that are subjected to nonsense-mediated decay (NMD) in approximately half of the aberrantly spliced transcripts.58 Some of the most well defined targets of this NMD such as ABCB7, SLC25A37, TMEM14C, and ALAS2 have provided some insights into a potential causal link between SF3B1 mutations and MDS-RS.	('SLC25A37', 'Gene', '51312', (314, 322))	('mutations', 'Var', (414, 423))	('SF3B1', 'Gene', (408, 413))	('TMEM14C', 'Gene', '51522', (324, 331))	('SF3B1', 'Gene', (48, 53))	('MDS', 'Disease', 'MESH:D007951', (428, 431))	('SLC25A37', 'Gene', (314, 322))	('SF3B1', 'Gene', '23451', (408, 413))	('MDS', 'Disease', (428, 431))	('cryptic', 'Gene', '55997', (62, 69))	('ALAS2', 'Gene', '212', (337, 342))	('SF3B1', 'Gene', '23451', (48, 53))	('cryptic', 'Gene', (62, 69))	('MDS', 'Phenotype', 'HP:0002863', (428, 431))	('TMEM14C', 'Gene', (324, 331))	('ALAS2', 'Gene', (337, 342))
95780	31334570	SF3B1 mutation induces mis-splicing of ABCB7 by aberrant 3' splice site usage that results in NMD, and subsequent downregulation of ABCB7 mRNA and protein.	('NMD', 'MPA', (94, 97))	('induces', 'Reg', (15, 22))	("3' splice site usage", 'MPA', (57, 77))	('results in', 'Reg', (83, 93))	('SF3B1', 'Gene', (0, 5))	('splicing', 'biological_process', 'GO:0045292', ('27', '35'))	('mutation', 'Var', (6, 14))	('SF3B1', 'Gene', '23451', (0, 5))	('mis-splicing', 'MPA', (23, 35))	('ABCB7', 'Gene', (39, 44))	('ABCB7', 'Gene', (132, 137))	('downregulation', 'NegReg', (114, 128))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))
95781	31334570	ABCB7 is a mitochondrial iron exporter responsible for maintaining iron homeostasis,63 and there is a strong correlation between MDS-RS and dysregulation of ABCB7.64, 65 SLC25A37 is also another iron transporter mis-spliced by mutant SF3B1.	('SLC25A37', 'Gene', '51312', (170, 178))	('iron', 'Chemical', 'MESH:D007501', (25, 29))	('iron', 'Chemical', 'MESH:D007501', (195, 199))	('iron homeostasis', 'biological_process', 'GO:0055072', ('67', '83'))	('mutant', 'Var', (227, 233))	('SF3B1', 'Gene', (234, 239))	('MDS', 'Disease', (129, 132))	('SLC25A37', 'Gene', (170, 178))	('MDS', 'Disease', 'MESH:D007951', (129, 132))	('MDS', 'Phenotype', 'HP:0002863', (129, 132))	('iron homeostasis', 'biological_process', 'GO:0006879', ('67', '83'))	('SF3B1', 'Gene', '23451', (234, 239))	('iron', 'Chemical', 'MESH:D007501', (67, 71))
95782	31334570	Mice engineered to inducibly express Sf3b1K700E mutation at physiologic level66, 67 exhibited mild defects in erythropoiesis, but did not develop RS.	('erythropoiesis', 'biological_process', 'GO:0030218', ('110', '124'))	('defects', 'NegReg', (99, 106))	('defects in erythropoiesis', 'Phenotype', 'HP:0010972', (99, 124))	('Sf3b1K700E mutation', 'Var', (37, 56))	('Mice', 'Species', '10090', (0, 4))	('erythropoiesis', 'MPA', (110, 124))
95784	31334570	Other MDS-RS associated genes such as Tmem14c, Alas2, and Slc25a37, were not aberrantly spliced or expressed in Sf3b1K700E mice.66 Additionally, mice lacking Abcb7 did not develop any RARS-associated phenotypes65; therefore, it is possible that other aberrant splicing events in addition to that in ABCB7 are required to drive MDS-RARS.	('MDS', 'Phenotype', 'HP:0002863', (327, 330))	('splicing', 'biological_process', 'GO:0045292', ('260', '268'))	('Slc25a37', 'Gene', (58, 66))	('Alas2', 'Gene', (47, 52))	('lacking', 'Var', (150, 157))	('mice', 'Species', '10090', (123, 127))	('RARS', 'Phenotype', 'HP:0004828', (331, 335))	('Slc25a37', 'Gene', '67712', (58, 66))	('Tmem14c', 'Gene', (38, 45))	('Tmem14c', 'Gene', '66154', (38, 45))	('MDS', 'Phenotype', 'HP:0002863', (6, 9))	('RARS-associated', 'Disease', (184, 199))	('Alas2', 'Gene', '11656', (47, 52))	('MDS', 'Disease', 'MESH:D007951', (327, 330))	('MDS', 'Disease', (327, 330))	('Abcb7', 'Gene', '11306', (158, 163))	('mice', 'Species', '10090', (145, 149))	('Abcb7', 'Gene', (158, 163))	('ABCB7', 'Gene', (299, 304))	('MDS', 'Disease', 'MESH:D007951', (6, 9))	('RARS', 'Phenotype', 'HP:0004828', (184, 188))	('MDS', 'Disease', (6, 9))
95785	31334570	SRSF2 mutations are found commonly in ~50% of CMML, ~15% of MDS, ~20% of s-AML patients, and are often associated with poor prognosis and a higher risk of transformation to acute leukemia.26, 51, 68, 69 SRSF2 is a member of the serine/arginine-rich (SR) family of proteins that recognizes specific RNA motifs, and is generally a positive regulator of exon inclusion.70 Somatic mutations in SRSF2 are restricted to the P95 amino acid residue near the RNA recognition motif.	('SRSF2', 'Gene', (390, 395))	('arginine', 'Chemical', 'MESH:D001127', (235, 243))	('MDS', 'Disease', 'MESH:D007951', (60, 63))	('acute leukemia', 'Phenotype', 'HP:0002488', (173, 187))	('acute leukemia', 'Disease', 'MESH:D054198', (173, 187))	('MDS', 'Disease', (60, 63))	('RNA', 'cellular_component', 'GO:0005562', ('450', '453'))	('CMML', 'Disease', (46, 50))	('CMML', 'Disease', 'MESH:D015477', (46, 50))	('CMML', 'Phenotype', 'HP:0012325', (46, 50))	('serine', 'Chemical', 'MESH:C047902', (228, 234))	('leukemia', 'Phenotype', 'HP:0001909', (179, 187))	('acute leukemia', 'Disease', (173, 187))	('MDS', 'Phenotype', 'HP:0002863', (60, 63))	('AML', 'Disease', 'MESH:D015470', (75, 78))	('RNA', 'cellular_component', 'GO:0005562', ('298', '301'))	('AML', 'Disease', (75, 78))	('patients', 'Species', '9606', (79, 87))	('mutations', 'Var', (377, 386))
95786	31334570	Extensive analysis using primary patient materials and complementary model systems revealed that the amino acid substitution at the proline 95 position alters the RNA binding activity of SRSF2 in a sequence specific manner.	('SRSF2', 'Gene', (187, 192))	('patient', 'Species', '9606', (33, 40))	('RNA binding', 'molecular_function', 'GO:0003723', ('163', '174'))	('RNA', 'MPA', (163, 166))	('RNA', 'cellular_component', 'GO:0005562', ('163', '166'))	('amino acid substitution', 'Var', (101, 124))	('men', 'Species', '9606', (61, 64))	('proline', 'Chemical', 'MESH:C489032', (132, 139))	('alters', 'Reg', (152, 158))
95787	31334570	Several prominent targets include chromatin modifiers EZH2 (inclusion of a "poison" exon that induces NMD and global transcript downregulation), BCOR (cassette exon splicing), CASP8 (cassette exon splicing that results in generation of a novel truncated isoform73), and FYN (mutually exclusive exons).72, 74 Interestingly, EZH2 loss-of-function mutations and SRSF2 missense mutations are highly mutually exclusive in MDS patients, and the ability of mutant SRSF2 to suppress EZH2 may represent a mechanistic explanation for this observation.53, 68   U2AF1 mutations are found in ~15% of MDS patients without RARS, in ~10% of CMML, ~10% of s-AML,15, 18, 68 ~10% of hairy cell leukemia variant (HCL-v),75 and is generally associated with poor prognosis, and increased risk of leukemic transformation.	('MDS', 'Disease', 'MESH:D007951', (417, 420))	('MDS', 'Disease', (417, 420))	('BCOR', 'Gene', '54880', (145, 149))	('FYN', 'Gene', '2534', (270, 273))	('CASP8', 'Gene', (176, 181))	('mutations', 'Var', (556, 565))	('hairy cell leukemia', 'Disease', 'MESH:D007943', (664, 683))	('splicing', 'biological_process', 'GO:0045292', ('163', '171'))	('MDS', 'Phenotype', 'HP:0002863', (587, 590))	('U2AF1', 'Gene', (550, 555))	('BCOR', 'Gene', (145, 149))	('leukemic transformation', 'Disease', 'MESH:D007938', (774, 797))	('EZH2', 'Gene', '2146', (54, 58))	('EZH2', 'Gene', (54, 58))	('patients', 'Species', '9606', (591, 599))	('AML', 'Disease', 'MESH:D015470', (641, 644))	('CMML', 'Disease', (625, 629))	('CMML', 'Disease', 'MESH:D015477', (625, 629))	('U2AF1', 'Gene', '7307', (550, 555))	('CMML', 'Phenotype', 'HP:0012325', (625, 629))	('MDS', 'Phenotype', 'HP:0002863', (417, 420))	('AML', 'Disease', (641, 644))	('EZH2', 'Gene', '2146', (475, 479))	('RARS', 'Phenotype', 'HP:0004828', (608, 612))	('leukemic transformation', 'Disease', (774, 797))	('EZH2', 'Gene', '2146', (323, 327))	('U2AF', 'cellular_component', 'GO:0089701', ('548', '552'))	('hairy cell leukemia', 'Disease', (664, 683))	('EZH2', 'Gene', (475, 479))	('MDS', 'Disease', 'MESH:D007951', (587, 590))	('EZH2', 'Gene', (323, 327))	('chromatin', 'cellular_component', 'GO:0000785', ('34', '43'))	('MDS', 'Disease', (587, 590))	('patients', 'Species', '9606', (421, 429))	('FYN', 'Gene', (270, 273))	('splicing', 'biological_process', 'GO:0045292', ('195', '203'))	('CASP8', 'Gene', '841', (176, 181))	('leukemia', 'Phenotype', 'HP:0001909', (675, 683))
95788	31334570	It is also found in a subset of pancreatic ductal adenocarcinomas28 and nonsmall cell lung adenocarcinomas.21 U2AF1 normally recognizes the AG-dinucleotide at the 3' splice site during the early steps of splicing catalysis in a sequence-specific manner.76 Mutations in U2AF1 are concentrated on two distinct amino acid residues, S34 and Q157, both of which are located within the two distinct zinc finger domains.	('U2AF', 'cellular_component', 'GO:0089701', ('269', '273'))	('nonsmall cell lung adenocarcinomas', 'Disease', (72, 106))	('U2AF1', 'Gene', '7307', (110, 115))	('U2AF1', 'Gene', (269, 274))	('U2AF1', 'Gene', '7307', (269, 274))	('Mutations', 'Var', (256, 265))	('U2AF', 'cellular_component', 'GO:0089701', ('110', '114'))	('U2AF1', 'Gene', (110, 115))	('nonsmall cell lung adenocarcinomas', 'Disease', 'MESH:D002289', (72, 106))	('pancreatic ductal adenocarcinomas28', 'Disease', 'MESH:D021441', (32, 67))	('pancreatic ductal adenocarcinomas28', 'Disease', (32, 67))	('Q157', 'Var', (337, 341))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('splicing', 'biological_process', 'GO:0045292', ('204', '212'))	('AG-dinucleotide', 'Chemical', 'MESH:C015772', (140, 155))
95789	31334570	RNA-seq analyses from human patient samples revealed that U2AF1 mutations induces aberrant splicing of ~5% of total transcripts predominantly via aberrant cassette exon skipping or inclusion, and to a lesser extent, alternative 3' splice site usage.	('induces', 'Reg', (74, 81))	('U2AF1', 'Gene', (58, 63))	('U2AF', 'cellular_component', 'GO:0089701', ('58', '62'))	('aberrant splicing', 'MPA', (82, 99))	('cassette', 'MPA', (155, 163))	('inclusion', 'Var', (181, 190))	('patient', 'Species', '9606', (28, 35))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('mutations', 'Var', (64, 73))	('human', 'Species', '9606', (22, 27))	('U2AF1', 'Gene', '7307', (58, 63))	('splicing', 'biological_process', 'GO:0045292', ('91', '99'))
95790	31334570	The exact splicing pattern mediated by mutant U2AF1 is dictated by consensus sequences around the AG-dinucleotide at the 3' splice site.	('U2AF', 'cellular_component', 'GO:0089701', ('46', '50'))	('U2AF1', 'Gene', '7307', (46, 51))	('dictated', 'Reg', (55, 63))	('U2AF1', 'Gene', (46, 51))	('mutant', 'Var', (39, 45))	('splicing', 'biological_process', 'GO:0045292', ('10', '18'))	('AG-dinucleotide', 'Chemical', 'MESH:C015772', (98, 113))
95791	31334570	The S34 mutation generally promotes cassette exon inclusion if the nucleotide immediately preceding the AG-dinucleotide is C/A over T (ie, the "-3" signature), whereas the Q157 mutation preferentially includes exons containing G over A immediately after the AG-dinucleotide (ie, the "+1" signature; Figure 2).29, 77, 78, 79 Direct mis-spliced targets include H2AFY, BCOR, ATR, FANCA, STRAP, CASP8, PICALM, and GNAS.	('PICALM', 'Gene', (398, 404))	('STRAP', 'Gene', '11171', (384, 389))	('CASP8', 'Gene', (391, 396))	('FANCA', 'Gene', (377, 382))	('BCOR', 'Gene', '54880', (366, 370))	('ATR', 'Gene', (372, 375))	('PICALM', 'Gene', '8301', (398, 404))	('H2AFY', 'Gene', (359, 364))	('H2AFY', 'Gene', '9555', (359, 364))	('promotes', 'PosReg', (27, 35))	('AG-dinucleotide', 'Chemical', 'MESH:C015772', (258, 273))	('BCOR', 'Gene', (366, 370))	('mutation', 'Var', (8, 16))	('GNAS', 'Gene', (410, 414))	('STRAP', 'Gene', (384, 389))	('AG-dinucleotide', 'Chemical', 'MESH:C015772', (104, 119))	('GNAS', 'Gene', '2778', (410, 414))	('ATR', 'Gene', '545', (372, 375))	('cassette exon inclusion', 'MPA', (36, 59))	('CASP8', 'Gene', '841', (391, 396))	('FANCA', 'Gene', '2175', (377, 382))	('S34', 'Gene', (4, 7))
95792	31334570	Functional studies using human CD34+ cells from the cord blood expressing aberrant isoforms of H2AFY and STRAP resulted in skewed myelomonocytic differentiation at the expense of erythroid differentiation that phenocopies U2AF1 S34F cells, suggesting a potential causal link.80 Moreover, pathway analysis revealed key signatures are dysregulated by U2AF1 mutations, including DNA damage response, pre-mRNA splicing, RNA localization and transport, epigenetic regulation and cell cycle.29, 77, 79, 81   ZRSR2 mutations are found in ~5%-10% of MDS patients, and are located sporadically across the entire coding region, and are predicted to be loss-of-function mutations.	('regulation', 'biological_process', 'GO:0065007', ('459', '469'))	('ZRSR2', 'Gene', '8233', (502, 507))	('pre', 'molecular_function', 'GO:0003904', ('397', '400'))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('397', '414'))	('CD34', 'Gene', '947', (31, 35))	('STRAP', 'Gene', '11171', (105, 110))	('mutations', 'Var', (508, 517))	('patients', 'Species', '9606', (546, 554))	('S34F', 'Mutation', 'rs371769427', (228, 232))	('MDS', 'Disease', 'MESH:D007951', (542, 545))	('human', 'Species', '9606', (25, 30))	('MDS', 'Disease', (542, 545))	('RNA', 'cellular_component', 'GO:0005562', ('416', '419'))	('DNA damage response', 'biological_process', 'GO:0006974', ('376', '395'))	('ZRSR2', 'Gene', (502, 507))	('loss-of-function', 'NegReg', (642, 658))	('U2AF', 'cellular_component', 'GO:0089701', ('349', '353'))	('U2AF1', 'Gene', (222, 227))	('cell cycle', 'biological_process', 'GO:0007049', ('474', '484'))	('H2AFY', 'Gene', (95, 100))	('U2AF1', 'Gene', (349, 354))	('U2AF', 'cellular_component', 'GO:0089701', ('222', '226'))	('CD34', 'Gene', (31, 35))	('STRAP', 'Gene', (105, 110))	('H2AFY', 'Gene', '9555', (95, 100))	('DNA', 'cellular_component', 'GO:0005574', ('376', '379'))	('U2AF1', 'Gene', '7307', (222, 227))	('MDS', 'Phenotype', 'HP:0002863', (542, 545))	('RNA localization', 'biological_process', 'GO:0006403', ('416', '432'))	('transport', 'biological_process', 'GO:0006810', ('437', '446'))	('U2AF1', 'Gene', '7307', (349, 354))
95793	31334570	Mutations of ZRSR2 are found predominantly in male patients, most likely because ZRSR2 is an X-linked gene.15 Usually X chromosome genes are functionally haploid in both men and women due to X-inactivation in females; however, tumor suppressor genes on the X chromosome have been observed to "escape" inactivation to have biallelic expression in females.82 As males have only a single X chromosome, inactivating mutations in tumor suppressors decrease the gene dosage but females are able to maintain a functional copy by escaping X-inactivation, resulting in a male predominance in cancers related to these X-linked tumor suppressor genes.	('tumor', 'Disease', (425, 430))	('cancer', 'Phenotype', 'HP:0002664', (583, 589))	('tumor', 'Disease', (227, 232))	('men', 'Species', '9606', (170, 173))	('tumor', 'Disease', 'MESH:D009369', (425, 430))	('tumor', 'Phenotype', 'HP:0002664', (617, 622))	('ZRSR2', 'Gene', '8233', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('X chromosome', 'cellular_component', 'GO:0000805', ('118', '130'))	('ZRSR2', 'Gene', (13, 18))	('cancers', 'Disease', 'MESH:D009369', (583, 590))	('inactivating mutations', 'Var', (399, 421))	('patients', 'Species', '9606', (51, 59))	('X-linked tumor', 'Disease', (608, 622))	('tumor', 'Phenotype', 'HP:0002664', (425, 430))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('X chromosome', 'cellular_component', 'GO:0000805', ('383', '395'))	('ZRSR2', 'Gene', (81, 86))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('227', '243'))	('tumor', 'Disease', (617, 622))	('ZRSR2', 'Gene', '8233', (13, 18))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('615', '631'))	('tumor', 'Disease', 'MESH:D009369', (617, 622))	('X chromosome', 'cellular_component', 'GO:0000805', ('257', '269'))	('men', 'Species', '9606', (180, 183))	('cancers', 'Phenotype', 'HP:0002664', (583, 590))	('tumor suppressor', 'biological_process', 'GO:0051726', ('227', '243'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('615', '631'))	('cancers', 'Disease', (583, 590))	('women', 'Species', '9606', (178, 183))	('X-linked tumor', 'Disease', 'MESH:D040181', (608, 622))
95795	31334570	Initial work done in vitro identified several mis-spliced genes involved in cell cycle regulation and MAP kinase signaling pathways.83  Insights into the functional consequences of splicing factors alterations in vivo have emerged using isogenic models of genetically engineered mouse models and human cell lines.	('cell cycle regulation', 'biological_process', 'GO:0051726', ('76', '97'))	('signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('splicing factor', 'Gene', (181, 196))	('human', 'Species', '9606', (296, 301))	('MAP', 'molecular_function', 'GO:0004239', ('102', '105'))	('splicing', 'biological_process', 'GO:0045292', ('181', '189'))	('mouse', 'Species', '10090', (279, 284))	('splicing factor', 'Gene', '10569', (181, 196))	('alterations', 'Var', (198, 209))
95797	31334570	In the setting of native hematopoiesis, expression of Srsf2P95H and U2af1S34F mutations resulted in mild leukopenia, and macrocytic anemia in the blood, as well as defects in erythroid and B-cell differentiation and myeloid skewing in the bone marrow.72, 79, 84, 85, 86 Mice expressing the Sf3b1K700E mutation exhibited erythroid differentiation defect and mild anemia, but these mice did not develop signs of ring sideroblasts.66, 67 Functional assessment of hematopoietic stem and progenitor cells (HSPCs) by competitive bone marrow transplantation assays showed that mutations in Sf3b1, Srsf2, and U2af1 uniformly resulted in reduced repopulating potential compared with wildtype HSPCs.66, 67, 72, 79, 84, 85, 86 Similarly, reduced proliferation was also observed in isogenic induced pluripotent stem cells derived from primary MDS patients with spliceosome gene mutations,71 and isogenic cancer cells lines.90 Less is known about the effects of defective U12 intron splicing driven by Zrsr2 mutations on hematopoiesis in vivo due to the lack of Zrsf2 knockout mice.	('U2af', 'cellular_component', 'GO:0089701', ('601', '605'))	('mice', 'Species', '10090', (380, 384))	('Mice', 'Species', '10090', (270, 274))	('hematopoiesis', 'biological_process', 'GO:0030097', ('1008', '1021'))	('cancer', 'Disease', (892, 898))	('macrocytic anemia', 'Disease', (121, 138))	('P95H', 'Mutation', 'rs751713049', (59, 63))	('ring sideroblasts', 'Phenotype', 'HP:0004828', (410, 427))	('Sf3b1', 'Gene', (290, 295))	('U2af1', 'Gene', (601, 606))	('leukopenia', 'Disease', 'MESH:D007970', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (892, 898))	('Zrsr2', 'Gene', (989, 994))	('U2af1', 'Gene', '108121', (68, 73))	('Sf3b1', 'Gene', (583, 588))	('splicing', 'biological_process', 'GO:0045292', ('970', '978'))	('macrocytic anemia', 'Phenotype', 'HP:0001972', (121, 138))	('leukopenia', 'Phenotype', 'HP:0001882', (105, 115))	('anemia', 'Disease', 'MESH:D000740', (132, 138))	('anemia', 'Disease', 'MESH:D000740', (362, 368))	('leukopenia', 'Disease', (105, 115))	('U2af1', 'Gene', (68, 73))	('MDS', 'Phenotype', 'HP:0002863', (831, 834))	('mutations', 'Var', (995, 1004))	('Sf3b1', 'Gene', '81898', (290, 295))	('Sf3b1', 'Gene', '81898', (583, 588))	('spliceosome', 'cellular_component', 'GO:0005681', ('849', '860'))	('anemia', 'Phenotype', 'HP:0001903', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (892, 898))	('anemia', 'Phenotype', 'HP:0001903', (362, 368))	('hematopoiesis', 'Disease', 'MESH:C536227', (25, 38))	('men', 'Species', '9606', (452, 455))	('patients', 'Species', '9606', (835, 843))	('hematopoiesis', 'Disease', 'MESH:C536227', (1008, 1021))	('anemia', 'Disease', (132, 138))	('macrocytic anemia', 'Disease', 'MESH:D000748', (121, 138))	('mice', 'Species', '10090', (1064, 1068))	('Zrsr2', 'Gene', '8233', (989, 994))	('anemia', 'Disease', (362, 368))	('hematopoiesis', 'Disease', (25, 38))	('U2af', 'cellular_component', 'GO:0089701', ('68', '72'))	('MDS', 'Disease', 'MESH:D007951', (831, 834))	('B-cell differentiation', 'biological_process', 'GO:0030183', ('189', '211'))	('hematopoiesis', 'Disease', (1008, 1021))	('MDS', 'Disease', (831, 834))	('hematopoiesis', 'biological_process', 'GO:0030097', ('25', '38'))	('U12 intron splicing', 'MPA', (959, 978))	('defective', 'NegReg', (949, 958))	('U2af1', 'Gene', '108121', (601, 606))
95799	31334570	Although these isogenic models recapitulate certain aspects of human MDS based on longitudinal follow-up studies, none of the splicing factor mutant models developed acute leukemia, suggesting a role for additional cooperating mutations and/or nongenetic factors in disease progression.	('MDS', 'Disease', (69, 72))	('MDS', 'Phenotype', 'HP:0002863', (69, 72))	('human', 'Species', '9606', (63, 68))	('leukemia', 'Phenotype', 'HP:0001909', (172, 180))	('acute leukemia', 'Disease', (166, 180))	('acute leukemia', 'Phenotype', 'HP:0002488', (166, 180))	('mutant', 'Var', (142, 148))	('acute leukemia', 'Disease', 'MESH:D054198', (166, 180))	('splicing factor', 'Gene', '10569', (126, 141))	('splicing', 'biological_process', 'GO:0045292', ('126', '134'))	('MDS', 'Disease', 'MESH:D007951', (69, 72))	('splicing factor', 'Gene', (126, 141))
95800	31334570	Despite the recent advances gained from modeling mutant splicing factors in vivo, there are several outstanding questions that remain.	('splicing factor', 'Gene', (56, 71))	('splicing', 'biological_process', 'GO:0045292', ('56', '64'))	('splicing factor', 'Gene', '10569', (56, 71))	('mutant', 'Var', (49, 55))
95803	31334570	Although recent large-scale transcriptomic analysis of mutations affecting SF3B1, SRSF2, and U2AF1 revealed global splicing dysregulation consistent with their predicted effects, there was minimal overlap between mis-spliced transcripts altered by each of the mutant proteins.93, 94 To identify key splicing abnormalities induced by mutant splicing factors, several studies provided functional evidence that expression of the abnormal splice isoforms in normal cells, or reintroduction of the canonical isoforms in spliceosomal mutant cells, can only partially phenocopy or rescue the effects of mutant spliceosome proteins.72, 80, 95, 96 These findings suggest that the pathological effects of spliceosome mutations are imparted through multiple mis-spliced products simultaneously.	('U2AF1', 'Gene', '7307', (93, 98))	('mutations', 'Var', (707, 716))	('splicing', 'biological_process', 'GO:0045292', ('299', '307'))	('U2AF1', 'Gene', (93, 98))	('splicing', 'biological_process', 'GO:0045292', ('340', '348'))	('splicing', 'biological_process', 'GO:0045292', ('115', '123'))	('SF3B1', 'Gene', '23451', (75, 80))	('splicing factor', 'Gene', '10569', (340, 355))	('spliceosome', 'Gene', (695, 706))	('U2AF', 'cellular_component', 'GO:0089701', ('93', '97'))	('spliceosome', 'cellular_component', 'GO:0005681', ('603', '614'))	('spliceosome', 'cellular_component', 'GO:0005681', ('695', '706'))	('SF3B1', 'Gene', (75, 80))	('splicing factor', 'Gene', (340, 355))
95814	31334570	These compounds were identified to have antitumor properties by causing cell cycle arrest in the G1 and G2/M phases and it was not until later that the SF3B component of the U2 snRNP was identified as the primary target.110, 111, 112 Biochemical assays identified that pladienolides and spliceostatin A inhibit splicing by abolishing the interaction between the U2snRNP/SF3B complex to the branchpoint region of the pre-mRNA.113, 114 The discovery that a mutation in SF3B1 R1074H conferred resistance to pladienolides demonstrated that SF3B1 was a direct target of this class of splicing inhibitory compounds.115 This was validated in a more recent study that identified a series of acquired mutations in SF3B1 (K1071 and V1078) in addition to R1074H, and in PHF5A Y36C that also conferred resistance to pladienolides.116 The crystal structure of pladienolide B bound to the human SF3B complex was recently solved and confirmed that, in addition to SF3B1, pladienolide B also interacts with PHF5A, a PHD-finger-like domain containing member of the SF3B complex.117 Structural analysis showed that pladienolide B fits into a hinge area that prevents the transition to a closed confirmation and precludes recognition of the branchpoint adenosine.	('R1074H', 'SUBSTITUTION', 'None', (744, 750))	('human', 'Species', '9606', (875, 880))	('spliceostatin A', 'Chemical', 'MESH:C553684', (287, 302))	('adenosine', 'Chemical', 'MESH:D000241', (1234, 1243))	('V1078', 'Chemical', 'MESH:C559087', (722, 727))	('pladienolide B', 'Chemical', 'MESH:C522342', (847, 861))	('PHD', 'molecular_function', 'GO:0050175', ('1000', '1003'))	('prevents', 'NegReg', (1140, 1148))	('pladienolide B', 'Chemical', 'MESH:C522342', (956, 970))	('R1074H', 'SUBSTITUTION', 'None', (473, 479))	('Y36C', 'Mutation', 'rs1462120663', (765, 769))	('transition', 'MPA', (1153, 1163))	('tumor', 'Disease', (44, 49))	('SF3B1', 'Gene', '23451', (536, 541))	('splicing', 'biological_process', 'GO:0045292', ('579', '587'))	('SF3B1', 'Gene', '23451', (949, 954))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('174', '182'))	('R1074H', 'Var', (744, 750))	('pladienolides', 'Chemical', 'MESH:C522343', (269, 282))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('72', '89'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (72, 89))	('R1074H', 'Var', (473, 479))	('pladienolide B', 'Chemical', 'MESH:C522342', (1097, 1111))	('SF3B1', 'Gene', (467, 472))	('SF3B1', 'Gene', (705, 710))	('U2snRNP', 'cellular_component', 'GO:0005686', ('362', '369'))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('snRNP', 'molecular_function', 'GO:0003734', ('364', '369'))	('pladienolides', 'Chemical', 'MESH:C522343', (504, 517))	('splicing', 'biological_process', 'GO:0045292', ('311', '319'))	('snRNP', 'molecular_function', 'GO:0003734', ('177', '182'))	('pre', 'molecular_function', 'GO:0003904', ('416', '419'))	('SF3B1', 'Gene', (536, 541))	('pladienolides', 'Chemical', 'MESH:C522343', (804, 817))	('SF3B1', 'Gene', (949, 954))	('SF3B1', 'Gene', '23451', (467, 472))	('SF3B1', 'Gene', '23451', (705, 710))
95816	31334570	The first clinical trials with small molecule SF3B inhibitors were performed in unselected epithelial malignancies with E7107, a semisynthetic derivative of pladienolide B.	('epithelial malignancies', 'Phenotype', 'HP:0031492', (91, 114))	('epithelial malignancies', 'Disease', (91, 114))	('SF3B', 'Gene', (46, 50))	('epithelial malignancies', 'Disease', 'MESH:D002277', (91, 114))	('E7107', 'Var', (120, 125))	('E7107', 'Chemical', 'MESH:C557411', (120, 125))	('pladienolide B', 'Chemical', 'MESH:C522342', (157, 171))
95824	31334570	These episodes of vision loss were considered to be related to optic neuritis and potentially related to E7107 toxicity.	('neuritis', 'Phenotype', 'HP:0031002', (69, 77))	('E7107', 'Var', (105, 110))	('vision', 'biological_process', 'GO:0007601', ('18', '24'))	('E7107', 'Chemical', 'MESH:C557411', (105, 110))	('optic neuritis', 'Disease', 'MESH:D009902', (63, 77))	('toxicity', 'Disease', 'MESH:D064420', (111, 119))	('optic neuritis', 'Disease', (63, 77))	('vision loss', 'Phenotype', 'HP:0000572', (18, 29))	('toxicity', 'Disease', (111, 119))	('vision loss', 'Disease', 'MESH:D014786', (18, 29))	('optic neuritis', 'Phenotype', 'HP:0100653', (63, 77))	('vision loss', 'Disease', (18, 29))
95828	31334570	This hypothesis has been tested in vitro and in vivo in preclinical models and in clinical trials.31, 67, 90, 91, 92 As discussed above, simultaneous preclinical efforts to discover the biology underlying splicing factor mutations in hematologic neoplasms identified that Srsf2 P95H/+ mutant hematopoietic cells required the wildtype allele of Srsf2 to survive.	('splicing factor', 'Gene', '10569', (205, 220))	('hematologic neoplasms', 'Disease', (234, 255))	('hematologic neoplasms', 'Disease', 'MESH:D019337', (234, 255))	('splicing', 'biological_process', 'GO:0045292', ('205', '213'))	('neoplasms', 'Phenotype', 'HP:0002664', (246, 255))	('P95H/+ mutant', 'Var', (278, 291))	('splicing factor', 'Gene', (205, 220))	('hematologic neoplasms', 'Phenotype', 'HP:0004377', (234, 255))	('Srsf2', 'Gene', (272, 277))	('P95H', 'Mutation', 'rs751713049', (278, 282))
95829	31334570	In a murine leukemia model driven by MLL-AF9 fusion oncogene, Srsf2 P95H/+ leukemias were more sensitive to E7107 than Srsf2 +/+ wildtype leukemias.31 Similarly, increased sensitivity to spliceosome inhibitors were also observed in Sf3b1 K700E/+ and U2af1 S34F/+ murine hematopoietic cells in vivo,67, 92 and in SRSF2-mutant CMML patient-derived xenograft model.32 These studies provided proof-of-concept that a therapeutic window might exist for SF3B inhibitors to achieve the requisite splicing inhibition to selectively kill spliceosomal mutant cells.	('leukemia', 'Disease', 'MESH:D007938', (75, 83))	('leukemia', 'Disease', (75, 83))	('P95H', 'Mutation', 'rs751713049', (68, 72))	('U2af1', 'Gene', '108121', (250, 255))	('inhibitors', 'Var', (452, 462))	('spliceosomal mutant', 'MPA', (528, 547))	('K700E', 'Mutation', 'rs559063155', (238, 243))	('U2af1', 'Gene', (250, 255))	('leukemias', 'Disease', 'MESH:D007938', (138, 147))	('MLL', 'Gene', '214162', (37, 40))	('Sf3b1', 'Gene', (232, 237))	('leukemia', 'Phenotype', 'HP:0001909', (12, 20))	('AF9', 'Gene', '70122', (41, 44))	('spliceosome', 'cellular_component', 'GO:0005681', ('187', '198'))	('leukemias', 'Phenotype', 'HP:0001909', (138, 147))	('CMML', 'Disease', (325, 329))	('leukemias', 'Disease', 'MESH:D007938', (75, 84))	('CMML', 'Disease', 'MESH:D015477', (325, 329))	('CMML', 'Phenotype', 'HP:0012325', (325, 329))	('U2af', 'cellular_component', 'GO:0089701', ('250', '254'))	('E7107', 'Chemical', 'MESH:C557411', (108, 113))	('murine', 'Species', '10090', (5, 11))	('leukemia', 'Phenotype', 'HP:0001909', (138, 146))	('leukemias', 'Phenotype', 'HP:0001909', (75, 84))	('patient', 'Species', '9606', (330, 337))	('leukemia', 'Disease', (12, 20))	('leukemia', 'Disease', 'MESH:D007938', (12, 20))	('SF3B', 'Gene', (447, 451))	('Sf3b1', 'Gene', '81898', (232, 237))	('leukemias', 'Disease', (138, 147))	('leukemia', 'Phenotype', 'HP:0001909', (75, 83))	('murine', 'Species', '10090', (263, 269))	('MLL', 'Gene', (37, 40))	('AF9', 'Gene', (41, 44))	('leukemia', 'Disease', (138, 146))	('S34F', 'Mutation', 'rs371769427', (256, 260))	('leukemia', 'Disease', 'MESH:D007938', (138, 146))	('leukemias', 'Disease', (75, 84))	('splicing inhibition', 'MPA', (488, 507))	('splicing', 'biological_process', 'GO:0045292', ('488', '496'))
95832	31334570	A phase 1 clinical trial of H3B-8800 has recently been initiated targeting patients with relapsed/refractory myeloid neoplasms (MDS, CMML, and AML) that carry splicing factor mutations (NCT02841540).	('CMML', 'Disease', (133, 137))	('MDS', 'Disease', (128, 131))	('splicing factor', 'Gene', (159, 174))	('MDS', 'Disease', 'MESH:D007951', (128, 131))	('H3B-8800', 'Chemical', 'MESH:C045568', (28, 36))	('CMML', 'Disease', 'MESH:D015477', (133, 137))	('CMML', 'Phenotype', 'HP:0012325', (133, 137))	('MDS', 'Phenotype', 'HP:0002863', (128, 131))	('patients', 'Species', '9606', (75, 83))	('AML', 'Disease', 'MESH:D015470', (143, 146))	('NCT02841540', 'Var', (186, 197))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (109, 126))	('refractory myeloid neoplasms', 'Disease', (98, 126))	('splicing factor', 'Gene', '10569', (159, 174))	('refractory myeloid neoplasms', 'Disease', 'MESH:D000753', (98, 126))	('AML', 'Disease', (143, 146))	('neoplasms', 'Phenotype', 'HP:0002664', (117, 126))	('splicing', 'biological_process', 'GO:0045292', ('159', '167'))
95839	31334570	Moreover, a recent study suggests that pharmacologic inhibition of type-I PRMTs also perturbs RNA splicing globally and synergizes with PRMT5 inhibition to induce antitumor effects.129 Based on these observations, it would be tempting to speculate that leukemias bearing spliceosome gene mutations may also confer differential sensitivity to PRMT5 and/or type-I PRMT inhibitors.	('spliceosome', 'cellular_component', 'GO:0005681', ('271', '282'))	('spliceosome gene', 'Gene', (271, 287))	('leukemias', 'Phenotype', 'HP:0001909', (253, 262))	('leukemias', 'Disease', (253, 262))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('RNA splicing', 'biological_process', 'GO:0008380', ('94', '106'))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('RNA', 'cellular_component', 'GO:0005562', ('94', '97'))	('mutations', 'Var', (288, 297))	('leukemias', 'Disease', 'MESH:D007938', (253, 262))	('tumor', 'Disease', (167, 172))	('leukemia', 'Phenotype', 'HP:0001909', (253, 261))
95840	31334570	Two elegant studies focused on identifying the molecular targets of anticancer sulfonamides have revealed a potential therapeutic application for spliceosomal mutant leukemias.	('sulfonamides', 'Chemical', 'MESH:D013449', (79, 91))	('leukemias', 'Phenotype', 'HP:0001909', (166, 175))	('leukemias', 'Disease', (166, 175))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('leukemia', 'Phenotype', 'HP:0001909', (166, 174))	('leukemias', 'Disease', 'MESH:D007938', (166, 175))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('spliceosomal mutant', 'Var', (146, 165))	('cancer', 'Disease', (72, 78))
95843	31334570	The authors provided evidence that RBM39 depletion resulted in global splicing alterations including preferential cassette exon skipping and intron retention.	('RBM39', 'Gene', '9584', (35, 40))	('cassette', 'MPA', (114, 122))	('retention', 'biological_process', 'GO:0051235', ('148', '157'))	('preferential', 'PosReg', (101, 113))	('depletion', 'Var', (41, 50))	('global splicing alterations', 'MPA', (63, 90))	('RBM39', 'Gene', (35, 40))	('splicing', 'biological_process', 'GO:0045292', ('70', '78'))	('intron retention', 'MPA', (141, 157))
95844	31334570	A recent study by Wang et al confirmed that RBM39 loss resulted in repressed cassette exon splicing and increased intron retention, and that spliceosome-mutant leukemias showed preferential sensitivity to pharmacologic targeting of RBM39.138 These studies have raised the interesting possibility that spliceosome mutant leukemias may be sensitized to anticancer sulfonamide compounds, and is an interesting research area that may potentially motivate future clinical trials.	('leukemias', 'Disease', (160, 169))	('sulfonamide', 'Chemical', 'MESH:D013449', (362, 373))	('leukemias', 'Disease', (320, 329))	('RBM39', 'Gene', '9584', (44, 49))	('spliceosome mutant', 'Var', (301, 319))	('spliceosome', 'cellular_component', 'GO:0005681', ('141', '152'))	('RBM39', 'Gene', '9584', (232, 237))	('cancer', 'Disease', (355, 361))	('RBM39', 'Gene', (44, 49))	('retention', 'biological_process', 'GO:0051235', ('121', '130'))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('leukemias', 'Disease', 'MESH:D007938', (160, 169))	('leukemias', 'Disease', 'MESH:D007938', (320, 329))	('leukemias', 'Phenotype', 'HP:0001909', (320, 329))	('RBM39', 'Gene', (232, 237))	('leukemias', 'Phenotype', 'HP:0001909', (160, 169))	('spliceosome', 'cellular_component', 'GO:0005681', ('301', '312'))	('leukemia', 'Phenotype', 'HP:0001909', (320, 328))	('leukemia', 'Phenotype', 'HP:0001909', (160, 168))	('cancer', 'Disease', 'MESH:D009369', (355, 361))	('splicing', 'biological_process', 'GO:0045292', ('91', '99'))
95850	31334570	Despite these recent technological advances and clinical achievements in neuromuscular disorders, the utility of ASOs in spliceosome mutant leukemias remains challenging, primarily due to our insufficient understanding of the key mis-spliced targets responsible for disease initiation and/or progression.	('neuromuscular disorders', 'Disease', (73, 96))	('neuromuscular disorders', 'Disease', 'MESH:D009468', (73, 96))	('leukemias', 'Disease', 'MESH:D007938', (140, 149))	('leukemia', 'Phenotype', 'HP:0001909', (140, 148))	('spliceosome', 'cellular_component', 'GO:0005681', ('121', '132'))	('leukemias', 'Phenotype', 'HP:0001909', (140, 149))	('leukemias', 'Disease', (140, 149))	('men', 'Species', '9606', (64, 67))	('mutant', 'Var', (133, 139))
95852	31334570	The major idea leading the field so far and currently being tested in an early phase clinical trial is the use of spliceosomal modulation to induce synthetic lethality in splicing factor mutant malignancies.	('malignancies', 'Disease', (194, 206))	('splicing factor', 'Gene', '10569', (171, 186))	('synthetic lethality', 'MPA', (148, 167))	('splicing', 'biological_process', 'GO:0045292', ('171', '179'))	('mutant', 'Var', (187, 193))	('malignancies', 'Disease', 'MESH:D009369', (194, 206))	('splicing factor', 'Gene', (171, 186))
95856	31334570	Further developments in understanding the oncogenic mechanisms of splicing factor mutations may lead to novel approaches as well.	('splicing factor', 'Gene', (66, 81))	('men', 'Species', '9606', (15, 18))	('mutations', 'Var', (82, 91))	('lead', 'Reg', (96, 100))	('splicing factor', 'Gene', '10569', (66, 81))	('splicing', 'biological_process', 'GO:0045292', ('66', '74'))
95857	31334570	For example, increased R-loop formation is observed in spliceosome mutant leukemias and this has been shown to sensitize them to ATR inhibition.147 Moreover, unbiased genetic and chemical screening approaches in the context of spliceosome mutant cancers will be crucial for uncovering novel biological features, as well as uncovering therapeutically actionable targets.	('ATR', 'Gene', '545', (129, 132))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('cancers', 'Disease', (246, 253))	('leukemias', 'Phenotype', 'HP:0001909', (74, 83))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('ATR', 'Gene', (129, 132))	('leukemias', 'Disease', (74, 83))	('formation', 'biological_process', 'GO:0009058', ('30', '39'))	('spliceosome', 'cellular_component', 'GO:0005681', ('227', '238'))	('spliceosome', 'cellular_component', 'GO:0005681', ('55', '66'))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('leukemias', 'Disease', 'MESH:D007938', (74, 83))	('mutant', 'Var', (239, 245))	('leukemia', 'Phenotype', 'HP:0001909', (74, 82))
95860	31334570	As acquisition of spliceosome gene mutations appear to be the initiating events in clonal hematopoiesis and MDS pathogenesis, reversing the pathogenic splicing events by gene editing would ameliorate disease progression.	('pathogenesis', 'biological_process', 'GO:0009405', ('112', '124'))	('MDS', 'Disease', (108, 111))	('MDS', 'Disease', 'MESH:D007951', (108, 111))	('MDS', 'Phenotype', 'HP:0002863', (108, 111))	('clonal hematopoiesis', 'Disease', 'MESH:C536227', (83, 103))	('spliceosome gene', 'Gene', (18, 34))	('hematopoiesis', 'biological_process', 'GO:0030097', ('90', '103'))	('splicing', 'biological_process', 'GO:0045292', ('151', '159'))	('clonal hematopoiesis', 'Disease', (83, 103))	('spliceosome', 'cellular_component', 'GO:0005681', ('18', '29'))	('mutations', 'Var', (35, 44))
95862	31334570	Future clinical trials may also use a combination of the above agents (such as an ATR inhibitor with an SF3B complex inhibitor) or using the above agents in combination with nonsplicing specific therapies such as hypomethylating agents, apoptosis inducers (eg, BH-3 mimetics), checkpoint blockade immunotherapies, or a number of mutation specific targeted agents in the case of patients with splicing factor mutation plus other mutations (eg, mutant IDH2 inhibitors).	('ATR', 'Gene', '545', (82, 85))	('ATR', 'Gene', (82, 85))	('mutations', 'Var', (428, 437))	('splicing factor', 'Gene', (392, 407))	('apoptosis', 'CPA', (237, 246))	('IDH2', 'Gene', (450, 454))	('apoptosis', 'biological_process', 'GO:0097194', ('237', '246'))	('patients', 'Species', '9606', (378, 386))	('methyl', 'Chemical', 'MESH:C031105', (217, 223))	('splicing factor', 'Gene', '10569', (392, 407))	('IDH2', 'Gene', '3418', (450, 454))	('splicing', 'biological_process', 'GO:0045292', ('392', '400'))	('apoptosis', 'biological_process', 'GO:0006915', ('237', '246'))
95863	31334570	The future looks promising for finding means to address the very large need of novel therapies for the great number of patients with splicing factor mutant hematologic malignancies and for nonsplicing factor mutant malignancies that are dependent on splicing.	('splicing factor', 'Gene', '10569', (133, 148))	('malignancies', 'Disease', (215, 227))	('hematologic malignancies', 'Disease', 'MESH:D019337', (156, 180))	('splicing factor', 'Gene', '10569', (192, 207))	('patients', 'Species', '9606', (119, 127))	('mutant', 'Var', (149, 155))	('malignancies', 'Disease', 'MESH:D009369', (168, 180))	('splicing', 'biological_process', 'GO:0045292', ('133', '141'))	('hematologic malignancies', 'Disease', (156, 180))	('splicing factor', 'Gene', (133, 148))	('malignancies', 'Disease', (168, 180))	('malignancies', 'Disease', 'MESH:D009369', (215, 227))	('splicing factor', 'Gene', (192, 207))	('splicing', 'biological_process', 'GO:0045292', ('250', '258'))
95866	24392146	Functionally, they represent four categories: (i) DNA repair and RNA regulation (VCP, MVP, STRAP, FAB-2, Lamine A/C, GAPDH), (ii) cell survival and stress response (STRAP, MCM7, Annexin 7, MVP, Caprin-1, PDCD6, VCP, HSP70), (iii) cell metabolism (TIM, GAPDH, VCP), and (iv) cytoskeleton and motility (Moesin, Actinin 4, FAB-2, Vimentin, Annexin 7, Lamine A/C, Lamine B).	('VCP', 'Gene', '7415', (81, 84))	('TIM', 'Gene', (247, 250))	('Vimentin', 'cellular_component', 'GO:0045098', ('327', '335'))	('STRAP', 'Gene', (165, 170))	('Caprin-1', 'Gene', (194, 202))	('Actinin 4', 'Gene', '81', (309, 318))	('FAB-2', 'Gene', '8570', (320, 325))	('MVP', 'Gene', '9961', (86, 89))	('HSP70', 'Gene', (216, 221))	('RNA', 'cellular_component', 'GO:0005562', ('65', '68'))	('regulation', 'biological_process', 'GO:0065007', ('69', '79'))	('metabolism', 'biological_process', 'GO:0008152', ('235', '245'))	('TIM', 'Gene', '7167', (247, 250))	('Actinin 4', 'Gene', (309, 318))	('Lamine A/C', 'Var', (348, 358))	('FAB-2', 'Gene', (98, 103))	('cell metabolism', 'CPA', (230, 245))	('MVP', 'Gene', '9961', (189, 192))	('VCP', 'Gene', (211, 214))	('STRAP', 'Gene', (91, 96))	('Moesin', 'Gene', '4478', (301, 307))	('GAPDH', 'Gene', '2597', (117, 122))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('VCP', 'Gene', (259, 262))	('STRAP', 'Gene', '11171', (165, 170))	('FAB-2', 'Gene', (320, 325))	('MCM7', 'Gene', (172, 176))	('Annexin 7', 'Gene', '310', (337, 346))	('HSP70', 'Gene', '3308', (216, 221))	('MVP', 'Gene', (86, 89))	('DNA repair', 'biological_process', 'GO:0006281', ('50', '60'))	('Vimentin', 'cellular_component', 'GO:0045099', ('327', '335'))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('274', '286'))	('Annexin 7', 'Gene', (337, 346))	('GAPDH', 'Gene', '2597', (252, 257))	('Annexin 7', 'Gene', '310', (178, 187))	('VCP', 'Gene', '7415', (211, 214))	('VCP', 'Gene', (81, 84))	('MCM7', 'Gene', '4176', (172, 176))	('MVP', 'Gene', (189, 192))	('VCP', 'Gene', '7415', (259, 262))	('GAPDH', 'Gene', (117, 122))	('Caprin-1', 'Gene', '4076', (194, 202))	('PDCD6', 'Gene', '10016', (204, 209))	('PDCD6', 'Gene', (204, 209))	('Annexin 7', 'Gene', (178, 187))	('Moesin', 'Gene', (301, 307))	('FAB-2', 'Gene', '8570', (98, 103))	('GAPDH', 'Gene', (252, 257))	('STRAP', 'Gene', '11171', (91, 96))
95968	24392146	MCM7 overexpreession fosters tumorigenesis in combination with the action of miRNAs.	('MCM7', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('fosters', 'PosReg', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('overexpreession', 'Var', (5, 20))	('MCM7', 'Gene', '4176', (0, 4))
95978	24392146	Tumor progression and resistance to chemotherapy and radiotherapy may also be activated through the suppression of Bax and upregulation of IGF-1R, resulting in increased proliferation and reduced apoptosis caused by upregulation of Bcl-2 and overexpression of altered p53.	('Bax', 'Gene', (115, 118))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('altered', 'Var', (260, 267))	('Bax', 'Gene', '581', (115, 118))	('Tumor progression', 'CPA', (0, 17))	('overexpression', 'PosReg', (242, 256))	('apoptosis', 'CPA', (196, 205))	('suppression', 'NegReg', (100, 111))	('p53', 'Gene', '7157', (268, 271))	('increased', 'PosReg', (160, 169))	('proliferation', 'CPA', (170, 183))	('Bcl-2', 'Gene', (232, 237))	('Bcl-2', 'molecular_function', 'GO:0015283', ('232', '237'))	('upregulation', 'PosReg', (123, 135))	('reduced', 'NegReg', (188, 195))	('apoptosis', 'biological_process', 'GO:0097194', ('196', '205'))	('apoptosis', 'biological_process', 'GO:0006915', ('196', '205'))	('IGF-1R', 'Gene', (139, 145))	('IGF-1R', 'Gene', '3480', (139, 145))	('activated', 'PosReg', (78, 87))	('p53', 'Gene', (268, 271))	('Bcl-2', 'Gene', '596', (232, 237))	('upregulation', 'PosReg', (216, 228))
96036	24392146	In turn, B lamin deficiency is involved in the development of prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (62, 77))	('involved', 'Reg', (31, 39))	('lamin', 'Gene', (11, 16))	('deficiency', 'Var', (17, 27))	('prostate cancer', 'Disease', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lamin', 'Gene', '4000', (11, 16))	('prostate cancer', 'Disease', 'MESH:D011471', (62, 77))
96041	24392146	For example, in B16 melanoma cells treated with cyclohexamide a decrease in vimentin mRNa was seen, together with a decrease in the formation of lung metastastes in mice.	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('mice', 'Species', '10090', (165, 169))	('decrease', 'NegReg', (64, 72))	('cyclohexamide', 'Chemical', '-', (48, 61))	('vimentin', 'Protein', (76, 84))	('decrease', 'NegReg', (116, 124))	('B16', 'CellLine', 'CVCL:N540', (16, 19))	('cyclohexamide', 'Var', (48, 61))	('vimentin', 'cellular_component', 'GO:0045099', ('76', '84'))	('formation', 'biological_process', 'GO:0009058', ('132', '141'))	('formation of lung metastastes', 'CPA', (132, 161))	('vimentin', 'cellular_component', 'GO:0045098', ('76', '84'))	('mRNa', 'MPA', (85, 89))	('melanoma', 'Disease', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))
82217	20844676	Any vertical movement of the blade may cause perforation of the retina or nonpigmented ciliary epithelium and vitreous loss.	('cause', 'Reg', (39, 44))	('vertical movement', 'Var', (4, 21))	('vitreous loss', 'Phenotype', 'HP:0100832', (110, 123))	('perforation of the retina', 'Phenotype', 'HP:0011958', (45, 70))	('vitreous loss', 'Disease', 'MESH:D014823', (110, 123))	('nonpigmented ciliary epithelium', 'CPA', (74, 105))	('vitreous loss', 'Disease', (110, 123))	('perforation of the retina', 'CPA', (45, 70))
96126	20844676	found that the incidence of secondary glaucoma was significantly higher after I-125 brachytherapy (33.3%) than after PLSU surgery (5.6%) (P = 0.03).	('glaucoma', 'Disease', (38, 46))	('glaucoma', 'Disease', 'MESH:D005901', (38, 46))	('I-125', 'Chemical', 'MESH:C000614960', (78, 83))	('I-125 brachytherapy', 'Var', (78, 97))	('higher', 'PosReg', (65, 71))	('glaucoma', 'Phenotype', 'HP:0000501', (38, 46))
96149	20844676	Unfortunately, there are no prospective comparative data available addressing this issue, but there is considerable concern by numerous specialists in this field, that endoresecion without prior irradiation to the tumor, that is tumor "devitalization," will increase the recurrence and metastasis rates.	('endoresecion', 'Var', (168, 180))	('increase', 'PosReg', (258, 266))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', (214, 219))
96151	20844676	By removing or debulking the irradiated tumor and reattaching the detached retina, long-term ocular morbidity could be reduced significantly, especially in large uveal melanomas that have undergone irradiation.	('uveal melanoma', 'Phenotype', 'HP:0007716', (162, 176))	('uveal melanomas', 'Disease', 'MESH:C536494', (162, 177))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('detached retina', 'Phenotype', 'HP:0000541', (66, 81))	('debulking', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('melanomas', 'Phenotype', 'HP:0002861', (168, 177))	('reduced', 'NegReg', (119, 126))	('uveal melanomas', 'Disease', (162, 177))	('uveal melanomas', 'Phenotype', 'HP:0007716', (162, 177))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))
96165	20844676	However, in the long run local tumor resection either by means of exoresection (transscleral resection) or by means of endoresection can be advantegeous to primary irradiation modalities, that can cause significant radiation-induced side effects, especially in the case of large tumors.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('large tumors', 'Disease', (273, 285))	('tumor', 'Disease', (31, 36))	('endoresection', 'Var', (119, 132))	('tumor', 'Disease', (279, 284))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('large tumors', 'Disease', 'MESH:D009369', (273, 285))	('tumor', 'Disease', 'MESH:D009369', (279, 284))
96171	19843243	Both types of melanoma have activating oncogene mutations that provide autonomous pro-proliferative signals, yet the consensus is that those are not sufficient for tumor progression.	('melanoma', 'Disease', (14, 22))	('tumor', 'Disease', (164, 169))	('oncogene', 'Gene', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('mutations', 'Var', (48, 57))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('rat', 'Species', '10116', (93, 96))
96173	19843243	To stimulate further debate and inquiry we describe here a few examples of potential signals that might modify the fate of disseminated cell and provide brief description of the current knowledge on dormancy in other cancers.	('fate of disseminated cell', 'CPA', (115, 140))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('dormancy', 'biological_process', 'GO:0030431', ('199', '207'))	('cancers', 'Disease', 'MESH:D009369', (217, 224))	('cancers', 'Disease', (217, 224))	('modify', 'Reg', (104, 110))	('signals', 'Var', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
96176	19843243	Until recently, the prevailing theory was that metastases arise from a late-forming small sub-population of cancer cells which, through mutation and selections, become highly adapted to processes of dissemination and growth in secondary sites.	('mutation', 'Var', (136, 144))	('metastases', 'Disease', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('metastases', 'Disease', 'MESH:D009362', (47, 57))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
96210	19843243	Also, blockade of signaling through the protease receptor uPAR leads to alpha5beta1 integrin inactivation, decrease in the EGFR signaling and induction of dormancy.	('EGFR', 'Gene', (123, 127))	('beta1 integrin', 'Gene', (78, 92))	('signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('uPAR', 'Gene', '5329', (58, 62))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('inactivation', 'NegReg', (93, 105))	('signaling', 'biological_process', 'GO:0023052', ('18', '27'))	('induction', 'Reg', (142, 151))	('induction of dormancy', 'biological_process', 'GO:0097436', ('142', '163'))	('blockade', 'Var', (6, 14))	('beta1 integrin', 'Gene', '3688', (78, 92))	('decrease', 'NegReg', (107, 115))	('uPAR', 'Gene', (58, 62))	('EGFR', 'Gene', '1956', (123, 127))	('uPAR', 'molecular_function', 'GO:0030377', ('58', '62'))
96225	19843243	As Notch-1 has been implicated in melanoma progression, and melanoma appears to evade senescence, it is tempting to speculate that, during expansion and/or quiescent phases, Notch and HES-1 may protect melanoma from entering senescence.	('Notch', 'Var', (174, 179))	('Notch-1', 'Gene', (3, 10))	('HES-1', 'Gene', (184, 189))	('Notch-1', 'Gene', '4851', (3, 10))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('HES-1', 'Gene', '3280', (184, 189))	('melanoma', 'Disease', (60, 68))	('implicated', 'Reg', (20, 30))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', (202, 210))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))	('senescence', 'biological_process', 'GO:0010149', ('225', '235'))	('senescence', 'biological_process', 'GO:0010149', ('86', '96'))
96247	19843243	Inhibition of the ABCB5 pump significantly reversed resistance to doxorubicin.	('ABCB5', 'Gene', (18, 23))	('ABCB5', 'Gene', '340273', (18, 23))	('reversed', 'Reg', (43, 51))	('resistance to doxorubicin', 'MPA', (52, 77))	('doxorubicin', 'Chemical', 'MESH:D004317', (66, 77))	('Inhibition', 'Var', (0, 10))
96261	19843243	To accept TICs quiescence one would have to accept the possibility that therapy, microenvironment or the stem cell-dependent reprogramming into dormancy might neutralize the action of mutant B-Raf once senescence is bypassed or more importantly antagonize mutant N-Ras signals or restore PTEN pathway function.	('antagonize', 'NegReg', (245, 255))	('mutant', 'Var', (184, 190))	('B-Raf', 'Gene', '673', (191, 196))	('TIC', 'Disease', 'None', (10, 13))	('mutant', 'Var', (256, 262))	('senescence', 'biological_process', 'GO:0010149', ('202', '212'))	('action', 'MPA', (174, 180))	('neutralize', 'NegReg', (159, 169))	('PTEN', 'Gene', (288, 292))	('N-Ras', 'Gene', (263, 268))	('TIC', 'Disease', (10, 13))	('N-Ras', 'Gene', '4893', (263, 268))	('restore', 'Reg', (280, 287))	('B-Raf', 'Gene', (191, 196))	('function', 'MPA', (301, 309))	('TICs', 'Phenotype', 'HP:0100033', (10, 14))	('PTEN', 'Gene', '5728', (288, 292))	('TIC', 'Phenotype', 'HP:0100033', (10, 13))	('quiescence', 'biological_process', 'GO:0044838', ('15', '25'))	('dormancy', 'biological_process', 'GO:0030431', ('144', '152'))
96281	19843243	It is also possible that in spite of carrying genetic alterations that favor growth, the DTCs are forced into quiescence by the micro-environment, or epigenetic or therapy-derived mechanisms.	('growth', 'MPA', (77, 83))	('favor', 'PosReg', (71, 76))	('quiescence', 'biological_process', 'GO:0044838', ('110', '120'))	('rat', 'Species', '10116', (58, 61))	('alterations', 'Var', (54, 65))
96284	19843243	This suggests that the bone microenvironment may delay cancer progression and thus prolong patient survival but also, that perturbations of this microenvironment might trigger growth.	('prolong', 'PosReg', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('perturbations', 'Var', (123, 136))	('delay', 'NegReg', (49, 54))	('trigger', 'Reg', (168, 175))	('patient', 'Species', '9606', (91, 98))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('patient survival', 'CPA', (91, 107))	('growth', 'MPA', (176, 182))	('cancer', 'Disease', (55, 61))
96286	19843243	In melanoma cell lines, targeting of specific integrins can curtail growth, while interaction of melanoma cells with fibrillar collagen induces cell cycle inhibitor p15INK4b expression and growth arrest.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('p15INK4b', 'Gene', '1030', (165, 173))	('cell cycle', 'biological_process', 'GO:0007049', ('144', '154'))	('p15INK4b', 'Gene', (165, 173))	('curtail', 'NegReg', (60, 67))	('cell', 'MPA', (144, 148))	('targeting', 'Var', (24, 33))	('growth', 'MPA', (68, 74))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('growth arrest', 'Phenotype', 'HP:0001510', (189, 202))	('growth arrest', 'CPA', (189, 202))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('expression', 'MPA', (174, 184))	('integrins', 'Protein', (46, 55))	('induces', 'Reg', (136, 143))	('interaction', 'Interaction', (82, 93))	('collagen', 'molecular_function', 'GO:0005202', ('127', '135'))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))
96290	19843243	On the other hand, others have shown that adhesion regulated ERK1/2 activation in melanocytes is by-passed by mutation of B-Raf in malignant melanoma cells, although melanoma cells may still be dependent on integrin activated PI3K and Akt signaling for survival.	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('B-Raf', 'Gene', (122, 127))	('PI3K', 'molecular_function', 'GO:0016303', ('226', '230'))	('activation', 'PosReg', (68, 78))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('Akt', 'Gene', (235, 238))	('malignant melanoma', 'Disease', (131, 149))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('Akt', 'Gene', '207', (235, 238))	('Akt signaling', 'biological_process', 'GO:0043491', ('235', '248'))	('B-Raf', 'Gene', '673', (122, 127))	('mutation', 'Var', (110, 118))	('ERK1/2', 'Gene', '5595;5594', (61, 67))	('ERK1/2', 'Gene', (61, 67))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('malignant melanoma', 'Phenotype', 'HP:0002861', (131, 149))	('malignant melanoma', 'Disease', 'MESH:D008545', (131, 149))	('ERK1', 'molecular_function', 'GO:0004707', ('61', '65'))
96292	19843243	Several interesting transgenic melanoma mouse models have been developed, including two very recent ones, in which conditionally activated B-rafV600E alone, or in combination with PTEN-tumor suppressor gene silencing led to melanoma generation.	('B-rafV600E', 'Var', (139, 149))	('rat', 'Species', '10116', (237, 240))	('PTEN-tumor', 'Disease', 'MESH:D006223', (180, 190))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('tumor suppressor', 'biological_process', 'GO:0051726', ('185', '201'))	('gene silencing', 'biological_process', 'GO:0016458', ('202', '216'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('185', '201'))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('transgenic', 'Species', '10090', (20, 30))	('PTEN-tumor', 'Disease', (180, 190))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Disease', (224, 232))	('melanoma', 'Disease', 'MESH:D008545', (224, 232))	('melanoma', 'Disease', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('led to', 'Reg', (217, 223))	('mouse', 'Species', '10090', (40, 45))
96296	19843243	At day 12-14 only ~3.5% of the inoculated cells remained as solitary cells, of this only 3% was stained with Ki-67, a marker of proliferation, while ~40% of cells in small, medium or large metastases stained positively for this marker.	('rat', 'Species', '10116', (135, 138))	('metastases', 'Disease', (189, 199))	('Ki-67', 'Var', (109, 114))	('metastases', 'Disease', 'MESH:D009362', (189, 199))
96340	19843243	Uveal melanomas develop characteristic chromosomal abnormalities, such as loss of chromosome 3, abnormalities in chromosome 6 and, less frequently, gains in chromosome 8q.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (39, 64))	('abnormalities', 'Var', (96, 109))	('chromosome', 'cellular_component', 'GO:0005694', ('82', '92'))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanomas', 'Disease', (6, 15))	('loss', 'NegReg', (74, 78))	('gains', 'Var', (148, 153))	('chromosome', 'cellular_component', 'GO:0005694', ('113', '123'))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('chromosomal abnormalities', 'Disease', (39, 64))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))	('chromosome', 'cellular_component', 'GO:0005694', ('157', '167'))
96351	19843243	While B-Raf and N-Ras mutations, which are mutually exclusive, are predominant in cutaneous melanoma, they are almost completely absent in uveal melanoma.	('N-Ras', 'Gene', '4893', (16, 21))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 100))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('uveal melanoma', 'Disease', 'MESH:C536494', (139, 153))	('B-Raf', 'Gene', (6, 11))	('predominant', 'Reg', (67, 78))	('uveal melanoma', 'Disease', (139, 153))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('B-Raf', 'Gene', '673', (6, 11))	('mutations', 'Var', (22, 31))	('N-Ras', 'Gene', (16, 21))	('cutaneous melanoma', 'Disease', (82, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (82, 100))
96352	19843243	Instead, 46% of uveal melanoma and 83% of blue nevi carry mutations in the GNAQ gene, a Gq protein a-subunit that when mutated in the 209 position has transforming capacity.	('mutations', 'Var', (58, 67))	('blue nevi', 'Phenotype', 'HP:0100814', (42, 51))	('GNAQ', 'Gene', (75, 79))	('transforming capacity', 'CPA', (151, 172))	('uveal melanoma', 'Disease', (16, 30))	('blue nevi', 'Disease', (42, 51))	('uveal melanoma', 'Disease', 'MESH:C536494', (16, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('nevi', 'Phenotype', 'HP:0003764', (47, 51))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('GNAQ', 'Gene', '2776', (75, 79))
96354	19843243	It is possible that progression driven by this genetic variation follows different kinetics from that of B-Raf or N-ras mutation and that it maintains responsiveness to yet unidentified growth suppressive microenvironmental cues.	('responsiveness', 'MPA', (151, 165))	('B-Raf', 'Gene', '673', (105, 110))	('B-Raf', 'Gene', (105, 110))	('genetic variation', 'Var', (47, 64))	('N-ras', 'Gene', '4893', (114, 119))	('N-ras', 'Gene', (114, 119))
96355	19843243	The direct link between the different genetic and epigenetic alterations in melanoma and tumor progression remains elusive.	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('epigenetic alterations', 'Var', (50, 72))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('rat', 'Species', '10116', (65, 68))
96358	19843243	A small study showed an association between the disease-free survival periods with the presence of B-Raf and N-Ras mutations.	('mutations', 'Var', (115, 124))	('association', 'Interaction', (24, 35))	('N-Ras', 'Gene', '4893', (109, 114))	('B-Raf', 'Gene', '673', (99, 104))	('B-Raf', 'Gene', (99, 104))	('N-Ras', 'Gene', (109, 114))
96359	19843243	In this study of around 40 patients, 21% had disease free periods longer than 5 yr and median DFS was 10 yr. Of the patients that showed long disease free periods an impressive 75% had B-Raf mutations (V600E or K601E); none had N-Ras mutations.	('N-Ras', 'Gene', '4893', (228, 233))	('V600E', 'Var', (202, 207))	('long disease', 'Disease', (137, 149))	('patients', 'Species', '9606', (116, 124))	('long disease', 'Disease', 'MESH:D008133', (137, 149))	('B-Raf', 'Gene', (185, 190))	('N-Ras', 'Gene', (228, 233))	('K601E)', 'Var', (211, 217))	('K601E', 'Mutation', 'rs121913364', (211, 216))	('patients', 'Species', '9606', (27, 35))	('B-Raf', 'Gene', '673', (185, 190))	('V600E', 'Mutation', 'rs113488022', (202, 207))
96360	19843243	Three patients (7.9%) bearing V-600E B-raf mutations were free of disease for 13-16.7 yr. Other authors have noticed no effect on DFI in patients with B-Raf mutations.	('B-raf', 'Gene', (37, 42))	('B-Raf', 'Gene', '673', (151, 156))	('patients', 'Species', '9606', (137, 145))	('mutations', 'Var', (157, 166))	('patients', 'Species', '9606', (6, 14))	('B-raf', 'Gene', '673', (37, 42))	('B-Raf', 'Gene', (151, 156))
96361	19843243	Although very limited, this study suggests that even activating mutations, considered to be responsible for cancer progression in oncogene 'addicted' tumors appear to, at least temporarily respond to host-imposed controls.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	("'addicted' tumors", 'Disease', (139, 156))	("'addicted' tumors", 'Disease', 'MESH:D019966', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('mutations', 'Var', (64, 73))	('activating', 'PosReg', (53, 63))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
96362	19843243	Is it possible, as evidenced in patients, that these controls can silence tumor cells with activating mutations for a decade or longer?	('patients', 'Species', '9606', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('silence', 'NegReg', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', (74, 79))
96363	19843243	In conditional transgenic models, oncogene inactivation can induce tumor cell elimination, or terminal differentiation/senescence and, as in case of Myc inactivation in hepatocellular carcinoma, induction of cancer cell dormancy (for review see), suggesting that the outcome might be specific to cellular and genetic context.	('induce', 'PosReg', (60, 66))	('cancer', 'Disease', (208, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('senescence', 'biological_process', 'GO:0010149', ('119', '129'))	('Myc', 'Gene', (149, 152))	('tumor', 'Disease', (67, 72))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (169, 193))	('terminal differentiation/senescence', 'CPA', (94, 129))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('dormancy', 'biological_process', 'GO:0030431', ('220', '228'))	('Myc', 'Gene', '17869', (149, 152))	('terminal differentiation', 'biological_process', 'GO:0048468', ('94', '118'))	('inactivation', 'Var', (43, 55))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('transgenic', 'Species', '10090', (15, 25))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (169, 193))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('oncogene', 'Gene', (34, 42))	('induction', 'Reg', (195, 204))	('hepatocellular carcinoma', 'Disease', (169, 193))
96366	19843243	For example, as already mentioned, in melanoma with mutated B-Raf the activation of ERK was shown to be independent of integrin/matrix engagement.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('ERK', 'Gene', '5594', (84, 87))	('mutated', 'Var', (52, 59))	('B-Raf', 'Gene', (60, 65))	('ERK', 'Gene', (84, 87))	('B-Raf', 'Gene', '673', (60, 65))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('ERK', 'molecular_function', 'GO:0004707', ('84', '87'))	('melanoma', 'Disease', (38, 46))
96368	19843243	Does it mean that once ERK pathway is activated through B-Raf or N-Ras mutation, its activity, and thus melanoma cell proliferation, must continue unabated?	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('rat', 'Species', '10116', (125, 128))	('cell proliferation', 'biological_process', 'GO:0008283', ('113', '131'))	('mutation', 'Var', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('ERK', 'Gene', '5594', (23, 26))	('ERK', 'molecular_function', 'GO:0004707', ('23', '26'))	('ERK', 'Gene', (23, 26))	('N-Ras', 'Gene', '4893', (65, 70))	('activated', 'PosReg', (38, 47))	('B-Raf', 'Gene', '673', (56, 61))	('B-Raf', 'Gene', (56, 61))	('N-Ras', 'Gene', (65, 70))
96370	19843243	It is possible then that, although the mutant B-Raf stimulus to ERK activation is autonomous, the downstream effectors of the pathway might be dependent on the microenvironment and/or epigenetic mechanisms.	('B-Raf', 'Gene', '673', (46, 51))	('ERK', 'Gene', '5594', (64, 67))	('ERK', 'Gene', (64, 67))	('mutant', 'Var', (39, 45))	('B-Raf', 'Gene', (46, 51))	('ERK', 'molecular_function', 'GO:0004707', ('64', '67'))
96371	19843243	For example have shown that expression of B-RafV600E mutant in primary cells leads to synthesis and secretion of IGFBP7, which through autocrine/paracrine pathways inhibits BRAF-MEK-ERK signaling and, by inducing a pro-apoptotic protein BNIP3L, leads to senescence and apoptosis.	('IGFBP7', 'Gene', '3490', (113, 119))	('ERK', 'molecular_function', 'GO:0004707', ('182', '185'))	('IGFBP7', 'Gene', (113, 119))	('apoptosis', 'CPA', (269, 278))	('MEK', 'Gene', '5609', (178, 181))	('synthesis', 'MPA', (86, 95))	('BNIP3L', 'Gene', (237, 243))	('ERK', 'Gene', '5594', (182, 185))	('leads to', 'Reg', (245, 253))	('secretion', 'biological_process', 'GO:0046903', ('100', '109'))	('apoptosis', 'biological_process', 'GO:0097194', ('269', '278'))	('apoptosis', 'biological_process', 'GO:0006915', ('269', '278'))	('B-RafV600E', 'Var', (42, 52))	('MEK', 'Gene', (178, 181))	('inhibits', 'NegReg', (164, 172))	('BRAF', 'Gene', '673', (173, 177))	('BRAF', 'Gene', (173, 177))	('ERK', 'Gene', (182, 185))	('secretion', 'MPA', (100, 109))	('senescence', 'biological_process', 'GO:0010149', ('254', '264'))	('synthesis', 'biological_process', 'GO:0009058', ('86', '95'))	('signaling', 'biological_process', 'GO:0023052', ('186', '195'))	('inducing', 'PosReg', (204, 212))	('BNIP3L', 'Gene', '665', (237, 243))	('protein', 'cellular_component', 'GO:0003675', ('229', '236'))	('senescence', 'CPA', (254, 264))
96374	19843243	B-Raf and GNAQ, in addition to being mutated in melanoma, are also mutated in benign nevi.	('melanoma', 'Disease', (48, 56))	('GNAQ', 'Gene', '2776', (10, 14))	('benign nevi', 'Disease', (78, 89))	('B-Raf', 'Gene', (0, 5))	('GNAQ', 'Gene', (10, 14))	('mutated', 'Var', (67, 74))	('B-Raf', 'Gene', '673', (0, 5))	('nevi', 'Phenotype', 'HP:0003764', (85, 89))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
96376	19843243	In a recently developed mouse model of melanoma conditional activation of mutant B-RafV600E was sufficient to yield melanomas but those formed only after very long latency.	('mouse', 'Species', '10090', (24, 29))	('melanomas', 'Disease', (116, 125))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('melanoma', 'Disease', (116, 124))	('activation', 'PosReg', (60, 70))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('B-RafV600E', 'Gene', (81, 91))	('melanomas', 'Disease', 'MESH:D008545', (116, 125))	('mutant', 'Var', (74, 80))
96378	19843243	PTEN, tumor suppressor, which resides on human chromosome 10q23.3, has been shown to be deleted in a proportion of melanoma cell lines and in a small number of primary melanomas.	('primary melanomas', 'Disease', 'MESH:D008545', (160, 177))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('human', 'Species', '9606', (41, 46))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('deleted', 'Var', (88, 95))	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('PTEN', 'Gene', (0, 4))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('6', '22'))	('tumor', 'Disease', (6, 11))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('primary melanomas', 'Disease', (160, 177))	('tumor suppressor', 'biological_process', 'GO:0051726', ('6', '22'))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('melanomas', 'Phenotype', 'HP:0002861', (168, 177))	('PTEN', 'Gene', '5728', (0, 4))
96379	19843243	Importantly, it was found to be epigenetically silenced by several mechanisms, including by promoter methylation, in nearly 40% of melanoma samples, an event linked to activation of the PI3K/Akt pathway.	('Akt', 'Gene', '207', (191, 194))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('Akt', 'Gene', (191, 194))	('promoter', 'MPA', (92, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('186', '190'))	('methylation', 'biological_process', 'GO:0032259', ('101', '112'))	('epigenetically', 'Var', (32, 46))
96380	19843243	In melanoma, expression of some 50 genes has been shown to be deregulated through aberrant DNA methylation, and/or inappropriate targeting of histone modifications and chromatin remodeling.	('histone', 'Protein', (142, 149))	('DNA methylation', 'biological_process', 'GO:0006306', ('91', '106'))	('expression', 'MPA', (13, 23))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('168', '188'))	('chromatin', 'cellular_component', 'GO:0000785', ('168', '177'))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('DNA', 'Protein', (91, 94))	('deregulated', 'PosReg', (62, 73))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('aberrant', 'Var', (82, 90))
96382	19843243	The silencing of PTEN in melanoma allows for activation of Akt/PKB which in turn, activates the transcription of genes involved in immune activation, cell proliferation, apoptosis and cell survival.	('cell proliferation', 'biological_process', 'GO:0008283', ('150', '168'))	('transcription of genes', 'MPA', (96, 118))	('transcription', 'biological_process', 'GO:0006351', ('96', '109'))	('PTEN', 'Gene', (17, 21))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('apoptosis', 'biological_process', 'GO:0097194', ('170', '179'))	('apoptosis', 'biological_process', 'GO:0006915', ('170', '179'))	('silencing', 'Var', (4, 13))	('Akt', 'Gene', (59, 62))	('PKB', 'Gene', '207', (63, 66))	('cell proliferation', 'CPA', (150, 168))	('PKB', 'Gene', (63, 66))	('activates', 'PosReg', (82, 91))	('Akt', 'Gene', '207', (59, 62))	('PTEN', 'Gene', '5728', (17, 21))	('rat', 'Species', '10116', (162, 165))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))	('activation', 'PosReg', (45, 55))
96389	19843243	Although, in growing melanomas the mutated B-Raf overrides this pathway, its complexity suggests possibilities for control by the microenvironment.	('mutated', 'Var', (35, 42))	('B-Raf', 'Gene', '673', (43, 48))	('B-Raf', 'Gene', (43, 48))	('melanomas', 'Disease', (21, 30))	('overrides', 'PosReg', (49, 58))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))
96394	19843243	It is also conceivable that signals from the microenvironment restore expression of the epigenetically silenced PTEN.	('restore', 'PosReg', (62, 69))	('epigenetically silenced', 'Var', (88, 111))	('expression', 'MPA', (70, 80))	('PTEN', 'Gene', (112, 116))	('PTEN', 'Gene', '5728', (112, 116))
96410	19843243	One exception is the study which found no gene expression patterns that correlate with activating mutations in B-Raf or N-Ras, but instead identified transcriptional signatures specific to 'proliferative' melanoma sensitive, and invasive melanoma resistant to TGFbeta inhibition.	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('melanoma', 'Disease', (238, 246))	('invasive melanoma', 'Disease', (229, 246))	('melanoma', 'Disease', 'MESH:D008545', (238, 246))	('rat', 'Species', '10116', (197, 200))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('melanoma', 'Disease', (205, 213))	('N-Ras', 'Gene', '4893', (120, 125))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('mutations', 'Var', (98, 107))	('invasive melanoma', 'Disease', 'MESH:D008545', (229, 246))	('transcriptional', 'MPA', (150, 165))	('N-Ras', 'Gene', (120, 125))	('gene expression', 'biological_process', 'GO:0010467', ('42', '57'))	("'proliferative", 'PosReg', (189, 203))	('B-Raf', 'Gene', '673', (111, 116))	('B-Raf', 'Gene', (111, 116))
96411	19843243	The proliferative cohort had highly activated Wnt signaling pathway with high SOX10, MITF1 and TFAP.	('SOX10', 'Gene', (78, 83))	('SOX10', 'Gene', '6663', (78, 83))	('TFAP', 'Gene', (95, 99))	('activated', 'PosReg', (36, 45))	('rat', 'Species', '10116', (11, 14))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('46', '67'))	('high', 'Var', (73, 77))	('MITF1', 'Gene', (85, 90))	('Wnt signaling pathway', 'Pathway', (46, 67))
96431	19843243	Other lines of research might need to explore whether there is a difference in the way the microenvironment cross-talks with melanoma cells bearing B-Raf versus N-Ras mutations.	('B-Raf', 'Gene', '673', (148, 153))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('N-Ras', 'Gene', '4893', (161, 166))	('mutations', 'Var', (167, 176))	('N-Ras', 'Gene', (161, 166))	('B-Raf', 'Gene', (148, 153))
96445	28056125	In a critique of the TNM staging system, Burke commented that "carcinogen-esis is not defined by what stage the patient is in at detection but rather by the molecular...characteristics of the tumor and host,"(p1409) and that "the TNM staging system has difficulty dealing with continuous biomarkers and adding new biomarkers.	('TNM', 'Gene', '10178', (230, 233))	('TNM', 'Gene', '10178', (21, 24))	('tumor', 'Disease', (192, 197))	('patient', 'Species', '9606', (112, 119))	('TNM', 'Gene', (21, 24))	('p1409', 'Var', (209, 214))	('TNM', 'Gene', (230, 233))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
96493	33381588	Meanwhile, there was an obvious relationship between the high PRAME expression and the OS of patients with sample sizes of >=100 (HR = 1.49, 95% CI: 1.04-2.15, P < 0.001) and <100 (HR = 2.14, 95% CI: 1.60-2.85, P < 0.001).	('PRAME', 'Gene', '23532', (62, 67))	('PRAME', 'Gene', (62, 67))	('patients', 'Species', '9606', (93, 101))	('<100', 'Var', (175, 179))
96507	33381588	PRAME has been reported to be epigenetically regulated by DNA methylation in malignancies.	('malignancies', 'Disease', (77, 89))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('DNA methylation', 'biological_process', 'GO:0006306', ('58', '73'))	('DNA methylation', 'Var', (58, 73))	('PRAME', 'Gene', '23532', (0, 5))	('PRAME', 'Gene', (0, 5))	('malignancies', 'Disease', 'MESH:D009369', (77, 89))
96511	33381588	Together, these studies show that the PRAME expression is associated with aberrant hypomethylation of the PRAME promoter and may have therapeutic implications.	('associated', 'Reg', (58, 68))	('PRAME', 'Gene', (38, 43))	('hypomethylation', 'MPA', (83, 98))	('PRAME', 'Gene', '23532', (106, 111))	('PRAME', 'Gene', '23532', (38, 43))	('PRAME', 'Gene', (106, 111))	('aberrant', 'Var', (74, 82))
96512	33381588	To note, most of the studies included in this meta-analysis have not identified the association between PRAME promoter DNA hypomethylation and its expression, which warrants further investigations.	('PRAME', 'Gene', '23532', (104, 109))	('expression', 'MPA', (147, 157))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('PRAME', 'Gene', (104, 109))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('119', '138'))	('hypomethylation', 'Var', (123, 138))
96515	33381588	PRAME knockdown was shown to decrease the proliferation of cancer cells.	('decrease', 'NegReg', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('knockdown', 'Var', (6, 15))	('PRAME', 'Gene', '23532', (0, 5))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('PRAME', 'Gene', (0, 5))
96516	33381588	found that PRAME siRNA knockdown significantly suppressed the proliferation, colony formation, and G1 cell cycle arrest in primary osteosarcoma.	('suppressed', 'NegReg', (47, 57))	('arrest', 'Disease', (113, 119))	('formation', 'biological_process', 'GO:0009058', ('84', '93'))	('proliferation', 'CPA', (62, 75))	('PRAME', 'Gene', (11, 16))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('102', '119'))	('knockdown', 'Var', (23, 32))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (102, 119))	('colony formation', 'CPA', (77, 93))	('osteosarcoma', 'Phenotype', 'HP:0002669', (131, 143))	('osteosarcoma', 'Disease', (131, 143))	('arrest', 'Disease', 'MESH:D006323', (113, 119))	('osteosarcoma', 'Disease', 'MESH:D012516', (131, 143))	('PRAME', 'Gene', '23532', (11, 16))
96518	33381588	Downregulation of PRAME suppresses proliferation and promotes apoptosis in hepatocellular carcinoma through the activation of the P53-mediated pathway.	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('promotes', 'PosReg', (53, 61))	('PRAME', 'Gene', '23532', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('PRAME', 'Gene', (18, 23))	('activation', 'PosReg', (112, 122))	('P53', 'Gene', (130, 133))	('proliferation', 'CPA', (35, 48))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('Downregulation', 'Var', (0, 14))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (75, 99))	('apoptosis', 'CPA', (62, 71))	('hepatocellular carcinoma', 'Disease', (75, 99))	('suppresses', 'NegReg', (24, 34))	('P53', 'Gene', '7157', (130, 133))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (75, 99))
96547	32422649	Germline BAP1 mutations are associated with the development of several tumors including renal cell carcinoma, mesothelioma, uveal melanoma, and various other malignancies.	('uveal melanoma', 'Disease', (124, 138))	('uveal melanoma', 'Disease', 'MESH:C536494', (124, 138))	('associated with', 'Reg', (28, 43))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (88, 108))	('tumors', 'Disease', (71, 77))	('BAP1', 'Gene', (9, 13))	('uveal melanoma', 'Phenotype', 'HP:0007716', (124, 138))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('mutations', 'Var', (14, 23))	('malignancies', 'Disease', 'MESH:D009369', (158, 170))	('renal cell carcinoma', 'Disease', (88, 108))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (88, 108))	('mesothelioma', 'Disease', (110, 122))	('malignancies', 'Disease', (158, 170))	('mesothelioma', 'Disease', 'MESH:D008654', (110, 122))	('BAP1', 'Gene', '8314', (9, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
96548	32422649	Somatic BAP1 mutations are frequently associated with various tumors, including metastatic uveal melanomas, small cell lung carcinoma, and malignant mesotheliomas ( et al., 2013; and Testa, 2017).	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('BAP1', 'Gene', '8314', (8, 12))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (139, 162))	('uveal melanomas', 'Disease', 'MESH:C536494', (91, 106))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('associated', 'Reg', (38, 48))	('tumors', 'Disease', (62, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (91, 105))	('malignant mesotheliomas', 'Disease', (139, 162))	('BAP1', 'Gene', (8, 12))	('small cell lung carcinoma', 'Disease', 'MESH:D055752', (108, 133))	('uveal melanomas', 'Disease', (91, 106))	('uveal melanomas', 'Phenotype', 'HP:0007716', (91, 106))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (139, 162))	('mutations', 'Var', (13, 22))	('melanomas', 'Phenotype', 'HP:0002861', (97, 106))	('small cell lung carcinoma', 'Disease', (108, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (108, 133))
96565	32422649	The nPfu-Forte DNA polymerase was used to construct a BAP1 C91S mutant plasmid by site-directed mutagenesis.	('mutagenesis', 'biological_process', 'GO:0006280', ('96', '107'))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('BAP1', 'Gene', '8314', (54, 58))	('C91S', 'Mutation', 'p.C91S', (59, 63))	('BAP1', 'Gene', (54, 58))	('C91S', 'Var', (59, 63))
96567	32422649	The following antibodies were used in this study: anti-BAP1 (sc-28383, Santa Cruz), anti-vimentin (sc-32322, Santa Cruz), anti-E-cadherin (610181, BD Transduction Laboratories), anti-Flag-M2 (F3165, Sigma-Aldrich), and anti-beta-actin (A1978, Sigma-Aldrich).	('vimentin', 'Gene', (89, 97))	('vimentin', 'cellular_component', 'GO:0045098', ('89', '97'))	('Transduction', 'biological_process', 'GO:0009293', ('150', '162'))	('BAP1', 'Gene', (55, 59))	('cadherin', 'molecular_function', 'GO:0008014', ('129', '137'))	('F3165', 'Var', (192, 197))	('E-cadherin', 'Gene', (127, 137))	('E-cadherin', 'Gene', '999', (127, 137))	('vimentin', 'cellular_component', 'GO:0045099', ('89', '97'))	('vimentin', 'Gene', '7431', (89, 97))	('BAP1', 'Gene', '8314', (55, 59))
96581	32422649	The percentage of wound closure area at 17 h (PC3 and DU145) or 20 h (RWPE1) was analyzed using the ImageJ software.	('RWPE1', 'CellLine', 'CVCL:3791', (70, 75))	('PC3', 'Gene', (46, 49))	('DU145', 'Var', (54, 59))	('DU145', 'CellLine', 'CVCL:0105', (54, 59))	('PC3', 'Gene', '7832', (46, 49))
96595	32422649	Kaplan-Meier analysis of a total of 492 patients with prostate cancer showed that patients with high BAP1 expression had worse disease-free survival compared with that of patients with relatively low BAP1 expression (p < 0.01, log-rank test) (Figure 1C).	('prostate cancer', 'Disease', (54, 69))	('patients', 'Species', '9606', (40, 48))	('BAP1', 'Gene', '8314', (101, 105))	('worse', 'NegReg', (121, 126))	('BAP1', 'Gene', '8314', (200, 204))	('patients', 'Species', '9606', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('disease-free survival', 'CPA', (127, 148))	('patients', 'Species', '9606', (171, 179))	('prostate cancer', 'Disease', 'MESH:D011471', (54, 69))	('high', 'Var', (96, 100))	('BAP1', 'Gene', (101, 105))	('expression', 'Var', (106, 116))	('BAP1', 'Gene', (200, 204))	('prostate cancer', 'Phenotype', 'HP:0012125', (54, 69))
96613	32422649	Knockdown of BAP1 also inhibited the expression of MMP2, MMP7, and MMP9 (Figure 2E).	('MMP7', 'Gene', (57, 61))	('BAP1', 'Gene', (13, 17))	('MMP2', 'Gene', (51, 55))	('Knockdown', 'Var', (0, 9))	('inhibited', 'NegReg', (23, 32))	('MMP7', 'Gene', '4316', (57, 61))	('MMP9', 'molecular_function', 'GO:0004229', ('67', '71'))	('MMP2', 'molecular_function', 'GO:0004228', ('51', '55'))	('MMP9', 'Gene', (67, 71))	('MMP2', 'Gene', '4313', (51, 55))	('BAP1', 'Gene', '8314', (13, 17))	('expression', 'MPA', (37, 47))	('MMP9', 'Gene', '4318', (67, 71))	('MMP7', 'molecular_function', 'GO:0004235', ('57', '61'))
96623	32422649	As shown in Figure 4B, BAP1 overexpression increased the proliferation of RWPE1 cells, but BAP1 C91S did not.	('BAP1', 'Gene', (23, 27))	('overexpression', 'Var', (28, 42))	('BAP1', 'Gene', (91, 95))	('RWPE1', 'CellLine', 'CVCL:3791', (74, 79))	('BAP1', 'Gene', '8314', (23, 27))	('increased', 'PosReg', (43, 52))	('proliferation', 'CPA', (57, 70))	('BAP1', 'Gene', '8314', (91, 95))	('C91S', 'Mutation', 'p.C91S', (96, 100))
96625	32422649	However, BAP1 C91S did not induce the invasive and migratory properties in RWPE1 cells.	('C91S', 'Var', (14, 18))	('RWPE1', 'CellLine', 'CVCL:3791', (75, 80))	('BAP1', 'Gene', '8314', (9, 13))	('C91S', 'Mutation', 'p.C91S', (14, 18))	('BAP1', 'Gene', (9, 13))
96628	32422649	However, BAP1 mutation has rarely been identified in prostate cancer (Je et al., 2012).	('prostate cancer', 'Disease', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('BAP1', 'Gene', '8314', (9, 13))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('mutation', 'Var', (14, 22))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('BAP1', 'Gene', (9, 13))
96632	32422649	Additionally, high BAP1 expression in patients was associated with low disease-free survival.	('disease-free survival', 'CPA', (71, 92))	('expression', 'MPA', (24, 34))	('patients', 'Species', '9606', (38, 46))	('BAP1', 'Gene', '8314', (19, 23))	('high', 'Var', (14, 18))	('BAP1', 'Gene', (19, 23))	('low', 'NegReg', (67, 70))
96638	32422649	Further, the inhibition of EMT upon BAP1 knockdown resulted in a decrease in the proliferation, migration, and invasion of PC3 and DU145 cells.	('EMT', 'biological_process', 'GO:0001837', ('27', '30'))	('PC3', 'Gene', '7832', (123, 126))	('migration', 'CPA', (96, 105))	('knockdown', 'Var', (41, 50))	('EMT', 'Gene', (27, 30))	('EMT', 'Gene', '3702', (27, 30))	('DU145', 'CellLine', 'CVCL:0105', (131, 136))	('PC3', 'Gene', (123, 126))	('BAP1', 'Gene', '8314', (36, 40))	('decrease', 'NegReg', (65, 73))	('inhibition', 'NegReg', (13, 23))	('BAP1', 'Gene', (36, 40))	('proliferation', 'CPA', (81, 94))	('invasion', 'CPA', (111, 119))
96643	32422649	Depletion of BAP1 in breast cancer cell lines caused growth inhibition that was dependent on its deubiquitinating activity ( et al., 2009).	('BAP1', 'Gene', (13, 17))	('growth', 'MPA', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('deubiquitinating activity', 'MPA', (97, 122))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('breast cancer', 'Disease', (21, 34))	('Depletion', 'Var', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('BAP1', 'Gene', '8314', (13, 17))
96644	32422649	identified that BAP1 knockdown resulted in inhibition of growth and metastasis of breast cancer cells (Qin et al., 2015).	('Qin', 'Gene', (103, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('metastasis of breast cancer', 'Disease', 'MESH:D001943', (68, 95))	('inhibition', 'NegReg', (43, 53))	('inhibition of growth', 'biological_process', 'GO:0045926', ('43', '63'))	('BAP1', 'Gene', '8314', (16, 20))	('metastasis of breast cancer', 'Disease', (68, 95))	('knockdown', 'Var', (21, 30))	('Qin', 'Gene', '2290', (103, 106))	('BAP1', 'Gene', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
96653	32422649	The TCGA dataset analysis suggested that high BAP1 expression is inversely correlated with disease-free survival in the context of prostate cancers.	('prostate cancers', 'Disease', (131, 147))	('BAP1', 'Gene', '8314', (46, 50))	('high', 'Var', (41, 45))	('prostate cancer', 'Phenotype', 'HP:0012125', (131, 146))	('prostate cancers', 'Disease', 'MESH:D011471', (131, 147))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('inversely', 'NegReg', (65, 74))	('expression', 'MPA', (51, 61))	('BAP1', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('disease-free', 'Disease', (91, 103))	('prostate cancers', 'Phenotype', 'HP:0012125', (131, 147))
96657	32422649	Histone H2A (Lys119) is a target of BAP1 (Scheuermann et al., 2010).	('Histone H2A', 'Protein', (0, 11))	('BAP1', 'Gene', '8314', (36, 40))	('Lys119', 'Chemical', '-', (13, 19))	('Lys119', 'Var', (13, 19))	('BAP1', 'Gene', (36, 40))
96658	32422649	Recently, it has been reported that increase in H2AK119ub on Snail in response to the loss of BAP1 inhibited the transcription of Snail, and thus lead to the induction of MET in clear cell renal cell carcinoma ( et al., 2019).	('transcription', 'MPA', (113, 126))	('Snail', 'Gene', (61, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (178, 209))	('Snail', 'Gene', (130, 135))	('BAP1', 'Gene', '8314', (94, 98))	('loss', 'Var', (86, 90))	('inhibited', 'NegReg', (99, 108))	('increase', 'PosReg', (36, 44))	('lead to', 'Reg', (146, 153))	('H2AK119ub', 'Var', (48, 57))	('induction', 'Reg', (158, 167))	('Snail', 'Gene', '6615', (61, 66))	('H2AK119ub', 'Chemical', '-', (48, 57))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (178, 209))	('BAP1', 'Gene', (94, 98))	('transcription', 'biological_process', 'GO:0006351', ('113', '126'))	('Snail', 'Gene', '6615', (130, 135))	('MET', 'Disease', (171, 174))	('clear cell renal cell carcinoma', 'Disease', (178, 209))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (189, 209))
96659	32422649	In the present study, we also confirmed the downregulation of Snail in prostate cancer cells upon BAP1 knockdown.	('BAP1', 'Gene', (98, 102))	('prostate cancer', 'Disease', (71, 86))	('downregulation', 'NegReg', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('prostate cancer', 'Disease', 'MESH:D011471', (71, 86))	('Snail', 'Gene', (62, 67))	('BAP1', 'Gene', '8314', (98, 102))	('Snail', 'Gene', '6615', (62, 67))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))	('knockdown', 'Var', (103, 112))
96761	28573105	The uveal tract is composed of iris, ciliary body, and choroid, with uveal melanoma developing in any of these parts, after mutations in the melanocytes of this layer.	('uvea', 'Disease', (69, 73))	('iris', 'Disease', 'MESH:D007499', (31, 35))	('uvea', 'Disease', 'MESH:C536494', (4, 8))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('uveal melanoma', 'Disease', (69, 83))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('uvea', 'Disease', 'MESH:C536494', (69, 73))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('iris', 'Disease', (31, 35))	('mutations in', 'Var', (124, 136))	('uvea', 'Disease', (4, 8))
96771	28573105	It is known that uveal melanoma does not have a high frequency of BRAF mutations.	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))	('mutations', 'Var', (71, 80))	('BRAF', 'Gene', '673', (66, 70))	('BRAF', 'Gene', (66, 70))	('uveal melanoma', 'Disease', (17, 31))	('uveal melanoma', 'Disease', 'MESH:C536494', (17, 31))
96772	28573105	By contrast, mutations in GNAQ or GNA11 (G protein subunit coders) are expressed in about 80% of the cases, being responsible by the cascade of MAPK pathway activation.	('MAPK', 'molecular_function', 'GO:0004707', ('144', '148'))	('GNAQ', 'Gene', (26, 30))	('GNA11', 'Gene', '2767', (34, 39))	('GNA11', 'Gene', (34, 39))	('activation', 'PosReg', (157, 167))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('mutations', 'Var', (13, 22))	('GNAQ', 'Gene', '2776', (26, 30))	('responsible', 'Reg', (114, 125))	('MAPK pathway', 'Pathway', (144, 156))
96773	28573105	Genetic determinant prognostic changes include mutations of BRCA1-associated protein:present in 84% of metastatic cases.	('BRCA1-associated protein', 'Gene', (60, 84))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('BRCA1-associated protein', 'Gene', '8315', (60, 84))	('mutations', 'Var', (47, 56))
96774	28573105	A good prognosis has been associated with mutations in the SF3B1 gene, present in 18.6% of primary uveal melanomas.	('uveal melanomas', 'Disease', (99, 114))	('uveal melanomas', 'Phenotype', 'HP:0007716', (99, 114))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('SF3B1', 'Gene', (59, 64))	('uveal melanomas', 'Disease', 'MESH:C536494', (99, 114))	('melanomas', 'Phenotype', 'HP:0002861', (105, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('SF3B1', 'Gene', '23451', (59, 64))	('mutations', 'Var', (42, 51))
96786	28573105	When treated with ocular globe irradiation, the subsequent onset of metastasis reaches 23-50%, depending on prognostic factors involved, i.e., increased tumor diameter, extrascleral extension, ciliary body involvement, advanced age, iris color, tumor pigmentation, symptomatic disease, and chromosomal monosomy 3.	('increased', 'PosReg', (143, 152))	('tumor pigmentation', 'Disease', 'MESH:D010859', (245, 263))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('chromosomal monosomy 3', 'Var', (290, 312))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('iris', 'Disease', (233, 237))	('tumor', 'Disease', (245, 250))	('iris', 'Disease', 'MESH:D007499', (233, 237))	('pigmentation', 'biological_process', 'GO:0043473', ('251', '263'))	('tumor pigmentation', 'Disease', (245, 263))
96807	28573105	Although uveal melanoma does not express direct changes in the BRAF gene (rendering its indication of vemurafenib and dabrafenib unfeasible), it has mutations in the GNAQ or GNA11 (G protein subunit encoding) genes within 80% of cases.	('vemurafenib', 'Chemical', 'MESH:D000077484', (102, 113))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('mutations', 'Var', (149, 158))	('dabrafenib', 'Chemical', 'MESH:C561627', (118, 128))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (9, 23))	('uveal melanoma', 'Disease', (9, 23))	('uveal melanoma', 'Disease', 'MESH:C536494', (9, 23))	('GNA11', 'Gene', (174, 179))	('GNAQ', 'Gene', '2776', (166, 170))	('GNA11', 'Gene', '2767', (174, 179))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', (63, 67))	('GNAQ', 'Gene', (166, 170))
96813	28573105	Another possibility that arises is the association of MEK and AKT double inhibition (whose phosphorylation is observed in >50% of uveal melanomas).	('MEK', 'Gene', '5609', (54, 57))	('uveal melanomas', 'Phenotype', 'HP:0007716', (130, 145))	('AKT', 'Gene', (62, 65))	('double', 'Var', (66, 72))	('uveal melanomas', 'Disease', (130, 145))	('uveal melanomas', 'Disease', 'MESH:C536494', (130, 145))	('melanomas', 'Phenotype', 'HP:0002861', (136, 145))	('uveal melanoma', 'Phenotype', 'HP:0007716', (130, 144))	('phosphorylation', 'biological_process', 'GO:0016310', ('91', '106'))	('AKT', 'Gene', '207', (62, 65))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('MEK', 'Gene', (54, 57))
96814	28573105	GNAQ and GNA11 lead mutations generate an upregulation of MET factor (related to the appearance of liver metastasis by uveal melanoma).	('GNA11', 'Gene', (9, 14))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('GNAQ', 'Gene', '2776', (0, 4))	('GNAQ', 'Gene', (0, 4))	('uveal melanoma', 'Disease', 'MESH:C536494', (119, 133))	('uveal melanoma', 'Phenotype', 'HP:0007716', (119, 133))	('MET factor', 'Protein', (58, 68))	('uveal melanoma', 'Disease', (119, 133))	('mutations', 'Var', (20, 29))	('upregulation', 'PosReg', (42, 54))	('GNA11', 'Gene', '2767', (9, 14))
96828	28138035	Targeting HGF-cMET signaling with LY2875358, a neutralizing and internalizing anti-cMET bivalent antibody, and LY2801653, a dual cMET/RON inhibitor, overcomes resistance to trametinib provided by exogenous HGF and by conditioned medium from primary hepatic stellate cells.	('antibody', 'cellular_component', 'GO:0019814', ('97', '105'))	('LY2875358', 'Chemical', 'MESH:C000599789', (34, 43))	('HGF', 'Gene', '3082', (10, 13))	('cMET', 'Gene', '4233', (83, 87))	('trametinib', 'Chemical', 'MESH:C560077', (173, 183))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('antibody', 'molecular_function', 'GO:0003823', ('97', '105'))	('HGF', 'Gene', (10, 13))	('cMET', 'Gene', '4233', (129, 133))	('LY2875358', 'Var', (34, 43))	('RON', 'Gene', (134, 137))	('HGF', 'Gene', '3082', (206, 209))	('antibody', 'cellular_component', 'GO:0042571', ('97', '105'))	('LY2801653', 'Var', (111, 120))	('RON', 'Gene', '4486', (134, 137))	('cMET', 'Gene', (14, 18))	('HGF', 'Gene', (206, 209))	('LY2801653', 'Chemical', 'MESH:C586252', (111, 120))	('overcomes', 'NegReg', (149, 158))	('antibody', 'cellular_component', 'GO:0019815', ('97', '105'))	('resistance', 'MPA', (159, 169))	('cMET', 'Gene', (83, 87))	('cMET', 'Gene', (129, 133))	('cMET', 'Gene', '4233', (14, 18))
96830	28138035	Combination of LY2801653 with trametinib decreases AKT phosphorylation and promotes pro-apoptotic PARP cleavage in metastatic UM explants.	('PARP', 'Gene', '1302', (98, 102))	('phosphorylation', 'biological_process', 'GO:0016310', ('55', '70'))	('trametinib', 'Chemical', 'MESH:C560077', (30, 40))	('PARP', 'Gene', (98, 102))	('LY2801653', 'Var', (15, 24))	('decreases', 'NegReg', (41, 50))	('promotes', 'PosReg', (75, 83))	('AKT', 'Gene', (51, 54))	('LY2801653', 'Chemical', 'MESH:C586252', (15, 24))	('UM', 'Phenotype', 'HP:0007716', (126, 128))	('AKT', 'Gene', '207', (51, 54))
96831	28138035	Together, our data support the notion that selectively blocking cMET signaling or PI3K isoforms in metastatic UM may break the intrinsic resistance to MEK inhibitors provided by factors from stromal cells in liver.	('PI3K', 'Var', (82, 86))	('break', 'NegReg', (117, 122))	('blocking', 'NegReg', (55, 63))	('MEK', 'Gene', (151, 154))	('metastatic UM', 'CPA', (99, 112))	('UM', 'Phenotype', 'HP:0007716', (110, 112))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('MEK', 'Gene', '5609', (151, 154))	('signaling', 'biological_process', 'GO:0023052', ('69', '78'))	('cMET', 'Gene', '4233', (64, 68))	('cMET', 'Gene', (64, 68))
96835	28138035	Activating mutations in GNAQ and GNA11 (typically Q209 and less commonly R183), which encode alpha subunits of the heterotrimeric G proteins, Galphaq and Galpha11, are found in 80-90% of UM.	('GNAQ', 'Gene', '2776', (24, 28))	('GNA11', 'Gene', (33, 38))	('GNA11', 'Gene', '2767', (33, 38))	('UM', 'Phenotype', 'HP:0007716', (187, 189))	('GNAQ', 'Gene', (24, 28))	('Galphaq', 'Gene', (142, 149))	('Galphaq', 'Gene', '2776', (142, 149))	('Galpha11', 'Gene', (154, 162))	('Galpha11', 'Gene', '2767', (154, 162))	('Q209', 'Var', (50, 54))
96836	28138035	Silencing GNAQ induces apoptosis in mutant but not wild-type UM cells.	('induces', 'Reg', (15, 22))	('GNAQ', 'Gene', '2776', (10, 14))	('apoptosis', 'CPA', (23, 32))	('apoptosis', 'biological_process', 'GO:0097194', ('23', '32'))	('GNAQ', 'Gene', (10, 14))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('mutant', 'Var', (36, 42))	('apoptosis', 'biological_process', 'GO:0006915', ('23', '32'))	('Silencing', 'Var', (0, 9))
96837	28138035	Mutant Galphaq and Galpha11 activate phospholipase C-beta (PLC-beta), which regulates several pathways including MEK-ERK1/2 and protein kinase C (PKC) signaling.	('Galphaq', 'Gene', (7, 14))	('C-beta', 'Species', '10703', (61, 67))	('Galphaq', 'Gene', '2776', (7, 14))	('MEK', 'Gene', '5609', (113, 116))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('PKC', 'molecular_function', 'GO:0004697', ('146', '149'))	('PLC', 'cellular_component', 'GO:0042824', ('59', '62'))	('phospholipase C-beta', 'Enzyme', (37, 57))	('activate', 'PosReg', (28, 36))	('Galpha11', 'Gene', (19, 27))	('ERK1', 'molecular_function', 'GO:0004707', ('117', '121'))	('C-beta', 'Species', '10703', (51, 57))	('Galpha11', 'Gene', '2767', (19, 27))	('PLC-beta', 'Gene', (59, 67))	('regulates', 'Reg', (76, 85))	('signaling', 'biological_process', 'GO:0023052', ('151', '160'))	('Mutant', 'Var', (0, 6))	('MEK', 'Gene', (113, 116))
96839	28138035	In UM, GNAQ and GNA11 mutations occur early in disease progression; however, additional alterations are required.	('GNA11', 'Gene', (16, 21))	('GNAQ', 'Gene', '2776', (7, 11))	('GNA11', 'Gene', '2767', (16, 21))	('mutations', 'Var', (22, 31))	('GNAQ', 'Gene', (7, 11))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
96840	28138035	Mutations in the tumor-suppressor BRCA1-associated protein 1 (BAP1) on chromosome 3 are found in 32-50% of primary melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('17', '33'))	('BAP1', 'Gene', '8314', (62, 66))	('BRCA1-associated protein 1', 'Gene', '8314', (34, 60))	('tumor', 'Disease', (17, 22))	('melanomas', 'Disease', 'MESH:D008545', (115, 124))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('BRCA1-associated protein 1', 'Gene', (34, 60))	('found', 'Reg', (88, 93))	('BAP1', 'Gene', (62, 66))	('Mutations', 'Var', (0, 9))	('melanomas', 'Disease', (115, 124))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('chromosome', 'cellular_component', 'GO:0005694', ('71', '81'))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('17', '33'))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
96841	28138035	BAP1 mutations associate with aggressive disease and higher likelihood of metastasis.	('BAP1', 'Gene', (0, 4))	('aggressive disease', 'Disease', 'MESH:D001523', (30, 48))	('mutations', 'Var', (5, 14))	('metastasis', 'CPA', (74, 84))	('aggressive disease', 'Disease', (30, 48))	('BAP1', 'Gene', '8314', (0, 4))
96842	28138035	Silencing BAP1 in primary UM cell lines results in a gain of stem-like properties with little/no effect on proliferation and invasion.	('BAP1', 'Gene', (10, 14))	('stem-like properties', 'CPA', (61, 81))	('UM', 'Phenotype', 'HP:0007716', (26, 28))	('gain', 'PosReg', (53, 57))	('Silencing', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (10, 14))
96843	28138035	Additional genes mutated in UM are SF3B1 and EIF1AX, which associate with a favorable prognosis, PLCB4 and CYSLTR2.	('PLCB4', 'Gene', (97, 102))	('SF3B1', 'Gene', '23451', (35, 40))	('UM', 'Phenotype', 'HP:0007716', (28, 30))	('EIF1AX', 'Gene', '1964', (45, 51))	('CYSLTR2', 'Gene', '57105', (107, 114))	('PLCB4', 'Gene', '5332', (97, 102))	('CYSLTR2', 'Gene', (107, 114))	('SF3B1', 'Gene', (35, 40))	('EIF1AX', 'Gene', (45, 51))	('mutated', 'Var', (17, 24))
96844	28138035	A major effector pathway downstream of mutant Galphaq and Galpha11 is RAF-MEK1/2-ERK1/2 signaling.	('Galpha11', 'Gene', '2767', (58, 66))	('signaling', 'biological_process', 'GO:0023052', ('88', '97'))	('RAF', 'Gene', '22882', (70, 73))	('RAF', 'Gene', (70, 73))	('Galphaq', 'Gene', (46, 53))	('MEK1/2', 'Gene', '5604;5605', (74, 80))	('mutant', 'Var', (39, 45))	('Galphaq', 'Gene', '2776', (46, 53))	('MEK1/2', 'Gene', (74, 80))	('Galpha11', 'Gene', (58, 66))	('ERK1', 'molecular_function', 'GO:0004707', ('81', '85'))	('MEK1', 'molecular_function', 'GO:0004708', ('74', '78'))
96845	28138035	Inhibition of MEK1/2 with trametinib or selumetinib induces either cell cycle arrest or apoptosis in UM cell lines; however, clinical studies in advanced stage UM patients indicate that MEK inhibitors have limited clinical benefit.	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('MEK1', 'molecular_function', 'GO:0004708', ('14', '18'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (67, 84))	('UM', 'Phenotype', 'HP:0007716', (101, 103))	('MEK', 'Gene', '5609', (14, 17))	('arrest', 'Disease', (78, 84))	('MEK1/2', 'Gene', '5604;5605', (14, 20))	('MEK1/2', 'Gene', (14, 20))	('MEK', 'Gene', (14, 17))	('MEK', 'Gene', '5609', (186, 189))	('patients', 'Species', '9606', (163, 171))	('UM', 'Phenotype', 'HP:0007716', (160, 162))	('arrest', 'Disease', 'MESH:D006323', (78, 84))	('selumetinib', 'Chemical', 'MESH:C517975', (40, 51))	('Inhibition', 'Var', (0, 10))	('induces', 'Reg', (52, 59))	('MEK', 'Gene', (186, 189))	('apoptosis', 'CPA', (88, 97))	('trametinib', 'Chemical', 'MESH:C560077', (26, 36))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('67', '84'))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))
96853	28138035	Consistent with the presence of HGF in tumor microenvironment, the majority of UM liver metastases express phosphorylated/activated cMET.	('cMET', 'Gene', '4233', (132, 136))	('metastases', 'Disease', (88, 98))	('cMET', 'Gene', (132, 136))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('metastases', 'Disease', 'MESH:D009362', (88, 98))	('tumor', 'Disease', (39, 44))	('HGF', 'Gene', (32, 35))	('phosphorylated/activated', 'Var', (107, 131))	('HGF', 'Gene', '3082', (32, 35))
96859	28138035	Together, these data provide a pre-clinical basis for combinational therapies targeting mutant Galphaq/11 signaling and signaling initiated by factors from tumor microenvironment in advanced-stage UM patients.	('patients', 'Species', '9606', (200, 208))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('UM', 'Phenotype', 'HP:0007716', (197, 199))	('mutant', 'Var', (88, 94))	('pre', 'molecular_function', 'GO:0003904', ('31', '34'))	('tumor', 'Disease', (156, 161))	('Galphaq', 'Gene', (95, 102))	('Galphaq', 'Gene', '2776', (95, 102))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))
96865	28138035	UM001 and UM004 cells were confirmed as harboring GNAQ mutations as determined by Sanger DNA sequencing.	('UM', 'Phenotype', 'HP:0007716', (10, 12))	('mutations', 'Var', (55, 64))	('GNAQ', 'Gene', '2776', (50, 54))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('GNAQ', 'Gene', (50, 54))
96867	28138035	Trametinib (GSK1120212), MK2206 (PubChem compound database (CID, 24964624)), GDC0032, TGX221, BYL710 and IPI145 were purchased from Selleck Chemicals (Houston, TX).	('GSK1120212', 'Var', (12, 22))	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('GDC0032', 'Chemical', 'MESH:C582924', (77, 84))	('GSK1120212', 'Chemical', 'MESH:C560077', (12, 22))	('MK2206', 'Chemical', 'MESH:C548887', (25, 31))	('CID', 'Disease', (60, 63))	('CID', 'Disease', 'None', (60, 63))	('GSK', 'molecular_function', 'GO:0050321', ('12', '15'))	('TGX221', 'Chemical', 'MESH:C504718', (86, 92))	('IPI145', 'Chemical', 'MESH:C586691', (105, 111))
96869	28138035	The neutralizing and internalizing anti-cMET antibody, LY2875358, and the cMET/RON inhibitor, LY2801653, were provided by Eli Lilly and Company (Indianapolis, IN).	('antibody', 'cellular_component', 'GO:0019815', ('45', '53'))	('LY2875358', 'Var', (55, 64))	('LY2801653', 'Chemical', 'MESH:C586252', (94, 103))	('RON', 'Gene', '4486', (79, 82))	('antibody', 'cellular_component', 'GO:0019814', ('45', '53'))	('antibody', 'molecular_function', 'GO:0003823', ('45', '53'))	('cMET', 'Gene', '4233', (40, 44))	('cMET', 'Gene', '4233', (74, 78))	('cMET', 'Gene', (40, 44))	('cMET', 'Gene', (74, 78))	('antibody', 'cellular_component', 'GO:0042571', ('45', '53'))	('LY2875358', 'Chemical', 'MESH:C000599789', (55, 64))	('RON', 'Gene', (79, 82))	('LY2801653', 'Var', (94, 103))
96903	28138035	MEK inhibition increased expression of the apoptotic markers, cleaved PARP and cleaved caspase 3.	('MEK', 'Gene', (0, 3))	('expression', 'MPA', (25, 35))	('MEK', 'Gene', '5609', (0, 3))	('PARP', 'Gene', '1302', (70, 74))	('increased', 'PosReg', (15, 24))	('inhibition', 'Var', (4, 14))	('PARP', 'Gene', (70, 74))	('cleaved', 'MPA', (62, 69))	('cleaved', 'MPA', (79, 86))
96910	28138035	HGF promoted the phosphorylation of AKT in the presence of trametinib, an effect that was diminished by MK2206 (Fig 2A).	('phosphorylation', 'biological_process', 'GO:0016310', ('17', '32'))	('AKT', 'Gene', '207', (36, 39))	('HGF', 'Gene', (0, 3))	('phosphorylation', 'MPA', (17, 32))	('promoted', 'PosReg', (4, 12))	('MK2206', 'Chemical', 'MESH:C548887', (104, 110))	('HGF', 'Gene', '3082', (0, 3))	('trametinib', 'Chemical', 'MESH:C560077', (59, 69))	('AKT', 'Gene', (36, 39))	('trametinib', 'Var', (59, 69))
96918	28138035	Individual knockdown of Bim-EL and Bmf each partially rescued cells from trametinib with cell viability inhibited by 32-39%; however, simultaneous silencing of Bim-EL and Bmf further restored the viability of trametinib-treated cells with cell growth decreased by ~26% of the control (Fig 2C).	('cell growth', 'biological_process', 'GO:0016049', ('239', '250'))	('Bmf', 'Gene', (171, 174))	('trametinib', 'Chemical', 'MESH:C560077', (209, 219))	('Bim-EL', 'Gene', (160, 166))	('Bmf', 'Gene', '90427', (171, 174))	('Bmf', 'Gene', (35, 38))	('Bim-EL', 'Chemical', '-', (160, 166))	('restored', 'PosReg', (183, 191))	('viability', 'MPA', (196, 205))	('trametinib', 'Chemical', 'MESH:C560077', (73, 83))	('Bmf', 'Gene', '90427', (35, 38))	('Bim-EL', 'Chemical', '-', (24, 30))	('silencing', 'Var', (147, 156))
96919	28138035	To examine whether Bim-EL and Bmf are sufficient to promote UM cell apoptosis, UM001 and UM004 cells were infected with adenoviruses to express Bim-EL, Bmf and enhanced green fluorescence protein (eGFP), as a control.	('Bmf', 'Gene', (30, 33))	('Bmf', 'Gene', '90427', (152, 155))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('Bmf', 'Gene', '90427', (30, 33))	('UM', 'Phenotype', 'HP:0007716', (89, 91))	('apoptosis', 'biological_process', 'GO:0097194', ('68', '77'))	('Bmf', 'Gene', (152, 155))	('Bim-EL', 'Chemical', '-', (19, 25))	('Bim-EL', 'Var', (144, 150))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('UM cell apoptosis', 'CPA', (60, 77))	('apoptosis', 'biological_process', 'GO:0006915', ('68', '77'))	('Bim-EL', 'Chemical', '-', (144, 150))	('enhanced', 'PosReg', (160, 168))
96923	28138035	Of these two agents, LY2801653 is a type II kinase inhibitor with cMET as one of its target and displays anti-tumor activity in non-small cell lung carcinoma and cholangiocarcinoma preclinical models.	('cMET', 'Gene', '4233', (66, 70))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (138, 157))	('cMET', 'Gene', (66, 70))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (128, 157))	('cholangiocarcinoma', 'Disease', (162, 180))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('44', '60'))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('LY2801653', 'Var', (21, 30))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (162, 180))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (132, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (162, 180))	('cell lung carcinoma', 'Disease', (138, 157))	('LY2801653', 'Chemical', 'MESH:C586252', (21, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
96924	28138035	LY2875358 is a neutralizing and internalizing anti-cMET bivalent antibody that showed potent anti-tumor activity in both HGF-dependent and cMET amplified preclinical tumor models.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('antibody', 'cellular_component', 'GO:0042571', ('65', '73'))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('LY2875358', 'Chemical', 'MESH:C000599789', (0, 9))	('cMET', 'Gene', '4233', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', (166, 171))	('antibody', 'cellular_component', 'GO:0019815', ('65', '73'))	('cMET', 'Gene', (139, 143))	('HGF', 'Gene', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('LY2875358', 'Var', (0, 9))	('antibody', 'cellular_component', 'GO:0019814', ('65', '73'))	('antibody', 'molecular_function', 'GO:0003823', ('65', '73'))	('tumor', 'Disease', (98, 103))	('cMET', 'Gene', '4233', (51, 55))	('HGF', 'Gene', '3082', (121, 124))	('cMET', 'Gene', (51, 55))
96925	28138035	Initially, UM001 and UM004 cells were treated with increasing doses of LY2801653 and LY2875358 followed by HGF stimulation.	('LY2801653', 'Var', (71, 80))	('UM', 'Phenotype', 'HP:0007716', (11, 13))	('LY2801653', 'Chemical', 'MESH:C586252', (71, 80))	('LY2875358', 'Chemical', 'MESH:C000599789', (85, 94))	('LY2875358', 'Var', (85, 94))	('HGF', 'Gene', (107, 110))	('UM', 'Phenotype', 'HP:0007716', (21, 23))	('HGF', 'Gene', '3082', (107, 110))
96927	28138035	Phosphorylation at tyrosine 1349 in the cMET cytoplasmic domain provides a direct binding site for Gab1, which promotes AKT pathway activation.	('AKT', 'Gene', (120, 123))	('activation', 'PosReg', (132, 142))	('binding', 'molecular_function', 'GO:0005488', ('82', '89'))	('Gab1', 'Gene', (99, 103))	('Phosphorylation', 'Var', (0, 15))	('cMET', 'Gene', '4233', (40, 44))	('tyrosine', 'Chemical', 'MESH:D014443', (19, 27))	('cMET', 'Gene', (40, 44))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('promotes', 'PosReg', (111, 119))	('AKT', 'Gene', '207', (120, 123))	('Gab1', 'Gene', '2549', (99, 103))	('binding', 'Interaction', (82, 89))
96928	28138035	Of note, LY2875358 had minimal effect on HGF-induced phosphorylation of cMET at tyrosine 1234/5 (Fig 3A and 3B), critical sites for kinase activation.	('LY2875358', 'Var', (9, 18))	('cMET', 'Gene', '4233', (72, 76))	('cMET', 'Gene', (72, 76))	('tyrosine', 'Chemical', 'MESH:D014443', (80, 88))	('HGF', 'Gene', (41, 44))	('HGF', 'Gene', '3082', (41, 44))	('phosphorylation', 'MPA', (53, 68))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))	('LY2875358', 'Chemical', 'MESH:C000599789', (9, 18))
96930	28138035	LY2801653 alone did not significantly alter UM001 and UM004 cell growth at 100 nM; however, growth of trametinib-treated UM cells which decreased by ~57% compared to the vehicle control was further inhibited when treated with LY2801653 (Fig 3B).	('UM', 'Phenotype', 'HP:0007716', (121, 123))	('growth', 'MPA', (92, 98))	('trametinib', 'Chemical', 'MESH:C560077', (102, 112))	('cell growth', 'biological_process', 'GO:0016049', ('60', '71'))	('LY2801653', 'Var', (226, 235))	('LY2801653', 'Chemical', 'MESH:C586252', (0, 9))	('LY2801653', 'Chemical', 'MESH:C586252', (226, 235))	('UM', 'Phenotype', 'HP:0007716', (54, 56))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('inhibited', 'NegReg', (198, 207))
96932	28138035	Importantly, HGF-mediated growth protection from trametinib treatment was abrogated by LY2801653 (Fig 3B).	('HGF', 'Gene', (13, 16))	('growth protection', 'CPA', (26, 43))	('HGF', 'Gene', '3082', (13, 16))	('abrogated', 'NegReg', (74, 83))	('trametinib', 'Chemical', 'MESH:C560077', (49, 59))	('LY2801653', 'Var', (87, 96))	('LY2801653', 'Chemical', 'MESH:C586252', (87, 96))
96933	28138035	Similarly, LY2875358 alone had little effects on UM001 and UM004 cell growth.	('UM', 'Phenotype', 'HP:0007716', (49, 51))	('cell growth', 'biological_process', 'GO:0016049', ('65', '76'))	('UM001', 'CPA', (49, 54))	('LY2875358', 'Chemical', 'MESH:C000599789', (11, 20))	('LY2875358', 'Var', (11, 20))	('UM', 'Phenotype', 'HP:0007716', (59, 61))
96934	28138035	Although LY2875358 did not further inhibit growth of trametinib-treated cells, LY2875358 blocked HGF-mediated protection from trametinib (Fig 3C).	('trametinib', 'Chemical', 'MESH:C560077', (126, 136))	('blocked', 'NegReg', (89, 96))	('LY2875358', 'Chemical', 'MESH:C000599789', (79, 88))	('HGF', 'Gene', (97, 100))	('LY2875358', 'Var', (79, 88))	('HGF', 'Gene', '3082', (97, 100))	('trametinib', 'Chemical', 'MESH:C560077', (53, 63))	('LY2875358', 'Chemical', 'MESH:C000599789', (9, 18))
96935	28138035	The viability of trametinib-treated UM001 and UM004 cells was increased to levels similar to the vehicle control when cells were treated with HGF; an effect that was decreased with LY2875358 by 44% in UM001 and 25% in UM004 compared to vehicle control (Fig 3C).	('increased', 'PosReg', (62, 71))	('viability', 'CPA', (4, 13))	('trametinib', 'Chemical', 'MESH:C560077', (17, 27))	('UM', 'Phenotype', 'HP:0007716', (201, 203))	('UM', 'Phenotype', 'HP:0007716', (218, 220))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('LY2875358', 'Chemical', 'MESH:C000599789', (181, 190))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('LY2875358', 'Var', (181, 190))	('HGF', 'Gene', (142, 145))	('HGF', 'Gene', '3082', (142, 145))
96947	28138035	Importantly, stellate cell conditioned medium protection to trametinib was restored by LY2875358 and LY2801653, with LY2801653 being more potent in sensitizing UM cells (85-90% reduction in cell viability compared to the vehicle control).	('LY2801653', 'Chemical', 'MESH:C586252', (117, 126))	('LY2801653', 'Chemical', 'MESH:C586252', (101, 110))	('trametinib', 'Chemical', 'MESH:C560077', (60, 70))	('reduction', 'NegReg', (177, 186))	('sensitizing', 'MPA', (148, 159))	('UM', 'Phenotype', 'HP:0007716', (160, 162))	('LY2875358', 'Chemical', 'MESH:C000599789', (87, 96))	('LY2801653', 'Var', (117, 126))	('LY2875358', 'Var', (87, 96))	('LY2801653', 'Var', (101, 110))
96948	28138035	This suggests that LY2801653 is a more effective cMET inhibitor and/or signaling molecules other than cMET may play a role in response to trametinib in UM cells (Fig 4C).	('play', 'Reg', (111, 115))	('cMET', 'Gene', (49, 53))	('signaling', 'biological_process', 'GO:0023052', ('71', '80'))	('cMET', 'Gene', '4233', (49, 53))	('LY2801653', 'Chemical', 'MESH:C586252', (19, 28))	('UM', 'Phenotype', 'HP:0007716', (152, 154))	('response', 'MPA', (126, 134))	('cMET', 'Gene', '4233', (102, 106))	('trametinib', 'Chemical', 'MESH:C560077', (138, 148))	('cMET', 'Gene', (102, 106))	('LY2801653', 'Var', (19, 28))
96951	28138035	We utilized PI3K isoform specific inhibitors: GDC0032 is a PI3Kbeta-sparing isoform inhibitor targeting PI3Kalpha/delta/gamma; TGX221 is a p110beta-specific inhibitor; BYL719 is a selective PI3Kalpha inhibitor; and IPI145 is a selective PI3K delta/gamma inhibitor.	('PI3Kalpha', 'Gene', (104, 113))	('PI3Kalpha', 'Gene', (190, 199))	('PI3Kalpha/delta/gamma', 'Gene', (104, 125))	('IPI145', 'Chemical', 'MESH:C586691', (215, 221))	('PI3Kbeta', 'Gene', (59, 67))	('TGX221', 'Var', (127, 133))	('PI3Kbeta', 'Gene', '5291', (59, 67))	('GDC0032', 'Chemical', 'MESH:C582924', (46, 53))	('PI3K delta', 'Gene', (237, 247))	('PI3Kalpha', 'Gene', '5290', (104, 113))	('PI3Kalpha', 'Gene', '5290', (190, 199))	('p110', 'Gene', (139, 143))	('GDC0032', 'Gene', (46, 53))	('PI3K', 'molecular_function', 'GO:0016303', ('237', '241'))	('BYL719', 'Var', (168, 174))	('PI3K', 'molecular_function', 'GO:0016303', ('12', '16'))	('p110', 'Gene', '100616443', (139, 143))	('TGX221', 'Chemical', 'MESH:C504718', (127, 133))	('PI3Kalpha/delta/gamma', 'Gene', '5290', (104, 125))	('PI3K delta', 'Gene', '5293', (237, 247))
96955	28138035	PI3Kalpha inhibitor BYL719 and PI3K delta/gamma inhibitor IPI145 significantly inhibited HGF-mediated AKT phosphorylation at 500 nM, whereas the PI3Kbeta specific inhibitor TGX221 did not block AKT phosphorylation even at 2.5 microM (Fig 5A, Suppl.	('PI3K delta', 'Gene', '5293', (31, 41))	('AKT', 'Gene', '207', (194, 197))	('TGX221', 'Chemical', 'MESH:C504718', (173, 179))	('HGF', 'Gene', '3082', (89, 92))	('BYL719', 'Var', (20, 26))	('AKT', 'Gene', (102, 105))	('HGF', 'Gene', (89, 92))	('PI3K', 'molecular_function', 'GO:0016303', ('31', '35'))	('PI3Kalpha', 'Gene', '5290', (0, 9))	('phosphorylation', 'biological_process', 'GO:0016310', ('106', '121'))	('PI3Kbeta', 'Gene', (145, 153))	('PI3K delta', 'Gene', (31, 41))	('AKT', 'Gene', (194, 197))	('AKT', 'Gene', '207', (102, 105))	('inhibited', 'NegReg', (79, 88))	('IPI145', 'Chemical', 'MESH:C586691', (58, 64))	('phosphorylation', 'biological_process', 'GO:0016310', ('198', '213'))	('PI3Kbeta', 'Gene', '5291', (145, 153))	('PI3Kalpha', 'Gene', (0, 9))
96957	28138035	HGF-mediated growth protection in trametinib-treated UM001 cells (Suppl Fig 5B) and UM004 cells (Fig 5B) was reverted by GDC0032 (37% reduction in UM004 cell growth compared to vehicle control) and partially reverted by BYL719 and IPI145 (12-17% inhibition of UM004 cell growth compared to vehicle control).	('UM004 cell growth', 'CPA', (147, 164))	('HGF', 'Gene', (0, 3))	('trametinib', 'Chemical', 'MESH:C560077', (34, 44))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('reduction', 'NegReg', (134, 143))	('growth protection', 'CPA', (13, 30))	('HGF', 'Gene', '3082', (0, 3))	('cell growth', 'biological_process', 'GO:0016049', ('266', '277'))	('UM', 'Phenotype', 'HP:0007716', (53, 55))	('cell growth', 'biological_process', 'GO:0016049', ('153', '164'))	('UM', 'Phenotype', 'HP:0007716', (260, 262))	('GDC0032', 'Var', (121, 128))	('IPI145', 'Chemical', 'MESH:C586691', (231, 237))	('GDC0032', 'Chemical', 'MESH:C582924', (121, 128))	('UM', 'Phenotype', 'HP:0007716', (147, 149))
96960	28138035	To test whether combined therapies targeting MEK1/2 and HGF-cMET signaling improves the response in metastatic UM, We next extended our study to analyze a mutant GNAQ harboring UM patient sample using an ex vivo treatment approach (Fig 6A Supplementary Table S1).	('MEK1/2', 'Gene', (45, 51))	('response', 'MPA', (88, 96))	('UM', 'Phenotype', 'HP:0007716', (111, 113))	('GNAQ', 'Gene', '2776', (162, 166))	('mutant', 'Var', (155, 161))	('cMET', 'Gene', '4233', (60, 64))	('UM', 'Phenotype', 'HP:0007716', (177, 179))	('MEK1', 'molecular_function', 'GO:0004708', ('45', '49'))	('cMET', 'Gene', (60, 64))	('HGF', 'Gene', (56, 59))	('GNAQ', 'Gene', (162, 166))	('patient', 'Species', '9606', (180, 187))	('HGF', 'Gene', '3082', (56, 59))	('MEK1/2', 'Gene', '5604;5605', (45, 51))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))
96961	28138035	Tumor tissue pieces were treated with DMSO, trametinib, LY2875358, or a combination of trametinib and LY2875358.	('LY2875358', 'Chemical', 'MESH:C000599789', (56, 65))	('trametinib', 'Chemical', 'MESH:C560077', (44, 54))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('LY2875358', 'Chemical', 'MESH:C000599789', (102, 111))	('LY2875358', 'Var', (102, 111))	('DMSO', 'Chemical', 'MESH:D004121', (38, 42))	('trametinib', 'Chemical', 'MESH:C560077', (87, 97))	('LY2875358', 'Var', (56, 65))
96964	28138035	Interestingly, combination of trametinib with LY2875358 further upregulated the expression of cleaved-PARP.	('LY2875358', 'Chemical', 'MESH:C000599789', (46, 55))	('trametinib', 'Chemical', 'MESH:C560077', (30, 40))	('LY2875358', 'Var', (46, 55))	('PARP', 'Gene', (102, 106))	('combination', 'Interaction', (15, 26))	('upregulated', 'PosReg', (64, 75))	('expression', 'MPA', (80, 90))	('PARP', 'Gene', '1302', (102, 106))
96968	28138035	We provide evidence that the use of cMET targeting agents as a part of combinational approach may counteract tumor microenvironment-mediated primary resistance to MEK inhibitors in mutant GNAQ/11 metastatic UM.	('mutant', 'Var', (181, 187))	('GNAQ', 'Gene', (188, 192))	('cMET', 'Gene', '4233', (36, 40))	('metastatic UM', 'CPA', (196, 209))	('UM', 'Phenotype', 'HP:0007716', (207, 209))	('cMET', 'Gene', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('MEK', 'Gene', (163, 166))	('MEK', 'Gene', '5609', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('GNAQ', 'Gene', '2776', (188, 192))	('tumor', 'Disease', (109, 114))
96970	28138035	These results are in contrast to findings in cutaneous melanoma, which led to the FDA approval of trametinib for the treatment of BRAF V600E/K unresectable or metastatic cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('cutaneous melanoma', 'Disease', (45, 63))	('BRAF', 'Gene', '673', (130, 134))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (45, 63))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (45, 63))	('cutaneous melanoma', 'Disease', (170, 188))	('unresectable', 'Disease', (143, 155))	('V600E', 'Var', (135, 140))	('BRAF', 'Gene', (130, 134))	('V600E', 'SUBSTITUTION', 'None', (135, 140))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (170, 188))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (170, 188))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('trametinib', 'Chemical', 'MESH:C560077', (98, 108))
96971	28138035	HGF is abundant in the liver microenvironment and, when supplied exogenously, rescues the growth of MEK-inhibited mutant GNAQ human metastatic UM cell lines.	('rescues', 'PosReg', (78, 85))	('human', 'Species', '9606', (126, 131))	('MEK', 'Gene', (100, 103))	('HGF', 'Gene', (0, 3))	('UM', 'Phenotype', 'HP:0007716', (143, 145))	('GNAQ', 'Gene', '2776', (121, 125))	('mutant', 'Var', (114, 120))	('MEK', 'Gene', '5609', (100, 103))	('HGF', 'Gene', '3082', (0, 3))	('growth', 'MPA', (90, 96))	('GNAQ', 'Gene', (121, 125))
96983	28138035	We demonstrate that cMET targeting agents such as LY2801653 and LY2875358 may improve the response to MEK inhibitors in metastatic UM patients.	('LY2801653', 'Var', (50, 59))	('MEK', 'Gene', '5609', (102, 105))	('response', 'MPA', (90, 98))	('improve', 'PosReg', (78, 85))	('UM', 'Phenotype', 'HP:0007716', (131, 133))	('LY2801653', 'Chemical', 'MESH:C586252', (50, 59))	('patients', 'Species', '9606', (134, 142))	('LY2875358', 'Chemical', 'MESH:C000599789', (64, 73))	('LY2875358', 'Var', (64, 73))	('metastatic UM', 'Disease', (120, 133))	('cMET', 'Gene', '4233', (20, 24))	('cMET', 'Gene', (20, 24))	('MEK', 'Gene', (102, 105))
96985	28138035	Interestingly, we observed that LY2801653 treatment promoted the expression of cleaved PARP, an indicator of apoptosis.	('PARP', 'Gene', '1302', (87, 91))	('LY2801653', 'Var', (32, 41))	('PARP', 'Gene', (87, 91))	('LY2801653', 'Chemical', 'MESH:C586252', (32, 41))	('expression', 'MPA', (65, 75))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))	('promoted', 'PosReg', (52, 60))
96993	28138035	In summary, the data presented here show for the first time that stellate cells from the liver provide innate resistance to MEK inhibitors in metastatic UM though HGF-cMET signaling.	('HGF', 'Gene', '3082', (163, 166))	('signaling', 'biological_process', 'GO:0023052', ('172', '181'))	('UM', 'Phenotype', 'HP:0007716', (153, 155))	('metastatic UM though', 'MPA', (142, 162))	('cMET', 'Gene', '4233', (167, 171))	('HGF', 'Gene', (163, 166))	('MEK', 'Gene', (124, 127))	('MEK', 'Gene', '5609', (124, 127))	('cMET', 'Gene', (167, 171))	('inhibitors', 'Var', (128, 138))
97001	27060663	Emerging studies also uncover diverse mutations in components, particularly GPCRs and small G proteins, of GPCR signaling pathways that render the constitutive activation of proliferative and survival signal, which contributes to the oncogenesis of various human cancers.	('human', 'Species', '9606', (257, 262))	('activation', 'PosReg', (160, 170))	('cancers', 'Disease', 'MESH:D009369', (263, 270))	('cancers', 'Phenotype', 'HP:0002664', (263, 270))	('cancers', 'Disease', (263, 270))	('signaling', 'biological_process', 'GO:0023052', ('112', '121'))	('GPCR', 'Gene', (107, 111))	('oncogenesis', 'biological_process', 'GO:0007048', ('234', '245'))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('mutations', 'Var', (38, 47))	('contributes', 'Reg', (215, 226))	('proliferative and', 'MPA', (174, 191))
97002	27060663	Hijacking GPCR-mediated signaling is a signature shared by diseases associated with constitutively active viral GPCRs and cellular mutations activating GPCR signaling, exposing key molecules that can be targeted for anti-viral and anti-tumor therapy.	('mutations', 'Var', (131, 140))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('activating', 'PosReg', (141, 151))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('Hijacking GPCR-mediated signaling', 'MPA', (0, 33))	('tumor', 'Disease', (236, 241))	('signaling', 'biological_process', 'GO:0023052', ('157', '166'))	('signaling', 'biological_process', 'GO:0023052', ('24', '33'))
97009	27060663	Surprisingly, nearly 20% of all human tumors carry mutations in GPCRs, highlighting the importance of elucidating the oncogenic potential of these mutations.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('GPCRs', 'Gene', (64, 69))	('mutations', 'Var', (51, 60))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('human', 'Species', '9606', (32, 37))
97010	27060663	Indeed, mutations in human GPCRs that result in constitutive activation have been linked to diverse human diseases.	('constitutive activation', 'MPA', (48, 71))	('human', 'Species', '9606', (21, 26))	('GPCRs', 'Gene', (27, 32))	('mutations', 'Var', (8, 17))	('human', 'Species', '9606', (100, 105))	('linked', 'Reg', (82, 88))
97011	27060663	Moreover, mutations in Galpha proteins, especially Galphas and Galphaq, are highly represented in various tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('Galpha', 'Gene', '8802', (23, 29))	('Galpha', 'Gene', (23, 29))	('tumors', 'Disease', (106, 112))	('Galphaq', 'Gene', '2776', (63, 70))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('Galphaq', 'Gene', (63, 70))	('Galpha', 'Gene', '8802', (51, 57))	('Galpha', 'Gene', '8802', (63, 69))	('Galpha', 'Gene', (51, 57))	('Galpha', 'Gene', (63, 69))	('Galphas', 'Chemical', '-', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mutations', 'Var', (10, 19))
97020	27060663	The study of the constitutive activity of these viral GPCRs may provide significant insight into how emerging mutations in components of GPCR-mediated signaling relate to human pathology, especially cancer.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('mutations', 'Var', (110, 119))	('relate', 'Reg', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))	('signaling', 'biological_process', 'GO:0023052', ('151', '160'))	('human', 'Species', '9606', (171, 176))
97021	27060663	We will review the signaling events downstream of herpesvirus GPCRs and compare them to pathological signaling events induced by aberrant expression or mutations of cellular GPCRs or Galpha proteins.	('herpesvirus', 'Species', '39059', (50, 61))	('mutations', 'Var', (152, 161))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('Galpha', 'Gene', '8802', (183, 189))	('Galpha', 'Gene', (183, 189))
97026	27060663	In particular, vGPCR (ORF74) is a viral constitutively active GPCR and its expression leads to cell transformation and tumorigenesis in xenograft mouse model.	('vGPCR', 'Gene', '4961465', (15, 20))	('tumor', 'Disease', (119, 124))	('expression', 'Var', (75, 85))	('mouse', 'Species', '10090', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('vGPCR', 'Gene', (15, 20))	('leads to', 'Reg', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('ORF74', 'Gene', '934952', (22, 27))	('cell transformation', 'CPA', (95, 114))	('ORF74', 'Gene', (22, 27))
97027	27060663	This was further confirmed by several studies showing that vGPCR transgenic expression in mice can lead to KS-like tumor development.	('transgenic', 'Species', '10090', (65, 75))	('vGPCR', 'Gene', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('lead to', 'Reg', (99, 106))	('KS', 'Phenotype', 'HP:0100726', (107, 109))	('vGPCR', 'Gene', '4961465', (59, 64))	('tumor', 'Disease', (115, 120))	('mice', 'Species', '10090', (90, 94))	('transgenic expression', 'Var', (65, 86))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
97030	27060663	An elegant study employed an endothelial cell specific retroviral delivery system to demonstrate that the expression of vGPCR, among multiple suspected KSHV oncogenes, was sufficient to induce KS-like tumors in mice.	('vGPCR', 'Gene', '4961465', (120, 125))	('KS', 'Phenotype', 'HP:0100726', (152, 154))	('KS-like tumors', 'Disease', (193, 207))	('KSHV', 'Species', '37296', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('expression', 'Var', (106, 116))	('induce', 'PosReg', (186, 192))	('mice', 'Species', '10090', (211, 215))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('KS', 'Phenotype', 'HP:0100726', (193, 195))	('vGPCR', 'Gene', (120, 125))	('KS-like tumors', 'Disease', 'MESH:D009369', (193, 207))
97031	27060663	Murine gamma herpesvirus 68 (gammaHV68) carrying KSHV vGPCR, rather than murine gammaHV68 GPCR (mGPCR), induced angiogenic lesions in virus-infected mice, offering a murine model of viral oncogenesis in the context of true viral infection.	('viral infection', 'Disease', 'MESH:D001102', (223, 238))	('murine', 'Species', '10090', (73, 79))	('mice', 'Species', '10090', (149, 153))	('vGPCR', 'Gene', (54, 59))	('induced', 'Reg', (104, 111))	('angiogenic lesions', 'CPA', (112, 130))	('virus-infected', 'Disease', (134, 148))	('viral infection', 'biological_process', 'GO:0016032', ('223', '238'))	('murine', 'Species', '10090', (166, 172))	('KSHV', 'Var', (49, 53))	('vGPCR', 'Gene', '4961465', (54, 59))	('KS', 'Phenotype', 'HP:0100726', (49, 51))	('herpesvirus', 'Species', '39059', (13, 24))	('mGPCR', 'Gene', '227289', (96, 101))	('virus-infected', 'Disease', 'MESH:D015658', (134, 148))	('KSHV', 'Species', '37296', (49, 53))	('viral infection', 'Disease', (223, 238))	('oncogenesis', 'biological_process', 'GO:0007048', ('188', '199'))	('Murine', 'Species', '10090', (0, 6))	('mGPCR', 'Gene', (96, 101))
97035	27060663	To reconcile this paradox, it is postulated that dysregulated abortive lytic replication may permit the expression of a subset of lytic genes, including vGPCR, to avoid late gene expression and lysis of host cells.	('dysregulated', 'Var', (49, 61))	('lysis', 'biological_process', 'GO:0019835', ('194', '199'))	('gene expression', 'biological_process', 'GO:0010467', ('174', '189'))	('vGPCR', 'Gene', (153, 158))	('expression', 'MPA', (104, 114))	('lysis', 'CPA', (194, 199))	('late gene expression', 'MPA', (169, 189))	('vGPCR', 'Gene', '4961465', (153, 158))
97041	27060663	This is further supported by the observations that lytic replicating cells are invariably found in KS tumors and that inhibition of KSHV lytic replication by antiviral treatment suppresses KSHV tumorigenesis.	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('KSHV', 'Species', '37296', (189, 193))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('KSHV', 'Species', '37296', (132, 136))	('KS', 'Phenotype', 'HP:0100726', (99, 101))	('KS tumors', 'Disease', 'MESH:D009369', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('KS', 'Phenotype', 'HP:0100726', (189, 191))	('KS', 'Phenotype', 'HP:0100726', (132, 134))	('KS tumors', 'Disease', (99, 108))	('suppresses', 'NegReg', (178, 188))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('KSHV', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('inhibition', 'Var', (118, 128))
97044	27060663	Thus, antagonists targeting vGPCR and its downstream signaling components may provide new therapeutic strategies to treat KSHV-associated malignancies.	('antagonists', 'Var', (6, 17))	('vGPCR', 'Gene', (28, 33))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('malignancies', 'Disease', 'MESH:D009369', (138, 150))	('vGPCR', 'Gene', '4961465', (28, 33))	('malignancies', 'Disease', (138, 150))	('KSHV', 'Species', '37296', (122, 126))	('KS', 'Phenotype', 'HP:0100726', (122, 124))
97047	27060663	In contrast to its KSHV homologue, gammaHV68 mGPCR doesn't have constitutive activity and it has an HRC motif rather than the conventional DRY motif.	('mGPCR', 'Gene', (45, 50))	('gammaHV68', 'Var', (35, 44))	('HRC motif', 'MPA', (100, 109))	('KSHV', 'Species', '37296', (19, 23))	('KS', 'Phenotype', 'HP:0100726', (19, 21))	('mGPCR', 'Gene', '227289', (45, 50))
97048	27060663	Interestingly, KSHV vGPCR has a VRY motif, rather than a DRY motif and the V142D revertant mutation didn't alter the constitutive activity of vGPCR.	('V142D', 'Mutation', 'p.V142D', (75, 80))	('vGPCR', 'Gene', (142, 147))	('V142D', 'Var', (75, 80))	('vGPCR', 'Gene', '4961465', (20, 25))	('KSHV', 'Species', '37296', (15, 19))	('VRY motif', 'MPA', (32, 41))	('KS', 'Phenotype', 'HP:0100726', (15, 17))	('vGPCR', 'Gene', '4961465', (142, 147))	('vGPCR', 'Gene', (20, 25))
97049	27060663	Surprisingly, introduction of the mutation of residues within the transmembrane helix that are expected to face the lipid bilayer, either Leu91Asp or Leu94Asp, reduced the constitutive activity of vGPCR, but it retained its responsiveness to its agonists such as CXCL1.	('Leu94Asp', 'Var', (150, 158))	('CXCL1', 'Gene', (263, 268))	('lipid', 'Chemical', 'MESH:D008055', (116, 121))	('responsiveness', 'MPA', (224, 238))	('vGPCR', 'Gene', '4961465', (197, 202))	('constitutive activity', 'MPA', (172, 193))	('Leu91Asp', 'Mutation', 'p.L91D', (138, 146))	('transmembrane', 'cellular_component', 'GO:0044214', ('66', '79'))	('reduced', 'NegReg', (160, 167))	('Leu91Asp', 'Var', (138, 146))	('transmembrane', 'cellular_component', 'GO:0016021', ('66', '79'))	('Leu94Asp', 'Mutation', 'p.L94D', (150, 158))	('vGPCR', 'Gene', (197, 202))	('CXCL1', 'Gene', '2919', (263, 268))
97050	27060663	In another study, the V142D vGPCR mutant showed >70% increased activity compared to WT vGPCR.	('vGPCR', 'Gene', (28, 33))	('activity', 'MPA', (63, 71))	('V142D', 'Mutation', 'p.V142D', (22, 27))	('V142D', 'Var', (22, 27))	('vGPCR', 'Gene', (87, 92))	('vGPCR', 'Gene', '4961465', (28, 33))	('vGPCR', 'Gene', '4961465', (87, 92))	('increased', 'PosReg', (53, 62))
97052	27060663	In contrast, the R to A mutation in the VRY motif abolishes the constitutive activity of vGPCR.	('VRY motif', 'Gene', (40, 49))	('abolishes', 'NegReg', (50, 59))	('vGPCR', 'Gene', (89, 94))	('vGPCR', 'Gene', '4961465', (89, 94))	('mutation', 'Var', (24, 32))	('constitutive activity', 'MPA', (64, 85))
97053	27060663	Importantly, murine endothelial cells stably expressing the inactive vGPCR R143A mutant are not tumorigenic in vivo, supporting the notion that that the constitutive activity of vGPCR is required for its tumorigenesis.	('vGPCR', 'Gene', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('vGPCR', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('R143A', 'Mutation', 'p.R143A', (75, 80))	('tumor', 'Disease', (96, 101))	('R143A', 'Var', (75, 80))	('murine', 'Species', '10090', (13, 19))	('tumor', 'Disease', (204, 209))	('vGPCR', 'Gene', '4961465', (178, 183))	('vGPCR', 'Gene', '4961465', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
97054	27060663	Although the afore-mentioned studies identified key residues that contribute to the constitutive activity of vGPCR, it is believed that a remarkably large number of residue substitutions in KSHV vGPCR compensate for the negative effect caused by the individual substitutions.	('vGPCR', 'Gene', (195, 200))	('vGPCR', 'Gene', '4961465', (195, 200))	('vGPCR', 'Gene', '4961465', (109, 114))	('substitutions', 'Var', (173, 186))	('KS', 'Phenotype', 'HP:0100726', (190, 192))	('KSHV', 'Species', '37296', (190, 194))	('constitutive', 'MPA', (84, 96))	('vGPCR', 'Gene', (109, 114))
97055	27060663	Consequently, the conformational changes induced by these substitutions shift vGPCR towards an active state, leading to its constitutive activity in triggering downstream G protein-dependent signaling.	('substitutions', 'Var', (58, 71))	('vGPCR', 'Gene', '4961465', (78, 83))	('constitutive', 'MPA', (124, 136))	('G protein-dependent signaling', 'MPA', (171, 200))	('conformational changes', 'MPA', (18, 40))	('signaling', 'biological_process', 'GO:0023052', ('191', '200'))	('vGPCR', 'Gene', (78, 83))	('protein', 'cellular_component', 'GO:0003675', ('173', '180'))	('shift', 'Reg', (72, 77))
97058	27060663	vGPCR with point mutations that makes it unresponsive to agonist stimulation has reduced oncogenic potential in transgenic mice, suggesting that responsiveness to agonist stimulation, in addition to its constitutive activity, is required for its oncogenic activity.	('oncogenic potential', 'CPA', (89, 108))	('vGPCR', 'Gene', '4961465', (0, 5))	('point mutations', 'Var', (11, 26))	('transgenic mice', 'Species', '10090', (112, 127))	('reduced', 'NegReg', (81, 88))	('vGPCR', 'Gene', (0, 5))
97068	27060663	Further studies indicate that the activation of NF-kappaB is dependent on PI3K-AKT, but not p38.	('p38', 'Gene', '1432', (92, 95))	('PI3K-AKT', 'Var', (74, 82))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('34', '57'))	('p38', 'Gene', (92, 95))	('activation', 'PosReg', (34, 44))	('PI3K', 'molecular_function', 'GO:0016303', ('74', '78'))	('NF-kappaB', 'Protein', (48, 57))
97080	27060663	Downstream of PI3K, AKT plays essential roles in vGPCR-induced tumorigenesis and pharmacologic inhibition of AKT reduces tumor formation in mouse models.	('mouse', 'Species', '10090', (140, 145))	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('pharmacologic', 'Var', (81, 94))	('vGPCR', 'Gene', (49, 54))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('vGPCR', 'Gene', '4961465', (49, 54))	('reduces', 'NegReg', (113, 120))	('AKT', 'Gene', (109, 112))	('PI3K', 'molecular_function', 'GO:0016303', ('14', '18'))	('formation', 'biological_process', 'GO:0009058', ('127', '136'))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
97085	27060663	Interestingly, inhibition of Rac1, rather than Rho, blocks vGPCR-induced cytokine secretion and reduces vGPCR-induced tumor growth in vivo.	('Rac1', 'Gene', (29, 33))	('vGPCR', 'Gene', (59, 64))	('reduces', 'NegReg', (96, 103))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('vGPCR', 'Gene', (104, 109))	('vGPCR', 'Gene', '4961465', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('cytokine secretion', 'biological_process', 'GO:0050663', ('73', '91'))	('blocks', 'NegReg', (52, 58))	('tumor', 'Disease', (118, 123))	('vGPCR', 'Gene', '4961465', (104, 109))	('inhibition', 'Var', (15, 25))
97086	27060663	Expression of a constitutively active mutant Rac1 in mice is sufficient to produce high levels of reactive oxygen species (ROS), which drive the development of KS-like tumors.	('mutant', 'Var', (38, 44))	('ROS', 'Chemical', 'MESH:D017382', (123, 126))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('KS-like tumors', 'Disease', (160, 174))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (98, 121))	('Rac1', 'Gene', (45, 49))	('KS', 'Phenotype', 'HP:0100726', (160, 162))	('development', 'CPA', (145, 156))	('drive', 'PosReg', (135, 140))	('mice', 'Species', '10090', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('KS-like tumors', 'Disease', 'MESH:D009369', (160, 174))
97094	27060663	Given the inflammatory nature of KS tumors, it is not surprising to find that inhibiting NFAT activation impairs vGPCR-induced tumorigenesis in a xenograph mouse model.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('KS tumors', 'Disease', 'MESH:D009369', (33, 42))	('impairs', 'NegReg', (105, 112))	('KS tumors', 'Disease', (33, 42))	('NFAT', 'Protein', (89, 93))	('vGPCR', 'Gene', '4961465', (113, 118))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('KS', 'Phenotype', 'HP:0100726', (33, 35))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('mouse', 'Species', '10090', (156, 161))	('vGPCR', 'Gene', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Disease', (36, 41))	('inhibiting', 'Var', (78, 88))
97102	27060663	As such, shRNA interference or pharmacological inhibition of PKM2 reduces the tumorigenesis of vGPCR.	('PKM2', 'Gene', (61, 65))	('reduces', 'NegReg', (66, 73))	('PKM2', 'Gene', '5315', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('vGPCR', 'Gene', '4961465', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('vGPCR', 'Gene', (95, 100))	('shRNA interference', 'MPA', (9, 27))	('pharmacological inhibition', 'Var', (31, 57))
97104	27060663	Inhibition of ANGPTL4 potently blocks vGPCR-induced tumor formation, similar to the extent of VEGF inhibition, suggesting that ANGPTL4 may be a viable therapeutic target for KS treatment.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('ANGPTL4', 'Gene', (127, 134))	('KS', 'Phenotype', 'HP:0100726', (174, 176))	('vGPCR', 'Gene', (38, 43))	('tumor', 'Disease', (52, 57))	('ANGPTL4', 'Gene', '51129', (127, 134))	('ANGPTL4', 'Gene', (14, 21))	('vGPCR', 'Gene', '4961465', (38, 43))	('ANGPTL4', 'Gene', '51129', (14, 21))	('blocks', 'NegReg', (31, 37))	('formation', 'biological_process', 'GO:0009058', ('58', '67'))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
97121	27060663	US28 expression induces multiple proliferative and inflammatory factors such as VEGF and IL8, thereby promoting angiogenesis, aberrant cell proliferation and tumor formation in a xenograft mouse model.	('tumor', 'Disease', (158, 163))	('IL8', 'molecular_function', 'GO:0005153', ('89', '92'))	('mouse', 'Species', '10090', (189, 194))	('aberrant cell proliferation', 'CPA', (126, 153))	('cell proliferation', 'biological_process', 'GO:0008283', ('135', '153'))	('angiogenesis', 'CPA', (112, 124))	('angiogenesis', 'biological_process', 'GO:0001525', ('112', '124'))	('expression', 'Var', (5, 15))	('US28', 'Gene', (0, 4))	('IL8', 'Gene', (89, 92))	('induces', 'PosReg', (16, 23))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('US28', 'Gene', '3077536', (0, 4))	('promoting', 'PosReg', (102, 111))	('aberrant cell proliferation', 'Phenotype', 'HP:0031377', (126, 153))	('formation', 'biological_process', 'GO:0009058', ('164', '173'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('IL8', 'Gene', '20309', (89, 92))
97125	27060663	The R to A mutantin the DRY motif of US28 cannot activate PLCbeta, and fails to induce COX-2 or VEGF production, ultimately demonstrating much weaker oncogenic activity in vivo.	('COX-2', 'Gene', (87, 92))	('COX-2', 'Gene', '5743', (87, 92))	('US28', 'Gene', (37, 41))	('US28', 'Gene', '3077536', (37, 41))	('weaker', 'NegReg', (143, 149))	('oncogenic activity', 'CPA', (150, 168))	('mutantin', 'Var', (11, 19))	('PLCbeta', 'Enzyme', (58, 65))	('VEGF production', 'biological_process', 'GO:0010573', ('96', '111'))
97147	27060663	VUF2274, originally discovered as a CCR1 antagonist, is among the first to be characterized as a full inverse agonist of US28.	('CCR1', 'Gene', (36, 40))	('CCR1', 'Gene', '1230', (36, 40))	('CCR', 'molecular_function', 'GO:0043880', ('36', '39'))	('VUF2274', 'Chemical', 'MESH:C473351', (0, 7))	('US28', 'Gene', (121, 125))	('US28', 'Gene', '3077536', (121, 125))	('VUF2274', 'Var', (0, 7))
97148	27060663	VUF2274 and its derivatives abrogate PLCbeta activation induced by US28.	('US28', 'Gene', (67, 71))	('US28', 'Gene', '3077536', (67, 71))	('VUF2274', 'Chemical', 'MESH:C473351', (0, 7))	('PLCbeta', 'Enzyme', (37, 44))	('abrogate', 'NegReg', (28, 36))	('VUF2274', 'Var', (0, 7))
97151	27060663	A recent study suggests that some inverse agonists of US28 desensitize its downstream signaling via constitutive endocytosis of US28.	('inverse agonists', 'Var', (34, 50))	('US28', 'Gene', '3077536', (54, 58))	('desensitize', 'NegReg', (59, 70))	('endocytosis', 'biological_process', 'GO:0006897', ('113', '124'))	('constitutive endocytosis', 'MPA', (100, 124))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('US28', 'Gene', (128, 132))	('downstream signaling', 'MPA', (75, 95))	('US28', 'Gene', '3077536', (128, 132))	('US28', 'Gene', (54, 58))
97152	27060663	Using a US28 mutant that lacks most of its constitutive endocytosis activity, Nuska Tschammer showed that some of the previously reported US28 inverse agonists can actually function as 'camouflage' agonists.	('US28', 'Gene', (8, 12))	('mutant', 'Var', (13, 19))	('US28', 'Gene', '3077536', (8, 12))	("'camouflage", 'PosReg', (185, 196))	('US28', 'Gene', (138, 142))	('US28', 'Gene', '3077536', (138, 142))	('endocytosis', 'biological_process', 'GO:0006897', ('56', '67'))
97154	27060663	A synthetic CX3CL1 variant fused with the cytotoxic domain of Pseudomonas exotoxin A demonstrated high affinity for US28.	('affinity', 'Interaction', (103, 111))	('US28', 'Gene', (116, 120))	('US28', 'Gene', '3077536', (116, 120))	('variant', 'Var', (19, 26))	('CX3CL1', 'Gene', '6376', (12, 18))	('CX3CL1', 'Gene', (12, 18))
97163	27060663	The most important contributing factor is Glu1243.45, which forms an ionic interaction with Arg139 in the second intracellular loop and prevents interaction between Arg139 and Asp1283.49.	('Arg139', 'Chemical', '-', (92, 98))	('intracellular', 'cellular_component', 'GO:0005622', ('113', '126'))	('interaction', 'Interaction', (145, 156))	('prevents', 'NegReg', (136, 144))	('Glu1243', 'Chemical', '-', (42, 49))	('Arg139', 'Chemical', '-', (165, 171))	('Glu1243.45', 'Var', (42, 52))	('Asp1283', 'Chemical', '-', (176, 183))
97165	27060663	The M257Y6.40 mutation, located in a series of highly conserved hydrophobic residues between the DRY motif in TM3 and the NPxxY motif in TM7, stabilizes the G protein binding site and constitutively activates rhodopsin.	('stabilizes', 'PosReg', (142, 152))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('rhodopsin', 'Gene', '6010', (209, 218))	('M257Y6.40', 'Var', (4, 13))	('protein binding', 'molecular_function', 'GO:0005515', ('159', '174'))	('activates', 'PosReg', (199, 208))	('rhodopsin', 'Gene', (209, 218))
97166	27060663	The presence of Glu1243.45 seems to be unique for US28, and is not present in human GPCRs or other viral GPCRs such as KSHV vGPCR (Cysteine) and BILF1 (Glycine).	('vGPCR', 'Gene', (124, 129))	('Glu1243.45', 'Var', (16, 26))	('vGPCR', 'Gene', '4961465', (124, 129))	('KSHV', 'Species', '37296', (119, 123))	('BILF1', 'Gene', '3783707', (145, 150))	('Glu1243', 'Chemical', '-', (16, 23))	('KS', 'Phenotype', 'HP:0100726', (119, 121))	('Glycine', 'Chemical', 'MESH:D005998', (152, 159))	('US28', 'Gene', (50, 54))	('human', 'Species', '9606', (78, 83))	('Cysteine', 'Chemical', 'MESH:D003545', (131, 139))	('US28', 'Gene', '3077536', (50, 54))	('BILF1', 'Gene', (145, 150))
97167	27060663	Although the presence of VRY in KSHV vGPCR abrogates the ionic interaction in the conventional DRY motif, the V142D revertant mutant doesn't reduce its constitutive activity.	('ionic interaction', 'MPA', (57, 74))	('V142D', 'Var', (110, 115))	('constitutive activity', 'MPA', (152, 173))	('abrogates', 'NegReg', (43, 52))	('KSHV', 'Species', '37296', (32, 36))	('KS', 'Phenotype', 'HP:0100726', (32, 34))	('vGPCR', 'Gene', (37, 42))	('V142D', 'Mutation', 'p.V142D', (110, 115))	('vGPCR', 'Gene', '4961465', (37, 42))
97169	27060663	Alternatively, vGPCR may possess another negatively charged residue that functions similarly to Glu1243.45 in US28.	('vGPCR', 'Gene', '4961465', (15, 20))	('Glu1243', 'Chemical', '-', (96, 103))	('vGPCR', 'Gene', (15, 20))	('US28', 'Gene', (110, 114))	('US28', 'Gene', '3077536', (110, 114))	('Glu1243.45', 'Var', (96, 106))
97172	27060663	It constitutively activates PLC via Galphaq/11 and partly via Galphai/o, and it also stimulates the transcription factor CREB through the Rho/p38 pathway via Gbetagamma.	('transcription factor', 'molecular_function', 'GO:0000981', ('100', '120'))	('p38', 'Gene', (142, 145))	('Gbetagamma', 'Chemical', '-', (158, 168))	('Galphai', 'Chemical', '-', (62, 69))	('stimulates', 'PosReg', (85, 95))	('Galphai/o', 'Var', (62, 71))	('PLC', 'cellular_component', 'GO:0042824', ('28', '31'))	('PLC', 'MPA', (28, 31))	('CREB', 'Gene', (121, 125))	('p38', 'Gene', '1432', (142, 145))	('transcription', 'biological_process', 'GO:0006351', ('100', '113'))	('Galphaq', 'Gene', (36, 43))	('Galphaq', 'Gene', '2776', (36, 43))	('CREB', 'Gene', '1385', (121, 125))	('activates', 'PosReg', (18, 27))
97185	27060663	The EKT motif is vital as the K to A mutation in the motif abolishes BILF1 constitutive activity.	('abolishes', 'NegReg', (59, 68))	('BILF1', 'Gene', '3783707', (69, 74))	('BILF1', 'Gene', (69, 74))	('mutation', 'Var', (37, 45))
97186	27060663	Interestingly, a BILF1 revertant mutant containing the DRY motif demonstrates reduced signaling and transformation activity.	('transformation activity', 'CPA', (100, 123))	('BILF1', 'Gene', '3783707', (17, 22))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('mutant', 'Var', (33, 39))	('signaling', 'MPA', (86, 95))	('reduced', 'NegReg', (78, 85))	('BILF1', 'Gene', (17, 22))
97192	27060663	Surprisingly, the mutant that lacks constitutive activity can still induce tumor formation, suggesting that the oncogenic signaling downstream of BILF1 is partly independent of coupling to G proteins.	('BILF1', 'Gene', (146, 151))	('induce', 'Reg', (68, 74))	('formation', 'biological_process', 'GO:0009058', ('81', '90'))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('mutant', 'Var', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('BILF1', 'Gene', '3783707', (146, 151))	('tumor', 'Disease', (75, 80))
97202	27060663	The rhesus rhadinovirus (RRV) GPCR shares highly sequence identity with KSHV vGPCR and its expression induces constitutive signaling activity and promotes tumor formation in nude mice.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('constitutive signaling activity', 'MPA', (110, 141))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('vGPCR', 'Gene', '4961465', (77, 82))	('expression', 'Var', (91, 101))	('KS', 'Phenotype', 'HP:0100726', (72, 74))	('KSHV', 'Species', '37296', (72, 76))	('tumor', 'Disease', (155, 160))	('RRV', 'Species', '154334', (25, 28))	('formation', 'biological_process', 'GO:0009058', ('161', '170'))	('nude mice', 'Species', '10090', (174, 183))	('rhesus rhadinovirus', 'Species', '154334', (4, 23))	('vGPCR', 'Gene', (77, 82))	('induces', 'PosReg', (102, 109))	('promotes', 'PosReg', (146, 154))
97205	27060663	Those GPCRs detect chemokines in order to mobilize immune cells, while deregulation of chemokine signaling induces inflammation.	('inflammation', 'Disease', 'MESH:D007249', (115, 127))	('inflammation', 'biological_process', 'GO:0006954', ('115', '127'))	('inflammation', 'Disease', (115, 127))	('signaling', 'biological_process', 'GO:0023052', ('97', '106'))	('induces', 'Reg', (107, 114))	('chemokine signaling', 'MPA', (87, 106))	('mobilize immune cells', 'MPA', (42, 63))	('deregulation', 'Var', (71, 83))
97217	27060663	In contrast, vGPCR cannot down-regulate MHC class I. Down-regulation of MHC class I by BILF1 is independent of its constitutive GPCR signaling, becausea BILF1 mutant that is unable to activate G-protein signaling is still capable of down-regulating MHC class I.	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))	('BILF1', 'Gene', (153, 158))	('signaling', 'biological_process', 'GO:0023052', ('133', '142'))	('mutant', 'Var', (159, 165))	('signaling', 'biological_process', 'GO:0023052', ('203', '212'))	('vGPCR', 'Gene', '4961465', (13, 18))	('down-regulate MHC class I', 'Phenotype', 'HP:0031390', (26, 51))	('BILF1', 'Gene', '3783707', (87, 92))	('MHC', 'Gene', (249, 252))	('BILF1', 'Gene', (87, 92))	('BILF1', 'Gene', '3783707', (153, 158))	('down-regulating', 'NegReg', (233, 248))	('regulation', 'biological_process', 'GO:0065007', ('58', '68'))	('vGPCR', 'Gene', (13, 18))
97222	27060663	Inhibition of COX synergized with antibody disruption of programmed cell death 1 (PD-1) to reduce tumor growth in mice.	('antibody', 'cellular_component', 'GO:0019814', ('34', '42'))	('disruption', 'Var', (43, 53))	('reduce', 'NegReg', (91, 97))	('antibody', 'cellular_component', 'GO:0042571', ('34', '42'))	('PD-1', 'Disease', (82, 86))	('PD-1', 'Disease', 'MESH:D010300', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('antibody', 'cellular_component', 'GO:0019815', ('34', '42'))	('mice', 'Species', '10090', (114, 118))	('programmed cell death', 'biological_process', 'GO:0012501', ('57', '78'))	('tumor', 'Disease', (98, 103))	('antibody', 'molecular_function', 'GO:0003823', ('34', '42'))
97226	27060663	For example, COX2 inhibition can significantly reduce tumor occurrence in patients with mutations in adenomatous polyposis coli (APC) tumor suppressor.	('inhibition', 'NegReg', (18, 28))	('reduce', 'NegReg', (47, 53))	('COX2', 'Gene', (13, 17))	('patients', 'Species', '9606', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mutations', 'Var', (88, 97))	('COX2', 'Gene', '4513', (13, 17))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (101, 127))	('APC', 'cellular_component', 'GO:0005680', ('129', '132'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('134', '150'))	('adenomatous polyposis coli (APC) tumor', 'Disease', 'MESH:D011125', (101, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (54, 59))	('APC', 'Phenotype', 'HP:0005227', (129, 132))	('tumor suppressor', 'biological_process', 'GO:0051726', ('134', '150'))	('tumor', 'Disease', (134, 139))
97229	27060663	Moreover, US28 expression can promote intestinal neoplasia in a transgenic mouse model by inhibiting GSK-3beta and stabilizing beta-catenin.	('stabilizing', 'NegReg', (115, 126))	('expression', 'Var', (15, 25))	('beta-catenin', 'MPA', (127, 139))	('promote', 'PosReg', (30, 37))	('GSK', 'molecular_function', 'GO:0050321', ('101', '104'))	('GSK-3beta', 'Gene', (101, 110))	('US28', 'Gene', (10, 14))	('US28', 'Gene', '3077536', (10, 14))	('neoplasia', 'Phenotype', 'HP:0002664', (49, 58))	('intestinal neoplasia', 'Disease', (38, 58))	('transgenic', 'Species', '10090', (64, 74))	('GSK-3beta', 'Gene', '56637', (101, 110))	('mouse', 'Species', '10090', (75, 80))	('inhibiting', 'NegReg', (90, 100))	('intestinal neoplasia', 'Disease', 'MESH:D009369', (38, 58))
97233	27060663	The aberrant activation of PI3K-AKT-mTOR signaling represents one of the most frequent events in cancer, hence the molecular targets of this signaling pathway have been extensively explored to develop cancer therapy.	('PI3K', 'molecular_function', 'GO:0016303', ('27', '31'))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', (201, 207))	('mTOR', 'Gene', (36, 40))	('aberrant', 'Var', (4, 12))	('mTOR', 'Gene', '2475', (36, 40))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('activation', 'PosReg', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('signaling pathway', 'biological_process', 'GO:0007165', ('141', '158'))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
97237	27060663	Although the signaling network induced by gain-of-function mutations of TSHR is not fully understood, it is believed that the Gbetagamma-dependent activation of PI3K, in addition to cAMP signaling, contributes to thyroid adenoma development.	('contributes', 'Reg', (198, 209))	('Gbetagamma', 'Chemical', '-', (126, 136))	('PI3K', 'molecular_function', 'GO:0016303', ('161', '165'))	('TSHR', 'Gene', '7253', (72, 76))	('signaling', 'biological_process', 'GO:0023052', ('13', '22'))	('cAMP signaling', 'biological_process', 'GO:0019933', ('182', '196'))	('thyroid adenoma', 'Disease', 'MESH:D013964', (213, 228))	('TSHR', 'Gene', (72, 76))	('gain-of-function', 'PosReg', (42, 58))	('mutations', 'Var', (59, 68))	('cAMP', 'Chemical', 'MESH:D000242', (182, 186))	('thyroid adenoma', 'Phenotype', 'HP:0000854', (213, 228))	('thyroid adenoma', 'Disease', (213, 228))
97238	27060663	Smoothened (SMO) is an important component of the Hedgehog signaling pathway and mutations of SMO are often found in sporadic basal-cell carcinoma.	('found', 'Reg', (108, 113))	('SMO', 'Gene', '6608', (94, 97))	('SMO', 'Gene', (94, 97))	('SMO', 'Gene', '6608', (12, 15))	('SMO', 'Gene', (12, 15))	('Hedgehog signaling pathway', 'biological_process', 'GO:0007224', ('50', '76'))	('Smoothened', 'Gene', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('basal-cell carcinoma', 'Disease', (126, 146))	('basal-cell carcinoma', 'Phenotype', 'HP:0002671', (126, 146))	('mutations', 'Var', (81, 90))	('basal-cell carcinoma', 'Disease', 'MESH:D002280', (126, 146))	('Smoothened', 'Gene', '6608', (0, 10))
97239	27060663	Recent sequencing revealed that mutations of SMO arise in the colon and neural systems, among other cancer types.	('colon', 'Disease', 'MESH:D015179', (62, 67))	('SMO', 'Gene', '6608', (45, 48))	('SMO', 'Gene', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colon', 'Disease', (62, 67))	('mutations', 'Var', (32, 41))	('arise', 'Reg', (49, 54))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
97242	27060663	Despite the constitutive activation of PLC through Galphaq by US28, US28 cannot activate PI3K, suggesting that KSHV vGPCR may rewire a larger signaling network compared with US28.	('PI3K', 'molecular_function', 'GO:0016303', ('89', '93'))	('US28', 'Gene', (68, 72))	('PLC', 'cellular_component', 'GO:0042824', ('39', '42'))	('Galphaq', 'Gene', (51, 58))	('signaling', 'biological_process', 'GO:0023052', ('142', '151'))	('US28', 'Gene', '3077536', (68, 72))	('Galphaq', 'Gene', '2776', (51, 58))	('US28', 'Gene', (174, 178))	('vGPCR', 'Gene', '4961465', (116, 121))	('KSHV', 'Species', '37296', (111, 115))	('KSHV', 'Var', (111, 115))	('US28', 'Gene', (62, 66))	('US28', 'Gene', '3077536', (174, 178))	('KS', 'Phenotype', 'HP:0100726', (111, 113))	('US28', 'Gene', '3077536', (62, 66))	('signaling network', 'Pathway', (142, 159))	('vGPCR', 'Gene', (116, 121))	('activation', 'PosReg', (25, 35))
97245	27060663	vGPCR acts mainly through Galphaq/11 and Galpha12/13 to inhibit the Hippo pathway kinases, thereby promoting the activation of YAP/TAZ.	('activation', 'MPA', (113, 123))	('Galpha12/13', 'Var', (41, 52))	('Galphaq', 'Gene', '2776', (26, 33))	('vGPCR', 'Gene', (0, 5))	('TAZ', 'Gene', '6901', (131, 134))	('vGPCR', 'Gene', '4961465', (0, 5))	('Hippo pathway kinases', 'Pathway', (68, 89))	('Galphaq', 'Gene', (26, 33))	('TAZ', 'Gene', (131, 134))	('promoting', 'PosReg', (99, 108))	('inhibit', 'NegReg', (56, 63))
97249	27060663	Galphaq or Galpha11 mutations are found in more than 80% of UM.	('Galphaq', 'Gene', (0, 7))	('Galpha11', 'Gene', '2767', (11, 19))	('Galphaq', 'Gene', '2776', (0, 7))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('Galpha11', 'Gene', (11, 19))	('mutations', 'Var', (20, 29))
97250	27060663	Interestingly, all mutations in Galphaq or Galpha11 occur in a mutually exclusive manner at either arginine 183 (R183) or glutamine 209 (Q209), respectively, suggesting that these mutations in Galphaq or Galpha11 have similar functions in uveal tumor development.	('uveal tumor', 'Disease', 'MESH:D014604', (239, 250))	('mutations', 'Var', (180, 189))	('Galpha11', 'Gene', (204, 212))	('uveal tumor', 'Disease', (239, 250))	('Galpha11', 'Gene', (43, 51))	('mutations', 'Var', (19, 28))	('Galpha11', 'Gene', '2767', (204, 212))	('arginine', 'Chemical', 'MESH:D001120', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('Galphaq', 'Gene', (193, 200))	('Galphaq', 'Gene', (32, 39))	('glutamine', 'Chemical', 'MESH:D005973', (122, 131))	('Galpha11', 'Gene', '2767', (43, 51))	('Galphaq', 'Gene', '2776', (193, 200))	('Galphaq', 'Gene', '2776', (32, 39))
97251	27060663	These mutations render Galpha defective of GTPase activity and lock it in a constitutively active state.	('Galpha', 'Gene', '8802', (23, 29))	('Galpha', 'Gene', (23, 29))	('GTPase', 'Protein', (43, 49))	('defective', 'NegReg', (30, 39))	('activity', 'MPA', (50, 58))	('GTPase activity', 'molecular_function', 'GO:0003924', ('43', '58'))	('mutations', 'Var', (6, 15))	('lock', 'Reg', (63, 67))
97252	27060663	Recent evidence indicate that the Galphaq and Galpha11 mutations activate the transcriptional coactivator, YAP, a critical component of the Hippo signaling pathway that has been extensively studied in controlling tissue homeostasis and organ size.	('tissue homeostasis', 'biological_process', 'GO:0001894', ('213', '231'))	('Galpha11', 'Gene', (46, 54))	('Galphaq', 'Gene', (34, 41))	('mutations', 'Var', (55, 64))	('Galphaq', 'Gene', '2776', (34, 41))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('140', '163'))	('YAP', 'Gene', (107, 110))	('activate', 'PosReg', (65, 73))	('Galpha11', 'Gene', '2767', (46, 54))
97253	27060663	The role of aberrant Hippo signaling in cancer development is also under active investigation.	('Hippo', 'Protein', (21, 26))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('Hippo signaling', 'biological_process', 'GO:0035329', ('21', '36'))	('aberrant', 'Var', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
97255	27060663	Interestingly, the Galphaq/11 mutations in UM add another layer of activation of the Hippo pathway by GPCRs.	('activation', 'PosReg', (67, 77))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('Hippo pathway', 'Pathway', (85, 98))	('mutations', 'Var', (30, 39))	('Galphaq', 'Gene', '2776', (19, 26))	('Galphaq', 'Gene', (19, 26))
97256	27060663	It was found that mutations in Galphaq/11 largely activate YAP through a LATS-independent pathway.	('Galphaq', 'Gene', '2776', (31, 38))	('Galphaq', 'Gene', (31, 38))	('YAP', 'Disease', (59, 62))	('activate', 'PosReg', (50, 58))	('LATS-independent pathway', 'Pathway', (73, 97))	('mutations', 'Var', (18, 27))
97257	27060663	Specifically, mutated Galphaq and Galpha11 act through Trio-Rho/Rac signaling to promote actin polymerization.	('Galpha11', 'Gene', '2767', (34, 42))	('mutated', 'Var', (14, 21))	('promote', 'PosReg', (81, 88))	('actin polymerization', 'MPA', (89, 109))	('Rac', 'Gene', (64, 67))	('actin polymerization', 'biological_process', 'GO:0030041', ('89', '109'))	('Trio', 'Gene', '7204', (55, 59))	('Galpha11', 'Gene', (34, 42))	('Galphaq', 'Gene', (22, 29))	('Trio', 'Gene', (55, 59))	('Rac', 'Gene', '5879;19353', (64, 67))	('Galphaq', 'Gene', '2776', (22, 29))	('signaling', 'biological_process', 'GO:0023052', ('68', '77'))
97258	27060663	Indeed, the expression of Galphaq and Galpha11 mutants enhance F-actin accumulation and disrupt the angiomotin-YAP complex to release YAP, promoting the nuclear translocation and activation of YAP.	('nuclear translocation', 'CPA', (153, 174))	('Galpha11', 'Gene', '2767', (38, 46))	('Galphaq', 'Gene', '2776', (26, 33))	('YAP', 'CPA', (193, 196))	('angiomotin-YAP', 'Protein', (100, 114))	('enhance', 'PosReg', (55, 62))	('F-actin accumulation', 'MPA', (63, 83))	('promoting', 'PosReg', (139, 148))	('release', 'MPA', (126, 133))	('F-actin', 'cellular_component', 'GO:0031941', ('63', '70'))	('activation', 'PosReg', (179, 189))	('disrupt', 'NegReg', (88, 95))	('Galpha11', 'Gene', (38, 46))	('Galphaq', 'Gene', (26, 33))	('mutants', 'Var', (47, 54))
97259	27060663	Importantly, treatment with a specific YAP inhibitor blocks tumor growth of UM cells harboring Galphaq/11 mutations.	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('blocks tumor', 'Disease', (53, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('blocks tumor', 'Disease', 'MESH:D006327', (53, 65))	('mutations', 'Var', (106, 115))	('Galphaq', 'Gene', (95, 102))	('Galphaq', 'Gene', '2776', (95, 102))
97260	27060663	These studies collectively support the conclusion that YAP represents a therapeutic target for the treatment of UM and other tumors that are driven by GPCRs and gain-of-function mutations in Galphaq/11 or Galpha12/13.	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('gain-of-function', 'PosReg', (161, 177))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('Galpha12/13', 'Gene', (205, 216))	('UM', 'Phenotype', 'HP:0007716', (112, 114))	('Galphaq', 'Gene', (191, 198))	('Galphaq', 'Gene', '2776', (191, 198))	('mutations', 'Var', (178, 187))
97261	27060663	Deregulation of the Wnt/beta-catenin signaling pathway is frequently found in diverse cancer types.	('Wnt/beta-catenin signaling pathway', 'Pathway', (20, 54))	('signaling pathway', 'biological_process', 'GO:0007165', ('37', '54'))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
97272	27060663	Interestingly, the simultaneously transgenic expression of US28 and its ligand CCL2 increases intestinal epithelial cell proliferation and tumor burden, suggesting that CCL2 may further simulate US28 to promote the activation of beta-catenin signaling in vivo.	('signaling', 'biological_process', 'GO:0023052', ('242', '251'))	('US28', 'Gene', (195, 199))	('US28', 'Gene', (59, 63))	('US28', 'Gene', '3077536', (195, 199))	('tumor', 'Disease', (139, 144))	('CCL', 'molecular_function', 'GO:0044101', ('79', '82'))	('US28', 'Gene', '3077536', (59, 63))	('transgenic', 'Species', '10090', (34, 44))	('epithelial cell proliferation', 'biological_process', 'GO:0050673', ('105', '134'))	('CCL2', 'Gene', '20296', (169, 173))	('expression', 'Var', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('CCL2', 'Gene', '20296', (79, 83))	('ligand', 'molecular_function', 'GO:0005488', ('72', '78'))	('intestinal epithelial cell proliferation', 'CPA', (94, 134))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('CCL2', 'Gene', (169, 173))	('CCL2', 'Gene', (79, 83))	('CCL', 'molecular_function', 'GO:0044101', ('169', '172'))	('increases', 'PosReg', (84, 93))	('promote', 'PosReg', (203, 210))
97273	27060663	Since both vGPCR and US28 strongly induce COX-2 expression, the production of PGE2 will further enhance beta-catenin signaling in vGPCR- or US28-expressing cells, and their neighboring cells.	('COX-2', 'Gene', '5743', (42, 47))	('vGPCR', 'Gene', (11, 16))	('US28', 'Gene', (140, 144))	('PGE2', 'Gene', (78, 82))	('enhance', 'PosReg', (96, 103))	('US28', 'Gene', (21, 25))	('expression', 'MPA', (48, 58))	('US28', 'Gene', '3077536', (140, 144))	('US28', 'Gene', '3077536', (21, 25))	('vGPCR', 'Gene', '4961465', (11, 16))	('vGPCR', 'Gene', '4961465', (130, 135))	('production', 'Var', (64, 74))	('induce', 'PosReg', (35, 41))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))	('COX-2', 'Gene', (42, 47))	('vGPCR', 'Gene', (130, 135))	('beta-catenin signaling', 'MPA', (104, 126))	('PGE2', 'Chemical', 'MESH:D015232', (78, 82))
97280	27060663	The wide-spread of GPCR and G protein mutations in cancers highlight the oncogenic potential of these proteins.	('GPCR', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('G protein', 'Protein', (28, 37))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('mutations', 'Var', (38, 47))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
97298	23478236	Finally, mutations in the GNAQ/GNA11 genes activating the MAP kinase pathway and in the BAP1 (BRCA1-associated protein 1) gene have recently been described in UM.	('GNAQ/GNA11', 'Gene', (26, 36))	('mutations', 'Var', (9, 18))	('MAP kinase pathway', 'Pathway', (58, 76))	('BRCA1-associated protein 1', 'Gene', '8314', (94, 120))	('BRCA1-associated protein 1', 'Gene', (94, 120))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('activating', 'PosReg', (43, 53))	('BAP1', 'Gene', (88, 92))	('MAP', 'molecular_function', 'GO:0004239', ('58', '61'))
97299	23478236	Whereas GNAQ and GNA11 mutational status does not impact the outcome of UM patients, BAP1 mutations have been correlated with high-risk metastatic Class 2 patients.	('BAP1', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))	('metastatic Class 2', 'Disease', (136, 154))	('patients', 'Species', '9606', (75, 83))	('correlated with', 'Reg', (110, 125))	('patients', 'Species', '9606', (155, 163))
97309	23478236	Among these 25 preclinical models, 15 were included in this study, 110 obtained from primary intraocular tumors (MP034/038/041/042/047/055/065/071/077/080), 4 from liver metastases (MM026/052/066/074), and 1 from cutaneous metastasis (MM033).	('intraocular tumors', 'Disease', (93, 111))	('liver metastases', 'Disease', (164, 180))	('cutaneous metastasis', 'Disease', (213, 233))	('MM026/052/066/074', 'Var', (182, 199))	('liver metastases', 'Disease', 'MESH:D009362', (164, 180))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cutaneous metastasis', 'Disease', 'MESH:D009362', (213, 233))	('intraocular tumors', 'Disease', 'MESH:D064090', (93, 111))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('ocular tumors', 'Phenotype', 'HP:0100012', (98, 111))	('MP034/038/041/042/047/055/065/071/077/080', 'Var', (113, 154))
97316	23478236	As uveal melanoma genomes show monosomy or isodisomy for chromosome 3, a normal DNA was mixed with the samples to form he terodimers during the EMMA process.	('uveal melanoma', 'Disease', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('isodisomy', 'Var', (43, 52))	('chromosome', 'cellular_component', 'GO:0005694', ('57', '67'))	('monosomy', 'Var', (31, 39))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))
97331	23478236	A specific primer/probes set (assay id: Hs01109276_g1, Life Technologies) that measures the junction of exon 16 and 17 was used to performed the relative quantification to GAPDH expression (Hs03929097_g1).	('Hs03929097_g1', 'Var', (190, 203))	('GAPDH', 'Gene', (172, 177))	('GAPDH', 'Gene', '2597', (172, 177))
97351	23478236	Overall, 94% of the xenografted tumors studied display GNAQ or GNA11 mutations, a percentage fairly similar to that reported in UM patients.	('patients', 'Species', '9606', (131, 139))	('mutations', 'Var', (69, 78))	('tumors', 'Disease', (32, 38))	('GNA11', 'Gene', (63, 68))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('GNAQ', 'Gene', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
97352	23478236	Most of the GNAQ mutations observed were missense mutations in exon 5 (c.626A > C) changing a glycine to a proline, leading to a major modification of the alpha subunit.	('c.626A > C', 'Var', (71, 81))	('GNAQ', 'Gene', (12, 16))	('glycine', 'Chemical', 'MESH:D005998', (94, 101))	('alpha subunit', 'MPA', (155, 168))	('missense mutations', 'Var', (41, 59))	('c.626A > C', 'Mutation', 'rs121913492', (71, 81))	('proline', 'Chemical', 'MESH:D011392', (107, 114))	('modification', 'Reg', (135, 147))	('changing', 'Reg', (83, 91))	('mutations', 'Var', (17, 26))	('glycine', 'MPA', (94, 101))
97353	23478236	GNA11 mutations were mostly found in exon 5 on the same Gln209.	('Gln209', 'Chemical', '-', (56, 62))	('Gln209', 'Var', (56, 62))	('GNA11', 'Gene', (0, 5))
97354	23478236	BAP1 deleterious mutations were detected in 7/15 xenografts (47%) and also showed complete concordance with the mutational status of the corresponding patient tumors (Table 1).	('BAP1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('patient', 'Species', '9606', (151, 158))	('tumors', 'Disease', (159, 165))	('detected', 'Reg', (32, 40))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('mutations', 'Var', (17, 26))
97355	23478236	Frameshift truncated mutations were found in 4 models (MP042: c.662del/p.Glu221GlyfsX10; MP047: c.862_920del, p.Ala288GlnfsX90; MP065: c.1717del, p.Leu573TrpfsX3; MM074: c.790del, p.Arg264GlufsX2).	('p.Arg264GlufsX2', 'Mutation', 'p.R264EfsX2', (180, 195))	('p.Ala288GlnfsX90', 'Mutation', 'p.A288QfsX90', (110, 126))	('p.Leu573TrpfsX3', 'FRAMESHIFT', 'None', (146, 161))	('c.862_920del', 'Mutation', 'c.862_920del', (96, 108))	('p.Arg264GlufsX2', 'Var', (180, 195))	('c.790del', 'Mutation', 'c.790del', (170, 178))	('c.662del', 'Mutation', 'c.662del', (62, 70))	('p.Glu221GlyfsX10', 'Var', (71, 87))	('p.Leu573TrpfsX3', 'Var', (146, 161))	('p.Ala288GlnfsX90; MP065: c.1717del', 'Var', (110, 144))	('p.Glu221GlyfsX10', 'FRAMESHIFT', 'None', (71, 87))	('c.1717del', 'Mutation', 'c.1717del', (135, 144))
97356	23478236	A nonsense mutation was found in MM052 (c.781C > T, p.Gln261X).	('p.Gln261X', 'Var', (52, 61))	('c.781C > T', 'Mutation', 'rs772448753', (40, 50))	('p.Gln261X', 'Mutation', 'rs772448753', (52, 61))	('MM052', 'Gene', (33, 38))	('c.781C > T', 'Var', (40, 50))
97357	23478236	A non-truncated mutation was detected in MP055 modifying the aminoacid 172, a serine to an arginine (c.516C > G, p.Ser172Arg).	('serine', 'Chemical', 'MESH:D012694', (78, 84))	('Ser', 'cellular_component', 'GO:0005790', ('115', '118'))	('arginine', 'Chemical', 'MESH:D001120', (91, 99))	('c.516C > G', 'Var', (101, 111))	('c.516C > G', 'Mutation', 'rs953102685', (101, 111))	('p.Ser172Arg', 'Mutation', 'rs768933780', (113, 124))	('p.Ser172Arg', 'Var', (113, 124))	('aminoacid 172', 'MPA', (61, 74))
97358	23478236	Finally, in MP038 was detected a deletion of 14 pb in intron 2 (c.68-9_72del) leading putatively to the loss of a splice site.	('a splice site', 'MPA', (112, 125))	('loss', 'NegReg', (104, 108))	('c.68-9_72del', 'Mutation', 'c.68-9_72del', (64, 76))	('deletion', 'Var', (33, 41))
97359	23478236	No BRAF mutations were detected, as previously reported in UM patients (Table 1).	('BRAF', 'Gene', (3, 7))	('BRAF', 'Gene', '673', (3, 7))	('patients', 'Species', '9606', (62, 70))	('mutations', 'Var', (8, 17))
97360	23478236	We then evaluated whether mutational status could impact in vivo growth of patient tumors transplanted into mice.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('impact', 'Reg', (50, 56))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('mice', 'Species', '10090', (108, 112))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('mutational', 'Var', (26, 36))	('patient', 'Species', '9606', (75, 82))
97364	23478236	No correlation was observed between the capacity of tumors to grow in immunodeficient mice and their mutational status of BAP1 (Table 4S supplementary data).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('BAP1', 'Gene', (122, 126))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('mice', 'Species', '10090', (86, 90))	('immunodeficient', 'Disease', (70, 85))	('mutational', 'Var', (101, 111))	('immunodeficient', 'Disease', 'MESH:D007153', (70, 85))
97366	23478236	Among all these tumor samples, detection of copy number alterations revealed that 18 tumors (51%) presented a loss of chromosome 1p, 22 tumors (63%) a gain of 1q, 26 tumors (74%) a loss of 3, 16 tumors (46%) a gain of 6p, 27 tumors (77%) a loss of 6q, 30 tumors (86%) a gain of entire 8q and 4 with a partial gain of 8q, and 16 tumors (46%) a loss of 16q.	('tumor', 'Disease', (85, 90))	('tumors', 'Disease', (136, 142))	('tumor', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumors', 'Disease', (328, 334))	('gain', 'PosReg', (210, 214))	('tumors', 'Disease', (255, 261))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('tumor', 'Disease', (328, 333))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (328, 334))	('tumors', 'Disease', 'MESH:D009369', (255, 261))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('gain', 'PosReg', (270, 274))	('loss', 'NegReg', (343, 347))	('tumors', 'Disease', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumors', 'Disease', (85, 91))	('gain', 'PosReg', (151, 155))	('loss', 'NegReg', (240, 244))	('tumors', 'Disease', (195, 201))	('tumor', 'Disease', (255, 260))	('chromosome', 'cellular_component', 'GO:0005694', ('118', '128'))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('chromosome 1p', 'Protein', (118, 131))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('loss', 'NegReg', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('alterations', 'Var', (56, 67))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('loss', 'NegReg', (181, 185))	('tumors', 'Disease', (225, 231))
97379	23478236	Based on this genomic classification, among the 10 primary tumors models, 7 models were class 2, 1 was class 1 and 2 were undetermined (MP034 presented a partial deletion of chromosome 3 and MP042 was only analyzed by FISH).	('MP034', 'Var', (136, 141))	('partial deletion', 'Var', (154, 170))	('primary tumors', 'Disease', (51, 65))	('chromosome', 'cellular_component', 'GO:0005694', ('174', '184'))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('primary tumors', 'Disease', 'MESH:D009369', (51, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
97402	23478236	Nevertheless, we observed lower expression levels in BAP1 deleterious mutated tumors (Figure 3A) and a good correlation of BAP1 mRNA expression between xenografted tumors and corresponding patients' tumors.	('tumors', 'Disease', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('patients', 'Species', '9606', (189, 197))	('expression levels', 'MPA', (32, 49))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('deleterious mutated', 'Var', (58, 77))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('mRNA expression', 'MPA', (128, 143))	('lower', 'NegReg', (26, 31))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', (164, 170))	('BAP1', 'Gene', (53, 57))	('BAP1', 'Gene', (123, 127))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
97405	23478236	It is noteworthy to note that, in all BAP1 non-mutated tumors except one model (MP71), BAP1 protein was localized into the nucleus (Figure 3C).	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('nucleus', 'cellular_component', 'GO:0005634', ('123', '130'))	('BAP1', 'Gene', (38, 42))	('non-mutated', 'Var', (43, 54))	('BAP1', 'Gene', (87, 91))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('protein', 'Protein', (92, 99))
97406	23478236	Mutations in the GNAQ/GNA11 genes are known to activate the MAP kinase pathway, which possibly contributes to the tumorigenesis process.	('contributes', 'Reg', (95, 106))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('MAP kinase pathway', 'Pathway', (60, 78))	('activate', 'PosReg', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('MAP', 'molecular_function', 'GO:0004239', ('60', '63'))	('GNAQ/GNA11', 'Gene', (17, 27))	('tumor', 'Disease', (114, 119))	('Mutations', 'Var', (0, 9))
97415	23478236	A majority of studied tumors were defined by at least genomic alterations of chromosomes 3 and 8, as previously associated with high risk of metastasis in UM patients, and were classified as class 2 after SVM classification by gene expression profiling assay.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('gene expression', 'biological_process', 'GO:0010467', ('227', '242'))	('patients', 'Species', '9606', (158, 166))	('genomic alterations', 'Var', (54, 73))	('tumors', 'Disease', (22, 28))	('associated', 'Reg', (112, 122))
97419	23478236	Focusing on two specific markers (KRAS gene mutation and SMAD4/DPC4 expression) in 12 models of pancreatic carcinoma, Rubio-Viqueira et al.	('KRAS', 'Gene', '3845', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('mutation', 'Var', (44, 52))	('DPC4', 'Gene', (63, 67))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (96, 116))	('SMAD4', 'Gene', (57, 62))	('DPC4', 'Gene', '4089', (63, 67))	('Rubio-Viqueira', 'Phenotype', 'HP:0040154', (118, 132))	('SMAD4', 'Gene', '4089', (57, 62))	('KRAS', 'Gene', (34, 38))	('pancreatic carcinoma', 'Disease', (96, 116))
97446	27183847	Our data imply that dysregulation of piRNA expression may be associated with development of melanoma.	('piRNA', 'Gene', (37, 42))	('dysregulation', 'Var', (20, 33))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('associated', 'Reg', (61, 71))
97467	27183847	With a spacing of 1 kb this procedure resulted in 175698 unique clusters for medaka and 114741 unique clusters for Xiphophorus.	('175698', 'Var', (50, 56))	('resulted in', 'Reg', (38, 49))	('medaka', 'Species', '8090', (77, 83))	('Xiphophorus', 'Species', '8084', (115, 126))	('114741', 'Var', (88, 94))
97480	27183847	piRNAs processed in the secondary pathway are defined as having any base but uridine at position 1 and adenine at position 10.	('adenine', 'Chemical', 'MESH:D000225', (103, 110))	('secondary pathway', 'Pathway', (24, 41))	('uridine', 'Chemical', 'MESH:D014529', (77, 84))	('uridine', 'Var', (77, 84))
97493	27183847	70582 clusters were expressed in tumor samples and hyperpigmented skin as the non-malignant control.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('70582', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('hyperpigmented skin', 'Phenotype', 'HP:0000953', (51, 70))
97513	27183847	Changing the criterion for defining a cluster from 1 kb to 10 kb would result in 11173 clusters for medaka and 30473 clusters for Xiphophorus.	('11173', 'Var', (81, 86))	('result in', 'Reg', (71, 80))	('30473', 'Var', (111, 116))	('Xiphophorus', 'Species', '8084', (130, 141))	('medaka', 'Species', '8090', (100, 106))
97514	27183847	The high number of clusters for Xiphophorus with a 10 kb spacing can be caused by an almost 3x higher number of genomic scaffolds and a 4.6x shorter scaffold N50 in the Xiphophorus genome compared to medaka.	('medaka', 'Species', '8090', (200, 206))	('higher', 'PosReg', (95, 101))	('Xiphophorus', 'Species', '8084', (169, 180))	('N50', 'Var', (158, 161))	('shorter', 'NegReg', (141, 148))	('Xiphophorus genome', 'Disease', (169, 187))	('Xiphophorus genome', 'Disease', 'MESH:D042822', (169, 187))	('Xiphophorus', 'Species', '8084', (32, 43))
97527	27183847	Our dataset showed overexpression of piwi genes, and the same result is frequently found in human cancers, The murine PIWI/AGO gene subfamily MILI has been found to be able to methylate LINE1, which is crucial for the expression of melanoma antigen family A (MAGEA) and thus for tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('melanoma', 'Disease', (232, 240))	('cancers', 'Disease', (98, 105))	('overexpression', 'PosReg', (19, 33))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('piwi', 'Gene', (37, 41))	('methylate', 'Var', (176, 185))	('MILI', 'Gene', '57746', (142, 146))	('MILI', 'Gene', (142, 146))	('tumor', 'Disease', (279, 284))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('melanoma', 'Disease', 'MESH:D008545', (232, 240))	('LINE1', 'Gene', (186, 191))	('human', 'Species', '9606', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('piwi', 'Gene', '9271', (37, 41))	('murine', 'Species', '10090', (111, 117))
97532	27183847	PIWIL1,2,3 and PIWIL4 have been found to be mutated in skin cancer.	('PIWIL1,2,3', 'Gene', '100301587;100301588', (0, 10))	('mutated', 'Var', (44, 51))	('skin cancer', 'Phenotype', 'HP:0008069', (55, 66))	('skin cancer', 'Disease', (55, 66))	('skin cancer', 'Disease', 'MESH:D012878', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
97533	27183847	Human piRNA_015520 was shown to negatively regulate the human melatonin receptor 1A gene, which is expressed in adult human testes and brain.	('Human', 'Species', '9606', (0, 5))	('human', 'Species', '9606', (56, 61))	('piRNA_015520', 'Var', (6, 18))	('melatonin receptor 1A', 'Gene', '4543', (62, 83))	('negatively', 'NegReg', (32, 42))	('human', 'Species', '9606', (118, 123))	('melatonin receptor 1A', 'Gene', (62, 83))
97535	27183847	In previous studies we showed that in Xiphophorus TX-1, an active LTR-containing retrotransposon, causes a disruption of the Xmrk oncogene and thus repressed tumor formation.	('tumor', 'Disease', (158, 163))	('causes', 'Reg', (98, 104))	('Xmrk oncogene', 'Gene', (125, 138))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('disruption', 'Var', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('formation', 'biological_process', 'GO:0009058', ('164', '173'))	('Xiphophorus', 'Species', '8084', (38, 49))
97606	26846877	Overall survival analysis revealed that the patients with high legumain expression exhibited poorer survival than patients with low/negative legumain expression.	('survival', 'MPA', (100, 108))	('legumain', 'Gene', (141, 149))	('patients', 'Species', '9606', (44, 52))	('legumain', 'Gene', '5641', (63, 71))	('poorer', 'NegReg', (93, 99))	('legumain', 'Gene', (63, 71))	('high', 'Var', (58, 62))	('patients', 'Species', '9606', (114, 122))	('legumain', 'Gene', '5641', (141, 149))
97654	26846877	The total score was defined as the sum of the extent and intensity of legumain staining, and the specimens were divided into two groups based on their total scores: Negative or low legumain expression was defined as a total score of 0-2, while high legumain expression was defined as a total score of 3-4.	('legumain', 'Gene', '5641', (249, 257))	('legumain', 'Gene', (249, 257))	('Negative', 'Var', (165, 173))	('legumain', 'Gene', (181, 189))	('legumain', 'Gene', '5641', (181, 189))	('legumain', 'Gene', '5641', (70, 78))	('low', 'NegReg', (177, 180))	('legumain', 'Gene', (70, 78))
97692	26846877	These results indicated that high legumain expression is a negative prognostic factor for UM.	('high', 'Var', (29, 33))	('UM', 'Phenotype', 'HP:0007716', (90, 92))	('legumain', 'Gene', '5641', (34, 42))	('legumain', 'Gene', (34, 42))	('expression', 'MPA', (43, 53))
97699	26846877	Considering the general mechanism of tumor progression, legumain expression may have a causal association with metastasis by promoting UM metastasis via enhancing the local invasion of UM cells.	('legumain', 'Gene', '5641', (56, 64))	('UM', 'Phenotype', 'HP:0007716', (185, 187))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('UM', 'Phenotype', 'HP:0007716', (135, 137))	('metastasis', 'Disease', (111, 121))	('promoting', 'PosReg', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('local invasion of UM cells', 'CPA', (167, 193))	('UM metastasis', 'CPA', (135, 148))	('enhancing', 'PosReg', (153, 162))	('expression', 'Var', (65, 75))	('legumain', 'Gene', (56, 64))
97700	26846877	While no causal association was present between large tumor size and high legumain expression, the likelihood of local invasion may have been increased in large-size tumors, which was promoted by legumain in parallel.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('legumain', 'Gene', '5641', (74, 82))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('local invasion', 'CPA', (113, 127))	('tumors', 'Disease', (166, 172))	('legumain', 'Gene', (74, 82))	('legumain', 'Gene', '5641', (196, 204))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('legumain', 'Gene', (196, 204))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('high', 'Var', (69, 73))	('expression', 'MPA', (83, 93))	('tumor', 'Disease', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
97717	26846877	Patients with UM tissues exhibiting high and extensive staining of legumain exhibited shorter survival than those with weak and confined legumain staining.	('legumain', 'Gene', (67, 75))	('staining', 'Var', (55, 63))	('legumain', 'Gene', '5641', (67, 75))	('legumain', 'Gene', '5641', (137, 145))	('UM', 'Phenotype', 'HP:0007716', (14, 16))	('shorter', 'NegReg', (86, 93))	('legumain', 'Gene', (137, 145))	('Patients', 'Species', '9606', (0, 8))	('survival', 'CPA', (94, 102))
97722	24478219	Using two published whole exome datasets of uveal melanoma and bladder cancer, we demonstrated gNOME's accuracy of variant annotation and the enrichment of loss of function variants in known cancer pathways.	('bladder cancer', 'Disease', 'MESH:D001749', (63, 77))	('bladder cancer', 'Disease', (63, 77))	('cancer', 'Disease', (191, 197))	('variant', 'Var', (115, 122))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', (71, 77))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (63, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('variants', 'Var', (173, 181))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('uveal melanoma', 'Disease', (44, 58))
97723	24478219	Although studies using whole genome sequencing (WGS) in a large disease population might still be a few years away, proof-of-concept studies on WGS and whole exome sequencing (WES) have already proven the technology to be useful in identifying disease-causing mutations in rare Mendelian disorders.	('mutations', 'Var', (260, 269))	('Mendelian disorders', 'Disease', (278, 297))	('Mendelian disorders', 'Disease', 'MESH:D030342', (278, 297))
97727	24478219	The LoF variants at highly conserved loci that are rare or novel in the European population are selected by setting 1) Allele Frequency::Ancestry 'European' (Figure 2A-1), 2) Allele Frequency::Allele Frequency '<= 1% (rare)' (Figure 2A-2), 3) Functional Impact::Gene impact 'LoF' (Figure 2A-3), and 4) Knowledge Enrichment::GERP++ score >= '2' (Figure 2A-4).	('GERP', 'Gene', '81603', (324, 328))	('GERP', 'Gene', (324, 328))	('variants', 'Var', (8, 16))
97734	24478219	We also annotate predicted impacts on protein function using the database for nonsynonymous SNPs' functional predictions (dbNSFP, https://sites.google.com/site/jpopgen/dbNSFP) that comprises the predicted impacts estimated using the Sorting Intolerant From Tolerant (SIFT), PolyPhen2, MutationTaster, and a likelihood ratio test (LRT).	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('SIFT', 'Disease', 'None', (267, 271))	('SIFT', 'Disease', (267, 271))	('MutationTaster', 'Var', (285, 299))
97735	24478219	Conservation scores according to the Genomic Evolutionary Rate Profiling (GERP++, http://mendel.stanford.org/Sidowlab/downloads/gerp) are used to filter variants per locus, and we used an average score of GERP++ for insertions and deletions (indels).	('gerp', 'Gene', (128, 132))	('GERP', 'Gene', (205, 209))	('GERP', 'Gene', '81603', (205, 209))	('gerp', 'Gene', '81603', (128, 132))	('insertions', 'Var', (216, 226))	('GERP', 'Gene', (74, 78))	('GERP', 'Gene', '81603', (74, 78))	('deletions', 'Var', (231, 240))
97739	24478219	The most burden tests assume that all variants of interest contribute to the phenotype in the same direction while kernel-based tests such as Sequence Kernel Association Test (SKAT) and C-alpha combine both protective and deleterious effects as well as variant-variant interactions.	('variants', 'Var', (38, 46))	('interactions', 'Interaction', (269, 281))	('C-alpha', 'Species', '342041', (186, 193))	('variant-variant', 'CellLine', 'CVCL:7204', (253, 268))	('SKAT', 'Disease', (176, 180))	('SKAT', 'Disease', 'None', (176, 180))
97746	24478219	Of 92 - 137 splice site disrupting (SSD) variants that were found by 4 tools, 69 were discovered in common.	('SSD', 'Disease', 'MESH:C563928', (36, 39))	('variants', 'Var', (41, 49))	('SSD', 'Disease', (36, 39))
97747	24478219	SeattleSeq missed 37 SSD variants that were found by 3 other tools, most of which were suspected from differences in gene models.	('SSD', 'Disease', 'MESH:C563928', (21, 24))	('variants', 'Var', (25, 33))	('SSD', 'Disease', (21, 24))
97748	24478219	ANNOVAR and gNOME took different approaches in describing the SSD variants due to insertions and deletions (indels).	('insertions', 'Var', (82, 92))	('variants', 'Var', (66, 74))	('SSD', 'Disease', 'MESH:C563928', (62, 65))	('deletions', 'Var', (97, 106))	('SSD', 'Disease', (62, 65))
97749	24478219	In gNOME, SSD has priority over other functional consequences if indels were found in canonical splice sites, and vice versa in ANNOVAR.	('SSD', 'Disease', 'MESH:C563928', (10, 13))	('indels', 'Var', (65, 71))	('SSD', 'Disease', (10, 13))
97750	24478219	In 21 cases of ambiguous SSD variants, e.g., insertions at exon-intron junctions, gNOME classified all ambiguous cases as SSD, while other programs report only part of them.	('insertions at', 'Var', (45, 58))	('SSD', 'Disease', 'MESH:C563928', (122, 125))	('SSD', 'Disease', 'MESH:C563928', (25, 28))	('SSD', 'Disease', (122, 125))	('SSD', 'Disease', (25, 28))
97751	24478219	For nonstop variants, 11 out of 15 discordant annotations between gNOME and other tools resulted from the annotation for possible selenocysteine, which was recognized only in gNOME.	('resulted from', 'Reg', (88, 101))	('variants', 'Var', (12, 20))	('nonstop', 'Gene', (4, 11))	('selenocysteine', 'Disease', 'None', (130, 144))	('selenocysteine', 'Disease', (130, 144))
97753	24478219	Harbour and colleagues sequenced two cases of matched tumor and peripheral blood samples using WES to find tumor specific somatic mutations on chromosome 3.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('chromosome', 'cellular_component', 'GO:0005694', ('143', '153'))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mutations', 'Var', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (54, 59))
97754	24478219	They found an inactivating mutation in each tumor sample on BAP1.	('inactivating mutation', 'Var', (14, 35))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('BAP1', 'Gene', '8314', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('BAP1', 'Gene', (60, 64))	('tumor', 'Disease', (44, 49))
97755	24478219	One patient (MM56) had a nonsense mutation (p.W196X) whereas the other (MM70) had an 11-bp deletion (p.Q322fsX100) on the same gene.	('MM56', 'CellLine', 'CVCL:L794', (13, 17))	('patient', 'Species', '9606', (4, 11))	('p.W196X', 'Mutation', 'p.W196X', (44, 51))	('p.Q322fsX100', 'Mutation', 'p.Q322fsX100', (101, 113))	('p.W196X', 'Var', (44, 51))	('p.Q322fsX100', 'Var', (101, 113))
97756	24478219	We processed the downloaded data as described in Materials and Methods, and uploaded the variant files from tumor tissues as cases and those from blood as controls to our pipeline and analyzed as depicted in Figure 2.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('variant', 'Var', (89, 96))	('tumor', 'Disease', (108, 113))
97757	24478219	The variant level analysis of gNOME for MM56 revealed 670 possible somatic mutation candidates in protein coding regions including p.W196X in BAP1.	('MM56', 'CellLine', 'CVCL:L794', (40, 44))	('BAP1', 'Gene', '8314', (142, 146))	('p.W196X', 'Mutation', 'p.W196X', (131, 138))	('p.W196X', 'Var', (131, 138))	('BAP1', 'Gene', (142, 146))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))
97759	24478219	Of these, four nonsynonymous variants - 3 missense and 1 nonsense (p.W196X in BAP1) - were found on chromosome 3.	('p.W196X', 'Mutation', 'p.W196X', (67, 74))	('p.W196X', 'Var', (67, 74))	('BAP1', 'Gene', '8314', (78, 82))	('chromosome', 'cellular_component', 'GO:0005694', ('100', '110'))	('BAP1', 'Gene', (78, 82))
97760	24478219	Similarly, in MM70, the 11bp frameshift deletion in BAP1 was the only high impact tumor-specific nonsynonymous variant on chromosome 3.	('BAP1', 'Gene', '8314', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('chromosome', 'cellular_component', 'GO:0005694', ('122', '132'))	('BAP1', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('11bp frameshift deletion', 'Var', (24, 48))	('tumor', 'Disease', (82, 87))
97762	24478219	Of these genes, frequent somatic mutations in GNAQ from patients with uveal melanoma were previously reported, and the increased protein expression of HEXA was found in metastatic uveal melanoma.	('protein expression', 'MPA', (129, 147))	('patients', 'Species', '9606', (56, 64))	('GNAQ', 'Gene', (46, 50))	('uveal melanoma', 'Disease', (70, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('uveal melanoma', 'Disease', (180, 194))	('uveal melanoma', 'Disease', 'MESH:C536494', (180, 194))	('uveal melanoma', 'Phenotype', 'HP:0007716', (180, 194))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('HEXA', 'Gene', '3073', (151, 155))	('HEXA', 'Gene', (151, 155))	('mutations', 'Var', (33, 42))	('GNAQ', 'Gene', '2776', (46, 50))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('increased', 'PosReg', (119, 128))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
97767	24478219	One variant (g.chr1:22186113T>G on hg19) was found in the blood sample of B17 individual, but not in B17's tumor sample.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('chr1:22186113T>G', 'Var', (15, 31))	('chr1:22186113T>G', 'SUBSTITUTION', 'None', (15, 31))	('hg19', 'Gene', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
97770	24478219	Ninety six genes with the variants that met the criteria were enriched for the cancer related KEGG pathways such as cell cycle (adjusted p-value 0.0014), prostate cancer (adjusted p-value 0.0017), pathways in cancer (adjusted p-value 0.010), arrythmogenic right ventricular cardiomyopathy (adjusted p-value 0.008), and bladder cancer (adjusted p-value 0.013) (Supp.	('prostate cancer', 'Disease', (154, 169))	('bladder cancer', 'Disease', 'MESH:D001749', (319, 333))	('bladder cancer', 'Disease', (319, 333))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('arrythmogenic right ventricular cardiomyopathy', 'Disease', 'MESH:C566255', (242, 288))	('cancer', 'Disease', (327, 333))	('cell', 'CPA', (116, 120))	('bladder cancer', 'Phenotype', 'HP:0009725', (319, 333))	('arrythmogenic right ventricular cardiomyopathy', 'Disease', (242, 288))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (274, 288))	('cancer', 'Disease', (79, 85))	('variants', 'Var', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('KEGG pathways', 'Pathway', (94, 107))	('cell cycle', 'biological_process', 'GO:0007049', ('116', '126'))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('right ventricular cardiomyopathy', 'Phenotype', 'HP:0011663', (256, 288))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (209, 215))	('prostate cancer', 'Disease', 'MESH:D011471', (154, 169))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (154, 169))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
97772	24478219	All validated genomic variants in the uveal melanoma dataset and 93% of 208 validated variants in the TCC dataset were accurately identified with gNOME, and new candidate variants and genes were found.	('uveal melanoma', 'Disease', (38, 52))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('variants', 'Var', (86, 94))	('TCC', 'cellular_component', 'GO:0005579', ('102', '105'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('uveal melanoma', 'Disease', 'MESH:C536494', (38, 52))	('variants', 'Var', (22, 30))
97773	24478219	Additionally, the cancer related pathways were found to be enriched with LoF variants that were exclusively found in tumor samples.	('LoF', 'NegReg', (73, 76))	('variants', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
97790	24376839	Similarly, PTP4A3 promotes cell invasion by increasing MMP2 activity and decreasing the expression of the MMP inhibitor, TIMP2.	('MMP2', 'molecular_function', 'GO:0004228', ('55', '59'))	('MMP2', 'Gene', (55, 59))	('cell invasion', 'CPA', (27, 40))	('increasing', 'PosReg', (44, 54))	('TIMP2', 'Gene', '447572', (121, 126))	('TIMP2', 'Gene', (121, 126))	('promotes', 'PosReg', (18, 26))	('PTP4A3', 'Var', (11, 17))	('activity', 'MPA', (60, 68))	('MMP', 'molecular_function', 'GO:0004235', ('106', '109'))	('expression', 'MPA', (88, 98))	('decreasing', 'NegReg', (73, 83))	('MMP2', 'Gene', '380389', (55, 59))
97793	24376839	For example, knockdown of the protein tyrosine phosphatase SHP2, encoded by PTPN11 in established breast tumors, blocked their growth and reduced metastasis.	('tumors', 'Disease', (105, 111))	('SHP2', 'Gene', (59, 63))	('breast tumors', 'Phenotype', 'HP:0100013', (98, 111))	('reduced', 'NegReg', (138, 145))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('knockdown', 'Var', (13, 22))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('phosphatase', 'molecular_function', 'GO:0016791', ('47', '58'))	('tyrosine phosphatase', 'Gene', (38, 58))	('PTPN11', 'Gene', (76, 82))	('growth', 'CPA', (127, 133))	('PTPN11', 'Gene', '399291', (76, 82))	('SHP2', 'Gene', '399291', (59, 63))	('blocked', 'NegReg', (113, 120))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tyrosine phosphatase', 'Gene', '397709', (38, 58))	('metastasis', 'CPA', (146, 156))	('breast tumors', 'Disease', (98, 111))	('breast tumors', 'Disease', 'MESH:D001943', (98, 111))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
97795	24376839	After establishing PTP4A3 expression pattern during early development in Xenopus laevis embryos, we conducted gain and loss of function experiments in vivo, by microinjecting either PTP4A3 mRNA or morpholinos to target PTP4A3 protein translation.	('protein', 'cellular_component', 'GO:0003675', ('226', '233'))	('protein translation', 'biological_process', 'GO:0006412', ('226', '245'))	('microinjecting', 'Var', (160, 174))	('PTP4A3', 'Gene', (182, 188))	('PTP4A3', 'Gene', (19, 25))	('PTP4A3', 'Gene', (219, 225))	('morpholino', 'Chemical', 'MESH:D060172', (197, 207))
97812	24376839	This was not observed upon co-injection of xlPTP4A3-MO with the mmPTP4A3(C104S) mutant which is devoid of pro-migrating activity (data not shown).	('mmPTP4A3', 'Gene', (64, 72))	('C104S', 'SUBSTITUTION', 'None', (73, 78))	('C104S', 'Var', (73, 78))
97814	24376839	Injection of HA-xlPTP4A3 in one blastomere at two-cell stage embryos induced an enlarged NC domain (Figure 3A, a-d), as shown by xlTWIST expression at stage 21-23 (45% of embryos displayed this phenotype on the injected side, n=46).	('HA-xlPTP4A3', 'Var', (13, 24))	('xlTWIST', 'Gene', (129, 136))	('NC domain', 'MPA', (89, 98))	('xlTWIST', 'Gene', '378698', (129, 136))
97815	24376839	Similar results were obtained upon injection of mmPTP4A3 mRNA, but not with injection of the mutant mmPTP4A3(C104S) (Figure 3C, e-e' and f vs. g-g' and h, n=66 and n=38 respectively).	('C104S', 'SUBSTITUTION', 'None', (109, 114))	('C104S', 'Var', (109, 114))	('mmPTP4A3', 'Gene', (100, 108))	('mmPTP4A3 mRNA', 'Var', (48, 61))
97816	24376839	We tested whether xlPTP4A3 overexpression increased cell proliferation, using phosphoHistone 3 (Ser10) immunodetection (PTP4A3 expressing UM did not show an increase in cell proliferation when compared to the inactive PTP4A3(C104S) mutant, but proliferative response seems to depend on the cell type).	('increased', 'PosReg', (42, 51))	('cell proliferation', 'biological_process', 'GO:0008283', ('169', '187'))	('C104S', 'Var', (225, 230))	('UM', 'Phenotype', 'HP:0007716', (138, 140))	('Ser', 'cellular_component', 'GO:0005790', ('96', '99'))	('cell proliferation', 'CPA', (52, 70))	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('C104S', 'SUBSTITUTION', 'None', (225, 230))
97817	24376839	PRL-3 Inhibitor I specifically reduced uveal melanoma cell OCM1 EGFP-PTP4A3 migration on collagen I, to the value observed for the mutant OCM1 EGFP-PTP4A3(C104S) or OCM1 EGFP expressing cells (Figure 4C).	('collagen', 'molecular_function', 'GO:0005202', ('89', '97'))	('C104S', 'Var', (155, 160))	('reduced', 'NegReg', (31, 38))	('mutant', 'Var', (131, 137))	('PRL-3', 'Gene', (0, 5))	('OCM1', 'Species', '83984', (59, 63))	('OCM1', 'Species', '83984', (165, 169))	('uveal melanoma', 'Phenotype', 'HP:0007716', (39, 53))	('uveal melanoma cell', 'CPA', (39, 58))	('OCM1', 'Species', '83984', (138, 142))	('C104S', 'SUBSTITUTION', 'None', (155, 160))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))
97821	24376839	This effect could be rescued by mmPTP4A3, but not by the phosphatase-dead PTP4A3(C104S) mutant which is devoid of pro-migratory potential.	('C104S', 'SUBSTITUTION', 'None', (81, 86))	('mmPTP4A3', 'Var', (32, 40))	('PTP4A3', 'Gene', (74, 80))	('C104S', 'Var', (81, 86))	('phosphatase', 'molecular_function', 'GO:0016791', ('57', '68'))
97830	21571184	Monosomy 3 and gain of chromosome 8q within the tumor associate with a metastatic phenotype whereas gain of chromosome 6p occurs in tumors with low metastatic risk.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('metastatic', 'Disease', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('chromosome', 'cellular_component', 'GO:0005694', ('23', '33'))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('chromosome', 'cellular_component', 'GO:0005694', ('108', '118'))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('Monosomy 3', 'Var', (0, 10))
97833	21571184	Gain-of-function mutations in BRAF (40-50%) or NRAS (15-25%) are common among cutaneous melanomas of the trunk and extremities.	('trunk', 'cellular_component', 'GO:0043198', ('105', '110'))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (78, 96))	('NRAS', 'Gene', (47, 51))	('BRAF', 'Gene', (30, 34))	('Gain-of-function', 'PosReg', (0, 16))	('BRAF', 'Gene', '673', (30, 34))	('cutaneous melanomas of the trunk', 'Disease', (78, 110))	('NRAS', 'Gene', '4893', (47, 51))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (78, 97))	('cutaneous melanomas of the trunk', 'Disease', 'MESH:C562393', (78, 110))	('mutations', 'Var', (17, 26))
97834	21571184	Increase gene dosage or mutations of KIT (39%) are observed among acral melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('KIT', 'molecular_function', 'GO:0005020', ('37', '40'))	('acral melanomas', 'Phenotype', 'HP:0012060', (66, 81))	('acral melanomas', 'Disease', 'MESH:D008545', (66, 81))	('KIT', 'Gene', (37, 40))	('gene dosage', 'Var', (9, 20))	('mutations', 'Var', (24, 33))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('acral melanomas', 'Disease', (66, 81))
97836	21571184	These genetic alterations lead to activation of the RAS-ERK pathway that is critical for proliferation, survival, migration, and differentiation signals and is virtually activated in the majority of melanomas.	('melanomas', 'Disease', (199, 208))	('RAS-ERK pathway', 'Pathway', (52, 67))	('activation', 'PosReg', (34, 44))	('ERK', 'molecular_function', 'GO:0004707', ('56', '59'))	('melanomas', 'Disease', 'MESH:D008545', (199, 208))	('melanomas', 'Phenotype', 'HP:0002861', (199, 208))	('genetic alterations', 'Var', (6, 25))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))
97837	21571184	Recently, gain-of-function mutations in the GNAQ gene that leads to RAS-ERK activation have been reported in uveal melanoma (83%) as well as in other melanocytic tumors (summarized in Table 1).	('mutations', 'Var', (27, 36))	('melanocytic tumors', 'Disease', (150, 168))	('melanocytic tumors', 'Disease', 'MESH:D009508', (150, 168))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('GNAQ', 'Gene', (44, 48))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('GNAQ', 'Gene', '2776', (44, 48))	('uveal melanoma', 'Disease', 'MESH:C536494', (109, 123))	('gain-of-function', 'PosReg', (10, 26))	('ERK', 'molecular_function', 'GO:0004707', ('72', '75'))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('uveal melanoma', 'Disease', (109, 123))	('RAS-ERK', 'Protein', (68, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('activation', 'PosReg', (76, 86))
97840	21571184	Due to sequence homology to GNAQ, mutations in GNA11 gene were also tested.	('GNAQ', 'Gene', '2776', (28, 32))	('GNA11', 'Gene', '2767', (47, 52))	('GNA11', 'Gene', (47, 52))	('GNAQ', 'Gene', (28, 32))	('mutations', 'Var', (34, 43))
97841	21571184	BRAF mutations were found in 53 (44%) and NRAS in 23 cases (19%), however no mutations in GNAQ or GNA11 were identified.	('NRAS', 'Gene', '4893', (42, 46))	('GNA11', 'Gene', (98, 103))	('GNA11', 'Gene', '2767', (98, 103))	('GNAQ', 'Gene', '2776', (90, 94))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('found', 'Reg', (20, 25))	('BRAF', 'Gene', (0, 4))	('GNAQ', 'Gene', (90, 94))	('NRAS', 'Gene', (42, 46))
97843	21571184	Benign melanocytic proliferations have also been associated with somatic mutations of the oncogenes associated with melanoma suggesting that these events occur early during development of melanocytic tumors.	('oncogenes', 'Gene', (90, 99))	('melanocytic tumors', 'Disease', (188, 206))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('associated', 'Reg', (49, 59))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('Benign melanocytic proliferations', 'Disease', (0, 33))	('Benign melanocytic proliferations', 'Disease', 'MESH:D059545', (0, 33))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('mutations', 'Var', (73, 82))	('melanocytic tumors', 'Disease', 'MESH:D009508', (188, 206))
97844	21571184	Large number of nevi is a risk factor for cutaneous melanoma; BRAF mutations are common in these nevi.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (42, 60))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (42, 60))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('Large number of nevi', 'Phenotype', 'HP:0001054', (0, 20))	('nevi', 'Phenotype', 'HP:0003764', (97, 101))	('mutations', 'Var', (67, 76))	('nevi', 'Phenotype', 'HP:0003764', (16, 20))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('cutaneous melanoma', 'Disease', (42, 60))
97845	21571184	Giant congenital melanocytic nevus is a risk factor for cutanenous melanoma; NRAS mutations are common in this nevus subset.	('nevus', 'Phenotype', 'HP:0003764', (111, 116))	('congenital melanocytic nevus', 'Phenotype', 'HP:0100814', (6, 34))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('nevus', 'Phenotype', 'HP:0003764', (29, 34))	('NRAS', 'Gene', (77, 81))	('melanoma', 'Disease', (67, 75))	('congenital melanocytic nevus', 'Disease', (6, 34))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('mutations', 'Var', (82, 91))	('NRAS', 'Gene', '4893', (77, 81))	('melanocytic nevus', 'Phenotype', 'HP:0000995', (17, 34))	('Giant congenital melanocytic nevus', 'Phenotype', 'HP:0005600', (0, 34))	('congenital melanocytic nevus', 'Disease', 'MESH:C536819', (6, 34))
97846	21571184	GNAQ mutations are found in blue nevus and nevus of Ota.	('blue nevus', 'Disease', (28, 38))	('nevus of Ota', 'Phenotype', 'HP:0009920', (43, 55))	('GNAQ', 'Gene', '2776', (0, 4))	('found', 'Reg', (19, 24))	('nevus', 'Phenotype', 'HP:0003764', (33, 38))	('nevus of Ota', 'Disease', (43, 55))	('mutations', 'Var', (5, 14))	('nevus', 'Phenotype', 'HP:0003764', (43, 48))	('GNAQ', 'Gene', (0, 4))	('blue nevus', 'Phenotype', 'HP:0100814', (28, 38))
97848	21571184	In conclusion, mutations in GNAQ are unique to uveal melanoma subtype and are rare, if any, in cutaneous melanoma.	('uveal melanoma subtype', 'Disease', 'MESH:C536494', (47, 69))	('GNAQ', 'Gene', '2776', (28, 32))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('mutations', 'Var', (15, 24))	('uveal melanoma subtype', 'Disease', (47, 69))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('cutaneous melanoma', 'Disease', (95, 113))	('GNAQ', 'Gene', (28, 32))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (95, 113))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (95, 113))
97854	31755428	For TCGA, UM was classified based on chromosomes 3 and 8 findings including disomy 3 (D3), monosomy 3 (M3), disomy 8 (D8), 8q gain (8qG), or 8q gain multiple (8qGm) and combined into four classes including Class A (D3/D8), Class B (D3/8qG), Class C (M3/8qG), and Class D (M3/8qGm).	('gain', 'PosReg', (126, 130))	('disomy 3', 'Disease', (76, 84))	('gain', 'PosReg', (144, 148))	('UM', 'Disease', 'MESH:C536494', (10, 12))	('monosomy 3', 'Var', (91, 101))
97870	31755428	Subclassification of each T category is judged by (a) the absence of ciliary body (CB) involvement and extraocular extension, (b) the presence of CB involvement, (c) the presence of extraocular extension <=5 mm, (d) the presence of both CB involvement and extraocular extension <=5 mm, and (e) any tumor size category with extraocular extension >5 mm diameter.	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('tumor', 'Disease', (298, 303))	('<=5', 'Var', (204, 207))	('tumor', 'Disease', 'MESH:D009369', (298, 303))
97891	31755428	By combination of cytogenetic abnormalities, Kaplan-Meier risk estimates (3, 5 years) for melanoma-related metastasis for 3, 6, and 8 disomy (1%, 4%) were low compared with higher-risk combinations of monosomy 3, 6p gain, and 8q gain (29%, 29%), monosomy 3, disomy 6, 8q gain, and 8p gain (14%, (not evaluable)), monosomy 3, disomy 6, and 8q gain (27%, 39%), and monosomy 3, disomy 6, 8q gain, and 8p loss (28%, (not evaluable)) [Table 2].	('gain', 'PosReg', (388, 392))	('melanoma', 'Disease', (90, 98))	('disomy 6', 'Disease', 'MESH:D024182', (325, 333))	('monosomy 3', 'Var', (363, 373))	('disomy 6', 'Disease', (258, 266))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('disomy 6', 'Disease', (375, 383))	('monosomy 3', 'Var', (313, 323))	('disomy 6', 'Disease', (325, 333))	('disomy 6', 'Disease', 'MESH:D024182', (258, 266))	('loss', 'NegReg', (401, 405))	('disomy 6', 'Disease', 'MESH:D024182', (375, 383))	('gain', 'PosReg', (342, 346))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
97892	31755428	Later, they correlated melanoma cytogenetics with clinical features and found those with any mutation in chromosomes 3, 6, or 8 (vs. no mutation) showed significant differences in mean age (58 vs. 55 years, P = 0.02), ocular melanocytosis (5% vs. 1%, P = 0.03), mean visual acuity (VA) (20/50 vs. 20/30, P = 0.01), poor VA <=20/200) (15% vs. 9%, P = 0.04), ciliary body location (11% vs. 5%, P < 0.001), increased mean distance to optic disc (5.0 vs. 3.3 mm, P < 0.001), and foveola (4.7 vs. 3.1 mm, P < 0.001), and increased mean basal diameter (12.6 vs. 9.8 mm, P < 0.001) and thickness (5.9 vs. 3.8 mm, P < 0.001).	('ocular melanocytosis', 'Disease', 'MESH:C535835', (218, 238))	('increased', 'PosReg', (516, 525))	('ocular melanocytosis', 'Phenotype', 'HP:0025534', (218, 238))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('increased', 'PosReg', (404, 413))	('melanoma', 'Disease', (23, 31))	('thickness', 'CPA', (579, 588))	('ocular melanocytosis', 'Disease', (218, 238))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('ciliary body location', 'CPA', (357, 378))	('mutation', 'Var', (93, 101))
97896	31755428	They noted 5-year cumulative rate of melanoma-related death differed from those with AJCC stage I and no monosomy 3 or 8q gain (0%) to those with AJCC stage III and monosomy 3 and 8 q gain (73%) [Table 3].	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('monosomy', 'Var', (165, 173))
97897	31755428	By multivariable Cox regression analysis, the largest HRs identified AJCC stage III tumors (HR 8.8 P < 0.001) and tumors with monosomy 3 plus 8q gain (HR 7.95, P < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('III tumors', 'Disease', 'MESH:D009369', (80, 90))	('III tumors', 'Disease', (80, 90))	('monosomy 3 plus 8q gain', 'Var', (126, 149))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('AJCC', 'Gene', (69, 73))
97904	31755428	Furthermore, it was noted that most M3 tumors demonstrated BAP1 alteration and BAP1 mutated tumors revealed unique global DNA methylation profile.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('BAP1', 'Gene', '8314', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('BAP1', 'Gene', (59, 63))	('DNA methylation', 'biological_process', 'GO:0006306', ('122', '137'))	('alteration', 'Var', (64, 74))	('BAP1', 'Gene', (79, 83))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('mutated', 'Var', (84, 91))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (92, 98))	('DNA', 'cellular_component', 'GO:0005574', ('122', '125'))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('BAP1', 'Gene', '8314', (59, 63))	('tumors', 'Disease', (39, 45))	('global DNA methylation profile', 'MPA', (115, 145))
97906	31755428	TCGA used a comprehensive multiplatform assessment of this cohort of UM and found four molecularly distinct and clinically relevant subgroups based on alterations in chromosomes 3 and 8 (disomy 3 (D3), monosomy 3 (M3), disomy 8 (D8), 8q gain (8qG), or 8q gain multiple (8qGm)).	('UM', 'Disease', 'MESH:C536494', (69, 71))	('monosomy 3', 'Var', (202, 212))	('gain', 'PosReg', (237, 241))	('disomy 3', 'Var', (187, 195))	('alterations', 'Var', (151, 162))	('8q gain multiple', 'Var', (252, 268))
97961	31650085	An inflammatory phenotype of uveal melanoma has also been described which features an increased presence of different types of lymphocytes and macrophages, increased HLA class I and II expression, and association with a loss of one chromosome 3.	('loss', 'Var', (220, 224))	('expression', 'MPA', (185, 195))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('increased', 'PosReg', (156, 165))	('increased HLA class', 'Phenotype', 'HP:0002853', (156, 175))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('chromosome', 'cellular_component', 'GO:0005694', ('232', '242'))
98020	30951308	Compound 35, 3R-(4'-hydroxybenzyl)-6,8-dihydroxy-5,7-dimethoxy-4-chromanone, is a homoisoflavonoid that has not been reported previously with a fully substituted ring A. HRMS showed a protonated molecular ion at m/z 347.11254 corresponding to a molecular formula of C18H18O7.	('homoisoflavonoid', 'Chemical', '-', (82, 98))	("35, 3R-(4'-hydroxybenzyl)-6,8-dihydroxy-5,7-dimethoxy-4-chromanone", 'Chemical', '-', (9, 75))	('m/z 347.11254', 'Var', (212, 225))	('C', 'Chemical', 'MESH:D002244', (266, 267))	('C18H18O7', 'Var', (266, 274))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C18H18O7', 'Chemical', '-', (266, 274))
98021	30951308	Characteristic peaks at deltaH 4.37 (H-2alpha, dd, 11.4, 4.1 Hz), deltaH 4.20 (H-2beta, dd, 11.4, 7.2 Hz), 2.79 (H-3, m), deltaH 3.17 (H-9A, dd, 14.0, 4.4 Hz) and deltaH 2.70 (H-9B, dd, 14.0, 10.6 Hz) were indicative of a 3-benzyl-4-chromanone structure and resonances at deltaH 6.79 (2H, 3',5', 8.1 Hz) and deltaH 7.11 (2H, 2' and 6', 8.1 Hz) showed that the B ring was para-disubstituted.	('deltaH', 'Chemical', '-', (122, 128))	('2H', 'Chemical', 'MESH:D003903', (321, 323))	('deltaH', 'Chemical', '-', (308, 314))	('deltaH', 'Chemical', '-', (24, 30))	('deltaH', 'Chemical', '-', (272, 278))	('2H', 'Chemical', 'MESH:D003903', (285, 287))	('deltaH', 'Var', (122, 128))	('deltaH', 'Chemical', '-', (163, 169))	('deltaH', 'Chemical', '-', (66, 72))	('deltaH', 'Var', (24, 30))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('3-benzyl-4-chromanone structure', 'MPA', (222, 253))	('deltaH', 'Var', (66, 72))
98023	30951308	Two methoxy group proton resonances and three exchangeable hydroxy group proton resonances (deltaH 5.59, 6-OH; deltaH 5.39, 8-OH and deltaH 4.74, 4'-OH) could be assigned from correlations seen in the HMBC spectrum (Figure 1).	('deltaH', 'Chemical', '-', (133, 139))	('deltaH 5.39', 'Var', (111, 122))	('deltaH 4.74', 'Var', (133, 144))	('C', 'Chemical', 'MESH:D002244', (204, 205))	('deltaH', 'Chemical', '-', (111, 117))	('deltaH 5.59', 'Var', (92, 103))	('deltaH', 'Chemical', '-', (92, 98))
98040	30951308	This reaction resulted in the reduction of both the 3,9-double bond as well as the carbonyl group at C-4 as shown by the loss of the fully-substituted carbon resonance at deltaC 179.8 (C-4) and the new methylene resonance at deltaC 37.5 (C-4).	('carbonyl group', 'MPA', (83, 97))	('C', 'Chemical', 'MESH:D002244', (176, 177))	('loss', 'NegReg', (121, 125))	('carbon', 'Chemical', 'MESH:D002244', (151, 157))	('C', 'Chemical', 'MESH:D002244', (101, 102))	('carbon', 'Chemical', 'MESH:D002244', (83, 89))	('C', 'Chemical', 'MESH:D002244', (238, 239))	('methylene resonance', 'MPA', (202, 221))	('deltaC', 'Chemical', '-', (225, 231))	('reduction', 'NegReg', (30, 39))	('fully-substituted carbon resonance', 'MPA', (133, 167))	('deltaC', 'Chemical', '-', (171, 177))	('C', 'Chemical', 'MESH:D002244', (185, 186))	('C', 'Chemical', 'MESH:D002244', (230, 231))	('deltaC', 'Var', (171, 177))
98041	30951308	Coupling could clearly be seen in the COSY spectrum between the resonance at deltaH 2.14 (1H, m, H-3) and the resonance at deltaH 2.53 (2H, dd, J = 4.1 and 7.4 Hz, H-4).	('deltaH', 'Chemical', '-', (77, 83))	('2H', 'Chemical', 'MESH:D003903', (136, 138))	('deltaH 2.14', 'Var', (77, 88))	('deltaH', 'Chemical', '-', (123, 129))	('1H', 'Chemical', '-', (90, 92))	('deltaH 2.53', 'Var', (123, 134))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (38, 39))
98047	30951308	A HRESIMS value of m/z 377.0786 [M + H]+ indicated a molecular formula of C19H17O6Cl.	('m/z', 'Var', (19, 22))	('C19H17O6Cl', 'Chemical', '-', (74, 84))	('C19H17O6Cl', 'Var', (74, 84))
98048	30951308	The structure of the product was confirmed by key 1H NMR resonances at deltaH 4.99 (2H, d, J = 1.8 Hz, H-2), 7.75 (1H, bs, H-9), 6.16 (1H, s, H-8) and three methoxy group three-proton resonances at deltaH 3.75 (3H, s), 3.82 (3H, s) and 3.91(3H, s).	('deltaH', 'Chemical', '-', (71, 77))	('deltaH', 'Var', (198, 204))	('3H', 'Chemical', 'MESH:D014316', (241, 243))	('deltaH', 'Var', (71, 77))	('1H', 'Chemical', '-', (115, 117))	('1H', 'Chemical', '-', (135, 137))	('3H', 'Chemical', 'MESH:D014316', (211, 213))	('3H', 'Chemical', 'MESH:D014316', (225, 227))	('1H', 'Chemical', '-', (50, 52))	('2H', 'Chemical', 'MESH:D003903', (84, 86))	('deltaH', 'Chemical', '-', (198, 204))
98061	30951308	The presence of a cyclobutane ring rendered the homoisoflavonoid inactive, regardless of the substituents on rings A and B.	('presence', 'Var', (4, 12))	('homoisoflavonoid', 'Chemical', '-', (48, 64))	('cyclobutane', 'Chemical', 'MESH:D003503', (18, 29))	('inactive', 'MPA', (65, 73))
98228	30237818	Posterior uveal melanomas are very resistant tumors, so doses to eradicate them are associated with a substantial risk of radiation damage to the structures attached, mainly the lens, retina, fovea, and optic nerve.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('uveal melanoma', 'Phenotype', 'HP:0007716', (10, 24))	('tumors', 'Disease', (45, 51))	('doses', 'Var', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('melanomas', 'Phenotype', 'HP:0002861', (16, 25))	('uveal melanomas', 'Disease', (10, 25))	('uveal melanomas', 'Phenotype', 'HP:0007716', (10, 25))	('uveal melanomas', 'Disease', 'MESH:C536494', (10, 25))
98272	30237818	Although, the mechanisms are not fully understood, NGV often causes a profound and irreversible loss of vision.	('loss of vision', 'Disease', 'MESH:D014786', (96, 110))	('causes', 'Reg', (61, 67))	('vision', 'biological_process', 'GO:0007601', ('104', '110'))	('loss of vision', 'Phenotype', 'HP:0000572', (96, 110))	('NGV', 'Var', (51, 54))	('loss of vision', 'Disease', (96, 110))
98276	30237818	Multivariate studies carried out by some authors obtained significant values in many different features depending on the variables analyzed: higher the dose in the opposite retina, high preoperative intraocular pressure, a previous retinal detachment, larger tumor size, high-dose to sclera, high-dose to lens, high-dose to fovea, and male gender.	('retinal detachment', 'Disease', 'MESH:D012163', (232, 250))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('dose', 'MPA', (152, 156))	('high-dose', 'Var', (271, 280))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('higher', 'PosReg', (141, 147))	('tumor', 'Disease', (259, 264))	('retinal detachment', 'Phenotype', 'HP:0000541', (232, 250))	('high preoperative intraocular pressure', 'Phenotype', 'HP:0007906', (181, 219))	('retinal detachment', 'Disease', (232, 250))
98300	28573988	The evolution of molecular science has made it possible to recognize the presence or absence of specific sequences of nucleic acids and abnormalities within certain chromosomal regions that are characteristic of various ocular disease entities.	('absence', 'NegReg', (85, 92))	('various ocular disease entities', 'Disease', (212, 243))	('ocular disease', 'Phenotype', 'HP:0000478', (220, 234))	('abnormalities', 'Var', (136, 149))	('various ocular disease entities', 'Disease', 'MESH:D005128', (212, 243))
98304	28573988	NGS-based approaches have also been developed for the detection of RB1 gene mutations in retinoblastoma.	('retinoblastoma', 'Gene', (89, 103))	('retinoblastoma', 'Gene', '5925', (89, 103))	('mutations', 'Var', (76, 85))	('retinoblastoma', 'Phenotype', 'HP:0009919', (89, 103))	('RB1', 'Gene', (67, 70))	('RB1', 'Gene', '5925', (67, 70))
98311	28573988	In particular, most alveolar but not embryonal variants are characterized by chromosomal translocations t(2;13)(q35;q14) and t(1;13)(p36;q14), which result in the fusion transcripts PAX3/FOXO1 (FKHR) and PAX7/FOXO1 (FKHR), respectively.	('t(2;13)(q35;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (104, 120))	('PAX7', 'Gene', (204, 208))	('FKHR', 'Gene', (194, 198))	('FOXO1', 'Gene', '2308', (209, 214))	('t(1;13)(p36;q14)', 'STRUCTURAL_ABNORMALITY', 'None', (125, 141))	('alveolar', 'Disease', 'MESH:D002282', (20, 28))	('FOXO1', 'Gene', (209, 214))	('PAX7', 'Gene', '5081', (204, 208))	('t(2;13)(q35;q14', 'Var', (104, 119))	('FOXO1', 'Gene', '2308', (187, 192))	('FKHR', 'Gene', (216, 220))	('t(1;13)(p36;q14', 'Var', (125, 140))	('FKHR', 'Gene', '2308', (194, 198))	('PAX3', 'Gene', (182, 186))	('FOXO1', 'Gene', (187, 192))	('PAX3', 'Gene', '5077', (182, 186))	('alveolar', 'Disease', (20, 28))	('FKHR', 'Gene', '2308', (216, 220))
98312	28573988	FISH for rearrangements for FOXO1 can be used for diagnostic confirmation.	('rearrangements', 'Var', (9, 23))	('FOXO1', 'Gene', '2308', (28, 33))	('FOXO1', 'Gene', (28, 33))
98319	28573988	More than 80% of uveal melanomas have mutations in the GNAQ gene or its paralog GNA11 that encodes a G-protein-coupled receptor that is involved in the RAF/MEK/ERK pathway.	('RAF', 'Gene', '22882', (152, 155))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('MEK', 'Gene', '5609', (156, 159))	('ERK', 'Gene', '5594', (160, 163))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('RAF', 'Gene', (152, 155))	('MEK', 'Gene', (156, 159))	('uveal melanomas', 'Disease', 'MESH:C536494', (17, 32))	('mutations', 'Var', (38, 47))	('GNA11', 'Gene', '2767', (80, 85))	('ERK', 'Gene', (160, 163))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))	('ERK', 'molecular_function', 'GO:0004707', ('160', '163'))	('uveal melanomas', 'Disease', (17, 32))	('uveal melanomas', 'Phenotype', 'HP:0007716', (17, 32))	('GNAQ', 'Gene', '2776', (55, 59))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('GNAQ', 'Gene', (55, 59))	('GNA11', 'Gene', (80, 85))
98320	28573988	GNAQ/GNA11 mutations are also found in benign precursor lesions such as congenital ocular melanocytosis and are thought to be initiating events in the pathogenesis of uveal melanoma.	('mutations', 'Var', (11, 20))	('GNA11', 'Gene', (5, 10))	('congenital ocular melanocytosis', 'Disease', (72, 103))	('GNAQ', 'Gene', '2776', (0, 4))	('GNA11', 'Gene', '2767', (5, 10))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('uveal melanoma', 'Phenotype', 'HP:0007716', (167, 181))	('uveal melanoma', 'Disease', 'MESH:C536494', (167, 181))	('pathogenesis', 'biological_process', 'GO:0009405', ('151', '163'))	('GNAQ', 'Gene', (0, 4))	('uveal melanoma', 'Disease', (167, 181))	('ocular melanocytosis', 'Phenotype', 'HP:0025534', (83, 103))	('congenital ocular melanocytosis', 'Disease', 'MESH:C535835', (72, 103))
98321	28573988	The most common chromosomal aberration in uveal melanoma is loss of chromosome 3, which correlates with high mortality.	('loss of', 'Var', (60, 67))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (16, 38))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('uveal melanoma', 'Disease', (42, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
98329	28573988	In addition, Class II tumors typically have major chromosomal abnormalities such as loss of chromosome 3 (monosomy 3) or harbor inactivating mutations in the BAP1 (breast cancer 1-associated protein 1) gene located on chromosome 3.	('breast cancer 1-associated protein 1', 'Gene', '8314', (164, 200))	('Class II tumors', 'Disease', 'MESH:D008312', (13, 28))	('protein', 'cellular_component', 'GO:0003675', ('191', '198'))	('BAP1', 'Gene', (158, 162))	('breast cancer 1-associated protein 1', 'Gene', (164, 200))	('loss', 'NegReg', (84, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('inactivating mutations', 'Var', (128, 150))	('Class II tumors', 'Disease', (13, 28))	('chromosome', 'cellular_component', 'GO:0005694', ('92', '102'))	('chromosome', 'cellular_component', 'GO:0005694', ('218', '228'))	('chromosomal abnormalities', 'Disease', (50, 75))	('BAP1', 'Gene', '8314', (158, 162))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (50, 75))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
98332	28573988	Differentially expressed miRNAs have been correlated with clinicopathologic features in uveal melanomas with monosomy/disomy 3 chromosomal aberrations.	('chromosomal aberration', 'Phenotype', 'HP:0040012', (127, 149))	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (127, 150))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('uveal melanomas', 'Disease', 'MESH:C536494', (88, 103))	('miRNAs', 'Protein', (25, 31))	('monosomy/disomy 3 chromosomal aberrations', 'Var', (109, 150))	('uveal melanomas', 'Disease', (88, 103))	('uveal melanomas', 'Phenotype', 'HP:0007716', (88, 103))
98335	28573988	Development of retinoblastoma is due to inactivation of both alleles of the retinoblastoma susceptibility gene RB1.	('RB1', 'Gene', (111, 114))	('retinoblastoma', 'Gene', (76, 90))	('retinoblastoma', 'Gene', '5925', (76, 90))	('RB1', 'Gene', '5925', (111, 114))	('retinoblastoma', 'Phenotype', 'HP:0009919', (76, 90))	('retinoblastoma', 'Gene', (15, 29))	('retinoblastoma', 'Gene', '5925', (15, 29))	('retinoblastoma', 'Phenotype', 'HP:0009919', (15, 29))	('inactivation', 'Var', (40, 52))
98342	28573988	Chromosomal abnormalities such as 1q and 6p gain, and 16q loss in retinoblastoma suggests that genes on these chromosomes contribute to the development of the disease (for example MDM4 and KIF14 on 1q, E2F3 on 6p, CDH11, and RBL2/p30 on 16q).	('KIF14', 'Gene', '9928', (189, 194))	('retinoblastoma', 'Gene', (66, 80))	('E2F3', 'Var', (202, 206))	('Chromosomal abnormalities', 'Disease', 'MESH:D002869', (0, 25))	('p30', 'Gene', '201161', (230, 233))	('contribute', 'Reg', (122, 132))	('Chromosomal abnormalities', 'Disease', (0, 25))	('loss', 'NegReg', (58, 62))	('MDM4', 'Gene', '4194', (180, 184))	('retinoblastoma', 'Gene', '5925', (66, 80))	('RBL2', 'Gene', (225, 229))	('retinoblastoma', 'Phenotype', 'HP:0009919', (66, 80))	('MDM4', 'Gene', (180, 184))	('RBL2', 'Gene', '5934', (225, 229))	('KIF14', 'Gene', (189, 194))	('p30', 'Gene', (230, 233))	('CDH11', 'Gene', '1009', (214, 219))	('gain', 'PosReg', (44, 48))	('CDH11', 'Gene', (214, 219))
98344	28573988	Recently, a rare subset of unilateral retinoblastoma tumors has been described that lack RB1 gene mutations but instead have amplification of the MYCN oncogene.	('RB1', 'Gene', '5925', (89, 92))	('retinoblastoma', 'Phenotype', 'HP:0009919', (38, 52))	('unilateral retinoblastoma tumors', 'Disease', (27, 59))	('MYCN', 'Gene', (146, 150))	('unilateral retinoblastoma tumors', 'Disease', 'MESH:D012175', (27, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutations', 'Var', (98, 107))	('MYCN', 'Gene', '4613', (146, 150))	('RB1', 'Gene', (89, 92))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('lack', 'NegReg', (84, 88))	('amplification', 'MPA', (125, 138))
98346	28573988	For patients with retinoblastoma, genetic testing is typically done for the detection of mutations in the RB1 gene (sequence analysis, copy number changes, splice site analysis, and promoter methylation).	('RB1', 'Gene', '5925', (106, 109))	('retinoblastoma', 'Phenotype', 'HP:0009919', (18, 32))	('retinoblastoma', 'Gene', (18, 32))	('retinoblastoma', 'Gene', '5925', (18, 32))	('mutations', 'Var', (89, 98))	('patients', 'Species', '9606', (4, 12))	('RB1', 'Gene', (106, 109))	('methylation', 'biological_process', 'GO:0032259', ('191', '202'))
98354	28573988	The identification of immunoglobulin gene rearrangements indicative of clonal B cells populations is useful for the diagnosis of B-cell lymphomas when histology and immunophenotyping are equivocal.	('lymphomas', 'Phenotype', 'HP:0002665', (136, 145))	('rearrangements', 'Var', (42, 56))	('immunoglobulin', 'Protein', (22, 36))	('B-cell lymphomas', 'Disease', 'MESH:D016393', (129, 145))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (129, 145))	('B-cell lymphomas', 'Disease', (129, 145))	('lymphoma', 'Phenotype', 'HP:0002665', (136, 144))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('22', '36'))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (129, 144))
98356	28573988	Rearrangements of the IGH and IGK genes can be tested by PCR if malignant lymphoma is highly suspected [Fig.	('IGH', 'Gene', '3492', (22, 25))	('Rearrangements', 'Var', (0, 14))	('tested', 'Reg', (47, 53))	('IGK', 'Gene', (30, 33))	('IGH', 'Gene', (22, 25))	('lymphoma', 'Phenotype', 'HP:0002665', (74, 82))	('malignant lymphoma', 'Disease', (64, 82))	('IGK', 'Gene', '50802', (30, 33))	('malignant lymphoma', 'Disease', 'MESH:D008223', (64, 82))
98357	28573988	The most common lymphoma of the orbit and ocular adnexa is MALT lymphoma and specific chromosomal translocations have been identified: t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), and t(3;14)(p14.1;q32).	('lymphoma', 'Disease', (64, 72))	('lymphoma', 'Disease', 'MESH:D008223', (64, 72))	('t(14;18)(q32;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (172, 189))	('lymphoma', 'Phenotype', 'HP:0002665', (64, 72))	('t(11;18)(q21;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (135, 152))	('lymphoma', 'Disease', 'MESH:D008223', (16, 24))	('t(1;14)(p22;q32', 'Var', (154, 169))	('lymphoma', 'Phenotype', 'HP:0002665', (16, 24))	('lymphoma of the orbit', 'Phenotype', 'HP:0500091', (16, 37))	('t(11;18)(q21;q21', 'Var', (135, 151))	('MALT lymphoma', 'Disease', (59, 72))	('t(1;14)(p22;q32)', 'STRUCTURAL_ABNORMALITY', 'None', (154, 170))	('MALT lymphoma', 'Disease', 'MESH:D018442', (59, 72))	('t(14;18)(q32;q21', 'Var', (172, 188))	('t(3;14)(p14.1;q32)', 'STRUCTURAL_ABNORMALITY', 'None', (195, 213))	('lymphoma', 'Disease', (16, 24))	('t(3;14)(p14.1;q32', 'Var', (195, 212))
98381	28573988	In uveal melanoma, the loss of chromosome 3 and biallelic inactivating mutations in the BAP1 gene located on chromosome 3p21 encoding the BRCA1-associated protein 1 are known to be strong prognostic features of aggressive tumors and predictors of metastasis.	('chromosome', 'cellular_component', 'GO:0005694', ('31', '41'))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('aggressive tumors', 'Disease', 'MESH:D001523', (211, 228))	('BRCA1-associated protein 1', 'Gene', '8314', (138, 164))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('loss of chromosome', 'Var', (23, 41))	('biallelic inactivating mutations', 'Var', (48, 80))	('BRCA1-associated protein 1', 'Gene', (138, 164))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('aggressive tumors', 'Disease', (211, 228))	('BAP1', 'Gene', '8314', (88, 92))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('BAP1', 'Gene', (88, 92))	('uveal melanoma', 'Disease', (3, 17))
98382	28573988	Given the cost of BAP1 mutation analysis, immunohistochemical staining to assess BAP1 expression is a practical alternative that is more economical and gives faster results.	('BAP1', 'Gene', '8314', (18, 22))	('BAP1', 'Gene', (81, 85))	('mutation', 'Var', (23, 31))	('BAP1', 'Gene', (18, 22))	('BAP1', 'Gene', '8314', (81, 85))
98383	28573988	Negative staining for the BAP1 protein connotes lack of expression, and therefore, a likelihood of BAP1 mutation within the tumor.	('BAP1', 'Gene', (26, 30))	('BAP1', 'Gene', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('lack', 'NegReg', (48, 52))	('tumor', 'Disease', (124, 129))	('expression', 'MPA', (56, 66))	('mutation', 'Var', (104, 112))	('BAP1', 'Gene', '8314', (26, 30))	('BAP1', 'Gene', '8314', (99, 103))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
98384	28573988	A study has demonstrated the strong association between BAP1 staining and BAP1 mutation status with a sensitivity of 88% and specificity of 97%.	('BAP1', 'Gene', '8314', (56, 60))	('BAP1', 'Gene', '8314', (74, 78))	('BAP1', 'Gene', (56, 60))	('mutation', 'Var', (79, 87))	('BAP1', 'Gene', (74, 78))
98387	28573988	Studies on conjunctival melanoma show similarities with cutaneous melanoma, including the presence of mutations in the BRAF proto-oncogene.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('cutaneous melanoma', 'Disease', (56, 74))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (56, 74))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (56, 74))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', (119, 123))	('mutations', 'Var', (102, 111))	('conjunctival melanoma', 'Disease', (11, 32))	('presence', 'Reg', (90, 98))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (11, 32))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (11, 32))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))
98390	28573988	BRAF V600E mutations have been identified in up to 50% of conjunctival melanomas and shown to be associated with a distinct clinicopathological profile, similar to BRAF-mutated cutaneous melanoma.	('V600E mutations', 'Var', (5, 20))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('identified', 'Reg', (31, 41))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('cutaneous melanoma', 'Disease', (177, 195))	('BRAF', 'Gene', '673', (164, 168))	('BRAF', 'Gene', '673', (0, 4))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (177, 195))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (58, 80))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (177, 195))	('conjunctival melanomas', 'Disease', (58, 80))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (58, 79))	('BRAF', 'Gene', (164, 168))	('BRAF', 'Gene', (0, 4))	('associated', 'Reg', (97, 107))
98391	28573988	Immunohistochemical staining can also be used to detect BRAF mutations in the primary conjunctival melanomas.	('BRAF', 'Gene', (56, 60))	('mutations', 'Var', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('conjunctival melanomas', 'Disease', (86, 108))	('melanomas', 'Phenotype', 'HP:0002861', (99, 108))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (86, 108))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (86, 107))	('BRAF', 'Gene', '673', (56, 60))
98402	27060446	Diagnosing a Primary Leptomeningeal Melanoma by Gene Mutation Signature Melanocytic tumors originating in the central nervous system, also termed primary leptomeningeal melanocytic tumors (PLMTs), are rare.	('Melanocytic tumors', 'Disease', (72, 90))	('Gene Mutation', 'Var', (48, 61))	('Primary Leptomeningeal Melanoma', 'Disease', 'MESH:D008577', (13, 44))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Melanocytic tumors', 'Disease', 'MESH:D009508', (72, 90))	('tumors originating in the central nervous system', 'Phenotype', 'HP:0100006', (84, 132))	('leptomeningeal melanocytic tumors', 'Disease', 'MESH:D008577', (154, 187))	('Melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('PLMT', 'Gene', '10400', (189, 193))	('PLMT', 'Gene', (189, 193))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('leptomeningeal melanocytic tumors', 'Disease', (154, 187))	('Primary Leptomeningeal Melanoma', 'Disease', (13, 44))
98417	27060446	Two known mutations were identified, a GNAQ R183C (c.548G>A) and an SF3B1 R625H (c.1874G>A) mutation (Figure 1c).	('R183C', 'Mutation', 'rs397514698', (44, 49))	('c.548G>A', 'Mutation', 'rs397514698', (51, 59))	('GNAQ', 'Gene', (39, 43))	('SF3B1', 'Gene', (68, 73))	('c.1874G>A', 'Mutation', 'rs1057519961', (81, 90))	('c.1874G>A', 'Var', (81, 90))	('SF3B1', 'Gene', '23451', (68, 73))	('R625H (c.1874G>A', 'Var', (74, 90))	('GNAQ', 'Gene', '2776', (39, 43))	('R625H', 'Mutation', 'rs1057519961', (74, 79))
98418	27060446	GNAQ mutations are frequent in uveal melanomas and PLMTs, but they are exceedingly rare in cutaneous melanoma.	('uveal melanomas', 'Disease', 'MESH:C536494', (31, 46))	('uveal melanoma', 'Phenotype', 'HP:0007716', (31, 45))	('GNAQ', 'Gene', '2776', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('frequent', 'Reg', (19, 27))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanomas', 'Phenotype', 'HP:0002861', (37, 46))	('mutations', 'Var', (5, 14))	('uveal melanomas', 'Disease', (31, 46))	('PLMT', 'Gene', '10400', (51, 55))	('PLMT', 'Gene', (51, 55))	('uveal melanomas', 'Phenotype', 'HP:0007716', (31, 46))	('GNAQ', 'Gene', (0, 4))	('cutaneous melanoma', 'Disease', (91, 109))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (91, 109))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (91, 109))
98419	27060446	SF3B1 R625 mutations occur almost exclusively in uveal melanomas, in particular in nonmetastasizing tumors, and to our knowledge have not been described in PLMTs.	('PLMT', 'Gene', '10400', (156, 160))	('mutations', 'Var', (11, 20))	('PLMT', 'Gene', (156, 160))	('SF3B1', 'Gene', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanomas', 'Phenotype', 'HP:0002861', (55, 64))	('R625 mutations', 'Var', (6, 20))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', (100, 106))	('nonmetastasizing', 'Disease', (83, 99))	('SF3B1', 'Gene', '23451', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('uveal melanomas', 'Disease', (49, 64))	('uveal melanomas', 'Phenotype', 'HP:0007716', (49, 64))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('uveal melanomas', 'Disease', 'MESH:C536494', (49, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (49, 63))
98420	27060446	Activating GNAQ mutations co-occurring with SF3B1 R625 mutations have been reported in nonmetastasizing uveal melanomas.	('R625 mutations', 'Var', (50, 64))	('uveal melanomas', 'Disease', 'MESH:C536494', (104, 119))	('Activating', 'PosReg', (0, 10))	('SF3B1', 'Gene', (44, 49))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('mutations', 'Var', (55, 64))	('GNAQ', 'Gene', '2776', (11, 15))	('mutations', 'Var', (16, 25))	('SF3B1', 'Gene', '23451', (44, 49))	('uveal melanomas', 'Disease', (104, 119))	('uveal melanomas', 'Phenotype', 'HP:0007716', (104, 119))	('GNAQ', 'Gene', (11, 15))
98422	27060446	Additionally, metastatic uveal melanomas rarely harbor SF3B1 R625 mutations and generally show loss of BAP1.	('mutations', 'Var', (66, 75))	('SF3B1', 'Gene', '23451', (55, 60))	('BAP1', 'Gene', '8314', (103, 107))	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('R625 mutations', 'Var', (61, 75))	('BAP1', 'Gene', (103, 107))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('uveal melanomas', 'Disease', (25, 40))	('uveal melanomas', 'Phenotype', 'HP:0007716', (25, 40))	('SF3B1', 'Gene', (55, 60))	('uveal melanomas', 'Disease', 'MESH:C536494', (25, 40))	('loss', 'NegReg', (95, 99))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))
98423	27060446	Our tumor lacked a BAP1 mutation and showed preserved nuclear BAP1 protein expression (Figure 1b, BAP1).	('tumor', 'Disease', (4, 9))	('BAP1', 'Gene', (98, 102))	('BAP1', 'Gene', '8314', (62, 66))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('BAP1', 'Gene', '8314', (19, 23))	('BAP1', 'Gene', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('lacked', 'NegReg', (10, 16))	('BAP1', 'Gene', '8314', (98, 102))	('mutation', 'Var', (24, 32))	('BAP1', 'Gene', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
98428	27060446	Tumor progression can then occur by loss of a copy of chromosome 3 and acquisition of inactivating BAP1 mutations, which are associated with a poor prognosis.	('inactivating', 'Var', (86, 98))	('BAP1', 'Gene', (99, 103))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (104, 113))	('chromosome', 'cellular_component', 'GO:0005694', ('54', '64'))	('loss', 'NegReg', (36, 40))	('BAP1', 'Gene', '8314', (99, 103))	('Tumor progression', 'CPA', (0, 17))
98429	27060446	Alternatively, tumor progression can take place by acquisition of mutations in SF3B1 or EIF1AX, which are associated with a favorable prognosis.	('mutations', 'Var', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('EIF1AX', 'Gene', '1964', (88, 94))	('EIF1AX', 'Gene', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('SF3B1', 'Gene', (79, 84))	('tumor', 'Disease', (15, 20))	('SF3B1', 'Gene', '23451', (79, 84))
98430	27060446	Benign PLMTs (melanocytomas) frequently harbor GNAQ or GNA11 mutations, but only rarely EIF1AX, SF3B1, or BAP1 mutations.	('melanocytomas', 'Disease', 'None', (14, 27))	('BAP1', 'Gene', (106, 110))	('EIF1AX', 'Gene', '1964', (88, 94))	('EIF1AX', 'Gene', (88, 94))	('GNAQ', 'Gene', (47, 51))	('SF3B1', 'Gene', (96, 101))	('mutations', 'Var', (61, 70))	('harbor', 'Reg', (40, 46))	('melanocytomas', 'Disease', (14, 27))	('BAP1', 'Gene', '8314', (106, 110))	('GNAQ', 'Gene', '2776', (47, 51))	('SF3B1', 'Gene', '23451', (96, 101))	('PLMT', 'Gene', (7, 11))	('PLMT', 'Gene', '10400', (7, 11))	('GNA11', 'Gene', '2767', (55, 60))	('GNA11', 'Gene', (55, 60))
98431	27060446	However, our recent report of a recurring PLMT having lost a copy of chromosome 3 and harboring an inactivating BAP1 mutation, resulting in BAP1 protein loss, and our current case of a primary leptomeningeal melanoma (malignant PLMT) with an aggressive phenotype harboring a SF3B1 R625 mutation, support the theory that the mutation spectrum in PLMTs is related to uveal melanomas, and that if alterations in the genes SF3B1 or BAP1 are identified, this is likely associated with more malignant tumor behavior.	('PLMT', 'Gene', '10400', (228, 232))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('BAP1', 'Gene', '8314', (428, 432))	('melanomas', 'Phenotype', 'HP:0002861', (371, 380))	('SF3B1', 'Gene', '23451', (275, 280))	('uveal melanomas', 'Disease', (365, 380))	('uveal melanomas', 'Phenotype', 'HP:0007716', (365, 380))	('PLMT', 'molecular_function', 'GO:0000773', ('42', '46'))	('lost', 'NegReg', (54, 58))	('BAP1', 'Gene', (112, 116))	('PLMT', 'Gene', '10400', (345, 349))	('primary leptomeningeal melanoma', 'Disease', 'MESH:D008577', (185, 216))	('PLMT', 'Gene', (228, 232))	('melanoma', 'Phenotype', 'HP:0002861', (371, 379))	('PLMT', 'Gene', '10400', (42, 46))	('BAP1', 'Gene', '8314', (140, 144))	('BAP1', 'Gene', (428, 432))	('PLMT', 'Gene', (345, 349))	('loss', 'NegReg', (153, 157))	('SF3B1', 'Gene', (419, 424))	('PLMT', 'Gene', (42, 46))	('mutation', 'Var', (286, 294))	('malignant tumor', 'Disease', (485, 500))	('primary leptomeningeal melanoma', 'Disease', (185, 216))	('BAP1', 'Gene', (140, 144))	('protein', 'Protein', (145, 152))	('malignant tumor', 'Disease', 'MESH:D018198', (485, 500))	('associated', 'Reg', (464, 474))	('uveal melanomas', 'Disease', 'MESH:C536494', (365, 380))	('uveal melanoma', 'Phenotype', 'HP:0007716', (365, 379))	('tumor', 'Phenotype', 'HP:0002664', (495, 500))	('SF3B1', 'Gene', (275, 280))	('PLMT', 'molecular_function', 'GO:0000773', ('228', '232'))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('chromosome', 'cellular_component', 'GO:0005694', ('69', '79'))	('BAP1', 'Gene', '8314', (112, 116))	('mutation', 'Var', (117, 125))	('SF3B1', 'Gene', '23451', (419, 424))	('alterations', 'Var', (394, 405))
98432	27060446	The presented case identifies an SF3B1 R625 mutation in a PLMT and shows the diagnostic value of genetic analysis in determining the origin of melanocytic tumors in the central nervous system.	('melanocytic tumors', 'Disease', (143, 161))	('melanocytic tumors', 'Disease', 'MESH:D009508', (143, 161))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('SF3B1', 'Gene', '23451', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('R625', 'Var', (39, 43))	('tumors in the central nervous system', 'Phenotype', 'HP:0100006', (155, 191))	('PLMT', 'Gene', '10400', (58, 62))	('PLMT', 'Gene', (58, 62))	('SF3B1', 'Gene', (33, 38))	('PLMT', 'molecular_function', 'GO:0000773', ('58', '62'))
98433	27060446	This report is in line with prior data indicating that activating GNAQ or GNA11 mutations argue for a PLMT.	('GNA11', 'Gene', (74, 79))	('PLMT', 'molecular_function', 'GO:0000773', ('102', '106'))	('mutations', 'Var', (80, 89))	('GNA11', 'Gene', '2767', (74, 79))	('GNAQ', 'Gene', '2776', (66, 70))	('PLMT', 'Gene', '10400', (102, 106))	('PLMT', 'Gene', (102, 106))	('activating', 'PosReg', (55, 65))	('GNAQ', 'Gene', (66, 70))
98434	27060446	Additional alterations in genes, such as SF3B1 or BAP1, could signify more aggressive tumor behavior and, in conjunction with careful evaluation of the histological and clinical presentation, might warrant the diagnosis of a primary leptomeningeal melanoma.	('alterations', 'Var', (11, 22))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('aggressive tumor', 'Disease', 'MESH:D001523', (75, 91))	('signify', 'Reg', (62, 69))	('aggressive tumor', 'Disease', (75, 91))	('BAP1', 'Gene', '8314', (50, 54))	('SF3B1', 'Gene', (41, 46))	('primary leptomeningeal melanoma', 'Disease', (225, 256))	('primary leptomeningeal melanoma', 'Disease', 'MESH:D008577', (225, 256))	('BAP1', 'Gene', (50, 54))	('warrant', 'Reg', (198, 205))	('more', 'PosReg', (70, 74))	('SF3B1', 'Gene', '23451', (41, 46))	('melanoma', 'Phenotype', 'HP:0002861', (248, 256))
98455	28003323	Results revealed that the upregulation of Six3os inhibited normal photoreceptors' cell specification, whereas the knockdown of Six3os prevented the differentiation of bipolar cell and Muller glial.	('prevented', 'NegReg', (134, 143))	('Six3os', 'Var', (127, 133))	('knockdown', 'Var', (114, 123))	('Muller glia', 'Disease', (184, 195))	('upregulation', 'PosReg', (26, 38))	('Muller glia', 'Disease', 'MESH:C537370', (184, 195))	('Six3os', 'Gene', (42, 48))	('inhibited', 'NegReg', (49, 58))
98458	28003323	Results found that the knockdown of MIAT in the developing retinas inhibited amacrine cell and Muller glia differentiation.	('inhibited', 'NegReg', (67, 76))	('MIAT', 'Gene', (36, 40))	('knockdown', 'Var', (23, 32))	('Muller glia', 'Disease', (95, 106))	('Muller glia', 'Disease', 'MESH:C537370', (95, 106))	('MIAT', 'Gene', '440823', (36, 40))
98459	28003323	Furthermore, the overexpression of MIAT-IRES-GFP phenocopies the effects of the knockdown of MIAT by inducing mislocalisation of this nuclear-retained lncRNA.	('mislocalisation', 'MPA', (110, 125))	('knockdown', 'Var', (80, 89))	('MIAT', 'Gene', (35, 39))	('inducing', 'Reg', (101, 109))	('overexpression', 'PosReg', (17, 31))	('MIAT', 'Gene', '440823', (93, 97))	('MIAT', 'Gene', '440823', (35, 39))	('MIAT', 'Gene', (93, 97))
98461	28003323	lncRNA BB283400 To explore the molecular mechanism that controls the uniformity of various retina layers, Krol and colleagues have portrayed a regulatory network consisting of lncRNA BB283400, a retina-specific lncRNA, RNA helicase Ddx3x and miR-183/96/182; this network controls the timing of miR-183/96/182 accumulation in photoreceptors.	('miR-183', 'Gene', '406959', (242, 249))	('miR-183', 'Gene', (242, 249))	('RNA', 'cellular_component', 'GO:0005562', ('219', '222'))	('miR-183', 'Gene', '406959', (294, 301))	('miR-183', 'Gene', (294, 301))	('Ddx3x', 'Gene', '1654', (232, 237))	('lncRNA BB283400', 'Var', (176, 191))	('Ddx3x', 'Gene', (232, 237))
98465	28003323	In the newborn retina, knockdown of TUG1 resulted in malformed or absent outer segments of transfected photoreceptors compared with normal photoreceptors.	('absent', 'NegReg', (66, 72))	('outer segments', 'CPA', (73, 87))	('TUG1', 'Gene', '55000', (36, 40))	('knockdown', 'Var', (23, 32))	('TUG1', 'Gene', (36, 40))
98469	28003323	Meola et al demonstrated that spatiotemporal misexpression of Vax2os disturbs the progression of the cell cycle in photoreceptor progenitor cells.	('cell cycle', 'biological_process', 'GO:0007049', ('101', '111'))	('misexpression', 'Var', (45, 58))	('Vax2os', 'Gene', (62, 68))	('disturbs', 'NegReg', (69, 77))	('rat', 'Species', '10116', (19, 22))	('Vax2os', 'Gene', '574519', (62, 68))
98474	28003323	Defects in photoreceptor phagocytosis would cause severe retinal pathology, but the biochemical mechanisms remain poorly defined.	('cause', 'Reg', (44, 49))	('retinal pathology', 'Disease', 'MESH:D012173', (57, 74))	('photoreceptor phagocytosis', 'CPA', (11, 37))	('Defects', 'Var', (0, 7))	('retinal pathology', 'Disease', (57, 74))	('phagocytosis', 'biological_process', 'GO:0006909', ('25', '37'))
98476	28003323	Eighty-six differentially expressed lncRNAs were identified through comprehensively comparing the transcriptomes of these two cell types, such as RP23-237H8.2, AC135859.1, AL663030.1 and Meg3.	('RP23', 'Gene', '8481', (146, 150))	('RP23', 'Gene', (146, 150))	('Meg3', 'Gene', '55384', (187, 191))	('AL663030.1', 'Var', (172, 182))	('Meg3', 'Gene', (187, 191))
98479	28003323	Joo et al  studied the lncRNA profiles of the corneal epithelium and focused on a small group of lncRNAs that exhibit splicing changes attributed to PNN knockdown, which is responsible for the maintenance of epithelial phenotypes.	('knockdown', 'Var', (153, 162))	('PNN', 'Gene', (149, 152))	('splicing', 'MPA', (118, 126))	('PNN', 'Gene', '5411', (149, 152))	('PNN', 'cellular_component', 'GO:0072534', ('149', '152'))	('splicing', 'biological_process', 'GO:0045292', ('118', '126'))
98488	28003323	SF3B1 mutations that related to differential alternative splicing of lncRNA CRNDE were identified and further confirmed to be associated with good prognosis in an extensive cohort of 105 samples.	('CRNDE', 'Gene', '643911', (76, 81))	('associated', 'Reg', (126, 136))	('SF3B1', 'Gene', (0, 5))	('SF3B1', 'Gene', '23451', (0, 5))	('splicing', 'biological_process', 'GO:0045292', ('57', '65'))	('CRNDE', 'Gene', (76, 81))	('mutations', 'Var', (6, 15))
98498	28003323	Knocking down lncRNA BANCR expression significantly suppressed the retinoblastoma cell proliferation, migration and invasion in vitro.	('rat', 'Species', '10116', (94, 97))	('invasion in vitro', 'CPA', (116, 133))	('BANCR', 'Gene', (21, 26))	('rat', 'Species', '10116', (105, 108))	('cell proliferation', 'biological_process', 'GO:0008283', ('82', '100'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (67, 81))	('suppressed', 'NegReg', (52, 62))	('BANCR', 'Gene', '100885775', (21, 26))	('retinoblastoma', 'Gene', '5925', (67, 81))	('retinoblastoma', 'Gene', (67, 81))	('Knocking', 'Var', (0, 8))
98504	28003323	Furthermore, knocking down lncRNA BANCR expression significantly suppressed the retinoblastoma cell proliferation, migration and invasion in vitro.	('knocking down', 'Var', (13, 26))	('cell proliferation', 'biological_process', 'GO:0008283', ('95', '113'))	('BANCR', 'Gene', (34, 39))	('rat', 'Species', '10116', (118, 121))	('suppressed', 'NegReg', (65, 75))	('retinoblastoma', 'Gene', (80, 94))	('retinoblastoma', 'Gene', '5925', (80, 94))	('BANCR', 'Gene', '100885775', (34, 39))	('retinoblastoma', 'Phenotype', 'HP:0009919', (80, 94))	('rat', 'Species', '10116', (107, 110))
98513	28003323	To illustrate the function of MALAT1, MALAT1 knockdown was carried out, and it was found that the downregulation could obviously ameliorate DR, which is characterised by pericyte loss, capillary degeneration, microvascular leakage and retinal inflammation.	('rat', 'Species', '10116', (201, 204))	('capillary degeneration', 'Disease', 'MESH:C562760', (185, 207))	('rat', 'Species', '10116', (135, 138))	('rat', 'Species', '10116', (9, 12))	('ameliorate', 'PosReg', (129, 139))	('retinal inflammation', 'Disease', (235, 255))	('retinal inflammation', 'Disease', 'MESH:D012164', (235, 255))	('inflammation', 'biological_process', 'GO:0006954', ('243', '255'))	('capillary degeneration', 'Disease', (185, 207))	('downregulation', 'Var', (98, 112))
98514	28003323	Moreover, MALAT1 knockdown could regulate retinal endothelial cell proliferation, migration and tube formation in vitro by functioning as a competing endogenous RNA in the regulation of vascular endothelial growth factor (VEGF) levels by miR-150-5p.	('regulation', 'MPA', (172, 182))	('MALAT1', 'Gene', (10, 16))	('regulation', 'biological_process', 'GO:0065007', ('172', '182'))	('tube formation', 'biological_process', 'GO:0035148', ('96', '110'))	('endothelial cell proliferation', 'biological_process', 'GO:0001935', ('50', '80'))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('186', '220'))	('RNA', 'cellular_component', 'GO:0005562', ('161', '164'))	('tube formation', 'CPA', (96, 110))	('rat', 'Species', '10116', (85, 88))	('miR-150-5p', 'Var', (238, 248))	('retinal endothelial cell proliferation', 'CPA', (42, 80))	('vascular endothelial growth factor', 'Gene', '7422', (186, 220))	('migration', 'CPA', (82, 91))	('vascular endothelial growth factor', 'Gene', (186, 220))	('knockdown', 'Var', (17, 26))	('VEGF', 'Gene', '7422', (222, 226))	('regulate', 'Reg', (33, 41))	('rat', 'Species', '10116', (74, 77))	('VEGF', 'Gene', (222, 226))
98515	28003323	The upregulation of tumour necrosis factor-alpha (TNF-alpha) and ICAM-1 was inhibited by MIAT knockdown, thereby alleviating vascular leakage and inflammation.	('knockdown', 'Var', (94, 103))	('necrosis', 'biological_process', 'GO:0008220', ('27', '35'))	('inflammation', 'biological_process', 'GO:0006954', ('146', '158'))	('inhibited', 'NegReg', (76, 85))	('necrosis', 'biological_process', 'GO:0070265', ('27', '35'))	('inflammation', 'Disease', 'MESH:D007249', (146, 158))	('necrosis', 'biological_process', 'GO:0019835', ('27', '35'))	('ICAM-1', 'Gene', (65, 71))	('necrosis', 'biological_process', 'GO:0001906', ('27', '35'))	('TNF-alpha', 'Gene', '7124', (50, 59))	('alleviating', 'NegReg', (113, 124))	('TNF-alpha', 'Gene', (50, 59))	('tumour necrosis', 'Disease', 'MESH:D009336', (20, 35))	('inflammation', 'Disease', (146, 158))	('tumour necrosis', 'Disease', (20, 35))	('upregulation', 'PosReg', (4, 16))	('necrosis', 'biological_process', 'GO:0008219', ('27', '35'))	('ICAM-1', 'Gene', '3383', (65, 71))	('vascular leakage', 'CPA', (125, 141))	('MIAT', 'Gene', '440823', (89, 93))	('MIAT', 'Gene', (89, 93))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
98517	28003323	Inhibition of MALAT1 may serve as a potential target for antiangiogenic therapy for diabetes-related microvascular complications.	('diabetes', 'Disease', 'MESH:D003920', (84, 92))	('MALAT1', 'Gene', (14, 20))	('diabetes', 'Disease', (84, 92))	('Inhibition', 'Var', (0, 10))
98520	28003323	MEG3 knockdown aggravates retinal vessel dysfunction in vivo and retinal endothelial cell in vitro.	('retinal endothelial cell', 'CPA', (65, 89))	('knockdown', 'Var', (5, 14))	('aggravates', 'PosReg', (15, 25))	('retinal vessel dysfunction', 'Disease', (26, 52))	('retinal vessel dysfunction', 'Disease', 'MESH:D012173', (26, 52))	('MEG3', 'Gene', (0, 4))
98522	28003323	The most probable loci in their association analysis was a lincRNA rs9362054 in an intron of RP1-90L14.1.	('rs9362054', 'Mutation', 'rs9362054', (67, 76))	('RP1', 'Gene', (93, 96))	('RP1', 'Gene', '6101', (93, 96))	('rs9362054', 'Var', (67, 76))
98529	28003323	The lncRNA NR_033585 was significantly upregulated in neovascularised corneas and acts as a pro-angiogenic factor, such as VEGF, whereas the lincRNA chr8:129102060-129109035 reverse strand was found to be markedly downregulated in neovascularised corneas, exhibiting antiangiogenic effects.	('lncRNA', 'Var', (4, 10))	('VEGF', 'Gene', '7422', (123, 127))	('upregulated', 'PosReg', (39, 50))	('NR_033585', 'Var', (11, 20))	('VEGF', 'Gene', (123, 127))	('neovascularised corneas', 'Phenotype', 'HP:0011496', (231, 254))	('neovascularised corneas', 'Phenotype', 'HP:0011496', (54, 77))	('downregulated', 'NegReg', (214, 227))
98532	28003323	Silencing of MALAT1 induced a promigratory response and promoted basal sprouting and migration, whereas proliferation of endothelial cells was inhibited.	('rat', 'Species', '10116', (111, 114))	('MALAT1', 'Gene', (13, 19))	('promigratory response', 'CPA', (30, 51))	('rat', 'Species', '10116', (36, 39))	('rat', 'Species', '10116', (88, 91))	('migration', 'CPA', (85, 94))	('promoted', 'PosReg', (56, 64))	('Silencing', 'Var', (0, 9))	('basal sprouting', 'CPA', (65, 80))
98533	28003323	When angiogenesis was further stimulated by VEGF, MALAT1 knockdown caused discontinuous sprouts indicative of defective proliferation of stalk cells.	('discontinuous sprouts', 'CPA', (74, 95))	('knockdown', 'Var', (57, 66))	('VEGF', 'Gene', (44, 48))	('rat', 'Species', '10116', (127, 130))	('angiogenesis', 'biological_process', 'GO:0001525', ('5', '17'))	('VEGF', 'Gene', '7422', (44, 48))	('MALAT1', 'Gene', (50, 56))	('defective', 'NegReg', (110, 119))
98534	28003323	In vivo studies confirmed that genetic ablation of MALAT1 inhibited proliferation of endothelial cells and reduced neonatal retina vascularisation.	('neonatal retina vascularisation', 'CPA', (115, 146))	('proliferation of endothelial cells', 'CPA', (68, 102))	('retina vascularisation', 'Phenotype', 'HP:0030666', (124, 146))	('rat', 'Species', '10116', (75, 78))	('reduced', 'NegReg', (107, 114))	('MALAT1', 'Gene', (51, 57))	('genetic ablation', 'Var', (31, 47))	('inhibited', 'NegReg', (58, 67))
98535	28003323	Knocking down MALAT1 shifts the balance from a proliferative to a migratory endothelial cell phenotype in vitro, and its genetic deletion restrains vascular growth in vivo.	('shifts', 'Reg', (21, 27))	('vascular growth', 'CPA', (148, 163))	('rat', 'Species', '10116', (54, 57))	('MALAT1', 'Gene', (14, 20))	('rat', 'Species', '10116', (69, 72))	('Knocking', 'Var', (0, 8))	('restrains', 'NegReg', (138, 147))
98543	28003323	MIAT knockdown could repress TNF-alpha-induced abnormal proliferation and migration of human lens epithelial cells (HLECs).	('repress', 'NegReg', (21, 28))	('rat', 'Species', '10116', (77, 80))	('knockdown', 'Var', (5, 14))	('human', 'Species', '9606', (87, 92))	('TNF-alpha', 'Gene', '7124', (29, 38))	('abnormal proliferation and migration', 'Phenotype', 'HP:0002269', (47, 83))	('migration', 'CPA', (74, 83))	('MIAT', 'Gene', '440823', (0, 4))	('abnormal proliferation', 'CPA', (47, 69))	('MIAT', 'Gene', (0, 4))	('TNF-alpha', 'Gene', (29, 38))	('rat', 'Species', '10116', (63, 66))
98548	28003323	MALAT1 knockdown decreases reactive gliosis, Muller cell activation and RGC survival in vivo and in vitro through CREB signalling.	('gliosis', 'Disease', (36, 43))	('decreases', 'NegReg', (17, 26))	('CREB', 'Gene', '1385', (114, 118))	('signalling', 'biological_process', 'GO:0023052', ('119', '129'))	('reactive gliosis', 'biological_process', 'GO:0150103', ('27', '43'))	('MALAT1', 'Gene', (0, 6))	('gliosis', 'Phenotype', 'HP:0002171', (36, 43))	('gliosis', 'Disease', 'MESH:D005911', (36, 43))	('cell activation', 'biological_process', 'GO:0001775', ('52', '67'))	('Muller cell activation', 'CPA', (45, 67))	('RGC survival', 'CPA', (72, 84))	('knockdown', 'Var', (7, 16))	('CREB', 'Gene', (114, 118))
98549	28003323	Thus, the experimental evidence suggests that MALAT1 dysregulation is crucial in neurodegenerative processes.	('rat', 'Species', '10116', (92, 95))	('dysregulation', 'Var', (53, 66))	('neurodegenerative processes', 'Phenotype', 'HP:0002180', (81, 108))	('MALAT1', 'Gene', (46, 52))
98553	28003323	Evidence from recent studies has shown that genetic variants at the chromosome 9p21 locus execute predominant roles in the development and progression of POAG, including the CDKN2B-AS1 and CDKN2B genes and SIX1/SIX6.	('SIX1/SIX6', 'Disease', 'None', (206, 215))	('CDKN2B-AS1', 'Gene', '100048912', (174, 184))	('CDKN2B genes', 'Gene', (189, 201))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('variants', 'Var', (52, 60))	('POAG', 'Disease', (154, 158))	('SIX1/SIX6', 'Disease', (206, 215))	('CDKN2B-AS1', 'Gene', (174, 184))
98560	28003323	In addition, scientists have confirmed five variants of lncRNA CDKN2B-AS1, which have been reported as a significant locus associated with glaucoma in the Caucasian population, in 2219 Japanese individuals.	('associated', 'Reg', (123, 133))	('variants', 'Var', (44, 52))	('CDKN2B-AS1', 'Gene', (63, 73))	('glaucoma', 'Phenotype', 'HP:0000501', (139, 147))	('CDKN2B-AS1', 'Gene', '100048912', (63, 73))	('glaucoma', 'Disease', (139, 147))	('glaucoma', 'Disease', 'MESH:D005901', (139, 147))
98562	28003323	In the subgroup analyses, significant associations were raised for rs10965245 in the CDKN2B-AS1 region with high-pressure glaucoma and rs11849906 in the SIX1/SIX6 region with NPG.	('rs10965245', 'Mutation', 'rs10965245', (67, 77))	('glaucoma', 'Disease', 'MESH:D005901', (122, 130))	('CDKN2B-AS1', 'Gene', '100048912', (85, 95))	('SIX1/SIX6', 'Disease', 'None', (153, 162))	('rs10965245', 'Var', (67, 77))	('glaucoma', 'Disease', (122, 130))	('glaucoma', 'Phenotype', 'HP:0000501', (122, 130))	('CDKN2B-AS1', 'Gene', (85, 95))	('SIX1/SIX6', 'Disease', (153, 162))	('rs11849906', 'Mutation', 'rs11849906', (135, 145))	('rs11849906', 'Var', (135, 145))
98569	28003323	This transgenic mouse model was carried out to study whether this deletion leads to a discernible phenotype in ocular structures implicated in glaucoma.	('leads to', 'Reg', (75, 83))	('glaucoma', 'Disease', 'MESH:D005901', (143, 151))	('glaucoma', 'Disease', (143, 151))	('glaucoma', 'Phenotype', 'HP:0000501', (143, 151))	('mouse', 'Species', '10090', (16, 21))	('deletion', 'Var', (66, 74))
98574	28003323	To identify the genomic basis of XFS, the entire LOXL1 genomic locus was nominated as candidate functional variants in 50 black South African XFS cases and 50 matched controls.	('LOXL1', 'Gene', '4016', (49, 54))	('LOXL1', 'Gene', (49, 54))	('variants', 'Var', (107, 115))
98585	28003323	Although no chromosomal or molecular abnormality has been identified so far, Vu's team revealed a disruption of a novel gene named LINC00237 that is expressed in lymphocytes of control individuals, while normal transcripts were absent in lymphocytes of this patient with MOMO.	('LINC00237', 'Gene', '101180898', (131, 140))	('disruption', 'Var', (98, 108))	('patient', 'Species', '9606', (258, 265))	('LINC00237', 'Gene', (131, 140))
98590	28003323	Mutations in FOXL2, a gene located at 3q23, have been shown to attribute to the syndrome.	('FOXL2', 'Gene', '668', (13, 18))	('syndrome', 'Disease', (80, 88))	('Mutations', 'Var', (0, 9))	('attribute', 'Reg', (63, 72))	('FOXL2', 'Gene', (13, 18))
98660	20458209	A Pilot Study of Bevacizumab and Interferon-alpha2b in Ocular Melanoma We hypothesized that administration of bevacizumab, a monoclonal antibody that neutralizes vascular endothelial growth factor, in combination with high-dose interferon-alpha2b (IFN-alpha2b), an inhibitor of basic fibroblast growth factor, would have clinical activity in patients with metastatic ocular melanoma.	('bevacizumab', 'Chemical', 'MESH:D000068258', (110, 121))	('Ocular Melanoma', 'Disease', 'MESH:D008545', (55, 70))	('IFN', 'Gene', '3439', (248, 251))	('Interferon-alpha2b', 'Gene', '3440', (33, 51))	('melanoma', 'Phenotype', 'HP:0002861', (374, 382))	('antibody', 'cellular_component', 'GO:0019815', ('136', '144'))	('ocular melanoma', 'Disease', (367, 382))	('neutralizes', 'Var', (150, 161))	('IFN', 'Gene', (248, 251))	('vascular endothelial growth factor', 'Gene', '7422', (162, 196))	('antibody', 'cellular_component', 'GO:0019814', ('136', '144'))	('Interferon-alpha2b', 'Gene', (33, 51))	('ocular melanoma', 'Phenotype', 'HP:0007716', (367, 382))	('interferon-alpha2b', 'Gene', '3440', (228, 246))	('interferon-alpha2b', 'Gene', (228, 246))	('vascular endothelial growth factor', 'Gene', (162, 196))	('Bevacizumab', 'Chemical', 'MESH:D000068258', (17, 28))	('ocular melanoma', 'Disease', 'MESH:D008545', (367, 382))	('antibody', 'molecular_function', 'GO:0003823', ('136', '144'))	('Melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('162', '196'))	('patients', 'Species', '9606', (342, 350))	('Ocular Melanoma', 'Phenotype', 'HP:0007716', (55, 70))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('284', '308'))	('antibody', 'cellular_component', 'GO:0042571', ('136', '144'))	('Ocular Melanoma', 'Disease', (55, 70))
98679	20458209	Inhibition of VEGF-induced angiogenesis slows tumor growth in murine models.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('VEGF-induced', 'Gene', (14, 26))	('angiogenesis', 'CPA', (27, 39))	('Inhibition', 'Var', (0, 10))	('murine', 'Species', '10090', (62, 68))	('angiogenesis', 'biological_process', 'GO:0001525', ('27', '39'))	('slows', 'NegReg', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
98684	20458209	A randomized phase III trial demonstrated that the administration of bevacizumab with irinotecan, 5-fluorouracil, and leucovorin led to improved overall survival, progression-free survival, clinical response rate, and duration of response as compared with chemotherapy alone in patients with metastatic colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (303, 320))	('colorectal cancer', 'Phenotype', 'HP:0003003', (303, 320))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (98, 112))	('overall survival', 'CPA', (145, 161))	('progression-free survival', 'CPA', (163, 188))	('colorectal cancer', 'Disease', (303, 320))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('leucovorin', 'Var', (118, 128))	('irinotecan', 'Chemical', 'MESH:D000077146', (86, 96))	('leucovorin', 'Chemical', 'MESH:D002955', (118, 128))	('patients', 'Species', '9606', (278, 286))	('clinical response rate', 'CPA', (190, 212))	('bevacizumab', 'Chemical', 'MESH:D000068258', (69, 80))	('improved', 'PosReg', (136, 144))
98696	20458209	Patients included in this analysis had histologically or cytologically confirmed ocular melanoma, clinical evidence of metastatic disease, and met the following criteria: the ability to provide informed written consent, age >= 18 years, life expectancy >6 months, Eastern Cooperative Oncology Group (ECOG) performance status <=2, normal organ and marrow function: leukocytes >=3000/microL, absolute neutrophil count >=1500/microL, platelets >=100,000/microL, total bilirubin <=2.0 mg/dL, AST and ALT <=2.5 x upper limit of normal, and creatinine <=1.5 mg/dL or creatinine clearance >=60 mL/min/1.73 m2 for patients with creatinine > 1.5 mg/dL.	('platelets', 'MPA', (431, 440))	('>=3000/microL', 'Var', (375, 388))	('Oncology', 'Phenotype', 'HP:0002664', (284, 292))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('AST', 'Gene', (488, 491))	('>=1500/microL', 'Var', (416, 429))	('AST', 'Gene', '26503', (488, 491))	('Patients', 'Species', '9606', (0, 8))	('ALT', 'molecular_function', 'GO:0004021', ('496', '499'))	('creatinine', 'MPA', (535, 545))	('ocular melanoma', 'Disease', 'MESH:D008545', (81, 96))	('ocular melanoma', 'Disease', (81, 96))	('creatinine clearance', 'MPA', (561, 581))	('patients', 'Species', '9606', (606, 614))	('ocular melanoma', 'Phenotype', 'HP:0007716', (81, 96))
98701	20458209	Patients with the factor V Leiden mutation, a history of arterial thromboembolic phenomena, or inadequately controlled hypertension were excluded.	('factor V Leiden', 'Gene', (18, 33))	('hypertension', 'Phenotype', 'HP:0000822', (119, 131))	('factor V Leiden', 'Gene', '2153', (18, 33))	('hypertension', 'Disease', (119, 131))	('mutation', 'Var', (34, 42))	('arterial thromboembolic phenomena', 'Disease', 'MESH:D013923', (57, 90))	('Patients', 'Species', '9606', (0, 8))	('arterial thromboembolic phenomena', 'Disease', (57, 90))	('thromboembolic phenomena', 'Phenotype', 'HP:0001907', (66, 90))	('hypertension', 'Disease', 'MESH:D006973', (119, 131))
98801	24551032	The majority (>85%) of UM express mutations in the G-alpha proteins, that drive the MEK-ERK1/2 pathway.	('G-alpha', 'Gene', '8802', (51, 58))	('G-alpha', 'Gene', (51, 58))	('ERK1', 'molecular_function', 'GO:0004707', ('88', '92'))	('ERK1/2', 'Gene', (88, 94))	('ERK1/2', 'Gene', '5595;5594', (88, 94))	('drive', 'Reg', (74, 79))	('UM', 'Phenotype', 'HP:0007716', (23, 25))	('MEK', 'Gene', (84, 87))	('mutations', 'Var', (34, 43))	('MEK', 'Gene', '5609', (84, 87))
98802	24551032	Thus, we proposed that the combination of MET and MEK inhibition would inhibit the growth and migration of G-alpha protein mutant versus non-mutant UM cells.	('MEK', 'Gene', '5609', (50, 53))	('inhibit', 'NegReg', (71, 78))	('G-alpha', 'Gene', '8802', (107, 114))	('MET', 'Gene', (42, 45))	('UM', 'Phenotype', 'HP:0007716', (148, 150))	('inhibition', 'NegReg', (54, 64))	('MET', 'Gene', '4233', (42, 45))	('G-alpha', 'Gene', (107, 114))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('MEK', 'Gene', (50, 53))	('mutant', 'Var', (123, 129))
98804	24551032	Cells were treated with the small molecule inhibitors AZD6244 (MEKi) and/or MK-8033 (METi) and downstream markers evaluated.	('AZD6244', 'Var', (54, 61))	('MEK', 'Gene', (63, 66))	('MEK', 'Gene', '5609', (63, 66))	('AZD6244', 'Chemical', 'MESH:C517975', (54, 61))	('MK-8033', 'Chemical', 'MESH:C581209', (76, 83))	('MK-8033', 'Var', (76, 83))	('METi', 'Chemical', '-', (85, 89))
98806	24551032	All G-alpha protein mutant UM cell lines express MET mRNA and protein.	('protein', 'cellular_component', 'GO:0003675', ('12', '19'))	('G-alpha', 'Gene', (4, 11))	('UM', 'Phenotype', 'HP:0007716', (27, 29))	('MET', 'Gene', '4233', (49, 52))	('MET', 'Gene', (49, 52))	('G-alpha', 'Gene', '8802', (4, 11))	('mutant', 'Var', (20, 26))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
98809	24551032	The combination MEKi+METi results in significant reduction of proliferation in G-alpha protein mutant cells.	('G-alpha', 'Gene', '8802', (79, 86))	('reduction', 'NegReg', (49, 58))	('METi', 'Chemical', '-', (21, 25))	('proliferation', 'CPA', (62, 75))	('G-alpha', 'Gene', (79, 86))	('MEK', 'Gene', (16, 19))	('mutant', 'Var', (95, 101))	('MEK', 'Gene', '5609', (16, 19))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
98810	24551032	UM cell migration was blocked by METi, but not MEKi treatment.	('MEK', 'Gene', (47, 50))	('MEK', 'Gene', '5609', (47, 50))	('METi', 'Var', (33, 37))	('cell migration', 'biological_process', 'GO:0016477', ('3', '17'))	('METi', 'Chemical', '-', (33, 37))	('UM cell migration', 'CPA', (0, 17))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
98812	24551032	Combining MEKi with METi treatment has added benefit to either treatment alone in reducing G-alpha protein mutant UM cell growth.	('reducing', 'NegReg', (82, 90))	('mutant', 'Var', (107, 113))	('G-alpha', 'Gene', '8802', (91, 98))	('UM', 'Phenotype', 'HP:0007716', (114, 116))	('MEK', 'Gene', (10, 13))	('MEK', 'Gene', '5609', (10, 13))	('cell growth', 'biological_process', 'GO:0016049', ('117', '128'))	('G-alpha', 'Gene', (91, 98))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('METi treatment', 'Chemical', '-', (20, 34))
98818	24551032	The recent identification of activating mutations in the G-alpha protein from the GNAQ gene in uveal melanoma has provided a key insight into potential strategies in which to target uveal melanoma cell growth and survival.	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('GNAQ', 'Gene', (82, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (182, 196))	('cell growth', 'biological_process', 'GO:0016049', ('197', '208'))	('uveal melanoma', 'Disease', 'MESH:C536494', (95, 109))	('mutations', 'Var', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('G-alpha', 'Gene', '8802', (57, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (95, 109))	('uveal melanoma', 'Disease', (95, 109))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('activating', 'PosReg', (29, 39))	('GNAQ', 'Gene', '2776', (82, 86))	('G-alpha', 'Gene', (57, 64))	('uveal melanoma', 'Disease', 'MESH:C536494', (182, 196))	('uveal melanoma', 'Disease', (182, 196))
98819	24551032	The mutations are somatic and occur in either amino acid sites R183 or Q209 turning GNAQ into a dominant oncogene with constitutive RAS/MEK/ERK1/2 signaling activation.	('MEK', 'Gene', (136, 139))	('GNAQ', 'Gene', (84, 88))	('Q209', 'Var', (71, 75))	('MEK', 'Gene', '5609', (136, 139))	('signaling', 'biological_process', 'GO:0023052', ('147', '156'))	('GNAQ', 'Gene', '2776', (84, 88))	('ERK1', 'molecular_function', 'GO:0004707', ('140', '144'))	('R183', 'Var', (63, 67))	('ERK1/2', 'Gene', '5595;5594', (140, 146))	('ERK1/2', 'Gene', (140, 146))
98820	24551032	However, we and others have shown that although small molecule MEK inhibitors can decrease cell growth in GNAQ mutant cells, MEK inhibition alone often fails to mediate significant apoptotic responses in these cells.	('mutant', 'Var', (111, 117))	('decrease', 'NegReg', (82, 90))	('cell growth', 'CPA', (91, 102))	('MEK', 'Gene', (63, 66))	('GNAQ', 'Gene', (106, 110))	('MEK', 'Gene', '5609', (63, 66))	('cell growth', 'biological_process', 'GO:0016049', ('91', '102'))	('MEK', 'Gene', (125, 128))	('MEK', 'Gene', '5609', (125, 128))	('decrease cell growth', 'Phenotype', 'HP:0001510', (82, 102))	('GNAQ', 'Gene', '2776', (106, 110))
98821	24551032	In addition, similar somatic mutations in R183 or Q209 in the GNA11 gene have been reported, and together with the GNAQ, represent approximately 85% of all primary uveal tumors.	('GNAQ', 'Gene', (115, 119))	('uveal tumors', 'Disease', (164, 176))	('uveal tumors', 'Disease', 'MESH:D014604', (164, 176))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('GNAQ', 'Gene', '2776', (115, 119))	('R183', 'Var', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('GNA11', 'Gene', '2767', (62, 67))	('GNA11', 'Gene', (62, 67))	('Q209', 'Var', (50, 54))
98829	24551032	In this study we investigate the effect of MEKi and/or METi treatment on GNAQ mutant and wild-type uveal melanoma cell lines.	('MEK', 'Gene', '5609', (43, 46))	('GNAQ', 'Gene', '2776', (73, 77))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('METi treatment', 'Chemical', '-', (55, 69))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('uveal melanoma', 'Disease', 'MESH:C536494', (99, 113))	('GNAQ', 'Gene', (73, 77))	('uveal melanoma', 'Disease', (99, 113))	('mutant', 'Var', (78, 84))	('MEK', 'Gene', (43, 46))
98830	24551032	Our goal is to determine whether any biological basis exists for combined METi and MEKi treatments as a potential targeted therapy option, and whether the effects are more pronounced in mutant G-alpha protein cells or not.	('protein', 'cellular_component', 'GO:0003675', ('201', '208'))	('G-alpha', 'Gene', '8802', (193, 200))	('MEK', 'Gene', (83, 86))	('mutant', 'Var', (186, 192))	('MEK', 'Gene', '5609', (83, 86))	('G-alpha', 'Gene', (193, 200))	('METi', 'Chemical', '-', (74, 78))
98834	24551032	MK-8033 or AZD6244 were dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution of 10 mM, and then diluted as indicated in fresh medium.	('AZD6244', 'Chemical', 'MESH:C517975', (11, 18))	('DMSO', 'Chemical', 'MESH:D004121', (57, 61))	('MK-8033', 'Chemical', 'MESH:C581209', (0, 7))	('MK-8033', 'Var', (0, 7))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (37, 55))	('AZD6244', 'Var', (11, 18))
98842	24551032	Melanoma cells were plated at a density of 1x104 cells/well in triplicate wells in a 24-well plate in RPMI 1640 growth medium, treated with MK-8033 (0 or 2 microM) and/or AZD6244 (0 or 25 nM) for 72 hours.	('MK-8033', 'Chemical', 'MESH:C581209', (140, 147))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanoma', 'Disease', (0, 8))	('RPMI', 'Chemical', '-', (102, 106))	('MK-8033', 'Var', (140, 147))	('AZD6244', 'Chemical', 'MESH:C517975', (171, 178))
98860	24551032	Cell lines that have been stated to be of uveal melanoma origin, but for which we and others have documented the presence of the BRAF V600E mutation, do not show significant MET protein expression despite displaying detectable MET transcript levels (Figure S1A&B).	('MET', 'Gene', (174, 177))	('MET', 'Gene', '4233', (174, 177))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('V600E', 'Mutation', 'rs113488022', (134, 139))	('MET', 'Gene', (227, 230))	('MET', 'Gene', '4233', (227, 230))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('V600E', 'Var', (134, 139))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('uveal melanoma', 'Disease', (42, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
98862	24551032	To determine the capacity of the small molecule MET inhibitor (MK-8033) to inhibit MET phosphorylation in uveal melanoma cell lines with a GNAQ mutation versus no GNAQ mutation (hereafter "wild-type"), cells were treated with MK-8033 at either 0, 1 or 2.5 microM concentrations (Figure 2A).	('MK-8033', 'Chemical', 'MESH:C581209', (226, 233))	('inhibit', 'NegReg', (75, 82))	('MK-8033', 'Chemical', 'MESH:C581209', (63, 70))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))	('GNAQ', 'Gene', '2776', (163, 167))	('MET', 'Gene', '4233', (48, 51))	('mutation', 'Var', (144, 152))	('MET', 'Gene', (83, 86))	('GNAQ', 'Gene', '2776', (139, 143))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('MET', 'Gene', (48, 51))	('MET', 'Gene', '4233', (83, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('uveal melanoma', 'Disease', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('GNAQ', 'Gene', (163, 167))	('GNAQ', 'Gene', (139, 143))
98863	24551032	METi treatment reduced MET phosphorylation in both GNAQ mutant or wild-type cells by a relatively similar proportion, relative to baseline MET phosphorylation levels.	('GNAQ', 'Gene', '2776', (51, 55))	('MET', 'Gene', (23, 26))	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('MET', 'Gene', '4233', (0, 3))	('mutant', 'Var', (56, 62))	('MET', 'Gene', (0, 3))	('reduced', 'NegReg', (15, 22))	('GNAQ', 'Gene', (51, 55))	('phosphorylation', 'biological_process', 'GO:0016310', ('143', '158'))	('MET', 'Gene', '4233', (139, 142))	('MET', 'Gene', '4233', (23, 26))	('METi treatment', 'Chemical', '-', (0, 14))	('MET', 'Gene', (139, 142))
98864	24551032	To test the combined effect of MEKi and/or METi treatment, GNAQ mutant and wild-type cells were treated with AZD6244 (MEKi) at 25 nM and/or MK-8033 (METi) at 2.5 microM.	('MK-8033', 'Chemical', 'MESH:C581209', (140, 147))	('AZD6244', 'Var', (109, 116))	('MEK', 'Gene', (31, 34))	('MEK', 'Gene', '5609', (31, 34))	('MK-8033', 'Var', (140, 147))	('MEK', 'Gene', (118, 121))	('METi', 'Chemical', '-', (149, 153))	('METi treatment', 'Chemical', '-', (43, 57))	('GNAQ', 'Gene', (59, 63))	('AZD6244', 'Chemical', 'MESH:C517975', (109, 116))	('MEK', 'Gene', '5609', (118, 121))	('mutant', 'Var', (64, 70))	('METi', 'Chemical', '-', (43, 47))	('GNAQ', 'Gene', '2776', (59, 63))
98865	24551032	MEKi treatment resulted in a marked decrease in Erk1/2 phosphorylation in both GNAQ mutant and wild-type cells, although complete inhibition was not observed in wild-type cells.	('phosphorylation', 'biological_process', 'GO:0016310', ('55', '70'))	('Erk1/2', 'Gene', '5595;5594', (48, 54))	('GNAQ', 'Gene', '2776', (79, 83))	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('Erk1/2', 'Gene', (48, 54))	('Erk1', 'molecular_function', 'GO:0004707', ('48', '52'))	('mutant', 'Var', (84, 90))	('GNAQ', 'Gene', (79, 83))	('phosphorylation', 'MPA', (55, 70))	('decrease', 'NegReg', (36, 44))
98866	24551032	METi treatment up to 2.5 microM failed to reduce Erk1/2 phosphorylation in either GNAQ mutant or wild-type cells.	('phosphorylation', 'biological_process', 'GO:0016310', ('56', '71'))	('Erk1/2', 'Gene', '5595;5594', (49, 55))	('GNAQ', 'Gene', (82, 86))	('Erk1', 'molecular_function', 'GO:0004707', ('49', '53'))	('mutant', 'Var', (87, 93))	('Erk1/2', 'Gene', (49, 55))	('phosphorylation', 'MPA', (56, 71))	('GNAQ', 'Gene', '2776', (82, 86))	('METi treatment', 'Chemical', '-', (0, 14))
98867	24551032	The combination MEKi+METi treatment recapitulated the effect of MEKi treatment alone in GNAQ mutant cells, but served to enhance the reduction of MEKi alone treatment in wild-type cells (Figure 2B).	('METi treatment', 'Chemical', '-', (21, 35))	('MEK', 'Gene', (64, 67))	('GNAQ', 'Gene', (88, 92))	('MEK', 'Gene', '5609', (64, 67))	('MEK', 'Gene', (146, 149))	('mutant', 'Var', (93, 99))	('MEK', 'Gene', (16, 19))	('enhance', 'PosReg', (121, 128))	('MEK', 'Gene', '5609', (146, 149))	('GNAQ', 'Gene', '2776', (88, 92))	('MEK', 'Gene', '5609', (16, 19))
98872	24551032	Treatment with either the METi or MEKi alone resulted in a noted decrease in cell proliferation in GNAQ mutant uveal melanoma cells.	('uveal melanoma', 'Phenotype', 'HP:0007716', (111, 125))	('uveal melanoma', 'Disease', 'MESH:C536494', (111, 125))	('cell proliferation', 'biological_process', 'GO:0008283', ('77', '95'))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('uveal melanoma', 'Disease', (111, 125))	('MEK', 'Gene', (34, 37))	('mutant', 'Var', (104, 110))	('MEK', 'Gene', '5609', (34, 37))	('GNAQ', 'Gene', (99, 103))	('decrease', 'NegReg', (65, 73))	('METi', 'Chemical', '-', (26, 30))	('GNAQ', 'Gene', '2776', (99, 103))	('cell proliferation', 'CPA', (77, 95))
98876	24551032	The relative degree of MET knockdown, as determined by MET protein expression, was similar in mutant and wild-type cells (Figure S2A).	('MET', 'Gene', (23, 26))	('MET', 'Gene', '4233', (55, 58))	('mutant', 'Var', (94, 100))	('MET', 'Gene', (55, 58))	('MET', 'Gene', '4233', (23, 26))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
98877	24551032	The siRNA knockdown of MET resulted in a decrease in proliferation in all uveal melanoma cell lines, with a more pronounced effect being observed in mutant cells (Figure S2B).	('MET', 'Gene', (23, 26))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('decrease', 'NegReg', (41, 49))	('mutant', 'Var', (149, 155))	('proliferation', 'CPA', (53, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('uveal melanoma', 'Disease', (74, 88))	('MET', 'Gene', '4233', (23, 26))
98880	24551032	Similarly increased levels of cleaved PARP were observed in GNAQ mutant uveal melanoma cells following either MEKi or METi treatment alone.	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('uveal melanoma', 'Disease', (72, 86))	('GNAQ', 'Gene', (60, 64))	('PARP', 'Gene', '1302', (38, 42))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('cleaved', 'MPA', (30, 37))	('mutant', 'Var', (65, 71))	('PARP', 'Gene', (38, 42))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('MEK', 'Gene', (110, 113))	('METi treatment', 'Chemical', '-', (118, 132))	('MEK', 'Gene', '5609', (110, 113))	('GNAQ', 'Gene', '2776', (60, 64))	('levels', 'MPA', (20, 26))	('increased', 'PosReg', (10, 19))
98881	24551032	The level of cleaved PARP was more enhanced by MEKi+METi combination treatment in GNAQ mutant cells.	('MEK', 'Gene', (47, 50))	('PARP', 'Gene', '1302', (21, 25))	('MEK', 'Gene', '5609', (47, 50))	('level', 'MPA', (4, 9))	('GNAQ', 'Gene', (82, 86))	('PARP', 'Gene', (21, 25))	('METi', 'Chemical', '-', (52, 56))	('enhanced', 'PosReg', (35, 43))	('mutant', 'Var', (87, 93))	('GNAQ', 'Gene', '2776', (82, 86))
98884	24551032	Although low concentrations of each drug were employed in order to identify additive effects, the sub-G0 cell fraction in flow cytometry-based cell cycle analysis was observed to be slightly increased following combination AZD6244+ MK-8033 treatment in the GNAQ mutant cells, consistent with the cleaved PARP results (data not shown).	('sub-G0 cell fraction', 'CPA', (98, 118))	('AZD6244+ MK-8033', 'Var', (223, 239))	('flow cytometry-based', 'CPA', (122, 142))	('PARP', 'Gene', (304, 308))	('AZD6244', 'Chemical', 'MESH:C517975', (223, 230))	('GNAQ', 'Gene', '2776', (257, 261))	('cell fraction', 'cellular_component', 'GO:0000267', ('105', '118'))	('mutant', 'Var', (262, 268))	('GNAQ', 'Gene', (257, 261))	('increased', 'PosReg', (191, 200))	('MK-8033', 'Chemical', 'MESH:C581209', (232, 239))	('cell cycle', 'biological_process', 'GO:0007049', ('143', '153'))	('PARP', 'Gene', '1302', (304, 308))	('MK-8033', 'Var', (232, 239))
98885	24551032	To determine the effect of MEK and/or MET inhibition on cell migration, uveal melanoma cells with a GNAQ mutation were treated with MEKi and/or METi.	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('uveal melanoma', 'Disease', (72, 86))	('mutation', 'Var', (105, 113))	('GNAQ', 'Gene', '2776', (100, 104))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('MEK', 'Gene', (27, 30))	('METi', 'Chemical', '-', (144, 148))	('MEK', 'Gene', '5609', (27, 30))	('MET', 'Gene', (144, 147))	('MET', 'Gene', '4233', (38, 41))	('MET', 'Gene', '4233', (144, 147))	('MET', 'Gene', (38, 41))	('MEK', 'Gene', (132, 135))	('GNAQ', 'Gene', (100, 104))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('MEK', 'Gene', '5609', (132, 135))	('cell migration', 'biological_process', 'GO:0016477', ('56', '70'))
98886	24551032	Figure 6A shows images of stained migrated GNAQ mutant or wild-type cells following 0, 1 and 2.5 microM METi treatment.	('METi treatment', 'Chemical', '-', (104, 118))	('GNAQ', 'Gene', (43, 47))	('GNAQ', 'Gene', '2776', (43, 47))	('mutant', 'Var', (48, 54))
98887	24551032	A marked reduction in cell migration was observed following METi treatment at micromolar concentration levels in all uveal melanoma cells, regardless of mutation or wild-type status (Figure 6B).	('cell migration', 'biological_process', 'GO:0016477', ('22', '36'))	('uveal melanoma', 'Disease', (117, 131))	('reduction', 'NegReg', (9, 18))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('METi', 'Var', (60, 64))	('METi treatment', 'Chemical', '-', (60, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (117, 131))	('uveal melanoma', 'Disease', 'MESH:C536494', (117, 131))	('cell migration', 'CPA', (22, 36))
98888	24551032	Of note, METi treatment had no significant effect on cell migration in the BRAF mutant cell lines tested (Figure S3A), consistent with the lack of MET protein expression in these cells as shown in Figure S1B.	('MET', 'Gene', '4233', (147, 150))	('mutant', 'Var', (80, 86))	('BRAF', 'Gene', '673', (75, 79))	('MET', 'Gene', (147, 150))	('cell migration', 'biological_process', 'GO:0016477', ('53', '67'))	('BRAF', 'Gene', (75, 79))	('METi treatment', 'Chemical', '-', (9, 23))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('MET', 'Gene', '4233', (9, 12))	('cell migration', 'CPA', (53, 67))	('MET', 'Gene', (9, 12))
98892	24551032	We have shown that small molecule inhibition of MEK is insufficient to drive cellular death in the majority of cells with GNAQ/11 mutations, suggesting that other important pathways contributing to cell survival and are active in cells harboring these mutations.	('cellular death', 'CPA', (77, 91))	('GNAQ', 'Gene', (122, 126))	('MEK', 'Gene', (48, 51))	('MEK', 'Gene', '5609', (48, 51))	('mutations', 'Var', (130, 139))	('inhibition', 'NegReg', (34, 44))	('GNAQ', 'Gene', '2776', (122, 126))
98893	24551032	In this study we demonstrate that uveal melanoma cells with a GNAQ mutation express the MET receptor at high levels.	('mutation', 'Var', (67, 75))	('GNAQ', 'Gene', '2776', (62, 66))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('MET', 'Gene', '4233', (88, 91))	('GNAQ', 'Gene', (62, 66))	('uveal melanoma', 'Phenotype', 'HP:0007716', (34, 48))	('uveal melanoma', 'Disease', 'MESH:C536494', (34, 48))	('MET', 'Gene', (88, 91))	('uveal melanoma', 'Disease', (34, 48))
98895	24551032	The METi had the added effect of inhibiting the migration of uveal melanoma cells regardless of GNAQ mutation or wild-type status in all cell lines expressing the MET receptor, suggesting that the migration inhibitory effects of METi are present across all uveal melanoma cell lines with MET expression.	('migration', 'CPA', (48, 57))	('melanoma', 'Phenotype', 'HP:0002861', (263, 271))	('uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('METi', 'Chemical', '-', (229, 233))	('uveal melanoma', 'Disease', 'MESH:C536494', (257, 271))	('uveal melanoma', 'Disease', (257, 271))	('migration', 'CPA', (197, 206))	('MET', 'Gene', (229, 232))	('MET', 'Gene', '4233', (229, 232))	('inhibiting', 'NegReg', (33, 43))	('GNAQ', 'Gene', '2776', (96, 100))	('METi', 'Chemical', '-', (4, 8))	('uveal melanoma', 'Phenotype', 'HP:0007716', (257, 271))	('MET', 'Gene', '4233', (163, 166))	('GNAQ', 'Gene', (96, 100))	('MET', 'Gene', (163, 166))	('MET', 'Gene', (4, 7))	('MET', 'Gene', '4233', (4, 7))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('uveal melanoma', 'Disease', 'MESH:C536494', (61, 75))	('uveal melanoma', 'Disease', (61, 75))	('mutation', 'Var', (101, 109))	('MET', 'Gene', (288, 291))	('MET', 'Gene', '4233', (288, 291))
98896	24551032	An interesting observation in the current study was that the METi alone treatment had growth inhibitory effects on GNAQ mutant cells, but not wild-type cells, at the concentration of METi used in this study.	('METi', 'Chemical', '-', (61, 65))	('GNAQ', 'Gene', (115, 119))	('METi', 'Chemical', '-', (183, 187))	('GNAQ', 'Gene', '2776', (115, 119))	('mutant', 'Var', (120, 126))	('growth inhibitory effects', 'MPA', (86, 111))
98897	24551032	who showed the MET inhibitor SU11274 to more markedly inhibit the proliferation of the uveal melanoma cell lines 92.1 and MEL202, compared to other cell lines tested.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('SU11274', 'Var', (29, 36))	('uveal melanoma', 'Disease', (87, 101))	('inhibit', 'NegReg', (54, 61))	('SU11274', 'Chemical', 'MESH:C478479', (29, 36))	('proliferation', 'CPA', (66, 79))	('MET', 'Gene', '4233', (15, 18))	('MET', 'Gene', (15, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (87, 101))	('uveal melanoma', 'Disease', 'MESH:C536494', (87, 101))
98898	24551032	It has since been determined that the 92.1 and MEL202 cell lines harbor GNAQ mutations, and the other cell lines treated in that study have neither GNAQ nor GNA11 mutations.	('GNAQ', 'Gene', '2776', (72, 76))	('GNAQ', 'Gene', '2776', (148, 152))	('GNA11', 'Gene', '2767', (157, 162))	('GNA11', 'Gene', (157, 162))	('mutations', 'Var', (77, 86))	('GNAQ', 'Gene', (148, 152))	('GNAQ', 'Gene', (72, 76))
98899	24551032	At the doses used in the current study, METi treatment resulted in marked loss of MET phosphorylation in both GNAQ mutant and wild-type cells, although complete extinguishment of MET phosphorylation was not observed in wild-type cells.	('phosphorylation', 'biological_process', 'GO:0016310', ('86', '101'))	('MET', 'Gene', (40, 43))	('MET', 'Gene', (82, 85))	('MET', 'Gene', '4233', (82, 85))	('phosphorylation', 'biological_process', 'GO:0016310', ('183', '198'))	('GNAQ', 'Gene', '2776', (110, 114))	('MET', 'Gene', '4233', (179, 182))	('mutant', 'Var', (115, 121))	('MET', 'Gene', (179, 182))	('loss', 'NegReg', (74, 78))	('GNAQ', 'Gene', (110, 114))	('METi treatment', 'Chemical', '-', (40, 54))	('MET', 'Gene', '4233', (40, 43))
98900	24551032	MET inhibition did not result in marked loss of ERK1/2 phosphorylation in either GNAQ or wild-type cells, thus the growth inhibiting effect of METi treatment in GNAQ mutant uveal melanoma cells may be mediated through a distinctly different signaling pathway.	('uveal melanoma', 'Phenotype', 'HP:0007716', (173, 187))	('signaling pathway', 'biological_process', 'GO:0007165', ('241', '258'))	('ERK1/2', 'Gene', (48, 54))	('MET', 'Gene', '4233', (143, 146))	('MET', 'Gene', '4233', (0, 3))	('MET', 'Gene', (143, 146))	('ERK1/2', 'Gene', '5595;5594', (48, 54))	('MET', 'Gene', (0, 3))	('GNAQ', 'Gene', '2776', (161, 165))	('phosphorylation', 'biological_process', 'GO:0016310', ('55', '70'))	('GNAQ', 'Gene', (161, 165))	('mutant', 'Var', (166, 172))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('GNAQ', 'Gene', '2776', (81, 85))	('growth', 'CPA', (115, 121))	('uveal melanoma', 'Disease', (173, 187))	('uveal melanoma', 'Disease', 'MESH:C536494', (173, 187))	('ERK1', 'molecular_function', 'GO:0004707', ('48', '52'))	('GNAQ', 'Gene', (81, 85))	('METi treatment', 'Chemical', '-', (143, 157))
98902	24551032	The elimination of the HGF induced PI3K phosphorylation following METi treatment (Figure 3) suggests a significant role for MET - PI3K/AKT signaling in growth and survival in uveal melanoma.	('PI3K', 'molecular_function', 'GO:0016303', ('130', '134'))	('HGF', 'Gene', (23, 26))	('AKT', 'Gene', '207', (135, 138))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('METi treatment', 'Chemical', '-', (66, 80))	('MET', 'Gene', (66, 69))	('HGF', 'Gene', '3082', (23, 26))	('MET', 'Gene', '4233', (66, 69))	('MET', 'Gene', (124, 127))	('AKT', 'Gene', (135, 138))	('MET', 'Gene', '4233', (124, 127))	('PI3K', 'Var', (35, 39))	('uveal melanoma', 'Disease', 'MESH:C536494', (175, 189))	('uveal melanoma', 'Phenotype', 'HP:0007716', (175, 189))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('uveal melanoma', 'Disease', (175, 189))	('AKT signaling', 'biological_process', 'GO:0043491', ('135', '148'))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))
98905	24551032	GNAQ mutant cells clearly demonstrated the induction of cleaved PARP with either of the MEKi or METi treatment doses employed.	('MEK', 'Gene', '5609', (88, 91))	('PARP', 'Gene', (64, 68))	('GNAQ', 'Gene', '2776', (0, 4))	('METi treatment', 'Chemical', '-', (96, 110))	('GNAQ', 'Gene', (0, 4))	('mutant', 'Var', (5, 11))	('MEK', 'Gene', (88, 91))	('cleaved', 'MPA', (56, 63))	('PARP', 'Gene', '1302', (64, 68))
98908	24551032	Thus, GNAQ mutant uveal melanoma cell lines appear more sensitive to the combination of MEK and MET.	('MEK', 'Gene', '5609', (88, 91))	('mutant', 'Var', (11, 17))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (18, 32))	('uveal melanoma', 'Disease', 'MESH:C536494', (18, 32))	('GNAQ', 'Gene', '2776', (6, 10))	('MET', 'Gene', '4233', (96, 99))	('uveal melanoma', 'Disease', (18, 32))	('more', 'PosReg', (51, 55))	('MET', 'Gene', (96, 99))	('GNAQ', 'Gene', (6, 10))	('MEK', 'Gene', (88, 91))	('sensitive', 'MPA', (56, 65))
98911	24551032	The observation in the current study that PARP cleavage occurred primarily in GNAQ mutant cells with MEKi and/or METi treatment suggests that the pathways driven by these molecules are important for cell survival, in a manner distinct from wild-type cells.	('GNAQ', 'Gene', (78, 82))	('mutant', 'Var', (83, 89))	('PARP', 'Gene', '1302', (42, 46))	('PARP', 'Gene', (42, 46))	('MEK', 'Gene', (101, 104))	('GNAQ', 'Gene', '2776', (78, 82))	('MEK', 'Gene', '5609', (101, 104))	('METi treatment', 'Chemical', '-', (113, 127))
98912	24551032	Two prior studies that investigated the use of single agent MET inhibitors, and used cell lines that did not harbor GNAQ mutations (e.g., OCM1, OCM3, OCM8, C918), but rather have BRAF mutations (published and unpublished data).	('mutations', 'Var', (184, 193))	('GNAQ', 'Gene', (116, 120))	('BRAF', 'Gene', '673', (179, 183))	('C918', 'Var', (156, 160))	('BRAF', 'Gene', (179, 183))	('GNAQ', 'Gene', '2776', (116, 120))	('OCM1', 'Species', '83984', (138, 142))	('MET', 'Gene', (60, 63))	('MET', 'Gene', '4233', (60, 63))
98914	24551032	Prior to this study it was not known whether combined inhibition of MEK and MET caused further growth inhibition in G-alpha protein mutant uveal melanoma cells or whether the combination treatment further diminished the migration in these cells.	('migration', 'CPA', (220, 229))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('MEK', 'Gene', '5609', (68, 71))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('uveal melanoma', 'Disease', 'MESH:C536494', (139, 153))	('mutant', 'Var', (132, 138))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('uveal melanoma', 'Disease', (139, 153))	('MET', 'Gene', (76, 79))	('inhibition', 'NegReg', (102, 112))	('MET', 'Gene', '4233', (76, 79))	('G-alpha', 'Gene', '8802', (116, 123))	('growth', 'CPA', (95, 101))	('G-alpha', 'Gene', (116, 123))	('MEK', 'Gene', (68, 71))	('diminished', 'NegReg', (205, 215))
98915	24551032	Our data show that combined treatment of uveal melanoma cells with small molecule MEK and MET inhibitors simultaneously enhances the growth inhibitory effect of each agent in a GNAQ mutation-dependent manner, and yet the small molecule METi also served as a powerful blocker of migration in both GNAQ mutant and wild-type cells.	('migration', 'CPA', (278, 287))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('enhances', 'PosReg', (120, 128))	('mutant', 'Var', (301, 307))	('growth inhibitory effect', 'MPA', (133, 157))	('MET', 'Gene', (236, 239))	('MET', 'Gene', '4233', (236, 239))	('METi', 'Chemical', '-', (236, 240))	('mutation-dependent', 'Var', (182, 200))	('uveal melanoma', 'Disease', (41, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (41, 55))	('GNAQ', 'Gene', '2776', (296, 300))	('MEK', 'Gene', '5609', (82, 85))	('GNAQ', 'Gene', (296, 300))	('GNAQ', 'Gene', '2776', (177, 181))	('MEK', 'Gene', (82, 85))	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('GNAQ', 'Gene', (177, 181))	('MET', 'Gene', '4233', (90, 93))	('MET', 'Gene', (90, 93))	('blocker', 'NegReg', (267, 274))
98916	24551032	This study greatly enhances our knowledge of the role played by the MET pathway in uveal melanoma cells, with new information proposing the combination treatment of small molecule MEK and MET inhibitors in cells harboring G-alpha protein gene mutations.	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('uveal melanoma', 'Disease', (83, 97))	('MET', 'Gene', (188, 191))	('MET', 'Gene', (68, 71))	('MET', 'Gene', '4233', (68, 71))	('MET', 'Gene', '4233', (188, 191))	('enhances', 'PosReg', (19, 27))	('mutations', 'Var', (243, 252))	('MEK', 'Gene', (180, 183))	('MEK', 'Gene', '5609', (180, 183))	('G-alpha', 'Gene', '8802', (222, 229))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('uveal melanoma', 'Disease', 'MESH:C536494', (83, 97))	('protein', 'cellular_component', 'GO:0003675', ('230', '237'))	('G-alpha', 'Gene', (222, 229))
98918	24551032	Finally, the data presented in this paper may also be placed in the greater context of primary drug resistance given the observation by Straussman et al, that HGF derived from stromal cells results in reactivation of the mitogen-activated protein kinase (a.k.a., Erk1/2) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signaling pathways, in BRAF inhibitor treated cutaneous BRAF mutant melanoma cells.	('BRAF', 'Gene', '673', (344, 348))	('BRAF', 'Gene', (344, 348))	('AKT', 'Gene', (317, 320))	('AKT signaling', 'biological_process', 'GO:0043491', ('317', '330'))	('HGF', 'Gene', '3082', (159, 162))	('Erk1/2', 'Gene', (263, 269))	('HGF', 'Gene', (159, 162))	('mutant', 'Var', (382, 388))	('Erk1/2', 'Gene', '5595;5594', (263, 269))	('PI(3)K', 'molecular_function', 'GO:0016303', ('309', '315'))	('Erk1', 'molecular_function', 'GO:0004707', ('263', '267'))	('AKT', 'Gene', '207', (317, 320))	('melanoma', 'Disease', 'MESH:D008545', (389, 397))	('BRAF', 'Gene', '673', (377, 381))	('drug resistance', 'biological_process', 'GO:0009315', ('95', '110'))	('BRAF', 'Gene', (377, 381))	('drug resistance', 'biological_process', 'GO:0042493', ('95', '110'))	('drug resistance', 'Phenotype', 'HP:0020174', (95, 110))	('reactivation', 'PosReg', (201, 213))	('melanoma', 'Phenotype', 'HP:0002861', (389, 397))	('protein', 'cellular_component', 'GO:0003675', ('239', '246'))	('melanoma', 'Disease', (389, 397))
98933	23527118	Since the discovery of BCR-ABL mutations conferring resistance to imatinib, it has become clear that focusing on a single target is not sufficient to yield sustained growth inhibition, and relapse usually occurs due to the ability of cancer cells to escape from blockage of a single essential pathway.	('resistance', 'MPA', (52, 62))	('mutations', 'Var', (31, 40))	('imatinib', 'Chemical', 'MESH:D000068877', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('BCR-ABL', 'Gene', (23, 30))	('BCR-ABL', 'Gene', '25', (23, 30))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (234, 240))
98965	23527118	A549 cells were grown in F12K media supplemented with 10% (v/v) FBS.	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('F12K', 'SUBSTITUTION', 'None', (25, 29))	('F12K', 'Var', (25, 29))	('FBS', 'Disease', 'MESH:D005198', (64, 67))	('FBS', 'Disease', (64, 67))
98992	23527118	Activity profiling of confirmed positives was performed in dose response studies toward a panel of 13 cancer cell lines using the following cell seeding densities: 500 cells per well for OCM290, 1,000 cells per well for A2780, BE(2)-C, CWR22, HCC70 and MDA-MB-231, 2,500 cells per well for Jurkat, 3,000 cells per well for HL-60 and HL-60/RV+, 4,000 cells per well for NCC-RbC-51 and NCC-RbC-60, 7,000 cells per well for BE(1)-N. The assay was performed according to the workflow previously described.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('HCC70', 'CellLine', 'CVCL:1270', (243, 248))	('A2780', 'Var', (220, 225))	('HL-60', 'CellLine', 'CVCL:0002', (333, 338))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Jurkat', 'CellLine', 'CVCL:0065', (290, 296))	('CWR22', 'CellLine', 'CVCL:3967', (236, 241))	('HL-60', 'CellLine', 'CVCL:0002', (323, 328))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (253, 263))
99010	23527118	To determine the optimal concentration of resveratrol for screening, we assessed the dose response of resveratrol toward Y79 and RB355 in 384 well format using the previously optimized assay conditions.	('Y79', 'Var', (121, 124))	('resveratrol', 'Chemical', 'MESH:D000077185', (42, 53))	('RB355', 'Gene', (129, 134))	('RB355', 'Chemical', '-', (129, 134))	('resveratrol', 'Chemical', 'MESH:D000077185', (102, 113))
99033	23527118	This result indicates that our screening strategy was successful, in that we have confirmed combinations with resveratrol that potentiate the effect of the selected compounds as a single agent.	('potentiate', 'PosReg', (127, 137))	('combinations', 'Var', (92, 104))	('effect', 'MPA', (142, 148))	('resveratrol', 'Chemical', 'MESH:D000077185', (110, 121))
99034	23527118	Among the 13 resupplied potential antagonists, we found that five of them had their potency decreased at least two-fold in presence of 80 microM resveratrol in at least one cell line: nocodazole, chelidonine, albendazole, ZM 447439 and SKF 96365 ( Table 1 ).	('albendazole', 'Chemical', 'MESH:D015766', (209, 220))	('potency', 'MPA', (84, 91))	('chelidonine', 'Chemical', 'MESH:C062047', (196, 207))	('resveratrol', 'Chemical', 'MESH:D000077185', (145, 156))	('ZM 447439', 'Var', (222, 231))	('SKF 96365', 'Var', (236, 245))	('decreased', 'NegReg', (92, 101))	('nocodazole', 'Chemical', 'MESH:D015739', (184, 194))
99058	23527118	However, the current approach consisting of testing combinations in patients is slow and expensive and as of today, while an initiative derived from the NCI60 anticancer screen is under way, current preclinical studies of drug combinations are often biased toward certain targets and may very well yield increased toxicity in patients due to the combination of off-target effects.	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('yield', 'Reg', (298, 303))	('patients', 'Species', '9606', (326, 334))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('patients', 'Species', '9606', (68, 76))	('combinations', 'Var', (227, 239))	('increased', 'PosReg', (304, 313))	('toxicity', 'Disease', 'MESH:D064420', (314, 322))	('cancer', 'Disease', (163, 169))	('toxicity', 'Disease', (314, 322))
99071	23527118	In addition, among the confirmed antagonists was the Aurora B kinase inhibitor ZM447439, which is known to interfere with mitotic spindle assembly by inhibiting the formation of microtubules.	('kinase inhibitor', 'biological_process', 'GO:0033673', ('62', '78'))	('inhibiting', 'NegReg', (150, 160))	('formation', 'biological_process', 'GO:0009058', ('165', '174'))	('ZM447439', 'Chemical', 'MESH:C474722', (79, 87))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('122', '137'))	('ZM447439', 'Var', (79, 87))	('mitotic spindle assembly', 'biological_process', 'GO:0090307', ('122', '146'))	('formation of microtubules', 'MPA', (165, 190))
99075	23527118	Regardless of any validation in patients, our observations further support the use of caution with resveratrol supplements, as resveratrol is already known to inhibit platelet aggregation, potentially inducing additive effects with anticoagulant drugs, and may also interfere with the metabolism of other drugs by inhibiting cytochrome expression or activity.	('cytochrome', 'molecular_function', 'GO:0045156', ('325', '335'))	('inhibiting', 'NegReg', (314, 324))	('resveratrol', 'Var', (127, 138))	('platelet aggregation', 'Disease', (167, 187))	('activity', 'MPA', (350, 358))	('additive effects', 'MPA', (210, 226))	('platelet aggregation', 'Phenotype', 'HP:0003540', (167, 187))	('cytochrome', 'molecular_function', 'GO:0009458', ('325', '335'))	('resveratrol', 'Chemical', 'MESH:D000077185', (127, 138))	('cytochrome', 'molecular_function', 'GO:0045153', ('325', '335'))	('cytochrome', 'Enzyme', (325, 335))	('interfere', 'NegReg', (266, 275))	('cytochrome', 'molecular_function', 'GO:0045157', ('325', '335'))	('cytochrome', 'molecular_function', 'GO:0045154', ('325', '335'))	('platelet aggregation', 'Disease', 'MESH:D001791', (167, 187))	('cytochrome', 'molecular_function', 'GO:0045155', ('325', '335'))	('metabolism', 'MPA', (285, 295))	('patients', 'Species', '9606', (32, 40))	('metabolism', 'biological_process', 'GO:0008152', ('285', '295'))	('cytochrome', 'molecular_function', 'GO:0045158', ('325', '335'))	('platelet aggregation', 'biological_process', 'GO:0070527', ('167', '187'))	('inducing', 'Reg', (201, 209))	('resveratrol', 'Chemical', 'MESH:D000077185', (99, 110))	('inhibit', 'NegReg', (159, 166))
99081	19245247	We here report on the interactions of micelles composed of a palmitoylated, pro-apoptotic peptide derived from p53 tumor suppressor protein with a human cancer cell line.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('115', '131'))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('interactions', 'Interaction', (22, 34))	('cancer', 'Disease', (153, 159))	('human', 'Species', '9606', (147, 152))	('p53', 'Gene', (111, 114))	('tumor', 'Disease', (115, 120))	('p53', 'Gene', '7157', (111, 114))	('palmitoylated', 'Var', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('115', '131'))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
99082	19245247	We conclude that palmitoylation of peptides is an efficient way to increase peptide permeability inside SJSA-1 cells and that increased micelle stability would be required for intact micelle internalization.	('increase', 'PosReg', (67, 75))	('peptide permeability', 'MPA', (76, 96))	('palmitoylation', 'Var', (17, 31))	('SJSA-1', 'CellLine', 'CVCL:1697', (104, 110))
99185	19245247	Nevertheless, our findings substantiate the use of lipid-modification of p5314-29 as an efficient way to enter cells via adsorptive-mediated endocytosis and point to the possibility of this being a general methodology for preparing cell-permeable peptides.	('endocytosis', 'biological_process', 'GO:0006897', ('141', '152'))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('lipid', 'Chemical', 'MESH:D008055', (51, 56))	('lipid-modification', 'Var', (51, 69))	('lipid-modification', 'biological_process', 'GO:0030258', ('51', '69'))	('adsorptive-mediated endocytosis', 'MPA', (121, 152))
99188	31954372	Metastatic uveal melanoma samples frequently exhibit monosomy 3 or BAP1 deficiency.	('exhibit', 'Reg', (45, 52))	('uveal melanoma', 'Phenotype', 'HP:0007716', (11, 25))	('Metastatic uveal melanoma', 'Disease', (0, 25))	('Metastatic uveal melanoma', 'Disease', 'MESH:C536494', (0, 25))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('deficiency', 'Var', (72, 82))	('BAP1', 'Gene', '8314', (67, 71))	('monosomy 3', 'Var', (53, 63))	('BAP1', 'Gene', (67, 71))
99190	31954372	We first performed Gene Set Enrichment/Variation Analyses to detect immunological pathways that are altered in tumors with monosomy 3 or BAP1 deficiency.	('BAP1', 'Gene', (137, 141))	('altered', 'Reg', (100, 107))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('monosomy 3', 'Gene', (123, 133))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('BAP1', 'Gene', '8314', (137, 141))	('deficiency', 'Var', (142, 152))	('immunological pathways', 'Pathway', (68, 90))
99205	31954372	Monosomy 3 (M3) tumors were found to be enriched for genes in immune pathways such as interferon signaling, T cell invasion and cytotoxicity.	('T cell invasion', 'CPA', (108, 123))	('cytotoxicity', 'Disease', 'MESH:D064420', (128, 140))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('interferon', 'Pathway', (86, 96))	('signaling', 'biological_process', 'GO:0023052', ('97', '106'))	('cytotoxicity', 'Disease', (128, 140))	('tumors', 'Disease', (16, 22))	('immune pathways', 'Pathway', (62, 77))	('Monosomy 3', 'Var', (0, 10))
99210	31954372	Mutation of GNA11/GNAQ was not found to significantly alter the immune infiltration and HLA Class I expression of primary UM.	('GNA11', 'Gene', '2767', (12, 17))	('GNA11', 'Gene', (12, 17))	('GNAQ', 'Gene', '2776', (18, 22))	('Mutation', 'Var', (0, 8))	('HLA Class I expression', 'CPA', (88, 110))	('immune infiltration', 'CPA', (64, 83))	('GNAQ', 'Gene', (18, 22))	('UM', 'Phenotype', 'HP:0007716', (122, 124))	('UM', 'Disease', 'MESH:C536494', (122, 124))
99211	31954372	However, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway was found to be associated with the inflammatory phenotype and high HLA Class I expression, and was upregulated upon the inactivation of BAP1 in UM.	('UM', 'Disease', 'MESH:C536494', (237, 239))	('HLA Class I', 'Protein', (160, 171))	('inactivation', 'Var', (213, 225))	('upregulated', 'PosReg', (192, 203))	('expression', 'MPA', (172, 182))	('BAP1', 'Gene', '8314', (229, 233))	('associated', 'Reg', (108, 118))	('nuclear factor kappa-light-chain-enhancer of', 'Pathway', (13, 57))	('BAP1', 'Gene', (229, 233))	('UM', 'Phenotype', 'HP:0007716', (237, 239))
99229	31954372	As shown in Figure 1C, the levels of infiltrating CD8 T cells and T follicular helper cells were significantly higher in M3-subtype tumors (n = 42) than in D3 tumors (n = 38) (P<0.01, Mann-Whitney test).	('CD8', 'Gene', (50, 53))	('CD8', 'Gene', '925', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('higher', 'PosReg', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumors', 'Disease', (132, 138))	('M3-subtype', 'Var', (121, 131))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('levels', 'MPA', (27, 33))
99237	31954372	Our analysis suggested that BAP1 mutations and chromosome alterations may determine the tumor immune state and immune infiltration of UM.	('BAP1', 'Gene', '8314', (28, 32))	('immune infiltration', 'CPA', (111, 130))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('BAP1', 'Gene', (28, 32))	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('mutations', 'Var', (33, 42))	('UM', 'Phenotype', 'HP:0007716', (134, 136))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('UM', 'Disease', 'MESH:C536494', (134, 136))	('tumor', 'Disease', (88, 93))	('determine', 'Reg', (74, 83))
99267	31954372	For example, an immune score based on gene expression data was found to correlate significantly with recurrence-free survival in thyroid cancer patients, regardless of their BRAF(V600E) status.	('V600E', 'Var', (179, 184))	('V600E', 'SUBSTITUTION', 'None', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('gene expression', 'biological_process', 'GO:0010467', ('38', '53'))	('patients', 'Species', '9606', (144, 152))	('thyroid cancer', 'Disease', (129, 143))	('thyroid cancer', 'Phenotype', 'HP:0002890', (129, 143))	('thyroid cancer', 'Disease', 'MESH:D013964', (129, 143))	('recurrence-free survival', 'CPA', (101, 125))
99278	31954372	In UM, high levels of immune cells are associated with poor prognostic factors, such as M3 and BAP1 mutation.	('BAP1', 'Gene', (95, 99))	('mutation', 'Var', (100, 108))	('BAP1', 'Gene', '8314', (95, 99))	('UM', 'Disease', 'MESH:C536494', (3, 5))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
99280	31954372	Crosstalk in the tumor microenvironment can promote the inflammatory response in cancer cells.	('promote', 'PosReg', (44, 51))	('inflammatory response', 'CPA', (56, 77))	('tumor', 'Disease', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('inflammatory response', 'biological_process', 'GO:0006954', ('56', '77'))	('cancer', 'Disease', (81, 87))	('Crosstalk', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
99287	31954372	Consistent with the previous studies, we demonstrated that BAP1 inactivation was associated with immune infiltration and immune marker gene set expression, indicating the BAP1 may regulate tumor immunology.	('inactivation', 'Var', (64, 76))	('BAP1', 'Gene', (171, 175))	('tumor', 'Disease', (189, 194))	('immune infiltration', 'CPA', (97, 116))	('BAP1', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('BAP1', 'Gene', '8314', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('BAP1', 'Gene', '8314', (171, 175))	('immune marker gene set expression', 'MPA', (121, 154))	('regulate', 'Reg', (180, 188))	('associated', 'Reg', (81, 91))
99338	31086060	Although the vast majority of studies on melanoma-derived EVs have focused only on the exosome population, ectosomes may also facilitate disease development and progression.	('exosome', 'cellular_component', 'GO:0070062', ('87', '94'))	('disease development', 'CPA', (137, 156))	('progression', 'CPA', (161, 172))	('ectosomes', 'Var', (107, 116))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('facilitate', 'PosReg', (126, 136))
99344	31086060	Ectosome-mediated transformation of normal fibroblasts to tumor-associated fibroblasts has already been described in melanoma, as well as suppression of immune response by vesicle-associated Fas ligand (FasL).	('immune', 'MPA', (153, 159))	('tumor', 'Disease', (58, 63))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('ligand', 'molecular_function', 'GO:0005488', ('195', '201'))	('FasL', 'Gene', '356', (203, 207))	('suppression', 'NegReg', (138, 149))	('FasL', 'Gene', (203, 207))	('Fas ligand', 'Gene', (191, 201))	('vesicle', 'cellular_component', 'GO:0031982', ('172', '179'))	('Ectosome', 'cellular_component', 'GO:1990742', ('0', '8'))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('immune response', 'biological_process', 'GO:0006955', ('153', '168'))	('suppression of immune response', 'Phenotype', 'HP:0002721', (138, 168))	('Fas ligand', 'Gene', '356', (191, 201))	('Ectosome-mediated', 'Var', (0, 17))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
99348	31086060	Additionally, mice inoculated with B16-F1 apoptotic bodies prior to inoculation with tumorigenic B16-F1 cells were protected from tumor development for up to 60 days, while a shorter tumor-free period was observed in mice immunized with B16-F1 exosomes or ectosomes.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('mice', 'Species', '10090', (217, 221))	('mice', 'Species', '10090', (14, 18))	('B16-F1', 'CellLine', 'CVCL:0158', (237, 243))	('B16-F1', 'Var', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('B16-F1', 'CellLine', 'CVCL:0158', (35, 41))	('tumor', 'Disease', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', (130, 135))	('B16-F1', 'CellLine', 'CVCL:0158', (97, 103))
99390	31086060	This method has an obvious advantage over traditional 2D SDS-PAGE, because it allows separation of up to three samples, stained differentially by fluorescent dyes (Cy3, Cy5, and Cy2) on one gel, thus overcoming in-gel differences.	('Cy3', 'Var', (164, 167))	('Cy5', 'Chemical', 'MESH:C085321', (169, 172))	('SDS', 'Chemical', 'MESH:D012967', (57, 60))	('Cy3', 'Chemical', '-', (164, 167))	('Cy2', 'Chemical', '-', (178, 181))	('Cy5', 'Var', (169, 172))	('Cy2', 'Var', (178, 181))
99453	31086060	Studies using Western Blot, flow cytometry, and lectin microarrays revealed the enrichment of melanoma-derived exosomes in high mannose, polylactosamine, alpha-2,6 sialic acid, and complex N-linked glycans, with the latter being directly involved in exosomal protein sorting.	('complex N-linked glycans', 'Protein', (181, 205))	('protein', 'cellular_component', 'GO:0003675', ('259', '266'))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('high mannose', 'Protein', (123, 135))	('polylactosamine', 'Chemical', 'MESH:C066929', (137, 152))	('polylactosamine', 'Var', (137, 152))	('lectin', 'molecular_function', 'GO:0005530', ('48', '54'))	('N-linked glycans', 'Chemical', '-', (189, 205))	('alpha-2,6 sialic acid', 'Chemical', '-', (154, 175))	('mannose', 'Chemical', 'MESH:D008358', (128, 135))
99460	31086060	Therefore, identification of particular proteins with aberrant glycosylation within EVs by MS should become a considerable direction in melanoma biomarker discovery.	('glycosylation', 'MPA', (63, 76))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (54, 76))	('glycosylation', 'biological_process', 'GO:0070085', ('63', '76'))	('aberrant', 'Var', (54, 62))
99464	31086060	The presence of these modifications may also affect protein sorting, EV aggregation, or their binding to the recipient cells, and has not been evaluated in melanoma-derived EVs so far.	('affect', 'Reg', (45, 51))	('EV aggregation', 'Disease', 'MESH:D004819', (69, 83))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('binding', 'molecular_function', 'GO:0005488', ('94', '101'))	('melanoma', 'Disease', (156, 164))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('binding', 'Interaction', (94, 101))	('protein', 'Protein', (52, 59))	('modifications', 'Var', (22, 35))	('EV aggregation', 'Disease', (69, 83))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
99495	30478979	First, heuristics are not confined to isolated lapses in otherwise logical decision processes, but people routinely use heuristics to encode and process risk information during decision making.32 Moreover, heuristics can facilitate high-quality decision making.	('heuristics', 'Var', (206, 216))	('facilitate', 'PosReg', (221, 231))	('people', 'Species', '9606', (99, 105))	('high-quality decision making', 'CPA', (232, 260))
99583	31110912	In binary logistic regression, manual and DIA of BAP-1 and gene expression class 2 were associated with metastasis, but none retained significance in multiple regression.	('BAP-1', 'Gene', (49, 54))	('metastasis', 'CPA', (104, 114))	('DIA', 'Var', (42, 45))	('gene expression', 'biological_process', 'GO:0010467', ('59', '74'))	('manual', 'Var', (31, 37))	('associated', 'Reg', (88, 98))	('BAP-1', 'Gene', '8314', (49, 54))
99594	31110912	Mutations in the SF3B1 or EIF1AX genes identify uveal melanomas with intermediate and low risk for metastasis.	('uveal melanomas', 'Disease', 'MESH:C536494', (48, 63))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('uveal melanomas', 'Phenotype', 'HP:0007716', (48, 63))	('SF3B1', 'Gene', (17, 22))	('EIF1AX', 'Gene', '1964', (26, 32))	('EIF1AX', 'Gene', (26, 32))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('Mutations', 'Var', (0, 9))	('uveal melanomas', 'Disease', (48, 63))	('SF3B1', 'Gene', '23451', (17, 22))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))
99595	31110912	Inactivating mutations in the tumor suppressor BRCA associated protein-1 (BAP-1) gene located on chromosome 3p21.1 has been identified in >80% of metastasizing uveal melanomas and is strongly associated with gene expression classifications.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('melanomas', 'Phenotype', 'HP:0002861', (166, 175))	('associated', 'Reg', (192, 202))	('BRCA associated protein-1', 'Gene', (47, 72))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('BAP-1', 'Gene', '8314', (74, 79))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('BRCA associated protein-1', 'Gene', '8314', (47, 72))	('BAP-1', 'Gene', (74, 79))	('Inactivating mutations', 'Var', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('chromosome', 'cellular_component', 'GO:0005694', ('97', '107'))	('uveal melanomas', 'Disease', 'MESH:C536494', (160, 175))	('metastasizing', 'CPA', (146, 159))	('identified', 'Reg', (124, 134))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))	('gene expression', 'biological_process', 'GO:0010467', ('208', '223'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (160, 174))	('tumor', 'Disease', (30, 35))	('uveal melanomas', 'Disease', (160, 175))	('uveal melanomas', 'Phenotype', 'HP:0007716', (160, 175))
99649	31110912	In this study, DIA of BAP-1 expression outperformed the manual method in interobserver concordance and time required for classification.	('DIA', 'Var', (15, 18))	('BAP-1', 'Gene', '8314', (22, 27))	('expression', 'MPA', (28, 38))	('BAP-1', 'Gene', (22, 27))	('outperformed', 'PosReg', (39, 51))
99733	29152277	Supporting the notion of neural crest origin of ocular tissue, a substantial proportion of feline restrictive orbital myofibrosarcomas are also S100 positive 14.	('sarcomas', 'Phenotype', 'HP:0100242', (126, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('S100 positive 14', 'Var', (144, 160))	('orbital myofibrosarcomas', 'Disease', (110, 134))	('orbital myofibrosarcomas', 'Disease', 'MESH:D009916', (110, 134))
99858	27089179	Instead, they are characterized by activating mutations in GNAQ and GNA11, two highly homologous alpha subunits of Galphaq/11 heterotrimeric G proteins, and in PLCB4 (phospholipase C beta4), the downstream effector of Galphaq signaling .	('PLCB4', 'Gene', '5332', (160, 165))	('signaling', 'biological_process', 'GO:0023052', ('226', '235'))	('mutations', 'Var', (46, 55))	('phospholipase C beta4', 'Gene', (167, 188))	('phospholipase C beta4', 'Gene', '5332', (167, 188))	('PLCB4', 'Gene', (160, 165))	('GNA11', 'Gene', (68, 73))	('activating', 'PosReg', (35, 45))	('Galphaq', 'Gene', (115, 122))	('GNAQ', 'Gene', (59, 63))	('GNA11', 'Gene', '2767', (68, 73))	('Galphaq', 'Gene', '2776', (115, 122))	('Galphaq', 'Gene', (218, 225))	('Galphaq', 'Gene', '2776', (218, 225))	('GNAQ', 'Gene', '2776', (59, 63))
99859	27089179	We analyzed genomics data from 136 uveal melanoma samples and found a recurrent mutation in CYSLTR2 (cysteinyl leukotriene receptor 2) encoding a p.Leu129Gln substitution in 4 of 9 samples that lacked mutations in GNAQ, GNA11, and PLCB4 but in 0 of 127 samples that harbored mutations in these genes.	('PLCB4', 'Gene', (231, 236))	('uveal melanoma', 'Disease', 'MESH:C536494', (35, 49))	('GNAQ', 'Gene', (214, 218))	('p.Leu129Gln', 'Var', (146, 157))	('uveal melanoma', 'Disease', (35, 49))	('CYSLTR2', 'Gene', '57105', (92, 99))	('p.Leu129Gln', 'Mutation', 'rs1060500250', (146, 157))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))	('PLCB4', 'Gene', '5332', (231, 236))	('cysteinyl leukotriene receptor 2', 'Gene', '57105', (101, 133))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('GNA11', 'Gene', '2767', (220, 225))	('GNA11', 'Gene', (220, 225))	('GNAQ', 'Gene', '2776', (214, 218))	('cysteinyl leukotriene receptor 2', 'Gene', (101, 133))	('CYSLTR2', 'Gene', (92, 99))
99860	27089179	The Leu129Gln CysLT2R mutant protein constitutively activates endogenous Galphaq and is unresponsive to stimulation by leukotriene.	('Galphaq', 'Gene', (73, 80))	('endogenous', 'MPA', (62, 72))	('CysLT2R', 'Gene', (14, 21))	('Galphaq', 'Gene', '2776', (73, 80))	('Leu129Gln', 'Var', (4, 13))	('Leu129Gln', 'Chemical', '-', (4, 13))	('leukotriene', 'Chemical', 'MESH:D015289', (119, 130))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('activates', 'PosReg', (52, 61))
99861	27089179	Expression of Leu129Gln CysLT2R in melanocytes enforces expression of a melanocyte-lineage signature, drives phorbol ester-independent growth in vitro, and promotes tumorigenesis in vivo.	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('drives', 'PosReg', (102, 108))	('phorbol ester-independent growth', 'MPA', (109, 141))	('CysLT2R', 'Gene', (24, 31))	('expression', 'Species', '29278', (56, 66))	('enforces', 'PosReg', (47, 55))	('Expression', 'Species', '29278', (0, 10))	('expression', 'MPA', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('melanocyte-lineage', 'MPA', (72, 90))	('Leu129Gln', 'Var', (14, 23))	('phorbol ester', 'Chemical', 'MESH:D010703', (109, 122))	('Leu129Gln', 'Chemical', '-', (14, 23))	('promotes', 'PosReg', (156, 164))	('tumor', 'Disease', (165, 170))
99865	27089179	We identified seven significantly mutated (q < 0.05) codons in six genes, including known mutations in GNAQ, GNA11, PLCB4, SF3B1, and EIF1AX.	('mutations', 'Var', (90, 99))	('GNAQ', 'Gene', '2776', (103, 107))	('PLCB4', 'Gene', (116, 121))	('SF3B1', 'Gene', (123, 128))	('GNA11', 'Gene', (109, 114))	('EIF1AX', 'Gene', '1964', (134, 140))	('EIF1AX', 'Gene', (134, 140))	('GNA11', 'Gene', '2767', (109, 114))	('SF3B1', 'Gene', '23451', (123, 128))	('GNAQ', 'Gene', (103, 107))	('PLCB4', 'Gene', '5332', (116, 121))
99866	27089179	In addition, we found a new c.386T>A mutation in CYSLTR2 encoding a p.Leu129Gln substitution in four samples (q = 3.3 x 10-8) (Fig.	('c.386T>A', 'Var', (28, 36))	('CYSLTR2', 'Gene', '57105', (49, 56))	('CYSLTR2', 'Gene', (49, 56))	('p.Leu129Gln', 'Var', (68, 79))	('p.Leu129Gln', 'Mutation', 'rs1060500250', (68, 79))	('c.386T>A', 'Mutation', 'rs776734905', (28, 36))
99867	27089179	RNA-seq data validated the presence of the CYSLTR2 mutation encoding p.Leu129Gln and confirmed expression of the mutant allele (Supplementary Figs.	('p.Leu129Gln', 'Var', (69, 80))	('CYSLTR2', 'Gene', (43, 50))	('p.Leu129Gln', 'Mutation', 'rs1060500250', (69, 80))	('expression', 'Species', '29278', (95, 105))	('CYSLTR2', 'Gene', '57105', (43, 50))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
99868	27089179	For further validation, we performed Sanger sequencing on two Memorial Sloan Kettering Cancer Center (MSKCC) patient samples that lacked GNAQ and GNA11 mutations (2/28) and found one sample with a CYSLTR2 mutation encoding p.Leu129Gln (Supplementary Fig.	('GNA11', 'Gene', '2767', (146, 151))	('patient', 'Species', '9606', (109, 116))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))	('GNAQ', 'Gene', (137, 141))	('CYSLTR2', 'Gene', '57105', (197, 204))	('p.Leu129Gln', 'Var', (223, 234))	('CYSLTR2', 'Gene', (197, 204))	('Cancer', 'Disease', (87, 93))	('GNAQ', 'Gene', '2776', (137, 141))	('GNA11', 'Gene', (146, 151))	('p.Leu129Gln', 'Mutation', 'rs1060500250', (223, 234))	('Cancer', 'Disease', 'MESH:D009369', (87, 93))
99869	27089179	Although CYSLTR2 is sporadically mutated in other cancer types sequenced by TCGA, these mutations do not occur at hotspots (except for mutations mapping to Arg136 (p.Arg136Cys or p.Arg136His) in three samples), the corresponding transcripts are not expressed at high levels, and the mutations are found in high-mutation-burden tumors, suggesting that CYSLTR2 might not be an oncogenic driver in other tumor types and that the CYSLTR2 hotspot mutation encoding p.Leu129Gln is unique to uveal melanoma (Supplementary Fig.	('cancer', 'Disease', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (401, 406))	('p.Arg136Cys', 'Mutation', 'rs764117879', (164, 175))	('tumors', 'Disease', (327, 333))	('melanoma', 'Phenotype', 'HP:0002861', (491, 499))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('CYSLTR2', 'Gene', (426, 433))	('tumor', 'Disease', (327, 332))	('tumor', 'Phenotype', 'HP:0002664', (401, 406))	('tumors', 'Disease', 'MESH:D009369', (327, 333))	('uveal melanoma', 'Disease', 'MESH:C536494', (485, 499))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('p.Leu129Gln', 'Mutation', 'rs1060500250', (460, 471))	('uveal melanoma', 'Disease', (485, 499))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('CYSLTR2', 'Gene', '57105', (351, 358))	('CYSLTR2', 'Gene', (9, 16))	('p.Arg136His', 'Mutation', 'rs201503697', (179, 190))	('CYSLTR2', 'Gene', '57105', (9, 16))	('Arg136', 'Chemical', '-', (166, 172))	('uveal melanoma', 'Phenotype', 'HP:0007716', (485, 499))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('CYSLTR2', 'Gene', '57105', (426, 433))	('Arg136', 'Chemical', '-', (181, 187))	('CYSLTR2', 'Gene', (351, 358))	('tumors', 'Phenotype', 'HP:0002664', (327, 333))	('Arg136', 'Chemical', '-', (156, 162))	('tumor', 'Disease', (401, 406))	('p.Leu129Gln', 'Var', (460, 471))
99870	27089179	Because mutations that activate the same pathway or mutations that define molecular subtypes tend to be mutually exclusive, we used CoMEt to identify mutually exclusive mutational modules de novo in the data set with 136 uveal melanomas .	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('CoMEt', 'Species', '302767', (132, 137))	('uveal melanomas', 'Disease', 'MESH:C536494', (221, 236))	('uveal melanoma', 'Phenotype', 'HP:0007716', (221, 235))	('mutations', 'Var', (8, 17))	('melanomas', 'Phenotype', 'HP:0002861', (227, 236))	('uveal melanomas', 'Disease', (221, 236))	('uveal melanomas', 'Phenotype', 'HP:0007716', (221, 236))
99871	27089179	We found that mutations in GNAQ, GNA11, PLCB4, and CYSLTR2 formed a highly significantly mutually exclusive module (P = 4.2 x 10-33), suggesting that these genes are in the same pathway.	('PLCB4', 'Gene', '5332', (40, 45))	('GNAQ', 'Gene', '2776', (27, 31))	('GNA11', 'Gene', (33, 38))	('CYSLTR2', 'Gene', '57105', (51, 58))	('GNA11', 'Gene', '2767', (33, 38))	('CYSLTR2', 'Gene', (51, 58))	('PLCB4', 'Gene', (40, 45))	('GNAQ', 'Gene', (27, 31))	('mutations', 'Var', (14, 23))
99873	27089179	), SF3B1, and EIF1AX formed a second mutually exclusive module (P = 2.0 x 10-5), consistent with the observation that BAP1 mutations primarily occur in tumors with monosomy 3 and SF3B1 and EIF1AX mutations primarily occur in tumors with disomy 3 (Fig.	('occur', 'Reg', (216, 221))	('SF3B1', 'Gene', (3, 8))	('SF3B1', 'Gene', '23451', (179, 184))	('tumors', 'Disease', (152, 158))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('monosomy 3', 'Var', (164, 174))	('BAP1', 'Gene', '8314', (118, 122))	('SF3B1', 'Gene', '23451', (3, 8))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('EIF1AX', 'Gene', (189, 195))	('EIF1AX', 'Gene', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('occur', 'Reg', (143, 148))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('BAP1', 'Gene', (118, 122))	('EIF1AX', 'Gene', '1964', (189, 195))	('mutations', 'Var', (196, 205))	('disomy 3', 'Disease', (237, 245))	('EIF1AX', 'Gene', '1964', (14, 20))	('SF3B1', 'Gene', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('tumors', 'Disease', (225, 231))	('mutations', 'Var', (123, 132))
99875	27089179	CysLT2R belongs to the rhodopsin-like family of GPCRs and is known to activate Galphaq (Fig.	('rhodopsin', 'Gene', '6010', (23, 32))	('GPCR', 'Gene', '10663', (48, 52))	('Galphaq', 'Gene', (79, 86))	('Galphaq', 'Gene', '2776', (79, 86))	('activate', 'PosReg', (70, 78))	('CysLT2R', 'Var', (0, 7))	('GPCR', 'Gene', (48, 52))	('rhodopsin', 'Gene', (23, 32))
99876	27089179	Leu129 of CysLT2R is located in transmembrane helix 3 (TM3), a functional hub of the receptor that makes contact with the ligand extracellularly, associates with other transmembrane helices within the membrane, and interacts with the Galpha subunit intracellularly (Fig.	('CysLT2R', 'Gene', (10, 17))	('associates', 'Interaction', (146, 156))	('interacts', 'Interaction', (215, 224))	('Galpha', 'Gene', '8802', (234, 240))	('Leu129', 'Chemical', '-', (0, 6))	('transmembrane', 'cellular_component', 'GO:0016021', ('32', '45'))	('membrane', 'cellular_component', 'GO:0016020', ('201', '209'))	('Galpha', 'Gene', (234, 240))	('transmembrane', 'cellular_component', 'GO:0044214', ('32', '45'))	('Leu129', 'Var', (0, 6))	('transmembrane', 'cellular_component', 'GO:0016021', ('168', '181'))	('transmembrane', 'cellular_component', 'GO:0044214', ('168', '181'))	('ligand', 'molecular_function', 'GO:0005488', ('122', '128'))
99878	27089179	Alteration at the 3.43 position has been shown to confer constitutive activity in a number of GPCRs, including the beta-adrenergic, luteinizing hormone, and thyroid-stimulating hormone receptors .	('beta-adrenergic', 'Protein', (115, 130))	('Alteration', 'Var', (0, 10))	('thyroid-stimulating hormone receptor', 'Gene', (157, 193))	('GPCR', 'Gene', '10663', (94, 98))	('thyroid-stimulating hormone receptor', 'Gene', '7253', (157, 193))	('luteinizing hormone', 'MPA', (132, 151))	('constitutive activity', 'MPA', (57, 78))	('GPCR', 'Gene', (94, 98))
99879	27089179	To further understand the role of Leu129, we modeled the structure of CysLT2R on the basis of the known structure of its close homolog, protease-activated receptor 1 (PAR1) .	('protease-activated receptor 1', 'Gene', '2149', (136, 165))	('protease-activated receptor 1', 'Gene', (136, 165))	('PAR1', 'Gene', '2149', (167, 171))	('CysLT2R', 'Gene', (70, 77))	('Leu129', 'Chemical', '-', (34, 40))	('PAR1', 'Gene', (167, 171))	('Leu129', 'Var', (34, 40))
99880	27089179	Leu129 (3.43) resides in a hydrophobic core of the GPCR, which is highly enriched in hydrophobic residues (Leu80 (1.45), Ser125 (3.39), Leu132 (3.46), Thr252 (6.41), Ile255 (6.44), Phe256 (6.45), Phe260 (6.49), Asn297 (7.45), Asn301 (7.49), and Leu304 (7.52)) (Fig.	('Leu80', 'Var', (107, 112))	('GPCR', 'Gene', '10663', (51, 55))	('Leu304', 'Var', (245, 251))	('Leu132', 'Var', (136, 142))	('Leu129', 'Chemical', '-', (0, 6))	('GPCR', 'Gene', (51, 55))	('core', 'cellular_component', 'GO:0019013', ('39', '43'))	('Ser', 'cellular_component', 'GO:0005790', ('121', '124'))
99881	27089179	2a), suggesting that substitution with a more hydrophilic glutamine residue (p.Leu129Gln) might disrupt structural organization.	('disrupt', 'NegReg', (96, 103))	('structural', 'MPA', (104, 114))	('p.Leu129Gln', 'Var', (77, 88))	('p.Leu129Gln', 'Mutation', 'rs1060500250', (77, 88))	('structural organization', 'biological_process', 'GO:0048532', ('104', '127'))
99882	27089179	To determine the ability of the wild-type and Leu129Gln CysLT2R proteins to couple with Galphaq, we generated synthetic genes encoding wild-type CYSLTR2 and the mutant, transiently expressed them in HEK293 T cells, and measured calcium mobilization (Fig.	('mutant', 'Var', (161, 167))	('calcium mobilization', 'MPA', (228, 248))	('CYSLTR2', 'Gene', '57105', (145, 152))	('calcium', 'Chemical', 'MESH:D002118', (228, 235))	('HEK293 T', 'CellLine', 'CVCL:0063', (199, 207))	('Leu129Gln', 'Chemical', '-', (46, 55))	('calcium mobilization', 'biological_process', 'GO:0051209', ('228', '248'))	('CYSLTR2', 'Gene', (145, 152))	('Galphaq', 'Gene', (88, 95))	('Galphaq', 'Gene', '2776', (88, 95))	('measured', 'Reg', (219, 227))	('Leu129Gln', 'Var', (46, 55))
99884	27089179	Cells expressing Leu129Gln CysLT2R exhibited high basal calcium levels that were not augmented by increasing concentrations of LTD4, indicating that the receptor is constitutively active (Fig.	('calcium', 'Chemical', 'MESH:D002118', (56, 63))	('LTD', 'biological_process', 'GO:0060292', ('127', '130'))	('LTD4', 'Chemical', 'MESH:D017998', (127, 131))	('CysLT2R', 'Gene', (27, 34))	('basal calcium levels', 'MPA', (50, 70))	('Leu129Gln', 'Chemical', '-', (17, 26))	('Leu129Gln', 'Var', (17, 26))
99886	27089179	To determine whether wild-type and Leu129Gln CysLT2R are coupled to the Galphas activating or Galphai inhibitory adenylyl cyclase pathway, we measured the ligand-mediated increase in cAMP levels, indicative of Galphas coupling, and the ligand-mediated decrease in forskolin-induced cAMP levels, indicative of Galphai coupling.	('cAMP', 'Chemical', '-', (282, 286))	('decrease', 'NegReg', (252, 260))	('ligand', 'molecular_function', 'GO:0005488', ('236', '242'))	('Leu129Gln CysLT2R', 'Var', (35, 52))	('ligand', 'molecular_function', 'GO:0005488', ('155', '161'))	('Galphai', 'Chemical', '-', (94, 101))	('cAMP levels', 'MPA', (183, 194))	('Galphai', 'Chemical', '-', (309, 316))	('forskolin', 'Chemical', 'MESH:D005576', (264, 273))	('Galphas', 'Chemical', '-', (210, 217))	('Galphas', 'Chemical', '-', (72, 79))	('CysLT2R', 'Var', (45, 52))	('Leu129Gln', 'Chemical', '-', (35, 44))	('increase', 'PosReg', (171, 179))	('cAMP', 'Chemical', '-', (183, 187))	('forskolin-induced cAMP levels', 'MPA', (264, 293))
99888	27089179	2d), arguing against coupling of Leu129Gln CysLT2R with Galphas.	('Leu129Gln CysLT2R', 'Var', (33, 50))	('Leu129Gln', 'Chemical', '-', (33, 42))	('Galphas', 'Disease', (56, 63))	('Galphas', 'Chemical', '-', (56, 63))
99889	27089179	After stimulation with forskolin, LTD4 minimally inhibited the increase in cAMP levels in cells expressing wild-type CysLT2R in comparison to those transfected with vector control, but cAMP levels were unaffected by LTD4 in cells expressing Leu129Gln CysLT2R (Fig.	('Leu129Gln', 'Chemical', '-', (241, 250))	('LTD4', 'Chemical', 'MESH:D017998', (216, 220))	('LTD', 'biological_process', 'GO:0060292', ('216', '219'))	('LTD4', 'Chemical', 'MESH:D017998', (34, 38))	('cAMP', 'Chemical', '-', (75, 79))	('cAMP', 'Chemical', '-', (185, 189))	('cAMP levels', 'MPA', (75, 86))	('LTD', 'biological_process', 'GO:0060292', ('34', '37'))	('Leu129Gln', 'Var', (241, 250))	('inhibited', 'NegReg', (49, 58))	('forskolin', 'Chemical', 'MESH:D005576', (23, 32))
99890	27089179	2e), indicating that Leu129Gln CysLT2R was not coupled with Galphai.	('Leu129Gln CysLT2R', 'Var', (21, 38))	('Leu129Gln', 'Chemical', '-', (21, 30))	('Galphai', 'Disease', (60, 67))	('Galphai', 'Chemical', '-', (60, 67))
99891	27089179	These data, in combination with the calcium flux data, suggest that Leu129Gln CysLT2R is a gain-of-function mutant that primarily couples through Galphaq.	('CysLT2R', 'Gene', (78, 85))	('couples', 'Reg', (130, 137))	('calcium', 'Chemical', 'MESH:D002118', (36, 43))	('Galphaq', 'Gene', '2776', (146, 153))	('Leu129Gln', 'Var', (68, 77))	('Leu129Gln', 'Chemical', '-', (68, 77))	('Galphaq', 'Gene', (146, 153))
99892	27089179	To determine whether Leu129Gln CysLT2R possesses oncogenic properties, we stably expressed empty-vector control, wild-type CysLT2R, and Leu129Gln CysLT2R, as well as the Arg136His CysLT2R mutant receptor found in three independent TCGA samples (Supplementary Fig.	('Arg136His', 'Var', (170, 179))	('Leu129Gln', 'Chemical', '-', (136, 145))	('Leu129Gln', 'Var', (136, 145))	('Leu129Gln', 'Var', (21, 30))	('Leu129Gln', 'Chemical', '-', (21, 30))	('Arg136His', 'SUBSTITUTION', 'None', (170, 179))
99894	27089179	We found that only cells expressing Leu129Gln CysLT2R were able to form tumors in vivo (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Leu129Gln CysLT2R', 'Var', (36, 53))	('Leu129Gln', 'Chemical', '-', (36, 45))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Disease', (72, 78))
99895	27089179	4a), indicating that Leu129Gln CysLT2R has oncogenic activities.	('Leu129Gln CysLT2R', 'Var', (21, 38))	('oncogenic activities', 'CPA', (43, 63))	('Leu129Gln', 'Chemical', '-', (21, 30))
99896	27089179	To determine the melanocyte-lineage-specific effects of the CysLT2R p.Leu129Gln substitution, we stably expressed the empty-vector control, wild-type CysLT2R, and Leu129Gln CysLT2R in melan-a cells, an immortalized mouse melanocytic cell line.	('p.Leu129Gln', 'Var', (68, 79))	('Leu129Gln', 'Var', (163, 172))	('p.Leu129Gln', 'Mutation', 'rs1060500250', (68, 79))	('mouse', 'Species', '10090', (215, 220))	('Leu129Gln', 'Chemical', '-', (70, 79))	('Leu129Gln', 'Chemical', '-', (163, 172))
99898	27089179	Leu129Gln but not wild-type CysLT2R conferred TPA-independent growth (Fig.	('TPA', 'molecular_function', 'GO:0031299', ('46', '49'))	('TPA-independent growth', 'CPA', (46, 68))	('Leu129Gln', 'Chemical', '-', (0, 9))	('Leu129Gln', 'Var', (0, 9))	('TPA', 'Chemical', 'MESH:D013755', (46, 49))
99899	27089179	We next sought to phenotypically characterize expression of Leu129Gln CysLT2R in the melanocyte lineage.	('CysLT2R', 'Gene', (70, 77))	('Leu129Gln', 'Chemical', '-', (60, 69))	('Leu129Gln', 'Var', (60, 69))	('expression', 'Species', '29278', (46, 56))
99901	27089179	Notably, Leu129Gln CysLT2R expression dramatically augmented pigmentation in melan-a cells cultured in TPA-containing medium, with increased numbers of large pigmented melanosomes (Fig.	('CysLT2R', 'Gene', (19, 26))	('pigmentation', 'Disease', (61, 73))	('Leu129Gln', 'Var', (9, 18))	('Leu129Gln', 'Chemical', '-', (9, 18))	('increased', 'PosReg', (131, 140))	('expression', 'Species', '29278', (27, 37))	('augmented', 'PosReg', (51, 60))	('TPA', 'Chemical', 'MESH:D013755', (103, 106))	('large pigmented melanosomes', 'Phenotype', 'HP:0005592', (152, 179))	('TPA', 'molecular_function', 'GO:0031299', ('103', '106'))	('pigmentation', 'Disease', 'MESH:D010859', (61, 73))	('pigmentation', 'biological_process', 'GO:0043473', ('61', '73'))
99903	27089179	Remarkably, Leu129Gln CysLT2R expression rescued both pigmentation and cell morphology (Fig.	('pigmentation', 'biological_process', 'GO:0043473', ('54', '66'))	('cell morphology', 'CPA', (71, 86))	('Leu129Gln', 'Var', (12, 21))	('Leu129Gln', 'Chemical', '-', (12, 21))	('rescued', 'PosReg', (41, 48))	('pigmentation', 'Disease', 'MESH:D010859', (54, 66))	('pigmentation', 'Disease', (54, 66))	('CysLT2R', 'Gene', (22, 29))	('expression', 'Species', '29278', (30, 40))
99905	27089179	Leu129Gln CysLT2R expression modestly increased expression of these genes in the presence of TPA but dramatically increased their expression in the absence of TPA (Fig.	('expression', 'MPA', (130, 140))	('TPA', 'molecular_function', 'GO:0031299', ('93', '96'))	('TPA', 'molecular_function', 'GO:0031299', ('159', '162'))	('expression', 'Species', '29278', (48, 58))	('CysLT2R', 'Gene', (10, 17))	('expression', 'MPA', (48, 58))	('increased', 'PosReg', (114, 123))	('expression', 'Species', '29278', (18, 28))	('Leu129Gln', 'Var', (0, 9))	('Leu129Gln', 'Chemical', '-', (0, 9))	('TPA', 'Chemical', 'MESH:D013755', (159, 162))	('TPA', 'Chemical', 'MESH:D013755', (93, 96))	('expression', 'Species', '29278', (130, 140))	('increased', 'PosReg', (38, 47))
99906	27089179	To determine whether Leu129Gln CysLT2R also promotes melanocyte-lineage specification in the human context, we stably expressed the empty-vector control, wild-type CysLT2R, and Leu129Gln CysLT2R in MEL290 cells, a human uveal melanoma cell line that is wild type for GNA11 and GNAQ .	('promotes', 'PosReg', (44, 52))	('uveal melanoma', 'Disease', (220, 234))	('GNA11', 'Gene', (267, 272))	('uveal melanoma', 'Disease', 'MESH:C536494', (220, 234))	('Leu129Gln', 'Var', (177, 186))	('MEL290', 'CellLine', 'CVCL:C304', (198, 204))	('Leu129Gln', 'Chemical', '-', (177, 186))	('GNAQ', 'Gene', (277, 281))	('human', 'Species', '9606', (93, 98))	('GNA11', 'Gene', '2767', (267, 272))	('uveal melanoma', 'Phenotype', 'HP:0007716', (220, 234))	('Leu129Gln CysLT2R', 'Var', (21, 38))	('Leu129Gln', 'Chemical', '-', (21, 30))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('melanocyte-lineage specification', 'CPA', (53, 85))	('human', 'Species', '9606', (214, 219))	('GNAQ', 'Gene', '2776', (277, 281))
99907	27089179	Expression of Leu129Gln CysLT2R but not controls significantly increased expression of melanocyte-lineage-specific genes (for example, DCT, TYRP1, and TYR) (Fig.	('increased', 'PosReg', (63, 72))	('CysLT2R', 'Gene', (24, 31))	('expression', 'Species', '29278', (73, 83))	('DCT', 'Gene', '1638', (135, 138))	('melanocyte-lineage-specific genes', 'Gene', (87, 120))	('expression', 'MPA', (73, 83))	('Expression', 'Species', '29278', (0, 10))	('TYRP1', 'Gene', '7306', (140, 145))	('Leu129Gln', 'Var', (14, 23))	('TYRP1', 'Gene', (140, 145))	('Leu129Gln', 'Chemical', '-', (14, 23))	('TYR', 'Chemical', 'MESH:D014443', (140, 143))	('DCT', 'Gene', (135, 138))	('TYR', 'Chemical', 'MESH:D014443', (151, 154))	('TYR', 'Gene', (151, 154))
99908	27089179	To determine the role of the CysLT2R p.Leu129Gln substitution in melanoma tumorigenesis in vivo, we grafted melan-a cells expressing empty-vector control, wild-type CysLT2R, and Leu129Gln CysLT2R into SCID mice and found that Leu129Gln CysLT2R significantly accelerated tumor formation in comparison to empty vector (P < 0.001; Fig.	('tumor', 'Disease', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('SCID', 'Disease', 'MESH:D053632', (201, 205))	('formation', 'biological_process', 'GO:0009058', ('276', '285'))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('Leu129Gln', 'Chemical', '-', (39, 48))	('SCID', 'Disease', (201, 205))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Leu129Gln', 'Var', (226, 235))	('Leu129Gln', 'Chemical', '-', (226, 235))	('accelerated', 'PosReg', (258, 269))	('tumor', 'Disease', (270, 275))	('mice', 'Species', '10090', (206, 210))	('Leu129Gln', 'Chemical', '-', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('Leu129Gln', 'Var', (178, 187))	('p.Leu129Gln', 'Mutation', 'rs1060500250', (37, 48))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))
99909	27089179	Examination of melan-a tumor grafts showed that tumors expressing Leu129Gln CysLT2R were highly pigmented and expressed higher levels of melanocyte-lineage-specific markers (for example, Mitf, Kit, Dct, Tyrp1, and Tyr) than grafts expressing empty-vector control and wild-type CysLT2R (Fig.	('Tyrp1', 'Gene', '7306', (203, 208))	('Dct', 'Gene', '1638', (198, 201))	('tumors', 'Disease', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('Leu129Gln', 'Var', (66, 75))	('levels', 'MPA', (127, 133))	('Tyr', 'Chemical', 'MESH:D014443', (203, 206))	('Dct', 'Gene', (198, 201))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('Mitf', 'Gene', '4286', (187, 191))	('Kit', 'MPA', (193, 196))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (23, 28))	('Mitf', 'Gene', (187, 191))	('Tyrp1', 'Gene', (203, 208))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('higher', 'PosReg', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('Tyr', 'Chemical', 'MESH:D014443', (214, 217))	('CysLT2R', 'Gene', (76, 83))	('Leu129Gln', 'Chemical', '-', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
99910	27089179	These data indicate that, within the melanocyte lineage, Leu129Gln CysLT2R enforces a master melanocyte-lineage-specific transcriptional program and promotes transformation.	('Leu129Gln', 'Chemical', '-', (57, 66))	('Leu129Gln', 'Var', (57, 66))	('enforces', 'PosReg', (75, 83))	('promotes', 'PosReg', (149, 157))	('transformation', 'CPA', (158, 172))	('CysLT2R', 'Gene', (67, 74))
99911	27089179	Because Leu129Gln CysLT2R conferred TPA-independent growth in melan-a cells, we asked whether melan-a cells expressing Leu129Gln CysLT2R had become dependent on it for proliferation.	('Leu129Gln', 'Var', (8, 17))	('Leu129Gln', 'Chemical', '-', (8, 17))	('TPA-independent growth', 'MPA', (36, 58))	('Leu129Gln', 'Chemical', '-', (119, 128))	('Leu129Gln', 'Var', (119, 128))	('TPA', 'molecular_function', 'GO:0031299', ('36', '39'))	('TPA', 'Chemical', 'MESH:D013755', (36, 39))
99912	27089179	We performed small interfering RNA (siRNA)-mediated knockdown of the exogenous human CYSLTR2 in cells expressing wild-type CysLT2R and Leu129Gln CysLT2R.	('CYSLTR2', 'Gene', (85, 92))	('human', 'Species', '9606', (79, 84))	('RNA', 'cellular_component', 'GO:0005562', ('31', '34'))	('CYSLTR2', 'Gene', '57105', (85, 92))	('Leu129Gln', 'Var', (135, 144))	('Leu129Gln', 'Chemical', '-', (135, 144))
99913	27089179	Knockdown of CYSLTR2 reduced growth in cells with Leu129Gln CysLT2R grown in the presence or absence of TPA and caused the cells to have a flattened morphology, but it did not affect the growth or morphology of cells with wild-type CysLT2R grown in the presence of TPA (Fig.	('reduced', 'NegReg', (21, 28))	('Leu129Gln', 'Var', (50, 59))	('CYSLTR2', 'Gene', (13, 20))	('Leu129Gln', 'Chemical', '-', (50, 59))	('TPA', 'Chemical', 'MESH:D013755', (265, 268))	('TPA', 'Chemical', 'MESH:D013755', (104, 107))	('flattened morphology', 'CPA', (139, 159))	('TPA', 'molecular_function', 'GO:0031299', ('104', '107'))	('caused', 'Reg', (112, 118))	('TPA', 'molecular_function', 'GO:0031299', ('265', '268'))	('growth', 'MPA', (29, 35))	('CYSLTR2', 'Gene', '57105', (13, 20))	('CysLT2R', 'Gene', (60, 67))
99914	27089179	Further, knockdown of CYSLTR2 in cells expressing Leu129Gln CysLT2R decreased the expression of melanocyte-lineage genes (Fig.	('expression', 'Species', '29278', (82, 92))	('decreased', 'NegReg', (68, 77))	('Leu129Gln', 'Var', (50, 59))	('Leu129Gln', 'Chemical', '-', (50, 59))	('expression', 'MPA', (82, 92))	('CYSLTR2', 'Gene', '57105', (22, 29))	('melanocyte-lineage genes', 'Gene', (96, 120))	('CysLT2R', 'Gene', (60, 67))	('CYSLTR2', 'Gene', (22, 29))
99915	27089179	These data suggest that inhibiting CysLT2R in cell lines with the CYSLTR2 mutation encoding p.Leu129Gln can have therapeutic potential.	('p.Leu129Gln', 'Var', (92, 103))	('CYSLTR2', 'Gene', (66, 73))	('CYSLTR2', 'Gene', '57105', (66, 73))	('p.Leu129Gln', 'Mutation', 'rs1060500250', (92, 103))
99916	27089179	GPCR mutations drive several benign endocrine neoplasms, including mutations of thyroid-stimulating hormone receptor in thyroid adenoma  and luteinizing hormone receptor in testicular Leydig adenoma .	('thyroid adenoma', 'Disease', (120, 135))	('neoplasms', 'Phenotype', 'HP:0002664', (46, 55))	('endocrine neoplasms', 'Phenotype', 'HP:0100568', (36, 55))	('endocrine neoplasms', 'Disease', (36, 55))	('GPCR', 'Gene', '10663', (0, 4))	('Leydig adenoma', 'Disease', (184, 198))	('thyroid-stimulating hormone receptor', 'Gene', '7253', (80, 116))	('endocrine neoplasms', 'Disease', 'MESH:D004701', (36, 55))	('mutations', 'Var', (5, 14))	('mutations', 'Var', (67, 76))	('Leydig adenoma', 'Disease', 'MESH:D000236', (184, 198))	('GPCR', 'Gene', (0, 4))	('thyroid adenoma', 'Phenotype', 'HP:0000854', (120, 135))	('thyroid adenoma', 'Disease', 'MESH:D013964', (120, 135))	('thyroid-stimulating hormone receptor', 'Gene', (80, 116))	('drive', 'Reg', (15, 20))
99917	27089179	In addition, many GPCRs can be oncogenic in experimental systems, and analysis of whole-exome studies has shown that GPCRs are among the most commonly mutated genes, mutated in approximately 20% of all cancers .	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('mutated', 'Var', (166, 173))	('GPCR', 'Gene', '10663', (18, 22))	('GPCR', 'Gene', '10663', (117, 121))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancers', 'Disease', (202, 209))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('GPCR', 'Gene', (18, 22))	('GPCR', 'Gene', (117, 121))
99918	27089179	Despite the high mutation rate, to our knowledge, no single GPCR has been identified as a significantly mutated gene in any malignant tumor type , possibly because GPCR genes generally lack hotspot mutations and mutations in these genes co-occur with mutations in other well-known driver oncogenes.	('hotspot mutations', 'MPA', (190, 207))	('malignant tumor', 'Disease', (124, 139))	('lack', 'NegReg', (185, 189))	('GPCR', 'Gene', '10663', (164, 168))	('GPCR', 'Gene', (60, 64))	('GPCR', 'Gene', (164, 168))	('malignant tumor', 'Disease', 'MESH:D018198', (124, 139))	('mutations', 'Var', (212, 221))	('GPCR', 'Gene', '10663', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
99919	27089179	We have defined a recurrent hotspot mutation of CYSLTR2 in uveal melanoma, which represents a bona fide mutated GPCR driver oncogene.	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('uveal melanoma', 'Disease', (59, 73))	('CYSLTR2', 'Gene', '57105', (48, 55))	('GPCR', 'Gene', (112, 116))	('hotspot', 'PosReg', (28, 35))	('CYSLTR2', 'Gene', (48, 55))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('GPCR', 'Gene', '10663', (112, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (59, 73))	('mutation', 'Var', (36, 44))
99920	27089179	Leu129Gln CysLT2R exhibits high basal activity and couples through Galphaq, thereby activating a signaling pathway convergent with the one activated by GNAQ and GNA11 oncogenic mutations (Fig.	('basal activity', 'MPA', (32, 46))	('signaling pathway', 'biological_process', 'GO:0007165', ('97', '114'))	('GNA11', 'Gene', (161, 166))	('CysLT2R', 'Gene', (10, 17))	('signaling pathway', 'Pathway', (97, 114))	('Leu129Gln', 'Var', (0, 9))	('Leu129Gln', 'Chemical', '-', (0, 9))	('GNAQ', 'Gene', '2776', (152, 156))	('GNA11', 'Gene', '2767', (161, 166))	('activating', 'PosReg', (84, 94))	('Galphaq', 'Gene', '2776', (67, 74))	('GNAQ', 'Gene', (152, 156))	('Galphaq', 'Gene', (67, 74))
99921	27089179	We further demonstrated that Leu129Gln CysLT2R enforces expression of the melanocyte-lineage-specific transcriptional program, possibly having a role similar to that of MITF amplification in enforcing lineage in cutaneous melanoma .	('CysLT2R', 'Gene', (39, 46))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (212, 230))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (212, 230))	('Leu129Gln', 'Var', (29, 38))	('Leu129Gln', 'Chemical', '-', (29, 38))	('expression', 'Species', '29278', (56, 66))	('enforces', 'PosReg', (47, 55))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('expression', 'MPA', (56, 66))	('cutaneous melanoma', 'Disease', (212, 230))
99925	27089179	Transition of wild-type GPCR between the inactive and active conformations depends on the ligand environment, but mutations conferring constitutive activity strongly bias the protein toward the active conformation, either through destabilization of the inactive state or stabilization of the active state.	('protein', 'Protein', (175, 182))	('GPCR', 'Gene', '10663', (24, 28))	('mutations', 'Var', (114, 123))	('ligand', 'molecular_function', 'GO:0005488', ('90', '96'))	('inactive', 'MPA', (253, 261))	('active', 'MPA', (194, 200))	('bias', 'PosReg', (166, 170))	('GPCR', 'Gene', (24, 28))	('protein', 'cellular_component', 'GO:0003675', ('175', '182'))
99926	27089179	Development of such drugs to inhibit Leu129Gln CysLT2R will have therapeutic potential in uveal melanoma with CYSLTR2 mutation encoding p.Leu129Gln, a disease that currently has no effective therapy.	('Leu129Gln', 'Chemical', '-', (37, 46))	('uveal melanoma', 'Disease', (90, 104))	('uveal melanoma', 'Disease', 'MESH:C536494', (90, 104))	('CYSLTR2', 'Gene', '57105', (110, 117))	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('Leu129Gln', 'Var', (37, 46))	('inhibit', 'NegReg', (29, 36))	('CYSLTR2', 'Gene', (110, 117))	('p.Leu129Gln', 'Var', (136, 147))	('p.Leu129Gln', 'Mutation', 'rs1060500250', (136, 147))	('Leu129Gln', 'Chemical', '-', (138, 147))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))
99932	27089179	To examine raw DNA and RNA sequencing reads with CYSLTR2 mutation, we obtained TCGA BAM files from the Cancer Genomics Hub and UNI-UDE fastq files from the European Nucleotide Archive (study accession ERP003230) and mapped reads to the hg19 reference genome using Bowtie 2 (ref.).	('mutation', 'Var', (57, 65))	('CYSLTR2', 'Gene', '57105', (49, 56))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('Cancer', 'Disease', (103, 109))	('CYSLTR2', 'Gene', (49, 56))	('RNA', 'cellular_component', 'GO:0005562', ('23', '26'))	('Cancer', 'Disease', 'MESH:D009369', (103, 109))	('Cancer', 'Phenotype', 'HP:0002664', (103, 109))
99933	27089179	To determine the number of wild-type and mutant reads at CYSLTR2, we used SAMtools mpileup after filtering for base quality of at least 13 (ref.).	('CYSLTR2', 'Gene', '57105', (57, 64))	('CYSLTR2', 'Gene', (57, 64))	('mutant', 'Var', (41, 47))
99938	27089179	For pan-TCGA analysis of CYSLTR2 mutations, we obtained curated data from MSKCC cBioPortal.	('CYSLTR2', 'Gene', '57105', (25, 32))	('CYSLTR2', 'Gene', (25, 32))	('mutations', 'Var', (33, 42))
99943	27089179	The construct encoding Leu129Gln CysLT2R mutant receptor was generated by QuikChange (Agilent Technologies) site-directed mutagenesis of CYSLTR2 to introduce a c.386T>A mutation (NM_020377.2) encoding the p.Leu129Gln substitution using synthetic CYSLTR2 L129Q QuikChange primers (Supplementary Table 1).	('Leu129Gln', 'Chemical', '-', (207, 216))	('CYSLTR2', 'Gene', (137, 144))	('p.Leu129Gln', 'Var', (205, 216))	('c.386T>A', 'Mutation', 'rs776734905', (160, 168))	('Leu129Gln', 'Var', (23, 32))	('Leu129Gln', 'Chemical', '-', (23, 32))	('p.Leu129Gln', 'Mutation', 'rs1060500250', (205, 216))	('mutagenesis', 'biological_process', 'GO:0006280', ('122', '133'))	('c.386T>A', 'Var', (160, 168))	('L129Q', 'Mutation', 'rs1060500250', (254, 259))	('CYSLTR2', 'Gene', '57105', (246, 253))	('CYSLTR2', 'Gene', (246, 253))	('CYSLTR2', 'Gene', '57105', (137, 144))
99946	27089179	QuikChange site-directed mutagenesis was performed using CYSLTR2 L129Q QuikChange primers (Supplementary Table 1) on wild-type CYSLTR2 to introduce a c.386T>A mutation encoding the p.Leu129Gln substitution.	('CYSLTR2', 'Gene', (57, 64))	('CYSLTR2', 'Gene', (127, 134))	('p.Leu129Gln', 'Mutation', 'rs1060500250', (181, 192))	('mutagenesis', 'biological_process', 'GO:0006280', ('25', '36'))	('c.386T>A', 'Mutation', 'rs776734905', (150, 158))	('L129Q', 'Mutation', 'rs1060500250', (65, 70))	('CYSLTR2', 'Gene', '57105', (57, 64))	('CYSLTR2', 'Gene', '57105', (127, 134))	('p.Leu129Gln', 'Var', (181, 192))	('c.386T>A', 'Var', (150, 158))
99947	27089179	In addition, site-directed mutagenesis was performed using CYSLTR2 R136H QuikChange primers (Supplementary Table 1) on wild-type CYSLTR2 to introduce a c.407G>A mutation encoding the p.Arg136His substitution.	('p.Arg136His', 'Mutation', 'rs201503697', (183, 194))	('CYSLTR2', 'Gene', (129, 136))	('R136H', 'Mutation', 'rs201503697', (67, 72))	('c.407G>A', 'Var', (152, 160))	('CYSLTR2', 'Gene', '57105', (59, 66))	('c.407G>A', 'Mutation', 'rs201503697', (152, 160))	('CYSLTR2', 'Gene', (59, 66))	('mutagenesis', 'biological_process', 'GO:0006280', ('27', '38'))	('p.Arg136His', 'Var', (183, 194))	('CYSLTR2', 'Gene', '57105', (129, 136))
99956	27089179	HEK293T cells were transiently cotransfected with empty vector (pcDNA3.1(+)) or vector encoding wild-type or Leu129Gln CysLT2R along with the RLuc3-EPAC-GFP10 cAMP sensor in 96-well plates.	('Leu129Gln CysLT2R', 'Var', (109, 126))	('cAMP', 'Chemical', '-', (159, 163))	('Leu129Gln', 'Chemical', '-', (109, 118))	('EPAC', 'Gene', (148, 152))	('EPAC', 'Gene', '10411', (148, 152))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))
99972	27089179	All cell culture media contained 10% FBS, penicillin (100 U/ml), streptomycin (100 mug/ml), and l-glutamine (2 mM).	('streptomycin', 'Chemical', 'MESH:D013307', (65, 77))	('FBS', 'Disease', 'MESH:D005198', (37, 40))	('mug', 'molecular_function', 'GO:0043739', ('83', '86'))	('100 mug/ml', 'Var', (79, 89))	('l-glutamine', 'Chemical', 'MESH:D005973', (96, 107))	('FBS', 'Disease', (37, 40))	('penicillin', 'Chemical', 'MESH:D010406', (42, 52))
99984	27089179	Two tumors from the melan-a Leu129Gln CysLT2R group were excluded because of growth that differed from the mean.	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumors', 'Disease', (4, 10))	('Leu129Gln CysLT2R', 'Var', (28, 45))	('Leu129Gln', 'Chemical', '-', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
100070	27356499	The development of UM is a multistep process involving genetic and epigenetic alterations of proto-oncogenes and tumor suppressor genes.	('tumor', 'Disease', (113, 118))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('113', '129'))	('epigenetic alterations', 'Var', (67, 89))	('genetic', 'Var', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor suppressor', 'biological_process', 'GO:0051726', ('113', '129'))
100144	24868139	The final concentrations of ranibizumab in malignant melanoma cells and ARPE-19 were 0, 0.1, 0.25, 0.5, and 1 mg/ml, respectively.	('0.25', 'Var', (93, 97))	('malignant melanoma', 'Disease', 'MESH:D008545', (43, 61))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('ranibizumab', 'Chemical', 'MESH:D000069579', (28, 39))	('malignant melanoma', 'Phenotype', 'HP:0002861', (43, 61))	('malignant melanoma', 'Disease', (43, 61))
100184	24868139	When ranibizumab was 0.1 mg/ml, 0.25 mg/ml, and 0.5 mg/ml, the survival rates of malignant melanoma cells decreased to 12%, 57.5%, and 72% compared with the untreated cells (Figure 5B).	('decreased', 'NegReg', (106, 115))	('malignant melanoma', 'Disease', (81, 99))	('0.25 mg/ml', 'Var', (32, 42))	('malignant melanoma', 'Disease', 'MESH:D008545', (81, 99))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('0.1 mg/ml', 'Var', (21, 30))	('ranibizumab', 'Chemical', 'MESH:D000069579', (5, 16))	('malignant melanoma', 'Phenotype', 'HP:0002861', (81, 99))
100189	24868139	When ranibizumab was 0.1 mg/ml, 0.25 mg/ml, 0.5 mg/ml, and 1 mg/ml, the survival rates of malignant melanoma cells were 98.1%, 91.05%, 88.55%, and 79.2%, respectively, and the survival rates of ARPE-19 were 98.96%, 96.1%, 89.6%, and 88.03%, respectively.	('survival rates', 'CPA', (72, 86))	('0.25 mg/ml', 'Var', (32, 42))	('malignant melanoma', 'Phenotype', 'HP:0002861', (90, 108))	('0.5 mg/ml', 'Var', (44, 53))	('0.1 mg/ml', 'Var', (21, 30))	('malignant melanoma', 'Disease', 'MESH:D008545', (90, 108))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('ranibizumab', 'Chemical', 'MESH:D000069579', (5, 16))	('malignant melanoma', 'Disease', (90, 108))
100190	24868139	When ranibizumab was 0.1 mg/ml and 0.25 mg/ml, the surviving rate decreased slightly comparing with ARPE-19 without ranibizumab (p=0.77, p=0.26, respectively).	('ranibizumab', 'Chemical', 'MESH:D000069579', (116, 127))	('0.25', 'Var', (35, 39))	('decreased', 'NegReg', (66, 75))	('ranibizumab', 'Chemical', 'MESH:D000069579', (5, 16))	('surviving rate', 'CPA', (51, 65))
100199	24868139	PIGF is also dispensable for embryonic and adult physiological angiogenesis, but promotes pathological angiogenesis in several diseases.	('PIGF', 'Var', (0, 4))	('pathological angiogenesis', 'CPA', (90, 115))	('embryonic', 'Disease', (29, 38))	('promotes', 'PosReg', (81, 89))	('angiogenesis', 'biological_process', 'GO:0001525', ('63', '75'))	('angiogenesis', 'biological_process', 'GO:0001525', ('103', '115'))	('embryonic', 'Disease', 'MESH:D009373', (29, 38))
100238	24868139	The possible mechanism of the inhibitory effect may be antagonizing VEGFR1.	('antagonizing', 'Var', (55, 67))	('VEGFR1', 'Gene', (68, 74))	('VEGFR1', 'Gene', '2321', (68, 74))
100277	24082672	Eyes with monosomy 3 or abnormalities of chromosome 8 within the melanoma demonstrate poorer prognosis and necessitate more intense systemic follow-up.	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))	('monosomy 3', 'Var', (10, 20))	('abnormalities of chromosome', 'Var', (24, 51))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
100312	33440679	The anti-inflammatory effect was tested on mice that consumed L. barbarum juice, and the results showed a significant effect on basal and stimulated cytokine production In human skin, L. barbarum has the ability to influence the matrix metalloproteinase, which can lead to the tissues protection.	('mice', 'Species', '10090', (43, 47))	('cytokine production', 'biological_process', 'GO:0001816', ('149', '168'))	('influence', 'Reg', (215, 224))	('L. barbarum', 'Species', '112863', (184, 195))	('human', 'Species', '9606', (172, 177))	('lead to', 'Reg', (265, 272))	('L. barbarum', 'Var', (184, 195))	('matrix metalloproteinase', 'Pathway', (229, 253))	('L. barbarum', 'Species', '112863', (62, 73))	('tissues protection', 'CPA', (277, 295))
100319	33440679	The mesenchymal membrane marker CD44 and the adhesion-related protein CD105 (or endoglin) are important markers of stemness in skin-derived fibroblasts and in melanoma cells; the malignant melanoma is abundant in CD44 and CD105, including the melanoma-initiating cells, which confer aggressivity to the tumor growth.	('melanoma', 'Disease', (159, 167))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('aggressivity', 'Disease', (283, 295))	('melanoma', 'Disease', 'MESH:D008545', (243, 251))	('CD105', 'Var', (222, 227))	('malignant melanoma', 'Disease', (179, 197))	('endoglin', 'molecular_function', 'GO:0070123', ('80', '88'))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', (189, 197))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('aggressivity', 'Disease', 'MESH:D001523', (283, 295))	('endoglin', 'Gene', (80, 88))	('membrane', 'cellular_component', 'GO:0016020', ('16', '24'))	('melanoma', 'Phenotype', 'HP:0002861', (243, 251))	('melanoma', 'Disease', (243, 251))	('tumor', 'Disease', (303, 308))	('endoglin', 'Gene', '13805', (80, 88))	('malignant melanoma', 'Phenotype', 'HP:0002861', (179, 197))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('malignant melanoma', 'Disease', 'MESH:D008545', (179, 197))	('CD44', 'Var', (213, 217))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
100361	33440679	To evaluate the intracellular protein expression, we used the goat anti-human p65 NF-kbeta antibody (acquired from R&D Systems Europe Ltd., Abingdon, UK) with the appropriate PE anti-goat secondary antibody; goat anti-human phosphorilated ERK1+ERK2 (pT202/pY204 and pT185/pY187), phospho p38 (pT180/Y182) and phosphorilated JNK1/2 (pT183/Y185) (all from Abcam, Cambridge, UK).	('ERK1', 'Gene', '5595', (239, 243))	('JNK1/2', 'Gene', '5599;5601', (324, 330))	('p65', 'Gene', '5970', (78, 81))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('antibody', 'cellular_component', 'GO:0019815', ('91', '99'))	('antibody', 'cellular_component', 'GO:0019815', ('198', '206'))	('human', 'Species', '9606', (72, 77))	('intracellular', 'cellular_component', 'GO:0005622', ('16', '29'))	('JNK1/2', 'Gene', (324, 330))	('antibody', 'cellular_component', 'GO:0019814', ('198', '206'))	('antibody', 'cellular_component', 'GO:0019814', ('91', '99'))	('ERK1', 'molecular_function', 'GO:0004707', ('239', '243'))	('and pT185/pY187', 'Var', (262, 277))	('JNK', 'molecular_function', 'GO:0004705', ('324', '327'))	('antibody', 'molecular_function', 'GO:0003823', ('91', '99'))	('ERK2', 'Gene', '5594', (244, 248))	('antibody', 'molecular_function', 'GO:0003823', ('198', '206'))	('ERK2', 'molecular_function', 'GO:0004707', ('244', '248'))	('p65', 'Gene', (78, 81))	('antibody', 'cellular_component', 'GO:0042571', ('91', '99'))	('ERK1', 'Gene', (239, 243))	('antibody', 'cellular_component', 'GO:0042571', ('198', '206'))	('ERK2', 'Gene', (244, 248))	('human', 'Species', '9606', (218, 223))
100433	33440679	CD105 targeting through natural compounds such zeaxanthin could be a promising therapeutic approach for malignant melanoma and the disruption of membrane endoglin can suppress the tumor progression.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('CD105', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('endoglin', 'molecular_function', 'GO:0070123', ('154', '162'))	('malignant melanoma', 'Phenotype', 'HP:0002861', (104, 122))	('zeaxanthin', 'Chemical', 'MESH:D065146', (47, 57))	('tumor', 'Disease', (180, 185))	('membrane', 'cellular_component', 'GO:0016020', ('145', '153'))	('endoglin', 'Gene', (154, 162))	('malignant melanoma', 'Disease', 'MESH:D008545', (104, 122))	('malignant melanoma', 'Disease', (104, 122))	('suppress', 'NegReg', (167, 175))	('disruption', 'Var', (131, 141))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('endoglin', 'Gene', '13805', (154, 162))
100453	33333932	Spliceosome Mutations in Uveal Melanoma Uveal melanoma (UM) is the most common primary intraocular malignancy of the eye.	('Melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('primary intraocular malignancy', 'Disease', (79, 109))	('Spliceosome', 'Var', (0, 11))	('Melanoma', 'Disease', (31, 39))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('ocular malignancy', 'Phenotype', 'HP:0100012', (92, 109))	('Spliceosome', 'cellular_component', 'GO:0005681', ('0', '11'))	('primary intraocular malignancy', 'Disease', 'MESH:D009798', (79, 109))	('malignancy of the eye', 'Phenotype', 'HP:0100012', (99, 120))	('Melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('UM', 'Phenotype', 'HP:0007716', (56, 58))
100455	33333932	Recurrent mutations in components of the spliceosome complex are observed in UM and other malignancies, suggesting an important role in tumorigenesis.	('malignancies', 'Disease', (90, 102))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('observed', 'Reg', (65, 73))	('mutations', 'Var', (10, 19))	('spliceosome complex', 'cellular_component', 'GO:0005681', ('41', '60'))	('tumor', 'Disease', (136, 141))
100468	33333932	Activating mutations in GNAQ or GNA11 are seen as primary driver oncogenes in UM and mutations in these genes are usually mutually exclusive.	('GNAQ', 'Gene', '2776', (24, 28))	('GNA11', 'Gene', '2767', (32, 37))	('Activating mutations', 'Var', (0, 20))	('GNA11', 'Gene', (32, 37))	('GNAQ', 'Gene', (24, 28))	('UM', 'Phenotype', 'HP:0007716', (78, 80))
100470	33333932	Recurrent mutations in CYSLTR2 (Cysteinyl Leukotriene Receptor 2) and PLCB4 (Phospholipase C Beta 4) were found in some of the cases lacking mutations in GNAQ or GNA11.	('GNAQ', 'Gene', '2776', (154, 158))	('CYSLTR2', 'Gene', (23, 30))	('Cysteinyl Leukotriene Receptor 2', 'Gene', '57105', (32, 64))	('CYSLTR2', 'Gene', '57105', (23, 30))	('PLCB4', 'Gene', '5332', (70, 75))	('GNAQ', 'Gene', (154, 158))	('found', 'Reg', (106, 111))	('Phospholipase C Beta 4', 'Gene', (77, 99))	('mutations', 'Var', (10, 19))	('Phospholipase C Beta 4', 'Gene', '5332', (77, 99))	('GNA11', 'Gene', (162, 167))	('PLCB4', 'Gene', (70, 75))	('Cysteinyl Leukotriene Receptor 2', 'Gene', (32, 64))	('GNA11', 'Gene', '2767', (162, 167))
100474	33333932	Loss of function mutations in BAP1 are often concurrent with monosomy 3, often resulting in loss of BAP1 protein expression and are associated with poor prognosis.	('BAP1', 'Gene', '8314', (100, 104))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('BAP1', 'Gene', (30, 34))	('BAP1', 'Gene', (100, 104))	('BAP1', 'Gene', '8314', (30, 34))	('Loss of function', 'NegReg', (0, 16))	('loss', 'NegReg', (92, 96))	('monosomy 3', 'Disease', (61, 71))	('protein', 'Protein', (105, 112))	('mutations', 'Var', (17, 26))
100475	33333932	In our cohort of 808 patients, BAP1 mutations are seen in up to 82% of all metastasized UM patients and are correlated with monosomy 3 (87%).	('correlated', 'Reg', (108, 118))	('patients', 'Species', '9606', (91, 99))	('BAP1', 'Gene', '8314', (31, 35))	('monosomy 3', 'Disease', (124, 134))	('mutations', 'Var', (36, 45))	('metastasized', 'CPA', (75, 87))	('patients', 'Species', '9606', (21, 29))	('BAP1', 'Gene', (31, 35))	('UM', 'Phenotype', 'HP:0007716', (88, 90))
100476	33333932	EIF1AX encodes the eukaryotic translation initiation factor 1A, an X-chromosomal protein and mutations in the N terminal region of this gene are found in approximately 20% of UM patients.	('eukaryotic translation initiation factor 1A', 'Gene', (19, 62))	('found', 'Reg', (145, 150))	('UM', 'Phenotype', 'HP:0007716', (175, 177))	('patients', 'Species', '9606', (178, 186))	('translation initiation', 'biological_process', 'GO:0006413', ('30', '52'))	('EIF1AX', 'Gene', '1964', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('eukaryotic translation initiation factor 1A', 'Gene', '1964', (19, 62))	('mutations in', 'Var', (93, 105))	('EIF1AX', 'Gene', (0, 6))
100478	33333932	The EIF1AX mutations are change-of-function mutations and they are associated with a more favorable prognosis in UM.	('EIF1AX', 'Gene', (4, 10))	('mutations', 'Var', (11, 20))	('UM', 'Phenotype', 'HP:0007716', (113, 115))	('EIF1AX', 'Gene', '1964', (4, 10))
100479	33333932	SF3B1 encodes splicing factor 3B subunit 1 and mutations in the SF3B1 gene occur in approximately 20% of UM cases.	('splicing', 'biological_process', 'GO:0045292', ('14', '22'))	('SF3B1', 'Gene', (64, 69))	('splicing factor 3B subunit 1', 'Gene', (14, 42))	('mutations', 'Var', (47, 56))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('splicing factor 3B subunit 1', 'Gene', '23451', (14, 42))	('occur', 'Reg', (75, 80))
100480	33333932	Although mutations in SF3B1 were initially supposedly associated with a better prognosis compared to SF3B1 wild-type patients, our group has been able to demonstrate a biphasic development in SF3B1 mutated UM.	('SF3B1', 'Gene', (192, 197))	('mutations', 'Var', (9, 18))	('mutated', 'Var', (198, 205))	('associated', 'Reg', (54, 64))	('patients', 'Species', '9606', (117, 125))	('SF3B1', 'Gene', (22, 27))	('UM', 'Phenotype', 'HP:0007716', (206, 208))
100481	33333932	Recurrent mutations in components of the spliceosome suggests these mutations are expressed and that a change in splicing accuracy that is caused by these mutations plays an important role in cancer.	('splicing', 'biological_process', 'GO:0045292', ('113', '121'))	('mutations', 'Var', (155, 164))	('change', 'Reg', (103, 109))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('spliceosome', 'cellular_component', 'GO:0005681', ('41', '52'))	('mutations', 'Var', (10, 19))	('splicing accuracy', 'MPA', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
100482	33333932	Each of these spliceosome complexes include five crucial small nuclear ribonucleoprotein particles (snRNP): U1, U2, U4, U5 and U6 in the major spliceosome and U11, U12, U4atac, U5 and U6atac in the minor spliceosome.	('U11', 'Var', (159, 162))	('spliceosome', 'cellular_component', 'GO:0005681', ('204', '215'))	('U4atac', 'Gene', '100151683', (169, 175))	('U6atac', 'Gene', '100151684', (184, 190))	('U4atac', 'Gene', (169, 175))	('snRNP): U1', 'cellular_component', 'GO:0005685', ('100', '110'))	('U12', 'Var', (164, 167))	('snRNP', 'Gene', (100, 105))	('U6atac', 'Gene', (184, 190))	('spliceosome', 'cellular_component', 'GO:0005681', ('143', '154'))	('small nuclear ribonucleoprotein', 'molecular_function', 'GO:0003734', ('57', '88'))	('snRNP', 'molecular_function', 'GO:0003734', ('100', '105'))	('small nuclear ribonucleoprotein', 'cellular_component', 'GO:0030532', ('57', '88'))	('snRNP', 'Gene', '57819', (100, 105))	('spliceosome', 'cellular_component', 'GO:0005681', ('14', '25'))
100487	33333932	The SF3B1 gene, hence an essential protein in the U2 snRNP complex, is the most frequently mutated spliceosome gene and mutations are present in various malignant diseases such as UM, myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), breast cancer, pancreatic cancer and mucosal melanoma (especially in anorectal and vulvovaginal melanomas).	('breast cancer', 'Phenotype', 'HP:0003002', (253, 266))	('snRNP', 'Gene', (53, 58))	('snRNP', 'Gene', '57819', (53, 58))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (217, 245))	('melanoma', 'Phenotype', 'HP:0002861', (349, 357))	('anorectal', 'Disease', (322, 331))	('MDS', 'Disease', (211, 214))	('vulvovaginal melanomas', 'Disease', (336, 358))	('pancreatic cancer', 'Disease', 'MESH:D010190', (268, 285))	('chronic lymphocytic leukemia', 'Disease', (217, 245))	('melanomas', 'Phenotype', 'HP:0002861', (349, 358))	('mutations', 'Var', (120, 129))	('breast cancer', 'Disease', 'MESH:D001943', (253, 266))	('breast cancer', 'Disease', (253, 266))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (217, 245))	('pancreatic cancer', 'Disease', (268, 285))	('leukemia', 'Phenotype', 'HP:0001909', (237, 245))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('spliceosome', 'cellular_component', 'GO:0005681', ('99', '110'))	('vulvovaginal melanomas', 'Phenotype', 'HP:0030418', (336, 358))	('CLL', 'Phenotype', 'HP:0005550', (247, 250))	('malignant diseases', 'Disease', (153, 171))	('MDS', 'Phenotype', 'HP:0002863', (211, 214))	('melanoma', 'Phenotype', 'HP:0002861', (298, 306))	('snRNP', 'molecular_function', 'GO:0003734', ('53', '58'))	('vulvovaginal melanoma', 'Phenotype', 'HP:0030418', (336, 357))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('malignant diseases', 'Disease', 'MESH:D009369', (153, 171))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (268, 285))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (184, 209))	('myelodysplastic syndromes', 'Disease', (184, 209))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('50', '58'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (290, 306))	('SF3B1', 'Gene', (4, 9))	('UM', 'Phenotype', 'HP:0007716', (180, 182))	('MDS', 'Disease', 'MESH:D009190', (211, 214))	('vulvovaginal melanomas', 'Disease', 'MESH:D014848', (336, 358))	('mucosal melanoma', 'Disease', (290, 306))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (184, 209))
100488	33333932	SF3B1 mutations have an incidence of approximately 20% in UM, 42% in mucosal melanoma (60% in anorectal melanoma and 44% in vulvovaginal melanoma), 7% in MDS (80% in refractory anemia with ring sideroblasts (RARS)-MDS, a subset of MDS), 10% in CLL and approximately 1.8% in breast cancer.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('anemia', 'Disease', (177, 183))	('CLL', 'Phenotype', 'HP:0005550', (244, 247))	('vulvovaginal melanoma', 'Disease', (124, 145))	('MDS', 'Phenotype', 'HP:0002863', (231, 234))	('MDS', 'Disease', (154, 157))	('anorectal melanoma', 'Disease', (94, 112))	('UM', 'Phenotype', 'HP:0007716', (58, 60))	('vulvovaginal melanoma', 'Phenotype', 'HP:0030418', (124, 145))	('SF3B1', 'Gene', (0, 5))	('MDS', 'Disease', 'MESH:D009190', (231, 234))	('refractory anemia with ring sideroblasts', 'Phenotype', 'HP:0004828', (166, 206))	('MDS', 'Phenotype', 'HP:0002863', (214, 217))	('refractory anemia', 'Phenotype', 'HP:0005505', (166, 183))	('mutations', 'Var', (6, 15))	('CLL', 'Disease', (244, 247))	('anemia', 'Disease', 'MESH:D000740', (177, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (274, 287))	('anorectal melanoma', 'Disease', 'MESH:D008545', (94, 112))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('MDS', 'Disease', (231, 234))	('MDS', 'Phenotype', 'HP:0002863', (154, 157))	('mucosal melanoma', 'Disease', 'MESH:D008545', (69, 85))	('MDS', 'Disease', 'MESH:D009190', (214, 217))	('breast cancer', 'Disease', 'MESH:D001943', (274, 287))	('mucosal melanoma', 'Disease', (69, 85))	('breast cancer', 'Disease', (274, 287))	('MDS', 'Disease', 'MESH:D009190', (154, 157))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('anemia', 'Phenotype', 'HP:0001903', (177, 183))	('MDS', 'Disease', (214, 217))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('vulvovaginal melanoma', 'Disease', 'MESH:D014848', (124, 145))
100489	33333932	Mutated SF3B1 leads to deregulation of the U2 snRNP splicing due to an alternative usage of the 3'ss AG.	('snRNP', 'Gene', '57819', (46, 51))	('deregulation', 'MPA', (23, 35))	('splicing', 'biological_process', 'GO:0045292', ('52', '60'))	('snRNP', 'Gene', (46, 51))	('Mutated', 'Var', (0, 7))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('43', '51'))	('SF3B1', 'Gene', (8, 13))	('snRNP', 'molecular_function', 'GO:0003734', ('46', '51'))
100490	33333932	Mutated SF3B1 recognizes an alternative BPS located upstream of original BPS and this alternative BPS has a higher affinity to U2/SF3B1mut snRNA compared to the canonical BPS.	('SF3B1', 'Gene', (8, 13))	('BPS', 'Chemical', '-', (73, 76))	('BPS', 'Chemical', '-', (40, 43))	('BPS', 'Chemical', '-', (98, 101))	('BPS', 'Chemical', '-', (171, 174))	('Mutated', 'Var', (0, 7))	('higher', 'PosReg', (108, 114))	('affinity', 'MPA', (115, 123))
100491	33333932	This alternate BPS usage results in aberrant splicing.	('BPS', 'Chemical', '-', (15, 18))	('aberrant', 'Var', (36, 44))	('results in', 'Reg', (25, 35))	('splicing', 'biological_process', 'GO:0045292', ('45', '53'))
100492	33333932	Mutations in SF3B1 are almost exclusively clustered in a specific repeat sequence motif: the 22 non-identical HEAT (Huntington, Elongation factor 3, protein phosphatase 2A, Targets of rapamycin 1) repeats domain region.	('rapamycin', 'Chemical', 'MESH:D020123', (184, 193))	('Huntington', 'Disease', 'MESH:D006816', (116, 126))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('SF3B1', 'Gene', (13, 18))	('Huntington', 'Disease', (116, 126))	('Mutations', 'Var', (0, 9))	('protein phosphatase 2A', 'molecular_function', 'GO:0050115', ('149', '171'))
100493	33333932	Mutations in this motif have been shown to affect the interaction with the DDX46 (DEAD-Box Helicase 46) protein (prp5 in yeast) necessary for stable association of U2 snRNP to the pre-mRNA.	('DDX46', 'Gene', (75, 80))	('yeast', 'Species', '4932', (121, 126))	('snRNP', 'Gene', (167, 172))	('snRNP', 'Gene', '57819', (167, 172))	('association', 'Interaction', (149, 160))	('affect', 'Reg', (43, 49))	('prp5', 'Gene', '852539', (113, 117))	('Mutations', 'Var', (0, 9))	('pre', 'molecular_function', 'GO:0003904', ('180', '183'))	('prp5', 'Gene', (113, 117))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('interaction', 'Interaction', (54, 65))	('DDX46', 'Gene', '9879', (75, 80))	('snRNP', 'molecular_function', 'GO:0003734', ('167', '172'))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('164', '172'))
100495	33333932	In contrast, hotspot mutations in the sixth and seventh HEAT repeat codon position lysine (K) 666 and K700, respectively, are seen in the other cancers such as hematologic cancer and breast cancer (Figure 3).	('lysine', 'Chemical', 'MESH:D008239', (83, 89))	('hematologic cancer', 'Disease', 'MESH:D009369', (160, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('hematologic cancer', 'Phenotype', 'HP:0004377', (160, 178))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('cancers', 'Disease', (144, 151))	('K700', 'Var', (102, 106))	('hematologic cancer', 'Disease', (160, 178))	('breast cancer', 'Disease', (183, 196))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
100496	33333932	The few mutations outside the HEAT repeat domains do not display aberrant splicing, suggesting they have different effects on cancer cells or have no effect and are simply passenger mutations.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('splicing', 'biological_process', 'GO:0045292', ('74', '82'))	('cancer', 'Disease', (126, 132))	('mutations', 'Var', (8, 17))	('cancer', 'Disease', 'MESH:D009369', (126, 132))
100497	33333932	The outcome of a large study of 533 patients with MDS indicated that patients with SF3B1 mutations were associated with a better overall survival and a lower risk of progression to acute myeloid leukemia compared to patients without SF3B1 mutations.	('better', 'PosReg', (122, 128))	('patients', 'Species', '9606', (36, 44))	('leukemia', 'Phenotype', 'HP:0001909', (195, 203))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (181, 203))	('acute myeloid leukemia', 'Disease', (181, 203))	('MDS', 'Disease', (50, 53))	('SF3B1', 'Gene', (83, 88))	('MDS', 'Disease', 'MESH:D009190', (50, 53))	('patients', 'Species', '9606', (216, 224))	('MDS', 'Phenotype', 'HP:0002863', (50, 53))	('mutations', 'Var', (89, 98))	('patients', 'Species', '9606', (69, 77))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (187, 203))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (181, 203))
100498	33333932	Moreover, SF3B1 mutations in MDS is an independent predictor of favorable outcome, although other studies indicated no significant effect on overall survival and were associated with shorter leukemia-free survival.	('mutations', 'Var', (16, 25))	('shorter', 'NegReg', (183, 190))	('SF3B1', 'Gene', (10, 15))	('MDS', 'Disease', (29, 32))	('MDS', 'Disease', 'MESH:D009190', (29, 32))	('leukemia-free', 'Disease', 'MESH:D008569', (191, 204))	('MDS', 'Phenotype', 'HP:0002863', (29, 32))	('leukemia', 'Phenotype', 'HP:0001909', (191, 199))	('leukemia-free', 'Disease', (191, 204))
100499	33333932	In breast cancer, SF3B1 mutations are associated with poor prognosis in PR-negative and luminal B subgroups.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('SF3B1', 'Gene', (18, 23))	('mutations', 'Var', (24, 33))
100501	33333932	assessed SRSF2 mutations in UM patients and found five patients with SRSF2 mutations.	('UM', 'Phenotype', 'HP:0007716', (28, 30))	('mutations', 'Var', (15, 24))	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (55, 63))	('SRSF2', 'Gene', (9, 14))
100503	33333932	Mutations in SRSF2 occur in approximately 12% of MDS patients, however not as in-frame deletions but the more common missense mutations at hotspot P95.	('MDS', 'Disease', (49, 52))	('MDS', 'Disease', 'MESH:D009190', (49, 52))	('MDS', 'Phenotype', 'HP:0002863', (49, 52))	('patients', 'Species', '9606', (53, 61))	('P95', 'Gene', (147, 150))	('SRSF2', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('P95', 'Gene', '4683', (147, 150))
100504	33333932	As in case of the SF3B1 mutations, these in-frame deletions are typical for UM and are not observed in other malignancies where nucleotide change are more prevalent.	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('malignancies', 'Disease', (109, 121))	('SF3B1', 'Gene', (18, 23))	('mutations', 'Var', (24, 33))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))
100505	33333932	Chromosomal instability is characteristic for most cancers.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (0, 23))	('Chromosomal instability', 'Var', (0, 23))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
100508	33333932	BAP1 mutated UM is strongly associated with loss of chromosome 3.	('chromosome', 'cellular_component', 'GO:0005694', ('52', '62'))	('BAP1', 'Gene', (0, 4))	('associated', 'Reg', (28, 38))	('loss', 'NegReg', (44, 48))	('mutated', 'Var', (5, 12))	('BAP1', 'Gene', '8314', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (13, 15))
100510	33333932	BAP1 mutated UM are characterized by gains or losses of entire chromosomes or chromosome arms.	('BAP1', 'Gene', (0, 4))	('chromosome', 'cellular_component', 'GO:0005694', ('78', '88'))	('losses', 'NegReg', (46, 52))	('gains', 'PosReg', (37, 42))	('mutated', 'Var', (5, 12))	('BAP1', 'Gene', '8314', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (13, 15))
100511	33333932	Furthermore, SF3B1 mutated UM are most likely to have more than 3 chromosomal structural variants (CSV) per tumor, with 70% of UM with >3 CSV harboring SF3B1 mutations.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('UM', 'Phenotype', 'HP:0007716', (27, 29))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('SF3B1', 'Gene', (13, 18))	('mutated', 'Var', (19, 26))	('tumor', 'Disease', (108, 113))	('UM', 'Phenotype', 'HP:0007716', (127, 129))
100512	33333932	Between 20-36% of SF3B1 mutated CLL tumors have deletions in chromosome 11q resulting in a worse prognosis.	('mutated', 'Var', (24, 31))	('CLL tumors', 'Disease', (32, 42))	('CLL tumors', 'Disease', 'MESH:D015451', (32, 42))	('SF3B1', 'Gene', (18, 23))	('CLL', 'Phenotype', 'HP:0005550', (32, 35))	('deletions', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('chromosome', 'cellular_component', 'GO:0005694', ('61', '71'))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
100514	33333932	Aberrant methylation can cause aberrant gene regulation, which plays an important role in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('regulation', 'biological_process', 'GO:0065007', ('45', '55'))	('Aberrant methylation', 'Var', (0, 20))	('cause', 'Reg', (25, 30))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('aberrant gene regulation', 'MPA', (31, 55))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
100515	33333932	We and others have assessed aberrant methylation in metastatic uveal melanoma and the results indicate a distinct hypomethylation pattern in SF3B1 mutated patients compared to the BAP1 mutated patients.	('patients', 'Species', '9606', (193, 201))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (63, 77))	('uveal melanoma', 'Disease', (63, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (63, 77))	('BAP1', 'Gene', '8314', (180, 184))	('SF3B1', 'Gene', (141, 146))	('BAP1', 'Gene', (180, 184))	('patients', 'Species', '9606', (155, 163))	('hypomethylation', 'MPA', (114, 129))	('mutated', 'Var', (147, 154))
100516	33333932	Loss of expression of genes such as tumorsupressor genes or enhanced or ectopic expression of oncogenes could play a crucial role in spliceosome induced tumorigenesis, including UM.	('ectopic expression', 'Var', (72, 90))	('Loss of', 'NegReg', (0, 7))	('tumorsupressor', 'Disease', 'None', (36, 50))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('oncogenes', 'Gene', (94, 103))	('spliceosome', 'cellular_component', 'GO:0005681', ('133', '144'))	('spliceosome', 'Var', (133, 144))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumorsupressor', 'Disease', (36, 50))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('expression', 'MPA', (8, 18))	('UM', 'Phenotype', 'HP:0007716', (178, 180))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('enhanced', 'PosReg', (60, 68))	('tumor', 'Disease', (36, 41))
100521	33333932	TERT was expressed in 73% of all tumors and a third of these had TERT abnormalities, including TERT promotor mutations and amplification or chromosomal rearrangement.	('TERT abnormalities', 'Disease', (65, 83))	('TERT', 'Gene', (95, 99))	('TERT', 'Gene', '7015', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('TERT', 'Gene', (0, 4))	('chromosomal rearrangement', 'Var', (140, 165))	('TERT', 'Gene', (65, 69))	('TERT', 'Gene', '7015', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('TERT', 'Gene', '7015', (65, 69))	('TERT abnormalities', 'Disease', 'MESH:D018376', (65, 83))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('amplification', 'Var', (123, 136))	('tumors', 'Disease', (33, 39))
100522	33333932	However, mutations in TERT promotor occur at extremely low frequency (1%) in UM compared to other types of ocular lesions.	('ocular lesions', 'Disease', (107, 121))	('TERT', 'Gene', (22, 26))	('mutations', 'Var', (9, 18))	('TERT', 'Gene', '7015', (22, 26))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('ocular lesions', 'Disease', 'MESH:D005128', (107, 121))
100523	33333932	Interestingly, the TERT promotor mutated UM had normal BAP1 staining and had wild type SF3B1 as well as EIF1AX.	('EIF1AX', 'Gene', (104, 110))	('TERT', 'Gene', (19, 23))	('TERT', 'Gene', '7015', (19, 23))	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('BAP1', 'Gene', (55, 59))	('mutated', 'Var', (33, 40))	('EIF1AX', 'Gene', '1964', (104, 110))	('BAP1', 'Gene', '8314', (55, 59))
100524	33333932	Our group has studied the length of telomeres in UM tumors harboring SF3B1 and BAP1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('BAP1', 'Gene', '8314', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('UM', 'Phenotype', 'HP:0007716', (49, 51))	('tumors', 'Disease', (52, 58))	('BAP1', 'Gene', (79, 83))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('mutations', 'Var', (84, 93))	('SF3B1', 'Gene', (69, 74))
100528	33333932	Interestingly, we found that SF3B1 mutated tumors had longer telomeres in chromosome 6 compared to controls and the CCCCAA repeats were significantly more expressed in chromosomes 6 p-arm and 8 p-arm in SF3B1 mutated UM compared to BAP1 mutated UM (p < 0.05).	('telomeres in chromosome 6', 'CPA', (61, 86))	('mutated', 'Var', (35, 42))	('expressed', 'MPA', (155, 164))	('BAP1', 'Gene', (232, 236))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('longer', 'PosReg', (54, 60))	('more', 'PosReg', (150, 154))	('chromosome', 'cellular_component', 'GO:0005694', ('74', '84'))	('UM', 'Phenotype', 'HP:0007716', (245, 247))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('BAP1', 'Gene', '8314', (232, 236))	('mutated', 'Var', (209, 216))	('tumors', 'Disease', (43, 49))	('SF3B1', 'Gene', (29, 34))	('SF3B1 mutated', 'Var', (203, 216))	('UM', 'Phenotype', 'HP:0007716', (217, 219))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
100529	33333932	observed increased levels of DNA-PK (DNA-dependent protein kinase) in UM and this activity could indeed be instrumental for the observed increase in structural changes in SF3B1-mutated UM.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('UM', 'Phenotype', 'HP:0007716', (185, 187))	('structural changes', 'MPA', (149, 167))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('DNA-dependent protein kinase', 'Gene', (37, 65))	('increased', 'PosReg', (9, 18))	('DNA-PK', 'Gene', (29, 35))	('SF3B1-mutated', 'Var', (171, 184))	('increase', 'PosReg', (137, 145))	('DNA-PK', 'Gene', '5591', (29, 35))	('DNA-dependent protein kinase', 'Gene', '5591', (37, 65))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
100531	33333932	The prominent role of altered splicing in tumorigenesis makes it an alluring target for novel therapeutic approaches.	('tumor', 'Disease', (42, 47))	('altered splicing', 'Var', (22, 38))	('splicing', 'biological_process', 'GO:0045292', ('30', '38'))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
100534	33333932	These splicing inhibitors have been evaluated in SF3B1 mutant breast cancer cell lines and cells of MDS patients.	('MDS', 'Disease', (100, 103))	('MDS', 'Disease', 'MESH:D009190', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('mutant', 'Var', (55, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('SF3B1', 'Gene', (49, 54))	('MDS', 'Phenotype', 'HP:0002863', (100, 103))	('patients', 'Species', '9606', (104, 112))	('splicing', 'biological_process', 'GO:0045292', ('6', '14'))
100535	33333932	Mutant SF3B1 cells showed selective growth inhibition, altered splicing and increased cell death.	('cell death', 'biological_process', 'GO:0008219', ('86', '96'))	('death', 'Disease', 'MESH:D003643', (91, 96))	('death', 'Disease', (91, 96))	('increased', 'PosReg', (76, 85))	('growth inhibition', 'CPA', (36, 53))	('altered', 'Reg', (55, 62))	('SF3B1', 'Gene', (7, 12))	('splicing', 'MPA', (63, 71))	('Mutant', 'Var', (0, 6))	('splicing', 'biological_process', 'GO:0045292', ('63', '71'))
100539	33333932	E7107, an analog of pladienolide B only affects wildtype SF3B1 and treating SF3B1 mutated colorectal cancer cells with E7107 will result in cell death.	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('affects', 'Reg', (40, 47))	('E7107', 'Var', (119, 124))	('E7107', 'Var', (0, 5))	('cell death', 'biological_process', 'GO:0008219', ('140', '150'))	('result in', 'Reg', (130, 139))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('E7107', 'Chemical', 'MESH:C557411', (119, 124))	('SF3B1', 'Gene', (76, 81))	('mutated', 'Var', (82, 89))	('E7107', 'Chemical', 'MESH:C557411', (0, 5))	('pladienolide B', 'Chemical', 'MESH:C522342', (20, 34))	('death', 'Disease', 'MESH:D003643', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('colorectal cancer', 'Disease', (90, 107))	('death', 'Disease', (145, 150))
100540	33333932	Our hypothesis is that the same results will also be seen in UM cells: E7107 exposure affecting wild type SF3B1, resulting in exclusively altered splicing by mutated SF3B1 and subsequent cell death.	('E7107 exposure', 'Var', (71, 85))	('SF3B1', 'Gene', (106, 111))	('cell death', 'biological_process', 'GO:0008219', ('187', '197'))	('altered', 'Reg', (138, 145))	('E7107', 'Chemical', 'MESH:C557411', (71, 76))	('death', 'Disease', 'MESH:D003643', (192, 197))	('death', 'Disease', (192, 197))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('mutated', 'Var', (158, 165))	('SF3B1', 'Gene', (166, 171))	('splicing', 'biological_process', 'GO:0045292', ('146', '154'))	('splicing', 'MPA', (146, 154))
100541	33333932	In vivo treatment of E7107 in SRSF2 mutated murine myeloid leukemia cells resulted in preferential cell death of cells harboring mutant SRSF2.	('myeloid leukemia', 'Disease', (51, 67))	('SRSF2', 'Gene', (136, 141))	('SRSF2', 'Gene', (30, 35))	('preferential', 'PosReg', (86, 98))	('leukemia', 'Phenotype', 'HP:0001909', (59, 67))	('murine', 'Species', '10090', (44, 50))	('E7107', 'Chemical', 'MESH:C557411', (21, 26))	('myeloid leukemia', 'Disease', 'MESH:D007951', (51, 67))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (51, 67))	('cell death', 'biological_process', 'GO:0008219', ('99', '109'))	('E7107', 'Var', (21, 26))	('death', 'Disease', 'MESH:D003643', (104, 109))	('death', 'Disease', (104, 109))	('mutant', 'Var', (129, 135))
100542	33333932	E7107 has since been studied in two separate phase I clinical studies in patients with solid cancers.	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('E7107', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('E7107', 'Chemical', 'MESH:C557411', (0, 5))	('patients', 'Species', '9606', (73, 81))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
100548	33333932	In this study, BCL2A1 (BCL2 related protein A1) and MCL1 (MCL1 apoptosis regulator), members of the BCL2 family genes, were sensitive to E7107, whereas BCL2L1 (BCL2 like 1), which encodes BCLxL (B-cell lymphoma-extra large), was highly resistant to E7107-induced splicing modulation.	('BCL2', 'Gene', (23, 27))	('BCL2', 'Gene', (100, 104))	('BCL2', 'molecular_function', 'GO:0015283', ('152', '156'))	('E7107', 'Var', (137, 142))	('MCL1', 'Gene', (52, 56))	('BCL2 like 1', 'Gene', '598', (160, 171))	('BCL2 related protein A1', 'Gene', '597', (23, 46))	('BCL2A1', 'Gene', '597', (15, 21))	('BCL2', 'molecular_function', 'GO:0015283', ('100', '104'))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('BCL2', 'molecular_function', 'GO:0015283', ('160', '164'))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))	('BCL2L1', 'Gene', (152, 158))	('BCL2', 'Gene', '596', (152, 156))	('BCL2', 'Gene', '596', (160, 164))	('MCL1', 'Gene', '4170', (52, 56))	('MCL1', 'Gene', (58, 62))	('BCL2A1', 'Gene', (15, 21))	('BCL2', 'molecular_function', 'GO:0015283', ('23', '27'))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (195, 210))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('E7107', 'Chemical', 'MESH:C557411', (249, 254))	('BCL2', 'Gene', '596', (15, 19))	('MCL1', 'Gene', '4170', (58, 62))	('BCL2 related protein A1', 'Gene', (23, 46))	('BCL2 like 1', 'Gene', (160, 171))	('BCL2', 'Gene', '596', (23, 27))	('BCL2', 'Gene', (152, 156))	('BCLxL', 'Gene', '598', (188, 193))	('BCL2', 'Gene', (160, 164))	('sensitive', 'MPA', (124, 133))	('BCL2', 'Gene', '596', (100, 104))	('splicing', 'biological_process', 'GO:0045292', ('263', '271'))	('BCL2', 'molecular_function', 'GO:0015283', ('15', '19'))	('BCL2L1', 'Gene', '598', (152, 158))	('BCLxL', 'Gene', (188, 193))	('E7107', 'Chemical', 'MESH:C557411', (137, 142))	('lymphoma', 'Phenotype', 'HP:0002665', (202, 210))	('BCL2', 'Gene', (15, 19))
100549	33333932	Furthermore, when E7107 was combined with BCLxL inhibitors, this enhanced the cytotoxicity in numerous cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cytotoxicity', 'Disease', (78, 90))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('enhanced', 'PosReg', (65, 73))	('cytotoxicity', 'Disease', 'MESH:D064420', (78, 90))	('E7107', 'Var', (18, 23))	('BCLxL', 'Gene', (42, 47))	('cancer', 'Disease', (103, 109))	('E7107', 'Chemical', 'MESH:C557411', (18, 23))	('BCLxL', 'Gene', '598', (42, 47))
100550	33333932	These results indicate an increased cytotoxicity can be achieved with splicing inhibitors in combination with targeting MCL1 and BCLxL.	('MCL1', 'Gene', '4170', (120, 124))	('BCLxL', 'Gene', (129, 134))	('MCL1', 'Gene', (120, 124))	('cytotoxicity', 'Disease', 'MESH:D064420', (36, 48))	('BCLxL', 'Gene', '598', (129, 134))	('splicing', 'biological_process', 'GO:0045292', ('70', '78'))	('splicing inhibitors', 'Var', (70, 89))	('cytotoxicity', 'Disease', (36, 48))
100556	33333932	Intriguingly, SF3B1 mutated UM are associated with gain of 8q, and proto-oncogene c-MYC is located in the 8q.	('c-MYC', 'Gene', '4609', (82, 87))	('UM', 'Phenotype', 'HP:0007716', (28, 30))	('gain', 'PosReg', (51, 55))	('SF3B1', 'Gene', (14, 19))	('c-MYC', 'Gene', (82, 87))	('mutated', 'Var', (20, 27))
100559	33333932	Mutated SF3B1 recognizes aberrant deep intronic branchpoint in BRD9, a core component of the non-canonical BAF (ncBAF) chromatin remodeling complex.	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('119', '147'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('119', '139'))	('BRD9', 'Gene', '65980', (63, 67))	('aberrant', 'Var', (25, 33))	('core', 'cellular_component', 'GO:0019013', ('71', '75'))	('Mutated', 'Var', (0, 7))	('SF3B1', 'Gene', (8, 13))	('BRD9', 'Gene', (63, 67))
100561	33333932	Loss of BRD9 promotes melanoma tumorigenesis through perturbation of ncBAF.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('promotes', 'PosReg', (13, 21))	('perturbation', 'NegReg', (53, 65))	('BRD9', 'Gene', '65980', (8, 12))	('tumor', 'Disease', (31, 36))	('BRD9', 'Gene', (8, 12))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma', 'Disease', (22, 30))	('Loss', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('ncBAF', 'Gene', (69, 74))
100562	33333932	When mis-splicing of BRD9 in SF3B1-mutated cells was corrected, tumor growth was suppressed.	('suppressed', 'NegReg', (81, 91))	('tumor', 'Disease', (64, 69))	('splicing', 'biological_process', 'GO:0045292', ('9', '17'))	('BRD9', 'Gene', '65980', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mis-splicing', 'Var', (5, 17))	('BRD9', 'Gene', (21, 25))
100564	33333932	Targeting mis-splicing of BRD9 could therefore be a potential cancer therapy in SF3B1 mutated malignancies.	('mutated', 'Var', (86, 93))	('splicing', 'biological_process', 'GO:0045292', ('14', '22'))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Targeting mis-splicing', 'Var', (0, 22))	('BRD9', 'Gene', '65980', (26, 30))	('malignancies', 'Disease', 'MESH:D009369', (94, 106))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('SF3B1', 'Gene', (80, 85))	('BRD9', 'Gene', (26, 30))	('malignancies', 'Disease', (94, 106))
100566	33333932	However, delivery of the CRISPR gene therapy in vivo (off-target effects, targeted delivery, delivery efficiency and editing efficiency) remains challenging, and should be studied extensively before eventually applying this potential therapeutic method to patients with metastasized SF3B1 mutated UM.	('mutated', 'Var', (289, 296))	('SF3B1', 'Gene', (283, 288))	('patients', 'Species', '9606', (256, 264))	('UM', 'Phenotype', 'HP:0007716', (297, 299))
100567	33333932	Furthermore, SF3B1 mutated UM show similarities to other spliceosome mutated malignancies.	('spliceosome', 'cellular_component', 'GO:0005681', ('57', '68'))	('UM', 'Phenotype', 'HP:0007716', (27, 29))	('SF3B1', 'Gene', (13, 18))	('malignancies', 'Disease', (77, 89))	('mutated', 'Var', (19, 26))	('malignancies', 'Disease', 'MESH:D009369', (77, 89))
100568	33333932	The following are available online at , Figure S1: Multiple comparison using TelomereHunter data, Table S1: Missense mutation frequency of SF3B1 mutation in patients with hematological cancers, breast cancer and mucosal melanoma.	('mucosal melanoma', 'Disease', (212, 228))	('hematological cancers', 'Disease', (171, 192))	('mucosal melanoma', 'Disease', 'MESH:D008545', (212, 228))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('patients', 'Species', '9606', (157, 165))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('hematological cancers', 'Disease', 'MESH:D009369', (171, 192))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('SF3B1', 'Gene', (139, 144))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('Missense mutation frequency', 'Var', (108, 135))	('breast cancer', 'Disease', (194, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
100571	32560575	Genetic alterations in tumor suppressor genes involved in chromatin, transcription and hypoxia regulation have also been described.	('Genetic alterations', 'Var', (0, 19))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('23', '39'))	('regulation', 'biological_process', 'GO:0065007', ('95', '105'))	('transcription', 'biological_process', 'GO:0006351', ('69', '82'))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('chromatin', 'cellular_component', 'GO:0000785', ('58', '67'))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('hypoxia', 'Disease', 'MESH:D000860', (87, 94))	('tumor suppressor', 'biological_process', 'GO:0051726', ('23', '39'))	('tumor', 'Disease', (23, 28))	('hypoxia', 'Disease', (87, 94))
100572	32560575	Furthermore, we identified several single nucleotide polymorphisms (SNPs) that may promote MM tumorigenesis as a result of an asbestos-gene interaction, including SNPs in DNA repair, carcinogen detoxification and other genes previously associated with other malignancies.	('SNPs', 'Var', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('DNA', 'Gene', (171, 174))	('promote', 'PosReg', (83, 90))	('detoxification', 'biological_process', 'GO:0098754', ('194', '208'))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('malignancies', 'Disease', 'MESH:D009369', (258, 270))	('tumor', 'Disease', (94, 99))	('DNA', 'cellular_component', 'GO:0005574', ('171', '174'))	('malignancies', 'Disease', (258, 270))	('interaction', 'Interaction', (140, 151))	('asbestos', 'Chemical', 'MESH:D001194', (126, 134))	('DNA repair', 'biological_process', 'GO:0006281', ('171', '181'))
100573	32560575	The identification of inherited mutations for MM and an understanding of the underlying pathways may allow early detection and prevention of malignancies in high-risk individuals and pave the way for targeted therapies.	('malignancies', 'Disease', 'MESH:D009369', (141, 153))	('mutations', 'Var', (32, 41))	('malignancies', 'Disease', (141, 153))
100590	32560575	The functional roles of BAP1 are partially through its deubiquitinase activity and synergy with other proteins, such as HCFC1, YY1, OGT, ASXL1/2 and FOXK1/2, but the impact of the distinct BAP1 mutations on the function of these complexes is not fully understood.	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('55', '78'))	('ASXL1/2', 'Gene', (137, 144))	('synergy', 'MPA', (83, 90))	('OGT', 'Gene', (132, 135))	('BAP1', 'Gene', '8314', (189, 193))	('HCFC1', 'Gene', '3054', (120, 125))	('OGT', 'Gene', '8473', (132, 135))	('YY1', 'Gene', '7528', (127, 130))	('BAP1', 'Gene', (24, 28))	('ASXL1/2', 'Gene', '171023;55252', (137, 144))	('YY1', 'Gene', (127, 130))	('HCFC1', 'Gene', (120, 125))	('BAP1', 'Gene', (189, 193))	('deubiquitinase activity', 'MPA', (55, 78))	('FOXK1/2', 'Gene', (149, 156))	('FOXK1/2', 'Gene', '221937;3607', (149, 156))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('55', '78'))	('mutations', 'Var', (194, 203))	('BAP1', 'Gene', '8314', (24, 28))
100591	32560575	Germline BAP1 mutations underlie the BAP1 tumor predisposition syndrome, associated with uveal (UM) and cutaneous melanoma (CM), MM, renal cell carcinoma (RCC), non-melanoma skin cancer, meningioma and cholangiocarcinoma as well as other cancers (Figure 2).	('RCC', 'Disease', (155, 158))	('meningioma', 'Phenotype', 'HP:0002858', (187, 197))	('cutaneous melanoma', 'Disease', (104, 122))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (104, 122))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (104, 122))	('associated', 'Reg', (73, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (202, 220))	('melanoma skin cancer', 'Disease', (165, 185))	('melanoma skin cancer', 'Disease', 'MESH:D012878', (165, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('BAP1', 'Gene', (9, 13))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))	('RCC', 'Disease', 'MESH:C538614', (155, 158))	('cancers', 'Disease', (238, 245))	('uveal', 'Disease', (89, 94))	('tumor', 'Disease', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('BAP1', 'Gene', '8314', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (133, 153))	('mutations', 'Var', (14, 23))	('meningioma and cholangiocarcinoma', 'Disease', 'MESH:D018281', (187, 220))	('CM', 'Phenotype', 'HP:0012056', (124, 126))	('BAP1', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('skin cancer', 'Phenotype', 'HP:0008069', (174, 185))	('cancers', 'Disease', 'MESH:D009369', (238, 245))	('renal cell carcinoma', 'Disease', (133, 153))	('BAP1', 'Gene', '8314', (9, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (133, 153))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))
100592	32560575	BAP1 genetic alterations appear typically with one mutant allele in all cells, while the somatic inactivation of the second allele results in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('results in', 'Reg', (131, 141))	('BAP1', 'Gene', (0, 4))	('tumor', 'Disease', (142, 147))	('genetic alterations', 'Var', (5, 24))	('inactivation', 'Var', (97, 109))	('BAP1', 'Gene', '8314', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
100593	32560575	The gene-environment interaction is suspected to play an important role in cancer susceptibility for BAP1 mutation carriers.	('carriers', 'Reg', (115, 123))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('BAP1', 'Gene', '8314', (101, 105))	('cancer', 'Disease', (75, 81))	('mutation', 'Var', (106, 114))	('BAP1', 'Gene', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
100594	32560575	The pathogenic BAP1 variants are known with a high penetration and approximately 85% of the mutation carriers are diagnosed with more than one malignancy.	('malignancy', 'Disease', 'MESH:D009369', (143, 153))	('variants', 'Var', (20, 28))	('malignancy', 'Disease', (143, 153))	('BAP1', 'Gene', '8314', (15, 19))	('BAP1', 'Gene', (15, 19))	('pathogenic', 'Reg', (4, 14))
100595	32560575	Beside malignancies, individuals with germline BAP1 mutations often present with BAP1-inactivated nevi, previously called melanocytic BAP1-mutated atypical intradermal tumors (MBAITs), that are atypical melanocytes proliferations with spitzoid morphology.	('mutations', 'Var', (52, 61))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('BAP1', 'Gene', (81, 85))	('BAP1', 'Gene', (134, 138))	('malignancies', 'Disease', 'MESH:D009369', (7, 19))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('BAP1', 'Gene', '8314', (47, 51))	('nevi', 'Phenotype', 'HP:0003764', (98, 102))	('malignancies', 'Disease', (7, 19))	('BAP1', 'Gene', '8314', (134, 138))	('BAP1', 'Gene', '8314', (81, 85))	('BAP1', 'Gene', (47, 51))	('present', 'Reg', (68, 75))
100596	32560575	BAP1 mutations are infrequent in the general population and there are no homozygotes.	('BAP1', 'Gene', '8314', (0, 4))	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
100597	32560575	Patients carrying BAP1 genetic variations were shown to have a higher incidence of peritoneal versus pleural MM.	('BAP1', 'Gene', '8314', (18, 22))	('genetic variations', 'Var', (23, 41))	('peritoneal versus pleural MM', 'Disease', (83, 111))	('BAP1', 'Gene', (18, 22))	('Patients', 'Species', '9606', (0, 8))	('peritoneal versus pleural MM', 'Disease', 'MESH:D010534', (83, 111))
100598	32560575	In comparison with sporadic MM, the BAP1 mutated patients tend to have sevenfold longer overall survival even when they have other cancers as well.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('mutated', 'Var', (41, 48))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('longer', 'PosReg', (81, 87))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('overall survival', 'MPA', (88, 104))	('BAP1', 'Gene', '8314', (36, 40))	('patients', 'Species', '9606', (49, 57))	('BAP1', 'Gene', (36, 40))
100600	32560575	Patients with UM and inherited BAP1 mutations present often with a more aggressive and metastatic disease and more advanced tumor staging, and thus worse survival.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('BAP1', 'Gene', '8314', (31, 35))	('aggressive and metastatic disease', 'Disease', 'MESH:C538445', (72, 105))	('tumor', 'Disease', (124, 129))	('mutations', 'Var', (36, 45))	('Patients', 'Species', '9606', (0, 8))	('BAP1', 'Gene', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
100603	32560575	Asbestos fibers are known to induce DNA damage, which is repaired by HR and double-strand breaks repair, MMR and NER, thus individuals with defects in the DNA repair processes are more prone to develop MM.	('Asbestos', 'Chemical', 'MESH:D001194', (0, 8))	('DNA', 'cellular_component', 'GO:0005574', ('155', '158'))	('MMR', 'biological_process', 'GO:0006298', ('105', '108'))	('NER', 'biological_process', 'GO:0006289', ('113', '116'))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('DNA repair', 'biological_process', 'GO:0006281', ('155', '165'))	('develop', 'PosReg', (194, 201))	('defects', 'Var', (140, 147))
100610	32560575	Hence, TP53 and p53 are crucial for regulating DNA repair and cell division and genetic mutations in this gene may predispose to several malignancies.	('DNA', 'cellular_component', 'GO:0005574', ('47', '50'))	('malignancies', 'Disease', 'MESH:D009369', (137, 149))	('genetic mutations', 'Var', (80, 97))	('TP53', 'Gene', '7157', (7, 11))	('predispose', 'Reg', (115, 125))	('TP53', 'Gene', (7, 11))	('DNA repair', 'biological_process', 'GO:0006281', ('47', '57'))	('cell division', 'biological_process', 'GO:0051301', ('62', '75'))	('p53', 'Gene', (16, 19))	('malignancies', 'Disease', (137, 149))	('p53', 'Gene', '7157', (16, 19))
100618	32560575	They are necessary in order to maintain genomic stability and defects in the MMR may result in microsatellite instability and or malignant diseases, such as hereditary nonpolyposis colon cancer (HNPCC) and cancers of the NHPCC spectrum.	('MMR', 'Gene', (77, 80))	('result in', 'Reg', (85, 94))	('hereditary nonpolyposis colon cancer', 'Phenotype', 'HP:0006716', (157, 193))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Disease', (206, 213))	('HNPCC', 'Phenotype', 'HP:0006716', (195, 200))	('defects', 'Var', (62, 69))	('microsatellite instability', 'Disease', 'MESH:D053842', (95, 121))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('colon cancer', 'Phenotype', 'HP:0003003', (181, 193))	('NHPCC spectrum', 'Disease', (221, 235))	('microsatellite instability', 'Disease', (95, 121))	('malignant diseases', 'Disease', (129, 147))	('MMR', 'biological_process', 'GO:0006298', ('77', '80'))	('hereditary nonpolyposis colon cancer', 'Disease', (157, 193))	('malignant diseases', 'Disease', 'MESH:D009369', (129, 147))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('hereditary nonpolyposis colon cancer', 'Disease', 'MESH:D003123', (157, 193))	('HNPCC', 'Disease', 'None', (195, 200))	('HNPCC', 'Disease', (195, 200))
100620	32560575	An interesting observation is that MPM patients with inherited mutations in these genes tend to have improved survival compared with those with no genetic alteration, mirroring patients with BRCA1- and BRCA2-associated malignancies (Figure 3).	('mutations', 'Var', (63, 72))	('BRCA1', 'Gene', (191, 196))	('BRCA1', 'Gene', '672', (191, 196))	('survival', 'MPA', (110, 118))	('patients', 'Species', '9606', (39, 47))	('patients', 'Species', '9606', (177, 185))	('BRCA2', 'Gene', '675', (202, 207))	('malignancies', 'Disease', 'MESH:D009369', (219, 231))	('improved', 'PosReg', (101, 109))	('malignancies', 'Disease', (219, 231))	('BRCA2', 'Gene', (202, 207))
100621	32560575	Patients with ovarian, breast or prostate cancer who carry germline BRCA1 or BRCA2 mutations are more likely to respond to cisplatin-based chemotherapy and have better prognosis.	('mutations', 'Var', (83, 92))	('ovarian, breast or prostate cancer', 'Disease', 'MESH:D011472', (14, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('BRCA1', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('BRCA2', 'Gene', (77, 82))	('Patients', 'Species', '9606', (0, 8))	('BRCA2', 'Gene', '675', (77, 82))	('respond to cisplatin-based chemotherapy', 'MPA', (112, 151))	('prostate cancer', 'Phenotype', 'HP:0012125', (33, 48))	('BRCA1', 'Gene', '672', (68, 73))
100623	32560575	PARPi are proven to be effective for various solid tumors with somatic or germline mutations in HR deficit genes, including breast, prostate, ovarian and pancreatic cancer.	('prostate', 'Disease', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast', 'Disease', (124, 130))	('germline mutations', 'Var', (74, 92))	('ovarian and pancreatic cancer', 'Disease', 'MESH:D010195', (142, 171))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (154, 171))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('HR deficit', 'Gene', (96, 106))
100625	32560575	The literature suggests that germline mutations in DNA repair and other tumor suppressor genes may be a prognostic biomarker for cisplatin chemotherapy in MPM.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('DNA repair', 'biological_process', 'GO:0006281', ('51', '61'))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('tumor', 'Disease', (72, 77))	('tumor suppressor', 'biological_process', 'GO:0051726', ('72', '88'))	('DNA repair', 'Gene', (51, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('72', '88'))	('MPM', 'Disease', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('germline mutations', 'Var', (29, 47))
100630	32560575	Their mutations collectively occur in ~20% of all human cancer types that have been genomically characterized so far.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('occur', 'Reg', (29, 34))	('human', 'Species', '9606', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('mutations', 'Var', (6, 15))	('cancer', 'Disease', (56, 62))
100638	32560575	Genetic testing would be of high benefit for MM patients and their relatives, as it would allow early detection and prevention of malignancies in high-risk individuals.	('malignancies', 'Disease', (130, 142))	('patients', 'Species', '9606', (48, 56))	('malignancies', 'Disease', 'MESH:D009369', (130, 142))	('Genetic', 'Var', (0, 7))
100641	32560575	Most importantly, the patients and their physicians should also be aware of the better survival that mutation-carriers have, as this would have a big impact on their lives and on their treatment considerations and planning.	('mutation-carriers', 'Var', (101, 118))	('impact', 'Reg', (150, 156))	('patients', 'Species', '9606', (22, 30))
100645	32560575	There is no compelling evidence in the two studies that the identified SNPs can cause MM in the absence of asbestos exposure.	('cause', 'Reg', (80, 85))	('asbestos', 'Chemical', 'MESH:D001194', (107, 115))	('SNPs', 'Var', (71, 75))
100652	32560575	SLC7A14 is involved in arginine transport and although this gene has not been previously linked to MM, there are indications of neighboring genes involvement due to identified chromosomal gain in this region.	('involvement', 'Reg', (146, 157))	('chromosomal', 'Var', (176, 187))	('SLC7A14', 'Gene', '57709', (0, 7))	('arginine', 'MPA', (23, 31))	('arginine transport', 'biological_process', 'GO:0015809', ('23', '41'))	('SLC7A14', 'Gene', (0, 7))	('gain', 'PosReg', (188, 192))	('arginine', 'Chemical', 'MESH:D001120', (23, 31))
100655	32560575	Especially the GSTM1 and GSTT1 subfamilies present with homozygous deletion polymorphisms (null genotype) that have been considered as modulators of susceptibility to environmentally induced malignancies.	('GSTM1', 'Gene', '2944', (15, 20))	('GSTM1', 'Gene', (15, 20))	('deletion polymorphisms', 'Var', (67, 89))	('malignancies', 'Disease', 'MESH:D009369', (191, 203))	('GSTT1', 'Gene', '2952', (25, 30))	('GSTT1', 'Gene', (25, 30))	('malignancies', 'Disease', (191, 203))
100658	32560575	Genetic polymorphisms of EPHX may result in an increase or decrease in enzyme activity, which may promote cancer susceptibility.	('EPHX', 'Gene', '2052', (25, 29))	('promote', 'PosReg', (98, 105))	('enzyme activity', 'molecular_function', 'GO:0003824', ('71', '86'))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('enzyme activity', 'MPA', (71, 86))	('EPHX', 'Gene', (25, 29))	('cancer', 'Disease', (106, 112))	('decrease', 'NegReg', (59, 67))	('Genetic polymorphisms', 'Var', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
100660	32560575	The most common polymorphism of MnSOD occurs at codon 16 and results in an Alanine (Ala) to Valine amino acid transformation, which alters the protein secondary structure, and thus impairs the transport of the protein into the mitochondria.	('transport', 'biological_process', 'GO:0006810', ('193', '202'))	('protein', 'cellular_component', 'GO:0003675', ('210', '217'))	('common', 'Reg', (9, 15))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('polymorphism', 'Var', (16, 28))	('Ala', 'Chemical', 'MESH:D000409', (75, 78))	('results in', 'Reg', (61, 71))	('MnSOD', 'Gene', '6648', (32, 37))	('protein secondary structure', 'MPA', (143, 170))	('Valine amino acid', 'Chemical', '-', (92, 109))	('impairs', 'NegReg', (181, 188))	('Ala', 'Chemical', 'MESH:D000409', (84, 87))	('MnSOD', 'Gene', (32, 37))	('Alanine', 'Chemical', 'MESH:D000409', (75, 82))	('alters', 'Reg', (132, 138))	('mitochondria', 'cellular_component', 'GO:0005739', ('227', '239'))	('transport of the protein into the mitochondria', 'MPA', (193, 239))
100665	32560575	The low-activity-associated EPHX1 genotype was a risk factor for MM in the Italian, but not in the Finnish population.	('low-activity-associated', 'Var', (4, 27))	('risk', 'Reg', (49, 53))	('EPHX1', 'Gene', '2052', (28, 33))	('EPHX1', 'Gene', (28, 33))
100667	32560575	The nucleotidic change 282C > T within NAT2 was also found to be significantly associated with MPM risk in another Italian study of 50 SNPs within oxidative metabolism enzymes and 75 SNPs in genome stability genes.	('oxidative metabolism', 'biological_process', 'GO:0045333', ('147', '167'))	('MPM', 'Disease', (95, 98))	('NAT2', 'Gene', (39, 43))	('associated with', 'Reg', (79, 94))	('NAT2', 'Gene', '10', (39, 43))	('nucleotidic change 282C > T', 'Var', (4, 31))	('282C > T', 'Mutation', 'rs1041983', (23, 31))
100669	32560575	genotyped 90 MPM patients versus 395 control subjects and found a higher MPM risk for individuals with a GSTM1 null allele and in those with the Ala/Ala genotypes at codon 16 within MnSOD.	('Ala', 'Chemical', 'MESH:D000409', (145, 148))	('Ala', 'Chemical', 'MESH:D000409', (149, 152))	('GSTM1', 'Gene', '2944', (105, 110))	('MnSOD', 'Gene', (182, 187))	('null', 'Var', (111, 115))	('GSTM1', 'Gene', (105, 110))	('patients', 'Species', '9606', (17, 25))	('higher', 'PosReg', (66, 72))	('MPM', 'Disease', (73, 76))	('MnSOD', 'Gene', '6648', (182, 187))
100670	32560575	focused on four DNA repair genes, XRCC1, XRCC3, XPD and OGG1, hypothesizing that deficient DNA repair mechanisms would fail to protect against the oxidative stress induced by asbestos fibers and eventually result in a higher risk of carcinogenesis.	('XRCC1', 'Gene', '7515', (34, 39))	('XPD', 'Gene', (48, 51))	('DNA repair', 'biological_process', 'GO:0006281', ('91', '101'))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('XRCC3', 'Gene', (41, 46))	('oxidative stress', 'MPA', (147, 163))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('DNA', 'cellular_component', 'GO:0005574', ('16', '19'))	('DNA repair', 'biological_process', 'GO:0006281', ('16', '26'))	('carcinogenesis', 'Disease', (233, 247))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('carcinogenesis', 'Disease', 'MESH:D063646', (233, 247))	('oxidative stress', 'Phenotype', 'HP:0025464', (147, 163))	('XRCC1', 'Gene', (34, 39))	('XPD', 'Gene', '2068', (48, 51))	('XRCC3', 'Gene', '7517', (41, 46))	('asbestos', 'Chemical', 'MESH:D001194', (175, 183))	('OGG1', 'Gene', (56, 60))	('OGG1', 'Gene', '4968', (56, 60))	('deficient', 'Var', (81, 90))	('result in', 'Reg', (206, 215))
100676	32560575	A significant association with MM was noticed for the XRCC1-R399Q Q homozygotes and Q/R heterozygotes versus the R homozygotes and for the XRCC3-T241M T homozygotes and M/T heterozygotes versus the M homozygotes.	('XRCC3', 'Gene', (139, 144))	('R399Q', 'Mutation', 'rs25487', (60, 65))	('XRCC1', 'Gene', (54, 59))	('Q/R', 'Var', (84, 87))	('XRCC3', 'Gene', '7517', (139, 144))	('T241M', 'Mutation', 'rs861539', (145, 150))	('XRCC1', 'Gene', '7515', (54, 59))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('M/T', 'Var', (169, 172))
100723	32211561	Immunohistochemical staining showed tumor cells positive for SOX-10, Melan-A, patchy HMB45, weak and patchy S100 staining, with negative AE1/AE3, SMA, p63, consistent with malignant melanoma (Fig.	('AE3', 'Gene', '6508', (141, 144))	('tumor', 'Disease', (36, 41))	('AE1', 'Gene', '6521', (137, 140))	('SOX-10', 'Gene', (61, 67))	('patchy HMB45', 'Var', (78, 90))	('p63', 'Gene', (151, 154))	('SOX-10', 'Gene', '6663', (61, 67))	('malignant melanoma', 'Disease', (172, 190))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('p63', 'Gene', '8626', (151, 154))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('Melan-A', 'Gene', (69, 76))	('AE1', 'Gene', (137, 140))	('positive', 'Reg', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('AE3', 'Gene', (141, 144))	('malignant melanoma', 'Phenotype', 'HP:0002861', (172, 190))	('malignant melanoma', 'Disease', 'MESH:D008545', (172, 190))	('S100', 'Gene', (108, 112))
100762	31253977	Uveal melanomas commonly harbor mutations that activate the G-protein alpha-q signaling cascade, affecting GNAQ, GNA11, PLCB4, or CYSLTR2 that, with rare exceptions, occur in a mutually exclusive pattern.	('activate', 'PosReg', (47, 55))	('G-protein alpha-q signaling cascade', 'Pathway', (60, 95))	('PLCB4', 'Gene', (120, 125))	('GNA11', 'Gene', (113, 118))	('GNAQ', 'Gene', '2776', (107, 111))	('Uveal melanomas', 'Disease', 'MESH:C536494', (0, 15))	('mutations', 'Var', (32, 41))	('GNA11', 'Gene', '2767', (113, 118))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('CYSLTR2', 'Gene', '57105', (130, 137))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('signaling cascade', 'biological_process', 'GO:0007165', ('78', '95'))	('Uveal melanomas', 'Disease', (0, 15))	('GNAQ', 'Gene', (107, 111))	('CYSLTR2', 'Gene', (130, 137))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))	('PLCB4', 'Gene', '5332', (120, 125))
100772	31253977	On average, each sample was sequenced to 423-fold unique coverage, enabling sensitive mutation detection and helping to overcome the well-documented challenge of detecting certain BAP1 mutations.	('mutations', 'Var', (185, 194))	('BAP1', 'Gene', '8314', (180, 184))	('BAP1', 'Gene', (180, 184))	('mutation', 'Var', (86, 94))
100777	31253977	Both mutations, a heterozygous, gain-of-function GNA11 variant and a hemizygous, loss-of-function BAP1 variant, were shared between all three melanoma samples (Fig.	('BAP1', 'Gene', (98, 102))	('variant', 'Var', (55, 62))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('gain-of-function', 'PosReg', (32, 48))	('loss-of-function', 'NegReg', (81, 97))	('BAP1', 'Gene', '8314', (98, 102))	('GNA11', 'Gene', '2767', (49, 54))	('GNA11', 'Gene', (49, 54))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma', 'Disease', (142, 150))
100781	31253977	In the example case, some copy number alterations were shared between all samples, including a deletion of chromosome 3 that encompassed the BAP1 gene and thus explains how the BAP1 mutation became hemizygous.	('BAP1', 'Gene', '8314', (141, 145))	('deletion', 'Var', (95, 103))	('BAP1', 'Gene', (141, 145))	('chromosome', 'cellular_component', 'GO:0005694', ('107', '117'))	('BAP1', 'Gene', '8314', (177, 181))	('BAP1', 'Gene', (177, 181))
100786	31253977	These observations indicate stepwise deletion of CDKN2A paralleled by stepwise amplification of 8q during the evolution of this case.	('CDKN2A', 'Gene', '1029', (49, 55))	('CDKN2A', 'Gene', (49, 55))	('deletion', 'Var', (37, 45))
100787	31253977	The distribution of somatic mutations and copy number changes among the three tumor areas made it possible to delineate the sequential order in which they arose during tumor evolution.	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('copy number changes', 'Var', (42, 61))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
100788	31253977	All three tumor samples shared the GNA11Q209L mutation, bi-allelic BAP1 alterations, mono-allelic deletion of CDKN2A, and gain of at least three copies of chromosomal arm 8q - this indicates that these alterations arose comparatively early and thus reside on the trunk of the evolutionary tree (Fig.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('CDKN2A', 'Gene', (110, 116))	('trunk', 'cellular_component', 'GO:0043198', ('263', '268'))	('alterations', 'Var', (72, 83))	('tumor', 'Disease', (10, 15))	('mono-allelic', 'Var', (85, 97))	('CDKN2A', 'Gene', '1029', (110, 116))	('BAP1', 'Gene', '8314', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('GNA11', 'Gene', '2767', (35, 40))	('GNA11', 'Gene', (35, 40))	('gain', 'PosReg', (122, 126))	('BAP1', 'Gene', (67, 71))
100789	31253977	The Mel1 area of the primary tumor and the metastasis shared a homozygous deletion of CDKN2A and additional levels of 8q gain, placing these somatic alterations on a shared branch of the evolutionary tree (Fig.	('CDKN2A', 'Gene', '1029', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('deletion', 'Var', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('gain', 'PosReg', (121, 125))	('tumor', 'Disease', (29, 34))	('Mel1', 'Gene', '63976', (4, 8))	('Mel1', 'Gene', (4, 8))	('CDKN2A', 'Gene', (86, 92))
100792	31253977	We next annotated the driver mutations in each sequenced region from all 35 patients' tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('patients', 'Species', '9606', (76, 84))	('mutations', 'Var', (29, 38))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))
100793	31253977	As expected, based on prior studies, we observed mutually exclusive mutations involving genes in the Galphaq signaling cascade as well as alterations affecting BAP1, SF3B1, and EIF1AX that tended to not overlap.	('SF3B1', 'Gene', '23451', (166, 171))	('signaling cascade', 'biological_process', 'GO:0007165', ('109', '126'))	('EIF1AX', 'Gene', '1964', (177, 183))	('EIF1AX', 'Gene', (177, 183))	('BAP1', 'Gene', '8314', (160, 164))	('Galphaq', 'Gene', (101, 108))	('SF3B1', 'Gene', (166, 171))	('BAP1', 'Gene', (160, 164))	('Galphaq', 'Gene', '2776', (101, 108))	('mutations', 'Var', (68, 77))
100794	31253977	2) that included loss-of-function mutations affecting CDKN2A, PBRM1, PIK3R2, and PTEN, loss-of-heterozygosity over the GNAQ locus, and gain-of-function mutations affecting EZH2, PIK3CA, and MED12.	('gain-of-function', 'PosReg', (135, 151))	('mutations', 'Var', (152, 161))	('CDKN2A', 'Gene', '1029', (54, 60))	('MED12', 'Gene', '9968', (190, 195))	('loss-of-function', 'NegReg', (17, 33))	('PIK3CA', 'Gene', (178, 184))	('PBRM1', 'Gene', '55193', (62, 67))	('PIK3R2', 'Gene', (69, 75))	('PTEN', 'Gene', (81, 85))	('PBRM1', 'Gene', (62, 67))	('GNAQ', 'Gene', '2776', (119, 123))	('MED12', 'Gene', (190, 195))	('loss-of-heterozygosity', 'NegReg', (87, 109))	('EZH2', 'Gene', '2146', (172, 176))	('GNAQ', 'Gene', (119, 123))	('PIK3R2', 'Gene', '5296', (69, 75))	('CDKN2A', 'Gene', (54, 60))	('EZH2', 'Gene', (172, 176))	('PIK3CA', 'Gene', '5290', (178, 184))	('PTEN', 'Gene', '5728', (81, 85))	('mutations', 'Var', (34, 43))
100795	31253977	The majority of these alterations were in just one region of the primary tumor or private to their metastases (designated in Figure 2 by the faded tiles), indicating that they arose later during progression, after mutational activation of Galphaq and mutations of BAP1, SF3B1, and EIF1AX.	('mutations', 'Var', (251, 260))	('SF3B1', 'Gene', (270, 275))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('BAP1', 'Gene', '8314', (264, 268))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mutational', 'Var', (214, 224))	('activation', 'PosReg', (225, 235))	('SF3B1', 'Gene', '23451', (270, 275))	('EIF1AX', 'Gene', '1964', (281, 287))	('BAP1', 'Gene', (264, 268))	('tumor', 'Disease', (73, 78))	('metastases', 'Disease', (99, 109))	('EIF1AX', 'Gene', (281, 287))	('Galphaq', 'Gene', (239, 246))	('metastases', 'Disease', 'MESH:D009362', (99, 109))	('Galphaq', 'Gene', '2776', (239, 246))
100796	31253977	These mutations are thus considered tertiary driver mutations, likely explaining why they were not apparent in prior bulk sequencing of primary uveal melanomas.	('uveal melanomas', 'Disease', (144, 159))	('uveal melanomas', 'Phenotype', 'HP:0007716', (144, 159))	('uveal melanomas', 'Disease', 'MESH:C536494', (144, 159))	('melanomas', 'Phenotype', 'HP:0002861', (150, 159))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('uveal melanoma', 'Phenotype', 'HP:0007716', (144, 158))	('mutations', 'Var', (6, 15))
100797	31253977	Activation of Galphaq signaling was ubiquitous with mutations affecting GNA11, GNAQ, CYSTLR2, or PLCB4 in a mutually exclusive pattern in all 35 cases in our cohort, consistent with prior findings.	('PLCB4', 'Gene', (97, 102))	('mutations', 'Var', (52, 61))	('GNAQ', 'Gene', '2776', (79, 83))	('Galphaq', 'Gene', (14, 21))	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('Galphaq', 'Gene', '2776', (14, 21))	('CYSTLR2', 'Gene', (85, 92))	('PLCB4', 'Gene', '5332', (97, 102))	('Activation', 'PosReg', (0, 10))	('GNAQ', 'Gene', (79, 83))	('GNA11', 'Gene', (72, 77))	('GNA11', 'Gene', '2767', (72, 77))
100798	31253977	The mutations activating the Galphaq signaling pathway were always shared among all samples from a given patient, indicating that they undergo selection early and are required for tumor formation (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('formation', 'biological_process', 'GO:0009058', ('186', '195'))	('patient', 'Species', '9606', (105, 112))	('signaling pathway', 'biological_process', 'GO:0007165', ('37', '54'))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('activating', 'PosReg', (14, 24))	('mutations', 'Var', (4, 13))	('Galphaq', 'Gene', (29, 36))	('Galphaq', 'Gene', '2776', (29, 36))
100799	31253977	This is also consistent with the recent finding that these mutations are common in choroidal nevi, which is likely a precursor for a subset of uveal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('choroidal nevi', 'Phenotype', 'HP:0025314', (83, 97))	('common', 'Reg', (73, 79))	('uveal melanomas', 'Disease', (143, 158))	('choroidal nevi', 'Disease', 'MESH:D009506', (83, 97))	('uveal melanomas', 'Phenotype', 'HP:0007716', (143, 158))	('melanomas', 'Phenotype', 'HP:0002861', (149, 158))	('nevi', 'Phenotype', 'HP:0003764', (93, 97))	('uveal melanomas', 'Disease', 'MESH:C536494', (143, 158))	('mutations', 'Var', (59, 68))	('choroidal nevi', 'Disease', (83, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (143, 157))
100800	31253977	Galphaq-signaling-pathway mutations were heterozygous in the majority of cases.	('mutations', 'Var', (26, 35))	('signaling-pathway', 'biological_process', 'GO:0007165', ('8', '25'))	('Galphaq', 'Gene', (0, 7))	('Galphaq', 'Gene', '2776', (0, 7))
100801	31253977	However, in six cases, GNAQ mutations were hemizygous or homozygous (Supplementary Fig.	('GNAQ', 'Gene', (23, 27))	('GNAQ', 'Gene', '2776', (23, 27))	('mutations', 'Var', (28, 37))
100802	31253977	Loss-of-heterozygosity of mutant GNAQ tended to take place later during progression (Supplementary Fig.	('mutant', 'Var', (26, 32))	('GNAQ', 'Gene', (33, 37))	('Loss-of-heterozygosity', 'NegReg', (0, 22))	('GNAQ', 'Gene', '2776', (33, 37))
100803	31253977	Preferential expression of mutant over wild-type GNAQ has been observed previously, and our data offer a mechanism as to how this can occur.	('Preferential', 'PosReg', (0, 12))	('mutant', 'Var', (27, 33))	('expression', 'MPA', (13, 23))	('GNAQ', 'Gene', '2776', (49, 53))	('GNAQ', 'Gene', (49, 53))
100804	31253977	We next sought to investigate the relative timing of BAP1, SF3B1, and EIF1AX mutations.	('SF3B1', 'Gene', (59, 64))	('EIF1AX', 'Gene', (70, 76))	('mutations', 'Var', (77, 86))	('BAP1', 'Gene', '8314', (53, 57))	('SF3B1', 'Gene', '23451', (59, 64))	('EIF1AX', 'Gene', '1964', (70, 76))	('BAP1', 'Gene', (53, 57))
100805	31253977	Patients whose uveal melanomas have SF3B1 or EIF1AX mutations tend to have a better prognosis than those with BAP1 mutations.	('mutations', 'Var', (52, 61))	('SF3B1', 'Gene', (36, 41))	('BAP1', 'Gene', '8314', (110, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (15, 29))	('uveal melanomas', 'Disease', 'MESH:C536494', (15, 30))	('BAP1', 'Gene', (110, 114))	('SF3B1', 'Gene', '23451', (36, 41))	('Patients', 'Species', '9606', (0, 8))	('uveal melanomas', 'Phenotype', 'HP:0007716', (15, 30))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('EIF1AX', 'Gene', (45, 51))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('uveal melanomas', 'Disease', (15, 30))	('EIF1AX', 'Gene', '1964', (45, 51))
100808	31253977	However, one EIF1AX-mutant tumor also had bi-allelic BAP1 mutations (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (58, 67))	('tumor', 'Disease', (27, 32))	('EIF1AX', 'Gene', '1964', (13, 19))	('EIF1AX', 'Gene', (13, 19))	('BAP1', 'Gene', '8314', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('BAP1', 'Gene', (53, 57))
100809	31253977	This case was further unusual because the EIF1AX mutation resided at codon 70, a site that is recurrently mutated but less frequently affected than the N-terminal region of EIF1AX.	('EIF1AX', 'Gene', '1964', (173, 179))	('EIF1AX', 'Gene', (173, 179))	('N', 'Chemical', 'MESH:D009584', (152, 153))	('mutation', 'Var', (49, 57))	('EIF1AX', 'Gene', '1964', (42, 48))	('EIF1AX', 'Gene', (42, 48))
100810	31253977	Finally, the Gq-pathway mutation in this atypical case involved CYSTLR2, which is rare compared to GNAQ and GNA11 mutations.	('GNA11', 'Gene', '2767', (108, 113))	('involved', 'Reg', (55, 63))	('GNAQ', 'Gene', (99, 103))	('CYSTLR2', 'Gene', (64, 71))	('mutation', 'Var', (24, 32))	('Gq-pathway', 'Pathway', (13, 23))	('GNAQ', 'Gene', '2776', (99, 103))	('GNA11', 'Gene', (108, 113))
100811	31253977	The cases with SF3B1 or EIF1AX mutations tended to have additional oncogenic alterations.	('mutations', 'Var', (31, 40))	('SF3B1', 'Gene', '23451', (15, 20))	('oncogenic alterations', 'CPA', (67, 88))	('EIF1AX', 'Gene', '1964', (24, 30))	('EIF1AX', 'Gene', (24, 30))	('SF3B1', 'Gene', (15, 20))
100812	31253977	Two had homozygous CDKN2A deletions, three had PI3-kinase pathway mutations (PTENC218*, PIK3CAH1047R, and PIK3R2N485S), and one had a MED12 hotspot mutation (Supplementary Fig.	('mutations', 'Reg', (66, 75))	('PIK3CA', 'Gene', '5290', (88, 94))	('PIK3R2N485S', 'Var', (106, 117))	('deletions', 'Var', (26, 35))	('CDKN2A', 'Gene', (19, 25))	('MED12', 'Gene', (134, 139))	('CDKN2A', 'Gene', '1029', (19, 25))	('PTEN', 'Gene', (77, 81))	('MED12', 'Gene', '9968', (134, 139))	('PTEN', 'Gene', '5728', (77, 81))	('PIK3CA', 'Gene', (88, 94))	('PI3-kinase pathway', 'Pathway', (47, 65))
100813	31253977	In one EIF1AX-mutant case, we sequenced two areas of primary tumor, and the more histologically advanced area acquired a deletion of chromosome 3 (Supplementary Fig.	('chromosome', 'cellular_component', 'GO:0005694', ('133', '143'))	('deletion', 'Var', (121, 129))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('EIF1AX', 'Gene', '1964', (7, 13))	('EIF1AX', 'Gene', (7, 13))	('tumor', 'Disease', (61, 66))
100814	31253977	3b) - this was notable because it has been proposed that primary tumors without monosomy 3 may progress towards a more malignant stage by losing chromosome 3.	('progress', 'PosReg', (95, 103))	('primary tumors', 'Disease', 'MESH:D001932', (57, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('145', '155'))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('monosomy 3', 'Var', (80, 90))	('chromosome', 'Protein', (145, 155))	('primary tumors', 'Disease', (57, 71))	('losing', 'NegReg', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
100816	31253977	This pattern suggests that SF3B1 and EIF1AX mutations undergo selection early but may require additional oncogenic alterations to complement their likely limited ability to drive disease progression and metastatic dissemination.	('EIF1AX', 'Gene', '1964', (37, 43))	('EIF1AX', 'Gene', (37, 43))	('SF3B1', 'Gene', (27, 32))	('mutations', 'Var', (44, 53))	('SF3B1', 'Gene', '23451', (27, 32))
100818	31253977	BAP1 mutations were expectedly common in our cohort of uveal melanomas that became metastatic and were usually shared among all samples from a given patient, placing them on the trunks of evolutionary trees (Fig.	('common', 'Reg', (31, 37))	('BAP1', 'Gene', (0, 4))	('uveal melanoma', 'Phenotype', 'HP:0007716', (55, 69))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('uveal melanomas', 'Disease', (55, 70))	('patient', 'Species', '9606', (149, 156))	('uveal melanomas', 'Phenotype', 'HP:0007716', (55, 70))	('BAP1', 'Gene', '8314', (0, 4))	('uveal melanomas', 'Disease', 'MESH:C536494', (55, 70))
100819	31253977	These observations suggest that bi-allelic BAP1 mutations tend to precede metastatic dissemination.	('BAP1', 'Gene', (43, 47))	('bi-allelic', 'Var', (32, 42))	('BAP1', 'Gene', '8314', (43, 47))	('metastatic dissemination', 'CPA', (74, 98))	('mutations', 'Var', (48, 57))
100820	31253977	There were, however, two cases in which BAP1 alterations had a different distribution between primary tumors and their metastases (Fig.	('alterations', 'Var', (45, 56))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('BAP1', 'Gene', '8314', (40, 44))	('primary tumors', 'Disease', (94, 108))	('metastases', 'Disease', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('BAP1', 'Gene', (40, 44))	('primary tumors', 'Disease', 'MESH:D001932', (94, 108))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
100821	31253977	In case A29, the primary tumor had a frameshift mutation and a deletion affecting BAP1, but its metastasis had only very few reads of the frameshift mutation and did not have a deletion on chromosome 3 (Fig.	('BAP1', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('A29', 'Gene', (8, 11))	('tumor', 'Disease', (25, 30))	('A29', 'Gene', '28926', (8, 11))	('frameshift mutation', 'Var', (37, 56))	('deletion', 'Var', (63, 71))	('BAP1', 'Gene', '8314', (82, 86))	('chromosome', 'cellular_component', 'GO:0005694', ('189', '199'))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
100823	31253977	3c), the primary tumor and the metastasis shared a point mutation in BAP1, but only the primary had eliminated the second allele of BAP1, whereas the mutation in the metastasis remained heterozygous.	('BAP1', 'Gene', '8314', (132, 136))	('tumor', 'Disease', (17, 22))	('BAP1', 'Gene', (69, 73))	('point mutation', 'Var', (51, 65))	('BAP1', 'Gene', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('BAP1', 'Gene', '8314', (69, 73))
100826	31253977	Overall, these two cases raise the possibility that bi-allelic loss of BAP1 is not absolutely required for metastatic dissemination.	('BAP1', 'Gene', '8314', (71, 75))	('bi-allelic loss', 'Var', (52, 67))	('BAP1', 'Gene', (71, 75))
100828	31253977	We also observed mutations in other chromatin remodeling factors, including hemizygous, loss-of-function mutations in PBRM1 and gain-of-function EZH2 mutations (Fig.	('chromatin', 'cellular_component', 'GO:0000785', ('36', '45'))	('PBRM1', 'Gene', '55193', (118, 123))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('36', '56'))	('EZH2', 'Gene', '2146', (145, 149))	('mutations', 'Var', (105, 114))	('mutations', 'Var', (150, 159))	('EZH2', 'Gene', (145, 149))	('gain-of-function', 'PosReg', (128, 144))	('PBRM1', 'Gene', (118, 123))	('loss-of-function', 'NegReg', (88, 104))
100831	31253977	The SWI/SNF chromatin remodeling complex also opposes PRC2 activity in maintaining cell-state appropriate chromatin modifications; therefore, the alterations in PBRM1 and EZH2 likely shift the balance of chromatin remodeling activity further towards PRC2 dominance.	('EZH2', 'Gene', '2146', (171, 175))	('PBRM1', 'Gene', (161, 166))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('12', '40'))	('EZH2', 'Gene', (171, 175))	('alterations', 'Var', (146, 157))	('PBRM1', 'Gene', '55193', (161, 166))	('chromatin', 'cellular_component', 'GO:0000785', ('204', '213'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('204', '224'))	('chromatin', 'cellular_component', 'GO:0000785', ('106', '115'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('12', '32'))	('N', 'Chemical', 'MESH:D009584', (9, 10))	('shift', 'Reg', (183, 188))
100832	31253977	In contrast to BAP1 mutations, which occurred earlier in most cases, mutations affecting PBRM1 or EZH2 occurred later, as they were generally not shared among all tumor areas of a given patient.	('mutations', 'Var', (69, 78))	('EZH2', 'Gene', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('PBRM1', 'Gene', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('PBRM1', 'Gene', '55193', (89, 94))	('BAP1', 'Gene', '8314', (15, 19))	('tumor', 'Disease', (163, 168))	('BAP1', 'Gene', (15, 19))	('patient', 'Species', '9606', (186, 193))	('EZH2', 'Gene', '2146', (98, 102))
100833	31253977	Copy number gains of chromosome 8q arise in the primary tumor and ramp up during metastatic progression.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Copy number gains', 'Var', (0, 17))	('tumor', 'Disease', (56, 61))	('chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
100834	31253977	Copy number gains of chromosome 8q were present in nearly every case and were typically shared among the different tumor areas of a given patient (Fig.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Copy number gains', 'Var', (0, 17))	('tumor', 'Disease', (115, 120))	('patient', 'Species', '9606', (138, 145))	('chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
100837	31253977	We delved deeper into the amplitudes of 8q gain and observed that the copy number of 8q tended to increase from primaries to metastases.	('copy', 'Var', (70, 74))	('metastases', 'Disease', (125, 135))	('increase', 'PosReg', (98, 106))	('metastases', 'Disease', 'MESH:D009362', (125, 135))
100841	31253977	Overall, metastases had more copies of 8q than their corresponding primary tumors in most patients, with an average of 6 versus 4 copies (P = 0.002 two-tailed t-test) (Fig.	('copies', 'Var', (29, 35))	('metastases', 'Disease', (9, 19))	('primary tumors', 'Disease', 'MESH:D001932', (67, 81))	('metastases', 'Disease', 'MESH:D009362', (9, 19))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('primary tumors', 'Disease', (67, 81))	('patients', 'Species', '9606', (90, 98))
100843	31253977	This analysis confirmed that Galphaq-pathway mutations are the earliest mutations to undergo selection, followed by gain of chromosomal arm 8q as well as BAP1, SF3B1, or EIF1AX mutations.	('SF3B1', 'Gene', (160, 165))	('mutations', 'Var', (45, 54))	('BAP1', 'Gene', (154, 158))	('EIF1AX', 'Gene', '1964', (170, 176))	('EIF1AX', 'Gene', (170, 176))	('SF3B1', 'Gene', '23451', (160, 165))	('BAP1', 'Gene', '8314', (154, 158))	('Galphaq', 'Gene', '2776', (29, 36))	('Galphaq', 'Gene', (29, 36))	('gain', 'PosReg', (116, 120))	('chromosomal', 'Gene', (124, 135))
100844	31253977	Selective pressures continue to operate on these pathways at comparatively later points in the progression cascade by way of GNAQ loss-of-heterozygosity, additional chromatin remodeling mutations, and further ramp-up of 8q copy number (Fig.	('8q copy number', 'Var', (220, 234))	('ramp-up', 'PosReg', (209, 216))	('chromatin', 'cellular_component', 'GO:0000785', ('165', '174'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('165', '185'))	('mutations', 'Var', (186, 195))	('GNAQ', 'Gene', '2776', (125, 129))	('GNAQ', 'Gene', (125, 129))	('loss-of-heterozygosity', 'NegReg', (130, 152))
100846	31253977	Most somatic alterations were somewhat enriched in metastases, but only copy number changes of 6q, 1q, and high-level gains of 8q (copy number increase by at least 3 copies) reached statistical significance (Fig.	('metastases', 'Disease', 'MESH:D009362', (51, 61))	('metastases', 'Disease', (51, 61))	('changes', 'Var', (84, 91))	('gains', 'PosReg', (118, 123))
100859	31253977	Our multi-region sequencing of primaries and metastases revealed multiple novel mutations, expanding the catalog of driver mutations for this aggressive melanoma subtype.	('mutations', 'Var', (80, 89))	('metastases', 'Disease', 'MESH:D009362', (45, 55))	('aggressive melanoma', 'Disease', (142, 161))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('metastases', 'Disease', (45, 55))	('aggressive melanoma', 'Disease', 'MESH:D008545', (142, 161))
100860	31253977	These novel mutations were more common in uveal melanomas with SF3B1 or EIF1AX mutations, and they possibly complement the otherwise limited ability of SF3B1 and EIF1AX mutations to drive metastatic disease.	('SF3B1', 'Gene', '23451', (152, 157))	('EIF1AX', 'Gene', '1964', (162, 168))	('EIF1AX', 'Gene', (162, 168))	('metastatic disease', 'CPA', (188, 206))	('SF3B1', 'Gene', (63, 68))	('uveal melanomas', 'Disease', (42, 57))	('uveal melanomas', 'Phenotype', 'HP:0007716', (42, 57))	('common', 'Reg', (32, 38))	('SF3B1', 'Gene', '23451', (63, 68))	('drive', 'PosReg', (182, 187))	('SF3B1', 'Gene', (152, 157))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('uveal melanomas', 'Disease', 'MESH:C536494', (42, 57))	('EIF1AX', 'Gene', '1964', (72, 78))	('EIF1AX', 'Gene', (72, 78))	('mutations', 'Var', (79, 88))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
100861	31253977	The earliest driver mutations in primary uveal melanoma are not easily druggable, but there is hope that some of the newly recognized mutations found in some metastases can be targeted therapeutically.	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (41, 55))	('uveal melanoma', 'Disease', (41, 55))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('metastases', 'Disease', (158, 168))	('mutations', 'Var', (20, 29))	('metastases', 'Disease', 'MESH:D009362', (158, 168))
100862	31253977	We also observed loss-of-heterozygosity of mutant GNAQ, but not GNA11, in multiple samples, indicating hidden complexity in oncogenic signaling through mutant Galphaq subunits.	('loss-of-heterozygosity', 'NegReg', (17, 39))	('Galphaq', 'Gene', (159, 166))	('Galphaq', 'Gene', '2776', (159, 166))	('signaling', 'biological_process', 'GO:0023052', ('134', '143'))	('GNA11', 'Gene', '2767', (64, 69))	('GNA11', 'Gene', (64, 69))	('mutant', 'Var', (152, 158))	('mutant', 'Var', (43, 49))	('GNAQ', 'Gene', '2776', (50, 54))	('GNAQ', 'Gene', (50, 54))
100863	31253977	The Q209 alterations in GNAQ and GNA11 abrogate their GTPase activity, similar to mutant RAS.	('GNAQ', 'Gene', '2776', (24, 28))	('GNA11', 'Gene', (33, 38))	('GTPase activity', 'molecular_function', 'GO:0003924', ('54', '69'))	('GNA11', 'Gene', '2767', (33, 38))	('Q209 alterations', 'Var', (4, 20))	('abrogate', 'NegReg', (39, 47))	('GNAQ', 'Gene', (24, 28))	('activity', 'MPA', (61, 69))	('GTPase', 'Enzyme', (54, 60))
100864	31253977	Earlier studies using Sanger sequencing have reported increased frequency of GNA11 mutations in metastatic uveal melanomas, whereas GNAQ mutations are more common in benign lesions, such as blue nevi.	('mutations', 'Var', (83, 92))	('uveal melanomas', 'Disease', 'MESH:C536494', (107, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('GNA11', 'Gene', (77, 82))	('GNAQ', 'Gene', '2776', (132, 136))	('GNA11', 'Gene', '2767', (77, 82))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('blue nevi', 'Phenotype', 'HP:0100814', (190, 199))	('blue nevi', 'Disease', (190, 199))	('uveal melanomas', 'Disease', (107, 122))	('uveal melanomas', 'Phenotype', 'HP:0007716', (107, 122))	('nevi', 'Phenotype', 'HP:0003764', (195, 199))	('GNAQ', 'Gene', (132, 136))
100865	31253977	This led to the proposition that GNA11 mutations are more potent.	('GNA11', 'Gene', '2767', (33, 38))	('GNA11', 'Gene', (33, 38))	('mutations', 'Var', (39, 48))
100866	31253977	The finding of recurrent loss-of-heterozygosity of GNAQ mutations later in progression may indicate that GNAQ, but not GNA11, requires a second hit to fully activate the pathway, which could explain the association with GNA11 mutations with more aggressive disease.	('GNAQ', 'Gene', '2776', (51, 55))	('loss-of-heterozygosity', 'NegReg', (25, 47))	('mutations', 'Var', (56, 65))	('GNAQ', 'Gene', (105, 109))	('aggressive disease', 'Disease', (246, 264))	('GNA11', 'Gene', '2767', (119, 124))	('GNA11', 'Gene', (119, 124))	('GNAQ', 'Gene', (51, 55))	('mutations', 'Var', (226, 235))	('GNA11', 'Gene', '2767', (220, 225))	('GNA11', 'Gene', (220, 225))	('GNAQ', 'Gene', '2776', (105, 109))	('aggressive disease', 'Disease', 'MESH:D001523', (246, 264))
100867	31253977	Uveal melanomas have been proposed to arise after an early, punctuated burst of mutations followed by a period of neutral evolution.	('mutations', 'Var', (80, 89))	('Uveal melanomas', 'Disease', 'MESH:C536494', (0, 15))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('Uveal melanomas', 'Disease', (0, 15))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))
100890	31253977	We include any mutation affecting GNAQ, GNA11, PLCB4, CYSTLR2, BAP1, EIF1AX, or SF3B1 - this is based on these genes' previously described roles in driving uveal melanoma.	('mutation', 'Var', (15, 23))	('SF3B1', 'Gene', '23451', (80, 85))	('EIF1AX', 'Gene', (69, 75))	('EIF1AX', 'Gene', '1964', (69, 75))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('GNA11', 'Gene', (40, 45))	('BAP1', 'Gene', (63, 67))	('BAP1', 'Gene', '8314', (63, 67))	('CYSTLR2', 'Gene', (54, 61))	('PLCB4', 'Gene', (47, 52))	('GNA11', 'Gene', '2767', (40, 45))	('uveal melanoma', 'Disease', (156, 170))	('uveal melanoma', 'Disease', 'MESH:C536494', (156, 170))	('uveal melanoma', 'Phenotype', 'HP:0007716', (156, 170))	('GNAQ', 'Gene', (34, 38))	('SF3B1', 'Gene', (80, 85))	('PLCB4', 'Gene', '5332', (47, 52))	('GNAQ', 'Gene', '2776', (34, 38))
100891	31253977	We also include alterations affecting CDKN2A, PBRM1, and EZH2 due to their recurrence in our study and known roles as cancer genes in other tumor types.	('EZH2', 'Gene', (57, 61))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('alterations', 'Var', (16, 27))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('CDKN2A', 'Gene', (38, 44))	('PBRM1', 'Gene', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('EZH2', 'Gene', '2146', (57, 61))	('CDKN2A', 'Gene', '1029', (38, 44))	('PBRM1', 'Gene', '55193', (46, 51))	('tumor', 'Disease', (140, 145))
100892	31253977	Moreover, we include hotspot mutations affecting PIK3CA and MED12, which were observed once in our study but are common in pan-tumor analyses.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('MED12', 'Gene', (60, 65))	('mutations', 'Var', (29, 38))	('PIK3CA', 'Gene', (49, 55))	('MED12', 'Gene', '9968', (60, 65))	('PIK3CA', 'Gene', '5290', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
100893	31253977	Finally, we include inactivating mutations affecting PTEN and PIK3R2, which are prominent tumor suppressors in other cancers and are lost in a bi-allelic fashion in our study.	('PIK3R2', 'Gene', (62, 68))	('PIK3R2', 'Gene', '5296', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('PTEN', 'Gene', (53, 57))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('PTEN', 'Gene', '5728', (53, 57))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('inactivating mutations', 'Var', (20, 42))	('cancers', 'Disease', (117, 124))
100895	31253977	In Figure 1, we present the detailed evolution of an example case, including the distribution of point mutations, copy number alterations, and allelic imbalances over each tumor region from a single patient.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('imbalance', 'Phenotype', 'HP:0002172', (151, 160))	('tumor', 'Disease', (172, 177))	('patient', 'Species', '9606', (199, 206))	('imbalances', 'Phenotype', 'HP:0002172', (151, 161))	('copy number alterations', 'Var', (114, 137))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('point mutations', 'Var', (97, 112))
100897	31253977	It is important to accurately measure tumor cell content in order to ensure that sequencing depth is sufficiently powered to detect mutations and also to measure the zygosity of somatic mutations.	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('mutations', 'Var', (132, 141))
100899	31253977	Specifically, copy number alterations induce allelic imbalances over germline heterozygous SNPs, and we used the extent of allelic imbalance to measure tumor cellularity.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('induce', 'Reg', (38, 44))	('allelic imbalances', 'MPA', (45, 63))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('imbalance', 'Phenotype', 'HP:0002172', (131, 140))	('copy number alterations', 'Var', (14, 37))	('tumor', 'Disease', (152, 157))	('imbalance', 'Phenotype', 'HP:0002172', (53, 62))	('imbalances', 'Phenotype', 'HP:0002172', (53, 63))
100901	31253977	When possible, tumor cell content was calculated from both germline and somatic variant allele fractions to produce a consensus estimate (see Supplementary Table 1).	('tumor', 'Disease', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('variant', 'Var', (80, 87))
100906	31253977	In particular, tumors with high levels of 8q gain were more likely to have greater ratios of major to minor allelic reads.	('major to minor allelic reads', 'MPA', (93, 121))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('ratios', 'MPA', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('greater', 'PosReg', (75, 82))	('8q gain', 'Var', (42, 49))	('tumors', 'Disease', (15, 21))
100919	31253977	In Figure 4c, we performed a two-tailed t-test, assuming equal variance, to compare the level of copy number gain of chromosomal arm 8q in primary tumors (n = 53) versus metastases (n = 36) (degrees of freedom = 87).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('metastases', 'Disease', (170, 180))	('primary tumors', 'Disease', (139, 153))	('metastases', 'Disease', 'MESH:D009362', (170, 180))	('gain', 'PosReg', (109, 113))	('chromosomal arm', 'Var', (117, 132))	('primary tumors', 'Disease', 'MESH:D001932', (139, 153))
101069	27476775	In our prior study, we found three Stages of metastases: Stage I: <50microm diameter micrometastases within the sinusoidal space; Stage II: 51-500microm diameter metastases that formed expanded collections of cells within the sinusoidal space; and Stage III: >500microm diameter collections of cells that formed two patterns.	('metastases', 'Disease', (162, 172))	('metastases', 'Disease', (90, 100))	('metastases', 'Disease', 'MESH:D009362', (162, 172))	('metastases', 'Disease', 'MESH:D009362', (90, 100))	('51-500microm diameter', 'Var', (140, 161))	('metastases', 'Disease', 'MESH:D009362', (45, 55))	('<50microm', 'Var', (66, 75))	('metastases', 'Disease', (45, 55))
101109	27476775	Somatic GNAQ or GNA11 mutations initiate the melanocytic neoplastic proliferation leading to nevi and UM in 85% of cases.	('GNA11', 'Gene', (16, 21))	('neoplastic proliferation', 'Phenotype', 'HP:0002664', (57, 81))	('GNAQ', 'Gene', (8, 12))	('melanocytic neoplastic', 'Disease', (45, 67))	('initiate', 'PosReg', (32, 40))	('GNA11', 'Gene', '2767', (16, 21))	('nevi', 'Phenotype', 'HP:0003764', (93, 97))	('leading to', 'Reg', (82, 92))	('UM', 'Phenotype', 'HP:0007716', (102, 104))	('mutations', 'Var', (22, 31))	('GNAQ', 'Gene', '2776', (8, 12))	('nevi', 'Disease', (93, 97))	('melanocytic neoplastic', 'Disease', 'MESH:D009508', (45, 67))
101110	27476775	Metastasis predictors in UM include clinical factors (tumor size, ciliary body involvement, extraocular spread); histological features (epithelioid cytomorphology, mitotic count, closed laminin loops); and genetic findings (chromosome 3 loss, chromosome 8q gain, BAP1 deletion, class 2 gene expression profile, and lack of SF3B1 and EIF1AX mutations).	('gain', 'PosReg', (257, 261))	('lack', 'NegReg', (315, 319))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('EIF1AX', 'Gene', (333, 339))	('BAP1', 'Gene', (263, 267))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('EIF1AX', 'Gene', '1964', (333, 339))	('mutations', 'Var', (340, 349))	('deletion', 'Var', (268, 276))	('UM', 'Phenotype', 'HP:0007716', (25, 27))	('men', 'Species', '9606', (86, 89))	('SF3B1', 'Gene', (323, 328))	('chromosome', 'cellular_component', 'GO:0005694', ('224', '234'))	('chromosome', 'cellular_component', 'GO:0005694', ('243', '253'))	('chromosome', 'Var', (224, 234))	('BAP1', 'Gene', '8314', (263, 267))	('gene expression', 'biological_process', 'GO:0010467', ('286', '301'))	('tumor', 'Disease', (54, 59))	('SF3B1', 'Gene', '23451', (323, 328))	('loss', 'NegReg', (237, 241))
101112	27476775	That being said, it is clear that many metastatic UM cases demonstrate chromosome 3 loss, polysomy 8q, and have BAP1 inactivating mutations.	('BAP1', 'Gene', (112, 116))	('chromosome', 'Var', (71, 81))	('loss', 'NegReg', (84, 88))	('metastatic UM', 'Disease', (39, 52))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('BAP1', 'Gene', '8314', (112, 116))	('chromosome', 'cellular_component', 'GO:0005694', ('71', '81'))	('polysomy 8q', 'Var', (90, 101))
101114	27476775	Our finding in this study of variable BAP1 expression in hepatic metastases of UM in both infiltrative and nodular tumors, including variable expression within a given liver section, supports the concept that although BAP1 mutations are important for promoting UM metastasis, the BAP1 mutation may or may not be lost in the metastases in the liver.	('mutations', 'Var', (223, 232))	('BAP1', 'Gene', '8314', (38, 42))	('nodular tumors', 'Disease', 'MESH:D020518', (107, 121))	('promoting', 'PosReg', (251, 260))	('metastases', 'Disease', 'MESH:D009362', (65, 75))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('metastases', 'Disease', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('BAP1', 'Gene', (38, 42))	('BAP1', 'Gene', '8314', (280, 284))	('BAP1', 'Gene', '8314', (218, 222))	('metastases', 'Disease', 'MESH:D009362', (324, 334))	('UM', 'Phenotype', 'HP:0007716', (261, 263))	('metastases', 'Disease', (324, 334))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('nodular tumors', 'Disease', (107, 121))	('UM metastasis', 'CPA', (261, 274))	('BAP1', 'Gene', (280, 284))	('BAP1', 'Gene', (218, 222))
101127	27476775	Alternatively, tumor cells may arise in the perivascular tissue of the portal triad, and in this study we demonstrate a predominance of CD3+ T cells in that area.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('CD3+', 'Var', (136, 140))	('tumor', 'Disease', (15, 20))	('triad', 'cellular_component', 'GO:0030315', ('78', '83'))	('perivascular tissue', 'Phenotype', 'HP:0012520', (44, 63))
101216	27584665	Uveal melanoma (UM) tumours of high risk have a propensity to metastasise to the liver and are characterised by chromosomal abnormalities, including loss of chromosome 3 (monosomy 3) or partial gains of chromosome 1, 6 or 8.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (112, 137))	('chromosomal abnormalities', 'Disease', (112, 137))	('metastasise', 'CPA', (62, 73))	('chromosome', 'cellular_component', 'GO:0005694', ('203', '213'))	('chromosome', 'cellular_component', 'GO:0005694', ('157', '167'))	('loss', 'Var', (149, 153))	('tumours', 'Phenotype', 'HP:0002664', (20, 27))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('UM', 'Phenotype', 'HP:0007716', (16, 18))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('tumours', 'Disease', 'MESH:D009369', (20, 27))	('tumours', 'Disease', (20, 27))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
101218	27584665	Approximately 50% of human solid tumours present direct p53 mutations and the majority of adult cancers present impairment of the p53 signalling pathway and/or its downstream targets.	('tumours', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('p53', 'Gene', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('human', 'Species', '9606', (21, 26))	('tumours', 'Disease', 'MESH:D009369', (33, 40))	('tumours', 'Disease', (33, 40))	('impairment', 'NegReg', (112, 122))	('p53 signalling pathway', 'Pathway', (130, 152))	('signalling pathway', 'biological_process', 'GO:0007165', ('134', '152'))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('adult cancers', 'Disease', (90, 103))	('mutations', 'Var', (60, 69))	('adult cancers', 'Disease', 'MESH:C535836', (90, 103))
101219	27584665	The latter scenario appears to be the mechanism for evasion of apoptosis that is used by UM since there is no consistent evidence of frequent direct p53 inactivation, mutation or altered signalling upstream to p53 in these tumours.	('altered', 'Reg', (179, 186))	('tumours', 'Disease', (223, 230))	('p53', 'Gene', (149, 152))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('mutation', 'Var', (167, 175))	('signalling', 'MPA', (187, 197))	('signalling', 'biological_process', 'GO:0023052', ('187', '197'))	('inactivation', 'NegReg', (153, 165))	('tumours', 'Phenotype', 'HP:0002664', (223, 230))	('UM', 'Phenotype', 'HP:0007716', (89, 91))	('tumours', 'Disease', 'MESH:D009369', (223, 230))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))
101223	27584665	Taken together, these studies indicate that the endogenous levels of PERP can influence both upstream and downstream regulation of the p53 pathway and place PERP at a key signalling junction of p53-mediated apoptosis in UM, thus rendering it a potential target for developing apoptosis-based cancer therapies.	('apoptosis', 'biological_process', 'GO:0097194', ('207', '216'))	('apoptosis', 'biological_process', 'GO:0006915', ('207', '216'))	('influence', 'Reg', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('PERP', 'Var', (157, 161))	('UM', 'Phenotype', 'HP:0007716', (220, 222))	('upstream', 'MPA', (93, 101))	('signalling', 'biological_process', 'GO:0023052', ('171', '181'))	('p53 pathway', 'Pathway', (135, 146))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('apoptosis', 'biological_process', 'GO:0097194', ('276', '285'))	('cancer', 'Disease', (292, 298))	('regulation', 'biological_process', 'GO:0065007', ('117', '127'))	('apoptosis', 'biological_process', 'GO:0006915', ('276', '285'))
101243	27584665	The proteins were separated by 12% gel electrophoresis (10% for the detection of p63-tGFP because of its larger size, 103 kDa), transferred to nitrocellulose membrane and probed with respective primary antibodies: PERP (ab5986; Abcam, Cambridge, UK), p53 (P-6874; Sigma-Aldrich) and GAPDH (ab8245; Abcam).	('membrane', 'cellular_component', 'GO:0016020', ('158', '166'))	('p63-tGFP', 'Var', (81, 89))	('GAPDH', 'Gene', '2597', (283, 288))	('GAPDH', 'Gene', (283, 288))
101268	27584665	A significant increase in PERP mRNA compared with GFP control (Student's t-test, *P<= 0.04) was observed at 16-24 h post-transfection when OCM-1 cells expressed p63-tGFP (Figure 4).	('PERP mRNA', 'MPA', (26, 35))	('OCM-1', 'Species', '83984', (139, 144))	('increase', 'PosReg', (14, 22))	('p63-tGFP', 'Var', (161, 169))
101275	27584665	Taking into account the common abnormalities of chromosome 3 described in UM cells, ranging from complex rearrangements/deletions at chromosome 3q, such as in OCM-1 cells, to complete loss of a chromosome (monosomy 3), we screened the UM cell lines for the level/presence of p63 protein.	('chromosome', 'cellular_component', 'GO:0005694', ('194', '204'))	('OCM-1', 'Species', '83984', (159, 164))	('loss', 'NegReg', (184, 188))	('chromosome', 'cellular_component', 'GO:0005694', ('48', '58'))	('UM', 'Phenotype', 'HP:0007716', (235, 237))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('rearrangements/deletions', 'Var', (105, 129))	('chromosome', 'cellular_component', 'GO:0005694', ('133', '143'))	('protein', 'cellular_component', 'GO:0003675', ('279', '286'))
101278	27584665	By using the E1A programmed murine embryo fibroblasts, showed that the combined loss of p63 and p73 resulted in the failure of cells exhibiting functional p53 to undergo apoptosis in response to DNA damage.	('response to DNA damage', 'MPA', (183, 205))	('p53', 'Gene', (155, 158))	('p73', 'Var', (96, 99))	('loss', 'NegReg', (80, 84))	('p63', 'Var', (88, 91))	('failure', 'NegReg', (116, 123))	('murine', 'Species', '10090', (28, 34))	('apoptosis', 'biological_process', 'GO:0097194', ('170', '179'))	('DNA', 'cellular_component', 'GO:0005574', ('195', '198'))	('apoptosis', 'biological_process', 'GO:0006915', ('170', '179'))	('apoptosis', 'CPA', (170, 179))
101284	27584665	Furthermore, the findings provide for the first time a functional link between a molecular determinant (p63) highly likely to be affected by the well-described alterations of chromosome 3 in UM and the pathogenesis of this tumour.	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('affected', 'Reg', (129, 137))	('chromosome', 'cellular_component', 'GO:0005694', ('175', '185'))	('UM', 'Phenotype', 'HP:0007716', (191, 193))	('p63', 'Gene', (104, 107))	('alterations', 'Var', (160, 171))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('tumour', 'Disease', (223, 229))	('pathogenesis', 'biological_process', 'GO:0009405', ('202', '214'))
101366	19862332	PPIX at 5 uM had no significant effect on the increase in ATP content in the culture and caused a slightly decrease (p<0.05) in the cell number at approximately 84% of the increase in control cell number ( Figures 3A and S3A ).	('PPIX', 'Chemical', 'MESH:C028025', (0, 4))	('ATP content', 'MPA', (58, 69))	('ATP', 'Chemical', 'MESH:D000255', (58, 61))	('PPIX', 'Var', (0, 4))	('S3A', 'Gene', (221, 224))	('S3A', 'Gene', '6189', (221, 224))	('decrease', 'NegReg', (107, 115))	('cell number', 'CPA', (132, 143))
101367	19862332	However PPIX dramatically increased the cytotoxicity from DHA, which resulted in 33% loss of ATP content (p<0.05) relative to control cells and a similar net loss of cell number (p<0.05) from the initial culture ( Figures 3A and S3A ).	('cytotoxicity', 'Disease', (40, 52))	('S3A', 'Gene', (229, 232))	('S3A', 'Gene', '6189', (229, 232))	('cytotoxicity', 'Disease', 'MESH:D064420', (40, 52))	('ATP content', 'MPA', (93, 104))	('ATP', 'Chemical', 'MESH:D000255', (93, 96))	('loss', 'NegReg', (85, 89))	('increased', 'PosReg', (26, 35))	('DHA', 'Chemical', 'MESH:C039060', (58, 61))	('PPIX', 'Chemical', 'MESH:C028025', (8, 12))	('loss', 'NegReg', (158, 162))	('cell number', 'CPA', (166, 177))	('PPIX', 'Var', (8, 12))
101384	19862332	Deformations of porphyrins are known to result in significant changes in the chemical and spectroscopic properties of the porphyrin ring.	('Deformations', 'Var', (0, 12))	('changes', 'Reg', (62, 69))	('porphyrin', 'Chemical', 'MESH:D011166', (122, 131))	('porphyrin', 'Chemical', 'MESH:D011166', (16, 25))
101423	19862332	The compound 5alpha-cholestan-3beta-ol-6-one caused a moderate reduction in heme Soret band absorption along with the generation of a new absorption peak(s) over-lapping the Soret 415 nm peak (right shoulder in  Figure 7 ).	('5alpha-cholestan-3beta-ol-6-one', 'Chemical', 'MESH:C063833', (13, 44))	('heme', 'Chemical', 'MESH:D006418', (76, 80))	('5alpha-cholestan-3beta-ol-6-one', 'Var', (13, 44))	('Soret', 'MPA', (174, 179))	('over-lapping', 'PosReg', (157, 169))	('reduction', 'NegReg', (63, 72))	('heme Soret band absorption', 'MPA', (76, 102))
101435	19862332	Co-incubation of ALA with artemisinin, however, caused a great reduction in cell viability, with a net 27% reduction in ATP content from the initial culture at time = 0.	('ATP content', 'MPA', (120, 131))	('ATP', 'Chemical', 'MESH:D000255', (120, 123))	('cell viability', 'CPA', (76, 90))	('artemisinin', 'Var', (26, 37))	('artemisinin', 'Chemical', 'MESH:C031327', (26, 37))	('reduction', 'NegReg', (63, 72))	('ALA', 'Chemical', 'MESH:D000622', (17, 20))	('reduction', 'NegReg', (107, 116))
101439	19862332	We conclude that modulation of heme synthesis has little effects upon cytotoxicity from these two compounds, consistent with their much lower reactivity towards heme than either artemisinin or coralyne.	('lower', 'NegReg', (136, 141))	('artemisinin', 'Chemical', 'MESH:C031327', (178, 189))	('heme', 'Chemical', 'MESH:D006418', (31, 35))	('modulation', 'Var', (17, 27))	('cytotoxicity', 'Disease', 'MESH:D064420', (70, 82))	('heme', 'Chemical', 'MESH:D006418', (161, 165))	('coralyne', 'Chemical', 'MESH:C000666', (193, 201))	('reactivity towards heme', 'MPA', (142, 165))	('heme synthesis', 'biological_process', 'GO:0006783', ('31', '45'))	('cytotoxicity', 'Disease', (70, 82))
101442	19862332	We conclude that modulation of heme synthesis has significant effects upon cytotoxicity from artemisinin and coralyne, consistent with their high reactivity towards heme in vitro.	('heme', 'Chemical', 'MESH:D006418', (31, 35))	('effects', 'Reg', (62, 69))	('modulation', 'Var', (17, 27))	('cytotoxicity', 'Disease', (75, 87))	('heme synthesis', 'MPA', (31, 45))	('artemisinin', 'Chemical', 'MESH:C031327', (93, 104))	('cytotoxicity', 'Disease', 'MESH:D064420', (75, 87))	('heme', 'Chemical', 'MESH:D006418', (165, 169))	('heme synthesis', 'biological_process', 'GO:0006783', ('31', '45'))	('coralyne', 'Chemical', 'MESH:C000666', (109, 117))
101469	19862332	The large reduction of the Soret band A415 from coralyne, without the appearance of any other spectroscopically detectable species, is consistent with breakage of the heme ring structure, analogous to the cleavage of DNA by coralyne.	('Soret band A415', 'MPA', (27, 42))	('DNA', 'cellular_component', 'GO:0005574', ('217', '220'))	('coralyne', 'Chemical', 'MESH:C000666', (224, 232))	('heme', 'Chemical', 'MESH:D006418', (167, 171))	('coralyne', 'Chemical', 'MESH:C000666', (48, 56))	('breakage', 'Var', (151, 159))	('heme', 'Protein', (167, 171))	('reduction', 'NegReg', (10, 19))
101476	19862332	HIF may also be involved in the inhibition of tumor lymphangiogenesis by artemisinin through suppression of vascular endothelial growth factor C. Artemisinin has also been reported to activate p38 mitogen-activated protein kinase (p38 MAPK) in human lung cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (250, 261))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('lung cancer', 'Disease', (250, 261))	('human', 'Species', '9606', (244, 249))	('artemisinin', 'Chemical', 'MESH:C031327', (73, 84))	('Artemisinin', 'Var', (146, 157))	('tumor', 'Disease', (46, 51))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('HI', 'Chemical', 'MESH:D006639', (0, 2))	('activate', 'PosReg', (184, 192))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('p38 mitogen-activated protein kinase', 'Gene', (193, 229))	('p38 MAPK', 'Gene', '1432', (231, 239))	('lung cancer', 'Disease', 'MESH:D008175', (250, 261))	('Artemisinin', 'Chemical', 'MESH:C031327', (146, 157))	('p38 MAPK', 'Gene', (231, 239))	('p38 mitogen-activated protein kinase', 'Gene', '1432', (193, 229))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('108', '142'))	('lymphangiogenesis', 'biological_process', 'GO:0001946', ('52', '69'))	('MAPK', 'molecular_function', 'GO:0004707', ('235', '239'))
101512	15886706	Following conversion, alkylation of DNA and subsequent formation of DNA interstrand crosslinks is considered to be the mechanism by which treosulfan elicits its cytotoxicity (Hartley et al, 1999a, 1999b).	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('elicits', 'Reg', (149, 156))	('cytotoxicity', 'Disease', (161, 173))	('alkylation', 'Var', (22, 32))	('treosulfan', 'Chemical', 'MESH:C018404', (138, 148))	('formation', 'biological_process', 'GO:0009058', ('55', '64'))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('cytotoxicity', 'Disease', 'MESH:D064420', (161, 173))
101517	15886706	Pretreatment laboratory requirements were as follows: haemoglobin >=10 g dl-1, platelets >=100 x 109 l-1, ANC >=1.5 x 109 l-1, total bilirubin <1.3 x upper limit of normal (ULN), liver enzymes (ALT and ALP) <5 x ULN, Cr <1.5 x ULN.	('ALT', 'molecular_function', 'GO:0004021', ('194', '197'))	('haemoglobin', 'MPA', (54, 65))	('>=10', 'Var', (66, 70))	('ALP', 'Gene', '470', (202, 205))	('liver enzymes', 'MPA', (179, 192))	('>=100 x', 'Var', (89, 96))	('total bilirubin', 'MPA', (127, 142))	('ALP', 'Gene', (202, 205))	('bilirubin', 'Chemical', 'MESH:D001663', (133, 142))
101642	32781743	PHD hydroxylation of Pro402 HIF-1alpha, Pro564 HIF-1alpha, Pro405 HIF-2alpha, and Pro531 HIF-2alpha results in the ubiquitination by the von Hippel-Lindau protein (pVHL), which leads to proteasomal degradation of HIF-alpha.	('HIF-2alpha', 'Gene', '2034', (66, 76))	('von Hippel-Lindau', 'Disease', (137, 154))	('leads to', 'Reg', (177, 185))	('HIF-1alpha', 'Gene', (28, 38))	('HIF-2alpha', 'Gene', '2034', (89, 99))	('pVHL', 'Gene', '7428', (164, 168))	('HIF-2alpha', 'Gene', (66, 76))	('pVHL', 'Gene', (164, 168))	('Pro402', 'Var', (21, 27))	('Pro564', 'Var', (40, 46))	('Pro402', 'Chemical', '-', (21, 27))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (137, 154))	('HIF-1alpha', 'Gene', '3091', (47, 57))	('proteasomal degradation', 'MPA', (186, 209))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('HIF-2alpha', 'Gene', (89, 99))	('Pro531', 'Var', (82, 88))	('degradation', 'biological_process', 'GO:0009056', ('198', '209'))	('PHD', 'molecular_function', 'GO:0050175', ('0', '3'))	('ubiquitination', 'MPA', (115, 129))	('HIF-1alpha', 'Gene', '3091', (28, 38))	('HIF-1alpha', 'Gene', (47, 57))	('Pro405', 'Var', (59, 65))	('results in', 'Reg', (100, 110))
101643	32781743	At the same time, hydroxylation of Asn803 HIF-1alpha and Asn847 HIF-2alpha by FIH does not lead to degradation of HIF-alpha but prevents the interaction between HIF-alpha and CREB-binding protein (CBP) /p300 transcriptional coactivator.	('Asn803', 'Chemical', '-', (35, 41))	('CREB-binding', 'molecular_function', 'GO:0008140', ('175', '187'))	('interaction', 'Interaction', (141, 152))	('CREB-binding protein', 'Gene', '1387', (175, 195))	('HIF-1alpha', 'Gene', '3091', (42, 52))	('Asn847', 'Var', (57, 63))	('Asn803', 'Var', (35, 41))	('CREB-binding protein', 'Gene', (175, 195))	('HIF-1alpha', 'Gene', (42, 52))	('HIF-2alpha', 'Gene', '2034', (64, 74))	('Asn847', 'Chemical', '-', (57, 63))	('degradation', 'biological_process', 'GO:0009056', ('99', '110'))	('CBP)', 'Gene', '1387', (197, 201))	('prevents', 'NegReg', (128, 136))	('p300', 'Gene', (203, 207))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('CBP', 'molecular_function', 'GO:0008140', ('197', '200'))	('CBP', 'Gene', (197, 200))	('p300', 'Gene', '2033', (203, 207))	('HIF-2alpha', 'Gene', (64, 74))
101709	32781743	This methylation leads to a decrease in CCL2/MCP-1 expression.	('methylation', 'Var', (5, 16))	('CCL', 'molecular_function', 'GO:0044101', ('40', '43'))	('CCL2', 'Gene', '6347', (40, 44))	('MCP', 'molecular_function', 'GO:0004298', ('45', '48'))	('expression', 'MPA', (51, 61))	('MCP-1', 'Gene', (45, 50))	('decrease', 'NegReg', (28, 36))	('CCL2', 'Gene', (40, 44))	('methylation', 'biological_process', 'GO:0032259', ('5', '16'))	('MCP-1', 'Gene', '6347', (45, 50))
101733	32781743	HIF-1 is directly responsible for increasing ZEB1 expression due to the presence of the HRE sequence in the ZEB1 gene promoter.	('ZEB1', 'Gene', (108, 112))	('HIF-1', 'Gene', (0, 5))	('presence', 'Var', (72, 80))	('increasing', 'PosReg', (34, 44))	('HIF-1', 'Gene', '3091', (0, 5))	('HRE', 'Protein', (88, 91))	('ZEB1', 'Gene', (45, 49))	('ZEB1', 'Gene', '6935', (45, 49))	('ZEB1', 'Gene', '6935', (108, 112))	('expression', 'MPA', (50, 60))
101809	32781743	For this reason, CCR5 expression is increased by HIF-1 and HIF-2.	('CCR5', 'Gene', (17, 21))	('HIF-1', 'Gene', '3091', (49, 54))	('CCR', 'molecular_function', 'GO:0043880', ('17', '20'))	('HIF-1', 'Gene', (49, 54))	('increased', 'PosReg', (36, 45))	('HIF-2', 'Var', (59, 64))	('CCR5', 'Gene', '1234', (17, 21))	('expression', 'MPA', (22, 32))
101839	32781743	The same mechanism causes the retention of cancer cells with CCR7 expression in a lymph node and the formation of metastasis to this peripheral lymphoid organ.	('CCR7', 'Gene', (61, 65))	('CCR7', 'Gene', '1236', (61, 65))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('causes', 'Reg', (19, 25))	('metastasis', 'CPA', (114, 124))	('cancer', 'Disease', (43, 49))	('retention', 'biological_process', 'GO:0051235', ('30', '39'))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('expression', 'Var', (66, 76))	('formation', 'biological_process', 'GO:0009058', ('101', '110'))	('CCR', 'molecular_function', 'GO:0043880', ('61', '64'))
101878	32781743	Therefore, on some models the inactivation of these chemokines does not have pro-cancer but anti-cancer effects.	('cancer', 'Disease', (97, 103))	('inactivation', 'Var', (30, 42))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
101882	32781743	For this reason, inactivation of the CCL2/MCP-1 CCR2 axis by using anti-CCL2 antibodies or CCR2 antagonists increases the effectiveness of immunotherapy.	('CCR', 'molecular_function', 'GO:0043880', ('48', '51'))	('inactivation', 'Var', (17, 29))	('MCP', 'molecular_function', 'GO:0004298', ('42', '45'))	('CCL2', 'Gene', '6347', (72, 76))	('increases', 'PosReg', (108, 117))	('MCP-1', 'Gene', (42, 47))	('effectiveness of immunotherapy', 'CPA', (122, 152))	('CCL2', 'Gene', (72, 76))	('CCL2', 'Gene', '6347', (37, 41))	('CCL', 'molecular_function', 'GO:0044101', ('72', '75'))	('CCL', 'molecular_function', 'GO:0044101', ('37', '40'))	('MCP-1', 'Gene', '6347', (42, 47))	('CCR', 'molecular_function', 'GO:0043880', ('91', '94'))	('CCL2', 'Gene', (37, 41))
101886	32781743	Some researchers also postulate targeting the CCL20/LARC CCR6 axis, which causes chemoresistance and migration of neoplastic cells, and so any disorder in the function of CCL20/LARC should increase the activity of anticancer drugs.	('causes', 'Reg', (74, 80))	('CCL20', 'Gene', '6364', (46, 51))	('disorder', 'Var', (143, 151))	('LARC', 'Gene', (52, 56))	('CCL20', 'Gene', (46, 51))	('increase', 'PosReg', (189, 197))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('LARC', 'Gene', '6364', (52, 56))	('CCR6', 'Gene', '1235', (57, 61))	('CCL20', 'Gene', '6364', (171, 176))	('LARC', 'Gene', (177, 181))	('CCL20', 'Gene', (171, 176))	('CCR', 'molecular_function', 'GO:0043880', ('57', '60'))	('LARC', 'Gene', '6364', (177, 181))	('chemoresistance', 'CPA', (81, 96))	('CCL', 'molecular_function', 'GO:0044101', ('46', '49'))	('activity', 'MPA', (202, 210))	('cancer', 'Disease', (218, 224))	('CCL', 'molecular_function', 'GO:0044101', ('171', '174'))	('CCR6', 'Gene', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('rat', 'Species', '10116', (104, 107))
101894	32781743	This is the result of genetic instability and selective pressure due to adverse conditions of the tumor microenvironment.	('result', 'Reg', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('genetic instability', 'Var', (22, 41))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))
101933	32143295	Mutations in BRAF and NRAS genes lead to constitutive activation of the MAPK/ERK signalling pathway, which promotes CM proliferation and survival.	('w', 'Chemical', 'MESH:D014414', (101, 102))	('MAPK', 'molecular_function', 'GO:0004707', ('72', '76'))	('CM', 'Chemical', '-', (116, 118))	('survival', 'CPA', (137, 145))	('signalling pathway', 'biological_process', 'GO:0007165', ('81', '99'))	('NRAS', 'Gene', (22, 26))	('BRAF', 'Gene', (13, 17))	('activation', 'PosReg', (54, 64))	('ERK', 'molecular_function', 'GO:0004707', ('77', '80'))	('Mutations', 'Var', (0, 9))	('promotes', 'PosReg', (107, 115))	('CM proliferation', 'CPA', (116, 132))	('NRAS', 'Gene', '30380', (22, 26))	('BRAF', 'Gene', '403065', (13, 17))	('MAPK/ERK signalling pathway', 'Pathway', (72, 99))	('w', 'Chemical', 'MESH:D014414', (96, 97))	('P', 'Chemical', 'MESH:D010758', (74, 75))
101934	32143295	New treatments for CM are being actively looked for, for example by knocking down the over-expressed gene EZH2 in CM cell lines, using e.g., zebrafish xenograft models for faster and more predictive drug testing, and by CM-specific gene discovery for targeted therapy.	('EZH2', 'Gene', (106, 110))	('CM', 'Chemical', '-', (220, 222))	('w', 'Chemical', 'MESH:D014414', (2, 3))	('CM', 'Chemical', '-', (19, 21))	('zebrafish', 'Species', '7955', (141, 150))	('CM', 'Chemical', '-', (114, 116))	('w', 'Chemical', 'MESH:D014414', (79, 80))	('knocking', 'Var', (68, 76))	('EZH2', 'Gene', '768133', (106, 110))
101936	32143295	In addition, cancer cells proliferate and mutate under single-treatment, often creating resistance against the common cancer drugs or gene-targeting therapies.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('resistance', 'MPA', (88, 98))	('creating', 'Reg', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (13, 19))	('mutate', 'Var', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
101941	32143295	ROS generation inside a malignant tissue may directly destroy cancer cells via ROS-induced cell death, as demonstrated with 5-aminolevulinic acid (5-ALA)-derived protoporphyrin IX (PpIX).	('ROS', 'Var', (0, 3))	('cell death', 'CPA', (91, 101))	('cell death', 'biological_process', 'GO:0008219', ('91', '101'))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('PpIX', 'Chemical', 'MESH:C028025', (181, 185))	('ROS', 'Chemical', 'MESH:D017382', (79, 82))	('protoporphyrin IX', 'Chemical', 'MESH:C028025', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('ROS generation', 'biological_process', 'GO:1903409', ('0', '14'))	('5-ALA', 'Chemical', 'MESH:C000614854', (147, 152))	('w', 'Chemical', 'MESH:D014414', (119, 120))	('destroy', 'NegReg', (54, 61))	('cancer', 'Disease', (62, 68))	('5-aminolevulinic acid', 'Chemical', 'MESH:C000614854', (124, 145))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('ROS-induced', 'Gene', (79, 90))
101970	32143295	TLD1433 is known to generate reactive oxygen species (ROS) with high quantum efficacy in many cancer cell lines.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (29, 52))	('generate', 'PosReg', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('reactive oxygen species', 'MPA', (29, 52))	('TLD1433', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('w', 'Chemical', 'MESH:D014414', (14, 15))	('w', 'Chemical', 'MESH:D014414', (59, 60))	('ROS', 'Chemical', 'MESH:D017382', (54, 57))	('cancer', 'Disease', (94, 100))	('TLD1433', 'Chemical', '-', (0, 7))
101972	32143295	We determined the cell viability of three conjunctival melanoma cell lines (CRMM1, CRMM2 and CM2005.1), and three uveal melanoma cell lines (OMM1, OMM2.5, MEL270) in the presence of TLD1433, both in the dark or under green light irradiation (21 mW/cm2, 19 J/cm2, 520 nm, 15 min), and compared this viability to epidermoid carcinoma A431 and cutaneous melanoma A375 cell lines under the same conditions.	('cutaneous melanoma', 'Disease', (341, 359))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (341, 359))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (341, 359))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('CM', 'Chemical', '-', (93, 95))	('TLD1433', 'Var', (182, 189))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('TLD1433', 'Chemical', '-', (182, 189))	('melanoma', 'Disease', (55, 63))	('A375', 'CellLine', 'CVCL:0132', (360, 364))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (42, 63))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (42, 63))	('melanoma', 'Disease', 'MESH:D008545', (351, 359))	('epidermoid carcinoma', 'Disease', (311, 331))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('A431', 'CellLine', 'CVCL:0037', (332, 336))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('conjunctival melanoma', 'Disease', (42, 63))	('epidermoid carcinoma', 'Disease', 'MESH:D002294', (311, 331))	('melanoma', 'Phenotype', 'HP:0002861', (351, 359))	('melanoma', 'Disease', (351, 359))
101978	32143295	In eye melanoma cells, the dark toxicity of TLD1433 was relatively high, with EC50 values around 1 microM.	('EC50', 'MPA', (78, 82))	('w', 'Chemical', 'MESH:D014414', (73, 74))	('toxicity', 'Disease', 'MESH:D064420', (32, 40))	('TLD1433', 'Var', (44, 51))	('TLD1433', 'Chemical', '-', (44, 51))	('eye melanoma', 'Disease', 'MESH:D008545', (3, 15))	('eye melanoma', 'Disease', (3, 15))	('melanoma', 'Phenotype', 'HP:0002861', (7, 15))	('toxicity', 'Disease', (32, 40))	('w', 'Chemical', 'MESH:D014414', (52, 53))
101985	32143295	Regardless, we chose CM cells for further studies given that TLD1433 had the largest PI and was most phototoxic toward this particular cell line.	('CM', 'Chemical', '-', (21, 23))	('P', 'Chemical', 'MESH:D010758', (85, 86))	('phototoxic', 'Disease', (101, 111))	('w', 'Chemical', 'MESH:D014414', (114, 115))	('w', 'Chemical', 'MESH:D014414', (12, 13))	('phototoxic', 'Disease', 'MESH:D017484', (101, 111))	('w', 'Chemical', 'MESH:D014414', (92, 93))	('TLD1433', 'Var', (61, 68))	('TLD1433', 'Chemical', '-', (61, 68))
101986	32143295	Depending on the nature and intracellular localization of a PS, the light dose, and the cell type, PDT is known to provoke either necrosis, apoptosis, or autophagy.	('necrosis', 'biological_process', 'GO:0070265', ('130', '138'))	('necrosis', 'biological_process', 'GO:0019835', ('130', '138'))	('necrosis', 'biological_process', 'GO:0001906', ('130', '138'))	('autophagy', 'biological_process', 'GO:0006914', ('154', '163'))	('PDT', 'Var', (99, 102))	('P', 'Chemical', 'MESH:D010758', (99, 100))	('P', 'Chemical', 'MESH:D010758', (60, 61))	('apoptosis', 'CPA', (140, 149))	('provoke', 'PosReg', (115, 122))	('intracellular', 'cellular_component', 'GO:0005622', ('28', '41'))	('intracellular localization', 'biological_process', 'GO:0051641', ('28', '54'))	('necrosis', 'biological_process', 'GO:0008219', ('130', '138'))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('autophagy', 'CPA', (154, 163))	('necrosis', 'Disease', 'MESH:D009336', (130, 138))	('w', 'Chemical', 'MESH:D014414', (109, 110))	('autophagy', 'biological_process', 'GO:0016236', ('154', '163'))	('necrosis', 'biological_process', 'GO:0008220', ('130', '138'))	('necrosis', 'Disease', (130, 138))
101990	32143295	Overall, these results suggest that the CM cells treated with TLD1433 and light did not die via apoptosis, but probably by necrosis.	('necrosis', 'biological_process', 'GO:0001906', ('123', '131'))	('necrosis', 'Disease', 'MESH:D009336', (123, 131))	('necrosis', 'biological_process', 'GO:0008219', ('123', '131'))	('w', 'Chemical', 'MESH:D014414', (57, 58))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('TLD1433', 'Var', (62, 69))	('necrosis', 'biological_process', 'GO:0070265', ('123', '131'))	('CM', 'Chemical', '-', (40, 42))	('necrosis', 'Disease', (123, 131))	('TLD1433', 'Chemical', '-', (62, 69))	('necrosis', 'biological_process', 'GO:0019835', ('123', '131'))	('necrosis', 'biological_process', 'GO:0008220', ('123', '131'))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
102009	32143295	Delivery of TLD1433 at the MTD by WA did not inhibit tumour burden in the ectopic or orthotopic tumour model after engraftment of CRMM1 and CRMM2 cells (Figure 7).	('TLD1433', 'Var', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', (53, 59))	('TLD1433', 'Chemical', '-', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('inhibit', 'NegReg', (45, 52))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('tumour', 'Disease', (96, 102))
102017	32143295	In contrast, delivery of the same concentration of TLD1433 (2.3 mM) by RO administration toward CRMM1 and CRMM2-induced tumours diminished the fluorescence intensity and tumour area in both ectopic (47%, 40%, 64%, 52%) and orthotopic models (35%, 55%, 69%, 71%) upon green light activation (114 J.cm-2, 520 nm) (Figure 9 and Table 3 and Table 4).	('TLD1433', 'Chemical', '-', (51, 58))	('tumour', 'Disease', (170, 176))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('fluorescence intensity', 'MPA', (143, 165))	('RO', 'Chemical', '-', (71, 73))	('tumour', 'Disease', (120, 126))	('w', 'Chemical', 'MESH:D014414', (91, 92))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumours', 'Disease', (120, 127))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('diminished', 'NegReg', (128, 138))	('tumour', 'Disease', 'MESH:D009369', (170, 176))	('TLD1433', 'Var', (51, 58))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
102056	32143295	Such a mode of administration turns out to be reminiscent of that used in bladder cancer patient, where TLD1433 is injected in the bladder and taken up very selectively by the tumour cells.	('S', 'Chemical', 'MESH:D013455', (0, 1))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TLD1433', 'Chemical', '-', (104, 111))	('patient', 'Species', '9606', (89, 96))	('bladder cancer', 'Phenotype', 'HP:0009725', (74, 88))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('w', 'Chemical', 'MESH:D014414', (98, 99))	('bladder cancer', 'Disease', 'MESH:D001749', (74, 88))	('bladder cancer', 'Disease', (74, 88))	('tumour', 'Disease', 'MESH:D009369', (176, 182))	('tumour', 'Disease', (176, 182))	('TLD1433', 'Var', (104, 111))
102061	32143295	TLD1433, like most Ru polypyridyl compounds, shows broad absorption bands (Deltalambda ~ 150 nm) between the blue and red regions of the spectrum, thereby allowing to fine-tune the excitation wavelength and optimise light absorption by the sensitizer vs. light absorption by the pigment.	('excitation', 'MPA', (181, 191))	('TLD1433', 'Gene', (0, 7))	('Ru polypyridyl compounds', 'Chemical', '-', (19, 43))	('TLD1433', 'Chemical', '-', (0, 7))	('light absorption', 'MPA', (216, 232))	('fine-tune', 'Var', (167, 176))	('light absorption', 'biological_process', 'GO:0016037', ('255', '271'))	('w', 'Chemical', 'MESH:D014414', (192, 193))	('w', 'Chemical', 'MESH:D014414', (48, 49))	('light absorption', 'biological_process', 'GO:0016037', ('216', '232'))	('w', 'Chemical', 'MESH:D014414', (100, 101))	('w', 'Chemical', 'MESH:D014414', (159, 160))
102110	32143295	After 24 h incubation, TLD1433 (0.0059 muM for CRMM1, 0.0048 muM for CRMM2) was added into the medium.	('0.0059 muM', 'Var', (32, 42))	('w', 'Chemical', 'MESH:D014414', (76, 77))	('0.0048 muM', 'Var', (54, 64))	('TLD1433', 'Chemical', '-', (23, 30))
102165	32143295	We hence propose, as a third and last conclusion of this work, that TLD1433 can be repurposed as a treatment against conjunctival melanoma.	('w', 'Chemical', 'MESH:D014414', (57, 58))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (117, 138))	('conjunctival melanoma', 'Disease', (117, 138))	('TLD1433', 'Var', (68, 75))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (117, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('TLD1433', 'Chemical', '-', (68, 75))
102249	32002036	Among the cell lines derived from non-metastasis (92.1, MEL202, MEL270 and MEL290), MEL270 exhibited the lowest SNHG7 expression levels.	('SNHG7', 'Gene', '84973', (112, 117))	('lowest', 'NegReg', (105, 111))	('SNHG7', 'Gene', (112, 117))	('MEL270', 'Var', (84, 90))
102363	31588174	PAS density was statistically significantly greater in tumors with gene expression class 2 (p=0.02).	('PAS density', 'CPA', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('PAS', 'cellular_component', 'GO:0000407', ('0', '3'))	('gene expression', 'biological_process', 'GO:0010467', ('67', '82'))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('gene expression class 2', 'Var', (67, 90))	('greater', 'PosReg', (44, 51))
102365	31588174	Intratumor regions with low BAP-1 expression were more likely to harbor VM (p<0.0001), and had statistically significantly greater PAS density (p<0.0001) and number of CD68 positive cells (p=0.01).	('greater', 'PosReg', (123, 130))	('CD68', 'Gene', '968', (168, 172))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('expression', 'Var', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('BAP-1', 'Gene', '8314', (28, 33))	('PAS', 'cellular_component', 'GO:0000407', ('131', '134'))	('PAS density', 'CPA', (131, 142))	('tumor', 'Disease', (5, 10))	('low', 'Var', (24, 27))	('BAP-1', 'Gene', (28, 33))	('CD68', 'Gene', (168, 172))
102393	31588174	The other four sections were pretreated in EDTA buffer at pH 9.0 for 20 min, and incubated with mouse monoclonal antibodies against BAP-1 (sc-28383; Santa Cruz Biotechnology, Dallas, TX) at dilution 1:40, against CD31 (ab134168; Abcam PLC, Cambridge, UK) at dilution 1:400, against laminin (m063801-2; Dako, Agilent Technologies, Santa Clara, CA) at dilution 1:20, and against CD68 (M087601-2, Dako) at dilution 1:200, according to the manufacturers' instructions.	('BAP-1', 'Gene', '8314', (132, 137))	('CD31', 'Gene', '5175', (213, 217))	('M087601-2', 'Chemical', 'MESH:D008775', (383, 392))	('CD68', 'Gene', '968', (377, 381))	('mouse', 'Species', '10090', (96, 101))	('BAP-1', 'Gene', (132, 137))	('m063801-2', 'Var', (291, 300))	('CD31', 'Gene', (213, 217))	('EDTA', 'Chemical', 'MESH:D004492', (43, 47))	('CD68', 'Gene', (377, 381))	('m063801-2', 'Chemical', 'MESH:C014762', (291, 300))	('PLC', 'cellular_component', 'GO:0042824', ('235', '238'))
102409	31588174	Nine patterns were evaluated: normal (within the portion of the tumor beneath Bruch's membrane), silent, straight, parallel, parallel with crosslinks, arcs, arcs with branches, closed loops, and networks.	('arcs', 'Var', (151, 155))	('tumor', 'Disease', (64, 69))	('arcs', 'molecular_function', 'GO:0002948', ('151', '155'))	('crosslinks', 'Var', (139, 149))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('arcs', 'molecular_function', 'GO:0002948', ('157', '161'))	('closed', 'Disease', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('membrane', 'cellular_component', 'GO:0016020', ('86', '94'))
102448	31588174	PAS density was statistically significantly greater in tumors of gene expression class 2, when gene expression class was dichotomized (1 versus 2, Mann-Whitney U test p=0.007) and three-tiered (1a versus 1b versus 2, Kruskal-Wallis p=0.02, Figure 2D).	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('PAS', 'CPA', (0, 3))	('PAS', 'cellular_component', 'GO:0000407', ('0', '3'))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('gene expression', 'biological_process', 'GO:0010467', ('95', '110'))	('gene expression', 'biological_process', 'GO:0010467', ('65', '80'))	('gene expression class 2', 'Var', (65, 88))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('greater', 'PosReg', (44, 51))
102451	31588174	PAS density was statistically significantly higher in tumors with low BAP-1 expression (Mann-Whitney U test p=0.004, Figure 2E).	('BAP-1', 'Gene', (70, 75))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('PAS density', 'CPA', (0, 11))	('higher', 'PosReg', (44, 50))	('PAS', 'cellular_component', 'GO:0000407', ('0', '3'))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('expression', 'MPA', (76, 86))	('BAP-1', 'Gene', '8314', (70, 75))	('low', 'Var', (66, 69))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
102464	31588174	Tumors with BAP-1 heterogeneity had worse metastasis-free survival (log rank p=0.03).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('BAP-1', 'Gene', '8314', (12, 17))	('metastasis-free survival', 'CPA', (42, 66))	('BAP-1', 'Gene', (12, 17))	('heterogeneity', 'Var', (18, 31))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('worse', 'NegReg', (36, 41))
102466	31588174	Regions with low BAP-1 expression were more likely to harbor VM (Fisher's exact p<0.0001), and had a mean PAS density of 13.4%, which was statistically significantly greater than the mean PAS density of 3.4% in regions with high BAP-1 expression (Mann-Whitney U p<0.0001).	('PAS', 'cellular_component', 'GO:0000407', ('106', '109'))	('PAS', 'cellular_component', 'GO:0000407', ('188', '191'))	('BAP-1', 'Gene', (229, 234))	('expression', 'Var', (23, 33))	('BAP-1', 'Gene', '8314', (17, 22))	('low', 'Var', (13, 16))	('greater', 'PosReg', (166, 173))	('BAP-1', 'Gene', (17, 22))	('BAP-1', 'Gene', '8314', (229, 234))
102490	31588174	Although mutations in BAP-1 (Gene ID 8314, OMIM 603089) have been described as random events, we do not know if there is a behavioral difference in response to hypoxia between BAP-1 mutants and a residual population of BAP-1 wild-type tumor cells.	('BAP-1', 'Gene', (219, 224))	('BAP-1', 'Gene', '8314', (22, 27))	('BAP-1', 'Gene', (176, 181))	('hypoxia', 'Disease', (160, 167))	('hypoxia', 'Disease', 'MESH:D000860', (160, 167))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('behavioral difference', 'Phenotype', 'HP:0000708', (123, 144))	('response to hypoxia', 'biological_process', 'GO:0001666', ('148', '167'))	('mutations', 'Var', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('BAP-1', 'Gene', (22, 27))	('tumor', 'Disease', (235, 240))	('BAP-1', 'Gene', '8314', (219, 224))	('OMIM 603089', 'Chemical', 'MESH:C446740', (43, 54))	('BAP-1', 'Gene', '8314', (176, 181))	('mutants', 'Var', (182, 189))
102499	31216772	Targeted Therapy of Uveal Melanoma: Recent Failures and New Perspectives Among Uveal Melanoma (UM) driver mutations, those involving GNAQ or GNA11 genes are the most frequent, while a minor fraction of tumors bears mutations in the PLCB4 or CYSLTR2 genes.	('Melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('GNAQ', 'Gene', (133, 137))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('PLCB4', 'Gene', '5332', (232, 237))	('GNA11', 'Gene', (141, 146))	('Uveal Melanoma', 'Disease', (20, 34))	('CYSLTR2', 'Gene', '57105', (241, 248))	('Uveal Melanoma', 'Disease', 'MESH:C536494', (20, 34))	('frequent', 'Reg', (166, 174))	('Melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('CYSLTR2', 'Gene', (241, 248))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (20, 34))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('GNA11', 'Gene', '2767', (141, 146))	('Uveal Melanoma', 'Disease', (79, 93))	('PLCB4', 'Gene', (232, 237))	('tumors', 'Disease', (202, 208))	('Uveal Melanoma', 'Disease', 'MESH:C536494', (79, 93))	('mutations', 'Var', (106, 115))
102500	31216772	Direct inhibition of constitutively active oncoproteins deriving from these mutations is still in its infancy in UM, whereas BRAFV600E-targeted therapy has obtained relevant results in cutaneous melanoma.	('BRAFV600E-targeted', 'Var', (125, 143))	('oncoproteins', 'Protein', (43, 55))	('mutations', 'Var', (76, 85))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (185, 203))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (185, 203))	('BRAFV600E', 'Mutation', 'rs113488022', (125, 134))	('UM', 'Phenotype', 'HP:0007716', (113, 115))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('cutaneous melanoma', 'Disease', (185, 203))
102501	31216772	However, UM driver mutations converge on common downstream signaling pathways such as PKC/MAPK, PI3K/AKT, and YAP/TAZ, which are presently considered as actionable targets.	('AKT', 'Gene', '207', (101, 104))	('PKC', 'Gene', (86, 89))	('PKC', 'Gene', '112476', (86, 89))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('MAPK', 'molecular_function', 'GO:0004707', ('90', '94'))	('YAP', 'Gene', (110, 113))	('mutations', 'Var', (19, 28))	('AKT', 'Gene', (101, 104))	('PKC', 'molecular_function', 'GO:0004697', ('86', '89'))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('converge', 'Reg', (29, 37))	('YAP', 'Gene', '10413', (110, 113))	('PI3K', 'molecular_function', 'GO:0016303', ('96', '100'))
102509	31216772	In particular, mutually exclusive activating mutations involve the GNAQ or GNA11 genes, which encode for Galpha subunits of G-proteins and drive oncogenesis in most of UM.	('UM', 'Phenotype', 'HP:0007716', (168, 170))	('mutations', 'Var', (45, 54))	('Galpha', 'Gene', (105, 111))	('activating', 'PosReg', (34, 44))	('GNAQ', 'Gene', (67, 71))	('GNA11', 'Gene', '2767', (75, 80))	('GNA11', 'Gene', (75, 80))	('oncogenesis', 'CPA', (145, 156))	('oncogenesis', 'biological_process', 'GO:0007048', ('145', '156'))	('drive', 'PosReg', (139, 144))	('Galpha', 'Gene', '8802', (105, 111))
102510	31216772	Additional driver mutations involve the PLCB4 or the Cysteinyl Leukotriene Receptor 2 (CYSLTR2) genes, in a minor fraction of UM cases.	('PLCB4', 'Gene', '5332', (40, 45))	('Cysteinyl Leukotriene Receptor 2', 'Gene', '57105', (53, 85))	('CYSLTR2', 'Gene', '57105', (87, 94))	('PLCB4', 'Gene', (40, 45))	('UM', 'Phenotype', 'HP:0007716', (126, 128))	('CYSLTR2', 'Gene', (87, 94))	('Cysteinyl Leukotriene Receptor 2', 'Gene', (53, 85))	('mutations', 'Var', (18, 27))
102511	31216772	In addition to driver mutations, monosomy of chromosome 3, loss of chromosome 3 heterozygosity, and inactivating mutations of the BRCA1-associated protein 1 (BAP1) oncosuppressor gene are highly associated with the metastatic risk.	('associated', 'Reg', (195, 205))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))	('chromosome', 'cellular_component', 'GO:0005694', ('67', '77'))	('metastatic', 'Disease', (215, 225))	('monosomy', 'Var', (33, 41))	('inactivating mutations', 'Var', (100, 122))	('BAP1', 'Gene', (158, 162))	('chromosome', 'cellular_component', 'GO:0005694', ('45', '55'))	('BAP1', 'Gene', '8314', (158, 162))	('BRCA1-associated protein 1', 'Gene', '8314', (130, 156))	('loss', 'Var', (59, 63))	('BRCA1-associated protein 1', 'Gene', (130, 156))
102513	31216772	Importantly, BAP1 loss-of-function mutations correlate with a distinct DNA methylation profile.	('DNA methylation', 'biological_process', 'GO:0006306', ('71', '86'))	('BAP1', 'Gene', (13, 17))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('loss-of-function', 'NegReg', (18, 34))	('BAP1', 'Gene', '8314', (13, 17))	('DNA methylation profile', 'MPA', (71, 94))	('mutations', 'Var', (35, 44))
102515	31216772	A high mutational load may result in the frequent generation of neo-antigens, which render the cutaneous melanoma highly immunogenic and sensitive to immune-checkpoint blockers such as anti-CTLA-4 and anti-PD-1 monoclonal antibodies.	('CTLA-4', 'Gene', '1493', (190, 196))	('neo-antigens', 'MPA', (64, 76))	('mutational load', 'Var', (7, 22))	('sensitive', 'MPA', (137, 146))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('rat', 'Species', '10116', (54, 57))	('CTLA-4', 'Gene', (190, 196))	('result in', 'Reg', (27, 36))	('cutaneous melanoma', 'Disease', (95, 113))	('immunogenic', 'MPA', (121, 132))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (95, 113))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (95, 113))
102517	31216772	Targeting of driver mutations such as the B-RAF V600E by small-molecule inhibitors has provided a therapeutic option for a subset of cutaneous melanomas bearing such a mutation, although responses are transient.	('V600E', 'Mutation', 'p.V600E', (48, 53))	('cutaneous melanomas', 'Disease', (133, 152))	('V600E', 'Var', (48, 53))	('B-RAF', 'Gene', '673', (42, 47))	('B-RAF', 'Gene', (42, 47))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (133, 152))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (133, 152))	('melanomas', 'Phenotype', 'HP:0002861', (143, 152))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (133, 151))
102518	31216772	However, B-RAF mutations only rarely occur in UMs, which in about 90% of cases bear an activating mutation of the GNAQ/GNA11 genes, driving tumor initiation.	('B-RAF', 'Gene', (9, 14))	('mutation', 'Var', (98, 106))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('GNA11', 'Gene', '2767', (119, 124))	('GNA11', 'Gene', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('activating', 'PosReg', (87, 97))	('B-RAF', 'Gene', '673', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
102521	31216772	The R183C mutation is less frequent and has been predicted to display a less strong inhibitory activity on GalphaQ or Galpha11.	('R183C', 'Var', (4, 9))	('GalphaQ', 'Gene', (107, 114))	('Galpha11', 'Gene', '2767', (118, 126))	('R183C', 'Mutation', 'p.R183C', (4, 9))	('inhibitory activity', 'MPA', (84, 103))	('GalphaQ', 'Gene', '2776', (107, 114))	('Galpha11', 'Gene', (118, 126))
102522	31216772	GNAQ/11 Q209L mutations are early or initiating events, which are present at any stage of UM.	('Q209L', 'Var', (8, 13))	('GNAQ/11', 'Gene', (0, 7))	('Q209L', 'Mutation', 'rs1057519742', (8, 13))	('UM', 'Phenotype', 'HP:0007716', (90, 92))
102523	31216772	However, GNA11 mutations are more frequently found in UM metastases (57%) than GNAQ mutations (22%), suggesting that GNA11 mutation is associated with higher metastatic risk.	('GNA11', 'Gene', (9, 14))	('mutation', 'Var', (123, 131))	('GNA11', 'Gene', '2767', (117, 122))	('mutations', 'Var', (15, 24))	('metastases', 'Disease', (57, 67))	('UM', 'Phenotype', 'HP:0007716', (54, 56))	('metastases', 'Disease', 'MESH:D009362', (57, 67))	('GNA11', 'Gene', (117, 122))	('metastatic', 'CPA', (158, 168))	('found', 'Reg', (45, 50))	('GNA11', 'Gene', '2767', (9, 14))
102524	31216772	In addition, Q209L mutations in GNAQ or GNA11 have been found in 55% or 7% of blue nevi, respectively.	('Q209L', 'Mutation', 'rs1057519742', (13, 18))	('GNAQ', 'Gene', (32, 36))	('nevi', 'Phenotype', 'HP:0003764', (83, 87))	('GNA11', 'Gene', (40, 45))	('Q209L', 'Var', (13, 18))	('GNA11', 'Gene', '2767', (40, 45))	('blue nevi', 'Phenotype', 'HP:0100814', (78, 87))	('blue nevi', 'Disease', (78, 87))	('found', 'Reg', (56, 61))
102525	31216772	Mutated Galpha proteins mediate the activation of the PLCalpha/PKC pathway and multiple downstream signaling pathways, including the RAF/MEK/ERK, PI3K/AKT/MTOR, and Trio/Rho/Rac/YAP1 pathways.	('AKT', 'Gene', (151, 154))	('MTOR', 'Gene', (155, 159))	('YAP1', 'Gene', (178, 182))	('MTOR', 'Gene', '2475', (155, 159))	('PKC', 'molecular_function', 'GO:0004697', ('63', '66'))	('activation', 'PosReg', (36, 46))	('Trio', 'Gene', (165, 169))	('Rac', 'Gene', (174, 177))	('PI3K', 'molecular_function', 'GO:0016303', ('146', '150'))	('signaling', 'biological_process', 'GO:0023052', ('99', '108'))	('ERK', 'molecular_function', 'GO:0004707', ('141', '144'))	('AKT', 'Gene', '207', (151, 154))	('Galpha', 'Gene', (8, 14))	('RAF', 'Gene', '22882', (133, 136))	('ERK', 'Gene', '5594', (141, 144))	('MEK', 'Gene', '5609', (137, 140))	('PKC', 'Gene', '112476', (63, 66))	('Trio', 'Gene', '7204', (165, 169))	('Galpha', 'Gene', '8802', (8, 14))	('Mutated', 'Var', (0, 7))	('RAF', 'Gene', (133, 136))	('MEK', 'Gene', (137, 140))	('ERK', 'Gene', (141, 144))	('PKC', 'Gene', (63, 66))	('YAP1', 'Gene', '10413', (178, 182))	('Rac', 'Gene', '207', (174, 177))
102526	31216772	Therefore, mutated Galpha proteins or downstream signaling molecules represent potential targets for therapy (Figure 1).	('Galpha', 'Gene', '8802', (19, 25))	('Galpha', 'Gene', (19, 25))	('mutated', 'Var', (11, 18))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))
102527	31216772	Less frequently, driver mutations involve the genes encoding for phospholipase C4 (PLCB4) or the G protein-coupled receptor (GPCR) cysteinyl leukotriene receptor-2 (CYSLTR2).	('PLCB4', 'Gene', (83, 88))	('CYSLTR2', 'Gene', '57105', (165, 172))	('CYSLTR2', 'Gene', (165, 172))	('PLCB4', 'Gene', '5332', (83, 88))	('cysteinyl leukotriene receptor-2', 'Gene', '57105', (131, 163))	('cysteinyl leukotriene receptor-2', 'Gene', (131, 163))	('mutations', 'Var', (24, 33))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))
102528	31216772	The PLCB4 D630Y gain-of-function mutation is mutually exclusive with GNA11 and GNAQ mutations, indicating PLCB4 as a downstream target of Galpha proteins.	('PLCB4', 'Gene', '5332', (106, 111))	('PLCB4', 'Gene', '5332', (4, 9))	('D630Y', 'Var', (10, 15))	('PLCB4', 'Gene', (106, 111))	('PLCB4', 'Gene', (4, 9))	('Galpha', 'Gene', '8802', (138, 144))	('Galpha', 'Gene', (138, 144))	('GNA11', 'Gene', (69, 74))	('D630Y', 'Mutation', 'p.D630Y', (10, 15))	('GNA11', 'Gene', '2767', (69, 74))	('gain-of-function', 'PosReg', (16, 32))
102529	31216772	However, the development of targeted therapy for mutated Galpha proteins is still in an initial phase.	('mutated', 'Var', (49, 56))	('Galpha', 'Gene', (57, 63))	('Galpha', 'Gene', '8802', (57, 63))
102530	31216772	The downregulation of GNAQ mutant expression using specific short interfering RNA (siRNA) decreased GalphaQ protein levels in UM cell lines, resulting in a decrease in Extracellular signal-Regulated Kinases (ERK) and AKT Serine/Threonine Kinase (AKT) signaling and in 5' Adenosine Monophosphate-activated Protein Kinase (AMPK)-dependent autophagic cell death.	('expression', 'MPA', (34, 44))	('mutant', 'Var', (27, 33))	('decreased', 'NegReg', (90, 99))	('decrease', 'NegReg', (156, 164))	('AKT', 'Gene', '207', (217, 220))	('Adenosine Monophosphate-activated Protein Kinase', 'Gene', (271, 319))	('GalphaQ', 'Gene', (100, 107))	('AKT', 'Gene', '207', (246, 249))	('ERK', 'Gene', '5594', (208, 211))	('AMPK', 'Gene', (321, 325))	('GNAQ', 'Gene', (22, 26))	('ERK', 'molecular_function', 'GO:0004707', ('208', '211'))	('AMPK', 'molecular_function', 'GO:0050405', ('321', '325'))	('ERK', 'Gene', (208, 211))	('GalphaQ', 'Gene', '2776', (100, 107))	('UM', 'Phenotype', 'HP:0007716', (126, 128))	('downregulation', 'NegReg', (4, 18))	('Extracellular signal-Regulated Kinases', 'Gene', '5594', (168, 206))	('AMPK', 'molecular_function', 'GO:0004691', ('321', '325'))	('Extracellular', 'cellular_component', 'GO:0005576', ('168', '181'))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('autophagic cell death', 'biological_process', 'GO:0048102', ('337', '358'))	('AKT', 'Gene', (217, 220))	('AKT) signaling', 'biological_process', 'GO:0043491', ('246', '260'))	('Extracellular signal-Regulated Kinases', 'Gene', (168, 206))	('Adenosine Monophosphate-activated Protein Kinase', 'Gene', '5563', (271, 319))	('AKT', 'Gene', (246, 249))	('RNA', 'cellular_component', 'GO:0005562', ('78', '81'))	('AMPK', 'molecular_function', 'GO:0047322', ('321', '325'))	('AMPK', 'Gene', '5563', (321, 325))
102532	31216772	The GalphaQ bearing the Q209P mutation is also GTPase-deficient and constitutively active but has distinct molecular characteristics.	('GTPase-deficient', 'Protein', (47, 63))	('GalphaQ', 'Gene', (4, 11))	('GTP', 'Chemical', 'MESH:D006160', (47, 50))	('GalphaQ', 'Gene', '2776', (4, 11))	('Q209P', 'Var', (24, 29))	('Q209P', 'Mutation', 'rs121913492', (24, 29))
102534	31216772	The cyclic depsipeptide FR900359, isolated from the Ardisia crenata Sims plant, specifically inhibits the activity of the wild-type GalphaQ, resulting in vasorelaxant effects on rat aortic arteries.	('GalphaQ', 'Gene', (132, 139))	('Ardisia crenata Sims plant', 'Disease', (52, 78))	('inhibits', 'NegReg', (93, 101))	('depsipeptide', 'Chemical', 'MESH:D047630', (11, 23))	('activity', 'MPA', (106, 114))	('rat', 'Species', '10116', (178, 181))	('FR900359', 'Var', (24, 32))	('vasorelaxant effects', 'MPA', (154, 174))	('GalphaQ', 'Gene', '2776', (132, 139))	('FR900359', 'Chemical', 'MESH:C000607068', (24, 32))	('Ardisia crenata Sims plant', 'Disease', 'MESH:D010939', (52, 78))
102535	31216772	FR900359 inhibits GalphaQ/11/14 but not other mammalian Galpha isoforms, by binding with high affinity to these molecules and acting as a pseudo-irreversible inhibitor.	('GalphaQ', 'Gene', (18, 25))	('mammalian', 'Species', '9606', (46, 55))	('Galpha', 'Gene', '8802', (56, 62))	('binding', 'molecular_function', 'GO:0005488', ('76', '83'))	('Galpha', 'Gene', '8802', (18, 24))	('Galpha', 'Gene', (56, 62))	('FR900359', 'Var', (0, 8))	('inhibits', 'NegReg', (9, 17))	('binding', 'Interaction', (76, 83))	('Galpha', 'Gene', (18, 24))	('FR900359', 'Chemical', 'MESH:C000607068', (0, 8))	('GalphaQ', 'Gene', '2776', (18, 25))
102537	31216772	A more recent study found that FR900359 also suppressed signaling of mutated GalphaQ in UM cells, through the allosteric inhibition of the Guanosine Diphosphate/Guanosine triphosphate (GDP/GTP) exchange.	('Guanosine Diphosphate', 'Chemical', 'MESH:D006153', (139, 160))	('GalphaQ', 'Gene', '2776', (77, 84))	('GDP', 'Chemical', 'MESH:D006153', (185, 188))	('mutated', 'Var', (69, 76))	('GTP', 'Chemical', 'MESH:D006160', (189, 192))	('Guanosine triphosphate', 'Chemical', 'MESH:D006160', (161, 183))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))	('suppressed', 'NegReg', (45, 55))	('GalphaQ', 'Gene', (77, 84))	('signaling', 'MPA', (56, 65))	('FR900359', 'Var', (31, 39))	('UM', 'Phenotype', 'HP:0007716', (88, 90))	('FR900359', 'Chemical', 'MESH:C000607068', (31, 39))	('allosteric inhibition', 'MPA', (110, 131))
102538	31216772	In GalphaQ-mutated UM cells, FR900359 inhibited downstream signaling and cell proliferation and induced melanocytic differentiation.	('FR900359', 'Var', (29, 37))	('cell proliferation', 'biological_process', 'GO:0008283', ('73', '91'))	('induced', 'PosReg', (96, 103))	('FR900359', 'Chemical', 'MESH:C000607068', (29, 37))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('melanocytic', 'Disease', 'MESH:D009508', (104, 115))	('melanocytic', 'Disease', (104, 115))	('GalphaQ', 'Gene', '2776', (3, 10))	('rat', 'Species', '10116', (85, 88))	('inhibited', 'NegReg', (38, 47))	('downstream signaling', 'Pathway', (48, 68))	('cell proliferation', 'CPA', (73, 91))	('UM', 'Phenotype', 'HP:0007716', (19, 21))	('GalphaQ', 'Gene', (3, 10))
102539	31216772	Similarly, another report showed that FR900359 inhibits oncogenic signaling in UM cells bearing activating mutations in either GalphaQ or Galpha11 and induces cell cycle arrest and apoptosis.	('arrest', 'Disease', 'MESH:D006323', (170, 176))	('induces', 'Reg', (151, 158))	('apoptosis', 'CPA', (181, 190))	('inhibits', 'NegReg', (47, 55))	('GalphaQ', 'Gene', '2776', (127, 134))	('oncogenic signaling', 'MPA', (56, 75))	('FR900359', 'Var', (38, 46))	('FR900359', 'Chemical', 'MESH:C000607068', (38, 46))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (159, 176))	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('Galpha11', 'Gene', '2767', (138, 146))	('arrest', 'Disease', (170, 176))	('apoptosis', 'biological_process', 'GO:0097194', ('181', '190'))	('mutations', 'Var', (107, 116))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('apoptosis', 'biological_process', 'GO:0006915', ('181', '190'))	('GalphaQ', 'Gene', (127, 134))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('159', '176'))	('Galpha11', 'Gene', (138, 146))
102540	31216772	In addition, FR900359 prevented colony formation in a 3D-cell culture model of UM cells.	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('FR900359', 'Var', (13, 21))	('FR900359', 'Chemical', 'MESH:C000607068', (13, 21))	('formation', 'biological_process', 'GO:0009058', ('39', '48'))	('colony formation in a 3D-cell culture model', 'CPA', (32, 75))	('prevented', 'NegReg', (22, 31))
102541	31216772	A very recent study reported that FR900359 predominantly blocks the ERK signaling pathway rather than the PLCbeta pathway.	('FR900359', 'Chemical', 'MESH:C000607068', (34, 42))	('signaling pathway', 'biological_process', 'GO:0007165', ('72', '89'))	('ERK', 'Gene', '5594', (68, 71))	('FR900359', 'Var', (34, 42))	('ERK', 'Gene', (68, 71))	('PLCbeta pathway', 'Pathway', (106, 121))	('blocks', 'NegReg', (57, 63))	('ERK', 'molecular_function', 'GO:0004707', ('68', '71'))	('rat', 'Species', '10116', (90, 93))
102542	31216772	Importantly, FR900359 inhibited the growth of UM xenografts bearing the GalphaQ-activating mutation, leaving unaffected the growth of xenografts driven by mutated B-RafV600E.	('inhibited', 'NegReg', (22, 31))	('growth', 'MPA', (36, 42))	('FR900359', 'Var', (13, 21))	('B-RafV600E', 'Var', (163, 173))	('FR900359', 'Chemical', 'MESH:C000607068', (13, 21))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('GalphaQ', 'Gene', '2776', (72, 79))	('mutated B-RafV600E', 'Var', (155, 173))	('GalphaQ', 'Gene', (72, 79))
102543	31216772	Altogether, these studies indicate that FR900359 or its derivatives may represent a new, potential treatment option for UM bearing activating GNAQ or GNA11 gene mutations.	('FR900359', 'Var', (40, 48))	('GNA11', 'Gene', (150, 155))	('FR900359', 'Chemical', 'MESH:C000607068', (40, 48))	('GNA11', 'Gene', '2767', (150, 155))	('activating', 'PosReg', (131, 141))	('UM', 'Phenotype', 'HP:0007716', (120, 122))	('mutations', 'Var', (161, 170))	('GNAQ', 'Gene', (142, 146))
102544	31216772	The depsipeptide YM-254890 is structurally similar to FR900359 and is a selective inhibitor of the GalphaQ/11 G proteins.	('GalphaQ', 'Gene', '2776', (99, 106))	('depsipeptide', 'Chemical', 'MESH:D047630', (4, 16))	('YM-254890', 'Var', (17, 26))	('FR900359', 'Chemical', 'MESH:C000607068', (54, 62))	('GalphaQ', 'Gene', (99, 106))	('YM-254890', 'Chemical', 'MESH:C475455', (17, 26))
102546	31216772	Several signaling pathways are activated downstream of mutation-activated GalphaQ and Galpha11, including the Mitogen-Activated Protein Kinase (MAPK), RAF/MEK/ERK, Phosphatidylinositol 3-Kinase/AKT/Mechanistic Target Of Rapamycin Kinase (PI3K/AKT/MTOR), and Trio Rho Guanine Nucleotide Exchange Factor/Ras Homolog Family Member/Rac Family Small GTPase 1/ Yes Associated Protein (Trio/Rho/RAC/YAP1) pathways, and provide several potential targets for therapy (Figure 1, Table 1).	('GalphaQ', 'Gene', '2776', (74, 81))	('AKT', 'Gene', '207', (194, 197))	('mutation-activated', 'Var', (55, 73))	('MEK', 'Gene', '5609', (155, 158))	('RAC', 'Gene', (388, 391))	('MTOR', 'Gene', (247, 251))	('GTP', 'Chemical', 'MESH:D006160', (345, 348))	('ERK', 'Gene', '5594', (159, 162))	('ERK', 'molecular_function', 'GO:0004707', ('159', '162'))	('signaling pathways', 'Pathway', (8, 26))	('Rho Guanine Nucleotide Exchange Factor', 'molecular_function', 'GO:0005089', ('263', '301'))	('RAF', 'Gene', '22882', (151, 154))	('MTOR', 'Gene', '2475', (247, 251))	('RAC', 'Gene', '207', (388, 391))	('Trio', 'Gene', (379, 383))	('Guanine Nucleotide Exchange Factor', 'Gene', (267, 301))	('MEK', 'Gene', (155, 158))	('Galpha11', 'Gene', '2767', (86, 94))	('signaling', 'biological_process', 'GO:0023052', ('8', '17'))	('Trio', 'Gene', (258, 262))	('AKT', 'Gene', (243, 246))	('ERK', 'Gene', (159, 162))	('RAF', 'Gene', (151, 154))	('Rac', 'Gene', '207', (328, 331))	('AKT', 'Gene', (194, 197))	('YAP1', 'Gene', '10413', (392, 396))	('GalphaQ', 'Gene', (74, 81))	('Trio', 'Gene', '7204', (379, 383))	('Galpha11', 'Gene', (86, 94))	('Mitogen-Activated Protein Kinase', 'Pathway', (110, 142))	('MAPK', 'molecular_function', 'GO:0004707', ('144', '148'))	('AKT', 'Gene', '207', (243, 246))	('YAP1', 'Gene', (392, 396))	('PI3K', 'molecular_function', 'GO:0016303', ('238', '242'))	('Guanine Nucleotide Exchange Factor', 'Gene', '5923', (267, 301))	('Trio', 'Gene', '7204', (258, 262))	('activated', 'PosReg', (31, 40))	('Rac', 'Gene', (328, 331))
102565	31216772	Intriguingly, however, the PKCdelta inhibitor B106 induced apoptosis in several UM cell lines, but apparently independent of activated PKCdelta.	('PKCdelta', 'Gene', (27, 35))	('apoptosis', 'biological_process', 'GO:0097194', ('59', '68'))	('apoptosis', 'biological_process', 'GO:0006915', ('59', '68'))	('inhibitor B106', 'Var', (36, 50))	('PKCdelta', 'Gene', '5580', (135, 143))	('UM', 'Phenotype', 'HP:0007716', (80, 82))	('PKCdelta', 'Gene', (135, 143))	('apoptosis', 'CPA', (59, 68))	('B106', 'Var', (46, 50))	('PKCdelta', 'molecular_function', 'GO:0004697', ('135', '143'))	('PKCdelta', 'molecular_function', 'GO:0004697', ('27', '35'))	('PKCdelta', 'Gene', '5580', (27, 35))
102569	31216772	Although the PKC inhibitors AEB071 or AHT956 inhibited MAPK signaling and induced G1 arrest in GNAQ/11-mutated UM cells, they failed to induce UM tumor regressions in xenograft models.	('PKC', 'Gene', '112476', (13, 16))	('MAPK', 'molecular_function', 'GO:0004707', ('55', '59'))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('inhibited', 'NegReg', (45, 54))	('MAPK signaling', 'Pathway', (55, 69))	('UM', 'Phenotype', 'HP:0007716', (111, 113))	('MAPK signaling', 'biological_process', 'GO:0000165', ('55', '69'))	('induced', 'Reg', (74, 81))	('tumor', 'Disease', (146, 151))	('PKC', 'molecular_function', 'GO:0004697', ('13', '16'))	('AEB071', 'Var', (28, 34))	('arrest', 'Disease', 'MESH:D006323', (85, 91))	('PKC', 'Gene', (13, 16))	('AHT956', 'Var', (38, 44))	('UM', 'Phenotype', 'HP:0007716', (143, 145))	('arrest', 'Disease', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
102573	31216772	A preclinical study showed that the combination of the MEK inhibitor GSK1120212 and the pan-PI3K inhibitor GSK2126458 cooperatively induced apoptosis in the majority of UM cell lines, in a GNAQ/11 mutant-dependent manner, while PI3K inhibition "per se" had limited effect.	('UM', 'Phenotype', 'HP:0007716', (169, 171))	('PI3K', 'molecular_function', 'GO:0016303', ('228', '232'))	('apoptosis', 'CPA', (140, 149))	('MEK', 'Gene', (55, 58))	('GSK2126458', 'Var', (107, 117))	('MEK', 'Gene', '5609', (55, 58))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('rat', 'Species', '10116', (123, 126))	('PI3K', 'molecular_function', 'GO:0016303', ('92', '96'))	('GSK1120212', 'Var', (69, 79))	('GSK', 'molecular_function', 'GO:0050321', ('107', '110'))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('GSK', 'molecular_function', 'GO:0050321', ('69', '72'))	('induced', 'Reg', (132, 139))
102588	31216772	Mutation-activated GalphaQ or Galpha11 induced YAP/TAZ dephosphorylation and signaling, which is an essential mediator of oncogenic activity in UM development.	('signaling', 'MPA', (77, 86))	('GalphaQ', 'Gene', '2776', (19, 26))	('Mutation-activated', 'Var', (0, 18))	('GalphaQ', 'Gene', (19, 26))	('Galpha11', 'Gene', (30, 38))	('YAP', 'Gene', '10413', (47, 50))	('dephosphorylation', 'biological_process', 'GO:0016311', ('55', '72'))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))	('YAP', 'Gene', (47, 50))	('UM', 'Phenotype', 'HP:0007716', (144, 146))	('Galpha11', 'Gene', '2767', (30, 38))
102590	31216772	Knockdown of mutated GalphaQ decreased the nuclear localization of YAP and its interaction with the transcription factor TEA domain transcription factor (TEAD), which is essential for YAP-mediated proliferation, epithelial-mesenchymal transition, and oncogenesis.	('YAP', 'Gene', '10413', (67, 70))	('transcription factor', 'molecular_function', 'GO:0000981', ('100', '120'))	('transcription', 'biological_process', 'GO:0006351', ('132', '145'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('212', '245'))	('GalphaQ', 'Gene', '2776', (21, 28))	('YAP', 'Gene', '10413', (184, 187))	('transcription factor', 'molecular_function', 'GO:0000981', ('132', '152'))	('interaction', 'Interaction', (79, 90))	('rat', 'Species', '10116', (204, 207))	('YAP', 'Gene', (184, 187))	('YAP', 'Gene', (67, 70))	('localization', 'biological_process', 'GO:0051179', ('51', '63'))	('nuclear localization', 'MPA', (43, 63))	('transcription', 'biological_process', 'GO:0006351', ('100', '113'))	('decreased', 'NegReg', (29, 38))	('oncogenesis', 'biological_process', 'GO:0007048', ('251', '262'))	('mutated', 'Var', (13, 20))	('GalphaQ', 'Gene', (21, 28))
102592	31216772	Altogether, these data indicate that YAP is a potentially useful target for the therapy of UM-bearing mutations in GNAQ or GNA11 genes.	('GNAQ', 'Gene', (115, 119))	('YAP', 'Gene', '10413', (37, 40))	('UM', 'Phenotype', 'HP:0007716', (91, 93))	('GNA11', 'Gene', (123, 128))	('mutations', 'Var', (102, 111))	('YAP', 'Gene', (37, 40))	('GNA11', 'Gene', '2767', (123, 128))
102594	31216772	Ablation of the FAK-encoding gene (PTK2) or blockade of FAK activity by the small molecules VS-4718 or PF562771 inhibits YAP signaling and UM growth, suggesting that FAK is a new actionable target in UM and for other GalphaQ-dependent diseases.	('FAK', 'molecular_function', 'GO:0004717', ('56', '59'))	('PF562771', 'Var', (103, 111))	('PTK2', 'Gene', (35, 39))	('UM', 'Phenotype', 'HP:0007716', (139, 141))	('YAP', 'Gene', '10413', (121, 124))	('UM growth', 'CPA', (139, 148))	('UM', 'Phenotype', 'HP:0007716', (200, 202))	('VS-4718', 'Var', (92, 99))	('PTK2', 'Gene', '5747', (35, 39))	('blockade', 'NegReg', (44, 52))	('GalphaQ', 'Gene', (217, 224))	('FAK', 'molecular_function', 'GO:0004717', ('16', '19'))	('FAK', 'Gene', (16, 19))	('Ablation', 'Var', (0, 8))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('activity', 'MPA', (60, 68))	('FAK', 'molecular_function', 'GO:0004717', ('166', '169'))	('FAK', 'Gene', (56, 59))	('FAK', 'Gene', (166, 169))	('FAK', 'Gene', '5747', (16, 19))	('GalphaQ', 'Gene', '2776', (217, 224))	('YAP', 'Gene', (121, 124))	('inhibits', 'NegReg', (112, 120))	('FAK', 'Gene', '5747', (166, 169))	('FAK', 'Gene', '5747', (56, 59))
102599	31216772	In UM, several HDAC inhibitors, including valproic acid, panobinostat, vorinostat, tricostatin A, tenovin-6, depsipeptide, MS-275, quisinostat, JSL-1, MC1568, and MCI1575, have shown antitumor activities, including growth arrest or apoptosis in vitro and/or suppression of UM xenograft growth.	('MS-275', 'Var', (123, 129))	('valproic acid', 'Chemical', 'MESH:D014635', (42, 55))	('tumor', 'Disease', (187, 192))	('UM', 'Phenotype', 'HP:0007716', (273, 275))	('MCI1575', 'Gene', (163, 170))	('UM xenograft growth', 'CPA', (273, 292))	('depsipeptide', 'Chemical', 'MESH:D047630', (109, 121))	('UM', 'Phenotype', 'HP:0007716', (3, 5))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('MC1568', 'CellLine', 'CVCL:E432', (151, 157))	('quisinostat', 'Chemical', 'MESH:C541788', (131, 142))	('HDAC', 'Gene', '9734', (15, 19))	('growth arrest', 'Phenotype', 'HP:0001510', (215, 228))	('vorinostat', 'Chemical', 'MESH:D000077337', (71, 81))	('tenovin-6', 'Chemical', 'MESH:C574854', (98, 107))	('growth arrest', 'Disease', 'MESH:D006323', (215, 228))	('MC1568', 'Var', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('apoptosis', 'biological_process', 'GO:0097194', ('232', '241'))	('apoptosis', 'biological_process', 'GO:0006915', ('232', '241'))	('HDAC', 'Gene', (15, 19))	('tricostatin A', 'Chemical', 'MESH:C012589', (83, 96))	('MCI1575', 'Chemical', '-', (163, 170))	('panobinostat', 'Chemical', 'MESH:D000077767', (57, 69))	('suppression', 'NegReg', (258, 269))	('apoptosis', 'CPA', (232, 241))	('growth arrest', 'Disease', (215, 228))
102610	31216772	The rationale for this study relies not only on the direct effect of HDAC inhibitors on UM cells, but also on their immune-modulatory activity, which may cooperate with the anti-PD-1 effects.	('HDAC', 'Gene', (69, 73))	('HDAC', 'Gene', '9734', (69, 73))	('inhibitors', 'Var', (74, 84))	('UM', 'Phenotype', 'HP:0007716', (88, 90))	('rat', 'Species', '10116', (4, 7))	('rat', 'Species', '10116', (159, 162))
102611	31216772	Alterations of DNA methylation represent another important epigenetic mechanism of cancer development.	('methylation', 'Var', (19, 30))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('DNA', 'Protein', (15, 18))	('DNA methylation', 'biological_process', 'GO:0006306', ('15', '30'))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('rat', 'Species', '10116', (4, 7))	('cancer', 'Disease', (83, 89))
102612	31216772	These mechanisms can be a target for epigenetic therapy with drugs such as azacitidine and its derivatives that inhibit DNA methyltransferase I and mediate hypomethylation of DNA.	('DNA', 'Gene', (120, 123))	('hypomethylation', 'Var', (156, 171))	('inhibit', 'NegReg', (112, 119))	('DNA', 'cellular_component', 'GO:0005574', ('120', '123'))	('azacitidine', 'Chemical', 'MESH:D001374', (75, 86))	('DNA', 'cellular_component', 'GO:0005574', ('175', '178'))
102613	31216772	On the other hand, hypomethylation has also been implicated in the development and progression of cancer through the activation of oncogene expression.	('oncogene', 'Protein', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('expression', 'MPA', (140, 150))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('activation', 'PosReg', (117, 127))	('hypomethylation', 'Var', (19, 34))	('implicated', 'Reg', (49, 59))
102614	31216772	Examples of genes silenced by hypermethylation in UM are INK4a, TIMP3, and S100A2.	('INK4a', 'Gene', '1029', (57, 62))	('S100A2', 'Gene', '6273', (75, 81))	('S100A2', 'Gene', (75, 81))	('TIMP3', 'Gene', (64, 69))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('TIMP3', 'Gene', '7078', (64, 69))	('hypermethylation', 'Var', (30, 46))	('INK4a', 'Gene', (57, 62))
102619	31216772	Another study performed on 87 UM samples revealed phylogenetic clusters of global DNA methylation that correlated with the gene expression profile (class-1 versus class-2) and with BAP1, SF3B1 or EIF1AX mutations.	('SF3B1', 'Gene', '23451', (187, 192))	('BAP1', 'Gene', '8314', (181, 185))	('BAP1', 'Gene', (181, 185))	('DNA methylation', 'biological_process', 'GO:0006306', ('82', '97'))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('gene expression', 'biological_process', 'GO:0010467', ('123', '138'))	('gene expression profile', 'MPA', (123, 146))	('SF3B1', 'Gene', (187, 192))	('EIF1AX', 'Gene', '1964', (196, 202))	('EIF1AX', 'Gene', (196, 202))	('mutations', 'Var', (203, 212))	('correlated', 'Reg', (103, 113))	('UM', 'Phenotype', 'HP:0007716', (30, 32))
102620	31216772	Altogether, these studies indicate that the global methylation profile is related to the almost mutually exclusive mutations in BAP1, SF3B1 or EIF1AX genes, which are associated with a distinct metastatic risk.	('mutations', 'Var', (115, 124))	('SF3B1', 'Gene', (134, 139))	('related', 'Reg', (74, 81))	('BAP1', 'Gene', '8314', (128, 132))	('methylation profile', 'MPA', (51, 70))	('associated', 'Reg', (167, 177))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('SF3B1', 'Gene', '23451', (134, 139))	('BAP1', 'Gene', (128, 132))	('EIF1AX', 'Gene', '1964', (143, 149))	('EIF1AX', 'Gene', (143, 149))
102626	31216772	JQ1 inhibits the expression of genes involved in the regulation of cell cycle, apoptosis, and DNA repair, such as BCL-XL and RAD51.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('inhibits', 'NegReg', (4, 12))	('DNA repair', 'biological_process', 'GO:0006281', ('94', '104'))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('BCL-XL', 'Gene', '598', (114, 120))	('RAD51', 'Gene', (125, 130))	('RAD', 'biological_process', 'GO:1990116', ('125', '128'))	('expression', 'MPA', (17, 27))	('RAD51', 'Gene', '5888', (125, 130))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('JQ1', 'Var', (0, 3))	('BCL-XL', 'Gene', (114, 120))	('regulation of cell cycle', 'biological_process', 'GO:0051726', ('53', '77'))
102628	31216772	As JQ1 has a short half-life and was not suitable for clinical trials, the second-generation BET inhibitor PLX51107 is now undergoing clinical testing in patients with different advanced cancers, including UM patients (NCT02683395).	('BET', 'Gene', '92737', (93, 96))	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('PLX51107', 'Var', (107, 115))	('cancers', 'Disease', (187, 194))	('BET', 'Gene', (93, 96))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (209, 217))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('PLX51107', 'Chemical', '-', (107, 115))	('rat', 'Species', '10116', (86, 89))	('UM', 'Phenotype', 'HP:0007716', (206, 208))
102633	31216772	The combination of the FGFR inhibitor AZD4547 with PLX51107 inhibited the growth of UM cells co-implanted with human stellate cells in immune-deficient mice.	('FGFR', 'molecular_function', 'GO:0005007', ('23', '27'))	('AZD4547', 'Var', (38, 45))	('FGFR', 'Gene', (23, 27))	('AZD4547', 'Chemical', 'MESH:C572463', (38, 45))	('PLX51107', 'Gene', (51, 59))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('human', 'Species', '9606', (111, 116))	('inhibited', 'NegReg', (60, 69))	('PLX51107', 'Chemical', '-', (51, 59))	('mice', 'Species', '10090', (152, 156))	('growth of UM cells co-implanted', 'CPA', (74, 105))	('combination', 'Interaction', (4, 15))
102635	31216772	Accordingly, UM cells were sensitive to inhibitors of these protein kinases, including the PLK1 inhibitor BI6727 (volasertib).	('BI6727', 'Chemical', 'MESH:C541363', (106, 112))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('PLK1', 'Gene', (91, 95))	('UM', 'Phenotype', 'HP:0007716', (13, 15))	('PLK1', 'Gene', '5347', (91, 95))	('BI6727', 'Var', (106, 112))
102638	31216772	Gene silencing showed an important role of mda-9/syntenin in UM cell migration, invasion, and FAK activation, suggesting that mda-9/syntenin is involved in uveal melanoma progression and may represent a potential therapeutic target.	('Gene silencing', 'biological_process', 'GO:0016458', ('0', '14'))	('uveal melanoma', 'Disease', (156, 170))	('uveal melanoma', 'Disease', 'MESH:C536494', (156, 170))	('Gene silencing', 'Var', (0, 14))	('cell migration', 'biological_process', 'GO:0016477', ('64', '78'))	('syntenin', 'Gene', '6386', (49, 57))	('syntenin', 'Gene', (49, 57))	('rat', 'Species', '10116', (72, 75))	('mda-9', 'Gene', (43, 48))	('involved', 'Reg', (144, 152))	('uveal melanoma', 'Phenotype', 'HP:0007716', (156, 170))	('FAK', 'molecular_function', 'GO:0004717', ('94', '97'))	('mda-9', 'Gene', '6386', (43, 48))	('UM cell migration', 'CPA', (61, 78))	('FAK', 'Gene', (94, 97))	('invasion', 'CPA', (80, 88))	('mda-9', 'Gene', (126, 131))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('syntenin', 'Gene', '6386', (132, 140))	('syntenin', 'Gene', (132, 140))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('FAK', 'Gene', '5747', (94, 97))	('mda-9', 'Gene', '6386', (126, 131))
102645	31216772	Inhibition of MMP14 expression decreased UM cell invasiveness, suggesting that PTP4A3-mediated localization of MMP14 is relevant for metastasis induction.	('PTP4A3', 'Gene', (79, 85))	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('MMP', 'molecular_function', 'GO:0004235', ('14', '17'))	('localization', 'biological_process', 'GO:0051179', ('95', '107'))	('decreased', 'NegReg', (31, 40))	('PTP4A3', 'Gene', '11156', (79, 85))	('MMP14', 'Gene', '4323', (14, 19))	('UM cell invasiveness', 'CPA', (41, 61))	('Inhibition', 'Var', (0, 10))	('MMP14', 'Gene', '4323', (111, 116))	('MMP14', 'Gene', (14, 19))	('MMP', 'molecular_function', 'GO:0004235', ('111', '114'))	('MMP14', 'Gene', (111, 116))
102647	31216772	In addition, ADAM10 silencing inhibits UM cell invasion in vitro, indicating that ADAM10 may contribute to UM progression and may represent a potential target for adjuvant therapy.	('UM', 'Phenotype', 'HP:0007716', (107, 109))	('contribute', 'Reg', (93, 103))	('ADAM10', 'Gene', '102', (82, 88))	('UM cell invasion', 'CPA', (39, 55))	('ADAM10', 'Gene', '102', (13, 19))	('UM', 'Phenotype', 'HP:0007716', (39, 41))	('ADAM10', 'Gene', (82, 88))	('ADAM10', 'Gene', (13, 19))	('silencing', 'Var', (20, 29))	('inhibits', 'NegReg', (30, 38))
102659	31216772	Altogether, these studies support the potential benefit of IGF-1 or IGF-1R blockade in UM therapy.	('IGF-1R', 'Gene', (68, 74))	('UM', 'Phenotype', 'HP:0007716', (87, 89))	('blockade', 'Var', (75, 83))	('IGF-1', 'Gene', '3479', (68, 73))	('IGF-1', 'Gene', (68, 73))	('IGF-1R', 'Gene', '3480', (68, 74))	('IGF-1', 'Gene', '3479', (59, 64))	('IGF-1', 'Gene', (59, 64))	('UM therapy', 'Disease', (87, 97))
102691	31216772	A recent report showed that NAE1 is highly expressed in UM cells, and that blockade of neddylation by the small molecule MLN4924 inhibited the stem-cell phenotype, paracrine secretion of VEGF-C, and angiogenic properties in UM cells.	('inhibited', 'NegReg', (129, 138))	('UM', 'Phenotype', 'HP:0007716', (224, 226))	('NAE1', 'Gene', (28, 32))	('secretion', 'biological_process', 'GO:0046903', ('174', '183'))	('MLN4924', 'Var', (121, 128))	('angiogenic properties', 'CPA', (199, 220))	('VEGF-C', 'Gene', (187, 193))	('UM', 'Phenotype', 'HP:0007716', (56, 58))	('stem-cell phenotype', 'CPA', (143, 162))	('NAE1', 'Gene', '8883', (28, 32))	('VEGF-C', 'Gene', '7424', (187, 193))
102692	31216772	Inhibition of neddylation suppressed the development of hepatic metastases in an UM xenograft model, suggesting that the neddylation pathway represents a new target for the prevention or treatment of metastasis in UM.	('suppressed', 'NegReg', (26, 36))	('development', 'CPA', (41, 52))	('UM', 'Phenotype', 'HP:0007716', (214, 216))	('Inhibition', 'Var', (0, 10))	('neddylation', 'Protein', (14, 25))	('UM', 'Phenotype', 'HP:0007716', (81, 83))	('hepatic metastases', 'Disease', (56, 74))	('hepatic metastases', 'Disease', 'MESH:D009362', (56, 74))
102703	31216772	In particular, the failure of MEK inhibitors to significantly improve survival may relate to the redundancy of signaling pathways downstream the mutated Galpha proteins.	('mutated', 'Var', (145, 152))	('improve', 'PosReg', (62, 69))	('signaling', 'biological_process', 'GO:0023052', ('111', '120'))	('inhibitors', 'Var', (34, 44))	('signaling pathways', 'Pathway', (111, 129))	('survival', 'CPA', (70, 78))	('Galpha', 'Gene', (153, 159))	('MEK', 'Gene', (30, 33))	('Galpha', 'Gene', '8802', (153, 159))	('MEK', 'Gene', '5609', (30, 33))
102704	31216772	Recent preclinical studies provided new chances of directly blocking mutated Galpha proteins activity and their downstream signaling pathways through the natural depsipeptide FR900359, which acts as an allosteric inhibitor of Galpha.	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('Galpha', 'Gene', (77, 83))	('activity', 'MPA', (93, 101))	('mutated', 'Var', (69, 76))	('Galpha', 'Gene', '8802', (226, 232))	('Galpha', 'Gene', (226, 232))	('depsipeptide', 'Chemical', 'MESH:D047630', (162, 174))	('FR900359', 'Var', (175, 183))	('blocking', 'NegReg', (60, 68))	('FR900359', 'Chemical', 'MESH:C000607068', (175, 183))	('Galpha', 'Gene', '8802', (77, 83))
102705	31216772	However, FR900359 is active on both activation-mutated and nonmutated Galpha proteins, raising the question about potential side-effects.	('FR900359', 'Var', (9, 17))	('FR900359', 'Chemical', 'MESH:C000607068', (9, 17))	('Galpha', 'Gene', '8802', (70, 76))	('Galpha', 'Gene', (70, 76))	('activation-mutated', 'PosReg', (36, 54))
102707	31216772	High-risk UM-bearing BAP1 mutation and chromosome 3 monosomy displayed distinct epigenetic and gene expression profiles.	('UM', 'Phenotype', 'HP:0007716', (10, 12))	('mutation', 'Var', (26, 34))	('BAP1', 'Gene', (21, 25))	('gene expression', 'biological_process', 'GO:0010467', ('95', '110'))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))	('BAP1', 'Gene', '8314', (21, 25))
102711	31216772	The possibility to identify high-risk patients through the assessment of monosomy 3, BAP1 status or gene expression profiling opens up the possibility of testing agents inhibiting UM invasiveness and progression in an adjuvant setting.	('BAP1', 'Gene', (85, 89))	('invasiveness', 'CPA', (183, 195))	('UM', 'Phenotype', 'HP:0007716', (180, 182))	('gene expression', 'biological_process', 'GO:0010467', ('100', '115'))	('monosomy 3', 'Var', (73, 83))	('patients', 'Species', '9606', (38, 46))	('BAP1', 'Gene', '8314', (85, 89))	('inhibiting', 'NegReg', (169, 179))
102716	30395583	Loss of BAP1 expression is associated with genetic mutation and can predict outcomes in gallbladder cancer BRCA-1 associated protein (BAP1) is a de-ubiquitinating enzyme that regulates gene expression.	('BAP1', 'Gene', (134, 138))	('gene expression', 'biological_process', 'GO:0010467', ('185', '200'))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('BAP1', 'Gene', '8314', (8, 12))	('gallbladder cancer', 'Disease', (88, 106))	('genetic mutation', 'Var', (43, 59))	('Loss', 'NegReg', (0, 4))	('BRCA-1 associated protein', 'Gene', '8315', (107, 132))	('gallbladder cancer', 'Disease', 'MESH:D005706', (88, 106))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('BAP1', 'Gene', (8, 12))	('BAP1', 'Gene', '8314', (134, 138))	('BRCA-1 associated protein', 'Gene', (107, 132))
102717	30395583	Recently, the BAP1 mutation and its involvement in cancer survival have been reported in a range of tumor types, including uveal melanoma, mesothelioma, renal cancers, and biliary tract cancers.	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('tumor', 'Disease', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('men', 'Species', '9606', (43, 46))	('mesothelioma', 'Disease', (139, 151))	('uveal melanoma', 'Disease', 'MESH:C536494', (123, 137))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('uveal melanoma', 'Disease', (123, 137))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('cancer', 'Disease', (159, 165))	('BAP1', 'Gene', '8314', (14, 18))	('mesothelioma', 'Disease', 'MESH:D008654', (139, 151))	('mutation', 'Var', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('biliary tract cancers', 'Disease', (172, 193))	('renal cancers', 'Disease', (153, 166))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (123, 137))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('BAP1', 'Gene', (14, 18))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (186, 192))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (172, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('renal cancers', 'Disease', 'MESH:D007680', (153, 166))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('biliary tract cancers', 'Disease', 'MESH:D001661', (172, 193))	('reported', 'Reg', (77, 85))
102718	30395583	However, the frequency of BAP1 mutation and down-regulation varies among tumor types, and little is known about the function of BAP1 silencing in cancer cells.	('regulation', 'biological_process', 'GO:0065007', ('49', '59'))	('BAP1', 'Gene', (26, 30))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('BAP1', 'Gene', '8314', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('down-regulation', 'NegReg', (44, 59))	('mutation', 'Var', (31, 39))	('tumor', 'Disease', (73, 78))	('BAP1', 'Gene', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('BAP1', 'Gene', '8314', (26, 30))
102721	30395583	GBC cells were studied by following the small interfering RNA mediated silencing of BAP1 with regard to proliferation, migration, invasion, and drug sensitivity.	('RNA', 'cellular_component', 'GO:0005562', ('58', '61'))	('silencing', 'NegReg', (71, 80))	('BAP1', 'Gene', '8314', (84, 88))	('drug sensitivity', 'Phenotype', 'HP:0020174', (144, 160))	('BAP1', 'Gene', (84, 88))	('small interfering RNA', 'Var', (40, 61))
102722	30395583	We carried out genomic, epigenomic and immunohistochemical analyses to detect somatic BAP1 alterations in 47 GBC patients undergoing surgical resection.	('BAP1', 'Gene', (86, 90))	('alterations', 'Var', (91, 102))	('patients', 'Species', '9606', (113, 121))	('BAP1', 'Gene', '8314', (86, 90))
102723	30395583	BAP1 depletion resulted in increased migration and invasion, but not proliferation, and also resulted in decreased sensitivity to bortezomib, a proteasome inhibitor.	('bortezomib', 'Chemical', 'MESH:D000069286', (130, 140))	('depletion', 'Var', (5, 14))	('increased', 'PosReg', (27, 36))	('BAP1', 'Gene', (0, 4))	('sensitivity to bortezomib', 'MPA', (115, 140))	('migration', 'CPA', (37, 46))	('proteasome', 'cellular_component', 'GO:0000502', ('144', '154'))	('proteasome', 'molecular_function', 'GO:0004299', ('144', '154'))	('invasion', 'CPA', (51, 59))	('BAP1', 'Gene', '8314', (0, 4))	('decreased', 'NegReg', (105, 114))
102725	30395583	Sanger sequencing revealed a loss-of-function mutation of BAP1 in 11 out of these 22 GBC cases (50%) with low BAP1 expression, whereas 2 out of 25 GBC cases (8%) were detected in cases with high BAP1 expression.	('BAP1', 'Gene', '8314', (110, 114))	('BAP1', 'Gene', (195, 199))	('BAP1', 'Gene', (58, 62))	('mutation', 'Var', (46, 54))	('BAP1', 'Gene', (110, 114))	('low', 'NegReg', (106, 109))	('expression', 'MPA', (115, 125))	('GBC', 'Disease', (85, 88))	('BAP1', 'Gene', '8314', (195, 199))	('loss-of-function', 'NegReg', (29, 45))	('BAP1', 'Gene', '8314', (58, 62))
102731	30395583	Recently, various mutations of BAP1 have been found in several tumors, including uveal melanoma (UM), mesothelioma, renal cell carcinoma (RCC), and intrahepatic cholangiocarcinoma (ICC), but the frequency of BAP1 mutations varies widely among different tumor types.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (148, 179))	('renal cell carcinoma', 'Disease', (116, 136))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (116, 136))	('intrahepatic cholangiocarcinoma', 'Disease', (148, 179))	('BAP1', 'Gene', (208, 212))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('RCC', 'Disease', (138, 141))	('BAP1', 'Gene', '8314', (31, 35))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (161, 179))	('tumors', 'Disease', (63, 69))	('uveal melanoma', 'Disease', (81, 95))	('uveal melanoma', 'Disease', 'MESH:C536494', (81, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('found', 'Reg', (46, 51))	('tumor', 'Disease', (63, 68))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('BAP1', 'Gene', (31, 35))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', (253, 258))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (116, 136))	('mesothelioma', 'Disease', (102, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('BAP1', 'Gene', '8314', (208, 212))	('mesothelioma', 'Disease', 'MESH:D008654', (102, 114))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mutations', 'Var', (18, 27))
102732	30395583	detected somatic BAP1 mutations in 50.7% of UM specimens (33 of 65), whereas Nasu M et al detected mutations in 63.6% of mesotheliomas (14 of 22).	('mesotheliomas', 'Disease', 'MESH:D008654', (121, 134))	('men', 'Species', '9606', (52, 55))	('mesotheliomas', 'Disease', (121, 134))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('BAP1', 'Gene', (17, 21))
102733	30395583	reported that BAP1 showed mutations in 11 out of 185 clear cell RCC cases (5.9%).	('BAP1', 'Gene', '8314', (14, 18))	('BAP1', 'Gene', (14, 18))	('mutations', 'Var', (26, 35))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))
102734	30395583	revealed BAP1 mutations in 10 out of 70 ICC cases (14.3%) and 1 out of 26 cases (3.8%) of gallbladder carcinoma (GBC), whereas Jiao.Y et al.	('gallbladder carcinoma', 'Disease', (90, 111))	('ICC', 'Disease', (40, 43))	('BAP1', 'Gene', '8314', (9, 13))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (90, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
102735	30395583	The germline BAP1 mutation is associated with an increased risk of UM, mesothelioma, cutaneous melanoma, meningioma, RCC and MBAITs (melanocytic BAP1-mutated atypical intradermal tumors) and is known as BAP1 hereditary cancer predisposition syndrome.	('RCC', 'Disease', (117, 120))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('MBAITs', 'Disease', (125, 131))	('BAP1', 'Gene', '8314', (13, 17))	('BAP1', 'Gene', (145, 149))	('intradermal tumors', 'Disease', 'MESH:D018330', (167, 185))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('intradermal tumors', 'Disease', (167, 185))	('meningioma', 'Disease', (105, 115))	('meningioma', 'Phenotype', 'HP:0002858', (105, 115))	('mutation', 'Var', (18, 26))	('cutaneous melanoma', 'Disease', (85, 103))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (85, 103))	('BAP1', 'Gene', '8314', (203, 207))	('BAP1', 'Gene', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('meningioma', 'Disease', 'MESH:D008577', (105, 115))	('hereditary cancer', 'Disease', (208, 225))	('mesothelioma', 'Disease', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('mesothelioma', 'Disease', 'MESH:D008654', (71, 83))	('germline', 'Var', (4, 12))	('BAP1', 'Gene', (203, 207))	('BAP1', 'Gene', '8314', (145, 149))	('hereditary cancer', 'Disease', 'MESH:D009369', (208, 225))
102737	30395583	Currently, the relationship between BAP1 mutations and the prognosis of GBC is unknown, and no functional analysis of BAP1 in GBC cell lines has yet been reported.	('mutations', 'Var', (41, 50))	('GBC', 'Disease', (72, 75))	('BAP1', 'Gene', '8314', (36, 40))	('BAP1', 'Gene', '8314', (118, 122))	('BAP1', 'Gene', (36, 40))	('BAP1', 'Gene', (118, 122))
102756	30395583	For the proliferation assay, BAP1 knocked-down GBC cells were seeded on 96-well plates and measured with the MTS assay on days 0, 1, 3, 5, and 7.	('BAP1', 'Gene', '8314', (29, 33))	('knocked-down', 'Var', (34, 46))	('BAP1', 'Gene', (29, 33))
102760	30395583	The BAP1 knocked-down GBC cells that invaded through the pores to the lower surface of the filters after 20 hours were fixed and stained using 1% crystal violet (Wako, Osaka, Japan).	('crystal violet', 'Chemical', 'MESH:D005840', (146, 160))	('GBC cells', 'CPA', (22, 31))	('BAP1', 'Gene', (4, 8))	('BAP1', 'Gene', '8314', (4, 8))	('knocked-down', 'Var', (9, 21))
102779	30395583	This indicated the expression of BAP1 mRNA in G-415 and the down-regulation in OCUG-1.	('expression', 'MPA', (19, 29))	('BAP1', 'Gene', '8314', (33, 37))	('down-regulation', 'NegReg', (60, 75))	('G-415', 'Var', (46, 51))	('regulation', 'biological_process', 'GO:0065007', ('65', '75'))	('BAP1', 'Gene', (33, 37))	('OCUG-1', 'Gene', (79, 85))
102780	30395583	The band of BAP1 was observed strongly in G-415 but hardly recognized in OCUG-1 (S2 Fig).	('BAP1', 'Gene', (12, 16))	('G-415', 'Var', (42, 47))	('BAP1', 'Gene', '8314', (12, 16))
102786	30395583	To investigate the change in cell proliferation by the down-regulation of BAP1, MTS assay was performed on BAP1 knocked-down G-415 cells.	('BAP1', 'Gene', '8314', (107, 111))	('knocked-down', 'Var', (112, 124))	('regulation', 'biological_process', 'GO:0065007', ('60', '70'))	('BAP1', 'Gene', (107, 111))	('BAP1', 'Gene', '8314', (74, 78))	('cell proliferation', 'biological_process', 'GO:0008283', ('29', '47'))	('BAP1', 'Gene', (74, 78))	('down-regulation', 'NegReg', (55, 70))
102788	30395583	To investigate the migratory ability of the BAP1 down-regulated cells, scratch assay was performed on BAP1 knocked-down G-415 cells (Fig 2A).	('BAP1', 'Gene', (102, 106))	('BAP1', 'Gene', '8314', (44, 48))	('BAP1', 'Gene', '8314', (102, 106))	('knocked-down', 'Var', (107, 119))	('BAP1', 'Gene', (44, 48))
102790	30395583	To investigate the invasive ability, invasion assay using a Matrigel invasion chamber was performed on BAP1 knocked-down G-415 cells (Fig 3A).	('BAP1', 'Gene', '8314', (103, 107))	('BAP1', 'Gene', (103, 107))	('knocked-down', 'Var', (108, 120))
102792	30395583	We suspected that the main mechanism of the enhanced ability of migration and invasion in BAP1 knocked-down GBC cells was epithelial mesenchymal transition (EMT).	('knocked-down', 'Var', (95, 107))	('epithelial mesenchymal transition', 'CPA', (122, 155))	('BAP1', 'Gene', '8314', (90, 94))	('EMT', 'biological_process', 'GO:0001837', ('157', '160'))	('BAP1', 'Gene', (90, 94))	('epithelial mesenchymal transition', 'biological_process', 'GO:0001837', ('122', '155'))	('enhanced', 'PosReg', (44, 52))
102794	30395583	Compared to the control group, no difference was observed in the expression of E-cadherin or vimentin in BAP1 knocked-down G-415 cells (S4 Fig).	('vimentin', 'Gene', '7431', (93, 101))	('vimentin', 'Gene', (93, 101))	('BAP1', 'Gene', '8314', (105, 109))	('E-cadherin', 'Gene', (79, 89))	('knocked-down', 'Var', (110, 122))	('vimentin', 'cellular_component', 'GO:0045099', ('93', '101'))	('E-cadherin', 'Gene', '999', (79, 89))	('cadherin', 'molecular_function', 'GO:0008014', ('81', '89'))	('BAP1', 'Gene', (105, 109))	('vimentin', 'cellular_component', 'GO:0045098', ('93', '101'))
102798	30395583	A significant decrease in susceptibility to bortezomib, a proteosome inhibitor, was observed in BAP1 knocked-down cells compared with the control group (control vs siRNA1; p < 0.001, control vs siRNA2; p < 0.001, Fig 4F).	('knocked-down', 'Var', (101, 113))	('bortezomib', 'Chemical', 'MESH:D000069286', (44, 54))	('BAP1', 'Gene', (96, 100))	('decrease', 'NegReg', (14, 22))	('susceptibility', 'MPA', (26, 40))	('BAP1', 'Gene', '8314', (96, 100))
102799	30395583	Immunohistochemistry of BAP1 in 47 cases of GBC revealed 25 cases with high BAP1 expression and 22 cases with low BAP1 expression (Table 1).	('high', 'Var', (71, 75))	('BAP1', 'Gene', (24, 28))	('BAP1', 'Gene', '8314', (76, 80))	('BAP1', 'Gene', '8314', (114, 118))	('BAP1', 'Gene', '8314', (24, 28))	('BAP1', 'Gene', (76, 80))	('BAP1', 'Gene', (114, 118))	('expression', 'MPA', (81, 91))
102800	30395583	The average age was 68 (46-86) years in the high BAP1 expression group (BAP1-H), 69.1 (46-83) years in the low BAP1 expression group (BAP1-L), and there was no significant difference (p = 0.71).	('high', 'Var', (44, 48))	('BAP1', 'Gene', (134, 138))	('BAP1', 'Gene', '8314', (111, 115))	('BAP1', 'Gene', '8314', (72, 76))	('BAP1', 'Gene', (49, 53))	('BAP1', 'Gene', (72, 76))	('BAP1', 'Gene', (111, 115))	('BAP1', 'Gene', '8314', (134, 138))	('BAP1', 'Gene', '8314', (49, 53))
102812	30395583	Representative examples of BAP1 mutation and BAP1 expression are shown in Fig 6 and S6 Fig.	('BAP1', 'Gene', (45, 49))	('BAP1', 'Gene', (27, 31))	('BAP1', 'Gene', '8314', (45, 49))	('mutation', 'Var', (32, 40))	('BAP1', 'Gene', '8314', (27, 31))
102814	30395583	The mutations found in the BAP1-H group were: ID2, c.705C>A (p.Pro235 = ), and c.2166C>A (p.Arg722 = ); ID3, c.651C>T (p.Ala217 = ); ID6, c.747G>A (p.Lys249 = ); ID10, c.591G>A (p.Gly197 = ); ID16, c.652A>T (p.Thr218Ser), and c.1219G>T (p.Asp407Tyr); ID38, c.1012C>T (p.Pro338Ser), c.1020C>T (p.Gly340Gly), and c.1024A>T (p.Ser342Cys); ID45, c.249C>T (p.Ala83 = ).	('Ser', 'cellular_component', 'GO:0005790', ('216', '219'))	('c.1020C>T', 'Mutation', 'c.1020C>T', (282, 291))	('p.Pro235 =', 'Mutation', 'p.P235=', (61, 71))	('c.249C>T', 'Mutation', 'rs764485127', (342, 350))	('p.Pro338Ser', 'Mutation', 'rs761029538', (268, 279))	('p.Lys249 =', 'Mutation', 'p.K249=', (148, 158))	('p.Ala217 =', 'Mutation', 'rs202170860', (119, 129))	('c.2166C>A', 'Mutation', 'c.2166C>A', (79, 88))	('ID3', 'Gene', (104, 107))	('ID3', 'Gene', '3399', (251, 254))	('c.1219G>T', 'Mutation', 'c.1219G>T', (226, 235))	('p.Gly340Gly', 'Var', (293, 304))	('p.Gly197 =', 'Mutation', 'p.G197=', (178, 188))	('Ala83', 'Chemical', '-', (354, 359))	('BAP1', 'Gene', '8314', (27, 31))	('p.Arg722 =', 'Mutation', 'p.R722=', (90, 100))	('c.249C>T', 'Var', (342, 350))	('p.Ser342Cys', 'Mutation', 'p.S342C', (322, 333))	('c.1020C>T', 'Var', (282, 291))	('c.747G>A', 'Mutation', 'c.747G>A', (138, 146))	('Ser', 'cellular_component', 'GO:0005790', ('276', '279'))	('c.652A>T', 'Mutation', 'c.652A>T', (198, 206))	('ID4', 'Gene', (336, 339))	('ID4', 'Gene', '3400', (336, 339))	('c.1219G>T', 'Var', (226, 235))	('ID3', 'Gene', (251, 254))	('c.1012C>T', 'Var', (257, 266))	('ID2', 'Gene', '3398', (46, 49))	('c.705C>A', 'Mutation', 'c.705C>A', (51, 59))	('ID2', 'Gene', (46, 49))	('BAP1', 'Gene', (27, 31))	('c.591G>A', 'Mutation', 'c.591G>A', (168, 176))	('p.Asp407Tyr', 'Mutation', 'p.D407Y', (237, 248))	('c.651C>T', 'Mutation', 'rs202170860', (109, 117))	('Ser', 'cellular_component', 'GO:0005790', ('324', '327'))	('c.1024A>T', 'Mutation', 'c.1024A>T', (311, 320))	('ID3', 'Gene', '3399', (104, 107))	('c.1012C>T', 'Mutation', 'rs761029538', (257, 266))	('c.1024A>T', 'Var', (311, 320))	('c.2166C>A', 'Var', (79, 88))	('p.Thr218Ser', 'Mutation', 'p.T218S', (208, 219))	('p.Gly340Gly', 'SUBSTITUTION', 'None', (293, 304))
102816	30395583	On the other hand, the mutations in the BAP1-L group were: ID11, c.163G>T (p.Glu55Ter), and c.747G>A (p. Lys249 = ); ID12, c.128T>A (p.Val43Glu), c.197T>A (p.Val66Glu), and c.587G>A (p.Trp196Ter); ID14, c.616G>A (p.Ala206Thr), c.697_698delinsTA (p.Val233Ter), and c.1729G>T (p.Glu577Ter); ID17, c.232A>T (p.Asn78Tyr), c.243C>A (p.Phe81Leu), c.985C>T (p.Pro329Ser), c.1021A>T (p.His341Leu) and c.1903C>A (p. Leu 635Met); ID18, c.996C>T (p.Pro332 = ); ID19, c.1027C>A (p.Leu343Ile), and c.1048C>A (p.Pro350Thr); ID24, c.733C>T (p.Leu245 = ) and c.1036G>T (p.Val346Phe); ID28, c.746_747delinsTA (p.Lys249Ile); ID32, c.4_5insC c.9_10GG>TA (p.Asn2ThrfsTer3) and c.1831G>T (p.Glu611Ter); ID35, c.131A>T (p.Tyr44Phe), and c.1002A>G (p.Leu334 = ); ID40, c.721T>A (p.Tyr241Asn), and c.746_747delinsTA (p.Lys249Ile); ID46, c.965A>T (p.Gln322Leu).	('Ser', 'cellular_component', 'GO:0005790', ('359', '362'))	('ID4', 'Gene', (807, 810))	('p.Glu577Ter', 'Mutation', 'rs397508903', (275, 286))	('ID4', 'Gene', '3400', (807, 810))	('BAP1', 'Gene', (40, 44))	('c.163G>T', 'Mutation', 'rs765090650', (65, 73))	('c.4_5insC', 'Var', (613, 622))	('ID3', 'Gene', '3399', (682, 685))	('ID2', 'Gene', (510, 513))	('p.Val43Glu', 'Mutation', 'rs752628149', (133, 143))	('Ter', 'cellular_component', 'GO:0097047', ('191', '194'))	('c.747G>A', 'Mutation', 'c.747G>A', (92, 100))	('c.131A>T', 'Mutation', 'rs372117829', (688, 696))	('p.Asn78Tyr', 'Mutation', 'rs1206609823', (305, 315))	('c.1002A>G', 'Var', (715, 724))	('p.Tyr241Asn', 'Mutation', 'p.Y241N', (756, 767))	('c.9_10GG>TA', 'Var', (623, 634))	('p.Asn2Thr', 'Var', (636, 645))	('p.Glu611Ter', 'Mutation', 'p.E611X', (668, 679))	('p.Lys249Ile', 'Mutation', 'p.K249I', (593, 604))	('c.4_5insC', 'INSERTION', 'None', (613, 622))	('ID2', 'Gene', (568, 571))	('c.1027C>A', 'Mutation', 'c.1027C>A', (456, 465))	('c.721T>A', 'Var', (746, 754))	('p. Lys249 =', 'Mutation', 'p.K249=', (102, 113))	('Ter', 'cellular_component', 'GO:0097047', ('676', '679'))	('p.Leu343Ile', 'Mutation', 'p.L343I', (467, 478))	('c.746_747delinsTA', 'Var', (774, 791))	('c.746_747delinsTA', 'Mutation', 'c.746_747delinsTA', (574, 591))	('Leu334', 'Chemical', '-', (728, 734))	('Ter', 'cellular_component', 'GO:0097047', ('283', '286'))	('Leu 635Met', 'SUBSTITUTION', 'None', (407, 417))	('c.996C>T', 'Mutation', 'rs730881445', (426, 434))	('c.587G>A', 'Mutation', 'rs786202232', (173, 181))	('p.Pro329Ser', 'Mutation', 'rs769493354', (351, 362))	('c.985C>T', 'Mutation', 'rs1281904866', (341, 349))	('ID3', 'Gene', (682, 685))	('p.Phe81Leu', 'Mutation', 'p.F81L', (328, 338))	('c.243C>A', 'Mutation', 'c.243C>A', (318, 326))	('p.Pro350Thr', 'Mutation', 'rs1458757274', (496, 507))	('c.9_10GG>TA', 'SUBSTITUTION', 'None', (623, 634))	('c.721T>A', 'Mutation', 'c.721T>A', (746, 754))	('p.Asn2Thr', 'SUBSTITUTION', 'None', (636, 645))	('ID2', 'Gene', '3398', (568, 571))	('c.616G>A', 'Mutation', 'rs142328046', (203, 211))	('p.Val346Phe', 'Mutation', 'p.V346F', (554, 565))	('c.1002A>G', 'Mutation', 'rs28997577', (715, 724))	('ID2', 'Gene', '3398', (510, 513))	('c.697_698delinsTA', 'Mutation', 'c.697_698delinsTA', (227, 244))	('c.1831G>T', 'Mutation', 'c.1831G>T', (657, 666))	('p.His341Leu', 'Mutation', 'p.H341L', (376, 387))	('c.1831G>T', 'Var', (657, 666))	('c.1048C>A', 'Mutation', 'rs1458757274', (485, 494))	('ID3', 'Gene', '3399', (607, 610))	('c.128T>A', 'Mutation', 'rs752628149', (123, 131))	('p.Glu55Ter', 'Mutation', 'rs765090650', (75, 85))	('ID4', 'Gene', '3400', (740, 743))	('p.Trp196Ter', 'Mutation', 'rs786202232', (183, 194))	('c.965A>T', 'Mutation', 'c.965A>T', (813, 821))	('p.Val233Ter', 'Mutation', 'p.V233X', (246, 257))	('p.Leu245 =', 'Mutation', 'rs587781430', (526, 536))	('c.733C>T', 'Mutation', 'rs587781430', (516, 524))	('Leu 635Met', 'Var', (407, 417))	('c.1036G>T', 'Mutation', 'c.1036G>T', (543, 552))	('c.197T>A', 'Mutation', 'c.197T>A', (146, 154))	('Ter', 'cellular_component', 'GO:0097047', ('254', '257'))	('p.Gln322Leu', 'Mutation', 'p.Q322L', (823, 834))	('c.965A>T', 'Var', (813, 821))	('c.1903C>A', 'Mutation', 'c.1903C>A', (393, 402))	('Ter', 'cellular_component', 'GO:0097047', ('82', '85'))	('ID4', 'Gene', (740, 743))	('p.Lys249Ile', 'Mutation', 'p.K249I', (793, 804))	('c.232A>T', 'Mutation', 'rs1206609823', (295, 303))	('c.1021A>T', 'Mutation', 'c.1021A>T', (365, 374))	('p.Val66Glu', 'Mutation', 'p.V66E', (156, 166))	('BAP1', 'Gene', '8314', (40, 44))	('c.131A>T', 'Var', (688, 696))	('p.Tyr44Phe', 'Mutation', 'rs372117829', (698, 708))	('p.Ala206Thr', 'Mutation', 'rs771852699', (213, 224))	('ID3', 'Gene', (607, 610))	('c.746_747delinsTA', 'Mutation', 'c.746_747delinsTA', (774, 791))	('c.1729G>T', 'Mutation', 'rs397508903', (264, 273))
102817	30395583	The genetic mutations affecting the protein expression of BAP1 were significantly higher in the BAP1-L group (11 cases, 50%) than in the BAP1-H group (2 cases, 8%) (p = 0.003).	('BAP1', 'Gene', (137, 141))	('BAP1', 'Gene', (96, 100))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('BAP1', 'Gene', (58, 62))	('higher', 'PosReg', (82, 88))	('genetic mutations', 'Var', (4, 21))	('BAP1', 'Gene', '8314', (137, 141))	('protein expression', 'MPA', (36, 54))	('BAP1', 'Gene', '8314', (96, 100))	('BAP1', 'Gene', '8314', (58, 62))
102818	30395583	Synonymous substitution mutations found in three cases of the BAP1-H group and two cases of the BAP1-L group are reported in polymorphic databases (dbSNP http://www.ncbi.nlm.nih In .gov / projects / SNP /); these were thought to be single-nucleotide polymorphisms (SNPs).	('Synonymous substitution mutations', 'Var', (0, 33))	('BAP1', 'Gene', '8314', (62, 66))	('BAP1', 'Gene', (96, 100))	('BAP1', 'Gene', (62, 66))	('BAP1', 'Gene', '8314', (96, 100))
102820	30395583	The summary of mutations and homozygous deletion in the 47 cases of GBC patients are shown in Table 3.	('GBC', 'Disease', (68, 71))	('mutations', 'Var', (15, 24))	('patients', 'Species', '9606', (72, 80))
102822	30395583	In the clinical specimens of GBC, 41 of 47 cases did not show bands for the M product (S7A Fig) and the other six showed weak bands for the M product (ID4, ID6, ID25, ID39, ID40, ID43) (S7B Fig), suggesting that partial methylation had occurred.	('ID4', 'Gene', (173, 176))	('ID4', 'Gene', '3400', (173, 176))	('ID3', 'Gene', '3399', (167, 170))	('clinical', 'Species', '191496', (7, 15))	('ID2', 'Gene', '3398', (161, 164))	('ID4', 'Gene', '3400', (151, 154))	('ID2', 'Gene', (161, 164))	('ID4', 'Gene', '3400', (179, 182))	('methylation', 'biological_process', 'GO:0032259', ('220', '231'))	('ID4', 'Gene', (179, 182))	('ID4', 'Gene', (151, 154))	('ID3', 'Gene', (167, 170))	('men', 'Species', '9606', (21, 24))	('ID6', 'Var', (156, 159))
102826	30395583	The expression level of BAP1 in OCUG-1 after demethylation was 1.83 +- 0.35 fold higher than that in the control (S8 Fig).	('expression level', 'MPA', (4, 20))	('BAP1', 'Gene', (24, 28))	('higher', 'PosReg', (81, 87))	('demethylation', 'biological_process', 'GO:0070988', ('45', '58'))	('demethylation', 'Var', (45, 58))	('BAP1', 'Gene', '8314', (24, 28))
102827	30395583	The suppressed expression of BAP1 in OCUG-1 was therefore thought to be due to methylation.	('OCUG-1', 'Gene', (37, 43))	('BAP1', 'Gene', '8314', (29, 33))	('suppressed', 'NegReg', (4, 14))	('expression', 'MPA', (15, 25))	('methylation', 'Var', (79, 90))	('methylation', 'biological_process', 'GO:0032259', ('79', '90'))	('BAP1', 'Gene', (29, 33))
102831	30395583	In our study by knocking-down the expression of BAP1 by siRNA, the cell proliferation ability did not change, while the migratory and invasive abilities were enhanced, though we use one kind of GBC cell line.	('BAP1', 'Gene', '8314', (48, 52))	('enhanced', 'PosReg', (158, 166))	('knocking-down', 'Var', (16, 29))	('BAP1', 'Gene', (48, 52))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('cell proliferation', 'CPA', (67, 85))
102837	30395583	The mechanism involved in the acquisition of tolerance to bortezomib has not been clarified, but the involvement of mutations of proteasome and chaperones in the endoplasmic reticulum has been reported in multiple myeloma.	('involvement', 'Reg', (101, 112))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('162', '183'))	('proteasome', 'molecular_function', 'GO:0004299', ('129', '139'))	('men', 'Species', '9606', (108, 111))	('proteasome', 'cellular_component', 'GO:0000502', ('129', '139'))	('multiple myeloma', 'Phenotype', 'HP:0006775', (205, 221))	('bortezomib', 'Chemical', 'MESH:D000069286', (58, 68))	('multiple myeloma', 'Disease', 'MESH:D009101', (205, 221))	('multiple myeloma', 'Disease', (205, 221))	('reported', 'Reg', (193, 201))	('mutations', 'Var', (116, 125))
102840	30395583	The frequency of mutation affecting protein expression in GBC detected in our study (8% in the BAP1-H group, 50% in the BAP1-L group, 27.6% in total) is higher than in previous reports (13%, 3.8%).	('BAP1', 'Gene', (95, 99))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('mutation', 'Var', (17, 25))	('GBC', 'Gene', (58, 61))	('BAP1', 'Gene', '8314', (120, 124))	('BAP1', 'Gene', '8314', (95, 99))	('protein expression', 'MPA', (36, 54))	('BAP1', 'Gene', (120, 124))
102841	30395583	The detected mutations tended to be more common in the first half of BAP1, which contains domains such as UCH domain and BRCA 1 associated RING domain 1 (BARD 1) binding domain.	('binding', 'molecular_function', 'GO:0005488', ('162', '169'))	('BAP1', 'Gene', (69, 73))	('common', 'Reg', (41, 47))	('mutations', 'Var', (13, 22))	('BAP1', 'Gene', '8314', (69, 73))
102844	30395583	Accordingly, it is speculated that mutations involved particularly in these regions greatly affect the decrease in the functional expression of BAP1.	('BAP1', 'Gene', (144, 148))	('functional expression', 'MPA', (119, 140))	('mutations', 'Var', (35, 44))	('decrease', 'NegReg', (103, 111))	('BAP1', 'Gene', '8314', (144, 148))
102845	30395583	FFPE samples show frequent sequence changes due to DNA damage resulting from formalin fixation and storage, most commonly manifesting as a cytosine to thymine transition caused by the deamination of cytosine (artifactual C>T and G>A transitions).	('cytosine', 'Chemical', 'MESH:D003596', (139, 147))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('storage', 'biological_process', 'GO:0051235', ('99', '106'))	('formalin', 'Chemical', 'MESH:D005557', (77, 85))	('deamination', 'MPA', (184, 195))	('thymine', 'Chemical', 'MESH:D013941', (151, 158))	('cytosine', 'Chemical', 'MESH:D003596', (199, 207))	('C>T', 'Var', (221, 224))	('cytosine to thymine transition', 'MPA', (139, 169))
102848	30395583	As for methylation, it might suppress the expression of BAP1 in OCUG-1 but, in clinical samples, methylation was occasional and weak and did not correlate with the BAP1 expression or prognosis of GBC.	('clinical samples', 'Species', '191496', (79, 95))	('suppress', 'NegReg', (29, 37))	('BAP1', 'Gene', '8314', (56, 60))	('expression', 'MPA', (42, 52))	('BAP1', 'Gene', (164, 168))	('methylation', 'Var', (7, 18))	('BAP1', 'Gene', (56, 60))	('methylation', 'biological_process', 'GO:0032259', ('97', '108'))	('BAP1', 'Gene', '8314', (164, 168))	('methylation', 'biological_process', 'GO:0032259', ('7', '18'))
102851	30395583	Although we could not demonstrate that the cause of low BAP1 expression was comprehensively analyzed, our study has revealed that genomic mutations of BAP1 are strongly related to the suppression of BAP1 expression in GBC.	('BAP1', 'Gene', (151, 155))	('BAP1', 'Gene', (199, 203))	('BAP1', 'Gene', '8314', (56, 60))	('suppression', 'NegReg', (184, 195))	('BAP1', 'Gene', (56, 60))	('expression', 'MPA', (204, 214))	('BAP1', 'Gene', '8314', (151, 155))	('BAP1', 'Gene', '8314', (199, 203))	('mutations', 'Var', (138, 147))
102852	30395583	Our study suggests that the suppressed expression of BAP1 mainly due to genetic mutations promotes the migratory and invasive ability of GBC cells and consequently correlates with a poor prognosis.	('suppressed', 'NegReg', (28, 38))	('BAP1', 'Gene', '8314', (53, 57))	('expression', 'MPA', (39, 49))	('promotes', 'PosReg', (90, 98))	('genetic mutations', 'Var', (72, 89))	('BAP1', 'Gene', (53, 57))
102951	28487752	Fine needle aspiration (FNA) confirmed melanoma with inactivation of the BAP1 gene.	('BAP1', 'Gene', '8314', (73, 77))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('aspiration', 'Phenotype', 'HP:0002835', (12, 22))	('melanoma', 'Disease', (39, 47))	('BAP1', 'Gene', (73, 77))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('inactivation', 'Var', (53, 65))
102957	28487752	Risk factors for uveal melanomas are predominantly non-modifiable, and include Caucasian descent, lighter iris colour, and inactivation of the BAP1 gene occurring in 84% of metastasising tumours.	('BAP1', 'Gene', (143, 147))	('inactivation', 'Var', (123, 135))	('tumours', 'Disease', 'MESH:D009369', (187, 194))	('uveal melanomas', 'Disease', (17, 32))	('uveal melanomas', 'Phenotype', 'HP:0007716', (17, 32))	('tumours', 'Disease', (187, 194))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('BAP1', 'Gene', '8314', (143, 147))	('lighter iris colour', 'Phenotype', 'HP:0007730', (98, 117))	('uveal melanomas', 'Disease', 'MESH:C536494', (17, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))
102962	28487752	FNA confirmed melanoma with a mix of oval spindle and polyhedral epithelioid cells, and an inactivation of the BAP1 gene (Figures 4 and 5).	('melanoma', 'Disease', (14, 22))	('BAP1', 'Gene', '8314', (111, 115))	('spindle', 'cellular_component', 'GO:0005819', ('42', '49'))	('BAP1', 'Gene', (111, 115))	('inactivation', 'Var', (91, 103))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
102965	28487752	Malignancies without BAP1 inactivation generally have a favourable prognosis because of their lower rates of visual morbidity and metastasis and a five-year mortality rate of 2%-3%.	('inactivation', 'Var', (26, 38))	('BAP1', 'Gene', (21, 25))	('Malignancies', 'Disease', 'MESH:D009369', (0, 12))	('lower', 'NegReg', (94, 99))	('Malignancies', 'Disease', (0, 12))	('visual morbidity', 'CPA', (109, 125))	('BAP1', 'Gene', '8314', (21, 25))
102979	27660484	In recent years, germline mutations in the BAP1 gene have been found to segregate in an autosomal dominant pattern with numerous different cancer types including UM in cancer-prone families.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('BAP1', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('UM', 'Phenotype', 'HP:0007716', (162, 164))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('germline mutations', 'Var', (17, 35))	('BAP1', 'Gene', '8314', (43, 47))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', (139, 145))
102992	27660484	The frequency of predicted pathogenic germline BAP1 mutations observed in different cohorts of UM patients ranges from 1.6% to 3%, with mutations predominantly found in patients with a family history of UM.	('mutations', 'Var', (52, 61))	('patients', 'Species', '9606', (169, 177))	('found', 'Reg', (160, 165))	('patients', 'Species', '9606', (98, 106))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('BAP1', 'Gene', '8314', (47, 51))	('UM', 'Phenotype', 'HP:0007716', (203, 205))	('BAP1', 'Gene', (47, 51))	('pathogenic', 'Reg', (27, 37))
102993	27660484	The cancer risk mediated by germline BAP1 mutations is inherited in an autosomal dominant pattern with incomplete penetrance.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('BAP1', 'Gene', '8314', (37, 41))	('mutations', 'Var', (42, 51))	('germline', 'Var', (28, 36))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('BAP1', 'Gene', (37, 41))	('cancer', 'Disease', (4, 10))
102995	27660484	While carrying a germline mutation in the CDKN2A gene is the strongest known inherited risk factor for CM, such mutations do not seem to increase the risk of UM.	('CM', 'Phenotype', 'HP:0012056', (103, 105))	('CDKN2A', 'Gene', (42, 48))	('UM', 'Phenotype', 'HP:0007716', (158, 160))	('CDKN2A', 'Gene', '1029', (42, 48))	('germline mutation', 'Var', (17, 34))
102996	27660484	Poor prognosis and high risk of metastatic disease are often accompanied with loss of chromosome 3 in the tumor, while tumors with intact chromosome 3 correlates with good prognosis and rarely leads to disseminated disease.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', (119, 124))	('metastatic disease', 'CPA', (32, 50))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('chromosome', 'cellular_component', 'GO:0005694', ('138', '148'))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('chromosome', 'cellular_component', 'GO:0005694', ('86', '96'))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('loss', 'Var', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', (106, 111))
102997	27660484	The metastatic rate for tumors with partial loss of chromosome 3 has shown a great variation depending on the study (ranging from 0% to 48%).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('chromosome', 'cellular_component', 'GO:0005694', ('52', '62'))	('metastatic', 'CPA', (4, 14))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Disease', (24, 30))	('partial loss', 'Var', (36, 48))
102998	27660484	Loss of chromosome 1 or parts of this chromosome is also frequent aberration, affecting ~25% of all tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('chromosome', 'cellular_component', 'GO:0005694', ('38', '48'))	('Loss', 'Var', (0, 4))
103001	27660484	Inactivation of CDKN2A may be part of UM pathogenesis, either through methylation of the CDKN2A promotor region or through loss of chromosome 9p or a smaller region surrounding the 9p21, harboring the CDKN2A locus.	('p21', 'Gene', (182, 185))	('p21', 'Gene', '644914', (182, 185))	('CDKN2A', 'Gene', (201, 207))	('CDKN2A', 'Gene', '1029', (201, 207))	('chromosome', 'cellular_component', 'GO:0005694', ('131', '141'))	('methylation', 'biological_process', 'GO:0032259', ('70', '81'))	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('pathogenesis', 'biological_process', 'GO:0009405', ('41', '53'))	('CDKN2A', 'Gene', (89, 95))	('loss', 'NegReg', (123, 127))	('methylation', 'Var', (70, 81))	('CDKN2A', 'Gene', '1029', (89, 95))	('UM', 'Phenotype', 'HP:0007716', (38, 40))	('Inactivation', 'Var', (0, 12))
103002	27660484	Both promotor methylation and chromosomal loss affect up to one-third of the tumors each.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('chromosomal loss', 'Var', (30, 46))	('affect', 'Reg', (47, 53))	('methylation', 'Var', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))
103004	27660484	Mutations in the genes encoding for these proteins, RB1 and TP53, are infrequent in UM tumors suggesting other ways of inactivation.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RB1', 'Gene', (52, 55))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('RB1', 'Gene', '5925', (52, 55))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (60, 64))	('tumors', 'Disease', (87, 93))	('TP53', 'Gene', (60, 64))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
103006	27660484	Also, constitutively activation of the PI3K/AKT pathway and inactivation of the tumor suppressor PTEN (mainly by LOH of the PTEN locus) are common events in UM tumors.	('PI3K', 'molecular_function', 'GO:0016303', ('39', '43'))	('PTEN', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))	('PTEN', 'Gene', '5728', (124, 128))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('AKT', 'Gene', (44, 47))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('PTEN', 'Gene', (97, 101))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('PTEN', 'Gene', '5728', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('AKT', 'Gene', '207', (44, 47))	('inactivation', 'MPA', (60, 72))	('activation', 'PosReg', (21, 31))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('UM', 'Phenotype', 'HP:0007716', (157, 159))	('LOH', 'Var', (113, 116))
103008	27660484	Also the mutational load in UM tumors is low, and the mean mutation rate of UM tumors has been determined to be around 0.5 per Mb sequence, both concerning genomic and protein coding regions.	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('UM', 'Phenotype', 'HP:0007716', (28, 30))	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('mutational', 'Var', (9, 19))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
103009	27660484	In UM tumors, several frequent driver mutations have been described, none of them being described as key drivers in other melanoma subtypes.	('melanoma subtypes', 'Disease', (122, 139))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('melanoma subtypes', 'Disease', 'MESH:D008545', (122, 139))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('mutations', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
103014	27660484	Loss of chromosome 3 was for a long time the best predictor for metastatic disease in UM patients.	('UM', 'Phenotype', 'HP:0007716', (86, 88))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('metastatic disease', 'CPA', (64, 82))	('patients', 'Species', '9606', (89, 97))	('Loss', 'Var', (0, 4))
103016	27660484	Using next-generation sequencing, it was discovered that a vast majority of the class 2 tumors carried a mutation in the BAP1 gene, mapped to chromosome 3p21.1, while very few of the class 1 tumors harbored a mutation in this gene.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('mutation', 'Var', (105, 113))	('BAP1', 'Gene', '8314', (121, 125))	('chromosome', 'cellular_component', 'GO:0005694', ('142', '152'))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('BAP1', 'Gene', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('carried', 'Reg', (95, 102))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('p21', 'Gene', (154, 157))	('p21', 'Gene', '644914', (154, 157))	('tumors', 'Disease', (191, 197))
103017	27660484	Thus, inactivating hemizygous mutations of BAP1 leads to protein inactivation and loss of BAP1 expression.	('BAP1', 'Gene', (43, 47))	('inactivation', 'NegReg', (65, 77))	('BAP1', 'Gene', '8314', (90, 94))	('protein', 'MPA', (57, 64))	('BAP1', 'Gene', '8314', (43, 47))	('inactivating hemizygous mutations', 'Var', (6, 39))	('BAP1', 'Gene', (90, 94))	('loss', 'NegReg', (82, 86))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('expression', 'MPA', (95, 105))
103018	27660484	This implicate BAP1 to function as a tumor suppressor gene, with loss of one copy of chromosome 3 and mutation in the other allele, fulfilling the Knudsen two hits hypothesis definition of a tumor suppressor gene.	('loss', 'NegReg', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('mutation', 'Var', (102, 110))	('chromosome', 'cellular_component', 'GO:0005694', ('85', '95'))	('BAP1', 'Gene', '8314', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('tumor suppressor', 'biological_process', 'GO:0051726', ('191', '207'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('37', '53'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('191', '207'))	('BAP1', 'Gene', (15, 19))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('37', '53'))	('implicate', 'Reg', (5, 14))
103020	27660484	BAP1 mutations strongly correlate with metastatic disease in UM; over 80% of metastasizing UM has been found to carry a mutation in this gene.	('metastatic disease', 'Disease', (39, 57))	('BAP1', 'Gene', (0, 4))	('mutation', 'Var', (120, 128))	('mutations', 'Var', (5, 14))	('UM', 'Phenotype', 'HP:0007716', (91, 93))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('metastasizing UM', 'Disease', (77, 93))	('BAP1', 'Gene', '8314', (0, 4))
103021	27660484	The frequency of BAP1 mutations in primary UM has been estimated to be approximately 30%-40%.	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('primary UM', 'Disease', (35, 45))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('BAP1', 'Gene', (17, 21))
103022	27660484	Most of the BAP1 mutations are truncating variants or missense variants affecting the ubiquitin carboxyl-terminal hydrolase domain.	('ubiquitin carboxyl-terminal hydrolase domain', 'MPA', (86, 130))	('ubiquitin', 'molecular_function', 'GO:0031386', ('86', '95'))	('BAP1', 'Gene', '8314', (12, 16))	('affecting', 'Reg', (72, 81))	('missense', 'Var', (54, 62))	('BAP1', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
103023	27660484	In some cases, BAP1 is not altered by a sequence mutation but by hemizygous deletion of one or more exons.	('BAP1', 'Gene', '8314', (15, 19))	('deletion', 'Var', (76, 84))	('BAP1', 'Gene', (15, 19))
103024	27660484	Loss of BAP1 expression using IHC has strongly been correlated with risk of metastasis, BAP1 mutation status, and loss of chromosome 3 and has, therefore, been proposed as a valid prognostic test.	('metastasis', 'CPA', (76, 86))	('mutation status', 'Var', (93, 108))	('expression', 'MPA', (13, 23))	('BAP1', 'Gene', '8314', (8, 12))	('chromosome', 'cellular_component', 'GO:0005694', ('122', '132'))	('Loss', 'NegReg', (0, 4))	('BAP1', 'Gene', '8314', (88, 92))	('BAP1', 'Gene', (8, 12))	('BAP1', 'Gene', (88, 92))
103025	27660484	BAP1 is also frequently mutated in other tumor types, including cholangiocarcinoma, renal cell carcinoma, mesothelioma, and bladder cancer (www.cbioportal.org).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutated', 'Var', (24, 31))	('renal cell carcinoma', 'Disease', (84, 104))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (84, 104))	('mesothelioma', 'Disease', (106, 118))	('BAP1', 'Gene', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (106, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('tumor', 'Disease', (41, 46))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (64, 82))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (84, 104))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('cholangiocarcinoma', 'Disease', (64, 82))	('bladder cancer', 'Disease', 'MESH:D001749', (124, 138))	('bladder cancer', 'Disease', (124, 138))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (64, 82))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (124, 138))	('BAP1', 'Gene', '8314', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
103026	27660484	Several of these cancer types are part of the hereditary cancer syndrome known as tumor predisposition syndrome that is characterized by germline mutations of BAP1 in patients belonging to cancer-prone families (discussed in detail in section Inherited susceptibility).	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('mutations', 'Var', (146, 155))	('BAP1', 'Gene', '8314', (159, 163))	('cancer', 'Disease', (57, 63))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (46, 72))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('patients', 'Species', '9606', (167, 175))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('BAP1', 'Gene', (159, 163))	('tumor', 'Disease', (82, 87))	('hereditary cancer syndrome', 'Disease', (46, 72))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('cancer', 'Disease', (189, 195))
103031	27660484	EIF1AX mutations usually occur in nonmetastatic cases, are associated with class 1 GEP tumors and good prognosis, and are inversely associated with metastasis.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('associated', 'Reg', (59, 69))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('EIF1AX', 'Gene', (0, 6))	('tumors', 'Disease', (87, 93))	('EIF1AX', 'Gene', '1964', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('mutations', 'Var', (7, 16))
103032	27660484	EIF1AX mutations are usually mutually exclusive with BAP1 mutations and to a large extent also to SF3B1 mutations.	('mutations', 'Var', (58, 67))	('mutations', 'Var', (104, 113))	('mutations', 'Var', (7, 16))	('SF3B1', 'Gene', '23451', (98, 103))	('BAP1', 'Gene', '8314', (53, 57))	('SF3B1', 'Gene', (98, 103))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('BAP1', 'Gene', (53, 57))
103033	27660484	As expected most EIF1AX mutations are identified in tumors with disomy 3 (48%) and rarely occur in monosomy 3 tumors (3%).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('disomy 3', 'Disease', (64, 72))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('EIF1AX', 'Gene', '1964', (17, 23))	('EIF1AX', 'Gene', (17, 23))	('mutations', 'Var', (24, 33))
103034	27660484	In contrast to, for example, BAP1 mutations, which mainly are truncating and loss-of-function variants, the majority of the EIF1AX mutations are heterozygous nonsynonymous variants, or in some cases splicing variants, leading to deletions of one or two amino acids.	('EIF1AX', 'Gene', '1964', (124, 130))	('EIF1AX', 'Gene', (124, 130))	('mutations', 'Var', (131, 140))	('splicing', 'biological_process', 'GO:0045292', ('199', '207'))	('BAP1', 'Gene', '8314', (29, 33))	('BAP1', 'Gene', (29, 33))	('deletions', 'MPA', (229, 238))
103036	27660484	EIF1AX mutations are usually seen as heterozygous mutations in the tumor-DNA, suggesting that EIF1AX serves as a dominant acting oncogene.	('EIF1AX', 'Gene', '1964', (94, 100))	('EIF1AX', 'Gene', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
103037	27660484	However, it has been reported that UM tumors carrying an EIF1AX mutation only express the mutant allele, which indicates that EIF1AX also may function in a recessive manner.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('mutation', 'Var', (64, 72))	('EIF1AX', 'Gene', '1964', (57, 63))	('tumors', 'Disease', (38, 44))	('EIF1AX', 'Gene', (57, 63))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('EIF1AX', 'Gene', '1964', (126, 132))	('EIF1AX', 'Gene', (126, 132))
103038	27660484	Mutations in this gene have also been described in other cancers such as thyroid and ovarian cancers and in the rare melanocytic neoplasm primary leptomeningeal melanocytic neoplasms (LMNs).	('described', 'Reg', (38, 47))	('cancers', 'Disease', (93, 100))	('neoplasms', 'Phenotype', 'HP:0002664', (173, 182))	('thyroid and ovarian cancers', 'Disease', 'MESH:D010049', (73, 100))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (161, 182))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('ovarian cancers', 'Phenotype', 'HP:0100615', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('neoplasm', 'Phenotype', 'HP:0002664', (173, 181))	('neoplasm', 'Phenotype', 'HP:0002664', (129, 137))	('melanocytic neoplasm primary leptomeningeal melanocytic neoplasms', 'Disease', 'MESH:D009508', (117, 182))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
103039	27660484	LMNs are also prevalent for mutations in GNAQ, GNA11 and SF3B1.	('SF3B1', 'Gene', (57, 62))	('GNAQ', 'Gene', '2776', (41, 45))	('LMNs', 'Disease', (0, 4))	('GNA11', 'Gene', '2767', (47, 52))	('GNA11', 'Gene', (47, 52))	('SF3B1', 'Gene', '23451', (57, 62))	('GNAQ', 'Gene', (41, 45))	('prevalent', 'Reg', (14, 23))	('mutations', 'Var', (28, 37))
103042	27660484	Activating mutations in GNAQ/GNA11 were the first described driver mutations in UMs.	('GNA11', 'Gene', (29, 34))	('GNAQ', 'Gene', '2776', (24, 28))	('GNA11', 'Gene', '2767', (29, 34))	('Activating mutations', 'Var', (0, 20))	('UM', 'Phenotype', 'HP:0007716', (80, 82))	('GNAQ', 'Gene', (24, 28))	('UMs', 'Disease', (80, 83))
103043	27660484	GNAQ and GNA11 mutations occur in a mutual exclusive pattern and are exclusively found in codon 209 and in some cases in codon 183.	('GNA11', 'Gene', (9, 14))	('codon 209', 'Var', (90, 99))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('found', 'Reg', (81, 86))	('GNAQ', 'Gene', (0, 4))	('GNA11', 'Gene', '2767', (9, 14))
103044	27660484	Mutations at these positions lead to a constitutive activation of the Galphaq and Galpha11 subunits by abolishing their intrinsic GTPase activity, thereby preventing the return to an inactive state.	('preventing', 'NegReg', (155, 165))	('Galphaq', 'Gene', (70, 77))	('return to an inactive state', 'MPA', (170, 197))	('Galphaq', 'Gene', '2776', (70, 77))	('GTP', 'Chemical', 'MESH:D006160', (130, 133))	('GTPase activity', 'molecular_function', 'GO:0003924', ('130', '145'))	('GTPase', 'Protein', (130, 136))	('abolishing', 'NegReg', (103, 113))	('Galpha11', 'Gene', (82, 90))	('Mutations', 'Var', (0, 9))	('activity', 'MPA', (137, 145))	('intrinsic', 'MPA', (120, 129))	('Galpha11', 'Gene', '2767', (82, 90))	('activation', 'PosReg', (52, 62))
103045	27660484	Both GNAQ and GNA11 have been found to upregulate the MAP kinase pathway when constitutively activated in a similar fashion as BRAF and NRAS mutations.	('upregulate', 'PosReg', (39, 49))	('MAP kinase pathway', 'Pathway', (54, 72))	('GNAQ', 'Gene', (5, 9))	('mutations', 'Var', (141, 150))	('MAP', 'molecular_function', 'GO:0004239', ('54', '57'))	('BRAF', 'Gene', '673', (127, 131))	('BRAF', 'Gene', (127, 131))	('GNA11', 'Gene', (14, 19))	('NRAS', 'Gene', (136, 140))	('GNAQ', 'Gene', '2776', (5, 9))	('GNA11', 'Gene', '2767', (14, 19))	('NRAS', 'Gene', '4893', (136, 140))
103047	27660484	The activation of the MAPK pathway in the absence of BRAF/NRAS mutations in UMs was at first unforeseen until the identification of GNAQ and later GNA11 mutations that had the same effect as the V600EBRAF mutation.	('mutations', 'Var', (63, 72))	('NRAS', 'Gene', '4893', (58, 62))	('MAPK', 'molecular_function', 'GO:0004707', ('22', '26'))	('BRAF', 'Gene', (200, 204))	('BRAF', 'Gene', '673', (53, 57))	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('mutations', 'Var', (153, 162))	('BRAF', 'Gene', (53, 57))	('BRAF', 'Gene', '673', (200, 204))	('GNAQ', 'Gene', '2776', (132, 136))	('GNA11', 'Gene', '2767', (147, 152))	('GNA11', 'Gene', (147, 152))	('MAPK pathway', 'Pathway', (22, 34))	('NRAS', 'Gene', (58, 62))	('GNAQ', 'Gene', (132, 136))	('activation', 'PosReg', (4, 14))
103048	27660484	Interestingly, BRAF mutations have been seen in up to nearly half of all iris melanomas.	('iris melanomas', 'Disease', (73, 87))	('BRAF', 'Gene', '673', (15, 19))	('iris melanomas', 'Phenotype', 'HP:0011524', (73, 87))	('BRAF', 'Gene', (15, 19))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('iris melanomas', 'Disease', 'MESH:D007499', (73, 87))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('mutations', 'Var', (20, 29))
103049	27660484	Cell lines with a GNAQ Q209L mutation have also been found to be highly sensitive to mitogen-activated protein kinase (MEK) inhibition.	('MEK', 'Gene', (119, 122))	('MEK', 'Gene', '5609', (119, 122))	('mitogen-activated', 'MPA', (85, 102))	('GNAQ', 'Gene', '2776', (18, 22))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('Q209L', 'Mutation', 'rs121913492', (23, 28))	('GNAQ', 'Gene', (18, 22))	('sensitive', 'MPA', (72, 81))	('Q209L', 'Var', (23, 28))
103050	27660484	Mutations in these genes have not been associated with the two different molecular classes of UM tumors.	('UM', 'Phenotype', 'HP:0007716', (94, 96))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
103051	27660484	In addition, GNAQ/GNA11 mutations have not been reported to be of prognostic value and they occur at similar frequencies in metastatic and nonmetastatic lesions.	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', (18, 23))	('mutations', 'Var', (24, 33))	('GNA11', 'Gene', '2767', (18, 23))	('GNAQ', 'Gene', '2776', (13, 17))
103054	27660484	The hotspot mutations in GNAQ or GNA11 are also commonly found in benign nevi such as blue nevi.	('nevi', 'Phenotype', 'HP:0003764', (73, 77))	('GNA11', 'Gene', (33, 38))	('mutations', 'Var', (12, 21))	('found', 'Reg', (57, 62))	('GNA11', 'Gene', '2767', (33, 38))	('blue nevi', 'Phenotype', 'HP:0100814', (86, 95))	('GNAQ', 'Gene', (25, 29))	('benign nevi', 'Disease', (66, 77))	('blue nevi', 'Disease', (86, 95))	('nevi', 'Phenotype', 'HP:0003764', (91, 95))	('GNAQ', 'Gene', '2776', (25, 29))
103057	27660484	Mutations affecting codon R183 are less frequent, present in 2% of the blue nevi and 5% of primary UM tumors, GNAQ and GNA11 mutations combined.	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('GNAQ', 'Gene', '2776', (110, 114))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('codon R183', 'Var', (20, 30))	('nevi', 'Phenotype', 'HP:0003764', (76, 80))	('GNA11', 'Gene', '2767', (119, 124))	('GNA11', 'Gene', (119, 124))	('Mutations', 'Var', (0, 9))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('GNAQ', 'Gene', (110, 114))	('blue nevi', 'Phenotype', 'HP:0100814', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('blue nevi', 'Disease', (71, 80))
103061	27660484	Missense mutations in specific regions of the SF3B1gene have been found to alter the splicing of many target genes.	('splicing', 'biological_process', 'GO:0045292', ('85', '93'))	('alter', 'Reg', (75, 80))	('Missense mutations', 'Var', (0, 18))	('splicing', 'MPA', (85, 93))	('SF3B1', 'Gene', (46, 51))	('SF3B1', 'Gene', '23451', (46, 51))
103062	27660484	These mutations predominantly alter codon Arg625 in exon 14 of the SF3B1 gene and have been identified in UMs with a reported mutation rate between 10% and 21%.	('alter', 'Reg', (30, 35))	('SF3B1', 'Gene', '23451', (67, 72))	('codon Arg625', 'Var', (36, 48))	('Arg625', 'Chemical', '-', (42, 48))	('SF3B1', 'Gene', (67, 72))	('UM', 'Phenotype', 'HP:0007716', (106, 108))
103063	27660484	Some studies report an association between SF3B1 mutations and good prognosis, lower age at diagnosis (a favorable prognostic factor), and tumors with disomy 3.	('good', 'Disease', (63, 67))	('SF3B1', 'Gene', (43, 48))	('mutations', 'Var', (49, 58))	('SF3B1', 'Gene', '23451', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('disomy 3', 'Disease', (151, 159))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
103064	27660484	However, in a study with longer follow-up time, tumors with disomy 3 and a SF3B1 mutation showed significant worse prognosis and development of late metastasis compared to wild-type tumors.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', (182, 188))	('mutation', 'Var', (81, 89))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('SF3B1', 'Gene', '23451', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('disomy 3', 'Var', (60, 68))	('late metastasis', 'CPA', (144, 159))	('SF3B1', 'Gene', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
103065	27660484	In patients with a SF3B1 mutation, most metastasis occurred more than 5 years after diagnosis (median 8.2 years, range 23-145 months).	('SF3B1', 'Gene', '23451', (19, 24))	('mutation', 'Var', (25, 33))	('patients', 'Species', '9606', (3, 11))	('metastasis', 'CPA', (40, 50))	('SF3B1', 'Gene', (19, 24))
103066	27660484	In a study by Martin et al, 29% of the tumors with disomy 3 carried a heterozygous mutation in SF3B1 compared to only 3% in tumors with monosomy 3.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('SF3B1', 'Gene', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('disomy 3', 'Var', (51, 59))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('SF3B1', 'Gene', '23451', (95, 100))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumors', 'Disease', (39, 45))
103067	27660484	Furthermore, in tumors with partial monosomy 3, preferentially with loss of 3q and retention of 3p, 54% were found to carry Arg625 mutation in SF3B1.	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('Arg625', 'Var', (124, 130))	('Arg625', 'Chemical', '-', (124, 130))	('SF3B1', 'Gene', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('retention', 'biological_process', 'GO:0051235', ('83', '92'))	('loss', 'NegReg', (68, 72))	('SF3B1', 'Gene', '23451', (143, 148))	('tumors', 'Disease', (16, 22))
103068	27660484	In hematological and lymphoid malignancies, mutational hotspots have been detected in specific codons, for example, codon 700, coding for the HEAT repeats (HD) 4-9.	('codon 700', 'Var', (116, 125))	('hematological', 'Disease', (3, 16))	('HEAT repeats (HD) 4-9', 'Gene', (142, 163))	('lymphoid malignancies', 'Disease', 'MESH:D008223', (21, 42))	('lymphoid malignancies', 'Disease', (21, 42))	('HEAT repeats (HD) 4-9', 'Gene', '9759;10014;1671;51564;55869;9734', (142, 163))	('lymphoid malignancies', 'Phenotype', 'HP:0002665', (21, 42))
103069	27660484	Resequencing of the exons encoding for this region in UM tumors revealed a mutation rate of 15% in UM tumors (n=66).	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('mutation', 'Var', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('UM', 'Phenotype', 'HP:0007716', (54, 56))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
103070	27660484	SF3B1 mutations often occur in tumors that express the oncogene PRAME.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('PRAME', 'Gene', (64, 69))	('SF3B1', 'Gene', (0, 5))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('SF3B1', 'Gene', '23451', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('PRAME', 'Gene', '23532', (64, 69))	('occur', 'Reg', (22, 27))	('mutations', 'Var', (6, 15))
103071	27660484	expression of PRAME has been found to be associated with class 1 tumors with an intermediate risk of metastasis, suggesting that there is a risk class of tumors lying between the high-risk tumors characterized by BAP1 mutations and low-risk tumors frequently harboring EIF1AX mutations.	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('tumors', 'Disease', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('BAP1', 'Gene', '8314', (213, 217))	('PRAME', 'Gene', '23532', (14, 19))	('EIF1AX', 'Gene', (269, 275))	('PRAME', 'Gene', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('EIF1AX', 'Gene', '1964', (269, 275))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('BAP1', 'Gene', (213, 217))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('tumors', 'Disease', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumors', 'Disease', (154, 160))	('mutations', 'Var', (218, 227))	('tumors', 'Disease', (241, 247))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))
103072	27660484	By whole-genome and whole exome sequencing of UM tumors, a recurrent gain-of-function mutation in the phospholipase C, beta 4 (PLCB4), gene was identified.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('PLCB4', 'Gene', '5332', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('mutation', 'Var', (86, 94))	('PLCB4', 'Gene', (127, 132))	('gain-of-function', 'PosReg', (69, 85))	('phospholipase C, beta 4', 'Gene', '5332', (102, 125))
103074	27660484	The mutation (c.G1888T, p.D630Y) lies in the Y-domain of the highly conserved catalytic core of PLCB4 and was predicted to be deleterious/probably damaging using the prediction tools SIFT and PolyPhen.	('p.D630Y', 'Mutation', 'p.D630Y', (24, 31))	('core', 'cellular_component', 'GO:0019013', ('88', '92'))	('c.G1888T', 'Var', (14, 22))	('SIFT', 'Disease', (183, 187))	('PLCB4', 'Gene', '5332', (96, 101))	('c.G1888T', 'Mutation', 'c.1888G>T', (14, 22))	('SIFT', 'Disease', 'None', (183, 187))	('p.D630Y', 'Var', (24, 31))	('PLCB4', 'Gene', (96, 101))
103075	27660484	Interestingly, the PLCB4 protein is a downstream target of GNA11/GNAQ and the p.D630Y PLCB4 mutation was mutually exclusive with mutations in GNA11 and GNAQ.	('PLCB4', 'Gene', (19, 24))	('GNAQ', 'Gene', '2776', (65, 69))	('PLCB4', 'Gene', '5332', (86, 91))	('p.D630Y', 'Var', (78, 85))	('GNAQ', 'Gene', '2776', (152, 156))	('GNA11', 'Gene', '2767', (59, 64))	('GNA11', 'Gene', (59, 64))	('p.D630Y', 'Mutation', 'p.D630Y', (78, 85))	('GNAQ', 'Gene', (65, 69))	('PLCB4', 'Gene', '5332', (19, 24))	('GNA11', 'Gene', (142, 147))	('PLCB4', 'Gene', (86, 91))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('GNAQ', 'Gene', (152, 156))	('GNA11', 'Gene', '2767', (142, 147))
103076	27660484	In CM, recurrent mutations in the core promotor of the telomerase reverse transcriptase (TERT) gene are common.	('transcriptase', 'molecular_function', 'GO:0003899', ('74', '87'))	('core', 'cellular_component', 'GO:0019013', ('34', '38'))	('telomerase reverse transcriptase', 'Gene', (55, 87))	('CM', 'Phenotype', 'HP:0012056', (3, 5))	('transcriptase', 'molecular_function', 'GO:0034062', ('74', '87'))	('telomerase reverse transcriptase', 'Gene', '7015', (55, 87))	('TERT', 'Gene', (89, 93))	('TERT', 'Gene', '7015', (89, 93))	('mutations', 'Var', (17, 26))	('transcriptase', 'molecular_function', 'GO:0003968', ('74', '87'))
103078	27660484	Deregulation of telomerase and aberrant expression of TERT have been found in several different cancer forms such as thyroid and bladder cancers (www.cbioportal.org).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('TERT', 'Gene', '7015', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('aberrant', 'Var', (31, 39))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('Deregulation', 'MPA', (0, 12))	('cancer', 'Disease', (137, 143))	('thyroid and bladder cancers', 'Disease', 'MESH:D001749', (117, 144))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('telomerase', 'Protein', (16, 26))	('bladder cancers', 'Phenotype', 'HP:0009725', (129, 144))	('found', 'Reg', (69, 74))	('cancer', 'Disease', (96, 102))	('TERT', 'Gene', (54, 58))
103079	27660484	Approximately 70% of CM tumors have been reported to carry any of the two mutual exclusive recurrent mutations in the TERT promotor, both being consistent with the typical UV-damage signature.	('CM tumors', 'Disease', (21, 30))	('TERT', 'Gene', '7015', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mutations', 'Var', (101, 110))	('CM', 'Phenotype', 'HP:0012056', (21, 23))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('CM tumors', 'Disease', 'MESH:D009369', (21, 30))	('TERT', 'Gene', (118, 122))
103080	27660484	These mutations affect the expression levels of TERT by creating a novel binding site for the transcription factor E-twenty-six.	('transcription', 'biological_process', 'GO:0006351', ('94', '107'))	('expression levels', 'MPA', (27, 44))	('binding', 'Interaction', (73, 80))	('TERT', 'Gene', (48, 52))	('affect', 'Reg', (16, 22))	('TERT', 'Gene', '7015', (48, 52))	('transcription factor', 'molecular_function', 'GO:0000981', ('94', '114'))	('mutations', 'Var', (6, 15))	('binding', 'molecular_function', 'GO:0005488', ('73', '80'))
103081	27660484	A germline TERT promotor mutation with the same functional effect as the described somatic mutations has been found to segregate with high penetrance in two large melanoma-prone families in two separate studies.	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('mutation', 'Var', (25, 33))	('TERT', 'Gene', (11, 15))	('TERT', 'Gene', '7015', (11, 15))
103083	27660484	In a study by Dono et al, one out of 50 patients carried one of the previously described TERT promotor mutations.	('patients', 'Species', '9606', (40, 48))	('mutations', 'Var', (103, 112))	('TERT', 'Gene', '7015', (89, 93))	('TERT', 'Gene', (89, 93))
103084	27660484	Here, the promotor mutation was observed in combination with mutations in GNA11 and EIF1AX as well as two normal copies of chromosome 3.	('GNA11', 'Gene', (74, 79))	('EIF1AX', 'Gene', '1964', (84, 90))	('EIF1AX', 'Gene', (84, 90))	('GNA11', 'Gene', '2767', (74, 79))	('mutations', 'Var', (61, 70))	('chromosome', 'cellular_component', 'GO:0005694', ('123', '133'))
103087	27660484	The first report of a germline mutation in BAP1 was published in 2010.	('BAP1', 'Gene', '8314', (43, 47))	('germline mutation', 'Var', (22, 39))	('BAP1', 'Gene', (43, 47))
103088	27660484	One year later, two independent groups described inactivating germline mutations segregating in cancer-prone families, mainly characterized by distinct melanocytic neoplasms and mesothelioma in combination with UM and other cancers.	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (152, 173))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancers', 'Disease', (224, 231))	('mesothelioma', 'Disease', 'MESH:D008654', (178, 190))	('neoplasm', 'Phenotype', 'HP:0002664', (164, 172))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('neoplasms', 'Phenotype', 'HP:0002664', (164, 173))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (152, 173))	('UM', 'Phenotype', 'HP:0007716', (211, 213))	('inactivating germline mutations', 'Var', (49, 80))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('melanocytic neoplasms', 'Disease', (152, 173))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (224, 230))	('mesothelioma', 'Disease', (178, 190))
103090	27660484	The neoplasms associated with BAP1 germline mutations, also called the tumor predisposition syndrome, have been expanded to include CM, renal cell carcinoma, meningioma, and basal cell carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('neoplasms', 'Phenotype', 'HP:0002664', (4, 13))	('basal cell carcinoma', 'Disease', (174, 194))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (136, 156))	('neoplasm', 'Phenotype', 'HP:0002664', (4, 12))	('BAP1', 'Gene', '8314', (30, 34))	('neoplasms', 'Disease', 'MESH:D009369', (4, 13))	('meningioma', 'Disease', (158, 168))	('meningioma', 'Phenotype', 'HP:0002858', (158, 168))	('renal cell carcinoma', 'Disease', (136, 156))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (136, 156))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (174, 194))	('CM', 'Phenotype', 'HP:0012056', (132, 134))	('tumor', 'Disease', (71, 76))	('germline mutations', 'Var', (35, 53))	('neoplasms', 'Disease', (4, 13))	('BAP1', 'Gene', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (174, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('meningioma', 'Disease', 'MESH:D008577', (158, 168))
103092	27660484	In a review by Rai et al, it was reported that 56 out of 57 families with a reported BAP1 germline mutation had one or more family members diagnosed with any of the main cancer types associated with this cancer syndrome (UM, CM, mesothelioma, or renal cell carcinoma).	('CM', 'Phenotype', 'HP:0012056', (225, 227))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (246, 266))	('cancer syndrome', 'Disease', 'MESH:D009369', (204, 219))	('mutation', 'Var', (99, 107))	('BAP1', 'Gene', '8314', (85, 89))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (204, 210))	('renal cell carcinoma', 'Disease', (246, 266))	('cancer syndrome', 'Disease', (204, 219))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (246, 266))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('mesothelioma', 'Disease', (229, 241))	('BAP1', 'Gene', (85, 89))	('mesothelioma', 'Disease', 'MESH:D008654', (229, 241))	('UM', 'Phenotype', 'HP:0007716', (221, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
103097	27660484	In contrast, activating BRAF mutations are very rare in UM and, consequently, BRAF inhibitory treatment is not applicable.	('BRAF', 'Gene', '673', (78, 82))	('mutations', 'Var', (29, 38))	('BRAF', 'Gene', (78, 82))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('UM', 'Phenotype', 'HP:0007716', (56, 58))
103098	27660484	A high burden of coding mutations has been associated with a better response to immune checkpoint inhibitors, such as CTLA-4.	('response', 'MPA', (68, 76))	('coding mutations', 'Var', (17, 33))	('CTLA-4', 'Gene', '1493', (118, 124))	('CTLA-4', 'Gene', (118, 124))
103101	27660484	Targeting mutated GNQ/GNA11 directly is difficult because of the molecular nature of the mutations causing an inactivation of intrinsic GTPase within the cell.	('inactivation', 'MPA', (110, 122))	('GNA11', 'Gene', (22, 27))	('GTP', 'Chemical', 'MESH:D006160', (136, 139))	('GNA11', 'Gene', '2767', (22, 27))	('mutations', 'Var', (89, 98))	('intrinsic GTPase', 'Protein', (126, 142))
103103	27660484	These include mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) that is shown to be upregulated in GNAQ/GNA11 mutated tumors.	('GNAQ', 'Gene', '2776', (126, 130))	('extracellular', 'cellular_component', 'GO:0005576', ('47', '60'))	('MEK', 'Gene', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mitogen-activated protein kinase/extracellular signal-regulated kinase', 'Gene', '5609', (14, 84))	('GNAQ', 'Gene', (126, 130))	('tumors', 'Disease', (145, 151))	('MEK', 'Gene', '5609', (86, 89))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('mutated', 'Var', (137, 144))	('upregulated', 'PosReg', (111, 122))	('GNA11', 'Gene', '2767', (131, 136))	('GNA11', 'Gene', (131, 136))
103104	27660484	Inhibition of MEK has actually been found to decrease the proliferation of UM tumors both in vivo and in vitro.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('proliferation', 'CPA', (58, 71))	('MEK', 'Gene', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MEK', 'Gene', '5609', (14, 17))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('decrease', 'NegReg', (45, 53))	('Inhibition', 'Var', (0, 10))
103107	27660484	Other putative downstream targets of GNAQ/GNA11 mutated tumors are protein kinas C and molecules of the protein kinase B (AKT)/mammalian target of rapamycin pathway.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mutated', 'Var', (48, 55))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('GNAQ', 'Gene', (37, 41))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('GNA11', 'Gene', (42, 47))	('AKT', 'Gene', '207', (122, 125))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('protein kinas C', 'Enzyme', (67, 82))	('GNA11', 'Gene', '2767', (42, 47))	('GNAQ', 'Gene', '2776', (37, 41))	('mammalian', 'Species', '9606', (127, 136))	('AKT', 'Gene', (122, 125))
103108	27660484	Also BAP1 mutations are difficult to target directly because of their recessive nature.	('mutations', 'Var', (10, 19))	('BAP1', 'Gene', '8314', (5, 9))	('BAP1', 'Gene', (5, 9))
103118	27660484	Additional research will be of importance to elucidate the penetrance and risk of developing different types of cancer in mutation carriers.	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('mutation', 'Var', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', (112, 118))
103122	27660484	Mutations occurring in the other driver genes are likely to have arisen later in the tumor development and thus are of importance for patient outcome.	('tumor', 'Disease', (85, 90))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('patient', 'Species', '9606', (134, 141))
103123	27660484	EIF1AX-mutated tumors show in general a strong correlation with class 1 GEP tumors and increased patient survival; BAP1 mutations, in contrast, associate with GEP class 2 tumors and poor survival; and SF3B1-mutated tumors seem to fall in between, which associate with late-onset metastatic disease.	('late-onset metastatic disease', 'Disease', (268, 297))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('fall', 'Phenotype', 'HP:0002527', (230, 234))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('mutations', 'Var', (120, 129))	('patient', 'Species', '9606', (97, 104))	('GEP', 'Disease', (159, 162))	('tumors', 'Disease', (215, 221))	('EIF1AX', 'Gene', (0, 6))	('SF3B1', 'Gene', (201, 206))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('tumors', 'Disease', (15, 21))	('EIF1AX', 'Gene', '1964', (0, 6))	('tumors', 'Disease', (171, 177))	('BAP1', 'Gene', '8314', (115, 119))	('SF3B1', 'Gene', '23451', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('increased', 'PosReg', (87, 96))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('BAP1', 'Gene', (115, 119))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
103124	27660484	As being a complement to the GEP classification, mutation status of UM driver genes will hopefully increase the prognostic accuracy and be of help for deciding different treatment regimens, such as MEK inhibition therapy in GNAQ- and GNA11-mutated tumors.	('mutation status', 'Var', (49, 64))	('GNAQ', 'Gene', '2776', (224, 228))	('tumors', 'Disease', (248, 254))	('GNAQ', 'Gene', (224, 228))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('GNA11', 'Gene', (234, 239))	('UM', 'Phenotype', 'HP:0007716', (68, 70))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('GNA11', 'Gene', '2767', (234, 239))	('increase', 'PosReg', (99, 107))	('MEK', 'Gene', (198, 201))	('MEK', 'Gene', '5609', (198, 201))	('prognostic', 'MPA', (112, 122))
103126	27660484	Germline mutations in BAP1, mainly truncating mutations, have been found to segregate with reduced penetrance in families with many different cancer diagnoses, including but not exclusively to UM, CM, mesothelioma, and renal cell carcinoma.	('truncating', 'MPA', (35, 45))	('Germline mutations', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (219, 239))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (219, 239))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('UM', 'Phenotype', 'HP:0007716', (193, 195))	('mesothelioma', 'Disease', (201, 213))	('BAP1', 'Gene', '8314', (22, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('renal cell carcinoma', 'Disease', (219, 239))	('CM', 'Phenotype', 'HP:0012056', (197, 199))	('mesothelioma', 'Disease', 'MESH:D008654', (201, 213))	('BAP1', 'Gene', (22, 26))	('cancer', 'Disease', (142, 148))
103161	26761211	Deregulated VEGF expression contributes to the development of solid tumors by promoting angiogenesis, but also by promoting intravasation leading to hematogenous metastasis, which is the major determinant of patient mortality.	('patient', 'Species', '9606', (208, 215))	('Deregulated', 'Var', (0, 11))	('hematogenous metastasis', 'CPA', (149, 172))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('VEGF', 'Gene', (12, 16))	('angiogenesis', 'CPA', (88, 100))	('intravasation', 'MPA', (124, 137))	('promoting', 'PosReg', (114, 123))	('promoting', 'PosReg', (78, 87))	('solid tumors', 'Disease', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('angiogenesis', 'biological_process', 'GO:0001525', ('88', '100'))	('solid tumors', 'Disease', 'MESH:D009369', (62, 74))	('VEGF', 'Gene', '7422', (12, 16))
103186	26761211	When endothelial cells were treated with conditioned medium from UM cells in which VEGF expression was knocked down, we observed only partial inhibition of tubule formation (Figure 3G).	('UM', 'Phenotype', 'HP:0007716', (65, 67))	('VEGF', 'Gene', (83, 87))	('formation', 'biological_process', 'GO:0009058', ('163', '172'))	('inhibition', 'NegReg', (142, 152))	('VEGF', 'Gene', '7422', (83, 87))	('knocked down', 'Var', (103, 115))	('tubule formation', 'CPA', (156, 172))
103200	26761211	To interrogate the role of ANGPTL4 in the regulation of angiogenesis by UM tumor cells, we next knocked down expression of ANGPTL4.	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('expression', 'MPA', (109, 119))	('ANGPTL4', 'Gene', '51129', (123, 130))	('ANGPTL4', 'Gene', (123, 130))	('ANGPTL4', 'Gene', (27, 34))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('ANGPTL4', 'Gene', '51129', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('knocked', 'Var', (96, 103))	('regulation of angiogenesis', 'biological_process', 'GO:0045765', ('42', '68'))	('tumor', 'Disease', (75, 80))
103202	26761211	Inhibition of ANGPTL4 expression in UM tumor cells, in turn, reduced the induction by conditioned medium of endothelial cell tubule formation in vitro (Figure 5D) and the promotion of angiogenesis in vivo (Figure 5E).	('angiogenesis', 'CPA', (184, 196))	('angiogenesis', 'biological_process', 'GO:0001525', ('184', '196'))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('ANGPTL4', 'Gene', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('formation', 'biological_process', 'GO:0009058', ('132', '141'))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('ANGPTL4', 'Gene', '51129', (14, 21))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (39, 44))	('promotion', 'PosReg', (171, 180))	('reduced', 'NegReg', (61, 68))	('endothelial cell tubule formation', 'CPA', (108, 141))
103214	26761211	Combined RNAi knockdown blocked the mRNA and protein expression of both secreted factors and had an additive effect on the inhibition of tubule formation by endothelial cells treated with conditioned medium from the 92.1 UM cells (Figure 6F and 6G).	('RNAi', 'biological_process', 'GO:0016246', ('9', '13'))	('formation', 'biological_process', 'GO:0009058', ('144', '153'))	('UM', 'Phenotype', 'HP:0007716', (221, 223))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('92.1 UM', 'CellLine', 'CVCL:7796', (216, 223))	('inhibition', 'NegReg', (123, 133))	('knockdown', 'Var', (14, 23))	('RNAi', 'Gene', (9, 13))	('blocked', 'NegReg', (24, 31))	('tubule formation', 'CPA', (137, 153))
103227	26761211	Our studies using RNAi and neutralizing antibody against VEGF lend further support for the possible benefit of bevacizumab as an adjuvant therapy for UM.	('bevacizumab', 'Chemical', 'MESH:D000068258', (111, 122))	('antibody', 'cellular_component', 'GO:0042571', ('40', '48'))	('neutralizing antibody', 'Var', (27, 48))	('RNAi', 'biological_process', 'GO:0016246', ('18', '22'))	('VEGF', 'Gene', (57, 61))	('antibody', 'cellular_component', 'GO:0019814', ('40', '48'))	('antibody', 'cellular_component', 'GO:0019815', ('40', '48'))	('UM', 'Phenotype', 'HP:0007716', (150, 152))	('antibody', 'molecular_function', 'GO:0003823', ('40', '48'))	('VEGF', 'Gene', '7422', (57, 61))
103241	26761211	Inhibition of ANGPTL4 expression by UM tumor cells reduced the induction of endothelial cell tubule formation in vitro and the promotion of angiogenesis in vivo.	('promotion', 'PosReg', (127, 136))	('reduced', 'NegReg', (51, 58))	('endothelial cell tubule formation', 'CPA', (76, 109))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('ANGPTL4', 'Gene', (14, 21))	('angiogenesis', 'biological_process', 'GO:0001525', ('140', '152'))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('angiogenesis', 'CPA', (140, 152))	('ANGPTL4', 'Gene', '51129', (14, 21))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('Inhibition', 'Var', (0, 10))	('formation', 'biological_process', 'GO:0009058', ('100', '109'))	('tumor', 'Disease', (39, 44))
103254	26761211	Further studies are needed to determine whether inhibiting ANGPTL4, by preventing its promotion of endothelial cell barrier disruption, may also be an effective approach for the prevention of UM cell extravasation and metastatic spread.	('UM cell', 'CPA', (192, 199))	('inhibiting', 'Var', (48, 58))	('promotion', 'PosReg', (86, 95))	('metastatic spread', 'CPA', (218, 235))	('ANGPTL4', 'Gene', '51129', (59, 66))	('ANGPTL4', 'Gene', (59, 66))	('endothelial cell barrier disruption', 'CPA', (99, 134))	('UM', 'Phenotype', 'HP:0007716', (192, 194))
103257	26761211	Collectively, these observations support a possible role for ANGPTL4 in the promotion of metastasis in UM and provide a foundation for future studies to determine whether combined inhibition of both ANGPTL4 and VEGF could simultaneously target tumor-induced angiogenesis and metastasis, and thereby provide more effective therapies for patients with primary and metastatic UM.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('UM', 'Phenotype', 'HP:0007716', (373, 375))	('metastasis', 'CPA', (275, 285))	('ANGPTL4', 'Gene', (61, 68))	('ANGPTL4', 'Gene', '51129', (61, 68))	('angiogenesis', 'biological_process', 'GO:0001525', ('258', '270'))	('tumor', 'Disease', (244, 249))	('ANGPTL4', 'Gene', (199, 206))	('promotion', 'PosReg', (76, 85))	('VEGF', 'Gene', (211, 215))	('ANGPTL4', 'Gene', '51129', (199, 206))	('patients', 'Species', '9606', (336, 344))	('target', 'Reg', (237, 243))	('inhibition', 'Var', (180, 190))	('metastasis', 'CPA', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('VEGF', 'Gene', '7422', (211, 215))	('UM', 'Phenotype', 'HP:0007716', (103, 105))
103300	26933176	PRAME as an independent biomarker for metastasis in uveal melanoma Uveal melanoma (UM) can be classified by gene expression profiling (GEP) into Class 1 (low metastatic risk) and Class 2 (high metastatic risk), the latter being strongly associated with mutational inactivation of the tumor suppressor BAP1.	('melanoma', 'Disease', (73, 81))	('uveal melanoma', 'Disease', (52, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (52, 66))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('BAP1', 'Gene', '8314', (301, 305))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('284', '300'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('associated', 'Reg', (237, 247))	('UM', 'Phenotype', 'HP:0007716', (83, 85))	('gene expression', 'biological_process', 'GO:0010467', ('108', '123'))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('tumor suppressor', 'biological_process', 'GO:0051726', ('284', '300'))	('BAP1', 'Gene', (301, 305))	('tumor', 'Disease', (284, 289))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('mutational inactivation', 'Var', (253, 276))	('PRAME', 'Gene', '23532', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('PRAME', 'Gene', (0, 5))	('melanoma', 'Disease', (58, 66))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
103310	26933176	PRAME expression was associated with larger tumor diameter (P=0.05) and SF3B1 mutations (P=0.003).	('larger', 'PosReg', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mutations', 'Var', (78, 87))	('SF3B1', 'Gene', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('PRAME', 'Gene', '23532', (0, 5))	('SF3B1', 'Gene', '23451', (72, 77))	('tumor', 'Disease', (44, 49))	('PRAME', 'Gene', (0, 5))
103314	26933176	The Class 2 signature is strongly associated with mutations in BAP1 on chromosome 3p21, usually accompanied by loss of the other copy of chromosome 3, consistent with the "two hit" model of tumor suppressor gene inactivation.	('associated', 'Reg', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('mutations', 'Var', (50, 59))	('BAP1', 'Gene', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (190, 195))	('chromosome', 'cellular_component', 'GO:0005694', ('71', '81'))	('chromosome', 'cellular_component', 'GO:0005694', ('137', '147'))	('BAP1', 'Gene', '8314', (63, 67))
103315	26933176	Hemizygous mutations in the G-protein subunits GNAQ and GNA11 are early or initiating events in UM.	('Hemizygous', 'Var', (0, 10))	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('GNAQ', 'Gene', (47, 51))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('GNAQ', 'Gene', '2776', (47, 51))	('GNA11', 'Gene', (56, 61))	('GNA11', 'Gene', '2767', (56, 61))
103316	26933176	GNAQ and GNA11 mutations are mutually exclusive, and one or the other is found in ~83% of UMs.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (90, 92))	('mutations', 'Var', (15, 24))	('GNAQ', 'Gene', (0, 4))	('UMs', 'Disease', (90, 93))	('GNA11', 'Gene', '2767', (9, 14))
103317	26933176	Hemizygous mutations in SF3B1 and EIF1AX are virtually mutually exclusive with each other, and with BAP1 mutations, and they have been linked to good prognosis.	('Hemizygous mutations', 'Var', (0, 20))	('BAP1', 'Gene', '8314', (100, 104))	('linked to', 'Reg', (135, 144))	('SF3B1', 'Gene', (24, 29))	('BAP1', 'Gene', (100, 104))	('EIF1AX', 'Gene', '1964', (34, 40))	('EIF1AX', 'Gene', (34, 40))	('mutations', 'Var', (105, 114))	('SF3B1', 'Gene', '23451', (24, 29))
103337	26933176	TaqMan  primers were Hs01022301_m1 (PRAME), Hs00230458_m1 (MRPS21), Hs00216503_m1 (RBM23), and Hs00368617_m1 (SAP130).	('MRPS21', 'Gene', (59, 65))	('Hs00230458_m1', 'Var', (44, 57))	('Hs00368617_m1', 'Var', (95, 108))	('RBM23', 'Gene', '55147', (83, 88))	('Hs00216503_m1', 'Var', (68, 81))	('SAP130', 'Gene', '79595', (110, 116))	('Hs01022301_m1', 'Var', (21, 34))	('SAP130', 'Gene', (110, 116))	('MRPS21', 'Gene', '54460', (59, 65))	('RBM23', 'Gene', (83, 88))	('PRAME', 'Gene', '23532', (36, 41))	('PRAME', 'Gene', (36, 41))
103344	26933176	The third dataset contained 25 tumors classified as low risk based on disomy 3, which is significantly associated with the Class 1 signature, and was performed at Leiden University on the Illumina Human HT12v4 BeadChip Array platform.	('Human', 'Species', '9606', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('disomy 3', 'Var', (70, 78))	('tumors', 'Disease', 'MESH:D009369', (31, 37))
103351	26933176	For PRAME+ and PRAME- samples, SNP analysis was performed using the Affymetrix Genome-Wide Human SNP 6.0 array and data were analyzed for copy number gains and losses as described in the Affymetrix Genotyping Console software user manual and then plotted with Integrative Genomics Viewer.	('PRAME', 'Gene', (4, 9))	('losses', 'NegReg', (160, 166))	('PRAME', 'Gene', '23532', (15, 20))	('PRAME', 'Gene', (15, 20))	('copy number', 'Var', (138, 149))	('PRAME', 'Gene', '23532', (4, 9))	('Human', 'Species', '9606', (91, 96))
103357	26933176	Detailed clinicopathologic and molecular features of all the Class1met+ tumors are summarized in Supplementary Table 3.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('Class1met+', 'Var', (61, 71))
103360	26933176	Compared to Class2met+ tumors, Class1met+ tumors were associated with younger patient age and less frequent ciliary body involvement (Mann-Whitney test, P=0.04 and P=0.02, respectively).	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('patient', 'Species', '9606', (78, 85))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('Class1met+', 'Var', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('ciliary body involvement', 'CPA', (108, 132))
103362	26933176	There were no significant differences between Class1met+ and Class1met- tumors with regard to age, sex, tumor diameter or thickness, ciliary body involvement or cell type.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', (104, 109))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('Class1met+', 'Var', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
103363	26933176	For Class1met+ tumors, mutations were identified in BAP1 in none of 8, EIF1AX in none of 6, GNAQ in 5 of 8, GNA11 in 1 of 7 and SF3B1 in 4 of 8 samples in which DNA was still available for sequencing (Supplementary Table 3).	('SF3B1', 'Gene', '23451', (128, 133))	('GNA11', 'Gene', '2767', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('BAP1', 'Gene', '8314', (52, 56))	('GNAQ', 'Gene', (92, 96))	('EIF1AX', 'Gene', (71, 77))	('EIF1AX', 'Gene', '1964', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('BAP1', 'Gene', (52, 56))	('mutations', 'Var', (23, 32))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('SF3B1', 'Gene', (128, 133))	('GNAQ', 'Gene', '2776', (92, 96))	('GNA11', 'Gene', (108, 113))	('tumors', 'Disease', (15, 21))
103364	26933176	Among the 5 known UM driver mutations, SF3B1 mutations were most strongly associated with Class 1 metastasis, but since these mutations were only present in 50% of metastatic cases, it is not an adequate biomarker for Class 1 metastasis.	('mutations', 'Var', (45, 54))	('Class 1 metastasis', 'CPA', (90, 108))	('UM', 'Phenotype', 'HP:0007716', (18, 20))	('SF3B1', 'Gene', '23451', (39, 44))	('associated', 'Reg', (74, 84))	('SF3B1', 'Gene', (39, 44))
103366	26933176	1C), indicating that there were potentially meaningful transcriptomic differences between Class1met+ and Class1met- tumors.	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumors', 'Disease', (116, 122))	('Class1met+', 'Var', (90, 100))	('Class1met-', 'Var', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
103367	26933176	To identify genes that were differentially expressed between Class1met+ and Class1met- tumors, we performed a genome-wide transcriptomic analysis of 5 Class1met+ tumors and 8 Class1met- tumors with at least 1 year of follow-up using the Illumina Human HT12v4 Expression BeadChip array.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Class1met+', 'Var', (151, 161))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('Human', 'Species', '9606', (246, 251))
103369	26933176	By far, the most highly overexpressed gene in Class1met+ tumors was PRAME (Mann-Whitney test, P=0.003) (Fig.	('PRAME', 'Gene', (68, 73))	('overexpressed', 'PosReg', (24, 37))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Class1met+', 'Var', (46, 56))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('PRAME', 'Gene', '23532', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
103371	26933176	Consistent with the array data, 16/19 (84%) Class1met- tumors showed minimal PRAME expression (Class1PRAME-), whereas 7/7 (100%) of Class1met+ tumors showed elevated PRAME expression (Class1PRAME+, Mann-Whitney test, P=0.001) (Fig.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('PRAME', 'Gene', '23532', (166, 171))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('PRAME', 'Gene', (166, 171))	('PRAME', 'Gene', '23532', (190, 195))	('PRAME', 'Gene', (190, 195))	('Class1met-', 'Var', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('PRAME', 'Gene', '23532', (101, 106))	('tumors', 'Disease', (143, 149))	('PRAME', 'Gene', (101, 106))	('tumors', 'Disease', (55, 61))	('PRAME', 'Gene', '23532', (77, 82))	('PRAME', 'Gene', (77, 82))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('minimal', 'NegReg', (69, 76))	('elevated', 'PosReg', (157, 165))
103381	26933176	PRAME expression showed a significant association with larger basal tumor diameter (Spearman correlation, P = 0.04) and with SF3B1 mutations (Mann-Whitney test, P = 0.003) (Supplementary Fig.	('larger', 'PosReg', (55, 61))	('mutations', 'Var', (131, 140))	('SF3B1', 'Gene', '23451', (125, 130))	('basal tumor', 'Disease', 'MESH:D002280', (62, 73))	('basal tumor', 'Disease', (62, 73))	('SF3B1', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('PRAME', 'Gene', '23532', (0, 5))	('PRAME', 'Gene', (0, 5))	('basal tumor', 'Phenotype', 'HP:0002671', (62, 73))
103382	26933176	To further validate the association of high PRAME levels with metastasis, we combined two independent published datasets with long follow-up (GSE22138 and GSE44295), which included 20 Class1PRAME- and 31 Class1PRAME+ cases (median follow-up 68.0 months, mean 80.4 months, interquartile range 41.4-101.5 months).	('PRAME', 'Gene', '23532', (210, 215))	('GSE22138', 'Var', (142, 150))	('PRAME', 'Gene', (210, 215))	('GSE44295', 'Var', (155, 163))	('PRAME', 'Gene', '23532', (190, 195))	('PRAME', 'Gene', (190, 195))	('PRAME', 'Gene', '23532', (44, 49))	('PRAME', 'Gene', (44, 49))
103399	26933176	In the Leiden dataset, gain or amplification of 8q was observed in 6/16 Disomy3PRAME- and in 8/9 Disomy3PRAME+ tumors (Fisher exact test, P = 0.03).	('PRAME', 'Gene', '23532', (79, 84))	('PRAME', 'Gene', (79, 84))	('PRAME', 'Gene', '23532', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('PRAME', 'Gene', (104, 109))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('gain', 'PosReg', (23, 27))	('amplification', 'Var', (31, 44))
103403	26933176	Class 1 UMs that metastasized tended to occur in younger patients, less frequently involved the ciliary body, less frequently metastasized to the liver, lacked BAP1 mutations, frequently had SF3B1 mutations, and exhibited a distinct GEP.	('SF3B1', 'Gene', '23451', (191, 196))	('patients', 'Species', '9606', (57, 65))	('BAP1', 'Gene', '8314', (160, 164))	('UM', 'Phenotype', 'HP:0007716', (8, 10))	('mutations', 'Var', (197, 206))	('involved', 'Reg', (83, 91))	('BAP1', 'Gene', (160, 164))	('mutations', 'Var', (165, 174))	('SF3B1', 'Gene', (191, 196))	('lacked', 'NegReg', (153, 159))
103421	26933176	NCT01149343 and NCT01853878), and other immunotherapies directed against PRAME-expressing cancers are in development.	('cancers', 'Disease', (90, 97))	('NCT01853878', 'Var', (16, 27))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('PRAME', 'Gene', '23532', (73, 78))	('NCT01149343', 'Var', (0, 11))	('PRAME', 'Gene', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
103426	26933176	These findings suggest that PRAME up-regulation may cooperate with copy number gains on 1q and 6p to facilitate chromosomal instability associated with tumor progression (Fig.	('PRAME', 'Gene', '23532', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('up-regulation', 'PosReg', (34, 47))	('regulation', 'biological_process', 'GO:0065007', ('37', '47'))	('PRAME', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('chromosomal instability', 'MPA', (112, 135))	('tumor', 'Disease', (152, 157))	('facilitate', 'PosReg', (101, 111))	('chromosomal instability', 'Phenotype', 'HP:0040012', (112, 135))	('copy number', 'Var', (67, 78))
103427	26933176	Mutations in SF3B1 and EIF1AX are associated with Class 1 GEP and have been reported to be good prognostic factors in UM, whereas BAP1 mutations are associated with Class 2 GEP and poor prognosis.	('associated', 'Reg', (34, 44))	('BAP1', 'Gene', (130, 134))	('SF3B1', 'Gene', (13, 18))	('mutations', 'Var', (135, 144))	('UM', 'Phenotype', 'HP:0007716', (118, 120))	('associated', 'Reg', (149, 159))	('Mutations', 'Var', (0, 9))	('EIF1AX', 'Gene', (23, 29))	('SF3B1', 'Gene', '23451', (13, 18))	('EIF1AX', 'Gene', '1964', (23, 29))	('BAP1', 'Gene', '8314', (130, 134))	('Class 1 GEP', 'Disease', (50, 61))
103428	26933176	While this study affirms that SF3B1 mutations are associated with better prognosis than BAP1 mutations, we found that SF3B1 mutations were associated with increased metastatic risk among Class 1 tumors, which almost never have BAP1 mutations.	('tumors', 'Disease', (195, 201))	('SF3B1', 'Gene', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('mutations', 'Var', (124, 133))	('SF3B1', 'Gene', '23451', (118, 123))	('BAP1', 'Gene', '8314', (227, 231))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('mutations', 'Var', (36, 45))	('BAP1', 'Gene', (227, 231))	('SF3B1', 'Gene', '23451', (30, 35))	('BAP1', 'Gene', '8314', (88, 92))	('associated', 'Reg', (139, 149))	('SF3B1', 'Gene', (118, 123))	('BAP1', 'Gene', (88, 92))	('metastatic risk', 'CPA', (165, 180))
103429	26933176	Similarly, another group recently reported that patients with disomy 3 have a worse disease-free survival when an SF3B1 mutation is present.	('SF3B1', 'Gene', '23451', (114, 119))	('mutation', 'Var', (120, 128))	('SF3B1', 'Gene', (114, 119))	('disease-free survival', 'CPA', (84, 105))	('patients', 'Species', '9606', (48, 56))	('worse', 'NegReg', (78, 83))
103430	26933176	In the same way, 6p gain is a good prognostic factor relative to Class 2 GEP (and monosomy 3), 6p gain should not be thought of as "protective" against metastasis because it is strongly associated with metastasis in Class 1 tumors.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('6p gain', 'Var', (95, 102))	('associated with', 'Reg', (186, 201))	('metastasis', 'CPA', (202, 212))
103431	26933176	On the other hand, EIF1AX mutations were not found in any of the metastasizing Class 1 tumors and were almost always mutually exclusive with SF3B1 and BAP1 mutations, suggesting that this mutation may have value as a favorable prognostic factor.	('SF3B1', 'Gene', '23451', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('BAP1', 'Gene', (151, 155))	('EIF1AX', 'Gene', '1964', (19, 25))	('EIF1AX', 'Gene', (19, 25))	('mutations', 'Var', (26, 35))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('SF3B1', 'Gene', (141, 146))	('tumors', 'Disease', (87, 93))	('BAP1', 'Gene', '8314', (151, 155))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
103432	26933176	A limitation of this study was the small number of Class1met+ cases, but this is a reflection of the infrequency of metastasis in Class 1 tumors.	('Class1met+', 'Var', (51, 61))	('tumors', 'Disease', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
103445	26397223	Furthermore, nearly 40% of UM has amplification of the chromosomal arm 8q and monosomy of chromosome 3, with consequent anomalies of MYC copy number.	('monosomy', 'Var', (78, 86))	('anomalies of MYC copy number', 'Disease', 'MESH:D000014', (120, 148))	('chromosome', 'cellular_component', 'GO:0005694', ('90', '100'))	('anomalies of MYC copy number', 'Disease', (120, 148))	('amplification', 'Var', (34, 47))
103448	26397223	Further analysis of selected genes determined that the concomitant silencing of Bcl-xL and Rad51 represented the minimal requirement to mimic the apoptotic effects of JQ1 in the mutant cells, independently of c-Myc.	('mutant', 'Var', (178, 184))	('Rad', 'biological_process', 'GO:1990116', ('91', '94'))	('silencing', 'NegReg', (67, 76))	('Bcl-xL', 'Gene', '598', (80, 86))	('Rad51', 'Gene', (91, 96))	('Rad51', 'Gene', '5888', (91, 96))	('c-Myc', 'Gene', '4609', (209, 214))	('Bcl-xL', 'Gene', (80, 86))	('c-Myc', 'Gene', (209, 214))
103449	26397223	In addition, administration of JQ1 to mouse xenograft models of Gnaq-mutant UM resulted in significant inhibition of tumor growth.	('Gnaq-mutant', 'Var', (64, 75))	('mouse', 'Species', '10090', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('Gnaq-mutant', 'Gene', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('inhibition', 'NegReg', (103, 113))
103450	26397223	Collectively, our results define BRD4 targeting as a novel therapeutic intervention against UM with Gnaq/Gna11 mutations.	('mutations', 'Var', (111, 120))	('Gna11', 'Gene', '2767', (105, 110))	('BRD4', 'Gene', (33, 37))	('Gna11', 'Gene', (105, 110))	('BRD4', 'Gene', '23476', (33, 37))
103451	26397223	Aberrant epigenetic regulation plays a central role into the genesis of cancer.	('regulation', 'biological_process', 'GO:0065007', ('20', '30'))	('Aberrant epigenetic', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
103458	26397223	These studies also demonstrated that although BET inhibitors influence predominantly the MYC transcriptome, other genes undergo expressional changes and simultaneously contributed to the decrease of cell viability.	('cell viability', 'CPA', (199, 213))	('inhibitors', 'Var', (50, 60))	('BET', 'Gene', '92737', (46, 49))	('influence', 'Reg', (61, 70))	('BET', 'Gene', (46, 49))	('undergo', 'Reg', (120, 127))	('expressional', 'MPA', (128, 140))	('MYC', 'Gene', '4609', (89, 92))	('decrease', 'NegReg', (187, 195))	('MYC', 'Gene', (89, 92))
103460	26397223	UM is biologically distinct from cutaneous melanoma, as 85% of primary and metastatic UM carry oncogenic mutations of G-protein alpha-subunits q or 11, and have a high tendency to metastasize to the liver.	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('metastasize', 'CPA', (180, 191))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('cutaneous melanoma', 'Disease', (33, 51))	('mutations', 'Var', (105, 114))	('G-protein alpha-subunits q or 11', 'Protein', (118, 150))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (33, 51))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (33, 51))
103461	26397223	UM are also characterized by genetic abnormalities, including the amplification of the chromosomal arm 8q and monosomy of chromosome 3, which are significantly associated with poor prognosis.	('amplification', 'Var', (66, 79))	('genetic abnormalities', 'Disease', (29, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('122', '132'))	('monosomy', 'Var', (110, 118))	('genetic abnormalities', 'Disease', 'MESH:D030342', (29, 50))	('chromosomal', 'Gene', (87, 98))
103465	26397223	We found that JQ1 induces cell cycle arrest and apoptosis, especially in cells with Gnaq/11 mutations.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('26', '43'))	('apoptosis', 'biological_process', 'GO:0006915', ('48', '57'))	('JQ1', 'Gene', (14, 17))	('arrest', 'Disease', 'MESH:D006323', (37, 43))	('mutations', 'Var', (92, 101))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (26, 43))	('arrest', 'Disease', (37, 43))	('induces', 'Reg', (18, 25))	('apoptosis', 'CPA', (48, 57))	('Gnaq/11', 'Gene', (84, 91))	('apoptosis', 'biological_process', 'GO:0097194', ('48', '57'))
103467	26397223	These observations support the evidence that BET inhibition represent a promising therapeutic approach for UM with Gnaq/11 mutations.	('BET', 'Gene', '92737', (45, 48))	('Gnaq/11', 'Gene', (115, 122))	('BET', 'Gene', (45, 48))	('mutations', 'Var', (123, 132))
103472	26397223	Figure 1A shows that the level of expression of these two genes was similar in the Gnaq/11 mutant cell lines, while it varied among the non-mutant cells, with lower expression in Mel290 and C8161, and high RNA expression of both genes in Mel285.	('expression', 'MPA', (165, 175))	('Gnaq/11', 'Gene', (83, 90))	('lower', 'NegReg', (159, 164))	('C8161', 'CellLine', 'CVCL:6813', (190, 195))	('RNA expression', 'MPA', (206, 220))	('RNA', 'cellular_component', 'GO:0005562', ('206', '209'))	('mutant', 'Var', (91, 97))
103473	26397223	In order to test whether BRD4 is active and regulates expression of c-Myc in these cells, BRD4 was knocked down by siRNA transfection, and c-Myc was analyzed by immunoblotting.	('BRD4', 'Gene', '23476', (25, 29))	('c-Myc', 'Gene', (68, 73))	('c-Myc', 'Gene', '4609', (139, 144))	('knocked', 'Var', (99, 106))	('regulates', 'Reg', (44, 53))	('BRD4', 'Gene', (25, 29))	('BRD4', 'Gene', '23476', (90, 94))	('c-Myc', 'Gene', (139, 144))	('c-Myc', 'Gene', '4609', (68, 73))	('BRD4', 'Gene', (90, 94))
103478	26397223	However, the cells with Gnaq/11 mutations were the most sensitive to the treatments with IC50 of 100-250 nM, suggesting a dependency on functional BET proteins.	('BET', 'Gene', (147, 150))	('mutations', 'Var', (32, 41))	('BET', 'Gene', '92737', (147, 150))	('Gnaq/11', 'Gene', (24, 31))
103480	26397223	All four cell lines underwent cell cycle arrest in G1 (Figure 2B), while a marked apoptotic sub-G1 peak appeared in the Gnaq mutant cells after 48 and 72 hours of treatment.	('Gnaq', 'Gene', (120, 124))	('mutant', 'Var', (125, 131))	('arrest', 'Disease', (41, 47))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('30', '47'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (30, 47))	('arrest', 'Disease', 'MESH:D006323', (41, 47))
103481	26397223	Finally, apoptosis was detected in the Gnaq mutant cells by the induction of cleaved PARP, an apoptotic marker, after 48 and 72 hours of treatment (Figure 2D, upper panel), while no PARP cleavage was induced in the WT cells at any time point (Figure 2D, lower panel).	('PARP', 'Gene', '1302', (85, 89))	('PARP', 'Gene', (85, 89))	('PARP', 'Gene', '1302', (182, 186))	('cleaved', 'Var', (77, 84))	('apoptosis', 'biological_process', 'GO:0097194', ('9', '18'))	('PARP', 'Gene', (182, 186))	('apoptosis', 'biological_process', 'GO:0006915', ('9', '18'))	('mutant', 'Var', (44, 50))
103482	26397223	Thus, JQ1 regulates c-Myc expression in all UM cell lines, but triggers apoptosis only in a subset of cell lines, specifically cells carrying Gnaq/11 mutations.	('c-Myc', 'Gene', (20, 25))	('triggers', 'Reg', (63, 71))	('Gnaq/11', 'Gene', (142, 149))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('regulates', 'Reg', (10, 19))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('mutations', 'Var', (150, 159))	('apoptosis', 'CPA', (72, 81))	('JQ1', 'Var', (6, 9))	('c-Myc', 'Gene', '4609', (20, 25))
103483	26397223	Mutant Gnaq and Gna11 proteins have long been known to activate downstream signaling targets, including MEK, PI3-kinase/Akt and protein kinase C, and the combination of specific inhibitors of these pathways were reported to effectively block proliferation of UM cells.	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('protein kinase C', 'Pathway', (128, 144))	('Akt', 'Gene', '207', (120, 123))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('Gnaq', 'Gene', (7, 11))	('activate', 'PosReg', (55, 63))	('MEK', 'Gene', (104, 107))	('Gna11', 'Gene', (16, 21))	('MEK', 'Gene', '5609', (104, 107))	('proteins', 'Protein', (22, 30))	('Mutant', 'Var', (0, 6))	('proliferation', 'CPA', (242, 255))	('block', 'NegReg', (236, 241))	('Akt', 'Gene', (120, 123))	('Gna11', 'Gene', '2767', (16, 21))
103485	26397223	In order to investigate the effect of BRD4 inhibition on gene expression, we performed transcriptional analysis of seven UM cell lines and one cutaneous melanoma cell line with different G protein mutational status.	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (143, 161))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (143, 161))	('BRD4', 'Gene', '23476', (38, 42))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('BRD4', 'Gene', (38, 42))	('mutational', 'Var', (197, 207))	('gene expression', 'biological_process', 'GO:0010467', ('57', '72'))	('cutaneous melanoma', 'Disease', (143, 161))
103487	26397223	Thus, a much larger number of genes were regulated by JQ1 in the Gnaq/11 mutant cells, suggesting that BRD4 is particularly active in these cells lines.	('BRD4', 'Gene', '23476', (103, 107))	('Gnaq/11', 'Gene', (65, 72))	('mutant', 'Var', (73, 79))	('JQ1', 'Gene', (54, 57))	('BRD4', 'Gene', (103, 107))
103491	26397223	We have shown that MEK and ATK pathways are both activated in Gnaq/11 mutant cells.	('MEK', 'Gene', '5609', (19, 22))	('ATK pathways', 'Pathway', (27, 39))	('mutant', 'Var', (70, 76))	('Gnaq/11', 'Gene', (62, 69))	('MEK', 'Gene', (19, 22))	('activated', 'PosReg', (49, 58))
103492	26397223	However, inhibition of one or both pathways induced cell cycle arrest and autophagy.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (52, 69))	('arrest', 'Disease', 'MESH:D006323', (63, 69))	('autophagy', 'biological_process', 'GO:0006914', ('74', '83'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('52', '69'))	('autophagy', 'CPA', (74, 83))	('arrest', 'Disease', (63, 69))	('autophagy', 'biological_process', 'GO:0016236', ('74', '83'))	('inhibition', 'Var', (9, 19))
103494	26397223	There was nearly complete inhibition of the proteins tested in cells with Gnaq/11 mutations (Figure 3C, top panel), while no inhibition was detected in the WT cell lines C8161 and Mel285 (Figure 3C, lower panel).	('Gnaq/11', 'Gene', (74, 81))	('inhibition', 'NegReg', (26, 36))	('C8161', 'CellLine', 'CVCL:6813', (170, 175))	('mutations', 'Var', (82, 91))	('proteins', 'Protein', (44, 52))
103498	26397223	In contrast, silencing of Bcl-xL together with c-Myc, Brca1 or Wee1 had no effect.	('Brca1', 'Gene', (54, 59))	('Bcl-xL', 'Gene', (26, 32))	('Wee1', 'Gene', (63, 67))	('Wee1', 'Gene', '7465', (63, 67))	('Brca1', 'Gene', '672', (54, 59))	('c-Myc', 'Gene', '4609', (47, 52))	('c-Myc', 'Gene', (47, 52))	('Bcl-xL', 'Gene', '598', (26, 32))	('silencing', 'Var', (13, 22))
103501	26397223	In contrast, Bcl-xL silencing alone or together with other gene-specific siRNA, induced a significant decrease in cell viability and PARP cleavage (Figure 4C and 4D).	('PARP', 'Gene', (133, 137))	('Bcl-xL', 'Gene', '598', (13, 19))	('decrease', 'NegReg', (102, 110))	('Bcl-xL', 'Gene', (13, 19))	('cell viability', 'CPA', (114, 128))	('silencing', 'Var', (20, 29))	('PARP', 'Gene', '1302', (133, 137))
103504	26397223	These findings would also suggest that although JQ1 inhibits expression of numerous genes, the concomitant down-regulation of Bcl-xL and Rad51 is the minimal requirement for inducing apoptosis in UM cells with Gnaq mutation.	('mutation', 'Var', (215, 223))	('apoptosis', 'biological_process', 'GO:0006915', ('183', '192'))	('down-regulation', 'NegReg', (107, 122))	('Bcl-xL', 'Gene', (126, 132))	('Bcl-xL', 'Gene', '598', (126, 132))	('Gnaq', 'Gene', (210, 214))	('Rad51', 'Gene', '5888', (137, 142))	('inhibits', 'NegReg', (52, 60))	('Rad', 'biological_process', 'GO:1990116', ('137', '140'))	('apoptosis', 'biological_process', 'GO:0097194', ('183', '192'))	('regulation', 'biological_process', 'GO:0065007', ('112', '122'))	('expression', 'MPA', (61, 71))	('Rad51', 'Gene', (137, 142))
103508	26397223	Silencing of the indicated genes (Figure 5C) did not induce inhibition of viability (Figure 5D), and the concomitant suppression of Bcl-xL and Rad51 had partial effects that were not statistically significant.	('Rad51', 'Gene', (143, 148))	('Rad51', 'Gene', '5888', (143, 148))	('suppression', 'NegReg', (117, 128))	('Rad', 'biological_process', 'GO:1990116', ('143', '146'))	('Bcl-xL', 'Gene', '598', (132, 138))	('Silencing', 'Var', (0, 9))	('Bcl-xL', 'Gene', (132, 138))
103510	26397223	Bcl-xL was identified in the microarray analysis among the genes involved in the regulation of apoptosis, and it was exclusively down-regulated by JQ1 in the Gnaq/11 mutant cells.	('JQ1', 'Gene', (147, 150))	('down-regulated', 'NegReg', (129, 143))	('regulation of apoptosis', 'biological_process', 'GO:0042981', ('81', '104'))	('Bcl-xL', 'Gene', '598', (0, 6))	('mutant', 'Var', (166, 172))	('Bcl-xL', 'Gene', (0, 6))
103518	26397223	Using chromatin immunoprecipitation assay (ChIP), we found that BRD4 was enriched at the Bcl-xL promoter in the Gnaq-mutant cells (Figure 6C), and the treatment with JQ1 diminished this binding.	('diminished', 'NegReg', (170, 180))	('Bcl-xL', 'Gene', '598', (89, 95))	('Bcl-xL', 'Gene', (89, 95))	('BRD4', 'Gene', (64, 68))	('Gnaq-mutant', 'Var', (112, 123))	('BRD4', 'Gene', '23476', (64, 68))	('binding', 'molecular_function', 'GO:0005488', ('186', '193'))	('chromatin', 'cellular_component', 'GO:0000785', ('6', '15'))
103520	26397223	A similar displacement of BRD4 binding by JQ1 was found at the Rad51 promoter in the mutant cells (Figure 6D), but not in the WT cells.	('Rad51', 'Gene', '5888', (63, 68))	('binding', 'Interaction', (31, 38))	('BRD4', 'Gene', (26, 30))	('Rad', 'biological_process', 'GO:1990116', ('63', '66'))	('binding', 'molecular_function', 'GO:0005488', ('31', '38'))	('mutant', 'Var', (85, 91))	('Rad51', 'Gene', (63, 68))	('BRD4', 'Gene', '23476', (26, 30))
103521	26397223	Finally, we sought to demonstrate that BRD4 depletion could specifically down-regulate these two proteins.	('depletion', 'Var', (44, 53))	('BRD4', 'Gene', '23476', (39, 43))	('down-regulate', 'NegReg', (73, 86))	('BRD4', 'Gene', (39, 43))
103522	26397223	BRD4 silencing caused a decrease of both Bcl-xL and Rad51 expression in the Gnaq-mutant cells (Figure 6E).	('BRD4', 'Gene', '23476', (0, 4))	('Rad51', 'Gene', (52, 57))	('Rad51', 'Gene', '5888', (52, 57))	('silencing', 'NegReg', (5, 14))	('expression', 'MPA', (58, 68))	('Bcl-xL', 'Gene', '598', (41, 47))	('Rad', 'biological_process', 'GO:1990116', ('52', '55'))	('Gnaq-mutant', 'Var', (76, 87))	('decrease', 'NegReg', (24, 32))	('Bcl-xL', 'Gene', (41, 47))	('BRD4', 'Gene', (0, 4))
103523	26397223	Instead, BRD4 depletion caused a slight decrease in Rad51, but not Bcl-xL, in the Mel290 WT cells.	('Bcl-xL', 'Gene', (67, 73))	('Rad51', 'Gene', (52, 57))	('BRD4', 'Gene', (9, 13))	('decrease', 'NegReg', (40, 48))	('Rad51', 'Gene', '5888', (52, 57))	('Rad', 'biological_process', 'GO:1990116', ('52', '55'))	('BRD4', 'Gene', '23476', (9, 13))	('depletion', 'Var', (14, 23))	('Bcl-xL', 'Gene', '598', (67, 73))
103525	26397223	Taken together these data indicate that BRD4 is required for Bcl-xL and Rad51 expression, and JQ1 inhibits BRD4 recruitment to their promoters in the Gnaq mutant cells.	('Bcl-xL', 'Gene', '598', (61, 67))	('BRD4', 'Gene', (40, 44))	('Rad51', 'Gene', (72, 77))	('Rad51', 'Gene', '5888', (72, 77))	('Bcl-xL', 'Gene', (61, 67))	('BRD4', 'Gene', '23476', (107, 111))	('mutant', 'Var', (155, 161))	('BRD4', 'Gene', '23476', (40, 44))	('recruitment', 'MPA', (112, 123))	('inhibits', 'NegReg', (98, 106))	('Rad', 'biological_process', 'GO:1990116', ('72', '75'))	('BRD4', 'Gene', (107, 111))
103527	26397223	Bcl-xL was ectopically expressed alone or together with Rad51 in the mutant cells, and protein levels are shown in Figure 7A.	('Rad', 'biological_process', 'GO:1990116', ('56', '59'))	('Rad51', 'Gene', '5888', (56, 61))	('Rad51', 'Gene', (56, 61))	('mutant', 'Var', (69, 75))	('Bcl-xL', 'Gene', '598', (0, 6))	('Bcl-xL', 'Gene', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
103529	26397223	However, when both constructs were expressed there was a significant increase in cell survival in the presence of JQ1 (Figure 7B), which also corresponded to a decrease of cleaved PARP (Figure 7A).	('JQ1', 'Var', (114, 117))	('decrease', 'NegReg', (160, 168))	('increase', 'PosReg', (69, 77))	('PARP', 'Gene', '1302', (180, 184))	('PARP', 'Gene', (180, 184))	('cell survival', 'CPA', (81, 94))
103537	26397223	Here we report that the BET inhibitor JQ1 induces cell cycle arrest in a panel of genetically diverse UM, and it has potent cytotoxic effects only in cells with Gnaq/11 mutations, irrespective of MYC status.	('arrest', 'Disease', (61, 67))	('MYC', 'Gene', (196, 199))	('BET', 'Gene', (24, 27))	('JQ1', 'Gene', (38, 41))	('mutations', 'Var', (169, 178))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (50, 67))	('Gnaq/11', 'Gene', (161, 168))	('arrest', 'Disease', 'MESH:D006323', (61, 67))	('induces', 'Reg', (42, 49))	('MYC', 'Gene', '4609', (196, 199))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('50', '67'))	('BET', 'Gene', '92737', (24, 27))
103540	26397223	While the down-regulation of both genes represented the minimal requirement to mimic JQ1 effects, we cannot rule out the possibility that other genes may be responsible for mediating the apoptotic effects of BET inhibition, as JQ1 treatment led to down- and up-regulation of numerous genes with potential roles in tumorigenesis and cell survival.	('up-regulation', 'PosReg', (258, 271))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('regulation', 'biological_process', 'GO:0065007', ('15', '25'))	('genes', 'Gene', (284, 289))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('BET', 'Gene', '92737', (208, 211))	('down-', 'NegReg', (248, 253))	('tumor', 'Disease', (314, 319))	('BET', 'Gene', (208, 211))	('regulation', 'biological_process', 'GO:0065007', ('261', '271'))	('JQ1', 'Var', (227, 230))
103544	26397223	On the other hand, knockdown of Bcl-xL was sufficient to induce cell death in the MYC-amplified cell line, confirming that Bcl-xL expression is critical for UM survival.	('Bcl-xL', 'Gene', '598', (123, 129))	('Bcl-xL', 'Gene', (32, 38))	('Bcl-xL', 'Gene', (123, 129))	('knockdown', 'Var', (19, 28))	('cell death', 'CPA', (64, 74))	('MYC', 'Gene', '4609', (82, 85))	('induce', 'Reg', (57, 63))	('Bcl-xL', 'Gene', '598', (32, 38))	('MYC', 'Gene', (82, 85))	('cell death', 'biological_process', 'GO:0008219', ('64', '74'))
103548	26397223	This is in contrast with the effect of JQ1 in UM cell lines, where the induction of apoptosis was dependent on Gnaq/11 mutations, suggesting that these cells rely on BRD4 activity for the regulation of gene transcription.	('transcription', 'biological_process', 'GO:0006351', ('207', '220'))	('BRD4', 'Gene', '23476', (166, 170))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('71', '93'))	('Gnaq/11', 'Gene', (111, 118))	('regulation', 'biological_process', 'GO:0065007', ('188', '198'))	('mutations', 'Var', (119, 128))	('BRD4', 'Gene', (166, 170))
103549	26397223	This is of particular interest, as nearly 85% of UM carry Gnaq/11 mutations, and BRD4 inhibition could translate in targeted therapies for the majority of UM.	('mutations', 'Var', (66, 75))	('Gnaq/11', 'Gene', (58, 65))	('BRD4', 'Gene', '23476', (81, 85))	('BRD4', 'Gene', (81, 85))
103550	26397223	The regulation of DNA repair genes such as Rad51 by JQ1 also contributed to the survival of cells with Gnaq mutation.	('regulation of DNA repair', 'biological_process', 'GO:0006282', ('4', '28'))	('JQ1', 'Gene', (52, 55))	('Gnaq', 'Gene', (103, 107))	('contributed', 'Reg', (61, 72))	('Rad', 'biological_process', 'GO:1990116', ('43', '46'))	('Rad51', 'Gene', (43, 48))	('Rad51', 'Gene', '5888', (43, 48))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('mutation', 'Var', (108, 116))	('regulation', 'MPA', (4, 14))
103551	26397223	BRD4 was recruited to the promoter of Rad51 and Bcl-xL, and was displaced by JQ1 in the mutant cells, confirming regulation of expression of this gene by BET-proteins.	('BRD4', 'Gene', '23476', (0, 4))	('recruited', 'PosReg', (9, 18))	('Bcl-xL', 'Gene', '598', (48, 54))	('BET', 'Gene', '92737', (154, 157))	('Rad51', 'Gene', '5888', (38, 43))	('Bcl-xL', 'Gene', (48, 54))	('Rad', 'biological_process', 'GO:1990116', ('38', '41'))	('mutant', 'Var', (88, 94))	('BRD4', 'Gene', (0, 4))	('BET', 'Gene', (154, 157))	('regulation', 'biological_process', 'GO:0065007', ('113', '123'))	('Rad51', 'Gene', (38, 43))
103558	26397223	This data strongly supports the rationale for the targeting of BRD4 in patients with UM harboring Gnaq/11 mutations.	('BRD4', 'Gene', '23476', (63, 67))	('patients', 'Species', '9606', (71, 79))	('mutations', 'Var', (106, 115))	('BRD4', 'Gene', (63, 67))	('Gnaq/11', 'Gene', (98, 105))
103560	26397223	All the cell lines have been sequenced for the presence of activating mutations in codons 209 (exon 5) and 183 (exon 4) of Gnaq and Gna11.	('mutations in', 'Var', (70, 82))	('Gnaq', 'Gene', (123, 127))	('Gna11', 'Gene', (132, 137))	('activating', 'PosReg', (59, 69))	('Gna11', 'Gene', '2767', (132, 137))
103561	26397223	C8161 cells were recently characterized as cutaneous melanoma.	('C8161', 'CellLine', 'CVCL:6813', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('C8161', 'Var', (0, 5))	('cutaneous melanoma', 'Disease', (43, 61))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (43, 61))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (43, 61))
103562	26397223	SK-Mel19 and SK-Mel29 were a gift from Dr Taha Merghoub (Memorial Sloan-Kettering Cancer Center, New York, NY).	('Memorial Sloan-Kettering Cancer', 'Disease', (57, 88))	('SK-Mel29', 'Var', (13, 21))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Memorial Sloan-Kettering Cancer', 'Disease', 'MESH:D008569', (57, 88))
103564	26397223	FISH was performed using red-labeled probe from PAC clone RP1-80K22 spanning MYC in 8q24, together with green-labeled centromeric probe (pJM128) as reference.	('PAC', 'Phenotype', 'HP:0006699', (48, 51))	('MYC', 'Gene', (77, 80))	('RP1-80K22', 'Var', (58, 67))	('MYC', 'Gene', '4609', (77, 80))
103577	26397223	Small interfering RNA against c-Myc (sc-29226), Rad51 (sc-36361), Brca1 (sc-29219), Wee1 (sc-36835) and control siRNA (sc-37007) were purchased from Santa Cruz Biotechnology.	('sc-29226', 'Var', (37, 45))	('Rad51', 'Gene', '5888', (48, 53))	('RNA', 'cellular_component', 'GO:0005562', ('18', '21'))	('Rad', 'biological_process', 'GO:1990116', ('48', '51'))	('sc-29219', 'Var', (73, 81))	('sc-36361', 'Var', (55, 63))	('Brca1', 'Gene', (66, 71))	('c-Myc', 'Gene', '4609', (30, 35))	('Wee1', 'Gene', '7465', (84, 88))	('Wee1', 'Gene', (84, 88))	('Brca1', 'Gene', '672', (66, 71))	('sc-36835', 'Var', (90, 98))	('c-Myc', 'Gene', (30, 35))	('Rad51', 'Gene', (48, 53))
103578	26397223	Bcl-xL siRNA was from Cell Signaling (#6362), and siRNA-2 SMARTpool from Dharmacon (L-004937-00).	('Bcl-xL', 'Gene', '598', (0, 6))	('#6362', 'Var', (38, 43))	('Bcl-xL', 'Gene', (0, 6))	('Signaling', 'biological_process', 'GO:0023052', ('27', '36'))
103579	26397223	siRNA-2 for Rad51 (L-003530-00) and BRD4 (L-004937-00) were also from Dharmacon.	('BRD4', 'Gene', (36, 40))	('Rad51', 'Gene', (12, 17))	('L-003530-00', 'Var', (19, 30))	('Rad51', 'Gene', '5888', (12, 17))	('Rad', 'biological_process', 'GO:1990116', ('12', '15'))	('BRD4', 'Gene', '23476', (36, 40))	('L-004937-00', 'Var', (42, 53))
103600	24454684	However, when S44563 was concomitantly administered with fotemustine, we observed a synergistic activity in 3 out of the 4 tested models.	('S44563', 'Chemical', 'MESH:C000599183', (14, 20))	('synergistic activity', 'MPA', (84, 104))	('fotemustine', 'Chemical', 'MESH:C054368', (57, 68))	('S44563', 'Var', (14, 20))
103601	24454684	In addition, S44563 administered after fotemustine induced a tumour growth delay in 2 out of 3 tested xenografts.	('S44563', 'Var', (13, 19))	('growth delay', 'Phenotype', 'HP:0001510', (68, 80))	('tumour growth delay', 'Disease', 'MESH:D006130', (61, 80))	('tumour growth delay', 'Disease', (61, 80))	('S44563', 'Chemical', 'MESH:C000599183', (13, 19))	('fotemustine', 'Chemical', 'MESH:C054368', (39, 50))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
103603	24454684	The novel anti-apoptotic experimental compound S44563, despite a relative low efficacy when administered alone, increased the efficacy of fotemustine in either concomitant or sequential combinations or indeed subsequent to fotemustine.	('fotemustine', 'Chemical', 'MESH:C054368', (138, 149))	('S44563', 'Chemical', 'MESH:C000599183', (47, 53))	('increased', 'PosReg', (112, 121))	('efficacy', 'MPA', (126, 134))	('S44563', 'Var', (47, 53))	('fotemustine', 'Chemical', 'MESH:C054368', (223, 234))
103612	24454684	A variety of approaches to target these anti-apoptotic oncoproteins have been pursued in order to try and restore the natural process of programmed cell death, notably bcl-2 anti-sense oligonucleotides such as Oblimersen (Genasense ) with contrasted positive or negative impact in randomized clinical trials performed in cutaneous melanoma, chronic lymphoid leukemia, multiple myeloma, and prostate cancer patients.	('bcl-2', 'Gene', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (399, 405))	('lymphoid leukemia', 'Disease', (349, 366))	('lymphoid leukemia', 'Disease', 'MESH:D007945', (349, 366))	('multiple myeloma', 'Phenotype', 'HP:0006775', (368, 384))	('chronic lymphoid leukemia', 'Phenotype', 'HP:0005550', (341, 366))	('oligonucleotides', 'Chemical', 'MESH:D009841', (185, 201))	('prostate cancer', 'Disease', 'MESH:D011471', (390, 405))	('bcl-2', 'Gene', '596', (168, 173))	('prostate cancer', 'Phenotype', 'HP:0012125', (390, 405))	('melanoma', 'Phenotype', 'HP:0002861', (331, 339))	('multiple myeloma', 'Disease', 'MESH:D009101', (368, 384))	('prostate cancer', 'Disease', (390, 405))	('bcl-2', 'molecular_function', 'GO:0015283', ('168', '173'))	('cutaneous melanoma', 'Disease', (321, 339))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (321, 339))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (321, 339))	('programmed cell death', 'biological_process', 'GO:0012501', ('137', '158'))	('lymphoid leukemia', 'Phenotype', 'HP:0005526', (349, 366))	('patients', 'Species', '9606', (406, 414))	('multiple myeloma', 'Disease', (368, 384))	('leukemia', 'Phenotype', 'HP:0001909', (358, 366))	('anti-sense', 'Var', (174, 184))
103632	24454684	Three UM cell lines have been used, all derived from UM PDXs established from intraocular lesion (MP41, MM26, and MM66).	('intraocular lesion', 'Disease', 'MESH:D064090', (78, 96))	('MP41', 'Gene', (98, 102))	('intraocular lesion', 'Disease', (78, 96))	('MM26', 'CellLine', 'CVCL:L791', (104, 108))	('MM66', 'Var', (114, 118))	('MP41', 'Gene', '26930', (98, 102))
103633	24454684	Four UM PDXs obtained from patients after enucleation (MP41 and MP77) or liver metastasis surgery (MM26 and MM66), established, characterized and maintained into SCID mice have been used.	('MP41', 'Gene', '26930', (55, 59))	('MP77', 'Var', (64, 68))	('MM26', 'CellLine', 'CVCL:L791', (99, 103))	('liver metastasis', 'Disease', 'MESH:D009362', (73, 89))	('liver metastasis', 'Disease', (73, 89))	('patients', 'Species', '9606', (27, 35))	('enucleation', 'biological_process', 'GO:0090601', ('42', '53'))	('MP41', 'Gene', (55, 59))	('SCID', 'Disease', 'MESH:D053632', (162, 166))	('SCID', 'Disease', (162, 166))	('mice', 'Species', '10090', (167, 171))
103639	24454684	Cell autophagy was assessed by detecting cleaved and non-cleaved LC3, cells were seeded and treated by 2 and 4 microM of S44563 in 6-well plates for 24 hours.	('LC3', 'Gene', '84557', (65, 68))	('S44563', 'Var', (121, 127))	('LC3', 'Gene', (65, 68))	('autophagy', 'biological_process', 'GO:0016236', ('5', '14'))	('autophagy', 'biological_process', 'GO:0006914', ('5', '14'))	('Cell autophagy', 'CPA', (0, 14))	('S44563', 'Chemical', 'MESH:C000599183', (121, 127))
103666	24454684	The Figures 1A and 1B show the inhibition of Bcl-2 and Bcl-XL respectively by S44563.	('inhibition', 'NegReg', (31, 41))	('Bcl-XL', 'MPA', (55, 61))	('S44563', 'Var', (78, 84))	('S44563', 'Chemical', 'MESH:C000599183', (78, 84))	('Bcl-2', 'MPA', (45, 50))	('Bcl-2', 'molecular_function', 'GO:0015283', ('45', '50'))
103667	24454684	S44563 is a potent inhibitor of Bcl-2 and Bcl-XL.	('Bcl-XL', 'Enzyme', (42, 48))	('Bcl-2', 'Enzyme', (32, 37))	('S44563', 'Var', (0, 6))	('Bcl-2', 'molecular_function', 'GO:0015283', ('32', '37'))	('S44563', 'Chemical', 'MESH:C000599183', (0, 6))
103670	24454684	The expression of Bcl-2 was high for 3 UM xenografts used for in vivo experiments (MP41, MP77, and MM26), where the median H-score ranged between 150 and 175, and low for the MM66 model for which the median Bcl-2 H-score was lower than 5 (Table S2) (Figure 2).	('Bcl-2', 'Gene', (18, 23))	('MP41', 'Gene', '26930', (83, 87))	('Bcl-2', 'molecular_function', 'GO:0015283', ('207', '212'))	('MM26', 'CellLine', 'CVCL:L791', (99, 103))	('expression', 'MPA', (4, 14))	('Bcl-2', 'molecular_function', 'GO:0015283', ('18', '23'))	('MP41', 'Gene', (83, 87))	('MP77', 'Var', (89, 93))
103674	24454684	For the 3 uveal melanoma xenograft-derived cell lines MP41, MM26, and MM66 incubated with increased concentrations of S44563, 17 microM and 34 microM for 24 hours, the IC50s were 4 microM, 7 microM, and 6 microM for the MP41, MM26, and MM66 cell lines, respectively (Figure S2).	('uveal melanoma', 'Disease', 'MESH:C536494', (10, 24))	('MP41', 'Gene', '26930', (220, 224))	('S44563', 'Chemical', 'MESH:C000599183', (118, 124))	('MM26', 'CellLine', 'CVCL:L791', (60, 64))	('uveal melanoma', 'Disease', (10, 24))	('MP41', 'Gene', (54, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (10, 24))	('50s', 'Species', '1214577', (170, 173))	('S44563', 'Var', (118, 124))	('MP41', 'Gene', (220, 224))	('MM26', 'CellLine', 'CVCL:L791', (226, 230))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('MP41', 'Gene', '26930', (54, 58))
103675	24454684	Similarly, to evaluate apoptosis induction, the MP41, MM26, and MM66 cell lines were incubated with 17 microM and 34 microM S44563 for 24 hours, after which the samples were labeled with DAPI/annexin V-FITC or JC1.	('MM26', 'CellLine', 'CVCL:L791', (54, 58))	('S44563', 'Chemical', 'MESH:C000599183', (124, 130))	('MP41', 'Gene', '26930', (48, 52))	('apoptosis', 'biological_process', 'GO:0097194', ('23', '32'))	('DAPI', 'Chemical', 'MESH:C007293', (187, 191))	('S44563', 'Var', (124, 130))	('FITC', 'Chemical', 'MESH:D016650', (202, 206))	('JC1', 'Chemical', 'MESH:C068624', (210, 213))	('apoptosis', 'biological_process', 'GO:0006915', ('23', '32'))	('MP41', 'Gene', (48, 52))
103677	24454684	Similarly, in the two UM cell lines MP41 and MM66 that are more sensitive to S44563, we observed a significant decrease of the G2/M phases which were not modified in the less sensitive MM26 cell line (Figure 3C).	('G2/M phases', 'CPA', (127, 138))	('S44563', 'Chemical', 'MESH:C000599183', (77, 83))	('MP41', 'Gene', '26930', (36, 40))	('decrease', 'NegReg', (111, 119))	('MM26', 'CellLine', 'CVCL:L791', (185, 189))	('MP41', 'Gene', (36, 40))	('S44563', 'Var', (77, 83))
103680	24454684	We observed that both the proportion and the total amount of cleaved LC3 protein relative to beta-actin, were not significantly modified after S44563 administration in the 3 studied UM cell lines (Figure 3D).	('LC3', 'Gene', '84557', (69, 72))	('S44563', 'Var', (143, 149))	('LC3', 'Gene', (69, 72))	('S44563', 'Chemical', 'MESH:C000599183', (143, 149))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))
103681	24454684	In the 4 UM PDXs, S44563 administered alone at 50 and 100 mg/kg, for 2 cycles of treatment (5 days a week for 2 weeks and 1 week off, each cycle), induced a significant antitumor effect in one model (MP41), with a dose-dependent response and an optimal TGI of 61% at day 53 after start of treatment (Table 1) (Figure 4A).	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('S44563', 'Var', (18, 24))	('tumor', 'Disease', (173, 178))	('MP41', 'Gene', '26930', (200, 204))	('MP41', 'Gene', (200, 204))	('S44563', 'Chemical', 'MESH:C000599183', (18, 24))
103682	24454684	To evaluate responses to S44563 observed in the 4 models according to individual mouse variability, we decided to consider each mouse as one tumor-bearing entity.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('S44563', 'Var', (25, 31))	('tumor', 'Disease', (141, 146))	('mouse', 'Species', '10090', (128, 133))	('mouse', 'Species', '10090', (81, 86))	('S44563', 'Chemical', 'MESH:C000599183', (25, 31))
103683	24454684	In this, when relative tumor volume variation [(RTVV)-1] of each S44563-treated mouse was calculated, regardless of the doses of S44563, we observed that 68% of all S44563-treated mice (59/87) had a negative ratio compared to control groups, and that 22% had a ratio lower than 50%, which constitute the threshold to consider a model as responding.	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('negative', 'NegReg', (199, 207))	('mouse', 'Species', '10090', (80, 85))	('S44563', 'Chemical', 'MESH:C000599183', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mice', 'Species', '10090', (180, 184))	('S44563', 'Chemical', 'MESH:C000599183', (165, 171))	('tumor', 'Disease', (23, 28))	('S44563', 'Chemical', 'MESH:C000599183', (65, 71))	('S44563-treated', 'Var', (165, 179))
103687	24454684	concomitant fotemustine/S44563, fotemustine first then S44563 since day 43, and concomitant fotemustine/S44563 then S44563 since day 43 (data not shown).	('S44563', 'Chemical', 'MESH:C000599183', (55, 61))	('fotemustine', 'Chemical', 'MESH:C054368', (92, 103))	('S44563', 'Var', (55, 61))	('fotemustine', 'Chemical', 'MESH:C054368', (12, 23))	('S44563', 'Chemical', 'MESH:C000599183', (116, 122))	('S44563', 'Chemical', 'MESH:C000599183', (24, 30))	('fotemustine', 'Chemical', 'MESH:C054368', (32, 43))	('S44563', 'Var', (116, 122))	('S44563', 'Chemical', 'MESH:C000599183', (104, 110))
103689	24454684	In the MP77 xenograft, concomitant S44563 (100 mg/kg per injection) and fotemustine (15 mg/kg) induced a more significant TGI at day 35 after start of treatment than fotemustine alone (p = 0.04) (Figure 4C).	('S44563', 'Chemical', 'MESH:C000599183', (35, 41))	('S44563', 'Var', (35, 41))	('fotemustine', 'Chemical', 'MESH:C054368', (72, 83))	('fotemustine', 'Chemical', 'MESH:C054368', (166, 177))	('TGI', 'MPA', (122, 125))
103690	24454684	Moreover, an increased median overall survival was observed when S44563 was administered in an adjuvant setting after fotemustine-induced complete remission.	('fotemustine', 'Chemical', 'MESH:C054368', (118, 129))	('S44563', 'Var', (65, 71))	('overall survival', 'MPA', (30, 46))	('increased', 'PosReg', (13, 22))	('S44563', 'Chemical', 'MESH:C000599183', (65, 71))
103691	24454684	In the MM26 xenograft, concomitant S44563 (50 mg/kg per injection) and fotemustine (30 mg/kg) slightly improved the TGI in comparison to fotemustine alone, but significantly improved the complete remission rate (p<0.02) (Table 2).	('S44563', 'Chemical', 'MESH:C000599183', (35, 41))	('S44563', 'Var', (35, 41))	('improved', 'PosReg', (103, 111))	('TGI', 'MPA', (116, 119))	('fotemustine', 'Chemical', 'MESH:C054368', (71, 82))	('fotemustine', 'Chemical', 'MESH:C054368', (137, 148))	('MM26', 'CellLine', 'CVCL:L791', (7, 11))	('improved', 'PosReg', (174, 182))	('complete remission rate', 'CPA', (187, 210))
103698	24454684	In contrast, only MP41 xenograft with a high Bcl-XL expression was sensitive to S44563, whereas the 3 other models characterized by a low Bcl-XL expression were resistant to S44563 administered alone.	('S44563', 'Chemical', 'MESH:C000599183', (80, 86))	('Bcl-XL expression', 'MPA', (45, 62))	('S44563', 'Var', (80, 86))	('MP41', 'Gene', '26930', (18, 22))	('S44563', 'Chemical', 'MESH:C000599183', (174, 180))	('MP41', 'Gene', (18, 22))	('sensitive', 'Reg', (67, 76))
103700	24454684	In order to evaluate the impact of S44563 on the expression of Bcl-2, Bcl-XL, and Mcl-1 proteins, two to four tumor samples have been collected at the time of mice sacrifice for immunohistochemical studies.	('S44563', 'Chemical', 'MESH:C000599183', (35, 41))	('Bcl-2', 'molecular_function', 'GO:0015283', ('63', '68'))	('S44563', 'Var', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('mice', 'Species', '10090', (159, 163))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
103703	24454684	Consequently, the expression of both Bcl-2 and Mcl-1 was highly increased after concomitant administration of fotemustine and S44563 in the MM66 xenograft (Figure 5).	('S44563', 'Var', (126, 132))	('Mcl-1', 'Gene', (47, 52))	('fotemustine', 'Chemical', 'MESH:C054368', (110, 121))	('Bcl-2', 'Gene', (37, 42))	('S44563', 'Chemical', 'MESH:C000599183', (126, 132))	('expression', 'MPA', (18, 28))	('Bcl-2', 'molecular_function', 'GO:0015283', ('37', '42'))	('increased', 'PosReg', (64, 73))
103704	24454684	In order to evaluate in vivo apoptosis induction, we have studied cleaved caspase-3 expression before and after S44563 +/- fotemustine administration.	('fotemustine', 'Chemical', 'MESH:C054368', (123, 134))	('S44563 +/-', 'Var', (112, 122))	('S44563', 'Chemical', 'MESH:C000599183', (112, 118))	('caspase-3', 'Gene', (74, 83))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('caspase-3', 'Gene', '836', (74, 83))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))
103710	24454684	Indeed, in 3 out of the 4 tested xenografts (MP41, MP77, and MM66), S44563 increased tumor growth inhibition when combined to fotemustine in comparison to fotemustine alone.	('fotemustine', 'Chemical', 'MESH:C054368', (126, 137))	('tumor', 'Disease', (85, 90))	('S44563', 'Var', (68, 74))	('MP41', 'Gene', '26930', (45, 49))	('fotemustine', 'Chemical', 'MESH:C054368', (155, 166))	('increased', 'PosReg', (75, 84))	('MP41', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('S44563', 'Chemical', 'MESH:C000599183', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
103717	24454684	Such an observation is confirmed by the report of Jain and Meyer-Hermann who showed that inhibition of Bcl-XL may decrease the reparation of DNA damages induced by carboplatin.	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('carboplatin', 'Chemical', 'MESH:D016190', (164, 175))	('inhibition', 'Var', (89, 99))	('Bcl-XL', 'Protein', (103, 109))	('reparation of DNA damages', 'CPA', (127, 152))	('decrease', 'NegReg', (114, 122))
103719	24454684	In our in vitro experiments testing the effect of S44563 in 3 human UM cell lines, S44563 did not modify the proportion and the total amount of cleaved LC3 protein.	('S44563', 'Chemical', 'MESH:C000599183', (83, 89))	('S44563', 'Chemical', 'MESH:C000599183', (50, 56))	('human', 'Species', '9606', (62, 67))	('S44563', 'Var', (83, 89))	('LC3', 'Gene', '84557', (152, 155))	('LC3', 'Gene', (152, 155))	('cleaved', 'MPA', (144, 151))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('S44563', 'Var', (50, 56))
103722	24454684	Despite a modest efficacy when used alone, S44563 significantly increased efficacy of fotemustine.	('fotemustine', 'Chemical', 'MESH:C054368', (86, 97))	('efficacy', 'MPA', (74, 82))	('S44563', 'Chemical', 'MESH:C000599183', (43, 49))	('S44563', 'Var', (43, 49))	('increased', 'PosReg', (64, 73))
103724	24454684	In our in vivo experiments, we have evaluated this targeted approach in relevant preclinical models and showed that both in concomitant and differed administration, S44563 were able to increase the effect of fotemustine.	('increase', 'PosReg', (185, 193))	('effect', 'MPA', (198, 204))	('S44563', 'Var', (165, 171))	('fotemustine', 'Chemical', 'MESH:C054368', (208, 219))	('S44563', 'Chemical', 'MESH:C000599183', (165, 171))
103788	24092966	While it has been suggested that intravitreal injections of triamcinolone acetonide may be associated with side effects, including glaucoma, cataracts, retinal detachment, and endophthalmitis, no patients in our series developed endophthalmitis or underwent enucleation.	('retinal detachment', 'Disease', (152, 170))	('glaucoma', 'Phenotype', 'HP:0000501', (131, 139))	('endophthalmitis', 'Disease', (229, 244))	('cataracts', 'Disease', 'MESH:D002386', (141, 150))	('cataracts', 'Disease', (141, 150))	('retinal detachment', 'Disease', 'MESH:D012163', (152, 170))	('triamcinolone', 'Var', (60, 73))	('glaucoma', 'Disease', (131, 139))	('patients', 'Species', '9606', (196, 204))	('cataracts', 'Phenotype', 'HP:0000518', (141, 150))	('enucleation', 'biological_process', 'GO:0090601', ('258', '269'))	('endophthalmitis', 'Disease', 'MESH:D009877', (176, 191))	('retinal detachment', 'Phenotype', 'HP:0000541', (152, 170))	('glaucoma', 'Disease', 'MESH:D005901', (131, 139))	('triamcinolone acetonide', 'Chemical', 'MESH:D014222', (60, 83))	('endophthalmitis', 'Disease', 'MESH:D009877', (229, 244))	('endophthalmitis', 'Disease', (176, 191))
103797	22003361	Tumors with monosomy 3 that have an unfavorable prognosis exhibited significantly more M2-type macrophages than tumors with disomy of chromosome 3.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('more', 'PosReg', (82, 86))	('disomy', 'Disease', (124, 130))	('disomy', 'Disease', 'MESH:D024182', (124, 130))	('tumors', 'Disease', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('chromosome', 'cellular_component', 'GO:0005694', ('134', '144'))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('M2-type macrophages', 'MPA', (87, 106))	('monosomy 3', 'Var', (12, 22))
103819	22003361	Monosomy of chromosome 3 turned out to be significantly associated with a higher CD68, CD163 and CD68-CD163 double staining, compared with tumors with disomy of chromosome 3.	('Monosomy', 'Var', (0, 8))	('disomy', 'Disease', 'MESH:D024182', (151, 157))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))	('higher', 'PosReg', (74, 80))	('CD68', 'Gene', (97, 101))	('CD68', 'Gene', '968', (97, 101))	('CD163', 'Gene', '9332', (87, 92))	('CD163', 'Gene', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('CD68', 'Gene', (81, 85))	('CD163', 'Gene', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('CD68', 'Gene', '968', (81, 85))	('chromosome', 'cellular_component', 'GO:0005694', ('161', '171'))	('disomy', 'Disease', (151, 157))	('CD163', 'Gene', '9332', (102, 107))
103822	22003361	In the majority of tumors investigated to date, M2 macrophages were associated with a reduced patient survival, for example, in ovarian cancer, pancreatic cancer and skin melanoma.	('tumors', 'Disease', (19, 25))	('pancreatic cancer', 'Disease', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('skin melanoma', 'Disease', 'MESH:D008545', (166, 179))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (144, 161))	('patient', 'Species', '9606', (94, 101))	('ovarian cancer', 'Disease', 'MESH:D010051', (128, 142))	('reduced', 'NegReg', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('skin melanoma', 'Disease', (166, 179))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('M2 macrophages', 'Var', (48, 62))	('pancreatic cancer', 'Disease', 'MESH:D010190', (144, 161))	('ovarian cancer', 'Disease', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ovarian cancer', 'Phenotype', 'HP:0100615', (128, 142))	('patient survival', 'CPA', (94, 110))
103839	22003361	Tumors with the prognostic unfavorable monosomy of chromosome 3 consisted of significantly more M2-type macrophages than their disomy 3 counterparts.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('monosomy', 'Var', (39, 47))	('more', 'PosReg', (91, 95))	('chromosome', 'cellular_component', 'GO:0005694', ('51', '61'))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('disomy', 'Disease', 'MESH:D024182', (127, 133))	('M2-type macrophages', 'MPA', (96, 115))	('disomy', 'Disease', (127, 133))
103847	18689700	Later, Girnita et al from the same group expanded upon this finding to suggest a novel therapeutic approach to uveal melanoma using the pharmacological manipulation of ILGRF-1 in human uveal melanoma cell lines.	('uveal melanoma', 'Phenotype', 'HP:0007716', (111, 125))	('uveal melanoma', 'Disease', 'MESH:C536494', (111, 125))	('human', 'Species', '9606', (179, 184))	('pharmacological', 'Var', (136, 151))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('uveal melanoma', 'Disease', (111, 125))	('ILGRF-1', 'Gene', (168, 175))	('uveal melanoma', 'Phenotype', 'HP:0007716', (185, 199))	('uveal melanoma', 'Disease', (185, 199))	('uveal melanoma', 'Disease', 'MESH:C536494', (185, 199))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
103864	18689700	Our laboratory was interested in identifying novel BRAF mutations in uveal melanoma cell lines.	('mutations', 'Var', (56, 65))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('uveal melanoma', 'Disease', (69, 83))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('BRAF', 'Gene', '673', (51, 55))	('BRAF', 'Gene', (51, 55))
103865	18689700	It has already been shown that the OCM1 cell line was positive for the V599E mutation, a finding of interest because in contrast with cutaneous melanoma and conjunctival melanomas, the V599E (also known as V600E) mutation is not commonly found in uveal melanomas except for those tumors originating in the iris.	('cutaneous melanoma and conjunctival melanomas', 'Disease', 'MESH:D008545', (134, 179))	('melanomas', 'Phenotype', 'HP:0002861', (253, 262))	('V599E', 'Var', (71, 76))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (134, 152))	('V599E', 'Mutation', 'p.V599E', (71, 76))	('tumors', 'Disease', 'MESH:D009369', (280, 286))	('melanoma', 'Phenotype', 'HP:0002861', (253, 261))	('uveal melanomas', 'Disease', 'MESH:C536494', (247, 262))	('OCM1', 'Species', '83984', (35, 39))	('melanomas', 'Phenotype', 'HP:0002861', (170, 179))	('tumors', 'Phenotype', 'HP:0002664', (280, 286))	('uveal melanoma', 'Phenotype', 'HP:0007716', (247, 261))	('V599E', 'Var', (185, 190))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('V599E', 'Mutation', 'p.V599E', (185, 190))	('uveal melanomas', 'Disease', (247, 262))	('uveal melanomas', 'Phenotype', 'HP:0007716', (247, 262))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumors', 'Disease', (280, 286))	('V600E', 'Mutation', 'rs113488022', (206, 211))
103866	18689700	Recently, Maat et al identified the V600E mutation in OCM1 and OCM3, and we confirmed the V599E mutation in the OCM1 and OCM3 cell lines, and determined that the M619, C918, and MUM2B cell lines were negative for this mutation.	('OCM1', 'Species', '83984', (54, 58))	('V599E', 'Var', (90, 95))	('OCM1', 'Species', '83984', (112, 116))	('V600E', 'Var', (36, 41))	('V600E', 'Mutation', 'rs113488022', (36, 41))	('V599E', 'Mutation', 'p.V599E', (90, 95))	('MUM2', 'Gene', (178, 182))	('MUM2', 'Gene', '58485', (178, 182))
103867	18689700	We were surprised to discover that the MUM2C cell line was also positive for the V599E mutation, because according to the literature, the MUM2B and MUM2C cell lines were cloned from cells originating in a single hepatic metastasis.	('MUM2', 'Gene', (148, 152))	('MUM2', 'Gene', '58485', (138, 142))	('V599E', 'Mutation', 'p.V599E', (81, 86))	('MUM2', 'Gene', '58485', (148, 152))	('MUM2', 'Gene', (39, 43))	('V599E', 'Var', (81, 86))	('MUM2', 'Gene', '58485', (39, 43))	('MUM2', 'Gene', (138, 142))
103878	18689700	The STR profiles for the cell lines tested, summarized in Table 1, indicate that OCM1 and MUM2C are from the same patient, and that M619, C918, and MUM2B are from the same patient.	('MUM2', 'Gene', (148, 152))	('MUM2', 'Gene', (90, 94))	('MUM2', 'Gene', '58485', (148, 152))	('MUM2', 'Gene', '58485', (90, 94))	('patient', 'Species', '9606', (172, 179))	('C918', 'Var', (138, 142))	('OCM1', 'Species', '83984', (81, 85))	('patient', 'Species', '9606', (114, 121))	('M619', 'Var', (132, 136))
103885	18689700	We have not been able to obtain tissue from the patient's tumor sample from which C918 was developed, but we believe that it is reasonable to infer that MUM2B, C918, and M619 are all derived from the tumor that gave rise to C918.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('MUM2', 'Gene', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('M619', 'Var', (170, 174))	('MUM2', 'Gene', '58485', (153, 157))	('tumor', 'Disease', (200, 205))	('C918', 'Var', (160, 164))	('patient', 'Species', '9606', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
103891	18689700	Finally, although investigators should not refer to MUM2B cells as originating from a metastasis, it is appropriate to refer to cells labeled as C918, M619, or MUM2B as either invasive or aggressive.	('MUM2', 'Gene', '58485', (52, 56))	('MUM2', 'Gene', (160, 164))	('MUM2', 'Gene', '58485', (160, 164))	('C918', 'Var', (145, 149))	('M619', 'Var', (151, 155))	('MUM2', 'Gene', (52, 56))
103909	14612903	Other defined factors are, for instance, the expression of the epidermal growth factor receptor (Hurks et al, 2000) and the reduced CDKN2A expression caused by promoter hypermethylation (van der Velden et al, 2001).	('CDKN2A', 'Gene', (132, 138))	('reduced', 'NegReg', (124, 131))	('CDKN2A', 'Gene', '1029', (132, 138))	('promoter hypermethylation', 'Var', (160, 185))	('epidermal growth factor receptor', 'Gene', (63, 95))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('63', '86'))	('epidermal growth factor receptor', 'Gene', '1956', (63, 95))	('expression', 'MPA', (139, 149))
103914	14612903	For instance, loss of chromosome 3 and gain of the q arm of chromosome 8 are significantly associated with poor survival and loss of 1p is a specific hallmark of primary uveal melanoma metastases (White et al, 1998; Aalto et al, 2001).	('chromosome', 'cellular_component', 'GO:0005694', ('22', '32'))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('loss of', 'Var', (125, 132))	('uveal melanoma', 'Phenotype', 'HP:0007716', (170, 184))	('uveal melanoma metastases', 'Disease', (170, 195))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (170, 195))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))	('gain', 'PosReg', (39, 43))	('poor', 'NegReg', (107, 111))	('loss', 'NegReg', (14, 18))
28489	33196683	During the past few decades, genetic or epigenetic alterations have been confirmed to be associated with the tumorigenesis and progression of UM.	('associated', 'Reg', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('epigenetic alterations', 'Var', (40, 62))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('genetic', 'Var', (29, 36))	('tumor', 'Disease', (109, 114))
28490	33196683	According to reports, GNAQ and GNA11 mutations can promote cell proliferation and metastasis.	('GNAQ', 'Gene', (22, 26))	('cell proliferation', 'CPA', (59, 77))	('mutations', 'Var', (37, 46))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('promote', 'PosReg', (51, 58))	('GNAQ', 'Gene', '2776', (22, 26))	('GNA11', 'Gene', (31, 36))	('GNA11', 'Gene', '2767', (31, 36))
104025	33196683	Other chromosomal abnormalities have been shown to correlate with poor prognosis, including 8q gain, 6q loss, lack of 6p gain, 1p loss, and 16q loss.	('loss', 'NegReg', (104, 108))	('chromosomal abnormalities', 'Disease', (6, 31))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (6, 31))	('lack', 'Var', (110, 114))	('16q', 'Disease', (140, 143))	('gain', 'PosReg', (95, 99))
104034	33196683	The results showed that 52 genes were significantly correlated with copy numbers of chromosome 3, 50 genes were significantly correlated with copy numbers of chromosome 8q, and 22 genes were significantly correlated with tumor metastasis.	('correlated', 'Reg', (52, 62))	('chromosome', 'cellular_component', 'GO:0005694', ('158', '168'))	('copy numbers', 'Var', (68, 80))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('correlated', 'Reg', (205, 215))	('correlated', 'Reg', (126, 136))	('tumor metastasis', 'Disease', 'MESH:D009362', (221, 237))	('tumor metastasis', 'Disease', (221, 237))
104048	33196683	On the "road" to find the prognostic genes of UM, we are the first to combine tumor microenvironment scores and double screening (Kaplan-Meier and univariate Cox methods) for training and introduce chromosome copy number variation for gene screen.	('chromosome', 'cellular_component', 'GO:0005694', ('196', '206'))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('chromosome copy number variation', 'Var', (198, 230))	('tumor', 'Disease', (78, 83))
104054	33196683	One recent study has demonstrated that loss of BAP1 expression is strongly associated with immune modulation of the microenvironment, and it makes an impact on the immunotherapy of UM.	('makes', 'Reg', (141, 146))	('impact', 'Reg', (150, 156))	('expression', 'MPA', (52, 62))	('BAP1', 'Gene', '8314', (47, 51))	('immunotherapy', 'CPA', (164, 177))	('loss', 'Var', (39, 43))	('associated', 'Reg', (75, 85))	('BAP1', 'Gene', (47, 51))
104057	33196683	In addition to chromosome 3 and 8q, other chromosomal abnormalities have been shown to correlate with poor prognosis and these include 6q loss, lack of 6p gain, 1p loss, and 16q loss.	('loss', 'NegReg', (138, 142))	('chromosome', 'cellular_component', 'GO:0005694', ('15', '25'))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (42, 67))	('gain', 'PosReg', (155, 159))	('chromosomal abnormalities', 'Disease', (42, 67))	('lack', 'Var', (144, 148))	('16q', 'CPA', (174, 177))
104245	32923156	It is important to note is that the anti-tumor effect of the TIL is likely not mainly due to the recognition of shared TAA but to the recognition of neoepitopes generated by the high mutational load in melanomas.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('melanomas', 'Disease', 'MESH:D008545', (202, 211))	('tumor', 'Disease', (41, 46))	('high mutational load', 'Var', (178, 198))	('melanomas', 'Disease', (202, 211))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('melanomas', 'Phenotype', 'HP:0002861', (202, 211))
104288	31561508	Innovative data fusion techniques confirm, as expected, the existence of two main types of uveal melanoma mainly characterized by copy number alterations.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('uveal melanoma', 'Disease', 'MESH:C536494', (91, 105))	('characterized', 'Reg', (113, 126))	('uveal melanoma', 'Phenotype', 'HP:0007716', (91, 105))	('uveal melanoma', 'Disease', (91, 105))	('copy number alterations', 'Var', (130, 153))
104295	31561508	UM shows a mean of 17 mutations in coding regions of protein coding genes, approximately 80% of cases show a mutation in the alpha subunit of one of the two G-protein alpha subunits, GNAQ and GNA11.	('UM', 'Disease', 'MESH:C536494', (0, 2))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('GNAQ', 'Gene', '2776', (183, 187))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('GNA11', 'Gene', (192, 197))	('GNA11', 'Gene', '2767', (192, 197))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('GNAQ', 'Gene', (183, 187))	('mutation', 'Var', (109, 117))
104296	31561508	Mutations in the tumor suppressor gene BAP1 are associated with elevated metastatic risk and mutations in SF3B1, a gene encoding a component of the splicing machinery, confer intermediate risk with retarded development of metastases.	('retarded development', 'Phenotype', 'HP:0001263', (198, 218))	('splicing', 'biological_process', 'GO:0045292', ('148', '156'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('17', '33'))	('tumor', 'Disease', (17, 22))	('mutations', 'Var', (93, 102))	('SF3B1', 'Gene', (106, 111))	('associated', 'Reg', (48, 58))	('metastatic risk', 'CPA', (73, 88))	('metastases', 'Disease', (222, 232))	('retarded', 'NegReg', (198, 206))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('17', '33'))	('SF3B1', 'Gene', '23451', (106, 111))	('Mutations', 'Var', (0, 9))	('metastases', 'Disease', 'MESH:D009362', (222, 232))	('BAP1', 'Gene', '8314', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('BAP1', 'Gene', (39, 43))
104297	31561508	The relatively frequent mutations of the translational elongation factor gene EIF1AX do apparently not influence metastatic risk.	('EIF1AX', 'Gene', '1964', (78, 84))	('EIF1AX', 'Gene', (78, 84))	('influence', 'Reg', (103, 112))	('metastatic', 'CPA', (113, 123))	('mutations', 'Var', (24, 33))	('translational elongation', 'biological_process', 'GO:0006414', ('41', '65'))
104299	31561508	The initially two prognostic classes, mainly distinguished by chromosome 3 status, have been extended to three classes since cases with disomy of chromosome 3 and SF3B1 mutations tend to develop metastases with time.	('metastases', 'Disease', 'MESH:D009362', (195, 205))	('mutations', 'Var', (169, 178))	('SF3B1', 'Gene', '23451', (163, 168))	('chromosome', 'cellular_component', 'GO:0005694', ('62', '72'))	('chromosome', 'cellular_component', 'GO:0005694', ('146', '156'))	('disomy', 'Disease', 'MESH:D024182', (136, 142))	('develop', 'PosReg', (187, 194))	('metastases', 'Disease', (195, 205))	('disomy', 'Disease', (136, 142))	('SF3B1', 'Gene', (163, 168))
104302	31561508	This analysis subdivided the two cytogenetic classes (di- versus monosomy of chr3) into two subclasses each, characterized by SF3B1/SRSF2 and EIF1AX mutations in association with distinct transcriptional and methylation profiles in disomic cases, and distinct gene expression and copy number alterations in monosomic cases.	('EIF1AX', 'Gene', '1964', (142, 148))	('EIF1AX', 'Gene', (142, 148))	('mutations', 'Var', (149, 158))	('SF3B1', 'Gene', (126, 131))	('gene expression', 'biological_process', 'GO:0010467', ('260', '275'))	('transcriptional', 'MPA', (188, 203))	('methylation', 'biological_process', 'GO:0032259', ('208', '219'))	('SRSF2', 'Gene', '6427', (132, 137))	('SF3B1', 'Gene', '23451', (126, 131))	('methylation', 'MPA', (208, 219))	('disomic', 'Disease', (232, 239))	('SRSF2', 'Gene', (132, 137))
104315	31561508	BAP1 mutations are typical for group 3 and 4 cases, a single BAP1 mutation occurs in metastatic case of group 2.	('BAP1', 'Gene', (61, 65))	('BAP1', 'Gene', (0, 4))	('BAP1', 'Gene', '8314', (61, 65))	('mutations', 'Var', (5, 14))	('BAP1', 'Gene', '8314', (0, 4))
104316	31561508	EIF1AX mutations are almost exclusively observed in group 1 whereas SF3B1 mutations show a similar frequency in groups 1 and 2.	('SF3B1', 'Gene', (68, 73))	('observed', 'Reg', (40, 48))	('SF3B1', 'Gene', '23451', (68, 73))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
104317	31561508	However, jCMF groups together cases with SF3B1 mutations in group 2 (see comutation plot, Figure 2b).	('SF3B1', 'Gene', '23451', (41, 46))	('mutations', 'Var', (47, 56))	('SF3B1', 'Gene', (41, 46))
104318	31561508	Again, the distinction of subgroups 1 and 2 is weak although SF3B1 mutations almost exclusively occur in group 2.	('SF3B1', 'Gene', '23451', (61, 66))	('occur', 'Reg', (96, 101))	('SF3B1', 'Gene', (61, 66))	('mutations', 'Var', (67, 76))
104325	31561508	Two well distinguished classes with di- and monosomy of chromosome 3 are well known since the application of cytogenetics to UM.	('di-', 'Var', (36, 39))	('UM', 'Phenotype', 'HP:0007716', (125, 127))	('monosomy', 'Var', (44, 52))	('UM', 'Disease', 'MESH:C536494', (125, 127))	('chromosome', 'cellular_component', 'GO:0005694', ('56', '66'))
104328	31561508	The importance of this subclass might be underestimated using the TCGA dataset since it has limited follow-up and cases with SF3B1 mutations develop metastases several years after diagnosis of primary UM.	('mutations', 'Var', (131, 140))	('SF3B1', 'Gene', '23451', (125, 130))	('metastases', 'Disease', (149, 159))	('metastases', 'Disease', 'MESH:D009362', (149, 159))	('UM', 'Phenotype', 'HP:0007716', (201, 203))	('develop', 'Reg', (141, 148))	('UM', 'Disease', 'MESH:C536494', (201, 203))	('SF3B1', 'Gene', (125, 130))
104333	31561508	The dataset shows several particularities: cases were selected for having either GNAQ or GNA11 mutations, double wild types were excluded, the dataset contains two unusual cases with mutations in both GNAQ and GNA11 that have never been observed in other cohorts, one case shows an unusual high mutational burden.	('GNA11', 'Gene', '2767', (210, 215))	('mutations', 'Var', (183, 192))	('GNAQ', 'Gene', '2776', (201, 205))	('GNAQ', 'Gene', (81, 85))	('GNA11', 'Gene', '2767', (89, 94))	('GNA11', 'Gene', (89, 94))	('GNAQ', 'Gene', (201, 205))	('GNA11', 'Gene', (210, 215))	('GNAQ', 'Gene', '2776', (81, 85))
104340	31561508	We have adapted data fusion techniques that have been developed for non-biological data to multi-domain cancer data using the TCGA uveal melanoma copy number alteration, DNA-methylation and transcriptome data as a test set.	('uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))	('uveal melanoma', 'Disease', 'MESH:C536494', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('uveal melanoma', 'Disease', (131, 145))	('alteration', 'Var', (158, 168))	('DNA-methylation', 'biological_process', 'GO:0006306', ('170', '185'))	('copy number alteration', 'Var', (146, 168))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))
104341	31561508	Molecular classification of UM, that is predominantly determined by copy number alterations, is not improved by data fusion but this is expected to be different for more heterogeneous and complex cancers.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('UM', 'Phenotype', 'HP:0007716', (28, 30))	('copy', 'Var', (68, 72))	('UM', 'Disease', 'MESH:C536494', (28, 30))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('cancers', 'Disease', (196, 203))	('cancers', 'Disease', 'MESH:D009369', (196, 203))
104376	31382537	Reactions with the same panel of lectins revealed that >92% of Mel202 cells possessed alpha2,3- and alpha2,6-linked sialic acids, fucose residues, and bisecting GlcNAc in complex type N-glycans, as well as beta1,6-branched tri- and/or tetra-antennary complex type N-glycans (Figure 6A,B).	('fucose', 'Chemical', 'MESH:D005643', (130, 136))	('tetra-antennary', 'Protein', (235, 250))	('N-glycans', 'Chemical', '-', (264, 273))	('bisecting', 'Var', (151, 160))	('tetra', 'Species', '42554', (235, 240))	('beta1,6-branched', 'Chemical', '-', (206, 222))	('N-glycans', 'Chemical', '-', (184, 193))	('GlcNAc', 'Chemical', '-', (161, 167))	('alpha2,3- and alpha2,6-linked sialic acids', 'Chemical', '-', (86, 128))	('fucose residues', 'Protein', (130, 145))
104379	31382537	Finally, the lowest RFI was measured for GNA-positive cells, suggesting that high-mannose and/or hybrid type oligosaccharides were mostly intracellular.	('high-mannose', 'Chemical', '-', (77, 89))	('intracellular', 'cellular_component', 'GO:0005622', ('138', '151'))	('oligosaccharides', 'Chemical', 'MESH:D009844', (109, 125))	('high-mannose', 'Protein', (77, 89))	('hybrid type', 'Var', (97, 108))
104422	31382537	Similarly, deoxymannojirimycin, an alpha-mannosidase I inhibitor, decreased the level of EWI-2 glycoprotein in Sk-Mel-5-derived exosomes, while its level on the cell surface was not affected.	('EWI-2', 'Gene', '93185', (89, 94))	('deoxymannojirimycin', 'Var', (11, 30))	('decreased', 'NegReg', (66, 75))	('EWI-2', 'Gene', (89, 94))	('mannosidase I', 'molecular_function', 'GO:0004571', ('41', '54'))	('cell surface', 'cellular_component', 'GO:0009986', ('161', '173'))	('Sk-Mel-5', 'Chemical', '-', (111, 119))
104430	31382537	The release of glycoproteins with bisecting GlcNAc via ectosomes might be a mechanism that allows cancer cells to retain their metastatic potential.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('bisecting', 'Var', (34, 43))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('glycoproteins', 'Protein', (15, 28))	('GlcNAc', 'Chemical', '-', (44, 50))	('release', 'MPA', (4, 11))	('cancer', 'Disease', (98, 104))	('metastatic potential', 'CPA', (127, 147))
104468	31413738	Verteporfin significantly inhibited HNSCC cell proliferation, migration and invasion, induced apoptosis, and arrested the cell cycle at the S/G2 phase.	('arrested', 'NegReg', (109, 117))	('migration', 'CPA', (62, 71))	('inhibited', 'NegReg', (26, 35))	('HNSCC cell proliferation', 'CPA', (36, 60))	('Verteporfin', 'Chemical', 'MESH:D000077362', (0, 11))	('cell cycle', 'biological_process', 'GO:0007049', ('122', '132'))	('G2 phase', 'biological_process', 'GO:0051319', ('142', '150'))	('HNSCC', 'Phenotype', 'HP:0012288', (36, 41))	('cell proliferation', 'biological_process', 'GO:0008283', ('42', '60'))	('induced', 'Reg', (86, 93))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))	('S/G2', 'Var', (140, 144))	('S/G2', 'SUBSTITUTION', 'None', (140, 144))	('apoptosis', 'CPA', (94, 103))	('invasion', 'CPA', (76, 84))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))
104480	31413738	Dysregulation of the Hippo pathway has been implicated in many human diseases, including cancer.	('human', 'Species', '9606', (63, 68))	('Dysregulation', 'Var', (0, 13))	('implicated', 'Reg', (44, 54))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('Hippo pathway', 'Pathway', (21, 34))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
104549	31413738	In the present study, the migration of cells treated with 0.25 and 0.5 microM VP was significantly decreased in a dose-dependent manner compared with the DMSO group cells (Fig.	('migration of cells', 'CPA', (26, 44))	('decreased', 'NegReg', (99, 108))	('VP', 'Chemical', 'MESH:D000077362', (78, 80))	('DMSO', 'Chemical', 'MESH:D004121', (154, 158))	('0.25', 'Var', (58, 62))
104563	31413738	Moreover, our data showed that YAP1 expression was highest in UM-SCC-47 cells, moderate in UPCI-SCC-090 cells and lowest in 93-VU-147T cells in the three HPV-positive HNSCC cell lines, consistent with a previous report, in which authors show that UM-SCC-47 cell line has YAP1 gene amplification and 93-VU-147T cell line has YAP1 gene deep deletion.	('YAP1', 'Gene', (271, 275))	('YAP1', 'Gene', '10413', (271, 275))	('deep deletion', 'Var', (334, 347))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (247, 256))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (62, 71))	('YAP1', 'Gene', (31, 35))	('YAP1', 'Gene', '10413', (31, 35))	('93-VU-147T', 'CellLine', 'CVCL:L895', (299, 309))	('93-VU-147T', 'CellLine', 'CVCL:L895', (124, 134))	('HNSCC', 'Phenotype', 'HP:0012288', (167, 172))	('YAP1', 'Gene', (324, 328))	('YAP1', 'Gene', '10413', (324, 328))	('HPV', 'Species', '10566', (154, 157))	('expression', 'MPA', (36, 46))
104645	31235702	Vitamin D is activated through sequential hydroxylations at C25 (by CYP27A1 and/or CYP2R) with following hydroxylation at C12 by CYP27B1 and inactivated by CYP24A1 through hydroxylation at C24 with further shortening at the side chain to produce calcitroic acid.	('CYP27A1', 'molecular_function', 'GO:0047749', ('68', '75'))	('CYP27A1', 'Gene', (68, 75))	('calcitroic acid', 'Chemical', 'MESH:C021640', (246, 261))	('CYP27B1', 'Gene', '1594', (129, 136))	('CYP24A1', 'Gene', (156, 163))	('CYP2R', 'Var', (83, 88))	('CYP24A1', 'Gene', '1591', (156, 163))	('CYP27A1', 'Gene', '1593', (68, 75))	('CYP27B1', 'Gene', (129, 136))	('activated', 'PosReg', (13, 22))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))
38238	31235702	It was shown that vitamin D deficiency or dysregulated vitamin D signaling can play an important role in oncogenesis, clinical advancement and prognosis in such neoplasms as cutaneous melanomas, bladder, breast, lung, ovarian, pancreatic, thyroid, prostate and colorectal cancers.	('neoplasms', 'Disease', (161, 170))	('deficiency', 'Disease', (28, 38))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('dysregulated vitamin D', 'Phenotype', 'HP:0100512', (42, 64))	('breast', 'Disease', (204, 210))	('colorectal cancers', 'Disease', (261, 279))	('thyroid', 'Disease', (239, 246))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (174, 193))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (174, 193))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (174, 192))	('pancreatic', 'Disease', (227, 237))	('vitamin D', 'Chemical', 'MESH:D014807', (18, 27))	('neoplasms', 'Phenotype', 'HP:0002664', (161, 170))	('oncogenesis', 'biological_process', 'GO:0007048', ('105', '116'))	('bladder', 'Disease', (195, 202))	('ovarian', 'Disease', (218, 225))	('ovarian', 'Disease', 'MESH:D010051', (218, 225))	('lung', 'Disease', (212, 216))	('dysregulated', 'Var', (42, 54))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))	('cutaneous melanomas', 'Disease', (174, 193))	('prostate', 'Disease', (248, 256))	('colorectal cancers', 'Disease', 'MESH:D015179', (261, 279))	('neoplasms', 'Disease', 'MESH:D009369', (161, 170))	('melanomas', 'Phenotype', 'HP:0002861', (184, 193))	('deficiency', 'Disease', 'MESH:D007153', (28, 38))	('vitamin D', 'Chemical', 'MESH:D014807', (55, 64))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (18, 38))	('pancreatic', 'Disease', 'MESH:D010195', (227, 237))
104712	31235702	Our study provides evidence showing the presence of VDR and CYB27B1 and CYP24A1, hydroxylases taking part in vitamin D metabolism, as well as RORalpha and RORgamma, alternative receptors for vitamin D-hydroxyderivatives.	('CYP24A1', 'Gene', '1591', (72, 79))	('VDR', 'Gene', (52, 55))	('vitamin D metabolism', 'biological_process', 'GO:0042359', ('109', '129'))	('eta', 'Gene', (120, 123))	('RORalpha and RORgamma', 'Gene', '6095', (142, 163))	('VDR', 'Gene', '7421', (52, 55))	('vitamin D', 'Chemical', 'MESH:D014807', (191, 200))	('vitamin D', 'Chemical', 'MESH:D014807', (109, 118))	('eta', 'Gene', '1909', (120, 123))	('CYP24A1', 'Gene', (72, 79))	('CYB27B1', 'Var', (60, 67))
104713	31235702	In all of the tissues examined the presence of nuclear receptors for vitamin D (VDRn), RORalphan and RORgamman, as well as CYB27B1 and CYP24A1, were confirmed.	('vitamin D', 'Chemical', 'MESH:D014807', (69, 78))	('RORalphan', 'Chemical', '-', (87, 96))	('VDR', 'Gene', (80, 83))	('CYB27B1', 'Var', (123, 130))	('CYP24A1', 'Gene', (135, 142))	('CYP24A1', 'Gene', '1591', (135, 142))	('VDR', 'Gene', '7421', (80, 83))	('RORgamman', 'Chemical', '-', (101, 110))
104722	31235702	Also in skin melanoma, a significantly decrease in the expression of VDR, CYB27B1, CYP24A1, RORalpha and RORgamma was observed in comparison to normal melanocytes or perilesional keratinocytes.	('CYP24A1', 'Gene', (83, 90))	('decrease', 'NegReg', (39, 47))	('CYB27B1', 'Var', (74, 81))	('CYP24A1', 'Gene', '1591', (83, 90))	('VDR', 'Gene', '7421', (69, 72))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('expression', 'MPA', (55, 65))	('skin melanoma', 'Disease', 'MESH:D008545', (8, 21))	('RORalpha and RORgamma', 'Gene', '6095', (92, 113))	('VDR', 'Gene', (69, 72))	('skin melanoma', 'Disease', (8, 21))
104753	31235702	In conclusion, we provide an evidence for the presence of the VDR, CYB27B1, CYP24A1, RORalpha and RORgamma in uveal cells, which changes in uveal melanomas and suggest that these proteins are involved in clinical presentation and represent targets for novel therapeutic approaches.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanomas', 'Phenotype', 'HP:0002861', (146, 155))	('uveal melanomas', 'Disease', (140, 155))	('uveal melanomas', 'Phenotype', 'HP:0007716', (140, 155))	('VDR', 'Gene', '7421', (62, 65))	('CYP24A1', 'Gene', (76, 83))	('CYP24A1', 'Gene', '1591', (76, 83))	('uveal melanomas', 'Disease', 'MESH:C536494', (140, 155))	('uveal melanoma', 'Phenotype', 'HP:0007716', (140, 154))	('VDR', 'Gene', (62, 65))	('RORalpha and RORgamma', 'Gene', '6095', (85, 106))	('CYB27B1', 'Var', (67, 74))
104841	30890735	Burden of unique and low prevalence somatic mutations correlates with cancer survival Tumor mutational burden correlates with improved survival and immunotherapy response in some malignancies, and with tumor aggressiveness in others.	('improved', 'PosReg', (126, 134))	('tumor aggressiveness', 'Disease', (202, 222))	('aggressiveness', 'Phenotype', 'HP:0000718', (208, 222))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('malignancies', 'Disease', 'MESH:D009369', (179, 191))	('malignancies', 'Disease', (179, 191))	('Tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (202, 222))	('mutations', 'Var', (44, 53))	('survival', 'CPA', (135, 143))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
104844	30890735	High TEMMB was associated with improved survival in cutaneous melanoma: hazard ratio (HR) = 0.71 [0.60-0.85], p = 0.0002, urothelial bladder carcinoma: HR = 0.74 [0.59-0.93], p = 0.01, and ovarian carcinoma: HR = 0.80 [0.70-0.93], p = 0.003.	('improved', 'PosReg', (31, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('cutaneous melanoma', 'Disease', (52, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (52, 70))	('TEMMB', 'Chemical', '-', (5, 10))	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (122, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('urothelial bladder carcinoma', 'Disease', (122, 150))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (189, 206))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (133, 150))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (189, 206))	('High TEMMB', 'Var', (0, 10))	('ovarian carcinoma', 'Disease', (189, 206))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
104845	30890735	High TEMMB was associated with decreased survival in colorectal adenocarcinoma: HR = 1.32 [1.00-1.74], p < 0.05.	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (53, 78))	('TEMMB', 'Chemical', '-', (5, 10))	('decreased', 'NegReg', (31, 40))	('survival', 'MPA', (41, 49))	('colorectal adenocarcinoma', 'Disease', (53, 78))	('High TEMMB', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
104847	30890735	In cancers with a low RS, high TEMMB was correlated with better survival outcomes (r = 0.49, p = 0.02).	('high TEMMB', 'Var', (26, 36))	('survival outcomes', 'CPA', (64, 81))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('better', 'PosReg', (57, 63))	('TEMMB', 'Chemical', '-', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
104848	30890735	In conclusion, TEMMB effects on survival depend on recurrent mutation enrichment; tumor types that are highly enriched in passenger mutations show a survival benefit in the setting of high tumor mutational burden.	('tumor', 'Disease', (189, 194))	('TEMMB', 'Chemical', '-', (15, 20))	('mutations', 'Var', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('survival', 'CPA', (149, 157))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('benefit', 'PosReg', (158, 165))
104851	30890735	Alternatively, highly mutated tumors may develop many novel peptides and thus display more neoantigens, rendering them more susceptible T-cell targets.	('tumors', 'Disease', (30, 36))	('peptides', 'MPA', (60, 68))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('develop', 'PosReg', (41, 48))	('neoantigens', 'MPA', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('more', 'PosReg', (86, 90))	('highly mutated', 'Var', (15, 29))
104852	30890735	For example, patients with melanomas with a high mutational load showed improved survival with ipilimumab and improved overall survival; patients with highly mutated ovarian cancer had improved postoperative chemotherapy response and higher overall survival.	('melanomas', 'Disease', 'MESH:D008545', (27, 36))	('improved', 'PosReg', (185, 193))	('overall', 'MPA', (241, 248))	('improved', 'PosReg', (110, 118))	('highly mutated', 'Var', (151, 165))	('improved', 'PosReg', (72, 80))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (137, 145))	('ovarian cancer', 'Phenotype', 'HP:0100615', (166, 180))	('melanomas', 'Disease', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('ipilimumab', 'Chemical', 'MESH:D000074324', (95, 105))	('higher', 'PosReg', (234, 240))	('ovarian cancer', 'Disease', 'MESH:D010051', (166, 180))	('overall', 'MPA', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))	('ovarian cancer', 'Disease', (166, 180))
104857	30890735	Furthermore, missense variants specifically have been suggested to be the most frequent class of alterations to carry the potential for neoepitope generation in chronic lymphocytic leukemia malignancy (as compared to frameshift or splice-site variants).	('neoepitope generation', 'MPA', (136, 157))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (161, 189))	('leukemia', 'Phenotype', 'HP:0001909', (181, 189))	('chronic lymphocytic leukemia malignancy', 'Disease', (161, 200))	('chronic lymphocytic leukemia malignancy', 'Disease', 'MESH:D015451', (161, 200))	('missense variants', 'Var', (13, 30))	('lymphocytic leukemia malignancy', 'Phenotype', 'HP:0005526', (169, 200))
104858	30890735	In multiple myeloma, missense mutational load was found to be highly correlated with predicted neoantigen loads.	('multiple myeloma', 'Disease', (3, 19))	('correlated', 'Reg', (69, 79))	('neoantigen loads', 'MPA', (95, 111))	('missense mutational load', 'Var', (21, 45))	('multiple myeloma', 'Phenotype', 'HP:0006775', (3, 19))	('multiple myeloma', 'Disease', 'MESH:D009101', (3, 19))
104859	30890735	Total missense mutational burden across all cohorts ranged from a low of 8 (median) missense mutations among acute myeloid leukemia (LAML) and thymoma (THYM), to 256 median mutations among the skin cutaneous melanoma (SKCM) cohort (Fig.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (109, 131))	('leukemia', 'Phenotype', 'HP:0001909', (123, 131))	('thymoma', 'Disease', 'MESH:D013945', (143, 150))	('THYM', 'Phenotype', 'HP:0100522', (152, 156))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('thymoma', 'Disease', (143, 150))	('acute myeloid leukemia', 'Disease', (109, 131))	('mutations', 'Var', (173, 182))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (193, 216))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (115, 131))	('thymoma', 'Phenotype', 'HP:0100522', (143, 150))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (198, 216))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (109, 131))	('skin cutaneous melanoma', 'Disease', (193, 216))	('missense mutations', 'Var', (84, 102))
104861	30890735	Total (TEMB) and missense (TEMMB) tumor exonic mutational burden were found to be closely correlated among all cohorts: Pearson's r ranged from 0.95-1.00 for all cohorts other than uveal melanoma (UVM) which also revealed a strong positive correlation with r = 0.88 likely due to a small (N = 79) sample size (p < 2.2 x 10-16 for all cohorts) (Fig.	('missense', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('UVM', 'Phenotype', 'HP:0007716', (197, 200))	('uveal melanoma', 'Phenotype', 'HP:0007716', (181, 195))	('uveal melanoma', 'Disease', 'MESH:C536494', (181, 195))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('TEMMB', 'Chemical', '-', (27, 32))	('uveal melanoma', 'Disease', (181, 195))
104863	30890735	Male sex was significantly associated with high TEMMB in renal papillary cell carcinoma (KIRP), sarcoma (SARC), and cutaneous melanoma (SKCM).	('high TEMMB', 'Var', (43, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('SARC', 'Phenotype', 'HP:0100242', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('associated', 'Reg', (27, 37))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (57, 87))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('cutaneous melanoma', 'Disease', (116, 134))	('TEMMB', 'Chemical', '-', (48, 53))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (116, 134))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (116, 134))	('renal papillary cell carcinoma', 'Disease', (57, 87))	('sarcoma', 'Disease', (96, 103))
104864	30890735	Female sex was significantly associated with high TEMMB in colorectal adenocarcinoma (COAD) and glioblastoma multiforme (GBM).	('COAD', 'Disease', 'MESH:D029424', (86, 90))	('colorectal adenocarcinoma', 'Disease', (59, 84))	('TEMMB', 'Chemical', '-', (50, 55))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (59, 84))	('COAD', 'Disease', (86, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('glioblastoma multiforme', 'Disease', (96, 119))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('high TEMMB', 'Var', (45, 55))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (96, 119))
104867	30890735	High TEMMB correlated with improved survival in skin cutaneous melanoma (SKCM): HR = 0.71 [0.60-0.85], p = 0.0002, bladder urothelial carcinoma (BLCA): HR = 0.74 [0.59-0.93], p = 0.01, and ovarian carcinoma (OV): HR = 0.80 [0.70-0.93], p = 0.003.	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 71))	('improved', 'PosReg', (27, 35))	('OV', 'Phenotype', 'HP:0025318', (208, 210))	('TEMMB', 'Chemical', '-', (5, 10))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (115, 143))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('survival', 'MPA', (36, 44))	('skin cutaneous melanoma', 'Disease', (48, 71))	('bladder urothelial carcinoma', 'Disease', (115, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (189, 206))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (53, 71))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (189, 206))	('High TEMMB', 'Var', (0, 10))	('ovarian carcinoma', 'Disease', (189, 206))
104868	30890735	High TEMMB was associated with decreased survival in colorectal adenocarcinoma (COAD): HR = 1.32 [1.00-1.74], p < 0.05 (p = 0.0497).	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (53, 78))	('TEMMB', 'Chemical', '-', (5, 10))	('decreased', 'NegReg', (31, 40))	('COAD', 'Disease', (80, 84))	('colorectal adenocarcinoma', 'Disease', (53, 78))	('High TEMMB', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('COAD', 'Disease', 'MESH:D029424', (80, 84))
104870	30890735	To characterize the somatic mutational profile of each cancer, we determined the relative burden of recurrent mutations to total mutations within each cohort, expressed as a recurrence score (RS).	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (110, 119))	('cancer', 'Disease', (55, 61))
104872	30890735	Several cohorts, notably adrenocortical carcinoma (ACC), acute myeloid leukemia (LAML), brain lower grade glioma (LGG), pheochromocytoma and paraganglioma (PCPG), thyroid carcinoma (THCA), thymoma (THYM), and uveal melanoma (UVM), revealed mutations occurring at high prevalence among the sequenced population.	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('UVM', 'Phenotype', 'HP:0007716', (225, 228))	('glioma', 'Disease', (148, 154))	('THCA', 'Phenotype', 'HP:0002890', (182, 186))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (63, 79))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (57, 79))	('uveal melanoma', 'Disease', 'MESH:C536494', (209, 223))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (57, 79))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (163, 180))	('uveal melanoma', 'Disease', (209, 223))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (25, 49))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('mutations', 'Var', (240, 249))	('thyroid carcinoma', 'Disease', (163, 180))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (120, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('glioma', 'Disease', (106, 112))	('paraganglioma', 'Phenotype', 'HP:0002668', (141, 154))	('uveal melanoma', 'Phenotype', 'HP:0007716', (209, 223))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (25, 49))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (163, 180))	('thymoma', 'Disease', 'MESH:D013945', (189, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('adrenocortical carcinoma', 'Disease', (25, 49))	('THYM', 'Phenotype', 'HP:0100522', (198, 202))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('acute myeloid leukemia', 'Disease', (57, 79))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (120, 136))	('thymoma', 'Disease', (189, 196))	('ACC', 'Phenotype', 'HP:0006744', (51, 54))	('thymoma', 'Phenotype', 'HP:0100522', (189, 196))
104873	30890735	The recurrent mutations can be readily visualized as sharp peaks in the cancers' mutational profiles.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('mutations', 'Var', (14, 23))
104876	30890735	In the adrenocortical carcinoma (ACC) cohort, 0.29% of all pooled missense mutations were in the ZNF517 gene (p.V349A), and 0.29% of missense mutations were recurrent GARS (p.P42A) mutations.	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (7, 31))	('ZNF517', 'Gene', '340385', (97, 103))	('ZNF517', 'Gene', (97, 103))	('missense mutations', 'Var', (133, 151))	('ACC', 'Phenotype', 'HP:0006744', (33, 36))	('missense mutations', 'Var', (66, 84))	('p.V349A', 'Mutation', 'rs2976653', (110, 117))	('p.P42A', 'Mutation', 'rs1049402', (173, 179))	('adrenocortical carcinoma', 'Disease', (7, 31))	('GARS', 'Gene', '2617', (167, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('GARS', 'Gene', (167, 171))	('p.P42A', 'Var', (173, 179))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (7, 31))
104877	30890735	In uveal melanoma (UVM) cohort, 2.54% were recurrent GNA11 (p.Q209P) mutations, 2.01% were recurrent GNAQ p.Q209P, and 0.75% GNAQ p.Q1209L.	('p.Q1209L', 'Var', (130, 138))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('GNA11', 'Gene', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('p.Q1209L', 'Mutation', 'p.Q1209L', (130, 138))	('GNA11', 'Gene', '2767', (53, 58))	('UVM', 'Phenotype', 'HP:0007716', (19, 22))	('p.Q209P', 'Mutation', 'rs1057519742', (60, 67))	('p.Q209P', 'Mutation', 'rs1057519742', (106, 113))	('p.Q209P', 'Var', (106, 113))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
104878	30890735	In thyroid carcinoma (THCA), 5.23% were BRAF p.V600E, 0.65% were NRAS p.Q61R, and 0.25% HRAS p.Q61R.	('p.Q61R', 'Mutation', 'rs755829919', (70, 76))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (3, 20))	('thyroid carcinoma', 'Disease', (3, 20))	('THCA', 'Phenotype', 'HP:0002890', (22, 26))	('p.Q61R', 'Mutation', 'rs755829919', (93, 99))	('p.V600E', 'Mutation', 'p.V600E', (45, 52))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (3, 20))	('p.V600E', 'Var', (45, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
104879	30890735	In the acute myeloid leukemia (LAML) cohort, 1.38% of missense mutations were in DNMT3A gene (p.R882H), 1.05% were IDH2 p.R140Q, and 0.79% were IDH1 p.R132C.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (7, 29))	('p.R882H', 'Mutation', 'rs147001633', (94, 101))	('leukemia', 'Phenotype', 'HP:0001909', (21, 29))	('missense mutations', 'Var', (54, 72))	('DNMT3A', 'Gene', (81, 87))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (7, 29))	('DNMT3A', 'Gene', '1788', (81, 87))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (13, 29))	('p.R140Q', 'Var', (120, 127))	('p.R132C', 'Mutation', 'rs121913499', (149, 156))	('p.R140Q', 'Mutation', 'rs121913502', (120, 127))	('acute myeloid leukemia', 'Disease', (7, 29))
104880	30890735	In pheochromocytoma and paraganglioma (PCPG), 0.64% of mutations were recurrent HRAS p.Q61R, and 0.36% were CHEK2 p.K152E.	('p.Q61R', 'Var', (85, 91))	('mutations', 'Var', (55, 64))	('paraganglioma', 'Phenotype', 'HP:0002668', (24, 37))	('CHEK2', 'Gene', '11200', (108, 113))	('p.K152E', 'Mutation', 'rs74751600', (114, 121))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('p.Q61R', 'Mutation', 'rs755829919', (85, 91))	('CHEK2', 'Gene', (108, 113))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (3, 19))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (3, 37))
104882	30890735	Cancers with low RS tended to exhibit survival benefit (HR < 1) with increased adjusted-TEMMB.	('adjusted-TEMMB', 'Var', (79, 93))	('increased', 'PosReg', (69, 78))	('TEMMB', 'Chemical', '-', (88, 93))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('survival benefit', 'CPA', (38, 54))
104883	30890735	Conversely, cancers with high RS were observed to have a decrease in survival (HR > 1) with increased adjusted-TEMMB.	('decrease', 'NegReg', (57, 65))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('high RS', 'Var', (25, 32))	('cancers', 'Disease', (12, 19))	('increased', 'PosReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('adjusted-TEMMB', 'Var', (102, 116))	('TEMMB', 'Chemical', '-', (111, 116))	('survival', 'MPA', (69, 77))
104884	30890735	Exonic missense mutation distribution displays considerable variability among cancers studied in TCGA.	('Exonic missense mutation', 'Var', (0, 24))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
104886	30890735	Somatic missense mutations strongly contribute to the generation of novel tumor epitopes.	('tumor epitopes', 'Disease', (74, 88))	('tumor epitopes', 'Disease', 'MESH:D009369', (74, 88))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('missense mutations', 'Var', (8, 26))
104891	30890735	Interestingly, low tumor stage was correlated (after Bonferroni adjustment) with high TEMMB in breast carcinoma, colon and rectal adenocarcinoma, and uveal melanoma.	('breast carcinoma', 'Disease', 'MESH:D001943', (95, 111))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('high TEMMB', 'Var', (81, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('low tumor', 'Disease', 'MESH:D009800', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('low tumor', 'Disease', (15, 24))	('breast carcinoma', 'Phenotype', 'HP:0003002', (95, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (150, 164))	('uveal melanoma', 'Disease', (150, 164))	('uveal melanoma', 'Disease', 'MESH:C536494', (150, 164))	('colon and rectal adenocarcinoma', 'Disease', 'MESH:D012004', (113, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('TEMMB', 'Chemical', '-', (86, 91))	('breast carcinoma', 'Disease', (95, 111))
104898	30890735	Given the high propensity for rapid metastasis in uveal melanoma, it is possible that intercepting such tumors at an early stage may partially be explained by a higher mutational load and thus more favorable immune response.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mutational load', 'Var', (168, 183))	('immune response', 'biological_process', 'GO:0006955', ('208', '223'))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('uveal melanoma', 'Disease', 'MESH:C536494', (50, 64))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('uveal melanoma', 'Disease', (50, 64))	('higher', 'PosReg', (161, 167))
104899	30890735	Driver mutations impart tumor growth advantage and are positively selected in cancer evolution, while biologically inert passengers accumulate without directional selection over the tumor growth timespan.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (24, 29))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('mutations', 'Var', (7, 16))
104900	30890735	Many established bioinformatics methods to study drivers rely on techniques that identify recurrent mutations, and thus we quantified recurrent and non-recurrent mutations to serve as proxy for relative amounts of drivers and passengers within a cancer type.	('cancer', 'Disease', (246, 252))	('mutations', 'Var', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))
104901	30890735	Our results suggest high TEMMB tends to confer survival benefit in cancers with more non-recurrent (likely passenger) mutations, and decreased survival in cancers with high recurrent (likely driver) fractions.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('mutations', 'Var', (118, 127))	('benefit', 'PosReg', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('survival', 'MPA', (47, 55))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('TEMMB', 'Chemical', '-', (25, 30))	('cancers', 'Disease', (155, 162))	('decreased', 'NegReg', (133, 142))
104902	30890735	We propose that in malignancies with large enrichments of non-recurrent mutations, high TEMMB marks a high passenger count, and increasing passenger mutation load increases neoantigen presentation without imparting additional growth advantage or aggressiveness.	('aggressiveness', 'Disease', (246, 260))	('malignancies', 'Disease', (19, 31))	('TEMMB', 'Chemical', '-', (88, 93))	('passenger mutation load', 'Var', (139, 162))	('aggressiveness', 'Phenotype', 'HP:0000718', (246, 260))	('increases', 'PosReg', (163, 172))	('aggressiveness', 'Disease', 'MESH:D001523', (246, 260))	('increasing', 'PosReg', (128, 138))	('malignancies', 'Disease', 'MESH:D009369', (19, 31))	('neoantigen presentation', 'MPA', (173, 196))
104903	30890735	Our observed benefit with high TEMMB supports literature findings for melanoma and ovarian carcinoma.	('melanoma', 'Disease', (70, 78))	('ovarian carcinoma', 'Disease', (83, 100))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('high TEMMB', 'Var', (26, 36))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (83, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (83, 100))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('TEMMB', 'Chemical', '-', (31, 36))	('benefit', 'PosReg', (13, 20))
104906	30890735	Recent work has suggested a "double-edged" effect of increased DNA variants, noting that on the one hand, high DNA variation increases accumulation of drivers which are beneficial to tumor adaptation; conversely, high concurrent passenger loads may outweigh the driver effects.	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('high', 'Var', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('tumor', 'Disease', (183, 188))	('accumulation', 'MPA', (135, 147))
104919	30890735	Cancers with higher proportions of non-recurrent and thus likely passenger mutations showed survival benefit with high TEMMB, while cancers with higher recurrent mutation fractions (likely drivers) revealed a decrease in survival.	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('decrease', 'NegReg', (209, 217))	('TEMMB', 'Chemical', '-', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('benefit', 'PosReg', (101, 108))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('survival', 'MPA', (92, 100))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('high TEMMB', 'Var', (114, 124))
104920	30890735	Mutational signatures for some cancers might contribute significantly to overall TEMMB (e.g.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('TEMMB', 'Disease', (81, 86))	('TEMMB', 'Chemical', '-', (81, 86))	('cancers', 'Disease', (31, 38))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('Mutational signatures', 'Var', (0, 21))	('contribute', 'Reg', (45, 55))	('cancers', 'Disease', 'MESH:D009369', (31, 38))
104939	30890735	We aggregated all nonsynonymous missense mutations among all individuals in each cancer.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('nonsynonymous missense mutations', 'Var', (18, 50))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
104940	30890735	A somatic recurrence score (RS) was calculated as the fraction of total mutations in the cohort's pool comprised by recurrent mutations as defined above: A RS was assigned to each cancer type, and the correlation between log10-adjusted survival HR and log10-adjusted RS was computed with Pearson's correlation.	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (180, 186))	('mutations', 'Var', (126, 135))
104969	30781402	In the current study, a lymphatic vessel was identified when it showed expression of the following markers: D2-40, Prox-1, LYVE-1, and CD31, and lacked expression of CD34.	('CD34', 'Gene', (166, 170))	('expression', 'MPA', (71, 81))	('CD34', 'Gene', '947', (166, 170))	('CD31', 'Gene', (135, 139))	('D2-40', 'Var', (108, 113))
104981	30781402	Specifically, we did not find one sample that had an intraocular vascular structure positive for D2-40, Prox-1, LYVE-1, and CD31, with concurrent negative staining for CD34, as in the conjunctival control (Appendix A, Figure A3).	('CD34', 'Gene', (168, 172))	('D2-40', 'Var', (97, 102))	('CD34', 'Gene', '947', (168, 172))	('CD31', 'Var', (124, 128))
104992	30781402	In that study, supposed lymphatic vessels were identified with D2-40 in combination with negative staining for the blood vessel marker CD34.	('D2-40', 'Var', (63, 68))	('CD34', 'Gene', (135, 139))	('CD34', 'Gene', '947', (135, 139))
104995	30781402	In addition, we observed peritumoral positive staining of the ciliary body and choroidal stroma by D2-40 without co-expression of LYVE-1 or Prox-1.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('choroidal stroma', 'Disease', (79, 95))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('choroidal stroma', 'Disease', 'MESH:D002833', (79, 95))	('D2-40', 'Var', (99, 104))
105219	26103195	Adjusting the range shifter thickness to an optimized value of 43 mm and inserting a brass collimator of an appropriate aperture , the dose deposited on the tumor could be highly enhanced with respect to the dose delivered to the surrounding normal structures, as shown by graphical representation of dose deposition and comparative DVH built for all the eye components in the eye detector.	('tumor', 'Disease', (157, 162))	('enhanced', 'PosReg', (179, 187))	('dose', 'MPA', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('Adjusting', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
105224	26103195	Since the beam transversal dose profile is broadening as a consequence of both insertion of the range shifter and the existing air gap, the patient positioning is suggested to be at a minimal distance from the last passive element along the beamline (5 cm was the optimal value found).	('patient', 'Species', '9606', (140, 147))	('beam transversal', 'MPA', (10, 26))	('insertion', 'Var', (79, 88))
105261	28060744	The potential anti-tumor activity of human macrophages, grown in macrophage colony stimulating factor (M-CSF), was examined in mice homozygous for the severe combined immune deficiency (SCID) mutation, bearing xenografts of autologous human melanoma.	('melanoma', 'Disease', 'MESH:D008545', (241, 249))	('mice', 'Species', '10090', (127, 131))	('SCID', 'Disease', 'MESH:D053632', (186, 190))	('melanoma', 'Disease', (241, 249))	('SCID', 'Phenotype', 'HP:0004430', (186, 190))	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('combined immune deficiency', 'Phenotype', 'HP:0005387', (158, 184))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('mutation', 'Var', (192, 200))	('immune deficiency', 'Phenotype', 'HP:0002721', (167, 184))	('severe combined immune deficiency', 'Phenotype', 'HP:0004430', (151, 184))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('immune deficiency', 'Disease', (167, 184))	('immune deficiency', 'Disease', 'MESH:D007153', (167, 184))	('human', 'Species', '9606', (235, 240))	('tumor', 'Disease', (19, 24))	('human', 'Species', '9606', (37, 42))	('SCID', 'Disease', (186, 190))
105267	28060744	Moreover, it was observed that encapsulation of MDP within liposomes substantially augments the MDP-induced cytotoxicity.	('MDP', 'Chemical', 'MESH:D000119', (48, 51))	('MDP', 'molecular_function', 'GO:0004237', ('48', '51'))	('cytotoxicity', 'Disease', 'MESH:D064420', (108, 120))	('encapsulation', 'Var', (31, 44))	('MDP', 'molecular_function', 'GO:0004237', ('96', '99'))	('augments', 'NegReg', (83, 91))	('cytotoxicity', 'Disease', (108, 120))	('MDP', 'Chemical', 'MESH:D000119', (96, 99))
105294	28060744	It was reported that polyhydroxylated fullerenols (Gd@C82(OH)22 nanoparticles) could induce murine melanoma cell death in vitro, and inhibit tumor formation and metastasis in vivo, by directly promoting macrophage viability, phagocytosis, and the secretion of cytokines by macrophages.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('melanoma cell death', 'Disease', 'MESH:D008545', (99, 118))	('Gd', 'Chemical', 'MESH:D005682', (51, 53))	('macrophage viability', 'CPA', (203, 223))	('phagocytosis', 'CPA', (225, 237))	('secretion', 'biological_process', 'GO:0046903', ('247', '256'))	('polyhydroxylated fullerenols', 'Chemical', '-', (21, 49))	('secretion of cytokines', 'MPA', (247, 269))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('murine', 'Species', '10090', (92, 98))	('inhibit', 'NegReg', (133, 140))	('formation', 'biological_process', 'GO:0009058', ('147', '156'))	('melanoma cell death', 'Disease', (99, 118))	('phagocytosis', 'biological_process', 'GO:0006909', ('225', '237'))	('cell death', 'biological_process', 'GO:0008219', ('108', '118'))	('promoting', 'PosReg', (193, 202))	('induce', 'PosReg', (85, 91))	('tumor', 'Disease', (141, 146))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('polyhydroxylated', 'Var', (21, 37))
105364	22864522	ADI-PEG 20 is well tolerated in advanced melanoma patients and leads to consistent, but transient, arginine depletion.	('arginine depletion', 'MPA', (99, 117))	('ADI-PEG 20', 'Var', (0, 10))	('patients', 'Species', '9606', (50, 58))	('ADI-PEG 20', 'Chemical', '-', (0, 10))	('arginine', 'Chemical', 'MESH:D001120', (99, 107))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))
105438	22864522	Arginine levels were completely depleted by ADI-PEG 20 in 27/30 (90 %) patients by day 4 and in 30/31 (96.8 %) by day 8.	('Arginine levels', 'MPA', (0, 15))	('patients', 'Species', '9606', (71, 79))	('Arginine', 'Chemical', 'MESH:D001120', (0, 8))	('ADI-PEG 20', 'Var', (44, 54))	('depleted', 'NegReg', (32, 40))	('ADI-PEG 20', 'Chemical', '-', (44, 54))
105482	22864522	ADI-PEG 20 in combination with an immune suppressing agent may therefore result in greater clinical efficacy.	('ADI-PEG 20', 'Chemical', '-', (0, 10))	('clinical', 'MPA', (91, 99))	('result', 'Reg', (73, 79))	('ADI-PEG', 'Var', (0, 7))
105489	22864522	In conclusion, monotherapy with ADI-PEG 20 in unselected patients with advanced melanoma is generally well-tolerated, but at the doses used had limited clinical activity.	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('patients', 'Species', '9606', (57, 65))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('ADI-PEG 20', 'Var', (32, 42))	('ADI-PEG 20', 'Chemical', '-', (32, 42))
105492	23825798	Lack of GNAQ and GNA11 Germ-Line Mutations in Familial Melanoma Pedigrees with Uveal Melanoma or Blue Nevi Approximately 10% of melanoma cases are familial, but only 25-40% of familial melanoma cases can be attributed to germ-line mutations in the CDKN2A - the most significant high-risk melanoma susceptibility locus identified to date.	('Melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('familial melanoma', 'Disease', (176, 193))	('GNAQ', 'Gene', (8, 12))	('mutations', 'Var', (231, 240))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('familial melanoma', 'Disease', 'OMIM:155600', (176, 193))	('melanoma', 'Disease', 'MESH:D008545', (288, 296))	('GNA11', 'Gene', '2767', (17, 22))	('Familial Melanoma', 'Disease', (46, 63))	('CDKN2A', 'Gene', (248, 254))	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('Melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('Blue Nevi', 'Phenotype', 'HP:0100814', (97, 106))	('Nevi', 'Phenotype', 'HP:0003764', (102, 106))	('Familial Melanoma', 'Disease', 'OMIM:155600', (46, 63))	('CDKN2A', 'Gene', '1029', (248, 254))	('Uveal Melanoma', 'Disease', (79, 93))	('Uveal Melanoma', 'Disease', 'MESH:C536494', (79, 93))	('melanoma', 'Phenotype', 'HP:0002861', (288, 296))	('melanoma', 'Disease', (288, 296))	('GNA11', 'Gene', (17, 22))	('GNAQ', 'Gene', '2776', (8, 12))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
105494	23825798	The most common mutations in nevi and sporadic melanoma are found in BRAF and NRAS, both of which result in constitutive activation of the MAPK pathway.	('nevi', 'Disease', (29, 33))	('MAPK', 'molecular_function', 'GO:0004707', ('139', '143'))	('sporadic melanoma', 'Disease', (38, 55))	('BRAF', 'Gene', (69, 73))	('MAPK pathway', 'Pathway', (139, 151))	('mutations', 'Var', (16, 25))	('NRAS', 'Gene', (78, 82))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('sporadic melanoma', 'Disease', 'MESH:D008545', (38, 55))	('nevi', 'Phenotype', 'HP:0003764', (29, 33))	('activation', 'PosReg', (121, 131))
105495	23825798	However, these mutations are not found in uveal melanomas or the intradermal melanocytic proliferations known as blue nevi.	('blue nevi', 'Disease', (113, 122))	('uveal melanomas', 'Disease', (42, 57))	('uveal melanomas', 'Phenotype', 'HP:0007716', (42, 57))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('mutations', 'Var', (15, 24))	('blue nevi', 'Phenotype', 'HP:0100814', (113, 122))	('nevi', 'Phenotype', 'HP:0003764', (118, 122))	('intradermal melanocytic proliferations', 'Disease', 'MESH:D059545', (65, 103))	('uveal melanomas', 'Disease', 'MESH:C536494', (42, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('intradermal melanocytic proliferations', 'Disease', (65, 103))
105496	23825798	Rather, multiple studies report a strong association between these lesions and somatic mutations in Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ), Guanine nucleotide-binding protein G(q) subunit alpha-11 (GNA11), and BRCA1-associated protein-1 (BAP1).	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('protein', 'cellular_component', 'GO:0003675', ('249', '256'))	('BRCA1-associated protein-1', 'Gene', (232, 258))	('GNAQ', 'Gene', (155, 159))	('BAP1', 'Gene', (260, 264))	('GNAQ', 'Gene', '2776', (155, 159))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('108', '126'))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('BRCA1-associated protein-1', 'Gene', '8314', (232, 258))	('Guanine nucleotide-binding protein G(q) subunit alpha', 'Gene', '2776', (100, 153))	('G(q) subunit alpha-11', 'Gene', '2767', (197, 218))	('BAP1', 'Gene', '8314', (260, 264))	('GNA11', 'Gene', '2767', (220, 225))	('GNA11', 'Gene', (220, 225))	('Guanine nucleotide-binding protein G(q) subunit alpha', 'Gene', '2776', (162, 215))	('G(q) subunit alpha-11', 'Gene', (197, 218))	('mutations', 'Var', (87, 96))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('170', '188'))
105497	23825798	Recently, germ-line mutations in BAP1, the gene encoding a tumor suppressing deubiquitinating enzyme, have been associated with predisposition to a variety of cancers including uveal melanoma, but no studies have examined the association of germ-line mutations in GNAQ and GNA11 with uveal melanoma and blue nevi.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('tumor', 'Disease', (59, 64))	('GNA11', 'Gene', '2767', (273, 278))	('uveal melanoma', 'Phenotype', 'HP:0007716', (284, 298))	('nevi', 'Phenotype', 'HP:0003764', (308, 312))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('BAP1', 'Gene', (33, 37))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('cancers', 'Disease', (159, 166))	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('77', '100'))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('blue nevi', 'Disease', (303, 312))	('uveal melanoma', 'Disease', 'MESH:C536494', (177, 191))	('uveal melanoma', 'Disease', (177, 191))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('blue nevi', 'Phenotype', 'HP:0100814', (303, 312))	('association', 'Interaction', (226, 237))	('GNAQ', 'Gene', '2776', (264, 268))	('melanoma', 'Phenotype', 'HP:0002861', (290, 298))	('GNA11', 'Gene', (273, 278))	('uveal melanoma', 'Phenotype', 'HP:0007716', (177, 191))	('GNAQ', 'Gene', (264, 268))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('mutations', 'Var', (20, 29))	('mutations', 'Var', (251, 260))	('BAP1', 'Gene', '8314', (33, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (284, 298))	('uveal melanoma', 'Disease', (284, 298))	('associated', 'Reg', (112, 122))
105500	23825798	However, only 25-40% of familial melanoma cases can be specifically attributed to pathogenic germ-line mutations in cyclin-dependant kinase inhibitor 2A (CDKN2A/p16) - the most significant high-risk melanoma susceptibility gene identified to date (Goldstein and Tucker,; Eliason et al.,; Leachman et al.,).	('mutations', 'Var', (103, 112))	('familial melanoma', 'Disease', 'OMIM:155600', (24, 41))	('p16', 'Gene', (161, 164))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('CDKN2A', 'Gene', (154, 160))	('cyclin', 'molecular_function', 'GO:0016538', ('116', '122'))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('CDKN2A', 'Gene', '1029', (154, 160))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('133', '149'))	('p16', 'Gene', '1029', (161, 164))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('familial melanoma', 'Disease', (24, 41))	('melanoma', 'Disease', (199, 207))
105504	23825798	The most common mutations in sporadic melanoma are those of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral oncogene homolog (NRAS), both of which result in constitutive activation of the MAPK pathway and subsequent activation of pro-proliferative genes such as cyclin-D1 (CCND1) (Onken et al.,).	('CCND1', 'Gene', (307, 312))	('activation', 'PosReg', (250, 260))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('cyclin-D1', 'Gene', (296, 305))	('v-Raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (60, 106))	('mutations', 'Var', (16, 25))	('neuroblastoma RAS viral', 'Disease', 'MESH:D009447', (118, 141))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('MAPK', 'molecular_function', 'GO:0004707', ('222', '226'))	('CCND1', 'Gene', '12443', (307, 312))	('neuroblastoma', 'Phenotype', 'HP:0003006', (118, 131))	('MAPK pathway', 'Pathway', (222, 234))	('sporadic melanoma', 'Disease', 'MESH:D008545', (29, 46))	('activation', 'PosReg', (204, 214))	('neuroblastoma RAS viral', 'Disease', (118, 141))	('v-Raf murine sarcoma viral oncogene homolog B1', 'Gene', (60, 106))	('cyclin', 'molecular_function', 'GO:0016538', ('296', '302'))	('sporadic melanoma', 'Disease', (29, 46))	('cyclin-D1', 'Gene', '12443', (296, 305))
105506	23825798	Rather, multiple studies have reported a strong association between these melanocytic lesions and somatic guanine nucleotide-binding protein G(q) subunit alpha (GNAQ), guanine nucleotide-binding protein G(q) subunit alpha-11 (GNA11), and BRCA1-associated protein-1 (BAP1) mutations in the absence of BRAF, NRAS, and KIT mutations (Harbour et al.,; Van Raamsdonk et al.,).	('mutations', 'Var', (272, 281))	('G(q) subunit alpha-11', 'Gene', '2767', (203, 224))	('melanocytic lesions', 'Disease', (74, 93))	('BRAF', 'Disease', (300, 304))	('guanine nucleotide-binding protein G(q) subunit alpha', 'Gene', '2776', (168, 221))	('guanine nucleotide-binding protein G(q) subunit alpha', 'Gene', '2776', (106, 159))	('G(q) subunit alpha-11', 'Gene', (203, 224))	('BAP1', 'Gene', '8314', (266, 270))	('GNA11', 'Gene', (226, 231))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('114', '132'))	('melanocytic lesions', 'Disease', 'MESH:D009508', (74, 93))	('BRCA1-associated protein-1', 'Gene', '8314', (238, 264))	('GNAQ', 'Gene', '2776', (161, 165))	('BRCA1-associated protein-1', 'Gene', (238, 264))	('GNAQ', 'Gene', (161, 165))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('BAP1', 'Gene', (266, 270))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))	('KIT', 'Gene', (316, 319))	('NRAS', 'Disease', (306, 310))	('KIT', 'molecular_function', 'GO:0005020', ('316', '319'))	('GNA11', 'Gene', '2767', (226, 231))	('protein', 'cellular_component', 'GO:0003675', ('255', '262'))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('176', '194'))
105507	23825798	Recently, germ-line mutations in BAP1, the gene encoding a tumor suppressing deubiquitinating enzyme, have been associated with predisposition to a variety of cancers including uveal and cutaneous melanoma as well as mesothelioma (Abdel-Rahman et al.,; Testa et al.,; Harbour,; Wadt et al.,), but no studies have examined the association of germ-line mutations in GNAQ and GNA11 with uveal melanoma and blue nevi.	('GNAQ', 'Gene', '2776', (364, 368))	('tumor', 'Disease', (59, 64))	('melanoma', 'Phenotype', 'HP:0002861', (390, 398))	('GNAQ', 'Gene', (364, 368))	('GNA11', 'Gene', (373, 378))	('blue nevi', 'Phenotype', 'HP:0100814', (403, 412))	('uveal melanoma', 'Disease', 'MESH:C536494', (384, 398))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('BAP1', 'Gene', (33, 37))	('uveal', 'Disease', (177, 182))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('uveal melanoma', 'Disease', (384, 398))	('cancers', 'Disease', (159, 166))	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('77', '100'))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('mesothelioma', 'Disease', (217, 229))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('uveal melanoma', 'Phenotype', 'HP:0007716', (384, 398))	('mesothelioma', 'Disease', 'MESH:D008654', (217, 229))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('cutaneous melanoma', 'Disease', (187, 205))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (187, 205))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (187, 205))	('GNA11', 'Gene', '2767', (373, 378))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('mutations', 'Var', (20, 29))	('nevi', 'Phenotype', 'HP:0003764', (408, 412))	('BAP1', 'Gene', '8314', (33, 37))	('blue nevi', 'Disease', (403, 412))	('associated', 'Reg', (112, 122))
105509	23825798	The GNAQ and GNA11 mutations associated with uveal melanoma and blue nevi occur almost exclusively in exon 5 (most commonly Q209L; Figure 1) and involve the glutamine residue within the ras-like domain, which plays an essential role in the GTP hydrolysis activity of this gene's protein products (Van Raamsdonk et al.,).	('uveal melanoma', 'Disease', (45, 59))	('protein', 'cellular_component', 'GO:0003675', ('279', '286'))	('involve', 'Reg', (145, 152))	('GNAQ', 'Gene', '2776', (4, 8))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('nevi', 'Phenotype', 'HP:0003764', (69, 73))	('GTP', 'Chemical', 'MESH:D006160', (240, 243))	('Q209L', 'Mutation', 'rs1057519742', (124, 129))	('GNAQ', 'Gene', (4, 8))	('GNA11', 'Gene', (13, 18))	('associated', 'Reg', (29, 39))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('240', '254'))	('glutamine', 'Chemical', 'MESH:D005973', (157, 166))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('Q209L', 'Var', (124, 129))	('blue nevi', 'Disease', (64, 73))	('mutations', 'Var', (19, 28))	('GNA11', 'Gene', '2767', (13, 18))	('blue nevi', 'Phenotype', 'HP:0100814', (64, 73))	('uveal melanoma', 'Disease', 'MESH:C536494', (45, 59))
105510	23825798	Activating GNAQ and GNA11 mutations, such as those at codon 209, lock the GTP-binding protein in their active, GTP-bound state resulting in constitutive activation of the MAPK pathway in the absence of BRAF and NRAS mutations (Van Raamsdonk et al.,).	('MAPK', 'molecular_function', 'GO:0004707', ('171', '175'))	('Activating', 'PosReg', (0, 10))	('NRAS', 'Gene', (211, 215))	('activation', 'PosReg', (153, 163))	('GNAQ', 'Gene', '2776', (11, 15))	('GNA11', 'Gene', (20, 25))	('mutations', 'Var', (26, 35))	('GNA11', 'Gene', '2767', (20, 25))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('GTP-binding', 'molecular_function', 'GO:0005525', ('74', '85'))	('BRAF', 'Gene', (202, 206))	('MAPK pathway', 'Pathway', (171, 183))	('GTP', 'Chemical', 'MESH:D006160', (111, 114))	('GNAQ', 'Gene', (11, 15))	('GTP', 'Chemical', 'MESH:D006160', (74, 77))
105511	23825798	In mice, these activating mutations ultimately function as oncogenes resulting in proliferation of intradermal and transformed melanocytes (Van Raamsdonk et al.,).	('mutations', 'Var', (26, 35))	('mice', 'Species', '10090', (3, 7))	('proliferation', 'CPA', (82, 95))
105513	23825798	and others suggest that mutations in GNAQ and GNA11 represent an early event in the development of melanocytic tumors and may contribute directly to the increased melanoma risk in hereditary melanoma families that also have an increased incidence of uveal melanoma and/or blue nevi.	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('melanoma', 'Disease', (191, 199))	('uveal melanoma', 'Disease', 'MESH:C536494', (250, 264))	('melanoma', 'Phenotype', 'HP:0002861', (256, 264))	('melanoma', 'Disease', (256, 264))	('uveal melanoma', 'Disease', (250, 264))	('nevi', 'Phenotype', 'HP:0003764', (277, 281))	('mutations', 'Var', (24, 33))	('GNAQ', 'Gene', '2776', (37, 41))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('GNAQ', 'Gene', (37, 41))	('blue nevi', 'Disease', (272, 281))	('uveal melanoma', 'Phenotype', 'HP:0007716', (250, 264))	('GNA11', 'Gene', '2767', (46, 51))	('blue nevi', 'Phenotype', 'HP:0100814', (272, 281))	('melanoma', 'Disease', 'MESH:D008545', (191, 199))	('hereditary melanoma', 'Disease', (180, 199))	('melanoma', 'Disease', 'MESH:D008545', (256, 264))	('melanocytic tumors', 'Disease', 'MESH:D009508', (99, 117))	('melanocytic tumors', 'Disease', (99, 117))	('hereditary melanoma', 'Disease', 'MESH:D008545', (180, 199))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('contribute', 'Reg', (126, 136))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('GNA11', 'Gene', (46, 51))
105514	23825798	We hypothesized that an increased melanoma risk in familial melanoma families with uveal melanoma and/or blue nevi is due to GNAQ and GNA11 germ-line mutations in exon 5 which result in constitutive activation of the MAPK pathway.	('uveal melanoma', 'Disease', (83, 97))	('nevi', 'Phenotype', 'HP:0003764', (110, 114))	('familial melanoma', 'Disease', (51, 68))	('MAPK', 'molecular_function', 'GO:0004707', ('217', '221'))	('GNAQ', 'Gene', '2776', (125, 129))	('GNA11', 'Gene', (134, 139))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('familial melanoma', 'Disease', 'OMIM:155600', (51, 68))	('mutations in', 'Var', (150, 162))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('GNAQ', 'Gene', (125, 129))	('melanoma', 'Disease', (89, 97))	('MAPK pathway', 'Pathway', (217, 229))	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('activation', 'PosReg', (199, 209))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('GNA11', 'Gene', '2767', (134, 139))	('blue nevi', 'Phenotype', 'HP:0100814', (105, 114))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))	('uveal melanoma', 'Disease', 'MESH:C536494', (83, 97))
105515	23825798	To test this hypothesis, we investigated the frequency of GNAQ and GNA11 exon 5 germ-line mutations in 22 patients who had a personal history of uveal melanoma and/or blue nevi from a total of 13 unique familial melanoma pedigrees previously identified as being high-risk for the development of melanoma.	('mutations', 'Var', (90, 99))	('GNA11', 'Gene', '2767', (67, 72))	('melanoma', 'Phenotype', 'HP:0002861', (295, 303))	('melanoma', 'Disease', (295, 303))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('uveal melanoma', 'Disease', 'MESH:C536494', (145, 159))	('uveal melanoma', 'Disease', (145, 159))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Disease', (212, 220))	('uveal melanoma', 'Phenotype', 'HP:0007716', (145, 159))	('GNA11', 'Gene', (67, 72))	('nevi', 'Phenotype', 'HP:0003764', (172, 176))	('GNAQ', 'Gene', '2776', (58, 62))	('patients', 'Species', '9606', (106, 114))	('melanoma', 'Disease', 'MESH:D008545', (295, 303))	('GNAQ', 'Gene', (58, 62))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('blue nevi', 'Phenotype', 'HP:0100814', (167, 176))	('familial melanoma', 'Disease', (203, 220))	('familial melanoma', 'Disease', 'OMIM:155600', (203, 220))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))
105526	23825798	The results collected from this subset of high-risk melanoma families indicate that the inherited risk observed in these hereditary melanoma families is not due to activating germ-line mutations in exon 5 of GNAQ and GNA11.	('GNA11', 'Gene', '2767', (217, 222))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('GNAQ', 'Gene', (208, 212))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('activating', 'PosReg', (164, 174))	('GNA11', 'Gene', (217, 222))	('GNAQ', 'Gene', '2776', (208, 212))	('mutations in', 'Var', (185, 197))	('hereditary melanoma', 'Disease', 'MESH:D008545', (121, 140))	('hereditary melanoma', 'Disease', (121, 140))
105528	23825798	Additionally, screening for BAP1 mutations in exons 9 and 12 was performed on all 22 study subjects.	('BAP1', 'Gene', '8314', (28, 32))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
105532	23825798	The major aim of the current investigation was to determine whether or not germ-line mutations in exon 5 of GNAQ and GNA11 represent an early event in the development of melanocytic tumors and/or potential genetic biomarkers associated with the increased melanoma risk observed in hereditary melanoma families that lack other known pathogenic germ-line mutations.	('GNA11', 'Gene', (117, 122))	('mutations in', 'Var', (85, 97))	('melanoma', 'Disease', 'MESH:D008545', (292, 300))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('GNAQ', 'Gene', '2776', (108, 112))	('GNA11', 'Gene', '2767', (117, 122))	('hereditary melanoma', 'Disease', 'MESH:D008545', (281, 300))	('melanocytic tumors', 'Disease', 'MESH:D009508', (170, 188))	('melanoma', 'Phenotype', 'HP:0002861', (255, 263))	('hereditary melanoma', 'Disease', (281, 300))	('melanoma', 'Disease', (255, 263))	('melanocytic tumors', 'Disease', (170, 188))	('GNAQ', 'Gene', (108, 112))	('associated', 'Reg', (225, 235))	('melanoma', 'Disease', 'MESH:D008545', (255, 263))	('melanoma', 'Phenotype', 'HP:0002861', (292, 300))	('melanoma', 'Disease', (292, 300))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
105534	23825798	Nevertheless, the functional consequence of activating GNAQ and GNA11 mutations on the MAPK pathway highlights an important concept: that specific gene mutations may result in an alternate route of MAPK pathway activation and subsequent melanocyte proliferation in the absence of more common gene mutations such as those in BRAF, NRAS, and KIT.	('result in', 'Reg', (166, 175))	('mutations', 'Var', (70, 79))	('activating', 'PosReg', (44, 54))	('MAPK', 'molecular_function', 'GO:0004707', ('87', '91'))	('mutations', 'Var', (152, 161))	('KIT', 'molecular_function', 'GO:0005020', ('340', '343'))	('MAPK', 'molecular_function', 'GO:0004707', ('198', '202'))	('GNAQ', 'Gene', '2776', (55, 59))	('activation', 'PosReg', (211, 221))	('GNA11', 'Gene', '2767', (64, 69))	('GNA11', 'Gene', (64, 69))	('melanocyte proliferation', 'CPA', (237, 261))	('MAPK pathway', 'Pathway', (198, 210))	('GNAQ', 'Gene', (55, 59))	('melanocyte proliferation', 'biological_process', 'GO:0097325', ('237', '261'))
105539	23825798	In summary, we report the absence of germ-line mutations in exon 5 of GNAQ and GNA11 in familial melanoma pedigrees with an increased incidence of uveal melanoma and/or blue nevi.	('uveal melanoma', 'Disease', (147, 161))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('familial melanoma', 'Disease', 'OMIM:155600', (88, 105))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('GNAQ', 'Gene', '2776', (70, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (147, 161))	('familial melanoma', 'Disease', (88, 105))	('blue nevi', 'Phenotype', 'HP:0100814', (169, 178))	('GNA11', 'Gene', '2767', (79, 84))	('GNA11', 'Gene', (79, 84))	('mutations in', 'Var', (47, 59))	('blue nevi', 'Disease', (169, 178))	('GNAQ', 'Gene', (70, 74))	('uveal melanoma', 'Disease', 'MESH:C536494', (147, 161))	('nevi', 'Phenotype', 'HP:0003764', (174, 178))
105576	22707951	reported that administration of neutralizing antibody to CRPs in rats resulted in spontaneous ocular inflammation.	('antibody', 'cellular_component', 'GO:0019815', ('45', '53'))	('ocular inflammation', 'Phenotype', 'HP:0100533', (94, 113))	('ocular inflammation', 'Disease', (94, 113))	('inflammation', 'biological_process', 'GO:0006954', ('101', '113'))	('antibody', 'cellular_component', 'GO:0019814', ('45', '53'))	('antibody', 'molecular_function', 'GO:0003823', ('45', '53'))	('ocular inflammation', 'Disease', 'MESH:D007249', (94, 113))	('rats', 'Species', '10116', (65, 69))	('neutralizing antibody', 'Var', (32, 53))	('resulted in', 'Reg', (70, 81))	('antibody', 'cellular_component', 'GO:0042571', ('45', '53'))	('CRPs', 'Gene', (57, 61))
105594	22707951	Within the thymus the ocular APCs evoke the generation of CD4-,CD8-, NK1.1+ T cells (NKT cells), which subsequently emerge from the thymus and migrate to the spleen via the blood vascular route (Wang et al.,).	('APC', 'Disease', 'MESH:D011125', (29, 32))	('NK1.1+', 'Var', (69, 75))	('APC', 'Disease', (29, 32))	('CD4-', 'Var', (58, 62))	('CD8', 'Gene', (63, 66))	('CD8', 'Gene', '925', (63, 66))
105612	22707951	In both humans and mice, there is a steep increase in the number of CD4+CD25+ T regs during pregnancy and depletion of CD4+CD25+ T regs induces abortion in mice (Aluvihare et al.,; Somerset et al.,).	('abortion', 'Disease', (144, 152))	('humans', 'Species', '9606', (8, 14))	('depletion', 'Var', (106, 115))	('CD4+CD25+ T', 'Var', (119, 130))	('mice', 'Species', '10090', (156, 160))	('abortion', 'Disease', 'MESH:D000031', (144, 152))	('mice', 'Species', '10090', (19, 23))	('induces', 'Reg', (136, 143))
105666	33922591	Drugs targeting the YAP-TAZ pathway that is also activated in UM, the tumor-suppressor gene BRCA1 Associated Protein 1 (BAP1) and the Splicing Factor 3b Subunit 1 gene (SF3B1) whose mutations are associated with metastatic risk, have not been developed yet.	('metastatic', 'CPA', (212, 222))	('Splicing', 'biological_process', 'GO:0045292', ('134', '142'))	('SF3B1', 'Gene', (169, 174))	('BAP1', 'Gene', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mutations', 'Var', (182, 191))	('Splicing Factor 3b Subunit 1', 'Gene', (134, 162))	('Splicing Factor 3b Subunit 1', 'Gene', '23451', (134, 162))	('YAP', 'Gene', (20, 23))	('SF3B1', 'Gene', '23451', (169, 174))	('associated', 'Reg', (196, 206))	('BRCA1 Associated Protein 1', 'Gene', (92, 118))	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('tumor', 'Disease', (70, 75))	('TAZ', 'Gene', (24, 27))	('TAZ', 'Gene', '6901', (24, 27))	('BAP1', 'Gene', '8314', (120, 124))	('YAP', 'Gene', '10413', (20, 23))	('BRCA1 Associated Protein 1', 'Gene', '8314', (92, 118))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
105675	33922591	Mutations in GNAQ and GNA11 are present in 75-95% of cases and occur early in the development of UM.	('GNA11', 'Gene', (22, 27))	('occur', 'Reg', (63, 68))	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (22, 27))	('UM', 'Phenotype', 'HP:0007716', (97, 99))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', '2776', (13, 17))
105678	33922591	Additional mutations in the calcium-signaling pathway, to which also GNAQ and GNA11 belong, might also influence tumorigenesis.	('tumor', 'Disease', (113, 118))	('mutations', 'Var', (11, 20))	('GNA11', 'Gene', (78, 83))	('GNAQ', 'Gene', '2776', (69, 73))	('GNA11', 'Gene', '2767', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('signaling pathway', 'biological_process', 'GO:0007165', ('36', '53'))	('influence', 'Reg', (103, 112))	('GNAQ', 'Gene', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('calcium', 'Chemical', 'MESH:D002118', (28, 35))	('calcium-signaling pathway', 'Pathway', (28, 53))	('calcium-signaling', 'biological_process', 'GO:0019722', ('28', '45'))
105679	33922591	The monosomy of chromosome 3, loss of chromosome 3 heterozygosity, and inactivating mutations of the BRCA1-associated protein 1 (BAP1) oncosuppressor gene are strongly associated with metastatic risk.	('metastatic', 'Disease', (184, 194))	('associated', 'Reg', (168, 178))	('BRCA1-associated protein 1', 'Gene', '8314', (101, 127))	('chromosome', 'cellular_component', 'GO:0005694', ('38', '48'))	('BAP1', 'Gene', '8314', (129, 133))	('monosomy', 'Var', (4, 12))	('BRCA1-associated protein 1', 'Gene', (101, 127))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))	('chromosome', 'cellular_component', 'GO:0005694', ('16', '26'))	('inactivating mutations', 'Var', (71, 93))	('loss', 'Var', (30, 34))	('BAP1', 'Gene', (129, 133))
105680	33922591	On the contrary, somatic mutations in Eukaryotic Translation Initiation Factor 1A X-Linked (EIF1AX) and Splicing Factor 3b subunit 1 (SF3B1) genes prevalently occur in UM with disomy 3.	('disomy 3', 'Disease', (176, 184))	('Splicing Factor 3b subunit 1', 'Gene', (104, 132))	('mutations', 'Var', (25, 34))	('Eukaryotic Translation Initiation Factor 1A X-Linked', 'Gene', '1964', (38, 90))	('UM', 'Phenotype', 'HP:0007716', (168, 170))	('SF3B1', 'Gene', (134, 139))	('Splicing', 'biological_process', 'GO:0045292', ('104', '112'))	('EIF1AX', 'Gene', '1964', (92, 98))	('EIF1AX', 'Gene', (92, 98))	('Translation Initiation', 'biological_process', 'GO:0006413', ('49', '71'))	('occur', 'Reg', (159, 164))	('SF3B1', 'Gene', '23451', (134, 139))	('Splicing Factor 3b subunit 1', 'Gene', '23451', (104, 132))
105681	33922591	According to data from whole-genome sequencing (WGS) and Sanger sequencing, SF3B1, EIF1AX, and BAP1 mutations classify UM patients in different categories with different survival and metastatic risk.	('mutations', 'Var', (100, 109))	('EIF1AX', 'Gene', '1964', (83, 89))	('BAP1', 'Gene', (95, 99))	('patients', 'Species', '9606', (122, 130))	('SF3B1', 'Gene', (76, 81))	('BAP1', 'Gene', '8314', (95, 99))	('EIF1AX', 'Gene', (83, 89))	('UM', 'Phenotype', 'HP:0007716', (119, 121))	('SF3B1', 'Gene', '23451', (76, 81))
105682	33922591	EIF1AX mutations are not associated with risk of metastasis and show, similar to tumors without BAP1 and SF3B1 mutations, prolonged survival.	('SF3B1', 'Gene', (105, 110))	('tumors', 'Disease', (81, 87))	('prolonged', 'PosReg', (122, 131))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('BAP1', 'Gene', (96, 100))	('SF3B1', 'Gene', '23451', (105, 110))	('EIF1AX', 'Gene', '1964', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('survival', 'CPA', (132, 140))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('BAP1', 'Gene', '8314', (96, 100))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
105683	33922591	UM-bearing mutated SF3B1 undergoes metastatic progression later, and tumors with mutated BAP1 metastasize early and rapidly progress with poor survival rates.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('BAP1', 'Gene', (89, 93))	('metastatic', 'CPA', (35, 45))	('SF3B1', 'Gene', '23451', (19, 24))	('undergoes', 'Reg', (25, 34))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('progress', 'PosReg', (124, 132))	('mutated', 'Var', (81, 88))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('BAP1', 'Gene', '8314', (89, 93))	('SF3B1', 'Gene', (19, 24))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('mutated', 'Var', (11, 18))
105685	33922591	Inactivating mutations of BAP1 occur in nearly half of UM patients and approximately 84% of metastatic cases.	('BAP1', 'Gene', (26, 30))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('Inactivating mutations', 'Var', (0, 22))	('occur', 'Reg', (31, 36))	('BAP1', 'Gene', '8314', (26, 30))	('patients', 'Species', '9606', (58, 66))
105686	33922591	BAP1 loss-of-function mutations correlate with a distinct DNA methylation profile.	('BAP1', 'Gene', (0, 4))	('DNA methylation profile', 'MPA', (58, 81))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('DNA methylation', 'biological_process', 'GO:0006306', ('58', '73'))	('mutations', 'Var', (22, 31))	('BAP1', 'Gene', '8314', (0, 4))	('loss-of-function', 'NegReg', (5, 21))
105687	33922591	Finally, germline BAP1 mutations are associated with an early and increased incidence of UM but also with an increased incidence of other malignancies.	('BAP1', 'Gene', '8314', (18, 22))	('malignancies', 'Disease', 'MESH:D009369', (138, 150))	('BAP1', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('malignancies', 'Disease', (138, 150))	('UM', 'Phenotype', 'HP:0007716', (89, 91))
105688	33922591	Many secondary mutations were found by next-generation sequencing to occur in UM patients in the same G-protein-related pathways known as drivers, in particular in the calcium-signaling pathway.	('G-protein-related pathways', 'Pathway', (102, 128))	('mutations', 'Var', (15, 24))	('patients', 'Species', '9606', (81, 89))	('calcium-signaling', 'biological_process', 'GO:0019722', ('168', '185'))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('calcium', 'Chemical', 'MESH:D002118', (168, 175))	('UM', 'Phenotype', 'HP:0007716', (78, 80))	('signaling pathway', 'biological_process', 'GO:0007165', ('176', '193'))	('calcium-signaling pathway', 'Pathway', (168, 193))
105689	33922591	These secondary driver mutations are likely to affect tumor development and progression.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mutations', 'Var', (23, 32))	('affect', 'Reg', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('progression', 'CPA', (76, 87))	('tumor', 'Disease', (54, 59))
105695	33922591	The presence of germline mutations of methyl-CpG-binding domain protein 4 (MBD4) was detected in a group of UM patients who experienced a disease stabilization and prolonged survival after ICB immunotherapy, thus suggesting a role for MBD4 as a new predictor of response to immunotherapy in UM.	('MBD4', 'Gene', '8930', (235, 239))	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('methyl-CpG-binding domain protein 4', 'Gene', (38, 73))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('germline mutations', 'Var', (16, 34))	('MBD4', 'Gene', (235, 239))	('MBD4', 'Gene', '8930', (75, 79))	('MBD4', 'Gene', (75, 79))	('methyl-CpG-binding domain protein 4', 'Gene', '8930', (38, 73))	('UM', 'Phenotype', 'HP:0007716', (291, 293))	('methyl-CpG-binding', 'molecular_function', 'GO:0008327', ('38', '56'))	('detected', 'Reg', (85, 93))	('patients', 'Species', '9606', (111, 119))
105696	33922591	MBD4 is thought to act as a tumor suppressor gene; it is located on chromosome 3, and mutations have recently been identified in approximately 2% of UM characterized by a high mutational burden and hypermutated tumors.	('mutations', 'Var', (86, 95))	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('identified', 'Reg', (115, 125))	('UM', 'Phenotype', 'HP:0007716', (149, 151))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('MBD4', 'Gene', '8930', (0, 4))	('MBD4', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor suppressor', 'biological_process', 'GO:0051726', ('28', '44'))	('tumors', 'Disease', (211, 217))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('28', '44'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
105723	33922591	proposed a stratification based on CD8+ T-cell immune infiltrates and an altered transcriptional immune profile for P-UM bearing monosomy 3 and BAP1 loss of function mutations.	('mutations', 'Var', (166, 175))	('BAP1', 'Gene', (144, 148))	('UM', 'Phenotype', 'HP:0007716', (118, 120))	('CD8', 'Gene', (35, 38))	('CD8', 'Gene', '925', (35, 38))	('loss of function', 'NegReg', (149, 165))	('BAP1', 'Gene', '8314', (144, 148))
105737	33922591	T cells displayed exhausted phenotype (PD-1+, CD39+, TIM-3+, TIGIT+, and LAG-3+).	('TIGIT', 'Gene', '201633', (61, 66))	('TIGIT', 'Gene', (61, 66))	('TIM-3', 'Gene', (53, 58))	('TIM-3', 'Gene', '84868', (53, 58))	('PD-1+', 'Var', (39, 44))	('CD39', 'Gene', (46, 50))	('CD39', 'Gene', '953', (46, 50))
105770	33922591	reported a single institutional experience using antibodies against CTLA-4, PD-1, and/or PD-L1 to treat 428 patients with metastatic melanoma histologically diagnosed as cutaneous, unknown, acral, mucosal, or uveal.	('PD-L1', 'Gene', '29126', (89, 94))	('cutaneous', 'Disease', (170, 179))	('patients', 'Species', '9606', (108, 116))	('CTLA-4', 'Gene', '1493', (68, 74))	('PD-L1', 'Gene', (89, 94))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('antibodies', 'Var', (49, 59))	('PD-1', 'Gene', (76, 80))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('acral', 'Disease', (190, 195))	('CTLA-4', 'Gene', (68, 74))	('unknown', 'Disease', (181, 188))
105772	33922591	Most of the longer survivors received both anti-CTLA-4 and anti-PD-1 or anti-PD-L1 either sequentially or in combination (Table 1).	('CTLA-4', 'Gene', (48, 54))	('anti-PD-1', 'Var', (59, 68))	('PD-L1', 'Gene', (77, 82))	('PD-L1', 'Gene', '29126', (77, 82))	('CTLA-4', 'Gene', '1493', (48, 54))
105786	33922591	GNAQ, GNA11, and SF3B1 gene mutational analysis and Multiplex Ligation Probe Amplification (MLPA) analysis to detect deletions and duplications in chromosomes 3 and 8 were performed in 25 patients (50% of total patients).	('GNAQ', 'Gene', '2776', (0, 4))	('patients', 'Species', '9606', (211, 219))	('SF3B1', 'Gene', (17, 22))	('patients', 'Species', '9606', (188, 196))	('GNA11', 'Gene', '2767', (6, 11))	('GNA11', 'Gene', (6, 11))	('GNAQ', 'Gene', (0, 4))	('SF3B1', 'Gene', '23451', (17, 22))	('deletions', 'Var', (117, 126))	('duplications', 'Var', (131, 143))
105791	33922591	The influence of BAP1 mutation or chromosome 3 monosomy has been considered only in a small fraction of patients.	('mutation', 'Var', (22, 30))	('chromosome', 'cellular_component', 'GO:0005694', ('34', '44'))	('monosomy', 'Var', (47, 55))	('BAP1', 'Gene', '8314', (17, 21))	('patients', 'Species', '9606', (104, 112))	('BAP1', 'Gene', (17, 21))
105792	33922591	Patients at high risk of metastasis with monosomy 3 and/or BAP1 mutation should be included in clinical trials of adjuvant therapy.	('mutation', 'Var', (64, 72))	('BAP1', 'Gene', (59, 63))	('monosomy 3', 'Var', (41, 51))	('Patients', 'Species', '9606', (0, 8))	('BAP1', 'Gene', '8314', (59, 63))	('metastasis', 'CPA', (25, 35))
105816	33922591	However, results from validation studies of this signature in larger cohorts of patients (GEM1402 and CA184-187) will provide more information on the resistance and response mechanisms of M-UM to immunotherapy, and prospective testing will establish clinical value.	('GEM1402', 'Var', (90, 97))	('CA184-187', 'Var', (102, 111))	('patients', 'Species', '9606', (80, 88))	('UM', 'Phenotype', 'HP:0007716', (190, 192))
105817	33922591	Among the high-risk UM, mostly metastatic cases with BAP1 mutations, chromosome 3 monosomy, and chromosome 8q gain, 1 group (light blue) contains potential responders to immunotherapy.	('mutations', 'Var', (58, 67))	('monosomy', 'Var', (82, 90))	('chromosome', 'cellular_component', 'GO:0005694', ('69', '79'))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('BAP1', 'Gene', '8314', (53, 57))	('metastatic', 'Disease', (31, 41))	('UM', 'Phenotype', 'HP:0007716', (20, 22))	('BAP1', 'Gene', (53, 57))
105832	33922591	The clinical trial ClinicalTrials.gov Identifier: NCT02519322 that uses the association of anti-LAG-3 with Ipilimumab and Nivolumab and is, at present, enrolling patients will eventually show the advantage of LAG-3 targeting (Table 2).	('patients', 'Species', '9606', (162, 170))	('Nivolumab', 'Chemical', 'MESH:D000077594', (122, 131))	('association', 'Interaction', (76, 87))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (107, 117))	('anti-LAG-3', 'Var', (91, 101))
105862	30787124	Mutation load was quantified for each sample and compared between uveal and cutaneous melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (76, 95))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (76, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (76, 94))	('Mutation', 'Var', (0, 8))	('cutaneous melanomas', 'Disease', (76, 95))
105870	30787124	Of note, tumors from patients who benefited were confirmed by molecular sequencing to harbor either GNAQ or GNA11 mutations but the patients had either no liver involvement or liver metastases of maximal diameter <1.2cm.	('patients', 'Species', '9606', (132, 140))	('GNA11', 'Gene', '2767', (108, 113))	('GNAQ', 'Gene', '2776', (100, 104))	('mutations', 'Var', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('GNA11', 'Gene', (108, 113))	('liver metastases', 'Disease', (176, 192))	('liver metastases', 'Disease', 'MESH:D009362', (176, 192))	('patients', 'Species', '9606', (21, 29))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('GNAQ', 'Gene', (100, 104))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('harbor', 'Reg', (86, 92))
105879	30787124	Consistent with prior investigations, mutational burden was an order of magnitude lower in UM without a significant difference between T cell-inflamed and non-inflamed tumors (Figure 2).	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('mutational', 'Var', (38, 48))	('lower', 'NegReg', (82, 87))
105890	30787124	Additionally epigenetic modifier programs targeting MYC have been proposed and have begun to be explored in clinical trials (NCT02959437).	('MYC', 'Gene', '4609', (52, 55))	('epigenetic modifier', 'Var', (13, 32))	('MYC', 'Gene', (52, 55))
105896	33333852	We found that copy-number variation alterations in some olaparib-modulated lncRNAs had a statistically significant correlation with alterations in some key tumor suppressor genes.	('copy-number variation alterations', 'Var', (14, 47))	('olaparib-modulated', 'Gene', (56, 74))	('correlation', 'Reg', (115, 126))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('lncRNAs', 'Gene', (75, 82))	('tumor suppressor', 'biological_process', 'GO:0051726', ('156', '172'))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('156', '172'))	('olaparib', 'Chemical', 'MESH:C531550', (56, 64))	('tumor', 'Disease', (156, 161))
105905	33333852	VM describes the generation of perfusion pathways in tumors by highly aggressive and genetically deregulated tumor cells, independently of angiogenesis or pre-existing normal blood vessels.	('genetically deregulated', 'Var', (85, 108))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('perfusion', 'MPA', (31, 40))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (53, 59))	('angiogenesis', 'biological_process', 'GO:0001525', ('139', '151'))	('tumor', 'Disease', (109, 114))	('pre', 'molecular_function', 'GO:0003904', ('155', '158'))
105906	33333852	The presence of VM is reportedly correlated with increased metastasis, poor prognosis and decreased survival in cancer patients.	('metastasis', 'CPA', (59, 69))	('poor', 'CPA', (71, 75))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('increased', 'PosReg', (49, 58))	('patients', 'Species', '9606', (119, 127))	('decreased', 'NegReg', (90, 99))	('survival', 'CPA', (100, 108))	('presence', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
105915	33333852	In a previous study, we showed that PARP inhibition altered the ability of melanoma to undergo VM, interfering with the expression and phosphorylation of VE-cadherin.	('expression', 'MPA', (120, 130))	('ability', 'MPA', (64, 71))	('PARP', 'Gene', '142', (36, 40))	('phosphorylation', 'biological_process', 'GO:0016310', ('135', '150'))	('cadherin', 'molecular_function', 'GO:0008014', ('157', '165'))	('VE-cadherin', 'Gene', '1003', (154, 165))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('inhibition', 'Var', (41, 51))	('melanoma', 'Disease', (75, 83))	('VE-cadherin', 'Gene', (154, 165))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('phosphorylation', 'MPA', (135, 150))	('PARP', 'Gene', (36, 40))	('interfering', 'NegReg', (99, 110))
105937	33333852	We previously reported that PARP inhibition could hinder the potential of melanoma cells for VM formation on Matrigel.	('inhibition', 'Var', (33, 43))	('formation', 'biological_process', 'GO:0009058', ('96', '105'))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('PARP', 'Gene', (28, 32))	('melanoma', 'Disease', (74, 82))	('PARP', 'Gene', '142', (28, 32))	('hinder', 'NegReg', (50, 56))
105938	33333852	Moreover, PARP inhibition markedly reduced the expression of VE-cadherin, a well-known marker of VM, as well as the phosphorylation of VE-cadherin on Y658, which we reported to be crucial for VM signaling.	('cadherin', 'molecular_function', 'GO:0008014', ('138', '146'))	('reduced', 'NegReg', (35, 42))	('phosphorylation', 'MPA', (116, 131))	('VE-cadherin', 'Gene', (135, 146))	('Y658', 'Chemical', '-', (150, 154))	('cadherin', 'molecular_function', 'GO:0008014', ('64', '72'))	('PARP', 'Gene', (10, 14))	('VE-cadherin', 'Gene', (61, 72))	('VE-cadherin', 'Gene', '1003', (135, 146))	('expression', 'MPA', (47, 57))	('signaling', 'biological_process', 'GO:0023052', ('195', '204'))	('phosphorylation', 'biological_process', 'GO:0016310', ('116', '131'))	('VE-cadherin', 'Gene', '1003', (61, 72))	('PARP', 'Gene', '142', (10, 14))	('inhibition', 'Var', (15, 25))
105950	33333852	The generally large size of lncRNAs makes them prone to accumulate alterations in a genomically unstable context such as cancer, so it should be taken into account that most of the alterations that we found probably fall in the definition of passenger mutations.	('alterations', 'Var', (181, 192))	('fall', 'Phenotype', 'HP:0002527', (216, 220))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
105952	33333852	Out of 80 samples in the UM cohort, only one was altered, with a deletion in the SNHG4 gene.	('SNHG4', 'Gene', '724102', (81, 86))	('deletion', 'Var', (65, 73))	('UM', 'Phenotype', 'HP:0007716', (25, 27))	('SNHG4', 'Gene', (81, 86))
105963	33333852	Alterations in SMC5-AS1 and MAMDC2-AS1 have the highest co-occurrence, which can be easily explained by the fact that the loci for these lncRNAs partially overlap.	('MAMDC2-AS1', 'Gene', (28, 38))	('SMC5-AS1', 'Gene', (15, 23))	('Alterations', 'Var', (0, 11))	('MAMDC2-AS1', 'Gene', '100507244;256691;5729', (28, 38))	('SMC5-AS1', 'Gene', '100507299;23137;5729', (15, 23))	('co-occurrence', 'Interaction', (56, 69))	('SMC', 'cellular_component', 'GO:0016029', ('15', '18'))
105968	33333852	Alterations in TP53 were significantly enriched in samples harboring an amplification in FLG-AS1 (q-value = 2.761 x 10-3), while this amplification was negatively correlated with alterations in IDH1 (q-value = 0.0204) or PTEN (q-value = 0.0384) (Figure 5A).	('amplification', 'Var', (72, 85))	('PTEN', 'Gene', (221, 225))	('Alterations', 'Var', (0, 11))	('IDH1', 'Gene', (194, 198))	('PTEN', 'Gene', '5728', (221, 225))	('FLG-AS1', 'Gene', (89, 96))	('IDH1', 'Gene', '3417', (194, 198))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('FLG-AS1', 'Gene', '339400', (89, 96))
105969	33333852	Alterations in VHL were significantly enriched in samples with amplifications in SNHG4 (q-value = 5.98 x 10-9) (Figure 5B) or PRR7-AS1 (q-value = 2.94 x 10-7) (Figure 5D), and alterations in SPOP were significantly enriched in samples with deep deletion in RGMB-AS1 (q-value < 10-10) (Figure 5C).	('PRR7-AS1', 'Gene', '340037;80758;5729', (126, 134))	('VHL', 'Gene', (15, 18))	('SPOP', 'Gene', '8405', (191, 195))	('PRR', 'molecular_function', 'GO:0038187', ('126', '129'))	('SPOP', 'Gene', (191, 195))	('alterations', 'Var', (176, 187))	('SNHG4', 'Gene', (81, 86))	('VHL', 'Gene', '7428', (15, 18))	('RGMB-AS1', 'Gene', (257, 265))	('amplifications', 'Var', (63, 77))	('SNHG4', 'Gene', '724102', (81, 86))	('RGMB-AS1', 'Gene', '503569', (257, 265))	('deep deletion', 'Var', (240, 253))	('Alterations', 'Reg', (0, 11))	('PRR7-AS1', 'Gene', (126, 134))
105970	33333852	It is not surprising that samples with amplifications in SNHG4 and PRR7-AS1 have enrichment for alterations in the same gene since, as stated above, alterations in these two lncRNAs significantly co-occur in pan-cancer samples.	('alterations', 'Var', (149, 160))	('SNHG4', 'Gene', (57, 62))	('PRR', 'molecular_function', 'GO:0038187', ('67', '70'))	('PRR7-AS1', 'Gene', (67, 75))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('PRR7-AS1', 'Gene', '340037;80758;5729', (67, 75))	('SNHG4', 'Gene', '724102', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
105971	33333852	Assessing whether the co-occurrence of these alterations with the alterations in TP53, IDH1, PTEN, VHL and SPOP has a biological significance would require further research, which, while not within the scope of the present work, represents an interesting niche for future studies.	('PTEN', 'Gene', (93, 97))	('alterations', 'Var', (66, 77))	('PTEN', 'Gene', '5728', (93, 97))	('IDH1', 'Gene', '3417', (87, 91))	('SPOP', 'Gene', '8405', (107, 111))	('VHL', 'Gene', (99, 102))	('SPOP', 'Gene', (107, 111))	('VHL', 'Gene', '7428', (99, 102))	('IDH1', 'Gene', (87, 91))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
105972	33333852	As for possible effects on survival, we checked how amplification or deep deletion of olaparib-modulated lncRNAs affected overall survival in pan-cancer patients (Figure S4).	('overall', 'MPA', (122, 129))	('deep deletion', 'Var', (69, 82))	('affected', 'Reg', (113, 121))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('olaparib-modulated', 'Gene', (86, 104))	('patients', 'Species', '9606', (153, 161))	('olaparib', 'Chemical', 'MESH:C531550', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('amplification', 'Var', (52, 65))
105973	33333852	Significant differences in survival can only be found for MAMDC2-AS1 (p = 0.0365 amplification vs. deletion; p = 0.002384 amplification vs. unaltered), SNHG15 (p = 2.23 x 10-5 amplification vs. unaltered) and LINC01135 (p = 0.0138 amplification vs. deletion; p = 5.72 x 10-8 amplification vs. unaltered).	('SNHG15', 'Gene', '285958', (152, 158))	('MAMDC2-AS1', 'Gene', '100507244;256691;5729', (58, 68))	('LINC01135', 'Gene', '100131060', (209, 218))	('LINC01135', 'Gene', (209, 218))	('deletion', 'Var', (99, 107))	('SNHG15', 'Gene', (152, 158))	('MAMDC2-AS1', 'Gene', (58, 68))
105975	33333852	However, it is important to point out that in many cases, samples with amplifications in olaparib-modulated lncRNAs have, in fact, whole chromosome amplifications.	('amplifications', 'Var', (71, 85))	('olaparib-modulated', 'Gene', (89, 107))	('olaparib', 'Chemical', 'MESH:C531550', (89, 97))	('chromosome', 'cellular_component', 'GO:0005694', ('137', '147'))	('lncRNAs', 'Gene', (108, 115))
105976	33333852	Therefore, many other genes are altered in these samples, and it is the global effect of these alterations that determines tumor aggressiveness and, eventually, patient survival.	('tumor aggressiveness', 'Disease', (123, 143))	('determines', 'Reg', (112, 122))	('patient', 'Species', '9606', (161, 168))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (123, 143))	('altered', 'Reg', (32, 39))	('aggressiveness', 'Phenotype', 'HP:0000718', (129, 143))	('alterations', 'Var', (95, 106))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
105992	33333852	We have previously reported that PARP inhibition can decrease VM formation and VM markers (VE-cadherin and its phosphorylation on Y658) in melanoma.	('VM formation', 'CPA', (62, 74))	('decrease', 'NegReg', (53, 61))	('Y658', 'Chemical', '-', (130, 134))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('PARP', 'Gene', '142', (33, 37))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('VE-cadherin', 'Gene', (91, 102))	('inhibition', 'Var', (38, 48))	('cadherin', 'molecular_function', 'GO:0008014', ('94', '102'))	('VE-cadherin', 'Gene', '1003', (91, 102))	('formation', 'biological_process', 'GO:0009058', ('65', '74'))	('PARP', 'Gene', (33, 37))	('phosphorylation', 'MPA', (111, 126))	('phosphorylation', 'biological_process', 'GO:0016310', ('111', '126'))
106003	33333852	In many of these cancer types, high SNHG1 expression is correlated with poor prognosis and lower progression-free survival.	('lower', 'NegReg', (91, 96))	('expression', 'MPA', (42, 52))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('SNHG1', 'Gene', '23642', (36, 41))	('progression-free survival', 'CPA', (97, 122))	('cancer', 'Disease', (17, 23))	('high', 'Var', (31, 35))	('SNHG1', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
106014	33333852	A positive correlation, as the one found for SNHG4 and MIR17HG, would be expected in our model since inhibition of PARP1/2 leads to reduced lncRNA expression.	('PARP1/2', 'Gene', '64761;142;10038', (115, 122))	('inhibition', 'Var', (101, 111))	('MIR17HG', 'Gene', (55, 62))	('PARP1/2', 'Gene', (115, 122))	('lncRNA expression', 'MPA', (140, 157))	('reduced', 'NegReg', (132, 139))	('SNHG4', 'Gene', '724102', (45, 50))	('MIR17HG', 'Gene', '407975', (55, 62))	('SNHG4', 'Gene', (45, 50))
106018	33333852	Surprisingly, we found that CNV alterations in some olaparib-modulated lncRNAs had a statistically significant correlation with alterations in some key tumor suppressors genes (Figure 5 and Figure S3): samples harboring amplification in FLG-AS1 were frequently mutated in TP53, while there was a negative correlation with mutations in PTEN and IDH1; alterations in SPOP co-occurred with a deep deletion in RGMB-AS1, and alterations in VHL were enriched in samples containing amplification in SNHG4 or in PRR7-AS1.	('amplification', 'Var', (475, 488))	('TP53', 'Gene', '7157', (272, 276))	('VHL', 'Gene', (435, 438))	('IDH1', 'Gene', (344, 348))	('alterations', 'Reg', (420, 431))	('PRR7-AS1', 'Gene', (504, 512))	('FLG-AS1', 'Gene', (237, 244))	('co-occurred', 'Reg', (370, 381))	('VHL', 'Gene', '7428', (435, 438))	('tumor', 'Disease', (152, 157))	('IDH1', 'Gene', '3417', (344, 348))	('FLG-AS1', 'Gene', '339400', (237, 244))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('TP53', 'Gene', (272, 276))	('SPOP', 'Gene', '8405', (365, 369))	('PRR7-AS1', 'Gene', '340037;80758;5729', (504, 512))	('PTEN', 'Gene', (335, 339))	('RGMB-AS1', 'Gene', (406, 414))	('deep deletion', 'Var', (389, 402))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('SNHG4', 'Gene', '724102', (492, 497))	('SPOP', 'Gene', (365, 369))	('olaparib', 'Chemical', 'MESH:C531550', (52, 60))	('RGMB-AS1', 'Gene', '503569', (406, 414))	('PRR', 'molecular_function', 'GO:0038187', ('504', '507'))	('alterations', 'Reg', (350, 361))	('SNHG4', 'Gene', (492, 497))	('PTEN', 'Gene', '5728', (335, 339))
106022	33333852	Wildtype p53 can arrest cell cycle progression after DNA damage, hindering the accumulation of potentially oncogenic mutations in the cell.	('mutations', 'Var', (117, 126))	('cell cycle progression', 'CPA', (24, 46))	('hindering', 'NegReg', (65, 74))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', (9, 12))	('cell cycle', 'biological_process', 'GO:0007049', ('24', '34'))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))
106023	33333852	Malfunction of p53 can lead to evasion of tumor cell death, which in turn allows tumor growth.	('tumor cell death', 'Disease', (42, 58))	('tumor', 'Disease', (42, 47))	('lead to', 'Reg', (23, 30))	('cell death', 'biological_process', 'GO:0008219', ('48', '58'))	('tumor cell death', 'Disease', 'MESH:D003643', (42, 58))	('evasion of', 'MPA', (31, 41))	('Malfunction', 'Var', (0, 11))	('p53', 'Gene', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('p53', 'Gene', '7157', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('allows', 'PosReg', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', (81, 86))
106024	33333852	TP53 is altered in over half of the samples containing FLG-AS1 amplification (192 out of 376 samples) (Figure S3A), having a significant co-occurrence in the pan-cancer cohort.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('FLG-AS1', 'Gene', '339400', (55, 62))	('cancer', 'Disease', (162, 168))	('altered', 'Reg', (8, 15))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('amplification', 'Var', (63, 76))	('FLG-AS1', 'Gene', (55, 62))
106025	33333852	As expected for this gene, most TP53 alterations in those 192 samples are classed as putative drivers, most of the missense mutations, but also truncating mutations and a few in-frame mutations.	('TP53', 'Gene', '7157', (32, 36))	('truncating mutations', 'Var', (144, 164))	('TP53', 'Gene', (32, 36))	('alterations', 'Var', (37, 48))	('missense mutations', 'Var', (115, 133))
106026	33333852	Samples harboring alterations in both genes are mostly from non-small cell lung cancer and invasive breast carcinoma.	('lung cancer', 'Disease', (75, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('alterations', 'Var', (18, 29))	('invasive breast carcinoma', 'Disease', (91, 116))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (64, 86))	('invasive breast carcinoma', 'Disease', 'MESH:D001943', (91, 116))	('breast carcinoma', 'Phenotype', 'HP:0003002', (100, 116))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (60, 86))
106030	33333852	In the TCGA pan-cancer cohort, PTEN alterations occur most frequently in uterine corpus endometrial carcinoma (UCEC) (66.54% of all UCEC samples; data not shown), while FLG-AS1 amplification is most prevalent in hepatocellular carcinoma, lung adenocarcinoma and breast invasive carcinoma (Figure S2), with only two UCEC samples harboring an amplification in this lncRNA.	('PTEN', 'Gene', (31, 35))	('FLG-AS1', 'Gene', '339400', (169, 176))	('alterations', 'Var', (36, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('prevalent', 'Reg', (199, 208))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (212, 236))	('PTEN', 'Gene', '5728', (31, 35))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('endometrial carcinoma', 'Disease', (88, 109))	('hepatocellular carcinoma', 'Disease', (212, 236))	('amplification', 'Var', (177, 190))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (262, 287))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (238, 257))	('FLG-AS1', 'Gene', (169, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (88, 109))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (88, 109))	('lung adenocarcinoma and breast invasive carcinoma', 'Disease', 'MESH:D001943', (238, 287))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (212, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
106032	33333852	Isocitrate dehydrogenase 1 and 2 (IDH1/2) mutations are also frequent in several types of cancer, especially in a number of brain tumors.	('IDH1/2', 'Gene', '3417;3418', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('IDH1/2', 'Gene', (34, 40))	('frequent', 'Reg', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('brain tumors', 'Phenotype', 'HP:0030692', (124, 136))	('brain tumors', 'Disease', 'MESH:D001932', (124, 136))	('cancer', 'Disease', (90, 96))	('mutations', 'Var', (42, 51))	('brain tumors', 'Disease', (124, 136))
106033	33333852	In fact, IDH1/2 mutations are indicators of good prognosis in astrocytomas and glioblastomas since these mutations can lead to improved responses to irradiation and chemotherapy.	('IDH1/2', 'Gene', (9, 15))	('glioblastomas', 'Phenotype', 'HP:0012174', (79, 92))	('mutations', 'Var', (16, 25))	('responses to irradiation', 'MPA', (136, 160))	('astrocytomas', 'Disease', 'MESH:D001254', (62, 74))	('glioblastomas', 'Disease', 'MESH:D005909', (79, 92))	('IDH1/2', 'Gene', '3417;3418', (9, 15))	('glioblastomas', 'Disease', (79, 92))	('astrocytomas', 'Disease', (62, 74))	('improved', 'PosReg', (127, 135))
106034	33333852	IDH1 alterations were mostly found in the lower grade glioma (LGG) TCGA cohort in cBioPortal, with 78% of all LGG samples having alterations in this gene (data not shown).	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('glioma', 'Disease', (54, 60))	('alterations', 'Var', (5, 16))	('alterations', 'Var', (129, 140))	('IDH1', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('IDH1', 'Gene', '3417', (0, 4))
106035	33333852	However, as stated above, FLG-AS1 amplification is most common in other cancer types, and was only present in two LGG samples, hence the mutual exclusivity between alterations in these genes in the pan-cancer context.	('common', 'Reg', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('FLG-AS1', 'Gene', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('FLG-AS1', 'Gene', '339400', (26, 33))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('amplification', 'Var', (34, 47))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
106037	33333852	The co-occurrence between SPOP mutations and RGMB-AS1 deletion happened exclusively in prostate adenocarcinoma (PRAD).	('RGMB-AS1', 'Gene', '503569', (45, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('deletion', 'Var', (54, 62))	('prostate adenocarcinoma', 'Disease', (87, 110))	('happened', 'Reg', (63, 71))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (87, 110))	('RGMB-AS1', 'Gene', (45, 53))	('co-occurrence', 'Reg', (4, 17))	('SPOP', 'Gene', '8405', (26, 30))	('SPOP', 'Gene', (26, 30))
106039	33333852	SPOP alterations and RGMB-AS1 deletions significantly co-occurred in the PRAD cohort, with 20 out of 489 samples containing alterations in both genes (Figure S3E).	('SPOP', 'Gene', (0, 4))	('co-occurred', 'Reg', (54, 65))	('deletions', 'Var', (30, 39))	('RGMB-AS1', 'Gene', (21, 29))	('PRAD', 'Disease', (73, 77))	('RGMB-AS1', 'Gene', '503569', (21, 29))	('SPOP', 'Gene', '8405', (0, 4))
106040	33333852	RGMB-AS1 was deleted in all these 20 samples, while SPOP had suffered some kind of missense mutation, affecting the residues Y87, F102, F125, K129, W131 or F133.	('RGMB-AS1', 'Gene', '503569', (0, 8))	('SPOP', 'Gene', '8405', (52, 56))	('affecting', 'Reg', (102, 111))	('SPOP', 'Gene', (52, 56))	('W131', 'Var', (148, 152))	('RGMB-AS1', 'Gene', (0, 8))	('F102', 'Var', (130, 134))	('K129', 'Var', (142, 146))	('F125', 'Var', (136, 140))	('Y87', 'Var', (125, 128))	('F133', 'Var', (156, 160))
106041	33333852	Most of these residues are part of SPOP substrate-binding cleft, and all mutations were classed as putative drivers of cancer.	('SPOP', 'Gene', '8405', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('SPOP', 'Gene', (35, 39))	('binding', 'molecular_function', 'GO:0005488', ('50', '57'))	('mutations', 'Var', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
106042	33333852	Deletions in the chromodomain helicase DNA binding protein 1(CHD1) have also been associated with SPOP mutations.	('CHD1', 'Gene', (61, 65))	('associated', 'Reg', (82, 92))	('DNA binding', 'molecular_function', 'GO:0003677', ('39', '50'))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('SPOP', 'Gene', (98, 102))	('CHD1', 'Gene', '1105', (61, 65))	('chromodomain helicase DNA binding protein 1', 'Gene', (17, 60))	('chromodomain helicase DNA binding protein 1', 'Gene', '1105', (17, 60))	('SPOP', 'Gene', '8405', (98, 102))	('Deletions', 'Var', (0, 9))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
106043	33333852	A query for SPOP, CHD1 and deletions in RGMB-AS1 in the PRAD cohort (Figure S3F) confirmed a co-occurrence between alterations in all three genes.	('RGMB-AS1', 'Gene', (40, 48))	('SPOP', 'Gene', '8405', (12, 16))	('alterations', 'Var', (115, 126))	('RGMB-AS1', 'Gene', '503569', (40, 48))	('CHD1', 'Gene', (18, 22))	('deletions', 'Var', (27, 36))	('SPOP', 'Gene', (12, 16))	('CHD1', 'Gene', '1105', (18, 22))
106044	33333852	In fact, CHD1 and RGMB-AS1 are located in the same cytogenetic band (5q15) in the genome; hence a deletion in RGMB-AS1 always involves a deletion in CHD1 too.	('CHD1', 'Gene', '1105', (9, 13))	('RGMB-AS1', 'Gene', '503569', (110, 118))	('RGMB-AS1', 'Gene', '503569', (18, 26))	('deletion', 'Var', (137, 145))	('deletion', 'Var', (98, 106))	('RGMB-AS1', 'Gene', (18, 26))	('CHD1', 'Gene', (9, 13))	('CHD1', 'Gene', (149, 153))	('RGMB-AS1', 'Gene', (110, 118))	('CHD1', 'Gene', '1105', (149, 153))
106045	33333852	To our knowledge, there are no available publications analyzing the role of RGMB-AS1 in prostate cancer, though it would be of great interest to find out if the pro-tumoral effect of deletions in the 5q15 region is due exclusively to the loss of CHD1 or if RGMB-AS1 could be playing an important role as well.	('loss of CHD1', 'Disease', 'MESH:D014786', (238, 250))	('prostate cancer', 'Disease', (88, 103))	('RGMB-AS1', 'Gene', '503569', (76, 84))	('tumoral', 'Disease', (165, 172))	('tumoral', 'Disease', 'MESH:D009369', (165, 172))	('RGMB-AS1', 'Gene', (257, 265))	('prostate cancer', 'Disease', 'MESH:D011471', (88, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))	('RGMB-AS1', 'Gene', (76, 84))	('loss of CHD1', 'Disease', (238, 250))	('RGMB-AS1', 'Gene', '503569', (257, 265))	('deletions', 'Var', (183, 192))
106046	33333852	This is of particular interest since SPOP mutation in PRAD has been reported to impair homologous recombination-mediated DNA repair, sensitizing to PARP inhibitors, and CHD1 deletions have been associated with increased nonhomologous end joining (NHEJ) DNA-repair, which could lead to sensitivity to PARP inhibitors as well.	('NHEJ', 'biological_process', 'GO:0006303', ('247', '251'))	('PARP', 'Gene', '142', (148, 152))	('PARP', 'Gene', '142', (300, 304))	('PRAD', 'Gene', (54, 58))	('PARP', 'Gene', (300, 304))	('PARP', 'Gene', (148, 152))	('SPOP', 'Gene', (37, 41))	('CHD1', 'Gene', (169, 173))	('sensitizing', 'MPA', (133, 144))	('mutation', 'Var', (42, 50))	('homologous recombination', 'biological_process', 'GO:0035825', ('87', '111'))	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('increased', 'PosReg', (210, 219))	('DNA-repair', 'biological_process', 'GO:0006281', ('253', '263'))	('DNA', 'cellular_component', 'GO:0005574', ('253', '256'))	('nonhomologous end joining', 'MPA', (220, 245))	('DNA repair', 'biological_process', 'GO:0006281', ('121', '131'))	('homologous recombination-mediated DNA repair', 'MPA', (87, 131))	('deletions', 'Var', (174, 183))	('impair', 'NegReg', (80, 86))	('SPOP', 'Gene', '8405', (37, 41))	('CHD1', 'Gene', '1105', (169, 173))
106048	33333852	Loss of VHL interferes with the degradation of hypoxia-inducible factors HIF1alpha and HIF2alpha and therefore promotes the expression of hypoxic genes, which is directly associated with tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('VHL', 'Gene', '7428', (8, 11))	('HIF2alpha', 'Gene', (87, 96))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('hypoxia', 'Disease', (47, 54))	('HIF2alpha', 'Gene', '2034', (87, 96))	('degradation', 'MPA', (32, 43))	('tumor', 'Disease', (187, 192))	('interferes', 'NegReg', (12, 22))	('HIF1alpha', 'Gene', (73, 82))	('expression', 'MPA', (124, 134))	('promotes', 'PosReg', (111, 119))	('hypoxic genes', 'Gene', (138, 151))	('HIF1alpha', 'Gene', '3091', (73, 82))	('degradation', 'biological_process', 'GO:0009056', ('32', '43'))	('Loss', 'Var', (0, 4))	('VHL', 'Gene', (8, 11))
106049	33333852	VHL alterations were present in 16 samples with amplification in SNHG4 (Figure S3D), all of them ccRCC except a PRAD sample.	('SNHG4', 'Gene', '724102', (65, 70))	('alterations', 'Var', (4, 15))	('VHL', 'Gene', (0, 3))	('SNHG4', 'Gene', (65, 70))	('VHL', 'Gene', '7428', (0, 3))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('amplification', 'Var', (48, 61))
106052	33333852	VHL alterations in these samples were mainly truncating mutations classed as putative drivers.	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', (0, 3))	('alterations', 'Reg', (4, 15))	('truncating mutations', 'Var', (45, 65))
106066	33333852	Amplifications in the MZF1 gene, as well as high MZF1 expression, are frequent in cancer, as shown by TCGA data, and MZF1 has been associated with cancer progression in a variety of solid tumors.	('MZF1', 'Gene', '7593', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('MZF1', 'Gene', (49, 53))	('MZF1', 'Gene', '7593', (22, 26))	('cancer', 'Disease', (82, 88))	('solid tumors', 'Disease', 'MESH:D009369', (182, 194))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('Amplifications', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('MZF1', 'Gene', '7593', (49, 53))	('MZF1', 'Gene', (117, 121))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('expression', 'MPA', (54, 64))	('MZF1', 'Gene', (22, 26))	('solid tumors', 'Disease', (182, 194))	('associated with', 'Reg', (131, 146))	('cancer', 'Disease', (147, 153))
106086	33333852	The following are available online at , Figure S1: Alteration of each olaparib-modulated lncRNAs across cancer types, Figure S2: Co-expression between olaparib-targeted PARPs and olaparib-modulated lncRNAs in SKCM, Figure S3: Co-alteration between olaparib-modulated lncRNAs and other genes in cancer (detailed), Figure S4: Survival of cancer patients with alterations in olaparib-modulated genes.	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('patients', 'Species', '9606', (343, 351))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('olaparib', 'Chemical', 'MESH:C531550', (179, 187))	('PARPs', 'Gene', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('olaparib', 'Chemical', 'MESH:C531550', (151, 159))	('PARPs', 'Gene', '142;10038;64761', (169, 174))	('olaparib', 'Chemical', 'MESH:C531550', (248, 256))	('cancer', 'Disease', (294, 300))	('cancer', 'Disease', (104, 110))	('olaparib', 'Chemical', 'MESH:C531550', (372, 380))	('cancer', 'Disease', 'MESH:D009369', (336, 342))	('olaparib', 'Chemical', 'MESH:C531550', (70, 78))	('cancer', 'Disease', (336, 342))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('alterations', 'Var', (357, 368))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
106093	31924735	RNA-Seq analysis showed CSF to induce PI3K/AKT, integrin, B-cell activation, S-phase entry, TNFR2, TGF-beta and oxidative stress responses in the melanoma cells.	('TNFR2', 'Gene', '7133', (92, 97))	('AKT', 'Gene', '207', (43, 46))	('oxidative stress', 'Phenotype', 'HP:0025464', (112, 128))	('TGF-beta', 'MPA', (99, 107))	('oxidative stress responses', 'MPA', (112, 138))	('B-cell activation', 'biological_process', 'GO:0042113', ('58', '75'))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('CSF', 'Var', (24, 27))	('S-phase', 'biological_process', 'GO:0051320', ('77', '84'))	('B-cell activation', 'MPA', (58, 75))	('induce', 'PosReg', (31, 37))	('S-phase entry', 'MPA', (77, 90))	('AKT', 'Gene', (43, 46))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('integrin', 'Pathway', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('PI3K', 'molecular_function', 'GO:0016303', ('38', '42'))	('TNFR2', 'Gene', (92, 97))
106187	31924735	To determine which pathways were increased following CSF treatment, we performed kinome arrays from CSF from Patient #9 and demonstrated that their CSF increased signaling through the PI3K/AKT/mTOR pathway, some SRC-family kinases (Src and Hck) and the cAMP responsive transcription factor CREB (Figure 4B).	('signaling', 'biological_process', 'GO:0023052', ('162', '171'))	('mTOR', 'Gene', (193, 197))	('Patient', 'Species', '9606', (109, 116))	('Hck', 'Gene', (240, 243))	('transcription', 'biological_process', 'GO:0006351', ('269', '282'))	('AKT', 'Gene', (189, 192))	('mTOR', 'Gene', '2475', (193, 197))	('CSF increased', 'Phenotype', 'HP:0002922', (148, 161))	('SRC', 'Gene', '6714', (212, 215))	('CREB', 'Gene', (290, 294))	('transcription factor', 'molecular_function', 'GO:0000981', ('269', '289'))	('increased', 'PosReg', (152, 161))	('SRC', 'Gene', (212, 215))	('CSF', 'Var', (148, 151))	('AKT', 'Gene', '207', (189, 192))	('Src', 'Gene', (232, 235))	('Hck', 'Gene', '3055', (240, 243))	('CREB', 'Gene', '1385', (290, 294))	('cAMP', 'Chemical', '-', (253, 257))	('PI3K', 'molecular_function', 'GO:0016303', ('184', '188'))	('signaling', 'MPA', (162, 171))	('Src', 'Gene', '6714', (232, 235))
106192	31924735	To investigate if these changes in AKT signaling were associated with downregulation of PTEN, we performed IHC analysis of samples of the leptomeninges collected from a separate LMM patient at autopsy and noted a trend towards a decrease in PTEN staining in the leptomeninges relative to the levels in surrounding normal brain (p-value = 0.1241, Figure 4D).	('decrease', 'NegReg', (229, 237))	('PTEN', 'Gene', (241, 245))	('staining', 'MPA', (246, 254))	('AKT', 'Gene', (35, 38))	('PTEN', 'Gene', '5728', (241, 245))	('AKT signaling', 'biological_process', 'GO:0043491', ('35', '48'))	('patient', 'Species', '9606', (182, 189))	('PTEN', 'Gene', (88, 92))	('PTEN', 'Gene', '5728', (88, 92))	('AKT', 'Gene', '207', (35, 38))	('downregulation', 'NegReg', (70, 84))	('changes', 'Var', (24, 31))
106203	31924735	An analysis of autopsy samples from an LMM patient from a separate cohort demonstrated a trend for increased levels of TGF-beta positivity in the leptomeningeal melanoma metastases compared to matched visceral melanoma samples (p-value = 0.0787, Figure 5C).	('visceral melanoma', 'Disease', 'MESH:D008545', (201, 218))	('leptomeningeal melanoma metastases', 'Disease', 'MESH:D009362', (146, 180))	('patient', 'Species', '9606', (43, 50))	('visceral melanoma', 'Disease', (201, 218))	('visceral melanoma', 'Phenotype', 'HP:0007716', (201, 218))	('positivity', 'Var', (128, 138))	('leptomeningeal melanoma metastases', 'Disease', (146, 180))	('increased', 'PosReg', (99, 108))	('TGF-beta', 'Gene', (119, 127))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))
106205	31924735	As the final step, we determined whether exogenous TGF-beta could mediated escape from BRAF inhibitor therapy, as has been previously suggested.	('exogenous', 'Var', (41, 50))	('escape', 'MPA', (75, 81))	('TGF-beta', 'Protein', (51, 59))	('BRAF', 'Gene', (87, 91))	('BRAF', 'Gene', '673', (87, 91))
106229	31924735	Our unbiased analyses of CSF from patients with melanoma leptomeningeal metastases demonstrated increased expression of multiple complement components including C2, C3, C6, C5, C9, C8alpha, C8beta, and C8gamma.	('C8alpha', 'Gene', (181, 188))	('C8beta', 'Gene', '731', (190, 196))	('increased', 'PosReg', (96, 105))	('melanoma leptomeningeal metastases', 'Disease', (48, 82))	('C8alpha', 'Gene', '731', (181, 188))	('C8beta', 'Gene', (190, 196))	('expression', 'MPA', (106, 116))	('patients', 'Species', '9606', (34, 42))	('C8gamma', 'Var', (202, 209))	('C2, C3, C6, C5, C9', 'Gene', '717;718;4704;727', (161, 179))	('melanoma leptomeningeal metastases', 'Disease', 'MESH:D009362', (48, 82))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
106245	31924735	There is already evidence that increased AKT signaling following BRAF inhibition can suppress cell death through the modulation of pro-apoptotic proteins and through downstream effects upon cell metabolism.	('cell death', 'biological_process', 'GO:0008219', ('94', '104'))	('increased', 'PosReg', (31, 40))	('cell metabolism', 'CPA', (190, 205))	('death', 'Disease', 'MESH:D003643', (99, 104))	('death', 'Disease', (99, 104))	('metabolism', 'biological_process', 'GO:0008152', ('195', '205'))	('effects', 'Reg', (177, 184))	('BRAF', 'Gene', '673', (65, 69))	('AKT', 'Gene', '207', (41, 44))	('inhibition', 'Var', (70, 80))	('AKT signaling', 'biological_process', 'GO:0043491', ('41', '54'))	('BRAF', 'Gene', (65, 69))	('suppress', 'NegReg', (85, 93))	('AKT', 'Gene', (41, 44))	('modulation of pro-apoptotic proteins', 'MPA', (117, 153))
106246	31924735	At this time, multiple studies have implicated adaptive PI3K/AKT signaling, whether through loss or silencing of PTEN, activating AKT mutations or increased RTK signaling, in the escape from BRAF inhibitor targeted therapy.	('activating', 'PosReg', (119, 129))	('RTK signaling', 'MPA', (157, 170))	('BRAF', 'Gene', (191, 195))	('increased', 'PosReg', (147, 156))	('silencing', 'Var', (100, 109))	('AKT', 'Gene', '207', (61, 64))	('PTEN', 'Gene', (113, 117))	('loss', 'NegReg', (92, 96))	('AKT', 'Gene', '207', (130, 133))	('PTEN', 'Gene', '5728', (113, 117))	('signaling', 'biological_process', 'GO:0023052', ('161', '170'))	('mutations', 'Var', (134, 143))	('AKT', 'Gene', (61, 64))	('BRAF', 'Gene', '673', (191, 195))	('PI3K', 'molecular_function', 'GO:0016303', ('56', '60'))	('AKT', 'Gene', (130, 133))	('AKT signaling', 'biological_process', 'GO:0043491', ('61', '74'))
106253	31924735	Upon uptake into the cancer cells, these miRNAs epigenetically silenced PTEN, increasing cancer cell survival in the brain microenvironment through a mechanism involving CCL2 release and the recruitment of pro-tumorigenic MDSCs.	('uptake', 'biological_process', 'GO:0098657', ('5', '11'))	('PTEN', 'Gene', '5728', (72, 76))	('epigenetically', 'Var', (48, 62))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('uptake', 'biological_process', 'GO:0098739', ('5', '11'))	('increasing', 'PosReg', (78, 88))	('tumor', 'Disease', (210, 215))	('CCL', 'molecular_function', 'GO:0044101', ('170', '173'))	('CCL2', 'Gene', (170, 174))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('iron', 'Chemical', 'MESH:D007501', (131, 135))	('cancer', 'Disease', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('PTEN', 'Gene', (72, 76))	('CCL2', 'Gene', '6347', (170, 174))	('silenced', 'NegReg', (63, 71))
106254	31924735	One of the major drivers of the adaptive PI3K/AKT signaling following BRAF inhibition is the IGF1R receptor.	('AKT', 'Gene', '207', (46, 49))	('PI3K', 'molecular_function', 'GO:0016303', ('41', '45'))	('inhibition', 'Var', (75, 85))	('adaptive', 'MPA', (32, 40))	('BRAF', 'Gene', '673', (70, 74))	('AKT', 'Gene', (46, 49))	('IGF1R', 'Gene', (93, 98))	('AKT signaling', 'biological_process', 'GO:0043491', ('46', '59'))	('BRAF', 'Gene', (70, 74))
106266	31924735	Our results support a role for TGF-beta in the CSF-mediated protection from BRAF inhibitor therapy we observed, demonstrating that exogenous TGF-beta increased melanoma cell survival under BRAF inhibitor therapy.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (189, 193))	('BRAF', 'Gene', '673', (76, 80))	('exogenous', 'Var', (131, 140))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('TGF-beta', 'Gene', (141, 149))	('BRAF', 'Gene', (189, 193))	('increased', 'PosReg', (150, 159))
106268	31924735	The autoimmunity observed was T cell mediated and could be rescued following the silencing of MHCII or beta2-microglobulin.	('MHCII', 'Gene', (94, 99))	('beta2-microglobulin', 'Gene', (103, 122))	('autoimmunity', 'Phenotype', 'HP:0002960', (4, 16))	('silencing', 'Var', (81, 90))	('beta2-microglobulin', 'Gene', '567', (103, 122))
106284	31924735	CSF from patients with LMM also conveyed protection to melanoma cells from BRAF inhibitor-targeted therapy through increased AKT and TGF-beta signaling.	('AKT', 'Gene', '207', (125, 128))	('patients', 'Species', '9606', (9, 17))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('TGF-beta signaling', 'MPA', (133, 151))	('signaling', 'biological_process', 'GO:0023052', ('142', '151'))	('increased', 'PosReg', (115, 124))	('BRAF', 'Gene', '673', (75, 79))	('AKT', 'Gene', (125, 128))	('LMM', 'Disease', (23, 26))	('BRAF', 'Gene', (75, 79))	('inhibitor-targeted therapy', 'Var', (80, 106))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
106288	31957195	Given the frequent involvement of chromosome 3 in multiple human cancers, in particular in the form of the prognostically highly relevant monosomy 3 in uveal melanoma (UM), we investigated the cumulative impact of cancer-associated genes on chromosome 3.	('chromosome', 'cellular_component', 'GO:0005694', ('241', '251'))	('at', 'Gene', '9407', (198, 200))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('cancer', 'Disease', (65, 71))	('at', 'Gene', '9407', (227, 229))	('cancer', 'Disease', (214, 220))	('chromosome', 'cellular_component', 'GO:0005694', ('34', '44'))	('involvement', 'Reg', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (158, 166))	('at', 'Gene', '9407', (184, 186))	('monosomy 3', 'Var', (138, 148))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('human', 'Species', '9606', (59, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (152, 166))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))
106295	31957195	Based on our results, we hypothesize that monosomy of chromosome 3 will have important clinical and molecular consequences in the respective diseases and in particular in UM.	('consequences', 'Reg', (110, 122))	('chromosome', 'cellular_component', 'GO:0005694', ('54', '64'))	('monosomy', 'Var', (42, 50))	('at', 'Gene', '9407', (39, 41))
106299	31957195	Over the years it has been established that the accumulation of genetic and epigenetic alterations contribute significantly to cancer progression.	('genetic', 'Var', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('at', 'Gene', '9407', (55, 57))	('contribute', 'Reg', (99, 109))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('at', 'Gene', '9407', (92, 94))	('cancer', 'Disease', (127, 133))	('at', 'Gene', '9407', (41, 43))
106330	31957195	Briefly, this analysis indicates that, although these genes harbor cancer potential, the repetitive sequences around their promoter might influence their role in other significant pathways that are not necessarily associated with cancer.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('at', 'Gene', '9407', (220, 222))	('at', 'Gene', '9407', (28, 30))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Disease', (67, 73))	('repetitive sequences', 'Var', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('at', 'Gene', '9407', (191, 193))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (230, 236))	('at', 'Gene', '9407', (181, 183))	('influence', 'Reg', (138, 147))	('at', 'Gene', '9407', (35, 37))
106332	31957195	Based on the information from respective databases, the genes located in the hotspot region of chromosome 3 were apparently found to be associated with 27 (out of 72 identified) different types of cancer (Figure 3A).	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('at', 'Gene', '9407', (142, 144))	('cancer', 'Disease', (197, 203))	('chromosome', 'cellular_component', 'GO:0005694', ('95', '105'))	('at', 'Gene', '9407', (19, 21))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('genes', 'Var', (56, 61))	('at', 'Gene', '9407', (42, 44))	('at', 'Gene', '9407', (65, 67))
106344	31957195	Rhesus macaque and baboon also showed inversions and rearrangements for these genes; moreover, their variations were comparable due to their phylogenetic relationship.	('baboon', 'Species', '9555', (19, 25))	('at', 'Gene', '9407', (105, 107))	('at', 'Gene', '9407', (157, 159))	('inversions', 'Var', (38, 48))	('Rhesus macaque', 'Species', '9544', (0, 14))	('rearrangements', 'Var', (53, 67))
106350	31957195	Hence, we could speculate that the disruption of synteny could play a role in the development of cancer.	('at', 'Gene', '9407', (28, 30))	('cancer', 'Disease', (97, 103))	('role', 'Reg', (70, 74))	('synteny', 'Protein', (49, 56))	('play', 'Reg', (63, 67))	('at', 'Gene', '9407', (22, 24))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('disruption', 'Var', (35, 45))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
106359	31957195	Whether the loss of other constituents, such as microRNAs (miRNAs) or lncRNAs, at chromosome 3 also affects the chromatin conformation, which could in turn contribute to or against the cancer development, is yet to be determined.	('chromatin', 'cellular_component', 'GO:0000785', ('112', '121'))	('at', 'Gene', '9407', (79, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('82', '92'))	('contribute', 'Reg', (156, 166))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('at', 'Gene', '9407', (129, 131))	('loss', 'Var', (12, 16))	('affects', 'Reg', (100, 107))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('at', 'Gene', '9407', (117, 119))	('cancer', 'Disease', (185, 191))
106362	31957195	Previously, 1 study using breast cancer cell lines discussed the potential involvement of epigenetic repression for the downregulation of a few genes located in this hotspot region,34 hence indicating the possibility of peculiar genome organization around these genes.	('breast cancer', 'Disease', (26, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('at', 'Gene', '9407', (153, 155))	('at', 'Gene', '9407', (129, 131))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('at', 'Gene', '9407', (195, 197))	('at', 'Gene', '9407', (243, 245))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('epigenetic repression', 'Var', (90, 111))
106374	31957195	These results support the hypothesis that UM in particular (but also other types of cancer) is affected by important clinical and molecular consequences due to monosomy of chromosome 3.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('monosomy', 'Var', (160, 168))	('at', 'Gene', '9407', (39, 41))	('cancer', 'Disease', (84, 90))	('chromosome', 'cellular_component', 'GO:0005694', ('172', '182'))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('affected', 'Reg', (95, 103))
106381	32148939	So far, several risk factors, including light eyes, Caucasian population, and certain skin conditions such as cutaneous nevi, dysplastic nevus syndrome, iris nevi, and BAP1 mutation, have been identified.	('BAP1', 'Gene', '8314', (168, 172))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (126, 142))	('cutaneous nevi', 'Disease', (110, 124))	('dysplastic nevus syndrome', 'Disease', 'MESH:D004416', (126, 151))	('nevi', 'Phenotype', 'HP:0003764', (120, 124))	('BAP1', 'Gene', (168, 172))	('iris nevi', 'Disease', (153, 162))	('light eyes', 'Disease', (40, 50))	('iris nevi', 'Phenotype', 'HP:0011525', (153, 162))	('nevus', 'Phenotype', 'HP:0003764', (137, 142))	('dysplastic nevus syndrome', 'Disease', (126, 151))	('nevi', 'Phenotype', 'HP:0003764', (158, 162))	('mutation', 'Var', (173, 181))
106463	31527536	The mobile phase was composed of 0.15 mol/L NaCl, 0.025 mol/L NaH2PO4, 0.025 mol/L Na2HPO4 (pH 7.0) and a flow rate of 0.5 mL/min was applied.	('NaCl', 'Chemical', 'MESH:D012965', (44, 48))	('Na2HPO4', 'Chemical', 'MESH:D012964', (83, 90))	('0.025 mol/L', 'Var', (71, 82))	('0.025 mol/L', 'Var', (50, 61))	('NaH2PO4', 'Chemical', 'MESH:D012964', (62, 69))
106595	31053116	A possible mechanism for this paradoxical phenomenon is that alteration of VEGF, one of the most potent tumor angiogenic factors, by IVB may affect the dormancy, which is a distinctive feature of melanoma that differentiates it from other cancers.	('dormancy', 'biological_process', 'GO:0030431', ('152', '160'))	('VEGF', 'Gene', '7422', (75, 79))	('affect', 'Reg', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('alteration', 'Var', (61, 71))	('cancers', 'Disease', (239, 246))	('tumor', 'Disease', (104, 109))	('cancers', 'Disease', 'MESH:D009369', (239, 246))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('dormancy', 'CPA', (152, 160))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('VEGF', 'Gene', (75, 79))	('melanoma', 'Disease', (196, 204))	('man', 'Species', '9606', (155, 158))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
106601	31053116	In one notable study in the field of cancer biology, it has been experimentally demonstrated that the inhibition of angiogenesis pathway, such as VEGF, could alter the natural history of a tumor by increasing its invasion and metastasis.	('increasing', 'PosReg', (198, 208))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('tumor', 'Disease', (189, 194))	('VEGF', 'Gene', (146, 150))	('natural', 'MPA', (168, 175))	('cancer', 'Disease', (37, 43))	('inhibition', 'Var', (102, 112))	('alter', 'Reg', (158, 163))	('angiogenesis pathway', 'Pathway', (116, 136))	('VEGF', 'Gene', '7422', (146, 150))	('inhibition of angiogenesis', 'biological_process', 'GO:0016525', ('102', '128'))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
106616	30847022	Recurrent hotspot SF3B1 mutations at codon 625 in vulvovaginal mucosal melanoma identified in a study of 27 Australian mucosal melanomas Clinical outcomes for mucosal melanomas are often poor due to a lack of effective systemic drug therapies.	('mucosal melanomas', 'Disease', 'MESH:D008545', (159, 176))	('mucosal melanomas', 'Disease', (119, 136))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('SF3B1', 'Gene', (18, 23))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanomas', 'Phenotype', 'HP:0002861', (167, 176))	('mucosal melanomas', 'Disease', 'MESH:D008545', (119, 136))	('vulvovaginal mucosal melanoma', 'Phenotype', 'HP:0030418', (50, 79))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('mucosal melanomas', 'Disease', (159, 176))	('SF3B1', 'Gene', '23451', (18, 23))	('vulvovaginal mucosal melanoma', 'Disease', 'MESH:D014848', (50, 79))	('mutations at codon', 'Var', (24, 42))	('vulvovaginal mucosal melanoma', 'Disease', (50, 79))
106620	30847022	Recurrent SF3B1 p.R625 hotspot mutations were exclusively detected in vulvovaginal (5 of 19: 26%) and anorectal melanomas (3 of 5:60%).	('detected', 'Reg', (58, 66))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('SF3B1', 'Gene', (10, 15))	('anorectal melanomas', 'Disease', 'MESH:D008545', (102, 121))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('vulvovaginal', 'Disease', (70, 82))	('anorectal melanomas', 'Disease', (102, 121))	('p.R625', 'Var', (16, 22))	('SF3B1', 'Gene', '23451', (10, 15))
106621	30847022	The only other SF3B1 mutation was a p.C1123Y mutation that occurred in a conjunctival mucosal melanoma.	('p.C1123Y', 'Mutation', 'p.C1123Y', (36, 44))	('SF3B1', 'Gene', '23451', (15, 20))	('conjunctival mucosal melanoma', 'Phenotype', 'HP:0007716', (73, 102))	('conjunctival mucosal melanoma', 'Disease', (73, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('conjunctival mucosal melanoma', 'Disease', 'MESH:D003229', (73, 102))	('p.C1123Y', 'Var', (36, 44))	('SF3B1', 'Gene', (15, 20))
106623	30847022	Molecular subgroups of mucosal melanoma with SF3B1 mutations occurred predominantly in the vulvovaginal region.	('mucosal melanoma', 'Disease', 'MESH:D008545', (23, 39))	('mutations', 'Var', (51, 60))	('SF3B1', 'Gene', (45, 50))	('occurred', 'Reg', (61, 69))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('SF3B1', 'Gene', '23451', (45, 50))	('mucosal melanoma', 'Disease', (23, 39))
106624	30847022	SF3B1 mutations may have a negative prognostic impact.	('SF3B1', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('SF3B1', 'Gene', '23451', (0, 5))
106633	30847022	Molecular drivers such as BRAF p.V600 mutations that are amenable to therapeutic intervention (with a combination of BRAF and MEK inhibitors) are uncommon in mucosal melanomas (<10% of cases) as compared to cutaneous melanoma, where approximately 40% are BRAF mutant; of these 74% are the V600E genotype and 22% are V600K.	('melanomas', 'Phenotype', 'HP:0002861', (166, 175))	('BRAF', 'Gene', '673', (26, 30))	('mucosal melanomas', 'Disease', (158, 175))	('MEK', 'Gene', '5609', (126, 129))	('BRAF', 'Gene', (26, 30))	('cutaneous melanoma', 'Disease', (207, 225))	('V600K', 'Mutation', 'rs121913227', (316, 321))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (207, 225))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (207, 225))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('MEK', 'Gene', (126, 129))	('p.V600 mutations', 'Var', (31, 47))	('BRAF', 'Gene', '673', (117, 121))	('BRAF', 'Gene', (117, 121))	('V600K', 'Var', (316, 321))	('V600E', 'Mutation', 'rs113488022', (289, 294))	('BRAF', 'Gene', '673', (255, 259))	('V600E', 'Var', (289, 294))	('mucosal melanomas', 'Disease', 'MESH:D008545', (158, 175))	('BRAF', 'Gene', (255, 259))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))
106634	30847022	Mutations in NRAS only occur in 10-20% of mucosal melanomas, while mutations in GNAQ and GNA11 that are commonly detected in uveal melanoma, occur in approximately 9.5% of mucosal melanomas.	('uveal melanoma', 'Phenotype', 'HP:0007716', (125, 139))	('NRAS', 'Gene', '4893', (13, 17))	('mucosal melanomas', 'Disease', 'MESH:D008545', (172, 189))	('melanomas', 'Phenotype', 'HP:0002861', (180, 189))	('mucosal melanomas', 'Disease', (172, 189))	('GNA11', 'Gene', '2767', (89, 94))	('Mutations', 'Var', (0, 9))	('mucosal melanomas', 'Disease', 'MESH:D008545', (42, 59))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('mucosal melanomas', 'Disease', (42, 59))	('NRAS', 'Gene', (13, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (125, 139))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('uveal melanoma', 'Disease', (125, 139))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('mutations', 'Var', (67, 76))	('GNAQ', 'Gene', '2776', (80, 84))	('GNA11', 'Gene', (89, 94))	('GNAQ', 'Gene', (80, 84))
106635	30847022	Other activating oncogenic events, including the gain-of-function mutations of KIT, are present in approximately 15% of mucosal melanomas but are rare in cutaneous melanomas.	('mutations', 'Var', (66, 75))	('mucosal melanomas', 'Disease', (120, 137))	('melanomas', 'Phenotype', 'HP:0002861', (128, 137))	('cutaneous melanomas', 'Disease', (154, 173))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('mucosal melanomas', 'Disease', 'MESH:D008545', (120, 137))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanomas', 'Phenotype', 'HP:0002861', (164, 173))	('gain-of-function', 'PosReg', (49, 65))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (154, 173))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (154, 173))	('KIT', 'Gene', (79, 82))	('KIT', 'molecular_function', 'GO:0005020', ('79', '82'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (154, 172))
106638	30847022	SF3B1 mutations are the most common spliceosomal component gene mutation implicated in the pathogenesis of cancer and act by causing aberrant RNA splicing events.	('SF3B1', 'Gene', (0, 5))	('mutation', 'Var', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('causing', 'Reg', (125, 132))	('SF3B1', 'Gene', '23451', (0, 5))	('RNA splicing', 'biological_process', 'GO:0008380', ('142', '154'))	('RNA', 'cellular_component', 'GO:0005562', ('142', '145'))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('pathogenesis', 'biological_process', 'GO:0009405', ('91', '103'))	('RNA splicing events', 'MPA', (142, 161))	('cancer', 'Disease', (107, 113))	('mutations', 'Var', (6, 15))
106640	30847022	Several studies have identified mutations in SF3B1 in subsets of solid tumors, as well as in myelodysplastic syndrome and chronic lymphocytic leukemia (CLL), in which they occurred in almost 15% of the reported cases.	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (122, 150))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (93, 117))	('CLL', 'Phenotype', 'HP:0005550', (152, 155))	('chronic lymphocytic leukemia', 'Disease', (122, 150))	('myelodysplastic syndrome', 'Disease', (93, 117))	('leukemia', 'Phenotype', 'HP:0001909', (142, 150))	('solid tumors', 'Disease', (65, 77))	('mutations', 'Var', (32, 41))	('SF3B1', 'Gene', (45, 50))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (93, 117))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (122, 150))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('solid tumors', 'Disease', 'MESH:D009369', (65, 77))	('SF3B1', 'Gene', '23451', (45, 50))
106641	30847022	Common molecular drivers and mutations affecting spliceosomal components such as SF3B1 have been reported to be associated with disease outcome in some cancer types, but not in mucosal melanoma.	('associated with', 'Reg', (112, 127))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('SF3B1', 'Gene', (81, 86))	('mucosal melanoma', 'Disease', 'MESH:D008545', (177, 193))	('mutations', 'Var', (29, 38))	('SF3B1', 'Gene', '23451', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('mucosal melanoma', 'Disease', (177, 193))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))
106642	30847022	In this study, we sought to determine the prevalence of genetic alterations in SF3B1 and of common oncogenic driver genes in mucosal melanomas, and investigate their impact on clinicopathologic characteristics and patient outcomes.	('mucosal melanomas', 'Disease', 'MESH:D008545', (125, 142))	('patient', 'Species', '9606', (214, 221))	('genetic alterations', 'Var', (56, 75))	('SF3B1', 'Gene', (79, 84))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('mucosal melanomas', 'Disease', (125, 142))	('SF3B1', 'Gene', '23451', (79, 84))
106652	30847022	Both SF3B1 (50%) and KIT (67%) mutations were most frequently mutated in tumors of female genital origin and anorectal region (33.3% for SF3B1 and KIT) compared to a single SF3B1 mutant conjunctival melanoma in the upper body sites (Figure 1B).	('anorectal region', 'Phenotype', 'HP:0012732', (109, 125))	('SF3B1', 'Gene', '23451', (173, 178))	('SF3B1', 'Gene', '23451', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('KIT', 'molecular_function', 'GO:0005020', ('21', '24'))	('tumors', 'Disease', (73, 79))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (186, 207))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('melanoma', 'Disease', (199, 207))	('KIT', 'molecular_function', 'GO:0005020', ('147', '150'))	('SF3B1', 'Gene', (137, 142))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('mutations', 'Var', (31, 40))	('female genital origin', 'Phenotype', 'HP:0008730', (83, 104))	('SF3B1', 'Gene', '23451', (137, 142))	('SF3B1', 'Gene', (173, 178))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('SF3B1', 'Gene', (5, 10))	('anorectal region', 'Disease', (109, 125))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('KIT', 'Gene', (21, 24))	('mutated', 'Var', (62, 69))
106653	30847022	All five SF3B1 mutations (5 of 6: 83%) that occurred in the known hotspot p.R625H/L originated in the anorectal or female genital region, while the conjunctival primary harbored a SF3B1 p.C1123Y mutation (Figure 1B).	('SF3B1', 'Gene', '23451', (180, 185))	('p.R625H', 'SUBSTITUTION', 'None', (74, 81))	('SF3B1', 'Gene', '23451', (9, 14))	('p.C1123Y', 'Var', (186, 194))	('p.R625H', 'Var', (74, 81))	('SF3B1', 'Gene', (180, 185))	('p.C1123Y', 'Mutation', 'p.C1123Y', (186, 194))	('SF3B1', 'Gene', (9, 14))
106654	30847022	The KIT mutations were all missense, and of these, two were the hotspot mutation p.L576P in exon 11, and the other a p.T670I mutation in exon 14.	('KIT', 'molecular_function', 'GO:0005020', ('4', '7'))	('p.T670I', 'Var', (117, 124))	('p.L576P', 'Var', (81, 88))	('p.T670I', 'Mutation', 'rs121913516', (117, 124))	('p.L576P', 'Mutation', 'rs121913513', (81, 88))
106655	30847022	KIT mutations in exon 11 and 14 are known to occur in thymic cancer and cutaneous melanoma, and gastrointestinal stromal tumors, respectively.	('gastrointestinal stromal tumors', 'Disease', (96, 127))	('cutaneous melanoma', 'Disease', (72, 90))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (61, 67))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (96, 127))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (72, 90))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (72, 90))	('occur', 'Reg', (45, 50))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (96, 127))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))
106656	30847022	Recurrent hotspot SF3B1 mutations at codon 625 in anorectal and vulva/vaginal melanomas We previously reported splicing factor SF3B1 as a significantly mutated gene in mucosal melanoma using OncodriveFML (Hayward et al.	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('SF3B1', 'Gene', (127, 132))	('vaginal melanomas', 'Disease', (70, 87))	('anorectal', 'Disease', (50, 59))	('mucosal melanoma', 'Disease', (168, 184))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('SF3B1', 'Gene', (18, 23))	('mucosal melanoma', 'Disease', 'MESH:D008545', (168, 184))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('splicing', 'biological_process', 'GO:0045292', ('111', '119'))	('hotspot', 'PosReg', (10, 17))	('SF3B1', 'Gene', '23451', (18, 23))	('vaginal melanomas', 'Disease', 'MESH:D008545', (70, 87))	('mutations', 'Var', (24, 33))	('SF3B1', 'Gene', '23451', (127, 132))	('vaginal melanomas', 'Phenotype', 'HP:0030418', (70, 87))
106657	30847022	Similar to The Cancer Genome Atlas cohort and our previous published work, the recurrent SF3B1 mutations occured at codon 625, comprising four p.R625H and one p.R625L alterations (Figure 2A).	('SF3B1', 'Gene', (89, 94))	('p.R625L', 'Mutation', 'p.R625L', (159, 166))	('Cancer', 'Phenotype', 'HP:0002664', (15, 21))	('Cancer Genome Atlas cohort', 'Disease', (15, 41))	('Cancer Genome Atlas cohort', 'Disease', 'MESH:D009369', (15, 41))	('SF3B1', 'Gene', '23451', (89, 94))	('p.R625H', 'Mutation', 'rs1057519961', (143, 150))	('mutations', 'Var', (95, 104))	('p.R625H', 'Var', (143, 150))	('p.R625L', 'Var', (159, 166))
106658	30847022	These recurrent SF3B1 mutations were only identified in anorectal and vulva/vagina mucosal melanomas and not in melanoma samples from the conjunctiva, nasopharynx or palate (representative histological images in Figure 2B and 2C).	('anorectal', 'Disease', (56, 65))	('palate', 'Disease', (166, 172))	('SF3B1', 'Gene', '23451', (16, 21))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('vulva/vagina mucosal melanomas', 'Disease', (70, 100))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('vulva/vagina mucosal melanomas', 'Disease', 'MESH:D008545', (70, 100))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('mutations', 'Var', (22, 31))	('palate', 'Disease', 'MESH:D002972', (166, 172))	('SF3B1', 'Gene', (16, 21))
106660	30847022	The clinicopathological characteristics of tumors with SF3B1 and non-SF3B1 mutations are detailed and compared in Table 2.	('SF3B1', 'Gene', '23451', (55, 60))	('SF3B1', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutations', 'Var', (75, 84))	('SF3B1', 'Gene', (55, 60))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('SF3B1', 'Gene', '23451', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
106661	30847022	Representative histological images of SF3B1 mutant tumors are presented in Figures 2B and 2C.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('SF3B1', 'Gene', (38, 43))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('SF3B1', 'Gene', '23451', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('mutant', 'Var', (44, 50))
106662	30847022	Of all the patients with SF3B1 mutations, two (33.3%) had T2 disease, one (16.7%) had T3 disease, and the remaining three (50%) had T4 disease.	('mutations', 'Var', (31, 40))	('T2 disease', 'Disease', (58, 68))	('SF3B1', 'Gene', (25, 30))	('patients', 'Species', '9606', (11, 19))	('SF3B1', 'Gene', '23451', (25, 30))
106663	30847022	The depth of invasion of SF3B1 mutant tumors ranged from 1.9 to 12 mm.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('mutant', 'Var', (31, 37))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('SF3B1', 'Gene', (25, 30))	('SF3B1', 'Gene', '23451', (25, 30))
106664	30847022	Melanomas with SF3B1 mutations had a similar mitotic rate when compared to non-SF3B1 mutated cases (15.6+-4.4 vs 15.5+-2.54 mitoses/mm2) but were more often ulcerated (SF3B1: 6 out of 6 cases vs non-SF3B1: 10 of 16 cases with ulceration data), and were comprised of heterogeneous cell types.	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('SF3B1', 'Gene', '23451', (15, 20))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('SF3B1', 'Gene', (199, 204))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('Melanomas', 'Disease', (0, 9))	('SF3B1', 'Gene', (79, 84))	('SF3B1', 'Gene', (168, 173))	('ulcerated', 'CPA', (157, 166))	('SF3B1', 'Gene', '23451', (199, 204))	('SF3B1', 'Gene', '23451', (168, 173))	('SF3B1', 'Gene', (15, 20))	('SF3B1', 'Gene', '23451', (79, 84))	('mutations', 'Var', (21, 30))
106665	30847022	We tested whether SF3B1 mutated and non-SF3B1 cases had different prognosis.	('SF3B1', 'Gene', (40, 45))	('mutated', 'Var', (24, 31))	('SF3B1', 'Gene', '23451', (40, 45))	('SF3B1', 'Gene', (18, 23))	('tested', 'Reg', (3, 9))	('SF3B1', 'Gene', '23451', (18, 23))
106666	30847022	Median overall survival (OS) was 34.9 months in patients harboring SF3B1 mutations compared to 79.7 months in patients with non-SF3B1 mutations (HR: 2.44, 95% CI: 0.54 to 11, Log-rank test P = 0.117; Figure 3A).	('SF3B1', 'Gene', '23451', (128, 133))	('OS', 'Chemical', '-', (25, 27))	('patients', 'Species', '9606', (110, 118))	('SF3B1', 'Gene', '23451', (67, 72))	('SF3B1', 'Gene', (128, 133))	('patients', 'Species', '9606', (48, 56))	('mutations', 'Var', (73, 82))	('SF3B1', 'Gene', (67, 72))
106667	30847022	Median progression-free survival (PFS) was 16.9 months in the SF3B1 mutant group and 35.7 months in non-SF3B1 patients (HR: 0.474, 95% CI: 0.139 to 1.62, Log-rank test P = 0.0963; Figure 3B).	('SF3B1', 'Gene', '23451', (62, 67))	('SF3B1', 'Gene', (62, 67))	('SF3B1', 'Gene', (104, 109))	('patients', 'Species', '9606', (110, 118))	('SF3B1', 'Gene', '23451', (104, 109))	('mutant', 'Var', (68, 74))
106668	30847022	In this study, 27 cases of mucosal melanoma were screened for mutations across 45 key oncogenes identified in our previous whole-genome sequencing study of major melanoma subtypes.	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('mucosal melanoma', 'Disease', (27, 43))	('melanoma subtypes', 'Disease', (162, 179))	('mucosal melanoma', 'Disease', 'MESH:D008545', (27, 43))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma subtypes', 'Disease', 'MESH:D008545', (162, 179))	('mutations', 'Var', (62, 71))
106669	30847022	We found that SF3B1 and KIT mutations predominantly occurred in melanomas originating in vulval/vaginal sites.	('occurred', 'Reg', (52, 60))	('melanomas', 'Disease', (64, 73))	('KIT', 'molecular_function', 'GO:0005020', ('24', '27'))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('SF3B1', 'Gene', (14, 19))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('SF3B1', 'Gene', '23451', (14, 19))	('melanomas', 'Disease', 'MESH:D008545', (64, 73))	('mutations', 'Var', (28, 37))	('KIT', 'Gene', (24, 27))
106671	30847022	Mutations within exons 12-15 of SF3B1, encoding the C-terminal portion of the protein, have been described in 20% of uveal melanoma, 19% of CLL and 1.8% of breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('CLL', 'Phenotype', 'HP:0005550', (140, 143))	('uveal melanoma', 'Disease', (117, 131))	('described', 'Reg', (97, 106))	('SF3B1', 'Gene', '23451', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('breast cancers', 'Phenotype', 'HP:0003002', (156, 170))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('SF3B1', 'Gene', (32, 37))	('uveal melanoma', 'Phenotype', 'HP:0007716', (117, 131))	('uveal melanoma', 'Disease', 'MESH:C536494', (117, 131))	('breast cancers', 'Disease', 'MESH:D001943', (156, 170))	('CLL', 'Disease', (140, 143))	('breast cancers', 'Disease', (156, 170))
106673	30847022	Five patients harbored a mutation at exon 14, including p.R625H (n = 4) and p.R625L (n = 1), while one patient carried a p.C1123Y mutation within exon 23 in SF3B1.	('SF3B1', 'Gene', (157, 162))	('patient', 'Species', '9606', (5, 12))	('p.R625H', 'Var', (56, 63))	('p.R625L', 'Var', (76, 83))	('patients', 'Species', '9606', (5, 13))	('SF3B1', 'Gene', '23451', (157, 162))	('p.R625L', 'Mutation', 'p.R625L', (76, 83))	('p.C1123Y', 'Mutation', 'p.C1123Y', (121, 129))	('p.C1123Y', 'Var', (121, 129))	('patient', 'Species', '9606', (103, 110))	('p.R625H', 'Mutation', 'rs1057519961', (56, 63))
106674	30847022	Of particular interest is the confirmation that the SF3B1 hotspot mutant cases are apparently unique to mucosal melanomas of the lower body sites, hinting to divergent biology with those of upper body sites.	('hotspot', 'PosReg', (58, 65))	('mutant', 'Var', (66, 72))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('SF3B1', 'Gene', (52, 57))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('mucosal melanomas', 'Disease', (104, 121))	('SF3B1', 'Gene', '23451', (52, 57))	('mucosal melanomas', 'Disease', 'MESH:D008545', (104, 121))
106675	30847022	Furthermore, somatic mutations in KIT have been reported in 15-20% of mucosal melanomas, and are more commonly observed in anorectal and vulval/vaginal tumors (15-25%).	('observed', 'Reg', (111, 119))	('vaginal tumors', 'Phenotype', 'HP:0100650', (144, 158))	('KIT', 'molecular_function', 'GO:0005020', ('34', '37'))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('vaginal tumors', 'Disease', (144, 158))	('mucosal melanomas', 'Disease', 'MESH:D008545', (70, 87))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('reported', 'Reg', (48, 56))	('somatic mutations', 'Var', (13, 30))	('vaginal tumors', 'Disease', 'MESH:D014625', (144, 158))	('mucosal melanomas', 'Disease', (70, 87))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('anorectal', 'Disease', (123, 132))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('KIT', 'Gene', (34, 37))
106676	30847022	Our study supports these previous reports, and detected KIT mutations in 11% of mucosal melanomas, particularly in the vulval and vaginal sites.	('mucosal melanomas', 'Disease', 'MESH:D008545', (80, 97))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('KIT', 'Gene', (56, 59))	('KIT', 'molecular_function', 'GO:0005020', ('56', '59'))	('mucosal melanomas', 'Disease', (80, 97))	('detected', 'Reg', (47, 55))	('mutations', 'Var', (60, 69))
106678	30847022	The aberrant MAPK/MEK and PI3K/AKT pathways impact a variety of cellular activities including cell proliferation and differentiation, which can result in neoplastic growth.	('differentiation', 'CPA', (117, 132))	('PI3', 'Gene', '5266', (26, 29))	('AKT', 'Gene', (31, 34))	('MAPK', 'molecular_function', 'GO:0004707', ('13', '17'))	('PI3', 'Gene', (26, 29))	('cellular activities', 'CPA', (64, 83))	('impact', 'Reg', (44, 50))	('neoplastic growth', 'CPA', (154, 171))	('aberrant', 'Var', (4, 12))	('MEK', 'Gene', (18, 21))	('PI3K', 'molecular_function', 'GO:0016303', ('26', '30'))	('cell proliferation', 'biological_process', 'GO:0008283', ('94', '112'))	('result in', 'Reg', (144, 153))	('MEK', 'Gene', '5609', (18, 21))	('cell proliferation', 'CPA', (94, 112))	('AKT', 'Gene', '207', (31, 34))
106679	30847022	Furthermore, besides SF3B1 and KIT mutations, other variants have been described in the context of mucosal melanoma, including amplifications of CCND1, MDM2 and KRAS , however this was not assessed this cohort and could represent a source of additional driver eventsin this cohort.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('CCND1', 'Gene', (145, 150))	('mucosal melanoma', 'Disease', 'MESH:D008545', (99, 115))	('SF3B1', 'Gene', '23451', (21, 26))	('amplifications', 'Var', (127, 141))	('CCND1', 'Gene', '595', (145, 150))	('SF3B1', 'Gene', (21, 26))	('variants', 'Var', (52, 60))	('KIT', 'molecular_function', 'GO:0005020', ('31', '34'))	('mucosal melanoma', 'Disease', (99, 115))	('KRAS', 'Gene', (161, 165))	('MDM2', 'Gene', '4193', (152, 156))	('KRAS', 'Gene', '3845', (161, 165))	('MDM2', 'Gene', (152, 156))
106680	30847022	Our findings are in line with the growing evidence that the recurrent hotspot mutation at codon 625 of SF3B1 has functional impact in initiating aberrant 3' splice site selection causing down-regulation of canonical protein expression to promote tumorigenesis.	('splice site selection', 'biological_process', 'GO:0000380', ('157', '178'))	('splice site selection', 'biological_process', 'GO:0000381', ('157', '178'))	('mutation', 'Var', (78, 86))	('down-regulation', 'NegReg', (187, 202))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('SF3B1', 'Gene', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	("3' splice site selection", 'MPA', (154, 178))	('canonical protein expression', 'MPA', (206, 234))	('regulation', 'biological_process', 'GO:0065007', ('192', '202'))	('protein', 'cellular_component', 'GO:0003675', ('216', '223'))	('tumor', 'Disease', (246, 251))	('promote', 'PosReg', (238, 245))	('SF3B1', 'Gene', '23451', (103, 108))
106682	30847022	In melanoma, there has been significant interest in establishing whether the splicing inhibition contributes to cancer development and progression by specific pathologic splicing events.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('contributes', 'Reg', (97, 108))	('splicing', 'biological_process', 'GO:0045292', ('170', '178'))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('splicing inhibition', 'Var', (77, 96))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('splicing', 'biological_process', 'GO:0045292', ('77', '85'))
106684	30847022	As an example, E7107 was tested in the phase I, open-label and single-arm clinical trial (Study E7107-A001-101; Trial registration ID: NCT00499499) for solid tumors, including colorectal, esophageal and pancreatic carcinomas.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('E7107', 'Var', (15, 20))	('esophageal', 'Disease', (188, 198))	('solid tumors', 'Disease', 'MESH:D009369', (152, 164))	('pancreatic carcinomas', 'Disease', 'MESH:C562463', (203, 224))	('carcinomas', 'Phenotype', 'HP:0030731', (214, 224))	('pancreatic carcinomas', 'Disease', (203, 224))	('solid tumors', 'Disease', (152, 164))	('esophageal', 'Disease', 'MESH:D004941', (188, 198))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('colorectal', 'Disease', (176, 186))
106687	30847022	Elucidating the impact of SF3B1 mutation in mucosal melanomas may provide more understanding of its role in tumorigenesis, and facilitate the development of new drugs (i.e.	('SF3B1', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('mucosal melanomas', 'Disease', (44, 61))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('SF3B1', 'Gene', '23451', (26, 31))	('mucosal melanomas', 'Disease', 'MESH:D008545', (44, 61))	('tumor', 'Disease', (108, 113))	('mutation', 'Var', (32, 40))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))
106688	30847022	SF3B1 inhibitors) for mucosal melanomas with SF3B1 mutations.	('mucosal melanomas', 'Disease', (22, 39))	('mutations', 'Var', (51, 60))	('SF3B1', 'Gene', (0, 5))	('mucosal melanomas', 'Disease', 'MESH:D008545', (22, 39))	('SF3B1', 'Gene', '23451', (0, 5))	('melanomas', 'Phenotype', 'HP:0002861', (30, 39))	('SF3B1', 'Gene', (45, 50))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('SF3B1', 'Gene', '23451', (45, 50))
106689	30847022	SF3B1 mutations have different prognostic associations in different types of cancers.	('SF3B1', 'Gene', (0, 5))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('SF3B1', 'Gene', '23451', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutations', 'Var', (6, 15))
106690	30847022	In uveal melanoma and myelodysplastic syndrome, SF3B1 mutations are associated with a better prognosis, whereas in CLL, SF3B1 mutations are correlated with a worse prognosis.	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('SF3B1', 'Gene', (120, 125))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (22, 46))	('mutations', 'Var', (54, 63))	('SF3B1', 'Gene', (48, 53))	('CLL', 'Phenotype', 'HP:0005550', (115, 118))	('SF3B1', 'Gene', '23451', (120, 125))	('myelodysplastic syndrome', 'Disease', (22, 46))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (22, 46))	('SF3B1', 'Gene', '23451', (48, 53))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
106692	30847022	In summary, we discovered a SF3B1 C1123Y mutation in a conjunctival mucosal melanoma, and a recurrent SF3B1 R625 mutation, which predominantly occurred in female genital tract mucosal melanomas.	('C1123Y', 'Mutation', 'p.C1123Y', (34, 40))	('SF3B1', 'Gene', (102, 107))	('conjunctival mucosal melanoma', 'Phenotype', 'HP:0007716', (55, 84))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('conjunctival mucosal melanoma', 'Disease', (55, 84))	('genital tract mucosal melanomas', 'Disease', (162, 193))	('conjunctival mucosal melanoma', 'Disease', 'MESH:D003229', (55, 84))	('melanomas', 'Phenotype', 'HP:0002861', (184, 193))	('SF3B1', 'Gene', (28, 33))	('SF3B1', 'Gene', '23451', (102, 107))	('SF3B1', 'Gene', '23451', (28, 33))	('C1123Y', 'Var', (34, 40))	('genital tract mucosal melanomas', 'Disease', 'MESH:D060737', (162, 193))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
106712	30847022	Variants were further parsed to OncodriveMut in Cancer Genome Interpreter to identify biological and clinical relevance somatic genes.	('Cancer', 'Disease', 'MESH:D009369', (48, 54))	('Cancer', 'Disease', (48, 54))	('Variants', 'Var', (0, 8))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))
106817	30249817	Genetic predictors: Chromosome 3 deletion (partial or total), BAP1 loss, chromosome 8q gain, chromosome 1p loss, and chromosome 9q loss are associated with poor prognosis.	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('BAP1', 'Gene', '8314', (62, 66))	('gain', 'PosReg', (87, 91))	('chromosome', 'cellular_component', 'GO:0005694', ('117', '127'))	('loss', 'NegReg', (107, 111))	('Chromosome', 'cellular_component', 'GO:0005694', ('20', '30'))	('chromosome 8q', 'Gene', (73, 86))	('chromosome 1p', 'Gene', (93, 106))	('loss', 'NegReg', (131, 135))	('BAP1', 'Gene', (62, 66))	('deletion', 'Var', (33, 41))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('loss', 'NegReg', (67, 71))	('Chromosome 3', 'Gene', (20, 32))	('chromosome 9q', 'Gene', (117, 130))
106822	30249817	The correlation between tumor size and increased mortality is attributed to the higher prevalence of monosomy-3 in large tumors rather than to any therapeutic effect.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (24, 29))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('monosomy-3', 'Var', (101, 111))	('tumor', 'Disease', (121, 126))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
106879	27486750	The strongest risk factor of BPULs was neonatal blue light phototherapy, which resulted in a relative risk of 4.88 for the development of BPULs (Table 5 and S1 Table).	('neonatal blue light phototherapy', 'Var', (39, 71))	('BPULs', 'Chemical', '-', (138, 143))	('BPULs', 'Chemical', '-', (29, 34))	('BPULs', 'Disease', (29, 34))
106915	26316887	Positivity for SOX-10 was also noted in the inner and outer nuclear layers of the retina in 78% of the enucleated eyes.	('SOX-10', 'Gene', (15, 21))	('Positivity', 'Var', (0, 10))	('SOX-10', 'Gene', '6663', (15, 21))
106937	26316887	Positivity for SOX-10 was also noted in the inner and outer nuclear layers of the retina in 78% of the enucleated eyes (Figure 3A).	('SOX-10', 'Gene', (15, 21))	('Positivity', 'Var', (0, 10))	('SOX-10', 'Gene', '6663', (15, 21))
106980	26059332	Study design and rationale for a randomised, placebo-controlled, double-blind study to assess the efficacy of selumetinib (AZD6244; ARRY-142886) in combination with dacarbazine in patients with metastatic uveal melanoma (SUMIT) Uveal melanoma is characterised by mutations in GNAQ and GNA11, resulting in Ras/Raf/MEK/ERK pathway activation.	('GNAQ', 'Gene', (276, 280))	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('mutations', 'Var', (263, 272))	('uveal melanoma', 'Phenotype', 'HP:0007716', (205, 219))	('activation', 'PosReg', (329, 339))	('GNA11', 'Gene', (285, 290))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))	('patients', 'Species', '9606', (180, 188))	('MEK', 'Gene', '5609', (313, 316))	('Raf', 'Gene', (309, 312))	('ERK', 'Gene', '5594', (317, 320))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Disease', (211, 219))	('MEK', 'Gene', (313, 316))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('melanoma', 'Disease', (234, 242))	('GNA11', 'Gene', '2767', (285, 290))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (228, 242))	('ERK', 'Gene', (317, 320))	('selumetinib', 'Chemical', 'MESH:C517975', (110, 121))	('Raf', 'Gene', '22882', (309, 312))	('uveal melanoma', 'Disease', (205, 219))	('uveal melanoma', 'Disease', 'MESH:C536494', (205, 219))	('GNAQ', 'Gene', '2776', (276, 280))	('dacarbazine', 'Chemical', 'MESH:D003606', (165, 176))	('ERK', 'molecular_function', 'GO:0004707', ('317', '320'))	('AZD6244', 'Chemical', 'MESH:C517975', (123, 130))
106987	26059332	Exploratory endpoints include efficacy in tumours with GNAQ or GNA11 mutations.	('mutations', 'Var', (69, 78))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('GNAQ', 'Gene', '2776', (55, 59))	('GNA11', 'Gene', (63, 68))	('tumours', 'Phenotype', 'HP:0002664', (42, 49))	('GNA11', 'Gene', '2767', (63, 68))	('GNAQ', 'Gene', (55, 59))	('tumours', 'Disease', 'MESH:D009369', (42, 49))	('tumours', 'Disease', (42, 49))
107003	26059332	Vemurafenib and dabrafenib are small molecule inhibitors of BRAF approved for use in patients with advanced melanoma harbouring a V600 BRAF mutation (NCCN Practice Guidelines in Oncology melanoma version 4.2014 [www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf]).	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('V600', 'Var', (130, 134))	('melanoma', 'Disease', 'MESH:D008545', (257, 265))	('BRAF', 'Gene', '673', (135, 139))	('dabrafenib', 'Chemical', 'MESH:C561627', (16, 26))	('BRAF', 'Gene', (135, 139))	('patients', 'Species', '9606', (85, 93))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('Oncology melanoma', 'Disease', (178, 195))	('melanoma', 'Disease', (187, 195))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('Oncology', 'Phenotype', 'HP:0002664', (178, 186))	('melanoma', 'Phenotype', 'HP:0002861', (257, 265))	('melanoma', 'Disease', (257, 265))	('V600 BRAF', 'Mutation', 'rs113488022', (130, 139))	('Oncology melanoma', 'Disease', 'MESH:D008545', (178, 195))
107004	26059332	Antitumour efficacy is only observed in cells harbouring a BRAF mutation, with paradoxical activation of the Ras/Raf/MEK/ERK pathway observed in cells with wild-type BRAF.	('ERK', 'Gene', '5594', (121, 124))	('ERK', 'Gene', (121, 124))	('BRAF', 'Gene', (166, 170))	('mutation', 'Var', (64, 72))	('Raf', 'Gene', (113, 116))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('activation', 'PosReg', (91, 101))	('MEK', 'Gene', (117, 120))	('MEK', 'Gene', '5609', (117, 120))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('ERK', 'molecular_function', 'GO:0004707', ('121', '124'))	('tumour', 'Disease', (4, 10))	('Raf', 'Gene', '22882', (113, 116))	('BRAF', 'Gene', '673', (166, 170))
107005	26059332	Given that BRAF mutations are absent or rare in uveal melanoma, there is no utility for these agents in this disease.	('uveal melanoma', 'Disease', (48, 62))	('mutations', 'Var', (16, 25))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('BRAF', 'Gene', (11, 15))	('BRAF', 'Gene', '673', (11, 15))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (48, 62))
107006	26059332	Importantly, 80-96 % of uveal melanomas harbour mutations in either the guanidine nucleotide binding protein (G protein), Q polypeptide 1 (GNAQ) or the G protein alpha 11 (GNA11) gene, in a mutually exclusive pattern.	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('82', '100'))	('mutations', 'Var', (48, 57))	('G protein alpha 11', 'Gene', '2767', (152, 170))	('uveal melanoma', 'Phenotype', 'HP:0007716', (24, 38))	('melanomas', 'Phenotype', 'HP:0002861', (30, 39))	('GNAQ', 'Gene', '2776', (139, 143))	('uveal melanomas', 'Disease', (24, 39))	('uveal melanomas', 'Phenotype', 'HP:0007716', (24, 39))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('GNA11', 'Gene', (172, 177))	('GNA11', 'Gene', '2767', (172, 177))	('uveal melanomas', 'Disease', 'MESH:C536494', (24, 39))	('G protein alpha 11', 'Gene', (152, 170))	('GNAQ', 'Gene', (139, 143))
107007	26059332	Oncogenic mutations in GNAQ and GNA11 result in constitutive activation of these proteins and downstream signalling of pathways such as the YAP pathway, the phosphoinositide-3 kinase/AKT and the Ras/Raf/MEK/ERK pathway, thus playing a key role in the development and progression of uveal melanomas.	('GNAQ', 'Gene', (23, 27))	('GNA11', 'Gene', (32, 37))	('uveal melanoma', 'Phenotype', 'HP:0007716', (282, 296))	('AKT', 'Gene', '207', (183, 186))	('ERK', 'Gene', '5594', (207, 210))	('uveal melanomas', 'Disease', 'MESH:C536494', (282, 297))	('signalling', 'biological_process', 'GO:0023052', ('105', '115'))	('MEK', 'Gene', '5609', (203, 206))	('Raf', 'Gene', (199, 202))	('YAP', 'Gene', (140, 143))	('MEK', 'Gene', (203, 206))	('ERK', 'Gene', (207, 210))	('GNA11', 'Gene', '2767', (32, 37))	('uveal melanomas', 'Disease', (282, 297))	('uveal melanomas', 'Phenotype', 'HP:0007716', (282, 297))	('proteins', 'Protein', (81, 89))	('ERK', 'molecular_function', 'GO:0004707', ('207', '210'))	('Raf', 'Gene', '22882', (199, 202))	('AKT', 'Gene', (183, 186))	('activation', 'PosReg', (61, 71))	('melanoma', 'Phenotype', 'HP:0002861', (288, 296))	('melanomas', 'Phenotype', 'HP:0002861', (288, 297))	('YAP', 'Gene', '10413', (140, 143))	('mutations', 'Var', (10, 19))	('GNAQ', 'Gene', '2776', (23, 27))
107008	26059332	This biology suggests that inhibition of one or more of these signalling pathways may result in antitumour activity.	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('signalling', 'biological_process', 'GO:0023052', ('62', '72'))	('inhibition', 'Var', (27, 37))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('tumour', 'Disease', (100, 106))
107010	26059332	In pre-clinical tumour models, selumetinib demonstrates single agent anti-cancer activity, including in models of uveal melanoma harbouring GNAQ or GNA11 mutations.	('GNAQ', 'Gene', '2776', (140, 144))	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('tumour', 'Disease', (16, 22))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('GNAQ', 'Gene', (140, 144))	('uveal melanoma', 'Disease', (114, 128))	('cancer', 'Disease', (74, 80))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('mutations', 'Var', (154, 163))	('pre', 'molecular_function', 'GO:0003904', ('3', '6'))	('GNA11', 'Gene', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('selumetinib', 'Chemical', 'MESH:C517975', (31, 42))	('GNA11', 'Gene', '2767', (148, 153))
107016	26059332	Selumetinib in combination with temozolomide, which has the same active metabolite as dacarbazine, enhanced tumour growth inhibition, DNA damage and apoptosis in a RAS-mutant tumour model versus temozolomide monotherapy.	('tumour', 'Disease', (108, 114))	('apoptosis', 'CPA', (149, 158))	('DNA damage', 'CPA', (134, 144))	('temozolomide', 'Chemical', 'MESH:D000077204', (195, 207))	('tumour', 'Disease', 'MESH:D009369', (175, 181))	('enhanced', 'PosReg', (99, 107))	('tumour', 'Disease', (175, 181))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('apoptosis', 'biological_process', 'GO:0097194', ('149', '158'))	('apoptosis', 'biological_process', 'GO:0006915', ('149', '158'))	('temozolomide', 'Chemical', 'MESH:D000077204', (32, 44))	('dacarbazine', 'Chemical', 'MESH:D003606', (86, 97))	('Selumetinib', 'Chemical', 'MESH:C517975', (0, 11))	('tumour', 'Disease', 'MESH:D009369', (108, 114))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('RAS-mutant', 'Var', (164, 174))
107017	26059332	A series of clinical trials assessing the efficacy of selumetinib in combination with chemotherapy have shown promise in patients with mutations associated with the KRAS and BRAF pathways, including in combination with dacarbazine in patients with BRAF mutation-positive cutaneous or unknown melanoma.	('KRAS', 'Gene', '3845', (165, 169))	('melanoma', 'Disease', 'MESH:D008545', (292, 300))	('melanoma', 'Phenotype', 'HP:0002861', (292, 300))	('mutations', 'Var', (135, 144))	('BRAF', 'Gene', '673', (174, 178))	('dacarbazine', 'Chemical', 'MESH:D003606', (219, 230))	('patients', 'Species', '9606', (234, 242))	('BRAF', 'Gene', (174, 178))	('selumetinib', 'Chemical', 'MESH:C517975', (54, 65))	('BRAF', 'Gene', '673', (248, 252))	('patients', 'Species', '9606', (121, 129))	('KRAS', 'Gene', (165, 169))	('melanoma', 'Disease', (292, 300))	('BRAF', 'Gene', (248, 252))
107023	26059332	Exploratory objectives include assessment of mutations in GNAQ/GNA11, health-related quality of life (HRQoL) and biomarkers for response or development of cancer.	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('GNAQ', 'Gene', '2776', (58, 62))	('GNA11', 'Gene', (63, 68))	('GNA11', 'Gene', '2767', (63, 68))	('GNAQ', 'Gene', (58, 62))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
107034	26059332	Archival tumour samples will be collected for all randomised patients for the assessment of GNAQ/GNA11 mutation status.	('GNAQ', 'Gene', '2776', (92, 96))	('tumour', 'Disease', (9, 15))	('GNAQ', 'Gene', (92, 96))	('patients', 'Species', '9606', (61, 69))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('tumour', 'Disease', 'MESH:D009369', (9, 15))	('mutation', 'Var', (103, 111))	('GNA11', 'Gene', '2767', (97, 102))	('GNA11', 'Gene', (97, 102))
107054	26059332	A comparable PFS improvement to that in the overall population was observed in patients with tumours harbouring a mutation in GNAQ or GNA11.	('GNAQ', 'Gene', '2776', (126, 130))	('tumours', 'Disease', (93, 100))	('PFS', 'MPA', (13, 16))	('GNA11', 'Gene', (134, 139))	('GNAQ', 'Gene', (126, 130))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('GNA11', 'Gene', '2767', (134, 139))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('patients', 'Species', '9606', (79, 87))	('mutation', 'Var', (114, 122))	('tumours', 'Disease', 'MESH:D009369', (93, 100))	('improvement', 'PosReg', (17, 28))
107059	26059332	As noted, tumours dependent on the Ras/Raf/MEK/ERK pathway include uveal melanomas harbouring oncogenic GNAQ/GNA11 mutations.	('uveal melanomas', 'Disease', 'MESH:C536494', (67, 82))	('tumours', 'Disease', (10, 17))	('GNA11', 'Gene', (109, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('tumours', 'Phenotype', 'HP:0002664', (10, 17))	('tumours', 'Disease', 'MESH:D009369', (10, 17))	('uveal melanomas', 'Disease', (67, 82))	('uveal melanomas', 'Phenotype', 'HP:0007716', (67, 82))	('MEK', 'Gene', '5609', (43, 46))	('GNAQ', 'Gene', '2776', (104, 108))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('Raf', 'Gene', (39, 42))	('ERK', 'Gene', '5594', (47, 50))	('GNAQ', 'Gene', (104, 108))	('ERK', 'molecular_function', 'GO:0004707', ('47', '50'))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('MEK', 'Gene', (43, 46))	('mutations', 'Var', (115, 124))	('GNA11', 'Gene', '2767', (109, 114))	('Raf', 'Gene', '22882', (39, 42))	('ERK', 'Gene', (47, 50))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
107133	24403233	Immunohistochemical stains of c-kit were performed in one study, mutational analysis of c-kit in another study and GNAQ sequencing in a limited number of patients in two studies.	('GNAQ', 'Gene', (115, 119))	('c-kit', 'Gene', '3815', (30, 35))	('GNAQ', 'Gene', '2776', (115, 119))	('patients', 'Species', '9606', (154, 162))	('mutational analysis', 'Var', (65, 84))	('c-kit', 'Gene', (88, 93))	('c-kit', 'Gene', '3815', (88, 93))	('c-kit', 'Gene', (30, 35))
107173	24403233	Activating somatic mutations in GNAQ/GNA11, two members of the guanine nucleotide-binding protein family (G-proteins), were found in 83% of UMs.	('Activating', 'PosReg', (0, 10))	('GNAQ', 'Gene', (32, 36))	('UMs', 'Disease', (140, 143))	('GNA11', 'Gene', (37, 42))	('GNA11', 'Gene', '2767', (37, 42))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('mutations', 'Var', (19, 28))	('GNAQ', 'Gene', '2776', (32, 36))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('71', '89'))
107188	24403233	Mutations in BAP1, a deubiquitinating enzyme located on chromosome 3p, are seen in 85% of high-risk ("class-2") UMs and correlate with development of metastatic disease.	('correlate with', 'Reg', (120, 134))	('BAP1', 'Gene', (13, 17))	('metastatic disease', 'CPA', (150, 168))	('chromosome', 'cellular_component', 'GO:0005694', ('56', '66'))	('Mutations', 'Var', (0, 9))	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('21', '44'))	('BAP1', 'Gene', '8314', (13, 17))
107189	24403233	One substrate of BAP1 is histone H2A; histone-deacetylase inhibitors were shown to reverse the H2A hyperubiquitination caused by BAP1 knock-down in vitro and might therefore be a therapeutic strategy.	('knock-down', 'Var', (134, 144))	('H2A', 'Protein', (95, 98))	('hyperubiquitination', 'Disease', 'None', (99, 118))	('BAP1', 'Gene', '8314', (129, 133))	('hyperubiquitination', 'Disease', (99, 118))	('BAP1', 'Gene', '8314', (17, 21))	('BAP1', 'Gene', (129, 133))	('BAP1', 'Gene', (17, 21))
107215	24403233	GNAQ/GNA11 mutations in over 80% of MUM leading to aberrant activation of the MAPK pathway especially makes MEK an attractive therapeutic target.	('mutations', 'Var', (11, 20))	('GNA11', 'Gene', (5, 10))	('GNAQ', 'Gene', '2776', (0, 4))	('GNA11', 'Gene', '2767', (5, 10))	('MEK', 'Gene', (108, 111))	('MAPK', 'molecular_function', 'GO:0004707', ('78', '82'))	('MEK', 'Gene', '5609', (108, 111))	('activation', 'PosReg', (60, 70))	('MAPK pathway', 'Pathway', (78, 90))	('GNAQ', 'Gene', (0, 4))
107219	24403233	According to preliminary data, there is no proven correlation of ORR or PFS with GNAQ/GNA11 mutational status.	('mutational', 'Var', (92, 102))	('GNAQ', 'Gene', (81, 85))	('GNA11', 'Gene', (86, 91))	('GNA11', 'Gene', '2767', (86, 91))	('GNAQ', 'Gene', '2776', (81, 85))
38876	21105715	As a GPCR, CXCR4 binds CXCL12 and activates G-protein mediated signaling through the Galphai pathway that reduces cAMP levels within cells.	('reduces', 'NegReg', (106, 113))	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('cAMP', 'Chemical', 'MESH:D000242', (114, 118))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('CXCR4', 'Var', (11, 16))	('cAMP levels', 'MPA', (114, 125))	('CXCL12', 'MPA', (23, 29))	('CXCR4', 'molecular_function', 'GO:0038147', ('11', '16'))	('activates', 'PosReg', (34, 43))	('G-protein', 'MPA', (44, 53))	('Galphai pathway', 'Pathway', (85, 100))
107280	21105715	As reported in the literature, bleomycin caused marked alterations in lung architecture with increased interstitial wall thickness and mononuclear cell infiltrates.	('lung architecture', 'CPA', (70, 87))	('alterations', 'Reg', (55, 66))	('increased', 'PosReg', (93, 102))	('bleomycin', 'Var', (31, 40))	('bleomycin', 'Chemical', 'MESH:D001761', (31, 40))	('interstitial wall thickness', 'CPA', (103, 130))	('mononuclear cell infiltrates', 'CPA', (135, 163))
107281	21105715	Mice receiving bleomycin and treated separately with 4 and compound 26 led to a decrease in interstitial and alveolar structural distortion (Figure 5 B and C) compared to the lung tissue of untreated mice (5A).	('compound 26', 'Var', (59, 70))	('mice', 'Species', '10090', (200, 204))	('Mice', 'Species', '10090', (0, 4))	('bleomycin', 'Chemical', 'MESH:D001761', (15, 24))	('decrease', 'NegReg', (80, 88))
107283	21105715	Blocking CXCR4 has been shown to block metastasis of various cancers.	('Blocking', 'Var', (0, 8))	('CXCR4', 'molecular_function', 'GO:0038147', ('9', '14'))	('metastasis', 'CPA', (39, 49))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('block', 'NegReg', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
107306	21105715	Intriguingly, the present class of anti-CXCR4 compounds can intervene in the Galphai signaling pathway (cAMP modulation), but not the Gq pathway (Ca2+ flux).	('signaling pathway', 'biological_process', 'GO:0007165', ('85', '102'))	('intervene', 'Reg', (60, 69))	('anti-CXCR4', 'Var', (35, 45))	('Ca2+', 'Chemical', 'MESH:D000069285', (146, 150))	('cAMP', 'Chemical', 'MESH:D000242', (104, 108))	('Galphai signaling pathway', 'Pathway', (77, 102))	('CXCR4', 'molecular_function', 'GO:0038147', ('40', '45'))
107314	21105715	either benzenoid or pyridinoid), then ortho substitution by a ring nitrogen, fluorine or N-alkyl can lead to less effective competition with 4.	('nitrogen', 'Chemical', 'MESH:D009584', (67, 75))	('less', 'NegReg', (109, 113))	('N-alkyl', 'Chemical', '-', (89, 96))	('fluorine', 'Chemical', 'MESH:D005461', (77, 85))	('benzenoid', 'Chemical', '-', (7, 16))	('pyridinoid', 'Chemical', '-', (20, 30))	('ortho', 'Var', (38, 43))
107315	21105715	On the other hand, when both terminal rings are dipyrimidines, activity is high and substitution effects are marginal for the latter as shown, among others, by lead 26 (Table 3).	('dipyrimidines', 'Chemical', '-', (48, 61))	('activity', 'MPA', (63, 71))	('dipyrimidines', 'Var', (48, 61))
107316	21105715	The improved antagonistic effects of double pyrimidine substitution cannot be rationalized on a molecular level, since the geometry of the specific binding site is presently unknown.	('pyrimidine', 'Chemical', 'MESH:C030986', (44, 54))	('improved', 'PosReg', (4, 12))	('binding', 'molecular_function', 'GO:0005488', ('148', '155'))	('antagonistic effects', 'MPA', (13, 33))	('double pyrimidine substitution', 'Var', (37, 67))
107376	21105715	(C22H25N5) C, H, N. The boc-protected 3-(pyrrolidin-1-yl)aniline (0.29mg, 1.1 mmol) was converted to 10i (0.19 g, 58%, 2 steps) according to the procedure described above for 10h as a pale white solid: mp 136-138  C (dec.); 1H NMR (400 MHz, CDCl3) delta 8.19 (bs, 2H), 7.38-7.33 (m, 4H), 7.06 (t, J =8.0 Hz, 1H), 6.50 (t, J = 4.8, 4.8 Hz, 1H), 6.28 (t, J = 5.6, 5.6 Hz, 1H), 6.03 (dd, J = 6.0, 2.0 Hz, 2H), 5.88 (t, J = 2.0, 2.0 Hz, 1H), 4.64 (d, J = 5.6, 5.6 Hz, 2H), 4.34 (s, 2H), 4.01 (bs, 1H), 3.30-3.24 (m, 4H), 2.01-1.95 (m, 4H); 13C NMR (100 MHz,CDCl3) delta 162.41, 158.14, 149.36, 149.15, 139.10, 138.04, 129.97, 127.90, 110.77, 102.24, 101.17, 96.34, 48.23, 47.65, 45.29, 25.54; HRMS Calcd for C22H26N5 360.21882 [M+H]+, found 360.21805; Anal.	('N', 'Chemical', 'MESH:D009584', (540, 541))	('C22H25N5', 'Chemical', '-', (1, 9))	('C22H26N5', 'Var', (704, 712))	('aniline', 'Chemical', 'MESH:C023650', (57, 64))	('N', 'Chemical', 'MESH:D009584', (227, 228))	('N', 'Chemical', 'MESH:D009584', (710, 711))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('360.21882 [', 'Var', (713, 724))	('CDCl3', 'Chemical', '-', (241, 246))	('N', 'Chemical', 'MESH:D009584', (7, 8))	('CDCl3', 'Chemical', '-', (553, 558))
107381	21105715	The solvent was removed under reduced pressure, and the white solid residue was sequentially washed with water and ethanol to afford pure title compound 15 (2.04 g, 94%) as a white solid: mp > 400  C (dec); 1H NMR(400 MHz, DMSO-d6) delta 9.61 (t, J = 6.1, 6.1 Hz, 2H), 7.27 (s, 4H), 4.50 (d, J = 6.2 Hz, 4H); 13C NMR (150 MHz, DMSO-d6) delta 169.51, 168.63, 165.46, 136.51, 127.45, 43.71.	('DMSO-d6', 'Chemical', '-', (223, 230))	('water', 'Chemical', 'MESH:D014867', (105, 110))	('DMSO-d6', 'Chemical', '-', (327, 334))	('N', 'Chemical', 'MESH:D009584', (313, 314))	('mp > 400', 'Var', (188, 196))	('a 9', 'Gene', '394435', (236, 239))	('pure', 'molecular_function', 'GO:0034023', ('133', '137'))	('a 9', 'Gene', (236, 239))	('N', 'Chemical', 'MESH:D009584', (210, 211))
107403	21105715	(C17H14F4N6) C, H, N. Starting with compound 19a (1.66 g, 5.0 mmol), the same procedure to compound 21a furnished the title product 21b (1.19 g, 67%) as a white solid: mp 162-163  C (dec); 1H NMR (600 MHz, DMSO-d6) delta 8.16 (s, 2H), 7.99 (d, J = 3 Hz, 1H), 7.30 (m, 4H), 6.01 (m, 1H), 5.55(bs, 1H), 5.24(bs, 1H), 4.59 (m, 2H), 4.54 (bs, 2H), 2.49 (s, 3H); 13C NMR (150 MHz, DMSO-d6) delta 171.90, 159.44, 155.70, 153.29, 151.64, 145.86, 145.71, 138.74, 137.23, 128.04, 100.00, 45.83, 45.16, 14.16.	('N', 'Chemical', 'MESH:D009584', (362, 363))	('DMSO-d6', 'Chemical', '-', (206, 213))	('DMSO-d6', 'Chemical', '-', (376, 383))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('(C17H14F4N6) C', 'Chemical', '-', (0, 14))	('145.71', 'Var', (439, 445))	('N', 'Chemical', 'MESH:D009584', (192, 193))	('145.86', 'Var', (431, 437))	('N', 'Chemical', 'MESH:D009584', (9, 10))
107430	33579337	Moreover, overexpression of circ_0119872 promotes the malignancy of UM cells, while silencing of circ_0119872 inhibits it.	('circ_0119872', 'Var', (28, 40))	('inhibits', 'NegReg', (110, 118))	('silencing', 'Var', (84, 93))	('promotes', 'PosReg', (41, 49))	('circ_0119872', 'Gene', (97, 109))	('malignancy', 'Disease', 'MESH:D009369', (54, 64))	('malignancy', 'Disease', (54, 64))
107432	33579337	Circ_0119872 may act as an oncogene in UM through a novel circ_0119872/miR-622/G3BP1 axis, activating the Wnt/beta-catenin and mTOR signalling pathways, which in turn may provide potential biomarkers and therapeutic targets for the management of UM.	('signalling', 'biological_process', 'GO:0023052', ('132', '142'))	('Circ_0119872', 'Var', (0, 12))	('beta-catenin', 'Gene', (110, 122))	('G3BP1', 'Gene', (79, 84))	('beta-catenin', 'Gene', '1499', (110, 122))	('G3BP1', 'Gene', '10146', (79, 84))	('mTOR', 'Gene', (127, 131))	('mTOR', 'Gene', '2475', (127, 131))	('miR-622', 'Gene', (71, 78))	('activating', 'PosReg', (91, 101))	('miR-622', 'Gene', '693207', (71, 78))
107452	33579337	66009-1-Ig, Proteintech, USA), anti-P84 (Cat.	('anti-P84', 'Var', (31, 39))	('Cat', 'Gene', (41, 44))	('Cat', 'molecular_function', 'GO:0004096', ('41', '44'))	('Cat', 'Gene', '847', (41, 44))
107466	33579337	On the one hand, the levels of circ_0119872 and RASGRP3 were detected by qRT-PCR on the StepOnePlus Real-Time PCR System (Life Technologies, Carlsbad, CA).	('circ_0119872', 'Var', (31, 43))	('RASGRP3', 'Gene', '25780', (48, 55))	('RASGRP3', 'Gene', (48, 55))
107488	33579337	The genomic structure indicates that circ_0119872 is composed of exons 4 and 5 of the RASGRP3 gene.	('circ_0119872', 'Var', (37, 49))	('RASGRP3', 'Gene', (86, 93))	('RASGRP3', 'Gene', '25780', (86, 93))
107489	33579337	The results of the RNase R treatment assay indicate that circ_0119872 is much more resistant to RNase R than linear RASGRP3 mRNA (Fig.	('RASGRP3', 'Gene', (116, 123))	('circ_0119872', 'Var', (57, 69))	('RASGRP3', 'Gene', '25780', (116, 123))
107491	33579337	To investigate the biological role of circ_0119872 in UM, we performed gain-of-function assays by transfecting circ_0119872 overexpression (circ_0119872) or interference (circ_0119872-sh#1 and circ_0119872-sh#2) vectors into OCM-1A and MUM-2B cells (Fig.	('circ_0119872-sh', 'Var', (171, 186))	('overexpression', 'PosReg', (124, 138))	('OCM-1', 'Species', '83984', (225, 230))
107492	33579337	Ectopic expression of circ_0119872 promoted cell proliferation, while silencing of circ_0119872 expression inhibited the proliferation of both OCM-1A and MUM-2B cells (Fig.	('silencing', 'NegReg', (70, 79))	('cell proliferation', 'CPA', (44, 62))	('proliferation', 'CPA', (121, 134))	('OCM-1', 'Species', '83984', (143, 148))	('circ_0119872', 'Gene', (83, 95))	('promoted', 'PosReg', (35, 43))	('circ_0119872', 'Var', (22, 34))	('inhibited', 'NegReg', (107, 116))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))	('Ectopic expression', 'MPA', (0, 18))
107494	33579337	The in vivo study showed that tumours in the circ_0119872-overexpressing group were significantly larger and heavier than those in the control group (Fig.	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('tumours', 'Disease', (30, 37))	('circ_0119872-overexpressing', 'Var', (45, 72))	('heavier', 'PosReg', (109, 116))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
107498	33579337	In turn, the enrichment of circ_0119872 in the miR-622 mutant-captured fraction (Bio-miR-622-mut) was largely diminished compared with that in the wild-type-captured fraction (Bio-miR-622) (Fig.	('miR-622', 'Gene', (85, 92))	('miR-622', 'Gene', '693207', (180, 187))	('miR-622', 'Gene', (47, 54))	('miR-622', 'Gene', '693207', (85, 92))	('enrichment', 'MPA', (13, 23))	('miR-622', 'Gene', '693207', (47, 54))	('diminished', 'NegReg', (110, 120))	('miR-622', 'Gene', (180, 187))	('mutant-captured', 'Var', (55, 70))
107499	33579337	Furthermore, RNA-FISH detection indicated that circ_0119872 and miR-622 were colocalized in the cytoplasm (Fig.	('miR-622', 'Gene', (64, 71))	('miR-622', 'Gene', '693207', (64, 71))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('circ_0119872', 'Var', (47, 59))	('cytoplasm', 'cellular_component', 'GO:0005737', ('96', '105'))
107500	33579337	Collectively, these results demonstrate that circ_0119872 can directly interact with miR-622 in UM cells and suggest that circ_0119872 functions as a miRNA sponge for miR-622.	('miR-622', 'Gene', (85, 92))	('miR-622', 'Gene', (167, 174))	('miR-622', 'Gene', '693207', (85, 92))	('miR-622', 'Gene', '693207', (167, 174))	('interact', 'Interaction', (71, 79))	('circ_0119872', 'Var', (122, 134))
107501	33579337	To further confirm the co-regulatory effect of circ_0119872 and miR-622 on cell proliferation and angiogenesis, we upregulated circ_0119872 and then overexpressed miR-622 in UM cells (Fig.	('miR-622', 'Gene', (64, 71))	('miR-622', 'Gene', '693207', (64, 71))	('angiogenesis', 'biological_process', 'GO:0001525', ('98', '110'))	('overexpressed', 'PosReg', (149, 162))	('miR-622', 'Gene', (163, 170))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('miR-622', 'Gene', '693207', (163, 170))	('circ_0119872', 'Var', (127, 139))	('upregulated', 'PosReg', (115, 126))
107503	33579337	These results indicate that miR-622 can act as a target of circ_0119872 to reverse the effects of circ_0119872 on biofunction in UM cells.	('miR-622', 'Gene', (28, 35))	('circ_0119872', 'Var', (98, 110))	('miR-622', 'Gene', '693207', (28, 35))	('biofunction in UM cells', 'MPA', (114, 137))
107513	33579337	The results of EdU and CCK-8 assays demonstrated that high G3BP1 expression levels promoted cell proliferation, while silencing of G3BP1 expression inhibited cell proliferation in both OCM-1A and MUM-2B cells (Fig.	('cell proliferation', 'CPA', (158, 176))	('G3BP1', 'Gene', (59, 64))	('OCM-1', 'Species', '83984', (185, 190))	('cell proliferation', 'biological_process', 'GO:0008283', ('158', '176'))	('inhibited', 'NegReg', (148, 157))	('G3BP1', 'Gene', '10146', (59, 64))	('silencing', 'Var', (118, 127))	('cell proliferation', 'biological_process', 'GO:0008283', ('92', '110'))	('G3BP1', 'Gene', (131, 136))	('promoted', 'PosReg', (83, 91))	('cell proliferation', 'CPA', (92, 110))	('G3BP1', 'Gene', '10146', (131, 136))
107514	33579337	The HUVEC tube formation assay also indicated that cells with ectopic G3BP1 levels exhibited significantly increased angiogenesis (Fig.	('angiogenesis', 'biological_process', 'GO:0001525', ('117', '129'))	('increased', 'PosReg', (107, 116))	('G3BP1', 'Gene', (70, 75))	('G3BP1', 'Gene', '10146', (70, 75))	('ectopic', 'Var', (62, 69))	('angiogenesis', 'CPA', (117, 129))	('tube formation', 'biological_process', 'GO:0035148', ('10', '24'))
107518	33579337	Knowing that the expression of G3BP1 could be regulated by circ_0119872, western blotting was performed to clarify the role of circ_0119872 in these two pathways.	('circ_0119872', 'Var', (59, 71))	('regulated', 'Reg', (46, 55))	('expression', 'MPA', (17, 27))	('G3BP1', 'Gene', (31, 36))	('G3BP1', 'Gene', '10146', (31, 36))
107519	33579337	7b, the ectopic expression of circ_0119872 resulted in increased expression of beta-catenin in the nucleus and enhanced the expression of cyclin D1 and c-Myc.	('cyclin D1', 'Gene', (138, 147))	('c-Myc', 'Gene', '4609', (152, 157))	('cyclin', 'molecular_function', 'GO:0016538', ('138', '144'))	('nucleus', 'cellular_component', 'GO:0005634', ('99', '106'))	('beta-catenin', 'Gene', '1499', (79, 91))	('increased', 'PosReg', (55, 64))	('beta-catenin', 'Gene', (79, 91))	('c-Myc', 'Gene', (152, 157))	('enhanced', 'PosReg', (111, 119))	('expression', 'MPA', (65, 75))	('expression', 'MPA', (124, 134))	('cyclin D1', 'Gene', '595', (138, 147))	('circ_0119872', 'Var', (30, 42))
107520	33579337	In addition, the overexpression of circ_0119872 promoted the phosphorylation of mTOR, S6K1, and 4E-BP1 (Fig.	('phosphorylation', 'MPA', (61, 76))	('circ_0119872', 'Var', (35, 47))	('4E-BP1', 'Gene', (96, 102))	('mTOR', 'Gene', (80, 84))	('mTOR', 'Gene', '2475', (80, 84))	('S6K1', 'Gene', (86, 90))	('4E-BP1', 'Gene', '1978', (96, 102))	('overexpression', 'PosReg', (17, 31))	('S6K1', 'Gene', '6198', (86, 90))	('promoted', 'PosReg', (48, 56))	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))
107521	33579337	Moreover, this effect was reversed by knocking down the expression of G3BP1.	('knocking', 'Var', (38, 46))	('G3BP1', 'Gene', '10146', (70, 75))	('G3BP1', 'Gene', (70, 75))
107522	33579337	These results suggest that circ_0119872 activates Wnt/beta-catenin and mTOR signalling pathways by regulating G3BP1 expression.	('expression', 'MPA', (116, 126))	('regulating', 'Reg', (99, 109))	('G3BP1', 'Gene', '10146', (110, 115))	('activates', 'PosReg', (40, 49))	('mTOR', 'Gene', '2475', (71, 75))	('beta-catenin', 'Gene', (54, 66))	('signalling', 'biological_process', 'GO:0023052', ('76', '86'))	('mTOR', 'Gene', (71, 75))	('G3BP1', 'Gene', (110, 115))	('beta-catenin', 'Gene', '1499', (54, 66))	('circ_0119872', 'Var', (27, 39))
107526	33579337	Our results indicate that circ_0119872 acts as a molecular sponge for miR-622 to weaken its inhibitory effect on the downstream target gene G3BP1 and then activates Wnt/beta-catenin and mTOR signalling pathways to promote the metastatic potential of UM cells.	('G3BP1', 'Gene', (140, 145))	('promote', 'PosReg', (214, 221))	('activates', 'PosReg', (155, 164))	('signalling', 'biological_process', 'GO:0023052', ('191', '201'))	('G3BP1', 'Gene', '10146', (140, 145))	('mTOR', 'Gene', (186, 190))	('weaken', 'NegReg', (81, 87))	('miR-622', 'Gene', (70, 77))	('metastatic potential of UM cells', 'CPA', (226, 258))	('beta-catenin', 'Gene', (169, 181))	('inhibitory effect', 'MPA', (92, 109))	('mTOR', 'Gene', '2475', (186, 190))	('miR-622', 'Gene', '693207', (70, 77))	('beta-catenin', 'Gene', '1499', (169, 181))	('circ_0119872', 'Var', (26, 38))
107532	33579337	We found that circ_0119872 is derived from exon 4 and exon 5 of RASGRP3 and is located mainly in the cytoplasm.	('RASGRP3', 'Gene', (64, 71))	('RASGRP3', 'Gene', '25780', (64, 71))	('cytoplasm', 'cellular_component', 'GO:0005737', ('101', '110'))	('circ_0119872', 'Var', (14, 26))
107533	33579337	In addition, bioinformatics prediction, RNA pull-down and luciferase reporter assays showed that both circ_0119872 and the G3BP1 3' UTR can bind with miR-622 in a reverse complementary manner.	('miR-622', 'Gene', (150, 157))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('G3BP1', 'Gene', (123, 128))	('miR-622', 'Gene', '693207', (150, 157))	('G3BP1', 'Gene', '10146', (123, 128))	('bind', 'Interaction', (140, 144))	('circ_0119872', 'Var', (102, 114))
107534	33579337	In vitro and in vivo experiments further indicated that circ_0119872 and miR-622 can co-regulate cell biofunction in UM and the expression of G3BP1.	('cell biofunction in UM', 'CPA', (97, 119))	('circ_0119872', 'Var', (56, 68))	('miR-622', 'Gene', (73, 80))	('G3BP1', 'Gene', (142, 147))	('co-regulate', 'Reg', (85, 96))	('G3BP1', 'Gene', '10146', (142, 147))	('miR-622', 'Gene', '693207', (73, 80))
107539	33579337	Loss of G3BP1 suppresses the proliferation, migration, and invasion of oesophageal cancer cells via inactivation of the Wnt/beta-catenin and PI3K/AKT signalling pathways.	('G3BP1', 'Gene', (8, 13))	('inactivation', 'NegReg', (100, 112))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('AKT', 'Gene', '207', (146, 149))	('beta-catenin', 'Gene', (124, 136))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('beta-catenin', 'Gene', '1499', (124, 136))	('signalling', 'biological_process', 'GO:0023052', ('150', '160'))	('proliferation', 'CPA', (29, 42))	('AKT', 'Gene', (146, 149))	('suppresses', 'NegReg', (14, 24))	('invasion', 'CPA', (59, 67))	('migration', 'CPA', (44, 53))	('PI3K', 'molecular_function', 'GO:0016303', ('141', '145'))	('Loss', 'Var', (0, 4))	('cancer', 'Disease', (83, 89))	('G3BP1', 'Gene', '10146', (8, 13))
107540	33579337	demonstrated that silencing G3BP1 inhibits the activation of the transforming growth factor (TGF)-beta/Smad signalling pathway in gastric cancer.	('silencing', 'Var', (18, 27))	('inhibits', 'NegReg', (34, 42))	('G3BP1', 'Gene', '10146', (28, 33))	('G3BP1', 'Gene', (28, 33))	('gastric cancer', 'Disease', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('gastric cancer', 'Disease', 'MESH:D013274', (130, 144))	('signalling pathway', 'biological_process', 'GO:0007165', ('108', '126'))	('transforming growth factor (TGF)-beta', 'Gene', '7039', (65, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (130, 144))
107543	33579337	Furthermore, circ_0119872 alleviates the inhibitory effect of miR-622 on G3BP1 and then activates Wnt/beta-catenin and mTOR signalling pathways.	('beta-catenin', 'Gene', '1499', (102, 114))	('signalling', 'biological_process', 'GO:0023052', ('124', '134'))	('activates', 'PosReg', (88, 97))	('alleviates', 'NegReg', (26, 36))	('miR-622', 'Gene', (62, 69))	('miR-622', 'Gene', '693207', (62, 69))	('G3BP1', 'Gene', (73, 78))	('mTOR', 'Gene', (119, 123))	('mTOR', 'Gene', '2475', (119, 123))	('inhibitory effect', 'MPA', (41, 58))	('beta-catenin', 'Gene', (102, 114))	('G3BP1', 'Gene', '10146', (73, 78))	('circ_0119872', 'Var', (13, 25))
107545	33579337	Moreover, circ_0119872 acts as a sponge for miR-622 to reduce the inhibitory effect on G3BP1 and thus enhances the expression of G3BP1 and promotes the activity of the downstream Wnt/beta-catenin and mTOR signalling pathways.	('G3BP1', 'Gene', '10146', (129, 134))	('circ_0119872', 'Var', (10, 22))	('beta-catenin', 'Gene', (183, 195))	('miR-622', 'Gene', '693207', (44, 51))	('mTOR', 'Gene', (200, 204))	('activity', 'MPA', (152, 160))	('mTOR', 'Gene', '2475', (200, 204))	('G3BP1', 'Gene', (87, 92))	('enhances', 'PosReg', (102, 110))	('expression', 'MPA', (115, 125))	('beta-catenin', 'Gene', '1499', (183, 195))	('G3BP1', 'Gene', '10146', (87, 92))	('reduce', 'NegReg', (55, 61))	('signalling', 'biological_process', 'GO:0023052', ('205', '215'))	('G3BP1', 'Gene', (129, 134))	('promotes', 'PosReg', (139, 147))	('miR-622', 'Gene', (44, 51))	('inhibitory effect', 'MPA', (66, 83))
107546	33579337	Overall, our study clarifies that circ_0119872 acts as an oncogene by targeting the miR-622/G3BP1 axis and provides a new target for the diagnosis and treatment of UM.	('circ_0119872', 'Var', (34, 46))	('G3BP1', 'Gene', '10146', (92, 97))	('G3BP1', 'Gene', (92, 97))	('miR-622', 'Gene', '693207', (84, 91))	('targeting', 'Reg', (70, 79))	('miR-622', 'Gene', (84, 91))
107566	31856423	showed that BPD in the micromolar concentration range without light activation induces uveal melanoma apoptosis and eliminates cancer stem-like cells in vitro.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('uveal melanoma apoptosis', 'Disease', (87, 111))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('eliminates', 'NegReg', (116, 126))	('uveal melanoma', 'Phenotype', 'HP:0007716', (87, 101))	('apoptosis', 'biological_process', 'GO:0097194', ('102', '111'))	('BPD', 'Var', (12, 15))	('BPD', 'Chemical', '-', (12, 15))	('apoptosis', 'biological_process', 'GO:0006915', ('102', '111'))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('induces', 'Reg', (79, 86))	('cancer', 'Disease', (127, 133))	('uveal melanoma apoptosis', 'Disease', 'MESH:C536494', (87, 111))
107567	31856423	demonstrated that BPD inhibits YAP and sensitizes hepatocellular carcinoma BEL/FU cells to chemotherapy (i.e., doxorubicin and fluorouracil) through autophagy-related cell death pathway.	('autophagy-related', 'CPA', (149, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('sensitizes hepatocellular carcinoma BEL', 'Disease', (39, 78))	('YAP', 'Gene', (31, 34))	('cell death', 'biological_process', 'GO:0008219', ('167', '177'))	('BPD', 'Chemical', '-', (18, 21))	('sensitizes hepatocellular carcinoma BEL', 'Disease', 'MESH:D006528', (39, 78))	('autophagy', 'biological_process', 'GO:0006914', ('149', '158'))	('fluorouracil', 'Chemical', 'MESH:D005472', (127, 139))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (50, 74))	('inhibits', 'NegReg', (22, 30))	('autophagy', 'biological_process', 'GO:0016236', ('149', '158'))	('doxorubicin', 'Chemical', 'MESH:D004317', (111, 122))	('YAP', 'Gene', '10413', (31, 34))	('BPD', 'Var', (18, 21))
107573	31856423	In 90 patient-derived samples of glioma (grades I-IV) and non-cancerous brain specimens, the mRNA and protein levels of YAP/TAZ were found to be 3-4-folds higher in grade IV glioma compared to non-tumorous brain specimens.	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('glioma', 'Disease', (33, 39))	('cancerous brain', 'Phenotype', 'HP:0030692', (62, 77))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('YAP', 'Gene', '10413', (120, 123))	('glioma', 'Disease', 'MESH:D005910', (33, 39))	('higher', 'PosReg', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('patient', 'Species', '9606', (6, 13))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('glioma', 'Disease', (174, 180))	('grade IV', 'Var', (165, 173))	('glioma', 'Phenotype', 'HP:0009733', (33, 39))	('non-cancerous', 'Disease', 'MESH:D009369', (58, 71))	('tumorous brain', 'Disease', 'MESH:D001932', (197, 211))	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('tumorous brain', 'Phenotype', 'HP:0030692', (197, 211))	('tumorous brain', 'Disease', (197, 211))	('non-cancerous', 'Disease', (58, 71))	('YAP', 'Gene', (120, 123))
107588	31856423	In the clinic, light can be delivered and confined to brain tumors via optical fibers during open surgery to selectively induce photodynamic damage of glioma (e.g., NCT03048240, NCT03897491, NCT00003788, NCT01966809, NCT00002647, NCT01682746).	('NCT01682746', 'Var', (230, 241))	('brain tumors', 'Disease', 'MESH:D001932', (54, 66))	('brain tumors', 'Phenotype', 'HP:0030692', (54, 66))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('brain tumors', 'Disease', (54, 66))	('NCT03897491', 'Var', (178, 189))	('NCT01966809', 'Var', (204, 215))	('brain tumor', 'Phenotype', 'HP:0030692', (54, 65))	('photodynamic damage of glioma', 'Disease', 'MESH:D005910', (128, 157))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('NCT00003788', 'Var', (191, 202))	('NCT00002647', 'Var', (217, 228))	('photodynamic damage of glioma', 'Disease', (128, 157))	('NCT03048240', 'Var', (165, 176))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
107597	31856423	This is presumably because U251 cells (doubling time of ~23 h) are dividing and replicating faster than U87 cells (doubling time of ~34 h), so that U251 cells are more susceptible to paclitaxel-mediated microtubule stabilization and cisplatin-induced DNA damage.	('U87', 'Gene', (104, 107))	('U251', 'Var', (148, 152))	('U87', 'Gene', '641648', (104, 107))	('U251', 'CellLine', 'CVCL:0021', (27, 31))	('microtubule stabilization', 'biological_process', 'GO:0007026', ('203', '228'))	('susceptible', 'MPA', (168, 179))	('U251', 'CellLine', 'CVCL:0021', (148, 152))	('paclitaxel', 'Chemical', 'MESH:D017239', (183, 193))	('microtubule', 'cellular_component', 'GO:0005874', ('203', '214'))	('DNA', 'cellular_component', 'GO:0005574', ('251', '254'))	('more', 'PosReg', (163, 167))	('cisplatin', 'Chemical', 'MESH:D002945', (233, 242))
107602	31856423	In U87 cells, combination treatment of 5 muM BPD and 10 muM cisplatin resulted in a significant (P<0.05) increase in toxicity by ~20% relative to cisplatin treatment alone (Figure 2a).	('BPD', 'Chemical', '-', (45, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (146, 155))	('increase', 'PosReg', (105, 113))	('cisplatin', 'Var', (60, 69))	('toxicity', 'Disease', (117, 125))	('toxicity', 'Disease', 'MESH:D064420', (117, 125))	('U87', 'Gene', (3, 6))	('U87', 'Gene', '641648', (3, 6))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))
107604	31856423	In the U87 cells treated with the combination of BPD and paclitaxel, there were no significant changes in toxicity at all paclitaxel doses compared to the groups treated with paclitaxel alone (Figure 2b).	('BPD', 'Chemical', '-', (49, 52))	('toxicity', 'Disease', 'MESH:D064420', (106, 114))	('toxicity', 'Disease', (106, 114))	('U87', 'Gene', (7, 10))	('paclitaxel', 'Chemical', 'MESH:D017239', (57, 67))	('paclitaxel', 'Chemical', 'MESH:D017239', (122, 132))	('BPD', 'Var', (49, 52))	('paclitaxel', 'Chemical', 'MESH:D017239', (175, 185))	('U87', 'Gene', '641648', (7, 10))
107612	31856423	In U251 cells, the mean IC50 of cisplatin is 2.48+-0.45 muM for the BPD-cisplatin combination, and the mean IC50 of paclitaxel is 7.52+-0.47 nM for the BPD-paclitaxel combination.	('IC50', 'MPA', (24, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('U251', 'CellLine', 'CVCL:0021', (3, 7))	('BPD', 'Chemical', '-', (152, 155))	('BPD-cisplatin', 'Var', (68, 81))	('paclitaxel', 'Chemical', 'MESH:D017239', (156, 166))	('paclitaxel', 'Chemical', 'MESH:D017239', (116, 126))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('BPD', 'Chemical', '-', (68, 71))
107615	31856423	Only the combination of BPD and cisplatin in U87 demonstrated slightly synergism (CI = 0.9), while all other combinations showed potentially antagonistic effects (CI between 1.1 and 1.3).	('BPD', 'Chemical', '-', (24, 27))	('U87', 'Gene', '641648', (45, 48))	('synergism', 'MPA', (71, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('U87', 'Gene', (45, 48))	('BPD', 'Var', (24, 27))
107621	31856423	have shown that BPD-based PDT initiates apoptosis in part through the degradation of the anti-apoptotic Bcl family of proteins, Chen et al.	('degradation', 'MPA', (70, 81))	('apoptosis', 'CPA', (40, 49))	('degradation', 'biological_process', 'GO:0009056', ('70', '81'))	('apoptosis', 'biological_process', 'GO:0097194', ('40', '49'))	('apoptosis', 'biological_process', 'GO:0006915', ('40', '49'))	('BPD', 'Chemical', '-', (16, 19))	('anti-apoptotic Bcl family of proteins', 'MPA', (89, 126))	('BPD-based PDT', 'Var', (16, 29))	('PDT', 'Var', (26, 29))
107623	31856423	showed that in four uveal melanoma cell lines (92.1, Mel 270, Omm 1 and Omm 2.3), BPD without light activation attenuated Bcl-2 expression in a BPD dosage- and treatment time-dependent manner.	('BPD', 'Chemical', '-', (144, 147))	('attenuated', 'NegReg', (111, 121))	('Bcl-2', 'molecular_function', 'GO:0015283', ('122', '127'))	('BPD', 'Var', (82, 85))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (26, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (20, 34))	('Bcl-2', 'Gene', (122, 127))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))	('Bcl-2', 'Gene', '596', (122, 127))	('BPD', 'Chemical', '-', (82, 85))
107634	31856423	In U87 cells treated with the combination of BPD and paclitaxel, BPD attenuated the paclitaxel-induced upregulation of YAP, TAZ, Bcl-2, and EGFR expressions by 56%-67% (Figure 4f-i).	('BPD', 'Chemical', '-', (65, 68))	('EGFR', 'Gene', (140, 144))	('upregulation', 'PosReg', (103, 115))	('YAP', 'Gene', '10413', (119, 122))	('Bcl-2', 'Gene', (129, 134))	('Bcl-2', 'molecular_function', 'GO:0015283', ('129', '134'))	('U87', 'Gene', '641648', (3, 6))	('EGFR', 'Gene', '1956', (140, 144))	('BPD', 'Chemical', '-', (45, 48))	('Bcl-2', 'Gene', '596', (129, 134))	('expressions', 'MPA', (145, 156))	('TAZ', 'Protein', (124, 127))	('attenuated', 'NegReg', (69, 79))	('paclitaxel', 'Chemical', 'MESH:D017239', (84, 94))	('paclitaxel', 'Chemical', 'MESH:D017239', (53, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('140', '144'))	('U87', 'Gene', (3, 6))	('YAP', 'Gene', (119, 122))	('BPD', 'Var', (65, 68))
107635	31856423	Overall, relative to baseline protein expression, the combination of BPD and paclitaxel significantly downregulated Bcl-2 expression (Figure 4i, P<0.01), but did not significantly downregulate YAP, TAZ or EGFR expression in U87 cells (Figure 4f-h, P>0.05).	('BPD', 'Var', (69, 72))	('downregulate', 'NegReg', (180, 192))	('BPD', 'Chemical', '-', (69, 72))	('downregulated', 'NegReg', (102, 115))	('YAP', 'Gene', '10413', (193, 196))	('U87', 'Gene', '641648', (224, 227))	('TAZ', 'Gene', (198, 201))	('expression', 'MPA', (210, 220))	('EGFR', 'Gene', '1956', (205, 209))	('EGFR', 'Gene', (205, 209))	('EGFR', 'molecular_function', 'GO:0005006', ('205', '209'))	('YAP', 'Gene', (193, 196))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('paclitaxel', 'Chemical', 'MESH:D017239', (77, 87))	('Bcl-2', 'Gene', (116, 121))	('Bcl-2', 'Gene', '596', (116, 121))	('U87', 'Gene', (224, 227))	('Bcl-2', 'molecular_function', 'GO:0015283', ('116', '121'))
107650	31856423	The paclitaxel monotherapy (7.5 nM, 72h) in U251 cells caused modest increases in the YAP, TAZ, and EGFR expression levels (Figure 5f-h), though only the changes in YAP and EGFR were found to be statistically significant.	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('7.5 nM', 'Var', (28, 34))	('increases', 'PosReg', (69, 78))	('U251', 'CellLine', 'CVCL:0021', (44, 48))	('YAP', 'Gene', (165, 168))	('EGFR', 'Gene', '1956', (100, 104))	('YAP', 'Gene', (86, 89))	('EGFR', 'Gene', (100, 104))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))	('EGFR', 'Gene', '1956', (173, 177))	('EGFR', 'molecular_function', 'GO:0005006', ('173', '177'))	('expression levels', 'MPA', (105, 122))	('YAP', 'Gene', '10413', (165, 168))	('TAZ', 'MPA', (91, 94))	('EGFR', 'Gene', (173, 177))	('YAP', 'Gene', '10413', (86, 89))
107655	31856423	Higher concentrations of BPD may therefore be required for U251 than U87 to effectively attenuate the higher expression levels of TAZ.	('U251', 'CellLine', 'CVCL:0021', (59, 63))	('TAZ', 'MPA', (130, 133))	('U87', 'Gene', '641648', (69, 72))	('BPD', 'Chemical', '-', (25, 28))	('U251', 'Var', (59, 63))	('attenuate', 'NegReg', (88, 97))	('higher expression levels', 'MPA', (102, 126))	('U87', 'Gene', (69, 72))
107659	31856423	In fact, intravenous injection of high dose BPD may potentially lead to dark toxicity in other organs, such as liver, spleen and kidney.	('toxicity', 'Disease', 'MESH:D064420', (77, 85))	('toxicity', 'Disease', (77, 85))	('lead to', 'Reg', (64, 71))	('BPD', 'Var', (44, 47))	('BPD', 'Chemical', '-', (44, 47))	('high dose BPD', 'Var', (34, 47))
107681	31856423	After blocking with 5% milk in TBST solution, proteins were further detected using antibodies against EGFR (1:1000, CST #2239), YAP (1:1000, CST #4912), TAZ (1:1000, CST #70148), Bcl-2 (1:1000, CST 4223), 14-3-3 (1:1000, #CST 7413) or p-YAP (1:1000, CST #4911) according to manufacturer's guidelines.	('YAP', 'Gene', (237, 240))	('CST', 'Gene', (116, 119))	('detected', 'Reg', (68, 76))	('EGFR', 'molecular_function', 'GO:0005006', ('102', '106'))	('CST', 'Gene', (194, 197))	('EGFR', 'Gene', '1956', (102, 106))	('Bcl-2', 'Gene', (179, 184))	('YAP', 'Gene', '10413', (128, 131))	('CST', 'Gene', '106478911', (141, 144))	('CST', 'Gene', '106478911', (166, 169))	('CST', 'Gene', '106478911', (222, 225))	('YAP', 'Gene', '10413', (237, 240))	('Bcl-2', 'Gene', '596', (179, 184))	('1:1000', 'Var', (158, 164))	('14-3-3', 'Gene', (205, 211))	('CST', 'Gene', '106478911', (250, 253))	('CST', 'Gene', (141, 144))	('CST', 'Gene', '106478911', (116, 119))	('CST', 'Gene', (166, 169))	('EGFR', 'Gene', (102, 106))	('1:1000', 'Var', (133, 139))	('CST', 'Gene', (222, 225))	('YAP', 'Gene', (128, 131))	('Bcl-2', 'molecular_function', 'GO:0015283', ('179', '184'))	('1:1000', 'Var', (186, 192))	('1:1000', 'Var', (108, 114))	('proteins', 'Protein', (46, 54))	('CST', 'Gene', '106478911', (194, 197))	('1:1000', 'Var', (242, 248))	('14-3-3', 'Gene', '10971', (205, 211))	('CST', 'Gene', (250, 253))
107695	33100273	Early changes resulting in a gain of chromosome 8q are reported to activate macrophage infiltration, while sequential loss of BRCA1-associated protein-1 (BAP1) expression could drive T cell infiltration in UM.	('expression', 'MPA', (160, 170))	('drive', 'PosReg', (177, 182))	('chromosome', 'cellular_component', 'GO:0005694', ('37', '47'))	('BAP1', 'Gene', (154, 158))	('chromosome', 'Gene', (37, 47))	('UM', 'Phenotype', 'HP:0007716', (206, 208))	('macrophage infiltration', 'CPA', (76, 99))	('BRCA1-associated protein-1', 'Gene', (126, 152))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('loss', 'NegReg', (118, 122))	('changes', 'Var', (6, 13))	('T cell infiltration', 'CPA', (183, 202))	('gain', 'PosReg', (29, 33))	('BRCA1-associated protein-1', 'Gene', '8314', (126, 152))	('BAP1', 'Gene', '8314', (154, 158))	('activate', 'PosReg', (67, 75))
107709	33100273	The box plots in Figure 7B show that BAP1 mutant, subtype D, and monosomy 3 have a higher risk score than BAP1 wildtype, subtype A and disomy 3, respectively.	('monosomy 3', 'Disease', (65, 75))	('mutant', 'Var', (42, 48))	('BAP1', 'Gene', (106, 110))	('BAP1', 'Gene', '8314', (37, 41))	('BAP1', 'Gene', '8314', (106, 110))	('BAP1', 'Gene', (37, 41))
107713	33100273	Seven chemotherapeutic drugs, including AZD6482, JNK Inhibitor VIII, Lapatinib, Mitomycin C, PF.4708671, Temsirolimus and X17.AAG were identified as producing significant differences in the estimated IC50 between the high- and low-risk groups.	('Mitomycin C', 'Chemical', 'MESH:D016685', (80, 91))	('Lapatinib', 'Chemical', 'MESH:D000077341', (69, 78))	('AAG', 'Chemical', 'MESH:D000245', (126, 129))	('AZD6482', 'Var', (40, 47))	('PF.4708671', 'Var', (93, 103))	('AZD6482', 'Chemical', 'MESH:C578518', (40, 47))	('differences', 'Reg', (171, 182))	('IC50', 'MPA', (200, 204))	('JNK', 'molecular_function', 'GO:0004705', ('49', '52'))	('Temsirolimus', 'Disease', 'None', (105, 117))	('Temsirolimus', 'Disease', (105, 117))
107739	29663336	While mutations in BRAF V600 clearly confer sensitivity to BRAF and MEK inhibitors, the clinical implications of most other mutations are less often discussed and understood.	('sensitivity', 'MPA', (44, 55))	('MEK', 'Gene', '5609', (68, 71))	('BRAF', 'Gene', (19, 23))	('V600', 'Var', (24, 28))	('mutations', 'Var', (6, 15))	('MEK', 'Gene', (68, 71))
107740	29663336	In this review, we provide an overview of the high-frequency genomic alterations and their prognostic and therapeutic relevance in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('genomic alterations', 'Var', (61, 80))
107742	29663336	The detection of particular actionable mutations driving growth and progression of several cancers has led to the development of small molecule kinase inhibitors and/or monoclonal antibodies, which have in turn improved clinical outcomes.	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Disease', (91, 98))	('mutations', 'Var', (39, 48))	('improved', 'PosReg', (211, 219))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
107750	29663336	As such, determining the presence of relevant therapeutic mutations is now a routine procedure in many cancers, particularly melanoma, non-small cell lung cancer (NSCLC), colon adenocarcinoma, and others.	('mutations', 'Var', (58, 67))	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (139, 161))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (135, 161))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (171, 191))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('non-small cell lung cancer', 'Disease', (135, 161))	('melanoma', 'Disease', (125, 133))	('NSCLC', 'Disease', (163, 168))	('colon adenocarcinoma', 'Disease', (171, 191))	('NSCLC', 'Phenotype', 'HP:0030358', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (135, 161))
107752	29663336	Herein, we discuss the clinical and biologic implications of common mutations and other genomic alterations in melanoma.	('mutations', 'Var', (68, 77))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))
107759	29663336	Data published with The Cancer Genome Atlas (TCGA) Network found that whole exome sequence analysis of 333 primary and/or metastatic melanoma patients, melanomas could be classified into four genomic subtypes: mutant BRAF, mutant NRAS, mutant NF1, and triple-wildtype.	('NRAS', 'Gene', '4893', (230, 234))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('mutant', 'Var', (210, 216))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (24, 43))	('melanomas', 'Disease', 'MESH:D008545', (152, 161))	('mutant', 'Var', (223, 229))	('Cancer', 'Phenotype', 'HP:0002664', (24, 30))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('melanomas', 'Disease', (152, 161))	('Cancer Genome Atlas', 'Disease', (24, 43))	('NRAS', 'Gene', (230, 234))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('NF1', 'Gene', (243, 246))	('mutant', 'Var', (236, 242))	('melanomas', 'Phenotype', 'HP:0002861', (152, 161))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('BRAF', 'Gene', (217, 221))	('patients', 'Species', '9606', (142, 150))
107762	29663336	The combination of targeted inhibitors have had a very significant impact on survival in patients with BRAF mutant melanoma with a median overall survival exceeding 2 years.	('impact', 'Reg', (67, 73))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('mutant', 'Var', (108, 114))	('patients', 'Species', '9606', (89, 97))	('BRAF', 'Gene', (103, 107))
107763	29663336	On the other hand, the other common genomic subtypes, including mutant NRAS, mutant NF1, and triple-wildtype have thus far not been effectively targeted.	('NF1', 'Gene', (84, 87))	('NRAS', 'Gene', (71, 75))	('NRAS', 'Gene', '4893', (71, 75))	('mutant', 'Var', (77, 83))	('mutant', 'Var', (64, 70))
107765	29663336	Melanomas from chronically sun-exposed skin tend to have the highest numbers of mutations, and often have NF1, NRAS and occasionally BRAF V600K mutations present.	('NRAS', 'Gene', (111, 115))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('mutations', 'Var', (80, 89))	('NRAS', 'Gene', '4893', (111, 115))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('V600K', 'Mutation', 'rs121913227', (138, 143))	('Melanomas', 'Disease', (0, 9))	('BRAF', 'Gene', (133, 137))	('NF1', 'Gene', (106, 109))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))
107768	29663336	Tumors arising from noncutaneous sites (mucosal, acral, uveal) have significantly lower total numbers of mutations by several orders of magnitude, with uveal melanoma being a particularly genomically simple tumor, thus demonstrating that ultraviolet light is not the only driver of melanogenesis.	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('uveal melanoma', 'Phenotype', 'HP:0007716', (152, 166))	('uveal melanoma', 'Disease', (152, 166))	('uveal melanoma', 'Disease', 'MESH:C536494', (152, 166))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (105, 114))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('lower', 'NegReg', (82, 87))
107769	29663336	Age is also a factor with younger patients (<40 years) more likely to have BRAF V600E mutations.	('V600E', 'Var', (80, 85))	('BRAF', 'Gene', (75, 79))	('patients', 'Species', '9606', (34, 42))	('V600E', 'Mutation', 'rs113488022', (80, 85))
107770	29663336	Acral melanomas arising on the palms, soles, and nailbeds have mutations in BRAF, NRAS, and KIT in approximately 15% each.	('BRAF', 'Gene', (76, 80))	('mutations', 'Var', (63, 72))	('Acral melanomas', 'Disease', (0, 15))	('Acral melanomas', 'Disease', 'MESH:D008545', (0, 15))	('KIT', 'molecular_function', 'GO:0005020', ('92', '95'))	('NRAS', 'Gene', (82, 86))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('Acral melanomas', 'Phenotype', 'HP:0012060', (0, 15))	('KIT', 'Gene', (92, 95))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('NRAS', 'Gene', '4893', (82, 86))
107771	29663336	Mucosal melanomas, by contrast, have only infrequent BRAF or NRAS mutations, but have KIT mutations in about 15% (primarily in genitourinary or anal, rather than sinonasal melanomas).	('mutations', 'Var', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('mutations', 'Var', (90, 99))	('melanomas', 'Disease', 'MESH:D008545', (172, 181))	('melanomas', 'Disease', 'MESH:D008545', (8, 17))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('BRAF', 'Gene', (53, 57))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('Mucosal melanomas', 'Disease', (0, 17))	('melanomas', 'Disease', (172, 181))	('NRAS', 'Gene', (61, 65))	('genitourinary', 'Disease', (127, 140))	('KIT', 'molecular_function', 'GO:0005020', ('86', '89'))	('NRAS', 'Gene', '4893', (61, 65))	('melanomas', 'Phenotype', 'HP:0002861', (172, 181))	('Mucosal melanomas', 'Disease', 'MESH:D008545', (0, 17))	('melanomas', 'Disease', (8, 17))
107772	29663336	Uveal melanomas have totally distinct genomic patterns, and harbor mutations either in GNAQ or GNA11 in >90%, while, BAP1, SF3B1, and EIFAX are generally distinct subsets and non-overlapping.	('GNAQ', 'Gene', '2776', (87, 91))	('BAP1', 'Gene', '8314', (117, 121))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('SF3B1', 'Gene', (123, 128))	('GNA11', 'Gene', (95, 100))	('melanomas', 'Disease', (6, 15))	('mutations', 'Var', (67, 76))	('BAP1', 'Gene', (117, 121))	('GNA11', 'Gene', '2767', (95, 100))	('GNAQ', 'Gene', (87, 91))	('SF3B1', 'Gene', '23451', (123, 128))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))
107777	29663336	Intermediate lesions acquired other mutations, such as TERT promoter mutations, or by contrast, had NRAS mutations.	('NRAS', 'Gene', '4893', (100, 104))	('mutations', 'Var', (105, 114))	('TERT', 'Gene', (55, 59))	('TERT', 'Gene', '7015', (55, 59))	('NRAS', 'Gene', (100, 104))
107778	29663336	Invasive melanomas often acquired CDKN2A loss, PTEN loss, or TP53 mutations.	('mutations', 'Var', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('TP53', 'Gene', '7157', (61, 65))	('melanomas', 'Phenotype', 'HP:0002861', (9, 18))	('melanomas', 'Disease', 'MESH:D008545', (9, 18))	('PTEN loss', 'Disease', 'MESH:D006223', (47, 56))	('CDKN2A', 'Gene', (34, 40))	('loss', 'NegReg', (41, 45))	('melanomas', 'Disease', (9, 18))	('TP53', 'Gene', (61, 65))	('PTEN loss', 'Disease', (47, 56))
107780	29663336	While ultraviolet light is a major culprit in driving mutagenesis and progression, other pathways, such pheomelanin generated oxidative damage in the red hair/fair skin phenotype, exemplified by patients or mice with MC1R gene polymorphisms.	('oxidative damage', 'MPA', (126, 142))	('pheomelanin', 'Chemical', 'MESH:C018362', (104, 115))	('MC1R', 'Gene', '17199', (217, 221))	('hair/fair skin', 'Phenotype', 'HP:0002286', (154, 168))	('MC1R', 'Gene', (217, 221))	('fair skin', 'Phenotype', 'HP:0007513', (159, 168))	('mice', 'Species', '10090', (207, 211))	('patients', 'Species', '9606', (195, 203))	('mutagenesis', 'biological_process', 'GO:0006280', ('54', '65'))	('polymorphisms', 'Var', (227, 240))	('mutagenesis', 'Var', (54, 65))	('red hair', 'Disease', (150, 158))	('red hair', 'Phenotype', 'HP:0002297', (150, 158))	('red hair', 'Disease', 'MESH:C567091', (150, 158))
107785	29663336	On the higher end of the spectrum, carcinogen induced cancers, including cancers of the cervix, bladder, head and neck, and lung, typically have a median of 5-10 mutations/MB, although intratumoral variation is quite high.	('cancers', 'Disease', (73, 80))	('mutations/MB', 'Var', (162, 174))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('neck', 'cellular_component', 'GO:0044326', ('114', '118'))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('lung', 'Disease', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('tumor', 'Disease', (190, 195))	('bladder', 'Disease', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
107786	29663336	Melanoma is at the highest end of the spectrum, with a median of >10 mutations/MB and many tumors with 10-fold greater mutation numbers.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Disease', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanoma', 'Disease', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mutations/MB', 'Var', (69, 81))
107787	29663336	Interestingly, normal human skin has also been found to have approximately 2-6 mutations/MB, similar to many solid tumors.	('solid tumors', 'Disease', (109, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('solid tumors', 'Disease', 'MESH:D009369', (109, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('mutations/MB', 'Var', (79, 91))	('human', 'Species', '9606', (22, 27))
107795	29663336	Regardless of the mechanism, mutation burden has been clearly linked, in multiple tumor types to response to immune therapy.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mutation burden', 'Var', (29, 44))	('tumor', 'Disease', (82, 87))	('linked', 'Reg', (62, 68))
107797	29663336	In this study, patients who had durable clinical benefit (>6mos of stable or responsive disease) had substantially higher mutation numbers compared with those who failed to respond.	('higher', 'PosReg', (115, 121))	('patients', 'Species', '9606', (15, 23))	('mutation numbers', 'Var', (122, 138))
107800	29663336	Two studies that performed whole exome sequencing on pre-treatment melanoma samples, and found that high mutation numbers correlated with improved clinical outcomes after treatment.	('high mutation numbers', 'Var', (100, 121))	('improved', 'PosReg', (138, 146))	('clinical outcomes', 'CPA', (147, 164))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('pre', 'molecular_function', 'GO:0003904', ('53', '56'))
107801	29663336	Other studies have also strongly correlated mutation load, as determined by whole exome sequencing, with improved clinical outcomes to anti-PD-1 in non-small cell lung cancer  and microsatellite unstable cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('non-small cell lung cancer', 'Disease', (148, 174))	('mutation load', 'Var', (44, 57))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (152, 174))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (148, 174))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (148, 174))	('anti-PD-1', 'Gene', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('improved', 'PosReg', (105, 113))	('microsatellite unstable cancers', 'Disease', 'MESH:D053842', (180, 211))	('microsatellite unstable cancers', 'Disease', (180, 211))
107804	29663336	NF1 mutations, likely as a surrogate for highly mutated melanomas, also correlated with improved clinical outcomes.	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanomas', 'Disease', (56, 65))	('NF1', 'Gene', (0, 3))	('improved', 'PosReg', (88, 96))	('mutations', 'Var', (4, 13))	('melanomas', 'Disease', 'MESH:D008545', (56, 65))	('clinical outcomes', 'CPA', (97, 114))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
107806	29663336	Mutation burden calculated with a platform of 170 genes performed at MD Anderson also correlated with response to ipilimumab and adoptive T cell therapy (in melanoma) and anti-PD-1 (in NSCLC).	('anti-PD-1', 'Var', (171, 180))	('correlated', 'Reg', (86, 96))	('NSCLC', 'Disease', 'MESH:D002289', (185, 190))	('ipilimumab', 'Chemical', 'MESH:D000074324', (114, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (185, 190))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('NSCLC', 'Disease', (185, 190))
107809	29663336	In 2002, BRAF mutations were found to occur frequently in up to 66% of patients with melanoma.	('BRAF', 'Gene', (9, 13))	('patients', 'Species', '9606', (71, 79))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('mutations', 'Var', (14, 23))
107811	29663336	Subsequent studies have confirmed the incidence of BRAF mutations as approximately 40-50% in patients with cutaneous melanoma (Figure).	('mutations', 'Var', (56, 65))	('cutaneous melanoma', 'Disease', (107, 125))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (107, 125))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (107, 125))	('BRAF', 'Gene', (51, 55))	('patients', 'Species', '9606', (93, 101))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
107812	29663336	The most common mutation in BRAF is a substitution of glutamic acid for valine at amino acid 600 (V600E) accounting for 70-88% of all BRAF mutations.	('mutations', 'Var', (139, 148))	('glutamic acid for valine at amino acid 600', 'Mutation', 'rs113488022', (54, 96))	('V600E', 'Mutation', 'rs113488022', (98, 103))	('BRAF', 'Gene', (134, 138))	('substitution', 'Var', (38, 50))	('BRAF', 'Gene', (28, 32))	('V600E', 'Var', (98, 103))
107813	29663336	Less common mutations in BRAF include V600K, V600R, and V600M, comprising 11-20%, 2-5%, and 1-4% of BRAF mutations respectively.	('V600R', 'Mutation', 'rs121913227', (45, 50))	('V600K', 'Mutation', 'rs121913227', (38, 43))	('V600R', 'Var', (45, 50))	('V600M', 'Var', (56, 61))	('V600M', 'Mutation', 'rs121913378', (56, 61))	('BRAF', 'Gene', (25, 29))	('V600K', 'Var', (38, 43))
107814	29663336	Other, non-V600 alterations in BRAF occur in approximately 5% of all melanomas, most commonly at codons 466, 469, 597, and 601, and BRAF fusions.	('non-V600 alterations', 'Var', (7, 27))	('codons 466', 'Var', (97, 107))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanomas', 'Disease', (69, 78))	('fusions', 'Var', (137, 144))	('occur', 'Reg', (36, 41))	('melanomas', 'Disease', 'MESH:D008545', (69, 78))	('melanomas', 'Phenotype', 'HP:0002861', (69, 78))	('BRAF', 'Gene', (31, 35))
107815	29663336	Melanomas that arise on skin with intermittent sun exposure are more likely to have a BRAF mutation than melanomas on chronically sun-exposed skin, unexposed skin, or mucosal melanomas.	('mutation', 'Var', (91, 99))	('melanomas', 'Disease', (105, 114))	('melanomas', 'Disease', (175, 184))	('mucosal melanomas', 'Disease', (167, 184))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('unexposed skin', 'Phenotype', 'HP:0010648', (148, 162))	('Melanomas', 'Disease', (0, 9))	('mucosal melanomas', 'Disease', 'MESH:D008545', (167, 184))	('melanomas', 'Phenotype', 'HP:0002861', (105, 114))	('melanomas', 'Phenotype', 'HP:0002861', (175, 184))	('melanomas', 'Disease', 'MESH:D008545', (105, 114))	('melanomas', 'Disease', 'MESH:D008545', (175, 184))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('BRAF', 'Gene', (86, 90))
107816	29663336	Other clinicopathologic features that have been associated with BRAF mutant melanoma include younger age, superficial spreading or nodular melanoma, presence of mitoses, occult primary melanoma, and truncal location.	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('melanoma', 'Disease', (76, 84))	('nodular melanoma', 'Disease', 'MESH:D020518', (131, 147))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('mutant', 'Var', (69, 75))	('nodular melanoma', 'Disease', (131, 147))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('BRAF', 'Gene', (64, 68))	('melanoma', 'Disease', (139, 147))	('nodular melanoma', 'Phenotype', 'HP:0012058', (131, 147))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('mitoses', 'CPA', (161, 168))	('melanoma', 'Disease', (185, 193))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
107818	29663336	BRAF mutations are an acquired event and found in 70-80% of nevi, and tend to occur more often in melanomas arising from pre-existing nevi.	('melanomas', 'Disease', (98, 107))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('mutations', 'Var', (5, 14))	('nevi', 'Phenotype', 'HP:0003764', (60, 64))	('melanomas', 'Disease', 'MESH:D008545', (98, 107))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('BRAF', 'Gene', (0, 4))	('nevi', 'Phenotype', 'HP:0003764', (134, 138))	('occur', 'Reg', (78, 83))	('pre', 'molecular_function', 'GO:0003904', ('121', '124'))
107820	29663336	BRAF mutations are frequent in melanocytic nevi and vertical growth phase melanomas but infrequent in radial growth phase and in situ melanomas.	('situ melanomas', 'Disease', 'MESH:D008545', (129, 143))	('melanomas', 'Disease', (134, 143))	('frequent', 'Reg', (19, 27))	('melanomas', 'Phenotype', 'HP:0002861', (74, 83))	('mutations', 'Var', (5, 14))	('melanomas', 'Disease', 'MESH:D008545', (74, 83))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('situ melanomas', 'Disease', (129, 143))	('melanomas', 'Disease', 'MESH:D008545', (134, 143))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanomas', 'Phenotype', 'HP:0002861', (134, 143))	('nevi', 'Phenotype', 'HP:0003764', (43, 47))	('BRAF', 'Gene', (0, 4))	('melanocytic nevi', 'Disease', (31, 47))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (31, 47))	('melanomas', 'Disease', (74, 83))
107821	29663336	Thus, while BRAF mutations clearly drive melanoma growth and progression, they are insufficient by themselves to induce melanomas.	('BRAF', 'Gene', (12, 16))	('progression', 'CPA', (61, 72))	('melanoma growth', 'Disease', (41, 56))	('melanomas', 'Disease', (120, 129))	('melanoma growth', 'Disease', 'MESH:D008545', (41, 56))	('insufficient', 'Disease', (83, 95))	('drive', 'Reg', (35, 40))	('insufficient', 'Disease', 'MESH:D000309', (83, 95))	('melanomas', 'Disease', 'MESH:D008545', (120, 129))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanomas', 'Phenotype', 'HP:0002861', (120, 129))	('mutations', 'Var', (17, 26))
107822	29663336	Melanomagenesis requires cooperation between mutant BRAF and other pathways.	('mutant', 'Var', (45, 51))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanomagenesis', 'Disease', 'None', (0, 15))	('BRAF', 'Gene', (52, 56))	('Melanomagenesis', 'Disease', (0, 15))
107823	29663336	Mouse models have demonstrated that concurrent BRAF activating mutations and PTEN inactivating mutations result in melanomagenesis.	('activating mutations', 'Var', (52, 72))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('BRAF', 'Gene', (47, 51))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('inactivating', 'NegReg', (82, 94))	('result in', 'Reg', (105, 114))	('PTEN', 'Gene', (77, 81))	('Mouse', 'Species', '10090', (0, 5))
107825	29663336	However, when BRAF/CDKN2A mutant mice also have loss of Lkb1, they demonstrate marked activation of mTORC2/Akt resulting in rapidly progressive melanomas.	('loss', 'NegReg', (48, 52))	('mTORC2', 'cellular_component', 'GO:0031932', ('100', '106'))	('activation', 'PosReg', (86, 96))	('Akt', 'Gene', (107, 110))	('melanomas', 'Disease', (144, 153))	('Lkb1', 'Gene', '20869', (56, 60))	('melanomas', 'Disease', 'MESH:D008545', (144, 153))	('mice', 'Species', '10090', (33, 37))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanomas', 'Phenotype', 'HP:0002861', (144, 153))	('mutant', 'Var', (26, 32))	('mTORC2', 'Gene', (100, 106))	('Lkb1', 'Gene', (56, 60))	('Akt', 'Gene', '11651', (107, 110))	('mTORC2', 'Gene', '74343', (100, 106))
107827	29663336	The key clinical relevance of BRAF mutations lies in their response to BRAF and/or MEK inhibitors.	('MEK', 'Gene', (83, 86))	('MEK', 'Gene', '5609', (83, 86))	('BRAF', 'Gene', (30, 34))	('response', 'MPA', (59, 67))	('mutations', 'Var', (35, 44))
107828	29663336	Available evidence suggests that various BRAF V600 mutations have similar capacity to respond to these therapies, although response rates may be less with V600K mutations compared with V600E.	('less', 'NegReg', (145, 149))	('V600K', 'Var', (155, 160))	('V600K', 'Mutation', 'rs121913227', (155, 160))	('V600E', 'Mutation', 'rs113488022', (185, 190))	('BRAF V600', 'Gene', (41, 50))
107832	29663336	Importantly, available evidence suggests that BRAF mutations predispose to response to BRAF/MEK inhibition in other cancers, including lung cancer, thyroid cancer, and hematologic malignancies.	('mutations', 'Var', (51, 60))	('thyroid cancer', 'Disease', (148, 162))	('response', 'MPA', (75, 83))	('lung cancer', 'Disease', (135, 146))	('BRAF', 'Gene', (46, 50))	('MEK', 'Gene', '5609', (92, 95))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('thyroid cancer', 'Disease', 'MESH:D013964', (148, 162))	('MEK', 'Gene', (92, 95))	('thyroid cancer', 'Phenotype', 'HP:0002890', (148, 162))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('hematologic malignancies', 'Disease', (168, 192))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('hematologic malignancies', 'Disease', 'MESH:D019337', (168, 192))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancers', 'Disease', (116, 123))	('predispose', 'Reg', (61, 71))
107835	29663336	A variety of mutations appear to arise in the context of acquired resistance, and reignite MAPK signaling (or parallel signaling networks) despite the presence of BRAF inhibition, and include mutations in NRAS, PI3K/AKT pathway members, and amplification and alternative splicing of BRAF.	('BRAF', 'Gene', (163, 167))	('MAPK', 'molecular_function', 'GO:0004707', ('91', '95'))	('NRAS', 'Gene', (205, 209))	('alternative splicing', 'Var', (259, 279))	('BRAF', 'Gene', (283, 287))	('splicing', 'biological_process', 'GO:0045292', ('271', '279'))	('NRAS', 'Gene', '4893', (205, 209))	('reignite', 'NegReg', (82, 90))	('PI3K/AKT pathway', 'Pathway', (211, 227))	('inhibition', 'NegReg', (168, 178))	('MAPK signaling', 'Pathway', (91, 105))	('MAPK signaling', 'biological_process', 'GO:0000165', ('91', '105'))	('mutations', 'Var', (13, 22))	('amplification', 'Var', (241, 254))	('mutations', 'Var', (192, 201))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))	('PI3K', 'molecular_function', 'GO:0016303', ('211', '215'))
107836	29663336	Unraveling intrinsic resistance has been a greater challenge, although pre-existing mutations in PTEN and MAP2K1 appear to correlate with shorter responses .	('PTEN', 'Gene', (97, 101))	('shorter', 'NegReg', (138, 145))	('MAP2K', 'molecular_function', 'GO:0004708', ('106', '111'))	('mutations', 'Var', (84, 93))	('MAP2K1', 'Gene', '5604', (106, 112))	('MAP2K1', 'Gene', (106, 112))	('pre', 'molecular_function', 'GO:0003904', ('71', '74'))
107837	29663336	The 5% of melanomas harboring non-V600 mutations have less clear therapeutic relevance.	('non-V600 mutations', 'Var', (30, 48))	('melanomas', 'Disease', (10, 19))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('melanomas', 'Disease', 'MESH:D008545', (10, 19))
107842	29663336	It remains controversial whether to select targeted therapy (BRAF/MEK inhibitors) or immune therapy as initial therapy in the BRAF mutant population.	('mutant', 'Var', (131, 137))	('MEK', 'Gene', (66, 69))	('MEK', 'Gene', '5609', (66, 69))
107847	29663336	NRAS mutations constitutively activate the MAPK, PI3K, and other cell signaling pathways causing cell growth, proliferation, and cell cycle dysfunction.	('activate', 'PosReg', (30, 38))	('signaling', 'biological_process', 'GO:0023052', ('70', '79'))	('cell growth', 'CPA', (97, 108))	('cell growth', 'biological_process', 'GO:0016049', ('97', '108'))	('cell signaling pathways', 'Pathway', (65, 88))	('mutations', 'Var', (5, 14))	('MAPK', 'Pathway', (43, 47))	('PI3K', 'molecular_function', 'GO:0016303', ('49', '53'))	('NRAS', 'Gene', (0, 4))	('cell cycle dysfunction', 'Phenotype', 'HP:0011018', (129, 151))	('PI3K', 'Pathway', (49, 53))	('cell cycle dysfunction', 'CPA', (129, 151))	('MAPK', 'molecular_function', 'GO:0004707', ('43', '47'))	('NRAS', 'Gene', '4893', (0, 4))	('cell cycle', 'biological_process', 'GO:0007049', ('129', '139'))
107848	29663336	NRAS mutations occur in >20% of patients with cutaneous melanoma, most commonly in codon 61 and less commonly in codons 12 and 13.	('patients', 'Species', '9606', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mutations', 'Var', (5, 14))	('cutaneous melanoma', 'Disease', (46, 64))	('NRAS', 'Gene', (0, 4))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (46, 64))	('NRAS', 'Gene', '4893', (0, 4))
107849	29663336	Melanomas with NRAS mutations are associated with an aggressive clinical course and poor prognosis.	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('NRAS', 'Gene', (15, 19))	('Melanomas', 'Disease', (0, 9))	('NRAS', 'Gene', '4893', (15, 19))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('mutations', 'Var', (20, 29))
107851	29663336	Initial early responses to the MEK inhibitor binimetinib led to a phase III study where binimetinib was compared with chemotherapy in patients with NRAS mutant melanoma.	('NRAS', 'Gene', (148, 152))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('MEK', 'Gene', (31, 34))	('melanoma', 'Disease', (160, 168))	('MEK', 'Gene', '5609', (31, 34))	('NRAS', 'Gene', '4893', (148, 152))	('patients', 'Species', '9606', (134, 142))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('mutant', 'Var', (153, 159))	('binimetinib', 'Chemical', 'MESH:C581313', (88, 99))	('binimetinib', 'Chemical', 'MESH:C581313', (45, 56))
107854	29663336	One study suggested that NRAS mutations may correspond with response to anti-PD-1 but the sample size was small.	('NRAS', 'Gene', (25, 29))	('mutations', 'Var', (30, 39))	('correspond', 'Reg', (44, 54))	('NRAS', 'Gene', '4893', (25, 29))
107857	29663336	Mutations in KIT occur in 1-3% of all melanomas and are most commonly found in exon 11 (L576P) or exon 13 (K642E).	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('KIT', 'molecular_function', 'GO:0005020', ('13', '16'))	('melanomas', 'Disease', (38, 47))	('L576P', 'Var', (88, 93))	('K642E', 'Var', (107, 112))	('Mutations', 'Var', (0, 9))	('K642E', 'Mutation', 'rs121913512', (107, 112))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('L576P', 'Mutation', 'rs121913513', (88, 93))	('KIT', 'Gene', (13, 16))	('melanomas', 'Disease', 'MESH:D008545', (38, 47))	('found', 'Reg', (70, 75))
107858	29663336	KIT mutations occur more commonly found in acral or mucosal melanomas (~15% each, in vulvovaginal more often than sinonasal) and in areas of chronic sun damage (~2%).	('acral', 'Disease', (43, 48))	('sun damage', 'Phenotype', 'HP:0000992', (149, 159))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('mucosal melanomas', 'Disease', (52, 69))	('found', 'Reg', (34, 39))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('mutations', 'Var', (4, 13))	('mucosal melanomas', 'Disease', 'MESH:D008545', (52, 69))	('KIT', 'Gene', (0, 3))
107860	29663336	Responses to treatment in patients with exon 11 mutations occur in the range of 30-50%, although acquired resistance typically occurs within one year.	('mutations', 'Var', (48, 57))	('patients', 'Species', '9606', (26, 34))	('exon 11', 'Gene', (40, 47))
107862	29663336	The neurofibromatosis type 1, NF1, gene product is a GTPase activating protein dampens MAPK signaling by downregulating RAS activity, and mutations and/or loss of NF1 leads to MAPK activation.	('MAPK', 'molecular_function', 'GO:0004707', ('87', '91'))	('MAPK', 'Pathway', (176, 180))	('MAPK signaling', 'MPA', (87, 101))	('leads to', 'Reg', (167, 175))	('loss', 'NegReg', (155, 159))	('neurofibromatosis type 1', 'Gene', (4, 28))	('MAPK signaling', 'biological_process', 'GO:0000165', ('87', '101'))	('MAPK', 'molecular_function', 'GO:0004707', ('176', '180'))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (4, 21))	('NF1', 'Gene', (163, 166))	('RAS', 'Protein', (120, 123))	('activity', 'MPA', (124, 132))	('MAPK activation', 'biological_process', 'GO:0000187', ('176', '191'))	('activation', 'PosReg', (181, 191))	('downregulating', 'NegReg', (105, 119))	('mutations', 'Var', (138, 147))	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('dampens', 'NegReg', (79, 86))	('neurofibromatosis type 1', 'Gene', '4763', (4, 28))
107863	29663336	NF1 mutations define the third most common genomically defined subset of melanoma and occur in 14% of the TCGA melanoma samples, including up to 70% of BRAF/NRAS wildtype samples.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('NRAS', 'Gene', (157, 161))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('NRAS', 'Gene', '4893', (157, 161))
107864	29663336	Most NF1 mutations lead to a loss of function of this tumor suppressor, with about 80% of patients having a nonsense mutation, an insertion, or a deletion that leads to a truncated protein.	('leads', 'Reg', (160, 165))	('deletion', 'Var', (146, 154))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('54', '70'))	('NF1', 'Gene', (5, 8))	('insertion', 'Var', (130, 139))	('mutations', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('truncated protein', 'MPA', (171, 188))	('tumor suppressor', 'biological_process', 'GO:0051726', ('54', '70'))	('tumor', 'Disease', (54, 59))	('loss of function', 'NegReg', (29, 45))	('protein', 'cellular_component', 'GO:0003675', ('181', '188'))	('patients', 'Species', '9606', (90, 98))
107865	29663336	In co-occuring BRAF/NF1 mutant tumors in mice, there is insensitivity to BRAF inhibitor therapy, presumably due to NF1 loss of function leading to the dysregulation of the PI3K/AKT/mTOR pathway.	('mutant', 'Var', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('loss of function', 'NegReg', (119, 135))	('NF1', 'Gene', (115, 118))	('mice', 'Species', '10090', (41, 45))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('PI3K/AKT/mTOR pathway', 'Pathway', (172, 193))	('BRAF/NF1', 'Gene', (15, 23))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('PI3K', 'molecular_function', 'GO:0016303', ('172', '176'))	('dysregulation', 'MPA', (151, 164))
107867	29663336	"Pan-RAF" or type II RAF inhibitors in combination with MEK inhibitors, or PI3K/mTOR inhibitors could be considered in NF1 mutated melanomas.	('RAF', 'Gene', (21, 24))	('melanomas', 'Disease', 'MESH:D008545', (131, 140))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('MEK', 'Gene', '5609', (56, 59))	('PI3K', 'molecular_function', 'GO:0016303', ('73', '77'))	('NF1', 'Gene', (119, 122))	('melanomas', 'Phenotype', 'HP:0002861', (131, 140))	('melanomas', 'Disease', (131, 140))	('RAF', 'Gene', '22882', (5, 8))	('MEK', 'Gene', (56, 59))	('RAF', 'Gene', (5, 8))	('mutated', 'Var', (123, 130))	('RAF', 'Gene', '22882', (21, 24))
107868	29663336	NF1 mutations seem to be correlated with the strongest UV signature and a high mutational burden and so there is rationale for using immunotherapeutic agents in this patient population.	('UV signature', 'MPA', (55, 67))	('mutational burden', 'MPA', (79, 96))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('patient', 'Species', '9606', (166, 173))
107870	29663336	Mutations in CDKN2A specifically occurred in 13% of tumors with another ~30% harboring CKDN2A deletions.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('occurred', 'Reg', (33, 41))	('tumors', 'Disease', (52, 58))	('CDKN2A', 'Gene', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('Mutations', 'Var', (0, 9))	('deletions', 'Var', (94, 103))
107871	29663336	Mutations in the p16/CDK4/cyclinD1 pathway have been implicated in melanomagenesis.	('implicated', 'Reg', (53, 63))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('p16', 'Gene', (17, 20))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('CDK', 'molecular_function', 'GO:0004693', ('21', '24'))	('Mutations', 'Var', (0, 9))	('CDK4', 'Gene', (21, 25))	('CDK4', 'Gene', '1019', (21, 25))	('p16', 'Gene', '1029', (17, 20))
107872	29663336	CDKN2A mutations that result in p16 loss are often seen in familial melanomas.	('seen', 'Reg', (51, 55))	('familial melanomas', 'Disease', 'OMIM:155600', (59, 77))	('familial melanomas', 'Disease', (59, 77))	('p16', 'Gene', '1029', (32, 35))	('loss', 'NegReg', (36, 40))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanomas', 'Phenotype', 'HP:0002861', (68, 77))	('CDKN2A', 'Gene', (0, 6))	('p16', 'Gene', (32, 35))	('mutations', 'Var', (7, 16))
107874	29663336	CDK4 and CCND1 amplifications are seen more frequently in triple-wildtype melanomas.	('CCND1', 'Gene', (9, 14))	('melanomas', 'Phenotype', 'HP:0002861', (74, 83))	('CDK', 'molecular_function', 'GO:0004693', ('0', '3'))	('CCND1', 'Gene', '595', (9, 14))	('melanomas', 'Disease', 'MESH:D008545', (74, 83))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('CDK4', 'Gene', (0, 4))	('amplifications', 'Var', (15, 29))	('CDK4', 'Gene', '1019', (0, 4))	('melanomas', 'Disease', (74, 83))
107875	29663336	While it has been hypothesized that mutations in this pathway may contribute to sensitivity to CDK4/6 inhibitors, this has yet to be shown conclusively in the clinic.	('CDK4/6', 'Gene', '1019;1021', (95, 101))	('CDK', 'molecular_function', 'GO:0004693', ('95', '98'))	('mutations', 'Var', (36, 45))	('sensitivity to', 'MPA', (80, 94))	('CDK4/6', 'Gene', (95, 101))	('contribute', 'Reg', (66, 76))
107877	29663336	The TP53 mutations were frequently found in melanomas harboring any of the major subsets of BRAF, NRAS, and NF1 mutated tumors.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('melanomas', 'Disease', (44, 53))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('TP53', 'Gene', (4, 8))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('mutations', 'Var', (9, 18))	('NRAS', 'Gene', (98, 102))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('melanomas', 'Disease', 'MESH:D008545', (44, 53))	('NRAS', 'Gene', '4893', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('TP53', 'Gene', '7157', (4, 8))	('found', 'Reg', (35, 40))
107878	29663336	In comparison, in triple-wildtype tumors, there was an increased prevalence of MDM2 amplifications.	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Disease', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('amplifications', 'Var', (84, 98))	('MDM2', 'Gene', '4193', (79, 83))	('MDM2', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
107880	29663336	As mentioned, a host of other low-frequency mutations occur in melanoma and are difficult to interpret clinically.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('mutations', 'Var', (44, 53))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('occur', 'Reg', (54, 59))
107881	29663336	PTEN mutations or deep deletions occur in <10% of melanomas and activate P13K/AKT signaling.	('deep deletions', 'Var', (18, 32))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('melanomas', 'Disease', 'MESH:D008545', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('mutations', 'Var', (5, 14))	('P13K/AKT signaling', 'Pathway', (73, 91))	('P13K', 'Mutation', 'p.P13K', (73, 77))	('melanomas', 'Disease', (50, 59))	('PTEN', 'Gene', (0, 4))	('AKT signaling', 'biological_process', 'GO:0043491', ('78', '91'))	('activate', 'PosReg', (64, 72))
107883	29663336	Mutations in RAC1 occur in approximately 10% of sun-exposed melanomas and tend to co-occur with BRAF or NRAS mutations.	('co-occur', 'Reg', (82, 90))	('NRAS', 'Gene', '4893', (104, 108))	('melanomas', 'Disease', (60, 69))	('RAC1', 'Gene', '5879', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('Mutations', 'Var', (0, 9))	('melanomas', 'Disease', 'MESH:D008545', (60, 69))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('NRAS', 'Gene', (104, 108))	('RAC1', 'Gene', (13, 17))
107884	29663336	In vitro studies suggest that the primary "hotspot" mutation (RAC1 P29S) activates downstream signaling pathways, thus promoting proliferation and migration.	('RAC1', 'Gene', (62, 66))	('P29S', 'Mutation', 'rs1057519874', (67, 71))	('migration', 'CPA', (147, 156))	('signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('proliferation', 'CPA', (129, 142))	('RAC1', 'Gene', '5879', (62, 66))	('P29S', 'Var', (67, 71))	('activates', 'PosReg', (73, 82))	('promoting', 'PosReg', (119, 128))	('downstream signaling pathways', 'Pathway', (83, 112))
107885	29663336	Subsequent studies have suggested that this mutation may regulate PD-L1 expression and mediate resistance to BRAF and MEK inhibitors, although this mutation does not preclude clinical responses.	('mutation', 'Var', (44, 52))	('regulate', 'Reg', (57, 65))	('PD-L1', 'Gene', '29126', (66, 71))	('expression', 'MPA', (72, 82))	('MEK', 'Gene', (118, 121))	('mediate', 'Reg', (87, 94))	('MEK', 'Gene', '5609', (118, 121))	('PD-L1', 'Gene', (66, 71))
107886	29663336	Mutations in TERT (telomerase reverse transcriptase) are somewhat unique in that they usually occur in the promoter, rather than the coding region, leading to increased gene expression.	('TERT', 'Gene', (13, 17))	('TERT', 'Gene', '7015', (13, 17))	('increased', 'PosReg', (159, 168))	('transcriptase', 'molecular_function', 'GO:0003899', ('38', '51'))	('telomerase reverse transcriptase', 'Gene', (19, 51))	('Mutations', 'Var', (0, 9))	('gene expression', 'biological_process', 'GO:0010467', ('169', '184'))	('transcriptase', 'molecular_function', 'GO:0003968', ('38', '51'))	('transcriptase', 'molecular_function', 'GO:0034062', ('38', '51'))	('telomerase reverse transcriptase', 'Gene', '7015', (19, 51))	('gene expression', 'MPA', (169, 184))
107887	29663336	These mutations occur in most melanomas, including 69% of all melanomas, and 86% of cutaneous melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('melanomas', 'Disease', (30, 39))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('melanomas', 'Disease', 'MESH:D008545', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanomas', 'Disease', (62, 71))	('melanomas', 'Phenotype', 'HP:0002861', (30, 39))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (84, 103))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (84, 103))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (84, 102))	('melanomas', 'Disease', 'MESH:D008545', (30, 39))	('melanomas', 'Disease', 'MESH:D008545', (62, 71))	('melanomas', 'Disease', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('occur', 'Reg', (16, 21))	('mutations', 'Var', (6, 15))	('cutaneous melanomas', 'Disease', (84, 103))
107888	29663336	Mutations in these g-proteins occur in nearly 90% of uveal melanomas and occasionally non-uveal melanomas (but extremely rarely outside of the melanocytic tumor family).	('g-proteins', 'Protein', (19, 29))	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('uveal melanomas', 'Disease', (53, 68))	('uveal melanomas', 'Phenotype', 'HP:0007716', (53, 68))	('melanocytic tumor', 'Disease', (143, 160))	('uveal melanomas', 'Disease', 'MESH:C536494', (90, 105))	('Mutations', 'Var', (0, 9))	('melanomas', 'Phenotype', 'HP:0002861', (59, 68))	('non-uveal melanomas', 'Disease', 'MESH:C536494', (86, 105))	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('uveal melanomas', 'Phenotype', 'HP:0007716', (90, 105))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('occur', 'Reg', (30, 35))	('non-uveal melanomas', 'Disease', (86, 105))	('uveal melanomas', 'Disease', 'MESH:C536494', (53, 68))	('melanocytic tumor', 'Disease', 'MESH:D009508', (143, 160))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))
107889	29663336	These activating mutations trigger MAPK and PI3K/AKT signaling, likely through RasGRP3 and protein kinase C. The importance of MAPK signaling has led to trials of MEK inhibitors in uveal melanoma, although the results have largely been disappointing.	('MAPK', 'molecular_function', 'GO:0004707', ('127', '131'))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('MAPK', 'molecular_function', 'GO:0004707', ('35', '39'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('127', '141'))	('AKT signaling', 'biological_process', 'GO:0043491', ('49', '62'))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('RasGRP3', 'Gene', (79, 86))	('MEK', 'Gene', (163, 166))	('MEK', 'Gene', '5609', (163, 166))	('uveal melanoma', 'Phenotype', 'HP:0007716', (181, 195))	('uveal melanoma', 'Disease', 'MESH:C536494', (181, 195))	('RasGRP3', 'Gene', '25780', (79, 86))	('mutations', 'Var', (17, 26))	('uveal melanoma', 'Disease', (181, 195))	('PI3K', 'molecular_function', 'GO:0016303', ('44', '48'))
107890	29663336	Notably, several other genomic events correlate with prognosis in uveal melanoma, including SF3B1 mutations (good), BAP1 loss (poor), monosomy 3 (poor), and disomy 3 (good).	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('uveal melanoma', 'Disease', (66, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('BAP1', 'Gene', (116, 120))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('loss', 'NegReg', (121, 125))	('SF3B1', 'Gene', '23451', (92, 97))	('mutations', 'Var', (98, 107))	('disomy 3', 'Disease', (157, 165))	('monosomy 3', 'Disease', (134, 144))	('BAP1', 'Gene', '8314', (116, 120))	('SF3B1', 'Gene', (92, 97))
107891	29663336	MYC amplifications occur in up to 8% of melanomas and correlate with poor prognosis and lack of pigmentation .	('MYC', 'Gene', (0, 3))	('melanomas', 'Disease', (40, 49))	('pigmentation', 'Disease', 'MESH:D010859', (96, 108))	('pigmentation', 'Disease', (96, 108))	('amplifications', 'Var', (4, 18))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('pigmentation', 'biological_process', 'GO:0043473', ('96', '108'))	('melanomas', 'Disease', 'MESH:D008545', (40, 49))	('MYC', 'Gene', '4609', (0, 3))	('lack of pigmentation', 'Phenotype', 'HP:0200098', (88, 108))
107893	29663336	Mutations in the WNT/CTNNB1 pathway (primarily APC and CTNNB1) occur in approximately 10% of melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('APC', 'cellular_component', 'GO:0005680', ('47', '50'))	('APC', 'Disease', 'MESH:D011125', (47, 50))	('CTNNB1', 'Gene', '1499', (55, 61))	('occur', 'Reg', (63, 68))	('melanomas', 'Disease', 'MESH:D008545', (93, 102))	('APC', 'Disease', (47, 50))	('CTNNB1', 'Gene', (21, 27))	('CTNNB1', 'Gene', (55, 61))	('Mutations', 'Var', (0, 9))	('melanomas', 'Disease', (93, 102))	('CTNNB1', 'Gene', '1499', (21, 27))
107895	29663336	Finally, low frequency mutations in ARID2, PPP6C, MAP2K1, IDH1, RB1, and many others have been described .	('RB1', 'Gene', '5925', (64, 67))	('IDH1', 'Gene', '3417', (58, 62))	('MAP2K1', 'Gene', '5604', (50, 56))	('PPP6C', 'Gene', (43, 48))	('MAP2K1', 'Gene', (50, 56))	('ARID2', 'Gene', '196528', (36, 41))	('mutations', 'Var', (23, 32))	('ARID2', 'Gene', (36, 41))	('RB1', 'Gene', (64, 67))	('MAP2K', 'molecular_function', 'GO:0004708', ('50', '55'))	('PPP6C', 'Gene', '5537', (43, 48))	('IDH1', 'Gene', (58, 62))
107896	29663336	BRAF V600 mutations clearly predict sensitivity to inhibitors of BRAF and MEK, as do KIT exon 11 mutations to KIT inhibitors.	('MEK', 'Gene', '5609', (74, 77))	('predict', 'Reg', (28, 35))	('KIT', 'molecular_function', 'GO:0005020', ('85', '88'))	('V600 mutations', 'Var', (5, 19))	('BRAF', 'Gene', (0, 4))	('sensitivity', 'MPA', (36, 47))	('KIT', 'molecular_function', 'GO:0005020', ('110', '113'))	('MEK', 'Gene', (74, 77))
107897	29663336	In addition, other mutations such as NRAS or atypical BRAF mutations and others, may enable enrollment in clinical trials.	('NRAS', 'Gene', '4893', (37, 41))	('NRAS', 'Gene', (37, 41))	('mutations', 'Var', (59, 68))	('BRAF', 'Gene', (54, 58))
107957	29946532	C-KIT mutations occur most frequently in acral melanomas (10-20%) and MMs (15-20%).	('C-KIT', 'Gene', '3815', (0, 5))	('acral melanomas', 'Disease', (41, 56))	('acral melanomas', 'Phenotype', 'HP:0012060', (41, 56))	('acral melanomas', 'Disease', 'MESH:D008545', (41, 56))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('MMs', 'Chemical', 'MESH:D008741', (70, 73))	('C-KIT', 'Gene', (0, 5))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('MM', 'Phenotype', 'HP:0002861', (70, 72))	('KIT', 'molecular_function', 'GO:0005020', ('2', '5'))	('occur', 'Reg', (16, 21))	('mutations', 'Var', (6, 15))	('MMs', 'Disease', (70, 73))
107958	29946532	ALK mutations have been reported in spitzoid melanoma and can be associated with concomitant BRAF or NRAS mutation.	('BRAF', 'Gene', (93, 97))	('NRAS', 'Gene', (101, 105))	('reported', 'Reg', (24, 32))	('NRAS', 'Gene', '4893', (101, 105))	('spitzoid melanoma', 'Disease', 'MESH:D008545', (36, 53))	('spitzoid melanoma', 'Disease', (36, 53))	('associated', 'Reg', (65, 75))	('ALK', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('BRAF', 'Gene', '673', (93, 97))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('ALK', 'Gene', '238', (0, 3))
107960	29946532	The second layer is probably the site with the highest frequency of mutational events in melanoma ultimately responsible for constitutive activation of signaling pathways through G-protein, phosphatidyl-inositol or kinase-cascades.	('protein', 'cellular_component', 'GO:0003675', ('181', '188'))	('phosphatidyl-inositol', 'Chemical', 'MESH:D010716', (190, 211))	('G-protein', 'Protein', (179, 188))	('signaling', 'biological_process', 'GO:0023052', ('152', '161'))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('mutational', 'Var', (68, 78))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('signaling pathways', 'Pathway', (152, 170))	('activation', 'PosReg', (138, 148))	('phosphatidyl-inositol', 'MPA', (190, 211))
107961	29946532	For melanoma, point mutations have been described for the genes encoding G(q) alpha subunit proteins, GNAQ, and its paralog GNA11.	('GNA11', 'Gene', '2767', (124, 129))	('GNAQ', 'Gene', (102, 106))	('melanoma', 'Disease', (4, 12))	('point mutations', 'Var', (14, 29))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('GNA11', 'Gene', (124, 129))	('GNAQ', 'Gene', '2776', (102, 106))
107962	29946532	Mutations in these genes are often seen in UM, both in the primary tumor and metastases; however, they are infrequent (GNAQ) or absent (GNA11) in extraocular melanoma.	('ocular melanoma', 'Disease', 'MESH:D008545', (151, 166))	('ocular melanoma', 'Disease', (151, 166))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('GNA11', 'Gene', (136, 141))	('GNAQ', 'Gene', (119, 123))	('metastases', 'Disease', (77, 87))	('ocular melanoma', 'Phenotype', 'HP:0007716', (151, 166))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('GNA11', 'Gene', '2767', (136, 141))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (67, 72))	('metastases', 'Disease', 'MESH:D009362', (77, 87))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('GNAQ', 'Gene', '2776', (119, 123))
107964	29946532	Inactivation of PTEN promotes cell survival by downregulating pro-apoptotic signaling downstream of AKT and BAD pathways.	('cell survival', 'CPA', (30, 43))	('AKT', 'Gene', (100, 103))	('pro-apoptotic', 'MPA', (62, 75))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('promotes', 'PosReg', (21, 29))	('PTEN', 'Gene', (16, 20))	('downregulating', 'NegReg', (47, 61))	('PTEN', 'Gene', '5728', (16, 20))	('BAD pathways', 'Pathway', (108, 120))	('AKT', 'Gene', '207', (100, 103))	('Inactivation', 'Var', (0, 12))
107966	29946532	Within the third layer, several "effectors" were identified to be mutated in melanomas.	('mutated', 'Var', (66, 73))	('melanomas', 'Disease', (77, 86))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))
107969	29946532	Mutations in the TERT gene promoter are found in many cancers, including melanoma, where it has been reported that UVR signature mutations are seen in 33% of primary melanomas and in 85% of melanoma metastases.	('melanoma', 'Disease', (73, 81))	('melanomas', 'Phenotype', 'HP:0002861', (166, 175))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('melanoma metastases', 'Disease', 'MESH:D009362', (190, 209))	('cancers', 'Disease', (54, 61))	('TERT', 'Gene', (17, 21))	('melanomas', 'Disease', 'MESH:D008545', (166, 175))	('TERT', 'Gene', '7015', (17, 21))	('found', 'Reg', (40, 45))	('melanomas', 'Disease', (166, 175))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('mutations', 'Var', (129, 138))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('melanoma metastases', 'Disease', (190, 209))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
107989	29946532	Since dacarbazine was FDA approved in the 1970s, no other chemotherapy agents had been accepted for treatment of metastatic melanoma until two new main groups of drugs got the green light for clinical use: inhibitors of signaling of Ras-Raf-MEK-ERK pathway downstream different RTK (IGF-1R, KIT) and the immune checkpoint inhibitors.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('KIT', 'molecular_function', 'GO:0005020', ('291', '294'))	('melanoma', 'Disease', (124, 132))	('ERK', 'Gene', '5594', (245, 248))	('MEK', 'Gene', (241, 244))	('Raf', 'Gene', '22882', (237, 240))	('MEK', 'Gene', '5609', (241, 244))	('IGF-1R', 'Gene', '3480', (283, 289))	('ERK', 'Gene', (245, 248))	('IGF-1R', 'Gene', (283, 289))	('ERK', 'molecular_function', 'GO:0004707', ('245', '248'))	('men', 'Species', '9606', (105, 108))	('Raf', 'Gene', (237, 240))	('inhibitors', 'Var', (206, 216))	('dacarbazine', 'Chemical', 'MESH:D003606', (6, 17))	('signaling', 'biological_process', 'GO:0023052', ('220', '229'))
107991	29946532	One of the many results from this was the identification of high-frequency mutations in the BRAF and NRAS oncogenes.	('BRAF', 'Gene', '673', (92, 96))	('NRAS', 'Gene', (101, 105))	('NRAS', 'Gene', '4893', (101, 105))	('BRAF', 'Gene', (92, 96))	('mutations', 'Var', (75, 84))
107993	29946532	Activating BRAF mutations at codon 600 (mainly V600E) are found in approximately 50% of melanomas, particularly, in nodular and SSMs.	('Activating', 'PosReg', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('V600E', 'Mutation', 'rs113488022', (47, 52))	('SSM', 'Phenotype', 'HP:0012057', (128, 131))	('melanomas', 'Disease', 'MESH:D008545', (88, 97))	('V600E', 'Var', (47, 52))	('BRAF', 'Gene', '673', (11, 15))	('melanomas', 'Disease', (88, 97))	('BRAF', 'Gene', (11, 15))
108000	29946532	Currently, combination therapy with dual inhibition of BRAF and MEK is considered standard treatment for BRAF mutated melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('men', 'Species', '9606', (96, 99))	('MEK', 'Gene', (64, 67))	('melanoma', 'Disease', (118, 126))	('BRAF', 'Gene', '673', (105, 109))	('MEK', 'Gene', '5609', (64, 67))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('mutated', 'Var', (110, 117))	('BRAF', 'Gene', (105, 109))	('BRAF', 'Gene', '673', (55, 59))	('BRAF', 'Gene', (55, 59))
108013	29946532	Likewise, acquired resistance to drugs targeting RAF pathways develops in about 50% of responders 1 year after initiation of therapy and involved two main settings: (i) alternate activation of other components of the RAS/RAF/MEK/ERK (e.g., activating mutations in genes encoding MEK1, MEK2, or RAS proteins) or (ii) activations of the mechanisms initiating RAS/RAF pathways such as enhancement of RTKs signaling [e.g., platelet-derived growth factor receptor (PDGFR), MET, IGF-1R], hyper activation of the parallel PI3K-AKT pathway through PTEN mutations or upregulation of the transcription factors (e.g., STAT3, PAX3).	('RAF', 'Gene', '22882', (49, 52))	('AKT', 'Gene', '207', (520, 523))	('PTEN', 'Gene', '5728', (540, 544))	('MEK', 'Gene', (285, 288))	('enhancement', 'PosReg', (382, 393))	('upregulation', 'PosReg', (558, 570))	('RAF', 'Gene', (361, 364))	('MEK2', 'Gene', '5605', (285, 289))	('MEK2', 'Gene', (285, 289))	('PDGFR', 'Gene', (460, 465))	('MET', 'MPA', (468, 471))	('PDGFR', 'Gene', '5159', (460, 465))	('PI3K', 'molecular_function', 'GO:0016303', ('515', '519'))	('RTKs signaling', 'MPA', (397, 411))	('men', 'Species', '9606', (389, 392))	('ERK', 'molecular_function', 'GO:0004707', ('229', '232'))	('RAF', 'Gene', (49, 52))	('platelet-derived growth factor receptor', 'Gene', '5159', (419, 458))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('419', '449'))	('RAF', 'Gene', '22882', (221, 224))	('MEK1', 'Gene', '5604', (279, 283))	('platelet-derived growth factor receptor', 'Gene', (419, 458))	('MEK1', 'molecular_function', 'GO:0004708', ('279', '283'))	('MEK', 'Gene', '5609', (225, 228))	('ERK', 'Gene', '5594', (229, 232))	('MEK', 'Gene', '5609', (279, 282))	('AKT', 'Gene', (520, 523))	('mutations', 'Var', (545, 554))	('RAF', 'Gene', (221, 224))	('PAX3', 'Gene', (614, 618))	('signaling', 'biological_process', 'GO:0023052', ('402', '411'))	('MEK', 'Gene', (225, 228))	('STAT3', 'Gene', (607, 612))	('mutations', 'Var', (251, 260))	('hyper', 'PosReg', (482, 487))	('PTEN', 'Gene', (540, 544))	('transcription', 'biological_process', 'GO:0006351', ('578', '591'))	('MEK', 'Gene', (279, 282))	('RAF', 'Gene', '22882', (361, 364))	('MEK', 'Gene', '5609', (285, 288))	('ERK', 'Gene', (229, 232))	('IGF-1R', 'Gene', '3480', (473, 479))	('MEK2', 'molecular_function', 'GO:0004708', ('285', '289'))	('PAX3', 'Gene', '5077', (614, 618))	('STAT3', 'Gene', '6774', (607, 612))	('IGF-1R', 'Gene', (473, 479))	('MEK1', 'Gene', (279, 283))
108032	29946532	This is probably a result of the innate immunogenicity of melanomas tumors with their higher mutation burdens compared to other types of tumors.	('melanomas tumors', 'Disease', 'MESH:D008545', (58, 74))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('mutation', 'Var', (93, 101))	('melanomas tumors', 'Disease', (58, 74))	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))
108038	29946532	Few preclinical studies employing overexpression of specific RTKs or increased kinase activity mostly through activating mutations in melanoma have proved the concept of RTKs controlling the aggressive malignant melanoma phenotype as well as resistance to therapy.	('mutations', 'Var', (121, 130))	('malignant melanoma', 'Phenotype', 'HP:0002861', (202, 220))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))	('aggressive malignant melanoma', 'Disease', (191, 220))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('melanoma', 'Disease', (212, 220))	('kinase activity', 'molecular_function', 'GO:0016301', ('79', '94'))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('aggressive malignant melanoma', 'Disease', 'MESH:D008545', (191, 220))
108039	29946532	Mutations of the main RTKs transducer:RAS/BRAF:are events more frequent than mutations in RTKs, yet, mutated forms of RTK genes including KIT, ERBB1-4, PDGFR, the EPH and FGFR families, and others are known to govern abnormal signaling driving aberrant growth and survival of melanoma cells.	('BRAF', 'Gene', (42, 46))	('BRAF', 'Gene', '673', (42, 46))	('aberrant growth', 'Phenotype', 'HP:0001507', (244, 259))	('PDGFR', 'Gene', (152, 157))	('KIT', 'Gene', (138, 141))	('melanoma', 'Disease', (276, 284))	('PDGFR', 'Gene', '5159', (152, 157))	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('signaling', 'biological_process', 'GO:0023052', ('226', '235'))	('melanoma', 'Disease', 'MESH:D008545', (276, 284))	('ERBB1-4', 'Gene', '1956;2064;2065;2066', (143, 150))	('mutated', 'Var', (101, 108))	('KIT', 'molecular_function', 'GO:0005020', ('138', '141'))	('FGFR', 'molecular_function', 'GO:0005007', ('171', '175'))	('ERBB1-4', 'Gene', (143, 150))	('RTK genes', 'Gene', (118, 127))
108040	29946532	Among the RTK signaling activated through mutation, one of the best examples is probably represented by c-Kit.	('signaling', 'biological_process', 'GO:0023052', ('14', '23'))	('RTK signaling', 'MPA', (10, 23))	('mutation', 'Var', (42, 50))	('c-Kit', 'Gene', (104, 109))	('c-Kit', 'Gene', '3815', (104, 109))
108044	29946532	Even if c-kit seems to be downregulated during the development of normal melanocytes to melanoma with metastasizing potential, there is no evidence that c-kit-negative cells feature mutations in the KIT gene or in its promoter.	('downregulated', 'NegReg', (26, 39))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('c-kit', 'Gene', '3815', (153, 158))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('c-kit', 'Gene', (153, 158))	('mutations', 'Var', (182, 191))	('KIT', 'molecular_function', 'GO:0005020', ('199', '202'))	('c-kit', 'Gene', '3815', (8, 13))	('c-kit', 'Gene', (8, 13))	('men', 'Species', '9606', (58, 61))	('KIT', 'Gene', (199, 202))
108045	29946532	In contrast, among tumors expressing c-kit, gain-of-function mutations have been found in mastocytosis, seminomas, and in GISTs.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('gain-of-function', 'PosReg', (44, 60))	('mastocytosis', 'Phenotype', 'HP:0100495', (90, 102))	('GISTs', 'Disease', (122, 127))	('seminomas', 'Disease', 'MESH:D018239', (104, 113))	('seminomas', 'Disease', (104, 113))	('mutations', 'Var', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('c-kit', 'Gene', (37, 42))	('mastocytosis', 'Disease', 'MESH:D008415', (90, 102))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('c-kit', 'Gene', '3815', (37, 42))	('mastocytosis', 'Disease', (90, 102))
108046	29946532	Because all these neoplasms arise in tissues with development that is dependent on the activity of the SCF/c-kit axis, aberrant activation of this axis may be of pathogenic relevance.	('aberrant', 'Var', (119, 127))	('SCF', 'Gene', (103, 106))	('SCF', 'molecular_function', 'GO:0005173', ('103', '106'))	('SCF', 'Gene', '4254', (103, 106))	('c-kit', 'Gene', (107, 112))	('neoplasms', 'Disease', 'MESH:D009369', (18, 27))	('neoplasms', 'Disease', (18, 27))	('c-kit', 'Gene', '3815', (107, 112))	('neoplasms', 'Phenotype', 'HP:0002664', (18, 27))	('men', 'Species', '9606', (57, 60))
108047	29946532	Data from studies on GISTs showing a substantial proportion contain a mutation in exon 11 leading to ligand-independent c-kit activation, have shown that treatment with STI571, an inhibitor of PDGFR, Bcr-Abl, and c-kit tyrosine phosphorylation, causes tumor regression.	('c-kit', 'Gene', (120, 125))	('phosphorylation', 'biological_process', 'GO:0016310', ('228', '243'))	('c-kit', 'Gene', (213, 218))	('ligand', 'molecular_function', 'GO:0005488', ('101', '107'))	('men', 'Species', '9606', (159, 162))	('c-kit', 'Gene', '3815', (213, 218))	('STI571', 'Chemical', 'MESH:D000068877', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('PDGFR', 'Gene', (193, 198))	('tumor', 'Disease', (252, 257))	('activation', 'PosReg', (126, 136))	('PDGFR', 'Gene', '5159', (193, 198))	('Bcr-Abl', 'Gene', (200, 207))	('Bcr-Abl', 'Gene', '25', (200, 207))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('mutation in', 'Var', (70, 81))	('tyrosine', 'Chemical', 'MESH:D014443', (219, 227))	('c-kit', 'Gene', '3815', (120, 125))
108049	29946532	Yet, the clinical success of nearly all tyrosine-kinase inhibitors is predicted by the presence of activating mutations or substantial receptor overexpression as is the case with all RTKs presented in the section.	('activating', 'MPA', (99, 109))	('overexpression', 'PosReg', (144, 158))	('mutations', 'Var', (110, 119))	('tyrosine', 'Chemical', 'MESH:D014443', (40, 48))
108057	29946532	In melanoma, activating NRAS mutations (mainly at codon 61 and more rarely on codon 12-13) are found in approximately 20% of tumors.	('NRAS', 'Gene', '4893', (24, 28))	('activating', 'PosReg', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('mutations', 'Var', (29, 38))	('tumors', 'Disease', (125, 131))	('NRAS', 'Gene', (24, 28))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
108060	29946532	In melanoma, the MAPK pathway is hyper-activated in up to 75% of cases, primarily due to somatic-gain-of function mutations in BRAF (~50% of cases) or RAS (~25% of cases).	('mutations', 'Var', (114, 123))	('BRAF', 'Gene', '673', (127, 131))	('MAPK', 'molecular_function', 'GO:0004707', ('17', '21'))	('BRAF', 'Gene', (127, 131))	('hyper-activated', 'PosReg', (33, 48))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('somatic-gain-of function', 'PosReg', (89, 113))	('melanoma', 'Disease', (3, 11))	('MAPK pathway', 'Pathway', (17, 29))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('RAS', 'Gene', (151, 154))
108061	29946532	Activating BRAF mutations (mainly at codon 600) are found in approximately 50% of tumors, most often at V600E, V600K, or V600R.	('V600K', 'Var', (111, 116))	('Activating', 'PosReg', (0, 10))	('V600E', 'Mutation', 'rs113488022', (104, 109))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('V600R', 'Mutation', 'rs121913227', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('V600R', 'Var', (121, 126))	('V600E', 'Var', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('V600K', 'Mutation', 'rs121913227', (111, 116))	('BRAF', 'Gene', '673', (11, 15))	('BRAF', 'Gene', (11, 15))
108062	29946532	The second most frequent BRAF mutation target the K601 residue.	('BRAF', 'Gene', (25, 29))	('BRAF', 'Gene', '673', (25, 29))	('K601', 'Var', (50, 54))
108063	29946532	Both BRAF V600 and K601 hot-spot mutations are usually mutually exclusive with hot-spot NRAS mutations.	('BRAF', 'Gene', '673', (5, 9))	('K601', 'Var', (19, 23))	('BRAF', 'Gene', (5, 9))	('NRAS', 'Gene', (88, 92))	('NRAS', 'Gene', '4893', (88, 92))
108064	29946532	In contrast, BRAF non-hot-spot mutations (including eight exon, 11 mutations) co-occurred with RAS (N/H/K) hot-spot and NF1 mutations.	('mutations', 'Var', (31, 40))	('mutations', 'Var', (124, 133))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('NF1', 'Gene', (120, 123))	('NF1', 'Gene', '4763', (120, 123))
108078	29946532	Other critical events in melanoma progression are mutations or deletions of the BRCA1-associated protein (BAP1) gene locus 148.	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('BAP1', 'Gene', (106, 110))	('mutations', 'Var', (50, 59))	('BRCA1-associated protein', 'Gene', '8315', (80, 104))	('BRCA1-associated protein', 'Gene', (80, 104))	('deletions', 'Var', (63, 72))	('BAP1', 'Gene', '8314', (106, 110))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))
108083	29946532	When lost due to inactivating mutations, germline BAP1 mutations cause a cancer syndrome whose characteristics are early onset of atypical Spitz tumors and increased risk of uveal and CM, mesothelioma, renal cell carcinoma, and various other malignancies.	('cancer syndrome', 'Disease', 'MESH:D009369', (73, 88))	('germline', 'Var', (41, 49))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('renal cell carcinoma', 'Disease', (202, 222))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (202, 222))	('cancer syndrome', 'Disease', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('mutations', 'Var', (55, 64))	('BAP1', 'Gene', '8314', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('malignancies', 'Disease', 'MESH:D009369', (242, 254))	('malignancies', 'Disease', (242, 254))	('mesothelioma', 'Disease', (188, 200))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (202, 222))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mesothelioma', 'Disease', 'MESH:D008654', (188, 200))	('tumors', 'Disease', (145, 151))	('cause', 'Reg', (65, 70))	('CM', 'Phenotype', 'HP:0012056', (184, 186))	('BAP1', 'Gene', (50, 54))
108085	29946532	BAP1 alterations in UMs are often accompanied by somatic complete or partial loss of chromosome 3.	('rat', 'Species', '10116', (9, 12))	('BAP1', 'Gene', (0, 4))	('chromosome', 'cellular_component', 'GO:0005694', ('85', '95'))	('alterations', 'Var', (5, 16))	('loss', 'NegReg', (77, 81))	('UM', 'Phenotype', 'HP:0007716', (20, 22))	('BAP1', 'Gene', '8314', (0, 4))
108089	29946532	Aberrant expression, dysregulation of their enzymatic activity or imbalances between HDACs and histone acetyltransferases are likely involved in the development and progression of cancer.	('involved', 'Reg', (133, 141))	('Aberrant expression', 'Var', (0, 19))	('imbalances', 'MPA', (66, 76))	('imbalance', 'Phenotype', 'HP:0002172', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('men', 'Species', '9606', (156, 159))	('histone acetyltransferases', 'Enzyme', (95, 121))	('imbalances', 'Phenotype', 'HP:0002172', (66, 76))	('dysregulation', 'Var', (21, 34))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('enzymatic', 'MPA', (44, 53))	('cancer', 'Disease', (180, 186))
108100	29946532	While cells with low mutational burden will display mostly normal cellular protein antigens on their MHC surface molecules without any immune activation, melanoma cells will display mutant proteins (tumor antigens), initiating an activation of the immune system.	('tumor', 'Disease', (199, 204))	('proteins', 'Protein', (189, 197))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('activation', 'PosReg', (230, 240))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('mutant', 'Var', (182, 188))
108119	29946532	By targeting TLR9 in both the early and late endosomes of plasmacytoid dendritic cells, SD-101 is intended to stimulate multiple mechanisms of tumor killing and to elicit a potent and focused innate and adaptive immune response to cancer.	('TLR9', 'Gene', '54106', (13, 17))	('SD-101', 'Chemical', '-', (88, 94))	('tumor', 'Disease', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('TLR9', 'Gene', (13, 17))	('cancer', 'Disease', (231, 237))	('elicit', 'Reg', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('adaptive immune response', 'biological_process', 'GO:0002250', ('203', '227'))	('stimulate', 'PosReg', (110, 119))	('SD-101', 'Var', (88, 94))
108143	29946532	For instance, in the case of treatment with PLX4032, reported data indicate a PFS of 7 months in patients with hyper-activated B-RAF melanomas.	('PLX4032', 'Chemical', 'MESH:D000077484', (44, 51))	('melanomas', 'Disease', (133, 142))	('PLX4032', 'Var', (44, 51))	('B-RAF', 'Gene', '673', (127, 132))	('melanomas', 'Disease', 'MESH:D008545', (133, 142))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('patients', 'Species', '9606', (97, 105))	('B-RAF', 'Gene', (127, 132))	('men', 'Species', '9606', (34, 37))
108149	29946532	In melanoma cells, the MAPK pathway is additionally sustained by oncogenic RAS or B-RAF mutations.	('B-RAF', 'Gene', (82, 87))	('MAPK', 'molecular_function', 'GO:0004707', ('23', '27'))	('mutations', 'Var', (88, 97))	('MAPK pathway', 'Pathway', (23, 35))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('B-RAF', 'Gene', '673', (82, 87))
108152	29946532	Moreover, others and we have clearly demonstrated that clinical inhibition of IGF-1R would be beneficial for melanoma treatment.	('beneficial', 'PosReg', (94, 104))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('IGF-1R', 'Gene', (78, 84))	('inhibition', 'Var', (64, 74))	('IGF-1R', 'Gene', '3480', (78, 84))	('rat', 'Species', '10116', (44, 47))	('men', 'Species', '9606', (123, 126))
108155	29946532	IGF-1R inhibition reduced cell migration, invasion into basement membrane and endothelial cell barrier by decreasing cellular binding to several extracellular matrix proteins and blocking activity of matrix metalloproteinase 2.	('blocking', 'NegReg', (179, 187))	('rat', 'Species', '10116', (34, 37))	('basement membrane', 'cellular_component', 'GO:0005604', ('56', '73'))	('reduced', 'NegReg', (18, 25))	('cell migration', 'biological_process', 'GO:0016477', ('26', '40'))	('inhibition', 'Var', (7, 17))	('matrix metalloproteinase 2', 'Gene', '4313', (200, 226))	('activity', 'MPA', (188, 196))	('decreasing', 'NegReg', (106, 116))	('IGF-1R', 'Gene', '3480', (0, 6))	('men', 'Species', '9606', (60, 63))	('cell migration', 'CPA', (26, 40))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('145', '165'))	('IGF-1R', 'Gene', (0, 6))	('cellular binding to several extracellular matrix', 'MPA', (117, 165))	('matrix metalloproteinase 2', 'Gene', (200, 226))	('binding', 'molecular_function', 'GO:0005488', ('126', '133'))
108159	29946532	As explained before, the clinical success of nearly all tyrosine-kinase inhibitors is predicted by the presence of activating mutations or substantial receptor overexpression, but neither is the case with IGF-1R.	('overexpression', 'PosReg', (160, 174))	('tyrosine', 'Chemical', 'MESH:D014443', (56, 64))	('IGF-1R', 'Gene', '3480', (205, 211))	('IGF-1R', 'Gene', (205, 211))	('activating', 'MPA', (115, 125))	('mutations', 'Var', (126, 135))
108171	29946532	This study also revealed an additional cancer relevant scenario:while beta-arrestin 1 signaling downstream of IGF-1R acts to inhibit p53, removal of this through beta-arrestin 2 allows for p53 accumulation.	('IGF-1R', 'Gene', '3480', (110, 116))	('p53', 'MPA', (133, 136))	('inhibit', 'NegReg', (125, 132))	('beta-arrestin 1', 'Gene', '408', (70, 85))	('IGF-1R', 'Gene', (110, 116))	('beta-arrestin 1', 'Gene', (70, 85))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('p53', 'MPA', (189, 192))	('removal', 'Var', (138, 145))	('beta-arrestin 2', 'Gene', (162, 177))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('accumulation', 'PosReg', (193, 205))	('beta-arrestin 2', 'Gene', '409', (162, 177))
108172	29946532	This study suggests that strategies to imbalance beta-arrestin isoform expression toward beta-arre2 downstream of the IGF-1R limit MAPK activation while reactivating a tumor suppressor, a strong double-hit system for therapeutic targeting in cancer cells.	('MAPK activation', 'biological_process', 'GO:0000187', ('131', '146'))	('MAPK', 'Gene', (131, 135))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('168', '184'))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('tumor suppressor', 'biological_process', 'GO:0051726', ('168', '184'))	('imbalance', 'Phenotype', 'HP:0002172', (39, 48))	('IGF-1R', 'Gene', '3480', (118, 124))	('IGF-1R', 'Gene', (118, 124))	('tumor', 'Disease', (168, 173))	('beta-arrestin', 'Protein', (49, 62))	('imbalance', 'Var', (39, 48))	('rat', 'Species', '10116', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('activation', 'MPA', (136, 146))	('cancer', 'Disease', (242, 248))	('imbalance beta-', 'Phenotype', 'HP:0006279', (39, 54))	('limit', 'NegReg', (125, 130))	('MAPK', 'molecular_function', 'GO:0004707', ('131', '135'))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('reactivating', 'MPA', (153, 165))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
108176	29946532	Nutlin-3 is one such small-molecule inhibitor, which binds to Mdm2 in the p53-binding pocket, thus preventing Mdm2-mediated p53 degradation, stabilizing p53, and additionally increasing its synthesis rate causing growth arrest.	('p53-binding', 'molecular_function', 'GO:0002039', ('74', '85'))	('growth arrest', 'CPA', (213, 226))	('degradation', 'MPA', (128, 139))	('stabilizing p53', 'MPA', (141, 156))	('rat', 'Species', '10116', (200, 203))	('increasing', 'PosReg', (175, 185))	('synthesis rate', 'MPA', (190, 204))	('degradation', 'biological_process', 'GO:0009056', ('128', '139'))	('synthesis', 'biological_process', 'GO:0009058', ('190', '199'))	('preventing', 'NegReg', (99, 109))	('growth arrest', 'Phenotype', 'HP:0001510', (213, 226))	('Mdm2-mediated', 'Var', (110, 123))
108183	29946532	However, the receptor conformation activating the kinase signaling can be distinct from that which interacts with beta-arrestins, as demonstrated by the IGF-1R mutants constitutively binding beta-arrestin, that are degraded even in the absence of the ligand.	('IGF-1R', 'Gene', '3480', (153, 159))	('binding', 'molecular_function', 'GO:0005488', ('183', '190'))	('IGF-1R', 'Gene', (153, 159))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('beta-arrestin', 'Protein', (191, 204))	('binding', 'Interaction', (183, 190))	('mutants', 'Var', (160, 167))	('rat', 'Species', '10116', (140, 143))	('ligand', 'molecular_function', 'GO:0005488', ('251', '257'))
108186	29946532	IGF-1R conformational changes associated with its inhibition can preferentially activate MAPK-pathway in a kinase-independent manner, a process known as biased signaling thus limiting the efficacy of MAPK inhibition.	('preferentially', 'PosReg', (65, 79))	('inhibition', 'Var', (50, 60))	('MAPK', 'molecular_function', 'GO:0004707', ('200', '204'))	('MAPK-pathway', 'Pathway', (89, 101))	('conformational changes', 'Var', (7, 29))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('signaling', 'biological_process', 'GO:0023052', ('160', '169'))	('activate', 'PosReg', (80, 88))	('IGF-1R', 'Gene', '3480', (0, 6))	('IGF-1R', 'Gene', (0, 6))
108187	29946532	In a panel of skin melanoma cell lines with differing MAPK and p53 mutation status, specific siRNA toward IGF-1R downregulates the receptor and all its signaling in a balanced manner, while IGF-1R targeting by small molecule Nutlin-3 parallels receptor degradation with a transient biased pERK1/2 activity, with both strategies synergizing with MEK1/2 inhibition.	('IGF-1R', 'Gene', '3480', (106, 112))	('signaling', 'biological_process', 'GO:0023052', ('152', '161'))	('signaling', 'MPA', (152, 161))	('IGF-1R', 'Gene', (106, 112))	('MAPK', 'molecular_function', 'GO:0004707', ('54', '58'))	('IGF-1R', 'Gene', (190, 196))	('mutation', 'Var', (67, 75))	('IGF-1R', 'Gene', '3480', (190, 196))	('MEK1/2', 'Gene', '5604;5605', (345, 351))	('MEK1/2', 'Gene', (345, 351))	('ERK1/2', 'Gene', (290, 296))	('receptor degradation', 'biological_process', 'GO:0032801', ('244', '264'))	('MEK1', 'molecular_function', 'GO:0004708', ('345', '349'))	('p53', 'Gene', (63, 66))	('skin melanoma', 'Disease', 'MESH:D008545', (14, 27))	('downregulates', 'NegReg', (113, 126))	('MAPK', 'Gene', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('skin melanoma', 'Disease', (14, 27))	('rat', 'Species', '10116', (319, 322))	('ERK1/2', 'Gene', '5595;5594', (290, 296))
108192	29946532	Personalized medicine, based on specific markers and mutations, is a rapidly growing field and the increased knowledge of molecular targets and drugs tailored accordingly will undoubtedly continue to move the field of melanoma treatments further forward.	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('men', 'Species', '9606', (232, 235))	('melanoma', 'Disease', (218, 226))	('mutations', 'Var', (53, 62))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))
108206	28283772	About 45% of these familial melanomas have been attributed to inheritance of a mutation in a highly penetrant predisposition gene.	('familial melanomas', 'Disease', (19, 37))	('familial melanomas', 'Disease', 'OMIM:155600', (19, 37))	('mutation', 'Var', (79, 87))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
108211	28283772	Within the melanoma-dominant syndromes caused by cyclin-dependent kinase inhibitor 2A (CDKN2A), and BRCA1-associated protein 1 (BAP1), pathogenic mutations in these genes cause increased incidence of other cancer types (e.g., pancreatic cancer, neurological tumors, renal cell carcinoma, mesothelioma) but with lower penetrance than melanoma.	('neurological tumors', 'Disease', (245, 264))	('melanoma-dominant syndromes', 'Disease', 'MESH:D008545', (11, 38))	('renal cell carcinoma', 'Disease', (266, 286))	('CDKN2A', 'Gene', '1029', (87, 93))	('BRCA1-associated protein 1', 'Gene', '8314', (100, 126))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (266, 286))	('BAP1', 'Gene', (128, 132))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('49', '82'))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (49, 85))	('mesothelioma', 'Disease', (288, 300))	('neurological tumors', 'Disease', 'MESH:D009423', (245, 264))	('pancreatic cancer', 'Disease', 'MESH:D010190', (226, 243))	('mesothelioma', 'Disease', 'MESH:D008654', (288, 300))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('BRCA1-associated protein 1', 'Gene', (100, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('melanoma-dominant syndromes', 'Disease', (11, 38))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('66', '82'))	('melanoma', 'Phenotype', 'HP:0002861', (333, 341))	('melanoma', 'Disease', (333, 341))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (49, 85))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', (237, 243))	('pancreatic cancer', 'Disease', (226, 243))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (266, 286))	('CDKN2A', 'Gene', (87, 93))	('mutations', 'Var', (146, 155))	('BAP1', 'Gene', '8314', (128, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (226, 243))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('melanoma', 'Disease', 'MESH:D008545', (333, 341))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
108218	28283772	Genetic testing of appropriate individuals and the tailored follow-up recommendations that ensue can improve early detection, reduce mortality, and enhance compliance with prevention recommendations.	('early detection', 'MPA', (109, 124))	('reduce', 'NegReg', (126, 132))	('Genetic testing', 'Var', (0, 15))	('mortality', 'CPA', (133, 142))	('compliance', 'MPA', (156, 166))	('men', 'Species', '9606', (75, 78))	('enhance', 'PosReg', (148, 155))	('improve', 'PosReg', (101, 108))	('men', 'Species', '9606', (188, 191))
108235	28283772	Families that carry a pathogenic mutation in CDKN2A have an increased risk for melanoma, pancreatic cancer, and perhaps neurological tumors like astrocytoma.	('CDKN2A', 'Gene', '1029', (45, 51))	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('neurological tumors', 'Disease', 'MESH:D009423', (120, 139))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('mutation', 'Var', (33, 41))	('astrocytoma', 'Disease', 'MESH:D001254', (145, 156))	('neurological tumors', 'Disease', (120, 139))	('astrocytoma', 'Disease', (145, 156))	('pathogenic', 'Reg', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('astrocytoma', 'Phenotype', 'HP:0009592', (145, 156))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('CDKN2A', 'Gene', (45, 51))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('pancreatic cancer', 'Disease', (89, 106))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
108236	28283772	A substantially increased number of atypical moles in the setting of a CDKN2A mutation has been termed familial atypical mole and malignant melanoma syndrome (FAMMM), although it is also called the familial melanoma and pancreatic cancer syndrome (FMPC) or the familial atypical multiple mole melanoma-pancreatic carcinoma syndrome (FAMMPC), because of the increased risk of pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (220, 237))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('mole', 'Phenotype', 'HP:0003764', (288, 292))	('FAMMM', 'Gene', '1243', (159, 164))	('atypical mole', 'Phenotype', 'HP:0001062', (36, 49))	('melanoma-pancreatic carcinoma syndrome', 'Disease', (293, 331))	('mole', 'Phenotype', 'HP:0003764', (121, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (375, 392))	('melanoma', 'Phenotype', 'HP:0002861', (293, 301))	('FMPC', 'Disease', (248, 252))	('familial melanoma', 'Disease', (198, 215))	('familial melanoma', 'Disease', 'OMIM:155600', (198, 215))	('melanoma and pancreatic cancer', 'Disease', 'MESH:C563985', (207, 237))	('pancreatic cancer syndrome', 'Disease', 'MESH:D010190', (220, 246))	('FAMMM', 'Gene', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('moles', 'Phenotype', 'HP:0003764', (45, 50))	('atypical multiple mole', 'Phenotype', 'HP:0001062', (270, 292))	('atypical mole', 'Phenotype', 'HP:0001062', (112, 125))	('malignant melanoma syndrome', 'Disease', 'MESH:D008545', (130, 157))	('CDKN2A', 'Gene', (71, 77))	('atypical moles', 'Phenotype', 'HP:0001062', (36, 50))	('melanoma-pancreatic carcinoma syndrome', 'Disease', 'MESH:C563985', (293, 331))	('pancreatic cancer', 'Disease', 'MESH:D010190', (375, 392))	('malignant melanoma syndrome', 'Disease', (130, 157))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (220, 237))	('mole', 'Phenotype', 'HP:0003764', (45, 49))	('FMPC', 'Disease', 'None', (248, 252))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (357, 392))	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('mutation', 'Var', (78, 86))	('multiple mole', 'Phenotype', 'HP:0001054', (279, 292))	('pancreatic cancer', 'Disease', (375, 392))	('pancreatic cancer syndrome', 'Disease', (220, 246))	('CDKN2A', 'Gene', '1029', (71, 77))	('familial', 'Disease', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('malignant melanoma', 'Phenotype', 'HP:0002861', (130, 148))
108237	28283772	Clinical genetic testing for CDKN2A mutations has been widely available since the mid-2000s, and guidelines for use of this test were published in 2009 and are detailed below.	('CDKN2A', 'Gene', (29, 35))	('mutations', 'Var', (36, 45))	('CDKN2A', 'Gene', '1029', (29, 35))
108240	28283772	Deleterious mutations in these genes lead to a disproportionately high risk of melanoma development relative to other cancers.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('Deleterious mutations', 'Var', (0, 21))	('lead to', 'Reg', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('men', 'Species', '9606', (95, 98))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
108243	28283772	Families shown to be mutation negative at the CDKN2A locus are sometimes tested reflexively for the most common CDK4 mutation site, Arg24.	('tested', 'Reg', (73, 79))	('CDKN2A', 'Gene', (46, 52))	('CDKN2A', 'Gene', '1029', (46, 52))	('CDK4', 'Gene', (112, 116))	('Arg24', 'Chemical', '-', (132, 137))	('CDK', 'molecular_function', 'GO:0004693', ('112', '115'))	('CDK4', 'Gene', '1019', (112, 116))	('Arg24', 'Var', (132, 137))
108244	28283772	This CDKN2A/p16 binding site (Arg24) is required for CDK4 inhibition by CDKN2A/p16 and mutation transforms the protein into an unregulated oncoprotein, making single site testing of this codon a reasonable consideration.	('p16', 'Gene', '1029', (79, 82))	('Arg24', 'Var', (30, 35))	('p16', 'Gene', '1029', (12, 15))	('CDKN2A', 'Gene', (5, 11))	('CDKN2A', 'Gene', '1029', (72, 78))	('binding', 'molecular_function', 'GO:0005488', ('16', '23'))	('CDK4', 'Gene', '1019', (53, 57))	('CDK4', 'Gene', (53, 57))	('CDKN2A', 'Gene', '1029', (5, 11))	('p16', 'Gene', (79, 82))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('CDK', 'molecular_function', 'GO:0004693', ('53', '56'))	('p16', 'Gene', (12, 15))	('mutation', 'Var', (87, 95))	('CDKN2A', 'Gene', (72, 78))	('Arg24', 'Chemical', '-', (30, 35))
108245	28283772	Melanoma is also observed at higher-than-expected rates in other hereditary cancer syndromes arising from germline mutations in tumor susceptibility genes (melanoma-subordinate syndromes).	('melanoma-subordinate syndromes', 'Disease', 'MESH:D008545', (156, 186))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('germline mutations', 'Var', (106, 124))	('Melanoma', 'Disease', (0, 8))	('melanoma-subordinate syndromes', 'Disease', (156, 186))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('arising', 'Reg', (93, 100))	('hereditary cancer syndromes', 'Disease', (65, 92))	('hereditary cancer syndromes', 'Disease', 'MESH:D009386', (65, 92))	('tumor', 'Disease', (128, 133))
108249	28283772	Furthermore, use of genetic panel testing for a variety of syndromes, including those with a predominance of melanoma, will begin to refine the constellation of cancers seen in association with various mutations.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('constellation of cancers', 'Disease', 'MESH:D009369', (144, 168))	('constellation of cancers', 'Disease', (144, 168))	('mutations', 'Var', (202, 211))
108250	28283772	In 2009, international guidelines were published suggesting that individuals with an estimated 10% or greater pre-test probability of carrying a mutation in CDKN2A should be referred for genetic counseling.	('pre', 'molecular_function', 'GO:0003904', ('110', '113'))	('CDKN2A', 'Gene', '1029', (157, 163))	('CDKN2A', 'Gene', (157, 163))	('mutation', 'Var', (145, 153))
108251	28283772	However, accurate estimates of pre-test probabilities of mutation carriage were complicated by the interdependence upon ethnicity and geography that underlie a general population's risk for melanoma.	('mutation', 'Var', (57, 65))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('pre', 'molecular_function', 'GO:0003904', ('31', '34'))
108257	28283772	Use of this "rule of twos or threes" criteria for melanoma genetic testing leads to approximately 10% positive results for CDKN2A mutation.	('mutation', 'Var', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('CDKN2A', 'Gene', (123, 129))	('CDKN2A', 'Gene', '1029', (123, 129))
108259	28283772	For instance, it is unclear how environment, other prognostic risk factors such as the hair, eye, and skin color, and/or ethnicity contribute to the overall risk in individuals with CDKN2A (or other melanoma gene) mutations.	('mutations', 'Var', (214, 223))	('CDKN2A', 'Gene', (182, 188))	('men', 'Species', '9606', (39, 42))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('CDKN2A', 'Gene', '1029', (182, 188))	('melanoma', 'Disease', (199, 207))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))
108263	28283772	To accomplish this task, we have created a simplified scoring system that identifies individuals or families that have a pattern of cancer development suspicious for germline inheritance of a pathogenic mutation.	('cancer', 'Disease', (132, 138))	('men', 'Species', '9606', (146, 149))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutation', 'Var', (203, 211))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
108268	28283772	Third, we account for clinical findings consistent with the melanoma-dominant tumor syndrome caused by a BAP1 mutation.	('caused by', 'Reg', (93, 102))	('melanoma-dominant tumor syndrome', 'Disease', 'MESH:D008545', (60, 92))	('BAP1', 'Gene', '8314', (105, 109))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('melanoma-dominant tumor syndrome', 'Disease', (60, 92))	('mutation', 'Var', (110, 118))	('BAP1', 'Gene', (105, 109))
108270	28283772	The original "rule of twos and threes" was based on finding criteria that would provide at least a 10% pre-test probability of finding an actionable CDKN2A mutation.	('CDKN2A', 'Gene', '1029', (149, 155))	('CDKN2A', 'Gene', (149, 155))	('mutation', 'Var', (156, 164))
108281	28283772	Once an individual or family has met criteria for genetic testing and has received genetic counseling with informed consent, our centers create a tailored panel test that includes the genes that are most likely to be mutated, based on the other cancer types observed in the pedigree.	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Disease', (245, 251))	('mutated', 'Var', (217, 224))	('cancer', 'Disease', 'MESH:D009369', (245, 251))
108290	28283772	Co-occurrence of pancreatic cancer and melanoma usually occurs in the setting of a CDKN2A mutation.	('CDKN2A', 'Gene', '1029', (83, 89))	('pancreatic cancer', 'Disease', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('pancreatic cancer', 'Disease', 'MESH:D010190', (17, 34))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (17, 34))	('mutation', 'Var', (90, 98))	('CDKN2A', 'Gene', (83, 89))
108328	28283772	Analysis of a Lynch syndrome registry has observed melanoma in patients with pathogenic mutations in these mismatch repair enzymes; however, the increased incidence was not found to be statistically significant.	('mismatch repair', 'biological_process', 'GO:0006298', ('107', '122'))	('Lynch syndrome', 'Disease', (14, 28))	('Lynch syndrome', 'Disease', 'MESH:D003123', (14, 28))	('mutations', 'Var', (88, 97))	('patients', 'Species', '9606', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
108329	28283772	Cowden Syndrome (CS) arises from a pathogenic mutation in the PTEN gene.	('PTEN', 'Gene', (62, 66))	('PTEN', 'Gene', '5728', (62, 66))	('Cowden Syndrome', 'Disease', (0, 15))	('Cowden Syndrome', 'Disease', 'MESH:D006223', (0, 15))	('mutation', 'Var', (46, 54))
108335	28283772	Germline mutation carriers of TP53 have a substantial lifetime risk for a variety of cancers including childhood cancers and multiple primary cancers.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('Germline mutation carriers', 'Var', (0, 26))	('childhood cancers', 'Disease', 'MESH:C536928', (103, 120))	('childhood cancers', 'Disease', (103, 120))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('TP53', 'Gene', (30, 34))	('multiple primary cancers', 'Disease', 'MESH:D009369', (125, 149))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('cancers', 'Disease', (142, 149))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancers', 'Disease', (85, 92))	('TP53', 'Gene', '7157', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('multiple primary cancers', 'Disease', (125, 149))
108351	28283772	In melanoma-dominant or melanoma-subordinate pedigrees or in individuals carrying a BAP1, CDK4, CDKN2A, MITF, or POT1 mutation, individuals should be educated on the importance of melanoma prevention and early detection.	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('melanoma-dominant or melanoma-subordinate', 'Disease', (3, 44))	('MITF', 'Gene', (104, 108))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))	('BAP1', 'Gene', '8314', (84, 88))	('CDKN2A', 'Gene', (96, 102))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('CDK', 'molecular_function', 'GO:0004693', ('90', '93'))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('CDK4', 'Gene', (90, 94))	('melanoma-dominant or melanoma-subordinate', 'Disease', 'MESH:D008545', (3, 44))	('POT1', 'Gene', '25913', (113, 117))	('mutation', 'Var', (118, 126))	('BAP1', 'Gene', (84, 88))	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('CDKN2A', 'Gene', '1029', (96, 102))	('CDK4', 'Gene', '1019', (90, 94))	('POT1', 'Gene', (113, 117))	('MITF', 'Gene', '4286', (104, 108))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))
108357	28283772	Annual screening for uveal melanoma, mesothelioma, and renal cancer should be considered for carriers of BAP1 germline mutations.	('uveal melanoma', 'Disease', (21, 35))	('carriers', 'Reg', (93, 101))	('mesothelioma', 'Disease', 'MESH:D008654', (37, 49))	('renal cancer', 'Disease', (55, 67))	('BAP1', 'Gene', '8314', (105, 109))	('renal cancer', 'Phenotype', 'HP:0009726', (55, 67))	('germline', 'Var', (110, 118))	('renal cancer', 'Disease', 'MESH:D007680', (55, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (21, 35))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mesothelioma', 'Disease', (37, 49))	('BAP1', 'Gene', (105, 109))	('uveal melanoma', 'Phenotype', 'HP:0007716', (21, 35))
108363	28283772	For women who have high-risk breast cancer genetic mutations, breast awareness with self-breast exams and clinical breast exams is recommended starting at age 18.	('genetic mutations', 'Var', (43, 60))	('women', 'Species', '9606', (4, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (29, 42))	('men', 'Species', '9606', (136, 139))	('men', 'Species', '9606', (6, 9))
108364	28283772	Imaging may begin as early as age 20 for TP53 mutation carriers or age 25 for BRCA1 and BRCA2 mutation carriers.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('BRCA2', 'Gene', (88, 93))	('BRCA1', 'Gene', '672', (78, 83))	('BRCA2', 'Gene', '675', (88, 93))	('mutation', 'Var', (46, 54))	('BRCA1', 'Gene', (78, 83))
108366	28283772	Consideration of risk-reducing mastectomy (RRM) is an option for women who have mutations in risk genes conferring a 50% or greater lifetime risk for breast cancer or have a mutation in a moderate risk gene with significant family history.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('mutations', 'Var', (80, 89))	('mutation', 'Var', (174, 182))	('breast cancer', 'Disease', (150, 163))	('women', 'Species', '9606', (65, 70))
108367	28283772	If a woman has a mutation in a gene associated with an increased risk for ovarian cancer, the option of a salpingo-oophorectomy (RRSO) should be discussed between 35 and 40 years of age and upon completion of child bearing.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('woman', 'Species', '9606', (5, 10))	('ovarian cancer', 'Phenotype', 'HP:0100615', (74, 88))	('ovarian cancer', 'Disease', 'MESH:D010051', (74, 88))	('mutation', 'Var', (17, 25))	('ovarian cancer', 'Disease', (74, 88))	('child', 'Species', '9606', (209, 214))
108369	28283772	Guidelines for patients with a high-risk prostate cancer mutations have not been established by the NCCN; however, recent results from the IMPACT study have shown that the positive predictive values of prostate serum antigen (PSA) of 3.0 ng/mL are higher in patients with a high-risk genetic mutation compared to controls and that the former is more likely to have an intermediate or high-risk for disease.	('patients', 'Species', '9606', (15, 23))	('prostate cancer', 'Disease', 'MESH:D011471', (41, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (41, 56))	('genetic mutation', 'Var', (284, 300))	('prostate cancer', 'Disease', (41, 56))	('patients', 'Species', '9606', (258, 266))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('higher', 'PosReg', (248, 254))
108370	28283772	Generally, patients who have a high-risk colon cancer mutation should have a colonoscopy at age 20-25 years or 2 to 5 years prior to the earliest colon cancer if it is diagnosed before age 25 years.	('mutation', 'Var', (54, 62))	('colon cancer', 'Disease', 'MESH:D015179', (146, 158))	('colon cancer', 'Disease', (146, 158))	('colon cancer', 'Phenotype', 'HP:0003003', (41, 53))	('colon cancer', 'Disease', 'MESH:D015179', (41, 53))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('patients', 'Species', '9606', (11, 19))	('colon cancer', 'Phenotype', 'HP:0003003', (146, 158))	('colon cancer', 'Disease', (41, 53))
108372	28283772	Lynch syndrome is caused by autosomal dominantly inherited mutations in the mismatch repair genes MLH1, MSH2, EPCAM, MSH6, and PMS2.	('PMS2', 'Gene', (127, 131))	('EPCAM', 'Gene', '4072', (110, 115))	('PMS2', 'Gene', '5395', (127, 131))	('mismatch repair', 'biological_process', 'GO:0006298', ('76', '91'))	('MLH1', 'Gene', '4292', (98, 102))	('MSH6', 'Gene', (117, 121))	('MLH1', 'Gene', (98, 102))	('MSH2', 'Gene', (104, 108))	('MSH6', 'Gene', '2956', (117, 121))	('Lynch syndrome', 'Disease', (0, 14))	('MSH2', 'Gene', '4436', (104, 108))	('mutations', 'Var', (59, 68))	('caused by', 'Reg', (18, 27))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('EPCAM', 'Gene', (110, 115))
108373	28283772	Individuals who carry mutations tend to form colon polyps at an earlier age and are at a high lifetime risk for colon cancer (up to 80%) unless frequent surveillance is done.	('colon polyps', 'Disease', (45, 57))	('colon cancer', 'Phenotype', 'HP:0003003', (112, 124))	('colon cancer', 'Disease', 'MESH:D015179', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('colon cancer', 'Disease', (112, 124))	('form', 'Reg', (40, 44))	('mutations', 'Var', (22, 31))	('colon polyps', 'Disease', 'MESH:D003111', (45, 57))
108381	28283772	FAP is caused by autosomal dominantly inherited mutations in the APC gene, although 20-25% of probands have a de novo mutation.	('APC', 'Gene', (65, 68))	('APC', 'cellular_component', 'GO:0005680', ('65', '68'))	('APC', 'Gene', '324', (65, 68))	('caused by', 'Reg', (7, 16))	('FAP', 'Disease', (0, 3))	('mutations', 'Var', (48, 57))
108385	28283772	Attenuated FAP is characterized by an increased risk for colon cancer but fewer colon polyps, more proximally located polyps, and diagnosis of colon cancer at a later age.	('polyps', 'Disease', 'MESH:D011127', (118, 124))	('colon polyps', 'Disease', 'MESH:D003111', (80, 92))	('colon cancer', 'Phenotype', 'HP:0003003', (143, 155))	('colon cancer', 'Phenotype', 'HP:0003003', (57, 69))	('colon cancer', 'Disease', 'MESH:D015179', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('fewer', 'NegReg', (74, 79))	('Attenuated', 'Var', (0, 10))	('colon cancer', 'Disease', 'MESH:D015179', (143, 155))	('polyps', 'Disease', (86, 92))	('colon cancer', 'Disease', (143, 155))	('colon cancer', 'Disease', (57, 69))	('polyps', 'Disease', (118, 124))	('colon polyps', 'Disease', (80, 92))	('FAP', 'Disease', (11, 14))	('polyps', 'Disease', 'MESH:D011127', (86, 92))
108391	28283772	MUTYH-associated polyposis is caused by biallelic mutations in the MUTYH gene and tends to have a similar number of polyps as patients who have AFAP.	('MUTYH', 'Gene', (67, 72))	('MUTYH', 'Gene', '4595', (67, 72))	('biallelic mutations', 'Var', (40, 59))	('polyposis', 'Disease', (17, 26))	('MUTYH', 'Gene', (0, 5))	('MUTYH', 'Gene', '4595', (0, 5))	('polyps', 'Disease', 'MESH:D011127', (116, 122))	('caused by', 'Reg', (30, 39))	('patients', 'Species', '9606', (126, 134))	('polyposis', 'Disease', 'MESH:D011125', (17, 26))	('AFAP', 'Disease', 'MESH:D011125', (144, 148))	('polyps', 'Disease', (116, 122))	('AFAP', 'Disease', (144, 148))
108398	28283772	Screening is recommended for high-risk individuals, including patients with a family history of pancreatic cancer or patients with an STK11, CDKN2A/p16, or a BRCA2 mutation with >=1 affected first-degree relative.	('CDKN2A', 'Gene', '1029', (141, 147))	('STK11', 'molecular_function', 'GO:0033868', ('134', '139'))	('STK11', 'Gene', (134, 139))	('pancreatic cancer', 'Disease', (96, 113))	('p16', 'Gene', '1029', (148, 151))	('men', 'Species', '9606', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('pancreatic cancer', 'Disease', 'MESH:D010190', (96, 113))	('STK11', 'Gene', '6794', (134, 139))	('patients', 'Species', '9606', (62, 70))	('mutation', 'Var', (164, 172))	('p16', 'Gene', (148, 151))	('patients', 'Species', '9606', (117, 125))	('BRCA2', 'Gene', (158, 163))	('CDKN2A', 'Gene', (141, 147))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))	('BRCA2', 'Gene', '675', (158, 163))
108402	28283772	Any pedigree that carries a mutation that overlaps with cancer predisposition genes for these syndromes or that has these types of cancers in the pedigree needs to be monitored carefully for signs and symptoms of these cancers.	('cancer', 'Disease', (131, 137))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('mutation', 'Var', (28, 36))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('cancer', 'Disease', (219, 225))	('cancers', 'Disease', (219, 226))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
108403	28283772	For example, ophthalmologic examinations should be performed every 6-12 months in BAP1 mutation carriers.	('mutation', 'Var', (87, 95))	('BAP1', 'Gene', '8314', (82, 86))	('BAP1', 'Gene', (82, 86))
108404	28283772	BAP1 mutation carriers should also be explicitly warned about asbestos exposures, given their predisposition toward mesothelioma.	('mesothelioma', 'Disease', (116, 128))	('asbestos', 'Chemical', 'MESH:D001194', (62, 70))	('BAP1', 'Gene', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (116, 128))	('BAP1', 'Gene', '8314', (0, 4))	('mutation', 'Var', (5, 13))
108409	28283772	The field of cancer genetics is quickly moving from a descriptive era, in which predisposition is defined primarily by disease phenotypes, into a whole-genome era, in which the relative contributions of high- and low-penetrance mutations, polymorphisms of modifier genes, and environmentally-induced somatic mutations are understood.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (228, 237))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('low-penetrance', 'NegReg', (213, 227))	('men', 'Species', '9606', (283, 286))
108469	28356703	The UM cell counts, in contrast, were lower in the 3% O2 group (Figure 2B; T111: 5.50 versus 2.80 x 106, p = 0.045; T131: 3.70 versus 2.87 x 106, p = 0.0004; M3: 3.10 versus 2.48 x 106, p = 0.028).	('UM', 'Phenotype', 'HP:0007716', (4, 6))	('lower', 'NegReg', (38, 43))	('O2', 'Chemical', 'MESH:D010100', (54, 56))	('UM cell counts', 'CPA', (4, 18))	('T131', 'Var', (116, 120))
108478	28356703	The population of Ki67-positive cells was constantly greater in the choroidal melanocytes cultured at 3% O2 (Figure 4B; M1: 40.5% versus 24.6%, p = 0.0003; M2: 36.0% versus 8.5%, p = 0.0003; M3: 38.4% versus 25.5%, p = 0.0019).	('Ki67-positive', 'Var', (18, 31))	('O2', 'Chemical', 'MESH:D010100', (105, 107))	('choroidal melanocytes', 'Phenotype', 'HP:0012054', (68, 89))	('greater', 'PosReg', (53, 60))
108481	28356703	As shown in Figure 5A, the nuclei of the cells exposed to low physiologic oxygen were rounder (circularity values closer to 1) than those of the melanocytes grown in hyperoxia, coherent with an increase in DNA synthesis.	('low physiologic', 'Var', (58, 73))	('DNA synthesis', 'biological_process', 'GO:0071897', ('206', '219'))	('DNA synthesis', 'MPA', (206, 219))	('oxygen', 'Chemical', 'MESH:D010100', (74, 80))	('DNA', 'cellular_component', 'GO:0005574', ('206', '209'))	('hyperoxia', 'Disease', 'MESH:D018496', (166, 175))	('increase', 'PosReg', (194, 202))	('hyperoxia', 'Disease', (166, 175))
108543	28356703	For instance, the accumulation of irreversible oxidative damages to biomolecules, dysregulation of posttranslational modifications on proteins involved in cell cycle progression, as well as reduced MCT4 activity, could play a role in the decreased viability and proliferation observed in choroidal melanocytes cultured under hyperoxia.	('MCT', 'biological_process', 'GO:0120197', ('198', '201'))	('cell cycle', 'biological_process', 'GO:0007049', ('155', '165'))	('dysregulation', 'Var', (82, 95))	('MCT4', 'Gene', (198, 202))	('hyperoxia', 'Disease', (325, 334))	('proliferation', 'CPA', (262, 275))	('viability', 'CPA', (248, 257))	('MCT4', 'Gene', '9123', (198, 202))	('reduced', 'NegReg', (190, 197))	('decreased', 'NegReg', (238, 247))	('hyperoxia', 'Disease', 'MESH:D018496', (325, 334))	('choroidal melanocytes', 'Phenotype', 'HP:0012054', (288, 309))	('activity', 'MPA', (203, 211))
108554	25702974	It was also found in Drosophila that phosphorylated Yorkie (the Drosophila ortholog of YAP/TAZ) is actively excluded from the nucleus in an Exportin 1 (XPO1)-dependent manner.	('nucleus', 'cellular_component', 'GO:0005634', ('126', '133'))	('Yorkie', 'Gene', '37851', (52, 58))	('XPO1', 'Gene', '34167', (152, 156))	('Exportin 1', 'Gene', '34167', (140, 150))	('Exportin 1', 'Gene', (140, 150))	('Drosophila', 'Species', '7227', (64, 74))	('Drosophila', 'Species', '7227', (21, 31))	('XPO1', 'Gene', (152, 156))	('Exportin', 'cellular_component', 'GO:0005651', ('140', '148'))	('Yorkie', 'Gene', (52, 58))	('phosphorylated', 'Var', (37, 51))
108567	25702974	Hepatocyte-specific MST1/2 knockout is sufficient to dramatically increase hepatocyte proliferation, resulting in massive liver overgrowth due to aberrant YAP activity.	('increase', 'PosReg', (66, 74))	('liver overgrowth', 'Disease', (122, 138))	('MST1/2', 'Gene', (20, 26))	('knockout', 'Var', (27, 35))	('overgrowth', 'Phenotype', 'HP:0001548', (128, 138))	('hepatocyte proliferation', 'biological_process', 'GO:0072574', ('75', '99'))	('YAP activity', 'CPA', (155, 167))	('hepatocyte', 'MPA', (75, 85))	('liver overgrowth', 'Disease', 'MESH:D008107', (122, 138))	('massive liver', 'Phenotype', 'HP:0002240', (114, 127))
108571	25702974	Deleting MST1/2 to activate YAP also protects the liver from acetaminophen-induced liver injury.	('liver injury', 'Disease', 'MESH:D056486', (83, 95))	('liver injury', 'Disease', (83, 95))	('acetaminophen', 'Chemical', 'MESH:D000082', (61, 74))	('protects', 'Reg', (37, 45))	('Deleting', 'Var', (0, 8))
108574	25702974	Liver-specific knockdown of alpha-catenin also results in increased YAP activity and liver overgrowth following partial hepatectomy, indicating that alpha-catenin may play a role in inactivating YAP following regeneration.	('overgrowth', 'Phenotype', 'HP:0001548', (91, 101))	('increased', 'PosReg', (58, 67))	('knockdown', 'Var', (15, 24))	('liver overgrowth', 'Disease', (85, 101))	('YAP activity', 'CPA', (68, 80))	('regeneration', 'biological_process', 'GO:0031099', ('209', '221'))	('liver overgrowth', 'Disease', 'MESH:D008107', (85, 101))	('alpha-catenin', 'Protein', (28, 41))
108576	25702974	Knocking down YAP is sufficient to block pancreatic progenitor cell proliferation.	('block pancreatic', 'Disease', 'MESH:D010195', (35, 51))	('Knocking down', 'Var', (0, 13))	('block pancreatic', 'Disease', (35, 51))	('YAP', 'Gene', (14, 17))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))
108578	25702974	Pancreas-specific MST1/2 knockout and ectopic YAP overexpression both result in decreased pancreas size.	('MST1/2', 'Gene', (18, 24))	('decreased pancreas size', 'Phenotype', 'HP:0002594', (80, 103))	('decreased pancreas', 'Disease', (80, 98))	('knockout', 'Var', (25, 33))	('decreased pancreas', 'Disease', 'MESH:D010190', (80, 98))
108579	25702974	Dysregulation of the Hippo pathway does not appear to play a significant role for the endocrine compartment, and MST1/2 knockout mice have normal fed blood glucose levels.	('glucose', 'Chemical', 'MESH:D005947', (156, 163))	('MST1/2', 'Gene', (113, 119))	('normal fed blood glucose levels', 'MPA', (139, 170))	('knockout', 'Var', (120, 128))	('Hippo pathway', 'Pathway', (21, 34))	('mice', 'Species', '10090', (129, 133))
108580	25702974	However, the exocrine compartment of MST1/2 knockout mice shows a dramatic increase in cell proliferation, accompanied by a similar increase in cell death.	('MST1/2', 'Gene', (37, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('87', '105'))	('knockout', 'Var', (44, 52))	('cell proliferation', 'CPA', (87, 105))	('increase', 'PosReg', (75, 83))	('cell death', 'biological_process', 'GO:0008219', ('144', '154'))	('mice', 'Species', '10090', (53, 57))
108581	25702974	This appears to be YAP-dependent because deleting a single allele of YAP in the MST1/2 knockout mice results in improved pancreatic growth and structure.	('mice', 'Species', '10090', (96, 100))	('YAP', 'Gene', (69, 72))	('pancreatic growth', 'Disease', 'MESH:D006130', (121, 138))	('deleting', 'Var', (41, 49))	('pancreatic growth', 'Disease', (121, 138))	('improved', 'PosReg', (112, 120))
108582	25702974	For instance, Sveinsson's Chorioretinal Atrophy (SCRA), a rare genetic disease resulting in degeneration of the choroid and retina, is caused by a mutation in TEAD1.	('caused by', 'Reg', (135, 144))	('TEAD1', 'Gene', '21676', (159, 164))	('mutation', 'Var', (147, 155))	('genetic disease', 'Disease', (63, 78))	('Chorioretinal Atrophy', 'Phenotype', 'HP:0000533', (26, 47))	('genetic disease', 'Disease', 'MESH:D030342', (63, 78))	('TEAD1', 'Gene', (159, 164))	('degeneration of the choroid', 'Disease', (92, 119))	("Sveinsson's Chorioretinal Atrophy", 'Disease', 'MESH:C566236', (14, 47))	('degeneration of the choroid', 'Disease', 'MESH:D002833', (92, 119))	("Sveinsson's Chorioretinal Atrophy", 'Disease', (14, 47))
108583	25702974	This mutant TEAD1 is defective in YAP/TAZ binding and has no transcriptional activity.	('YAP/TAZ', 'Protein', (34, 41))	('transcriptional activity', 'MPA', (61, 85))	('TEAD1', 'Gene', '21676', (12, 17))	('mutant', 'Var', (5, 11))	('defective', 'NegReg', (21, 30))	('TEAD1', 'Gene', (12, 17))	('binding', 'molecular_function', 'GO:0005488', ('42', '49'))
108591	25702974	found that YAP is silenced in a subset of human CRC, and YAP blocks regeneration by inhibiting Wnt signaling and preventing Dishevelled (DVL) nuclear translocation.	('Wnt signaling', 'MPA', (95, 108))	('regeneration', 'biological_process', 'GO:0031099', ('68', '80'))	('blocks', 'NegReg', (61, 67))	('signaling', 'biological_process', 'GO:0023052', ('99', '108'))	('human', 'Species', '9606', (42, 47))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('YAP', 'Var', (57, 60))	('regeneration', 'CPA', (68, 80))	('preventing', 'NegReg', (113, 123))	('inhibiting', 'NegReg', (84, 94))
108595	25702974	Conversely, overexpressing dominant-negative MST1 or LATS2 showed improved cardiac function following either myocardial infarction or ischemia and reperfusion.	('MST1', 'Gene', '15235', (45, 49))	('improved cardiac function', 'Phenotype', 'HP:0001635', (66, 91))	('LATS2', 'Gene', (53, 58))	('MST1', 'Gene', (45, 49))	('myocardial infarction', 'Phenotype', 'HP:0001658', (109, 130))	('overexpressing', 'PosReg', (12, 26))	('improved', 'PosReg', (66, 74))	('dominant-negative', 'Var', (27, 44))	('ischemia', 'Disease', (134, 142))	('cardiac', 'MPA', (75, 82))	('ischemia', 'Disease', 'MESH:D007511', (134, 142))	('myocardial infarction', 'Disease', (109, 130))	('myocardial infarction', 'Disease', 'MESH:D009203', (109, 130))
108596	25702974	In addition, SAV1 deficient cardiomyocytes can re-enter the cell cycle and undergo cell division, and SAV1 heart-specific knockout mice show improved recovery following ischemia with ejection fraction and fractional shortening values comparable to control, non-ischemic mice.	('ischemia', 'Disease', (169, 177))	('ejection', 'MPA', (183, 191))	('ischemia', 'Disease', 'MESH:D007511', (169, 177))	('SAV1', 'Gene', (13, 17))	('improved', 'PosReg', (141, 149))	('SAV1', 'Gene', (102, 106))	('recovery', 'MPA', (150, 158))	('knockout', 'Var', (122, 130))	('mice', 'Species', '10090', (131, 135))	('mice', 'Species', '10090', (270, 274))	('deficient', 'Var', (18, 27))	('cell division', 'biological_process', 'GO:0051301', ('83', '96'))	('cell division', 'CPA', (83, 96))	('cell cycle', 'biological_process', 'GO:0007049', ('60', '70'))
108599	25702974	Thus, manipulating the Hippo pathway following injury could be key to improving heart regeneration, decreasing fibrosis, and increasing survival.	('improving', 'PosReg', (70, 79))	('Hippo pathway', 'Pathway', (23, 36))	('survival', 'CPA', (136, 144))	('regeneration', 'biological_process', 'GO:0031099', ('86', '98'))	('manipulating', 'Var', (6, 18))	('fibrosis', 'Disease', 'MESH:D005355', (111, 119))	('fibrosis', 'Disease', (111, 119))	('heart regeneration', 'CPA', (80, 98))	('increasing', 'PosReg', (125, 135))	('decreasing', 'NegReg', (100, 110))
108600	25702974	Not surprisingly, dysregulation of the Hippo pathway can lead to uncontrolled proliferation, resulting in a wide range of diseases (Boxes 1-3) and cancers.	('uncontrolled', 'MPA', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Hippo pathway', 'Pathway', (39, 52))	('lead to', 'Reg', (57, 64))	('resulting in', 'Reg', (93, 105))	('dysregulation', 'Var', (18, 31))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('diseases', 'Disease', (122, 130))	('cancers', 'Disease', (147, 154))
108601	25702974	The Hippo pathway can become dysregulated by a variety of mechanisms, including YAP gene amplification, methylation or deletion of upstream Hippo pathway components, mutations in upstream GPCRs, or by crosstalk with other signaling pathways including Wnt signaling.	('dysregulated', 'Reg', (29, 41))	('Hippo', 'Gene', (140, 145))	('mutations', 'Var', (166, 175))	('signaling', 'biological_process', 'GO:0023052', ('222', '231'))	('GPCR', 'Gene', (188, 192))	('deletion', 'Var', (119, 127))	('signaling', 'biological_process', 'GO:0023052', ('255', '264'))	('crosstalk', 'Reg', (201, 210))	('Wnt signaling', 'Pathway', (251, 264))	('YAP gene', 'Gene', (80, 88))	('methylation', 'Var', (104, 115))	('amplification', 'Var', (89, 102))	('Hippo pathway', 'Pathway', (4, 17))	('GPCR', 'Gene', '23890', (188, 192))	('methylation', 'biological_process', 'GO:0032259', ('104', '115'))
108602	25702974	Polycystic kidney disease (PKD) is a life-threatening disease caused by cyst formation throughout the kidneys, and is frequently caused by inactivating mutations in either the PKD1 or PKD2.	('PKD1', 'Gene', '18763', (176, 180))	('Polycystic kidney', 'Phenotype', 'HP:0000113', (0, 17))	('PKD2', 'Gene', '18764', (184, 188))	('PKD', 'Disease', (27, 30))	('caused by', 'Reg', (129, 138))	('PKD', 'Disease', 'MESH:C537180', (27, 30))	('inactivating mutations', 'Var', (139, 161))	('kidney disease', 'Phenotype', 'HP:0000112', (11, 25))	('PKD2', 'Gene', (184, 188))	('PKD1', 'Gene', (176, 180))	('Polycystic kidney disease', 'Disease', (0, 25))	('PKD', 'Disease', (176, 179))	('formation', 'biological_process', 'GO:0009058', ('77', '86'))	('PKD', 'Disease', 'MESH:C537180', (184, 187))	('PKD', 'Disease', 'MESH:C537180', (176, 179))	('PKD', 'Disease', (184, 187))	('Polycystic kidney disease', 'Disease', 'MESH:D007690', (0, 25))
108611	25702974	TAZ knockout results in PC2 accumulation, leading to PKD, and also results in the down-regulation of other genes necessary for proper cilia development and function.	('PC2', 'Gene', (24, 27))	('PKD', 'Disease', 'MESH:C537180', (53, 56))	('PKD', 'Disease', (53, 56))	('PC2', 'Gene', '18764', (24, 27))	('accumulation', 'PosReg', (28, 40))	('TAZ', 'Gene', (0, 3))	('down-regulation', 'NegReg', (82, 97))	('knockout', 'Var', (4, 12))	('regulation', 'biological_process', 'GO:0065007', ('87', '97'))	('leading', 'Reg', (42, 49))
108618	25702974	TBX5, which is essential for cardiac and limb development, is often mutated in Holt-Oram patients.	('limb development', 'biological_process', 'GO:0060173', ('41', '57'))	('patients', 'Species', '9606', (89, 97))	('Holt-Oram', 'Disease', (79, 88))	('TBX5', 'Gene', (0, 4))	('mutated', 'Var', (68, 75))
108619	25702974	TBX5 normally interacts with YAP/TAZ, but mutations in TBX5 prevent its binding to TAZ and results in a congenital heart defect called Tetralogy of Fallot (TOF).	('prevent', 'NegReg', (60, 67))	('heart defect', 'Phenotype', 'HP:0030680', (115, 127))	('Tetralogy of Fallot', 'Disease', (135, 154))	('congenital heart defect', 'Disease', 'MESH:D006330', (104, 127))	('congenital heart defect', 'Disease', (104, 127))	('results in', 'Reg', (91, 101))	('binding', 'Interaction', (72, 79))	('congenital heart defect', 'Phenotype', 'HP:0001627', (104, 127))	('mutations', 'Var', (42, 51))	('Tetralogy of Fallot', 'Phenotype', 'HP:0001636', (135, 154))	('TOF', 'Phenotype', 'HP:0001636', (156, 159))	('binding', 'molecular_function', 'GO:0005488', ('72', '79'))	('TAZ', 'Protein', (83, 86))	('TBX5', 'Gene', (55, 59))
108625	25702974	When MST1 is knocked out in these mice, they show increased motor neuron viability, delayed symptom onset, and extended survival, although it is not clear whether YAP or TAZ are involved in this phenotype.	('increased motor neuron', 'Phenotype', 'HP:0002450', (50, 72))	('motor neuron viability', 'CPA', (60, 82))	('mice', 'Species', '10090', (34, 38))	('increased', 'PosReg', (50, 59))	('MST1', 'Gene', '15235', (5, 9))	('MST1', 'Gene', (5, 9))	('knocked out', 'Var', (13, 24))
108633	25702974	One study deleted MOB1A, with a heterozygous mutation for MOB1B, and found that these mice have an increased lifetime chance of developing HCC.	('HCC', 'Disease', (139, 142))	('deleted', 'Var', (10, 17))	('MOB1A', 'Gene', (18, 23))	('MOB1B', 'Gene', (58, 63))	('HCC', 'Phenotype', 'HP:0001402', (139, 142))	('mice', 'Species', '10090', (86, 90))	('MOB1B', 'Gene', '68473', (58, 63))	('mutation', 'Var', (45, 53))	('MOB1A', 'Gene', '232157', (18, 23))
108634	25702974	Increased liver growth and HCC have also been reported in liver-specific SAV1 knockout, NF2 knockout, and MST1/2 knockout mice.	('mice', 'Species', '10090', (122, 126))	('knockout', 'Var', (92, 100))	('knockout', 'Var', (78, 86))	('Increased', 'PosReg', (0, 9))	('NF2', 'Gene', (88, 91))	('HCC', 'Phenotype', 'HP:0001402', (27, 30))	('SAV1', 'Gene', (73, 77))	('HCC', 'CPA', (27, 30))	('liver growth', 'CPA', (10, 22))	('Increased liver', 'Phenotype', 'HP:0002240', (0, 15))
108637	25702974	However, much of the current understanding of the Hippo pathway in HCC has been derived from genetic models, and few mutations or deletions in Hippo pathway components have been observed in human HCC.	('HCC', 'Disease', (67, 70))	('deletions', 'Var', (130, 139))	('HCC', 'Phenotype', 'HP:0001402', (67, 70))	('human', 'Species', '9606', (190, 195))	('HCC', 'Phenotype', 'HP:0001402', (196, 199))
108641	25702974	Although research on the role of YAP/TAZ in EHE is at its infancy, the observation that YAP/TAZ chromosome translocations occur in virtually all cases of EHE strongly suggest that dysregulated YAP/TAZ fusion proteins may act as cancer drivers.	('cancer', 'Disease', (228, 234))	('EHE', 'Phenotype', 'HP:0032060', (44, 47))	('EHE', 'Phenotype', 'HP:0032060', (154, 157))	('YAP/TAZ', 'Protein', (193, 200))	('dysregulated', 'Var', (180, 192))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('EHE', 'Disease', (154, 157))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
108645	25702974	Similarly, overexpressing YAP in breast cancer cell lines induces tumor formation and growth in xenograft experiments, and deleting YAP prevents tumor growth in an oncogene-induced breast cancer model.	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('tumor', 'Disease', (66, 71))	('breast cancer', 'Disease', (181, 194))	('YAP', 'Gene', (132, 135))	('tumor', 'Disease', (145, 150))	('formation', 'biological_process', 'GO:0009058', ('72', '81'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('deleting', 'Var', (123, 131))	('growth', 'CPA', (86, 92))	('induces', 'PosReg', (58, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('prevents', 'NegReg', (136, 144))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('breast cancer', 'Disease', (33, 46))
108648	25702974	YAP protein expression is decreased in luminal breast cancer tissues, and YAP knockdown in breast cancer cell lines actually enhances tumor migration, invasion, and tumor growth in nude mice.	('YAP', 'Gene', (0, 3))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('nude mice', 'Species', '10090', (181, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('invasion', 'CPA', (151, 159))	('luminal breast cancer', 'Disease', (39, 60))	('YAP', 'Gene', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', (165, 170))	('breast cancer', 'Disease', (91, 104))	('enhances', 'PosReg', (125, 133))	('protein', 'Protein', (4, 11))	('luminal breast cancer', 'Disease', 'MESH:D001943', (39, 60))	('knockdown', 'Var', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
108649	25702974	A recent study reported that hyperactivation of YAP alone is not sufficient to drive mammary tumorigenesis in vivo, and YAP-induced oncogenic growth may be dependent on the presence of additional mutations or amplifications.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('YAP', 'Gene', (48, 51))	('hyperactivation', 'Var', (29, 44))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
108650	25702974	YAP/TAZ are both highly expressed in non-small cell lung cancer (NSCLC) in humans, and knockdown of either YAP or TAZ in NSCLC cells is sufficient to suppress proliferation, invasion, and tumor growth in mice.	('tumor', 'Disease', (188, 193))	('proliferation', 'CPA', (159, 172))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mice', 'Species', '10090', (204, 208))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (37, 63))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (41, 63))	('TAZ', 'Gene', (114, 117))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (37, 63))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('YAP', 'Gene', (107, 110))	('invasion', 'CPA', (174, 182))	('humans', 'Species', '9606', (75, 81))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('suppress', 'NegReg', (150, 158))	('NSCLC', 'Disease', (65, 70))	('knockdown', 'Var', (87, 96))	('NSCLC', 'Disease', (121, 126))	('non-small cell lung cancer', 'Disease', (37, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
108651	25702974	In fact, it has been shown that knockdown of either YAP or TAZ is sufficient to decrease cell migration in vitro and metastasis in vivo, and expression of constitutively active YAP is sufficient to drive lung cancer progression in vivo.	('lung cancer', 'Disease', 'MESH:D008175', (204, 215))	('knockdown', 'Var', (32, 41))	('YAP', 'Gene', (177, 180))	('YAP', 'Gene', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cell migration', 'biological_process', 'GO:0016477', ('89', '103'))	('lung cancer', 'Disease', (204, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('cell migration', 'CPA', (89, 103))	('decrease', 'NegReg', (80, 88))	('drive', 'PosReg', (198, 203))
108653	25702974	Overexpression of MST1 is sufficient to inhibit cell proliferation and apoptosis in NSCLC cells.	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('MST1', 'Gene', (18, 22))	('inhibit', 'NegReg', (40, 47))	('apoptosis', 'CPA', (71, 80))	('MST1', 'Gene', '15235', (18, 22))	('cell proliferation', 'CPA', (48, 66))	('NSCLC', 'Disease', (84, 89))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('Overexpression', 'Var', (0, 14))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('cell proliferation', 'biological_process', 'GO:0008283', ('48', '66'))
108656	25702974	Vestigial-like family member 4 (VGLL4) is frequently down-regulated in lung cancer, and expressing VGLL4 in lung cancer cells suppresses cell proliferation and tumor growth in mice by competitively inhibiting YAP-TEAD binding and transcriptional activity.	('VGLL4', 'Gene', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cell proliferation', 'biological_process', 'GO:0008283', ('137', '155'))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('VGLL4', 'Gene', '232334', (32, 37))	('transcriptional activity', 'CPA', (230, 254))	('cell proliferation', 'CPA', (137, 155))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('lung cancer', 'Disease', (108, 119))	('Vestigial-like family member 4', 'Gene', (0, 30))	('expressing', 'Var', (88, 98))	('down-regulated', 'NegReg', (53, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('suppresses', 'NegReg', (126, 136))	('mice', 'Species', '10090', (176, 180))	('VGLL4', 'Gene', (99, 104))	('tumor', 'Disease', (160, 165))	('Vestigial-like family member 4', 'Gene', '232334', (0, 30))	('inhibiting', 'NegReg', (198, 208))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('VGLL4', 'Gene', '232334', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('YAP-TEAD', 'Protein', (209, 217))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('binding', 'molecular_function', 'GO:0005488', ('218', '225'))	('lung cancer', 'Disease', (71, 82))
108657	25702974	Another study found that high YAP expression was correlated with increased AXL receptor tyrosine kinase (Axl) expression in lung adenocarcinomas, and that knocking down YAP also resulted in loss of Axl, proliferating cell nuclear antigen (PCNA), and matrix metalloproteinase-9 (MMP-9).	('expression', 'MPA', (34, 44))	('proliferating cell nuclear antigen', 'molecular_function', 'GO:0003892', ('203', '237'))	('YAP', 'Gene', (30, 33))	('PCNA', 'Gene', (239, 243))	('Axl', 'Gene', '26362', (105, 108))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (124, 144))	('Axl', 'Gene', (198, 201))	('AXL', 'Gene', (75, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('increased', 'PosReg', (65, 74))	('proliferating cell nuclear antigen', 'Gene', '18538', (203, 237))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (124, 144))	('YAP', 'Gene', (169, 172))	('AXL', 'Gene', '26362', (75, 78))	('expression', 'MPA', (110, 120))	('MMP-9', 'molecular_function', 'GO:0004229', ('278', '283'))	('PCNA', 'molecular_function', 'GO:0003892', ('239', '243'))	('matrix metalloproteinase-9', 'Gene', (250, 276))	('lung adenocarcinomas', 'Disease', (124, 144))	('MMP-9', 'Gene', '17395', (278, 283))	('proliferating cell nuclear antigen', 'Gene', (203, 237))	('Axl', 'Gene', (105, 108))	('MMP-9', 'Gene', (278, 283))	('loss', 'NegReg', (190, 194))	('knocking down', 'Var', (155, 168))	('Axl', 'Gene', '26362', (198, 201))	('PCNA', 'Gene', '18538', (239, 243))	('matrix metalloproteinase-9', 'Gene', '17395', (250, 276))
108658	25702974	This study further confirmed that knocking down YAP inhibits proliferation and invasion of lung cancer cells, an effect which is potentially mediated through Axl.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('YAP', 'Gene', (48, 51))	('Axl', 'Gene', (158, 161))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('inhibits', 'NegReg', (52, 60))	('Axl', 'Gene', '26362', (158, 161))	('invasion', 'CPA', (79, 87))	('proliferation', 'CPA', (61, 74))	('lung cancer', 'Disease', (91, 102))	('knocking down', 'Var', (34, 47))
108659	25702974	Finally, miR-135b expression increases lung cancer metastasis by targeting LATS2, and inhibiting miR-135b suppresses tumor growth and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('miR-135b', 'Gene', (9, 17))	('miR-135b', 'Gene', '723818', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('increases lung cancer', 'Disease', 'MESH:D008175', (29, 50))	('LATS2', 'Gene', (75, 80))	('tumor', 'Disease', (117, 122))	('inhibiting', 'Var', (86, 96))	('miR-135b', 'Gene', '723818', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('targeting', 'Reg', (65, 74))	('suppresses', 'NegReg', (106, 116))	('miR-135b', 'Gene', (97, 105))	('increases lung cancer', 'Disease', (29, 50))
108660	25702974	Expression of miR-135b is regulated by DNA demethylation and nuclear factor-kappa B (NFKb) signaling, raising the possibility that inflammatory and epigenetic modifications may regulate expression of miR-135b, thereby resulting in LATS2 inhibition, YAP/TAZ nuclear translocation, and cancer.	('miR-135b', 'Gene', '723818', (14, 22))	('miR-135b', 'Gene', (200, 208))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('regulate', 'Reg', (177, 185))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('DNA demethylation', 'biological_process', 'GO:0080111', ('39', '56'))	('cancer', 'Disease', (284, 290))	('modifications', 'Var', (159, 172))	('miR-135b', 'Gene', '723818', (200, 208))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('expression', 'MPA', (186, 196))	('miR-135b', 'Gene', (14, 22))	('LATS2', 'Protein', (231, 236))	('inhibition', 'NegReg', (237, 247))	('resulting in', 'Reg', (218, 230))	('YAP/TAZ', 'MPA', (249, 256))
108662	25702974	Recent work has found that homozygous deletion or inactivating mutations in NF2, SAV1, or LATS2 are frequently observed in human malignant mesothelioma tissues and cell lines.	('observed', 'Reg', (111, 119))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (129, 151))	('human', 'Species', '9606', (123, 128))	('NF2', 'Gene', (76, 79))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (129, 151))	('SAV1', 'Gene', (81, 85))	('inactivating mutations', 'Var', (50, 72))	('malignant mesothelioma', 'Disease', (129, 151))	('LATS2', 'Gene', (90, 95))
108664	25702974	These deletions or mutations contribute to increased YAP protein levels and aberrant YAP-TEAD transcriptional activity, which drive increased cell proliferation and anchorage-independent growth by up-regulating the cell cycle-promoting Cyclin D1 and Forkhead box M1.	('Cyclin', 'molecular_function', 'GO:0016538', ('236', '242'))	('cell cycle', 'biological_process', 'GO:0007049', ('215', '225'))	('YAP protein', 'Protein', (53, 64))	('anchorage-independent growth', 'CPA', (165, 193))	('cell cycle-promoting', 'CPA', (215, 235))	('mutations', 'Var', (19, 28))	('up-regulating', 'PosReg', (197, 210))	('aberrant', 'Var', (76, 84))	('deletions', 'Var', (6, 15))	('cell proliferation', 'CPA', (142, 160))	('Cyclin D1', 'Gene', (236, 245))	('increased', 'PosReg', (132, 141))	('YAP-TEAD', 'Gene', (85, 93))	('increased', 'PosReg', (43, 52))	('cell proliferation', 'biological_process', 'GO:0008283', ('142', '160'))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('Cyclin D1', 'Gene', '12443', (236, 245))	('Forkhead', 'Protein', (250, 258))
108665	25702974	Knocking down YAP in malignant mesothelioma cells is sufficient to inhibit cell proliferation and anchorage-independent growth.	('inhibit', 'NegReg', (67, 74))	('anchorage-independent growth', 'CPA', (98, 126))	('Knocking down', 'Var', (0, 13))	('YAP', 'Gene', (14, 17))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (21, 43))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (21, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('malignant mesothelioma', 'Disease', (21, 43))	('cell proliferation', 'CPA', (75, 93))
108666	25702974	Together, these findings strongly implicate dysregulation of the Hippo pathway in malignant mesothelioma and YAP as a potential therapeutic target.	('YAP', 'Disease', (109, 112))	('dysregulation', 'Var', (44, 57))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (82, 104))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (82, 104))	('Hippo pathway', 'Pathway', (65, 78))	('malignant mesothelioma', 'Disease', (82, 104))
108667	25702974	As cases of malignant mesothelioma are primarily associated with asbestos exposure, it may be informative to determine whether there is something about asbestos that is pre-inclined to inducing mutations in Hippo pathway components.	('asbestos', 'Chemical', 'MESH:D001194', (65, 73))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (12, 34))	('associated', 'Reg', (49, 59))	('mutations', 'Var', (194, 203))	('asbestos', 'Chemical', 'MESH:D001194', (152, 160))	('malignant mesothelioma', 'Disease', (12, 34))	('pre', 'molecular_function', 'GO:0003904', ('169', '172'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (12, 34))
108669	25702974	Moreover, in pancreatic cancer cells, YAP knockdown results in reduced proliferation and reduced anchorage-independent growth, suggesting YAP may play an important role in PDAC progression.	('pancreatic cancer', 'Disease', (13, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (13, 30))	('YAP', 'Gene', (38, 41))	('reduced', 'NegReg', (63, 70))	('PDAC', 'Phenotype', 'HP:0006725', (172, 176))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (13, 30))	('PDAC', 'Disease', (172, 176))	('reduced', 'NegReg', (89, 96))	('proliferation', 'CPA', (71, 84))	('anchorage-independent growth', 'CPA', (97, 125))	('knockdown', 'Var', (42, 51))
108671	25702974	KRAS is frequently mutated in PDAC, but in a mouse model expressing mutated KRAS, deleting YAP is sufficient to prevent PDAC.	('KRAS', 'Gene', '16653', (76, 80))	('deleting', 'Var', (82, 90))	('KRAS', 'Gene', (76, 80))	('PDAC', 'Disease', (120, 124))	('mouse', 'Species', '10090', (45, 50))	('PDAC', 'Phenotype', 'HP:0006725', (120, 124))	('PDAC', 'Phenotype', 'HP:0006725', (30, 34))	('YAP', 'Gene', (91, 94))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '16653', (0, 4))
108672	25702974	In addition, deleting YAP in pancreatic cancer cells harboring the mutant KRAS is sufficient to prevent proliferation and growth in mice.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (29, 46))	('proliferation', 'CPA', (104, 117))	('deleting', 'Var', (13, 21))	('prevent', 'NegReg', (96, 103))	('KRAS', 'Gene', '16653', (74, 78))	('pancreatic cancer', 'Disease', 'MESH:D010190', (29, 46))	('KRAS', 'Gene', (74, 78))	('pancreatic cancer', 'Disease', (29, 46))	('mice', 'Species', '10090', (132, 136))	('mutant', 'Var', (67, 73))	('YAP', 'Gene', (22, 25))	('growth', 'CPA', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
108673	25702974	A similar study found that in an inducible KRAS-driven PDAC mouse model where removal of KRAS resulted in complete tumor regression, some mice later developed spontaneous tumors due to YAP amplification and increased YAP-TEAD2 transcriptional activity.	('PDAC', 'Phenotype', 'HP:0006725', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('transcriptional activity', 'MPA', (227, 251))	('mice', 'Species', '10090', (138, 142))	('developed', 'PosReg', (149, 158))	('KRAS', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('KRAS', 'Gene', '16653', (43, 47))	('mouse', 'Species', '10090', (60, 65))	('KRAS', 'Gene', (89, 93))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('YAP', 'Gene', (185, 188))	('increased', 'PosReg', (207, 216))	('amplification', 'Var', (189, 202))	('TEAD2', 'Gene', '21677', (221, 226))	('tumor', 'Disease', (171, 176))	('TEAD2', 'Gene', (221, 226))	('KRAS', 'Gene', '16653', (89, 93))
108681	25702974	Although overexpression of mutant Gq/11 is sufficient to transform melanocytes, the signaling events downstream of Gq/11 were unknown.	('Gq/11', 'Gene', (34, 39))	('transform', 'Reg', (57, 66))	('mutant', 'Var', (27, 33))	('melanocytes', 'CPA', (67, 78))	('Gq/11', 'Chemical', '-', (115, 120))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('Gq/11', 'Chemical', '-', (34, 39))
108687	25702974	Indeed, RCC tissues show elevated levels of YAP, and knocking down YAP in RCC cell lines blocks cell proliferation and increases apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('RCC', 'Disease', (8, 11))	('increases', 'PosReg', (119, 128))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('blocks', 'NegReg', (89, 95))	('apoptosis', 'CPA', (129, 138))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('cell proliferation', 'CPA', (96, 114))	('YAP', 'Gene', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('cell proliferation', 'biological_process', 'GO:0008283', ('96', '114'))	('knocking down', 'Var', (53, 66))
108689	25702974	Although the most common mutations in CRC involve adenomatous polyposis coli (APC) and dysregulated beta-catenin signaling, YAP/TAZ may be required downstream mediators of these mutations.	('APC', 'Phenotype', 'HP:0005227', (78, 81))	('beta-catenin', 'Gene', (100, 112))	('mutations', 'Var', (25, 34))	('APC', 'Disease', 'MESH:D011125', (78, 81))	('signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('CRC', 'Phenotype', 'HP:0003003', (38, 41))	('CRC', 'Gene', (38, 41))	('APC', 'Disease', (78, 81))	('beta-catenin', 'Gene', '12387', (100, 112))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (50, 76))	('adenomatous polyposis coli', 'Gene', '11789', (50, 76))	('adenomatous polyposis coli', 'Gene', (50, 76))	('APC', 'cellular_component', 'GO:0005680', ('78', '81'))
108696	25702974	LATS1 promoter methylation has also been reported in CRC, which may lead to increased YAP activity.	('methylation', 'Var', (15, 26))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('increased', 'PosReg', (76, 85))	('LATS1', 'Gene', (0, 5))	('CRC', 'Disease', (53, 56))	('LATS1', 'Gene', '16798', (0, 5))	('YAP activity', 'CPA', (86, 98))	('CRC', 'Phenotype', 'HP:0003003', (53, 56))
108702	25702974	These cancers are typically characterized by genetic instability and inactivating mutations in tumor protein p53 (TP53).	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('inactivating mutations', 'Var', (69, 91))	('TP53', 'Gene', '22059', (114, 118))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('p53', 'Gene', (109, 112))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('p53', 'Gene', '22059', (109, 112))	('TP53', 'Gene', (114, 118))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancers', 'Disease', (6, 13))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('tumor', 'Disease', (95, 100))
108708	25702974	Loss of function mutations in NF2 causes Neurofibromatosis Type 2, a genetic disorder characterized by the development of schwannomas and meningiomas with increased YAP expression and nuclear localization.	('schwannomas and meningiomas', 'Disease', 'MESH:D009442', (122, 149))	('genetic disorder', 'Disease', 'MESH:D030342', (69, 85))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (41, 58))	('Loss of function', 'NegReg', (0, 16))	('schwannomas', 'Phenotype', 'HP:0100008', (122, 133))	('Neurofibromatosis Type 2', 'Disease', (41, 65))	('NF2', 'Gene', (30, 33))	('meningiomas', 'Phenotype', 'HP:0002858', (138, 149))	('genetic disorder', 'Disease', (69, 85))	('Neurofibromatosis Type 2', 'Disease', 'MESH:C537392', (41, 65))	('mutations', 'Var', (17, 26))	('localization', 'biological_process', 'GO:0051179', ('192', '204'))
108709	25702974	Loss of function mutations in NF2 results in increased LATS degradation and YAP accumulation, so loss of NF2 and subsequent tumor growth could be due to aberrant YAP activity.	('loss', 'NegReg', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('increased', 'PosReg', (45, 54))	('LATS degradation', 'MPA', (55, 71))	('tumor', 'Disease', (124, 129))	('YAP accumulation', 'MPA', (76, 92))	('Loss of function', 'NegReg', (0, 16))	('NF2', 'Gene', (105, 108))	('NF2', 'Gene', (30, 33))	('degradation', 'biological_process', 'GO:0009056', ('60', '71'))	('mutations', 'Var', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
108710	25702974	In the central nervous system, NF2 expression is also significantly reduced in human malignant gliomas, and expression of NF2 has been shown to inhibit human glioma growth both in vitro and in vivo.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('NF2', 'Gene', (122, 125))	('malignant gliomas', 'Disease', (85, 102))	('NF2', 'Gene', (31, 34))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('human', 'Species', '9606', (79, 84))	('malignant gliomas', 'Disease', 'MESH:D005910', (85, 102))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('expression', 'MPA', (35, 45))	('glioma', 'Disease', (95, 101))	('glioma', 'Disease', 'MESH:D005910', (95, 101))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('human', 'Species', '9606', (152, 157))	('glioma', 'Disease', (158, 164))	('inhibit', 'NegReg', (144, 151))	('reduced', 'NegReg', (68, 75))	('expression', 'Var', (108, 118))
108723	25702974	APC is frequently mutated in colorectal cancer Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) a genetic disease caused by mutations in desmosome components.	('Arrhythmogenic Right Ventricular Cardiomyopathy', 'Disease', 'MESH:D019571', (47, 94))	('APC', 'Phenotype', 'HP:0005227', (0, 3))	('Cardiomyopathy', 'Phenotype', 'HP:0001638', (80, 94))	('APC', 'cellular_component', 'GO:0005680', ('0', '3'))	('Arrhythmogenic Right Ventricular Cardiomyopathy', 'Disease', (47, 94))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('colorectal cancer', 'Disease', 'MESH:D015179', (29, 46))	('caused by', 'Reg', (120, 129))	('genetic disease', 'Disease', (104, 119))	('APC', 'Disease', (0, 3))	('mutations', 'Var', (130, 139))	('genetic disease', 'Disease', 'MESH:D030342', (104, 119))	('Right Ventricular Cardiomyopathy', 'Phenotype', 'HP:0011663', (62, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (29, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('colorectal cancer', 'Disease', (29, 46))	('desmosome', 'cellular_component', 'GO:0030057', ('143', '152'))
108725	25702974	YAP may block intestinal regeneration by preventing DVL nuclear translocation FBJ Murine Osteosarcoma Viral Oncogene Homolog B (FOSB) a transcription factor that is frequently fused with TAZ due to a chromosomal translocation in epithelioid hemangioendothelioma Gq/11 GNAQ and GNA11 encode the GPCR subunits Gq and G11.	('Osteosarcoma Viral', 'Disease', 'MESH:D012516', (89, 107))	('regeneration', 'biological_process', 'GO:0031099', ('25', '37'))	('Osteosarcoma Viral', 'Disease', (89, 107))	('FOSB', 'Gene', '14282', (128, 132))	('GNA11', 'Gene', (277, 282))	('epithelioid hemangioendothelioma', 'Disease', (229, 261))	('transcription', 'biological_process', 'GO:0006351', ('136', '149'))	('transcription factor', 'molecular_function', 'GO:0000981', ('136', '156'))	('epithelioid hemangioendothelioma', 'Phenotype', 'HP:0032060', (229, 261))	('GNAQ', 'Gene', (268, 272))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('GNA11', 'Gene', '14672', (277, 282))	('chromosomal translocation', 'Var', (200, 225))	('GNAQ', 'Gene', '14682', (268, 272))	('Murine', 'Species', '10090', (82, 88))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('epithelioid hemangioendothelioma', 'Disease', 'MESH:D018323', (229, 261))	('intestinal regeneration', 'CPA', (14, 37))	('GPCR', 'Gene', '23890', (294, 298))	('G11', 'Gene', (315, 318))	('G11', 'Gene', '319922', (315, 318))	('FOSB', 'Gene', (128, 132))	('Gq/11', 'Chemical', '-', (262, 267))	('Gq/11', 'Gene', (262, 267))	('GPCR', 'Gene', (294, 298))	('block', 'NegReg', (8, 13))	('DVL', 'MPA', (52, 55))
108726	25702974	Mutations in GNAQ and GNA11 are frequently observed in uveal melanoma G-Protein Coupled Receptors (GPCR) GPCRs make up the largest class of receptors in the cell, and are responsible for regulating a variety of important cellular responses including cell proliferation and survival Plakoglobin (JUP) Plakoglobin is a required component for intact desmosome assembly.	('uveal melanoma', 'Phenotype', 'HP:0007716', (55, 69))	('GNAQ', 'Gene', (13, 17))	('G-Protein Coupled Receptors', 'Gene', (70, 97))	('G-Protein Coupled Receptors', 'Gene', '23890', (70, 97))	('GNA11', 'Gene', (22, 27))	('GNAQ', 'Gene', '14682', (13, 17))	('Mutations', 'Var', (0, 9))	('responsible', 'Reg', (171, 182))	('GPCR', 'Gene', '23890', (105, 109))	('regulating', 'Reg', (187, 197))	('GPCR', 'Gene', '23890', (99, 103))	('GPCR', 'Gene', (105, 109))	('GNA11', 'Gene', '14672', (22, 27))	('GPCR', 'Gene', (99, 103))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('desmosome assembly', 'biological_process', 'GO:0002159', ('347', '365'))	('uveal melanoma', 'Disease', (55, 69))	('uveal melanoma', 'Disease', 'MESH:C536494', (55, 69))	('desmosome', 'cellular_component', 'GO:0030057', ('347', '356'))	('cell proliferation', 'biological_process', 'GO:0008283', ('250', '268'))	('JUP', 'Gene', '16480', (295, 298))	('JUP', 'Gene', (295, 298))	('cell proliferation', 'CPA', (250, 268))
108728	25702974	Mutations in JUP are associated with ARVC Large Tumor Suppressor 1/2 (LATS1/2) LATS1 and 2 are serine/threonine kinases that are phosphorylated and activated by MST1/2 and MOB1.	('JUP', 'Gene', (13, 16))	('Tumor', 'Phenotype', 'HP:0002664', (48, 53))	('JUP', 'Gene', '16480', (13, 16))	('Tumor Suppressor', 'biological_process', 'GO:0051726', ('48', '64'))	('LATS1 and 2', 'Gene', '16798;50523', (79, 90))	('Large Tumor Suppressor 1/2', 'Gene', (42, 68))	('Mutations', 'Var', (0, 9))	('Tumor Suppressor', 'molecular_function', 'GO:0008181', ('48', '64'))	('Large Tumor Suppressor 1/2', 'Gene', '50523', (42, 68))
108729	25702974	Once activated, LATS1/2 phosphorylate and inactivate YAP Lysophosphatidic Acid (LPA) a potent inducer of YAP activity via signaling through GPCRs Mob1 Homolog (MOB1) MOB1 is phosphorylated by MST1/2.	('GPCR', 'Gene', '23890', (140, 144))	('Mob1', 'Gene', '232157', (146, 150))	('Mob1', 'Gene', (146, 150))	('inactivate', 'Var', (42, 52))	('Lysophosphatidic Acid', 'Chemical', 'MESH:C032881', (57, 78))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('LPA', 'Chemical', 'MESH:C032881', (80, 83))	('GPCR', 'Gene', (140, 144))
108734	25702974	Mutations in TBX5 are associated with Holt-Oram Syndrome TEA Domain Family Members 1-4 (TEAD1-4) the main transcription factors that interact with YAP/TAZ to drive transcription.	('TEAD1-4', 'Gene', (88, 95))	('TEAD1-4', 'Gene', '21676;21677;21678;21679', (88, 95))	('Holt-Oram Syndrome', 'Disease', (38, 56))	('transcription', 'biological_process', 'GO:0006351', ('164', '177'))	('TBX5', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('transcription', 'biological_process', 'GO:0006351', ('106', '119'))	('associated', 'Reg', (22, 32))
108736	25702974	When dephosphorylated, YAP translocates to the nucleus and interacts with a variety of transcription factors, including TEAD1-4, to induce gene expression Dysregulation of the Hippo pathway is implicated in a variety of cancers and diseases Hippo pathway may be a therapeutic target in a number of cancers Manipulating the Hippo pathway may improve regeneration following injury	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('TEAD1-4', 'Gene', (120, 127))	('TEAD1-4', 'Gene', '21676;21677;21678;21679', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (298, 305))	('cancers', 'Phenotype', 'HP:0002664', (298, 305))	('Dysregulation', 'Var', (155, 168))	('cancers', 'Disease', (298, 305))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('nucleus', 'cellular_component', 'GO:0005634', ('47', '54'))	('improve', 'PosReg', (341, 348))	('cancers', 'Disease', (220, 227))	('regeneration following', 'CPA', (349, 371))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('gene expression', 'biological_process', 'GO:0010467', ('139', '154'))	('transcription', 'biological_process', 'GO:0006351', ('87', '100'))	('regeneration', 'biological_process', 'GO:0031099', ('349', '361'))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
108820	25580155	Adjuvant cryotherapy induces necrosis of tumor cells during the thawing portion due to the efflux of intracellular contents, and reduces recurrence in comparison to excision alone.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('intracellular', 'cellular_component', 'GO:0005622', ('101', '114'))	('necrosis', 'biological_process', 'GO:0019835', ('29', '37'))	('necrosis', 'biological_process', 'GO:0001906', ('29', '37'))	('efflux of intracellular contents', 'MPA', (91, 123))	('necrosis', 'biological_process', 'GO:0008220', ('29', '37'))	('efflux', 'biological_process', 'GO:0140115', ('91', '97'))	('efflux', 'biological_process', 'GO:0140352', ('91', '97'))	('cryotherapy', 'Var', (9, 20))	('recurrence', 'CPA', (137, 147))	('necrosis of tumor', 'Disease', (29, 46))	('necrosis', 'biological_process', 'GO:0070265', ('29', '37'))	('necrosis', 'biological_process', 'GO:0008219', ('29', '37'))	('necrosis of tumor', 'Disease', 'MESH:D009336', (29, 46))	('reduces', 'NegReg', (129, 136))
108827	25580155	Less commonly, damage to the eyelids, uvea, and extraocular muscles may result in ectropion, uveitis, and possible paralysis of extraocular muscles especially if muscle insertion sites are involved.	('paralysis', 'Phenotype', 'HP:0003470', (115, 124))	('uvea', 'Disease', 'MESH:C536494', (38, 42))	('ectropion', 'Disease', (82, 91))	('paralysis', 'Disease', (115, 124))	('paralysis', 'Disease', 'MESH:D010243', (115, 124))	('uveitis', 'Phenotype', 'HP:0000554', (93, 100))	('ectropion', 'Phenotype', 'HP:0000656', (82, 91))	('uveitis', 'Disease', 'MESH:D014605', (93, 100))	('uvea', 'Disease', (38, 42))	('result in', 'Reg', (72, 81))	('damage', 'Var', (15, 21))	('uveitis', 'Disease', (93, 100))
108842	25580155	The regimen in this case is most commonly 0.04% four times a day for cycles of 14 consecutive days with 1-week intervals in between cycles to avoid toxicity from prolonged exposure to MMC.	('MMC', 'Chemical', 'MESH:D016685', (184, 187))	('toxicity', 'Disease', (148, 156))	('0.04%', 'Var', (42, 47))	('toxicity', 'Disease', 'MESH:D064420', (148, 156))
108853	25580155	The regimens when MMC was used as adjuvant therapy following surgical excision of CMM, were 0.04% MMC four times a day for 1 week, for three weeks followed by one week of topical corticosteroid, for 4 weeks, or for 3 weeks followed by 3 weeks without MMC over an average of 2.0 cycles.	('CMM', 'Gene', (82, 85))	('topical', 'molecular_function', 'GO:0003809', ('171', '178'))	('MMC', 'Chemical', 'MESH:D016685', (98, 101))	('CMM', 'Gene', '1243', (82, 85))	('0.04%', 'Var', (92, 97))	('CMM', 'Phenotype', 'HP:0007716', (82, 85))	('MMC', 'Chemical', 'MESH:D016685', (251, 254))	('MMC', 'Chemical', 'MESH:D016685', (18, 21))
108857	25580155	In a study of 91 patients with OSSN treated with 0.04% MMC four times a day for 1-3 cycles of 7 consecutive days, patients most commonly complained of an allergic reaction (31/91 or 34%) after the second or third cycle, and epiphora secondary to punctal stenosis after a median of 2 months (14/91 or 15%).	('epiphora', 'Phenotype', 'HP:0009926', (224, 232))	('OSSN', 'Chemical', '-', (31, 35))	('allergic reaction', 'Phenotype', 'HP:0012393', (154, 171))	('0.04%', 'Var', (49, 54))	('epiphora secondary to punctal stenosis', 'Disease', 'MESH:D007766', (224, 262))	('MMC', 'Chemical', 'MESH:D016685', (55, 58))	('allergic reaction', 'Disease', 'MESH:D004342', (154, 171))	('epiphora secondary to punctal stenosis', 'Disease', (224, 262))	('patients', 'Species', '9606', (17, 25))	('punctal stenosis', 'Phenotype', 'HP:0025572', (246, 262))	('complained', 'Reg', (137, 147))	('patients', 'Species', '9606', (114, 122))	('allergic reaction', 'Disease', (154, 171))
108877	25580155	Brachytherapy has also been reported to reduce recurrence in comparison to excision alone, excision with cryotherapy, or excision with MMC, although results were only statistically significant when compared against excision with cryotherapy.	('reduce', 'NegReg', (40, 46))	('MMC', 'Chemical', 'MESH:D016685', (135, 138))	('Brachytherapy', 'Var', (0, 13))	('recurrence', 'MPA', (47, 57))
108912	25580155	A trial is currently underway to evaluate SLNB through the outcome measures of: frequency of SLNB positivity in CMM, false negative rate for this measure, and identifying any ocular or periocular complications of the technique and risk of facial nerve damage (ClinicalTrials.gov Identifier: NCT00386906).	('false', 'biological_process', 'GO:0071878', ('117', '122'))	('facial nerve damage', 'Disease', 'MESH:D005155', (239, 258))	('facial nerve damage', 'Phenotype', 'HP:0010628', (239, 258))	('CMM', 'Gene', '1243', (112, 115))	('CMM', 'Phenotype', 'HP:0007716', (112, 115))	('SLNB', 'Gene', (93, 97))	('false', 'biological_process', 'GO:0071877', ('117', '122'))	('facial nerve damage', 'Disease', (239, 258))	('positivity', 'Var', (98, 108))	('CMM', 'Gene', (112, 115))
108940	25580155	The treatment of cutaneous melanoma has been revolutionized by the discovery of unique genetic mutations in affected tissues, and the novel biological therapies that have been developed to target the downstream effects of these mutations.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (17, 35))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (17, 35))	('mutations', 'Var', (228, 237))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('mutations', 'Var', (95, 104))	('cutaneous melanoma', 'Disease', (17, 35))
108947	25580155	Vemurafenib and dabrafenib are highly selective BRAF-kinase inhibitors, a mutation found in 60 percent of cutaneous melanomas, primarily at the V600E position.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (106, 125))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (106, 125))	('V600E', 'Var', (144, 149))	('dabrafenib', 'Chemical', 'MESH:C561627', (16, 26))	('cutaneous melanomas', 'Disease', (106, 125))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('V600E', 'Mutation', 'rs113488022', (144, 149))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (106, 124))
108953	25580155	BRAF has received the most attention, due to a high level of concordance in the BRAF mutation between cutaneous and conjunctival melanoma.	('BRAF', 'Gene', (80, 84))	('conjunctival melanoma', 'Disease', (116, 137))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (116, 137))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (116, 137))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('cutaneous', 'Disease', (102, 111))	('mutation', 'Var', (85, 93))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (80, 84))
108954	25580155	A total of 6 case series were found in the literature assessing the presence of BRAF mutations in CMM, covering a total of 163 cases (Table 9).	('BRAF', 'Gene', (80, 84))	('CMM', 'Gene', '1243', (98, 101))	('CMM', 'Phenotype', 'HP:0007716', (98, 101))	('mutations', 'Var', (85, 94))	('BRAF', 'Gene', '673', (80, 84))	('CMM', 'Gene', (98, 101))
108958	25580155	Interestingly, the idea has been proposed that there is the potential for synergistic effect should ipilimumab and vemurafenib be combined, as BRAF inhibitors can cause higher tumor recognition by T-cells which would be activated by the effects of ipilimumab, and this treatment may be explored in clinical trials in the future.	('inhibitors', 'Var', (148, 158))	('higher', 'PosReg', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('ipilimumab', 'Chemical', 'MESH:D000074324', (100, 110))	('ipilimumab', 'Chemical', 'MESH:D000074324', (248, 258))	('tumor', 'Disease', (176, 181))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('vemurafenib', 'Chemical', 'MESH:D000077484', (115, 126))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
108968	25580155	NRAS is an oncogene in the Ras family that encodes a GTPase which, when mutated, activates a signal transduction pathway that leads to unregulated cell division.	('mutated', 'Var', (72, 79))	('leads to', 'Reg', (126, 134))	('signal transduction', 'biological_process', 'GO:0007165', ('93', '112'))	('signal transduction pathway', 'Pathway', (93, 120))	('NRAS', 'Gene', (0, 4))	('activates', 'PosReg', (81, 90))	('unregulated', 'MPA', (135, 146))	('cell division', 'biological_process', 'GO:0051301', ('147', '160'))	('NRAS', 'Gene', '4893', (0, 4))
108972	25580155	Other genetic patterns in CMM reported include amplification of copy numbers CDKN1A and RUNX2 in primary tumors, and amplification of MLH1 and TIMP2, and deletion of MGMT and ECHS1 in metastasis-origin tumors.	('tumors', 'Disease', (105, 111))	('ECHS1', 'Gene', '1892', (175, 180))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('metastasis-origin', 'CPA', (184, 201))	('amplification', 'Reg', (47, 60))	('MLH1', 'Gene', (134, 138))	('CMM', 'Gene', (26, 29))	('RUNX2', 'Gene', (88, 93))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('TIMP2', 'Gene', (143, 148))	('RUNX2', 'Gene', '860', (88, 93))	('MGMT', 'Gene', '4255', (166, 170))	('MLH1', 'Gene', '4292', (134, 138))	('primary tumors', 'Disease', (97, 111))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('CMM', 'Gene', '1243', (26, 29))	('ECHS1', 'Gene', (175, 180))	('primary tumors', 'Disease', 'MESH:D009369', (97, 111))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('MGMT', 'molecular_function', 'GO:0003908', ('166', '170'))	('TIMP2', 'Gene', '7077', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('CDKN1A', 'Gene', (77, 83))	('MGMT', 'Gene', (166, 170))	('CMM', 'Phenotype', 'HP:0007716', (26, 29))	('tumors', 'Disease', (202, 208))	('CDKN1A', 'Gene', '1026', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('deletion', 'Var', (154, 162))	('amplification', 'Var', (117, 130))
108975	25580155	found that monosomy 3 was found in uveal melanoma whereas losses in 9p, gains in chromosome 7 or amplifications of CCND1 centromere proximal chromosomal areas of chromosome 11 favored CMM.	('uveal melanoma', 'Disease', 'MESH:C536494', (35, 49))	('CCND1', 'Gene', (115, 120))	('gains', 'PosReg', (72, 77))	('CMM', 'Gene', '1243', (184, 187))	('uveal melanoma', 'Disease', (35, 49))	('chromosome 7', 'Gene', (81, 93))	('CMM', 'Phenotype', 'HP:0007716', (184, 187))	('centromere', 'cellular_component', 'GO:0005698', ('121', '131'))	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('monosomy', 'Disease', (11, 19))	('CCND1', 'Gene', '595', (115, 120))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('CMM', 'Gene', (184, 187))	('centromere', 'cellular_component', 'GO:0000775', ('121', '131'))	('losses', 'NegReg', (58, 64))	('chromosome', 'cellular_component', 'GO:0005694', ('162', '172'))	('amplifications', 'Var', (97, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))
108984	25580155	The exciting advent of tumor specific mutations, and biological therapies that combat these mutations, have yielded promising results in cutaneous melanoma and this approach is currently being mirrored in CMM.	('CMM', 'Gene', '1243', (205, 208))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (137, 155))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('CMM', 'Phenotype', 'HP:0007716', (205, 208))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('CMM', 'Gene', (205, 208))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('mutations', 'Var', (38, 47))	('cutaneous melanoma', 'Disease', (137, 155))
108988	25580155	With regards to treatment, genetic evaluation of tumor and tumor specific biological therapies to combat mutations are an exciting new frontier.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('mutations', 'Var', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
108996	24882516	Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP Uveal melanoma (UM) is the most common cancer in adult eyes.	('uveal melanoma', 'Disease', (21, 35))	('Gq/11', 'Gene', (7, 12))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('uveal melanoma', 'Phenotype', 'HP:0007716', (21, 35))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('activating', 'PosReg', (53, 63))	('tumorigenesis', 'CPA', (36, 49))	('promote', 'PosReg', (13, 20))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('melanoma', 'Disease', (27, 35))	('Mutant', 'Var', (0, 6))	('cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('uveal melanoma', 'Disease', 'MESH:C536494', (21, 35))
108998	24882516	Herein, we show in both cell culture and human tumors that cancer-associated Gq/11 mutants activate YAP, a major effector of the Hippo tumor suppressor pathway that is also regulated by G-protein coupled receptor (GPCR) signaling.	('GPCR', 'Gene', (214, 218))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('GPCR', 'Gene', '9170', (214, 218))	('Gq/11', 'Chemical', '-', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor suppressor', 'biological_process', 'GO:0051726', ('135', '151'))	('Gq/11', 'Gene', (77, 82))	('activate', 'PosReg', (91, 99))	('YAP', 'Gene', (100, 103))	('tumors', 'Disease', (47, 53))	('mutants', 'Var', (83, 90))	('human', 'Species', '9606', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('G-protein coupled receptor', 'Gene', (186, 212))	('tumor', 'Disease', (135, 140))	('G-protein coupled receptor', 'Gene', '9170', (186, 212))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('135', '151'))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('signaling', 'biological_process', 'GO:0023052', ('220', '229'))	('cancer', 'Disease', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
108999	24882516	YAP mediates the oncogenic activity of mutant Gq/11 in UM development, and the YAP inhibitor verteporfin blocks tumor growth of UM cells containing Gq/11 mutations.	('Gq/11', 'Chemical', '-', (148, 153))	('verteporfin', 'Chemical', 'MESH:D000077362', (93, 104))	('Gq/11', 'Chemical', '-', (46, 51))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('blocks tumor', 'Disease', (105, 117))	('UM', 'Phenotype', 'HP:0007716', (128, 130))	('Gq/11', 'Gene', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Gq/11', 'Gene', (46, 51))	('blocks tumor', 'Disease', 'MESH:D006327', (105, 117))	('mutant', 'Var', (39, 45))	('mutations', 'Var', (154, 163))	('UM development', 'CPA', (55, 69))	('oncogenic activity', 'MPA', (17, 35))
109000	24882516	This study reveals an essential role of the Hippo-YAP pathway in Gq/11-induced tumorigenesis and suggests YAP as a potential drug target for UM patients carrying mutations in GNAQ or GNA11.	('Gq/11', 'Chemical', '-', (65, 70))	('GNA11', 'Gene', '2767', (183, 188))	('mutations', 'Var', (162, 171))	('GNA11', 'Gene', (183, 188))	('UM', 'Phenotype', 'HP:0007716', (141, 143))	('tumor', 'Disease', (79, 84))	('GNAQ', 'Gene', (175, 179))	('patients', 'Species', '9606', (144, 152))	('Gq/11-induced', 'Gene', (65, 78))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('GNAQ', 'Gene', '2776', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
109004	24882516	Instead of the BRAF or NRAS mutations common in cutaneous melanoma, more than 80% of UMs carry activating mutations in either GNAQ or GNA11.	('cutaneous melanoma', 'Disease', (48, 66))	('BRAF', 'Gene', '673', (15, 19))	('UMs', 'Disease', (85, 88))	('GNAQ', 'Gene', '2776', (126, 130))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (48, 66))	('BRAF', 'Gene', (15, 19))	('NRAS', 'Gene', (23, 27))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 66))	('GNA11', 'Gene', (134, 139))	('GNAQ', 'Gene', (126, 130))	('GNA11', 'Gene', '2767', (134, 139))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('mutations', 'Var', (106, 115))	('NRAS', 'Gene', '4893', (23, 27))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('activating', 'PosReg', (95, 105))
109005	24882516	Only UM derived from the iris, a minor fraction (5%) of total UM cases, harbors BRAF mutations.	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('BRAF', 'Gene', (80, 84))	('mutations', 'Var', (85, 94))	('UM', 'Phenotype', 'HP:0007716', (5, 7))	('BRAF', 'Gene', '673', (80, 84))	('harbors', 'Reg', (72, 79))
109006	24882516	Notably, the GNAQ mutation is frequent in benign blue naevi, while the GNA11 mutation is frequent in malignant UM.	('GNA11', 'Gene', (71, 76))	('GNAQ', 'Gene', (13, 17))	('UM', 'Phenotype', 'HP:0007716', (111, 113))	('frequent', 'Reg', (30, 38))	('GNA11', 'Gene', '2767', (71, 76))	('mutation', 'Var', (18, 26))	('blue naevi', 'Phenotype', 'HP:0100814', (49, 59))	('GNAQ', 'Gene', '2776', (13, 17))	('naevi', 'Phenotype', 'HP:0003764', (54, 59))	('benign blue naevi', 'Disease', (42, 59))
109008	24882516	Interestingly, all mutations in Gq or G11 occur at either arginine 183 (R183) or glutamine 209 (Q209) in a mutually exclusive manner, suggesting that these mutations in Gq and G11 have a similar function in tumor promotion.	('R183', 'Var', (72, 76))	('G11', 'Gene', (38, 41))	('mutations', 'Var', (156, 165))	('occur', 'Reg', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('mutations', 'Var', (19, 28))	('G11', 'Gene', (176, 179))	('arginine', 'Chemical', 'MESH:D001120', (58, 66))	('Gq', 'Chemical', 'MESH:C039788', (169, 171))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('Q209', 'Var', (96, 100))	('glutamine', 'Chemical', 'MESH:D005973', (81, 90))	('tumor', 'Disease', (207, 212))	('Gq', 'Chemical', 'MESH:C039788', (32, 34))
109009	24882516	R183 and Q209 are located in the switch I and switch II domains of Gq/11 proteins, respectively, and these mutations convert the G-proteins into a constitutively active form by decreasing their GTPase activity.	('mutations', 'Var', (107, 116))	('decreasing', 'NegReg', (177, 187))	('G-proteins', 'Protein', (129, 139))	('activity', 'MPA', (201, 209))	('GTPase activity', 'molecular_function', 'GO:0003924', ('194', '209'))	('GTPase', 'Enzyme', (194, 200))	('Gq/11', 'Chemical', '-', (67, 72))	('R183', 'Var', (0, 4))	('Gq/11', 'Gene', (67, 72))	('convert', 'Reg', (117, 124))	('Q209', 'Var', (9, 13))
109010	24882516	Therefore, the cancer-associated mutant Gq/11 would induce constitutive downstream signaling that presumably contributes to tumor development.	('induce', 'Reg', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Disease', (124, 129))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('constitutive downstream signaling', 'MPA', (59, 92))	('mutant', 'Var', (33, 39))	('Gq/11', 'Chemical', '-', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('Gq/11', 'Gene', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
109012	24882516	Moreover, down-regulation of mutant Gq/11 in UM cells abolished their ability to form tumors in immunocompromised mice, demonstrating a direct cancer driving function of the active Gq/11 in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', (86, 92))	('abolished', 'NegReg', (54, 63))	('cancer', 'Disease', (143, 149))	('Gq/11', 'Chemical', '-', (36, 41))	('Gq/11', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('regulation', 'biological_process', 'GO:0065007', ('15', '25'))	('mutant', 'Var', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('ability', 'MPA', (70, 77))	('tumor', 'Disease', (190, 195))	('mice', 'Species', '10090', (114, 118))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', (86, 91))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('down-regulation', 'NegReg', (10, 25))	('Gq/11', 'Chemical', '-', (181, 186))	('UM', 'Phenotype', 'HP:0007716', (45, 47))
109013	24882516	Although it has been proposed that Gq/11 activates the MAP kinase, the precise molecular mechanism of these activating Gq/11 mutations in UM development remains to be defined.	('Gq/11', 'Gene', (119, 124))	('mutations', 'Var', (125, 134))	('MAP kinase', 'Enzyme', (55, 65))	('Gq/11', 'Chemical', '-', (35, 40))	('UM', 'Phenotype', 'HP:0007716', (138, 140))	('MAP', 'molecular_function', 'GO:0004239', ('55', '58'))	('activating', 'PosReg', (108, 118))	('Gq/11', 'Chemical', '-', (119, 124))
109020	24882516	Interestingly, expression of active Gq/11 (containing the Q209L mutation), but not the wild type, is able to stimulate YAP/TAZ dephosphorylation, indicating that YAP can be activated by Gq/11.	('TAZ', 'Gene', '6901', (123, 126))	('dephosphorylation', 'biological_process', 'GO:0016311', ('127', '144'))	('stimulate', 'PosReg', (109, 118))	('TAZ', 'Gene', (123, 126))	('Q209L', 'Var', (58, 63))	('Q209L', 'Mutation', 'p.Q209L', (58, 63))	('Gq/11', 'Chemical', '-', (186, 191))	('Gq/11', 'Chemical', '-', (36, 41))	('Gq/11', 'Gene', (36, 41))
109022	24882516	To test whether YAP can be activated by the cancer-associated mutant Gq/11, we firstly determined the effect of GNAQ and GNA11 hotspot mutations found in UM on YAP activity.	('GNA11', 'Gene', '2767', (121, 126))	('Gq/11', 'Chemical', '-', (69, 74))	('mutant', 'Var', (62, 68))	('GNAQ', 'Gene', (112, 116))	('cancer', 'Disease', (44, 50))	('mutations', 'Var', (135, 144))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('GNAQ', 'Gene', '2776', (112, 116))	('UM', 'Phenotype', 'HP:0007716', (154, 156))	('GNA11', 'Gene', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
109023	24882516	In HEK293A cells, ectopic expression of mutant Gq/11 (GqR183Q, GqQ209L, or G11Q209L), but not the wild type Gq or G11, caused a dramatic dephosphorylation of co-transfected YAP, as indicated by faster migration of YAP on a phos-tag-containing gel (Figure 1A).	('HEK293A', 'CellLine', 'CVCL:6910', (3, 10))	('migration', 'CPA', (201, 210))	('dephosphorylation', 'MPA', (137, 154))	('faster', 'PosReg', (194, 200))	('dephosphorylation', 'biological_process', 'GO:0016311', ('137', '154'))	('GqQ209L', 'Var', (63, 70))	('Gq', 'Chemical', 'MESH:C039788', (63, 65))	('Gq', 'Chemical', 'MESH:C039788', (108, 110))	('Gq/11', 'Chemical', '-', (47, 52))	('mutant', 'Var', (40, 46))	('GqR183Q', 'Var', (54, 61))	('Gq/11', 'Gene', (47, 52))	('Gq', 'Chemical', 'MESH:C039788', (54, 56))	('G11Q209L', 'Mutation', 'p.G11,209L', (75, 83))	('Gq', 'Chemical', 'MESH:C039788', (47, 49))
109024	24882516	Because phosphorylation inhibits YAP, these data suggests that mutant Gq/11 activates YAP.	('activates', 'PosReg', (76, 85))	('Gq/11', 'Chemical', '-', (70, 75))	('mutant', 'Var', (63, 69))	('Gq/11', 'Gene', (70, 75))	('YAP', 'CPA', (86, 89))	('inhibits', 'NegReg', (24, 32))	('phosphorylation', 'biological_process', 'GO:0016310', ('8', '23'))	('YAP', 'CPA', (33, 36))
109026	24882516	As expected, the endogenous TAZ protein levels were significantly increased in the presence of mutant Gq/11 (Figure 1A).	('Gq/11', 'Gene', (102, 107))	('increased', 'PosReg', (66, 75))	('TAZ', 'Gene', '6901', (28, 31))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('TAZ', 'Gene', (28, 31))	('mutant', 'Var', (95, 101))	('Gq/11', 'Chemical', '-', (102, 107))
109028	24882516	Consistently, over-expression of active Gq/11 mutants, but not wild-type Gq/11, induced nuclear localization of endogenous YAP/TAZ, as assessed by immunofluorescence staining with an antibody that recognizes both YAP and TAZ (Figure S1A-C).	('induced', 'Reg', (80, 87))	('antibody', 'cellular_component', 'GO:0019815', ('183', '191'))	('TAZ', 'Gene', '6901', (127, 130))	('over-expression', 'PosReg', (14, 29))	('antibody', 'cellular_component', 'GO:0019814', ('183', '191'))	('antibody', 'molecular_function', 'GO:0003823', ('183', '191'))	('TAZ', 'Gene', (127, 130))	('Gq/11', 'Chemical', '-', (73, 78))	('localization', 'biological_process', 'GO:0051179', ('96', '108'))	('TAZ', 'Gene', '6901', (221, 224))	('mutants', 'Var', (46, 53))	('nuclear localization', 'MPA', (88, 108))	('antibody', 'cellular_component', 'GO:0042571', ('183', '191'))	('Gq/11', 'Chemical', '-', (40, 45))	('TAZ', 'Gene', (221, 224))	('Gq/11', 'Gene', (40, 45))
109029	24882516	These results show that the mutant Gq/11 found in UM potently activates YAP/TAZ, and suggest a model that activation of YAP/TAZ may contribute to mutant Gq/11-induced UM development, given the known oncogenic function of these two transcription co-activators.	('contribute', 'Reg', (132, 142))	('mutant', 'Var', (28, 34))	('transcription', 'biological_process', 'GO:0006351', ('231', '244'))	('Gq/11', 'Chemical', '-', (35, 40))	('UM development', 'CPA', (167, 181))	('Gq/11', 'Gene', (35, 40))	('Gq/11', 'Chemical', '-', (153, 158))	('mutant', 'Var', (146, 152))	('TAZ', 'Gene', '6901', (124, 127))	('TAZ', 'Gene', '6901', (76, 79))	('UM', 'Phenotype', 'HP:0007716', (167, 169))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('TAZ', 'Gene', (76, 79))	('TAZ', 'Gene', (124, 127))	('activates', 'PosReg', (62, 71))	('Gq/11-induced', 'Gene', (153, 166))
109032	24882516	Among these UM cell lines, seven (92.1, Mel202, Mel270, OMM1.3, OMM2.2, OMM2.3, and OMM2.5) contain the GqQ209 mutation, one (OMM1) contains the G11Q209L mutation, and the remaining five tumor lines (OCM1, OCM3, OCM8, Mel285, and Mel290) have no mutation in Gq/11 (Figure 1B).	('Gq/11', 'Chemical', '-', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('Gq/11', 'Gene', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('Gq', 'Chemical', 'MESH:C039788', (258, 260))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('Gq', 'Chemical', 'MESH:C039788', (104, 106))	('tumor', 'Disease', (187, 192))	('G11Q209L', 'Mutation', 'p.G11,209L', (145, 153))	('OCM1', 'Species', '83984', (200, 204))	('G11Q209L', 'Var', (145, 153))	('GqQ209 mutation', 'Var', (104, 119))
109035	24882516	Interestingly, all UM cell lines with Gq/11 mutations displayed low or moderate YAP phosphorylation and strong nuclear YAP (or YAP/TAZ) localization (Figure 1B).	('YAP phosphorylation', 'MPA', (80, 99))	('Gq/11', 'Chemical', '-', (38, 43))	('Gq/11', 'Gene', (38, 43))	('low', 'NegReg', (64, 67))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('localization', 'biological_process', 'GO:0051179', ('136', '148'))	('mutations', 'Var', (44, 53))	('UM', 'Phenotype', 'HP:0007716', (19, 21))	('nuclear YAP', 'MPA', (111, 122))	('TAZ', 'Gene', (131, 134))	('TAZ', 'Gene', '6901', (131, 134))
109036	24882516	On the other hand, YAP was highly phosphorylated and exhibited exclusive cytoplasmic localization in BRAF mutant cells (Figure 1B).	('BRAF', 'Gene', (101, 105))	('BRAF', 'Gene', '673', (101, 105))	('localization', 'biological_process', 'GO:0051179', ('85', '97'))	('mutant', 'Var', (106, 112))
109037	24882516	These observations demonstrate that YAP is activated in Gq/11 mutant UM cells but inactivated in BRAF mutant cells.	('mutant', 'Var', (62, 68))	('Gq/11', 'Chemical', '-', (56, 61))	('YAP', 'MPA', (36, 39))	('activated', 'PosReg', (43, 52))	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('Gq/11', 'Gene', (56, 61))	('BRAF', 'Gene', '673', (97, 101))	('BRAF', 'Gene', (97, 101))	('inactivated', 'NegReg', (82, 93))
109041	24882516	In contrast, in UM cells containing mutated Gq/11, YAP was dephosphorylated and localized in the nucleus regardless of the serum or LPA conditions.	('Gq/11', 'Gene', (44, 49))	('LPA', 'Chemical', 'MESH:C032881', (132, 135))	('nucleus', 'cellular_component', 'GO:0005634', ('97', '104'))	('YAP', 'Protein', (51, 54))	('mutated', 'Var', (36, 43))	('UM', 'Phenotype', 'HP:0007716', (16, 18))	('Gq/11', 'Chemical', '-', (44, 49))
109042	24882516	Our findings show that YAP/TAZ are indeed more active in UM cell lines containing Gq/11 mutations and are no longer sensitive to serum or LPA.	('TAZ', 'Gene', (27, 30))	('mutations', 'Var', (88, 97))	('TAZ', 'Gene', '6901', (27, 30))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('active', 'MPA', (47, 53))	('more', 'PosReg', (42, 46))	('Gq/11', 'Chemical', '-', (82, 87))	('Gq/11', 'Gene', (82, 87))	('LPA', 'Chemical', 'MESH:C032881', (138, 141))
109043	24882516	Notably, in UM cells with mutant BRAF, YAP was heavily phosphorylated and the serum and LPA-induced YAP dephosphorylation and nuclear localization were blunted (Figures 1B-D, S1D and S1E).	('blunted', 'NegReg', (152, 159))	('BRAF', 'Gene', '673', (33, 37))	('dephosphorylation', 'biological_process', 'GO:0016311', ('104', '121'))	('BRAF', 'Gene', (33, 37))	('LPA', 'Chemical', 'MESH:C032881', (88, 91))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('dephosphorylation', 'MPA', (104, 121))	('heavily', 'PosReg', (47, 54))	('mutant', 'Var', (26, 32))	('localization', 'biological_process', 'GO:0051179', ('134', '146'))	('nuclear localization', 'MPA', (126, 146))
109044	24882516	In support, Lats phosphorylation status, an indicator of kinase activity, was higher in BRAF mutant cells compare to that in Gq/11 mutant cells (Figure S1F).	('phosphorylation', 'biological_process', 'GO:0016310', ('17', '32'))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('higher', 'PosReg', (78, 84))	('Gq/11', 'Chemical', '-', (125, 130))	('Lats phosphorylation status', 'MPA', (12, 39))	('mutant', 'Var', (93, 99))	('kinase activity', 'molecular_function', 'GO:0016301', ('57', '72'))
109045	24882516	These data suggest that YAP activation is not needed for tumor growth of BRAF mutant cells and, moreover, active BRAF might suppress YAP activation.	('BRAF', 'Gene', '673', (113, 117))	('BRAF', 'Gene', '673', (73, 77))	('suppress', 'NegReg', (124, 132))	('BRAF', 'Gene', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('BRAF', 'Gene', (73, 77))	('YAP activation', 'MPA', (133, 147))	('mutant', 'Var', (78, 84))
109046	24882516	Previously, Gq/11 mutant-induced activation of the extracellular-signal-regulated kinases (ERK), also known as MAP-kinase (MAPK), was proposed as a potential mechanism for mutant Gq/11 in UM development.	('extracellular-signal-regulated kinases', 'Gene', (51, 89))	('mutant', 'Var', (172, 178))	('Gq/11', 'Chemical', '-', (179, 184))	('Gq/11', 'Gene', (179, 184))	('activation', 'PosReg', (33, 43))	('ERK', 'Gene', '5594', (91, 94))	('extracellular-signal-regulated kinases', 'Gene', '5594', (51, 89))	('MAPK', 'molecular_function', 'GO:0004707', ('123', '127'))	('UM development', 'CPA', (188, 202))	('ERK', 'Gene', (91, 94))	('mutant-induced', 'Var', (18, 32))	('Gq/11', 'Chemical', '-', (12, 17))	('extracellular', 'cellular_component', 'GO:0005576', ('51', '64'))	('MAP', 'molecular_function', 'GO:0004239', ('111', '114'))	('Gq/11', 'Gene', (12, 17))	('UM', 'Phenotype', 'HP:0007716', (188, 190))	('ERK', 'molecular_function', 'GO:0004707', ('91', '94'))
109047	24882516	Indeed, over-expression of Gq/11 mutants moderately induces phosphorylation of ERK.	('phosphorylation', 'MPA', (60, 75))	('ERK', 'Gene', (79, 82))	('Gq/11', 'Chemical', '-', (27, 32))	('Gq/11', 'Gene', (27, 32))	('over-expression', 'PosReg', (8, 23))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('ERK', 'molecular_function', 'GO:0004707', ('79', '82'))	('mutants', 'Var', (33, 40))	('induces', 'Reg', (52, 59))	('ERK', 'Gene', '5594', (79, 82))
109048	24882516	Based on Western analyses of the 13 UM cell lines, ERK phosphorylation in Gq/11 mutant UM cell lines was evident, however it was much lower than that of BRAF mutant UM cells (Figure 1B, S1D).	('UM', 'Phenotype', 'HP:0007716', (165, 167))	('phosphorylation', 'biological_process', 'GO:0016310', ('55', '70'))	('ERK', 'Gene', (51, 54))	('lower', 'NegReg', (134, 139))	('BRAF', 'Gene', (153, 157))	('UM', 'Phenotype', 'HP:0007716', (87, 89))	('mutant', 'Var', (80, 86))	('Gq/11', 'Chemical', '-', (74, 79))	('ERK', 'Gene', '5594', (51, 54))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('ERK', 'molecular_function', 'GO:0004707', ('51', '54'))	('Gq/11', 'Gene', (74, 79))	('BRAF', 'Gene', '673', (153, 157))
109049	24882516	Moreover, ERK phosphorylation in the Gq/11 mutant UM cells was no higher than that in UM cells (Mel285 and Mel290) without Gq/11 mutation, suggesting that the ERK pathway is unlikely a major mediator for UM driven by mutant Gq/11.	('ERK', 'Gene', (159, 162))	('mutant', 'Var', (217, 223))	('ERK', 'molecular_function', 'GO:0004707', ('10', '13'))	('UM', 'Phenotype', 'HP:0007716', (86, 88))	('UM', 'Phenotype', 'HP:0007716', (204, 206))	('Gq/11', 'Chemical', '-', (224, 229))	('ERK', 'molecular_function', 'GO:0004707', ('159', '162'))	('phosphorylation', 'biological_process', 'GO:0016310', ('14', '29'))	('phosphorylation', 'MPA', (14, 29))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('mutant', 'Var', (43, 49))	('Gq/11', 'Chemical', '-', (37, 42))	('ERK', 'Gene', '5594', (10, 13))	('higher', 'PosReg', (66, 72))	('Gq/11', 'Gene', (37, 42))	('ERK', 'Gene', '5594', (159, 162))	('ERK', 'Gene', (10, 13))	('Gq/11', 'Chemical', '-', (123, 128))
109052	24882516	We collected 23 UM samples and performed genomic DNA sequencing for exon 4 (R183) and exon 5 (Q209) of Gq/11.	('Gq/11', 'Chemical', '-', (103, 108))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('UM', 'Phenotype', 'HP:0007716', (16, 18))	('Q209', 'Var', (94, 98))	('R183', 'Var', (76, 80))
109055	24882516	When YAP localization data were compared with the mutation status of Gq/11, we observed a strong correlation between mutated Gq/11 and YAP nuclear localization (Figure 2B).	('Gq/11', 'Chemical', '-', (69, 74))	('mutated', 'Var', (117, 124))	('YAP nuclear localization', 'MPA', (135, 159))	('localization', 'biological_process', 'GO:0051179', ('9', '21'))	('localization', 'biological_process', 'GO:0051179', ('147', '159'))	('Gq/11', 'Chemical', '-', (125, 130))	('Gq/11', 'Gene', (125, 130))	('correlation', 'Interaction', (97, 108))
109056	24882516	Based on these observations, we conclude that mutated Gq/11 is associated with YAP activation in UM, supporting a possible pathological role of YAP in Gq/11 mutation-induced tumorigenesis.	('tumor', 'Disease', (174, 179))	('YAP', 'Gene', (79, 82))	('Gq/11', 'Chemical', '-', (151, 156))	('UM', 'Phenotype', 'HP:0007716', (97, 99))	('mutated', 'Var', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('Gq/11', 'Chemical', '-', (54, 59))	('Gq/11', 'Gene', (54, 59))	('activation', 'PosReg', (83, 93))
109057	24882516	In a subcutaneous xenograft mouse model, 92.1 (GqQ209L) cells transfected with shRNA targeting Gq failed to develop tumor (Figure 3A), confirming an essential role for mutant Gq in tumorigenicity of 92.1 cells.	('Gq', 'Chemical', 'MESH:C039788', (95, 97))	('tumor', 'Disease', (181, 186))	('mutant', 'Var', (168, 174))	('Gq', 'Chemical', 'MESH:C039788', (175, 177))	('mouse', 'Species', '10090', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('failed', 'NegReg', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('Gq', 'Chemical', 'MESH:C039788', (47, 49))
109061	24882516	We observed that YAP phosphorylation (as indicated by the pYAP western blot) was increased in cells expressing Gq shRNA (Figure 3B).	('Gq shRNA', 'Var', (111, 119))	('Gq', 'Chemical', 'MESH:C039788', (111, 113))	('phosphorylation', 'biological_process', 'GO:0016310', ('21', '36'))	('YAP phosphorylation', 'MPA', (17, 36))	('increased', 'PosReg', (81, 90))
109062	24882516	In Gq knockdown cells, the interaction of YAP and TEAD was decreased while Gq knockdown had no effect on TEAD1 expression (Figure 3C).	('TEAD1', 'Gene', (105, 110))	('interaction', 'Interaction', (27, 38))	('decreased', 'NegReg', (59, 68))	('Gq', 'Chemical', 'MESH:C039788', (3, 5))	('knockdown', 'Var', (6, 15))	('Gq', 'Chemical', 'MESH:C039788', (75, 77))	('TEAD1', 'Gene', '7003', (105, 110))
109063	24882516	In addition, YAP nuclear localization was decreased in Gq knockdown cells (Figure3D and 3E), consistent with YAP inactivation.	('YAP', 'Protein', (13, 16))	('decreased', 'NegReg', (42, 51))	('Gq', 'Chemical', 'MESH:C039788', (55, 57))	('localization', 'biological_process', 'GO:0051179', ('25', '37'))	('nuclear localization', 'MPA', (17, 37))	('knockdown', 'Var', (58, 67))
109067	24882516	The above data support a function for mutant Gq in maintaining YAP in a dephosphorylated and activated status in UM cells.	('YAP', 'MPA', (63, 66))	('UM', 'Phenotype', 'HP:0007716', (113, 115))	('Gq', 'Chemical', 'MESH:C039788', (45, 47))	('mutant', 'Var', (38, 44))
109068	24882516	Expression of active Gq/11 (Q209L) in immortalized melanocytes (Melan-a cells) is sufficient to induce cell transformation.	('Gq/11', 'Chemical', '-', (21, 26))	('active Gq/11 (Q209L', 'Var', (14, 33))	('induce', 'Reg', (96, 102))	('cell transformation', 'CPA', (103, 122))	('Q209L', 'Mutation', 'p.Q209L', (28, 33))
109069	24882516	This offers a well-defined and cleaner system for functional studies than UM-derived cell lines, which certainly contain mutations besides Gq/11.	('Gq/11', 'Chemical', '-', (139, 144))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('mutations', 'Var', (121, 130))	('Gq/11', 'Gene', (139, 144))
109070	24882516	In melan-a cells expressing GqQ209L or G11Q209L, YAP phosphorylation was reduced (Figure S2A and S2B), and the YAP-TEAD interaction was increased (Figure S2C), indicating higher YAP activity.	('G11Q209L', 'Var', (39, 47))	('reduced', 'NegReg', (73, 80))	('YAP-TEAD', 'CPA', (111, 119))	('higher', 'PosReg', (171, 177))	('YAP phosphorylation', 'CPA', (49, 68))	('GqQ209L', 'Var', (28, 35))	('G11Q209L', 'Mutation', 'p.G11,209L', (39, 47))	('increased', 'PosReg', (136, 145))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))
109071	24882516	To test the role of YAP/TAZ in GqQ209L-induced cell transformation, we generated GqQ209L-stable melan-a cells expressing control, YAP and/or TAZ shRNAs (Figure 4A).	('GqQ209L-stable', 'Var', (81, 95))	('TAZ', 'Gene', (24, 27))	('TAZ', 'Gene', '6901', (141, 144))	('TAZ', 'Gene', (141, 144))	('TAZ', 'Gene', '6901', (24, 27))
109072	24882516	Importantly, GqQ209L-stable melan-a cells expressing YAP and/or TAZ shRNAs failed to form colonies (Figures 4B and S2D).	('TAZ', 'Gene', (64, 67))	('GqQ209L-stable', 'Var', (13, 27))	('TAZ', 'Gene', '6901', (64, 67))
109073	24882516	In addition, when subcutaneously grafted into nude mice, GqQ209L-stable melan-a cells with YAP knockdown exhibited a significant reduction in tumor growth (Figures 4C and S2H).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('GqQ209L-stable', 'Var', (57, 71))	('nude mice', 'Species', '10090', (46, 55))	('reduction', 'NegReg', (129, 138))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
109075	24882516	To investigate the role of YAP in the tumorigenesis of UM-derived cell lines, we attempted to knockdown YAP in 92.1 cells (GqQ209L), which has high YAP activity, and OCM1 (BRAFV600E) cells, which have low YAP activity.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('knockdown', 'Var', (94, 103))	('BRAFV600E', 'Mutation', 'rs113488022', (172, 181))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('YAP', 'Gene', (104, 107))	('YAP activity', 'MPA', (148, 160))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('OCM1', 'Species', '83984', (166, 170))
109080	24882516	Again knockdown of YAP in 92.1 but not OCM1 cells reduced cell migration in a trans-well assay (Figures 4E and S2G).	('OCM1', 'Species', '83984', (39, 43))	('cell migration', 'biological_process', 'GO:0016477', ('58', '72'))	('YAP', 'Gene', (19, 22))	('reduced', 'NegReg', (50, 57))	('knockdown', 'Var', (6, 15))	('cell migration in a trans-well assay', 'CPA', (58, 94))
109081	24882516	Furthermore, knockdown of YAP greatly impaired tumor formation of 92.1 cells (Figure 4F) but not OCM1 (Figure 4G) or OCM8 cells (Figure 4H) in nude mice (Figure S2H).	('formation', 'biological_process', 'GO:0009058', ('53', '62'))	('impaired tumor', 'Disease', 'MESH:D015417', (38, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('OCM1', 'Species', '83984', (97, 101))	('nude mice', 'Species', '10090', (143, 152))	('YAP', 'Gene', (26, 29))	('impaired tumor', 'Disease', (38, 52))	('knockdown', 'Var', (13, 22))
109082	24882516	Together, these observations suggest that YAP plays a pivotal role in tumorigenesis of Gq/11Q209L-induced, but not BRAFV600E-induced, UM.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('BRAFV600E', 'Mutation', 'rs113488022', (115, 124))	('tumor', 'Disease', (70, 75))	('Gq/11Q209L-induced', 'Var', (87, 105))	('UM', 'Phenotype', 'HP:0007716', (134, 136))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
109083	24882516	The strong correlation between the Gq/11 mutation and YAP activation in UM specimens and UM cell lines and the effectiveness of YAP knockdown in preventing tumor growth of Gq/11 mutated UM cells in a mouse xenograft model promoted us to test the effect of pharmacological inhibition of YAP on the tumorigenesis of UM cells.	('Gq/11', 'Chemical', '-', (172, 177))	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('preventing', 'NegReg', (145, 155))	('Gq/11', 'Gene', (172, 177))	('Gq/11', 'Chemical', '-', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('UM', 'Phenotype', 'HP:0007716', (314, 316))	('UM', 'Phenotype', 'HP:0007716', (186, 188))	('Gq/11', 'Gene', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('mutation', 'Var', (41, 49))	('mouse', 'Species', '10090', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('mutated', 'Var', (178, 185))	('tumor', 'Disease', (156, 161))	('UM', 'Phenotype', 'HP:0007716', (89, 91))	('tumor', 'Disease', (297, 302))
109086	24882516	Interestingly, when treated with verteporfin, the UM cells with Gq/11 mutations were effectively killed, as indicated by the cleavage of poly (ADP-ribose) polymerase-1 (PARP-1, an apoptosis marker; Figures 5A and S3A).	('Gq/11', 'Gene', (64, 69))	('mutations', 'Var', (70, 79))	('verteporfin', 'Chemical', 'MESH:D000077362', (33, 44))	('PARP-1', 'Gene', (169, 175))	('apoptosis', 'biological_process', 'GO:0097194', ('180', '189'))	('PARP-1', 'Gene', '142', (169, 175))	('poly (ADP-ribose) polymerase-1', 'Gene', '142', (137, 167))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('apoptosis', 'biological_process', 'GO:0006915', ('180', '189'))	('poly (ADP-ribose) polymerase-1', 'Gene', (137, 167))	('cleavage', 'MPA', (125, 133))	('Gq/11', 'Chemical', '-', (64, 69))
109087	24882516	Similarly, the Gq/11 mutant UM cells were sensitive to growth inhibition by verteporfin (Figure S3B).	('UM', 'Phenotype', 'HP:0007716', (28, 30))	('mutant', 'Var', (21, 27))	('Gq/11', 'Chemical', '-', (15, 20))	('Gq/11', 'Gene', (15, 20))	('growth', 'MPA', (55, 61))	('verteporfin', 'Chemical', 'MESH:D000077362', (76, 87))
109088	24882516	In comparison, the BRAF mutant cells were more resistant to both growth inhibition and apoptosis in response to verteporfin treatment (Figures 5A, S3A, and S3B).	('mutant', 'Var', (24, 30))	('BRAF', 'Gene', '673', (19, 23))	('BRAF', 'Gene', (19, 23))	('verteporfin', 'Chemical', 'MESH:D000077362', (112, 123))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))
109090	24882516	These results suggest a model that YAP activation is more important for Gq/11 mutant tumor cells, whereas ERK activation is more important for BRAF mutant tumor cells.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('Gq/11', 'Chemical', '-', (72, 77))	('BRAF', 'Gene', (143, 147))	('Gq/11', 'Gene', (72, 77))	('tumor', 'Disease', (155, 160))	('BRAF', 'Gene', '673', (143, 147))	('ERK', 'Gene', '5594', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('ERK', 'molecular_function', 'GO:0004707', ('106', '109'))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ERK', 'Gene', (106, 109))	('mutant', 'Var', (78, 84))
109091	24882516	Our data indicate that verteporfin may be used to selectively kill tumor cells with elevated YAP activity, such as UM containing mutations in Gq/11.	('Gq/11', 'Chemical', '-', (142, 147))	('YAP', 'MPA', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('mutations', 'Var', (129, 138))	('activity', 'MPA', (97, 105))	('UM', 'Phenotype', 'HP:0007716', (115, 117))	('Gq/11', 'Gene', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('verteporfin', 'Chemical', 'MESH:D000077362', (23, 34))	('tumor', 'Disease', (67, 72))
109099	24882516	After 6 weeks, when compared to the control group, vertepofin treatment significantly reduced tumor growth of the Gq mutant 92.1 and Mel270 cells (Figures 5C, 5D, S3E and S3F).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('reduced', 'NegReg', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutant', 'Var', (117, 123))	('tumor', 'Disease', (94, 99))	('vertepofin', 'Chemical', '-', (51, 61))	('Gq', 'Chemical', 'MESH:C039788', (114, 116))
109100	24882516	In contrast, vertepofin treatment had little effect on tumor growth of the BRAF mutant OCM1 cells (Figure5E and 5F).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('vertepofin', 'Chemical', '-', (13, 23))	('mutant', 'Var', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('BRAF', 'Gene', '673', (75, 79))	('tumor', 'Disease', (55, 60))	('BRAF', 'Gene', (75, 79))	('OCM1', 'Species', '83984', (87, 91))
109101	24882516	Therefore, these mouse model studies demonstrate that verteporfin is effective in inhibiting tumor cell growth and might be considered for targeted treatment of UM with Gq/11 mutations and elevated YAP activity.	('mouse', 'Species', '10090', (17, 22))	('inhibiting', 'NegReg', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cell growth', 'biological_process', 'GO:0016049', ('99', '110'))	('verteporfin', 'Chemical', 'MESH:D000077362', (54, 65))	('tumor', 'Disease', (93, 98))	('Gq/11', 'Chemical', '-', (169, 174))	('Gq/11', 'Gene', (169, 174))	('mutations', 'Var', (175, 184))	('elevated', 'PosReg', (189, 197))	('activity', 'MPA', (202, 210))	('UM', 'Phenotype', 'HP:0007716', (161, 163))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
109105	24882516	The high penetrance of Gq/11-activating mutations and the essential role of mutant Gq/11 in UM oncogenisis warrants the need for an in-depth mechanistic understanding of Gq/11 in tumorigenesis.	('Gq/11', 'Chemical', '-', (83, 88))	('Gq/11', 'Gene', (83, 88))	('mutant', 'Var', (76, 82))	('Gq/11', 'Chemical', '-', (170, 175))	('Gq/11-activating', 'Gene', (23, 39))	('mutations', 'Var', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('Gq/11', 'Chemical', '-', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('UM', 'Phenotype', 'HP:0007716', (92, 94))	('tumor', 'Disease', (179, 184))
109106	24882516	Moreover, the establishment of mutant Gq/11 as a cancer driver suggests a potential of developing targeted therapies for UM treatment.	('UM', 'Phenotype', 'HP:0007716', (121, 123))	('Gq/11', 'Chemical', '-', (38, 43))	('mutant', 'Var', (31, 37))	('Gq/11', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
109109	24882516	In this report, we reveal a strong correlation between Gq/11 mutations and YAP activation in UM.	('Gq/11', 'Chemical', '-', (55, 60))	('Gq/11', 'Gene', (55, 60))	('mutations', 'Var', (61, 70))	('UM', 'Phenotype', 'HP:0007716', (93, 95))	('activation', 'PosReg', (79, 89))	('YAP', 'Disease', (75, 78))
109110	24882516	We have established a causal relationship between Gq/11 mutation and YAP activation, and show that YAP is essential in transducing the oncogenic activity of mutant Gq/11 to induce UM.	('mutant', 'Var', (157, 163))	('Gq/11', 'Gene', (164, 169))	('UM', 'Phenotype', 'HP:0007716', (180, 182))	('oncogenic activity', 'MPA', (135, 153))	('Gq/11', 'Chemical', '-', (50, 55))	('mutation', 'Var', (56, 64))	('Gq/11', 'Gene', (50, 55))	('Gq/11', 'Chemical', '-', (164, 169))
109111	24882516	Indeed, this concept is strongly supported by our data that down-regulation of YAP selectively inhibits tumor growth of UM cells containing mutated Gq/11.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('YAP', 'Gene', (79, 82))	('Gq/11', 'Chemical', '-', (148, 153))	('tumor', 'Disease', (104, 109))	('down-regulation', 'NegReg', (60, 75))	('Gq/11', 'Gene', (148, 153))	('UM', 'Phenotype', 'HP:0007716', (120, 122))	('regulation', 'biological_process', 'GO:0065007', ('65', '75'))	('inhibits', 'NegReg', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('mutated', 'Var', (140, 147))
109112	24882516	Furthermore, verteporfin inhibits proliferation of UM cells with Gq/11 mutations in vitro and is effective in suppressing their growth in a mouse model.	('Gq/11', 'Chemical', '-', (65, 70))	('proliferation', 'CPA', (34, 47))	('mouse', 'Species', '10090', (140, 145))	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('Gq/11', 'Gene', (65, 70))	('inhibits', 'NegReg', (25, 33))	('mutations', 'Var', (71, 80))	('suppressing', 'NegReg', (110, 121))	('verteporfin', 'Chemical', 'MESH:D000077362', (13, 24))	('growth', 'MPA', (128, 134))
109119	24882516	It is equally important to note that verteporfin is ineffective towards the BRAF mutant UM cells, which are sensitive to MEK inhibitors.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('MEK', 'Gene', (121, 124))	('verteporfin', 'Chemical', 'MESH:D000077362', (37, 48))	('MEK', 'Gene', '5609', (121, 124))	('UM', 'Phenotype', 'HP:0007716', (88, 90))	('mutant', 'Var', (81, 87))
109120	24882516	These observations suggest that the therapeutic effects of verteporfin observed on the Gq/11 mutant UM cells are not due to general toxicity, but rather target specific and mechanism based inhibition of the Gq/11 mutant UM cells.	('UM', 'Phenotype', 'HP:0007716', (100, 102))	('UM', 'Phenotype', 'HP:0007716', (220, 222))	('Gq/11', 'Chemical', '-', (87, 92))	('Gq/11', 'Gene', (87, 92))	('mutant', 'Var', (93, 99))	('toxicity', 'Disease', 'MESH:D064420', (132, 140))	('toxicity', 'Disease', (132, 140))	('Gq/11', 'Chemical', '-', (207, 212))	('verteporfin', 'Chemical', 'MESH:D000077362', (59, 70))	('inhibition', 'NegReg', (189, 199))
109121	24882516	It has been previously shown that the active Gq/11 mutant also stimulates the ERK pathway.	('Gq/11', 'Chemical', '-', (45, 50))	('ERK', 'Gene', '5594', (78, 81))	('mutant', 'Var', (51, 57))	('ERK', 'molecular_function', 'GO:0004707', ('78', '81'))	('Gq/11', 'Gene', (45, 50))	('ERK', 'Gene', (78, 81))	('stimulates', 'PosReg', (63, 73))
109122	24882516	However, activation of the ERK pathway by active Gq/11 is less potent compared to that of the BRAFV600E mutation, which is frequently found in cutaneous melanoma (Figures 1B and S1D).	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (143, 161))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (143, 161))	('Gq/11', 'Chemical', '-', (49, 54))	('BRAFV600E', 'Mutation', 'rs113488022', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('ERK', 'molecular_function', 'GO:0004707', ('27', '30'))	('active Gq/11', 'Var', (42, 54))	('ERK', 'Gene', '5594', (27, 30))	('cutaneous melanoma', 'Disease', (143, 161))	('ERK', 'Gene', (27, 30))
109125	24882516	Consistent with this notion, down-regulation of YAP or verteporfin treatment induces more cell death and tumor inhibition in Gq/11 mutant UM cells than BRAF mutant UM cells (Figures 4F-H and 5).	('BRAF', 'Gene', (152, 156))	('verteporfin', 'Chemical', 'MESH:D000077362', (55, 66))	('cell death', 'biological_process', 'GO:0008219', ('90', '100'))	('death', 'Disease', 'MESH:D003643', (95, 100))	('down-regulation', 'NegReg', (29, 44))	('death', 'Disease', (95, 100))	('mutant', 'Var', (131, 137))	('Gq/11', 'Chemical', '-', (125, 130))	('BRAF', 'Gene', '673', (152, 156))	('4F-H and 5', 'Gene', '8293', (182, 192))	('Gq/11', 'Gene', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('UM', 'Phenotype', 'HP:0007716', (138, 140))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('UM', 'Phenotype', 'HP:0007716', (164, 166))	('tumor', 'Disease', (105, 110))	('regulation', 'biological_process', 'GO:0065007', ('34', '44'))
109126	24882516	Further studies are needed to determine the effect of a combined treatment inhibiting both MEK and YAP in treating UM with the Gq/11 mutation.	('Gq/11', 'Chemical', '-', (127, 132))	('inhibiting', 'NegReg', (75, 85))	('mutation', 'Var', (133, 141))	('Gq/11', 'Gene', (127, 132))	('UM', 'Phenotype', 'HP:0007716', (115, 117))	('MEK', 'Gene', (91, 94))	('MEK', 'Gene', '5609', (91, 94))
109129	24882516	Mutations in the Hippo pathway components are rare in human cancers.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('Hippo', 'Gene', (17, 22))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (54, 59))
109131	24882516	Mutation in NF2 activates YAP, and YAP activation is required for NF2-induced tumorigenesis.	('NF2', 'Gene', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('YAP', 'MPA', (26, 29))	('Mutation', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('NF2', 'Gene', (12, 15))	('activates', 'PosReg', (16, 25))	('NF2', 'Gene', '4771', (66, 69))	('tumor', 'Disease', (78, 83))	('NF2', 'Gene', '4771', (12, 15))
109133	24882516	In addition to UM, other types of neoplastic lesions, such as blue naevi and leptomeningeal melanocytic lesions also contain prevalent Gq/11 mutations.	('leptomeningeal melanocytic lesions', 'Disease', 'MESH:D008577', (77, 111))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (34, 52))	('mutations', 'Var', (141, 150))	('neoplastic lesions', 'Disease', (34, 52))	('blue naevi', 'Disease', (62, 72))	('Gq/11', 'Chemical', '-', (135, 140))	('Gq/11', 'Gene', (135, 140))	('UM', 'Phenotype', 'HP:0007716', (15, 17))	('neoplastic lesions', 'Disease', 'MESH:D051437', (34, 52))	('leptomeningeal melanocytic lesions', 'Disease', (77, 111))	('naevi', 'Phenotype', 'HP:0003764', (67, 72))	('blue naevi', 'Phenotype', 'HP:0100814', (62, 72))
109134	24882516	More recently, the GqR183Q mutation has been identified in the 80-90% of Sturge-Weber Syndrome and Port-Wine Stains patients.	('Port-Wine Stains', 'Phenotype', 'HP:0001052', (99, 115))	('Sturge-Weber Syndrome', 'Disease', (73, 94))	('patients', 'Species', '9606', (116, 124))	('Port-Wine Stains', 'Disease', (99, 115))	('Weber Syndrome', 'Phenotype', 'HP:0002277', (80, 94))	('GqR183Q', 'Var', (19, 26))	('Gq', 'Chemical', 'MESH:C039788', (19, 21))
109135	24882516	We also showed that GqR183Q also potently activated YAP (Figures 1A and S1A-C).	('Gq', 'Chemical', 'MESH:C039788', (20, 22))	('activated', 'PosReg', (42, 51))	('GqR183Q', 'Var', (20, 27))	('YAP', 'CPA', (52, 55))
109136	24882516	Interestingly, most of these tumors or overgrowths, including those caused by NF2 loss-of-function mutations, are derived from the neuroectoderm.	('loss-of-function', 'NegReg', (82, 98))	('NF2', 'Gene', '4771', (78, 81))	('overgrowths', 'Phenotype', 'HP:0001548', (39, 50))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('mutations', 'Var', (99, 108))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('NF2', 'Gene', (78, 81))
109137	24882516	Activation of YAP/TAZ by Gq/11 or NF2 mutations in these tumors suggests that the Hippo pathway plays an important role in the development and differentiation of the neuroectoderm, consistent with a role of the Hippo pathway in regulating neural progenitor cells.	('NF2', 'Gene', (34, 37))	('Gq/11', 'Chemical', '-', (25, 30))	('TAZ', 'Gene', (18, 21))	('development', 'CPA', (127, 138))	('Gq/11', 'Gene', (25, 30))	('NF2', 'Gene', '4771', (34, 37))	('TAZ', 'Gene', '6901', (18, 21))	('Activation', 'PosReg', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('mutations', 'Var', (38, 47))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
109139	24882516	Although cancer-associated mutations in GPCR signaling is less frequent than receptor tyrosine kinases, extensive cancer genome sequencing has revealed that approximately 20% of all human cancers may have altered GPCR signaling.	('mutations', 'Var', (27, 36))	('cancer', 'Disease', (9, 15))	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('GPCR', 'Gene', (213, 217))	('GPCR', 'Gene', '9170', (213, 217))	('altered', 'Reg', (205, 212))	('signaling', 'biological_process', 'GO:0023052', ('218', '227'))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('human', 'Species', '9606', (182, 187))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancers', 'Disease', (188, 195))	('cancer', 'Disease', (188, 194))	('GPCR', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('GPCR', 'Gene', '9170', (40, 44))	('cancer', 'Disease', (114, 120))
109140	24882516	For example, mutation of metabotropic glutamate receptor occurs at an appreciable frequency in cutaneous melanoma.	('metabotropic glutamate receptor', 'Protein', (25, 56))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('mutation', 'Var', (13, 21))	('cutaneous melanoma', 'Disease', (95, 113))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (95, 113))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (95, 113))
109141	24882516	Besides genetic alterations (mutation or amplification), GPCRs are stimulated by their cognate ligands, and therefore altered ligand levels can also lead to abnormal GPCR signaling.	('ligand', 'MPA', (126, 132))	('GPCR', 'Gene', (166, 170))	('ligand', 'molecular_function', 'GO:0005488', ('126', '132'))	('GPCR', 'Gene', (57, 61))	('signaling', 'biological_process', 'GO:0023052', ('171', '180'))	('altered', 'Var', (118, 125))	('GPCR', 'Gene', '9170', (166, 170))	('GPCR', 'Gene', '9170', (57, 61))	('abnormal GPCR', 'Phenotype', 'HP:0031821', (157, 170))	('lead to', 'Reg', (149, 156))
109142	24882516	For example, LPA is a potent mitogen and strongly activates YAP/TAZ.	('TAZ', 'Gene', '6901', (64, 67))	('LPA', 'Var', (13, 16))	('activates', 'PosReg', (50, 59))	('TAZ', 'Gene', (64, 67))	('LPA', 'Chemical', 'MESH:C032881', (13, 16))
109148	24882516	HEK293A, HEK293T, and HEK293P cells were cultured in DMEM medium with 10% FBS.	('HEK293T', 'CellLine', 'CVCL:0063', (9, 16))	('FBS', 'Disease', 'MESH:D005198', (74, 77))	('HEK293T', 'Var', (9, 16))	('DMEM medium', 'Chemical', '-', (53, 64))	('FBS', 'Disease', (74, 77))	('HEK293P', 'Var', (22, 29))	('HEK293P', 'CellLine', 'CVCL:0045', (22, 29))	('HEK293A', 'CellLine', 'CVCL:6910', (0, 7))
109152	24882516	Cells (Melan-a, 92.1, OCM1, or OCM8) with manipulations of YAP or Gq expression were grafted subcutaneously into both flanks of mice, and tumor growth was monitored three times a week.	('YAP', 'Gene', (59, 62))	('OCM1', 'Species', '83984', (22, 26))	('tumor', 'Disease', (138, 143))	('Gq expression', 'Gene', (66, 79))	('Gq', 'Chemical', 'MESH:C039788', (66, 68))	('mice', 'Species', '10090', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('manipulations', 'Var', (42, 55))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
109162	24882516	Uveal Melanoma-associated mutant Gq/11 activates YAP YAP activation correlates with mutations of Gq/11 in uveal melanomas YAP is essential for mutant Gq/11-induced uveal melanoma growth YAP inhibitor suppresses mutant Gq/11-induced uveal melanoma development Uveal melanoma (UM) is the most common type of adult eye cancer, currently there is no effective treatment especially for metastatic UM.	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('melanoma', 'Disease', (238, 246))	('UM', 'Phenotype', 'HP:0007716', (275, 277))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('mutant', 'Var', (26, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (164, 178))	('eye cancer', 'Disease', 'MESH:D005134', (312, 322))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('Melanoma', 'Disease', 'MESH:D008545', (6, 14))	('UM', 'Phenotype', 'HP:0007716', (392, 394))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('uveal melanoma', 'Disease', 'MESH:C536494', (232, 246))	('uveal melanoma', 'Disease', (232, 246))	('Gq/11', 'Chemical', '-', (218, 223))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('uveal melanomas', 'Disease', 'MESH:C536494', (106, 121))	('melanoma', 'Disease', 'MESH:D008545', (238, 246))	('eye cancer', 'Disease', (312, 322))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('Gq/11', 'Chemical', '-', (97, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (232, 246))	('Melanoma', 'Disease', (6, 14))	('Gq/11', 'Chemical', '-', (33, 38))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('melanoma', 'Disease', (265, 273))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (259, 273))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('Melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (170, 178))	('uveal melanomas', 'Phenotype', 'HP:0007716', (106, 121))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('eye cancer', 'Phenotype', 'HP:0100012', (312, 322))	('uveal melanomas', 'Disease', (106, 121))	('uveal melanoma', 'Disease', 'MESH:C536494', (164, 178))	('Gq/11', 'Chemical', '-', (150, 155))	('uveal melanoma', 'Disease', (164, 178))
109164	24882516	We found that the Hippo pathway effector YAP is activated in UM containing mutant Gq/11, and inhibition of YAP by either genetic or pharmacological approaches blocks tumor growth of Gq/11-mutanted UM cells in mouse models, suggesting a strategy for UM intervention by inhibiting YAP.	('Gq/11', 'Chemical', '-', (182, 187))	('blocks tumor', 'Disease', (159, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('blocks tumor', 'Disease', 'MESH:D006327', (159, 171))	('UM', 'Phenotype', 'HP:0007716', (197, 199))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('Gq/11', 'Chemical', '-', (82, 87))	('mutant', 'Var', (75, 81))	('Hippo pathway', 'Pathway', (18, 31))	('UM', 'Phenotype', 'HP:0007716', (249, 251))	('Gq/11', 'Gene', (82, 87))	('activated', 'PosReg', (48, 57))	('mouse', 'Species', '10090', (209, 214))
109165	24882516	This mechanism that YAP activation mediates mutant Gq/11 signaling in tumorigenesis may serve as a paradigm for general pathogenesis of human cancers with aberrant expression or mutations of G-protein-coupled receptor (GPCR) or G-proteins.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('human', 'Species', '9606', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mutant', 'Var', (44, 50))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('GPCR', 'Gene', (219, 223))	('activation', 'PosReg', (24, 34))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('GPCR', 'Gene', '9170', (219, 223))	('cancers', 'Disease', (142, 149))	('Gq/11', 'Chemical', '-', (51, 56))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Gq/11', 'Gene', (51, 56))	('pathogenesis', 'biological_process', 'GO:0009405', ('120', '132'))	('tumor', 'Disease', (70, 75))	('mutations', 'Var', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('G-proteins', 'Protein', (228, 238))
109166	22693581	Conserved Expression Signatures between Medaka and Human Pigment Cell Tumors Aberrations in gene expression are a hallmark of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Pigment Cell Tumors', 'Disease', (57, 76))	('Pigment Cell Tumors', 'Disease', 'MESH:D010859', (57, 76))	('Tumor', 'Phenotype', 'HP:0002664', (70, 75))	('gene expression', 'MPA', (92, 107))	('Medaka', 'Species', '8090', (40, 46))	('gene expression', 'biological_process', 'GO:0010467', ('92', '107'))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('Human', 'Species', '9606', (51, 56))	('Aberrations', 'Var', (77, 88))	('Tumors', 'Phenotype', 'HP:0002664', (70, 76))	('Pigment Cell Tumors', 'Phenotype', 'HP:0002861', (57, 76))
109183	22693581	Depending on a homogeneous, strain-specific genetic background, carriers of the transgene develop pigment cell tumors of different characteristics.	('pigment cell tumors', 'Disease', (98, 117))	('pigment cell tumors', 'Phenotype', 'HP:0002861', (98, 117))	('pigment cell tumors', 'Disease', 'MESH:D010859', (98, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('develop', 'PosReg', (90, 97))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('pigment cell tumor', 'Phenotype', 'HP:0002861', (98, 116))	('transgene', 'Var', (80, 89))
109263	22693581	Previous studies have used these systems as surrogates for analyzing the action of mutated oncogenes in eliciting melanoma formation and the interaction of known melanoma pathways with the primary oncogene.	('mutated', 'Var', (83, 90))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('eliciting', 'MPA', (104, 113))	('interaction', 'Interaction', (141, 152))	('melanoma', 'Disease', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
109264	22693581	One study compared the expression profile of 16 candidate genes for cancer progression in a mutant HRAS transgenic zebrafish melanoma model with data from human melanoma, but found no consistent expression changes.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('human', 'Species', '9606', (155, 160))	('HRAS transgenic zebrafish melanoma', 'Disease', (99, 133))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('HRAS transgenic zebrafish melanoma', 'Disease', 'MESH:D008545', (99, 133))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('mutant', 'Var', (92, 98))	('cancer', 'Disease', (68, 74))	('melanoma', 'Disease', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('expression', 'MPA', (23, 33))
109265	22693581	Another study reported microarray analyses of melanoma in mutant NRAS;p53-/- zebrafish in comparison to normal skin and human melanoma.	('mutant', 'Var', (58, 64))	('human', 'Species', '9606', (120, 125))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))	('NRAS', 'Gene', '30380', (65, 69))	('zebrafish', 'Species', '7955', (77, 86))	('NRAS', 'Gene', (65, 69))
109280	22693581	An interesting aspect is the consistent downregulation of p53, p63 and p73.	('downregulation', 'NegReg', (40, 54))	('p63', 'Gene', (63, 66))	('p73', 'Gene', '7161', (71, 74))	('p53', 'Var', (58, 61))	('p73', 'Gene', (71, 74))	('p63', 'Gene', '8626', (63, 66))
109293	22693581	SLC45A2 has earlier been associated with melanoma only in the context of pigmentation, where mutations in the gene confer higher melanoma risk.	('mutations', 'Var', (93, 102))	('associated', 'Reg', (25, 35))	('pigmentation', 'Disease', 'MESH:D010859', (73, 85))	('higher', 'PosReg', (122, 128))	('pigmentation', 'Disease', (73, 85))	('pigmentation', 'biological_process', 'GO:0043473', ('73', '85'))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('SLC45A2', 'Gene', '51151', (0, 7))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('SLC45A2', 'Gene', (0, 7))
109308	21874003	Germline mutations in BAP1 predispose to melanocytic tumors Common acquired melanocytic nevi are benign neoplasms that are composed of small uniform melanocytes and typically present as flat or slightly elevated, pigmented lesions on the skin.	('Germline mutations', 'Var', (0, 18))	('pigmented lesions', 'Disease', (213, 230))	('acquired melanocytic nevi', 'Disease', (67, 92))	('neoplasms', 'Phenotype', 'HP:0002664', (104, 113))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (76, 92))	('melanocytic tumors', 'Disease', (41, 59))	('melanocytic tumors', 'Disease', 'MESH:D009508', (41, 59))	('neoplasm', 'Phenotype', 'HP:0002664', (104, 112))	('nevi', 'Phenotype', 'HP:0003764', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('predispose to', 'Reg', (27, 40))	('BAP1', 'Gene', '8314', (22, 26))	('benign neoplasms', 'Disease', (97, 113))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('benign neoplasms', 'Disease', 'MESH:D009369', (97, 113))	('pigmented lesions', 'Disease', 'MESH:D010859', (213, 230))	('BAP1', 'Gene', (22, 26))
109312	21874003	Segregating with this phenotype, we found inactivating germline mutations of the BAP1 gene.	('BAP1', 'Gene', '8314', (81, 85))	('inactivating', 'Var', (42, 54))	('BAP1', 'Gene', (81, 85))
109314	21874003	In addition, we found BAP1 mutations in a subset of sporadic melanocytic neoplasms showing histologic similarities to the familial tumors.	('mutations', 'Var', (27, 36))	('familial tumors', 'Disease', (122, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('neoplasm', 'Phenotype', 'HP:0002664', (73, 81))	('found', 'Reg', (16, 21))	('familial tumors', 'Disease', 'MESH:D009386', (122, 137))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('BAP1', 'Gene', '8314', (22, 26))	('sporadic melanocytic neoplasms', 'Disease', 'MESH:D009508', (52, 82))	('sporadic melanocytic neoplasms', 'Disease', (52, 82))	('neoplasms', 'Phenotype', 'HP:0002664', (73, 82))	('BAP1', 'Gene', (22, 26))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (61, 82))
109315	21874003	These findings suggest that loss of BAP1 is associated with a clinically and morphologically distinct type of melanocytic neoplasm.	('associated', 'Reg', (44, 54))	('loss', 'Var', (28, 32))	('neoplasm', 'Phenotype', 'HP:0002664', (122, 130))	('BAP1', 'Gene', '8314', (36, 40))	('melanocytic neoplasm', 'Disease', 'MESH:D009508', (110, 130))	('BAP1', 'Gene', (36, 40))	('melanocytic neoplasm', 'Disease', (110, 130))
109321	21874003	In addition, 37 of 42 (88%) tumors in the families showed BRAF mutations, which are typically absent in Spitz nevi.	('mutations', 'Var', (63, 72))	('nevi', 'Phenotype', 'HP:0003764', (110, 114))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('BRAF', 'Gene', '673', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('BRAF', 'Gene', (58, 62))
109331	21874003	This analysis revealed a frameshift mutation in the BAP1 gene (c.1305delG, p.Gln436Asnfs*135) that was subsequently found to segregate with the phenotype (Fig.	('p.Gln436Asnfs*135', 'FRAMESHIFT', 'None', (75, 92))	('BAP1', 'Gene', '8314', (52, 56))	('p.Gln436Asnfs*135', 'Var', (75, 92))	('c.1305delG', 'Mutation', 'rs587776877', (63, 73))	('c.1305delG', 'Var', (63, 73))	('BAP1', 'Gene', (52, 56))	('frameshift', 'Var', (25, 35))
109337	21874003	In four other neoplasms without 3p21 deletions, we found additional acquired somatic nonsense (2 cases), frameshift (1 case) and missense (1 case) mutations in BAP1.	('neoplasms', 'Disease', 'MESH:D009369', (14, 23))	('neoplasms', 'Disease', (14, 23))	('BAP1', 'Gene', '8314', (160, 164))	('neoplasm', 'Phenotype', 'HP:0002664', (14, 22))	('frameshift', 'Var', (105, 115))	('neoplasms', 'Phenotype', 'HP:0002664', (14, 23))	('BAP1', 'Gene', (160, 164))	('missense', 'Var', (129, 137))
109340	21874003	In family 2, we found a different germline mutation in BAP1 that segregated with the phenotype and removed the acceptor splice site at the last exon (c.2057-2A>G, p.Met687Glufs*28, Fig.	('BAP1', 'Gene', '8314', (55, 59))	('BAP1', 'Gene', (55, 59))	('c.2057-2A>G', 'Mutation', 'rs587776878', (150, 161))	('p.Met687Glufs*28', 'Mutation', 'p.M687EfsX28', (163, 179))	('removed', 'NegReg', (99, 106))	('acceptor splice site', 'MPA', (111, 131))	('c.2057-2A>G', 'Var', (150, 161))	('segregated', 'Reg', (65, 75))	('p.Met687Glufs*', 'Var', (163, 177))
109341	21874003	In family 2, inactivation of the remaining wild-type BAP1 allele was found in 9 of 13 skin tumors, in the uveal melanoma (II-1), and in the cutaneous melanoma from patient II-3 (Fig.	('skin tumors', 'Disease', (86, 97))	('inactivation', 'Var', (13, 25))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('uveal melanoma', 'Disease', (106, 120))	('I-1', 'Gene', '5502', (123, 126))	('skin tumors', 'Disease', 'MESH:D012878', (86, 97))	('BAP1', 'Gene', '8314', (53, 57))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('cutaneous melanoma', 'Disease', (140, 158))	('skin tumors', 'Phenotype', 'HP:0008069', (86, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (140, 158))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (140, 158))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('patient', 'Species', '9606', (164, 171))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('found', 'Reg', (69, 74))	('BAP1', 'Gene', (53, 57))	('I-1', 'Gene', (123, 126))
109345	21874003	To address the role of BAP1 mutations in sporadic melanocytic neoplasms, we sequenced BAP1 in 156 randomly selected tumors without family history: common nevi with uniform small melanocytes (n=28); Spitz nevi (n=17); neoplasms with overlapping features between Spitz nevus and melanoma (so-called "atypical Spitz tumors", n=18); primary melanomas originating from acral skin (n=15), mucosa (n=15), or skin with (n=15) or without (n=15) chronic sun-induced damage, and uvea (n=33).	('melanomas', 'Disease', 'MESH:D008545', (337, 346))	('neoplasms', 'Disease', (217, 226))	('neoplasm', 'Phenotype', 'HP:0002664', (62, 70))	('BAP1', 'Gene', '8314', (23, 27))	('tumors', 'Disease', 'MESH:D009369', (313, 319))	('melanomas', 'Disease', (337, 346))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('Spitz tumors', 'Disease', (307, 319))	('melanoma', 'Disease', 'MESH:D008545', (337, 345))	('BAP1', 'Gene', '8314', (86, 90))	('neoplasms', 'Disease', 'MESH:D009369', (62, 71))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (50, 71))	('nevi', 'Phenotype', 'HP:0003764', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('melanoma', 'Phenotype', 'HP:0002861', (277, 285))	('melanoma', 'Disease', (277, 285))	('neoplasms', 'Phenotype', 'HP:0002664', (217, 226))	('uvea', 'Disease', (468, 472))	('melanomas', 'Phenotype', 'HP:0002861', (337, 346))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('tumors', 'Disease', (116, 122))	('BAP1', 'Gene', (23, 27))	('nevus', 'Phenotype', 'HP:0003764', (267, 272))	('neoplasms', 'Disease', (62, 71))	('neoplasm', 'Phenotype', 'HP:0002664', (217, 225))	('Spitz tumors', 'Disease', 'MESH:D018332', (307, 319))	('BAP1', 'Gene', (86, 90))	('tumors', 'Phenotype', 'HP:0002664', (313, 319))	('Spitz nevus', 'Disease', (261, 272))	('sporadic melanocytic neoplasms', 'Disease', 'MESH:D009508', (41, 71))	('nevi', 'Phenotype', 'HP:0003764', (154, 158))	('mutations', 'Var', (28, 37))	('melanoma', 'Phenotype', 'HP:0002861', (337, 345))	('melanoma', 'Disease', (337, 345))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('neoplasms', 'Disease', 'MESH:D009369', (217, 226))	('uvea', 'Disease', 'MESH:C536494', (468, 472))	('tumors', 'Disease', (313, 319))	('melanoma', 'Disease', 'MESH:D008545', (277, 285))	('sporadic melanocytic neoplasms', 'Disease', (41, 71))	('neoplasms', 'Phenotype', 'HP:0002664', (62, 71))
109346	21874003	Thirteen (40%) uveal melanomas, two (11%) atypical Spitz tumors and three (5%) of the melanomas (2 melanoma on skin without chronic sun-induced damage and 1 acral melanoma) had somatic BAP1 mutations.	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('acral melanoma', 'Disease', 'MESH:D008545', (157, 171))	('BAP1', 'Gene', (185, 189))	('melanomas', 'Disease', (21, 30))	('acral melanoma', 'Phenotype', 'HP:0012060', (157, 171))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('uveal melanomas', 'Disease', (15, 30))	('uveal melanomas', 'Phenotype', 'HP:0007716', (15, 30))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('mutations', 'Var', (190, 199))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('Spitz tumors', 'Disease', (51, 63))	('melanoma', 'Disease', (21, 29))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('acral melanoma', 'Disease', (157, 171))	('BAP1', 'Gene', '8314', (185, 189))	('melanomas', 'Disease', 'MESH:D008545', (86, 95))	('Spitz tumors', 'Disease', 'MESH:D018332', (51, 63))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('uveal melanoma', 'Phenotype', 'HP:0007716', (15, 29))	('uveal melanomas', 'Disease', 'MESH:C536494', (15, 30))	('melanomas', 'Disease', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))
109348	21874003	Two of five sporadic cutaneous melanomas that arose in nevi harbored BAP1 mutations.	('harbored', 'Reg', (60, 68))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (21, 40))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (21, 40))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (21, 39))	('nevi', 'Phenotype', 'HP:0003764', (55, 59))	('cutaneous melanomas', 'Disease', (21, 40))	('BAP1', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('BAP1', 'Gene', '8314', (69, 73))
109350	21874003	The two atypical Spitz tumors with somatic BAP1 mutations had similar morphologic features to the melanocytic neoplasms seen in both families, lacked immunohistochemical expression of BAP1, and harbored BRAF mutations (Supplementary Figure 14).	('neoplasms', 'Phenotype', 'HP:0002664', (110, 119))	('BAP1', 'Gene', (43, 47))	('Spitz tumors', 'Disease', 'MESH:D018332', (17, 29))	('BAP1', 'Gene', '8314', (184, 188))	('melanocytic neoplasms', 'Disease', (98, 119))	('lacked', 'NegReg', (143, 149))	('Spitz tumors', 'Disease', (17, 29))	('neoplasm', 'Phenotype', 'HP:0002664', (110, 118))	('BRAF', 'Gene', '673', (203, 207))	('BAP1', 'Gene', '8314', (43, 47))	('BAP1', 'Gene', (184, 188))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (98, 119))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('BRAF', 'Gene', (203, 207))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (98, 119))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('harbored', 'Reg', (194, 202))	('mutations', 'Var', (48, 57))
109351	21874003	This finding suggests that bi-allelic inactivation of BAP1 is associated with a clinically and morphologically distinct type of melanocytic neoplasm.	('bi-allelic inactivation', 'Var', (27, 50))	('associated', 'Reg', (62, 72))	('BAP1', 'Gene', '8314', (54, 58))	('melanocytic neoplasm', 'Disease', 'MESH:D009508', (128, 148))	('BAP1', 'Gene', (54, 58))	('melanocytic neoplasm', 'Disease', (128, 148))	('neoplasm', 'Phenotype', 'HP:0002664', (140, 148))
109354	21874003	As illustrated by the families, inheriting one mutant copy of BAP1 results in a markedly increased number of these neoplasms.	('neoplasms', 'Phenotype', 'HP:0002664', (115, 124))	('BAP1', 'Gene', '8314', (62, 66))	('BAP1', 'Gene', (62, 66))	('neoplasms', 'Disease', 'MESH:D009369', (115, 124))	('neoplasms', 'Disease', (115, 124))	('neoplasm', 'Phenotype', 'HP:0002664', (115, 123))	('increased', 'PosReg', (89, 98))	('mutant', 'Var', (47, 53))
109356	21874003	This indicates that the risk of malignant progression in individual tumors is low, and that bi-allelic loss of BAP1 in conjunction with mutations in BRAF is not sufficient for melanoma formation in the skin.	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('tumors', 'Disease', (68, 74))	('BAP1', 'Gene', '8314', (111, 115))	('melanoma', 'Disease', (176, 184))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('formation', 'biological_process', 'GO:0009058', ('185', '194'))	('BAP1', 'Gene', (111, 115))	('mutations', 'Var', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('loss', 'NegReg', (103, 107))
109357	21874003	proposed that bi-allelic loss of BAP1 in uveal melanoma, which carry mutations in GNAQ or GNA11 but not in BRAF, marks the transition to metastatic disease.	('GNA11', 'Gene', '2767', (90, 95))	('mutations', 'Var', (69, 78))	('GNA11', 'Gene', (90, 95))	('uveal melanoma', 'Disease', (41, 55))	('BRAF', 'Gene', (107, 111))	('uveal melanoma', 'Disease', 'MESH:C536494', (41, 55))	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('GNAQ', 'Gene', (82, 86))	('BAP1', 'Gene', '8314', (33, 37))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('BAP1', 'Gene', (33, 37))	('loss', 'NegReg', (25, 29))	('BRAF', 'Gene', '673', (107, 111))	('GNAQ', 'Gene', '2776', (82, 86))	('metastatic', 'CPA', (137, 147))
109361	21874003	In cancer, mutations and deletions in BAP1 have been reported in breast and lung cancers, but none of the individuals in our study developed breast or lung cancers.	('mutations', 'Var', (11, 20))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast or lung cancers', 'Disease', (141, 163))	('BAP1', 'Gene', '8314', (38, 42))	('lung cancers', 'Phenotype', 'HP:0100526', (76, 88))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('breast and lung cancers', 'Disease', 'MESH:D001943', (65, 88))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('BAP1', 'Gene', (38, 42))	('deletions', 'Var', (25, 34))	('lung cancers', 'Phenotype', 'HP:0100526', (151, 163))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancer', 'Disease', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', (3, 9))	('breast or lung cancers', 'Disease', 'MESH:D001943', (141, 163))	('reported', 'Reg', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
109362	21874003	In summary, we describe a novel autosomal dominant syndrome that is caused by germline mutations of BAP1, characterized by a high penetrance of melanocytic neoplasms with distinctive clinical and histopathological features, and possibly associated with an increased risk for uveal and cutaneous melanoma.	('BAP1', 'Gene', '8314', (100, 104))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (144, 165))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (144, 165))	('cutaneous melanoma', 'Disease', (285, 303))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (285, 303))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (285, 303))	('BAP1', 'Gene', (100, 104))	('melanocytic neoplasms', 'Disease', (144, 165))	('uveal', 'Disease', (275, 280))	('autosomal dominant syndrome', 'Disease', (32, 59))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (32, 59))	('melanoma', 'Phenotype', 'HP:0002861', (295, 303))	('neoplasm', 'Phenotype', 'HP:0002664', (156, 164))	('caused by', 'Reg', (68, 77))	('uveal', 'Disease', 'MESH:D014603', (275, 280))	('mutations', 'Var', (87, 96))	('neoplasms', 'Phenotype', 'HP:0002664', (156, 165))
109375	21874003	Briefly, 250 to 500ng test and reference DNA (Promega, Madison, WI) were differentially labeled with dCTP-Cy5 and dCTP-Cy3, respectively (GE Healthcare, Piscataway, NJ).	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('dCTP-Cy3', 'Var', (114, 122))	('dCTP-Cy5', 'Var', (101, 109))	('dCTP-Cy5', 'Chemical', '-', (101, 109))	('dCTP-Cy3', 'Chemical', '-', (114, 122))
109386	21874003	FISH probes were synthesized from BAC clones and labeled by nick translation with SpectrumGreen-dUTP, SpectrumRed-dUTP and SpectrumOrange-dUTP (Abbott, Des Plaines, IL) with standard procedures.	('SpectrumRed-dUTP', 'Var', (102, 118))	('SpectrumOrange-dUTP', 'Var', (123, 142))	('SpectrumRed-dUTP', 'Chemical', '-', (102, 118))	('translation', 'biological_process', 'GO:0006412', ('65', '76'))	('SpectrumGreen-dUTP', 'Chemical', '-', (82, 100))	('SpectrumOrange-dUTP', 'Chemical', '-', (123, 142))
109387	21874003	The SpectrumRed probe mapped to 3p21 (RP11-447A21 and RP5-966M1), SpectrumOrange to 3p25 (RP11-614E19 and RP11-963B11RP), and SpectrumGreen to 4q12 (RP11-117E8 and RP11-231C18).	('RP11-447A21', 'Var', (38, 49))	('RP11-231C18', 'Var', (164, 175))	('RP11-963B11RP', 'Gene', '26121', (106, 119))	('RP11-963B11RP', 'Gene', (106, 119))	('RP11-117E8', 'Var', (149, 159))	('RP11-614E19', 'Var', (90, 101))
109388	21874003	The functional consequences of missense mutations in BAP1 were assessed with three computational functional significance predictors (Supplementary Table 7 and 8).	('missense mutations', 'Var', (31, 49))	('BAP1', 'Gene', '8314', (53, 57))	('BAP1', 'Gene', (53, 57))
109390	19718445	The mutations exclusively affect codon 209 and result in GNAQ constitutive activation which, in turn, acts as a dominant oncogene.	('codon 209', 'Var', (33, 42))	('GNAQ', 'Gene', (57, 61))	('affect', 'Reg', (26, 32))	('result in', 'Reg', (47, 56))	('mutations', 'Var', (4, 13))	('GNAQ', 'Gene', '2776', (57, 61))
109393	19718445	Our data indicate that the occurrence of GNAQ mutations display a unique pattern being present in a subset of melanocytic tumors but not in malignancies of glial, epithelial and stromal origin analyzed in this study.	('malignancies', 'Disease', 'MESH:D009369', (140, 152))	('GNAQ', 'Gene', '2776', (41, 45))	('mutations', 'Var', (46, 55))	('malignancies', 'Disease', (140, 152))	('GNAQ', 'Gene', (41, 45))	('melanocytic tumors', 'Disease', 'MESH:D009508', (110, 128))	('melanocytic tumors', 'Disease', (110, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
109396	19718445	Most melanocytic neoplasms show oncogenic mutations in components of the MAPKinase cascade, particularly in BRAF and NRAS .	('melanocytic neoplasms', 'Disease', (5, 26))	('NRAS', 'Gene', (117, 121))	('NRAS', 'Gene', '4893', (117, 121))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (5, 26))	('neoplasms', 'Phenotype', 'HP:0002664', (17, 26))	('BRAF', 'Gene', '673', (108, 112))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (5, 26))	('mutations', 'Var', (42, 51))	('BRAF', 'Gene', (108, 112))
109397	19718445	A recent study has reported frequent somatic mutations in the heterotrimeric G protein alpha-subunit (GNAQ) in a subset of melanocytic neoplasms which do not present alterations in the RAS or BRAF genes.	('neoplasms', 'Phenotype', 'HP:0002664', (135, 144))	('mutations', 'Var', (45, 54))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('62', '86'))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (123, 144))	('GNAQ', 'Gene', (102, 106))	('BRAF', 'Gene', '673', (192, 196))	('melanocytic neoplasms', 'Disease', (123, 144))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('BRAF', 'Gene', (192, 196))	('GNAQ', 'Gene', '2776', (102, 106))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (123, 144))
109400	19718445	It has been previously shown that in other RAS family members, mutations at this site cause loss of GTPase activity with constitutive activation.	('mutations', 'Var', (63, 72))	('activity', 'MPA', (107, 115))	('GTP', 'Chemical', 'MESH:D006160', (100, 103))	('loss', 'NegReg', (92, 96))	('GTPase activity', 'molecular_function', 'GO:0003924', ('100', '115'))	('GTPase', 'Protein', (100, 106))
109404	19718445	Gqalpha (GNAQ), G11alpha (GNA11), G14alpha (GNA14) and G15alpha (GNA15) each have very different tissue and cell expression patterns.	('GNA14', 'Gene', (44, 49))	('GNAQ', 'Gene', (9, 13))	('G11alpha', 'Var', (16, 24))	('G14alpha', 'Var', (34, 42))	('GNA14', 'Gene', '9630', (44, 49))	('GNA15', 'Gene', (65, 70))	('GNA11', 'Gene', '2767', (26, 31))	('GNA11', 'Gene', (26, 31))	('GNA15', 'Gene', '2769', (65, 70))	('GNAQ', 'Gene', '2776', (9, 13))	('G15alpha', 'Var', (55, 63))
109409	19718445	Of note exon 5 of GNA11 contains an equivalent residue to Q209 of GNAQ.	('GNAQ', 'Gene', '2776', (66, 70))	('GNA11', 'Gene', (18, 23))	('Q209', 'Var', (58, 62))	('GNAQ', 'Gene', (66, 70))	('GNA11', 'Gene', '2767', (18, 23))
109410	19718445	We hypothesized that mutations in GNAQ may also be present in tumor types from non melanocytic origin where they could represent alternative route to MAPKinase activation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('non melanocytic', 'Disease', (79, 94))	('tumor', 'Disease', (62, 67))	('GNAQ', 'Gene', (34, 38))	('GNAQ', 'Gene', '2776', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('mutations', 'Var', (21, 30))
109422	19718445	To assess whether these results were statistically significant we performed the Fisher's exact test to determine the tissue specificity for GNAQ mutation in blue naevi tumors as compared to the other tumor types.	('GNAQ', 'Gene', '2776', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Disease', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('GNAQ', 'Gene', (140, 144))	('blue naevi tumors', 'Disease', (157, 174))	('tumor', 'Disease', (200, 205))	('naevi', 'Phenotype', 'HP:0003764', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('blue naevi tumors', 'Disease', 'MESH:C536473', (157, 174))	('blue naevi', 'Phenotype', 'HP:0100814', (157, 167))	('mutation', 'Var', (145, 153))
109426	19718445	Sequences analysis identified the presence of the Q209L (c.A627T) mutation in GNAQ in 6/13 (46%) of blue naevi tumors (Figure 1 and Table 2), thus confirming previous data.	('naevi', 'Phenotype', 'HP:0003764', (105, 110))	('blue naevi', 'Phenotype', 'HP:0100814', (100, 110))	('Q209L (c.A627T', 'Var', (50, 64))	('blue naevi tumors', 'Disease', 'MESH:C536473', (100, 117))	('GNAQ', 'Gene', (78, 82))	('c.A627T', 'Mutation', 'rs121913492', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('Q209L', 'Mutation', 'rs121913492', (50, 55))	('GNAQ', 'Gene', '2776', (78, 82))	('blue naevi tumors', 'Disease', (100, 117))
109429	19718445	To assess whether these results were statistically significant we performed the Fisher's exact test to determine the tissue specificity for GNAQ mutation in blue naevi tumor as compared to the other tumor types (Table 2).	('tumor', 'Disease', (199, 204))	('GNAQ', 'Gene', '2776', (140, 144))	('tumor', 'Disease', (168, 173))	('GNAQ', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('naevi', 'Phenotype', 'HP:0003764', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('blue naevi', 'Phenotype', 'HP:0100814', (157, 167))	('mutation', 'Var', (145, 153))
109430	19718445	Our data confirm that GNAQ is a pivotal cancer gene in blue naevi while at the same time unveils a striking tissue-specific pattern of the GNAQQ209 mutations in human cancer.	('human', 'Species', '9606', (161, 166))	('blue naevi', 'Phenotype', 'HP:0100814', (55, 65))	('mutations', 'Var', (148, 157))	('naevi', 'Phenotype', 'HP:0003764', (60, 65))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('GNAQ', 'Gene', (22, 26))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', (40, 46))	('GNAQ', 'Gene', '2776', (139, 143))	('GNAQ', 'Gene', '2776', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('GNAQ', 'Gene', (139, 143))
109435	19718445	Until the discovery of the GNAQQ209 mutations there were no oncogenes altered at high frequency in uveal melanomas and blue naevi.	('GNAQ', 'Gene', '2776', (27, 31))	('uveal melanomas', 'Disease', (99, 114))	('blue naevi', 'Disease', (119, 129))	('uveal melanomas', 'Phenotype', 'HP:0007716', (99, 114))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('mutations', 'Var', (36, 45))	('uveal melanomas', 'Disease', 'MESH:C536494', (99, 114))	('melanomas', 'Phenotype', 'HP:0002861', (105, 114))	('GNAQ', 'Gene', (27, 31))	('naevi', 'Phenotype', 'HP:0003764', (124, 129))	('blue naevi', 'Phenotype', 'HP:0100814', (119, 129))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))
109436	19718445	The tissue-specificity of GNAQ mutations may be linked to its involvement in endothelin signaling, which is important for development of melanocytes and also is required for the migration of melanoblasts.	('endothelin signaling', 'MPA', (77, 97))	('mutations', 'Var', (31, 40))	('signaling', 'biological_process', 'GO:0023052', ('88', '97'))	('GNAQ', 'Gene', (26, 30))	('involvement', 'Reg', (62, 73))	('GNAQ', 'Gene', '2776', (26, 30))
109438	19718445	Gqalpha, G11alpha, bind and stimulate PLC-beta enzymes to initiate inositol lipid signalling.	('PLC-beta enzymes', 'Enzyme', (38, 54))	('initiate', 'Reg', (58, 66))	('signalling', 'biological_process', 'GO:0023052', ('82', '92'))	('stimulate', 'PosReg', (28, 37))	('inositol lipid', 'Chemical', '-', (67, 81))	('PLC', 'cellular_component', 'GO:0042824', ('38', '41'))	('G11alpha', 'Var', (9, 17))
109441	19718445	One hypothesis is that GNAQ regulates cell growth through a RAS dependent or RAS- independent signaling mechanism involving the PKC-dependent ERK pathway.. Functional assays are now required to assess this possibility and to understand in details the oncogenic signaling mechanisms regulated by GNAQ mutant alleles.	('mutant', 'Var', (300, 306))	('GNAQ', 'Gene', (23, 27))	('signaling', 'biological_process', 'GO:0023052', ('261', '270'))	('signaling', 'biological_process', 'GO:0023052', ('94', '103'))	('GNAQ', 'Gene', (295, 299))	('ERK', 'molecular_function', 'GO:0004707', ('142', '145'))	('cell growth', 'biological_process', 'GO:0016049', ('38', '49'))	('GNAQ', 'Gene', '2776', (23, 27))	('PKC', 'molecular_function', 'GO:0004697', ('128', '131'))	('GNAQ', 'Gene', '2776', (295, 299))
109442	19718445	Targeting either the mutated GNAQQ209 protein or the oncogenic signaling pathway controlled by mutated GNAQ may open up new therapeutic strategies for melanocytic tumors.	('GNAQ', 'Gene', (29, 33))	('signaling pathway', 'biological_process', 'GO:0007165', ('63', '80'))	('GNAQ', 'Gene', '2776', (103, 107))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('melanocytic tumors', 'Disease', (151, 169))	('oncogenic signaling pathway', 'Pathway', (53, 80))	('melanocytic tumors', 'Disease', 'MESH:D009508', (151, 169))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('mutated', 'Var', (95, 102))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('GNAQ', 'Gene', '2776', (29, 33))	('GNAQ', 'Gene', (103, 107))	('mutated', 'Var', (21, 28))
109449	17726528	Cell lines with high TfR expression significantly correlated with high degrees of modulation indicating that high TfR expressing tumor cells would be more efficiently inhibited by this combination treatment than low TfR expressing ones.	('TfR', 'Gene', '7037', (216, 219))	('modulation', 'MPA', (82, 92))	('TfR', 'Gene', '7037', (21, 24))	('inhibited', 'NegReg', (167, 176))	('high', 'Var', (109, 113))	('TfR', 'Gene', '7037', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('TfR', 'Gene', (216, 219))	('TfR', 'Gene', (21, 24))	('tumor', 'Disease', (129, 134))	('TfR', 'Gene', (114, 117))
109453	17726528	Down-regulation of ABCB6 by antisense oligonucleotides inhibited differentiation of MEL cells indicating that artesunate and ABCB6 may cooperate.	('differentiation of MEL cells', 'CPA', (65, 93))	('regulation', 'biological_process', 'GO:0065007', ('5', '15'))	('artesunate', 'Chemical', 'MESH:D000077332', (110, 120))	('Down-regulation', 'NegReg', (0, 15))	('oligonucleotides', 'Chemical', 'MESH:D009841', (38, 54))	('ABCB6', 'Gene', (19, 24))	('inhibited', 'NegReg', (55, 64))	('antisense oligonucleotides', 'Var', (28, 54))
109454	17726528	In conclusion, our results indicate that ferrous iron improves the activity of artesunate in some but not all tumor cell lines.	('ferrous iron', 'Chemical', 'MESH:D007501', (41, 53))	('ferrous', 'Var', (41, 48))	('improves', 'PosReg', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('artesunate', 'Chemical', 'MESH:D000077332', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('activity', 'MPA', (67, 75))	('artesunate', 'Protein', (79, 89))
109463	17726528	These radical molecules cause macromolecular damage by alkylating essential malarial proteins inducing cell death of parasites.	('alkylating', 'Var', (55, 65))	('malarial proteins', 'Disease', 'MESH:D011488', (76, 93))	('macromolecular damage', 'MPA', (30, 51))	('malarial proteins', 'Disease', (76, 93))	('cause', 'Reg', (24, 29))	('cell death', 'CPA', (103, 113))	('cell death', 'biological_process', 'GO:0008219', ('103', '113'))
109504	17726528	The assay IDs were: B2M: Hs00187842_m1; ABL1: Hs00245445_m1; ABCB6: Hs00180568_m1 and ABCB7: Hs00188776_m1.	('ABL1', 'Gene', '25', (40, 44))	('Hs00180568_m1', 'Var', (68, 81))	('B2M', 'Gene', (20, 23))	('B2M', 'Gene', '567', (20, 23))	('Hs00188776_m1', 'Var', (93, 106))	('ABL1', 'Gene', (40, 44))	('Hs00245445_m1', 'Var', (46, 59))	('Hs00187842_m1', 'Var', (25, 38))
109516	17726528	However, in 11 out of the 36 cell lines (31%; OVXF 1619L, CNXF, 498NL, MCF7, RXF 393NL, MEXF 514L, MEXF 394NL, LXFL 529L, H460, 22RV1, RXF1781L, OVXL 899L) the combination treatment was not superior to treatment with artesunate alone (degree of modulation <1.2).	('RXF 393NL', 'Var', (77, 86))	('H460', 'Var', (122, 126))	('artesunate', 'Chemical', 'MESH:D000077332', (217, 227))	('OVXF 1619L', 'Var', (46, 56))	('MEXF 394NL', 'Var', (99, 109))	('MCF7', 'CellLine', 'CVCL:0031', (71, 75))	('MEXF 514L', 'Var', (88, 97))	('RXF1781L', 'Var', (135, 143))	('498NL', 'Var', (64, 69))	('MCF7', 'Var', (71, 75))	('LXFL 529L', 'Var', (111, 120))	('CNXF', 'Var', (58, 62))
109520	17726528	We found that cell lines with high TfR expression significantly correlated with high degrees of modulation ( Table 2 ) indicating that high TfR expressing tumor cells could be more efficiently inhibited by a combination of artesunate and iron(II) glycine sulfate than low TfR expressing ones.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('high', 'Var', (135, 139))	('iron(II) glycine sulfate', 'Chemical', '-', (238, 262))	('artesunate', 'Chemical', 'MESH:D000077332', (223, 233))	('inhibited', 'NegReg', (193, 202))	('TfR', 'Gene', '7037', (272, 275))	('TfR', 'Gene', '7037', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('TfR', 'Gene', (140, 143))	('TfR', 'Gene', (272, 275))	('TfR', 'Gene', (35, 38))	('TfR', 'Gene', '7037', (140, 143))
109538	17726528	We previously reported that an antisense oligonucleotide directed against ABCB6 depressed the erythroid differentiation of MEL cells to 75%.	('oligonucleotide', 'Chemical', 'MESH:D009841', (41, 56))	('depressed', 'NegReg', (80, 89))	('erythroid differentiation of MEL cells', 'CPA', (94, 132))	('ABCB6', 'Gene', (74, 79))	('antisense', 'Var', (31, 40))
109539	17726528	When MEL cells were transfected with this antisense oligonucleotide and treated with artesunate (0.18 microg/ml, 0.468 microM) in combination, the heme content decreased to about 30% control ( Figure 2D ).	('artesunate', 'Chemical', 'MESH:D000077332', (85, 95))	('antisense oligonucleotide', 'Var', (42, 67))	('heme content', 'MPA', (147, 159))	('heme', 'Chemical', 'MESH:D006418', (147, 151))	('oligonucleotide', 'Chemical', 'MESH:D009841', (52, 67))	('decreased', 'NegReg', (160, 169))
109578	17726528	Down-regulation of ABCB6 by transfection with antisense oligonucleotides inhibited DMSO-induced heme biosynthesis indicating that this protein might play a role in differentiation.	('oligonucleotides', 'Chemical', 'MESH:D009841', (56, 72))	('regulation', 'biological_process', 'GO:0065007', ('5', '15'))	('DMSO-induced heme biosynthesis', 'MPA', (83, 113))	('Down-regulation', 'NegReg', (0, 15))	('inhibited', 'NegReg', (73, 82))	('antisense oligonucleotides', 'Var', (46, 72))	('DMSO', 'Chemical', 'MESH:D004121', (83, 87))	('heme', 'Chemical', 'MESH:D006418', (96, 100))	('ABCB6', 'Gene', (19, 24))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('heme biosynthesis', 'biological_process', 'GO:0006783', ('96', '113'))
109586	33396957	In uveal melanoma, GNAQ and GNA11 gene mutations are frequently found and prognosis is based on mutation status of BAP1, SF3B1 and EIF1AX genes.	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('EIF1AX', 'Gene', '1964', (131, 137))	('EIF1AX', 'Gene', (131, 137))	('GNAQ', 'Gene', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('BAP1', 'Gene', '8314', (115, 119))	('mutations', 'Var', (39, 48))	('GNA11', 'Gene', (28, 33))	('BAP1', 'Gene', (115, 119))	('SF3B1', 'Gene', (121, 126))	('found', 'Reg', (64, 69))	('GNAQ', 'Gene', '2776', (19, 23))	('GNA11', 'Gene', '2767', (28, 33))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))	('SF3B1', 'Gene', '23451', (121, 126))
109587	33396957	Iris melanoma, also originating from the uvea, has similarities to the genetic makeups of both posterior uveal melanoma (UM) and conjunctival melanoma since mutations in GNAQ and GNA11 are less common and genes involved in conjunctival melanoma such as BRAF have been described.	('conjunctival melanoma', 'Disease', (223, 244))	('Iris melanoma', 'Disease', 'MESH:D008545', (0, 13))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (129, 150))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('UM', 'Phenotype', 'HP:0007716', (121, 123))	('BRAF', 'Gene', '673', (253, 257))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (129, 150))	('BRAF', 'Gene', (253, 257))	('GNA11', 'Gene', (179, 184))	('mutations', 'Var', (157, 166))	('GNAQ', 'Gene', '2776', (170, 174))	('uveal melanoma', 'Disease', (105, 119))	('uveal melanoma', 'Disease', 'MESH:C536494', (105, 119))	('GNAQ', 'Gene', (170, 174))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (223, 244))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (223, 244))	('uveal melanoma', 'Phenotype', 'HP:0007716', (105, 119))	('Iris melanoma', 'Phenotype', 'HP:0011524', (0, 13))	('conjunctival melanoma', 'Disease', (129, 150))	('Iris melanoma', 'Disease', (0, 13))	('GNA11', 'Gene', '2767', (179, 184))
109588	33396957	The genetic spectrum of conjunctival melanoma, however, includes frequent mutations in the BRAF, NRAS and TERT promoter genes, which are found in cutaneous melanoma as well.	('NRAS', 'Gene', (97, 101))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('BRAF', 'Gene', '673', (91, 95))	('TERT', 'Gene', (106, 110))	('NRAS', 'Gene', '4893', (97, 101))	('conjunctival melanoma', 'Disease', (24, 45))	('mutations', 'Var', (74, 83))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (24, 45))	('cutaneous melanoma', 'Disease', (146, 164))	('BRAF', 'Gene', (91, 95))	('TERT', 'Gene', '7015', (106, 110))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (146, 164))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (146, 164))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (24, 45))
109589	33396957	The BRAF status of the tumor is not correlated to prognosis, whereas the TERT promoter gene mutations are.	('TERT', 'Gene', '7015', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('mutations', 'Var', (92, 101))	('TERT', 'Gene', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('tumor', 'Disease', (23, 28))
109590	33396957	Clinical presentation, histopathological characteristics and copy number alterations are associated with survival in ocular melanoma.	('associated', 'Reg', (89, 99))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('ocular melanoma', 'Disease', (117, 132))	('ocular melanoma', 'Disease', 'MESH:D008545', (117, 132))	('ocular melanoma', 'Phenotype', 'HP:0007716', (117, 132))	('copy number alterations', 'Var', (61, 84))
109614	33396957	Since GNAQ and GNA11 genes, in which mutations occur in UM, are related to the MAPK-Erk Pathway, inhibitors of this pathway (MEK inhibitors) could have an effect of metastatic disease.	('GNA11', 'Gene', (15, 20))	('MAPK', 'Gene', '5594', (79, 83))	('effect', 'Reg', (155, 161))	('GNAQ', 'Gene', '2776', (6, 10))	('GNA11', 'Gene', '2767', (15, 20))	('related', 'Reg', (64, 71))	('MAPK', 'Gene', (79, 83))	('MAPK', 'molecular_function', 'GO:0004707', ('79', '83'))	('Erk', 'Gene', (84, 87))	('mutations', 'Var', (37, 46))	('metastatic disease', 'Disease', (165, 183))	('Erk', 'molecular_function', 'GO:0004707', ('84', '87'))	('GNAQ', 'Gene', (6, 10))	('MEK', 'Gene', (125, 128))	('MEK', 'Gene', '5609', (125, 128))	('Erk', 'Gene', '5594', (84, 87))	('UM', 'Phenotype', 'HP:0007716', (56, 58))
109645	33396957	Chromosomal aberrations are a key feature of genomic instability of cancer cells and the observation of chromosome 3 loss in metastasizing UM by Prescher et al.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Chromosomal aberrations', 'Var', (0, 23))	('loss', 'NegReg', (117, 121))	('metastasizing UM', 'Disease', 'MESH:D009362', (125, 141))	('metastasizing UM', 'Disease', (125, 141))	('UM', 'Phenotype', 'HP:0007716', (139, 141))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('chromosome 3', 'Gene', (104, 116))	('chromosome', 'cellular_component', 'GO:0005694', ('104', '114'))
109647	33396957	The most frequently mutated genes in UM are GNAQ and GNA11.	('GNAQ', 'Gene', (44, 48))	('GNA11', 'Gene', (53, 58))	('GNA11', 'Gene', '2767', (53, 58))	('UM', 'Phenotype', 'HP:0007716', (37, 39))	('GNAQ', 'Gene', '2776', (44, 48))	('mutated', 'Var', (20, 27))
109648	33396957	Mutations in these genes occur in 71-93% of all UM tumors; we and others have shown that they have no predictive value.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', (51, 57))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))
109651	33396957	Prognosis of UM patients can be predicted with the mutation status of secondary driver genes EIF1AX, SF3B1 and BAP1 which are almost always mutually exclusive.	('BAP1', 'Gene', '8314', (111, 115))	('EIF1AX', 'Gene', (93, 99))	('EIF1AX', 'Gene', '1964', (93, 99))	('patients', 'Species', '9606', (16, 24))	('BAP1', 'Gene', (111, 115))	('SF3B1', 'Gene', (101, 106))	('mutation', 'Var', (51, 59))	('UM', 'Phenotype', 'HP:0007716', (13, 15))	('SF3B1', 'Gene', '23451', (101, 106))
109652	33396957	Patients with a BAP1 mutation or absent BAP1 expression with immunohistochemistry (IHC) have a high metastatic risk while patients with an EIF1AX mutation have a low risk of metastatic disease.	('metastatic', 'CPA', (100, 110))	('EIF1AX', 'Gene', '1964', (139, 145))	('EIF1AX', 'Gene', (139, 145))	('mutation', 'Var', (21, 29))	('BAP1', 'Gene', '8314', (40, 44))	('Patients', 'Species', '9606', (0, 8))	('absent', 'NegReg', (33, 39))	('patients', 'Species', '9606', (122, 130))	('BAP1', 'Gene', '8314', (16, 20))	('BAP1', 'Gene', (40, 44))	('BAP1', 'Gene', (16, 20))
109653	33396957	Mutations in BAP1 are less frequently found in iris melanoma and not correlated with survival.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('BAP1', 'Gene', (13, 17))	('iris melanoma', 'Phenotype', 'HP:0011524', (47, 60))	('iris melanoma', 'Disease', 'MESH:D008545', (47, 60))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (13, 17))	('iris melanoma', 'Disease', (47, 60))
109654	33396957	When looked at the chromosomal profile of UM, there is a decreased disease-free survival in tumors with loss of chromosome 3 (monosomy 3) which is associated with BAP1 mutations.	('loss', 'NegReg', (104, 108))	('chromosome', 'cellular_component', 'GO:0005694', ('112', '122'))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('BAP1', 'Gene', '8314', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('BAP1', 'Gene', (163, 167))	('decreased', 'NegReg', (57, 66))	('mutations', 'Var', (168, 177))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('disease-free survival', 'CPA', (67, 88))	('UM', 'Phenotype', 'HP:0007716', (42, 44))
109655	33396957	In patients harboring a disomy 3 UM, two genes are mainly mutated: EIF1AX and SF3B1.	('SF3B1', 'Gene', '23451', (78, 83))	('disomy 3', 'Var', (24, 32))	('EIF1AX', 'Gene', (67, 73))	('EIF1AX', 'Gene', '1964', (67, 73))	('UM', 'Phenotype', 'HP:0007716', (33, 35))	('patients', 'Species', '9606', (3, 11))	('SF3B1', 'Gene', (78, 83))
109657	33396957	In UM, mutations in EIF1AX primarily occur as heterozygous amino acid substitutions in exon 1 and 2, causing an in-frame mutation affecting the proteins N-terminus.	('UM', 'Phenotype', 'HP:0007716', (3, 5))	('affecting', 'Reg', (130, 139))	('EIF1AX', 'Gene', '1964', (20, 26))	('causing', 'Reg', (101, 108))	('EIF1AX', 'Gene', (20, 26))	('mutation', 'Var', (121, 129))	('proteins N-terminus', 'MPA', (144, 163))	('mutations', 'Var', (7, 16))
109658	33396957	As EIF1AX acts as a regulator for translation initiation, mutations herein result in wrong selection of start sites, which might cause suppressed translation of canonical transcripts or upregulation of oncogenes.	('selection', 'MPA', (91, 100))	('mutations', 'Var', (58, 67))	('translation', 'MPA', (146, 157))	('translation', 'biological_process', 'GO:0006412', ('146', '157'))	('canonical transcripts', 'MPA', (161, 182))	('upregulation', 'PosReg', (186, 198))	('result in', 'Reg', (75, 84))	('translation initiation', 'biological_process', 'GO:0006413', ('34', '56'))	('EIF1AX', 'Gene', '1964', (3, 9))	('EIF1AX', 'Gene', (3, 9))	('suppressed', 'NegReg', (135, 145))	('oncogenes', 'Gene', (202, 211))
109661	33396957	EIF1AX mutations are reported to occur in 8% to 19%.	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
109663	33396957	The majority of recurrent hotspot mutations in SF3B1 occur at the edge of the C-terminal HEAT domains, near the precursor mRNA binding region and might be important for RNA or protein interactions.	('SF3B1', 'Gene', (47, 52))	('RNA', 'cellular_component', 'GO:0005562', ('169', '172'))	('SF3B1', 'Gene', '23451', (47, 52))	('mRNA binding', 'molecular_function', 'GO:0003729', ('122', '134'))	('interactions', 'Interaction', (184, 196))	('mutations', 'Var', (34, 43))	('hotspot', 'PosReg', (26, 33))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))
109664	33396957	Mutations in SF3B1 lead to aberrant transcripts, primarily caused by alternative 3' splice site selection upstream of the canonical splice site, coincided by misregulated branch point usage.	('lead to', 'Reg', (19, 26))	('SF3B1', 'Gene', (13, 18))	('caused', 'Reg', (59, 65))	('Mutations', 'Var', (0, 9))	('SF3B1', 'Gene', '23451', (13, 18))	('transcripts', 'MPA', (36, 47))	('splice site selection', 'biological_process', 'GO:0000380', ('84', '105'))	('splice site selection', 'biological_process', 'GO:0000381', ('84', '105'))
109665	33396957	As a result, mutations in spliceosome components, such as SF3B1 mutant tumors, can have alternative 3' acceptor splice sites, alternative cassette exons and intron retention in protein coding and noncoding genes as shown by Furney et al.. Yavuzyigitoglu et al.	('spliceosome', 'cellular_component', 'GO:0005681', ('26', '37'))	('retention', 'biological_process', 'GO:0051235', ('164', '173'))	('SF3B1', 'Gene', (58, 63))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('SF3B1', 'Gene', '23451', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('mutations', 'Var', (13, 22))	('mutant', 'Var', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
109666	33396957	reported UM patients harboring an SF3B1 mutation were diagnosed younger at 54.5 years than patients harboring an EIF1AX or BAP1 mutated tumor, diagnosed at 64 years.	('BAP1', 'Gene', (123, 127))	('mutation', 'Var', (40, 48))	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (91, 99))	('SF3B1', 'Gene', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('EIF1AX', 'Gene', '1964', (113, 119))	('EIF1AX', 'Gene', (113, 119))	('BAP1', 'Gene', '8314', (123, 127))	('SF3B1', 'Gene', '23451', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
109668	33396957	described that 18.6% of the UM mutations occur in SF3B1.	('mutations', 'Var', (31, 40))	('SF3B1', 'Gene', (50, 55))	('UM', 'Phenotype', 'HP:0007716', (28, 30))	('occur', 'Reg', (41, 46))	('SF3B1', 'Gene', '23451', (50, 55))
109670	33396957	Although genes involved in posterior uveal melanoma are mutated in iris melanoma as well, there are some differences.	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('iris melanoma', 'Disease', 'MESH:D008545', (67, 80))	('mutated', 'Var', (56, 63))	('uveal melanoma', 'Disease', 'MESH:C536494', (37, 51))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('uveal melanoma', 'Phenotype', 'HP:0007716', (37, 51))	('uveal melanoma', 'Disease', (37, 51))	('iris melanoma', 'Disease', (67, 80))	('iris melanoma', 'Phenotype', 'HP:0011524', (67, 80))
109671	33396957	Iris melanoma harbor GNAQ, GNA11 and EIF1AX mutations while BAP1 mutations and mutations in SF3B1 are less common or rare.	('GNAQ', 'Gene', '2776', (21, 25))	('EIF1AX', 'Gene', '1964', (37, 43))	('EIF1AX', 'Gene', (37, 43))	('SF3B1', 'Gene', '23451', (92, 97))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('GNAQ', 'Gene', (21, 25))	('GNA11', 'Gene', '2767', (27, 32))	('BAP1', 'Gene', '8314', (60, 64))	('mutations', 'Var', (44, 53))	('Iris melanoma harbor', 'Disease', 'MESH:C537062', (0, 20))	('Iris melanoma harbor', 'Disease', (0, 20))	('GNA11', 'Gene', (27, 32))	('Iris melanoma', 'Phenotype', 'HP:0011524', (0, 13))	('BAP1', 'Gene', (60, 64))	('SF3B1', 'Gene', (92, 97))
109672	33396957	A mutation in BRAF, a gene often mutated in cutaneous melanoma, was identified in iris melanoma.	('iris melanoma', 'Disease', (82, 95))	('mutation', 'Var', (2, 10))	('iris melanoma', 'Phenotype', 'HP:0011524', (82, 95))	('iris melanoma', 'Disease', 'MESH:D008545', (82, 95))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('BRAF', 'Gene', '673', (14, 18))	('cutaneous melanoma', 'Disease', (44, 62))	('BRAF', 'Gene', (14, 18))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (44, 62))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (44, 62))	('identified', 'Reg', (68, 78))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
109673	33396957	Loss of chromosome 3 is described in iris melanoma as well as loss of 9p.	('iris melanoma', 'Disease', 'MESH:D008545', (37, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('iris melanoma', 'Disease', (37, 50))	('loss of 9p', 'Var', (62, 72))	('Loss', 'Var', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('iris melanoma', 'Phenotype', 'HP:0011524', (37, 50))
109674	33396957	Moreover, aberrations of chromosome 1, 6 and 8, chromosomes that are involved in posterior uveal melanoma as well, were described in iris melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('iris melanoma', 'Phenotype', 'HP:0011524', (133, 146))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('aberrations', 'Var', (10, 21))	('iris melanoma', 'Disease', 'MESH:D008545', (133, 146))	('chromosome', 'cellular_component', 'GO:0005694', ('25', '35'))	('uveal melanoma', 'Disease', 'MESH:C536494', (91, 105))	('uveal melanoma', 'Phenotype', 'HP:0007716', (91, 105))	('uveal melanoma', 'Disease', (91, 105))	('described', 'Reg', (120, 129))	('iris melanoma', 'Disease', (133, 146))
109676	33396957	Mutations in PLCB4, a downstream effector of Galphaq signaling are described in <10% of uveal melanoma.	('PLCB4', 'Gene', '5332', (13, 18))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('Galphaq', 'Gene', (45, 52))	('Galphaq', 'Gene', '2776', (45, 52))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (88, 102))	('PLCB4', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Disease', (88, 102))
109677	33396957	A study aimed at identifying gene mutations in 139 UM showed mutations in GNAQ and GNA11 in 93% being mutually exclusive except for one UM harboring a GNAQ and GNA11 mutation.	('GNAQ', 'Gene', '2776', (151, 155))	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('GNAQ', 'Gene', (74, 78))	('GNA11', 'Gene', (160, 165))	('mutations', 'Var', (61, 70))	('GNAQ', 'Gene', (151, 155))	('GNA11', 'Gene', '2767', (160, 165))	('GNAQ', 'Gene', '2776', (74, 78))	('GNA11', 'Gene', (83, 88))	('UM', 'Phenotype', 'HP:0007716', (136, 138))	('GNA11', 'Gene', '2767', (83, 88))
109678	33396957	Mutations in PLCB4 (2%) were found in tumors with or without a GNA11 mutation, whereas mutations in CYSLTR2 (5%) were identified in UM with no mutation in one of the other genes.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('PLCB4', 'Gene', '5332', (13, 18))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('CYSLTR2', 'Gene', '57105', (100, 107))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('UM', 'Phenotype', 'HP:0007716', (132, 134))	('GNA11', 'Gene', (63, 68))	('mutation', 'Var', (69, 77))	('PLCB4', 'Gene', (13, 18))	('CYSLTR2', 'Gene', (100, 107))	('Mutations', 'Var', (0, 9))	('GNA11', 'Gene', '2767', (63, 68))
109679	33396957	Deletions in spliceosome factors RBM10, in-frame deletions of SRSF2 and homozygous deletion SF3A1 were found in only a few tumors.	('tumors', 'Disease', (123, 129))	('SF3A1', 'Gene', '10291', (92, 97))	('SRSF2', 'Gene', '6427', (62, 67))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('spliceosome', 'cellular_component', 'GO:0005681', ('13', '24'))	('SF3A1', 'Gene', (92, 97))	('RBM10', 'Gene', '8241', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('RBM10', 'Gene', (33, 38))	('SRSF2', 'Gene', (62, 67))	('Deletions', 'Var', (0, 9))
109680	33396957	Mutations in SRSF2 were all heterozygous in-frame deletions and starting at residue 92 or 03, except for one case described in The Cancer Genome Atlas (TCGA) starting at 174.	('SRSF2', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('Cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Cancer', 'Disease', (131, 137))	('SRSF2', 'Gene', '6427', (13, 18))	('Cancer', 'Disease', 'MESH:D009369', (131, 137))
109681	33396957	Mutations in BRAF are identified in 25-35% of conjunctival melanoma of which the vast majority is the BRAF V600E mutation.	('V600E', 'Var', (107, 112))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', '673', (102, 106))	('BRAF', 'Gene', (13, 17))	('BRAF', 'Gene', (102, 106))	('identified', 'Reg', (22, 32))	('Mutations', 'Var', (0, 9))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (46, 67))	('conjunctival melanoma', 'Disease', (46, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('V600E', 'Mutation', 'rs113488022', (107, 112))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (46, 67))
109684	33396957	BRAF mutations were more often identified in conjunctival melanoma with a bulbar localization.	('identified', 'Reg', (31, 41))	('conjunctival melanoma', 'Disease', (45, 66))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (45, 66))	('localization', 'biological_process', 'GO:0051179', ('81', '93'))	('mutations', 'Var', (5, 14))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (45, 66))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
109687	33396957	GNAQ and GNA11 mutations are identified, but not the activating hotspot mutations that occur in UM.	('GNA11', 'Gene', (9, 14))	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('GNAQ', 'Gene', (0, 4))	('GNA11', 'Gene', '2767', (9, 14))
109688	33396957	Amplification of chromosome 6 is found in more than half of the conjunctival melanoma.	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (64, 85))	('conjunctival melanoma', 'Disease', (64, 85))	('Amplification', 'Var', (0, 13))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (64, 85))	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))
109689	33396957	TERT promoter mutations have recently been identified to correlate to metastatic disease.	('correlate', 'Reg', (57, 66))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('metastatic disease', 'Disease', (70, 88))	('mutations', 'Var', (14, 23))
109690	33396957	Only 2-4% of all uveal melanoma patients harbor a germline BAP1 mutation and although familial uveal melanoma is rare, BAP1 has been identified as a predisposition gene for UM as well as a variety of other cancers.	('familial uveal melanoma', 'Disease', 'MESH:C536494', (86, 109))	('familial uveal melanoma', 'Disease', (86, 109))	('BAP1', 'Gene', (119, 123))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Disease', (206, 213))	('BAP1', 'Gene', '8314', (59, 63))	('uveal melanoma', 'Disease', (17, 31))	('uveal melanoma', 'Disease', 'MESH:C536494', (17, 31))	('mutation', 'Var', (64, 72))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('uveal melanoma', 'Disease', 'MESH:C536494', (95, 109))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))	('patients', 'Species', '9606', (32, 40))	('BAP1', 'Gene', (59, 63))	('UM', 'Phenotype', 'HP:0007716', (173, 175))	('BAP1', 'Gene', '8314', (119, 123))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('uveal melanoma', 'Phenotype', 'HP:0007716', (95, 109))
109691	33396957	When focused on familial UM, the incidence of BAP1 germline mutations is higher and is reported up to 19%.	('familial UM', 'Disease', (16, 27))	('BAP1', 'Gene', '8314', (46, 50))	('BAP1', 'Gene', (46, 50))	('UM', 'Phenotype', 'HP:0007716', (25, 27))	('germline mutations', 'Var', (51, 69))
109693	33396957	Almost all UM in patients with a germline BAP1 mutation have tumors that are located posteriorly, although one iris melanoma has been described.	('BAP1', 'Gene', '8314', (42, 46))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('UM', 'Phenotype', 'HP:0007716', (11, 13))	('mutation', 'Var', (47, 55))	('BAP1', 'Gene', (42, 46))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('iris melanoma', 'Disease', (111, 124))	('patients', 'Species', '9606', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('iris melanoma', 'Phenotype', 'HP:0011524', (111, 124))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('germline', 'Var', (33, 41))	('iris melanoma', 'Disease', 'MESH:D008545', (111, 124))
109694	33396957	In general, more cutaneous melanoma and ocular melanoma in the family history was reported in patients with uveal melanoma and a BAP1 germline mutation compared to patients without this germline mutation.	('more', 'PosReg', (12, 16))	('uveal melanoma', 'Disease', 'MESH:C536494', (108, 122))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (17, 35))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (17, 35))	('ocular melanoma', 'Phenotype', 'HP:0007716', (40, 55))	('patients', 'Species', '9606', (94, 102))	('germline', 'Var', (134, 142))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('uveal melanoma', 'Disease', (108, 122))	('BAP1', 'Gene', '8314', (129, 133))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('patients', 'Species', '9606', (164, 172))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('ocular melanoma', 'Disease', 'MESH:D008545', (40, 55))	('ocular melanoma', 'Disease', (40, 55))	('BAP1', 'Gene', (129, 133))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('cutaneous melanoma', 'Disease', (17, 35))
109695	33396957	Moreover, germline mutated BAP1 carriers have a larger tumor diameter and more frequently reported ciliary body involvement.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('BAP1', 'Gene', (27, 31))	('reported', 'Reg', (90, 98))	('ciliary', 'Disease', (99, 106))	('tumor', 'Disease', (55, 60))	('men', 'Species', '9606', (119, 122))	('germline mutated', 'Var', (10, 26))	('larger', 'PosReg', (48, 54))	('BAP1', 'Gene', '8314', (27, 31))
109696	33396957	Multivariate analysis did not show that germline BAP1 mutations are an independent risk factor for the development of metastasis.	('men', 'Species', '9606', (110, 113))	('BAP1', 'Gene', (49, 53))	('germline', 'Var', (40, 48))	('BAP1', 'Gene', '8314', (49, 53))
109697	33396957	When metastasis-free survival of UM patients with a germline BAP1 mutation was compared to those with a somatic BAP1 mutation, it was shown that the germline BAP1 mutated group has a more favorable prognosis.	('BAP1', 'Gene', (112, 116))	('BAP1', 'Gene', (61, 65))	('patients', 'Species', '9606', (36, 44))	('BAP1', 'Gene', (158, 162))	('UM', 'Phenotype', 'HP:0007716', (33, 35))	('BAP1', 'Gene', '8314', (112, 116))	('mutation', 'Var', (66, 74))	('BAP1', 'Gene', '8314', (158, 162))	('BAP1', 'Gene', '8314', (61, 65))	('germline', 'Var', (149, 157))
109698	33396957	In contrast, another study showed that germline BAP1 mutations occur more often in metastatic ocular melanoma compared to nonmetastatic ocular melanoma, even though this difference was not significant and not adjusted for the greater risk of metastatic disease in BAP1-mutated UM in general.	('BAP1', 'Gene', '8314', (48, 52))	('ocular melanoma', 'Phenotype', 'HP:0007716', (136, 151))	('BAP1', 'Gene', '8314', (264, 268))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('ocular melanoma', 'Disease', (94, 109))	('BAP1', 'Gene', (48, 52))	('ocular melanoma', 'Disease', 'MESH:D008545', (94, 109))	('mutations', 'Var', (53, 62))	('BAP1', 'Gene', (264, 268))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('ocular melanoma', 'Phenotype', 'HP:0007716', (94, 109))	('ocular melanoma', 'Disease', 'MESH:D008545', (136, 151))	('UM', 'Phenotype', 'HP:0007716', (277, 279))	('ocular melanoma', 'Disease', (136, 151))
109699	33396957	The median age of diagnosis does not differ between patients with a somatic or germline BAP1 mutation.	('BAP1', 'Gene', '8314', (88, 92))	('mutation', 'Var', (93, 101))	('BAP1', 'Gene', (88, 92))	('patients', 'Species', '9606', (52, 60))
109701	33396957	The frequency of BAP1 germline mutations is higher in families with cutaneous and uveal melanoma compared to families without uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('germline mutations', 'Var', (22, 40))	('uveal melanoma', 'Disease', 'MESH:C536494', (126, 140))	('uveal melanoma', 'Disease', 'MESH:C536494', (82, 96))	('higher', 'Reg', (44, 50))	('cutaneous', 'Disease', (68, 77))	('BAP1', 'Gene', '8314', (17, 21))	('uveal melanoma', 'Phenotype', 'HP:0007716', (126, 140))	('uveal melanoma', 'Disease', (126, 140))	('uveal melanoma', 'Disease', (82, 96))	('BAP1', 'Gene', (17, 21))
109702	33396957	In families with a positive family history of UM, the frequency of BAP1 germline mutations was 22%.	('BAP1', 'Gene', '8314', (67, 71))	('germline mutations', 'Var', (72, 90))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('BAP1', 'Gene', (67, 71))
109703	33396957	In addition, it has been shown that germline null mutations in BAP1 are more frequently observed compared to controls and the BAP1-TPDS is probably underreported.	('observed', 'Reg', (88, 96))	('BAP1', 'Gene', (126, 130))	('BAP1', 'Gene', (63, 67))	('germline null mutations', 'Var', (36, 59))	('BAP1', 'Gene', '8314', (126, 130))	('BAP1', 'Gene', '8314', (63, 67))
109705	33396957	Other germline mutations described in UM are mutations in the TP53 gene, although these are rare and the role of these mutations should be elucidated TP53 mutations associated with UM and breast cancer in a family are already described in 1905.	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('TP53', 'Gene', (150, 154))	('TP53', 'Gene', '7157', (62, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('mutations', 'Var', (155, 164))	('breast cancer', 'Disease', (188, 201))	('associated', 'Reg', (165, 175))	('TP53', 'Gene', (62, 66))	('TP53', 'Gene', '7157', (150, 154))	('UM', 'Phenotype', 'HP:0007716', (38, 40))	('UM', 'Phenotype', 'HP:0007716', (181, 183))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
109719	33396957	In addition, monosomy 3 was an independent risk factor for the development of metastasis, and thus poor prognosis, when corrected for tumor diameter and tumor site.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('monosomy 3', 'Var', (13, 23))	('men', 'Species', '9606', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('metastasis', 'CPA', (78, 88))	('tumor', 'Disease', (134, 139))
109721	33396957	Further research validates the fact that patients with a UM showing monosomy 3 have a significantly lower disease-free survival.	('monosomy 3', 'Var', (68, 78))	('disease-free survival', 'CPA', (106, 127))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('lower', 'NegReg', (100, 105))	('patients', 'Species', '9606', (41, 49))
109722	33396957	For example, greater tumor thickness or larger diameter correlates with partial or complete monosomy 3.	('tumor', 'Disease', (21, 26))	('monosomy 3', 'Disease', (92, 102))	('partial', 'Var', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
109724	33396957	This study also showed that the patients with UM harboring partial monosomy have better prognoses compared to those with complete monosomy 3, although later studies showed no significant difference in survival between patients with monosomy 3 or partial loss of chromosome 3 of the primary UM.	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (218, 226))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('UM', 'Phenotype', 'HP:0007716', (290, 292))	('partial loss', 'Var', (246, 258))	('partial monosomy', 'Var', (59, 75))	('chromosome', 'cellular_component', 'GO:0005694', ('262', '272'))
109729	33396957	It was shown that BAP1 mutations often results in the absence of BAP1 expression using IHC.	('absence', 'NegReg', (54, 61))	('BAP1', 'Gene', '8314', (65, 69))	('BAP1', 'Gene', '8314', (18, 22))	('BAP1', 'Gene', (65, 69))	('BAP1', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('expression', 'MPA', (70, 80))
109731	33396957	When looking at specific gene mutations, there are several other genes described which can be used for prognostication besides BAP1.	('BAP1', 'Gene', '8314', (127, 131))	('BAP1', 'Gene', (127, 131))	('mutations', 'Var', (30, 39))
109733	33396957	Another mutation frequently found in disomy 3 UM is a hotspot missense mutation in SF3B1 at codon 625.	('SF3B1', 'Gene', (83, 88))	('SF3B1', 'Gene', '23451', (83, 88))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('missense mutation', 'Var', (62, 79))
109734	33396957	Mutations in SF3B1 are associated with alternative splicing of a wide range of target genes.	('associated with', 'Reg', (23, 38))	('alternative splicing of', 'MPA', (39, 62))	('SF3B1', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('SF3B1', 'Gene', '23451', (13, 18))	('splicing', 'biological_process', 'GO:0045292', ('51', '59'))
109735	33396957	The clinical relevance of these splicing events is not completely clear, but it has been shown that SF3B1 mutated tumors are at risk to metastasize.	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('splicing', 'biological_process', 'GO:0045292', ('32', '40'))	('SF3B1', 'Gene', (100, 105))	('metastasize', 'CPA', (136, 147))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('SF3B1', 'Gene', '23451', (100, 105))	('mutated', 'Var', (106, 113))
109736	33396957	Patients with UM harboring an SF3B1 mutation can develop late onset metastases.	('SF3B1', 'Gene', (30, 35))	('UM', 'Phenotype', 'HP:0007716', (14, 16))	('develop', 'PosReg', (49, 56))	('SF3B1', 'Gene', '23451', (30, 35))	('Patients', 'Species', '9606', (0, 8))	('metastases', 'Disease', (68, 78))	('metastases', 'Disease', 'MESH:D009362', (68, 78))	('mutation', 'Var', (36, 44))
109753	33396957	Recurrent disease was higher in patients treated with iodine-125 radioactive plaque therapy in which there was reduced cornea surface coverage by the plaque and the presence of glaucoma after treatment.	('glaucoma', 'Disease', 'MESH:D005901', (177, 185))	('iodine', 'Chemical', 'MESH:D007455', (54, 60))	('higher', 'PosReg', (22, 28))	('patients', 'Species', '9606', (32, 40))	('cornea surface coverage', 'CPA', (119, 142))	('glaucoma', 'Phenotype', 'HP:0000501', (177, 185))	('reduced', 'NegReg', (111, 118))	('men', 'Species', '9606', (197, 200))	('glaucoma', 'Disease', (177, 185))	('iodine-125', 'Var', (54, 64))	('Recurrent', 'Disease', (0, 9))
109768	33396957	BRAF mutations occur frequently in conjunctival melanoma, especially in the sun-exposed area of the bulbar conjunctiva.	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (35, 56))	('mutations', 'Var', (5, 14))	('conjunctival melanoma', 'Disease', (35, 56))	('BRAF', 'Gene', '673', (0, 4))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (35, 56))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
109770	33396957	This was confirmed in another study in which no relation between BRAF mutation status and local recurrence, metastasis and death is observed.	('metastasis', 'CPA', (108, 118))	('death', 'Disease', 'MESH:D003643', (123, 128))	('local recurrence', 'CPA', (90, 106))	('death', 'Disease', (123, 128))	('BRAF', 'Gene', '673', (65, 69))	('mutation', 'Var', (70, 78))	('BRAF', 'Gene', (65, 69))
109771	33396957	The presence of BRAF mutations might be important in the future because BRAF/MEK inhibitors could possibly play a role in treatment of metastatic disease, as they is used in cutaneous melanoma where BRAF mutations at the same residue are present.	('BRAF', 'Gene', (72, 76))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('BRAF', 'Gene', (199, 203))	('BRAF', 'Gene', '673', (199, 203))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (174, 192))	('MEK', 'Gene', '5609', (77, 80))	('MEK', 'Gene', (77, 80))	('metastatic disease', 'Disease', (135, 153))	('cutaneous melanoma', 'Disease', (174, 192))	('men', 'Species', '9606', (127, 130))	('BRAF', 'Gene', '673', (72, 76))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (174, 192))	('mutations', 'Var', (21, 30))
109772	33396957	TERT promotor mutations correlate with prognosis which could act as a therapeutic strategy in the future.	('prognosis', 'Disease', (39, 48))	('TERT', 'Gene', '7015', (0, 4))	('mutations', 'Var', (14, 23))	('TERT', 'Gene', (0, 4))
109781	33396957	Moreover, tumor-specific mutations could be detected in cfDNA from plasma, indicating that this technique can be used as a diagnostic as well as predictive tool.	('tumor', 'Disease', (10, 15))	('mutations', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))
109790	33396957	Moreover, GNAQ and GNA11 mutations were detected in ctDNA of UM patients.	('mutations', 'Var', (25, 34))	('GNAQ', 'Gene', '2776', (10, 14))	('GNA11', 'Gene', (19, 24))	('patients', 'Species', '9606', (64, 72))	('GNA11', 'Gene', '2767', (19, 24))	('detected', 'Reg', (40, 48))	('GNAQ', 'Gene', (10, 14))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('ctDNA', 'Disease', (52, 57))
109803	33396957	However, challenges will be faced due to tumor size and the heterogeneity in affected genes, especially the nonhotspot mutations that occur in BAP1.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('BAP1', 'Gene', (143, 147))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('BAP1', 'Gene', '8314', (143, 147))	('mutations', 'Var', (119, 128))
109806	33396957	Mutations that are common in posterior UM such as GNAQ and GNA11 are described in iris melanoma but in lower frequency.	('iris melanoma', 'Disease', (82, 95))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('iris melanoma', 'Phenotype', 'HP:0011524', (82, 95))	('iris melanoma', 'Disease', 'MESH:D008545', (82, 95))	('UM', 'Phenotype', 'HP:0007716', (39, 41))	('GNAQ', 'Gene', '2776', (50, 54))	('Mutations', 'Var', (0, 9))	('GNA11', 'Gene', (59, 64))	('GNA11', 'Gene', '2767', (59, 64))	('GNAQ', 'Gene', (50, 54))
109807	33396957	Moreover, mutations in BRAF were detected in only one iris melanoma, whereas BRAF mutations are common in conjunctival melanoma.	('iris melanoma', 'Phenotype', 'HP:0011524', (54, 67))	('conjunctival melanoma', 'Disease', (106, 127))	('BRAF', 'Gene', '673', (23, 27))	('BRAF', 'Gene', '673', (77, 81))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (106, 127))	('iris melanoma', 'Disease', 'MESH:D008545', (54, 67))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (106, 127))	('BRAF', 'Gene', (23, 27))	('BRAF', 'Gene', (77, 81))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('detected', 'Reg', (33, 41))	('mutations', 'Var', (10, 19))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('iris melanoma', 'Disease', (54, 67))
109808	33396957	Germline mutations in BAP1 are described in UM, but conjunctival melanoma is not part of the BAP1 tumor predisposition syndrome.	('Germline mutations', 'Var', (0, 18))	('BAP1', 'Gene', '8314', (93, 97))	('described', 'Reg', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('conjunctival melanoma', 'Disease', (52, 73))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (52, 73))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', (93, 97))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (52, 73))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('tumor', 'Disease', (98, 103))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('BAP1', 'Gene', (22, 26))
109810	33396957	Therefore, it is recommended to test for germline BAP1 mutations when the family history is suspect.	('mutations', 'Var', (55, 64))	('germline', 'Var', (41, 49))	('BAP1', 'Gene', '8314', (50, 54))	('men', 'Species', '9606', (22, 25))	('test', 'Reg', (32, 36))	('BAP1', 'Gene', (50, 54))
109815	33396957	It has been shown that BAP1 mutations are correlated with poor prognosis in UM patients.	('BAP1', 'Gene', (23, 27))	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('BAP1', 'Gene', '8314', (23, 27))	('patients', 'Species', '9606', (79, 87))	('mutations', 'Var', (28, 37))
109816	33396957	Since about half of all patients with posterior UM harbor a mutation in the BAP1 gene, prognosis is poor.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('mutation', 'Var', (60, 68))	('BAP1', 'Gene', '8314', (76, 80))	('BAP1', 'Gene', (76, 80))	('posterior UM', 'Disease', (38, 50))	('patients', 'Species', '9606', (24, 32))
109817	33396957	SF3B1 mutations, correlated with late onset metastases, have been found more often in posterior UM compared to iris melanoma.	('found', 'Reg', (66, 71))	('posterior UM', 'Disease', (86, 98))	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('SF3B1', 'Gene', (0, 5))	('metastases', 'Disease', (44, 54))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('iris melanoma', 'Disease', (111, 124))	('SF3B1', 'Gene', '23451', (0, 5))	('iris melanoma', 'Phenotype', 'HP:0011524', (111, 124))	('metastases', 'Disease', 'MESH:D009362', (44, 54))	('mutations', 'Var', (6, 15))	('iris melanoma', 'Disease', 'MESH:D008545', (111, 124))
109829	33396957	Targeted treatment for conjunctival melanoma harboring a BRAF mutation could be considered since the genetic profile is similar to that of cutaneous melanoma in which BRAF/MEK inhibitors are used.	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (23, 44))	('men', 'Species', '9606', (14, 17))	('MEK', 'Gene', (172, 175))	('BRAF', 'Gene', '673', (57, 61))	('MEK', 'Gene', '5609', (172, 175))	('BRAF', 'Gene', (167, 171))	('cutaneous melanoma', 'Disease', (139, 157))	('BRAF', 'Gene', '673', (167, 171))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (139, 157))	('BRAF', 'Gene', (57, 61))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (23, 44))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (139, 157))	('mutation', 'Var', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('conjunctival melanoma', 'Disease', (23, 44))
109833	32313009	BAP1 alterations are overrepresented and found in 29/32 of cases.	('alterations', 'Var', (5, 16))	('BAP1', 'Gene', (0, 4))	('BAP1', 'Gene', '8314', (0, 4))
109836	32313009	CDKN2A deletions also occur, which are rarely present in primaries.	('CDKN2A', 'Gene', '1029', (0, 6))	('deletions', 'Var', (7, 16))	('CDKN2A', 'Gene', (0, 6))
109844	32313009	Recurrent mutations in GNAQ or GNA11 are common, whereas mutations in PLCB4 and CYSLTR2, downstream and upstream of GNAQ/11, are seen in occasional cases.	('GNAQ', 'Gene', (23, 27))	('GNAQ', 'Gene', (116, 120))	('PLCB4', 'Gene', '5332', (70, 75))	('CYSLTR2', 'Gene', '57105', (80, 87))	('mutations', 'Var', (10, 19))	('CYSLTR2', 'Gene', (80, 87))	('GNA11', 'Gene', (31, 36))	('GNAQ', 'Gene', '2776', (23, 27))	('PLCB4', 'Gene', (70, 75))	('GNAQ', 'Gene', '2776', (116, 120))	('GNA11', 'Gene', '2767', (31, 36))
109845	32313009	Additional recurrent mutations have been found in EIF1AX, SF3B1, and BAP1, where the latter connotes poor prognosis and development of metastatic disease.	('mutations', 'Var', (21, 30))	('SF3B1', 'Gene', (58, 63))	('EIF1AX', 'Gene', (50, 56))	('BAP1', 'Gene', (69, 73))	('EIF1AX', 'Gene', '1964', (50, 56))	('SF3B1', 'Gene', '23451', (58, 63))	('BAP1', 'Gene', '8314', (69, 73))
109855	32313009	Variant calling with MuTect 2 revealed mutations in BAP1, GNA11, GNAQ, SF3B1, CYSLTR2, and PLCB4 (Fig.	('SF3B1', 'Gene', (71, 76))	('BAP1', 'Gene', '8314', (52, 56))	('GNAQ', 'Gene', '2776', (65, 69))	('PLCB4', 'Gene', (91, 96))	('CYSLTR2', 'Gene', '57105', (78, 85))	('SF3B1', 'Gene', '23451', (71, 76))	('mutations', 'Var', (39, 48))	('BAP1', 'Gene', (52, 56))	('GNAQ', 'Gene', (65, 69))	('GNA11', 'Gene', '2767', (58, 63))	('GNA11', 'Gene', (58, 63))	('PLCB4', 'Gene', '5332', (91, 96))	('CYSLTR2', 'Gene', (78, 85))
109857	32313009	In all, 29/32 (91%) of metastases were found to have BAP1 mutations.	('mutations', 'Var', (58, 67))	('metastases', 'Disease', (23, 33))	('BAP1', 'Gene', '8314', (53, 57))	('metastases', 'Disease', 'MESH:D009362', (23, 33))	('BAP1', 'Gene', (53, 57))
109858	32313009	Notably, BAP1 was also the subject of alterations not detected by standard variant calling, including one large deletion spanning the first three exons.	('BAP1', 'Gene', (9, 13))	('deletion', 'Var', (112, 120))	('BAP1', 'Gene', '8314', (9, 13))
109860	32313009	A previous study has described a mutation that activates a cryptic splice site within an exon in BAP1.	('mutation', 'Var', (33, 41))	('BAP1', 'Gene', '8314', (97, 101))	('activates', 'PosReg', (47, 56))	('BAP1', 'Gene', (97, 101))	('cryptic splice site within', 'MPA', (59, 85))
109862	32313009	Among the three patients where BAP1 mutations could not be established, two had SF3B1 mutations.	('mutations', 'Var', (86, 95))	('SF3B1', 'Gene', '23451', (80, 85))	('BAP1', 'Gene', '8314', (31, 35))	('patients', 'Species', '9606', (16, 24))	('BAP1', 'Gene', (31, 35))	('SF3B1', 'Gene', (80, 85))
109863	32313009	We also detected mutations in SF3B1 that occurred outside the common hotspots K666 or R625.	('SF3B1', 'Gene', (30, 35))	('mutations', 'Var', (17, 26))	('SF3B1', 'Gene', '23451', (30, 35))
109864	32313009	These included K700E and an in-frame deletion at V577.	('K700E', 'Mutation', 'rs559063155', (15, 20))	('V577', 'Var', (49, 53))	('K700E', 'Var', (15, 20))
109866	32313009	Some SF3B1 mutations also co-occurred with BAP1 mutations, illustrating that mutual exclusivity between these events is imperfect.	('BAP1', 'Gene', (43, 47))	('mutations', 'Var', (11, 20))	('SF3B1', 'Gene', '23451', (5, 10))	('BAP1', 'Gene', '8314', (43, 47))	('SF3B1', 'Gene', (5, 10))	('mutations', 'Var', (48, 57))	('co-occurred', 'Reg', (26, 37))
109870	32313009	Mutated genes in these regions included YEATS2 and ZMAT3 on chromosome 3 and AKT1 on chromosome 14.	('ZMAT3', 'Gene', '64393', (51, 56))	('AKT1', 'Gene', (77, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('85', '95'))	('YEATS2', 'Gene', '55689', (40, 46))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))	('AKT1', 'Gene', '207', (77, 81))	('Mutated', 'Var', (0, 7))	('YEATS2', 'Gene', (40, 46))	('ZMAT3', 'Gene', (51, 56))
109871	32313009	Lack of BAP1 mutations is characteristic for tumors of the class I subtype, among which only a small subset tends to metastasize.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('BAP1', 'Gene', '8314', (8, 12))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('BAP1', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))	('metastasize', 'CPA', (117, 128))
109875	32313009	In addition, we found two metastases with mutations in the tumor suppressor TET2, in one case leading to a stop-gain.	('TET2', 'Gene', '54790', (76, 80))	('stop-gain', 'MPA', (107, 116))	('tumor', 'Disease', (59, 64))	('TET2', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('metastases', 'Disease', (26, 36))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor suppressor', 'biological_process', 'GO:0051726', ('59', '75'))	('mutations', 'Var', (42, 51))	('metastases', 'Disease', 'MESH:D009362', (26, 36))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('59', '75'))	('leading to', 'Reg', (94, 104))
109878	32313009	Some metastases also had mutations in genes that interact with BAP1, including ASXL2 and FOXK2 (Supplementary Data 1).	('mutations', 'Var', (25, 34))	('ASXL2', 'Gene', (79, 84))	('BAP1', 'Gene', (63, 67))	('FOXK2', 'Gene', '3607', (89, 94))	('metastases', 'Disease', (5, 15))	('FOXK2', 'Gene', (89, 94))	('metastases', 'Disease', 'MESH:D009362', (5, 15))	('ASXL2', 'Gene', '55252', (79, 84))	('BAP1', 'Gene', '8314', (63, 67))
109884	32313009	We could exclude a sample mix-up from the presence of the same GNA11 Q209L mutation and BAP1 frame-shift deletion in RNA, together with transcriptomic classification against ~10,000 tumors from TCGA (Supplementary Fig.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('Q209L', 'Mutation', 'rs1057519742', (69, 74))	('frame-shift deletion', 'Var', (93, 113))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('GNA11', 'Gene', (63, 68))	('BAP1', 'Gene', '8314', (88, 92))	('RNA', 'cellular_component', 'GO:0005562', ('117', '120'))	('Q209L', 'Var', (69, 74))	('GNA11', 'Gene', '2767', (63, 68))	('BAP1', 'Gene', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
109889	32313009	A number of arm-level changes were also significantly overrepresented in the metastatic tumors compared with tumors studied by TCGA (Fisher's exact test, q < 0.05).	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('changes', 'Var', (22, 29))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('arm-level', 'MPA', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('tumors', 'Disease', (109, 115))	('overrepresented', 'PosReg', (54, 69))
109890	32313009	Previous studies have also found loss of 6q and 8p to be overrepresented in metastatic tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('loss', 'Var', (33, 37))	('overrepresented', 'PosReg', (57, 72))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
109892	32313009	Overall, genomic losses tended to be more frequent in these metastases than observed in TCGA tumors.	('genomic losses', 'Var', (9, 23))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('metastases', 'Disease', (60, 70))	('metastases', 'Disease', 'MESH:D009362', (60, 70))	('tumors', 'Disease', (93, 99))
109893	32313009	Notably, however, we discovered somatic focal deletions affecting CDKN2A and the nearby gene MTAP in two samples (Fig.	('MTAP', 'Gene', (93, 97))	('MTAP', 'Gene', '4507', (93, 97))	('CDKN2A', 'Gene', '1029', (66, 72))	('deletions', 'Var', (46, 55))	('CDKN2A', 'Gene', (66, 72))
109896	32313009	This suggests that either a pre-existing clone with a homozygous deletion or a second loss event was selected for as the tumor established itself in this new environment, supporting CDKN2A loss as a late event that may be relevant in the metastatic setting.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('pre', 'molecular_function', 'GO:0003904', ('28', '31'))	('tumor', 'Disease', (121, 126))	('CDKN2A', 'Gene', (182, 188))	('CDKN2A', 'Gene', '1029', (182, 188))	('deletion', 'Var', (65, 73))	('loss', 'NegReg', (189, 193))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
109901	32313009	Thus, these recurrent arm-level copy number changes contribute to shaping the transcriptomic subtypes of UM and regulate genes that may conceivably contribute a fitness advantage.	('transcriptomic', 'MPA', (78, 92))	('changes', 'Var', (44, 51))	('copy number changes', 'Var', (32, 51))	('regulate', 'Reg', (112, 120))	('shaping', 'Reg', (66, 73))	('fitness', 'Disease', (161, 168))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('genes', 'Gene', (121, 126))	('fitness', 'Disease', 'MESH:D012640', (161, 168))
109902	32313009	We next asked to what extent BAP1 mutations could influence the transcriptome of metastatic UM.	('metastatic UM', 'CPA', (81, 94))	('BAP1', 'Gene', '8314', (29, 33))	('UM', 'Phenotype', 'HP:0007716', (92, 94))	('BAP1', 'Gene', (29, 33))	('influence', 'Reg', (50, 59))	('mutations', 'Var', (34, 43))	('transcriptome', 'MPA', (64, 77))
109903	32313009	For this purpose, we used the UM22 cell line, which had been established from one of the metastases grown as a PDX, and which had a homozygous frame-shift deletion in BAP1, but no copy number loss on chromosome 3 (Supplementary Fig.	('chromosome', 'cellular_component', 'GO:0005694', ('200', '210'))	('BAP1', 'Gene', '8314', (167, 171))	('metastases', 'Disease', (89, 99))	('UM', 'Phenotype', 'HP:0007716', (30, 32))	('metastases', 'Disease', 'MESH:D009362', (89, 99))	('frame-shift deletion', 'Var', (143, 163))	('BAP1', 'Gene', (167, 171))
109904	32313009	Mutations do not always cause a complete loss of the BAP1 protein and in UM22 the mutation generated a translation stop before the nuclear localization signal.	('protein', 'Protein', (58, 65))	('localization', 'biological_process', 'GO:0051179', ('139', '151'))	('UM', 'Phenotype', 'HP:0007716', (73, 75))	('mutation', 'Var', (82, 90))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('Mutations', 'Var', (0, 9))	('translation', 'biological_process', 'GO:0006412', ('103', '114'))	('BAP1', 'Gene', '8314', (53, 57))	('BAP1', 'Gene', (53, 57))
109911	32313009	These genes were all expressed in the inverse fashion expected for class II tumors, with CDH1, ECM1, and HTR2B decreasing upon BAP1 reintroduction and LMCD1, LTA4H, MTUS1, ROBO1, SATB1, and FXR1 increasing, whereas the remaining three genes, RAB31, ID2, and EIF1B, were not significant.	('HTR2B', 'Gene', '3357', (105, 110))	('SATB1', 'Gene', '6304', (179, 184))	('II tumors', 'Disease', 'MESH:D009369', (73, 82))	('HTR2B', 'Gene', (105, 110))	('LTA4H', 'Gene', '4048', (158, 163))	('BAP1', 'Gene', (127, 131))	('ID2', 'Gene', '3398', (249, 252))	('BAP1', 'Gene', '8314', (127, 131))	('FXR1', 'Gene', '8087', (190, 194))	('ID2', 'Gene', (249, 252))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('FXR1', 'Gene', (190, 194))	('II tumors', 'Disease', (73, 82))	('LTA4H', 'molecular_function', 'GO:0004463', ('158', '163'))	('EIF1B', 'Gene', '10289', (258, 263))	('LMCD1', 'Gene', '29995', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('LTA4H', 'Gene', (158, 163))	('LMCD1', 'Gene', (151, 156))	('ROBO1', 'Gene', (172, 177))	('decreasing', 'NegReg', (111, 121))	('RAB31', 'Gene', (242, 247))	('EIF1B', 'Gene', (258, 263))	('ECM1', 'Gene', (95, 99))	('MTUS1', 'Gene', (165, 170))	('reintroduction', 'Var', (132, 146))	('CDH1', 'Gene', '999', (89, 93))	('SATB1', 'Gene', (179, 184))	('RAB31', 'Gene', '11031', (242, 247))	('MTUS1', 'Gene', '57509', (165, 170))	('ROBO1', 'Gene', '6091', (172, 177))	('ECM1', 'Gene', '1893', (95, 99))	('CDH1', 'Gene', (89, 93))
109914	32313009	Moreover, 2358 of the genes (q < 0.05) also differed between BAP1 mutated and wild-type TCGA tumors in a way that corresponded to changes observed when reintroducing the gene (Supplementary Fig.	('mutated', 'Var', (66, 73))	('differed', 'Reg', (44, 52))	('BAP1', 'Gene', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('BAP1', 'Gene', '8314', (61, 65))
109934	32313009	Compatible with this, we observed BAP1 mutations in 91% of the metastases.	('BAP1', 'Gene', (34, 38))	('metastases', 'Disease', 'MESH:D009362', (63, 73))	('mutations', 'Var', (39, 48))	('BAP1', 'Gene', '8314', (34, 38))	('metastases', 'Disease', (63, 73))
109936	32313009	It has been reported that mutations in the epigenetic regulators PBRM1 and EZH2 can occur late during metastatic development of UM.	('EZH2', 'Gene', (75, 79))	('UM', 'Phenotype', 'HP:0007716', (128, 130))	('PBRM1', 'Gene', (65, 70))	('PBRM1', 'Gene', '55193', (65, 70))	('mutations', 'Var', (26, 35))	('EZH2', 'Gene', '2146', (75, 79))
109937	32313009	Consistent with those observations, we also find a mutation in EZH2 in one of the samples.	('EZH2', 'Gene', '2146', (63, 67))	('mutation', 'Var', (51, 59))	('EZH2', 'Gene', (63, 67))
109938	32313009	In addition, we find mutations in other not previously implicated epigenetic regulators, including TET1, TET2, and ASXL2, the latter of which is known to interact with BAP1.	('TET2', 'Gene', '54790', (105, 109))	('BAP1', 'Gene', '8314', (168, 172))	('TET1', 'Gene', '80312', (99, 103))	('ASXL2', 'Gene', '55252', (115, 120))	('BAP1', 'Gene', (168, 172))	('TET2', 'Gene', (105, 109))	('ASXL2', 'Gene', (115, 120))	('TET1', 'Gene', (99, 103))	('mutations', 'Var', (21, 30))
109945	32313009	Furthermore, two tumors had focal deletions of CDKN2A, an event that may have a larger relevance in the metastatic setting, as it has not been detected in recent large-scale studies of primary UM tumors and since it has also been observed to be deleted in a step-wise fashion during metastatic progression in UM.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('UM', 'Phenotype', 'HP:0007716', (309, 311))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (17, 23))	('CDKN2A', 'Gene', (47, 53))	('tumors', 'Disease', (196, 202))	('deletions', 'Var', (34, 43))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('UM', 'Phenotype', 'HP:0007716', (193, 195))	('CDKN2A', 'Gene', '1029', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
109946	32313009	The latter is consistent with our finding that a PDX model established from a tumor with a hemizygous deletion was revealed to have homozygous loss of CDKN2A, suggesting a selective advantage for a secondary inactivating event.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('deletion', 'Var', (102, 110))	('CDKN2A', 'Gene', (151, 157))	('loss', 'NegReg', (143, 147))	('tumor', 'Disease', (78, 83))	('CDKN2A', 'Gene', '1029', (151, 157))
109952	32313009	It is tempting to speculate that the genetic make-up of this cell line, with a diploid chromosome 3 and  a downstream mutation of BAP1 that impairs the nuclear localization signal, but leaves the remainder of the protein unaffected, is the reason for this favorable growth in culture.	('BAP1', 'Gene', (130, 134))	('chromosome', 'cellular_component', 'GO:0005694', ('87', '97'))	('impairs', 'NegReg', (140, 147))	('protein', 'cellular_component', 'GO:0003675', ('213', '220'))	('mutation', 'Var', (118, 126))	('localization', 'biological_process', 'GO:0051179', ('160', '172'))	('BAP1', 'Gene', '8314', (130, 134))	('nuclear localization signal', 'MPA', (152, 179))
109953	32313009	Nevertheless, we show in this one, and potentially unique, cell line that reintroduction of a wild-type BAP1 resulted in a reversal of the transcriptomic subtype from class II to class I, which was also seen at the protein level.	('BAP1', 'Gene', '8314', (104, 108))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('BAP1', 'Gene', (104, 108))	('reintroduction', 'Var', (74, 88))	('transcriptomic', 'MPA', (139, 153))
109982	32313009	Low-quality variants in BAP1 were inspected further for support on DNA and RNA alignments.	('BAP1', 'Gene', (24, 28))	('variants', 'Var', (12, 20))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('RNA', 'cellular_component', 'GO:0005562', ('75', '78'))	('BAP1', 'Gene', '8314', (24, 28))
109985	32313009	Known mutational signature trinucleotide frequencies, obtained via COSMIC (http://cancer.sanger.ac.uk/cancergenome/assets/signatures_probabilities.txt; accessed October 27, 2017), were then fitted to the observed mutations using the function "fit_to_signatures" from the same R package.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('trinucleotide', 'Chemical', '-', (27, 40))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('mutations', 'Var', (213, 222))
109993	32313009	Copy number neutral loss of heterozygosity was determined using the CNVkit (v. 0.9.6a0) "scatter" command, with variants concordant with matching normal DNA as input.	('kit', 'Gene', (71, 74))	('kit', 'Gene', '3815', (71, 74))	('loss', 'NegReg', (20, 24))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))	('variants', 'Var', (112, 120))
110009	32313009	Surviving cells were expanded and transduced with either a retrovirus expressing HA-tagged BAP1 or a control retrovirus (MSCV-IRES-GFP), both of which were made using plasmids from Addgene.	('BAP1', 'Gene', '8314', (91, 95))	('BAP1', 'Gene', (91, 95))	('HA-tagged', 'Var', (81, 90))
110030	32313009	A list of BAP1 mutated tumors was compiled from earlier publications and three additional likely cases (Supplementary Fig.	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('BAP1', 'Gene', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutated', 'Var', (15, 22))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('BAP1', 'Gene', '8314', (10, 14))
110039	32313009	6a, b. TILs tested for dextramer binding were those from HLA-A*02-positive tumors (Supplementary Data 7), for which commercial dextramers with MART-1, gp100 and NY-ESO-1 were available: UM1, UM2, UM9, UM11, UM13, UM21, UM22, UM24, UM25, UM26, UM27, UM29, UM30, UM31, and UM32.	('UM', 'Phenotype', 'HP:0007716', (196, 198))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('dextramer', 'Chemical', '-', (23, 32))	('UM27', 'Var', (243, 247))	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('UM', 'Phenotype', 'HP:0007716', (186, 188))	('dextramer', 'Chemical', '-', (127, 136))	('UM32', 'Var', (271, 275))	('NY-ESO-1', 'Gene', '246100', (161, 169))	('MART-1', 'Gene', '2315', (143, 149))	('UM', 'Phenotype', 'HP:0007716', (201, 203))	('NY-ESO-1', 'Gene', (161, 169))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('UM30', 'Var', (255, 259))	('UM1', 'Var', (186, 189))	('HLA-A', 'Gene', (57, 62))	('UM24', 'Var', (225, 229))	('UM', 'Phenotype', 'HP:0007716', (207, 209))	('UM', 'Phenotype', 'HP:0007716', (191, 193))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('UM31', 'Var', (261, 265))	('tumors', 'Disease', (75, 81))	('gp100', 'Gene', (151, 156))	('UM26', 'Var', (237, 241))	('gp100', 'Gene', '6490', (151, 156))	('UM25', 'Var', (231, 235))	('UM29', 'Var', (249, 253))	('MART-1', 'Gene', (143, 149))	('HLA-A', 'Gene', '3105', (57, 62))
110041	32313009	Whole-genome, exome, and RNA sequence data generated for this study have been deposited at the European Genome-Phenome Archive, which is hosted by the EBI and the CRG under accession numbers EGAS00001004296 and EGAS00001003026.	('CRG', 'Gene', '55636', (163, 166))	('EBI', 'Gene', (151, 154))	('RNA', 'cellular_component', 'GO:0005562', ('25', '28'))	('CRG', 'Gene', (163, 166))	('EGAS00001003026', 'Var', (211, 226))	('EBI', 'Gene', '6907', (151, 154))
110047	31757690	Longitudinal prospective study of 21 patients undergoing treatment for uveal melanoma with I125 plaque brachytherapy.	('men', 'Species', '9606', (62, 65))	('patients', 'Species', '9606', (37, 45))	('uveal melanoma', 'Disease', 'MESH:C536494', (71, 85))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('I125', 'Var', (91, 95))	('uveal melanoma', 'Disease', (71, 85))	('uveal melanoma', 'Phenotype', 'HP:0007716', (71, 85))	('I125', 'Chemical', 'MESH:C000614960', (91, 95))
110058	31757690	OCT angiography demonstrated early emergence of peripapillary and macular capillary vasculature changes after I125 plaque brachytherapy.	('I125', 'Chemical', 'MESH:C000614960', (110, 114))	('I125 plaque', 'Var', (110, 121))	('OCT', 'Gene', (0, 3))	('OCT', 'Gene', '5362', (0, 3))	('vasculature changes', 'Phenotype', 'HP:0002597', (84, 103))
110098	31757690	We previously demonstrated an inverse linear correlation between radiation dose (radiation dose to 50% of the optic disc) and the peripapillary capillary density (now called the NFLP_CD) among patients treated with I125 plaque brachytherapy for uveal melanoma who demonstrated clinically apparent radiation retinopathy.	('patients', 'Species', '9606', (193, 201))	('uveal melanoma', 'Phenotype', 'HP:0007716', (245, 259))	('uveal melanoma', 'Disease', 'MESH:C536494', (245, 259))	('radiation retinopathy', 'Disease', 'MESH:D012164', (297, 318))	('retinopathy', 'Phenotype', 'HP:0000488', (307, 318))	('uveal melanoma', 'Disease', (245, 259))	('radiation retinopathy', 'Disease', (297, 318))	('I125', 'Chemical', 'MESH:C000614960', (215, 219))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('I125 plaque', 'Var', (215, 226))
110134	31750244	The majority of CMs (~80%) present mutations in BRAF, NRAS, and NF1 genes.	('NRAS', 'Gene', (54, 58))	('NF1', 'Gene', (64, 67))	('NRAS', 'Gene', '4893', (54, 58))	('CM', 'Disease', 'MESH:C562393', (16, 18))	('NF1', 'Gene', '4763', (64, 67))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('CM', 'Phenotype', 'HP:0012056', (16, 18))	('mutations', 'Var', (35, 44))
110135	31750244	Instead, in UM, the most common mutations involve GNAQ/11 (83% of the cases) and recurrent alterations can be found on the BAP1 gene (~40%).	('BAP1', 'Gene', (123, 127))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('GNAQ', 'Gene', '2776', (50, 54))	('mutations', 'Var', (32, 41))	('UM', 'Disease', 'MESH:C536494', (12, 14))	('BAP1', 'Gene', '8314', (123, 127))	('GNAQ', 'Gene', (50, 54))
110138	31750244	UM tumors with monosomy 3 and polysomy 8q have high metastatic risk and a poor prognosis.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('UM', 'Disease', 'MESH:C536494', (0, 2))	('metastatic', 'CPA', (52, 62))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('polysomy 8q', 'Var', (30, 41))	('monosomy 3', 'Var', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
110140	31750244	It is believed that a high mutational burden is predictive of the response to immunotherapy, as the neoantigens that derive from tumor-specific mutations can be targets for anti-tumor immune responses.	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (129, 134))	('mutations', 'Var', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
110142	31750244	However, as a low mutational load may also bring the activation of neoantigen-specific T cells, it is reasonable to believe that the tumor microenvironment and intrinsic cancer cell phenotypic patterns may be pivotal in the regulation of the ability of T cells to respond to cancer-specific antigens.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('low mutational load', 'Var', (14, 33))	('activation', 'PosReg', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('regulation', 'biological_process', 'GO:0065007', ('224', '234'))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tumor', 'Disease', (133, 138))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', (275, 281))
110182	31750244	In a recent study by Rothermel et al., analysis of TILs cultures from cutaneous and UM showed that UM TILs were predominantly CD4+, while in CM were mainly composed of CD8+ T cells.	('CD4+', 'Var', (126, 130))	('CM', 'Disease', 'MESH:C562393', (141, 143))	('CD8', 'Gene', (168, 171))	('CM', 'Phenotype', 'HP:0012056', (141, 143))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('CD8', 'Gene', '925', (168, 171))	('UM', 'Disease', 'MESH:C536494', (84, 86))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('UM', 'Disease', 'MESH:C536494', (99, 101))
110188	31750244	Accordingly, Streilein and Niederkorn showed that elimination of CD8+ Treg in a murine model of UM was sufficient to induce tumor rejection.	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('murine', 'Species', '10090', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('induce', 'Reg', (117, 123))	('UM', 'Disease', 'MESH:C536494', (96, 98))	('tumor', 'Disease', (124, 129))	('CD8', 'Gene', (65, 68))	('CD8', 'Gene', '925', (65, 68))	('elimination', 'Var', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
110229	31750244	Interestingly, deconvolution analysis of infiltrating immune cell populations showed a significantly higher proportion of CD4+ and CD8+ T cells in patients with high CD47 levels, with the most represented populations being the Th2, Treg, and CD8+ TCM cells.	('higher', 'PosReg', (101, 107))	('CM', 'Disease', 'MESH:C562393', (248, 250))	('CD47', 'Gene', '961', (166, 170))	('CD4+', 'MPA', (122, 126))	('high', 'Var', (161, 165))	('CD47', 'Gene', (166, 170))	('patients', 'Species', '9606', (147, 155))	('CM', 'Phenotype', 'HP:0012056', (248, 250))	('CD8', 'Gene', (242, 245))	('CD8', 'Gene', (131, 134))	('CD8', 'Gene', '925', (242, 245))	('CD8', 'Gene', '925', (131, 134))
110234	31750244	CD200 has been found to be a good predictor of recurrent disease in UM.	('CD200', 'Var', (0, 5))	('recurrent disease', 'Disease', (47, 64))	('UM', 'Disease', 'MESH:C536494', (68, 70))	('UM', 'Phenotype', 'HP:0007716', (68, 70))
110247	31750244	As a matter of fact, expression of iNOS has been shown to represent a negative prognostic factors for multiple types of cancer, including primary UM.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('UM', 'Phenotype', 'HP:0007716', (146, 148))	('iNOS', 'Gene', '4843', (35, 39))	('cancer', 'Disease', (120, 126))	('UM', 'Disease', 'MESH:C536494', (146, 148))	('iNOS', 'Gene', (35, 39))	('negative', 'NegReg', (70, 78))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('expression', 'Var', (21, 31))
110249	31750244	However, despite these above-mentioned data that strongly support the concept that endogenous NO represents a powerful oncogenic mediator in the maintenance and progression of UM, data by ourselves and others indicate that exogenous NO-derivatives of parental drugs possess enhanced anticancer properties in preclinical models of blood cancer, bladder and prostate cancer, and cutaneous melanoma.	('cancer', 'Disease', (287, 293))	('blood cancer', 'Disease', (330, 342))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('cancer', 'Disease', (336, 342))	('blood cancer', 'Phenotype', 'HP:0001909', (330, 342))	('UM', 'Phenotype', 'HP:0007716', (176, 178))	('cancer', 'Disease', (365, 371))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('melanoma', 'Phenotype', 'HP:0002861', (387, 395))	('exogenous', 'Var', (223, 232))	('bladder and prostate cancer', 'Disease', 'MESH:D001749', (344, 371))	('UM', 'Disease', 'MESH:C536494', (176, 178))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (336, 342))	('blood cancer', 'Disease', 'MESH:D009369', (330, 342))	('cancer', 'Disease', 'MESH:D009369', (365, 371))	('enhanced', 'PosReg', (274, 282))	('cutaneous melanoma', 'Disease', (377, 395))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (377, 395))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (377, 395))	('prostate cancer', 'Phenotype', 'HP:0012125', (356, 371))
110259	31750244	Recent data have also demonstrated that exosomes from UM cells expressing integrin alphavbeta5 are taken up by liver cells, inducing the establishment of a pre-metastatic niche that promote liver tropism.	('inducing', 'PosReg', (124, 132))	('liver tropism', 'Disease', 'MESH:D008113', (190, 203))	('pre', 'molecular_function', 'GO:0003904', ('156', '159'))	('promote', 'PosReg', (182, 189))	('tropism', 'biological_process', 'GO:0009606', ('196', '203'))	('UM', 'Phenotype', 'HP:0007716', (54, 56))	('UM', 'Disease', 'MESH:C536494', (54, 56))	('integrin', 'Var', (74, 82))	('liver tropism', 'Disease', (190, 203))
110273	31750244	have recently characterized the immune cell infiltrates in liver metastatic UM and found that CD4+ TILs were located within the tumor, whereas CD8+ TILs tended to be peritumoral.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumoral', 'Disease', (170, 177))	('tumoral', 'Disease', 'MESH:D009369', (170, 177))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('CD8', 'Gene', (143, 146))	('UM', 'Disease', 'MESH:C536494', (76, 78))	('CD8', 'Gene', '925', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (170, 175))	('CD4+ TILs', 'Var', (94, 103))	('tumor', 'Disease', (128, 133))
110295	31750244	Again, this is in strong contrast with data from patients with stage III CM, where ipilimumab was associated with a 5-year rate of recurrence-free survival of 40.8%, as compared with 30.3% in the placebo group, and to a rate of OS at 5 years of 65.4%, as compared with 54.4% in the placebo group.	('CM', 'Disease', 'MESH:C562393', (73, 75))	('CM', 'Phenotype', 'HP:0012056', (73, 75))	('recurrence-free', 'CPA', (131, 146))	('patients', 'Species', '9606', (49, 57))	('ipilimumab', 'Var', (83, 93))
110309	31750244	In two Phase I trials, i.e., NCT01211262 and NCT2570308, IMCgp100 treatment was associated with prolonged disease stabilization with a 1-year OS of 73%.	('disease stabilization', 'CPA', (106, 127))	('NCT2570308', 'Chemical', 'MESH:C079985', (45, 55))	('NCT01211262', 'Var', (29, 40))	('NCT2570308', 'Var', (45, 55))	('gp100', 'Gene', (60, 65))	('gp100', 'Gene', '6490', (60, 65))
110323	31750244	Though not even preclinical proof of concept efficacy has so far been generated, with other "pathogenic"-tailored therapeutic approaches it can be expected that the emerging families of specific inhibitors of TGF-beta and MIF also have the potential to be effective in some cases of UM.	('MIF', 'Gene', '4282', (222, 225))	('inhibitors', 'Var', (195, 205))	('UM', 'Phenotype', 'HP:0007716', (283, 285))	('UM', 'Disease', 'MESH:C536494', (283, 285))	('MIF', 'Gene', (222, 225))	('TGF-beta', 'Gene', '7040', (209, 217))	('TGF-beta', 'Gene', (209, 217))
110403	31660262	found that miRNA-25 directly regulates P57 (a tumor suppressor gene), and the abnormal expression of this miRNA in gastric cancer patients can advance cancer cells from G1 to S phase.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('advance', 'PosReg', (143, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('miR', 'Gene', '220972', (11, 14))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('46', '62'))	('abnormal', 'Var', (78, 86))	('S phase', 'biological_process', 'GO:0051320', ('175', '182'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('46', '62'))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('miR', 'Gene', '220972', (106, 109))	('miR', 'Gene', (11, 14))	('cancer', 'Disease', (151, 157))	('gastric cancer', 'Disease', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('miR', 'Gene', (106, 109))	('tumor', 'Disease', (46, 51))	('patients', 'Species', '9606', (130, 138))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('P57', 'MPA', (39, 42))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('G1 to S phase', 'CPA', (169, 182))	('regulates', 'Reg', (29, 38))
110420	31660262	Early research of miR-510 did not examine its relationship with cancer, only its aberrant expression in irritable bowel syndrome.	('irritable bowel syndrome', 'Disease', 'MESH:D043183', (104, 128))	('aberrant expression', 'Var', (81, 100))	('irritable', 'Phenotype', 'HP:0000737', (104, 113))	('irritable bowel syndrome', 'Disease', (104, 128))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('miR-510', 'Gene', '574515', (18, 25))	('miR-510', 'Gene', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
110432	31660262	For example, abnormal PI3K-Akt-mTOR signaling is one of the most common dysfunctions present in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mTOR', 'Gene', (31, 35))	('mTOR', 'Gene', '2475', (31, 35))	('human', 'Species', '9606', (96, 101))	('Akt', 'Gene', '207', (27, 30))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('PI3K', 'molecular_function', 'GO:0016303', ('22', '26'))	('signaling', 'biological_process', 'GO:0023052', ('36', '45'))	('cancers', 'Disease', (102, 109))	('Akt', 'Gene', (27, 30))	('abnormal', 'Var', (13, 21))
110438	31660262	increased the sensitivity of hepatoma stem cells to TRAIL (Tumor necrosis factor (TNF) -related apoptosis-inducing ligand), reducing apoptosis by knocking out miR-25.	('apoptosis', 'CPA', (133, 142))	('TRAIL', 'Gene', (52, 57))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('miR-25', 'Gene', (159, 165))	('necrosis', 'biological_process', 'GO:0008219', ('65', '73'))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('hepatoma', 'Disease', (29, 37))	('Tumor', 'Phenotype', 'HP:0002664', (59, 64))	('Tumor necrosis factor', 'molecular_function', 'GO:0005164', ('59', '80'))	('necrosis', 'biological_process', 'GO:0008220', ('65', '73'))	('reducing', 'NegReg', (124, 132))	('Tumor necrosis', 'Disease', 'MESH:D009336', (59, 73))	('miR-25', 'Gene', '407014', (159, 165))	('necrosis', 'biological_process', 'GO:0070265', ('65', '73'))	('ligand', 'molecular_function', 'GO:0005488', ('115', '121'))	('Tumor necrosis', 'Disease', (59, 73))	('necrosis', 'biological_process', 'GO:0019835', ('65', '73'))	('knocking out', 'Var', (146, 158))	('TRAIL', 'Gene', '8743', (52, 57))	('necrosis', 'biological_process', 'GO:0001906', ('65', '73'))	('sensitivity', 'MPA', (14, 25))	('hepatoma', 'Disease', 'MESH:D006528', (29, 37))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
110462	30421448	One of the main challenges in ocular imaging is in-plane and through-plane eye motion, often associated with eye blinking.11, 12, 13 The motion results in corrupted k-space data that introduces artifacts and blurring throughout the entire image.	('motion', 'Var', (137, 143))	('eye blinking', 'Disease', 'MESH:D005124', (109, 121))	('eye blinking', 'Disease', (109, 121))	('artifacts', 'MPA', (194, 203))
110484	30421448	The error has a more noise-like behavior for the MC-based reconstruction compared with the CS reconstruction, and is much lower in the sensitive region of the eye coil.	('lower', 'NegReg', (122, 127))	('CS', 'Chemical', '-', (91, 93))	('noise-like behavior', 'Phenotype', 'HP:0025112', (21, 40))	('MC', 'Chemical', '-', (49, 51))	('MC-based', 'Var', (49, 57))	('noise-like behavior', 'MPA', (21, 40))
110521	29361821	Overall incidence of genetic aberrations of the primary melanomas in KMC was 17.6% of BRAF V600, 12.6% of NRAS mutation, and 28.6% of KIT amplification.	('primary melanoma', 'Disease', (48, 64))	('NRAS', 'Gene', '4893', (106, 110))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('primary melanoma', 'Disease', 'MESH:D008545', (48, 64))	('KIT', 'molecular_function', 'GO:0005020', ('134', '137'))	('NRAS', 'Gene', (106, 110))	('BRAF', 'Gene', '673', (86, 90))	('KIT amplification', 'Var', (134, 151))	('melanomas', 'Disease', (56, 65))	('BRAF', 'Gene', (86, 90))	('melanomas', 'Disease', 'MESH:D008545', (56, 65))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
110523	29361821	Patients with BRAF mutation were associated with advanced stage and correlated to poor prognosis (p < 0.01).	('advanced stage', 'CPA', (49, 63))	('mutation', 'Var', (19, 27))	('BRAF', 'Gene', '673', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('associated', 'Reg', (33, 43))	('BRAF', 'Gene', (14, 18))
110525	29361821	The frequency of BRAF mutation and KIT amplification significantly increased in the metastatic lesions compared to primary melanomas.	('primary melanoma', 'Disease', (115, 131))	('mutation', 'Var', (22, 30))	('metastatic', 'Disease', (84, 94))	('primary melanoma', 'Disease', 'MESH:D008545', (115, 131))	('BRAF', 'Gene', '673', (17, 21))	('melanomas', 'Disease', (123, 132))	('BRAF', 'Gene', (17, 21))	('increased', 'PosReg', (67, 76))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('KIT', 'molecular_function', 'GO:0005020', ('35', '38'))	('melanomas', 'Disease', 'MESH:D008545', (123, 132))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('KIT', 'Gene', (35, 38))
110527	29361821	Our data demonstrated heterogeneity between primary melanomas and corresponding metastatic lesions for BRAF, NRAS mutation and KIT amplification.	('melanomas', 'Disease', 'MESH:D008545', (52, 61))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('KIT', 'molecular_function', 'GO:0005020', ('127', '130'))	('NRAS', 'Gene', (109, 113))	('primary melanoma', 'Disease', (44, 60))	('primary melanoma', 'Disease', 'MESH:D008545', (44, 60))	('NRAS', 'Gene', '4893', (109, 113))	('melanomas', 'Disease', (52, 61))	('BRAF', 'Gene', '673', (103, 107))	('mutation', 'Var', (114, 122))	('KIT', 'Gene', (127, 130))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))	('BRAF', 'Gene', (103, 107))
110554	29361821	Recent study of genetic alterations in 333 cutaneous melanomas showed that mutations in BRAF V600 and NRAS Q61 were found in 46% and 24%, respectively.	('BRAF', 'Gene', (88, 92))	('cutaneous melanomas', 'Disease', (43, 62))	('BRAF', 'Gene', '673', (88, 92))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('NRAS', 'Gene', (102, 106))	('found', 'Reg', (116, 121))	('mutations', 'Var', (75, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (43, 61))	('NRAS', 'Gene', '4893', (102, 106))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (43, 62))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (43, 62))
110555	29361821	Although other genes, including NF1, HRAS, and NRAS, were highly mutated in cutaneous melanoma, there are no specific hot spots, which are frequently mutated as BRAF V600 and NRAS Q61, in these genes.	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('NF1', 'Gene', (32, 35))	('cutaneous melanoma', 'Disease', (76, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (76, 94))	('mutated', 'Var', (65, 72))	('NF1', 'Gene', '4763', (32, 35))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (76, 94))	('NRAS', 'Gene', (47, 51))	('BRAF', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (161, 165))	('HRAS', 'Gene', '3265', (37, 41))	('NRAS', 'Gene', (175, 179))	('NRAS', 'Gene', '4893', (47, 51))	('NRAS', 'Gene', '4893', (175, 179))	('HRAS', 'Gene', (37, 41))
110556	29361821	According to a previous study, KIT amplification was found in 40% of acral melanoma and 31% of mucosal melanoma in Korea.	('mucosal melanoma', 'Disease', 'MESH:D008545', (95, 111))	('acral melanoma', 'Disease', (69, 83))	('acral melanoma', 'Disease', 'MESH:D008545', (69, 83))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('mucosal melanoma', 'Disease', (95, 111))	('KIT', 'molecular_function', 'GO:0005020', ('31', '34'))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('acral melanoma', 'Phenotype', 'HP:0012060', (69, 83))	('KIT amplification', 'Var', (31, 48))
110557	29361821	Since our cohort mainly comprised acral (47.3%) and mucosal (16.5%) melanoma, we evaluated genetic status of BRAF (V600) and NRAS (G12, G13, and Q61), as well as KIT amplification for cutaneous melanoma in study.	('NRAS', 'Gene', (125, 129))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('NRAS', 'Gene', '4893', (125, 129))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Disease', (194, 202))	('cutaneous melanoma', 'Disease', (184, 202))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('melanoma', 'Disease', (68, 76))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (184, 202))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (184, 202))	('KIT', 'molecular_function', 'GO:0005020', ('162', '165'))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('Q61', 'Var', (145, 148))
110559	29361821	Therefore, we sequenced GNAQ/11 (R183 and Q209) only for uveal melanoma in this study.	('GNAQ', 'Gene', '2776', (24, 28))	('R183', 'Var', (33, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('GNAQ', 'Gene', (24, 28))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('uveal melanoma', 'Disease', (57, 71))	('Q209', 'Var', (42, 46))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))
110563	29361821	Compared to other subtypes, non-CSD type and acral type were highly associated with BRAFmutation (41.9%) and KIT amplification (35.8%), respectively.	('CSD', 'Gene', '7045', (32, 35))	('associated', 'Reg', (68, 78))	('BRAF', 'Gene', '673', (84, 88))	('KIT', 'molecular_function', 'GO:0005020', ('109', '112'))	('KIT amplification', 'Var', (109, 126))	('BRAF', 'Gene', (84, 88))	('CSD', 'Gene', (32, 35))
110564	29361821	The BRAF V600E mutation was the most common genetic alteration in this study (n=27).	('V600E', 'Mutation', 'rs113488022', (9, 14))	('BRAF', 'Gene', (4, 8))	('V600E', 'Var', (9, 14))	('BRAF', 'Gene', '673', (4, 8))
110566	29361821	In this study, patients with BRAF mutation were significantly younger (median age, 54 years) than those with wildtype BRAF (median age, 60 years) (p < 0.01) (Table 3).	('BRAF', 'Gene', '673', (118, 122))	('BRAF', 'Gene', '673', (29, 33))	('patients', 'Species', '9606', (15, 23))	('BRAF', 'Gene', (29, 33))	('BRAF', 'Gene', (118, 122))	('mutation', 'Var', (34, 42))
110567	29361821	Also advanced tumors in stages III and IV (67.8%) were more significantly noticed in patients with BRAF mutation whereas patients with wild-type BRAF were more in stage I and II (68.8%).	('BRAF', 'Gene', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('BRAF', 'Gene', (99, 103))	('tumors', 'Disease', (14, 20))	('BRAF', 'Gene', '673', (99, 103))	('patients', 'Species', '9606', (85, 93))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('mutation', 'Var', (104, 112))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('patients', 'Species', '9606', (121, 129))	('BRAF', 'Gene', '673', (145, 149))
110568	29361821	No such tendency was seen in patients with NRAS mutation or KIT amplification (Table 3).	('patients', 'Species', '9606', (29, 37))	('KIT amplification', 'Var', (60, 77))	('NRAS', 'Gene', (43, 47))	('NRAS', 'Gene', '4893', (43, 47))	('KIT', 'molecular_function', 'GO:0005020', ('60', '63'))
110572	29361821	Interestingly, the effect of the BRAF mutation was much stronger in the patients with localized stage tumors (stage I and II) rather than patients with regional or metastasized tumors (stage III and IV) (Fig.	('BRAF', 'Gene', '673', (33, 37))	('localized stage tumors', 'Disease', (86, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('BRAF', 'Gene', (33, 37))	('metastasized tumors', 'Disease', (164, 183))	('metastasized tumors', 'Disease', 'MESH:D009362', (164, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('stronger', 'PosReg', (56, 64))	('mutation', 'Var', (38, 46))	('localized stage tumors', 'Disease', 'MESH:D009364', (86, 108))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('patients', 'Species', '9606', (138, 146))	('patients', 'Species', '9606', (72, 80))
110573	29361821	By Cox multivariate analysis, BRAF mutation was found to be an independent prognostic factor with the hazard ratio of 2.258 (p=0.029; 95% confidence interval, 1.08 to 4.69) (Table 4).	('Cox', 'Gene', '1351', (3, 6))	('Cox', 'Gene', (3, 6))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('mutation', 'Var', (35, 43))
110576	29361821	Among the 43 patients, 55.8% (n=24) showed discordance in the mutational status between the primary and the corresponding metastatic lesion suggesting tumor heterogeneity (S2 Table).	('mutational', 'Var', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
110583	29361821	In the 31 metachronous metastatic tumors, the frequency of BRAF mutation and KIT amplification increased in metastatic tumors compared to its corresponding primary tumor.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', (164, 169))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', (34, 39))	('tumors', 'Disease', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('KIT', 'molecular_function', 'GO:0005020', ('77', '80'))	('mutation', 'Var', (64, 72))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (119, 124))	('tumors', 'Disease', (34, 40))	('KIT', 'Gene', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('increased', 'PosReg', (95, 104))
110588	29361821	Thus, this study aimed to identify the genetic heterogeneity within a set of well-known genetic alterations including BRAF V600, NRAS, and GNAQ/11 mutations, and KIT amplification in 188 Korean melanoma patients and its association with clinical features and impact on survival.	('BRAF', 'Gene', '673', (118, 122))	('mutations', 'Var', (147, 156))	('BRAF', 'Gene', (118, 122))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Disease', (194, 202))	('NRAS', 'Gene', (129, 133))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('GNAQ', 'Gene', (139, 143))	('GNAQ', 'Gene', '2776', (139, 143))	('patients', 'Species', '9606', (203, 211))	('NRAS', 'Gene', '4893', (129, 133))	('KIT', 'molecular_function', 'GO:0005020', ('162', '165'))	('KIT amplification', 'Var', (162, 179))
110591	29361821	Comparing with the Caucasian data, the frequency of NRAS mutation were less in our study especially in non-CSD type and CSD type (6.45% and 5.5%, respectively).	('NRAS', 'Gene', (52, 56))	('mutation', 'Var', (57, 65))	('CSD', 'Gene', (120, 123))	('NRAS', 'Gene', '4893', (52, 56))	('less', 'NegReg', (71, 75))	('CSD', 'Gene', '7045', (120, 123))	('CSD', 'Gene', (107, 110))	('CSD', 'Gene', '7045', (107, 110))
110597	29361821	Activating mutations of the BRAF oncogene have been reported in 33% to 47% of primary melanomas and 41% to 55% of metastatic melanoma.	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('BRAF', 'Gene', '673', (28, 32))	('melanomas', 'Disease', 'MESH:D008545', (86, 95))	('melanoma', 'Disease', (125, 133))	('melanoma', 'Disease', (86, 94))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('Activating mutations', 'Var', (0, 20))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('primary melanoma', 'Disease', (78, 94))	('primary melanoma', 'Disease', 'MESH:D008545', (78, 94))	('melanomas', 'Disease', (86, 95))	('BRAF', 'Gene', (28, 32))	('metastatic', 'Disease', (114, 124))
110599	29361821	Although prognostic role of BRAF mutation in melanoma progression is still controversial, Long et al.	('BRAF', 'Gene', '673', (28, 32))	('mutation', 'Var', (33, 41))	('BRAF', 'Gene', (28, 32))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
110601	29361821	In this study, although patients with BRAF mutation were in advanced stage at the time of diagnosis compared to BRAF wild-type patients, multivariate analysis revealed that BRAF mutation can also act as an independent prognostic factor, especially in the early stage melanomas (stage 1 and 2).	('BRAF', 'Gene', '673', (173, 177))	('mutation', 'Var', (43, 51))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('melanomas', 'Phenotype', 'HP:0002861', (267, 276))	('mutation', 'Var', (178, 186))	('BRAF', 'Gene', (173, 177))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('BRAF', 'Gene', '673', (38, 42))	('melanomas', 'Disease', 'MESH:D008545', (267, 276))	('patients', 'Species', '9606', (127, 135))	('BRAF', 'Gene', (38, 42))	('patients', 'Species', '9606', (24, 32))	('melanomas', 'Disease', (267, 276))
110602	29361821	Also, patients with BRAF mutation were younger compared to the BRAF wild-type patients which is consistent with previous reports.	('mutation', 'Var', (25, 33))	('patients', 'Species', '9606', (78, 86))	('BRAF', 'Gene', '673', (20, 24))	('patients', 'Species', '9606', (6, 14))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', (20, 24))	('BRAF', 'Gene', (63, 67))
110604	29361821	In our study, among the 43 patients with corresponding metastatic lesions, 55.8% of the patients showed discordance in the mutational status suggesting tumor heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('patients', 'Species', '9606', (88, 96))	('tumor', 'Disease', (152, 157))	('patients', 'Species', '9606', (27, 35))	('mutational', 'Var', (123, 133))
110608	29361821	The frequency of BRAF mutation increased significantly in metastatic lesions compared to primary lesions.	('metastatic lesions', 'Disease', (58, 76))	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (17, 21))	('mutation', 'Var', (22, 30))
110609	29361821	Our results are contrary to previous data indicating that BRAF mutations occur early in the development of melanoma and the incidence may not vary significantly during tumor progression.	('mutations', 'Var', (63, 72))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('tumor', 'Disease', (168, 173))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('BRAF', 'Gene', '673', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('BRAF', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
110611	29361821	Together, it is likely that BRAF mutations is not merely initial event in melanomagenesis but has a role in progression of melanoma.	('BRAF', 'Gene', '673', (28, 32))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('mutations', 'Var', (33, 42))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('BRAF', 'Gene', (28, 32))
110613	29361821	GNAQ and GNA11 mutations are known to occur in majority of uveal melanoma patients and are considered to occur early in uveal melanoma development.	('GNA11', 'Gene', (9, 14))	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('uveal melanoma', 'Disease', (59, 73))	('GNAQ', 'Gene', '2776', (0, 4))	('patients', 'Species', '9606', (74, 82))	('mutations', 'Var', (15, 24))	('uveal melanoma', 'Disease', 'MESH:C536494', (120, 134))	('GNAQ', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('uveal melanoma', 'Phenotype', 'HP:0007716', (120, 134))	('uveal melanoma', 'Disease', (120, 134))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('uveal melanoma', 'Disease', 'MESH:C536494', (59, 73))	('GNA11', 'Gene', '2767', (9, 14))
110615	29361821	In conclusion, our study revealed that BRAF mutation was an independent prognostic factor of poor survival.	('BRAF', 'Gene', '673', (39, 43))	('BRAF', 'Gene', (39, 43))	('mutation', 'Var', (44, 52))
110616	29361821	Also, our data demonstrated tumor heterogeneity between primary melanomas and corresponding metastatic lesions for BRAF, NRAS mutations and KIT amplification, and genetic homogeneity in uveal melanoma for GNAQ/11.	('tumor', 'Disease', (28, 33))	('uveal melanoma', 'Disease', (186, 200))	('uveal melanoma', 'Disease', 'MESH:C536494', (186, 200))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('KIT', 'molecular_function', 'GO:0005020', ('140', '143'))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('KIT', 'Gene', (140, 143))	('NRAS', 'Gene', (121, 125))	('uveal melanoma', 'Phenotype', 'HP:0007716', (186, 200))	('mutations', 'Var', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('primary melanoma', 'Disease', 'MESH:D008545', (56, 72))	('primary melanoma', 'Disease', (56, 72))	('melanomas', 'Disease', 'MESH:D008545', (64, 73))	('BRAF', 'Gene', '673', (115, 119))	('NRAS', 'Gene', '4893', (121, 125))	('melanomas', 'Disease', (64, 73))	('BRAF', 'Gene', (115, 119))	('GNAQ', 'Gene', '2776', (205, 209))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('GNAQ', 'Gene', (205, 209))
110649	27321895	C-MIN 6 or greater corresponds to conjunctival melanoma in situ.	('conjunctival melanoma', 'Disease', (34, 55))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (34, 55))	('C-MIN 6', 'Var', (0, 7))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (34, 55))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))
110655	27321895	The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) is an oncogenic mutation in one of the RAF genes and a known contributor to the formation of cutaneous melanoma.	('cutaneous melanoma', 'Disease', (151, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('mutation', 'Var', (74, 82))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (151, 169))	('RAF', 'Gene', (97, 100))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (151, 169))	('RAF', 'Gene', '673;109880', (97, 100))	('RAF', 'Gene', '673;109880', (53, 56))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('formation', 'biological_process', 'GO:0009058', ('138', '147'))	('RAF', 'Gene', (53, 56))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (4, 50))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', (4, 50))
110658	27321895	conducted a large genetic analysis of 78 conjunctival melanoma samples using oncogene hotspot array to screen for known cancer-relevant mutations and found BRAF (of which 91% were V600E) mutations in 29% of the tumors and NRAS in 18% of the tumors, similar to cutaneous melanomas.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('melanoma', 'Phenotype', 'HP:0002861', (270, 278))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', (120, 126))	('melanomas', 'Phenotype', 'HP:0002861', (270, 279))	('NRAS', 'Gene', '4893', (222, 226))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('V600E', 'Var', (180, 185))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (41, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (41, 62))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (260, 279))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (260, 279))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (260, 278))	('BRAF', 'Gene', (156, 160))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('NRAS', 'Gene', (222, 226))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('cutaneous melanomas', 'Disease', (260, 279))	('conjunctival melanoma', 'Disease', (41, 62))	('tumors', 'Disease', (241, 247))	('V600E', 'Mutation', 'rs113488022', (180, 185))
110659	27321895	GNAQ and GNA11 mutations, often found in uveal melanomas, were not detected in the conjunctival melanomas.	('GNA11', 'Gene', (9, 14))	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('uveal melanomas', 'Disease', (41, 56))	('uveal melanomas', 'Phenotype', 'HP:0007716', (41, 56))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (83, 105))	('GNAQ', 'Gene', (0, 4))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (83, 104))	('conjunctival melanomas', 'Disease', (83, 105))	('uveal melanomas', 'Disease', 'MESH:C536494', (41, 56))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('GNA11', 'Gene', '2767', (9, 14))
110660	27321895	also detected the BRAF V600E mutation in 50% of primary tumor samples and 67% in the metastatic samples.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('V600E', 'Mutation', 'rs113488022', (23, 28))	('tumor', 'Disease', (56, 61))	('detected', 'Reg', (5, 13))	('V600E', 'Var', (23, 28))	('BRAF', 'Gene', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
110663	27321895	used CGH in two conjunctival melanoma samples and found multiple chromosomal changes, most notably 10q and 16q loss that is also found in cutaneous melanomas.	('loss', 'NegReg', (111, 115))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (16, 37))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (16, 37))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (138, 157))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (138, 157))	('16q', 'CPA', (107, 110))	('10q', 'Var', (99, 102))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (138, 156))	('melanomas', 'Phenotype', 'HP:0002861', (148, 157))	('cutaneous melanomas', 'Disease', (138, 157))	('multiple chromosomal changes', 'Phenotype', 'HP:0040012', (56, 84))	('conjunctival melanoma', 'Disease', (16, 37))
110664	27321895	reported frequent copy number amplifications of CDKN1A and RUNX2 in primary tumors (6p21.2), both of which have been implicated in cutaneous melanoma tumorigenesis.	('primary tumors', 'Disease', (68, 82))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('primary tumors', 'Disease', 'MESH:D009369', (68, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('CDKN1A', 'Gene', (48, 54))	('CDKN1A', 'Gene', '1026', (48, 54))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('cutaneous melanoma', 'Disease', (131, 149))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (131, 149))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (131, 149))	('implicated', 'Reg', (117, 127))	('tumor', 'Disease', (150, 155))	('copy number amplifications', 'Var', (18, 44))	('RUNX2', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('RUNX2', 'Gene', '860', (59, 64))
110671	27321895	Mutation of the CDKN2A gene, resulting in decreased p16 protein production, leads to increase mitotic activity and replication and hence melanoma genesis.	('p16', 'Gene', '1029', (52, 55))	('decreased', 'NegReg', (42, 51))	('hence melanoma genesis', 'Disease', 'MESH:D008545', (131, 153))	('hence melanoma genesis', 'Disease', (131, 153))	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('Mutation', 'Var', (0, 8))	('mitotic activity', 'CPA', (94, 110))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('p16', 'Gene', (52, 55))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('replication', 'CPA', (115, 126))	('increase', 'PosReg', (85, 93))
110677	27321895	It has been suggested that PLX4023 (vemurafenib), a BRAF inhibitor specific for the V600E mutation, could be used for treatment of metastases.	('metastases', 'Disease', (131, 141))	('V600E', 'Mutation', 'rs113488022', (84, 89))	('PLX4023', 'Chemical', '-', (27, 34))	('metastases', 'Disease', 'MESH:D009362', (131, 141))	('V600E', 'Var', (84, 89))	('vemurafenib', 'Chemical', 'MESH:D000077484', (36, 47))	('men', 'Species', '9606', (123, 126))
110852	22723080	Driver Mutations in Melanoma: Lessons Learned From Bench-to-Bedside Studies The identification of somatic driver mutations in human samples has allowed for the development of a molecular classification for melanoma.	('human', 'Species', '9606', (126, 131))	('Melanoma', 'Disease', 'MESH:D008545', (20, 28))	('Melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('Melanoma', 'Disease', (20, 28))	('mutations', 'Var', (113, 122))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('melanoma', 'Disease', (206, 214))	('melanoma', 'Disease', 'MESH:D008545', (206, 214))
110858	22723080	Similarly, specific mutations have been identified in melanomas of mucosal or acral-lentiginous origin, which differ from ocular or sun-induced cutaneous melanomas, and mutations in chronic sun damaged skin differ from those found in skin exposed to intermittent ultraviolet irradiation.	('mutations', 'Var', (169, 178))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('cutaneous melanomas', 'Disease', (144, 163))	('sun damage', 'Phenotype', 'HP:0000992', (190, 200))	('melanomas of mucosal', 'Disease', 'MESH:D008545', (54, 74))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanomas', 'Phenotype', 'HP:0002861', (154, 163))	('melanomas of mucosal', 'Disease', (54, 74))	('sun damaged skin', 'Phenotype', 'HP:0000992', (190, 206))	('mutations', 'Var', (20, 29))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (144, 163))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (144, 163))
110861	22723080	Identification of novel mutations has led to progress in systemic therapy for patients with unresectable disease, and the survival for patients with advanced melanoma has finally started to improve.	('patients', 'Species', '9606', (135, 143))	('patients', 'Species', '9606', (78, 86))	('mutations', 'Var', (24, 33))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (158, 166))
110862	22723080	Identification of "driver" somatic mutations (mutations that are necessary to promote the malignant process) in this disease have, for the most part, resulted from studies employing human samples and newer high throughput screening platforms.	('malignant process', 'CPA', (90, 107))	('human', 'Species', '9606', (182, 187))	('promote', 'PosReg', (78, 85))	('mutations', 'Var', (35, 44))
110863	22723080	The first frequently occurring somatic mutation to be identified in cutaneous melanomas was the activating mutation in BRAF, an observation that was followed by mechanistic studies demonstrating that mutated BRAF is critical for the malignant process.	('cutaneous melanomas', 'Disease', (68, 87))	('BRAF', 'Gene', (208, 212))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('mutated', 'Var', (200, 207))	('BRAF', 'Gene', (119, 123))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('mutation', 'Var', (107, 115))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (68, 87))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (68, 87))
110864	22723080	Subsequently, drug development efforts focused on targeting BRAF in this and other diseases featuring an activating BRAF mutation, and specific inhibitors of mutant BRAF have already been shown to improve survival in advanced melanoma patients whose disease harbors BRAF mutations.	('melanoma', 'Disease', (226, 234))	('survival', 'CPA', (205, 213))	('patients', 'Species', '9606', (235, 243))	('BRAF', 'Gene', (116, 120))	('BRAF', 'Gene', (165, 169))	('mutation', 'Var', (121, 129))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('improve', 'PosReg', (197, 204))	('activating', 'PosReg', (105, 115))
110866	22723080	While much additional research is needed, the bulk of the evidence suggests that more than one critical mutation is necessary to transform a benign melanocyte into an invasive, malignant tumor.	('malignant tumor', 'Disease', 'MESH:D018198', (177, 192))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('mutation', 'Var', (104, 112))	('malignant tumor', 'Disease', (177, 192))
110867	22723080	In 2002, Davies et al, conducted a genome-wide screen in a number of tumor types using array- based comparative genomic hybridization focusing on the mitogen-activated protein kinase (MAPK) pathway, one of the major intracellular signal transduction pathways responsible for cellular proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis, and reported that 66 % of melanoma samples harbored a single substitution (V599E) mutation in the activating segment of the kinase domain.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('intracellular', 'cellular_component', 'GO:0005622', ('216', '229'))	('melanoma', 'Disease', (398, 406))	('intracellular signal transduction', 'biological_process', 'GO:0035556', ('216', '249'))	('tumor', 'Disease', (69, 74))	('V599E', 'Mutation', 'p.V599E', (447, 452))	('apoptosis', 'biological_process', 'GO:0097194', ('361', '370'))	('mitosis', 'Disease', (333, 340))	('mitosis', 'biological_process', 'GO:0000278', ('333', '340'))	('gene expression', 'biological_process', 'GO:0010467', ('299', '314'))	('apoptosis', 'biological_process', 'GO:0006915', ('361', '370'))	('V599E', 'Var', (447, 452))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('melanoma', 'Disease', 'MESH:D008545', (398, 406))	('melanoma', 'Phenotype', 'HP:0002861', (398, 406))	('MAPK', 'molecular_function', 'GO:0004707', ('184', '188'))	('mitosis', 'Disease', 'None', (333, 340))
110868	22723080	They found that melanoma cell lines with BRAFV599E mutations (subsequently found to be at BRAFV600E) can signal through the MAPK pathway without upstream activation by RAS, indicating that these cells lose their dependence on upstream signaling.	('MAPK pathway', 'Pathway', (124, 136))	('BRAFV600E', 'Mutation', 'rs113488022', (90, 99))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanoma', 'Disease', (16, 24))	('signal', 'Reg', (105, 111))	('MAPK', 'molecular_function', 'GO:0004707', ('124', '128'))	('BRAFV599E', 'Var', (41, 50))	('signaling', 'biological_process', 'GO:0023052', ('235', '244'))
110869	22723080	Moreover, these early studies showed that when BRAFV600E is ectopically expressed in immortalized cell lines, it causes hyperstimulation of the MAPK cascade and malignant cellular transformation.	('malignant cellular transformation', 'CPA', (161, 194))	('MAPK', 'molecular_function', 'GO:0004707', ('144', '148'))	('MAPK cascade', 'biological_process', 'GO:0000165', ('144', '156'))	('causes', 'Reg', (113, 119))	('MAPK cascade', 'Pathway', (144, 156))	('BRAFV600E', 'Var', (47, 56))	('BRAFV600E', 'Mutation', 'rs113488022', (47, 56))	('hyperstimulation', 'PosReg', (120, 136))
110873	22723080	BRAF mutations were not found in uveal melanoma, as demonstrated by Rimoldi et al.	('uveal melanoma', 'Disease', 'MESH:C536494', (33, 47))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('uveal melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('mutations', 'Var', (5, 14))	('uveal melanoma', 'Disease', (33, 47))
110874	22723080	and Cruz et al.. Maldonado et al., in a study of primary invasive cutaneous melanomas, reported that BRAF mutations were more common in melanomas occurring on skin that had been exposed to intermittent sun exposure, whereas skin on the palms, soles, and under nailbeds (acral lentiginous) as well as melanomas arising in mucosal surfaces only rarely harbor BRAF mutations (15 % and 10 %, respectively).	('melanomas', 'Disease', 'MESH:D008545', (76, 85))	('invasive cutaneous melanomas', 'Disease', (57, 85))	('melanomas', 'Disease', (76, 85))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanomas', 'Phenotype', 'HP:0002861', (300, 309))	('melanomas', 'Disease', 'MESH:D008545', (136, 145))	('invasive cutaneous melanomas', 'Disease', 'MESH:C562393', (57, 85))	('BRAF', 'Gene', (101, 105))	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('melanoma', 'Phenotype', 'HP:0002861', (300, 308))	('melanomas', 'Disease', (136, 145))	('melanomas occurring on skin', 'Phenotype', 'HP:0002861', (136, 163))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('melanomas', 'Disease', 'MESH:D008545', (300, 309))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (66, 85))	('melanomas', 'Phenotype', 'HP:0002861', (136, 145))	('mutations', 'Var', (106, 115))	('common', 'Reg', (126, 132))	('melanomas', 'Disease', (300, 309))
110875	22723080	A specific study of oral mucosal melanoma demonstrated that only one out of 15 (6 %) cases had an activating BRAF mutation, and similar validation studies on acral lentiginous cutaneous melanomas demonstrated that BRAF mutations were a rare event.	('oral mucosal melanoma', 'Disease', (20, 41))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanomas', 'Phenotype', 'HP:0002861', (186, 195))	('BRAF', 'Gene', (109, 113))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (176, 195))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('oral mucosal melanoma', 'Disease', 'MESH:D013280', (20, 41))	('activating', 'Reg', (98, 108))	('acral lentiginous cutaneous melanomas', 'Phenotype', 'HP:0012060', (158, 195))	('acral lentiginous cutaneous melanomas', 'Disease', 'MESH:C562393', (158, 195))	('mutation', 'Var', (114, 122))	('acral lentiginous cutaneous melanomas', 'Disease', (158, 195))
110876	22723080	Early stage primary melanomas and metastatic lesions appear to have BRAF mutations at a similar frequency.	('metastatic lesions', 'CPA', (34, 52))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('BRAF', 'Gene', (68, 72))	('melanomas', 'Disease', (20, 29))	('melanomas', 'Disease', 'MESH:D008545', (20, 29))	('melanomas', 'Phenotype', 'HP:0002861', (20, 29))	('mutations', 'Var', (73, 82))
110877	22723080	Moreover, benign nevi harbor BRAF mutations in a high percentage, indicating that this is an early event in development of pigmented neoplasias, and insufficient in itself to result in malignant transformation.	('BRAF', 'Gene', (29, 33))	('pigmented neoplasias', 'Disease', (123, 143))	('pigmented neoplasias', 'Disease', 'MESH:D009369', (123, 143))	('insufficient', 'Disease', 'MESH:D000309', (149, 161))	('benign nevi', 'Disease', (10, 21))	('nevi', 'Phenotype', 'HP:0003764', (17, 21))	('insufficient', 'Disease', (149, 161))	('mutations', 'Var', (34, 43))	('neoplasias', 'Phenotype', 'HP:0002664', (133, 143))
110878	22723080	However, in metastatic melanoma patients, BRAF mutations were associated with worse prognosis if not treated with BRAF inhibitors, providing clinical evidence that although BRAF mutations are an early event, BRAF remains activated, even once tumors have metastasized.	('patients', 'Species', '9606', (32, 40))	('BRAF', 'Gene', (173, 177))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('mutations', 'Var', (178, 187))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('tumors', 'Disease', (242, 248))
110879	22723080	Since the identification a decade ago of mutations in BRAF in about half of cutaneous melanomas, intense efforts have been made to develop pharmacologic agents that inhibit BRAF for treatment of advanced melanoma.	('mutations', 'Var', (41, 50))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('melanoma', 'Disease', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('melanoma', 'Disease', (204, 212))	('BRAF', 'Gene', (54, 58))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (76, 95))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (76, 95))	('melanoma', 'Disease', 'MESH:D008545', (204, 212))	('BRAF', 'Gene', (173, 177))	('cutaneous melanomas', 'Disease', (76, 95))	('inhibit', 'NegReg', (165, 172))
110882	22723080	Additional, more specific pan-RAF inhibitors, such as RAF265, have been tried, and responses have been seen in both BRAF mutant and WT tumors, as supported by preclinical data showing that sensitivity to this drug is not associated with BRAF mutation status.	('mutant', 'Var', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('RAF', 'Gene', '22882', (117, 120))	('RAF', 'Gene', '22882', (238, 241))	('RAF', 'Gene', (117, 120))	('RAF', 'Gene', (238, 241))	('RAF265', 'Chemical', 'MESH:C559019', (54, 60))	('RAF', 'Gene', '22882', (54, 57))	('WT tumors', 'Disease', 'MESH:C536751', (132, 141))	('RAF', 'Gene', '22882', (30, 33))	('RAF', 'Gene', (54, 57))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('RAF', 'Gene', (30, 33))	('WT tumors', 'Disease', (132, 141))
110883	22723080	The most promising clinical trial results for patients whose tumors harbor BRAF mutations have been obtained with drugs specifically designed to target the mutated form of BRAF.	('tumors', 'Disease', (61, 67))	('patients', 'Species', '9606', (46, 54))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('mutations', 'Var', (80, 89))	('BRAF', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
110884	22723080	Two such inhibitors have been studied in advanced stage clinical trials; PLX4032 and GSK2118436, now known as vemurafenib and dabrafenib, respectively.	('vemurafenib', 'Chemical', 'MESH:D000077484', (110, 121))	('dabrafenib', 'Chemical', 'MESH:C561627', (126, 136))	('GSK2118436', 'Chemical', 'MESH:C561627', (85, 95))	('GSK', 'molecular_function', 'GO:0050321', ('85', '88'))	('PLX4032', 'Var', (73, 80))	('GSK2118436', 'Var', (85, 95))
110885	22723080	These studies only include patients whose tumors harbor BRAF mutations.	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mutations', 'Var', (61, 70))	('patients', 'Species', '9606', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('BRAF', 'Gene', (56, 60))
110889	22723080	The activity of these drugs in BRAF mutant tumors that are not BRAFV600E is unknown, although anecdotal reports of activity have been published.	('BRAFV600E', 'Mutation', 'rs113488022', (63, 72))	('BRAF', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutant', 'Var', (36, 42))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
110893	22723080	However, the assay was less sensitive in detecting BRAFV600K or BRAFV600D mutations, and it cannot differentiate between heterozygous and homozygous BRAF mutant cells.	('BRAFV600K', 'Var', (51, 60))	('BRAFV600K', 'Mutation', 'rs121913227', (51, 60))	('BRAFV600D', 'Var', (64, 73))
110895	22723080	A number of preclinical studies have been conducted to identify and overcome mechanisms of resistance, which have primarily been attributed to secondary molecular alterations including new mutations in NRAS, nonmutational up-regulation of PDGFR, MEK, C-Raf, and COTactivation.	('PDGFR', 'Gene', (239, 244))	('regulation', 'biological_process', 'GO:0065007', ('225', '235'))	('PDGFR', 'Gene', '5159', (239, 244))	('NRAS', 'Gene', (202, 206))	('up-regulation', 'PosReg', (222, 235))	('MEK', 'Gene', (246, 249))	('C-Raf', 'Gene', '5894', (251, 256))	('MEK', 'Gene', '5609', (246, 249))	('mutations', 'Var', (189, 198))	('C-Raf', 'Gene', (251, 256))
110897	22723080	The bench-to-bedside and bedside-to-bench paradigms that have been employed in the past decade have thus successfully started to change the therapeutic approach to metastatic melanomas harboring BRAF mutations, and additional advances are anticipated in the near future.	('melanomas', 'Disease', (175, 184))	('mutations', 'Var', (200, 209))	('melanomas', 'Phenotype', 'HP:0002861', (175, 184))	('BRAF', 'Gene', (195, 199))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('melanomas', 'Disease', 'MESH:D008545', (175, 184))
110899	22723080	Mutations in NRAS, reported in 15 %-20 % of human melanomas at exon 2 and exon 3 (formerly exon 1 and exon 2), were among the first described in malignant melanoma.	('human', 'Species', '9606', (44, 49))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('melanomas', 'Disease', 'MESH:D008545', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('malignant melanoma', 'Disease', 'MESH:D008545', (145, 163))	('malignant melanoma', 'Phenotype', 'HP:0002861', (145, 163))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', (13, 17))	('malignant melanoma', 'Disease', (145, 163))	('melanomas', 'Disease', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))
110900	22723080	The most common mutation occurs at codon 61, exon 3, resulting in the replacement of the Q61 glutamine residue usually by lysine or arginine.	('lysine', 'MPA', (122, 128))	('glutamine', 'Chemical', 'MESH:D005973', (93, 102))	('Q61', 'Var', (89, 92))	('lysine', 'Chemical', 'MESH:D008239', (122, 128))	('arginine', 'Chemical', 'MESH:D001120', (132, 140))
110901	22723080	This substitution irreversibly activates the RAS protein, resulting in an inability to cleave GTP, which would otherwise terminate downstream growth.	('activates', 'PosReg', (31, 40))	('substitution', 'Var', (5, 17))	('inability', 'NegReg', (74, 83))	('GTP', 'Chemical', 'MESH:D006160', (94, 97))	('RAS protein', 'Protein', (45, 56))	('terminate', 'NegReg', (121, 130))	('cleave', 'MPA', (87, 93))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('GTP', 'Protein', (94, 97))
110902	22723080	Of note, the presence of NRAS mutations in melanoma causes a switch in MAPK signaling from BRAF to CRAF, initiating dysregulated cAMP signaling that allows CRAF to signal to MEK.	('MEK', 'Gene', (174, 177))	('cAMP', 'Chemical', 'MESH:D000242', (129, 133))	('CRAF', 'Gene', (156, 160))	('NRAS', 'Gene', (25, 29))	('CRAF', 'molecular_function', 'GO:0004709', ('156', '160'))	('CRAF', 'molecular_function', 'GO:0004709', ('99', '103'))	('dysregulated cAMP signaling', 'MPA', (116, 143))	('MAPK signaling', 'MPA', (71, 85))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('CRAF', 'Gene', '5894', (156, 160))	('CRAF', 'Gene', (99, 103))	('mutations', 'Var', (30, 39))	('cAMP signaling', 'biological_process', 'GO:0019933', ('129', '143'))	('initiating', 'Reg', (105, 115))	('CRAF', 'Gene', '5894', (99, 103))	('MAPK signaling', 'biological_process', 'GO:0000165', ('71', '85'))	('MEK', 'Gene', '5609', (174, 177))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('MAPK', 'molecular_function', 'GO:0004707', ('71', '75'))	('melanoma', 'Disease', (43, 51))	('switch', 'Reg', (61, 67))
110903	22723080	Like BRAF, NRAS mutations have also been identified in benign nevi, appearing most associated with congenital melanocytic nevi, particularly those of medium to large size.	('nevi', 'Phenotype', 'HP:0003764', (62, 66))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (110, 126))	('congenital melanocytic nevi', 'Phenotype', 'HP:0100814', (99, 126))	('congenital melanocytic', 'Disease', 'MESH:C536819', (99, 121))	('mutations', 'Var', (16, 25))	('associated', 'Reg', (83, 93))	('nevi', 'Phenotype', 'HP:0003764', (122, 126))	('NRAS', 'Gene', (11, 15))	('congenital melanocytic', 'Disease', (99, 121))
110905	22723080	Multiple recent studies seeking to analyze clinical characteristics of NRAS mutant melanomas, with the intention of improving biologic insights to ultimately lead to more sophisticated drug development and clinical trials for this patient subset, have yielded conflicting results.	('NRAS', 'Gene', (71, 75))	('mutant', 'Var', (76, 82))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('melanomas', 'Disease', (83, 92))	('melanomas', 'Disease', 'MESH:D008545', (83, 92))	('patient', 'Species', '9606', (231, 238))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
110906	22723080	Two recent, large (>240 samples) studies of melanomas with NRAS mutations indicate that these tumors appear to exhibit more aggressive behavior, being associated with shorter overall survival.	('shorter', 'NegReg', (167, 174))	('melanomas', 'Disease', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('tumors', 'Disease', (94, 100))	('mutations', 'Var', (64, 73))	('NRAS', 'Gene', (59, 63))	('melanomas', 'Disease', 'MESH:D008545', (44, 53))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('aggressive behavior', 'biological_process', 'GO:0002118', ('124', '143'))	('overall survival', 'MPA', (175, 191))	('aggressive behavior', 'Phenotype', 'HP:0000718', (124, 143))
110908	22723080	Finally, patients with BRAF and NRAS mutations were more likely to present with advanced AJCC stages, specifically stage III disease, and were more likely to have CNS disease at diagnosis of stage IV melanoma.	('IV melanoma', 'Disease', 'MESH:D008545', (197, 208))	('patients', 'Species', '9606', (9, 17))	('stage III disease', 'Disease', (115, 132))	('NRAS', 'Gene', (32, 36))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('BRAF', 'Gene', (23, 27))	('mutations', 'Var', (37, 46))	('AJCC stages', 'Disease', (89, 100))	('IV melanoma', 'Disease', (197, 208))
110909	22723080	Historically, targeting mutant NRAS has proven to be challenging, in part due to the dynamics of the Ras cycle; this approach would require displacement of GTP from Ras, which has strong affinity for GTP binding, in a GTP rich environment, or reconstitution of its GTPase activity.	('mutant', 'Var', (24, 30))	('GTP', 'Chemical', 'MESH:D006160', (265, 268))	('binding', 'Interaction', (204, 211))	('GTPase activity', 'molecular_function', 'GO:0003924', ('265', '280'))	('GTP', 'Chemical', 'MESH:D006160', (200, 203))	('GTP', 'Chemical', 'MESH:D006160', (156, 159))	('GTP binding', 'molecular_function', 'GO:0005525', ('200', '211'))	('NRAS', 'Gene', (31, 35))	('GTP', 'Chemical', 'MESH:D006160', (218, 221))
110911	22723080	For instance, activated c-Met has been demonstrated in NRAS mutant tumor cell lines, which also showed sensitivity to pharmacologic c-Met inhibition, suggesting a novel therapeutic target.	('c-Met', 'Gene', (24, 29))	('c-Met', 'Gene', '4233', (24, 29))	('c-Met', 'Gene', '4233', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('c-Met', 'Gene', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('activated', 'PosReg', (14, 23))	('tumor', 'Disease', (67, 72))	('mutant', 'Var', (60, 66))	('NRAS', 'Gene', (55, 59))
110913	22723080	Two decades ago, Larue et al showed that mutations in the kinase domain of c-Kit can transform melanocytes to the malignant phenotype, suggesting that c-Kit might have a role as a therapeutic target in this disease, although expression levels of the receptor tyrosine kinase have not been shown to increase with melanoma progression.	('c-Kit', 'Gene', (75, 80))	('c-Kit', 'Gene', '3815', (75, 80))	('transform', 'Reg', (85, 94))	('melanoma', 'Disease', 'MESH:D008545', (312, 320))	('melanoma', 'Phenotype', 'HP:0002861', (312, 320))	('melanoma', 'Disease', (312, 320))	('c-Kit', 'Gene', (151, 156))	('c-Kit', 'Gene', '3815', (151, 156))	('mutations in', 'Var', (41, 53))	('melanocytes to the malignant phenotype', 'CPA', (95, 133))
110922	22723080	When amplification on 4q12 was noted, targeted sequencing revealed oncogenic mutations in c-kit in 39 % of mucosal, 36 % of acral, and 28 % of melanomas arising in chronically sun damaged skin, while no mutations were found in cutaneous melanomas without chronic sun damage.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (227, 246))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (227, 246))	('sun damage', 'Phenotype', 'HP:0000992', (176, 186))	('melanomas', 'Disease', (237, 246))	('c-kit', 'Gene', (90, 95))	('cutaneous melanomas', 'Disease', (227, 246))	('melanomas', 'Disease', (143, 152))	('revealed', 'Reg', (58, 66))	('sun damage', 'Phenotype', 'HP:0000992', (263, 273))	('mutations', 'Var', (77, 86))	('c-kit', 'Gene', '3815', (90, 95))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('sun damaged skin', 'Phenotype', 'HP:0000992', (176, 192))	('melanomas', 'Phenotype', 'HP:0002861', (237, 246))	('melanomas', 'Disease', 'MESH:D008545', (143, 152))	('melanomas', 'Phenotype', 'HP:0002861', (143, 152))	('melanomas', 'Disease', 'MESH:D008545', (237, 246))
110925	22723080	In a trial conducted in Asia for patients with C-kit mutation or amplification, a response rate of 23 % was observed, with most responses seen in patients with mutations in exons 11 or 13.	('mutation', 'Var', (53, 61))	('mutations in exons 11', 'Var', (160, 181))	('patients', 'Species', '9606', (33, 41))	('C-kit', 'Gene', (47, 52))	('amplification', 'Var', (65, 78))	('patients', 'Species', '9606', (146, 154))
110926	22723080	Studies with other inhibitors of c-Kit have since been conducted and show tumor shrinkage in subsets of patients with melanomas harboring c-kit mutations, as reviewed.	('c-Kit', 'Gene', (33, 38))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('c-Kit', 'Gene', '3815', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('melanomas', 'Phenotype', 'HP:0002861', (118, 127))	('c-kit', 'Gene', '3815', (138, 143))	('c-kit', 'Gene', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('melanomas', 'Disease', 'MESH:D008545', (118, 127))	('patients', 'Species', '9606', (104, 112))	('tumor', 'Disease', (74, 79))	('mutations', 'Var', (144, 153))	('melanomas', 'Disease', (118, 127))
110927	22723080	For example, clinical response to the multi-kinase inhibitor, dasatinib, which inhibits c-Kit as well as PDGFR and src kinases, was seen in two patients with a L576P mutations in exon 11 of c-Kit.	('L576P', 'Var', (160, 165))	('c-Kit', 'Gene', (88, 93))	('c-Kit', 'Gene', '3815', (88, 93))	('inhibits', 'NegReg', (79, 87))	('seen', 'Reg', (132, 136))	('PDGFR', 'Gene', (105, 110))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('44', '60'))	('dasatinib', 'Chemical', 'MESH:D000069439', (62, 71))	('patients', 'Species', '9606', (144, 152))	('PDGFR', 'Gene', '5159', (105, 110))	('L576P', 'Mutation', 'rs121913513', (160, 165))	('c-Kit', 'Gene', (190, 195))	('c-Kit', 'Gene', '3815', (190, 195))
110928	22723080	A study of unselected melanoma patients treated with dasatinib showed a dramatic response in one patient with an exon 13 c-Kit mutation and disease progression in a second patient with an exon 11 mutation, while protein expression analysis showed no association between c-Kit expression and clinical response or in vitro sensitivity to dasatinib.	('dasatinib', 'Chemical', 'MESH:D000069439', (53, 62))	('dasatinib', 'Chemical', 'MESH:D000069439', (336, 345))	('c-Kit', 'Gene', (270, 275))	('mutation', 'Var', (127, 135))	('exon 13', 'Var', (113, 120))	('c-Kit', 'Gene', '3815', (270, 275))	('patient', 'Species', '9606', (172, 179))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma', 'Disease', (22, 30))	('patient', 'Species', '9606', (31, 38))	('patients', 'Species', '9606', (31, 39))	('patient', 'Species', '9606', (97, 104))	('c-Kit', 'Gene', (121, 126))	('c-Kit', 'Gene', '3815', (121, 126))
110929	22723080	In summary, c-Kit is currently viewed as a good therapeutic target in a very small subset of metastatic melanomas, primarily patients with exon 11 and 13 mutations, based on both clinical and preclinical evidence.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanomas', 'Phenotype', 'HP:0002861', (104, 113))	('c-Kit', 'Gene', (12, 17))	('c-Kit', 'Gene', '3815', (12, 17))	('melanomas', 'Disease', 'MESH:D008545', (104, 113))	('melanomas', 'Disease', (104, 113))	('exon 11', 'Var', (139, 146))	('patients', 'Species', '9606', (125, 133))
110930	22723080	Expression of c-Kit protein does not appear to correlate with sensitivity to c-Kit inhibitors, whereas presence of activating c-Kit gene mutations does correlate.	('c-Kit', 'Gene', (77, 82))	('c-Kit', 'Gene', '3815', (77, 82))	('c-Kit', 'Gene', (126, 131))	('c-Kit', 'Gene', '3815', (126, 131))	('c-Kit', 'Gene', (14, 19))	('mutations', 'Var', (137, 146))	('activating', 'PosReg', (115, 125))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('c-Kit', 'Gene', '3815', (14, 19))
110931	22723080	A multicenter trial lead by the Eastern Cooperative Oncology Group (ECOG) assessing activity of dasatinib in unresectable acral, mucosal, or vulvovaginal melanomas harboring mutations in exons 9, 11, 13, 17, or 18 of the c-Kit gene (ECOG 2607) is ongoing.	('vulvovaginal melanomas', 'Disease', 'MESH:D014848', (141, 163))	('vulvovaginal melanomas', 'Phenotype', 'HP:0030418', (141, 163))	('dasatinib', 'Chemical', 'MESH:D000069439', (96, 105))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanomas', 'Phenotype', 'HP:0002861', (154, 163))	('Oncology', 'Phenotype', 'HP:0002664', (52, 60))	('vulvovaginal melanomas', 'Disease', (141, 163))	('c-Kit', 'Gene', (221, 226))	('mutations in exons 9', 'Var', (174, 194))	('c-Kit', 'Gene', '3815', (221, 226))
110932	22723080	Studies of human tissues obtained from patients enrolled in clinical trials, coupled with preclinical studies demonstrating the importance of certain mutations in melanoma tumorigenesis, were necessary for gaining this insight.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('human', 'Species', '9606', (11, 16))	('patients', 'Species', '9606', (39, 47))	('tumor', 'Disease', (172, 177))	('melanoma', 'Disease', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('mutations', 'Var', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
110934	22723080	Germline mutations in PTEN result in Cowden syndrome, an autosomal dominant disorder in which patients develop hamartomas and are at increased risk for certain cancers.	('Germline mutations', 'Var', (0, 18))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (57, 84))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('patients', 'Species', '9606', (94, 102))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('hamartomas', 'Disease', 'MESH:D006222', (111, 121))	('cancers', 'Disease', (160, 167))	('hamartomas', 'Phenotype', 'HP:0010566', (111, 121))	('Cowden syndrome', 'Disease', (37, 52))	('PTEN', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('autosomal dominant disorder', 'Disease', (57, 84))	('result in', 'Reg', (27, 36))	('hamartomas', 'Disease', (111, 121))	('Cowden syndrome', 'Disease', 'MESH:D006223', (37, 52))
110935	22723080	The importance of PTEN as a tumor suppressor in melanoma pathogenesis has been supported by functional studies showing that PTEN is targeted for LOH in melanoma, and that both ectopic expression and overexpression of PTEN suppress tumor growth.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('PTEN', 'Gene', (124, 128))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanoma', 'Disease', (48, 56))	('pathogenesis', 'biological_process', 'GO:0009405', ('57', '69'))	('tumor', 'Disease', (231, 236))	('LOH', 'NegReg', (145, 148))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('28', '44'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('PTEN', 'Gene', (217, 221))	('ectopic expression', 'Var', (176, 194))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('suppress', 'NegReg', (222, 230))	('overexpression', 'PosReg', (199, 213))	('tumor suppressor', 'biological_process', 'GO:0051726', ('28', '44'))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))
110937	22723080	In addition to mutational inactivation or deletion of the PTEN gene, loss of PTEN activity can occur through epigenetic silencing, potentially by hypermethylation of the PTEN promoter, a feature that has recently been reported as having an independent unfavorable impact on patient survival.	('patient', 'Species', '9606', (274, 281))	('loss', 'NegReg', (69, 73))	('epigenetic', 'MPA', (109, 119))	('hypermethylation', 'Var', (146, 162))	('PTEN', 'Gene', (77, 81))	('activity', 'MPA', (82, 90))	('deletion', 'Var', (42, 50))	('PTEN activity', 'molecular_function', 'GO:0051800', ('77', '90'))	('PTEN', 'Gene', (58, 62))
110938	22723080	Loss of PTEN function through mutation or deletion has been seen in up to 60 % of melanoma cell lines but 10 % of uncultured tumor material.	('function', 'MPA', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('mutation', 'Var', (30, 38))	('PTEN', 'Gene', (8, 12))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('Loss', 'NegReg', (0, 4))	('tumor', 'Disease', (125, 130))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('deletion', 'Var', (42, 50))
110939	22723080	With reports suggesting that epigenetic silencing may occur in up to 30 %-40 % of metastatic tumors, loss of PTEN function could be an important event in 40 %-50 % of sporadic melanomas.	('melanomas', 'Disease', 'MESH:D008545', (176, 185))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('loss', 'NegReg', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', (93, 99))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('PTEN', 'Gene', (109, 113))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('melanomas', 'Disease', (176, 185))	('epigenetic silencing', 'Var', (29, 49))	('occur', 'Reg', (54, 59))	('melanomas', 'Phenotype', 'HP:0002861', (176, 185))
110941	22723080	While NRAS mutation alone is sufficient for downstream activation of the PI3K pathway, somatic mutations of PTEN often occur in association with BRAF, a finding possibly explained by preclinical murine models in which inactivation of PTEN in the presence of mutant BRAF leads to spontaneous development of metastatic melanoma.	('mutant', 'Var', (258, 264))	('melanoma', 'Disease', 'MESH:D008545', (317, 325))	('PI3K pathway', 'Pathway', (73, 85))	('PTEN', 'Gene', (108, 112))	('PI3K', 'molecular_function', 'GO:0016303', ('73', '77'))	('murine', 'Species', '10090', (195, 201))	('mutations', 'Var', (95, 104))	('mutation', 'Var', (11, 19))	('leads to', 'Reg', (270, 278))	('inactivation', 'Var', (218, 230))	('melanoma', 'Phenotype', 'HP:0002861', (317, 325))	('melanoma', 'Disease', (317, 325))	('BRAF', 'Gene', (265, 269))
110943	22723080	Co-targeting of these two pathways is an area of active research, and predictive biomarkers, including but not limited to BRAF mutations and PTEN deletions will likely facilitate future patient selection.	('PTEN', 'Gene', (141, 145))	('BRAF', 'Gene', (122, 126))	('deletions', 'Var', (146, 155))	('mutations', 'Var', (127, 136))	('patient', 'Species', '9606', (186, 193))
110944	22723080	Cyclin-dependent kinase 2a (CDKN2A, also called MTS1 or p16INK4A), located on chromosome 9p21, is mutated in a variety of cancers, including a small percentage of familial melanoma.	('MTS1', 'Gene', '1029', (48, 52))	('p16INK4A', 'Gene', '1029', (56, 64))	('chromosome', 'cellular_component', 'GO:0005694', ('78', '88'))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('familial melanoma', 'Disease', (163, 180))	('CDKN2A', 'Gene', (28, 34))	('familial melanoma', 'Disease', 'OMIM:155600', (163, 180))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancers', 'Disease', (122, 129))	('Cyclin', 'molecular_function', 'GO:0016538', ('0', '6'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('mutated', 'Var', (98, 105))	('CDKN2A', 'Gene', '1029', (28, 34))	('p16INK4A', 'Gene', (56, 64))	('MTS1', 'Gene', (48, 52))
110945	22723080	Unlike the somatic mutations described in the rest of this review, p16 mutations are hereditary (germline) mutations.	('mutations', 'Var', (71, 80))	('p16', 'Gene', '1029', (67, 70))	('p16', 'Gene', (67, 70))
110947	22723080	When mutated, the ability of p16 to interact with cyclin-dependent kinase 4 (CDK4) in regulatory arrest of the cell cycle is disrupted, allowing unchecked progression through the cell cycle.	('p16', 'Gene', (29, 32))	('regulatory arrest of the cell cycle', 'MPA', (86, 121))	('cell cycle', 'biological_process', 'GO:0007049', ('111', '121'))	('cyclin-dependent kinase 4', 'Gene', '1019', (50, 75))	('CDK4', 'Gene', (77, 81))	('interact', 'Interaction', (36, 44))	('p16', 'Gene', '1029', (29, 32))	('cyclin-dependent kinase 4', 'Gene', (50, 75))	('CDK4', 'Gene', '1019', (77, 81))	('cell cycle', 'biological_process', 'GO:0007049', ('179', '189'))	('allowing', 'Reg', (136, 144))	('mutated', 'Var', (5, 12))	('ability', 'MPA', (18, 25))	('cyclin', 'molecular_function', 'GO:0016538', ('50', '56'))	('disrupted', 'NegReg', (125, 134))	('CDK', 'molecular_function', 'GO:0004693', ('77', '80'))
110948	22723080	Germline CDK4 mutations have also been described in a smaller percentage of familial melanoma kindreds.	('CDK4', 'Gene', (9, 13))	('familial melanoma', 'Disease', (76, 93))	('CDK4', 'Gene', '1019', (9, 13))	('familial melanoma', 'Disease', 'OMIM:155600', (76, 93))	('CDK', 'molecular_function', 'GO:0004693', ('9', '12'))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('mutations', 'Var', (14, 23))
110951	22723080	Therapeutic targeting of these mutations may be possible with the development of newer, selective CDK4 inhibitors.	('CDK4', 'Gene', (98, 102))	('mutations', 'Var', (31, 40))	('CDK', 'molecular_function', 'GO:0004693', ('98', '101'))	('CDK4', 'Gene', '1019', (98, 102))
110955	22723080	Two recently published studies showed that germline mutations of MITF can confer a familial melanoma risk, further supporting a role for MITF in this disease.	('familial melanoma', 'Disease', (83, 100))	('germline mutations', 'Var', (43, 61))	('familial melanoma', 'Disease', 'OMIM:155600', (83, 100))	('MITF', 'Gene', '4286', (137, 141))	('MITF', 'Gene', (137, 141))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('MITF', 'Gene', '4286', (65, 69))	('MITF', 'Gene', (65, 69))
110956	22723080	Rare mutations in AKT1 and AKT3 have been found in melanoma samples; the functional importance of these mutations has not yet been determined.	('AKT3', 'Gene', '10000', (27, 31))	('AKT1', 'Gene', '207', (18, 22))	('mutations', 'Var', (5, 14))	('AKT1', 'Gene', (18, 22))	('found', 'Reg', (42, 47))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('AKT3', 'Gene', (27, 31))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
110957	22723080	High throughput sequencing technologies are leading to identification of novel driver mutations in melanoma.	('mutations', 'Var', (86, 95))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))
110958	22723080	Most of the studies to date have been conducted on small cohorts of melanomas; however, as the cost of sequencing declines, we are likely to identify new driver mutations in subsets of melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanomas', 'Disease', (68, 77))	('melanomas', 'Disease', (185, 194))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('mutations', 'Var', (161, 170))	('melanomas', 'Phenotype', 'HP:0002861', (185, 194))	('melanomas', 'Phenotype', 'HP:0002861', (68, 77))	('melanomas', 'Disease', 'MESH:D008545', (185, 194))	('melanomas', 'Disease', 'MESH:D008545', (68, 77))
110959	22723080	showed that 8 % of melanomas harbor mutations in MAP2K1 (MEK1) and MAP2K2 (MEK2), which lead to constitutive ERK activation.	('MAP2K', 'molecular_function', 'GO:0004708', ('67', '72'))	('MAP2K1', 'Gene', (49, 55))	('MAP2K2', 'Gene', '5605', (67, 73))	('melanomas', 'Disease', 'MESH:D008545', (19, 28))	('MEK1', 'Gene', (57, 61))	('melanomas', 'Disease', (19, 28))	('activation', 'PosReg', (113, 123))	('MEK1', 'Gene', '5604', (57, 61))	('MEK1', 'molecular_function', 'GO:0004708', ('57', '61'))	('ERK', 'Pathway', (109, 112))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('MEK2', 'molecular_function', 'GO:0004708', ('75', '79'))	('MAP2K2', 'Gene', (67, 73))	('ERK', 'molecular_function', 'GO:0004707', ('109', '112'))	('MAP2K', 'molecular_function', 'GO:0004708', ('49', '54'))	('MEK2', 'Gene', (75, 79))	('MEK2', 'Gene', '5605', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('mutations', 'Var', (36, 45))	('MAP2K1', 'Gene', '5604', (49, 55))
110960	22723080	showing that inactivating mutations in MAP3K5 and MAP3K9 in a small percentage of melanomas are similarly important for maintaining the malignant phenotype.	('inactivating mutations', 'Var', (13, 35))	('melanomas', 'Disease', (82, 91))	('MAP3K5', 'Gene', '4217', (39, 45))	('MAP3K9', 'Gene', (50, 56))	('MAP3K5', 'Gene', (39, 45))	('MAP3K', 'molecular_function', 'GO:0004709', ('50', '55'))	('melanomas', 'Disease', 'MESH:D008545', (82, 91))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('MAP3K', 'molecular_function', 'GO:0004709', ('39', '44'))	('MAP3K9', 'Gene', '4293', (50, 56))
110961	22723080	A study of 14 melanoma samples and matched normal DNA subjected to exome sequencing showed that GRIN2A, the gene that encodes a part of the ionotropic glutamate receptor, was mutated in some.	('melanoma', 'Disease', (14, 22))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('GRIN2A', 'Gene', '2903', (96, 102))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('mutated', 'Var', (175, 182))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('GRIN2A', 'Gene', (96, 102))
110963	22723080	This effort also identified mutations in TRRAP, a co-activator of several transcription factors including Mdm-2, MYC, and E2F.	('transcription', 'biological_process', 'GO:0006351', ('74', '87'))	('Mdm-2', 'Gene', '4193', (106, 111))	('Mdm-2', 'Gene', (106, 111))	('TRRAP', 'Gene', '8295', (41, 46))	('TRRAP', 'Gene', (41, 46))	('mutations', 'Var', (28, 37))
110966	22723080	By subjecting murine uveal melanoma models to genetic screening, Van Raamsdonk et al identified two q-class G-protein alpha subunits that are mutated in intradermal (but not epidermal) melanocytes, GNAQ and GNA11.	('uveal melanoma', 'Disease', (21, 35))	('murine', 'Species', '10090', (14, 20))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('mutated', 'Var', (142, 149))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('G-protein alpha subunits', 'Protein', (108, 132))	('uveal melanoma', 'Disease', 'MESH:C536494', (21, 35))	('uveal melanoma', 'Phenotype', 'HP:0007716', (21, 35))
110967	22723080	These studies were complemented with analysis of a cohort of 48 paraffin embedded uveal melanoma samples sequenced for mutations in GNAQ and GNA11, which showed that the former was mutated in 46 % of uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (200, 215))	('uveal melanomas', 'Disease', (200, 215))	('GNA11', 'Gene', (141, 146))	('uveal melanoma', 'Disease', 'MESH:C536494', (200, 214))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('uveal melanoma', 'Phenotype', 'HP:0007716', (200, 214))	('uveal melanoma', 'Disease', 'MESH:C536494', (82, 96))	('uveal melanomas', 'Phenotype', 'HP:0007716', (200, 215))	('paraffin', 'Chemical', 'MESH:D010232', (64, 72))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('uveal melanoma', 'Disease', (82, 96))	('mutations', 'Var', (119, 128))	('GNAQ', 'Gene', (132, 136))	('mutated', 'Var', (181, 188))	('melanomas', 'Phenotype', 'HP:0002861', (206, 215))
110968	22723080	No GNA11 mutations were found in this set of tumors, yet additional studies conducted by Van Raamsdonk et al.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('mutations', 'Var', (9, 18))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('GNA11', 'Gene', (3, 8))
110969	22723080	The majority of the mutations were in codon Q209 of exon 5; 45 % of primary and 22 % of metastatic uveal melanomas harbored a Q209 mutation in GNAQ, whereas 32 % of primary and 57 % of metastatic specimens harbored Q209 mutations in GNA11.	('uveal melanomas', 'Disease', (99, 114))	('uveal melanomas', 'Phenotype', 'HP:0007716', (99, 114))	('GNAQ', 'Gene', (143, 147))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('uveal melanomas', 'Disease', 'MESH:C536494', (99, 114))	('melanomas', 'Phenotype', 'HP:0002861', (105, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('Q209', 'Var', (126, 130))	('GNA11', 'Gene', (233, 238))	('Q209', 'Var', (215, 219))
110970	22723080	Forced expression of mutated GNA11 resulted in metastases in uveal melanoma mouse models.	('GNA11', 'Gene', (29, 34))	('metastases', 'Disease', 'MESH:D009362', (47, 57))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('mouse', 'Species', '10090', (76, 81))	('metastases', 'Disease', (47, 57))	('uveal melanoma', 'Disease', 'MESH:C536494', (61, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('uveal melanoma', 'Disease', (61, 75))	('resulted in', 'Reg', (35, 46))	('mutated', 'Var', (21, 28))
110971	22723080	Stable transfection of GNAQQ209L into normal melanocytes resulted in increased anchorage-independent growth with efficiency similar to that of transfection with NRASQ61R, and tumorigenicity in mice was similarly demonstrated with GNAQQ209L transfection, resulting in activation of the MAPK pathway.	('MAPK pathway', 'Pathway', (285, 297))	('tumor', 'Disease', (175, 180))	('increased', 'PosReg', (69, 78))	('activation', 'PosReg', (267, 277))	('GNAQQ209L', 'Var', (23, 32))	('GNAQQ209L', 'Var', (230, 239))	('mice', 'Species', '10090', (193, 197))	('anchorage-independent growth', 'CPA', (79, 107))	('MAPK', 'molecular_function', 'GO:0004707', ('285', '289'))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
110972	22723080	Preclinical studies have shown that uveal melanoma cell lines harboring GNAQ or GNA11 mutations are more resistant to MAPK pathway inhibitors than WT cell lines.	('mutations', 'Var', (86, 95))	('MAPK pathway', 'Pathway', (118, 130))	('MAPK', 'molecular_function', 'GO:0004707', ('118', '122'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (36, 50))	('uveal melanoma', 'Disease', 'MESH:C536494', (36, 50))	('uveal melanoma', 'Disease', (36, 50))	('resistant', 'MPA', (105, 114))	('GNA11', 'Gene', (80, 85))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('GNAQ', 'Gene', (72, 76))
110973	22723080	High throughput sequencing of uveal melanomas led to identification of mutations in BAP1 (BRCA1 associated protein 1) in uveal melanomas with high metastatic potential.	('uveal melanomas', 'Disease', (30, 45))	('uveal melanomas', 'Phenotype', 'HP:0007716', (30, 45))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('uveal melanoma', 'Phenotype', 'HP:0007716', (121, 135))	('BAP1', 'Gene', '8314', (84, 88))	('uveal melanomas', 'Disease', (121, 136))	('mutations', 'Var', (71, 80))	('uveal melanomas', 'Disease', 'MESH:C536494', (30, 45))	('uveal melanomas', 'Phenotype', 'HP:0007716', (121, 136))	('BRCA1 associated protein 1', 'Gene', '8314', (90, 116))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('BAP1', 'Gene', (84, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('uveal melanomas', 'Disease', 'MESH:C536494', (121, 136))	('BRCA1 associated protein 1', 'Gene', (90, 116))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
110975	22723080	Mutations leading to loss of protein expression were found in 84 % of the poor prognosis tumors and only 4 % of the good prognosis tumors.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', (131, 137))	('protein', 'Protein', (29, 36))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('loss', 'NegReg', (21, 25))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))
110976	22723080	One patient was found to have a germline mutation in BAP1, indicating that in rare cases, this might be a tumor susceptibility gene.	('germline mutation', 'Var', (32, 49))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('BAP1', 'Gene', '8314', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))	('BAP1', 'Gene', (53, 57))
110981	22723080	As the field moves forward toward unraveling mechanisms of vemurafenib resistance for patients with BRAF mutant melanoma, additional advances are anticipated in the development of therapies for molecularly selected patients within other melanoma subsets.	('melanoma', 'Disease', (237, 245))	('patients', 'Species', '9606', (215, 223))	('melanoma', 'Disease', 'MESH:D008545', (237, 245))	('vemurafenib', 'Chemical', 'MESH:D000077484', (59, 70))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('BRAF', 'Gene', (100, 104))	('mutant', 'Var', (105, 111))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('patients', 'Species', '9606', (86, 94))
110982	22723080	The discovery of additional somatic driver mutations in human melanomas, as well as strategies for inhibiting their activity and those of the emerging mutations discussed in this review, will require continued collaboration between basic and clinical scientists.	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('melanomas', 'Disease', (62, 71))	('human', 'Species', '9606', (56, 61))	('mutations', 'Var', (43, 52))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('melanomas', 'Disease', 'MESH:D008545', (62, 71))
110995	24597767	Several clinical and histopathological features have been correlated with survival, including patient age (>60), anterior location of the tumor, tumor cell histology, largest diameter of the tumor, mitotic activity, and chromosome 3 monosomy.	('chromosome', 'cellular_component', 'GO:0005694', ('220', '230'))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('mitotic activity', 'CPA', (198, 214))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('patient', 'Species', '9606', (94, 101))	('chromosome', 'Var', (220, 230))	('correlated', 'Reg', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
110996	24597767	The most frequent chromosomal imbalances in uveal melanoma are loss of chromosome 3 and gains of 8q and 6p .	('imbalances', 'Phenotype', 'HP:0002172', (30, 40))	('loss', 'Var', (63, 67))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('chromosome', 'cellular_component', 'GO:0005694', ('71', '81'))	('gains', 'Var', (88, 93))	('uveal melanoma', 'Disease', (44, 58))
111016	24597767	Though the tumor location, extrascleral extension, tumor cell type and chromosome 3 data were incomplete, the first two appeared no differences while the mixed subtype tumor and chromosome 3 monosomy showed positive correlation with liver metastases of uveal melanoma (Table  1).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', (11, 16))	('melanoma', 'Phenotype', 'HP:0002861', (259, 267))	('tumor', 'Disease', (51, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (253, 267))	('liver metastases of uveal melanoma', 'Disease', (233, 267))	('liver metastases of uveal melanoma', 'Disease', 'MESH:D009362', (233, 267))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('chromosome', 'cellular_component', 'GO:0005694', ('71', '81'))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('chromosome', 'cellular_component', 'GO:0005694', ('178', '188'))	('monosomy', 'Var', (191, 199))
111046	24597767	had reported gap junction may affect cancer metastases since connections are made between the primary tumor cells and foreign host cells at the secondary metastatic site .	('connections', 'Interaction', (61, 72))	('gap junction', 'cellular_component', 'GO:0005921', ('13', '25'))	('gap junction', 'Var', (13, 25))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer metastases', 'Disease', 'MESH:D009362', (37, 54))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('affect', 'Reg', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('cancer metastases', 'Disease', (37, 54))
111055	24597767	These genes encode proteins involved in different GOs and signal pathways, the disruption of which can promote cancer metastases.	('cancer metastases', 'Disease', 'MESH:D009362', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('disruption', 'Var', (79, 89))	('cancer metastases', 'Disease', (111, 128))	('promote', 'PosReg', (103, 110))
111109	24514165	Interestingly, considering the positivity rate calculated on the basis of tumor stage classification, it is evident that ISET could detect a higher rate of CTC positivity in T1 and T2 stages in comparison to Ulmer and coworkers' results corresponding to an overall lower frequency of CTC detection (see Table 1).	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('CTC', 'Gene', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('positivity', 'Var', (160, 170))
111139	24077773	A high percentage of uveal melanomas express mRNA and protein for type-I LHRH receptors.	('express', 'Reg', (37, 44))	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('uveal melanomas', 'Disease', (21, 36))	('uveal melanomas', 'Phenotype', 'HP:0007716', (21, 36))	('mRNA', 'Var', (45, 49))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('uveal melanomas', 'Disease', 'MESH:C536494', (21, 36))	('type-I LHRH receptors', 'Protein', (66, 87))	('uveal melanoma', 'Phenotype', 'HP:0007716', (21, 35))
111194	24077773	The high incidence of positivity for type I LHRH receptor in uveal melanoma suggests that this tumor type might be a good candidate for therapy with LHRH analogs including the targeted cytotoxic peptide, AN-152 (AEZS-108).	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('uveal melanoma', 'Disease', 'MESH:C536494', (61, 75))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('uveal melanoma', 'Disease', (61, 75))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('positivity', 'Var', (22, 32))	('tumor', 'Disease', (95, 100))
111236	22048237	Among patients with BRAF mutations, objective responses were similar between selumetinib and temozolomide groups (11.1% and 10.7%, respectively).	('mutations', 'Var', (25, 34))	('temozolomide', 'Chemical', 'MESH:D000077204', (93, 105))	('BRAF', 'Gene', '673', (20, 24))	('patients', 'Species', '9606', (6, 14))	('selumetinib', 'Chemical', 'MESH:C517975', (77, 88))	('BRAF', 'Gene', (20, 24))
111239	22048237	No significant difference in progression-free survival was observed between patients with unresectable stage III/IV melanoma unselected for BRAF/NRAS mutations, who received therapy with selumetinib or temozolomide.	('IV melanoma', 'Disease', (113, 124))	('NRAS', 'Gene', (145, 149))	('patients', 'Species', '9606', (76, 84))	('temozolomide', 'Chemical', 'MESH:D000077204', (202, 214))	('selumetinib', 'Chemical', 'MESH:C517975', (187, 198))	('BRAF', 'Gene', '673', (140, 144))	('IV melanoma', 'Disease', 'MESH:D008545', (113, 124))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('NRAS', 'Gene', '4893', (145, 149))	('BRAF', 'Gene', (140, 144))	('mutations', 'Var', (150, 159))
111242	22048237	Mutations affecting signaling molecules, including Ras and Raf, activate this pathway and contribute to malignant progression in many human cancers.	('contribute to', 'Reg', (90, 103))	('human', 'Species', '9606', (134, 139))	('Raf', 'Gene', '22882', (59, 62))	('Ras', 'Gene', (51, 54))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('Raf', 'Gene', (59, 62))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('malignant progression', 'CPA', (104, 125))	('activate', 'PosReg', (64, 72))
111243	22048237	BRAF and NRAS mutations are generally mutually exclusive in melanoma.	('NRAS', 'Gene', (9, 13))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('NRAS', 'Gene', '4893', (9, 13))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))
111245	22048237	However, recent estimates suggest that the frequency for BRAF mutations may be as low as 41%.	('mutations', 'Var', (62, 71))	('BRAF', 'Gene', (57, 61))	('BRAF', 'Gene', '673', (57, 61))
111246	22048237	Agents targeting mutated BRAF are in development; however, they may be associated with paradoxical activation of the mitogen-activated protein (MAP) kinase pathway in BRAF wild-type cells.	('MAP', 'molecular_function', 'GO:0004239', ('144', '147'))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('activation', 'PosReg', (99, 109))	('BRAF', 'Gene', '673', (25, 29))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('BRAF', 'Gene', (25, 29))	('mutated', 'Var', (17, 24))
111254	22048237	It is the first multicenter randomized study conducted in patients with melanoma assessed for both BRAF and NRAS mutations.	('NRAS', 'Gene', (108, 112))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('NRAS', 'Gene', '4893', (108, 112))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('mutations', 'Var', (113, 122))	('patients', 'Species', '9606', (58, 66))
111275	22048237	Exploratory analyses included assessment of the treatment effect in the following subgroups; disease stage (stage III vs. stage IV), uveal melanoma versus non-uveal, mucosal melanoma versus non-mucosal, and BRAF and NRAS mutation status.	('BRAF', 'Gene', (207, 211))	('BRAF', 'Gene', '673', (207, 211))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('mutation status', 'Var', (221, 236))	('NRAS', 'Gene', (216, 220))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('NRAS', 'Gene', '4893', (216, 220))	('uveal melanoma', 'Phenotype', 'HP:0007716', (133, 147))	('uveal melanoma versus non-uveal, mucosal melanoma versus non-mucosal', 'Disease', 'MESH:C536494', (133, 201))
111277	22048237	The methods used for mutation detection including sequences of primers and probes for detection of BRAF and NRAS mutations have been previously described.	('NRAS', 'Gene', (108, 112))	('NRAS', 'Gene', '4893', (108, 112))	('BRAF', 'Gene', '673', (99, 103))	('BRAF', 'Gene', (99, 103))	('mutations', 'Var', (113, 122))
111278	22048237	The allele-specific PCR detects BRAF V600E as well as V600K and V600D (1799T>A) and the allele-specific PCR for NRAS detects NRAS Q61K mutation (C181A) and the Q61R mutation (A182G).	('NRAS', 'Gene', (125, 129))	('BRAF', 'Gene', '673', (32, 36))	('Q61R', 'Mutation', 'rs11554290', (160, 164))	('V600D', 'Mutation', 'rs121913377', (64, 69))	('BRAF', 'Gene', (32, 36))	('NRAS', 'Gene', '4893', (125, 129))	('Q61K', 'Mutation', 'rs121913254', (130, 134))	('A182G', 'Mutation', 'rs11554290', (175, 180))	('V600E', 'Mutation', 'rs113488022', (37, 42))	('1799T>A', 'Mutation', 'rs113488022', (71, 78))	('NRAS', 'Gene', (112, 116))	('V600K', 'Var', (54, 59))	('C181A', 'Mutation', 'rs121913254', (145, 150))	('NRAS', 'Gene', '4893', (112, 116))	('V600K', 'Mutation', 'rs121913227', (54, 59))	('A182G', 'Var', (175, 180))	('V600D (1799T>A', 'Var', (64, 78))
111283	22048237	A sample size of 182 patients (91 per arm) was required to provide adequate power for comparison of PFS between the two treatment groups both in the overall population and in the BRAF mutant subpopulation.	('patients', 'Species', '9606', (21, 29))	('mutant', 'Var', (184, 190))	('BRAF', 'Gene', (179, 183))	('BRAF', 'Gene', '673', (179, 183))
111286	22048237	The target PFS HR in the BRAF mutant subgroup was 0.67 (and was to be tested as a secondary endpoint at the one-sided significance level of 20%).	('BRAF', 'Gene', (25, 29))	('BRAF', 'Gene', '673', (25, 29))	('mutant', 'Var', (30, 36))
111287	22048237	This assumed that the BRAF wild-type subpopulation contained NRAS mutant patients (~30%), who might derive clinical benefit.	('mutant', 'Var', (66, 72))	('BRAF', 'Gene', '673', (22, 26))	('BRAF', 'Gene', (22, 26))	('NRAS', 'Gene', (61, 65))	('patients', 'Species', '9606', (73, 81))	('NRAS', 'Gene', '4893', (61, 65))
111289	22048237	PFS and TTD were analyzed using a Cox proportional hazards model allowing for the effect of treatment and fitting for the following baseline covariates: BRAF mutation status (positive vs. negative vs. unknown), WHO performance status (0 vs. 1 or 2), tumor type [non-uveal (cutaneous, mucosal, unknown) vs. uveal], and level of lactate dehydrogenase (<2 x ULN vs. >=2 x ULN) at baseline.	('level of lactate dehydrogenase', 'MPA', (318, 348))	('BRAF', 'Gene', (153, 157))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('mutation', 'Var', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Disease', (250, 255))	('BRAF', 'Gene', '673', (153, 157))
111299	22048237	BRAF mutant tumors were identified in 73 of 158 patients (46.2%; V600E, 66; V600K, 5; K601E, 1; K581S, 1); 28 of 158 patients' tumors (17.7%) were NRAS mutated (Q61K, 15; Q61R, 12; G13R, 1).	('K601E', 'Mutation', 'rs121913364', (86, 91))	('G13R', 'Var', (181, 185))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('G13R', 'Mutation', 'rs121434595', (181, 185))	('Q61K', 'Var', (161, 165))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('patients', 'Species', '9606', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('V600K', 'Mutation', 'rs121913227', (76, 81))	('Q61K', 'Mutation', 'rs121913254', (161, 165))	('V600E', 'Mutation', 'rs113488022', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('NRAS', 'Gene', '4893', (147, 151))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('V600E', 'Var', (65, 70))	('K581S', 'Mutation', 'p.K581S', (96, 101))	('V600K', 'Var', (76, 81))	('Q61R', 'Var', (171, 175))	('NRAS', 'Gene', (147, 151))	('Q61R', 'Mutation', 'rs11554290', (171, 175))	('patients', 'Species', '9606', (48, 56))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
111300	22048237	No tumors were both BRAF and NRAS mutated; therefore, 101 of 158 patients' tumors (63.9%) were either BRAF mutant or NRAS mutant.	('NRAS', 'Gene', (117, 121))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('mutant', 'Var', (107, 113))	('BRAF', 'Gene', '673', (102, 106))	('tumors', 'Disease', (3, 9))	('NRAS', 'Gene', '4893', (117, 121))	('NRAS', 'Gene', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('BRAF', 'Gene', (102, 106))	('BRAF', 'Gene', '673', (20, 24))	('NRAS', 'Gene', '4893', (29, 33))	('patients', 'Species', '9606', (65, 73))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('BRAF', 'Gene', (20, 24))	('tumors', 'Disease', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
111304	22048237	In addition, more patients were BRAF mutant in the selumetinib group (43.3%) than in the temozolomide group (29.2%), and more patients in the selumetinib group had WHO performance status 1 or 2 than those receiving temozolomide (33.7% and 26.1%, respectively).	('BRAF', 'Gene', '673', (32, 36))	('temozolomide', 'Chemical', 'MESH:D000077204', (89, 101))	('selumetinib', 'Chemical', 'MESH:C517975', (51, 62))	('BRAF', 'Gene', (32, 36))	('selumetinib', 'Chemical', 'MESH:C517975', (142, 153))	('mutant', 'Var', (37, 43))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (18, 26))	('temozolomide', 'Chemical', 'MESH:D000077204', (215, 227))
111305	22048237	In the BRAF and NRAS mutant subpopulation, more patients had WHO performance status 1 or 2 in the selumetinib group (38.2%) than in the temozolomide group (23.9%).	('temozolomide', 'Chemical', 'MESH:D000077204', (136, 148))	('mutant', 'Var', (21, 27))	('NRAS', 'Gene', (16, 20))	('patients', 'Species', '9606', (48, 56))	('BRAF', 'Gene', '673', (7, 11))	('NRAS', 'Gene', '4893', (16, 20))	('selumetinib', 'Chemical', 'MESH:C517975', (98, 109))	('BRAF', 'Gene', (7, 11))
111306	22048237	Furthermore, more BRAF or NRAS mutant patients in the selumetinib group (12.7%) had lactate dehydrogenase levels >=2 x ULN than those in the temozolomide group (8.7%).	('mutant', 'Var', (31, 37))	('temozolomide', 'Chemical', 'MESH:D000077204', (141, 153))	('lactate dehydrogenase levels >', 'MPA', (84, 114))	('NRAS', 'Gene', (26, 30))	('selumetinib', 'Chemical', 'MESH:C517975', (54, 65))	('BRAF', 'Gene', '673', (18, 22))	('patients', 'Species', '9606', (38, 46))	('NRAS', 'Gene', '4893', (26, 30))	('BRAF', 'Gene', (18, 22))
111307	22048237	Twenty (10%) patients in the study had uveal melanoma, with 15 evaluable for BRAF/NRAS mutations; no mutations in BRAF or NRAS were detected.	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('BRAF', 'Gene', '673', (77, 81))	('uveal melanoma', 'Disease', 'MESH:C536494', (39, 53))	('patients', 'Species', '9606', (13, 21))	('had', 'Reg', (35, 38))	('BRAF', 'Gene', (77, 81))	('uveal melanoma', 'Disease', (39, 53))	('uveal melanoma', 'Phenotype', 'HP:0007716', (39, 53))	('NRAS', 'Gene', (82, 86))	('NRAS', 'Gene', (122, 126))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('NRAS', 'Gene', '4893', (82, 86))	('NRAS', 'Gene', '4893', (122, 126))	('mutations', 'Var', (87, 96))
111323	22048237	There were no significant differences in PFS between the two treatment groups in the BRAF mutant (Fig.	('BRAF', 'Gene', '673', (85, 89))	('mutant', 'Var', (90, 96))	('BRAF', 'Gene', (85, 89))
111324	22048237	2C) and BRAF or NRAS mutant subsets (not shown).	('BRAF', 'Gene', '673', (8, 12))	('mutant', 'Var', (21, 27))	('BRAF', 'Gene', (8, 12))	('NRAS', 'Gene', (16, 20))	('NRAS', 'Gene', '4893', (16, 20))
111325	22048237	Among patients with BRAF mutation, objective tumor response was observed in 11.1% (5 of 45) of patients receiving selumetinib and 10.7% (3 of 28) of the temozolomide group.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('patients', 'Species', '9606', (95, 103))	('selumetinib', 'Chemical', 'MESH:C517975', (114, 125))	('tumor', 'Disease', (45, 50))	('mutation', 'Var', (25, 33))	('temozolomide', 'Chemical', 'MESH:D000077204', (153, 165))	('BRAF', 'Gene', '673', (20, 24))	('patients', 'Species', '9606', (6, 14))	('BRAF', 'Gene', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
111326	22048237	Similarly, in the patient subpopulation with BRAF or NRAS mutations, the objective tumor responses were 9.1% (5 of 55) and 8.7% (4 of 46) in the selumetinib and temozolomide groups, respectively (Table 3).	('mutations', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('selumetinib', 'Chemical', 'MESH:C517975', (145, 156))	('temozolomide', 'Chemical', 'MESH:D000077204', (161, 173))	('tumor', 'Disease', (83, 88))	('NRAS', 'Gene', (53, 57))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('patient', 'Species', '9606', (18, 25))	('NRAS', 'Gene', '4893', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
111327	22048237	Of the 6 selumetinib responders, 5 were BRAF mutant compared with 3 of the 9 temozolomide responders.	('BRAF', 'Gene', '673', (40, 44))	('mutant', 'Var', (45, 51))	('temozolomide', 'Chemical', 'MESH:D000077204', (77, 89))	('BRAF', 'Gene', (40, 44))	('selumetinib', 'Chemical', 'MESH:C517975', (9, 20))
111328	22048237	As with the overall population, BRAF mutant patients randomized to temozolomide had improved TTD compared with those randomized to selumetinib (Fig.	('temozolomide', 'Chemical', 'MESH:D000077204', (67, 79))	('BRAF', 'Gene', '673', (32, 36))	('patients', 'Species', '9606', (44, 52))	('BRAF', 'Gene', (32, 36))	('TTD', 'CPA', (93, 96))	('mutant', 'Var', (37, 43))	('selumetinib', 'Chemical', 'MESH:C517975', (131, 142))	('improved', 'PosReg', (84, 92))
111354	22048237	No significant difference was seen in the primary endpoint of PFS between the 2 treatment arms for either the overall population or the subpopulations of patients with BRAF or BRAF/NRAS mutant tumors.	('mutant', 'Var', (186, 192))	('patients', 'Species', '9606', (154, 162))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('BRAF', 'Gene', '673', (168, 172))	('NRAS', 'Gene', (181, 185))	('BRAF', 'Gene', '673', (176, 180))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('BRAF', 'Gene', (168, 172))	('NRAS', 'Gene', '4893', (181, 185))	('BRAF', 'Gene', (176, 180))
111358	22048237	Cell lines expressing BRAF or RAS mutations (including melanoma cell lines) have increased sensitivity to selumetinib.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('selumetinib', 'Chemical', 'MESH:C517975', (106, 117))	('BRAF', 'Gene', '673', (22, 26))	('BRAF', 'Gene', (22, 26))	('RAS', 'Gene', (30, 33))	('increased', 'PosReg', (81, 90))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('mutations', 'Var', (34, 43))	('melanoma', 'Disease', (55, 63))	('sensitivity', 'MPA', (91, 102))
111362	22048237	The observed BRAF mutation rate of 46.2% is lower than had been expected when planning this study but similar to recent reports.	('BRAF', 'Gene', '673', (13, 17))	('mutation', 'Var', (18, 26))	('BRAF', 'Gene', (13, 17))
111364	22048237	This finding raises the possibility that BRAF mutation may be an important, but not exclusive, requirement for response to selumetinib.	('selumetinib', 'Chemical', 'MESH:C517975', (123, 134))	('mutation', 'Var', (46, 54))	('BRAF', 'Gene', (41, 45))	('BRAF', 'Gene', '673', (41, 45))
111365	22048237	Data from other compounds in development have shown that patients with BRAF mutant tumors can show a high response rate to MEK or BRAF inhibition.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('MEK', 'Gene', (123, 126))	('MEK', 'Gene', '5609', (123, 126))	('BRAF', 'Gene', '673', (71, 75))	('BRAF', 'Gene', '673', (130, 134))	('patients', 'Species', '9606', (57, 65))	('mutant', 'Var', (76, 82))	('tumors', 'Disease', (83, 89))	('BRAF', 'Gene', (71, 75))	('BRAF', 'Gene', (130, 134))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
111366	22048237	For example, a phase I trial of the MEK inhibitor GSK112012 showed disease control in 8 of 11 patients with BRAF mutant melanoma.	('GSK', 'molecular_function', 'GO:0050321', ('50', '53'))	('patients', 'Species', '9606', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('MEK', 'Gene', '5609', (36, 39))	('melanoma', 'Disease', (120, 128))	('MEK', 'Gene', (36, 39))	('BRAF', 'Gene', '673', (108, 112))	('disease control', 'CPA', (67, 82))	('GSK112012', 'Chemical', '-', (50, 59))	('mutant', 'Var', (113, 119))	('BRAF', 'Gene', (108, 112))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))
111371	22048237	Preliminary clinical results from a phase I trial of selumetinib in combination with dacarbazine, docetaxel, or temsirolimus have shown objective response in 5 of 9 patients with BRAF mutation-positive tumors.	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('dacarbazine', 'Chemical', 'MESH:D003606', (85, 96))	('tumors', 'Disease', (202, 208))	('BRAF', 'Gene', '673', (179, 183))	('docetaxel', 'Chemical', 'MESH:D000077143', (98, 107))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('selumetinib', 'Chemical', 'MESH:C517975', (53, 64))	('BRAF', 'Gene', (179, 183))	('patients', 'Species', '9606', (165, 173))	('temsirolimus', 'Chemical', 'MESH:C401859', (112, 124))	('mutation-positive', 'Var', (184, 201))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
111372	22048237	Selumetinib is currently beinginvestigated for advanced melanoma in combination with dacarbazine for patients with prospectively determined BRAF mutant tumors (NCT00936221).	('patients', 'Species', '9606', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('melanoma', 'Disease', (56, 64))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('mutant', 'Var', (145, 151))	('dacarbazine', 'Chemical', 'MESH:D003606', (85, 96))	('BRAF', 'Gene', '673', (140, 144))	('BRAF', 'Gene', (140, 144))	('tumors', 'Disease', (152, 158))	('Selumetinib', 'Chemical', 'MESH:C517975', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
111395	22048237	For example, in a phase I trial of the MEK inhibitor GSK1120212 which had disease control rate of 73%, the frequency of rash was 77%.	('GSK1120212', 'Chemical', 'MESH:C560077', (53, 63))	('rash', 'Disease', 'MESH:D005076', (120, 124))	('rash', 'Disease', (120, 124))	('rash', 'Phenotype', 'HP:0000988', (120, 124))	('GSK', 'molecular_function', 'GO:0050321', ('53', '56'))	('MEK', 'Gene', (39, 42))	('MEK', 'Gene', '5609', (39, 42))	('GSK1120212', 'Var', (53, 63))
111400	22048237	The objective tumor responses observed were comparable in both the overall and BRAF and NRAS mutant populations; however, 5 of 6 selumetinib responders had BRAF mutant tumors.	('mutant', 'Var', (161, 167))	('tumor', 'Disease', (14, 19))	('BRAF', 'Gene', (156, 160))	('tumor', 'Disease', (168, 173))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('NRAS', 'Gene', (88, 92))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('BRAF', 'Gene', '673', (79, 83))	('NRAS', 'Gene', '4893', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('selumetinib', 'Chemical', 'MESH:C517975', (129, 140))	('BRAF', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('BRAF', 'Gene', '673', (156, 160))
111401	22048237	Further development of selumetinib in this disease will therefore focus on combination with other agents and upon the selection of patients for therapy, using BRAF mutation status.	('patients', 'Species', '9606', (131, 139))	('BRAF', 'Gene', (159, 163))	('mutation', 'Var', (164, 172))	('selumetinib', 'Chemical', 'MESH:C517975', (23, 34))	('BRAF', 'Gene', '673', (159, 163))
111404	22048237	Preclinical studies have shown antitumor activity of selumetinib in melanoma xenograft models particularly those harboring BRAF mutations.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('mutations', 'Var', (128, 137))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('tumor', 'Disease', (35, 40))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('selumetinib', 'Chemical', 'MESH:C517975', (53, 64))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))
111405	22048237	In this study, there was no significant difference in efficacy between selumetinib and temozolomide as first-line therapy for patients with advanced melanoma not selected for activating BRAF mutations.	('BRAF', 'Gene', (186, 190))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('mutations', 'Var', (191, 200))	('selumetinib', 'Chemical', 'MESH:C517975', (71, 82))	('temozolomide', 'Chemical', 'MESH:D000077204', (87, 99))	('patients', 'Species', '9606', (126, 134))	('BRAF', 'Gene', '673', (186, 190))
111429	21041723	CD3zeta-chain expression may be modulated by CD11b+ myeloid-derived suppressor cells (MDSCs), which expand in the blood and within tumors of patients with certain malignancies, including uveal melanoma.	('CD3zeta-chain', 'Gene', (0, 13))	('CD11b+', 'Var', (45, 51))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('modulated', 'Reg', (32, 41))	('uveal melanoma', 'Disease', 'MESH:C536494', (187, 201))	('patients', 'Species', '9606', (141, 149))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('uveal melanoma', 'Phenotype', 'HP:0007716', (187, 201))	('uveal melanoma', 'Disease', (187, 201))	('malignancies', 'Disease', 'MESH:D009369', (163, 175))	('blood and within tumors', 'Disease', 'MESH:D001929', (114, 137))	('CD3zeta-chain', 'Gene', '919', (0, 13))	('malignancies', 'Disease', (163, 175))
111435	21041723	Transferred CTLs infiltrated both tumor sites and surprisingly displayed similar effector function in terms of cytokine production (TNF, IFN-gamma) and granule exocytosis, despite the presence of CD11b+ cells, which were suppressive to CTL responses in vitro via NO production.	('CD11b+', 'Var', (196, 202))	('granule exocytosis', 'MPA', (152, 170))	('cytokine production', 'MPA', (111, 130))	('cytokine production', 'biological_process', 'GO:0001816', ('111', '130'))	('tumor', 'Disease', (34, 39))	('rat', 'Species', '10116', (23, 26))	('exocytosis', 'biological_process', 'GO:0006887', ('160', '170'))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
111440	21041723	OT-I mice were backcrossed with B6.PL mice to generate CD90.1+/CD90.2+ and CD90.1+ congenic OT-I mice.	('OT-I', 'Chemical', '-', (0, 4))	('mice', 'Species', '10090', (5, 9))	('mice', 'Species', '10090', (38, 42))	('rat', 'Species', '10116', (50, 53))	('mice', 'Species', '10090', (97, 101))	('OT-I', 'Chemical', '-', (92, 96))	('CD90.1+/CD90.2+', 'Var', (55, 70))	('CD90.1+', 'Var', (75, 82))
111441	21041723	EL-4 cells, EL-4 transduced to express OVA (E.G7-OVA, H-2b, CD90.2+), and P815 (H-2d) cells were obtained from American Type Culture Collection (Manassas, VA).	('EL-4', 'Gene', '111979', (12, 16))	('CD90.2+', 'Var', (60, 67))	('H-2d', 'Gene', '83772', (80, 84))	('EL-4', 'Gene', (12, 16))	('EL-4', 'Gene', '111979', (0, 4))	('H-2d', 'Gene', (80, 84))	('G7-OVA', 'Chemical', '-', (46, 52))	('EL-4', 'Gene', (0, 4))
111452	21041723	Tumor cells were identified as CD45+, CD90.2+, CD8-, and CD4low high forward scatter events.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD8', 'Gene', (47, 50))	('CD45+', 'Var', (31, 36))	('CD8', 'Gene', '925', (47, 50))	('CD4low', 'Var', (57, 63))	('CD90.2+', 'Var', (38, 45))
111455	21041723	No further enrichment of the purified activated effector splenocytes was performed because more than 95% of live cells after Ficoll separation were CD90.2+, CD8+, and OVA257-264 Kb tetramer+ T cells (Supplemental Fig.	('OVA257-264 Kb', 'Var', (167, 180))	('CD8', 'Gene', (157, 160))	('CD8', 'Gene', '925', (157, 160))	('rat', 'Species', '10116', (136, 139))	('CD90.2+', 'Var', (148, 155))
111472	21041723	Skin or eye tumors were rendered into single-cell suspensions, then magnetic cell sorting with the EasySep PE selection kit (Stem Cell Technologies, Vancouver, British Columbia, Canada) was performed to exclude CD90.2+ tumor cells from cell suspensions previous to flow cytometric cell sorting.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (219, 224))	('eye tumors', 'Disease', 'MESH:D005134', (8, 18))	('eye tumors', 'Disease', (8, 18))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('eye tumors', 'Phenotype', 'HP:0100012', (8, 18))	('British Columbia', 'Disease', 'OMIM:176500', (160, 176))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('eye tumor', 'Phenotype', 'HP:0100012', (8, 17))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('British Columbia', 'Disease', (160, 176))	('CD90.2+', 'Var', (211, 218))
111473	21041723	Nonselected cells were stained with fluorochrome-conjugated anti-CD45, anti-CD11b, and anti-Gr-1 mAbs, and CD11b+Gr-1+ and CD11b+Gr-1- cells were then isolated by flow cytometric cell sorting for use in T cell suppression and tumoricidal assays.	('Gr-1', 'Gene', '546644', (129, 133))	('Gr-1', 'Gene', '546644', (113, 117))	('Gr-1', 'Gene', '546644', (92, 96))	('Gr-1', 'Gene', (129, 133))	('anti-CD11b', 'Var', (71, 81))	('Gr-1', 'Gene', (113, 117))	('Gr-1', 'Gene', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('T cell suppression', 'CPA', (203, 221))	('tumor', 'Disease', (226, 231))
111481	21041723	Tumor cells were identified as CD45+, CD90.2+, CD8-, CD11b- high forward scatter events, and Count Bright absolute counting beads (Invitrogen) were used to collect half of each total cell sample to determine the number of tumor cells per sample.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('CD8', 'Gene', (47, 50))	('CD45+', 'Var', (31, 36))	('CD8', 'Gene', '925', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('CD90.2+', 'Var', (38, 45))	('CD11b-', 'Var', (53, 59))
111503	21041723	Five days after injection of E.G7-OVA in the a.c. or 10 d after tumor injection in the skin, mice received an i.v.	('G7-OVA', 'Chemical', '-', (31, 37))	('tumor', 'Disease', (64, 69))	('E.G7-OVA', 'Var', (29, 37))	('mice', 'Species', '10090', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
111505	21041723	Six days later, flow cytometric analysis was performed and demonstrated that intratumoral CD90.1+ OT-I CTLs were present in both tumor sites and were easily distinguished from CD90.2+ tumor cells and endogenous CD90.2+ T cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('rat', 'Species', '10116', (80, 83))	('OT-I', 'Chemical', '-', (98, 102))	('rat', 'Species', '10116', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (82, 87))	('CD90.1+ OT-I', 'Var', (90, 102))
111509	21041723	This analysis demonstrated that CD90.1+ OT-I CTLs extensively infiltrated ocular tumors and were in close proximity to CD90.2+ tumor cells and infiltrating CD11b+ myeloid cells (Fig.	('rat', 'Species', '10116', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('infiltrated', 'Reg', (62, 73))	('ocular tumors', 'Disease', 'MESH:D009369', (74, 87))	('OT-I', 'Chemical', '-', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('rat', 'Species', '10116', (21, 24))	('rat', 'Species', '10116', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ocular tumors', 'Phenotype', 'HP:0100012', (74, 87))	('CD90.1+', 'Var', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('ocular tumor', 'Phenotype', 'HP:0100012', (74, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('ocular tumors', 'Disease', (74, 87))	('tumor', 'Disease', (81, 86))
111522	21041723	Greater than 95% of CD45+ cells within ocular and skin tumors of C57BL/6 mice were composed of CD90.2+ cells and CD11b+ cells (Fig.	('skin tumor', 'Phenotype', 'HP:0008069', (50, 60))	('skin tumors', 'Phenotype', 'HP:0008069', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('skin tumors', 'Disease', (50, 61))	('mice', 'Species', '10090', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('CD90.2+ cells', 'Var', (95, 108))	('skin tumors', 'Disease', 'MESH:D012878', (50, 61))	('CD11b+ cells', 'Var', (113, 125))
111526	21041723	The number of tumors was comparable in B6.PL and RAG-1-/- mice, whereas a modest (2-fold) reduction was observed in CD11b numbers in RAG1-/- mice indicating that T cells were largely not required for CD11b+ cell infiltration (Supplemental Fig.	('RAG-1', 'Gene', (49, 54))	('reduction', 'NegReg', (90, 99))	('B6.PL', 'Var', (39, 44))	('RAG1', 'Gene', '19373', (133, 137))	('tumors', 'Disease', (14, 20))	('mice', 'Species', '10090', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('rat', 'Species', '10116', (218, 221))	('mice', 'Species', '10090', (141, 145))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('RAG-1', 'Gene', '19373', (49, 54))	('CD11b', 'Gene', (116, 121))	('RAG1', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
111527	21041723	Ocular tumors were composed of a greater percentage of CD11b+ cells in comparison with skin tumors (Fig.	('skin tumors', 'Phenotype', 'HP:0008069', (87, 98))	('Ocular tumor', 'Phenotype', 'HP:0100012', (0, 12))	('skin tumors', 'Disease', (87, 98))	('Ocular tumors', 'Disease', (0, 13))	('CD11b+ cells', 'Var', (55, 67))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('Ocular tumors', 'Disease', 'MESH:D009369', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('skin tumors', 'Disease', 'MESH:D012878', (87, 98))	('skin tumor', 'Phenotype', 'HP:0008069', (87, 97))	('Ocular tumors', 'Phenotype', 'HP:0100012', (0, 13))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
111548	21041723	This suppression by tumor-associated CD11b+cells was mediated by NO, as nitrite levels, an indirect measure of NO production, were elevated in supernatants of cultures containing tumor-associated CD11b+ cells, and the addition of NMMA, an inhibitory L-arginine analogue, inhibited NO production and restored lytic activity.	('CD11b+', 'Var', (196, 202))	('elevated', 'PosReg', (131, 139))	('nitrite', 'Chemical', 'MESH:D009573', (72, 79))	('restored', 'PosReg', (299, 307))	('nitrite levels', 'MPA', (72, 86))	('L-arginine', 'Chemical', 'MESH:D001120', (250, 260))	('NMMA', 'Chemical', 'MESH:D019323', (230, 234))	('NO production', 'MPA', (281, 294))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('inhibited', 'NegReg', (271, 280))	('NMMA', 'Gene', (230, 234))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('lytic activity', 'CPA', (308, 322))	('tumor', 'Disease', (20, 25))	('tumor', 'Disease', (179, 184))
111557	21041723	CTL transfer increased NT levels in skin but not eye tumors, which showed NT levels equivalent to tumors in NOS2-/- mice.	('tumors', 'Disease', (98, 104))	('eye tumors', 'Phenotype', 'HP:0100012', (49, 59))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('increased', 'PosReg', (13, 22))	('eye tumors', 'Disease', 'MESH:D005134', (49, 59))	('mice', 'Species', '10090', (116, 120))	('NT levels', 'MPA', (23, 32))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('NT', 'Chemical', 'MESH:C002744', (23, 25))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Disease', (53, 59))	('eye tumors', 'Disease', (49, 59))	('eye tumor', 'Phenotype', 'HP:0100012', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('transfer', 'Var', (4, 12))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('NT', 'Chemical', 'MESH:C002744', (74, 76))	('skin but', 'Disease', (36, 44))
111597	21041723	In addition, UV5C25, an ultraviolet-induced fibrosarcoma, is spontaneously rejected by tumor-specific CD8+ T cells in the eye providing further support that CTL effector function is not compromised within the a.c. of normal or tumor-bearing eyes.	('fibrosarcoma', 'Disease', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('CD8', 'Gene', (102, 105))	('tumor', 'Disease', (227, 232))	('CD8', 'Gene', '925', (102, 105))	('tumor', 'Disease', (87, 92))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (44, 56))	('fibrosarcoma', 'Disease', 'MESH:D005354', (44, 56))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('UV5C25', 'Var', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
111599	21041723	showed that direct lysis of E.G7-OVA tumor cells by CTLs is not required to promote skin tumor rejection, as transferred CTLs deficient in perforin, TNF, or FasL eliminated established skin tumors.	('perforin', 'Protein', (139, 147))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('skin tumors', 'Disease', 'MESH:D012878', (185, 196))	('deficient', 'Var', (126, 135))	('eliminated', 'NegReg', (162, 172))	('G7-OVA', 'Chemical', '-', (30, 36))	('FasL', 'Gene', '14103', (157, 161))	('skin tumors', 'Phenotype', 'HP:0008069', (185, 196))	('TNF', 'Protein', (149, 152))	('OVA tumor', 'Phenotype', 'HP:0100615', (33, 42))	('skin tumor', 'Disease', 'MESH:D012878', (84, 94))	('skin tumor', 'Phenotype', 'HP:0008069', (185, 195))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (89, 94))	('skin tumor', 'Disease', (84, 94))	('lysis', 'biological_process', 'GO:0019835', ('19', '24'))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', (190, 195))	('skin tumor', 'Disease', 'MESH:D012878', (185, 195))	('FasL', 'Gene', (157, 161))	('skin tumors', 'Disease', (185, 196))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('skin tumor', 'Phenotype', 'HP:0008069', (84, 94))
111625	21041723	In our previous study, we also showed that after 7 d of E.G7-OVA growth in the a.c., mice were protected from a subsequent injection of E.G7-OVA in the skin or opposite eye reproducing previous observations by Niederkorn and Streinlein using P815 mastocytomas.	('mice', 'Species', '10090', (85, 89))	('G7-OVA', 'Chemical', '-', (138, 144))	('mastocytomas', 'Disease', 'MESH:D034801', (247, 259))	('G7-OVA', 'Chemical', '-', (58, 64))	('mastocytomas', 'Disease', (247, 259))	('E.G7-OVA', 'Var', (56, 64))
111636	21041723	Destructive immune responses culminating in ocular phthisis were observed when P91 tumors, a variant of P815 mastocytomas, were injected in the a.c. of BALB/c mice.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('ocular phthisis', 'Disease', (44, 59))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('ocular phthisis', 'Phenotype', 'HP:0000667', (44, 59))	('mice', 'Species', '10090', (159, 163))	('mastocytomas', 'Disease', (109, 121))	('P91', 'Var', (79, 82))	('mastocytomas', 'Disease', 'MESH:D034801', (109, 121))
111639	21041723	UV5C25 and Ad5E1 induce CD8+ and CD4+ T cell responses, respectively, which are required for tumor elimination.	('UV5C25', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('CD4+ T cell responses', 'CPA', (33, 54))	('tumor', 'Disease', (93, 98))	('CD8', 'Gene', (24, 27))	('Ad5E1', 'Gene', (11, 16))	('CD8', 'Gene', '925', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
111640	21041723	Indeed, CD4+ T cell-expressed IFN-gamma acts directly on Ad5E1 tumors to upregulate TRAIL-R2 to induce apoptosis.	('TRAIL-R2', 'Gene', (84, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('induce', 'PosReg', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('TRAIL-R2', 'Gene', '21933', (84, 92))	('apoptosis', 'CPA', (103, 112))	('CD4+ T', 'Var', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('upregulate', 'PosReg', (73, 83))
111642	21041723	Notably, although these data suggest that UV5C25 and Ad5E1 break ocular immune privilege, some immune regulation within the eye is not lost because Mphis selectively destroy tumor cells without causing damage to innocent bystander cells.	('tumor', 'Disease', (174, 179))	('destroy', 'NegReg', (166, 173))	('Ad5E1', 'Var', (53, 58))	('regulation', 'biological_process', 'GO:0065007', ('102', '112'))	('ocular immune privilege', 'CPA', (65, 88))	('break', 'NegReg', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('UV5C25', 'Var', (42, 48))
111685	33262254	Based on these variants, candidate tumor-specific neoepitopes were predicted and annotated using an in-house epitope prediction pipeline, which uses a random forest model to score the probability of surface expression of candidate neoepitopes based on the major prerequisites for (neo-)antigen presentation: RNA expression level (Salmon V.0.9.1), proteasomal processing (NetChop V.3.1) and human leukocyte antigen binding (netMHCpan V.4).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('RNA', 'cellular_component', 'GO:0005562', ('308', '311'))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('proteasomal processing', 'biological_process', 'GO:0043161', ('347', '369'))	('human', 'MPA', (390, 395))	('tumor', 'Disease', (35, 40))	('antigen binding', 'molecular_function', 'GO:0003823', ('406', '421'))	('RNA expression level', 'MPA', (308, 328))	('netMHCpan', 'Chemical', '-', (423, 432))	('variants', 'Var', (15, 23))	('human', 'Species', '9606', (390, 395))	('antigen presentation', 'biological_process', 'GO:0019882', ('286', '306'))
111705	33262254	Previous analyzes indicated that CM patients most frequently harbor alterations in BRAF, RAS, NF1, TP53 and CDKN2A, resulting in deregulation of the MAPK/ERK pathway in the majority of the CM patients.	('NF1', 'Gene', '4763', (94, 97))	('MAPK', 'Gene', '5594', (149, 153))	('ERK', 'Gene', (154, 157))	('alterations', 'Var', (68, 79))	('NF1', 'Gene', (94, 97))	('CDKN2A', 'Gene', '1029', (108, 114))	('patients', 'Species', '9606', (36, 44))	('deregulation', 'MPA', (129, 141))	('MAPK', 'molecular_function', 'GO:0004707', ('149', '153'))	('TP53', 'Gene', (99, 103))	('patients', 'Species', '9606', (192, 200))	('CM', 'Phenotype', 'HP:0012056', (189, 191))	('ERK', 'molecular_function', 'GO:0004707', ('154', '157'))	('BRAF', 'Gene', '673', (83, 87))	('BRAF', 'Gene', (83, 87))	('RAS', 'Gene', (89, 92))	('ERK', 'Gene', '5594', (154, 157))	('CM', 'Phenotype', 'HP:0012056', (33, 35))	('TP53', 'Gene', '7157', (99, 103))	('MAPK', 'Gene', (149, 153))	('CDKN2A', 'Gene', (108, 114))
111706	33262254	In UM, the most commonly mutated genes are GNA11, GNAQ, BAP1, EIF1AX and SF3B1, which leads to upregulated signaling via MEK, Akt and protein kinase C. These CM-specific and UM-specific mutations were also observed in the liver metastases samples (figure 1A).	('signaling', 'biological_process', 'GO:0023052', ('107', '116'))	('BAP1', 'Gene', '8314', (56, 60))	('GNA11', 'Gene', '2767', (43, 48))	('protein', 'Enzyme', (134, 141))	('EIF1AX', 'Gene', (62, 68))	('Akt', 'Gene', (126, 129))	('UM', 'Phenotype', 'HP:0007716', (3, 5))	('CM', 'Phenotype', 'HP:0012056', (158, 160))	('liver metastases', 'Disease', 'MESH:D009362', (222, 238))	('Akt', 'Gene', '207', (126, 129))	('GNAQ', 'Gene', '2776', (50, 54))	('BAP1', 'Gene', (56, 60))	('EIF1AX', 'Gene', '1964', (62, 68))	('SF3B1', 'Gene', (73, 78))	('GNAQ', 'Gene', (50, 54))	('GNA11', 'Gene', (43, 48))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('MEK', 'Gene', '5609', (121, 124))	('UM', 'Phenotype', 'HP:0007716', (174, 176))	('liver metastases', 'Disease', (222, 238))	('upregulated', 'PosReg', (95, 106))	('SF3B1', 'Gene', '23451', (73, 78))	('mutations', 'Var', (186, 195))	('MEK', 'Gene', (121, 124))	('signaling', 'MPA', (107, 116))
111707	33262254	BRAF kinase mutations were present in 81% of the CM patients, 46% were located at codon 600 (figure 1D).	('mutations', 'Var', (12, 21))	('BRAF', 'Gene', '673', (0, 4))	('CM', 'Phenotype', 'HP:0012056', (49, 51))	('BRAF', 'Gene', (0, 4))	('patients', 'Species', '9606', (52, 60))
111708	33262254	In addition, BRAF mutations at other codons were observed, which could be a consequence of a high TMB and are therefore most likely passenger mutations (figure 1A, D).	('BRAF', 'Gene', '673', (13, 17))	('mutations', 'Var', (18, 27))	('TMB', 'Chemical', '-', (98, 101))	('BRAF', 'Gene', (13, 17))
111709	33262254	Most UM liver metastases carried mutations in GNA11 (67%), BAP1 (80%) and/or GNAQ (27%).	('GNA11', 'Gene', '2767', (46, 51))	('BAP1', 'Gene', (59, 63))	('BAP1', 'Gene', '8314', (59, 63))	('GNAQ', 'Gene', (77, 81))	('mutations', 'Var', (33, 42))	('liver metastases', 'Disease', (8, 24))	('liver metastases', 'Disease', 'MESH:D009362', (8, 24))	('UM', 'Phenotype', 'HP:0007716', (5, 7))	('GNA11', 'Gene', (46, 51))	('GNAQ', 'Gene', '2776', (77, 81))
111710	33262254	Only one CM tumor carried a GNA11 mutation, which has previously been described in a rare subgroup of CM which is also characterized by a lower mutational burden.	('CM tumor', 'Disease', 'MESH:D009369', (9, 17))	('CM', 'Phenotype', 'HP:0012056', (102, 104))	('CM tumor', 'Disease', (9, 17))	('mutation', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('GNA11', 'Gene', (28, 33))	('GNA11', 'Gene', '2767', (28, 33))	('CM', 'Phenotype', 'HP:0012056', (9, 11))
111711	33262254	The UM-specific mutations in EIF1AX and SF3B1 were observed less frequently than the UM-specific GNAQ/11 and BAP1 mutations, which may potentially be explained by a lower metastatic rate of UM tumors with EIF1AX and SF3B1 mutations.	('SF3B1', 'Gene', (216, 221))	('BAP1', 'Gene', '8314', (109, 113))	('UM', 'Phenotype', 'HP:0007716', (4, 6))	('EIF1AX', 'Gene', (29, 35))	('EIF1AX', 'Gene', (205, 211))	('UM tumors', 'Disease', (190, 199))	('UM tumors', 'Disease', 'MESH:D009369', (190, 199))	('SF3B1', 'Gene', '23451', (216, 221))	('mutations', 'Var', (222, 231))	('BAP1', 'Gene', (109, 113))	('SF3B1', 'Gene', (40, 45))	('EIF1AX', 'Gene', '1964', (29, 35))	('EIF1AX', 'Gene', '1964', (205, 211))	('UM', 'Phenotype', 'HP:0007716', (190, 192))	('GNAQ', 'Gene', '2776', (97, 101))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('GNAQ', 'Gene', (97, 101))	('lower', 'NegReg', (165, 170))	('SF3B1', 'Gene', '23451', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('metastatic', 'CPA', (171, 181))
111713	33262254	Specifically, loss of chromosome 6q, 8p, 9 and 10, and copy number gains in chromosome 6p, 7, 8, 20 were observed in CM metastases (figure 1E).	('chromosome', 'cellular_component', 'GO:0005694', ('22', '32'))	('CM', 'Phenotype', 'HP:0012056', (117, 119))	('chromosome', 'cellular_component', 'GO:0005694', ('76', '86'))	('gains', 'PosReg', (67, 72))	('copy number', 'Var', (55, 66))	('CM metastases', 'Disease', 'MESH:D009362', (117, 130))	('CM metastases', 'Disease', (117, 130))	('loss', 'NegReg', (14, 18))
111714	33262254	Copy number aberrations on chromosome 1 (1p loss, 1q gain), chromosome 3 (loss), chromosome 6 (6p gain, 6q loss) and chromosome 8 (8p loss, 8q gain) were observed in UM metastases (figure 1E).	('1p loss', 'Var', (41, 48))	('metastases', 'Disease', (169, 179))	('chromosome', 'cellular_component', 'GO:0005694', ('117', '127'))	('chromosome', 'cellular_component', 'GO:0005694', ('27', '37'))	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('UM', 'Phenotype', 'HP:0007716', (166, 168))	('metastases', 'Disease', 'MESH:D009362', (169, 179))	('loss', 'NegReg', (134, 138))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))	('gain', 'PosReg', (53, 57))	('gain', 'PosReg', (98, 102))	('gain', 'PosReg', (143, 147))
111722	33262254	Loss of MHC has previously been described as an escape mechanism from ICB therapy.	('MHC', 'Gene', (8, 11))	('Loss', 'Var', (0, 4))	('ICB', 'Chemical', '-', (70, 73))
111737	33262254	Furthermore, a high IFN-gamma score (defined as average expression IFN-gamma signature) was likewise associated with a lower ratio of exhausted CD8+ T cells to CD8+ T cells in UM metastases (p=0.0386) (figure 3I).	('high', 'Var', (15, 19))	('CD8', 'Gene', '925', (160, 163))	('metastases', 'Disease', 'MESH:D009362', (179, 189))	('lower', 'NegReg', (119, 124))	('UM', 'Phenotype', 'HP:0007716', (176, 178))	('CD8', 'Gene', (144, 147))	('CD8', 'Gene', '925', (144, 147))	('IFN-gamma', 'Gene', '3458', (67, 76))	('IFN-gamma', 'Gene', (67, 76))	('metastases', 'Disease', (179, 189))	('IFN-gamma', 'Gene', '3458', (20, 29))	('IFN-gamma', 'Gene', (20, 29))	('CD8', 'Gene', (160, 163))
111738	33262254	These data are both consistent with a model in which the relative level of T cell exhaustion is associated with melanoma subtype and with a model in which low TMB:and consequently low immunogenicity:is associated with increased T cell exhaustion.	('T cell exhaustion', 'Phenotype', 'HP:0005435', (228, 245))	('TMB', 'Chemical', '-', (159, 162))	('T cell exhaustion', 'Phenotype', 'HP:0005435', (75, 92))	('associated', 'Reg', (96, 106))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('low', 'Var', (155, 158))	('increased T cell', 'Phenotype', 'HP:0100828', (218, 234))	('immunogenicity', 'MPA', (184, 198))	('TMB', 'MPA', (159, 162))
111751	33262254	The higher expression of PTEN in UM liver metastases is in line with the previous observation that a part of CM liver samples have a missense mutation in the tumor suppressor gene Pten and a loss of chromosome 10 (location Pten) (figure 1A, E), and as a consequence lower or absent protein expression (figure 5B).	('Pten', 'Gene', (180, 184))	('protein expression', 'MPA', (282, 300))	('expression', 'MPA', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('lower', 'NegReg', (266, 271))	('protein', 'cellular_component', 'GO:0003675', ('282', '289'))	('UM', 'Phenotype', 'HP:0007716', (33, 35))	('absent', 'NegReg', (275, 281))	('PTEN', 'Gene', (25, 29))	('liver metastases', 'Disease', 'MESH:D009362', (36, 52))	('CM', 'Phenotype', 'HP:0012056', (109, 111))	('loss', 'NegReg', (191, 195))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('158', '174'))	('Pten', 'Gene', '5728', (223, 227))	('Pten', 'Gene', (223, 227))	('missense mutation', 'Var', (133, 150))	('chromosome', 'cellular_component', 'GO:0005694', ('199', '209'))	('PTEN', 'Gene', '5728', (25, 29))	('tumor', 'Disease', (158, 163))	('tumor suppressor', 'biological_process', 'GO:0051726', ('158', '174'))	('liver metastases', 'Disease', (36, 52))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('Pten', 'Gene', '5728', (180, 184))
111766	33262254	The neoantigens that are generated as a consequence of tumor-specific mutations can induce a tumor-specific immune response, likely explaining the observed relationship.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('mutations', 'Var', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('immune response', 'biological_process', 'GO:0006955', ('108', '123'))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (55, 60))	('induce', 'Reg', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
111772	33262254	Genetic alterations in the MHC and IFN-gamma pathways have been shown to be predictors for response to ICB.	('Genetic alterations', 'Var', (0, 19))	('ICB', 'Chemical', '-', (103, 106))	('IFN-gamma', 'Gene', '3458', (35, 44))	('IFN-gamma', 'Gene', (35, 44))
111782	33262254	Moreover, clonal expansion of T cells, indicative of prior antigen driven proliferation, was found in UM tumors.	('expansion of T cells', 'Phenotype', 'HP:0100828', (17, 37))	('clonal expansion', 'Var', (10, 26))	('UM tumors', 'Disease', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('UM', 'Phenotype', 'HP:0007716', (102, 104))	('UM tumors', 'Disease', 'MESH:D009369', (102, 111))	('found', 'Reg', (93, 98))
111819	32512881	Mutually-exclusive mutations in the GNAQ or GNA11 genes, which encode signaling proteins associated with G-protein-coupled receptors, are specific drivers of UM.	('GNA11', 'Gene', (44, 49))	('mutations', 'Var', (19, 28))	('GNA11', 'Gene', '2767', (44, 49))	('GNAQ', 'Gene', '2776', (36, 40))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('UM', 'Phenotype', 'HP:0007716', (158, 160))	('signaling', 'biological_process', 'GO:0023052', ('70', '79'))	('GNAQ', 'Gene', (36, 40))
111820	32512881	In addition, inactivating mutations in the BAP1 gene, which is located on chromosome 3, confer a more aggressive behavior to UM.	('inactivating mutations', 'Var', (13, 35))	('BAP1', 'Gene', (43, 47))	('UM', 'Phenotype', 'HP:0007716', (125, 127))	('chromosome', 'cellular_component', 'GO:0005694', ('74', '84'))	('aggressive behavior', 'CPA', (102, 121))	('BAP1', 'Gene', '8314', (43, 47))	('more', 'PosReg', (97, 101))	('aggressive behavior', 'Phenotype', 'HP:0000718', (102, 121))	('aggressive behavior', 'biological_process', 'GO:0002118', ('102', '121'))
111821	32512881	In contrast, mutations in TP53, BRAF, NRAS, TERT and the CDKN2 genes, which are common in cutaneous melanoma, are rare in UM.	('TP53', 'Gene', (26, 30))	('TERT', 'Gene', (44, 48))	('NRAS', 'Gene', '4893', (38, 42))	('CDKN2', 'Gene', (57, 62))	('TERT', 'Gene', '7015', (44, 48))	('CDKN2', 'Gene', '1029', (57, 62))	('BRAF', 'Gene', '673', (32, 36))	('cutaneous melanoma', 'Disease', (90, 108))	('BRAF', 'Gene', (32, 36))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (90, 108))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (90, 108))	('NRAS', 'Gene', (38, 42))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('TP53', 'Gene', '7157', (26, 30))	('mutations', 'Var', (13, 22))	('UM', 'Phenotype', 'HP:0007716', (122, 124))
111839	32512881	To address the potential role of miR122 and miR144 in UM, we first analyzed the miR Cancer Genome Atlas data portal (TCGA) dataset that includes 78 primary UM bearing GNAQ or GNA11 mutations.	('miR122', 'Gene', '406906', (33, 39))	('GNAQ', 'Gene', (167, 171))	('GNA11', 'Gene', '2767', (175, 180))	('GNA11', 'Gene', (175, 180))	('UM', 'Phenotype', 'HP:0007716', (156, 158))	('UM', 'Phenotype', 'HP:0007716', (54, 56))	('mutations', 'Var', (181, 190))	('miR144', 'Gene', '406936', (44, 50))	('GNAQ', 'Gene', '2776', (167, 171))	('miR Cancer', 'Disease', 'MESH:D009369', (80, 90))	('miR144', 'Gene', (44, 50))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))	('miR122', 'Gene', (33, 39))	('miR Cancer', 'Disease', (80, 90))
111856	32512881	Indeed, the 92.1 cell line is disomic for chromosome 3 and BAP1 wild-type, whereas UPMM3 is monosomic for chromosome-3 and BAP1 mutated.	('BAP1', 'Gene', (123, 127))	('BAP1', 'Gene', (59, 63))	('mutated', 'Var', (128, 135))	('chromosome', 'cellular_component', 'GO:0005694', ('106', '116'))	('BAP1', 'Gene', '8314', (123, 127))	('BAP1', 'Gene', '8314', (59, 63))	('chromosome', 'cellular_component', 'GO:0005694', ('42', '52'))
111858	32512881	MiR144 expression increased much more upon transfection than miR122, particularly in cell line UPMM3.	('increased', 'PosReg', (18, 27))	('miR122', 'Gene', (61, 67))	('transfection', 'Var', (43, 55))	('miR122', 'Gene', '406906', (61, 67))	('expression', 'MPA', (7, 17))	('MiR144', 'Gene', (0, 6))	('MiR144', 'Gene', '406936', (0, 6))
111877	32512881	Furthermore, Flow-cytometric analysis showed that miR144 mimic transfection significantly increased the proportion of cells in the G0/G1 phase and reduced the proportion of cells in the G2/M phase in comparison with irrelevant miR (Figure 7).	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('increased', 'PosReg', (90, 99))	('miR144', 'Gene', '406936', (50, 56))	('miR144', 'Gene', (50, 56))	('mimic transfection', 'Var', (57, 75))	('M phase', 'biological_process', 'GO:0000279', ('189', '196'))	('miR', 'Gene', '220972', (227, 230))	('miR', 'Gene', (227, 230))	('reduced', 'NegReg', (147, 154))	('G1 phase', 'biological_process', 'GO:0051318', ('134', '142'))
111884	32512881	Alteration of several miRs has been described as potentially pathogenic in UM.	('miR', 'Gene', '220972', (22, 25))	('Alteration', 'Var', (0, 10))	('pathogenic', 'Reg', (61, 71))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('miR', 'Gene', (22, 25))
111905	32512881	Chromosomal aberrations and BAP1 mutation in UPMM3 cells may influence the onco-suppressive activity of miR122 and miR144.	('BAP1', 'Gene', '8314', (28, 32))	('mutation', 'Var', (33, 41))	('miR144', 'Gene', '406936', (115, 121))	('influence', 'Reg', (61, 70))	('miR144', 'Gene', (115, 121))	('BAP1', 'Gene', (28, 32))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('miR122', 'Gene', (104, 110))	('onco-suppressive activity', 'CPA', (75, 100))	('miR122', 'Gene', '406906', (104, 110))
111906	32512881	However, the analysis of miR expression in UM TCGA found a cluster of miRs associated with monosomy 3 and BAP1 mutation, but miR122/144 are not present in this cluster, and thus may not be regulated by them.	('miR', 'Gene', (70, 73))	('BAP1', 'Gene', (106, 110))	('miR122/144', 'Gene', '406906;406936', (125, 135))	('miR122/144', 'Gene', (125, 135))	('miR', 'Gene', '220972', (25, 28))	('miR', 'Gene', (25, 28))	('UM', 'Phenotype', 'HP:0007716', (43, 45))	('monosomy 3', 'Disease', (91, 101))	('BAP1', 'Gene', '8314', (106, 110))	('miR', 'Gene', '220972', (70, 73))	('miR', 'Gene', '220972', (125, 128))	('mutation', 'Var', (111, 119))	('associated', 'Reg', (75, 85))	('miR', 'Gene', (125, 128))
111927	32512881	The miScript primer assay in combination with miScript SYBR Green PCR kit from Qiagen was used for detection of miR122, 144, 221 and 222.	('221 and', 'Var', (125, 132))	('miR122', 'Gene', '406906', (112, 118))	('miR122', 'Gene', (112, 118))
111962	32468072	Retinoblastoma is a retinal embryo malignancy that occurs in childhood and is triggered by mutations in the retinoblastoma gene (RB1) in cells of the developing retina.	('RB1', 'Gene', '5925', (129, 132))	('triggered by', 'Reg', (78, 90))	('Retinoblastoma', 'Gene', '5925', (0, 14))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (0, 14))	('retinal embryo malignancy', 'Disease', (20, 45))	('retinoblastoma', 'Gene', '5925', (108, 122))	('Retinoblastoma', 'Gene', (0, 14))	('embryo malignancy', 'Phenotype', 'HP:0002898', (28, 45))	('retinoblastoma', 'Gene', (108, 122))	('mutations', 'Var', (91, 100))	('retinal embryo malignancy', 'Disease', 'MESH:D020964', (20, 45))	('RB1', 'Gene', (129, 132))	('retinoblastoma', 'Phenotype', 'HP:0009919', (108, 122))
111988	32468072	2B, two outlier samples (GSM3017126 and GSM3017124) were removed.	('GSM3017124', 'Chemical', '-', (40, 50))	('GSM3017126', 'Chemical', '-', (25, 35))	('GSM3017124', 'Var', (40, 50))	('GSM3017126', 'Var', (25, 35))
111990	32468072	To explore meaningful modules associated with clinical traits, correlations between MEs and the following clinical traits were analyzed: Age; HRPF; metastasis; mild; moderate; severe; unilateral; survival time (months); mutation germline (mutation G); mutation not known or test not done (mutation ND); mutation none; and mutation nongermline (mutation NG; Fig.	('mutation germline', 'Var', (220, 237))	('ME', 'Chemical', '-', (84, 86))	('HRPF', 'Disease', (142, 146))
112001	32468072	High parental age is associated with increased risk of sporadic hereditary retinoblastoma.	('sporadic hereditary retinoblastoma', 'Disease', (55, 89))	('sporadic hereditary retinoblastoma', 'Disease', 'MESH:D012175', (55, 89))	('retinoblastoma', 'Phenotype', 'HP:0009919', (75, 89))	('High parental age', 'Var', (0, 17))
112009	32468072	The top 10 hub genes in the yellow module included: BAF chromatin remodeling complex subunit BCL11A (BCL11A); SSBP3 antisense RNA 1 (SSBP3-AS1); EBF transcription factor 3, KCNQ5 intronic transcript 1 (KCNQ5-IT1); uncharacterized LOC101929633 (LOC101929633); carbonic anhydrase 2 (CA2); ArfGAP with SH3 domain, ankyrin repeat and PH domain 2; roundabout guidance receptor 1 (ROBO1); INSM transcriptional repressor 2; and leucine rich repeat LGI family member 2 (LGI2).	('SSBP3', 'Gene', (133, 138))	('KCNQ5', 'Gene', (202, 207))	('CA2', 'Gene', '760', (281, 284))	('BAF', 'Gene', '8815', (52, 55))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('56', '84'))	('AS1', 'Gene', '5729', (139, 142))	('KCNQ5', 'Gene', '56479', (173, 178))	('LGI2', 'Gene', (462, 466))	('BCL11A', 'Gene', (93, 99))	('BCL11A', 'Gene', (101, 107))	('ROBO1', 'Gene', '6091', (375, 380))	('SSBP3', 'Gene', (110, 115))	('carbonic anhydrase 2', 'Gene', (259, 279))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('56', '76'))	('leucine rich repeat LGI family member 2', 'Gene', (421, 460))	('INSM transcriptional repressor 2', 'Gene', (383, 415))	('SSBP3', 'Gene', '23648', (133, 138))	('transcription factor', 'molecular_function', 'GO:0000981', ('149', '169'))	('LGI2', 'Gene', '55203', (462, 466))	('roundabout guidance receptor 1', 'Gene', (343, 373))	('transcription', 'biological_process', 'GO:0006351', ('149', '162'))	('antisense RNA', 'molecular_function', 'GO:0009388', ('116', '129'))	('INSM transcriptional repressor 2', 'Gene', '84684', (383, 415))	('KCNQ5', 'Gene', '56479', (202, 207))	('SSBP3', 'Gene', '23648', (110, 115))	('SSBP3 antisense RNA 1', 'Gene', '619518;23648', (110, 131))	('AS1', 'Gene', (139, 142))	('KCNQ5', 'Gene', (173, 178))	('BCL11A', 'Gene', '53335', (101, 107))	('BCL11A', 'Gene', '53335', (93, 99))	('KCNQ5-IT1', 'Gene', (202, 211))	('BAF', 'Gene', (52, 55))	('carbonic anhydrase 2', 'Gene', '760', (259, 279))	('hub', 'Gene', (11, 14))	('LOC101929633', 'Var', (244, 256))	('RNA', 'cellular_component', 'GO:0005562', ('126', '129'))	('CA2', 'Gene', (281, 284))	('SSBP3 antisense RNA 1', 'Gene', (110, 131))	('hub', 'Gene', '1993', (11, 14))	('roundabout guidance receptor 1', 'Gene', '6091', (343, 373))	('leucine rich repeat LGI family member 2', 'Gene', '55203', (421, 460))	('ROBO1', 'Gene', (375, 380))	('KCNQ5-IT1', 'Gene', '100507381;56479;79441', (202, 211))
112033	32468072	Second, the biological mechanisms of the hub genes, such as SSBP3-AS1, KCNQ5-IT1, LOC101929633 and CA2, are still unknown.	('CA2', 'Gene', (99, 102))	('KCNQ5-IT1', 'Gene', (71, 80))	('CA2', 'Gene', '760', (99, 102))	('SSBP3', 'Gene', '23648', (60, 65))	('SSBP3', 'Gene', (60, 65))	('hub', 'Gene', '1993', (41, 44))	('KCNQ5-IT1', 'Gene', '100507381;56479;79441', (71, 80))	('LOC101929633', 'Var', (82, 94))	('hub', 'Gene', (41, 44))	('AS1', 'Gene', (66, 69))	('AS1', 'Gene', '5729', (66, 69))
112106	31927011	ESI-MS analysis gave a [M + Na]+ peak at m/z 643.2728, indicating a molecular formula of C32H44O12 for the compound.	('[M + Na]+ peak', 'MPA', (23, 37))	('C32H44O12', 'Chemical', '-', (89, 98))	('C32H44O12', 'Var', (89, 98))
112116	31927011	The NMR spectra indicated the presence of a substituted coumarin with the C-2 lactone carbonyl resonance occurring at deltaC 167.5 and the H-3 and H-4 resonances appearing as a pair of doublets at deltaH 5.64 and deltaH 7.41 (both d, J = 7.8 Hz) respectively.	('lactone', 'Chemical', 'MESH:D007783', (78, 85))	('deltaH', 'Chemical', '-', (197, 203))	('deltaH', 'Chemical', '-', (213, 219))	('deltaC', 'Chemical', '-', (118, 124))	('carbon', 'Chemical', 'MESH:D002244', (86, 92))	('coumarin', 'Chemical', 'MESH:C030123', (56, 64))	('C', 'Chemical', 'MESH:D002244', (74, 75))	('deltaH 5.64', 'Var', (197, 208))	('C-2 lactone carbonyl resonance', 'MPA', (74, 104))	('deltaH', 'Var', (213, 219))	('C', 'Chemical', 'MESH:D002244', (123, 124))	('deltaC 167.5', 'Var', (118, 130))
112134	31927011	There is a growing body of evidence showing that homoisoflavonoids have antiangiogenic activity relevant to these diseases, in some cases with limited effects on nontarget cells.	('homoisoflavonoids', 'Chemical', '-', (49, 66))	('homoisoflavonoids', 'Var', (49, 66))	('antiangiogenic activity', 'CPA', (72, 95))
112152	31871618	Knockdown of BAP1 in uveal melanoma cell lines causes dedifferentiation and the adoption of a phenotype that confers metastatic behavior.	('uveal melanoma', 'Disease', (21, 35))	('dedifferentiation', 'CPA', (54, 71))	('BAP1', 'Gene', (13, 17))	('causes', 'Reg', (47, 53))	('Knockdown', 'Var', (0, 9))	('dedifferentiation', 'biological_process', 'GO:0043696', ('54', '71'))	('adoption', 'Reg', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('uveal melanoma', 'Disease', 'MESH:C536494', (21, 35))	('metastatic behavior', 'CPA', (117, 136))	('uveal melanoma', 'Phenotype', 'HP:0007716', (21, 35))
112162	31871618	There is already some evidence that MEK inhibitor monotherapy leads to an increase in signaling through the PI3K/AKT/mTOR pathway and increased RAS protein expression mediated by the RNA helicase DDX43.	('mTOR', 'Gene', (117, 121))	('DDX43', 'Gene', '55510', (196, 201))	('mTOR', 'Gene', '2475', (117, 121))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('AKT', 'Gene', '207', (113, 116))	('RAS protein', 'Protein', (144, 155))	('PI3K', 'molecular_function', 'GO:0016303', ('108', '112'))	('increase', 'PosReg', (74, 82))	('RNA', 'cellular_component', 'GO:0005562', ('183', '186'))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('MEK', 'Gene', (36, 39))	('monotherapy', 'Var', (50, 61))	('signaling', 'MPA', (86, 95))	('AKT', 'Gene', (113, 116))	('DDX43', 'Gene', (196, 201))	('increased', 'PosReg', (134, 143))
112163	31871618	Other studies have proposed that host liver cells may also contribute to resistance, with work suggesting that hepatic stellate cells drive the escape from targeted therapies such as MEK inhibitors (via HGF secretion) and BRD inhibitors (via FGF-2 signaling).	('inhibitors', 'Var', (187, 197))	('FGF-2', 'Gene', '2247', (242, 247))	('secretion', 'biological_process', 'GO:0046903', ('207', '216'))	('signaling', 'biological_process', 'GO:0023052', ('248', '257'))	('FGF-2', 'Gene', (242, 247))	('HGF', 'Gene', (203, 206))	('MEK', 'Gene', (183, 186))	('HGF', 'Gene', '3082', (203, 206))
112175	31871618	Some recent evidence from both X. laevis and human uveal melanoma cell line models have demonstrated that the BAP1 loss phenotype can be rescued in part through the silencing of HDAC4.	('uveal melanoma', 'Phenotype', 'HP:0007716', (51, 65))	('uveal melanoma', 'Disease', (51, 65))	('loss', 'NegReg', (115, 119))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('BAP1', 'Gene', (110, 114))	('human', 'Species', '9606', (45, 50))	('HDAC4', 'Gene', '9759', (178, 183))	('HDAC4', 'Gene', (178, 183))	('silencing', 'Var', (165, 174))	('X. laevis', 'Species', '8355', (31, 40))	('uveal melanoma', 'Disease', 'MESH:C536494', (51, 65))
112176	31871618	Here, it was found that HDAC4 preferentially localized to the nucleus of BAP1 mutant uveal melanoma cells, and that shRNA-mediated silencing of HDAC4 significantly decreased uveal melanoma cell growth.	('nucleus', 'cellular_component', 'GO:0005634', ('62', '69'))	('BAP1', 'Gene', (73, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (85, 99))	('HDAC4', 'Gene', (24, 29))	('HDAC4', 'Gene', (144, 149))	('cell growth', 'biological_process', 'GO:0016049', ('189', '200'))	('preferentially', 'PosReg', (30, 44))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('silencing', 'Var', (131, 140))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('uveal melanoma', 'Disease', 'MESH:C536494', (174, 188))	('uveal melanoma', 'Disease', (174, 188))	('mutant', 'Var', (78, 84))	('decreased', 'NegReg', (164, 173))	('uveal melanoma', 'Disease', 'MESH:C536494', (85, 99))	('HDAC4', 'Gene', '9759', (24, 29))	('HDAC4', 'Gene', '9759', (144, 149))	('uveal melanoma', 'Phenotype', 'HP:0007716', (174, 188))	('uveal melanoma', 'Disease', (85, 99))
112180	31871618	Recent work from our group, which focused on BRAF-mutant melanoma, identified an increased dependency on HDAC8 activity following MAPK pathway inhibition.	('HDAC8', 'Gene', '55869', (105, 110))	('activity', 'MPA', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('MAPK', 'molecular_function', 'GO:0004707', ('130', '134'))	('HDAC8', 'Gene', (105, 110))	('dependency', 'MPA', (91, 101))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('MAPK pathway', 'Pathway', (130, 142))	('inhibition', 'NegReg', (143, 153))	('BRAF-mutant', 'Var', (45, 56))
112185	31871618	Although follow-up experiments demonstrated that co-inhibition of MEK and AKT improved the durability of the response, it did not prevent resistance.	('co-inhibition', 'Var', (49, 62))	('MEK', 'Protein', (66, 69))	('AKT', 'Gene', '207', (74, 77))	('AKT', 'Gene', (74, 77))	('improved', 'PosReg', (78, 86))	('durability of the response', 'CPA', (91, 117))
112186	31871618	Among these, the endothelin-B receptor was found to be upregulated upon MEK inhibition.	('upregulated', 'PosReg', (55, 66))	('MEK', 'Gene', (72, 75))	('inhibition', 'Var', (76, 86))	('endothelin-B receptor', 'Gene', '1910', (17, 38))	('endothelin-B receptor', 'Gene', (17, 38))
112192	31871618	There is growing evidence across multiple tumor types that the use of targeted therapies such as BRAF and MEK inhibitors lead to epigenetic genetic changes that allow for therapeutic escape.	('BRAF', 'Gene', (97, 101))	('tumor', 'Disease', (42, 47))	('allow', 'Reg', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('MEK', 'Gene', (106, 109))	('epigenetic', 'MPA', (129, 139))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('lead to', 'Reg', (121, 128))	('therapeutic escape', 'CPA', (171, 189))	('inhibitors', 'Var', (110, 120))
112205	30716094	Both somatic and germline mutations in the BRCA1 associated protein-1 (BAP1) gene have been observed in many cancers.	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('BRCA1 associated protein-1', 'Gene', '8314', (43, 69))	('germline mutations', 'Var', (17, 35))	('observed', 'Reg', (92, 100))	('BAP1', 'Gene', '8314', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('BRCA1 associated protein-1', 'Gene', (43, 69))	('BAP1', 'Gene', (71, 75))
112209	30716094	Although mutations in BAP1 are strongly associated with metastatic UMs (84%), it is not frequent in non-metastatic tumors (4%).	('metastatic UMs', 'Disease', (56, 70))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutations', 'Var', (9, 18))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('BAP1', 'Gene', '8314', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('associated with', 'Reg', (40, 55))	('BAP1', 'Gene', (22, 26))
112210	30716094	Moreover, germline BAP1 mutations are associated with more aggressive UM.	('associated with', 'Reg', (38, 53))	('aggressive', 'CPA', (59, 69))	('BAP1', 'Gene', '8314', (19, 23))	('BAP1', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))
112217	30716094	To determine the genes that may be critical to BAP1 functional pathways, we used the UM data set which is known to have a high level of BAP1 alteration to identify candidates, which were validated in the breast and colon cancer data sets.	('colon cancer', 'Phenotype', 'HP:0003003', (215, 227))	('BAP1', 'Gene', (136, 140))	('BAP1', 'Gene', '8314', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('breast and colon cancer', 'Disease', 'MESH:D001943', (204, 227))	('alteration', 'Var', (141, 151))	('BAP1', 'Gene', '8314', (136, 140))	('BAP1', 'Gene', (47, 51))
112237	30716094	In patients with breast invasive carcinomas, BAP1 is highly positively correlated with NSG00000132153.13 (DHX30), ENSG00000259956.1 (RBM15B), and ENSG00000172046.17 (USP19), in all four categories (Table 5).	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('breast invasive carcinomas', 'Disease', (17, 43))	('USP19', 'Gene', '10869', (166, 171))	('carcinomas', 'Phenotype', 'HP:0030731', (33, 43))	('DHX30', 'Gene', '22907', (106, 111))	('correlated', 'Interaction', (71, 81))	('BAP1', 'Gene', '8314', (45, 49))	('USP19', 'Gene', (166, 171))	('ENSG00000259956.1', 'Var', (114, 131))	('RBM15B', 'Gene', '29890', (133, 139))	('breast invasive carcinomas', 'Disease', 'MESH:D018270', (17, 43))	('BAP1', 'Gene', (45, 49))	('ENSG00000172046.17', 'Var', (146, 164))	('patients', 'Species', '9606', (3, 11))	('NSG00000132153.13', 'Var', (87, 104))	('DHX30', 'Gene', (106, 111))	('RBM15B', 'Gene', (133, 139))	('positively', 'PosReg', (60, 70))	('USP', 'molecular_function', 'GO:0051748', ('166', '169'))
112244	30716094	There are three genes other than BAP1, ENSG00000259956.1 (RBM15B), ENSG00000172046.17 (USP19), and ENSG00000176095.10 (IP6K1), that belong to all three tables.	('RBM15B', 'Gene', '29890', (58, 64))	('USP19', 'Gene', (87, 92))	('IP6K1', 'Gene', (119, 124))	('ENSG00000172046.17', 'Var', (67, 85))	('RBM15B', 'Gene', (58, 64))	('BAP1', 'Gene', '8314', (33, 37))	('USP19', 'Gene', '10869', (87, 92))	('ENSG00000176095.10', 'Var', (99, 117))	('BAP1', 'Gene', (33, 37))	('IP6K1', 'Gene', '9807', (119, 124))	('ENSG00000259956.1', 'Var', (39, 56))	('USP', 'molecular_function', 'GO:0051748', ('87', '90'))
112254	30716094	There is a study showing that mutation of BAP1 only significantly affected overall survival in female patients with RCC.	('BAP1', 'Gene', '8314', (42, 46))	('mutation', 'Var', (30, 38))	('patients', 'Species', '9606', (102, 110))	('BAP1', 'Gene', (42, 46))	('affected', 'Reg', (66, 74))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))
112268	30716094	Also, a recent study shows that biallelic inactivation of BAP1 is rare in breast cancer.	('breast cancer', 'Disease', (74, 87))	('BAP1', 'Gene', (58, 62))	('biallelic inactivation', 'Var', (32, 54))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('BAP1', 'Gene', '8314', (58, 62))
112275	30716094	BAP1, which is expressed in a temporal and spatial pattern during breast development and remodeling, binds to the BRCA1 RING finger motif, and pathogenic mutations in that domain negatively impact BAP1 binding.	('BAP1', 'Gene', (0, 4))	('binding', 'Interaction', (202, 209))	('binds', 'Interaction', (101, 106))	('BRCA1', 'Gene', '672', (114, 119))	('negatively impact', 'NegReg', (179, 196))	('BAP1', 'Gene', '8314', (197, 201))	('mutations in', 'Var', (154, 166))	('BRCA1', 'Gene', (114, 119))	('binding', 'molecular_function', 'GO:0005488', ('202', '209'))	('BAP1', 'Gene', '8314', (0, 4))	('BAP1', 'Gene', (197, 201))
112276	30716094	Additionally, a decrease in the level of BRCA1 protein has been observed in the malignant mesothelioma cells with BAP1 deletion, while transduction of the mutants as well as WT BAP1 results in an increase in the level of BRCA1 protein.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (80, 102))	('protein', 'cellular_component', 'GO:0003675', ('227', '234'))	('decrease', 'NegReg', (16, 24))	('BRCA1', 'Gene', '672', (41, 46))	('malignant mesothelioma', 'Disease', (80, 102))	('BRCA1', 'Gene', '672', (221, 226))	('level', 'MPA', (32, 37))	('deletion', 'Var', (119, 127))	('BAP1', 'Gene', '8314', (114, 118))	('BRCA1', 'Gene', (41, 46))	('BAP1', 'Gene', '8314', (177, 181))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('transduction', 'biological_process', 'GO:0009293', ('135', '147'))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (80, 102))	('BAP1', 'Gene', (114, 118))	('BRCA1', 'Gene', (221, 226))	('increase', 'PosReg', (196, 204))	('BAP1', 'Gene', (177, 181))
112282	30716094	Importantly, a mutation in USP19 and LAMB2 has been observed in 12 patients with UM at high-risk of metastasis.	('observed', 'Reg', (52, 60))	('mutation', 'Var', (15, 23))	('patients', 'Species', '9606', (67, 75))	('USP19', 'Gene', '10869', (27, 32))	('LAMB2', 'Gene', '3913', (37, 42))	('USP', 'molecular_function', 'GO:0051748', ('27', '30'))	('LAMB2', 'Gene', (37, 42))	('USP19', 'Gene', (27, 32))
112288	30716094	In metastatic UM, monosomy of chromosome 3 has been associated with short survival, compared to metastases with disomy or partial change in chromosome 3.	('chromosome', 'cellular_component', 'GO:0005694', ('30', '40'))	('metastases', 'Disease', 'MESH:D009362', (96, 106))	('disomy', 'Disease', (112, 118))	('disomy', 'Disease', 'MESH:D024182', (112, 118))	('monosomy', 'Var', (18, 26))	('chromosome', 'cellular_component', 'GO:0005694', ('140', '150'))	('metastases', 'Disease', (96, 106))
112290	30716094	Importantly, allelic loss of several distinct regions on chromosome 3p including 3p25, 3p21.22, 3p21.3, 3p12.13 and 3p14 is one of the earliest and most frequent genomic abnormalities involved in a wide spectrum of major epithelial cancers including breast and colon.	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('3p21.3', 'Var', (96, 102))	('allelic loss', 'Var', (13, 25))	('epithelial cancers', 'Disease', (221, 239))	('3p12.13', 'Var', (104, 111))	('chromosome', 'cellular_component', 'GO:0005694', ('57', '67'))	('p14', 'Gene', (117, 120))	('breast', 'Disease', (250, 256))	('colon', 'Disease', (261, 266))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('p14', 'Gene', '1029', (117, 120))	('epithelial cancers', 'Disease', 'MESH:D000077216', (221, 239))	('involved', 'Reg', (184, 192))
112291	30716094	Chromosome 3p deletions occur in more than 80% of breast carcinomas.	('breast carcinomas', 'Phenotype', 'HP:0003002', (50, 67))	('occur', 'Reg', (24, 29))	('breast carcinoma', 'Phenotype', 'HP:0003002', (50, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('deletions', 'Var', (14, 23))	('breast carcinomas', 'Disease', 'MESH:D001943', (50, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('breast carcinomas', 'Disease', (50, 67))
112320	29085693	The molecular study of the urinary bladder tumor specimen identified mutation of the GNAQ gene, which has been suggested to be an early molecular event in the pathogenetic course of over 80% of uveal melanomas.	('bladder tumor', 'Disease', 'MESH:D001749', (35, 48))	('uveal melanomas', 'Phenotype', 'HP:0007716', (194, 209))	('melanomas', 'Phenotype', 'HP:0002861', (200, 209))	('bladder tumor', 'Phenotype', 'HP:0009725', (35, 48))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('uveal melanoma', 'Phenotype', 'HP:0007716', (194, 208))	('GNAQ', 'Gene', (85, 89))	('mutation', 'Var', (69, 77))	('bladder tumor', 'Disease', (35, 48))	('uveal melanomas', 'Disease', 'MESH:C536494', (194, 209))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('GNAQ', 'Gene', '2776', (85, 89))	('uveal melanomas', 'Disease', (194, 209))
112347	29085693	The genetic analysis proved positive for the exon 4 c.548G>A p.R183Q GNAQ mutation while it provided negative results for the rest of all.	('c.548G>A', 'Mutation', 'rs397514698', (52, 60))	('GNAQ', 'Gene', '2776', (69, 73))	('positive', 'Reg', (28, 36))	('c.548G>A p.R183Q', 'Var', (52, 68))	('GNAQ', 'Gene', (69, 73))	('p.R183Q', 'Var', (61, 68))	('p.R183Q', 'Mutation', 'rs397514698', (61, 68))
112361	29085693	In fact, it has been suggested that GNAQ mutations are an early event characterizing over 80% of uveal melanomas.	('mutations', 'Var', (41, 50))	('uveal melanomas', 'Disease', 'MESH:C536494', (97, 112))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('GNAQ', 'Gene', '2776', (36, 40))	('uveal melanomas', 'Disease', (97, 112))	('uveal melanomas', 'Phenotype', 'HP:0007716', (97, 112))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))	('GNAQ', 'Gene', (36, 40))
112362	29085693	Therefore, the presence of that specific mutation in the material retrieved from the TURBT specimen confirmed the fact that the metastasis to the urinary bladder originated from the uveal melanoma diagnosed 25 years ago.	('uveal melanoma', 'Disease', (182, 196))	('mutation', 'Var', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('uveal melanoma', 'Phenotype', 'HP:0007716', (182, 196))	('uveal melanoma', 'Disease', 'MESH:C536494', (182, 196))
112364	28809862	GNAQ and GNA11 mutations and downstream YAP activation in choroidal nevi Mutations in GNAQ/11 genes are considered an early event in the development of uveal melanoma that may derive from a pre-existing nevus.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('choroidal nevi', 'Phenotype', 'HP:0025314', (58, 72))	('GNAQ', 'Gene', '2776', (86, 90))	('YAP', 'Gene', '10413', (40, 43))	('activation', 'PosReg', (44, 54))	('uveal melanoma', 'Disease', (152, 166))	('uveal melanoma', 'Disease', 'MESH:C536494', (152, 166))	('uveal melanoma', 'Phenotype', 'HP:0007716', (152, 166))	('pre', 'molecular_function', 'GO:0003904', ('190', '193'))	('GNAQ', 'Gene', (0, 4))	('nevi', 'Phenotype', 'HP:0003764', (68, 72))	('GNA11', 'Gene', '2767', (9, 14))	('YAP', 'Gene', (40, 43))	('Mutations', 'Var', (73, 82))	('nevus', 'Phenotype', 'HP:0003764', (203, 208))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('GNAQ', 'Gene', (86, 90))
112365	28809862	The Hippo pathway, by way of YAP activation, rather than MAP kinase, has a role in the oncogenic capacity of GNAQ/11 mutations.	('mutations', 'Var', (117, 126))	('MAP', 'molecular_function', 'GO:0004239', ('57', '60'))	('activation', 'PosReg', (33, 43))	('GNAQ', 'Gene', (109, 113))	('YAP', 'Gene', '10413', (29, 32))	('GNAQ', 'Gene', '2776', (109, 113))	('oncogenic capacity', 'CPA', (87, 105))	('Hippo pathway', 'Pathway', (4, 17))	('YAP', 'Gene', (29, 32))
112366	28809862	We investigated 16 nevi from 13 human eyes for driver GNAQ/11 mutations using droplet digital PCR and determined whether nevi are clonal by quantifying mutant nevus cell fractions.	('GNAQ', 'Gene', (54, 58))	('nevus', 'Phenotype', 'HP:0003764', (159, 164))	('nevi', 'Phenotype', 'HP:0003764', (121, 125))	('nevi', 'Phenotype', 'HP:0003764', (19, 23))	('GNAQ', 'Gene', '2776', (54, 58))	('human', 'Species', '9606', (32, 37))	('mutations', 'Var', (62, 71))
112368	28809862	For 15 out of 16 nevi, a GNAQ/11 mutation was detected in the nevus cells albeit at a low frequency with a median of 13%.	('mutation', 'Var', (33, 41))	('GNAQ', 'Gene', (25, 29))	('nevi', 'Phenotype', 'HP:0003764', (17, 21))	('nevus', 'Phenotype', 'HP:0003764', (62, 67))	('GNAQ', 'Gene', '2776', (25, 29))
112370	28809862	Our analysis suggests that a mutation in GNAQ/11 occurs in a subset of choroidal nevus cells.	('mutation', 'Var', (29, 37))	('GNAQ', 'Gene', '2776', (41, 45))	('choroidal nevus', 'Phenotype', 'HP:0025314', (71, 86))	('nevus', 'Phenotype', 'HP:0003764', (81, 86))	('GNAQ', 'Gene', (41, 45))	('occurs', 'Reg', (49, 55))
112371	28809862	We hypothesise that GNAQ/11 mutant-driven extracellular mitogenic signalling involving YAP activation leads to accumulation of wild-type nevus cells.	('GNAQ', 'Gene', '2776', (20, 24))	('extracellular', 'cellular_component', 'GO:0005576', ('42', '55'))	('mutant-driven', 'Var', (28, 41))	('YAP', 'Gene', (87, 90))	('signalling', 'biological_process', 'GO:0023052', ('66', '76'))	('accumulation', 'PosReg', (111, 123))	('GNAQ', 'Gene', (20, 24))	('nevus', 'Phenotype', 'HP:0003764', (137, 142))	('extracellular mitogenic signalling', 'MPA', (42, 76))	('YAP', 'Gene', '10413', (87, 90))
112374	28809862	We hypothesise that a choroidal nevus, as a potential precursor of UM, may already harbour clonal driver mutations, just as many cutaneous nevi are reported to present the typical V600E BRAF mutation associated with CM.	('BRAF', 'Gene', (186, 190))	('choroidal nevus', 'Phenotype', 'HP:0025314', (22, 37))	('V600E', 'Var', (180, 185))	('nevus', 'Phenotype', 'HP:0003764', (32, 37))	('nevi', 'Phenotype', 'HP:0003764', (139, 143))	('CM', 'Phenotype', 'HP:0012056', (216, 218))	('UM', 'Phenotype', 'HP:0007716', (67, 69))	('associated', 'Reg', (200, 210))	('BRAF', 'Gene', '673', (186, 190))	('V600E', 'Mutation', 'rs113488022', (180, 185))
112375	28809862	Mutations in BRAF are found in about 66% of CM while 83-95% of UM carry a mutation in either the GNAQ or GNA11 gene.	('CM', 'Phenotype', 'HP:0012056', (44, 46))	('mutation', 'Var', (74, 82))	('BRAF', 'Gene', '673', (13, 17))	('GNA11', 'Gene', (105, 110))	('GNAQ', 'Gene', '2776', (97, 101))	('UM', 'Phenotype', 'HP:0007716', (63, 65))	('BRAF', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (105, 110))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', (97, 101))
112376	28809862	Although MAPK (mitogen-activated protein kinase) signalling is activated by the BRAF V600E mutation, the oncogenic effect of GNAQ/11 is still to be defined.	('BRAF', 'Gene', (80, 84))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('GNAQ', 'Gene', '2776', (125, 129))	('signalling', 'biological_process', 'GO:0023052', ('49', '59'))	('V600E', 'Mutation', 'rs113488022', (85, 90))	('activated', 'PosReg', (63, 72))	('GNAQ', 'Gene', (125, 129))	('V600E', 'Var', (85, 90))	('BRAF', 'Gene', '673', (80, 84))	('MAPK', 'molecular_function', 'GO:0004707', ('9', '13'))
112377	28809862	A recent publication showed that MAPK activation has a minimal role in the oncogenic potential of GNAQ mutations; however, a central role has been attributed to the YAP/Hippo pathway.	('mutations', 'Var', (103, 112))	('YAP', 'Gene', (165, 168))	('MAPK', 'molecular_function', 'GO:0004707', ('33', '37'))	('GNAQ', 'Gene', (98, 102))	('YAP', 'Gene', '10413', (165, 168))	('GNAQ', 'Gene', '2776', (98, 102))	('MAPK', 'Gene', (33, 37))	('MAPK activation', 'biological_process', 'GO:0000187', ('33', '48'))
112382	28809862	Yu et al showed that GNAQ/11 mutant activity is controlled by YAP activation (nuclear YAP expression) in several UM cell lines.	('GNAQ', 'Gene', '2776', (21, 25))	('YAP', 'Gene', (86, 89))	('mutant', 'Var', (29, 35))	('activity', 'MPA', (36, 44))	('GNAQ', 'Gene', (21, 25))	('UM', 'Phenotype', 'HP:0007716', (113, 115))	('YAP', 'Gene', '10413', (62, 65))	('YAP', 'Gene', '10413', (86, 89))	('YAP', 'Gene', (62, 65))
112383	28809862	In this study, we analysed the frequency of GNAQ/11 mutations in choroidal nevi and analysed YAP activation as a possible downstream effect.	('mutations', 'Var', (52, 61))	('GNAQ', 'Gene', (44, 48))	('choroidal nevi', 'Phenotype', 'HP:0025314', (65, 79))	('YAP', 'Gene', (93, 96))	('GNAQ', 'Gene', '2776', (44, 48))	('nevi', 'Phenotype', 'HP:0003764', (75, 79))	('YAP', 'Gene', '10413', (93, 96))
112386	28809862	GNAQ/11 mutations (GNAQ Q209L, GNAQ Q209P, GNAQ R1830, GNA11 Q209L and GNA11 R183C) and the BRAF (V600E) mutation were analysed in choroidal nevi and dermal nevi using digital PCR.	('Q209P', 'Var', (36, 41))	('GNA11', 'Gene', (71, 76))	('GNAQ', 'Gene', '2776', (31, 35))	('Q209L', 'Mutation', 'rs121913492', (61, 66))	('GNAQ', 'Gene', (31, 35))	('nevi', 'Phenotype', 'HP:0003764', (157, 161))	('GNA11', 'Gene', (55, 60))	('nevi', 'Phenotype', 'HP:0003764', (141, 145))	('dermal nevi', 'Disease', (150, 161))	('V600E', 'Mutation', 'rs113488022', (98, 103))	('choroidal nevi', 'Phenotype', 'HP:0025314', (131, 145))	('GNAQ', 'Gene', '2776', (19, 23))	('GNAQ', 'Gene', '2776', (43, 47))	('choroidal nevi', 'Disease', (131, 145))	('BRAF', 'Gene', '673', (92, 96))	('GNAQ', 'Gene', (19, 23))	('GNAQ', 'Gene', (43, 47))	('BRAF', 'Gene', (92, 96))	('Q209P', 'Mutation', 'rs121913492', (36, 41))	('GNA11', 'Gene', '2767', (71, 76))	('R183C', 'Var', (77, 82))	('GNA11', 'Gene', '2767', (55, 60))	('Q209L', 'Mutation', 'rs121913492', (24, 29))	('GNAQ', 'Gene', '2776', (0, 4))	('R183C', 'Mutation', 'p.R183C', (77, 82))	('R1830', 'Var', (48, 53))	('GNAQ', 'Gene', (0, 4))
112391	28809862	In the current study, 16 nevi from 13 post-mortem eyes of 12 donors were analysed for GNAQ/11 hotspot mutations.	('nevi', 'Phenotype', 'HP:0003764', (25, 29))	('GNAQ', 'Gene', '2776', (86, 90))	('donor', 'Species', '9606', (61, 66))	('mutations', 'Var', (102, 111))	('GNAQ', 'Gene', (86, 90))
112394	28809862	Mutations in GNAQ and GNA11 were distributed equally in this cohort, similar to our observations in UM.	('GNA11', 'Gene', (22, 27))	('UM', 'Phenotype', 'HP:0007716', (100, 102))	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (22, 27))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', '2776', (13, 17))
112399	28809862	We examined tissues for the presence of chromosome aberrations as potential progression markers and as the absence of BAP1 is correlated with monosomy 3 in UM, we also performed immunohistochemistry for BAP1 as another progression marker.	('BAP1', 'Gene', '8314', (203, 207))	('chromosome', 'cellular_component', 'GO:0005694', ('40', '50'))	('BAP1', 'Gene', (203, 207))	('monosomy 3', 'Disease', (142, 152))	('BAP1', 'Gene', '8314', (118, 122))	('UM', 'Phenotype', 'HP:0007716', (156, 158))	('BAP1', 'Gene', (118, 122))	('absence', 'Var', (107, 114))
112401	28809862	We determined the presence of GNAQ/11 and BRAF mutations in dermal cutaneous nevi (n=5) as a control.	('BRAF', 'Gene', '673', (42, 46))	('GNAQ', 'Gene', (30, 34))	('mutations', 'Var', (47, 56))	('nevi', 'Phenotype', 'HP:0003764', (77, 81))	('BRAF', 'Gene', (42, 46))	('GNAQ', 'Gene', '2776', (30, 34))
112403	28809862	The mutant fraction of dermal nevi is in marked contrast with the 13% GNAQ/11 mutant cells in choroidal nevi and emphasises potential differences between BRAF and GNAQ/11-driven nevus development.	('nevi', 'Phenotype', 'HP:0003764', (104, 108))	('mutant', 'Var', (4, 10))	('GNAQ', 'Gene', '2776', (70, 74))	('BRAF', 'Gene', '673', (154, 158))	('GNAQ', 'Gene', '2776', (163, 167))	('choroidal nevi', 'Phenotype', 'HP:0025314', (94, 108))	('dermal nevi', 'Disease', (23, 34))	('BRAF', 'Gene', (154, 158))	('nevi', 'Phenotype', 'HP:0003764', (30, 34))	('GNAQ', 'Gene', (70, 74))	('nevus', 'Phenotype', 'HP:0003764', (178, 183))	('GNAQ', 'Gene', (163, 167))
112404	28809862	This suggests besides that either other genetic factors are involved or that GNAQ/11 mutant clones can also drive the proliferation of the wild-type melanocytes in the nevus.	('GNAQ', 'Gene', (77, 81))	('proliferation', 'CPA', (118, 131))	('nevus', 'Phenotype', 'HP:0003764', (168, 173))	('mutant', 'Var', (85, 91))	('GNAQ', 'Gene', '2776', (77, 81))	('drive', 'PosReg', (108, 113))
112408	28809862	In the only nevus (12B) without a GNAQ/11 mutation, positive YAP expression in nuclei was also detected.	('nevus', 'Phenotype', 'HP:0003764', (12, 17))	('mutation', 'Var', (42, 50))	('detected', 'Reg', (95, 103))	('YAP', 'Gene', '10413', (61, 64))	('GNAQ', 'Gene', (34, 38))	('YAP', 'Gene', (61, 64))	('GNAQ', 'Gene', '2776', (34, 38))
112409	28809862	This indicates that YAP activation may occur independently of the presence of a GNAQ/11 mutation.	('mutation', 'Var', (88, 96))	('YAP', 'Gene', (20, 23))	('GNAQ', 'Gene', '2776', (80, 84))	('YAP', 'Gene', '10413', (20, 23))	('activation', 'PosReg', (24, 34))	('GNAQ', 'Gene', (80, 84))
112412	28809862	As hypothesised, human choroidal nevi did harbour a GNAQ/11 mutation.	('mutation', 'Var', (60, 68))	('human', 'Species', '9606', (17, 22))	('GNAQ', 'Gene', '2776', (52, 56))	('nevi', 'Phenotype', 'HP:0003764', (33, 37))	('GNAQ', 'Gene', (52, 56))	('choroidal nevi', 'Phenotype', 'HP:0025314', (23, 37))
112415	28809862	described a positive correlation between mutant GNAQ/11 and aberrant YAP activation (nuclear expression) in UM cell lines.	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('GNAQ', 'Gene', '2776', (48, 52))	('mutant', 'Var', (41, 47))	('YAP', 'Gene', (69, 72))	('GNAQ', 'Gene', (48, 52))	('YAP', 'Gene', '10413', (69, 72))	('aberrant', 'Var', (60, 68))
112416	28809862	In our study, the nevi with a GNAQ/11 mutation all showed nuclear YAP, confirming this positive correlation between mutant GNAQ/11 and YAP activation.	('nevi', 'Phenotype', 'HP:0003764', (18, 22))	('YAP', 'Gene', '10413', (135, 138))	('GNAQ', 'Gene', (123, 127))	('YAP', 'Gene', (66, 69))	('GNAQ', 'Gene', (30, 34))	('GNAQ', 'Gene', '2776', (123, 127))	('YAP', 'Gene', (135, 138))	('mutation', 'Var', (38, 46))	('YAP', 'Gene', '10413', (66, 69))	('GNAQ', 'Gene', '2776', (30, 34))
112417	28809862	Moreover, the one nevus without GNAQ/11 mutations still possessed YAP activity in the nucleus.	('GNAQ', 'Gene', (32, 36))	('YAP', 'Gene', (66, 69))	('GNAQ', 'Gene', '2776', (32, 36))	('mutations', 'Var', (40, 49))	('nevus', 'Phenotype', 'HP:0003764', (18, 23))	('YAP', 'Gene', '10413', (66, 69))	('nucleus', 'cellular_component', 'GO:0005634', ('86', '93'))
112418	28809862	This is in accordance with the results of Yu et al who also found evidence of nuclear YAP activity in wild-type UM cell lines (Mel285 and Mel290), suggesting that YAP activation is not solely dependent on GNAQ/11 mutations, and that other factors may contribute to YAP activity.	('YAP', 'Gene', (265, 268))	('YAP', 'Gene', (86, 89))	('activation', 'PosReg', (167, 177))	('YAP', 'Gene', (163, 166))	('GNAQ', 'Gene', '2776', (205, 209))	('UM', 'Phenotype', 'HP:0007716', (112, 114))	('mutations', 'Var', (213, 222))	('YAP', 'Gene', '10413', (86, 89))	('YAP', 'Gene', '10413', (265, 268))	('GNAQ', 'Gene', (205, 209))	('YAP', 'Gene', '10413', (163, 166))
112419	28809862	In summary, we found that GNAQ/11 mutant clones make up a fraction of the cells in choroidal nevi.	('choroidal nevi', 'Disease', (83, 97))	('GNAQ', 'Gene', (26, 30))	('nevi', 'Phenotype', 'HP:0003764', (93, 97))	('choroidal nevi', 'Phenotype', 'HP:0025314', (83, 97))	('GNAQ', 'Gene', '2776', (26, 30))	('mutant', 'Var', (34, 40))
112432	28544818	The most common genetic targets, BRAF and NRAS, are frequently mutated in nearly 50% and 20% melanomas, respectively 11, which result in hyperactivation of MAPK and PI3K pathways and subsequent uncontrolled proliferation of melanoma cells 6, 12.	('mutated', 'Var', (63, 70))	('MAPK', 'molecular_function', 'GO:0004707', ('156', '160'))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('BRAF', 'Gene', (33, 37))	('MAPK', 'Gene', '5594', (156, 160))	('NRAS', 'Gene', (42, 46))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('PI3K', 'molecular_function', 'GO:0016303', ('165', '169'))	('uncontrolled proliferation', 'CPA', (194, 220))	('melanoma', 'Disease', 'MESH:D008545', (224, 232))	('hyperactivation', 'PosReg', (137, 152))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('NRAS', 'Gene', '4893', (42, 46))	('melanomas', 'Disease', 'MESH:D008545', (93, 102))	('MAPK', 'Gene', (156, 160))	('melanomas', 'Disease', (93, 102))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('melanoma', 'Disease', (224, 232))
112433	28544818	In addition, genetic variations of key cell cycle regulators and transcriptional factors, such as CDKN2A and microphthalmia-associated transcription factor (MITF), have also greatly contributed to melanoma carcinogenesis 13, 14, 15.	('cell cycle', 'biological_process', 'GO:0007049', ('39', '49'))	('melanoma carcinogenesis', 'Disease', (197, 220))	('transcription factor', 'molecular_function', 'GO:0000981', ('135', '155'))	('transcription', 'biological_process', 'GO:0006351', ('135', '148'))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('microphthalmia', 'Phenotype', 'HP:0000568', (109, 123))	('microphthalmia-associated transcription factor', 'Gene', '4286', (109, 155))	('MITF', 'Gene', '4286', (157, 161))	('MITF', 'Gene', (157, 161))	('CDKN2A', 'Gene', (98, 104))	('genetic variations', 'Var', (13, 31))	('CDKN2A', 'Gene', '1029', (98, 104))	('microphthalmia-associated transcription factor', 'Gene', (109, 155))	('contributed to', 'Reg', (182, 196))	('melanoma carcinogenesis', 'Disease', 'MESH:D063646', (197, 220))
112438	28544818	Thus, dysregulation of ubiquitination has broad consequences that may lead to aberration of tumor-promoting pathways and tumor-suppressing pathways.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (121, 126))	('dysregulation', 'Var', (6, 19))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('lead to', 'Reg', (70, 77))	('ubiquitination', 'MPA', (23, 37))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
112445	28544818	Therefore, dysregulated deubiquitination can lead to improper protein localization and protein-protein interactions, intracellular metabolic disorder, accumulation of misfolded proteins, amplification of inflammatory response, as well as aberrant activation of enzymes and signaling pathways, which are detrimental to the cellular homeostasis and greatly involve in the pathogenesis of many diseases 26, 41.	('protein-protein interactions', 'MPA', (87, 115))	('aberrant', 'Var', (238, 246))	('lead to', 'Reg', (45, 52))	('intracellular', 'cellular_component', 'GO:0005622', ('117', '130'))	('signaling', 'biological_process', 'GO:0023052', ('273', '282'))	('protein', 'Protein', (62, 69))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('pathogenesis', 'biological_process', 'GO:0009405', ('370', '382'))	('amplification', 'PosReg', (187, 200))	('activation', 'PosReg', (247, 257))	('inflammatory response', 'biological_process', 'GO:0006954', ('204', '225'))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('deubiquitination', 'biological_process', 'GO:0016579', ('24', '40'))	('dysregulated', 'Var', (11, 23))	('accumulation', 'PosReg', (151, 163))	('protein localization', 'biological_process', 'GO:0008104', ('62', '82'))	('metabolic disorder', 'Disease', 'MESH:D008659', (131, 149))	('improper', 'MPA', (53, 61))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('metabolic disorder', 'Disease', (131, 149))	('inflammatory response', 'CPA', (204, 225))	('metabolic disorder', 'Phenotype', 'HP:0001939', (131, 149))	('cellular homeostasis', 'biological_process', 'GO:0019725', ('322', '342'))	('deubiquitination', 'MPA', (24, 40))	('involve', 'Reg', (355, 362))
112451	28544818	Conventionally, the precise site of ubiquitination for a single protein is revealed by mutagenesis of the putative target residues from lysine into arginine, which abolished the capacity to be ubiquitinated, and the subsequent detection is usually achieved through immunoblotting analysis 44, 45.	('abolished', 'NegReg', (164, 173))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('mutagenesis', 'Var', (87, 98))	('be ubiquitinated', 'MPA', (190, 206))	('mutagenesis', 'biological_process', 'GO:0006280', ('87', '98'))	('lysine', 'Chemical', 'MESH:D008239', (136, 142))	('arginine', 'Chemical', 'MESH:D001120', (148, 156))	('capacity', 'MPA', (178, 186))
112462	28544818	In addition to the already known driver mutations, the genetic variations of ubiquitination-related enzymes uncovered by high-throughput sequencing are also greatly implicated in melanoma tumorigenesis, with BRCA1-associated protein-1 (BAP1), F-box and WD repeat domain-containing 7 (FBXW7) and PARK2 as the best representations.	('tumor', 'Disease', (188, 193))	('BRCA1-associated protein-1', 'Gene', (208, 234))	('FBXW7', 'Gene', (284, 289))	('FBXW7', 'Gene', '55294', (284, 289))	('implicated', 'Reg', (165, 175))	('variations', 'Var', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('protein', 'cellular_component', 'GO:0003675', ('225', '232'))	('F-box and WD repeat domain-containing 7', 'Gene', '55294', (243, 282))	('BAP1', 'Gene', '8314', (236, 240))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('BRCA1-associated protein-1', 'Gene', '8314', (208, 234))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanoma', 'Disease', (179, 187))	('PARK2', 'Gene', (295, 300))	('BAP1', 'Gene', (236, 240))	('PARK2', 'Gene', '5071', (295, 300))
112464	28544818	The mutations of BAP1 have been first reported in a small number of breast and lung cancer samples, and recently implicated in the pathogenesis of melanoma 60, 61.	('breast and lung cancer', 'Disease', 'MESH:D001943', (68, 90))	('pathogenesis', 'biological_process', 'GO:0009405', ('131', '143'))	('implicated', 'Reg', (113, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('BAP1', 'Gene', '8314', (17, 21))	('melanoma', 'Disease', (147, 155))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('mutations', 'Var', (4, 13))	('BAP1', 'Gene', (17, 21))
112465	28544818	discovered that the inactivating somatic mutations of BAP1 were frequently identified in 84% metastasizing uveal melanomas, including 15 mutations causing premature protein termination, and six affecting its ubiquitin UCH domains, which were associated with the significant decrease in BAP1 mRNA level 62.	('BAP1', 'Gene', '8314', (286, 290))	('BAP1', 'Gene', '8314', (54, 58))	('inactivating', 'Reg', (20, 32))	('mutations', 'Var', (41, 50))	('uveal melanomas', 'Disease', 'MESH:C536494', (107, 122))	('decrease', 'NegReg', (274, 282))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('ubiquitin UCH domains', 'MPA', (208, 229))	('BAP1', 'Gene', (286, 290))	('BAP1', 'Gene', (54, 58))	('affecting', 'Reg', (194, 203))	('causing', 'Reg', (147, 154))	('uveal melanomas', 'Disease', (107, 122))	('uveal melanomas', 'Phenotype', 'HP:0007716', (107, 122))	('ubiquitin', 'molecular_function', 'GO:0031386', ('208', '217'))	('premature protein termination', 'MPA', (155, 184))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('mutations', 'Var', (137, 146))
112466	28544818	The knockdown of BAP1 gene in melanoma cell harboring undetectable BAP1 mutation developed a rounded epithelioid morphology and grew as multicellular nonadherent spheroids, paralleled with the gene expression profile shifting to a metastasizing pattern.	('multicellular nonadherent spheroids', 'CPA', (136, 171))	('grew', 'CPA', (128, 132))	('gene expression', 'biological_process', 'GO:0010467', ('193', '208'))	('BAP1', 'Gene', '8314', (17, 21))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('BAP1', 'Gene', (17, 21))	('mutation', 'Var', (72, 80))	('melanoma', 'Disease', (30, 38))	('BAP1', 'Gene', '8314', (67, 71))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('BAP1', 'Gene', (67, 71))
112467	28544818	This study evidently implicates mutational inactivation of BAP1 in the acquisition of metastatic competence in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (111, 125))	('uveal melanoma', 'Disease', 'MESH:C536494', (111, 125))	('mutational inactivation', 'Var', (32, 55))	('BAP1', 'Gene', (59, 63))	('uveal melanoma', 'Disease', (111, 125))	('BAP1', 'Gene', '8314', (59, 63))	('implicates', 'Reg', (21, 31))	('metastatic competence', 'CPA', (86, 107))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
112468	28544818	Later on, the germline mutations of BAP1 have been linked to a novel autosomal dominant syndrome characterized by a high penetrance of melanocytic neoplasms.	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (69, 96))	('autosomal dominant syndrome', 'Disease', (69, 96))	('linked to', 'Reg', (51, 60))	('BAP1', 'Gene', '8314', (36, 40))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (135, 156))	('neoplasms', 'Phenotype', 'HP:0002664', (147, 156))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (135, 156))	('BAP1', 'Gene', (36, 40))	('germline mutations', 'Var', (14, 32))	('melanocytic neoplasms', 'Disease', (135, 156))
112469	28544818	More importantly, some affected patients developed uveal or cutaneous melanomas, demonstrating the role of BAP1 mutations in conferring increased melanoma risk 63.Therefore, the mutations of BAP1 contribute to not only melanoma tumorigenesis, but also melanoma metastasis.	('cutaneous melanomas', 'Disease', (60, 79))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('uveal', 'Disease', (51, 56))	('melanoma', 'Disease', 'MESH:D008545', (252, 260))	('melanoma metastasis', 'Disease', (252, 271))	('BAP1', 'Gene', (191, 195))	('melanoma', 'Disease', 'MESH:D008545', (219, 227))	('uveal', 'Disease', 'MESH:D014603', (51, 56))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))	('melanoma metastasis', 'Disease', 'MESH:D009362', (252, 271))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('contribute to', 'Reg', (196, 209))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanoma', 'Disease', (70, 78))	('BAP1', 'Gene', '8314', (107, 111))	('uveal or cutaneous melanomas', 'Phenotype', 'HP:0007716', (51, 79))	('melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('melanoma', 'Disease', (252, 260))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (60, 79))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (60, 79))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('melanoma', 'Disease', (219, 227))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (60, 78))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('patients', 'Species', '9606', (32, 40))	('BAP1', 'Gene', '8314', (191, 195))	('BAP1', 'Gene', (107, 111))	('tumor', 'Disease', (228, 233))	('mutations', 'Var', (178, 187))
112470	28544818	Furthermore, it has been revealed that low BAP1 expression exhibited a worse survival than those with high BAP1 levels 64.	('BAP1', 'Gene', (43, 47))	('BAP1', 'Gene', '8314', (107, 111))	('expression', 'MPA', (48, 58))	('BAP1', 'Gene', (107, 111))	('low', 'Var', (39, 42))	('BAP1', 'Gene', '8314', (43, 47))
112472	28544818	Aside from BAP1, the genetic mutation of another ubiquitin ligase FBXW7 has also contributed to the tumorigenesis of melanoma.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('ubiquitin', 'molecular_function', 'GO:0031386', ('49', '58'))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('BAP1', 'Gene', '8314', (11, 15))	('tumor', 'Disease', (100, 105))	('FBXW7', 'Gene', '55294', (66, 71))	('BAP1', 'Gene', (11, 15))	('contributed', 'Reg', (81, 92))	('genetic mutation', 'Var', (21, 37))	('FBXW7', 'Gene', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
112474	28544818	In a previous study, the inactivated mutations of FBXW7 were reported to occur in 8.1% melanoma patients, with the majority of these mutations in its WD40 domain that disrupts substrate binding and lead to sustained activation of its substrate oncoproteins 68.	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('FBXW7', 'Gene', (50, 55))	('disrupts', 'NegReg', (167, 175))	('oncoproteins', 'Protein', (244, 256))	('substrate binding', 'Interaction', (176, 193))	('mutations', 'Var', (133, 142))	('binding', 'molecular_function', 'GO:0005488', ('186', '193'))	('patients', 'Species', '9606', (96, 104))	('activation', 'PosReg', (216, 226))	('FBXW7', 'Gene', '55294', (50, 55))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
112475	28544818	Notch1, one of the most canonical substrates of FBXW7 69, was remarkably accumulated in cells upon the loss of FBXW7, and then promoted tumor growth and angiogenesis of melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('accumulated', 'PosReg', (73, 84))	('Notch1', 'Gene', (0, 6))	('loss', 'Var', (103, 107))	('angiogenesis', 'CPA', (153, 165))	('melanoma', 'Disease', (169, 177))	('FBXW7', 'Gene', '55294', (48, 53))	('Notch1', 'Gene', '4851', (0, 6))	('FBXW7', 'Gene', '55294', (111, 116))	('FBXW7', 'Gene', (48, 53))	('promoted', 'PosReg', (127, 135))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('angiogenesis', 'biological_process', 'GO:0001525', ('153', '165'))	('FBXW7', 'Gene', (111, 116))	('tumor', 'Disease', (136, 141))
112477	28544818	Notch1 inhibition could potently prevent inactive FBXW7-induced melanoma tumorigenesis, rendering Notch signaling as a promising therapeutic target in the subset of melanoma patients harboring FBXW7 mutations 45.	('prevent', 'NegReg', (33, 40))	('FBXW7', 'Gene', (193, 198))	('FBXW7', 'Gene', (50, 55))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('melanoma', 'Disease', (64, 72))	('Notch', 'Gene', '4851', (98, 103))	('mutations', 'Var', (199, 208))	('inhibition', 'NegReg', (7, 17))	('Notch', 'Gene', (98, 103))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('FBXW7', 'Gene', '55294', (193, 198))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('Notch', 'Gene', '4851', (0, 5))	('melanoma', 'Disease', (165, 173))	('FBXW7', 'Gene', '55294', (50, 55))	('Notch', 'Gene', (0, 5))	('Notch1', 'Gene', (0, 6))	('Notch1', 'Gene', '4851', (0, 6))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('patients', 'Species', '9606', (174, 182))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
112479	28544818	Furthermore, knockdown of FBXW7 showed minimal impact on melanoma cell proliferation, but markedly potentiated the migratory capacity.	('FBXW7', 'Gene', (26, 31))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('potentiated', 'PosReg', (99, 110))	('melanoma', 'Disease', (57, 65))	('FBXW7', 'Gene', '55294', (26, 31))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('knockdown', 'Var', (13, 22))	('migratory capacity', 'CPA', (115, 133))
112480	28544818	Therefore, the inactivation of FBXW7 participates in both the tumorigenesis and progression of melanoma 71.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('tumor', 'Disease', (62, 67))	('melanoma', 'Disease', (95, 103))	('participates', 'Reg', (37, 49))	('FBXW7', 'Gene', '55294', (31, 36))	('FBXW7', 'Gene', (31, 36))	('inactivation', 'Var', (15, 27))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
112483	28544818	An in depth PARK2 gene dosage analysis and sequencing revealed that germline PARK2 mutations were present in 25 cases out of 512 melanoma patients, but only 4 in 562 healthy controls.	('mutations', 'Var', (83, 92))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('PARK2', 'Gene', '5071', (12, 17))	('PARK2', 'Gene', '5071', (77, 82))	('PARK2', 'Gene', (12, 17))	('PARK2', 'Gene', (77, 82))	('patients', 'Species', '9606', (138, 146))
112484	28544818	Through the odds ratio (OR) calculations, the putative PARK2-inactivating variants (including splicing, frameshift, CNVs, and predicted deleterious missense mutations) were strongly associated with melanoma risk when compared with control groups (OR = 3.95, 95% confidence interval = 1.34-15.75).	('frameshift', 'Var', (104, 114))	('splicing', 'Var', (94, 102))	('associated with', 'Reg', (182, 197))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('PARK2', 'Gene', '5071', (55, 60))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('PARK2', 'Gene', (55, 60))	('splicing', 'biological_process', 'GO:0045292', ('94', '102'))	('CNVs', 'Var', (116, 120))	('missense mutations', 'Var', (148, 166))
112485	28544818	In addition, most of the PARK2 germline alterations were heterozygous in these melanoma patients, suggesting that one mutated PARK2 allele is sufficient to modulate melanoma risk 75.	('PARK2', 'Gene', '5071', (25, 30))	('modulate', 'Reg', (156, 164))	('PARK2', 'Gene', (25, 30))	('patients', 'Species', '9606', (88, 96))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('mutated', 'Var', (118, 125))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('PARK2', 'Gene', '5071', (126, 131))	('melanoma', 'Disease', (79, 87))	('melanoma', 'Disease', (165, 173))	('PARK2', 'Gene', (126, 131))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
112512	28544818	The amplification of MITF frequently occurs in melanoma, which results in the transcription of numerous oncogenic genes and tumor growth 14, 90, 91.	('oncogenic genes', 'Gene', (104, 119))	('transcription', 'biological_process', 'GO:0006351', ('78', '91'))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('MITF', 'Gene', '4286', (21, 25))	('MITF', 'Gene', (21, 25))	('amplification', 'Var', (4, 17))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('results in', 'Reg', (63, 73))	('occurs', 'Reg', (37, 43))	('transcription', 'MPA', (78, 91))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
112515	28544818	The serine73 phosphorylation site was essential for MITF ubiquitination and hUBC9-dependent degradation, since the serine to alanine mutation at amino acid 73 (S73A) almost completely abrogated MITF ubiquitination.	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('S73A', 'Mutation', 'p.S73A', (160, 164))	('S73A', 'Var', (160, 164))	('abrogated', 'NegReg', (184, 193))	('MITF ubiquitination', 'Disease', (194, 213))	('MITF ubiquitination', 'Disease', 'MESH:C563003', (52, 71))	('degradation', 'biological_process', 'GO:0009056', ('92', '103'))	('hUBC9', 'Gene', (76, 81))	('serine to alanine mutation at amino acid 73', 'Mutation', 'p.S73A', (115, 158))	('hUBC9', 'Gene', '7329', (76, 81))	('serine73', 'Chemical', '-', (4, 12))	('MITF ubiquitination', 'Disease', 'MESH:C563003', (194, 213))	('MITF ubiquitination', 'Disease', (52, 71))
112516	28544818	Further, lysine 201 was identified as the potential ubiquitination site, for lysine to arginine mutation (K201R) prevented the degradation of MITF by hUBC9 92.	('K201R', 'Mutation', 'p.K201R', (106, 111))	('prevented', 'NegReg', (113, 122))	('hUBC9', 'Gene', (150, 155))	('hUBC9', 'Gene', '7329', (150, 155))	('lysine', 'Chemical', 'MESH:D008239', (9, 15))	('lysine', 'Chemical', 'MESH:D008239', (77, 83))	('arginine', 'Chemical', 'MESH:D001120', (87, 95))	('degradation', 'MPA', (127, 138))	('K201R', 'Var', (106, 111))	('MITF', 'Gene', '4286', (142, 146))	('MITF', 'Gene', (142, 146))	('degradation', 'biological_process', 'GO:0009056', ('127', '138'))
112517	28544818	Since protein phosphorylation may lead to a conformational alteration that exposes regions required for proteolysis, phosphorylation on S73 may favor hUBC9 association and targets MITF protein for ubiquitination on K201.	('protein phosphorylation', 'biological_process', 'GO:0006468', ('6', '29'))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('hUBC9', 'Gene', '7329', (150, 155))	('conformational alteration', 'MPA', (44, 69))	('phosphorylation', 'biological_process', 'GO:0016310', ('117', '132'))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('lead to', 'Reg', (34, 41))	('favor', 'PosReg', (144, 149))	('association', 'Interaction', (156, 167))	('ubiquitination', 'MPA', (197, 211))	('phosphorylation', 'Var', (117, 132))	('proteolysis', 'biological_process', 'GO:0006508', ('104', '115'))	('hUBC9', 'Gene', (150, 155))	('MITF', 'Gene', '4286', (180, 184))	('MITF', 'Gene', (180, 184))
112524	28544818	More importantly, USP13 deficiency resulted in impaired melanoma growth both in vitro and in vivo, and reintroduction of MITF reversed the inhibitory effect of USP13, demonstrating that MITF contributed to melanoma progression under the ubiquitination modification of USP13 95.	('MITF', 'Gene', (186, 190))	('USP', 'molecular_function', 'GO:0051748', ('160', '163'))	('USP13', 'Gene', '8975', (18, 23))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('melanoma', 'Disease', (206, 214))	('MITF', 'Gene', (121, 125))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('impaired melanoma growth', 'Disease', (47, 71))	('USP13', 'Gene', (18, 23))	('USP', 'molecular_function', 'GO:0051748', ('268', '271'))	('USP13', 'Gene', '8975', (160, 165))	('USP', 'molecular_function', 'GO:0051748', ('18', '21'))	('USP13', 'Gene', '8975', (268, 273))	('melanoma', 'Disease', 'MESH:D008545', (206, 214))	('USP13', 'Gene', (160, 165))	('MITF', 'Gene', '4286', (186, 190))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('deficiency', 'Var', (24, 34))	('USP13', 'Gene', (268, 273))	('impaired melanoma growth', 'Disease', 'MESH:D006130', (47, 71))	('MITF', 'Gene', '4286', (121, 125))
112527	28544818	The point mutation analysis showed that lysine 182 and lysine 316 are the two sites essential for MITF's SUMO-conjugation both in vitro and in vivo.	('lysine', 'Chemical', 'MESH:D008239', (55, 61))	('lysine 316', 'Var', (55, 65))	('conjugation', 'biological_process', 'GO:0000746', ('110', '121'))	('MITF', 'Gene', '4286', (98, 102))	('MITF', 'Gene', (98, 102))	('SUMO-conjugation', 'MPA', (105, 121))	('lysine', 'Chemical', 'MESH:D008239', (40, 46))	('lysine', 'Var', (40, 46))
112528	28544818	Furthermore, the SUMOylation-resistant MITF led to the increase of transcriptional activity on some but not other MITF-responsive promoters, implying that MITF's transcriptional output is subtly regulated by the extent of SUMOylation 93.	('MITF', 'Gene', '4286', (114, 118))	('MITF', 'Gene', (114, 118))	('SUMOylation', 'biological_process', 'GO:0016925', ('222', '233'))	('increase', 'PosReg', (55, 63))	('SUMOylation', 'biological_process', 'GO:0016925', ('17', '28'))	('MITF', 'Gene', '4286', (39, 43))	('MITF', 'Gene', (39, 43))	('transcriptional activity', 'MPA', (67, 91))	('MITF', 'Gene', (155, 159))	('SUMOylation-resistant', 'Var', (17, 38))	('MITF', 'Gene', '4286', (155, 159))
112529	28544818	Recently, a germline missense substitution in MITF (Mi-E318K) was identified to occur at a significantly higher frequency in melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('MITF', 'Gene', '4286', (46, 50))	('melanoma', 'Disease', (125, 133))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('patients', 'Species', '9606', (134, 142))	('E318K', 'Mutation', 'rs149617956', (55, 60))	('Mi', 'Chemical', 'MESH:C011506', (52, 54))	('Mi-E318K', 'Var', (52, 60))	('MITF', 'Gene', (46, 50))
112530	28544818	The Mi-E318K mutation severely impaired the SUMOylation of MITF and augmented the MITF protein binding to the HIF1A promoter and increased its transcriptional activity.	('augmented', 'PosReg', (68, 77))	('SUMOylation', 'biological_process', 'GO:0016925', ('44', '55'))	('E318K', 'Mutation', 'rs149617956', (7, 12))	('MITF', 'Gene', (82, 86))	('protein binding', 'molecular_function', 'GO:0005515', ('87', '102'))	('protein', 'Protein', (87, 94))	('increased', 'PosReg', (129, 138))	('Mi-E318K', 'Var', (4, 12))	('HIF1A', 'Gene', (110, 115))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('MITF', 'Gene', '4286', (59, 63))	('impaired', 'NegReg', (31, 39))	('binding', 'Interaction', (95, 102))	('transcriptional activity', 'MPA', (143, 167))	('MITF', 'Gene', '4286', (82, 86))	('SUMOylation', 'MPA', (44, 55))	('MITF', 'Gene', (59, 63))	('Mi', 'Chemical', 'MESH:C011506', (4, 6))	('HIF1A', 'Gene', '3091', (110, 115))
112531	28544818	Moreover, melanoma cells stably expressing Mi-E318K showed enhanced migratory, invasive and clonogenic capacity, but little alteration of proliferation, which were reminiscent of melanoma-initiating cells with increased invasive and division potential but with a slow growth rate 96.	('Mi', 'Chemical', 'MESH:C011506', (43, 45))	('slow growth', 'Phenotype', 'HP:0001510', (263, 274))	('Mi-E318K', 'Var', (43, 51))	('enhanced', 'PosReg', (59, 67))	('E318K', 'Mutation', 'rs149617956', (46, 51))	('migratory', 'CPA', (68, 77))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanoma', 'Disease', 'MESH:D008545', (10, 18))	('melanoma', 'Disease', (179, 187))	('melanoma', 'Disease', (10, 18))
112535	28544818	Loss of p16INK4a abrogates the inhibition of cyclin-dependent kinase 4/6 (CDK4/6)-cyclin D pathway, and then cooperates with hyperactivated RAS-RAF to induce melanoma 98, 99, 100, 101.	('p16INK4a', 'Gene', '1029', (8, 16))	('induce', 'Reg', (151, 157))	('hyperactivated RAS-RAF', 'Disease', (125, 147))	('inhibition', 'MPA', (31, 41))	('abrogates', 'NegReg', (17, 26))	('CDK4/6', 'Gene', (74, 80))	('cyclin', 'molecular_function', 'GO:0016538', ('82', '88'))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('CDK', 'molecular_function', 'GO:0004693', ('74', '77'))	('cyclin-dependent kinase 4/6', 'Gene', (45, 72))	('hyperactivated RAS-RAF', 'Disease', 'MESH:D011504', (125, 147))	('p16INK4a', 'Gene', (8, 16))	('cyclin', 'molecular_function', 'GO:0016538', ('45', '51'))	('Loss', 'Var', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('cyclin-dependent kinase 4/6', 'Gene', '1019;1021', (45, 72))	('melanoma', 'Disease', (158, 166))	('CDK4/6', 'Gene', '1019;1021', (74, 80))
112545	28544818	proved that FBXO4 deficiency induces melanoma in BRAF-activated mice, with the expression of cyclin D accumulated in the nucleus of melanoma cells in the presence of FBXO4 inactivation.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('induces', 'Reg', (29, 36))	('cyclin', 'Gene', (93, 99))	('melanoma', 'Disease', (132, 140))	('expression', 'MPA', (79, 89))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('cyclin', 'molecular_function', 'GO:0016538', ('93', '99'))	('FBXO4', 'Gene', (12, 17))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('deficiency', 'Var', (18, 28))	('accumulated', 'PosReg', (102, 113))	('mice', 'Species', '10090', (64, 68))	('nucleus', 'cellular_component', 'GO:0005634', ('121', '128'))
112546	28544818	Moreover, the FBXO4 I377M mutant in which isoleucine 377 is replaced by methionine was identified to occur at a frequency of 8%, and led to impaired cyclin D1 recruitment and subsequent ubiquitination.	('recruitment', 'MPA', (159, 170))	('cyclin D1', 'Gene', '595', (149, 158))	('I377M', 'Mutation', 'rs149145775', (20, 25))	('cyclin D1', 'Gene', (149, 158))	('isoleucine 377 is replaced by methionine', 'Mutation', 'rs149145775', (42, 82))	('I377M', 'Var', (20, 25))	('ubiquitination', 'MPA', (186, 200))	('impaired', 'NegReg', (140, 148))	('FBXO4', 'Gene', (14, 19))	('isoleucine 377', 'Var', (42, 56))	('cyclin', 'molecular_function', 'GO:0016538', ('149', '155'))
112547	28544818	The function of this mutation seems to be specific for cyclin D1, for FBXO4 I377M is still capable of regulating Trf1, another known substrate of FBXO4.	('Trf1', 'Gene', '7013', (113, 117))	('cyclin D1', 'Gene', '595', (55, 64))	('Trf1', 'Gene', (113, 117))	('cyclin D1', 'Gene', (55, 64))	('regulating', 'Reg', (102, 112))	('I377M', 'Mutation', 'rs149145775', (76, 81))	('cyclin', 'molecular_function', 'GO:0016538', ('55', '61'))	('FBXO4', 'Gene', (70, 75))	('I377M', 'Var', (76, 81))
112554	28544818	Moreover, knockdown of Skp2 led to the accumulation of p27Kip1 and impaired tumorigenicity in melanoma cells, implying the significant role it plays in ubiquitin ligase activity of Skp2 in melanoma growth and cell cycle progression (Fig.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('tumor', 'Disease', (76, 81))	('melanoma growth', 'Disease', (189, 204))	('cell cycle', 'biological_process', 'GO:0007049', ('209', '219'))	('Skp2', 'Gene', (23, 27))	('p27Kip1', 'Gene', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('ubiquitin ligase activity', 'molecular_function', 'GO:0061630', ('152', '177'))	('ubiquitin ligase activity', 'molecular_function', 'GO:0004842', ('152', '177'))	('impaired', 'NegReg', (67, 75))	('p27Kip1', 'Gene', '1027', (55, 62))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', (189, 197))	('knockdown', 'Var', (10, 19))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('melanoma growth', 'Disease', 'MESH:D008545', (189, 204))	('accumulation', 'PosReg', (39, 51))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))	('cell cycle', 'CPA', (209, 219))
112564	28544818	found that USP15 was abundantly expressed in immune cells, and the USP15 deficiency promoted the TCR+CD28-stimulated production of cytokines, such as interleukin 2 (IL-2) and interferon-gamma in naive CD4+ T cells.	('CD28', 'Gene', '940', (101, 105))	('USP', 'molecular_function', 'GO:0051748', ('67', '70'))	('interferon-gamma', 'Gene', '3458', (175, 191))	('IL-2', 'Gene', '3558', (165, 169))	('USP15', 'Gene', (67, 72))	('interleukin 2', 'Gene', (150, 163))	('promoted', 'PosReg', (84, 92))	('interleukin 2', 'Gene', '3558', (150, 163))	('USP15', 'Gene', '9958', (67, 72))	('USP15', 'Gene', (11, 16))	('TCR', 'cellular_component', 'GO:0042101', ('97', '100'))	('production of cytokines', 'MPA', (117, 140))	('TCR', 'biological_process', 'GO:0006283', ('97', '100'))	('CD28', 'Gene', (101, 105))	('USP15', 'Gene', '9958', (11, 16))	('USP', 'molecular_function', 'GO:0051748', ('11', '14'))	('IL-2', 'molecular_function', 'GO:0005134', ('165', '169'))	('IL-2', 'Gene', (165, 169))	('deficiency', 'Var', (73, 83))	('interferon-gamma', 'Gene', (175, 191))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('175', '191'))
112565	28544818	In response to Listeria infection, the Usp15 -/- T-cell reconstituted hosts had reduced bacterial load in the liver and increased survival rate, implying that USP15 is dispensable for T-cell function under infectious challenges.	('survival rate', 'CPA', (130, 143))	('Usp', 'molecular_function', 'GO:0051748', ('39', '42'))	('USP15', 'Gene', '9958', (159, 164))	('bacterial load in the liver', 'MPA', (88, 115))	('USP15', 'Gene', (159, 164))	('reduced', 'NegReg', (80, 87))	('Listeria infection', 'Disease', (15, 33))	('Listeria infection', 'Disease', 'MESH:D008088', (15, 33))	('USP', 'molecular_function', 'GO:0051748', ('159', '162'))	('increased', 'PosReg', (120, 129))	('Usp15 -/-', 'Var', (39, 48))
112569	28544818	Therefore, targeting USP15 could be a valuable strategy for restraining melanoma growth by activating antitumor immunity.	('USP', 'molecular_function', 'GO:0051748', ('21', '24'))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('USP15', 'Gene', (21, 26))	('melanoma growth', 'Disease', (72, 87))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('targeting', 'Var', (11, 20))	('melanoma growth', 'Disease', 'MESH:D008545', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('USP15', 'Gene', '9958', (21, 26))	('activating', 'PosReg', (91, 101))	('tumor', 'Disease', (106, 111))
112570	28544818	reported that B16 melanoma growth and LN metastases were prominently suppressed in T-cell-specific Smad4 knockout mice.	('metastases', 'Disease', 'MESH:D009362', (41, 51))	('knockout', 'Var', (105, 113))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('suppressed', 'NegReg', (69, 79))	('melanoma growth', 'Disease', (18, 33))	('mice', 'Species', '10090', (114, 118))	('metastases', 'Disease', (41, 51))	('melanoma growth', 'Disease', 'MESH:D008545', (18, 33))
112571	28544818	In line with this, CD8+T-cell infiltration was remarkable in the melanomas of Smad4 -/-mice, while it was absent in those of Smad4 +/+ mice, suggesting that the inhibition of Smad4 signaling could potentiate antitumor immunity.	('melanomas', 'Disease', 'MESH:D008545', (65, 74))	('CD8+T-cell infiltration', 'CPA', (19, 42))	('mice', 'Species', '10090', (87, 91))	('signaling', 'biological_process', 'GO:0023052', ('181', '190'))	('melanomas', 'Disease', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('Smad4 -/-mice', 'Var', (78, 91))	('mice', 'Species', '10090', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanomas', 'Phenotype', 'HP:0002861', (65, 74))	('potentiate', 'PosReg', (197, 207))	('tumor', 'Disease', (212, 217))
112577	28544818	Cbl-b-promoting monoubiquitination of CARMA1, a critical signaling molecule in NF-kappaB activation, disrupts its complex formation with Bcl10, which in turn leads to NK-T cells' anergy induction.	('CARMA1', 'Gene', (38, 44))	('Bcl10', 'Gene', '8915', (137, 142))	('complex formation', 'MPA', (114, 131))	('leads to', 'Reg', (158, 166))	('formation', 'biological_process', 'GO:0009058', ('122', '131'))	('Bcl10', 'Gene', (137, 142))	('CARMA1', 'Gene', '84433', (38, 44))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('79', '99'))	('NF-kappaB', 'Gene', '4790', (79, 88))	('signaling molecule', 'molecular_function', 'GO:0048018', ('57', '75'))	("NK-T cells' anergy induction", 'CPA', (167, 195))	('monoubiquitination', 'Var', (16, 34))	('NF-kappaB', 'Gene', (79, 88))	('disrupts', 'NegReg', (101, 109))
112578	28544818	Cbl-b deficiency prominently rescued the decreased IFN-gamma production and failed melanoma rejection observed in inactivated NK cells 119.In addition, genetic deletion of the Cbl-b or targeted inactivation of its E3 ligase activity licensed NK cells to spontaneously reject melanoma metastasis through the ubiquitination of Tyro3, Axl, and Mer, which are members of TAM tyrosine kinase receptors.	('activity', 'MPA', (224, 232))	('Cbl-b', 'Gene', (176, 181))	('inactivation', 'NegReg', (194, 206))	('genetic deletion', 'Var', (152, 168))	('ligase activity', 'molecular_function', 'GO:0016874', ('217', '232'))	('Axl', 'Gene', '558', (332, 335))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('melanoma metastasis', 'Disease', (275, 294))	('Axl', 'Gene', (332, 335))	('melanoma metastasis', 'Disease', 'MESH:D009362', (275, 294))	('E3 ligase', 'Enzyme', (214, 223))	('Tyro3', 'Gene', '7301', (325, 330))	('melanoma', 'Phenotype', 'HP:0002861', (275, 283))	('melanoma', 'Disease', (275, 283))	('Tyro3', 'Gene', (325, 330))	('reject', 'NegReg', (268, 274))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))	('ubiquitination', 'MPA', (307, 321))	('melanoma', 'Disease', 'MESH:D008545', (275, 283))
112599	28544818	Recently, a NAE inhibitor named Pevonedistat (MLN4924) finished its study in phase I clinical trial of melanoma treatment.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('MLN4924', 'Var', (46, 53))	('Pevonedistat', 'Chemical', 'MESH:C539933', (32, 44))	('NAE', 'Chemical', '-', (12, 15))	('melanoma', 'Disease', (103, 111))
112601	28544818	In melanoma, MLN4924 competitively inhibits NAE activity and prevents NEDDylation, resulting in the stabilization of proteins with cullin such as MLX, EID1, and MAGEA6 131.	('cullin', 'Gene', '143384', (131, 137))	('MAGEA6', 'Gene', (161, 167))	('NAE', 'Chemical', '-', (44, 47))	('proteins', 'Protein', (117, 125))	('NEDDylation', 'MPA', (70, 81))	('EID1', 'Gene', '23741', (151, 155))	('prevents', 'NegReg', (61, 69))	('MAGEA6', 'Gene', '4105', (161, 167))	('EID1', 'Gene', (151, 155))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('inhibits', 'NegReg', (35, 43))	('MLX', 'Gene', '6945', (146, 149))	('stabilization', 'MPA', (100, 113))	('MLN4924', 'Var', (13, 20))	('cullin', 'Gene', (131, 137))	('MLX', 'Gene', (146, 149))	('NAE', 'Enzyme', (44, 47))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))
112603	28544818	Cdt1, which mediates DNA replication and accumulates in S phase of cell, and promotes the cancer cell death, is stabilized by MLN4924 through blocking the function of CRL1-Skp2 and the formation of Cul4-Rbx1-Ddb1-Cdt2 complex 129.During a phase I trial of MLN4924 in melanoma, 37 patients received different dosages of MLN4924.	('S phase', 'biological_process', 'GO:0051320', ('56', '63'))	('DNA replication', 'biological_process', 'GO:0006260', ('21', '36'))	('formation', 'biological_process', 'GO:0009058', ('185', '194'))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Ddb1', 'Gene', '1642', (208, 212))	('melanoma', 'Disease', 'MESH:D008545', (267, 275))	('CRL1', 'Gene', '9466', (167, 171))	('MLN4924', 'Var', (256, 263))	('Ddb1', 'Gene', (208, 212))	('cell death', 'biological_process', 'GO:0008219', ('97', '107'))	('Cdt1', 'Gene', '81620', (0, 4))	('Cdt1', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('patients', 'Species', '9606', (280, 288))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('melanoma', 'Disease', (267, 275))	('Cdt2', 'Gene', '51514', (213, 217))	('Rbx1', 'Gene', (203, 207))	('Cdt2', 'Gene', (213, 217))	('Rbx1', 'Gene', '9978', (203, 207))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('cancer', 'Disease', (90, 96))	('CRL1', 'Gene', (167, 171))
112613	28544818	Benzyl ITC (BITC) and phenethyl ITC (PEITC) belong to the isothiocyanates (ITCs) class, both of which can increase the ubiquitination of Mcl-1 through targeting USP9X and attenuate the cells' viability 138, 139.	('ubiquitination', 'MPA', (119, 133))	('Mcl-1', 'Gene', '4170', (137, 142))	('USP', 'molecular_function', 'GO:0051748', ('161', '164'))	('phenethyl', 'Var', (22, 31))	('USP9X', 'Gene', (161, 166))	("cells' viability 138", 'CPA', (185, 205))	('PEITC', 'Chemical', 'MESH:C058305', (37, 42))	('Mcl-1', 'Gene', (137, 142))	('USP9X', 'Gene', '8239', (161, 166))	('targeting', 'Reg', (151, 160))	('increase', 'PosReg', (106, 114))	('isothiocyanates', 'Chemical', 'MESH:D017879', (58, 73))	('attenuate', 'NegReg', (171, 180))
112619	28544818	Moreover, it was reported that MLN4924 could impact the proliferation and cytokine production of T cells in response to alpha-CD3/CD28 stimulation 142, 143.	('MLN4924', 'Var', (31, 38))	('cytokine production', 'biological_process', 'GO:0001816', ('74', '93'))	('CD28', 'Gene', (130, 134))	('proliferation', 'CPA', (56, 69))	('impact', 'NegReg', (45, 51))	('CD28', 'Gene', '940', (130, 134))	('cytokine production', 'MPA', (74, 93))
112620	28544818	However, under high doses of alpha-CD3/CD28 stimulation, MLN4924 tends to impair the proliferation, differentiation, and cytokine (such as IL-2) production of the CD4+T cells 142, 143.	('impair', 'NegReg', (74, 80))	('CD28', 'Gene', (39, 43))	('differentiation', 'CPA', (100, 115))	('CD28', 'Gene', '940', (39, 43))	('IL-2) production', 'biological_process', 'GO:0032623', ('139', '155'))	('IL-2', 'Gene', '3558', (139, 143))	('MLN4924', 'Var', (57, 64))	('IL-2', 'Gene', (139, 143))	('IL-2', 'molecular_function', 'GO:0005134', ('139', '143'))	('proliferation', 'CPA', (85, 98))
112621	28544818	It has been revealed that MLN4924 modulated T cells proliferation and cytokine production through the suppression of CRL activity and the reduction of Ubc12 expression 143, 144.	('reduction', 'NegReg', (138, 147))	('cytokine production', 'biological_process', 'GO:0001816', ('70', '89'))	('cytokine production', 'MPA', (70, 89))	('T cells proliferation', 'CPA', (44, 65))	('CRL', 'Gene', (117, 120))	('modulated', 'Reg', (34, 43))	('MLN4924', 'Var', (26, 33))	('Ubc12', 'Gene', '9040', (151, 156))	('CRL', 'Gene', '133396', (117, 120))	('Ubc12', 'Gene', (151, 156))	('suppression', 'NegReg', (102, 113))
112622	28544818	Based on this, we speculate that the MLN4924-mediated T cells proliferation and cytokine production is dependent on microenvironment, and may subsequently impact the killing effect of T cells on melanoma cells.	('melanoma', 'Disease', (195, 203))	('T cells proliferation', 'CPA', (54, 75))	('MLN4924-mediated', 'Var', (37, 53))	('cytokine production', 'biological_process', 'GO:0001816', ('80', '99'))	('cytokine production', 'MPA', (80, 99))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('impact', 'NegReg', (155, 161))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))
112626	28544818	Mutations of several ubiquitination-associated enzymes, such as BAP1, FBXW7 and PARK2, can lead to melanoma tumorigenesis.	('lead to', 'Reg', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('PARK2', 'Gene', (80, 85))	('tumor', 'Disease', (108, 113))	('FBXW7', 'Gene', '55294', (70, 75))	('PARK2', 'Gene', '5071', (80, 85))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (64, 68))	('FBXW7', 'Gene', (70, 75))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('BAP1', 'Gene', (64, 68))
112627	28544818	While BRAF and NRAS mutation are the most two common mutations in cutaneous melanoma, BAP1 mutation frequently occurs in uveal melanomas exclusively with BRAF or NRAS mutations 146, suggesting that BAP1 mutation may be a specific genetic marker for uveal melanoma.	('mutation', 'Var', (91, 99))	('uveal melanoma', 'Disease', (249, 263))	('uveal melanoma', 'Disease', 'MESH:C536494', (249, 263))	('BAP1', 'Gene', '8314', (198, 202))	('NRAS', 'Gene', '4893', (15, 19))	('occurs', 'Reg', (111, 117))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('uveal melanomas', 'Disease', 'MESH:C536494', (121, 136))	('uveal melanoma', 'Disease', 'MESH:C536494', (121, 135))	('BAP1', 'Gene', '8314', (86, 90))	('uveal melanoma', 'Phenotype', 'HP:0007716', (249, 263))	('BAP1', 'Gene', (198, 202))	('uveal melanoma', 'Phenotype', 'HP:0007716', (121, 135))	('NRAS', 'Gene', '4893', (162, 166))	('NRAS', 'Gene', (15, 19))	('BAP1', 'Gene', (86, 90))	('uveal melanomas', 'Disease', (121, 136))	('uveal melanomas', 'Phenotype', 'HP:0007716', (121, 136))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('cutaneous melanoma', 'Disease', (66, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (66, 84))	('melanoma', 'Phenotype', 'HP:0002861', (255, 263))	('NRAS', 'Gene', (162, 166))
85066	23008756	There is a familial tendency from mutation of the cerebral cavernous malformation gene located in chromosome 7 in which cerebral or cutaneous cavernous hemangiomas may also be present.	('cerebral', 'Disease', (120, 128))	('hemangioma', 'Phenotype', 'HP:0001028', (152, 162))	('chromosome', 'cellular_component', 'GO:0005694', ('98', '108'))	('hemangiomas', 'Disease', 'MESH:D006391', (152, 163))	('cavernous hemangiomas', 'Phenotype', 'HP:0001048', (142, 163))	('mutation', 'Var', (34, 42))	('hemangiomas', 'Disease', (152, 163))	('hemangiomas', 'Phenotype', 'HP:0001028', (152, 163))	('cavernous hemangioma', 'Phenotype', 'HP:0001048', (142, 162))	('cerebral cavernous malformation', 'Phenotype', 'HP:0002408', (50, 81))
112819	20300190	A congenital giant nevus (MM653), an acral melanoma (D10), a mucosal melanoma (D11), a primary uveal melanoma (MEL202), a melanoma cell line derived from a metastasis of a primary tumor occurring on a chronically sun exposed body site (MM472), and various cell lines derived from melanoma metastases arising from primary tumors occurring on intermittently sun-exposed body sites (D20, MM386, MM426, MM466, and MM603) were included in the library preparation.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('acral melanoma', 'Phenotype', 'HP:0012060', (37, 51))	('melanoma metastases', 'Disease', 'MESH:D009362', (280, 299))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('MM603', 'Var', (410, 415))	('MM466', 'CellLine', 'CVCL:4449', (399, 404))	('MM386', 'Var', (385, 390))	('tumor', 'Disease', (321, 326))	('MM653', 'Var', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('melanoma', 'Disease', 'MESH:D008545', (280, 288))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('D20', 'Var', (380, 383))	('melanoma metastases', 'Disease', (280, 299))	('melanoma', 'Disease', (69, 77))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('MM466', 'Var', (399, 404))	('tumors', 'Phenotype', 'HP:0002664', (321, 327))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('acral melanoma', 'Disease', (37, 51))	('uveal melanoma', 'Disease', 'MESH:C536494', (95, 109))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('MM603', 'CellLine', 'CVCL:2612', (410, 415))	('uveal melanoma', 'Disease', (95, 109))	('tumors', 'Disease', (321, 327))	('mucosal melanoma', 'Disease', 'MESH:D008545', (61, 77))	('melanoma', 'Phenotype', 'HP:0002861', (280, 288))	('MM426', 'Var', (392, 397))	('melanoma', 'Disease', (280, 288))	('nevus', 'Phenotype', 'HP:0003764', (19, 24))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('tumor', 'Disease', (180, 185))	('melanoma', 'Disease', (43, 51))	('giant nevus', 'Phenotype', 'HP:0005600', (13, 24))	('uveal melanoma', 'Phenotype', 'HP:0007716', (95, 109))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('acral melanoma', 'Disease', 'MESH:D008545', (37, 51))	('mucosal melanoma', 'Disease', (61, 77))	('tumors', 'Disease', 'MESH:D009369', (321, 327))
112906	18836566	In vivo AA is rapidly deacetylated into AL-4940, and AL-4940 is therefore the predominantly present active form.	('AL-4940', 'Chemical', 'MESH:C108424', (53, 60))	('AL-4940', 'Var', (53, 60))	('AL-4940', 'Chemical', 'MESH:C108424', (40, 47))	('AL-4940', 'Var', (40, 47))
112998	32550863	Changes in iris color (heterochromia), distortion of pupil margin, corectopia, and hyphema were found upon clinical examinations.	('hyphema', 'Disease', (83, 90))	('heterochromia', 'Disease', (23, 36))	('hyphema', 'Disease', 'MESH:D006988', (83, 90))	('hyphema', 'Phenotype', 'HP:0011886', (83, 90))	('Changes in iris color', 'Phenotype', 'HP:0007730', (0, 21))	('corectopia', 'Phenotype', 'HP:0009918', (67, 77))	('distortion', 'Var', (39, 49))	('corectopia', 'Disease', (67, 77))	('iris', 'Disease', (11, 15))	('corectopia', 'Disease', 'MESH:C563581', (67, 77))	('heterochromia', 'Disease', 'MESH:C538115', (23, 36))	('Changes', 'Reg', (0, 7))
113006	32550863	GNAQ or GNA11 mutations in primary UM are not associated with clinical demographic characteristics, such as sex, age, overall survival (OS), metastasis-free survival, tumor thickness, diameter, pigment, extracellular matrix, cytogenetic, or molecular signal differences.	('extracellular matrix', 'cellular_component', 'GO:0031012', ('203', '223'))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('GNA11', 'Gene', (8, 13))	('metastasis-free', 'CPA', (141, 156))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('GNAQ', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', (167, 172))
113008	32550863	Multiple downstream signaling pathways of GNAQ or GNA11 gene mutations, including the RAF (v-raf murine sarcoma viral oncogene homologue)/MEK [mitogen-activated protein kinase (MAPK) extracellular signal regulated kinase]/ERK (extracellular signal regulated kinase) pathway, PI3 (phosphatidylinositol 3)-kinase/AKT (v-akt murine thymoma viral oncogene homolog), protein kinase C, and YAP (yes-associate protein) pathways, have been investigated.	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('thymoma', 'Phenotype', 'HP:0100522', (329, 336))	('protein', 'cellular_component', 'GO:0003675', ('362', '369'))	('extracellular', 'cellular_component', 'GO:0005576', ('183', '196'))	('extracellular', 'cellular_component', 'GO:0005576', ('227', '240'))	('protein kinase C', 'Gene', '112476', (362, 378))	('v-raf', 'Gene', (91, 96))	('GNA11 gene', 'Gene', (50, 60))	('MAPK', 'molecular_function', 'GO:0004707', ('177', '181'))	('murine', 'Species', '10090', (322, 328))	('protein kinase C', 'Gene', (362, 378))	('MAPK', 'Gene', (177, 181))	('mutations', 'Var', (61, 70))	('GNAQ', 'Gene', (42, 46))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))	('ERK', 'molecular_function', 'GO:0004707', ('222', '225'))	('sarcoma', 'Disease', (104, 111))	('protein', 'cellular_component', 'GO:0003675', ('403', '410'))	('v-raf', 'Gene', '110157', (91, 96))	('MAPK', 'Gene', '5595;5594;26413;5595', (177, 181))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))	('murine', 'Species', '10090', (97, 103))
113009	32550863	Activation of YAP induces uncontrolled cell growth, inhibits cell death, and leads to the formation of malignant tumors.	('cell growth', 'biological_process', 'GO:0016049', ('39', '50'))	('YAP', 'Gene', (14, 17))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('cell death', 'biological_process', 'GO:0008219', ('61', '71'))	('formation', 'biological_process', 'GO:0009058', ('90', '99'))	('inhibits', 'NegReg', (52, 60))	('death', 'Disease', 'MESH:D003643', (66, 71))	('death', 'Disease', (66, 71))	('induces', 'Reg', (18, 25))	('malignant tumors', 'Disease', (103, 119))	('Activation', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('malignant tumors', 'Disease', 'MESH:D009369', (103, 119))	('uncontrolled', 'MPA', (26, 38))	('leads to', 'Reg', (77, 85))
113010	32550863	In addition, GNA11 mutation might induce the MAPK pathway to promote spontaneously metastasizing tumors (Figure 2).	('MAPK', 'Gene', '5595;5594;26413;5595', (45, 49))	('induce', 'Reg', (34, 40))	('mutation', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('MAPK', 'Gene', (45, 49))	('promote', 'PosReg', (61, 68))	('GNA11', 'Gene', (13, 18))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('metastasizing tumors', 'Disease', 'MESH:D009362', (83, 103))	('MAPK', 'molecular_function', 'GO:0004707', ('45', '49'))	('metastasizing tumors', 'Disease', (83, 103))
113011	32550863	Comparative analysis of genes on chromosome 3 in class 1 and class 2 tumors revealed that 85% of the class 2 tumors had mutations in BAP1 [breast cancer susceptibility gene 1 (BRCA1)-associated protein 1], while no mutations were detected in class 1 tumors.	('cancer susceptibility gene 1 (BRCA1)-associated protein 1', 'Gene', '8314', (146, 203))	('chromosome', 'cellular_component', 'GO:0005694', ('33', '43'))	('BAP1', 'Gene', '8314', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('mutations', 'Var', (120, 129))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('tumors', 'Disease', (109, 115))	('BAP1', 'Gene', (133, 137))	('rat', 'Species', '10116', (5, 8))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('tumors', 'Disease', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumors', 'Disease', (250, 256))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (250, 256))
113017	32550863	Further, BAP1 deletion de-differentiates UM cells, exhibiting stem cell-like morphology and promoting tumor metastasis.	('stem cell-like morphology', 'CPA', (62, 87))	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('tumor metastasis', 'Disease', 'MESH:D009362', (102, 118))	('tumor metastasis', 'Disease', (102, 118))	('BAP1', 'Gene', '8314', (9, 13))	('promoting', 'PosReg', (92, 101))	('deletion', 'Var', (14, 22))	('BAP1', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
113018	32550863	that included 507 UM patients, germline BAP1 mutations were found to be associated with tumor diameter, ciliary body involvement, and metastases.	('mutations', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('BAP1', 'Gene', (40, 44))	('UM', 'Phenotype', 'HP:0007716', (18, 20))	('germline', 'Var', (31, 39))	('associated', 'Reg', (72, 82))	('metastases', 'Disease', (134, 144))	('patients', 'Species', '9606', (21, 29))	('BAP1', 'Gene', '8314', (40, 44))	('metastases', 'Disease', 'MESH:D009362', (134, 144))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('ciliary body involvement', 'CPA', (104, 128))
113019	32550863	These data suggest that BAP1 mutations are involved in aggressive tumor progression and associated with larger tumors, higher rates of ciliary body involvement, and metastases.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('larger', 'Disease', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('BAP1', 'Gene', (24, 28))	('metastases', 'Disease', 'MESH:D009362', (165, 175))	('mutations', 'Var', (29, 38))	('tumors', 'Disease', (111, 117))	('rat', 'Species', '10116', (126, 129))	('aggressive tumor', 'Disease', 'MESH:D001523', (55, 71))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('BAP1', 'Gene', '8314', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('aggressive tumor', 'Disease', (55, 71))	('ciliary body involvement', 'Disease', (135, 159))	('associated', 'Reg', (88, 98))	('metastases', 'Disease', (165, 175))	('involved', 'Reg', (43, 51))
113021	32550863	A mutation in SF3B1 is found in 19% of UM cases, and is significantly associated with prognosis.	('mutation', 'Var', (2, 10))	('UM', 'Phenotype', 'HP:0007716', (39, 41))	('SF3B1', 'Gene', (14, 19))	('associated with', 'Reg', (70, 85))	('SF3B1', 'Gene', '23451', (14, 19))
113022	32550863	SF3B1 mutation results in selective splicing of a range of mRNAs; however, it is unclear how these mutations contribute to tumorigenesis.	('SF3B1', 'Gene', (0, 5))	('tumor', 'Disease', (123, 128))	('results in', 'Reg', (15, 25))	('mRNAs', 'MPA', (59, 64))	('mutation', 'Var', (6, 14))	('SF3B1', 'Gene', '23451', (0, 5))	('splicing', 'biological_process', 'GO:0045292', ('36', '44'))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
113024	32550863	EIFlAX mutation in UM patients is associated with a good prognosis; however, the carcinogenic mechanism of this mutation is still unclear.	('carcinogenic', 'Disease', 'MESH:D063646', (81, 93))	('EIFlAX mutation', 'Var', (0, 15))	('carcinogenic', 'Disease', (81, 93))	('patients', 'Species', '9606', (22, 30))	('UM', 'Phenotype', 'HP:0007716', (19, 21))
113025	32550863	Interestingly, the appearance of BAP1, SF3B1, and EIFlAX mutations is almost mutually exclusive, suggesting that development of a mutation in one of the genes will not necessarily lead to another mutation in patients.	('patients', 'Species', '9606', (208, 216))	('mutation', 'Var', (130, 138))	('SF3B1', 'Gene', '23451', (39, 44))	('BAP1', 'Gene', '8314', (33, 37))	('BAP1', 'Gene', (33, 37))	('lead', 'Reg', (180, 184))	('SF3B1', 'Gene', (39, 44))
113026	32550863	MEK/MAPK and P13K/AKT signaling pathways are activated in UM.	('P13K', 'Var', (13, 17))	('MAPK', 'Gene', '5595;5594;26413;5595', (4, 8))	('P13K', 'SUBSTITUTION', 'None', (13, 17))	('MAPK', 'Gene', (4, 8))	('AKT signaling', 'biological_process', 'GO:0043491', ('18', '31'))	('MAPK', 'molecular_function', 'GO:0004707', ('4', '8'))	('activated', 'PosReg', (45, 54))	('UM', 'Phenotype', 'HP:0007716', (58, 60))
113027	32550863	High activation of the P13K/AKT signaling pathway is attributed to GNAQ mutations and PTEN (phosphatase and tensin homolog) deletions.	('mutations', 'Var', (72, 81))	('signaling pathway', 'biological_process', 'GO:0007165', ('32', '49'))	('PTEN', 'Gene', (86, 90))	('GNAQ', 'Gene', (67, 71))	('PTEN', 'Gene', '5728', (86, 90))	('P13K', 'SUBSTITUTION', 'None', (23, 27))	('activation', 'PosReg', (5, 15))	('phosphatase', 'molecular_function', 'GO:0016791', ('92', '103'))	('P13K', 'Var', (23, 27))	('phosphatase and tensin homolog', 'Gene', '5728', (92, 122))	('deletions', 'Var', (124, 133))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('92', '122'))	('AKT signaling', 'biological_process', 'GO:0043491', ('28', '41'))
113028	32550863	Mutant GNAQ and GNA11 are considered to be upstream molecules of the MEK/MAPK signaling pathway.	('signaling pathway', 'biological_process', 'GO:0007165', ('78', '95'))	('GNA11', 'Gene', (16, 21))	('MAPK', 'Gene', '5595;5594;26413;5595', (73, 77))	('MAPK', 'molecular_function', 'GO:0004707', ('73', '77'))	('MAPK', 'Gene', (73, 77))	('GNAQ', 'Gene', (7, 11))	('MAPK signaling', 'biological_process', 'GO:0000165', ('73', '87'))	('Mutant', 'Var', (0, 6))
113031	32550863	Exogenously expressed mutant GNAQ upregulates MAPK phosphorylation, whereas knockdown of the GNAQ mutant reduces MAPK phosphorylation and increases G0/G1 phase cell population.	('GNAQ', 'Gene', (29, 33))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('MAPK', 'Gene', (113, 117))	('increases', 'PosReg', (138, 147))	('G1 phase', 'biological_process', 'GO:0051318', ('151', '159'))	('MAPK', 'molecular_function', 'GO:0004707', ('113', '117'))	('MAPK', 'Gene', '5595;5594;26413;5595', (46, 50))	('MAPK', 'molecular_function', 'GO:0004707', ('46', '50'))	('phosphorylation', 'MPA', (51, 66))	('upregulates', 'PosReg', (34, 45))	('G0/G1 phase cell population', 'CPA', (148, 175))	('mutant', 'Var', (22, 28))	('MAPK', 'Gene', '5595;5594;26413;5595', (113, 117))	('phosphorylation', 'biological_process', 'GO:0016310', ('118', '133'))	('MAPK', 'Gene', (46, 50))	('reduces', 'NegReg', (105, 112))	('GNAQ', 'Gene', (93, 97))	('mutant', 'Var', (98, 104))
113034	32550863	In addition, mutant GNAQ/11 promoted UM tumorigenesis via YAP, independent of PLC beta.	('mutant', 'Var', (13, 19))	('GNAQ/11', 'Gene', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('UM', 'Phenotype', 'HP:0007716', (37, 39))	('promoted', 'PosReg', (28, 36))	('tumor', 'Disease', (40, 45))	('PLC', 'cellular_component', 'GO:0042824', ('78', '81'))
113035	32550863	The tumor suppressor gene, PTEN, was also found to be lost in 75% of primary UM, and PTEN mutation occurred in 25% of these losses.	('tumor', 'Disease', (4, 9))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('4', '20'))	('primary UM', 'CPA', (69, 79))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor suppressor', 'biological_process', 'GO:0051726', ('4', '20'))	('PTEN', 'Gene', '5728', (85, 89))	('PTEN', 'Gene', (85, 89))	('PTEN', 'Gene', (27, 31))	('mutation', 'Var', (90, 98))	('PTEN', 'Gene', '5728', (27, 31))	('lost', 'NegReg', (54, 58))
113036	32550863	The downstream signaling of mutant Galphaq and Galpha11 was investigated, especially in RAF-MEK1/2-ERK1/2 signaling.	('MEK1', 'molecular_function', 'GO:0004708', ('92', '96'))	('ERK1', 'molecular_function', 'GO:0004707', ('99', '103'))	('mutant', 'Var', (28, 34))	('Galphaq', 'Gene', (35, 42))	('Galphaq', 'Gene', '2776', (35, 42))	('MEK1/2', 'Gene', '5604;5605', (92, 98))	('Galpha11', 'Gene', (47, 55))	('MEK1/2', 'Gene', (92, 98))	('ERK1/2', 'Gene', (99, 105))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))	('Galpha11', 'Gene', '2767', (47, 55))	('ERK1/2', 'Gene', '5595;5594', (99, 105))	('signaling', 'biological_process', 'GO:0023052', ('15', '24'))
113048	32550863	In addition, previous studies have demonstrated that hepatic stellate cells provide innate resistance to MEK inhibitors in metastatic UM through HGF-cMET signaling.	('inhibitors', 'Var', (109, 119))	('cMET', 'Gene', '4233', (149, 153))	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('metastatic UM', 'CPA', (123, 136))	('cMET', 'Gene', (149, 153))	('resistance', 'MPA', (91, 101))	('HGF', 'Gene', (145, 148))	('UM', 'Phenotype', 'HP:0007716', (134, 136))	('HGF', 'Gene', '3082', (145, 148))	('MEK', 'Gene', (105, 108))	('rat', 'Species', '10116', (42, 45))
113055	32550863	Inactivation or gene mutations in BAP1 are considered to be an important feature of advanced UM metastasis, resulting in lower survival rate.	('survival rate', 'CPA', (127, 140))	('BAP1', 'Gene', (34, 38))	('gene mutations', 'Var', (16, 30))	('UM', 'Phenotype', 'HP:0007716', (93, 95))	('lower', 'NegReg', (121, 126))	('rat', 'Species', '10116', (136, 139))	('BAP1', 'Gene', '8314', (34, 38))	('Inactivation', 'Var', (0, 12))
113056	32550863	Histone H2A ubiquitin hydrolase inhibitors can reverse the downstream effects of BAP1 deletions, and therefore have therapeutic value.	('BAP1', 'Gene', '8314', (81, 85))	('ubiquitin', 'molecular_function', 'GO:0031386', ('12', '21'))	('BAP1', 'Gene', (81, 85))	('deletions', 'Var', (86, 95))
113060	32550863	Novel PKC antagonists, enzastaurin, AEB071, and AHT956, inhibit GNAQ/GNA11 mutations by reducing PKC and MAPK signaling, thereby causing tumor cell apoptosis.	('PKC', 'Gene', (6, 9))	('MAPK', 'Gene', (105, 109))	('reducing', 'NegReg', (88, 96))	('inhibit', 'NegReg', (56, 63))	('PKC', 'molecular_function', 'GO:0004697', ('6', '9'))	('MAPK', 'molecular_function', 'GO:0004707', ('105', '109'))	('GNAQ/GNA11', 'Gene', (64, 74))	('PKC', 'Gene', '112476', (97, 100))	('tumor', 'Disease', (137, 142))	('PKC', 'Gene', (97, 100))	('enzastaurin', 'Chemical', 'MESH:C504878', (23, 34))	('MAPK', 'Gene', '5595;5594;26413;5595', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('causing', 'Reg', (129, 136))	('MAPK signaling', 'biological_process', 'GO:0000165', ('105', '119'))	('PKC', 'Gene', '112476', (6, 9))	('apoptosis', 'biological_process', 'GO:0097194', ('148', '157'))	('apoptosis', 'biological_process', 'GO:0006915', ('148', '157'))	('mutations', 'Var', (75, 84))	('PKC', 'molecular_function', 'GO:0004697', ('97', '100'))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
113061	32550863	In addition, studies have shown that a combination of PKC antagonist, AEB071, and MEK antagonist, PD0325901, inhibits GNAQ/GNA11 and increases apoptosis through different pathways.	('PD0325901', 'Var', (98, 107))	('GNAQ/GNA11', 'Protein', (118, 128))	('PKC', 'molecular_function', 'GO:0004697', ('54', '57'))	('PD0325901', 'Chemical', 'MESH:C506614', (98, 107))	('inhibits', 'NegReg', (109, 117))	('apoptosis', 'CPA', (143, 152))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('increases', 'PosReg', (133, 142))	('PKC', 'Gene', (54, 57))	('PKC', 'Gene', '112476', (54, 57))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))
113062	32550863	In addition, selumetinib indirectly inhibits the mutant GNAQ/GNA11 by antagonizing MAPK, which can increase the drug response rate by 14% compared with that of the traditional chemotherapy drugs, temozolomide and dacarbazine.	('MAPK', 'Gene', '5595;5594;26413;5595', (83, 87))	('mutant', 'Var', (49, 55))	('drug response', 'MPA', (112, 125))	('temozolomide', 'Chemical', 'MESH:D000077204', (196, 208))	('selumetinib', 'Chemical', 'MESH:C517975', (13, 24))	('MAPK', 'Gene', (83, 87))	('antagonizing', 'NegReg', (70, 82))	('dacarbazine', 'Chemical', 'MESH:D003606', (213, 224))	('inhibits', 'NegReg', (36, 44))	('GNAQ/GNA11', 'Gene', (56, 66))	('MAPK', 'molecular_function', 'GO:0004707', ('83', '87'))	('rat', 'Species', '10116', (126, 129))	('increase', 'PosReg', (99, 107))
113068	32550863	It has been found that imatinib has significant therapeutic effects in patients with c-Kit mutations, especially in patients with exon 11 and 13 mutations.	('patients', 'Species', '9606', (71, 79))	('patients', 'Species', '9606', (116, 124))	('c-Kit', 'Gene', (85, 90))	('therapeutic', 'MPA', (48, 59))	('c-Kit', 'Gene', '3815', (85, 90))	('imatinib', 'Chemical', 'MESH:D000068877', (23, 31))	('mutations', 'Var', (91, 100))	('exon 11', 'Var', (130, 137))
113076	32550863	In the UM population, sunitinib was associated with better OS.	('better OS', 'Disease', (52, 61))	('UM', 'Phenotype', 'HP:0007716', (7, 9))	('sunitinib', 'Chemical', 'MESH:D000077210', (22, 31))	('sunitinib', 'Var', (22, 31))
113080	32550863	A combination of IGF-1 and epidermal growth factor (EGF) signaling induces UM cell migration and invasion, thereby increasing the risk of metastasis.	('metastasis', 'CPA', (138, 148))	('EGF', 'Gene', '1950', (52, 55))	('epidermal growth factor', 'Gene', (27, 50))	('EGF', 'molecular_function', 'GO:0005154', ('52', '55'))	('epidermal growth factor', 'Gene', '1950', (27, 50))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('cell migration', 'biological_process', 'GO:0016477', ('78', '92'))	('invasion', 'CPA', (97, 105))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('IGF-1', 'Gene', '3479', (17, 22))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('27', '50'))	('IGF-1', 'Gene', (17, 22))	('induces', 'Reg', (67, 74))	('UM cell migration', 'CPA', (75, 92))	('combination', 'Var', (2, 13))	('increasing', 'PosReg', (115, 125))	('rat', 'Species', '10116', (86, 89))	('EGF', 'Gene', (52, 55))
113148	32550863	Anti-CTLA4 antibodies may promote activity of the T cell immune response.	('activity', 'MPA', (34, 42))	('promote', 'PosReg', (26, 33))	('immune response', 'biological_process', 'GO:0006955', ('57', '72'))	('antibodies', 'Var', (11, 21))	('T cell immune response', 'CPA', (50, 72))	('CTLA4', 'Gene', '1493', (5, 10))	('CTLA4', 'Gene', (5, 10))
113155	32550863	In a study by Middleton et al., 84 HLA-A2+ advanced melanoma patients received IMCgp100 (ClinicalTrials.gov identifier: NCT01211262), which induced a transient increase in IFN-inducible cytokines.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('IFN', 'Gene', '3439', (172, 175))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('IMCgp100', 'Var', (79, 87))	('patients', 'Species', '9606', (61, 69))	('increase', 'PosReg', (160, 168))	('IMCgp100', 'Chemical', '-', (79, 87))	('IFN', 'Gene', (172, 175))
113157	32550863	In a study by Sato et al., 19 metastatic UM patients with HLA-A*0201+ were investigated and treated with IMCgp100.	('IMCgp100', 'Chemical', '-', (105, 113))	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('patients', 'Species', '9606', (44, 52))	('HLA-A*0201+', 'Var', (58, 69))	('metastatic UM', 'Disease', (30, 43))
113263	29133632	There was significant difference in treatment by mean age for OBS versus OCS (72 vs. 66 years, P = 0.042), gender male for PCS versus OBS (100% vs. 54%, P = 0.002), and PCS versus TCS (100% vs. 64%, P = 0.037), decreased vision/VF loss in PCS versus OBS (83% vs. 50%, P = 0.018), and lack of symptoms in OCS versus OBS (0% vs. 28%, P = 0.001).	('decreased vision/VF loss in PCS versus OBS', 'Disease', 'OMIM:176430', (211, 253))	('PCS versus OBS', 'Disease', (123, 137))	('vision', 'biological_process', 'GO:0007601', ('221', '227'))	('PCS versus OBS', 'Disease', 'OMIM:176430', (239, 253))	('PCS', 'Chemical', '-', (239, 242))	('OCS versus OBS', 'Disease', (304, 318))	('PCS', 'Chemical', '-', (123, 126))	('PCS versus OBS', 'Disease', 'OMIM:176430', (123, 137))	('PCS', 'Var', (169, 172))	('OBS versus OCS', 'Disease', (62, 76))	('TCS', 'Chemical', '-', (180, 183))	('OCS versus OBS', 'Disease', 'MESH:D006086', (304, 318))	('decreased vision/VF loss in PCS versus OBS', 'Disease', (211, 253))	('PCS', 'Chemical', '-', (169, 172))	('OBS versus OCS', 'Disease', 'MESH:D006086', (62, 76))	('decreased vision', 'Phenotype', 'HP:0007663', (211, 227))
113264	29133632	In general, eyes receiving OCS, PCS, and TCS showed more advanced features than those treated with OBS.	('TCS', 'Chemical', '-', (41, 44))	('OCS', 'Var', (27, 30))	('TCS', 'Var', (41, 44))	('PCS', 'Var', (32, 35))	('OBS', 'Disease', (99, 102))	('OBS', 'Disease', 'None', (99, 102))	('PCS', 'Chemical', '-', (32, 35))
113302	28662141	SDHD promoter mutations are rare events in cutaneous melanomas but SDHD protein expression is downregulated in advanced cutaneous melanoma SDHD promoter mutations were reported in 4-10% of cutaneous melanomas.	('SDHD', 'Gene', (139, 143))	('mutations', 'Var', (153, 162))	('SDHD', 'Gene', (67, 71))	('SDHD', 'Gene', '6392', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (189, 207))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (189, 207))	('cutaneous melanomas', 'Disease', (43, 62))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('expression', 'MPA', (80, 90))	('SDHD', 'Gene', (0, 4))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (189, 208))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (189, 208))	('downregulated', 'NegReg', (94, 107))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (43, 61))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (43, 61))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (43, 62))	('SDHD', 'Gene', '6392', (139, 143))	('melanomas', 'Phenotype', 'HP:0002861', (199, 208))	('SDHD', 'Gene', '6392', (67, 71))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('cutaneous melanomas', 'Disease', (189, 208))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('cutaneous melanoma', 'Disease', (120, 138))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (120, 138))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (120, 138))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (43, 62))
113303	28662141	The advanced clinico-pathological and patient survival association with SDHD mutation and/or expression in cutaneous melanoma remains controversial.	('SDHD', 'Gene', (72, 76))	('cutaneous melanoma', 'Disease', (107, 125))	('mutation', 'Var', (77, 85))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (107, 125))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (107, 125))	('patient', 'Species', '9606', (38, 45))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('SDHD', 'Gene', '6392', (72, 76))
113304	28662141	To evaluate the presence of SDHD promoter mutations and SDHD protein expression in a melanoma series and its possible association with prognosis and survival of the patients.	('SDHD', 'Gene', (28, 32))	('SDHD', 'Gene', (56, 60))	('SDHD', 'Gene', '6392', (56, 60))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('patients', 'Species', '9606', (165, 173))	('melanoma', 'Disease', (85, 93))	('SDHD', 'Gene', '6392', (28, 32))	('protein', 'Protein', (61, 68))	('mutations', 'Var', (42, 51))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
113307	28662141	We detected 2% of SDHD promoter mutations in CM, but none in OM and cell lines.	('OM', 'Phenotype', 'HP:0025534', (61, 63))	('CM', 'Phenotype', 'HP:0012056', (45, 47))	('mutations', 'Var', (32, 41))	('SDHD', 'Gene', (18, 22))	('SDHD', 'Gene', '6392', (18, 22))
113314	28662141	SDHD alterations where reported in sporadic and familial paraganglioma, phaeochromocytoma and gastrointestinal stromal tumour (GIST).	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('GIST', 'Phenotype', 'HP:0100723', (127, 131))	('familial paraganglioma, phaeochromocytoma and gastrointestinal stromal tumour', 'Disease', 'MESH:C564650', (48, 125))	('alterations', 'Var', (5, 16))	('SDHD', 'Gene', '6392', (0, 4))	('gastrointestinal stromal tumour', 'Phenotype', 'HP:0100723', (94, 125))	('sporadic', 'Disease', (35, 43))	('SDHD', 'Gene', (0, 4))	('paraganglioma', 'Phenotype', 'HP:0002668', (57, 70))
113315	28662141	Following the identification of TERT promoter mutations in cancer, several authors have screened other promoter regions searching for mutations that can be relevant in cancer.	('TERT', 'Gene', '7015', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('TERT', 'Gene', (32, 36))
113316	28662141	Promoter mutations in SDHD where recently described by Weinhold et al in 10% of cutaneous melanoma, based on data mining, using the whole-genome sequences of human tumours collected from The Cancer Genome Atlas and other public sources.	('Cancer', 'Phenotype', 'HP:0002664', (191, 197))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (191, 210))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('human', 'Species', '9606', (158, 163))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('mutations', 'Var', (9, 18))	('cutaneous melanoma', 'Disease', (80, 98))	('SDHD', 'Gene', '6392', (22, 26))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (80, 98))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (80, 98))	('SDHD', 'Gene', (22, 26))	('tumours', 'Disease', 'MESH:D009369', (164, 171))	('tumours', 'Disease', (164, 171))	('Cancer Genome Atlas', 'Disease', (191, 210))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
113317	28662141	The mutations in SDHD promoter associated with reduced gene expression and decrease patient survival.	('gene expression', 'biological_process', 'GO:0010467', ('55', '70'))	('decrease', 'NegReg', (75, 83))	('SDHD', 'Gene', '6392', (17, 21))	('SDHD', 'Gene', (17, 21))	('gene expression', 'MPA', (55, 70))	('mutations', 'Var', (4, 13))	('reduced', 'NegReg', (47, 54))	('patient survival', 'CPA', (84, 100))	('patient', 'Species', '9606', (84, 91))
113318	28662141	Scholz et al reported 4% of SDHD promoter mutations in a cohort of cutaneous melanomas, but not related with clinico-pathologic factors or patient survival, and no mutations were found in ocular, mucosal and occult melanomas.	('SDHD', 'Gene', (28, 32))	('occult melanomas', 'Disease', 'MESH:D008545', (208, 224))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('melanomas', 'Phenotype', 'HP:0002861', (215, 224))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (67, 86))	('occult melanomas', 'Disease', (208, 224))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (67, 86))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (67, 85))	('SDHD', 'Gene', '6392', (28, 32))	('mutations', 'Var', (42, 51))	('patient', 'Species', '9606', (139, 146))	('cutaneous melanomas', 'Disease', (67, 86))
113324	28662141	Genetically, CM harbour a high frequency of activating mutations in oncogenes, such as BRAF, NRAS and c-KIT; loss of tumour suppressors, such as CDKN2A and PTEN, and also the recently discovered TERT promoter mutations.	('c-KIT', 'Gene', '3815', (102, 107))	('PTEN', 'Gene', (156, 160))	('BRAF', 'Gene', '673', (87, 91))	('BRAF', 'Gene', (87, 91))	('CDKN2A', 'Gene', (145, 151))	('TERT', 'Gene', (195, 199))	('PTEN', 'Gene', '5728', (156, 160))	('NRAS', 'Gene', '4893', (93, 97))	('TERT', 'Gene', '7015', (195, 199))	('KIT', 'molecular_function', 'GO:0005020', ('104', '107'))	('CDKN2A', 'Gene', '1029', (145, 151))	('CM', 'Phenotype', 'HP:0012056', (13, 15))	('mutations', 'Var', (55, 64))	('NRAS', 'Gene', (93, 97))	('activating', 'PosReg', (44, 54))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('loss', 'NegReg', (109, 113))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('tumour', 'Disease', (117, 123))	('c-KIT', 'Gene', (102, 107))
113327	28662141	BRAF and NRAS mutations were reported in 14-40% and 0-18%, respectively, of conjunctival melanomas, whereas they seem to be absent in uveal melanomas, in which GNAQ and GNA11 activating mutations and loss of BAP1 are prevalent.	('uveal melanomas', 'Disease', (134, 149))	('activating', 'PosReg', (175, 185))	('uveal melanomas', 'Phenotype', 'HP:0007716', (134, 149))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('BRAF', 'Gene', (0, 4))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (76, 98))	('BAP1', 'Gene', (208, 212))	('GNA11', 'Gene', '2767', (169, 174))	('NRAS', 'Gene', (9, 13))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('conjunctival melanomas', 'Disease', (76, 98))	('mutations', 'Var', (14, 23))	('loss', 'NegReg', (200, 204))	('GNAQ', 'Gene', '2776', (160, 164))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('uveal melanomas', 'Disease', 'MESH:C536494', (134, 149))	('GNAQ', 'Gene', (160, 164))	('GNA11', 'Gene', (169, 174))	('BAP1', 'Gene', '8314', (208, 212))	('NRAS', 'Gene', '4893', (9, 13))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('uveal melanoma', 'Phenotype', 'HP:0007716', (134, 148))
113328	28662141	TERT promoter mutations were reported in conjunctival melanomas, ranging from 0 to 32% and, so far, only one case of uveal melanoma harbouring a TERT promoter mutation was reported.	('uveal melanoma', 'Disease', (117, 131))	('TERT', 'Gene', (145, 149))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('TERT', 'Gene', (0, 4))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (41, 63))	('TERT', 'Gene', '7015', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('conjunctival melanomas', 'Disease', (41, 63))	('uveal melanoma', 'Phenotype', 'HP:0007716', (117, 131))	('mutations', 'Var', (14, 23))	('TERT', 'Gene', '7015', (145, 149))	('uveal melanoma', 'Disease', 'MESH:C536494', (117, 131))
113329	28662141	In this study, we assessed the presence of SDHD promoter mutations and SDHD protein expression in CM, OM and in melanoma cell lines, in which we already determined BRAF, NRAS, GNAQ and TERT promoter mutational status.	('NRAS', 'Gene', (170, 174))	('CM', 'Phenotype', 'HP:0012056', (98, 100))	('SDHD', 'Gene', (43, 47))	('mutations', 'Var', (57, 66))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('OM', 'Phenotype', 'HP:0025534', (102, 104))	('SDHD', 'Gene', '6392', (71, 75))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('GNAQ', 'Gene', '2776', (176, 180))	('SDHD', 'Gene', (71, 75))	('BRAF', 'Gene', '673', (164, 168))	('NRAS', 'Gene', '4893', (170, 174))	('TERT', 'Gene', (185, 189))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('TERT', 'Gene', '7015', (185, 189))	('BRAF', 'Gene', (164, 168))	('GNAQ', 'Gene', (176, 180))	('SDHD', 'Gene', '6392', (43, 47))
113359	28662141	86 CM were analysed for SDHD promoter mutations.	('mutations', 'Var', (38, 47))	('CM', 'Phenotype', 'HP:0012056', (3, 5))	('SDHD', 'Gene', (24, 28))	('SDHD', 'Gene', '6392', (24, 28))
113360	28662141	11:111,957,523 (TTCC>TTTC) SDHD alteration [one of the mutations reported by Weinhold et al ] in two CM (2%) (Fig 1).	('SDHD', 'Gene', '6392', (27, 31))	('alteration', 'Var', (32, 42))	('CM', 'Phenotype', 'HP:0012056', (101, 103))	('SDHD', 'Gene', (27, 31))
113376	28662141	No association was found between the expression of SDHD and BRAF/NRAS mutations, pERK expression (the readout of MAPK pathway activation) or with TERT promoter mutations and TERT protein expression.	('pERK', 'Gene', (81, 85))	('mutations', 'Var', (70, 79))	('NRAS', 'Gene', '4893', (65, 69))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('pERK', 'Gene', '9451', (81, 85))	('TERT', 'Gene', (174, 178))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('TERT', 'Gene', '7015', (174, 178))	('MAPK', 'molecular_function', 'GO:0004707', ('113', '117'))	('SDHD', 'Gene', '6392', (51, 55))	('TERT', 'Gene', (146, 150))	('TERT', 'Gene', '7015', (146, 150))	('SDHD', 'Gene', (51, 55))	('NRAS', 'Gene', (65, 69))
113377	28662141	Due to the low number of mutated cases, we cannot infer if there is a reduction in the protein expression associated with the presence of SDHD promoter mutation, but moderate/high staining scores (6 and 9) were found in the two cases with SDHD promoter mutations.	('SDHD', 'Gene', '6392', (138, 142))	('SDHD', 'Gene', '6392', (239, 243))	('SDHD', 'Gene', (239, 243))	('SDHD', 'Gene', (138, 142))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('mutation', 'Var', (152, 160))
113381	28662141	SDHD alterations result in the disruption of the SDH complex and loss of SDH enzymatic activity.	('loss', 'NegReg', (65, 69))	('SDH', 'Gene', '6390', (49, 52))	('disruption', 'Reg', (31, 41))	('SDH', 'Gene', '6390', (73, 76))	('SDH', 'Gene', (0, 3))	('SDH', 'Gene', (49, 52))	('alterations', 'Var', (5, 16))	('SDHD', 'Gene', '6392', (0, 4))	('SDH', 'Gene', (73, 76))	('SDHD', 'Gene', (0, 4))	('SDH', 'Gene', '6390', (0, 3))
113382	28662141	In paragangliomas, SDHB alterations were linked to malignancy and SDHD alterations are more frequent in head-and-neck localized tumours.	('localized tumours', 'Disease', (118, 135))	('SDHD', 'Gene', (66, 70))	('linked', 'Reg', (41, 47))	('paragangliomas', 'Disease', (3, 17))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('SDHB', 'Gene', '6390', (19, 23))	('malignancy', 'Disease', 'MESH:D009369', (51, 61))	('alterations', 'Var', (71, 82))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('neck', 'cellular_component', 'GO:0044326', ('113', '117'))	('paragangliomas', 'Disease', 'MESH:D010235', (3, 17))	('alterations', 'Var', (24, 35))	('localized tumours', 'Disease', 'MESH:D009364', (118, 135))	('frequent', 'Reg', (92, 100))	('paraganglioma', 'Phenotype', 'HP:0002668', (3, 16))	('paragangliomas', 'Phenotype', 'HP:0002668', (3, 17))	('SDHB', 'Gene', (19, 23))	('malignancy', 'Disease', (51, 61))	('SDHD', 'Gene', '6392', (66, 70))
113383	28662141	Recently, SDHD promoter mutations were reported in melanomas, associated with reduced gene expression and reduced patient survival.	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('gene expression', 'biological_process', 'GO:0010467', ('86', '101'))	('melanomas', 'Disease', 'MESH:D008545', (51, 60))	('patient survival', 'CPA', (114, 130))	('patient', 'Species', '9606', (114, 121))	('melanomas', 'Disease', (51, 60))	('gene expression', 'MPA', (86, 101))	('SDHD', 'Gene', (10, 14))	('reduced', 'NegReg', (78, 85))	('mutations', 'Var', (24, 33))	('SDHD', 'Gene', '6392', (10, 14))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('reduced', 'NegReg', (106, 113))
113386	28662141	Although C>T alterations are generally considered a marker of UV-exposure, we found a 523C>T SDHD mutation in an acral melanoma case that occur in skin without sun exposure, at variance with Scholz et al that did not find SDHD mutations in acral melanomas.	('acral melanomas', 'Phenotype', 'HP:0012060', (240, 255))	('acral melanoma', 'Disease', 'MESH:D008545', (113, 127))	('SDHD', 'Gene', (93, 97))	('mutation', 'Var', (98, 106))	('SDHD', 'Gene', '6392', (93, 97))	('SDHD', 'Gene', '6392', (222, 226))	('melanoma', 'Phenotype', 'HP:0002861', (246, 254))	('523C>T', 'Mutation', 'c.523C>T', (86, 92))	('melanomas', 'Phenotype', 'HP:0002861', (246, 255))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('acral melanoma', 'Phenotype', 'HP:0012060', (113, 127))	('SDHD', 'Gene', (222, 226))	('acral melanomas', 'Disease', 'MESH:D008545', (240, 255))	('523C>T', 'Var', (86, 92))	('acral melanoma', 'Disease', (113, 127))	('acral melanoma', 'Disease', 'MESH:D008545', (240, 254))	('acral melanoma', 'Phenotype', 'HP:0012060', (240, 254))	('acral melanomas', 'Disease', (240, 255))
113389	28662141	The rarity of SDHD mutations detected in our series does not allow us to validate the association between the presence of SDHD promoter mutation and a reduction in the expression of SDHD gene or the association between this mutation and prognostic parameters of CM, as reported by Weinhold et al.	('SDHD', 'Gene', '6392', (182, 186))	('expression', 'MPA', (168, 178))	('mutation', 'Var', (136, 144))	('SDHD', 'Gene', '6392', (14, 18))	('SDHD', 'Gene', (122, 126))	('SDHD', 'Gene', '6392', (122, 126))	('CM', 'Phenotype', 'HP:0012056', (262, 264))	('SDHD', 'Gene', (14, 18))	('SDHD', 'Gene', (182, 186))	('reduction', 'NegReg', (151, 160))
113393	28662141	Although the molecular and cellular mechanisms linking SDH inactivation and tumorigenesis it is not completely understood, SDHD mutation/inactivation results in a loss of electron transport chain complex II activity and in the activation of the hypoxia-angiogenic pathway, namely an increase of EPAS-1, HIF-1 and VEGF expression, which may be the involved mechanism in tumorigenesis.	('SDH', 'Gene', (123, 126))	('activity', 'MPA', (207, 215))	('VEGF', 'Gene', '7422', (313, 317))	('complex II', 'molecular_function', 'GO:0008177', ('196', '206'))	('mutation/inactivation', 'Var', (128, 149))	('electron transport chain complex II', 'Enzyme', (171, 206))	('VEGF', 'Gene', (313, 317))	('expression', 'MPA', (318, 328))	('HIF-1', 'Gene', '3091', (303, 308))	('SDH', 'Gene', '6390', (55, 58))	('loss', 'NegReg', (163, 167))	('electron transport chain', 'biological_process', 'GO:0022900', ('171', '195'))	('HIF-1', 'Gene', (303, 308))	('increase', 'PosReg', (283, 291))	('hypoxia', 'Disease', (245, 252))	('EPAS-1', 'Gene', '2034', (295, 301))	('SDHD', 'Gene', '6392', (123, 127))	('SDH', 'Gene', (55, 58))	('SDH', 'Gene', '6390', (123, 126))	('EPAS-1', 'Gene', (295, 301))	('hypoxia', 'Disease', 'MESH:D000860', (245, 252))	('SDHD', 'Gene', (123, 127))	('activation', 'PosReg', (227, 237))
113397	28662141	In conclusion, our results indicate that SDHD promoter mutation is a rare event in CM and is absent in OM.	('SDHD', 'Gene', (41, 45))	('SDHD', 'Gene', '6392', (41, 45))	('CM', 'Phenotype', 'HP:0012056', (83, 85))	('OM', 'Phenotype', 'HP:0025534', (103, 105))	('mutation', 'Var', (55, 63))
113400	28662141	Importantly, the metabolic reshape created by SDHD alteration may open a possible therapeutic window that can benefit CM patients, through drugs that can revert this metabolism shift.	('SDHD', 'Gene', '6392', (46, 50))	('SDHD', 'Gene', (46, 50))	('metabolism', 'biological_process', 'GO:0008152', ('166', '176'))	('alteration', 'Var', (51, 61))	('CM', 'Phenotype', 'HP:0012056', (118, 120))	('patients', 'Species', '9606', (121, 129))
113416	27087480	Melanoma arises through progressive accumulation of genetic and (epi)genetic alterations that disrupt homeostatic pathways, resulting in uncontrolled tumor cell proliferation followed by invasion and lymphatic or hematogenous dissemination of the tumor cells to distant sites.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('lymphatic or hematogenous dissemination', 'CPA', (200, 239))	('tumor', 'Disease', (247, 252))	('Melanoma', 'Disease', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('alterations', 'Var', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cell proliferation', 'biological_process', 'GO:0008283', ('156', '174'))	('homeostatic pathways', 'Pathway', (102, 122))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', (150, 155))	('invasion', 'CPA', (187, 195))
113417	27087480	In cutaneous melanocytic neoplasms, UV radiation is the primary cause of mutations on sun-exposed skin.	('cutaneous melanocytic neoplasms', 'Disease', 'MESH:D009508', (3, 34))	('cause', 'Reg', (64, 69))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (13, 34))	('neoplasms', 'Phenotype', 'HP:0002664', (25, 34))	('mutations', 'Var', (73, 82))	('cutaneous melanocytic neoplasms', 'Disease', (3, 34))
113420	27087480	There is strong evidence for UV-independent mutagenesis in melanoma, a possibility suggested by the occurrence of melanomas at cutaneous locations that are not sun exposed, as well as in the eye and in mucous membranes.	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('melanomas', 'Phenotype', 'HP:0002861', (114, 123))	('melanomas', 'Disease', (114, 123))	('mutagenesis', 'biological_process', 'GO:0006280', ('44', '55'))	('melanomas', 'Disease', 'MESH:D008545', (114, 123))	('mucous', 'cellular_component', 'GO:0070701', ('202', '208'))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('mutagenesis', 'Var', (44, 55))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('melanoma', 'Disease', (114, 122))
113428	27087480	They also have a high mutation burden and often harbor mutations in NF1, NRAS, BRAFnon-V600E, or KIT.	('KIT', 'molecular_function', 'GO:0005020', ('97', '100'))	('NRAS', 'Gene', '4893', (73, 77))	('mutations', 'Var', (55, 64))	('KIT', 'Gene', (97, 100))	('V600E', 'Mutation', 'p.V600E', (87, 92))	('NF1', 'Gene', (68, 71))	('mutation burden', 'MPA', (22, 37))	('NF1', 'Gene', '4763', (68, 71))	('BRAF', 'Gene', '673', (79, 83))	('harbor', 'Reg', (48, 54))	('BRAF', 'Gene', (79, 83))	('NRAS', 'Gene', (73, 77))
113431	27087480	Both types are associated with distinct precursor lesions, 'non-CSD' with acquired nevi that already exhibit BRAFV600E mutations and 'CSD' with atypical melanocytic neoplasms and melanoma in situ.	('BRAFV600E', 'Gene', (109, 118))	('CSD', 'Gene', (134, 137))	('atypical melanocytic neoplasms', 'Disease', (144, 174))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('nevi', 'Phenotype', 'HP:0003764', (83, 87))	('CSD', 'Gene', '7045', (64, 67))	('acquired nevi', 'Disease', (74, 87))	('atypical melanocytic neoplasms', 'Disease', 'MESH:D009508', (144, 174))	('CSD', 'Gene', '7045', (134, 137))	('neoplasms', 'Phenotype', 'HP:0002664', (165, 174))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (153, 174))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('BRAFV600E', 'Mutation', 'rs113488022', (109, 118))	('mutations', 'Var', (119, 128))	('melanoma', 'Disease', (179, 187))	('CSD', 'Gene', (64, 67))
113445	27087480	In addition, informing individuals without a personal history of disease that they are carriers of a CDKN2A/p16 mutation leads to improvement of photoprotection, self-skin examination and professional examination behaviors, in the absence of melanoma diagnosis.	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('melanoma', 'Disease', (242, 250))	('CDKN2A', 'Gene', (101, 107))	('mutation', 'Var', (112, 120))	('p16', 'Gene', '1029', (108, 111))	('photoprotection', 'CPA', (145, 160))	('melanoma', 'Disease', 'MESH:D008545', (242, 250))	('CDKN2A', 'Gene', '1029', (101, 107))	('self-skin examination', 'CPA', (162, 183))	('improvement', 'PosReg', (130, 141))	('p16', 'Gene', (108, 111))	('men', 'Species', '9606', (137, 140))	('photoprotection', 'biological_process', 'GO:0010117', ('145', '160'))	('professional examination behaviors', 'CPA', (188, 222))
113457	27087480	(iii) Sulforaphane: Experimental studies indicate that sulforaphane upregulates antioxidant genes and may affect immune pathways.	('sulforaphane', 'Var', (55, 67))	('antioxidant genes', 'Gene', (80, 97))	('sulforaphane', 'Chemical', 'MESH:C016766', (55, 67))	('upregulates', 'PosReg', (68, 79))	('Sulforaphane', 'Chemical', 'MESH:C016766', (6, 18))	('men', 'Species', '9606', (26, 29))	('immune pathways', 'Pathway', (113, 128))	('affect', 'Reg', (106, 112))
113464	27087480	Interestingly, both mouse models of melanoma and xenografts of human melanoma in mice show that relief from oxidative stress by treatment with the antioxidant N-acetyl cysteine leads to disease progression, suggesting that these approaches be reassessed in carefully crafted human and animal-model based studies.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('mice', 'Species', '10090', (81, 85))	('melanoma', 'Disease', (36, 44))	('oxidative stress', 'MPA', (108, 124))	('human', 'Species', '9606', (63, 68))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('N-acetyl cysteine', 'Chemical', 'MESH:D000111', (159, 176))	('human', 'Species', '9606', (275, 280))	('disease progression', 'CPA', (186, 205))	('oxidative stress', 'Phenotype', 'HP:0025464', (108, 124))	('men', 'Species', '9606', (133, 136))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('relief', 'Var', (96, 102))	('melanoma', 'Disease', (69, 77))	('mouse', 'Species', '10090', (20, 25))
113467	27087480	The approach was found to offer mutant mice significant protection against UV-induced mutagenesis and skin carcinogenesis, although it was tested in a squamous cell carcinoma model.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (151, 174))	('skin carcinogenesis', 'Disease', (102, 121))	('squamous cell carcinoma', 'Disease', (151, 174))	('UV-induced mutagenesis', 'MPA', (75, 97))	('mutant', 'Var', (32, 38))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (102, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))	('mice', 'Species', '10090', (39, 43))	('mutagenesis', 'biological_process', 'GO:0006280', ('86', '97'))
113485	27087480	Current work that addresses discrimination of melanoma from benign or low-grade dyplastic nevi is based on gene expression or DNA copy number changes by comprehensive genomic hybridization (CGH) or fluorescence in situ hybridization (FISH), while gene expression profiling (GEP) based analyses is gaining traction.	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('nevi', 'Phenotype', 'HP:0003764', (90, 94))	('melanoma', 'Disease', (46, 54))	('gene expression', 'biological_process', 'GO:0010467', ('247', '262'))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('gene expression', 'biological_process', 'GO:0010467', ('107', '122'))	('changes', 'Var', (142, 149))	('dyplastic nevi', 'Phenotype', 'HP:0001062', (80, 94))
113487	27087480	For example, high mole density is positively associated with non-CSD melanoma, whereas actinic keratosis and solar lentigines are positively associated with CSD melanoma.	('CSD melanoma', 'Disease', (65, 77))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('high', 'Var', (13, 17))	('keratosis', 'Disease', 'MESH:D007642', (95, 104))	('actinic keratosis', 'Phenotype', 'HP:0025127', (87, 104))	('keratosis', 'Disease', (95, 104))	('associated', 'Reg', (45, 55))	('CSD melanoma', 'Disease', 'MESH:C562576', (157, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('CSD melanoma', 'Disease', 'MESH:C562576', (65, 77))	('mole', 'Phenotype', 'HP:0003764', (18, 22))	('CSD melanoma', 'Disease', (157, 169))
113492	27087480	(ii) Development of refined risk phenotypes could be improved by increasing the sensitivity and specificity of markers tailored to melanoma subtypes (iii) Additional standards useful to identify individuals with increased risk could include clinical or molecular markers indicating mutation load in skin as well as biomarkers for immune-competence and the state of the tumor stroma.	('tumor stroma', 'Disease', (369, 381))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('clinical', 'Species', '191496', (241, 249))	('mole', 'Phenotype', 'HP:0003764', (253, 257))	('tumor', 'Phenotype', 'HP:0002664', (369, 374))	('men', 'Species', '9606', (12, 15))	('melanoma subtypes', 'Disease', (131, 148))	('mutation load', 'Var', (282, 295))	('tumor stroma', 'Disease', 'MESH:D009369', (369, 381))	('melanoma subtypes', 'Disease', 'MESH:D008545', (131, 148))
113493	27087480	(iv) Improved understanding of how melanomas evolve from precursor lesions will allow development of objective criteria for diagnosis based on the number and type of pathogenic mutations or perturbations in critical signaling pathways.	('melanomas', 'Disease', 'MESH:D008545', (35, 44))	('melanomas', 'Phenotype', 'HP:0002861', (35, 44))	('men', 'Species', '9606', (93, 96))	('mutations', 'Var', (177, 186))	('melanomas', 'Disease', (35, 44))	('signaling', 'biological_process', 'GO:0023052', ('216', '225'))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))
113541	27087480	Tumor dormancy is thought to depend on at least three elements: (1) cellular dormancy, in which tumor cells survive in a quiescent, slowly dividing state; (2) angiogenic dormancy, in which lack of vascularization holds growth of micrometastases in check and promotes programmed cell death, known as apoptosis; and/or (3) immune-mediated dormancy, where the immune system continues to limit the tumor population.	('tumor', 'Disease', (394, 399))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('metastases', 'Disease', 'MESH:D009362', (234, 244))	('tumor', 'Disease', 'MESH:D009369', (394, 399))	('angiogenic dormancy', 'CPA', (159, 178))	('metastases', 'Disease', (234, 244))	('dormancy', 'biological_process', 'GO:0030431', ('77', '85'))	('man', 'Species', '9606', (9, 12))	('dormancy', 'biological_process', 'GO:0030431', ('6', '14'))	('lack', 'Var', (189, 193))	('promotes', 'PosReg', (258, 266))	('man', 'Species', '9606', (173, 176))	('men', 'Species', '9606', (57, 60))	('man', 'Species', '9606', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (394, 399))	('apoptosis', 'biological_process', 'GO:0097194', ('299', '308'))	('dormancy', 'biological_process', 'GO:0030431', ('337', '345'))	('apoptosis', 'biological_process', 'GO:0006915', ('299', '308'))	('man', 'Species', '9606', (340, 343))	('tumor', 'Disease', (96, 101))	('programmed cell death', 'biological_process', 'GO:0012501', ('267', '288'))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('immune-mediated dormancy', 'CPA', (321, 345))	('programmed cell death', 'CPA', (267, 288))	('dormancy', 'biological_process', 'GO:0030431', ('170', '178'))
113542	27087480	Disruption of these processes can awaken dormant micrometastases and stimulate their expansion into overt metastases, leading to patient morbidity and mortality.	('metastases', 'Disease', 'MESH:D009362', (106, 116))	('leading to', 'Reg', (118, 128))	('man', 'Species', '9606', (44, 47))	('patient', 'Species', '9606', (129, 136))	('metastases', 'Disease', (54, 64))	('stimulate', 'PosReg', (69, 78))	('metastases', 'Disease', 'MESH:D009362', (54, 64))	('expansion', 'MPA', (85, 94))	('metastases', 'Disease', (106, 116))	('Disruption', 'Var', (0, 10))
113582	27087480	by exploiting VEGFR3-driven luciferase knock-in models); (xi) Methodology to image metastatic and premetastatic niches; (xii) Ability to test how mutational burden affects dormancy; (xiii) Ability to detect conversion from dormant to growing cells in live animals.	('VEGFR3', 'Gene', '2324', (14, 20))	('man', 'Species', '9606', (175, 178))	('dormancy', 'CPA', (172, 180))	('man', 'Species', '9606', (226, 229))	('affects', 'Reg', (164, 171))	('VEGFR3', 'Gene', (14, 20))	('mutational burden', 'Var', (146, 163))	('dormancy', 'biological_process', 'GO:0030431', ('172', '180'))
113621	27087480	Among those, tumors harboring BRAF or NRAS mutations are most prevalent.	('NRAS', 'Gene', '4893', (38, 42))	('prevalent', 'Reg', (62, 71))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('mutations', 'Var', (43, 52))	('NRAS', 'Gene', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
113622	27087480	Other groups include melanomas with genetic changes in the NF1, KIT or RAC1 genes.	('RAC1', 'Gene', '5879', (71, 75))	('KIT', 'molecular_function', 'GO:0005020', ('64', '67'))	('RAC1', 'Gene', (71, 75))	('melanomas', 'Disease', (21, 30))	('genetic changes', 'Var', (36, 51))	('KIT', 'Gene', (64, 67))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('NF1', 'Gene', (59, 62))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('NF1', 'Gene', '4763', (59, 62))
113623	27087480	The genomic landscape of melanoma is also defined by epigenetic changes in complexes of proteins that interact with DNA to regulate gene expression.	('epigenetic changes', 'Var', (53, 71))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))	('complexes', 'Protein', (75, 84))	('gene expression', 'biological_process', 'GO:0010467', ('132', '147'))
113634	27087480	In particular, availability of therapies for patients with BRAFV600 mutations, which occur in ~45% of non-acral cutaneous melanomas, has been promising but also identified key challenges that must be overcome to maximize long-term clinical benefits of this strategy.	('cutaneous melanomas', 'Disease', (112, 131))	('acral cutaneous melanoma', 'Phenotype', 'HP:0012060', (106, 130))	('acral cutaneous melanomas', 'Phenotype', 'HP:0012060', (106, 131))	('clinical', 'Species', '191496', (231, 239))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (59, 63))	('patients', 'Species', '9606', (45, 53))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (112, 131))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('mutations', 'Var', (68, 77))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (112, 131))
113637	27087480	To date, no targeted therapies have demonstrated significant clinical efficacy in patients whose disease progresses following BRAF/MEK inhibition, thus driving an active area of research.	('MEK', 'Gene', '5609', (131, 134))	('patients', 'Species', '9606', (82, 90))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('MEK', 'Gene', (131, 134))	('clinical', 'Species', '191496', (61, 69))	('inhibition', 'Var', (135, 145))
113638	27087480	In addition to new mutations, epigenetic factors and tumor interaction with the microenvironment likely play roles in drug resistance, activities that present diagnostic challenges but also new therapeutic avenues.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('drug resistance', 'biological_process', 'GO:0009315', ('118', '133'))	('mutations', 'Var', (19, 28))	('drug resistance', 'Phenotype', 'HP:0020174', (118, 133))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('epigenetic factors', 'Var', (30, 48))	('tumor', 'Disease', (53, 58))	('men', 'Species', '9606', (92, 95))	('play roles', 'Reg', (104, 114))	('drug resistance', 'MPA', (118, 133))	('drug resistance', 'biological_process', 'GO:0042493', ('118', '133'))
113643	27087480	Finally, it is also critical to identify effective strategies to treat metastatic melanoma in patients lacking BRAFV600 mutations.	('patients', 'Species', '9606', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('mutations', 'Var', (120, 129))	('BRAF', 'Gene', '673', (111, 115))	('BRAF', 'Gene', (111, 115))
113645	27087480	The lessons learned from the still-evolving treatment of patients with BRAFV600 mutations should facilitate progress in developing therapies aimed at patients who lack them, most of whose melanomas harbor activating NRAS or inactivating NF1 mutations.	('men', 'Species', '9606', (49, 52))	('mutations', 'Var', (80, 89))	('BRAF', 'Gene', '673', (71, 75))	('melanomas', 'Disease', (188, 197))	('patients', 'Species', '9606', (57, 65))	('BRAF', 'Gene', (71, 75))	('NRAS', 'Gene', (216, 220))	('patients', 'Species', '9606', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('NF1', 'Gene', '4763', (237, 240))	('melanomas', 'Phenotype', 'HP:0002861', (188, 197))	('NF1', 'Gene', (237, 240))	('NRAS', 'Gene', '4893', (216, 220))	('melanomas', 'Disease', 'MESH:D008545', (188, 197))	('activating', 'PosReg', (205, 215))	('inactivating', 'Var', (224, 236))	('mutations', 'Var', (241, 250))
113646	27087480	Both alterations perturb RAS signaling; thus a key question, which is also relevant to multiple other cancers, is whether to directly target RAS or consider targeting of effectors of RAS signaling, such as RAF protein kinases or phosphatidylinositide (PI)-3' kinases.	('signaling', 'biological_process', 'GO:0023052', ('29', '38'))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('protein', 'cellular_component', 'GO:0003675', ('210', '217'))	('signaling', 'biological_process', 'GO:0023052', ('187', '196'))	('perturb', 'Reg', (17, 24))	('phosphatidylinositide', 'Chemical', '-', (229, 250))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('alterations', 'Var', (5, 16))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('RAS signaling', 'MPA', (25, 38))
113713	25424858	SF3B1 mutations constitute a novel therapeutic target in breast cancer Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in several tumour types including myelodysplastic syndromes, chronic lymphocytic leukaemia, uveal melanoma, and pancreatic cancer, and at lower frequencies in breast cancer.	('breast cancer', 'Disease', (57, 70))	('RNA', 'cellular_component', 'GO:0005562', ('120', '123'))	('melanoma', 'Phenotype', 'HP:0002861', (287, 295))	('occur', 'Reg', (152, 157))	('tumour type', 'Disease', (200, 211))	('uveal melanoma', 'Disease', (281, 295))	('pancreatic cancer', 'Disease', (301, 318))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (223, 248))	('uveal melanoma', 'Disease', 'MESH:C536494', (281, 295))	('breast cancer', 'Phenotype', 'HP:0003002', (348, 361))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('SF3B1', 'Gene', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('uveal melanoma', 'Phenotype', 'HP:0007716', (281, 295))	('RNA splicing', 'biological_process', 'GO:0008380', ('120', '132'))	('breast cancer', 'Disease', 'MESH:D001943', (348, 361))	('breast cancer', 'Disease', (348, 361))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('chronic lymphocytic leukaemia', 'Phenotype', 'HP:0005550', (250, 279))	('Mutations', 'Var', (71, 80))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (301, 318))	('SF3B1', 'Gene', '23451', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('lymphocytic leukaemia', 'Disease', (258, 279))	('lymphocytic leukaemia', 'Disease', 'MESH:D007945', (258, 279))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('pancreatic cancer', 'Disease', 'MESH:D010190', (301, 318))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (223, 248))	('myelodysplastic syndromes', 'Disease', (223, 248))	('tumour type', 'Disease', 'MESH:D009369', (200, 211))
113714	25424858	To investigate whether dysfunction in RNA splicing is implicated in the pathogenesis of breast cancer, we performed a re-analysis of published exome and whole genome sequencing data.	('dysfunction', 'Var', (23, 34))	('RNA', 'cellular_component', 'GO:0005562', ('38', '41'))	('RNA splicing', 'biological_process', 'GO:0008380', ('38', '50'))	('implicated', 'Reg', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('pathogenesis', 'biological_process', 'GO:0009405', ('72', '84'))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
113715	25424858	This analysis revealed that mutations in spliceosomal component genes occurred in 5.6% of unselected breast cancers, including hotspot mutations in the SF3B1 gene, which were found in 1.8% of unselected breast cancers.	('SF3B1', 'Gene', '23451', (152, 157))	('occurred', 'Reg', (70, 78))	('breast cancers', 'Phenotype', 'HP:0003002', (203, 217))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('breast cancers', 'Disease', 'MESH:D001943', (203, 217))	('breast cancers', 'Disease', (203, 217))	('mutations', 'Var', (135, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancers', 'Phenotype', 'HP:0003002', (101, 115))	('SF3B1', 'Gene', (152, 157))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('breast cancers', 'Disease', 'MESH:D001943', (101, 115))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('breast cancers', 'Disease', (101, 115))	('mutations', 'Var', (28, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
113716	25424858	SF3B1 mutations were significantly associated with ER-positive disease, AKT1 mutations, and distinct copy number alterations.	('SF3B1', 'Gene', (0, 5))	('associated', 'Reg', (35, 45))	('AKT1', 'Gene', '207', (72, 76))	('SF3B1', 'Gene', '23451', (0, 5))	('AKT1', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))	('copy number alterations', 'Var', (101, 124))	('ER-positive disease', 'Disease', (51, 70))	('mutations', 'Var', (6, 15))
113717	25424858	Additional profiling of hotspot mutations in a panel of special histological subtypes of breast cancer showed that 16% and 6% of papillary and mucinous carcinomas of the breast harboured the SF3B1 K700E mutation.	('mucinous carcinomas', 'Disease', (143, 162))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (143, 162))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('SF3B1', 'Gene', '23451', (191, 196))	('carcinomas of the breast', 'Phenotype', 'HP:0100013', (152, 176))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('K700E', 'Mutation', 'rs559063155', (197, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('K700E', 'Var', (197, 202))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('SF3B1', 'Gene', (191, 196))
113718	25424858	RNA sequencing identified differentially spliced events expressed in tumours with SF3B1 mutations including the protein coding genes TMEM14C, RPL31, DYNL11, UQCC, and ABCC5, and the long non-coding RNA CRNDE.	('SF3B1', 'Gene', (82, 87))	('mutations', 'Var', (88, 97))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('CRNDE', 'Gene', '643911', (202, 207))	('CRNDE', 'Gene', (202, 207))	('RNA', 'cellular_component', 'GO:0005562', ('198', '201'))	('ABCC5', 'Gene', '10057', (167, 172))	('RPL31', 'Gene', '6160', (142, 147))	('TMEM14C', 'Gene', (133, 140))	('SF3B1', 'Gene', '23451', (82, 87))	('UQCC', 'Gene', '55245', (157, 161))	('UQCC', 'Gene', (157, 161))	('ABCC5', 'Gene', (167, 172))	('RPL31', 'Gene', (142, 147))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('TMEM14C', 'Gene', '51522', (133, 140))	('tumours', 'Disease', (69, 76))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
113719	25424858	Moreover, SF3B1 mutant cell lines were found to be sensitive to the SF3b complex inhibitor spliceostatin A and treatment resulted in perturbation of the splicing signature.	('spliceostatin A', 'Chemical', 'MESH:C553684', (91, 106))	('splicing', 'biological_process', 'GO:0045292', ('153', '161'))	('perturbation', 'Reg', (133, 145))	('SF3B1', 'Gene', (10, 15))	('mutant', 'Var', (16, 22))	('splicing signature', 'MPA', (153, 171))	('SF3B1', 'Gene', '23451', (10, 15))	('sensitive', 'MPA', (51, 60))	('spliceostatin A', 'MPA', (91, 106))
113720	25424858	Albeit rare, SF3B1 mutations result in alternative splicing events, and may constitute drivers and a novel therapeutic target in a subset of breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('result in', 'Reg', (29, 38))	('SF3B1', 'Gene', (13, 18))	('breast cancers', 'Phenotype', 'HP:0003002', (141, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('mutations', 'Var', (19, 28))	('breast cancers', 'Disease', (141, 155))	('SF3B1', 'Gene', '23451', (13, 18))	('breast cancers', 'Disease', 'MESH:D001943', (141, 155))	('splicing', 'biological_process', 'GO:0045292', ('51', '59'))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('alternative splicing events', 'MPA', (39, 66))
113723	25424858	These seminal studies have highlighted that there are a few highly recurrent mutations in breast cancer, including TP53 and PIK3CA, and a wide spectrum of genes mutated in a small minority of tumours.	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('tumours', 'Phenotype', 'HP:0002664', (192, 199))	('TP53', 'Gene', '7157', (115, 119))	('tumours', 'Disease', 'MESH:D009369', (192, 199))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('PIK3CA', 'Gene', (124, 130))	('breast cancer', 'Disease', (90, 103))	('mutations', 'Var', (77, 86))	('TP53', 'Gene', (115, 119))	('tumours', 'Disease', (192, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('PIK3CA', 'Gene', '5290', (124, 130))
113726	25424858	In fact, mutations in the splicing factor 3B subunit 1 gene (SF3B1) are rather prevalent in MDS and found to be associated with a distinct phenotype (i.e.	('associated with', 'Reg', (112, 127))	('SF3B1', 'Gene', (61, 66))	('splicing factor 3B subunit 1', 'Gene', '23451', (26, 54))	('mutations', 'Var', (9, 18))	('splicing', 'biological_process', 'GO:0045292', ('26', '34'))	('SF3B1', 'Gene', '23451', (61, 66))	('splicing factor 3B subunit 1', 'Gene', (26, 54))	('MDS', 'Disease', (92, 95))	('MDS', 'Disease', 'MESH:D009190', (92, 95))	('MDS', 'Phenotype', 'HP:0002863', (92, 95))	('prevalent', 'Reg', (79, 88))
113727	25424858	Mutations in other splicing genes, such as the U2 small nuclear RNA auxiliary factor 1 gene (U2AF1), the serine/arginine-rich splicing factor 2 gene (SRSF2), and the U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit-related protein 2 gene (ZRSR2), have also been reported; however, these are less frequent and not associated with ring sideroblasts in MDS patients.	('U2AF1', 'Gene', '7307', (93, 98))	('MDS', 'Disease', 'MESH:D009190', (368, 371))	('ZRSR2', 'Gene', '8233', (257, 262))	('SRSF2', 'Gene', (150, 155))	('ring sideroblasts', 'Phenotype', 'HP:0004828', (347, 364))	('serine/arginine-rich splicing factor 2', 'Gene', '6427', (105, 143))	('splicing', 'biological_process', 'GO:0045292', ('126', '134'))	('small nuclear ribonucleoprotein', 'molecular_function', 'GO:0003734', ('169', '200'))	('small nuclear ribonucleoprotein', 'cellular_component', 'GO:0030532', ('169', '200'))	('serine/arginine-rich splicing factor 2', 'Gene', (105, 143))	('MDS', 'Disease', (368, 371))	('Mutations', 'Var', (0, 9))	('ZRSR2', 'Gene', (257, 262))	('U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit-related protein 2', 'Gene', '8233', (166, 250))	('MDS', 'Phenotype', 'HP:0002863', (368, 371))	('U2AF1', 'Gene', (93, 98))	('small nuclear RNA', 'molecular_function', 'GO:0005570', ('50', '67'))	('U2AF', 'cellular_component', 'GO:0089701', ('93', '97'))	('splicing', 'biological_process', 'GO:0045292', ('19', '27'))	('protein', 'cellular_component', 'GO:0003675', ('241', '248'))	('SRSF2', 'Gene', '6427', (150, 155))	('RNA', 'cellular_component', 'GO:0005562', ('64', '67'))	('patients', 'Species', '9606', (372, 380))
113728	25424858	More recently, studies have identified mutations in SF3B1 in subsets of solid tumours from multiple anatomic sites (see ref 11 for a recent review), including 15% of chronic lymphocytic leukaemias (CLLs), 9.7% of uveal melanomas, 4% of pancreatic cancers, and 1.8% of breast cancers.	('uveal melanomas', 'Disease', (213, 228))	('uveal melanomas', 'Phenotype', 'HP:0007716', (213, 228))	('breast cancers', 'Phenotype', 'HP:0003002', (268, 282))	('solid tumours', 'Disease', (72, 85))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('breast cancer', 'Phenotype', 'HP:0003002', (268, 281))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (236, 254))	('SF3B1', 'Gene', '23451', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('CLLs', 'Phenotype', 'HP:0005550', (198, 202))	('pancreatic cancers', 'Disease', (236, 254))	('mutations', 'Var', (39, 48))	('melanomas', 'Phenotype', 'HP:0002861', (219, 228))	('lymphocytic leukaemias', 'Disease', 'MESH:D007945', (174, 196))	('solid tumours', 'Disease', 'MESH:D009369', (72, 85))	('lymphocytic leukaemias', 'Disease', (174, 196))	('pancreatic cancers', 'Disease', 'MESH:D010190', (236, 254))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('uveal melanomas', 'Disease', 'MESH:C536494', (213, 228))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('chronic lymphocytic leukaemias', 'Phenotype', 'HP:0005550', (166, 196))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('breast cancers', 'Disease', 'MESH:D001943', (268, 282))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (236, 253))	('breast cancers', 'Disease', (268, 282))	('SF3B1', 'Gene', (52, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (213, 227))	('chronic lymphocytic leukaemia', 'Phenotype', 'HP:0005550', (166, 195))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
113729	25424858	Although these mutations have been shown to result in phenotypic changes exemplified by their impact on RNA splicing events in CLLs and uveal melanomas, their impact on outcome seems to vary according to tumour type.	('uveal melanomas', 'Phenotype', 'HP:0007716', (136, 151))	('uveal melanomas', 'Disease', (136, 151))	('mutations', 'Var', (15, 24))	('CLLs', 'Phenotype', 'HP:0005550', (127, 131))	('RNA', 'cellular_component', 'GO:0005562', ('104', '107'))	('uveal melanomas', 'Disease', 'MESH:C536494', (136, 151))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('RNA splicing events', 'MPA', (104, 123))	('uveal melanoma', 'Phenotype', 'HP:0007716', (136, 150))	('RNA splicing', 'biological_process', 'GO:0008380', ('104', '116'))	('melanomas', 'Phenotype', 'HP:0002861', (142, 151))	('tumour type', 'Disease', 'MESH:D009369', (204, 215))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('tumour type', 'Disease', (204, 215))	('impact', 'Reg', (94, 100))
113730	25424858	Whilst in patients with CLL these mutations are associated with a poor outcome, in patients with uveal melanoma, SF3B1 mutations are reported to be associated with a good prognosis.	('SF3B1', 'Gene', (113, 118))	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('uveal melanoma', 'Disease', (97, 111))	('SF3B1', 'Gene', '23451', (113, 118))	('associated', 'Reg', (148, 158))	('patients', 'Species', '9606', (10, 18))	('patients', 'Species', '9606', (83, 91))	('mutations', 'Var', (119, 128))	('mutations', 'Var', (34, 43))
113731	25424858	Given that mutations affecting spliceosomal component genes have been reported in multiple tumour types, including breast cancer, and may constitute driver events in a subset of cancers, we performed a systematic re-analysis of publicly available exome, whole genome, and RNA sequencing data available for breast cancers.	('mutations', 'Var', (11, 20))	('cancers', 'Disease', (313, 320))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('spliceosomal component genes', 'Gene', (31, 59))	('tumour type', 'Disease', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('breast cancers', 'Disease', 'MESH:D001943', (306, 320))	('breast cancers', 'Disease', (306, 320))	('RNA', 'cellular_component', 'GO:0005562', ('272', '275'))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancers', 'Phenotype', 'HP:0003002', (306, 320))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (306, 319))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('cancers', 'Disease', 'MESH:D009369', (313, 320))	('breast cancer', 'Disease', 'MESH:D001943', (306, 319))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('breast cancer', 'Disease', (115, 128))	('tumour type', 'Disease', 'MESH:D009369', (91, 102))	('reported', 'Reg', (70, 78))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Phenotype', 'HP:0002664', (313, 320))
113732	25424858	Our aims were to determine whether mutations affecting spliceosomal component genes are associated with specific breast cancer subtypes and, if present, whether these mutations were associated with distinct splicing events and would constitute targets for therapy in these tumours.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('associated', 'Reg', (182, 192))	('breast cancer', 'Disease', (113, 126))	('tumours', 'Phenotype', 'HP:0002664', (273, 280))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('tumours', 'Disease', 'MESH:D009369', (273, 280))	('tumour', 'Phenotype', 'HP:0002664', (273, 279))	('tumours', 'Disease', (273, 280))	('splicing', 'biological_process', 'GO:0045292', ('207', '215'))	('associated', 'Reg', (88, 98))	('splicing', 'MPA', (207, 215))	('mutations', 'Var', (35, 44))
113734	25424858	Binary alignment mapping (BAM) files of SF3B1 mutant tumours available in TCGA were used to assess the heterozygosity at the SF3B1 locus using ASCAT.	('SF3B1', 'Gene', (40, 45))	('SF3B1', 'Gene', '23451', (125, 130))	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('tumours', 'Disease', (53, 60))	('SF3B1', 'Gene', '23451', (40, 45))	('mutant', 'Var', (46, 52))	('SF3B1', 'Gene', (125, 130))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))
113735	25424858	Representative frozen or formalin-fixed, paraffin-embedded (FFPE) samples from 65 breast cancers classified as papillary (n = 19), mucinous (n = 18), and micropapillary (n = 28) carcinomas were retrieved from the authors' institutions and surveyed for the presence of the SF3B1 K700E hotspot mutation (Supplementary Table 1).	('carcinomas', 'Disease', (178, 188))	('paraffin', 'Chemical', 'MESH:D010232', (41, 49))	('carcinomas', 'Disease', 'MESH:D002277', (178, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('breast cancers', 'Disease', 'MESH:D001943', (82, 96))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('breast cancers', 'Disease', (82, 96))	('SF3B1', 'Gene', (272, 277))	('formalin', 'Chemical', 'MESH:D005557', (25, 33))	('SF3B1', 'Gene', '23451', (272, 277))	('carcinomas', 'Phenotype', 'HP:0030731', (178, 188))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('breast cancers', 'Phenotype', 'HP:0003002', (82, 96))	('K700E', 'Var', (278, 283))	('K700E', 'Mutation', 'rs559063155', (278, 283))
113738	25424858	Normalised circular binary segmented (cbs) SNP6 data were retrieved from TCGA for available SF3B1 mutant and wild-type tumours, matched on a 1 : 2 ratio for ER, PR, HER2 status, and PIK3CA and TP53 mutational status (Supplementary Table 3).	('PR', 'Gene', '5241', (161, 163))	('type tumours', 'Disease', (114, 126))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumours', 'Phenotype', 'HP:0002664', (119, 126))	('SF3B1', 'Gene', '23451', (92, 97))	('TP53', 'Gene', '7157', (193, 197))	('PIK3CA', 'Gene', (182, 188))	('PIK3CA', 'Gene', '5290', (182, 188))	('type tumours', 'Disease', 'MESH:D009369', (114, 126))	('TP53', 'Gene', (193, 197))	('HER2', 'Gene', (165, 169))	('HER2', 'Gene', '2064', (165, 169))	('mutant', 'Var', (98, 104))	('SF3B1', 'Gene', (92, 97))
113739	25424858	Targeted DNA sequencing of ten recurrently mutated genes identified in SF3B1 mutated (n = 3) and wild-type (n = 16) breast cancers was performed using the Ion Torrent AmpliSeq technology according to the manufacturer's instructions (Life Technologies, Paisley, UK) (Supplementary methods and Supplementary Table 4).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('SF3B1', 'Gene', (71, 76))	('breast cancers', 'Disease', 'MESH:D001943', (116, 130))	('breast cancers', 'Disease', (116, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('SF3B1', 'Gene', '23451', (71, 76))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('mutated', 'Var', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('breast cancers', 'Phenotype', 'HP:0003002', (116, 130))
113740	25424858	RNA sequencing was performed using 16 ng of ribosomal-depleted RNA of 14 papillary carcinomas of the breast (three SF3B1 mutant and 11 SF3B1 wild-type) (Supplementary methods).	('papillary carcinomas of the breast', 'Disease', (73, 107))	('papillary carcinomas of the breast', 'Disease', 'MESH:D002291', (73, 107))	('carcinomas of the breast', 'Phenotype', 'HP:0100013', (83, 107))	('mutant', 'Var', (121, 127))	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('SF3B1', 'Gene', (115, 120))	('SF3B1', 'Gene', (135, 140))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('SF3B1', 'Gene', '23451', (115, 120))	('SF3B1', 'Gene', '23451', (135, 140))
113744	25424858	FASTQ files from available TCGA RNA-sequencing data from SF3B1 K700E mutant (n = 8) and ER, PR, HER2 status, and PIK3CA and TP53 mutational status, and randomly matched controls (n = 16) were downloaded from the Cancer Genomics Hub (CGHub; https://cghub.ucsc.edu) and processed as above (TCGA project access number 6223).	('SF3B1', 'Gene', (57, 62))	('K700E mutant', 'Var', (63, 75))	('PIK3CA', 'Gene', (113, 119))	('mutant', 'Var', (69, 75))	('K700E', 'Mutation', 'rs559063155', (63, 68))	('TP53', 'Gene', '7157', (124, 128))	('Cancer', 'Disease', (212, 218))	('PIK3CA', 'Gene', '5290', (113, 119))	('SF3B1', 'Gene', '23451', (57, 62))	('TP53', 'Gene', (124, 128))	('Cancer', 'Disease', 'MESH:D009369', (212, 218))	('Cancer', 'Phenotype', 'HP:0002664', (212, 218))	('PR', 'Gene', '5241', (92, 94))	('HER2', 'Gene', (96, 100))	('RNA', 'cellular_component', 'GO:0005562', ('32', '35'))	('HER2', 'Gene', '2064', (96, 100))
113746	25424858	SF3B1 K700E mutations were screened by PCR and RT-PCR using KAPA Taq DNA Polymerase (KAPA Biosystems, MA, USA) and sequenced as previously described.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('SF3B1', 'Gene', (0, 5))	('SF3B1', 'Gene', '23451', (0, 5))	('K700E', 'Mutation', 'rs559063155', (6, 11))	('Taq DNA Polymerase', 'molecular_function', 'GO:0003887', ('65', '83'))	('K700E', 'Var', (6, 11))
113749	25424858	For each splicing event, a two-tailed Mann-Whitney U-test was applied between SF3B1 mutated (n = 3) and wild-type (n = 11) cases.	('mutated', 'Var', (84, 91))	('SF3B1', 'Gene', '23451', (78, 83))	('splicing', 'biological_process', 'GO:0045292', ('9', '17'))	('SF3B1', 'Gene', (78, 83))
113751	25424858	SF3B1 mutant cell lines were identified through COSMIC (http://cancer.sanger.ac.uk/cosmic) and verified by means of Sanger sequencing using the methods and primers described above.	('mutant', 'Var', (6, 12))	('SF3B1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('SF3B1', 'Gene', '23451', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
113752	25424858	SF3B1 plus eight genes that were consistently differentially spliced in SF3B1 mutant versus wild-type samples - namely ABCC5, ANKHD1, DYNLL1, F8, RPL31, TMEM14C, UQCC, and CRNDE - were selected for functional evaluation.	('ANKHD1', 'Gene', '54882', (126, 132))	('TMEM14C', 'Gene', '51522', (153, 160))	('DYNLL1', 'Gene', (134, 140))	('DYNLL1', 'Gene', '8655', (134, 140))	('SF3B1', 'Gene', (0, 5))	('SF3B1', 'Gene', (72, 77))	('ANKHD1', 'Gene', (126, 132))	('ABCC5', 'Gene', '10057', (119, 124))	('SF3B1', 'Gene', '23451', (0, 5))	('UQCC', 'Gene', '55245', (162, 166))	('ABCC5', 'Gene', (119, 124))	('SF3B1', 'Gene', '23451', (72, 77))	('UQCC', 'Gene', (162, 166))	('mutant', 'Var', (78, 84))	('TMEM14C', 'Gene', (153, 160))	('RPL31', 'Gene', '6160', (146, 151))	('CRNDE', 'Gene', '643911', (172, 177))	('CRNDE', 'Gene', (172, 177))	('RPL31', 'Gene', (146, 151))
113755	25424858	The Mann-Whitney U-test and Student's t-test were employed to compare the mean expression of alternatively spliced exons between SF3B1 wild-type and mutant tumours, and between drug- and DMSO-treated cells.	('SF3B1', 'Gene', (129, 134))	('tumours', 'Disease', 'MESH:D009369', (156, 163))	('tumours', 'Disease', (156, 163))	('SF3B1', 'Gene', '23451', (129, 134))	('mutant', 'Var', (149, 155))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumours', 'Phenotype', 'HP:0002664', (156, 163))	('DMSO', 'Chemical', 'MESH:D004121', (187, 191))
113756	25424858	A systematic re-analysis of exome and whole genome sequencing data from TCGA and other published studies identified recurrent mutations in distinct spliceosomal component genes previously reported in other tumour types (Figure 1A, Table 1, and Supplementary Table 6).	('TCGA', 'Gene', (72, 76))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('spliceosomal component genes', 'Gene', (148, 176))	('mutations', 'Var', (126, 135))	('tumour type', 'Disease', 'MESH:D009369', (206, 217))	('tumour type', 'Disease', (206, 217))
113757	25424858	Some mutations in spliceosome genes appeared to be mutually exclusive, including SF3B1 and PRPF8, and SF3B1 and SON (odds ratio = 0, p < 0.05, Fisher's exact test).	('SF3B1', 'Gene', (102, 107))	('PRPF8', 'Gene', '10594', (91, 96))	('SF3B1', 'Gene', (81, 86))	('PRPF8', 'Gene', (91, 96))	('spliceosome genes', 'Gene', (18, 35))	('mutations', 'Var', (5, 14))	('SF3B1', 'Gene', '23451', (81, 86))	('SF3B1', 'Gene', '23451', (102, 107))	('spliceosome', 'cellular_component', 'GO:0005681', ('18', '29'))
113758	25424858	Coincident spliceosome mutations were also identified in SF3B1 and LUC7L2, and in LUC7L2 and SAP130 in two patients (Figure 1A).	('SF3B1', 'Gene', (57, 62))	('LUC7L2', 'Gene', '51631', (67, 73))	('SF3B1', 'Gene', '23451', (57, 62))	('SAP130', 'Gene', '79595', (93, 99))	('spliceosome', 'cellular_component', 'GO:0005681', ('11', '22'))	('mutations', 'Var', (23, 32))	('LUC7L2', 'Gene', '51631', (82, 88))	('LUC7L2', 'Gene', (67, 73))	('SAP130', 'Gene', (93, 99))	('patients', 'Species', '9606', (107, 115))	('LUC7L2', 'Gene', (82, 88))
113759	25424858	Although not significant, mutations in LUC7L2 and SAP130 showed a trend towards co-occurrence (odds ratio = 2.883, p = 0.9434, Fisher's exact test).	('SAP130', 'Gene', (50, 56))	('LUC7L2', 'Gene', '51631', (39, 45))	('mutations', 'Var', (26, 35))	('SAP130', 'Gene', '79595', (50, 56))	('LUC7L2', 'Gene', (39, 45))	('co-occurrence', 'Interaction', (80, 93))
113760	25424858	Of the most common spliceosome gene mutations (overall frequency > 0.5%), mutations in SF3B1 were more common in ER-positive breast cancer (2.2%, 21/936 ER-positive versus 0.3%, 1/289 ER-negative, p = 0.03914, Fisher's exact test) and mutations in SAP130 were more common in ER-negative tumours (0.1%, 1/936 ER-positive versus 1.4%, 4/289 ER-negative, p = 0.012, Fisher's exact test).	('common', 'Reg', (103, 109))	('tumours', 'Phenotype', 'HP:0002664', (287, 294))	('mutations', 'Var', (74, 83))	('SF3B1', 'Gene', (87, 92))	('SAP130', 'Gene', '79595', (248, 254))	('tumours', 'Disease', 'MESH:D009369', (287, 294))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('SF3B1', 'Gene', '23451', (87, 92))	('spliceosome', 'cellular_component', 'GO:0005681', ('19', '30'))	('SAP130', 'Gene', (248, 254))	('tumours', 'Disease', (287, 294))	('breast cancer', 'Disease', (125, 138))	('tumour', 'Phenotype', 'HP:0002664', (287, 293))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))
113761	25424858	Overall, mutations in SF3B1 were the most common spliceosomal component gene mutation and were identified in 1.8% of unselected breast cancers (23/1293), and occurred as a recurrent hotspot T > C base-pair substitution at codon 700, leading to a glutamic acid from lysine (K700E) in 74% (17/23) of mutant cases (Figure 1B and Table 1).	('glutamic acid from lysine', 'MPA', (246, 271))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('SF3B1', 'Gene', '23451', (22, 27))	('mutations', 'Var', (9, 18))	('K700E', 'Mutation', 'rs559063155', (273, 278))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('K700E', 'Var', (273, 278))	('glutamic acid', 'Chemical', 'MESH:D018698', (246, 259))	('breast cancers', 'Phenotype', 'HP:0003002', (128, 142))	('breast cancers', 'Disease', 'MESH:D001943', (128, 142))	('breast cancers', 'Disease', (128, 142))	('T > C base-pair substitution at codon 700', 'Mutation', 'c.700T>C', (190, 231))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('mutant', 'Var', (298, 304))	('SF3B1', 'Gene', (22, 27))	('lysine', 'Chemical', 'MESH:D008239', (265, 271))
113762	25424858	Additional recurrent mutations in SF3B1 occurred at codon 666 (K666Q and K666E) in 9% of mutant tumours (2/23), and non-recurrent mutations included G241*, N626D, A633V, Y765C, and D781E, which were found in 22% (5/23; Supplementary Table 6).	('G241*', 'SUBSTITUTION', 'None', (149, 154))	('SF3B1', 'Gene', (34, 39))	('G241*', 'Var', (149, 154))	('A633V', 'Mutation', 'p.A633V', (163, 168))	('tumours', 'Disease', (96, 103))	('K666E', 'Var', (73, 78))	('N626D', 'Var', (156, 161))	('K666Q', 'Var', (63, 68))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('D781E', 'Var', (181, 186))	('A633V', 'Var', (163, 168))	('tumours', 'Disease', 'MESH:D009369', (96, 103))	('SF3B1', 'Gene', '23451', (34, 39))	('Y765C', 'Var', (170, 175))	('Y765C', 'Mutation', 'p.Y765C', (170, 175))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('K666E', 'Mutation', 'rs754688962', (73, 78))	('D781E', 'Mutation', 'p.D781E', (181, 186))	('K666Q', 'Mutation', 'rs754688962', (63, 68))	('N626D', 'Mutation', 'rs769888451', (156, 161))
113763	25424858	A comparison of the genomic features of SF3B1 K700E mutant tumours with available phenotypic information (n = 16) with those of stage, ER, PR, HER2, PIK3CA, and TP53 mutation status-matched SF3B1 K700E wild-type tumours (n = 32; Supplementary Table 3) revealed that SF3B1 K700E mutant tumours displayed a higher frequency of chromosomal gains on 16q12-q13 and 16q21-q22 and losses on 1p36-p35, 16q11-q13, and 16q21-q23 (adjusted p < 0.05, multi-Fisher's exact test).	('16q12-q13', 'Var', (346, 355))	('SF3B1', 'Gene', (266, 271))	('K700E mutant', 'Var', (272, 284))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('p35', 'cellular_component', 'GO:0070745', ('389', '392'))	('16q11-q13', 'Var', (394, 403))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('HER2', 'Gene', '2064', (143, 147))	('mutant', 'Var', (278, 284))	('K700E', 'Mutation', 'rs559063155', (46, 51))	('16q21-q22', 'Var', (360, 369))	('type tumours', 'Disease', (207, 219))	('SF3B1', 'Gene', '23451', (266, 271))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('p35', 'cellular_component', 'GO:0043514', ('389', '392'))	('losses', 'NegReg', (374, 380))	('SF3B1', 'Gene', (190, 195))	('gains', 'PosReg', (337, 342))	('PIK3CA', 'Gene', '5290', (149, 155))	('SF3B1', 'Gene', (40, 45))	('TP53', 'Gene', (161, 165))	('tumours', 'Disease', (285, 292))	('PR', 'Gene', '5241', (139, 141))	('HER2', 'Gene', (143, 147))	('16q21-q23', 'Var', (409, 418))	('tumours', 'Disease', (212, 219))	('tumours', 'Phenotype', 'HP:0002664', (285, 292))	('type tumours', 'Disease', 'MESH:D009369', (207, 219))	('tumours', 'Disease', 'MESH:D009369', (285, 292))	('K700E', 'Mutation', 'rs559063155', (196, 201))	('1p36-p35', 'Var', (384, 392))	('SF3B1', 'Gene', '23451', (190, 195))	('tumours', 'Phenotype', 'HP:0002664', (212, 219))	('SF3B1', 'Gene', '23451', (40, 45))	('tumour', 'Phenotype', 'HP:0002664', (285, 291))	('PIK3CA', 'Gene', (149, 155))	('tumours', 'Disease', 'MESH:D009369', (212, 219))	('K700E', 'Mutation', 'rs559063155', (272, 277))	('TP53', 'Gene', '7157', (161, 165))	('tumours', 'Disease', (59, 66))
113764	25424858	These observations suggest that SF3B1 K700E mutant tumours have a distinct repertoire of copy number alterations (Supplementary Figure 1 and Supplementary Table 7).	('K700E mutant', 'Var', (38, 50))	('SF3B1', 'Gene', '23451', (32, 37))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('copy number alterations', 'MPA', (89, 112))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('tumours', 'Disease', 'MESH:D009369', (51, 58))	('K700E', 'Mutation', 'rs559063155', (38, 43))	('SF3B1', 'Gene', (32, 37))	('tumours', 'Disease', (51, 58))
113765	25424858	No differences in the frequency of amplifications between SF3B1 K700E mutant and wild-type tumours were detected.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('type tumours', 'Disease', (86, 98))	('SF3B1', 'Gene', (58, 63))	('K700E', 'Mutation', 'rs559063155', (64, 69))	('SF3B1', 'Gene', '23451', (58, 63))	('type tumours', 'Disease', 'MESH:D009369', (86, 98))	('K700E', 'Var', (64, 69))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
113766	25424858	Although no difference was seen in the total number of somatic coding mutations between SF3B1 K700E mutant and wild-type samples (p = 0.597, t-test; SF3B1 K700E mutant average 23.3, range 9-59; SF3B1 wild-type average 25.59, range 1-85), 56.3% (9/16) of the SF3B1 mutant samples also carried PIK3CA mutations, while mutations in TP53 were not as prevalent (6.3%, Figure 1C).	('K700E', 'Var', (94, 99))	('TP53', 'Gene', '7157', (329, 333))	('K700E', 'Mutation', 'rs559063155', (94, 99))	('SF3B1', 'Gene', '23451', (149, 154))	('SF3B1', 'Gene', '23451', (194, 199))	('SF3B1', 'Gene', '23451', (88, 93))	('SF3B1', 'Gene', (149, 154))	('mutant', 'Var', (264, 270))	('carried', 'Reg', (284, 291))	('SF3B1', 'Gene', (258, 263))	('PIK3CA', 'Gene', (292, 298))	('PIK3CA', 'Gene', '5290', (292, 298))	('mutations', 'Var', (299, 308))	('SF3B1', 'Gene', '23451', (258, 263))	('SF3B1', 'Gene', (88, 93))	('SF3B1', 'Gene', (194, 199))	('K700E', 'Mutation', 'rs559063155', (155, 160))	('TP53', 'Gene', (329, 333))
113767	25424858	In addition, AKT1 hotspot E17K mutations were found to be significantly more frequent in SF3B1 K700E mutated tumours (4/16) than in matched wild-type cancers (0/32, p = 0.009353, Fisher's exact test).	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('SF3B1', 'Gene', (89, 94))	('AKT1', 'Gene', (13, 17))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Disease', (150, 157))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('K700E', 'Mutation', 'rs559063155', (95, 100))	('K700E mutated', 'Var', (95, 108))	('tumours', 'Disease', (109, 116))	('SF3B1', 'Gene', '23451', (89, 94))	('E17K', 'Mutation', 'rs121434592', (26, 30))	('E17K mutations', 'Var', (26, 40))	('AKT1', 'Gene', '207', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
113768	25424858	Interestingly, 2 out of 24 (8.3%) mucinous carcinomas of the breast annotated in the data were identified as having SF3B1 K700E mutations and lacked mutations in additional significantly mutated genes or known cancer genes (Figure 1C).	('mucinous carcinomas', 'Disease', (34, 53))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (34, 53))	('SF3B1', 'Gene', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('SF3B1', 'Gene', '23451', (116, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('K700E', 'Var', (122, 127))	('K700E', 'Mutation', 'rs559063155', (122, 127))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('carcinomas of the breast', 'Phenotype', 'HP:0100013', (43, 67))	('cancer', 'Disease', (210, 216))
113769	25424858	Given the apparent association of SF3B1 mutations with mucinous carcinomas of the breast, we screened additional cohorts of ER-positive special histological types of breast cancer for SF3B1 K700E mutations.	('K700E', 'Mutation', 'rs559063155', (190, 195))	('SF3B1', 'Gene', '23451', (184, 189))	('K700E', 'Var', (190, 195))	('association', 'Reg', (19, 30))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (55, 74))	('SF3B1', 'Gene', (34, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('mutations', 'Var', (40, 49))	('mucinous carcinomas', 'Disease', (55, 74))	('carcinomas of the breast', 'Phenotype', 'HP:0100013', (64, 88))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancer', 'Disease', (166, 179))	('SF3B1', 'Gene', '23451', (34, 39))	('SF3B1', 'Gene', (184, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))
113771	25424858	K700E mutations were identified in 6% (1/18), 16% (3/19), and 0% (0/28) of mucinous, papillary, and micropapillary carcinomas, respectively.	('micropapillary carcinomas', 'Disease', 'MESH:D002277', (100, 125))	('mucinous', 'Disease', (75, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('micropapillary carcinomas', 'Disease', (100, 125))	('K700E', 'Mutation', 'rs559063155', (0, 5))	('K700E', 'Var', (0, 5))	('papillary', 'Disease', (85, 94))
113772	25424858	These mutations were expressed at the RNA level in all papillary carcinomas tested, where matched RNA was available.	('RNA', 'cellular_component', 'GO:0005562', ('98', '101'))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('RNA', 'cellular_component', 'GO:0005562', ('38', '41'))	('papillary carcinomas', 'Disease', 'MESH:D002291', (55, 75))	('papillary carcinomas', 'Disease', (55, 75))	('mutations', 'Var', (6, 15))
113773	25424858	Although the small number of cases subjected to SF3B1 mutation profiling could have resulted in a type I or alpha error resulting in a higher frequency of mutations than the mutation rate in unselected breast cancers, the probability of finding three samples harbouring an SF3B1 mutation by chance is less than 0.5% (based on a binomial distribution assuming a mutation rate of 1.8% in unselected breast cancers).	('SF3B1', 'Gene', (273, 278))	('SF3B1', 'Gene', '23451', (273, 278))	('SF3B1', 'Gene', (48, 53))	('breast cancers', 'Disease', 'MESH:D001943', (202, 216))	('breast cancers', 'Disease', (202, 216))	('cancers', 'Phenotype', 'HP:0002664', (404, 411))	('breast cancers', 'Phenotype', 'HP:0003002', (202, 216))	('resulted', 'Reg', (84, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('breast cancers', 'Disease', 'MESH:D001943', (397, 411))	('breast cancers', 'Disease', (397, 411))	('SF3B1', 'Gene', '23451', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (404, 410))	('mutation', 'Var', (54, 62))	('mutations', 'Var', (155, 164))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('breast cancers', 'Phenotype', 'HP:0003002', (397, 411))	('higher', 'PosReg', (135, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (397, 410))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
113774	25424858	Given the higher frequency of SF3B1 K700E mutations in papillary carcinomas of the breast, we hypothesised that these mutations may underpin their biology and may be present at additional hotspots and/or be sub-clonal in the 'wild-type' samples.	('carcinomas of the breast', 'Phenotype', 'HP:0100013', (65, 89))	('SF3B1', 'Gene', (30, 35))	('papillary carcinomas of the breast', 'Disease', (55, 89))	('papillary carcinomas of the breast', 'Disease', 'MESH:D002291', (55, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('K700E', 'Mutation', 'rs559063155', (36, 41))	('SF3B1', 'Gene', '23451', (30, 35))	('K700E', 'Var', (36, 41))
113775	25424858	To address these questions, the 19 papillary carcinomas were subjected to targeted DNA re-sequencing of SF3B1 exons 14-16 and of nine additional genes, which are recurrently mutated in ER-positive breast cancers harbouring SF3B1 mutations and have been postulated as drivers.	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('19 papillary carcinomas', 'Disease', 'MESH:D002291', (32, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('mutations', 'Var', (229, 238))	('SF3B1', 'Gene', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('SF3B1', 'Gene', (104, 109))	('SF3B1', 'Gene', '23451', (223, 228))	('breast cancers', 'Phenotype', 'HP:0003002', (197, 211))	('19 papillary carcinomas', 'Disease', (32, 55))	('breast cancers', 'Disease', 'MESH:D001943', (197, 211))	('breast cancers', 'Disease', (197, 211))	('SF3B1', 'Gene', '23451', (104, 109))
113776	25424858	This analysis failed to identify additional or sub-clonal SF3B1 mutations in the 16 papillary carcinomas that had been shown be SF3B1 wild-type by Sanger sequencing analysis.	('SF3B1', 'Gene', '23451', (128, 133))	('SF3B1', 'Gene', (58, 63))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('SF3B1', 'Gene', '23451', (58, 63))	('mutations', 'Var', (64, 73))	('SF3B1', 'Gene', (128, 133))	('papillary carcinomas', 'Disease', (84, 104))	('papillary carcinomas', 'Disease', 'MESH:D002291', (84, 104))
113777	25424858	Overall, 63% (12/19) of the samples were found to display mutations in additional cancer genes including PIK3CA in 37% (7/19), TP53 in 5% (1/19), GATA3 in 11% (2/19), MAP3K1 11% (2/19), and MAP3K4 in 21% (4/19) (Figure 1D and Supplementary Table 8).	('PIK3CA', 'Gene', (105, 111))	('mutations', 'Var', (58, 67))	('MAP3K1', 'Gene', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('GATA3', 'Gene', '2625', (146, 151))	('MAP3K', 'molecular_function', 'GO:0004709', ('190', '195'))	('PIK3CA', 'Gene', '5290', (105, 111))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('MAP3K4', 'Gene', '4216', (190, 196))	('MAP3K4', 'Gene', (190, 196))	('TP53', 'Gene', (127, 131))	('MAP3K', 'molecular_function', 'GO:0004709', ('167', '172'))	('TP53', 'Gene', '7157', (127, 131))	('GATA3', 'Gene', (146, 151))
113778	25424858	In contrast to SF3B1 mutant unselected breast cancers, no papillary carcinomas in this series were found to harbour AKT1 hotspot mutations.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('AKT1', 'Gene', (116, 120))	('SF3B1', 'Gene', '23451', (15, 20))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('mutations', 'Var', (129, 138))	('papillary carcinomas', 'Disease', 'MESH:D002291', (58, 78))	('breast cancers', 'Phenotype', 'HP:0003002', (39, 53))	('papillary carcinomas', 'Disease', (58, 78))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancers', 'Disease', 'MESH:D001943', (39, 53))	('breast cancers', 'Disease', (39, 53))	('AKT1', 'Gene', '207', (116, 120))	('SF3B1', 'Gene', (15, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))
113779	25424858	Given the previous association of SF3B1 mutations with differential splicing in uveal melanoma, we hypothesised that SF3B1 K700E mutations in breast cancer would also lead to differential splicing.	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('SF3B1', 'Gene', (34, 39))	('differential splicing', 'MPA', (175, 196))	('breast cancer', 'Disease', (142, 155))	('differential splicing', 'MPA', (55, 76))	('splicing', 'biological_process', 'GO:0045292', ('68', '76'))	('mutations', 'Var', (40, 49))	('SF3B1', 'Gene', '23451', (34, 39))	('K700E', 'Var', (123, 128))	('splicing', 'biological_process', 'GO:0045292', ('188', '196'))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('uveal melanoma', 'Disease', (80, 94))	('uveal melanoma', 'Disease', 'MESH:C536494', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('SF3B1', 'Gene', (117, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('lead to', 'Reg', (167, 174))	('K700E', 'Mutation', 'rs559063155', (123, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('SF3B1', 'Gene', '23451', (117, 122))
113780	25424858	Massively parallel RNA sequencing of SF3B1 mutant (n = 3) versus wild-type (n = 11) papillary carcinomas of the breast identified differential exon usage in 122 transcripts (p < 0.1 FDR, Supplementary Table 9).	('carcinomas of the breast', 'Phenotype', 'HP:0100013', (94, 118))	('SF3B1', 'Gene', '23451', (37, 42))	('differential', 'Reg', (130, 142))	('papillary carcinomas of the breast', 'Disease', (84, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('papillary carcinomas of the breast', 'Disease', 'MESH:D002291', (84, 118))	('mutant', 'Var', (43, 49))	('RNA', 'cellular_component', 'GO:0005562', ('19', '22'))	('SF3B1', 'Gene', (37, 42))
113781	25424858	In addition, re-analysis of available RNA-sequencing data of (n = 8) SF3B1 K700E mutant and stage, ER, PR, HER2, PIK3CA, and TP53 mutation status-matched SF3B1 wild-type breast cancers (n = 16) from TCGA revealed differential exon usage in 218 transcripts (p < 0.1 FDR, Supplementary Table 10).	('PR', 'Gene', '5241', (103, 105))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('SF3B1', 'Gene', (154, 159))	('PIK3CA', 'Gene', '5290', (113, 119))	('TP53', 'Gene', (125, 129))	('mutant', 'Var', (81, 87))	('breast cancers', 'Disease', 'MESH:D001943', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('breast cancers', 'Disease', (170, 184))	('HER2', 'Gene', (107, 111))	('breast cancers', 'Phenotype', 'HP:0003002', (170, 184))	('SF3B1', 'Gene', '23451', (154, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('PIK3CA', 'Gene', (113, 119))	('TP53', 'Gene', '7157', (125, 129))	('differential', 'Reg', (213, 225))	('SF3B1', 'Gene', (69, 74))	('HER2', 'Gene', '2064', (107, 111))	('RNA', 'cellular_component', 'GO:0005562', ('38', '41'))	('K700E', 'Mutation', 'rs559063155', (75, 80))	('K700E mutant', 'Var', (75, 87))	('SF3B1', 'Gene', '23451', (69, 74))
113783	25424858	In addition, four transcripts (ie TMEM14C, RPL31, CRNDE, and DYNLL1) were found in common with uveal melanoma (p = 7.047575e-11, hypergeometric test) and these showed identical differential splicing in papillary carcinomas of the breast, invasive breast carcinomas of no special type, and uveal melanomas displaying SF3B1 mutations (Figure 2 and Table 2).	('RPL31', 'Gene', (43, 48))	('melanoma', 'Phenotype', 'HP:0002861', (295, 303))	('carcinomas', 'Phenotype', 'HP:0030731', (254, 264))	('uveal melanomas', 'Disease', 'MESH:C536494', (289, 304))	('splicing', 'biological_process', 'GO:0045292', ('190', '198'))	('CRNDE', 'Gene', (50, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (289, 303))	('TMEM14C', 'Gene', '51522', (34, 41))	('papillary carcinomas of the breast, invasive breast carcinomas', 'Disease', 'MESH:D001943', (202, 264))	('CRNDE', 'Gene', '643911', (50, 55))	('DYNLL1', 'Gene', (61, 67))	('DYNLL1', 'Gene', '8655', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('uveal melanoma', 'Phenotype', 'HP:0007716', (289, 303))	('mutations', 'Var', (322, 331))	('uveal melanoma', 'Disease', 'MESH:C536494', (95, 109))	('breast carcinomas', 'Phenotype', 'HP:0003002', (247, 264))	('SF3B1', 'Gene', (316, 321))	('uveal melanoma', 'Disease', (95, 109))	('uveal melanomas', 'Disease', (289, 304))	('uveal melanomas', 'Phenotype', 'HP:0007716', (289, 304))	('carcinomas', 'Phenotype', 'HP:0030731', (212, 222))	('carcinomas of the breast', 'Phenotype', 'HP:0100013', (212, 236))	('melanomas', 'Phenotype', 'HP:0002861', (295, 304))	('TMEM14C', 'Gene', (34, 41))	('RPL31', 'Gene', '6160', (43, 48))	('uveal melanoma', 'Phenotype', 'HP:0007716', (95, 109))	('SF3B1', 'Gene', '23451', (316, 321))
113784	25424858	We next additionally tested alternative splicing of seven genes shown to be differentially spliced from Furney et al (GUSBP11, UQCC, ANKHD1, GAS8, F8, ADAM12, and ABCC5) using qRT-PCR in SF3B1 mutant and wild-type papillary carcinomas.	('ADAM12', 'Gene', (151, 157))	('UQCC', 'Gene', '55245', (127, 131))	('UQCC', 'Gene', (127, 131))	('ABCC5', 'Gene', (163, 168))	('mutant', 'Var', (193, 199))	('papillary carcinomas', 'Disease', 'MESH:D002291', (214, 234))	('GUSBP11', 'Gene', '91316', (118, 125))	('SF3B1', 'Gene', '23451', (187, 192))	('carcinomas', 'Phenotype', 'HP:0030731', (224, 234))	('ANKHD1', 'Gene', '54882', (133, 139))	('tested', 'Reg', (21, 27))	('GAS8', 'Gene', (141, 145))	('papillary carcinomas', 'Disease', (214, 234))	('ANKHD1', 'Gene', (133, 139))	('GAS', 'molecular_function', 'GO:0034005', ('141', '144'))	('SF3B1', 'Gene', (187, 192))	('GAS8', 'Gene', '2622', (141, 145))	('splicing', 'biological_process', 'GO:0045292', ('40', '48'))	('GUSBP11', 'Gene', (118, 125))	('ABCC5', 'Gene', '10057', (163, 168))	('ADAM12', 'Gene', '8038', (151, 157))
113786	25424858	Our results suggest that SF3B1 mutations are associated with alternative splicing of key genes in ER-positive breast cancer that are independent of tumour type.	('tumour type', 'Disease', 'MESH:D009369', (148, 159))	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('splicing', 'biological_process', 'GO:0045292', ('73', '81'))	('associated', 'Reg', (45, 55))	('SF3B1', 'Gene', (25, 30))	('alternative splicing', 'MPA', (61, 81))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('breast cancer', 'Disease', (110, 123))	('SF3B1', 'Gene', '23451', (25, 30))	('tumour type', 'Disease', (148, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
113787	25424858	Based on our observations that SF3B1 mutant tumours display a conserved splicing signature, we posited that differential splicing of the downstream targets may drive tumour growth.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('tumour', 'Disease', (166, 172))	('tumours', 'Disease', 'MESH:D009369', (44, 51))	('drive', 'PosReg', (160, 165))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('splicing', 'biological_process', 'GO:0045292', ('121', '129'))	('tumour', 'Disease', (44, 50))	('conserved splicing signature', 'MPA', (62, 90))	('tumours', 'Disease', (44, 51))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('mutant', 'Var', (37, 43))	('SF3B1', 'Gene', (31, 36))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('splicing', 'biological_process', 'GO:0045292', ('72', '80'))	('SF3B1', 'Gene', '23451', (31, 36))
113788	25424858	Treatment of two SF3B1 mutant cell lines, Panc 05.04 (pancreatic, K700E) and ESS-1 (endometrial, K666N), and six wild-type controls (three pancreatic and three endometrial) with an SF3b complex inhibitor, spliceostatin A, revealed that SF3B1 mutant cell lines were significantly more sensitive to this agent (p = 0.0118, t-test, Figure 3A).	('pancreatic', 'Disease', 'MESH:D010195', (139, 149))	('SF3B1', 'Gene', '23451', (236, 241))	('pancreatic', 'Disease', (54, 64))	('more', 'PosReg', (279, 283))	('endometrial', 'Disease', 'MESH:D014591', (160, 171))	('ESS-1', 'Gene', (77, 82))	('sensitive', 'MPA', (284, 293))	('pancreatic', 'Disease', (139, 149))	('ESS-1', 'Gene', '7046', (77, 82))	('SF3B1', 'Gene', (17, 22))	('endometrial', 'Disease', (160, 171))	('spliceostatin A', 'Chemical', 'MESH:C553684', (205, 220))	('SF3B1', 'Gene', '23451', (17, 22))	('endometrial', 'Disease', 'MESH:D014591', (84, 95))	('mutant', 'Var', (23, 29))	('SF3B1', 'Gene', (236, 241))	('pancreatic', 'Disease', 'MESH:D010195', (54, 64))	('endometrial', 'Disease', (84, 95))	('mutant', 'Var', (242, 248))	('K666N', 'Mutation', 'rs377023736', (97, 102))	('K700E', 'Mutation', 'rs559063155', (66, 71))
113792	25424858	These results suggest that SF3B1 mutations are likely driving the malignant phenotype of the cells through perturbations in RNA splicing; however, this driving effect could not be ascribed to a single differentially spliced transcript tested.	('RNA splicing', 'biological_process', 'GO:0008380', ('124', '136'))	('RNA splicing', 'MPA', (124, 136))	('mutations', 'Var', (33, 42))	('SF3B1', 'Gene', (27, 32))	('driving', 'Reg', (54, 61))	('malignant phenotype of', 'CPA', (66, 88))	('RNA', 'cellular_component', 'GO:0005562', ('124', '127'))	('SF3B1', 'Gene', '23451', (27, 32))
113793	25424858	Taken together, our findings demonstrate that although SF3B1 mutations are unlikely to account for the histological characteristics of papillary carcinomas of the breast, these mutations affect mRNA splicing and likely constitute driver genetic events.	('SF3B1', 'Gene', '23451', (55, 60))	('mRNA splicing', 'biological_process', 'GO:0000374', ('194', '207'))	('mRNA splicing', 'MPA', (194, 207))	('papillary carcinomas of the breast', 'Disease', (135, 169))	('carcinomas of the breast', 'Phenotype', 'HP:0100013', (145, 169))	('carcinomas', 'Phenotype', 'HP:0030731', (145, 155))	('mRNA splicing', 'biological_process', 'GO:0006371', ('194', '207'))	('papillary carcinomas of the breast', 'Disease', 'MESH:D002291', (135, 169))	('mutations', 'Var', (177, 186))	('affect', 'Reg', (187, 193))	('mutations', 'Var', (61, 70))	('mRNA splicing', 'biological_process', 'GO:0000373', ('194', '207'))	('mRNA splicing', 'biological_process', 'GO:0000372', ('194', '207'))	('mRNA splicing', 'biological_process', 'GO:0000398', ('194', '207'))	('mRNA splicing', 'biological_process', 'GO:0000394', ('194', '207'))	('SF3B1', 'Gene', (55, 60))
113794	25424858	Here we describe the repertoire of mutations in spliceosomal components in breast cancer through a re-analysis of public exome and whole genome sequencing data.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('mutations', 'Var', (35, 44))
113795	25424858	Our data reveal that some spliceosome mutations are mutually exclusive in breast cancer, consistent with the observations made in myelodysplastic lesions; however, a small proportion of tumours harboured mutations in more than one spliceosome component.	('breast cancer', 'Disease', (74, 87))	('spliceosome', 'cellular_component', 'GO:0005681', ('26', '37'))	('tumours', 'Disease', 'MESH:D009369', (186, 193))	('tumours', 'Disease', (186, 193))	('mutations', 'Var', (204, 213))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('spliceosome', 'cellular_component', 'GO:0005681', ('231', '242'))	('myelodysplastic lesions', 'Disease', 'MESH:D009190', (130, 153))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('myelodysplastic lesions', 'Disease', (130, 153))	('myelodysplastic lesions', 'Phenotype', 'HP:0002863', (130, 153))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
113796	25424858	Moreover, we demonstrate that SF3B1 is the most commonly mutated spliceosomal component gene in breast cancer and that mutations affecting this gene are significantly associated with ER-positive disease.	('SF3B1', 'Gene', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('associated', 'Reg', (167, 177))	('SF3B1', 'Gene', '23451', (30, 35))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('mutations', 'Var', (119, 128))	('ER-positive disease', 'Disease', (183, 202))
113797	25424858	In addition, SF3B1 mutations are found to be associated with specific genomic alterations including concurrent AKT1 hotspot mutations and a lower frequency of the hallmark chromosomal aberrations reported in ER-positive IC-NST (ie loss of 16q) akin to mucinous carcinomas of the breast.	('carcinomas of the breast', 'Phenotype', 'HP:0100013', (261, 285))	('carcinomas', 'Phenotype', 'HP:0030731', (261, 271))	('mutations', 'Var', (124, 133))	('SF3B1', 'Gene', (13, 18))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (172, 195))	('IC-NST', 'Disease', (220, 226))	('mutations', 'Var', (19, 28))	('AKT1', 'Gene', '207', (111, 115))	('AKT1', 'Gene', (111, 115))	('SF3B1', 'Gene', '23451', (13, 18))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (252, 271))	('mucinous carcinomas', 'Disease', (252, 271))
113798	25424858	Our exploratory, hypothesis-generating analysis of special histological types of breast cancer provides evidence to suggest that the codon 700 SF3B1 hotspot mutations may be more prevalent in mucinous and papillary carcinomas of the breast than in usual types of breast cancer of the same grade, ER, and HER2 status.	('breast cancer', 'Disease', (263, 276))	('breast cancer', 'Disease', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('HER2', 'Gene', (304, 308))	('mutations', 'Var', (157, 166))	('carcinomas', 'Phenotype', 'HP:0030731', (215, 225))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('codon 700', 'Var', (133, 142))	('carcinomas of the breast', 'Phenotype', 'HP:0100013', (215, 239))	('SF3B1', 'Gene', (143, 148))	('prevalent', 'Reg', (179, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (263, 276))	('papillary carcinomas of the breast', 'Disease', (205, 239))	('papillary carcinomas of the breast', 'Disease', 'MESH:D002291', (205, 239))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('HER2', 'Gene', '2064', (304, 308))	('SF3B1', 'Gene', '23451', (143, 148))	('breast cancer', 'Disease', 'MESH:D001943', (263, 276))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
113802	25424858	Studies have highlighted that primary tumours with SF3B1 mutations display alternative splicing in selected key genes in CLL, MDS, and uveal melanoma, and that this signature is conserved between cancer sites and is independent of the mutant amino acid.	('CLL', 'Disease', (121, 124))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('mutations', 'Var', (57, 66))	('SF3B1', 'Gene', (51, 56))	('MDS', 'Phenotype', 'HP:0002863', (126, 129))	('SF3B1', 'Gene', '23451', (51, 56))	('primary tumours', 'Disease', (30, 45))	('primary tumours', 'Disease', 'MESH:D009369', (30, 45))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('uveal melanoma', 'Disease', 'MESH:C536494', (135, 149))	('alternative splicing', 'MPA', (75, 95))	('uveal melanoma', 'Disease', (135, 149))	('cancer', 'Disease', (196, 202))	('MDS', 'Disease', 'MESH:D009190', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('uveal melanoma', 'Phenotype', 'HP:0007716', (135, 149))	('splicing', 'biological_process', 'GO:0045292', ('87', '95'))	('tumours', 'Phenotype', 'HP:0002664', (38, 45))	('MDS', 'Disease', (126, 129))
113803	25424858	Using a combination of RNA sequencing and qRT-PCR, we identified eight differentially spliced transcripts between mutant SF3B1 and wild-type breast cancers that were also reported to be differentially spliced in SF3B1 mutant melanomas, highlighting that this signature is additionally conserved in breast cancer.	('melanomas', 'Disease', 'MESH:D008545', (225, 234))	('breast cancers', 'Phenotype', 'HP:0003002', (141, 155))	('mutant', 'Var', (114, 120))	('SF3B1', 'Gene', (121, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('melanomas', 'Disease', (225, 234))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('SF3B1', 'Gene', '23451', (121, 126))	('melanomas', 'Phenotype', 'HP:0002861', (225, 234))	('SF3B1', 'Gene', (212, 217))	('breast cancer', 'Phenotype', 'HP:0003002', (298, 311))	('RNA', 'cellular_component', 'GO:0005562', ('23', '26'))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('breast cancer', 'Disease', 'MESH:D001943', (298, 311))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('breast cancer', 'Disease', (298, 311))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancers', 'Disease', (141, 155))	('SF3B1', 'Gene', '23451', (212, 217))	('breast cancers', 'Disease', 'MESH:D001943', (141, 155))	('mutant', 'Var', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
113804	25424858	Given that the spliceosome SF3b complex has emerged as a potential therapeutic target, we sought to define whether cancer models harbouring SF3B1 hotspot mutations would be sensitive to chemical inhibition of SF3B1and RNA-interference silencing of SF3B1 and genes abnormally spliced in SF3B1 mutant tumours.	('SF3B1', 'Gene', (209, 214))	('SF3B1', 'Gene', (248, 253))	('silencing', 'NegReg', (235, 244))	('tumour', 'Phenotype', 'HP:0002664', (299, 305))	('spliceosome', 'cellular_component', 'GO:0005681', ('15', '26'))	('SF3B1', 'Gene', '23451', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('SF3B1', 'Gene', (286, 291))	('SF3B1', 'Gene', '23451', (248, 253))	('SF3B1', 'Gene', '23451', (209, 214))	('mutant', 'Var', (292, 298))	('SF3B1', 'Gene', '23451', (286, 291))	('tumours', 'Disease', (299, 306))	('cancer', 'Disease', (115, 121))	('SF3B1', 'Gene', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumours', 'Phenotype', 'HP:0002664', (299, 306))	('RNA', 'cellular_component', 'GO:0005562', ('218', '221'))	('mutations', 'Var', (154, 163))	('tumours', 'Disease', 'MESH:D009369', (299, 306))	('RNA-interference', 'biological_process', 'GO:0016246', ('218', '234'))
113805	25424858	Here we demonstrate that treatment of SF3B1 mutant and wild-type cell lines with spliceostatin A resulted in selective inhibition of the growth of mutant cells and in the disruption of the conserved splicing signature.	('mutant', 'Var', (147, 153))	('spliceostatin A', 'Chemical', 'MESH:C553684', (81, 96))	('SF3B1', 'Gene', (38, 43))	('splicing', 'biological_process', 'GO:0045292', ('199', '207'))	('growth', 'MPA', (137, 143))	('disruption', 'NegReg', (171, 181))	('inhibition', 'NegReg', (119, 129))	('conserved splicing signature', 'MPA', (189, 217))	('SF3B1', 'Gene', '23451', (38, 43))	('mutant', 'Var', (44, 50))
113806	25424858	Although it is plausible that the differentially spliced genes investigated in this study did not account for the dependency of SF3B1 mutant cells on aberrant splicing, it is conceivable that the differences in pre-mRNA splicing act in concert to produce a cell survival advantage.	('SF3B1', 'Gene', '23451', (128, 133))	('pre', 'molecular_function', 'GO:0003904', ('211', '214'))	('cell survival advantage', 'CPA', (257, 280))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('211', '228'))	('SF3B1', 'Gene', (128, 133))	('mutant', 'Var', (134, 140))	('splicing', 'biological_process', 'GO:0045292', ('159', '167'))
113807	25424858	In conclusion, our findings demonstrate that spliceosomal mutations occur in a mutually exclusive manner in breast cancer and that distinct components of the spliceosome are targeted by somatic mutations in different types of breast cancer (eg SF3B1 and SAP130 were found to be preferentially mutated in ER-positive and ER-negative disease, respectively).	('SAP130', 'Gene', '79595', (254, 260))	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('breast cancer', 'Disease', (226, 239))	('ER-negative disease', 'Disease', (320, 339))	('ER-positive', 'Disease', (304, 315))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('SAP130', 'Gene', (254, 260))	('spliceosome', 'cellular_component', 'GO:0005681', ('158', '169'))	('mutations', 'Var', (194, 203))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('SF3B1', 'Gene', (244, 249))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('SF3B1', 'Gene', '23451', (244, 249))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))
113808	25424858	We have demonstrated that SF3B1 K700E mutations are more frequently found in some special histological types of breast cancer and have provided direct evidence that these are associated with consistent differential splicing patterns in breast cancer.	('SF3B1', 'Gene', (26, 31))	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (236, 249))	('breast cancer', 'Disease', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (236, 249))	('K700E', 'Mutation', 'rs559063155', (32, 37))	('splicing', 'biological_process', 'GO:0045292', ('215', '223'))	('SF3B1', 'Gene', '23451', (26, 31))	('K700E', 'Var', (32, 37))	('found', 'Reg', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('breast cancer', 'Disease', 'MESH:D001943', (236, 249))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
113809	25424858	Finally, our study emphasizes the importance of driver genetic alterations found in minor subgroups of breast cancer, given that SF3B1 mutant cells were shown to be selectively sensitive to a potent SF3b complex inhibitor, spliceostatin A, suggesting that inhibition of the spliceosome complex may constitute a novel therapeutic strategy for patients with SF3B1 mutations independent of tumour type.	('SF3B1', 'Gene', (129, 134))	('SF3B1', 'Gene', (356, 361))	('tumour', 'Phenotype', 'HP:0002664', (387, 393))	('mutations', 'Var', (362, 371))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('mutant', 'Var', (135, 141))	('patients', 'Species', '9606', (342, 350))	('SF3B1', 'Gene', '23451', (129, 134))	('tumour type', 'Disease', (387, 398))	('tumour type', 'Disease', 'MESH:D009369', (387, 398))	('breast cancer', 'Disease', (103, 116))	('spliceostatin A', 'Chemical', 'MESH:C553684', (223, 238))	('SF3B1', 'Gene', '23451', (356, 361))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('spliceosome complex', 'cellular_component', 'GO:0005681', ('274', '293'))
113811	25764247	Recurrent mutations in GNAQ and GNA11 initiate UM development while tumour progression is correlated with monosomy of chromosome 3 and gain of chromosome 8q.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('8q', 'Chemical', '-', (154, 156))	('GNA11', 'Gene', '2767', (32, 37))	('GNAQ', 'Gene', (23, 27))	('GNA11', 'Gene', (32, 37))	('monosomy of chromosome 3', 'Var', (106, 130))	('UM development', 'CPA', (47, 61))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('chromosome', 'cellular_component', 'GO:0005694', ('118', '128'))	('chromosome', 'cellular_component', 'GO:0005694', ('143', '153'))	('tumour', 'Disease', (68, 74))	('gain', 'PosReg', (135, 139))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('mutations', 'Var', (10, 19))	('GNAQ', 'Gene', '2776', (23, 27))	('initiate', 'PosReg', (38, 46))
113812	25764247	A series of 66 UM was analysed with dPCR for three hotspot mutations in GNAQ/GNA11 with mutation specific probes.	('GNA11', 'Gene', (77, 82))	('GNAQ', 'Gene', '2776', (72, 76))	('GNA11', 'Gene', '2767', (77, 82))	('UM', 'Phenotype', 'HP:0007716', (15, 17))	('mutations', 'Var', (59, 68))	('GNAQ', 'Gene', (72, 76))
113813	25764247	With digital PCR, GNAQ/GNA11 mutations were detected in 60 of the 66 UM.	('digital PCR', 'Disease', (5, 16))	('GNA11', 'Gene', '2767', (23, 28))	('GNA11', 'Gene', (23, 28))	('GNAQ', 'Gene', '2776', (18, 22))	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('mutations', 'Var', (29, 38))	('detected', 'Reg', (44, 52))	('GNAQ', 'Gene', (18, 22))
113814	25764247	Sanger sequencing revealed three rare variants, and, combined, these assays revealed GNAQ/GNA11 mutations in 95% of UM.	('GNA11', 'Gene', '2767', (90, 95))	('GNA11', 'Gene', (90, 95))	('GNAQ', 'Gene', (85, 89))	('UM', 'Phenotype', 'HP:0007716', (116, 118))	('revealed', 'Reg', (76, 84))	('GNAQ', 'Gene', '2776', (85, 89))	('mutations', 'Var', (96, 105))
113816	25764247	Just like the recurrent genomic aberrations of chromosome 3 and 8, hotspot mutations in GNAQ and GNA11 are effectively detected in heterogeneous samples.	('GNAQ', 'Gene', (88, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('GNAQ', 'Gene', '2776', (88, 92))	('mutations', 'Var', (75, 84))	('GNA11', 'Gene', '2767', (97, 102))	('GNA11', 'Gene', (97, 102))
113819	25764247	The primary event in UM is either a mutation in the GNAQ or the GNA11 gene, located respectively on chromosome 9q21.2 and 19p13.3.	('GNAQ', 'Gene', '2776', (52, 56))	('GNA11', 'Gene', '2767', (64, 69))	('GNA11', 'Gene', (64, 69))	('GNAQ', 'Gene', (52, 56))	('UM', 'Phenotype', 'HP:0007716', (21, 23))	('chromosome', 'cellular_component', 'GO:0005694', ('100', '110'))	('mutation', 'Var', (36, 44))
113820	25764247	With classical karyotyping, monosomy of chromosome 3 and gain of chromosome 8q have been discovered and shown to be correlated with UM progression.	('chromosome', 'cellular_component', 'GO:0005694', ('40', '50'))	('UM', 'Phenotype', 'HP:0007716', (132, 134))	('8q', 'Chemical', '-', (76, 78))	('monosomy', 'Var', (28, 36))	('gain', 'PosReg', (57, 61))	('chromosome', 'cellular_component', 'GO:0005694', ('65', '75'))	('UM progression', 'Disease', (132, 146))
113822	25764247	In this model an increased risk of metastases is observed with increasing 8q copy numbers.	('8q copy numbers', 'Var', (74, 89))	('metastases', 'Disease', 'MESH:D009362', (35, 45))	('8q', 'Chemical', '-', (74, 76))	('metastases', 'Disease', (35, 45))
113832	25764247	Presence of a mutation in either the GNAQ or GNA11 gene was analysed using hydrolysis probes in a multiplex dPCR.	('GNAQ', 'Gene', (37, 41))	('mutation', 'Var', (14, 22))	('GNA11', 'Gene', (45, 50))	('GNAQ', 'Gene', '2776', (37, 41))	('GNA11', 'Gene', '2767', (45, 50))
113840	25764247	For validation of the GNAQ and GNA11 mutation status, as acquired by dPCR, Sanger sequencing was performed on all 66 UM DNA samples by PCR using a Sybr green premixture from Bio-Rad Laboratories, Inc. Primers used are summarized in S2 Table, and the following PCR protocol was used for amplification of exon 4 and exon 5 of GNAQ and GNA11 genes: 94 C, 3min; (96 C, 15sec; 63 C, 15sec; 72 C, 1min) 7x; (96 C, 15sec; 61 C, 15sec; 71 C, 1min) 8x; (96 C, 15sec; 60 C, 15sec; 72 C, 1min) 36x;72 C, 1min; till end.	('GNAQ', 'Gene', (324, 328))	('Rad', 'biological_process', 'GO:1990116', ('178', '181'))	('GNAQ', 'Gene', (22, 26))	('GNA11', 'Gene', '2767', (333, 338))	('GNA11', 'Gene', (333, 338))	('GNAQ', 'Gene', '2776', (324, 328))	('DNA', 'cellular_component', 'GO:0005574', ('120', '123'))	('96 C, 15sec;', 'Var', (445, 457))	('GNAQ', 'Gene', '2776', (22, 26))	('GNA11', 'Gene', (31, 36))	('UM', 'Phenotype', 'HP:0007716', (117, 119))	('GNA11', 'Gene', '2767', (31, 36))
113847	25764247	Using dPCR and mutation-specific probes, we analysed GNAQ and GNA11 mutations in UM samples.	('analysed', 'Reg', (44, 52))	('GNAQ', 'Gene', (53, 57))	('UM', 'Phenotype', 'HP:0007716', (81, 83))	('mutations', 'Var', (68, 77))	('GNAQ', 'Gene', '2776', (53, 57))	('GNA11', 'Gene', (62, 67))	('GNA11', 'Gene', '2767', (62, 67))
113848	25764247	Assuming each UM cell contains a mutated and a wildtype allele of either GNAQ or GNA11, samples presenting equal numbers of mutant and wildtype alleles are considered homogenous.	('UM', 'Phenotype', 'HP:0007716', (14, 16))	('GNAQ', 'Gene', '2776', (73, 77))	('GNA11', 'Gene', '2767', (81, 86))	('GNA11', 'Gene', (81, 86))	('mutated', 'Var', (33, 40))	('GNAQ', 'Gene', (73, 77))
113850	25764247	1 shows two UM samples sharing the GNAQ Q209L mutation, caused by a substitution of an adenine for a thymine (c.626 A>T).	('adenine', 'Chemical', 'MESH:D000225', (87, 94))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('GNAQ', 'Gene', '2776', (35, 39))	('c.626 A>T', 'Mutation', 'rs121913492', (110, 119))	('c.626 A>T', 'Var', (110, 119))	('Q209L', 'Mutation', 'rs121913492', (40, 45))	('GNAQ', 'Gene', (35, 39))	('thymine', 'Chemical', 'MESH:D013941', (101, 108))
113852	25764247	UM 04-075, on the other hand, clearly presents a mixed tumour with an excess of normal alleles (179 mutant/302 WT) (Fig.	('tumour', 'Disease', (55, 61))	('179 mutant/302', 'Var', (96, 110))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
113855	25764247	The aberrant fractions with the GNAQ Q209P assay and the positive fractions with the GNAQ Q209L assay are similar in size and this supports the idea that the Q209L mutant allele in UM 01-074 and 04-075 gave rise to the aberrant fraction in the Q209P assay (Fig.	('Q209P', 'Mutation', 'rs121913492', (37, 42))	('GNAQ', 'Gene', (32, 36))	('gave rise to', 'Reg', (202, 214))	('Q209L', 'Mutation', 'rs121913492', (158, 163))	('Q209L', 'Mutation', 'rs121913492', (90, 95))	('Q209L', 'Var', (158, 163))	('GNAQ', 'Gene', '2776', (32, 36))	('GNAQ', 'Gene', (85, 89))	('GNAQ', 'Gene', '2776', (85, 89))	('Q209P assay', 'MPA', (244, 255))	('Q209P', 'Mutation', 'rs121913492', (244, 249))	('aberrant fraction', 'MPA', (219, 236))	('UM', 'Phenotype', 'HP:0007716', (181, 183))
113856	25764247	Mutations in the GNAQ were observed in 27 UM, with 17 presenting the Q209P mutation and ten the Q209L mutation.	('Q209L', 'Mutation', 'rs121913492', (96, 101))	('GNAQ', 'Gene', (17, 21))	('Q209P', 'Var', (69, 74))	('Q209L', 'Var', (96, 101))	('UM', 'Phenotype', 'HP:0007716', (42, 44))	('Q209P', 'Mutation', 'rs121913492', (69, 74))	('GNAQ', 'Gene', '2776', (17, 21))
113857	25764247	Mutations in GNA11 were more common as 33 UM tested positive for the GNA11 Q209L mutation (Table 2).	('Q209L', 'Var', (75, 80))	('GNA11', 'Gene', (13, 18))	('positive', 'Reg', (52, 60))	('Mutations', 'Var', (0, 9))	('GNA11', 'Gene', '2767', (13, 18))	('Q209L', 'Mutation', 'rs121913492', (75, 80))	('GNA11', 'Gene', (69, 74))	('GNA11', 'Gene', '2767', (69, 74))	('UM', 'Phenotype', 'HP:0007716', (42, 44))
113859	25764247	However, rare mutations were detected in GNAQ and GNA11 due to a minor cross reactivity of the probes, similar to what we observed in the GNAQ Q209P assay with GNAQ Q209L mutant alleles (Fig.	('GNAQ', 'Gene', (160, 164))	('GNAQ', 'Gene', '2776', (41, 45))	('GNAQ', 'Gene', '2776', (138, 142))	('GNA11', 'Gene', '2767', (50, 55))	('GNA11', 'Gene', (50, 55))	('GNAQ', 'Gene', '2776', (160, 164))	('GNAQ', 'Gene', (41, 45))	('GNAQ', 'Gene', (138, 142))	('cross', 'Interaction', (71, 76))	('Q209P', 'Mutation', 'rs121913492', (143, 148))	('mutations', 'Var', (14, 23))	('Q209L', 'Mutation', 'rs121913492', (165, 170))
113861	25764247	Sanger sequencing revealed the c.627 A>C mutation that encodes for the GNAQ Q209H mutant (Fig.	('Q209H', 'Var', (76, 81))	('GNAQ', 'Gene', (71, 75))	('c.627 A>C', 'Var', (31, 40))	('Q209H', 'Mutation', 'p.Q209H', (76, 81))	('GNAQ', 'Gene', '2776', (71, 75))	('c.627 A>C', 'Mutation', 'c.627A>C', (31, 40))
113862	25764247	Validation of an aberrant amplicon in GNA11 of UM 02-167 revealed a double mutation (c.626_627 AG>TC).	('c.626_627 AG>TC', 'Mutation', 'rs121913492', (85, 100))	('GNA11', 'Gene', '2767', (38, 43))	('GNA11', 'Gene', (38, 43))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('c.626_627 AG>TC', 'Var', (85, 100))
113863	25764247	This mutation encodes also for the GNA11 Q209L mutant because the additional base substitution does not alter the coding capacity.	('Q209L', 'Mutation', 'rs121913492', (41, 46))	('Q209L', 'Var', (41, 46))	('GNA11', 'Gene', '2767', (35, 40))	('GNA11', 'Gene', (35, 40))
113864	25764247	Since the second substitution is contained within the recognition sequence of the probe for the GNA11 Q209L mutation, it interferes with accumulation of a positive signal in dPCR.	('accumulation', 'MPA', (137, 149))	('interferes', 'NegReg', (121, 131))	('Q209L', 'Var', (102, 107))	('dPCR', 'MPA', (174, 178))	('Q209L', 'Mutation', 'rs121913492', (102, 107))	('GNA11', 'Gene', '2767', (96, 101))	('GNA11', 'Gene', (96, 101))
113865	25764247	Direct detection with dPCR and indirect detection of mutants combined, we detected exon 5 GNAQ and GNA11 mutations in 94% of the UM.	('exon', 'Var', (83, 87))	('GNAQ', 'Gene', '2776', (90, 94))	('GNA11', 'Gene', '2767', (99, 104))	('detected', 'Reg', (74, 82))	('GNA11', 'Gene', (99, 104))	('mutations', 'Var', (105, 114))	('UM', 'Phenotype', 'HP:0007716', (129, 131))	('GNAQ', 'Gene', (90, 94))
113866	25764247	In 4 out of the 62 cases with mutations detected with dPCR, sequence analysis only showed a minor mutant signal that on itself would be insufficient to call a tumour mutant.	('tumour', 'Disease', (159, 165))	('insufficient', 'Disease', 'MESH:D000309', (136, 148))	('insufficient', 'Disease', (136, 148))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('mutations', 'Var', (30, 39))	('tumour', 'Disease', 'MESH:D009369', (159, 165))
113867	25764247	The remaining 4 UM that do not present mutations in exon 5 were analysed for exon 4 mutations of GNAQ and GNA11.	('GNAQ', 'Gene', '2776', (97, 101))	('GNA11', 'Gene', (106, 111))	('mutations', 'Var', (84, 93))	('UM', 'Phenotype', 'HP:0007716', (16, 18))	('GNA11', 'Gene', '2767', (106, 111))	('GNAQ', 'Gene', (97, 101))
113868	25764247	This revealed a mutation at codon 183 (c.548G>A) of GNAQ in UM 08-004.	('c.548G>A', 'Var', (39, 47))	('GNAQ', 'Gene', '2776', (52, 56))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('c.548G>A', 'Mutation', 'rs397514698', (39, 47))	('GNAQ', 'Gene', (52, 56))
113869	25764247	In a total of 66 UM, 63 carried mutations in GNAQ and GNA11.	('GNA11', 'Gene', (54, 59))	('GNA11', 'Gene', '2767', (54, 59))	('mutations', 'Var', (32, 41))	('GNAQ', 'Gene', (45, 49))	('UM', 'Phenotype', 'HP:0007716', (17, 19))	('GNAQ', 'Gene', '2776', (45, 49))
113876	25764247	A balanced increase of 8q and 8p copy number (Table 3) furthermore indicated that 8q gain is in 8/24 cases (99-187, 02-158, 02-174, 04-018, 05-034, 06-009, 06-033, 06-036) due to trisomy 8.	('trisomy', 'Var', (179, 186))	('gain', 'PosReg', (85, 89))	('8q', 'Chemical', '-', (23, 25))	('increase', 'PosReg', (11, 19))	('8q', 'Chemical', '-', (82, 84))	('99-187', 'Var', (108, 114))
113878	25764247	Amplification of 8q coincided with 8q/8p imbalance and isochromosome formation.	('Amplification', 'Var', (0, 13))	('formation', 'biological_process', 'GO:0009058', ('69', '78'))	('imbalance', 'Phenotype', 'HP:0002172', (41, 50))	('8q', 'Chemical', '-', (17, 19))	('8q', 'Chemical', '-', (35, 37))	('isochromosome', 'Disease', (55, 68))	('8q/8p', 'MPA', (35, 40))
113881	25764247	Monosomy 3 and 8q aberrations mostly occurred together (n = 40) (p<0.01) (Fig.	('occurred', 'Reg', (37, 45))	('8q', 'Chemical', '-', (15, 17))	('Monosomy 3', 'Var', (0, 10))	('8q aberrations', 'Var', (15, 29))
113882	25764247	Monosomy 3 is highly prognostic for death due to metastasis, and 5-year survival is 37% in this group compared to 90% 5-year survival in the UM expressing disomy 3 (Fig.	('death', 'Disease', (36, 41))	('UM', 'Phenotype', 'HP:0007716', (141, 143))	('Monosomy 3', 'Var', (0, 10))	('death', 'Disease', 'MESH:D003643', (36, 41))
113887	25764247	The survival of UM patients is significantly (p 0.011) worse if monosomy 3 is combined with 8q amplification (Fig.	('8q', 'Chemical', '-', (92, 94))	('monosomy 3', 'Var', (64, 74))	('patients', 'Species', '9606', (19, 27))	('survival', 'CPA', (4, 12))	('8q amplification', 'Var', (92, 108))	('worse', 'NegReg', (55, 60))	('UM', 'Phenotype', 'HP:0007716', (16, 18))
113888	25764247	The 5-year survival drops from 44% to 25% in patients with a UM that present monosomy 3 in combination with 8q amplification compared to UM presenting monosomy 3 in combination with 8q gain.	('drops', 'NegReg', (20, 25))	('8q', 'Chemical', '-', (182, 184))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('8q', 'Chemical', '-', (108, 110))	('patients', 'Species', '9606', (45, 53))	('UM', 'Phenotype', 'HP:0007716', (137, 139))	('monosomy 3', 'Var', (77, 87))
113891	25764247	Two samples presented rare mutations in GNAQ (c.627A>C) and GNA11 (c.626_627 AG>TC) which resulted in false-negative results in dPCR.	('GNAQ', 'Gene', (40, 44))	('c.627A>C', 'Var', (46, 54))	('GNA11', 'Gene', (60, 65))	('false', 'biological_process', 'GO:0071877', ('102', '107'))	('GNA11', 'Gene', '2767', (60, 65))	('c.626_627 AG>TC', 'Var', (67, 82))	('dPCR', 'Disease', (128, 132))	('GNAQ', 'Gene', '2776', (40, 44))	('c.627A>C', 'Mutation', 'c.627A>C', (46, 54))	('false', 'biological_process', 'GO:0071878', ('102', '107'))	('c.626_627 AG>TC', 'Mutation', 'rs121913492', (67, 82))
113893	25764247	Whether all possible rare variants in GNAQ and GNA11 will result in aberrant signals when analysed with the standard assays is not certain but in this panel of 66 UM, no additional variants were detected with sequence analysis.	('GNAQ', 'Gene', '2776', (38, 42))	('UM', 'Phenotype', 'HP:0007716', (163, 165))	('GNA11', 'Gene', '2767', (47, 52))	('GNA11', 'Gene', (47, 52))	('result', 'Reg', (58, 64))	('GNAQ', 'Gene', (38, 42))	('variants', 'Var', (26, 34))
113894	25764247	Direct and indirect mutation detection with dPCR revealed GNAQ/GNA11 mutations in 94% of the UM.	('mutations', 'Var', (69, 78))	('GNAQ', 'Gene', '2776', (58, 62))	('UM', 'Phenotype', 'HP:0007716', (93, 95))	('GNA11', 'Gene', (63, 68))	('GNA11', 'Gene', '2767', (63, 68))	('GNAQ', 'Gene', (58, 62))
113899	25764247	Amplifications are correlated with isochromosome 8q formation which we validated with imbalance of 8q/8p copy numbers in dPCR.	('formation', 'biological_process', 'GO:0009058', ('52', '61'))	('imbalance', 'Var', (86, 95))	('imbalance', 'Phenotype', 'HP:0002172', (86, 95))	('correlated', 'Reg', (19, 29))	('8q', 'Chemical', '-', (49, 51))	('Amplifications', 'Var', (0, 14))	('isochromosome 8q formation', 'Disease', (35, 61))	('8q', 'Chemical', '-', (99, 101))
113900	25764247	Coexistence of clones with isochromosome 8q and trisomy 8 has been interpreted as the consequence of independent events.	('8q', 'Chemical', '-', (41, 43))	('trisomy 8', 'Var', (48, 57))	('isochromosome 8q', 'Var', (27, 43))
113902	25764247	As isochromosome 8q formation in UM is often associated with 8p loss, we propose that isochromosome formation may be an underlying cause.	('8q', 'Chemical', '-', (17, 19))	('isochromosome', 'Var', (3, 16))	('UM', 'Phenotype', 'HP:0007716', (33, 35))	('associated', 'Reg', (45, 55))	('formation', 'biological_process', 'GO:0009058', ('100', '109'))	('formation', 'biological_process', 'GO:0009058', ('20', '29'))
113903	25764247	Superimposing monosomy 3 in this progression model furthermore suggests that increasing 8q copy numbers due to isochromosome 8q formation is accompanied by monosomy 3 formation.	('increasing', 'PosReg', (77, 87))	('8q', 'Chemical', '-', (125, 127))	('monosomy 3', 'Disease', (156, 166))	('isochromosome 8q formation', 'Var', (111, 137))	('formation', 'biological_process', 'GO:0009058', ('128', '137'))	('formation', 'biological_process', 'GO:0009058', ('167', '176'))	('8q', 'Chemical', '-', (88, 90))
113905	25764247	Moreover, an increased risk of metastasis formation in the presence of 8q amplification in combination with monosomy 3 compared to monosomy 3 in combination with gain of 8q supports a dominant role for 8q dosage in UM metastases (Fig.	('metastases', 'Disease', (218, 228))	('8q', 'Chemical', '-', (202, 204))	('metastasis formation', 'CPA', (31, 51))	('8q amplification', 'Var', (71, 87))	('UM', 'Phenotype', 'HP:0007716', (215, 217))	('metastases', 'Disease', 'MESH:D009362', (218, 228))	('8q', 'Chemical', '-', (71, 73))	('8q', 'Chemical', '-', (170, 172))	('formation', 'biological_process', 'GO:0009058', ('42', '51'))
113908	25764247	Moreover, the sensitivity of dPCR specifically facilitates the analysis of mutations and copy number aberrations in small and highly diluted samples such as circulating tumour cells and free circulating tumour DNA.	('facilitates', 'PosReg', (47, 58))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('DNA', 'cellular_component', 'GO:0005574', ('210', '213'))	('tumour', 'Disease', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (203, 209))	('tumour', 'Disease', (203, 209))	('mutations', 'Var', (75, 84))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('copy number aberrations', 'Var', (89, 112))	('tumour', 'Disease', 'MESH:D009369', (169, 175))
113930	25097799	Given that DNA damage and oxidative stress play critical roles in the pathogenesis of ARC, variants in four DNA repair genes (BLM, WRN, ERCC6, and OGG1) were explored for possible association with ARC in the Han Chinese population.	('pathogenesis', 'biological_process', 'GO:0009405', ('70', '82'))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('ERCC6', 'Gene', '2074', (136, 141))	('WRN', 'Gene', (131, 134))	('ARC', 'Disease', (197, 200))	('ERCC6', 'Gene', (136, 141))	('WRN', 'Gene', '7486', (131, 134))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('OGG1', 'Gene', (147, 151))	('DNA repair', 'biological_process', 'GO:0006281', ('108', '118'))	('variants', 'Var', (91, 99))	('association', 'Interaction', (180, 191))	('OGG1', 'Gene', '4968', (147, 151))	('BLM', 'Gene', (126, 129))	('oxidative stress', 'Phenotype', 'HP:0025464', (26, 42))	('ARC', 'Disease', (86, 89))
113931	25097799	SNPs in the WRN gene were strongly associated with risk for cataract in this study.	('cataract', 'Disease', 'MESH:D002386', (60, 68))	('cataract', 'Disease', (60, 68))	('cataract', 'Phenotype', 'HP:0000518', (60, 68))	('WRN', 'Gene', '7486', (12, 15))	('WRN', 'Gene', (12, 15))	('SNPs', 'Var', (0, 4))	('associated with', 'Reg', (35, 50))
113932	25097799	SNP rs156697 (Asn142Asp) in the GSTO2 gene increased risk for ARC in smokers and in individuals with work-related exposure to UV irradiation.	('GSTO2', 'Gene', (32, 37))	('rs156697', 'Mutation', 'rs156697', (4, 12))	('GSTO2', 'Gene', '119391', (32, 37))	('ARC', 'Disease', (62, 65))	('SNP rs156697', 'Var', (0, 12))
113934	25097799	CNVs in heat shock factor protein 4 (HSF4) were significantly associated with ARC risk in this population.	('ARC risk', 'Disease', (78, 86))	('heat shock factor protein 4', 'Gene', '3299', (8, 35))	('associated', 'Reg', (62, 72))	('heat shock factor protein 4', 'Gene', (8, 35))	('HSF4', 'Gene', (37, 41))	('HSF4', 'Gene', '3299', (37, 41))	('shock', 'Phenotype', 'HP:0031273', (13, 18))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('CNVs', 'Var', (0, 4))
113941	25097799	One study identified rare missense variants in the CFI, C3 and C9 genes that were strongly associated with advanced AMD.	('CFI', 'Gene', '3426', (51, 54))	('missense variants', 'Var', (26, 43))	('CFI', 'molecular_function', 'GO:0034029', ('51', '54'))	('AMD', 'Disease', 'MESH:D006009', (116, 119))	('CFI', 'Gene', (51, 54))	('AMD', 'Disease', (116, 119))	('associated with', 'Reg', (91, 106))
113942	25097799	The risk allele for the rare variant in C3 (Gln155) resulted in resistance to proteolytic inactivation by CFH and CFI, suggesting that this variant may have a functional role in excessive complement activation.	('Gln155', 'Var', (44, 50))	('CFI', 'Gene', '3426', (114, 117))	('CFI', 'molecular_function', 'GO:0034029', ('114', '117'))	('men', 'Species', '9606', (194, 197))	('CFH', 'Gene', (106, 109))	('resistance to proteolytic inactivation', 'MPA', (64, 102))	('CFI', 'Gene', (114, 117))	('complement activation', 'biological_process', 'GO:0006956', ('188', '209'))	('Gln155', 'Chemical', '-', (44, 50))	('CFH', 'Gene', '3075', (106, 109))
113943	25097799	A rare, highly penetrant missense variant (p.Gly119Arg) in the CFI gene may also play a functional role in AMD pathogenesis.	('CFI', 'molecular_function', 'GO:0034029', ('63', '66'))	('AMD', 'Disease', (107, 110))	('pathogenesis', 'biological_process', 'GO:0009405', ('111', '123'))	('p.Gly119Arg', 'Var', (43, 54))	('play', 'Reg', (81, 85))	('CFI', 'Gene', (63, 66))	('p.Gly119Arg', 'Mutation', 'rs141853578', (43, 54))	('CFI', 'Gene', '3426', (63, 66))	('AMD', 'Disease', 'MESH:D006009', (107, 110))
113945	25097799	Moreover, the mutant protein is less effective at mediating degradation of C3b when compared to the wild-type protein.	('C3b', 'Gene', (75, 78))	('less', 'NegReg', (32, 36))	('C3b', 'Gene', '718', (75, 78))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('mutant', 'Var', (14, 20))	('degradation', 'biological_process', 'GO:0009056', ('60', '71'))	('degradation', 'MPA', (60, 71))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))
113946	25097799	Functional studies in zebrafish found that the Arg119 mutant caused smaller average hyaloid vessel diameter compared to the wild-type, confirming the functional nature of this gene variant.	('zebrafish', 'Species', '7955', (22, 31))	('smaller', 'NegReg', (68, 75))	('Arg119', 'Chemical', '-', (47, 53))	('Arg119', 'Var', (47, 53))
113950	25097799	Interestingly, genetic variants affect AMD treatment response.	('genetic variants', 'Var', (15, 31))	('men', 'Species', '9606', (48, 51))	('AMD', 'Disease', 'MESH:D006009', (39, 42))	('affect', 'Reg', (32, 38))	('AMD', 'Disease', (39, 42))
113951	25097799	For instance, variants in VEGFA, HTRA1, and LOC387715/ARMS2 were found to influence visual outcome in patients receiving anti-VEGF injections for NVAMD.	('AMD', 'Disease', 'MESH:D006009', (148, 151))	('AMD', 'Disease', (148, 151))	('influence', 'Reg', (74, 83))	('ARMS2', 'Gene', '387715', (54, 59))	('VEGFA', 'Gene', '7422', (26, 31))	('variants', 'Var', (14, 22))	('patients', 'Species', '9606', (102, 110))	('VEGF', 'Gene', '7422', (126, 130))	('visual outcome', 'CPA', (84, 98))	('HTRA1', 'Gene', (33, 38))	('HTRA1', 'Gene', '5654', (33, 38))	('VEGF', 'Gene', (26, 30))	('VEGF', 'Gene', (126, 130))	('VEGFA', 'Gene', (26, 31))	('ARMS2', 'Gene', (54, 59))	('VEGF', 'Gene', '7422', (26, 30))
113952	25097799	Moreover, CFH and ARMS2 variants influence response to zinc and antioxidant treatment for NNVAMD.	('CFH', 'Gene', '3075', (10, 13))	('influence', 'Reg', (33, 42))	('ARMS2', 'Gene', (18, 23))	('AMD', 'Disease', (93, 96))	('variants', 'Var', (24, 32))	('ARMS2', 'Gene', '387715', (18, 23))	('men', 'Species', '9606', (81, 84))	('CFH', 'Gene', (10, 13))	('AMD', 'Disease', 'MESH:D006009', (93, 96))	('response to zinc', 'biological_process', 'GO:0010043', ('43', '59'))
113954	25097799	In another study, patients with risk alleles for both the CFH rs1061170 and ARMS2 rs10490924 polymorphisms were found to benefit from dietary antioxidant and fish consumption, whereas individuals who had low genetic risk (one or no risk alleles) did not benefit.	('rs1061170', 'Var', (62, 71))	('rs10490924', 'Mutation', 'rs10490924', (82, 92))	('rs1061170', 'Mutation', 'rs1061170', (62, 71))	('rs10490924', 'Var', (82, 92))	('ARMS2', 'Gene', (76, 81))	('CFH', 'Gene', (58, 61))	('benefit', 'PosReg', (121, 128))	('patients', 'Species', '9606', (18, 26))	('dietary antioxidant', 'MPA', (134, 153))	('ARMS2', 'Gene', '387715', (76, 81))	('CFH', 'Gene', '3075', (58, 61))
113955	25097799	The LDL cholesterol-lowering medication simvastatin has also been shown to slow progression of NNVAMD, especially in those homozygous for the risk allele (CC) for the CFH rs1061170 (Y402H) variant.	('CFH', 'Gene', (167, 170))	('rs1061170 (Y402H', 'Var', (171, 187))	('slow', 'NegReg', (75, 79))	('AMD', 'Disease', 'MESH:D006009', (98, 101))	('Y402H', 'Mutation', 'rs1061170', (182, 187))	('AMD', 'Disease', (98, 101))	('CFH', 'Gene', '3075', (167, 170))	('LDL', 'molecular_function', 'GO:0005322', ('4', '7'))	('cholesterol', 'Chemical', 'MESH:D002784', (8, 19))	('rs1061170', 'Mutation', 'rs1061170', (171, 180))	('simvastatin', 'Chemical', 'MESH:D019821', (40, 51))
113956	25097799	Two studies recently examined the role of epigenetic factors in AMD pathogenesis and reported conflicting findings.	('examined', 'Reg', (21, 29))	('pathogenesis', 'biological_process', 'GO:0009405', ('68', '80'))	('AMD', 'Disease', 'MESH:D006009', (64, 67))	('AMD', 'Disease', (64, 67))	('epigenetic factors', 'Var', (42, 60))
113958	25097799	However, a replication study found no evidence of IL17RC hypomethylation in AMD patients, highlighting the need for replication of epigenetic association studies prior to clinical application.	('AMD', 'Disease', 'MESH:D006009', (76, 79))	('IL17', 'molecular_function', 'GO:0030367', ('50', '54'))	('patients', 'Species', '9606', (80, 88))	('AMD', 'Disease', (76, 79))	('IL17RC', 'Gene', '84818', (50, 56))	('hypomethylation', 'Var', (57, 72))	('IL17RC', 'Gene', (50, 56))
113967	25097799	Conditional analysis suggested that rs3118515 in LOC100506532 is the dominant contributor to association with CCT in Latinos, as every SNP in the RXRA-COL5A1 region lost significance after conditioning on rs3118515.	('rs3118515', 'Var', (205, 214))	('rs3118515', 'Var', (36, 45))	('rs3118515', 'Mutation', 'rs3118515', (205, 214))	('CCT', 'Disease', (110, 113))	('rs3118515', 'Mutation', 'rs3118515', (36, 45))	('COL5A1', 'Gene', (151, 157))	('COL5A1', 'Gene', '1289', (151, 157))	('RXRA', 'Gene', '6256', (146, 150))	('association', 'Interaction', (93, 104))	('LOC100506532', 'Var', (49, 61))	('RXRA', 'Gene', (146, 150))
113971	25097799	One meta-analysis explored the association of paraoxonase (PON) gene polymorphisms with DR. PON1-L55M (rs854560) was significantly associated with DR, though PON1-Q192R (rs662) and PON2 gene polymorphisms were not strongly associated in this meta-analysis.	('PON', 'Gene', (158, 161))	('PON', 'Gene', '5444', (92, 95))	('PON', 'Gene', '5444', (59, 62))	('rs854560', 'Mutation', 'rs854560', (103, 111))	('PON1', 'Gene', (158, 162))	('L55M', 'Mutation', 'rs854560', (97, 101))	('PON', 'Gene', (181, 184))	('PON1', 'Gene', (92, 96))	('PON', 'Gene', (92, 95))	('PON', 'Gene', (59, 62))	('associated', 'Reg', (131, 141))	('PON', 'Gene', '5444', (158, 161))	('PON2', 'Gene', (181, 185))	('paraoxonase', 'Gene', (46, 57))	('Q192R', 'Mutation', 'rs662', (163, 168))	('rs854560', 'Var', (103, 111))	('PON1', 'Gene', '5444', (158, 162))	('PON2', 'Gene', '5445', (181, 185))	('paraoxonase', 'Gene', '5444', (46, 57))	('rs662', 'Mutation', 'rs662', (170, 175))	('PON', 'Gene', '5444', (181, 184))	('PON1', 'Gene', '5444', (92, 96))
113975	25097799	Meta-analyses also found strong associations with DR risk for the ICAM-1 K469E and the plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphisms.	('K469E', 'Var', (73, 78))	('PAI-1', 'Gene', (122, 127))	('associations', 'Interaction', (32, 44))	('ICAM-1', 'Gene', (66, 72))	('plasminogen activator inhibitor-1', 'Gene', '5054', (87, 120))	('PAI-1', 'Gene', '5054', (122, 127))	('K469E', 'Mutation', 'rs369180720', (73, 78))	('plasminogen activator inhibitor-1', 'Gene', (87, 120))
113976	25097799	For instance, variants in the TCF7L2 gene were found to promote pathological retinal neovascularization via ER stress-dependent upregulation of VEGFA.	('upregulation', 'PosReg', (128, 140))	('retinal neovascularization', 'Phenotype', 'HP:0030666', (77, 103))	('variants', 'Var', (14, 22))	('TCF7L2', 'Gene', (30, 36))	('pathological retinal neovascularization', 'CPA', (64, 103))	('TCF7L2', 'Gene', '6934', (30, 36))	('VEGFA', 'Gene', '7422', (144, 149))	('promote', 'PosReg', (56, 63))	('VEGFA', 'Gene', (144, 149))
113978	25097799	This suggests that RAGE gene polymorphisms may play a functional role via modulation of the NF-kappaB mediated inflammatory pathway.	('RAGE', 'Gene', (19, 23))	('NF-kappaB mediated inflammatory pathway', 'Pathway', (92, 131))	('modulation', 'Reg', (74, 84))	('RAGE', 'Gene', '177', (19, 23))	('polymorphisms', 'Var', (29, 42))
113979	25097799	For instance, a GWAS conducted in a Chinese population identified three novel loci for DR: TBC1D4-COMMD6-UCHL3 (rs9565164), LRP2-BBS5 (rs1399634) and ARL4C-SH3BP4 (rs2380261).	('UCHL3', 'Gene', '7347', (105, 110))	('rs2380261', 'Var', (164, 173))	('rs1399634', 'Var', (135, 144))	('DR', 'Gene', (87, 89))	('rs1399634', 'Mutation', 'rs1399634', (135, 144))	('ARL4C', 'Gene', '10123', (150, 155))	('rs9565164', 'Mutation', 'rs9565164', (112, 121))	('ARL4C', 'Gene', (150, 155))	('LRP2', 'Gene', '4036', (124, 128))	('rs9565164', 'Var', (112, 121))	('TBC1D4', 'Gene', (91, 97))	('TBC', 'cellular_component', 'GO:0036284', ('91', '94'))	('COMMD6', 'Gene', (98, 104))	('UCHL3', 'Gene', (105, 110))	('BBS5', 'Gene', (129, 133))	('SH3BP4', 'Gene', (156, 162))	('BBS5', 'Gene', '129880', (129, 133))	('SH3BP4', 'Gene', '23677', (156, 162))	('LRP2', 'Gene', (124, 128))	('TBC1D4', 'Gene', '9882', (91, 97))	('COMMD6', 'Gene', '170622', (98, 104))	('rs2380261', 'Mutation', 'rs2380261', (164, 173))
113988	25097799	Variants in the COL8A2, SLC4A11, and ZEB1 genes were detected in African American patients.	('SLC4A11', 'Gene', (24, 31))	('Variants', 'Var', (0, 8))	('COL8A2', 'Gene', '1296', (16, 22))	('SLC4A11', 'Gene', '83959', (24, 31))	('patients', 'Species', '9606', (82, 90))	('ZEB1', 'Gene', (37, 41))	('ZEB1', 'Gene', '6935', (37, 41))	('COL8A2', 'Gene', (16, 22))
113989	25097799	However, similar to the case in Caucasian and Asian populations, these variants were found in only a small fraction of patients examined, suggesting that these genes are not the major contributor to FECD pathogenesis.	('variants', 'Var', (71, 79))	('FECD', 'Gene', '1296', (199, 203))	('patients', 'Species', '9606', (119, 127))	('FECD', 'Gene', (199, 203))	('pathogenesis', 'biological_process', 'GO:0009405', ('204', '216'))
113991	25097799	A study of a three-generation family affected by FECD utilized genome-wide linkage mapping and subsequent next-generation sequencing to identify a nonsense mutation in the AGBL1 gene on chromosome 15q.	('FECD', 'Gene', '1296', (49, 53))	('AGBL1', 'Gene', '123624', (172, 177))	('nonsense mutation', 'Var', (147, 164))	('chromosome', 'cellular_component', 'GO:0005694', ('186', '196'))	('AGBL1', 'Gene', (172, 177))	('FECD', 'Gene', (49, 53))
113993	25097799	Moreover, AGBL1 was shown to interact with the FECD-associated gene TCF4, and the AGBL1 nonsense mutation diminished this interaction.	('interaction', 'Interaction', (122, 133))	('AGBL1', 'Gene', (82, 87))	('nonsense mutation', 'Var', (88, 105))	('FECD', 'Gene', (47, 51))	('AGBL1', 'Gene', '123624', (10, 15))	('AGBL1', 'Gene', (10, 15))	('diminished', 'NegReg', (106, 116))	('interact', 'Interaction', (29, 37))	('FECD', 'Gene', '1296', (47, 51))	('TCF4', 'Gene', (68, 72))	('TCF4', 'Gene', '6925', (68, 72))	('AGBL1', 'Gene', '123624', (82, 87))
113995	25097799	Variants in RAD51, which encodes a protein involved in homologous recombination and repair of double-stranded breaks, were associated with risk for FECD in this study.	('Variants', 'Var', (0, 8))	('FECD', 'Gene', '1296', (148, 152))	('associated with risk', 'Reg', (123, 143))	('RAD', 'biological_process', 'GO:1990116', ('12', '15'))	('homologous recombination', 'biological_process', 'GO:0035825', ('55', '79'))	('RAD51', 'Gene', (12, 17))	('RAD51', 'Gene', '5888', (12, 17))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('FECD', 'Gene', (148, 152))
113998	25097799	Studies of Col8a2L450W/L450W and Col8a2Q455K/Q455K knock-in mouse models of FECD were also recently performed, which revealed dilation of rough endoplasmic reticulum (RER) consistent with upregulation of the unfolded protein response.	('FECD', 'Gene', (76, 80))	('Col8a2L450W/L450W', 'Var', (11, 28))	('Col8a2Q455K/Q455K', 'Var', (33, 50))	('L450W', 'Mutation', 'rs80358192', (23, 28))	('Q455K', 'Mutation', 'rs80358191', (45, 50))	('dilation', 'MPA', (126, 134))	('RER', 'cellular_component', 'GO:0005791', ('167', '170'))	('FECD', 'Gene', '1296', (76, 80))	('protein', 'cellular_component', 'GO:0003675', ('217', '224'))	('rough endoplasmic reticulum', 'cellular_component', 'GO:0005791', ('138', '165'))	('Q455K', 'Mutation', 'rs80358191', (39, 44))	('upregulation', 'PosReg', (188, 200))	('L450W', 'Mutation', 'rs80358192', (17, 22))	('mouse', 'Species', '10090', (60, 65))
114002	25097799	Compared to wild-type mice, Col8a2Q455K/Q455K mutant mice had increased COX2 and JUN expression, both of which are involved in cell stress responses.	('increased', 'PosReg', (62, 71))	('Q455K', 'Mutation', 'rs80358191', (34, 39))	('mice', 'Species', '10090', (22, 26))	('Col8a2Q455K/Q455K', 'Var', (28, 45))	('COX2', 'Gene', '17709', (72, 76))	('Q455K', 'Mutation', 'rs80358191', (40, 45))	('mice', 'Species', '10090', (53, 57))	('COX2', 'Gene', (72, 76))
114009	25097799	For instance, TNFalpha gene polymorphisms were associated with open angle glaucoma in certain populations, though this finding was not replicated in others.	('open angle glaucoma', 'Disease', 'MESH:D005902', (63, 82))	('open angle glaucoma', 'Disease', (63, 82))	('associated with', 'Reg', (47, 62))	('TNFalpha', 'Gene', (14, 22))	('glaucoma', 'Phenotype', 'HP:0000501', (74, 82))	('polymorphisms', 'Var', (28, 41))	('TNFalpha', 'Gene', '7124', (14, 22))	('open angle glaucoma', 'Phenotype', 'HP:0012108', (63, 82))
114010	25097799	A recent meta-analysis identified an association with the TNFalpha -308G/A polymorphism (rs1800629) in POAG patients.	('association', 'Interaction', (37, 48))	('TNFalpha', 'Gene', (58, 66))	('TNFalpha', 'Gene', '7124', (58, 66))	('rs1800629', 'Var', (89, 98))	('-308G/A', 'Mutation', 'rs1800629', (67, 74))	('rs1800629', 'Mutation', 'rs1800629', (89, 98))	('POAG', 'Disease', (103, 107))	('patients', 'Species', '9606', (108, 116))
114011	25097799	This variant was strongly associated with risk for high-tension glaucoma, but not in normal-tension glaucoma cases.	('tension glaucoma', 'Disease', (56, 72))	('tension glaucoma', 'Disease', (92, 108))	('tension glaucoma', 'Disease', 'MESH:D005901', (56, 72))	('variant', 'Var', (5, 12))	('glaucoma', 'Phenotype', 'HP:0000501', (64, 72))	('tension glaucoma', 'Disease', 'MESH:D005901', (92, 108))	('glaucoma', 'Phenotype', 'HP:0000501', (100, 108))	('associated', 'Reg', (26, 36))
114014	25097799	Similar to the case with TNFalpha polymorphisms, studies of CAV1/CAV2 variants in different populations have generated inconsistent findings.	('TNFalpha', 'Gene', (25, 33))	('CAV1', 'Gene', (60, 64))	('CAV2', 'Gene', (65, 69))	('TNFalpha', 'Gene', '7124', (25, 33))	('CAV2', 'Gene', '858', (65, 69))	('variants', 'Var', (70, 78))	('CAV1', 'Gene', '857', (60, 64))
114015	25097799	This year, a study was conducted to explore the association of CAV1/CAV2 variants with normal-tension glaucoma in Japanese patients.	('CAV1', 'Gene', '857', (63, 67))	('tension glaucoma', 'Disease', (94, 110))	('CAV2', 'Gene', '858', (68, 72))	('variants', 'Var', (73, 81))	('association', 'Interaction', (48, 59))	('patients', 'Species', '9606', (123, 131))	('tension glaucoma', 'Disease', 'MESH:D005901', (94, 110))	('CAV1', 'Gene', (63, 67))	('CAV2', 'Gene', (68, 72))	('glaucoma', 'Phenotype', 'HP:0000501', (102, 110))
114016	25097799	These findings suggest that known SNPs in the CAV1/CAV2 locus are not uniformly associated with normal tension glaucoma among different populations.	('glaucoma', 'Phenotype', 'HP:0000501', (111, 119))	('tension glaucoma', 'Disease', 'MESH:D005901', (103, 119))	('CAV1', 'Gene', '857', (46, 50))	('CAV2', 'Gene', '858', (51, 55))	('SNPs', 'Var', (34, 38))	('associated', 'Reg', (80, 90))	('tension glaucoma', 'Disease', (103, 119))	('CAV1', 'Gene', (46, 50))	('CAV2', 'Gene', (51, 55))
114020	25097799	SNPs in CDKN2B-AS1, an antisense noncoding RNA, were found to modulate optic nerve degeneration, as POAG patients with minor alleles for these SNPs had altered cup-to-disk ratios.	('patients', 'Species', '9606', (105, 113))	('modulate', 'Reg', (62, 70))	('RNA', 'cellular_component', 'GO:0005562', ('43', '46'))	('CDKN2B-AS1', 'Gene', (8, 18))	('SNPs', 'Var', (0, 4))	('altered', 'Reg', (152, 159))	('optic nerve degeneration', 'Disease', 'MESH:D009410', (71, 95))	('optic nerve degeneration', 'Phenotype', 'HP:0000648', (71, 95))	('cup-to-disk ratios', 'CPA', (160, 178))	('CDKN2B-AS1', 'Gene', '100048912', (8, 18))	('optic nerve degeneration', 'Disease', (71, 95))
114025	25097799	Mutations in ASB10 could potentially affect these pathways and lead to alterations in TM outflow, thereby contributing to the pathogenesis of POAG.	('contributing', 'Reg', (106, 118))	('lead to alterations', 'Reg', (63, 82))	('affect', 'Reg', (37, 43))	('Mutations', 'Var', (0, 9))	('ASB10', 'Gene', '136371', (13, 18))	('pathogenesis', 'biological_process', 'GO:0009405', ('126', '138'))	('TM outflow', 'MPA', (86, 96))	('ASB10', 'Gene', (13, 18))	('POAG', 'Disease', (142, 146))
114026	25097799	A SNP in the SIX1-SIX6 locus (rs10483727) was previously identified in a GWAS study and was strongly associated with vertical cup-disk ratio (VCDR) and POAG.	('POAG', 'Disease', (152, 156))	('SIX1-SIX6', 'Disease', (13, 22))	('vertical cup-disk ratio', 'Disease', (117, 140))	('SIX1-SIX6', 'Disease', 'None', (13, 22))	('rs10483727', 'Var', (30, 40))	('associated', 'Reg', (101, 111))	('rs10483727', 'Mutation', 'rs10483727', (30, 40))
114027	25097799	A recent study identified two missense variants in SIX6, rs33912345 (His141Asn) and rs146737847 (Glu129Lys), that were associated with VCDR (rs33912345 and rs146737847) and POAG (rs33912345).	('SIX6', 'Gene', (51, 55))	('rs33912345', 'Var', (57, 67))	('rs33912345', 'Mutation', 'rs33912345', (141, 151))	('POAG', 'Disease', (173, 177))	('rs146737847', 'Mutation', 'rs146737847', (156, 167))	('rs146737847', 'Var', (156, 167))	('rs33912345', 'Var', (179, 189))	('rs33912345', 'Mutation', 'rs33912345', (57, 67))	('rs146737847', 'Var', (84, 95))	('rs33912345', 'Mutation', 'rs33912345', (179, 189))	('VCDR', 'Disease', (135, 139))	('rs33912345', 'Var', (141, 151))	('rs146737847', 'Mutation', 'rs146737847', (84, 95))	('associated', 'Reg', (119, 129))
114030	25097799	Interestingly, in POAG patients who were homozygous for the risk allele for SNP rs33912345 (His 141) were found to have a thinner retinal nerve fiber layer compared to patients homozygous for the non-risk allele (Asn141).	('nerve fiber', 'cellular_component', 'GO:0043005', ('138', '149'))	('rs33912345', 'Mutation', 'rs33912345', (80, 90))	('patients', 'Species', '9606', (23, 31))	('SNP', 'Gene', (76, 79))	('thinner', 'NegReg', (122, 129))	('patients', 'Species', '9606', (168, 176))	('rs33912345', 'Var', (80, 90))
114031	25097799	For instance, myocilin mutations are more prevalent in patients with advanced POAG (defined as more severe visual loss) compared to patients with clinically less severe POAG in an Australasian disease registry.	('prevalent', 'Reg', (42, 51))	('visual loss', 'Disease', 'MESH:C531604', (107, 118))	('visual loss', 'Phenotype', 'HP:0000572', (107, 118))	('severe visual loss', 'Phenotype', 'HP:0001141', (100, 118))	('visual loss', 'Disease', (107, 118))	('myocilin', 'Gene', (14, 22))	('Australasian disease', 'Disease', (180, 200))	('mutations', 'Var', (23, 32))	('Australasian disease', 'Disease', 'MESH:D004194', (180, 200))	('patients', 'Species', '9606', (55, 63))	('myocilin', 'Gene', '4653', (14, 22))	('patients', 'Species', '9606', (132, 140))
114032	25097799	In addition, disease-causing mutations in COL15A1 and COL18A1 have been found to influence age of onset of both juvenile and adult open angle glaucoma.	('COL15A1', 'Gene', '1306', (42, 49))	('open angle glaucoma', 'Disease', 'MESH:D005902', (131, 150))	('juvenile', 'Disease', (112, 120))	('influence', 'Reg', (81, 90))	('mutations', 'Var', (29, 38))	('disease-causing', 'Reg', (13, 28))	('open angle glaucoma', 'Disease', (131, 150))	('glaucoma', 'Phenotype', 'HP:0000501', (142, 150))	('COL15A1', 'Gene', (42, 49))	('COL18A1', 'Gene', (54, 61))	('open angle glaucoma', 'Phenotype', 'HP:0012108', (131, 150))	('COL18A1', 'Gene', '80781', (54, 61))
114033	25097799	Patients who carried a COL15A1 variant had a mean age of onset of 25 years, compared to 44 years for patients without the COL15A1 variant.	('patients', 'Species', '9606', (101, 109))	('COL15A1', 'Gene', (23, 30))	('COL15A1', 'Gene', (122, 129))	('Patients', 'Species', '9606', (0, 8))	('COL15A1', 'Gene', '1306', (23, 30))	('COL15A1', 'Gene', '1306', (122, 129))	('variant', 'Var', (31, 38))
114034	25097799	Similarly, patients who carried a COL18A1 variant had a mean age of onset of 32.2 years, compared to 48.8 years for patients without the variant.	('COL18A1', 'Gene', (34, 41))	('patients', 'Species', '9606', (116, 124))	('COL18A1', 'Gene', '80781', (34, 41))	('patients', 'Species', '9606', (11, 19))	('variant', 'Var', (42, 49))
114035	25097799	For instance, a GWAS identified SNPs in the complement component C7 gene that are strongly associated with POAG risk.	('POAG', 'Disease', (107, 111))	('SNPs', 'Var', (32, 36))	('complement component C7', 'Disease', 'MESH:C566443', (44, 67))	('complement component C7', 'Disease', (44, 67))	('associated', 'Reg', (91, 101))
114042	25097799	A GWAS previously performed on a large cohort of multiple ethnicities (Chinese, Malaysian, Indian, Vietnamese, Saudi Arabian and European) identified three susceptibility loci for PACG: rs11024102 in PLEKHA7, rs3753841 in COL11A1, and rs1015213 located between PCMTD1 and ST18 on chromosome 8q.	('PLEKHA7', 'Gene', '144100', (200, 207))	('ST18', 'Gene', (272, 276))	('ST18', 'Gene', '9705', (272, 276))	('PCMTD1', 'Gene', '115294', (261, 267))	('rs11024102', 'Mutation', 'rs11024102', (186, 196))	('rs3753841', 'Mutation', 'rs3753841', (209, 218))	('PCMTD1', 'Gene', (261, 267))	('PACG', 'Gene', (180, 184))	('chromosome', 'cellular_component', 'GO:0005694', ('280', '290'))	('COL11A1', 'Gene', '1301', (222, 229))	('rs3753841', 'Var', (209, 218))	('PLEKHA7', 'Gene', (200, 207))	('rs1015213', 'Var', (235, 244))	('COL11A1', 'Gene', (222, 229))	('rs1015213', 'Mutation', 'rs1015213', (235, 244))
114043	25097799	A fourth association, rs3788317 in TXNRD2, did not reach genome-wide significance in the meta-analysis.	('rs3788317', 'Mutation', 'rs3788317', (22, 31))	('rs3788317', 'Var', (22, 31))	('TXNRD2', 'Gene', '10587', (35, 41))	('TXNRD2', 'Gene', (35, 41))
114045	25097799	For instance, SNPs in frizzled-related protein (MFRP) and heat shock protein 70 (HSP70) showed possible association with primary angle closure in the Han Chinese population, although significance was lost after Bonferroni correction.	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('heat shock protein 70', 'Gene', (58, 79))	('HSP70', 'Gene', '3308', (81, 86))	('MFRP', 'Gene', (48, 52))	('primary angle closure', 'Phenotype', 'HP:0012109', (121, 142))	('shock', 'Phenotype', 'HP:0031273', (63, 68))	('frizzled-related protein', 'Gene', '2487', (22, 46))	('association', 'Interaction', (104, 115))	('heat shock protein 70', 'Gene', '3308', (58, 79))	('primary angle closure', 'Disease', (121, 142))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('HSP70', 'Gene', (81, 86))	('SNPs', 'Var', (14, 18))	('MFRP', 'Gene', '83552', (48, 52))	('frizzled-related protein', 'Gene', (22, 46))
114046	25097799	In an Australian cohort, SNP rs3793342 in the endothelial nitric oxide synthase (eNOS) gene showed association with PACG.	('SNP rs3793342', 'Var', (25, 38))	('eNOS', 'Gene', '4846', (81, 85))	('PACG', 'Disease', (116, 120))	('endothelial nitric oxide synthase', 'Gene', '4846', (46, 79))	('association', 'Reg', (99, 110))	('eNOS', 'Gene', (81, 85))	('endothelial nitric oxide synthase', 'Gene', (46, 79))	('rs3793342', 'Mutation', 'rs3793342', (29, 38))
114047	25097799	Variants in serine protease 56 (PRSS56) have also been found to be associated with PACG.	('Variants', 'Var', (0, 8))	('PRSS56', 'Gene', (32, 38))	('associated', 'Reg', (67, 77))	('PACG', 'Disease', (83, 87))	('PRSS56', 'Gene', '646960', (32, 38))	('serine protease 56', 'Gene', (12, 30))	('serine protease 56', 'Gene', '646960', (12, 30))
114048	25097799	Lastly, SNPs rs5745718 and rs17427817 in the hepatocyte growth factor (HGF) gene were associated with decreased risk of PACG in the Han Chinese population.	('rs5745718', 'Mutation', 'rs5745718', (13, 22))	('HGF', 'Gene', '3082', (71, 74))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('45', '69'))	('PACG', 'Disease', (120, 124))	('hepatocyte growth factor', 'Gene', (45, 69))	('rs17427817', 'Var', (27, 37))	('hepatocyte growth factor', 'Gene', '3082', (45, 69))	('SNPs rs5745718', 'Var', (8, 22))	('decreased', 'NegReg', (102, 111))	('rs17427817', 'Mutation', 'rs17427817', (27, 37))	('HGF', 'Gene', (71, 74))
114059	25097799	Dysregulation of NF-kB activity has been observed to play a role in a number of disease states, including glaucoma.	('Dysregulation', 'Var', (0, 13))	('glaucoma', 'Disease', 'MESH:D005901', (106, 114))	('play', 'Reg', (53, 57))	('activity', 'MPA', (23, 31))	('glaucoma', 'Phenotype', 'HP:0000501', (106, 114))	('NF-kB', 'Protein', (17, 22))	('glaucoma', 'Disease', (106, 114))
114062	25097799	Moreover, CYP1B1 gene mutations were associated with a better surgical outcome in this population, defined as postoperative IOP<= 21mmHg with or without use of glaucoma medications.	('glaucoma', 'Disease', 'MESH:D005901', (160, 168))	('CYP1B1', 'Gene', '1545', (10, 16))	('CYP1B1', 'Gene', (10, 16))	('glaucoma', 'Phenotype', 'HP:0000501', (160, 168))	('glaucoma', 'Disease', (160, 168))	('surgical outcome', 'CPA', (62, 78))	('mutations', 'Var', (22, 31))	('better', 'PosReg', (55, 61))
114068	25097799	Recently, disease-causing VSX1 mutations were identified in New Zealand and Han Chinese cohorts.	('VSX1', 'Gene', '30813', (26, 30))	('mutations', 'Var', (31, 40))	('disease-causing', 'Reg', (10, 25))	('VSX1', 'Gene', (26, 30))
114069	25097799	However, studies conducted in South Indian, Iranian, and Greek populations found no significant association between VSX1 mutations and susceptibility to KC.	('VSX1', 'Gene', '30813', (116, 120))	('VSX1', 'Gene', (116, 120))	('mutations', 'Var', (121, 130))	('susceptibility', 'Reg', (135, 149))
114070	25097799	A candidate gene study recently performed in Poland found that SNPs rs8177178 and rs8177179 in the transferrin gene were also associated with KC.	('rs8177178', 'Mutation', 'rs8177178', (68, 77))	('associated', 'Reg', (126, 136))	('rs8177179', 'Var', (82, 91))	('rs8177179', 'Mutation', 'rs8177179', (82, 91))	('transferrin', 'Gene', '7018', (99, 110))	('transferrin', 'Gene', (99, 110))
114072	25097799	To further explore the connection between oxidative stress and KC, variants in the RAD51 gene were also studied in a Polish population and found to be associated with disease risk.	('RAD51', 'Gene', (83, 88))	('associated', 'Reg', (151, 161))	('RAD51', 'Gene', '5888', (83, 88))	('oxidative stress', 'Phenotype', 'HP:0025464', (42, 58))	('variants', 'Var', (67, 75))	('RAD', 'biological_process', 'GO:1990116', ('83', '86'))
114075	25097799	A recent study further explored this hypothesis by examining whether variants in the CAST gene confer susceptibility to KC.	('variants', 'Var', (69, 77))	('CAST', 'Gene', '831', (85, 89))	('susceptibility', 'Reg', (102, 116))	('CAST', 'Gene', (85, 89))
114076	25097799	SNP rs4434401 was found to be strongly associated with KC risk in 2 independent Caucasian cohorts.	('SNP rs4434401', 'Var', (0, 13))	('associated', 'Reg', (39, 49))	('rs4434401', 'Mutation', 'rs4434401', (4, 13))
114079	25097799	FOXO1 and FNDC3B variants were found to increase risk for keratoconus in two different cohorts.	('variants', 'Var', (17, 25))	('FNDC3B', 'Gene', '64778', (10, 16))	('FOXO1', 'Gene', (0, 5))	('FOXO1', 'Gene', '2308', (0, 5))	('FNDC3B', 'Gene', (10, 16))	('keratoconus', 'Disease', (58, 69))	('keratoconus', 'Phenotype', 'HP:0000563', (58, 69))	('increase', 'Reg', (40, 48))
114080	25097799	A replication study performed in an Australian cohort found no association between the FOXO1 and FNDC3B variants and KC risk, however.	('variants', 'Var', (104, 112))	('FNDC3B', 'Gene', '64778', (97, 103))	('FOXO1', 'Gene', '2308', (87, 92))	('FNDC3B', 'Gene', (97, 103))	('FOXO1', 'Gene', (87, 92))
114081	25097799	The CCT-associated SNPs rs1324183 (in the MPDZ-NF1B gene) and rs9938149 (between BANP and ZNF4659) were strongly associated with KC risk in the Australian cohort, though the association was via a non-corneal curvature route.	('MPDZ', 'Gene', (42, 46))	('associated with', 'Reg', (113, 128))	('rs9938149', 'Mutation', 'rs9938149', (62, 71))	('NF1B', 'Gene', '4781', (47, 51))	('rs1324183', 'Mutation', 'rs1324183', (24, 33))	('CCT-associated', 'Disease', (4, 18))	('rs1324183', 'Var', (24, 33))	('corneal curvature', 'Phenotype', 'HP:0100692', (200, 217))	('BANP', 'Gene', '54971', (81, 85))	('BANP', 'Gene', (81, 85))	('rs9938149', 'Var', (62, 71))	('NF1B', 'Gene', (47, 51))	('MPDZ', 'Gene', '8777', (42, 46))
114083	25097799	In LCA patients with RPE65 mutations, a recombinant adeno-associated virus vector carrying the human RPE65 gene has been shown to improve vision without apparent side effects in both animal models and in clinical trials.	('improve', 'PosReg', (130, 137))	('mutations', 'Var', (27, 36))	('human', 'Species', '9606', (95, 100))	('patients', 'Species', '9606', (7, 15))	('LCA', 'Disease', 'MESH:C536600', (3, 6))	('LCA', 'Disease', (3, 6))	('improve vision', 'Phenotype', 'HP:0000505', (130, 144))	('vision', 'Disease', (138, 144))	('RPE65', 'Gene', (21, 26))	('RPE65', 'Gene', '6121', (21, 26))	('RPE65', 'Gene', '6121', (101, 106))	('vision', 'biological_process', 'GO:0007601', ('138', '144'))	('adeno-associated virus', 'Species', '272636', (52, 74))	('RPE65', 'Gene', (101, 106))
114085	25097799	In LCA patients, RPE65 gene therapy resulted in significant visual improvement in the short term, though retinal degeneration continued to progress unabated.	('LCA', 'Disease', 'MESH:C536600', (3, 6))	('visual', 'MPA', (60, 66))	('LCA', 'Disease', (3, 6))	('RPE65', 'Gene', (17, 22))	('RPE65', 'Gene', '6121', (17, 22))	('improvement', 'PosReg', (67, 78))	('retinal degeneration', 'Disease', 'MESH:D012162', (105, 125))	('retinal degeneration', 'Disease', (105, 125))	('men', 'Species', '9606', (74, 77))	('gene therapy', 'Var', (23, 35))	('patients', 'Species', '9606', (7, 15))	('retinal degeneration', 'Phenotype', 'HP:0000546', (105, 125))
114089	25097799	It is associated with three point mutations in mitochondrial DNA: m.3460G>A (MT-ND1), m.11778G>A (MT-ND4), and m.14484T>C (MT-ND6).	('m.11778G>A', 'Mutation', 'm.11778G>A', (86, 96))	('MT-ND6', 'Gene', '4541', (123, 129))	('MT-ND6', 'Gene', (123, 129))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('47', '64'))	('associated', 'Reg', (6, 16))	('m.3460G>A', 'Mutation', 'rs199476118', (66, 75))	('m.3460G>A', 'Var', (66, 75))	('m.11778G>A', 'Var', (86, 96))	('m.14484T>C', 'Mutation', 'm.14484T>C', (111, 121))	('m.14484T>C', 'Var', (111, 121))	('MT-ND1', 'Gene', '4535', (77, 83))	('mitochondrial', 'Gene', (47, 60))	('MT-ND4', 'Gene', '4538', (98, 104))	('MT-ND1', 'Gene', (77, 83))	('MT-ND4', 'Gene', (98, 104))
114090	25097799	SNPs in the PARL gene, which encodes a serine protease of the inner mitochondrial membrane, were previously shown to be associated with LHON in a genome-wide linkage analysis performed in Thailand.	('LHON', 'Disease', (136, 140))	('associated', 'Reg', (120, 130))	('inner mitochondrial membrane', 'cellular_component', 'GO:0005743', ('62', '90'))	('PARL', 'Gene', '55486', (12, 16))	('SNPs', 'Var', (0, 4))	('PARL', 'Gene', (12, 16))
114091	25097799	To determine whether PARL may have a role in penetrance of this mitochondrial disease, the PARL gene was examined in patients with the m.11778G>A genotype who had LHON and in patients with the m.11778G>A genotype who were unaffected.	('PARL', 'Gene', (21, 25))	('m.11778G>A', 'Mutation', 'm.11778G>A', (135, 145))	('m.11778G>A', 'Var', (135, 145))	('LHON', 'Disease', (163, 167))	('patients', 'Species', '9606', (175, 183))	('PARL', 'Gene', '55486', (91, 95))	('m.11778G>A', 'Mutation', 'm.11778G>A', (193, 203))	('PARL', 'Gene', '55486', (21, 25))	('patients', 'Species', '9606', (117, 125))	('PARL', 'Gene', (91, 95))
114092	25097799	Two SNPs, rs3749446 and rs1402000, had significantly different frequencies in the two groups, suggesting that PARL may be a potential modifier in the pathogenesis of LHON.	('rs3749446', 'Var', (10, 19))	('PARL', 'Gene', '55486', (110, 114))	('rs3749446', 'Mutation', 'rs3749446', (10, 19))	('rs1402000', 'Var', (24, 33))	('PARL', 'Gene', (110, 114))	('pathogenesis', 'biological_process', 'GO:0009405', ('150', '162'))	('rs1402000', 'Mutation', 'rs1402000', (24, 33))	('LHON', 'Disease', (166, 170))
114097	25097799	SOX2 gene mutations account for 10-15% of severe A/M cases.	('SOX2', 'Gene', '6657', (0, 4))	('mutations', 'Var', (10, 19))	('severe A/M', 'Disease', (42, 52))	('SOX2', 'Gene', (0, 4))
114098	25097799	Although they account for a small percent of cases, mutations in several other genes, including GDF6, FOXE3, OTX2, PAX6, RAX and VSX2 have been described in A/M cases.	('mutations', 'Var', (52, 61))	('FOXE3', 'Gene', (102, 107))	('VSX2', 'Gene', (129, 133))	('OTX2', 'Gene', '5015', (109, 113))	('OTX2', 'Gene', (109, 113))	('PAX6', 'Gene', '5080', (115, 119))	('FOXE3', 'Gene', '2301', (102, 107))	('VSX2', 'Gene', '338917', (129, 133))	('GDF6', 'Gene', (96, 100))	('RAX', 'Gene', (121, 124))	('GDF6', 'Gene', '392255', (96, 100))	('RAX', 'Gene', '30062', (121, 124))	('PAX6', 'Gene', (115, 119))	('described', 'Reg', (144, 153))
114099	25097799	Antisense morpholino studies to knockdown ALDH1A3 gene expression in zebrafish produced a significant reduction in eye size and aberrant axonal connections to the tectum.	('tectum', 'cellular_component', 'GO:0043676', ('163', '169'))	('eye size', 'CPA', (115, 123))	('ALDH', 'molecular_function', 'GO:0004030', ('42', '46'))	('zebrafish', 'Species', '7955', (69, 78))	('knockdown', 'Var', (32, 41))	('aberrant axonal connections', 'Phenotype', 'HP:0500032', (128, 155))	('reduction', 'NegReg', (102, 111))	('ALDH1A3', 'Gene', (42, 49))	('aberrant axonal connections to the tectum', 'CPA', (128, 169))	('gene expression', 'biological_process', 'GO:0010467', ('50', '65'))
114103	25097799	Autozygome analysis and exome sequencing was recently used to identify mutations in C12orf57, which produced a syndomic form of colobomatous microphthalmia associated with global developmental delay, intractable seizures, and corpus callosum abnormalities.	('global', 'Disease', (172, 178))	('seizures', 'Disease', 'MESH:D012640', (212, 220))	('colobomatous microphthalmia', 'Disease', (128, 155))	('produced', 'Reg', (100, 108))	('corpus callosum abnormalities', 'Phenotype', 'HP:0001273', (226, 255))	('C12orf57', 'Gene', '113246', (84, 92))	('seizures', 'Disease', (212, 220))	('global developmental delay', 'Phenotype', 'HP:0001263', (172, 198))	('C12orf57', 'Gene', (84, 92))	('seizures', 'Phenotype', 'HP:0001250', (212, 220))	('men', 'Species', '9606', (186, 189))	('mutations', 'Var', (71, 80))	('corpus callosum abnormalities', 'Disease', 'MESH:D061085', (226, 255))	('associated', 'Reg', (156, 166))	('corpus callosum abnormalities', 'Disease', (226, 255))	('colobomatous microphthalmia', 'Disease', 'MESH:C537462', (128, 155))	('microphthalmia', 'Phenotype', 'HP:0000568', (141, 155))
114108	25097799	The vast majority of aniridia cases are due to mutations or deletions of the PAX6 gene, which encodes a transcription factor necessary for eye and central nervous system development.	('PAX6', 'Gene', (77, 81))	('PAX6', 'Gene', '5080', (77, 81))	('transcription factor', 'molecular_function', 'GO:0000981', ('104', '124'))	('deletions', 'Var', (60, 69))	('aniridia', 'Disease', (21, 29))	('aniridia', 'Phenotype', 'HP:0000526', (21, 29))	('due', 'Reg', (40, 43))	('mutations', 'Var', (47, 56))	('men', 'Species', '9606', (177, 180))	('central nervous system development', 'biological_process', 'GO:0007417', ('147', '181'))	('aniridia', 'Disease', 'MESH:D015783', (21, 29))	('transcription', 'biological_process', 'GO:0006351', ('104', '117'))
114111	25097799	The efficacy of this drug in a mouse model of aniridia offers promise for a viable therapeutic option for patients with PAX6 nonsense mutations.	('PAX6', 'Gene', (120, 124))	('nonsense mutations', 'Var', (125, 143))	('mouse', 'Species', '10090', (31, 36))	('PAX6', 'Gene', '5080', (120, 124))	('aniridia', 'Disease', 'MESH:D015783', (46, 54))	('patients', 'Species', '9606', (106, 114))	('aniridia', 'Phenotype', 'HP:0000526', (46, 54))	('aniridia', 'Disease', (46, 54))
114115	25097799	For instance, a GWAS performed using 7,280 samples from five Caucasian cohorts found that SNP rs1050035 in the RBFOX1 gene was strongly associated with risk for refractive error.	('RBFOX1', 'Gene', '54715', (111, 117))	('refractive error', 'Disease', (161, 177))	('SNP rs1050035', 'Var', (90, 103))	('rs1050035', 'Mutation', 'rs1050035', (94, 103))	('RBFOX1', 'Gene', (111, 117))	('refractive error', 'Phenotype', 'HP:0000545', (161, 177))	('associated with', 'Reg', (136, 151))
114118	25097799	In the Han Chinese population, a genome-wide meta-analysis found that variants in the VIPR2 and SNTB1 genes increase risk for high myopia.	('VIPR2', 'Gene', (86, 91))	('SNTB1', 'Gene', '6641', (96, 101))	('variants', 'Var', (70, 78))	('increase', 'Reg', (108, 116))	('myopia', 'Phenotype', 'HP:0000545', (131, 137))	('high myopia', 'Disease', 'MESH:D009216', (126, 137))	('SNTB1', 'Gene', (96, 101))	('high myopia', 'Phenotype', 'HP:0011003', (126, 137))	('VIPR2', 'Gene', '7434', (86, 91))	('high myopia', 'Disease', (126, 137))
114119	25097799	Another GWAS performed in a European population found that variants in the platelet-derived growth factor receptor alpha (PDGFRA) influence corneal curvature and corneal astigmatism.	('corneal curvature', 'Phenotype', 'HP:0100692', (140, 157))	('astigmatism', 'Phenotype', 'HP:0000483', (170, 181))	('influence', 'Reg', (130, 139))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('75', '105'))	('variants', 'Var', (59, 67))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (75, 120))	('corneal curvature', 'CPA', (140, 157))	('corneal astigmatism', 'Phenotype', 'HP:0025612', (162, 181))	('platelet-derived growth factor receptor alpha', 'Gene', (75, 120))	('PDGFRA', 'Gene', (122, 128))	('PDGFRA', 'Gene', '5156', (122, 128))	('corneal astigmatism', 'Disease', 'MESH:D001251', (162, 181))	('corneal astigmatism', 'Disease', (162, 181))
114123	25097799	Exome sequencing was also recently employed to find genes associated with myopia, which led to identification of mutations in LRPAP1, CCDC111, LEPREL1, and SCO2 that resulted in disease development.	('resulted in', 'Reg', (166, 177))	('LEPREL1', 'Gene', '55214', (143, 150))	('myopia', 'Phenotype', 'HP:0000545', (74, 80))	('SCO2', 'Gene', (156, 160))	('men', 'Species', '9606', (193, 196))	('LEPREL1', 'Gene', (143, 150))	('LRPAP1', 'Gene', (126, 132))	('mutations', 'Var', (113, 122))	('SCO2', 'Gene', '9997', (156, 160))	('myopia', 'Disease', (74, 80))	('LRPAP1', 'Gene', '4043', (126, 132))	('CCDC111', 'Gene', (134, 141))	('disease', 'Disease', (178, 185))	('CCDC111', 'Gene', '201973', (134, 141))	('myopia', 'Disease', 'MESH:D009216', (74, 80))
114128	25097799	The VKORC1 gene is a component of the vitamin K epoxide reductase complex, which is necessary for gamma carboxylation of clotting factors II, VII, IX, X, and proteins C and S. However, a larger replication study conducted in patients of Caucasian descent found no significant association between the VKORC1 -1639G>A polymorphism and risk for either central or branch RVO.	('patients', 'Species', '9606', (225, 233))	('polymorphism', 'Var', (316, 328))	('VKORC1', 'Gene', (4, 10))	('VKORC1', 'Gene', (300, 306))	('VKORC1', 'Gene', '79001', (4, 10))	('-1639G>A', 'Mutation', 'rs9923231', (307, 315))	('VKORC1', 'Gene', '79001', (300, 306))	('central or branch RVO', 'Disease', (349, 370))	('clotting', 'biological_process', 'GO:0050817', ('121', '129'))
114132	25097799	A variant (rs2194025) near the myocyte enhancer factor 2C (MEF2C) gene was significantly associated with retinal arteriolar caliber in this cohort and this finding was replicated in a second independent cohort of 3,939 European individuals.	('associated', 'Reg', (89, 99))	('myocyte enhancer factor 2C', 'Gene', '4208', (31, 57))	('rs2194025', 'Mutation', 'rs2194025', (11, 20))	('retinal arteriolar caliber', 'MPA', (105, 131))	('rs2194025', 'Var', (11, 20))	('myocyte enhancer factor 2C', 'Gene', (31, 57))	('retinal arteriolar caliber', 'Phenotype', 'HP:0008043', (105, 131))	('MEF2C', 'Gene', '4208', (59, 64))	('MEF2C', 'Gene', (59, 64))
114135	25097799	Prognosis is heavily influenced by chromosome 3 status: loss of one copy (monosomy 3) in the tumor is associated with metastatic disease, which carries a poor prognosis.	('metastatic disease', 'Disease', (118, 136))	('loss of', 'Var', (56, 63))	('associated', 'Reg', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('chromosome', 'cellular_component', 'GO:0005694', ('35', '45'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
114137	25097799	Loss of function mutations in the BAP1 gene have previously been shown to be associated with monosomy 3 and are therefore associated with a poorer prognosis.	('BAP1', 'Gene', (34, 38))	('monosomy 3', 'Disease', (93, 103))	('Loss of function', 'NegReg', (0, 16))	('BAP1', 'Gene', '8314', (34, 38))	('mutations', 'Var', (17, 26))
114138	25097799	Recently, whole-exome sequencing was utilized to identify other mutations associated with uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('uveal melanoma', 'Disease', 'MESH:C536494', (90, 104))	('uveal melanoma', 'Disease', (90, 104))	('mutations', 'Var', (64, 73))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('associated', 'Reg', (74, 84))
114140	25097799	In another study, all SF3B1 mutations identified in uveal melanomas with disomy 3 occurred exclusively at codon 625, leading to amino acid changes at this codon.	('uveal melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('uveal melanomas', 'Disease', 'MESH:C536494', (52, 67))	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))	('SF3B1', 'Gene', '23451', (22, 27))	('uveal melanomas', 'Phenotype', 'HP:0007716', (52, 67))	('occurred', 'Reg', (82, 90))	('amino acid changes', 'MPA', (128, 146))	('uveal melanomas', 'Disease', (52, 67))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('mutations', 'Var', (28, 37))	('SF3B1', 'Gene', (22, 27))
114141	25097799	The SF3B1 gene encodes subunit 1 of the splicing factor 3b complex; mutations of this gene in uveal melanoma leads to differential alternative splicing of protein coding genes (ABCC5, UQCC) and long noncoding RNAs (CRNDE).	('UQCC', 'Gene', (184, 188))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('UQCC', 'Gene', '55245', (184, 188))	('alternative splicing', 'MPA', (131, 151))	('SF3B1', 'Gene', (4, 9))	('uveal melanoma', 'Disease', (94, 108))	('CRNDE', 'Gene', (215, 220))	('CRNDE', 'Gene', '643911', (215, 220))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('SF3B1', 'Gene', '23451', (4, 9))	('ABCC5', 'Gene', (177, 182))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('mutations', 'Var', (68, 77))	('leads to', 'Reg', (109, 117))	('splicing', 'biological_process', 'GO:0045292', ('143', '151'))	('splicing', 'biological_process', 'GO:0045292', ('40', '48'))	('ABCC5', 'Gene', '10057', (177, 182))
114145	25097799	This finding suggests that the ocular microenvironment induces methylation and epigenetic downregulation of CXCR4 expression by tumors.	('CXCR4', 'Gene', (108, 113))	('methylation', 'MPA', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CXCR4', 'molecular_function', 'GO:0038147', ('108', '113'))	('methylation', 'biological_process', 'GO:0032259', ('63', '74'))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('epigenetic', 'Var', (79, 89))	('CXCR4', 'Gene', '7852', (108, 113))
114154	24982724	HIF1 activity promotes the production of a wide range of pro-angiogenic factors, including VEGF-A, and of immune system modifiers, such as MCP-1, TNF-alpha, each capable of attracting myeloid cells to hypoxic areas.	('MCP-1', 'Gene', (139, 144))	('VEGF-A', 'Gene', (91, 97))	('MCP-1', 'Gene', '17224', (139, 144))	('TNF-alpha', 'Gene', (146, 155))	('production', 'MPA', (27, 37))	('MCP', 'molecular_function', 'GO:0004298', ('139', '142'))	('HIF1', 'Gene', (0, 4))	('activity', 'Var', (5, 13))	('VEGF-A', 'Gene', '22339', (91, 97))	('TNF-alpha', 'Gene', '21926', (146, 155))
114342	34030647	The inclusion criteria were as follows: 1) diagnosed from 2010 to 2015; 2) pathologically confirmed UM; 3) the International Classification of Diseases for Oncology-3 (ICD-3) histology code (morphology code 8720-8790); 4) ICD-O-3 site code of C69.3 (choroid) and C69.4 (ciliary body and iris); 5) only one malignant primary tumor of UM; 6) patients with active follow up and age of 18 or more than 18.	('C69.4', 'Var', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumor', 'Disease', (324, 329))	('patients', 'Species', '9606', (340, 348))	('Oncology', 'Phenotype', 'HP:0002664', (156, 164))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
114427	33798262	UM is known to have driver mutations in GNAQ/11, CYSLTR2, and PLCB4, with subsequent mutations in BAP1 (associated with adverse prognosis), SF3B1 (associated with late metastasis), or EIF1AX (associated with good prognosis).	('BAP1', 'Gene', (98, 102))	('mutations', 'Var', (27, 36))	('GNAQ', 'Gene', (40, 44))	('SF3B1', 'Gene', (140, 145))	('associated', 'Reg', (147, 157))	('CYSLTR2', 'Gene', '57105', (49, 56))	('PLCB4', 'Gene', '5332', (62, 67))	('associated', 'Reg', (104, 114))	('CYSLTR2', 'Gene', (49, 56))	('mutations', 'Var', (85, 94))	('SF3B1', 'Gene', '23451', (140, 145))	('GNAQ', 'Gene', '2776', (40, 44))	('BAP1', 'Gene', '8314', (98, 102))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('PLCB4', 'Gene', (62, 67))	('EIF1AX', 'Gene', '1964', (184, 190))	('EIF1AX', 'Gene', (184, 190))
114428	33798262	CoM on the other hand resembles cutaneous melanoma and has driver mutations in BRAF, NRAS, Kit, TERT, or NF1.	('mutations', 'Var', (66, 75))	('NF1', 'Gene', (105, 108))	('TERT', 'Gene', (96, 100))	('NF1', 'Gene', '4763', (105, 108))	('Kit', 'Gene', (91, 94))	('NRAS', 'Gene', (85, 89))	('CoM', 'Phenotype', 'HP:0007716', (0, 3))	('TERT', 'Gene', '7015', (96, 100))	('cutaneous melanoma', 'Disease', (32, 50))	('Kit', 'Gene', '3815', (91, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (32, 50))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (32, 50))	('NRAS', 'Gene', '4893', (85, 89))	('BRAF', 'Gene', (79, 83))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
114434	33798262	In various cancers, including cutaneous melanoma, increased activity of the YAP/TAZ pathway has been related to worse survival, and inhibition of YAP/TAZ has been suggested as a potential new therapy.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('increased', 'PosReg', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('YAP/TAZ pathway', 'Pathway', (76, 91))	('activity', 'MPA', (60, 68))	('cutaneous melanoma', 'Disease', (30, 48))	('cancers', 'Disease', (11, 18))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (30, 48))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('inhibition', 'Var', (132, 142))
114440	33798262	Approximately 90% of UM harbor a GNAQ/11 mutation, which was found to activate the YAP/TAZ cascade.	('GNAQ', 'Gene', (33, 37))	('mutation', 'Var', (41, 49))	('GNAQ', 'Gene', '2776', (33, 37))	('activate', 'PosReg', (70, 78))	('YAP/TAZ', 'MPA', (83, 90))	('UM', 'Phenotype', 'HP:0007716', (21, 23))
114441	33798262	Inhibition of this pathway by shRNA or drugs led to decreased cell growth in vitro as well as tumor regression in mouse models carrying a GNAQ/11 mutation.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('Inhibition', 'NegReg', (0, 10))	('GNAQ', 'Gene', '2776', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('decreased', 'NegReg', (52, 61))	('tumor', 'Disease', (94, 99))	('mouse', 'Species', '10090', (114, 119))	('GNAQ', 'Gene', (138, 142))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))	('mutation', 'Var', (146, 154))	('cell growth', 'CPA', (62, 73))
114443	33798262	YAP1 expression was detected in cutaneous melanoma cell lines lacking a GNAQ/11 mutation (but harboring BRAF or NRAS mutations instead), and in human cutaneous melanoma tissue where a high expression was related to worse survival.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (150, 168))	('mutations', 'Var', (117, 126))	('YAP1', 'Gene', (0, 4))	('YAP1', 'Gene', '10413', (0, 4))	('human', 'Species', '9606', (144, 149))	('NRAS', 'Gene', '4893', (112, 116))	('GNAQ', 'Gene', '2776', (72, 76))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('lacking', 'NegReg', (62, 69))	('NRAS', 'Gene', (112, 116))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (32, 50))	('cutaneous melanoma', 'Disease', (32, 50))	('cutaneous melanoma', 'Disease', (150, 168))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (32, 50))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (150, 168))	('mutation', 'Var', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('GNAQ', 'Gene', (72, 76))
114446	33798262	This mechanism is poorly understood, however, and it is unknown if the YAP/TAZ pathway (activated by the early GNAQ/11 mutation) is altered by chromosome changes or other mutations, such as in BAP1, which is known to be related to adverse prognosis.	('YAP/TAZ pathway', 'Pathway', (71, 86))	('mutation', 'Var', (119, 127))	('BAP1', 'Gene', '8314', (193, 197))	('GNAQ', 'Gene', '2776', (111, 115))	('chromosome', 'cellular_component', 'GO:0005694', ('143', '153'))	('mutations', 'Var', (171, 180))	('BAP1', 'Gene', (193, 197))	('GNAQ', 'Gene', (111, 115))
114450	33798262	Next, we studied the effect of YAP1-inhibition using VP without light activation on multiple UM cell lines with different genetic profiles (including cell lines with and without BAP1 expression), and included CoM cell lines with either a BRAF or NRAS mutation as a control.	('BAP1', 'Gene', '8314', (178, 182))	('VP', 'Chemical', 'MESH:D000077362', (53, 55))	('BAP1', 'Gene', (178, 182))	('mutation', 'Var', (251, 259))	('YAP1', 'Gene', (31, 35))	('YAP1', 'Gene', '10413', (31, 35))	('CoM', 'Phenotype', 'HP:0007716', (209, 212))	('UM', 'Phenotype', 'HP:0007716', (93, 95))	('NRAS', 'Gene', (246, 250))	('NRAS', 'Gene', '4893', (246, 250))
114480	33798262	Antibodies were purchased from Cell Signaling Technology (Danvers, MA, USA): YAP (4912S), TEAD1 (12292S), and c-Myc (9402S).	('12292S', 'Var', (97, 103))	('c-Myc', 'Gene', '4609', (110, 115))	('4912S', 'Var', (82, 87))	('TEAD1', 'Gene', '7003', (90, 95))	('c-Myc', 'Gene', (110, 115))	('TEAD1', 'Gene', (90, 95))	('Signaling', 'biological_process', 'GO:0023052', ('36', '45'))
114488	33798262	As the YAP/TAZ pathway is activated by mutations in GNAQ/11, we examined the expression of mRNA in tumors with and without these mutations.	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('GNAQ', 'Gene', '2776', (52, 56))	('activated', 'PosReg', (26, 35))	('YAP/TAZ pathway', 'Pathway', (7, 22))	('mutations', 'Var', (39, 48))	('GNAQ', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (99, 105))
114489	33798262	In the TCGA dataset, tumors with either a GNAQ or GNA11 mutation (n = 72) did not differ in their expression of YAP1-related genes compared with tumors without these mutations (n = 6; see Table 1).	('YAP1', 'Gene', '10413', (112, 116))	('GNAQ', 'Gene', '2776', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('GNA11', 'Gene', '2767', (50, 55))	('GNA11', 'Gene', (50, 55))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('GNAQ', 'Gene', (42, 46))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('mutation', 'Var', (56, 64))	('YAP1', 'Gene', (112, 116))	('expression', 'MPA', (98, 108))
114490	33798262	In the Leiden dataset, the four tumors that lacked a GNAQ/11 mutation had a higher YAP1 expression, but a similar TEAD4 expression, than the tumors with a GNAQ/11 mutation (n = 60, P = 0.033 and P = 0.84, respectively; see Table 2); the interpretation of this finding is hampered, however, due to low numbers of cases lacking a GNAQ/11-mutation.	('lacked', 'NegReg', (44, 50))	('mutation', 'Var', (61, 69))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('GNAQ', 'Gene', '2776', (53, 57))	('tumors', 'Disease', (32, 38))	('expression', 'MPA', (88, 98))	('GNAQ', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('GNAQ', 'Gene', '2776', (155, 159))	('tumors', 'Disease', (141, 147))	('TEAD4', 'Gene', (114, 119))	('higher', 'PosReg', (76, 82))	('GNAQ', 'Gene', '2776', (328, 332))	('GNAQ', 'Gene', (155, 159))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('GNAQ', 'Gene', (328, 332))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('YAP1', 'Gene', '10413', (83, 87))	('TEAD4', 'Gene', '7004', (114, 119))	('YAP1', 'Gene', (83, 87))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))
114491	33798262	We then tested whether YAP1 activity relates to the genetic status of UM, such as monosomy 3 (M3)/BAP1-loss, or gain of chromosome 8q, two adverse prognostic factors.	('tested', 'Reg', (8, 14))	('BAP1', 'Gene', (98, 102))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('monosomy', 'Var', (82, 90))	('gain', 'Var', (112, 116))	('BAP1', 'Gene', '8314', (98, 102))	('YAP1', 'Gene', '10413', (23, 27))	('YAP1', 'Gene', (23, 27))	('chromosome', 'cellular_component', 'GO:0005694', ('120', '130'))
114499	33798262	First, we analyzed the inhibitory effect of VP treatment on BAP1-positive UM cell lines with a mutation in GNAQ or GNA11.	('GNA11', 'Gene', '2767', (115, 120))	('VP', 'Chemical', 'MESH:D000077362', (44, 46))	('GNAQ', 'Gene', '2776', (107, 111))	('BAP1', 'Gene', '8314', (60, 64))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('GNAQ', 'Gene', (107, 111))	('GNA11', 'Gene', (115, 120))	('BAP1', 'Gene', (60, 64))	('mutation', 'Var', (95, 103))
114502	33798262	We compared the results in the UM cell lines with the effect on cell lines with a BRAF or NRAS mutation (i.e.	('NRAS', 'Gene', (90, 94))	('UM', 'Phenotype', 'HP:0007716', (31, 33))	('NRAS', 'Gene', '4893', (90, 94))	('BRAF', 'Gene', (82, 86))	('mutation', 'Var', (95, 103))
114509	33798262	We included two recently developed UM cell lines with a GNAQ/11 mutation, which lack expression of BAP1 (i.e.	('expression', 'MPA', (85, 95))	('BAP1', 'Gene', (99, 103))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('mutation', 'Var', (64, 72))	('GNAQ', 'Gene', '2776', (56, 60))	('BAP1', 'Gene', '8314', (99, 103))	('GNAQ', 'Gene', (56, 60))
114522	33798262	It can be deduced that, in order to be susceptible to VP, cell lines need a certain amount of cell growth, and a GNAQ/11 mutation may lower the threshold for VP sensitivity.	('GNAQ', 'Gene', (113, 117))	('lower', 'NegReg', (134, 139))	('VP', 'Chemical', 'MESH:D000077362', (54, 56))	('VP', 'Chemical', 'MESH:D000077362', (158, 160))	('mutation', 'Var', (121, 129))	('GNAQ', 'Gene', '2776', (113, 117))	('cell growth', 'biological_process', 'GO:0016049', ('94', '105'))	('threshold for VP sensitivity', 'MPA', (144, 172))
114535	33798262	Our experiments showed that exposure to VP decreased cell viability in BAP1-positive UM cell lines harboring mutations in GNAQ/11, as has been reported before.	('VP', 'Chemical', 'MESH:D000077362', (40, 42))	('GNAQ', 'Gene', (122, 126))	('BAP1', 'Gene', '8314', (71, 75))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('mutations', 'Var', (109, 118))	('cell viability', 'CPA', (53, 67))	('BAP1', 'Gene', (71, 75))	('decreased', 'NegReg', (43, 52))	('GNAQ', 'Gene', '2776', (122, 126))
114536	33798262	A mutation in GNAQ/11 was no exclusive predictor of a response to VP, however, as we report on cell lines with a GNAQ/11 mutation without a clear response (MM28 and MP46), and a cell line lacking GNAQ/11 mutations that did demonstrate decreased survival (OCM3).	('GNAQ', 'Gene', '2776', (196, 200))	('GNAQ', 'Gene', (113, 117))	('GNAQ', 'Gene', '2776', (14, 18))	('GNAQ', 'Gene', (196, 200))	('GNAQ', 'Gene', (14, 18))	('mutation', 'Var', (121, 129))	('GNAQ', 'Gene', '2776', (113, 117))	('VP', 'Chemical', 'MESH:D000077362', (66, 68))
114541	33798262	We also studied cell lines lacking a mutation in GNAQ/11.	('mutation', 'Var', (37, 45))	('GNAQ', 'Gene', '2776', (49, 53))	('GNAQ', 'Gene', (49, 53))
114542	33798262	We identified no convincing effect of VP in the two CoM cell lines with either a BRAF or NRAS mutation (CRMM1 and CRMM2), whereas the cutaneous melanoma cell line OCM3 did show a response to VP.	('NRAS', 'Gene', '4893', (89, 93))	('VP', 'Chemical', 'MESH:D000077362', (191, 193))	('BRAF', 'Gene', (81, 85))	('VP', 'Chemical', 'MESH:D000077362', (38, 40))	('NRAS', 'Gene', (89, 93))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('cutaneous melanoma', 'Disease', (134, 152))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (134, 152))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (134, 152))	('mutation', 'Var', (94, 102))	('CoM', 'Phenotype', 'HP:0007716', (52, 55))
114566	33798262	Even so, knockdown of YAP and TAZ caused reduced expression of PD-L1 in cutaneous melanoma cell lines, which would theoretically make these cells more vulnerable to CD8+ T cell attack.	('reduced', 'NegReg', (41, 48))	('cutaneous melanoma', 'Disease', (72, 90))	('make', 'Reg', (129, 133))	('knockdown', 'Var', (9, 18))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (72, 90))	('expression', 'MPA', (49, 59))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (72, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('CD8', 'Gene', (165, 168))	('PD-L1', 'Gene', (63, 68))	('CD8', 'Gene', '925', (165, 168))	('PD-L1', 'Gene', '29126', (63, 68))
114574	33798262	YAP1 inhibition may be used as a cotreatment with both targeted and immunotherapy, to overcome mechanisms of resistance and escape.	('YAP1', 'Gene', (0, 4))	('inhibition', 'Var', (5, 15))	('YAP1', 'Gene', '10413', (0, 4))
114599	33050649	Here, we showed that as opposed to NCM-EVs, UM-EVs increased the proliferation of target SOM cells such as BRCA1-deficient fibroblasts (Fibro-BKO) and induced their malignant transformation.	('proliferation', 'CPA', (65, 78))	('malignant transformation', 'CPA', (165, 189))	('induced', 'PosReg', (151, 158))	('increased', 'PosReg', (51, 60))	('UM-EVs', 'Chemical', '-', (44, 50))	('BRCA1-deficient', 'Disease', (107, 122))	('UM-EVs', 'Var', (44, 50))	('NCM-EVs', 'Chemical', '-', (35, 42))	('BRCA1-deficient', 'Disease', 'OMIM:604370', (107, 122))
114607	33050649	Of note, EVs derived from donors 2G.PPccF1968Y and 2G.PPXG1981Y (NCM cells) were used for NanoSight, transmission electron microscopy (TEM), and Western blots.	('NCM', 'Chemical', '-', (65, 68))	('2G.PPXG1981Y', 'Var', (51, 63))	('2G.PPccF1968Y', 'Var', (33, 46))	('TEM', 'cellular_component', 'GO:0097197', ('135', '138'))
114608	33050649	EVs derived from donors 2G.PPwC1963Y and 2G.PPXG1981Y (NCM cells) were used for mice experiments (Table S1B).	('2G.PPwC1963Y', 'Var', (24, 36))	('NCM', 'Chemical', '-', (55, 58))	('2G.PPXG1981Y', 'Var', (41, 53))	('mice', 'Species', '10090', (80, 84))
114626	33050649	EVs derived from NCM (2G.PPccF68Y) and UM cells (MEL270 and OMM2.5) were incubated with Fibro-BKO for 12 h and 24 h to analyze cell migration and invasion, respectively (Figure 3C-F).	('NCM', 'Chemical', '-', (17, 20))	('cell migration', 'CPA', (127, 141))	('2G.PPccF68Y', 'Var', (22, 33))	('cell migration', 'biological_process', 'GO:0016477', ('127', '141'))	('invasion', 'CPA', (146, 154))
114627	33050649	Fibro-BKO cells treated with UM-EVs exhibited higher migration and invasion compared to Fibro-BKO cells treated with NCM-EVs or only Phosphate Buffer Saline (PBS, vehicle).	('UM-EVs', 'Var', (29, 35))	('higher', 'PosReg', (46, 52))	('invasion', 'CPA', (67, 75))	('PBS', 'Chemical', '-', (158, 161))	('Phosphate Buffer Saline', 'Chemical', '-', (133, 156))	('migration', 'CPA', (53, 62))	('NCM-EVs', 'Chemical', '-', (117, 124))	('UM-EVs', 'Chemical', '-', (29, 35))
114630	33050649	Overall, these results indicate that UM-EVs enhance the proliferation, migration and invasion capabilities of Fibro-BKO cells compared to control groups (NCM-EVs or PBS).	('UM-EVs', 'Chemical', '-', (37, 43))	('UM-EVs', 'Var', (37, 43))	('invasion capabilities of Fibro-BKO cells', 'CPA', (85, 125))	('proliferation', 'CPA', (56, 69))	('migration', 'CPA', (71, 80))	('NCM-EVs or PBS', 'Disease', (154, 168))	('enhance', 'PosReg', (44, 51))	('NCM-EVs or PBS', 'Disease', 'MESH:D011535', (154, 168))
114632	33050649	Furthermore, we have previously shown that cancer EVs carrying mutated DNA and RNA induced malignant transformation of Fibro-BKO.	('mutated', 'Var', (63, 70))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('cancer', 'Disease', (43, 49))	('malignant transformation', 'CPA', (91, 115))	('RNA', 'cellular_component', 'GO:0005562', ('79', '82'))	('RNA', 'Gene', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('DNA', 'Gene', (71, 74))	('induced', 'Reg', (83, 90))
114666	33050649	Our analyses identified 1630 proteins of which 676 (42%) were shared, while 868 (53%) and 86 (5%) were exclusively expressed in MEL270 UM-EVs and OMM2.5 UM-EVs, respectively (Figure 8A).	('MEL270 UM-EVs', 'Var', (128, 141))	('UM-EVs', 'Chemical', '-', (135, 141))	('proteins', 'Protein', (29, 37))	('UM-EVs', 'Chemical', '-', (153, 159))
114668	33050649	Of the upregulated proteins, 116 were exclusively present in MEL270 UM-EVs (Table S3).	('MEL270', 'Var', (61, 67))	('UM-EVs', 'Chemical', '-', (68, 74))	('upregulated', 'PosReg', (7, 18))
114670	33050649	When referring to biological processes, the proteins upregulated in MEL270 UM-EVs clustered into leukocyte migration, small GTPase mediated signal transduction, integrin and tumor necrosis factor mediated signaling pathways, and MAPK cascade.	('tumor necrosis', 'Disease', (174, 188))	('small GTPase mediated signal transduction', 'biological_process', 'GO:0007264', ('118', '159'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('174', '195'))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('MAPK', 'molecular_function', 'GO:0004707', ('229', '233'))	('signaling', 'biological_process', 'GO:0023052', ('205', '214'))	('necrosis', 'biological_process', 'GO:0008219', ('180', '188'))	('leukocyte migration', 'biological_process', 'GO:0050900', ('97', '116'))	('UM-EVs', 'Chemical', '-', (75, 81))	('leukocyte migration', 'CPA', (97, 116))	('MAPK cascade', 'biological_process', 'GO:0000165', ('229', '241'))	('necrosis', 'biological_process', 'GO:0008220', ('180', '188'))	('small GTPase', 'Protein', (118, 130))	('necrosis', 'biological_process', 'GO:0070265', ('180', '188'))	('necrosis', 'biological_process', 'GO:0019835', ('180', '188'))	('MEL270', 'Var', (68, 74))	('tumor necrosis', 'Disease', 'MESH:D009336', (174, 188))	('necrosis', 'biological_process', 'GO:0001906', ('180', '188'))	('upregulated', 'PosReg', (53, 64))
114685	33050649	Recently, we provided evidence that cancer EVs actively transfer mutated cancer genes to target cells as well as a bulk of coding and non-coding RNAs acting as modulators of essential cellular pathways that impact cancer growth and progression.	('cancer', 'Disease', (73, 79))	('impact', 'Reg', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('mutated', 'Var', (65, 72))
114696	33050649	HSP90 is a molecular chaperone reported to be of crucial importance in cancer cell growth and survival owing to its involvement in promoting the MAPK and P13K/AKT pathways.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('P13K', 'Var', (154, 158))	('HSP90', 'Gene', (0, 5))	('AKT', 'Gene', (159, 162))	('HSP90', 'Gene', '3320', (0, 5))	('cancer', 'Disease', (71, 77))	('MAPK', 'molecular_function', 'GO:0004707', ('145', '149'))	('cell growth', 'biological_process', 'GO:0016049', ('78', '89'))	('promoting', 'PosReg', (131, 140))	('P13K', 'SUBSTITUTION', 'None', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('AKT', 'Gene', '207', (159, 162))
114699	33050649	Other proteins involved in the process of metastasis were also identified in a set of UM-EVs (i.e., hepatocyte growth factor receptor tyrosine kinase (MET, in MP41 UM-EVs and MP46 UM-EVs), tenascin C (TNC, in MEL270 UM-EVs and MEL285 UM-EVs), ephrin-B2 (EFNB2, in MEL285 UM-EVs)).	('tenascin C', 'Gene', (189, 199))	('EFNB2', 'Gene', '1948', (254, 259))	('ephrin-B2', 'Gene', '1948', (243, 252))	('ephrin', 'molecular_function', 'GO:0005106', ('243', '249'))	('UM-EVs', 'Chemical', '-', (86, 92))	('UM-EVs', 'Chemical', '-', (180, 186))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('100', '124'))	('MET', 'Gene', (151, 154))	('tenascin C', 'cellular_component', 'GO:0090733', ('189', '199'))	('MP46', 'Var', (175, 179))	('UM-EVs', 'Chemical', '-', (164, 170))	('EFNB2', 'Gene', (254, 259))	('UM-EVs', 'Chemical', '-', (234, 240))	('TNC', 'Gene', (201, 204))	('ephrin', 'molecular_function', 'GO:0046875', ('243', '249'))	('MET', 'Gene', '79811', (151, 154))	('tenascin C', 'Gene', '3371', (189, 199))	('TNC', 'Gene', '3371', (201, 204))	('MP41', 'Var', (159, 163))	('UM-EVs', 'Chemical', '-', (271, 277))	('UM-EVs', 'Chemical', '-', (216, 222))	('ephrin-B2', 'Gene', (243, 252))
114703	33050649	Similarly, HSPB1 was also increased in EVs derived from MEL270.	('MEL270', 'Var', (56, 62))	('HSPB1', 'Gene', (11, 16))	('increased', 'PosReg', (26, 35))	('HSPB1', 'Gene', '3315', (11, 16))
114752	33050649	Cells (20,000) were plated in four-well chamber slides for 24 h, fixed with 4% paraformaldehyde for 30 min, permeabilized with 0.1% Triton X for 15 min, and incubated in blocking buffer (1% BSA in PBS) for 1 h. Primary antibodies against MLANA (MelanA) (TA801623), Vimentin (ab92547), HMB45 (sc-59305), S100 (ab4066), cytokeratin 18 (ab32118), cytokeratin 8 (ab59400) were added to cells at 1:1000 in blocking buffer and incubated overnight at 4 C. Slides were washed 5 times in PBS, and cells were counterstained for 1 h with fluorophore-conjugated secondary antibodies (1:1000 in blocking buffer).	('Vimentin', 'Gene', (265, 273))	('cytokeratin 8', 'Gene', (344, 357))	('TA801623', 'Var', (254, 262))	('cytokeratin 18', 'Gene', (318, 332))	('PBS', 'Chemical', '-', (197, 200))	('PBS', 'Chemical', '-', (479, 482))	('Vimentin', 'Gene', '7431', (265, 273))	('Vimentin', 'cellular_component', 'GO:0045098', ('265', '273'))	('cytokeratin 8', 'Gene', '3856', (344, 357))	('cytokeratin 18', 'Gene', '3875', (318, 332))	('S100', 'Gene', (303, 307))	('Vimentin', 'cellular_component', 'GO:0045099', ('265', '273'))	('S100', 'Gene', '6271', (303, 307))
114788	33050649	Figure S8: Measuring size and concentration of EVs derived from NCM (blue), MEL270 UM-EVs (red) and OMM2.5 UM-EVs (black).	('OMM2.5 UM-EVs', 'Var', (100, 113))	('MEL270 UM-EVs', 'Var', (76, 89))	('UM-EVs', 'Chemical', '-', (107, 113))	('UM-EVs', 'Chemical', '-', (83, 89))	('NCM', 'Chemical', '-', (64, 67))
114802	31336704	The anti-CD3 domain recruits CD3+ T cells (and, indirectly, other immune cells), redirecting these to the melanoma cells.	('redirecting', 'Reg', (81, 92))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('anti-CD3 domain', 'Var', (4, 19))	('melanoma', 'Disease', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
114814	31336704	Approximately 80% of UMs arise from mutations in the G alpha pathway (via mutually exclusive mutations in GNAQ, GNA11, PLCB4 or CYSLTR2).	('PLCB4', 'Gene', '5332', (119, 124))	('mutations', 'Var', (93, 102))	('GNA11', 'Gene', (112, 117))	('UMs', 'Disease', (21, 24))	('arise from', 'Reg', (25, 35))	('CYSLTR2', 'Gene', '57105', (128, 135))	('GNA11', 'Gene', '2767', (112, 117))	('GNAQ', 'Gene', (106, 110))	('mutations', 'Var', (36, 45))	('CYSLTR2', 'Gene', (128, 135))	('PLCB4', 'Gene', (119, 124))	('G alpha pathway', 'Pathway', (53, 68))	('UM', 'Phenotype', 'HP:0007716', (21, 23))	('GNAQ', 'Gene', '2776', (106, 110))
114815	31336704	This is in contrast to cutaneous melanoma (CM), the most common form of melanoma, which commonly harbours BRAF and NRAS mutations.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('NRAS', 'Gene', (115, 119))	('melanoma', 'Disease', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('BRAF', 'Gene', '673', (106, 110))	('NRAS', 'Gene', '4893', (115, 119))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('BRAF', 'Gene', (106, 110))	('cutaneous melanoma', 'Disease', (23, 41))	('mutations', 'Var', (120, 129))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (23, 41))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (23, 41))	('CM', 'Phenotype', 'HP:0012056', (43, 45))
114823	31336704	Metastatic disease develops almost exclusively in patients who have tumours that show chromosome 3 deletion, BAP1 loss or a class 2 gene expression profile (as defined by expression of 12 genes that influence the metastatic spread).	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('develops', 'Reg', (19, 27))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('patients', 'Species', '9606', (50, 58))	('loss', 'NegReg', (114, 118))	('gene expression', 'biological_process', 'GO:0010467', ('132', '147'))	('BAP1', 'Gene', '8314', (109, 113))	('tumours', 'Disease', 'MESH:D009369', (68, 75))	('chromosome', 'cellular_component', 'GO:0005694', ('86', '96'))	('tumours', 'Disease', (68, 75))	('deletion', 'Var', (99, 107))	('BAP1', 'Gene', (109, 113))	('Metastatic disease', 'Disease', (0, 18))	('chromosome', 'Gene', (86, 96))
114830	31336704	Cancerous mutations can generate non-self neoantigens (non-native proteins), so that the cancer cells might be recognised and killed by cytotoxic T cells; however, T cell immunity to cancer neoantigens is frequently limited.	('cancer', 'Disease', (183, 189))	('Cancerous', 'Disease', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('Cancerous', 'Disease', 'MESH:D009369', (0, 9))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', (89, 95))	('mutations', 'Var', (10, 19))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
114875	31336704	By mutating the hypervariable regions of the TCR, affinity to target is increased 106-fold (resulting Kd in the picomolar range), without increasing cross-reactivity.	('TCR', 'Gene', (45, 48))	('increased', 'PosReg', (72, 81))	('affinity', 'MPA', (50, 58))	('hypervariable', 'Protein', (16, 29))	('TCR', 'biological_process', 'GO:0006283', ('45', '48'))	('TCR', 'Gene', '6962', (45, 48))	('TCR', 'cellular_component', 'GO:0042101', ('45', '48'))	('mutating', 'Var', (3, 11))
114950	31323802	In 63 (36%) patients, mutation analysis was performed, showing a GNA11 mutation in 28.6% and a GNAQ mutation in 49.2% of the analyzed patients.	('patients', 'Species', '9606', (12, 20))	('mutation', 'Var', (71, 79))	('GNAQ', 'Gene', (95, 99))	('patients', 'Species', '9606', (134, 142))	('GNA11', 'Gene', '2767', (65, 70))	('GNA11', 'Gene', (65, 70))	('GNAQ', 'Gene', '2776', (95, 99))
114968	31323802	Unlike cutaneous melanoma, uveal melanoma is not characterised by frequent BRAF or NRAS mutations, so that advances in targeted therapy for cutaneous melanoma are not applicable to metastatic uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('mutations', 'Var', (88, 97))	('uveal melanoma', 'Disease', (27, 41))	('cutaneous melanoma', 'Disease', (7, 25))	('uveal melanoma', 'Disease', 'MESH:C536494', (27, 41))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (7, 25))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (7, 25))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('cutaneous melanoma', 'Disease', (140, 158))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (140, 158))	('uveal melanoma', 'Disease', 'MESH:C536494', (192, 206))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (140, 158))	('uveal melanoma', 'Phenotype', 'HP:0007716', (27, 41))	('NRAS', 'Gene', '4893', (83, 87))	('uveal melanoma', 'Disease', (192, 206))	('uveal melanoma', 'Phenotype', 'HP:0007716', (192, 206))	('BRAF', 'Gene', '673', (75, 79))	('BRAF', 'Gene', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('NRAS', 'Gene', (83, 87))
114969	31323802	Early activating mutations in GNAQ or GNA11 are present in about 80% of primary uveal melanomas.	('primary uveal melanoma', 'Disease', (72, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('uveal melanomas', 'Disease', 'MESH:C536494', (80, 95))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (72, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('activating', 'PosReg', (6, 16))	('GNAQ', 'Gene', (30, 34))	('uveal melanomas', 'Disease', (80, 95))	('uveal melanomas', 'Phenotype', 'HP:0007716', (80, 95))	('GNA11', 'Gene', '2767', (38, 43))	('GNA11', 'Gene', (38, 43))	('mutations', 'Var', (17, 26))	('GNAQ', 'Gene', '2776', (30, 34))
114970	31323802	Inactivating somatic mutations are present in the gene encoding BRCA1-associated protein 1 (BAP1) in more than 80% of metastasising tumors, implicating a role in the progression of uveal melanoma.	('BRCA1-associated protein 1', 'Gene', (64, 90))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Inactivating', 'Var', (0, 12))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('BAP1', 'Gene', '8314', (92, 96))	('uveal melanoma', 'Phenotype', 'HP:0007716', (181, 195))	('uveal melanoma', 'Disease', 'MESH:C536494', (181, 195))	('tumors', 'Disease', (132, 138))	('BRCA1-associated protein 1', 'Gene', '8314', (64, 90))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('uveal melanoma', 'Disease', (181, 195))	('BAP1', 'Gene', (92, 96))
114971	31323802	Mutations in SF3B1 and EIF1AX in primary uveal melanoma are associated with a relatively good prognosis.	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('SF3B1', 'Gene', (13, 18))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (33, 55))	('primary uveal melanoma', 'Disease', (33, 55))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('Mutations', 'Var', (0, 9))	('EIF1AX', 'Gene', (23, 29))	('SF3B1', 'Gene', '23451', (13, 18))	('EIF1AX', 'Gene', '1964', (23, 29))
114985	31323802	Molecular analysis of the activating mutation in the GNAQ or GNA11 genes was performed in 63 patients (36%) (Figure 3).	('activating', 'PosReg', (26, 36))	('GNAQ', 'Gene', (53, 57))	('mutation', 'Var', (37, 45))	('GNA11', 'Gene', '2767', (61, 66))	('GNA11', 'Gene', (61, 66))	('GNAQ', 'Gene', '2776', (53, 57))	('patients', 'Species', '9606', (93, 101))
114986	31323802	In 31 of these 63 (49.2%) patients a mutation in the GNAQ was discovered and in 18 patients (28.6%) a GNA11 mutation was confirmed.	('GNAQ', 'Gene', (53, 57))	('mutation', 'Var', (37, 45))	('GNA11', 'Gene', (102, 107))	('patients', 'Species', '9606', (26, 34))	('GNA11', 'Gene', '2767', (102, 107))	('patients', 'Species', '9606', (83, 91))	('GNAQ', 'Gene', '2776', (53, 57))
114987	31323802	These results are consistent with the known literature describing most primary uveal melanoma having a GNAQ or GNA11 mutation.	('GNAQ', 'Gene', '2776', (103, 107))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (71, 93))	('primary uveal melanoma', 'Disease', (71, 93))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('mutation', 'Var', (117, 125))	('GNAQ', 'Gene', (103, 107))	('GNA11', 'Gene', '2767', (111, 116))	('GNA11', 'Gene', (111, 116))
114992	31323802	All patients receiving a targeted drug participated in a clinical trial; for example, in the NCT01430416 trial (phase 1 trial with AEB071), NCT01801358 trial (phase 1b/II study with AEB071 + MEK162), NCT01974752 trial (phase 3 trial with selumetinib, or NCT02601378 (phase 1 trial with LXS196).	('NCT01801358', 'Gene', (140, 151))	('selumetinib', 'Chemical', 'MESH:C517975', (238, 249))	('NCT01974752', 'Var', (200, 211))	('patients', 'Species', '9606', (4, 12))	('LXS196', 'Chemical', '-', (286, 292))	('participated', 'Reg', (39, 51))	('NCT01430416', 'Gene', (93, 104))
115029	31323802	Another registration flaw was detected in the documentation of the molecular analysis, reporting a GNAQ and GNA11 mutation in 6.4% of the analysed patients.	('GNA11', 'Gene', '2767', (108, 113))	('GNAQ', 'Gene', (99, 103))	('patients', 'Species', '9606', (147, 155))	('mutation', 'Var', (114, 122))	('GNAQ', 'Gene', '2776', (99, 103))	('GNA11', 'Gene', (108, 113))
115099	29942182	The use of Iodine-125 COMs plaque therapy at the inspection of implementation of plaque therapy in the developing countries can lead to eye salvage in more than 90% of cases, and reserves functional vision in more than 50% of cases.	('eye salvage', 'CPA', (136, 147))	('Iodine-125', 'Chemical', 'MESH:C000614960', (11, 21))	('vision', 'biological_process', 'GO:0007601', ('199', '205'))	('Iodine-125', 'Var', (11, 21))	('lead to', 'Reg', (128, 135))	('functional vision', 'CPA', (188, 205))
115167	29532607	Because of its important roles in normal development and homeostasis, abnormal regulation of this pathway has been shown to lead to pathological outcomes such as tissue overgrowth, tumor formation and abnormal organogenesis, including ocular-specific disorders.	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('formation', 'biological_process', 'GO:0009058', ('187', '196'))	('homeostasis', 'biological_process', 'GO:0042592', ('57', '68'))	('ocular-specific disorders', 'Disease', (235, 260))	('tissue overgrowth', 'CPA', (162, 179))	('organogenesis', 'biological_process', 'GO:0048513', ('210', '223'))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('regulation', 'biological_process', 'GO:0065007', ('79', '89'))	('abnormal regulation', 'Var', (70, 89))	('lead to', 'Reg', (124, 131))	('overgrowth', 'Phenotype', 'HP:0001548', (169, 179))	('organogenesis', 'CPA', (210, 223))
115171	29532607	The Lats1/2 kinases phosphorylate Yap; this phosphorylation sequesters Yap in the cytoplasm, which prevents nuclear translocation and instead signals its proteasomal degradation.	('degradation', 'biological_process', 'GO:0009056', ('166', '177'))	('phosphorylation', 'biological_process', 'GO:0016310', ('44', '59'))	('signals', 'Reg', (142, 149))	('Yap', 'Var', (71, 74))	('soma', 'Disease', (160, 164))	('prevents', 'NegReg', (99, 107))	('soma', 'Disease', 'None', (160, 164))	('nuclear translocation', 'MPA', (108, 129))	('cytoplasm', 'cellular_component', 'GO:0005737', ('82', '91'))
115173	29532607	Binding to Tead causes transcription of target genes responsible for cellular proliferation and inhibition of cellular apoptosis, among them cyclins, inhibitors of apoptosis (IAP), and connective tissue growth factor (Ctgf).	('transcription', 'biological_process', 'GO:0006351', ('23', '36'))	('connective tissue growth factor', 'Gene', (185, 216))	('cyclins', 'Protein', (141, 148))	('transcription', 'MPA', (23, 36))	('connective tissue growth factor', 'Gene', '14219', (185, 216))	('Ctgf', 'Gene', '14219', (218, 222))	('Tead', 'Gene', (11, 15))	('apoptosis', 'biological_process', 'GO:0097194', ('119', '128'))	('apoptosis', 'biological_process', 'GO:0006915', ('164', '173'))	('Binding', 'Var', (0, 7))	('apoptosis', 'biological_process', 'GO:0006915', ('119', '128'))	('apoptosis', 'biological_process', 'GO:0097194', ('164', '173'))	('cellular apoptosis', 'CPA', (110, 128))	('inhibition', 'NegReg', (96, 106))	('Ctgf', 'Gene', (218, 222))	('causes', 'Reg', (16, 22))
115183	29532607	Perturbed regulation of the Hippo-Yap pathway can contribute to pathological tissue overgrowth and tumor progression, which result in unchecked proliferation and evasion of apoptosis, two major aspects of cancer development.	('tumor', 'Disease', (99, 104))	('unchecked', 'MPA', (134, 143))	('evasion', 'MPA', (162, 169))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('regulation', 'MPA', (10, 20))	('contribute', 'Reg', (50, 60))	('apoptosis', 'CPA', (173, 182))	('regulation', 'biological_process', 'GO:0065007', ('10', '20'))	('cancer', 'Disease', (205, 211))	('Hippo-Yap', 'Gene', (28, 37))	('Perturbed', 'Var', (0, 9))	('pathological tissue overgrowth', 'CPA', (64, 94))	('apoptosis', 'biological_process', 'GO:0006915', ('173', '182'))	('apoptosis', 'biological_process', 'GO:0097194', ('173', '182'))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('overgrowth', 'Phenotype', 'HP:0001548', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
115185	29532607	Abnormal regulation of the Hippo-Yap signaling pathway may also be associated with diseases other than cancer, including ocular-specific disorders such as ocular colobomas, Sveinsson chorioretinal atrophy (SCRA; OMIM #108985), and retinal degeneration.	('ocular coloboma', 'Phenotype', 'HP:0000589', (155, 170))	('signaling pathway', 'biological_process', 'GO:0007165', ('37', '54'))	('ocular colobomas', 'Disease', 'MESH:D003103', (155, 171))	('Sveinsson chorioretinal atrophy', 'Disease', (173, 204))	('retinal degeneration', 'Disease', 'MESH:D012162', (231, 251))	('retinal degeneration', 'Disease', (231, 251))	('retinal degeneration', 'Phenotype', 'HP:0000546', (231, 251))	('cancer', 'Disease', (103, 109))	('Sveinsson chorioretinal atrophy', 'Disease', 'MESH:C566236', (173, 204))	('ocular colobomas', 'Disease', (155, 171))	('ocular-specific disorders', 'Disease', (121, 146))	('chorioretinal atrophy', 'Phenotype', 'HP:0000533', (183, 204))	('regulation', 'biological_process', 'GO:0065007', ('9', '19'))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Abnormal', 'Var', (0, 8))	('associated', 'Reg', (67, 77))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('Hippo-Yap signaling pathway', 'Pathway', (27, 54))	('ocular colobomas', 'Phenotype', 'HP:0000589', (155, 171))	('coloboma', 'Phenotype', 'HP:0000589', (162, 170))
115190	29532607	The second is by phosphorylation at Ser 127, which facilitates Yap's interaction and stabilization with protein 14-3-3 that sequesters it in the cytoplasm.	('phosphorylation', 'biological_process', 'GO:0016310', ('17', '32'))	('Yap', 'Gene', (63, 66))	('protein', 'Protein', (104, 111))	('Ser', 'cellular_component', 'GO:0005790', ('36', '39'))	('facilitates', 'PosReg', (51, 62))	('interaction', 'Interaction', (69, 80))	('stabilization', 'MPA', (85, 98))	('phosphorylation', 'Var', (17, 32))	('Ser', 'Chemical', 'MESH:D012694', (36, 39))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('Ser 127', 'Var', (36, 43))	('cytoplasm', 'cellular_component', 'GO:0005737', ('145', '154'))
115205	29532607	Intriguingly, a novel missense mutation in a conserved amino acid in the C-terminal domain of the Tead1, putative Yap binding region, has been proposed to cause an ocular disorder, SCRA.	('Tead1', 'Gene', (98, 103))	('ocular disorder', 'Disease', 'MESH:D005128', (164, 179))	('ocular disorder', 'Phenotype', 'HP:0000478', (164, 179))	('SCRA', 'Disease', (181, 185))	('ocular disorder', 'Disease', (164, 179))	('cause', 'Reg', (155, 160))	('missense mutation in', 'Var', (22, 42))	('binding', 'molecular_function', 'GO:0005488', ('118', '125'))
115206	29532607	Overexpression in the optic vesicle of dominant negative Tead1a, which is incapable of binding to Yap, induced RPE loss in zebrafish, similar to that in human SCRA patients with Tead1 mutation.	('zebrafish', 'Species', '7955', (123, 132))	('binding', 'molecular_function', 'GO:0005488', ('87', '94'))	('vesicle', 'cellular_component', 'GO:0031982', ('28', '35'))	('RPE loss', 'Disease', (111, 119))	('dominant negative', 'Var', (39, 56))	('RPE loss', 'Disease', 'MESH:D015431', (111, 119))	('Tead1a', 'Gene', (57, 63))	('human', 'Species', '9606', (153, 158))	('patients', 'Species', '9606', (164, 172))	('Tead1a', 'Gene', '405773', (57, 63))
115208	29532607	Since Yap partners with multiple transcriptional factors, including Tead, Runx1/2 and p73, the Tead mutant phenotype may represent a subset of that of Yap mutant.	('p73', 'Gene', (86, 89))	('mutant', 'Var', (100, 106))	('Runx1/2', 'Gene', '12394;12393', (74, 81))	('p73', 'Gene', '22062', (86, 89))	('Runx1/2', 'Gene', (74, 81))
115214	29532607	Moreover, cells transfected with both Yap and Taz siRNAs exhibited a larger reduction in proliferation, migration, and invasion than cells transfected with either Yap or Taz siRNA alone, which highlighted the potential synergy between Yap and Taz in growth and spread of CRC cells.	('proliferation', 'CPA', (89, 102))	('reduction', 'NegReg', (76, 85))	('CRC', 'Disease', 'MESH:D015179', (271, 274))	('invasion', 'CPA', (119, 127))	('migration', 'CPA', (104, 113))	('spread', 'CPA', (261, 267))	('Taz siRNAs', 'Var', (46, 56))	('Yap', 'Var', (38, 41))	('CRC', 'Disease', (271, 274))
115217	29532607	In addition, whereas deletion of both Yap and Taz in mouse epicardium resulted in cardiomyopathy, impaired coronary vasculature development, and lethality, Yap compensation produced viable mice following removal of Taz alone.	('coronary vasculature development', 'CPA', (107, 139))	('Yap', 'Gene', (38, 41))	('cardiomyopathy', 'Disease', (82, 96))	('lethality', 'CPA', (145, 154))	('mice', 'Species', '10090', (189, 193))	('Taz', 'Gene', (46, 49))	('coronary vasculature development', 'biological_process', 'GO:0060976', ('107', '139'))	('deletion', 'Var', (21, 29))	('impaired', 'NegReg', (98, 106))	('resulted in', 'Reg', (70, 81))	('cardiomyopathy', 'Disease', 'MESH:D009202', (82, 96))	('mouse', 'Species', '10090', (53, 58))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (82, 96))
115218	29532607	Studies of ocular development in zebrafish provide further evidence of the compensatory interaction: loss of RPE was amplified in Yap mutant embryos when a Taz allele was also mutated.	('Yap', 'Gene', (130, 133))	('loss', 'NegReg', (101, 105))	('amplified', 'PosReg', (117, 126))	('zebrafish', 'Species', '7955', (33, 42))	('ocular development', 'CPA', (11, 29))	('mutant', 'Var', (134, 140))	('RPE', 'Gene', (109, 112))
115222	29532607	Ablation of Yap in early primordial retinal tissue led to defective retinal and RPE laminal organization, destabilization of apical complex proteins in the retina, increased apoptosis of retinal cells, mildly compromised RPC proliferation, altered cell cycle progression, rosette formation and, ultimately, retinal degeneration.	('destabilization', 'NegReg', (106, 121))	('altered', 'Reg', (240, 247))	('apoptosis', 'CPA', (174, 183))	('defective', 'NegReg', (58, 67))	('retinal and', 'CPA', (68, 79))	('RPC proliferation', 'CPA', (221, 238))	('increased', 'PosReg', (164, 173))	('apical complex proteins', 'Protein', (125, 148))	('apoptosis', 'biological_process', 'GO:0097194', ('174', '183'))	('cell cycle progression', 'CPA', (248, 270))	('apoptosis', 'biological_process', 'GO:0006915', ('174', '183'))	('retinal degeneration', 'Disease', 'MESH:D012162', (307, 327))	('retinal degeneration', 'Disease', (307, 327))	('Ablation', 'Var', (0, 8))	('Yap', 'Gene', (12, 15))	('rosette formation', 'CPA', (272, 289))	('retinal degeneration', 'Phenotype', 'HP:0000546', (307, 327))	('compromised', 'NegReg', (209, 220))	('cell cycle', 'biological_process', 'GO:0007049', ('248', '258'))	('formation', 'biological_process', 'GO:0009058', ('280', '289'))	('rosette', 'Phenotype', 'HP:0031925', (272, 279))	('apical complex', 'cellular_component', 'GO:0020007', ('125', '139'))
115223	29532607	Yap's essential function in RPE was similarly documented in zebrafish in which double mutants of Yap and Taz showed agenesis of RPE in addition to the coloboma phenotype.	('zebrafish', 'Species', '7955', (60, 69))	('RPE', 'MPA', (128, 131))	('double mutants', 'Var', (79, 93))	('Taz', 'Gene', (105, 108))	('Yap', 'Gene', (97, 100))	('coloboma', 'Disease', 'MESH:D003103', (151, 159))	('agenesis', 'NegReg', (116, 124))	('coloboma', 'Disease', (151, 159))	('coloboma', 'Phenotype', 'HP:0000589', (151, 159))
115231	29532607	In addition, a CKO of Yap in the developing mouse lens reduced the lens epithelial progenitor cell (LEC) pool, which was partially due to increased apoptosis of LECs.	('increased', 'PosReg', (138, 147))	('apoptosis', 'biological_process', 'GO:0097194', ('148', '157'))	('apoptosis', 'biological_process', 'GO:0006915', ('148', '157'))	('reduced', 'NegReg', (55, 62))	('CKO', 'Var', (15, 18))	('apoptosis', 'CPA', (148, 157))	('mouse', 'Species', '10090', (44, 49))
115237	29532607	Intriguingly, in mouse Yap mutant eyes, RPE, normally a cuboidal epithelial sheet consisting of a single layer, transdifferentiates into multilayered pseudostratified epithelial cells that express retinal markers, including Chx10 and Tubulin beta III, rather than the RPE markers Ezrin and Mitf, as in WT.	('Mitf', 'Gene', '17342', (290, 294))	('mouse', 'Species', '10090', (17, 22))	('mutant', 'Var', (27, 33))	('Mitf', 'Gene', (290, 294))	('Chx10', 'Gene', '12677', (224, 229))	('Tubulin beta III', 'Protein', (234, 250))	('Chx10', 'Gene', (224, 229))
115240	29532607	First, a knockdown of zebrafish Mst2, a homolog of Hippo kinase, resulted in abnormal eye development and retinal pigmentation.	('eye development', 'CPA', (86, 101))	('pigmentation', 'biological_process', 'GO:0043473', ('114', '126'))	('knockdown', 'Var', (9, 18))	('retinal pigmentation', 'Phenotype', 'HP:0000580', (106, 126))	('retinal pigmentation', 'Disease', 'MESH:D012173', (106, 126))	('abnormal eye', 'Phenotype', 'HP:0000478', (77, 89))	('Mst2', 'Gene', '324125', (32, 36))	('Mst2', 'Gene', (32, 36))	('resulted in', 'Reg', (65, 76))	('eye development', 'biological_process', 'GO:0001654', ('86', '101'))	('zebrafish', 'Species', '7955', (22, 31))	('retinal pigmentation', 'Disease', (106, 126))
115241	29532607	Second, similar phenotypes were subsequently observed in zebrafish when constitutively active Yap (Yap5SA) was overexpressed by mutating five serine residues to alanine to produce phosphorylation-defective Yap.	('mutating', 'Var', (128, 136))	('alanine', 'Chemical', 'MESH:D000409', (161, 168))	('phosphorylation-defective', 'MPA', (180, 205))	('serine', 'Chemical', 'MESH:D012694', (142, 148))	('phosphorylation', 'biological_process', 'GO:0016310', ('180', '195'))	('zebrafish', 'Species', '7955', (57, 66))
115248	29532607	Ablation of Yap in developing mouse lens and retina disrupted cellular and laminar organization.	('Ablation', 'Var', (0, 8))	('Yap', 'Gene', (12, 15))	('disrupted', 'NegReg', (52, 61))	('mouse', 'Species', '10090', (30, 35))
115251	29532607	Thus deletion of Lats1/2 was found to cause cell migration defects.	('cell migration defects', 'Disease', (44, 66))	('deletion', 'Var', (5, 13))	('cell migration defects', 'Disease', 'MESH:D014085', (44, 66))	('cause', 'Reg', (38, 43))	('cell migration', 'biological_process', 'GO:0016477', ('44', '58'))	('Lats1/2', 'Gene', (17, 24))
115254	29532607	Human Yap mutations are therefore thought to be difficult to find because of their potential fetal lethality.	('mutations', 'Var', (10, 19))	('Human', 'Species', '9606', (0, 5))	('Yap', 'Gene', (6, 9))
115257	29532607	Whole exome sequencing analysis of two families with autosomal-dominant inheritance of coloboma revealed two novel heterozygous nonsense mutations in the Yap gene.	('Yap', 'Gene', (154, 157))	('coloboma', 'Disease', 'MESH:D003103', (87, 95))	('coloboma', 'Phenotype', 'HP:0000589', (87, 95))	('coloboma', 'Disease', (87, 95))	('nonsense mutations', 'Var', (128, 146))	('soma', 'Disease', 'None', (57, 61))	('soma', 'Disease', (57, 61))
115258	29532607	One of these two nonsense mutations, c.370C>T, was specifically identified within the Tead-binding domain, and the other, c.1066G>T, within the transactivation domain of the Yap gene.	('Yap', 'Gene', (174, 177))	('c.370C>T', 'Mutation', 'rs587777249', (37, 45))	('transactivation', 'biological_process', 'GO:2000144', ('144', '159'))	('c.1066G>T', 'Var', (122, 131))	('binding', 'molecular_function', 'GO:0005488', ('91', '98'))	('c.370C>T', 'Var', (37, 45))	('c.1066G>T', 'Mutation', 'rs587777250', (122, 131))
115259	29532607	Specifically characterized as heterozygous loss-of-function Yap mutations segregating with the optic fissure closure defect phenotype of coloboma, these mutations may be related to the incomplete penetrance of the disease.	('loss-of-function', 'NegReg', (43, 59))	('optic fissure closure defect phenotype of coloboma', 'Disease', 'MESH:C535970', (95, 145))	('optic fissure closure defect phenotype of coloboma', 'Disease', (95, 145))	('mutations', 'Var', (64, 73))	('coloboma', 'Phenotype', 'HP:0000589', (137, 145))	('Yap', 'Gene', (60, 63))
115260	29532607	Consistent with the observation of Yap loss-of-function mutations in humans, Yap zebrafish mutants (Yapn113/n113 mutants, and, to a lesser degree, Yap-/-) also exhibited coloboma.	('zebrafish', 'Species', '7955', (81, 90))	('mutations', 'Var', (56, 65))	('coloboma', 'Disease', 'MESH:D003103', (170, 178))	('coloboma', 'Phenotype', 'HP:0000589', (170, 178))	('coloboma', 'Disease', (170, 178))	('exhibited', 'Reg', (160, 169))	('mutants', 'Var', (113, 120))	('humans', 'Species', '9606', (69, 75))	('loss-of-function', 'NegReg', (39, 55))
115261	29532607	Injections of wild-type Yap mRNA rescued the coloboma phenotype in the zebrafish embryos, confirming the Yap mutation as the cause of the ocular phenotype.	('rescued', 'PosReg', (33, 40))	('coloboma', 'Phenotype', 'HP:0000589', (45, 53))	('mutation', 'Var', (109, 117))	('coloboma', 'Disease', 'MESH:D003103', (45, 53))	('zebrafish', 'Species', '7955', (71, 80))	('coloboma', 'Disease', (45, 53))
115263	29532607	Ocular diseases are associated not only with Yap-specific mutations, but with mutations in regulators of the Hippo-Yap pathway.	('mutations', 'Var', (58, 67))	('associated', 'Reg', (20, 30))	('Ocular diseases', 'Disease', (0, 15))	('Ocular diseases', 'Disease', 'MESH:D005128', (0, 15))	('mutations', 'Var', (78, 87))	('Yap-specific', 'Disease', (45, 57))	('Ocular diseases', 'Phenotype', 'HP:0000478', (0, 15))
115264	29532607	SCRA, an eye disorder causing bilateral chorioretinal degeneration, is genetically linked to a missense mutation in the gene encoding Tead1.	('bilateral chorioretinal degeneration', 'Disease', 'OMIM:613710', (30, 66))	('Tead1', 'Gene', (134, 139))	('linked', 'Reg', (83, 89))	('eye disorder', 'Disease', 'MESH:D005128', (9, 21))	('eye disorder', 'Phenotype', 'HP:0000478', (9, 21))	('eye disorder', 'Disease', (9, 21))	('SCRA', 'Disease', (0, 4))	('retinal degeneration', 'Phenotype', 'HP:0000546', (46, 66))	('chorioretinal degeneration', 'Phenotype', 'HP:0200065', (40, 66))	('missense mutation in', 'Var', (95, 115))	('bilateral chorioretinal degeneration', 'Disease', (30, 66))
115265	29532607	In mice this mutation causes the interaction between the C-terminal domain of Tead1 and Yap/Taz cofactors to be lost, and reduces transcriptional activity of Tead1 in the presence of Yap/Taz.	('transcriptional activity', 'MPA', (130, 154))	('reduces', 'NegReg', (122, 129))	('Tead1', 'Gene', (78, 83))	('lost', 'NegReg', (112, 116))	('mutation', 'Var', (13, 21))	('mice', 'Species', '10090', (3, 7))	('Tead1', 'Gene', (158, 163))	('interaction', 'Interaction', (33, 44))
115266	29532607	While its precise contribution to pathogenesis in SCRA is unclear, it has been suggested that lack of Yap/Taz-Tead1 may cause RPE pathology because RPE and choroidal loss are followed by photoreceptor loss.	('pathogenesis', 'biological_process', 'GO:0009405', ('34', '46'))	('loss', 'NegReg', (201, 205))	('cause', 'Reg', (120, 125))	('choroidal loss', 'Disease', 'MESH:D002833', (156, 170))	('photoreceptor', 'Disease', (187, 200))	('choroidal loss', 'Disease', (156, 170))	('RPE pathology', 'Disease', (126, 139))	('Yap/Taz-Tead1', 'Gene', (102, 115))	('lack', 'Var', (94, 98))	('RPE', 'Disease', (148, 151))
115267	29532607	Another ocular disorder related to defects in components of the Hippo-Yap signaling pathway is UM, a non-cutaneous melanoma that is one of the most common intraocular defects in adults.	('signaling pathway', 'biological_process', 'GO:0007165', ('74', '91'))	('ocular disorder', 'Disease', (8, 23))	('intraocular defects', 'Disease', 'MESH:D064090', (155, 174))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('ocular disorder', 'Disease', 'MESH:D005128', (8, 23))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('intraocular defects', 'Disease', (155, 174))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (105, 123))	('ocular disorder', 'Phenotype', 'HP:0000478', (8, 23))	('defects', 'Var', (35, 42))
115268	29532607	It is primarily caused by mutations in guanine nucleotide-binding protein subunit alpha-Q (GNAQ gene), which encodes for Galphaq, and in guanine nucleotide binding protein subunit alpha 11 (GNA11 gene), which encodes Galpha11; both are alpha subunits of the heterotrimeric G proteins that play a role in transmembrane signaling systems.	('GNA11', 'Gene', (190, 195))	('Galphaq', 'Gene', '14682', (121, 128))	('transmembrane', 'cellular_component', 'GO:0016021', ('304', '317'))	('Galpha11', 'Gene', '14672', (217, 225))	('GNA11', 'Gene', '14672', (190, 195))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('47', '65'))	('GNAQ', 'Gene', (91, 95))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('GNAQ', 'Gene', '14682', (91, 95))	('guanine nucleotide binding protein subunit alpha 11', 'Gene', '14672', (137, 188))	('caused by', 'Reg', (16, 25))	('mutations', 'Var', (26, 35))	('Galphaq', 'Gene', (121, 128))	('transmembrane', 'cellular_component', 'GO:0044214', ('304', '317'))	('Galpha11', 'Gene', (217, 225))	('signaling', 'biological_process', 'GO:0023052', ('318', '327'))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('145', '163'))
115269	29532607	Yap activity increases in mutated mice and, when Yap is knocked down, tumor growth of UM mice is blocked.	('increases', 'PosReg', (13, 22))	('blocked', 'NegReg', (97, 104))	('mice', 'Species', '10090', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mice', 'Species', '10090', (89, 93))	('tumor', 'Disease', (70, 75))	('mutated', 'Var', (26, 33))	('activity', 'MPA', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('Yap', 'MPA', (0, 3))
115274	29532607	Mouse mutants with lens-specific ablation of Nf2 developed a phenotype mimicking posterior subcapsular cataracts.	('cataracts', 'Disease', 'MESH:D002386', (103, 112))	('cataracts', 'Disease', (103, 112))	('ablation', 'Var', (33, 41))	('cataracts', 'Phenotype', 'HP:0000518', (103, 112))	('subcapsular cataracts', 'Phenotype', 'HP:0000523', (91, 112))	('Nf2', 'Gene', (45, 48))	('developed', 'Reg', (49, 58))	('Mouse', 'Species', '10090', (0, 5))	('posterior subcapsular cataracts', 'Phenotype', 'HP:0007787', (81, 112))	('Nf2', 'Gene', '18016', (45, 48))
115277	29532607	Lens-specific Yap deletion induced a phenotype opposite to that of Nf2 mutants, which strengthens the notion that NF2 is a major upstream inhibitor of Yap in lens.	('Nf2', 'Gene', '18016', (67, 70))	('Yap', 'Gene', (14, 17))	('mutants', 'Var', (71, 78))	('induced', 'Reg', (27, 34))	('deletion', 'Var', (18, 26))	('Nf2', 'Gene', (67, 70))
115292	29532607	Perturbations of Hippo-Yap signaling result in diverse ocular disorders.	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('Hippo-Yap', 'Protein', (17, 26))	('result in', 'Reg', (37, 46))	('ocular disorders', 'Phenotype', 'HP:0000478', (55, 71))	('ocular disorders', 'Disease', 'MESH:D005128', (55, 71))	('ocular disorders', 'Disease', (55, 71))	('Perturbations', 'Var', (0, 13))	('ocular disorder', 'Phenotype', 'HP:0000478', (55, 70))
115307	29332125	Sequencing studies have shown that approximately 85% of UMs harbor an activating somatic mutation in the G-protein alpha subunits, Galphaq or Galpha11, leading to constitutive activation of the protein kinase C (PKC) and the MEK signaling pathways.	('PKC', 'Gene', (212, 215))	('PKC', 'Gene', '112476', (212, 215))	('Galpha11', 'Gene', '2767', (142, 150))	('activating', 'PosReg', (70, 80))	('mutation', 'Var', (89, 97))	('MEK', 'Gene', (225, 228))	('Galphaq', 'Gene', (131, 138))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('Galphaq', 'Gene', '2776', (131, 138))	('signaling', 'biological_process', 'GO:0023052', ('229', '238'))	('PKC', 'molecular_function', 'GO:0004697', ('212', '215'))	('Galpha11', 'Gene', (142, 150))	('activation', 'PosReg', (176, 186))	('MEK', 'Gene', '5609', (225, 228))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
115308	29332125	Cytogenetic profiling identified frequent large-scale aberrations in chromosomes 1, 3, 6, and 8, as well as small scale changes, such as deletions (e.g., loss of the tumor suppressor gene PTEN located on chromosome 10q), and amplifications (e.g., gain of proto-oncogenes, such as MYC (43%) and BCL2 (95%).	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('BCL2', 'Gene', (294, 298))	('deletions', 'Var', (137, 146))	('MYC', 'Gene', '4609', (280, 283))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('PTEN', 'Gene', (188, 192))	('chromosome', 'cellular_component', 'GO:0005694', ('204', '214'))	('BCL2', 'molecular_function', 'GO:0015283', ('294', '298'))	('PTEN', 'Gene', '5728', (188, 192))	('tumor suppressor', 'biological_process', 'GO:0051726', ('166', '182'))	('BCL2', 'Gene', '596', (294, 298))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('166', '182'))	('MYC', 'Gene', (280, 283))	('loss', 'NegReg', (154, 158))	('amplifications', 'Var', (225, 239))	('gain', 'PosReg', (247, 251))
115316	29332125	Our study revealed that ICG-001 induces cell death in UM cell lines.	('ICG-001', 'Var', (24, 31))	('cell death', 'biological_process', 'GO:0008219', ('40', '50'))	('cell death', 'CPA', (40, 50))	('ICG', 'cellular_component', 'GO:0035061', ('24', '27'))	('ICG-001', 'Chemical', 'MESH:C492448', (24, 31))
115323	29332125	The Mel202 cell line (carrying GNAQ Q209L and GNAQ R210K mutations) was established from a previously irradiated, locally recurrent primary UM by Bruce R. Ksander (Schepens Eye Research Institute, Boston, MA, USA) and was generously provided by Demetrios Vavvas (Massachusetts Eye and Ear Infirmary and Schepens Eye Research Institute, Harvard Medical School, Boston, MA, USA).	('GNAQ', 'Gene', (46, 50))	('GNAQ', 'Gene', '2776', (31, 35))	('GNAQ', 'Gene', '2776', (46, 50))	('R210K', 'Mutation', 'p.R210K', (51, 56))	('mutations', 'Var', (57, 66))	('Q209L', 'Mutation', 'rs121913492', (36, 41))	('GNAQ', 'Gene', (31, 35))
115346	29332125	Gene set enrichment analysis (GSEA) showed that ICG-001 suppressed a large set of genes involved in key cell cycle processes: DNA replication/synthesis, DNA repair, regulation of the mitotic cell cycle, and cell cycle checkpoints.	('DNA repair', 'MPA', (153, 163))	('DNA', 'cellular_component', 'GO:0005574', ('153', '156'))	('DNA replication', 'biological_process', 'GO:0006260', ('126', '141'))	('regulation', 'biological_process', 'GO:0065007', ('165', '175'))	('DNA repair', 'biological_process', 'GO:0006281', ('153', '163'))	('ICG-001', 'Var', (48, 55))	('cell cycle', 'biological_process', 'GO:0007049', ('104', '114'))	('mitotic cell cycle', 'biological_process', 'GO:0000278', ('183', '201'))	('synthesis', 'biological_process', 'GO:0009058', ('142', '151'))	('cell', 'CPA', (104, 108))	('cell cycle', 'biological_process', 'GO:0007049', ('207', '217'))	('suppressed', 'NegReg', (56, 66))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('DNA replication/synthesis', 'MPA', (126, 151))	('GSEA', 'Chemical', '-', (30, 34))	('ICG-001', 'Chemical', 'MESH:C492448', (48, 55))	('ICG', 'cellular_component', 'GO:0035061', ('48', '51'))
115347	29332125	Our GSEA also demonstrated that ICG-001 suppressed the mTORC1 signaling cascade (Fig.	('suppressed', 'NegReg', (40, 50))	('ICG-001', 'Chemical', 'MESH:C492448', (32, 39))	('ICG-001', 'Var', (32, 39))	('mTORC1', 'Gene', '382056', (55, 61))	('mTORC1', 'cellular_component', 'GO:0031931', ('55', '61'))	('signaling cascade', 'biological_process', 'GO:0007165', ('62', '79'))	('ICG', 'cellular_component', 'GO:0035061', ('32', '35'))	('mTORC1', 'Gene', (55, 61))	('GSEA', 'Chemical', '-', (4, 8))
115349	29332125	Previous studies have suggested that ICG-001 can suppress the Wnt/beta-catenin signaling pathway.	('beta-catenin', 'Gene', (66, 78))	('signaling pathway', 'biological_process', 'GO:0007165', ('79', '96'))	('beta-catenin', 'Gene', '1499', (66, 78))	('ICG-001', 'Chemical', 'MESH:C492448', (37, 44))	('ICG-001', 'Var', (37, 44))	('ICG', 'cellular_component', 'GO:0035061', ('37', '40'))	('suppress', 'NegReg', (49, 57))
115352	29332125	We also compared our ICG-001 signature against a signature that we had generated previously upon silencing WNT5A with siRNA.	('WNT5A', 'Gene', (107, 112))	('silencing', 'Var', (97, 106))	('ICG', 'cellular_component', 'GO:0035061', ('21', '24'))	('WNT5A', 'Gene', '7474', (107, 112))	('ICG-001', 'Chemical', 'MESH:C492448', (21, 28))
115360	29332125	Interestingly, the ICG-001 signature also mimicked the transcriptomic footprint of C646, a selective SMI of p300 histone acetyltransferase.	('p300', 'Gene', (108, 112))	('C646', 'Var', (83, 87))	('ICG-001', 'Chemical', 'MESH:C492448', (19, 26))	('ICG', 'cellular_component', 'GO:0035061', ('19', '22'))	('C646', 'Chemical', '-', (83, 87))	('p300', 'Gene', '2033', (108, 112))
115361	29332125	Moreover, the ICG-001 signature from UM also had high concordance with a signature generated upon silencing EP300 (p300) via siRNA (Fig.	('p300', 'Gene', '2033', (115, 119))	('silencing', 'Var', (98, 107))	('EP300', 'Gene', (108, 113))	('EP300', 'Gene', '2033', (108, 113))	('ICG', 'cellular_component', 'GO:0035061', ('14', '17'))	('p300', 'Gene', (115, 119))	('ICG-001', 'Chemical', 'MESH:C492448', (14, 21))
115363	29332125	Collectively, these results suggested that ICG-001 can elicit global epigenetic changes in the UM cells that mimic the effects of p300 and BRD inhibition.	('ICG', 'cellular_component', 'GO:0035061', ('43', '46'))	('p300', 'Gene', '2033', (130, 134))	('ICG-001', 'Chemical', 'MESH:C492448', (43, 50))	('elicit', 'Reg', (55, 61))	('epigenetic changes', 'MPA', (69, 87))	('ICG-001', 'Var', (43, 50))	('p300', 'Gene', (130, 134))
115375	29332125	Further evidence of MAPK/ERK pathway inhibition was provided by immunoblotting, which demonstrated that ICG-001 decreases phospho-ERK1/2 levels (Supplementary Fig.	('ICG-001', 'Var', (104, 111))	('MAPK', 'molecular_function', 'GO:0004707', ('20', '24'))	('ERK', 'molecular_function', 'GO:0004707', ('25', '28'))	('ICG', 'cellular_component', 'GO:0035061', ('104', '107'))	('ERK', 'Gene', '5594', (130, 133))	('ERK', 'Gene', '5594', (25, 28))	('ICG-001', 'Chemical', 'MESH:C492448', (104, 111))	('ERK', 'Gene', (130, 133))	('ERK', 'Gene', (25, 28))	('ERK1', 'molecular_function', 'GO:0004707', ('130', '134'))	('decreases', 'NegReg', (112, 121))
115382	29332125	We also found that numerous genes that are upregulated in Class1met+ over Class1met- UMs, including PRAME, also were suppressed by ICG-001 treatment (Supplementary Fig.	('ICG-001', 'Chemical', 'MESH:C492448', (131, 138))	('Class1met+', 'Var', (58, 68))	('upregulated', 'PosReg', (43, 54))	('PRAME', 'Gene', '23532', (100, 105))	('PRAME', 'Gene', (100, 105))	('ICG', 'cellular_component', 'GO:0035061', ('131', '134'))	('suppressed', 'NegReg', (117, 127))	('Class1met- UMs', 'Var', (74, 88))	('ICG-001', 'Gene', (131, 138))
115395	29332125	First, ICG-001 resulted in potent suppression of cell cycle genes (such as CDK2, MCM4, MCM7, and CCNB2) and many transcriptional targets of E2F.	('CCNB2', 'Gene', '9133', (97, 102))	('CDK2', 'Gene', (75, 79))	('CDK', 'molecular_function', 'GO:0004693', ('75', '78'))	('CDK2', 'Gene', '1017', (75, 79))	('MCM7', 'Gene', (87, 91))	('CCNB2', 'Gene', (97, 102))	('cell', 'CPA', (49, 53))	('MCM4', 'Gene', '4173', (81, 85))	('ICG-001', 'Chemical', 'MESH:C492448', (7, 14))	('cell cycle', 'biological_process', 'GO:0007049', ('49', '59'))	('transcriptional', 'MPA', (113, 128))	('ICG', 'cellular_component', 'GO:0035061', ('7', '10'))	('MCM4', 'Gene', (81, 85))	('ICG-001', 'Var', (7, 14))	('suppression', 'NegReg', (34, 45))	('MCM7', 'Gene', '4176', (87, 91))
115396	29332125	Second, we found that ICG-001 resulted in suppression of the Wnt signaling pathway and inhibited the expression of genes involved in cell "stemness."	('Wnt signaling pathway', 'Pathway', (61, 82))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('61', '82'))	('suppression', 'NegReg', (42, 53))	('ICG-001', 'Chemical', 'MESH:C492448', (22, 29))	('ICG', 'cellular_component', 'GO:0035061', ('22', '25'))	('ICG-001', 'Var', (22, 29))	('inhibited', 'NegReg', (87, 96))	('expression of genes', 'MPA', (101, 120))
115404	29332125	Recent studies also have highlighted the GAGE cancer/testis antigen family to be an important player in metastasis; specifically, knockdown of GAGE family members abolished the migratory capacity of cutaneous melanoma cells.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('GAGE', 'Gene', (143, 147))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (199, 217))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (199, 217))	('cancer', 'Disease', (46, 52))	('knockdown', 'Var', (130, 139))	('abolished', 'NegReg', (163, 172))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('cutaneous melanoma', 'Disease', (199, 217))
115425	29332125	A water-soluble version of ICG-001 (PRI-724) that can be administered systemically to patients currently is in clinical trials for solid and hematopoietic malignancies (NCT01606579; NCT01764477).	('water', 'Chemical', 'MESH:D014867', (2, 7))	('soluble', 'cellular_component', 'GO:0005625', ('8', '15'))	('hematopoietic malignancies', 'Disease', (141, 167))	('ICG', 'cellular_component', 'GO:0035061', ('27', '30'))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (141, 167))	('ICG-001', 'Chemical', 'MESH:C492448', (27, 34))	('NCT01606579; NCT01764477', 'Var', (169, 193))	('patients', 'Species', '9606', (86, 94))
115430	26427407	Hsp90 has multiple roles in the retina and the use of different Hsp90 inhibitors has been shown to prevent retinal degeneration in models of retinitis pigmentosa and age-related macular degeneration.	('retinitis pigmentosa', 'Disease', 'MESH:C538365', (141, 161))	('retinitis', 'Phenotype', 'HP:0032118', (141, 150))	('Hsp90', 'Gene', '3320', (64, 69))	('Hsp90', 'Gene', '3320', (0, 5))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (141, 161))	('Hsp90', 'Gene', (0, 5))	('prevent', 'NegReg', (99, 106))	('retinitis pigmentosa', 'Disease', (141, 161))	('retinal degeneration', 'Disease', 'MESH:D012162', (107, 127))	('macular degeneration', 'Phenotype', 'HP:0000608', (178, 198))	('retinal degeneration', 'Disease', (107, 127))	('age-related macular degeneration', 'Disease', (166, 198))	('rat', 'Species', '10116', (192, 195))	('inhibitors', 'Var', (70, 80))	('retinal degeneration', 'Phenotype', 'HP:0000546', (107, 127))	('Hsp90', 'Gene', (64, 69))	('rat', 'Species', '10116', (121, 124))
115442	26427407	Inhibition of Hsp90 leads to the release of HSF-1 and the activation of the stress response and an increase in molecular chaperones.	('Hsp90', 'Gene', (14, 19))	('molecular chaperones', 'MPA', (111, 131))	('release', 'MPA', (33, 40))	('Hsp90', 'Gene', '3320', (14, 19))	('stress response', 'CPA', (76, 91))	('Inhibition', 'Var', (0, 10))	('HSF-1', 'Protein', (44, 49))	('activation', 'PosReg', (58, 68))	('increase', 'PosReg', (99, 107))
115448	26427407	RP is the most common form of inherited photoreceptor degeneration and mutations in the rhodopsin gene are the most common cause of autosomal dominant RP.	('autosomal dominant RP', 'Disease', (132, 153))	('cause', 'Reg', (123, 128))	('inherited photoreceptor degeneration', 'Disease', 'MESH:D013132', (30, 66))	('mutations', 'Var', (71, 80))	('inherited photoreceptor degeneration', 'Disease', (30, 66))	('rhodopsin', 'Gene', (88, 97))
115449	26427407	It has been previously shown that the Hsp90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) can protect against rhodopsin aggregation and toxicity in a cell model of a class II misfolding mutation in rhodopsin, P23H, which is the most common rhodopsin mutation in the USA.	('Hsp90', 'Gene', (38, 43))	('AAG', 'Gene', (99, 102))	('Hsp90', 'Gene', '3320', (38, 43))	('toxicity', 'Disease', 'MESH:D064420', (150, 158))	('toxicity', 'Disease', (150, 158))	('P23H', 'Var', (223, 227))	('17-N-allylamino-17-demethoxygeldanamycin', 'Chemical', 'MESH:C112765', (54, 94))	('AAG', 'Gene', '4350', (99, 102))	('P23H', 'Mutation', 'rs104893768', (223, 227))	('rhodopsin aggregation', 'MPA', (124, 145))
115450	26427407	This protection appears to be dependent on HSF-1, as mouse embryonic fibroblasts from HSF-1 knock-out mice were not protected against P23H rhodopsin aggregation by 17-AAG, suggesting that the protective effect is dependent on induction of the stress response.	('mice', 'Species', '10090', (102, 106))	('P23H', 'Var', (134, 138))	('AAG', 'Gene', (167, 170))	('AAG', 'Gene', '4350', (167, 170))	('P23H', 'Mutation', 'rs104893768', (134, 138))	('mouse', 'Species', '10090', (53, 58))	('HSF-1', 'Gene', (86, 91))
115452	26427407	In a P23H rhodopsin transgenic rat model with progressive retinal degeneration, a single low dose of HSP990 was sufficient to mediate an improvement in visual function and photoreceptor survival several weeks later.	('rat', 'Species', '10116', (72, 75))	('photoreceptor survival', 'CPA', (172, 194))	('retinal degeneration', 'Disease', 'MESH:D012162', (58, 78))	('retinal degeneration', 'Disease', (58, 78))	('P23H', 'Mutation', 'rs104893768', (5, 9))	('HSP990', 'Gene', (101, 107))	('retinal degeneration', 'Phenotype', 'HP:0000546', (58, 78))	('improvement', 'PosReg', (137, 148))	('P23H', 'Var', (5, 9))	('visual function', 'CPA', (152, 167))	('rat', 'Species', '10116', (31, 34))
115453	26427407	Importantly, this treatment did not affect any phototransduction component, but did induce molecular chaperones and reduced rhodopsin aggregation, showing the ability of Hsp90 inhibition to stimulate the proteostasis machinery that protects against misfolded proteins.	('molecular chaperones', 'CPA', (91, 111))	('Hsp90', 'Gene', (170, 175))	('induce', 'Reg', (84, 90))	('inhibition', 'Var', (176, 186))	('phototransduction', 'biological_process', 'GO:0007602', ('47', '64'))	('Hsp90', 'Gene', '3320', (170, 175))	('reduced', 'NegReg', (116, 123))	('stimulate', 'PosReg', (190, 199))	('rhodopsin aggregation', 'MPA', (124, 145))
115455	26427407	In this instance, claudin 5 RNAi was used to transiently permeabilize the blood retinal barrier and allow 17-AAG to stimulate a protective response in photoreceptors expressing R224P mutant IMPDH, with a concomitant reduction in mutant IMPDH aggregation and protection of ONL structure.	('R224P', 'Mutation', 'p.R224P', (177, 182))	('AAG', 'Gene', (109, 112))	('R224P', 'Var', (177, 182))	('IMPDH', 'Gene', (190, 195))	('AAG', 'Gene', '4350', (109, 112))	('reduction', 'NegReg', (216, 225))	('IMPDH', 'Gene', (236, 241))	('protective response', 'MPA', (128, 147))	('RNAi', 'biological_process', 'GO:0016246', ('28', '32'))	('aggregation', 'MPA', (242, 253))
115456	26427407	Interestingly, in a disease model for a different class of rhodopsin mutation (R135L) inhibition of Hsp90 was also protective, but this was independent of HSF-1.	('R135L', 'Mutation', 'rs104893774', (79, 84))	('Hsp90', 'Gene', (100, 105))	('R135L', 'Var', (79, 84))	('Hsp90', 'Gene', '3320', (100, 105))	('inhibition', 'NegReg', (86, 96))
115457	26427407	The R135L mutation causes rhodopsin hyperphosphorylation, arrestin binding and aberrant rhodopsin endocytosis (Fig.	('R135L', 'Mutation', 'rs104893774', (4, 9))	('causes', 'Reg', (19, 25))	('arrest', 'Disease', (58, 64))	('binding', 'molecular_function', 'GO:0005488', ('67', '74'))	('hyperphosphorylation', 'biological_process', 'GO:0048151', ('36', '56'))	('R135L', 'Var', (4, 9))	('endocytosis', 'biological_process', 'GO:0006897', ('98', '109'))	('rhodopsin hyperphosphorylation', 'Disease', (26, 56))	('aberrant', 'MPA', (79, 87))	('binding', 'Interaction', (67, 74))	('arrest', 'Disease', 'MESH:D006323', (58, 64))
115458	26427407	Hsp90 inhibition blocked the recruitment of arrestin to R135L mutant rhodopsin and thereby alleviated aberrant endocytosis.	('Hsp90', 'Gene', '3320', (0, 5))	('inhibition blocked', 'NegReg', (6, 24))	('rhodopsin', 'Gene', (69, 78))	('alleviated', 'NegReg', (91, 101))	('R135L', 'Mutation', 'rs104893774', (56, 61))	('endocytosis', 'biological_process', 'GO:0006897', ('111', '122'))	('recruitment', 'MPA', (29, 40))	('arrest', 'Disease', 'MESH:D006323', (44, 50))	('R135L', 'Var', (56, 61))	('aberrant endocytosis', 'MPA', (102, 122))	('Hsp90', 'Gene', (0, 5))	('arrest', 'Disease', (44, 50))
115459	26427407	Further investigation revealed that, like many kinases, rhodopsin kinase (GRK1) is an obligate Hsp90 client protein and the effect of Hsp90 inhibition on R135L rhodopsin arrestin binding was mediated by an upstream reduction in phosphorylation of R135L because of lack of an appropriate kinase.	('GRK1', 'Gene', '6011', (74, 78))	('arrest', 'Disease', 'MESH:D006323', (170, 176))	('GRK1', 'Gene', (74, 78))	('phosphorylation', 'biological_process', 'GO:0016310', ('228', '243'))	('Hsp90', 'Gene', '3320', (134, 139))	('Hsp90', 'Gene', '3320', (95, 100))	('binding', 'Interaction', (179, 186))	('inhibition', 'NegReg', (140, 150))	('rhodopsin kinase', 'Gene', (56, 72))	('phosphorylation', 'MPA', (228, 243))	('Hsp90', 'Gene', (95, 100))	('Hsp90', 'Gene', (134, 139))	('R135L', 'Mutation', 'rs104893774', (154, 159))	('binding', 'molecular_function', 'GO:0005488', ('179', '186'))	('rhodopsin kinase', 'Gene', '6011', (56, 72))	('arrest', 'Disease', (170, 176))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('R135L', 'Var', (154, 159))	('GRK1', 'molecular_function', 'GO:0050254', ('74', '78'))	('R135L', 'Mutation', 'rs104893774', (247, 252))	('reduction', 'NegReg', (215, 224))
115460	26427407	Overall, these data suggest that Hsp90 has multiple roles in the retina and that the use of Hsp90 inhibitors can be potentially protective against different types of RP through different mechanisms.	('inhibitors', 'Var', (98, 108))	('Hsp90', 'Gene', (33, 38))	('Hsp90', 'Gene', '3320', (33, 38))	('Hsp90', 'Gene', (92, 97))	('Hsp90', 'Gene', '3320', (92, 97))
115470	26427407	Hsp90 is crucial for the stability and functional conformation of FAK, as inhibition of Hsp90 interferes with its phosphorylation and stimulates its proteasome-mediated degradation.	('Hsp90', 'Gene', '3320', (0, 5))	('inhibition', 'Var', (74, 84))	('stimulates', 'PosReg', (134, 144))	('proteasome', 'molecular_function', 'GO:0004299', ('149', '159'))	('proteasome-mediated degradation', 'MPA', (149, 180))	('FAK', 'molecular_function', 'GO:0004717', ('66', '69'))	('proteasome', 'cellular_component', 'GO:0000502', ('149', '159'))	('interferes', 'NegReg', (94, 104))	('Hsp90', 'Gene', (88, 93))	('FAK', 'Gene', (66, 69))	('phosphorylation', 'MPA', (114, 129))	('FAK', 'Gene', '5747', (66, 69))	('degradation', 'biological_process', 'GO:0009056', ('169', '180'))	('Hsp90', 'Gene', '3320', (88, 93))	('phosphorylation', 'biological_process', 'GO:0016310', ('114', '129'))	('Hsp90', 'Gene', (0, 5))
115477	26427407	Recent reports from oncology clinical trials have suggested that some Hsp90 inhibitors, such as 17-DMAG and AUY922, might lead to visual disturbances.	('visual disturbances', 'Disease', (130, 149))	('AUY922', 'Var', (108, 114))	('Hsp90', 'Gene', (70, 75))	('oncology', 'Phenotype', 'HP:0002664', (20, 28))	('AUY922', 'Chemical', 'MESH:C528044', (108, 114))	('visual disturbances', 'Phenotype', 'HP:0000505', (130, 149))	('lead to', 'Reg', (122, 129))	('Hsp90', 'Gene', '3320', (70, 75))	('17-DMAG', 'Chemical', 'MESH:C448659', (96, 103))	('visual disturbances', 'Disease', 'MESH:D010468', (130, 149))
115478	26427407	In a recent clinical trial for advanced solid tumors using AUY922, 43% of the patients reported grades 1-3 visual symptoms, including night blindness, photopsia, blurred vision and visual impairment.	('blurred vision', 'Phenotype', 'HP:0000622', (162, 176))	('AUY922', 'Var', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('visual impairment', 'Disease', 'MESH:D014786', (181, 198))	('AUY922', 'Chemical', 'MESH:C528044', (59, 65))	('blindness', 'Phenotype', 'HP:0000618', (140, 149))	('solid tumors', 'Disease', 'MESH:D009369', (40, 52))	('patients', 'Species', '9606', (78, 86))	('visual impairment', 'Disease', (181, 198))	('night blindness', 'Phenotype', 'HP:0000662', (134, 149))	('photopsia', 'Phenotype', 'HP:0030786', (151, 160))	('photopsia, blurred vision', 'Disease', 'MESH:D014786', (151, 176))	('blindness', 'Disease', (140, 149))	('vision', 'biological_process', 'GO:0007601', ('170', '176'))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('solid tumors', 'Disease', (40, 52))	('visual impairment', 'Phenotype', 'HP:0000505', (181, 198))	('blindness', 'Disease', 'MESH:D001766', (140, 149))
115479	26427407	It is therefore important to identify the molecular mechanism by which Hsp90 inhibitors affect vision.	('Hsp90', 'Gene', '3320', (71, 76))	('vision', 'biological_process', 'GO:0007601', ('95', '101'))	('inhibitors', 'Var', (77, 87))	('affect', 'Reg', (88, 94))	('Hsp90', 'Gene', (71, 76))	('vision', 'Disease', (95, 101))
115481	26427407	Furthermore, phosphodiesterase (PDE) levels were also specifically reduced in the retina following Hsp90 inhibition.	('Hsp90', 'Gene', '3320', (99, 104))	('inhibition', 'Var', (105, 115))	('reduced', 'NegReg', (67, 74))	('PDE', 'molecular_function', 'GO:0004114', ('32', '35'))	('Hsp90', 'Gene', (99, 104))	('phosphodiesterase', 'molecular_function', 'GO:0008081', ('13', '30'))
115483	26427407	Reduction in GRK1 and PDE could cause some of the most common visual side-effects of Hsp90 inhibitors observed in oncology patients.	('Hsp90', 'Gene', '3320', (85, 90))	('PDE', 'molecular_function', 'GO:0004114', ('22', '25'))	('inhibitors', 'Var', (91, 101))	('PDE', 'Gene', (22, 25))	('GRK1', 'Gene', '6011', (13, 17))	('patients', 'Species', '9606', (123, 131))	('GRK1', 'molecular_function', 'GO:0050254', ('13', '17'))	('visual', 'Disease', (62, 68))	('Reduction', 'NegReg', (0, 9))	('oncology', 'Phenotype', 'HP:0002664', (114, 122))	('GRK1', 'Gene', (13, 17))	('Hsp90', 'Gene', (85, 90))
115488	26427407	Collectively, the data show that Hsp90 has multiple roles in the retina and that the use of Hsp90 inhibitors can be potentially protective against retinal degeneration and ocular oncology, but their possible adverse effects on visual function also need to be considered.	('ocular oncology', 'Phenotype', 'HP:0100012', (172, 187))	('retinal degeneration', 'Phenotype', 'HP:0000546', (147, 167))	('inhibitors', 'Var', (98, 108))	('oncology', 'Phenotype', 'HP:0002664', (179, 187))	('Hsp90', 'Gene', (33, 38))	('ocular oncology', 'Disease', (172, 187))	('Hsp90', 'Gene', '3320', (33, 38))	('Hsp90', 'Gene', (92, 97))	('retinal degeneration', 'Disease', 'MESH:D012162', (147, 167))	('retinal degeneration', 'Disease', (147, 167))	('Hsp90', 'Gene', '3320', (92, 97))
115495	25952648	Inhibition of AKT also effectively reverses the protective effect of NRG1 and HGF in trametinib-treated cells.	('protective effect', 'CPA', (48, 65))	('NRG1', 'Gene', '3084', (69, 73))	('reverses', 'NegReg', (35, 43))	('AKT', 'Gene', (14, 17))	('trametinib', 'Chemical', 'MESH:C560077', (85, 95))	('NRG1', 'Gene', (69, 73))	('Inhibition', 'Var', (0, 10))	('AKT', 'Gene', '207', (14, 17))
115502	25952648	In contrast to its cutaneous counterpart, oncogenic BRAF mutations are infrequent in UM.	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('mutations', 'Var', (57, 66))	('BRAF', 'Gene', (52, 56))	('BRAF', 'Gene', '673', (52, 56))
115503	25952648	Activating mutations in two alpha subunits of the heterotrimeric G proteins, GNAQ and GNA11, are found in 80% of UMs in mutually exclusive manner and are believed to occur at an early stage of disease.	('mutations', 'Var', (11, 20))	('UMs', 'Disease', (113, 116))	('Activating', 'PosReg', (0, 10))	('GNAQ', 'Gene', (77, 81))	('heterotrimeric G proteins', 'Protein', (50, 75))	('UM', 'Phenotype', 'HP:0007716', (113, 115))	('GNA11', 'Gene', (86, 91))	('GNAQ', 'Gene', '2776', (77, 81))	('GNA11', 'Gene', '2767', (86, 91))
115504	25952648	The GNAQ and GNA11 mutations are typically in Q209 but less frequently in R183.	('Q209', 'Var', (46, 50))	('GNAQ', 'Gene', '2776', (4, 8))	('GNAQ', 'Gene', (4, 8))	('GNA11', 'Gene', (13, 18))	('GNA11', 'Gene', '2767', (13, 18))
115505	25952648	Other studies have also identified recurrent mutations in SF3B1, a RNA splicing factor, and EIF1AX in primary UM with disomy 3 and associate with low metastatic potential.	('disomy 3', 'Disease', (118, 126))	('mutations', 'Var', (45, 54))	('RNA', 'cellular_component', 'GO:0005562', ('67', '70'))	('UM', 'Phenotype', 'HP:0007716', (110, 112))	('SF3B1', 'Gene', (58, 63))	('EIF1AX', 'Gene', '1964', (92, 98))	('EIF1AX', 'Gene', (92, 98))	('RNA splicing', 'biological_process', 'GO:0008380', ('67', '79'))	('SF3B1', 'Gene', '23451', (58, 63))	('low metastatic potential', 'CPA', (146, 170))
115506	25952648	Inactivating mutations in the tumor suppressor BRCA1 associated protein 1 (BAP1) on chromosome 3 are found in 32-50% of primary UM and associate with a more aggressive/higher likelihood of metastasis.	('primary UM', 'Disease', (120, 130))	('found', 'Reg', (101, 106))	('BAP1', 'Gene', (75, 79))	('BRCA1 associated protein 1', 'Gene', (47, 73))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))	('UM', 'Phenotype', 'HP:0007716', (128, 130))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('Inactivating mutations', 'Var', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('BAP1', 'Gene', '8314', (75, 79))	('tumor', 'Disease', (30, 35))	('metastasis', 'CPA', (189, 199))	('BRCA1 associated protein 1', 'Gene', '8314', (47, 73))
115507	25952648	Oncogenic mutations in GNAQ and GNA11 abrogate their intrinsic GTPase activities, resulting in activation of the RAF/MEK/ERK1/2 and protein kinase C (PKC) signaling, JNK and p38 via regulation of the small GTPases of RhoA and Rac1.	('ERK1/2', 'Gene', (121, 127))	('RhoA', 'Gene', '387', (217, 221))	('regulation', 'biological_process', 'GO:0065007', ('182', '192'))	('GNAQ', 'Gene', (23, 27))	('GNA11', 'Gene', (32, 37))	('ERK1/2', 'Gene', '5595;5594', (121, 127))	('p38', 'Gene', '5594', (174, 177))	('MEK', 'Gene', '5609', (117, 120))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('ERK1', 'molecular_function', 'GO:0004707', ('121', '125'))	('RAF', 'Gene', (113, 116))	('JNK', 'Gene', (166, 169))	('Rac1', 'Gene', (226, 230))	('MEK', 'Gene', (117, 120))	('JNK', 'Gene', '5599', (166, 169))	('JNK', 'molecular_function', 'GO:0004705', ('166', '169'))	('abrogate', 'NegReg', (38, 46))	('PKC', 'Disease', (150, 153))	('GNA11', 'Gene', '2767', (32, 37))	('PKC', 'molecular_function', 'GO:0004697', ('150', '153'))	('intrinsic', 'MPA', (53, 62))	('activation', 'PosReg', (95, 105))	('p38', 'Gene', (174, 177))	('RhoA', 'Gene', (217, 221))	('Rac1', 'Gene', '5879', (226, 230))	('activities', 'MPA', (70, 80))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('PKC', 'Disease', 'MESH:C537180', (150, 153))	('RAF', 'Gene', '22882', (113, 116))	('mutations', 'Var', (10, 19))	('GNAQ', 'Gene', '2776', (23, 27))
115509	25952648	Knockdown of GNAQ in mutant but not wild type UM cell lines diminishes ERK1/2 activation, induces cell cycle arrest and AMP-activated protein kinase-dependent autophagic cell death.	('AMP-activated', 'CPA', (120, 133))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('98', '115'))	('mutant', 'Var', (21, 27))	('activation', 'MPA', (78, 88))	('autophagic cell death', 'biological_process', 'GO:0048102', ('159', '180'))	('GNAQ', 'Gene', (13, 17))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('ERK1/2', 'Gene', (71, 77))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (98, 115))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('arrest', 'Disease', 'MESH:D006323', (109, 115))	('induces', 'Reg', (90, 97))	('ERK1/2', 'Gene', '5595;5594', (71, 77))	('ERK1', 'molecular_function', 'GO:0004707', ('71', '75'))	('arrest', 'Disease', (109, 115))	('diminishes', 'NegReg', (60, 70))	('GNAQ', 'Gene', '2776', (13, 17))
115510	25952648	While these findings emphasize the potential of targeted therapy in UM, directly targeting mutant GNAQ and GNA11 has proved to be structurally challenging.	('GNAQ', 'Gene', (98, 102))	('UM', 'Phenotype', 'HP:0007716', (68, 70))	('GNAQ', 'Gene', '2776', (98, 102))	('mutant', 'Var', (91, 97))	('GNA11', 'Gene', (107, 112))	('GNA11', 'Gene', '2767', (107, 112))
115511	25952648	Targeting MEK with small molecule inhibitors such as trametinib (GSK1120212) and selumetinib (AZD6244) has been pursued in clinical trials for melanoma.	('AZD6244', 'Chemical', 'MESH:C517975', (94, 101))	('GSK', 'molecular_function', 'GO:0050321', ('65', '68'))	('MEK', 'Gene', (10, 13))	('MEK', 'Gene', '5609', (10, 13))	('selumetinib', 'Chemical', 'MESH:C517975', (81, 92))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('GSK1120212', 'Var', (65, 75))	('melanoma', 'Disease', (143, 151))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('trametinib', 'Chemical', 'MESH:C560077', (53, 63))	('GSK1120212', 'Chemical', 'MESH:C560077', (65, 75))
115512	25952648	Trametinib monotherapy has achieved 25-40% partial/complete response rates in BRAF V600E/K cutaneous melanoma patients.	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('V600E', 'Var', (83, 88))	('BRAF', 'Gene', '673', (78, 82))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('V600E', 'SUBSTITUTION', 'None', (83, 88))	('BRAF', 'Gene', (78, 82))	('cutaneous melanoma', 'Disease', (91, 109))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (91, 109))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (91, 109))	('patients', 'Species', '9606', (110, 118))
115518	25952648	In UM cells line studies, MEK inhibition alone elicited a cell cycle arrest but did not induce apoptosis.	('MEK', 'Gene', '5609', (26, 29))	('arrest', 'Disease', 'MESH:D006323', (69, 75))	('inhibition', 'Var', (30, 40))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('58', '75'))	('arrest', 'Disease', (69, 75))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (58, 75))	('MEK', 'Gene', (26, 29))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
115521	25952648	Mechanistically, MEK inhibition enhances responsiveness to NRG1 and promotes sustained HGF-induced phosphorylation of cMET.	('enhances', 'PosReg', (32, 40))	('MEK', 'Gene', (17, 20))	('promotes', 'PosReg', (68, 76))	('responsiveness', 'MPA', (41, 55))	('MEK', 'Gene', '5609', (17, 20))	('inhibition', 'Var', (21, 31))	('NRG1', 'Gene', (59, 63))	('cMET', 'Gene', (118, 122))	('HGF-induced phosphorylation', 'MPA', (87, 114))	('NRG1', 'Gene', '3084', (59, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('99', '114'))
115525	25952648	Together, these data suggest that co-targeting MEK with ERBB3 and/or cMET may enhance the efficacy of MEK inhibitor in advanced stage UM patients.	('MEK', 'Gene', (47, 50))	('efficacy', 'MPA', (90, 98))	('enhance', 'PosReg', (78, 85))	('MEK', 'Gene', '5609', (102, 105))	('MEK', 'Gene', '5609', (47, 50))	('co-targeting', 'Var', (34, 46))	('patients', 'Species', '9606', (137, 145))	('ERBB3', 'Gene', (56, 61))	('UM', 'Phenotype', 'HP:0007716', (134, 136))	('MEK', 'Gene', (102, 105))
115573	25952648	These data demonstrate that NRG1 and HGF partially restore growth and viability of metastatic UM cells treated with MEK inhibitors.	('UM', 'Phenotype', 'HP:0007716', (94, 96))	('NRG1', 'Gene', '3084', (28, 32))	('MEK', 'Gene', (116, 119))	('inhibitors', 'Var', (120, 130))	('growth', 'CPA', (59, 65))	('MEK', 'Gene', '5609', (116, 119))	('restore', 'PosReg', (51, 58))	('viability', 'CPA', (70, 79))	('metastatic UM cells', 'CPA', (83, 102))	('NRG1', 'Gene', (28, 32))	('HGF', 'Gene', (37, 40))
115575	25952648	Treatment with trametinib sensitized UM001 and UM003 cells to NRG1-stimulated ERBB3 phosphorylation at Y1197 and Y1289 in dose and time course experiments (Fig.	('NRG1', 'Gene', '3084', (62, 66))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('UM', 'Phenotype', 'HP:0007716', (37, 39))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('NRG1', 'Gene', (62, 66))	('trametinib', 'Chemical', 'MESH:C560077', (15, 25))	('Y1289', 'Var', (113, 118))	('ERBB3 phosphorylation', 'MPA', (78, 99))
115577	25952648	Phosphorylated Y1197 and Y1298 in ERBB3 are within YXXM-motifs, which dock phosphoinositide 3-kinase (PI3K) leading to AKT phosphorylation.	('phosphoinositide 3-kinase', 'Gene', (75, 100))	('ERBB3', 'Gene', (34, 39))	('AKT', 'Gene', '207', (119, 122))	('phosphoinositide 3-kinase', 'Gene', '5294', (75, 100))	('Y1197', 'Var', (15, 20))	('phosphorylation', 'biological_process', 'GO:0016310', ('123', '138'))	('AKT', 'Gene', (119, 122))	('Y1298', 'Var', (25, 30))	('dock', 'Reg', (70, 74))	('PI3K', 'molecular_function', 'GO:0016303', ('102', '106'))
115578	25952648	In line with enhanced phospho-ERBB3 levels, AKT phosphorylation at S473 and T308 was elevated following NRG1 stimulation in trametinib-treated UM001 and UM003 cells (Fig.	('enhanced', 'PosReg', (13, 21))	('T308', 'Var', (76, 80))	('UM', 'Phenotype', 'HP:0007716', (153, 155))	('AKT', 'Gene', '207', (44, 47))	('UM', 'Phenotype', 'HP:0007716', (143, 145))	('elevated', 'PosReg', (85, 93))	('NRG1', 'Gene', (104, 108))	('stimulation', 'Var', (109, 120))	('AKT', 'Gene', (44, 47))	('trametinib', 'Chemical', 'MESH:C560077', (124, 134))	('phosphorylation', 'biological_process', 'GO:0016310', ('48', '63'))	('phospho-ERBB3 levels', 'MPA', (22, 42))	('NRG1', 'Gene', '3084', (104, 108))
115582	25952648	Furthermore, silencing ERBB2 effectively inhibited NRG1-stimulated ERBB3 and AKT phosphorylation in UM001 (Fig.	('ERBB2', 'Gene', (23, 28))	('UM', 'Phenotype', 'HP:0007716', (100, 102))	('AKT', 'Gene', '207', (77, 80))	('NRG1', 'Gene', (51, 55))	('phosphorylation', 'biological_process', 'GO:0016310', ('81', '96'))	('inhibited', 'NegReg', (41, 50))	('AKT', 'Gene', (77, 80))	('ERBB3', 'Enzyme', (67, 72))	('silencing', 'Var', (13, 22))	('NRG1', 'Gene', '3084', (51, 55))
115586	25952648	U3-1287 effectively blocked NRG1-stimulated phosphorylation of ERBB3 and downstream AKT activation in UM001 cells (Fig.	('U3-1287', 'Var', (0, 7))	('phosphorylation', 'MPA', (44, 59))	('phosphorylation', 'biological_process', 'GO:0016310', ('44', '59'))	('activation', 'PosReg', (88, 98))	('NRG1', 'Gene', '3084', (28, 32))	('AKT', 'Gene', '207', (84, 87))	('ERBB3', 'Protein', (63, 68))	('AKT', 'Gene', (84, 87))	('NRG1', 'Gene', (28, 32))	('blocked', 'NegReg', (20, 27))	('UM', 'Phenotype', 'HP:0007716', (102, 104))
115605	25952648	As a second approach, we tested the effect of silencing cMET expression on sensitivity to trametinib in UM cells.	('UM', 'Phenotype', 'HP:0007716', (104, 106))	('silencing', 'Var', (46, 55))	('cMET', 'Gene', (56, 60))	('tested', 'Reg', (25, 31))	('trametinib', 'Chemical', 'MESH:C560077', (90, 100))
115610	25952648	Addition of MK2206 completely abrogated the protective effect of NRG1 and HGF in trametinib-treated UM001 (Fig.	('trametinib', 'Chemical', 'MESH:C560077', (81, 91))	('UM', 'Phenotype', 'HP:0007716', (100, 102))	('MK2206', 'Var', (12, 18))	('NRG1', 'Gene', (65, 69))	('MK2206', 'Chemical', 'MESH:C548887', (12, 18))	('protective effect', 'CPA', (44, 61))	('HGF', 'Protein', (74, 77))	('abrogated', 'NegReg', (30, 39))	('NRG1', 'Gene', '3084', (65, 69))
115611	25952648	Notably, MK2206 alone slightly inhibited growth of UM001 cells, while it did not affect the growth of UM003 cells.	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('MK2206', 'Var', (9, 15))	('MK2206', 'Chemical', 'MESH:C548887', (9, 15))	('growth', 'MPA', (41, 47))	('inhibited', 'NegReg', (31, 40))	('UM', 'Phenotype', 'HP:0007716', (102, 104))
115612	25952648	MK2206 effectively blocked NRG1 and HGF-initiated signaling leading to AKT phosphorylation and downstream AKT targets in trametinib-treated UM001 cells (Fig.	('AKT', 'Gene', (106, 109))	('AKT', 'Gene', '207', (71, 74))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('blocked', 'NegReg', (19, 26))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('phosphorylation', 'biological_process', 'GO:0016310', ('75', '90'))	('NRG1', 'Gene', (27, 31))	('HGF-initiated signaling', 'MPA', (36, 59))	('trametinib', 'Chemical', 'MESH:C560077', (121, 131))	('AKT', 'Gene', '207', (106, 109))	('AKT', 'Gene', (71, 74))	('MK2206', 'Var', (0, 6))	('UM', 'Phenotype', 'HP:0007716', (140, 142))	('NRG1', 'Gene', '3084', (27, 31))
115625	25952648	UM001 xenografts growing in NSG mice stained positive for phospho ERBB2 (Fig.	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('phospho ERBB2', 'Var', (58, 71))	('mice', 'Species', '10090', (32, 36))	('positive', 'Reg', (45, 53))
115629	25952648	Biopsies from seven UM patients with liver metastasis were stained with anti-phospho ERBB2 and anti-phospho cMET antibodies.	('patients', 'Species', '9606', (23, 31))	('anti-phospho cMET', 'Var', (95, 112))	('UM', 'Phenotype', 'HP:0007716', (20, 22))	('liver metastasis', 'Disease', 'MESH:D009362', (37, 53))	('liver metastasis', 'Disease', (37, 53))
115634	25952648	Here, we describe that both innate and adaptive mechanisms occur in mutant GNAQ metastatic UM cells responding to clinical-grade MEK inhibitors.	('occur', 'Reg', (59, 64))	('MEK', 'Gene', '5609', (129, 132))	('GNAQ', 'Gene', (75, 79))	('UM', 'Phenotype', 'HP:0007716', (91, 93))	('metastatic UM cells', 'CPA', (80, 99))	('MEK', 'Gene', (129, 132))	('GNAQ', 'Gene', '2776', (75, 79))	('mutant', 'Var', (68, 74))
115635	25952648	Our studies utilize GNAQ mutant human metastatic UM cell lines.	('mutant', 'Var', (25, 31))	('GNAQ', 'Gene', '2776', (20, 24))	('UM', 'Phenotype', 'HP:0007716', (49, 51))	('GNAQ', 'Gene', (20, 24))	('human', 'Species', '9606', (32, 37))
115636	25952648	These represent an important resource to the field given the high percentage of UMs harboring GNAQ or GNA11 mutations, the noted lack of available cell lines for UM, the concern that lines may be cutaneous melanoma and the common use of lines derived from non-metastatic lesions for drug response studies in the UM literature.	('cutaneous melanoma', 'Disease', (196, 214))	('UM', 'Phenotype', 'HP:0007716', (312, 314))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (196, 214))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (196, 214))	('mutations', 'Var', (108, 117))	('GNA11', 'Gene', (102, 107))	('UM', 'Phenotype', 'HP:0007716', (80, 82))	('UM', 'Phenotype', 'HP:0007716', (162, 164))	('GNA11', 'Gene', '2767', (102, 107))	('GNAQ', 'Gene', '2776', (94, 98))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('harboring', 'Reg', (84, 93))	('GNAQ', 'Gene', (94, 98))
115643	25952648	These data are similar to findings in cutaneous mutant BRAF melanoma cells, in which NRG1 adaptively up-regulate ERBB3-AKT signaling in response to vemurafenib/PLX4720 and in which HGF promotes resistance via adaptive and innate mechanisms depending on the cell line.	('mutant', 'Var', (48, 54))	('promotes', 'PosReg', (185, 193))	('NRG1', 'Gene', (85, 89))	('AKT', 'Gene', '207', (119, 122))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Disease', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('response', 'MPA', (136, 144))	('vemurafenib', 'Chemical', 'MESH:D000077484', (148, 159))	('AKT signaling', 'biological_process', 'GO:0043491', ('119', '132'))	('up-regulate', 'PosReg', (101, 112))	('resistance', 'CPA', (194, 204))	('BRAF', 'Gene', '673', (55, 59))	('AKT', 'Gene', (119, 122))	('NRG1', 'Gene', '3084', (85, 89))	('BRAF', 'Gene', (55, 59))
115644	25952648	Both ERBB3 and cMET activate the PI3K-AKT pathway and the addition of a PI3K inhibitor to MEK treatment enhances apoptosis in mutant GNAQ cells in vitro.	('apoptosis', 'biological_process', 'GO:0006915', ('113', '122'))	('AKT', 'Gene', (38, 41))	('activate', 'PosReg', (20, 28))	('PI3K', 'molecular_function', 'GO:0016303', ('33', '37'))	('apoptosis', 'CPA', (113, 122))	('GNAQ', 'Gene', (133, 137))	('MEK', 'Gene', (90, 93))	('MEK', 'Gene', '5609', (90, 93))	('PI3K', 'molecular_function', 'GO:0016303', ('72', '76'))	('apoptosis', 'biological_process', 'GO:0097194', ('113', '122'))	('AKT', 'Gene', '207', (38, 41))	('enhances', 'PosReg', (104, 112))	('GNAQ', 'Gene', '2776', (133, 137))	('mutant', 'Var', (126, 132))
115647	25952648	For example, recent preclinical studies show that combined inhibition of MEK and PKC improves efficacy compared to treatment with either single agent in GNAQ/11 mutant UM.	('inhibition', 'NegReg', (59, 69))	('mutant', 'Var', (161, 167))	('PKC', 'Disease', (81, 84))	('UM', 'Phenotype', 'HP:0007716', (168, 170))	('PKC', 'molecular_function', 'GO:0004697', ('81', '84'))	('efficacy', 'MPA', (94, 102))	('PKC', 'Disease', 'MESH:C537180', (81, 84))	('MEK', 'Gene', (73, 76))	('GNAQ', 'Gene', '2776', (153, 157))	('improves', 'PosReg', (85, 93))	('MEK', 'Gene', '5609', (73, 76))	('GNAQ', 'Gene', (153, 157))
115649	25952648	Targeting the ERBB3/ERBB2 complex with U3-1287/AMG88 or lapatinib effectively reversed the NRG1-mediated resistance to MEK inhibitors.	('MEK', 'Gene', (119, 122))	('AMG88', 'Chemical', '-', (47, 52))	('MEK', 'Gene', '5609', (119, 122))	('U3-1287/AMG88', 'Var', (39, 52))	('lapatinib', 'Chemical', 'MESH:D000077341', (56, 65))	('reversed', 'NegReg', (78, 86))	('ERBB3/ERBB2 complex', 'cellular_component', 'GO:0038143', ('14', '33'))	('NRG1', 'Gene', (91, 95))	('NRG1', 'Gene', '3084', (91, 95))
115654	25952648	Others have utilized the cMET inhibitor, MK-8033, to inhibit growth in mutant GNAQ UM cells.	('growth', 'MPA', (61, 67))	('inhibit', 'NegReg', (53, 60))	('GNAQ', 'Gene', (78, 82))	('MK-8033', 'Chemical', 'MESH:C581209', (41, 48))	('UM', 'Phenotype', 'HP:0007716', (83, 85))	('mutant', 'Var', (71, 77))	('GNAQ', 'Gene', '2776', (78, 82))
115656	25952648	Furthermore, our findings suggest that targeting ERBB3 and/or cMET may enhance the effect of MEK inhibitor in advanced-stage, mutant GNAQ UM patients.	('cMET', 'Gene', (62, 66))	('UM', 'Phenotype', 'HP:0007716', (138, 140))	('patients', 'Species', '9606', (141, 149))	('GNAQ', 'Gene', (133, 137))	('MEK', 'Gene', (93, 96))	('MEK', 'Gene', '5609', (93, 96))	('ERBB3', 'Gene', (49, 54))	('enhance', 'PosReg', (71, 78))	('effect', 'MPA', (83, 89))	('GNAQ', 'Gene', '2776', (133, 137))	('mutant', 'Var', (126, 132))
115667	25952648	On-going efforts are focused on utilizing clinical grade anti-ERBB3 and anti-cMET monoclonal antibodies in combination with MEK inhibitors in pre-clinical studies.	('anti-cMET', 'Var', (72, 81))	('MEK', 'Gene', (124, 127))	('pre', 'molecular_function', 'GO:0003904', ('142', '145'))	('MEK', 'Gene', '5609', (124, 127))
115668	23620406	Adverse Outcomes in Clear Cell Renal Cell Carcinoma with Mutations of 3p21 Epigenetic Regulators BAP1 and SETD2: a Report by MSKCC and the KIRC TCGA Research Network To investigate the impact of newly identified chromosome 3p21 epigenetic tumor suppressors PBRM1, SETD2, and BAP1 on cancer specific survival (CSS) of 609 clear cell renal cell carcinoma (ccRCC) patients from two distinct cohorts.	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('PBRM1', 'Gene', (257, 262))	('BAP1', 'Gene', (97, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (343, 352))	('SETD2', 'Gene', (106, 111))	('SETD2', 'Gene', (264, 269))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (321, 352))	('RCC', 'Disease', 'MESH:C538614', (356, 359))	('BAP1', 'Gene', '8314', (275, 279))	('Clear Cell Renal Cell Carcinoma', 'Disease', (20, 51))	('Mutations', 'Var', (57, 66))	('SETD2', 'Gene', '29072', (106, 111))	('SETD2', 'Gene', '29072', (264, 269))	('tumor', 'Disease', (239, 244))	('patients', 'Species', '9606', (361, 369))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (20, 51))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (321, 352))	('BAP1', 'Gene', (275, 279))	('cancer', 'Disease', (283, 289))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (31, 51))	('Carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('chromosome', 'cellular_component', 'GO:0005694', ('212', '222'))	('CSS', 'Chemical', '-', (309, 312))	('BAP1', 'Gene', '8314', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('clear cell renal cell carcinoma', 'Disease', (321, 352))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (332, 352))	('PBRM1', 'Gene', '55193', (257, 262))	('RCC', 'Phenotype', 'HP:0005584', (356, 359))	('ccRCC', 'Phenotype', 'HP:0006770', (354, 359))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (20, 51))	('RCC', 'Disease', (356, 359))
115671	23620406	3p21 tumor suppressors are frequently mutated in both the MSKCC (PBRM1, 30.3%; SETD2, 7.4%; BAP1, 6.4%) and the TCGA (PBRM1, 33.5%; SETD2, 11.6%; BAP1, 9.7%) cohorts.	('mutated', 'Var', (38, 45))	('SETD2', 'Gene', '29072', (132, 137))	('BAP1', 'Gene', '8314', (146, 150))	('PBRM1', 'Gene', '55193', (118, 123))	('SETD2', 'Gene', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('SETD2', 'Gene', '29072', (79, 84))	('PBRM1', 'Gene', (65, 70))	('MSKCC', 'Gene', (58, 63))	('BAP1', 'Gene', (146, 150))	('PBRM1', 'Gene', '55193', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('SETD2', 'Gene', (79, 84))	('BAP1', 'Gene', '8314', (92, 96))	('tumor', 'Disease', (5, 10))	('PBRM1', 'Gene', (118, 123))	('BAP1', 'Gene', (92, 96))
115672	23620406	BAP1 mutations are associated with worse CSS in both cohorts (MSKCC, p=0.002, HR 7.71 (2.08-28.6); TCGA, p=0.002, HR 2.21 (1.35-3.63)).	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('CSS', 'Disease', (41, 44))	('BAP1', 'Gene', '8314', (0, 4))	('CSS', 'Chemical', '-', (41, 44))
115674	23620406	On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS.	('CSS', 'Chemical', '-', (100, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('PBRM1', 'Gene', (17, 22))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('mutations', 'Var', (23, 32))	('CSS', 'Disease', (100, 103))	('PBRM1', 'Gene', '55193', (17, 22))
115676	23620406	BAP1 and SETD2 mutations (6-12%) are associated with worse CSS, suggesting their roles in disease progression.	('SETD2', 'Gene', (9, 14))	('CSS', 'Chemical', '-', (59, 62))	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (15, 24))	('CSS', 'Disease', (59, 62))	('SETD2', 'Gene', '29072', (9, 14))	('BAP1', 'Gene', '8314', (0, 4))
115677	23620406	PBRM1 mutations (30-34%) do not impact CSS, implicating its principal role in the tumor initiation.	('tumor initiation', 'Disease', (82, 98))	('PBRM1', 'Gene', (0, 5))	('CSS', 'MPA', (39, 42))	('PBRM1', 'Gene', '55193', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('CSS', 'Chemical', '-', (39, 42))	('tumor initiation', 'Disease', 'MESH:D009369', (82, 98))	('mutations', 'Var', (6, 15))
115683	23620406	Recent large scale targeted and whole exome sequencing studies of ccRCC, including our TCGA (the Cancer Genome Atlas) Consortium, have discovered novel, prevalent genomic alterations (Submitted, Nature, Copy for Reference), including frequent inactivation of several chromatin remodeling genes, PBRM1 (41%), SETD2 (3-12%), and BAP1 (8-11%).	('Cancer Genome Atlas', 'Disease', (97, 116))	('SETD2', 'Gene', '29072', (308, 313))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (97, 116))	('PBRM1', 'Gene', (295, 300))	('SETD2', 'Gene', (308, 313))	('BAP1', 'Gene', '8314', (327, 331))	('chromatin', 'cellular_component', 'GO:0000785', ('267', '276'))	('PBRM1', 'Gene', '55193', (295, 300))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('BAP1', 'Gene', (327, 331))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('267', '287'))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('alterations', 'Var', (171, 182))	('inactivation', 'NegReg', (243, 255))
115686	23620406	Strikingly, these mutations in ccRCC take place in the setting of a near ubiquitous single copy loss of 3p (>90%) (revised in Nature).	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))	('single copy loss of', 'Var', (84, 103))	('mutations', 'Var', (18, 27))
115687	23620406	Our previous single-institutional sequencing effort on 185 ccRCC patients focusing on pathologic correlations, not only consolidated recently reported mutation frequencies but also demonstrated the association of PBRM1, BAP1, and/or SETD2 mutations with higher tumor stage and, for BAP1, with higher tumor grade.	('mutations', 'Var', (239, 248))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('SETD2', 'Gene', (233, 238))	('BAP1', 'Gene', '8314', (220, 224))	('association', 'Interaction', (198, 209))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('SETD2', 'Gene', '29072', (233, 238))	('PBRM1', 'Gene', '55193', (213, 218))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('BAP1', 'Gene', '8314', (282, 286))	('PBRM1', 'Gene', (213, 218))	('BAP1', 'Gene', (220, 224))	('patients', 'Species', '9606', (65, 73))	('tumor', 'Disease', (261, 266))	('tumor', 'Disease', (300, 305))	('BAP1', 'Gene', (282, 286))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('tumor', 'Disease', 'MESH:D009369', (261, 266))
115688	23620406	Here, we focus on the impact of individual mutations of PBRM1, BAP1, and SETD2 on cancer specific survival in an expanded version of our original cohort (3 additional patients and several more months of followup and events) and further demonstrate the association of BAP1 and SETD2 mutations with worse cancer specific survival (the TCGA cohort n=421), providing a molecular link between gene mutations and cancer specific outcomes in ccRCC.	('cancer', 'Disease', (407, 413))	('cancer', 'Disease', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (407, 413))	('PBRM1', 'Gene', '55193', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (303, 309))	('BAP1', 'Gene', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('PBRM1', 'Gene', (56, 61))	('BAP1', 'Gene', '8314', (267, 271))	('worse', 'NegReg', (297, 302))	('SETD2', 'Gene', (276, 281))	('SETD2', 'Gene', (73, 78))	('cancer', 'Disease', 'MESH:D009369', (407, 413))	('RCC', 'Disease', (437, 440))	('RCC', 'Phenotype', 'HP:0005584', (437, 440))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('SETD2', 'Gene', '29072', (276, 281))	('SETD2', 'Gene', '29072', (73, 78))	('mutations', 'Var', (282, 291))	('BAP1', 'Gene', (267, 271))	('cancer', 'Disease', 'MESH:D009369', (303, 309))	('RCC', 'Disease', 'MESH:C538614', (437, 440))	('ccRCC', 'Phenotype', 'HP:0006770', (435, 440))	('patients', 'Species', '9606', (167, 175))	('mutations', 'Var', (43, 52))	('BAP1', 'Gene', '8314', (63, 67))
115709	23620406	Of the MSKCC cohort, VHL was mutated in 51.1% of tumors; PBRM1 in 30.3%; SETD2 in 7.4%; and BAP1 in 6.4%.	('SETD2', 'Gene', (73, 78))	('PBRM1', 'Gene', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('PBRM1', 'Gene', '55193', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('mutated', 'Var', (29, 36))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('VHL', 'Gene', (21, 24))	('BAP1', 'Gene', '8314', (92, 96))	('SETD2', 'Gene', '29072', (73, 78))	('VHL', 'Gene', '7428', (21, 24))	('BAP1', 'Gene', (92, 96))
115712	23620406	Similar co-occurrences of VHL and PBRM1 mutations (p=0.0002, OR 2.2, 95% CI 1.4, 3.4) as well as PBRM1 and SETD2 mutations (p=0.01, OR 2.3, 95% CI 1.3, 4.2) were seen as well.	('VHL', 'Gene', (26, 29))	('PBRM1', 'Gene', (34, 39))	('VHL', 'Gene', '7428', (26, 29))	('PBRM1', 'Gene', '55193', (34, 39))	('mutations', 'Var', (40, 49))	('SETD2', 'Gene', '29072', (107, 112))	('PBRM1', 'Gene', (97, 102))	('PBRM1', 'Gene', '55193', (97, 102))	('SETD2', 'Gene', (107, 112))
115713	23620406	In the MSKCC cohort, tumors with mutations of either PBRM1 or BAP1 were more likely to present with higher tumor stage 3-4 (p=0.01, OR 2.34, 95% CI 1.23, 4.58) and (p=0.04, OR 4.57, 95% CI 1.16, 30.26), respectively.	('PBRM1', 'Gene', '55193', (53, 58))	('BAP1', 'Gene', '8314', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (21, 26))	('tumors', 'Disease', (21, 27))	('BAP1', 'Gene', (62, 66))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('PBRM1', 'Gene', (53, 58))
115714	23620406	BAP1 mutations were associated with Fuhrman nuclear grade 3-4 tumors (p=0.03, OR 8.17, 95% CI 1.54, 150.94), while mutations of the remaining genes were not associated with grade.	('associated', 'Reg', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('BAP1', 'Gene', (0, 4))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (5, 14))	('Fuhrman nuclear', 'Disease', (36, 51))	('BAP1', 'Gene', '8314', (0, 4))
115715	23620406	In our TCGA cohort BAP1 mutations were significantly associated with multiple adverse tumor features including higher T stages (p=0.004, OR 2.62, 95% CI 1.36, 5.16), higher nuclear grades (p=0.02, OR 2.43, 95% CI 1.19, 5.36), larger tumor sizes (p=0.002, OR 3.8, 95% CI 1.68, 10.25), and the presence of metastasis at presentation (p=0.01, OR 2.74, 95% CI 1.3, 5.53).	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', (86, 91))	('higher T stages', 'CPA', (111, 126))	('BAP1', 'Gene', '8314', (19, 23))	('metastasis', 'CPA', (304, 314))	('associated', 'Reg', (53, 63))	('BAP1', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('adverse tumor', 'Disease', (78, 91))	('higher nuclear grades', 'CPA', (166, 187))	('adverse tumor', 'Disease', 'MESH:D064420', (78, 91))
115716	23620406	BAP1 mutations are significantly associated with worse CSS in the competing risk model (p=0.002, HR 7.71, 95% CI 2.08, 28.6 relative to patients without BAP1 mutations).	('BAP1', 'Gene', (0, 4))	('BAP1', 'Gene', '8314', (153, 157))	('mutations', 'Var', (5, 14))	('BAP1', 'Gene', '8314', (0, 4))	('patients', 'Species', '9606', (136, 144))	('BAP1', 'Gene', (153, 157))	('CSS', 'Disease', (55, 58))	('CSS', 'Chemical', '-', (55, 58))
115717	23620406	Interestingly, mutations of PBRM1 as well as VHL had no survival impact in both cohorts (Fig.	('VHL', 'Gene', '7428', (45, 48))	('mutations', 'Var', (15, 24))	('PBRM1', 'Gene', (28, 33))	('PBRM1', 'Gene', '55193', (28, 33))	('VHL', 'Gene', (45, 48))
115718	23620406	Median overall survival for BAP1 mutants in TCGA cohort is 31.2 months (95% CI 23.2, NA) vs 78.2 months (95% CI 70.3, NA) in wild type patients; median is not reached in the MSKCC cohort.	('BAP1', 'Gene', '8314', (28, 32))	('patients', 'Species', '9606', (135, 143))	('BAP1', 'Gene', (28, 32))	('mutants', 'Var', (33, 40))
115719	23620406	In the TCGA cohort mutations in SETD2 were also associated with CSS (p=0.036, HR 1.68, 95% CI 1.04, 2.73)).	('SETD2', 'Gene', '29072', (32, 37))	('SETD2', 'Gene', (32, 37))	('associated', 'Reg', (48, 58))	('mutations', 'Var', (19, 28))	('CSS', 'Disease', (64, 67))	('CSS', 'Chemical', '-', (64, 67))
115720	23620406	Median overall survival for SETD2 mutant in TCGA cohort is 62.7 months (95%CI 43.8, NA) vs 78.2 months (95% CI 71.8, NA) in wild type patients; in the MSKCC cohort median is 80.1 months (95% CI not estimable) for mutants and not reached for wild type.	('SETD2', 'Gene', (28, 33))	('SETD2', 'Gene', '29072', (28, 33))	('patients', 'Species', '9606', (134, 142))	('mutant', 'Var', (34, 40))
115722	23620406	In the MSKCC cohort 50% of the 12 BAP1 mutations were truncating mutations and had a substantially worse prognosis on cancer-specific survival (HR=17.83, 95% CI 5.1, 62.3, relative to patients without BAP1 mutation) compared to missense mutations (HR=3.63, 95% CI 0.4, 32.6).	('cancer', 'Disease', (118, 124))	('BAP1', 'Gene', (34, 38))	('patients', 'Species', '9606', (184, 192))	('BAP1', 'Gene', '8314', (201, 205))	('truncating', 'MPA', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mutations', 'Var', (39, 48))	('BAP1', 'Gene', (201, 205))	('BAP1', 'Gene', '8314', (34, 38))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('worse', 'NegReg', (99, 104))
115723	23620406	There were too few patients with SETD2 mutation to estimate the hazard ratios.	('SETD2', 'Gene', '29072', (33, 38))	('SETD2', 'Gene', (33, 38))	('mutation', 'Var', (39, 47))	('patients', 'Species', '9606', (19, 27))
115724	23620406	In the TCGA cohort 59% of mutations in BAP1 were truncating and they had similar effect on prognosis (HR=2.33, 95% CI 1.2, 4.5) as missense mutations (HR =2.06, 95% CI 1.05, 4.04) in the CSS model.	('truncating', 'MPA', (49, 59))	('CSS', 'Chemical', '-', (187, 190))	('mutations', 'Var', (26, 35))	('BAP1', 'Gene', '8314', (39, 43))	('missense mutations', 'Var', (131, 149))	('BAP1', 'Gene', (39, 43))
115725	23620406	Among SETD2 mutations 71% were truncating and they also had similar effect on prognosis as missense mutations (HR= 1.85, 95% CI 0.89, 3.84, and HR=1.59, 95% CI 0.87, 2.9, respectively) ((Supplemental Fig 1 for all curves).	('mutations', 'Var', (12, 21))	('SETD2', 'Gene', (6, 11))	('SETD2', 'Gene', '29072', (6, 11))	('truncating', 'MPA', (31, 41))
115726	23620406	Time to recurrence analysis within the TCGA data on 336 patients (72 recurrences) identified SETD2 mutations as a univariate predictor (p= 0.002, HR 2.5, 95% CI 1.38, 4.5).	('patients', 'Species', '9606', (56, 64))	('mutations', 'Var', (99, 108))	('SETD2', 'Gene', (93, 98))	('SETD2', 'Gene', '29072', (93, 98))
115727	23620406	No other 3p mutations were associated with disease recurrence (Supplemental Fig 2 for time to recurrence curves for SETD2).	('SETD2', 'Gene', (116, 121))	('SETD2', 'Gene', '29072', (116, 121))	('mutations', 'Var', (12, 21))	('disease', 'Disease', (43, 50))
115731	23620406	For example, BAP1 and SETD2 mutations co-occurred in only 3 patients (Figure 1).	('BAP1', 'Gene', (13, 17))	('SETD2', 'Gene', '29072', (22, 27))	('patients', 'Species', '9606', (60, 68))	('SETD2', 'Gene', (22, 27))	('BAP1', 'Gene', '8314', (13, 17))	('mutations', 'Var', (28, 37))
115732	23620406	There was no significant interaction between mutations affecting CSS with the exception of BAP1 and PBRM1 mutations (p=0.035).	('mutations', 'Var', (45, 54))	('BAP1', 'Gene', (91, 95))	('CSS', 'Gene', (65, 68))	('CSS', 'Chemical', '-', (65, 68))	('PBRM1', 'Gene', (100, 105))	('mutations', 'Var', (106, 115))	('BAP1', 'Gene', '8314', (91, 95))	('PBRM1', 'Gene', '55193', (100, 105))
115733	23620406	Having a BAP1 mutation alone leads to increased risk of cancer death with HR=1.78 (95% CI 0.99, 3.23), having PBRM1 alone has HR 0.86 (95% CI 0.54, 1.37), but having both BAP1 and PBRM1 has a HR of 4.18, (95% CI 2.17, 8.05) consistent with a recent report (Supplemental Fig 3 & 4).	('cancer death', 'Disease', 'MESH:D003643', (56, 68))	('BAP1', 'Gene', (171, 175))	('cancer death', 'Disease', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('BAP1', 'Gene', '8314', (9, 13))	('mutation', 'Var', (14, 22))	('PBRM1', 'Gene', (180, 185))	('BAP1', 'Gene', '8314', (171, 175))	('PBRM1', 'Gene', '55193', (180, 185))	('BAP1', 'Gene', (9, 13))	('PBRM1', 'Gene', (110, 115))	('PBRM1', 'Gene', '55193', (110, 115))
115734	23620406	To further explore the impact of BAP1 and SETD2 mutations on postoperative prognostic modeling of CSS, the effects of each of these mutations were estimated after adjusting for clinical stage (1 and 2 vs 3 vs 4) and nuclear grade (1, 2 vs 3,4) in the TCGA cohort.	('BAP1', 'Gene', '8314', (33, 37))	('CSS', 'Disease', (98, 101))	('SETD2', 'Gene', '29072', (42, 47))	('CSS', 'Chemical', '-', (98, 101))	('BAP1', 'Gene', (33, 37))	('SETD2', 'Gene', (42, 47))	('mutations', 'Var', (48, 57))
115735	23620406	As expected, given the strong link of these mutations to adverse tumor features, both BAP1 (p=0.73, HR 1.09, 95% CI, 0.67,1.76), and SETD2 (p=0.73, HR 1.1, 95% CI 0.64, 1.9) mutations were no longer significant after inclusion of stage and grade.	('adverse tumor', 'Disease', 'MESH:D064420', (57, 70))	('SETD2', 'Gene', '29072', (133, 138))	('BAP1', 'Gene', '8314', (86, 90))	('SETD2', 'Gene', (133, 138))	('BAP1', 'Gene', (86, 90))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('adverse tumor', 'Disease', (57, 70))
115736	23620406	Given the near ubiquitous loss of one copy of 3p (>90%) and the prevalent concurrent mutations of VHL, PBRM1, SETD2, and BAP1 in ccRCC, we exploited the wealth of genomic information available on the TCGA cohort to interrogate the contribution of individual 3p tumor suppressor mutations to disease progression.	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('BAP1', 'Gene', (121, 125))	('PBRM1', 'Gene', '55193', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('PBRM1', 'Gene', (103, 108))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('261', '277'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('261', '277'))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('VHL', 'Gene', (98, 101))	('mutations', 'Var', (85, 94))	('loss', 'NegReg', (26, 30))	('SETD2', 'Gene', (110, 115))	('BAP1', 'Gene', '8314', (121, 125))	('tumor', 'Disease', (261, 266))	('VHL', 'Gene', '7428', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('SETD2', 'Gene', '29072', (110, 115))
115737	23620406	We first determined the number of potential tumor suppressor mutations (concurrent copy number loss and mutations) present through disease progression, according to size, nuclear grade, and clinical stage.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('mutations', 'Var', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('copy number loss', 'Var', (83, 99))	('tumor', 'Disease', (44, 49))
115738	23620406	There is a trend of a small, but statistically significant steady increase (~3 to ~6) of mutations in candidate tumor suppressor genes (TSG) with advancing disease (Size (continuous) p=0.006; Grade, p=0.001; Stage, p=0.0002) (Fig 4 top panels), highlighting the fact that loss of function in a small number of TSGs is likely critical in both disease initiation and progression of ccRCC.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('112', '128'))	('increase', 'PosReg', (66, 74))	('RCC', 'Phenotype', 'HP:0005584', (382, 385))	('RCC', 'Disease', 'MESH:C538614', (382, 385))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('RCC', 'Disease', (382, 385))	('ccRCC', 'Phenotype', 'HP:0006770', (380, 385))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutations', 'Var', (89, 98))	('tumor', 'Disease', (112, 117))	('tumor suppressor', 'biological_process', 'GO:0051726', ('112', '128'))
115739	23620406	Importantly, the sum mutations of these four 3p TSGs makes up a very large portion of the total candidate TSG mutations discovered in ccRCC, further pinpointing the unique clustering of critical ccRCC TSGs on chromosome 3p21-25.	('mutations', 'Var', (110, 119))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('RCC', 'Phenotype', 'HP:0005584', (197, 200))	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('ccRCC', 'Phenotype', 'HP:0006770', (195, 200))	('RCC', 'Disease', (197, 200))	('chromosome', 'cellular_component', 'GO:0005694', ('209', '219'))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))
115740	23620406	The relatively steady in frequency, predominant mutations of VHL and PBRM1 through disease progression suggest their principal role in the initiation rather than the progression phase of the disease (Fig 4 middle and bottom panels and Supplemental Fig 5).	('PBRM1', 'Gene', (69, 74))	('VHL', 'Gene', (61, 64))	('VHL', 'Gene', '7428', (61, 64))	('PBRM1', 'Gene', '55193', (69, 74))	('mutations', 'Var', (48, 57))
115741	23620406	Increased rates of BAP1 mutations trended with increasing nuclear grades and clinical stages.	('mutations', 'Var', (24, 33))	('nuclear grades', 'CPA', (58, 72))	('BAP1', 'Gene', '8314', (19, 23))	('BAP1', 'Gene', (19, 23))
115746	23620406	Both cohorts identified VHL mutations in more than half of the 609 tumors examined.	('VHL', 'Gene', '7428', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('VHL', 'Gene', (24, 27))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('mutations', 'Var', (28, 37))
115748	23620406	Additionally, we saw no correlation between the status of VHL mutations and clinical/pathologic features or CSS, which concurs with most prior reports.	('CSS', 'Chemical', '-', (108, 111))	('VHL', 'Gene', (58, 61))	('VHL', 'Gene', '7428', (58, 61))	('CSS', 'Disease', (108, 111))	('mutations', 'Var', (62, 71))
115753	23620406	Recent genomic data also implicated PBRM1 mutations in the evolution of pancreatic cancer.	('PBRM1', 'Gene', (36, 41))	('PBRM1', 'Gene', '55193', (36, 41))	('pancreatic cancer', 'Disease', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (72, 89))	('implicated', 'Reg', (25, 35))	('mutations', 'Var', (42, 51))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (72, 89))
115754	23620406	In line with the initial PBRM1 mutation study in ccRCC, PBRM1 was mutated at 32.5% (198/609) in our patients and nearly all of which were truncating mutants.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('mutated', 'Var', (66, 73))	('PBRM1', 'Gene', (25, 30))	('PBRM1', 'Gene', (56, 61))	('patients', 'Species', '9606', (100, 108))	('truncating', 'Var', (138, 148))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('PBRM1', 'Gene', '55193', (25, 30))	('PBRM1', 'Gene', '55193', (56, 61))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
115755	23620406	Intriguingly, analysis of our MSKCC cohort demonstrated a significant association of PBRM1 mutations with higher T stages, which was at odds with the data obtained from the TCGA cohort.	('higher T stages', 'CPA', (106, 121))	('PBRM1', 'Gene', (85, 90))	('PBRM1', 'Gene', '55193', (85, 90))	('mutations', 'Var', (91, 100))
115757	23620406	Of note, 30% of small tumors (<4cm) in our MSKCC cohort were classified as pT3a diseases and such pathologic upstaging strongly associated with PBRM1 mutations, whereas only 7% of small tumors in the TCGA cohort were at pT3a.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('PBRM1', 'Gene', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('small tumors', 'Disease', 'MESH:D058405', (180, 192))	('PBRM1', 'Gene', '55193', (144, 149))	('associated', 'Reg', (128, 138))	('pT3a', 'Disease', (75, 79))	('small tumors', 'Disease', (16, 28))	('mutations', 'Var', (150, 159))	('small tumors', 'Disease', (180, 192))	('small tumors', 'Disease', 'MESH:D058405', (16, 28))
115758	23620406	Although PBRM1 mutations may be associated with earlier invasion in smaller tumors, both our cohorts did not find any other clinical associations.	('mutations', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('associated', 'Reg', (32, 42))	('PBRM1', 'Gene', (9, 14))	('PBRM1', 'Gene', '55193', (9, 14))
115759	23620406	These data coupled with the high, stable mutation frequency of PBRM1 across tumor size, nuclear grade, and clinical stage (Fig 4) suggests that inactivation of PBRM1 likely constitute an early, essential event in kidney tumorigenesis.	('PBRM1', 'Gene', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (220, 225))	('PBRM1', 'Gene', '55193', (160, 165))	('tumor', 'Disease', (76, 81))	('inactivation', 'Var', (144, 156))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('PBRM1', 'Gene', (63, 68))	('PBRM1', 'Gene', '55193', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
115760	23620406	Importantly, both cohorts identified BAP1 mutation as a poor prognostic factor.	('mutation', 'Var', (42, 50))	('BAP1', 'Gene', (37, 41))	('BAP1', 'Gene', '8314', (37, 41))
115761	23620406	BAP1 mutations were also identified in uveal melanoma and mesothelioma.	('BAP1', 'Gene', (0, 4))	('identified', 'Reg', (25, 35))	('mesothelioma', 'Disease', (58, 70))	('uveal melanoma', 'Disease', 'MESH:C536494', (39, 53))	('mutations', 'Var', (5, 14))	('uveal melanoma', 'Phenotype', 'HP:0007716', (39, 53))	('uveal melanoma', 'Disease', (39, 53))	('mesothelioma', 'Disease', 'MESH:D008654', (58, 70))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('BAP1', 'Gene', '8314', (0, 4))
115763	23620406	In contrast, BAP1 mutations in mesothelioma did not associate with worse clinical outcomes in a recent report.	('BAP1', 'Gene', (13, 17))	('mesothelioma', 'Disease', (31, 43))	('mesothelioma', 'Disease', 'MESH:D008654', (31, 43))	('BAP1', 'Gene', '8314', (13, 17))	('mutations', 'Var', (18, 27))
115766	23620406	Our study interconnected BAP1 mutations with essentially all known, validated poor prognostic factors, including higher tumor stage, higher nuclear grade, larger size, more necrosis, and the presence of metastatic disease at presentation (Table 2), which further supports the strong association between BAP1 mutations and cancer specific survival.	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('BAP1', 'Gene', (25, 29))	('BAP1', 'Gene', (303, 307))	('mutations', 'Var', (308, 317))	('necrosis', 'biological_process', 'GO:0008219', ('173', '181'))	('necrosis', 'Disease', 'MESH:D009336', (173, 181))	('tumor', 'Disease', (120, 125))	('cancer', 'Disease', (322, 328))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('necrosis', 'biological_process', 'GO:0008220', ('173', '181'))	('mutations', 'Var', (30, 39))	('necrosis', 'Disease', (173, 181))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('BAP1', 'Gene', '8314', (25, 29))	('BAP1', 'Gene', '8314', (303, 307))	('necrosis', 'biological_process', 'GO:0070265', ('173', '181'))	('necrosis', 'biological_process', 'GO:0019835', ('173', '181'))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('necrosis', 'biological_process', 'GO:0001906', ('173', '181'))
115767	23620406	In addition to BAP1 mutations, we demonstrated a strong association between SETD2 mutations and worse cancer specific survival in the TCGA cohort.	('SETD2', 'Gene', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('mutations', 'Var', (82, 91))	('BAP1', 'Gene', '8314', (15, 19))	('SETD2', 'Gene', '29072', (76, 81))	('BAP1', 'Gene', (15, 19))
115768	23620406	Intriguingly, mutations of SETD2 but not other 3p tumor suppressors were associated with increased likelihood of developing recurrent and/or metastatic diseases.	('recurrent and/or', 'CPA', (124, 140))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('SETD2', 'Gene', '29072', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('SETD2', 'Gene', (27, 32))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', (50, 55))
115769	23620406	Since macro- and microscopic prognostic surrogates can only be defined postoperatively, clinical implications of mutations in these chromatin modulators/modifiers could impact preoperative risk stratification given their strong association with known adverse tumor features.	('chromatin', 'cellular_component', 'GO:0000785', ('132', '141'))	('adverse tumor', 'Disease', (251, 264))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('mutations', 'Var', (113, 122))	('adverse tumor', 'Disease', 'MESH:D064420', (251, 264))	('association', 'Interaction', (228, 239))	('impact', 'Reg', (169, 175))
115770	23620406	As BAP1 mutations are highly correlative with the protein loss determined by immunohistochemistry, it might be beneficial to determine its mutation/expression status in smaller renal masses, which could guide treatment planning, i.e.	('BAP1', 'Gene', '8314', (3, 7))	('loss', 'NegReg', (58, 62))	('BAP1', 'Gene', (3, 7))	('renal masses', 'Phenotype', 'HP:0009726', (177, 189))	('mutations', 'Var', (8, 17))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('protein', 'Protein', (50, 57))
115773	23620406	Loss of function mutations of PBRM1 (30-34%) constitute the second most common genetic event in ccRCC but do not impact clinical outcome, implicating its principal role in tumor initiation.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('PBRM1', 'Gene', (30, 35))	('tumor initiation', 'Disease', 'MESH:D009369', (172, 188))	('PBRM1', 'Gene', '55193', (30, 35))	('tumor initiation', 'Disease', (172, 188))	('RCC', 'Disease', (98, 101))	('Loss of function', 'NegReg', (0, 16))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (96, 101))	('mutations', 'Var', (17, 26))
115774	23620406	BAP1 and SETD2 mutations are associated with worse cancer specific survival and likely take place during the disease progression phase.	('SETD2', 'Gene', (9, 14))	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('worse', 'NegReg', (45, 50))	('SETD2', 'Gene', '29072', (9, 14))	('BAP1', 'Gene', '8314', (0, 4))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
115775	23620406	Several recurrent mutations in 3p chromatin modulators/modifiers (PBRM1, SETD2, and BAP1) have been reported in clear cell renal cell carcinoma (ccRCC) in the past two years.	('SETD2', 'Gene', (73, 78))	('reported', 'Reg', (100, 108))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (112, 143))	('BAP1', 'Gene', '8314', (84, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (145, 150))	('PBRM1', 'Gene', (66, 71))	('clear cell renal cell carcinoma', 'Disease', (112, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (123, 143))	('chromatin', 'cellular_component', 'GO:0000785', ('34', '43'))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (112, 143))	('SETD2', 'Gene', '29072', (73, 78))	('BAP1', 'Gene', (84, 88))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('PBRM1', 'Gene', '55193', (66, 71))	('mutations', 'Var', (18, 27))
115776	23620406	We report the association of adverse cancer specific outcomes with mutations of BAP1 and SETD2 in two large, distinct cohorts.	('adverse cancer', 'Disease', 'MESH:D064420', (29, 43))	('SETD2', 'Gene', '29072', (89, 94))	('association', 'Interaction', (14, 25))	('BAP1', 'Gene', '8314', (80, 84))	('adverse cancer', 'Disease', (29, 43))	('mutations', 'Var', (67, 76))	('SETD2', 'Gene', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('BAP1', 'Gene', (80, 84))
115834	23691329	Patients who received HAIC compared to patients who received IV chemotherapy had a significantly higher RR (47% versus 24%, P = 0.012) and a longer median OS (24.4 months versus 20.0 months; P = 0.003).	('Patients', 'Species', '9606', (0, 8))	('higher', 'PosReg', (97, 103))	('patients', 'Species', '9606', (39, 47))	('HAIC', 'Var', (22, 26))
115835	23691329	Patients treated with HAIC had a significantly longer time to hepatic progression compared to patients who received IV chemotherapy (9.8 months versus 7.3 months; P = 0.034), but a significantly shorter time to extrahepatic progression (7.7 months versus 14.8 months; P = 0.029).	('patients', 'Species', '9606', (94, 102))	('hepatic progression', 'MPA', (62, 81))	('shorter', 'NegReg', (195, 202))	('HAIC', 'Var', (22, 26))	('Patients', 'Species', '9606', (0, 8))	('extrahepatic progression', 'MPA', (211, 235))
115849	23691329	Although the RR was significantly higher in patients receiving HAIC than in patients receiving intravenous chemotherapy (42.9% versus 18.4%, P < 0.001), the median OS was not significantly longer (15.9 months versus 12.4 months, P = 0.240).	('patients', 'Species', '9606', (76, 84))	('HAIC', 'Var', (63, 67))	('higher', 'PosReg', (34, 40))	('patients', 'Species', '9606', (44, 52))
115894	23691329	The overall RR was significantly higher for patients who received HAIC than those patients who received intravenous chemotherapy (21.7% versus 8.0%).	('patients', 'Species', '9606', (82, 90))	('HAIC', 'Var', (66, 70))	('higher', 'PosReg', (33, 39))	('patients', 'Species', '9606', (44, 52))
115982	32631003	According to the AJCC TNM classification, 4 cases (11.1%) were T1aN0M0, 8 cases (22.3%) were T2aN0M0, 2 cases (5.5%) were T2bN0M0, 15 cases (41.7%) were T3aN0M0, 4 cases (11.1%) were T3bN0M0, 1 case (2.8%) was T4aN0M0, and 2 cases (5.5%) were T4bN0M0.	('TNM', 'Gene', (22, 25))	('T2aN0M0', 'Var', (93, 100))	('T2bN0M0', 'Var', (122, 129))	('T3bN0M0', 'Var', (183, 190))	('T1aN0M0', 'Var', (63, 70))	('TNM', 'Gene', '10178', (22, 25))	('T3aN0M0', 'Var', (153, 160))
116056	31416209	Overall, we identified monosomy 3 in two cases, 8q gain in six cases, and both alterations in three cases.	('monosomy 3', 'Var', (23, 33))	('thre', 'Chemical', '-', (94, 98))	('gain', 'PosReg', (51, 55))
116057	31416209	All cases presented GNAQ or GNA11 mutations assessed by a custom next-generation sequencing panel.	('GNAQ', 'Gene', '2776', (20, 24))	('GNA11', 'Gene', (28, 33))	('GNAQ', 'Gene', (20, 24))	('GNA11', 'Gene', '2767', (28, 33))	('mutations', 'Var', (34, 43))
116064	31416209	Moreover, choroidal melanoma cells frequently acquire chromosomal aberrations, that include chromosome 3 monosomy and chromosome 8q gain, and less frequently, partial chromosome 6 additions or deletions.	('deletions', 'Var', (193, 202))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (10, 28))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (54, 77))	('partial chromosome', 'Var', (159, 177))	('chromosome', 'Var', (118, 128))	('chromosome', 'cellular_component', 'GO:0005694', ('118', '128'))	('chromosome', 'Var', (92, 102))	('gain', 'PosReg', (132, 136))	('choroidal melanoma', 'Disease', 'MESH:D008545', (10, 28))	('chromosome', 'cellular_component', 'GO:0005694', ('92', '102'))	('chromosome', 'cellular_component', 'GO:0005694', ('167', '177'))	('choroidal melanoma', 'Disease', (10, 28))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))
116065	31416209	In the clinical setting, chromosomal modifications of the primary uveal tumor are of high clinical relevance since they have been extensively shown by numerous investigators to correlate with the metastatic prognosis.	('correlate', 'Reg', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('metastatic prognosis', 'CPA', (196, 216))	('chromosomal modifications', 'Var', (25, 50))	('uveal tumor', 'Disease', 'MESH:D014604', (66, 77))	('uveal tumor', 'Disease', (66, 77))
116089	31416209	They observed concordant chromosome 3 status among all four cases, concordant chromosome 8 status (among thre cases with pre- and post-irradiation exploration of chromosome 8), and one case with discordant chromosome 6p status (among two cases with exploitable pre- and post-irradiation data).	('thre', 'Chemical', '-', (105, 109))	('chromosome', 'cellular_component', 'GO:0005694', ('206', '216'))	('pre', 'molecular_function', 'GO:0003904', ('261', '264'))	('chromosome', 'cellular_component', 'GO:0005694', ('78', '88'))	('chromosome', 'cellular_component', 'GO:0005694', ('25', '35'))	('concordant', 'Var', (14, 24))	('chromosome', 'Var', (25, 35))	('chromosome', 'cellular_component', 'GO:0005694', ('162', '172'))	('pre', 'molecular_function', 'GO:0003904', ('121', '124'))
116100	31416209	showed that uveal melanomas accumulate copy number alterations not only during the metastatic process but also during local progression with more copy number alterations being present in larger primary tumors than in smaller ones, suggesting that these aberrations accumulate since early stages.	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('uveal melanomas', 'Disease', 'MESH:C536494', (12, 27))	('uveal melanoma', 'Phenotype', 'HP:0007716', (12, 26))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('copy number alterations', 'Var', (146, 169))	('copy number alterations', 'Var', (39, 62))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))	('uveal melanomas', 'Disease', (12, 27))	('uveal melanomas', 'Phenotype', 'HP:0007716', (12, 27))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
116104	31416209	Among aberrations affecting chromosomes other than 3 and 8 detected in this study, the more frequent were chromosome 6 additions (6p) or more rarely deletions (6q), present in 20 of the 24 studied tumors (83%).	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('chromosome', 'cellular_component', 'GO:0005694', ('106', '116'))	('tumors', 'Disease', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('chromosome 6 additions', 'Var', (106, 128))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('deletions', 'Var', (149, 158))
116105	31416209	Additions of 6p have been long considered to result from alternative genetic tumorigenesis pathways, and to be associated with a favorable prognosis.	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Additions', 'Var', (0, 9))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (77, 82))
116106	31416209	Similarly, chromosome 6 alterations were also more frequent in metastatic tumors than in primary tumors according to the article of Rodrigues et al..	('alterations', 'Var', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('chromosome 6', 'Gene', (11, 23))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('chromosome', 'cellular_component', 'GO:0005694', ('11', '21'))	('frequent', 'Reg', (51, 59))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
116143	31416209	Presence of total or partial chromosome 3 loss and/or chromosome 8q gain; Absence of alteration on chromosomes 3 and 8, but presence of other chromosomal alterations or identification of GNAQ and/or GNA11 mutations on the NGS Panel, confirming the diagnosis of choroidal melanoma; Non-contributive sample: insufficient DNA amount or quality.	('chromosome', 'cellular_component', 'GO:0005694', ('54', '64'))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (261, 279))	('chromosome', 'cellular_component', 'GO:0005694', ('29', '39'))	('mutations', 'Var', (205, 214))	('GNAQ', 'Gene', '2776', (187, 191))	('GNA11', 'Gene', (199, 204))	('DNA', 'cellular_component', 'GO:0005574', ('319', '322'))	('melanoma', 'Phenotype', 'HP:0002861', (271, 279))	('choroidal melanoma', 'Disease', 'MESH:D008545', (261, 279))	('GNA11', 'Gene', '2767', (199, 204))	('choroidal melanoma', 'Disease', (261, 279))	('chromosome 8q', 'Gene', (54, 67))	('GNAQ', 'Gene', (187, 191))	('gain', 'PosReg', (68, 72))	('loss', 'NegReg', (42, 46))
116144	31416209	The NGS panel was employed to confirm the presence of GNAQ or GNA11 mutations, as expected in uveal melanoma samples.	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('GNAQ', 'Gene', (54, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('uveal melanoma', 'Disease', (94, 108))	('GNAQ', 'Gene', '2776', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('mutations', 'Var', (68, 77))	('GNA11', 'Gene', '2767', (62, 67))	('GNA11', 'Gene', (62, 67))
116148	31357444	Infectious Knockdown of CREB and HIF-1 for the Treatment of Metastatic Uveal Melanoma Uveal melanoma (UM) is the most prevalent primary intraocular cancer in adults.	('intraocular cancer', 'Disease', (136, 154))	('Metastatic Uveal Melanoma', 'Disease', (60, 85))	('HIF-1', 'Gene', '3091', (33, 38))	('Knockdown', 'Var', (11, 20))	('CREB', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('intraocular cancer', 'Disease', 'MESH:D064090', (136, 154))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('HIF-1', 'Gene', (33, 38))	('UM', 'Phenotype', 'HP:0007716', (102, 104))	('CREB', 'Gene', '1385', (24, 28))	('Melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('Metastatic Uveal Melanoma', 'Disease', 'MESH:C536494', (60, 85))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (71, 85))
116156	31357444	Here, we demonstrate that the knockdown of CREB or HIF-1 in UM cells dramatically decreases UM tumor progression.	('HIF-1', 'Gene', (51, 56))	('HIF-1', 'Gene', '3091', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('knockdown', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('UM', 'Phenotype', 'HP:0007716', (92, 94))	('decreases', 'NegReg', (82, 91))	('tumor', 'Disease', (95, 100))	('CREB', 'Gene', (43, 47))
116181	31357444	We have previously demonstrated that the overexpression of a dominant-positive, hypoxia-insensitive CREB300/310 mutant enhanced tumor growth, vascularization, and abrogated hypoxia-induced apoptosis, while the dominant-negative form of CREB (KCREB) or knock-down of CREB abolished mouse hepatocellular carcinoma (HCC) tumor growth.	('apoptosis', 'biological_process', 'GO:0097194', ('189', '198'))	('mouse', 'CPA', (281, 286))	('apoptosis', 'biological_process', 'GO:0006915', ('189', '198'))	('KCREB', 'Chemical', '-', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mutant', 'Var', (112, 118))	('enhanced', 'PosReg', (119, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('abolished', 'NegReg', (271, 280))	('tumor', 'Disease', (318, 323))	('hepatocellular carcinoma (HCC) tumor', 'Disease', 'MESH:D006528', (287, 323))	('hypoxia', 'Disease', (173, 180))	('hypoxia', 'Disease', (80, 87))	('vascularization', 'CPA', (142, 157))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('abrogated', 'NegReg', (163, 172))	('CREB300/310', 'Gene', (100, 111))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (287, 311))	('tumor', 'Disease', (128, 133))	('overexpression', 'PosReg', (41, 55))	('hypoxia', 'Disease', 'MESH:D000860', (173, 180))	('mouse', 'Species', '10090', (281, 286))	('hypoxia', 'Disease', 'MESH:D000860', (80, 87))	('HCC', 'Phenotype', 'HP:0001402', (313, 316))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))
116184	31357444	CREB knockdown increased UM cells' sensitivity to chemotherapy (decarbazin:DTIC and doxorubicin:DOX), as in the HCC cells, an effect that was stronger in hypoxia.	('decarbazin', 'Chemical', '-', (64, 74))	('doxorubicin', 'Chemical', 'MESH:D004317', (84, 95))	('DOX', 'Chemical', 'MESH:D004317', (96, 99))	('hypoxia', 'Disease', (154, 161))	('CREB', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('hypoxia', 'Disease', 'MESH:D000860', (154, 161))	('increased', 'PosReg', (15, 24))	('DTIC', 'Chemical', 'MESH:D003606', (75, 79))	('HCC', 'Phenotype', 'HP:0001402', (112, 115))	('UM', 'Phenotype', 'HP:0007716', (25, 27))
116187	31357444	A point mutation in the target sequence against which we design shRNAs can result in tumor resistance to the treatment.	('tumor', 'Disease', (85, 90))	('result in', 'Reg', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('point mutation', 'Var', (2, 16))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
116207	31357444	The mean weight of the tumors infected with an armed virus knocked down HIF-1 was only 42% of the mean tumor weight of the control tumors, and the mean weight of the tumors infected with an armed virus that knocked down CREB was only 16% of the mean control tumor.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (258, 263))	('knocked down', 'Var', (59, 71))	('tumor', 'Disease', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('HIF-1', 'Gene', '3091', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('HIF-1', 'Gene', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumors infected', 'Disease', 'MESH:D009369', (166, 181))	('tumors', 'Disease', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (103, 108))	('tumors infected', 'Disease', 'MESH:D009369', (23, 38))	('tumor', 'Disease', (166, 171))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors infected', 'Disease', (166, 181))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumors infected', 'Disease', (23, 38))	('tumors', 'Disease', 'MESH:D009369', (131, 137))
116216	31357444	In a previous work, we demonstrated in vitro that knockdown of CREB in hypoxia, following infection with vACE-CREB, increased apoptosis by 50% and decreased the expression of CREB-regulated genes such VEGF in two UM cell lines Mel270 and OMM2.5.	('vACE-CREB', 'Gene', (105, 114))	('VEGF', 'Gene', (201, 205))	('hypoxia', 'Disease', (71, 78))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('expression', 'MPA', (161, 171))	('knockdown', 'Var', (50, 59))	('decreased', 'NegReg', (147, 156))	('apoptosis', 'CPA', (126, 135))	('vACE-CREB', 'Gene', '1385', (105, 114))	('VEGF', 'Gene', '7422', (201, 205))	('increased', 'PosReg', (116, 125))	('UM', 'Phenotype', 'HP:0007716', (213, 215))	('hypoxia', 'Disease', 'MESH:D000860', (71, 78))
116217	31357444	In this work we demonstrate for the first-time inhibition of uveal melanoma growth in a mouse model, following knockdown of either CREB or HIF-1 by a replication competent retrovirus vector.	('knockdown', 'Var', (111, 120))	('HIF-1', 'Gene', '3091', (139, 144))	('inhibition', 'NegReg', (47, 57))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('mouse', 'Species', '10090', (88, 93))	('HIF-1', 'Gene', (139, 144))	('uveal melanoma growth', 'Disease', (61, 82))	('uveal melanoma growth', 'Disease', 'MESH:C536494', (61, 82))
116224	31357444	These results suggest that even partial knockdown (about 50% in vitro) of either one of these transcription factors had a major effect on tumor progression.	('transcription', 'biological_process', 'GO:0006351', ('94', '107'))	('tumor', 'Disease', (138, 143))	('knockdown', 'Var', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
116225	31357444	Moreover, we have previously shown in hepatocellular carcinoma that knockdown of either CREB or HIF-1 reduced the expression of VEGF within the tumors which resulted in a decrease in hypoxia-guided neovascularization.	('tumors', 'Disease', (144, 150))	('HIF-1', 'Gene', '3091', (96, 101))	('VEGF', 'Gene', (128, 132))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (38, 62))	('hepatocellular carcinoma', 'Disease', (38, 62))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (38, 62))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('decrease', 'NegReg', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('HIF-1', 'Gene', (96, 101))	('VEGF', 'Gene', '7422', (128, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('knockdown', 'Var', (68, 77))	('expression', 'MPA', (114, 124))	('hypoxia', 'Disease', 'MESH:D000860', (183, 190))	('reduced', 'NegReg', (102, 109))	('hypoxia', 'Disease', (183, 190))
116226	31357444	The abrogation of VEGF may be responsible for the stronger effect in UM seen in vivo in the current study compared to the in vitro results in our previous study.	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('abrogation', 'Var', (4, 14))	('VEGF', 'Gene', '7422', (18, 22))	('VEGF', 'Gene', (18, 22))
116229	31357444	However, when the expression of either CREB or HIF-1 was knocked down, the expression of their downstream gene glut-1 was abolished.	('expression', 'MPA', (75, 85))	('glut-1', 'Gene', '6513', (111, 117))	('glut-1', 'Gene', (111, 117))	('knocked', 'Var', (57, 64))	('HIF-1', 'Gene', '3091', (47, 52))	('expression', 'MPA', (18, 28))	('HIF-1', 'Gene', (47, 52))	('abolished', 'NegReg', (122, 131))
116234	31357444	Following the knockdown of either CREB or HIF-1, there was a reduction in Glut-1 expression resulting in limited energy supply preventing UM tumors proliferation in hypoxia.	('Glut-1', 'Gene', (74, 80))	('HIF-1', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('UM', 'Phenotype', 'HP:0007716', (138, 140))	('tumors', 'Disease', (141, 147))	('reduction', 'NegReg', (61, 70))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('hypoxia', 'Disease', 'MESH:D000860', (165, 172))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('HIF-1', 'Gene', '3091', (42, 47))	('hypoxia', 'Disease', (165, 172))	('knockdown', 'Var', (14, 23))	('limited', 'NegReg', (105, 112))	('energy supply', 'MPA', (113, 126))	('expression', 'MPA', (81, 91))
116245	31357444	Our previous results, demonstrated that knockdown of CREB resulted in increased sensitivity to chemotherapeutic agents (doxorubicin and decarbazin).	('increased', 'PosReg', (70, 79))	('knockdown', 'Var', (40, 49))	('doxorubicin', 'Chemical', 'MESH:D004317', (120, 131))	('sensitivity to chemotherapeutic agents', 'MPA', (80, 118))	('CREB', 'Gene', (53, 57))	('decarbazin', 'Chemical', '-', (136, 146))
116251	31357444	HIF-1:  fp-5'_GGGATTAACTCAGTTTGAACTAACTGG_3', rp-5'_CCTTTTTCACAAGGCCATTTCTGTGTG_3'.	('HIF-1', 'Gene', '3091', (0, 5))	("fp-5'_GGGATTAACTCAGTTTGAACTAACTGG_3", 'Var', (8, 43))	('HIF-1', 'Gene', (0, 5))	("rp-5'_CCTTTTTCACAAGGCCATTTCTGTGTG_3", 'Var', (46, 81))
116252	31357444	beta-actin:  fp-5'_CCTTCCTGGGCATGGAGTCC_3', rp-5'_GTGTTGGCGTACAGGTCTTTGC_3'.	('beta-actin', 'Gene', '728378', (0, 10))	("rp-5'_GTGTTGGCGTACAGGTCTTTGC_3", 'Var', (44, 74))	('beta-actin', 'Gene', (0, 10))
116271	31357444	We have confirmed UM's resistance to hypoxia in vitro, and used armed viruses that knock down the expression of the regulators of cellular response to hypoxia, CREB, and HIF-1 to learn whether inhibiting the cells' response to hypoxia would result in diminished tumor growth.	('hypoxia', 'Disease', 'MESH:D000860', (227, 234))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('HIF-1', 'Gene', '3091', (170, 175))	('response to hypoxia', 'biological_process', 'GO:0001666', ('215', '234'))	('cellular response to hypoxia', 'biological_process', 'GO:0071456', ('130', '158'))	('UM', 'Phenotype', 'HP:0007716', (18, 20))	('hypoxia', 'Disease', (37, 44))	('hypoxia', 'Disease', 'MESH:D000860', (37, 44))	('tumor', 'Disease', (262, 267))	('diminished', 'NegReg', (251, 261))	('HIF-1', 'Gene', (170, 175))	('hypoxia', 'Disease', 'MESH:D000860', (151, 158))	('knock', 'Var', (83, 88))	('hypoxia', 'Disease', (151, 158))	('hypoxia', 'Disease', (227, 234))	('tumor', 'Disease', 'MESH:D009369', (262, 267))
116272	31357444	Despite the lack of response in vitro, here we found that knockdown of CREB or HIF-1 in vivo resulted in a markedly decreased tumor growth rate.	('HIF-1', 'Gene', (79, 84))	('CREB', 'Gene', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('HIF-1', 'Gene', '3091', (79, 84))	('knockdown', 'Var', (58, 67))	('decreased', 'NegReg', (116, 125))	('tumor', 'Disease', (126, 131))
116273	31357444	The resulting tumors were smaller in size and weight, had no vasculature growing into them, and had increased expression of vasculogenic mimicry patterns (more so with the knockdown of CREB).	('increased', 'PosReg', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('expression', 'MPA', (110, 120))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('vasculogenic mimicry patterns', 'MPA', (124, 153))	('smaller', 'NegReg', (26, 33))	('knockdown', 'Var', (172, 181))
116274	31357444	The expression of the major cancer glucose transporter Glut-1, which is regulated by CREB and HIF-1, was diminished in UM tumors following the knockdown of either CREB or HIF-1.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('glucose', 'Chemical', 'MESH:D005947', (35, 42))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('HIF-1', 'Gene', '3091', (94, 99))	('diminished', 'NegReg', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('HIF-1', 'Gene', '3091', (171, 176))	('expression', 'MPA', (4, 14))	('HIF-1', 'Gene', (94, 99))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('knockdown', 'Var', (143, 152))	('cancer', 'Disease', (28, 34))	('UM', 'Phenotype', 'HP:0007716', (119, 121))	('HIF-1', 'Gene', (171, 176))
116276	31357444	In summary, the results presented here, demonstrating that the knockdown of either CREB or HIF-1 reduced UM tumor growth, may lead to the development of a novel therapeutic approach for metastatic UM, which is currently incurable.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('metastatic UM', 'Disease', (186, 199))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('HIF-1', 'Gene', '3091', (91, 96))	('reduced', 'NegReg', (97, 104))	('tumor', 'Disease', (108, 113))	('UM', 'Phenotype', 'HP:0007716', (197, 199))	('lead to', 'Reg', (126, 133))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('HIF-1', 'Gene', (91, 96))	('knockdown', 'Var', (63, 72))
116277	30567972	Effects of Oncogenic Galphaq and Galpha11 Inhibition by FR900359 in Uveal Melanoma Uveal melanoma is the most common intraocular tumor in adults and often metastasizes to the liver, leaving patients with few options.	('patients', 'Species', '9606', (190, 198))	('Melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('FR900359', 'Chemical', 'MESH:C000607068', (56, 64))	('Galpha11', 'Gene', (33, 41))	('Galphaq', 'Gene', (21, 28))	('Inhibition', 'NegReg', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('intraocular tumor', 'Disease', 'MESH:D009798', (117, 134))	('Melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('FR900359', 'Var', (56, 64))	('intraocular tumor', 'Disease', (117, 134))	('Galphaq', 'Gene', '2776', (21, 28))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('Galpha11', 'Gene', '2767', (33, 41))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('Melanoma', 'Disease', (74, 82))
116279	30567972	While therapeutic intervention of downstream Galphaq/11 targets has been unsuccessful in treating uveal melanoma, we have found that the Galphaq/11 inhibitor, FR900359 (FR), effectively inhibits oncogenic Galphaq/11 signaling in uveal melanoma cells expressing either mutant Galphaq or Galpha11.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('uveal melanoma', 'Phenotype', 'HP:0007716', (229, 243))	('melanoma', 'Disease', 'MESH:D008545', (235, 243))	('Galphaq/11', 'Chemical', '-', (205, 215))	('uveal melanoma', 'Phenotype', 'HP:0007716', (98, 112))	('signaling', 'biological_process', 'GO:0023052', ('216', '225'))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('Galphaq/11', 'Chemical', '-', (45, 55))	('Galpha11', 'Gene', (286, 294))	('Galphaq', 'Gene', (275, 282))	('FR', 'Chemical', 'MESH:C000607068', (169, 171))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('melanoma', 'Disease', (235, 243))	('inhibits', 'NegReg', (186, 194))	('mutant', 'Var', (268, 274))	('FR', 'Chemical', 'MESH:C000607068', (159, 161))	('oncogenic Galphaq/11 signaling', 'MPA', (195, 225))	('Galphaq/11', 'Chemical', '-', (137, 147))	('FR900359', 'Chemical', 'MESH:C000607068', (159, 167))
116282	30567972	This suggests direct inhibition of activating Galphaq/11 mutants may be a potential means of treating uveal melanoma.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('Galphaq/11', 'Chemical', '-', (46, 56))	('activating', 'PosReg', (35, 45))	('Galphaq/11', 'Gene', (46, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('mutants', 'Var', (57, 64))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))
116287	30567972	The mutations in UM are distinct from those commonly found in cutaneous melanoma, such as the driver mutations in BRAF and NRAS.	('cutaneous melanoma', 'Disease', (62, 80))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (62, 80))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (62, 80))	('mutations', 'Var', (101, 110))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('NRAS', 'Gene', (123, 127))	('NRAS', 'Gene', '4893', (123, 127))	('mutations', 'Var', (4, 13))	('UM', 'Phenotype', 'HP:0007716', (17, 19))
116288	30567972	UM predominately involves activating mutations in either GNAQ or GNA11 genes that encode the highly conserved Galphaq and Galpha11 subunits of heterotrimeric G proteins.	('activating', 'PosReg', (26, 36))	('GNAQ', 'Gene', (57, 61))	('mutations', 'Var', (37, 46))	('GNA11', 'Gene', '2767', (65, 70))	('GNA11', 'Gene', (65, 70))	('GNAQ', 'Gene', '2776', (57, 61))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
116289	30567972	Point mutations occur at the Q209 and R183 residues in the GTPase domain of Galphaq/11 proteins.	('Q209', 'Var', (29, 33))	('Galphaq/11', 'Chemical', '-', (76, 86))	('GTP', 'Chemical', 'MESH:D006160', (59, 62))	('R183', 'Var', (38, 42))	('GTPase', 'Protein', (59, 65))
116292	30567972	The introduction of the Galphaq- or Galpha11-Q209L mutant into human or mouse melanocytes results in anchorage-independent growth and gives rise to heavily pigmented tumors in mice.	('anchorage-independent growth', 'CPA', (101, 129))	('gives rise to', 'Reg', (134, 147))	('human', 'Species', '9606', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('mouse', 'Species', '10090', (72, 77))	('Galphaq-', 'Var', (24, 32))	('mice', 'Species', '10090', (176, 180))	('Q209L', 'SUBSTITUTION', 'None', (45, 50))	('Q209L', 'Var', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('pigmented tumors', 'Disease', 'MESH:D010859', (156, 172))	('pigmented tumors', 'Disease', (156, 172))
116293	30567972	For example, GNAQ and GNA11 mutations are responsible for the upregulation of the mitogen-activated protein kinase (MAPK) pathway in the absence of BRAF mutations in UM.	('GNA11', 'Gene', (22, 27))	('mutations', 'Var', (153, 162))	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (22, 27))	('GNAQ', 'Gene', '2776', (13, 17))	('upregulation', 'PosReg', (62, 74))	('MAPK', 'molecular_function', 'GO:0004707', ('116', '120'))	('UM', 'Phenotype', 'HP:0007716', (166, 168))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('BRAF', 'Gene', '673', (148, 152))	('mutations', 'Var', (28, 37))	('BRAF', 'Gene', (148, 152))
116296	30567972	Oncogenic Galphaq/11 leads to aberrant Akt signaling and increased activation of small GTPases RhoA and Rac1, which promote cell growth through JNK, p38, and yes-associated protein (YAP) directed transcription of growth promoting genes.	('Oncogenic Galphaq/11', 'Var', (0, 20))	('Galphaq/11', 'Chemical', '-', (10, 20))	('Rac1', 'Gene', '5879', (104, 108))	('Akt', 'Gene', (39, 42))	('RhoA', 'Gene', (95, 99))	('JNK', 'Gene', (144, 147))	('p38', 'Gene', '5594', (149, 152))	('protein', 'cellular_component', 'GO:0003675', ('173', '180'))	('JNK', 'Gene', '5599', (144, 147))	('Akt', 'Gene', '207', (39, 42))	('yes-associated protein', 'Gene', (158, 180))	('JNK', 'molecular_function', 'GO:0004705', ('144', '147'))	('RhoA', 'Gene', '387', (95, 99))	('Galphaq/11', 'Var', (10, 20))	('transcription', 'MPA', (196, 209))	('aberrant', 'MPA', (30, 38))	('GTP', 'Chemical', 'MESH:D006160', (87, 90))	('transcription', 'biological_process', 'GO:0006351', ('196', '209'))	('Rac1', 'Gene', (104, 108))	('increased activation', 'PosReg', (57, 77))	('cell growth', 'CPA', (124, 135))	('p38', 'Gene', (149, 152))	('yes-associated protein', 'Gene', '10413', (158, 180))	('Akt signaling', 'biological_process', 'GO:0043491', ('39', '52'))	('promote', 'PosReg', (116, 123))	('cell growth', 'biological_process', 'GO:0016049', ('124', '135'))
116303	30567972	QS3666, has been shown to potently and selectively inhibit wild type Galphaq/11 and the R183 mutant, but not the Q209L mutant protein, by inhibiting GDP dissociation from GDP-bound Galphaq.	('GDP-bound', 'MPA', (171, 180))	('R183', 'Var', (88, 92))	('Q209L', 'Var', (113, 118))	('Galphaq/11', 'Gene', (69, 79))	('GDP', 'Chemical', 'MESH:D006153', (171, 174))	('Q209L', 'SUBSTITUTION', 'None', (113, 118))	('GDP', 'Chemical', 'MESH:D006153', (149, 152))	('inhibiting', 'NegReg', (138, 148))	('QS3666', 'Var', (0, 6))	('GDP dissociation', 'MPA', (149, 165))	('Galphaq', 'Protein', (181, 188))	('inhibit', 'NegReg', (51, 58))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('Galphaq/11', 'Chemical', '-', (69, 79))
116306	30567972	Interestingly, recent studies revealed an effect of FR900359 (FR) on cell cycle regulation in melanoma cell lines containing wild type or oncogenic Galphaq/11.	('effect', 'Reg', (42, 48))	('FR900359', 'Chemical', 'MESH:C000607068', (52, 60))	('FR', 'Chemical', 'MESH:C000607068', (62, 64))	('FR', 'Chemical', 'MESH:C000607068', (52, 54))	('Galphaq/11', 'Chemical', '-', (148, 158))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('cell', 'MPA', (69, 73))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('69', '90'))	('FR900359', 'Var', (52, 60))
116308	30567972	In this study, we present evidence that FR effectively inhibits Galphaq-Q209L, Galphaq-Q209P and Galpha11-Q209L mutant proteins resulting in decreased Galphaq/11 signaling, cell cycle arrest and eventual cell death of UM cells harboring a GNAQ/11-Q209 mutation.	('signaling', 'biological_process', 'GO:0023052', ('162', '171'))	('arrest', 'Disease', 'MESH:D006323', (184, 190))	('Q209L', 'SUBSTITUTION', 'None', (106, 111))	('inhibits', 'NegReg', (55, 63))	('UM', 'Phenotype', 'HP:0007716', (218, 220))	('Q209L', 'Var', (72, 77))	('Galphaq/11', 'Chemical', '-', (151, 161))	('death', 'Disease', 'MESH:D003643', (209, 214))	('GNAQ/11', 'Chemical', '-', (239, 246))	('Galphaq/11 signaling', 'MPA', (151, 171))	('Q209L', 'SUBSTITUTION', 'None', (72, 77))	('cell death', 'biological_process', 'GO:0008219', ('204', '214'))	('arrest', 'Disease', (184, 190))	('decreased', 'NegReg', (141, 150))	('GNAQ/11-Q209', 'Gene', (239, 251))	('proteins', 'Protein', (119, 127))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('173', '190'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (173, 190))	('Q209L', 'Var', (106, 111))	('Galphaq-Q209P', 'Var', (79, 92))	('death', 'Disease', (209, 214))	('Q209P', 'Mutation', 'rs121913492', (87, 92))	('FR', 'Chemical', 'MESH:C000607068', (40, 42))
116309	30567972	These data provide evidence that direct inhibition of activating Galphaq/11 mutants may be a potential strategy to treat UM.	('activating', 'PosReg', (54, 64))	('Galphaq/11', 'Chemical', '-', (65, 75))	('Galphaq/11', 'Gene', (65, 75))	('UM', 'Phenotype', 'HP:0007716', (121, 123))	('rat', 'Species', '10116', (105, 108))	('mutants', 'Var', (76, 83))
116316	30567972	OMM1.3 cells were obtained from Dr. Bruce Ksander's lab and were confirmed to harbor the Q209P mutation in GNAQ by Sanger sequencing.	('Q209P', 'Mutation', 'rs121913492', (89, 94))	('GNAQ', 'Gene', (107, 111))	('Q209P', 'Var', (89, 94))	('GNAQ', 'Gene', '2776', (107, 111))
116317	30567972	92.1 cells were obtained from Dr. Martine Jager and contained a GNAQ-Q209L mutation that was confirmed by Sanger sequencing, while OCM3 cells were obtained from Dr. Bruce Ksander and contained a BRAF-V600E mutation and wild type GNAQ/11 as confirmed by Sanger sequencing.	('GNAQ', 'Gene', (229, 233))	('V600E', 'Mutation', 'rs113488022', (200, 205))	('GNAQ', 'Gene', (64, 68))	('GNAQ/11', 'Chemical', '-', (229, 236))	('BRAF', 'Gene', (195, 199))	('BRAF', 'Gene', '673', (195, 199))	('GNAQ', 'Gene', '2776', (229, 233))	('Q209L', 'SUBSTITUTION', 'None', (69, 74))	('Q209L', 'Var', (69, 74))	('GNAQ', 'Gene', '2776', (64, 68))
116318	30567972	UM002B cells were derived from a brain metastasis and are PTEN negative and contain a heterozygous Q209L mutation in GNA11 and no change in GNAQ as determined by Sanger sequencing (supplementary Fig.	('GNAQ', 'Gene', '2776', (140, 144))	('PTEN', 'Gene', '5728', (58, 62))	('Q209L', 'Var', (99, 104))	('Q209L', 'SUBSTITUTION', 'None', (99, 104))	('GNAQ', 'Gene', (140, 144))	('GNA11', 'Gene', '2767', (117, 122))	('GNA11', 'Gene', (117, 122))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('PTEN', 'Gene', (58, 62))
116325	30567972	GalphaqDelta34-Q209L was engineered for high level expression using a chimeric form of Galphaq/i that contained an N-terminal hexahistidine tag followed by residues 1-28 of rat Galphai1, a tobacco etch virus protease site, and residues 35-359 of mouse Galphaq-Q209L.	('Q209L', 'SUBSTITUTION', 'None', (15, 20))	('Galpha', 'Gene', (252, 258))	('rat', 'Species', '10116', (173, 176))	('Q209L', 'Var', (260, 265))	('Q209L', 'SUBSTITUTION', 'None', (260, 265))	('hexahistidine', 'Chemical', 'MESH:C471213', (126, 139))	('Galpha', 'Gene', '8802', (0, 6))	('Galpha', 'Gene', (0, 6))	('mouse', 'Species', '10090', (246, 251))	('tobacco etch virus', 'Species', '12227', (189, 207))	('Galpha', 'Gene', '8802', (87, 93))	('Galpha', 'Gene', '8802', (177, 183))	('Galpha', 'Gene', (87, 93))	('Galpha', 'Gene', (177, 183))	('Galpha', 'Gene', '8802', (252, 258))	('Q209L', 'Var', (15, 20))
116327	30567972	GTPgammaS binding of purified Galphaq and Galphaq-Q209L was measured using a filter-binding method.	('Q209L', 'Var', (50, 55))	('Q209L', 'SUBSTITUTION', 'None', (50, 55))	('binding', 'Interaction', (10, 17))	('GTP', 'Chemical', 'MESH:D006160', (0, 3))	('binding', 'molecular_function', 'GO:0005488', ('84', '91'))	('binding', 'molecular_function', 'GO:0005488', ('10', '17'))
116337	30567972	HER3/ErbB3 (#4754), p-STAT3 (Tyr705, #4113), p-S6 (Ser235/236, #2211), p-S6 (Ser240/244, #2215), p-Rb (Ser807/811, #9308), and PLK1 (#4513) antibodies were all from Cell Signaling Technology.	('#2215', 'Var', (89, 94))	('HER3', 'Gene', '2065', (0, 4))	('Tyr705', 'Chemical', '-', (29, 35))	('Ser807/811', 'Var', (103, 113))	('Ser240', 'Chemical', '-', (77, 83))	('ErbB3', 'Gene', (5, 10))	('#4754', 'Var', (12, 17))	('#9308', 'Var', (115, 120))	('#4513', 'Var', (133, 138))	('STAT3', 'Gene', (22, 27))	('Ser', 'cellular_component', 'GO:0005790', ('77', '80'))	('PLK1', 'Gene', (127, 131))	('ErbB3', 'Gene', '2065', (5, 10))	('HER3', 'Gene', (0, 4))	('STAT3', 'Gene', '6774', (22, 27))	('PLK1', 'Gene', '5347', (127, 131))	('Ser', 'cellular_component', 'GO:0005790', ('51', '54'))	('Tyr705', 'Var', (29, 35))	('Ser', 'cellular_component', 'GO:0005790', ('103', '106'))	('Signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('#2211', 'Var', (63, 68))	('Ser235', 'Chemical', '-', (51, 57))	('Ser807', 'Chemical', '-', (103, 109))
116358	30567972	Because the Q209L mutation is unlikely to alter the structure of Galphaq/11, it is possible that FR might be able to bind to and inhibit Galphaq/11-Q209L.	('Galphaq/11', 'Chemical', '-', (65, 75))	('bind', 'Interaction', (117, 121))	('Q209L', 'SUBSTITUTION', 'None', (12, 17))	('inhibit', 'NegReg', (129, 136))	('FR', 'Chemical', 'MESH:C000607068', (97, 99))	('Q209L', 'SUBSTITUTION', 'None', (148, 153))	('Q209L', 'Var', (148, 153))	('Galphaq/11', 'Chemical', '-', (137, 147))	('Q209L', 'Var', (12, 17))
116359	30567972	Indeed, FR effectively blocked spontaneous [35S]GTPgammaS binding to both purified Galphaq and Galphaq-Q209L in a dose-dependent manner with an IC50 ~75 nM (Fig.	('35S', 'Chemical', 'MESH:C000615320', (44, 47))	('binding', 'Interaction', (58, 65))	('blocked', 'NegReg', (23, 30))	('binding', 'molecular_function', 'GO:0005488', ('58', '65'))	('[35S]GTPgammaS', 'Protein', (43, 57))	('GTP', 'Chemical', 'MESH:D006160', (48, 51))	('FR', 'Chemical', 'MESH:C000607068', (8, 10))	('Q209L', 'SUBSTITUTION', 'None', (103, 108))	('Q209L', 'Var', (103, 108))	('Galphaq', 'Protein', (83, 90))
116360	30567972	This provides evidence that FR can inhibit nucleotide binding to Galphaq-Q209L, suggesting that FR can directly bind to mutant Galphaq.	('Q209L', 'SUBSTITUTION', 'None', (73, 78))	('Galphaq', 'Gene', (127, 134))	('FR', 'Chemical', 'MESH:C000607068', (96, 98))	('nucleotide binding', 'MPA', (43, 61))	('FR', 'Chemical', 'MESH:C000607068', (28, 30))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('43', '61'))	('bind', 'Interaction', (112, 116))	('inhibit', 'NegReg', (35, 42))	('mutant', 'Var', (120, 126))	('Q209L', 'Var', (73, 78))
116361	30567972	To determine if FR can inhibit the Galphaq mutant protein in cells, we next treated UM cells containing GNAQ-Q209L/P or GNA11-Q209L mutations with varying concentrations of FR and tracked their growth over 4 days (Fig.	('rat', 'Species', '10116', (162, 165))	('GNAQ', 'Gene', '2776', (104, 108))	('Q209L', 'SUBSTITUTION', 'None', (109, 114))	('Q209L', 'Var', (109, 114))	('mutations', 'Var', (132, 141))	('GNA11', 'Gene', (120, 125))	('Q209L', 'Var', (126, 131))	('Q209L', 'SUBSTITUTION', 'None', (126, 131))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('GNA11', 'Gene', '2767', (120, 125))	('GNAQ', 'Gene', (104, 108))	('FR', 'Chemical', 'MESH:C000607068', (173, 175))	('FR', 'Chemical', 'MESH:C000607068', (16, 18))
116362	30567972	The growth of primary 92.1 and metastatic OMM1.3 cells, containing GNAQ-Q209L and GNAQ-Q209P mutations, respectively, was effectively inhibited by treatment of FR at concentrations as low as 100 nM.	('FR', 'Chemical', 'MESH:C000607068', (160, 162))	('growth', 'CPA', (4, 10))	('rat', 'Species', '10116', (173, 176))	('GNAQ', 'Gene', (67, 71))	('GNAQ', 'Gene', (82, 86))	('inhibited', 'NegReg', (134, 143))	('Q209L', 'SUBSTITUTION', 'None', (72, 77))	('Q209L', 'Var', (72, 77))	('Q209P', 'Mutation', 'rs121913492', (87, 92))	('GNAQ', 'Gene', '2776', (67, 71))	('GNAQ', 'Gene', '2776', (82, 86))
116363	30567972	We also observed inhibited growth of metastatic UM002B cells, containing a GNA11-Q209L mutation, suggesting FR is also able to inhibit mutant Galpha11 (Fig.	('UM', 'Phenotype', 'HP:0007716', (48, 50))	('Q209L', 'Var', (81, 86))	('Q209L', 'SUBSTITUTION', 'None', (81, 86))	('GNA11', 'Gene', '2767', (75, 80))	('GNA11', 'Gene', (75, 80))	('mutant', 'Var', (135, 141))	('FR', 'Chemical', 'MESH:C000607068', (108, 110))	('inhibited', 'NegReg', (17, 26))	('inhibit', 'NegReg', (127, 134))	('growth', 'MPA', (27, 33))	('Galpha11', 'Gene', (142, 150))
116392	30567972	Therefore, FR induces G1 cell growth arrest and leads to apoptosis of UM cells containing activating mutations of Galphaq/11.	('mutations', 'Var', (101, 110))	('Galphaq/11', 'Chemical', '-', (114, 124))	('Galphaq/11', 'Gene', (114, 124))	('apoptosis', 'CPA', (57, 66))	('FR', 'Chemical', 'MESH:C000607068', (11, 13))	('leads to', 'Reg', (48, 56))	('growth arrest', 'Disease', 'MESH:D006323', (30, 43))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('growth arrest', 'Disease', (30, 43))	('cell growth', 'biological_process', 'GO:0016049', ('25', '36'))	('apoptosis', 'biological_process', 'GO:0006915', ('57', '66'))	('growth arrest', 'Phenotype', 'HP:0001510', (30, 43))	('apoptosis', 'biological_process', 'GO:0097194', ('57', '66'))
116400	30567972	UM is predominantly driven by activating mutations in Galphaq/11 proteins, which promotes increased signaling in various cell proliferative pathways, such as the ERK1/2-MAPK and Hippo/YAP pathways.	('mutations', 'Var', (41, 50))	('cell proliferative pathways', 'Pathway', (121, 148))	('proteins', 'Protein', (65, 73))	('increased', 'PosReg', (90, 99))	('MAPK', 'molecular_function', 'GO:0004707', ('169', '173'))	('ERK1/2', 'Gene', (162, 168))	('Hippo/YAP pathways', 'Pathway', (178, 196))	('Galphaq/11', 'Chemical', '-', (54, 64))	('rat', 'Species', '10116', (133, 136))	('ERK1/2', 'Gene', '5595;5594', (162, 168))	('ERK1', 'molecular_function', 'GO:0004707', ('162', '166'))	('Galphaq/11', 'Gene', (54, 64))	('signaling', 'MPA', (100, 109))	('activating', 'Reg', (30, 40))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
116404	30567972	Previous studies have shown that the related compounds YM-254890 and FR900359 act as GDIs to inhibit GDP dissociation from Galphaq and thereby inhibit GTP binding and activation of Galphaq.	('activation', 'MPA', (167, 177))	('inhibit', 'NegReg', (93, 100))	('YM-254890', 'Chemical', 'MESH:C475455', (55, 64))	('GTP binding', 'molecular_function', 'GO:0005525', ('151', '162'))	('Galphaq', 'Protein', (181, 188))	('GTP', 'Chemical', 'MESH:D006160', (151, 154))	('binding', 'Interaction', (155, 162))	('FR900359', 'Var', (69, 77))	('Galphaq', 'Protein', (123, 130))	('inhibit', 'NegReg', (143, 150))	('GDP dissociation from', 'MPA', (101, 122))	('GTP', 'Protein', (151, 154))	('YM-254890', 'Var', (55, 64))	('GDP', 'Chemical', 'MESH:D006153', (101, 104))	('FR900359', 'Chemical', 'MESH:C000607068', (69, 77))
116405	30567972	FR has been shown to bind specifically to Galphaq, Galpha11 and Galpha14 and inhibit activity in a pseudo-irreversible manner.	('FR', 'Chemical', 'MESH:C000607068', (0, 2))	('inhibit', 'NegReg', (77, 84))	('Galpha14', 'Gene', (64, 72))	('Galpha11', 'Var', (51, 59))	('Galpha14', 'Gene', '9630', (64, 72))	('Galphaq', 'Protein', (42, 49))	('bind', 'Interaction', (21, 25))	('activity', 'MPA', (85, 93))
116406	30567972	These studies also demonstrated that FR can inhibit basal signaling mediated by Galphaq-R183C and Galphaq-Q209L expressed in HEK293 cells as well as signaling in some melanoma cell lines expressing mutant Galphaq.	('R183C', 'Mutation', 'p.R183C', (88, 93))	('signaling', 'biological_process', 'GO:0023052', ('149', '158'))	('basal signaling', 'MPA', (52, 67))	('Galphaq-R183C', 'Var', (80, 93))	('inhibit', 'NegReg', (44, 51))	('Q209L', 'Var', (106, 111))	('Q209L', 'SUBSTITUTION', 'None', (106, 111))	('rat', 'Species', '10116', (26, 29))	('basal signaling', 'biological_process', 'GO:0038034', ('52', '67'))	('mutant', 'Var', (198, 204))	('HEK293', 'CellLine', 'CVCL:0045', (125, 131))	('melanoma', 'Disease', (167, 175))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('Galphaq', 'Gene', (205, 212))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('FR', 'Chemical', 'MESH:C000607068', (37, 39))
116407	30567972	Moreover, a very recent study has shown that FR is capable of inhibiting oncogenic Galphaq/11-Q209L in UM cells.	('Galphaq/11', 'Chemical', '-', (83, 93))	('FR', 'Chemical', 'MESH:C000607068', (45, 47))	('inhibiting', 'NegReg', (62, 72))	('Q209L', 'SUBSTITUTION', 'None', (94, 99))	('Q209L', 'Var', (94, 99))	('UM', 'Phenotype', 'HP:0007716', (103, 105))
116408	30567972	FR appears to function by trapping mutant Galphaq in the inactive GDP-bound form by inhibiting nucleotide exchange and promoting Galphaq association with Gbetagamma.	('association', 'Interaction', (137, 148))	('FR', 'Chemical', 'MESH:C000607068', (0, 2))	('GDP', 'Chemical', 'MESH:D006153', (66, 69))	('nucleotide exchange', 'MPA', (95, 114))	('Galphaq', 'Gene', (42, 49))	('Galphaq', 'Protein', (129, 136))	('mutant', 'Var', (35, 41))	('Gbetagamma', 'Protein', (154, 164))	('inhibiting', 'NegReg', (84, 94))	('promoting', 'PosReg', (119, 128))
116409	30567972	In the present study, we show that FR effectively inhibits signaling in UM cells expressing Galphaq-Q209L, Galphaq-Q209P and Galpha11-Q209L.	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('Q209L', 'SUBSTITUTION', 'None', (134, 139))	('Q209L', 'Var', (134, 139))	('signaling', 'MPA', (59, 68))	('FR', 'Chemical', 'MESH:C000607068', (35, 37))	('Q209L', 'SUBSTITUTION', 'None', (100, 105))	('Q209L', 'Var', (100, 105))	('Galphaq-Q209P', 'Var', (107, 120))	('inhibits', 'NegReg', (50, 58))	('Q209P', 'Mutation', 'rs121913492', (115, 120))
116410	30567972	We show in vitro that FR inhibits GTPgammaS-binding to Galphaq-Q209L with an IC50 ~75 nM (Fig.	('inhibits', 'NegReg', (25, 33))	('GTP', 'Chemical', 'MESH:D006160', (34, 37))	('Q209L', 'SUBSTITUTION', 'None', (63, 68))	('Q209L', 'Var', (63, 68))	('binding', 'molecular_function', 'GO:0005488', ('44', '51'))	('FR', 'Chemical', 'MESH:C000607068', (22, 24))	('GTPgammaS-binding', 'Protein', (34, 51))
116412	30567972	In addition, the high IC50 may also reflect the fact that we used Galphaq in these studies while YM-254890 interacts with both the Galphaq and Gbetagamma subunits in the heterotrimer (presumably FR does as well).	('YM-254890', 'Chemical', 'MESH:C475455', (97, 106))	('Galphaq', 'Protein', (131, 138))	('Gbetagamma subunits', 'Protein', (143, 162))	('FR', 'Chemical', 'MESH:C000607068', (195, 197))	('YM-254890', 'Var', (97, 106))	('interacts', 'Interaction', (107, 116))	('heterotrimer', 'Protein', (170, 182))
116413	30567972	Since mutationally activated Galpha subunits are thought to be constitutively associated with GTP, it is unclear how FR might inhibit the activity of activated Galphaq/11.	('associated', 'Reg', (78, 88))	('Galpha', 'Gene', (29, 35))	('activity', 'MPA', (138, 146))	('FR', 'Chemical', 'MESH:C000607068', (117, 119))	('GTP', 'Disease', (94, 97))	('GTP', 'Chemical', 'MESH:D006160', (94, 97))	('Galphaq/11', 'Chemical', '-', (160, 170))	('Galpha', 'Gene', '8802', (29, 35))	('Galpha', 'Gene', (160, 166))	('mutationally', 'Var', (6, 18))	('Galpha', 'Gene', '8802', (160, 166))
116414	30567972	It might bind to GTP loaded Galphaq/11-Q209L and promote GTP dissociation, or there may be a slow exchange of GDP/GTP on Galphaq/11-Q209L such that FR can bind in the GDP state.	('GTP', 'Chemical', 'MESH:D006160', (57, 60))	('Q209L', 'SUBSTITUTION', 'None', (39, 44))	('Q209L', 'Var', (39, 44))	('GDP', 'Chemical', 'MESH:D006153', (167, 170))	('GTP', 'Chemical', 'MESH:D006160', (17, 20))	('bind', 'Interaction', (155, 159))	('bind', 'Interaction', (9, 13))	('GTP dissociation', 'MPA', (57, 73))	('GDP', 'Chemical', 'MESH:D006153', (110, 113))	('FR', 'Chemical', 'MESH:C000607068', (148, 150))	('GTP', 'Chemical', 'MESH:D006160', (114, 117))	('promote', 'PosReg', (49, 56))	('Galphaq/11', 'Chemical', '-', (28, 38))	('Galphaq/11', 'Chemical', '-', (121, 131))	('Q209L', 'SUBSTITUTION', 'None', (132, 137))	('Q209L', 'Var', (132, 137))
116418	30567972	3C) while the half-life of Galphaq/11 is reported to be about 5 h. While further characterization of the mechanism of FR inhibition of mutant Galphaq/11 is warranted, the effects of FR treatment on UM cells are striking.	('FR', 'Chemical', 'MESH:C000607068', (182, 184))	('Galphaq/11', 'Chemical', '-', (142, 152))	('mutant', 'Var', (135, 141))	('Galphaq/11', 'Gene', (142, 152))	('FR', 'Chemical', 'MESH:C000607068', (118, 120))	('UM', 'Phenotype', 'HP:0007716', (198, 200))	('Galphaq/11', 'Chemical', '-', (27, 37))
116420	30567972	FR-mediated G1 cell growth arrest is also detected in melanoma cells with (Hcmel12) or without (B16) a GNAQ-Q209L mutation as well as in primary UM cell lines containing a GNAQ-Q209L mutation.	('Q209L', 'Var', (177, 182))	('FR', 'Chemical', 'MESH:C000607068', (0, 2))	('B16', 'CellLine', 'CVCL:N540', (96, 99))	('growth arrest', 'Disease', (20, 33))	('mutation', 'Var', (114, 122))	('cell growth', 'biological_process', 'GO:0016049', ('15', '26'))	('Q209L', 'SUBSTITUTION', 'None', (177, 182))	('GNAQ', 'Gene', '2776', (172, 176))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('GNAQ', 'Gene', (172, 176))	('growth arrest', 'Phenotype', 'HP:0001510', (20, 33))	('Q209L', 'Var', (108, 113))	('GNAQ', 'Gene', '2776', (103, 107))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('growth arrest', 'Disease', 'MESH:D006323', (20, 33))	('GNAQ', 'Gene', (103, 107))	('Q209L', 'SUBSTITUTION', 'None', (108, 113))
116421	30567972	Additionally, we show that FR treatment is capable of producing similar results in metastatic UM cells containing GNAQ-Q209P or GNA11-Q209L mutations.	('UM', 'Phenotype', 'HP:0007716', (94, 96))	('GNA11', 'Gene', '2767', (128, 133))	('GNA11', 'Gene', (128, 133))	('FR', 'Chemical', 'MESH:C000607068', (27, 29))	('Q209L', 'SUBSTITUTION', 'None', (134, 139))	('Q209L', 'Var', (134, 139))	('GNAQ', 'Gene', '2776', (114, 118))	('Q209P', 'Mutation', 'rs121913492', (119, 124))	('GNAQ', 'Gene', (114, 118))
116422	30567972	Given the prevalence of Q209L and Q209P mutations in UM, it is worth noting that Galphaq-Q209P has been shown to have altered binding to various effectors and Gbetagamma compared to Galphaq-Q209L, although it still effectively activates downstream signaling.	('Gbetagamma', 'Protein', (159, 169))	('signaling', 'biological_process', 'GO:0023052', ('248', '257'))	('Galphaq-Q209P', 'Var', (81, 94))	('binding', 'Interaction', (126, 133))	('Q209L', 'Var', (24, 29))	('Q209P', 'Var', (34, 39))	('Q209P', 'Mutation', 'rs121913492', (89, 94))	('altered', 'Reg', (118, 125))	('UM', 'Phenotype', 'HP:0007716', (53, 55))	('Q209L', 'SUBSTITUTION', 'None', (24, 29))	('Q209P', 'Mutation', 'rs121913492', (34, 39))	('activates', 'PosReg', (227, 236))	('binding', 'molecular_function', 'GO:0005488', ('126', '133'))	('Q209L', 'SUBSTITUTION', 'None', (190, 195))	('Q209L', 'Var', (190, 195))
116426	30567972	Inhibition of Galphaq/11 in UM cells harboring GNAQ-Q209L/P or GNA11-Q209L, but not in melanoma cells containing wild type GNAQ/11, abolishes MAPK signaling (Fig.	('MAPK signaling', 'biological_process', 'GO:0000165', ('142', '156'))	('GNAQ', 'Gene', (47, 51))	('GNAQ', 'Gene', '2776', (123, 127))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('melanoma', 'Disease', (87, 95))	('UM', 'Phenotype', 'HP:0007716', (28, 30))	('GNAQ', 'Gene', (123, 127))	('MAPK', 'molecular_function', 'GO:0004707', ('142', '146'))	('Q209L', 'Var', (69, 74))	('GNA11', 'Gene', '2767', (63, 68))	('Galphaq/11', 'Chemical', '-', (14, 24))	('MAPK signaling', 'MPA', (142, 156))	('abolishes', 'NegReg', (132, 141))	('Q209L', 'Var', (52, 57))	('Q209L', 'SUBSTITUTION', 'None', (69, 74))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('GNA11', 'Gene', (63, 68))	('GNAQ/11', 'Chemical', '-', (123, 130))	('Q209L', 'SUBSTITUTION', 'None', (52, 57))	('GNAQ', 'Gene', '2776', (47, 51))
116428	30567972	In general, these results are similar to studies of mutant GNAQ-Q209L melanoma and UM cells treated with GNAQ siRNA or FR.	('melanoma', 'Disease', (70, 78))	('FR', 'Chemical', 'MESH:C000607068', (119, 121))	('GNAQ', 'Gene', (105, 109))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('mutant', 'Var', (52, 58))	('Q209L', 'Var', (64, 69))	('UM', 'Phenotype', 'HP:0007716', (83, 85))	('Q209L', 'SUBSTITUTION', 'None', (64, 69))	('GNAQ', 'Gene', (59, 63))	('GNAQ', 'Gene', '2776', (105, 109))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('GNAQ', 'Gene', '2776', (59, 63))
116431	30567972	The effects of FR on YAP localization in UM002B cells are not as dramatic since YAP is not highly localized in the nucleus in UM002B cells, although FR does significantly decrease the YAP levels in the nucleus.	('YAP levels', 'MPA', (184, 194))	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('UM002B', 'Var', (126, 132))	('decrease', 'NegReg', (171, 179))	('FR', 'Chemical', 'MESH:C000607068', (149, 151))	('UM', 'Phenotype', 'HP:0007716', (126, 128))	('localization', 'biological_process', 'GO:0051179', ('25', '37'))	('FR', 'Chemical', 'MESH:C000607068', (15, 17))	('nucleus', 'cellular_component', 'GO:0005634', ('115', '122'))	('nucleus', 'cellular_component', 'GO:0005634', ('202', '209'))
116439	30567972	The differentiation of B16 melanoma cells by FR has previously been reported, while recent studies suggest FR promotes differentiation of primary 92.1 and Mel202 UM cells containing Galphaq-Q209L by promoting polycomb-mediated gene repression.	('promoting', 'PosReg', (199, 208))	('FR', 'Chemical', 'MESH:C000607068', (45, 47))	('FR', 'Chemical', 'MESH:C000607068', (107, 109))	('UM', 'Phenotype', 'HP:0007716', (162, 164))	('promotes', 'PosReg', (110, 118))	('B16', 'CellLine', 'CVCL:N540', (23, 26))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('differentiation', 'CPA', (119, 134))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('polycomb-mediated gene repression', 'MPA', (209, 242))	('Q209L', 'SUBSTITUTION', 'None', (190, 195))	('Q209L', 'Var', (190, 195))
116448	30567972	C cytoplasmic DMSO dimethylsulfoxide FR FR900359 GDI guanosine nucleotide dissociation inhibitor Gq, Galphaqbetagamma heterotrimer GST glutathione S-transferase GTPgammaS guanosine 5'-O-[gamma-thio]triphosphate MAPK mitogen activated protein kinase N nuclear RPPA reverse phase protein array UM uveal melanoma YAP yes associated protein Oncogenic Galphaq/11 inhibition by FR900359 may be a potential treatment option for those with uveal melanoma.	('inhibition', 'NegReg', (358, 368))	('melanoma', 'Phenotype', 'HP:0002861', (438, 446))	('melanoma', 'Disease', (438, 446))	('protein', 'cellular_component', 'GO:0003675', ('278', '285'))	('FR900359', 'Chemical', 'MESH:C000607068', (40, 48))	('GDI', 'molecular_function', 'GO:0005092', ('49', '52'))	('FR', 'Chemical', 'MESH:C000607068', (372, 374))	('guanosine nucleotide', 'Chemical', '-', (53, 73))	('FR', 'Chemical', 'MESH:C000607068', (37, 39))	('GST', 'Gene', '373156', (131, 134))	('dimethylsulfoxide', 'Chemical', 'MESH:D004121', (19, 36))	('FR900359', 'Chemical', 'MESH:C000607068', (372, 380))	('Galphaq/11', 'Chemical', '-', (347, 357))	('protein', 'cellular_component', 'GO:0003675', ('234', '241'))	('GTP', 'Chemical', 'MESH:D006160', (161, 164))	('MAPK', 'molecular_function', 'GO:0004707', ('211', '215'))	('melanoma', 'Phenotype', 'HP:0002861', (301, 309))	('melanoma', 'Disease', (301, 309))	('DMSO', 'Chemical', 'MESH:D004121', (14, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (432, 446))	('protein', 'cellular_component', 'GO:0003675', ('329', '336'))	('melanoma', 'Disease', 'MESH:D008545', (438, 446))	('Gq', 'Chemical', 'MESH:C039788', (97, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (295, 309))	('glutathione', 'Chemical', 'MESH:D005978', (135, 146))	('FR900359', 'Var', (372, 380))	('UM', 'Phenotype', 'HP:0007716', (292, 294))	('GST', 'Gene', (131, 134))	('melanoma', 'Disease', 'MESH:D008545', (301, 309))	('FR', 'Chemical', 'MESH:C000607068', (40, 42))	("guanosine 5'-O-[gamma-thio]triphosphate", 'Chemical', '-', (171, 210))
116512	29757889	As depicted in Figure 2C (left graph), TIL lines such as TIL#3102 and #3103 expanded more CD3- (grey bar), most likely NK cells, when the propagation was executed with anti-4-1BB alone.	('#3103', 'Var', (70, 75))	('4-1BB', 'Gene', '3604', (173, 178))	('CD3', 'Gene', (90, 93))	('expanded', 'PosReg', (76, 84))	('TIL#3102', 'Var', (57, 65))	('CD3', 'Gene', '12501', (90, 93))	('4-1BB', 'Gene', (173, 178))
116513	29757889	On the other hand, the combination with OKT3 gave rise to a more uniform CD3+ T-cell product (Figure 2C, left graph).	('CD3', 'Gene', (73, 76))	('CD3', 'Gene', '12501', (73, 76))	('combination', 'Var', (23, 34))	('more', 'PosReg', (60, 64))
116528	29757889	Thus, providing the 3 signals attributed to T-cell activation lead to expansion of TIL capable of recognizing their tumor counterpart in cutaneous and uveal melanoma.	('uveal melanoma', 'Disease', (151, 165))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('T-cell activation', 'biological_process', 'GO:0042110', ('44', '61'))	('tumor', 'Disease', (116, 121))	('expansion', 'Var', (70, 79))	('uveal melanoma', 'Phenotype', 'HP:0007716', (151, 165))	('uveal melanoma', 'Disease', 'MESH:C536494', (151, 165))
116543	29757889	NK cells can also be stimulated through targeting the 4-1BB axis, which is what was observed when 4-1BB was targeted alone.	('targeting', 'Var', (40, 49))	('4-1BB', 'Gene', (54, 59))	('4-1BB', 'Gene', '3604', (98, 103))	('4-1BB', 'Gene', '3604', (54, 59))	('NK cells', 'CPA', (0, 8))	('stimulated', 'PosReg', (21, 31))	('4-1BB', 'Gene', (98, 103))
116565	29949880	One of the most significant predictors for UM-related death is loss of chromosome 3.	('death', 'Disease', 'MESH:D003643', (54, 59))	('death', 'Disease', (54, 59))	('chromosome', 'cellular_component', 'GO:0005694', ('71', '81'))	('loss', 'Var', (63, 67))
116610	29949880	Thus, the binding of [125I]RC-160 was detected to be reversible, temperature- and time-dependent, and linear with protein concentration in the human UM specimens examined (data not shown).	('[125I]', 'Var', (21, 27))	('human', 'Species', '9606', (143, 148))	('binding', 'Interaction', (10, 17))	('RC-160', 'Gene', (27, 33))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('binding', 'molecular_function', 'GO:0005488', ('10', '17'))	('men', 'Species', '9606', (157, 160))
116655	29949880	Thirty-one (65.2%) samples showed SSTR-2 positivity and 6 of nine samples (66.6%) were SSTR-5 positive.	('positivity', 'Var', (41, 51))	('SSTR-2', 'Gene', (34, 40))	('SSTR-5', 'Gene', (87, 93))	('SSTR-2', 'Gene', '6752', (34, 40))	('SSTR-5', 'Gene', '6755', (87, 93))
116794	29755525	Due to the UM class, the risk of developing metastases varies pronouncedly: the mortality rates due to metastasis were 13.2% for UM with disomy 3 and 75.1% for UM with monosomy 3 (median follow-up time of 5.2 years).	('UM', 'Phenotype', 'HP:0007716', (11, 13))	('metastases', 'Disease', (44, 54))	('UM', 'Phenotype', 'HP:0007716', (160, 162))	('UM', 'Phenotype', 'HP:0007716', (129, 131))	('metastases', 'Disease', 'MESH:D009362', (44, 54))	('disomy 3', 'Var', (137, 145))	('metastasis', 'CPA', (103, 113))
116805	29755525	Patients diagnosed with monosomy 3 were "more depressed" than others at each time point, with no decrease over-time (as reported in the previous studies), but again the HADS mean score was always below the cut-off scores for "clinically relevant" depression.	('depression', 'Disease', 'MESH:D000275', (247, 257))	('depression', 'Phenotype', 'HP:0000716', (247, 257))	('monosomy 3', 'Var', (24, 34))	('depression', 'Disease', (247, 257))	('Patients', 'Species', '9606', (0, 8))	('HADS', 'Chemical', '-', (169, 173))
116835	27588500	In addition, patients in the low miR-454 expression cohort had better response to anthracycline compared to non-anthracycline chemotherapy (P = 0.056), but this difference was not observed in the high miR-454 expression cohort.	('response', 'MPA', (70, 78))	('miR-454', 'Gene', (33, 40))	('low', 'Var', (29, 32))	('patients', 'Species', '9606', (13, 21))	('anthracycline', 'Chemical', 'MESH:D018943', (112, 125))	('better', 'PosReg', (63, 69))	('anthracycline', 'Chemical', 'MESH:D018943', (82, 95))	('expression', 'Var', (41, 51))	('miR-454', 'Gene', '768216', (201, 208))	('miR-454', 'Gene', (201, 208))	('miR-454', 'Gene', '768216', (33, 40))
116842	27588500	In hepatocellular carcinoma, knockdown of miR-454 inhibited HCC cell proliferation, and invasion and EMT, and miR-454 was proposed be a valuable prognostic factor.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('HCC cell proliferation', 'CPA', (60, 82))	('knockdown', 'Var', (29, 38))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('miR-454', 'Gene', '768216', (42, 49))	('miR-454', 'Gene', '768216', (110, 117))	('EMT', 'biological_process', 'GO:0001837', ('101', '104'))	('EMT', 'Gene', (101, 104))	('miR-454', 'Gene', (42, 49))	('EMT', 'Gene', '3702', (101, 104))	('miR-454', 'Gene', (110, 117))	('HCC', 'CellLine', 'CVCL:0C54', (60, 63))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('inhibited', 'NegReg', (50, 59))
116844	27588500	The prognosis of glioma with high miR-454 expression was significantly worse than that of glioma with low miR-454 expression, suggesting that miR-454 could be a novel potential prognosis biomarker.	('high', 'Var', (29, 33))	('glioma', 'Disease', (90, 96))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('miR-454', 'Gene', '768216', (106, 113))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('miR-454', 'Gene', '768216', (34, 41))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('miR-454', 'Gene', (106, 113))	('miR-454', 'Gene', '768216', (142, 149))	('glioma', 'Disease', (17, 23))	('miR-454', 'Gene', (34, 41))	('worse', 'NegReg', (71, 76))	('miR-454', 'Gene', (142, 149))
116854	27588500	Dysregulation of miRNAs in breast cancer be involved in the response and resistance to chemotherapy, and can therefore serve as predictive biomarkers of therapeutic outcomes.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('involved', 'Reg', (44, 52))	('Dysregulation', 'Var', (0, 13))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('miRNAs', 'Protein', (17, 23))	('breast cancer', 'Disease', (27, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))
116870	27588500	In conclusion, high expression of miR-454 indicated a worse clinical outcome in the overall population and the TNBC subtype.	('high', 'Var', (15, 19))	('miR-454', 'Gene', '768216', (34, 41))	('expression', 'MPA', (20, 30))	('miR-454', 'Gene', (34, 41))
116872	27588500	Multivariate analysis considering the relationship between clinical factors revealed that high expression of miR-454 was independently associated with a worse DFS (HR = 2.02, 95% CI 1.10-3.72, P = 0.023 for training set; HR = 2.16, 95% CI 1.16-4.03, P = 0.015 for validation set).	('miR-454', 'Gene', '768216', (109, 116))	('high', 'Var', (90, 94))	('miR-454', 'Gene', (109, 116))	('DFS', 'MPA', (159, 162))
116873	27588500	In the TNBC subtype, cases with high miR-454 expression had a high probability of disease recurrence in univariate analysis (HR = 2.80, 95% CI 1.20-6.56, P = 0.018 for training set; HR = 2.50, 95% CI 1.17-5.31, P = 0.018 for validation set; Table 3).	('miR-454', 'Gene', '768216', (37, 44))	('high', 'Var', (32, 36))	('TNBC', 'Disease', (7, 11))	('miR-454', 'Gene', (37, 44))	('disease', 'Disease', (82, 89))
116876	27588500	High expression of miR-454 was associated with worse OS in both univariate and multivariate analyses (Table S2 & S3).	('High', 'Var', (0, 4))	('miR-454', 'Gene', (19, 26))	('OS', 'Chemical', '-', (53, 55))	('worse OS', 'Disease', (47, 55))	('miR-454', 'Gene', '768216', (19, 26))
116882	27588500	In the total population, high expression of miR-454 correlated with worse DFS (P = 0.003, Figure S4).	('miR-454', 'Gene', (44, 51))	('high', 'Var', (25, 29))	('DFS', 'Disease', (74, 77))	('miR-454', 'Gene', '768216', (44, 51))
116906	27588500	In our study, the TNBC patients with positive miR-454 status derived less benefit from anthracycline chemotherapy than those without miR-454 expression.	('positive', 'Var', (37, 45))	('benefit', 'MPA', (74, 81))	('TNBC', 'Disease', (18, 22))	('anthracycline chemotherapy', 'MPA', (87, 113))	('miR-454', 'Gene', '768216', (133, 140))	('miR-454', 'Gene', (46, 53))	('anthracycline', 'Chemical', 'MESH:D018943', (87, 100))	('patients', 'Species', '9606', (23, 31))	('miR-454', 'Gene', (133, 140))	('miR-454', 'Gene', '768216', (46, 53))	('less', 'NegReg', (69, 73))
116918	27588500	In addition, high expression of miR-454 correlated with increased risk of disease events, and miR-454 might be a predictor of therapeutic response in TNBC.	('miR-454', 'Gene', (32, 39))	('high', 'Var', (13, 17))	('miR-454', 'Gene', '768216', (94, 101))	('disease', 'Disease', (74, 81))	('miR-454', 'Gene', (94, 101))	('miR-454', 'Gene', '768216', (32, 39))	('TNBC', 'Disease', (150, 154))
116932	27588500	TMAs were subjected to a stringent washing procedure with 2x saline sodium citrate (SSC, preheated at 37 C, two washes, 5 min each), 0.5xSSC (one wash, 15 min), and 0.2xSSC (one wash, 15 min).	('SSC', 'Chemical', '-', (169, 172))	('0.5xSSC', 'Var', (133, 140))	('SSC', 'Chemical', '-', (84, 87))	('saline sodium citrate', 'Chemical', '-', (61, 82))	('TMAs', 'Chemical', 'MESH:C071868', (0, 4))	('SSC', 'Chemical', '-', (137, 140))	('0.2xSSC', 'Var', (165, 172))
116947	25827538	Monosomy 3, 1p loss, 6q loss, and 8q and those classified as Class II by gene expression are predictive of poor prognosis of uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (125, 139))	('uveal melanoma', 'Disease', 'MESH:C536494', (125, 139))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('uveal melanoma', 'Disease', (125, 139))	('1p loss', 'Var', (12, 19))	('gene expression', 'biological_process', 'GO:0010467', ('73', '88'))	('loss', 'NegReg', (24, 28))	('Monosomy 3', 'Var', (0, 10))
116974	25827538	In a meta-analysis of 8 articles by Diener-West et al., the combined weighted estimates of 5-year mortality rates associated with uveal melanoma were 16% for small tumors (<2 or 3 mm tumor thickness and <10 or 11 mm basal diameter), 32% for medium tumors (3-8 mm tumor thickness and <15 or 16 mm basal diameter), and 53% for large tumors (>8 mm tumor thickness and >15 mm basal diameter).	('tumor', 'Disease', 'MESH:D009369', (331, 336))	('tumor', 'Disease', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumors', 'Disease', (248, 254))	('tumor', 'Disease', (345, 350))	('uveal melanoma', 'Disease', (130, 144))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('uveal melanoma', 'Disease', 'MESH:C536494', (130, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (345, 350))	('tumor', 'Disease', (248, 253))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('<10 or 11', 'Var', (203, 212))	('tumor', 'Disease', (263, 268))	('uveal melanoma', 'Phenotype', 'HP:0007716', (130, 144))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('tumors', 'Phenotype', 'HP:0002664', (331, 337))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumors', 'Disease', (164, 170))	('tumor', 'Disease', (183, 188))	('tumors', 'Disease', (331, 337))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('small tumors', 'Disease', (158, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('small tumors', 'Disease', 'MESH:D058405', (158, 170))	('tumor', 'Disease', (331, 336))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('tumors', 'Disease', 'MESH:D009369', (331, 337))	('3-8', 'Var', (256, 259))	('<2 or 3 mm', 'Var', (172, 182))
116979	25827538	By competing risks regression analysis, the Hazard ratio was 1.08 for each millimeter increase in tumor diameter.	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('millimeter', 'Var', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))
116994	25827538	The poor prognosis of ciliary body melanoma has been related to larger tumor size, predilection for monosomy 3 and 8q gain, and tumor microvascular patterns.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('body melanoma', 'Disease', (30, 43))	('body melanoma', 'Disease', 'MESH:D008545', (30, 43))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('monosomy 3', 'Var', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (128, 133))	('ciliary body melanoma', 'Phenotype', 'HP:0012055', (22, 43))	('tumor', 'Disease', (71, 76))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))
117014	25827538	EOE is more commonly associated with larger tumors, anterior tumor extension, large basal tumor diameter, diffuse uveal melanoma, epithelioid cellularity, closed vascular loops, high mitotic rate, and monosomy 3, resulting in poor prognosis.	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('vascular loop', 'Phenotype', 'HP:0010775', (162, 175))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('anterior tumor', 'Disease', 'MESH:C537775', (52, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('uveal melanoma', 'Disease', (114, 128))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('basal tumor', 'Disease', (84, 95))	('basal tumor', 'Disease', 'MESH:D002280', (84, 95))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('high mitotic rate', 'CPA', (178, 195))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('anterior tumor', 'Disease', (52, 66))	('associated', 'Reg', (21, 31))	('EOE', 'Disease', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('monosomy 3', 'Var', (201, 211))	('tumors', 'Disease', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('larger', 'Disease', (37, 43))	('basal tumor', 'Phenotype', 'HP:0002671', (84, 95))	('vascular loops', 'Phenotype', 'HP:0010775', (162, 176))
117039	25827538	A high fraction of PC-10 and Ki-67 in uveal melanoma cells is associated with decreased melanoma-specific survival.	('uveal melanoma', 'Disease', (38, 52))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('Ki-67', 'Gene', (29, 34))	('decreased', 'NegReg', (78, 87))	('uveal melanoma', 'Disease', 'MESH:C536494', (38, 52))	('PC-10', 'Var', (19, 24))
117046	25827538	The 10-year Kaplan-Meier estimate for melanoma-specific survival was 74% for small, 60% for medium, and 42% for large MLN.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('MLN', 'Gene', '4295', (118, 121))	('large', 'Var', (112, 117))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))	('MLN', 'Gene', (118, 121))
117060	25827538	In a matched case control study by Folberg et al., it was shown that the presence of at least one closed vascular loop in a uveal melanoma is the most significant vascular pattern associated with death from metastatic melanoma.	('presence', 'Var', (73, 81))	('uveal melanoma', 'Disease', (124, 138))	('uveal melanoma', 'Disease', 'MESH:C536494', (124, 138))	('uveal melanoma', 'Phenotype', 'HP:0007716', (124, 138))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('death', 'Disease', 'MESH:D003643', (196, 201))	('vascular loop', 'Phenotype', 'HP:0010775', (105, 118))	('death', 'Disease', (196, 201))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('associated with', 'Reg', (180, 195))	('melanoma', 'Disease', (130, 138))
117064	25827538	An association between monosomy 3 and influx of tumor-infiltrating lymphocytes has been established.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('monosomy 3', 'Var', (23, 33))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
117076	25827538	The significant association between high IGF-1R expression and death due to metastatic disease may be related to the fact that IGF-1 is mainly produced in the liver, which is the preferential site for uveal melanoma metastases.	('IGF-1', 'Gene', '3479', (41, 46))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('uveal melanoma', 'Phenotype', 'HP:0007716', (201, 215))	('death', 'Disease', 'MESH:D003643', (63, 68))	('death', 'Disease', (63, 68))	('expression', 'MPA', (48, 58))	('high IGF-1R', 'Phenotype', 'HP:0030269', (36, 47))	('uveal melanoma metastases', 'Disease', (201, 226))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (201, 226))	('IGF-1', 'Gene', '3479', (127, 132))	('IGF-1', 'Gene', (127, 132))	('IGF-1R', 'Gene', '3480', (41, 47))	('metastatic disease', 'Disease', (76, 94))	('IGF-1R', 'Gene', (41, 47))	('IGF-1', 'Gene', (41, 46))	('high', 'Var', (36, 40))
117078	25827538	In a study of 36 cases of uveal melanoma with more than 15 years follow-up, Kaplan-Meier analysis showed a significant association between a high IGF-1R (expression in >50% melanoma cells) and melanoma-related mortality.	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('IGF-1R', 'Gene', '3480', (146, 152))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Disease', (193, 201))	('melanoma', 'Disease', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('IGF-1R', 'Gene', (146, 152))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (173, 181))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('uveal melanoma', 'Disease', (26, 40))	('uveal melanoma', 'Disease', 'MESH:C536494', (26, 40))	('uveal melanoma', 'Phenotype', 'HP:0007716', (26, 40))	('high', 'Var', (141, 145))	('high IGF-1R', 'Phenotype', 'HP:0030269', (141, 152))
117079	25827538	Over a period of 15 years follow-up, 56% of patients with high IGF-1R, and 42% with low IGF-1R (expression in 15 to 50% cells), and 0% with very low IGF-1R (expression in <15% cells) died due to metastasis.	('IGF-1R', 'Gene', '3480', (149, 155))	('IGF-1R', 'Gene', (149, 155))	('IGF-1R', 'Gene', (88, 94))	('IGF-1R', 'Gene', '3480', (88, 94))	('patients', 'Species', '9606', (44, 52))	('low IGF', 'Phenotype', 'HP:0002850', (84, 91))	('high IGF-1R', 'Phenotype', 'HP:0030269', (58, 69))	('high', 'Var', (58, 62))	('metastasis', 'CPA', (195, 205))	('IGF-1R', 'Gene', '3480', (63, 69))	('low IGF', 'Phenotype', 'HP:0002850', (145, 152))	('IGF-1R', 'Gene', (63, 69))
117090	25827538	Aberrations in chromosome 1, 3, 6, and 8 determine the survival in patients with uveal melanoma.	('patients', 'Species', '9606', (67, 75))	('determine', 'Reg', (41, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('15', '25'))	('uveal melanoma', 'Disease', (81, 95))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('uveal melanoma', 'Disease', 'MESH:C536494', (81, 95))	('Aberrations', 'Var', (0, 11))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
117092	25827538	Partial aberrations on chromosome 3 (partial deletion of one copy of chromosome 3) and isodisomy (loss of one copy of chromosome 3 and then duplication of the remaining defective copy) have also been reported, both of which have a metastatic potential.	('chromosome', 'cellular_component', 'GO:0005694', ('23', '33'))	('duplication', 'Var', (140, 151))	('metastatic potential', 'CPA', (231, 251))	('chromosome', 'cellular_component', 'GO:0005694', ('118', '128'))	('chromosome', 'cellular_component', 'GO:0005694', ('69', '79'))	('isodisomy', 'Disease', 'MESH:D024182', (87, 96))	('isodisomy', 'Disease', (87, 96))	('loss', 'NegReg', (98, 102))	('partial deletion', 'Var', (37, 53))
117094	25827538	In a study of uveal melanomas by Schoenfield et al., monosomy 3 was noted at the base and disomy 3 at apex of the tumor.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('uveal melanoma', 'Phenotype', 'HP:0007716', (14, 28))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('monosomy 3', 'Disease', (53, 63))	('disomy 3', 'Var', (90, 98))	('tumor', 'Disease', (114, 119))	('uveal melanomas', 'Disease', (14, 29))	('uveal melanomas', 'Phenotype', 'HP:0007716', (14, 29))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanomas', 'Phenotype', 'HP:0002861', (20, 29))	('apex', 'cellular_component', 'GO:0097683', ('102', '106'))	('uveal melanomas', 'Disease', 'MESH:C536494', (14, 29))
117095	25827538	In a landmark publication by Prescher et al., monosomy 3 was established as a significant prognostic factor for uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('uveal melanoma', 'Disease', 'MESH:C536494', (112, 126))	('uveal melanoma', 'Phenotype', 'HP:0007716', (112, 126))	('uveal melanoma', 'Disease', (112, 126))	('monosomy 3', 'Var', (46, 56))
117096	25827538	Of 54 patients with uveal melanoma, monosomy 3 was identified in 30 (56%) patients.	('monosomy 3', 'Var', (36, 46))	('patients', 'Species', '9606', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('patients', 'Species', '9606', (6, 14))	('uveal melanoma', 'Disease', 'MESH:C536494', (20, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (20, 34))	('uveal melanoma', 'Disease', (20, 34))
117097	25827538	Three-year mortality rate in patients with tumors harboring monosomy 3 was 50%, and those with no monosomy 3 was 0%.	('patients', 'Species', '9606', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('monosomy 3', 'Var', (60, 70))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
117098	25827538	Subsequent studies have shown that monosomy 3 occurs in 21 to 56% cases and is associated with melanoma-related mortality in 42-54% over a follow-up period ranging from 2 to 8 years.	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('associated with', 'Reg', (79, 94))	('monosomy 3', 'Var', (35, 45))
117099	25827538	Presence of monosomy 3 indicates high-risk melanoma, with an increased risk for metastasis.	('metastasis', 'CPA', (80, 90))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('monosomy 3', 'Var', (12, 22))
117100	25827538	Monosomy 3 is associated with clinical and histopathological risk factors including larger tumor diameter, ciliary body tumor location, epithelioid cell type, high mitotic rate, vascular loops, and extraocular extension.	('vascular loop', 'Phenotype', 'HP:0010775', (178, 191))	('larger', 'PosReg', (84, 90))	('high mitotic rate', 'CPA', (159, 176))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('extraocular extension', 'CPA', (198, 219))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('epithelioid', 'Disease', (136, 147))	('vascular loops', 'CPA', (178, 192))	('vascular loops', 'Phenotype', 'HP:0010775', (178, 192))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (91, 96))	('Monosomy 3', 'Var', (0, 10))	('tumor', 'Disease', (120, 125))
117103	25827538	In majority of cases with aberrations in chromosome 8, 8q gain is more common occurring in 41 to 53% cases of uveal melanoma, while 8p loss occurs rarely.	('uveal melanoma', 'Phenotype', 'HP:0007716', (110, 124))	('uveal melanoma', 'Disease', (110, 124))	('uveal melanoma', 'Disease', 'MESH:C536494', (110, 124))	('gain', 'PosReg', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('aberrations', 'Var', (26, 37))	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))
117104	25827538	The most common forms of 8q gain are trisomy 8, isochromosome 8q, and amplification of the c-myc gene.	('trisomy', 'Disease', (37, 44))	('isochromosome 8q', 'Var', (48, 64))	('8q gain', 'Disease', (25, 32))	('c-myc', 'Gene', '4609', (91, 96))	('c-myc', 'Gene', (91, 96))	('amplification', 'Var', (70, 83))
117105	25827538	Chromosome 8q gain is an important prognostic factor for uveal melanoma either when it presents alone or co-exists with monosomy 3.	('gain', 'PosReg', (14, 18))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('Chromosome 8q', 'Var', (0, 13))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('uveal melanoma', 'Disease', (57, 71))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))
117106	25827538	In a study of 356 patients with uveal melanoma by Damato et al., the tumors showed no cytogenetic abnormalities of chromosomes 3 or 8 in 42%, 8q gain in 11%, monosomy 3 in 21%, and combined 8q gain and monosomy 3 in 27%.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('monosomy 3', 'Var', (158, 168))	('monosomy 3', 'Var', (202, 212))	('uveal melanoma', 'Disease', 'MESH:C536494', (32, 46))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (32, 46))	('gain', 'PosReg', (145, 149))	('uveal melanoma', 'Disease', (32, 46))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('patients', 'Species', '9606', (18, 26))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))
117107	25827538	Five-year disease specific mortality rates were 6% in the absence of chromosomal abnormality, 31% with only 8q gain, 40% with only monosomy 3, and 66% with combined 8q gain and monosomy 3.	('chromosomal abnormality', 'Disease', (69, 92))	('monosomy', 'Var', (177, 185))	('chromosomal abnormality', 'Disease', 'MESH:D002869', (69, 92))
117109	25827538	Chromosome 1p loss occurs more frequently in tumors with monosomy 3 (40%) than those with disomy 3 (10%).	('Chromosome', 'Gene', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('monosomy 3', 'Var', (57, 67))	('loss', 'NegReg', (14, 18))
117111	25827538	In a study 0f 120 patients with uveal melanoma by Kilic et al., it was noted that the effect of monosomy 3 on survival was largely modified by changes in 1p36.	('uveal melanoma', 'Phenotype', 'HP:0007716', (32, 46))	('uveal melanoma', 'Disease', 'MESH:C536494', (32, 46))	('modified', 'Reg', (131, 139))	('changes', 'Var', (143, 150))	('uveal melanoma', 'Disease', (32, 46))	('patients', 'Species', '9606', (18, 26))	('1p36', 'Protein', (154, 158))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))
117115	25827538	The coexistence of 6p gain and monosomy 3 occurs in only 4% cases of uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('uveal melanoma', 'Disease', (69, 83))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('monosomy 3', 'Var', (31, 41))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))
117121	25827538	Chromosome 6p gain occurred in 80% Class I tumors, and monosomy 3 was noted in 80% Class II tumors and no Class I tumors.	('Class I tumors', 'Disease', (35, 49))	('gain', 'PosReg', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('Class I tumors', 'Disease', 'MESH:D008311', (35, 49))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('Class I tumors', 'Disease', (106, 120))	('Chromosome', 'Var', (0, 10))	('Class II tumors', 'Disease', 'MESH:D008312', (83, 98))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('Class I tumors', 'Disease', 'MESH:D008311', (106, 120))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('Class II tumors', 'Disease', (83, 98))
117124	25827538	Patients with Class II tumors tend to be older, and are associated with thicker tumors, epithelioid cytology, higher proliferative rate (higher Ki-67 positivity), and mutations in BAP1 tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mutations', 'Var', (167, 176))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('Class II tumors', 'Disease', 'MESH:D008312', (14, 29))	('higher', 'PosReg', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Disease', (185, 190))	('BAP1', 'Gene', '8314', (180, 184))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('thicker tumors', 'Disease', 'MESH:D009369', (72, 86))	('Class II tumors', 'Disease', (14, 29))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('185', '201'))	('tumor', 'Disease', (80, 85))	('proliferative rate', 'CPA', (117, 135))	('BAP1', 'Gene', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('thicker tumors', 'Disease', (72, 86))	('tumor', 'Disease', (23, 28))	('epithelioid cytology', 'CPA', (88, 108))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor suppressor', 'biological_process', 'GO:0051726', ('185', '201'))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))
117134	25827540	Features that suggest a poor prognosis include higher blood levels of tyrosinase m-RNA, vascular endothelial growth factor, insulin-like growth factor; monosomy 3 and gains in chromosome 8.	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('88', '122'))	('vascular endothelial growth factor', 'Gene', '7422', (88, 122))	('gains', 'Var', (167, 172))	('RNA', 'cellular_component', 'GO:0005562', ('83', '86'))	('higher', 'PosReg', (47, 53))	('tyrosinase', 'Gene', '7299', (70, 80))	('higher blood levels of tyrosinase', 'Phenotype', 'HP:0003231', (47, 80))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('124', '150'))	('chromosome', 'cellular_component', 'GO:0005694', ('176', '186'))	('tyrosinase', 'Gene', (70, 80))	('vascular endothelial growth factor', 'Gene', (88, 122))	('monosomy', 'Var', (152, 160))	('insulin-like growth factor', 'MPA', (124, 150))
117193	25827540	studied 7872 patients with uveal melanoma and concluded that the presence of oculodermal melanocytosis doubles the risk for metastasis in melanoma patients when compared with those with no melanocytosis.	('melanocytosis', 'Disease', 'MESH:C535835', (189, 202))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('patients', 'Species', '9606', (13, 21))	('melanoma', 'Disease', (33, 41))	('oculodermal melanocytosis', 'Phenotype', 'HP:0009920', (77, 102))	('melanocytosis', 'Disease', (89, 102))	('oculodermal melanocytosis', 'Disease', 'MESH:C535835', (77, 102))	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('uveal melanoma', 'Disease', (27, 41))	('uveal melanoma', 'Disease', 'MESH:C536494', (27, 41))	('patients', 'Species', '9606', (147, 155))	('oculodermal melanocytosis', 'Disease', (77, 102))	('melanocytosis', 'Disease', (189, 202))	('uveal melanoma', 'Phenotype', 'HP:0007716', (27, 41))	('metastasis', 'CPA', (124, 134))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('melanocytosis', 'Disease', 'MESH:C535835', (89, 102))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('presence', 'Var', (65, 73))
117202	25827540	Heavy pigmentation has been found to be associated with epithelioid cell type and larger sized tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('Heavy pigmentation', 'Var', (0, 18))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('epithelioid cell', 'Disease', (56, 72))	('pigmentation', 'biological_process', 'GO:0043473', ('6', '18'))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('associated', 'Reg', (40, 50))
117222	25827540	The co-expression of IGF-1 and c-met in uveal melanoma samples is highly predictive of metastasis.	('metastasis', 'CPA', (87, 97))	('c-met', 'Gene', (31, 36))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('co-expression', 'Var', (4, 17))	('uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))	('uveal melanoma', 'Disease', (40, 54))	('c-met', 'Gene', '4233', (31, 36))	('uveal melanoma', 'Disease', 'MESH:C536494', (40, 54))	('predictive', 'Reg', (73, 83))	('IGF-1', 'Gene', '3479', (21, 26))	('IGF-1', 'Gene', (21, 26))
117228	25827540	Loss of one copy of chromosome 3 in tumor cell is seen in nearly half of choroidal melanomas and is a risk factor most strongly associated with metastatic death.	('choroidal melanomas', 'Phenotype', 'HP:0012054', (73, 92))	('Loss of one', 'Var', (0, 11))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (73, 91))	('choroidal melanomas', 'Disease', (73, 92))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('choroidal melanomas', 'Disease', 'MESH:D008545', (73, 92))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('associated', 'Reg', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('death', 'Disease', 'MESH:D003643', (155, 160))	('death', 'Disease', (155, 160))	('chromosome', 'cellular_component', 'GO:0005694', ('20', '30'))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('tumor', 'Disease', (36, 41))
117229	25827540	in their study on 500 melanoma cases concluded that patients with uveal melanoma demonstrating complete monosomy 3 have substantially poorer prognosis at 3 years than those with partial monosomy 3 or disomy 3.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('uveal melanoma', 'Disease', (66, 80))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma', 'Disease', (22, 30))	('patients', 'Species', '9606', (52, 60))	('complete monosomy 3', 'Var', (95, 114))	('poorer', 'NegReg', (134, 140))
117230	25827540	Using gene expression profiling, melanomas have been categorized into two groups: Class I denotes tumors with two copies of chromosome 3 (disomy 3) and other beneficial chromosome changes including gain in chromosome 6p Class II denotes tumors with only one copy of chromosome 3 (monosomy 3) and other deleterious chromosome changes including gain of chromosome 8p and/or isochromosome 8p.	('chromosome', 'cellular_component', 'GO:0005694', ('314', '324'))	('tumors', 'Disease', (98, 104))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('chromosome', 'cellular_component', 'GO:0005694', ('169', '179'))	('gain', 'PosReg', (343, 347))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('isochromosome 8p', 'Var', (372, 388))	('tumors', 'Disease', (237, 243))	('Class II denotes tumors', 'Disease', (220, 243))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('melanomas', 'Disease', 'MESH:D008545', (33, 42))	('chromosome', 'cellular_component', 'GO:0005694', ('266', '276'))	('chromosome', 'cellular_component', 'GO:0005694', ('351', '361'))	('melanomas', 'Disease', (33, 42))	('chromosome', 'cellular_component', 'GO:0005694', ('124', '134'))	('chromosome', 'cellular_component', 'GO:0005694', ('206', '216'))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('gene expression', 'biological_process', 'GO:0010467', ('6', '21'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('Class II denotes tumors', 'Disease', 'MESH:D008312', (220, 243))
117233	25827540	Mutations in genes GNAQ and GNA11 have been associated with the development of uveal melanoma.	('GNAQ', 'Gene', (19, 23))	('GNA11', 'Gene', (28, 33))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Disease', (79, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('GNAQ', 'Gene', '2776', (19, 23))	('GNA11', 'Gene', '2767', (28, 33))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('associated with', 'Reg', (44, 59))
117235	25827540	Nearly 83.0% of uveal melanomas have been found to have a constitutively active mutation in either GNAQ or GNA11, suggesting that activation of the Galphaq-Galpha11 pathway is the predominant route to the development of uveal melanoma.	('uveal melanomas', 'Disease', (16, 31))	('uveal melanoma', 'Phenotype', 'HP:0007716', (220, 234))	('uveal melanoma', 'Disease', (220, 234))	('uveal melanoma', 'Disease', 'MESH:C536494', (220, 234))	('Galphaq-Galpha11 pathway', 'Pathway', (148, 172))	('activation', 'PosReg', (130, 140))	('uveal melanomas', 'Disease', 'MESH:C536494', (16, 31))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('uveal melanoma', 'Disease', 'MESH:C536494', (16, 30))	('GNAQ', 'Gene', (99, 103))	('GNAQ', 'Gene', '2776', (99, 103))	('uveal melanomas', 'Phenotype', 'HP:0007716', (16, 31))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('GNA11', 'Gene', '2767', (107, 112))	('GNA11', 'Gene', (107, 112))	('mutation', 'Var', (80, 88))
74642	25827540	GNAQ and GNA11 mutations at codon 209 were encountered in 21.7% and 56.5% of metastatic uveal melanoma samples, respectively.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations at', 'Var', (15, 27))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (88, 102))	('GNAQ', 'Gene', (0, 4))	('encountered', 'Reg', (43, 54))	('uveal melanoma', 'Disease', (88, 102))	('GNA11', 'Gene', '2767', (9, 14))
117236	25827540	In the same study, GNA11 mutations were more common in locally advanced tumors and tumors of the ciliochoroidal region.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mutations', 'Var', (25, 34))	('common', 'Reg', (45, 51))	('GNA11', 'Gene', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('GNA11', 'Gene', '2767', (19, 24))	('tumors', 'Disease', (83, 89))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
117272	25106493	The study showed a 14-month increased survival (26 versus 12 months) when comparing patients treated with IHP with the longest surviving patients in Sweden during the same time period.	('increased', 'PosReg', (28, 37))	('IHP', 'Var', (106, 109))	('patients', 'Species', '9606', (84, 92))	('patients', 'Species', '9606', (137, 145))	('survival', 'MPA', (38, 46))
117282	25106493	Adequate hepatic function (defined as aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin < = 3 times upper limit of normal (ULN) and prothrombin time international normalized ratio (PT-INR) < = 1.5) and no medical history of liver cirrhosis or portal hypertension.	('hypertension', 'Disease', (276, 288))	('portal hypertension', 'Phenotype', 'HP:0001409', (269, 288))	('bilirubin', 'MPA', (104, 113))	('aspartate aminotransferase', 'Gene', (38, 64))	('liver cirrhosis', 'Disease', (250, 265))	('AST', 'Gene', (66, 69))	('hypertension', 'Phenotype', 'HP:0000822', (276, 288))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (250, 265))	('bilirubin', 'Chemical', 'MESH:D001663', (104, 113))	('< =', 'Var', (114, 117))	('AST', 'Gene', '26503', (66, 69))	('hepatic function', 'MPA', (9, 25))	('aspartate aminotransferase', 'Gene', '26503', (38, 64))	('ALT', 'molecular_function', 'GO:0004021', ('98', '101'))	('liver cirrhosis', 'Disease', 'MESH:D008103', (250, 265))	('hypertension', 'Disease', 'MESH:D006973', (276, 288))	('alanine aminotransferase', 'Gene', (72, 96))	('alanine aminotransferase', 'Gene', '2875', (72, 96))
117321	25106493	Uveal melanoma most frequently carry mutations in the GNAQ, GNA11, and BAP1 genes, where GNAQ/GNA11 mutations are mutually exclusive.	('GNAQ', 'Gene', (54, 58))	('GNA11', 'Gene', '2767', (94, 99))	('GNAQ', 'Gene', '2776', (89, 93))	('GNA11', 'Gene', (60, 65))	('carry', 'Reg', (31, 36))	('GNA11', 'Gene', '2767', (60, 65))	('BAP1', 'Gene', '8314', (71, 75))	('mutations', 'Var', (37, 46))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('GNAQ', 'Gene', (89, 93))	('GNAQ', 'Gene', '2776', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('BAP1', 'Gene', (71, 75))	('GNA11', 'Gene', (94, 99))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
117322	25106493	With the genetic information obtained from the material in our IHP biobank, we can investigate if different mutations impact response rates or OS.	('OS', 'Chemical', '-', (143, 145))	('impact', 'Reg', (118, 124))	('response', 'MPA', (125, 133))	('mutations', 'Var', (108, 117))
117323	25106493	It is possible, and even likely, that knowing the mutation status of the tumor sample would impact the treatment in arm B upon crossover.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('impact', 'Reg', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('treatment', 'MPA', (103, 112))	('mutation', 'Var', (50, 58))
117367	24281096	The presence of microsatellites suggests aggressiveness of melanoma and correlates with dismal prognosis similar to that for patients with regional nodal metastases, therefore wider margins of surgical resection are unlikely to cure this group of patients.	('aggressiveness of melanoma', 'Disease', (41, 67))	('aggressiveness of melanoma', 'Disease', 'MESH:D008545', (41, 67))	('metastases', 'Disease', (154, 164))	('patients', 'Species', '9606', (247, 255))	('microsatellites', 'Var', (16, 31))	('aggressiveness', 'Phenotype', 'HP:0000718', (41, 55))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('metastases', 'Disease', 'MESH:D009362', (154, 164))	('patients', 'Species', '9606', (125, 133))
117480	21647268	In the past decade, many details of the pathogenesis of UM have emerged, e.g., the gene-expression signatures with prognostic significance, as well as guanine nucleotide-binding proteins alpha-q and alpha 11 (GNAQ/GNA11) and BRCA1 associated protein-1 (BAP1) mutations.	('gene-expression', 'biological_process', 'GO:0010467', ('83', '98'))	('protein', 'cellular_component', 'GO:0003675', ('242', '249'))	('GNA11', 'Gene', (214, 219))	('mutations', 'Var', (259, 268))	('BRCA1 associated protein-1', 'Gene', '8314', (225, 251))	('GNA11', 'Gene', '2767', (214, 219))	('GNAQ', 'Gene', (209, 213))	('BRCA1 associated protein-1', 'Gene', (225, 251))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('159', '177'))	('BAP1', 'Gene', '8314', (253, 257))	('pathogenesis', 'biological_process', 'GO:0009405', ('40', '52'))	('GNAQ', 'Gene', '2776', (209, 213))	('BAP1', 'Gene', (253, 257))	('UM', 'Phenotype', 'HP:0007716', (56, 58))
117507	21647268	We next examined both mRNA and protein expression of ANLN and TYRP1 between TP31 cell line, UM primary tumors, and UVM (Figure 3).	('primary tumors', 'Disease', (95, 109))	('UM', 'Phenotype', 'HP:0007716', (92, 94))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('primary tumors', 'Disease', 'MESH:D009369', (95, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('ANLN', 'Var', (53, 57))	('TYRP1', 'Var', (62, 67))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('examined', 'Reg', (8, 16))
117510	21647268	In addition, PPP3CA mRNA or protein was not detected in UVM compared to TP31 and primary tumors (Figure 4).	('primary tumors', 'Disease', (81, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('primary tumors', 'Disease', 'MESH:D009369', (81, 95))	('PPP3CA', 'Var', (13, 19))	('UVM', 'Disease', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
117513	21647268	When using several UM primary tumors separately, some expressed both the native PPP3CA protein and the splice variant, while others expressed only the splice variant (Figure 4B, right panel).	('primary tumors', 'Disease', 'MESH:D009369', (22, 36))	('PPP3CA', 'Var', (80, 86))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('UM', 'Phenotype', 'HP:0007716', (19, 21))	('primary tumors', 'Disease', (22, 36))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
117518	21647268	Moreover, ANLN overexpression was shown to increase levels of active RhoA and subsequently cell motility.	('RhoA', 'Gene', (69, 73))	('cell motility', 'CPA', (91, 104))	('RhoA', 'Gene', '387', (69, 73))	('cell motility', 'biological_process', 'GO:0048870', ('91', '104'))	('overexpression', 'Var', (15, 29))	('increase', 'PosReg', (43, 51))
117525	21647268	Indeed, the expression of TYRP1 was inversely correlated with tumor stage in malignant melanoma.	('TYRP1', 'Var', (26, 31))	('malignant melanoma', 'Disease', 'MESH:D008545', (77, 95))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('malignant melanoma', 'Disease', (77, 95))	('tumor', 'Disease', (62, 67))	('correlated', 'Reg', (46, 56))	('malignant melanoma', 'Phenotype', 'HP:0002861', (77, 95))	('expression', 'MPA', (12, 22))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
117533	21647268	It is noteworthy that the TP31 cell line is devoided of the GNAQ/GNA11 mutations and that, consequently, the genes reported in the present study could allow to establish a new mechanism for early gene expression changes leading to malignant transformation and proliferation of uveal melanocytes.	('GNAQ', 'Gene', (60, 64))	('malignant transformation', 'CPA', (231, 255))	('gene expression', 'biological_process', 'GO:0010467', ('196', '211'))	('changes', 'Var', (212, 219))	('GNA11', 'Gene', '2767', (65, 70))	('GNA11', 'Gene', (65, 70))	('GNAQ', 'Gene', '2776', (60, 64))	('leading to', 'Reg', (220, 230))	('proliferation', 'CPA', (260, 273))
117542	19898689	A significant correlation was observed in monosomy 3 and 1p36 positive cases in the tumor samples (p=0.039).	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('p36', 'Gene', (58, 61))	('tumor', 'Disease', (84, 89))	('monosomy', 'Var', (42, 50))	('p36', 'Gene', '302', (58, 61))
117555	19898689	Uveal melanoma is known to carry deletions in 3p25, 3q24, all of chromosome3, 1p36, 6q23, 9p21-9p23, 13q14, 13q12.3-q13, and 17p13.	('chromosome', 'cellular_component', 'GO:0005694', ('65', '75'))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('Uveal melanoma', 'Disease', 'MESH:C536494', (0, 14))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('p36', 'Gene', (79, 82))	('p36', 'Gene', '302', (79, 82))	('Uveal melanoma', 'Disease', (0, 14))	('deletions', 'Var', (33, 42))
117556	19898689	Conventional cytogenetics including fluorescent in situ hybridization (FISH) and Chromogenic in situ hybridization (CISH) have demonstrated that non-random chromosomal abnormalities, the loss of chromosome 3, and amplification of 8q are related to high mortality and the loss of 1p36 in metastasizing tumors is associated with concurrent monosomy 3.	('p36', 'Gene', (280, 283))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))	('p36', 'Gene', '302', (280, 283))	('tumors', 'Disease', 'MESH:D009369', (301, 307))	('amplification of', 'Var', (213, 229))	('loss', 'Var', (187, 191))	('monosomy 3', 'Disease', (338, 348))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('related', 'Reg', (237, 244))	('chromosomal abnormalities', 'Disease', (156, 181))	('chromosome', 'cellular_component', 'GO:0005694', ('195', '205'))	('chromosome 3', 'Protein', (195, 207))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (156, 181))	('tumors', 'Disease', (301, 307))	('loss', 'Var', (271, 275))	('associated', 'Reg', (311, 321))
117557	19898689	Aberrations in 6p and 6q regions have been observed to be involved in tumor initiation and development rather than tumor progression.	('development', 'CPA', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor initiation', 'Disease', 'MESH:D009369', (70, 86))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (115, 120))	('involved', 'Reg', (58, 66))	('tumor initiation', 'Disease', (70, 86))	('Aberrations', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
117558	19898689	has identified monosomy 3 in metastasizing melanoma by CISH.	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('melanoma', 'Disease', (43, 51))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('monosomy 3', 'Var', (15, 25))
117567	19898689	A study reports amplification of DDEF1 located in 8q24.	('DDEF1', 'Gene', (33, 38))	('DDEF1', 'Gene', '50807', (33, 38))	('amplification', 'Var', (16, 29))
117573	19898689	Our CISH studies confirmed that the selected tumor sections harbored monosomy 3 aberration, in the metastasizing case and no aberration in the non -metastasizing case.	('harbored', 'Reg', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('monosomy 3 aberration', 'Var', (69, 90))
117593	19898689	Chromosome 8 amplification was defined as disomy in case of two dots, extra chromosome - trisomy and amplified (4-8 copies).	('extra chromosome - trisomy', 'Var', (70, 96))	('chromosome', 'cellular_component', 'GO:0005694', ('76', '86'))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('disomy', 'Disease', (42, 48))	('disomy', 'Disease', 'MESH:D024182', (42, 48))
117594	19898689	The tumor samples had to show chromosomal loss by both CI and SD to be regarded as monosomy or deleted.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('chromosomal loss', 'Var', (30, 46))
117602	19898689	Other examples of metastatic melanoma, choroidal melanoma and normal retina hybridized with 1p36 are shown in (Figure 2D-F ), 8q22 (Figure 1D-F), whole chromosome 8 (Figure 2A-C), and chromosome 18 (Figure 3A-C).	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('choroidal melanoma', 'Disease', 'MESH:D008545', (39, 57))	('chromosome', 'cellular_component', 'GO:0005694', ('152', '162'))	('choroidal melanoma', 'Disease', (39, 57))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('chromosome', 'cellular_component', 'GO:0005694', ('184', '194'))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (39, 57))	('p36', 'Gene', (93, 96))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('8q22', 'Var', (126, 130))	('melanoma', 'Disease', (49, 57))	('p36', 'Gene', '302', (93, 96))
117603	19898689	8q22 amplification in breast carcinoma is seen as large clusters as shown in Figure 3D.	('breast carcinoma', 'Disease', 'MESH:D001943', (22, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('8q22 amplification', 'Var', (0, 18))	('breast carcinoma', 'Phenotype', 'HP:0003002', (22, 38))	('breast carcinoma', 'Disease', (22, 38))
117605	19898689	A significant correlation was observed in monosomy and 1p36 positive cases in the tumor samples (p=0.039).	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('monosomy', 'Var', (42, 50))	('tumor', 'Disease', (82, 87))	('p36', 'Gene', '302', (56, 59))	('p36', 'Gene', (56, 59))
117615	19898689	As our aim was to analyze aberrations in chromosome 1, 3, and 8 in uveal melanoma, an in depth study on intra tumor heterogeneity was not performed.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('intra tumor', 'Disease', (104, 115))	('uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('aberrations', 'Var', (26, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (67, 81))	('uveal melanoma', 'Disease', (67, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))	('intra tumor', 'Disease', 'MESH:D009369', (104, 115))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
117628	19898689	Rather it was found that the differentially expressed miRNAs bind to 3'UTR segments of genes that were often found to be deleted in chromosomal regions 8p22, 13q, and 17p in uveal melanoma (Table 2 and Table 3).	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('uveal melanoma', 'Disease', (174, 188))	('deleted', 'Var', (121, 128))	('uveal melanoma', 'Phenotype', 'HP:0007716', (174, 188))	('uveal melanoma', 'Disease', 'MESH:C536494', (174, 188))
117631	19898689	have observed that hypermethylation and silencing of CASP8 is correlated to glioblastoma multiforme.	('CASP8', 'Gene', '841', (53, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (76, 99))	('silencing', 'MPA', (40, 49))	('hypermethylation', 'Var', (19, 35))	('glioblastoma multiforme', 'Disease', (76, 99))	('CASP8', 'Gene', (53, 58))	('correlated', 'Reg', (62, 72))
117657	31807898	Patients were included aged 18 years or more with UM that underwent I125 plaque brachytherapy with concurrent uveal tumor biopsy (trans-vitreal or trans-scleral) from January 1, 2010, to June 30, 2014, with tissue sent for GEP (DecisionDx-UM, Friendswood, TX) and at least 3-month follow-up (+- 40 days).	('I125', 'Var', (68, 72))	('uveal tumor', 'Disease', 'MESH:D014604', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('Patients', 'Species', '9606', (0, 8))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('UM', 'Phenotype', 'HP:0007716', (239, 241))	('uveal tumor', 'Disease', (110, 121))
117681	31807898	Tumors in the > 6 mm group were more likely to have exudative retinal detachment and less likely to have overlying lipofuscin compared with those in the < 3 mm and 3-6 mm groups (all, p < 0.001) (Table 3).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('exudative retinal detachment', 'Phenotype', 'HP:0012231', (52, 80))	('retinal detachment', 'Phenotype', 'HP:0000541', (62, 80))	('less', 'NegReg', (85, 89))	('Tumors', 'Disease', (0, 6))	('retinal detachment', 'Disease', (62, 80))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('retinal detachment', 'Disease', 'MESH:D012163', (62, 80))	('lipofuscin', 'Chemical', 'MESH:D008062', (115, 125))	('> 6 mm', 'Var', (14, 20))
117742	31807898	In this study, uveal melanoma biopsies were performed on a large scale with minimal short-term complications with 8 (4%) of trans-vitreal biopsies resulting in persistent symptomatic vitreous hemorrhage and one (0.5%) trans-scleral biopsy resulting in a deep pass with subsequent rhegmatogenous retinal detachment.	('retinal detachment', 'Disease', (295, 313))	('rhegmatogenous retinal detachment', 'Phenotype', 'HP:0012230', (280, 313))	('persistent symptomatic vitreous', 'Phenotype', 'HP:0007968', (160, 191))	('trans-vitreal', 'Gene', (124, 137))	('uveal melanoma', 'Phenotype', 'HP:0007716', (15, 29))	('uveal melanoma', 'Disease', (15, 29))	('retinal detachment', 'Disease', 'MESH:D012163', (295, 313))	('vitreous hemorrhage', 'Disease', 'MESH:D014823', (183, 202))	('uveal melanoma', 'Disease', 'MESH:C536494', (15, 29))	('vitreous hemorrhage', 'Disease', (183, 202))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('deep pass', 'MPA', (254, 263))	('retinal detachment', 'Phenotype', 'HP:0000541', (295, 313))	('rhegmatogenous', 'Disease', (280, 294))	('vitreous hemorrhage', 'Phenotype', 'HP:0007902', (183, 202))	('biopsies', 'Var', (138, 146))
117788	32832244	As seen with the UM cell lines, the PUM spheroids that formed from cells isolated from different tumors (S121, S093, S084, S104, S143, and S119) varied in shape, size, and compactness, despite being plated at similar cell densities (Fig.	('compactness', 'CPA', (172, 183))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('S084', 'Var', (117, 121))	('UM', 'Phenotype', 'HP:0007716', (37, 39))	('S143', 'Var', (129, 133))	('S093', 'Var', (111, 115))	('S121', 'Var', (105, 109))	('tumors', 'Disease', (97, 103))	('varied', 'Reg', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('S119', 'Var', (139, 143))	('S104', 'Var', (123, 127))	('UM', 'Phenotype', 'HP:0007716', (17, 19))
117789	32832244	Five of the six PUM samples (S121, S093, S084, S104, and S119) formed compact spheroids by day 9 (similar to 92.1, OMM2.5, and MP46 cells); however, the morphological features of S119 suggest that this was concomitant with some cell death.	('S084', 'Var', (41, 45))	('S119', 'Var', (57, 61))	('S119', 'Var', (179, 183))	('cell death', 'biological_process', 'GO:0008219', ('228', '238'))	('S121', 'Var', (29, 33))	('death', 'Disease', 'MESH:D003643', (233, 238))	('death', 'Disease', (233, 238))	('S104', 'Var', (47, 51))	('UM', 'Phenotype', 'HP:0007716', (17, 19))
117790	32832244	To determine whether there was genetic drift between the spheroids and the original sampled tumor tissue, MLPA was undertaken from both the original patient tissue and pooled PUM spheroids from S121, S093, S084, S104, and S119 at day 9.	('S084', 'Var', (206, 210))	('S104', 'Var', (212, 216))	('S119', 'Var', (222, 226))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('S121', 'Var', (194, 198))	('patient', 'Species', '9606', (149, 156))	('S093', 'Var', (200, 204))	('tumor', 'Disease', (92, 97))	('UM', 'Phenotype', 'HP:0007716', (176, 178))
117792	32832244	Of note is the clear necrotic core observed in S093.	('necrotic', 'Disease', 'MESH:D009336', (21, 29))	('core', 'cellular_component', 'GO:0019013', ('30', '34'))	('S093', 'Var', (47, 51))	('necrotic', 'Disease', (21, 29))
117794	32832244	Both 92.1 and MM66 UM cell lines were chosen to represent a primary and metastatic tumor phenotype, respectively, and they showed compacted cores at day 4 with visibly proliferating cells at the periphery of the spheroid.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('MM66 UM', 'CellLine', 'CVCL:4D17', (14, 21))	('MM66', 'Var', (14, 18))	('UM', 'Phenotype', 'HP:0007716', (19, 21))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
117853	32013263	This stage of progression is characterized by the disruption of the p16INK4a-retinoblastoma (Rb) pathway, mostly by inactivation of CDKN2A, due to its mutations.	('CDKN2A', 'Gene', (132, 138))	('inactivation', 'NegReg', (116, 128))	('Rb', 'Disease', 'MESH:D012175', (93, 95))	('Rb', 'Phenotype', 'HP:0009919', (93, 95))	('retinoblastoma', 'Phenotype', 'HP:0009919', (77, 91))	('CDKN2A', 'Gene', '1029', (132, 138))	('p16INK4a-retinoblastoma', 'Disease', (68, 91))	('p16INK4a-retinoblastoma', 'Disease', 'MESH:D012175', (68, 91))	('disruption', 'NegReg', (50, 60))	('mutations', 'Var', (151, 160))
117855	32013263	The final stage of melanoma progression is characterized by a vertical growth phase (VGP), requiring mutations repressing apoptosis, which allow cells to survive in the absence of keratinocytes as well as PTEN loss, over-expression of various protein kinases or RAS activation, and beta-catenin activation (reviewed in Bennett et al.).	('PTEN', 'Gene', (205, 209))	('beta-catenin', 'Gene', (282, 294))	('over-expression', 'PosReg', (216, 231))	('mutations', 'Var', (101, 110))	('PTEN', 'Gene', '5728', (205, 209))	('melanoma progression', 'Disease', (19, 39))	('activation', 'PosReg', (266, 276))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('protein', 'cellular_component', 'GO:0003675', ('243', '250'))	('beta-catenin', 'Gene', '1499', (282, 294))	('RAS', 'Protein', (262, 265))	('protein', 'Enzyme', (243, 250))	('loss', 'NegReg', (210, 214))	('melanoma progression', 'Disease', 'MESH:D008545', (19, 39))
117877	32013263	Despite this, it has been demonstrated that some melanomas in stage III (rarely IV), having not been widely spread and carrying the BRAF mutation, can be treated surgically.	('BRAF', 'Gene', (132, 136))	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('mutation', 'Var', (137, 145))	('melanomas', 'Disease', 'MESH:D008545', (49, 58))	('melanomas', 'Disease', (49, 58))	('BRAF', 'Gene', '673', (132, 136))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
117884	32013263	Some of the genes encoding the proteins belonging to the MAPK cascade are mutated in melanoma cells, compared to melanocytes, providing a solid strategy for the development of target-based therapies.	('MAPK', 'molecular_function', 'GO:0004707', ('57', '61'))	('MAPK cascade', 'biological_process', 'GO:0000165', ('57', '69'))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('mutated', 'Var', (74, 81))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))
117886	32013263	The most frequent has been found in exon 15 and it is responsible for substitution of valine in glutamic acid at position 600 of the BRAF protein (BRAF-V600E-).	('valine', 'Chemical', 'MESH:D014633', (86, 92))	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('glutamic acid', 'Chemical', 'MESH:D018698', (96, 109))	('BRAF', 'Gene', '673', (133, 137))	('responsible', 'Reg', (54, 65))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', (133, 137))	('BRAF', 'Gene', '673', (147, 151))	('V600E', 'Mutation', 'rs113488022', (152, 157))	('substitution', 'Var', (70, 82))
117887	32013263	It constitutes about 90% of the BRAF mutations observed in melanoma and in almost 50% of melanoma patients.	('BRAF', 'Gene', '673', (32, 36))	('BRAF', 'Gene', (32, 36))	('patients', 'Species', '9606', (98, 106))	('mutations', 'Var', (37, 46))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
117888	32013263	The mutated BRAF gene encodes for an active BRAF protein inducing the constitutive MAPK pathway activation and subsequently promoting cell proliferation and preventing apoptosis in melanoma cells.	('apoptosis', 'biological_process', 'GO:0097194', ('168', '177'))	('apoptosis', 'biological_process', 'GO:0006915', ('168', '177'))	('preventing', 'NegReg', (157, 167))	('promoting', 'PosReg', (124, 133))	('inducing', 'PosReg', (57, 65))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('melanoma', 'Disease', (181, 189))	('activation', 'PosReg', (96, 106))	('cell proliferation', 'CPA', (134, 152))	('mutated', 'Var', (4, 11))	('BRAF', 'Gene', '673', (44, 48))	('BRAF', 'Gene', (44, 48))	('cell proliferation', 'biological_process', 'GO:0008283', ('134', '152'))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('apoptosis', 'CPA', (168, 177))	('MAPK', 'molecular_function', 'GO:0004707', ('83', '87'))	('melanoma', 'Disease', 'MESH:D008545', (181, 189))	('constitutive MAPK pathway', 'Pathway', (70, 95))
117889	32013263	Other mutations have been also identified in the NRAS gene in approximately 15-20% of melanomas.	('NRAS', 'Gene', '4893', (49, 53))	('melanomas', 'Disease', 'MESH:D008545', (86, 95))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('identified', 'Reg', (31, 41))	('melanomas', 'Disease', (86, 95))	('NRAS', 'Gene', (49, 53))	('mutations', 'Var', (6, 15))
117891	32013263	Based on these findings, several agents inhibiting the mutated BRAF and MEK proteins have been developed and, since 2011, different target-based therapeutics have been approved by the Food & Drug Administration (FDA), as shown in Figure 2A.	('mutated', 'Var', (55, 62))	('MEK', 'Gene', (72, 75))	('BRAF', 'Gene', '673', (63, 67))	('MEK', 'Gene', '5609', (72, 75))	('BRAF', 'Gene', (63, 67))	('inhibiting', 'NegReg', (40, 50))
117892	32013263	However, recent investigations have shown that the continuous treatment with BRAF and MEK inhibitor agents (BRAFi, MEKi) of patients carrying BRAF-mutant melanoma consistently failed due to the selection of genetic mutations conferring disease resistance or the ability of melanoma endorsing drug resistance-associated transcriptional programs.	('MEK', 'Gene', (86, 89))	('BRAF', 'Gene', '673', (142, 146))	('patients', 'Species', '9606', (124, 132))	('BRAF', 'Gene', (142, 146))	('drug resistance', 'biological_process', 'GO:0009315', ('292', '307'))	('BRAFi', 'Chemical', '-', (108, 113))	('drug resistance', 'biological_process', 'GO:0042493', ('292', '307'))	('mutations', 'Var', (215, 224))	('melanoma', 'Disease', 'MESH:D008545', (273, 281))	('BRAF', 'Gene', '673', (108, 112))	('disease resistance', 'biological_process', 'GO:0009614', ('236', '254'))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('MEK', 'Gene', '5609', (115, 118))	('BRAF', 'Gene', (108, 112))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (77, 81))	('MEK', 'Gene', (115, 118))	('disease', 'MPA', (236, 243))	('failed', 'NegReg', (176, 182))	('drug resistance', 'Phenotype', 'HP:0020174', (292, 307))	('melanoma', 'Phenotype', 'HP:0002861', (273, 281))	('melanoma', 'Disease', (273, 281))	('MEK', 'Gene', '5609', (86, 89))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))
117915	32013263	Tumor cells are characterized by genetic instability, resulting in the occurrence of a large number of mutations, as well as the expression of non-synonymous mutations producing tumor-specific antigens, also known as neo-antigens.	('mutations', 'Var', (103, 112))	('tumor', 'Disease', (178, 183))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
117947	32013263	Regarding miR-137, it has been observed that miR-148 negatively regulates MITF expression in melanoma cells by targeting a binding site found in its 3'UTR sequence.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('binding', 'Interaction', (123, 130))	('melanoma', 'Disease', (93, 101))	('miR-148', 'Chemical', '-', (45, 52))	('MITF', 'Gene', '4286', (74, 78))	('MITF', 'Gene', (74, 78))	('miR-137', 'Gene', (10, 17))	('expression', 'MPA', (79, 89))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('binding', 'molecular_function', 'GO:0005488', ('123', '130'))	('miR-148', 'Var', (45, 52))	('miR-137', 'Gene', '406928', (10, 17))	('regulates', 'Reg', (64, 73))	('negatively', 'NegReg', (53, 63))	('targeting', 'Reg', (111, 120))
117948	32013263	However, the combined miR-137 and miR-148 overexpression does not result in a cumulative effect.	('miR-148', 'Chemical', '-', (34, 41))	('miR-148', 'Var', (34, 41))	('miR-137', 'Gene', '406928', (22, 29))	('miR-137', 'Gene', (22, 29))
117955	32013263	Additionally, miR-26a and miR-101 have been demonstrated to be capable of inhibiting the invasion and proliferation of melanoma cells by targeting MITF.	('inhibiting', 'NegReg', (74, 84))	('targeting', 'Reg', (137, 146))	('miR-26a', 'Gene', '407015', (14, 21))	('MITF', 'Gene', (147, 151))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('miR-26a', 'Gene', (14, 21))	('miR-101', 'Var', (26, 33))	('MITF', 'Gene', '4286', (147, 151))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('miR-101', 'Chemical', '-', (26, 33))
117958	32013263	It has been demonstrated that miR-211 inhibits the migration and invasion of melanoma cells.	('inhibits', 'NegReg', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('miR-211', 'Var', (30, 37))
117972	32013263	Notably, BRAFi monotherapy may provide profound initial tumor regression in patients with BRAF V600-mutated metastatic melanoma.	('BRAF', 'Gene', (90, 94))	('patients', 'Species', '9606', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('BRAF', 'Gene', (9, 13))	('BRAFi', 'Chemical', '-', (9, 14))	('tumor', 'Disease', (56, 61))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('V600-mutated', 'Var', (95, 107))	('BRAF', 'Gene', '673', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('BRAF', 'Gene', '673', (9, 13))
117980	32013263	MiR-34a, miR-100, and miR-125b have also been shown to be highly expressed in both resistant cells and treated patient tumor biopsies.	('tumor', 'Disease', (119, 124))	('miR-125b', 'Var', (22, 30))	('MiR-34a', 'Gene', (0, 7))	('miR-125b', 'Chemical', '-', (22, 30))	('miR-100', 'Gene', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('patient', 'Species', '9606', (111, 118))	('MiR-34a', 'Gene', '407040', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('miR-100', 'Gene', '406892', (9, 16))
117986	32013263	Upregulation of miR-204 5p and miR-211 5p improved vemurafenib's responses, facilitating the emergence of resistance.	('Upregulation', 'PosReg', (0, 12))	('miR-204 5p', 'Var', (16, 26))	('vemurafenib', 'Gene', (51, 62))	('responses', 'MPA', (65, 74))	('miR-204 5p', 'Chemical', '-', (16, 26))	('improved', 'PosReg', (42, 50))	('miR-211 5p', 'Var', (31, 41))	('vemurafenib', 'Chemical', 'MESH:D000077484', (51, 62))	('emergence', 'MPA', (93, 102))
117989	32013263	Moreover, while miR-7, miR-34a, miR-100, and miR-125b have been shown to be able to reverse/restore melanoma resistance in target-based therapies by targeting different signaling pathways, miR-579-3p has been found to be associated with resistance development in melanoma.	('miR-579', 'Gene', '693164', (189, 196))	('miR-7', 'Gene', (16, 21))	('miR-34a', 'Gene', '407040', (23, 30))	('melanoma', 'Disease', (263, 271))	('melanoma', 'Phenotype', 'HP:0002861', (263, 271))	('miR-125b', 'Chemical', '-', (45, 53))	('miR-579', 'Gene', (189, 196))	('miR-100', 'Gene', (32, 39))	('miR-125b', 'Var', (45, 53))	('associated', 'Reg', (221, 231))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('miR-7', 'Gene', '10859', (16, 21))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (263, 271))	('miR-100', 'Gene', '406892', (32, 39))	('signaling', 'biological_process', 'GO:0023052', ('169', '178'))	('miR-34a', 'Gene', (23, 30))	('resistance development', 'Disease', (237, 259))	('targeting', 'Reg', (149, 158))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('reverse/restore', 'PosReg', (84, 99))
117990	32013263	MiR-579-3p is observed to be downregulated in melanoma patients upon the development of resistance to target-based therapies.	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('MiR-579-3p', 'Var', (0, 10))	('patients', 'Species', '9606', (55, 63))	('downregulated', 'NegReg', (29, 42))
117998	32013263	MiR-514a, a well-known key player in initiating melanocyte transformation and enhancing melanoma growth, has been reported to regulate the sensitivity of BRAF-targeted therapy by modulating the tumor suppressor NF1 gene.	('enhancing', 'PosReg', (78, 87))	('modulating', 'Reg', (179, 189))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('NF1', 'Gene', (211, 214))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanocyte transformation', 'CPA', (48, 73))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('BRAF', 'Gene', '673', (154, 158))	('NF1', 'Gene', '4763', (211, 214))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('BRAF', 'Gene', (154, 158))	('tumor', 'Disease', (194, 199))	('tumor suppressor', 'biological_process', 'GO:0051726', ('194', '210'))	('MiR-514a', 'Var', (0, 8))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('194', '210'))
118047	32013263	Among them, they confirmed the differential expression of miR-211 5p, miR-21 5p, and miR-125b 5p that has been previously linked to melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('miR-211 5p', 'Var', (58, 68))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('miR-21 5p', 'Gene', (70, 79))	('miR-125b', 'Var', (85, 93))	('linked', 'Reg', (122, 128))	('miR-21 5p', 'Gene', '406997', (70, 79))	('miR-125b', 'Chemical', '-', (85, 93))
118055	32013263	showed miR-205-5p gradually decreased during melanomagenesis in mice and was able to reduce cell invasiveness and proliferation, and delay tumor initiation.	('delay tumor initiation', 'Disease', 'MESH:D009369', (133, 155))	('decreased', 'NegReg', (28, 37))	('reduce', 'NegReg', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('mice', 'Species', '10090', (64, 68))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))	('delay tumor initiation', 'Disease', (133, 155))	('miR-205-5p', 'Var', (7, 17))	('cell invasiveness', 'CPA', (92, 109))
118056	32013263	Several studies have focused on miR-205-5p and its dual role in cancer.	('miR-205-5p', 'Var', (32, 42))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
118073	32013263	MiR-30b-5p acts as a tumor suppressor microRNA in esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (50, 84))	('tumor', 'Disease', (21, 26))	('tumor suppressor', 'biological_process', 'GO:0051726', ('21', '37'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('MiR-30b-5p', 'Var', (0, 10))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('21', '37'))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('esophageal squamous cell carcinoma', 'Disease', (50, 84))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
118080	32013263	High expression levels of miR-224-5p have been detected in a large variety of tumors, such as glioma, colorectal cancer, and renal carcinoma, and is downregulated in uveal melanoma.	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('renal carcinoma', 'Disease', (125, 140))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('expression levels', 'MPA', (5, 22))	('tumors', 'Disease', (78, 84))	('colorectal cancer', 'Disease', (102, 119))	('miR-224-5p', 'Var', (26, 36))	('uveal melanoma', 'Disease', (166, 180))	('uveal melanoma', 'Disease', 'MESH:C536494', (166, 180))	('downregulated', 'NegReg', (149, 162))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('renal carcinoma', 'Disease', 'MESH:D002292', (125, 140))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('uveal melanoma', 'Phenotype', 'HP:0007716', (166, 180))	('glioma', 'Disease', (94, 100))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('detected', 'Reg', (47, 55))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('renal carcinoma', 'Phenotype', 'HP:0005584', (125, 140))
118081	32013263	showed that miR-224-5p is involved in the proliferation, invasion, and migration of uveal melanoma (UM) cells via regulation of the expression of PIK3R3 and AKT3.	('involved', 'Reg', (26, 34))	('invasion', 'CPA', (57, 65))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma', 'Disease', (84, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('UM', 'Disease', 'MESH:C536494', (100, 102))	('regulation', 'biological_process', 'GO:0065007', ('114', '124'))	('migration', 'CPA', (71, 80))	('regulation', 'Reg', (114, 124))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('AKT3', 'Gene', '10000', (157, 161))	('expression', 'MPA', (132, 142))	('AKT3', 'Gene', (157, 161))	('PIK3R3', 'Gene', '8503', (146, 152))	('PIK3R3', 'Gene', (146, 152))	('miR-224-5p', 'Var', (12, 22))
118082	32013263	highlighted the correlation of the downregulated expression of miR-224-5p with the clinical progression and prognosis of prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (121, 136))	('clinical', 'Species', '191496', (83, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (121, 136))	('expression', 'MPA', (49, 59))	('miR-224-5p', 'Var', (63, 73))	('prostate cancer', 'Disease', (121, 136))	('downregulated', 'NegReg', (35, 48))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
118083	32013263	showed that the miR-224/miR-452 cluster is significantly increased in advanced melanoma and that ectopic expression of miR-224/miR-452 induces EMT and cytoskeletal rearrangements, and enhances migration/invasion.	('EMT', 'biological_process', 'GO:0001837', ('143', '146'))	('enhances', 'PosReg', (184, 192))	('miR-224/miR-452', 'Gene', (16, 31))	('migration/invasion', 'CPA', (193, 211))	('cytoskeletal rearrangements', 'CPA', (151, 178))	('increased', 'PosReg', (57, 66))	('induces', 'PosReg', (135, 142))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('EMT', 'CPA', (143, 146))	('miR-224/miR-452', 'Var', (119, 134))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
118084	32013263	Conversely, miR-224/miR-452 depletion in metastatic cells induces the reversal of EMT, inhibition of motility, loss of the invasive phenotype, and an absence of lung metastases in mice.	('inhibition', 'NegReg', (87, 97))	('loss', 'NegReg', (111, 115))	('motility', 'CPA', (101, 109))	('absence of lung', 'Phenotype', 'HP:0005944', (150, 165))	('depletion', 'Var', (28, 37))	('EMT', 'biological_process', 'GO:0001837', ('82', '85'))	('miR-224/miR-452 depletion', 'Var', (12, 37))	('mice', 'Species', '10090', (180, 184))	('EMT', 'CPA', (82, 85))	('invasive phenotype', 'CPA', (123, 141))	('absence of lung metastases', 'Disease', 'MESH:D009362', (150, 176))	('absence of lung metastases', 'Disease', (150, 176))
118085	32013263	It has been shown that miR-224/miR-452 targets the metastasis suppressor TXNIP and induces feedback inhibition of E2F1.	('TXNIP', 'Gene', '10628', (73, 78))	('feedback inhibition', 'MPA', (91, 110))	('E2F1', 'Gene', '1869', (114, 118))	('TXNIP', 'Gene', (73, 78))	('E2F1', 'Gene', (114, 118))	('induces', 'Reg', (83, 90))	('metastasis', 'MPA', (51, 61))	('miR-224/miR-452', 'Var', (23, 38))
118146	30744698	Antitumor response to microscopic melanoma in the gastric mucosa mimicking ipilimumab-induced gastritis Alongside its clinical success, checkpoint blockade has also given rise to a set of immune-related adverse events (irAEs).	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('gastritis', 'Phenotype', 'HP:0005263', (94, 103))	('ipilimumab', 'Chemical', 'MESH:D000074324', (75, 85))	('gastritis', 'Disease', 'MESH:D005756', (94, 103))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))	('gastritis', 'Disease', (94, 103))	('microscopic', 'Var', (22, 33))
118189	30744698	Furthermore, successful treatment of checkpoint colitis using blockade of the gut homing integrin alpha4beta7 suggests that migration of T cells from the blood into the colonic mucosa plays an important role in continuing this inflammatory response.	('colitis', 'Disease', 'MESH:D003092', (48, 55))	('colitis', 'Disease', (48, 55))	('blockade', 'Var', (62, 70))	('colitis', 'Phenotype', 'HP:0002583', (48, 55))	('inflammatory response', 'biological_process', 'GO:0006954', ('227', '248'))
118207	29509591	Therefore, we hypothesized that HAI of nab-paclitaxel would deliver an effective dose of drug to the end-organ of interest, with minimal systemic exposure.	('effective dose of drug', 'MPA', (71, 93))	('nab-paclitaxel', 'Var', (39, 53))	('nab', 'Chemical', '-', (39, 42))	('paclitaxel', 'Chemical', 'MESH:D017239', (43, 53))	('HAI', 'Var', (32, 35))
118252	29509591	In the group receiving HAI paclitaxel 130mg/m2 (n=3), all the patients were removed from study after 2 cycles of treatment because of rapid tumor progression.	('HAI paclitaxel', 'Var', (23, 37))	('paclitaxel', 'Chemical', 'MESH:D017239', (27, 37))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('patients', 'Species', '9606', (62, 70))	('tumor', 'Disease', (140, 145))
118255	29509591	In the 285mg/m2 cohort (n=5), 4 patients were removed from the study for tumor progression, and 1 patient was withdrawn for difficulty with compliance.	('patients', 'Species', '9606', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('patient', 'Species', '9606', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('285mg/m2', 'Var', (7, 15))	('patient', 'Species', '9606', (32, 39))
118257	29509591	Toxicities outside the DLT period with 285mg/m2 resulted in frequent dose delays, notably neuropathy and myelosuppression.	('Toxicities', 'Disease', (0, 10))	('285mg/m2', 'Var', (39, 47))	('neuropathy and myelosuppression', 'Disease', 'MESH:D009422', (90, 121))	('Toxicities', 'Disease', 'MESH:D064420', (0, 10))	('neuropathy', 'Phenotype', 'HP:0009830', (90, 100))	('dose delays', 'MPA', (69, 80))
118270	29509591	Landmark analyses demonstrate the 3-year overall survival of metastatic melanoma patients treated with ipilimumab is 21%, and patients treated with pembrolizumab is 40%.	('pembrolizumab', 'Chemical', 'MESH:C582435', (148, 161))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('ipilimumab', 'Chemical', 'MESH:D000074324', (103, 113))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (126, 134))	('ipilimumab', 'Var', (103, 113))
118289	29509591	In that study, median progression-free survival was 4.8 months with nab-paclitaxel and 2.5 months with dacarbazine in a population where only 8% of patients had received prior treatment for metastatic melanoma.	('melanoma', 'Disease', (201, 209))	('dacarbazine', 'Chemical', 'MESH:D003606', (103, 114))	('patients', 'Species', '9606', (148, 156))	('paclitaxel', 'Chemical', 'MESH:D017239', (72, 82))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('nab', 'Chemical', '-', (68, 71))	('nab-paclitaxel', 'Var', (68, 82))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))
118309	29180934	The primary tumor was treated with brachytherapy Ru106.	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('Ru106', 'Var', (49, 54))
118342	29180934	BRAF, RAS and KIT mutations are generally rare in ocular melanoma and therefore the targeted therapies developed for cutaneous melanoma are unlikely to be efficacious in treatment of UM.	('KIT', 'Gene', (14, 17))	('cutaneous melanoma', 'Disease', (117, 135))	('RAS', 'Gene', (6, 9))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (117, 135))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (117, 135))	('UM', 'Phenotype', 'HP:0007716', (183, 185))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('KIT', 'molecular_function', 'GO:0005020', ('14', '17'))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('ocular melanoma', 'Disease', (50, 65))	('BRAF', 'Gene', (0, 4))	('ocular melanoma', 'Disease', 'MESH:D008545', (50, 65))	('ocular melanoma', 'Phenotype', 'HP:0007716', (50, 65))	('mutations', 'Var', (18, 27))
118361	29180934	reported a significantly better survival in patients with nodular angiographic pattern of liver metastases compared to patients with diffuse tumors (mean 621 days vs. 115 days).	('diffuse tumors', 'Disease', 'MESH:D009369', (133, 147))	('patients', 'Species', '9606', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('nodular angiographic pattern', 'Var', (58, 86))	('better', 'PosReg', (25, 31))	('survival', 'MPA', (32, 40))	('liver metastases', 'Disease', (90, 106))	('diffuse tumors', 'Disease', (133, 147))	('patients', 'Species', '9606', (119, 127))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('liver metastases', 'Disease', 'MESH:D009362', (90, 106))
118459	15318944	Some recent studies suggests that mutations in the breast cancer susceptibility locus, BRCA2 on chromosome 13, may be involved in the development of uveal melanoma.	('men', 'Species', '9606', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (149, 163))	('uveal melanoma', 'Disease', 'MESH:C536494', (149, 163))	('BRCA2', 'Gene', '675', (87, 92))	('uveal melanoma', 'Disease', (149, 163))	('involved', 'Reg', (118, 126))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('breast cancer', 'Disease', (51, 64))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('mutations', 'Var', (34, 43))	('BRCA2', 'Gene', (87, 92))
118521	26505679	BAP1 mutations have been indeed shown to be enriched in tumours, which eventually gave rise to metastasis.	('tumours', 'Disease', 'MESH:D009369', (56, 63))	('tumours', 'Disease', (56, 63))	('BAP1', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (5, 14))	('metastasis', 'CPA', (95, 105))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('gave rise to', 'Reg', (82, 94))
118522	26505679	Therefore, BAP1 mutations and LOH of chromosome 3 define a class of primary tumours with a more aggressive biological behaviour.	('aggressive biological behaviour', 'Phenotype', 'HP:0000718', (96, 127))	('primary tumours', 'Disease', 'MESH:D009369', (68, 83))	('chromosome', 'cellular_component', 'GO:0005694', ('37', '47'))	('primary tumours', 'Disease', (68, 83))	('mutations', 'Var', (16, 25))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('behaviour', 'biological_process', 'GO:0007610', ('118', '127'))	('BAP1', 'Gene', (11, 15))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))
118523	26505679	On the other hand, tumours with heterozygosity of chromosome 3 have better prognosis and are often mutated in EIF1AX (15%) or SF3B1 (14-29%).	('EIF1AX', 'Gene', (110, 116))	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('SF3B1', 'Gene', (126, 131))	('better', 'PosReg', (68, 74))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('mutated', 'Var', (99, 106))	('chromosome', 'cellular_component', 'GO:0005694', ('50', '60'))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
118528	26505679	The recent establishment of BAP1-mutated UM cell lines and patient-derived xenografts (PDXs) will probably foster the advancement in the understanding of the role of BAP1 mutations in UM.	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('UM', 'Phenotype', 'HP:0007716', (184, 186))	('patient', 'Species', '9606', (59, 66))	('BAP1', 'Gene', (166, 170))	('mutations', 'Var', (171, 180))
118529	26505679	BAP1 is also mutated in other tumour types, such as clear cell renal carcinoma and mesothelioma, as well as in the germline of patients affected by familial cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (52, 78))	('BAP1', 'Gene', (0, 4))	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('tumour', 'Disease', (30, 36))	('mesothelioma', 'Disease', (83, 95))	('patients', 'Species', '9606', (127, 135))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('renal carcinoma', 'Phenotype', 'HP:0005584', (63, 78))	('clear cell renal carcinoma', 'Disease', (52, 78))	('mesothelioma', 'Disease', 'MESH:D008654', (83, 95))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (52, 78))	('familial cancer', 'Disease', (148, 163))	('mutated', 'Var', (13, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('familial cancer', 'Disease', 'MESH:D009369', (148, 163))
118531	26505679	Interestingly, investigation of splicing patterns in other SF3B1-mutated neoplasias (chronic lymphocytic leukemia and myelodysplastic syndrome) demonstrates that different hotspot mutations lead to the same splicing signature.	('chronic lymphocytic leukemia', 'Disease', (85, 113))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (85, 113))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (118, 142))	('mutations', 'Var', (180, 189))	('splicing', 'biological_process', 'GO:0045292', ('207', '215'))	('splicing', 'biological_process', 'GO:0045292', ('32', '40'))	('neoplasias', 'Phenotype', 'HP:0002664', (73, 83))	('SF3B1-mutated', 'Gene', (59, 72))	('myelodysplastic syndrome', 'Disease', (118, 142))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (118, 142))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (85, 113))	('neoplasias', 'Disease', 'MESH:D009369', (73, 83))	('leukemia', 'Phenotype', 'HP:0001909', (105, 113))	('splicing signature', 'MPA', (207, 225))	('neoplasias', 'Disease', (73, 83))
118534	26505679	Galphaq proteins are known to activate via phospholipase C and protein kinase C (PKC) the mitogen-activated protein kinase (MAPK) pathway, which was shown in several reports to be constitutively upregulated in UM bearing GNAQ/11 mutations.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('UM', 'Phenotype', 'HP:0007716', (210, 212))	('PKC', 'molecular_function', 'GO:0004697', ('81', '84'))	('activate', 'PosReg', (30, 38))	('Galphaq', 'Gene', (0, 7))	('phospholipase C', 'Enzyme', (43, 58))	('Galphaq', 'Gene', '2776', (0, 7))	('protein kinase C', 'Enzyme', (63, 79))	('mutations', 'Var', (229, 238))	('upregulated', 'PosReg', (195, 206))	('MAPK', 'molecular_function', 'GO:0004707', ('124', '128'))	('GNAQ/11', 'Gene', (221, 228))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
118535	26505679	Mutant GNAQ/11 were also shown to activate the guanine nucleotide exchange factor Trio and to induce, via the small GTPases RhoA and Rac1, its release from the associated protein AMOT.	('RhoA', 'Gene', (124, 128))	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('activate', 'PosReg', (34, 42))	('Trio', 'Gene', '7204', (82, 86))	('RhoA', 'Gene', '387', (124, 128))	('Rac1', 'Gene', '5879', (133, 137))	('Rac1', 'Gene', (133, 137))	('AMOT', 'Gene', '154796', (179, 183))	('AMOT', 'Gene', (179, 183))	('Trio', 'Gene', (82, 86))	('induce', 'PosReg', (94, 100))	('Mutant', 'Var', (0, 6))	('release from the', 'MPA', (143, 159))	('GNAQ/11', 'Gene', (7, 14))
118537	26505679	Moreover, the activation of Trio by Galphaq mutants is also suggested to have a role in the activation of the AP-1 transcription factor and possibly also of JNK and p38-dependent cascades.	('activation', 'PosReg', (14, 24))	('transcription factor', 'molecular_function', 'GO:0000981', ('115', '135'))	('activation', 'PosReg', (92, 102))	('JNK', 'Pathway', (157, 160))	('transcription', 'biological_process', 'GO:0006351', ('115', '128'))	('AP-1 transcription factor', 'Pathway', (110, 135))	('AP-1', 'cellular_component', 'GO:0005907', ('110', '114'))	('p38', 'Gene', '1432', (165, 168))	('mutants', 'Var', (44, 51))	('Trio', 'Gene', '7204', (28, 32))	('Galphaq', 'Gene', (36, 43))	('Galphaq', 'Gene', '2776', (36, 43))	('Trio', 'Gene', (28, 32))	('p38', 'Gene', (165, 168))	('JNK', 'molecular_function', 'GO:0004705', ('157', '160'))
118540	26505679	Even if genetic alterations such as deletions in PTEN and mutations of PI3K appear to be rare events, the PI3K/mTOR pathway was suggested to be activated in UM by immunohistochemical detection of phosphorylated AKT in several tumour samples.	('mutations', 'Var', (58, 67))	('PTEN', 'Gene', '5728', (49, 53))	('deletions', 'Var', (36, 45))	('mTOR', 'Gene', '2475', (111, 115))	('PI3K', 'Gene', (71, 75))	('AKT', 'Gene', '207', (211, 214))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('tumour', 'Disease', 'MESH:D009369', (226, 232))	('mTOR', 'Gene', (111, 115))	('AKT', 'Gene', (211, 214))	('tumour', 'Disease', (226, 232))	('PI3K', 'molecular_function', 'GO:0016303', ('106', '110'))	('UM', 'Phenotype', 'HP:0007716', (157, 159))	('PTEN', 'Gene', (49, 53))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))
118563	26505679	Indeed, trials testing the combination of MEK inhibitors with PKC (NCT01801358), PI3K (NCT02273219), AKT (NCT01979523) and chemotherapy such as Dacarbazine (NCT01974752) have been started.	('PI3K', 'molecular_function', 'GO:0016303', ('81', '85'))	('PKC', 'molecular_function', 'GO:0004697', ('62', '65'))	('AKT', 'Gene', '207', (101, 104))	('NCT01979523', 'Var', (106, 117))	('Dacarbazine', 'Chemical', 'MESH:D003606', (144, 155))	('NCT02273219', 'Var', (87, 98))	('MEK', 'Gene', (42, 45))	('AKT', 'Gene', (101, 104))	('MEK', 'Gene', '5609', (42, 45))	('NCT01801358', 'Var', (67, 78))
118567	26505679	The definition of high-risk (class II) and low-risk (class I) patients based on gene expression profile appears to correlate strongly with copy number status of chromosome 3 and BAP1 loss of function, which is easily tested with immunohistochemical staining.	('copy number status', 'Var', (139, 157))	('BAP1', 'Gene', (178, 182))	('gene expression', 'biological_process', 'GO:0010467', ('80', '95'))	('loss of function', 'NegReg', (183, 199))	('chromosome', 'cellular_component', 'GO:0005694', ('161', '171'))	('patients', 'Species', '9606', (62, 70))
118570	26505679	The presence in almost all UMs of hotspot mutations in GNAQ/11 genes and the dependence on blood circulation for the spread of metastatic cells could make of liquid biopsies, and circulating tumour DNA in particular, a valuable tool for surveillance and treatment monitoring.	('tumour', 'Disease', 'MESH:D009369', (191, 197))	('UM', 'Phenotype', 'HP:0007716', (27, 29))	('tumour', 'Disease', (191, 197))	('GNAQ/11', 'Gene', (55, 62))	('DNA', 'cellular_component', 'GO:0005574', ('198', '201'))	('blood circulation', 'biological_process', 'GO:0008015', ('91', '108'))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('mutations', 'Var', (42, 51))
118577	26505679	Moreover, establishing genetically modified mice displaying the genetic alterations of UM will also be an avenue for better understanding of the oncogenesis and progression, but for this purpose, along with mutated GNAQ/11 alleles, genome editing on BAP1, SF3B1 or EIF1AX will probably be necessary, as GNAQ/11 mutations are found in benign proliferations, such as blue nevi, and are therefore considered not sufficient for the progression into malignancy.	('oncogenesis', 'biological_process', 'GO:0007048', ('145', '156'))	('SF3B1', 'Gene', (256, 261))	('UM', 'Phenotype', 'HP:0007716', (87, 89))	('GNAQ/11', 'Gene', (303, 310))	('blue nevi', 'Phenotype', 'HP:0100814', (365, 374))	('mutations', 'Var', (311, 320))	('blue nevi', 'Disease', (365, 374))	('malignancy', 'Disease', 'MESH:D009369', (445, 455))	('malignancy', 'Disease', (445, 455))	('mice', 'Species', '10090', (44, 48))	('nevi', 'Phenotype', 'HP:0003764', (370, 374))
118583	26892651	In addition to CDKN2A and CDK4, germline variants in TERT, MITF, and BAP1 have been added to the list of genes harboring melanoma-predisposing mutations.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('variants', 'Var', (41, 49))	('TERT', 'Gene', (53, 57))	('melanoma', 'Disease', (121, 129))	('TERT', 'Gene', '7015', (53, 57))	('CDKN2A', 'Gene', (15, 21))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('CDK', 'molecular_function', 'GO:0004693', ('26', '29'))	('BAP1', 'Gene', (69, 73))	('CDKN2A', 'Gene', '1029', (15, 21))	('MITF', 'Gene', '4286', (59, 63))	('MITF', 'Gene', (59, 63))	('CDK4', 'Gene', '1019', (26, 30))	('CDK4', 'Gene', (26, 30))	('BAP1', 'Gene', '8314', (69, 73))
118592	26892651	These include mutations in BAP1, MITF, Shelterin complex and PTEN During the last few years sequencing efforts in the field of melanoma research have led to a number of scientific breakthroughs.	('MITF', 'Gene', (33, 37))	('Shelterin complex', 'cellular_component', 'GO:0070187', ('39', '56'))	('MITF', 'Gene', '4286', (33, 37))	('BAP1', 'Gene', (27, 31))	('PTEN', 'Gene', (61, 65))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('PTEN', 'Gene', '5728', (61, 65))	('melanoma', 'Disease', (127, 135))	('mutations', 'Var', (14, 23))	('BAP1', 'Gene', '8314', (27, 31))
118601	26892651	However, in recent years, mutations in BAP1, Shelterin complex, MITF and PTEN have also been associated with melanoma and internal organ cancers.	('melanoma and internal organ cancers', 'Disease', 'MESH:C563985', (109, 144))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('PTEN', 'Gene', (73, 77))	('PTEN', 'Gene', '5728', (73, 77))	('MITF', 'Gene', '4286', (64, 68))	('MITF', 'Gene', (64, 68))	('Shelterin complex', 'cellular_component', 'GO:0070187', ('45', '62'))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('associated', 'Reg', (93, 103))	('mutations', 'Var', (26, 35))	('BAP1', 'Gene', '8314', (39, 43))	('BAP1', 'Gene', (39, 43))
118606	26892651	Subsequently, germline BAP1 mutations were also reported in multi-cancer families.	('BAP1', 'Gene', (23, 27))	('multi-cancer', 'Disease', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('multi-cancer', 'Disease', 'MESH:D009369', (60, 72))	('reported', 'Reg', (48, 56))	('BAP1', 'Gene', '8314', (23, 27))	('mutations', 'Var', (28, 37))
118609	26892651	Although a single germline BAP1 mutation was reported in the original paper by Harbour and colleagues, the association of germline BAP1 mutations with a multitude of cancers was independently described in families with uveal melanoma and mesothelioma, and in kindreds with both uveal melanoma and cutaneous melanoma.	('uveal melanoma', 'Disease', (219, 233))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('mutations', 'Var', (136, 145))	('uveal melanoma', 'Phenotype', 'HP:0007716', (219, 233))	('melanoma', 'Phenotype', 'HP:0002861', (284, 292))	('uveal melanoma', 'Disease', 'MESH:C536494', (278, 292))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('BAP1', 'Gene', '8314', (27, 31))	('melanoma', 'Phenotype', 'HP:0002861', (307, 315))	('uveal melanoma', 'Disease', (278, 292))	('cancers', 'Disease', (166, 173))	('BAP1', 'Gene', '8314', (131, 135))	('cutaneous melanoma', 'Disease', (297, 315))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (297, 315))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (297, 315))	('association', 'Interaction', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('uveal melanoma', 'Phenotype', 'HP:0007716', (278, 292))	('described', 'Reg', (192, 201))	('uveal melanoma and mesothelioma', 'Disease', 'MESH:C536494', (219, 250))	('BAP1', 'Gene', (27, 31))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('germline', 'Gene', (122, 130))	('BAP1', 'Gene', (131, 135))	('uveal melanoma', 'Disease', 'MESH:C536494', (219, 233))
118613	26892651	The pathogenetic mechanisms through which BAP1 mutations (rearrangements, homozygous deletions, and missense mutations) directly or indirectly promote melanomagenesis have not been fully elucidated.	('BAP1', 'Gene', '8314', (42, 46))	('men', 'Species', '9606', (67, 70))	('BAP1', 'Gene', (42, 46))	('promote', 'PosReg', (143, 150))	('mutations', 'Var', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('missense mutations', 'Var', (100, 118))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))
118614	26892651	Some authors have suggested that patients with the mutation may exhibit altered patterns of gene expression through histone 2A modification or impaired DNA damage repair in response to UV-induced damage.	('histone 2A', 'Gene', '8337', (116, 126))	('patients', 'Species', '9606', (33, 41))	('altered', 'Reg', (72, 79))	('modification', 'Reg', (127, 139))	('gene expression', 'biological_process', 'GO:0010467', ('92', '107'))	('patterns', 'MPA', (80, 88))	('histone 2A', 'Gene', (116, 126))	('response to UV', 'biological_process', 'GO:0009411', ('173', '187'))	('DNA', 'cellular_component', 'GO:0005574', ('152', '155'))	('mutation', 'Var', (51, 59))	('impaired', 'NegReg', (143, 151))	('DNA damage repair', 'MPA', (152, 169))
118617	26892651	More studies are needed in order to fully understand the precise carcinogenic mechanisms of BAP1 mutations.	('mutations', 'Var', (97, 106))	('carcinogenic', 'Disease', 'MESH:D063646', (65, 77))	('BAP1', 'Gene', '8314', (92, 96))	('carcinogenic', 'Disease', (65, 77))	('BAP1', 'Gene', (92, 96))
118623	26892651	Wiesner et al., after investigating 32 sporadic ASTs, reported that nine (28%) showed loss of BAP1 expression, of which 8 (89%) had concomitant BRAF mutations, and exhibited a very similar histologic picture to that of MBAITs.	('expression', 'MPA', (99, 109))	('loss', 'NegReg', (86, 90))	('mutations', 'Var', (149, 158))	('BAP1', 'Gene', '8314', (94, 98))	('BRAF', 'Gene', '673', (144, 148))	('BRAF', 'Gene', (144, 148))	('BAP1', 'Gene', (94, 98))
118625	26892651	In a recent study, 66.7% of patients with germline BAP1 mutations had MBAITs, compared to none of the controls.	('mutations', 'Var', (56, 65))	('BAP1', 'Gene', (51, 55))	('MBAITs', 'Disease', (70, 76))	('patients', 'Species', '9606', (28, 36))	('BAP1', 'Gene', '8314', (51, 55))
118629	26892651	However, since these lesions can appear early in life, they should be viewed as potential markers of germline BAP1 mutagenesis.	('mutagenesis', 'biological_process', 'GO:0006280', ('115', '126'))	('BAP1', 'Gene', '8314', (110, 114))	('mutagenesis', 'Var', (115, 126))	('BAP1', 'Gene', (110, 114))
118631	26892651	have demonstrated that BAP1 mutations are more frequent among metastatic UM cases compared to non-metastatic UM controls (8% vs. 0%, p = 0.059), which has subsequently been confirmed in a separate cohort of 507 patients with OM.	('BAP1', 'Gene', (23, 27))	('patients', 'Species', '9606', (211, 219))	('BAP1', 'Gene', '8314', (23, 27))	('frequent', 'Reg', (47, 55))	('mutations', 'Var', (28, 37))	('metastatic UM', 'Disease', (62, 75))
118632	26892651	In addition, BAP1 mutations were more common in families with both CMM and UM compared to those with only CMM (29% vs. 0.52%; p= 0.003).	('BAP1', 'Gene', (13, 17))	('CMM', 'Gene', (106, 109))	('CMM', 'Gene', (67, 70))	('CMM', 'Gene', '1243', (106, 109))	('BAP1', 'Gene', '8314', (13, 17))	('common', 'Reg', (38, 44))	('CMM', 'Gene', '1243', (67, 70))	('mutations', 'Var', (18, 27))
118633	26892651	have recently reported that patients with UM, positive for germline BAP1 mutations, developed larger tumors (mean diameter, 15.9 vs 12.3 mm), exhibited higher rates of ciliary body involvement (75.0% vs 21.6%), had a higher metastatic potential (71.4% vs 18.0%) and had an increased frequency of family cancer history (especially for CM and OM) compared to controls.	('higher', 'PosReg', (152, 158))	('cancer', 'Disease', (303, 309))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('larger', 'PosReg', (94, 100))	('CM', 'Disease', 'MESH:D009202', (334, 336))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('ciliary body involvement', 'CPA', (168, 192))	('higher', 'PosReg', (217, 223))	('BAP1', 'Gene', '8314', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('men', 'Species', '9606', (188, 191))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('patients', 'Species', '9606', (28, 36))	('BAP1', 'Gene', (68, 72))	('metastatic potential', 'CPA', (224, 244))	('mutations', 'Var', (73, 82))	('tumors', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
118635	26892651	Beyond these select studies, many more have demonstrated an association between CMM and BAP1 mutations.	('CMM', 'Gene', '1243', (80, 83))	('mutations', 'Var', (93, 102))	('BAP1', 'Gene', '8314', (88, 92))	('CMM', 'Gene', (80, 83))	('BAP1', 'Gene', (88, 92))
118638	26892651	Given the rarity of the BAP1 tumor syndrome, there are no codified recommendations for the management of patients with BAP1 mutations.	('BAP1', 'Gene', (119, 123))	('patients', 'Species', '9606', (105, 113))	('mutations', 'Var', (124, 133))	('BAP1', 'Gene', (24, 28))	('men', 'Species', '9606', (72, 75))	('men', 'Species', '9606', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('BAP1', 'Gene', '8314', (119, 123))	('tumor syndrome', 'Disease', (29, 43))	('tumor syndrome', 'Disease', 'MESH:D009369', (29, 43))	('BAP1', 'Gene', '8314', (24, 28))
118639	26892651	It is extremely important for known BAP1 mutation carriers to be closely monitored with at least bi-annual skin examinations accompanied by removal of all changing lesions.	('mutation', 'Var', (41, 49))	('BAP1', 'Gene', (36, 40))	('BAP1', 'Gene', '8314', (36, 40))
118641	26892651	An example of a BAP1 mutation positive family pedigree is shown in Figure 1c.	('BAP1', 'Gene', '8314', (16, 20))	('BAP1', 'Gene', (16, 20))	('mutation positive', 'Var', (21, 38))
118642	26892651	BAP1 mutations have also been associated with a number of other types of malignancy (Table 1).	('associated', 'Reg', (30, 40))	('BAP1', 'Gene', (0, 4))	('malignancy', 'Disease', 'MESH:D009369', (73, 83))	('mutations', 'Var', (5, 14))	('malignancy', 'Disease', (73, 83))	('BAP1', 'Gene', '8314', (0, 4))
118643	26892651	have reported that 63.5% of patients with BAP1 mutations, compared to 9.1% of controls, developed at least one cancer (OR 17.39, 95% CI: 6.07-49.83).	('BAP1', 'Gene', '8314', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('BAP1', 'Gene', (42, 46))	('to 9', 'Species', '1214577', (67, 71))	('mutations', 'Var', (47, 56))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('developed', 'Reg', (88, 97))	('patients', 'Species', '9606', (28, 36))
118645	26892651	No specific screening protocols for internal malignancies have been currently established for individuals who carry a germline BAP1 variant.	('BAP1', 'Gene', (127, 131))	('variant', 'Var', (132, 139))	('malignancies', 'Disease', 'MESH:D009369', (45, 57))	('malignancies', 'Disease', (45, 57))	('BAP1', 'Gene', '8314', (127, 131))
118646	26892651	The shelterin complex and telomerase protect telomeres from gradual erosion, a process that leads to cell senescence Mutations in TERT, the protein component of telomerase, and in various components of the shelterin complex have been associated with a higher incidence of melanoma and other internal malignancies The association of these mutations with inherited melanoma syndromes remains to be elucidated Telomeres are DNA protein structures comprised of tandem repeats of the six-nucleotide unit sequence TTAGGG that extend for thousands of bases at chromosome ends.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('chromosome', 'cellular_component', 'GO:0005694', ('553', '563'))	('shelterin complex', 'cellular_component', 'GO:0070187', ('4', '21'))	('melanoma', 'Phenotype', 'HP:0002861', (363, 371))	('protein', 'cellular_component', 'GO:0003675', ('425', '432'))	('melanoma', 'Disease', (363, 371))	('TTAGGG', 'Gene', (508, 514))	('melanoma', 'Disease', 'MESH:D008545', (272, 280))	('melanoma syndromes', 'Disease', 'MESH:D008545', (363, 381))	('TERT', 'Gene', (130, 134))	('TERT', 'Gene', '7015', (130, 134))	('shelterin complex', 'cellular_component', 'GO:0070187', ('206', '223'))	('malignancies', 'Disease', 'MESH:D009369', (300, 312))	('senescence', 'biological_process', 'GO:0010149', ('106', '116'))	('DNA', 'cellular_component', 'GO:0005574', ('421', '424'))	('malignancies', 'Disease', (300, 312))	('Mutations', 'Var', (117, 126))	('melanoma syndromes', 'Disease', (363, 381))	('associated', 'Reg', (234, 244))	('mutations', 'Var', (338, 347))	('melanoma', 'Disease', 'MESH:D008545', (363, 371))	('melanoma', 'Phenotype', 'HP:0002861', (272, 280))	('melanoma', 'Disease', (272, 280))
118648	26892651	The shelterin complex contains 6 proteins: TRF1, TRF2, and TPP1, which can specifically recognize and bind to double-stranded TTAGGG repeats; POT1, which binds to the single-stranded telomeric overhang; and TIN2 and RAP1 (Figure 3).	('TRF2', 'Gene', '7014', (49, 53))	('TPP1', 'Gene', '1200', (59, 63))	('TRF2', 'Gene', (49, 53))	('POT1', 'Gene', '25913', (142, 146))	('TPP', 'molecular_function', 'GO:0004294', ('59', '62'))	('RAP1', 'Gene', (216, 220))	('TIN2', 'Gene', '26277', (207, 211))	('shelterin complex', 'cellular_component', 'GO:0070187', ('4', '21'))	('bind', 'Interaction', (102, 106))	('RAP1', 'Gene', '54386', (216, 220))	('TRF1', 'Gene', (43, 47))	('TPP1', 'Gene', (59, 63))	('TRF1', 'Gene', '7013', (43, 47))	('TIN2', 'Gene', (207, 211))	('POT1', 'Gene', (142, 146))	('double-stranded TTAGGG repeats', 'Var', (110, 140))
118649	26892651	POT1 mutations lead to insufficient capping of telomeres by shelterin.	('POT1', 'Gene', '25913', (0, 4))	('capping', 'MPA', (36, 43))	('mutations', 'Var', (5, 14))	('POT1', 'Gene', (0, 4))
118653	26892651	Mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene have been described both at the germline level and at the somatic level in sporadic cases of melanoma.	('TERT', 'Gene', '7015', (74, 78))	('transcriptase', 'molecular_function', 'GO:0003899', ('59', '72'))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('Mutations', 'Var', (0, 9))	('transcriptase', 'molecular_function', 'GO:0003968', ('59', '72'))	('telomerase reverse transcriptase', 'Gene', (40, 72))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('described', 'Reg', (95, 104))	('transcriptase', 'molecular_function', 'GO:0034062', ('59', '72'))	('telomerase reverse transcriptase', 'Gene', '7015', (40, 72))	('TERT', 'Gene', (74, 78))
118654	26892651	These mutations have been found in the promoter region of the TERT isoform that encodes a catalytic reverse transcriptase subunit of telomerase responsible for telomere length maintenance (Figure 2b).	('transcriptase', 'molecular_function', 'GO:0003899', ('108', '121'))	('telomere', 'cellular_component', 'GO:0000781', ('160', '168'))	('transcriptase', 'molecular_function', 'GO:0003968', ('108', '121'))	('transcriptase', 'molecular_function', 'GO:0034062', ('108', '121'))	('TERT', 'Gene', (62, 66))	('telomere', 'cellular_component', 'GO:0005696', ('160', '168'))	('TERT', 'Gene', '7015', (62, 66))	('mutations', 'Var', (6, 15))
118656	26892651	have described TERT mutations in a kindred with 14 CMM patients, yet they also described somatic mutations of TERT, which bore a clear UV-signature, in sporadic CMMs.	('TERT', 'Gene', '7015', (15, 19))	('mutations', 'Var', (97, 106))	('CMM', 'Gene', (161, 164))	('CMM', 'Gene', (51, 54))	('CMM', 'Gene', '1243', (161, 164))	('TERT', 'Gene', (110, 114))	('TERT', 'Gene', '7015', (110, 114))	('patients', 'Species', '9606', (55, 63))	('CMM', 'Gene', '1243', (51, 54))	('mutations', 'Var', (20, 29))	('TERT', 'Gene', (15, 19))
118658	26892651	Several studies have demonstrated UV-signature mutations at various positions in the TERT promoter.	('TERT', 'Gene', '7015', (85, 89))	('UV-signature', 'Gene', (34, 46))	('TERT', 'Gene', (85, 89))	('mutations', 'Var', (47, 56))
118659	26892651	These alterations may increase the transcription of TERT by creating novel Ets transcription factor binding sites.	('alterations', 'Var', (6, 17))	('transcription', 'biological_process', 'GO:0006351', ('79', '92'))	('binding sites', 'Interaction', (100, 113))	('transcription', 'biological_process', 'GO:0006351', ('35', '48'))	('increase', 'PosReg', (22, 30))	('TERT', 'Gene', (52, 56))	('transcription', 'MPA', (35, 48))	('TERT', 'Gene', '7015', (52, 56))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('79', '107'))	('Ets transcription', 'Protein', (75, 92))
118660	26892651	The GA binding protein (GABP) transcription factor, an Ets family member, has now been shown to be recruited to the sites of TERT promoter mutations.	('binding', 'molecular_function', 'GO:0005488', ('7', '14'))	('transcription factor', 'molecular_function', 'GO:0000981', ('30', '50'))	('mutations', 'Var', (139, 148))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('recruited', 'PosReg', (99, 108))	('TERT', 'Gene', (125, 129))	('GABP', 'Gene', (24, 28))	('transcription', 'biological_process', 'GO:0006351', ('30', '43'))	('TERT', 'Gene', '7015', (125, 129))
118661	26892651	As reported in a recent study, melanomas with TERT promoter variants were more likely to be nodular and superficial spreading in subtype and had increased thickness, ulceration, high mitotic rate, and frequent BRAFV600E mutations.	('TERT', 'Gene', '7015', (46, 50))	('melanomas', 'Disease', 'MESH:D008545', (31, 40))	('high mitotic rate', 'CPA', (178, 195))	('BRAFV600E', 'Var', (210, 219))	('BRAFV600E', 'Mutation', 'rs113488022', (210, 219))	('ulceration', 'CPA', (166, 176))	('increased', 'PosReg', (145, 154))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))	('nodular', 'Disease', 'MESH:D020518', (92, 99))	('melanomas', 'Disease', (31, 40))	('TERT', 'Gene', (46, 50))	('variants', 'Var', (60, 68))	('superficial spreading', 'CPA', (104, 125))	('thickness', 'CPA', (155, 164))	('nodular', 'Disease', (92, 99))
118663	26892651	a significant association between multiple primary melanomas and mutations in TERT has been demonstrated (TERT/CLPTM1L rs401681,(P = 0.004).	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('TERT', 'Gene', (78, 82))	('TERT', 'Gene', '7015', (78, 82))	('melanomas', 'Disease', 'MESH:D008545', (51, 60))	('TERT', 'Gene', (106, 110))	('TERT', 'Gene', '7015', (106, 110))	('rs401681', 'Var', (119, 127))	('melanomas', 'Disease', (51, 60))	('CLPTM1L', 'Gene', '81037', (111, 118))	('rs401681', 'Mutation', 'rs401681', (119, 127))	('CLPTM1L', 'Gene', (111, 118))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('mutations', 'Var', (65, 74))
118668	26892651	researched the role of 39 single-nucleotide polymorphisms (SNPs) associated with telomere length in 218 patients with CMM and found a positive association with telomere length and CMM risk.	('CMM', 'Gene', '1243', (118, 121))	('CMM', 'Gene', '1243', (180, 183))	('telomere', 'cellular_component', 'GO:0000781', ('81', '89'))	('telomere', 'MPA', (160, 168))	('telomere', 'cellular_component', 'GO:0000781', ('160', '168'))	('telomere', 'cellular_component', 'GO:0005696', ('81', '89'))	('CMM', 'Gene', (180, 183))	('single-nucleotide polymorphisms', 'Var', (26, 57))	('associated', 'Reg', (65, 75))	('CMM', 'Gene', (118, 121))	('telomere', 'cellular_component', 'GO:0005696', ('160', '168'))	('patients', 'Species', '9606', (104, 112))
118669	26892651	In addition, two SNPs in the TRF2 gene, rs153045 and rs251796, showed significant associations with both total number of moles and the number of raised moles on upper extremities.	('rs251796', 'Mutation', 'rs251796', (53, 61))	('mole', 'Phenotype', 'HP:0003764', (152, 156))	('rs153045', 'Mutation', 'rs153045', (40, 48))	('rs153045', 'Var', (40, 48))	('moles', 'Phenotype', 'HP:0003764', (121, 126))	('moles', 'Phenotype', 'HP:0003764', (152, 157))	('TRF2', 'Gene', '7014', (29, 33))	('TRF2', 'Gene', (29, 33))	('rs251796', 'Var', (53, 61))	('mole', 'Phenotype', 'HP:0003764', (121, 125))	('associations', 'Reg', (82, 94))
118671	26892651	A strong association between increased telomere score and increased risk of melanoma (P = 8.92 x 10-9) was consistent across geographic regions, and 4 SNPs with a p value <0.05 were reported (rs10936599 (TERC), p=0.0003; rs2736100 (TERT), p=0.02; rs7675998 (NAF1), p=0.03, rs9420907 (OBFC1), p=0.001).	('OBFC1', 'Gene', (284, 289))	('increased', 'PosReg', (29, 38))	('telomere', 'cellular_component', 'GO:0000781', ('39', '47'))	('rs7675998', 'Var', (247, 256))	('telomere', 'cellular_component', 'GO:0005696', ('39', '47'))	('OBFC1', 'Gene', '79991', (284, 289))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('TERC', 'Gene', '7012', (204, 208))	('rs2736100', 'Var', (221, 230))	('TERC', 'Gene', (204, 208))	('rs9420907', 'Var', (273, 282))	('telomere score', 'MPA', (39, 53))	('NAF1', 'Gene', '92345', (258, 262))	('rs2736100', 'Mutation', 'rs2736100', (221, 230))	('rs10936599', 'Var', (192, 202))	('rs9420907', 'Mutation', 'rs9420907', (273, 282))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('melanoma', 'Disease', (76, 84))	('TERT', 'Gene', (232, 236))	('TERT', 'Gene', '7015', (232, 236))	('NAF1', 'Gene', (258, 262))	('rs7675998', 'Mutation', 'rs7675998', (247, 256))	('rs10936599', 'Mutation', 'rs10936599', (192, 202))
118673	26892651	Beyond telomerase, other components of the telomeric apparatus have also been shown to harbor mutations in melanoma-prone families.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('mutations', 'Var', (94, 103))
118675	26892651	Mutations in the POT1 gene have been described in a small number of unrelated Italian, French, and U.S. melanoma families.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('POT1', 'Gene', '25913', (17, 21))	('POT1', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
118676	26892651	In addition to POT1 mutations, other mutations affecting the function of the shelterin complex have also been described.	('POT1', 'Gene', '25913', (15, 19))	('mutations', 'Var', (20, 29))	('POT1', 'Gene', (15, 19))	('shelterin complex', 'cellular_component', 'GO:0070187', ('77', '94'))
118677	26892651	For instance, mutations in the adrenocortical dysplasia (ACD) protein gene have been observed in a small number of melanoma families.	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('adrenocortical dysplasia (ACD)', 'Gene', '65057', (31, 61))	('melanoma', 'Disease', (115, 123))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('adrenocortical dysplasia (ACD', 'Gene', (31, 60))	('observed', 'Reg', (85, 93))	('mutations', 'Var', (14, 23))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
118679	26892651	Other mutations of the shelterin complex observed in CMM families include mutations in the TERF2IP gene.	('CMM', 'Gene', '1243', (53, 56))	('mutations', 'Var', (74, 83))	('TERF2IP', 'Gene', (91, 98))	('shelterin complex', 'cellular_component', 'GO:0070187', ('23', '40'))	('CMM', 'Gene', (53, 56))	('TERF2IP', 'Gene', '54386', (91, 98))
118680	26892651	Families harboring such mutations may present with early onset melanomas (appearing in patients as young as 15 years), as well as multiple primary melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanomas', 'Disease', 'MESH:D008545', (63, 72))	('melanomas', 'Disease', (63, 72))	('melanomas', 'Disease', (147, 156))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('mutations', 'Var', (24, 33))	('patients', 'Species', '9606', (87, 95))	('melanomas', 'Disease', 'MESH:D008545', (147, 156))	('melanomas', 'Phenotype', 'HP:0002861', (147, 156))
118682	26892651	(Table 1) Cowden syndrome belongs to the family of PTEN hamartoma tumor syndromes and is characterized by the appearance of trichilemmomas, papillomatous papules, mucosal lesions (papules) and palmar-plantar keratosis within the 3 first decades of life Newer data suggest that Cowden syndrome patients have a higher risk of presenting with melanoma compared to healthy controls Patients that harbor MITF mutations may exhibit a high atypical nevus count and have a tendency to develop melanomas at young age Patients with pancreatic or renal cancer who harbor MITF mutations have a higher risk of developing CMM PTEN hamartoma tumor syndrome (PHTS) is a rare condition that encompasses four major, clinically distinct entities associated with germline mutations in the tumor suppressor gene PTEN.	('MITF', 'Gene', '4286', (399, 403))	('PTEN hamartoma tumor syndromes', 'Disease', (51, 81))	('PTEN', 'Gene', (791, 795))	('mutations', 'Var', (565, 574))	('CMM', 'Gene', (608, 611))	('Cowden syndrome', 'Disease', 'MESH:D006223', (277, 292))	('atypical nevus', 'Phenotype', 'HP:0001062', (433, 447))	('tumor', 'Phenotype', 'HP:0002664', (627, 632))	('PHTS', 'Disease', 'MESH:D006223', (643, 647))	('pancreatic or renal cancer', 'Disease', 'MESH:D007680', (522, 548))	('pancreatic or renal cancer', 'Disease', (522, 548))	('tumor', 'Phenotype', 'HP:0002664', (769, 774))	('hamartoma', 'Phenotype', 'HP:0010566', (617, 626))	('PTEN', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (542, 548))	('tumor suppressor', 'biological_process', 'GO:0051726', ('769', '785'))	('hamartoma tumor syndrome', 'Disease', (617, 641))	('MITF', 'Gene', (399, 403))	('mucosal lesions', 'Disease', (163, 178))	('tumor', 'Disease', (66, 71))	('PTEN', 'Gene', '5728', (791, 795))	('papillomatous', 'Disease', (140, 153))	('palmar-plantar keratosis', 'Disease', 'MESH:C536338', (193, 217))	('PHTS', 'Disease', (643, 647))	('Cowden syndrome', 'Disease', (277, 292))	('MITF', 'Gene', '4286', (560, 564))	('melanoma', 'Disease', 'MESH:D008545', (485, 493))	('renal cancer', 'Phenotype', 'HP:0009726', (536, 548))	('melanoma', 'Phenotype', 'HP:0002861', (340, 348))	('melanoma', 'Disease', (340, 348))	('PTEN hamartoma tumor syndromes', 'Disease', 'MESH:D006223', (51, 81))	('CMM', 'Gene', '1243', (608, 611))	('patients', 'Species', '9606', (293, 301))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('PTEN', 'Gene', '5728', (51, 55))	('Patients', 'Species', '9606', (508, 516))	('hamartoma tumor syndrome', 'Disease', 'MESH:D006222', (56, 80))	('Cowden syndrome', 'Disease', (10, 25))	('mucosal lesions', 'Disease', 'MESH:D009059', (163, 178))	('melanomas', 'Disease', 'MESH:D008545', (485, 494))	('PTEN', 'Gene', (612, 616))	('papules', 'Phenotype', 'HP:0200034', (180, 187))	('hamartoma tumor syndrome', 'Disease', 'MESH:D006222', (617, 641))	('Cowden syndrome', 'Disease', 'MESH:D006223', (10, 25))	('nevus', 'Phenotype', 'HP:0003764', (442, 447))	('papules', 'Phenotype', 'HP:0200034', (154, 161))	('tumor', 'Disease', (627, 632))	('melanomas', 'Disease', (485, 494))	('MITF', 'Gene', (560, 564))	('tumor', 'Disease', (769, 774))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('769', '785'))	('tumor', 'Disease', 'MESH:D009369', (627, 632))	('hamartoma', 'Phenotype', 'HP:0010566', (56, 65))	('PTEN', 'Gene', '5728', (612, 616))	('papillomatous', 'Disease', 'MESH:D058066', (140, 153))	('papillomatous papules', 'Phenotype', 'HP:0012500', (140, 161))	('tumor', 'Disease', 'MESH:D009369', (769, 774))	('Patients', 'Species', '9606', (378, 386))	('melanoma', 'Disease', 'MESH:D008545', (340, 348))	('melanoma', 'Phenotype', 'HP:0002861', (485, 493))	('melanoma', 'Disease', (485, 493))	('palmar-plantar keratosis', 'Disease', (193, 217))	('melanomas', 'Phenotype', 'HP:0002861', (485, 494))
118689	26892651	investigated 368 individuals carrying PTEN mutations and demonstrated an elevated standardized incidence ratio (SIR) for CMM of 8.5 (95% CI, 4.1-15.6), with an estimated lifetime risk of 6%.	('PTEN', 'Gene', '5728', (38, 42))	('CMM', 'Gene', (121, 124))	('mutations', 'Var', (43, 52))	('CMM', 'Gene', '1243', (121, 124))	('PTEN', 'Gene', (38, 42))
118693	26892651	(Level of evidence IV) For those with documented germline PTEN mutations, referral to specialized centers for coordinated cancer care (e.g.	('mutations', 'Var', (63, 72))	('PTEN', 'Gene', '5728', (58, 62))	('men', 'Species', '9606', (42, 45))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('PTEN', 'Gene', (58, 62))
118698	26892651	The E318K mutation affects MITF sumoylation (Figure 2c), therefore altering MITF's transcriptional properties.	('sumoylation', 'MPA', (32, 43))	('E318K', 'Mutation', 'rs149617956', (4, 9))	('affects', 'Reg', (19, 26))	('MITF', 'Gene', '4286', (76, 80))	('sumoylation', 'biological_process', 'GO:0016925', ('32', '43'))	('E318K', 'Var', (4, 9))	('MITF', 'Gene', '4286', (27, 31))	('MITF', 'Gene', (27, 31))	('altering', 'Reg', (67, 75))	('MITF', 'Gene', (76, 80))	('transcriptional properties', 'MPA', (83, 109))
118707	26892651	The exact incidence of MITF (E318K)-mutation is not defined in the overall population.	('MITF', 'Gene', '4286', (23, 27))	('MITF', 'Gene', (23, 27))	('E318K', 'Mutation', 'rs149617956', (29, 34))	('E318K)-mutation', 'Var', (29, 44))
118709	26892651	Although most studies largely corroborate one another, additional studies are needed in order to fully understand the way that these mutations alter the risk for cancer development and the clinical utility of testing for this single variant.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('men', 'Species', '9606', (176, 179))	('alter', 'Reg', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('mutations', 'Var', (133, 142))
118727	26892651	Nonsense mutations in the TERT exons c. Frequent deletions of the TERT locus d. Missense mutations of the TERT protein that cause aberrant sumoylation e. Promoter mutations in the TERC gene Answer: A Question 5: A patient with a strong family history of melanoma and other internal malignancies presents for a dermatological checkup.	('Missense mutations', 'Var', (80, 98))	('melanoma', 'Phenotype', 'HP:0002861', (254, 262))	('melanoma', 'Disease', (254, 262))	('TERC', 'Gene', '7012', (180, 184))	('TERC', 'Gene', (180, 184))	('patient', 'Species', '9606', (214, 221))	('TERT', 'Gene', (106, 110))	('TERT', 'Gene', '7015', (106, 110))	('sumoylation', 'biological_process', 'GO:0016925', ('139', '150'))	('TERT', 'Gene', (66, 70))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('deletions', 'Var', (49, 58))	('TERT', 'Gene', '7015', (66, 70))	('cause', 'Reg', (124, 129))	('melanoma', 'Disease', 'MESH:D008545', (254, 262))	('TERT', 'Gene', (26, 30))	('mutations', 'Var', (163, 172))	('TERT', 'Gene', '7015', (26, 30))	('malignancies', 'Disease', 'MESH:D009369', (282, 294))	('malignancies', 'Disease', (282, 294))	('sumoylation', 'MPA', (139, 150))
118730	26892651	If his mother and brother share a melanoma-causing mutation, what is the patient's probability of being a carrier?	('patient', 'Species', '9606', (73, 80))	('mutation', 'Var', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('carrier', 'molecular_function', 'GO:0005215', ('106', '113'))	('melanoma', 'Disease', (34, 42))
118732	26096145	Germline mutations in this tumor suppressor gene predispose families to the development of various malignancies.	('Germline mutations', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('predispose', 'Reg', (49, 59))	('malignancies', 'Disease', (99, 111))	('tumor suppressor', 'biological_process', 'GO:0051726', ('27', '43'))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('27', '43'))	('malignancies', 'Disease', 'MESH:D009369', (99, 111))
118733	26096145	Current evidence demonstrates that germline BAP1 mutations predispose families to uveal melanoma, renal cell carcinoma, malignant mesothelioma, cutaneous melanoma, and possibly to a range of other cancers as well.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (144, 162))	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('malignant mesothelioma', 'Disease', (120, 142))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (120, 142))	('predispose', 'Reg', (59, 69))	('mutations', 'Var', (49, 58))	('renal cell carcinoma', 'Disease', (98, 118))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (98, 118))	('uveal melanoma', 'Disease', 'MESH:C536494', (82, 96))	('uveal melanoma', 'Disease', (82, 96))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('cancers', 'Disease', (197, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('BAP1', 'Gene', (44, 48))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (120, 142))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (98, 118))	('cutaneous melanoma', 'Disease', (144, 162))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (144, 162))
118734	26096145	Some of these cancers tend to be more aggressive, have a propensity to metastasize, and onset earlier in life in patients with BAP1 mutations as compared to non-predisposed patients with equivalent cancers.	('cancers', 'Disease', (14, 21))	('equivalent cancers', 'Disease', (187, 205))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('BAP1', 'Gene', (127, 131))	('aggressive', 'CPA', (38, 48))	('patients', 'Species', '9606', (173, 181))	('metastasize', 'CPA', (71, 82))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('patients', 'Species', '9606', (113, 121))	('mutations', 'Var', (132, 141))	('equivalent cancers', 'Disease', 'MESH:D009369', (187, 205))	('cancers', 'Disease', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('more', 'PosReg', (33, 37))
118736	26096145	Germline mutation in BRCA1-associated protein-1 (BAP1) underlies the recently identified tumor predisposition syndrome (BAP1-TPDS) OMIM 614327.	('BRCA1-associated protein-1', 'Gene', '8314', (21, 47))	('BAP1', 'Gene', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('BRCA1-associated protein-1', 'Gene', (21, 47))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('Germline mutation', 'Var', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
118739	26096145	An increasing number of patients with germline BAP1 mutations have been reported since (Appendix S1, Supporting Information).	('mutations', 'Var', (52, 61))	('BAP1', 'Gene', (47, 51))	('patients', 'Species', '9606', (24, 32))
118740	26096145	Although the full phenotype of the syndrome is still being characterized, the literature suggests that several other cancers reported in patients and relatives of patients with germline BAP1 mutations may also be associated and that some cancers associated with this syndrome may have a poorer prognosis.	('cancers', 'Disease', (238, 245))	('patients', 'Species', '9606', (163, 171))	('associated', 'Reg', (213, 223))	('cancers', 'Disease', 'MESH:D009369', (238, 245))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('mutations', 'Var', (191, 200))	('patients', 'Species', '9606', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('BAP1', 'Gene', (186, 190))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))	('cancers', 'Disease', (117, 124))
118747	26096145	Of these, 27 articles described patients with germline BAP1 mutations.	('mutations', 'Var', (60, 69))	('BAP1', 'Gene', (55, 59))	('patients', 'Species', '9606', (32, 40))
118760	26096145	Including the two new families reported herein, there have been 57 families with 174 individuals reported to carry BAP1 mutations; 67 are male (39%), 95 are female (55%), and 12 patients have no gender information reported.	('patients', 'Species', '9606', (178, 186))	('BAP1', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))
118767	26096145	Both germline and somatic BAP1 mutations have been found in patients with UM, the most common ocular malignancy in adults (Table 1).	('BAP1', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('ocular malignancy', 'Phenotype', 'HP:0100012', (94, 111))	('patients', 'Species', '9606', (60, 68))	('ocular malignancy', 'Disease', 'MESH:D009369', (94, 111))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('ocular malignancy', 'Disease', (94, 111))	('found', 'Reg', (51, 56))
118768	26096145	The earliest reported age of cancer onset in a germline BAP1 mutation carrier is for UM at age 16, and there have been a total of four UM diagnosed by age 20.	('cancer', 'Disease', (29, 35))	('germline', 'Var', (47, 55))	('UM', 'Phenotype', 'HP:0007716', (135, 137))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('BAP1', 'Gene', (56, 60))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('carrier', 'molecular_function', 'GO:0005215', ('70', '77'))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
118769	26096145	Median age of onset is earlier in UM patients with germline BAP1 mutation (51 years, range 16-72) compared with the general population (62 years).	('patients', 'Species', '9606', (37, 45))	('UM', 'Phenotype', 'HP:0007716', (34, 36))	('BAP1', 'Gene', (60, 64))	('germline', 'Var', (51, 59))
118770	26096145	Genetic analysis of UM tumor tissue from seven patients with germline BAP1 mutations showed loss-of-heterozygosity (LOH) or loss of expression of the wild-type allele.	('loss', 'NegReg', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('patients', 'Species', '9606', (47, 55))	('UM', 'Phenotype', 'HP:0007716', (20, 22))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('BAP1', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('loss-of-heterozygosity', 'NegReg', (92, 114))	('tumor', 'Disease', (23, 28))	('expression', 'MPA', (132, 142))
118771	26096145	Somatic BAP1 mutations have also been widely reported in sporadic UM, and protein expression studies have also shown lack of BAP1 expression in UM tumors (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('expression', 'MPA', (130, 140))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('reported', 'Reg', (45, 53))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('BAP1', 'Gene', (125, 129))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('BAP1', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))	('UM', 'Phenotype', 'HP:0007716', (144, 146))
118772	26096145	A total of 39/174 patients (22%) with germline mutations have been diagnosed with MMe with median age of onset earlier than that in the general population (Table 1).	('MMe', 'Disease', (82, 85))	('germline mutations', 'Var', (38, 56))	('patients', 'Species', '9606', (18, 26))
118781	26096145	MMe tumors from seven germline BAP1 mutation carriers have been shown to have loss of the wild-type BAP1 allele or its expression.	('expression', 'MPA', (119, 129))	('tumors', 'Disease', (4, 10))	('BAP1', 'Gene', (100, 104))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('loss', 'NegReg', (78, 82))	('BAP1', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mutation', 'Var', (36, 44))
118782	26096145	There are 23/174 (13%) reported patients with germline BAP1 mutations diagnosed with CM; median age of onset is earlier than in the general population (Table 1).	('CM', 'Disease', (85, 87))	('patients', 'Species', '9606', (32, 40))	('BAP1', 'Gene', (55, 59))	('mutations', 'Var', (60, 69))	('diagnosed', 'Reg', (70, 79))	('CM', 'Phenotype', 'HP:0012056', (85, 87))
118789	26096145	Eighteen of 174 (10%) of the reported patients with germline BAP1 mutations had RCC with median age of diagnosis earlier than that seen in the general population (Table 1).	('mutations', 'Var', (66, 75))	('BAP1', 'Gene', (61, 65))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('patients', 'Species', '9606', (38, 46))
118790	26096145	Tumor tissue studies demonstrating LOH, somatic BAP1 mutations, and IHC staining all support an association between germline BAP1 mutation and RCC (Table 1).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (53, 62))	('BAP1', 'Gene', (125, 129))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))
118799	26096145	A number of other tumor types including a range of sarcomas and carcinomas have been reported in germline BAP1 mutation carriers; however, there are limited data supporting their inclusion in BAP1-TPDS (Table 1; Appendix S1).	('BAP1', 'Gene', (106, 110))	('tumor', 'Disease', (18, 23))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('mutation', 'Var', (111, 119))	('sarcomas and carcinomas', 'Disease', 'MESH:D012509', (51, 74))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))
118803	26096145	Conflicting reports regarding the association have been published, however, as germline BAP1 mutations are not common in breast cancer, including in patients with family histories consistent with hereditary cancer predisposition.	('hereditary cancer', 'Disease', (196, 213))	('patients', 'Species', '9606', (149, 157))	('mutations', 'Var', (93, 102))	('germline', 'Var', (79, 87))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('hereditary cancer', 'Disease', 'MESH:D009369', (196, 213))	('BAP1', 'Gene', (88, 92))
118805	26096145	Current data suggest that germline mutations in patients with UM, CM, and RCC are associated with more aggressive disease, while in MMe they are associated with less aggressive disease, as discussed below.	('aggressive disease', 'Disease', (103, 121))	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('associated with', 'Reg', (82, 97))	('aggressive disease', 'Disease', (166, 184))	('germline mutations', 'Var', (26, 44))	('RCC', 'Disease', (74, 77))	('associated', 'Reg', (145, 155))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('CM', 'Phenotype', 'HP:0012056', (66, 68))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('patients', 'Species', '9606', (48, 56))	('aggressive disease', 'Disease', 'MESH:D001523', (103, 121))	('aggressive disease', 'Disease', 'MESH:D001523', (166, 184))
118806	26096145	In UM, patients with germline BAP1 mutations tend to have more aggressive cancers with higher tumor staging and a greater likelihood of metastasis.	('UM', 'Phenotype', 'HP:0007716', (3, 5))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('BAP1', 'Gene', (30, 34))	('aggressive cancers', 'Disease', (63, 81))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('germline', 'Var', (21, 29))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('aggressive cancers', 'Disease', 'MESH:D009369', (63, 81))	('tumor', 'Disease', (94, 99))	('metastasis', 'CPA', (136, 146))	('more', 'PosReg', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('patients', 'Species', '9606', (7, 15))	('mutations', 'Var', (35, 44))
118807	26096145	Tumors with somatic BAP1 mutations have also demonstrated larger tumor sizes, more aggressive disease with poorer outcomes, and higher rates of metastasis, and they may represent a precursor event to the more aggressive 'class 2' UM.	('mutations', 'Var', (25, 34))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('BAP1', 'Gene', (20, 24))	('aggressive disease', 'Disease', 'MESH:D001523', (83, 101))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('UM', 'Phenotype', 'HP:0007716', (230, 232))	('metastasis', 'CPA', (144, 154))	('aggressive disease', 'Disease', (83, 101))	('larger', 'PosReg', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
118810	26096145	found an average of 31.2 month survival in RCC patients with somatic BAP1 mutations compared to 78.2 month survival in patients without in a cohort of 421 patients.	('BAP1', 'Gene', (69, 73))	('patients', 'Species', '9606', (119, 127))	('mutations', 'Var', (74, 83))	('patients', 'Species', '9606', (47, 55))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('patients', 'Species', '9606', (155, 163))
118812	26096145	determined similar survival rates with an average of 1.9-year survival in RCC patients with tumors with somatic BAP1 mutations vs 5.4-year survival in patients with tumors with PBRM1 mutations in a cohort of 327 patients.	('BAP1', 'Gene', (112, 116))	('mutations', 'Var', (117, 126))	('PBRM1', 'Gene', (177, 182))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('PBRM1', 'Gene', '55193', (177, 182))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('RCC', 'Disease', (74, 77))	('patients', 'Species', '9606', (212, 220))	('patients', 'Species', '9606', (78, 86))	('patients', 'Species', '9606', (151, 159))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))
118813	26096145	A smaller cohort in the study showed 4.6-year survival in BAP1 mutant tumors vs 10.6-year survival in PBRM1 mutant tumors.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutant', 'Var', (63, 69))	('BAP1', 'Gene', (58, 62))	('PBRM1', 'Gene', (102, 107))	('PBRM1', 'Gene', '55193', (102, 107))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))
118816	26096145	In contrast, a cohort of 23 MMe patients with germline BAP1 mutations appeared to have sevenfold longer overall survival as compared with sporadic MMe patients.	('patients', 'Species', '9606', (32, 40))	('BAP1', 'Gene', (55, 59))	('patients', 'Species', '9606', (151, 159))	('mutations', 'Var', (60, 69))	('germline', 'Var', (46, 54))	('longer', 'PosReg', (97, 103))	('overall survival', 'MPA', (104, 120))
118817	26096145	Patients with germline BAP1 mutations had improved survival in both peritoneal and pleural MMe.	('BAP1', 'Gene', (23, 27))	('pleural MMe', 'Disease', 'MESH:D010995', (83, 94))	('improved', 'PosReg', (42, 50))	('pleural MMe', 'Disease', (83, 94))	('Patients', 'Species', '9606', (0, 8))	('survival', 'CPA', (51, 59))	('germline', 'Var', (14, 22))	('mutations', 'Var', (28, 37))
118819	26096145	A potential explanation could be differences in treatment response in tumors with and without BAP1 inactivation.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('BAP1', 'Gene', (94, 98))	('inactivation', 'Var', (99, 111))
118820	26096145	Another explanation could be the well-differentiated morphology of some MMe in patients with germline BAP1 mutations in contrast to high grade tumors in other patients, although the mechanism for this is unknown.	('BAP1', 'Gene', (102, 106))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('mutations', 'Var', (107, 116))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('germline', 'Var', (93, 101))	('patients', 'Species', '9606', (79, 87))	('patients', 'Species', '9606', (159, 167))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
118821	26096145	Also, the increased rate of peritoneal MMe in BAP1 carriers, which has a better prognosis than pleural MMe, may be causing the increase in overall survival.	('peritoneal MMe', 'Disease', (28, 42))	('overall survival', 'MPA', (139, 155))	('pleural MMe', 'Disease', 'MESH:D010995', (95, 106))	('BAP1', 'Gene', (46, 50))	('increase', 'PosReg', (127, 135))	('pleural MMe', 'Disease', (95, 106))	('carriers', 'Var', (51, 59))
118822	26096145	Current evidence suggests that the penetrance of BAP1 mutations is high with 148/174 (85%) reported mutation carriers affected with cancer.	('cancer', 'Disease', (132, 138))	('BAP1', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('affected', 'Reg', (118, 126))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
118827	26096145	Of 57 families, 46 had unique mutations, two families had the c.2050C>T, p.Q684* mutation, two families had the c.1882_1885delTCAC, p.S628Pfs*8 mutation, two families had the c.1717delC, p.L573Wfs*3 mutation, two families had the c.588G>A, p.Trp196* mutation, while three families had the c.178C>T, p.R60* mutation.	('p.S628Pfs*8', 'Mutation', 'rs878853289', (132, 143))	('p.R60*', 'Var', (299, 305))	('c.1882_1885delTCAC', 'Mutation', 'c.1882_1885delTCAC', (112, 130))	('p.Trp196*', 'Mutation', 'p.W196*', (240, 249))	('p.Q684* mutation', 'Var', (73, 89))	('c.178C>T', 'Var', (289, 297))	('p.S628Pfs', 'Var', (132, 141))	('c.178C>T', 'Mutation', 'rs769257927', (289, 297))	('c.2050C>T', 'Mutation', 'rs387906848', (62, 71))	('c.1717delC', 'Mutation', 'rs869025212', (175, 185))	('p.R60*', 'Mutation', 'p.R60*', (299, 305))	('c.2050C>T', 'Var', (62, 71))	('c.588G>A', 'Mutation', 'rs1027008091', (230, 238))	('p.L573Wfs', 'Var', (187, 196))	('p.L573Wfs*3', 'Mutation', 'rs869025212', (187, 198))	('c.588G>A', 'Var', (230, 238))	('p.Q684*', 'Mutation', 'p.Q684*', (73, 80))	('p.Trp196* mutation', 'Var', (240, 258))
118828	26096145	Discussions between the authors concluded that the families carrying the c.2050C>T, p.Q684*and c.1882_1885delTCAC, p.S628Pfs*8 mutations were unrelated.	('c.1882_1885delTCAC', 'Var', (95, 113))	('p.Q684*', 'Mutation', 'p.Q684*', (84, 91))	('p.S628Pfs*8', 'Var', (115, 126))	('p.Q684*', 'Var', (84, 91))	('c.2050C>T', 'Mutation', 'rs387906848', (73, 82))	('c.2050C>T', 'Var', (73, 82))	('c.1882_1885delTCAC', 'Mutation', 'c.1882_1885delTCAC', (95, 113))	('p.S628Pfs*8', 'Mutation', 'rs878853289', (115, 126))
118829	26096145	However, discussions and haplotype analysis suggested that the two families from Denmark carrying the c.178C>T, p.R60* mutation were related, whereas the family carrying this mutation from the United States was not.	('c.178C>T', 'Var', (102, 110))	('c.178C>T', 'Mutation', 'rs769257927', (102, 110))	('p.R60*', 'Mutation', 'p.R60*', (112, 118))	('p.R60*', 'Var', (112, 118))
118830	26096145	With the exception of one patient, all reported pathogenic mutations in BAP1, including truncating, missense, and splice-site mutations, were associated with at least one of the four main cancers in the family (Fig.	('patient', 'Species', '9606', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('truncating', 'MPA', (88, 98))	('missense', 'Var', (100, 108))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancers', 'Disease', (188, 195))	('BAP1', 'Gene', (72, 76))	('splice-site mutations', 'Var', (114, 135))	('associated with', 'Reg', (142, 157))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('mutations', 'Var', (59, 68))
118831	26096145	All four cancers were observed with all classes of mutations.	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('mutations', 'Var', (51, 60))	('cancers', 'Disease', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
118832	26096145	Taken together, the available data suggest no clear genotype-phenotype correlation between type or location of the mutation and the type of cancer in patients.	('mutation', 'Var', (115, 123))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('patients', 'Species', '9606', (150, 158))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
118833	26096145	Of the 174 reported patients with BAP1 mutations 130 (75%) were diagnosed with UM, MMe, CM, RCC, and/or BAP1-deficient ASTs, and 90% of these families had at least two of these tumors in first or second-degree relatives.	('BAP1-deficient', 'Gene', (104, 118))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('BAP1', 'Gene', (34, 38))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('MMe', 'Disease', (83, 86))	('diagnosed', 'Reg', (64, 73))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('mutations', 'Var', (39, 48))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('patients', 'Species', '9606', (20, 28))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('tumors', 'Disease', (177, 183))	('CM', 'Phenotype', 'HP:0012056', (88, 90))
118835	26096145	Thus, we recommend that genetic assessment and testing for BAP1 mutations should be considered in patients with two or more of these tumors in themselves and/or first or second-degree relatives, with the exclusion of families with only multiple CM cases, given its frequency in the general population.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('BAP1', 'Gene', (59, 63))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('patients', 'Species', '9606', (98, 106))	('mutations', 'Var', (64, 73))	('CM', 'Phenotype', 'HP:0012056', (245, 247))
118836	26096145	We recognize, however, that if a melanoma-only family is undergoing CDKN2A testing for hereditary melanoma, it may be reasonable and cost effective to also test them for mutations in BAP1 at the same time.	('hereditary melanoma', 'Disease', (87, 106))	('mutations', 'Var', (170, 179))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('CDKN2A', 'Gene', (68, 74))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('BAP1', 'Gene', (183, 187))	('test', 'Reg', (156, 160))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('CDKN2A', 'Gene', '1029', (68, 74))	('hereditary melanoma', 'Disease', 'MESH:D008545', (87, 106))
118838	26096145	Families in which a germline BAP1 mutation is found should receive counseling regarding cancer risk management options and risks to family members.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('mutation', 'Var', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('BAP1', 'Gene', (29, 33))
118842	26096145	ASTs have a unique clinical, morphological, and molecular characterization and their high frequency in patients with germline BAP1 mutation indicate they might serve as a potential marker of BAP1-TPDS.	('patients', 'Species', '9606', (103, 111))	('BAP1', 'Gene', (126, 130))	('mutation', 'Var', (131, 139))
118844	26096145	UM, MMe, CM, RCC, and ASTs are clearly established as part of the phenotypic spectrum associated with germline BAP1 mutations.	('BAP1', 'Gene', (111, 115))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('mutations', 'Var', (116, 125))	('RCC', 'Disease', (13, 16))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('CM', 'Phenotype', 'HP:0012056', (9, 11))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
118846	26096145	Although UM, CM, and RCC tumors in patients with germline BAP1 mutations tend to be more aggressive and have poorer outcomes, patients with MMe appear to have longer survival.	('mutations', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('more', 'PosReg', (84, 88))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('CM', 'Phenotype', 'HP:0012056', (13, 15))	('BAP1', 'Gene', (58, 62))	('RCC tumors', 'Disease', 'MESH:C538614', (21, 31))	('germline', 'Var', (49, 57))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (35, 43))	('longer', 'PosReg', (159, 165))	('RCC tumors', 'Disease', (21, 31))	('aggressive', 'CPA', (89, 99))
118965	22706174	Recently, mutations have been described in the alpha-subunit of an intracellular G-protein known as GNAQ.	('intracellular', 'cellular_component', 'GO:0005622', ('67', '80'))	('GNAQ', 'Gene', '2776', (100, 104))	('GNAQ', 'Gene', (100, 104))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('mutations', 'Var', (10, 19))
118971	22706174	It is possible that presence of some of these molecular markers is associated with high risk for tumor recurrence.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('associated', 'Reg', (67, 77))	('presence', 'Var', (20, 28))
118986	26075084	Other recognized risk factors include Caucasian ethnicity, preexisting choroidal nevi, and genetic factors such as specific chromosomal abnormalities and GNAQ/11 mutations.	('GNAQ', 'Gene', '2776', (154, 158))	('mutations', 'Var', (162, 171))	('GNAQ', 'Gene', (154, 158))	('choroidal nevi', 'Phenotype', 'HP:0025314', (71, 85))	('nevi', 'Phenotype', 'HP:0003764', (81, 85))	('specific chromosomal', 'Disease', (115, 135))
118989	26075084	It has been known for many years that ultraviolet exposure, coupled with specific skin pigment gene polymorphisms, is a prominent factor in the development of cutaneous melanoma.	('men', 'Species', '9606', (151, 154))	('men', 'Species', '9606', (90, 93))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('cutaneous melanoma', 'Disease', (159, 177))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (159, 177))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (159, 177))	('polymorphisms', 'Var', (100, 113))
118991	26075084	For example, the oncogenic V600E bRAF mutation, expressed in the majority of patients with cutaneous melanoma, is thought to be the result of solar ultraviolet exposure and is absent from melanomas occurring in body locations that are naturally protected from ultraviolet radiation.	('bRAF', 'Gene', '673', (33, 37))	('V600E', 'Var', (27, 32))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanomas', 'Disease', (188, 197))	('patients', 'Species', '9606', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('melanomas', 'Phenotype', 'HP:0002861', (188, 197))	('cutaneous melanoma', 'Disease', (91, 109))	('V600E', 'Mutation', 'rs113488022', (27, 32))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (91, 109))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (91, 109))	('melanomas', 'Disease', 'MESH:D008545', (188, 197))	('bRAF', 'Gene', (33, 37))
118992	26075084	Genetic analysis of V600E bRAF expression in patients with UM has uncovered a relationship between the frequency of this mutation and the ocular location of the melanoma.	('bRAF', 'Gene', '673', (26, 30))	('UM', 'Phenotype', 'HP:0007716', (59, 61))	('bRAF', 'Gene', (26, 30))	('ocular location', 'Disease', (138, 153))	('V600E', 'Mutation', 'rs113488022', (20, 25))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('patients', 'Species', '9606', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))	('V600E', 'Var', (20, 25))
118993	26075084	V600E mutations have been detected in patients with anterior UM, such as those of the iris, consistent with ultraviolet exposure; however, most UM cases arise in the posterior uveal tract and V600E mutation rates here are negligible.	('UM', 'Phenotype', 'HP:0007716', (144, 146))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('V600E', 'Mutation', 'rs113488022', (192, 197))	('V600E', 'Mutation', 'rs113488022', (0, 5))	('patients', 'Species', '9606', (38, 46))	('V600E', 'Var', (192, 197))	('V600E', 'Var', (0, 5))
119007	26075084	This study described the development of an ocular tumor in one animal following blue light exposure (434-475 nm) coupled with the administration of an antiapoptotic agent.	('434-475 nm', 'Var', (101, 111))	('men', 'Species', '9606', (32, 35))	('ocular tumor', 'Disease', 'MESH:D009369', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('ocular tumor', 'Disease', (43, 55))	('ocular tumor', 'Phenotype', 'HP:0100012', (43, 55))
119046	25961751	Furthermore, c-Met-mediated cell proliferation and invasion were inhibited by restoration of miR-144 in uveal melanoma cells.	('cell proliferation', 'biological_process', 'GO:0008283', ('28', '46'))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('uveal melanoma', 'Disease', (104, 118))	('uveal melanoma', 'Disease', 'MESH:C536494', (104, 118))	('c-Met-mediated', 'Protein', (13, 27))	('miR-144', 'Gene', (93, 100))	('inhibited', 'NegReg', (65, 74))	('miR-144', 'Gene', '406936', (93, 100))	('restoration', 'Var', (78, 89))	('invasion', 'CPA', (51, 59))
119059	25961751	Aberrant miRNA expression is proved to associate with various human cancers, functioning as oncogenes or tumor suppressors.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Aberrant', 'Var', (0, 8))	('human', 'Species', '9606', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('associate', 'Reg', (39, 48))	('tumor', 'Disease', (105, 110))	('miR', 'Gene', '220972', (9, 12))	('miR', 'Gene', (9, 12))
119061	25961751	Ectopic expression of miR-144 could inhibit uveal melanoma cell proliferation and invasion in vitro.	('inhibit', 'NegReg', (36, 43))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('Ectopic expression', 'Var', (0, 18))	('invasion in vitro', 'CPA', (82, 99))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('uveal melanoma', 'Disease', (44, 58))	('miR-144', 'Gene', (22, 29))	('miR-144', 'Gene', '406936', (22, 29))
119081	25961751	The expression of miR-144 was increased in MUM-2B cells transfected with miR-144 mimics, and decreased in cells transfected with miR-144 inhibitor (Fig 2A).	('mimics', 'Var', (81, 87))	('MUM-2', 'Gene', '9589', (43, 48))	('miR-144', 'Gene', '406936', (129, 136))	('expression', 'MPA', (4, 14))	('MUM-2', 'Gene', (43, 48))	('decreased', 'NegReg', (93, 102))	('miR-144', 'Gene', (73, 80))	('miR-144', 'Gene', (18, 25))	('miR-144', 'Gene', '406936', (73, 80))	('miR-144', 'Gene', '406936', (18, 25))	('increased', 'PosReg', (30, 39))	('miR-144', 'Gene', (129, 136))
119084	25961751	The invasiveness of cells was decreased in cells transfected with miR-144 mimics compared with the scramble group and control group cells and increased in cells transfected with miR-144 inhibitor compared with the scramble group and control group (Fig 2C).	('miR-144', 'Gene', (178, 185))	('increased', 'PosReg', (142, 151))	('miR-144', 'Gene', '406936', (178, 185))	('miR-144', 'Gene', (66, 73))	('invasiveness of cells', 'CPA', (4, 25))	('miR-144', 'Gene', '406936', (66, 73))	('inhibitor', 'Var', (186, 195))	('decreased', 'NegReg', (30, 39))
119090	25961751	When miR-144 inhibitor and si-c-Met were cotransfected into MUM-2B cells, miR-144 inhibitor enhanced the si-c-Met-induced inhibition of proliferation and invasion in uveal melanoma cells (Fig 4B and 4C).	('miR-144', 'Gene', (74, 81))	('miR-144', 'Gene', '406936', (74, 81))	('miR-144', 'Gene', '406936', (5, 12))	('uveal melanoma', 'Phenotype', 'HP:0007716', (166, 180))	('si-c-Met-induced', 'Var', (105, 121))	('uveal melanoma', 'Disease', (166, 180))	('uveal melanoma', 'Disease', 'MESH:C536494', (166, 180))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('MUM-2', 'Gene', '9589', (60, 65))	('MUM-2', 'Gene', (60, 65))	('invasion', 'CPA', (154, 162))	('inhibition', 'NegReg', (122, 132))	('miR-144', 'Gene', (5, 12))	('enhanced', 'PosReg', (92, 100))
119092	25961751	In addition, when miR-144 mimic and pCDNA-c-Met was cotransfected into MUM-2B cells, miR-144 mimic repressed the pCDNA-c-Met-induced proliferation and invasion in uveal melanoma cells (Fig 5B and 5C).	('miR-144', 'Gene', (85, 92))	('miR-144', 'Gene', '406936', (85, 92))	('uveal melanoma', 'Phenotype', 'HP:0007716', (163, 177))	('uveal melanoma', 'Disease', 'MESH:C536494', (163, 177))	('MUM-2', 'Gene', '9589', (71, 76))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('uveal melanoma', 'Disease', (163, 177))	('MUM-2', 'Gene', (71, 76))	('invasion', 'CPA', (151, 159))	('pCDNA-c-Met-induced', 'Var', (113, 132))	('miR-144', 'Gene', (18, 25))	('miR-144', 'Gene', '406936', (18, 25))	('proliferation', 'CPA', (133, 146))
119094	25961751	Deregulation of miRNAs is common in cancers, where miRNAs might act as oncogene or putative tumor suppressor genes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('92', '108'))	('Deregulation', 'Var', (0, 12))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('miR', 'Gene', '220972', (51, 54))	('miR', 'Gene', (51, 54))	('tumor', 'Disease', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('miR', 'Gene', '220972', (16, 19))	('miR', 'Gene', (16, 19))	('tumor suppressor', 'biological_process', 'GO:0051726', ('92', '108'))
119104	25961751	also showed that knockdown of doublecort in and CaM kinase-like-1 (DCAMKL-1) increased miR-144 expression, which in turn inhibited epithelial-mesenchymal transition (EMT) of pancreatic cancer.	('pancreatic cancer', 'Disease', (174, 191))	('DCAMKL-1', 'Gene', '9201', (67, 75))	('pancreatic cancer', 'Disease', 'MESH:D010190', (174, 191))	('EMT', 'biological_process', 'GO:0001837', ('166', '169'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('131', '164'))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('knockdown', 'Var', (17, 26))	('DCAMKL-1', 'Gene', (67, 75))	('epithelial-mesenchymal transition', 'CPA', (131, 164))	('miR-144', 'Gene', (87, 94))	('miR-144', 'Gene', '406936', (87, 94))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (174, 191))	('increased', 'PosReg', (77, 86))	('inhibited', 'NegReg', (121, 130))	('expression', 'MPA', (95, 105))
119113	25961751	Alterations of c-Met may play a role in tumorigenesis of many cancers such as gastric cancer, bladder cancer, and colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('Alterations', 'Var', (0, 11))	('colorectal cancer', 'Disease', (114, 131))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('gastric cancer', 'Disease', (78, 92))	('c-Met', 'Protein', (15, 20))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('bladder cancer', 'Disease', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('tumor', 'Disease', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('role', 'Reg', (32, 36))	('play', 'Reg', (25, 29))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))
119114	25961751	Overexpression of c-Met is considered as a novel potential or even an independent predictor of poor prognosis for clinical patients.	('c-Met', 'Protein', (18, 23))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (123, 131))
119117	25961751	C-Met activation was observed in uveal melanoma through indirect gene activation.	('C-Met', 'Gene', '4233', (0, 5))	('uveal melanoma', 'Disease', 'MESH:C536494', (33, 47))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('uveal melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('uveal melanoma', 'Disease', (33, 47))	('indirect gene activation', 'Var', (56, 80))	('C-Met', 'Gene', (0, 5))	('activation', 'PosReg', (6, 16))
119118	25961751	In our study, c-Met enhanced uveal melanoma cell proliferation and invasion; inhibition of c-Met reduced the uveal melanoma cell proliferation and invasion.	('inhibition', 'Var', (77, 87))	('enhanced', 'PosReg', (20, 28))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('invasion', 'CPA', (67, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('invasion', 'CPA', (147, 155))	('reduced', 'NegReg', (97, 104))	('uveal melanoma', 'Disease', 'MESH:C536494', (109, 123))	('cell proliferation', 'biological_process', 'GO:0008283', ('124', '142'))	('c-Met', 'Gene', (91, 96))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('uveal melanoma', 'Disease', (109, 123))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))
119119	25961751	Restoration of miR-144 inhibited c-Met-mediated uveal melanoma cell proliferation and invasion.	('miR-144', 'Gene', (15, 22))	('miR-144', 'Gene', '406936', (15, 22))	('uveal melanoma', 'Disease', (48, 62))	('inhibited', 'NegReg', (23, 32))	('Restoration', 'Var', (0, 11))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('invasion', 'CPA', (86, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (48, 62))
119187	25780931	We observed that locoregional therapy was associated with a trend for longer survival, although this was not statistically significant in the multivariate model.	('al', 'Chemical', 'MESH:D000535', (27, 29))	('al', 'Chemical', 'MESH:D000535', (83, 85))	('al', 'Chemical', 'MESH:D000535', (87, 89))	('al', 'Chemical', 'MESH:D000535', (118, 120))	('locoregional therapy', 'Var', (17, 37))	('longer', 'PosReg', (70, 76))
119223	25780931	One reason for this could be that these alterations have been associated with the development of metastatic disease for patients with mUM, while this study looked at the prognosis of patients who have already developed metastatic disease.	('metastatic disease', 'Disease', (97, 115))	('associated with', 'Reg', (62, 77))	('UM', 'Phenotype', 'HP:0007716', (135, 137))	('alterations', 'Var', (40, 51))	('patients', 'Species', '9606', (120, 128))	('al', 'Chemical', 'MESH:D000535', (201, 203))	('al', 'Chemical', 'MESH:D000535', (40, 42))	('patients', 'Species', '9606', (183, 191))
119225	25780931	abnormalities are predictors of distant recurrence after UM primary diagnosis, then other biological factors, yet to be studied, may determine the aggressiveness of metastases when the disease has spread.	('abnormalities', 'Var', (0, 13))	('al', 'Chemical', 'MESH:D000535', (6, 8))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('aggressiveness of metastases when the disease', 'Disease', (147, 192))	('aggressiveness', 'Phenotype', 'HP:0000718', (147, 161))	('aggressiveness of metastases when the disease', 'Disease', 'MESH:D009362', (147, 192))	('al', 'Chemical', 'MESH:D000535', (98, 100))	('distant recurrence', 'CPA', (32, 50))
119247	24490833	Efforts have been made towards the identification of patients at high risk of metastatic disease with the use of prognostic fine needle biopsy, Monosomy 3 a risk factor for metastatic death thought to occur early in the development of uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('patients', 'Species', '9606', (53, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (235, 249))	('uveal melanoma', 'Disease', 'MESH:C536494', (235, 249))	('Monosomy 3', 'Var', (144, 154))	('uveal melanoma', 'Disease', (235, 249))	('death', 'Disease', 'MESH:D003643', (184, 189))	('death', 'Disease', (184, 189))
119252	24490833	Monosomy 3 is associated with a high risk of progression to metastatic death and is thought to occur early in the development of uveal melanoma.	('death', 'Disease', 'MESH:D003643', (71, 76))	('death', 'Disease', (71, 76))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('uveal melanoma', 'Disease', 'MESH:C536494', (129, 143))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('uveal melanoma', 'Disease', (129, 143))	('Monosomy 3', 'Var', (0, 10))
119269	24490833	Cytological examination of the non-pigmented tumour revealed no alterations on chromosomes 3 or 8, while the pigmented tumour contained monosomy 3 with alterations on chromosome 8 also.	('monosomy 3', 'Var', (136, 146))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('pigmented tumour', 'Disease', 'MESH:D010859', (109, 125))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('non-pigmented tumour', 'Disease', (31, 51))	('pigmented tumour', 'Disease', 'MESH:D010859', (35, 51))	('non-pigmented tumour', 'Disease', 'MESH:D010859', (31, 51))	('pigmented tumour', 'Disease', (109, 125))	('chromosome', 'cellular_component', 'GO:0005694', ('167', '177'))	('non-pigmented tumour', 'Phenotype', 'HP:0000995', (31, 51))
119276	24490833	Fresh tumour tissue was taken for single nucleotide polymorphism analysis following enucleation, and further processed to assess for chromosomal abnormalities.	('chromosomal abnormalities', 'Disease', (133, 158))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (133, 158))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('enucleation', 'biological_process', 'GO:0090601', ('84', '95'))	('tumour', 'Disease', 'MESH:D009369', (6, 12))	('tumour', 'Disease', (6, 12))	('single nucleotide polymorphism analysis', 'Var', (34, 73))
119284	24490833	This morphological heterogeneity corresponded with cytogenetic heterogeneity, the two areas showing different karyotypes, the pigmented tumor showing monosomy 3, and the non-pigmented tumour showing two normal chromosomes 3.	('monosomy 3', 'Var', (150, 160))	('non-pigmented tumour', 'Disease', 'MESH:D010859', (170, 190))	('non-pigmented tumour', 'Phenotype', 'HP:0000995', (170, 190))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('pigmented tumor', 'Disease', (126, 141))	('pigmented tumor', 'Disease', 'MESH:D010859', (126, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('non-pigmented tumour', 'Disease', (170, 190))
119285	24490833	DNA analysis of both pigmented and non-pigmented regions revealed loss of heterozygosity at all informative loci at chromosome 3, suggesting that duplication of the monosomy 3 chromosome had occurred (isodisomy 3) and that the non pigmented tumour had evolved from the pigmented tumour.	('pigmented tumour', 'Disease', 'MESH:D010859', (231, 247))	('pigmented tumour', 'Disease', (269, 285))	('tumour', 'Phenotype', 'HP:0002664', (241, 247))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumour', 'Phenotype', 'HP:0002664', (279, 285))	('chromosome', 'cellular_component', 'GO:0005694', ('116', '126'))	('pigmented tumour', 'Disease', 'MESH:D010859', (269, 285))	('pigmented tumour', 'Disease', (231, 247))	('chromosome', 'cellular_component', 'GO:0005694', ('176', '186'))	('non pigmented tumour', 'Phenotype', 'HP:0000995', (227, 247))	('duplication', 'Var', (146, 157))
119286	24490833	Isodisomy 3 is thought to occur in 5-10% of cases of uveal melanoma, and is prognostically equivalent to that of monosomy 3 status.	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('uveal melanoma', 'Disease', (53, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (53, 67))	('Isodisomy 3', 'Var', (0, 11))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))
119287	24490833	It is associated with the high risk class II expression signature and the development of metastasis, implying that chromosome 3 in monosomy 3 tumours, is defective at one or more tumour suppressor loci, this then being duplicated in isodisomy 3 tumours.	('tumour', 'Disease', (142, 148))	('tumour', 'Disease', 'MESH:D009369', (245, 251))	('tumour', 'Disease', (245, 251))	('defective', 'NegReg', (154, 163))	('isodisomy 3 tumours', 'Disease', 'MESH:D024182', (233, 252))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('tumour', 'Disease', 'MESH:D009369', (179, 185))	('isodisomy 3 tumours', 'Disease', (233, 252))	('metastasis', 'Disease', (89, 99))	('tumour', 'Disease', (179, 185))	('tumours', 'Disease', (142, 149))	('associated', 'Reg', (6, 16))	('chromosome', 'cellular_component', 'GO:0005694', ('115', '125'))	('tumours', 'Disease', (245, 252))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('tumours', 'Disease', 'MESH:D009369', (142, 149))	('monosomy', 'Var', (131, 139))	('tumours', 'Phenotype', 'HP:0002664', (245, 252))	('tumours', 'Disease', 'MESH:D009369', (245, 252))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('tumour', 'Disease', 'MESH:D009369', (142, 148))
119303	22521086	Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54/260 (20.8%) tumors were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log rank test, P=0.0001).	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('monosomy 3', 'Var', (58, 68))	('chromosome', 'cellular_component', 'GO:0005694', ('150', '160'))	('GEP', 'Gene', (42, 45))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('association', 'Interaction', (22, 33))
119308	22521086	Gene expression profiling (GEP) has revealed that primary uveal melanomas cluster into two highly prognostic molecular subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk) Recently, it was shown that the class 2 GEP correlates with mutations in the BAP1 tumor suppressor gene.	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('uveal melanomas', 'Disease', (58, 73))	('uveal melanomas', 'Phenotype', 'HP:0007716', (58, 73))	('tumor suppressor', 'biological_process', 'GO:0051726', ('277', '293'))	('BAP1', 'Gene', (272, 276))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('277', '293'))	('uveal melanomas', 'Disease', 'MESH:C536494', (58, 73))	('tumor', 'Disease', (277, 282))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('BAP1', 'Gene', '8314', (272, 276))	('mutations', 'Var', (255, 264))
119310	22521086	In most metastasizing class 2 tumors, one copy of BAP1 is mutated and the other is absent through loss of the entire chromosome, consistent with the "two hit" model for mutation of tumor suppressor genes.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('chromosome', 'cellular_component', 'GO:0005694', ('117', '127'))	('BAP1', 'Gene', '8314', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutated', 'Var', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('BAP1', 'Gene', (50, 54))	('tumor', 'Disease', (30, 35))
119340	22521086	Since monosomy 3 has been widely used as a prognostic marker for uveal melanoma, we wished to study more closely the relationship between GEP and chromosome 3 status.	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('uveal melanoma', 'Disease', (65, 79))	('chromosome', 'cellular_component', 'GO:0005694', ('146', '156'))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('monosomy 3', 'Var', (6, 16))	('uveal melanoma', 'Disease', 'MESH:C536494', (65, 79))
119356	22521086	The identification of BAP1 mutations associated with class 2 tumors may soon lead to new targeted therapeutic agents for such clinical trials.	('mutations', 'Var', (27, 36))	('lead to', 'Reg', (77, 84))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('BAP1', 'Gene', '8314', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('associated', 'Reg', (37, 47))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('BAP1', 'Gene', (22, 26))
119360	21575142	ABCB1+ cells also exhibited enhanced clonogenicity, anchorage independent growth, tumorigenicity and mitochondrial activity compared to ABCB1- cells.	('enhanced', 'PosReg', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('anchorage independent growth', 'CPA', (52, 80))	('tumor', 'Disease', (82, 87))	('clonogenicity', 'CPA', (37, 50))	('ABCB1+', 'Var', (0, 6))	('mitochondrial activity', 'CPA', (101, 123))
119373	21575142	Similarly, OCM1A uveal melanoma cells, which are frequently used in studies of tumorigenicity and metastasis, displayed a dye-effluxing side population of 0.2%, which could be blocked by the addition of reserpine (Figure 1B).	('uveal melanoma cells', 'Disease', (17, 37))	('uveal melanoma cells', 'Disease', 'MESH:C536494', (17, 37))	('tumor', 'Disease', (79, 84))	('dye-effluxing side population', 'MPA', (122, 151))	('OCM1', 'Species', '83984', (11, 15))	('reserpine', 'Chemical', 'MESH:D012110', (203, 212))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('OCM1A', 'Var', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
119384	21575142	In soft agar assays, ABCB1+ cells exhibited greater capacity for anchorage independent colony formation than ABCB1- cells (P=0.02) (Figure 3B).	('ABCB1+', 'Var', (21, 27))	('agar', 'Chemical', 'MESH:D000362', (8, 12))	('formation', 'biological_process', 'GO:0009058', ('94', '103'))	('anchorage independent colony formation', 'CPA', (65, 103))
119387	21575142	At day 40, ABCB1+ cells had formed palpable tumors in 100% of animals, compared to 0% for ABCB1- cells (Figure 4A).	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('ABCB1+', 'Var', (11, 17))
119389	21575142	When final tumor volumes were measured at day 60, all tumors derived from ABCB1+ cells were >= 110 mm3, whereas all ABCB1- tumors were < 25 mm3 (P=0.03) (Figure 4B).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumor', 'Disease', (123, 128))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('ABCB1- tumors', 'Disease', (116, 129))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('ABCB1- tumors', 'Disease', 'MESH:D009369', (116, 129))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('ABCB1+ cells', 'Var', (74, 86))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Disease', (54, 60))
119395	21575142	ABCB1+ cells formed tumors more efficiently than ABCB1- cells.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumors', 'Disease', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('ABCB1+', 'Var', (0, 6))
119400	21575142	The number of liver metastases were significantly greater in mice injected with ABCB1+ cells compared to ABCB1- cells (P=0.01) (Figure 4E).	('mice', 'Species', '10090', (61, 65))	('liver metastases', 'Disease', (14, 30))	('liver metastases', 'Disease', 'MESH:D009362', (14, 30))	('ABCB1+ cells', 'Var', (80, 92))	('greater', 'PosReg', (50, 57))
119401	21575142	Further, the ABCB1+ metastatic liver tumors tended to be larger and more invasive than ABCB1- tumors (Figure 4F).	('liver tumors', 'Disease', 'MESH:D008113', (31, 43))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('liver tumors', 'Disease', (31, 43))	('ABCB1- tumors', 'Disease', (87, 100))	('liver tumors', 'Phenotype', 'HP:0002896', (31, 43))	('ABCB1+', 'Var', (13, 19))	('ABCB1- tumors', 'Disease', 'MESH:D009369', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))
119406	21575142	Even so, the number of lung metastases were significantly greater in mice injected with ABCB1+ cells compared to ABCB1- cells (P=0.05) (Figure 5B-C).	('greater', 'PosReg', (58, 65))	('mice', 'Species', '10090', (69, 73))	('lung metastases', 'Disease', 'MESH:D009362', (23, 38))	('ABCB1+ cells', 'Var', (88, 100))	('lung metastases', 'Disease', (23, 38))
119410	21575142	The ABCB1+ subpopulation of cells was highly tumorigenic and metastatic, and they showed up-regulated mitochondrial activity, compared to ABCB1- cells.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mitochondrial activity', 'MPA', (102, 124))	('tumor', 'Disease', (45, 50))	('metastatic', 'CPA', (61, 71))	('ABCB1+', 'Var', (4, 10))	('up-regulated', 'PosReg', (89, 101))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
119413	21575142	ABCB1 has been implicated as a marker for aggressive subpopulations in cutaneous melanoma, lung cancer and gastrointestinal malignancies, and expression of the ABCB1 protein has been linked to poor survival in uveal melanoma.	('expression', 'Var', (142, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('cutaneous melanoma', 'Disease', (71, 89))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (71, 89))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (71, 89))	('uveal melanoma', 'Disease', 'MESH:C536494', (210, 224))	('uveal melanoma', 'Disease', (210, 224))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('ABCB1', 'Gene', (0, 5))	('protein', 'Protein', (166, 173))	('gastrointestinal malignancies', 'Disease', (107, 136))	('gastrointestinal malignancies', 'Disease', 'MESH:D005767', (107, 136))	('lung cancer', 'Disease', (91, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (210, 224))	('ABCB1', 'Gene', (160, 165))	('linked to', 'Reg', (183, 192))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))
119421	21575142	We recently found that the vast majority of metastasizing class 2 tumors harbor inactivating mutations in the tumor suppressor gene BAP1.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('BAP1', 'Gene', '8314', (132, 136))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumors', 'Disease', (66, 72))	('BAP1', 'Gene', (132, 136))	('inactivating mutations', 'Var', (80, 102))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
119422	21575142	Interestingly, depletion of BAP1 in class 1 uveal melanoma cells caused a phenotypic switch to class 2-like cells, and this was accompanied by a highly significant up-regulation of genes involved in ATP synthesis and mitochondrial respiration, similar to our findings in ABCB1+ cells (J.W.H., unpublished data).	('uveal melanoma cells', 'Disease', (44, 64))	('depletion', 'Var', (15, 24))	('BAP1', 'Gene', '8314', (28, 32))	('respiration', 'biological_process', 'GO:0045333', ('231', '242'))	('genes', 'MPA', (181, 186))	('phenotypic switch', 'MPA', (74, 91))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('regulation', 'biological_process', 'GO:0065007', ('167', '177'))	('BAP1', 'Gene', (28, 32))	('ATP', 'Chemical', 'MESH:D000255', (199, 202))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('respiration', 'biological_process', 'GO:0007585', ('231', '242'))	('ATP synthesis', 'biological_process', 'GO:0006754', ('199', '212'))	('uveal melanoma cells', 'Disease', 'MESH:C536494', (44, 64))	('up-regulation', 'PosReg', (164, 177))
119492	20668648	Retinoblastoma, often a hereditary condition, occurs in children under 5 years of age and is caused by inactivation of the RB gene.	('caused by', 'Reg', (93, 102))	('Retinoblastoma', 'Gene', '5925', (0, 14))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (0, 14))	('children', 'Species', '9606', (56, 64))	('inactivation', 'Var', (103, 115))	('Retinoblastoma', 'Gene', (0, 14))
119586	12177778	There is experimental and clinical evidence that immunotherapy based on administration of monoclonal antibodies or on specific tumour vaccines can also have an effect when based on non-mutated 'self-proteins' over-expressed in tumours, such as non-mutated p53, HER-2/neu, and gp100 (Ropke et al, 1996; Nagata et al, 1997; Rosenberg et al, 1998; Buchler et al, 2001; Slamon et al, 2001).	('gp100', 'Gene', (276, 281))	('over-expressed', 'PosReg', (209, 223))	('HER-2/neu', 'Gene', '2064', (261, 270))	('gp100', 'Gene', '6490', (276, 281))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Phenotype', 'HP:0002664', (227, 233))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('HER-2/neu', 'Gene', (261, 270))	('tumours', 'Phenotype', 'HP:0002664', (227, 234))	('p53', 'Gene', (256, 259))	('p53', 'Gene', '7157', (256, 259))	('tumour', 'Disease', 'MESH:D009369', (227, 233))	('tumour', 'Disease', (227, 233))	('tumour', 'Disease', (127, 133))	('non-mutated', 'Var', (244, 255))	('tumours', 'Disease', 'MESH:D009369', (227, 234))	('tumours', 'Disease', (227, 234))
119598	12177778	SW480 and SW620 are colon cancer cells from American Type Culture Collection (ATCC).	('SW480', 'CellLine', 'CVCL:0546', (0, 5))	('colon cancer', 'Phenotype', 'HP:0003003', (20, 32))	('colon cancer', 'Disease', 'MESH:D015179', (20, 32))	('SW620', 'Var', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('colon cancer', 'Disease', (20, 32))
119599	12177778	OVA3507, OVA6906, are colon cancer cells from American Type Culture Collection (ATCC).	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('OVA6906', 'Var', (9, 16))	('colon cancer', 'Phenotype', 'HP:0003003', (22, 34))	('colon cancer', 'Disease', 'MESH:D015179', (22, 34))	('colon cancer', 'Disease', (22, 34))
119617	12177778	Filters were incubated overnight at 4 C with the corresponding primary antibody; (MP1-1B7 or MP1-1C11) (Thornvall et al, 1997), for 1 h and then with a secondary antibody (horseradish peroxidase-conjugated sheep anti-mouse Ig; Amersham, Buckinghamshire, UK) for 30 min.	('sheep', 'Species', '9940', (206, 211))	('antibody', 'cellular_component', 'GO:0019815', ('71', '79'))	('mouse', 'Species', '10090', (217, 222))	('antibody', 'cellular_component', 'GO:0019814', ('162', '170'))	('MP1-1B7', 'Var', (82, 89))	('antibody', 'cellular_component', 'GO:0019814', ('71', '79'))	('antibody', 'molecular_function', 'GO:0003823', ('162', '170'))	('antibody', 'molecular_function', 'GO:0003823', ('71', '79'))	('antibody', 'cellular_component', 'GO:0042571', ('71', '79'))	('antibody', 'cellular_component', 'GO:0042571', ('162', '170'))	('horseradish', 'Species', '3704', (172, 183))	('antibody', 'cellular_component', 'GO:0019815', ('162', '170'))	('MP1-1C11', 'Var', (93, 101))
119626	12177778	After checking the permeability of the cells by trypan blue uptake, 3x105 cells per well were added to a 96 v-bottom well and incubated with 5 mug ml-1 of mAb MP4-1B7 (anti MC1R) (Thornvall et al, 1997), 2 mug ml-1 of mAb 9.2.27 (Morgan et al, 1981) or control IgG1 mAb for 30 min on ice.	('uptake', 'biological_process', 'GO:0098739', ('60', '66'))	('trypan blue', 'Chemical', 'MESH:D014343', (48, 59))	('ml-1', 'Gene', (147, 151))	('ml-1', 'Gene', '112744', (147, 151))	('ml-1', 'Gene', (210, 214))	('ml-1', 'Gene', '112744', (210, 214))	('mug', 'molecular_function', 'GO:0043739', ('143', '146'))	('IgG1', 'cellular_component', 'GO:0071735', ('261', '265'))	('mug', 'molecular_function', 'GO:0043739', ('206', '209'))	('uptake', 'biological_process', 'GO:0098657', ('60', '66'))	('MP4-1B7', 'Var', (159, 166))
119636	12177778	Excess of serum was drained and the sections were incubated with the primary antibody (MP1-1B7 or MP1-1C11 anti-MC1R) (Thornvall et al, 1997) at a concentration of 10 mug ml-1.	('mug', 'molecular_function', 'GO:0043739', ('167', '170'))	('antibody', 'cellular_component', 'GO:0042571', ('77', '85'))	('MP1-1C11 anti-MC1R', 'Var', (98, 116))	('ml-1', 'Gene', (171, 175))	('ml-1', 'Gene', '112744', (171, 175))	('antibody', 'cellular_component', 'GO:0019815', ('77', '85'))	('MP1-1B7', 'Var', (87, 94))	('antibody', 'cellular_component', 'GO:0019814', ('77', '85'))	('antibody', 'molecular_function', 'GO:0003823', ('77', '85'))
119644	12177778	The specificity of the mAbs MP1-1B7 and MP1-1C11, previously described to be specific for the extracellular domain of MC1R (Thornvall et al, 1997), was confirmed by Western blot analysis on melanoma lines and EBV immortalized B cell lines (LCL).	('extracellular', 'cellular_component', 'GO:0005576', ('94', '107'))	('melanoma lines', 'Disease', 'MESH:D008545', (190, 204))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma lines', 'Disease', (190, 204))	('MP1-1C11', 'Var', (40, 48))
119674	12177778	Using the same method, MC1R was also detected in some cell components of normal tissues, including adrenal medulla, cerebellum, and liver, although with a considerably lower intensity as compared to the melanomas (Table 2Table 2).	('melanomas', 'Disease', (203, 212))	('MC1R', 'Var', (23, 27))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanomas', 'Phenotype', 'HP:0002861', (203, 212))	('melanomas', 'Disease', 'MESH:D008545', (203, 212))
119708	12177778	Interestingly, uveal melanoma, the most common malignant intraocular tumour in adults, can only be partially recognised by the three most widely used immunohistochemical reagents for the diagnosis (HMB-45, S-100 and A103 (Melan-A/Mart-1 specific antibody).	('tumour', 'Disease', (69, 75))	('antibody', 'cellular_component', 'GO:0042571', ('246', '254'))	('Mart-1', 'Gene', (230, 236))	('S-100', 'Gene', '6271', (206, 211))	('uveal melanoma', 'Phenotype', 'HP:0007716', (15, 29))	('uveal melanoma', 'Disease', (15, 29))	('uveal melanoma', 'Disease', 'MESH:C536494', (15, 29))	('antibody', 'cellular_component', 'GO:0019815', ('246', '254'))	('A103', 'Var', (216, 220))	('S-100', 'Gene', (206, 211))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('antibody', 'cellular_component', 'GO:0019814', ('246', '254'))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('Melan-A', 'Gene', (222, 229))	('Melan-A', 'Gene', '2315', (222, 229))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('antibody', 'molecular_function', 'GO:0003823', ('246', '254'))	('Mart-1', 'Gene', '2315', (230, 236))
119720	12177778	We also confirmed the presence of MC1R in activated monocytes/macrophages and in the THP-1 cell line, but at lower levels than those found in melanomas (Figure 5A,B).	('THP-1', 'Gene', '2736', (85, 90))	('melanomas', 'Disease', 'MESH:D008545', (142, 151))	('melanomas', 'Disease', (142, 151))	('melanomas', 'Phenotype', 'HP:0002861', (142, 151))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('THP-1', 'Gene', (85, 90))	('MC1R', 'Var', (34, 38))
119743	33758365	Indeed, whilst cell surface molecules represent only ~22% of all proteins encoded in the human genome, many approved drugs target overexpressed/mutated cell surface molecules (or their natural ligands) to suppress aberrant signalling pathways.	('human', 'Species', '9606', (89, 94))	('cell surface', 'cellular_component', 'GO:0009986', ('15', '27'))	('overexpressed/mutated', 'Var', (130, 151))	('suppress', 'NegReg', (205, 213))	('aberrant signalling pathways', 'Pathway', (214, 242))	('cell surface', 'cellular_component', 'GO:0009986', ('152', '164'))	('signalling', 'biological_process', 'GO:0023052', ('223', '233'))
119755	33758365	Using the PR approach, the top two genes (gRNAs) were Lrrn4cl and Slc4a3 (Supplementary Table 1); using JACKS analysis, the top two genes were Lrrn4cl and Tm4sf19 (Supplementary Table 2).	('Tm4sf19', 'Gene', (155, 162))	('Lrrn4cl', 'Var', (143, 150))	('N', 'Chemical', 'MESH:D009584', (44, 45))	('Slc4a3', 'Gene', (66, 72))	('4cl', 'molecular_function', 'GO:0016207', ('147', '150'))	('Tm4sf19', 'Gene', '277203', (155, 162))	('4cl', 'molecular_function', 'GO:0016207', ('58', '61'))	('Slc4a3', 'Gene', '20536', (66, 72))
119757	33758365	Targeting of each gene resulted in a significant enhancement of the ability of the cells to colonise the lung, relative to cells transduced with a pool of three non-targeting control gRNAs (Fig.	('N', 'Chemical', 'MESH:D009584', (185, 186))	('enhancement', 'PosReg', (49, 60))	('Targeting', 'Var', (0, 9))
119758	33758365	Given that Lrrn4cl (Leucine-Rich Repeat Neuronal 4 C-Terminal Like) was identified as a 'hit' in both analyses, and showed the strongest enhancement of pulmonary metastatic capabilities, we chose to further characterise this gene.	('Leucine-Rich Repeat Neuronal 4 C-Terminal Like', 'Gene', '68852', (20, 66))	('Lrrn4cl', 'Var', (11, 18))	('enhancement', 'PosReg', (137, 148))	('pulmonary metastatic capabilities', 'CPA', (152, 185))	('4cl', 'molecular_function', 'GO:0016207', ('15', '18'))	('Leucine-Rich Repeat Neuronal 4 C-Terminal Like', 'Gene', (20, 66))
119759	33758365	Consistent with the phenotype observed when B16-F0 cells were virally transduced with the dCas9/CRISPRa system to upregulate Lrrn4cl expression, transfection of a Lrrn4cl cDNA-containing plasmid into B16-F0 cells also resulted in enhanced pulmonary metastatic colonisation (Fig.	('N', 'Chemical', 'MESH:D009584', (173, 174))	('expression', 'MPA', (133, 143))	('pulmonary metastatic colonisation', 'CPA', (239, 272))	('upregulate', 'PosReg', (114, 124))	('CRISPR', 'Gene', (96, 102))	('Lrrn4cl', 'Gene', (125, 132))	('enhanced', 'PosReg', (230, 238))	('CRISPR', 'Gene', '70873', (96, 102))	('Lrrn4cl', 'Var', (163, 170))	('4cl', 'molecular_function', 'GO:0016207', ('167', '170'))	('expression', 'Species', '29278', (133, 143))	('4cl', 'molecular_function', 'GO:0016207', ('129', '132'))
119761	33758365	The extracellular portion of the protein is predicted to undergo N-linked glycosylation (at position N132 in human and at N132 and N174 in mouse) and contains a fibronectin type-III (FN3) domain, found in many proteins involved in ligand binding (Fig.	('N', 'Chemical', 'MESH:D009584', (184, 185))	('human', 'Species', '9606', (109, 114))	('binding', 'molecular_function', 'GO:0005488', ('238', '245'))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('undergo', 'Reg', (57, 64))	('N-linked glycosylation', 'MPA', (65, 87))	('N', 'Chemical', 'MESH:D009584', (65, 66))	('N', 'Chemical', 'MESH:D009584', (122, 123))	('ligand', 'molecular_function', 'GO:0005488', ('231', '237'))	('mouse', 'Species', '10090', (139, 144))	('fibronectin', 'Gene', '14268', (161, 172))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('extracellular', 'cellular_component', 'GO:0005576', ('4', '17'))	('glycosylation', 'biological_process', 'GO:0070085', ('74', '87'))	('N174', 'Var', (131, 135))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('fibronectin', 'Gene', (161, 172))
119767	33758365	To confirm that the observed phenotype was not specific to B16-F0 melanoma cells, we expressed Lrrn4cl cDNA in three other mouse melanoma cell lines (HCmel12, YUMM1.7 and B16-BL6 cells [the latter of which already displays a high metastatic propensity]) and observed increased pulmonary metastatic colonisation relative to cells transfected with the empty vector alone (Fig.	('Lrrn4cl', 'Var', (95, 102))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('HCmel12', 'CellLine', 'CVCL:J992', (150, 157))	('melanoma', 'Disease', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('mouse', 'Species', '10090', (123, 128))	('pulmonary metastatic colonisation', 'CPA', (277, 310))	('YUMM1.7', 'CellLine', 'CVCL:L908', (159, 166))	('B16-BL6', 'CellLine', 'CVCL:0157', (171, 178))	('4cl', 'molecular_function', 'GO:0016207', ('99', '102'))	('N', 'Chemical', 'MESH:D009584', (105, 106))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('increased', 'PosReg', (267, 276))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('melanoma cells', 'Disease', 'MESH:D008545', (66, 80))	('melanoma cells', 'Disease', (66, 80))
119768	33758365	To assess whether the phenotype associated with Lrrn4cl upregulation was specific to melanoma cells, we expressed the Lrrn4cl cDNA in three non-melanoma mouse cancer cell lines (MC-38 colorectal cancer cells, MB-47 bladder cancer cells and EO771 breast cancer cells) and the same effect was observed (Fig.	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('non-melanoma mouse cancer', 'Disease', (140, 165))	('colorectal cancer', 'Disease', 'MESH:D015179', (184, 201))	('melanoma cells', 'Disease', (85, 99))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('colorectal cancer', 'Disease', (184, 201))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('breast cancer', 'Disease', (246, 259))	('MB-47 bladder cancer', 'Disease', 'MESH:D001749', (209, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('4cl', 'molecular_function', 'GO:0016207', ('52', '55'))	('bladder cancer', 'Phenotype', 'HP:0009725', (215, 229))	('melanoma cells', 'Disease', 'MESH:D008545', (85, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (184, 201))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('Lrrn4cl', 'Var', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('N', 'Chemical', 'MESH:D009584', (128, 129))	('non-melanoma mouse cancer', 'Disease', 'MESH:D009369', (140, 165))	('4cl', 'molecular_function', 'GO:0016207', ('122', '125'))	('MB-47 bladder cancer', 'Disease', (209, 229))	('MC-38', 'CellLine', 'CVCL:B288', (178, 183))
119772	33758365	Thus, although we identified Lrrn4cl in melanoma cells, it mediates pulmonary colonisation cell lines from other tumour types.	('mediates', 'Reg', (59, 67))	('pulmonary colonisation', 'Disease', (68, 90))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma cells', 'Disease', 'MESH:D008545', (40, 54))	('pulmonary colonisation', 'Disease', 'MESH:D008171', (68, 90))	('melanoma cells', 'Disease', (40, 54))	('tumour', 'Disease', (113, 119))	('4cl', 'molecular_function', 'GO:0016207', ('33', '36'))	('Lrrn4cl', 'Var', (29, 36))
119773	33758365	We next expressed the human LRRN4CL cDNA in two human melanoma cell lines, A375 and MeWo (Western blot confirming upregulated expression shown in Supplementary Fig.	('expression', 'Species', '29278', (126, 136))	('expression', 'MPA', (126, 136))	('human', 'Species', '9606', (48, 53))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('4CL', 'molecular_function', 'GO:0016207', ('32', '35'))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('LRRN4CL', 'Var', (28, 35))	('human', 'Species', '9606', (22, 27))	('upregulated', 'PosReg', (114, 125))	('A375', 'CellLine', 'CVCL:0132', (75, 79))
119774	33758365	Similarly, expression of human LRRN4CL cDNA in mouse B16-F0 cells resulted in increased pulmonary metastatic colonisation (Fig.	('expression', 'Species', '29278', (11, 21))	('pulmonary metastatic colonisation', 'CPA', (88, 121))	('human', 'Species', '9606', (25, 30))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('increased', 'PosReg', (78, 87))	('4CL', 'molecular_function', 'GO:0016207', ('35', '38'))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('mouse', 'Species', '10090', (47, 52))	('LRRN4CL cDNA', 'Var', (31, 43))
119776	33758365	It was interesting to note that the expression of Lrrn4cl cDNA did not result in increased hepatic metastatic colonisation (Fig.	('Lrrn4cl', 'Var', (50, 57))	('4cl', 'molecular_function', 'GO:0016207', ('54', '57'))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('expression', 'Species', '29278', (36, 46))	('hepatic metastatic colonisation', 'CPA', (91, 122))
119777	33758365	Similarly, when mouse B16-F0 melanoma cells were tail vein dosed into immunodeficient (NOD-SCID) mice, in addition to pulmonary metastases, hepatic metastases were also noted, and expression of Lrrn4cl cDNA resulted in the cells showing significantly decreased hepatic metastatic colonisation (Fig.	('N', 'Chemical', 'MESH:D009584', (204, 205))	('expression', 'Species', '29278', (180, 190))	('melanoma cells', 'Disease', (29, 43))	('immunodeficient', 'Disease', 'MESH:D007153', (70, 85))	('cDNA', 'Gene', (202, 206))	('immunodeficient', 'Disease', (70, 85))	('hepatic metastases', 'Disease', 'MESH:D009362', (140, 158))	('mouse', 'Species', '10090', (16, 21))	('4cl', 'molecular_function', 'GO:0016207', ('198', '201'))	('Lrrn4cl', 'Var', (194, 201))	('hepatic metastases', 'Disease', (140, 158))	('pulmonary metastases', 'Disease', (118, 138))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma cells', 'Disease', 'MESH:D008545', (29, 43))	('hepatic metastatic colonisation', 'CPA', (261, 292))	('mice', 'Species', '10090', (97, 101))	('N', 'Chemical', 'MESH:D009584', (87, 88))	('decreased', 'NegReg', (251, 260))	('pulmonary metastases', 'Disease', 'MESH:D009362', (118, 138))
119780	33758365	3a, there was no difference in the number of F0_LRN or F0_PB tumour cells present in the saline-rinsed lungs at either 1 or 3 h post dosing.	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('F0_PB', 'Var', (55, 60))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('saline', 'Chemical', 'MESH:D012965', (89, 95))	('tumour', 'Disease', (61, 67))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
119781	33758365	This suggests that expression of the Lrrn4cl cDNA did not enhance the ability of the tumour cells to extravasate.	('4cl', 'molecular_function', 'GO:0016207', ('41', '44'))	('Lrrn4cl', 'Var', (37, 44))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('N', 'Chemical', 'MESH:D009584', (47, 48))	('tumour', 'Disease', (85, 91))	('extravasate', 'MPA', (101, 112))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('expression', 'Species', '29278', (19, 29))
119782	33758365	To ascertain whether LRRN4CL expression aided evasion of NK, T and B cells, B16-F0 cells were tail vein dosed into immunocompromised (NOD-SCID) mice and, similar to results in the wildtype mice, F0_LRN cells had significantly increased pulmonary metastatic colonisation relative to F0_PB cells (Fig.	('N', 'Chemical', 'MESH:D009584', (57, 58))	('4CL', 'molecular_function', 'GO:0016207', ('25', '28'))	('mice', 'Species', '10090', (144, 148))	('pulmonary metastatic colonisation', 'CPA', (236, 269))	('F0_LRN', 'Var', (195, 201))	('mice', 'Species', '10090', (189, 193))	('evasion', 'MPA', (46, 53))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('expression', 'Species', '29278', (29, 39))	('increased', 'PosReg', (226, 235))	('LRRN4CL', 'Gene', (21, 28))	('N', 'Chemical', 'MESH:D009584', (200, 201))
119784	33758365	Furthermore, Lrrn4cl expression did not affect the primary tumour growth of B16-F0 melanoma cells subcutaneously administered to wildtype mice (Fig.	('melanoma cells', 'Disease', (83, 97))	('Lrrn4cl expression', 'Var', (13, 31))	('4cl', 'molecular_function', 'GO:0016207', ('17', '20'))	('expression', 'Species', '29278', (21, 31))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('mice', 'Species', '10090', (138, 142))	('melanoma cells', 'Disease', 'MESH:D008545', (83, 97))	('tumour', 'Disease', (59, 65))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
119790	33758365	This suggests that, at least in mice, LRRN4CL does not mediate the enhanced metastatic pulmonary colonisation phenotype through binding to CRTAC1.	('pulmonary colonisation', 'Disease', (87, 109))	('4CL', 'molecular_function', 'GO:0016207', ('42', '45'))	('binding', 'molecular_function', 'GO:0005488', ('128', '135'))	('CRTAC1', 'Gene', (139, 145))	('binding', 'Interaction', (128, 135))	('mice', 'Species', '10090', (32, 36))	('LRRN4CL', 'Var', (38, 45))	('pulmonary colonisation', 'Disease', 'MESH:D008171', (87, 109))
119791	33758365	We next applied in vitro assays to examine whether LRRN4CL affected the following intrinsic properties of melanoma cells that are generally associated with increased metastatic potential: general growth rate in vitro, invasion and migration, epithelial-mesenchymal transition, matrix metalloprotease (MMP) production, and self-renewal.	('general growth rate', 'CPA', (188, 207))	('associated', 'Reg', (140, 150))	('4CL', 'molecular_function', 'GO:0016207', ('55', '58'))	('self-renewal', 'CPA', (322, 334))	('invasion', 'CPA', (218, 226))	('melanoma cells', 'Disease', 'MESH:D008545', (106, 120))	('increased', 'PosReg', (156, 165))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('242', '275'))	('MMP', 'molecular_function', 'GO:0004235', ('301', '304'))	('epithelial-mesenchymal transition', 'CPA', (242, 275))	('matrix metalloprotease', 'CPA', (277, 299))	('affected', 'Reg', (59, 67))	('LRRN4CL', 'Var', (51, 58))	('melanoma cells', 'Disease', (106, 120))	('intrinsic properties', 'CPA', (82, 102))	('MMP', 'Gene', '79148;79148;79148;118453', (301, 304))	('MMP', 'Gene', (301, 304))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
119793	33758365	Based on these data, we considered a potential role for LRRN4CL in the later stages of the metastatic process, specifically DTC survival and subsequent outgrowth in the lung parenchyma.	('DTC', 'Chemical', '-', (124, 127))	('outgrowth in the', 'CPA', (152, 168))	('4CL', 'molecular_function', 'GO:0016207', ('60', '63'))	('LRRN4CL', 'Var', (56, 63))
119800	33758365	Thus, in the lung, the enhanced expression of LRRN4CL allows the cells to enter a pro-metastatic phenotype.	('LRRN4CL', 'Var', (46, 53))	('enhanced', 'PosReg', (23, 31))	('pro-metastatic phenotype', 'CPA', (82, 106))	('4CL', 'molecular_function', 'GO:0016207', ('50', '53'))	('expression', 'Species', '29278', (32, 42))	('expression', 'MPA', (32, 42))
119803	33758365	In melanoma patients, high expression of LRRN4CL significantly correlated with worse outcome, in both the TCGA dataset (Cox Log-rank P = 0.0008, age- and sex-adjusted; Fig.	('patients', 'Species', '9606', (12, 20))	('expression', 'Species', '29278', (27, 37))	('high', 'Var', (22, 26))	('4CL', 'molecular_function', 'GO:0016207', ('45', '48'))	('correlated with', 'Reg', (63, 78))	('LRRN4CL', 'Var', (41, 48))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
119814	33758365	In this analysis, the majority of enriched gRNAs were present in <=2 mice, however, two gRNAs were identified in 4 mice and 3 mice, which targeted Lrrn4cl and Slc4a3, respectively.	('mice', 'Species', '10090', (126, 130))	('Lrrn4cl', 'Var', (147, 154))	('4cl', 'molecular_function', 'GO:0016207', ('151', '154'))	('mice', 'Species', '10090', (69, 73))	('Slc4a3', 'Gene', (159, 165))	('mice', 'Species', '10090', (115, 119))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('N', 'Chemical', 'MESH:D009584', (90, 91))	('Slc4a3', 'Gene', '20536', (159, 165))
119824	33758365	As upregulated LRRN4CL expression only provided an advantage to metastatic tumour cells in the lung, with no phenotypic effect observed in vitro, we performed RNAseq of human A375 melanoma cells expressing LRRN4CL (A375_LRNmCherry cells; 'L') that had been colonising the lung for 21 days.	('melanoma cells', 'Disease', (180, 194))	('4CL', 'molecular_function', 'GO:0016207', ('210', '213'))	('human', 'Species', '9606', (169, 174))	('LRRN4CL', 'Gene', (15, 22))	('expression', 'Species', '29278', (23, 33))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('upregulated', 'PosReg', (3, 14))	('N', 'Chemical', 'MESH:D009584', (209, 210))	('tumour', 'Disease', (75, 81))	('N', 'Chemical', 'MESH:D009584', (18, 19))	('A375', 'CellLine', 'CVCL:0132', (215, 219))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('A375', 'CellLine', 'CVCL:0132', (175, 179))	('melanoma cells', 'Disease', 'MESH:D008545', (180, 194))	('4CL', 'molecular_function', 'GO:0016207', ('19', '22'))	('N', 'Chemical', 'MESH:D009584', (222, 223))	('N', 'Chemical', 'MESH:D009584', (160, 161))	('LRRN4CL', 'Var', (206, 213))
119828	33758365	A375_LRNmCherry cells also had strong in vivo upregulation of many genes with a known role in promoting metastasis.	('A375', 'CellLine', 'CVCL:0132', (0, 4))	('upregulation', 'PosReg', (46, 58))	('metastasis', 'CPA', (104, 114))	('promoting', 'PosReg', (94, 103))	('N', 'Chemical', 'MESH:D009584', (7, 8))	('A375_LRNmCherry', 'Var', (0, 15))
119833	33758365	Critically, high expression of LRRN4CL was significantly correlated with worse outcome in cancer patients, across all cancers represented in TCGA (Fig.	('Critically', 'Disease', (0, 10))	('cancers', 'Disease', (118, 125))	('cancer', 'Disease', (118, 124))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('expression', 'Species', '29278', (17, 27))	('high', 'Var', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('correlated', 'Reg', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('LRRN4CL', 'Var', (31, 38))	('4CL', 'molecular_function', 'GO:0016207', ('35', '38'))	('Critically', 'Disease', 'MESH:D016638', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('patients', 'Species', '9606', (97, 105))
119836	33758365	Taken together with previous findings that LRRN4CL is not highly expressed in normal tissues and Lrrn4cl knockout mice show no overt phenotypes, we conclude that LRRN4CL represents an attractive therapeutic candidate for the prevention of metastatic colonisation.	('4CL', 'molecular_function', 'GO:0016207', ('166', '169'))	('4CL', 'molecular_function', 'GO:0016207', ('47', '50'))	('mice', 'Species', '10090', (114, 118))	('metastatic colonisation', 'Disease', (239, 262))	('4cl', 'molecular_function', 'GO:0016207', ('101', '104'))	('LRRN4CL', 'Var', (162, 169))
119842	33758365	Wildtype mice were C57BL/6NTac and immunodeficient mice were NOD.CgPrkdcscid, Il2rgtm1Wjl/SzJ.	('mice', 'Species', '10090', (51, 55))	('N', 'Chemical', 'MESH:D009584', (61, 62))	('N', 'Chemical', 'MESH:D009584', (26, 27))	('immunodeficient', 'Disease', 'MESH:D007153', (35, 50))	('immunodeficient', 'Disease', (35, 50))	('mice', 'Species', '10090', (9, 13))	('Il2', 'molecular_function', 'GO:0005134', ('78', '81'))	('Il2rgtm1Wjl/SzJ', 'Var', (78, 93))
119843	33758365	Lrrn4cl 'knockout' (Lrrn4clem1(IMPC)Wtsi) mice were generated at the Welcome Sanger Institute using CRISPR technology to disrupt the coding exon of Lrrn4cl using published methods and phenotyped using an Ultrafocus100 densitometer (Faxitron).	('Lrrn4cl', 'Gene', (148, 155))	('CRISPR', 'Gene', (100, 106))	('4cl', 'molecular_function', 'GO:0016207', ('152', '155'))	('disrupt', 'Var', (121, 128))	('mice', 'Species', '10090', (42, 46))	('4cl', 'molecular_function', 'GO:0016207', ('4', '7'))	('CRISPR', 'Gene', '70873', (100, 106))	('(IMPC)Wtsi', 'Disease', 'None', (30, 40))
119879	33758365	The gRNAs from the m6 library used for validation were 'Lrrn4cl_+_8850757.23-P1P2', 'Slc4a3_+_75546398.23-P1P2', 'Tm4sf19_-_32400563.23-P1P2' and 'non-targeting_01320-01324'.	('Tm4sf19', 'Gene', '277203', (114, 121))	('Slc4a3', 'Gene', (85, 91))	('4cl', 'molecular_function', 'GO:0016207', ('60', '63'))	('N', 'Chemical', 'MESH:D009584', (6, 7))	('Slc4a3', 'Gene', '20536', (85, 91))	("'non-targeting_01320-01324'", 'Var', (146, 173))	('Tm4sf19', 'Gene', (114, 121))
119892	33758365	Deglycosylation of whole-cell lysates from B16-F0 cells expressing a FLAG/streptavidin-tagged Lrrn4cl cDNA (LRRN4CL-FSA) was carried out with PNGase F (New England Biolabs) according to the manufacturer's instructions.	('4CL', 'molecular_function', 'GO:0016207', ('112', '115'))	('4cl', 'molecular_function', 'GO:0016207', ('98', '101'))	('N', 'Chemical', 'MESH:D009584', (152, 153))	('PNGase', 'Gene', (142, 148))	('PNGase F', 'molecular_function', 'GO:0000224', ('142', '150'))	('PNGase', 'Gene', '59007', (142, 148))	('Lrrn4cl', 'Var', (94, 101))	('N', 'Chemical', 'MESH:D009584', (143, 144))	('N', 'Chemical', 'MESH:D009584', (111, 112))	('N', 'Chemical', 'MESH:D009584', (104, 105))
119907	33758365	Cells were washed and incubated with AF647 anti-human IgG Fc detection antibody as used in the cell microarray study.	('antibody', 'cellular_component', 'GO:0019815', ('71', '79'))	('AF647 anti-human', 'Var', (37, 53))	('antibody', 'cellular_component', 'GO:0019814', ('71', '79'))	('human', 'Species', '9606', (48, 53))	('antibody', 'molecular_function', 'GO:0003823', ('71', '79'))	('IgG Fc', 'Gene', (54, 60))	('antibody', 'cellular_component', 'GO:0042571', ('71', '79'))
119911	33758365	An example of the gating strategy to detect CDFA+ tumour cells in the lung is shown in Supplementary Fig.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', (50, 56))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('CDFA+', 'Var', (44, 49))
119913	33758365	Immunodeficient mice tail vein dosed with 2.5 x 105 A375_LRNmCherry or A375_EVmCherry cells were humanely sacrificed after 21 days and lung cell suspensions prepared using a human tumour dissociation kit (Miltenyi Biotec), followed by a mouse-cell depletion kit (Miltenyi Biotec), according to the manufacturer's instructions.	('human', 'Species', '9606', (174, 179))	('mouse', 'Species', '10090', (237, 242))	('A375_LRNmCherry', 'Var', (52, 67))	('mice', 'Species', '10090', (16, 20))	('human', 'Species', '9606', (97, 102))	('tumour dissociation', 'Disease', 'MESH:D009369', (180, 199))	('A375', 'CellLine', 'CVCL:0132', (52, 56))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('A375_E', 'Mutation', 'p.A375E', (71, 77))	('A375_EVmCherry', 'Var', (71, 85))	('A375', 'CellLine', 'CVCL:0132', (71, 75))	('tumour dissociation', 'Disease', (180, 199))
119949	33479026	PDT with Ce6-embedded nanophotosensitizer (FIC-PDT) elicited immunogenic cell death and stimulated antigen-presenting cells.	('antigen-presenting cells', 'CPA', (99, 123))	('stimulated', 'PosReg', (88, 98))	('PDT', 'Var', (0, 3))	('immunogenic cell death', 'CPA', (61, 83))	('Ce6', 'Chemical', 'MESH:C062985', (9, 12))	('FIC-PDT', 'Disease', 'None', (43, 50))	('cell death', 'biological_process', 'GO:0008219', ('73', '83'))	('FIC-PDT', 'Disease', (43, 50))
119988	33479026	The membranes were incubated with HMGB1 or HSP70 primary antibodies (ab18256 and ab181606, Abcam) overnight, washed, and incubated with secondary antibody (a0545, Sigma-Aldrich) for 1 hour at RT.	('HMGB1', 'Gene', (34, 39))	('antibody', 'cellular_component', 'GO:0019814', ('146', '154'))	('antibody', 'cellular_component', 'GO:0019815', ('146', '154'))	('HSP70', 'Gene', '15511', (43, 48))	('antibody', 'molecular_function', 'GO:0003823', ('146', '154'))	('ab181606', 'Var', (81, 89))	('HMGB1', 'Gene', '15289', (34, 39))	('HSP70', 'Gene', (43, 48))	('antibody', 'cellular_component', 'GO:0042571', ('146', '154'))
120067	33479026	Moreover, triple-combination therapy prolonged survival rates, and one mouse treated with this therapy remained completely tumor-free until day 60 (figure 4D).	('tumor', 'Disease', (123, 128))	('survival rates', 'CPA', (47, 61))	('triple-combination', 'Var', (10, 28))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('prolonged', 'PosReg', (37, 46))	('mouse', 'Species', '10090', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
120075	33479026	As expected, the percentage of CD103+ DCs was higher in the triple-combination group than in the other groups, suggesting increased priming of CD8+ T cells in TDLN (figure 5C).	('increased', 'PosReg', (122, 131))	('CD103', 'Gene', '16407', (31, 36))	('CD103', 'Gene', (31, 36))	('triple-combination', 'Var', (60, 78))
120079	33479026	There was a larger granzyme B+ population of CD8+ T cells after Ripa+PDT treatment compared with after PBS and alpha-PD-L1 treatment; moreover, after triple-combination therapy, the population was further expanded at both the primary and secondary tumor sites (figure 5F).	('Ripa+PDT', 'Var', (64, 72))	('secondary tumor', 'Disease', (238, 253))	('granzyme B', 'Gene', '14939', (19, 29))	('larger', 'PosReg', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('PBS', 'Chemical', '-', (103, 106))	('secondary tumor', 'Disease', 'MESH:D060085', (238, 253))	('granzyme B', 'Gene', (19, 29))
120082	33479026	There was a decreasing tendency of the numbers of Treg cells in both types of tumor sites after Ripa+PDT treatment and Ripa+PDT+alpha-PD-L1 treatment (online supplemental figure S9D).	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('Ripa+PDT', 'Var', (96, 104))	('tumor', 'Disease', (78, 83))
120086	33479026	To specifically target focused ocular tumor regions, laser-based FIC-PDT treatment was applied and showed similar cytotoxic effects and aspects of ICD induction to those of LED-based FIC-PDT treatment (online supplemental figure S10A, B).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('ocular tumor', 'Disease', 'MESH:D005134', (31, 43))	('ocular tumor', 'Phenotype', 'HP:0100012', (31, 43))	('FIC-PDT', 'Disease', 'None', (183, 190))	('FIC-PDT', 'Disease', (65, 72))	('S10A', 'SUBSTITUTION', 'None', (229, 233))	('FIC-PDT', 'Disease', (183, 190))	('S10A', 'Var', (229, 233))	('ocular tumor', 'Disease', (31, 43))	('FIC-PDT', 'Disease', 'None', (65, 72))
120089	33479026	Although the Ripa+PDT group treated with low doses showed slight therapeutic effect, triple-combination treatment inhibited tumor growth in the orthotopic model, similar to previous results obtained using a syngeneic model (figure 6B, online supplemental figure S11A).	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('S11A', 'Var', (262, 266))	('S11A', 'SUBSTITUTION', 'None', (262, 266))	('inhibited', 'NegReg', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
120090	33479026	H&E staining revealed impaired tumor structures after Ripa+PDT and Ripa+PDT+alpha-PD-L1 treatments (online supplemental figure S11B).	('S11B', 'SUBSTITUTION', 'None', (127, 131))	('S11B', 'Var', (127, 131))	('after', 'Var', (48, 53))	('revealed', 'NegReg', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('H&E', 'Chemical', 'MESH:D006371', (0, 3))	('impaired tumor', 'Disease', (22, 36))	('impaired tumor', 'Disease', 'MESH:D060825', (22, 36))
120104	33479026	Moreover, PDT treatment exhibits tumor-killing effects and induces dying tumor cells to become immunogenic by releasing DAMPs, which are natural immune adjuvants.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('DAMPs', 'MPA', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('induces', 'Reg', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('treatment', 'Var', (14, 23))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (33, 38))	('PDT', 'Gene', (10, 13))
120116	33479026	Consistent with the functions of CD103+ DCs, triple-combination therapy increased the number of antigen-experienced CD8+ T cells in TDLNs and channeled abundant tumor-specific CD8+ T cells to both primary and secondary tumor sites to drive the potent antitumor therapeutic efficacy.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('increased', 'PosReg', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('tumor', 'Disease', (219, 224))	('secondary tumor', 'Disease', 'MESH:D060085', (209, 224))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('secondary tumor', 'Disease', (209, 224))	('CD103', 'Gene', '16407', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('triple-combination', 'Var', (45, 63))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Disease', (161, 166))	('CD103', 'Gene', (33, 38))
120120	33479026	Therefore, we used UM mouse models intraocularly injected with B16F10 CM cells.	('B16F10', 'CellLine', 'CVCL:0159', (63, 69))	('intraocular', 'Disease', (35, 46))	('B16F10 CM', 'Var', (63, 72))	('CM', 'Phenotype', 'HP:0012056', (70, 72))	('UM', 'Phenotype', 'HP:0007716', (19, 21))	('mouse', 'Species', '10090', (22, 27))	('intraocular', 'Disease', 'MESH:D009798', (35, 46))
120130	33479026	While CM has common gene mutations in BRAF, NRAS, or NF1 that deregulates ERK pathway, UM carries GNAQ/GNA11, EIF1AX and, BAP1 mutations.	('BAP1', 'Gene', (122, 126))	('BRAF', 'Gene', '109880', (38, 42))	('EIF1AX', 'Gene', '66235', (110, 116))	('deregulates', 'Reg', (62, 73))	('GNA11', 'Gene', '14672', (103, 108))	('EIF1AX', 'Gene', (110, 116))	('mutations', 'Var', (25, 34))	('ERK', 'Gene', (74, 77))	('ERK', 'molecular_function', 'GO:0004707', ('74', '77'))	('BAP1', 'Gene', '104416', (122, 126))	('BRAF', 'Gene', (38, 42))	('NF1', 'Gene', '18015', (53, 56))	('mutations', 'Var', (127, 136))	('NF1', 'Gene', (53, 56))	('GNAQ', 'Gene', (98, 102))	('CM', 'Phenotype', 'HP:0012056', (6, 8))	('ERK', 'Gene', '26413', (74, 77))	('UM', 'Phenotype', 'HP:0007716', (87, 89))	('GNAQ', 'Gene', '14682', (98, 102))	('NRAS', 'Gene', '18176', (44, 48))	('NRAS', 'Gene', (44, 48))	('GNA11', 'Gene', (103, 108))
120135	33260500	FTH1 Pseudogenes in Cancer and Cell Metabolism Ferritin, the principal intracellular iron-storage protein localized in the cytoplasm, nucleus, and mitochondria, plays a major role in iron metabolism.	('metabolism', 'biological_process', 'GO:0008152', ('188', '198'))	('storage protein', 'molecular_function', 'GO:0005187', ('90', '105'))	('Metabolism', 'biological_process', 'GO:0008152', ('36', '46'))	('intracellular', 'cellular_component', 'GO:0005622', ('71', '84'))	('storage protein', 'molecular_function', 'GO:0045735', ('90', '105'))	('Cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Cancer', 'Disease', (20, 26))	('iron', 'Chemical', 'MESH:D007501', (183, 187))	('nucleus', 'cellular_component', 'GO:0005634', ('134', '141'))	('Cancer', 'Disease', 'MESH:D009369', (20, 26))	('storage', 'biological_process', 'GO:0051235', ('90', '97'))	('FTH1', 'Gene', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('mitochondria', 'cellular_component', 'GO:0005739', ('147', '159'))	('Pseudogenes', 'Var', (5, 16))	('cytoplasm', 'cellular_component', 'GO:0005737', ('123', '132'))	('FTH1', 'Gene', '2495', (0, 4))	('iron', 'Chemical', 'MESH:D007501', (85, 89))
120164	33260500	FTH1 may also physically interact with several signaling elements involved in critical cellular pathways, such as the C-X-C Motif Chemochine Receptor 4 (CXCR4) receptor, expressed in a variety of human malignancies and ALADIN protein (alacrima-acalasia-adrenal insufficiency neurological disorder), whose mutations determine the triple-A syndrome characterized by a deficiency of FTH1 nuclear import; moreover, FTH1 binds, stabilizes, and activates p53 under oxidative stress.	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))	('determine', 'Reg', (315, 324))	('oxidative stress', 'Phenotype', 'HP:0025464', (459, 475))	('nuclear import', 'biological_process', 'GO:0051170', ('385', '399'))	('binds', 'Interaction', (416, 421))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (253, 274))	('alacrima-acalasia-adrenal insufficiency neurological disorder', 'Disease', 'MESH:C536008', (235, 296))	('ALADIN', 'Gene', '8086', (219, 225))	('stabilizes', 'MPA', (423, 433))	('neurological disorder', 'Phenotype', 'HP:0000707', (275, 296))	('p53', 'Gene', '7157', (449, 452))	('activates', 'PosReg', (439, 448))	('protein', 'cellular_component', 'GO:0003675', ('226', '233'))	('malignancies', 'Disease', 'MESH:D009369', (202, 214))	('human', 'Species', '9606', (196, 201))	('FTH1', 'Gene', (380, 384))	('malignancies', 'Disease', (202, 214))	('FTH1', 'Var', (411, 415))	('ALADIN', 'Gene', (219, 225))	('mutations', 'Var', (305, 314))	('triple-A syndrome', 'Disease', (329, 346))	('p53', 'Gene', (449, 452))	('alacrima', 'Phenotype', 'HP:0000522', (235, 243))	('CXCR4', 'molecular_function', 'GO:0038147', ('153', '158'))	('nuclear import', 'MPA', (385, 399))
120166	33260500	Moreover, FTH1 knockdown determines an increased expression of a specific set of onco-miRNAs' activation of a H19/miR-675 axis and severe protein misfolding in K562 erythroleukemia cells, as well as an increased chemoresistance in K562 and SKOV3 cells.	('miR-675', 'Gene', '100033819', (114, 121))	('increased', 'PosReg', (202, 211))	('erythroleukemia', 'Disease', (165, 180))	('K562', 'CellLine', 'CVCL:0004', (231, 235))	('knockdown', 'Var', (15, 24))	('H19', 'Gene', '283120', (110, 113))	('erythroleukemia', 'Disease', 'MESH:D004915', (165, 180))	('H19', 'Gene', (110, 113))	('protein', 'Protein', (138, 145))	('expression', 'MPA', (49, 59))	('FTH1', 'Gene', (10, 14))	('increased', 'PosReg', (39, 48))	('SKOV3', 'CellLine', 'CVCL:0532', (240, 245))	('K562', 'CellLine', 'CVCL:0004', (160, 164))	('chemoresistance', 'CPA', (212, 227))	('miR-675', 'Gene', (114, 121))	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('activation', 'PosReg', (94, 104))
120174	33260500	The FTH1P2 ORF would potentially lead to a protein corresponding to the FTH1 carboxy region (aa 70-182) (Table 1).	('lead to', 'Reg', (33, 40))	('FTH1P2', 'Gene', '2497', (4, 10))	('FTH1P2', 'Gene', (4, 10))	('ORF', 'Var', (11, 14))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('protein', 'Protein', (43, 50))
120199	33260500	It was subsequently shown that FTHL17 has high levels of expression in tumors and low levels in normal somatic tissues; furthermore, the FTHL17 expression can be induced in cancerous cell lines by demethylating the DNA agents 5-aza-2'-deoxycytidine.	('demethylating', 'Var', (197, 210))	('FTHL17', 'Gene', (137, 143))	('cancerous', 'Disease', (173, 182))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('cancerous', 'Disease', 'MESH:D009369', (173, 182))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (226, 248))	('tumors', 'Disease', (71, 77))	('induced', 'Reg', (162, 169))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('DNA', 'cellular_component', 'GO:0005574', ('215', '218'))
120201	33260500	The FTHL17 gene encodes a ferritin without ferroxidase activity for the substitution of the critical Glu62 into Lys that was shown to be sufficient to abolish this activity.	('ferroxidase activity', 'molecular_function', 'GO:0004322', ('43', '63'))	('activity', 'MPA', (164, 172))	('abolish', 'NegReg', (151, 158))	('FTHL17', 'Gene', (4, 10))	('Glu62 into Lys', 'Mutation', 'p.E62K', (101, 115))	('substitution', 'Var', (72, 84))
120213	33260500	showed that the binding of FTH1P3 to LSD1 would be important to recruit the demethylase activity of LSD1 on the promoter regions of the Metalloproteinase inhibitor 3 (TIMP3), thus epigenetically repressing TIMP3 and accelerating the tumorigenesis of NSCLC.	('activity', 'MPA', (88, 96))	('LSD1', 'Gene', (100, 104))	('Metalloproteinase inhibitor 3', 'Gene', '7078', (136, 165))	('Metalloproteinase inhibitor 3', 'Gene', (136, 165))	('tumor', 'Disease', (233, 238))	('LSD1', 'Gene', '23028', (100, 104))	('accelerating', 'PosReg', (216, 228))	('TIMP3', 'Gene', '7078', (167, 172))	('demethylase activity', 'molecular_function', 'GO:0032451', ('76', '96'))	('TIMP3', 'Gene', (167, 172))	('LSD1', 'Gene', (37, 41))	('LSD1', 'Gene', '23028', (37, 41))	('epigenetically', 'Var', (180, 194))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('FTH1P3', 'Gene', (27, 33))	('NSCLC', 'Disease', 'MESH:D002289', (250, 255))	('FTH1P3', 'Gene', '2498', (27, 33))	('binding', 'molecular_function', 'GO:0005488', ('16', '23'))	('repressing', 'PosReg', (195, 205))	('TIMP3', 'Gene', '7078', (206, 211))	('NSCLC', 'Disease', (250, 255))	('TIMP3', 'Gene', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('NSCLC', 'Phenotype', 'HP:0030358', (250, 255))	('Metalloproteinase inhibitor', 'molecular_function', 'GO:0008191', ('136', '163'))	('recruit', 'PosReg', (64, 71))
120225	33260500	Many miRNAs are able to target FTH1, including miR-200b, miR-181a-5p, miR-19b-1-5p, miR-19b-3p, miR-210-3p, miR-362-5p, miR-616-3p, and miR-638..	('miR-210-3p', 'Var', (96, 106))	('miR-200b', 'Gene', '406984', (47, 55))	('miR-362', 'Gene', '574030', (108, 115))	('miR-200b', 'Gene', (47, 55))	('miR-638', 'Gene', '693223', (136, 143))	('miR-362', 'Gene', (108, 115))	('miR-19b-1', 'Gene', '406980', (70, 79))	('miR-19b-1', 'Gene', (70, 79))	('miR-638', 'Gene', (136, 143))	('miR-19b-3p', 'Var', (84, 94))	('FTH1', 'Gene', (31, 35))
120226	33260500	Indeed, the FTH1 gene:pseudogenes network has been reported to be relevant in prostate cancer, possibly by affecting iron balance.	('FTH1', 'Gene', (12, 16))	('prostate cancer', 'Phenotype', 'HP:0012125', (78, 93))	('iron balance', 'MPA', (117, 129))	('prostate cancer', 'Disease', (78, 93))	('iron', 'Chemical', 'MESH:D007501', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('affecting', 'Reg', (107, 116))	('pseudogenes', 'Var', (22, 33))	('prostate cancer', 'Disease', 'MESH:D011471', (78, 93))
120227	33260500	By miRNA pulldown experiments, FTH1 and some of its pseudogenes (FTH1P2, FTH1P8, FTH1P11, and FTH1P16) were identified as targets for miR-181a-5p, miR-19b-1-5p, miR-19b-3p, miR-210-3p, miR-362-5p, miR-616-3p, and miR-638, which also showed ceRNA activity.	('miR-362', 'Gene', '574030', (185, 192))	('miR-616-3p', 'Var', (197, 207))	('FTH1P8', 'Gene', (73, 79))	('miR-362', 'Gene', (185, 192))	('miR-19b-1', 'Gene', '406980', (147, 156))	('FTH1P8', 'Gene', '2501', (73, 79))	('miR-19b-3p', 'Var', (161, 171))	('miR-19b-1', 'Gene', (147, 156))	('FTH1P2', 'Gene', (65, 71))	('FTH1P16', 'Gene', '2508', (94, 101))	('FTH1P11', 'Gene', '2503', (81, 88))	('FTH1P2', 'Gene', '2497', (65, 71))	('miR-210-3p', 'Var', (173, 183))	('FTH1P16', 'Gene', (94, 101))	('FTH1P11', 'Gene', (81, 88))	('miR-638', 'Gene', '693223', (213, 220))	('miR-638', 'Gene', (213, 220))	('miR-181a-5p', 'Var', (134, 145))
120290	32825562	For that reason, we reviewed this challenging topic considering clinical and molecular perspectives, including uncommon CMs:not associated with classical V600E/K BRAF mutations:malignant mucosal and uveal melanomas, and some unusual independent entities, such as amelanotic, desmoplastic, or spitzoid melanomas.	('V600E', 'SUBSTITUTION', 'None', (154, 159))	('desmoplastic', 'Disease', (275, 287))	('CM', 'Phenotype', 'HP:0012056', (120, 122))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (292, 310))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('melanomas', 'Phenotype', 'HP:0002861', (205, 214))	('melanomas', 'Phenotype', 'HP:0002861', (301, 310))	('spitzoid melanomas', 'Disease', (292, 310))	('uveal melanomas', 'Disease', (199, 214))	('uveal melanomas', 'Phenotype', 'HP:0007716', (199, 214))	('melanoma', 'Phenotype', 'HP:0002861', (301, 309))	('BRAF', 'Gene', '673', (162, 166))	('V600E', 'Var', (154, 159))	('uveal melanomas', 'Disease', 'MESH:C536494', (199, 214))	('amelanotic', 'Disease', (263, 273))	('BRAF', 'Gene', (162, 166))
120297	32825562	Rare melanoma variants usually account for less than 5% of all melanomas, and often are associated with a poor prognosis.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('variants', 'Var', (14, 22))	('melanoma', 'Disease', (5, 13))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('melanomas', 'Disease', (63, 72))	('melanomas', 'Disease', 'MESH:D008545', (63, 72))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))	('melanoma', 'Disease', (63, 71))
120302	32825562	Between 40% and 60% of CMs harbor activating BRAF mutations, characterized by the substitution of the valine residue at position 600 by glutamate (V600E) or lysine (V600K), representing 70-90% and 10-20% of somatic alterations of this gene, respectively.	('V600K', 'Mutation', 'rs121913227', (165, 170))	('V600E', 'Var', (147, 152))	('valine residue at position 600 by glutamate', 'Mutation', 'rs113488022', (102, 145))	('activating', 'PosReg', (34, 44))	('CM', 'Phenotype', 'HP:0012056', (23, 25))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('V600K', 'Var', (165, 170))	('lysine', 'Chemical', 'MESH:D008239', (157, 163))	('V600E', 'Mutation', 'rs113488022', (147, 152))
120304	32825562	A dual MEK/BRAF blockade in patients harboring BRAF V600E/K mutant CMs has resulted in significant improvements in the overall survival (OS) in the adjuvant and advanced settings.	('MEK', 'Gene', (7, 10))	('BRAF blockade', 'Disease', (11, 24))	('MEK', 'Gene', '5609', (7, 10))	('V600E', 'Var', (52, 57))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('V600E', 'SUBSTITUTION', 'None', (52, 57))	('improvements', 'PosReg', (99, 111))	('overall survival', 'MPA', (119, 135))	('BRAF blockade', 'Disease', 'MESH:D055191', (11, 24))	('BRAF', 'Gene', '673', (11, 15))	('patients', 'Species', '9606', (28, 36))	('CM', 'Phenotype', 'HP:0012056', (67, 69))	('BRAF', 'Gene', (11, 15))	('men', 'Species', '9606', (106, 109))
120306	32825562	In light of current evidence, immune checkpoint inhibitors are considered a standard treatment for patients with CM, and BRAF/MEK inhibitors are recommended in patients with melanoma and BRAF V600E/K mutations.	('BRAF', 'Gene', (121, 125))	('patients', 'Species', '9606', (160, 168))	('V600E', 'SUBSTITUTION', 'None', (192, 197))	('men', 'Species', '9606', (90, 93))	('BRAF', 'Gene', '673', (187, 191))	('MEK', 'Gene', (126, 129))	('CM', 'Phenotype', 'HP:0012056', (113, 115))	('MEK', 'Gene', '5609', (126, 129))	('patients', 'Species', '9606', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Disease', (174, 182))	('men', 'Species', '9606', (150, 153))	('BRAF', 'Gene', '673', (121, 125))	('V600E', 'Var', (192, 197))	('BRAF', 'Gene', (187, 191))
120309	32825562	Tumors with BRAF V600E/K mutations will not be addressed in our review due to the fact that treatment strategies are based on phase 3 clinical trials that had evaluated this population.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('V600E', 'Var', (17, 22))	('V600E', 'SUBSTITUTION', 'None', (17, 22))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('men', 'Species', '9606', (97, 100))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
120311	32825562	NRAS gene mutations contribute to the activation of mitogen-activated protein kinase (MAPK) pathway signaling, inducing melanocytogenesis, and increasing cell proliferation and survival.	('survival', 'CPA', (177, 185))	('cell proliferation', 'CPA', (154, 172))	('inducing', 'PosReg', (111, 119))	('MAPK', 'molecular_function', 'GO:0004707', ('86', '90'))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('increasing', 'PosReg', (143, 153))	('melanocytogenesis', 'MPA', (120, 137))	('NRAS', 'Gene', (0, 4))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('activation', 'PosReg', (38, 48))	('mutations', 'Var', (10, 19))	('cell proliferation', 'biological_process', 'GO:0008283', ('154', '172'))	('NRAS', 'Gene', '4893', (0, 4))
120312	32825562	It is estimated that up to 25% of CMs harbor NRAS gene alterations, 80% of these being Q61R, Q61K, and Q61L point mutations.	('Q61L', 'Mutation', 'rs11554290', (103, 107))	('Q61L', 'Var', (103, 107))	('CM', 'Phenotype', 'HP:0012056', (34, 36))	('Q61R', 'Var', (87, 91))	('NRAS', 'Gene', (45, 49))	('Q61R', 'Mutation', 'rs11554290', (87, 91))	('Q61K', 'Mutation', 'rs121913254', (93, 97))	('NRAS', 'Gene', '4893', (45, 49))	('Q61K', 'Var', (93, 97))
120313	32825562	Particularly, NRAS mutations were found in 21% of superficial spreading, 31% of nodular and 8% of acral melanoma subtypes, and they are frequent among patients older than 55 years.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('NRAS', 'Gene', '4893', (14, 18))	('acral melanoma', 'Phenotype', 'HP:0012060', (98, 112))	('acral melanoma', 'Disease', (98, 112))	('mutations', 'Var', (19, 28))	('patients', 'Species', '9606', (151, 159))	('superficial spreading', 'Disease', (50, 71))	('found', 'Reg', (34, 39))	('nodular', 'Disease', (80, 87))	('acral melanoma', 'Disease', 'MESH:D008545', (98, 112))	('NRAS', 'Gene', (14, 18))
120317	32825562	The authors found that the response rates among patients with and without NRAS mutations were similar (31% vs. 26% for the anti-PD-1/anti-CTLA-4 combination and 21% vs. 13% for the anti-PD-1 monotherapy, respectively).	('CTLA-4', 'Gene', (138, 144))	('CTLA-4', 'Gene', '1493', (138, 144))	('NRAS', 'Gene', (74, 78))	('NRAS', 'Gene', '4893', (74, 78))	('PD-1', 'Gene', (128, 132))	('PD-1', 'Gene', '5133', (128, 132))	('PD-1', 'Gene', (186, 190))	('patients', 'Species', '9606', (48, 56))	('PD-1', 'Gene', '5133', (186, 190))	('mutations', 'Var', (79, 88))
120318	32825562	Interestingly, a better response rate with immunotherapy combination was observed in patients with Q61L NRAS mutations.	('NRAS', 'Gene', '4893', (104, 108))	('patients', 'Species', '9606', (85, 93))	('Q61L', 'Mutation', 'rs11554290', (99, 103))	('NRAS', 'Gene', (104, 108))	('Q61L', 'Var', (99, 103))
120319	32825562	A trend of superior PFS was also evidenced in subjects with a Q61L NRAS-mutant disease in another retrospective analysis.	('Q61L', 'Mutation', 'rs11554290', (62, 66))	('Q61L', 'Var', (62, 66))	('PFS', 'MPA', (20, 23))	('NRAS', 'Gene', (67, 71))	('NRAS', 'Gene', '4893', (67, 71))	('superior', 'PosReg', (11, 19))
120320	32825562	With the current evidence, the combination of immune checkpoint inhibitors is the common first treatment approach for patients with tumors harboring this mutation.	('men', 'Species', '9606', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('mutation', 'Var', (154, 162))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (132, 138))	('patients', 'Species', '9606', (118, 126))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
120325	32825562	NF1 mutations are particularly frequent in patients of an older age.	('patients', 'Species', '9606', (43, 51))	('frequent', 'Reg', (31, 39))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('NF1', 'Gene', '4763', (0, 3))
120326	32825562	Additionally, the associated clinical features include chronic sun exposure, desmoplastic melanoma, UV mutational signatures, and a high tumoral mutation burden.	('mutational signatures', 'Var', (103, 124))	('tumoral', 'Disease', 'MESH:D009369', (137, 144))	('tumoral', 'Disease', (137, 144))	('desmoplastic melanoma', 'Disease', 'MESH:D008545', (77, 98))	('desmoplastic melanoma', 'Disease', (77, 98))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
120328	32825562	Importantly, Garman and collaborators, after characterizing 30 NF1 mutant tumor biopsies, patient-derived xenografts and cell lines, documented the coexistence of non-V600E BRAF, RAS, and other characteristic MAP kinase-associated genes mutations in 87% of the analyzed cases.	('BRAF', 'Gene', '673', (173, 177))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('BRAF', 'Gene', (173, 177))	('V600E', 'Mutation', 'rs113488022', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('MAP', 'molecular_function', 'GO:0004239', ('209', '212'))	('non-V600E', 'Var', (163, 172))	('patient', 'Species', '9606', (90, 97))	('tumor', 'Disease', (74, 79))	('mutant', 'Var', (67, 73))	('men', 'Species', '9606', (137, 140))	('RAS', 'Disease', (179, 182))	('NF1', 'Gene', (63, 66))	('NF1', 'Gene', '4763', (63, 66))
120329	32825562	This finding is in accordance with functional studies that documented that not all NF1 mutant cell lines were sensitive to MEK inhibitors.	('NF1', 'Gene', '4763', (83, 86))	('men', 'Species', '9606', (63, 66))	('MEK', 'Gene', (123, 126))	('MEK', 'Gene', '5609', (123, 126))	('mutant', 'Var', (87, 93))	('NF1', 'Gene', (83, 86))
120330	32825562	Therefore, a further characterization of the NF1 mutant subgroup is needed, considering the occurrence of concurrent mutations.	('NF1', 'Gene', '4763', (45, 48))	('mutant', 'Var', (49, 55))	('NF1', 'Gene', (45, 48))
120332	32825562	In a study performed by Eroglu et al., among 17 evaluable patients with desmoplastic melanoma, 14 harbored NF1 alterations.	('desmoplastic melanoma', 'Disease', (72, 93))	('NF1', 'Gene', '4763', (107, 110))	('harbored', 'Reg', (98, 106))	('alterations', 'Var', (111, 122))	('desmoplastic melanoma', 'Disease', 'MESH:D008545', (72, 93))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('patients', 'Species', '9606', (58, 66))	('NF1', 'Gene', (107, 110))
120333	32825562	Considering the high overall response rate (ORR) observed in this histologic subgroup, a benefit of checkpoint inhibitors is expected in patients with CM and NF1 mutations and is the principal treatment option for this population.	('mutations', 'Var', (162, 171))	('subgroup, a', 'Species', '167158', (77, 88))	('CM', 'Phenotype', 'HP:0012056', (151, 153))	('NF1', 'Gene', (158, 161))	('patients', 'Species', '9606', (137, 145))	('NF1', 'Gene', '4763', (158, 161))	('men', 'Species', '9606', (198, 201))	('benefit', 'PosReg', (89, 96))
120334	32825562	Pivotal studies that determined the approval of available target combinations did not include subjects with gene alterations, apart from V600E and V600K.	('V600K', 'Var', (147, 152))	('V600E', 'Mutation', 'rs113488022', (137, 142))	('V600K', 'Mutation', 'rs121913227', (147, 152))	('V600E', 'Var', (137, 142))
120335	32825562	V600R represents 5-7% of BRAF mutations, constituting the third most frequent alteration.	('BRAF', 'Gene', (25, 29))	('V600R', 'Var', (0, 5))	('V600R', 'Mutation', 'rs121913227', (0, 5))	('BRAF', 'Gene', '673', (25, 29))
120336	32825562	Comparable to patients with melanoma and V600K mutations, V600R alterations are more prevalent in men and older patients.	('melanoma', 'Disease', (28, 36))	('V600R', 'Var', (58, 63))	('V600K', 'Mutation', 'rs121913227', (41, 46))	('patients', 'Species', '9606', (112, 120))	('prevalent', 'Reg', (85, 94))	('men', 'Species', '9606', (98, 101))	('patients', 'Species', '9606', (14, 22))	('V600R', 'Mutation', 'rs121913227', (58, 63))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
120338	32825562	Menzer and colleagues described the results of the largest multicenter retrospective study that included patients with uncommon BRAF mutations.	('patients', 'Species', '9606', (105, 113))	('mutations', 'Var', (133, 142))	('BRAF', 'Gene', (128, 132))	('BRAF', 'Gene', '673', (128, 132))
120339	32825562	Notably, among 26 patients with BRAF V600R mutations, a significant improvement in the median OS (22.9 vs. 7.3 months, p = 0.002), median PFS (8.0 vs. 3.8 months, p = 0.002) and ORR (57 vs. 22%) was observed when MEK inhibitors were administrated together with BRAF inhibitors in comparison to the group that was only assigned to the treatment with BRAF inhibitors.	('BRAF', 'Gene', '673', (32, 36))	('ORR', 'MPA', (178, 181))	('BRAF', 'Gene', '673', (349, 353))	('V600R', 'Mutation', 'rs121913227', (37, 42))	('BRAF', 'Gene', (32, 36))	('MEK', 'Gene', '5609', (213, 216))	('BRAF', 'Gene', (349, 353))	('men', 'Species', '9606', (75, 78))	('improvement', 'PosReg', (68, 79))	('PFS', 'MPA', (138, 141))	('BRAF', 'Gene', '673', (261, 265))	('V600R', 'Var', (37, 42))	('men', 'Species', '9606', (339, 342))	('patients', 'Species', '9606', (18, 26))	('BRAF', 'Gene', (261, 265))	('MEK', 'Gene', (213, 216))
120341	32825562	According to Menzer and colleagues' study, a tumoral response with BRAF or BRAF/MEK inhibition was observed in patients that harbored BRAF V600D (four of five) and V600M mutations (one of two).	('V600M mutations', 'Var', (164, 179))	('BRAF', 'Gene', '673', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('V600M', 'Mutation', 'rs121913378', (164, 169))	('V600D', 'Var', (139, 144))	('BRAF', 'Gene', '673', (75, 79))	('BRAF', 'Gene', (67, 71))	('BRAF', 'Gene', '673', (134, 138))	('tumoral', 'Disease', (45, 52))	('BRAF', 'Gene', (75, 79))	('BRAF', 'Gene', (134, 138))	('tumoral', 'Disease', 'MESH:D009369', (45, 52))	('V600D', 'Mutation', 'rs121913377', (139, 144))	('MEK', 'Gene', (80, 83))	('MEK', 'Gene', '5609', (80, 83))	('patients', 'Species', '9606', (111, 119))
120342	32825562	Although further study is needed, these results support that BRAF and MEK inhibition is an effective strategy for patients with melanoma and uncommon codon 600 BRAF mutations.	('BRAF', 'Gene', (160, 164))	('BRAF', 'Gene', '673', (160, 164))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('BRAF', 'Gene', '673', (61, 65))	('codon 600', 'Var', (150, 159))	('MEK', 'Gene', (70, 73))	('BRAF', 'Gene', (61, 65))	('MEK', 'Gene', '5609', (70, 73))	('patients', 'Species', '9606', (114, 122))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
120343	32825562	Unlike non-small cell lung cancer, BRAF mutations that do not affect codon 600 (non-600) are particularly infrequent in melanoma.	('lung cancer', 'Disease', (22, 33))	('BRAF', 'Gene', (35, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (7, 33))	('lung cancer', 'Disease', 'MESH:D008175', (22, 33))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (11, 33))	('mutations', 'Var', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('BRAF', 'Gene', '673', (35, 39))
120345	32825562	In a recent report published by Lokhandwala and collaborators, class II mutations (RAS-independent kinase-activating dimers not involving codon 600), such as L597Q/R/S, K601E and G469A/R/V, represented 7.4% of cases with BRAF mutations.	('BRAF', 'Gene', (221, 225))	('L597Q', 'Var', (158, 163))	('L597Q', 'SUBSTITUTION', 'None', (158, 163))	('K601E', 'Mutation', 'rs121913364', (169, 174))	('G469A', 'SUBSTITUTION', 'None', (179, 184))	('K601E', 'Var', (169, 174))	('G469A', 'Var', (179, 184))	('BRAF', 'Gene', '673', (221, 225))
120347	32825562	Examples of the latter include G466A/E/V, S467L, N581I, and D594E/G/N.	('D594E', 'SUBSTITUTION', 'None', (60, 65))	('N581I', 'Mutation', 'p.N581I', (49, 54))	('D594E', 'Var', (60, 65))	('G466A', 'SUBSTITUTION', 'None', (31, 36))	('S467L', 'Mutation', 'rs867748453', (42, 47))	('S467L', 'Var', (42, 47))	('N581I', 'Var', (49, 54))	('G466A', 'Var', (31, 36))
120348	32825562	Menzer and colleagues observed that only two out of nine patients with codon 597 and one out of four patients with K601E mutations presented tumoral responses with dual inhibition.	('patients', 'Species', '9606', (101, 109))	('K601E', 'Mutation', 'rs121913364', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('patients', 'Species', '9606', (57, 65))	('K601E', 'Var', (115, 120))	('tumoral', 'Disease', (141, 148))	('tumoral', 'Disease', 'MESH:D009369', (141, 148))	('codon 597', 'Var', (71, 80))
120349	32825562	Contrastingly, two of the three patients with codon 469 alterations achieved a tumor response.	('codon 469 alterations', 'Var', (46, 67))	('patients', 'Species', '9606', (32, 40))	('achieved', 'PosReg', (68, 76))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
120356	32825562	Gene fusions and chromosomic translocations were also evidenced in patients with acral melanoma.	('patients', 'Species', '9606', (67, 75))	('Gene fusions', 'Var', (0, 12))	('acral melanoma', 'Phenotype', 'HP:0012060', (81, 95))	('acral melanoma', 'Disease', (81, 95))	('acral melanoma', 'Disease', 'MESH:D008545', (81, 95))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
120363	32825562	It has been classically estimated that around 2-8% of melanomas that arise within cumulative sun-damaged skin exhibit KIT gene mutations.	('KIT', 'Gene', '3815', (118, 121))	('sun-damaged', 'Phenotype', 'HP:0000992', (93, 104))	('KIT', 'molecular_function', 'GO:0005020', ('118', '121'))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('KIT', 'Gene', (118, 121))	('melanomas', 'Disease', 'MESH:D008545', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('mutations', 'Var', (127, 136))	('melanomas', 'Disease', (54, 63))
120368	32825562	Interestingly, AM is commonly observed in patients with melanocortin 1 receptor gene (MC1R) genotypes linked to particular phenotypes, including red hair color.	('red hair', 'Phenotype', 'HP:0002297', (145, 153))	('melanocortin 1 receptor', 'Gene', '4157', (56, 79))	('melanocortin 1 receptor', 'Gene', (56, 79))	('MC1R', 'Gene', '4157', (86, 90))	('MC1R', 'Gene', (86, 90))	('genotypes', 'Var', (92, 101))	('patients', 'Species', '9606', (42, 50))	('red hair color', 'Disease', (145, 159))
120371	32825562	Notably, germline mutations in genes for MC1R, MITF, and p14ARF may also result in AM.	('p14ARF', 'Gene', (57, 63))	('MITF', 'Gene', '4286', (47, 51))	('MITF', 'Gene', (47, 51))	('MC1R', 'Gene', (41, 45))	('p14ARF', 'Gene', '1029', (57, 63))	('result in', 'Reg', (73, 82))	('germline mutations', 'Var', (9, 27))	('MC1R', 'Gene', '4157', (41, 45))
120373	32825562	found a BRAF V600E and KIT mutations rate of 70.3% and 12.1%, respectively.	('V600E', 'Var', (13, 18))	('BRAF', 'Gene', '673', (8, 12))	('KIT', 'Gene', '3815', (23, 26))	('BRAF', 'Gene', (8, 12))	('KIT', 'Gene', (23, 26))	('V600E', 'Mutation', 'rs113488022', (13, 18))	('KIT', 'molecular_function', 'GO:0005020', ('23', '26'))
120375	32825562	Considering these findings, BRAF mutation analysis in AM may be considered as a potentially valuable diagnostic tool.	('BRAF', 'Gene', (28, 32))	('BRAF', 'Gene', '673', (28, 32))	('mutation analysis', 'Var', (33, 50))
120376	32825562	As with other CM variants, treatment strategies include immune checkpoint inhibitors and the combination of BRAF/MEK inhibitors in the cases where BRAF mutations are present.	('combination', 'Interaction', (93, 104))	('MEK', 'Gene', '5609', (113, 116))	('mutations', 'Var', (152, 161))	('men', 'Species', '9606', (32, 35))	('CM', 'Phenotype', 'HP:0012056', (14, 16))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('BRAF', 'Gene', '673', (108, 112))	('BRAF', 'Gene', (108, 112))	('MEK', 'Gene', (113, 116))
120383	32825562	Hotspot mutations in BRAF or NRAS are not common in DM (0-6%).	('NRAS', 'Gene', (29, 33))	('BRAF', 'Gene', '673', (21, 25))	('mutations', 'Var', (8, 17))	('NRAS', 'Gene', '4893', (29, 33))	('DM', 'Disease', 'MESH:D009223', (52, 54))	('BRAF', 'Gene', (21, 25))
120385	32825562	Amplifications in EGFR, CDK4, MDM2, TERT, MAP3K1, MET, NFKBIE, and YAP1 are also commonly found in this melanoma subtype.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('EGFR', 'molecular_function', 'GO:0005006', ('18', '22'))	('MDM2', 'Gene', (30, 34))	('YAP1', 'Gene', (67, 71))	('NFKBIE', 'Gene', '4794', (55, 61))	('TERT', 'Gene', (36, 40))	('NFKBIE', 'Gene', (55, 61))	('found', 'Reg', (90, 95))	('TERT', 'Gene', '7015', (36, 40))	('MDM2', 'Gene', '4193', (30, 34))	('EGFR', 'Gene', (18, 22))	('Amplifications', 'Var', (0, 14))	('MET', 'Gene', '79811', (50, 53))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('YAP1', 'Gene', '10413', (67, 71))	('CDK4', 'Gene', (24, 28))	('MAP3K', 'molecular_function', 'GO:0004709', ('42', '47'))	('EGFR', 'Gene', '1956', (18, 22))	('CDK', 'molecular_function', 'GO:0004693', ('24', '27'))	('MAP3K1', 'Gene', (42, 48))	('CDK4', 'Gene', '1019', (24, 28))	('MAP3K1', 'Gene', '4214', (42, 48))	('MET', 'Gene', (50, 53))
120394	32825562	Spitz melanomas, according to the WHO 2018 classification, are defined by the presence of specific genetic hallmarks, such as HRAS mutations or fusions in activating genes, including BRAF, NTRK1, NTRK3, ROS1, ALK and MAP3K8.	('MAP3K8', 'Gene', (217, 223))	('HRAS', 'Gene', (126, 130))	('Spitz melanomas', 'Disease', 'MESH:D018332', (0, 15))	('ROS1', 'Gene', '6098', (203, 207))	('ALK', 'Gene', '238', (209, 212))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('ALK', 'Gene', (209, 212))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('MAP3K8', 'Gene', '1326', (217, 223))	('NTRK3', 'Gene', '4916', (196, 201))	('NTRK3', 'Gene', (196, 201))	('ROS1', 'Gene', (203, 207))	('NTRK1', 'Gene', '4914', (189, 194))	('NTRK1', 'Gene', (189, 194))	('mutations', 'Var', (131, 140))	('MAP3K', 'molecular_function', 'GO:0004709', ('217', '222'))	('BRAF', 'Gene', '673', (183, 187))	('Spitz melanomas', 'Disease', (0, 15))	('fusions', 'Var', (144, 151))	('BRAF', 'Gene', (183, 187))	('HRAS', 'Gene', '3265', (126, 130))
120399	32825562	A recent presentation highlighted that an 11-year-old patient with this tumor subtype and MAP3K8 fusion had a non-lasting response with the MEK inhibitor trametinib.	('non-lasting', 'MPA', (110, 121))	('MAP3K8', 'Gene', '1326', (90, 96))	('patient', 'Species', '9606', (54, 61))	('MEK', 'Gene', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('trametinib', 'Chemical', 'MESH:C560077', (154, 164))	('MAP3K', 'molecular_function', 'GO:0004709', ('90', '95'))	('tumor', 'Disease', (72, 77))	('MEK', 'Gene', '5609', (140, 143))	('MAP3K8', 'Gene', (90, 96))	('fusion', 'Var', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
120405	32825562	The frequency of BRAF mutations in ALM is estimated to be between 13% and 34%.	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (17, 21))	('ALM', 'Phenotype', 'HP:0012060', (35, 38))	('mutations', 'Var', (22, 31))
120406	32825562	KIT mutations and/or amplifications are relatively more common and are present in approximately 9% to 21% of cases.	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('amplifications', 'Var', (21, 35))	('KIT', 'Gene', '3815', (0, 3))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))
120409	32825562	Remarkably, 9-41% of ALMs carry activating mutations in TERT promoters.	('mutations', 'Var', (43, 52))	('ALM', 'Phenotype', 'HP:0012060', (21, 24))	('TERT', 'Gene', (56, 60))	('activating', 'PosReg', (32, 42))	('TERT', 'Gene', '7015', (56, 60))
120410	32825562	Although point mutations cause TERT deregulation in UV-exposed melanomas, about 45% of ALMs have TERT copy number gains.	('TERT', 'Gene', '7015', (97, 101))	('ALM', 'Phenotype', 'HP:0012060', (87, 90))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanomas', 'Disease', (63, 72))	('TERT', 'Gene', (97, 101))	('TERT', 'Gene', (31, 35))	('TERT', 'Gene', '7015', (31, 35))	('melanomas', 'Disease', 'MESH:D008545', (63, 72))	('ALMs', 'Disease', (87, 91))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))	('point mutations', 'Var', (9, 24))
120416	32825562	It should be highlighted that the NCCN guidelines describe that KIT inhibitors may be offered in patients with melanoma and activating KIT mutations.	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('KIT', 'Gene', '3815', (135, 138))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('KIT', 'molecular_function', 'GO:0005020', ('135', '138'))	('mutations', 'Var', (139, 148))	('KIT', 'Gene', (135, 138))	('KIT', 'Gene', '3815', (64, 67))	('KIT', 'molecular_function', 'GO:0005020', ('64', '67'))	('activating', 'PosReg', (124, 134))	('KIT', 'Gene', (64, 67))	('patients', 'Species', '9606', (97, 105))
120425	32825562	Particular alterations in the KIT and MAPK pathways should be specially addressed in this rare tumor due to the fact that they have led to the development of target therapies (Figure 1).	('alterations', 'Var', (11, 22))	('KIT', 'molecular_function', 'GO:0005020', ('30', '33'))	('MAPK pathways', 'Pathway', (38, 51))	('KIT', 'Gene', '3815', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('KIT', 'Gene', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('men', 'Species', '9606', (150, 153))	('tumor', 'Disease', (95, 100))	('MAPK', 'molecular_function', 'GO:0004707', ('38', '42'))
120426	32825562	BRAF mutations are present in MM but at a lower frequency (6-12%) compared to CM.	('CM', 'Phenotype', 'HP:0012056', (78, 80))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('MM', 'Phenotype', 'HP:0002861', (30, 32))
120427	32825562	In a whole-genome sequencing analysis of 67 MM samples performed by Newell et al., BRAF mutations were most commonly found in the protein tyrosine kinase domain, with V600E, V600K, and V600R being the most common BRAF mutations.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('MM', 'Phenotype', 'HP:0002861', (44, 46))	('V600K', 'Mutation', 'rs121913227', (174, 179))	('V600R', 'Var', (185, 190))	('mutations', 'Var', (88, 97))	('V600E', 'Mutation', 'rs113488022', (167, 172))	('BRAF', 'Gene', (213, 217))	('BRAF', 'Gene', '673', (213, 217))	('BRAF', 'Gene', '673', (83, 87))	('V600E', 'Var', (167, 172))	('V600R', 'Mutation', 'rs121913227', (185, 190))	('V600K', 'Var', (174, 179))	('found', 'Reg', (117, 122))	('BRAF', 'Gene', (83, 87))
120430	32825562	In a small cohort of 10 patients with metastatic or unresectable BRAF V600E-mutant MM, vemurafenib achieved a 40% ORR and 90% disease control rate (DCR).	('disease control', 'CPA', (126, 141))	('MM', 'Phenotype', 'HP:0002861', (83, 85))	('V600E-mutant', 'Var', (70, 82))	('vemurafenib', 'Chemical', 'MESH:D000077484', (87, 98))	('BRAF', 'Gene', '673', (65, 69))	('V600E', 'Mutation', 'rs113488022', (70, 75))	('patients', 'Species', '9606', (24, 32))	('BRAF', 'Gene', (65, 69))
120434	32825562	Its activation through dimerization regulates multiple downstream signaling pathways, including MAPK and AKT.	('AKT', 'Gene', '207', (105, 108))	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('regulates', 'Reg', (36, 45))	('dimerization', 'Var', (23, 35))	('MAPK', 'molecular_function', 'GO:0004707', ('96', '100'))	('AKT', 'Gene', (105, 108))	('activation', 'PosReg', (4, 14))	('MAPK', 'Pathway', (96, 100))
120435	32825562	KIT mutations, most commonly in exon 11 and 13, were found at a rate of 13-18% in MM.	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('KIT', 'Gene', '3815', (0, 3))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))	('MM', 'Phenotype', 'HP:0002861', (82, 84))
120436	32825562	Of note, KIT mutations are especially prevalent in vulvovaginal and anorectal localizations.	('KIT', 'Gene', '3815', (9, 12))	('KIT', 'Gene', (9, 12))	('KIT', 'molecular_function', 'GO:0005020', ('9', '12'))	('vulvovaginal', 'Disease', (51, 63))	('prevalent', 'Reg', (38, 47))	('mutations', 'Var', (13, 22))	('anorectal', 'Disease', (68, 77))
120437	32825562	have evidenced a worse survival outcome in 66 MM patients with KIT mutations, this finding was not replicated by several other studies.	('worse', 'NegReg', (17, 22))	('mutations', 'Var', (67, 76))	('survival', 'MPA', (23, 31))	('KIT', 'Gene', '3815', (63, 66))	('patients', 'Species', '9606', (49, 57))	('MM', 'Phenotype', 'HP:0002861', (46, 48))	('KIT', 'molecular_function', 'GO:0005020', ('63', '66'))	('KIT', 'Gene', (63, 66))
120440	32825562	A single-group, open-label, phase 2 trial conducted by Carvajal et al., included 28 imatinib mesylate-treated patients with different subtypes of melanomas and KIT mutations or amplifications.	('melanomas', 'Disease', 'MESH:D008545', (146, 155))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanomas', 'Phenotype', 'HP:0002861', (146, 155))	('KIT', 'Gene', '3815', (160, 163))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (84, 101))	('KIT', 'Gene', (160, 163))	('KIT', 'molecular_function', 'GO:0005020', ('160', '163'))	('melanomas', 'Disease', (146, 155))	('amplifications', 'Var', (177, 191))	('mutations', 'Var', (164, 173))	('patients', 'Species', '9606', (110, 118))
120442	32825562	included 17 patients suffering from metastatic MM harboring mutationally activated or amplified KIT and treated with imatinib mesylate.	('MM', 'Phenotype', 'HP:0002861', (47, 49))	('patients', 'Species', '9606', (12, 20))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (117, 134))	('metastatic MM', 'Disease', (36, 49))	('mutationally activated', 'Var', (60, 82))	('KIT', 'molecular_function', 'GO:0005020', ('96', '99'))	('KIT', 'Gene', '3815', (96, 99))	('KIT', 'Gene', (96, 99))
120443	32825562	Interestingly, the ORR among patients with KIT mutations (exon 11, 13, and 17) was 64% (7/11).	('patients', 'Species', '9606', (29, 37))	('KIT', 'Gene', '3815', (43, 46))	('mutations', 'Var', (47, 56))	('KIT', 'Gene', (43, 46))	('KIT', 'molecular_function', 'GO:0005020', ('43', '46'))
120448	32825562	These considerations support the development of clinical trials that evaluate KIT inhibitors along with other agents that target different signaling pathways, such as AKT, mTOR, and STAT3 inhibitors.	('AKT', 'Gene', (167, 170))	('STAT3', 'Gene', (182, 187))	('mTOR', 'Gene', (172, 176))	('KIT', 'Gene', '3815', (78, 81))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('inhibitors', 'Var', (82, 92))	('AKT', 'Gene', '207', (167, 170))	('KIT', 'Gene', (78, 81))	('men', 'Species', '9606', (40, 43))	('STAT3', 'Gene', '6774', (182, 187))	('KIT', 'molecular_function', 'GO:0005020', ('78', '81'))	('mTOR', 'Gene', '2475', (172, 176))
120451	32825562	NRAS Q61 mutations occur at a lower rate in this population, which may be explained by the association between this particular mutation and UV exposure.	('mutations', 'Var', (9, 18))	('NRAS', 'Gene', '4893', (0, 4))	('NRAS', 'Gene', (0, 4))
120453	32825562	SPRED1 loss is reported to co-occur in 30% of MMs with KIT mutations.	('KIT', 'Gene', (55, 58))	('MMs', 'Disease', (46, 49))	('loss', 'NegReg', (7, 11))	('SPRED1', 'Gene', '161742', (0, 6))	('SPRED1', 'Gene', (0, 6))	('mutations', 'Var', (59, 68))	('KIT', 'Gene', '3815', (55, 58))	('MM', 'Phenotype', 'HP:0002861', (46, 48))	('KIT', 'molecular_function', 'GO:0005020', ('55', '58'))
120458	32825562	Other potential drivers, such as NF1 and GNAQ/GNA11 mutations, have been described in 7-22% and 9.5% of patients with MM, respectively.	('mutations', 'Var', (52, 61))	('described', 'Reg', (73, 82))	('NF1', 'Gene', (33, 36))	('NF1', 'Gene', '4763', (33, 36))	('MM', 'Phenotype', 'HP:0002861', (118, 120))	('GNAQ/GNA11', 'Gene', (41, 51))	('patients', 'Species', '9606', (104, 112))
120459	32825562	Interestingly, tumors with NF1 alterations have shown to be more resistant to BRAF inhibitors in preclinical models.	('alterations', 'Var', (31, 42))	('resistant', 'MPA', (65, 74))	('BRAF', 'Gene', '673', (78, 82))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('BRAF', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('NF1', 'Gene', (27, 30))	('NF1', 'Gene', '4763', (27, 30))	('tumors', 'Disease', (15, 21))
120460	32825562	Finally, mutations in SF3B1 represent 35% of MMs, most commonly found in anorectal and vulvovaginal localizations.	('SF3B1', 'Gene', '23451', (22, 27))	('MM', 'Phenotype', 'HP:0002861', (45, 47))	('mutations', 'Var', (9, 18))	('found', 'Reg', (64, 69))	('SF3B1', 'Gene', (22, 27))	('anorectal', 'Disease', (73, 82))
120461	32825562	While clinical implications of this alteration are still not fully elucidated, a meta-analysis including 53 cases with SF3B1 mutations suggested a trend to better the OS.	('SF3B1', 'Gene', (119, 124))	('mutations', 'Var', (125, 134))	('SF3B1', 'Gene', '23451', (119, 124))	('better', 'PosReg', (156, 162))
120492	32825562	Instead, they show a specific somatic mutation profile characterized by oncogenic mutually-exclusive mutations in either GNAQ, GNA11, or sporadically in PLCB4 or CYSLTR2 genes.	('mutations', 'Var', (101, 110))	('PLCB4', 'Gene', (153, 158))	('CYSLTR2', 'Gene', '57105', (162, 169))	('CYSLTR2', 'Gene', (162, 169))	('GNA11', 'Gene', (127, 132))	('PLCB4', 'Gene', '5332', (153, 158))	('GNAQ', 'Gene', (121, 125))
120493	32825562	These mutations lead to Galphaq pathway activation with the subsequent stimulation of the MAPK and beta-catenin pathways, as well as the transcriptional co-activator Yes-associated protein 1 (YAP1) through the Trio-Rho/Rac signaling circuit.	('protein', 'cellular_component', 'GO:0003675', ('181', '188'))	('signaling', 'biological_process', 'GO:0023052', ('223', '232'))	('Yes-associated protein 1', 'Gene', (166, 190))	('beta-catenin', 'Gene', '1499', (99, 111))	('Galphaq', 'Gene', (24, 31))	('Galphaq', 'Gene', '2776', (24, 31))	('MAPK', 'molecular_function', 'GO:0004707', ('90', '94'))	('YAP1', 'Gene', '10413', (192, 196))	('activation', 'PosReg', (40, 50))	('beta-catenin', 'Gene', (99, 111))	('Yes-associated protein 1', 'Gene', '10413', (166, 190))	('stimulation', 'PosReg', (71, 82))	('mutations', 'Var', (6, 15))	('YAP1', 'Gene', (192, 196))
120494	32825562	Mutations in GNAQ and GNA11 genes are considered an early development event and are present in ~85% of all UMs.	('UM', 'Phenotype', 'HP:0007716', (107, 109))	('GNA11', 'Gene', (22, 27))	('men', 'Species', '9606', (65, 68))	('GNAQ', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))
3731	32825562	Hotspot GNAQ p.Q209 mutations are found in 45% of primary UM and 22% of metastases, while GNA11 p.Q209 mutations are found in 32% of primary tumors and 57% of UM metastases.	('GNA11', 'Gene', (90, 95))	('metastases', 'Disease', (72, 82))	('metastases', 'Disease', (162, 172))	('UM', 'Phenotype', 'HP:0007716', (58, 60))	('UM', 'Phenotype', 'HP:0007716', (159, 161))	('p.Q209 mutations', 'Var', (13, 29))	('metastases', 'Disease', 'MESH:D009362', (72, 82))	('metastases', 'Disease', 'MESH:D009362', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('p.Q209', 'Var', (96, 102))	('primary UM', 'Disease', (50, 60))	('mutations', 'Var', (20, 29))
120495	32825562	Consequently, it was proposed that GNA11 mutations have a more relevant effect on tumorigenesis since GNA11 Q209 mutations are more frequently observed in the metastasis of UM.	('Q209 mutations', 'Var', (108, 122))	('metastasis', 'CPA', (159, 169))	('GNA11', 'Gene', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('UM', 'Phenotype', 'HP:0007716', (173, 175))	('observed', 'Reg', (143, 151))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
120496	32825562	Additionally, in mouse models, GNA11 mutations demonstrated to be more tumorigenic than GNAQ mutations.	('mouse', 'Species', '10090', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('GNA11', 'Gene', (31, 36))	('tumor', 'Disease', (71, 76))
120498	32825562	The p.Leu129Gln substitution of CYSLTR2 produces a constitutive activation of endogenous Galphaq and can promote tumorigenesis in vivo.	('Galphaq', 'Gene', '2776', (89, 96))	('tumor', 'Disease', (113, 118))	('promote', 'PosReg', (105, 112))	('CYSLTR2', 'Gene', '57105', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('activation', 'PosReg', (64, 74))	('CYSLTR2', 'Gene', (32, 39))	('p.Leu129Gln', 'Mutation', 'p.L129Q', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('p.Leu129Gln', 'Var', (4, 15))	('endogenous', 'MPA', (78, 88))	('Galphaq', 'Gene', (89, 96))
120501	32825562	PLCB4 p.D630Y mutations are mutually exclusive with mutations in GNAQ/GNA11.	('p.D630Y', 'Var', (6, 13))	('p.D630Y', 'Mutation', 'p.D630Y', (6, 13))	('PLCB4', 'Gene', (0, 5))	('PLCB4', 'Gene', '5332', (0, 5))
120503	32825562	Notably, other strategies were developed, taking into account that the typical mutations in GNAQ/GNA11 in UM lead to constitutive activation of the MAPK and PI3K/AKT pathways.	('GNAQ/GNA11', 'Gene', (92, 102))	('AKT', 'Gene', '207', (162, 165))	('MAPK', 'molecular_function', 'GO:0004707', ('148', '152'))	('activation', 'PosReg', (130, 140))	('AKT', 'Gene', (162, 165))	('PI3K', 'molecular_function', 'GO:0016303', ('157', '161'))	('mutations', 'Var', (79, 88))	('UM', 'Phenotype', 'HP:0007716', (106, 108))
120512	32825562	The bi-allelic inactivation of the tumor suppressor gene BAP1 (BRCA1-associated protein 1), accounting for 60% of UMs, is another critical genetic alteration for UM development.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('bi-allelic inactivation', 'Var', (4, 27))	('BRCA1-associated protein 1', 'Gene', '8314', (63, 89))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('UM', 'Phenotype', 'HP:0007716', (114, 116))	('BRCA1-associated protein 1', 'Gene', (63, 89))	('UM', 'Phenotype', 'HP:0007716', (162, 164))	('tumor', 'Disease', (35, 40))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('BAP1', 'Gene', '8314', (57, 61))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('BAP1', 'Gene', (57, 61))	('men', 'Species', '9606', (172, 175))
120513	32825562	BAP1 germline mutations were also linked to a hereditary predisposition to UM.	('BAP1', 'Gene', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('linked to', 'Reg', (34, 43))	('BAP1', 'Gene', '8314', (0, 4))	('germline', 'Var', (5, 13))
120515	32825562	Together with BAP1 mutations, SF3B1 (splicing factor 3b subunit 1), and EIF1AX (eukaryotic translation initiation factor 1A, X-linked) formed a second mutually exclusive subgroup in UM.	('BAP1', 'Gene', '8314', (14, 18))	('UM', 'Phenotype', 'HP:0007716', (182, 184))	('SF3B1', 'Gene', (30, 35))	('BAP1', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('SF3B1', 'Gene', '23451', (30, 35))	('splicing factor 3b subunit 1', 'Gene', (37, 65))	('splicing factor 3b subunit 1', 'Gene', '23451', (37, 65))	('eukaryotic translation initiation factor 1A, X-linked', 'Gene', (80, 133))	('translation initiation', 'biological_process', 'GO:0006413', ('91', '113'))	('splicing', 'biological_process', 'GO:0045292', ('37', '45'))	('eukaryotic translation initiation factor 1A, X-linked)', 'Gene', '1964', (80, 134))	('EIF1AX', 'Gene', '1964', (72, 78))	('EIF1AX', 'Gene', (72, 78))
120516	32825562	Mutations in SF3B1, most commonly in amino acid 625 (R625), were reported in approximately 10-21% of UM cases.	('amino acid 625', 'Var', (37, 51))	('SF3B1', 'Gene', (13, 18))	('UM', 'Phenotype', 'HP:0007716', (101, 103))	('Mutations', 'Var', (0, 9))	('SF3B1', 'Gene', '23451', (13, 18))
120518	32825562	found that SF3B1 mutations were associated with a significantly worse prognosis and the development of late metastasis.	('late metastasis', 'CPA', (103, 118))	('SF3B1', 'Gene', (11, 16))	('men', 'Species', '9606', (95, 98))	('SF3B1', 'Gene', '23451', (11, 16))	('associated', 'Reg', (32, 42))	('mutations', 'Var', (17, 26))
120522	32825562	In summary, groups A and B harbor EIF1AX and SF3B1 mutations and have a more favorable prognosis, while groups C and D are characterized by BAP1 mutations and worse outcomes.	('mutations', 'Var', (51, 60))	('BAP1', 'Gene', (140, 144))	('EIF1AX', 'Gene', '1964', (34, 40))	('EIF1AX', 'Gene', (34, 40))	('SF3B1', 'Gene', (45, 50))	('BAP1', 'Gene', '8314', (140, 144))	('SF3B1', 'Gene', '23451', (45, 50))
120523	32825562	Supported by the role of BAP1 in DNA damage repair, an interesting phase 2 trial would be to explore the efficacy of the PARP inhibitor niraparib in several tumors, including UM, harboring BAP1 and other DNA damage response mutations (NCT03207347).	('BAP1', 'Gene', '8314', (189, 193))	('NCT03207347', 'Var', (235, 246))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('BAP1', 'Gene', (25, 29))	('DNA damage response', 'biological_process', 'GO:0006974', ('204', '223'))	('DNA', 'cellular_component', 'GO:0005574', ('204', '207'))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('BAP1', 'Gene', (189, 193))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('PARP', 'Gene', '1302', (121, 125))	('niraparib', 'Chemical', 'MESH:C545685', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('PARP', 'Gene', (121, 125))	('BAP1', 'Gene', '8314', (25, 29))	('UM', 'Phenotype', 'HP:0007716', (175, 177))
120551	32825562	Interestingly, the genetic characterization of this entity showed a higher rate of mutations in BRAF and NRAS genes, representing 53% and 14% of analyzed samples respectively, as well as more mutations in the TERT promoter.	('mutations', 'Var', (83, 92))	('NRAS', 'Gene', (105, 109))	('TERT', 'Gene', (209, 213))	('TERT', 'Gene', '7015', (209, 213))	('BRAF', 'Gene', (96, 100))	('NRAS', 'Gene', '4893', (105, 109))	('BRAF', 'Gene', '673', (96, 100))	('mutations', 'Var', (192, 201))
120572	32825562	These tumors have similar mutations to UM, including a high prevalence of GNAQ/GNA11 mutations, and infrequent BRAF mutations.	('GNAQ/GNA11', 'Gene', (74, 84))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('UM', 'Phenotype', 'HP:0007716', (39, 41))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('mutations', 'Var', (85, 94))	('BRAF', 'Gene', '673', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('BRAF', 'Gene', (111, 115))
120581	32825562	Teow and collaborators did not find evidence of BRAF mutations in a series of 12 cases of PDM.	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('DM', 'Disease', 'MESH:D009223', (91, 93))	('mutations', 'Var', (53, 62))
120610	32825562	Even in distinctive subgroups not prospectively evaluated in phase 3 randomized clinical trials, such as CM with NRAS mutations, treatment strategies typically include surgical approaches for localized melanoma and immune checkpoint inhibitors in advanced scenarios.	('CM', 'Phenotype', 'HP:0012056', (105, 107))	('mutations', 'Var', (118, 127))	('NRAS', 'Gene', (113, 117))	('NRAS', 'Gene', '4893', (113, 117))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', (202, 210))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('men', 'Species', '9606', (134, 137))
120613	32825562	Emerging agents, directed to other possible actionable mutations, support the necessity of the further comprehensive molecular profiling of the different melanoma models addressed in this review.	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('mutations', 'Var', (55, 64))
120614	32825562	Interestingly, the identification of ALK isoforms, and ROS1 or NTRK fusions, may bring new treatment options for CM patients.	('men', 'Species', '9606', (96, 99))	('ALK', 'Gene', (37, 40))	('patients', 'Species', '9606', (116, 124))	('ROS1', 'Gene', (55, 59))	('fusions', 'Var', (68, 75))	('ROS1', 'Gene', '6098', (55, 59))	('ALK', 'Gene', '238', (37, 40))	('NTRK', 'Gene', (63, 67))	('CM', 'Phenotype', 'HP:0012056', (113, 115))
120619	32825562	The current literature supports this categorization for some atypical localizations, such as the case of the high prevalence of GNAQ/GNA11 mutations in PIMMs, or the favorable prognosis and infrequent lymph node involvement evidenced in patients with PDMs.	('men', 'Species', '9606', (219, 222))	('PDMs', 'Disease', (251, 255))	('mutations', 'Var', (139, 148))	('PDMs', 'Disease', 'None', (251, 255))	('GNAQ/GNA11', 'Gene', (128, 138))	('MM', 'Phenotype', 'HP:0002861', (154, 156))	('patients', 'Species', '9606', (237, 245))
120623	32825562	An actionable finding was evidenced in 51% of the included cases, and notably, four patients with an original diagnosis of soft tissue tumors were genotypically recategorized as NF1 and high TMB melanomas with UV-induced mutations.	('high TMB melanomas', 'Disease', (186, 204))	('high TMB melanomas', 'Disease', 'MESH:D008545', (186, 204))	('mutations', 'Var', (221, 230))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (123, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('patients', 'Species', '9606', (84, 92))	('NF1', 'Gene', (178, 181))	('melanomas', 'Phenotype', 'HP:0002861', (195, 204))	('soft tissue tumors', 'Disease', (123, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('NF1', 'Gene', '4763', (178, 181))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('soft tissue tumors', 'Disease', 'MESH:D012983', (123, 141))
120751	31283110	Efforts to understand the molecular biology of the disease have revealed several markers that correlate with patient prognosis, including the copy number of chromosome 3, genetic alterations in BAP1, EIF1AX and SF3B1 genes, and other transcriptional features.	('EIF1AX', 'Gene', '1964', (200, 206))	('EIF1AX', 'Gene', (200, 206))	('patient', 'Species', '9606', (109, 116))	('SF3B1', 'Gene', '23451', (211, 216))	('correlate', 'Reg', (94, 103))	('BAP1', 'Gene', '8314', (194, 198))	('genetic alterations', 'Var', (171, 190))	('SF3B1', 'Gene', (211, 216))	('BAP1', 'Gene', (194, 198))	('copy number', 'Var', (142, 153))	('chromosome', 'cellular_component', 'GO:0005694', ('157', '167'))
120761	31283110	Loss of function of the 3p21 BRCA Associated Protein 1 (BAP1) gene, either through mutations or decreased expression, correlates with M3 phenotype.	('mutations', 'Var', (83, 92))	('M3 phenotype', 'Disease', (134, 146))	('decreased', 'NegReg', (96, 105))	('BRCA Associated Protein 1', 'Gene', '8314', (29, 54))	('BAP1', 'Gene', '8314', (56, 60))	('expression', 'MPA', (106, 116))	('Loss of function', 'NegReg', (0, 16))	('BAP1', 'Gene', (56, 60))	('BRCA Associated Protein 1', 'Gene', (29, 54))
120762	31283110	Conversely SRSF2/SF3B1 and EIF1AX mutant tumors have distinct copy number alterations and DNA methylation profiles that associate with the better overall prognosis of the disomy 3 (D3) phenotype.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('SRSF2', 'Gene', '6427', (11, 16))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('SF3B1', 'Gene', (17, 22))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('SRSF2', 'Gene', (11, 16))	('SF3B1', 'Gene', '23451', (17, 22))	('DNA methylation', 'biological_process', 'GO:0006306', ('90', '105'))	('EIF1AX', 'Gene', '1964', (27, 33))	('EIF1AX', 'Gene', (27, 33))	('mutant', 'Var', (34, 40))
120763	31283110	One such mechanism may relate to short non-coding RNAs (ncRNAs).	('ncRNA', 'Gene', (56, 61))	('short non-coding', 'Var', (33, 49))	('ncRNA', 'Gene', '54719', (56, 61))
120768	31283110	These novel miRNA loci produce isomiRs that drive tissue-specific regulatory events that are currently-uncharacterized and cannot be captured by mouse models.	('drive', 'Reg', (44, 49))	('mouse', 'Species', '10090', (145, 150))	('tissue-specific regulatory events', 'MPA', (50, 83))	('miRNA', 'Var', (12, 17))
120785	31283110	miR-21-5p, miR-183-5p, miR-143-3p) produce many isomiRs.	('miR-21', 'Gene', '406991', (0, 6))	('miR-143-3p', 'Var', (23, 33))	('miR-21', 'Gene', (0, 6))	('miR-183-5p', 'Var', (11, 21))
120787	31283110	We stress that because of the different seeds, these four isomiRs are expected to target genes that differ from the genes targeted by miR-140-3p's "0 0" isomiR, thereby contributing to UVM biology in currently uncharacterized ways.	('contributing', 'Reg', (169, 181))	('miR-140-3p', 'Chemical', '-', (134, 144))	('miR-140-3p', 'Var', (134, 144))	('UVM', 'Phenotype', 'HP:0007716', (185, 188))
120801	31283110	We stratified the UVM datasets by M3 status and somatic BAP1 mutation status (Supplemental Table 1) and searched for miRNA loci and isomiRs that are differentially abundant (DA) between the two groups.	('BAP1', 'Gene', '8314', (56, 60))	('mutation', 'Var', (61, 69))	('DA', 'Chemical', '-', (174, 176))	('BAP1', 'Gene', (56, 60))	('UVM', 'Phenotype', 'HP:0007716', (18, 21))
120803	31283110	Specifically, the expression of the miR-508/514 miRNA cluster from the X chromosome decreases considerably in M3 or BAP1 mutant patients.	('BAP1', 'Gene', (116, 120))	('mutant', 'Var', (121, 127))	('X chromosome', 'cellular_component', 'GO:0000805', ('71', '83'))	('miR-508', 'Gene', (36, 43))	('miR-508', 'Gene', '574513', (36, 43))	('expression', 'MPA', (18, 28))	('decreases', 'NegReg', (84, 93))	('BAP1', 'Gene', '8314', (116, 120))	('patients', 'Species', '9606', (128, 136))
120805	31283110	miR-199a/b whose paralogues are located on chromosomes 1, 9 and 19) increase in abundance in M3 and BAP1 mutant patients (Fig.	('BAP1', 'Gene', '8314', (100, 104))	('BAP1', 'Gene', (100, 104))	('patients', 'Species', '9606', (112, 120))	('increase', 'PosReg', (68, 76))	('mutant', 'Var', (105, 111))
120807	31283110	Stratifying the UVM datasets based on protective SRSF2/SF3B1 or EIF1AX mutations reveals the opposite trend (Fig.	('SF3B1', 'Gene', '23451', (55, 60))	('UVM', 'Phenotype', 'HP:0007716', (16, 19))	('SRSF2', 'Gene', '6427', (49, 54))	('EIF1AX', 'Gene', '1964', (64, 70))	('EIF1AX', 'Gene', (64, 70))	('mutations', 'Var', (71, 80))	('SF3B1', 'Gene', (55, 60))	('SRSF2', 'Gene', (49, 54))
120808	31283110	isomiRs from the miR-508/514 miRNA cluster of chromosome X show increased abundance, whereas isomiRs from miR-199a/b and miR-142 show decreased abundance with mutation status (Fig.	('miR-142', 'Gene', '406934', (121, 128))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('abundance', 'MPA', (74, 83))	('mutation', 'Var', (159, 167))	('miR-142', 'Gene', (121, 128))	('miR-508', 'Gene', (17, 24))	('increased', 'PosReg', (64, 73))	('miR-508', 'Gene', '574513', (17, 24))
120809	31283110	This is the exact opposite of the pattern observed in M3 or BAP1 mutant patients.	('BAP1', 'Gene', '8314', (60, 64))	('mutant', 'Var', (65, 71))	('BAP1', 'Gene', (60, 64))	('patients', 'Species', '9606', (72, 80))
120810	31283110	The miR-187-3p locus offers another such example: its abundance is increased in patients with an EIF1AX or SRSF2 mutation, and decreased in patients with M3 or BAP1 mutations (Fig.	('mutation', 'Var', (113, 121))	('decreased', 'NegReg', (127, 136))	('EIF1AX', 'Gene', (97, 103))	('EIF1AX', 'Gene', '1964', (97, 103))	('SRSF2', 'Gene', '6427', (107, 112))	('patients', 'Species', '9606', (80, 88))	('abundance', 'MPA', (54, 63))	('BAP1', 'Gene', '8314', (160, 164))	('increased', 'PosReg', (67, 76))	('BAP1', 'Gene', (160, 164))	('patients', 'Species', '9606', (140, 148))	('SRSF2', 'Gene', (107, 112))
120819	31283110	We found that patients who developed metastases showed a significantly higher proportion of 18-nt long tRFs (p-val=0.008) and a lower proportion of 20-nt-long tRFs (p-val=0.002) (Fig.	('tRF', 'Gene', '7013', (159, 162))	('metastases', 'Disease', (37, 47))	('tRF', 'Gene', '7013', (103, 106))	('metastases', 'Disease', 'MESH:D009362', (37, 47))	('tRF', 'Gene', (159, 162))	('patients', 'Species', '9606', (14, 22))	('tRF', 'Gene', (103, 106))	('18-nt long', 'Var', (92, 102))
120821	31283110	Conversely, EIF1AX mutant patients showed comparatively fewer 18-nt-long tRFs (p-val=0.021) and more 20-nt-long tRFs (p-val=0.003) (Fig.	('tRF', 'Gene', '7013', (73, 76))	('EIF1AX', 'Gene', (12, 18))	('fewer', 'NegReg', (56, 61))	('tRF', 'Gene', (112, 115))	('EIF1AX', 'Gene', '1964', (12, 18))	('patients', 'Species', '9606', (26, 34))	('mutant', 'Var', (19, 25))	('tRF', 'Gene', '7013', (112, 115))	('tRF', 'Gene', (73, 76))
120831	31283110	On the other hand, in SRSF2/SF3B1 or EIF1AX mutation carriers, the majority of DA tRFs that are statistically significant are nuclear 5 -tRFs.	('SRSF2', 'Gene', (22, 27))	('mutation', 'Var', (44, 52))	('EIF1AX', 'Gene', '1964', (37, 43))	('EIF1AX', 'Gene', (37, 43))	('SF3B1', 'Gene', (28, 33))	('tRF', 'Gene', (82, 85))	('SRSF2', 'Gene', '6427', (22, 27))	('tRF', 'Gene', (137, 140))	('SF3B1', 'Gene', '23451', (28, 33))	('tRF', 'Gene', '7013', (137, 140))	('tRF', 'Gene', '7013', (82, 85))	('DA', 'Chemical', '-', (79, 81))
120838	31283110	IsomiRs such as miR-21-5p -1 0 and miR-29a-3p -1 1 appear increased in abundance in patients with metastases (red curves in Fig.	('increased', 'PosReg', (58, 67))	('patients', 'Species', '9606', (84, 92))	('miR-21', 'Gene', '406991', (16, 22))	('miR-29a-3p -1 1', 'Var', (35, 50))	('metastases', 'Disease', (98, 108))	('metastases', 'Disease', 'MESH:D009362', (98, 108))	('miR-21', 'Gene', (16, 22))
120839	31283110	In contrast, isomiRs such as miR-99a-3p 1 1 and let-7c-5p -1 1 are decreased in abundance in patients with metastases (Fig.	('miR-99a-3p 1', 'Var', (29, 41))	('metastases', 'Disease', 'MESH:D009362', (107, 117))	('let-7c-5p -1 1', 'Var', (48, 62))	('decreased', 'NegReg', (67, 76))	('patients', 'Species', '9606', (93, 101))	('metastases', 'Disease', (107, 117))
120844	31283110	The two categories with poorer prognosis were characterized by M3 status and BAP1 mutations.	('BAP1', 'Gene', '8314', (77, 81))	('mutations', 'Var', (82, 91))	('BAP1', 'Gene', (77, 81))	('M3 status', 'Var', (63, 72))
120846	31283110	Patients with D3 and EIF1AX/SF3B1 mutations have decreased metastatic risk and better disease prognosis.	('metastatic risk', 'CPA', (59, 74))	('disease prognosis', 'CPA', (86, 103))	('SF3B1', 'Gene', (28, 33))	('decreased', 'NegReg', (49, 58))	('Patients', 'Species', '9606', (0, 8))	('SF3B1', 'Gene', '23451', (28, 33))	('EIF1AX', 'Gene', '1964', (21, 27))	('EIF1AX', 'Gene', (21, 27))	('mutations', 'Var', (34, 43))
120853	31283110	Previous work showed that a 5 -isomiR from miR-140-3p is increased in breast tumors compared to normal breast tissue, wherein it functions to suppress tumor growth and progression.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('breast tumors', 'Disease', (70, 83))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('breast tumors', 'Disease', 'MESH:D001943', (70, 83))	('miR-140-3p', 'Var', (43, 53))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('miR-140-3p', 'Chemical', '-', (43, 53))	('breast tumors', 'Phenotype', 'HP:0100013', (70, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('increased', 'PosReg', (57, 66))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('suppress', 'NegReg', (142, 150))
120855	31283110	Interestingly, these four isomiRs are increased in abundance in patients with EIFA1X or SF3B1 mutations, and decreased in M3 and BAP1 mutation carriers.	('decreased', 'NegReg', (109, 118))	('EIFA1X', 'Var', (78, 84))	('SF3B1', 'Gene', '23451', (88, 93))	('mutations', 'Var', (94, 103))	('patients', 'Species', '9606', (64, 72))	('BAP1', 'Gene', '8314', (129, 133))	('BAP1', 'Gene', (129, 133))	('SF3B1', 'Gene', (88, 93))	('increased', 'PosReg', (38, 47))
120859	31283110	Several of the 15 miRNAs in this cluster have been associated with functions upstream of several pathways involved in: tumor development, promotion of melanocyte transformation, and melanoma growth.	('tumor', 'Disease', (119, 124))	('miRNAs', 'Var', (18, 24))	('melanocyte transformation', 'CPA', (151, 176))	('melanoma growth', 'Disease', (182, 197))	('promotion', 'PosReg', (138, 147))	('melanoma growth', 'Disease', 'MESH:D008545', (182, 197))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
120864	31283110	Inhibition of miR-508-5p results in increased cell proliferation and cellular migration.	('miR-508', 'Gene', '574513', (14, 21))	('cellular migration', 'CPA', (69, 87))	('increased', 'PosReg', (36, 45))	('Inhibition', 'Var', (0, 10))	('cell proliferation', 'CPA', (46, 64))	('miR-508', 'Gene', (14, 21))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))
120865	31283110	Interestingly, this cluster shows the opposite effect in patients with protective SIF1AX and SF3B1 mutations.	('patients', 'Species', '9606', (57, 65))	('SF3B1', 'Gene', (93, 98))	('SIF1AX', 'Gene', (82, 88))	('mutations', 'Var', (99, 108))	('SF3B1', 'Gene', '23451', (93, 98))
120887	31283110	Conversely, patients with protective EIF1AX mutations show a decrease in 18-nt-long tRFs and an increase in 20-nt-long tRFs.	('patients', 'Species', '9606', (12, 20))	('decrease', 'NegReg', (61, 69))	('EIF1AX', 'Gene', (37, 43))	('EIF1AX', 'Gene', '1964', (37, 43))	('tRF', 'Gene', (84, 87))	('tRF', 'Gene', (119, 122))	('tRF', 'Gene', '7013', (84, 87))	('mutations', 'Var', (44, 53))	('tRF', 'Gene', '7013', (119, 122))
120892	31283110	Additionally, we found tRFs to be DA in the context of EIF1AX mutations, metastatic disease, and when considering the majority cell type of the underlying tumor.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('EIF1AX', 'Gene', '1964', (55, 61))	('EIF1AX', 'Gene', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tRF', 'Gene', (23, 26))	('tumor', 'Disease', (155, 160))	('DA', 'Chemical', '-', (34, 36))	('tRF', 'Gene', '7013', (23, 26))	('metastatic disease', 'Disease', (73, 91))	('mutations', 'Var', (62, 71))
120902	31058839	Programmed Cell Death 1 (PD-1) Inhibitors in Renal Transplant Patients with Advanced Cancer: A Double-Edged Sword?	('Programmed Cell Death 1', 'Gene', (0, 23))	('Cancer', 'Phenotype', 'HP:0002664', (85, 91))	('PD-1', 'Gene', (25, 29))	('PD-1', 'Gene', '5133', (25, 29))	('Renal Transplant', 'Disease', (45, 61))	('Programmed Cell Death 1', 'Gene', '5133', (0, 23))	('Inhibitors', 'Var', (31, 41))	('Advanced Cancer', 'Disease', 'MESH:D006223', (76, 91))	('Programmed Cell Death', 'biological_process', 'GO:0012501', ('0', '21'))	('Advanced Cancer', 'Disease', (76, 91))	('Patients', 'Species', '9606', (62, 70))	('Renal Transplant', 'Disease', 'MESH:D007674', (45, 61))
120905	31058839	However, whether PD-1 inhibitors should be administered to renal transplant patients with advanced cancer remains unclear because the T-cells produced after administration of these inhibitors act against not only tumor antigens but also donor alloantigens.	('tumor', 'Disease', (213, 218))	('patients', 'Species', '9606', (76, 84))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('inhibitors', 'Var', (181, 191))	('cancer', 'Disease', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('donor', 'Species', '9606', (237, 242))	('act', 'Reg', (192, 195))
120920	31058839	Given advancements in cancer therapy, development of immune checkpoint inhibitors employing antibodies targeting programmed cell death 1 (PD-1), PD-1 ligand (PD-L1), or monoclonal antibodies against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) in patients with various types of cancer has steadily increased.	('ligand', 'molecular_function', 'GO:0005488', ('150', '156'))	('antibodies', 'Var', (92, 102))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('CTLA-4', 'Gene', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('cancer', 'Disease', (22, 28))	('cytotoxic T-lymphocyte-associated antigen 4', 'Gene', (199, 242))	('programmed cell death', 'biological_process', 'GO:0012501', ('113', '134'))	('patients', 'Species', '9606', (255, 263))	('PD-1', 'Gene', (138, 142))	('cytotoxic T-lymphocyte-associated antigen 4', 'Gene', '1493', (199, 242))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('programmed cell death 1', 'Gene', (113, 136))	('CTLA-4', 'Gene', '1493', (244, 250))	('cancer', 'Disease', (286, 292))	('programmed cell death 1', 'Gene', '5133', (113, 136))
120938	31058839	Our data on the efficacy and safety of PD-1 inhibitors in kidney-transplanted patients with advanced malignancies mainly include case studies (Table 1 and Table 2), owing to the current lack of randomized control trials and the fact that kidney-transplanted patients are consistently excluded in clinical trials of immune checkpoint inhibitors.	('PD-1', 'Gene', (39, 43))	('malignancies', 'Disease', (101, 113))	('inhibitors', 'Var', (44, 54))	('patients', 'Species', '9606', (78, 86))	('malignancies', 'Disease', 'MESH:D009369', (101, 113))	('patients', 'Species', '9606', (258, 266))
120951	31058839	Unsurprisingly, lowering the dose of immunosuppressants before a PD-1 inhibitor significantly increases the risk of graft failure because immunosuppressive therapies are vital in regulating acute allograft rejection and inducing long-term transplanted kidney survival.	('inducing', 'Reg', (220, 228))	('inhibitor', 'Var', (70, 79))	('PD-1', 'Gene', (65, 69))	('graft failure', 'Disease', (116, 129))	('graft failure', 'Disease', 'MESH:D055589', (116, 129))	('long-term transplanted kidney survival', 'CPA', (229, 267))
120965	31058839	Tacrolimus was replaced by sirolimus before anti-PD-1, and serum sirolimus levels were initially maintained at 4-6 ng/mL after anti-PD-1 and then increased to 10-12 ng/mL 2 weeks after.	('sirolimus', 'Chemical', 'MESH:D020123', (65, 74))	('anti-PD-1', 'Var', (127, 136))	('Tacrolimus', 'Chemical', 'MESH:D016559', (0, 10))	('increased', 'PosReg', (146, 155))	('sirolimus', 'Chemical', 'MESH:D020123', (27, 36))	('serum sirolimus levels', 'MPA', (59, 81))
120972	31058839	Calcineurin inhibitor (CNI) minimization or elimination is a critical strategy to decrease CNI toxicities, such as nephrotoxicity, the worsening risk of cardiovascular disease, new-onset diabetes, increased incidence of neoplasms, and viral infections.	('cardiovascular disease', 'Disease', 'MESH:D002318', (153, 175))	('nephrotoxicity', 'Disease', (115, 129))	('Calcineurin', 'molecular_function', 'GO:0004722', ('0', '11'))	('viral infections', 'Disease', (235, 251))	('CNI toxicities', 'Disease', 'MESH:D064420', (91, 105))	('cardiovascular disease', 'Disease', (153, 175))	('diabetes', 'Disease', 'MESH:D003920', (187, 195))	('neoplasms', 'Disease', 'MESH:D009369', (220, 229))	('nephrotoxicity', 'Disease', 'MESH:D007674', (115, 129))	('Calcineurin inhibitor', 'Gene', (0, 21))	('neoplasms', 'Disease', (220, 229))	('Calcineurin inhibitor', 'Gene', '23523', (0, 21))	('minimization', 'Var', (28, 40))	('decrease', 'NegReg', (82, 90))	('diabetes', 'Disease', (187, 195))	('Calcineurin', 'molecular_function', 'GO:0004723', ('0', '11'))	('viral infections', 'Disease', 'MESH:D001102', (235, 251))	('new-onset diabetes', 'Phenotype', 'HP:0100651', (177, 195))	('neoplasms', 'Phenotype', 'HP:0002664', (220, 229))	('CNI toxicities', 'Disease', (91, 105))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (153, 175))
120977	31058839	Treatment with mTOR inhibitors and concomitant immune checkpoint inhibitors could maintain T-cell energy, and mTOR inhibitors have been demonstrated to stimulate naive T-cell differentiation into Tregs, especially in the presence of IL-2.	('T-cell differentiation', 'biological_process', 'GO:0030217', ('168', '190'))	('mTOR', 'Gene', (110, 114))	('IL-2', 'Gene', '3558', (233, 237))	('mTOR', 'Gene', '2475', (110, 114))	('T-cell energy', 'CPA', (91, 104))	('IL-2', 'Gene', (233, 237))	('naive T-cell differentiation', 'CPA', (162, 190))	('mTOR', 'Gene', (15, 19))	('maintain', 'Reg', (82, 90))	('mTOR', 'Gene', '2475', (15, 19))	('IL-2', 'molecular_function', 'GO:0005134', ('233', '237'))	('stimulate', 'PosReg', (152, 161))	('inhibitors', 'Var', (115, 125))
121019	31058839	In our review of published cases, PD-1 inhibitors showed anti-tumor effects on advanced malignancies, including metastatic melanoma, cSCC, urothelial tumors, and duodenal adenocarcinoma in renal transplant patients.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('malignancies', 'Disease', 'MESH:D009369', (88, 100))	('inhibitors', 'Var', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('PD-1', 'Gene', (34, 38))	('malignancies', 'Disease', (88, 100))	('cSCC', 'Disease', (133, 137))	('metastatic melanoma', 'Disease', (112, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('SCC', 'Phenotype', 'HP:0002860', (134, 137))	('metastatic melanoma', 'Disease', 'MESH:D008545', (112, 131))	('urothelial tumors', 'Disease', (139, 156))	('cSCC', 'Phenotype', 'HP:0006739', (133, 137))	('adenocarcinoma in renal transplant', 'Disease', 'MESH:D007674', (171, 205))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('tumor', 'Disease', (150, 155))	('adenocarcinoma in renal transplant', 'Disease', (171, 205))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('patients', 'Species', '9606', (206, 214))	('urothelial tumors', 'Disease', 'MESH:D001749', (139, 156))	('duodenal adenocarcinoma', 'Phenotype', 'HP:0006771', (162, 185))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
121021	31058839	Moreover, PD-1 inhibitors showed a high risk of severe graft rejection without regaining renal function even after treatment with high-dose steroids.	('steroids', 'Chemical', 'MESH:D013256', (140, 148))	('PD-1', 'Gene', (10, 14))	('inhibitors', 'Var', (15, 25))	('regaining renal function', 'Phenotype', 'HP:0012622', (79, 103))
121025	31058839	For patients who benefited from anti-tumor treatment with anti-PD-1 inhibitors without rejection, two renal transplant recipients were possibly due to the use of low-dose steroid and an mTOR inhibitor, one patient's advanced urothelial carcinoma regressed after combined treatment with anti-PD-1, anti-VEGF, and chemotherapy without immunosuppressant titration, and one patient had no information in the published article.	('steroid', 'Chemical', 'MESH:D013256', (171, 178))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('urothelial carcinoma', 'Disease', (225, 245))	('mTOR', 'Gene', (186, 190))	('patient', 'Species', '9606', (206, 213))	('mTOR', 'Gene', '2475', (186, 190))	('patient', 'Species', '9606', (4, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('patient', 'Species', '9606', (370, 377))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('anti-PD-1', 'Var', (286, 295))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (225, 245))	('patients', 'Species', '9606', (4, 12))
121059	29992995	The frequency of BRAF and NRAS mutations differs among the cutaneous melanoma subtypes.	('mutations', 'Var', (31, 40))	('cutaneous melanoma', 'Disease', (59, 77))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (59, 77))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (59, 77))	('NRAS', 'Gene', '30380', (26, 30))	('NRAS', 'Gene', (26, 30))	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', '403065', (17, 21))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))
121064	29992995	Mutually exclusive mutations in GNAQ or in GNA11, the principal driver oncogenes in uveal melanoma, occur in approximately 85% of cases.	('GNAQ', 'Gene', (32, 36))	('GNAQ', 'Gene', '570108', (32, 36))	('GNA11', 'Gene', (43, 48))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma', 'Disease', (84, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('occur', 'Reg', (100, 105))	('mutations', 'Var', (19, 28))	('GNA11', 'Gene', '563953', (43, 48))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
121065	29992995	Moreover, inactivating mutations in the tumour suppressor BAP1 occur in ~85% of metastatic tumours and are associated with disease dissemination and poor prognosis.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('inactivating mutations', 'Var', (10, 32))	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('tumours', 'Disease', 'MESH:D009369', (91, 98))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('occur', 'Reg', (63, 68))	('BAP1', 'Gene', (58, 62))	('tumour', 'Disease', (40, 46))	('tumour', 'Disease', (91, 97))	('tumours', 'Disease', (91, 98))	('BAP1', 'Gene', '558885', (58, 62))	('disease dissemination', 'CPA', (123, 144))	('associated with', 'Reg', (107, 122))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
121143	29992995	For this purpose, C8161-GFP or Hermes 2B-GFP cells were injected in the yolk of zebrafish embryos two days post-fertilization (dpf), and the differential migration was evaluated via live imaging after 2-3 days post-injection (dpi).	('fertilization', 'biological_process', 'GO:0009566', ('112', '125'))	('dpi', 'Chemical', '-', (226, 229))	('C8161-GFP', 'Var', (18, 27))	('zebrafish', 'Species', '7955', (80, 89))	('differential migration', 'CPA', (141, 163))	('yolk', 'cellular_component', 'GO:0060417', ('72', '76'))	('dpf', 'Chemical', '-', (127, 130))
121163	29992995	It is known that aberrant expression of embryonic epithelial-mesenchymal transition (EMT) factors triggers extensive plasticity of cancer cells, including melanoma cells via EMT plasticity, invading melanoma cells can use a broad spectrum of invasion strategies depending upon many environmental determinants leading to tumour resistance and metastasis.	('cancer', 'Disease', (131, 137))	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('aberrant', 'Var', (17, 25))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('50', '83'))	('EMT', 'biological_process', 'GO:0001837', ('85', '88'))	('tumour', 'Phenotype', 'HP:0002664', (320, 326))	('plasticity', 'MPA', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('EMT', 'biological_process', 'GO:0001837', ('174', '177'))	('tumour', 'Disease', 'MESH:D009369', (320, 326))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('tumour', 'Disease', (320, 326))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('melanoma', 'Disease', (199, 207))	('melanoma', 'Disease', (155, 163))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))
121187	26825879	GNA11 Mutation in a Patient With Cutaneous Origin Melanoma The rapid advances in the molecular biology and genetics have improved the understanding of molecular pathogenesis of v-Raf murine sarcoma viral oncogene homolog B (BRAF), feline sarcoma viral oncogene v-kit (KIT), and neuroblastoma v-Ras oncogene homolog (NRAS) mutant melanomas with the subsequent development of targeted therapeutic agents.	('v-kit', 'Gene', '16590', (261, 266))	('Mutation', 'Var', (6, 14))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', (177, 222))	('Cutaneous Origin Melanoma', 'Disease', (33, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('v-kit', 'Gene', (261, 266))	('melanomas', 'Disease', 'MESH:D008545', (329, 338))	('Melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('Cutaneous Origin Melanoma', 'Disease', 'MESH:C562393', (33, 58))	('neuroblastoma', 'Disease', (278, 291))	('KIT', 'molecular_function', 'GO:0005020', ('268', '271'))	('neuroblastoma', 'Phenotype', 'HP:0003006', (278, 291))	('melanomas', 'Disease', (329, 338))	('pathogenesis', 'biological_process', 'GO:0009405', ('161', '173'))	('GNA11', 'Gene', '2767', (0, 5))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', '673', (177, 222))	('neuroblastoma', 'Disease', 'MESH:D009447', (278, 291))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('Patient', 'Species', '9606', (20, 27))	('sarcoma viral', 'Disease', 'MESH:D001102', (190, 203))	('sarcoma viral', 'Disease', 'MESH:D001102', (238, 251))	('melanomas', 'Phenotype', 'HP:0002861', (329, 338))	('mutant', 'Var', (322, 328))	('sarcoma viral', 'Disease', (238, 251))	('GNA11', 'Gene', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (329, 337))
121188	26825879	However, only limited data are available for melanoma harboring other somatic than BRAF, KIT, and NRAS mutations.	('mutations', 'Var', (103, 112))	('NRAS', 'Gene', (98, 102))	('KIT', 'Gene', (89, 92))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('BRAF', 'Gene', (83, 87))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))	('KIT', 'molecular_function', 'GO:0005020', ('89', '92'))
121189	26825879	Mutations in guanine nucleotide-binding protein Q polypeptide (GNAQ) and guanine nucleotide-binding protein alpha-11 (GNA11), alpha subunits of heterotrimeric G proteins, constitutively activate mitogen-activated protein kinase (MAPK) pathway in uveal melanoma.	('GNA11', 'Gene', (118, 123))	('guanine nucleotide-binding protein alpha-11', 'Gene', (73, 116))	('MAPK', 'molecular_function', 'GO:0004707', ('229', '233'))	('GNA11', 'Gene', '2767', (118, 123))	('GNAQ', 'Gene', '2776', (63, 67))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('21', '39'))	('protein', 'cellular_component', 'GO:0003675', ('213', '220'))	('guanine nucleotide-binding protein alpha-11', 'Gene', '2767', (73, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (246, 260))	('uveal melanoma', 'Disease', (246, 260))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Disease', 'MESH:C536494', (246, 260))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('activate', 'PosReg', (186, 194))	('GNAQ', 'Gene', (63, 67))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('81', '99'))
121190	26825879	However, there are no reports of GNA11 mutations in cutaneous melanomas.	('GNA11', 'Gene', (33, 38))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (52, 71))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (52, 71))	('GNA11', 'Gene', '2767', (33, 38))	('mutations', 'Var', (39, 48))	('cutaneous melanomas', 'Disease', (52, 71))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
121192	26825879	Mutation analysis of the tumor revealed a GNA11 Q209L mutation.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('Q209L', 'Mutation', 'rs1057519742', (48, 53))	('tumor', 'Disease', (25, 30))	('Q209L', 'Var', (48, 53))	('GNA11', 'Gene', (42, 47))	('GNA11', 'Gene', '2767', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
121194	26825879	To our knowledge, this is the first case report to demonstrate cutaneous origin melanoma harboring a GNA11 Q209L mutation.	('GNA11', 'Gene', '2767', (101, 106))	('GNA11', 'Gene', (101, 106))	('Q209L', 'Mutation', 'rs1057519742', (107, 112))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('Q209L', 'Var', (107, 112))
121198	26825879	The discovery of BRAF mutations in melanoma and the development of BRAF inhibitors have changed the landscape of advanced melanoma treatment.	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('BRAF', 'Gene', (17, 21))	('changed', 'Reg', (88, 95))	('mutations', 'Var', (22, 31))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('melanoma', 'Disease', (35, 43))
121199	26825879	With the remarkable success of targeted therapy in BRAFV600 mutant melanoma, extensive research efforts have been made to discover targetable somatic mutations other than BRAF in melanoma.	('BRAFV600', 'Gene', (51, 59))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('mutant', 'Var', (60, 66))	('melanoma', 'Disease', (179, 187))
121200	26825879	The rapid advances in the molecular and genetic analysis of melanoma with the extensive research efforts have improved the understanding of clinicopathologic features of BRAF, KIT, and NRAS mutations in melanoma, which helps with development of targeted therapeutic agents.	('NRAS', 'Gene', (185, 189))	('KIT', 'molecular_function', 'GO:0005020', ('176', '179'))	('BRAF', 'Gene', (170, 174))	('KIT', 'Gene', (176, 179))	('improved', 'PosReg', (110, 118))	('mutations', 'Var', (190, 199))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))
121204	26825879	The mutations of GNAQ/GNA11 have been reported exclusively in primary uveal melanoma and they are critical for the development and progression of uveal melanoma by activation of the mitogen-activated protein kinase (MAPK) pathway.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('GNA11', 'Gene', (22, 27))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (146, 160))	('reported', 'Reg', (38, 46))	('GNA11', 'Gene', '2767', (22, 27))	('uveal melanoma', 'Phenotype', 'HP:0007716', (146, 160))	('uveal melanoma', 'Disease', (146, 160))	('GNAQ', 'Gene', (17, 21))	('activation', 'PosReg', (164, 174))	('MAPK', 'molecular_function', 'GO:0004707', ('216', '220'))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('protein', 'cellular_component', 'GO:0003675', ('200', '207'))	('mutations', 'Var', (4, 13))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (62, 84))	('primary uveal melanoma', 'Disease', (62, 84))	('GNAQ', 'Gene', '2776', (17, 21))
121205	26825879	Although GNAQ/GNA11 mutations are not rare in benign and malignant blue nevus,GNA11 mutations have never been reported in patients with cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('GNAQ', 'Gene', (9, 13))	('nevus', 'Phenotype', 'HP:0003764', (72, 77))	('GNA11', 'Gene', (78, 83))	('GNA11', 'Gene', '2767', (78, 83))	('blue nevus', 'Phenotype', 'HP:0100814', (67, 77))	('GNA11', 'Gene', (14, 19))	('patients', 'Species', '9606', (122, 130))	('GNAQ', 'Gene', '2776', (9, 13))	('cutaneous melanoma', 'Disease', (136, 154))	('GNA11', 'Gene', '2767', (14, 19))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (136, 154))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (136, 154))	('mutations', 'Var', (20, 29))
121206	26825879	Here, we report a patient with cutaneous origin melanoma harboring GNA11 mutation.	('melanoma', 'Disease', (48, 56))	('GNA11', 'Gene', (67, 72))	('GNA11', 'Gene', '2767', (67, 72))	('patient', 'Species', '9606', (18, 25))	('mutation', 'Var', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
121221	26825879	A molecular analysis of the liver lesion revealed a GNA11 mutation with wild-type BRAF, wild-type KIT, and wild-type NRAS genes.	('revealed', 'Reg', (41, 49))	('mutation', 'Var', (58, 66))	('liver lesion', 'Disease', 'MESH:D017093', (28, 40))	('KIT', 'molecular_function', 'GO:0005020', ('98', '101'))	('GNA11', 'Gene', (52, 57))	('liver lesion', 'Disease', (28, 40))	('GNA11', 'Gene', '2767', (52, 57))
121223	26825879	As GNA11 mutations have been reported in uveal melanoma frequently, extensive ophthalmology exams and a magnetic resonance imaging (MRI) of the brain were performed, which revealed no evidence of uveal melanoma (Figure 3).	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('uveal melanoma', 'Disease', (41, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (41, 55))	('mutations', 'Var', (9, 18))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('GNA11', 'Gene', (3, 8))	('reported', 'Reg', (29, 37))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('GNA11', 'Gene', '2767', (3, 8))	('uveal melanoma', 'Disease', 'MESH:C536494', (196, 210))	('uveal melanoma', 'Phenotype', 'HP:0007716', (196, 210))	('uveal melanoma', 'Disease', (196, 210))
121234	26825879	GNAQ or GNA11 mutations occur at either exon 4 R183 or exon 5 Q209 mostly, and these hotspot mutations are considered driver mutations in uveal melanoma by blocking intrinsic GTPase activity and activating downstream pathways constitutively.	('activating', 'Reg', (195, 205))	('activity', 'MPA', (182, 190))	('GTP', 'Chemical', 'MESH:D006160', (175, 178))	('intrinsic', 'Protein', (165, 174))	('GNA11', 'Gene', (8, 13))	('uveal melanoma', 'Disease', (138, 152))	('GNAQ', 'Gene', '2776', (0, 4))	('uveal melanoma', 'Disease', 'MESH:C536494', (138, 152))	('uveal melanoma', 'Phenotype', 'HP:0007716', (138, 152))	('GNA11', 'Gene', '2767', (8, 13))	('blocking', 'NegReg', (156, 164))	('downstream pathways', 'Pathway', (206, 225))	('GNAQ', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('GTPase activity', 'molecular_function', 'GO:0003924', ('175', '190'))	('mutations', 'Var', (14, 23))
121235	26825879	In our patient, GNA11 Q209L mutation was detected by a next-generation sequencing platform.	('Q209L', 'Var', (22, 27))	('GNA11', 'Gene', (16, 21))	('patient', 'Species', '9606', (7, 14))	('GNA11', 'Gene', '2767', (16, 21))	('Q209L', 'Mutation', 'rs1057519742', (22, 27))
121236	26825879	Most cutaneous melanomas (up to 70%) have a dysregulated MAPK pathway via BRAF (50%) or NRAS mutations (15-20%), which promote uncontrolled proliferation and growth.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (5, 23))	('dysregulated', 'Reg', (44, 56))	('mutations', 'Var', (93, 102))	('cutaneous melanomas', 'Disease', (5, 24))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('BRAF', 'Gene', (74, 78))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('promote', 'PosReg', (119, 126))	('MAPK', 'molecular_function', 'GO:0004707', ('57', '61'))	('NRAS', 'Gene', (88, 92))	('uncontrolled', 'MPA', (127, 139))	('MAPK pathway', 'Pathway', (57, 69))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (5, 24))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (5, 24))	('growth', 'CPA', (158, 164))
121237	26825879	However, cutaneous melanomas rarely harbor GNAQ/GNA11 mutations which were reported in primary uveal melanoma at a frequency up to 80%.	('primary uveal melanoma', 'Disease', 'MESH:C536494', (87, 109))	('primary uveal melanoma', 'Disease', (87, 109))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('GNAQ', 'Gene', (43, 47))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('mutations', 'Var', (54, 63))	('GNA11', 'Gene', '2767', (48, 53))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (9, 27))	('GNA11', 'Gene', (48, 53))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (9, 28))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (9, 28))	('uveal melanoma', 'Phenotype', 'HP:0007716', (95, 109))	('cutaneous melanomas', 'Disease', (9, 28))	('GNAQ', 'Gene', '2776', (43, 47))
121241	26825879	Recently, GNA11 R183C mutation has been identified in 1 cutaneous origin melanoma cell line.	('melanoma', 'Disease', (73, 81))	('R183C', 'Mutation', 'p.R183C', (16, 21))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('GNA11', 'Gene', '2767', (10, 15))	('R183C', 'Var', (16, 21))	('GNA11', 'Gene', (10, 15))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
121242	26825879	However, it is not clear whether the original cutaneous melanoma sample harbors GNA11 mutation as several studies have demonstrated significant genomic difference between cancer cell lines and original tissue samples.	('GNA11', 'Gene', '2767', (80, 85))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('cutaneous melanoma', 'Disease', (46, 64))	('mutation', 'Var', (86, 94))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('GNA11', 'Gene', (80, 85))
121243	26825879	In addition, Griewank et al reported abnormally high frequency of BRAF V600E mutations in uveal melanoma cell lines; suggesting contamination in laboratories that handle both cutaneous and uveal melanoma samples; furthermore, multiple studies failed to identify BRAF mutations in original uveal melanoma tissue, which also suggests genomic difference between melanoma cell lines and original melanoma tissues.	('melanoma', 'Phenotype', 'HP:0002861', (359, 367))	('melanoma', 'Disease', (359, 367))	('melanoma', 'Phenotype', 'HP:0002861', (295, 303))	('melanoma', 'Disease', (295, 303))	('original melanoma', 'Disease', (383, 400))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('uveal melanoma', 'Disease', (90, 104))	('uveal melanoma', 'Disease', 'MESH:C536494', (90, 104))	('uveal melanoma', 'Disease', 'MESH:C536494', (289, 303))	('melanoma', 'Disease', 'MESH:D008545', (392, 400))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('V600E mutations', 'Var', (71, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('original melanoma', 'Disease', 'MESH:D008545', (383, 400))	('uveal melanoma', 'Phenotype', 'HP:0007716', (289, 303))	('melanoma', 'Disease', (96, 104))	('melanoma', 'Disease', 'MESH:D008545', (359, 367))	('mutations', 'Var', (77, 86))	('melanoma', 'Disease', 'MESH:D008545', (295, 303))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('uveal melanoma', 'Disease', 'MESH:C536494', (189, 203))	('melanoma', 'Phenotype', 'HP:0002861', (392, 400))	('uveal melanoma', 'Disease', (189, 203))	('melanoma', 'Disease', (392, 400))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('original uveal melanoma', 'Disease', (280, 303))	('original uveal melanoma', 'Disease', 'MESH:C536494', (280, 303))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('uveal melanoma', 'Phenotype', 'HP:0007716', (189, 203))	('BRAF', 'Gene', (66, 70))
121244	26825879	Another possibility is that our patient has malignant blue nevus as GNAQ/GNA11 mutations have been described in benign and malignant blue nevus.	('GNA11', 'Gene', (73, 78))	('GNA11', 'Gene', '2767', (73, 78))	('GNAQ', 'Gene', (68, 72))	('malignant blue nevus', 'Disease', (44, 64))	('blue nevus', 'Phenotype', 'HP:0100814', (54, 64))	('blue nevus', 'Phenotype', 'HP:0100814', (133, 143))	('nevus', 'Phenotype', 'HP:0003764', (59, 64))	('patient', 'Species', '9606', (32, 39))	('GNAQ', 'Gene', '2776', (68, 72))	('mutations', 'Var', (79, 88))	('nevus', 'Phenotype', 'HP:0003764', (138, 143))
121246	26825879	Previously, an increase in frequency of GNA11 mutations from primary to metastatic uveal melanomas has been reported.	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('mutations', 'Var', (46, 55))	('GNA11', 'Gene', (40, 45))	('GNA11', 'Gene', '2767', (40, 45))	('primary', 'Disease', (61, 68))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('uveal melanomas', 'Disease', (83, 98))	('uveal melanomas', 'Phenotype', 'HP:0007716', (83, 98))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('uveal melanomas', 'Disease', 'MESH:C536494', (83, 98))
121248	26825879	Unfortunately, the GNA11 mutation test of the primary lesion and metastatic lymph nodes was not performed due to insufficient samples.	('GNA11', 'Gene', '2767', (19, 24))	('mutation', 'Var', (25, 33))	('GNA11', 'Gene', (19, 24))
121249	26825879	As GNAQ/GNA11 mutations are associated with activation of the MAPK pathway similar to BRAF and NRAS mutations, and a selective MEK inhibitor has demonstrated activity in metastatic uveal melanoma with GNAQ/GNA11 mutations in a Phase II clinical trial, the patient might have experienced clinical benefit from an MEK inhibitor.	('GNA11', 'Gene', (8, 13))	('MEK', 'Gene', (127, 130))	('activation', 'PosReg', (44, 54))	('GNA11', 'Gene', (206, 211))	('GNAQ', 'Gene', '2776', (201, 205))	('mutations', 'Var', (212, 221))	('GNAQ', 'Gene', (201, 205))	('mutations', 'Var', (14, 23))	('activity', 'MPA', (158, 166))	('GNAQ', 'Gene', '2776', (3, 7))	('MEK', 'Gene', '5609', (312, 315))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('GNA11', 'Gene', '2767', (8, 13))	('GNAQ', 'Gene', (3, 7))	('uveal melanoma', 'Disease', 'MESH:C536494', (181, 195))	('uveal melanoma', 'Disease', (181, 195))	('GNA11', 'Gene', '2767', (206, 211))	('MEK', 'Gene', (312, 315))	('MAPK pathway', 'Pathway', (62, 74))	('MEK', 'Gene', '5609', (127, 130))	('MAPK', 'molecular_function', 'GO:0004707', ('62', '66'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (181, 195))	('patient', 'Species', '9606', (256, 263))
121250	26825879	There is no data regarding any effects of GNAQ/11 mutations on BRAF or NRAS mutations, which are the most common oncogenic mutations in cutaneous melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (136, 154))	('melanomas', 'Phenotype', 'HP:0002861', (146, 155))	('mutations', 'Var', (76, 85))	('cutaneous melanomas', 'Disease', (136, 155))	('GNAQ', 'Gene', '2776', (42, 46))	('NRAS', 'Gene', (71, 75))	('GNAQ', 'Gene', (42, 46))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (136, 155))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (136, 155))	('BRAF', 'Gene', (63, 67))
121251	26825879	However, it is possible that mutations in GNAQ/11, BRAF, or NRAS are mutually exclusive similar to BRAF and NRAS mutations as co-mutations of GNAQ/11 and BRAF or NRAS have not been reported, and all these mutations activate the same MAPK pathway.	('MAPK pathway', 'Pathway', (233, 245))	('GNAQ', 'Gene', '2776', (42, 46))	('mutations', 'Var', (29, 38))	('mutations', 'Var', (205, 214))	('GNAQ', 'Gene', (142, 146))	('GNAQ', 'Gene', '2776', (142, 146))	('GNAQ', 'Gene', (42, 46))	('activate', 'PosReg', (215, 223))	('MAPK', 'molecular_function', 'GO:0004707', ('233', '237'))
121252	26825879	As far as we are aware, our case is the first documented cutaneous origin melanoma harboring a GNA11 mutation.	('GNA11', 'Gene', (95, 100))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('GNA11', 'Gene', '2767', (95, 100))	('mutation', 'Var', (101, 109))
121262	27043545	To date, the occurrence and development of eye diseases have been primarily attributed to specific gene mutations, such as RB1 for retinoblastoma and GNAQ, GNA11, EIF1AX, SF3B1, BAP1, and PLCB4 for uveal melanoma.	('BAP1', 'Gene', (178, 182))	('GNA11', 'Gene', '2767', (156, 161))	('SF3B1', 'Gene', '23451', (171, 176))	('GNAQ', 'Gene', (150, 154))	('mutations', 'Var', (104, 113))	('retinoblastoma', 'Gene', '5925', (131, 145))	('PLCB4', 'Gene', (188, 193))	('eye diseases', 'Disease', 'MESH:D005128', (43, 55))	('RB1', 'Gene', (123, 126))	('retinoblastoma', 'Phenotype', 'HP:0009919', (131, 145))	('EIF1AX', 'Gene', (163, 169))	('GNA11', 'Gene', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('uveal melanoma', 'Disease', 'MESH:C536494', (198, 212))	('uveal melanoma', 'Disease', (198, 212))	('SF3B1', 'Gene', (171, 176))	('RB1', 'Gene', '5925', (123, 126))	('PLCB4', 'Gene', '5332', (188, 193))	('EIF1AX', 'Gene', '1964', (163, 169))	('BAP1', 'Gene', '8314', (178, 182))	('eye diseases', 'Phenotype', 'HP:0000478', (43, 55))	('uveal melanoma', 'Phenotype', 'HP:0007716', (198, 212))	('retinoblastoma', 'Gene', (131, 145))	('eye diseases', 'Disease', (43, 55))	('attributed', 'Reg', (76, 86))	('GNAQ', 'Gene', '2776', (150, 154))
121263	27043545	Epigenetics has recently emerged as an increasingly powerful paradigm for understanding and potentially explaining the onset and progression of some ocular diseases.	('ocular diseases', 'Disease', (149, 164))	('ocular diseases', 'Phenotype', 'HP:0000478', (149, 164))	('Epigenetics', 'Var', (0, 11))	('ocular diseases', 'Disease', 'MESH:D005128', (149, 164))
121286	27043545	This study provides a novel insight into CN pathogenesis, namely that lncRNAs can perform pro-angiogenic or anti-angiogenicroles in vascularization, and dysregulated lncRNAs may, thus, become potential targets for prevention or treatment.	('pathogenesis', 'biological_process', 'GO:0009405', ('44', '56'))	('ncRNA', 'Gene', (167, 172))	('ncRNA', 'Gene', (71, 76))	('anti-angiogenicroles', 'CPA', (108, 128))	('vascularization', 'CPA', (132, 147))	('dysregulated', 'Var', (153, 165))	('ncRNA', 'Gene', '54719', (71, 76))	('ncRNA', 'Gene', '54719', (167, 172))	('pro-angiogenic', 'CPA', (90, 104))
121288	27043545	Evidence from several studies has shown that genetic variants at the chromosome 9p21 locus, including CDKN2B-AS1, CDKN2A, and CDKN2B genes, are associated with POAG.	('POAG', 'Disease', (160, 164))	('CDKN2A', 'Gene', '1029', (114, 120))	('CDKN2A', 'Gene', (114, 120))	('associated', 'Reg', (144, 154))	('CDKN2B-AS1', 'Gene', '100048912', (102, 112))	('chromosome', 'cellular_component', 'GO:0005694', ('69', '79'))	('CDKN2B', 'Gene', (126, 132))	('CDKN2B', 'Gene', (102, 108))	('CDKN2B-AS1', 'Gene', (102, 112))	('CDKN2B', 'Gene', '1030', (126, 132))	('CDKN2B', 'Gene', '1030', (102, 108))	('variants', 'Var', (53, 61))
121292	27043545	The extensive roles of ANRIL in disease were discovered in a series of linkage studies, in which single-nucleotide polymorphisms (SNPs) in a region spanning 120 kb around the INK4b-ARF-INK4a locus were associated with disease.	('INK4b', 'Gene', '1030', (175, 180))	('ANRIL', 'Gene', (23, 28))	('associated', 'Reg', (202, 212))	('single-nucleotide polymorphisms', 'Var', (97, 128))	('disease', 'Disease', (218, 225))	('ANRIL', 'Gene', '100048912', (23, 28))	('INK4b', 'Gene', (175, 180))
121294	27043545	One possible explanation is that the occurrence of polymorphisms at these loci alters the expression of target genes that regulate the cell cycle or acts through epigenetic mechanisms, subsequently inducing a tendency toward retinal ganglion cell apoptosis and glaucoma.	('apoptosis', 'biological_process', 'GO:0097194', ('247', '256'))	('glaucoma', 'Disease', 'MESH:D005901', (261, 269))	('cell cycle', 'biological_process', 'GO:0007049', ('135', '145'))	('apoptosis', 'biological_process', 'GO:0006915', ('247', '256'))	('expression', 'MPA', (90, 100))	('alters', 'Reg', (79, 85))	('inducing', 'Reg', (198, 206))	('retinal ganglion cell apoptosis', 'CPA', (225, 256))	('polymorphisms', 'Var', (51, 64))	('glaucoma', 'Phenotype', 'HP:0000501', (261, 269))	('occurrence', 'Var', (37, 47))	('glaucoma', 'Disease', (261, 269))
121295	27043545	Another study identified associations between 9p21 variants and glaucoma features, suggesting that the ANRIL region modifies the vulnerability of the optic nerve to glaucomatous change, further implying a role of ANRIL in modulating optic nerve degeneration.	('glaucoma', 'Disease', (165, 173))	('ANRIL', 'Gene', '100048912', (213, 218))	('glaucoma', 'Disease', 'MESH:D005901', (165, 173))	('variants', 'Var', (51, 59))	('ANRIL', 'Gene', (103, 108))	('glaucomatous change', 'Disease', 'MESH:D009402', (165, 184))	('associations', 'Interaction', (25, 37))	('optic nerve degeneration', 'Disease', (233, 257))	('glaucoma', 'Phenotype', 'HP:0000501', (165, 173))	('ANRIL', 'Gene', (213, 218))	('optic nerve degeneration', 'Phenotype', 'HP:0000648', (233, 257))	('vulnerability', 'MPA', (129, 142))	('glaucoma', 'Phenotype', 'HP:0000501', (64, 72))	('modifies', 'Reg', (116, 124))	('glaucoma', 'Disease', (64, 72))	('glaucoma', 'Disease', 'MESH:D005901', (64, 72))	('glaucomatous change', 'Disease', (165, 184))	('ANRIL', 'Gene', '100048912', (103, 108))	('glaucomatous change', 'Phenotype', 'HP:0000501', (165, 184))	('optic nerve degeneration', 'Disease', 'MESH:D009410', (233, 257))
121313	27043545	Moreover, MIAT knockdown inhibits the up-regulation of TNF-alpha and ICAM-1, thereby alleviating vascular leakage and inflammation; as these are the key features of different stages of DR, MIAT knockdown shows an impressive therapeutic benefit.	('up-regulation', 'PosReg', (38, 51))	('inflammation', 'Disease', 'MESH:D007249', (118, 130))	('ICAM-1', 'Gene', '3383', (69, 75))	('inhibits', 'NegReg', (25, 33))	('knockdown', 'Var', (15, 24))	('knockdown', 'Var', (194, 203))	('inflammation', 'Disease', (118, 130))	('alleviating', 'NegReg', (85, 96))	('vascular leakage', 'CPA', (97, 113))	('TNF-alpha', 'Gene', '7124', (55, 64))	('ICAM-1', 'Gene', (69, 75))	('MIAT', 'Gene', '440823', (10, 14))	('MIAT', 'Gene', '440823', (189, 193))	('regulation', 'biological_process', 'GO:0065007', ('41', '51'))	('inflammation', 'biological_process', 'GO:0006954', ('118', '130'))	('TNF-alpha', 'Gene', (55, 64))	('MIAT', 'Gene', (10, 14))	('MIAT', 'Gene', (189, 193))
121348	27043545	SF3B1 mutations are associated with a good prognosis for uveal melanoma.	('SF3B1', 'Gene', (0, 5))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('SF3B1', 'Gene', '23451', (0, 5))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('uveal melanoma', 'Disease', (57, 71))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('mutations', 'Var', (6, 15))
121349	27043545	Recently, an RNA-seq analysis showed that mutations in SF3B1 are associated with cryptic alternative splicing within exon 4 of CRNDE, indicating that this lncRNA has potential importance for determining how alternative splicing affects cellular function.	('SF3B1', 'Gene', '23451', (55, 60))	('affects', 'Reg', (228, 235))	('ncRNA', 'Gene', (156, 161))	('splicing', 'biological_process', 'GO:0045292', ('101', '109'))	('splicing', 'biological_process', 'GO:0045292', ('219', '227'))	('associated', 'Reg', (65, 75))	('ncRNA', 'Gene', '54719', (156, 161))	('CRNDE', 'Gene', (127, 132))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('SF3B1', 'Gene', (55, 60))	('CRNDE', 'Gene', '643911', (127, 132))	('cryptic alternative splicing', 'MPA', (81, 109))	('mutations', 'Var', (42, 51))
121361	27043545	studied the lncRNAs of the corneal epithelium by focusing on a small subset of lncRNAs that exhibit splicing changes in response to PNN knockdown.	('splicing', 'biological_process', 'GO:0045292', ('100', '108'))	('PNN', 'Gene', '5411', (132, 135))	('PNN', 'cellular_component', 'GO:0072534', ('132', '135'))	('ncRNA', 'Gene', '54719', (80, 85))	('knockdown', 'Var', (136, 145))	('ncRNA', 'Gene', (13, 18))	('splicing changes', 'MPA', (100, 116))	('ncRNA', 'Gene', '54719', (13, 18))	('PNN', 'Gene', (132, 135))	('ncRNA', 'Gene', (80, 85))
121364	27043545	performed an RNA-seq analysis and identified 86 differentially-expressed lncRNAs between lens epithelial cells and lens fiber cells; they included RP23-237H8.2, AC135859.1, AL663030.1, AC128663.1, and AC100730.1.	('AL663030.1', 'Var', (173, 183))	('ncRNA', 'Gene', (74, 79))	('RP23', 'Gene', '8481', (147, 151))	('RP23', 'Gene', (147, 151))	('AC135859.1', 'Var', (161, 171))	('AC128663.1', 'Var', (185, 195))	('ncRNA', 'Gene', '54719', (74, 79))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('AC100730.1', 'Var', (201, 211))
121381	21499235	Frequency, molecular pathology and potential clinical significance of partial chromosome 3 aberrations in uveal melanoma The clinical significance of partial chromosome 3 alteration in uveal melanoma is still not clear.	('partial chromosome 3 aberrations', 'Var', (70, 102))	('chromosome', 'cellular_component', 'GO:0005694', ('158', '168'))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('chromosome', 'cellular_component', 'GO:0005694', ('78', '88'))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('uveal melanoma', 'Disease', (106, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (185, 199))	('uveal melanoma', 'Disease', (185, 199))	('uveal melanoma', 'Disease', 'MESH:C536494', (185, 199))
121382	21499235	The aims of the following study were to identify the frequency, molecular pathology and potential clinical significance of partial chromosome 3 alteration in uveal melanoma.	('chromosome', 'cellular_component', 'GO:0005694', ('131', '141'))	('alteration', 'Var', (144, 154))	('partial chromosome 3', 'Gene', (123, 143))	('uveal melanoma', 'Disease', 'MESH:C536494', (158, 172))	('uveal melanoma', 'Phenotype', 'HP:0007716', (158, 172))	('uveal melanoma', 'Disease', (158, 172))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))
121385	21499235	Utilizing genotyping, partial chromosome 3 alteration was detected in 14/47 tumors (30%).	('detected', 'Reg', (58, 66))	('chromosome', 'cellular_component', 'GO:0005694', ('30', '40'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('partial chromosome', 'Var', (22, 40))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
121386	21499235	In the 23 tumors with available cytogenetic/CGH, partial chromosome 3 alteration was detected in 8/23 (38%) and was caused by both gains (4/8) and losses (4/8) of chromosome 3 with high frequency of complex chromosome 3 aberrations detected by cytogenetics.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('chromosome', 'cellular_component', 'GO:0005694', ('163', '173'))	('gains', 'PosReg', (131, 136))	('partial chromosome', 'Var', (49, 67))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('caused by', 'Reg', (116, 125))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('chromosome', 'cellular_component', 'GO:0005694', ('57', '67'))	('losses', 'NegReg', (147, 153))	('chromosome', 'cellular_component', 'GO:0005694', ('207', '217'))	('alteration', 'Reg', (70, 80))
121387	21499235	Out of the 14 tumors with confirmed metastasis, only 1 showed partial chromosome 3 alteration and the remaining showed monosomy 3.	('partial chromosome', 'Var', (62, 80))	('14 tumors', 'Disease', 'MESH:C567448', (11, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('chromosome', 'cellular_component', 'GO:0005694', ('70', '80'))	('14 tumors', 'Disease', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
121389	21499235	In conclusion, partial chromosome 3 alterations are common in uveal melanoma and mostly caused by complex cytogenetic changes leading to partial gains and/or partial losses of chromosome 3.	('gains', 'PosReg', (145, 150))	('uveal melanoma', 'Disease', (62, 76))	('caused by', 'Reg', (88, 97))	('chromosome', 'cellular_component', 'GO:0005694', ('23', '33'))	('losses', 'NegReg', (166, 172))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('partial chromosome', 'Var', (15, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('176', '186'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (62, 76))	('uveal melanoma', 'Disease', 'MESH:C536494', (62, 76))
121390	21499235	Partial chromosome 3 alteration is not likely to be associated with highly aggressive uveal melanoma that metastasizes within the first 3 years after treatment.	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('Partial chromosome 3', 'Gene', (0, 20))	('associated', 'Reg', (52, 62))	('aggressive uveal melanoma', 'Disease', (75, 100))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('alteration', 'Var', (21, 31))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('aggressive uveal melanoma', 'Disease', 'MESH:C536494', (75, 100))
121391	21499235	Microsatellite-based genotyping of chromosome 3 is highly sensitive for detection of aggressive uveal melanoma.	('Microsatellite-based', 'Var', (0, 20))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('aggressive uveal melanoma', 'Disease', (85, 110))	('chromosome', 'cellular_component', 'GO:0005694', ('35', '45'))	('aggressive uveal melanoma', 'Disease', 'MESH:C536494', (85, 110))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))
121392	21499235	Monosomy of chromosome 3 is one of the most common genetic alterations in uveal melanoma with reported frequencies ranging between 30 and 50%.	('Monosomy', 'Var', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('uveal melanoma', 'Disease', (74, 88))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))
121393	21499235	Based on such findings, monosomy 3 is currently being used in many clinical centers as a prognostic marker to identify aggressive uveal melanomas.	('uveal melanomas', 'Phenotype', 'HP:0007716', (130, 145))	('aggressive uveal melanomas', 'Disease', 'MESH:C536494', (119, 145))	('aggressive uveal melanomas', 'Disease', (119, 145))	('melanomas', 'Phenotype', 'HP:0002861', (136, 145))	('uveal melanoma', 'Phenotype', 'HP:0007716', (130, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('monosomy', 'Var', (24, 32))
121394	21499235	Contrary to the well-documented clinical significance of monosomy 3, little is known about the clinical significance of partial chromosome 3 alterations in uveal melanoma.	('alterations', 'Var', (141, 152))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('chromosome', 'cellular_component', 'GO:0005694', ('128', '138'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (156, 170))	('uveal melanoma', 'Disease', (156, 170))	('uveal melanoma', 'Disease', 'MESH:C536494', (156, 170))	('partial chromosome 3', 'Gene', (120, 140))
121395	21499235	The frequency of partial chromosome 3 alteration in uveal melanoma varies markedly in the published reports from 0 to 48% (Table 1).	('uveal melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('uveal melanoma', 'Disease', (52, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (52, 66))	('chromosome', 'cellular_component', 'GO:0005694', ('25', '35'))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('partial chromosome', 'Var', (17, 35))
121396	21499235	Although the vast majority of authors considered that it is caused by small deletions, it should be noted that genotyping, which was utilized by most of these reports, cannot reliably differentiate between deletions and other molecular mechanisms causing allelic imbalances, including mitotic recombination, aneuploidy and amplification.	('mitotic recombination', 'Disease', (285, 306))	('aneuploidy', 'Disease', 'MESH:D000782', (308, 318))	('mitotic recombination', 'biological_process', 'GO:0006312', ('285', '306'))	('imbalance', 'Phenotype', 'HP:0002172', (263, 272))	('aneuploidy', 'Disease', (308, 318))	('amplification', 'Disease', (323, 336))	('caused', 'Reg', (60, 66))	('deletions', 'Var', (76, 85))	('imbalances', 'Phenotype', 'HP:0002172', (263, 273))
121397	21499235	Few reports showed that partial chromosome 3 gains and unbalanced translocations could be involved in the pathogenesis of partial chromosome 3 alteration in uveal melanoma.	('gains', 'PosReg', (45, 50))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('partial chromosome 3 alteration', 'Var', (122, 153))	('involved', 'Reg', (90, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (157, 171))	('chromosome', 'cellular_component', 'GO:0005694', ('130', '140'))	('pathogenesis', 'biological_process', 'GO:0009405', ('106', '118'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (157, 171))	('partial', 'Gene', (24, 31))	('chromosome', 'cellular_component', 'GO:0005694', ('32', '42'))	('uveal melanoma', 'Disease', (157, 171))
121398	21499235	The aims of this study were to identify the frequency, clinical significance and potential molecular pathogenesis of partial chromosome 3 alteration in uveal melanoma.	('chromosome', 'cellular_component', 'GO:0005694', ('125', '135'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (152, 166))	('uveal melanoma', 'Disease', 'MESH:C536494', (152, 166))	('uveal melanoma', 'Disease', (152, 166))	('pathogenesis', 'biological_process', 'GO:0009405', ('101', '113'))	('partial', 'Var', (117, 124))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))
121421	21499235	Of the 11 samples with available cytogenetics, monosomy 3 was detected in 6 samples (55%), partial chromosome 3 alteration in 3 samples (27%) and heterodisomy 3 in 2 samples (18%) (Table 3).	('detected', 'Reg', (62, 70))	('monosomy 3', 'Var', (47, 57))	('heterodisomy', 'Disease', (146, 158))	('chromosome', 'cellular_component', 'GO:0005694', ('99', '109'))	('partial chromosome 3 alteration', 'Var', (91, 122))	('heterodisomy', 'Disease', 'MESH:D024182', (146, 158))
121422	21499235	Of the 12 samples with available CGH, 7 samples (58%) showed monosomy 3, 4 samples showed partial chromosome 3 alterations (33%) and 1 sample showed disomy of chromosome 3 (8%).	('monosomy 3', 'Var', (61, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('98', '108'))	('partial chromosome', 'Var', (90, 108))	('disomy', 'Disease', 'MESH:D024182', (149, 155))	('disomy', 'Disease', (149, 155))	('chromosome', 'cellular_component', 'GO:0005694', ('159', '169'))
121424	21499235	Only three tumors with partial chromosome 3 alterations showed areas with allelic imbalance factor of >=5.	('chromosome', 'cellular_component', 'GO:0005694', ('31', '41'))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('partial chromosome 3', 'Gene', (23, 43))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('imbalance', 'Phenotype', 'HP:0002172', (82, 91))	('tumors', 'Disease', (11, 17))	('alterations', 'Var', (44, 55))
121426	21499235	This observation suggests that in the majority of tumors with partial chromosome 3 alteration, the frequency of tumor heterogeneity, including tumor cells lacking genetic alteration in chromosome 3, is much higher than in monosomy 3 tumors.	('chromosome', 'cellular_component', 'GO:0005694', ('185', '195'))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Disease', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('chromosome', 'cellular_component', 'GO:0005694', ('70', '80'))	('partial chromosome 3 alteration', 'Var', (62, 93))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (143, 148))	('tumors', 'Disease', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumors', 'Disease', (50, 56))	('higher', 'PosReg', (207, 213))
121427	21499235	The clinical significance of partial chromosome 3 alteration was assessed in a subset of patients with confirmed metastasis (14 patients) or a clinical follow-up of at least 36 months (additional 18 patients), using metastasis as the marker for aggressive disease.	('partial', 'Var', (29, 36))	('chromosome', 'cellular_component', 'GO:0005694', ('37', '47'))	('aggressive disease', 'Disease', (245, 263))	('alteration', 'Var', (50, 60))	('patients', 'Species', '9606', (89, 97))	('metastasis', 'CPA', (113, 123))	('patients', 'Species', '9606', (199, 207))	('patients', 'Species', '9606', (128, 136))	('aggressive disease', 'Disease', 'MESH:D001523', (245, 263))
121429	21499235	The difference in the incidence of metastasis between patients with monosomy 3 (13/19) and partial chromosome 3 alteration (1/9) was statistically significant (P = 0.005, Fisher's exact test).	('metastasis', 'CPA', (35, 45))	('monosomy 3', 'Var', (68, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('99', '109'))	('partial chromosome 3 alteration', 'Var', (91, 122))	('patients', 'Species', '9606', (54, 62))
121430	21499235	Also, Kaplan-Meier analysis showed a significant association of monosomy 3, but not partial chromosome 3 alteration, with aggressive disease (log rank test, P = 0.01, Figure 3).	('monosomy 3', 'Var', (64, 74))	('aggressive disease', 'Disease', (122, 140))	('chromosome', 'cellular_component', 'GO:0005694', ('92', '102'))	('aggressive disease', 'Disease', 'MESH:D001523', (122, 140))
121431	21499235	Of the eight tumors with partial chromosome 3 alteration and >36 months of metastasis-free survival (mean 67 months, range 39-119 months), 3 showed partial gains and 5 had partial losses.	('chromosome', 'cellular_component', 'GO:0005694', ('33', '43'))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('partial chromosome', 'Var', (25, 43))
121432	21499235	Tumors from four of the patients with partial loss showed allelic imbalance in, or nearby, the smallest region of deletion overlap previously reported in uveal melanoma.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('imbalance', 'Phenotype', 'HP:0002172', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('allelic imbalance', 'Var', (58, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (154, 168))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('patients', 'Species', '9606', (24, 32))	('uveal melanoma', 'Disease', (154, 168))	('uveal melanoma', 'Disease', 'MESH:C536494', (154, 168))
121434	21499235	Combining monosomy 3 and partial chromosome 3 alterations as markers of tumor aggressiveness yielded 100% sensitivity but only 28% specificity for prediction of patients who developed metastasis.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (72, 92))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('chromosome', 'cellular_component', 'GO:0005694', ('33', '43'))	('aggressiveness', 'Phenotype', 'HP:0000718', (78, 92))	('alterations', 'Var', (46, 57))	('monosomy', 'Var', (10, 18))	('tumor aggressiveness', 'Disease', (72, 92))	('patients', 'Species', '9606', (161, 169))	('partial', 'Gene', (25, 32))
121435	21499235	Limiting the assay to monosomy 3 with exclusion of partial chromosome 3 alterations slightly diminished the sensitivity to 93% but improved the assay specificity to 67%, whereas inclusion of samples with partial chromosome 3 alterations with areas of allelic imbalance factor of >=5 (two tumors) showed 100% sensitivity and 61% specificity for detection of aggressive disease.	('specificity', 'MPA', (150, 161))	('tumors', 'Disease', (288, 294))	('chromosome', 'cellular_component', 'GO:0005694', ('59', '69'))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('alterations', 'Var', (72, 83))	('imbalance', 'Phenotype', 'HP:0002172', (259, 268))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('aggressive disease', 'Disease', 'MESH:D001523', (357, 375))	('sensitivity', 'MPA', (108, 119))	('improved', 'PosReg', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('aggressive disease', 'Disease', (357, 375))	('chromosome', 'cellular_component', 'GO:0005694', ('212', '222'))	('diminished', 'NegReg', (93, 103))
121436	21499235	These results suggest that the majority of partial chromosome 3 alterations are not associated with aggressive disease.	('partial chromosome', 'Gene', (43, 61))	('chromosome', 'cellular_component', 'GO:0005694', ('51', '61'))	('alterations', 'Var', (64, 75))	('aggressive disease', 'Disease', 'MESH:D001523', (100, 118))	('aggressive disease', 'Disease', (100, 118))
121440	21499235	Our results indicate that the majority of partial chromosome 3 alterations, especially the cases due to gains of chromosomal materials, are not associated with aggressive disease.	('aggressive disease', 'Disease', 'MESH:D001523', (160, 178))	('alterations', 'Var', (63, 74))	('aggressive disease', 'Disease', (160, 178))	('chromosome', 'cellular_component', 'GO:0005694', ('50', '60'))	('partial chromosome', 'Var', (42, 60))
121441	21499235	Only 1 of the 14 tumors with confirmed metastasis showed partial chromosome 3 alteration, whereas the remaining aggressive tumors showed allelic losses of all the markers on chromosome 3.	('14 tumors', 'Disease', 'MESH:C567448', (14, 23))	('losses', 'NegReg', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('chromosome', 'cellular_component', 'GO:0005694', ('65', '75'))	('aggressive tumors', 'Disease', 'MESH:D001523', (112, 129))	('partial chromosome', 'Var', (57, 75))	('chromosome', 'cellular_component', 'GO:0005694', ('174', '184'))	('14 tumors', 'Disease', (14, 23))	('aggressive tumors', 'Disease', (112, 129))	('alteration', 'Reg', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
121442	21499235	The partial chromosome 3 case with metastatic disease was rather unique, with a bi-lobed tumor showing molecular genetic heterogeneity with monosomy 3 in one of the two tumor lobes whereas the other part of the tumor showed partial chromosome 3 loss (Figure 2).	('monosomy 3', 'Var', (140, 150))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('loss', 'NegReg', (245, 249))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('partial chromosome 3', 'Var', (224, 244))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', (169, 174))	('chromosome', 'cellular_component', 'GO:0005694', ('232', '242'))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))
121443	21499235	There are few reports of metastatic uveal melanoma showing partial chromosome 3 alterations.	('chromosome', 'cellular_component', 'GO:0005694', ('67', '77'))	('partial chromosome', 'Var', (59, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (36, 50))	('uveal melanoma', 'Disease', 'MESH:C536494', (36, 50))	('uveal melanoma', 'Disease', (36, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
121445	21499235	Trolet et al, using array CGH, reported four cases of partial chromosome 3 losses who developed metastatic disease and several metastatic uveal melanoma lesions with partial chromosome 3 losses.	('uveal melanoma lesions', 'Disease', (138, 160))	('uveal melanoma', 'Phenotype', 'HP:0007716', (138, 152))	('chromosome', 'cellular_component', 'GO:0005694', ('62', '72'))	('developed', 'PosReg', (86, 95))	('losses', 'NegReg', (75, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('174', '184'))	('uveal melanoma lesions', 'Disease', 'MESH:C536494', (138, 160))	('partial chromosome', 'Var', (54, 72))	('metastatic disease', 'CPA', (96, 114))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))
121447	21499235	It is worth noting that the original publications linking monosomy 3 to aggressive uveal melanoma utilized 3-year follow-up duration.	('aggressive uveal melanoma', 'Disease', (72, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('monosomy 3', 'Var', (58, 68))	('aggressive uveal melanoma', 'Disease', 'MESH:C536494', (72, 97))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))
121450	21499235	It is worth noting that we identified partial chromosome 3 alteration in the metastatic lesion of a patient who developed metastatic disease 20 years after treatment of the primary tumor (data not shown).	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('metastatic disease', 'Disease', (122, 140))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('patient', 'Species', '9606', (100, 107))	('alteration', 'Var', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('partial chromosome', 'Var', (38, 56))
121452	21499235	Our study indicates that the frequency of partial chromosome 3 alteration is rather high in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (92, 106))	('uveal melanoma', 'Disease', (92, 106))	('uveal melanoma', 'Disease', 'MESH:C536494', (92, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('chromosome', 'cellular_component', 'GO:0005694', ('50', '60'))	('partial chromosome', 'Var', (42, 60))
121453	21499235	Potential explanations of such variation include the methodology utilized, threshold for detecting genetic alteration, size of the tissue fragment studied, sample fixation, difference in ethnicity, tumor size, tumor heterogeneity or a combination of any of these factors.	('genetic alteration', 'Var', (99, 117))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
121455	21499235	This could be because of either deletion of one copy of chromosome 3 or loss and reduplication leading to acquired parental isodisomy.	('deletion', 'Var', (32, 40))	('parental isodisomy', 'Disease', 'MESH:D063129', (115, 133))	('loss', 'NegReg', (72, 76))	('reduplication', 'Var', (81, 94))	('chromosome', 'cellular_component', 'GO:0005694', ('56', '66'))	('parental isodisomy', 'Disease', (115, 133))
121456	21499235	On the other hand, the majority of cases with partial chromosome 3 alteration (85.7%) showed low allelic imbalance factor (<1.7), indicating significant heterogeneity of the tumors.	('chromosome', 'cellular_component', 'GO:0005694', ('54', '64'))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumors', 'Disease', (174, 180))	('partial chromosome 3 alteration', 'Var', (46, 77))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('imbalance', 'Phenotype', 'HP:0002172', (105, 114))	('low', 'NegReg', (93, 96))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
121458	21499235	The molecular pathogenesis of partial chromosome 3 alterations in uveal melanoma is largely believed to be caused by small deletions.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('uveal melanoma', 'Disease', (66, 80))	('alterations', 'Var', (51, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('pathogenesis', 'biological_process', 'GO:0009405', ('14', '26'))	('chromosome', 'cellular_component', 'GO:0005694', ('38', '48'))	('partial', 'Var', (30, 37))
121459	21499235	It has been suggested that such smallest regions of deletion overlap are the location of tumor-suppressor genes important in the pathogenesis of metastasizing uveal melanoma.	('pathogenesis', 'biological_process', 'GO:0009405', ('129', '141'))	('uveal melanoma', 'Disease', 'MESH:C536494', (159, 173))	('uveal melanoma', 'Phenotype', 'HP:0007716', (159, 173))	('uveal melanoma', 'Disease', (159, 173))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('metastasizing', 'Disease', (145, 158))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('89', '105'))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('deletion', 'Var', (52, 60))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('89', '105'))
121460	21499235	Our study indicates the high sensitivity of microsatellite-based genotyping for detection of highly aggressive uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (111, 125))	('microsatellite-based', 'Var', (44, 64))	('aggressive uveal melanoma', 'Disease', (100, 125))	('aggressive uveal melanoma', 'Disease', 'MESH:C536494', (100, 125))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
121463	21499235	In conclusion, our results suggest that partial chromosome 3 alteration is common in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (85, 99))	('uveal melanoma', 'Disease', 'MESH:C536494', (85, 99))	('partial chromosome', 'Var', (40, 58))	('chromosome', 'cellular_component', 'GO:0005694', ('48', '58'))	('uveal melanoma', 'Disease', (85, 99))
121464	21499235	The majority of partial chromosome 3 alterations are not associated with metastatic disease, in particular, rapidly aggressive tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('chromosome', 'cellular_component', 'GO:0005694', ('24', '34'))	('partial chromosome 3', 'Gene', (16, 36))	('aggressive tumors', 'Disease', 'MESH:D001523', (116, 133))	('alterations', 'Var', (37, 48))	('aggressive tumors', 'Disease', (116, 133))
121465	22937170	Therapeutic Efficacy by Targeting Correction of Notch1-Induced Aberrants in Uveal Tumors There is a need for more effective treatments for uveal melanoma.	('Aberrants', 'Var', (63, 72))	('Notch1', 'Gene', (48, 54))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('Tumors', 'Phenotype', 'HP:0002664', (82, 88))	('uveal melanoma', 'Disease', 'MESH:C536494', (139, 153))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('Notch1', 'Gene', '4851', (48, 54))	('Uveal Tumors', 'Disease', 'MESH:D014604', (76, 88))	('uveal melanoma', 'Disease', (139, 153))	('Tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Uveal Tumors', 'Disease', (76, 88))
121468	22937170	Combined treatment with siNotch1 and H101 (H101-Notch1-siRNA) greatly enhanced apoptosis and cell cycle arrest in vitro as compared to treatment with H101 or siNotch1 alone.	('H101', 'Chemical', '-', (37, 41))	('H101', 'Chemical', '-', (43, 47))	('Notch1', 'Gene', (48, 54))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('H101', 'Var', (37, 41))	('Notch1', 'Gene', '4851', (48, 54))	('H101', 'Chemical', '-', (150, 154))	('cell cycle arrest', 'CPA', (93, 110))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('enhanced', 'PosReg', (70, 78))	('apoptosis', 'CPA', (79, 88))	('Notch1', 'Gene', (26, 32))	('Notch1', 'Gene', (160, 166))	('Notch1', 'Gene', '4851', (160, 166))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('93', '110'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (93, 110))	('Notch1', 'Gene', '4851', (26, 32))
121478	22937170	Deletion of a 78.3- to 85.8-mum gene segment in the E3 region, which includes the adenovirus death protein, potentially enhances the safety of the product.	('adenovirus death', 'Disease', (82, 98))	('adenovirus death', 'Disease', 'MESH:D000257', (82, 98))	('enhances', 'PosReg', (120, 128))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('safety', 'MPA', (133, 139))	('Deletion', 'Var', (0, 8))
121479	22937170	The lack of E1B allows H101 to selectively infect and kill tumor cells through specific cell lysis if p53 is mutated, whereas H101 does not exhibit a significant cytopathic effect on normal cells in which p53 is active.	('H101', 'Chemical', '-', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('specific cell lysis', 'CPA', (79, 98))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', (205, 208))	('E1B', 'Gene', '6080', (12, 15))	('infect', 'Disease', (43, 49))	('H101', 'Chemical', '-', (126, 130))	('mutated', 'Var', (109, 116))	('p53', 'Gene', '7157', (205, 208))	('E1B', 'Gene', (12, 15))	('p53', 'Gene', (102, 105))	('lysis', 'biological_process', 'GO:0019835', ('93', '98'))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('infect', 'Disease', 'MESH:D007239', (43, 49))
121480	22937170	H101 is the first therapeutic anticancer drug approved for clinical use by State FDA (China) that selectively attacks tumor cells with a modified virus and does not harm healthy cells.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('modified', 'Var', (137, 145))	('H101', 'Chemical', '-', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Disease', (118, 123))	('cancer', 'Disease', (34, 40))
121486	22937170	It has been reported that targeted knockdown of Notch1 gene expression by a small interfering RNA inhibits the invasion of tumor growth and enhances apoptosis in a variety of tumor cells.	('apoptosis', 'CPA', (149, 158))	('knockdown', 'Var', (35, 44))	('tumor', 'Disease', (175, 180))	('Notch1', 'Gene', (48, 54))	('tumor', 'Disease', (123, 128))	('gene expression', 'biological_process', 'GO:0010467', ('55', '70'))	('Notch1', 'Gene', '4851', (48, 54))	('enhances', 'PosReg', (140, 148))	('apoptosis', 'biological_process', 'GO:0097194', ('149', '158'))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('RNA', 'cellular_component', 'GO:0005562', ('94', '97'))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('apoptosis', 'biological_process', 'GO:0006915', ('149', '158'))	('inhibits', 'NegReg', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
121493	22937170	Both cell lines contained the same mutation (C. 797G>A, P. Gly133Glu) in exon 7 (Figure 1D, E), while ARPE-19 cell line showed the wild-type sequence of p53 (Figure 1C).	('Gly133Glu', 'SUBSTITUTION', 'None', (59, 68))	('797G>A', 'Mutation', 'rs193920774', (48, 54))	('C. 797G>A', 'Var', (45, 54))	('ARPE-19', 'CellLine', 'CVCL:0145', (102, 109))	('p53', 'Gene', (153, 156))	('p53', 'Gene', '7157', (153, 156))	('Gly133Glu', 'Var', (59, 68))
121509	22937170	However, the combined approach of H101 with siNotch1 as well as monotherapy with either agent alone showed very limited effect on cell growth in ARPE-19 cell line (Figure 4B).	('cell growth', 'CPA', (130, 141))	('H101', 'Chemical', '-', (34, 38))	('ARPE-19', 'CellLine', 'CVCL:0145', (145, 152))	('H101', 'Var', (34, 38))	('Notch1', 'Gene', (46, 52))	('Notch1', 'Gene', '4851', (46, 52))	('cell growth', 'biological_process', 'GO:0016049', ('130', '141'))
121512	22937170	Cells infected with H101 exhibited moderate accumulation in S-phase.	('H101', 'Chemical', '-', (20, 24))	('infect', 'Disease', 'MESH:D007239', (6, 12))	('S-phase', 'biological_process', 'GO:0051320', ('60', '67'))	('H101', 'Var', (20, 24))	('S-phase', 'MPA', (60, 67))	('infect', 'Disease', (6, 12))	('accumulation', 'PosReg', (44, 56))
121513	22937170	This S-phase accumulation was even more prominent in cells treated with combined H101 and siNotch1, with a corresponding decrease in cells in G1 (*: p<0.05, **: p<0.01).	('H101', 'Chemical', '-', (81, 85))	('H101', 'Var', (81, 85))	('Notch1', 'Gene', (92, 98))	('decrease', 'NegReg', (121, 129))	('S-phase', 'MPA', (5, 12))	('Notch1', 'Gene', '4851', (92, 98))	('S-phase', 'biological_process', 'GO:0051320', ('5', '12'))
121515	22937170	Monotherapy with siNC, siNotch1, and H101 in OCM1 cells induced apoptosis at 72 hours in 1.48%, 1.73% and 4.74% of cells respectively.	('H101', 'Chemical', '-', (37, 41))	('siNC', 'Chemical', '-', (17, 21))	('Notch1', 'Gene', (25, 31))	('H101', 'Var', (37, 41))	('apoptosis', 'CPA', (64, 73))	('Notch1', 'Gene', '4851', (25, 31))	('OCM1', 'Species', '83984', (45, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('64', '73'))	('apoptosis', 'biological_process', 'GO:0006915', ('64', '73'))
121516	22937170	While, combined H101 and siNotch1 induced apoptosis in 11% of cells (Figure 5C).	('H101', 'Chemical', '-', (16, 20))	('Notch1', 'Gene', (27, 33))	('H101', 'Var', (16, 20))	('Notch1', 'Gene', '4851', (27, 33))	('apoptosis', 'CPA', (42, 51))	('apoptosis', 'biological_process', 'GO:0097194', ('42', '51'))	('apoptosis', 'biological_process', 'GO:0006915', ('42', '51'))
121525	22937170	Monotreatment with siNotch1 or H101 resulted in 19% and 25% reduction in tumor weight respectively.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Notch1', 'Gene', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Notch1', 'Gene', '4851', (21, 27))	('reduction', 'NegReg', (60, 69))	('tumor', 'Disease', (73, 78))	('H101', 'Chemical', '-', (31, 35))	('H101', 'Var', (31, 35))
121526	22937170	However, the combined treatment of H101 and siNotch1 led to a tumor weight reduction of 61% compared to the PBS group (n = 5, **: p<0.01) (Figure 6B).	('PBS', 'Disease', 'MESH:D011535', (108, 111))	('PBS', 'Disease', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('reduction', 'NegReg', (75, 84))	('H101', 'Chemical', '-', (35, 39))	('Notch1', 'Gene', (46, 52))	('Notch1', 'Gene', '4851', (46, 52))	('H101', 'Var', (35, 39))
121535	22937170	We discovered that p53 was mutated in our UM cells, at a site that is also mutated in cutaneous melanoma.	('mutated', 'Var', (27, 34))	('cutaneous melanoma', 'Disease', (86, 104))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (86, 104))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (86, 104))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))
121537	22937170	Enhanced cytotoxic effects were observed for the UM cell lines OCM1 and VUP treated with H101 (Figure 4C, D).	('H101', 'Chemical', '-', (89, 93))	('cytotoxic effects', 'CPA', (9, 26))	('OCM1', 'Species', '83984', (63, 67))	('H101', 'Var', (89, 93))	('Enhanced', 'PosReg', (0, 8))
121549	22937170	Consequently, we investigated whether it was possible to combine H101 with knockdown of certain proto-oncogenes, which may enhance the efficacy of the treatment.	('enhance', 'PosReg', (123, 130))	('H101', 'Chemical', '-', (65, 69))	('H101', 'Var', (65, 69))	('knockdown', 'MPA', (75, 84))
121550	22937170	In our previous study, we also observed synergistic effect when we combined H101 and siBCL2 in Bcl2 elevated UM cells by enhancing apoptosis and cell cycle arrest through Bax-p53 induced apoptotic pathway.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('145', '162'))	('Bax', 'Gene', '581', (171, 174))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (145, 162))	('Bcl2', 'molecular_function', 'GO:0015283', ('95', '99'))	('apoptosis', 'biological_process', 'GO:0097194', ('131', '140'))	('siBCL2', 'Gene', (85, 91))	('enhancing', 'PosReg', (121, 130))	('Bax', 'Gene', (171, 174))	('cell cycle arrest', 'CPA', (145, 162))	('apoptotic pathway', 'Pathway', (187, 204))	('Bcl2', 'Gene', '596', (95, 99))	('apoptosis', 'biological_process', 'GO:0006915', ('131', '140'))	('H101', 'Chemical', '-', (76, 80))	('apoptosis', 'CPA', (131, 140))	('p53', 'Gene', (175, 178))	('Bcl2', 'Gene', (95, 99))	('H101', 'Var', (76, 80))	('p53', 'Gene', '7157', (175, 178))
121552	22937170	This informed our decision to attempt to downregulate Notch1 using a small interfering RNA in vitro and in vivo.	('small interfering', 'Var', (69, 86))	('downregulate', 'NegReg', (41, 53))	('Notch1', 'Gene', (54, 60))	('RNA', 'cellular_component', 'GO:0005562', ('87', '90'))	('Notch1', 'Gene', '4851', (54, 60))
121556	22937170	Our finding that knockdown of Notch1 inhibited cancer cell growth are consistent with earlier studies.	('Notch1', 'Gene', '4851', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('inhibited', 'NegReg', (37, 46))	('cancer', 'Disease', (47, 53))	('knockdown', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cell growth', 'biological_process', 'GO:0016049', ('54', '65'))	('Notch1', 'Gene', (30, 36))
121557	22937170	Combined treatment with H101 and siNotch1 augmented the anti-proliferative effect of H101 on UM cells in vitro (Figure 4), confirming the potential efficacy of this strategy.	('H101', 'Chemical', '-', (85, 89))	('Notch1', 'Gene', (35, 41))	('augmented', 'PosReg', (42, 51))	('H101', 'Chemical', '-', (24, 28))	('H101', 'Var', (24, 28))	('Notch1', 'Gene', '4851', (35, 41))	('H101', 'Gene', (85, 89))	('anti-proliferative effect', 'MPA', (56, 81))
121585	22937170	Cells were harvested at 72 hours after H101 (MOI = 100) infection and siNotch1 transfection.	('H101', 'Chemical', '-', (39, 43))	('Notch1', 'Gene', (72, 78))	('infection', 'Disease', (56, 65))	('infection', 'Disease', 'MESH:D007239', (56, 65))	('Notch1', 'Gene', '4851', (72, 78))	('transfection', 'Var', (79, 91))
121597	21083380	Mutations in GNA11 in Uveal Melanoma Uveal melanoma is the most common intraocular cancer.	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (22, 36))	('Melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (37, 51))	('Uveal melanoma', 'Disease', 'MESH:C536494', (37, 51))	('Melanoma', 'Disease', 'MESH:D008545', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('intraocular cancer', 'Disease', 'MESH:D064090', (71, 89))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('GNA11', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('Melanoma', 'Disease', (28, 36))	('GNA11', 'Gene', '14672', (13, 18))	('Uveal melanoma', 'Disease', (37, 51))	('intraocular cancer', 'Disease', (71, 89))
121598	21083380	Mutations in GNAQ, the gene encoding an alpha subunit of heterotrimeric G proteins, are found in 40% of uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (104, 119))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('GNAQ', 'Gene', (13, 17))	('found', 'Reg', (88, 93))	('Mutations', 'Var', (0, 9))	('uveal melanomas', 'Disease', (104, 119))	('uveal melanomas', 'Phenotype', 'HP:0007716', (104, 119))
121601	21083380	Mutations affecting Q209 in GNA11 were present in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases.	('uveal melanomas', 'Disease', (82, 97))	('Mutations affecting Q209', 'Var', (0, 24))	('uveal melanomas', 'Phenotype', 'HP:0007716', (82, 97))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (110, 124))	('blue nevi', 'Phenotype', 'HP:0100814', (56, 65))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('blue nevi', 'Disease', (56, 65))	('uveal melanoma metastases', 'Disease', (110, 135))	('GNA11', 'Gene', (28, 33))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (110, 135))	('uveal melanomas', 'Disease', 'MESH:C536494', (82, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('nevi', 'Phenotype', 'HP:0003764', (61, 65))	('present', 'Reg', (39, 46))
121602	21083380	In contrast, we observed Q209 mutations in GNAQ in 55% of blue nevi, 45% of uveal melanomas, and 22% of uveal melanoma metastases.	('uveal melanomas', 'Disease', 'MESH:C536494', (76, 91))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (104, 129))	('nevi', 'Phenotype', 'HP:0003764', (63, 67))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('uveal melanoma', 'Phenotype', 'HP:0007716', (76, 90))	('blue nevi', 'Phenotype', 'HP:0100814', (58, 67))	('GNAQ', 'Gene', (43, 47))	('uveal melanoma metastases', 'Disease', (104, 129))	('blue nevi', 'Disease', (58, 67))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('uveal melanomas', 'Disease', (76, 91))	('uveal melanomas', 'Phenotype', 'HP:0007716', (76, 91))	('Q209 mutations', 'Var', (25, 39))
121603	21083380	Mutations affecting R183 in either GNAQ or GNA11 were less prevalent (2% of blue nevi and 6% of uveal melanomas) than the Q209 mutations.	('GNA11', 'Gene', (43, 48))	('blue nevi', 'Phenotype', 'HP:0100814', (76, 85))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('blue nevi', 'Disease', (76, 85))	('uveal melanomas', 'Disease', (96, 111))	('uveal melanomas', 'Phenotype', 'HP:0007716', (96, 111))	('R183', 'Var', (20, 24))	('nevi', 'Phenotype', 'HP:0003764', (81, 85))	('uveal melanomas', 'Disease', 'MESH:C536494', (96, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))
121604	21083380	Mutations in GNA11 induced spontaneously metastasizing tumors in a mouse model and activated the mitogen-activated protein kinase pathway.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('induced', 'Reg', (19, 26))	('mouse', 'Species', '10090', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('GNA11', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('metastasizing tumors', 'Disease', 'MESH:D009362', (41, 61))	('mitogen-activated protein kinase pathway', 'Pathway', (97, 137))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('activated', 'PosReg', (83, 92))	('metastasizing tumors', 'Disease', (41, 61))
121608	21083380	Unlike cutaneous melanoma, uveal melanoma lacks mutations in BRAF, NRAS, or KIT and has characteristic cytogenetic alterations and a strong tendency to metastasize to the liver.	('uveal melanoma', 'Phenotype', 'HP:0007716', (27, 41))	('uveal melanoma', 'Disease', (27, 41))	('cutaneous melanoma', 'Disease', (7, 25))	('uveal melanoma', 'Disease', 'MESH:C536494', (27, 41))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (7, 25))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (7, 25))	('BRAF', 'Gene', '109880', (61, 65))	('metastasize', 'CPA', (152, 163))	('KIT', 'Gene', (76, 79))	('lacks', 'NegReg', (42, 47))	('NRAS', 'Gene', '18176', (67, 71))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('NRAS', 'Gene', (67, 71))	('BRAF', 'Gene', (61, 65))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('KIT', 'molecular_function', 'GO:0005020', ('76', '79'))	('mutations', 'Var', (48, 57))
121610	21083380	In mice, germline mutations that increase the activity of the closely related GTPases, Galphaq (V179M) and Galpha11 (I63V), cause dermal hyperpigmentation.	('dermal hyperpigmentation', 'Phenotype', 'HP:0000953', (130, 154))	('GTP', 'Chemical', 'MESH:D006160', (78, 81))	('Galphaq', 'Gene', '14682', (87, 94))	('mice', 'Species', '10090', (3, 7))	('dermal hyperpigmentation', 'Disease', (130, 154))	('Galphaq', 'Gene', (87, 94))	('Galpha11', 'Gene', '14672', (107, 115))	('activity', 'MPA', (46, 54))	('increase', 'PosReg', (33, 41))	('dermal hyperpigmentation', 'Disease', 'MESH:D017495', (130, 154))	('I63V', 'Mutation', 'p.I63V', (117, 121))	('cause', 'Reg', (124, 129))	('V179M', 'Mutation', 'p.V179M', (96, 101))	('GTPases', 'Protein', (78, 85))	('Galpha11', 'Gene', (107, 115))	('mutations', 'Var', (18, 27))
121611	21083380	The microscopical appearance of the skin of these mutant mice is reminiscent of that of human blue nevi, a finding that prompted us to sequence GNAQ and GNA11 in blue nevi, as well as in a variety of other cutaneous melanocytic neoplasms.	('mice', 'Species', '10090', (57, 61))	('neoplasms', 'Phenotype', 'HP:0002664', (228, 237))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (216, 237))	('GNA11', 'Gene', (153, 158))	('blue nevi', 'Phenotype', 'HP:0100814', (162, 171))	('cutaneous melanocytic neoplasms', 'Disease', 'MESH:D009508', (206, 237))	('blue nevi', 'Phenotype', 'HP:0100814', (94, 103))	('blue nevi', 'Disease', (162, 171))	('GNAQ', 'Gene', (144, 148))	('nevi', 'Phenotype', 'HP:0003764', (167, 171))	('blue nevi', 'Disease', (94, 103))	('mutant', 'Var', (50, 56))	('neoplasm', 'Phenotype', 'HP:0002664', (228, 236))	('nevi', 'Phenotype', 'HP:0003764', (99, 103))	('human', 'Species', '9606', (88, 93))	('cutaneous melanocytic neoplasms', 'Disease', (206, 237))
121612	21083380	Because of the link between the nevus of Ota, a form of blue nevus, and uveal melanoma, we subsequently genotyped the GNAQ mutational hotspot, predicted to affect the glutamine residue at amino acid position 209 (Q209), in uveal melanomas and observed that 46% of primary lesions carried mutations.	('melanomas', 'Phenotype', 'HP:0002861', (229, 238))	('GNAQ', 'Gene', (118, 122))	('melanoma', 'Phenotype', 'HP:0002861', (229, 237))	('nevus', 'Phenotype', 'HP:0003764', (32, 37))	('affect', 'Reg', (156, 162))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('glutamine', 'Chemical', 'MESH:D005973', (167, 176))	('uveal melanomas', 'Disease', 'MESH:C536494', (223, 238))	('uveal melanoma', 'Disease', 'MESH:C536494', (223, 237))	('uveal melanoma', 'Disease', (72, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('nevus', 'Phenotype', 'HP:0003764', (61, 66))	('Q209', 'Var', (213, 217))	('uveal melanoma', 'Phenotype', 'HP:0007716', (223, 237))	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('uveal melanomas', 'Disease', (223, 238))	('uveal melanomas', 'Phenotype', 'HP:0007716', (223, 238))	('nevus of Ota', 'Phenotype', 'HP:0009920', (32, 44))	('blue nevus', 'Phenotype', 'HP:0100814', (56, 66))
121614	21083380	In the alpha subunit, if there are substitutions of specific glutamine or arginine residues that contact the GTP molecule, then its intrinsic GTPase activity is blocked.	('arginine', 'Chemical', 'MESH:D001120', (74, 82))	('GTPase activity', 'molecular_function', 'GO:0003924', ('142', '157'))	('intrinsic', 'MPA', (132, 141))	('substitutions', 'Var', (35, 48))	('GTPase', 'Enzyme', (142, 148))	('glutamine', 'Protein', (61, 70))	('glutamine', 'Chemical', 'MESH:D005973', (61, 70))	('activity', 'MPA', (149, 157))	('GTP', 'Chemical', 'MESH:D006160', (142, 145))	('blocked', 'NegReg', (161, 168))	('arginine', 'Protein', (74, 82))	('GTP', 'Chemical', 'MESH:D006160', (109, 112))
121616	21083380	This critical glutamine is at position 209 (Q209) in Galphaq and is mutated to either leucine or proline in melanocytic lesions.	('melanocytic lesions', 'Disease', (108, 127))	('Q209', 'Var', (44, 48))	('Galphaq', 'Gene', '14682', (53, 60))	('leucine', 'Chemical', 'MESH:D007930', (86, 93))	('Galphaq', 'Gene', (53, 60))	('proline', 'Chemical', 'MESH:D011392', (97, 104))	('glutamine', 'Chemical', 'MESH:D005973', (14, 23))	('melanocytic lesions', 'Disease', 'MESH:D009508', (108, 127))
121618	21083380	The GTP-contacting arginines of Galphas (R201) and Galphai2 (R179) have been found to be mutant in pituitary and thyroid tumors (Galphas) and in adrenocortical and ovarian tumors (Galphai2).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('Galphas', 'Chemical', '-', (32, 39))	('GTP', 'Chemical', 'MESH:D006160', (4, 7))	('Galphai2', 'Gene', (51, 59))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('adrenocortical and ovarian tumors', 'Disease', 'MESH:D018268', (145, 178))	('Galphas', 'Chemical', '-', (129, 136))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('pituitary and thyroid tumors', 'Disease', 'MESH:D010911', (99, 127))	('Galphai2', 'Gene', (180, 188))	('Galphai2', 'Gene', '14678', (51, 59))	('Galphai2', 'Gene', '14678', (180, 188))	('ovarian tumors', 'Phenotype', 'HP:0100615', (164, 178))	('mutant', 'Var', (89, 95))	('arginines', 'Chemical', 'MESH:D001120', (19, 28))
121623	21083380	We found mutations affecting Q209 in GNA11 in the same specific subgroups of melanocytic tumors that were previously described for GNAQ (Tables 1 and 2).	('Q209', 'Var', (29, 33))	('melanocytic tumors', 'Disease', (77, 95))	('melanocytic tumors', 'Disease', 'MESH:D009508', (77, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('GNA11', 'Gene', (37, 42))	('mutations affecting Q209', 'Var', (9, 33))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
121624	21083380	The frequency of mutations in GNA11 at the codon encoding Q209 increased progressively from blue nevi (6.5%) to primary uveal melanomas (31.9%) to uveal melanoma metastases (56.5%), a pattern inverse to the distribution of Q209 mutations in GNAQ, which are most common in blue nevi (54.7%) and least common in uveal melanoma metastases (21.7%) (P<0.001) (Table 1).	('uveal melanoma metastases', 'Disease', (147, 172))	('Q209', 'Gene', (58, 62))	('uveal melanomas', 'Disease', (120, 135))	('uveal melanomas', 'Phenotype', 'HP:0007716', (120, 135))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanomas', 'Phenotype', 'HP:0002861', (126, 135))	('blue nevi', 'Phenotype', 'HP:0100814', (92, 101))	('nevi', 'Phenotype', 'HP:0003764', (277, 281))	('mutations', 'Var', (17, 26))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (147, 172))	('GNA11', 'Gene', (30, 35))	('Q209', 'Var', (223, 227))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('uveal melanoma', 'Phenotype', 'HP:0007716', (147, 161))	('melanoma', 'Phenotype', 'HP:0002861', (316, 324))	('blue nevi', 'Phenotype', 'HP:0100814', (272, 281))	('uveal melanoma', 'Phenotype', 'HP:0007716', (120, 134))	('uveal melanoma metastases', 'Disease', (310, 335))	('uveal melanomas', 'Disease', 'MESH:C536494', (120, 135))	('increased', 'PosReg', (63, 72))	('nevi', 'Phenotype', 'HP:0003764', (97, 101))	('uveal melanoma', 'Phenotype', 'HP:0007716', (310, 324))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (310, 335))	('blue nevi', 'Disease', (92, 101))
121625	21083380	Mutations affecting codon 209 in GNA11 were CAG CTG (94.5%), CAG CCG (2.7%), CAG CTA (1.4%), and CAG CTT (1.4%).	('CTG', 'Chemical', '-', (48, 51))	('GNA11', 'Gene', (33, 38))	('CAG CTA', 'Disease', (77, 84))	('CAG', 'Chemical', '-', (77, 80))	('CAG', 'Chemical', '-', (44, 47))	('CAG CTT', 'Disease', (97, 104))	('CAG', 'Chemical', '-', (61, 64))	('Mutations', 'Var', (0, 9))	('CAG', 'Chemical', '-', (97, 100))	('CAG CTG', 'Disease', (44, 51))	('CAG CCG', 'Disease', (61, 68))	('CTA', 'Chemical', 'MESH:C569473', (81, 84))
121626	21083380	These mutations predicted substitution by leucine (Q209L) in 97.3% of samples that were analyzed and by proline in 2.7% of these samples (Fig.	('leucine', 'Chemical', 'MESH:D007930', (42, 49))	('Q209L', 'Mutation', 'rs1057519742', (51, 56))	('proline', 'Chemical', 'MESH:D011392', (104, 111))	('Q209L', 'Var', (51, 56))	('predicted', 'Reg', (16, 25))
121627	21083380	We also discovered mutations in GNAQ and GNA11 in exon 4 at arginine 183, which is analogous to R201 in GNAS and R179 in GNAI2 (Table 2).	('arginine', 'Chemical', 'MESH:D001120', (60, 68))	('GNAQ', 'Gene', (32, 36))	('GNAI2', 'Gene', (121, 126))	('mutations', 'Var', (19, 28))	('GNAS', 'Gene', (104, 108))	('GNAI2', 'Gene', '14678', (121, 126))	('GNA11', 'Gene', (41, 46))	('GNAS', 'Gene', '14683', (104, 108))
121628	21083380	Mutations affecting R183 in either GNAQ or GNA11 were present in 2.1% of blue nevi and 4.8% of primary uveal melanomas.	('uveal melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('uveal melanomas', 'Disease', 'MESH:C536494', (103, 118))	('GNA11', 'Gene', (43, 48))	('blue nevi', 'Disease', (73, 82))	('blue nevi', 'Phenotype', 'HP:0100814', (73, 82))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('nevi', 'Phenotype', 'HP:0003764', (78, 82))	('uveal melanomas', 'Disease', (103, 118))	('uveal melanomas', 'Phenotype', 'HP:0007716', (103, 118))	('R183', 'Var', (20, 24))	('present', 'Reg', (54, 61))	('GNAQ', 'Gene', (35, 39))
121629	21083380	Most mutations affecting R183 in GNA11 resulted in a substitution to cysteine, caused by either a single (CGC TGC) or a double (GTC CGC GTT TGC) cytosine-to-thymine transition.	('cysteine', 'Chemical', 'MESH:D003545', (69, 77))	('GNA11', 'Gene', (33, 38))	('cytosine', 'Chemical', 'MESH:D003596', (145, 153))	('thymine', 'Chemical', 'MESH:D013941', (157, 164))	('resulted in', 'Reg', (39, 50))	('mutations', 'Var', (5, 14))	('R183', 'Var', (25, 29))	('caused by', 'Reg', (79, 88))	('substitution', 'MPA', (53, 65))
121630	21083380	A single blue nevus had a guanine-to-adenine transition (CGC CAC) at codon 183, predicting a substitution with histidine.	('histidine', 'Chemical', 'MESH:D006639', (111, 120))	('blue nevus', 'Phenotype', 'HP:0100814', (9, 19))	('guanine-to-adenine', 'Chemical', '-', (26, 44))	('guanine-to-adenine', 'MPA', (26, 44))	('substitution', 'Var', (93, 105))	('nevus', 'Phenotype', 'HP:0003764', (14, 19))
121631	21083380	This tumor also carried a concomitant GNA11 Q209L mutation and was the only tumor we analyzed that carried mutations at both codons 183 and 209.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('GNA11 Q209L', 'Var', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('Q209L', 'Mutation', 'rs1057519742', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
121632	21083380	In GNAQ all mutations in codon 183 were CGA-to-CAA transitions, predicting substitution with glutamine (Fig.	('glutamine', 'Chemical', 'MESH:D005973', (93, 102))	('substitution', 'Var', (75, 87))	('mutations', 'Var', (12, 21))	('CGA-to-CAA', 'Disease', (40, 50))	('predicting', 'Reg', (64, 74))
121633	21083380	A single sample of uveal melanoma had mutations in codons 175 (ACG AGG) and 182 (GTT ATT), both of which are of unknown functional significance.	('ACG AGG', 'Gene', (63, 70))	('uveal melanoma', 'Disease', 'MESH:C536494', (19, 33))	('uveal melanoma', 'Phenotype', 'HP:0007716', (19, 33))	('uveal melanoma', 'Disease', (19, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('mutations', 'Var', (38, 47))
121634	21083380	All 11 tumors with mutations at R183 showed a cytosine-to-thymine transition on either the forward or reverse strand.	('cytosine', 'Chemical', 'MESH:D003596', (46, 54))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Disease', (7, 13))	('mutations at R183', 'Var', (19, 36))	('thymine', 'Chemical', 'MESH:D013941', (58, 65))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('cytosine-to-thymine transition', 'MPA', (46, 76))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
121637	21083380	These alterations are characteristic mutational patterns induced by ultraviolet light and are found with markedly increased frequency in cutaneous melanomas arising on sun-exposed skin.	('alterations', 'Var', (6, 17))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (137, 156))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('cutaneous melanomas', 'Disease', (137, 156))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (137, 156))	('melanomas', 'Phenotype', 'HP:0002861', (147, 156))
121640	21083380	Similarly, a C T transition on the reverse strand in GNA11 at 209 would generate a silent mutation (CAG CAA).	('CAG', 'Chemical', '-', (100, 103))	('silent mutation', 'MPA', (83, 98))	('GNA11 at', 'Gene', (53, 61))	('C T transition', 'Var', (13, 27))
121643	21083380	Altogether, 83.0% of all primary uveal melanomas that we examined had oncogenic mutations in GNAQ or GNA11.	('uveal melanomas', 'Disease', (33, 48))	('GNA11', 'Gene', (101, 106))	('uveal melanomas', 'Phenotype', 'HP:0007716', (33, 48))	('mutations', 'Var', (80, 89))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanomas', 'Phenotype', 'HP:0002861', (39, 48))	('uveal melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('uveal melanomas', 'Disease', 'MESH:C536494', (33, 48))	('GNAQ', 'Gene', (93, 97))
121644	21083380	For the 118 samples of uveal melanoma in which it was possible to determine the location of the primary tumor, lesions arising in the ciliochoroidal region had an increased frequency of GNA11 mutations (P=0.048 by Fisher's exact test) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('uveal melanoma', 'Phenotype', 'HP:0007716', (23, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (23, 37))	('tumor', 'Disease', (104, 109))	('uveal melanoma', 'Disease', (23, 37))	('mutations', 'Var', (192, 201))	('GNA11', 'Gene', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
121645	21083380	Mutations in GNAQ and GNA11 were found more commonly in primary tumors with epithelioid cells or a mixture of epithelioid and spindle cells than in samples comprising only spindle cells, but the difference was not significant (Fig.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('GNA11', 'Gene', (22, 27))	('spindle', 'cellular_component', 'GO:0005819', ('126', '133'))	('found', 'Reg', (33, 38))	('GNAQ', 'Gene', (13, 17))	('primary tumors', 'Disease', (56, 70))	('primary tumors', 'Disease', 'MESH:D009369', (56, 70))	('Mutations', 'Var', (0, 9))	('spindle', 'cellular_component', 'GO:0005819', ('172', '179'))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
121647	21083380	Examination of overall survival and disease-free survival for the 81 patients for whom we had requisite data did not reveal a significant difference between those with tumors bearing a GNAQ mutation and those with tumors bearing a GNA11 mutation (Fig.	('mutation', 'Var', (190, 198))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Disease', (214, 220))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('GNAQ', 'Gene', (185, 189))	('patients', 'Species', '9606', (69, 77))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
121648	21083380	We observed a trend toward increased survival among patients with tumors carrying a GNA11 mutation, as compared with those carrying a GNAQ mutation or those not carrying either a GNA11 or a GNAQ mutation.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('increased', 'PosReg', (27, 36))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('survival', 'MPA', (37, 45))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('mutation', 'Var', (90, 98))	('patients', 'Species', '9606', (52, 60))	('GNA11', 'Gene', (84, 89))
121649	21083380	To validate two GNA11 variants, Q209L and R183C, as oncogenes, we transduced mouse melan-a cells with one or the other of these mutant genes.	('R183C', 'Var', (42, 47))	('R183C', 'Mutation', 'p.R183C', (42, 47))	('Q209L', 'Mutation', 'rs1057519742', (32, 37))	('mouse', 'Species', '10090', (77, 82))	('Q209L', 'Var', (32, 37))
121651	21083380	Mice that were injected with melanocytes that had been transduced with nonmutated GNA11, or lacZ, encoding beta-galactosidase, served as negative controls (Fig.	('beta-galactosidase', 'Gene', (107, 125))	('beta-galactosidase', 'Gene', '12091', (107, 125))	('GNA11', 'Gene', (82, 87))	('Mice', 'Species', '10090', (0, 4))	('nonmutated', 'Var', (71, 81))	('lacZ', 'Gene', (92, 96))
121652	21083380	Rapidly growing tumors developed at each of the six injection sites for the Q209L variant, as compared with tumors developing with increased latency in only three of eight injection sites for the R183C variant.	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Q209L', 'Mutation', 'rs1057519742', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('R183C', 'Mutation', 'p.R183C', (196, 201))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('Q209L', 'Var', (76, 81))	('tumors', 'Disease', (16, 22))
121653	21083380	This finding was consistent with data showing a reduced potency of the R183C variant, as compared with the Q209L variant.	('R183C', 'Var', (71, 76))	('Q209L', 'Mutation', 'rs1057519742', (107, 112))	('R183C', 'Mutation', 'p.R183C', (71, 76))	('potency', 'MPA', (56, 63))
121655	21083380	In contrast to the results in mice injected with melanocytes transduced with the GNAQ Q209L variant, metastases developed in all 3 mice injected with melan-a cells transduced with the GNA11 Q209L variant, including lung metastases in all 3 and liver metastases in 1.	('mice', 'Species', '10090', (30, 34))	('GNA11 Q209L', 'Var', (184, 195))	('metastases', 'Disease', 'MESH:D009362', (220, 230))	('Q209L', 'Mutation', 'rs1057519742', (86, 91))	('metastases', 'Disease', (101, 111))	('metastases', 'Disease', (250, 260))	('lung metastases', 'Disease', (215, 230))	('Q209L', 'Mutation', 'rs1057519742', (190, 195))	('lung metastases', 'Disease', 'MESH:D009362', (215, 230))	('metastases', 'Disease', 'MESH:D009362', (101, 111))	('mice', 'Species', '10090', (131, 135))	('metastases', 'Disease', 'MESH:D009362', (250, 260))	('metastases', 'Disease', (220, 230))
121656	21083380	Western blot analyses of melanocytes transduced with the GNA11 Q209L variant revealed mitogen-activated protein (MAP) kinase activation, as indicated by increased levels of phosphorylated extracellular signal-regulated kinase (ERK) (Fig.	('activation', 'PosReg', (125, 135))	('Q209L', 'Mutation', 'rs1057519742', (63, 68))	('ERK', 'Gene', (227, 230))	('ERK', 'Gene', '26413', (227, 230))	('increased', 'PosReg', (153, 162))	('Q209L', 'Var', (63, 68))	('extracellular', 'cellular_component', 'GO:0005576', ('188', '201'))	('MAP', 'molecular_function', 'GO:0004239', ('113', '116'))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('ERK', 'molecular_function', 'GO:0004707', ('227', '230'))	('extracellular signal-regulated kinase', 'Gene', (188, 225))	('extracellular signal-regulated kinase', 'Gene', '26413', (188, 225))	('mitogen-activated', 'Enzyme', (86, 103))
121658	21083380	Of the 13 uveal melanoma cell lines available in our laboratory, none carried a GNA11 mutation, so we were unable to test whether the GNA11 Q209L mutant cells are similarly sensitive to MEK inhibitors.	('uveal melanoma', 'Disease', 'MESH:C536494', (10, 24))	('uveal melanoma', 'Phenotype', 'HP:0007716', (10, 24))	('uveal melanoma', 'Disease', (10, 24))	('Q209L', 'Var', (140, 145))	('GNA11', 'Gene', (134, 139))	('MEK', 'Gene', '17242', (186, 189))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('MEK', 'Gene', (186, 189))	('GNA11', 'Gene', (80, 85))	('Q209L', 'Mutation', 'rs1057519742', (140, 145))
121659	21083380	However, the close functional relationship between Galphaq and Galpha11,  together with the data that we describe here, supports the prediction that the activation of MAP kinase is effected by GNA11 Q209 mutations in uveal melanoma cells and can be countered with MEK inhibitors.	('Galpha11', 'Gene', '14672', (63, 71))	('MEK', 'Gene', '17242', (264, 267))	('Galphaq', 'Gene', (51, 58))	('GNA11', 'Gene', (193, 198))	('activation', 'PosReg', (153, 163))	('MEK', 'Gene', (264, 267))	('activation of MAP kinase', 'biological_process', 'GO:0000187', ('153', '177'))	('MAP kinase', 'Enzyme', (167, 177))	('Q209 mutations', 'Var', (199, 213))	('uveal melanoma', 'Disease', 'MESH:C536494', (217, 231))	('Galpha11', 'Gene', (63, 71))	('Galphaq', 'Gene', '14682', (51, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (217, 231))	('uveal melanoma', 'Disease', (217, 231))	('MAP', 'molecular_function', 'GO:0004239', ('167', '170'))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))
121661	21083380	In our samples, 83.0% of uveal melanomas had a constitutively active mutation in either GNAQ or GNA11, suggesting that activation of the Galphaq-Galpha11 pathway is the predominant route to the development of uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('uveal melanoma', 'Disease', 'MESH:C536494', (209, 223))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('uveal melanoma', 'Disease', (209, 223))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))	('Galpha11', 'Gene', (145, 153))	('uveal melanoma', 'Phenotype', 'HP:0007716', (209, 223))	('uveal melanomas', 'Disease', 'MESH:C536494', (25, 40))	('uveal melanoma', 'Disease', 'MESH:C536494', (25, 39))	('Galpha11', 'Gene', '14672', (145, 153))	('activation', 'PosReg', (119, 129))	('Galphaq', 'Gene', '14682', (137, 144))	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('GNAQ', 'Gene', (88, 92))	('uveal melanomas', 'Disease', (25, 40))	('uveal melanomas', 'Phenotype', 'HP:0007716', (25, 40))	('mutation', 'Var', (69, 77))	('GNA11', 'Gene', (96, 101))	('Galphaq', 'Gene', (137, 144))
121663	21083380	First, GNA11 mutations were rare in blue nevi, which are benign neoplasms.	('blue nevi', 'Disease', (36, 45))	('benign neoplasms', 'Disease', 'MESH:D009369', (57, 73))	('nevi', 'Phenotype', 'HP:0003764', (41, 45))	('blue nevi', 'Phenotype', 'HP:0100814', (36, 45))	('neoplasms', 'Phenotype', 'HP:0002664', (64, 73))	('GNA11', 'Gene', (7, 12))	('neoplasm', 'Phenotype', 'HP:0002664', (64, 72))	('mutations', 'Var', (13, 22))	('benign neoplasms', 'Disease', (57, 73))
121664	21083380	Conversely, there were significantly more GNA11 Q209 mutations than GNAQ Q209 mutations in uveal melanoma metastases.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('mutations', 'Var', (53, 62))	('GNA11', 'Gene', (42, 47))	('uveal melanoma', 'Phenotype', 'HP:0007716', (91, 105))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (91, 116))	('uveal melanoma metastases', 'Disease', (91, 116))
121665	21083380	Furthermore, GNA11 mutations were more common in locally advanced primary tumors and in primary tumors originating from the ciliochoroidal region, a prognostically adverse feature.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('primary tumors', 'Disease', (66, 80))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutations', 'Var', (19, 28))	('GNA11', 'Gene', (13, 18))	('common', 'Reg', (39, 45))	('primary tumors', 'Disease', 'MESH:D009369', (66, 80))	('primary tumors', 'Disease', (88, 102))	('locally advanced', 'CPA', (49, 65))	('primary tumors', 'Disease', 'MESH:D009369', (88, 102))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
121666	21083380	Finally, the mouse Gna11 Dsk7 mutation is more tumorigenic than the Gnaq Dsk1 mutation, since it is better able to stimulate melanocyte growth that is impaired by heterozygous mutations in Kit, Pax3, and Ednrb (encoding endothelin receptor type B).	('Gnaq', 'Gene', (68, 72))	('endothelin receptor type B', 'Gene', '13618', (220, 246))	('Dsk7', 'Gene', (25, 29))	('mutation', 'Var', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Gna11', 'Gene', '14672', (19, 24))	('Dsk1', 'Gene', '14682', (73, 77))	('Pax3', 'Gene', '18505', (194, 198))	('Gna11', 'Gene', (19, 24))	('Dsk7', 'Gene', '14672', (25, 29))	('endothelin receptor type B', 'Gene', (220, 246))	('Kit', 'Gene', (189, 192))	('mouse', 'Species', '10090', (13, 18))	('Gnaq', 'Gene', '14682', (68, 72))	('stimulate', 'PosReg', (115, 124))	('tumor', 'Disease', (47, 52))	('Dsk1', 'Gene', (73, 77))	('melanocyte growth', 'CPA', (125, 142))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('Pax3', 'Gene', (194, 198))	('Ednrb', 'Gene', (204, 209))	('Ednrb', 'Gene', '13618', (204, 209))
121667	21083380	However, since the mutations found in mice occur at different residues in Gna11 and Gnaq (I63V and V179 M, respectively), we cannot dismiss the possibility that the difference is a functional consequence of the mutations themselves, rather than a difference in function between Gna11 and Gnaq.	('Gna11', 'Gene', (278, 283))	('Gnaq', 'Gene', (288, 292))	('mice', 'Species', '10090', (38, 42))	('Gna11', 'Gene', (74, 79))	('mutations', 'Var', (211, 220))	('Gna11', 'Gene', '14672', (278, 283))	('V179 M', 'Mutation', 'p.V179M', (99, 105))	('Gnaq', 'Gene', '14682', (288, 292))	('Gna11', 'Gene', '14672', (74, 79))	('Gnaq', 'Gene', '14682', (84, 88))	('I63V', 'Mutation', 'p.I63V', (90, 94))	('Gnaq', 'Gene', (84, 88))
121668	21083380	Although the survival of patients did not differ significantly among those with GNAQ mutations and those with GNA11 mutations in our study, the number of patients who were available for our analysis may have been too small to detect such a difference.	('patients', 'Species', '9606', (154, 162))	('mutations', 'Var', (85, 94))	('patients', 'Species', '9606', (25, 33))	('GNA11', 'Gene', (110, 115))	('GNAQ', 'Gene', (80, 84))
121669	21083380	The samples that we analyzed were typically from large tumors, which may have obscured any association between mutations in GNAQ or GNA11 and prognosis.	('GNA11', 'Gene', (132, 137))	('mutations', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('GNAQ', 'Gene', (124, 128))
121670	21083380	The level of activation of Galphaq R183 mutants is considerably lower than that of Galphaq Q209 mutants in vitro, which raises the possibility that R183-mutated oncoproteins may be less potent.	('Galphaq', 'Gene', '14682', (27, 34))	('activation', 'MPA', (13, 23))	('lower', 'NegReg', (64, 69))	('R183-mutated', 'Var', (148, 160))	('Galphaq', 'Gene', (27, 34))	('Galphaq', 'Gene', (83, 90))	('mutants', 'Var', (40, 47))	('Galphaq', 'Gene', '14682', (83, 90))
121672	21083380	Of possible clinical relevance is the finding that Galphaq R183 but not Galphaq Q209 can be inhibited with YM-254890, a naturally occurring toxin from chromobacteria.	('Galphaq', 'Gene', (51, 58))	('Galphaq', 'Gene', (72, 79))	('YM-254890', 'Var', (107, 116))	('Galphaq', 'Gene', '14682', (72, 79))	('Galphaq', 'Gene', '14682', (51, 58))
121673	21083380	In a recent study of GNAQ and GNA11 in 922 human neoplasms with various histopathological features, the only mutations that were found were in GNAQ in blue nevi.	('GNAQ', 'Gene', (143, 147))	('neoplasm', 'Phenotype', 'HP:0002664', (49, 57))	('blue nevi', 'Phenotype', 'HP:0100814', (151, 160))	('neoplasms', 'Disease', (49, 58))	('nevi', 'Phenotype', 'HP:0003764', (156, 160))	('blue nevi', 'Disease', (151, 160))	('neoplasms', 'Disease', 'MESH:D009369', (49, 58))	('mutations', 'Var', (109, 118))	('neoplasms', 'Phenotype', 'HP:0002664', (49, 58))	('human', 'Species', '9606', (43, 48))
121675	21083380	Another study showed that GNAQ mutations were present in 37% of melanocytic neoplasms of the central nervous system, making it likely that GNA11 mutations will also be found in this category of melanocytic tumors.	('neoplasms', 'Phenotype', 'HP:0002664', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('mutations', 'Var', (31, 40))	('neoplasms of the central nervous system', 'Phenotype', 'HP:0100006', (76, 115))	('GNAQ', 'Gene', (26, 30))	('melanocytic neoplasms', 'Disease', (64, 85))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('melanocytic tumors', 'Disease', 'MESH:D009508', (194, 212))	('neoplasm', 'Phenotype', 'HP:0002664', (76, 84))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (64, 85))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (64, 85))	('melanocytic tumors', 'Disease', (194, 212))
121676	21083380	The peculiar association among mutations in melanocytic neoplasms of the dermis, uvea, and central nervous system may indicate different cells of origin.	('uvea', 'Disease', 'MESH:C536494', (81, 85))	('association', 'Interaction', (13, 24))	('mutations', 'Var', (31, 40))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (44, 65))	('melanocytic neoplasms', 'Disease', (44, 65))	('neoplasm', 'Phenotype', 'HP:0002664', (56, 64))	('uvea', 'Disease', (81, 85))	('neoplasms', 'Phenotype', 'HP:0002664', (56, 65))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (44, 65))
121678	21083380	If so, the timing of the occurrence of mutations may determine the localization and extent of the neoplasm.	('localization', 'biological_process', 'GO:0051179', ('67', '79'))	('neoplasm', 'Phenotype', 'HP:0002664', (98, 106))	('mutations', 'Var', (39, 48))	('neoplasm', 'Disease', (98, 106))	('determine', 'Reg', (53, 62))	('neoplasm', 'Disease', 'MESH:D009369', (98, 106))
121679	21083380	Lesions that are confined to the central nervous system would arise from Galphaq-Galpha11 mutations in precursors before the onset of migration, and segmental lesions, such as the nevus of Ota, would result from mutations in a precursor early during migration, in contrast to mutations arising later along the migratory pathway, which would result in solitary lesions involving the skin or choroid.	('Galpha11', 'Gene', '14672', (81, 89))	('mutations', 'Var', (90, 99))	('nevus of Ota', 'Phenotype', 'HP:0009920', (180, 192))	('nevus', 'Phenotype', 'HP:0003764', (180, 185))	('Galphaq', 'Gene', (73, 80))	('Galpha11', 'Gene', (81, 89))	('arise', 'Reg', (62, 67))	('mutations', 'Var', (212, 221))	('result from', 'Reg', (200, 211))	('nevus of Ota', 'Disease', (180, 192))	('Galphaq', 'Gene', '14682', (73, 80))
121683	21083380	In summary, our findings suggest that a large majority of uveal melanomas and blue nevi carry mutations in either GNAQ or GNA11.	('nevi', 'Phenotype', 'HP:0003764', (83, 87))	('mutations', 'Var', (94, 103))	('GNA11', 'Gene', (122, 127))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('uveal melanomas', 'Disease', (58, 73))	('uveal melanomas', 'Phenotype', 'HP:0007716', (58, 73))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('blue nevi', 'Phenotype', 'HP:0100814', (78, 87))	('carry', 'Reg', (88, 93))	('uveal melanomas', 'Disease', 'MESH:C536494', (58, 73))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('blue nevi', 'Disease', (78, 87))	('GNAQ', 'Gene', (114, 118))
121829	33402823	Extracellular vesicles (EVs) are an umbrella term for all lipid bilayer-encased extracellular structures, which are typically divided into three subtypes: exosomes (~30-150 nm in diameter), microvesicles (~100-1000 nm in diameter), and apoptotic bodies (~100-5000 nm in diameter), based on their formation mode, particle size, and functional properties.	('lipid bilayer', 'Chemical', 'MESH:D008051', (58, 71))	('extracellular', 'cellular_component', 'GO:0005576', ('80', '93'))	('~30-150', 'Var', (165, 172))	('Extracellular', 'cellular_component', 'GO:0005576', ('0', '13'))	('~100-1000', 'Var', (205, 214))	('formation', 'biological_process', 'GO:0009058', ('296', '305'))
121860	33402823	These protein components include tetraspanins that contain CD63, CD9, CD81, and CD82; integrin proteins that take part in cell targeting and adhesion; membrane fusion proteins that are closely related to Rab GTPases, annexins, and flotillin; and several molecular chaperones that mediate the generation of MVBs such as heat shock proteins (HSP) 70 and 90.	('CD63', 'Var', (59, 63))	('CD8', 'Gene', '925', (80, 83))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('shock', 'Phenotype', 'HP:0031273', (324, 329))	('heat shock proteins', 'Disease', 'MESH:D012769', (319, 338))	('heat shock proteins', 'Disease', (319, 338))	('CD9', 'Gene', '928', (65, 68))	('CD9', 'Gene', (65, 68))	('CD8', 'Gene', (70, 73))	('membrane fusion', 'biological_process', 'GO:0061025', ('151', '166'))	('rat', 'Species', '10116', (296, 299))	('CD8', 'Gene', '925', (70, 73))	('CD8', 'Gene', (80, 83))	('membrane', 'cellular_component', 'GO:0016020', ('151', '159'))
121926	33402823	CP05, a peptide of phage display, can increase its efficiency in capturing and loading exosomes and increases the expression of corresponding proteins in muscles by attaching to exosomal CD63.	('increase', 'PosReg', (38, 46))	('CP05', 'Var', (0, 4))	('proteins', 'Protein', (142, 150))	('capturing', 'MPA', (65, 74))	('efficiency', 'MPA', (51, 61))	('increases', 'PosReg', (100, 109))	('age', 'Gene', (21, 24))	('attaching', 'Interaction', (165, 174))	('loading exosomes', 'MPA', (79, 95))	('expression', 'MPA', (114, 124))	('age', 'Gene', '5973', (21, 24))
121929	33402823	Comparison of intravitreal injection of traditional AAV2 with the novel exosome-associated AAV2 (exo-AAV2) revealed that exo-AAV2 carrying the GFP-coding gene adeno-associated virus (AAV) was more strongly expressed and had greater penetrability in the retina.	('AAV', 'Species', '272636', (183, 186))	('AAV', 'Species', '272636', (52, 55))	('AAV2', 'Species', '10804', (52, 56))	('AAV', 'Species', '272636', (125, 128))	('AAV', 'Species', '272636', (101, 104))	('AAV', 'Species', '272636', (91, 94))	('AAV2', 'Species', '10804', (101, 105))	('AAV2', 'Species', '10804', (125, 129))	('strongly', 'PosReg', (197, 205))	('exo-AAV2', 'Var', (121, 129))	('AAV2', 'Species', '10804', (91, 95))	('expressed', 'MPA', (206, 215))	('adeno-associated virus', 'Species', '272636', (159, 181))	('exosome', 'cellular_component', 'GO:0070062', ('72', '79'))
121939	33402823	Zhang et al have shown that exosomes in serum produced after hepatic ischemia-reperfusion may cause oxidative stress and damage hippocampal and cortical neurons.	('age', 'Gene', '5973', (124, 127))	('hepatic ischemia', 'Phenotype', 'HP:0002637', (61, 77))	('oxidative stress', 'Phenotype', 'HP:0025464', (100, 116))	('hepatic ischemia', 'Disease', 'MESH:D056486', (61, 77))	('age', 'Gene', (124, 127))	('exosomes', 'Var', (28, 36))	('cause', 'Reg', (94, 99))	('hepatic ischemia', 'Disease', (61, 77))	('oxidative stress', 'MPA', (100, 116))
121960	33402823	Finally, IRI causes necrosis, apoptosis, and autophagy resulting in a decrease in retinal neurons, especially RGCs.	('necrosis', 'biological_process', 'GO:0001906', ('20', '28'))	('necrosis', 'Disease', (20, 28))	('autophagy', 'CPA', (45, 54))	('IRI', 'Var', (9, 12))	('apoptosis', 'CPA', (30, 39))	('necrosis', 'Disease', 'MESH:D009336', (20, 28))	('autophagy', 'biological_process', 'GO:0006914', ('45', '54'))	('apoptosis', 'biological_process', 'GO:0006915', ('30', '39'))	('necrosis', 'biological_process', 'GO:0070265', ('20', '28'))	('necrosis', 'biological_process', 'GO:0008219', ('20', '28'))	('retinal neurons', 'CPA', (82, 97))	('autophagy', 'biological_process', 'GO:0016236', ('45', '54'))	('necrosis', 'biological_process', 'GO:0019835', ('20', '28'))	('RGCs', 'CPA', (110, 114))	('necrosis', 'biological_process', 'GO:0008220', ('20', '28'))	('decrease', 'NegReg', (70, 78))	('apoptosis', 'biological_process', 'GO:0097194', ('30', '39'))
121967	33402823	A study on diabetic microvascular complications found that exosomes can carry circular RNAs-cPWWP2A, an endogenous miR-579 sponge, and indirectly mediate the function of retinal vessels in patients with diabetes through different expression levels of cPWWP2A and miR-579.	('circular RNAs-cPWWP2A', 'Var', (78, 99))	('diabetes', 'Disease', (203, 211))	('function', 'MPA', (158, 166))	('diabetes', 'Disease', 'MESH:D003920', (203, 211))	('expression', 'MPA', (230, 240))	('miR-579', 'Gene', (115, 122))	('diabetic', 'Disease', 'MESH:D003920', (11, 19))	('miR-579', 'Gene', '693164', (115, 122))	('miR-579', 'Gene', '693164', (263, 270))	('mediate', 'Reg', (146, 153))	('miR-579', 'Gene', (263, 270))	('diabetic', 'Disease', (11, 19))	('patients', 'Species', '9606', (189, 197))
121989	33402823	A recent study found that the expression of three new circulating microRNAs, including miR-486-5p, miR-626, and miR-885-5p, significantly differed in control and individuals with AMD, but their effects were not identical.	('expression', 'MPA', (30, 40))	('miR-626', 'Gene', (99, 106))	('miR-885', 'Gene', (112, 119))	('miR-626', 'Gene', '693211', (99, 106))	('differed', 'Reg', (138, 146))	('AMD', 'Disease', 'MESH:D006009', (179, 182))	('miR-885', 'Gene', '100126334', (112, 119))	('miR-486-5p', 'Var', (87, 97))	('AMD', 'Disease', (179, 182))
121990	33402823	The results showed that the expression of miR-486-5p and miR-626 were up-regulated in patients, while the expression of miR-885-5p was down-regulated in patients.	('patients', 'Species', '9606', (153, 161))	('up-regulated', 'PosReg', (70, 82))	('miR-626', 'Gene', (57, 64))	('expression', 'MPA', (28, 38))	('miR-885', 'Gene', (120, 127))	('miR-626', 'Gene', '693211', (57, 64))	('miR-486-5p', 'Var', (42, 52))	('miR-885', 'Gene', '100126334', (120, 127))	('patients', 'Species', '9606', (86, 94))
122018	33402823	They conducted a large-scale study of TM gene expression in patients with POAG and healthy subjects, and for the first time demonstrated that TM gene expression occurred in patients with a Q368X myocilin mutation.	('myocilin', 'Gene', '4653', (195, 203))	('rat', 'Species', '10116', (131, 134))	('patients', 'Species', '9606', (173, 181))	('myocilin', 'Gene', (195, 203))	('gene expression', 'biological_process', 'GO:0010467', ('41', '56'))	('patients', 'Species', '9606', (60, 68))	('gene expression', 'biological_process', 'GO:0010467', ('145', '160'))	('Q368X', 'Var', (189, 194))	('occurred', 'Reg', (161, 169))	('Q368X', 'Mutation', 'rs74315329', (189, 194))
122021	33402823	One study used miRNA sequencing (miRNA-Seq) to detect the expression of miR-182 in various types of human eye tissues, human AH, and exosomes derived from human primary TM cells, respectively, to verify the correlation between miRNA variation and POAG.	('variation', 'Var', (233, 242))	('human', 'Species', '9606', (119, 124))	('human', 'Species', '9606', (155, 160))	('human', 'Species', '9606', (100, 105))	('miR-182', 'Gene', (72, 79))	('miR-182', 'Gene', '406958', (72, 79))	('AH', 'Disease', 'MESH:D007039', (125, 127))
122173	32765803	used comparative genomic hybridization assays to demonstrate that partial deletion of chromosome 3 encompassing the BAP1 locus was associated with strikingly worse 5-year metastasis-free and overall survival.	('BAP1', 'Gene', (116, 120))	('worse', 'NegReg', (158, 163))	('partial deletion', 'Var', (66, 82))	('overall survival', 'CPA', (191, 207))	('chromosome', 'cellular_component', 'GO:0005694', ('86', '96'))	('BAP1', 'Gene', '8314', (116, 120))	('metastasis-free', 'CPA', (171, 186))
122176	32765803	In line with Knudson's two-hit hypothesis, the most common driver mutations found in ccRCC involve the tumor suppressor genes found within a short stretch on chromosome 3p, including the histone deubiquitinase gene BAP1 in up to 15% of sporadic cases.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('chromosome', 'cellular_component', 'GO:0005694', ('158', '168'))	('tumor', 'Disease', (103, 108))	('ccRCC', 'Disease', (85, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('BAP1', 'Gene', '8314', (215, 219))	('tumor suppressor', 'biological_process', 'GO:0051726', ('103', '119'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('103', '119'))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('195', '209'))	('BAP1', 'Gene', (215, 219))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
122177	32765803	As in the case of UM, loss of the BAP1 protein has been consistently associated with more aggressive forms of disease and worse prognostic outcomes in ccRCC patients, leading further to the development of distinct molecular subclassifications of ccRCC.	('aggressive forms of disease', 'Disease', (90, 117))	('ccRCC', 'Disease', (246, 251))	('BAP1', 'Gene', '8314', (34, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (246, 251))	('BAP1', 'Gene', (34, 38))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('UM', 'Phenotype', 'HP:0007716', (18, 20))	('associated', 'Reg', (69, 79))	('patients', 'Species', '9606', (157, 165))	('ccRCC', 'Phenotype', 'HP:0006770', (151, 156))	('ccRCC', 'Disease', (151, 156))	('aggressive forms of disease', 'Disease', 'MESH:D006527', (90, 117))	('protein', 'Protein', (39, 46))	('loss', 'Var', (22, 26))
122178	32765803	speculate on different prognostic subtypes of UM defined by the presence of BAP1 alterations and/or chromosome 8q gains.	('chromosome 8q gains', 'Var', (100, 119))	('BAP1', 'Gene', '8314', (76, 80))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('alterations', 'Var', (81, 92))	('BAP1', 'Gene', (76, 80))	('chromosome', 'cellular_component', 'GO:0005694', ('100', '110'))
122192	32334433	Genetic predictors include a growing number of factors, such as chromosome 3 loss, chromosome 8q gain, BAP1 aberration, a class 2 gene expression profile, PRAME abnormality, and SF3B1 mutation.	('BAP1', 'Gene', '8314', (103, 107))	('chromosome 8q', 'Gene', (83, 96))	('SF3B1', 'Gene', (178, 183))	('BAP1', 'Gene', (103, 107))	('PRAME', 'Gene', '23532', (155, 160))	('PRAME', 'Gene', (155, 160))	('chromosome', 'cellular_component', 'GO:0005694', ('64', '74'))	('chromosome', 'cellular_component', 'GO:0005694', ('83', '93'))	('gain', 'PosReg', (97, 101))	('chromosome', 'Gene', (64, 74))	('gene expression', 'biological_process', 'GO:0010467', ('130', '145'))	('aberration', 'Var', (108, 118))	('SF3B1', 'Gene', '23451', (178, 183))	('loss', 'NegReg', (77, 81))	('mutation', 'Var', (184, 192))
122197	32334433	First, it does not account for genetic predictors of metastasis, such as chromosome 3 loss, BAP1 aberration, and class 2 gene expression profile.	('aberration', 'Var', (97, 107))	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('loss', 'NegReg', (86, 90))	('BAP1', 'Gene', '8314', (92, 96))	('gene expression', 'biological_process', 'GO:0010467', ('121', '136'))	('BAP1', 'Gene', (92, 96))
122210	32334433	Tumors were categorized as having (1) normal chromosome 3 and chromosome 8q; (2) chromosome 8q gain; (3) chromosome 3 loss; or (4) both chromosome 8q gain and chromosome 3 loss.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('loss', 'NegReg', (172, 176))	('chromosome', 'cellular_component', 'GO:0005694', ('62', '72'))	('chromosome', 'cellular_component', 'GO:0005694', ('105', '115'))	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('chromosome', 'Var', (81, 91))	('loss', 'NegReg', (118, 122))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('chromosome', 'cellular_component', 'GO:0005694', ('136', '146'))	('chromosome', 'cellular_component', 'GO:0005694', ('159', '169'))	('chromosome', 'cellular_component', 'GO:0005694', ('45', '55'))	('gain', 'PosReg', (150, 154))	('gain', 'PosReg', (95, 99))
122211	32334433	Patients found to have chromosome 3 abnormality were referred to a medical oncologist for systemic management, which involved liver imaging and long-term surveillance.	('abnormality', 'Var', (36, 47))	('chromosome 3', 'Gene', (23, 35))	('chromosome', 'cellular_component', 'GO:0005694', ('23', '33'))	('Patients', 'Species', '9606', (0, 8))
122228	32334433	The entire cohort was comprised of 8348 patients with choroidal melanoma; of these, 4174 had known chromosome 3 status, with monosomy 3 (M3) in 1705 patients and disomy 3 (D3) in 2469 (Table 1).	('patients', 'Species', '9606', (149, 157))	('choroidal melanoma', 'Disease', 'MESH:D008545', (54, 72))	('chromosome', 'cellular_component', 'GO:0005694', ('99', '109'))	('patients', 'Species', '9606', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('disomy 3', 'Var', (162, 170))	('choroidal melanoma', 'Disease', (54, 72))	('monosomy 3', 'Var', (125, 135))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (54, 72))
122256	32334433	This is because a significant proportion of small choroidal melanomas show lethal genetic aberrations and, conversely, such aberrations are not present in many large tumors.	('small choroidal melanomas', 'Disease', 'MESH:D008545', (44, 69))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (50, 69))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (50, 68))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('genetic aberrations', 'Var', (82, 101))	('tumors', 'Disease', (166, 172))	('small choroidal melanomas', 'Disease', (44, 69))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
122268	32028647	Opposite Roles of BAP1 in Overall Survival of Uveal Melanoma and Cutaneous Melanoma Background: BRCA1-Associated Protein 1 (BAP1) germline mutations predispose individuals to cancers, including uveal melanoma (UM) and cutaneous melanoma (CM).	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('uveal melanoma', 'Disease', (194, 208))	('BAP1', 'Gene', (18, 22))	('uveal melanoma', 'Disease', 'MESH:C536494', (194, 208))	('Melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('BRCA1-Associated Protein 1', 'Gene', (96, 122))	('Melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('BAP1', 'Gene', '8314', (124, 128))	('CM', 'Disease', 'MESH:C562393', (238, 240))	('uveal melanoma', 'Phenotype', 'HP:0007716', (194, 208))	('Melanoma and Cutaneous Melanoma', 'Disease', 'MESH:D008545', (52, 83))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('BRCA1-Associated Protein 1', 'Gene', '8314', (96, 122))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (46, 60))	('UM', 'Disease', 'MESH:C536494', (210, 212))	('BAP1', 'Gene', (124, 128))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('cutaneous melanoma', 'Disease', (218, 236))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (218, 236))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (218, 236))	('BAP1', 'Gene', '8314', (18, 22))	('predispose', 'Reg', (149, 159))	('mutations', 'Var', (139, 148))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (65, 83))
122272	32028647	Cox regression model was performed to examine whether BAP1 mRNA levels or copy number variations were associated with overall survival (OS).	('mRNA levels', 'MPA', (59, 70))	('associated', 'Reg', (102, 112))	('overall survival', 'MPA', (118, 134))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('copy number variations', 'Var', (74, 96))	('BAP1', 'Gene', '8314', (54, 58))	('BAP1', 'Gene', (54, 58))
122275	32028647	Additionally, low BAP1 mRNA predicted a better OS in CM patients older than 50 years but not in younger patients.	('patients', 'Species', '9606', (56, 64))	('BAP1', 'Gene', '8314', (18, 22))	('CM', 'Disease', 'MESH:C562393', (53, 55))	('BAP1', 'Gene', (18, 22))	('low', 'Var', (14, 17))	('patients', 'Species', '9606', (104, 112))
122276	32028647	Co-expression and enrichment analysis revealed differential genes and mutations that were correlated with BAP1 expression levels in UM and CM tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('mutations', 'Var', (70, 79))	('correlated', 'Reg', (90, 100))	('BAP1', 'Gene', (106, 110))	('CM', 'Disease', 'MESH:C562393', (139, 141))	('UM', 'Disease', 'MESH:C536494', (132, 134))	('expression levels', 'MPA', (111, 128))	('BAP1', 'Gene', '8314', (106, 110))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))
122278	32028647	High BAP1 expression in CM was significantly associated with over-expressed CDK1, BCL2, and KIT at the protein level which may explain the poor OS in this sub-group of patients.	('BCL2', 'Gene', (82, 86))	('High', 'Var', (0, 4))	('CM', 'Disease', 'MESH:C562393', (24, 26))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('BAP1', 'Gene', '8314', (5, 9))	('KIT', 'Gene', '3815', (92, 95))	('KIT', 'molecular_function', 'GO:0005020', ('92', '95'))	('associated', 'Reg', (45, 55))	('BCL2', 'molecular_function', 'GO:0015283', ('82', '86'))	('CDK', 'molecular_function', 'GO:0004693', ('76', '79'))	('KIT', 'Gene', (92, 95))	('patients', 'Species', '9606', (168, 176))	('BAP1', 'Gene', (5, 9))	('BCL2', 'Gene', '596', (82, 86))	('CDK1', 'Gene', '983', (76, 80))	('over-expressed', 'PosReg', (61, 75))	('CDK1', 'Gene', (76, 80))
122280	32028647	Germline mutations in BAP1 (BRCA1-Associated Protein 1) are associated with multiple types of hereditary cancers, which is now classified as BAP1-TPDS (BAP1 Tumor Predisposition Syndrome).	('Germline mutations', 'Var', (0, 18))	('hereditary cancers', 'Disease', (94, 112))	('BAP1', 'Gene', '8314', (141, 145))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('BAP1', 'Gene', '8314', (152, 156))	('BRCA1-Associated Protein 1', 'Gene', (28, 54))	('BAP1', 'Gene', (141, 145))	('hereditary cancers', 'Disease', 'MESH:D009369', (94, 112))	('BAP1', 'Gene', '8314', (22, 26))	('BRCA1-Associated Protein 1', 'Gene', '8314', (28, 54))	('BAP1', 'Gene', (22, 26))	('BAP1', 'Gene', (152, 156))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('associated', 'Reg', (60, 70))	('Tumor', 'Phenotype', 'HP:0002664', (157, 162))
122282	32028647	The BAP1 germline mutations are generally deletions or loss-of-function mutations, thus BAP1 was defined as a tumor suppressor gene.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('BAP1', 'Gene', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('loss-of-function', 'NegReg', (55, 71))	('deletions', 'Var', (42, 51))	('BAP1', 'Gene', '8314', (88, 92))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('BAP1', 'Gene', (88, 92))	('BAP1', 'Gene', '8314', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
122284	32028647	Somatic mutations in UM tumors are also common.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('UM', 'Disease', 'MESH:C536494', (21, 23))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Disease', (24, 30))	('Somatic mutations', 'Var', (0, 17))
122285	32028647	In an analysis of germline vs. somatic mutations in UM tumors, 8% of tumors were reported to have germline mutation while 43-45% of tumors had somatic mutations.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('UM', 'Disease', 'MESH:C536494', (52, 54))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('germline mutation', 'Var', (98, 115))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
122289	32028647	Loss of BAP1 in uveal melanoma cells did not impact cell proliferation or tumorigenesis; rather, loss of BAP1 led to de-differentiation accompanied by increased stem-like biomarkers.	('increased', 'PosReg', (151, 160))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('loss', 'Var', (97, 101))	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('BAP1', 'Gene', '8314', (105, 109))	('BAP1', 'Gene', '8314', (8, 12))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('uveal melanoma', 'Disease', (16, 30))	('uveal melanoma', 'Disease', 'MESH:C536494', (16, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('BAP1', 'Gene', (8, 12))	('de-differentiation', 'CPA', (117, 135))	('BAP1', 'Gene', (105, 109))
122290	32028647	In cutaneous melanoma cell lines, however, stable over-expression of BAP1 promoted cell growth while knockdown of BAP1 suppressed cell proliferation with concomitant decrease of survivin, an anti-apoptotic protein.	('cell proliferation', 'biological_process', 'GO:0008283', ('130', '148'))	('cell growth', 'biological_process', 'GO:0016049', ('83', '94'))	('knockdown', 'Var', (101, 110))	('BAP1', 'Gene', (114, 118))	('BAP1', 'Gene', '8314', (69, 73))	('suppressed', 'NegReg', (119, 129))	('protein', 'cellular_component', 'GO:0003675', ('206', '213'))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('survivin', 'Protein', (178, 186))	('decrease', 'NegReg', (166, 174))	('over-expression', 'PosReg', (50, 65))	('BAP1', 'Gene', (69, 73))	('cutaneous melanoma', 'Disease', (3, 21))	('promoted', 'PosReg', (74, 82))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('BAP1', 'Gene', '8314', (114, 118))	('cell proliferation', 'CPA', (130, 148))	('cell growth', 'CPA', (83, 94))
122292	32028647	BAP1 mutations are associated with worse prognosis and survival in UM patients due to increased metastatic potentials.	('patients', 'Species', '9606', (70, 78))	('increased', 'PosReg', (86, 95))	('BAP1', 'Gene', (0, 4))	('metastatic potentials', 'CPA', (96, 117))	('mutations', 'Var', (5, 14))	('UM', 'Disease', 'MESH:C536494', (67, 69))	('BAP1', 'Gene', '8314', (0, 4))
122293	32028647	A meta-analysis of various cancer types with BAP1 mutations indicated that BAP1 mutations were also associated with worse outcomes in renal cell carcinoma but not in other cancers.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('BAP1', 'Gene', (75, 79))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('BAP1', 'Gene', '8314', (45, 49))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (134, 154))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (134, 154))	('BAP1', 'Gene', (45, 49))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))	('cancer', 'Disease', (172, 178))	('BAP1', 'Gene', '8314', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('mutations', 'Var', (50, 59))	('renal cell carcinoma', 'Disease', (134, 154))	('cancer', 'Disease', (27, 33))
122302	32028647	The TCGA CM and UM patient information were level 1 and 2 raw data; mRNA expression data were RSEM-normalized (RNA-Seq by Expectation Maximization); mutations (single nucleotide changes or small insertion/deletions) and copy number variations (CNVs) in each tumor were level 3 processed data.	('small insertion/deletions', 'Var', (189, 214))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('RNA', 'cellular_component', 'GO:0005562', ('111', '114'))	('patient', 'Species', '9606', (19, 26))	('single nucleotide changes', 'Var', (160, 185))	('tumor', 'Disease', (258, 263))	('mRNA expression', 'MPA', (68, 83))	('CM', 'Disease', 'MESH:C562393', (9, 11))	('UM', 'Disease', 'MESH:C536494', (16, 18))	('tumor', 'Disease', 'MESH:D009369', (258, 263))
122303	32028647	Survival curves for mRNA expression levels of BAP1 or BAP1 copy number variation (CNV) were plotted using Kaplan-Meier method.	('BAP1', 'Gene', '8314', (46, 50))	('copy number variation', 'Var', (59, 80))	('BAP1', 'Gene', '8314', (54, 58))	('BAP1', 'Gene', (46, 50))	('BAP1', 'Gene', (54, 58))
122316	32028647	Among the 80 UM tumors, 13 tumors carried a BAP1 point mutation and 44 showed copy number variation (CNV = -1, all hemizygous deletion, defined as BAP1-CNV group).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('UM', 'Disease', 'MESH:C536494', (13, 15))	('BAP1', 'Gene', (147, 151))	('copy number variation', 'Var', (78, 99))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('point mutation', 'Var', (49, 63))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('BAP1', 'Gene', '8314', (44, 48))	('BAP1', 'Gene', '8314', (147, 151))	('tumors', 'Disease', (16, 22))	('BAP1', 'Gene', (44, 48))
122318	32028647	Hemizygous deletion may indicate monosomy 3, which was a driver cause for uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('monosomy 3', 'Disease', (33, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('Hemizygous deletion', 'Var', (0, 19))	('indicate', 'Reg', (24, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('uveal melanoma', 'Disease', (74, 88))
122327	32028647	Eleven tumors carried BAP1 point mutations, with four silent synonymous mutations and seven missense mutations with unknown significance (I643T, E30K, P629S, R417M, S143N (N = 2), L416F and R59W).	('L416F', 'Mutation', 'p.L416F', (180, 185))	('P629S', 'Var', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('E30K', 'Var', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('I643T', 'Mutation', 'rs376519545', (138, 143))	('R417M', 'Mutation', 'p.R417M', (158, 163))	('R417M', 'Var', (158, 163))	('tumors', 'Disease', (7, 13))	('R59W', 'Mutation', 'rs1404823823', (190, 194))	('BAP1', 'Gene', '8314', (22, 26))	('P629S', 'Mutation', 'p.P629S', (151, 156))	('E30K', 'Mutation', 'p.E30K', (145, 149))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('BAP1', 'Gene', (22, 26))	('L416F', 'Var', (180, 185))	('R59W', 'Var', (190, 194))	('I643T', 'Var', (138, 143))	('S143N', 'Mutation', 'p.S143N', (165, 170))
122328	32028647	It was not surprising that these mutations were not associated with overall survival in CM (HR = 0.58, p = 0.36).	('CM', 'Disease', 'MESH:C562393', (88, 90))	('associated', 'Reg', (52, 62))	('mutations', 'Var', (33, 42))
122331	32028647	Compared to patients with no BAP1 copy number alteration (i.e., BAP1 diploids), patients with BAP1 amplification or deletion both showed significant better survival (Table 1, Figure 1f).	('patients', 'Species', '9606', (12, 20))	('BAP1', 'Gene', '8314', (94, 98))	('patients', 'Species', '9606', (80, 88))	('deletion', 'Var', (116, 124))	('BAP1', 'Gene', '8314', (29, 33))	('better', 'PosReg', (149, 155))	('amplification', 'Var', (99, 112))	('BAP1', 'Gene', '8314', (64, 68))	('survival', 'CPA', (156, 164))	('BAP1', 'Gene', (94, 98))	('BAP1', 'Gene', (29, 33))	('BAP1', 'Gene', (64, 68))
122332	32028647	BAP1 deletion indicated non-significant better survival (HR = 0.74, p = 0.116); and BAP1 amplification (correlated with high level of mRNA) indicated significant better survival (HR = 0.56, p = 0.005) (Table 1).	('survival', 'CPA', (169, 177))	('deletion', 'Var', (5, 13))	('BAP1', 'Gene', (0, 4))	('better', 'PosReg', (162, 168))	('survival', 'CPA', (47, 55))	('BAP1', 'Gene', '8314', (84, 88))	('amplification', 'Var', (89, 102))	('BAP1', 'Gene', (84, 88))	('BAP1', 'Gene', '8314', (0, 4))	('better', 'PosReg', (40, 46))
122333	32028647	BAP1 amplification-predicted better survival remained significant after adjusting to age of diagnosis (HR 0.59, p = 0.013), but the significance was lost after adjusting to stage of disease (HR = 0.68, p = 0.08) (Supplemental Table S2).	('better', 'PosReg', (29, 35))	('BAP1', 'Gene', '8314', (0, 4))	('amplification-predicted', 'Var', (5, 28))	('BAP1', 'Gene', (0, 4))
122334	32028647	BAP1 amplified tumors had slightly lower percentage (12/55 = 21.8 vs. 42/178 = 23.6%) of stage T1 and slightly higher percentage of stage T4 disease (14/55 = 25.5% vs. 39/178 = 21.9%) as compared to diploid tumors.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('BAP1', 'Gene', (0, 4))	('stage T4 disease', 'Disease', (132, 148))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('amplified', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('lower', 'NegReg', (35, 40))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('higher', 'PosReg', (111, 117))	('tumors', 'Disease', (207, 213))	('diploid tumors', 'Disease', 'MESH:C548012', (199, 213))	('BAP1', 'Gene', '8314', (0, 4))	('diploid tumors', 'Disease', (199, 213))	('tumors', 'Disease', (15, 21))	('stage T1', 'Disease', (89, 97))
122359	32028647	Next, we asked whether specific mutations or CNVs were associated with high BAP1 expression in CM or low BAP1 expression in UM, each of which indicated worse overall survivals.	('high', 'Var', (71, 75))	('BAP1', 'Gene', '8314', (76, 80))	('BAP1', 'Gene', '8314', (105, 109))	('UM', 'Disease', 'MESH:C536494', (124, 126))	('expression', 'MPA', (110, 120))	('BAP1', 'Gene', (76, 80))	('CM', 'Disease', 'MESH:C562393', (95, 97))	('BAP1', 'Gene', (105, 109))	('expression', 'MPA', (81, 91))
122361	32028647	Enrichment analysis (embedded in cBioportal,) revealed that EIF1AX (unadjusted p = 0.0072) and SF3B1 (unadjusted p = 0.0072) mutations were exclusive with low expression of BAP1.	('mutations', 'Var', (125, 134))	('SF3B1', 'Gene', (95, 100))	('EIF1AX', 'Gene', '1964', (60, 66))	('EIF1AX', 'Gene', (60, 66))	('BAP1', 'Gene', '8314', (173, 177))	('SF3B1', 'Gene', '23451', (95, 100))	('BAP1', 'Gene', (173, 177))
122363	32028647	Exclusivity of SF3B1 and EIF1AX mutations with BAP1 was consistent with previous reports, and supported classification of UM in three sub-types by mutations in three genes: BAP1, SF3B1, and EIF1AX.	('mutations', 'Var', (147, 156))	('SF3B1', 'Gene', '23451', (15, 20))	('SF3B1', 'Gene', (179, 184))	('EIF1AX', 'Gene', (190, 196))	('EIF1AX', 'Gene', '1964', (190, 196))	('BAP1', 'Gene', '8314', (173, 177))	('SF3B1', 'Gene', '23451', (179, 184))	('mutations', 'Var', (32, 41))	('BAP1', 'Gene', '8314', (47, 51))	('EIF1AX', 'Gene', '1964', (25, 31))	('EIF1AX', 'Gene', (25, 31))	('BAP1', 'Gene', (173, 177))	('SF3B1', 'Gene', (15, 20))	('UM', 'Disease', 'MESH:C536494', (122, 124))	('BAP1', 'Gene', (47, 51))
122365	32028647	SF3B1 mRNA levels were not associated with overall survival (HR = 1.29, p = 0.66, bottom 30% vs. top 30%); but SF3B1 mutation alone or mutation plus amplification indicated better overall survival (Supplemental Figure S2).	('SF3B1', 'Gene', '23451', (111, 116))	('better', 'PosReg', (173, 179))	('SF3B1', 'Gene', (0, 5))	('overall survival', 'MPA', (180, 196))	('SF3B1', 'Gene', '23451', (0, 5))	('SF3B1', 'Gene', (111, 116))	('mutation', 'Var', (117, 125))	('mutation plus amplification', 'Var', (135, 162))
122366	32028647	This outcome was perhaps due to the presence of SF3B1 mutation/amplification exclusively in the BAP1-high group.	('mutation/amplification', 'Var', (54, 76))	('BAP1', 'Gene', (96, 100))	('SF3B1', 'Gene', (48, 53))	('mutation/amplification', 'MPA', (54, 76))	('SF3B1', 'Gene', '23451', (48, 53))	('BAP1', 'Gene', '8314', (96, 100))
122373	32028647	The worse outcome of BAP1-low patients (including hemizygous deletion of BAP1 and low BAP1 mRNA) was validated in UM patients, while a new discovery of low BAP1 mRNA indicating a better overall survival in CM patients was described.	('CM', 'Disease', 'MESH:C562393', (206, 208))	('BAP1', 'Gene', '8314', (73, 77))	('BAP1', 'Gene', '8314', (86, 90))	('BAP1', 'Gene', '8314', (156, 160))	('BAP1', 'Gene', (21, 25))	('deletion', 'Var', (61, 69))	('BAP1', 'Gene', (73, 77))	('low', 'NegReg', (82, 85))	('BAP1', 'Gene', (86, 90))	('patients', 'Species', '9606', (30, 38))	('patients', 'Species', '9606', (209, 217))	('patients', 'Species', '9606', (117, 125))	('UM', 'Disease', 'MESH:C536494', (114, 116))	('BAP1', 'Gene', (156, 160))	('BAP1', 'Gene', '8314', (21, 25))
122374	32028647	Furthermore, low BAP1 mRNA seemed to indicate a significantly better survival for CM patients of older age (>50 years) but did not predict survival for younger patients.	('patients', 'Species', '9606', (160, 168))	('better', 'PosReg', (62, 68))	('patients', 'Species', '9606', (85, 93))	('low', 'Var', (13, 16))	('survival', 'MPA', (69, 77))	('BAP1', 'Gene', '8314', (17, 21))	('CM', 'Disease', 'MESH:C562393', (82, 84))	('BAP1', 'Gene', (17, 21))
122375	32028647	The age-differentiated BAP1 role in CM survival is different than that in UM where loss of BAP1 predicted worse outcome in patients of all ages.	('BAP1', 'Gene', (23, 27))	('BAP1', 'Gene', (91, 95))	('loss', 'Var', (83, 87))	('patients', 'Species', '9606', (123, 131))	('BAP1', 'Gene', '8314', (23, 27))	('CM', 'Disease', 'MESH:C562393', (36, 38))	('BAP1', 'Gene', '8314', (91, 95))	('UM', 'Disease', 'MESH:C536494', (74, 76))
122378	32028647	These results are consistent with the cellular role of BAP1 in CM cell lines A375 and C918 where depletion of BAP1 expression led to an inhibition of cell growth but were different with the survival outcome in the same Kumar et al.	('BAP1', 'Gene', '8314', (110, 114))	('CM', 'Disease', 'MESH:C562393', (63, 65))	('BAP1', 'Gene', (55, 59))	('BAP1', 'Gene', (110, 114))	('inhibition', 'NegReg', (136, 146))	('cell growth', 'CPA', (150, 161))	('A375', 'CellLine', 'CVCL:0132;0.014568046475425634', (77, 81))	('inhibition of cell growth', 'biological_process', 'GO:0030308', ('136', '161'))	('depletion', 'Var', (97, 106))	('BAP1', 'Gene', '8314', (55, 59))
122383	32028647	It is also a mystery why BAP1 amplification was associated with better overall survival, even though BAP1 amplification was correlated with higher BAP1 mRNA levels.	('better', 'PosReg', (64, 70))	('BAP1', 'Gene', (147, 151))	('BAP1', 'Gene', (25, 29))	('BAP1', 'Gene', '8314', (101, 105))	('higher', 'PosReg', (140, 146))	('amplification', 'Var', (30, 43))	('overall survival', 'MPA', (71, 87))	('BAP1', 'Gene', (101, 105))	('BAP1', 'Gene', '8314', (147, 151))	('BAP1', 'Gene', '8314', (25, 29))
122386	32028647	Specifically, low BAP1 expression or loss of BAP1 in UM was exclusive to SF3B1 or EIF1AX mutations, while high BAP1 expression in CM was non-significantly exclusive to 9p21 deletion.	('SF3B1', 'Gene', '23451', (73, 78))	('BAP1', 'Gene', '8314', (18, 22))	('BAP1', 'Gene', (45, 49))	('BAP1', 'Gene', '8314', (111, 115))	('UM', 'Disease', 'MESH:C536494', (53, 55))	('BAP1', 'Gene', (18, 22))	('BAP1', 'Gene', (111, 115))	('CM', 'Disease', 'MESH:C562393', (130, 132))	('EIF1AX', 'Gene', (82, 88))	('mutations', 'Var', (89, 98))	('loss', 'NegReg', (37, 41))	('low', 'NegReg', (14, 17))	('to 9', 'Species', '1214577', (165, 169))	('SF3B1', 'Gene', (73, 78))	('EIF1AX', 'Gene', '1964', (82, 88))	('BAP1', 'Gene', '8314', (45, 49))	('expression', 'MPA', (23, 33))
122389	32028647	Nevertheless, BAP1 expression levels were not associated with GNAQ and GNA11 mutation status in UM tumors, nor with NRAS or PTEN mutation status in CM tumor.	('PTEN', 'Gene', (124, 128))	('GNAQ', 'Gene', '2776', (62, 66))	('GNA11', 'Gene', (71, 76))	('mutation', 'Var', (77, 85))	('GNAQ', 'Gene', (62, 66))	('tumor', 'Disease', (99, 104))	('BAP1', 'Gene', '8314', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('PTEN', 'Gene', '5728', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('NRAS', 'Gene', '4893', (116, 120))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('BAP1', 'Gene', (14, 18))	('GNA11', 'Gene', '2767', (71, 76))	('expression levels', 'MPA', (19, 36))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))	('UM', 'Disease', 'MESH:C536494', (96, 98))	('CM', 'Disease', 'MESH:C562393', (148, 150))	('tumor', 'Disease', (151, 156))	('NRAS', 'Gene', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
122391	32028647	When the BRAF mutation status was used for adjustment in the multivariate Cox model, low BAP1 mRNA levels were still significantly associated with a better OS (HR = 0.74, p = 0.026) while BRAF mutation status did not predict OS in either simple or multivariate Cox model.	('Cox', 'Gene', (74, 77))	('BAP1', 'Gene', (89, 93))	('BRAF', 'Gene', (9, 13))	('low', 'NegReg', (85, 88))	('BRAF', 'Gene', '673', (188, 192))	('Cox', 'Gene', '1351', (261, 264))	('Cox', 'Gene', (261, 264))	('BRAF', 'Gene', (188, 192))	('mutation', 'Var', (14, 22))	('Cox', 'Gene', '1351', (74, 77))	('BAP1', 'Gene', '8314', (89, 93))	('BRAF', 'Gene', '673', (9, 13))
122397	32028647	For example, BAP1-induced apoptosis in neuroblastoma cells is mediated via an interaction with the 14-3-3 protein; thus, the loss of the 14-3-3 protein may lead to loss of BAP1 function (at least partially), even when BAP1 mRNA and DNA are normally expressed.	('BAP1', 'Gene', (13, 17))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('loss', 'Var', (125, 129))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('BAP1', 'Gene', (172, 176))	('neuroblastoma', 'Disease', 'MESH:D009447', (39, 52))	('DNA', 'cellular_component', 'GO:0005574', ('232', '235'))	('apoptosis', 'biological_process', 'GO:0097194', ('26', '35'))	('BAP1', 'Gene', '8314', (218, 222))	('apoptosis', 'biological_process', 'GO:0006915', ('26', '35'))	('neuroblastoma', 'Disease', (39, 52))	('neuroblastoma', 'Phenotype', 'HP:0003006', (39, 52))	('14-3-3 protein', 'Protein', (137, 151))	('BAP1', 'Gene', '8314', (13, 17))	('BAP1', 'Gene', (218, 222))	('function', 'MPA', (177, 185))	('loss', 'NegReg', (164, 168))	('BAP1', 'Gene', '8314', (172, 176))
122399	32028647	However, it was reported that these additional structural variants were all associated with low BAP1 mRNA expression, therefore mRNA expression levels should not mis-classify these additional mutations.	('variants', 'Var', (58, 66))	('BAP1', 'Gene', (96, 100))	('low', 'NegReg', (92, 95))	('BAP1', 'Gene', '8314', (96, 100))
122406	32028647	Table S1: Mean BAP1 mRNA levels in UM and CM are correlated with copy number of BAP1 gene.	('correlated', 'Reg', (49, 59))	('CM', 'Disease', 'MESH:C562393', (42, 44))	('UM', 'Disease', 'MESH:C536494', (35, 37))	('BAP1', 'Gene', '8314', (80, 84))	('BAP1', 'Gene', '8314', (15, 19))	('BAP1', 'Gene', (80, 84))	('copy number', 'Var', (65, 76))	('BAP1', 'Gene', (15, 19))
122407	32028647	BAP1 amplification predicts better overall survival comparing to diploids.	('BAP1', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('better', 'PosReg', (28, 34))	('overall survival', 'MPA', (35, 51))	('BAP1', 'Gene', '8314', (0, 4))
122503	31366043	A histopathological examination of needle tracts revealed a lower number of seeded tumor cells following transvitreal biopsies compared to trans-scleral biopsies.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('transvitreal biopsies', 'Var', (105, 126))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('lower', 'NegReg', (60, 65))
122521	31366043	They found no significant increase in the all-cause mortality and melanoma-specific mortality among biopsied patients compared to non-biopsied patients.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('biopsied', 'Var', (100, 108))	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (143, 151))
122528	31366043	A rarer complication of ocular tumor biopsy is rhegmatogenous retinal detachment, with a slightly higher incidence following TVRC than after transvitreal FNAB.	('ocular tumor', 'Disease', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('ocular tumor', 'Phenotype', 'HP:0100012', (24, 36))	('TVRC', 'Chemical', '-', (125, 129))	('retinal detachment', 'Phenotype', 'HP:0000541', (62, 80))	('rhegmatogenous retinal detachment', 'Disease', 'MESH:C563710', (47, 80))	('rhegmatogenous retinal detachment', 'Phenotype', 'HP:0012230', (47, 80))	('TVRC', 'Var', (125, 129))	('rhegmatogenous retinal detachment', 'Disease', (47, 80))	('ocular tumor', 'Disease', 'MESH:D009369', (24, 36))
122541	31366043	Several analysis techniques have been developed, from karyotyping and fluorescence in situ hybridization (FISH) (Figure 2 and Figure 7), to multiplex ligation-dependent probe amplification (MLPA) (Figure 8), single nucleotide polymorphism (SNP) and gene expression profiling (GEP), which has been proposed to be less, but still affected by genetic tumor heterogeneity, compared to the other modalities.	('gene expression', 'biological_process', 'GO:0010467', ('249', '264'))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('single nucleotide polymorphism', 'Var', (208, 238))	('genetic tumor', 'Disease', 'MESH:D030342', (340, 353))	('genetic tumor', 'Disease', (340, 353))
122554	31366043	Tumors with monosomy 3 corresponded to class 2 tumors as classified by GEP, whereas tumors without a loss of chromosome 3 referred to class 1 tumors.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('monosomy 3', 'Var', (12, 22))
122557	31366043	One recently identified prognostic factor is the mutation of BRCA1-associated protein 1 (BAP1).	('BAP1', 'Gene', (89, 93))	('mutation', 'Var', (49, 57))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('BRCA1-associated protein 1', 'Gene', '8314', (61, 87))	('BRCA1-associated protein 1', 'Gene', (61, 87))	('BAP1', 'Gene', '8314', (89, 93))
122559	31366043	The presence of inactivating somatic or germline BAP1 mutations, often in conjunction with chromosome 3 monosomy, the loss of BAP1 expression, or the lack of immunohistochemical staining, have all been associated with metastasizing UM.	('inactivating', 'NegReg', (16, 28))	('BAP1', 'Gene', (126, 130))	('BAP1', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('associated', 'Reg', (202, 212))	('loss', 'NegReg', (118, 122))	('metastasizing UM', 'Disease', (218, 234))	('expression', 'MPA', (131, 141))	('chromosome', 'cellular_component', 'GO:0005694', ('91', '101'))	('BAP1', 'Gene', '8314', (126, 130))	('BAP1', 'Gene', '8314', (49, 53))
122560	31366043	Defining the germline vs. somatic nature of BAP1 mutations in UM may inform the individual about both the risk of metastasis, and the probable time to metastasis, which are critically important outcomes for the individual.	('inform', 'Reg', (69, 75))	('BAP1', 'Gene', '8314', (44, 48))	('mutations', 'Var', (49, 58))	('BAP1', 'Gene', (44, 48))
122561	31366043	PRAME and EIF1AX genes have been also correlated to a higher and decreased risk of metastases, respectively, in UM, whereas GNAQ or GNA11 gene mutations are characteristics of melanocytic origin cells, also of nevi, thus not being particularly informative about prognosis but confirming the origin of the sampled tissue.	('GNA11', 'Gene', (132, 137))	('metastases', 'Disease', (83, 93))	('decreased', 'NegReg', (65, 74))	('GNAQ', 'Gene', '2776', (124, 128))	('GNA11', 'Gene', '2767', (132, 137))	('metastases', 'Disease', 'MESH:D009362', (83, 93))	('melanocytic', 'Disease', 'MESH:D009508', (176, 187))	('GNAQ', 'Gene', (124, 128))	('melanocytic', 'Disease', (176, 187))	('PRAME', 'Gene', '23532', (0, 5))	('EIF1AX', 'Gene', '1964', (10, 16))	('EIF1AX', 'Gene', (10, 16))	('nevi', 'Phenotype', 'HP:0003764', (210, 214))	('PRAME', 'Gene', (0, 5))	('mutations', 'Var', (143, 152))
122563	31366043	Another gene involved in intermediate risk UM is SF3B1, whose mutations have been observed in late metastasizing tumors.	('SF3B1', 'Gene', '23451', (49, 54))	('metastasizing tumors', 'Disease', 'MESH:D009362', (99, 119))	('observed', 'Reg', (82, 90))	('SF3B1', 'Gene', (49, 54))	('metastasizing tumors', 'Disease', (99, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mutations', 'Var', (62, 71))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
122593	31200439	Risk factors include fair skin colour, red or blond hair, light eye colour, ocular melanocytosis and dysplastic nevi, and familial syndromes, i.e., germline BRCA1-associated protein-1 (BAP1) mutation).	('fair skin', 'Phenotype', 'HP:0007513', (21, 30))	('light eye', 'Disease', (58, 67))	('blond hair', 'Phenotype', 'HP:0002286', (46, 56))	('red or blond hair', 'Disease', (39, 56))	('light eye colour', 'Phenotype', 'HP:0007730', (58, 74))	('BAP1', 'Gene', (185, 189))	('fair skin colour', 'Disease', (21, 37))	('BRCA1-associated protein-1', 'Gene', (157, 183))	('ocular melanocytosis and dysplastic', 'Disease', 'MESH:C535835', (76, 111))	('familial syndromes', 'Disease', (122, 140))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (101, 116))	('ocular melanocytosis', 'Phenotype', 'HP:0025534', (76, 96))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('nevi', 'Phenotype', 'HP:0003764', (112, 116))	('BRCA1-associated protein-1', 'Gene', '8314', (157, 183))	('germline', 'Var', (148, 156))	('mutation', 'Var', (191, 199))	('BAP1', 'Gene', '8314', (185, 189))
122594	31200439	Patients with germline BAP1 mutation are predisposed to familial cancers including UM, mesothelioma, cutaneous melanoma, and renal cell carcinoma, among others.	('predisposed', 'Reg', (41, 52))	('renal cell carcinoma', 'Disease', (125, 145))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (125, 145))	('BAP1', 'Gene', '8314', (23, 27))	('mutation', 'Var', (28, 36))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('familial cancers', 'Disease', (56, 72))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Patients', 'Species', '9606', (0, 8))	('familial cancers', 'Disease', 'MESH:D009369', (56, 72))	('BAP1', 'Gene', (23, 27))	('mesothelioma', 'Disease', (87, 99))	('cutaneous melanoma', 'Disease', (101, 119))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (101, 119))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (125, 145))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (101, 119))	('germline', 'Var', (14, 22))	('mesothelioma', 'Disease', 'MESH:D008654', (87, 99))
122595	31200439	Clinicians should advise genetic testing and assessment for BAP1 germline mutation in suspected patients and families.	('BAP1', 'Gene', '8314', (60, 64))	('germline mutation', 'Var', (65, 82))	('BAP1', 'Gene', (60, 64))	('patients', 'Species', '9606', (96, 104))
122597	31200439	Moreover, UM is characterized by a very low mutational burden, and by activating and mutually exclusive mutations in genes encoding the G-protein-alpha subunits GNAQ or GNA11 in 90% of primary tumours).	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('GNA11', 'Gene', '2767', (169, 174))	('GNA11', 'Gene', (169, 174))	('mutations', 'Var', (104, 113))	('activating', 'PosReg', (70, 80))	('primary tumours', 'Disease', 'MESH:D009369', (185, 200))	('GNAQ', 'Gene', (161, 165))	('primary tumours', 'Disease', (185, 200))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('GNAQ', 'Gene', '2776', (161, 165))	('tumours', 'Phenotype', 'HP:0002664', (193, 200))
122598	31200439	Mutations in the CYSLTR2 or PLCB4 genes may be found in the remaining 10%.	('PLCB4', 'Gene', '5332', (28, 33))	('CYSLTR2', 'Gene', (17, 24))	('Mutations', 'Var', (0, 9))	('PLCB4', 'Gene', (28, 33))	('CYSLTR2', 'Gene', '57105', (17, 24))
122599	31200439	These mutations lead to the activation of the MAPK and PI3K/AKT pathways but also the transcriptional co-activator YAP through both a Hippo-independent and a Hippo-dependent circuit.	('YAP', 'Gene', '10413', (115, 118))	('AKT', 'Gene', '207', (60, 63))	('MAPK', 'molecular_function', 'GO:0004707', ('46', '50'))	('YAP', 'Gene', (115, 118))	('PI3K', 'molecular_function', 'GO:0016303', ('55', '59'))	('activation', 'PosReg', (28, 38))	('AKT', 'Gene', (60, 63))	('mutations', 'Var', (6, 15))
122610	31200439	Although extensive prospective data is missing, patients showing a limited extent of metastases seem to benefit from liver-directed therapies (e.g., hepatic intra-arterial chemotherapy, hepatic embolisation, radiofrequency ablation, or stereotactic radiation therapy).	('radiofrequency', 'Var', (208, 222))	('benefit', 'PosReg', (104, 111))	('hepatic embolisation', 'Disease', (186, 206))	('metastases', 'Disease', (85, 95))	('hepatic embolisation', 'Disease', 'MESH:D056486', (186, 206))	('patients', 'Species', '9606', (48, 56))	('hepatic embolisation', 'Phenotype', 'HP:0030243', (186, 206))	('metastases', 'Disease', 'MESH:D009362', (85, 95))
122633	31200439	Interfering with epigenetic dysregulation represents the most recent approach in UM treatment; trials are ongoing with the HDAC inhibitors vorinostat (NCT02068586, NCT01587352) and entinostat (PEMDAC trial with pembrolizumab, entinostat, NCT02697630), and the BRD4 inhibitor PLX51107 (NCT02683395).	('pembrolizumab', 'Chemical', 'MESH:C582435', (211, 224))	('NCT02068586', 'Var', (151, 162))	('BRD4', 'Gene', (260, 264))	('vorinostat', 'Chemical', 'MESH:D000077337', (139, 149))	('NCT01587352', 'Var', (164, 175))	('BRD4', 'Gene', '23476', (260, 264))
122743	31234419	However, the bivalence of bevacizumab would double the amount of available VEGF-binding sites.	('VEGF', 'Gene', '7422', (75, 79))	('bevacizumab', 'Chemical', 'MESH:D000068258', (26, 37))	('VEGF-binding', 'molecular_function', 'GO:0038085', ('75', '87'))	('VEGF', 'Gene', (75, 79))	('amount of available', 'MPA', (55, 74))	('bivalence', 'Var', (13, 22))	('double', 'PosReg', (44, 50))
122754	31234419	We have indeed previously demonstrated that blocking the VEGF-R2 could significantly impair the accumulation of ranibizumab in the early endosomes of RPE cells, suggesting that ranibizumab may be undergoing endocytosis together with the VEGF/VEGF-R2 complex.	('ranibizumab', 'Chemical', 'MESH:D000069579', (112, 123))	('impair', 'NegReg', (85, 91))	('VEGF', 'Gene', (237, 241))	('VEGF-R2', 'Gene', (57, 64))	('blocking', 'Var', (44, 52))	('endocytosis', 'biological_process', 'GO:0006897', ('207', '218'))	('VEGF', 'Gene', (242, 246))	('VEGF-R2', 'Gene', '3791', (242, 249))	('VEGF', 'Gene', '7422', (237, 241))	('VEGF', 'Gene', (57, 61))	('ranibizumab', 'Chemical', 'MESH:D000069579', (177, 188))	('VEGF-R2', 'Gene', '3791', (57, 64))	('VEGF-R2', 'Gene', (242, 249))	('VEGF', 'Gene', '7422', (242, 246))	('accumulation of ranibizumab in the early endosomes', 'MPA', (96, 146))	('VEGF', 'Gene', '7422', (57, 61))
122764	31234419	Moreover, the genes for the transferrin protein (Gene ID: 7018) and its receptor (Gene ID: 7037), which play central roles in the recycling of endosomal contents on to plasma membrane, reside on chromosome 3q22.1 and 3q29, respectively.	('Gene ID: 7037', 'Var', (82, 95))	('transferrin', 'Gene', '7018', (28, 39))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('transferrin', 'Gene', (28, 39))	('plasma membrane', 'cellular_component', 'GO:0005886', ('168', '183'))	('chromosome', 'cellular_component', 'GO:0005694', ('195', '205'))
122765	31234419	The loss of one copy of chromosome-3 (Monosomy-3) is indeed the most important prognostic factor in UM, which is significantly associated with a higher risk of metastases.	('UM', 'Phenotype', 'HP:0007716', (100, 102))	('associated', 'Reg', (127, 137))	('chromosome', 'cellular_component', 'GO:0005694', ('24', '34'))	('metastases', 'Disease', (160, 170))	('Monosomy-3', 'Var', (38, 48))	('metastases', 'Disease', 'MESH:D009362', (160, 170))	('loss', 'Var', (4, 8))
122767	31234419	Monosomy-3 was also detected in approximately 50% of the primary tumor cells of the patient, from whom the Mel-270 and OMM-2.5 cells were generated.	('tumor', 'Disease', (65, 70))	('Monosomy-3', 'Var', (0, 10))	('patient', 'Species', '9606', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
122796	31234419	These results, together with our recent findings on UM cells, therefore support the view that, even though the therapeutic VEGF-A antibodies may be cleared from the extracellular compartments of the eye, their retention inside the cells may lead to sustained effects, which deserves further consideration.	('sustained effects', 'MPA', (249, 266))	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('VEGF-A', 'Gene', (123, 129))	('antibodies', 'Var', (130, 140))	('retention', 'biological_process', 'GO:0051235', ('210', '219'))	('men', 'Species', '9606', (186, 189))	('lead to', 'Reg', (241, 248))	('extracellular', 'cellular_component', 'GO:0005576', ('165', '178'))
122822	31234419	To evaluate drug uptake, three randomly located confocal fluorescence images (200 x 300 microm2) were taken of each sample and they were analyzed semi-quantitatively with regard to the colocalized Dylight650/Alexa488 (drug/Rab5) particles using ImageJ as previously reported.	('Rab5', 'Gene', '5868', (223, 227))	('Alexa488', 'Chemical', '-', (208, 216))	('Rab5', 'Gene', (223, 227))	('uptake', 'biological_process', 'GO:0098657', ('17', '23'))	('uptake', 'biological_process', 'GO:0098739', ('17', '23'))	('Dylight650/Alexa488', 'Var', (197, 216))
122829	31234419	Since the UM cells with Monosomy-3 are very likely to have abnormal endosome dynamics, analysis of additional UM cell lines which differ in the extent of Monosomy-3 would provide valuable insight into the response or resistance of these highly heterogenous tumors to therapeutic antibodies.	('UM', 'Phenotype', 'HP:0007716', (10, 12))	('UM', 'Phenotype', 'HP:0007716', (110, 112))	('tumors', 'Disease', (257, 263))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('Monosomy-3', 'Var', (24, 34))	('abnormal endosome dynamics', 'MPA', (59, 85))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('endosome', 'cellular_component', 'GO:0005768', ('68', '76'))
122830	31234419	Moreover, the characterization of the VEGF-A splice variants which are mainly affected by bevacizumab and ranibizumab might enable a more comprehensive understanding of the downstream effects of these interventions in UM cells.	('bevacizumab', 'Chemical', 'MESH:D000068258', (90, 101))	('affected', 'Reg', (78, 86))	('VEGF-A', 'Gene', (38, 44))	('splice variants', 'Var', (45, 60))	('UM', 'Phenotype', 'HP:0007716', (218, 220))	('ranibizumab', 'Chemical', 'MESH:D000069579', (106, 117))
122838	31025552	CNA-based model comprising monosomy 3, 8q amplification, and LZTS1and NBL1 deletions emerged as the best predictor for disease-free survival.	('deletions', 'Var', (75, 84))	('NBL1', 'Gene', (70, 74))	('LZTS1', 'Gene', (61, 66))	('monosomy', 'Var', (27, 35))	('NBL1', 'Gene', '4681', (70, 74))	('LZTS1', 'Gene', '11178', (61, 66))
122842	31025552	This has led to development of treatments targeting the underlying genetic alterations with better patient stratification and improved survival rates in many solid tumors.	('patient', 'Species', '9606', (99, 106))	('improved', 'PosReg', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('genetic alterations', 'Var', (67, 86))	('solid tumors', 'Disease', (158, 170))	('solid tumors', 'Disease', 'MESH:D009369', (158, 170))
122879	31025552	Copy number alterations (CNA) by MLPA was analyzable for 84/89 tumors.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('Copy number alterations', 'Var', (0, 23))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
122880	31025552	The alterations observed were as follows: Monosomy 3 (M3) in 48/84 (57.1%), 8q gain (8q+) in 41/84 (48.8%), isochromosome 8q (i8q) in 16/84 (19%), 6p gain (6p+) in 27/84 (32.1%) tumors, respectively.	('gain', 'PosReg', (79, 83))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('8q+', 'Chemical', '-', (85, 88))	('Monosomy 3', 'Var', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
122883	31025552	In immune infiltrate-high group, M3 was present in 17/19 (89.5%) tumors, with 16/17 (94.1%) also having 8q+, which in some cases was part of i8q (12/16, 75%) or 8 gain (8+; 3/16, 18.8%).	('8q+', 'Chemical', '-', (104, 107))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('8q+', 'Var', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
122885	31025552	The immune infiltrate-low tumors without M3 had i6p (12/34, 35.3%), DeltaNBL1 (20/34, 58.8%) and DeltaLZTS1 (18/34, 52.9%) (Figure S3).	('NBL1', 'Gene', (73, 77))	('LZTS1', 'Gene', '11178', (102, 107))	('LZTS1', 'Gene', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('NBL1', 'Gene', '4681', (73, 77))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))	('i6p', 'Var', (48, 51))
122888	31025552	As copy number alterations (CNA), they included monosomy 3, isochromosome 8q, 8q gain (8q+), and 8p loss (Table S6, Figure S4a-e).	('8q+', 'Chemical', '-', (87, 90))	('monosomy 3', 'Var', (48, 58))	('isochromosome 8q', 'Var', (60, 76))	('loss', 'NegReg', (100, 104))	('gain', 'PosReg', (81, 85))
122891	31025552	This led to the identification of deletion of LZTS1(DeltaLZTS1) and NBL1 (DeltaNBL1) as novel variables (Table S7).	('NBL1', 'Gene', (79, 83))	('NBL1', 'Gene', '4681', (68, 72))	('LZTS1(DeltaLZTS1', 'Gene', '11178', (46, 62))	('deletion', 'Var', (34, 42))	('NBL1', 'Gene', '4681', (79, 83))	('NBL1', 'Gene', (68, 72))
122898	31025552	The low-risk groups of both stratifications remained similar, with the exception of three tumors with only M3+ that were now included in intermediate-low risk group.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('M3+', 'Var', (107, 110))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))
122905	31025552	The TCGA data from uveal melanomas were used for external validation of CNA and immune-CNA models.9 The TCGA tumors were classified into three risk groups based on the above described CNA model comprising M3, 8q gain, LZTS1, and NBL1 deletions.	('uveal melanomas', 'Disease', (19, 34))	('uveal melanomas', 'Phenotype', 'HP:0007716', (19, 34))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('LZTS1', 'Gene', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('deletions', 'Var', (234, 243))	('NBL1', 'Gene', (229, 233))	('uveal melanoma', 'Phenotype', 'HP:0007716', (19, 33))	('uveal melanomas', 'Disease', 'MESH:C536494', (19, 34))	('LZTS1', 'Gene', '11178', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('TCGA', 'Gene', (104, 108))	('tumors', 'Disease', (109, 115))	('melanomas', 'Phenotype', 'HP:0002861', (25, 34))	('NBL1', 'Gene', '4681', (229, 233))
122907	31025552	In addition to validating the present CNA model comprising M3, 8q gain, LZTS1, and NBL1 deletions on the TCGA data, the mutations associated with the tumors in high, intermediate and low-risk groups were assessed.	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Disease', (150, 156))	('deletions', 'Var', (88, 97))	('NBL1', 'Gene', (83, 87))	('LZTS1', 'Gene', '11178', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('NBL1', 'Gene', '4681', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('LZTS1', 'Gene', (72, 77))
122908	31025552	The majority of tumors, 29/35 (82.6%) in the high-risk group showed BAP1 mutations.	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('BAP1', 'Gene', '8314', (68, 72))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (16, 22))	('BAP1', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))
122909	31025552	These tumors had M3/8q gain with either 8p loss or LZTS1 deletion or NBL1 deletion.	('M3/8q', 'Var', (17, 22))	('NBL1', 'Gene', (69, 73))	('deletion', 'Var', (57, 65))	('deletion', 'Var', (74, 82))	('LZTS1', 'Gene', '11178', (51, 56))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('NBL1', 'Gene', '4681', (69, 73))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('gain', 'PosReg', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('LZTS1', 'Gene', (51, 56))
122910	31025552	The intermediate risk-group melanomas had either BAP1 (4/13, 30.7%) or SF3B1 (5/13, 38.5%) mutations.	('SF3B1', 'Gene', (71, 76))	('BAP1', 'Gene', (49, 53))	('SF3B1', 'Gene', '23451', (71, 76))	('melanomas', 'Disease', (28, 37))	('melanomas', 'Disease', 'MESH:D008545', (28, 37))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('mutations', 'Var', (91, 100))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('BAP1', 'Gene', '8314', (49, 53))
122911	31025552	The low-risk group tumors had either SF3B1 (10/32, 31.2%) or EIF1AX (10/32, 31.2%) mutations.	('mutations', 'Var', (83, 92))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('SF3B1', 'Gene', '23451', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('EIF1AX', 'Gene', '1964', (61, 67))	('EIF1AX', 'Gene', (61, 67))	('SF3B1', 'Gene', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
122912	31025552	All the tumors with EIF1AX mutations lacked M3, 8q gain, LZTS1 or NBL1 deletions.	('mutations', 'Var', (27, 36))	('deletions', 'Var', (71, 80))	('NBL1', 'Gene', (66, 70))	('LZTS1', 'Gene', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('EIF1AX', 'Gene', '1964', (20, 26))	('EIF1AX', 'Gene', (20, 26))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('LZTS1', 'Gene', '11178', (57, 62))	('NBL1', 'Gene', '4681', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('lacked', 'NegReg', (37, 43))
122916	31025552	The risk of developing metastasis within 48 months of diagnosis from this CNA-based nomogram was compared to those from PRiMeUM, a web-based tool.12 PRiMeUM predicts the metastatic risk based on alterations in chromosomes 1, 3, 6, and 8, patient age, tumor location, diameter, and thickness.	('alterations', 'Var', (195, 206))	('tumor', 'Disease', (251, 256))	('UM', 'Phenotype', 'HP:0007716', (125, 127))	('metastatic', 'CPA', (170, 180))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('UM', 'Phenotype', 'HP:0007716', (154, 156))	('patient', 'Species', '9606', (238, 245))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
122917	31025552	Immune cell infiltration in solid tumors is usually associated with a transcriptomic signature that includes genes regulated by interferon-gamma (IFNgamma), as illustrated in breast, colorectal, and ovarian carcinomas, as well as in cutaneous melanomas.13, 14, 15, 16 Similarly, gene expression profiling allowed us to identify a subset of uveal melanomas (UM) that expressed genes of the IFNgamma/STAT1-IRF1 pathway.	('cutaneous melanomas', 'Disease', (233, 252))	('gene expression', 'biological_process', 'GO:0010467', ('279', '294'))	('genes', 'Var', (376, 381))	('uveal melanoma', 'Phenotype', 'HP:0007716', (340, 354))	('STAT1', 'Gene', (398, 403))	('colorectal', 'Disease', (183, 193))	('solid tumors', 'Disease', (28, 40))	('melanomas', 'Phenotype', 'HP:0002861', (243, 252))	('uveal melanomas', 'Disease', (340, 355))	('uveal melanomas', 'Phenotype', 'HP:0007716', (340, 355))	('melanomas', 'Phenotype', 'HP:0002861', (346, 355))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (199, 217))	('carcinomas', 'Phenotype', 'HP:0030731', (207, 217))	('IRF1', 'Gene', (404, 408))	('IFNgamma', 'Gene', (146, 154))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('ovarian carcinomas', 'Disease', (199, 217))	('STAT1', 'Gene', '6772', (398, 403))	('IFNgamma', 'Gene', '3458', (146, 154))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (199, 217))	('melanoma', 'Phenotype', 'HP:0002861', (243, 251))	('melanoma', 'Phenotype', 'HP:0002861', (346, 354))	('UM', 'Phenotype', 'HP:0007716', (357, 359))	('colorectal', 'Disease', 'MESH:D015179', (183, 193))	('IFNgamma', 'Gene', '3458', (389, 397))	('IRF1', 'Gene', '3659', (404, 408))	('solid tumors', 'Disease', 'MESH:D009369', (28, 40))	('IFNgamma', 'Gene', (389, 397))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (233, 252))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('128', '144'))	('interferon-gamma', 'Gene', (128, 144))	('uveal melanomas', 'Disease', 'MESH:C536494', (340, 355))	('interferon-gamma', 'Gene', '3458', (128, 144))
122932	31025552	The CNA model was based on four DNA alterations: M3, 8q+, LZTS1 deletion (DeltaLZTS1), and NBL1deletion (DeltaNBL1).	('NBL1', 'Gene', (110, 114))	('LZTS1', 'Gene', '11178', (79, 84))	('LZTS1', 'Gene', '11178', (58, 63))	('NBL1', 'Gene', '4681', (91, 95))	('8q+', 'Var', (53, 56))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('deletion', 'Var', (64, 72))	('LZTS1', 'Gene', (79, 84))	('LZTS1', 'Gene', (58, 63))	('NBL1', 'Gene', '4681', (110, 114))	('NBL1', 'Gene', (91, 95))	('8q+', 'Chemical', '-', (53, 56))
122936	31025552	In this model, the addition of LZTS1 and NBL1status refined the prognostic significance of a published model based on two anomalies: M3 and 8q+.4 Indeed, combined M3+/8q + was observed in UM of both intermediate and high-risk groups, but only in the latter when associated with DeltaLZTS1 and/or DeltaNBL1.	('8q+', 'Chemical', '-', (140, 143))	('LZTS1', 'Gene', (31, 36))	('NBL1', 'Gene', '4681', (301, 305))	('LZTS1', 'Gene', (283, 288))	('LZTS1', 'Gene', '11178', (31, 36))	('NBL1', 'Gene', '4681', (41, 45))	('LZTS1', 'Gene', '11178', (283, 288))	('NBL1', 'Gene', (301, 305))	('UM', 'Phenotype', 'HP:0007716', (188, 190))	('M3+/8q +', 'Var', (163, 171))	('NBL1', 'Gene', (41, 45))
122939	31025552	To the best of our knowledge, there are no prognostic models in cancer incorporating copy number aberrations and immune infiltration.	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', (64, 70))	('copy number aberrations', 'Var', (85, 108))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
122942	31025552	The caveats of this study are: relatively small sample size, bias toward large sized tumors, and use of MLPA technique to assess copy number alterations.	('copy number alterations', 'Var', (129, 152))	('tumors', 'Disease', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
122943	31025552	It is true that the use of whole-exome or targeted sequencing has led to the identification of BAP1, SF3B1, and EIF1AX (BSE) mutations, each of which is associated with a specific set of copy number alterations.9, 33, 34 However, the use of next-generation sequencing (NGS) requires adequate infrastructure and bioinformatic support.	('mutations', 'Var', (125, 134))	('BAP1', 'Gene', (95, 99))	('EIF1AX', 'Gene', '1964', (112, 118))	('EIF1AX', 'Gene', (112, 118))	('SF3B1', 'Gene', (101, 106))	('BAP1', 'Gene', '8314', (95, 99))	('SF3B1', 'Gene', '23451', (101, 106))
122944	31025552	For example, BAP1 mutations can frequently be missed when they comprise large insertions/deletions, intronic/splice site alterations and other complex rearrangements.	('BAP1', 'Gene', '8314', (13, 17))	('BAP1', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
122948	31025552	Comparison of immune cell infiltration as a biomarker to other conventional markers established the superiority of a three risk group copy number alteration model for uveal melanoma prognostication.	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('uveal melanoma', 'Phenotype', 'HP:0007716', (167, 181))	('uveal melanoma', 'Disease', 'MESH:C536494', (167, 181))	('uveal melanoma', 'Disease', (167, 181))	('copy number alteration', 'Var', (134, 156))
122978	30107825	Exon 4 skipping in CIZ1 previously identified as a cancer variant, and reportedly used as an early serum biomarker in lung cancer was found.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('CIZ1', 'Gene', (19, 23))	('skipping', 'Var', (7, 15))	('CIZ1', 'Gene', '25792', (19, 23))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (123, 129))	('lung cancer', 'Disease', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
122979	30107825	Mismatch Repair protein MLH3 was found to have splicing variations with deletions to both Exon 5 and Exon 7 simultaneously.	('deletions', 'Var', (72, 81))	('protein', 'cellular_component', 'GO:0003675', ('16', '23'))	('MLH3', 'Gene', '27030', (24, 28))	('Mismatch Repair', 'biological_process', 'GO:0006298', ('0', '15'))	('splicing', 'MPA', (47, 55))	('MLH3', 'Gene', (24, 28))	('splicing', 'biological_process', 'GO:0045292', ('47', '55'))
122991	30107825	Endogenous causes include nucleotide pool availability, DNA structures, protein-DNA complexes, reactive oxidation species, transcription and replication complex collision, mutation and expression alteration in tumor suppressor and oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('expression', 'MPA', (185, 195))	('reactive oxidation species', 'MPA', (95, 121))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('tumor', 'Disease', (210, 215))	('mutation', 'Var', (172, 180))	('DNA structures', 'MPA', (56, 70))	('nucleotide pool availability', 'MPA', (26, 54))	('protein-DNA complexes', 'Protein', (72, 93))	('tumor suppressor', 'biological_process', 'GO:0051726', ('210', '226'))	('transcription', 'biological_process', 'GO:0006351', ('123', '136'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('210', '226'))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
123014	30107825	Half of the helicase complex components (MCM2-7) are located on chromosomes found by TCGA to have copy number alterations that include monosomy chromosome 3, 8q and 6p gains.	('chromosome', 'cellular_component', 'GO:0005694', ('144', '154'))	('helicase complex', 'Protein', (12, 28))	('monosomy chromosome 3', 'Var', (135, 156))	('MCM2-7', 'Gene', '4171;4172;4173;4174;4175;4176', (41, 47))	('MCM2-7', 'Gene', (41, 47))
123015	30107825	Conversely, MCM4 (8q11.21) expression is increased in clusters 3 and 4, with escalation correlating to worse survival that correlate with SCNA gains to chromosome 8q in cluster 4 (P = 0.0018) (Fig.	('MCM4', 'Gene', '4173', (12, 16))	('increased', 'PosReg', (41, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('152', '162'))	('gains', 'Var', (143, 148))	('expression', 'MPA', (27, 37))	('MCM4', 'Gene', (12, 16))
123022	30107825	Evidence of exon 4 skipping previously seen in Ewing tumor and Lung Cancer and in the C terminal region was found in the CIZ1 heatmap (Fig.	('Ewing tumor', 'Disease', (47, 58))	('Ewing tumor', 'Disease', 'MESH:C563168', (47, 58))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('skipping', 'Var', (19, 27))	('Ewing tumor', 'Phenotype', 'HP:0012254', (47, 58))	('CIZ1', 'Gene', (121, 125))	('Lung Cancer', 'Disease', (63, 74))	('Lung Cancer', 'Phenotype', 'HP:0100526', (63, 74))	('CIZ1', 'Gene', '25792', (121, 125))
123023	30107825	CIZ1 intron 3 contains a mononucleotide repeat previously associated with exon 4 skipping mechanistically, and hypothesized to be the result of MMR deficiency.	('MMR', 'biological_process', 'GO:0006298', ('144', '147'))	('CIZ1', 'Gene', (0, 4))	('MMR deficiency', 'Disease', (144, 158))	('mononucleotide', 'Chemical', '-', (25, 39))	('MMR deficiency', 'Disease', 'MESH:C536143', (144, 158))	('CIZ1', 'Gene', '25792', (0, 4))	('mononucleotide repeat', 'Var', (25, 46))
123033	30107825	RAD1 showed evidence of alternative splicing involving exon 3 previously reported as a natural isoform (Fig.	('RAD1', 'Gene', '5810', (0, 4))	('RAD1', 'Gene', (0, 4))	('splicing', 'biological_process', 'GO:0045292', ('36', '44'))	('RAD', 'biological_process', 'GO:1990116', ('0', '3'))	('alternative splicing', 'Var', (24, 44))
123044	30107825	On the basis of high frequency, the earliest mutations in UVM are thought to be to the guanine nucleotide binding proteins (GTPases) GNAQ and GNA11.	('mutations', 'Var', (45, 54))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('95', '113'))	('UVM', 'Gene', (58, 61))	('GNAQ', 'Gene', (133, 137))	('GTPases', 'Gene', (124, 131))	('UVM', 'Phenotype', 'HP:0007716', (58, 61))	('GNA11', 'Gene', (142, 147))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (87, 105))	('GNAQ', 'Gene', '2776', (133, 137))	('GNA11', 'Gene', '2767', (142, 147))
123048	30107825	Decrease in MCM2 is thought to reduce replication initiation in gene rich early replicating regions, and to increase genetic damage at a subset of gene rich locations without changing the replication rate.	('increase', 'PosReg', (108, 116))	('MCM2', 'Gene', '4171', (12, 16))	('MCM2', 'Gene', (12, 16))	('genetic damage', 'Disease', 'MESH:D030342', (117, 131))	('Decrease', 'Var', (0, 8))	('reduce', 'NegReg', (31, 37))	('genetic damage', 'Disease', (117, 131))	('replication initiation', 'MPA', (38, 60))
123059	30107825	Almost all UVM cases examined show evidence of exon 4 alteration previously reported in other cancers as well as alteration to the carboxyl end of the protein.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('alteration', 'Var', (54, 64))	('UVM', 'Disease', (11, 14))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('alteration', 'Reg', (113, 123))	('UVM', 'Phenotype', 'HP:0007716', (11, 14))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('exon 4', 'Protein', (47, 53))	('cancers', 'Disease', (94, 101))
123060	30107825	Variant mRNA created by alternative splicing are found in cancers and other disorders that appear to alter protein localization.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('alter', 'Reg', (101, 106))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('protein', 'Protein', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('splicing', 'biological_process', 'GO:0045292', ('36', '44'))	('protein localization', 'biological_process', 'GO:0008104', ('107', '127'))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('cancers', 'Disease', (58, 65))	('Variant', 'Var', (0, 7))	('found', 'Reg', (49, 54))
123061	30107825	Variant CIZ1 has recently been published as a circulating biomarker for early-stage lung cancer suggesting the same might be possible for UVM patients.	('lung cancer', 'Disease', (84, 95))	('CIZ1', 'Gene', (8, 12))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('UVM', 'Phenotype', 'HP:0007716', (138, 141))	('CIZ1', 'Gene', '25792', (8, 12))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('patients', 'Species', '9606', (142, 150))	('Variant', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
123062	30107825	The findings for CIZ1 led to identification a mononucleotide repeat in Intron 3 with possible MSI.	('mononucleotide', 'Chemical', '-', (46, 60))	('CIZ1', 'Gene', (17, 21))	('mononucleotide repeat', 'Var', (46, 67))	('MSI', 'Disease', 'None', (94, 97))	('Intron', 'Gene', (71, 77))	('CIZ1', 'Gene', '25792', (17, 21))	('MSI', 'Disease', (94, 97))
123064	30107825	Exon skipping was observed in MLH3 (MLH3   exon5/  exon7), a protein that interacts with MLH1 directly.	('MLH3', 'Gene', '27030', (30, 34))	('MLH3', 'Gene', (30, 34))	('MLH1', 'Gene', '4292', (89, 93))	('MLH1', 'Gene', (89, 93))	('MLH3', 'Gene', '27030', (36, 40))	('MLH3', 'Gene', (36, 40))	('Exon skipping', 'Var', (0, 13))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
123080	30107825	Dysregulated DDR in a tumor cell contributes to progressive genomic instability that is cancer enabling, and can make the tumor dependent on alternative repair pathways such as base excision repair (BER) that may be targetable (e.g.	('DDR', 'Gene', (13, 16))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('genomic instability', 'MPA', (60, 79))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('base excision repair', 'biological_process', 'GO:0006284', ('177', '197'))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('BER', 'biological_process', 'GO:0006284', ('199', '202'))	('Dysregulated', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Disease', (122, 127))
123083	30107825	PARADIGM and MARINa algorithms previously used to examine the pathway, found protein abundance for DDR components increased suggesting DDR was active in monosomy 3/BAP1 impaired UVM.	('monosomy', 'Var', (153, 161))	('UVM', 'MPA', (178, 181))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('BAP1', 'Gene', (164, 168))	('protein abundance', 'MPA', (77, 94))	('increased', 'PosReg', (114, 123))	('UVM', 'Phenotype', 'HP:0007716', (178, 181))	('BAP1', 'Gene', '8314', (164, 168))
123109	29503568	Monosomy 3 strongly relates to several clinical and histopathological parameters such as epithelioid cells, closed vascular patterns, large tumor diameter, and CB involvement.	('relates', 'Reg', (20, 27))	('CB involvement', 'Disease', (160, 174))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('closed', 'Disease', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('epithelioid', 'Disease', (89, 100))	('Monosomy 3', 'Var', (0, 10))	('tumor', 'Disease', (140, 145))
123111	29503568	Monosomy 3 is present in 50%-60% of UM tumors, and is associated with isochromosome 8q and high level of 8q gain.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('gain', 'PosReg', (108, 112))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('isochromosome 8q', 'Var', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('tumors', 'Disease', (39, 45))	('Monosomy 3', 'Var', (0, 10))
123113	29503568	Furthermore, a correlation was found between the copy number of chromosome 3 and 4 and the survival of patients.	('survival', 'CPA', (91, 99))	('chromosome', 'cellular_component', 'GO:0005694', ('64', '74'))	('correlation', 'Reg', (15, 26))	('copy number', 'Var', (49, 60))	('patients', 'Species', '9606', (103, 111))
123136	29503568	Hypoxanthine phosphoribosyltransferase 1 (HPRT1) was used as an internal reference gene (sense 5'-GTATTCATTATAGTCAAGGGCATATCC-3', antisense 5'-AGATGGTCAAGGTCGCAAG-3').	('HPRT1', 'Gene', '3251', (42, 47))	('Hypoxanthine phosphoribosyltransferase 1', 'Gene', (0, 40))	('antisense', 'Var', (130, 139))	('Hypoxanthine phosphoribosyltransferase 1', 'Gene', '3251', (0, 40))	('HPRT1', 'Gene', (42, 47))	('GTATTCATTATAGTCAAGGGCATATCC-3', 'Chemical', '-', (98, 127))	('HPRT', 'molecular_function', 'GO:0004422', ('42', '46'))
123170	29503568	The presence of specific LH-RH binding sites and characteristics of binding of [125I][D-Trp]LH-RH to membrane receptors on OCM-1 and OCM-3 human UM models were determined using ligand competition assays.	('binding', 'Interaction', (68, 75))	('membrane', 'cellular_component', 'GO:0016020', ('101', '109'))	('[125I][D-Trp]', 'Var', (79, 92))	('OCM-1', 'Species', '83984', (123, 128))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('[D-Trp', 'Chemical', '-', (85, 91))	('ligand', 'molecular_function', 'GO:0005488', ('177', '183'))	('binding', 'molecular_function', 'GO:0005488', ('68', '75'))	('human', 'Species', '9606', (139, 144))	('binding', 'molecular_function', 'GO:0005488', ('31', '38'))
123178	29503568	Thus, the binding of [125I][D-Trp]LH-RH was found to be reversible, time- and temperature-dependent, and linear with protein concentration in human UM samples.	('rat', 'Species', '10116', (83, 86))	('rat', 'Species', '10116', (132, 135))	('binding', 'Interaction', (10, 17))	('UM', 'Phenotype', 'HP:0007716', (148, 150))	('[125I][D-Trp]', 'Var', (21, 34))	('human', 'Species', '9606', (142, 147))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('binding', 'molecular_function', 'GO:0005488', ('10', '17'))	('[D-Trp', 'Chemical', '-', (27, 33))
123196	29503568	Targeted tumor therapy reduces peripheral toxicity and adverse reactions compared to systemic chemotherapeutic agents, and increases selective damage to cancer cells.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('adverse reactions', 'CPA', (55, 72))	('selective damage', 'CPA', (133, 149))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('cancer', 'Disease', (153, 159))	('toxicity', 'Disease', 'MESH:D064420', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('Targeted', 'Var', (0, 8))	('toxicity', 'Disease', (42, 50))	('tumor', 'Disease', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('reduces', 'NegReg', (23, 30))	('increases', 'PosReg', (123, 132))
123217	28448663	Positive PRAME expression was associated with a high largest basal diameter (15.0 vs 12.0 mm; P = .005), ciliary body involvement (59% vs 26%; P = .008), and amplification of chromosome 8q (66% vs 23%; P = .002).	('ciliary body involvement', 'CPA', (105, 129))	('chromosome', 'cellular_component', 'GO:0005694', ('175', '185'))	('men', 'Species', '9606', (125, 128))	('PRAME', 'Gene', (9, 14))	('amplification', 'Var', (158, 171))
123262	28448663	PRAME expression was associated with prognostically poor tumor characteristics; PRAME-positive tumors had the largest median basal diameter (15.0 vs 12.0 mm; P = .005) and a more frequent involvement of the ciliary body (59% vs 26%; P = .008) compared with PRAME-negative tumors.	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('basal diameter', 'CPA', (125, 139))	('tumors', 'Disease', (95, 101))	('tumor', 'Disease', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('tumor', 'Disease', (57, 62))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumors', 'Disease', (272, 278))	('involvement', 'Reg', (188, 199))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('PRAME-positive', 'Var', (80, 94))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('men', 'Species', '9606', (195, 198))
123263	28448663	Of the 29 PRAME-positive tumors, 21 (72%) showed monosomy of chromosome 3, whereas this was the case in 20 (57%) of the 35 PRAME-negative tumors (P = .21).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('monosomy', 'Var', (49, 57))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('PRAME-positive', 'Disease', (10, 24))	('chromosome', 'cellular_component', 'GO:0005694', ('61', '71'))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
123264	28448663	Tumors with chromosome 8q copies were categorized as follows: a copy number between 1.9 and 2.1 was categorized as normal, between 2.2 and 3.1 as gain, and more than 3.1 as amplification of chromosome 8q.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('copies', 'Var', (26, 32))	('gain', 'PosReg', (146, 150))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('chromosome', 'cellular_component', 'GO:0005694', ('190', '200'))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))
123276	28448663	One section of each tumor was stained using the GAPDH probe set labeled with the dye Quasar 570 together with the PRAME probe set labeled with Quasar 670, while the other section was stained with the same probe sets but labeled the other way around.	('GAPDH', 'Gene', '2597', (48, 53))	('Quasar', 'Var', (85, 91))	('GAPDH', 'Gene', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
123293	28448663	In the present study, we found that PRAME was expressed at the RNA level in 45% of primary UMs (29 of 64), and PRAME expression was associated with ciliary body involvement, largest basal diameter, and amplification of chromosome 8q.	('ciliary body involvement', 'CPA', (148, 172))	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))	('UM', 'Phenotype', 'HP:0007716', (91, 93))	('primary UMs', 'Disease', (83, 94))	('chromosome', 'cellular_component', 'GO:0005694', ('219', '229'))	('associated', 'Reg', (132, 142))	('amplification', 'Var', (202, 215))	('largest basal diameter', 'CPA', (174, 196))	('men', 'Species', '9606', (168, 171))
123294	28448663	PRAME expression occurred in disomy 3 as well as in monosomy 3 tumors, which confirms the findings reported by Field et al.	('disomy 3', 'Disease', (29, 37))	('monosomy 3', 'Var', (52, 62))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', (63, 69))	('occurred', 'Reg', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
123320	28529451	Role of Epigenetics in Uveal Melanoma Uveal melanoma (UM) is a severe human malignancy with a high mortality rate that demands continued research into new and alternative forms of prevention and treatment.	('malignancy', 'Disease', 'MESH:D009369', (76, 86))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('human', 'Species', '9606', (70, 75))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('malignancy', 'Disease', (76, 86))	('Melanoma', 'Disease', 'MESH:D008545', (29, 37))	('Melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('UM', 'Phenotype', 'HP:0007716', (54, 56))	('Epigenetics', 'Var', (8, 19))	('Melanoma', 'Disease', (29, 37))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (23, 37))
123322	28529451	Epigenetic changes have a high prevalence rate in cancer, are reversible in nature, and can lead to cancer characteristics even in mutation-free cells.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('lead to', 'Reg', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('Epigenetic changes', 'Var', (0, 18))
123323	28529451	The information contained in this review highlights and expands on the main mechanisms of epigenetic dysregulation in UM tumorigenesis, progression and metastasis, including microRNA expression, hypermethylation of genes and histone modification.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('microRNA', 'MPA', (174, 182))	('tumor', 'Disease', (121, 126))	('UM', 'Phenotype', 'HP:0007716', (118, 120))	('epigenetic dysregulation', 'Var', (90, 114))	('histone modification', 'biological_process', 'GO:0016570', ('225', '245'))	('histone modification', 'Var', (225, 245))	('hypermethylation', 'Var', (195, 211))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
123324	28529451	Epigenetic drugs have been shown to enhance tumor suppressor gene expression and drug sensitivity in many other cancer cell lines and animal models.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('drug sensitivity', 'CPA', (81, 97))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('drug sensitivity', 'Phenotype', 'HP:0020174', (81, 97))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('enhance', 'PosReg', (36, 43))	('Epigenetic drugs', 'Var', (0, 16))	('tumor', 'Disease', (44, 49))	('gene expression', 'biological_process', 'GO:0010467', ('61', '76'))
123328	28529451	In addition, studies revealed that a mutation in the alpha subunit of the heterotrimeric G gene (GNAQ) was present in almost 50% of all UMs examined, and that UM metastatic spread was closely related to mutations in the BRCA associated protein 1 (BAP1) gene on chromosome 3.	('BAP1', 'Gene', (247, 251))	('chromosome', 'cellular_component', 'GO:0005694', ('261', '271'))	('UM', 'Phenotype', 'HP:0007716', (159, 161))	('mutation', 'Var', (37, 45))	('GNAQ', 'Gene', '2776', (97, 101))	('BRCA associated protein 1', 'Gene', (220, 245))	('related', 'Reg', (192, 199))	('BRCA associated protein 1', 'Gene', '8314', (220, 245))	('protein', 'cellular_component', 'GO:0003675', ('236', '243'))	('UM', 'Phenotype', 'HP:0007716', (136, 138))	('BAP1', 'Gene', '8314', (247, 251))	('mutations', 'Var', (203, 212))	('GNAQ', 'Gene', (97, 101))
123331	28529451	Recent studies propose that epigenetic alterations may be another hallmark of cancer due to their role in the initiation of carcinogenesis.	('initiation of carcinogenesis', 'Disease', 'MESH:D063646', (110, 138))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('initiation of carcinogenesis', 'Disease', (110, 138))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('epigenetic alterations', 'Var', (28, 50))
123332	28529451	Epigenetic changes can lead to cancer characteristics even in mutation-free cells.	('lead to', 'Reg', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('Epigenetic changes', 'Var', (0, 18))
123333	28529451	Epigenetic mechanisms include microRNA expression level variations, hypermethylation of tumor suppressor genes, hypomethylation of oncogenes, and histone modification patterns.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('88', '104'))	('histone', 'MPA', (146, 153))	('microRNA expression level', 'MPA', (30, 55))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor suppressor', 'biological_process', 'GO:0051726', ('88', '104'))	('hypermethylation', 'Var', (68, 84))	('histone modification', 'biological_process', 'GO:0016570', ('146', '166'))	('tumor', 'Disease', (88, 93))	('hypomethylation', 'Var', (112, 127))	('oncogenes', 'Gene', (131, 140))
123334	28529451	In this review, we will discuss the role of epigenetics in UM tumorigenesis and the potential modes of therapy derived from this area of research.	('epigenetics', 'Var', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('UM', 'Phenotype', 'HP:0007716', (59, 61))
123339	28529451	Several studies have reported that dysregulation of miRNAs can promote cell-cycle progression, confer resistance to apoptosis, and enhance invasiveness and metastasis of cancer cells.	('resistance', 'CPA', (102, 112))	('cell-cycle progression', 'CPA', (71, 93))	('metastasis of cancer', 'Disease', (156, 176))	('metastasis of cancer', 'Disease', 'MESH:D009362', (156, 176))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('enhance', 'PosReg', (131, 138))	('promote', 'PosReg', (63, 70))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))	('dysregulation', 'Var', (35, 48))	('miR', 'Gene', '220972', (52, 55))	('miR', 'Gene', (52, 55))	('cell-cycle', 'biological_process', 'GO:0007049', ('71', '81'))
123356	28529451	Restoration of let-7b is regarded as a potential therapeutic option in many cancers.	('let-7b', 'Gene', '406884', (15, 21))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('let-7b', 'Gene', (15, 21))	('cancers', 'Disease', (76, 83))	('Restoration', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
123383	28529451	Besides, lncRNAs can also work together with other epigenetic mechanisms, such as histone methylation and microRNAs, to modulate the cancer behaviors.	('cancer behaviors', 'Disease', 'MESH:D009369', (133, 149))	('cancer behaviors', 'Disease', (133, 149))	('histone', 'Protein', (82, 89))	('methylation', 'Var', (90, 101))	('modulate', 'Reg', (120, 128))	('histone methylation', 'biological_process', 'GO:0016571', ('82', '101'))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
123394	28529451	Epigenetic modification of gene expression is an important mechanism in tumorigenesis, and may be reversed by specific treatment.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('gene expression', 'biological_process', 'GO:0010467', ('27', '42'))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Epigenetic modification', 'Var', (0, 23))
123398	28529451	Upon Rb phosphorylation, E2F is activated and enhances S-phase-specific gene expression.	('enhances', 'PosReg', (46, 54))	('S-phase', 'biological_process', 'GO:0051320', ('55', '62'))	('Rb', 'Chemical', 'MESH:D012413', (5, 7))	('phosphorylation', 'Var', (8, 23))	('E2F', 'Var', (25, 28))	('phosphorylation', 'biological_process', 'GO:0016310', ('8', '23'))	('S-phase-specific gene', 'Gene', (55, 76))	('gene expression', 'biological_process', 'GO:0010467', ('72', '87'))
123400	28529451	Although p16INK4a is commonly inactivated in a wide range of malignancies, germ-line mutations of p16 INK4a are uniquely associated with familial cutaneous melanoma instead of UM.	('INK4a', 'Gene', (102, 107))	('p16INK4a', 'Gene', '1029', (9, 17))	('UM', 'Phenotype', 'HP:0007716', (176, 178))	('INK4a', 'Gene', '1029', (102, 107))	('p16', 'Gene', (98, 101))	('p16', 'Gene', '1029', (98, 101))	('familial cutaneous melanoma', 'Disease', 'MESH:C562393', (137, 164))	('INK4a', 'Gene', (12, 17))	('p16', 'Gene', (9, 12))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('familial cutaneous melanoma', 'Disease', (137, 164))	('p16', 'Gene', '1029', (9, 12))	('mutations', 'Var', (85, 94))	('INK4a', 'Gene', '1029', (12, 17))	('p16INK4a', 'Gene', (9, 17))	('malignancies', 'Disease', 'MESH:D009369', (61, 73))	('associated', 'Reg', (121, 131))	('malignancies', 'Disease', (61, 73))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (146, 164))
123401	28529451	An alternative mechanism for tumor suppressor gene inactivation is de novo methylation of CpG islands, which generally reduces transcription.	('methylation', 'biological_process', 'GO:0032259', ('75', '86'))	('methylation', 'Var', (75, 86))	('inactivation', 'NegReg', (51, 63))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('transcription', 'MPA', (127, 140))	('tumor suppressor', 'biological_process', 'GO:0051726', ('29', '45'))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('29', '45'))	('tumor', 'Disease', (29, 34))	('transcription', 'biological_process', 'GO:0006351', ('127', '140'))	('reduces', 'NegReg', (119, 126))
123402	28529451	De novo methylation of the p16INK4a promoter region occurs in a wide range of malignancies and releases the cell from a potent cell cycle inhibitor.	('malignancies', 'Disease', (78, 90))	('p16INK4a', 'Gene', (27, 35))	('occurs', 'Reg', (52, 58))	('cell cycle', 'biological_process', 'GO:0007049', ('127', '137'))	('releases', 'PosReg', (95, 103))	('malignancies', 'Disease', 'MESH:D009369', (78, 90))	('methylation', 'biological_process', 'GO:0032259', ('8', '19'))	('p16INK4a', 'Gene', '1029', (27, 35))	('methylation', 'Var', (8, 19))
123403	28529451	A recent study found that in both primary UM and UM cell lines, p16INK4a is frequently inactivated by hypermethylation, which is accompanied by down-regulated expression of p16 INK4a .	('INK4a', 'Gene', (177, 182))	('p16', 'Gene', (64, 67))	('p16INK4a', 'Gene', (64, 72))	('p16', 'Gene', '1029', (173, 176))	('down-regulated', 'NegReg', (144, 158))	('UM', 'Phenotype', 'HP:0007716', (49, 51))	('p16INK4a', 'Gene', '1029', (64, 72))	('inactivated', 'NegReg', (87, 98))	('expression', 'MPA', (159, 169))	('p16', 'Gene', '1029', (64, 67))	('INK4a', 'Gene', '1029', (177, 182))	('p16', 'Gene', (173, 176))	('hypermethylation', 'Var', (102, 118))	('INK4a', 'Gene', (67, 72))	('UM', 'Phenotype', 'HP:0007716', (42, 44))	('INK4a', 'Gene', '1029', (67, 72))
123406	28529451	Another study showed that epigenetic alterations in the p14ARF and p16INK4A genes were frequently associated with cutaneous as well as UMs, and they used ChIP experiments to clearly demonstrate that DNMT1 and DNMT3b played a dominant role in p16INK4A repression.	('p16INK4A', 'Gene', (242, 250))	('p14ARF', 'Gene', '1029', (56, 62))	('DNMT3b', 'Gene', (209, 215))	('p16INK4A', 'Gene', '1029', (242, 250))	('p16INK4A', 'Gene', (67, 75))	('DNMT1', 'Gene', '1786', (199, 204))	('UM', 'Phenotype', 'HP:0007716', (135, 137))	('p16INK4A', 'Gene', '1029', (67, 75))	('epigenetic alterations', 'Var', (26, 48))	('p14ARF', 'Gene', (56, 62))	('DNMT1', 'Gene', (199, 204))	('DNMT3b', 'Gene', '1789', (209, 215))	('UMs', 'Disease', (135, 138))	('associated', 'Reg', (98, 108))	('cutaneous as well', 'Disease', (114, 131))
123409	28529451	The RASSF1A gene is located on chromosome 3p21.3, and its absence or inactivation has been shown to be a contributing factor in UM tumor formation and progression.	('chromosome', 'cellular_component', 'GO:0005694', ('31', '41'))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('absence', 'NegReg', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('UM', 'Phenotype', 'HP:0007716', (128, 130))	('RASSF1A', 'Gene', (4, 11))	('inactivation', 'Var', (69, 81))	('formation', 'biological_process', 'GO:0009058', ('137', '146'))	('progression', 'CPA', (151, 162))	('tumor', 'Disease', (131, 136))	('RASSF1A', 'Gene', '11186', (4, 11))	('p21', 'Gene', (43, 46))	('p21', 'Gene', '644914', (43, 46))
123410	28529451	One study showed that RASSF1A expression suppresses UM tumorigenesis and is frequently silenced in the UM-15 cell line and that re-expression of RASSF1A in UM-15 cells reverses the tumoral behavior, as demonstrated by a slower proliferation rate and restoration of sensitivity to cisplatin treatment.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('slower proliferation rate', 'CPA', (220, 245))	('expression', 'Var', (30, 40))	('UM', 'Phenotype', 'HP:0007716', (156, 158))	('RASSF1A', 'Gene', '11186', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('reverses', 'NegReg', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('RASSF1A', 'Gene', (145, 152))	('UM-15', 'CellLine', 'CVCL:7722', (156, 161))	('suppresses', 'NegReg', (41, 51))	('UM', 'Phenotype', 'HP:0007716', (103, 105))	('tumoral behavior', 'Disease', (181, 197))	('re-expression', 'Var', (128, 141))	('tumoral behavior', 'Disease', 'MESH:D001523', (181, 197))	('tumor', 'Disease', (181, 186))	('RASSF1A', 'Gene', '11186', (22, 29))	('UM-15', 'CellLine', 'CVCL:7722', (103, 108))	('tumor', 'Disease', (55, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (280, 289))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('RASSF1A', 'Gene', (22, 29))
123412	28529451	Methylation of these sites blocks cell-cycle progression from G1 to S phase by controlling entry at the retinoblastoma check point and inhibiting cyclin D1 protein accumulation at the post-transcriptional level.	('cyclin D1', 'Gene', (146, 155))	('retinoblastoma', 'Disease', 'MESH:D012175', (104, 118))	('retinoblastoma', 'Disease', (104, 118))	('Methylation', 'Var', (0, 11))	('cell-cycle progression', 'CPA', (34, 56))	('cell-cycle', 'biological_process', 'GO:0007049', ('34', '44'))	('blocks', 'NegReg', (27, 33))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('inhibiting', 'NegReg', (135, 145))	('retinoblastoma', 'Phenotype', 'HP:0009919', (104, 118))	('cyclin', 'molecular_function', 'GO:0016538', ('146', '152'))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('cyclin D1', 'Gene', '595', (146, 155))	('S phase', 'biological_process', 'GO:0051320', ('68', '75'))
123413	28529451	Hypermethylation-induced loss of RASSF1A expression leads to a reduction in G1/S-phase cell-cycle control.	('RASSF1A', 'Gene', '11186', (33, 40))	('expression', 'MPA', (41, 51))	('cell-cycle control', 'biological_process', 'GO:1901987', ('87', '105'))	('G1/S-phase cell-cycle control', 'CPA', (76, 105))	('loss', 'NegReg', (25, 29))	('Hypermethylation-induced', 'Var', (0, 24))	('reduction', 'NegReg', (63, 72))	('S-phase', 'biological_process', 'GO:0051320', ('79', '86'))	('RASSF1A', 'Gene', (33, 40))
123414	28529451	In human mammary epithelial cells, RASSF1A dominates the oncogenic RAS effects, which means that loss of RASSF1A may be a determining step for oncogenic transformation in the absence of RAS-activating mutations.	('RASSF1A', 'Gene', '11186', (105, 112))	('RASSF1A', 'Gene', (35, 42))	('loss', 'Var', (97, 101))	('human', 'Species', '9606', (3, 8))	('RASSF1A', 'Gene', '11186', (35, 42))	('RASSF1A', 'Gene', (105, 112))
123417	28529451	Given the location of RASSF1A on the p21.3 region of chromosome 3, it might serve as a tumor suppressor gene whose silencing by methylation acts as a 'second hit' after monosomy occurs.	('RASSF1A', 'Gene', '11186', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor suppressor', 'biological_process', 'GO:0051726', ('87', '103'))	('methylation', 'biological_process', 'GO:0032259', ('128', '139'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('87', '103'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('methylation', 'Var', (128, 139))	('p21', 'Gene', (37, 40))	('chromosome', 'cellular_component', 'GO:0005694', ('53', '63'))	('RASSF1A', 'Gene', (22, 29))	('p21', 'Gene', '644914', (37, 40))	('silencing', 'NegReg', (115, 124))
123418	28529451	Although the methylation of RASSF1A may not be considered wholly responsible for UM development, it could be a contributing factor in tumor formation and progression.	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('RASSF1A', 'Gene', (28, 35))	('methylation', 'Var', (13, 24))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('RASSF1A', 'Gene', '11186', (28, 35))	('UM', 'Phenotype', 'HP:0007716', (81, 83))	('contributing factor', 'Reg', (111, 130))	('formation', 'biological_process', 'GO:0009058', ('140', '149'))	('tumor', 'Disease', (134, 139))
123426	28529451	In a study by Maat et al., 11 UM cell lines and 35 primary UM samples were screened for mutations in the RASEF gene region by high-resolution melting-curve and digestion analysis.	('RASEF', 'Gene', '158158', (105, 110))	('digestion', 'biological_process', 'GO:0007586', ('160', '169'))	('mutations', 'Var', (88, 97))	('UM', 'Phenotype', 'HP:0007716', (30, 32))	('RASEF', 'Gene', (105, 110))	('UM', 'Phenotype', 'HP:0007716', (59, 61))
123428	28529451	Additional effects of the loss of heterozygosity seem to be related to the aggressive behavior of the tumor, because homozygous tumors with a methylated RASEF promoter region tend to display decreased survival compared with heterozygous tumors without methylation (P=0.019).	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('methylation', 'biological_process', 'GO:0032259', ('252', '263'))	('tumors', 'Disease', (237, 243))	('aggressive behavior', 'Phenotype', 'HP:0000718', (75, 94))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('decreased', 'NegReg', (191, 200))	('aggressive behavior', 'biological_process', 'GO:0002118', ('75', '94'))	('methylated', 'Var', (142, 152))	('RASEF', 'Gene', '158158', (153, 158))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('tumor', 'Disease', (128, 133))	('survival', 'CPA', (201, 209))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('RASEF', 'Gene', (153, 158))
123434	28529451	There was a significant association between high DSS1 expression levels and some clinicopathological features.	('expression levels', 'MPA', (54, 71))	('high', 'Var', (44, 48))	('DSS1', 'Gene', (49, 53))	('DSS1', 'Gene', '7979', (49, 53))
123438	28529451	Aberrant histone methylation due to gene mutation, translocation, or overexpression can often lead to initiation of a cancer.	('overexpression', 'PosReg', (69, 83))	('histone', 'Protein', (9, 16))	('cancer', 'Disease', (118, 124))	('Aberrant', 'Var', (0, 8))	('gene mutation', 'Var', (36, 49))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('translocation', 'Var', (51, 64))	('lead to', 'Reg', (94, 101))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('histone methylation', 'biological_process', 'GO:0016571', ('9', '28'))
123445	28529451	For example, Ser10 and Ser28 of H3 specifically at the promoter locus of FOS and JUN genes are often be phosphorylated by mitogen and stress-activated kinase 1 and 2 (MSK1/2) in tumors.	('Ser', 'cellular_component', 'GO:0005790', ('13', '16'))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('MSK1/2', 'Gene', (167, 173))	('FOS', 'Gene', (73, 76))	('MSK1/2', 'Gene', '9252;8986', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('JUN genes', 'Gene', (81, 90))	('Ser10', 'Chemical', '-', (13, 18))	('Ser10', 'Var', (13, 18))	('Ser28', 'Var', (23, 28))	('Ser', 'cellular_component', 'GO:0005790', ('23', '26'))	('FOS', 'Gene', '2353', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('Ser28', 'Chemical', '-', (23, 28))
123454	28529451	Exposure to epigenetic and non-epigenetic drugs that re-express tumor suppressor genes should enhance the efficiency of classical therapeutics of UM and sensitize the cancer cells to lower doses of traditional cytotoxic drugs.	('tumor', 'Disease', (64, 69))	('tumor suppressor', 'biological_process', 'GO:0051726', ('64', '80'))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('UM', 'Phenotype', 'HP:0007716', (146, 148))	('cancer', 'Disease', (167, 173))	('epigenetic', 'Var', (12, 22))	('enhance', 'PosReg', (94, 101))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('64', '80'))	('re-express', 'PosReg', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
123456	28529451	For example, miR-375 interference or destruction is a promising therapeutic avenue in the context of paclitaxel-resistant cervical cancer.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('miR-375', 'Gene', '494324', (13, 20))	('interference', 'Var', (21, 33))	('paclitaxel', 'Chemical', 'MESH:D017239', (101, 111))	('miR-375', 'Gene', (13, 20))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
123466	28529451	miR-34b/c expression, which is dramatically reduced in UM cells and clinical samples, can be up-regulated by doxorubicin and epigenetic drugs.	('epigenetic drugs', 'Var', (125, 141))	('up-regulated', 'PosReg', (93, 105))	('doxorubicin', 'Chemical', 'MESH:D004317', (109, 120))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('expression', 'MPA', (10, 20))	('miR-34b', 'Gene', (0, 7))	('miR-34b', 'Gene', '407041', (0, 7))	('clinical samples', 'Species', '191496', (68, 84))
123468	28529451	A prerequisite for re-expression of epigenetically-silenced tumor suppressor genes is demethylation of the regulatory regions.	('epigenetically-silenced', 'Var', (36, 59))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('demethylation', 'biological_process', 'GO:0070988', ('86', '99'))	('tumor', 'Disease', (60, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('60', '76'))
123471	28529451	In addition, miR-124a expression could be regulated via epigenetic mechanisms, such as those involving the DNA hypomethylating agent, 5-aza-2'-deoxycytidine, or the histone deacetylase inhibitor, trichostatin A. Epigenetics offers new promise for cancer therapeutics.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('miR-124a', 'Gene', '406907', (13, 21))	('Epigenetics', 'Var', (212, 223))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('trichostatin A', 'Chemical', 'MESH:C012589', (196, 210))	('miR-124a', 'Gene', (13, 21))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (134, 156))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))
123472	28529451	Many epigenetic changes, including miRNA expression level variations, hypomethylation of oncogenes, hypermethylation of tumor suppressor genes and histone modification patterns, are known to be associated with UM tumorigenesis and many other cancers.	('tumor suppressor', 'biological_process', 'GO:0051726', ('120', '136'))	('miR', 'Gene', '220972', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('cancers', 'Disease', 'MESH:D009369', (242, 249))	('UM', 'Phenotype', 'HP:0007716', (210, 212))	('oncogenes', 'Gene', (89, 98))	('miR', 'Gene', (35, 38))	('tumor', 'Disease', (120, 125))	('hypermethylation', 'Var', (100, 116))	('histone modification', 'biological_process', 'GO:0016570', ('147', '167'))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('associated', 'Reg', (194, 204))	('tumor', 'Disease', (213, 218))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('histone', 'MPA', (147, 154))	('epigenetic changes', 'Var', (5, 23))	('cancers', 'Disease', (242, 249))	('hypomethylation', 'Var', (70, 85))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('120', '136'))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
123473	28529451	Further studies are expected to elucidate how these variations are generated and, in turn, how they regulate the development and metastasis of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('development', 'CPA', (113, 124))	('variations', 'Var', (52, 62))	('regulate', 'Reg', (100, 108))	('metastasis of cancer', 'Disease', (129, 149))	('metastasis of cancer', 'Disease', 'MESH:D009362', (129, 149))
123484	28302097	We report the first case of a collision tumor composed of adenocarcinoma and melanoma with a TSC1 mutation that objectively and durably responded to mTOR inhibition.	('adenocarcinoma and melanoma', 'Disease', 'MESH:D008545', (58, 85))	('responded', 'Reg', (136, 145))	('mutation', 'Var', (98, 106))	('mTOR', 'Gene', '2475', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mTOR', 'Gene', (149, 153))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('TSC1', 'Gene', '7248', (93, 97))	('tumor', 'Disease', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('TSC1', 'Gene', (93, 97))
123487	28302097	Inactivating alterations of tumor suppressor genes TSC1 and TSC2 have been implicated in tuberous sclerosis and a wide variety of malignancies in which mTORC1 was found to be highly activated.	('mTORC1', 'cellular_component', 'GO:0031931', ('152', '158'))	('mTORC1', 'Gene', (152, 158))	('tumor', 'Disease', (28, 33))	('Inactivating alterations', 'Var', (0, 24))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (89, 107))	('malignancies', 'Disease', (130, 142))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('implicated', 'Reg', (75, 85))	('TSC1', 'Gene', '7248', (51, 55))	('tumor suppressor', 'biological_process', 'GO:0051726', ('28', '44'))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('TSC2', 'Gene', '7249', (60, 64))	('TSC1', 'Gene', (51, 55))	('TSC2', 'Gene', (60, 64))	('mTORC1', 'Gene', '382056', (152, 158))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('28', '44'))	('tuberous sclerosis', 'Disease', (89, 107))	('malignancies', 'Disease', 'MESH:D009369', (130, 142))
123488	28302097	Promising clinical trials have shown that tumors harboring TSC1 mutations respond to mTOR inhibitors and the clinical significance of such a mutation is highlighted in the present case.	('respond', 'Reg', (74, 81))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('TSC1', 'Gene', '7248', (59, 63))	('mutations', 'Var', (64, 73))	('mTOR', 'Gene', '2475', (85, 89))	('TSC1', 'Gene', (59, 63))	('mTOR', 'Gene', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
123491	28302097	The patient did not respond to several conventional chemotherapy agents but did respond to targeted mTOR inhibition after genomic sequencing revealed the presence of a TSC1 mutation.	('mTOR', 'Gene', '2475', (100, 104))	('presence', 'Reg', (154, 162))	('patient', 'Species', '9606', (4, 11))	('TSC1', 'Gene', '7248', (168, 172))	('TSC1', 'Gene', (168, 172))	('mTOR', 'Gene', (100, 104))	('mutation', 'Var', (173, 181))
123512	28302097	Several genomic alterations were identified as follows TSC1 loss (homozygous deletion) of exons 20-23, CDKN2A/B loss, BAP1 (E20fs*52), PBRM1 (R1095fs*39).	('R1095fs*39', 'Var', (142, 152))	('R1095fs*39', 'Mutation', 'p.R1095fsX39', (142, 152))	('CDKN2A/B', 'Gene', (103, 111))	('TSC1 loss', 'Disease', (55, 64))	('BAP1', 'Gene', '8314', (118, 122))	('loss', 'NegReg', (112, 116))	('PBRM1', 'Gene', (135, 140))	('E20fs*52', 'Var', (124, 132))	('TSC1 loss', 'Disease', 'MESH:C565346', (55, 64))	('BAP1', 'Gene', (118, 122))	('CDKN2A/B', 'Gene', '1029;1030', (103, 111))	('PBRM1', 'Gene', '55193', (135, 140))
123533	28302097	Mutations in TSC1 and TSC2 have been reported in a variety of neoplasms and benign tumors including pulmonary lymphangioleiomyomatosis (LAM), perivascular epitheloid cell tumors (PEComa), urothelial carcinomas, renal cell carcinoma and hepatocellular carcinomas.	('TSC1', 'Gene', '7248', (13, 17))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (211, 231))	('pulmonary lymphangioleiomyomatosis', 'Disease', (100, 134))	('epitheloid cell tumors', 'Disease', 'MESH:D005935', (155, 177))	('neoplasm', 'Phenotype', 'HP:0002664', (62, 70))	('TSC2', 'Gene', '7249', (22, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (236, 260))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('neoplasms', 'Phenotype', 'HP:0002664', (62, 71))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('neoplasms and benign tumors', 'Disease', 'MESH:D009369', (62, 89))	('pulmonary lymphangioleiomyomatosis', 'Phenotype', 'HP:0012798', (100, 134))	('PEComa', 'Disease', 'MESH:D054973', (179, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('Mutations', 'Var', (0, 9))	('PEComa', 'Disease', (179, 185))	('epitheloid cell tumors', 'Disease', (155, 177))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('TSC2', 'Gene', (22, 26))	('urothelial carcinomas', 'Disease', (188, 209))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (188, 209))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('renal cell carcinoma and hepatocellular carcinomas', 'Disease', 'MESH:C538614', (211, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('carcinomas', 'Phenotype', 'HP:0030731', (251, 261))	('pulmonary lymphangioleiomyomatosis', 'Disease', 'MESH:D018192', (100, 134))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (236, 261))	('TSC1', 'Gene', (13, 17))	('reported', 'Reg', (37, 45))
123534	28302097	Mutations in the tuberous sclerosis complex (TSC) has been reported in up to 14.5% of bladder cancer and 28.6% of hepatocellular carcinoma.	('TSC', 'Gene', '851634;7248;851634;7249', (45, 48))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (114, 138))	('bladder cancer', 'Disease', (86, 100))	('reported', 'Reg', (59, 67))	('bladder cancer', 'Disease', 'MESH:D001749', (86, 100))	('hepatocellular carcinoma', 'Disease', (114, 138))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (114, 138))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (17, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Mutations', 'Var', (0, 9))	('TSC', 'Gene', (45, 48))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('17', '43'))	('tuberous sclerosis', 'Disease', (17, 35))
123535	28302097	Alterations resulting in PTEN loss and PIK3CA amplification, which are also targets for mTOR/P13K inhibitors, have been implicated in 7% and 9% respectively, in carcinomas of unknown primary.	('P13K', 'Mutation', 'p.P13K', (93, 97))	('amplification', 'Reg', (46, 59))	('carcinomas', 'Disease', 'MESH:D002277', (161, 171))	('carcinomas', 'Disease', (161, 171))	('PIK3CA', 'Gene', '5290', (39, 45))	('Alterations', 'Var', (0, 11))	('implicated', 'Reg', (120, 130))	('mTOR', 'Gene', (88, 92))	('mTOR', 'Gene', '2475', (88, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('loss', 'NegReg', (30, 34))	('PTEN', 'Gene', (25, 29))	('PIK3CA', 'Gene', (39, 45))	('PTEN', 'Gene', '5728', (25, 29))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))
123536	28302097	Of greater clinical relevance, the presence of mutations involving TSC1 or TSC2 may predict a response to downstream inhibition of the mTOR pathway.	('TSC2', 'Gene', (75, 79))	('TSC1', 'Gene', '7248', (67, 71))	('TSC1', 'Gene', (67, 71))	('mTOR', 'Gene', '2475', (135, 139))	('mutations', 'Var', (47, 56))	('mTOR', 'Gene', (135, 139))	('predict', 'Reg', (84, 91))	('TSC2', 'Gene', '7249', (75, 79))	('response to downstream inhibition', 'MPA', (94, 127))
123538	28302097	In addition, the patient's CGP demonstrated mutation of BRCA1-associated protein 1 (BAP1) gene, which is frequently inactivated in metastatic uveal melanomas.	('mutation', 'Var', (44, 52))	('uveal melanomas', 'Disease', 'MESH:C536494', (142, 157))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('uveal melanoma', 'Phenotype', 'HP:0007716', (142, 156))	('BRCA1-associated protein 1', 'Gene', '8314', (56, 82))	('patient', 'Species', '9606', (17, 24))	('BAP1', 'Gene', '8314', (84, 88))	('BRCA1-associated protein 1', 'Gene', (56, 82))	('uveal melanomas', 'Disease', (142, 157))	('uveal melanomas', 'Phenotype', 'HP:0007716', (142, 157))	('BAP1', 'Gene', (84, 88))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('melanomas', 'Phenotype', 'HP:0002861', (148, 157))
123540	28302097	In uveal melanomas, somatic inactivating mutations of BAP1 have been highly associated with onset of metastatic behavior thus suggesting a potential novel target for therapy.	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('somatic inactivating mutations', 'Var', (20, 50))	('melanomas', 'Phenotype', 'HP:0002861', (9, 18))	('uveal melanomas', 'Disease', (3, 18))	('uveal melanomas', 'Phenotype', 'HP:0007716', (3, 18))	('associated', 'Reg', (76, 86))	('BAP1', 'Gene', '8314', (54, 58))	('uveal melanomas', 'Disease', 'MESH:C536494', (3, 18))	('BAP1', 'Gene', (54, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))
123543	28302097	Interestingly, germ line mutations in CDKN2A have been associated with familial melanoma syndromes and may have reflected genetic alterations from this patient's uveal melanoma.	('mutations', 'Var', (25, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (162, 176))	('uveal melanoma', 'Disease', (162, 176))	('uveal melanoma', 'Disease', 'MESH:C536494', (162, 176))	('familial melanoma syndromes', 'Disease', 'OMIM:155600', (71, 98))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('associated', 'Reg', (55, 65))	('CDKN2A', 'Gene', (38, 44))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('patient', 'Species', '9606', (152, 159))	('CDKN2A', 'Gene', '1029', (38, 44))	('familial melanoma syndromes', 'Disease', (71, 98))
123553	28302097	To our knowledge, this is the first case of a collision tumor composed of adenocarcinoma and melanoma with a mutation of the TSC1 gene locus.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('TSC1', 'Gene', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('adenocarcinoma and melanoma', 'Disease', 'MESH:D008545', (74, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('TSC1', 'Gene', '7248', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('mutation', 'Var', (109, 117))
123557	28302097	BAP1 BRCA1 associated protein 1 BARD1 BRCA1 Associated RING Domain 1 BRCA1 Breast cancer type 1 susceptibility protein CDKN2A/B Cyclin-dependent kinase inhibitor 2A/B CGP Comprehensive genomic profiling CK Cytokeratin CLIA Clinical Laboratory Improvement Act CT Computerized tomography GNAQ G protein subunit alpha q GNAS G protein subunit alpha S GTPase Guanosine-5'-triphosphate hydrolase HMB45 Human Melanoma Black common marker to confirm melanoma mTOR Mammalian target of rapamycin P13K Phosphatidylinositide 3-kinases PET/CT Positron emission tomography computerized tomography PIK3CA Phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha PRM1 Protein polybromo-1 PTEN Phosphatase and tensin homolog RECIST Response Evaluation Criteria in Solid Tumors S100 protein Common marker for neural tissues and melanoma SOX Sry-related HMG box TSC Tuberous sclerosis	('melanoma', 'Phenotype', 'HP:0002861', (826, 834))	('melanoma', 'Disease', (826, 834))	('PIK3CA', 'Gene', (584, 590))	('PTEN', 'Gene', (688, 692))	('Phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('693', '723'))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('Tuberous sclerosis', 'Disease', (863, 881))	('Human', 'Species', '9606', (397, 402))	('CDKN2A/B', 'Gene', (119, 127))	('TSC', 'Gene', '851634;7248;851634;7249', (859, 862))	('CLIA', 'Disease', 'None', (218, 222))	('BARD1', 'Gene', '580', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Tumors', 'Disease', (769, 775))	('BAP1', 'Gene', (0, 4))	('Phosphatidylinositol-4,', 'Chemical', '-', (591, 614))	('Cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('128', '161'))	('BARD1', 'Gene', (32, 37))	('PTEN', 'Gene', '5728', (688, 692))	('melanoma', 'Phenotype', 'HP:0002861', (443, 451))	('melanoma', 'Disease', (443, 451))	('Melanoma', 'Disease', 'MESH:D008545', (403, 411))	('protein', 'cellular_component', 'GO:0003675', ('781', '788'))	('CLIA', 'Disease', (218, 222))	('Breast cancer', 'Disease', 'MESH:D001943', (75, 88))	('Phosphatase', 'molecular_function', 'GO:0016791', ('693', '704'))	('protein', 'cellular_component', 'GO:0003675', ('293', '300'))	('Tumors', 'Disease', 'MESH:D009369', (769, 775))	('melanoma', 'Disease', 'MESH:D008545', (826, 834))	('P13K', 'Mutation', 'p.P13K', (487, 491))	('PIK3CA', 'Gene', '5290', (584, 590))	('TSC', 'Gene', (859, 862))	('CDKN2A/B', 'Gene', '1029;1030', (119, 127))	('BRCA1 associated protein', 'Gene', '8315', (5, 29))	('GNAQ', 'Chemical', '-', (286, 290))	('mTOR', 'Gene', (452, 456))	('Breast cancer', 'Disease', (75, 88))	('Tuberous sclerosis', 'Disease', 'MESH:D014402', (863, 881))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('protein', 'cellular_component', 'GO:0003675', ('324', '331'))	('Melanoma', 'Disease', (403, 411))	('BRCA1', 'Gene', '672', (38, 43))	('Breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('2A/B', 'SUBSTITUTION', 'None', (123, 127))	('2A/B', 'Var', (123, 127))	('BRCA1 associated protein', 'Gene', (5, 29))	('S100', 'Gene', (776, 780))	('BRCA1', 'Gene', '672', (69, 74))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('145', '161'))	('BRCA1', 'Gene', (38, 43))	('BRCA1', 'Gene', (69, 74))	('S100', 'Gene', '6271', (776, 780))	('Mammalian', 'Species', '9606', (457, 466))	('BRCA1', 'Gene', '672', (5, 10))	('2A/B', 'SUBSTITUTION', 'None', (162, 166))	('mTOR', 'Gene', '2475', (452, 456))	('2A/B', 'Var', (162, 166))	('Melanoma', 'Phenotype', 'HP:0002861', (403, 411))	('BAP1', 'Gene', '8314', (0, 4))	('BRCA1', 'Gene', (5, 10))	('melanoma', 'Disease', 'MESH:D008545', (443, 451))	('Tumors', 'Phenotype', 'HP:0002664', (769, 775))
123659	26682063	However, inhibiting IL-1 with IL-1ra (an antagonist of IL-1) slows tumor growth only in vivo but not in vitro.	('IL-1', 'molecular_function', 'GO:0005149', ('55', '59'))	('IL-1', 'Gene', (55, 59))	('IL-1', 'Gene', '3552', (20, 24))	('IL-1', 'molecular_function', 'GO:0005149', ('20', '24'))	('IL-1', 'Gene', '3552', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('IL-1ra', 'Gene', '3554', (30, 36))	('inhibiting', 'Var', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('IL-1ra', 'molecular_function', 'GO:0005152', ('30', '36'))	('tumor', 'Disease', (67, 72))	('IL-1ra', 'Gene', (30, 36))	('slows', 'NegReg', (61, 66))	('IL-1', 'Gene', '3552', (30, 34))	('IL-1', 'Gene', (30, 34))	('IL-1', 'Gene', (20, 24))
123820	33405963	UM cancers are driven by oncogenic mutations that activate Galphaq/11, and this activates TRIO, a guanine nucleotide exchange factor for RhoA and Rac1.	('Galphaq/', 'Chemical', '-', (59, 67))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (98, 116))	('RhoA', 'Gene', '387', (137, 141))	('TRIO', 'Gene', (90, 94))	('activates', 'Reg', (80, 89))	('Galphaq/11', 'Protein', (59, 69))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('RhoA', 'Gene', (137, 141))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('Rac1', 'Gene', '5879', (146, 150))	('activate', 'PosReg', (50, 58))	('TRIO', 'Gene', '7204', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('Rac1', 'Gene', (146, 150))	('mutations', 'Var', (35, 44))
123822	33405963	Inhibition of the RhoA pathway blocked amoeboid motility but led to enhanced TEM; in contrast, inhibition of the Rac1 pathway decreased mesenchymal motility and reduced TEM.	('decreased mesenchymal motility', 'Disease', (126, 156))	('enhanced', 'PosReg', (68, 76))	('Rac1', 'Gene', (113, 117))	('reduced', 'NegReg', (161, 168))	('Rac1', 'Gene', '5879', (113, 117))	('RhoA', 'Gene', '387', (18, 22))	('inhibition', 'Var', (95, 105))	('TEM', 'cellular_component', 'GO:0097197', ('169', '172'))	('decreased mesenchymal motility', 'Disease', 'MESH:D015835', (126, 156))	('TEM', 'CPA', (169, 172))	('TEM', 'cellular_component', 'GO:0097197', ('77', '80'))	('blocked', 'NegReg', (31, 38))	('TEM', 'CPA', (77, 80))	('amoeboid motility', 'CPA', (39, 56))	('RhoA', 'Gene', (18, 22))
123823	33405963	Inhibition of Arp2/3 complex allowed cells to transmigrate without intercalation, a direct mechanism similar to the one often displayed by immune cells.	('Arp2/3', 'Gene', '10097;10096', (14, 20))	('Inhibition', 'Var', (0, 10))	('Arp2/3', 'Gene', (14, 20))
123838	33405963	Spread of UM tumors to distant organs is known to be promoted by loss of BAP1, a chromatin remodeling factor, and we found that depletion of BAP1 increases the overall rate of TEM in our system.	('TEM', 'MPA', (176, 179))	('BAP1', 'Gene', '8314', (73, 77))	('promoted', 'PosReg', (53, 61))	('loss', 'Var', (65, 69))	('tumors', 'Disease', (13, 19))	('increases', 'PosReg', (146, 155))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('BAP1', 'Gene', '8314', (141, 145))	('Spread', 'CPA', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('BAP1', 'Gene', (73, 77))	('BAP1', 'Gene', (141, 145))	('TEM', 'cellular_component', 'GO:0097197', ('176', '179'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('81', '101'))	('chromatin', 'cellular_component', 'GO:0000785', ('81', '90'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('depletion', 'Var', (128, 137))
123854	33405963	Constitutively activating mutations in Gq/11 are the driving oncogenes for over 90% of UM tumors.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('mutations', 'Var', (26, 35))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('activating', 'PosReg', (15, 25))	('tumors', 'Disease', (90, 96))	('Gq/11', 'Gene', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))
123856	33405963	We used FR900359, a potent inhibitor of Gq/11 in UM cells, to block TRIO activation by Gq.	('FR900359', 'Chemical', 'MESH:C000607068', (8, 16))	('TRIO', 'Gene', (68, 72))	('TRIO', 'Gene', '7204', (68, 72))	('FR900359', 'Var', (8, 16))
123857	33405963	UM cells treated with FR900359 for 24 h showed significant decreases in progression for all steps of transmigration (Figure 1A and Supplemental Video S1).	('FR900359', 'Chemical', 'MESH:C000607068', (22, 30))	('FR900359', 'Var', (22, 30))	('progression', 'MPA', (72, 83))	('decreases', 'NegReg', (59, 68))
123859	33405963	Inhibition of ROCK, the immediate downstream effector of activated RhoA, by Y-27632 blocked the amoeboid blebbing activity of UM cells in suspension and on the surface of the monolayers (Figure 2A and Supplemental Video S2).	('amoeboid blebbing activity of UM cells', 'CPA', (96, 134))	('blocked', 'NegReg', (84, 91))	('RhoA', 'Gene', (67, 71))	('blebbing', 'biological_process', 'GO:0032060', ('105', '113'))	('Y-27632', 'Var', (76, 83))	('Y-27632', 'Chemical', 'MESH:C108830', (76, 83))	('RhoA', 'Gene', '387', (67, 71))
123860	33405963	Surprisingly, UM cells treated with Y-27632 showed significant increases in both the percentage of cells completing each step of TEM (Figure 2B) and the rates of cells progressing through each step (Figure 2, C and D).	('increases', 'PosReg', (63, 72))	('TEM', 'cellular_component', 'GO:0097197', ('129', '132'))	('cells progressing', 'CPA', (162, 179))	('Y-27632', 'Var', (36, 43))	('Y-27632', 'Chemical', 'MESH:C108830', (36, 43))
123862	33405963	For both UM cell lines dominant-negative RhoA expression caused increases in TEM similar to the effects of Y-27632 treatment (Figure 2, B-D).	('RhoA', 'Gene', '387', (41, 45))	('TEM', 'MPA', (77, 80))	('increases', 'PosReg', (64, 73))	('TEM', 'cellular_component', 'GO:0097197', ('77', '80'))	('Y-27632', 'Chemical', 'MESH:C108830', (107, 114))	('RhoA', 'Gene', (41, 45))	('dominant-negative', 'Var', (23, 40))
123870	33405963	Mel202 UM cells expressing dominant-negative Rac1 showed significant reduction of all steps of TEM, similar to the effects of NSC-23766 treatment.	('TEM', 'cellular_component', 'GO:0097197', ('95', '98'))	('dominant-negative', 'Var', (27, 44))	('Rac1', 'Gene', '5879', (45, 49))	('Rac1', 'Gene', (45, 49))	('reduction', 'NegReg', (69, 78))	('NSC-23766', 'Chemical', 'MESH:C487513', (126, 135))
123871	33405963	Taken together, these decreases in TEM parameters were similar to the stronger effects observed for cells treated with FR900359 above (Figure 1, C-E).	('TEM', 'cellular_component', 'GO:0097197', ('35', '38'))	('FR900359', 'Var', (119, 127))	('FR900359', 'Chemical', 'MESH:C000607068', (119, 127))	('TEM parameters', 'MPA', (35, 49))	('decreases', 'NegReg', (22, 31))
123874	33405963	Interestingly, UM cells treated with either NSC-23766 or IPA-3 also showed larger blebs and increased extracellular debris (Figure 3A and Supplemental Video S3) compared with untreated cells (Figure 1A and Supplemental Video S1), suggesting dysregulation of bleb size and retraction resulting from inhibition of the Rac pathway.	('NSC-23766', 'Var', (44, 53))	('IPA-3', 'Chemical', '-', (57, 62))	('retraction', 'CPA', (272, 282))	('extracellular', 'cellular_component', 'GO:0005576', ('102', '115'))	('bleb', 'cellular_component', 'GO:0032059', ('258', '262'))	('extracellular debris', 'MPA', (102, 122))	('Rac', 'Gene', (316, 319))	('IPA-3', 'Gene', (57, 62))	('larger', 'PosReg', (75, 81))	('increased', 'PosReg', (92, 101))	('NSC-23766', 'Chemical', 'MESH:C487513', (44, 53))	('blebs', 'CPA', (82, 87))	('Rac', 'Gene', '207', (316, 319))
123877	33405963	UM cells treated with CK-666 showed extensive blebbing, similar to the effects of NSC-23766 and IPA-3 (Figure 4A and Video S4).	('CK-666', 'Chemical', 'MESH:C543733', (22, 28))	('blebbing', 'biological_process', 'GO:0032060', ('46', '54'))	('NSC-23766', 'Chemical', 'MESH:C487513', (82, 91))	('CK-666', 'Var', (22, 28))	('IPA-3', 'Chemical', '-', (96, 101))	('blebbing', 'CPA', (46, 54))
123887	33405963	These results suggest that BAP1 expression favors activation of the RhoA pathway over the Rac1 pathway, such that loss of BAP1 shifts the balance toward Rac1-driven motility and increased TEM.	('Rac1', 'Gene', '5879', (153, 157))	('BAP1', 'Gene', (122, 126))	('BAP1', 'Gene', (27, 31))	('BAP1', 'Gene', '8314', (27, 31))	('loss', 'Var', (114, 118))	('RhoA', 'Gene', (68, 72))	('BAP1', 'Gene', '8314', (122, 126))	('RhoA', 'Gene', '387', (68, 72))	('Rac1', 'Gene', (90, 94))	('Rac1', 'Gene', '5879', (90, 94))	('TEM', 'cellular_component', 'GO:0097197', ('188', '191'))	('Rac1', 'Gene', (153, 157))
123890	33405963	In our previous work, FR900359 caused UM cells to stop dividing and to re-differentiate towards their melanocytic state.	('FR900359', 'Chemical', 'MESH:C000607068', (22, 30))	('FR900359', 'Var', (22, 30))	('re-differentiate', 'CPA', (71, 87))	('stop dividing', 'CPA', (50, 63))
123891	33405963	Together, the results suggest that FR900359 has promise as a novel therapeutic agent for UM tumors.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('FR900359', 'Var', (35, 43))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('FR900359', 'Chemical', 'MESH:C000607068', (35, 43))	('tumors', 'Disease', (92, 98))
123894	33405963	Inhibiting the Rho pathway blocked amoeboid motility but increased TEM (Supplemental Figure S2), while inhibiting the Rac pathway blocked mesenchymal motility and decreased TEM (Supplemental Figure S2).	('TEM', 'MPA', (173, 176))	('Inhibiting', 'Var', (0, 10))	('Rho pathway', 'Pathway', (15, 26))	('Rac', 'Gene', '207', (118, 121))	('blocked', 'NegReg', (130, 137))	('TEM', 'cellular_component', 'GO:0097197', ('67', '70'))	('Rac', 'Gene', (118, 121))	('TEM', 'cellular_component', 'GO:0097197', ('173', '176'))	('inhibiting', 'NegReg', (103, 113))	('amoeboid motility', 'CPA', (35, 52))	('TEM', 'CPA', (67, 70))	('increased', 'PosReg', (57, 66))	('decreased', 'NegReg', (163, 172))	('mesenchymal motility', 'CPA', (138, 158))
123906	33405963	This discovery is important because in human UM patients, the loss of BAP1 is the key genetic feature associated with a high risk of metastasis in the class 2 lethal genotype.	('loss', 'Var', (62, 66))	('associated', 'Reg', (102, 112))	('BAP1', 'Gene', '8314', (70, 74))	('human', 'Species', '9606', (39, 44))	('BAP1', 'Gene', (70, 74))	('metastasis', 'CPA', (133, 143))	('patients', 'Species', '9606', (48, 56))
123907	33405963	The clinical relationship of deletion of BAP1 to metastatic spread is consistent with the biological connection of BAP1 function with the mechanism of TEM discovered here.	('deletion', 'Var', (29, 37))	('BAP1', 'Gene', '8314', (115, 119))	('BAP1', 'Gene', (41, 45))	('BAP1', 'Gene', (115, 119))	('TEM', 'cellular_component', 'GO:0097197', ('151', '154'))	('metastatic spread', 'CPA', (49, 66))	('BAP1', 'Gene', '8314', (41, 45))
123916	33405963	Inhibitors were tested for cell toxicity using a tetrazolium-based Cell Counting Kit-8 (Bimake, Houston, TX), with treatment at working concentrations for 12 h. In these assays, the inhibitors did not significantly reduce cell viability, with the exception of FR900359, which has long-term effects that have been described elsewhere.	('reduce', 'NegReg', (215, 221))	('inhibitors', 'Var', (182, 192))	('FR900359', 'Chemical', 'MESH:C000607068', (260, 268))	('toxicity', 'Disease', 'MESH:D064420', (32, 40))	('toxicity', 'Disease', (32, 40))	('cell viability', 'CPA', (222, 236))
123921	33405963	Briefly, single guide RNAs were used to target Cas9 to exon 3 of BAP1 in 92.1 cells to generate frameshifted truncation mutants.	('BAP1', 'Gene', '8314', (65, 69))	('frameshifted truncation', 'Var', (96, 119))	('BAP1', 'Gene', (65, 69))	('Cas', 'cellular_component', 'GO:0005650', ('47', '50'))
123933	33405963	In the case of treatment with CK-666, UM cells that transmigrated directly beneath the monolayer, without intercalating, were only scored for "initiation" and "migration."	('CK-666', 'Var', (30, 36))	('migration', 'CPA', (160, 169))	('CK-666', 'Chemical', 'MESH:C543733', (30, 36))
123934	33405963	For dominant-negative expression experiments, epifluorescence images were collected to detect cells expressing YFP (RhoA-DN) or GFP (Rac1-DN) and only positive cells were analyzed by DIC imaging.	('Rac1', 'Gene', '5879', (133, 137))	('Rac1', 'Gene', (133, 137))	('GFP', 'Var', (128, 131))	('RhoA', 'Gene', (116, 120))	('YFP', 'Gene', (111, 114))	('RhoA', 'Gene', '387', (116, 120))
123950	32098099	Growing evidence has revealed that abnormal splicing events are closely related to carcinogenic processes including angiogenesis, apoptosis, proliferation, metastasis, and therapeutic drug resistance.	('carcinogenic processes', 'Disease', (83, 105))	('splicing', 'biological_process', 'GO:0045292', ('44', '52'))	('drug resistance', 'biological_process', 'GO:0009315', ('184', '199'))	('apoptosis', 'CPA', (130, 139))	('metastasis', 'CPA', (156, 166))	('angiogenesis', 'CPA', (116, 128))	('carcinogenic processes', 'Disease', 'MESH:D009385', (83, 105))	('proliferation', 'CPA', (141, 154))	('angiogenesis', 'biological_process', 'GO:0001525', ('116', '128'))	('related', 'Reg', (72, 79))	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('drug resistance', 'Phenotype', 'HP:0020174', (184, 199))	('therapeutic drug resistance', 'CPA', (172, 199))	('abnormal splicing events', 'Var', (35, 59))	('drug resistance', 'biological_process', 'GO:0042493', ('184', '199'))
123953	32098099	For instance, splicing events happen in CD44, Ron and MENA will lead to cellular proliferation, VEGF causes angiogenesis, Fas, Bclx, and caspase-2 result in apoptosis and p53 brings about multi-drug resistance.	('cellular proliferation', 'CPA', (72, 94))	('apoptosis', 'CPA', (157, 166))	('MENA', 'Gene', (54, 58))	('caspase-2', 'Gene', '835', (137, 146))	('CD44', 'Gene', '960', (40, 44))	('CD44', 'Gene', (40, 44))	('Bclx', 'Gene', (127, 131))	('VEGF', 'Gene', '7422', (96, 100))	('Fas', 'Disease', (122, 125))	('MENA', 'Gene', '55740', (54, 58))	('drug resistance', 'Phenotype', 'HP:0020174', (194, 209))	('apoptosis', 'biological_process', 'GO:0097194', ('157', '166'))	('caspase-2', 'Gene', (137, 146))	('apoptosis', 'biological_process', 'GO:0006915', ('157', '166'))	('Ron', 'Gene', '4486', (46, 49))	('result in', 'Reg', (147, 156))	('Ron', 'Gene', (46, 49))	('VEGF', 'Gene', (96, 100))	('multi-drug resistance', 'CPA', (188, 209))	('splicing', 'biological_process', 'GO:0045292', ('14', '22'))	('angiogenesis', 'biological_process', 'GO:0001525', ('108', '120'))	('angiogenesis', 'CPA', (108, 120))	('p53', 'Gene', '7157', (171, 174))	('causes', 'Reg', (101, 107))	('splicing events', 'Var', (14, 29))	('lead to', 'Reg', (64, 71))	('Bclx', 'Gene', '598', (127, 131))	('drug resistance', 'biological_process', 'GO:0009315', ('194', '209'))	('p53', 'Gene', (171, 174))	('drug resistance', 'biological_process', 'GO:0042493', ('194', '209'))
123955	32098099	Abnormal expression of splicing factors may lead to whole changes of AS events in tumors and in particular situation, and the mutations of splicing factor can cause specific splicing patterns to promote cancer progression.	('tumors', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cause', 'Reg', (159, 164))	('AS events', 'MPA', (69, 78))	('lead to', 'Reg', (44, 51))	('splicing factor', 'Gene', '10569', (139, 154))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('splicing', 'biological_process', 'GO:0045292', ('139', '147'))	('Abnormal', 'Var', (0, 8))	('mutations', 'Var', (126, 135))	('splicing factor', 'Gene', (23, 38))	('specific splicing patterns', 'MPA', (165, 191))	('changes', 'Reg', (58, 65))	('cancer', 'Disease', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('splicing', 'biological_process', 'GO:0045292', ('174', '182'))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('splicing factor', 'Gene', '10569', (23, 38))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('promote', 'PosReg', (195, 202))	('splicing factor', 'Gene', (139, 154))	('splicing', 'biological_process', 'GO:0045292', ('23', '31'))
123976	32098099	In total, 387 AAs in 349 genes, 354 ADs in 318 genes, 1271 APs in 679 genes, 1274 ATs in 676 genes, 1678 ESs in 1221 genes, 18 MEs in 18 genes, and 317 RIs in 268 genes were identified as prognosis-associated AS events (p < 0.05) (Figure 2A).	('MEs', 'Chemical', 'MESH:C004550', (127, 130))	('ES', 'Chemical', '-', (105, 107))	('1274', 'Var', (77, 81))	('ATs', 'Chemical', 'MESH:D001246', (82, 85))	('APs', 'Var', (59, 62))	('APs', 'Chemical', 'MESH:D000250', (59, 62))
123988	32098099	The mutant of GNAQ and SF3B1 also indicated a significantly longer OS time than the wild type (Figure 7D).	('OS time', 'CPA', (67, 74))	('mutant', 'Var', (4, 10))	('GNAQ', 'Gene', '2776', (14, 18))	('longer', 'PosReg', (60, 66))	('SF3B1', 'Gene', '23451', (23, 28))	('GNAQ', 'Gene', (14, 18))	('SF3B1', 'Gene', (23, 28))
123993	32098099	Abnormal alternative splicing is widely regarded as a new indicator of carcinogenic processes.	('splicing', 'biological_process', 'GO:0045292', ('21', '29'))	('Abnormal alternative splicing', 'Var', (0, 29))	('carcinogenic processes', 'Disease', (71, 93))	('carcinogenic processes', 'Disease', 'MESH:D009385', (71, 93))
123994	32098099	Although some specific mRNAs related to alternative splicing of UM have been identified: For instance, SF3B1 mutations can cause differential alternative splicing of protein coding genes and the aberrant of CD44 alternative splicing are commonly existed in UM.	('UM', 'Phenotype', 'HP:0007716', (257, 259))	('CD44', 'Gene', (207, 211))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('UM', 'Disease', 'MESH:C536494', (257, 259))	('splicing', 'biological_process', 'GO:0045292', ('224', '232'))	('cause', 'Reg', (123, 128))	('SF3B1', 'Gene', (103, 108))	('splicing', 'biological_process', 'GO:0045292', ('154', '162'))	('splicing', 'biological_process', 'GO:0045292', ('52', '60'))	('mutations', 'Var', (109, 118))	('UM', 'Phenotype', 'HP:0007716', (64, 66))	('CD44', 'Gene', '960', (207, 211))	('SF3B1', 'Gene', '23451', (103, 108))	('UM', 'Disease', 'MESH:C536494', (64, 66))	('alternative splicing of protein coding genes', 'MPA', (142, 186))
123997	32098099	A series of survival-associated alternative splicing events was identified, and their interaction network was also established, which could provide a novel intervention target for UM treatment.	('alternative splicing', 'Var', (32, 52))	('interaction', 'Interaction', (86, 97))	('UM', 'Disease', 'MESH:C536494', (180, 182))	('UM', 'Phenotype', 'HP:0007716', (180, 182))	('splicing', 'biological_process', 'GO:0045292', ('44', '52'))
124001	32098099	Remarkably, it is widely accepted that defects in the ribosome are associated with cancer.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('associated', 'Reg', (67, 77))	('defects', 'Var', (39, 46))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('ribosome', 'Protein', (54, 62))	('ribosome', 'cellular_component', 'GO:0005840', ('54', '62'))	('cancer', 'Disease', (83, 89))
124002	32098099	Recent studies have revealed that alternative splicing in ribosomal protein genes were identified in leukemias and solid tumor types.	('leukemias', 'Phenotype', 'HP:0001909', (101, 110))	('leukemias', 'Disease', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('58', '75'))	('tumor', 'Disease', (121, 126))	('identified', 'Reg', (87, 97))	('ribosomal protein genes', 'Gene', (58, 81))	('leukemias', 'Disease', 'MESH:D007938', (101, 110))	('splicing', 'biological_process', 'GO:0045292', ('46', '54'))	('alternative splicing', 'Var', (34, 54))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
124016	32098099	For example, recent researches revealed that high expression of RBM10 protein in lung cancer was associated with a shorter overall survival time and a poor prognosis.	('lung cancer', 'Disease', (81, 92))	('protein', 'Protein', (70, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('shorter', 'NegReg', (115, 122))	('high', 'Var', (45, 49))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('RBM10', 'Gene', '8241', (64, 69))	('overall survival time', 'CPA', (123, 144))	('RBM10', 'Gene', (64, 69))
124021	32098099	What is more, in this correlation network, we found most of alternative splicing events were associated with poor overall survival and positively co-related to splicing factors.	('poor', 'NegReg', (109, 113))	('co-related', 'Reg', (146, 156))	('alternative splicing events', 'Var', (60, 87))	('overall', 'MPA', (114, 121))	('splicing factor', 'Gene', (160, 175))	('splicing', 'biological_process', 'GO:0045292', ('72', '80'))	('splicing', 'biological_process', 'GO:0045292', ('160', '168'))	('splicing factor', 'Gene', '10569', (160, 175))
124022	32098099	It is reasonable to believe that there is an obvious trend for the expression of splicing factors are positively associated with the poor prognostic alternative splicing events in UM.	('splicing factor', 'Gene', '10569', (81, 96))	('splicing', 'biological_process', 'GO:0045292', ('161', '169'))	('alternative', 'Var', (149, 160))	('UM', 'Disease', 'MESH:C536494', (180, 182))	('UM', 'Phenotype', 'HP:0007716', (180, 182))	('splicing factor', 'Gene', (81, 96))	('splicing', 'biological_process', 'GO:0045292', ('81', '89'))	('associated', 'Reg', (113, 123))
124036	31880399	In the past decade, the collective work from several groups has led to the identification of important recurrent mutations and overactive signaling pathways in this cancer.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('mutations', 'Var', (113, 122))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('signaling', 'biological_process', 'GO:0023052', ('138', '147'))	('overactive', 'PosReg', (127, 137))
124037	31880399	This includes constitutively active variants of GNAQ and GNA11, which are found in over 90% of cases (Van Raamsdonk et al., 2009, 2010).	('GNA11', 'Gene', (57, 62))	('GNAQ', 'Gene', (48, 52))	('GNA11', 'Gene', '14672', (57, 62))	('variants', 'Var', (36, 44))
124038	31880399	A smaller subset of tumors harbor activating mutations in the G protein-coupled receptor cysteinyl leukotriene receptor 2 (CYSLTR2) or phospholipase C beta 4 (PLCB4) (Johansson et al., 2016; Moore et al., 2016).	('PLCB4', 'Gene', (159, 164))	('activating', 'Reg', (34, 44))	('mutations', 'Var', (45, 54))	('tumors', 'Disease', (20, 26))	('cysteinyl leukotriene receptor 2', 'Gene', '70086', (89, 121))	('CYSLTR2', 'Gene', '70086', (123, 130))	('cysteinyl leukotriene receptor 2', 'Gene', (89, 121))	('CYSLTR2', 'Gene', (123, 130))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('PLCB4', 'Gene', '18798', (159, 164))	('phospholipase C beta 4', 'Gene', '18798', (135, 157))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('phospholipase C beta 4', 'Gene', (135, 157))
124039	31880399	There is a second node of nearly mutually exclusive mutations that classifies uveal melanomas and affects prognosis.	('mutations', 'Var', (52, 61))	('melanomas', 'Disease', (84, 93))	('uveal melanomas', 'Phenotype', 'HP:0007716', (78, 93))	('affects', 'Reg', (98, 105))	('melanomas', 'Disease', 'MESH:D008545', (84, 93))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('uveal melanoma', 'Phenotype', 'HP:0007716', (78, 92))	('uveal melanoma', 'Disease', 'MESH:C536494', (78, 92))	('uveal melanoma', 'Disease', (78, 92))
124042	31880399	Most importantly, tumors with loss-of-function BAP1 mutations carry the worst prognosis, as approximately 84% of metastatic uveal melanomas are of this subtype (Harbour et al., 2010; Shain et al., 2019).	('mutations', 'Var', (52, 61))	('loss-of-function', 'NegReg', (30, 46))	('melanomas', 'Disease', (130, 139))	('uveal melanoma', 'Disease', (124, 138))	('uveal melanoma', 'Disease', 'MESH:C536494', (124, 138))	('uveal melanoma', 'Phenotype', 'HP:0007716', (124, 138))	('melanomas', 'Phenotype', 'HP:0002861', (130, 139))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('melanomas', 'Disease', 'MESH:D008545', (130, 139))	('BAP1', 'Gene', '104416', (47, 51))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('uveal melanomas', 'Phenotype', 'HP:0007716', (124, 139))	('BAP1', 'Gene', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
124044	31880399	Monosomy 3 co-occurs with BAP1 mutation, thereby eliminating both functional alleles (Field et al., 2018; Robertson et al., 2017).	('BAP1', 'Gene', (26, 30))	('eliminating', 'NegReg', (49, 60))	('mutation', 'Var', (31, 39))	('BAP1', 'Gene', '104416', (26, 30))	('Monosomy 3', 'Var', (0, 10))	('functional alleles', 'MPA', (66, 84))
124056	31880399	However, tumorigenesis in these models required mutation of p53, and metastasis was difficult to assess because of the induction of multiple primary tumors (Mouti et al., 2016; Perez et al., 2018).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('primary tumors', 'Disease', (141, 155))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('p53', 'Gene', (60, 63))	('tumor', 'Disease', (9, 14))	('mutation', 'Var', (48, 56))	('tumor', 'Disease', (149, 154))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('primary tumors', 'Disease', 'MESH:D001932', (141, 155))	('p53', 'Gene', '22060', (60, 63))
124088	31880399	Interestingly, there are a few syngeneic models that do carry canonical uveal melanoma mutations.	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('uveal melanoma', 'Disease', (72, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('mutations', 'Var', (87, 96))
124089	31880399	Immortalized mouse melanocytes transduced with driver mutations found in patients undergo oncogenic transformation and are capable of producing tumors and even metastases (Moore et al., 2016; Van Raamsdonk et al., 2010).	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('mouse', 'Species', '10090', (13, 18))	('undergo', 'Reg', (82, 89))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('metastases', 'Disease', (160, 170))	('mutations', 'Var', (54, 63))	('oncogenic transformation', 'CPA', (90, 114))	('metastases', 'Disease', 'MESH:D009362', (160, 170))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('patients', 'Species', '9606', (73, 81))	('producing', 'PosReg', (134, 143))
124091	31880399	Further details on other mutations in this cell line would allow for a more complete assessment of its suitability as a model for uveal melanoma.	('mutations', 'Var', (25, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (130, 144))	('uveal melanoma', 'Disease', 'MESH:C536494', (130, 144))	('uveal melanoma', 'Disease', (130, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))
124102	31880399	Frequently used cell lines with validated uveal melanoma mutations are included in Table 2a,b.	('mutations', 'Var', (57, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('uveal melanoma', 'Disease', (42, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
124107	31880399	Some lines historically thought to be uveal melanoma have been found to harbor BRAFV600E mutations and are now recognized as being of cutaneous origin (Griewank et al., 2012; Yu et al., 2015).	('uveal melanoma', 'Disease', (38, 52))	('BRAFV600E', 'Mutation', 'rs113488022', (79, 88))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('BRAFV600E', 'Gene', (79, 88))	('mutations', 'Var', (89, 98))	('uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('uveal melanoma', 'Disease', 'MESH:C536494', (38, 52))
124144	31880399	In the first, a Tet-on system was used to induce GNAQQ209L expression in mice deficient for p16Ink4a and p19Ink4b (Feng et al., 2014).	('GNAQQ209L', 'Gene', (49, 58))	('p16Ink4a', 'Gene', '12578', (92, 100))	('induce', 'PosReg', (42, 48))	('mice', 'Species', '10090', (73, 77))	('p19Ink4b', 'Var', (105, 113))	('Tet', 'Chemical', 'MESH:C010349', (16, 19))	('p16Ink4a', 'Gene', (92, 100))	('p19', 'cellular_component', 'GO:0070743', ('105', '108'))
124148	31880399	In a different model, the expression of GNAQQ209L in a lox-stop-lox conditional knock-in allele inserted at the Rosa26 locus produced uveal melanoma in 3 months with 100% penetrance (Huang, Urtatiz, & Van Raamsdonk, 2015).	('lox', 'Gene', (64, 67))	('Rosa26', 'Gene', '14910', (112, 118))	('GNAQQ209L', 'Var', (40, 49))	('lox', 'Gene', '16948', (64, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (134, 148))	('Rosa26', 'Gene', (112, 118))	('lox', 'Gene', (55, 58))	('produced', 'Reg', (125, 133))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('lox', 'Gene', '16948', (55, 58))	('uveal melanoma', 'Disease', (134, 148))	('uveal melanoma', 'Phenotype', 'HP:0007716', (134, 148))
124153	31880399	When Bap1 deletion was combined with GNA11Q209L expression, uveal melanomas were unexpectedly smaller.	('melanomas', 'Disease', 'MESH:D008545', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('uveal melanomas', 'Phenotype', 'HP:0007716', (60, 75))	('GNA11', 'Gene', (37, 42))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('GNA11', 'Gene', '14672', (37, 42))	('melanomas', 'Disease', (66, 75))	('smaller', 'NegReg', (94, 101))	('uveal melanoma', 'Disease', 'MESH:C536494', (60, 74))	('Bap1', 'Gene', '104416', (5, 9))	('deletion', 'Var', (10, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('uveal melanoma', 'Disease', (60, 74))	('Bap1', 'Gene', (5, 9))
124160	31880399	Interestingly, induction of Tyr-creER in 8-week-old mice in the GNAQQ209L model did not produce overt uveal melanoma.	('Tyr-creER', 'Var', (28, 37))	('Tyr', 'Chemical', 'MESH:D014443', (28, 31))	('mice', 'Species', '10090', (52, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('uveal melanoma', 'Disease', (102, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (102, 116))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))
124171	31880399	In this model, the suprachoroidal injection of an AAV5-CMV-Cre vector produced ocular melanocytic tumors in adult mice carrying conditional null alleles of the Hippo kinases Lats1 and Lats2, which normally function to suppress YAP/TAZ signaling.	('AAV5-CMV-Cre', 'Var', (50, 62))	('TAZ', 'Gene', (231, 234))	('melanocytic tumors in adult', 'Phenotype', 'HP:0002861', (86, 113))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('Lats1', 'Gene', '16798', (174, 179))	('YAP', 'Gene', (227, 230))	('Lats2', 'Gene', '50523', (184, 189))	('ocular melanocytic tumors', 'Disease', (79, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Lats2', 'Gene', (184, 189))	('YAP', 'Gene', '22601', (227, 230))	('TAZ', 'Gene', '66826', (231, 234))	('mice', 'Species', '10090', (114, 118))	('ocular melanocytic tumors', 'Disease', 'MESH:D009508', (79, 104))	('signaling', 'biological_process', 'GO:0023052', ('235', '244'))	('Lats1', 'Gene', (174, 179))
124186	31880399	Additionally, the loss of Bap1 did not enhance the aggressiveness of uveal melanomas; in fact, the ocular phenotype was weaker, and there was no increase in size or incidence of lung lesions compared with mice expressing GNA11Q209L alone (Moore et al., 2018).	('GNA11', 'Gene', (221, 226))	('GNA11', 'Gene', '14672', (221, 226))	('loss', 'Var', (18, 22))	('weaker', 'NegReg', (120, 126))	('lung lesions', 'Disease', 'MESH:D008171', (178, 190))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('lung lesions', 'Disease', (178, 190))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('mice', 'Species', '10090', (205, 209))	('uveal melanomas', 'Phenotype', 'HP:0007716', (69, 84))	('Bap1', 'Gene', '104416', (26, 30))	('aggressiveness of uveal melanomas', 'Disease', 'MESH:C536494', (51, 84))	('aggressiveness of uveal melanomas', 'Disease', (51, 84))	('aggressiveness', 'Phenotype', 'HP:0000718', (51, 65))	('Bap1', 'Gene', (26, 30))
124324	31426578	Tumours in sHLA-positive eyes were significantly larger, more frequently involved the ciliary body, and more often showed monosomy 3, gain of chromosome 8q and loss of BAP1 staining.	('monosomy 3', 'Var', (122, 132))	('BAP1', 'Gene', '8314', (168, 172))	('loss', 'NegReg', (160, 164))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('chromosome', 'cellular_component', 'GO:0005694', ('142', '152'))	('BAP1', 'Gene', (168, 172))	('involved', 'Reg', (73, 81))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('gain', 'PosReg', (134, 138))
124329	31426578	Important genetic prognostic parameters are the monosomy of chromosome 3 (M3), a gain of the long arm of chromosome 8 (8q) and a mutation in the BRCA1-Associated Protein 1 (BAP1) gene.	('BRCA1-Associated Protein 1', 'Gene', '8314', (145, 171))	('mutation', 'Var', (129, 137))	('chromosome', 'cellular_component', 'GO:0005694', ('105', '115'))	('BAP1', 'Gene', '8314', (173, 177))	('monosomy', 'Var', (48, 56))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))	('BAP1', 'Gene', (173, 177))	('BRCA1-Associated Protein 1', 'Gene', (145, 171))	('gain', 'PosReg', (81, 85))
124331	31426578	The relation between a high HLA Class I expression in UM and an increased risk of developing metastases has been reported.	('HLA Class I', 'Protein', (28, 39))	('metastases', 'Disease', (93, 103))	('high', 'Var', (23, 27))	('metastases', 'Disease', 'MESH:D009362', (93, 103))	('UM', 'Phenotype', 'HP:0007716', (54, 56))
124342	31426578	Our data show that it is possible to determine sHLA Class I levels in the aqueous humour of UM eyes, and that the presence of sHLA is related to survival, but that this is more related to the presence of a large, anteriorly-located tumour than to the expression of HLA on the tumour cells.	('UM', 'Phenotype', 'HP:0007716', (92, 94))	('presence', 'Var', (114, 122))	('tumour', 'Disease', (276, 282))	('tumour', 'Disease', (232, 238))	('related', 'Reg', (134, 141))	('tumour', 'Phenotype', 'HP:0002664', (276, 282))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('tumour', 'Disease', 'MESH:D009369', (276, 282))	('tumour', 'Disease', 'MESH:D009369', (232, 238))
124396	31426578	Twenty-three Tumours were analysed using a genome wide micro-array analysis of single-nucleotide polymorphisms (SNPs), performed with the Affymetrix 250K Nsp array (Affymetrix, Santa Clara, CA, USA), as previously described.	('single-nucleotide polymorphisms', 'Var', (79, 110))	('Nsp', 'Gene', (154, 157))	('Tumour', 'Phenotype', 'HP:0002664', (13, 19))	('Nsp', 'Gene', '92521', (154, 157))	('Tumours', 'Phenotype', 'HP:0002664', (13, 20))
124408	29850322	 GNQ-209P Mutation in Metastatic Uveal Melanoma and Treatment Outcome Metastatic prognosis in uveal melanoma is assessed by gene expression profiling (GEP) testing of the tumor cells, usually obtained by fine needle aspiration (FNA).	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('GNQ-209P', 'Var', (1, 9))	('uveal melanoma', 'Disease', (94, 108))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('gene expression', 'biological_process', 'GO:0010467', ('124', '139'))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('Melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('aspiration', 'Phenotype', 'HP:0002835', (216, 226))	('tumor', 'Disease', (171, 176))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('Melanoma', 'Disease', 'MESH:D008545', (39, 47))	('Melanoma', 'Disease', (39, 47))
124410	29850322	Transcriptomic studies identified distinct mutations including somatic mutations in GNAQ and GNA11, detected in more than 80%, and contribute to the upregulation of the mitogen-activated protein kinase (MAPK) pathway and the development of uveal melanoma (UM).	('uveal melanoma', 'Phenotype', 'HP:0007716', (240, 254))	('uveal melanoma', 'Disease', (240, 254))	('uveal melanoma', 'Disease', 'MESH:C536494', (240, 254))	('MAPK', 'molecular_function', 'GO:0004707', ('203', '207'))	('GNAQ', 'Gene', (84, 88))	('upregulation', 'PosReg', (149, 161))	('melanoma', 'Phenotype', 'HP:0002861', (246, 254))	('mutations', 'Var', (71, 80))	('GNAQ', 'Gene', '2776', (84, 88))	('GNA11', 'Gene', '2767', (93, 98))	('GNA11', 'Gene', (93, 98))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))
124412	29850322	One had significant liver metastases with proven GNQ-209P mutation on tissue biopsy while peripheral blood molecular profiling did not show these mutations.	('liver metastases', 'Disease', (20, 36))	('liver metastases', 'Disease', 'MESH:D009362', (20, 36))	('GNQ-209P mutation', 'Var', (49, 66))
124417	29850322	Key mutations in the disease are GNAQ and GNA11 mutations.	('GNAQ', 'Gene', (33, 37))	('GNAQ', 'Gene', '2776', (33, 37))	('GNA11', 'Gene', (42, 47))	('GNA11', 'Gene', '2767', (42, 47))	('mutations', 'Var', (48, 57))
124454	29850322	UM is genetically characterized by frequent, mutually exclusive mutations in guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) and guanine nucleotide-binding protein subunit alpha-11 (GNA11) which can be detected in 83% of patients with UM.	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('150', '168'))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('GNAQ', 'Gene', '2776', (132, 136))	('GNA11', 'Gene', '2767', (195, 200))	('GNA11', 'Gene', (195, 200))	('patients', 'Species', '9606', (234, 242))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('85', '103'))	('guanine nucleotide-binding protein G(q) subunit alpha', 'Gene', '2776', (77, 130))	('mutations', 'Var', (64, 73))	('guanine nucleotide-binding protein subunit alpha-11', 'Gene', '2767', (142, 193))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('GNAQ', 'Gene', (132, 136))
124455	29850322	GNAQ stimulates the mitogen-activated protein kinase (MAPK), which is parallel to the consequence of mutations in the BRAF or NRAS oncogenes in cutaneous melanomas.	('BRAF', 'Gene', '673', (118, 122))	('MAPK', 'molecular_function', 'GO:0004707', ('54', '58'))	('mutations', 'Var', (101, 110))	('GNAQ', 'Gene', '2776', (0, 4))	('stimulates', 'PosReg', (5, 15))	('BRAF', 'Gene', (118, 122))	('cutaneous melanomas', 'Disease', (144, 163))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (144, 162))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('GNAQ', 'Gene', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (154, 163))	('NRAS', 'Gene', (126, 130))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (144, 163))	('NRAS', 'Gene', '4893', (126, 130))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (144, 163))
124464	29850322	This might draw our attention that GNQ-209P might be a predictive marker of sensitivity to nab-paclitaxel in metastatic uveal melanoma.	('nab', 'Chemical', '-', (91, 94))	('uveal melanoma', 'Disease', 'MESH:C536494', (120, 134))	('paclitaxel', 'Chemical', 'MESH:D017239', (95, 105))	('uveal melanoma', 'Phenotype', 'HP:0007716', (120, 134))	('uveal melanoma', 'Disease', (120, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('GNQ-209P', 'Var', (35, 43))
124466	29850322	We suggest the implication of molecular profiling with specific attention to the status of not only GNAQ but also the exon 209P or Q209L for personalized use of therapies in future clinical trials designed to treat patients with metastatic UM.	('patients', 'Species', '9606', (215, 223))	('GNAQ', 'Gene', '2776', (100, 104))	('metastatic UM', 'Disease', (229, 242))	('exon 209P', 'Var', (118, 127))	('Q209L', 'Mutation', 'rs121913492', (131, 136))	('GNAQ', 'Gene', (100, 104))	('Q209L', 'Var', (131, 136))
124467	29850322	Such clinical trials are needed to prove the efficacy and survival advantages of nab-paclitaxel in patients with metastatic UM and to study its role in comparison to the evolving targeted or immunotherapeutic agents.	('nab', 'Chemical', '-', (81, 84))	('patients', 'Species', '9606', (99, 107))	('nab-paclitaxel', 'Var', (81, 95))	('metastatic UM', 'Disease', (113, 126))	('paclitaxel', 'Chemical', 'MESH:D017239', (85, 95))
124532	28859118	The applied dose to the tumor apex was < 80 Gy in 60 (42%) cases, 80-110 Gy in 37 (26%) cases and > 110 Gy in 46 (32%) cases.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('apex', 'cellular_component', 'GO:0097683', ('30', '34'))	('> 110 Gy', 'Var', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
124551	28859118	Other authors also identified cataract formation as one of the most frequent complications after ruthenium-106 brachytherapy, occurring in up to 37% and 33% of cases, as well as 21% and 28% three and five years after treatment.	('ruthenium-106', 'Chemical', 'MESH:C000615522', (97, 110))	('cataract', 'Disease', (30, 38))	('cataract', 'Phenotype', 'HP:0000518', (30, 38))	('cataract', 'Disease', 'MESH:D002386', (30, 38))	('formation', 'biological_process', 'GO:0009058', ('39', '48'))	('ruthenium-106', 'Var', (97, 110))
124630	28640204	OMM1 and OMM2.3 were not affected by fucoidan, while in OMM2.5 cells, fucoidan increased cell number significantly after one day of incubation (p < 0.001) (Figure 1).	('increased', 'PosReg', (79, 88))	('cell number', 'CPA', (89, 100))	('fucoidan', 'Var', (70, 78))	('fucoidan', 'Chemical', 'MESH:C007789', (70, 78))	('fucoidan', 'Chemical', 'MESH:C007789', (37, 45))
124667	28640204	Again, this cannot simply be explained by the molecular structure of this particular fucoidan, as we have shown before that this exact fucoidan reduced angiogenic structures in RPE-endothelial cells co-cultures.	('fucoidan', 'Chemical', 'MESH:C007789', (85, 93))	('reduced', 'NegReg', (144, 151))	('fucoidan', 'Var', (135, 143))	('angiogenic structures', 'CPA', (152, 173))	('fucoidan', 'Chemical', 'MESH:C007789', (135, 143))
124695	28640204	Cytotoxicity was induced by applying H2O2 in the respective concentration (92.1:250 microM, Mel270 and OMM1: 500 microM, OMM2.3 and OMM2.5:1000 microM).	('OMM1: 500 microM', 'Var', (103, 119))	('Mel270', 'Var', (92, 98))	('Cytotoxicity', 'Disease', (0, 12))	('H2O2', 'Chemical', 'MESH:D006861', (37, 41))	('H2O2', 'Var', (37, 41))	('Cytotoxicity', 'Disease', 'MESH:D064420', (0, 12))
124702	28640204	The blot was treated with the first antibodies, beta-actin (#4967, 1:1000), Akt (#9272, 1:1000), ERK1/2 (#9102, 1:1000), p-ERK1/2 (#9101, 1:1000) (all Cell-Signaling Technologies, CST, Denver, CO, USA; all rabbit), Bax (sc-20067, 1:1000) or Bcl-2 (sc-509, 1:1000) (all Santa Cruz, Heidelberg, Germany, all mouse), respectively, in 2% skim milk in Tris buffered saline with 0.1% Tween overnight at 4  C. After washing the blot, it was incubated with appropriate secondary antibody (anti-rabbit (#7074) or anti-mouse (#7076) IgG, HRP-linked antibody (all Cell-Signaling)) in 2% skim milk in Tris-buffered saline with 0.1% Tween (Merck, Darmstadt, Germany).	('HRP-linked antibody', 'Protein', (528, 547))	('mouse', 'Species', '10090', (509, 514))	('ERK1', 'molecular_function', 'GO:0004707', ('123', '127'))	('antibody', 'cellular_component', 'GO:0019815', ('471', '479'))	('antibody', 'molecular_function', 'GO:0003823', ('539', '547'))	('ERK1', 'molecular_function', 'GO:0004707', ('97', '101'))	('Tween', 'Chemical', 'MESH:D011136', (378, 383))	('antibody', 'cellular_component', 'GO:0042571', ('539', '547'))	('Signaling', 'biological_process', 'GO:0023052', ('156', '165'))	('IgG', 'Protein', (523, 526))	('rabbit', 'Species', '9986', (486, 492))	('Tris', 'Chemical', '-', (589, 593))	('Signaling', 'biological_process', 'GO:0023052', ('558', '567'))	('antibody', 'cellular_component', 'GO:0019814', ('471', '479'))	('Akt', 'Gene', (76, 79))	('Bcl-2', 'molecular_function', 'GO:0015283', ('241', '246'))	('mouse', 'Species', '10090', (306, 311))	('antibody', 'cellular_component', 'GO:0019815', ('539', '547'))	('Akt', 'Gene', '207', (76, 79))	('beta-actin', 'Gene', (48, 58))	('rabbit', 'Species', '9986', (206, 212))	('antibody', 'molecular_function', 'GO:0003823', ('471', '479'))	('#7076', 'Var', (516, 521))	('Tris', 'Chemical', '-', (347, 351))	('Tris buffered saline', 'Chemical', '-', (347, 367))	('antibody', 'cellular_component', 'GO:0042571', ('471', '479'))	('beta-actin', 'Gene', '100350495', (48, 58))	('Tween', 'Chemical', 'MESH:D011136', (620, 625))	('antibody', 'cellular_component', 'GO:0019814', ('539', '547'))
124704	23110010	We analyzed the frequency of BRAF mutation in patients with primary cutaneous melanoma (n=58) or non-cutaneous one (n=27) by performing dual priming oligonucleotide-based multiplex real-time polymerase chain reaction to isolate and to purify the DNA from the formalin-fixed and paraffin-embedded tumors.	('BRAF', 'Gene', '673', (29, 33))	('formalin', 'Chemical', 'MESH:D005557', (259, 267))	('patients', 'Species', '9606', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('BRAF', 'Gene', (29, 33))	('paraffin', 'Chemical', 'MESH:D010232', (278, 286))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('mutation', 'Var', (34, 42))	('oligonucleotide', 'Chemical', 'MESH:D009841', (149, 164))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (60, 86))	('tumors', 'Disease', (296, 302))	('tumors', 'Disease', 'MESH:D009369', (296, 302))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('primary cutaneous melanoma', 'Disease', (60, 86))	('DNA', 'cellular_component', 'GO:0005574', ('246', '249'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (68, 86))
124705	23110010	The BRAF mutation was found in 17.2% (10/58) of patients with primary cutaneous melanoma and 11.1% (3/27) of those with non-cutaneous melanoma.	('mutation', 'Var', (9, 17))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (70, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('found', 'Reg', (22, 27))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (124, 142))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (62, 88))	('patients', 'Species', '9606', (48, 56))	('non-cutaneous melanoma', 'Disease', (120, 142))	('non-cutaneous melanoma', 'Disease', 'MESH:C562393', (120, 142))	('primary cutaneous melanoma', 'Disease', (62, 88))
124706	23110010	The frequency of BRAF mutation was not correlated with any clinicopathologic parameters with the exception of the patient age.	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (17, 21))	('mutation', 'Var', (22, 30))	('patient', 'Species', '9606', (114, 121))
124707	23110010	The frequency of the BRAF mutation was significantly higher in patients younger than 60 years as compared with those older than 60 years (p=0.005).	('higher', 'PosReg', (53, 59))	('mutation', 'Var', (26, 34))	('BRAF', 'Gene', '673', (21, 25))	('BRAF', 'Gene', (21, 25))	('patients', 'Species', '9606', (63, 71))
124708	23110010	Compared with previous reports, our results showed that the frequency of the BRAF mutation was relatively lower in patients with primary cutaneous melanoma.	('patients', 'Species', '9606', (115, 123))	('lower', 'NegReg', (106, 111))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('mutation', 'Var', (82, 90))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (77, 81))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (129, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('primary cutaneous melanoma', 'Disease', (129, 155))
124709	23110010	Besides, our results also showed that the frequency of the BRAF mutation had an inverse correlation with the age.	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (59, 63))	('mutation', 'Var', (64, 72))
124710	23110010	Further studies are warranted to exclude methodological bias, to elucidate the difference in the frequency of the BRAF mutation from the previous reports from a Caucasian population and to provide an improved understanding of the molecular pathogenesis of malignant melanoma.	('malignant melanoma', 'Disease', (256, 274))	('mutation', 'Var', (119, 127))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('melanoma', 'Phenotype', 'HP:0002861', (266, 274))	('pathogenesis', 'biological_process', 'GO:0009405', ('240', '252'))	('malignant melanoma', 'Phenotype', 'HP:0002861', (256, 274))	('malignant melanoma', 'Disease', 'MESH:D008545', (256, 274))
124719	23110010	In more than 90% of total BRAF mutations, a glutamic acid for valine substitution at codon 600 in exon 15 has been identified up to present.	('glutamic acid for valine substitution at codon 600', 'Mutation', 'rs113488022', (44, 94))	('mutations', 'Var', (31, 40))	('BRAF', 'Gene', (26, 30))	('BRAF', 'Gene', '673', (26, 30))
124720	23110010	This genetic alteration of BRAF sequentially induces constitutive extracellular signal-regulated kinase (ERK) signaling through a hyperactivation of the RAS/RAF/mitogen-activated protein kinase/ERK (MAPK/ERK) pathway that is involved in promoting the proliferation, survival and development of tumor cells.	('RAF', 'Gene', (28, 31))	('ERK', 'Gene', '5594', (105, 108))	('ERK', 'Gene', '5594', (194, 197))	('ERK', 'Gene', (204, 207))	('hyperactivation', 'PosReg', (130, 145))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('ERK', 'molecular_function', 'GO:0004707', ('194', '197'))	('induces', 'Reg', (45, 52))	('ERK', 'Gene', (194, 197))	('ERK', 'Gene', (105, 108))	('RAF', 'Gene', '22882', (157, 160))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('MAPK', 'molecular_function', 'GO:0004707', ('199', '203'))	('ERK', 'molecular_function', 'GO:0004707', ('105', '108'))	('mitogen-activated protein kinase/ERK', 'Gene', '5594', (161, 197))	('men', 'Species', '9606', (286, 289))	('extracellular', 'cellular_component', 'GO:0005576', ('66', '79'))	('extracellular signal-regulated kinase', 'Gene', (66, 103))	('BRAF', 'Gene', '673', (27, 31))	('BRAF', 'Gene', (27, 31))	('tumor', 'Disease', (294, 299))	('RAF', 'Gene', (157, 160))	('extracellular signal-regulated kinase', 'Gene', '5594', (66, 103))	('ERK', 'Gene', '5594', (204, 207))	('genetic alteration', 'Var', (5, 23))	('RAF', 'Gene', '22882', (28, 31))	('mitogen-activated protein kinase/ERK', 'Gene', (161, 197))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('signaling', 'biological_process', 'GO:0023052', ('110', '119'))	('ERK', 'molecular_function', 'GO:0004707', ('204', '207'))	('promoting', 'PosReg', (237, 246))
124721	23110010	To date, several studies have been conducted to examine the relationship of BRAF mutation in MM with its clinicopathologic characteristics.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('mutation', 'Var', (81, 89))
124722	23110010	Nevertheless, to our knowledge, there are no reports about the associations between BRAF mutations in MM and its clinicopathologic features in the Korean population.	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('mutations', 'Var', (89, 98))
124723	23110010	Given the above background, we conducted this study to examine the frequency and potential clinicopathologic significance of the BRAF mutation in Korean patients with primary cutaneous or non-cutaneous melanoma.	('non-cutaneous melanoma', 'Disease', 'MESH:C562393', (188, 210))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (192, 210))	('BRAF', 'Gene', '673', (129, 133))	('BRAF', 'Gene', (129, 133))	('patients', 'Species', '9606', (153, 161))	('mutation', 'Var', (134, 142))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('primary cutaneous', 'Disease', (167, 184))	('non-cutaneous melanoma', 'Disease', (188, 210))
124732	23110010	The BRAF mutation was detected using the Anyplex BRAF V600E real time detection system (Seegene Inc., Seoul, Korea).	('mutation', 'Var', (9, 17))	('V600E', 'Mutation', 'rs113488022', (54, 59))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (49, 53))
124737	23110010	To evaluate the possible relationships between the BRAF mutation and various clinicopathologic parameters, we used either the Fisher's exact test or Mann-Whitney test.	('mutation', 'Var', (56, 64))	('BRAF', 'Gene', (51, 55))	('BRAF', 'Gene', '673', (51, 55))
124738	23110010	Using the Mann-Whitney test, we analyzed the relationship between the BRAF mutation and ordinal clinicopathologic variables including Breslow thickness and tumor, node and metastasis (TNM) stage.	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('mutation', 'Var', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('NM', 'Phenotype', 'HP:0012058', (185, 187))	('tumor', 'Disease', (156, 161))	('BRAF', 'Gene', '673', (70, 74))	('BRAF', 'Gene', (70, 74))
124739	23110010	In addition, we used the Kaplan-Meier method to analyze the impact of the BRAF mutation on overall survival (OS) and disease-free survival (DFS).	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('mutation', 'Var', (79, 87))
124751	23110010	The BRAF mutation was found in 17.2% (10/58) of patients with primary cutaneous melanoma (n=58).	('mutation', 'Var', (9, 17))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (70, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (62, 88))	('patients', 'Species', '9606', (48, 56))	('primary cutaneous melanoma', 'Disease', (62, 88))
124753	23110010	In patients with primary cutaneous melanoma, the age was the only variable that had a significant correlation with the BRAF mutation.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (25, 43))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', (119, 123))	('patients', 'Species', '9606', (3, 11))	('mutation', 'Var', (124, 132))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (17, 43))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('primary cutaneous melanoma', 'Disease', (17, 43))
124754	23110010	The frequency of the BRAF mutation was significantly higher in patients aged 60 years or younger as compared with those aged 60 years or older (p=0.005).	('higher', 'PosReg', (53, 59))	('mutation', 'Var', (26, 34))	('BRAF', 'Gene', '673', (21, 25))	('BRAF', 'Gene', (21, 25))	('patients', 'Species', '9606', (63, 71))
124756	23110010	In addition, we also analyzed the correlation between the specific site of the occurrence of primary cutaneous melanoma and the frequency of the BRAF mutation.	('primary cutaneous melanoma', 'Disease', (93, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('BRAF', 'Gene', (145, 149))	('mutation', 'Var', (150, 158))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (101, 119))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (93, 119))	('BRAF', 'Gene', '673', (145, 149))
124757	23110010	The BRAF mutation was found in 18.4% (7/38) of patients with ALM and 18.8% (3/16) of patients with NM.	('mutation', 'Var', (9, 17))	('NM', 'Phenotype', 'HP:0012058', (99, 101))	('patients', 'Species', '9606', (47, 55))	('patients', 'Species', '9606', (85, 93))	('ALM', 'Phenotype', 'HP:0012060', (61, 64))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('ALM', 'Disease', (61, 64))
124760	23110010	The mean thickness of the tumors was smaller in patients with the BRAF mutation as compared with those without the BRAF mutation (4.8+-7.2 mm vs 6.0+-8.4 mm).	('BRAF', 'Gene', '673', (115, 119))	('smaller', 'NegReg', (37, 44))	('BRAF', 'Gene', (115, 119))	('mutation', 'Var', (71, 79))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('BRAF', 'Gene', '673', (66, 70))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('patients', 'Species', '9606', (48, 56))	('BRAF', 'Gene', (66, 70))	('tumors', 'Disease', (26, 32))
124761	23110010	The frequency of BRAF mutation was higher in patients with a Breslow thickness of <=2 mm as compared with those with a Breslow thickness of >2 mm (25.0% vs 13.2%).	('patients', 'Species', '9606', (45, 53))	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (17, 21))	('mutation', 'Var', (22, 30))
124762	23110010	Neither the mean tumor thickness nor the Breslow thickness were variables that had a significant correlation with the frequency of BRAF mutation (p=0.328 and p=0.241, respectively).	('tumor', 'Disease', (17, 22))	('BRAF', 'Gene', (131, 135))	('mutation', 'Var', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('BRAF', 'Gene', '673', (131, 135))
124764	23110010	We also evaluated if the AJCC clinical stage, presence of ulceration, nodal metastasis and recurrence are significantly correlated with the frequency of the BRAF mutation.	('nodal', 'Gene', (70, 75))	('nodal', 'Gene', '4838', (70, 75))	('BRAF', 'Gene', '673', (157, 161))	('correlated', 'Reg', (120, 130))	('BRAF', 'Gene', (157, 161))	('mutation', 'Var', (162, 170))	('AJCC', 'Disease', (25, 29))
124765	23110010	But none of these factors had a statistically significant correlation with the frequency of the BRAF mutation.	('BRAF', 'Gene', '673', (96, 100))	('mutation', 'Var', (101, 109))	('BRAF', 'Gene', (96, 100))
124766	23110010	The frequency of BRAF mutation had no statistically significant impact on both the OS and DFS (p=0.561 and p=0.397, respectively).	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (17, 21))	('mutation', 'Var', (22, 30))
124767	23110010	In patients with the BRAF mutation, however, there was a slightly increased tendency in the OS and DFS (Fig.	('increased', 'PosReg', (66, 75))	('DFS', 'Disease', (99, 102))	('mutation', 'Var', (26, 34))	('BRAF', 'Gene', '673', (21, 25))	('patients', 'Species', '9606', (3, 11))	('BRAF', 'Gene', (21, 25))
124768	23110010	The BRAF mutation was found in 11.1% (3/27) of patients with non-cutaneous melanoma.	('mutation', 'Var', (9, 17))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (65, 83))	('patients', 'Species', '9606', (47, 55))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('non-cutaneous melanoma', 'Disease', 'MESH:C562393', (61, 83))	('non-cutaneous melanoma', 'Disease', (61, 83))
124770	23110010	Our results showed that the frequency of BRAF mutation was 17.2% in 58 patients with primary cutaneous melanoma.	('patients', 'Species', '9606', (71, 79))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (93, 111))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (85, 111))	('BRAF', 'Gene', '673', (41, 45))	('primary cutaneous melanoma', 'Disease', (85, 111))	('BRAF', 'Gene', (41, 45))	('mutation', 'Var', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
124771	23110010	This methodological difference, however, is not sufficient to explain the low frequency of the BRAF mutation seen in our results.	('mutation', 'Var', (100, 108))	('BRAF', 'Gene', (95, 99))	('BRAF', 'Gene', '673', (95, 99))
124772	23110010	compared the frequency of the BRAF mutation between the microdissected samples and those the DNA was extracted from an entire section without using a microdissection technique.	('BRAF', 'Gene', (30, 34))	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('BRAF', 'Gene', '673', (30, 34))	('mutation', 'Var', (35, 43))
124774	23110010	Other reasons for the difference in the frequency of BRAF mutation may be that there is a variability in types of BRAF mutation, the proportion of histological subtypes and the sensitivity of the methods for detecting it.	('mutation', 'Var', (119, 127))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))
124775	23110010	Some of the previous studies have detected various types of BRAF mutations including exon 11 mutations (G465A, G465E, and G468S changes) as well as exon 15 mutations (V600E, V600K, V600R, V600G, and V600D changes) although the BRAF V600E mutation accounted for more than 90% of the detected mutations.	('G465A', 'Var', (104, 109))	('V600K', 'Mutation', 'rs121913227', (174, 179))	('V600D', 'Mutation', 'rs121913377', (199, 204))	('V600R', 'Var', (181, 186))	('V600K', 'Var', (174, 179))	('G468S', 'Mutation', 'p.G468S', (122, 127))	('G465E', 'Mutation', 'p.G465E', (111, 116))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('V600E', 'Mutation', 'rs113488022', (232, 237))	('V600E', 'Mutation', 'rs113488022', (167, 172))	('G465E', 'Var', (111, 116))	('V600R', 'Mutation', 'rs121913227', (181, 186))	('V600G', 'Mutation', 'rs113488022', (188, 193))	('G468S changes', 'Var', (122, 135))	('BRAF', 'Gene', '673', (227, 231))	('BRAF', 'Gene', (227, 231))	('V600G', 'Var', (188, 193))	('V600D changes', 'Var', (199, 212))	('G465A', 'Mutation', 'c.465G>A', (104, 109))	('V600E', 'Var', (167, 172))
124778	23110010	It has also been reported that ALM has a low frequency of BRAF mutation compared to other subtypes of melanomas.	('ALM', 'Disease', (31, 34))	('melanomas', 'Disease', (102, 111))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('mutation', 'Var', (63, 71))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('melanomas', 'Disease', 'MESH:D008545', (102, 111))	('BRAF', 'Gene', '673', (58, 62))	('ALM', 'Phenotype', 'HP:0012060', (31, 34))	('BRAF', 'Gene', (58, 62))
124779	23110010	According to a recent study that has been conducted in the Asian population, the frequency of BRAF mutation was 15.0% and this value was similar to our results.	('BRAF', 'Gene', (94, 98))	('BRAF', 'Gene', '673', (94, 98))	('mutation', 'Var', (99, 107))
124780	23110010	The above mentioned reasons make it more difficult to interpret our results that the frequency of BRAF mutation was relatively lower as compared with previous published studies.	('men', 'Species', '9606', (10, 13))	('BRAF', 'Gene', '673', (98, 102))	('BRAF', 'Gene', (98, 102))	('lower', 'NegReg', (127, 132))	('mutation', 'Var', (103, 111))
124781	23110010	Our results showed that the age was the only clinicopathologic variable that has a significant correlation with the frequency of the BRAF mutation in patients with primary cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (172, 190))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (133, 137))	('patients', 'Species', '9606', (150, 158))	('mutation', 'Var', (138, 146))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (164, 190))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('primary cutaneous melanoma', 'Disease', (164, 190))
124782	23110010	Patients aged 60 years or younger had a higher frequency of the BRAF mutation as compared with those aged 60 years or older, which is consistent with previous reports.	('mutation', 'Var', (69, 77))	('Patients', 'Species', '9606', (0, 8))	('BRAF', 'Gene', (64, 68))	('BRAF', 'Gene', '673', (64, 68))
124786	23110010	In addition, to rule out the effects of histological subtypes, the site of occurrence and the degree of sunlight exposure, we also examined the correlation of the BRAF mutation with the age in patients with ALM.	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('patients', 'Species', '9606', (193, 201))	('ALM', 'Phenotype', 'HP:0012060', (207, 210))	('sunlight exposure', 'Phenotype', 'HP:0000992', (104, 121))	('mutation', 'Var', (168, 176))	('examined', 'Reg', (131, 139))
124787	23110010	This showed that the frequency of the BRAF mutation was higher in patients younger than 60 years than those older than 60 years in cases of ALM (p=0.011).	('mutation', 'Var', (43, 51))	('BRAF', 'Gene', '673', (38, 42))	('ALM', 'Phenotype', 'HP:0012060', (140, 143))	('BRAF', 'Gene', (38, 42))	('patients', 'Species', '9606', (66, 74))
124788	23110010	These results indicate not only that the age is an independent variable that is correlated with the BRAF mutation but also that there is a difference in the pathogenesis between the two groups.	('BRAF', 'Gene', '673', (100, 104))	('pathogenesis', 'biological_process', 'GO:0009405', ('157', '169'))	('mutation', 'Var', (105, 113))	('BRAF', 'Gene', (100, 104))
124789	23110010	It can be speculated, however, that the difference in the pathogenesis between the two age groups may be due to the mutations of NRAS and BRAF, both of which are mutually exclusive events in the pathogenesis of MM.	('pathogenesis', 'biological_process', 'GO:0009405', ('58', '70'))	('due', 'Reg', (105, 108))	('NRAS', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (138, 142))	('NRAS', 'Gene', '4893', (129, 133))	('mutations', 'Var', (116, 125))	('BRAF', 'Gene', (138, 142))	('pathogenesis', 'biological_process', 'GO:0009405', ('195', '207'))
124790	23110010	Previous studies have demonstrated that the NRAS mutation is associated with older age, thicker tumor and poor clinical outcome as compared with the BRAF one.	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('NRAS', 'Gene', (44, 48))	('mutation', 'Var', (49, 57))	('NRAS', 'Gene', '4893', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
124791	23110010	Based on these reports, we can assume that the BRAF mutation is more commonly involved in the pathogenesis of melanoma in younger patients.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('involved', 'Reg', (78, 86))	('melanoma', 'Disease', (110, 118))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('patients', 'Species', '9606', (130, 138))	('mutation', 'Var', (52, 60))	('pathogenesis', 'biological_process', 'GO:0009405', ('94', '106'))
124792	23110010	We can also presume that the NRAS mutation play a more predominant role in the pathogenesis of melanoma in older patients.	('pathogenesis', 'biological_process', 'GO:0009405', ('79', '91'))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('NRAS', 'Gene', (29, 33))	('mutation', 'Var', (34, 42))	('melanoma', 'Disease', (95, 103))	('patients', 'Species', '9606', (113, 121))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('NRAS', 'Gene', '4893', (29, 33))
124794	23110010	These studies have reported that SSM and NM more frequently harbor BRAF mutations than ALM.	('ALM', 'Phenotype', 'HP:0012060', (87, 90))	('mutations', 'Var', (72, 81))	('BRAF', 'Gene', '673', (67, 71))	('SSM', 'Disease', (33, 36))	('BRAF', 'Gene', (67, 71))	('SSM', 'cellular_component', 'GO:1990843', ('33', '36'))	('NM', 'Phenotype', 'HP:0012058', (41, 43))	('SSM', 'Phenotype', 'HP:0012057', (33, 36))
124795	23110010	In the current study, as compared with previous published data, the frequency of BRAF mutation (18.4%) seen in patients with ALM was similar but that seen in patients with SSM or NM was relatively lower (0% and 18.8%, respectively).	('ALM', 'Phenotype', 'HP:0012060', (125, 128))	('SSM', 'Phenotype', 'HP:0012057', (172, 175))	('BRAF', 'Gene', '673', (81, 85))	('ALM', 'Disease', (125, 128))	('BRAF', 'Gene', (81, 85))	('NM', 'Phenotype', 'HP:0012058', (179, 181))	('mutation', 'Var', (86, 94))	('patients', 'Species', '9606', (158, 166))	('SSM', 'cellular_component', 'GO:1990843', ('172', '175'))	('patients', 'Species', '9606', (111, 119))
124797	23110010	Further large-scale studies are therefore warranted to identify the correlation between the frequency of BRAF mutation and histological subtypes in Korean patients with cutaneous melanoma.	('BRAF', 'Gene', '673', (105, 109))	('cutaneous melanoma', 'Disease', (169, 187))	('BRAF', 'Gene', (105, 109))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (169, 187))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (169, 187))	('mutation', 'Var', (110, 118))	('patients', 'Species', '9606', (155, 163))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))
124798	23110010	Our results showed that the frequency of BRAF mutation had an inverse correlation with tumor thickness despite a lack of the statistical significance.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('BRAF', 'Gene', '673', (41, 45))	('inverse', 'NegReg', (62, 69))	('BRAF', 'Gene', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mutation', 'Var', (46, 54))
124799	23110010	Several previous reports have also shown that the frequency of BRAF mutation is associated with decreased tumor thickness.	('decreased tumor', 'Disease', (96, 111))	('mutation', 'Var', (68, 76))	('decreased tumor', 'Disease', 'MESH:D009369', (96, 111))	('BRAF', 'Gene', '673', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('BRAF', 'Gene', (63, 67))
124800	23110010	These observations indicate that the frequency of BRAF mutation may be related to more differentiated forms of cutaneous melanoma and a slower cell proliferation rate.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('BRAF', 'Gene', (50, 54))	('cutaneous melanoma', 'Disease', (111, 129))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (111, 129))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (111, 129))	('mutation', 'Var', (55, 63))	('slower cell proliferation rate', 'CPA', (136, 166))	('cell proliferation', 'biological_process', 'GO:0008283', ('143', '161'))	('BRAF', 'Gene', '673', (50, 54))
124801	23110010	In our series, the frequency of BRAF mutation had no significant correlations with the clinical stage, metastasis and cumulative survival rate.	('BRAF', 'Gene', (32, 36))	('BRAF', 'Gene', '673', (32, 36))	('mutation', 'Var', (37, 45))	('metastasis', 'CPA', (103, 113))
124802	23110010	To date, several studies have also revealed that the frequency of BRAF mutation is not correlated with a prognosis and a survival in patients with primary cutaneous melanoma.	('BRAF', 'Gene', (66, 70))	('mutation', 'Var', (71, 79))	('patients', 'Species', '9606', (133, 141))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (155, 173))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (147, 173))	('BRAF', 'Gene', '673', (66, 70))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('primary cutaneous melanoma', 'Disease', (147, 173))
124803	23110010	A lack of consistency and correlation may be due to the inclusion of a variety of histological subtypes and advanced tumors, as well as the inclusion or exclusion of NRAS mutant cases, known as an adverse prognostic factor, from the wild type category.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('NRAS', 'Gene', (166, 170))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('NRAS', 'Gene', '4893', (166, 170))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('mutant', 'Var', (171, 177))
124807	23110010	As described here, a lower prevalence of the BRAF mutation seen in patients with non-cutaneous melanoma is also in agreement with previous reports; the frequency of the BRAF mutation (0-9.5%) was relatively lower in non-cutaneous melanomas as compared with their cutaneous counterparts.	('BRAF', 'Gene', (169, 173))	('BRAF', 'Gene', '673', (169, 173))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('non-cutaneous melanoma', 'Disease', (81, 103))	('non-cutaneous melanoma', 'Disease', (216, 238))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('melanomas', 'Disease', 'MESH:D008545', (230, 239))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (220, 239))	('men', 'Species', '9606', (120, 123))	('melanomas', 'Disease', (230, 239))	('patients', 'Species', '9606', (67, 75))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (220, 238))	('mutation', 'Var', (174, 182))	('non-cutaneous melanoma', 'Disease', 'MESH:C562393', (81, 103))	('lower', 'NegReg', (207, 212))	('non-cutaneous melanoma', 'Disease', 'MESH:C562393', (216, 238))	('melanomas', 'Phenotype', 'HP:0002861', (230, 239))
124808	23110010	Three previous studies could not detect a single BRAF mutation in a total of 83 patients with uveal melanoma.	('mutation', 'Var', (54, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('patients', 'Species', '9606', (80, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('uveal melanoma', 'Disease', (94, 108))	('BRAF', 'Gene', '673', (49, 53))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('BRAF', 'Gene', (49, 53))
124809	23110010	But, we detected the BRAF mutation in one case of uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mutation', 'Var', (26, 34))	('detected', 'Reg', (8, 16))	('BRAF', 'Gene', '673', (21, 25))	('uveal melanoma', 'Disease', 'MESH:C536494', (50, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('BRAF', 'Gene', (21, 25))	('uveal melanoma', 'Disease', (50, 64))
124811	23110010	elucidated the important role that the KIT plays in the pathogenesis of ALM and mucosal melanomas which harbor the BRAF mutations at lower frequencies.	('BRAF', 'Gene', '673', (115, 119))	('mucosal melanomas', 'Disease', 'MESH:D008545', (80, 97))	('ALM', 'Phenotype', 'HP:0012060', (72, 75))	('KIT', 'molecular_function', 'GO:0005020', ('39', '42'))	('BRAF', 'Gene', (115, 119))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('ALM', 'Disease', (72, 75))	('mucosal melanomas', 'Disease', (80, 97))	('mutations', 'Var', (120, 129))	('pathogenesis', 'biological_process', 'GO:0009405', ('56', '68'))
124812	23110010	According to these authors, mutations and/or copy number increases of KIT were observed in 39% of mucosal melanomas, 36% of ALM and 28% of melanomas that occurred on the skin which was vulnerable to chronic sun-damage.	('copy number increases', 'Var', (45, 66))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('ALM', 'Disease', (124, 127))	('mucosal melanomas', 'Disease', (98, 115))	('melanomas', 'Disease', (106, 115))	('melanomas', 'Phenotype', 'HP:0002861', (139, 148))	('KIT', 'Gene', (70, 73))	('melanomas', 'Disease', 'MESH:D008545', (139, 148))	('mucosal melanomas', 'Disease', 'MESH:D008545', (98, 115))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('sun-damage', 'Phenotype', 'HP:0000992', (207, 217))	('KIT', 'molecular_function', 'GO:0005020', ('70', '73'))	('melanomas', 'Phenotype', 'HP:0002861', (106, 115))	('observed', 'Reg', (79, 87))	('melanomas', 'Disease', (139, 148))	('melanomas', 'Disease', 'MESH:D008545', (106, 115))	('mutations', 'Var', (28, 37))	('ALM', 'Phenotype', 'HP:0012060', (124, 127))
124818	23110010	BRAF-specific inhibitors, such as RAF-265 (CHIR-265) and PLX-4032 (Plexikkon), and MEK-specific inhibitors, such as PD0325901 (Pfizer Oncology) and ARRY-142886 (AZD6244), are currently being tested in clinical trials.	('RAF', 'Gene', '22882', (34, 37))	('PD0325901', 'Var', (116, 125))	('MEK', 'Gene', (83, 86))	('MEK', 'Gene', '5609', (83, 86))	('RAF', 'Gene', '22882', (1, 4))	('BRAF', 'Gene', '673', (0, 4))	('PD0325901', 'Chemical', 'MESH:C506614', (116, 125))	('Oncology', 'Phenotype', 'HP:0002664', (134, 142))	('RAF', 'Gene', (1, 4))	('BRAF', 'Gene', (0, 4))	('AZD6244', 'Chemical', 'MESH:C517975', (161, 168))	('RAF', 'Gene', (34, 37))
124819	23110010	Several preclinical and early clinical studies have shown that responses to these agents are associated with the BRAF mutation.	('BRAF', 'Gene', (113, 117))	('BRAF', 'Gene', '673', (113, 117))	('associated', 'Reg', (93, 103))	('mutation', 'Var', (118, 126))
124821	23110010	In Korea, however, ALM is a more prevalent type of cutaneous melanoma and it demonstrates a decreased number of BRAF mutations as compared with SSM and NM.	('mutations', 'Var', (117, 126))	('NM', 'Phenotype', 'HP:0012058', (152, 154))	('SSM', 'Phenotype', 'HP:0012057', (144, 147))	('SSM', 'cellular_component', 'GO:1990843', ('144', '147'))	('cutaneous melanoma', 'Disease', (51, 69))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (51, 69))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (51, 69))	('ALM', 'Phenotype', 'HP:0012060', (19, 22))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('ALM', 'Disease', (19, 22))
124822	23110010	To facilitate the development of effective targeted therapies for the treatment of melanomas in the near future, it is imperative that further studies be conducted to examine the prevalence and clincopathologic significance of the alterations of several genes which may contribute to the pathogenesis of melanoma in a Korean population, including KIT, CCND1 and NRAS as well as BRAF gene.	('melanomas', 'Disease', (83, 92))	('CCND1', 'Gene', '595', (352, 357))	('men', 'Species', '9606', (25, 28))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('NRAS', 'Gene', '4893', (362, 366))	('CCND1', 'Gene', (352, 357))	('melanoma', 'Disease', 'MESH:D008545', (304, 312))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('alterations', 'Var', (231, 242))	('BRAF', 'Gene', (378, 382))	('BRAF', 'Gene', '673', (378, 382))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))	('NRAS', 'Gene', (362, 366))	('melanoma', 'Phenotype', 'HP:0002861', (304, 312))	('contribute', 'Reg', (270, 280))	('melanoma', 'Disease', (304, 312))	('men', 'Species', '9606', (75, 78))	('pathogenesis', 'biological_process', 'GO:0009405', ('288', '300'))	('melanomas', 'Disease', 'MESH:D008545', (83, 92))	('KIT', 'molecular_function', 'GO:0005020', ('347', '350'))
124823	23110010	In conclusion, our study provides preliminary results concerning the frequency of the BRAF mutation and its association with clinicopathologic parameters in Korean patients with primary cutaneous or non-cutaneous melanoma.	('non-cutaneous melanoma', 'Disease', 'MESH:C562393', (199, 221))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (203, 221))	('mutation', 'Var', (91, 99))	('BRAF', 'Gene', '673', (86, 90))	('patients', 'Species', '9606', (164, 172))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('primary cutaneous', 'Disease', (178, 195))	('BRAF', 'Gene', (86, 90))	('non-cutaneous melanoma', 'Disease', (199, 221))
124824	23110010	This will enable us to identify more accurate frequency of the alterations of each gene, to improve an understanding of the molecular pathogenesis of melanoma and to develop new diagnostic/prognostic markers and targeted drug therapies.	('alterations', 'Var', (63, 74))	('pathogenesis', 'biological_process', 'GO:0009405', ('134', '146'))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))
124825	12778069	Absence of BRAF gene mutations in uveal melanomas in contrast to cutaneous melanomas Uveal melanoma is the most frequent primary intraocular tumour in Caucasian adults, having an annual incidence rate of 0.7 per 100 000 people (Prescher et al, 1996).	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (65, 84))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (65, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (65, 83))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('melanoma', 'Disease', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('uveal melanomas', 'Disease', 'MESH:C536494', (34, 49))	('cutaneous melanomas', 'Disease', (65, 84))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (34, 48))	('uveal melanomas', 'Phenotype', 'HP:0007716', (34, 49))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('uveal melanomas', 'Disease', (34, 49))	('melanoma', 'Disease', (91, 99))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('intraocular tumour', 'Disease', (129, 147))	('mutations', 'Var', (21, 30))	('people', 'Species', '9606', (220, 226))	('intraocular tumour', 'Disease', 'MESH:D064090', (129, 147))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (85, 99))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('BRAF', 'Gene', '673', (11, 15))	('Absence', 'NegReg', (0, 7))	('BRAF', 'Gene', (11, 15))
124832	12778069	It has recently been reported that a large proportion of cutaneous melanoma tumours contain activating oncogenic mutations in the BRAF gene (Davies et al, 2002).	('BRAF', 'Gene', '673', (130, 134))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('BRAF', 'Gene', (130, 134))	('mutations', 'Var', (113, 122))	('cutaneous melanoma tumours', 'Disease', (57, 83))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (57, 75))	('cutaneous melanoma tumours', 'Disease', 'MESH:C562393', (57, 83))	('activating', 'PosReg', (92, 102))
124834	12778069	Genetic alterations to key components of this pathway are known to contribute to the development of many cancers (Pollock and Meltzer, 2002).	('Genetic alterations', 'Var', (0, 19))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Pollock', 'Species', '8060', (114, 121))	('contribute', 'Reg', (67, 77))
124835	12778069	Activating RAS point mutations are known to be found in more than 30% of human tumours, predominantly pancreatic, colonic, and in up to 36% of cutaneous melanomas (Demunter et al, 2001).	('Activating', 'PosReg', (0, 10))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (143, 162))	('RAS', 'Gene', (11, 14))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (143, 161))	('point mutations', 'Var', (15, 30))	('cutaneous melanomas', 'Disease', (143, 162))	('melanomas', 'Phenotype', 'HP:0002861', (153, 162))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('human', 'Species', '9606', (73, 78))	('pancreatic', 'Disease', 'MESH:D010195', (102, 112))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('colonic', 'Disease', (114, 121))	('pancreatic', 'Disease', (102, 112))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (143, 162))	('tumours', 'Disease', 'MESH:D009369', (79, 86))	('tumours', 'Disease', (79, 86))
124836	12778069	BRAF is a gene that is regulated by RAS binding, and was shown to have missense mutations in 66% of primary melanoma tumours, 59% of melanoma cell lines, and 80% of melanoma short-term cultures (Brose et al, 2002; Davies et al, 2002).	('missense mutations', 'Var', (71, 89))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('melanoma tumours', 'Disease', 'MESH:D008545', (108, 124))	('melanoma tumours', 'Disease', (108, 124))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('BRAF', 'Gene', '673', (0, 4))	('binding', 'molecular_function', 'GO:0005488', ('40', '47'))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('tumours', 'Phenotype', 'HP:0002664', (117, 124))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
124837	12778069	Mutations have also been detected in up to 82% of cutaneous melanocytic nevi (Pollock et al, 2003).	('Pollock', 'Species', '8060', (78, 85))	('nevi', 'Phenotype', 'HP:0003764', (72, 76))	('cutaneous melanocytic nevi', 'Disease', (50, 76))	('Mutations', 'Var', (0, 9))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (60, 76))	('detected', 'Reg', (25, 33))
124839	12778069	This makes BRAF an interesting candidate gene to screen in uveal melanoma tumours because of BRAF mutation being a potential mechanism for the activation of this pathway, and the fact that BRAF mutations are not thought to be related to the effects of UV light (Davies et al, 2002).	('uveal melanoma tumours', 'Disease', (59, 81))	('BRAF', 'Gene', (93, 97))	('BRAF', 'Gene', '673', (189, 193))	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('mutation', 'Var', (98, 106))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('uveal melanoma tumours', 'Disease', 'MESH:C536494', (59, 81))	('activation', 'PosReg', (143, 153))	('BRAF', 'Gene', (189, 193))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('BRAF', 'Gene', '673', (93, 97))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('BRAF', 'Gene', (11, 15))	('BRAF', 'Gene', '673', (11, 15))
124840	12778069	BRAF mutations were predominantly found in two small regions of the kinase domain of the BRAF molecule.	('BRAF', 'Gene', (89, 93))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (89, 93))	('BRAF', 'Gene', '673', (0, 4))	('found', 'Reg', (34, 39))	('BRAF', 'Gene', (0, 4))
124841	12778069	The majority of the mutations were a single T A base substitution at nucleotide 1796 in exon 15 of the BRAF gene, and in some of the adjacent codons.	('mutations', 'Var', (20, 29))	('BRAF', 'Gene', (103, 107))	('BRAF', 'Gene', '673', (103, 107))
124849	12778069	As a positive control, the cutaneous melanoma cell-line SK-MEL-28 DNA was used, that was known to contain the exon 15 T1796A (V599E) mutation (Davies et al, 2002).	('SK-MEL-28', 'CellLine', 'CVCL:0526', (56, 65))	('cutaneous melanoma', 'Disease', (27, 45))	('V599E', 'Mutation', 'p.V599E', (126, 131))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (27, 45))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (27, 45))	('T1796A (V599E', 'Var', (118, 131))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('T1796A', 'Mutation', 'c.1796T>A', (118, 124))
124851	12778069	Particular attention was given to the sequence around the two small regions of the kinase domain of the BRAF molecule located in exons 11 and 15 that contain all of the published mutations.	('BRAF', 'Gene', (104, 108))	('BRAF', 'Gene', '673', (104, 108))	('mutations', 'Var', (179, 188))
124852	12778069	The SK-MEL-28 cell-line exon 15 T1796A (V599E) mutation was detected by sequencing, and the same mutation was also detected in two-thirds of the skin melanoma tumours studied.	('V599E', 'Mutation', 'p.V599E', (40, 45))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('skin melanoma tumours', 'Disease', (145, 166))	('skin melanoma tumours', 'Disease', 'MESH:D012878', (145, 166))	('T1796A', 'Var', (32, 38))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('SK-MEL-28', 'CellLine', 'CVCL:0526', (4, 13))	('T1796A', 'Mutation', 'c.1796T>A', (32, 38))
124853	12778069	This result was expected as Davies et al (2002) had shown that 66% of the malignant melanoma tumours screened had BRAF mutations, and predominantly the T1796A mutation.	('T1796A', 'Mutation', 'c.1796T>A', (152, 158))	('malignant melanoma tumours', 'Disease', (74, 100))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('T1796A', 'Var', (152, 158))	('malignant melanoma tumours', 'Disease', 'MESH:D008545', (74, 100))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('mutations', 'Var', (119, 128))	('malignant melanoma', 'Phenotype', 'HP:0002861', (74, 92))
124858	12778069	All previously reported mutations have been concentrated to these two hotspot regions in the BRAF kinase domain, hence, mutations in different regions of the molecule are unlikely to be able to activate the oncogene in such a strong manner.	('mutations', 'Var', (24, 33))	('BRAF', 'Gene', '673', (93, 97))	('BRAF', 'Gene', (93, 97))
124862	12778069	Epigenetic mechanisms of gene inactivation may play a more important role in this tumour.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))	('gene inactivation', 'Var', (25, 42))	('Epigenetic', 'Var', (0, 10))
124863	12778069	If the RAS/RAF pathway is activated in uveal melanoma, then it is unlikely to be because of activating mutations in RAS or B-RAF, but other members of this pathway have yet to be studied, including A-RAF, C-RAF (RAF1), and GAP1.	('RAF', 'Gene', (11, 14))	('B-RAF', 'Gene', '673', (123, 128))	('RAF1', 'Gene', (212, 216))	('RAF', 'Gene', '22882', (207, 210))	('RAF', 'Gene', '22882', (200, 203))	('mutations', 'Var', (103, 112))	('RAF', 'Gene', (200, 203))	('B-RAF', 'Gene', (123, 128))	('RAF', 'Gene', (207, 210))	('C-RAF', 'Gene', '5894', (205, 210))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('RAS', 'Gene', (116, 119))	('RAF', 'Gene', '22882', (212, 215))	('A-RAF', 'Gene', '369', (198, 203))	('uveal melanoma', 'Disease', 'MESH:C536494', (39, 53))	('RAF', 'Gene', '22882', (125, 128))	('activated', 'PosReg', (26, 35))	('uveal melanoma', 'Disease', (39, 53))	('RAF', 'Gene', (212, 215))	('RAF', 'Gene', '22882', (11, 14))	('C-RAF', 'Gene', (205, 210))	('RAF1', 'Gene', '5894', (212, 216))	('uveal melanoma', 'Phenotype', 'HP:0007716', (39, 53))	('RAF', 'Gene', (125, 128))	('A-RAF', 'Gene', (198, 203))
124914	33336379	For this study, parameters Psi and phi defined the patient field of view and ranged between -30 to +30 degrees with an increment of 3 degrees for both elevation/depression and add-/abduction.	('Psi', 'Disease', 'None', (27, 30))	('depression', 'Disease', (161, 171))	('depression', 'Phenotype', 'HP:0000716', (161, 171))	('Psi', 'Disease', (27, 30))	('patient', 'Species', '9606', (51, 58))	('add-/abduction', 'Var', (176, 190))	('depression', 'Disease', 'MESH:D000275', (161, 171))
124953	33336379	The optic nerve in EOPP TPS is of tube-like shape, and invariant during eye rotation.	('eye rotation', 'Disease', (72, 84))	('eye rotation', 'Disease', 'MESH:D015835', (72, 84))	('EOPP', 'Var', (19, 23))
125116	33172021	Around 80% of UM harbor mutually exclusive GNAQ and GNA11 primary driver mutations, which makes UM genetics radically different from cutaneous and even conjunctival melanomas.	('conjunctival melanomas', 'Disease', (152, 174))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (152, 174))	('GNAQ', 'Gene', (43, 47))	('melanomas', 'Phenotype', 'HP:0002861', (165, 174))	('GNA11', 'Gene', (52, 57))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (152, 173))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('GNAQ', 'Gene', '2776', (43, 47))	('GNA11', 'Gene', '2767', (52, 57))	('mutations', 'Var', (73, 82))
125119	33172021	Despite being of outstanding importance, Galpha11/Q pathway mutations are not sufficient to explain UM dissemination.	('mutations', 'Var', (60, 69))	('Galpha11', 'Gene', (41, 49))	('UM dissemination', 'Disease', (100, 116))	('Galpha11', 'Gene', '2767', (41, 49))
125121	33172021	Of them, BAP1 mutations located in chromosome 3 appear to the most meaningful for the clinician.	('BAP1', 'Gene', (9, 13))	('chromosome', 'cellular_component', 'GO:0005694', ('35', '45'))	('mutations', 'Var', (14, 23))	('BAP1', 'Gene', '8314', (9, 13))
125123	33172021	For unclear reasons, the loss of BAP1 is associated with a poorer UM prognosis.	('loss', 'Var', (25, 29))	('BAP1', 'Gene', '8314', (33, 37))	('BAP1', 'Gene', (33, 37))
125125	33172021	Several chromosomal abnormalities, such as loss of chromosome 3 and 8q gain, are found in high metastatic risk patients.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (8, 33))	('gain', 'PosReg', (71, 75))	('chromosome', 'cellular_component', 'GO:0005694', ('51', '61'))	('loss', 'Var', (43, 47))	('chromosomal abnormalities', 'Disease', (8, 33))	('patients', 'Species', '9606', (111, 119))
125127	33172021	Interestingly, class 1 UM are often associated with SF3B1 and EIF1AX mutations, whereas class 2 are more frequently associated with BAP1 mutations.	('mutations', 'Var', (69, 78))	('BAP1', 'Gene', '8314', (132, 136))	('BAP1', 'Gene', (132, 136))	('SF3B1', 'Gene', (52, 57))	('EIF1AX', 'Gene', '1964', (62, 68))	('EIF1AX', 'Gene', (62, 68))	('associated', 'Reg', (36, 46))	('SF3B1', 'Gene', '23451', (52, 57))	('associated', 'Reg', (116, 126))
125152	33172021	found that CTC detection was associated with lower disease-free survival (DFS) and overall survival (OS).	('lower disease-free', 'Disease', (45, 63))	('CTC detection', 'Var', (11, 24))	('overall survival', 'CPA', (83, 99))	('lower disease-free', 'Disease', 'MESH:D008569', (45, 63))
125153	33172021	Monosomy 3 was found in 23 of 40 (58%) patients and was associated with more advanced TNM stages.	('patients', 'Species', '9606', (39, 47))	('TNM', 'Gene', '10178', (86, 89))	('associated', 'Reg', (56, 66))	('TNM', 'Gene', (86, 89))	('Monosomy 3', 'Var', (0, 10))
125159	33172021	GNAQ and GNA11 are thought to be the driver and highly prevalent mutations in UM.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('GNAQ', 'Gene', (0, 4))	('mutations', 'Var', (65, 74))	('GNA11', 'Gene', '2767', (9, 14))
125160	33172021	investigated GNAQ and GNA11 mutations to detect circulating free nucleic acids.	('GNA11', 'Gene', (22, 27))	('GNA11', 'Gene', '2767', (22, 27))	('GNAQ', 'Gene', (13, 17))	('GNAQ', 'Gene', '2776', (13, 17))	('mutations', 'Var', (28, 37))
125173	33172021	They monitored CTC by using the Cellsearch device and ct-DNA by screening three different GNAQ and GNA11 mutations.	('GNAQ', 'Gene', '2776', (90, 94))	('GNA11', 'Gene', '2767', (99, 104))	('GNA11', 'Gene', (99, 104))	('mutations', 'Var', (105, 114))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('GNAQ', 'Gene', (90, 94))
125175	33172021	MiRNAs can be detected in tissue biopsy samples and many body fluids, and thus, would constitute a relevant cancer biomarker.	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('MiRNAs', 'Var', (0, 6))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
125177	33172021	Growing evidence has incriminated miRNAs as being a significant cancer player by upregulating several oncogenes.	('upregulating', 'PosReg', (81, 93))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('oncogenes', 'Gene', (102, 111))	('miRNAs', 'Var', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
125178	33172021	Stark et al., by collecting serum from 65 consecutive localized and metastatic UM patients, found a panel of 6 miRNAs (miRNA-16, miRNA-145, miRNA-146a, miRNA-204, miRNA-211, and miRNA-363-3p) as being useful for distinguishing benign uveal naevi from UM with a sensitivity and specificity of 93% and 100%, respectively.	('miRNA-16', 'Var', (119, 127))	('miRNA-146a', 'Gene', '406938', (140, 150))	('miRNA-145', 'Gene', (129, 138))	('patients', 'Species', '9606', (82, 90))	('naevi', 'Phenotype', 'HP:0003764', (240, 245))	('miRNA-211', 'Var', (163, 172))	('miRNA-363-3p', 'Var', (178, 190))	('benign uveal naevi', 'Disease', (227, 245))	('miRNA-145', 'Gene', '406937', (129, 138))	('miRNA-204', 'Gene', (152, 161))	('miRNA-204', 'Gene', '406987', (152, 161))	('miRNA-146a', 'Gene', (140, 150))
125182	33172021	found that among 754 mi-RNAs tested, mi-RNA-146a was significantly overexpressed in histological samples, as well as in venous blood of UM patients.	('overexpressed', 'PosReg', (67, 80))	('mi-RNA-146a', 'Var', (37, 48))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('patients', 'Species', '9606', (139, 147))
125183	33172021	Mi-RNA-146a has been previously incriminated in other malignancies, such as papillary thyroid cancer, hepatocellular carcinoma, or leukemia.	('malignancies', 'Disease', (54, 66))	('thyroid cancer', 'Phenotype', 'HP:0002890', (86, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('RNA', 'cellular_component', 'GO:0005562', ('3', '6'))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (102, 126))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (102, 126))	('leukemia', 'Disease', 'MESH:D007938', (131, 139))	('malignancies', 'Disease', 'MESH:D009369', (54, 66))	('Mi-RNA-146a', 'Var', (0, 11))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (76, 100))	('papillary thyroid cancer', 'Disease', (76, 100))	('leukemia', 'Disease', (131, 139))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (76, 100))	('hepatocellular carcinoma', 'Disease', (102, 126))
125184	33172021	Mi-RNA-146a has also been involved in the pigmentation and survival of UM cells.	('involved', 'Reg', (26, 34))	('pigmentation', 'Disease', 'MESH:D010859', (42, 54))	('RNA', 'cellular_component', 'GO:0005562', ('3', '6'))	('pigmentation', 'Disease', (42, 54))	('Mi-RNA-146a', 'Var', (0, 11))	('pigmentation', 'biological_process', 'GO:0043473', ('42', '54'))
125185	33172021	Other mi-RNAs have been incriminated in the metastatic spread of UM: mi-RNA-199a, mi-RNA-34a, mi-RNA-34b, among others.	('mi-RNA-34a', 'Var', (82, 92))	('RNA', 'cellular_component', 'GO:0005562', ('85', '88'))	('metastatic spread', 'CPA', (44, 61))	('RNA', 'cellular_component', 'GO:0005562', ('72', '75'))	('mi-RNA-34b', 'Gene', '407041', (94, 104))	('mi-RNA-34b', 'Gene', (94, 104))	('RNA', 'cellular_component', 'GO:0005562', ('97', '100'))	('mi-RNA-199a', 'Var', (69, 80))
125186	33172021	Mi-RNA-34a is thought to inhibit the oncogene c-Met, and several studies found decreased mi-RNA-34a rates in metastatic UM.	('Mi-RNA-34a', 'Var', (0, 10))	('metastatic UM', 'CPA', (109, 122))	('c-Met', 'Gene', (46, 51))	('decreased', 'NegReg', (79, 88))	('rates', 'MPA', (100, 105))	('RNA', 'cellular_component', 'GO:0005562', ('3', '6'))	('mi-RNA-34a', 'Gene', (89, 99))	('c-Met', 'Gene', '4233', (46, 51))	('inhibit', 'NegReg', (25, 32))	('RNA', 'cellular_component', 'GO:0005562', ('92', '95'))
125187	33172021	Mi-RNA-137 is known to play a role in the cycle cell arrest and downregulates the MITF and c-Met oncogenes.	('downregulates', 'NegReg', (64, 77))	('RNA', 'cellular_component', 'GO:0005562', ('3', '6'))	('MITF', 'Gene', '4286', (82, 86))	('MITF', 'Gene', (82, 86))	('arrest', 'Disease', 'MESH:D006323', (53, 59))	('Mi-RNA-137', 'Var', (0, 10))	('c-Met', 'Gene', (91, 96))	('c-Met', 'Gene', '4233', (91, 96))	('arrest', 'Disease', (53, 59))
125208	33172021	Several large sample-sized cohort studies evidence that antiplatelet medications were associated with a decreased metastatic spread in several cancers, and inversely, high platelet counts were found in disseminated cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('metastatic spread', 'CPA', (114, 131))	('antiplatelet medications', 'Var', (56, 80))	('cancers', 'Disease', 'MESH:D009369', (215, 222))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('cancers', 'Disease', (215, 222))	('decreased', 'NegReg', (104, 113))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('high platelet counts', 'Phenotype', 'HP:0001894', (167, 187))	('cancers', 'Disease', (143, 150))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))
125229	33172021	RB is the result of a mutation of the tumor suppressor gene RB1 located on chromosome 13q.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('RB', 'Gene', '5925', (0, 2))	('mutation', 'Var', (22, 30))	('RB1', 'Gene', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('RB1', 'Gene', '5925', (60, 63))	('RB', 'Gene', '5925', (60, 62))	('tumor suppressor', 'biological_process', 'GO:0051726', ('38', '54'))	('result of', 'Reg', (10, 19))	('chromosome', 'cellular_component', 'GO:0005694', ('75', '85'))
125238	33172021	Secondly, the tissue sample allows the assessment of Rb1 mutational status for prognostic counseling.	('Rb1', 'Gene', (53, 56))	('mutational status', 'Var', (57, 74))	('Rb1', 'Gene', '5925', (53, 56))
125251	33172021	recently demonstrated that circulating plasma DNA was able to assess RB1 mutation status non-invasively without the need for biopsy or enucleation.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('RB1', 'Gene', '5925', (69, 72))	('mutation', 'Var', (73, 81))	('enucleation', 'biological_process', 'GO:0090601', ('135', '146'))	('RB1', 'Gene', (69, 72))
125269	33172021	Unlike UM, conjunctival melanomas disseminate through lymphatics and hematogenous routes, harbor NF1, BRAF, NRAS, and KRAS mutations, and may be treated with targeted therapies and immunotherapies.	('harbor', 'Reg', (90, 96))	('NRAS', 'Gene', (108, 112))	('NF1', 'Gene', (97, 100))	('NF1', 'Gene', '4763', (97, 100))	('BRAF', 'Gene', '673', (102, 106))	('NRAS', 'Gene', '4893', (108, 112))	('KRAS', 'Gene', (118, 122))	('BRAF', 'Gene', (102, 106))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (11, 33))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (11, 32))	('KRAS', 'Gene', '3845', (118, 122))	('conjunctival melanomas', 'Disease', (11, 33))	('melanomas', 'Phenotype', 'HP:0002861', (24, 33))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('mutations', 'Var', (123, 132))
125288	33172021	In addition, EGFR mutation was identified, and targeted therapy was successfully initiated.	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('mutation', 'Var', (18, 26))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))
125308	32581057	Indeed, UM is biologically distinct from cutaneous and mucosal melanoma, as oncogenesis in the latter is spurred by BRAF and NRAS driver mutations that are rare in UM.	('NRAS', 'Gene', (125, 129))	('BRAF', 'Gene', '673', (116, 120))	('NRAS', 'Gene', '4893', (125, 129))	('UM', 'Phenotype', 'HP:0007716', (8, 10))	('mucosal melanoma', 'Disease', (55, 71))	('BRAF', 'Gene', (116, 120))	('mutations', 'Var', (137, 146))	('mucosal melanoma', 'Disease', 'MESH:D008545', (55, 71))	('oncogenesis', 'CPA', (76, 87))	('UM', 'Phenotype', 'HP:0007716', (164, 166))	('oncogenesis', 'biological_process', 'GO:0007048', ('76', '87'))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))
125309	32581057	Activating mutations in G-protein-alpha subunits GNAQ or GNA11 are observed in 83% of cases of primary UM, leading to stimulation of the MAPK and PI3K/Akt pathways.	('PI3K', 'molecular_function', 'GO:0016303', ('146', '150'))	('mutations', 'Var', (11, 20))	('GNA11', 'Gene', (57, 62))	('GNAQ', 'Gene', '2776', (49, 53))	('Akt', 'Gene', '207', (151, 154))	('GNA11', 'Gene', '2767', (57, 62))	('G-protein-alpha', 'Protein', (24, 39))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('primary UM', 'Disease', (95, 105))	('GNAQ', 'Gene', (49, 53))	('MAPK', 'molecular_function', 'GO:0004707', ('137', '141'))	('stimulation', 'PosReg', (118, 129))	('Akt', 'Gene', (151, 154))	('UM', 'Phenotype', 'HP:0007716', (103, 105))
125310	32581057	A phase II randomized clinical trial of selumetinib, a competitive small molecule inhibitor of MEK1/2, or chemotherapy (temozolomide or dacarbazine) demonstrated a median progression-free survival (PFS) of 15.9 weeks with selumetinib compared with 7 weeks with chemotherapy (p<0.001).	('progression-free survival', 'CPA', (171, 196))	('selumetinib', 'Var', (222, 233))	('selumetinib', 'Chemical', 'MESH:C517975', (222, 233))	('dacarbazine', 'Chemical', 'MESH:D003606', (136, 147))	('temozolomide', 'Chemical', 'MESH:D000077204', (120, 132))	('MEK1', 'molecular_function', 'GO:0004708', ('95', '99'))	('MEK1/2', 'Gene', '5604;5605', (95, 101))	('selumetinib', 'Chemical', 'MESH:C517975', (40, 51))	('MEK1/2', 'Gene', (95, 101))
125389	32581057	Furthermore, in our cohort, normal LDH was associated with improved OS, as described in patients with metastatic cutaneous melanoma and mUM, though other reports did not note a similar association between LDH and OS in mUM.	('mUM', 'Disease', (136, 139))	('UM', 'Phenotype', 'HP:0007716', (220, 222))	('improved', 'PosReg', (59, 67))	('LDH', 'Gene', (35, 38))	('normal', 'Var', (28, 34))	('patients', 'Species', '9606', (88, 96))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('UM', 'Phenotype', 'HP:0007716', (137, 139))	('cutaneous melanoma', 'Disease', (113, 131))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (113, 131))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (113, 131))
125395	32581057	Known tumor-specific immunogenic factors (ie, tumor mutational burden) as well as organ-specific microenvironment (ie, the relative immunotolerance of the liver) influence the degree of tumor immunogenicity as well as the immune response to the tumor.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('mutational', 'Var', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('immune response', 'CPA', (222, 237))	('influence', 'Reg', (162, 171))	('immune response', 'biological_process', 'GO:0006955', ('222', '237'))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Disease', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
125560	25557502	Rankin et al.16 demonstrated significantly reduced aqueous flare postexperimental paracentesis at 4, 8, and 26 h in eyes treated with prednisolone acetate compared to the untreated contralateral and at 8 and 26 h postparacentesis with 0.1% diclofenac.	('prednisolone acetate', 'Chemical', 'MESH:C009935', (134, 154))	('diclofenac', 'Chemical', 'MESH:D004008', (240, 250))	('aqueous flare', 'MPA', (51, 64))	('reduced', 'NegReg', (43, 50))	('prednisolone acetate', 'Var', (134, 154))
125579	31718679	The past decade witnessed an advance in pathophysiology of UM, discovering that exclusive mutations in GNAQ and GNA11 observed in ~ 80% of patients with UM can drive the growth of the primary UM lesions.	('mutations', 'Var', (90, 99))	('growth', 'MPA', (170, 176))	('GNA11', 'Gene', (112, 117))	('GNAQ', 'Gene', '2776', (103, 107))	('drive', 'PosReg', (160, 165))	('patients', 'Species', '9606', (139, 147))	('UM', 'Phenotype', 'HP:0007716', (153, 155))	('GNA11', 'Gene', '2767', (112, 117))	('GNAQ', 'Gene', (103, 107))	('UM', 'Phenotype', 'HP:0007716', (192, 194))	('UM', 'Phenotype', 'HP:0007716', (59, 61))
125585	31718679	In the present study, we envisaged that salinomycin might be capable of eradicating CSCs and thereby hampering hepatic metastasis in UM.	('hampering', 'NegReg', (101, 110))	('eradicating CSCs', 'Disease', (72, 88))	('CSCs', 'Disease', (84, 88))	('salinomycin', 'Var', (40, 51))	('hepatic metastasis', 'MPA', (111, 129))	('salinomycin', 'Chemical', 'MESH:C010327', (40, 51))	('UM', 'Phenotype', 'HP:0007716', (133, 135))
125586	31718679	We interrogated this hypothesis and found that salinomycin perturbed traits of CSCs and obviated hepatic metastasis in UM.	('salinomycin', 'Chemical', 'MESH:C010327', (47, 58))	('obviated hepatic metastasis', 'Disease', 'MESH:D009362', (88, 115))	('traits', 'MPA', (69, 75))	('perturbed', 'NegReg', (59, 68))	('salinomycin', 'Var', (47, 58))	('UM', 'Phenotype', 'HP:0007716', (119, 121))	('obviated hepatic metastasis', 'Disease', (88, 115))
125608	31718679	Immunoglobulin G fluorescent-conjugated secondary antibodies anti-mouse (0.5 mug, Cat#: 926-32,210) and anti-rabbit (0.5 mug, Cat#: 926-32,211) were from LI-COR Biotechnology (Nebraska, USA).	('Cat', 'molecular_function', 'GO:0004096', ('82', '85'))	('Cat', 'molecular_function', 'GO:0004096', ('126', '129'))	('mouse', 'Species', '10090', (66, 71))	('0.5', 'Var', (117, 120))	('CO', 'Chemical', 'MESH:D002245', (157, 159))	('0.5', 'Var', (73, 76))	('rabbit', 'Species', '9986', (109, 115))	('Immunoglobulin', 'molecular_function', 'GO:0003823', ('0', '14'))	('mug', 'molecular_function', 'GO:0043739', ('77', '80'))	('anti-mouse', 'Var', (61, 71))	('mug', 'molecular_function', 'GO:0043739', ('121', '124'))
125621	31718679	The relative expression of genes were normalized to GAPDH, by using 2-DeltaDeltaCt method, where DeltaDeltaCt = (Ct target gene - Ct GAPDH) treated cells - (Ct target gene - Ct GAPDH) control cells.	('DeltaDeltaCt', 'Var', (97, 109))	('GAPDH', 'Gene', '2597', (52, 57))	('GAPDH', 'Gene', (52, 57))	('GAPDH', 'Gene', '2597', (177, 182))	('GAPDH', 'Gene', '2597', (133, 138))	('GAPDH', 'Gene', (177, 182))	('GAPDH', 'Gene', (133, 138))
125622	31718679	BIRC5: (F) CATCTCTACATTCAAGAACTGG-3, (R) GGTTAATTCTTCAAACTGCTTC; TWIST1: (F) TAGATGTCATTGTTTCCA GAGAAGG, (R) ATTTCCAAGAAAATCTTTGGCA.	('TWIST1', 'Gene', (65, 71))	('TWIST1', 'Gene', '7291', (65, 71))	('BIRC5', 'Gene', '332', (0, 5))	('BIRC5', 'Gene', (0, 5))	('TAGATGTCATTGTTTCCA', 'Var', (77, 95))
125647	31718679	Meanwhile, UM cells incubated with salinomycin exhibited marked retardation in clonogenicity as measured in agarose-containing culture with IC50 values of 0.67 mumol/L, 0.31 mumol/L, 0.64 mumol/L, 0.56 mumol/L in 92.1, Mel270, Omm1, and Omm2.3 cells, respectively (Fig.	('UM', 'Phenotype', 'HP:0007716', (11, 13))	('salinomycin', 'Var', (35, 46))	('clonogenicity', 'CPA', (79, 92))	('salinomycin', 'Chemical', 'MESH:C010327', (35, 46))	('retardation', 'Disease', (64, 75))	('retardation', 'Disease', 'MESH:D008607', (64, 75))
125657	31718679	As it has been showed that the protein level of Survivin was highly expressed in 92.1 cells and lesser expressed in Mel270 and Omm1 cells, to functionally characterize the role of Survivin in apoptosis of UM cells in response to salinomycin, Mel270 and Omm1 cells were transduced with lentiviral construct encoding human BIRC5 and establish stable clones, and then treated with or without salinomycin for 24 h. The transfection efficiency of Mel270, Omm1 and 92.1 cells was 80.0%, 87.0% and 89.6%, respectively (Additional file 1: Figure S1A and B).	('Mel270', 'Var', (442, 448))	('human', 'Species', '9606', (315, 320))	('apoptosis', 'biological_process', 'GO:0097194', ('192', '201'))	('BIRC5', 'Gene', '332', (321, 326))	('BIRC5', 'Gene', (321, 326))	('salinomycin', 'Chemical', 'MESH:C010327', (389, 400))	('UM', 'Phenotype', 'HP:0007716', (205, 207))	('apoptosis', 'biological_process', 'GO:0006915', ('192', '201'))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('salinomycin', 'Chemical', 'MESH:C010327', (229, 240))	('transfection', 'CPA', (415, 427))
125659	31718679	3b), but enhanced by knockdown of Survivin-shRNA as reflected by the cell death assayed by trypan blue exclusion and the specific cleavage of PARP in 92.1 cells (Fig.	('cell death', 'biological_process', 'GO:0008219', ('69', '79'))	('Survivin-shRNA', 'Gene', (34, 48))	('PARP', 'Gene', '142', (142, 146))	('trypan blue', 'Chemical', 'MESH:D014343', (91, 102))	('PARP', 'Gene', (142, 146))	('knockdown', 'Var', (21, 30))	('enhanced', 'PosReg', (9, 17))
125678	31718679	These experimental results support the notion that salinomycin can markedly abrogate the hepatic metastasis of UM cells in vivo.	('abrogate', 'NegReg', (76, 84))	('UM', 'Phenotype', 'HP:0007716', (111, 113))	('salinomycin', 'Var', (51, 62))	('salinomycin', 'Chemical', 'MESH:C010327', (51, 62))	('hepatic metastasis', 'MPA', (89, 107))
125680	31718679	The results showed that not only the size and number of melanospheres but also the re-plating capacity were significantly diminished in the salinomycin-treated UM cells (Fig.	('salinomycin', 'Chemical', 'MESH:C010327', (140, 151))	('diminished', 'NegReg', (122, 132))	('UM', 'Phenotype', 'HP:0007716', (160, 162))	('salinomycin-treated', 'Var', (140, 159))	('re-plating capacity', 'CPA', (83, 102))
125692	31718679	Ectopic expression of Twist1 attenuated the salinomycin-induced reduction in Aldefluor+ cells percentage and serial melanosphere formation capacity (Fig.	('salinomycin', 'Chemical', 'MESH:C010327', (44, 55))	('formation', 'biological_process', 'GO:0009058', ('129', '138'))	('Ectopic expression', 'Var', (0, 18))	('attenuated', 'NegReg', (29, 39))	('reduction', 'NegReg', (64, 73))	('serial melanosphere formation capacity', 'CPA', (109, 147))	('Twist1', 'Gene', (22, 28))	('Aldefluor', 'Chemical', 'None', (77, 86))	('Aldefluor+ cells percentage', 'MPA', (77, 104))
125694	31718679	Silencing Twist1 by lentiviral shRNA potentiated the salinomycin-induced reduction in Aldefluor+ cells percentage and serial melanosphere formation capacity (Fig.	('salinomycin-induced', 'MPA', (53, 72))	('Twist1', 'Gene', (10, 16))	('serial melanosphere formation capacity', 'CPA', (118, 156))	('potentiated', 'PosReg', (37, 48))	('Aldefluor+ cells percentage', 'MPA', (86, 113))	('Aldefluor', 'Chemical', 'None', (86, 95))	('formation', 'biological_process', 'GO:0009058', ('138', '147'))	('salinomycin', 'Chemical', 'MESH:C010327', (53, 64))	('Silencing', 'Var', (0, 9))	('reduction', 'NegReg', (73, 82))
125695	31718679	Given that Twist1 can promote invasive properties of cancer cells, we next examined the role of Twist1 in salinomycin-mediated blockage in migration and invasion.	('promote', 'PosReg', (22, 29))	('salinomycin', 'Chemical', 'MESH:C010327', (106, 117))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Twist1', 'Var', (11, 17))
125696	31718679	Furthermore, the salinomycin-attenuated migration and invasion was considerably reversed by forced expression of Twist1, but potentiated by knockdown of Twsit1 by shRNA (Fig.	('potentiated', 'PosReg', (125, 136))	('salinomycin', 'Chemical', 'MESH:C010327', (17, 28))	('Twsit1', 'Gene', (153, 159))	('migration', 'CPA', (40, 49))	('Twist1', 'Gene', (113, 119))	('knockdown', 'Var', (140, 149))
125722	31718679	Our results shed light on the molecular mechanism of antineoplastic activity of salinomycin and demonstrated that salinomycin may be a potential agent to eliminate UM CSCs and to impede hepatic metastasis in UM.	('hepatic metastasis', 'MPA', (186, 204))	('impede', 'NegReg', (179, 185))	('UM', 'Phenotype', 'HP:0007716', (208, 210))	('UM CSCs', 'Disease', (164, 171))	('salinomycin', 'Var', (114, 125))	('salinomycin', 'Chemical', 'MESH:C010327', (80, 91))	('salinomycin', 'Chemical', 'MESH:C010327', (114, 125))	('UM', 'Phenotype', 'HP:0007716', (164, 166))	('eliminate', 'NegReg', (154, 163))
125771	31749765	Similarly, QUICKI showed a negative correlation with a BMI both in the melanoma (r = -0.39, p < 0.001) and in the control group (r = -0.28, p < 0.001).	('negative', 'NegReg', (27, 35))	('QUICKI', 'Var', (11, 17))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))
125775	31749765	In the whole population, QUICKI resulted to be inversely correlated with insulinemia (r = -0.76, p < 0.0001), weight (r = -0.31, p < 0.0001), but not with glycaemia (r = -0.07, P = 0.25), sex (chi2 test, p = 0.63), age (r = 0.03, p = 0.60), and height (r = -0.06, p = 0.36).	('glycaemia', 'Disease', (155, 164))	('QUICKI', 'Var', (25, 31))	('weight', 'MPA', (110, 116))	('correlated', 'Interaction', (57, 67))	('glycaemia', 'Disease', 'None', (155, 164))	('insulinemia', 'Disease', 'None', (73, 84))	('insulinemia', 'Disease', (73, 84))
125793	31749765	Similarly, QUICKY values were strongly inversely correlated with insulinaemia (r = -0.76, p < 0.0001) and weight (r = -0.31, p < 0.0001), but not with the other variables considered.	('inversely', 'NegReg', (39, 48))	('insulinaemia', 'Disease', 'None', (65, 77))	('QUICKY', 'Var', (11, 17))	('correlated', 'Interaction', (49, 59))	('weight', 'Disease', (106, 112))	('insulinaemia', 'Disease', (65, 77))
125806	31749765	Alternatively, unbalances of the insulin/IGF-1/IGF-2 signaling pathways might be more important for the progression of the disease in its later stages.	('unbalances', 'Var', (15, 25))	('insulin', 'Gene', (33, 40))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('important', 'Reg', (86, 95))	('insulin', 'Gene', '3630', (33, 40))	('insulin', 'molecular_function', 'GO:0016088', ('33', '40'))	('IGF-1', 'Gene', '3479', (41, 46))	('IGF-2', 'Gene', (47, 52))	('IGF-1', 'Gene', (41, 46))	('IGF-2', 'Gene', '3481', (47, 52))
125835	30669483	In this study, the chemosensitivity of human mesothelioma cell lines carrying BAP1 wild-type (WT), mutant and silenced was analysed.	('mesothelioma', 'Disease', (45, 57))	('mesothelioma', 'Disease', 'MESH:D008654', (45, 57))	('mutant', 'Var', (99, 105))	('human', 'Species', '9606', (39, 44))	('BAP1', 'Gene', (78, 82))
125836	30669483	The BAP1 mutant cells were significantly less sensitive than BAP1 WT cell lines to the clinically relevant drug gemcitabine.	('gemcitabine', 'Chemical', 'MESH:C056507', (112, 123))	('BAP1', 'Gene', (4, 8))	('mutant', 'Var', (9, 15))	('less', 'NegReg', (41, 45))	('sensitive', 'MPA', (46, 55))
125837	30669483	Silencing of BAP1 significantly increased resistance of MMe cells to gemcitabine.	('BAP1', 'Gene', (13, 17))	('gemcitabine', 'Chemical', 'MESH:C056507', (69, 80))	('resistance', 'MPA', (42, 52))	('increased', 'PosReg', (32, 41))	('Silencing', 'Var', (0, 9))
125838	30669483	Cell cycle analysis suggested that gemcitabine induced Sub-G1 phase accumulation of the BAP1 WT cells and increased in the S-phase in both BAP1 WT and mutant cells.	('G1 phase', 'biological_process', 'GO:0051318', ('59', '67'))	('accumulation', 'PosReg', (68, 80))	('S-phase', 'MPA', (123, 130))	('mutant', 'Var', (151, 157))	('gemcitabine', 'Chemical', 'MESH:C056507', (35, 46))	('S-phase', 'biological_process', 'GO:0051320', ('123', '130'))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('increased', 'PosReg', (106, 115))	('Sub-G1 phase', 'CPA', (55, 67))
125839	30669483	Analysis of the role of BAP1 in apoptosis suggested that gemcitabine induced early apoptosis in both BAP1 WT and BAP1 mutant cells but with a much higher degree in the WT cells.	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('apoptosis', 'biological_process', 'GO:0097194', ('32', '41'))	('apoptosis', 'biological_process', 'GO:0006915', ('32', '41'))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('mutant', 'Var', (118, 124))	('BAP1', 'Gene', (101, 105))	('gemcitabine', 'Chemical', 'MESH:C056507', (57, 68))	('BAP1', 'Gene', (113, 117))
125841	30669483	Significantly decreased DNA damage in the form of double-strand breaks was observed in gemcitabine-treated BAP1 mutant cells, compared to BAP1 WT cells under the same conditions.	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('decreased', 'NegReg', (14, 23))	('BAP1', 'Gene', (107, 111))	('double-strand breaks', 'MPA', (50, 70))	('gemcitabine', 'Chemical', 'MESH:C056507', (87, 98))	('DNA damage', 'MPA', (24, 34))	('mutant', 'Var', (112, 118))
125848	30669483	Among the latest advances towards better understanding of this tumour, the discovery of BAP1 gene mutations in MMe cells is one of the most intriguing due to potential translational implications.	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (98, 107))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('BAP1', 'Gene', (88, 92))	('tumour', 'Disease', (63, 69))
125851	30669483	Knockout of BAP1 in HeLa cervical cancer and renal cancer cells exposed to ionising radiation resulted in increased cell death.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('renal cancer', 'Disease', (45, 57))	('cell death', 'CPA', (116, 126))	('cell death', 'biological_process', 'GO:0008219', ('116', '126'))	('renal cancer', 'Phenotype', 'HP:0009726', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('renal cancer', 'Disease', 'MESH:D007680', (45, 57))	('Knockout', 'Var', (0, 8))	('HeLa cervical cancer', 'Disease', (20, 40))	('HeLa cervical cancer', 'Disease', 'MESH:D002583', (20, 40))	('BAP1', 'Gene', (12, 16))
125853	30669483	Loss of BAP1 due to mutations and deletions has been reported in various cancers including lung, renal, breast, uveal melanoma, and MMe.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('lung', 'Disease', (91, 95))	('cancers', 'Disease', (73, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (112, 126))	('breast', 'Disease', (104, 110))	('deletions', 'Var', (34, 43))	('MMe', 'Disease', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Loss', 'NegReg', (0, 4))	('uveal melanoma', 'Disease', (112, 126))	('renal', 'Disease', (97, 102))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (112, 126))	('BAP1', 'Gene', (8, 12))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('mutations', 'Var', (20, 29))
125854	30669483	reported somatic BAP1 mutations in malignant pleural mesothelioma and Testa et al also found MMe patients with germline BAP1 mutations in the same year.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (45, 65))	('malignant pleural mesothelioma', 'Disease', (35, 65))	('mutations', 'Var', (22, 31))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (35, 65))	('BAP1', 'Gene', (17, 21))	('patients', 'Species', '9606', (97, 105))
125856	30669483	BAP1 mutations are associated with worse prognosis in uveal and cutaneous melanoma and renal cell carcinoma whereas they mark better outcomes for MMe patients.	('cutaneous melanoma and renal cell carcinoma', 'Disease', 'MESH:C538614', (64, 107))	('BAP1', 'Gene', (0, 4))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (87, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('patients', 'Species', '9606', (150, 158))	('uveal', 'Disease', (54, 59))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (64, 82))
125857	30669483	The findings of this research are of high significance for clinical practice as they could be used to stratify MMe patients prior to treatment and avoid the use of a toxic drug as second line therapy that is unlikely to be effective in BAP1 mutant patients.	('patients', 'Species', '9606', (115, 123))	('mutant', 'Var', (241, 247))	('MMe', 'Disease', (111, 114))	('patients', 'Species', '9606', (248, 256))	('BAP1', 'Gene', (236, 240))
125858	30669483	Here, evidence has been provided that supports the view that BAP1 inactivation in MMe cells confers resistance to gemcitabine and provides further insight into the role of BAP1 in the cell cycle, cell death and DNA repair mechanisms in MMe cells.	('BAP1', 'Gene', (61, 65))	('DNA', 'cellular_component', 'GO:0005574', ('211', '214'))	('resistance to gemcitabine', 'MPA', (100, 125))	('gemcitabine', 'Chemical', 'MESH:C056507', (114, 125))	('inactivation', 'Var', (66, 78))	('cell cycle', 'biological_process', 'GO:0007049', ('184', '194'))	('DNA repair', 'biological_process', 'GO:0006281', ('211', '221'))	('cell death', 'biological_process', 'GO:0008219', ('196', '206'))
125862	30669483	Silencing of BAP1 expression in BAP1 WT PPM-Mill and REN cells:demonstrated using Western blot analysis and qRT-PCR (Figure 1B):led to a significant reduction in sensitivity to gemcitabine (Figure 1C).	('BAP1', 'Gene', (13, 17))	('sensitivity to gemcitabine', 'MPA', (162, 188))	('reduction', 'NegReg', (149, 158))	('REN', 'Gene', (53, 56))	('gemcitabine', 'Chemical', 'MESH:C056507', (177, 188))	('Silencing', 'Var', (0, 9))	('REN', 'Gene', '5972', (53, 56))
125865	30669483	Results demonstrated a significant increase of the percentage of cells in the Sub-G1 phase after gemcitabine treatment for PPM-Mill (Figure 2A) and REN (Figure 2B) cell lines (BAP1 WT) to a greater level than in Phi (Figure 2C) and Rob (Figure 2D) cells (BAP1 mutant) (Figure 2, compare Sub-G1 phase cell populations).	('G1 phase', 'biological_process', 'GO:0051318', ('291', '299'))	('increase', 'PosReg', (35, 43))	('cells in the Sub-G1 phase', 'CPA', (65, 90))	('REN', 'Gene', (148, 151))	('G1 phase', 'biological_process', 'GO:0051318', ('82', '90'))	('Phi', 'Gene', '2821', (212, 215))	('Phi', 'Gene', (212, 215))	('gemcitabine', 'Chemical', 'MESH:C056507', (97, 108))	('REN', 'Gene', '5972', (148, 151))	('PPM-Mill', 'Var', (123, 131))
125872	30669483	Late apoptotic cell population significantly increased by approximately 6-fold in PPM-Mill cells and 2-fold in REN cells, whereas there was no significant increase in Phi and Rob cell lines (Figure 3A,B, compared to Figure 3C,D).	('increased', 'PosReg', (45, 54))	('REN', 'Gene', (111, 114))	('Phi', 'Gene', (167, 170))	('Phi', 'Gene', '2821', (167, 170))	('REN', 'Gene', '5972', (111, 114))	('Late apoptotic cell population', 'CPA', (0, 30))	('PPM-Mill', 'Var', (82, 90))
125874	30669483	DNA damage was assessed in BAP1 WT (Figure 4A,B) and BAP1 mutated cell lines (Figure 4C,D) treated with gemcitabine (0.1 microM) for 24 h. Increased DNA double-strand breaks and gamma-Eta2Alpha.Chi phosphorylation were evident in gemcitabine-treated compared to non-treated PPM-Mill cells, whereas no ATM phosphorylation was detected in these cells under the same conditions.	('ATM', 'Gene', (301, 304))	('gemcitabine', 'Chemical', 'MESH:C056507', (230, 241))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('phosphorylation', 'biological_process', 'GO:0016310', ('198', '213'))	('gemcitabine-treated', 'Var', (230, 249))	('gemcitabine', 'Chemical', 'MESH:C056507', (104, 115))	('ATM', 'Gene', '472', (301, 304))	('phosphorylation', 'biological_process', 'GO:0016310', ('305', '320'))	('gamma-Eta2Alpha.Chi phosphorylation', 'CPA', (178, 213))	('DNA', 'cellular_component', 'GO:0005574', ('149', '152'))
125878	30669483	Malignant mesothelioma cells with functional BAP1 were more sensitive to gemcitabine treatment compared to cells bearing mutated and non-functional BAP1.	('functional', 'Var', (34, 44))	('BAP1', 'Gene', (45, 49))	('gemcitabine', 'Chemical', 'MESH:C056507', (73, 84))	('Malignant mesothelioma', 'Phenotype', 'HP:0100001', (0, 22))	('Malignant mesothelioma', 'Disease', (0, 22))	('more', 'PosReg', (55, 59))	('Malignant mesothelioma', 'Disease', 'MESH:C562839', (0, 22))	('sensitive to gemcitabine treatment', 'MPA', (60, 94))
125879	30669483	The results obtained from the analysis of cell viability indicate that functional BAP1 results in a better response to gemcitabine, that its status differentially affects the cell cycle progression in gemcitabine-treated versus non-treated cells and that BAP1 inactivation is linked to decreased DNA damage response after gemcitabine treatment.	('gemcitabine', 'Chemical', 'MESH:C056507', (322, 333))	('gemcitabine', 'Chemical', 'MESH:C056507', (119, 130))	('BAP1', 'Gene', (82, 86))	('inactivation', 'Var', (260, 272))	('response to gemcitabine', 'MPA', (107, 130))	('BAP1', 'Gene', (255, 259))	('DNA', 'cellular_component', 'GO:0005574', ('296', '299'))	('better', 'PosReg', (100, 106))	('cell cycle', 'biological_process', 'GO:0007049', ('175', '185'))	('decreased', 'NegReg', (286, 295))	('DNA damage response', 'biological_process', 'GO:0006974', ('296', '315'))	('gemcitabine', 'Chemical', 'MESH:C056507', (201, 212))	('cell cycle progression', 'CPA', (175, 197))	('DNA damage response', 'MPA', (296, 315))	('affects', 'Reg', (163, 170))	('functional', 'Var', (71, 81))	('response to gemcitabine', 'biological_process', 'GO:0036272', ('107', '130'))
125883	30669483	Increased NF-kappaB transcriptional activity and consequent repression of hCNT1 expression in BAP1 defective cells offers a potential explanation of the observed gemcitabine resistance in BAP1 mutant cells.	('transcriptional activity', 'MPA', (20, 44))	('hCNT1', 'Gene', (74, 79))	('NF-kappaB', 'Gene', '4790', (10, 19))	('repression', 'NegReg', (60, 70))	('gemcitabine', 'Chemical', 'MESH:C056507', (162, 173))	('mutant', 'Var', (193, 199))	('Increased', 'PosReg', (0, 9))	('NF-kappaB', 'Gene', (10, 19))	('BAP1', 'Gene', (94, 98))	('hCNT1', 'Gene', '9154', (74, 79))
125887	30669483	In uveal melanoma cells, BAP1 knockdown causes G1 arrest most likely through HCF1-mediated effects that involve histone deubiquitination and effects on E2F1-dependent transcription.	('HCF1', 'Gene', (77, 81))	('E2F1', 'Gene', '1869', (152, 156))	('causes', 'Reg', (40, 46))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('BAP1', 'Gene', (25, 29))	('effects', 'Reg', (141, 148))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('E2F1', 'Gene', (152, 156))	('G1 arrest', 'Disease', (47, 56))	('histone deubiquitination', 'MPA', (112, 136))	('transcription', 'biological_process', 'GO:0006351', ('167', '180'))	('HCF1', 'Gene', '3054', (77, 81))	('histone deubiquitination', 'biological_process', 'GO:0016578', ('112', '136'))	('knockdown', 'Var', (30, 39))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
125891	30669483	In uveal melanoma cells, depletion of BAP1 resulted in a 20-40% reduction in cell cycle progression; however, it seems that this change was of a transient nature.	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('cell cycle', 'biological_process', 'GO:0007049', ('77', '87'))	('BAP1', 'Gene', (38, 42))	('reduction', 'NegReg', (64, 73))	('cell cycle progression', 'CPA', (77, 99))	('depletion', 'Var', (25, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
125896	30669483	It is intriguing therefore to hypothesise that BAP1 could cause cell death through apoptosis, necrosis or necroptosis which needs to be investigated further in order to evaluate potential therapeutic targets involved in this pathway such as RIPK1, which can be inhibited through Necrostatin-1.	('necroptosis', 'biological_process', 'GO:0097528', ('106', '117'))	('necrosis', 'biological_process', 'GO:0008219', ('94', '102'))	('cell death', 'biological_process', 'GO:0008219', ('64', '74'))	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('RIPK1', 'Gene', (241, 246))	('apoptosis', 'CPA', (83, 92))	('necrosis', 'Disease', 'MESH:D009336', (94, 102))	('necrosis', 'biological_process', 'GO:0008220', ('94', '102'))	('RIPK1', 'Gene', '8737', (241, 246))	('BAP1', 'Var', (47, 51))	('necroptosis', 'CPA', (106, 117))	('cell death', 'CPA', (64, 74))	('necrosis', 'Disease', (94, 102))	('necrosis', 'biological_process', 'GO:0070265', ('94', '102'))	('necrosis', 'biological_process', 'GO:0019835', ('94', '102'))	('necrosis', 'biological_process', 'GO:0001906', ('94', '102'))	('cause', 'Reg', (58, 63))	('necroptosis', 'biological_process', 'GO:0070266', ('106', '117'))
125901	30669483	In cholangiocarcinoma, low BAP1 status conferred greater sensitivity to gemcitabine.	('cholangiocarcinoma', 'Disease', (3, 21))	('greater', 'PosReg', (49, 56))	('low', 'Var', (23, 26))	('BAP1', 'Gene', (27, 31))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('gemcitabine', 'Chemical', 'MESH:C056507', (72, 83))	('sensitivity to gemcitabine', 'MPA', (57, 83))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))
125902	30669483	The results presented herein demonstrate that in BAP1 WT cells gemcitabine induced an increase in DNA double strand breaks, whereas in cells with mutant BAP1 gemcitabine did not have the same effect.	('gemcitabine', 'Chemical', 'MESH:C056507', (158, 169))	('increase', 'PosReg', (86, 94))	('gemcitabine', 'Chemical', 'MESH:C056507', (63, 74))	('mutant', 'Var', (146, 152))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('BAP1', 'Gene', (153, 157))	('DNA double strand breaks', 'MPA', (98, 122))
125903	30669483	These differences are potentially due to specific dual role that BAP1 has in mesothelioma compared to other types of cancer, where BAP1 mutations increase predisposition to this cancer, but certain mutations can be associated with longer survival.	('BAP1', 'Gene', (131, 135))	('mesothelioma', 'Disease', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('increase', 'PosReg', (146, 154))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('mutations', 'Var', (136, 145))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Disease', (117, 123))
125905	30669483	The augmented resistance of mutated BAP1 cells seems to go against the clinical evidence that patients with MMe carrying BAP1 mutations survive longer.	('augmented', 'PosReg', (4, 13))	('resistance', 'MPA', (14, 24))	('patients', 'Species', '9606', (94, 102))	('BAP1', 'Gene', (121, 125))	('mutations', 'Var', (126, 135))
125907	30669483	The different sensitivity to DNA damage between BAP1 mutant and WT also suggests BAP1 status could be the basis of selection of patients for treatment with poly ADP ribose polymerase (PARP) inhibitors, given that patients with BAP1 mutated or BAP1 WT (less sensitive and more sensitive to DNA damage respectively) are likely to respond differently to this type of inhibitors.	('BAP1', 'Gene', (243, 247))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('PARP', 'Gene', '142', (184, 188))	('mutated', 'Var', (232, 239))	('BAP1', 'Gene', (48, 52))	('poly ADP ribose polymerase', 'Gene', (156, 182))	('BAP1', 'Gene', (227, 231))	('poly ADP ribose polymerase', 'Gene', '142', (156, 182))	('DNA', 'cellular_component', 'GO:0005574', ('289', '292'))	('mutant', 'Var', (53, 59))	('patients', 'Species', '9606', (213, 221))	('patients', 'Species', '9606', (128, 136))	('PARP', 'Gene', (184, 188))
125908	30669483	Finally, it has been already proposed that defective DNA repair leads to chromosomal instability and higher mutational load, which potentially provides a rationale for patient stratification with regard to immunotherapy, according to BAP1 status.	('chromosomal instability', 'MPA', (73, 96))	('leads', 'Reg', (64, 69))	('higher', 'PosReg', (101, 107))	('patient', 'Species', '9606', (168, 175))	('chromosomal instability', 'Phenotype', 'HP:0040012', (73, 96))	('DNA repair', 'Protein', (53, 63))	('DNA repair', 'biological_process', 'GO:0006281', ('53', '63'))	('mutational load', 'MPA', (108, 123))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('defective', 'Var', (43, 52))
125948	29281872	However, PD-1 inhibitors have not been demonstrated to improve the survival of patients with uveal melanoma, and previous studies reported a median progression-free survival (PFS) and overall response rate of only 3 months and 3.6%, respectively.	('uveal melanoma', 'Phenotype', 'HP:0007716', (93, 107))	('uveal melanoma', 'Disease', 'MESH:C536494', (93, 107))	('uveal melanoma', 'Disease', (93, 107))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('patients', 'Species', '9606', (79, 87))	('inhibitors', 'Var', (14, 24))	('PD-1', 'Gene', (9, 13))	('PD-1', 'Gene', '5133', (9, 13))
125950	29281872	reported an inactivating somatic mutation of BAP1, the gene encoding BRCA-associated protein 1 (BAP1), in predominantly metastatic uveal melanomas.	('uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))	('inactivating', 'Var', (12, 24))	('BAP1', 'Gene', (45, 49))	('BAP1', 'Gene', (96, 100))	('melanomas', 'Phenotype', 'HP:0002861', (137, 146))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('uveal melanomas', 'Disease', (131, 146))	('uveal melanomas', 'Phenotype', 'HP:0007716', (131, 146))	('BAP1', 'Gene', '8314', (45, 49))	('BAP1', 'Gene', '8314', (96, 100))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))	('uveal melanomas', 'Disease', 'MESH:C536494', (131, 146))
126012	29281872	A forward Cox regression model analysis subsequently identified male sex (HR, 3.79; 95% CI, 1.34 to 10.72; p=0.012), a largest linear metastatic tumor dimension >= 45 mm (HR, 5.48; 95% CI, 1.36 to 22.18; p=0.017), and short RFS (HR, 4.89; 95% CI, 1.38 to 17.29; p=0.014) as significantly poor prognostic factors for survival after recurrence.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('Cox', 'Gene', '1351', (10, 13))	('Cox', 'Gene', (10, 13))	('short RFS', 'Var', (218, 227))	('tumor', 'Disease', (145, 150))
126024	29281872	reported an inactivating somatic mutation in BAP1, located on chromosome 3p21.1, in 47% of all uveal melanomas; 96% of tumors harboring this mutation later metastasized.	('melanomas', 'Phenotype', 'HP:0002861', (101, 110))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('uveal melanomas', 'Disease', (95, 110))	('uveal melanomas', 'Phenotype', 'HP:0007716', (95, 110))	('inactivating', 'Reg', (12, 24))	('mutation', 'Var', (33, 41))	('BAP1', 'Gene', (45, 49))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('chromosome', 'cellular_component', 'GO:0005694', ('62', '72'))	('uveal melanomas', 'Disease', 'MESH:C536494', (95, 110))	('uveal melanoma', 'Phenotype', 'HP:0007716', (95, 109))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('BAP1', 'Gene', '8314', (45, 49))
126025	29281872	confirmed that this somatic BAP1 mutation correlated strongly with BAP1 expression, and reported an eight-fold increase in the risk of metastasis among patients with BAP1-negative or mutated BAP1-expressing uveal melanoma.	('BAP1', 'Gene', '8314', (28, 32))	('metastasis', 'CPA', (135, 145))	('increase', 'PosReg', (111, 119))	('mutation', 'Var', (33, 41))	('mutated', 'Var', (183, 190))	('uveal melanoma', 'Phenotype', 'HP:0007716', (207, 221))	('BAP1', 'Gene', '8314', (166, 170))	('BAP1', 'Gene', (28, 32))	('BAP1', 'Gene', '8314', (191, 195))	('uveal melanoma', 'Disease', 'MESH:C536494', (207, 221))	('expression', 'MPA', (72, 82))	('uveal melanoma', 'Disease', (207, 221))	('BAP1', 'Gene', '8314', (67, 71))	('BAP1', 'Gene', (191, 195))	('BAP1', 'Gene', (166, 170))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('patients', 'Species', '9606', (152, 160))	('BAP1', 'Gene', (67, 71))
126058	29281872	First, we did not conduct gene expression profiling or a full analysis of mutations in genes such as GNAQ, GNA11, or BAP1, which are known poor prognosticators in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (163, 177))	('uveal melanoma', 'Disease', 'MESH:C536494', (163, 177))	('BAP1', 'Gene', '8314', (117, 121))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('mutations', 'Var', (74, 83))	('uveal melanoma', 'Disease', (163, 177))	('GNAQ', 'Gene', '2776', (101, 105))	('gene expression', 'biological_process', 'GO:0010467', ('26', '41'))	('BAP1', 'Gene', (117, 121))	('GNA11', 'Gene', '2767', (107, 112))	('GNA11', 'Gene', (107, 112))	('GNAQ', 'Gene', (101, 105))
126063	29281872	These inter-study discrepancies suggest that we should validate our findings using a BAP1 mutation analysis.	('BAP1', 'Gene', (85, 89))	('mutation', 'Var', (90, 98))	('BAP1', 'Gene', '8314', (85, 89))
126235	28395880	These tumors originate within the pigmented uveal tract (which include the choroid, ciliary body, and iris) and are notable for characteristic cytogenetic changes, oncogenic mutations in GNAQ or GNA11, and an unusual predilection to aggressively metastasize to the liver resulting in a dismal prognosis.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('GNA11', 'Gene', '2767', (195, 200))	('tumors originate within the pigmented uveal tract', 'Disease', 'MESH:D001929', (6, 55))	('GNA11', 'Gene', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('mutations', 'Var', (174, 183))	('GNAQ', 'Gene', (187, 191))	('tumors originate within the pigmented uveal tract', 'Disease', (6, 55))
126250	28395880	One enrolled patient was confirmed after treatment to have had ocular melanoma arising from the conjunctiva based upon ophthalmologic history and whole exomic mutational sequencing of a metastatic tumor which revealed the presence of a characteristic NRAS driver mutation.	('mutation', 'Var', (263, 271))	('ocular melanoma', 'Disease', 'MESH:D008545', (63, 78))	('ocular melanoma', 'Disease', (63, 78))	('patient', 'Species', '9606', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('melanoma arising from the conjunctiva', 'Phenotype', 'HP:0500040', (70, 107))	('ocular melanoma', 'Phenotype', 'HP:0007716', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('NRAS', 'Gene', (251, 255))	('tumor', 'Disease', (197, 202))	('NRAS', 'Gene', '4893', (251, 255))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
126270	28395880	Patients experiencing sustained stable disease (>4 months), partial or complete response could receive a maximum of one additional TIL re-treatment when progression by RECIST criteria was documented after evaluation by the principal investigator.	('Patients', 'Species', '9606', (0, 8))	('sustained stable disease', 'Disease', 'MESH:D060050', (22, 46))	('partial', 'Var', (60, 67))	('sustained stable disease', 'Disease', (22, 46))
126272	28395880	For immunologic correlation studies, cryopreserved samples of the TIL infusion products underwent flow cytometric phenotyping with anti-human CD3, CD8, CD4, CD45RO, and CD62L monoclonal antibodies.	('human', 'Species', '9606', (136, 141))	('CD4', 'Gene', (157, 160))	('CD4', 'Gene', '920', (157, 160))	('CD45', 'Gene', '5788', (157, 161))	('CD8', 'Gene', (147, 150))	('CD62L', 'Gene', '6402', (169, 174))	('CD', 'Disease', 'MESH:D006223', (142, 144))	('CD', 'Disease', 'MESH:D006223', (157, 159))	('CD', 'Disease', 'MESH:D006223', (147, 149))	('CD4', 'Gene', (152, 155))	('CD8', 'Gene', '925', (147, 150))	('CD4', 'Gene', '920', (152, 155))	('anti-human', 'Var', (131, 141))	('CD', 'Disease', 'MESH:D006223', (152, 154))	('CD62L', 'Gene', (169, 174))	('CD45', 'Gene', (157, 161))	('CD', 'Disease', 'MESH:D006223', (169, 171))
126304	28395880	Driver mutational analysis performed on the resected metastases revealed somatic mutations in either GNAQ or GNA11 in 19 of the patients (90%), consistent with the frequencies of these mutations reported in primary uveal tumors.	('metastases', 'Disease', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('GNA11', 'Gene', (109, 114))	('GNA11', 'Gene', '2767', (109, 114))	('metastases', 'Disease', 'MESH:D009362', (53, 63))	('mutations', 'Var', (81, 90))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('patients', 'Species', '9606', (128, 136))	('GNAQ', 'Gene', (101, 105))	('uveal tumors', 'Disease', (215, 227))	('uveal tumors', 'Disease', 'MESH:D014604', (215, 227))
126305	28395880	Mutations of the tumor suppressor gene, BAP-1, which have been associated with early and aggressive metastasis, were found in 8 of the enrolled patients (38%; Appendix p.3).	('tumor suppressor', 'biological_process', 'GO:0051726', ('17', '33'))	('tumor', 'Disease', (17, 22))	('aggressive metastasis', 'CPA', (89, 110))	('BAP-1', 'Gene', '8314', (40, 45))	('associated', 'Reg', (63, 73))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('17', '33'))	('patients', 'Species', '9606', (144, 152))	('Mutations', 'Var', (0, 9))	('BAP-1', 'Gene', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('found', 'Reg', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
126306	28395880	Interestingly, the metastatic tumor from one patient did not express GNAQ, GNA11, or BAP-1 mutations, but instead harbored an NRAS (c.182A>G, p.Gln61Arg) mutation.	('p.Gln61Arg', 'Var', (142, 152))	('GNA11', 'Gene', '2767', (75, 80))	('GNA11', 'Gene', (75, 80))	('c.182A>G', 'Mutation', 'rs11554290', (132, 140))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('BAP-1', 'Gene', '8314', (85, 90))	('patient', 'Species', '9606', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('NRAS', 'Gene', (126, 130))	('p.Gln61Arg', 'Mutation', 'rs11554290', (142, 152))	('BAP-1', 'Gene', (85, 90))	('tumor', 'Disease', (30, 35))	('NRAS', 'Gene', '4893', (126, 130))
126307	28395880	Whole exomic sequencing performed upon this metastasis did confirm the additional presence of an SF3B1 mutation (c.1874G>A, p.Arg625His), strongly supporting its uveal origin.	('p.Arg625His', 'Mutation', 'rs1057519961', (124, 135))	('SF3B1', 'Gene', '23451', (97, 102))	('c.1874G>A', 'Mutation', 'rs1057519961', (113, 122))	('p.Arg625His', 'Var', (124, 135))	('c.1874G>A', 'Var', (113, 122))	('SF3B1', 'Gene', (97, 102))
126361	28395880	By clinically augmenting pre-existing anti-tumor T cell responses with either systemic cytokine, antibodies blocking checkpoint molecules, or adoptive transfer of autologous TIL, significant and potentially curative cancer regression can now be achieved in cutaneous melanoma patients.	('cutaneous melanoma', 'Disease', (257, 275))	('patients', 'Species', '9606', (276, 284))	('augmenting', 'PosReg', (14, 24))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (257, 275))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (257, 275))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('pre', 'molecular_function', 'GO:0003904', ('25', '28'))	('tumor', 'Disease', (43, 48))	('antibodies', 'Var', (97, 107))
126365	28395880	Another theory proposes that since sun-shielded ocular melanomas have far fewer somatic mutations compared to sun-exposed cutaneous melanomas, there are consequentially fewer potential mutated neo-epitope targets for effective anti-tumor immunity.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanomas', 'Phenotype', 'HP:0002861', (55, 64))	('ocular melanomas', 'Disease', 'MESH:D008545', (48, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (122, 140))	('melanomas', 'Phenotype', 'HP:0002861', (132, 141))	('fewer', 'NegReg', (169, 174))	('cutaneous melanomas', 'Disease', (122, 141))	('mutations', 'Var', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('fewer', 'NegReg', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('ocular melanomas', 'Disease', (48, 64))	('ocular melanoma', 'Phenotype', 'HP:0007716', (48, 63))	('ocular melanomas', 'Phenotype', 'HP:0025534', (48, 64))	('tumor', 'Disease', (232, 237))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (122, 141))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (122, 141))
126380	28395880	The combinations of these actions may explain how the transfer of TIL in the current study could induce tumor regression when prior immunotherapies were ineffective.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('transfer', 'Var', (54, 62))	('tumor', 'Disease', (104, 109))	('induce', 'Reg', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
126391	28395880	Although we observed that four of the seven clinical responders in this trial carried mutations of the BAP-1 tumor suppressor gene, more extensive correlative studies with other poor prognostic attributes such as size and location of the primary uveal tumor, gene expression profile (GEP) class, and clinical symptoms upon initial metastatic diagnosis were not evaluated in this pilot study.	('mutations', 'Var', (86, 95))	('tumor suppressor', 'biological_process', 'GO:0051726', ('109', '125'))	('BAP-1', 'Gene', (103, 108))	('uveal tumor', 'Disease', (246, 257))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('109', '125'))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('BAP-1', 'Gene', '8314', (103, 108))	('gene expression', 'biological_process', 'GO:0010467', ('259', '274'))	('tumor', 'Disease', (252, 257))	('uveal tumor', 'Disease', 'MESH:D014604', (246, 257))	('tumor', 'Disease', (109, 114))
126396	28395880	These findings provide compelling evidence that tumor specific mutations can generate neo-epitopes that elicit robust autologous immunologic responses in cutaneous melanoma patients.	('mutations', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('patients', 'Species', '9606', (173, 181))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('elicit', 'Reg', (104, 110))	('neo-epitopes', 'MPA', (86, 98))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cutaneous melanoma', 'Disease', (154, 172))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (154, 172))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (154, 172))
126398	27408703	Recent advances in molecular genetics of melanoma progression: implications for diagnosis and treatment According to the multi-step carcinogenesis model of cancer, initiation results in a benign tumor and subsequent genetic alterations lead to tumor progression and the acquisition of the hallmarks of cancer.	('lead to', 'Reg', (236, 243))	('tumor', 'Disease', (195, 200))	('benign tumor', 'Disease', 'MESH:D009369', (188, 200))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('genetic alterations', 'Var', (216, 235))	('cancer', 'Disease', (302, 308))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('benign tumor', 'Disease', (188, 200))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('multi-step carcinogenesis', 'Disease', 'MESH:D063646', (121, 146))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('multi-step carcinogenesis', 'Disease', (121, 146))	('cancer', 'Disease', (156, 162))	('tumor', 'Disease', (244, 249))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
126401	27408703	BRAF V600E satisfies these criteria in melanocytic neoplasia.	('melanocytic neoplasia', 'Disease', 'MESH:D009369', (39, 60))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('neoplasia', 'Phenotype', 'HP:0002664', (51, 60))	('melanocytic neoplasia', 'Disease', (39, 60))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))
126402	27408703	Studies demonstrate that BRAF mutations are typically present in all or none of the cells within nevi and melanomas , .	('nevi', 'Phenotype', 'HP:0003764', (97, 101))	('melanomas', 'Disease', (106, 115))	('BRAF', 'Gene', '673', (25, 29))	('melanomas', 'Phenotype', 'HP:0002861', (106, 115))	('mutations', 'Var', (30, 39))	('BRAF', 'Gene', (25, 29))	('melanomas', 'Disease', 'MESH:D008545', (106, 115))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
126404	27408703	The set of probable initiating oncogenes in melanocytic tumors includes activating point mutations in BRAF, NRAS, GNAQ, GNA11, and activating fusions of BRAF and the receptor tyrosine kinases (RTKs) ALK, ROS1, RET, MET, and NTRK1.	('fusions', 'Var', (142, 149))	('ROS1', 'Gene', '6098', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('BRAF', 'Gene', (153, 157))	('activating', 'PosReg', (72, 82))	('RET', 'Gene', (210, 213))	('MET', 'Gene', (215, 218))	('BRAF', 'Gene', '673', (102, 106))	('NRAS', 'Gene', '4893', (108, 112))	('BRAF', 'Gene', (102, 106))	('GNA11', 'Gene', '2767', (120, 125))	('point mutations', 'Var', (83, 98))	('ROS1', 'Gene', (204, 208))	('NTRK1', 'Gene', '4914', (224, 229))	('NTRK1', 'Gene', (224, 229))	('activating', 'Reg', (131, 141))	('GNAQ', 'Gene', '2776', (114, 118))	('GNAQ', 'Gene', (114, 118))	('melanocytic tumors', 'Disease', (44, 62))	('NRAS', 'Gene', (108, 112))	('melanocytic tumors', 'Disease', 'MESH:D009508', (44, 62))	('RET', 'Gene', '5979', (210, 213))	('ALK', 'Gene', '238', (199, 202))	('GNA11', 'Gene', (120, 125))	('ALK', 'Gene', (199, 202))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('BRAF', 'Gene', '673', (153, 157))
126405	27408703	These mutations have been identified in benign and malignant melanocytic tumors in a mutually exclusive pattern, e.g.	('malignant melanocytic tumors', 'Disease', (51, 79))	('malignant melanocytic tumors', 'Disease', 'MESH:D018198', (51, 79))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('malignant melanocytic tumors', 'Phenotype', 'HP:0002861', (51, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('identified', 'Reg', (26, 36))	('mutations', 'Var', (6, 15))
126410	27408703	Spitz nevi have the most diverse set of initiating mutations with activating HRAS mutations (22%) and activating fusions of BRAF (7%) and the RTKs ALK (12%), MET (2%), NTRK1 (12%), RET (4%), and ROS1 (25%) - .	('RET', 'Gene', '5979', (181, 184))	('NTRK1', 'Gene', (168, 173))	('nevi', 'Phenotype', 'HP:0003764', (6, 10))	('ROS1', 'Gene', (195, 199))	('ALK', 'Gene', (147, 150))	('fusions', 'Var', (113, 120))	('ROS1', 'Gene', '6098', (195, 199))	('BRAF', 'Gene', '673', (124, 128))	('RET', 'Gene', (181, 184))	('activating', 'PosReg', (66, 76))	('mutations', 'Var', (82, 91))	('HRAS', 'Gene', '3265', (77, 81))	('NTRK1', 'Gene', '4914', (168, 173))	('HRAS', 'Gene', (77, 81))	('BRAF', 'Gene', (124, 128))	('activating', 'Reg', (102, 112))	('ALK', 'Gene', '238', (147, 150))
126417	27408703	Owing to the high number of mutations observed in melanoma, distinguishing driver from passenger events is difficult and requires functional validation.	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('mutations', 'Var', (28, 37))
126419	27408703	First identified in 2012 in familial and sporadic cutaneous melanoma, TERT promoter mutations result in a de novo E26 transformation-specific (ETS) factor binding site and increased TERT expression - .	('increased', 'PosReg', (172, 181))	('E26', 'Var', (114, 117))	('binding', 'molecular_function', 'GO:0005488', ('155', '162'))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('mutations', 'Var', (84, 93))	('cutaneous melanoma', 'Disease', (50, 68))	('TERT', 'Gene', (182, 186))	('TERT', 'Gene', '7015', (182, 186))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (50, 68))	('TERT', 'Gene', (70, 74))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (50, 68))	('TERT', 'Gene', '7015', (70, 74))
126423	27408703	TERT promoter mutations were identified in several "likely benign" intermediate melanocytic tumors and melanomas .	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanocytic tumors', 'Disease', 'MESH:D009508', (80, 98))	('TERT', 'Gene', (0, 4))	('identified', 'Reg', (29, 39))	('TERT', 'Gene', '7015', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('melanomas', 'Disease', (103, 112))	('melanocytic tumors', 'Disease', (80, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('mutations', 'Var', (14, 23))	('melanomas', 'Disease', 'MESH:D008545', (103, 112))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))
126424	27408703	The presence of TERT promoter mutations in combination with either BRAF or NRAS activating mutations in "likely benign" intermediate tumors suggests that these combinations of oncogenic mutations are not sufficient for malignant transformation.	('TERT', 'Gene', (16, 20))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('BRAF', 'Gene', '673', (67, 71))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('TERT', 'Gene', '7015', (16, 20))	('BRAF', 'Gene', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('NRAS', 'Gene', (75, 79))	('mutations', 'Var', (30, 39))	('NRAS', 'Gene', '4893', (75, 79))
126428	27408703	Rather, it appears that the expression of ALK ATI occurs due to epigenetic modification.	('epigenetic modification', 'Var', (64, 87))	('ALK', 'Gene', '238', (42, 45))	('due', 'Reg', (57, 60))	('ATI', 'Chemical', '-', (46, 49))	('ALK', 'Gene', (42, 45))
126430	27408703	While the signaling output of ALK ATI is similar to that of ALK fusions, ALK ATI is seen in melanomas with and without activating BRAF and NRAS mutations, indicating that it is not an initiating event .	('melanomas', 'Disease', (92, 101))	('signaling', 'biological_process', 'GO:0023052', ('10', '19'))	('ALK', 'Gene', (60, 63))	('ALK', 'Gene', (30, 33))	('ALK', 'Gene', (73, 76))	('ALK', 'Gene', '238', (73, 76))	('NRAS', 'Gene', (139, 143))	('BRAF', 'Gene', '673', (130, 134))	('melanomas', 'Phenotype', 'HP:0002861', (92, 101))	('BRAF', 'Gene', (130, 134))	('NRAS', 'Gene', '4893', (139, 143))	('melanomas', 'Disease', 'MESH:D008545', (92, 101))	('ALK', 'Gene', '238', (30, 33))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('ATI', 'Chemical', '-', (77, 80))	('ALK', 'Gene', '238', (60, 63))	('mutations', 'Var', (144, 153))	('ATI', 'Chemical', '-', (34, 37))
126434	27408703	Germline loss-of-function variants increase the risk of melanoma, renal cell carcinoma, mesothelioma, and other cancers , .	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (66, 86))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('mesothelioma', 'Disease', 'MESH:D008654', (88, 100))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (66, 86))	('cancers', 'Disease', (112, 119))	('loss-of-function', 'NegReg', (9, 25))	('mesothelioma', 'Disease', (88, 100))	('renal cell carcinoma', 'Disease', (66, 86))	('variants', 'Var', (26, 34))
126435	27408703	The distinctive cutaneous melanocytic tumors in patients with BAP1 germline mutations are characterized by dermal epithelioid melanocytes with abundant eosinophilic cytoplasm and variably enlarged, pleomorphic, and eccentrically placed nuclei, often in a background of lymphocytic inflammation.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('BAP1', 'Gene', '8314', (62, 66))	('cytoplasm', 'cellular_component', 'GO:0005737', ('165', '174'))	('mutations', 'Var', (76, 85))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('lymphocytic inflammation', 'Disease', 'MESH:D007249', (269, 293))	('BAP1', 'Gene', (62, 66))	('lymphocytic inflammation', 'Disease', (269, 293))	('melanocytic tumors', 'Disease', 'MESH:D009508', (26, 44))	('eccentrically placed nuclei', 'Phenotype', 'HP:0003687', (215, 242))	('inflammation', 'biological_process', 'GO:0006954', ('281', '293'))	('patients', 'Species', '9606', (48, 56))	('melanocytic tumors', 'Disease', (26, 44))
126436	27408703	These neoplasms harbor activating BRAF or NRAS mutations in addition to biallelic loss of BAP1 and an adjacent common acquired nevus is often appreciated , .	('neoplasms', 'Disease', 'MESH:D009369', (6, 15))	('neoplasms', 'Disease', (6, 15))	('NRAS', 'Gene', '4893', (42, 46))	('BAP1', 'Gene', '8314', (90, 94))	('mutations', 'Var', (47, 56))	('BRAF', 'Gene', '673', (34, 38))	('neoplasms', 'Phenotype', 'HP:0002664', (6, 15))	('BAP1', 'Gene', (90, 94))	('loss', 'NegReg', (82, 86))	('nevus', 'Phenotype', 'HP:0003764', (127, 132))	('BRAF', 'Gene', (34, 38))	('NRAS', 'Gene', (42, 46))	('activating', 'PosReg', (23, 33))
126439	27408703	Epithelioid tumors with BAP1 loss (or Wiesner nevi) are distinct from other genetic categories of Spitz nevi in that three oncogenic mutations have occurred (activating BRAF or NRAS mutation and two hits to BAP1) in contrast to Spitz nevi with HRAS mutation or kinase fusions.	('BRAF', 'Gene', (169, 173))	('BRAF', 'Gene', '673', (169, 173))	('HRAS', 'Gene', (244, 248))	('nevi', 'Phenotype', 'HP:0003764', (46, 50))	('loss', 'NegReg', (29, 33))	('BAP1', 'Gene', (207, 211))	('Epithelioid tumors', 'Disease', 'MESH:D012509', (0, 18))	('BAP1', 'Gene', (24, 28))	('activating', 'PosReg', (158, 168))	('NRAS', 'Gene', (177, 181))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('nevi', 'Phenotype', 'HP:0003764', (234, 238))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('Epithelioid tumors', 'Disease', (0, 18))	('nevi', 'Phenotype', 'HP:0003764', (104, 108))	('BAP1', 'Gene', '8314', (207, 211))	('NRAS', 'Gene', '4893', (177, 181))	('mutation', 'Var', (182, 190))	('BAP1', 'Gene', '8314', (24, 28))	('HRAS', 'Gene', '3265', (244, 248))
126444	27408703	Loss of BAP1 is associated with poor prognosis in uveal melanoma .	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('BAP1', 'Gene', '8314', (8, 12))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('uveal melanoma', 'Disease', 'MESH:C536494', (50, 64))	('uveal melanoma', 'Disease', (50, 64))	('BAP1', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))
126447	27408703	Arm-level and whole chromosome gains and losses, as well as focal amplifications and deletions of the genome, are frequent in melanoma and uncommon in nevi.	('gains', 'PosReg', (31, 36))	('chromosome', 'cellular_component', 'GO:0005694', ('20', '30'))	('deletions', 'Var', (85, 94))	('nevi', 'Phenotype', 'HP:0003764', (151, 155))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('losses', 'NegReg', (41, 47))	('melanoma', 'Disease', (126, 134))
126448	27408703	The overrepresentation of specific copy number alterations in melanoma indicates selective advantage for specific CNAs (i.e.	('melanoma', 'Disease', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('copy number alterations', 'Var', (35, 58))
126449	27408703	loss of CDKN2A or amplification of CCND1) and a role in tumor progression.	('CDKN2A', 'Gene', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('CDKN2A', 'Gene', '1029', (8, 14))	('tumor', 'Disease', (56, 61))	('CCND1', 'Gene', '595', (35, 40))	('amplification', 'Var', (18, 31))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('CCND1', 'Gene', (35, 40))	('loss', 'NegReg', (0, 4))
126451	27408703	Not all types of melanoma demonstrate a high frequency of CNAs: for example, desmoplastic melanomas have few CNAs and a high number of single base substitutions .	('melanomas', 'Phenotype', 'HP:0002861', (90, 99))	('melanoma', 'Disease', (90, 98))	('desmoplastic melanomas', 'Disease', 'MESH:D008545', (77, 99))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('single base substitutions', 'Var', (135, 160))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('melanoma', 'Disease', (17, 25))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('desmoplastic melanomas', 'Disease', (77, 99))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
126452	27408703	These events include double-stranded DNA breaks and catastrophic events that lead to complex genomic rearrangements, such as chromothripsis .	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('lead to', 'Reg', (77, 84))	('chromothripsis', 'Disease', (125, 139))	('chromothripsis', 'Disease', 'MESH:D000072837', (125, 139))	('double-stranded', 'Var', (21, 36))
126455	27408703	Monosomy 3 or focal loss including 3p21 is often observed in epithelioid tumors with biallelic loss of BAP1 , .	('BAP1', 'Gene', '8314', (103, 107))	('loss', 'NegReg', (20, 24))	('3p21', 'Protein', (35, 39))	('epithelioid tumors', 'Disease', 'MESH:D012509', (61, 79))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('BAP1', 'Gene', (103, 107))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('epithelioid tumors', 'Disease', (61, 79))	('loss', 'NegReg', (95, 99))	('observed', 'Reg', (49, 57))	('Monosomy 3', 'Var', (0, 10))
126457	27408703	Assessment of copy number status has been used to supplement the histopathologic assessment of diagnostically challenging melanocytic tumors for over a decade.	('copy number status', 'Var', (14, 32))	('melanocytic tumors', 'Disease', (122, 140))	('melanocytic tumors', 'Disease', 'MESH:D009508', (122, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
126459	27408703	Additional FISH probes have been proposed for specific subtypes of melanocytic tumors (9p21 to assess for homozygous CDKN2A deletion in spitzoid tumors and 8q24 MYC gain to improve sensitivity in nevoid melanomas) , .	('gain', 'PosReg', (165, 169))	('spitzoid tumors', 'Disease', (136, 151))	('melanomas', 'Phenotype', 'HP:0002861', (203, 212))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('8q24 MYC', 'Var', (156, 164))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('melanomas', 'Disease', (203, 212))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('deletion', 'Var', (124, 132))	('melanocytic tumors', 'Disease', 'MESH:D009508', (67, 85))	('improve', 'PosReg', (173, 180))	('CDKN2A', 'Gene', (117, 123))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('spitzoid tumors', 'Disease', 'MESH:D009369', (136, 151))	('melanocytic tumors', 'Disease', (67, 85))	('melanomas', 'Disease', 'MESH:D008545', (203, 212))	('CDKN2A', 'Gene', '1029', (117, 123))
126469	27408703	Targeted therapy of BRAF V600E mutant melanoma with inhibitors of mutant BRAF is currently part of the standard of care.	('BRAF', 'Gene', (73, 77))	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('V600E mutant', 'Var', (25, 37))	('BRAF', 'Gene', '673', (73, 77))	('BRAF', 'Gene', '673', (20, 24))	('V600E', 'Mutation', 'rs113488022', (25, 30))	('BRAF', 'Gene', (20, 24))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))
126471	27408703	Approximately 50% of metastatic melanomas harbor a BRAF mutation, ~25% harbor an activating NRAS mutation, and 3-5% harbor an activating KIT mutation.	('melanomas', 'Disease', (32, 41))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('NRAS', 'Gene', (92, 96))	('melanomas', 'Phenotype', 'HP:0002861', (32, 41))	('BRAF', 'Gene', '673', (51, 55))	('metastatic', 'Disease', (21, 31))	('melanomas', 'Disease', 'MESH:D008545', (32, 41))	('NRAS', 'Gene', '4893', (92, 96))	('mutation', 'Var', (97, 105))	('mutation', 'Var', (56, 64))	('BRAF', 'Gene', (51, 55))	('KIT', 'molecular_function', 'GO:0005020', ('137', '140'))	('activating', 'MPA', (81, 91))
126472	27408703	Inhibitors of NRAS are currently unavailable, but initial clinical trials of MEK inhibitors in NRAS mutant melanomas show some efficacy .	('melanomas', 'Disease', 'MESH:D008545', (107, 116))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('NRAS', 'Gene', '4893', (14, 18))	('mutant', 'Var', (100, 106))	('NRAS', 'Gene', (95, 99))	('melanomas', 'Disease', (107, 116))	('MEK', 'Gene', (77, 80))	('MEK', 'Gene', '5609', (77, 80))	('NRAS', 'Gene', (14, 18))	('NRAS', 'Gene', '4893', (95, 99))
126473	27408703	Dramatic responses to KIT inhibitors such as imatinib and nilotinib have been observed in patients with KIT mutant melanoma - .	('imatinib', 'Chemical', 'MESH:D000068877', (45, 53))	('KIT', 'Gene', (104, 107))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('mutant', 'Var', (108, 114))	('nilotinib', 'Chemical', 'MESH:C498826', (58, 67))	('KIT', 'molecular_function', 'GO:0005020', ('22', '25'))	('KIT', 'molecular_function', 'GO:0005020', ('104', '107'))	('patients', 'Species', '9606', (90, 98))
126483	27408703	By broadening the regions of the genome assayed, these panels may detect alterations that are actionable in other cancer types and rare in melanoma.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('detect', 'Reg', (66, 72))	('alterations', 'Var', (73, 84))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
126484	27408703	One can take advantage of the mutual exclusivity of actionable alterations and their prevalence in melanoma to perform stratified testing of a tumor sample.	('alterations', 'Var', (63, 74))	('tumor', 'Disease', (143, 148))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
126485	27408703	Given the high rate of BRAF V600 mutations, V600E-specific testing (immunohistochemistry or real-time based assay) or BRAF exon 15 testing (Sanger) followed by a test for a broader panel of oncogenes (including NRAS and KIT) if a BRAF mutation is not detected could optimize cost and turn-around time for melanoma patients, depending on testing strategies employed.	('BRAF', 'Gene', '673', (118, 122))	('KIT', 'molecular_function', 'GO:0005020', ('220', '223'))	('patients', 'Species', '9606', (314, 322))	('BRAF', 'Gene', '673', (23, 27))	('NRAS', 'Gene', (211, 215))	('BRAF', 'Gene', (118, 122))	('V600E-specific', 'Var', (44, 58))	('V600E', 'Mutation', 'rs113488022', (44, 49))	('BRAF', 'Gene', (23, 27))	('BRAF', 'Gene', '673', (230, 234))	('melanoma', 'Disease', (305, 313))	('NRAS', 'Gene', '4893', (211, 215))	('melanoma', 'Phenotype', 'HP:0002861', (305, 313))	('melanoma', 'Disease', 'MESH:D008545', (305, 313))	('BRAF', 'Gene', (230, 234))	('V600 mutations', 'Var', (28, 42))
126555	24078811	It is now believed that p53 mutation is associated with a high proliferative activity.	('mutation', 'Var', (28, 36))	('p53', 'Gene', '7157', (24, 27))	('p53', 'Gene', (24, 27))
126578	24078811	use prior knowledge from the genomics field and search for monosomy 3 which is significantly associated with hepatic metastasis in UM.	('UM', 'Phenotype', 'HP:0007716', (131, 133))	('hepatic metastasis', 'Disease', (109, 127))	('hepatic metastasis', 'Disease', 'MESH:D009362', (109, 127))	('associated', 'Reg', (93, 103))	('monosomy 3', 'Var', (59, 69))
126588	24078811	), in addition to monosomy of chromosome 3 that is associated with a decreased survival due to hepatic metastasis.	('chromosome', 'cellular_component', 'GO:0005694', ('30', '40'))	('hepatic metastasis', 'Disease', (95, 113))	('decreased', 'NegReg', (69, 78))	('hepatic metastasis', 'Disease', 'MESH:D009362', (95, 113))	('monosomy', 'Var', (18, 26))
126593	24078811	Healthy cells become cancerous through genetic mutations, which are implemented through splicing in effector proteins found intra- as well as extracellularly including vitreous body and serum.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancerous', 'Disease', 'MESH:D009369', (21, 30))	('vitreous body', 'Phenotype', 'HP:0100832', (168, 181))	('genetic mutations', 'Var', (39, 56))	('splicing', 'Var', (88, 96))	('splicing', 'biological_process', 'GO:0045292', ('88', '96'))	('cancerous', 'Disease', (21, 30))
126626	23772126	Immunohistochemistry with melanoma markers indicated positivity with microphthalmia transcription factor-2, confirming the diagnosis of low-grade spindle melanoma of the ciliary body [Figure 1f].	('transcription', 'biological_process', 'GO:0006351', ('84', '97'))	('microphthalmia', 'Phenotype', 'HP:0000568', (69, 83))	('microphthalmia', 'Disease', 'MESH:D008850', (69, 83))	('spindle melanoma of the ciliary body', 'Phenotype', 'HP:0012055', (146, 182))	('microphthalmia', 'Disease', (69, 83))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (154, 162))	('melanoma', 'Disease', (26, 34))	('positivity', 'Var', (53, 63))	('transcription factor', 'molecular_function', 'GO:0000981', ('84', '104'))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))	('spindle', 'cellular_component', 'GO:0005819', ('146', '153'))
126686	23143976	This refers to the time when DTCs with a limited number of genetic alterations are able to survive, but are unable to efficiently proliferate to gain additional mutations that would favor growth ectopically.	('mutations', 'Var', (161, 170))	('DTC', 'Chemical', '-', (29, 32))	('genetic alterations', 'Var', (59, 78))
126694	23143976	Alternatively, DTCs carrying genetic alterations that favor growth or those originating from more progressed lesions may be kept "in-check" by the microenvironment, whereby epigenetic or therapy-derived mechanisms contribute to tumor cell dormancy during or after the "lead time".	('contribute', 'Reg', (214, 224))	('DTC', 'Chemical', '-', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('dormancy', 'biological_process', 'GO:0030431', ('237', '245'))	('alterations', 'Var', (37, 48))	('tumor', 'Disease', (228, 233))
126695	23143976	In support of the microenvironment playing a role, a recent report suggested that breast cancer patients with cells disseminated to the BM had longer disease-free periods than patients who were negative for cells in this site.	('breast cancer', 'Disease', (82, 95))	('patients', 'Species', '9606', (176, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('longer', 'PosReg', (143, 149))	('disease-free periods', 'CPA', (150, 170))	('patients', 'Species', '9606', (96, 104))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('cells disseminated', 'Var', (110, 128))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
126706	23143976	Because these genes suppress the growth and expansion of DTCs at target organs, yet fail to impede primary tumor growth, this further supports that the target organs with specific tissue microenvironments are required for these molecules to exert their growth-suppressing functions.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('primary tumor', 'Disease', 'MESH:D009369', (99, 112))	('growth', 'CPA', (33, 39))	('expansion', 'CPA', (44, 53))	('genes', 'Var', (14, 19))	('DTC', 'Chemical', '-', (57, 60))	('suppress', 'NegReg', (20, 28))	('primary tumor', 'Disease', (99, 112))
126746	23143976	In fact, inhibition of PERK made these cells susceptible to both glucose deprivation and chemotherapeutic drug-induced killing (see Fig.	('inhibition', 'Var', (9, 19))	('glucose deprivation', 'Disease', 'MESH:D012892', (65, 84))	('PERK', 'Gene', (23, 27))	('PERK', 'Gene', '9451', (23, 27))	('glucose deprivation', 'Disease', (65, 84))
126748	23143976	RNA interference (RNAi)-mediated targeting of ATF6alpha caused a decrease in the number of viable D-HEp3 cells in vivo without interrupting their dormancy.	('targeting', 'Var', (33, 42))	('RNA interference', 'biological_process', 'GO:0016246', ('0', '16'))	('RNAi', 'biological_process', 'GO:0016246', ('18', '22'))	('dormancy', 'biological_process', 'GO:0030431', ('146', '154'))	('ATF6alpha', 'Gene', (46, 55))	('D-HEp3', 'CellLine', 'CVCL:0326', (98, 104))	('decrease', 'NegReg', (65, 73))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('ATF6alpha', 'Gene', '22926', (46, 55))
126749	23143976	RNAi targeting of XBP-1, a transcription factor (TF) that is exclusively activated by IRE1alpha through noncanonical splicing, also induced dormant D-HEp3 cell killing (and unpublished results).	('targeting', 'Var', (5, 14))	('transcription factor', 'molecular_function', 'GO:0000981', ('27', '47'))	('D-HEp3', 'CellLine', 'CVCL:0326', (148, 154))	('XBP-1', 'Gene', (18, 23))	('XBP-1', 'Gene', '7494', (18, 23))	('transcription', 'biological_process', 'GO:0006351', ('27', '40'))	('IRE1alpha', 'Gene', (86, 95))	('IRE1alpha', 'Gene', '2081', (86, 95))	('splicing', 'biological_process', 'GO:0045292', ('117', '125'))	('cell killing', 'biological_process', 'GO:0001906', ('155', '167'))	('RNAi', 'biological_process', 'GO:0016246', ('0', '4'))	('dormant D-HEp3 cell killing', 'CPA', (140, 167))	('induced', 'Reg', (132, 139))
126762	23143976	Furthermore, RNAi targeting of BiP greatly sensitized dormant D-HEp3 cells to etoposide and doxorubicin treatment.	('doxorubicin', 'Chemical', 'MESH:D004317', (92, 103))	('etoposide', 'Chemical', 'MESH:D005047', (78, 87))	('RNAi', 'biological_process', 'GO:0016246', ('13', '17'))	('targeting', 'Var', (18, 27))	('BiP', 'Gene', (31, 34))	('BiP', 'Gene', '3309', (31, 34))	('sensitized', 'Reg', (43, 53))	('D-HEp3', 'CellLine', 'CVCL:0326', (62, 68))
126781	23143976	Thus, it is possible that, because DTCs cannot efficiently engage a foreign ECM, impaired integrin signaling may stimulate autophagy for survival and maintenance of the dormant state.	('autophagy', 'CPA', (123, 132))	('impaired', 'Var', (81, 89))	('autophagy', 'biological_process', 'GO:0006914', ('123', '132'))	('signaling', 'biological_process', 'GO:0023052', ('99', '108'))	('stimulate', 'PosReg', (113, 122))	('integrin signaling', 'MPA', (90, 108))	('DTC', 'Chemical', '-', (35, 38))	('autophagy', 'biological_process', 'GO:0016236', ('123', '132'))
126782	23143976	Consistent with this hypothesis, beta1-integrin signaling blockade is a potent inducer of autophagy in ECM-detached cells, and autophagy protects cells from detachment-induced apoptosis (anoikis) (see Fig.	('detachment-induced apoptosis', 'CPA', (157, 185))	('apoptosis', 'biological_process', 'GO:0006915', ('176', '185'))	('autophagy', 'biological_process', 'GO:0016236', ('127', '136'))	('autophagy', 'CPA', (90, 99))	('beta1-integrin', 'Gene', '3688', (33, 47))	('autophagy', 'biological_process', 'GO:0006914', ('127', '136'))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('anoikis', 'biological_process', 'GO:0043276', ('187', '194'))	('beta1-integrin', 'Gene', (33, 47))	('autophagy', 'biological_process', 'GO:0016236', ('90', '99'))	('blockade', 'Var', (58, 66))	('autophagy', 'biological_process', 'GO:0006914', ('90', '99'))	('autophagy', 'CPA', (127, 136))	('apoptosis', 'biological_process', 'GO:0097194', ('176', '185'))
126785	23143976	Interestingly, we found that D-HEp3 cells have constitutively higher levels of autophagy, as measured by green fluorescence protein-tagged LC3 and endogenous LC3 incorporation into autophagosomes, as well as elevated expression of specific autophagy-regulating genes including ATG6, ATG7, and ATG8 (unpublished results).	('LC3', 'Gene', (158, 161))	('autophagy', 'CPA', (79, 88))	('expression', 'MPA', (217, 227))	('autophagy', 'biological_process', 'GO:0016236', ('240', '249'))	('higher', 'PosReg', (62, 68))	('LC3', 'Gene', '84557', (139, 142))	('ATG8', 'Gene', (293, 297))	('D-HEp3', 'Var', (29, 35))	('autophagy', 'biological_process', 'GO:0016236', ('79', '88'))	('autophagy', 'biological_process', 'GO:0006914', ('240', '249'))	('ATG6', 'Gene', '8678', (277, 281))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('LC3', 'Gene', '84557', (158, 161))	('ATG6', 'Gene', (277, 281))	('ATG7', 'Gene', '10533', (283, 287))	('ATG8', 'Gene', '23710', (293, 297))	('elevated', 'PosReg', (208, 216))	('autophagy', 'biological_process', 'GO:0006914', ('79', '88'))	('LC3', 'Gene', (139, 142))	('D-HEp3', 'CellLine', 'CVCL:0326', (29, 35))	('ATG7', 'Gene', (283, 287))
126788	23143976	The tumor suppressor aplasia Ras homolog member I (ARHI) is downregulated in over 60% of ovarian cancers and the re-expression of ARHI in a variety of human ovarian cancer cell lines induces autophagy (see Fig.	('tumor', 'Disease', (4, 9))	('induces', 'PosReg', (183, 190))	('autophagy', 'CPA', (191, 200))	('ARHI', 'Gene', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('ovarian cancer', 'Disease', (157, 171))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('4', '20'))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('ARHI', 'Gene', (130, 134))	('ovarian cancer', 'Disease', 'MESH:D010051', (89, 103))	('ovarian cancer', 'Phenotype', 'HP:0100615', (157, 171))	('ovarian cancers', 'Phenotype', 'HP:0100615', (89, 104))	('aplasia Ras homolog member I', 'Gene', '9077', (21, 49))	('autophagy', 'biological_process', 'GO:0016236', ('191', '200'))	('re-expression', 'Var', (113, 126))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor suppressor', 'biological_process', 'GO:0051726', ('4', '20'))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('human', 'Species', '9606', (151, 156))	('autophagy', 'biological_process', 'GO:0006914', ('191', '200'))	('downregulated', 'NegReg', (60, 73))	('ovarian cancer', 'Phenotype', 'HP:0100615', (89, 103))	('ARHI', 'Gene', '9077', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ovarian cancers', 'Disease', (89, 104))	('ovarian cancer', 'Disease', 'MESH:D010051', (157, 171))	('ovarian cancers', 'Disease', 'MESH:D010051', (89, 104))	('aplasia Ras homolog member I', 'Gene', (21, 49))	('ARHI', 'Gene', '9077', (130, 134))
126840	23226069	NY-ESO-1 seropositivity predicted improved clinical benefit, defined as the combination of CR, PR, and SD (P = 0.02).	('improved', 'PosReg', (34, 42))	('seropositivity', 'Var', (9, 23))	('NY-ESO-1', 'Gene', (0, 8))	('CR', 'Chemical', '-', (91, 93))	('NY-ESO-1', 'Gene', '246100', (0, 8))	('clinical', 'MPA', (43, 51))
126841	23226069	Furthermore, analysis of NY-ESO-1-specific CD4+ and CD8+ T-cell responses by intracellular multicytokine staining revealed that patients with pretreatment anti-NY-ESO-1 antibodies who developed CD8+ T-cell responses were more likely to respond to the drug treatment (10 of 13; 77%) than those with undetectable CD8+ T-cell responses (one of seven; 14%; P = 0.02, relative risk = 5.4), and were more likely to live longer (P = 0.01).	('live longer', 'CPA', (409, 420))	('NY-ESO-1', 'Gene', (160, 168))	('respond to the drug treatment', 'MPA', (236, 265))	('CD8', 'Gene', (52, 55))	('antibodies', 'Var', (169, 179))	('NY-ESO-1', 'Gene', '246100', (25, 33))	('CD8', 'Gene', (311, 314))	('CD8', 'Gene', (194, 197))	('intracellular', 'cellular_component', 'GO:0005622', ('77', '90'))	('NY-ESO-1', 'Gene', '246100', (160, 168))	('men', 'Species', '9606', (150, 153))	('more', 'PosReg', (221, 225))	('CD4', 'Gene', '920', (43, 46))	('men', 'Species', '9606', (261, 264))	('patients', 'Species', '9606', (128, 136))	('CD4', 'Gene', (43, 46))	('CD8', 'Gene', '925', (52, 55))	('CD8', 'Gene', '925', (194, 197))	('CD8', 'Gene', '925', (311, 314))	('NY-ESO-1', 'Gene', (25, 33))
126848	23226069	In preclinical studies, inhibition of the interaction between PD-1 and PD-L1 has been shown to enhance T-cell responses and antitumor activity.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('interaction', 'Interaction', (42, 53))	('T-cell responses', 'CPA', (103, 119))	('PD-L1', 'Gene', (71, 76))	('PD-1', 'Gene', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('PD-L1', 'Gene', '29126', (71, 76))	('inhibition', 'Var', (24, 34))	('enhance T-cell responses', 'Phenotype', 'HP:0005419', (95, 119))	('tumor', 'Disease', (128, 133))	('enhance', 'PosReg', (95, 102))
126851	23226069	BMS-936558 was well tolerated overall, but was associated with immune-related adverse events, including pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis.	('colitis', 'Disease', (127, 134))	('pneumonitis', 'Disease', (104, 115))	('BMS-936558', 'Var', (0, 10))	('vitiligo', 'Phenotype', 'HP:0001045', (117, 125))	('thyroiditis', 'Disease', (165, 176))	('hypophysitis', 'Disease', (147, 159))	('pneumonitis', 'Disease', 'MESH:D011014', (104, 115))	('hepatitis', 'Disease', 'MESH:D056486', (136, 145))	('colitis', 'Phenotype', 'HP:0002583', (127, 134))	('thyroiditis', 'Phenotype', 'HP:0100646', (165, 176))	('vitiligo', 'Disease', (117, 125))	('hepatitis', 'Phenotype', 'HP:0012115', (136, 145))	('associated', 'Reg', (47, 57))	('colitis', 'Disease', 'MESH:D003092', (127, 134))	('thyroiditis', 'Disease', 'MESH:D013959', (165, 176))	('hepatitis', 'Disease', (136, 145))	('hypophysitis', 'Disease', 'MESH:D000072659', (147, 159))
126856	23226069	One of the most significant discoveries in the field of melanoma in recent years was the elucidation of the role of mitogen-activated protein kinase (MAPK) pathway, particularly the roles of mutant B-RAF and N-RAS.	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('MAPK', 'molecular_function', 'GO:0004707', ('150', '154'))	('melanoma', 'Disease', (56, 64))	('B-RAF', 'Gene', (198, 203))	('N-RAS', 'Gene', (208, 213))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('N-RAS', 'Gene', '4893', (208, 213))	('mutant', 'Var', (191, 197))	('B-RAF', 'Gene', '673', (198, 203))
126859	23226069	The MAPK pathway is activated in human melanomas either due to increased growth factor signaling or by genetic alterations in RAS and RAF proteins.	('melanomas', 'Disease', (39, 48))	('signaling', 'biological_process', 'GO:0023052', ('87', '96'))	('genetic alterations', 'Var', (103, 122))	('increased', 'PosReg', (63, 72))	('RAS', 'Protein', (126, 129))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanomas', 'Phenotype', 'HP:0002861', (39, 48))	('melanomas', 'Disease', 'MESH:D008545', (39, 48))	('human', 'Species', '9606', (33, 38))	('activated', 'PosReg', (20, 29))	('MAPK', 'molecular_function', 'GO:0004707', ('4', '8'))	('RAF', 'Gene', '22882', (134, 137))	('MAPK pathway', 'Pathway', (4, 16))	('growth factor signaling', 'MPA', (73, 96))	('RAF', 'Gene', (134, 137))
126861	23226069	By altering the levels and activity of transcription factors, MAPK leads to altered transcription of genes that are fundamental for cell division and survival.	('MAPK', 'Var', (62, 66))	('men', 'Species', '9606', (121, 124))	('altering', 'Reg', (3, 11))	('transcription', 'biological_process', 'GO:0006351', ('39', '52'))	('altered', 'Reg', (76, 83))	('MAPK', 'molecular_function', 'GO:0004707', ('62', '66'))	('levels', 'MPA', (16, 22))	('activity of transcription factors', 'MPA', (27, 60))	('transcription of genes', 'MPA', (84, 106))	('transcription', 'biological_process', 'GO:0006351', ('84', '97'))	('cell division', 'biological_process', 'GO:0051301', ('132', '145'))
126863	23226069	Inhibition of B-RAF signaling has been shown to decrease NFkappaB promoter activity associated with cell survival, invasiveness, and angiogenesis.	('promoter activity', 'MPA', (66, 83))	('NFkappaB', 'Gene', (57, 65))	('NFkappaB', 'Gene', '4790', (57, 65))	('invasiveness', 'CPA', (115, 127))	('angiogenesis', 'biological_process', 'GO:0001525', ('133', '145'))	('cell survival', 'CPA', (100, 113))	('angiogenesis', 'CPA', (133, 145))	('B-RAF', 'Gene', '673', (14, 19))	('B-RAF', 'Gene', (14, 19))	('decrease', 'NegReg', (48, 56))	('Inhibition', 'Var', (0, 10))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))
126864	23226069	Vemurafenib (PLX4032 [Genentech, South San Francisco, CA], Zelboraf), a B-RAFV600E inhibitor with increased selectivity for mutant B-RAFV600E, was recently approved by the FDA for treatment of unresectable melanoma harboring B-RAFV600E mutations.	('men', 'Species', '9606', (185, 188))	('PLX4032', 'Chemical', 'MESH:D000077484', (13, 20))	('B-RAFV600E', 'Gene', (131, 141))	('mutant', 'Var', (124, 130))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('melanoma', 'Disease', (206, 214))	('melanoma', 'Disease', 'MESH:D008545', (206, 214))
126867	23226069	These molecules, alone and in combination with additional inhibitors of the MAPK pathway or parallel pathways, hold the promise of expanding the therapeutic options for melanoma patients, and provide the first tools for personalized therapy for patients whose tumors harbor MAPK pathway-activating mutations.	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('patients', 'Species', '9606', (245, 253))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanoma', 'Disease', (169, 177))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('patients', 'Species', '9606', (178, 186))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('MAPK', 'molecular_function', 'GO:0004707', ('76', '80'))	('mutations', 'Var', (298, 307))	('MAPK', 'molecular_function', 'GO:0004707', ('274', '278'))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('tumors', 'Disease', (260, 266))	('MAPK', 'Gene', (274, 278))
126868	23226069	Mutations in the B-RAF gene are found early in the development of melanoma, and can also be seen in benign nevi.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('nevi', 'Phenotype', 'HP:0003764', (107, 111))	('B-RAF', 'Gene', '673', (17, 22))	('Mutations', 'Var', (0, 9))	('B-RAF', 'Gene', (17, 22))	('men', 'Species', '9606', (58, 61))
126869	23226069	The most common mutation of B-RAF (~80%) in melanoma is V600E and it involves substitution of valine to glutamic acid.	('glutamic acid', 'Chemical', 'MESH:D018698', (104, 117))	('valine', 'Chemical', 'MESH:D014633', (94, 100))	('B-RAF', 'Gene', '673', (28, 33))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('substitution', 'Var', (78, 90))	('melanoma', 'Disease', (44, 52))	('V600E', 'Var', (56, 61))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('B-RAF', 'Gene', (28, 33))	('V600E', 'Mutation', 'rs113488022', (56, 61))	('valine', 'MPA', (94, 100))
126870	23226069	Less common mutations are the V600K (~20%) and the V600D or V600R (~3%).	('V600D', 'Var', (51, 56))	('V600D', 'Mutation', 'rs121913377', (51, 56))	('V600R', 'Mutation', 'rs121913227', (60, 65))	('V600K', 'Var', (30, 35))	('V600R', 'Var', (60, 65))	('V600K', 'Mutation', 'rs121913227', (30, 35))
126871	23226069	B-RAF mutations are found in various categories of melanocytic growth, including melanocytic nevi (70%-80%), vertical growth-phase melanoma (40%-50%), and metastatic melanoma (40%-50%).	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('melanocytic growth', 'Disease', 'MESH:D006130', (51, 69))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('B-RAF', 'Gene', '673', (0, 5))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('nevi', 'Phenotype', 'HP:0003764', (93, 97))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('B-RAF', 'Gene', (0, 5))	('melanocytic nevi', 'Disease', (81, 97))	('found', 'Reg', (20, 25))	('melanocytic growth', 'Disease', (51, 69))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (81, 97))	('mutations', 'Var', (6, 15))
126872	23226069	The precise role of B-RAF mutations in oncogenesis is unclear, but resultant constitutive activation of the MAPK pathway causes cellular growth and vascular development in melanoma tumors.	('activation', 'PosReg', (90, 100))	('melanoma tumors', 'Disease', 'MESH:D008545', (172, 187))	('MAPK pathway', 'Pathway', (108, 120))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('cellular growth', 'biological_process', 'GO:0016049', ('128', '143'))	('B-RAF', 'Gene', '673', (20, 25))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('causes', 'PosReg', (121, 127))	('B-RAF', 'Gene', (20, 25))	('mutations', 'Var', (26, 35))	('oncogenesis', 'biological_process', 'GO:0007048', ('39', '50'))	('vascular development', 'CPA', (148, 168))	('cellular growth', 'CPA', (128, 143))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanoma tumors', 'Disease', (172, 187))	('men', 'Species', '9606', (164, 167))
126873	23226069	N-RAS mutations have been identified in 15%-20% of cutaneous melanoma and are presumed to be one of the important drivers of oncogenesis.	('oncogenesis', 'biological_process', 'GO:0007048', ('125', '136'))	('cutaneous melanoma', 'Disease', (51, 69))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (51, 69))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (51, 69))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('N-RAS', 'Gene', (0, 5))	('N-RAS', 'Gene', '4893', (0, 5))	('identified', 'Reg', (26, 36))	('mutations', 'Var', (6, 15))
126874	23226069	A somatic mutation in the N-RAS gene causes constitutive activation of the N-RAS protein, which leads to the successive activation of downstream serine/threonine kinases, which promote cell cycle progression, cellular transformation, and enhanced cell survival.	('cell cycle progression', 'CPA', (185, 207))	('promote', 'PosReg', (177, 184))	('cell survival', 'CPA', (247, 260))	('activation', 'PosReg', (57, 67))	('N-RAS', 'Gene', (75, 80))	('cellular transformation', 'CPA', (209, 232))	('activation', 'PosReg', (120, 130))	('mutation', 'Var', (10, 18))	('N-RAS', 'Gene', (26, 31))	('cell cycle', 'biological_process', 'GO:0007049', ('185', '195'))	('N-RAS', 'Gene', '4893', (75, 80))	('enhanced', 'PosReg', (238, 246))	('N-RAS', 'Gene', '4893', (26, 31))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))
126878	23226069	Substitutions at positions 60 and 61 accounted for 82.4% of N-RAS mutations, most frequently a glutamine to arginine/lysine/leucine substitution at position 61 (Q61R/K/L).	('mutations', 'Var', (66, 75))	('Q61R', 'Var', (161, 165))	('leucine', 'Chemical', 'MESH:D007930', (124, 131))	('N-RAS', 'Gene', (60, 65))	('Q61R', 'SUBSTITUTION', 'None', (161, 165))	('glutamine', 'Chemical', 'MESH:D005973', (95, 104))	('N-RAS', 'Gene', '4893', (60, 65))	('arginine', 'Chemical', 'MESH:D001120', (108, 116))	('accounted', 'Reg', (37, 46))	('lysine', 'Chemical', 'MESH:D008239', (117, 123))
126879	23226069	B-RAF and N-RAS mutations appear to be biologically different than wild-type (WT) tumors and clearly have an impact on the clinical course.	('N-RAS', 'Gene', '4893', (10, 15))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('impact', 'Reg', (109, 115))	('B-RAF', 'Gene', '673', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('B-RAF', 'Gene', (0, 5))	('mutations', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('N-RAS', 'Gene', (10, 15))	('have', 'Reg', (101, 105))
126880	23226069	In early stage melanoma, N-RAS mutations are associated with thicker tumors; 75% of N-RAS mutant melanomas are >1 mm in depth, while 40% of B-RAF and 34% of WT primary melanomas are thicker than 1 mm.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('mutant', 'Var', (90, 96))	('N-RAS', 'Gene', '4893', (84, 89))	('B-RAF', 'Gene', (140, 145))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', (168, 176))	('N-RAS', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('melanomas', 'Disease', 'MESH:D008545', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('melanomas', 'Disease', (97, 106))	('melanomas', 'Disease', 'MESH:D008545', (168, 177))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('N-RAS', 'Gene', (84, 89))	('melanomas', 'Disease', (168, 177))	('tumors', 'Disease', (69, 75))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))	('B-RAF', 'Gene', '673', (140, 145))	('melanomas', 'Phenotype', 'HP:0002861', (97, 106))	('N-RAS', 'Gene', '4893', (25, 30))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('melanomas', 'Phenotype', 'HP:0002861', (168, 177))
126881	23226069	N-RAS mutations were also associated with increased proliferation rates, with 75% having >1 mitosis/mm2, versus 40% for B-RAF mutations and 55% for WT.	('increased', 'PosReg', (42, 51))	('B-RAF', 'Gene', '673', (120, 125))	('proliferation rates', 'CPA', (52, 71))	('mitosis', 'Disease', (92, 99))	('B-RAF', 'Gene', (120, 125))	('mitosis', 'biological_process', 'GO:0000278', ('92', '99'))	('N-RAS', 'Gene', (0, 5))	('mitosis', 'Disease', 'None', (92, 99))	('N-RAS', 'Gene', '4893', (0, 5))	('mutations', 'Var', (6, 15))
126882	23226069	The majority of early stage melanomas with B-RAF mutations are the superficial spreading subtype (88%), and B-RAF mutations are more likely to be found in body areas with intermittent sun exposure compared to chronic or no sun exposure (P = 0.02).	('mutations', 'Var', (49, 58))	('mutations', 'Var', (114, 123))	('B-RAF', 'Gene', (43, 48))	('melanomas', 'Disease', (28, 37))	('melanomas', 'Disease', 'MESH:D008545', (28, 37))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('B-RAF', 'Gene', '673', (108, 113))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('B-RAF', 'Gene', '673', (43, 48))	('B-RAF', 'Gene', (108, 113))
126883	23226069	N-RAS mutation status has been identified as an independent predictor of shorter survival in patients with metastatic melanoma (N-RAS vs WT, 8.2 vs 15.1 months; P = 0.004).	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('N-RAS', 'Gene', (128, 133))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('mutation', 'Var', (6, 14))	('N-RAS', 'Gene', '4893', (128, 133))	('shorter', 'NegReg', (73, 80))	('N-RAS', 'Gene', (0, 5))	('survival', 'MPA', (81, 89))	('N-RAS', 'Gene', '4893', (0, 5))	('patients', 'Species', '9606', (93, 101))
126884	23226069	The risk of brain metastasis at the time of diagnosis of stage IV disease was also noted to be significantly higher in B-RAF mutant (24%) and N-RAS mutant (23%) patients compared with WT patients (12%).	('IV disease', 'Disease', (63, 73))	('patients', 'Species', '9606', (187, 195))	('IV disease', 'Disease', 'MESH:D020432', (63, 73))	('B-RAF', 'Gene', '673', (119, 124))	('N-RAS', 'Gene', '4893', (142, 147))	('mutant', 'Var', (125, 131))	('higher', 'PosReg', (109, 115))	('brain metastasis', 'CPA', (12, 28))	('mutant', 'Var', (148, 154))	('B-RAF', 'Gene', (119, 124))	('patients', 'Species', '9606', (161, 169))	('N-RAS', 'Gene', (142, 147))
126885	23226069	However, patients with B-RAF mutant melanoma treated with specific B-RAF inhibitors have an improved survival compared with N-RAS and tumors that are WT for both.	('B-RAF', 'Gene', '673', (67, 72))	('patients', 'Species', '9606', (9, 17))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('N-RAS and tumors', 'Disease', 'MESH:D009369', (124, 140))	('melanoma', 'Disease', (36, 44))	('B-RAF', 'Gene', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('B-RAF', 'Gene', (23, 28))	('survival', 'MPA', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('mutant', 'Var', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('improved', 'PosReg', (92, 100))	('B-RAF', 'Gene', '673', (23, 28))
126887	23226069	Patients with N-RAS mutations had nonstatistically significant longer overall survival (5.3 vs 2.4 years; P = 0.30) and progression-free survival (214 vs 70 days; P = 0.13).	('progression-free survival', 'CPA', (120, 145))	('N-RAS', 'Gene', '4893', (14, 19))	('overall', 'MPA', (70, 77))	('Patients', 'Species', '9606', (0, 8))	('longer', 'PosReg', (63, 69))	('N-RAS', 'Gene', (14, 19))	('mutations', 'Var', (20, 29))
126890	23226069	The Q209 mutation in GNAQ was seen in 45% of the uveal melanoma and 22% of the metastatic tumors.	('uveal melanoma', 'Disease', 'MESH:C536494', (49, 63))	('GNAQ', 'Gene', '2776', (21, 25))	('uveal melanoma', 'Disease', (49, 63))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('GNAQ', 'Gene', (21, 25))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('Q209', 'Var', (4, 8))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('uveal melanoma', 'Phenotype', 'HP:0007716', (49, 63))
126891	23226069	Transduction of mutated GNA11 in murine models showed enhanced growth and metastasis in xenografts and also revealed activation of the MAPK pathway.	('murine', 'Species', '10090', (33, 39))	('MAPK', 'molecular_function', 'GO:0004707', ('135', '139'))	('MAPK pathway', 'Pathway', (135, 147))	('mutated', 'Var', (16, 23))	('Transduction', 'biological_process', 'GO:0009293', ('0', '12'))	('GNA11', 'Gene', (24, 29))	('activation', 'PosReg', (117, 127))	('enhanced', 'PosReg', (54, 62))
126896	23226069	Several activating mutations in c-KIT have been described that result in ligand-independent constitutive activity of the tyrosine kinase.	('c-KIT', 'Gene', '3815', (32, 37))	('ligand', 'molecular_function', 'GO:0005488', ('73', '79'))	('mutations', 'Var', (19, 28))	('ligand-independent constitutive activity', 'MPA', (73, 113))	('c-KIT', 'Gene', (32, 37))	('activating', 'PosReg', (8, 18))	('KIT', 'molecular_function', 'GO:0005020', ('34', '37'))
126897	23226069	Activating c-KIT mutations are commonly found in gastrointestinal stromal tumors, which are thought to originate from interstitial cells of Cajal.	('KIT', 'molecular_function', 'GO:0005020', ('13', '16'))	('gastrointestinal stromal tumors', 'Disease', (49, 80))	('Activating', 'PosReg', (0, 10))	('c-KIT', 'Gene', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (49, 80))	('c-KIT', 'Gene', '3815', (11, 16))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (49, 80))	('mutations', 'Var', (17, 26))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
126898	23226069	In addition, c-KIT mutations are frequently present in three subpopulations of melanoma: mucosal (15%-27%), acral (9%-23%), and less frequently in sun-damaged cutaneous melanomas (0%-16%).	('c-KIT', 'Gene', (13, 18))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (159, 178))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (159, 178))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanomas', 'Phenotype', 'HP:0002861', (169, 178))	('melanoma', 'Disease', (169, 177))	('c-KIT', 'Gene', '3815', (13, 18))	('mutations', 'Var', (19, 28))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (159, 177))	('cutaneous melanomas', 'Disease', (159, 178))	('KIT', 'molecular_function', 'GO:0005020', ('15', '18'))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('sun-damaged', 'Phenotype', 'HP:0000992', (147, 158))	('melanoma', 'Disease', (79, 87))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
126899	23226069	Development of drugs targeting mutant B-RAFV600E is a major advance in personalized therapy for melanoma.	('mutant', 'Var', (31, 37))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('B-RAFV600E', 'Gene', (38, 48))	('men', 'Species', '9606', (7, 10))	('melanoma', 'Disease', (96, 104))
126901	23226069	A parental compound of vemurafenib, PLX4720, a 7-azaindole derivative, was discovered by using a structure-guided discovery approach, and therefore it preferentially inhibits the constitutively active mutant B-RAFV600E compared with other kinases, and potent cytotoxic effects are also exclusive to cells bearing the V600-mutated allele.	('vemurafenib', 'Chemical', 'MESH:D000077484', (23, 34))	('preferentially', 'PosReg', (151, 165))	('7-azaindole', 'Chemical', 'MESH:C023422', (47, 58))	('PLX4720', 'Var', (36, 43))	('V600-mutated', 'Var', (317, 329))	('B-RAFV600E', 'Var', (208, 218))	('inhibits', 'NegReg', (166, 174))
126903	23226069	In the expansion cohort, which consisted of patients with melanomas harboring B-RAFV600E mutations, 26 of the 32 patients had objective responses (81%), with a CR in two patients and a PR in 24 patients.	('patients', 'Species', '9606', (170, 178))	('patients', 'Species', '9606', (194, 202))	('patients', 'Species', '9606', (44, 52))	('patients', 'Species', '9606', (113, 121))	('melanomas', 'Disease', (58, 67))	('CR', 'Chemical', '-', (160, 162))	('mutations', 'Var', (89, 98))	('B-RAFV600E', 'Gene', (78, 88))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanomas', 'Disease', 'MESH:D008545', (58, 67))	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))
126904	23226069	B-RAF in Melanoma 2 (BRIM-2) was a Phase II study that enrolled 132 patients with previously treated stage IV melanoma with B-RAFV600E mutations, and demonstrated an RR of 53%, SD in 29%, median progression-free survival (PFS) of 6.7 months, and an OS at 6 and 12 months of 77% and 58%, respectively.	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('Melanoma 2', 'Disease', 'MESH:D008545', (9, 19))	('B-RAF', 'Gene', '673', (0, 5))	('B-RAF', 'Gene', (0, 5))	('mutations', 'Var', (135, 144))	('patients', 'Species', '9606', (68, 76))	('Melanoma 2', 'Disease', (9, 19))	('IV melanoma', 'Disease', (107, 118))	('Melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('B-RAF', 'Gene', '673', (124, 129))	('B-RAF', 'Gene', (124, 129))	('IV melanoma', 'Disease', 'MESH:D008545', (107, 118))
126905	23226069	The efficacy of vemurafenib was confirmed in a Phase III trial, BRIM-3, that compared vemurafenib to DTIC in 675 previously untreated patients, whose tumors harbored B-RAFV600E mutations.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('DTIC', 'Chemical', 'MESH:D003606', (101, 105))	('vemurafenib', 'Chemical', 'MESH:D000077484', (86, 97))	('B-RAFV600E mutations', 'Var', (166, 186))	('patients', 'Species', '9606', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('vemurafenib', 'Chemical', 'MESH:D000077484', (16, 27))
126909	23226069	Among the 57 melanoma patients with B-RAF mutations, a response rate of 27% was noted, including ten of 16 at the planned Phase II dose.	('B-RAF', 'Gene', '673', (36, 41))	('B-RAF', 'Gene', (36, 41))	('patients', 'Species', '9606', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanoma', 'Disease', (13, 21))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('mutations', 'Var', (42, 51))
126917	23226069	Furthermore, the short latency period until the development of these skin lesions is consistent with the presence of preexisting RAS mutations in the skin that become oncogenic when subjected to B-RAF inhibition.	('men', 'Species', '9606', (55, 58))	('B-RAF', 'Gene', '673', (195, 200))	('B-RAF', 'Gene', (195, 200))	('mutations', 'Var', (133, 142))	('RAS', 'Gene', (129, 132))
126918	23226069	Mutations in B-RAF in tumor samples can be detected by a number of molecular methods.	('B-RAF', 'Gene', '673', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('B-RAF', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (22, 27))
126919	23226069	The Cobas 4800 B-RAFV600 Mutation Test (LabCorp, Burlington, NC) is a PCR-based diagnostic test developed by Roche Molecular Systems (Pleasanton, CA) and was used to detect V600E mutations in tumor samples for patient selection for the BRIM-2 and BRIM-3 clinical trials.	('B-RAF', 'Gene', (15, 20))	('tumor', 'Disease', (192, 197))	('V600E', 'Mutation', 'rs113488022', (173, 178))	('V600E', 'Var', (173, 178))	('CR', 'Chemical', '-', (71, 73))	('patient', 'Species', '9606', (210, 217))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('B-RAF', 'Gene', '673', (15, 20))
126921	23226069	However, the Sanger sequencing method, which uses sequence-specific termination of a DNA synthesis reaction using modified nucleotide substrates, suffers from limited sensitivity for detecting mutations that are present in low percentages in a tumor tissue.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('tumor', 'Disease', (244, 249))	('mutations', 'Var', (193, 202))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('DNA synthesis', 'biological_process', 'GO:0071897', ('85', '98'))
126922	23226069	However, the sensitivity of this test to detect V600K (10%-20% of all B-RAF) is only 70%, and additional testing might be needed to identify V600K mutations to avoid exclusion of patients who might benefit from B-RAF-targeting drugs.	('B-RAF', 'Gene', (211, 216))	('V600K', 'Var', (141, 146))	('V600K', 'Mutation', 'rs121913227', (48, 53))	('B-RAF', 'Gene', '673', (70, 75))	('V600K', 'Mutation', 'rs121913227', (141, 146))	('patients', 'Species', '9606', (179, 187))	('B-RAF', 'Gene', (70, 75))	('V600K', 'Var', (48, 53))	('B-RAF', 'Gene', '673', (211, 216))
126923	23226069	Detection of B-RAF mutation by immunohistochemistry using mutation-specific antibodies has shown remarkable specificity when confirmed by direct sequencing methods.	('B-RAF', 'Gene', (13, 18))	('mutation', 'Var', (19, 27))	('B-RAF', 'Gene', '673', (13, 18))
126928	23226069	Importantly however, subsequent analysis of available melanoma cell lines showed no c-KIT mutations, and none of the analyzed melanomas demonstrated strong staining for C-KIT.	('C-KIT', 'Gene', (169, 174))	('mutations', 'Var', (90, 99))	('melanomas', 'Disease', (126, 135))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('C-KIT', 'Gene', '3815', (169, 174))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('c-KIT', 'Gene', (84, 89))	('melanomas', 'Phenotype', 'HP:0002861', (126, 135))	('KIT', 'molecular_function', 'GO:0005020', ('171', '174'))	('KIT', 'molecular_function', 'GO:0005020', ('86', '89'))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanomas', 'Disease', 'MESH:D008545', (126, 135))	('c-KIT', 'Gene', '3815', (84, 89))	('melanoma', 'Disease', (126, 134))
126931	23226069	In contrast, case reports were subsequently published showing substantial responses to imatinib in melanomas harboring c-KIT mutations.	('mutations', 'Var', (125, 134))	('imatinib', 'Chemical', 'MESH:D000068877', (87, 95))	('melanomas', 'Disease', (99, 108))	('KIT', 'molecular_function', 'GO:0005020', ('121', '124'))	('c-KIT', 'Gene', '3815', (119, 124))	('responses', 'MPA', (74, 83))	('melanomas', 'Disease', 'MESH:D008545', (99, 108))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanomas', 'Phenotype', 'HP:0002861', (99, 108))	('c-KIT', 'Gene', (119, 124))
126932	23226069	This led to the initiation of several Phase II trials in which metastatic melanoma patients, with either amplification or mutation of c-KIT in their tumors, were treated with imatinib.	('KIT', 'molecular_function', 'GO:0005020', ('136', '139'))	('c-KIT', 'Gene', '3815', (134, 139))	('amplification', 'Var', (105, 118))	('mutation', 'Var', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('patients', 'Species', '9606', (83, 91))	('imatinib', 'Chemical', 'MESH:D000068877', (175, 183))	('c-KIT', 'Gene', (134, 139))
126934	23226069	Most of the responses were seen in tumors with c-KIT mutations in exons 11 and 13.	('c-KIT', 'Gene', '3815', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('mutations in', 'Var', (53, 65))	('KIT', 'molecular_function', 'GO:0005020', ('49', '52'))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('c-KIT', 'Gene', (47, 52))
126935	23226069	In a second study of imatinib in patients with c-KIT mutations and/or amplifications, complete durable responses were seen in two out of 25 patients, while four patients achieved PRs (two durable), and prolonged stable disease (>=6 months) was achieved in two patients.	('PRs', 'MPA', (179, 182))	('patients', 'Species', '9606', (33, 41))	('c-KIT', 'Gene', '3815', (47, 52))	('mutations', 'Var', (53, 62))	('patients', 'Species', '9606', (260, 268))	('amplifications', 'Var', (70, 84))	('patients', 'Species', '9606', (161, 169))	('KIT', 'molecular_function', 'GO:0005020', ('49', '52'))	('patients', 'Species', '9606', (140, 148))	('imatinib', 'Chemical', 'MESH:D000068877', (21, 29))	('c-KIT', 'Gene', (47, 52))
126936	23226069	Similar to the previous study, most responders were found to have c-KIT mutations in exon 11 or exon 13.	('mutations in', 'Var', (72, 84))	('c-KIT', 'Gene', '3815', (66, 71))	('c-KIT', 'Gene', (66, 71))	('KIT', 'molecular_function', 'GO:0005020', ('68', '71'))
126937	23226069	Although most published case reports and Phase II studies used imatinib as a c-KIT inhibitor, clinical responses in patients with c-KIT mutant melanomas to treatment with other small molecule kinase inhibitors including dasatinib (Bristol-Myers Squibb, Princeton, NJ), sorafenib (Bayer Healthcare Pharmaceuticals, Inc, Leverkusen Germany and Onyx Pharm, Inc, South San Francisco, CA) nilotinib (Novartis, NY, NY), and sunitinib (Pfizer, NY, NY) have been reported.	('sorafenib', 'Chemical', 'MESH:D000077157', (269, 278))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('c-KIT', 'Gene', (77, 82))	('melanomas', 'Phenotype', 'HP:0002861', (143, 152))	('mutant', 'Var', (136, 142))	('men', 'Species', '9606', (161, 164))	('c-KIT', 'Gene', '3815', (77, 82))	('dasatinib', 'Chemical', 'MESH:D000069439', (220, 229))	('patients', 'Species', '9606', (116, 124))	('Novartis', 'Disease', 'None', (395, 403))	('c-KIT', 'Gene', (130, 135))	('sunitinib', 'Chemical', 'MESH:D000077210', (418, 427))	('Novartis', 'Disease', (395, 403))	('c-KIT', 'Gene', '3815', (130, 135))	('nilotinib', 'Chemical', 'MESH:C498826', (384, 393))	('KIT', 'molecular_function', 'GO:0005020', ('132', '135'))	('melanomas', 'Disease', 'MESH:D008545', (143, 152))	('KIT', 'molecular_function', 'GO:0005020', ('79', '82'))	('melanomas', 'Disease', (143, 152))	('imatinib', 'Chemical', 'MESH:D000068877', (63, 71))
126938	23226069	In summary, these studies indicate that treatment of melanoma with c-KIT inhibitors is only effective in the small subset of melanomas that harbor c-KIT mutations; melanoma tumors with strong c-KIT expression without mutation or amplification of the gene do not appear to respond to c-KIT inhibitors.	('mutations', 'Var', (153, 162))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('c-KIT', 'Gene', (283, 288))	('melanoma', 'Disease', 'MESH:D008545', (164, 172))	('c-KIT', 'Gene', '3815', (283, 288))	('melanomas', 'Phenotype', 'HP:0002861', (125, 134))	('KIT', 'molecular_function', 'GO:0005020', ('194', '197'))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('KIT', 'molecular_function', 'GO:0005020', ('285', '288'))	('expression', 'MPA', (198, 208))	('c-KIT', 'Gene', (67, 72))	('KIT', 'molecular_function', 'GO:0005020', ('149', '152'))	('c-KIT', 'Gene', '3815', (67, 72))	('KIT', 'molecular_function', 'GO:0005020', ('69', '72'))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma tumors', 'Disease', 'MESH:D008545', (164, 179))	('c-KIT', 'Gene', (147, 152))	('melanoma', 'Disease', (125, 133))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('c-KIT', 'Gene', '3815', (147, 152))	('melanoma tumors', 'Disease', (164, 179))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('c-KIT', 'Gene', (192, 197))	('melanoma', 'Disease', (164, 172))	('melanomas', 'Disease', 'MESH:D008545', (125, 134))	('men', 'Species', '9606', (45, 48))	('c-KIT', 'Gene', '3815', (192, 197))	('melanomas', 'Disease', (125, 134))
126939	23226069	Further characterization of the c-KIT mutations in relation to response to c-KIT inhibitors is needed, since early evidence suggests that mutations in exons 11 and 13 (ie, L576P and K642E) are more likely to respond to therapy.	('c-KIT', 'Gene', '3815', (32, 37))	('KIT', 'molecular_function', 'GO:0005020', ('77', '80'))	('L576P', 'Mutation', 'rs121913513', (172, 177))	('c-KIT', 'Gene', '3815', (75, 80))	('K642E', 'Var', (182, 187))	('L576P', 'Var', (172, 177))	('K642E', 'Mutation', 'rs121913512', (182, 187))	('respond', 'MPA', (208, 215))	('c-KIT', 'Gene', (32, 37))	('KIT', 'molecular_function', 'GO:0005020', ('34', '37'))	('c-KIT', 'Gene', (75, 80))
126940	23226069	MEK is an attractive therapeutic target since MEK inhibitors have shown significant antiproliferative activity in preclinical melanoma studies.	('antiproliferative activity', 'CPA', (84, 110))	('inhibitors', 'Var', (50, 60))	('MEK', 'Gene', (0, 3))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('MEK', 'Gene', '5609', (0, 3))	('MEK', 'Gene', (46, 49))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('MEK', 'Gene', '5609', (46, 49))	('melanoma', 'Disease', (126, 134))
126942	23226069	GSK1120212 (GlaxoSmithKline, Brentford, UK) is a potent and selective allosteric inhibitor of MEK1/2.	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('MEK1/2', 'Gene', '5604;5605', (94, 100))	('MEK1/2', 'Gene', (94, 100))	('GSK1120212', 'Var', (0, 10))	('GSK1120212', 'Chemical', 'MESH:C560077', (0, 10))	('MEK1', 'molecular_function', 'GO:0004708', ('94', '98'))
126943	23226069	A Phase I/II clinical trial including 20 evaluable patients with a B-RAF mutant melanoma treated with 2 mg of daily oral dose of GSK1120212 (the recommended Phase II dose) showed an RR of 40% and SD in 18%.	('B-RAF', 'Gene', '673', (67, 72))	('B-RAF', 'Gene', (67, 72))	('GSK1120212', 'Gene', (129, 139))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('GSK', 'molecular_function', 'GO:0050321', ('129', '132'))	('melanoma', 'Disease', (80, 88))	('mutant', 'Var', (73, 79))	('GSK1120212', 'Chemical', 'MESH:C560077', (129, 139))	('patients', 'Species', '9606', (51, 59))	('men', 'Species', '9606', (150, 153))
126946	23226069	A two-arm, open-label, randomized Phase III study comparing single-agent GSK1120212 to chemotherapy (either DTIC or paclitaxel [Bristol-Myers Squibb, Princeton, NJ]) in patients with unresectable melanoma harboring V600E mutations has recently been completed and results are awaited (NCT01245062).	('GSK1120212', 'Gene', (73, 83))	('patients', 'Species', '9606', (169, 177))	('V600E', 'Mutation', 'rs113488022', (215, 220))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('GSK', 'molecular_function', 'GO:0050321', ('73', '76'))	('melanoma', 'Disease', (196, 204))	('paclitaxel', 'Chemical', 'MESH:D017239', (116, 126))	('V600E', 'Var', (215, 220))	('unresectable', 'Disease', (183, 195))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))	('GSK1120212', 'Chemical', 'MESH:C560077', (73, 83))	('DTIC', 'Chemical', 'MESH:D003606', (108, 112))
126948	23226069	In a subset of patients with tumors harboring B-RAFV600E mutations (45 patients out of 200), five patients had an objective response (11%).	('patients', 'Species', '9606', (15, 23))	('patients', 'Species', '9606', (71, 79))	('B-RAFV600E mutations', 'Var', (46, 66))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('patients', 'Species', '9606', (98, 106))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))
126954	23226069	This may occur upstream (new N-RAS mutations, up regulation of C-RAF, and upregulation of receptor tyrosine kinases, PDGFRB, ERBB2), or downstream (such as new activating MEK mutations or activation of serine/threonine MAPK kinases [COT] or in parallel signaling pathways, particularly the PI3K-AKT pathway).	('AKT', 'Gene', (295, 298))	('C-RAF', 'Gene', '5894', (63, 68))	('PDGFRB', 'Gene', '5159', (117, 123))	('MAPK', 'molecular_function', 'GO:0004707', ('219', '223'))	('PDGFRB', 'Gene', (117, 123))	('N-RAS', 'Gene', '4893', (29, 34))	('mutations', 'Var', (175, 184))	('activating', 'PosReg', (160, 170))	('MEK', 'Gene', '5609', (171, 174))	('up regulation', 'PosReg', (46, 59))	('AKT', 'Gene', '207', (295, 298))	('C-RAF', 'Gene', (63, 68))	('ERBB2', 'Gene', (125, 130))	('MEK', 'Gene', (171, 174))	('N-RAS', 'Gene', (29, 34))	('signaling', 'biological_process', 'GO:0023052', ('253', '262'))	('ERBB2', 'Gene', '2064', (125, 130))	('regulation', 'biological_process', 'GO:0065007', ('49', '59'))	('PI3K', 'molecular_function', 'GO:0016303', ('290', '294'))	('upregulation', 'PosReg', (74, 86))	('mutations', 'Var', (35, 44))
126956	23226069	A Phase I/II clinical trial combining GSK436 (GlaxoSmithKline, Brentford, UK) (B-RAF inhibitor) and GSK212 (GlaxoSmithKline, Brentford, UK) (MEK inhibitor) demonstrated tolerability and dramatic clinical activity.	('GSK', 'molecular_function', 'GO:0050321', ('100', '103'))	('B-RAF', 'Gene', '673', (79, 84))	('GSK212', 'Gene', (100, 106))	('MEK', 'Gene', (141, 144))	('MEK', 'Gene', '5609', (141, 144))	('GSK', 'molecular_function', 'GO:0050321', ('38', '41'))	('GSK436', 'Chemical', 'MESH:C561627', (38, 44))	('B-RAF', 'Gene', (79, 84))	('GSK212', 'Chemical', 'MESH:C560077', (100, 106))	('GSK436', 'Var', (38, 44))
126957	23226069	In the cohort treated with the maximum tolerated dose combination (GSK436 200 mg daily and GSK212 1.5 mg daily, both given orally), of a total of 19 patients, the RR was 74% (CR in four and PR in ten patients), and SD was seen in five patients.	('GSK436 200 mg', 'Var', (67, 80))	('GSK436', 'Chemical', 'MESH:C561627', (67, 73))	('CR', 'Chemical', '-', (175, 177))	('patients', 'Species', '9606', (149, 157))	('patients', 'Species', '9606', (200, 208))	('GSK', 'molecular_function', 'GO:0050321', ('91', '94'))	('GSK212', 'Chemical', 'MESH:C560077', (91, 97))	('patients', 'Species', '9606', (235, 243))	('GSK', 'molecular_function', 'GO:0050321', ('67', '70'))	('GSK212', 'Var', (91, 97))
126958	23226069	Interestingly, the B-RAF and MEK inhibitor combination appears to be associated with a lower incidence of skin toxicities: fewer rashes were seen (25%) and only one case of cutaneous squamous cell carcinoma was seen in the whole Phase I/II cohort (109 patients).	('MEK', 'Gene', '5609', (29, 32))	('rashes', 'Disease', 'MESH:D005076', (129, 135))	('B-RAF', 'Gene', (19, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (183, 206))	('rashes', 'Phenotype', 'HP:0000988', (129, 135))	('patients', 'Species', '9606', (252, 260))	('rash', 'Phenotype', 'HP:0000988', (129, 133))	('skin toxicities', 'Disease', (106, 121))	('rashes', 'Disease', (129, 135))	('cutaneous squamous cell carcinoma', 'Disease', (173, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('skin toxicities', 'Disease', 'MESH:D012871', (106, 121))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (173, 206))	('combination', 'Var', (43, 54))	('B-RAF', 'Gene', '673', (19, 24))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (173, 206))	('MEK', 'Gene', (29, 32))
126959	23226069	Another combination of a B-RAF inhibitor (RAF265 [Chiron Corp, Emeryville, CA]) and an MEK inhibitor (MEK162) is currently being tested in advanced solid tumors harboring RAS and B-RAFV600E mutations (NCT01352273).	('MEK', 'Gene', '5609', (102, 105))	('solid tumors', 'Disease', 'MESH:D009369', (148, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('RAF265', 'Chemical', 'MESH:C559019', (42, 48))	('B-RAF', 'Gene', '673', (179, 184))	('B-RAF', 'Gene', '673', (25, 30))	('B-RAF', 'Gene', (179, 184))	('MEK', 'Gene', (87, 90))	('MEK', 'Gene', '5609', (87, 90))	('RAS', 'Var', (171, 174))	('solid tumors', 'Disease', (148, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('B-RAF', 'Gene', (25, 30))	('MEK', 'Gene', (102, 105))
126969	23226069	However, the decision about starting treatment with a B-RAF inhibitor is based on the individual clinical scenario, and many patients whose tumors harbor V600E mutations may initiate treatment with other therapies such as ipilimumab or IL-2.	('B-RAF', 'Gene', '673', (54, 59))	('tumors', 'Disease', (140, 146))	('men', 'Species', '9606', (42, 45))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('B-RAF', 'Gene', (54, 59))	('IL-2', 'molecular_function', 'GO:0005134', ('236', '240'))	('V600E', 'Mutation', 'rs113488022', (154, 159))	('ipilimumab', 'Chemical', 'MESH:D000074324', (222, 232))	('IL-2', 'Gene', '3558', (236, 240))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('initiate', 'Reg', (174, 182))	('V600E', 'Var', (154, 159))	('men', 'Species', '9606', (188, 191))	('IL-2', 'Gene', (236, 240))	('patients', 'Species', '9606', (125, 133))
126994	33492438	In fact, the activity of AR-42 was superior to that of vorinostat in Burkitt lymphoma mouse models.	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (69, 85))	('mouse', 'Species', '10090', (86, 91))	('vorinostat', 'Chemical', 'MESH:D000077337', (55, 65))	('lymphoma', 'Phenotype', 'HP:0002665', (77, 85))	('activity', 'MPA', (13, 21))	('Burkitt lymphoma', 'Disease', (69, 85))	('AR-42', 'Chemical', 'MESH:C524513', (25, 30))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (69, 85))	('AR-42', 'Var', (25, 30))
127103	33492438	The NF2 gene encodes the tumor suppressor protein merlin and loss of merlin in NF2 results in proliferation of Schwann and leptomeningeal cells, in part through activation of the PI3K/AKT pathway.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('25', '41'))	('NF2', 'Gene', '4771', (79, 82))	('merlin', 'Gene', (69, 75))	('loss of', 'Var', (61, 68))	('tumor suppressor', 'biological_process', 'GO:0051726', ('25', '41'))	('NF2', 'Gene', (79, 82))	('AKT', 'Gene', '207', (184, 187))	('activation', 'PosReg', (161, 171))	('merlin', 'Gene', (50, 56))	('proliferation', 'PosReg', (94, 107))	('merlin', 'Gene', '4771', (69, 75))	('tumor', 'Disease', (25, 30))	('PI3K', 'molecular_function', 'GO:0016303', ('179', '183'))	('NF2', 'Gene', '4771', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('NF2', 'Gene', (4, 7))	('merlin', 'Gene', '4771', (50, 56))	('AKT', 'Gene', (184, 187))
127104	33492438	AR-42 dephosphorylates and deactivates AKT.	('AR-42', 'Chemical', 'MESH:C524513', (0, 5))	('AR-42', 'Var', (0, 5))	('AKT', 'Gene', '207', (39, 42))	('deactivates', 'NegReg', (27, 38))	('AKT', 'Gene', (39, 42))	('dephosphorylates', 'MPA', (6, 22))
127105	33492438	In preclinical studies in vitro, AR-42 decreased AKT phosphorylation and suppressed proliferation of schwannoma and meningioma cell lines by cell cycle arrest at G2 and apoptosis.	('apoptosis', 'CPA', (169, 178))	('apoptosis', 'biological_process', 'GO:0097194', ('169', '178'))	('AKT', 'Gene', (49, 52))	('schwannoma', 'Phenotype', 'HP:0100008', (101, 111))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (141, 158))	('AR-42', 'Var', (33, 38))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('141', '158'))	('schwannoma and meningioma', 'Disease', 'MESH:D009442', (101, 126))	('arrest', 'Disease', (152, 158))	('apoptosis', 'biological_process', 'GO:0006915', ('169', '178'))	('arrest', 'Disease', 'MESH:D006323', (152, 158))	('meningioma', 'Phenotype', 'HP:0002858', (116, 126))	('proliferation', 'CPA', (84, 97))	('suppressed', 'NegReg', (73, 83))	('AKT', 'Gene', '207', (49, 52))	('decreased', 'NegReg', (39, 48))	('AR-42', 'Chemical', 'MESH:C524513', (33, 38))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))
127113	33492438	Specifically AR-42 has shown preclinical activity when combined with decitabine for AML, doxorubicin for osteosarcoma, 5-FU for breast cancer, cisplatin for urothelial carcinoma, and pazopanib for melanoma cells resistant to trametinib plus dabrafenib.	('doxorubicin', 'Chemical', 'MESH:D004317', (89, 100))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (157, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('melanoma', 'Disease', (197, 205))	('AR-42', 'Chemical', 'MESH:C524513', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('urothelial carcinoma', 'Disease', (157, 177))	('osteosarcoma', 'Disease', (105, 117))	('osteosarcoma', 'Disease', 'MESH:D012516', (105, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('5-FU', 'Chemical', 'MESH:D005472', (119, 123))	('decitabine', 'Chemical', 'MESH:D000077209', (69, 79))	('AR-42', 'Var', (13, 18))	('pazopanib', 'Chemical', 'MESH:C516667', (183, 192))	('trametinib', 'Chemical', 'MESH:C560077', (225, 235))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('AML', 'Disease', 'MESH:D015470', (84, 87))	('AML', 'Phenotype', 'HP:0004808', (84, 87))	('AML', 'Disease', (84, 87))	('osteosarcoma', 'Phenotype', 'HP:0002669', (105, 117))	('dabrafenib', 'Chemical', 'MESH:C561627', (241, 251))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))
127114	33492438	A recent preclinical study also demonstrated potential for AR-42 to overcome anabolic resistance in cancer-associated cachexia.	('cachexia', 'Disease', (118, 126))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('AR-42', 'Chemical', 'MESH:C524513', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cachexia', 'Phenotype', 'HP:0004326', (118, 126))	('anabolic resistance', 'MPA', (77, 96))	('AR-42', 'Var', (59, 64))	('cancer', 'Disease', (100, 106))	('overcome', 'PosReg', (68, 76))	('cachexia', 'Disease', 'MESH:D002100', (118, 126))
127119	33492438	Unfortunately, despite encouraging preclinical studies, in a phase II study that enrolled patients with urothelial carcinoma with mutations or deletions in CREB binding protein (CREBBP) and/or E1A binding protein p300 (EP300), mocetinostat failed to show efficacy.	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('EP300', 'Gene', '2033', (219, 224))	('CREBBP', 'Gene', (178, 184))	('CREB binding protein', 'Gene', (156, 176))	('EP300', 'Gene', (219, 224))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('E1A binding protein p300', 'Gene', (193, 217))	('CREBBP', 'Gene', '1387', (178, 184))	('E1A binding protein p300', 'Gene', '2033', (193, 217))	('CREB binding protein', 'Gene', '1387', (156, 176))	('mocetinostat', 'Chemical', 'MESH:C523184', (227, 239))	('CREB binding', 'molecular_function', 'GO:0008140', ('156', '168'))	('patients', 'Species', '9606', (90, 98))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (104, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('deletions', 'Var', (143, 152))	('mutations', 'Var', (130, 139))	('binding', 'molecular_function', 'GO:0005488', ('197', '204'))	('urothelial carcinoma', 'Disease', (104, 124))
127120	33492438	However, for example, mutations in BRCA1-associated protein (BAP1), which predispose to mesotheliomas, uveal melanomas, cutaneous melanoma, and renal cell carcinoma, dysregulate HDAC proteins and sensitize cells to HDAC inhibitors.	('HDAC', 'Gene', '9734', (178, 182))	('dysregulate HDAC proteins', 'Disease', (166, 191))	('HDAC', 'Gene', '9734', (215, 219))	('uveal melanomas', 'Disease', (103, 118))	('uveal melanomas', 'Phenotype', 'HP:0007716', (103, 118))	('mesotheliomas', 'Disease', (88, 101))	('HDAC', 'Gene', (178, 182))	('BRCA1-associated protein', 'Gene', '8315', (35, 59))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (144, 164))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('HDAC', 'Gene', (215, 219))	('mesotheliomas', 'Disease', 'MESH:D008654', (88, 101))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('BAP1', 'Gene', '8314', (61, 65))	('BRCA1-associated protein', 'Gene', (35, 59))	('mutations', 'Var', (22, 31))	('dysregulate HDAC proteins', 'Disease', 'MESH:D021081', (166, 191))	('renal cell carcinoma', 'Disease', (144, 164))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (144, 164))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('uveal melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('BAP1', 'Gene', (61, 65))	('uveal melanomas', 'Disease', 'MESH:C536494', (103, 118))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('sensitize', 'Reg', (196, 205))	('cutaneous melanoma', 'Disease', (120, 138))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (120, 138))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (120, 138))
127121	33492438	Targeting solid tumors with BAP1 mutations may reveal a subset of patients that respond to AR-42.	('AR-42', 'Chemical', 'MESH:C524513', (91, 96))	('BAP1', 'Gene', '8314', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('BAP1', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutations', 'Var', (33, 42))	('solid tumors', 'Disease', (10, 22))	('solid tumors', 'Disease', 'MESH:D009369', (10, 22))	('patients', 'Species', '9606', (66, 74))
127332	32072076	Monosomy 3 is most often used as an indicator for uveal melanoma metastases since it is rarely found in other cancers.	('cancers', 'Disease', (110, 117))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('uveal melanoma metastases', 'Disease', (50, 75))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('uveal melanoma metastases', 'Disease', 'MESH:C536494', (50, 75))	('Monosomy 3', 'Var', (0, 10))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
127344	32072076	There have also been studies of combining oncorine therapy with Bcl2 pathway downregulation and GNAQ expression downregulation, using small interfering RNA.	('GNAQ', 'Gene', '2776', (96, 100))	('downregulation', 'NegReg', (77, 91))	('downregulation', 'NegReg', (112, 126))	('Bcl2', 'Gene', '596', (64, 68))	('Bcl2', 'molecular_function', 'GO:0015283', ('64', '68'))	('RNA', 'cellular_component', 'GO:0005562', ('152', '155'))	('small interfering', 'Var', (134, 151))	('GNAQ', 'Gene', (96, 100))	('Bcl2', 'Gene', (64, 68))
127365	31375769	BRAF mutations were absent in 16 of 16 cases tested.	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('mutations', 'Var', (5, 14))
127366	31375769	Pathogenic NRAS mutations were detected in 3 of 11 cases tested and were associated with shorter overall survival compared to those without NRAS alterations, but the presence of NRAS mutations did not correlate with PRAME expression.	('PRAME', 'Gene', (216, 221))	('NRAS', 'Gene', '4893', (178, 182))	('overall survival', 'MPA', (97, 113))	('Pathogenic', 'Reg', (0, 10))	('NRAS', 'Gene', '4893', (11, 15))	('NRAS', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('NRAS', 'Gene', (140, 144))	('NRAS', 'Gene', (178, 182))	('shorter', 'NegReg', (89, 96))	('PRAME', 'Gene', '23532', (216, 221))	('NRAS', 'Gene', '4893', (140, 144))
127367	31375769	In conclusion, an increase in PRAME expression and the presence of a pathogenic NRAS were both associated with a worse prognosis in mucosal melanomas.	('NRAS', 'Gene', (80, 84))	('increase', 'PosReg', (18, 26))	('presence', 'Var', (55, 63))	('mucosal melanomas', 'Disease', 'MESH:D008545', (132, 149))	('NRAS', 'Gene', '4893', (80, 84))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('mucosal melanomas', 'Disease', (132, 149))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('PRAME', 'Gene', '23532', (30, 35))	('PRAME', 'Gene', (30, 35))	('expression', 'MPA', (36, 46))	('pathogenic', 'Reg', (69, 79))
127373	31375769	Whereas BRAF mutations have been implicated in the majority of cutaneous melanomas, they are rare in mucosal melanomas, and instead the molecular characteristics of mucosal melanomas are more similar to uveal melanomas and lack the molecular signature of ultraviolet damage.	('mucosal melanomas', 'Disease', (165, 182))	('mucosal melanomas', 'Disease', (101, 118))	('uveal melanoma', 'Phenotype', 'HP:0007716', (203, 217))	('uveal melanomas', 'Disease', 'MESH:C536494', (203, 218))	('BRAF', 'Gene', '673', (8, 12))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (63, 82))	('implicated', 'Reg', (33, 43))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (63, 82))	('BRAF', 'Gene', (8, 12))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (63, 81))	('melanomas', 'Phenotype', 'HP:0002861', (173, 182))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('uveal melanomas', 'Disease', (203, 218))	('uveal melanomas', 'Phenotype', 'HP:0007716', (203, 218))	('cutaneous melanomas', 'Disease', (63, 82))	('melanomas', 'Phenotype', 'HP:0002861', (209, 218))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('mutations', 'Var', (13, 22))	('mucosal melanomas', 'Disease', 'MESH:D008545', (165, 182))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('mucosal melanomas', 'Disease', 'MESH:D008545', (101, 118))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
127405	31375769	Three of 11 cases tested (27.3%) had pathogenic NRAS mutations, (p.Q61K, p.G12C, and p.G12D).	('NRAS', 'Gene', '4893', (48, 52))	('pathogenic', 'Reg', (37, 47))	('p.Q61K', 'Mutation', 'rs121913254', (65, 71))	('p.G12D', 'Var', (85, 91))	('p.G12C', 'Mutation', 'rs121913250', (73, 79))	('p.G12C', 'Var', (73, 79))	('p.G12D', 'Mutation', 'rs121913237', (85, 91))	('NRAS', 'Gene', (48, 52))	('p.Q61K', 'Var', (65, 71))
127407	31375769	Two variants of uncertain significance were identified in KIT (p.K492R) and HRAS (p.Q70*) as passenger mutations in a case where an NRAS mutation was also present.	('NRAS', 'Gene', '4893', (132, 136))	('p.Q70*', 'Mutation', 'p.Q70*', (82, 88))	('HRAS', 'Gene', '3265', (76, 80))	('p.Q70*', 'Var', (82, 88))	('KIT', 'Gene', '3815', (58, 61))	('p.K492R', 'Var', (63, 70))	('HRAS', 'Gene', (76, 80))	('KIT', 'molecular_function', 'GO:0005020', ('58', '61'))	('KIT', 'Gene', (58, 61))	('NRAS', 'Gene', (132, 136))	('p.K492R', 'Mutation', 'p.K492R', (63, 70))
127420	31375769	Kaplan-Meier curves and the log-rank test demonstrated that activating, clinically significant NRAS mutations conferred a lower survivability (p = 0.004) when compared to those that were negative for NRAS mutations (Figure 3B).	('mutations', 'Var', (100, 109))	('lower', 'NegReg', (122, 127))	('activating', 'PosReg', (60, 70))	('NRAS', 'Gene', (200, 204))	('survivability', 'MPA', (128, 141))	('NRAS', 'Gene', '4893', (200, 204))	('NRAS', 'Gene', (95, 99))	('NRAS', 'Gene', '4893', (95, 99))
127428	31375769	We observed a trend toward higher PRAME scores for epithelioid cell predominant tumors as compared to spindle cell predominant tumors, as well as for the presence of NRAS mutations relative to the absence of NRAS mutations (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('PRAME', 'Gene', '23532', (34, 39))	('PRAME', 'Gene', (34, 39))	('tumors', 'Disease', (127, 133))	('NRAS', 'Gene', (166, 170))	('NRAS', 'Gene', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('spindle', 'cellular_component', 'GO:0005819', ('102', '109'))	('NRAS', 'Gene', '4893', (166, 170))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (171, 180))	('tumors', 'Disease', (80, 86))	('higher', 'PosReg', (27, 33))	('NRAS', 'Gene', '4893', (208, 212))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('presence', 'Var', (154, 162))
127442	31375769	It is well known that BRAF mutations are frequently seen in cutaneous melanomas, however these are infrequent in mucosal melanomas.	('mutations', 'Var', (27, 36))	('mucosal melanomas', 'Disease', (113, 130))	('cutaneous melanomas', 'Disease', (60, 79))	('melanomas', 'Phenotype', 'HP:0002861', (121, 130))	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('mucosal melanomas', 'Disease', 'MESH:D008545', (113, 130))	('seen', 'Reg', (52, 56))	('BRAF', 'Gene', '673', (22, 26))	('BRAF', 'Gene', (22, 26))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (60, 79))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (60, 79))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (60, 78))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))
127443	31375769	This was observed in our cases as well, as all were negative for BRAF mutations.	('BRAF', 'Gene', (65, 69))	('mutations', 'Var', (70, 79))	('BRAF', 'Gene', '673', (65, 69))
127444	31375769	A whole genome sequencing study recently revealed KIT mutations to be more frequent in mucosal melanomas, at 25% of cases (2 of 8) as compared to the 4.3% of cases (6 of 140) of cutaneous melanomas.	('cutaneous melanomas', 'Disease', 'MESH:C562393', (178, 197))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (178, 196))	('cutaneous melanomas', 'Disease', (178, 197))	('KIT', 'Gene', '3815', (50, 53))	('mutations', 'Var', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('KIT', 'molecular_function', 'GO:0005020', ('50', '53'))	('KIT', 'Gene', (50, 53))	('frequent', 'Reg', (75, 83))	('mucosal melanomas', 'Disease', (87, 104))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('melanomas', 'Phenotype', 'HP:0002861', (188, 197))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('mucosal melanomas', 'Disease', 'MESH:D008545', (87, 104))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (178, 197))
127447	31375769	The prognostic significance of an NRAS mutation was recently studied in cutaneous melanomas by Heppt et al., who observed tumors with NRAS mutations exhibit more aggressive behavior.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('aggressive behavior', 'biological_process', 'GO:0002118', ('162', '181'))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (72, 91))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (72, 91))	('mutations', 'Var', (139, 148))	('aggressive behavior', 'Phenotype', 'HP:0000718', (162, 181))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (72, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('cutaneous melanomas', 'Disease', (72, 91))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('NRAS', 'Gene', (134, 138))	('NRAS', 'Gene', (34, 38))	('aggressive behavior', 'CPA', (162, 181))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('NRAS', 'Gene', '4893', (34, 38))	('NRAS', 'Gene', '4893', (134, 138))
127448	31375769	Similarly, we observed that cases with pathogenic NRAS mutations had shorter overall survival as compared to cases where no mutation was present, suggesting that the presence of a pathogenic NRAS mutation also portends a poor prognosis in mucosal melanomas.	('pathogenic', 'Reg', (180, 190))	('NRAS', 'Gene', (191, 195))	('presence', 'Var', (166, 174))	('mutations', 'Var', (55, 64))	('NRAS', 'Gene', (50, 54))	('mutation', 'Var', (196, 204))	('mucosal melanomas', 'Disease', 'MESH:D008545', (239, 256))	('NRAS', 'Gene', '4893', (191, 195))	('shorter', 'NegReg', (69, 76))	('NRAS', 'Gene', '4893', (50, 54))	('melanomas', 'Phenotype', 'HP:0002861', (247, 256))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('mucosal melanomas', 'Disease', (239, 256))
127449	31375769	who observed that NRAS mutations did not significantly affect survival in sinonasal mucosal melanomas, although the prevalence of NRAS mutations in their cases (30%, 22/66 cases) was similar to our present study.	('mucosal melanomas', 'Disease', 'MESH:D008545', (84, 101))	('sinonasal', 'Disease', (74, 83))	('NRAS', 'Gene', '4893', (18, 22))	('melanomas', 'Phenotype', 'HP:0002861', (92, 101))	('mutations', 'Var', (23, 32))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('NRAS', 'Gene', (130, 134))	('NRAS', 'Gene', '4893', (130, 134))	('mucosal melanomas', 'Disease', (84, 101))	('NRAS', 'Gene', (18, 22))
127450	31375769	The review of the current literature and the molecular findings in our study lead us to suggest that although BRAF mutation status may be important to determine eligibility for possible targeted therapy options, broadening the search to include pathogenic mutations in other genes such as NRAS is more appropriate in this clinical setting.	('NRAS', 'Gene', '4893', (289, 293))	('NRAS', 'Gene', (289, 293))	('BRAF', 'Gene', '673', (110, 114))	('mutation', 'Var', (115, 123))	('BRAF', 'Gene', (110, 114))
127453	30610114	 I BET on anti-FGFR to fight cancer resistance L. Altucci and R. Benedetti discuss the study by Chua et al (in this issue of EMBO Molecular Medicine), in which co-targeting of FGFR signaling increases the responses of metastatic uveal melanoma to BET inhibitors.	('cancer', 'Disease', (29, 35))	('FGFR', 'molecular_function', 'GO:0005007', ('15', '19'))	('FGFR', 'molecular_function', 'GO:0005007', ('176', '180'))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('signaling', 'biological_process', 'GO:0023052', ('181', '190'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (229, 243))	('responses', 'MPA', (205, 214))	('uveal melanoma', 'Disease', 'MESH:C536494', (229, 243))	('increases', 'PosReg', (191, 200))	('FGFR', 'Gene', (176, 180))	('uveal melanoma', 'Disease', (229, 243))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('co-targeting', 'Var', (160, 172))
127459	30610114	Inhibition of bromodomain and extraterminal domain (BET) proteins (French, 2016) is emerging as a promising anticancer strategy to block transcriptional dependencies, yet resistance development remains a challenge (Kurimchak et al, 2016).	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('transcriptional dependencies', 'MPA', (137, 165))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
127465	30610114	Interestingly, PLX51107 increased in vivo tumor growth of UM cells co-injected into mice with hematopoietic stem cells, and the combination of PLX51107 and the FGFR inhibitor AZD4547 suppressed tumor growth.	('tumor', 'Disease', (42, 47))	('AZD4547', 'Chemical', 'MESH:C572463', (175, 182))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('PLX51107', 'Var', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('PLX51107', 'Var', (143, 151))	('increased', 'PosReg', (24, 33))	('FGFR', 'molecular_function', 'GO:0005007', ('160', '164'))	('suppressed', 'NegReg', (183, 193))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('combination', 'Interaction', (128, 139))	('mice', 'Species', '10090', (84, 88))
127468	30610114	It may indicate that liver microenvironment plays an active role in reducing the efficacy of BET inhibitors, and co-inhibition of FGFRs by AZD4547 treatment significantly suppresses tumor growth compared to PLX51107-treated mice.	('reducing', 'NegReg', (68, 76))	('tumor', 'Disease', (182, 187))	('mice', 'Species', '10090', (224, 228))	('efficacy', 'MPA', (81, 89))	('suppresses', 'NegReg', (171, 181))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('co-inhibition', 'Var', (113, 126))	('AZD4547', 'Chemical', 'MESH:C572463', (139, 146))	('AZD4547', 'Gene', (139, 146))	('FGFRs', 'Gene', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
127479	30610114	The complex cross-talk between genome and epigenome deregulations in cancer may play a key role in resistance development.	('cross-talk', 'Reg', (12, 22))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('epigenome deregulations', 'Var', (42, 65))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
127481	30610114	It is tempting to speculate that different epigenome targeting may, in the future, lead to the use of "pure" epigenome player-targeted treatments of cancer and cancer resistance.	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('epigenome targeting', 'Var', (43, 62))	('lead', 'Reg', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('pure', 'molecular_function', 'GO:0034023', ('102', '106'))
127483	30610114	Vorinostat (a well-known HDACi) is entering a Phase I and II clinical trials for UMM (NCT00121225 and NCT01587352) (Moschos et al, 2018) (Haas et al, 2014), and in the near future, the potential of epigenome-targeting schemes will likely be better defined.	('Vorinostat', 'Chemical', 'MESH:D000077337', (0, 10))	('NCT01587352', 'Var', (102, 113))	('NCT00121225', 'Var', (86, 97))
127484	28409567	SF3B1 and BAP1 mutations in blue nevus-like melanoma Blue nevi are melanocytic tumors originating in the cutaneous dermis.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('SF3B1', 'Gene', (0, 5))	('nevi', 'Phenotype', 'HP:0003764', (58, 62))	('nevus', 'Phenotype', 'HP:0003764', (33, 38))	('BAP1', 'Gene', (10, 14))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('mutations', 'Var', (15, 24))	('Blue nevi', 'Phenotype', 'HP:0100814', (53, 62))	('nevus-like melanoma Blue', 'Phenotype', 'HP:0000995', (33, 57))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('SF3B1', 'Gene', '23451', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (33, 52))	('melanocytic tumors', 'Disease', 'MESH:D009508', (67, 85))	('melanocytic tumors', 'Disease', (67, 85))	('BAP1', 'Gene', '8314', (10, 14))	('blue nevus', 'Phenotype', 'HP:0100814', (28, 38))
127487	28409567	Identifying genetic alterations in such tumors may assist in their diagnosis and prognostication.	('assist', 'Reg', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('genetic alterations', 'Var', (12, 31))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
127488	28409567	Blue nevi are known to be genetically related to uveal melanomas (eg, both harboring GNAQ and GNA11 mutations).	('mutations', 'Var', (100, 109))	('GNA11', 'Gene', '2767', (94, 99))	('melanomas', 'Phenotype', 'HP:0002861', (55, 64))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('Blue nevi', 'Disease', (0, 9))	('GNAQ', 'Gene', (85, 89))	('Blue nevi', 'Phenotype', 'HP:0100814', (0, 9))	('uveal melanomas', 'Disease', (49, 64))	('uveal melanomas', 'Phenotype', 'HP:0007716', (49, 64))	('nevi', 'Phenotype', 'HP:0003764', (5, 9))	('GNAQ', 'Gene', '2776', (85, 89))	('uveal melanomas', 'Disease', 'MESH:C536494', (49, 64))	('GNA11', 'Gene', (94, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (49, 63))
127491	28409567	In addition, rare CYSLTR2 (1%) and PLCB4 (1%) mutations were identified.	('CYSLTR2', 'Gene', '57105', (18, 25))	('CYSLTR2', 'Gene', (18, 25))	('mutations', 'Var', (46, 55))	('PLCB4', 'Gene', (35, 40))
127492	28409567	EIF1AX, SF3B1, and BAP1 mutations were also detected, with BAP1 and SF3B1 R625 mutations being present only in clearly malignant tumors (17% (n=2) and 25% (n =3) of blue nevus-like melanoma, respectively).	('SF3B1', 'Gene', (68, 73))	('mutations', 'Var', (79, 88))	('EIF1AX', 'Gene', (0, 6))	('SF3B1', 'Gene', '23451', (68, 73))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('melanoma', 'Disease', (181, 189))	('BAP1', 'Gene', '8314', (59, 63))	('EIF1AX', 'Gene', '1964', (0, 6))	('SF3B1', 'Gene', (8, 13))	('blue nevus', 'Phenotype', 'HP:0100814', (165, 175))	('BAP1', 'Gene', '8314', (19, 23))	('malignant tumors', 'Disease', 'MESH:D018198', (119, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('BAP1', 'Gene', (59, 63))	('malignant tumors', 'Disease', (119, 135))	('SF3B1', 'Gene', '23451', (8, 13))	('nevus', 'Phenotype', 'HP:0003764', (170, 175))	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (170, 189))	('BAP1', 'Gene', (19, 23))	('melanoma', 'Disease', 'MESH:D008545', (181, 189))
127494	28409567	Our findings suggest that the genetic profile of coexistent GNAQ or GNA11 mutations with BAP1 or SF3B1 mutations can aid the histopathological diagnosis of blue nevus-like melanoma and distinguish blue nevus-like melanoma from conventional epidermal-derived melanomas.	('melanomas', 'Disease', 'MESH:D008545', (258, 267))	('melanomas', 'Disease', (258, 267))	('GNA11', 'Gene', '2767', (68, 73))	('GNAQ', 'Gene', '2776', (60, 64))	('SF3B1', 'Gene', (97, 102))	('melanoma', 'Disease', 'MESH:D008545', (258, 266))	('mutations', 'Var', (103, 112))	('GNAQ', 'Gene', (60, 64))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('BAP1', 'Gene', (89, 93))	('blue nevus', 'Phenotype', 'HP:0100814', (197, 207))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('melanoma', 'Disease', (213, 221))	('melanomas', 'Phenotype', 'HP:0002861', (258, 267))	('SF3B1', 'Gene', '23451', (97, 102))	('blue nevus', 'Phenotype', 'HP:0100814', (156, 166))	('GNA11', 'Gene', (68, 73))	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (202, 221))	('melanoma', 'Phenotype', 'HP:0002861', (258, 266))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('aid', 'PosReg', (117, 120))	('melanoma', 'Disease', (258, 266))	('melanoma', 'Disease', (172, 180))	('mutations', 'Var', (74, 83))	('nevus', 'Phenotype', 'HP:0003764', (161, 166))	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (161, 180))	('melanoma', 'Disease', 'MESH:D008545', (213, 221))	('BAP1', 'Gene', '8314', (89, 93))	('nevus', 'Phenotype', 'HP:0003764', (202, 207))
127512	28409567	Epidermal-derived nevi and melanoma frequently harbor mutations in BRAF and NRAS.	('nevi', 'Phenotype', 'HP:0003764', (18, 22))	('NRAS', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (67, 71))	('mutations', 'Var', (54, 63))	('BRAF', 'Gene', (67, 71))	('NRAS', 'Gene', '4893', (76, 80))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))
127514	28409567	All of these mutations were also identified in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('identified', 'Reg', (33, 43))	('uveal melanoma', 'Disease', (47, 61))	('mutations', 'Var', (13, 22))
127516	28409567	In uveal melanomas, BAP1 mutations resulting in loss of BAP1 protein function are associated with a poor prognosis, whereas SF3B1 and EIF1AX mutations are generally associated with tumors having a favorable prognosis.	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('BAP1', 'Gene', '8314', (56, 60))	('EIF1AX', 'Gene', (134, 140))	('uveal melanomas', 'Disease', 'MESH:C536494', (3, 18))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('SF3B1', 'Gene', '23451', (124, 129))	('mutations', 'Var', (25, 34))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('EIF1AX', 'Gene', '1964', (134, 140))	('BAP1', 'Gene', (56, 60))	('BAP1', 'Gene', '8314', (20, 24))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanomas', 'Disease', (3, 18))	('tumors', 'Disease', (181, 187))	('uveal melanomas', 'Phenotype', 'HP:0007716', (3, 18))	('function', 'MPA', (69, 77))	('protein', 'Protein', (61, 68))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))	('loss', 'NegReg', (48, 52))	('BAP1', 'Gene', (20, 24))	('melanomas', 'Phenotype', 'HP:0002861', (9, 18))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('SF3B1', 'Gene', (124, 129))
127517	28409567	The genetic similarity between blue nevi and uveal melanoma has been further demonstrated by a number of recent studies reporting BAP1 mutations or protein loss occurring in blue nevus-like melanoma.	('BAP1', 'Gene', (130, 134))	('uveal melanoma', 'Disease', (45, 59))	('blue nevi', 'Phenotype', 'HP:0100814', (31, 40))	('loss', 'NegReg', (156, 160))	('blue nevus', 'Phenotype', 'HP:0100814', (174, 184))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('mutations', 'Var', (135, 144))	('nevi', 'Phenotype', 'HP:0003764', (36, 40))	('protein', 'Protein', (148, 155))	('nevus', 'Phenotype', 'HP:0003764', (179, 184))	('BAP1', 'Gene', '8314', (130, 134))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (179, 198))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('uveal melanoma', 'Disease', 'MESH:C536494', (45, 59))
127518	28409567	Similar to uveal melanocytic tumors, this fits the classic progression model, where benign tumors (nevi) frequently harbor an initial mutation (ie, a GNAQ or GNA11 mutation) and acquisition of additional genetic alterations (ie, a SF3B1, EIF1AX or BAP1 mutation) results in progression to a malignant neoplasm (melanoma).	('EIF1AX', 'Gene', (238, 244))	('BAP1', 'Gene', (248, 252))	('GNA11', 'Gene', (158, 163))	('mutation', 'Var', (164, 172))	('GNAQ', 'Gene', (150, 154))	('benign tumors', 'Disease', (84, 97))	('melanoma', 'Disease', (311, 319))	('melanoma', 'Phenotype', 'HP:0002861', (311, 319))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('SF3B1', 'Gene', (231, 236))	('results in', 'Reg', (263, 273))	('EIF1AX', 'Gene', '1964', (238, 244))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('uveal melanocytic tumors', 'Disease', (11, 35))	('uveal melanocytic tumors', 'Phenotype', 'HP:0007716', (11, 35))	('malignant neoplasm', 'Disease', 'MESH:D009369', (291, 309))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('SF3B1', 'Gene', '23451', (231, 236))	('malignant neoplasm', 'Disease', (291, 309))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('melanoma', 'Disease', 'MESH:D008545', (311, 319))	('GNA11', 'Gene', '2767', (158, 163))	('nevi', 'Phenotype', 'HP:0003764', (99, 103))	('progression', 'PosReg', (274, 285))	('benign tumors', 'Disease', 'MESH:D009369', (84, 97))	('BAP1', 'Gene', '8314', (248, 252))	('uveal melanocytic tumors', 'Disease', 'MESH:D014604', (11, 35))	('GNAQ', 'Gene', '2776', (150, 154))	('neoplasm', 'Phenotype', 'HP:0002664', (301, 309))
127520	28409567	A targeted next-generation sequencing panel covering all known recurrent mutations in these genes in uveal melanoma was applied to a cohort of 301 blue nevi of various subtypes, including tumors diagnosed as atypical cellular blue nevi or blue nevus-like melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (101, 115))	('uveal melanoma', 'Disease', (101, 115))	('blue nevus', 'Phenotype', 'HP:0100814', (239, 249))	('blue nevi', 'Phenotype', 'HP:0100814', (226, 235))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('uveal melanoma', 'Phenotype', 'HP:0007716', (101, 115))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('nevus', 'Phenotype', 'HP:0003764', (244, 249))	('melanoma', 'Disease', 'MESH:D008545', (255, 263))	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (244, 263))	('tumors', 'Disease', (188, 194))	('blue nevi', 'Phenotype', 'HP:0100814', (147, 156))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('nevi', 'Phenotype', 'HP:0003764', (152, 156))	('nevi', 'Phenotype', 'HP:0003764', (231, 235))	('melanoma', 'Phenotype', 'HP:0002861', (255, 263))	('melanoma', 'Disease', (255, 263))	('mutations', 'Var', (73, 82))	('atypical cellular blue nevi', 'Disease', (208, 235))
127529	28409567	The database of sequenced melanoma samples (n=1121) in Essen was screened for tumors where an activating GNAQ or GNA11 hotspot mutation had been identified.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('GNAQ', 'Gene', (105, 109))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('mutation', 'Var', (127, 135))	('GNA11', 'Gene', '2767', (113, 118))	('GNA11', 'Gene', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (26, 34))	('activating', 'PosReg', (94, 104))	('GNAQ', 'Gene', '2776', (105, 109))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))
127530	28409567	Tumors harboring these mutations, not reported to be of uveal or central nervous system origin, were assessed in more detail, screening available clinical data.	('uveal', 'Disease', (56, 61))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (23, 32))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('uveal', 'Disease', 'MESH:D014603', (56, 61))
127532	28409567	Particular attention was given to potential BAP1, SF3B1 and EIF1AX mutations.	('SF3B1', 'Gene', (50, 55))	('EIF1AX', 'Gene', '1964', (60, 66))	('EIF1AX', 'Gene', (60, 66))	('mutations', 'Var', (67, 76))	('SF3B1', 'Gene', '23451', (50, 55))	('BAP1', 'Gene', '8314', (44, 48))	('BAP1', 'Gene', (44, 48))
127537	28409567	All samples assessed were primary tumors, with the exception of samples suggested to be blue nevus-like melanoma by genetic analysis (5 tumor samples, including 4 metastases and 1 primary), defined as melanomas of cutaneous origin where sequencing identified activating GNAQ or GNA11 mutations.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('metastases', 'Disease', (163, 173))	('melanomas', 'Disease', 'MESH:D008545', (201, 210))	('melanomas', 'Disease', (201, 210))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('tumor', 'Disease', (34, 39))	('mutations', 'Var', (284, 293))	('activating', 'PosReg', (259, 269))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', (136, 141))	('GNA11', 'Gene', '2767', (278, 283))	('nevus', 'Phenotype', 'HP:0003764', (93, 98))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('melanomas', 'Phenotype', 'HP:0002861', (201, 210))	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (93, 112))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('GNAQ', 'Gene', '2776', (270, 274))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('GNAQ', 'Gene', (270, 274))	('melanoma', 'Disease', (201, 209))	('tumors', 'Disease', (34, 40))	('blue nevus', 'Phenotype', 'HP:0100814', (88, 98))	('metastases', 'Disease', 'MESH:D009362', (163, 173))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('GNA11', 'Gene', (278, 283))
127539	28409567	Consistent with previously reported results, the most frequent activating mutations identified were in GNAQ, 53% (143 c.626A>T Q209L, 15 c.626A>C Q209P, 1 c.627A>T A209H and 1 c.548G>A R183Q) and GNA11, 15% (44 c.626A>T Q209L and 1 c.547C>T R183C) (Figure 1).	('R183C', 'Var', (241, 246))	('c.626A>T', 'SUBSTITUTION', 'None', (118, 126))	('A209H', 'SUBSTITUTION', 'None', (164, 169))	('c.626A>T', 'Var', (118, 126))	('Q209L', 'Var', (127, 132))	('activating', 'PosReg', (63, 73))	('GNA11', 'Gene', (196, 201))	('c.548G>A', 'Var', (176, 184))	('c.626A>T', 'SUBSTITUTION', 'None', (211, 219))	('R183Q', 'SUBSTITUTION', 'None', (185, 190))	('Q209P', 'SUBSTITUTION', 'None', (146, 151))	('Q209L', 'Var', (220, 225))	('c.626A>T', 'Var', (211, 219))	('c.627A>T', 'Var', (155, 163))	('Q209L', 'SUBSTITUTION', 'None', (127, 132))	('c.627A>T', 'SUBSTITUTION', 'None', (155, 163))	('R183Q', 'Var', (185, 190))	('c.626A>C', 'SUBSTITUTION', 'None', (137, 145))	('R183C', 'SUBSTITUTION', 'None', (241, 246))	('GNAQ', 'Gene', '2776', (103, 107))	('c.547C>T', 'Var', (232, 240))	('c.626A>C', 'Var', (137, 145))	('Q209L', 'SUBSTITUTION', 'None', (220, 225))	('Q209P', 'Var', (146, 151))	('c.547C>T', 'SUBSTITUTION', 'None', (232, 240))	('GNAQ', 'Gene', (103, 107))	('GNA11', 'Gene', '2767', (196, 201))	('A209H', 'Var', (164, 169))	('c.548G>A', 'SUBSTITUTION', 'None', (176, 184))
127540	28409567	Fifteen (5%) BRAF mutations (12 c.1799A>T V600E and 1 c.227G>C G469A) and 7 (2%) NRAS mutations (3 c.182A>G Q61R, 3 c.181C>A Q61K and 1 c.34G>C G12R) were detected, most of these occurring in the combined nevi group (and was likely derived from the non-blue nevus component of the lesion).	('c.34G>C', 'Var', (136, 143))	('V600E', 'SUBSTITUTION', 'None', (42, 47))	('nevi', 'Phenotype', 'HP:0003764', (205, 209))	('c.227G>C', 'Var', (54, 62))	('c.227G>C', 'SUBSTITUTION', 'None', (54, 62))	('c.181C>A', 'SUBSTITUTION', 'None', (116, 124))	('c.182A>G', 'Var', (99, 107))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('NRAS', 'Gene', (81, 85))	('G469A', 'Var', (63, 68))	('Q61R', 'SUBSTITUTION', 'None', (108, 112))	('c.1799A>T', 'Var', (32, 41))	('c.182A>G', 'SUBSTITUTION', 'None', (99, 107))	('c.34G>C', 'SUBSTITUTION', 'None', (136, 143))	('blue nevus', 'Phenotype', 'HP:0100814', (253, 263))	('G12R', 'SUBSTITUTION', 'None', (144, 148))	('Q61R', 'Var', (108, 112))	('Q61K', 'SUBSTITUTION', 'None', (125, 129))	('Q61K', 'Var', (125, 129))	('nevus', 'Phenotype', 'HP:0003764', (258, 263))	('G12R', 'Var', (144, 148))	('V600E', 'Var', (42, 47))	('G469A', 'SUBSTITUTION', 'None', (63, 68))	('c.1799A>T', 'SUBSTITUTION', 'None', (32, 41))	('c.181C>A', 'Var', (116, 124))	('NRAS', 'Gene', '4893', (81, 85))
127541	28409567	Three (1%) PLCB4 mutations (2 c.1888G>A D630N and 1 c.1888_1889delGAinsTT D630F) were identified.	('c.1888G>A', 'SUBSTITUTION', 'None', (30, 39))	('D630F', 'SUBSTITUTION', 'None', (74, 79))	('c.1888G>A', 'Var', (30, 39))	('D630F', 'Var', (74, 79))	('c.1888_1889delGAinsTT', 'DELETION_INSERTION', 'None', (52, 73))	('D630N', 'Var', (40, 45))	('PLCB4', 'Gene', (11, 16))	('D630N', 'SUBSTITUTION', 'None', (40, 45))
127542	28409567	Four tumors (1%) harbored activating CYSLTR2 mutations (c.386T>A L129Q).	('activating', 'PosReg', (26, 36))	('CYSLTR2', 'Gene', (37, 44))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('c.386T>A', 'SUBSTITUTION', 'None', (56, 64))	('L129Q', 'Var', (65, 70))	('L129Q', 'SUBSTITUTION', 'None', (65, 70))	('c.386T>A', 'Var', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('CYSLTR2', 'Gene', '57105', (37, 44))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
127543	28409567	Generally, activating mutations were found to be mutually exclusive, with the exception of a GNA11 Q209L and PLCB4 D630N occurring mutually in one common blue nevus sample.	('nevus', 'Phenotype', 'HP:0003764', (159, 164))	('D630N', 'Var', (115, 120))	('D630N', 'Mutation', 'p.D630N', (115, 120))	('Q209L', 'Var', (99, 104))	('PLCB4', 'Gene', (109, 114))	('blue nevus', 'Phenotype', 'HP:0100814', (154, 164))	('common blue', 'Species', '42299', (147, 158))	('Q209L', 'Mutation', 'rs1057519742', (99, 104))	('GNA11', 'Gene', '2767', (93, 98))	('GNA11', 'Gene', (93, 98))
127544	28409567	In combined nevi, which demonstrated a clear conventional epidermal or compound (epidermal and dermal) nevus component adjacent to or admixed with a blue nevus component, the mutations identified were primarily BRAF mutations (50%, 8 V600E and 1 G469A) and NRAS mutations (22%, 2 Q61R and 2 Q61K).	('BRAF', 'Gene', (211, 215))	('Q61R', 'Mutation', 'rs11554290', (280, 284))	('BRAF', 'Gene', '673', (211, 215))	('G469A', 'Var', (246, 251))	('blue nevus', 'Phenotype', 'HP:0100814', (149, 159))	('G469A', 'Mutation', 'rs121913355', (246, 251))	('nevi', 'Phenotype', 'HP:0003764', (12, 16))	('NRAS', 'Gene', '4893', (257, 261))	('Q61K', 'Mutation', 'rs121913254', (291, 295))	('nevus', 'Phenotype', 'HP:0003764', (154, 159))	('V600E', 'Mutation', 'rs113488022', (234, 239))	('NRAS', 'Gene', (257, 261))	('nevus', 'Phenotype', 'HP:0003764', (103, 108))	('Q61R', 'Var', (280, 284))	('V600E', 'Var', (234, 239))
127546	28409567	In the atypical cellular blue nevi, 66% (n= 14) of tumors harbored activating GNAQ mutations.	('mutations', 'Var', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('GNAQ', 'Gene', (78, 82))	('blue nevi', 'Phenotype', 'HP:0100814', (25, 34))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('activating', 'PosReg', (67, 77))	('GNAQ', 'Gene', '2776', (78, 82))	('nevi', 'Phenotype', 'HP:0003764', (30, 34))
127548	28409567	Two mutations in EIF1AX (exon 1 or 2) were noted, a P2L and Q33* mutation, respectively (Table 3 and Supplementary Figure 1).	('Q33*', 'Var', (60, 64))	('P2L', 'Var', (52, 55))	('Q33*', 'SUBSTITUTION', 'None', (60, 64))	('EIF1AX', 'Gene', '1964', (17, 23))	('EIF1AX', 'Gene', (17, 23))
127549	28409567	The 12 tumors diagnosed as blue nevus-like melanoma harbored mutations in GNAQ in 25% (n=3), GNA11 in 33% (n=4), and BRAF in 25% (n= 3) of cases (Figures 2, 3, 4 and Supplementary Figures 2).	('GNAQ', 'Gene', (74, 78))	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (32, 51))	('nevus', 'Phenotype', 'HP:0003764', (32, 37))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('mutations', 'Var', (61, 70))	('melanoma', 'Disease', (43, 51))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('GNAQ', 'Gene', '2776', (74, 78))	('harbored', 'Reg', (52, 60))	('BRAF', 'Gene', '673', (117, 121))	('GNA11', 'Gene', '2767', (93, 98))	('GNA11', 'Gene', (93, 98))	('blue nevus', 'Phenotype', 'HP:0100814', (27, 37))	('BRAF', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
127551	28409567	Three tumors (25%) harbored SF3B1 R625 mutations (2 R625H and 1 R625C mutation, Figures 2, 3, Supplementary Figure 2).	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('SF3B1', 'Gene', (28, 33))	('tumors', 'Disease', (6, 12))	('R625C', 'Var', (64, 69))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('R625C', 'Mutation', 'rs775623976', (64, 69))	('R625', 'Var', (34, 38))	('R625H', 'Mutation', 'rs1057519961', (52, 57))	('SF3B1', 'Gene', '23451', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
127552	28409567	Two inactivating BAP1 mutations were identified, with loss of protein confirmed by immunohistochemistry (Figure 4 and Supplementary Figure 3).	('protein', 'Protein', (62, 69))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('BAP1', 'Gene', (17, 21))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
127553	28409567	All tumors demonstrating SF3B1 or BAP1 mutations additionally harbored activating GNAQ or GNA11 mutations.	('GNA11', 'Gene', '2767', (90, 95))	('GNA11', 'Gene', (90, 95))	('GNAQ', 'Gene', '2776', (82, 86))	('BAP1', 'Gene', (34, 38))	('GNAQ', 'Gene', (82, 86))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('mutations', 'Var', (39, 48))	('SF3B1', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('activating', 'PosReg', (71, 81))	('BAP1', 'Gene', '8314', (34, 38))	('SF3B1', 'Gene', '23451', (25, 30))	('mutations', 'Var', (96, 105))
127554	28409567	In two tumors, the SF3B1 (Figure 3) and BAP1 (Figure 4) mutations were detected in the melanoma, but absent in the nevus portion of the tumor.	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('BAP1', 'Gene', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('melanoma', 'Disease', (87, 95))	('mutations', 'Var', (56, 65))	('SF3B1', 'Gene', '23451', (19, 24))	('tumors', 'Disease', (7, 13))	('tumor', 'Disease', (136, 141))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('nevus', 'Phenotype', 'HP:0003764', (115, 120))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('tumor', 'Disease', (7, 12))	('BAP1', 'Gene', '8314', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('detected', 'Reg', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('SF3B1', 'Gene', (19, 24))
127555	28409567	By screening existing mutation data for melanomas harboring GNAQ or GNA11 mutations not reported as tumors of uveal or CNS origin, we identified five tumors.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumors of uveal', 'Disease', (100, 115))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('GNA11', 'Gene', '2767', (68, 73))	('GNAQ', 'Gene', '2776', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumors', 'Disease', (150, 156))	('GNAQ', 'Gene', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors of uveal', 'Disease', 'MESH:D014604', (100, 115))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('GNA11', 'Gene', (68, 73))	('tumors', 'Disease', (100, 106))	('melanomas', 'Disease', 'MESH:D008545', (40, 49))	('melanomas', 'Disease', (40, 49))	('mutations', 'Var', (74, 83))	('tumors', 'Disease', 'MESH:D009369', (100, 106))
127558	28409567	Genetic screening of the tumor revealed mutations in GNA11, SF3B1, and BAP1 (case 34, Table 3 and Figure 5).	('SF3B1', 'Gene', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('GNA11', 'Gene', (53, 58))	('tumor', 'Disease', (25, 30))	('GNA11', 'Gene', '2767', (53, 58))	('SF3B1', 'Gene', '23451', (60, 65))	('BAP1', 'Gene', '8314', (71, 75))	('mutations', 'Var', (40, 49))	('BAP1', 'Gene', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
127561	28409567	One of these two tumors (case 38, Table 3) also had a clear inactivating BAP1 mutation, confirmed by loss of BAP1 expression with immunohistochemistry (Supplementary Figure 5) further fitting the genetic profile of a blue nevus-like melanoma.	('BAP1', 'Gene', '8314', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mutation', 'Var', (78, 86))	('inactivating', 'NegReg', (60, 72))	('loss', 'NegReg', (101, 105))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (222, 241))	('BAP1', 'Gene', (73, 77))	('BAP1', 'Gene', '8314', (109, 113))	('nevus', 'Phenotype', 'HP:0003764', (222, 227))	('BAP1', 'Gene', (109, 113))	('melanoma', 'Disease', 'MESH:D008545', (233, 241))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('melanoma', 'Disease', (233, 241))	('blue nevus', 'Phenotype', 'HP:0100814', (217, 227))
127565	28409567	In addition to documenting the distribution of activating driver mutations in these tumors, it also further elucidates the unique genetic profile of malignant tumors, in particular highlighting the significance of the presence of BAP1 and SF3B1 R625 mutations in supporting a diagnosis of malignancy.	('BAP1', 'Gene', '8314', (230, 234))	('malignant tumors', 'Disease', 'MESH:D018198', (149, 165))	('SF3B1', 'Gene', '23451', (239, 244))	('BAP1', 'Gene', (230, 234))	('malignancy', 'Disease', 'MESH:D009369', (289, 299))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('R625 mutations', 'Var', (245, 259))	('malignancy', 'Disease', (289, 299))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('SF3B1', 'Gene', (239, 244))	('mutations', 'Var', (65, 74))	('malignant tumors', 'Disease', (149, 165))
127567	28409567	CYSLTR2 L129 and PLCB4 D630 mutations were rare with a frequency of around 1% (4 and 3 cases, respectively).	('CYSLTR2', 'Gene', '57105', (0, 7))	('D630', 'Var', (23, 27))	('PLCB4', 'Gene', (17, 22))	('CYSLTR2', 'Gene', (0, 7))
127568	28409567	BRAF and NRAS mutations were mostly observed in combined nevi (Figure 1) and rarely in tumors diagnosed as blue nevi.	('observed', 'Reg', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('combined nevi', 'Disease', (48, 61))	('NRAS', 'Gene', (9, 13))	('blue nevi', 'Phenotype', 'HP:0100814', (107, 116))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('NRAS', 'Gene', '4893', (9, 13))	('BRAF', 'Gene', '673', (0, 4))	('nevi', 'Phenotype', 'HP:0003764', (112, 116))	('nevi', 'Phenotype', 'HP:0003764', (57, 61))	('tumors', 'Disease', (87, 93))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
127569	28409567	One can debate if tumors harboring BRAF and NRAS mutations should be considered blue nevi or not.	('BRAF', 'Gene', (35, 39))	('mutations', 'Var', (49, 58))	('blue nevi', 'Phenotype', 'HP:0100814', (80, 89))	('NRAS', 'Gene', (44, 48))	('tumors', 'Disease', (18, 24))	('blue nevi', 'Disease', (80, 89))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('NRAS', 'Gene', '4893', (44, 48))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('nevi', 'Phenotype', 'HP:0003764', (85, 89))	('BRAF', 'Gene', '673', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
127571	28409567	For atypical or malignant melanocytic proliferations, we believe that the term 'blue nevus' should be used with caution if a BRAF or NRAS mutation is detected.	("term 'blue nevus'", 'Phenotype', 'HP:0100814', (74, 91))	('blue nevus', 'Phenotype', 'HP:0100814', (80, 90))	("'blue nevus'", 'Disease', (79, 91))	('NRAS', 'Gene', (133, 137))	('malignant melanocytic proliferations', 'Disease', (16, 52))	('nevus', 'Phenotype', 'HP:0003764', (85, 90))	('BRAF', 'Gene', '673', (125, 129))	('NRAS', 'Gene', '4893', (133, 137))	('mutation', 'Var', (138, 146))	("'blue nevus", 'Phenotype', 'HP:0100814', (79, 90))	('malignant melanocytic proliferations', 'Disease', 'MESH:D059545', (16, 52))	('BRAF', 'Gene', (125, 129))
127573	28409567	Similar to uveal melanoma, our analysis found that EIF1AX, SF3B1, and BAP1 mutations also occur in blue nevus-like melanocytic proliferations.	('EIF1AX', 'Gene', (51, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (11, 25))	('uveal melanoma', 'Disease', (11, 25))	('uveal melanoma', 'Disease', 'MESH:C536494', (11, 25))	('nevus', 'Phenotype', 'HP:0003764', (104, 109))	('melanocytic proliferations', 'Disease', 'MESH:D059545', (115, 141))	('BAP1', 'Gene', '8314', (70, 74))	('nevus-like melanocytic proliferations', 'Phenotype', 'HP:0000995', (104, 141))	('SF3B1', 'Gene', (59, 64))	('nevus-like melanocytic proliferation', 'Phenotype', 'HP:0000995', (104, 140))	('melanocytic proliferations', 'Disease', (115, 141))	('occur', 'Reg', (90, 95))	('BAP1', 'Gene', (70, 74))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('mutations', 'Var', (75, 84))	('blue nevus', 'Phenotype', 'HP:0100814', (99, 109))	('SF3B1', 'Gene', '23451', (59, 64))	('EIF1AX', 'Gene', '1964', (51, 57))
127574	28409567	In our study, SF3B1 R625 and inactivating BAP1 mutations were only identified in tumors diagnosed as malignant (blue nevus-like melanoma).	('BAP1', 'Gene', '8314', (42, 46))	('tumors', 'Disease', (81, 87))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('inactivating', 'Var', (29, 41))	('SF3B1', 'Gene', (14, 19))	('BAP1', 'Gene', (42, 46))	('blue nevus', 'Phenotype', 'HP:0100814', (112, 122))	('mutations', 'Var', (47, 56))	('R625', 'Var', (20, 24))	('SF3B1', 'Gene', '23451', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (117, 136))	('nevus', 'Phenotype', 'HP:0003764', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
127575	28409567	The BAP1 mutant tumor where follow-up data was available metastasized (case 38, Tables 3 and 4).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('BAP1', 'Gene', (4, 8))	('mutant', 'Var', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('metastasized', 'CPA', (57, 69))	('tumor', 'Disease', (16, 21))	('BAP1', 'Gene', '8314', (4, 8))
127576	28409567	In 5 tumors harboring SF3B1 mutations, follow-up data >1 year was available for 3 patients.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('SF3B1', 'Gene', '23451', (22, 27))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('mutations', 'Var', (28, 37))	('SF3B1', 'Gene', (22, 27))
127580	28409567	Sequencing did not identify BAP1 mutations and immunohistochemistry was suboptimal and inconclusive (probably reflecting lack of antigen preservation because of the age of the tissue block, Supplementary Figure 1).	('BAP1', 'Gene', '8314', (28, 32))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
127584	28409567	This data is intriguing as in uveal melanomas SF3B1 mutations are associated with tumors which do not metastasize.	('uveal melanomas', 'Disease', (30, 45))	('mutations', 'Var', (52, 61))	('uveal melanomas', 'Phenotype', 'HP:0007716', (30, 45))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('associated', 'Reg', (66, 76))	('uveal melanomas', 'Disease', 'MESH:C536494', (30, 45))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('SF3B1', 'Gene', (46, 51))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('SF3B1', 'Gene', '23451', (46, 51))
127585	28409567	Although larger cohorts will be required, the preliminary data we present here argues that both SF3B1 and BAP1 mutant tumors can metastasize and affected patients should be regularly followed up after primary complete excision.	('tumors can metastasize', 'Disease', (118, 140))	('BAP1', 'Gene', (106, 110))	('mutant', 'Var', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('SF3B1', 'Gene', (96, 101))	('patients', 'Species', '9606', (154, 162))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('BAP1', 'Gene', '8314', (106, 110))	('SF3B1', 'Gene', '23451', (96, 101))	('tumors can metastasize', 'Disease', 'MESH:D009362', (118, 140))
127586	28409567	For EIF1AX mutations (in exon 1 and 2), which occur in uveal melanomas and are associated with a favorable prognosis, their significance in blue nevus-like melanocytic proliferations is less clear.	('mutations', 'Var', (11, 20))	('nevus', 'Phenotype', 'HP:0003764', (145, 150))	('uveal melanoma', 'Phenotype', 'HP:0007716', (55, 69))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('nevus-like melanocytic proliferation', 'Phenotype', 'HP:0000995', (145, 181))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanocytic proliferations', 'Disease', 'MESH:D059545', (156, 182))	('uveal melanomas', 'Disease', (55, 70))	('uveal melanomas', 'Phenotype', 'HP:0007716', (55, 70))	('blue nevus', 'Phenotype', 'HP:0100814', (140, 150))	('nevus-like melanocytic proliferations', 'Phenotype', 'HP:0000995', (145, 182))	('EIF1AX', 'Gene', '1964', (4, 10))	('EIF1AX', 'Gene', (4, 10))	('melanocytic proliferations', 'Disease', (156, 182))	('uveal melanomas', 'Disease', 'MESH:C536494', (55, 70))
127587	28409567	We identified EIF1AX mutations in two atypical cellular blue nevi and one blue nevus-like melanoma.	('melanoma', 'Disease', (90, 98))	('EIF1AX', 'Gene', '1964', (14, 20))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('blue nevi', 'Phenotype', 'HP:0100814', (56, 65))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('blue nevus', 'Phenotype', 'HP:0100814', (74, 84))	('nevus', 'Phenotype', 'HP:0003764', (79, 84))	('nevi', 'Phenotype', 'HP:0003764', (61, 65))	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (79, 98))	('EIF1AX', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
127589	28409567	Future studies will need to further elucidate the prognostic relevance of EIF1AX, SF3B1, and BAP1 mutations.	('SF3B1', 'Gene', (82, 87))	('BAP1', 'Gene', '8314', (93, 97))	('SF3B1', 'Gene', '23451', (82, 87))	('EIF1AX', 'Gene', '1964', (74, 80))	('EIF1AX', 'Gene', (74, 80))	('mutations', 'Var', (98, 107))	('BAP1', 'Gene', (93, 97))
127603	28409567	If a GNAQ or GNA11 mutation is detected, the tumor is assumed to be a blue nevus-like melanocytic proliferation and sequencing of EIF1AX, SF3B1, and BAP1 is performed.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mutation', 'Var', (19, 27))	('GNAQ', 'Gene', (5, 9))	('BAP1', 'Gene', '8314', (149, 153))	('tumor', 'Disease', (45, 50))	('SF3B1', 'Gene', (138, 143))	('GNA11', 'Gene', (13, 18))	('EIF1AX', 'Gene', (130, 136))	('EIF1AX', 'Gene', '1964', (130, 136))	('nevus', 'Phenotype', 'HP:0003764', (75, 80))	('BAP1', 'Gene', (149, 153))	('GNA11', 'Gene', '2767', (13, 18))	('GNAQ', 'Gene', '2776', (5, 9))	('SF3B1', 'Gene', '23451', (138, 143))	('nevus-like melanocytic proliferation', 'Phenotype', 'HP:0000995', (75, 111))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('blue nevus', 'Phenotype', 'HP:0100814', (70, 80))
127604	28409567	If a clear SF3B1 R625 or inactivating BAP1 mutation (with IHC loss) is observed, we interpret this as molecular evidence in support of a diagnosis of blue nevus-like melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('nevus', 'Phenotype', 'HP:0003764', (155, 160))	('melanoma', 'Disease', (166, 174))	('IHC loss', 'Disease', (58, 66))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('BAP1', 'Gene', (38, 42))	('R625', 'Var', (17, 21))	('SF3B1', 'Gene', (11, 16))	('blue nevus', 'Phenotype', 'HP:0100814', (150, 160))	('inactivating', 'Var', (25, 37))	('SF3B1', 'Gene', '23451', (11, 16))	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (155, 174))	('BAP1', 'Gene', '8314', (38, 42))	('IHC loss', 'Disease', 'MESH:D015431', (58, 66))
127605	28409567	The implications of an EIF1AX mutation are still unclear.	('EIF1AX', 'Gene', '1964', (23, 29))	('mutation', 'Var', (30, 38))	('EIF1AX', 'Gene', (23, 29))
127609	28409567	We believe our findings clearly demonstrate that in addition to known inactivating BAP1 mutations, SF3B1 R625 mutations in conjunction with GNAQ and GNA11 mutations are a genetic marker of malignancy in blue nevus-like melanocytic proliferations.	('melanocytic proliferations', 'Disease', (219, 245))	('SF3B1', 'Gene', (99, 104))	('mutations', 'Var', (88, 97))	('nevus', 'Phenotype', 'HP:0003764', (208, 213))	('GNAQ', 'Gene', '2776', (140, 144))	('GNA11', 'Gene', (149, 154))	('malignancy', 'Disease', 'MESH:D009369', (189, 199))	('GNAQ', 'Gene', (140, 144))	('SF3B1', 'Gene', '23451', (99, 104))	('blue nevus', 'Phenotype', 'HP:0100814', (203, 213))	('BAP1', 'Gene', '8314', (83, 87))	('mutations', 'Var', (110, 119))	('malignancy', 'Disease', (189, 199))	('nevus-like melanocytic proliferation', 'Phenotype', 'HP:0000995', (208, 244))	('R625 mutations', 'Var', (105, 119))	('nevus-like melanocytic proliferations', 'Phenotype', 'HP:0000995', (208, 245))	('GNA11', 'Gene', '2767', (149, 154))	('melanocytic proliferations', 'Disease', 'MESH:D059545', (219, 245))	('BAP1', 'Gene', (83, 87))
127612	28409567	Nevertheless, future studies will need to further assess the prognostic relevance of SF3B1 or BAP1 mutations in blue nevus-like melanoma.	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('BAP1', 'Gene', '8314', (94, 98))	('SF3B1', 'Gene', (85, 90))	('blue nevus', 'Phenotype', 'HP:0100814', (112, 122))	('mutations', 'Var', (99, 108))	('SF3B1', 'Gene', '23451', (85, 90))	('BAP1', 'Gene', (94, 98))	('nevus-like melanoma', 'Phenotype', 'HP:0000995', (117, 136))	('nevus', 'Phenotype', 'HP:0003764', (117, 122))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
127614	28228113	Identification of mutations in BRAF and c-KIT lead directly to targeted treatment, but it is also helpful to know if there are driver oncogene mutations in NRAS, GNAQ or GNA11 as these patients may benefit from alternative strategies such as immunotherapy.	('NRAS', 'Gene', (156, 160))	('mutations', 'Var', (18, 27))	('GNA11', 'Gene', '2767', (170, 175))	('c-KIT', 'Gene', '3815', (40, 45))	('KIT', 'molecular_function', 'GO:0005020', ('42', '45'))	('BRAF', 'Gene', (31, 35))	('NRAS', 'Gene', '4893', (156, 160))	('patients', 'Species', '9606', (185, 193))	('BRAF', 'Gene', '673', (31, 35))	('benefit', 'PosReg', (198, 205))	('c-KIT', 'Gene', (40, 45))	('mutations', 'Var', (143, 152))	('GNA11', 'Gene', (170, 175))
127615	28228113	While polymerase chain reaction (PCR) methods are often used to detect BRAF mutations, next generation sequencing (NGS) is able to determine all of the necessary information on several genes at once, with potential advantages in turnaround time.	('mutations', 'Var', (76, 85))	('BRAF', 'Gene', (71, 75))	('BRAF', 'Gene', '673', (71, 75))
127622	28228113	Demonstration of other mutations in other driver oncogenes, particularly NRAS, GNAQ and GNA11, can be useful in determining treatment strategy, such as an early decision to use immunotherapy with CTLA4 or PDL1 inhibitors.	('NRAS', 'Gene', '4893', (73, 77))	('GNA11', 'Gene', '2767', (88, 93))	('GNA11', 'Gene', (88, 93))	('CTLA4', 'Gene', '1493', (196, 201))	('PDL1', 'Gene', '29126', (205, 209))	('mutations', 'Var', (23, 32))	('CTLA4', 'Gene', (196, 201))	('GNAQ', 'Gene', (79, 83))	('PDL1', 'Gene', (205, 209))	('NRAS', 'Gene', (73, 77))
127632	28228113	Our current panel incorporates KRAS, NRAS, EGFR, and BRAF for combined screening of common mutations in colorectal cancer, lung cancer and melanoma, known as the REB array.	('KRAS', 'Gene', (31, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('EGFR', 'Gene', (43, 47))	('colorectal cancer', 'Disease', 'MESH:D015179', (104, 121))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('NRAS', 'Gene', '4893', (37, 41))	('colorectal cancer', 'Disease', (104, 121))	('BRAF', 'Gene', '673', (53, 57))	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('lung cancer', 'Disease', (123, 134))	('BRAF', 'Gene', (53, 57))	('EGFR', 'Gene', '1956', (43, 47))	('NRAS', 'Gene', (37, 41))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('KRAS', 'Gene', '3845', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))	('mutations', 'Var', (91, 100))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))
127640	28228113	The REB array method requires little operator time or experience: it covers all BRAF mutations of relevance and >95% of reported NRAS mutations.	('BRAF', 'Gene', (80, 84))	('NRAS', 'Gene', (129, 133))	('NRAS', 'Gene', '4893', (129, 133))	('mutations', 'Var', (85, 94))	('mutations', 'Var', (134, 143))	('BRAF', 'Gene', '673', (80, 84))
127650	28228113	Driver mutations were identified in 70% of the patients studied, and in 74% of the cutaneous melanomas (all types).	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (83, 101))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (83, 102))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (83, 102))	('patients', 'Species', '9606', (47, 55))	('cutaneous melanomas', 'Disease', (83, 102))	('mutations', 'Var', (7, 16))
127653	28228113	Both mucosal melanomas tested were wild-type, but 4 of the 6 melanomas of unknown primary origin had mutations, including one GNAQ mutation suggesting that this might have been of uveal origin.	('mutations', 'Var', (101, 110))	('mucosal melanomas', 'Disease', 'MESH:D008545', (5, 22))	('melanomas', 'Disease', (13, 22))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanomas', 'Disease', 'MESH:D008545', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('melanomas', 'Disease', 'MESH:D008545', (13, 22))	('mucosal melanomas', 'Disease', (5, 22))	('melanomas', 'Disease', (61, 70))
127654	28228113	Mutations were found in 10 of the 19 uveal melanomas, with equal numbers of GNA11 and GNAQ mutations, but there were also two NRAS mutations.	('GNA11', 'Gene', '2767', (76, 81))	('GNA11', 'Gene', (76, 81))	('uveal melanomas', 'Disease', (37, 52))	('uveal melanomas', 'Phenotype', 'HP:0007716', (37, 52))	('found', 'Reg', (15, 20))	('uveal melanomas', 'Disease', 'MESH:C536494', (37, 52))	('melanomas', 'Phenotype', 'HP:0002861', (43, 52))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('uveal melanoma', 'Phenotype', 'HP:0007716', (37, 51))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', (126, 130))	('NRAS', 'Gene', '4893', (126, 130))	('GNAQ', 'Gene', (86, 90))
127656	28228113	In the remaining 80 cases, molecular investigation for BRAF mutations was done by cobas PCR.	('mutations', 'Var', (60, 69))	('cobas', 'Chemical', '-', (82, 87))	('BRAF', 'Gene', (55, 59))	('BRAF', 'Gene', '673', (55, 59))
127659	28228113	The assay failed in 2 cases, but resulted in a further 15 cases with complete correlation BRAF mutation between PCR and NGS, including 2 cases with V600K mutations: the remainder were confirmed as wild-type (100% correlation).	('BRAF', 'Gene', (90, 94))	('V600K', 'Var', (148, 153))	('resulted in', 'Reg', (33, 44))	('V600K', 'Mutation', 'rs121913227', (148, 153))	('BRAF', 'Gene', '673', (90, 94))	('mutation', 'Var', (95, 103))
127660	28228113	NRAS is present on the REB array (though not on cobas) and was completely concordant in 5 samples found to have the Q61R mutation founds by NGS.	('cobas', 'Chemical', '-', (48, 53))	('Q61R', 'Var', (116, 120))	('Q61R', 'Mutation', 'rs11554290', (116, 120))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))
127662	28228113	MEK mutation was seen in 1 case, which was under treatment with a BRAF inhibitor (vemurafenib), and a KIT mutation was identified in another case on treatment (Table 3).	('vemurafenib', 'Chemical', 'MESH:D000077484', (82, 93))	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('mutation', 'Var', (4, 12))	('BRAF', 'Gene', '673', (66, 70))	('BRAF', 'Gene', (66, 70))	('KIT', 'molecular_function', 'GO:0005020', ('102', '105'))
127667	28228113	The sample contained a GNA11 mutation, indicative of metastasis from the uveal tumour.	('mutation', 'Var', (29, 37))	('GNA11', 'Gene', '2767', (23, 28))	('GNA11', 'Gene', (23, 28))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('uveal tumour', 'Disease', (73, 85))	('uveal tumour', 'Disease', 'MESH:D014604', (73, 85))
127670	28228113	The ability of NGS to look for MEK mutations associated with resistance to vemurafenib may be helpful in guiding patient treatment, and there is a case to be made for re-testing of samples taken on progression.	('patient', 'Species', '9606', (113, 120))	('MEK', 'Gene', (31, 34))	('MEK', 'Gene', '5609', (31, 34))	('associated', 'Reg', (45, 55))	('vemurafenib', 'Chemical', 'MESH:D000077484', (75, 86))	('mutations', 'Var', (35, 44))
127671	28228113	In this series, only two patients had documented resistance, one of whom developed a MEK mutation, while the other had a KIT mutation, both of which are potentially treatable.	('MEK', 'Gene', '5609', (85, 88))	('KIT', 'molecular_function', 'GO:0005020', ('121', '124'))	('developed', 'Reg', (73, 82))	('mutation', 'Var', (89, 97))	('patients', 'Species', '9606', (25, 33))	('MEK', 'Gene', (85, 88))
127675	28228113	We now use the REB array as a triage for NGS: those patients who show a BRAF or NRAS mutation can be excluded from further testing, while those in whom it is clinically relevant to identify other driver mutations (e.g.	('NRAS', 'Gene', (80, 84))	('clinical', 'Species', '191496', (158, 166))	('BRAF', 'Gene', (72, 76))	('NRAS', 'Gene', '4893', (80, 84))	('mutation', 'Var', (85, 93))	('BRAF', 'Gene', '673', (72, 76))	('patients', 'Species', '9606', (52, 60))
127677	28228113	In reality, the REB array can be used to exclude tumours with common BRAF or NRAS mutations from further testing, allowing resources to be concentrated on sequencing cases where the driver mutation is not known, and knowledge of the KIT status of the tumour may be helpful.	('tumours', 'Disease', (49, 56))	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('KIT', 'molecular_function', 'GO:0005020', ('233', '236'))	('NRAS', 'Gene', (77, 81))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (251, 257))	('mutations', 'Var', (82, 91))	('NRAS', 'Gene', '4893', (77, 81))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('tumour', 'Disease', (251, 257))	('BRAF', 'Gene', '673', (69, 73))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('BRAF', 'Gene', (69, 73))	('tumour', 'Disease', (49, 55))
127680	28228113	The methods compared here all have the ability to find mutations within melanoma, particularly those in BRAF.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('mutations', 'Var', (55, 64))	('BRAF', 'Gene', '673', (104, 108))	('BRAF', 'Gene', (104, 108))
127681	28228113	We have found it helpful to know of NRAS mutations to manage resources, and increasingly to direct patients towards immunotherapy at an earlier stage of their management.	('NRAS', 'Gene', (36, 40))	('patients', 'Species', '9606', (99, 107))	('mutations', 'Var', (41, 50))	('NRAS', 'Gene', '4893', (36, 40))
127683	27057633	Genetic profile of GNAQ-mutated blue melanocytic neoplasms reveals mutations in genes linked to genomic instability and the PI3K pathway Melanomas arising in association with a common or cellular blue nevus (MABN) comprise a relatively rare and heterogeneous group of lethal melanomas.	('blue melanocytic neoplasms', 'Disease', (32, 58))	('PI3K', 'molecular_function', 'GO:0016303', ('124', '128'))	('melanomas', 'Disease', 'MESH:D008545', (275, 284))	('nevus', 'Phenotype', 'HP:0003764', (201, 206))	('melanomas', 'Disease', (275, 284))	('Melanomas', 'Phenotype', 'HP:0002861', (137, 146))	('blue melanocytic neoplasms', 'Disease', 'MESH:D009508', (32, 58))	('PI3K pathway', 'Pathway', (124, 136))	('GNAQ', 'Gene', '2776', (19, 23))	('blue nevus', 'Phenotype', 'HP:0100814', (196, 206))	('melanomas', 'Phenotype', 'HP:0002861', (275, 284))	('melanoma', 'Phenotype', 'HP:0002861', (275, 283))	('GNAQ', 'Gene', (19, 23))	('Melanomas', 'Disease', 'MESH:D008545', (137, 146))	('BN', 'Phenotype', 'HP:0100814', (210, 212))	('Melanomas', 'Disease', (137, 146))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (37, 58))	('neoplasms', 'Phenotype', 'HP:0002664', (49, 58))	('mutations', 'Var', (67, 76))
127684	27057633	Although GNAQ is known to be frequently mutated in common blue nevus, cellular blue nevus (CBN) and MABN and these malignant lesions present gross chromosome alterations harboring BAP1 mutations, little is known about other mutations that contribute to the development and progression of these neoplasms.	('GNAQ', 'Gene', (9, 13))	('cellular blue nevus', 'Disease', (70, 89))	('BN', 'Phenotype', 'HP:0100814', (102, 104))	('chromosome', 'cellular_component', 'GO:0005694', ('147', '157'))	('nevus', 'Phenotype', 'HP:0003764', (84, 89))	('BAP1', 'Gene', '8314', (180, 184))	('neoplasms', 'Phenotype', 'HP:0002664', (294, 303))	('GNAQ', 'Gene', '2776', (9, 13))	('BAP1', 'Gene', (180, 184))	('common blue', 'Species', '42299', (51, 62))	('mutations', 'Var', (185, 194))	('nevus', 'Phenotype', 'HP:0003764', (63, 68))	('blue nevus', 'Phenotype', 'HP:0100814', (79, 89))	('BN', 'Phenotype', 'HP:0100814', (92, 94))	('neoplasms', 'Disease', 'MESH:D009369', (294, 303))	('blue nevus', 'Phenotype', 'HP:0100814', (58, 68))	('neoplasms', 'Disease', (294, 303))
127687	27057633	All of the samples harbored a GNAQ mutation, exhibited RAS pathway activation, and harbored additional mutations in genes associated with genomic instability and epigenetic regulation (KMT2C, FANCD2, ATR, ATRX, NBN, ERCC2, SETD2, and WHSC1).	('ATR', 'Gene', (200, 203))	('ERCC2', 'Gene', (216, 221))	('activation', 'PosReg', (67, 77))	('KMT2C', 'Gene', '58508', (185, 190))	('KMT2C', 'Gene', (185, 190))	('mutation', 'Var', (35, 43))	('ERCC2', 'Gene', '2068', (216, 221))	('GNAQ', 'Gene', '2776', (30, 34))	('ATR', 'Gene', (205, 208))	('mutations', 'Var', (103, 112))	('BN', 'Phenotype', 'HP:0100814', (212, 214))	('WHSC1', 'Gene', (234, 239))	('GNAQ', 'Gene', (30, 34))	('NBN', 'Gene', '4683', (211, 214))	('SETD2', 'Gene', (223, 228))	('FANCD2', 'Gene', (192, 198))	('regulation', 'biological_process', 'GO:0065007', ('173', '183'))	('ATR', 'Gene', '545', (200, 203))	('SETD2', 'Gene', '29072', (223, 228))	('NBN', 'Gene', (211, 214))	('FANCD2', 'Gene', '2177', (192, 198))	('RAS pathway', 'Pathway', (55, 66))	('ATR', 'Gene', '545', (205, 208))	('ATRX', 'Gene', (205, 209))	('WHSC1', 'Gene', '7468', (234, 239))	('harbored', 'Reg', (19, 27))	('ATRX', 'Gene', '546', (205, 209))
127688	27057633	In addition, all neoplasms harbored mutations that directly or indirectly affected either the regulation or activation of the PI3K pathway (PIK3CA, NF1, INPP5B and GSK3B).	('PIK3CA', 'Gene', (140, 146))	('neoplasms', 'Disease', 'MESH:D009369', (17, 26))	('INPP5B', 'Gene', (153, 159))	('PI3K', 'molecular_function', 'GO:0016303', ('126', '130'))	('PI3K pathway', 'Pathway', (126, 138))	('neoplasms', 'Disease', (17, 26))	('NF1', 'Gene', '4763', (148, 151))	('GSK', 'molecular_function', 'GO:0050321', ('164', '167'))	('activation', 'MPA', (108, 118))	('GSK3B', 'Gene', (164, 169))	('INPP5B', 'Gene', '3633', (153, 159))	('NF1', 'Gene', (148, 151))	('GSK3B', 'Gene', '2932', (164, 169))	('PIK3CA', 'Gene', '5290', (140, 146))	('neoplasms', 'Phenotype', 'HP:0002664', (17, 26))	('affected', 'Reg', (74, 82))	('regulation', 'biological_process', 'GO:0065007', ('94', '104'))	('regulation', 'MPA', (94, 104))	('mutations', 'Var', (36, 45))
127695	27057633	A large proportion of cutaneous melanomas harbor mutations in genes that are part of the mitogen activated protein kinase (MAPK) pathway (i.e., BRAF and NRAS), which deregulate several important biological processes (proliferation, senescence, survival, and differentiation) in melanocytes.	('MAPK', 'Gene', (123, 127))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanomas', 'Phenotype', 'HP:0002861', (32, 41))	('BRAF', 'Gene', '673', (144, 148))	('BRAF', 'Gene', (144, 148))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('differentiation', 'CPA', (258, 273))	('mutations', 'Var', (49, 58))	('NRAS', 'Gene', (153, 157))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (22, 41))	('survival', 'CPA', (244, 252))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (22, 41))	('deregulate', 'Reg', (166, 176))	('MAPK', 'molecular_function', 'GO:0004707', ('123', '127'))	('cutaneous melanomas', 'Disease', (22, 41))	('MAPK', 'Gene', '5595;5594;5595', (123, 127))	('senescence', 'biological_process', 'GO:0010149', ('232', '242'))	('senescence', 'CPA', (232, 242))	('NRAS', 'Gene', '4893', (153, 157))
127696	27057633	In contrast, BRAF mutations are rarely found in uveal melanomas or melanomas arising from the mucosa or internal organs, and mutations in the receptor tyrosine kinase KIT are found more frequently in lentigo maligna melanoma, acral melanoma and melanomas arising from the mucosa or internal organs.	('melanomas', 'Phenotype', 'HP:0002861', (245, 254))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('acral melanoma', 'Phenotype', 'HP:0012060', (226, 240))	('melanomas', 'Disease', 'MESH:D008545', (67, 76))	('uveal melanomas', 'Disease', (48, 63))	('uveal melanomas', 'Phenotype', 'HP:0007716', (48, 63))	('lentigo maligna melanoma', 'Phenotype', 'HP:0012059', (200, 224))	('melanomas', 'Disease', (67, 76))	('BRAF', 'Gene', '673', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('BRAF', 'Gene', (13, 17))	('lentigo maligna melanoma', 'Disease', (200, 224))	('found', 'Reg', (175, 180))	('mutations', 'Var', (125, 134))	('melanomas', 'Disease', 'MESH:D008545', (245, 254))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('melanomas', 'Disease', 'MESH:D008545', (54, 63))	('acral melanoma', 'Disease', (226, 240))	('lentigo maligna melanoma', 'Disease', 'MESH:D018327', (200, 224))	('melanomas', 'Disease', (245, 254))	('melanomas', 'Disease', (54, 63))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('uveal melanomas', 'Disease', 'MESH:C536494', (48, 63))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('KIT', 'molecular_function', 'GO:0005020', ('167', '170'))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('acral melanoma', 'Disease', 'MESH:D008545', (226, 240))	('mutations', 'Var', (18, 27))
127698	27057633	Activating mutations in GNAQ and GNA11 result in a permanent increase in the number of dermal melanoblast.	('GNAQ', 'Gene', '2776', (24, 28))	('GNA11', 'Gene', (33, 38))	('Activating mutations', 'Var', (0, 20))	('GNA11', 'Gene', '2767', (33, 38))	('GNAQ', 'Gene', (24, 28))	('increase', 'PosReg', (61, 69))
127699	27057633	The mutations occur in the RAS-like domain of the protein, leading to a constitutively activated GNAQ protein that essentially converts the GNAQ protein into an activated oncogene product.	('GNAQ', 'Gene', '2776', (140, 144))	('constitutively', 'MPA', (72, 86))	('GNAQ', 'Gene', '2776', (97, 101))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('GNAQ', 'Gene', (140, 144))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('mutations', 'Var', (4, 13))	('leading to', 'Reg', (59, 69))	('GNAQ', 'Gene', (97, 101))
127701	27057633	These rates may explain why patients with a nevus of Ota who also harbor GNAQ mutations are at a higher risk of developing uveal melanoma.	('GNAQ', 'Gene', '2776', (73, 77))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('mutations', 'Var', (78, 87))	('GNAQ', 'Gene', (73, 77))	('nevus', 'Phenotype', 'HP:0003764', (44, 49))	('uveal melanoma', 'Disease', 'MESH:C536494', (123, 137))	('patients', 'Species', '9606', (28, 36))	('uveal melanoma', 'Phenotype', 'HP:0007716', (123, 137))	('uveal melanoma', 'Disease', (123, 137))	('nevus of Ota', 'Phenotype', 'HP:0009920', (44, 56))
127715	27057633	Next, we analyzed 274 mutations in 24 cancer-relevant genes (Sequenom technology), including BRAF, NRAS, KIT c-MET, GNAS and GNAQ (Supplementary Table 1).	('BRAF', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('GNAS', 'Gene', (116, 120))	('GNAQ', 'Gene', '2776', (125, 129))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('NRAS', 'Gene', (99, 103))	('KIT', 'molecular_function', 'GO:0005020', ('105', '108'))	('mutations', 'Var', (22, 31))	('KIT c-MET', 'Gene', (105, 114))	('cancer', 'Disease', (38, 44))	('GNAQ', 'Gene', (125, 129))	('NRAS', 'Gene', '4893', (99, 103))	('BRAF', 'Gene', '673', (93, 97))	('GNAS', 'Gene', '2778', (116, 120))
127716	27057633	In agreement with previous results, our data showed that all melanocytic blue neoplasms harbored mutations in GNAQc.626A > T at different frequencies (T#1: 49%, T#2: 38%, T#3: 26%, T#4: 48%) (Figure 1C).	('mutations', 'Var', (97, 106))	('melanocytic blue neoplasms', 'Disease', 'MESH:D009508', (61, 87))	('neoplasms', 'Phenotype', 'HP:0002664', (78, 87))	('GNAQ', 'Gene', '2776', (110, 114))	('melanocytic blue neoplasms', 'Disease', (61, 87))	('GNAQ', 'Gene', (110, 114))	('harbored', 'Reg', (88, 96))
127717	27057633	Thus, the blue melanocytic neoplasms showed heterogeneous histological features and harbored mutations in GNAQ which confirmed the diagnosis of these type of lesions.	('mutations', 'Var', (93, 102))	('blue melanocytic neoplasms', 'Disease', 'MESH:D009508', (10, 36))	('GNAQ', 'Gene', (106, 110))	('blue melanocytic neoplasms', 'Disease', (10, 36))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (15, 36))	('neoplasms', 'Phenotype', 'HP:0002664', (27, 36))	('GNAQ', 'Gene', '2776', (106, 110))
127723	27057633	GNAQ mutations are reported to occur in 83% of blue nevi.	('blue nevi', 'Disease', (47, 56))	('nevi', 'Phenotype', 'HP:0003764', (52, 56))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (5, 14))	('occur', 'Reg', (31, 36))	('GNAQ', 'Gene', (0, 4))	('blue nevi', 'Phenotype', 'HP:0100814', (47, 56))
127725	27057633	Although the genetic mutations that arise during the progression of uveal melanomas and Nevus of Ota are now being clarified with the detection of mutations in BAP1 and TP53, the mutational profile of CBNs and rare MABN tumors remains largely unknown.	('mutations', 'Var', (147, 156))	('Nevus', 'Phenotype', 'HP:0003764', (88, 93))	('TP53', 'Gene', '7157', (169, 173))	('BAP1', 'Gene', (160, 164))	('uveal melanomas', 'Disease', 'MESH:C536494', (68, 83))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('uveal melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('BN', 'Phenotype', 'HP:0100814', (217, 219))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('uveal melanomas', 'Disease', (68, 83))	('uveal melanomas', 'Phenotype', 'HP:0007716', (68, 83))	('BN', 'Phenotype', 'HP:0100814', (202, 204))	('melanomas', 'Phenotype', 'HP:0002861', (74, 83))	('TP53', 'Gene', (169, 173))	('MABN tumors', 'Disease', 'MESH:D009369', (215, 226))	('BAP1', 'Gene', '8314', (160, 164))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('MABN tumors', 'Disease', (215, 226))	('Nevus of Ota', 'Phenotype', 'HP:0009920', (88, 100))
127727	27057633	A total of 37 mutations with an allele frequency higher than 20% were identified in 27 genes among the four tumor samples (32 nonsynonymous substitutions, 4 stop-gains and 1 frame-shift mutation).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('frame-shift', 'Var', (174, 185))	('tumor', 'Disease', (108, 113))	('stop-gains', 'Var', (157, 167))	('nonsynonymous substitutions', 'Var', (126, 153))
127728	27057633	In addition to GNAQ, all samples showed mutations in genes related to genomic instability and important signaling pathways (Figure 3A, Supplementary Figure 2 and Supplementary Table 3).	('mutations', 'Var', (40, 49))	('GNAQ', 'Gene', (15, 19))	('GNAQ', 'Gene', '2776', (15, 19))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))
127729	27057633	The identified mutated genes with high variant frequency that are associated with genomic instability included KMT2C, FANCD2, ATR, ATRX, NBN, ERCC2, SETD2, and WHSC1 (Figure 3A and Supplementary Table 3).	('FANCD2', 'Gene', '2177', (118, 124))	('ATR', 'Gene', '545', (131, 134))	('ERCC2', 'Gene', (142, 147))	('ATR', 'Gene', (126, 129))	('ATRX', 'Gene', (131, 135))	('ERCC2', 'Gene', '2068', (142, 147))	('ATRX', 'Gene', '546', (131, 135))	('KMT2C', 'Gene', '58508', (111, 116))	('KMT2C', 'Gene', (111, 116))	('SETD2', 'Gene', '29072', (149, 154))	('variant', 'Var', (39, 46))	('WHSC1', 'Gene', '7468', (160, 165))	('BN', 'Phenotype', 'HP:0100814', (138, 140))	('NBN', 'Gene', '4683', (137, 140))	('SETD2', 'Gene', (149, 154))	('ATR', 'Gene', (131, 134))	('genomic', 'MPA', (82, 89))	('FANCD2', 'Gene', (118, 124))	('associated', 'Reg', (66, 76))	('ATR', 'Gene', '545', (126, 129))	('WHSC1', 'Gene', (160, 165))	('NBN', 'Gene', (137, 140))
127731	27057633	Tumor #1 and Tumor #2, the two different sections that belong to the same patient, showed mutations in GSK3beta (at a variant allele frequency of approximately 50%).	('GSK3beta', 'Gene', (103, 111))	('patient', 'Species', '9606', (74, 81))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (90, 99))	('GSK3beta', 'Gene', '2932', (103, 111))	('GSK', 'molecular_function', 'GO:0050321', ('103', '106'))	('Tumor', 'Phenotype', 'HP:0002664', (13, 18))
127732	27057633	Tumor #1, in addition to the mutations observed in Tumor #2, also harbored mutations in CBL (56.7%), PIKFIVE (21%), PIK3CA (38.2%), and PIK3R3 (25%), (Figure 3A).	('PIK3CA', 'Gene', (116, 122))	('PIKFIVE', 'Gene', (101, 108))	('CBL', 'Gene', '867', (88, 91))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PIK3R3', 'Gene', '8503', (136, 142))	('PIK3R3', 'Gene', (136, 142))	('Tumor', 'Phenotype', 'HP:0002664', (51, 56))	('PIK3CA', 'Gene', '5290', (116, 122))	('mutations', 'Var', (75, 84))	('CBL', 'Gene', (88, 91))
127735	27057633	TSC2 was mutated in three of four samples, although with very low frequency (Figure 3B).	('TSC2', 'Gene', '7249', (0, 4))	('TSC2', 'Gene', (0, 4))	('mutated', 'Var', (9, 16))
127739	27057633	BAP1 has been found to be frequently mutated in uveal melanoma and in one case of melanoma associated with a nevus of Ota.	('nevus of Ota', 'Phenotype', 'HP:0009920', (109, 121))	('uveal melanoma', 'Disease', (48, 62))	('BAP1', 'Gene', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('nevus', 'Phenotype', 'HP:0003764', (109, 114))	('mutated', 'Var', (37, 44))	('BAP1', 'Gene', '8314', (0, 4))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (48, 62))	('associated', 'Reg', (91, 101))
127743	27057633	In cutaneous melanomas, alterations in the RAS pathway (BRAF, NRAS and NF1) are important for melanoma development and tumor maintenance, whereas the Galphaq class of G-protein alpha subunits GNAQ and GNA11 seem to be important founder molecules in uveal melanoma and other dermal lesions, such as blue nevus, nevus of Ota and nevus of Ito.	('nevus', 'Phenotype', 'HP:0003764', (327, 332))	('NF1', 'Gene', (71, 74))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('uveal melanoma', 'Disease', (249, 263))	('cutaneous melanomas', 'Disease', (3, 22))	('uveal melanoma', 'Disease', 'MESH:C536494', (249, 263))	('nevus of Ota', 'Phenotype', 'HP:0009920', (310, 322))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('nevus of Ito', 'Disease', (327, 339))	('nevus of Ota', 'Disease', (310, 322))	('Galphaq', 'Gene', (150, 157))	('BRAF', 'Gene', (56, 60))	('BRAF', 'Gene', '673', (56, 60))	('NRAS', 'Gene', '4893', (62, 66))	('GNA11', 'Gene', '2767', (201, 206))	('nevus', 'Phenotype', 'HP:0003764', (310, 315))	('nevus', 'Phenotype', 'HP:0003764', (303, 308))	('RAS pathway', 'Pathway', (43, 54))	('uveal melanoma', 'Phenotype', 'HP:0007716', (249, 263))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanoma', 'Disease', (13, 21))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('melanoma', 'Disease', 'MESH:D008545', (255, 263))	('GNAQ', 'Gene', '2776', (192, 196))	('Galphaq', 'Gene', '2776;2767', (150, 157))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('GNAQ', 'Gene', (192, 196))	('blue nevus', 'Phenotype', 'HP:0100814', (298, 308))	('blue nevus', 'Disease', (298, 308))	('NRAS', 'Gene', (62, 66))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (3, 22))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (3, 22))	('tumor', 'Disease', (119, 124))	('alterations', 'Var', (24, 35))	('GNA11', 'Gene', (201, 206))	('NF1', 'Gene', '4763', (71, 74))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('melanoma', 'Disease', (255, 263))	('melanoma', 'Phenotype', 'HP:0002861', (255, 263))
127746	27057633	In agreement with previous data illustrating that 83% of BNs and 50% of MABNs harbored GNAQ mutations, GNAQ was mutated in all of our tumor samples at a high frequency, thus confirming that GNAQ mutation is an initiating event.	('GNAQ', 'Gene', (190, 194))	('GNAQ', 'Gene', '2776', (103, 107))	('GNAQ', 'Gene', '2776', (87, 91))	('mutations', 'Var', (92, 101))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('GNAQ', 'Gene', '2776', (190, 194))	('GNAQ', 'Gene', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('BN', 'Phenotype', 'HP:0100814', (57, 59))	('GNAQ', 'Gene', (103, 107))	('tumor', 'Disease', (134, 139))	('BN', 'Phenotype', 'HP:0100814', (74, 76))
127747	27057633	Interestingly, the genetic profile of our samples revealed two main categories of mutated genes that affect either genomic instability or relevant melanoma signaling pathways.	('affect', 'Reg', (101, 107))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('mutated genes', 'Var', (82, 95))	('melanoma', 'Disease', (147, 155))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))	('genomic instability', 'MPA', (115, 134))
127749	27057633	Furthermore, ERCC2 (XPD) is involved in nucleotide excision repair (NER) and chromosome segregation, which alterations have been associated with an increased risk of skin cancer.	('associated with', 'Reg', (129, 144))	('ERCC2', 'Gene', (13, 18))	('skin cancer', 'Disease', 'MESH:D012878', (166, 177))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('40', '66'))	('XPD', 'Gene', (20, 23))	('alterations', 'Var', (107, 118))	('chromosome', 'cellular_component', 'GO:0005694', ('77', '87'))	('XPD', 'Gene', '2068', (20, 23))	('chromosome segregation', 'biological_process', 'GO:0007059', ('77', '99'))	('involved', 'Reg', (28, 36))	('chromosome segregation', 'CPA', (77, 99))	('skin cancer', 'Phenotype', 'HP:0008069', (166, 177))	('ERCC2', 'Gene', '2068', (13, 18))	('NER', 'biological_process', 'GO:0006289', ('68', '71'))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('skin cancer', 'Disease', (166, 177))
127754	27057633	Several studies have shown that MABNs harbor a number of gross chromosome losses and chromosome rearrangements, including the partial deletion of the BAP1 locus (3p2.1), evidencing the elevated genomic instability in these tumors.	('BN', 'Phenotype', 'HP:0100814', (34, 36))	('BAP1', 'Gene', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('partial deletion', 'Var', (126, 142))	('chromosome', 'cellular_component', 'GO:0005694', ('85', '95'))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('losses', 'NegReg', (74, 80))	('chromosome rearrangements', 'CPA', (85, 110))	('BAP1', 'Gene', '8314', (150, 154))	('genomic', 'MPA', (194, 201))
127758	27057633	Moreover, because BAP1 interacts with BRCA1/2 proteins, the contribution of these mutations to BAP1 functional inactivation (i.e., shuttling between nucleus and cytoplasm) should also be investigated.	('BAP1', 'Gene', '8314', (18, 22))	('BAP1', 'Gene', (95, 99))	('nucleus', 'cellular_component', 'GO:0005634', ('149', '156'))	('BRCA1/2', 'Gene', '672;675', (38, 45))	('shuttling', 'MPA', (131, 140))	('cytoplasm', 'cellular_component', 'GO:0005737', ('161', '170'))	('interacts', 'Reg', (23, 32))	('BAP1', 'Gene', (18, 22))	('mutations', 'Var', (82, 91))	('BAP1', 'Gene', '8314', (95, 99))	('BRCA1/2', 'Gene', (38, 45))
127759	27057633	Additionally, the copy number variation of the BAP1 locus could be responsible for the lack of BAP1 expression.	('BAP1', 'Gene', (95, 99))	('lack', 'NegReg', (87, 91))	('expression', 'MPA', (100, 110))	('BAP1', 'Gene', '8314', (47, 51))	('BAP1', 'Gene', '8314', (95, 99))	('copy number variation', 'Var', (18, 39))	('BAP1', 'Gene', (47, 51))
127760	27057633	However, Tumors #3 and #4 harbored mutations in the histone methyltransferases KMT2C, SETD2 and WHSC1, which may directly contribute to the epigenetic transcriptional regulation of BAP1.	('WHSC1', 'Gene', '7468', (96, 101))	('KMT2C', 'Gene', (79, 84))	('BAP1', 'Gene', (181, 185))	('BAP1', 'Gene', '8314', (181, 185))	('contribute', 'Reg', (122, 132))	('regulation', 'biological_process', 'GO:0065007', ('167', '177'))	('WHSC1', 'Gene', (96, 101))	('Tumor', 'Phenotype', 'HP:0002664', (9, 14))	('SETD2', 'Gene', '29072', (86, 91))	('KMT2C', 'Gene', '58508', (79, 84))	('Tumors', 'Disease', (9, 15))	('Tumors', 'Disease', 'MESH:D009369', (9, 15))	('Tumors', 'Phenotype', 'HP:0002664', (9, 15))	('SETD2', 'Gene', (86, 91))	('mutations', 'Var', (35, 44))
127761	27057633	Considering that BAP1 mutational status correlates with malignancy, and BAP1 appear to be functionally inactivated in CBNs, it could be inferred that these type of lesions represent a spectrum (benign to malignant) of blue melanocytic neoplasms very difficult to classify according to their histological features, which denotes the necessity of a stricter control of these patients.	('BN', 'Phenotype', 'HP:0100814', (119, 121))	('blue melanocytic neoplasms very', 'Disease', 'MESH:D009508', (218, 249))	('malignancy', 'Disease', 'MESH:D009369', (56, 66))	('blue melanocytic neoplasms very', 'Disease', (218, 249))	('BAP1', 'Gene', '8314', (72, 76))	('neoplasms', 'Phenotype', 'HP:0002664', (235, 244))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (223, 244))	('inactivated', 'NegReg', (103, 114))	('BAP1', 'Gene', (72, 76))	('malignancy', 'Disease', (56, 66))	('patients', 'Species', '9606', (373, 381))	('BAP1', 'Gene', '8314', (17, 21))	('mutational status', 'Var', (22, 39))	('BAP1', 'Gene', (17, 21))
127762	27057633	With respect to the signaling pathways altered in these tumors, mutations in GNAQ and GNA11 appear to activate the RAS pathway in MABN, uveal melanoma and other melanocytic lesions.	('activate', 'PosReg', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('GNA11', 'Gene', (86, 91))	('melanocytic lesions', 'Disease', (161, 180))	('GNAQ', 'Gene', '2776', (77, 81))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('RAS pathway', 'Pathway', (115, 126))	('GNAQ', 'Gene', (77, 81))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('BN', 'Phenotype', 'HP:0100814', (132, 134))	('mutations', 'Var', (64, 73))	('uveal melanoma', 'Disease', (136, 150))	('uveal melanoma', 'Disease', 'MESH:C536494', (136, 150))	('melanocytic lesions', 'Disease', 'MESH:D009508', (161, 180))	('uveal melanoma', 'Phenotype', 'HP:0007716', (136, 150))	('GNA11', 'Gene', '2767', (86, 91))	('MABN', 'Disease', (130, 134))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))
127763	27057633	Our set of samples harbored mutations at GNAQc.626A > T; consequently, all tumors were positive for p-ERK1/2.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('GNAQ', 'Gene', '2776', (41, 45))	('positive', 'Reg', (87, 95))	('GNAQ', 'Gene', (41, 45))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('p-ERK1/2', 'Protein', (100, 108))	('tumors', 'Disease', (75, 81))	('mutations', 'Var', (28, 37))	('ERK1', 'molecular_function', 'GO:0004707', ('102', '106'))
127764	27057633	Multiple genetic and epigenetic aberrations that activate this pathway have been identified de novo and in acquired resistance melanoma models.	('epigenetic aberrations', 'Var', (21, 43))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))
127765	27057633	In our set of samples, Tumor #1 and Tumor #3 carried mutations in PIK3CA, with variant allele frequencies of 38% and 26%, and Tumor #4 harbored an NF1 mutation, which might activate the PI3K signaling pathway.	('signaling pathway', 'biological_process', 'GO:0007165', ('191', '208'))	('PI3K signaling', 'biological_process', 'GO:0014065', ('186', '200'))	('PIK3CA', 'Gene', (66, 72))	('mutation', 'Var', (151, 159))	('mutations', 'Var', (53, 62))	('PI3K signaling pathway', 'Pathway', (186, 208))	('NF1', 'Gene', (147, 150))	('Tumor', 'Phenotype', 'HP:0002664', (23, 28))	('activate', 'PosReg', (173, 181))	('PI3K', 'molecular_function', 'GO:0016303', ('186', '190'))	('NF1', 'Gene', '4763', (147, 150))	('Tumor', 'Phenotype', 'HP:0002664', (36, 41))	('PIK3CA', 'Gene', '5290', (66, 72))	('Tumor', 'Phenotype', 'HP:0002664', (126, 131))
127766	27057633	Furthermore, the genetic profile of the two different sections from Patient #1 (Tumors #1 and #2) indicate that Tumor #1 may have clonally evolved from Tumor #2 by acquiring mutations in the PI3K pathway, which supports the relevance of the mutations in this pathway during the progression of this malignancy.	('malignancy', 'Disease', (298, 308))	('PI3K pathway', 'Pathway', (191, 203))	('Tumors', 'Phenotype', 'HP:0002664', (80, 86))	('Tumor', 'Phenotype', 'HP:0002664', (152, 157))	('Tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PI3K', 'molecular_function', 'GO:0016303', ('191', '195'))	('Patient', 'Species', '9606', (68, 75))	('Tumors', 'Disease', (80, 86))	('Tumors', 'Disease', 'MESH:D009369', (80, 86))	('mutations', 'Var', (174, 183))	('Tumor', 'Phenotype', 'HP:0002664', (112, 117))	('malignancy', 'Disease', 'MESH:D009369', (298, 308))
127768	27057633	Intriguingly, a SRC mutation (99% frequency, probably copy-neutral LOH), which is a very infrequent mutation in melanoma, was detected in Tumor #3, which was a rare acral CBNs with a cystic degeneration in the central part of the tumor.	('tumor', 'Disease', (230, 235))	('SRC', 'Gene', '6714', (16, 19))	('Tumor', 'Phenotype', 'HP:0002664', (138, 143))	('SRC', 'Gene', (16, 19))	('BN', 'Phenotype', 'HP:0100814', (172, 174))	('mutation', 'Var', (20, 28))	('cystic degeneration', 'Disease', 'MESH:C538364', (183, 202))	('cystic degeneration', 'Phenotype', 'HP:0007667', (183, 202))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('melanoma', 'Disease', (112, 120))	('cystic degeneration', 'Disease', (183, 202))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('detected', 'Reg', (126, 134))
127773	27057633	The results showed that these tumors harbor mutations in genes related to genomic instability, which correlates with the elevated number of chromosomal aberrations observed in this type of tumor.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumor', 'Disease', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('elevated number of chromosomal aberrations', 'Phenotype', 'HP:0040012', (121, 163))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('mutations', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (30, 35))
127787	27057633	Unincorporated dNTPs were deactivated by the addition of shrimp alkaline phosphatase (0.3 U) and incubation at 37 C for 40 min, followed by the heat inactivation of the enzyme for 5 min at 85 C. Subsequently, each mutation was analyzed as the single-base extension product of a probe that annealed immediately contiguous to the mutation position.	('phosphatase', 'molecular_function', 'GO:0016791', ('73', '84'))	('mutation', 'Var', (328, 336))	('dNTPs', 'Chemical', 'MESH:D010278', (15, 20))	('deactivated', 'NegReg', (26, 37))
127791	27057633	The resulting missense variants were prioritized based on their previous detection in tumors (COSMIC database, TCGA), the predicted impact on protein function (Polyphen-2, SIFT), and the location in relevant protein domains in these genes.	('SIFT', 'Disease', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('SIFT', 'Disease', 'None', (172, 176))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('protein function', 'MPA', (142, 158))	('missense variants', 'Var', (14, 31))	('protein', 'cellular_component', 'GO:0003675', ('208', '215'))	('impact', 'Reg', (132, 138))
127802	27589805	However, aberrant and sustained activation of YAP and TAZ can lead to the formation of malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('activation', 'PosReg', (32, 42))	('lead to', 'Reg', (62, 69))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('aberrant', 'Var', (9, 17))	('malignant tumors', 'Disease', (87, 103))	('formation', 'biological_process', 'GO:0009058', ('74', '83'))	('malignant tumors', 'Disease', 'MESH:D018198', (87, 103))
127831	27589805	Mechanistically, PTPN14 interacts and localizes YAP in the cytoplasm (Figure 2), whereby the interaction between the two proteins is mediated by the PPXY motifs of PTPN14 and the WW domains of YAP.	('cytoplasm', 'cellular_component', 'GO:0005737', ('59', '68'))	('PTPN14', 'Gene', '5784', (17, 23))	('PTPN14', 'Gene', '5784', (164, 170))	('interaction', 'Interaction', (93, 104))	('PPXY motifs', 'Var', (149, 160))	('mediated by', 'Reg', (133, 144))	('PTPN14', 'Gene', (164, 170))	('PTPN14', 'Gene', (17, 23))
127846	27589805	(2015) are consistent with an earlier report that showed that mutations in APC can activate YAP through a mechanism that does not involve the beta-catenin destruction complex.	('YAP', 'CPA', (92, 95))	('APC', 'Disease', (75, 78))	('beta-catenin', 'Gene', (142, 154))	('activate', 'PosReg', (83, 91))	('APC', 'Disease', 'MESH:D011125', (75, 78))	('APC', 'cellular_component', 'GO:0005680', ('75', '78'))	('beta-catenin', 'Gene', '1499', (142, 154))	('beta-catenin destruction complex', 'cellular_component', 'GO:0030877', ('142', '174'))	('APC', 'Phenotype', 'HP:0005227', (75, 78))	('mutations', 'Var', (62, 71))
127851	27589805	This leads to the suppression of YAP activity because phosphorylation of YAP at serine 94 disrupts the interaction between YAP and TEADs.	('suppression', 'NegReg', (18, 29))	('interaction', 'Interaction', (103, 114))	('phosphorylation', 'Var', (54, 69))	('serine', 'Chemical', 'MESH:D012694', (80, 86))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('disrupts', 'NegReg', (90, 98))	('YAP activity', 'MPA', (33, 45))
127863	27589805	Ligands for GPCRs coupled to Galpha12/13, such as LPA and S1P, have been observed to generate contractive actin bundles.	('S1P', 'Gene', (58, 61))	('generate', 'PosReg', (85, 93))	('LPA', 'Chemical', 'MESH:C032881', (50, 53))	('S1P', 'Gene', '13609', (58, 61))	('GPCRs', 'Var', (12, 17))	('rat', 'Species', '10116', (89, 92))	('Galpha12/13', 'Gene', '2768;10672', (29, 40))	('Galpha12/13', 'Gene', (29, 40))	('contractive actin bundles', 'CPA', (94, 119))
127867	27589805	In Drosophila, mutations of the Hippo pathway core kinases or ectopic expression of Yorkie lead to overgrowth of organs, such as the wings and the eyes.	('Hippo', 'Gene', (32, 37))	('lead to', 'Reg', (91, 98))	('Yorkie', 'Gene', (84, 90))	('overgrowth', 'Phenotype', 'HP:0001548', (99, 109))	('Hippo', 'Gene', '37247', (32, 37))	('mutations', 'Var', (15, 24))	('Drosophila', 'Species', '7227', (3, 13))	('Yorkie', 'Gene', '37851', (84, 90))	('core', 'cellular_component', 'GO:0019013', ('46', '50'))	('overgrowth of organs', 'CPA', (99, 119))
127869	27589805	Similarly, liver enlargement is also observed in mice with knockout of Mst1/2.	('Mst1/2', 'Gene', (71, 77))	('liver enlargement', 'Disease', (11, 28))	('mice', 'Species', '10090', (49, 53))	('liver enlargement', 'Disease', 'MESH:D006529', (11, 28))	('liver enlargement', 'Phenotype', 'HP:0002240', (11, 28))	('knockout', 'Var', (59, 67))
127870	27589805	However, there is no discernable change in the size of the kidney, intestines and lung in Mst1/2 knockout mice.	('knockout', 'Var', (97, 105))	('mice', 'Species', '10090', (106, 110))	('size of the kidney', 'Phenotype', 'HP:0000105', (47, 65))	('Mst1/2', 'Gene', (90, 96))
127872	27589805	Aberrant Hippo signaling leading to abnormal activation of YAP and TAZ is frequently observed in human cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('Hippo', 'Gene', '37247', (9, 14))	('YAP', 'Gene', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Aberrant', 'Var', (0, 8))	('Hippo signaling', 'biological_process', 'GO:0035329', ('9', '24'))	('human', 'Species', '9606', (97, 102))	('TAZ', 'Gene', (67, 70))	('Hippo', 'Gene', (9, 14))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('activation', 'PosReg', (45, 55))	('cancers', 'Disease', (103, 110))
127873	27589805	These observations suggest that hyperactivation of YAP and TAZ could play a role in the development and the progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('YAP', 'Gene', (51, 54))	('role', 'Reg', (76, 80))	('hyperactivation', 'Var', (32, 47))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('TAZ', 'Gene', (59, 62))	('play', 'Reg', (69, 73))
127876	27589805	Importantly, activation of YAP by abrogating Hippo signaling, such as knocking out Mst1 and Mst2 in the mouse liver, has been shown to be sufficient to drive tumor formation in mice.	('Mst1', 'Gene', '15235', (83, 87))	('tumor', 'Disease', (158, 163))	('knocking out', 'Var', (70, 82))	('Hippo', 'Gene', '37247', (45, 50))	('Mst1', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('Hippo signaling', 'biological_process', 'GO:0035329', ('45', '60'))	('abrogating', 'NegReg', (34, 44))	('mouse', 'Species', '10090', (104, 109))	('Hippo', 'Gene', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('drive', 'PosReg', (152, 157))	('Mst2', 'Gene', '56274', (92, 96))	('formation', 'biological_process', 'GO:0009058', ('164', '173'))	('mice', 'Species', '10090', (177, 181))	('Mst2', 'Gene', (92, 96))
127877	27589805	Conversely, loss of YAP or TAZ in cancer cell lines inhibits anchorage-independent growth, reduces cell migration and invasion and blocks the self-renewal capability of cancer stem cells.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', (169, 175))	('anchorage-independent growth', 'CPA', (61, 89))	('TAZ', 'Gene', (27, 30))	('YAP', 'Protein', (20, 23))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('inhibits', 'NegReg', (52, 60))	('loss', 'Var', (12, 16))	('reduces', 'NegReg', (91, 98))	('cancer', 'Disease', (34, 40))	('cell migration', 'biological_process', 'GO:0016477', ('99', '113'))	('blocks', 'NegReg', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('rat', 'Species', '10116', (107, 110))
127892	27589805	In contrast, knockdown of TAZ inhibits the self-renewal and tumor-initiating potential of breast cancer cells.	('TAZ', 'Gene', (26, 29))	('self-renewal', 'CPA', (43, 55))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('tumor', 'Disease', (60, 65))	('knockdown', 'Var', (13, 22))	('inhibits', 'NegReg', (30, 38))
127904	27589805	Importantly, shRNA knockdown of MST1 enhances YAP expression and triggers apoptosis in multiple myeloma cells.	('apoptosis', 'CPA', (74, 83))	('multiple myeloma', 'Phenotype', 'HP:0006775', (87, 103))	('multiple myeloma', 'Disease', 'MESH:D009101', (87, 103))	('multiple myeloma', 'Disease', (87, 103))	('knockdown', 'Var', (19, 28))	('MST1', 'Gene', '6789', (32, 36))	('enhances', 'PosReg', (37, 45))	('YAP expression', 'MPA', (46, 60))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('MST1', 'Gene', (32, 36))	('triggers', 'Reg', (65, 73))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))
127907	27589805	Strikingly, very few inactivating mutations of the Hippo pathway components have been identified, except for LATS2 and SAV1 in malignant mesothelioma, as well as mutations in NF2 in neurofibromatosis.	('mutations', 'Var', (162, 171))	('SAV1', 'Gene', '60485', (119, 123))	('Hippo', 'Gene', '37247', (51, 56))	('LATS2', 'Gene', (109, 114))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (127, 149))	('LATS2', 'Gene', '26524', (109, 114))	('NF2', 'Gene', '4771', (175, 178))	('neurofibromatosis', 'Disease', (182, 199))	('SAV1', 'Gene', (119, 123))	('Hippo', 'Gene', (51, 56))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (127, 149))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (182, 199))	('NF2', 'Gene', (175, 178))	('neurofibromatosis', 'Disease', 'MESH:C537392', (182, 199))	('malignant mesothelioma', 'Disease', (127, 149))
127909	27589805	Gene amplification is a mechanism for overexpressing YAP and TAZ in oral squamous cell carcinoma and ependymomas.	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (68, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('TAZ', 'Gene', (61, 64))	('oral squamous cell carcinoma', 'Disease', (68, 96))	('ependymomas', 'Disease', 'MESH:D004806', (101, 112))	('Gene amplification', 'Var', (0, 18))	('YAP', 'Gene', (53, 56))	('overexpressing', 'PosReg', (38, 52))	('ependymomas', 'Disease', (101, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
127912	27589805	Two recent studies have shown that activating mutations in the genes that encode for Galphaq and Galpha11 are observed in approximately 80% of uveal melanomas.	('Galpha11', 'Gene', (97, 105))	('mutations', 'Var', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanomas', 'Phenotype', 'HP:0002861', (149, 158))	('uveal melanomas', 'Disease', (143, 158))	('uveal melanomas', 'Phenotype', 'HP:0007716', (143, 158))	('Galpha11', 'Gene', '2767', (97, 105))	('activating', 'PosReg', (35, 45))	('uveal melanomas', 'Disease', 'MESH:C536494', (143, 158))	('Galphaq', 'Gene', (85, 92))	('Galphaq', 'Gene', '2776', (85, 92))	('uveal melanoma', 'Phenotype', 'HP:0007716', (143, 157))
127913	27589805	These mutations drive the development of uveal melanoma by activating YAP via LATS-dependent and LATS-independent mechanisms.	('drive', 'Reg', (16, 21))	('uveal melanoma', 'Disease', (41, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (41, 55))	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('YAP', 'Gene', (70, 73))	('activating', 'PosReg', (59, 69))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('mutations', 'Var', (6, 15))
127914	27589805	Importantly, the use of a YAP inhibitor can suppress the growth of uveal melanoma cells both in vitro and in vivo, which strongly supports the notion of targeting YAP to treat uveal melanomas with Galphaq and Galpha11 mutations.	('Galpha11', 'Gene', '2767', (209, 217))	('uveal melanoma', 'Phenotype', 'HP:0007716', (176, 190))	('uveal melanomas', 'Disease', 'MESH:C536494', (176, 191))	('mutations', 'Var', (218, 227))	('uveal melanomas', 'Phenotype', 'HP:0007716', (176, 191))	('uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('uveal melanoma', 'Disease', (67, 81))	('uveal melanoma', 'Disease', 'MESH:C536494', (67, 81))	('suppress', 'NegReg', (44, 52))	('Galpha11', 'Gene', (209, 217))	('Galphaq', 'Gene', (197, 204))	('Galphaq', 'Gene', '2776', (197, 204))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('melanomas', 'Phenotype', 'HP:0002861', (182, 191))	('uveal melanomas', 'Disease', (176, 191))	('uveal melanoma', 'Disease', 'MESH:C536494', (176, 190))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
127917	27589805	Intriguingly, coexpression of oncogenic KRAS with a YAP mutant that is refractory to LATS phosphorylation could further stimulate the expression of YAP target genes, such as CTGF and cysteine-rich angiogenic inducer 61 (CYR61).	('CTGF', 'Gene', (174, 178))	('CYR61', 'Gene', '3491', (220, 225))	('expression', 'MPA', (134, 144))	('stimulate', 'PosReg', (120, 129))	('phosphorylation', 'biological_process', 'GO:0016310', ('90', '105'))	('mutant', 'Var', (56, 62))	('YAP', 'Gene', (52, 55))	('cysteine-rich angiogenic inducer 61', 'Gene', (183, 218))	('cysteine-rich angiogenic inducer 61', 'Gene', '3491', (183, 218))	('CYR61', 'Gene', (220, 225))	('CTGF', 'Gene', '1490', (174, 178))
127918	27589805	These observations suggest that oncogenic KRAS can enhance the transcriptional activity of YAP through a mechanism that is independent of the Hippo signaling pathway.	('oncogenic', 'Var', (32, 41))	('Hippo', 'Gene', '37247', (142, 147))	('transcriptional activity', 'MPA', (63, 87))	('enhance', 'PosReg', (51, 58))	('Hippo', 'Gene', (142, 147))	('YAP', 'Gene', (91, 94))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('142', '165'))
127919	27589805	Crucially, loss of YAP in the pancreas inhibits the development of pancreatic ductal adenocarcinoma in a genetically-engineered Kras mouse model, implying that YAP is a promising target for cancers harboring activating mutations in KRAS.	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (67, 99))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('pancreatic ductal adenocarcinoma', 'Disease', (67, 99))	('cancers', 'Disease', (190, 197))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (67, 99))	('loss', 'Var', (11, 15))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('Kras', 'Gene', '16653', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('YAP', 'Gene', (19, 22))	('mouse', 'Species', '10090', (133, 138))	('Kras', 'Gene', (128, 132))	('inhibits', 'NegReg', (39, 47))	('development', 'CPA', (52, 63))
127938	27589805	Forced expression of a dominant-negative mutant of Yap in Xenopus tadpoles impedes the regeneration of the hindlimb after amputation.	('impedes', 'NegReg', (75, 82))	('mutant', 'Var', (41, 47))	('regeneration', 'biological_process', 'GO:0031099', ('87', '99'))	('Yap', 'Gene', (51, 54))	('regeneration of the hindlimb after amputation', 'CPA', (87, 132))	('Xenopus', 'Species', '8355', (58, 65))	('rat', 'Species', '10116', (93, 96))
127939	27589805	In M. lignano, a certain species of flatworm, knockdown of the core components of the Hippo signaling pathway promotes regeneration after cutting.	('Hippo', 'Gene', '37247', (86, 91))	('regeneration after', 'CPA', (119, 137))	('rat', 'Species', '10116', (125, 128))	('knockdown', 'Var', (46, 55))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('86', '109'))	('Hippo', 'Gene', (86, 91))	('promotes', 'PosReg', (110, 118))	('core', 'cellular_component', 'GO:0019013', ('63', '67'))	('regeneration', 'biological_process', 'GO:0031099', ('119', '131'))	('M. lignano', 'Species', '282301', (3, 13))
127942	27589805	(2013) have shown that conditional knockout of Salvador to inactivate Hippo signaling promotes heart regeneration in mice after resection of the cardiac apex, as well as after myocardial infarction.	('heart regeneration', 'CPA', (95, 113))	('regeneration', 'biological_process', 'GO:0031099', ('101', '113'))	('apex', 'cellular_component', 'GO:0097683', ('153', '157'))	('myocardial infarction', 'Disease', (176, 197))	('myocardial infarction', 'Phenotype', 'HP:0001658', (176, 197))	('myocardial infarction', 'Disease', 'MESH:D009203', (176, 197))	('mice', 'Species', '10090', (117, 121))	('Hippo', 'Gene', (70, 75))	('promotes', 'PosReg', (86, 94))	('Salvador', 'Gene', '252554', (47, 55))	('Hippo signaling', 'biological_process', 'GO:0035329', ('70', '85'))	('knockout', 'Var', (35, 43))	('inactivate', 'NegReg', (59, 69))	('Salvador', 'Gene', (47, 55))	('Hippo', 'Gene', '37247', (70, 75))	('rat', 'Species', '10116', (107, 110))
127954	27589805	A decrease in crypt proliferation after irradiation is also observed in mice with knockout of Yap specifically in intestinal epithelial cells and intestinal stem cells.	('decrease', 'NegReg', (2, 10))	('knockout', 'Var', (82, 90))	('Yap', 'Gene', (94, 97))	('rat', 'Species', '10116', (27, 30))	('mice', 'Species', '10090', (72, 76))	('crypt proliferation', 'CPA', (14, 33))
127956	27589805	Intriguingly, loss of YAP in intestinal epithelial cells promotes tissue hyperplasia in the long term by hyperactivating WNT signaling.	('hyperplasia', 'Disease', (73, 84))	('loss', 'Var', (14, 18))	('WNT signaling', 'Pathway', (121, 134))	('hyperplasia', 'Disease', 'MESH:D006965', (73, 84))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('YAP', 'Gene', (22, 25))	('hyperactivating', 'PosReg', (105, 120))	('promotes', 'PosReg', (57, 65))
127958	27589805	Mice with knockout of Yap in intestinal epithelial cells demonstrated a higher mortality rate and a more extensive loss of crypt compartments when compared to wildtype mice after DSS-induced colitis and regeneration.	('loss', 'NegReg', (115, 119))	('DSS', 'Chemical', 'MESH:D016264', (179, 182))	('mice', 'Species', '10090', (168, 172))	('colitis', 'Disease', 'MESH:D003092', (191, 198))	('rat', 'Species', '10116', (209, 212))	('rat', 'Species', '10116', (64, 67))	('knockout', 'Var', (10, 18))	('colitis', 'Disease', (191, 198))	('rat', 'Species', '10116', (89, 92))	('regeneration', 'biological_process', 'GO:0031099', ('203', '215'))	('Mice', 'Species', '10090', (0, 4))	('Yap', 'Gene', (22, 25))	('colitis', 'Phenotype', 'HP:0002583', (191, 198))
127984	27589805	As a result, tankyrase inhibitors antagonize YAP activity by stabilizing AMOTs.	('YAP activity', 'MPA', (45, 57))	('inhibitors', 'Var', (23, 33))	('tankyrase', 'Gene', '8658', (13, 22))	('AMOT', 'Gene', '154796', (73, 77))	('tankyrase', 'Gene', (13, 22))	('antagonize', 'NegReg', (34, 44))	('AMOT', 'Gene', (73, 77))	('stabilizing', 'Reg', (61, 72))
127985	27589805	There are several tankyrase inhibitors available, such as XAV939, inhibitor of WNT response 1 (IWR-1), G007-LK and G244-LM.	('G244-LM', 'Var', (115, 122))	('XAV939', 'Chemical', 'MESH:C544261', (58, 64))	('G007-LK', 'Var', (103, 110))	('tankyrase', 'Gene', '8658', (18, 27))	('tankyrase', 'Gene', (18, 27))	('XAV939', 'Var', (58, 64))
127992	27589805	These observations suggest that antagonizing the activity of CYR61 and CTGF could be a potential approach to treat YAP- and TAZ-dependent tumors.	('activity', 'MPA', (49, 57))	('CYR61', 'Gene', (61, 66))	('CTGF', 'Gene', '1490', (71, 75))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('CYR61', 'Gene', '3491', (61, 66))	('CTGF', 'Gene', (71, 75))	('antagonizing', 'Var', (32, 44))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
127995	27589805	Since siRNA knockdown of CTGF or CYR61 has been shown to inhibit the growth of transformed mammary epithelial cells that express high levels of YAP or TAZ, it will be interesting to test whether these antibodies have an effect on YAP/TAZ-dependent tumors in humans.	('CTGF', 'Gene', (25, 29))	('CYR61', 'Gene', (33, 38))	('growth', 'CPA', (69, 75))	('inhibit', 'NegReg', (57, 64))	('knockdown', 'Var', (12, 21))	('tumors', 'Disease', (248, 254))	('CYR61', 'Gene', '3491', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('humans', 'Species', '9606', (258, 264))	('CTGF', 'Gene', '1490', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
127997	27589805	RNAi-mediated knockdown of AXL inhibited cell survival and cell invasion in liver cancer cell lines that express high levels of YAP.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cell invasion', 'CPA', (59, 72))	('AXL', 'Gene', (27, 30))	('AXL', 'Gene', '558', (27, 30))	('liver cancer', 'Phenotype', 'HP:0002896', (76, 88))	('liver cancer', 'Disease', 'MESH:D006528', (76, 88))	('RNAi', 'biological_process', 'GO:0016246', ('0', '4'))	('knockdown', 'Var', (14, 23))	('inhibited', 'NegReg', (31, 40))	('liver cancer', 'Disease', (76, 88))	('cell survival', 'CPA', (41, 54))
128009	27589805	A recent study demonstrated that hyperactivated YAP signaling drives the recruitment of myeloid-derived suppressor cells, which promotes tumor progression in a mouse model of prostate cancer.	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('tumor', 'Disease', (137, 142))	('prostate cancer', 'Phenotype', 'HP:0012125', (175, 190))	('hyperactivated', 'Var', (33, 47))	('rat', 'Species', '10116', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('YAP', 'Protein', (48, 51))	('prostate cancer', 'Disease', (175, 190))	('recruitment', 'CPA', (73, 84))	('promotes', 'PosReg', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('mouse', 'Species', '10090', (160, 165))	('prostate cancer', 'Disease', 'MESH:D011471', (175, 190))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
128017	27589805	Remarkably, these anti-AREG antibodies have been shown to suppress the growth of ovarian cancer cells in a xenograft model.	('ovarian cancer', 'Phenotype', 'HP:0100615', (81, 95))	('ovarian cancer', 'Disease', 'MESH:D010051', (81, 95))	('anti-AREG', 'Protein', (18, 27))	('ovarian cancer', 'Disease', (81, 95))	('growth', 'CPA', (71, 77))	('antibodies', 'Var', (28, 38))	('suppress', 'NegReg', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
128024	27589805	For instance, in mammary epithelial cells, forced expression of YAP with mutations in the WW domains enhances cell migration and cell transformation when compared to cells expressing wildtype YAP.	('rat', 'Species', '10116', (118, 121))	('cell migration', 'CPA', (110, 124))	('cell migration', 'biological_process', 'GO:0016477', ('110', '124'))	('cell transformation', 'CPA', (129, 148))	('mutations in', 'Var', (73, 85))	('YAP', 'Gene', (64, 67))	('enhances', 'PosReg', (101, 109))
128031	27589805	Therefore, suppressing YES1 activity could be effective in cancers driven by aberrant YAP and beta-catenin activity.	('activity', 'MPA', (28, 36))	('YES1', 'Gene', '7525', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('beta-catenin', 'Gene', (94, 106))	('suppressing', 'NegReg', (11, 22))	('beta-catenin', 'Gene', '1499', (94, 106))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('YES1', 'Gene', (23, 27))	('cancers', 'Disease', (59, 66))	('YAP', 'MPA', (86, 89))	('aberrant', 'Var', (77, 85))
128036	27589805	Crucially, treatment with PI3K and PDK1 inhibitors can inhibit the accumulation of YAP in the nucleus by EGF.	('EGF', 'Gene', (105, 108))	('accumulation', 'MPA', (67, 79))	('EGF', 'molecular_function', 'GO:0005154', ('105', '108'))	('inhibitors', 'Var', (40, 50))	('EGF', 'Gene', '1950', (105, 108))	('nucleus', 'cellular_component', 'GO:0005634', ('94', '101'))	('PI3K', 'molecular_function', 'GO:0016303', ('26', '30'))	('PDK1', 'Gene', '5163', (35, 39))	('PDK1', 'molecular_function', 'GO:0004740', ('35', '39'))	('inhibit', 'NegReg', (55, 62))	('PDK1', 'Gene', (35, 39))
128038	27589805	However, it is important to note that targeting the EGFR signaling pathway does not exclusively target Hippo signaling, because targeting EGFR signaling also affects other oncogenic and non-oncogenic cellular functions.	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))	('oncogenic', 'CPA', (172, 181))	('EGFR', 'Gene', '1956', (138, 142))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('Hippo signaling', 'biological_process', 'GO:0035329', ('103', '118'))	('EGFR', 'molecular_function', 'GO:0005006', ('138', '142'))	('affects', 'Reg', (158, 165))	('Hippo', 'Gene', (103, 108))	('EGFR', 'Gene', (138, 142))	('EGFR signaling pathway', 'biological_process', 'GO:0007173', ('52', '74'))	('Hippo', 'Gene', '37247', (103, 108))	('signaling', 'biological_process', 'GO:0023052', ('143', '152'))	('targeting', 'Var', (128, 137))
128041	27589805	9E1 inhibits MST1 in the nanomolar range, and it can also inhibit endogenous MST1 kinase activity in cells.	('kinase activity', 'molecular_function', 'GO:0016301', ('82', '97'))	('inhibits', 'NegReg', (4, 12))	('MST1', 'Gene', (77, 81))	('9E1', 'Var', (0, 3))	('inhibit', 'NegReg', (58, 65))	('MST1', 'Gene', '6789', (13, 17))	('MST1', 'Gene', (13, 17))	('MST1', 'Gene', '6789', (77, 81))
128051	27589805	More importantly, treatment with BrP-LPA has been shown to suppress tumor growth in a lung cancer xenograft model.	('tumor', 'Disease', (68, 73))	('BrP-LPA', 'Var', (33, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('LPA', 'Chemical', 'MESH:C032881', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('suppress', 'NegReg', (59, 67))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
128057	27589805	ABC294640 is a small molecule inhibitor of SPHK2 that has been developed.	('SPHK2', 'Gene', (43, 48))	('SPHK2', 'Gene', '56848', (43, 48))	('ABC294640', 'Var', (0, 9))	('ABC294640', 'Chemical', 'MESH:C548780', (0, 9))
128064	27589805	Recent studies have demonstrated that some miRNAs play a role in tumorigenesis and disease progression in several cancer types by inactivating the Hippo signaling pathway.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('tumor', 'Disease', (65, 70))	('miRNAs', 'Var', (43, 49))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('147', '170'))	('inactivating', 'NegReg', (130, 142))	('Hippo', 'Gene', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('rat', 'Species', '10116', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Hippo', 'Gene', '37247', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('cancer', 'Disease', (114, 120))
128065	27589805	(2013) have reported that miR-135b expression is elevated in highly-invasive lung cancer cell lines and that high levels of miR-135b can enhance lung cancer invasion and metastasis in xenograft mouse models.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('enhance', 'PosReg', (137, 144))	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('expression', 'MPA', (35, 45))	('mouse', 'Species', '10090', (194, 199))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('miR-135b', 'Gene', (26, 34))	('miR-135b', 'Var', (124, 132))	('lung cancer', 'Disease', (145, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('elevated', 'PosReg', (49, 57))	('lung cancer', 'Disease', (77, 88))
128066	27589805	Mechanistically, miR-135b promotes lung cancer metastasis by repressing genes within the Hippo signaling pathway, such as LATS2, MOB1B and NDR2.	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('89', '112'))	('Hippo', 'Gene', (89, 94))	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('promotes', 'PosReg', (26, 34))	('NDR2', 'Gene', '23012', (139, 143))	('LATS2', 'Gene', (122, 127))	('MOB1B', 'Gene', '92597', (129, 134))	('LATS2', 'Gene', '26524', (122, 127))	('miR-135b', 'Var', (17, 25))	('repressing', 'NegReg', (61, 71))	('genes', 'MPA', (72, 77))	('lung cancer', 'Disease', (35, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('NDR2', 'Gene', (139, 143))	('Hippo', 'Gene', '37247', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('MOB1B', 'Gene', (129, 134))
128067	27589805	Crucially, the use of an antagomir against miR-135b is able to inhibit tumor growth and metastasis.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('miR-135b', 'Gene', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('inhibit', 'NegReg', (63, 70))	('antagomir', 'Var', (25, 34))
128166	25874144	Inactivation of the BAP1 gene which codes for an enzyme that binds to BRCA1 and BARD1 in regulating the tumor suppressor complex has been described in up to 84% of class 2 uveal melanomas.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('BARD1', 'Gene', '580', (80, 85))	('uveal melanoma', 'Phenotype', 'HP:0007716', (172, 186))	('BARD1', 'Gene', (80, 85))	('described', 'Reg', (138, 147))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('104', '120'))	('uveal melanomas', 'Disease', (172, 187))	('uveal melanomas', 'Phenotype', 'HP:0007716', (172, 187))	('BAP1', 'Gene', '8314', (20, 24))	('Inactivation', 'Var', (0, 12))	('tumor suppressor', 'biological_process', 'GO:0051726', ('104', '120'))	('tumor', 'Disease', (104, 109))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanomas', 'Phenotype', 'HP:0002861', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('BAP1', 'Gene', (20, 24))	('BRCA1', 'Gene', '672', (70, 75))	('BRCA1', 'Gene', (70, 75))	('uveal melanomas', 'Disease', 'MESH:C536494', (172, 187))
128167	25874144	Loss of BAP1, as is the case in monosomy 3, may predispose a patient to uveal melanoma for tumor recurrence.	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('patient', 'Species', '9606', (61, 68))	('BAP1', 'Gene', '8314', (8, 12))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('uveal melanoma for tumor', 'Disease', (72, 96))	('BAP1', 'Gene', (8, 12))	('uveal melanoma for tumor', 'Disease', 'MESH:C536494', (72, 96))	('Loss', 'Var', (0, 4))	('predispose', 'Reg', (48, 58))
128170	25874144	GNAQ and GNA11 mutations cause upregulation of the MAPK pathway, and responses to the MEK inhibitor selumetinib have been reported in early studies.	('GNA11', 'Gene', (9, 14))	('MAPK pathway', 'Pathway', (51, 63))	('selumetinib', 'Chemical', 'MESH:C517975', (100, 111))	('GNAQ', 'Gene', '2776', (0, 4))	('MEK', 'Gene', (86, 89))	('mutations', 'Var', (15, 24))	('MEK', 'Gene', '5609', (86, 89))	('MAPK', 'molecular_function', 'GO:0004707', ('51', '55'))	('GNAQ', 'Gene', (0, 4))	('GNA11', 'Gene', '2767', (9, 14))	('upregulation', 'PosReg', (31, 43))
128179	22411663	Therefore, modulation of TSP1 expression and/or activity may be beneficial in treatment of uveal melanoma.	('TSP1', 'Protein', (25, 29))	('modulation', 'Var', (11, 21))	('expression', 'MPA', (30, 40))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('activity', 'MPA', (48, 56))	('TSP1', 'molecular_function', 'GO:0004277', ('25', '29'))	('uveal melanoma', 'Disease', 'MESH:C536494', (91, 105))	('uveal melanoma', 'Phenotype', 'HP:0007716', (91, 105))	('uveal melanoma', 'Disease', (91, 105))
128184	22411663	The abrogation of this balance, under various pathological conditions such as cancer, promotes the growth of new blood vessels.	('growth of new blood vessels', 'CPA', (99, 126))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('promotes', 'PosReg', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('abrogation', 'Var', (4, 14))
128186	22411663	Re-expression of TSP1 attenuates the growth and metastasis of a variety of solid tumors.	('TSP1', 'Gene', (17, 21))	('solid tumors', 'Disease', 'MESH:D009369', (75, 87))	('Re-expression', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('TSP1', 'molecular_function', 'GO:0004277', ('17', '21'))	('attenuates', 'NegReg', (22, 32))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('solid tumors', 'Disease', (75, 87))
128236	22411663	Tumor development and progression was significantly delayed in Tyr-Tag; TSP1 transgenic mice compared to Tyr-Tag mice.	('progression', 'CPA', (22, 33))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (113, 117))	('Tyr', 'Chemical', 'MESH:D014443', (63, 66))	('Tag', 'Gene', (109, 112))	('Tumor development', 'CPA', (0, 17))	('Tag', 'Gene', '107423', (67, 70))	('transgenic', 'Var', (77, 87))	('transgenic mice', 'Species', '10090', (77, 92))	('TSP1', 'molecular_function', 'GO:0004277', ('72', '76'))	('delayed', 'NegReg', (52, 59))	('TSP1', 'Gene', (72, 76))	('Tag', 'Gene', '107423', (109, 112))	('Tyr', 'Chemical', 'MESH:D014443', (105, 108))	('mice', 'Species', '10090', (88, 92))	('Tag', 'Gene', (67, 70))
128248	22411663	Thus, modulation of TSP1 expression or its antiangiogenic mimetic peptides may provide a novel approach for treatment of uveal melanoma and inhibition of tumor growth.	('modulation', 'Var', (6, 16))	('tumor', 'Disease', (154, 159))	('uveal melanoma', 'Disease', (121, 135))	('uveal melanoma', 'Phenotype', 'HP:0007716', (121, 135))	('TSP1', 'Gene', (20, 24))	('peptides', 'Chemical', 'MESH:D010455', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('TSP1', 'molecular_function', 'GO:0004277', ('20', '24'))	('uveal melanoma', 'Disease', 'MESH:C536494', (121, 135))
128250	22411663	Although the most emphasis has been placed on identifying factors that promote angiogenesis, the alteration in expression of agents that normally inhibit angiogenesis has gained significant interest and, is shown to be critical in progression of many solid tumors.	('alteration', 'Var', (97, 107))	('promote', 'PosReg', (71, 78))	('rat', 'Species', '10116', (101, 104))	('solid tumors', 'Disease', (251, 263))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('angiogenesis', 'biological_process', 'GO:0001525', ('79', '91'))	('expression', 'MPA', (111, 121))	('solid tumors', 'Disease', 'MESH:D009369', (251, 263))	('angiogenesis', 'CPA', (79, 91))	('critical', 'Reg', (219, 227))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('angiogenesis', 'biological_process', 'GO:0001525', ('154', '166'))
128266	22411663	A number of studies have attempted to address the potential contribution of mutations in P53, a gene mutated in more than half of human tumors, to the pathogenesis of uveal melanoma.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('mutations', 'Var', (76, 85))	('P53', 'Gene', (89, 92))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('uveal melanoma', 'Phenotype', 'HP:0007716', (167, 181))	('uveal melanoma', 'Disease', 'MESH:C536494', (167, 181))	('pathogenesis', 'biological_process', 'GO:0009405', ('151', '163'))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('uveal melanoma', 'Disease', (167, 181))	('human', 'Species', '9606', (130, 135))
128267	22411663	A genetic link between P53 mutation and uveal melanoma has been previously reported.	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('P53', 'Gene', (23, 26))	('mutation', 'Var', (27, 35))	('uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))	('uveal melanoma', 'Disease', 'MESH:C536494', (40, 54))	('uveal melanoma', 'Disease', (40, 54))
128273	22411663	The presence of microcirculation patterns in uveal melanomas associated with lack of P53 expression further supports a role for decreased expression of P53 and TSP1 promoting angiogenesis and tumor growth.	('uveal melanomas', 'Disease', 'MESH:C536494', (45, 60))	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('tumor', 'Disease', (192, 197))	('microcirculation patterns', 'MPA', (16, 41))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('lack', 'Var', (77, 81))	('P53', 'Gene', (85, 88))	('uveal melanomas', 'Disease', (45, 60))	('uveal melanomas', 'Phenotype', 'HP:0007716', (45, 60))	('decreased', 'NegReg', (128, 137))	('angiogenesis', 'CPA', (175, 187))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('TSP1', 'Gene', (160, 164))	('angiogenesis', 'biological_process', 'GO:0001525', ('175', '187'))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('promoting', 'PosReg', (165, 174))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('TSP1', 'molecular_function', 'GO:0004277', ('160', '164'))
128335	18246031	The washed, pelleted MNCs and CMCs were resuspended in PBS/0.1% BSA and incubated with CELLection Pan Mouse IgG Dynabeads pre-labeled with either a combination of monoclonal antibodies, NKI/C3 and NKI/Beteb, or 9.2.27.	('NKI/C3', 'Var', (186, 192))	('pre', 'molecular_function', 'GO:0003904', ('122', '125'))	('NKI/Beteb', 'Var', (197, 206))	('CMC', 'Chemical', '-', (30, 33))	('Mouse', 'Species', '10090', (102, 107))	('Beteb', 'Chemical', '-', (201, 206))	('PBS', 'Chemical', '-', (55, 58))
128348	18246031	Pre-labeling of Dynabeads with a combination NKI/C3, NKI/Beteb, and PAL-M2 together failed to increase the sensitivity of the assay and actually prevented the isolation of 92.1, OCM-1, and SP6.5 below a concentration of 1x103 cells/ml PBS/0.1% BSA.	('PAL-M2', 'Gene', '114299', (68, 74))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('PAL', 'molecular_function', 'GO:0004598', ('68', '71'))	('OCM-1', 'Species', '83984', (178, 183))	('PBS', 'Chemical', '-', (235, 238))	('prevented', 'NegReg', (145, 154))	('PAL-M2', 'Gene', (68, 74))	('isolation', 'MPA', (159, 168))	('Beteb', 'Chemical', '-', (57, 62))	('NKI/C3', 'Var', (45, 51))
128362	18246031	Thus, CMC positivity in itself is not an inherent predictor of metastasis in uveal melanoma and in itself, not of prognostic value.	('CMC', 'Gene', (6, 9))	('uveal melanoma', 'Disease', 'MESH:C536494', (77, 91))	('positivity', 'Var', (10, 20))	('CMC', 'Chemical', '-', (6, 9))	('uveal melanoma', 'Phenotype', 'HP:0007716', (77, 91))	('uveal melanoma', 'Disease', (77, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
128366	18246031	Rather, the mutations associated with the emergence of a particular neoplasm confer its potential for metastasis with metastatic capability acquired early on in development.	('neoplasm', 'Disease', 'MESH:D009369', (68, 76))	('metastatic capability', 'CPA', (118, 139))	('mutations', 'Var', (12, 21))	('neoplasm', 'Disease', (68, 76))	('neoplasm', 'Phenotype', 'HP:0002664', (68, 76))
128393	32430489	Metabolic adaptations to MEK and CDK4/6 co-targeting in uveal melanoma Frequent GNAQ and GNA11 mutations in uveal melanoma (UM) hyperactivate the MEK-ERK signaling pathway, leading to aberrant regulation of cyclin dependent kinases (CDK) and cell cycle progression.	('ERK', 'molecular_function', 'GO:0004707', ('150', '153'))	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('CDK4/6', 'Gene', '1019;1021', (33, 39))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('ERK', 'Gene', '5594', (150, 153))	('CDK', 'Gene', (33, 36))	('regulation', 'MPA', (193, 203))	('cell cycle progression', 'CPA', (242, 264))	('GNA11', 'Gene', '2767', (89, 94))	('cyclin dependent kinases', 'Pathway', (207, 231))	('MEK', 'Gene', '5609', (146, 149))	('mutations', 'Var', (95, 104))	('CDK', 'Gene', '1019;12567;1021', (233, 236))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('melanoma', 'Disease', (62, 70))	('CDK', 'molecular_function', 'GO:0004693', ('233', '236'))	('hyperactivate', 'PosReg', (128, 141))	('MEK', 'Gene', '5609', (25, 28))	('aberrant', 'PosReg', (184, 192))	('cyclin', 'molecular_function', 'GO:0016538', ('207', '213'))	('MEK', 'Gene', (146, 149))	('ERK', 'Gene', (150, 153))	('cell cycle', 'biological_process', 'GO:0007049', ('242', '252'))	('signaling pathway', 'biological_process', 'GO:0007165', ('154', '171'))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('CDK', 'molecular_function', 'GO:0004693', ('33', '36'))	('CDK4/6', 'Gene', (33, 39))	('MEK', 'Gene', (25, 28))	('CDK', 'Gene', '1019;12567;1021', (33, 36))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('regulation', 'biological_process', 'GO:0065007', ('193', '203'))	('GNAQ', 'Gene', '2776', (80, 84))	('CDK', 'Gene', (233, 236))	('GNA11', 'Gene', (89, 94))	('GNAQ', 'Gene', (80, 84))
128401	32430489	IACS-010759, an OxPhos inhibitor, decreased UM cell survival in combination with MEKi + CDK4/6i.	('decreased', 'NegReg', (34, 43))	('OxPhos', 'biological_process', 'GO:0002082', ('16', '22'))	('CDK', 'molecular_function', 'GO:0004693', ('88', '91'))	('IACS-010759', 'Var', (0, 11))	('UM cell survival', 'CPA', (44, 60))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('MEK', 'Gene', (81, 84))	('MEK', 'Gene', '5609', (81, 84))
128407	32430489	The encoded mutant forms of Galphaq and Galpha11 signal to several pathways, including MEK-ERK1/2 and YAP/TAZ.	('TAZ', 'Gene', '6901', (106, 109))	('Galpha11', 'Gene', (40, 48))	('Galphaq', 'Gene', (28, 35))	('Galphaq', 'Gene', '2776', (28, 35))	('TAZ', 'Gene', (106, 109))	('MEK', 'Gene', (87, 90))	('mutant', 'Var', (12, 18))	('YAP', 'Gene', '10413', (102, 105))	('MEK', 'Gene', '5609', (87, 90))	('ERK1', 'molecular_function', 'GO:0004707', ('91', '95'))	('Galpha11', 'Gene', '2767', (40, 48))	('ERK1/2', 'Gene', (91, 97))	('YAP', 'Gene', (102, 105))	('ERK1/2', 'Gene', '5595;5594', (91, 97))	('signal', 'Reg', (49, 55))
128422	32430489	UM001, UM004, OMM1.3, and WM3618F were confirmed to harbor the Q209P mutation in GNAQ by Sanger sequencing.	('GNAQ', 'Gene', (81, 85))	('Q209P', 'Mutation', 'rs121913492', (63, 68))	('Q209P', 'Var', (63, 68))	('WM3618F', 'Chemical', '-', (26, 33))	('UM', 'Phenotype', 'HP:0007716', (7, 9))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('GNAQ', 'Gene', '2776', (81, 85))
128423	32430489	92.1 has the Q209L mutation in GNAQ, which was also confirmed.	('GNAQ', 'Gene', (31, 35))	('Q209L', 'Mutation', 'rs121913492', (13, 18))	('GNAQ', 'Gene', '2776', (31, 35))	('Q209L', 'Var', (13, 18))
128429	32430489	Primary antibodies were as follows: phospho-Rb (S780; #9307), RB (#9309), phospho-ERK1/2 (#9101), ERK1/2 (#9102), Cleaved PARP (#9541), and HSP90 (#4877), all purchased from Cell Signaling (Danvers, MA).	('#9309', 'Var', (66, 71))	('ERK1/2', 'Gene', '5595;5594', (98, 104))	('#9541', 'Var', (128, 133))	('RB', 'Disease', 'MESH:D012175', (62, 64))	('ERK1/2', 'Gene', '5595;5594', (82, 88))	('ERK1', 'molecular_function', 'GO:0004707', ('98', '102'))	('PARP', 'Gene', (122, 126))	('HSP90', 'Gene', (140, 145))	('#9102', 'Var', (106, 111))	('#4877', 'Var', (147, 152))	('HSP90', 'Gene', '3320', (140, 145))	('Signaling', 'biological_process', 'GO:0023052', ('179', '188'))	('ERK1', 'molecular_function', 'GO:0004707', ('82', '86'))	('#9101', 'Var', (90, 95))	('S780; #9307', 'Var', (48, 59))	('ERK1/2', 'Gene', (98, 104))	('ERK1/2', 'Gene', (82, 88))	('PARP', 'Gene', '1302', (122, 126))
128433	32430489	Cells were seeded in XF24 cell culture microplates (Seahorse Bioscience, #100777-004) and treated with DMSO (control), PD0325901, palbociclib, or PD0325901 plus palbociclib.	('palbociclib', 'Chemical', 'MESH:C500026', (161, 172))	('PD0325901', 'Var', (119, 128))	('PD0325901 plus palbociclib', 'Disease', 'MESH:D007625', (146, 172))	('DMSO', 'Chemical', 'MESH:D004121', (103, 107))	('palbociclib', 'Chemical', 'MESH:C500026', (130, 141))	('PD0325901', 'Chemical', 'MESH:C506614', (119, 128))	('PD0325901 plus palbociclib', 'Disease', (146, 172))	('PD0325901', 'Chemical', 'MESH:C506614', (146, 155))
128451	32430489	Nude mice with UM001 xenografts were treated with control chow, MEKi (PD0325901), CDK4/6i (palbociclib), or MEKi plus CDK4/6i chow.	('PD0325901', 'Chemical', 'MESH:C506614', (70, 79))	('MEK', 'Gene', (64, 67))	('Nude mice', 'Species', '10090', (0, 9))	('MEK', 'Gene', '5609', (64, 67))	('MEK', 'Gene', (108, 111))	('CDK', 'molecular_function', 'GO:0004693', ('82', '85'))	('MEK', 'Gene', '5609', (108, 111))	('UM', 'Phenotype', 'HP:0007716', (15, 17))	('CDK4/6i', 'Var', (82, 89))	('palbociclib', 'Chemical', 'MESH:C500026', (91, 102))	('CDK', 'molecular_function', 'GO:0004693', ('118', '121'))
128455	32430489	Ki67 staining demonstrated that CDK4/6i treatment (with or without MEKi) arrested most tumor cells, which was not seen with MEKi or control treatment (Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('arrest', 'Disease', 'MESH:D006323', (73, 79))	('CDK', 'molecular_function', 'GO:0004693', ('32', '35'))	('CDK4/6i', 'Var', (32, 39))	('tumor', 'Disease', (87, 92))	('MEK', 'Gene', (124, 127))	('MEK', 'Gene', '5609', (124, 127))	('arrest', 'Disease', (73, 79))	('MEK', 'Gene', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('MEK', 'Gene', '5609', (67, 70))
128468	32430489	To test whether the upregulation of OxPhos by MEK and CDK4/6 targeting has functional significance, we utilized IACS-010759, a small molecule inhibitor of complex I of the mitochondrial electron transport chain that reduces OCR in melanoma and other cell types and is currently being evaluated in clinical trials (NCT02882321, NCT03291938).	('reduces', 'NegReg', (216, 223))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('mitochondrial electron transport chain', 'cellular_component', 'GO:0005746', ('172', '210'))	('melanoma', 'Disease', (231, 239))	('mitochondrial electron transport', 'biological_process', 'GO:0042775', ('172', '204'))	('CDK4/6', 'Gene', (54, 60))	('OCR', 'MPA', (224, 227))	('electron transport chain', 'biological_process', 'GO:0022900', ('186', '210'))	('complex I', 'cellular_component', 'GO:0030964', ('155', '164'))	('CDK', 'molecular_function', 'GO:0004693', ('54', '57'))	('MEK', 'Gene', (46, 49))	('IACS-010759', 'Var', (112, 123))	('MEK', 'Gene', '5609', (46, 49))	('OxPhos', 'biological_process', 'GO:0002082', ('36', '42'))	('CDK4/6', 'Gene', '1019;1021', (54, 60))
128470	32430489	As apoptosis was observed with MEKi and CDK4/6i treatment in vivo (Supplemental Fig.	('apoptosis', 'biological_process', 'GO:0097194', ('3', '12'))	('MEK', 'Gene', (31, 34))	('MEK', 'Gene', '5609', (31, 34))	('CDK', 'molecular_function', 'GO:0004693', ('40', '43'))	('CDK4/6i', 'Var', (40, 47))	('apoptosis', 'biological_process', 'GO:0006915', ('3', '12'))
128473	32430489	Together, our data suggest that OxPhos inhibition may overcome the pro-survival effects of metabolic rewiring in UM cells treated with MEK inhibitors plus CDK4/6 inhibitors.	('inhibitors', 'Var', (139, 149))	('CDK', 'molecular_function', 'GO:0004693', ('155', '158'))	('metabolic rewiring', 'CPA', (91, 109))	('pro-survival', 'biological_process', 'GO:0043066', ('67', '79'))	('OxPhos', 'biological_process', 'GO:0002082', ('32', '38'))	('OxPhos', 'MPA', (32, 38))	('CDK4/6', 'Gene', '1019;1021', (155, 161))	('UM', 'Phenotype', 'HP:0007716', (113, 115))	('MEK', 'Gene', (135, 138))	('pro-survival', 'CPA', (67, 79))	('MEK', 'Gene', '5609', (135, 138))	('CDK4/6', 'Gene', (155, 161))
128474	32430489	Despite the high frequency of GNAQ and GNA11 mutations in UM that enhance MEK-ERK1/2 signaling, MEKi are not clinically effective in patients, perhaps due to activation of additional downstream or parallel pathways.	('MEK', 'Gene', '5609', (74, 77))	('UM', 'Phenotype', 'HP:0007716', (58, 60))	('mutations', 'Var', (45, 54))	('ERK1/2', 'Gene', '5595;5594', (78, 84))	('GNA11', 'Gene', (39, 44))	('enhance', 'PosReg', (66, 73))	('ERK1', 'molecular_function', 'GO:0004707', ('78', '82'))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('GNAQ', 'Gene', (30, 34))	('MEK', 'Gene', (96, 99))	('patients', 'Species', '9606', (133, 141))	('MEK', 'Gene', '5609', (96, 99))	('GNA11', 'Gene', '2767', (39, 44))	('ERK1/2', 'Gene', (78, 84))	('GNAQ', 'Gene', '2776', (30, 34))	('MEK', 'Gene', (74, 77))
128476	32430489	Our study shows that CDK4/6i caused cell cycle arrest in UM cell lines in vitro and in vivo, but there were no significant combinatorial effects with MEKi.	('arrest', 'Disease', (47, 53))	('MEK', 'Gene', '5609', (150, 153))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('36', '53'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (36, 53))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('CDK', 'molecular_function', 'GO:0004693', ('21', '24'))	('arrest', 'Disease', 'MESH:D006323', (47, 53))	('CDK4/6i', 'Var', (21, 28))	('MEK', 'Gene', (150, 153))
128481	32430489	For example, the combination of CDK4/6i + MEKi (ribociclib plus binimetinib) was tested in mutant NRAS cutaneous melanoma patients and yielded encouraging results (43% overall response rate).	('cutaneous melanoma', 'Disease', (103, 121))	('CDK', 'molecular_function', 'GO:0004693', ('32', '35'))	('CDK4/6i', 'Gene', (32, 39))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (103, 121))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (103, 121))	('binimetinib', 'Chemical', 'MESH:C581313', (64, 75))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('MEK', 'Gene', (42, 45))	('NRAS', 'Gene', (98, 102))	('MEK', 'Gene', '5609', (42, 45))	('patients', 'Species', '9606', (122, 130))	('ribociclib', 'Chemical', 'MESH:C000589651', (48, 58))	('NRAS', 'Gene', '4893', (98, 102))	('mutant', 'Var', (91, 97))
128487	32430489	Interestingly, these data contrast with previous findings in cutaneous melanoma xenograft models, in which CDK4/6i alone caused moderate delays in tumor growth and the combination of MEKi plus CDK4/6i caused tumor regressions.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('delays', 'NegReg', (137, 143))	('CDK', 'molecular_function', 'GO:0004693', ('193', '196'))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('CDK4/6i', 'Var', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('MEK', 'Gene', (183, 186))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', (208, 213))	('MEK', 'Gene', '5609', (183, 186))	('cutaneous melanoma', 'Disease', (61, 79))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (61, 79))	('CDK', 'molecular_function', 'GO:0004693', ('107', '110'))
128488	32430489	In pancreatic cancer, CDK4/6 inhibition enhances glycolysis and OxPhos, as well as increases mitochondrial mass.	('increases', 'PosReg', (83, 92))	('pancreatic cancer', 'Disease', (3, 20))	('enhances', 'PosReg', (40, 48))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('mitochondrial mass', 'MPA', (93, 111))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('CDK4/6', 'Gene', (22, 28))	('OxPhos', 'biological_process', 'GO:0002082', ('64', '70'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('CDK', 'molecular_function', 'GO:0004693', ('22', '25'))	('OxPhos', 'MPA', (64, 70))	('glycolysis', 'biological_process', 'GO:0006096', ('49', '59'))	('CDK4/6', 'Gene', '1019;1021', (22, 28))	('inhibition', 'Var', (29, 39))	('glycolysis', 'MPA', (49, 59))
128492	32430489	Although, we did not show effects on OCR in uveal melanoma cells in this study, we have previously shown that IACS-010759 reduces OCR in cutaneous melanoma cells.	('reduces', 'NegReg', (122, 129))	('IACS-010759', 'Var', (110, 121))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (137, 155))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('OCR', 'MPA', (130, 133))	('melanoma', 'Disease', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('cutaneous melanoma', 'Disease', (137, 155))
128493	32430489	Importantly, the addition of IACS-010759 to CDK4/6i + MEKi decreased cell growth and enhanced apoptosis, suggesting that direct OxPhos inhibition should be further analyzed as an approach to optimize targeted therapy treatment in UM.	('MEK', 'Gene', '5609', (54, 57))	('decreased', 'NegReg', (59, 68))	('OxPhos', 'biological_process', 'GO:0002082', ('128', '134'))	('enhanced', 'PosReg', (85, 93))	('CDK4/6i', 'Gene', (44, 51))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))	('IACS-010759', 'Var', (29, 40))	('cell growth', 'biological_process', 'GO:0016049', ('69', '80'))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))	('CDK', 'molecular_function', 'GO:0004693', ('44', '47'))	('UM', 'Phenotype', 'HP:0007716', (230, 232))	('apoptosis', 'CPA', (94, 103))	('MEK', 'Gene', (54, 57))	('cell growth', 'CPA', (69, 80))
128494	32430489	For example, inhibition of mTORC1/2 has been shown to decrease PGC1alpha expression and inhibit OxPhos.	('decrease', 'NegReg', (54, 62))	('mTORC1', 'cellular_component', 'GO:0031931', ('27', '33'))	('PGC1alpha', 'Gene', '10891', (63, 72))	('inhibition', 'Var', (13, 23))	('mTORC1/2', 'Gene', (27, 35))	('OxPhos', 'biological_process', 'GO:0002082', ('96', '102'))	('inhibit', 'NegReg', (88, 95))	('expression', 'MPA', (73, 83))	('PGC1alpha', 'Gene', (63, 72))	('OxPhos', 'MPA', (96, 102))	('mTORC1/2', 'Gene', '74343;382056', (27, 35))
128500	31623302	A partial response to first-line treatment was observed in 7% of patients treated with anti-programmed cell death protein (PD)-1 monotherapy and in 21% with combined anti-cytotoxic T lymphocyte antigen (CTLA)-4 plus anti-PD-1 therapy.	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('lymphocyte antigen', 'molecular_function', 'GO:0005557', ('183', '201'))	('programmed cell death', 'biological_process', 'GO:0012501', ('92', '113'))	('patients', 'Species', '9606', (65, 73))	('PD-1', 'Gene', (221, 225))	('PD-1', 'Gene', '5133', (221, 225))	('anti-programmed', 'Var', (87, 102))
128599	31623302	Besides clinical trials, further investigation to determine predictive biomarkers for response to ICI is warranted to select patients for ICI treatment, e.g., specific germline mutations, tumor mutational burden and the immune infiltrate in the tumor microenvironment.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('mutational', 'Var', (194, 204))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Disease', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('patients', 'Species', '9606', (125, 133))
128642	31344830	Activated HSteCs were recruited by both micro- (<50 microm, top panels) and macro-metastases (>500 microm, bottom panels; Figure 3B and Figure 4).	('Activated HSteCs', 'CPA', (0, 16))	('>500', 'Var', (94, 98))	('macro-metastases', 'Disease', (76, 92))	('macro-metastases', 'Disease', 'MESH:D009362', (76, 92))
128682	31344830	Tissue sections were also processed for immunohistological analysis with antibodies against Melan-A (clone A103, Agilent Dako, Mississauga, ON, Canada) and alphaSMA (clone 1A4, Agilent Dako) in a Dako Autostainer Plus Link, according to the manufacturer's protocol using the EnVision peroxidase procedure with the DAB or Magenta chromogen (Agilent Dako).	('clone A103', 'Var', (101, 111))	('alphaSMA', 'Gene', (156, 164))	('alphaSMA', 'Gene', '11475', (156, 164))	('Melan-A', 'Gene', (92, 99))	('Autostainer Plus Link', 'Disease', (201, 222))	('Autostainer Plus Link', 'Disease', 'MESH:D007625', (201, 222))	('DAB', 'Chemical', 'MESH:C000469', (314, 317))
128707	31212986	More recently, molecular and cytological factors such as monosomy of chromosome 3, additional copies of chromosome 8, and BRCA1 associated protein (BAP1) mutations, have been related to decreased survival.	('monosomy', 'Var', (57, 65))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('BAP1', 'Gene', '8314', (148, 152))	('BRCA1 associated protein', 'Gene', (122, 146))	('chromosome', 'cellular_component', 'GO:0005694', ('69', '79'))	('decreased', 'NegReg', (186, 195))	('BAP1', 'Gene', (148, 152))	('mutations', 'Var', (154, 163))	('BRCA1 associated protein', 'Gene', '8315', (122, 146))	('chromosome', 'cellular_component', 'GO:0005694', ('104', '114'))
128708	31212986	On the other hand, Splicing factor 3B subunit 1 (SF3B1) and Eukaryotic translation initiation factor 1A (EIF1AX) mutations seem to confer improved survival.	('SF3B1', 'Gene', '23451', (49, 54))	('survival', 'CPA', (147, 155))	('Splicing factor 3B subunit 1', 'Gene', '23451', (19, 47))	('improved', 'PosReg', (138, 146))	('EIF1AX', 'Gene', '1964', (105, 111))	('EIF1AX', 'Gene', (105, 111))	('mutations', 'Var', (113, 122))	('translation initiation', 'biological_process', 'GO:0006413', ('71', '93'))	('SF3B1', 'Gene', (49, 54))	('Splicing', 'biological_process', 'GO:0045292', ('19', '27'))	('Splicing factor 3B subunit 1', 'Gene', (19, 47))
128737	31212986	Moreover, inhibition of the HIF pathway with arylsulfonamide 64B in animal UM models results in tumour regression and improved survival, and inhibition of VEGF-A with bevacizumab in both mouse and human uveal melanoma inhibits the establishment of micrometastasis, further reflecting its importance.	('establishment of micrometastasis', 'CPA', (231, 263))	('survival', 'CPA', (127, 135))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (203, 217))	('tumour regression', 'Disease', (96, 113))	('improved', 'PosReg', (118, 126))	('arylsulfonamide 64B', 'Chemical', '-', (45, 64))	('inhibition', 'Var', (10, 20))	('uveal melanoma', 'Disease', (203, 217))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('mouse', 'Species', '10090', (187, 192))	('inhibition', 'Var', (141, 151))	('human', 'Species', '9606', (197, 202))	('inhibits', 'NegReg', (218, 226))	('tumour regression', 'Disease', 'MESH:D009365', (96, 113))	('HIF pathway', 'Pathway', (28, 39))	('bevacizumab', 'Chemical', 'MESH:D000068258', (167, 178))	('VEGF-A', 'Gene', (155, 161))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('uveal melanoma', 'Disease', 'MESH:C536494', (203, 217))
128751	31212986	Despite this relationship not being directly established in UM, the expression of EMT-associated factors does promote invasion and growth, which we believe could be partly explained by their role in vasculogenic mimicry, as has been demonstrated in other tumours.	('tumour', 'Phenotype', 'HP:0002664', (255, 261))	('tumours', 'Phenotype', 'HP:0002664', (255, 262))	('growth', 'CPA', (131, 137))	('EMT', 'biological_process', 'GO:0001837', ('82', '85'))	('expression', 'Var', (68, 78))	('promote', 'PosReg', (110, 117))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('tumours', 'Disease', 'MESH:D009369', (255, 262))	('invasion', 'CPA', (118, 126))	('tumours', 'Disease', (255, 262))
128757	31212986	The overexpression of MT1-MMP and MMP-2 is regulated by phosphoinositide 3-kinase (PI3K), and specific inhibitors of PI3K are able to abrogate vasculogenic mimicry in both uveal and cutaneous melanoma cells by decreasing the levels of MT1-MMP and MMP-2.	('MT1', 'molecular_function', 'GO:0043834', ('22', '25'))	('MT1-MMP', 'Gene', (235, 242))	('MMP', 'molecular_function', 'GO:0004235', ('239', '242'))	('inhibitors', 'Var', (103, 113))	('PI3K', 'molecular_function', 'GO:0016303', ('117', '121'))	('MMP', 'molecular_function', 'GO:0004235', ('26', '29'))	('melanoma cells', 'Disease', 'MESH:D008545', (192, 206))	('MMP-2', 'molecular_function', 'GO:0004228', ('247', '252'))	('MT1-MMP', 'Gene', '4323', (235, 242))	('cutaneous melanoma', 'Disease', (182, 200))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (182, 200))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (182, 200))	('abrogate', 'NegReg', (134, 142))	('decreasing', 'NegReg', (210, 220))	('MT1', 'molecular_function', 'GO:0043791', ('235', '238'))	('vasculogenic mimicry', 'CPA', (143, 163))	('phosphoinositide 3-kinase', 'Gene', '5295', (56, 81))	('MT1', 'molecular_function', 'GO:0043791', ('22', '25'))	('melanoma cells', 'Disease', (192, 206))	('MT1-MMP', 'Gene', (22, 29))	('MT1', 'molecular_function', 'GO:0047152', ('235', '238'))	('PI3K', 'molecular_function', 'GO:0016303', ('83', '87'))	('PI3K', 'Var', (117, 121))	('levels', 'MPA', (225, 231))	('MMP-2', 'MPA', (247, 252))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('MT1', 'molecular_function', 'GO:0043834', ('235', '238'))	('phosphoinositide 3-kinase', 'Gene', (56, 81))	('MT1-MMP', 'Gene', '4323', (22, 29))	('MT1', 'molecular_function', 'GO:0047152', ('22', '25'))	('MMP-2', 'molecular_function', 'GO:0004228', ('34', '39'))
128780	31212986	Pevonedistat, a selective and potent inhibitor of NEDD8-activating enzyme E1 subunit 1 (NAE1), an enzyme involved in neddylation, is able to repress the cancer stemness properties of UM cell lines, and could therefore potentially interfere with vasculogenic mimicry.	('UM', 'Phenotype', 'HP:0007716', (183, 185))	('interfere', 'NegReg', (230, 239))	('NEDD8-activating enzyme E1 subunit 1', 'Gene', (50, 86))	('repress the cancer stemness', 'Disease', 'MESH:D009369', (141, 168))	('NAE1', 'Gene', '8883', (88, 92))	('Pevonedistat', 'Chemical', 'MESH:C539933', (0, 12))	('NAE1', 'Gene', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('repress the cancer stemness', 'Disease', (141, 168))	('vasculogenic mimicry', 'CPA', (245, 265))	('NEDD8-activating enzyme E1 subunit 1', 'Gene', '8883', (50, 86))	('Pevonedistat', 'Var', (0, 12))
128787	31212986	PARP inhibitors suppress the metastatic potential of some human and murine melanoma cells, due in part to the inhibition of vasculogenic mimicry mediated by the downregulation of VE-cadherin and the inhibition of the EMT pathway.	('inhibition', 'NegReg', (110, 120))	('human', 'Species', '9606', (58, 63))	('PARP', 'Gene', '142', (0, 4))	('PARP', 'Gene', (0, 4))	('EMT', 'biological_process', 'GO:0001837', ('217', '220'))	('melanoma cells', 'Disease', 'MESH:D008545', (75, 89))	('inhibitors', 'Var', (5, 15))	('melanoma cells', 'Disease', (75, 89))	('vasculogenic mimicry', 'CPA', (124, 144))	('downregulation', 'NegReg', (161, 175))	('suppress', 'NegReg', (16, 24))	('metastatic potential', 'CPA', (29, 49))	('murine', 'Species', '10090', (68, 74))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('inhibition', 'NegReg', (199, 209))	('cadherin', 'molecular_function', 'GO:0008014', ('182', '190'))	('EMT pathway', 'Pathway', (217, 228))	('VE-cadherin', 'Protein', (179, 190))
128805	31212986	The immune infiltrate in UM seems to be related to genetic alterations, with the lack of BAP1 mutations showing a richer T-cell infiltration.	('BAP1', 'Gene', '8314', (89, 93))	('BAP1', 'Gene', (89, 93))	('UM', 'Phenotype', 'HP:0007716', (25, 27))	('mutations', 'Var', (94, 103))
128810	31212986	Indeed, the co-expression of both molecules leads to a high CD8+ T-cell infiltration in cutaneous melanoma, and upregulation of both CCR5/CXCR3 is associated to greater response to different immunotherapies, including checkpoint inhibitors and adoptive cell therapy.	('CCR5', 'Gene', (133, 137))	('CD8', 'Gene', '925', (60, 63))	('cutaneous melanoma', 'Disease', (88, 106))	('CCR', 'molecular_function', 'GO:0043880', ('133', '136'))	('CXCR3', 'Gene', (138, 143))	('upregulation', 'PosReg', (112, 124))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (88, 106))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (88, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('CCR5', 'Gene', '1234', (133, 137))	('co-expression', 'Var', (12, 25))	('CXCR3', 'Gene', '2833', (138, 143))	('CD8', 'Gene', (60, 63))
128847	30832716	A multi-gene panel analysis of the tumor showed somatic BAP-1 and GNA11 mutations.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('mutations', 'Var', (72, 81))	('BAP-1', 'Gene', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('GNA11', 'Gene', (66, 71))	('BAP-1', 'Gene', '8314', (56, 61))	('GNA11', 'Gene', '2767', (66, 71))
128862	30832716	GNA11, a G-protein-coupled receptor, contained the Q209L mutation present in 33 of 80 UM annotated by GDC.	('UM', 'Phenotype', 'HP:0007716', (86, 88))	('Q209L', 'Mutation', 'rs1057519742', (51, 56))	('GNA11', 'Gene', (0, 5))	('GNA11', 'Gene', '2767', (0, 5))	('Q209L', 'Var', (51, 56))	('GDC', 'Chemical', '-', (102, 105))	('protein', 'cellular_component', 'GO:0003675', ('11', '18'))
128864	30832716	None of the 21 deleterious mutations have been associated with vitiligo or VKH.	('mutations', 'Var', (27, 36))	('VKH', 'Disease', 'MESH:D014607', (75, 78))	('vitiligo', 'Phenotype', 'HP:0001045', (63, 71))	('vitiligo', 'Disease', (63, 71))	('VKH', 'Disease', (75, 78))
128865	30832716	The rate of SNVs resulting in potential neo-epitopes (21 SNVs) was similar to the rate described in the GDC UM dataset (median: 15) (Additional file 1: Figure S2) as well as for subjects with BAP1 mutation (median: 14) or stage III/IV disease (median: 13).	('stage III/IV disease', 'Disease', (222, 242))	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('GDC', 'Chemical', '-', (104, 107))	('BAP1', 'Gene', (192, 196))	('SNVs', 'Var', (12, 16))	('BAP1', 'Gene', '8314', (192, 196))	('neo-epitopes', 'MPA', (40, 52))	('mutation', 'Var', (197, 205))
128868	30832716	The gene signature of the patient's sample was the top ranked sample defined by the median reading for macrophage genes (CD163, IL4R & CD68), the 5th highest for genes associated with cytotoxic T lymphocytes (CD3D, CD3E, CD3EAP, CD3G, CD8A & CD8B) and the 22nd highest for genes expressed by NK cells (SLAMF7, KLRK1 & GZMB).	('patient', 'Species', '9606', (26, 33))	('SLAMF7', 'Gene', (302, 308))	('GZMB', 'Gene', (318, 322))	('CD68', 'Gene', '968', (135, 139))	('CD3EAP', 'Gene', '10849', (221, 227))	('CD3D', 'Gene', (209, 213))	('CD8B', 'Gene', '926', (242, 246))	('CD3G', 'Gene', (229, 233))	('CD3D', 'Gene', '915', (209, 213))	('CD3EAP', 'Gene', (221, 227))	('lymphocytes', 'Var', (196, 207))	('CD68', 'Gene', (135, 139))	('CD8A', 'Gene', '925', (235, 239))	('IL4R', 'Gene', '3566', (128, 132))	('CD163', 'Gene', '9332', (121, 126))	('CD3E', 'Gene', (215, 219))	('CD3E', 'Gene', '916', (215, 219))	('IL4R', 'molecular_function', 'GO:0004913', ('128', '132'))	('IL4R', 'Gene', (128, 132))	('KLRK1', 'Gene', (310, 315))	('CD3E', 'Gene', (221, 225))	('CD8A', 'Gene', (235, 239))	('CD163', 'Gene', (121, 126))	('CD3E', 'Gene', '916', (221, 225))	('GZMB', 'Gene', '3002', (318, 322))	('KLRK1', 'Gene', '22914', (310, 315))	('CD3G', 'Gene', '917', (229, 233))	('CD8B', 'Gene', (242, 246))	('SLAMF7', 'Gene', '57823', (302, 308))
128899	30832716	Thus, the value of a high mutational load may be to induce immunoreactivity against multiple neoantigens and simultaneously overwhelm any shared antigen response, thereby eliminating the tumor before significant shared antigen expansion and related organ toxicity develops.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('toxicity', 'Disease', 'MESH:D064420', (255, 263))	('toxicity', 'Disease', (255, 263))	('shared antigen response', 'MPA', (138, 161))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('high mutational load', 'Var', (21, 41))	('induce', 'PosReg', (52, 58))	('tumor', 'Disease', (187, 192))	('overwhelm', 'PosReg', (124, 133))	('eliminating', 'NegReg', (171, 182))	('immunoreactivity', 'MPA', (59, 75))
128933	30700934	The expression levels of seven circRNAs, hsa_circ_0119873, hsa_circ_0128533, hsa_circ_0047924, hsa_circ_0103232 and hsa-circRNA10628-6, were significantly higher in uveal tumor tissues than in normal uvea tissues, and hsa_circ_0032148 and hsa_circ_0133460 were significantly lower in uveal tumor tissues than in normal uvea tissues.	('expression levels', 'MPA', (4, 21))	('uveal tumor', 'Disease', 'MESH:D014604', (284, 295))	('hsa_circ_0128533', 'Var', (59, 75))	('uveal tumor', 'Disease', 'MESH:D014604', (165, 176))	('uveal tumor', 'Disease', (284, 295))	('hsa_circ_0047924', 'Var', (77, 93))	('lower', 'NegReg', (275, 280))	('uveal tumor', 'Disease', (165, 176))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('hsa_circ_0103232', 'Var', (95, 111))	('higher', 'PosReg', (155, 161))
128935	30700934	The most significant biological process of GO enrichment analysis was single-organism developmental process (GO:0044767, P=2.05469e-12), the most significant cellular components of GO enrichment analysis was plasma membrane (GO:0005886, P=7.496023e-21), and the most significant major molecular function of GO enrichment analysis was adenyl ribonucleotide binding (GO:0032559, P=2.52808e-15).	('adenyl ribonucleotide', 'Chemical', '-', (334, 355))	('plasma membrane', 'cellular_component', 'GO:0005886', ('208', '223'))	('adenyl ribonucleotide binding', 'MPA', (334, 363))	('biological process', 'biological_process', 'GO:0008150', ('21', '39'))	('P=2.05469e-12', 'Var', (121, 134))	('adenyl ribonucleotide binding', 'molecular_function', 'GO:0032559', ('334', '363'))	('single-organism developmental process', 'biological_process', 'GO:0032502', ('70', '107'))	('molecular function', 'molecular_function', 'GO:0003674', ('285', '303'))
128945	30700934	RasGRP3 plays an important role in UM, and some studies have indicated it acts as a potential therapeutic target for UM driven by oncogenic GNAQ/11 mutation.	('GNAQ', 'Gene', '2776', (140, 144))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('RasGRP3', 'Gene', (0, 7))	('RasGRP3', 'Gene', '25780', (0, 7))	('GNAQ', 'Gene', (140, 144))	('mutation', 'Var', (148, 156))	('UM', 'Phenotype', 'HP:0007716', (117, 119))
128948	30700934	The PI3K/Akt pathway is highly active in most UM cases, and elevated levels of AKT phosphorylation increase the risk of UM metastasis, while inhibition of the PI3K/Akt pathway can lead to tumor cell cycle arrest and reduced growth.	('tumor', 'Disease', (188, 193))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (194, 211))	('AKT', 'Gene', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('arrest', 'Disease', (205, 211))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('194', '211'))	('Akt', 'Gene', (164, 167))	('reduced', 'NegReg', (216, 223))	('lead to', 'Reg', (180, 187))	('growth', 'CPA', (224, 230))	('Akt', 'Gene', '207', (164, 167))	('UM', 'Phenotype', 'HP:0007716', (120, 122))	('AKT', 'Gene', '207', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('UM metastasis', 'CPA', (120, 133))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('arrest', 'Disease', 'MESH:D006323', (205, 211))	('inhibition', 'Var', (141, 151))	('Akt', 'Gene', (9, 12))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('phosphorylation', 'biological_process', 'GO:0016310', ('83', '98'))	('PI3K', 'molecular_function', 'GO:0016303', ('159', '163'))	('Akt', 'Gene', '207', (9, 12))
128950	30700934	It was also found that blocking the Wnt signaling pathway can inhibit the growth, migration and invasion of UM cells.	('blocking', 'Var', (23, 31))	('Wnt', 'Gene', '7474', (36, 39))	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('Wnt', 'Gene', (36, 39))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('36', '57'))	('growth', 'CPA', (74, 80))	('inhibit', 'NegReg', (62, 69))
128952	30700934	However, hsa_circ_0128533 can be predicted to bind miR-145; thus, hsa_circ_0128533 may be an oncogene and prevent UM apoptosis by targeting miR-145.	('miR-145', 'Gene', '406937', (140, 147))	('prevent', 'PosReg', (106, 113))	('hsa_circ_0128533', 'Var', (66, 82))	('targeting', 'Reg', (130, 139))	('UM', 'Phenotype', 'HP:0007716', (114, 116))	('apoptosis', 'biological_process', 'GO:0097194', ('117', '126'))	('UM apoptosis', 'CPA', (114, 126))	('miR-145', 'Gene', (140, 147))	('apoptosis', 'biological_process', 'GO:0006915', ('117', '126'))	('miR-145', 'Gene', (51, 58))	('miR-145', 'Gene', '406937', (51, 58))
128955	30700934	miR-193 also exerts direct effects on the proliferation, migration and invasion of human intrahepatic cholangiocarcinoma cells by regulating TGFBR3.	('intrahepatic cholangiocarcinoma', 'Disease', (89, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('regulating', 'Reg', (130, 140))	('effects', 'Reg', (27, 34))	('proliferation', 'CPA', (42, 55))	('miR-193', 'Var', (0, 7))	('TGFBR3', 'Gene', (141, 147))	('invasion', 'CPA', (71, 79))	('human', 'Species', '9606', (83, 88))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (102, 120))	('migration', 'CPA', (57, 66))	('TGFBR3', 'Gene', '7049', (141, 147))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (89, 120))
128972	28910167	Therefore, depending on tumour type and/or microenvironment, AMPs may positively or negatively impact the development of cancers.	('cancers', 'Disease', (121, 128))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('impact', 'Reg', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('negatively', 'NegReg', (84, 94))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('tumour', 'Disease', (24, 30))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('AMPs', 'Chemical', '-', (61, 65))	('AMPs', 'Var', (61, 65))
128973	28910167	Despite studies in a wide range of cancers, the expression profile of AMPs in uveal melanoma, the most common primary ocular tumour in adults, has not previously been investigated, and the effects of AMPs on behaviour of these cells are unknown.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('AMPs', 'Var', (70, 74))	('AMPs', 'Chemical', '-', (70, 74))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('uveal melanoma', 'Disease', (78, 92))	('AMPs', 'Chemical', '-', (200, 204))	('behaviour', 'biological_process', 'GO:0007610', ('208', '217'))	('ocular tumour', 'Disease', (118, 131))	('uveal melanoma', 'Phenotype', 'HP:0007716', (78, 92))	('uveal melanoma', 'Disease', 'MESH:C536494', (78, 92))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))	('ocular tumour', 'Disease', 'MESH:D005134', (118, 131))	('ocular tumour', 'Phenotype', 'HP:0100012', (118, 131))
128980	28910167	The detailed mechanisms underlying vasculogenic mimicry formation are still being elucidated, but it is associated with cancer cells with altered extracellular matrix gene expression that proliferate, migrate and organize into patent channels in response to angiogenesis promoting factors and the tumor microenvironment.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('angiogenesis', 'biological_process', 'GO:0001525', ('258', '270'))	('altered', 'Var', (138, 145))	('migrate', 'CPA', (201, 208))	('cancer', 'Disease', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('formation', 'biological_process', 'GO:0009058', ('56', '65'))	('proliferate', 'CPA', (188, 199))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('146', '166'))	('tumor', 'Disease', (297, 302))	('gene expression', 'biological_process', 'GO:0010467', ('167', '182'))
128981	28910167	In addition to stimulating migration of some tumour cells, AMPs such as LL-37, PR39 and alpha defensins, can promote blood vessel development and interfere with tumor-associated angiogenesis.	('LL-37', 'Gene', (72, 77))	('AMPs', 'Chemical', '-', (59, 63))	('promote', 'PosReg', (109, 116))	('PR39', 'Var', (79, 83))	('angiogenesis', 'biological_process', 'GO:0001525', ('178', '190'))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('blood vessel development', 'biological_process', 'GO:0001568', ('117', '141'))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('interfere', 'NegReg', (146, 155))	('LL-37', 'Gene', '820', (72, 77))	('blood vessel development', 'CPA', (117, 141))	('alpha defensins', 'Protein', (88, 103))	('tumor', 'Disease', (161, 166))	('tumour', 'Disease', (45, 51))
129028	28910167	Increased expression of endogenous LL-37 has been implicated in the development or progression of several cancers including breast, ovarian and lung, where it can stimulate proliferation, enhance metastatic capacity, and transactivate the epidermal growth factor receptor (EGFR).	('epidermal growth factor receptor', 'Gene', '1956', (239, 271))	('metastatic capacity', 'CPA', (196, 215))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('enhance', 'PosReg', (188, 195))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('EGFR', 'Gene', (273, 277))	('lung', 'Disease', (144, 148))	('implicated', 'Reg', (50, 60))	('proliferation', 'CPA', (173, 186))	('LL-37', 'Gene', '820', (35, 40))	('LL-37', 'Gene', (35, 40))	('breast, ovarian', 'Disease', 'MESH:D010051', (124, 139))	('transactivate', 'Var', (221, 234))	('EGFR', 'molecular_function', 'GO:0005006', ('273', '277'))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('EGFR', 'Gene', '1956', (273, 277))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('239', '262'))	('stimulate', 'PosReg', (163, 172))	('epidermal growth factor receptor', 'Gene', (239, 271))
129046	28910167	Given that AMPs can modulate behaviors such as migration, proliferation and vessel formation in melanoma and breast cancer, we hypothesized that AMPs may influence vasculogenic mimicry.	('breast cancer', 'Disease', (109, 122))	('proliferation', 'CPA', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('AMPs', 'Chemical', '-', (11, 15))	('vasculogenic mimicry', 'CPA', (164, 184))	('influence', 'Reg', (154, 163))	('formation', 'biological_process', 'GO:0009058', ('83', '92'))	('AMPs', 'Var', (145, 149))	('migration', 'CPA', (47, 56))	('AMPs', 'Chemical', '-', (145, 149))	('vessel formation', 'CPA', (76, 92))	('modulate', 'Reg', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
129057	28910167	In summary our data show expression of AMPs in uveal melanoma and cutaneous melanoma cells lines.	('cutaneous melanoma', 'Disease', (66, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (66, 84))	('AMPs', 'Var', (39, 43))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('uveal melanoma', 'Disease', (47, 61))	('AMPs', 'Chemical', '-', (39, 43))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
129060	28910167	Further, the AMPs LL-37 and HNP-1 do not significantly influence melanoma cell migration or vasculogenic mimicry.	('LL-37', 'Gene', (18, 23))	('melanoma cell migration', 'Disease', 'MESH:D008545', (65, 88))	('cell migration', 'biological_process', 'GO:0016477', ('74', '88'))	('LL-37', 'Gene', '820', (18, 23))	('HNP-1', 'Gene', '574045', (28, 33))	('AMPs', 'Chemical', '-', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('AMPs', 'Var', (13, 17))	('melanoma cell migration', 'Disease', (65, 88))	('influence', 'Reg', (55, 64))	('HNP-1', 'Gene', (28, 33))	('vasculogenic mimicry', 'CPA', (92, 112))
129061	28910167	Based on our current observations, we cannot confirm that AMPs have a significant role in the pathogenesis and progression of melanomas, but certainly they do not appear to influence major tumour characteristics associated with tumour progression in the cell lines analyzed.	('AMPs', 'Var', (58, 62))	('influence', 'Reg', (173, 182))	('tumour', 'Disease', (228, 234))	('melanomas', 'Disease', (126, 135))	('AMPs', 'Chemical', '-', (58, 62))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanomas', 'Phenotype', 'HP:0002861', (126, 135))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))	('pathogenesis', 'biological_process', 'GO:0009405', ('94', '106'))	('melanomas', 'Disease', 'MESH:D008545', (126, 135))	('tumour', 'Disease', (189, 195))	('tumour', 'Disease', 'MESH:D009369', (228, 234))
129064	29554022	Clinical Implications of Real-Time Integrative Sequencing in Management of Patients with Suspected Germline BAP1 Mutations The BAP (BRCA associated protein) gene encodes the BAP-1 enzyme that catalyzes de-ubiquitination of protein substrates involved in cell cycle regulation, cell differentiation and cell death.	('BAP1', 'Gene', '8314', (108, 112))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('254', '275'))	('cell death', 'biological_process', 'GO:0008219', ('302', '312'))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('protein', 'cellular_component', 'GO:0003675', ('223', '230'))	('BAP (BRCA associated protein', 'Gene', '11331', (127, 155))	('BAP-1', 'Gene', '8314', (174, 179))	('Mutations', 'Var', (113, 122))	('BAP1', 'Gene', (108, 112))	('Patients', 'Species', '9606', (75, 83))	('de-ubiquitination', 'MPA', (202, 219))	('BAP-1', 'Gene', (174, 179))	('cell differentiation', 'biological_process', 'GO:0030154', ('277', '297'))
129067	29554022	In this report, we present the case of a patient with recurrent metastatic melanoma who was subsequently found to have a pathogenic germline BAP1 and somatic BRAF mutation by clinical genomic sequencing.	('BAP1', 'Gene', '8314', (141, 145))	('patient', 'Species', '9606', (41, 48))	('BAP1', 'Gene', (141, 145))	('BRAF', 'Gene', '673', (158, 162))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('BRAF', 'Gene', (158, 162))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('mutation', 'Var', (163, 171))
129081	29554022	Sequencing revealed a somatic BRAF (V600E) point mutation, as well as a BAP1 (p. D567X) germline pathogenic variant.	('D567X', 'SUBSTITUTION', 'None', (81, 86))	('BAP1', 'Gene', '8314', (72, 76))	('D567X', 'Var', (81, 86))	('V600E', 'Mutation', 'rs113488022', (36, 41))	('BRAF', 'Gene', (30, 34))	('BAP1', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (30, 34))	('V600E', 'Var', (36, 41))
129086	29554022	This damage results in somatic mutations to genes, one of the most common being BRAF V600E, which is involved in 40-60% of melanomas.	('mutations', 'Var', (31, 40))	('results in', 'Reg', (12, 22))	('BRAF', 'Gene', (80, 84))	('melanomas', 'Disease', (123, 132))	('V600E', 'Mutation', 'rs113488022', (85, 90))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanomas', 'Disease', 'MESH:D008545', (123, 132))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('BRAF', 'Gene', '673', (80, 84))
129087	29554022	In addition to spontaneous somatic mutations, heterozygous germline mutations to a tumor suppressor gene such as BAP1 and the subsequent development of TPDS can also be involved in development of melanoma.	('involved', 'Reg', (169, 177))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('men', 'Species', '9606', (144, 147))	('tumor suppressor', 'biological_process', 'GO:0051726', ('83', '99'))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('83', '99'))	('BAP1', 'Gene', '8314', (113, 117))	('heterozygous', 'Var', (46, 58))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('melanoma', 'Disease', (196, 204))	('TPDS', 'Disease', (152, 156))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))	('TPDS', 'Disease', 'OMIM:614327', (152, 156))	('men', 'Species', '9606', (188, 191))	('BAP1', 'Gene', (113, 117))	('germline mutations', 'Var', (59, 77))
129090	29554022	However, this gene has high penetrance, with malignancy developing in 69.74% of carriers and nearly all individuals with germline BAP1 mutations develop malignancies by age 55.	('BAP1', 'Gene', (130, 134))	('malignancy', 'Disease', 'MESH:D009369', (45, 55))	('malignancies', 'Disease', (153, 165))	('develop', 'PosReg', (145, 152))	('mutations', 'Var', (135, 144))	('malignancy', 'Disease', (45, 55))	('BAP1', 'Gene', '8314', (130, 134))	('malignancies', 'Disease', 'MESH:D009369', (153, 165))
129093	29554022	The earliest reported case of cutaneous melanoma related to BAP1 mutations prior to this case was at the age of 25.	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('BAP1', 'Gene', '8314', (60, 64))	('related', 'Reg', (49, 56))	('cutaneous melanoma', 'Disease', (30, 48))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (30, 48))	('BAP1', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
129095	29554022	This sequencing revealed a somatic BRAF mutation that could be exploited with targeted therapy if needed in the future.	('mutation', 'Var', (40, 48))	('BRAF', 'Gene', (35, 39))	('BRAF', 'Gene', '673', (35, 39))
129096	29554022	Further, a germline BAP1 mutation (p. D567X) was identified.	('D567X', 'Var', (38, 43))	('BAP1', 'Gene', '8314', (20, 24))	('BAP1', 'Gene', (20, 24))	('D567X', 'SUBSTITUTION', 'None', (38, 43))
129097	29554022	The presence of both a somatic BRAF mutation and germline BAP1 mutation have been implicated in cutaneous melanoma.	('cutaneous melanoma', 'Disease', (96, 114))	('BAP1', 'Gene', (58, 62))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (96, 114))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (96, 114))	('mutation', 'Var', (63, 71))	('implicated', 'Reg', (82, 92))	('BRAF', 'Gene', '673', (31, 35))	('BAP1', 'Gene', '8314', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('mutation', 'Var', (36, 44))	('BRAF', 'Gene', (31, 35))
129098	29554022	Identification of specific, previously identified mutations allows for early screening of related malignancies, screening for family members and genetic counseling.	('mutations', 'Var', (50, 59))	('malignancies', 'Disease', 'MESH:D009369', (98, 110))	('malignancies', 'Disease', (98, 110))
129100	29554022	2016 proposed recommendations for families with germline BAP1 mutations.	('BAP1', 'Gene', '8314', (57, 61))	('BAP1', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('men', 'Species', '9606', (19, 22))
129104	29554022	In our case, evidence of confirmed germline BAP1 mutation led to screening for uveal melanoma by ophthalmology and close monitoring for cutaneous melanoma for the patient as well genetic screening for other family members.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('mutation', 'Var', (49, 57))	('BAP1', 'Gene', '8314', (44, 48))	('patient', 'Species', '9606', (163, 170))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('cutaneous melanoma', 'Disease', (136, 154))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (136, 154))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (136, 154))	('BAP1', 'Gene', (44, 48))	('uveal melanoma', 'Disease', (79, 93))
129114	29455668	However, in cancer cells, aberrant HGF/c-Met axis activation, which is closely related to c-Met gene mutations, overexpression, and amplification, promotes tumor development and progression by stimulating the PI3K/AKT, Ras/MAPK, JAK/STAT, SRC, Wnt/beta-catenin, and other signaling pathways.	('beta-catenin', 'Gene', (248, 260))	('SRC', 'Gene', '6714', (239, 242))	('HGF', 'Gene', (35, 38))	('beta-catenin', 'Gene', '1499', (248, 260))	('c-Met', 'Gene', '4233', (90, 95))	('PI3', 'Gene', (209, 212))	('tumor', 'Disease', (156, 161))	('JAK/STAT', 'Pathway', (229, 237))	('AKT', 'Gene', (214, 217))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('aberrant', 'Var', (26, 34))	('MAPK', 'molecular_function', 'GO:0004707', ('223', '227'))	('promotes', 'PosReg', (147, 155))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('activation', 'PosReg', (50, 60))	('SRC', 'Gene', (239, 242))	('c-Met', 'Gene', '4233', (39, 44))	('mutations', 'Var', (101, 110))	('c-Met', 'Gene', (90, 95))	('AKT', 'Gene', '207', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('stimulating', 'PosReg', (193, 204))	('PI3', 'Gene', '5266', (209, 212))	('cancer', 'Disease', (12, 18))	('progression', 'CPA', (178, 189))	('signaling', 'biological_process', 'GO:0023052', ('272', '281'))	('c-Met', 'Gene', (39, 44))	('PI3K', 'molecular_function', 'GO:0016303', ('209', '213'))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('HGF', 'Gene', '3082', (35, 38))	('Ras/MAPK', 'Pathway', (219, 227))	('JAK', 'molecular_function', 'GO:0004713', ('229', '232'))
129124	29455668	However, as a type of proto-oncogene, abnormal activation of c-Met can promote the development and progression of multiple cancers such as liver, lung, colon, breast, pancreatic, ovarian, prostate, and gastric carcinomas, in addition to cancers of the nervous system such as glioblastoma.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('carcinomas', 'Phenotype', 'HP:0030731', (210, 220))	('glioblastoma', 'Disease', (275, 287))	('c-Met', 'Gene', (61, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (275, 287))	('ovarian', 'Disease', (179, 186))	('promote', 'PosReg', (71, 78))	('multiple cancers', 'Disease', (114, 130))	('abnormal', 'Var', (38, 46))	('ovarian', 'Disease', 'MESH:D010051', (179, 186))	('prostate', 'Disease', (188, 196))	('pancreatic', 'Disease', 'MESH:D010195', (167, 177))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('colon', 'Disease', (152, 157))	('cancers', 'Disease', (237, 244))	('liver', 'Disease', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('activation', 'PosReg', (47, 57))	('pancreatic', 'Disease', (167, 177))	('abnormal activation of c', 'Phenotype', 'HP:0012175', (38, 62))	('c-Met', 'Gene', '4233', (61, 66))	('progression', 'CPA', (99, 110))	('breast', 'Disease', (159, 165))	('lung', 'Disease', (146, 150))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('glioblastoma', 'Disease', 'MESH:D005909', (275, 287))	('multiple cancers', 'Disease', 'MESH:D009369', (114, 130))	('cancers', 'Disease', (123, 130))	('gastric carcinomas', 'Disease', (202, 220))	('gastric carcinomas', 'Disease', 'MESH:D013274', (202, 220))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('cancers of the nervous system', 'Phenotype', 'HP:0004375', (237, 266))
129127	29455668	It has been determined that c-Met gene mutations, overexpression, and amplification also occur in a variety of human tumor types, and these events are closely related to the aberrant activation of the HGF/c-Met signaling pathway.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('activation', 'PosReg', (183, 193))	('overexpression', 'PosReg', (50, 64))	('c-Met', 'Gene', '4233', (28, 33))	('Met signaling pathway', 'biological_process', 'GO:0048012', ('207', '228'))	('tumor', 'Disease', (117, 122))	('human', 'Species', '9606', (111, 116))	('mutations', 'Var', (39, 48))	('c-Met', 'Gene', (205, 210))	('HGF', 'Gene', (201, 204))	('c-Met', 'Gene', '4233', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('HGF', 'Gene', '3082', (201, 204))	('c-Met', 'Gene', (28, 33))
129128	29455668	Meanwhile, high c-Met expression is closely associated with poor prognosis in cancer patients.	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('c-Met', 'Gene', (16, 21))	('patients', 'Species', '9606', (85, 93))	('high', 'Var', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('c-Met', 'Gene', '4233', (16, 21))
129130	29455668	Therefore, as abnormal c-Met function can increase the difficulty associated with tumor treatment, understanding its role in cancer is extremely important.	('abnormal', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('c-Met', 'Gene', (23, 28))	('c-Met', 'Gene', '4233', (23, 28))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('tumor', 'Disease', (82, 87))
129135	29455668	Ser-975 and Tyr-1003 sites at the juxtamembrane domain play an important role in the negative regulation of c-Met.	('Ser', 'Chemical', 'MESH:D012694', (0, 3))	('regulation', 'biological_process', 'GO:0065007', ('94', '104'))	('c-Met', 'Gene', (108, 113))	('c-Met', 'Gene', '4233', (108, 113))	('Tyr', 'Chemical', 'MESH:D014443', (12, 15))	('Tyr-1003', 'Var', (12, 20))	('juxtamembrane', 'cellular_component', 'GO:0005886', ('34', '47'))	('juxtamembrane', 'cellular_component', 'GO:0009898', ('34', '47'))	('negative regulation', 'MPA', (85, 104))	('juxtamembrane', 'cellular_component', 'GO:0009897', ('34', '47'))	('juxtamembrane', 'cellular_component', 'GO:0019897', ('34', '47'))	('Ser', 'cellular_component', 'GO:0005790', ('0', '3'))
129136	29455668	When HGF binds c-Met, Tyr-1234 and Tyr-1235 in the intracellular tyrosine kinase domain undergo autophosphorylation, which results in autophosphorylation of Tyr-1349 and Tyr-1356 in the C-terminal docking site.	('undergo', 'Reg', (88, 95))	('HGF', 'Gene', (5, 8))	('tyrosine', 'Chemical', 'MESH:D014443', (65, 73))	('intracellular', 'cellular_component', 'GO:0005622', ('51', '64'))	('Tyr', 'Chemical', 'MESH:D014443', (35, 38))	('Tyr-1356', 'Var', (170, 178))	('HGF', 'Gene', '3082', (5, 8))	('autophosphorylation', 'MPA', (134, 153))	('Tyr-1349', 'MPA', (157, 165))	('c-Met', 'Gene', (15, 20))	('Tyr', 'Chemical', 'MESH:D014443', (22, 25))	('Tyr', 'Chemical', 'MESH:D014443', (170, 173))	('results in', 'Reg', (123, 133))	('autophosphorylation', 'MPA', (96, 115))	('c-Met', 'Gene', '4233', (15, 20))	('Tyr-1235', 'Var', (35, 43))	('Tyr-1234', 'Var', (22, 30))	('Tyr', 'Chemical', 'MESH:D014443', (157, 160))
129151	29455668	In tumor cells, the mutation rate of the Ras gene is approximately 25%, whereas in pancreatic cancer and colon cancer, the mutation rates could be 85 and 40%, respectively.	('tumor', 'Disease', (3, 8))	('colon cancer', 'Disease', 'MESH:D015179', (105, 117))	('pancreatic cancer', 'Disease', (83, 100))	('colon cancer', 'Disease', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutation', 'Var', (20, 28))	('pancreatic cancer', 'Disease', 'MESH:D010190', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))	('Ras gene', 'Gene', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('colon cancer', 'Phenotype', 'HP:0003003', (105, 117))
129152	29455668	Upon mutation, its intrinsic GTPase activity is inhibited, which can lead to malignant cell transformation through sustained activation of Ras2GTP (Fig.	('activation', 'PosReg', (125, 135))	('GTPase', 'Protein', (29, 35))	('malignant cell transformation', 'CPA', (77, 106))	('GTPase activity', 'molecular_function', 'GO:0003924', ('29', '44'))	('Ras2GTP', 'Protein', (139, 146))	('Ras2GTP', 'Chemical', '-', (139, 146))	('lead to', 'Reg', (69, 76))	('mutation', 'Var', (5, 13))
129169	29455668	In tumor cells, mutations or deletions in PTEN are common, and enable the increased activation of the PI3K/AKT/mTOR pathway; this leads to aberrant activation of this pathway (Fig.	('PTEN', 'Gene', (42, 46))	('PI3', 'Gene', '5266', (102, 105))	('tumor', 'Disease', (3, 8))	('PTEN', 'Gene', '5728', (42, 46))	('mTOR', 'Gene', '2475', (111, 115))	('PI3K', 'molecular_function', 'GO:0016303', ('102', '106'))	('activation', 'PosReg', (148, 158))	('AKT', 'Gene', (107, 110))	('mTOR', 'Gene', (111, 115))	('activation', 'PosReg', (84, 94))	('mutations', 'Var', (16, 25))	('PI3', 'Gene', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('deletions', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('AKT', 'Gene', '207', (107, 110))
129171	29455668	Studies have shown that in colon cancer and glioblastoma, c-Met expression can enhance Wnt/beta-catenin signal transduction, and prevent GSK3beta from phosphorylating beta-catenin; this, in turn, promotes the translocation of beta-catenin to the nucleus, facilitating tumorigenesis.	('nucleus', 'cellular_component', 'GO:0005634', ('246', '253'))	('glioblastoma', 'Disease', 'MESH:D005909', (44, 56))	('promotes', 'PosReg', (196, 204))	('c-Met', 'Gene', '4233', (58, 63))	('signal transduction', 'biological_process', 'GO:0007165', ('104', '123'))	('GSK3beta', 'Gene', (137, 145))	('enhance', 'PosReg', (79, 86))	('colon cancer', 'Disease', 'MESH:D015179', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('beta-catenin', 'Gene', (167, 179))	('beta-catenin', 'Gene', '1499', (167, 179))	('glioblastoma', 'Disease', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('translocation', 'MPA', (209, 222))	('glioblastoma', 'Phenotype', 'HP:0012174', (44, 56))	('colon cancer', 'Disease', (27, 39))	('c-Met', 'Gene', (58, 63))	('beta-catenin', 'Gene', (91, 103))	('GSK', 'molecular_function', 'GO:0050321', ('137', '140'))	('GSK3beta', 'Gene', '2932', (137, 145))	('beta-catenin', 'Gene', '1499', (91, 103))	('beta-catenin', 'Gene', (226, 238))	('beta-catenin', 'Gene', '1499', (226, 238))	('prevent', 'NegReg', (129, 136))	('colon cancer', 'Phenotype', 'HP:0003003', (27, 39))	('tumor', 'Disease', (268, 273))	('expression', 'Var', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
129176	29455668	At the same time, it can be acetylated by acetyltransferase p300/CBP-associated factor (PCAF) at Lys-49.	('p300/CBP-associated factor', 'Gene', (60, 86))	('PCAF', 'Gene', (88, 92))	('Lys-49', 'Var', (97, 103))	('Lys', 'Chemical', 'MESH:D008239', (97, 100))	('p300/CBP-associated factor', 'Gene', '8850', (60, 86))	('acetylated', 'MPA', (28, 38))	('PCAF', 'Gene', '8850', (88, 92))	('CBP', 'molecular_function', 'GO:0008140', ('65', '68'))
129193	29455668	The fact that oncogenic addiction to c-Met requires RON implies that c-Met-RON heterodimers can promote the activation of diverse signaling cascades through different platforms.	('c-Met', 'Gene', (69, 74))	('RON', 'Gene', (52, 55))	('c-Met', 'Gene', '4233', (69, 74))	('RON', 'Gene', '4486', (52, 55))	('RON', 'Gene', (75, 78))	('promote', 'PosReg', (96, 103))	('c-Met', 'Gene', (37, 42))	('RON', 'Gene', '4486', (75, 78))	('c-Met', 'Gene', '4233', (37, 42))	('signaling', 'biological_process', 'GO:0023052', ('130', '139'))	('heterodimers', 'Var', (79, 91))
129200	29455668	With respect to this, we found that knockdown of RON enhances the level and duration of HGF-mediated activation of MAPK and AKT.	('RON', 'Gene', '4486', (49, 52))	('HGF', 'Gene', '3082', (88, 91))	('activation', 'PosReg', (101, 111))	('enhances', 'PosReg', (53, 61))	('AKT', 'Gene', (124, 127))	('MAPK', 'Pathway', (115, 119))	('knockdown', 'Var', (36, 45))	('MAPK', 'molecular_function', 'GO:0004707', ('115', '119'))	('HGF', 'Gene', (88, 91))	('AKT', 'Gene', '207', (124, 127))	('RON', 'Gene', (49, 52))
129201	29455668	Although the functional relevance of c-Met-RON heterodimers has not been fully explored, some studies suggest that general knockdown of RON leads to changes in c-Met signaling.	('RON', 'Gene', (136, 139))	('RON', 'Gene', (43, 46))	('c-Met', 'Gene', (37, 42))	('c-Met', 'Gene', (160, 165))	('c-Met', 'Gene', '4233', (160, 165))	('c-Met', 'Gene', '4233', (37, 42))	('RON', 'Gene', '4486', (43, 46))	('knockdown', 'Var', (123, 132))	('signaling', 'biological_process', 'GO:0023052', ('166', '175'))	('changes', 'Reg', (149, 156))	('RON', 'Gene', '4486', (136, 139))
129202	29455668	For example, it was found that silencing RON in pancreatic cancer cell lines leads to upregulation of c-Met expression and activity.	('silencing', 'Var', (31, 40))	('upregulation', 'PosReg', (86, 98))	('pancreatic cancer', 'Disease', (48, 65))	('RON', 'Gene', '4486', (41, 44))	('pancreatic cancer', 'Disease', 'MESH:D010190', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (48, 65))	('RON', 'Gene', (41, 44))	('activity', 'MPA', (123, 131))	('c-Met', 'Gene', (102, 107))	('c-Met', 'Gene', '4233', (102, 107))
129206	29455668	Studies have shown that 70% of EGFR-activating mutations in non-small cell lung carcinoma (NSCLC) are associated with an initial positive response to the EGFR inhibitors gefitinib or erlotinib.	('EGFR', 'Gene', (154, 158))	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('EGFR', 'Gene', '1956', (31, 35))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (64, 89))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (70, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('erlotinib', 'Chemical', 'MESH:D000069347', (183, 192))	('EGFR', 'Gene', (31, 35))	('mutations', 'Var', (47, 56))	('gefitinib', 'Chemical', 'MESH:D000077156', (170, 179))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (60, 89))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('cell lung carcinoma', 'Disease', (70, 89))	('NSCLC', 'Disease', (91, 96))	('EGFR', 'Gene', '1956', (154, 158))	('EGFR', 'molecular_function', 'GO:0005006', ('154', '158'))
129207	29455668	However, the vast majority of tumors that respond to EGFR inhibitors achieve acquired resistance.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('acquired resistance', 'MPA', (77, 96))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('inhibitors', 'Var', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))
129211	29455668	One study has already shown that the second mutation in EGFR, T790 M, and the amplification of the MET proto-oncogene will lead to the activation of its downstream ERBB3-initiated PI3K/AKT pathway, resulting in EGFR-TKI acquired resistance.	('ERBB3', 'Gene', '2065', (164, 169))	('AKT', 'Gene', (185, 188))	('activation', 'PosReg', (135, 145))	('PI3K', 'molecular_function', 'GO:0016303', ('180', '184'))	('PI3', 'Gene', (180, 183))	('ERBB3', 'Gene', (164, 169))	('T790 M', 'Mutation', 'rs121434569', (62, 68))	('EGFR', 'Gene', '1956', (56, 60))	('EGFR', 'Gene', '1956', (211, 215))	('T790 M', 'Var', (62, 68))	('AKT', 'Gene', '207', (185, 188))	('EGFR', 'molecular_function', 'GO:0005006', ('211', '215'))	('EGFR', 'Gene', (56, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('PI3', 'Gene', '5266', (180, 183))	('EGFR', 'Gene', (211, 215))	('acquired resistance', 'MPA', (220, 239))
129212	29455668	When the c-MET gene is amplified, the two downstream pathways (Grb2/MAPK and PI3K/AKT) are activated by the increase in the number of ERBB3 receptors.	('PI3K', 'molecular_function', 'GO:0016303', ('77', '81'))	('increase', 'PosReg', (108, 116))	('ERBB3', 'Gene', (134, 139))	('c-MET', 'Gene', (9, 14))	('PI3', 'Gene', '5266', (77, 80))	('Grb2', 'Gene', (63, 67))	('PI3', 'Gene', (77, 80))	('activated', 'PosReg', (91, 100))	('amplified', 'Var', (23, 32))	('AKT', 'Gene', '207', (82, 85))	('Grb2', 'Gene', '2885', (63, 67))	('ERBB3', 'Gene', '2065', (134, 139))	('MAPK', 'molecular_function', 'GO:0004707', ('68', '72'))	('c-MET', 'Gene', '4233', (9, 14))	('AKT', 'Gene', (82, 85))
129215	29455668	If EGFR and Met mutations exist simultaneously, drug resistance will be further exacerbated.	('EGFR', 'Gene', '1956', (3, 7))	('drug resistance', 'biological_process', 'GO:0042493', ('48', '63'))	('EGFR', 'Gene', (3, 7))	('EGFR', 'molecular_function', 'GO:0005006', ('3', '7'))	('exacerbated', 'PosReg', (80, 91))	('drug resistance', 'biological_process', 'GO:0009315', ('48', '63'))	('mutations', 'Var', (16, 25))	('drug resistance', 'Phenotype', 'HP:0020174', (48, 63))	('drug resistance', 'MPA', (48, 63))
129218	29455668	Another study found that EGFR mutation and Met activation were observed in tumor cells.	('Met', 'MPA', (43, 46))	('EGFR', 'Gene', (25, 29))	('mutation', 'Var', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('EGFR', 'Gene', '1956', (25, 29))	('tumor', 'Disease', (75, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))
129227	29455668	Experiments have shown that c-Met inhibition enhances EGFR signaling by increasing ErbB3 expression.	('EGFR', 'molecular_function', 'GO:0005006', ('54', '58'))	('expression', 'MPA', (89, 99))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('inhibition', 'Var', (34, 44))	('c-Met', 'Gene', '4233', (28, 33))	('ErbB3', 'Gene', (83, 88))	('ErbB3', 'Gene', '2065', (83, 88))	('EGFR', 'Gene', '1956', (54, 58))	('enhances', 'PosReg', (45, 53))	('increasing', 'PosReg', (72, 82))	('EGFR', 'Gene', (54, 58))	('c-Met', 'Gene', (28, 33))
129242	29455668	PF-22341066 targets the TK domain of c-Met, and after a series of reactions, some residues cause a conformational change, which interferes with the ATP binding site.	('conformational change', 'MPA', (99, 120))	('cause', 'Reg', (91, 96))	('PF-22341066', 'Var', (0, 11))	('c-Met', 'Gene', (37, 42))	('ATP binding', 'molecular_function', 'GO:0005524', ('148', '159'))	('c-Met', 'Gene', '4233', (37, 42))	('ATP', 'Chemical', 'MESH:D000255', (148, 151))
129265	29455668	In addition, studies have investigated the effect of LY2801653 on human cholangiocarcinoma (CCC) cell lines.	('LY2801653', 'Var', (53, 62))	('cholangiocarcinoma', 'Disease', (72, 90))	('human', 'Species', '9606', (66, 71))	('LY2801653', 'Chemical', 'MESH:C586252', (53, 62))	('CCC', 'Phenotype', 'HP:0030153', (92, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('CCC', 'cellular_component', 'GO:0030896', ('92', '95'))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 90))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))
129266	29455668	Using a xenograft mouse model, it was determined that LY2801653 blocks c-Met phosphorylation, down-regulates downstream target expression, and inhibits CCC cell proliferation and xenograft tumor growth.	('inhibits', 'NegReg', (143, 151))	('LY2801653', 'Var', (54, 63))	('blocks', 'NegReg', (64, 70))	('mouse', 'Species', '10090', (18, 23))	('LY2801653', 'Chemical', 'MESH:C586252', (54, 63))	('CCC', 'Phenotype', 'HP:0030153', (152, 155))	('CCC', 'Disease', (152, 155))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('c-Met', 'Gene', (71, 76))	('xenograft tumor', 'Disease', (179, 194))	('down-regulates', 'NegReg', (94, 108))	('c-Met', 'Gene', '4233', (71, 76))	('downstream target expression', 'MPA', (109, 137))	('CCC', 'cellular_component', 'GO:0030896', ('152', '155'))	('cell proliferation', 'biological_process', 'GO:0008283', ('156', '174'))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('xenograft tumor', 'Disease', 'MESH:D009369', (179, 194))
129268	29455668	It is effective in inhibiting the proto-oncogene c-Met mutants N1100Y, Y1230C, Y1230H, Y1235D, and M1250Tn1100y.	('Y1235D', 'Var', (87, 93))	('inhibiting', 'NegReg', (19, 29))	('N1100Y', 'Mutation', 'rs1057520030', (63, 69))	('proto-oncogene c-Met', 'Gene', '4233', (34, 54))	('Y1230C', 'Mutation', 'rs121913246', (71, 77))	('Y1230C', 'Var', (71, 77))	('M1250Tn1100y', 'Var', (99, 111))	('proto-oncogene c-Met', 'Gene', (34, 54))	('Y1235D', 'Mutation', 'rs1057519824', (87, 93))	('N1100Y', 'Var', (63, 69))	('Y1230H', 'Var', (79, 85))	('Y1230H', 'Mutation', 'rs121913247', (79, 85))
129277	29455668	ARQ197 directly binds the A-loop and P-loop phenylalanines by inducing "hydrophobic collapse", resulting in disruption of the ionic interaction in the catalytic residue with the help of Arg1227, Tyr1230, and other residues.	('ionic interaction in the catalytic residue', 'MPA', (126, 168))	('disruption', 'NegReg', (108, 118))	('inducing', 'Reg', (62, 70))	('phenylalanines', 'Chemical', 'MESH:D010649', (44, 58))	('Arg1227', 'Chemical', '-', (186, 193))	('Tyr1230', 'Chemical', '-', (195, 202))	('Arg1227', 'Var', (186, 193))	('Tyr1230', 'Var', (195, 202))	('ARQ197', 'Var', (0, 6))
129290	29455668	One study showed that in a nude mouse model of treatment-sensitive NSCLC, erlotinib resistance could be effectively reversed by the administration of SU1274.	('SU1274', 'Var', (150, 156))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('reversed', 'Reg', (116, 124))	('erlotinib', 'Chemical', 'MESH:D000069347', (74, 83))	('mouse', 'Species', '10090', (32, 37))	('NSCLC', 'Disease', (67, 72))	('erlotinib resistance', 'MPA', (74, 94))	('SU1274', 'Chemical', '-', (150, 156))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
129300	29455668	One study showed that in pancreatic cancer, silencing RON might modulate the c-Met signaling pathway, resulting in a compensatory reaction during the downregulation of either tyrosine kinase receptor.	('compensatory reaction', 'MPA', (117, 138))	('pancreatic cancer', 'Disease', (25, 42))	('pancreatic cancer', 'Disease', 'MESH:D010190', (25, 42))	('modulate', 'Reg', (64, 72))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (25, 42))	('Met signaling pathway', 'biological_process', 'GO:0048012', ('79', '100'))	('RON', 'Gene', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('c-Met', 'Gene', (77, 82))	('RON', 'Gene', '4486', (54, 57))	('tyrosine', 'Chemical', 'MESH:D014443', (175, 183))	('c-Met', 'Gene', '4233', (77, 82))	('silencing', 'Var', (44, 53))
129312	25687217	We identified one patient with a pathogenic mutation (c. 1717delC, p.L573fs*3) in BAP1.	('BAP1', 'Gene', (82, 86))	('1717delC', 'Var', (57, 65))	('p.L573fs*3', 'Mutation', 'rs869025212', (67, 77))	('pathogenic', 'Reg', (33, 43))	('1717delC', 'DELETION', 'None', (57, 65))	('patient', 'Species', '9606', (18, 25))	('BAP1', 'Gene', '8314', (82, 86))	('p.L573fs*3', 'Var', (67, 77))
129314	25687217	One additional patient had an intronic variant of uncertain significance (c.123-48T>G) in BAP1 while the remaining 12 patients had no alteration.	('patient', 'Species', '9606', (15, 22))	('BAP1', 'Gene', '8314', (90, 94))	('c.123-48T>G', 'Var', (74, 85))	('BAP1', 'Gene', (90, 94))	('c.123-48T>G', 'Mutation', 'rs143273211', (74, 85))	('patient', 'Species', '9606', (118, 125))	('patients', 'Species', '9606', (118, 126))
129318	25687217	This study suggests that a small subset of patients with early onset UM has germline mutation in BAP1.	('germline mutation', 'Var', (76, 93))	('BAP1', 'Gene', '8314', (97, 101))	('patients', 'Species', '9606', (43, 51))	('BAP1', 'Gene', (97, 101))	('early onset UM', 'Disease', (57, 71))
129319	25687217	While young patients with UM should be screened for germline BAP1 mutations, our results suggest that there is a need to identify other candidate genes which are responsible for UM in young patients.	('mutations', 'Var', (66, 75))	('patients', 'Species', '9606', (12, 20))	('BAP1', 'Gene', (61, 65))	('patients', 'Species', '9606', (190, 198))	('BAP1', 'Gene', '8314', (61, 65))
129325	25687217	Given that germline BAP1 mutations are associated with an early onset of UM, the purpose of this study was to analyze a series of young patients from two ocular oncology centers with a diagnosis of UM under age 30 for germline BAP1 mutations.	('mutations', 'Var', (25, 34))	('BAP1', 'Gene', '8314', (227, 231))	('BAP1', 'Gene', (20, 24))	('oncology', 'Phenotype', 'HP:0002664', (161, 169))	('BAP1', 'Gene', (227, 231))	('patients', 'Species', '9606', (136, 144))	('associated', 'Reg', (39, 49))	('ocular oncology', 'Phenotype', 'HP:0100012', (154, 169))	('BAP1', 'Gene', '8314', (20, 24))
129326	25687217	We hypothesized that: (1) there would be an increased prevalence of BAP1 germline mutations in young patients with UM, and (2) there would be an increased incidence of a positive family history for hereditary cancer predisposition in these young patients with UM.	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (246, 254))	('BAP1', 'Gene', '8314', (68, 72))	('hereditary cancer', 'Disease', 'MESH:D009369', (198, 215))	('germline', 'Var', (73, 81))	('hereditary cancer', 'Disease', (198, 215))	('BAP1', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
129339	25687217	One patient (FUM152, III-2) was found to have a germline single base pair deletion in the coding region of the BAP1 gene (c. 1717delC, p.L573fs*3) causing a frame shift and subsequent truncation of the BAP1 protein, see Figure 1.	('protein', 'cellular_component', 'GO:0003675', ('207', '214'))	('causing', 'Reg', (147, 154))	('BAP1', 'Gene', (202, 206))	('BAP1', 'Gene', '8314', (111, 115))	('p.L573fs*3', 'Mutation', 'rs869025212', (135, 145))	('1717delC', 'DELETION', 'None', (125, 133))	('patient', 'Species', '9606', (4, 11))	('BAP1', 'Gene', (111, 115))	('p.L573fs*3', 'Var', (135, 145))	('1717delC', 'Var', (125, 133))	('BAP1', 'Gene', '8314', (202, 206))	('truncation', 'MPA', (184, 194))	('frame', 'MPA', (157, 162))
129345	25687217	Importantly, the patient in the series with a germline BAP1 mutation was treated with brachy-therapy for AJCC T1a choroidal melanoma at age 18 years and developed biopsy-proven metastases to breast and bone at age 27.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('mutation', 'Var', (60, 68))	('choroidal melanoma', 'Disease', (114, 132))	('BAP1', 'Gene', (55, 59))	('patient', 'Species', '9606', (17, 24))	('metastases', 'Disease', (177, 187))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (114, 132))	('AJCC T1a', 'Gene', (105, 113))	('developed', 'PosReg', (153, 162))	('metastases', 'Disease', 'MESH:D009362', (177, 187))	('choroidal melanoma', 'Disease', 'MESH:D008545', (114, 132))	('BAP1', 'Gene', '8314', (55, 59))
129350	25687217	The cancer family history for the patient with the germline BAP1 mutation was significant for UM in the patient's father at age 45 and his subsequent death from metastatic disease at age 49 (FUM152, Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('germline', 'Var', (51, 59))	('BAP1', 'Gene', '8314', (60, 64))	('patient', 'Species', '9606', (34, 41))	('BAP1', 'Gene', (60, 64))	('mutation', 'Var', (65, 73))	('patient', 'Species', '9606', (104, 111))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))
129356	25687217	The proband of FUM152, with pathogenic BAP1 mutation, had no report of any abnormal skin lesions or sign of melanocytosis/nevus of Ota on clinical examination records.	('mutation', 'Var', (44, 52))	('nevus of Ota', 'Phenotype', 'HP:0009920', (122, 134))	('melanocytosis', 'Disease', (108, 121))	('skin lesions', 'Disease', (84, 96))	('melanocytosis', 'Disease', 'MESH:C535835', (108, 121))	('skin lesions', 'Disease', 'MESH:D012871', (84, 96))	('abnormal skin', 'Phenotype', 'HP:0000951', (75, 88))	('BAP1', 'Gene', '8314', (39, 43))	('melanocytosis/nevus', 'Phenotype', 'HP:0000995', (108, 127))	('nevus', 'Phenotype', 'HP:0003764', (122, 127))	('BAP1', 'Gene', (39, 43))
129359	25687217	Three patients reported significant cancer histories on both the maternal and paternal sides of their family FUM147, FUM063 and FUM013, see Figure 2.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('patients', 'Species', '9606', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('FUM013', 'Var', (128, 134))
129362	25687217	As such, it seems logical to test these patients for germline mutation in BAP1.	('BAP1', 'Gene', '8314', (74, 78))	('patients', 'Species', '9606', (40, 48))	('BAP1', 'Gene', (74, 78))	('germline mutation', 'Var', (53, 70))
129365	25687217	In this study, we identified a pathogenic germline mutation in BAP1 in 1/14 (7.1%) of patients with early onset UM.	('pathogenic', 'Reg', (31, 41))	('early onset UM', 'Disease', (100, 114))	('BAP1', 'Gene', (63, 67))	('germline mutation', 'Var', (42, 59))	('BAP1', 'Gene', '8314', (63, 67))	('patients', 'Species', '9606', (86, 94))
129366	25687217	These findings support the screening of young patients for germline BAP1 mutations, but also suggest the existence of other candidate genes predisposing to cancer in these patients.	('patients', 'Species', '9606', (46, 54))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('germline', 'Var', (59, 67))	('BAP1', 'Gene', '8314', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('patients', 'Species', '9606', (172, 180))	('BAP1', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))
129369	25687217	Therefore, it is important to consider that there may be germline mutations in genes other than BAP1, especially in patients with a strong family history of multiple malignancies.	('germline mutations', 'Var', (57, 75))	('BAP1', 'Gene', (96, 100))	('patients', 'Species', '9606', (116, 124))	('malignancies', 'Disease', 'MESH:D009369', (166, 178))	('BAP1', 'Gene', '8314', (96, 100))	('malignancies', 'Disease', (166, 178))
129370	25687217	Moreover, several of the youngest patients in the study had very limited family histories of malignancy which may simply be due to the fact that even though they harbor germline mutations, their family members may not have yet developed malignancies but could still be at high risk for developing them in the future, Table 1.	('malignancy', 'Disease', 'MESH:D009369', (93, 103))	('malignancies', 'Disease', 'MESH:D009369', (237, 249))	('malignancy', 'Disease', (93, 103))	('malignancies', 'Disease', (237, 249))	('patients', 'Species', '9606', (34, 42))	('germline', 'Var', (169, 177))
129375	25687217	For example, one possibility is the inheritance of a driver mutation for cancer from one side of the family with the inheritance of a modifier gene from the other side of the family.	('cancer', 'Disease', (73, 79))	('mutation', 'Var', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))
129379	25687217	Previous work looking for germline mutations in these genes as well as GNAQ, GNA11 and BRCA2, in patients with uveal melanoma revealed rare cases of mutations in BRCA2 and CDKN2A, while the other genes showed negative results.	('uveal melanoma', 'Phenotype', 'HP:0007716', (111, 125))	('uveal melanoma', 'Disease', 'MESH:C536494', (111, 125))	('BRCA2', 'Gene', (162, 167))	('mutations', 'Var', (149, 158))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('BRCA2', 'Gene', '675', (87, 92))	('uveal melanoma', 'Disease', (111, 125))	('GNA11', 'Gene', (77, 82))	('GNAQ', 'Gene', (71, 75))	('CDKN2A', 'Gene', '1029', (172, 178))	('BRCA2', 'Gene', '675', (162, 167))	('GNA11', 'Gene', '2767', (77, 82))	('CDKN2A', 'Gene', (172, 178))	('GNAQ', 'Gene', '2776', (71, 75))	('BRCA2', 'Gene', (87, 92))	('patients', 'Species', '9606', (97, 105))
129383	25687217	While this individual was not found to have a germline BAP1 mutation, the very early age of onset suggests that this child could harbor an underlying germline mutation in a gene other than BAP1.	('BAP1', 'Gene', '8314', (189, 193))	('mutation', 'Var', (60, 68))	('BAP1', 'Gene', (55, 59))	('BAP1', 'Gene', (189, 193))	('child', 'Species', '9606', (117, 122))	('BAP1', 'Gene', '8314', (55, 59))
129540	25868390	Of note, intraocular tumors were diagnosed significantly earlier in the thyroxine group compared to the PTU group (p = 0.003).	('ocular tumor', 'Phenotype', 'HP:0100012', (14, 26))	('thyroxine', 'Chemical', 'MESH:D013974', (72, 81))	('PTU', 'Chemical', 'MESH:D011441', (104, 107))	('intraocular tumors', 'Disease', (9, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('thyroxine', 'Var', (72, 81))	('intraocular tumors', 'Disease', 'MESH:D064090', (9, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
129543	25868390	The PTU group survived significantly longer (33.8 +- 3.3 days, p = 0.001) than the control group (28.9 +- 1.9 days), the latter representing the natural history of a melanoma-tumor bearing murine eye.	('longer', 'PosReg', (37, 43))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('PTU', 'Chemical', 'MESH:D011441', (4, 7))	('PTU', 'Var', (4, 7))	('melanoma-tumor', 'Disease', 'MESH:D008545', (166, 180))	('survived', 'CPA', (14, 22))	('murine', 'Species', '10090', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('melanoma-tumor', 'Disease', (166, 180))
129615	24565984	Down regulation of RhoC by microRNA-138 results in de-activation of FAK, Src and Erk1/2 signaling pathway in head and neck squamous cell carcinoma RhoC a pro-metastatic oncogene is constitutively active in many head and neck squamous cell carcinomas.	('neck squamous cell carcinomas', 'Disease', (220, 249))	('FAK', 'molecular_function', 'GO:0004717', ('68', '71'))	('Erk1/2', 'Gene', (81, 87))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (211, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('FAK', 'Gene', (68, 71))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (220, 249))	('Down regulation', 'NegReg', (0, 15))	('Src', 'Gene', '6714', (73, 76))	('regulation', 'biological_process', 'GO:0065007', ('5', '15'))	('microRNA-138', 'Var', (27, 39))	('FAK', 'Gene', '5747', (68, 71))	('neck squamous cell carcinoma', 'Disease', (118, 146))	('Erk1/2', 'Gene', '5595;5594', (81, 87))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (118, 146))	('carcinomas', 'Phenotype', 'HP:0030731', (239, 249))	('signaling pathway', 'biological_process', 'GO:0007165', ('88', '105'))	('de-activation', 'NegReg', (51, 64))	('RhoC', 'Gene', '389', (147, 151))	('RhoC', 'Gene', (147, 151))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (225, 249))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (220, 248))	('RhoC', 'Gene', (19, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('RhoC', 'Gene', '389', (19, 23))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (109, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (225, 248))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (211, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('Src', 'Gene', (73, 76))	('many head', 'Phenotype', 'HP:0000256', (206, 215))	('neck', 'cellular_component', 'GO:0044326', ('220', '224'))	('neck', 'cellular_component', 'GO:0044326', ('118', '122'))	('Erk1', 'molecular_function', 'GO:0004707', ('81', '85'))
129621	24565984	Moreover, this study for the first time shows that down regulation of FAK, Src and Erk1/2 by miR-138 overexpression is due to inhibition of RhoC in HNSCC.	('Src', 'Gene', (75, 78))	('Src', 'Gene', '6714', (75, 78))	('Erk1', 'molecular_function', 'GO:0004707', ('83', '87'))	('FAK', 'molecular_function', 'GO:0004717', ('70', '73'))	('FAK', 'Gene', '5747', (70, 73))	('down regulation', 'NegReg', (51, 66))	('HNSCC', 'Phenotype', 'HP:0012288', (148, 153))	('regulation', 'biological_process', 'GO:0065007', ('56', '66'))	('Erk1/2', 'Gene', (83, 89))	('inhibition', 'NegReg', (126, 136))	('miR-138', 'Gene', (93, 100))	('overexpression', 'Var', (101, 115))	('RhoC', 'Protein', (140, 144))	('FAK', 'Gene', (70, 73))
129643	24565984	compared expression patterns of miRNAs between the parental MDA-MB-231 human breast cancer line and its variants that are highly metastatic to the bone or lungs and identified eight miRNAs that are down regulated.	('breast cancer', 'Disease', (77, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('variants', 'Var', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (60, 70))	('human', 'Species', '9606', (71, 76))
129645	24565984	In a previous study we reported the role of miR-107, a tumor suppressor microRNA which inhibits the expression of PKCepsilon in head and neck cancer.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('neck', 'cellular_component', 'GO:0044326', ('137', '141'))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor suppressor', 'biological_process', 'GO:0051726', ('55', '71'))	('PKCepsilon', 'Gene', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('114', '124'))	('inhibits', 'NegReg', (87, 95))	('tumor', 'Disease', (55, 60))	('expression', 'MPA', (100, 110))	('miR-107', 'Var', (44, 51))	('PKCepsilon', 'Gene', '5581', (114, 124))	('head and neck cancer', 'Phenotype', 'HP:0012288', (128, 148))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('55', '71'))	('head and neck cancer', 'Disease', 'MESH:D006258', (128, 148))
129647	24565984	on head and neck cancer cell lines reported the role of miR-34a as a tumor suppressor and that dysregulation of this miR promotes angiogenesis in their mouse model.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('69', '85'))	('dysregulation', 'Var', (95, 108))	('tumor', 'Disease', (69, 74))	('miR-34a', 'Gene', (56, 63))	('angiogenesis', 'CPA', (130, 142))	('miR-34a', 'Gene', '723848', (56, 63))	('mouse', 'Species', '10090', (152, 157))	('head and neck cancer', 'Disease', 'MESH:D006258', (3, 23))	('promotes', 'PosReg', (121, 129))	('angiogenesis', 'biological_process', 'GO:0001525', ('130', '142'))	('neck', 'cellular_component', 'GO:0044326', ('12', '16'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('69', '85'))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('head and neck cancer', 'Phenotype', 'HP:0012288', (3, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
129653	24565984	We observed a significant down regulation of P-FAKY397, P-SrcY416, and P-Erk1/2 in miR-138 over expressing HNSCC cell lines, suggesting miR-138 activity affects downstream signaling molecules of RhoC that are involved in cancer cell growth, invasion, progression and metastasis.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('HNSCC', 'Phenotype', 'HP:0012288', (107, 112))	('signaling', 'biological_process', 'GO:0023052', ('172', '181'))	('Erk1', 'molecular_function', 'GO:0004707', ('73', '77'))	('cancer', 'Disease', (221, 227))	('SrcY416', 'Chemical', '-', (58, 65))	('P-FAKY397', 'Var', (45, 54))	('cell growth', 'biological_process', 'GO:0016049', ('228', '239'))	('P-SrcY416', 'Var', (56, 65))	('miR-138', 'Gene', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('down regulation', 'NegReg', (26, 41))	('FAKY397', 'Chemical', '-', (47, 54))	('affects', 'Reg', (153, 160))	('regulation', 'biological_process', 'GO:0065007', ('31', '41'))
129655	24565984	University of Michigan squamous cell carcinoma cell lines (UM-SCC)-1 and -47 are derived from the patients with T2N0 of floor of the mouth and T3N1 of the tongue respectively.	('T3N1', 'Var', (143, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('UM-SCC', 'CellLine', 'CVCL:7707', (59, 65))	('patients', 'Species', '9606', (98, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('T2N0', 'Var', (112, 116))	('squamous cell carcinoma', 'Disease', (23, 46))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (23, 46))
129660	24565984	Overexpression of miR-138 and miR-control (whose sequence does not match with the 3'UTR of any known mRNA) in UM-SCC-1 and -47 were achieved transiently using lipofectAMINE2000 in absence of antibiotic free DMEM supplemented with 10% FBS.	('SCC-1 and -47', 'Gene', '5795', (113, 126))	('FBS', 'Disease', 'MESH:D005198', (234, 237))	('DMEM', 'Chemical', '-', (207, 211))	('FBS', 'Disease', (234, 237))	('miR-138', 'Var', (18, 25))	('UM-SCC-1', 'CellLine', 'CVCL:7707', (110, 118))
129665	24565984	Then the membranes were incubated overnight with polyclonal RhoC, P-FAKY397, P-srcY416, and P-ERK1/2 primary antibodies or with Tubulin (as a loading control).	('P-srcY416', 'Var', (77, 86))	('ERK1/2', 'Gene', '5595', (94, 100))	('P-FAKY397', 'Var', (66, 75))	('ERK1/2', 'Gene', (94, 100))	('ERK1', 'molecular_function', 'GO:0004707', ('94', '98'))	('FAKY397', 'Chemical', '-', (68, 75))
129679	24565984	The inverse correlation observed in the expression of RhoC and miR-138 strongly supports and confirms previous findings that miR-138 is a tumor suppressor that down regulates RhoC expression.	('tumor', 'Disease', (138, 143))	('tumor suppressor', 'biological_process', 'GO:0051726', ('138', '154'))	('down regulates', 'NegReg', (160, 174))	('expression', 'MPA', (180, 190))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('138', '154'))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('miR-138', 'Var', (125, 132))	('RhoC', 'Protein', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
129680	24565984	Our data is also in accordance with the findings reported earlier that showed the binding of miR-138 at 3'UTR of RhoC mRNA could impair its function in tongue squamous cell carcinoma.	('impair', 'NegReg', (129, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('binding', 'molecular_function', 'GO:0005488', ('82', '89'))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (152, 182))	('function', 'MPA', (140, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('tongue squamous cell carcinoma', 'Disease', (152, 182))	('miR-138', 'Var', (93, 100))	('binding', 'Interaction', (82, 89))
129699	24565984	Phosphorylation of FAKY397 was decreased by 80% and 60% in UM-SCC-1 and -47 respectively.	('FAKY397', 'Var', (19, 26))	('decreased', 'NegReg', (31, 40))	('SCC-1 and -47', 'Gene', '5795', (62, 75))	('Phosphorylation', 'MPA', (0, 15))	('UM-SCC-1', 'CellLine', 'CVCL:7707', (59, 67))	('FAKY397', 'Chemical', '-', (19, 26))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))
129700	24565984	A similar decrease in phosphorylation of SrcY416 and Erk1/2 was also observed in UM-SCC-1 and -47 respectively upon miR-138 over expression in HNSCC cell lines (Fig.	('miR-138', 'Gene', (116, 123))	('UM-SCC-1', 'CellLine', 'CVCL:7707', (81, 89))	('SrcY416', 'Var', (41, 48))	('decrease', 'NegReg', (10, 18))	('SrcY416', 'Chemical', '-', (41, 48))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('Erk1', 'molecular_function', 'GO:0004707', ('53', '57'))	('over expression', 'PosReg', (124, 139))	('SCC-1 and -47', 'Gene', '5795', (84, 97))	('HNSCC', 'Phenotype', 'HP:0012288', (143, 148))	('phosphorylation', 'MPA', (22, 37))	('Erk1/2', 'Gene', (53, 59))
129714	24565984	We can conclude from these findings that miR-138 is a tumor suppressor microRNA that plays a significant role in regulation of RhoC expression.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('54', '70'))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('regulation', 'MPA', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('RhoC', 'Protein', (127, 131))	('miR-138', 'Var', (41, 48))	('regulation', 'biological_process', 'GO:0065007', ('113', '123'))	('tumor', 'Disease', (54, 59))	('tumor suppressor', 'biological_process', 'GO:0051726', ('54', '70'))
129715	24565984	These results suggest miR-138 is an important tumor suppressor that is needed to keep low expression levels of RhoC in the cells.	('miR-138', 'Var', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('RhoC', 'Protein', (111, 115))	('expression levels', 'MPA', (90, 107))	('tumor', 'Disease', (46, 51))	('tumor suppressor', 'biological_process', 'GO:0051726', ('46', '62'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('46', '62'))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
129719	24565984	This signifies a robust role for miR-138 which not only involves lowering the expression of RhoC, but also in disrupting various cancer phenotypes in HNSCC cell lines (Figs.	('miR-138', 'Var', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('expression', 'MPA', (78, 88))	('cancer', 'Disease', (129, 135))	('RhoC', 'Protein', (92, 96))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('lowering', 'NegReg', (65, 73))	('HNSCC', 'Phenotype', 'HP:0012288', (150, 155))	('disrupting', 'NegReg', (110, 120))
129733	24565984	Our results show the down regulation of both Src and Erk1/2 upon RhoC inactivation, signifying the role of RhoC in promoting the activation of cancer cell survival proteins in HNSCC.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('RhoC', 'Gene', (65, 69))	('promoting', 'PosReg', (115, 124))	('HNSCC', 'Phenotype', 'HP:0012288', (176, 181))	('inactivation', 'Var', (70, 82))	('activation', 'PosReg', (129, 139))	('Src', 'Gene', (45, 48))	('Src', 'Gene', '6714', (45, 48))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('Erk1', 'molecular_function', 'GO:0004707', ('53', '57'))	('down regulation', 'NegReg', (21, 36))	('regulation', 'biological_process', 'GO:0065007', ('26', '36'))
129734	24565984	A schema describing how miR-138 attenuates the activation of various onco-proteins is given in Fig.	('activation', 'MPA', (47, 57))	('schema', 'Disease', (2, 8))	('miR-138', 'Var', (24, 31))	('attenuates', 'NegReg', (32, 42))	('schema', 'Disease', 'None', (2, 8))
129736	24565984	The first could be loss of heterozygosity (LOH), a form of allelic imbalance that can result in the complete loss of an allele or from an increase in copy number of one allele relative to the other, and is an important mechanism by which there is loss of expression of tumor suppressor genes.	('copy', 'MPA', (150, 154))	('increase', 'PosReg', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumor suppressor', 'biological_process', 'GO:0051726', ('269', '285'))	('loss', 'NegReg', (109, 113))	('tumor', 'Disease', (269, 274))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('269', '285'))	('imbalance', 'Phenotype', 'HP:0002172', (67, 76))	('loss', 'Var', (19, 23))
129737	24565984	Recent studies using SNP array technology show that in addition to solid tumors, hematologic malignancies also have a high frequency of LOH due to genomic deletions or gains.	('solid tumors', 'Disease', (67, 79))	('hematologic malignancies', 'Disease', 'MESH:D019337', (81, 105))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('hematologic malignancies', 'Disease', (81, 105))	('LOH', 'Disease', (136, 139))	('genomic deletions', 'Var', (147, 164))	('solid tumors', 'Disease', 'MESH:D009369', (67, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('gains', 'PosReg', (168, 173))
129738	24565984	In this biological phenomenon, a region of the genome where a tumor suppressor gene is located is transcriptionally repressed due to methylation of cytosine residues.	('methylation', 'biological_process', 'GO:0032259', ('133', '144'))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('methylation', 'Var', (133, 144))	('tumor', 'Disease', (62, 67))	('tumor suppressor', 'biological_process', 'GO:0051726', ('62', '78'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('62', '78'))	('cytosine', 'Protein', (148, 156))	('cytosine', 'Chemical', 'MESH:D003596', (148, 156))
129741	24565984	In addition to this, over expressing miR-138 attenuates FAKY397, SrcY416, and Erk1/2 activation.	('activation', 'MPA', (85, 95))	('miR-138', 'Gene', (37, 44))	('FAKY397', 'Chemical', '-', (56, 63))	('Erk1/2', 'Enzyme', (78, 84))	('attenuates', 'NegReg', (45, 55))	('SrcY416', 'Chemical', '-', (65, 72))	('SrcY416', 'MPA', (65, 72))	('Erk1', 'molecular_function', 'GO:0004707', ('78', '82'))	('FAKY397', 'Var', (56, 63))
129759	24455304	Importantly, our previous work with 3D uveal melanoma cultures indicated that the presence of an ECM in 3D tumor cultures was contributing to tumor resistance against HSV-1 by more than one mechanism: the ECM inhibited HSV-1 spread and also mediated inhibition of viral replication following viral entry into tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('inhibition of viral replication', 'biological_process', 'GO:1903901', ('250', '281'))	('tumor', 'Disease', (107, 112))	('HSV-1 spread', 'CPA', (219, 231))	('3D uveal melanoma', 'Disease', 'MESH:C536494', (36, 53))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('inhibited', 'NegReg', (209, 218))	('viral', 'CPA', (264, 269))	('HSV-1', 'Species', '10298', (167, 172))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('tumor', 'Disease', (309, 314))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (142, 147))	('inhibition', 'NegReg', (250, 260))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('ECM', 'Var', (205, 208))	('uveal melanoma', 'Phenotype', 'HP:0007716', (39, 53))	('3D uveal melanoma', 'Disease', (36, 53))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('HSV-1', 'Species', '10298', (219, 224))
129766	24455304	Cells infected with HSV-1 strain K26GFP exhibit punctate nuclear fluorescence at early times in the replication cycle and at later times during infection; a generalized cytoplasmic and nuclear fluorescence, including fluorescence at the cell membranes, can be observed.	('infection', 'Disease', (144, 153))	('punctate nuclear fluorescence', 'MPA', (48, 77))	('infection', 'Disease', 'MESH:D007239', (144, 153))	('fluorescence', 'MPA', (217, 229))	('K26GFP', 'Var', (33, 39))	('HSV-1', 'Species', '10298', (20, 25))
129798	24455304	HSV-1 K26GFP exhibits fluorescence upon replication.	('HSV-1', 'Gene', (0, 5))	('fluorescence', 'MPA', (22, 34))	('HSV-1', 'Species', '10298', (0, 5))	('K26GFP', 'Var', (6, 12))
129812	24455304	In 3D cultures, tumor cell destruction was associated with GFP expression for several days following virus inoculation.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('GFP', 'Gene', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('expression', 'Var', (63, 73))
129845	22808163	MAPK activation occurs via somatic mutations in the heterotrimeric G protein subunits GNAQ and GNA11 for over 70% of tumors and less frequently via V600E BRAF mutations.	('V600E', 'Mutation', 'rs113488022', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('GNAQ', 'Gene', '2776', (86, 90))	('GNA11', 'Gene', (95, 100))	('activation', 'PosReg', (5, 15))	('GNAQ', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('MAPK', 'Gene', '5595;5594;5595', (0, 4))	('V600E', 'Var', (148, 153))	('tumors', 'Disease', (117, 123))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('MAPK', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('GNA11', 'Gene', '2767', (95, 100))	('BRAF', 'Gene', '673', (154, 158))	('heterotrimeric G protein', 'Protein', (52, 76))	('MAPK', 'molecular_function', 'GO:0004707', ('0', '4'))	('BRAF', 'Gene', (154, 158))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('52', '76'))	('MAPK activation', 'biological_process', 'GO:0000187', ('0', '15'))
129847	22808163	While synergistic reductions in cell viability were observed with AZD8055/selumetinib in both BRAF and GNAQ mutant cell lines, apoptosis was preferentially induced in BRAF mutant cells only.	('reductions', 'NegReg', (18, 28))	('BRAF', 'Gene', (94, 98))	('GNAQ', 'Gene', '2776', (103, 107))	('AZD8055', 'Chemical', 'MESH:C546624', (66, 73))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('apoptosis', 'CPA', (127, 136))	('mutant', 'Var', (108, 114))	('apoptosis', 'biological_process', 'GO:0006915', ('127', '136'))	('cell viability', 'CPA', (32, 46))	('selumetinib', 'Chemical', 'MESH:C517975', (74, 85))	('AZD8055/selumetinib', 'Gene', (66, 85))	('GNAQ', 'Gene', (103, 107))	('AZD8055/selumetinib', 'Var', (66, 85))	('BRAF', 'Gene', '673', (94, 98))	('apoptosis', 'biological_process', 'GO:0097194', ('127', '136'))
129848	22808163	In vitro apoptosis assay results were predictive of in vivo drug efficacy as tumor regressions were observed only in a BRAF mutant xenograft model, but not GNAQ mutant model.	('GNAQ', 'Gene', (156, 160))	('BRAF', 'Gene', '673', (119, 123))	('mutant', 'Var', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('BRAF', 'Gene', (119, 123))	('apoptosis', 'biological_process', 'GO:0097194', ('9', '18'))	('GNAQ', 'Gene', '2776', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('apoptosis', 'biological_process', 'GO:0006915', ('9', '18'))	('tumor', 'Disease', (77, 82))
129849	22808163	We went on to discover that GNAQ promotes relative resistance to AZD8055/selumetinib-induced apoptosis in GNAQ mutant cells.	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))	('selumetinib', 'Chemical', 'MESH:C517975', (73, 84))	('GNAQ', 'Gene', '2776', (28, 32))	('mutant', 'Var', (111, 117))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('AZD8055', 'Chemical', 'MESH:C546624', (65, 72))	('GNAQ', 'Gene', (106, 110))	('GNAQ', 'Gene', (28, 32))	('resistance', 'MPA', (51, 61))	('GNAQ', 'Gene', '2776', (106, 110))
129850	22808163	For BRAF mutant cells, both AKT and 4E-BP1 phosphorylation were modulated by the combination; however, decreasing AKT phosphorylation alone was not sufficient and decreasing 4E-BP1 phosphorylation was not required for apoptosis.	('AKT and 4E-BP1', 'Gene', '207;1978', (28, 42))	('AKT', 'Gene', '207', (114, 117))	('apoptosis', 'biological_process', 'GO:0097194', ('218', '227'))	('apoptosis', 'biological_process', 'GO:0006915', ('218', '227'))	('4E-BP1', 'Gene', '1978', (174, 180))	('AKT', 'Gene', (28, 31))	('phosphorylation', 'biological_process', 'GO:0016310', ('181', '196'))	('phosphorylation', 'biological_process', 'GO:0016310', ('43', '58'))	('mutant', 'Var', (9, 15))	('4E-BP1', 'Gene', (36, 42))	('AKT', 'Gene', (114, 117))	('modulated', 'Reg', (64, 73))	('BRAF', 'Gene', (4, 8))	('4E-BP1', 'Gene', (174, 180))	('BRAF', 'Gene', '673', (4, 8))	('phosphorylation', 'biological_process', 'GO:0016310', ('118', '133'))	('AKT', 'Gene', '207', (28, 31))	('4E-BP1', 'Gene', '1978', (36, 42))
129852	22808163	These results suggest that the clinical efficacy of combined MEK and mTOR kinase inhibition will be determined by tumor genotype, and that BRAF mutant malignancies will be particularly susceptible to this strategy.	('MEK', 'Gene', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('mTOR', 'Gene', (69, 73))	('BRAF', 'Gene', (139, 143))	('MEK', 'Gene', '5609', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('malignancies', 'Disease', 'MESH:D009369', (151, 163))	('inhibition', 'NegReg', (81, 91))	('tumor', 'Disease', (114, 119))	('malignancies', 'Disease', (151, 163))	('mutant', 'Var', (144, 150))	('BRAF', 'Gene', '673', (139, 143))	('mTOR', 'Gene', '2475', (69, 73))
129856	22808163	In contrast to cutaneous melanomas, the relevance of BRAF (T1799A V600E) mutations for MAPK activation in uveal melanoma is less clear.	('MAPK', 'molecular_function', 'GO:0004707', ('87', '91'))	('V600E', 'SUBSTITUTION', 'None', (66, 71))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('uveal melanoma', 'Disease', (106, 120))	('MAPK', 'Gene', '5595;5594;5595', (87, 91))	('MAPK activation', 'biological_process', 'GO:0000187', ('87', '102'))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (15, 34))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (15, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('MAPK', 'Gene', (87, 91))	('cutaneous melanomas', 'Disease', (15, 34))	('activation', 'PosReg', (92, 102))	('V600E', 'Var', (66, 71))	('T1799A', 'SUBSTITUTION', 'None', (59, 65))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('T1799A', 'Var', (59, 65))	('melanomas', 'Phenotype', 'HP:0002861', (25, 34))
129857	22808163	Though initial studies of uveal melanoma tumor samples reported that BRAF mutations are rare, several groups have detected the mutation in a disproportionate number of uveal melanoma cell lines.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('uveal melanoma', 'Disease', 'MESH:C536494', (168, 182))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('uveal melanoma tumor', 'Disease', (26, 46))	('mutations', 'Var', (74, 83))	('uveal melanoma tumor', 'Disease', 'MESH:C536494', (26, 46))	('uveal melanoma', 'Phenotype', 'HP:0007716', (26, 40))	('uveal melanoma', 'Disease', 'MESH:C536494', (26, 40))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('BRAF', 'Gene', '673', (69, 73))	('BRAF', 'Gene', (69, 73))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('uveal melanoma', 'Disease', (168, 182))
129858	22808163	Two studies utilizing more sensitive genetic approaches have reported higher rates of BRAF mutation and confirmed that the mutation can be limited to select areas within a tumor.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mutation', 'Var', (91, 99))	('tumor', 'Disease', (172, 177))	('BRAF', 'Gene', '673', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('BRAF', 'Gene', (86, 90))
129859	22808163	The possibility that techniques to establish cell lines may preferentially select for BRAF mutant tumors also can not be excluded.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('BRAF', 'Gene', '673', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutant', 'Var', (91, 97))	('BRAF', 'Gene', (86, 90))
129860	22808163	For over 40% of uveal melanomas, MAPK activation is driven by mutation of GNAQ , a gene that encodes for the alpha subunit of a heterotrimeric G protein complex (alphabetagamma) that mediates signaling between G-protein-coupled receptors (GPCRs) and downstream effectors.	('uveal melanomas', 'Disease', (16, 31))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('128', '152'))	('GNAQ', 'Gene', (74, 78))	('heterotrimeric G protein complex', 'cellular_component', 'GO:0005834', ('128', '160'))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('uveal melanomas', 'Disease', 'MESH:C536494', (16, 31))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('MAPK', 'molecular_function', 'GO:0004707', ('33', '37'))	('signaling', 'biological_process', 'GO:0023052', ('192', '201'))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('mutation', 'Var', (62, 70))	('GNAQ', 'Gene', '2776', (74, 78))	('MAPK', 'Gene', '5595;5594;5595', (33, 37))	('activation', 'PosReg', (38, 48))	('uveal melanomas', 'Phenotype', 'HP:0007716', (16, 31))	('MAPK', 'Gene', (33, 37))	('MAPK activation', 'biological_process', 'GO:0000187', ('33', '48'))
129861	22808163	Mutation of codon 209 in the ras-like domain blocks intrinsic GTPase activity, keeping Galpha in a GTP-bound, constitutively active state.	('GTP', 'Chemical', 'MESH:D006160', (99, 102))	('activity', 'MPA', (69, 77))	('GTP', 'Chemical', 'MESH:D006160', (62, 65))	('keeping', 'Reg', (79, 86))	('Mutation', 'Var', (0, 8))	('GTPase activity', 'molecular_function', 'GO:0003924', ('62', '77'))	('blocks', 'NegReg', (45, 51))	('GTPase', 'Protein', (62, 68))	('Galpha', 'Gene', '8802', (87, 93))	('Galpha', 'Gene', (87, 93))	('intrinsic', 'MPA', (52, 61))
129865	22808163	High rates of loss of heterozygosity (LOH) at the phosphatase and tensin homolog (PTEN) (a negative regulator of the PI3K/AKT/mTOR pathway) locus and mutations within the PTEN coding region translates to more than half of uveal melanomas having decreased or complete loss of PTEN expression.	('loss', 'NegReg', (267, 271))	('AKT', 'Gene', '207', (122, 125))	('PI3K', 'molecular_function', 'GO:0016303', ('117', '121'))	('PTEN', 'Gene', (171, 175))	('PTEN', 'Gene', '5728', (275, 279))	('expression', 'MPA', (280, 290))	('uveal melanomas', 'Disease', (222, 237))	('uveal melanomas', 'Phenotype', 'HP:0007716', (222, 237))	('melanomas', 'Phenotype', 'HP:0002861', (228, 237))	('mutations', 'Var', (150, 159))	('PTEN', 'Gene', (82, 86))	('PTEN', 'Gene', '5728', (171, 175))	('phosphatase', 'molecular_function', 'GO:0016791', ('50', '61'))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('mTOR', 'Gene', (126, 130))	('PTEN', 'Gene', '5728', (82, 86))	('heterozygosity', 'MPA', (22, 36))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('50', '80'))	('AKT', 'Gene', (122, 125))	('uveal melanomas', 'Disease', 'MESH:C536494', (222, 237))	('uveal melanoma', 'Phenotype', 'HP:0007716', (222, 236))	('PTEN', 'Gene', (275, 279))	('mTOR', 'Gene', '2475', (126, 130))	('loss', 'NegReg', (14, 18))
129873	22808163	AZD8055 potently inhibits the mTOR kinase in vitro (IC50 of 0.8+/-0.2 nM), while exhibiting >1000 fold selectivity against closely related kinases such as PI3K, ATM, and DNA-PK, and no activity against a panel of 260 other kinases at a concentration of 10 microM.	('inhibits', 'NegReg', (17, 25))	('AZD8055', 'Var', (0, 7))	('AZD8055', 'Chemical', 'MESH:C546624', (0, 7))	('PI3K', 'molecular_function', 'GO:0016303', ('155', '159'))	('ATM', 'Gene', (161, 164))	('ATM', 'Gene', '472', (161, 164))	('DNA-PK', 'Gene', (170, 176))	('mTOR', 'Gene', '2475', (30, 34))	('DNA-PK', 'Gene', '5591', (170, 176))	('mTOR', 'Gene', (30, 34))	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))
129877	22808163	This panel included two cell lines which lack activating mutations in BRAF, GNAQ, GNA11, and RAS (Mel290 and C918, referred to as "wild type" or "WT"), two cell lines which possess the V600E BRAF mutation (OCM3 and OCM1A, referred to as "BRAF"), and two cell lines which possess activating GNAQ mutations at Q209 (92.1 (Q209L) and Mel270 (Q209P), referred to as "GNAQ"); these cell lines were otherwise negative for common mutations in several receptor tyrosine kinases (RTKs), PIK3CA, and AKT1 (Table S1).	('BRAF', 'Gene', (191, 195))	('GNAQ', 'Gene', (363, 367))	('RTK', 'Gene', '5979', (471, 474))	('GNA11', 'Gene', '2767', (82, 87))	('activating', 'PosReg', (279, 289))	('GNAQ', 'Gene', '2776', (290, 294))	('AKT', 'Gene', (490, 493))	('PIK3CA', 'Gene', '5290', (478, 484))	('BRAF', 'Gene', '673', (238, 242))	('BRAF', 'Gene', (238, 242))	('GNAQ', 'Gene', (290, 294))	('GNAQ', 'Gene', '2776', (76, 80))	('Q209P', 'Mutation', 'rs121913492', (339, 344))	('V600E', 'Mutation', 'rs113488022', (185, 190))	('BRAF', 'Gene', '673', (70, 74))	('GNAQ', 'Gene', (76, 80))	('BRAF', 'Gene', (70, 74))	('OCM1', 'Species', '83984', (215, 219))	('AKT', 'Gene', '207', (490, 493))	('GNA11', 'Gene', (82, 87))	('Q209L', 'Mutation', 'rs121913492', (320, 325))	('PIK3CA', 'Gene', (478, 484))	('BRAF', 'Gene', '673', (191, 195))	('V600E', 'Var', (185, 190))	('GNAQ', 'Gene', '2776', (363, 367))	('RTK', 'Gene', (471, 474))
129880	22808163	In both GNAQ and BRAF cells, the AZD8055/selumetinib combination at different dose combinations consistently reduced cell viability by more than 50% ("fractional activity" (Fa) >0.5) in a synergistic manner (combination index (CI) values <1) ( Figure 1A ).	('selumetinib', 'Chemical', 'MESH:C517975', (41, 52))	('cell viability', 'CPA', (117, 131))	('GNAQ', 'Gene', (8, 12))	('GNAQ', 'Gene', '2776', (8, 12))	('BRAF', 'Gene', '673', (17, 21))	('AZD8055/selumetinib', 'Gene', (33, 52))	('AZD8055/selumetinib', 'Var', (33, 52))	('BRAF', 'Gene', (17, 21))	('reduced', 'NegReg', (109, 116))	('AZD8055', 'Chemical', 'MESH:C546624', (33, 40))
129883	22808163	The AZD8055/selumetinib combination increased apoptosis over that observed with either drug alone only in BRAF cells ( Figure 1B ).	('apoptosis', 'CPA', (46, 55))	('BRAF', 'Gene', '673', (106, 110))	('selumetinib', 'Chemical', 'MESH:C517975', (12, 23))	('AZD8055', 'Chemical', 'MESH:C546624', (4, 11))	('BRAF', 'Gene', (106, 110))	('increased', 'PosReg', (36, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))	('AZD8055/selumetinib', 'Var', (4, 23))
129886	22808163	We hypothesized that the preferential induction of apoptosis with the combination in BRAF mutant cells suggests that combined mTOR and MEK inhibition may be particularly effective for this tumor genotype.	('tumor', 'Disease', (189, 194))	('mTOR', 'Gene', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('mutant', 'Var', (90, 96))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('38', '60'))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('MEK', 'Gene', (135, 138))	('apoptosis', 'CPA', (51, 60))	('MEK', 'Gene', '5609', (135, 138))	('mTOR', 'Gene', '2475', (126, 130))
129887	22808163	To evaluate this in vivo, we tested AZD8055 and selumetinib in both a BRAF mutant (OCM1A) and GNAQ mutant (92.1) xenograft tumor model.	('tumor', 'Disease', (123, 128))	('selumetinib', 'Chemical', 'MESH:C517975', (48, 59))	('GNAQ', 'Gene', '2776', (94, 98))	('OCM1', 'Species', '83984', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('mutant', 'Var', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('BRAF', 'Gene', '673', (70, 74))	('AZD8055', 'Chemical', 'MESH:C546624', (36, 43))	('AZD8055', 'Var', (36, 43))	('tested', 'Reg', (29, 35))	('GNAQ', 'Gene', (94, 98))	('BRAF', 'Gene', (70, 74))
129888	22808163	In the BRAF mutant model, the combination resulted in tumor regressions at Day 19 with tumor volumes that were lower than those achieved with either drug alone ( Figure 2A , p-value = 0.008 for the comparison of the combination to either AZD8055 or selumetinib alone).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (87, 92))	('mutant', 'Var', (12, 18))	('AZD8055', 'Chemical', 'MESH:C546624', (238, 245))	('selumetinib', 'Chemical', 'MESH:C517975', (249, 260))	('BRAF', 'Gene', '673', (7, 11))	('lower', 'NegReg', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (54, 59))	('BRAF', 'Gene', (7, 11))
129890	22808163	In the GNAQ mutant model, only a non-statistically significant trend towards enhanced tumor growth inhibition with the combination was achieved; neither tumor regression nor changes in Ki67 and TUNEL staining were observed ( Figure 2B  and Figure S3B).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('enhanced', 'PosReg', (77, 85))	('GNAQ', 'Gene', '2776', (7, 11))	('tumor', 'Disease', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('mutant', 'Var', (12, 18))	('GNAQ', 'Gene', (7, 11))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
129893	22808163	In order to determine if GNAQ is necessary to block AZD8055/selumetinib-induced apoptosis, GNAQ expression was suppressed with pooled small interfering RNA (siRNA) constructs in the GNAQ mutant cell line 92.1 ( Figure 3A ).	('AZD8055/selumetinib-induced', 'Var', (52, 79))	('GNAQ', 'Gene', '2776', (182, 186))	('RNA', 'cellular_component', 'GO:0005562', ('152', '155'))	('GNAQ', 'Gene', (91, 95))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('expression', 'MPA', (96, 106))	('GNAQ', 'Gene', (25, 29))	('selumetinib', 'Chemical', 'MESH:C517975', (60, 71))	('GNAQ', 'Gene', (182, 186))	('suppressed', 'NegReg', (111, 121))	('AZD8055', 'Chemical', 'MESH:C546624', (52, 59))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('GNAQ', 'Gene', '2776', (91, 95))	('GNAQ', 'Gene', '2776', (25, 29))
129896	22808163	To investigate how AZD8055/selumetinib preferentially elicits apoptosis in BRAF mutant cells, we assessed the impact of the combination upon the phosphorylation status of mTOR and MEK substrates.	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('selumetinib', 'Chemical', 'MESH:C517975', (27, 38))	('mutant', 'Var', (80, 86))	('BRAF', 'Gene', '673', (75, 79))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('phosphorylation', 'biological_process', 'GO:0016310', ('145', '160'))	('preferentially', 'PosReg', (39, 53))	('AZD8055/selumetinib', 'Var', (19, 38))	('BRAF', 'Gene', (75, 79))	('MEK', 'Gene', (180, 183))	('apoptosis', 'CPA', (62, 71))	('MEK', 'Gene', '5609', (180, 183))	('elicits', 'Reg', (54, 61))	('mTOR', 'Gene', (171, 175))	('AZD8055', 'Chemical', 'MESH:C546624', (19, 26))	('mTOR', 'Gene', '2475', (171, 175))
129897	22808163	In WT cells, AZD8055 inhibited phosphorylation of both the mTORC1 substrate S6 Kinase 1 (S6K1) and the mTORC2 substrate AKT (at serine 473;  Figure 4A  , lane 2 of Blots #1 and 2); selumetinib, however, failed to inhibit ERK phosphorylation in a sustained manner ( Figure 4A  , lane 3 of Blot #3) due to rebound ERK phosphorylation (see Figure S2D and the accompanying figure legend for the selumetinib time course experiment demonstrating this phenomenon).	('AKT', 'Gene', (120, 123))	('phosphorylation', 'biological_process', 'GO:0016310', ('225', '240'))	('AZD8055', 'Chemical', 'MESH:C546624', (13, 20))	('rebound ERK', 'Phenotype', 'HP:0000550', (304, 315))	('ERK', 'Gene', '5594', (312, 315))	('mTORC1', 'cellular_component', 'GO:0031931', ('59', '65'))	('mTORC2', 'Gene', (103, 109))	('inhibited', 'NegReg', (21, 30))	('mTORC2', 'cellular_component', 'GO:0031932', ('103', '109'))	('mTORC1', 'Gene', (59, 65))	('mTORC1', 'Gene', '382056', (59, 65))	('ERK', 'molecular_function', 'GO:0004707', ('221', '224'))	('phosphorylation', 'MPA', (31, 46))	('ERK', 'Gene', (312, 315))	('AKT', 'Gene', '207', (120, 123))	('mTORC2', 'Gene', '74343', (103, 109))	('selumetinib', 'Chemical', 'MESH:C517975', (391, 402))	('S6K1', 'Gene', (89, 93))	('ERK', 'Gene', '5594', (221, 224))	('S6 Kinase 1', 'Gene', (76, 87))	('serine', 'Chemical', 'MESH:D012694', (128, 134))	('phosphorylation', 'biological_process', 'GO:0016310', ('316', '331'))	('ERK', 'molecular_function', 'GO:0004707', ('312', '315'))	('S6 Kinase 1', 'Gene', '6198', (76, 87))	('AZD8055', 'Var', (13, 20))	('ERK', 'Gene', (221, 224))	('S6K1', 'Gene', '6198', (89, 93))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))	('selumetinib', 'Chemical', 'MESH:C517975', (181, 192))
129900	22808163	In BRAF and GNAQ cells, AZD8055 potently suppressed S6K1 phosphorylation, but failed to completely inhibit AKT phosphorylation ( Figure 4A  , lane 2 of Blots #1 and #2; Figure S2A).	('GNAQ', 'Gene', (12, 16))	('AKT', 'Gene', (107, 110))	('AZD8055', 'Var', (24, 31))	('suppressed', 'NegReg', (41, 51))	('inhibit', 'NegReg', (99, 106))	('AZD8055', 'Chemical', 'MESH:C546624', (24, 31))	('S6K1', 'Gene', (52, 56))	('BRAF', 'Gene', '673', (3, 7))	('GNAQ', 'Gene', '2776', (12, 16))	('S6K1', 'Gene', '6198', (52, 56))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('BRAF', 'Gene', (3, 7))	('AKT', 'Gene', '207', (107, 110))	('phosphorylation', 'biological_process', 'GO:0016310', ('111', '126'))
129901	22808163	This was not due to ineffective mTORC2 inhibition, but instead rebound AKT phosphorylation: while 100 nM AZD8055 inhibited AKT phosphorylation after 2 hours in all three tumor genotypes, by 24 hours AKT phosphorylation rebounded only in BRAF and GNAQ cells (Figure S2C).	('AKT', 'Gene', (199, 202))	('GNAQ', 'Gene', (246, 250))	('tumor', 'Disease', (170, 175))	('AZD8055', 'Var', (105, 112))	('mTORC2', 'Gene', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('AKT', 'Gene', '207', (71, 74))	('AKT', 'Gene', '207', (199, 202))	('BRAF', 'Gene', '673', (237, 241))	('AZD8055', 'Chemical', 'MESH:C546624', (105, 112))	('AKT', 'Gene', (123, 126))	('BRAF', 'Gene', (237, 241))	('phosphorylation', 'biological_process', 'GO:0016310', ('127', '142'))	('inhibited', 'NegReg', (113, 122))	('mTORC2', 'Gene', '74343', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('phosphorylation', 'biological_process', 'GO:0016310', ('75', '90'))	('AKT', 'Gene', '207', (123, 126))	('mTORC2', 'cellular_component', 'GO:0031932', ('32', '38'))	('AKT', 'Gene', (71, 74))	('GNAQ', 'Gene', '2776', (246, 250))	('phosphorylation', 'biological_process', 'GO:0016310', ('203', '218'))
129903	22808163	Given evidence in other systems that the release of negative feedback pathways resulting in AKT phosphorylation represents a critical mechanism of intrinsic resistance to mTORC1 inhibition, we investigated the mechanism by which AKT is modulated by AZD8055/selumetinib.	('mTORC1', 'Gene', '382056', (171, 177))	('mTORC1', 'cellular_component', 'GO:0031931', ('171', '177'))	('AKT', 'Gene', '207', (229, 232))	('modulated', 'Reg', (236, 245))	('phosphorylation', 'biological_process', 'GO:0016310', ('96', '111'))	('AKT', 'Gene', '207', (92, 95))	('mTORC1', 'Gene', (171, 177))	('selumetinib', 'Chemical', 'MESH:C517975', (257, 268))	('AZD8055/selumetinib', 'Var', (249, 268))	('AKT', 'Gene', (229, 232))	('AKT', 'Gene', (92, 95))	('AZD8055', 'Chemical', 'MESH:C546624', (249, 256))
129904	22808163	Utilizing an RTK array assay, we found that mTORC1/mTORC2 inhibition with AZD8055 in the BRAF mutant cell line OCM1A increased phosphorylation of the insulin-like growth factor type 1 receptor (IGF-1R) ( Figure 4B ).	('increased', 'PosReg', (117, 126))	('mTORC1', 'cellular_component', 'GO:0031931', ('44', '50'))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('150', '176'))	('mTORC1', 'Gene', (44, 50))	('BRAF', 'Gene', '673', (89, 93))	('BRAF', 'Gene', (89, 93))	('mTORC2', 'cellular_component', 'GO:0031932', ('51', '57'))	('AZD8055', 'Var', (74, 81))	('mTORC2', 'Gene', '74343', (51, 57))	('mTORC1', 'Gene', '382056', (44, 50))	('phosphorylation', 'MPA', (127, 142))	('insulin-like growth factor type 1 receptor', 'Gene', '3480', (150, 192))	('mTORC2', 'Gene', (51, 57))	('AZD8055', 'Chemical', 'MESH:C546624', (74, 81))	('phosphorylation', 'biological_process', 'GO:0016310', ('127', '142'))	('mutant', 'Var', (94, 100))	('OCM1', 'Species', '83984', (111, 115))	('inhibition', 'NegReg', (58, 68))	('RTK', 'Gene', (13, 16))	('IGF-1R', 'Gene', '3480', (194, 200))	('IGF-1R', 'Gene', (194, 200))	('RTK', 'Gene', '5979', (13, 16))	('insulin-like growth factor type 1 receptor', 'Gene', (150, 192))
129908	22808163	At 1000 nM, NVP-AEW541 inhibited IGF-1R phosphorylation induced by serum or IGF-1 ligand alone (Figure S4).	('IGF-1R', 'Gene', '3480', (33, 39))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('inhibited', 'NegReg', (23, 32))	('IGF-1R', 'Gene', (33, 39))	('IGF-1', 'Gene', (33, 38))	('IGF-1', 'Gene', '3479', (33, 38))	('ligand', 'molecular_function', 'GO:0005488', ('82', '88'))	('phosphorylation', 'MPA', (40, 55))	('IGF-1', 'Gene', '3479', (76, 81))	('NVP-AEW541', 'Var', (12, 22))	('IGF-1', 'Gene', (76, 81))
129909	22808163	In combination with AZD8055, NVP-AEW541 suppressed AKT re-phosphorylation without impacting ERK phosphorylation ( Figure 4C  , lane 6), consistent with the model that IGF-1R activation regulates AKT downstream of MEK/ERK activity in these cells.	('IGF-1R', 'Gene', '3480', (167, 173))	('IGF-1R', 'Gene', (167, 173))	('ERK', 'Gene', (92, 95))	('ERK', 'molecular_function', 'GO:0004707', ('92', '95'))	('ERK', 'Gene', '5594', (217, 220))	('suppressed', 'NegReg', (40, 50))	('regulates', 'Reg', (185, 194))	('AZD8055', 'Chemical', 'MESH:C546624', (20, 27))	('phosphorylation', 'biological_process', 'GO:0016310', ('96', '111'))	('ERK', 'molecular_function', 'GO:0004707', ('217', '220'))	('ERK', 'Gene', (217, 220))	('AKT', 'Gene', (195, 198))	('AKT', 'Gene', (51, 54))	('phosphorylation', 'biological_process', 'GO:0016310', ('58', '73'))	('MEK', 'Gene', '5609', (213, 216))	('ERK', 'Gene', '5594', (92, 95))	('AKT', 'Gene', '207', (195, 198))	('AKT', 'Gene', '207', (51, 54))	('MEK', 'Gene', (213, 216))	('NVP-AEW541', 'Var', (29, 39))
129910	22808163	However, despite modulating AKT phosphorylation, the addition of NVP-AEW541 to AZD8055 was insufficient to induce apoptosis as assayed by PARP cleavage and quantifying sub-G1 cell populations ( Figure 4C  , lane 6 and  Figure 4D  , respectively).	('phosphorylation', 'biological_process', 'GO:0016310', ('32', '47'))	('apoptosis', 'CPA', (114, 123))	('modulating', 'Reg', (17, 27))	('AKT', 'Gene', (28, 31))	('induce', 'Reg', (107, 113))	('AZD8055', 'Chemical', 'MESH:C546624', (79, 86))	('PARP', 'Gene', (138, 142))	('AZD8055', 'Gene', (79, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('114', '123'))	('apoptosis', 'biological_process', 'GO:0006915', ('114', '123'))	('AKT', 'Gene', '207', (28, 31))	('PARP', 'Gene', '142', (138, 142))	('insufficient', 'Disease', (91, 103))	('insufficient', 'Disease', 'MESH:D000309', (91, 103))	('NVP-AEW541', 'Var', (65, 75))
129911	22808163	Hence, while selumetinib suppresses AZD8055-mediated activation of the IGF-1R/AKT axis, modulation of these targets alone is not sufficient for the apoptosis induced by the AZZD8055/selumetinib combination, implying that other target(s) downstream of selumetinib-mediated ERK inhibition is (are) critical for the induction of apoptosis.	('selumetinib', 'Chemical', 'MESH:C517975', (182, 193))	('AZZD8055/selumetinib', 'Var', (173, 193))	('apoptosis', 'biological_process', 'GO:0097194', ('148', '157'))	('IGF-1R', 'Gene', '3480', (71, 77))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('313', '335'))	('apoptosis', 'biological_process', 'GO:0006915', ('148', '157'))	('IGF-1R', 'Gene', (71, 77))	('ERK', 'Gene', '5594', (272, 275))	('AZZD8055', 'Chemical', '-', (173, 181))	('AKT', 'Gene', '207', (78, 81))	('suppresses', 'NegReg', (25, 35))	('ERK', 'molecular_function', 'GO:0004707', ('272', '275'))	('AKT', 'Gene', (78, 81))	('selumetinib', 'Chemical', 'MESH:C517975', (13, 24))	('AZD8055', 'Chemical', 'MESH:C546624', (36, 43))	('AZD8055-mediated', 'Gene', (36, 52))	('selumetinib', 'Chemical', 'MESH:C517975', (251, 262))	('ERK', 'Gene', (272, 275))
129912	22808163	4E-BP1 (eIF4E binding protein-1) has recently been implicated as the key protein target cooperatively modulated by an AKT and MEK inhibitor combination to induce apoptosis in tumors harboring both RAS and PIK3CA mutations.	('PIK3CA', 'Gene', (205, 211))	('tumors', 'Disease', (175, 181))	('MEK', 'Gene', '5609', (126, 129))	('eIF4', 'cellular_component', 'GO:0008304', ('8', '12'))	('AKT', 'Gene', (118, 121))	('4E-BP1', 'Gene', '1978', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('RAS', 'Gene', (197, 200))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('MEK', 'Gene', (126, 129))	('eIF4E binding protein-1', 'Gene', (8, 31))	('mutations', 'Var', (212, 221))	('apoptosis', 'CPA', (162, 171))	('4E-BP1', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (205, 211))	('AKT', 'Gene', '207', (118, 121))	('eIF4E binding protein-1', 'Gene', '1978', (8, 31))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('eIF4E binding', 'molecular_function', 'GO:0008190', ('8', '21'))	('induce', 'PosReg', (155, 161))	('apoptosis', 'biological_process', 'GO:0097194', ('162', '171'))	('apoptosis', 'biological_process', 'GO:0006915', ('162', '171'))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
129913	22808163	Therefore, we investigated the potential role of 4E-BP1 in AZD8055/selumetinib-induced apoptosis for BRAF mutant uveal melanomas.	('BRAF', 'Gene', (101, 105))	('mutant', 'Var', (106, 112))	('4E-BP1', 'Gene', (49, 55))	('uveal melanomas', 'Disease', (113, 128))	('uveal melanomas', 'Phenotype', 'HP:0007716', (113, 128))	('AZD8055', 'Chemical', 'MESH:C546624', (59, 66))	('uveal melanomas', 'Disease', 'MESH:C536494', (113, 128))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('selumetinib', 'Chemical', 'MESH:C517975', (67, 78))	('uveal melanoma', 'Phenotype', 'HP:0007716', (113, 127))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('4E-BP1', 'Gene', '1978', (49, 55))	('melanomas', 'Phenotype', 'HP:0002861', (119, 128))	('BRAF', 'Gene', '673', (101, 105))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))
129916	22808163	Phosphorylation at all the 4E-BP1 sites assayed was inhibited with AZD8055 alone in WT cells.	('4E-BP1', 'Gene', '1978', (27, 33))	('Phosphorylation', 'MPA', (0, 15))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('AZD8055', 'Var', (67, 74))	('inhibited', 'NegReg', (52, 61))	('AZD8055', 'Chemical', 'MESH:C546624', (67, 74))	('4E-BP1', 'Gene', (27, 33))
129917	22808163	In the GNAQ mutant cell line 92.1 and BRAF mutant cell line OCM1A, 4E-BP1 phosphorylation at T37/46 was only modestly suppressed by AZD8055; phosphorylation at S65 and T70 was more effectively inhibited by AZD8055 in these cells ( Figure 5A ).	('phosphorylation', 'MPA', (74, 89))	('OCM1', 'Species', '83984', (60, 64))	('GNAQ', 'Gene', '2776', (7, 11))	('AZD8055', 'Chemical', 'MESH:C546624', (206, 213))	('phosphorylation', 'biological_process', 'GO:0016310', ('141', '156'))	('4E-BP1', 'Gene', (67, 73))	('BRAF', 'Gene', '673', (38, 42))	('AZD8055', 'Var', (132, 139))	('mutant', 'Var', (43, 49))	('phosphorylation', 'MPA', (141, 156))	('BRAF', 'Gene', (38, 42))	('GNAQ', 'Gene', (7, 11))	('AZD8055', 'Chemical', 'MESH:C546624', (132, 139))	('phosphorylation', 'biological_process', 'GO:0016310', ('74', '89'))	('4E-BP1', 'Gene', '1978', (67, 73))	('suppressed', 'NegReg', (118, 128))
129920	22808163	Furthermore, pooled siRNA construct-mediated downregulation of 4E-BP1 (which reportedly protected tumors cells from apoptosis induced by combined AKT and MEK inhibition) failed to reduce PARP cleavage induced by the combination, confirming that 4E-BP1 is not an essential regulator of apoptosis in BRAF mutant cells ( Figure 5C  , lane 4 versus lane 8).	('tumors', 'Disease', (98, 104))	('AKT', 'Gene', '207', (146, 149))	('PARP', 'Gene', '142', (187, 191))	('4E-BP1', 'Gene', '1978', (63, 69))	('PARP', 'Gene', (187, 191))	('4E-BP1', 'Gene', '1978', (245, 251))	('MEK', 'Gene', '5609', (154, 157))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('mutant', 'Var', (303, 309))	('downregulation', 'NegReg', (45, 59))	('MEK', 'Gene', (154, 157))	('4E-BP1', 'Gene', (63, 69))	('BRAF', 'Gene', '673', (298, 302))	('4E-BP1', 'Gene', (245, 251))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('AKT', 'Gene', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('BRAF', 'Gene', (298, 302))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('apoptosis', 'biological_process', 'GO:0097194', ('285', '294'))	('apoptosis', 'biological_process', 'GO:0006915', ('285', '294'))
129921	22808163	We next compared the impact upon mutant BRAF cell apoptosis of mTORC1 versus mTORC2 inhibition in combination with selumetinib MEK inhibition.	('BRAF', 'Gene', '673', (40, 44))	('apoptosis', 'biological_process', 'GO:0006915', ('50', '59'))	('mTORC2', 'cellular_component', 'GO:0031932', ('77', '83'))	('inhibition', 'NegReg', (84, 94))	('MEK', 'Gene', (127, 130))	('BRAF', 'Gene', (40, 44))	('MEK', 'Gene', '5609', (127, 130))	('mTORC2', 'Gene', (77, 83))	('selumetinib', 'Chemical', 'MESH:C517975', (115, 126))	('mTORC1', 'Gene', '382056', (63, 69))	('mTORC2', 'Gene', '74343', (77, 83))	('mutant', 'Var', (33, 39))	('apoptosis', 'biological_process', 'GO:0097194', ('50', '59'))	('mTORC1', 'cellular_component', 'GO:0031931', ('63', '69'))	('mTORC1', 'Gene', (63, 69))
129922	22808163	First, AZD8055 effects were compared to those of rapamycin, an mTORC1 inhibitor.	('rapamycin', 'Chemical', 'MESH:D020123', (49, 58))	('AZD8055', 'Chemical', 'MESH:C546624', (7, 14))	('AZD8055', 'Var', (7, 14))	('mTORC1', 'Gene', '382056', (63, 69))	('mTORC1', 'cellular_component', 'GO:0031931', ('63', '69'))	('mTORC1', 'Gene', (63, 69))
129925	22808163	Hence, mTORC1 inhibition with rapamycin alone is not sufficient to replicate the apoptosis produced with AZD8055.	('apoptosis', 'biological_process', 'GO:0006915', ('81', '90'))	('AZD8055', 'Var', (105, 112))	('mTORC1', 'Gene', '382056', (7, 13))	('mTORC1', 'cellular_component', 'GO:0031931', ('7', '13'))	('rapamycin', 'Chemical', 'MESH:D020123', (30, 39))	('mTORC1', 'Gene', (7, 13))	('apoptosis', 'biological_process', 'GO:0097194', ('81', '90'))	('AZD8055', 'Chemical', 'MESH:C546624', (105, 112))
129927	22808163	In epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer cells, MCL-1 downregulation by a PI3K/mTOR kinase inhibitor in combination with BIM upregulation (a pro-apoptotic member of the bcl-2 family) by a MEK inhibitor has been shown to be critical for the induction of apoptosis.	('mTOR', 'Gene', (115, 119))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('120', '136'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('3', '26'))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('276', '298'))	('mTOR', 'Gene', '2475', (115, 119))	('MCL-1', 'Gene', '4170', (84, 89))	('EGFR', 'Gene', '1956', (37, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('epidermal growth factor receptor', 'Gene', (3, 35))	('bcl-2', 'Gene', (205, 210))	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('MEK', 'Gene', '5609', (224, 227))	('epidermal growth factor receptor', 'Gene', '1956', (3, 35))	('MCL-1', 'Gene', (84, 89))	('BIM', 'Gene', (157, 160))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (50, 76))	('downregulation', 'NegReg', (90, 104))	('bcl-2', 'Gene', '596', (205, 210))	('PI3K', 'molecular_function', 'GO:0016303', ('110', '114'))	('MEK', 'Gene', (224, 227))	('lung cancer', 'Disease', (65, 76))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (54, 76))	('mutant', 'Var', (43, 49))	('BIM', 'Gene', '10018', (157, 160))	('upregulation', 'PosReg', (161, 173))	('EGFR', 'Gene', (37, 41))	('bcl-2', 'molecular_function', 'GO:0015283', ('205', '210'))
129930	22808163	While all the drugs alone reduced MCL-1 levels to some degree, the AZD8055/selumetinib combination cooperatively reduced MCL-1 to the lowest levels observed with any condition ( Figure 6A  , lane 4); the rapamycin/selumetinib combination failed to further decrease MCL-1 levels over that observed with either drug alone ( Figure 6A  , lane 4 versus 6).	('rapamycin', 'Chemical', 'MESH:D020123', (204, 213))	('MCL-1', 'Gene', '4170', (34, 39))	('MCL-1', 'Gene', '4170', (265, 270))	('AZD8055/selumetinib', 'Var', (67, 86))	('MCL-1', 'Gene', (265, 270))	('MCL-1', 'Gene', '4170', (121, 126))	('MCL-1', 'Gene', (121, 126))	('decrease MCL', 'Phenotype', 'HP:0025066', (256, 268))	('selumetinib', 'Chemical', 'MESH:C517975', (75, 86))	('reduced', 'NegReg', (26, 33))	('reduced MCL', 'Phenotype', 'HP:0025066', (26, 37))	('selumetinib', 'Chemical', 'MESH:C517975', (214, 225))	('AZD8055', 'Chemical', 'MESH:C546624', (67, 74))	('reduced', 'NegReg', (113, 120))	('reduced MCL', 'Phenotype', 'HP:0025066', (113, 124))	('MCL-1', 'Gene', (34, 39))
129935	22808163	These observations suggest that in BRAF mutant uveal melanoma the modulation of MCL-1 levels and apoptosis by AZD8055 in combination with selumetinib may be dependent upon mTORC2, not mTORC1, inhibition.	('BRAF', 'Gene', (35, 39))	('MCL-1', 'Gene', '4170', (80, 85))	('mTORC1', 'cellular_component', 'GO:0031931', ('184', '190'))	('mTORC1', 'Gene', (184, 190))	('selumetinib', 'Chemical', 'MESH:C517975', (138, 149))	('MCL-1', 'Gene', (80, 85))	('mTORC1', 'Gene', '382056', (184, 190))	('mutant', 'Var', (40, 46))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('AZD8055', 'Var', (110, 117))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('mTORC2', 'Gene', (172, 178))	('uveal melanoma', 'Disease', (47, 61))	('mTORC2', 'cellular_component', 'GO:0031932', ('172', '178'))	('apoptosis', 'CPA', (97, 106))	('apoptosis', 'biological_process', 'GO:0097194', ('97', '106'))	('AZD8055', 'Chemical', 'MESH:C546624', (110, 117))	('apoptosis', 'biological_process', 'GO:0006915', ('97', '106'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('mTORC2', 'Gene', '74343', (172, 178))	('BRAF', 'Gene', '673', (35, 39))
129936	22808163	We went on to examine the levels of MCL-1 and BIM expressed in several uveal melanoma cell lines following exposure to AZD8055 and selumetinib ( Figure 7A ).	('AZD8055', 'Var', (119, 126))	('AZD8055', 'Chemical', 'MESH:C546624', (119, 126))	('BIM', 'Gene', '10018', (46, 49))	('BIM', 'Gene', (46, 49))	('uveal melanoma', 'Disease', 'MESH:C536494', (71, 85))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('selumetinib', 'Chemical', 'MESH:C517975', (131, 142))	('uveal melanoma', 'Phenotype', 'HP:0007716', (71, 85))	('uveal melanoma', 'Disease', (71, 85))	('MCL-1', 'Gene', (36, 41))	('MCL-1', 'Gene', '4170', (36, 41))
129937	22808163	While selumetinib upregulated BIM levels in WT, BRAF, and GNAQ cells, only in the BRAF mutant OCM1A cell line was the level of MCL-1 decreased by AZD8055 and selumetinib cooperatively ( Figure 7A ).	('MCL-1', 'Gene', (127, 132))	('upregulated', 'PosReg', (18, 29))	('selumetinib', 'Chemical', 'MESH:C517975', (6, 17))	('BRAF', 'Gene', '673', (82, 86))	('GNAQ', 'Gene', '2776', (58, 62))	('OCM1', 'Species', '83984', (94, 98))	('BRAF', 'Gene', (82, 86))	('BIM', 'Gene', '10018', (30, 33))	('mutant', 'Var', (87, 93))	('AZD8055', 'Var', (146, 153))	('BIM', 'Gene', (30, 33))	('AZD8055', 'Chemical', 'MESH:C546624', (146, 153))	('selumetinib', 'Chemical', 'MESH:C517975', (158, 169))	('GNAQ', 'Gene', (58, 62))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('MCL-1', 'Gene', '4170', (127, 132))	('decreased', 'NegReg', (133, 142))
129945	22808163	In the xenograft model of the BRAF mutant cell line OCM1A, Western analysis of frozen tumor tissue revealed that cooperative MCL-1 downregulation and increased BIM levels were also achieved in vivo (Figure S6).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('increased BIM', 'Phenotype', 'HP:0003573', (150, 163))	('MCL-1', 'Gene', '4170', (125, 130))	('BIM', 'Gene', '10018', (160, 163))	('MCL-1', 'Gene', (125, 130))	('tumor', 'Disease', (86, 91))	('mutant', 'Var', (35, 41))	('downregulation', 'NegReg', (131, 145))	('BRAF', 'Gene', (30, 34))	('BIM', 'Gene', (160, 163))	('BRAF', 'Gene', '673', (30, 34))	('OCM1', 'Species', '83984', (52, 56))	('increased', 'PosReg', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
129946	22808163	Taken together, these studies demonstrate that MCL-1 downregulation is both necessary and sufficient to induce apoptosis with selumetinib, and strongly argues that MCL-1 is a singular target that is cooperatively modulated by the combination to induce apoptosis in BRAF mutant uveal melanoma.	('MCL-1', 'Gene', (164, 169))	('downregulation', 'NegReg', (53, 67))	('apoptosis', 'biological_process', 'GO:0097194', ('252', '261'))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('BRAF', 'Gene', '673', (265, 269))	('uveal melanoma', 'Disease', 'MESH:C536494', (277, 291))	('melanoma', 'Phenotype', 'HP:0002861', (283, 291))	('selumetinib', 'Chemical', 'MESH:C517975', (126, 137))	('apoptosis', 'biological_process', 'GO:0006915', ('252', '261'))	('MCL-1', 'Gene', '4170', (164, 169))	('uveal melanoma', 'Phenotype', 'HP:0007716', (277, 291))	('uveal melanoma', 'Disease', (277, 291))	('MCL-1', 'Gene', (47, 52))	('MCL-1', 'Gene', '4170', (47, 52))	('induce', 'PosReg', (245, 251))	('mutant', 'Var', (270, 276))	('BRAF', 'Gene', (265, 269))
129948	22808163	AKT activation in BRAF mutant cutaneous melanomas mediates resistance to MEK inhibition with selumetinib.	('AKT', 'Gene', (0, 3))	('cutaneous melanomas', 'Disease', (30, 49))	('selumetinib', 'Chemical', 'MESH:C517975', (93, 104))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('MEK', 'Gene', (73, 76))	('MEK', 'Gene', '5609', (73, 76))	('AKT', 'Gene', '207', (0, 3))	('BRAF', 'Gene', '673', (18, 22))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (30, 49))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (30, 49))	('BRAF', 'Gene', (18, 22))	('activation', 'PosReg', (4, 14))	('mutant', 'Var', (23, 29))
129949	22808163	BRAF and RAS mutations mediate resistance to AKT targeted agents.	('mediate', 'Reg', (23, 30))	('AKT', 'Gene', (45, 48))	('BRAF', 'Gene', '673', (0, 4))	('RAS', 'Gene', (9, 12))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (13, 22))	('AKT', 'Gene', '207', (45, 48))
129950	22808163	Alternatively, drug combinations that inhibit both pathways may be more clinically effective for tumors with evidence of dual pathway activation, including those with RTK mutation/activation, other genetic alterations of the pathway (RAS, PIK3CA, BRAF mutations and/or PTEN loss), or simply expression of phosphorylated AKT or ERK.	('PTEN', 'Gene', (269, 273))	('loss', 'NegReg', (274, 278))	('tumors', 'Disease', (97, 103))	('ERK', 'Gene', '5594', (327, 330))	('PIK3CA', 'Gene', '5290', (239, 245))	('PTEN', 'Gene', '5728', (269, 273))	('RTK', 'Gene', (167, 170))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('mutation/activation', 'Var', (171, 190))	('AKT', 'Gene', (320, 323))	('RTK', 'Gene', '5979', (167, 170))	('ERK', 'Gene', (327, 330))	('activation', 'PosReg', (134, 144))	('ERK', 'molecular_function', 'GO:0004707', ('327', '330'))	('mutation/activation', 'PosReg', (171, 190))	('PIK3CA', 'Gene', (239, 245))	('BRAF', 'Gene', '673', (247, 251))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('BRAF', 'Gene', (247, 251))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('AKT', 'Gene', '207', (320, 323))
129952	22808163	AZD8055/selumetinib did not confer cooperative antitumor effects in WT cells, possibly related to incomplete suppression of MAPK activity with selumetinib.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('selumetinib', 'Chemical', 'MESH:C517975', (8, 19))	('AZD8055', 'Chemical', 'MESH:C546624', (0, 7))	('tumor', 'Disease', (51, 56))	('MAPK', 'Gene', '5595;5594;5595', (124, 128))	('MAPK', 'molecular_function', 'GO:0004707', ('124', '128'))	('MAPK', 'Gene', (124, 128))	('activity', 'MPA', (129, 137))	('suppression', 'NegReg', (109, 120))	('selumetinib', 'Chemical', 'MESH:C517975', (143, 154))	('AZD8055/selumetinib', 'Var', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
129953	22808163	Alternatively, the combination did synergistically suppress the viability of both BRAF and GNAQ mutant cells; however, apoptosis was only induced in BRAF mutant cells.	('BRAF', 'Gene', (149, 153))	('suppress', 'NegReg', (51, 59))	('BRAF', 'Gene', '673', (149, 153))	('viability', 'CPA', (64, 73))	('mutant', 'Var', (96, 102))	('BRAF', 'Gene', '673', (82, 86))	('GNAQ', 'Gene', (91, 95))	('apoptosis', 'biological_process', 'GO:0097194', ('119', '128'))	('BRAF', 'Gene', (82, 86))	('apoptosis', 'biological_process', 'GO:0006915', ('119', '128'))	('GNAQ', 'Gene', '2776', (91, 95))
129954	22808163	Ultimately, in vitro measurement of apoptosis correlated better than cell viability to in vivo effectiveness as tumor regressions were observed only in the BRAF mutant xenograft model.	('mutant', 'Var', (161, 167))	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('BRAF', 'Gene', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('BRAF', 'Gene', '673', (156, 160))
129955	22808163	These distinct drug induced fates may in fact reflect biologic differences in how BRAF and GNAQ mutations activate MAPK signaling: while the former directly activates MEK ERK activity, the latter does so via protein kinase C (PKC) activation which can mediate cell survival signals via several pathways parallel to MAPK.	('MEK', 'Gene', (167, 170))	('MAPK', 'Gene', (315, 319))	('activates', 'PosReg', (157, 166))	('MAPK signaling', 'biological_process', 'GO:0000165', ('115', '129'))	('ERK', 'Gene', (171, 174))	('MAPK', 'Gene', (115, 119))	('mutations', 'Var', (96, 105))	('activity', 'MPA', (175, 183))	('ERK', 'molecular_function', 'GO:0004707', ('171', '174'))	('PKC', 'molecular_function', 'GO:0004697', ('226', '229'))	('GNAQ', 'Gene', '2776', (91, 95))	('activate', 'PosReg', (106, 114))	('GNAQ', 'Gene', (91, 95))	('activation', 'PosReg', (231, 241))	('MAPK', 'molecular_function', 'GO:0004707', ('115', '119'))	('MAPK', 'molecular_function', 'GO:0004707', ('315', '319'))	('MEK', 'Gene', '5609', (167, 170))	('MAPK', 'Gene', '5595;5594;5595', (315, 319))	('BRAF', 'Gene', '673', (82, 86))	('BRAF', 'Gene', (82, 86))	('ERK', 'Gene', '5594', (171, 174))	('MAPK', 'Gene', '5595;5594;5595', (115, 119))	('protein', 'cellular_component', 'GO:0003675', ('208', '215'))	('PKC) activation', 'biological_process', 'GO:1990051', ('226', '241'))
129956	22808163	The observation that suppression of GNAQ expression in GNAQ mutant cells predisposes to AZD8055/selumetinib-induced apoptosis argues that GNAQ activity in these cells activates MEK- and mTOR- independent pro-survival signals.	('pro-survival', 'biological_process', 'GO:0043066', ('204', '216'))	('mTOR', 'Gene', (186, 190))	('GNAQ', 'Gene', '2776', (36, 40))	('GNAQ', 'Gene', (36, 40))	('apoptosis', 'CPA', (116, 125))	('expression', 'MPA', (41, 51))	('GNAQ', 'Gene', '2776', (138, 142))	('mTOR', 'Gene', '2475', (186, 190))	('MEK', 'Gene', '5609', (177, 180))	('GNAQ', 'Gene', (138, 142))	('suppression', 'NegReg', (21, 32))	('selumetinib', 'Chemical', 'MESH:C517975', (96, 107))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('MEK', 'Gene', (177, 180))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))	('AZD8055', 'Chemical', 'MESH:C546624', (88, 95))	('GNAQ', 'Gene', '2776', (55, 59))	('activates', 'PosReg', (167, 176))	('GNAQ', 'Gene', (55, 59))	('mutant', 'Var', (60, 66))
129957	22808163	Further elucidation of the differences in drug-induced outcomes for GNAQ and BRAF mutant uveal melanomas revealed that AKT, 4E-BP1, and MCL-1 were cooperatively regulated by the AZD8055/selumetinib combination only in BRAF mutant cells and not GNAQ cells ( Figure 8A ), suggesting these as candidate targets responsible for the distinct apoptotic outcomes observed.	('GNAQ', 'Gene', '2776', (244, 248))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('GNAQ', 'Gene', (244, 248))	('regulated', 'Reg', (161, 170))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('MCL-1', 'Gene', (136, 141))	('GNAQ', 'Gene', '2776', (68, 72))	('mutant', 'Var', (82, 88))	('AZD8055', 'Chemical', 'MESH:C546624', (178, 185))	('mutant', 'Var', (223, 229))	('GNAQ', 'Gene', (68, 72))	('AKT', 'Gene', '207', (119, 122))	('selumetinib', 'Chemical', 'MESH:C517975', (186, 197))	('uveal melanomas', 'Disease', 'MESH:C536494', (89, 104))	('4E-BP1', 'Gene', '1978', (124, 130))	('BRAF', 'Gene', '673', (77, 81))	('MCL-1', 'Gene', '4170', (136, 141))	('BRAF', 'Gene', (77, 81))	('AZD8055/selumetinib', 'Gene', (178, 197))	('uveal melanoma', 'Phenotype', 'HP:0007716', (89, 103))	('4E-BP1', 'Gene', (124, 130))	('BRAF', 'Gene', (218, 222))	('BRAF', 'Gene', '673', (218, 222))	('uveal melanomas', 'Disease', (89, 104))	('uveal melanomas', 'Phenotype', 'HP:0007716', (89, 104))	('AKT', 'Gene', (119, 122))
129960	22808163	Our data revealed that while 4E-BP1 is cooperatively regulated by AZD8055/selumetinib, this is not critical for the induction of apoptosis in BRAF mutant uveal melanoma cells.	('mutant', 'Var', (147, 153))	('uveal melanoma', 'Disease', 'MESH:C536494', (154, 168))	('AZD8055', 'Chemical', 'MESH:C546624', (66, 73))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('4E-BP1', 'Gene', (29, 35))	('uveal melanoma', 'Phenotype', 'HP:0007716', (154, 168))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('116', '138'))	('selumetinib', 'Chemical', 'MESH:C517975', (74, 85))	('BRAF', 'Gene', '673', (142, 146))	('uveal melanoma', 'Disease', (154, 168))	('AZD8055/selumetinib', 'Gene', (66, 85))	('4E-BP1', 'Gene', '1978', (29, 35))	('BRAF', 'Gene', (142, 146))
129962	22808163	Instead, AZD8055 suppression of mTORC2 cooperates with selumetinib to reduce MCL-1 protein expression, a change that in combination with selumetinib-mediated induction of BIM, is essential for combination-induced apoptosis ( Figure 8B ).	('reduce MCL', 'Phenotype', 'HP:0025066', (70, 80))	('mTORC2', 'Gene', (32, 38))	('mTORC2', 'Gene', '74343', (32, 38))	('selumetinib', 'Chemical', 'MESH:C517975', (55, 66))	('apoptosis', 'biological_process', 'GO:0006915', ('213', '222'))	('MCL-1', 'Gene', (77, 82))	('BIM', 'Gene', '10018', (171, 174))	('reduce', 'NegReg', (70, 76))	('apoptosis', 'biological_process', 'GO:0097194', ('213', '222'))	('BIM', 'Gene', (171, 174))	('AZD8055', 'Var', (9, 16))	('selumetinib', 'Chemical', 'MESH:C517975', (137, 148))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('suppression', 'NegReg', (17, 28))	('mTORC2', 'cellular_component', 'GO:0031932', ('32', '38'))	('MCL-1', 'Gene', '4170', (77, 82))	('AZD8055', 'Chemical', 'MESH:C546624', (9, 16))
129964	22808163	In EGFR mutant lung cancer cells, inhibition of PI3K/mTOR and MEK were directly linked to MCL-1 downregulation and BIM upregulation, respectively.	('MEK', 'Gene', (62, 65))	('EGFR', 'molecular_function', 'GO:0005006', ('3', '7'))	('BIM', 'Gene', (115, 118))	('MCL-1', 'Gene', (90, 95))	('upregulation', 'PosReg', (119, 131))	('PI3K', 'molecular_function', 'GO:0016303', ('48', '52'))	('mTOR', 'Gene', '2475', (53, 57))	('lung cancer', 'Disease', (15, 26))	('EGFR', 'Gene', (3, 7))	('BIM', 'Gene', '10018', (115, 118))	('mutant', 'Var', (8, 14))	('lung cancer', 'Disease', 'MESH:D008175', (15, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('EGFR', 'Gene', '1956', (3, 7))	('MEK', 'Gene', '5609', (62, 65))	('MCL-1', 'Gene', '4170', (90, 95))	('mTOR', 'Gene', (53, 57))	('downregulation', 'NegReg', (96, 110))
129967	22808163	Hence, different targeted approaches may achieve the dual pathway inhibition that can impact BIM/MCL-1 levels and induce apoptosis in BRAF mutant cells.	('BIM', 'Gene', '10018', (93, 96))	('BIM', 'Gene', (93, 96))	('MCL-1', 'Gene', (97, 102))	('BRAF', 'Gene', '673', (134, 138))	('MCL-1', 'Gene', '4170', (97, 102))	('mutant', 'Var', (139, 145))	('BRAF', 'Gene', (134, 138))	('induce', 'Reg', (114, 120))	('apoptosis', 'biological_process', 'GO:0097194', ('121', '130'))	('impact', 'Reg', (86, 92))	('apoptosis', 'CPA', (121, 130))	('apoptosis', 'biological_process', 'GO:0006915', ('121', '130'))
129969	22808163	We did observe that BRAF mutant cell lines had overall less PTEN protein expression compared to WT or GNAQ cells, though this did not result in baseline differences of AKT or S6K1 phosphorylation (Figure S8A).	('mutant', 'Var', (25, 31))	('S6K1', 'Gene', (175, 179))	('S6K1', 'Gene', '6198', (175, 179))	('GNAQ', 'Gene', (102, 106))	('AKT', 'Gene', '207', (168, 171))	('PTEN', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (20, 24))	('PTEN', 'Gene', '5728', (60, 64))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('phosphorylation', 'biological_process', 'GO:0016310', ('180', '195'))	('GNAQ', 'Gene', '2776', (102, 106))	('BRAF', 'Gene', (20, 24))	('AKT', 'Gene', (168, 171))	('less', 'NegReg', (55, 59))
129971	22808163	We did investigate how siRNA-mediated depletion of PTEN expression in the GNAQ cell line 92.1 impacted drug-induced apoptosis and found this did not change the drug effects upon the relevant signaling pathways or MCL-1 levels (Figure S8B).	('GNAQ', 'Gene', (74, 78))	('MCL-1', 'Gene', '4170', (213, 218))	('PTEN', 'Gene', '5728', (51, 55))	('drug-induced apoptosis', 'CPA', (103, 125))	('depletion', 'Var', (38, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('signaling', 'biological_process', 'GO:0023052', ('191', '200'))	('impacted', 'Reg', (94, 102))	('GNAQ', 'Gene', '2776', (74, 78))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))	('PTEN', 'Gene', (51, 55))	('MCL-1', 'Gene', (213, 218))
129973	22808163	We concluded that while PTEN status may modestly influence the induction of apoptosis, it does so in a manner distinct from the MCL-1 dependent mechanism we have delineated for BRAF mutant cells, though further study regarding the contribution of PTEN status apart from BRAF or GNAQ mutations is warranted.	('PTEN', 'Gene', '5728', (24, 28))	('BRAF', 'Gene', (270, 274))	('BRAF', 'Gene', '673', (270, 274))	('BRAF', 'Gene', (177, 181))	('BRAF', 'Gene', '673', (177, 181))	('GNAQ', 'Gene', '2776', (278, 282))	('MCL-1', 'Gene', '4170', (128, 133))	('MCL-1', 'Gene', (128, 133))	('PTEN', 'Gene', (24, 28))	('GNAQ', 'Gene', (278, 282))	('apoptosis', 'CPA', (76, 85))	('influence', 'Reg', (49, 58))	('PTEN', 'Gene', '5728', (247, 251))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('63', '85'))	('mutant', 'Var', (182, 188))	('PTEN', 'Gene', (247, 251))
129974	22808163	One question stemming from this study is how applicable the efficacy of combined mTOR and MEK inhibition may be for other BRAF mutant malignancies.	('mutant', 'Var', (127, 133))	('malignancies', 'Disease', 'MESH:D009369', (134, 146))	('inhibition', 'NegReg', (94, 104))	('BRAF', 'Gene', '673', (122, 126))	('malignancies', 'Disease', (134, 146))	('BRAF', 'Gene', (122, 126))	('MEK', 'Gene', (90, 93))	('MEK', 'Gene', '5609', (90, 93))	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (81, 85))
129975	22808163	We have evaluated the AZD8055/selumetinib combination in cutaneous melanomas and have found that the combination preferentially induced apoptosis in most BRAF mutant cell lines (3 out of 4 lines tested), but not N-RAS mutant cells or cells lacking these mutations (Figure S9), supporting observations from Gopal et.	('apoptosis', 'CPA', (136, 145))	('mutant', 'Var', (159, 165))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('BRAF', 'Gene', '673', (154, 158))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('apoptosis', 'biological_process', 'GO:0097194', ('136', '145'))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (57, 76))	('BRAF', 'Gene', (154, 158))	('AZD8055', 'Chemical', 'MESH:C546624', (22, 29))	('apoptosis', 'biological_process', 'GO:0006915', ('136', '145'))	('selumetinib', 'Chemical', 'MESH:C517975', (30, 41))	('preferentially', 'PosReg', (113, 127))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (57, 76))	('cutaneous melanomas', 'Disease', (57, 76))	('induced', 'Reg', (128, 135))
129976	22808163	al.. For GNAQ mutant cells, further study is warranted to develop more effective GNAQ targeting strategies in order to achieve better therapeutic efficacy.	('GNAQ', 'Gene', (9, 13))	('mutant', 'Var', (14, 20))	('GNAQ', 'Gene', (81, 85))	('GNAQ', 'Gene', '2776', (9, 13))	('GNAQ', 'Gene', '2776', (81, 85))
129982	22808163	The antibodies for phosphorylated ERK 1/2 (Y204) and Ku70 were obtained from Santa Cruz Biotechnology (Santa Cruz, CA).	('ERK 1', 'molecular_function', 'GO:0004707', ('34', '39'))	('Ku70', 'Gene', '2547', (53, 57))	('ERK 1/2', 'Gene', '5595;5594', (34, 41))	('Ku70', 'Gene', (53, 57))	('ERK 1/2', 'Gene', (34, 41))	('Y204', 'Var', (43, 47))
129983	22808163	Pooled siRNA constructs targeting 4E-BP1 (L-003005), RICTOR (L-016984), and RAPTOR (L-004107) were purchased from Dharmacon (ON-TARGET plus SMART pool; Lafayette, CO, USA).	('L-004107', 'Var', (84, 92))	('RAPTOR', 'Gene', (76, 82))	('4E-BP1', 'Gene', '1978', (34, 40))	('RICTOR', 'Gene', (53, 59))	('L-016984', 'Var', (61, 69))	('RAPTOR', 'Gene', '57521', (76, 82))	('RICTOR', 'Gene', '253260', (53, 59))	('4E-BP1', 'Gene', (34, 40))	('L-003005', 'Var', (42, 50))
130005	22260482	Melanoma originates in melanocytes whose genetic alterations may enable their continuous proliferation and evasion of the body's tumor surveillance mechanisms, ultimately resulting in the development of malignant melanomas.	('malignant melanoma', 'Phenotype', 'HP:0002861', (203, 221))	('genetic alterations', 'Var', (41, 60))	('resulting in', 'Reg', (171, 183))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('malignant melanomas', 'Disease', 'MESH:D008545', (203, 222))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanoma', 'Disease', (0, 8))	('malignant melanomas', 'Disease', (203, 222))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('evasion', 'CPA', (107, 114))	('tumor', 'Disease', (129, 134))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('melanomas', 'Phenotype', 'HP:0002861', (213, 222))	('malignant melanomas', 'Phenotype', 'HP:0002861', (203, 222))
130007	22260482	Inherited mutations and epigenetic factors known to contribute to the pathophysiology of melanoma have been reviewed previously.	('epigenetic factors', 'Var', (24, 42))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))
130009	22260482	Existing genomic data support that UV light is the primary arbiter of higher mutation rate in melanoma as it induces point mutation causing nucleotide substitutions of thymine with cytosine (C>T).	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('nucleotide substitutions', 'Var', (140, 164))	('thymine', 'Chemical', 'MESH:D013941', (168, 175))	('cytosine', 'Chemical', 'MESH:D003596', (181, 189))	('point mutation', 'MPA', (117, 131))	('induces', 'Reg', (109, 116))
130010	22260482	Broadly, the genes affected by mutations have been classified as oncogenes or tumor suppressors, and mutations identified in these genes have been classified as passenger or driver mutations.	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mutations', 'Var', (31, 40))	('tumor', 'Disease', (78, 83))
130013	22260482	In this comparison, mutations in oncogenes can lead to acceleration of growth while mutations in tumor suppressors release the inhibition that prevents tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('growth', 'MPA', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('acceleration', 'PosReg', (55, 67))	('oncogenes', 'Gene', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (152, 157))	('mutations', 'Var', (84, 93))	('tumor', 'Disease', (97, 102))	('mutations', 'Var', (20, 29))
130015	22260482	In contrast, mutations occur throughout the gene in tumor suppressor genes, which often induce loss or truncation of the encoded protein.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('protein', 'Protein', (129, 136))	('tumor', 'Disease', (52, 57))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('truncation of the', 'MPA', (103, 120))	('induce', 'Reg', (88, 94))	('tumor suppressor', 'biological_process', 'GO:0051726', ('52', '68'))	('mutations', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('loss', 'NegReg', (95, 99))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('52', '68'))
130016	22260482	Mutations in tumor suppressors usually become apparent when both alleles are affected, resulting in a homozygous genotype, although some evidence for significance of heterozygous loss is also emerging.	('tumor', 'Disease', (13, 18))	('homozygous genotype', 'MPA', (102, 121))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
130018	22260482	'Driver' mutations are genetic alterations that lead to the development of cancer cells and are pathogenic in nature.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	("'Driver'", 'PosReg', (0, 8))	('mutations', 'Var', (9, 18))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('lead to', 'Reg', (48, 55))
130019	22260482	In contrast, 'passenger' mutations can occur along with or after driver mutations, but possess no effect on tumor growth, while non-pathogenic, passenger mutations are valuable for documenting changes that cells have undergone in route to becoming malignant.	('mutations', 'Var', (72, 81))	('mutations', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))
130022	22260482	When multiple cancer samples have identical mutations at the exact same amino acid or in neighboring amino acids, there is a greater likelihood that the mutation is pathogenic.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (44, 53))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('pathogenic', 'Reg', (165, 175))	('mutation', 'Var', (153, 161))
130024	22260482	More specifically, 15-33% of metastatic melanomas bear Q61R as the main hotspot NRAS mutation.	('melanomas', 'Disease', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('melanomas', 'Disease', 'MESH:D008545', (40, 49))	('Q61R', 'Var', (55, 59))	('Q61R', 'Mutation', 'rs11554290', (55, 59))
130026	22260482	Notably, 80% of mutations in BRAF result in the V600E mutation.	('BRAF', 'Gene', '673', (29, 33))	('V600E', 'Var', (48, 53))	('BRAF', 'Gene', (29, 33))	('mutations', 'Var', (16, 25))	('V600E', 'Mutation', 'rs113488022', (48, 53))	('result in', 'Reg', (34, 43))
130027	22260482	Algorithms such as the Scale-Invariant Feature Transform (SIFT) are helpful in predicting the effect of a mutation.	('SIFT', 'Disease', 'None', (58, 62))	('SIFT', 'Disease', (58, 62))	('mutation', 'Var', (106, 114))
130028	22260482	SIFT calculates how likely an amino acid substitution is to contribute to protein function based on sequence homology and amino acid characteristics.	('protein function', 'MPA', (74, 90))	('contribute', 'Reg', (60, 70))	('SIFT', 'Disease', 'None', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('amino acid substitution', 'Var', (30, 53))	('SIFT', 'Disease', (0, 4))
130029	22260482	The gold standard for determining whether a mutation drives tumorigenesis is biochemical and biological analysis using various systems including overexpression, knockdown, knockout, and knockin model organisms as well as cell culture experiments.	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('mutation', 'Var', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (60, 65))
130030	22260482	UV light is a major cause of somatic mutations in melanoma, as shown through epidemiological and experimental studies.	('cause', 'Reg', (20, 25))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('mutations', 'Var', (37, 46))
130032	22260482	The characteristic signatures of UV-mediated damage are C>T and CC>TT changes; proposed mechanisms for this phenomenon include mutations via 6-4 photoproducts and formation of cyclobutane pyrimidine dimers.	('formation', 'biological_process', 'GO:0009058', ('163', '172'))	('mutations', 'Var', (127, 136))	('cyclobutane pyrimidine dimers', 'MPA', (176, 205))	('cyclobutane pyrimidine', 'Chemical', '-', (176, 198))
130034	22260482	Higher proportions of C>T mutations are commonly used as a predictor of UV-induced mutation signature in melanoma samples.	('C>T mutations', 'Var', (22, 35))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))
130035	22260482	Therefore, a non C>T mutation may be more likely to be a driver in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('non C>T', 'Var', (13, 20))
130036	22260482	When C>T mutations are identified, they need to fulfill criteria described in section 'Passenger versus Driver Mutations' below to strengthen the argument that they are melanoma drivers.	('C>T mutations', 'Var', (5, 18))	('melanoma', 'Disease', (169, 177))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))
130048	22260482	Importantly, normal and tumor samples need to be matched by genotyping single nucleotide polymorphisms (SNPs) to confirm that they are from the same individual before tumor-specific somatic mutations in candidate genes can be derived.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('single nucleotide polymorphisms', 'Var', (71, 102))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (167, 172))
130053	22260482	Mutations in genes like p16, p14, and CDK4 / 6 were identified but were later found to be accountable for only a portion of sporadic and familial melanomas.	('p14', 'Gene', '1029', (29, 32))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanomas', 'Phenotype', 'HP:0002861', (146, 155))	('p16', 'Gene', '1029', (24, 27))	('p16', 'Gene', (24, 27))	('Mutations', 'Var', (0, 9))	('CDK4', 'Gene', '1019', (38, 42))	('CDK', 'molecular_function', 'GO:0004693', ('38', '41'))	('p14', 'Gene', (29, 32))	('CDK4', 'Gene', (38, 42))	('familial melanomas', 'Disease', (137, 155))	('familial melanomas', 'Disease', 'OMIM:155600', (137, 155))
130059	22260482	Candidate gene sequencing led to the seminal discovery that BRAF is mutated in 42-60% of melanoma cell lines and tumor samples.	('tumor', 'Disease', (113, 118))	('melanoma cell', 'Disease', 'MESH:D008545', (89, 102))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mutated', 'Var', (68, 75))	('melanoma cell', 'Disease', (89, 102))
130060	22260482	Strikingly, about 80% of the mutations in BRAF are clustered at a kinase-activation domain in which the V600E point mutation induces constitutive BRAF activation.	('BRAF', 'Gene', '673', (42, 46))	('BRAF', 'Gene', (146, 150))	('V600E', 'Mutation', 'rs113488022', (104, 109))	('V600E', 'Var', (104, 109))	('activation', 'MPA', (151, 161))	('induces', 'Reg', (125, 132))	('BRAF', 'Gene', (42, 46))	('BRAF', 'Gene', '673', (146, 150))	('constitutive', 'MPA', (133, 145))
130061	22260482	Importantly, mutant BRAF has recently become a successful target for an FDA-approved small-molecule inhibitor, vemurafenib (PLX-4032).	('mutant', 'Var', (13, 19))	('vemurafenib', 'Chemical', 'MESH:D000077484', (111, 122))	('BRAF', 'Gene', '673', (20, 24))	('PLX-4032', 'Chemical', 'MESH:D000077484', (124, 132))	('BRAF', 'Gene', (20, 24))
130066	22260482	Although activated NRAS has been accepted as the key oncogene in human melanomas, it requires another stimulus to yield truly transformed melanoma cells such as by inactivation of p53 or CDKN2A.	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma cells', 'Disease', 'MESH:D008545', (138, 152))	('melanomas', 'Disease', (71, 80))	('melanoma cells', 'Disease', (138, 152))	('CDKN2A', 'Gene', (187, 193))	('CDKN2A', 'Gene', '1029', (187, 193))	('human', 'Species', '9606', (65, 70))	('p53', 'Gene', (180, 183))	('p53', 'Gene', '7157', (180, 183))	('inactivation', 'Var', (164, 176))	('melanomas', 'Disease', 'MESH:D008545', (71, 80))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))
130070	22260482	Germline-inactivating mutations cause loss of c-KIT kinase activity and lead to a loss of melanocytes and other abnormalities associated with piebaldism.	('activity', 'MPA', (59, 67))	('kinase activity', 'molecular_function', 'GO:0016301', ('52', '67'))	('piebaldism', 'Disease', (142, 152))	('piebaldism', 'Disease', 'MESH:D016116', (142, 152))	('piebaldism', 'Phenotype', 'HP:0007544', (142, 152))	('KIT', 'molecular_function', 'GO:0005020', ('48', '51'))	('c-KIT', 'Gene', (46, 51))	('loss', 'NegReg', (82, 86))	('Germline-inactivating mutations', 'Var', (0, 31))	('c-KIT', 'Gene', '3815', (46, 51))	('loss', 'NegReg', (38, 42))
130072	22260482	In a seminal paper by, analysis of 102 primary melanomas found c-KIT mutations in 21% of mucosal, 11% of acral, and 17% of sun-damaged skin.	('mutations', 'Var', (69, 78))	('c-KIT', 'Gene', (63, 68))	('c-KIT', 'Gene', '3815', (63, 68))	('sun-damaged', 'Phenotype', 'HP:0000992', (123, 134))	('melanomas', 'Disease', 'MESH:D008545', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('KIT', 'molecular_function', 'GO:0005020', ('65', '68'))	('melanomas', 'Disease', (47, 56))
130075	22260482	Recently, a study by investigated the signaling pathway regulated by c-KIT mutants K642E and L576P.	('signaling pathway', 'biological_process', 'GO:0007165', ('38', '55'))	('signaling pathway', 'Pathway', (38, 55))	('KIT', 'molecular_function', 'GO:0005020', ('71', '74'))	('c-KIT', 'Gene', (69, 74))	('L576P', 'Mutation', 'rs121913513', (93, 98))	('L576P', 'Var', (93, 98))	('c-KIT', 'Gene', '3815', (69, 74))	('K642E', 'Mutation', 'rs121913512', (83, 88))
130076	22260482	They found that under normoxic conditions, these mutations strongly activate the phosphatidyl-inositol-3 kinase (PI3K) pathway and weakly activate the Ras / Raf / Mek / Erk pathway.	('activate', 'PosReg', (68, 76))	('Erk', 'molecular_function', 'GO:0004707', ('169', '172'))	('mutations', 'Var', (49, 58))	('Erk', 'Gene', (169, 172))	('Raf', 'Gene', (157, 160))	('activate', 'PosReg', (138, 146))	('phosphatidyl-inositol-3 kinase', 'Gene', (81, 111))	('Erk', 'Gene', '2048', (169, 172))	('phosphatidyl-inositol-3 kinase', 'Gene', '5293', (81, 111))	('Mek', 'Gene', '5609', (163, 166))	('Mek', 'Gene', (163, 166))	('PI3K', 'molecular_function', 'GO:0016303', ('113', '117'))	('Raf', 'Gene', '22882', (157, 160))
130077	22260482	In contrast, under hypoxic conditions that mimic tumor microenvironment or with constitutive expression of hypoxia-inducible factor 1-alpha (HIF-1alpha), these mutations strongly activated the Ras / Raf / Mek / Erk pathway and stimulated melanocyte transformation and proliferation.	('mutations', 'Var', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('HIF-1alpha', 'Gene', (141, 151))	('activated', 'PosReg', (179, 188))	('hypoxic conditions', 'Disease', (19, 37))	('Erk', 'molecular_function', 'GO:0004707', ('211', '214'))	('stimulated', 'PosReg', (227, 237))	('proliferation', 'CPA', (268, 281))	('Raf', 'Gene', (199, 202))	('Erk', 'Gene', '2048', (211, 214))	('tumor', 'Disease', (49, 54))	('hypoxic conditions', 'Disease', 'MESH:D009135', (19, 37))	('HIF-1alpha', 'Gene', '3091', (141, 151))	('melanocyte transformation', 'CPA', (238, 263))	('Mek', 'Gene', (205, 208))	('hypoxia-inducible factor 1-alpha', 'Gene', (107, 139))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('Mek', 'Gene', '5609', (205, 208))	('hypoxia-inducible factor 1-alpha', 'Gene', '3091', (107, 139))	('Raf', 'Gene', '22882', (199, 202))	('Erk', 'Gene', (211, 214))
130078	22260482	found that wild-type c-KIT stimulation leads to activation of MITF transcription factor because of c-KIT phosphorylation at the PI3K-binding site (Y721) and Src-binding sites (Y568 and Y570).	('phosphorylation', 'MPA', (105, 120))	('KIT', 'molecular_function', 'GO:0005020', ('23', '26'))	('c-KIT', 'Gene', (21, 26))	('Src', 'Gene', (157, 160))	('c-KIT', 'Gene', '3815', (21, 26))	('KIT', 'molecular_function', 'GO:0005020', ('101', '104'))	('activation', 'PosReg', (48, 58))	('MITF', 'Gene', '4286', (62, 66))	('c-KIT', 'Gene', (99, 104))	('Y568', 'Var', (176, 180))	('c-KIT', 'Gene', '3815', (99, 104))	('Src', 'Gene', '6714', (157, 160))	('transcription factor', 'molecular_function', 'GO:0000981', ('67', '87'))	('transcription', 'biological_process', 'GO:0006351', ('67', '80'))	('MITF', 'Gene', (62, 66))	('binding', 'molecular_function', 'GO:0005488', ('161', '168'))	('PI3K-binding', 'molecular_function', 'GO:0043548', ('128', '140'))	('Y570', 'Var', (185, 189))	('Y721', 'Var', (147, 151))	('phosphorylation', 'biological_process', 'GO:0016310', ('105', '120'))
130079	22260482	In addition, c-KIT-induced activation of MITF is dependent on PI3K-, Akt-, Src-, p38- or Mek kinases and mutation of c-KIT phosphorylation sites restrict proliferation.	('c-KIT', 'Gene', (117, 122))	('MITF', 'Gene', (41, 45))	('c-KIT', 'Gene', '3815', (117, 122))	('activation', 'PosReg', (27, 37))	('Akt', 'Gene', (69, 72))	('mutation', 'Var', (105, 113))	('c-KIT', 'Gene', (13, 18))	('Mek', 'Gene', (89, 92))	('Mek', 'Gene', '5609', (89, 92))	('c-KIT', 'Gene', '3815', (13, 18))	('p38', 'Gene', (81, 84))	('KIT', 'molecular_function', 'GO:0005020', ('15', '18'))	('Akt', 'Gene', '207', (69, 72))	('Src', 'Gene', (75, 78))	('KIT', 'molecular_function', 'GO:0005020', ('119', '122'))	('restrict', 'NegReg', (145, 153))	('proliferation', 'CPA', (154, 167))	('phosphorylation', 'biological_process', 'GO:0016310', ('123', '138'))	('PI3K', 'molecular_function', 'GO:0016303', ('62', '66'))	('p38', 'Gene', '1432', (81, 84))	('Src', 'Gene', '6714', (75, 78))	('MITF', 'Gene', '4286', (41, 45))	('PI3K-', 'Var', (62, 67))
130081	22260482	Overall, c-KIT is an important regulator of melanocyte fate, and its activating mutations favor melanoma formation by dysregulating various cell-signaling pathways.	('cell-signaling pathways', 'Pathway', (140, 163))	('mutations', 'Var', (80, 89))	('favor', 'PosReg', (90, 95))	('c-KIT', 'Gene', (9, 14))	('c-KIT', 'Gene', '3815', (9, 14))	('formation', 'biological_process', 'GO:0009058', ('105', '114'))	('KIT', 'molecular_function', 'GO:0005020', ('11', '14'))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('dysregulating', 'Reg', (118, 131))	('melanoma', 'Disease', (96, 104))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))
130082	22260482	Importantly, recent Phase II clinical trials of the c-KIT inhibitor Imatinib, which is FDA approved for gastrointestinal stromal tumors, reported an overall durable response rate of 16-23%, specifically in patients who harbor mutations in exons 11 or 13 in c-Kit or with an amplification of c-KIT.	('c-KIT', 'Gene', '3815', (291, 296))	('Imatinib', 'Chemical', 'MESH:D000068877', (68, 76))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('gastrointestinal stromal tumors', 'Disease', (104, 135))	('mutations in exons 11 or 13', 'Var', (226, 253))	('c-KIT', 'Gene', (52, 57))	('c-Kit', 'Gene', (257, 262))	('c-KIT', 'Gene', '3815', (52, 57))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (104, 135))	('amplification', 'Var', (274, 287))	('patients', 'Species', '9606', (206, 214))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (104, 135))	('c-Kit', 'Gene', '3815', (257, 262))	('KIT', 'molecular_function', 'GO:0005020', ('54', '57'))	('c-KIT', 'Gene', (291, 296))	('KIT', 'molecular_function', 'GO:0005020', ('293', '296'))
130084	22260482	Unlike other types of melanoma, uveal melanomas lack BRAF and NRAS mutations.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('uveal melanomas lack BRAF', 'Disease', 'MESH:C536494', (32, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (32, 46))	('mutations', 'Var', (67, 76))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma', 'Disease', (22, 30))	('uveal melanomas lack BRAF', 'Disease', (32, 57))	('melanoma', 'Disease', (38, 46))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('NRAS', 'Gene', (62, 66))	('uveal melanomas', 'Phenotype', 'HP:0007716', (32, 47))
130085	22260482	The Bastian laboratory identified a novel mutation in a G-protein family of proteins called guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) that is mutated in 83% of blue nevi and in 46% of uveal melanomas.	('blue nevi', 'Disease', (179, 188))	('uveal melanomas', 'Disease', (203, 218))	('uveal melanomas', 'Phenotype', 'HP:0007716', (203, 218))	('nevi', 'Phenotype', 'HP:0003764', (184, 188))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('melanomas', 'Phenotype', 'HP:0002861', (209, 218))	('GNAQ', 'Gene', (147, 151))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('100', '118'))	('blue nevi', 'Phenotype', 'HP:0100814', (179, 188))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('uveal melanoma', 'Phenotype', 'HP:0007716', (203, 217))	('mutated', 'Var', (161, 168))	('GNAQ', 'Gene', '2776', (147, 151))	('uveal melanomas', 'Disease', 'MESH:C536494', (203, 218))
130086	22260482	They discovered the hotspot Q209L mutation in the Ras-like domain of GNAQ that produces a dominant oncogenic phenotype.	('GNAQ', 'Gene', (69, 73))	('GNAQ', 'Gene', '2776', (69, 73))	('Q209L', 'Var', (28, 33))	('Q209L', 'Mutation', 'rs121913492', (28, 33))
130087	22260482	This GNAQ Q209L mutation accelerates anchorage-independent growth and causes melanocytic transformation by inducing MAP kinase activation.	('Q209L', 'Mutation', 'rs121913492', (10, 15))	('MAP kinase', 'MPA', (116, 126))	('GNAQ', 'Gene', (5, 9))	('anchorage-independent growth', 'CPA', (37, 65))	('inducing', 'Reg', (107, 115))	('Q209L', 'Var', (10, 15))	('MAP', 'molecular_function', 'GO:0004239', ('116', '119'))	('causes', 'Reg', (70, 76))	('accelerates', 'PosReg', (25, 36))	('GNAQ', 'Gene', '2776', (5, 9))	('activation', 'PosReg', (127, 137))	('melanocytic', 'Disease', (77, 88))	('melanocytic', 'Disease', 'MESH:D009508', (77, 88))
130089	22260482	The glutamine residue at 209 is essential for conformation switching; mutations at this position cause the a subunit to lock in a constitutively active conformation, which produces oncogenic pro-survival signaling.	('mutations', 'Var', (70, 79))	('constitutively active conformation', 'MPA', (130, 164))	('pro-survival', 'biological_process', 'GO:0043066', ('191', '203'))	('lock', 'Reg', (120, 124))	('glutamine', 'Chemical', 'MESH:D005973', (4, 13))	('cause', 'Reg', (97, 102))	('signaling', 'biological_process', 'GO:0023052', ('204', '213'))
130091	22260482	They found that mutations in GNAQ and GNA11 are mutually exclusive and reported that 55% of blue nevi, 45% of uveal melanomas, and 22% of metastatic cells of uveal melanoma have GNAQ mutations at the glutamine in position 209.	('uveal melanoma', 'Phenotype', 'HP:0007716', (110, 124))	('blue nevi', 'Phenotype', 'HP:0100814', (92, 101))	('GNAQ', 'Gene', '2776', (29, 33))	('uveal melanomas', 'Disease', (110, 125))	('uveal melanomas', 'Phenotype', 'HP:0007716', (110, 125))	('GNAQ', 'Gene', (29, 33))	('glutamine', 'Chemical', 'MESH:D005973', (200, 209))	('mutations', 'Var', (16, 25))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('GNAQ', 'Gene', '2776', (178, 182))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('GNAQ', 'Gene', (178, 182))	('uveal melanoma', 'Disease', 'MESH:C536494', (158, 172))	('uveal melanoma', 'Disease', (158, 172))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('uveal melanomas', 'Disease', 'MESH:C536494', (110, 125))	('nevi', 'Phenotype', 'HP:0003764', (97, 101))	('uveal melanoma', 'Disease', 'MESH:C536494', (110, 124))	('uveal melanoma', 'Phenotype', 'HP:0007716', (158, 172))	('blue nevi', 'Disease', (92, 101))	('mutations at', 'Var', (183, 195))
130092	22260482	In addition, 7% of blue nevi, 32% of primary uveal melanomas, and 57% of metastatic uveal melanoma have GNA11 mutations affecting glutamine 209.	('uveal melanomas', 'Disease', 'MESH:C536494', (45, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('glutamine', 'Chemical', 'MESH:D005973', (130, 139))	('blue nevi', 'Disease', (19, 28))	('metastatic', 'Disease', (73, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('uveal melanoma', 'Disease', 'MESH:C536494', (45, 59))	('uveal melanomas', 'Disease', (45, 60))	('uveal melanomas', 'Phenotype', 'HP:0007716', (45, 60))	('blue nevi', 'Phenotype', 'HP:0100814', (19, 28))	('mutations', 'Var', (110, 119))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('uveal melanoma', 'Disease', (84, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('glutamine 209', 'Var', (130, 143))	('GNA11', 'Gene', (104, 109))	('nevi', 'Phenotype', 'HP:0003764', (24, 28))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
130093	22260482	Xenograft studies in mice with cells bearing GNA11 Q209L mutations produced large tumors that spontaneously metastasized.	('Q209L', 'Mutation', 'rs121913492', (51, 56))	('tumors', 'Disease', (82, 88))	('mice', 'Species', '10090', (21, 25))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('Q209L mutations', 'Var', (51, 66))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('GNA11', 'Gene', (45, 50))
130096	22260482	Candidate gene studies have recently also revealed genetic alterations in microphthalmia-associated transcription factor (MITF), which is involved in pigmentation, differentiation, and growth of melanocytes.	('pigmentation', 'Disease', (150, 162))	('transcription factor', 'molecular_function', 'GO:0000981', ('100', '120'))	('microphthalmia-associated transcription factor', 'Gene', '4286', (74, 120))	('MITF', 'Gene', '4286', (122, 126))	('MITF', 'Gene', (122, 126))	('microphthalmia', 'Phenotype', 'HP:0000568', (74, 88))	('involved', 'Reg', (138, 146))	('pigmentation', 'biological_process', 'GO:0043473', ('150', '162'))	('transcription', 'biological_process', 'GO:0006351', ('100', '113'))	('microphthalmia-associated transcription factor', 'Gene', (74, 120))	('pigmentation', 'Disease', 'MESH:D010859', (150, 162))	('genetic alterations', 'Var', (51, 70))
130097	22260482	identified MITF amplifications that were correlated with patient survival, metastatic events, chemotherapeutic resistance, BRAF mutations, and inactivation of p16.	('p16', 'Gene', '1029', (159, 162))	('inactivation', 'Var', (143, 155))	('patient', 'Species', '9606', (57, 64))	('mutations', 'Var', (128, 137))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('p16', 'Gene', (159, 162))	('MITF', 'Gene', '4286', (11, 15))	('MITF', 'Gene', (11, 15))
130101	22260482	Of the primary melanomas, 2 / 26 had mutations in MITF and 6 / 55 showed mutations in SOX10, a binding partner of MITF.	('MITF', 'Gene', '4286', (50, 54))	('MITF', 'Gene', (50, 54))	('MITF', 'Gene', (114, 118))	('MITF', 'Gene', '4286', (114, 118))	('SOX10', 'Gene', '6663', (86, 91))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('melanomas', 'Disease', 'MESH:D008545', (15, 24))	('mutations', 'Var', (37, 46))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('SOX10', 'Gene', (86, 91))	('melanomas', 'Disease', (15, 24))	('mutations', 'Var', (73, 82))
130102	22260482	While no amplifications of MITF were observed in the primary tumor samples, 4 / 50 metastatic samples had MITF amplifications, suggesting that MITF amplification may be a late-stage change in cancer progression.	('MITF', 'Gene', '4286', (143, 147))	('MITF', 'Gene', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('MITF', 'Gene', '4286', (106, 110))	('MITF', 'Gene', (106, 110))	('amplifications', 'Var', (111, 125))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cancer', 'Disease', (192, 198))	('MITF', 'Gene', (27, 31))	('MITF', 'Gene', '4286', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('amplification', 'Var', (148, 161))
130103	22260482	Moreover, the range of mutations observed in SOX10 was characteristic of a tumor suppressor gene.	('tumor suppressor', 'biological_process', 'GO:0051726', ('75', '91'))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('mutations', 'Var', (23, 32))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('75', '91'))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('SOX10', 'Gene', (45, 50))	('SOX10', 'Gene', '6663', (45, 50))	('tumor', 'Disease', (75, 80))
130104	22260482	Of the metastatic melanoma samples, three frameshift mutations were predicted to result in protein truncations before the DNA-binding domain or at the C-terminus.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('truncations', 'MPA', (99, 110))	('result', 'Reg', (81, 87))	('frameshift mutations', 'Var', (42, 62))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('protein', 'Protein', (91, 98))	('DNA', 'cellular_component', 'GO:0005574', ('122', '125'))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('DNA-binding', 'molecular_function', 'GO:0003677', ('122', '133'))	('melanoma', 'Disease', (18, 26))
130105	22260482	Functional analysis of SOX10 mutations showed reduced activity on target promoters and association with loss of heterozygosity.	('SOX10', 'Gene', '6663', (23, 28))	('SOX10', 'Gene', (23, 28))	('mutations', 'Var', (29, 38))	('reduced', 'NegReg', (46, 53))	('activity', 'MPA', (54, 62))
130106	22260482	As expected, MITF and SOX10 mutations were mutually exclusive, indicative of a disruption in a common genetic pathway.	('SOX10', 'Gene', '6663', (22, 27))	('MITF', 'Gene', '4286', (13, 17))	('MITF', 'Gene', (13, 17))	('SOX10', 'Gene', (22, 27))	('common genetic pathway', 'Pathway', (95, 117))	('disruption', 'Reg', (79, 89))	('mutations', 'Var', (28, 37))
130107	22260482	Functional analysis of the MITF 4TDelta2B mutation, a splice variant mutation that causes loss of exon 2B of MITF, in the presence of wild-type SOX10, showed significantly greater activation of human dopachrome tautomerase (HuDct) and tyrosinase promoter but not of cell cycle arrest marker p21.	('MITF', 'Gene', (109, 113))	('p21', 'Gene', '644914', (291, 294))	('dopachrome tautomerase', 'Gene', (200, 222))	('Dct', 'Gene', (226, 229))	('MITF', 'Gene', '4286', (109, 113))	('greater activation', 'PosReg', (172, 190))	('Dct', 'Gene', '1638', (226, 229))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('266', '283'))	('dopachrome tautomerase', 'Gene', '1638', (200, 222))	('mutation', 'Var', (42, 50))	('SOX10', 'Gene', (144, 149))	('MITF', 'Gene', (27, 31))	('SOX10', 'Gene', '6663', (144, 149))	('MITF', 'Gene', '4286', (27, 31))	('human', 'Species', '9606', (194, 199))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (266, 283))	('p21', 'Gene', (291, 294))	('4TDelta2B mutation', 'Var', (32, 50))
130108	22260482	This suggests that mutated MITF allows cells to escape p21-mediated cell cycle arrest.	('p21', 'Gene', (55, 58))	('p21', 'Gene', '644914', (55, 58))	('mutated', 'Var', (19, 26))	('MITF', 'Gene', '4286', (27, 31))	('MITF', 'Gene', (27, 31))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (68, 85))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('68', '85'))
130110	22260482	Furthermore, mutations resulting in early truncation of SOX10 abolished activity of MITF-mediated HuDct activation, suggesting that SOX10 is indispensable for MITF activity.	('MITF', 'Gene', '4286', (159, 163))	('MITF', 'Gene', (84, 88))	('MITF', 'Gene', (159, 163))	('SOX10', 'Gene', (132, 137))	('SOX10', 'Gene', '6663', (132, 137))	('abolished', 'NegReg', (62, 71))	('MITF', 'Gene', '4286', (84, 88))	('activity', 'MPA', (72, 80))	('Dct', 'Gene', (100, 103))	('Dct', 'Gene', '1638', (100, 103))	('SOX10', 'Gene', '6663', (56, 61))	('mutations', 'Var', (13, 22))	('SOX10', 'Gene', (56, 61))
130111	22260482	Further validation of the mutated MITF functional effects was recently published by who used a zebrafish model to show mutant MITF 4TDelta2B potentiated melanocyte cell division and differentiation compared with wild-type human MITF.	('zebrafish', 'Species', '7955', (95, 104))	('human', 'Species', '9606', (222, 227))	('MITF', 'Gene', '4286', (228, 232))	('MITF', 'Gene', (228, 232))	('MITF', 'Gene', (34, 38))	('MITF', 'Gene', (126, 130))	('MITF', 'Gene', '4286', (126, 130))	('MITF', 'Gene', '4286', (34, 38))	('4TDelta2B', 'Var', (131, 140))	('cell division', 'biological_process', 'GO:0051301', ('164', '177'))	('melanocyte cell division', 'CPA', (153, 177))	('mutant', 'Var', (119, 125))	('potentiated', 'PosReg', (141, 152))
130113	22260482	Two recent Nature articles identified a germline mutation leading to a substitution of glutamic acid 318 with lysine (E318K) in MITF that was associated with both sporadic melanoma and renal cell carcinoma (RCC).	('MITF', 'Gene', '4286', (128, 132))	('E318K', 'Var', (118, 123))	('glutamic', 'Protein', (87, 95))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (185, 205))	('RCC', 'Disease', (207, 210))	('substitution', 'Var', (71, 83))	('associated with', 'Reg', (142, 157))	('melanoma and renal cell carcinoma', 'Disease', 'MESH:C538614', (172, 205))	('E318K', 'Mutation', 'rs149617956', (118, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('glutamic acid 318 with lysine', 'Mutation', 'rs149617956', (87, 116))	('MITF', 'Gene', (128, 132))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))
130114	22260482	The E318K mutation is located in a small-ubiquitin-like modifier (SUMO) consensus site in MITF, which has been found to interrupt sumoylation and increase susceptibility to cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('interrupt', 'NegReg', (120, 129))	('sumoylation', 'MPA', (130, 141))	('E318K', 'Mutation', 'rs149617956', (4, 9))	('sumoylation', 'biological_process', 'GO:0016925', ('130', '141'))	('cancer', 'Disease', (173, 179))	('increase', 'PosReg', (146, 154))	('ubiquitin', 'molecular_function', 'GO:0031386', ('41', '50'))	('E318K', 'Var', (4, 9))	('susceptibility', 'Reg', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('MITF', 'Gene', '4286', (90, 94))	('MITF', 'Gene', (90, 94))
130115	22260482	sequenced MITF in 62 patients with both melanoma and renal cell cancer and observed a higher occurrence of E318K in cases over controls.	('renal cell cancer', 'Phenotype', 'HP:0005584', (53, 70))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma and renal cell cancer', 'Disease', 'MESH:C538614', (40, 70))	('patients', 'Species', '9606', (21, 29))	('MITF', 'Gene', '4286', (10, 14))	('MITF', 'Gene', (10, 14))	('E318K', 'Mutation', 'rs149617956', (107, 112))	('E318K', 'Var', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
130116	22260482	This study found MITF E318K increased the risk of either melanoma or RCC by more than fivefold.	('E318K', 'Mutation', 'rs149617956', (22, 27))	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('E318K', 'Var', (22, 27))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('MITF', 'Gene', '4286', (17, 21))	('MITF', 'Gene', (17, 21))	('melanoma', 'Disease', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
130117	22260482	Chromatin immunoprecipitation analysis of the genome-wide effects of E318K on MITF-occupied loci showed greater promoter occupancy by MITF E318K and an increase in MITF E318K occupancy at the HIF1A promoter.	('E318K', 'Var', (139, 144))	('MITF', 'Gene', '4286', (78, 82))	('increase', 'PosReg', (152, 160))	('MITF', 'Gene', (78, 82))	('HIF1A', 'Gene', (192, 197))	('occupancy', 'MPA', (175, 184))	('greater', 'PosReg', (104, 111))	('HIF1A', 'Gene', '3091', (192, 197))	('MITF', 'Gene', '4286', (134, 138))	('MITF', 'Gene', (134, 138))	('E318K', 'Mutation', 'rs149617956', (69, 74))	('promoter occupancy', 'MPA', (112, 130))	('MITF', 'Gene', '4286', (164, 168))	('MITF', 'Gene', (164, 168))	('Chromatin', 'cellular_component', 'GO:0000785', ('0', '9'))	('E318K', 'Var', (69, 74))	('E318K', 'Mutation', 'rs149617956', (169, 174))	('E318K', 'Mutation', 'rs149617956', (139, 144))
130118	22260482	propose that the E318K mutation induces hypoxia-inducible factor 1alpha (HIF1alpha) transcription, a pathway previously found to be dysregulated in RCC.	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('E318K', 'Mutation', 'rs149617956', (17, 22))	('hypoxia-inducible factor 1alpha', 'Gene', (40, 71))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('HIF1alpha', 'Gene', (73, 82))	('HIF1alpha', 'Gene', '3091', (73, 82))	('transcription', 'MPA', (84, 97))	('E318K', 'Var', (17, 22))	('transcription', 'biological_process', 'GO:0006351', ('84', '97'))	('induces', 'Reg', (32, 39))	('hypoxia-inducible factor 1alpha', 'Gene', '3091', (40, 71))
130119	22260482	The study concludes that MITF E318K expression augmented in vitro migration, invasion, and colony formation of both melanoma and RCC cell lines.	('E318K expression', 'Var', (30, 46))	('colony formation', 'CPA', (91, 107))	('invasion', 'CPA', (77, 85))	('MITF', 'Gene', (25, 29))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('MITF', 'Gene', '4286', (25, 29))	('formation', 'biological_process', 'GO:0009058', ('98', '107'))	('augmented', 'PosReg', (47, 56))	('E318K', 'Mutation', 'rs149617956', (30, 35))
130120	22260482	In a separate study, sequenced the genomes of a number of melanoma families and found a SNP in MITF that led to independent identification of the E318K substitution.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('MITF', 'Gene', '4286', (95, 99))	('MITF', 'Gene', (95, 99))	('E318K', 'Mutation', 'rs149617956', (146, 151))	('E318K', 'Var', (146, 151))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
130121	22260482	Researchers determined E318K had a log of odds (lod) score of 2.7, suggesting E318K represents an intermediate risk variant.	('E318K', 'Var', (23, 28))	('E318K', 'Var', (78, 83))	('lod', 'molecular_function', 'GO:0033736', ('48', '51'))	('E318K', 'Mutation', 'rs149617956', (78, 83))	('E318K', 'Mutation', 'rs149617956', (23, 28))
130122	22260482	The group performed functional analysis to confirm E318K led to impaired sumoylation and dysregulation of specific MITF targets.	('MITF', 'Gene', '4286', (115, 119))	('sumoylation', 'MPA', (73, 84))	('impaired', 'NegReg', (64, 72))	('sumoylation', 'biological_process', 'GO:0016925', ('73', '84'))	('E318K', 'Mutation', 'rs149617956', (51, 56))	('dysregulation', 'MPA', (89, 102))	('E318K', 'Var', (51, 56))	('MITF', 'Gene', (115, 119))
130123	22260482	The Bertolotto and Yokoyama papers used different methods to characterize the E318K mutation and its association with both melanoma and RCC.	('E318K', 'Mutation', 'rs149617956', (78, 83))	('E318K', 'Var', (78, 83))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('association', 'Interaction', (101, 112))	('melanoma', 'Disease', (123, 131))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))
130126	22260482	via EGFR mutation or HER2 / Neu amplification) are well-characterized hallmarks of cancer, inactivation of protein tyrosine phosphatases (PTPs) that regulate tyrosine phosphorylation and growth signaling was expected to produce a similar effect.	('EGFR', 'Gene', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('inactivation', 'Var', (91, 103))	('Neu', 'Gene', (28, 31))	('Neu', 'Gene', '2064', (28, 31))	('tyrosine', 'Chemical', 'MESH:D014443', (158, 166))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('regulate', 'Reg', (149, 157))	('HER2', 'Gene', '2064', (21, 25))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('EGFR', 'Gene', '1956', (4, 8))	('mutation', 'Var', (9, 17))	('signaling', 'biological_process', 'GO:0023052', ('194', '203'))	('tyrosine', 'Chemical', 'MESH:D014443', (115, 123))	('EGFR', 'molecular_function', 'GO:0005006', ('4', '8'))	('tyrosine phosphorylation', 'MPA', (158, 182))	('HER2', 'Gene', (21, 25))	('phosphorylation', 'biological_process', 'GO:0016310', ('167', '182'))	('cancer', 'Disease', (83, 89))
130127	22260482	In a genome-wide loss of heterozygosity and copy number alteration study, found that the PTPRD locus underwent homozygous deletions in 9% of melanoma cell lines, while candidate gene sequencing of PTPRD in malignant melanomas revealed somatic mutations in 12% of melanoma samples.	('malignant melanomas', 'Disease', (206, 225))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('PTPRD', 'Gene', (89, 94))	('melanoma', 'Phenotype', 'HP:0002861', (263, 271))	('melanoma', 'Disease', (263, 271))	('melanoma cell', 'Disease', 'MESH:D008545', (141, 154))	('PTPRD', 'Gene', '5789', (89, 94))	('deletions', 'Var', (122, 131))	('melanoma cell', 'Disease', (141, 154))	('malignant melanomas', 'Phenotype', 'HP:0002861', (206, 225))	('melanoma', 'Disease', 'MESH:D008545', (216, 224))	('PTPRD', 'Gene', (197, 202))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('malignant melanoma', 'Phenotype', 'HP:0002861', (206, 224))	('melanoma', 'Disease', 'MESH:D008545', (263, 271))	('melanomas', 'Phenotype', 'HP:0002861', (216, 225))	('PTPRD', 'Gene', '5789', (197, 202))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('melanoma', 'Disease', (216, 224))	('malignant melanomas', 'Disease', 'MESH:D008545', (206, 225))
130129	22260482	Functional studies have shown that reconstitution of PTPRD inhibited growth and induced apoptosis in cells harboring its deletions or mutations.	('induced', 'Reg', (80, 87))	('apoptosis', 'CPA', (88, 97))	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('growth', 'CPA', (69, 75))	('inhibited', 'NegReg', (59, 68))	('deletions', 'Var', (121, 130))	('mutations', 'Var', (134, 143))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))	('PTPRD', 'Gene', '5789', (53, 58))	('PTPRD', 'Gene', (53, 58))
130130	22260482	However, constitutive expression of somatic mutations alleviated the effect of wild-type PTPRD expression.	('PTPRD', 'Gene', (89, 94))	('alleviated', 'NegReg', (54, 64))	('mutations', 'Var', (44, 53))	('PTPRD', 'Gene', '5789', (89, 94))
130131	22260482	In addition to melanoma, PTPRD has been found to be deleted in a fraction of glioblastomas, adenocarcinomas of the colon and lung, and squamous carcinomas of the head and neck.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('glioblastomas', 'Phenotype', 'HP:0012174', (77, 90))	('neck', 'cellular_component', 'GO:0044326', ('171', '175'))	('squamous carcinomas', 'Disease', 'MESH:D002294', (135, 154))	('PTPRD', 'Gene', (25, 30))	('deleted', 'Var', (52, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('PTPRD', 'Gene', '5789', (25, 30))	('glioblastoma', 'Phenotype', 'HP:0012174', (77, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('glioblastomas', 'Disease', (77, 90))	('adenocarcinomas of the colon', 'Disease', 'MESH:D003110', (92, 120))	('squamous carcinomas', 'Disease', (135, 154))	('adenocarcinomas of the colon', 'Disease', (92, 120))	('glioblastomas', 'Disease', 'MESH:D005909', (77, 90))	('adenocarcinomas of the colon', 'Phenotype', 'HP:0040276', (92, 120))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))
130135	22260482	were the first to identify that AKT3 is deregulated in melanoma by copy number increases.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('deregulated', 'PosReg', (40, 51))	('increases', 'PosReg', (79, 88))	('AKT3', 'Gene', (32, 36))	('AKT3', 'Gene', '10000', (32, 36))	('melanoma', 'Disease', (55, 63))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('copy number', 'Var', (67, 78))
130136	22260482	Furthermore, this group reported that this amplification activates the AKT3 function that promotes cell survival.	('amplification', 'Var', (43, 56))	('activates', 'PosReg', (57, 66))	('AKT3', 'Gene', (71, 75))	('promotes', 'PosReg', (90, 98))	('AKT3', 'Gene', '10000', (71, 75))	('cell survival', 'CPA', (99, 112))
130137	22260482	Later, described a novel point mutation in AKT1, namely an E17K substitution in breast, colon, and ovarian cancer.	('colon', 'Disease', (88, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (99, 113))	('AKT1', 'Gene', (43, 47))	('ovarian cancer', 'Disease', 'MESH:D010051', (99, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('E17K', 'Var', (59, 63))	('breast', 'Disease', (80, 86))	('ovarian cancer', 'Disease', (99, 113))	('E17K', 'Mutation', 'rs121434592', (59, 63))
130138	22260482	Functionally, E17K translocates to the membrane and induces constitutive phosphorylation of AKT1 that is sufficient to produce fibroblast transformation and leukemia in transgenic mice.	('AKT1', 'Gene', (92, 96))	('E17K', 'Mutation', 'rs121434592', (14, 18))	('leukemia', 'Phenotype', 'HP:0001909', (157, 165))	('leukemia', 'Disease', 'MESH:D007938', (157, 165))	('membrane', 'cellular_component', 'GO:0016020', ('39', '47'))	('leukemia', 'Disease', (157, 165))	('E17K', 'Var', (14, 18))	('transgenic mice', 'Species', '10090', (169, 184))	('produce', 'Reg', (119, 126))	('induces', 'Reg', (52, 59))	('phosphorylation', 'biological_process', 'GO:0016310', ('73', '88'))	('constitutive phosphorylation', 'MPA', (60, 88))	('fibroblast transformation', 'CPA', (127, 152))
130139	22260482	investigated the significance of the AKT E17K mutation in 137 melanoma samples and 65 human melanoma cell lines.	('melanoma cell', 'Disease', 'MESH:D008545', (92, 105))	('melanoma', 'Disease', (62, 70))	('E17K', 'Var', (41, 45))	('AKT', 'Gene', '207', (37, 40))	('human', 'Species', '9606', (86, 91))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('AKT', 'Gene', (37, 40))	('melanoma cell', 'Disease', (92, 105))	('E17K', 'Mutation', 'rs121434592', (41, 45))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
130140	22260482	They found only one E17K mutation in AKT1 in all samples.	('AKT1', 'Gene', (37, 41))	('E17K', 'Var', (20, 24))	('E17K', 'Mutation', 'rs121434592', (20, 24))
130141	22260482	Surprisingly, they discovered activating E17K mutation in AKT3 in two melanoma samples obtained from one patient and two commercially available melanoma cell lines, WM46 and D40.	('melanoma', 'Disease', (70, 78))	('patient', 'Species', '9606', (105, 112))	('activating', 'PosReg', (30, 40))	('AKT3', 'Gene', (58, 62))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('melanoma cell', 'Disease', 'MESH:D008545', (144, 157))	('E17K', 'Var', (41, 45))	('AKT3', 'Gene', '10000', (58, 62))	('E17K', 'Mutation', 'rs121434592', (41, 45))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('melanoma cell', 'Disease', (144, 157))	('WM46', 'CellLine', 'CVCL:6803', (165, 169))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
130142	22260482	These findings suggest that the AKT3 E17K mutation may serve as another potential target for melanoma therapy.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('AKT3', 'Gene', (32, 36))	('E17K', 'Mutation', 'rs121434592', (37, 41))	('AKT3', 'Gene', '10000', (32, 36))	('E17K', 'Var', (37, 41))
130143	22260482	The Garraway laboratory identified several tumor samples containing amplifications on chromosome 7p, one of the most common sites of melanoma driver cancer gene mutations.	('amplifications on', 'Var', (68, 85))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('chromosome', 'cellular_component', 'GO:0005694', ('86', '96'))	('melanoma driver cancer', 'Disease', 'MESH:C563985', (133, 155))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('melanoma driver cancer', 'Disease', (133, 155))	('tumor', 'Disease', (43, 48))
130147	22260482	In immortalized melanocytes, ETV1 also increased MITF expression, which was necessary for ETV1-induced oncogenicity.	('expression', 'MPA', (54, 64))	('ETV1', 'Var', (29, 33))	('increased', 'PosReg', (39, 48))	('MITF', 'Gene', '4286', (49, 53))	('MITF', 'Gene', (49, 53))
130148	22260482	This study implicates ETV1 deregulation in melanoma genesis.	('deregulation', 'Var', (27, 39))	('ETV1', 'Gene', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('implicates', 'Reg', (11, 21))	('melanoma genesis', 'Disease', 'MESH:D008545', (43, 59))	('melanoma genesis', 'Disease', (43, 59))
130154	22260482	Melanoma and glioma were found to contain the largest incidences of mutations per megabase pairs of DNA, 18.54 and 22.37, respectively.	('glioma', 'Disease', 'MESH:D005910', (13, 19))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('glioma', 'Phenotype', 'HP:0009733', (13, 19))	('Melanoma', 'Disease', (0, 8))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('mutations', 'Var', (68, 77))	('glioma', 'Disease', (13, 19))
130155	22260482	Furthermore, a unique spectra of mutations were found in melanomas because of C:G>T:A, again implicating the role of UV light as a potential carcinogen.	('melanomas', 'Disease', (57, 66))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanomas', 'Disease', 'MESH:D008545', (57, 66))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('C:G>T:A', 'Var', (78, 85))
130156	22260482	Of the 518 genes encoding protein kinases, the top three most likely to carry at least one driver mutation based on selection pressure estimates were Titin (TTN), BRAF, and ATM.	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('mutation', 'Var', (98, 106))	('TTN', 'Gene', (157, 160))	('Titin', 'Gene', '7273', (150, 155))	('ATM', 'Gene', '472', (173, 176))	('TTN', 'Gene', '7273', (157, 160))	('Titin', 'Gene', (150, 155))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('ATM', 'Gene', (173, 176))
130158	22260482	Whether TTN mutations play a role in oncogenesis has yet to be biologically evaluated.	('mutations', 'Var', (12, 21))	('TTN', 'Gene', '7273', (8, 11))	('TTN', 'Gene', (8, 11))	('oncogenesis', 'biological_process', 'GO:0007048', ('37', '48'))
130164	22260482	An initial genetic screen of the kinase domain-encoding exons revealed somatic mutations in 19 of 86 tyrosine kinases.	('tyrosine', 'Chemical', 'MESH:D014443', (101, 109))	('mutations', 'Var', (79, 88))	('tyrosine kinases', 'Enzyme', (101, 117))
130165	22260482	Subsequent complete gene sequencing of the 19 PTKs showed 19% of the mutations were in ERBB4, 10% in FLT1, and 10% in PTK2B.	('PTK2B', 'Gene', (118, 123))	('mutations', 'Var', (69, 78))	('PTK2B', 'Gene', '2185', (118, 123))	('FLT1', 'Gene', (101, 105))	('ERBB4', 'Gene', (87, 92))	('FLT1', 'Gene', '2321', (101, 105))
130166	22260482	Furthermore, a recent study by identified an ERBB4 mutation in a melanoma patient found to be resistant to BRAF treatment.	('BRAF', 'Gene', (107, 111))	('patient', 'Species', '9606', (74, 81))	('melanoma', 'Disease', (65, 73))	('mutation', 'Var', (51, 59))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('BRAF', 'Gene', '673', (107, 111))	('ERBB4', 'Gene', (45, 50))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
130170	22260482	Moreover, another of the alterations identified in ERBB4 (E872K) has previously been discovered in lung adenocarcinoma forming a 'mini-hotspot'.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (99, 118))	('E872K', 'Mutation', 'rs776347334', (58, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('lung adenocarcinoma', 'Disease', (99, 118))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (99, 118))	('E872K', 'Var', (58, 63))	('ERBB4', 'Gene', (51, 56))
130171	22260482	showed that ERBB4 mutations imparted cells with an increased kinase activity and an ability to transform mouse fibroblast NIH3T3 cells as well as melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('ERBB4', 'Gene', (12, 17))	('kinase activity', 'molecular_function', 'GO:0016301', ('61', '76'))	('transform', 'Reg', (95, 104))	('increased', 'PosReg', (51, 60))	('melanoma cells', 'Disease', (146, 160))	('kinase activity', 'MPA', (61, 76))	('mouse', 'Species', '10090', (105, 110))	('melanoma cells', 'Disease', 'MESH:D008545', (146, 160))	('NIH3T3', 'CellLine', 'CVCL:0594', (122, 128))	('mutations', 'Var', (18, 27))
130172	22260482	Using shRNA, the study showed that ERBB4 knockdown in ERBB4 mutant melanoma cell lines inhibited growth compared with cells bearing wild-type ERBB4.	('melanoma cell', 'Disease', 'MESH:D008545', (67, 80))	('ERBB4', 'Gene', (54, 59))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma cell', 'Disease', (67, 80))	('inhibited', 'NegReg', (87, 96))	('ERBB4', 'Gene', (35, 40))	('mutant', 'Var', (60, 66))	('knockdown', 'Var', (41, 50))	('growth', 'MPA', (97, 103))
130173	22260482	Pharmacological inhibition of ERBB4 by lapatinib, a pan-ERBB kinase inhibitor, preferentially killed more ERBB4 mutant melanoma cell lines than cells expressing wild-type ERBB4.	('ERBB', 'Gene', '1956', (171, 175))	('melanoma cell', 'Disease', 'MESH:D008545', (119, 132))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('61', '77'))	('ERBB', 'Gene', (106, 110))	('ERBB', 'Gene', '1956', (56, 60))	('ERBB', 'Gene', (171, 175))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('lapatinib', 'Chemical', 'MESH:D000077341', (39, 48))	('ERBB', 'Gene', (30, 34))	('mutant', 'Var', (112, 118))	('ERBB', 'Gene', '1956', (106, 110))	('ERBB', 'Gene', (56, 60))	('melanoma cell', 'Disease', (119, 132))	('ERBB', 'Gene', '1956', (30, 34))
130174	22260482	Interestingly, distinct ERBB4 mutant cell lines showed variable sensitivity to lapatinib, suggesting that ERBB4 mutants contribute to drug sensitivity.	('lapatinib', 'Chemical', 'MESH:D000077341', (79, 88))	('drug sensitivity', 'MPA', (134, 150))	('contribute', 'Reg', (120, 130))	('ERBB4', 'Gene', (106, 111))	('ERBB4', 'Gene', (24, 29))	('mutants', 'Var', (112, 119))	('drug sensitivity', 'Phenotype', 'HP:0020174', (134, 150))	('mutant', 'Var', (30, 36))
130176	22260482	Furthermore, recent extension of the mutational data shows significant mutual exclusivity between mutations in ERBB4 and BRAF (P > 0.02 Fisher's exact test).	('mutations', 'Var', (98, 107))	('BRAF', 'Gene', (121, 125))	('BRAF', 'Gene', '673', (121, 125))	('ERBB4', 'Gene', (111, 116))
130180	22260482	Subsequent shRNA-mediated knockdown of AXL, HER3, and IGFR1R resulted in decreased melanoma cell proliferation, and AXL knockdown decreased melanoma cell migration.	('IGFR1R', 'Gene', (54, 60))	('decreased melanoma', 'Disease', (73, 91))	('AXL', 'Gene', '558', (116, 119))	('AXL', 'Gene', (39, 42))	('melanoma cell', 'Disease', 'MESH:D008545', (140, 153))	('melanoma cell', 'Disease', 'MESH:D008545', (83, 96))	('cell migration', 'biological_process', 'GO:0016477', ('149', '163'))	('decreased melanoma', 'Disease', 'MESH:D008545', (73, 91))	('HER3', 'Gene', '2065', (44, 48))	('AXL', 'Gene', (116, 119))	('melanoma cell', 'Disease', (140, 153))	('melanoma cell', 'Disease', (83, 96))	('knockdown', 'Var', (120, 129))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('cell proliferation', 'biological_process', 'GO:0008283', ('92', '110'))	('decreased melanoma', 'Disease', (130, 148))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('AXL', 'Gene', '558', (39, 42))	('HER3', 'Gene', (44, 48))	('decreased melanoma', 'Disease', 'MESH:D008545', (130, 148))
130183	22260482	Since the identification of PTPRD to be mutated in melanoma, researchers have performed genetic investigation of the entire family of PTPs.	('PTPRD', 'Gene', '5789', (28, 33))	('PTPRD', 'Gene', (28, 33))	('mutated', 'Var', (40, 47))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
130185	22260482	Biochemical functional assays suggest that PTPRT is a tumor suppressor, whose genetic inactivation results in survival advantage in tumor cells.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('54', '70'))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('genetic inactivation', 'Var', (78, 98))	('PTPRT', 'Gene', (43, 48))	('PTPRT', 'Gene', '11122', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (132, 137))	('survival advantage', 'CPA', (110, 128))	('tumor', 'Disease', (54, 59))	('tumor suppressor', 'biological_process', 'GO:0051726', ('54', '70'))
130187	22260482	As mentioned earlier, identified PTPRD mutations in 12% of melanomas and glioblastomas.	('glioblastoma', 'Phenotype', 'HP:0012174', (73, 85))	('melanomas', 'Disease', (59, 68))	('mutations', 'Var', (39, 48))	('glioblastomas', 'Phenotype', 'HP:0012174', (73, 86))	('glioblastomas', 'Disease', 'MESH:D005909', (73, 86))	('PTPRD', 'Gene', '5789', (33, 38))	('melanomas', 'Phenotype', 'HP:0002861', (59, 68))	('PTPRD', 'Gene', (33, 38))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanomas', 'Disease', 'MESH:D008545', (59, 68))	('glioblastomas', 'Disease', (73, 86))
130188	22260482	Ectopic expression of PTPRD in glioblastoma and malignant melanoma cell lines bearing deletions or mutations induced growth inhibition, whereas expression of mutant PTPRD alleviated this phenotype.	('PTPRD', 'Gene', (22, 27))	('melanoma cell', 'Disease', (58, 71))	('malignant melanoma', 'Phenotype', 'HP:0002861', (48, 66))	('PTPRD', 'Gene', '5789', (165, 170))	('PTPRD', 'Gene', (165, 170))	('melanoma cell', 'Disease', 'MESH:D008545', (58, 71))	('malignant melanoma', 'Disease', 'MESH:D008545', (48, 66))	('malignant melanoma', 'Disease', (48, 66))	('mutations', 'Var', (99, 108))	('glioblastoma', 'Disease', (31, 43))	('glioblastoma', 'Disease', 'MESH:D005909', (31, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (31, 43))	('deletions', 'Var', (86, 95))	('growth', 'MPA', (117, 123))	('mutant', 'Var', (158, 164))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('Ectopic expression', 'MPA', (0, 18))	('PTPRD', 'Gene', '5789', (22, 27))
130197	22260482	They are constitutively expressed until activated by enzymes cleaving prodomains or releasing cysteine bonds.	('cleaving', 'Var', (61, 69))	('releasing cysteine bonds', 'MPA', (84, 108))	('prodomains', 'Protein', (70, 80))	('cysteine', 'Chemical', 'MESH:D003545', (94, 102))
130199	22260482	MMP8-deficient mice showed a significantly elevated incidence of skin tumors and metastasis, suggesting that MMP8 hinders tumorigenesis and suppresses metastasis.	('hinders', 'NegReg', (114, 121))	('metastasis', 'CPA', (151, 161))	('skin tumors', 'Disease', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('skin tumors', 'Phenotype', 'HP:0008069', (65, 76))	('tumor', 'Disease', (70, 75))	('suppresses', 'NegReg', (140, 150))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('MMP8', 'Var', (109, 113))	('skin tumors', 'Disease', 'MESH:D012878', (65, 76))	('MMP8', 'molecular_function', 'GO:0008130', ('109', '113'))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('MMP8', 'molecular_function', 'GO:0008130', ('0', '4'))	('mice', 'Species', '10090', (15, 19))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
130200	22260482	Unfortunately, small-molecule inhibitors of MMPs developed as promising anticancer agents showed no significant benefit in human clinical trials.	('small-molecule', 'Var', (15, 29))	('MMPs', 'Gene', (44, 48))	('human', 'Species', '9606', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('MMPs', 'Gene', '4317;17394;79148;79148;79148', (44, 48))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
130201	22260482	Instead, MMP inhibitors accelerated tumor growth in some cases.	('inhibitors', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('accelerated', 'PosReg', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('MMP', 'Gene', (9, 12))	('MMP', 'molecular_function', 'GO:0004235', ('9', '12'))	('tumor', 'Disease', (36, 41))
130203	22260482	Most of these mutations were accompanied by loss of heterozygosity suggesting that MMP-8 acts as a tumor suppressor gene.	('tumor', 'Disease', (99, 104))	('MMP-8', 'Gene', (83, 88))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('99', '115'))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('MMP-8', 'molecular_function', 'GO:0008130', ('83', '88'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mutations', 'Var', (14, 23))	('tumor suppressor', 'biological_process', 'GO:0051726', ('99', '115'))
130204	22260482	Functional studies showed that in contrast to wild-type MMP-8, mutant MMP-8 possesses lower MMP enzymatic activity, promotes cell growth in soft agar, and forms tumor ulceration in xenograft mouse models.	('MMP-8', 'molecular_function', 'GO:0008130', ('56', '61'))	('mutant', 'Var', (63, 69))	('promotes', 'PosReg', (116, 124))	('MMP-8', 'molecular_function', 'GO:0008130', ('70', '75'))	('lower', 'NegReg', (86, 91))	('MMP enzymatic activity', 'MPA', (92, 114))	('cell growth in', 'CPA', (125, 139))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('mouse', 'Species', '10090', (191, 196))	('cell growth', 'biological_process', 'GO:0016049', ('125', '136'))	('MMP', 'molecular_function', 'GO:0004235', ('92', '95'))	('tumor', 'Disease', (161, 166))	('forms', 'Reg', (155, 160))	('MMP-8', 'Gene', (70, 75))
130206	22260482	Interestingly, a recent study testing the association of MMP-8 variation and increased risk of melanoma showed that particular MMP-8 polymorphisms are indeed associated with the risk of developing melanoma.	('polymorphisms', 'Var', (133, 146))	('MMP-8', 'molecular_function', 'GO:0008130', ('57', '62'))	('associated with', 'Reg', (158, 173))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Disease', (197, 205))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('variation', 'Var', (63, 72))	('MMP-8', 'Gene', (127, 132))	('MMP-8', 'molecular_function', 'GO:0008130', ('127', '132'))
130210	22260482	Functionally, ADAM29 mutations promote melanoma cell adhesion to collagen I, II, and IV, whereas mutations in ADAM7 reduce melanoma cell adhesion to collagen IV and laminin and increase cell migration compared with cells expressing wild-type ADAM7.	('melanoma cell', 'Disease', 'MESH:D008545', (39, 52))	('mutations', 'Var', (97, 106))	('ADAM29', 'Gene', '11086', (14, 20))	('cell migration', 'CPA', (186, 200))	('melanoma cell', 'Disease', (39, 52))	('cell migration', 'biological_process', 'GO:0016477', ('186', '200'))	('collagen', 'molecular_function', 'GO:0005202', ('149', '157'))	('reduce', 'NegReg', (116, 122))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('cell adhesion', 'biological_process', 'GO:0007155', ('48', '61'))	('promote', 'PosReg', (31, 38))	('ADAM7', 'Gene', '8756', (110, 115))	('cell adhesion', 'biological_process', 'GO:0007155', ('132', '145'))	('melanoma cell', 'Disease', 'MESH:D008545', (123, 136))	('collagen', 'molecular_function', 'GO:0005202', ('65', '73'))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('ADAM7', 'Gene', (110, 115))	('mutations', 'Var', (21, 30))	('melanoma cell', 'Disease', (123, 136))	('ADAM7', 'Gene', '8756', (242, 247))	('ADAM29', 'Gene', (14, 20))	('increase', 'PosReg', (177, 185))	('ADAM7', 'Gene', (242, 247))
130212	22260482	This indicates that mutated ADAM genes regulate migration and adhesion of melanoma cells to different extracellular matrix proteins.	('migration', 'CPA', (48, 57))	('regulate', 'Reg', (39, 47))	('adhesion', 'CPA', (62, 70))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('102', '122'))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma cells', 'Disease', 'MESH:D008545', (74, 88))	('melanoma cells', 'Disease', (74, 88))	('ADAM genes', 'Gene', (28, 38))	('mutated', 'Var', (20, 27))
130213	22260482	Future studies are needed to explore whether ADAM7 mutations promote intravasation and ADAM29 mutations promote extravasation during melanoma metastasis.	('extravasation', 'MPA', (112, 125))	('melanoma metastasis', 'Disease', 'MESH:D009362', (133, 152))	('mutations', 'Var', (51, 60))	('mutations', 'Var', (94, 103))	('ADAM29', 'Gene', '11086', (87, 93))	('promote', 'PosReg', (61, 68))	('ADAM29', 'Gene', (87, 93))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('intravasation', 'MPA', (69, 82))	('ADAM7', 'Gene', (45, 50))	('promote', 'Reg', (104, 111))	('melanoma metastasis', 'Disease', (133, 152))	('ADAM7', 'Gene', '8756', (45, 50))
130218	22260482	In melanoma xenograft models, mutated ADAMTS18 promotes growth, cell migration, and metastasis.	('ADAMTS18', 'Gene', '170692', (38, 46))	('growth', 'CPA', (56, 62))	('promotes', 'PosReg', (47, 55))	('metastasis', 'CPA', (84, 94))	('mutated', 'Var', (30, 37))	('cell migration', 'biological_process', 'GO:0016477', ('64', '78'))	('ADAMTS18', 'Gene', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('cell migration', 'CPA', (64, 78))
130221	22260482	Thus, future identification of specific substrates of ADAMTS18 will provide useful information about its mechanism of action and how its mutations modulate melanoma cell phenotypes.	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('ADAMTS18', 'Gene', (54, 62))	('melanoma cell', 'Disease', (156, 169))	('mutations', 'Var', (137, 146))	('modulate', 'Reg', (147, 155))	('melanoma cell', 'Disease', 'MESH:D008545', (156, 169))	('ADAMTS18', 'Gene', '170692', (54, 62))
130226	22260482	Filtering through approximately 4000 candidate somatic mutations, found seven novel recurrent non-synonymous mutations, in addition to the known BRAF recurrent mutation.	('BRAF', 'Gene', '673', (145, 149))	('BRAF', 'Gene', (145, 149))	('non-synonymous mutations', 'Var', (94, 118))
130227	22260482	Scale-up studies of these candidates in a prevalence panel of 153 melanoma samples revealed that the majority of the recurrent mutations only scaled up to a total of 1-4% of cases.	('mutations', 'Var', (127, 136))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))
130228	22260482	The recurrent alteration that scaled up the most was the S722F substitution in TRRAP that occurred in six different melanoma samples.	('S722F', 'Var', (57, 62))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('TRRAP', 'Gene', (79, 84))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('S722F', 'Mutation', 'rs147405090', (57, 62))
130230	22260482	Recurrent mutations of a single amino acid suggested that TRRAP acts as a melanoma oncogene, which was further validated by functional data described below.	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('TRRAP', 'Gene', (58, 63))	('mutations', 'Var', (10, 19))
130234	22260482	Although some functional work on the identified hotspot mutation has shown TRRAP mutations to be transforming in NIH3T3 fibroblast cells and to be involved in apoptosis, further understanding of its effect of on melanoma biology has yet to be determined.	('NIH3T3', 'CellLine', 'CVCL:0594', (113, 119))	('apoptosis', 'biological_process', 'GO:0097194', ('159', '168'))	('involved', 'Reg', (147, 155))	('TRRAP', 'Gene', (75, 80))	('apoptosis', 'biological_process', 'GO:0006915', ('159', '168'))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Disease', (212, 220))	('mutations', 'Var', (81, 90))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))	('apoptosis', 'CPA', (159, 168))
130235	22260482	Importantly, the identification of TRRAP recurrent mutations adds melanoma to the growing list of cancers driven by mutations in proteins with histone modifying activity.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('mutations', 'Var', (51, 60))	('melanoma', 'Disease', (66, 74))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('mutations', 'Var', (116, 125))	('cancers', 'Disease', (98, 105))	('TRRAP', 'Gene', (35, 40))	('proteins', 'Protein', (129, 137))
130236	22260482	Sixteen candidate driver genes that harbored a higher number of somatic mutations beyond what would be expected by chance were identified and re-sequenced in 38 untreated melanoma samples.	('mutations', 'Var', (72, 81))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', (171, 179))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))
130237	22260482	Most significantly, GRIN2A, which encodes a subunit of the ionotropic glutamate receptor, was found mutated in the largest fraction of melanoma cases.	('mutated', 'Var', (100, 107))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('glutamate', 'Chemical', 'MESH:D018698', (70, 79))	('GRIN2A', 'Gene', (20, 26))	('GRIN2A', 'Gene', '2903', (20, 26))
130238	22260482	A screen of 135 total melanomas using different cohorts of validation samples revealed 34 distinct mutations and indicated that GRIN2A is mutated in 25.2% of melanomas (33, 28.2, and 15.6% in three respective melanoma cohorts).	('GRIN2A', 'Gene', (128, 134))	('melanomas', 'Disease', (22, 31))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanomas', 'Phenotype', 'HP:0002861', (158, 167))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('melanoma', 'Disease', (158, 166))	('mutated', 'Var', (138, 145))	('GRIN2A', 'Gene', '2903', (128, 134))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma', 'Disease', (22, 30))	('melanomas', 'Disease', 'MESH:D008545', (158, 167))	('melanomas', 'Disease', (158, 167))	('melanomas', 'Disease', 'MESH:D008545', (22, 31))	('mutations', 'Var', (99, 108))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanoma', 'Disease', (209, 217))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))
130240	22260482	Importantly, GRIN2A mutations were identified at a similar frequency of 17% (14 somatic mutations in 80 melanoma samples) by Halaban et al.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('GRIN2A', 'Gene', (13, 19))	('GRIN2A', 'Gene', '2903', (13, 19))	('mutations', 'Var', (20, 29))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
130242	22260482	Further investigation on exactly how GRIN2A mutations affect melanoma biology is under investigation.	('GRIN2A', 'Gene', (37, 43))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('GRIN2A', 'Gene', '2903', (37, 43))	('mutations', 'Var', (44, 53))	('affect', 'Reg', (54, 60))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))
130254	22260482	linked GRM5 to melanoma via finding that the majority of the founders of GRM5 transgenic lines had severe, early-onset phenotypes of melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('transgenic', 'Species', '10090', (78, 88))	('GRM5', 'Gene', (73, 77))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('transgenic', 'Var', (78, 88))
130258	22260482	Finally, GRM3, which encodes another glutamate receptor, mGluR3, was recently identified through exomic sequencing to be mutated in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('mGluR3', 'Gene', (57, 63))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('mutated', 'Var', (121, 128))	('mGluR3', 'Gene', '53623', (57, 63))	('GRM3', 'Gene', '2913', (9, 13))	('GRM3', 'Gene', (9, 13))	('glutamate', 'Chemical', 'MESH:D018698', (37, 46))
130259	22260482	found that GRM3 was mutated in 16% of melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanomas', 'Disease', (38, 47))	('GRM3', 'Gene', '2913', (11, 15))	('GRM3', 'Gene', (11, 15))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('melanomas', 'Disease', 'MESH:D008545', (38, 47))	('mutated', 'Var', (20, 27))
130260	22260482	GRM3 mutations include 18 non-synonymous mutations and two hotspot mutations M547K (identified in two samples) and E870K (identified in four samples derived from two independent melanoma cohorts).	('GRM3', 'Gene', '2913', (0, 4))	('GRM3', 'Gene', (0, 4))	('M547K', 'Mutation', 'p.M547K', (77, 82))	('E870K', 'Var', (115, 120))	('M547K', 'Var', (77, 82))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('E870K', 'Mutation', 'p.E870K', (115, 120))
130261	22260482	Functional studies reveal that GRM3 alterations regulate MEK phosphorylation, thereby increasing anchorage-independent growth and migration.	('phosphorylation', 'MPA', (61, 76))	('regulate', 'Reg', (48, 56))	('MEK', 'Gene', '5609', (57, 60))	('GRM3', 'Gene', '2913', (31, 35))	('alterations', 'Var', (36, 47))	('GRM3', 'Gene', (31, 35))	('increasing', 'PosReg', (86, 96))	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))	('anchorage-independent growth', 'CPA', (97, 125))	('MEK', 'Gene', (57, 60))
130262	22260482	Moreover, shRNA-mediated knockdown of mutant GRM3 or treatment of cells with MEK inhibitor AZD-6244 significantly reduced melanoma cell growth, migration, and growth in vivo.	('mutant', 'Var', (38, 44))	('cell growth', 'biological_process', 'GO:0016049', ('131', '142'))	('GRM3', 'Gene', '2913', (45, 49))	('GRM3', 'Gene', (45, 49))	('melanoma cell', 'Disease', 'MESH:D008545', (122, 135))	('reduced', 'NegReg', (114, 121))	('growth in vivo', 'CPA', (159, 173))	('AZD-6244', 'Chemical', 'MESH:C517975', (91, 99))	('melanoma cell', 'Disease', (122, 135))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('MEK', 'Gene', (77, 80))	('MEK', 'Gene', '5609', (77, 80))	('migration', 'CPA', (144, 153))
130264	22260482	In addition to GRM1, 3 and 5 a GRM-signaling downstream effector called phospholipase C, beta 4 (PLCB4) was also shown to be mutated through whole-exome sequencing.	('PLCB4', 'Gene', (97, 102))	('phospholipase C, beta 4', 'Gene', '5332', (72, 95))	('mutated', 'Var', (125, 132))	('signaling', 'biological_process', 'GO:0023052', ('35', '44'))	('PLCB4', 'Gene', '5332', (97, 102))
130274	22260482	An additional whole-exome sequencing study by the Bowcock laboratory showed BRCA1-associated protein 1 (BAP1), which encodes a ubiquitin carboxy-terminal hydrolase, harbors inactivating somatic mutations in 84% (26 of 31) of metastasizing uveal melanoma.	('BAP1', 'Gene', '8314', (104, 108))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('127', '136'))	('BRCA1-associated protein 1', 'Gene', '8314', (76, 102))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('inactivating somatic mutations', 'Var', (173, 203))	('BAP1', 'Gene', (104, 108))	('BRCA1-associated protein 1', 'Gene', (76, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (239, 253))	('uveal melanoma', 'Disease', (239, 253))	('uveal melanoma', 'Disease', 'MESH:C536494', (239, 253))
130275	22260482	The authors concluded that loss of BAP1 might increase susceptibility to uveal melanoma metastasis and serve as a valuable therapeutic target.	('loss', 'Var', (27, 31))	('uveal melanoma metastasis', 'Disease', 'MESH:C536494', (73, 98))	('uveal melanoma', 'Phenotype', 'HP:0007716', (73, 87))	('BAP1', 'Gene', '8314', (35, 39))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('BAP1', 'Gene', (35, 39))	('uveal melanoma metastasis', 'Disease', (73, 98))
130276	22260482	In an independent study, the Bastian laboratory showed germline SNPs observed in BAP1 conferred a predisposition to melanocytic neoplasms.	('BAP1', 'Gene', '8314', (81, 85))	('neoplasms', 'Phenotype', 'HP:0002664', (128, 137))	('germline SNPs', 'Var', (55, 68))	('BAP1', 'Gene', (81, 85))	('neoplasm', 'Phenotype', 'HP:0002664', (128, 136))	('melanocytic neoplasms', 'Disease', (116, 137))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (116, 137))	('predisposition', 'Reg', (98, 112))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (116, 137))
130278	22260482	Several individuals in the families developed uveal or cutaneous melanomas and were found to have inactivating germline mutations of BAP1.	('developed', 'Reg', (36, 45))	('uveal', 'Disease', (46, 51))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (55, 74))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (55, 74))	('inactivating', 'Var', (98, 110))	('BAP1', 'Gene', '8314', (133, 137))	('cutaneous melanomas', 'Disease', (55, 74))	('uveal or cutaneous melanomas', 'Phenotype', 'HP:0007716', (46, 74))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanomas', 'Phenotype', 'HP:0002861', (65, 74))	('BAP1', 'Gene', (133, 137))	('uveal', 'Disease', 'MESH:D014603', (46, 51))
130279	22260482	Inactivating somatic mutations of the remaining wildtype BAP1 allele in these patients led to the development of melanocytic neoplasms.	('melanocytic neoplasms', 'Disease', (113, 134))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (113, 134))	('led to', 'Reg', (87, 93))	('patients', 'Species', '9606', (78, 86))	('BAP1', 'Gene', '8314', (57, 61))	('neoplasm', 'Phenotype', 'HP:0002664', (125, 133))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (113, 134))	('BAP1', 'Gene', (57, 61))	('neoplasms', 'Phenotype', 'HP:0002664', (125, 134))	('Inactivating somatic mutations', 'Var', (0, 30))
130280	22260482	In addition, the authors detected BAP1 mutations in a fraction of sporadic melanocytic tumors with similar histology as the familial tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('melanocytic tumors', 'Disease', (75, 93))	('familial tumors', 'Disease', 'MESH:D009386', (124, 139))	('BAP1', 'Gene', '8314', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('familial tumors', 'Disease', (124, 139))	('BAP1', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('mutations', 'Var', (39, 48))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('melanocytic tumors', 'Disease', 'MESH:D009508', (75, 93))	('detected', 'Reg', (25, 33))
130281	22260482	Taken together, these findings suggest loss of BAP1 is associated with a distinct type of melanocytic neoplasm in both clinical and morphologic presentation.	('associated', 'Reg', (55, 65))	('melanocytic neoplasm', 'Disease', 'MESH:D009508', (90, 110))	('melanocytic neoplasm', 'Disease', (90, 110))	('BAP1', 'Gene', '8314', (47, 51))	('loss', 'Var', (39, 43))	('neoplasm', 'Phenotype', 'HP:0002664', (102, 110))	('BAP1', 'Gene', (47, 51))
130282	22260482	Two recent papers also used exome sequencing to examine variations in melanoma exonic sequences, with specific focus on the MAPK family.	('melanoma', 'Disease', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('variations', 'Var', (56, 66))	('MAPK', 'molecular_function', 'GO:0004707', ('124', '128'))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
130284	22260482	Interesting, two melanoma samples with BRAF mutations contained gain-offunction MAP2K1 (MEK1) and MAP2K2 (MEK2) mutations, which led to constitutive ERK phosphorylation and encoded proteins with greater resistance to BRAF or MEK inhibitors.	('MEK1', 'Gene', (88, 92))	('MAP2K1', 'Gene', (80, 86))	('mutations', 'Var', (112, 121))	('MAP2K', 'molecular_function', 'GO:0004708', ('98', '103'))	('MEK1', 'molecular_function', 'GO:0004708', ('88', '92'))	('BRAF', 'Gene', '673', (39, 43))	('ERK', 'molecular_function', 'GO:0004707', ('149', '152'))	('BRAF', 'Gene', (39, 43))	('MAP2K2', 'Gene', '5605', (98, 104))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('MEK', 'Gene', '5609', (225, 228))	('MEK1', 'Gene', '5604', (88, 92))	('MAP2K', 'molecular_function', 'GO:0004708', ('80', '85'))	('gain-offunction', 'PosReg', (64, 79))	('MEK', 'Gene', '5609', (106, 109))	('MEK', 'Gene', (225, 228))	('phosphorylation', 'biological_process', 'GO:0016310', ('153', '168'))	('MEK2', 'molecular_function', 'GO:0004708', ('106', '110'))	('MEK', 'Gene', '5609', (88, 91))	('ERK', 'Gene', (149, 152))	('MEK2', 'Gene', (106, 110))	('MEK2', 'Gene', '5605', (106, 110))	('MEK', 'Gene', (106, 109))	('encoded', 'Reg', (173, 180))	('BRAF', 'Gene', '673', (217, 221))	('MAP2K1', 'Gene', '5604', (80, 86))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('melanoma', 'Disease', (17, 25))	('mutations', 'Var', (44, 53))	('phosphorylation', 'MPA', (153, 168))	('BRAF', 'Gene', (217, 221))	('MEK', 'Gene', (88, 91))	('ERK', 'Gene', '2048', (149, 152))	('MAP2K2', 'Gene', (98, 104))	('proteins', 'Protein', (181, 189))
130285	22260482	The authors analyzed a larger group of melanoma patients and found 8% harbored somatic MAP2K1 and MAP2K2 mutations.	('MAP2K1', 'Gene', '5604', (87, 93))	('MAP2K', 'molecular_function', 'GO:0004708', ('87', '92'))	('MAP2K1', 'Gene', (87, 93))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('harbored', 'Reg', (70, 78))	('mutations', 'Var', (105, 114))	('MAP2K2', 'Gene', '5605', (98, 104))	('MAP2K', 'molecular_function', 'GO:0004708', ('98', '103'))	('patients', 'Species', '9606', (48, 56))	('MAP2K2', 'Gene', (98, 104))
130286	22260482	In a separate study, sequenced eight melanoma exomes to detect novel somatic mutations and concentrated on the MAP3K family.	('MAP3K', 'Gene', '4217;4293', (111, 116))	('MAP3K', 'Gene', (111, 116))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('MAP3K', 'molecular_function', 'GO:0004709', ('111', '116'))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('mutations', 'Var', (77, 86))
130287	22260482	Overall, 24% of melanoma cell lines contained mutations in the protein-coding regions of either MAP3K5 or MAP3K9.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('MAP3K', 'molecular_function', 'GO:0004709', ('96', '101'))	('MAP3K9', 'Gene', '4293', (106, 112))	('mutations', 'Var', (46, 55))	('MAP3K', 'molecular_function', 'GO:0004709', ('106', '111'))	('MAP3K9', 'Gene', (106, 112))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('MAP3K5', 'Gene', '4217', (96, 102))	('melanoma cell', 'Disease', (16, 29))	('melanoma cell', 'Disease', 'MESH:D008545', (16, 29))	('MAP3K5', 'Gene', (96, 102))
130288	22260482	The MAPK mutations are likely inactivating given their location and resultant loss of heterozygosity in 85% of the MAP3K5 and 67% of the MAP3K9 melanoma samples.	('MAP3K', 'molecular_function', 'GO:0004709', ('137', '142'))	('MAP3K5', 'Gene', (115, 121))	('MAP3K9', 'Gene', '4293', (137, 143))	('mutations', 'Var', (9, 18))	('MAPK', 'Gene', (4, 8))	('heterozygosity', 'MPA', (86, 100))	('MAP3K9', 'Gene', (137, 143))	('MAP3K5', 'Gene', '4217', (115, 121))	('loss', 'NegReg', (78, 82))	('MAP3K', 'molecular_function', 'GO:0004709', ('115', '120'))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('MAPK', 'molecular_function', 'GO:0004707', ('4', '8'))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))
130289	22260482	The authors also used in vitro kinase assays to show MAP3K5 I780F and MAP3K9 W333 variants had decreased kinase activity.	('decreased', 'NegReg', (95, 104))	('MAP3K', 'molecular_function', 'GO:0004709', ('70', '75'))	('W333', 'Var', (77, 81))	('kinase activity', 'molecular_function', 'GO:0016301', ('105', '120'))	('MAP3K5', 'Gene', (53, 59))	('MAP3K9', 'Gene', '4293', (70, 76))	('kinase activity', 'MPA', (105, 120))	('MAP3K5', 'Gene', '4217', (53, 59))	('MAP3K', 'molecular_function', 'GO:0004709', ('53', '58'))	('MAP3K9', 'Gene', (70, 76))	('I780F', 'Mutation', 'rs868231630', (60, 65))	('I780F', 'Var', (60, 65))
130290	22260482	Moreover, when MAP3K5 or MAP3K9 mutations were overexpressed in HEK293T cells, the phosphorylation of downstream MAP kinases was reduced.	('MAP3K', 'molecular_function', 'GO:0004709', ('15', '20'))	('MAP3K5', 'Gene', '4217', (15, 21))	('MAP3K9', 'Gene', '4293', (25, 31))	('MAP3K5', 'Gene', (15, 21))	('phosphorylation', 'MPA', (83, 98))	('HEK293T', 'CellLine', 'CVCL:0063', (64, 71))	('phosphorylation', 'biological_process', 'GO:0016310', ('83', '98'))	('MAP3K', 'molecular_function', 'GO:0004709', ('25', '30'))	('mutations', 'Var', (32, 41))	('MAP', 'Enzyme', (113, 116))	('MAP', 'molecular_function', 'GO:0004239', ('113', '116'))	('MAP3K9', 'Gene', (25, 31))	('reduced', 'NegReg', (129, 136))	('overexpressed', 'PosReg', (47, 60))
130292	22260482	used whole-exome sequencing to evaluate the possible role of MAPK mutations in melanoma genesis and chemoresistance.	('mutations', 'Var', (66, 75))	('MAPK', 'Gene', (61, 65))	('MAPK', 'molecular_function', 'GO:0004707', ('61', '65'))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma genesis', 'Disease', 'MESH:D008545', (79, 95))	('melanoma genesis', 'Disease', (79, 95))
130305	22260482	In the future, the mechanistic understanding of identified melanoma mutations will be enhanced using some of the approaches described in this review.	('mutations', 'Var', (68, 77))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
130310	22260482	In the future, it will be important to develop inducible cell lines and animal models with driver mutants to test whether the genotype indeed drives the melanoma phenotype and to determine the efficacy of small molecular inhibitors.	('drives', 'Reg', (142, 148))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', (153, 161))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('mutants', 'Var', (98, 105))
130312	33826614	Identifying treatment options for BRAFV600 wild-type metastatic melanoma: A SU2C/MRA genomics-enabled clinical trial Although combination BRAF and MEK inhibitors are highly effective for the 40-50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas.	('melanomas', 'Disease', 'MESH:D008545', (338, 347))	('RAF', 'Gene', (35, 38))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('melanomas', 'Phenotype', 'HP:0002861', (222, 231))	('RAF', 'Gene', (139, 142))	('melanomas', 'Disease', (338, 347))	('MEK', 'Gene', '5609', (147, 150))	('cutaneous metastatic melanomas', 'Phenotype', 'HP:0012056', (201, 231))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('melanoma', 'Disease', (222, 230))	('melanoma', 'Phenotype', 'HP:0002861', (338, 346))	('melanoma', 'Disease', (338, 346))	('cutaneous', 'Disease', (201, 210))	('MEK', 'Gene', (147, 150))	('melanomas', 'Phenotype', 'HP:0002861', (338, 347))	('melanomas', 'Disease', 'MESH:D008545', (222, 231))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('RAF', 'Gene', '22882', (305, 308))	('RAF', 'Gene', '22882', (243, 246))	('mutations', 'Var', (251, 260))	('melanomas', 'Disease', (222, 231))	('RAF', 'Gene', '22882', (35, 38))	('RAF', 'Gene', '22882', (139, 142))	('RAF', 'Gene', (305, 308))	('melanoma', 'Disease', 'MESH:D008545', (222, 230))	('RAF', 'Gene', (243, 246))	('melanoma', 'Disease', 'MESH:D008545', (338, 346))
130322	33826614	In addition to BRAF, activating NRAS mutations in cutaneous melanomas (CMs) occur at a rate of 15 to 25%, and ten to 15% of melanomas have alterations leading to loss of function of NF1.	('melanomas', 'Disease', 'MESH:D008545', (124, 133))	('RAF', 'Gene', '22882', (16, 19))	('NF1', 'Gene', (182, 185))	('loss of function', 'NegReg', (162, 178))	('melanomas', 'Disease', 'MESH:D008545', (60, 69))	('melanomas', 'Disease', (124, 133))	('cutaneous melanomas', 'Disease', (50, 69))	('NRAS', 'Gene', (32, 36))	('melanomas', 'Disease', (60, 69))	('alterations', 'Var', (139, 150))	('RAF', 'Gene', (16, 19))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanomas', 'Phenotype', 'HP:0002861', (124, 133))	('activating', 'PosReg', (21, 31))	('CMs', 'Phenotype', 'HP:0012056', (71, 74))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('mutations', 'Var', (37, 46))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('NRAS', 'Gene', '4893', (32, 36))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (50, 69))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (50, 69))	('NF1', 'Gene', '4763', (182, 185))
130341	33826614	Variant calling and drug rule matching were performed for each patient to generate a personalized molecular report, which was then reviewed by both a molecular and clinical tumor board.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('patient', 'Species', '9606', (63, 70))	('Variant', 'Var', (0, 7))
130346	33826614	However, the trial was amended after consent of patient number 43 to allow all patients with NRAS mutations to be treated with binimetinib (MEK162) based on MTB recommendations and preliminary reported data from other clinical trials (Fig 1B).	('MEK', 'Gene', (140, 143))	('MEK', 'Gene', '5609', (140, 143))	('NRAS', 'Gene', '4893', (93, 97))	('mutations', 'Var', (98, 107))	('binimetinib', 'Chemical', 'MESH:C581313', (127, 138))	('patient', 'Species', '9606', (48, 55))	('patient', 'Species', '9606', (79, 86))	('patients', 'Species', '9606', (79, 87))	('MTB', 'cellular_component', 'GO:0015627', ('157', '160'))	('NRAS', 'Gene', (93, 97))
130366	33826614	Of the 12 patients treated with binimetinib, only four were NRAS-mutant, while the remaining patients harbored other alterations including concomitant loss of NF1, IGF1R, and TP53 with CCND1 amplification (one patient), HRAS point mutation (one patient), concomitant NF1 and BRAF (non-V600) point mutations (one patient), CCND1 and CDK6 amplification (one patient), GNA11 point mutation (three patients), and GNAQ point mutation (one patient).	('CCND1', 'Gene', '595', (185, 190))	('patient', 'Species', '9606', (312, 319))	('HRAS', 'Gene', (220, 224))	('binimetinib', 'Chemical', 'MESH:C581313', (32, 43))	('CDK', 'molecular_function', 'GO:0004693', ('332', '335'))	('patient', 'Species', '9606', (10, 17))	('CCND1', 'Gene', (185, 190))	('TP53', 'Gene', '7157', (175, 179))	('patients', 'Species', '9606', (93, 101))	('GNAQ', 'Gene', '2776', (409, 413))	('GNAQ', 'Gene', (409, 413))	('CDK6', 'Gene', '1021', (332, 336))	('GNA11', 'Gene', '2767', (366, 371))	('RAF', 'Gene', '22882', (276, 279))	('NF1', 'Gene', '4763', (267, 270))	('point mutation', 'Var', (372, 386))	('NRAS', 'Gene', '4893', (60, 64))	('patients', 'Species', '9606', (394, 402))	('patient', 'Species', '9606', (245, 252))	('patient', 'Species', '9606', (394, 401))	('NF1', 'Gene', (267, 270))	('CDK6', 'Gene', (332, 336))	('patient', 'Species', '9606', (356, 363))	('RAF', 'Gene', (276, 279))	('patient', 'Species', '9606', (93, 100))	('CCND1', 'Gene', '595', (322, 327))	('patients', 'Species', '9606', (10, 18))	('IGF1R', 'Gene', '3480', (164, 169))	('loss', 'NegReg', (151, 155))	('patient', 'Species', '9606', (434, 441))	('NF1', 'Gene', '4763', (159, 162))	('TP53', 'Gene', (175, 179))	('CCND1', 'Gene', (322, 327))	('NRAS', 'Gene', (60, 64))	('GNA11', 'Gene', (366, 371))	('patient', 'Species', '9606', (210, 217))	('IGF1R', 'Gene', (164, 169))	('HRAS', 'Gene', '3265', (220, 224))	('NF1', 'Gene', (159, 162))	('point mutations', 'Var', (291, 306))
130375	33826614	Overall, UMs lacked copy number alterations associated with drug rules and, as previously reported, demonstrated GNA11 and GNAQ point mutations with a subset of UMs also demonstrating BAP1 missense mutations.	('GNAQ', 'Gene', (123, 127))	('BAP1', 'Gene', '8314', (184, 188))	('missense mutations', 'Var', (189, 207))	('GNA11', 'Gene', '2767', (113, 118))	('GNA11', 'Gene', (113, 118))	('BAP1', 'Gene', (184, 188))	('point mutations', 'Var', (128, 143))	('GNAQ', 'Gene', '2776', (123, 127))
130376	33826614	A larger diversity of drug-associated alterations was observed across the remaining subtypes with NRAS single nucleotide variants (SNVs) and NF1 aberrations occurring across CM, MU, and AM subtypes.	('single nucleotide variants', 'Var', (103, 129))	('aberrations', 'Var', (145, 156))	('NRAS', 'Gene', (98, 102))	('NRAS', 'Gene', '4893', (98, 102))	('NF1', 'Gene', (141, 144))	('NF1', 'Gene', '4763', (141, 144))
130377	33826614	With respect to additional key aberrations, KIT alterations were found primarily in MUs, with the exception of a missense mutation in one CM, while TP53 and PTEN aberrations were specific to CMs and AMs.	('CMs', 'Phenotype', 'HP:0012056', (191, 194))	('KIT', 'molecular_function', 'GO:0005020', ('44', '47'))	('alterations', 'Var', (48, 59))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('KIT', 'Gene', '3815', (44, 47))	('KIT', 'Gene', (44, 47))	('PTEN', 'Gene', (157, 161))	('missense mutation', 'Var', (113, 130))	('PTEN', 'Gene', '5728', (157, 161))
130379	33826614	Elevated mutation burdens were observed in three hypermutated tumors of different subtypes, including a MU, although this subtype typically demonstrates low point mutation burden (SM0021 [MU], SM0024 [AM], SM0029 [CM]), with >150 mutations/Mb for each.	('SM0029 [CM', 'Var', (206, 216))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('SM0021 [MU', 'Var', (180, 190))	('SM0024 [AM]', 'Var', (193, 204))
130381	33826614	With respect to structural variants (SVs), 64% of patients did not demonstrate any SVs and a median of 13 SVs were observed across the remaining tumors with the highest number (n = 99) detected in SM0032 (MU).	('patients', 'Species', '9606', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('SM0032', 'Var', (197, 203))
130383	33826614	Across all tumors sequenced, the most prominent base substitution was C>T transitions (Fig 3A), which comprised a median of 41% of all SNVs (synonymous and non-synonymous) in the AMs, 83% in CMs, 39% in MUs, and 37% in UMs.	('CMs', 'Phenotype', 'HP:0012056', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('C>T transitions', 'Var', (70, 85))
130389	33826614	CDKN2A, for which LOF mutations have been frequently reported in AMs, MUs, and CMs, was predicted to have complete LOF in the largest percentage of patients (7/36 [19%]) and partial LOF in 31% of patients (11/36).	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (196, 204))	('mutations', 'Var', (22, 31))	('CDKN2A', 'Gene', (0, 6))	('CMs', 'Phenotype', 'HP:0012056', (79, 82))	('CDKN2A', 'Gene', '1029', (0, 6))
130391	33826614	NRAS was predicted to have GOF in the greatest percentage of patients (11/36 [31%]) primarily based on activating mutations.	('NRAS', 'Gene', '4893', (0, 4))	('activating mutations', 'Var', (103, 123))	('NRAS', 'Gene', (0, 4))	('patients', 'Species', '9606', (61, 69))
130398	33826614	Significant alterations (P<0.05) were observed in the context of mutation of cell cycle genes, TERT gene expression, overall mutational burden, and triple wild-type (WT) status of tumors (Table 2; S6 Table).	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cell cycle', 'biological_process', 'GO:0007049', ('77', '87'))	('TERT', 'Gene', (95, 99))	('alterations', 'Reg', (12, 23))	('TERT', 'Gene', '7015', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('gene expression', 'biological_process', 'GO:0010467', ('100', '115'))	('cell cycle genes', 'Gene', (77, 93))	('tumors', 'Disease', (180, 186))	('mutation', 'Var', (65, 73))	('tumors', 'Disease', 'MESH:D009369', (180, 186))
130399	33826614	In the context of cell cycle mutation, affecting 44% of tumors (11/25), Akt-mTor and MEK/ERK signaling, checkpoint signaling, as well as systemic activation of receptor tyrosine kinases were identified.	('mutation', 'Var', (29, 37))	('MEK', 'Gene', '5609', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mTor', 'Gene', (76, 80))	('Akt', 'Gene', (72, 75))	('ERK', 'Gene', '5594', (89, 92))	('tumors', 'Disease', (56, 62))	('Akt', 'Gene', '207', (72, 75))	('MEK', 'Gene', (85, 88))	('activation', 'PosReg', (146, 156))	('ERK', 'molecular_function', 'GO:0004707', ('89', '92'))	('signaling', 'biological_process', 'GO:0023052', ('93', '102'))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('ERK', 'Gene', (89, 92))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('cell cycle', 'biological_process', 'GO:0007049', ('18', '28'))	('checkpoint signaling', 'MPA', (104, 124))	('mTor', 'Gene', '2475', (76, 80))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
130401	33826614	Elevated mutation burden, observed in 32% (8/25) of tumors, was associated with systemic activation of HER3 (ERBB3) signaling, which may represent a potential therapeutic target for patients who have progressed following immunotherapy and/or whose tumor demonstrates high mutation burden.	('mutation', 'Var', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (248, 253))	('ERBB3', 'Gene', (109, 114))	('HER3', 'Gene', (103, 107))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('HER3', 'Gene', '2065', (103, 107))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('activation', 'PosReg', (89, 99))	('patients', 'Species', '9606', (182, 190))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('ERBB3', 'Gene', '2065', (109, 114))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))
130402	33826614	Lastly, in tumors demonstrating genomic alterations in the MAPK pathway (NRAS, HRAS, BRAF, or NF1; 68%; 17/25), activation of Akt-mTor and HER family signaling, RAF activation, STAT signaling, and RTK signaling was also observed.	('RAF', 'Gene', '22882', (161, 164))	('MAPK pathway', 'Pathway', (59, 71))	('NF1', 'Gene', '4763', (94, 97))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('mTor', 'Gene', (130, 134))	('NF1', 'Gene', (94, 97))	('RAF', 'Gene', (161, 164))	('NRAS', 'Gene', (73, 77))	('Akt', 'Gene', (126, 129))	('RAF', 'Gene', '22882', (86, 89))	('activation', 'PosReg', (112, 122))	('Akt', 'Gene', '207', (126, 129))	('STAT', 'Gene', (177, 181))	('RAF', 'Gene', (86, 89))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('MAPK', 'molecular_function', 'GO:0004707', ('59', '63'))	('alterations', 'Var', (40, 51))	('HRAS', 'Gene', '3265', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('NRAS', 'Gene', '4893', (73, 77))	('signaling', 'biological_process', 'GO:0023052', ('182', '191'))	('mTor', 'Gene', '2475', (130, 134))	('HRAS', 'Gene', (79, 83))	('tumors', 'Disease', (11, 17))	('STAT', 'Gene', '6772', (177, 181))	('signaling', 'biological_process', 'GO:0023052', ('150', '159'))	('signaling', 'biological_process', 'GO:0023052', ('201', '210'))	('activation', 'PosReg', (165, 175))	('HER family signaling', 'Pathway', (139, 159))
130407	33826614	These include high levels of Alk (SM0025 [MU]), EGFR Y1068 phosphorylation (SM0003 [CM]), ErbB4 (SM0019 [MU]), GSK-3a/b S21/9 phosphorylation (SM0014 [AM], SM0025 [MU]), and PDGFRA Y754 phosphorylation (SM0019 [MU], SM0018 [AM]).	('EGFR', 'Gene', '1956', (48, 52))	('ErbB4', 'Gene', (90, 95))	('SM0019 [MU', 'Var', (203, 213))	('ErbB4', 'Gene', '2066', (90, 95))	('SM0018 [AM', 'Var', (216, 226))	('EGFR', 'molecular_function', 'GO:0005006', ('48', '52'))	('phosphorylation', 'biological_process', 'GO:0016310', ('186', '201'))	('phosphorylation', 'biological_process', 'GO:0016310', ('59', '74'))	('SM0014 [AM]', 'Var', (143, 154))	('GSK-3a/b', 'Gene', '2931', (111, 119))	('GSK', 'molecular_function', 'GO:0050321', ('111', '114'))	('GSK-3a/b', 'Gene', (111, 119))	('phosphorylation', 'MPA', (126, 141))	('SM0025', 'Var', (34, 40))	('EGFR', 'Gene', (48, 52))	('phosphorylation', 'MPA', (186, 201))	('phosphorylation', 'biological_process', 'GO:0016310', ('126', '141'))	('Alk', 'Gene', (29, 32))	('S21/9', 'Gene', (120, 125))	('S21/9', 'Gene', '6227;5717', (120, 125))	('phosphorylation', 'MPA', (59, 74))	('SM0025 [', 'Var', (156, 164))	('PDGFRA', 'Gene', (174, 180))	('Alk', 'Gene', '238', (29, 32))	('PDGFRA', 'Gene', '5156', (174, 180))
130408	33826614	In one patient (SM0010 [UM]), RPPA revealed significantly elevated levels of EGFR Y1173 phosphorylation, but genomics analyses of this patient's tumor did not identify a genomic basis for EGFR activation.	('phosphorylation', 'biological_process', 'GO:0016310', ('88', '103'))	('patient', 'Species', '9606', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('patient', 'Species', '9606', (7, 14))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('levels', 'MPA', (67, 73))	('tumor', 'Disease', (145, 150))	('EGFR', 'Gene', '1956', (188, 192))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'molecular_function', 'GO:0005006', ('188', '192'))	('Y1173', 'Var', (82, 87))	('elevated', 'PosReg', (58, 66))	('EGFR', 'Gene', (188, 192))	('EGFR', 'Gene', (77, 81))
130410	33826614	SM0014 (AM), whose tumor demonstrated a BRAF fusion, harbored evidence of both MAPK and PI3K pathway activation based on multiple phosphorylation events (BRAF S445, MEK1/2 S217/221, ERK1/2 T202/Y204, GSK3a/b S21/9, p70S6 kinase S371, P70S6 kinase T389, Akt T308).	('activation', 'PosReg', (101, 111))	('MEK1', 'molecular_function', 'GO:0004708', ('165', '169'))	('Akt', 'Gene', (253, 256))	('tumor', 'Disease', (19, 24))	('P70S6 kinase T389', 'Var', (234, 251))	('MAPK', 'Pathway', (79, 83))	('MEK1/2', 'Gene', '5604;5605', (165, 171))	('S217/221', 'Var', (172, 180))	('MEK1/2', 'Gene', (165, 171))	('RAF', 'Gene', (41, 44))	('Akt', 'Gene', '207', (253, 256))	('GSK3a/b', 'Gene', '2931', (200, 207))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('MAPK', 'molecular_function', 'GO:0004707', ('79', '83'))	('GSK', 'molecular_function', 'GO:0050321', ('200', '203'))	('PI3K', 'molecular_function', 'GO:0016303', ('88', '92'))	('GSK3a/b', 'Gene', (200, 207))	('ERK1/2', 'Gene', (182, 188))	('ERK1/2', 'Gene', '5595;5594', (182, 188))	('RAF', 'Gene', '22882', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('phosphorylation', 'biological_process', 'GO:0016310', ('130', '145'))	('S21/9', 'Gene', (208, 213))	('S21/9', 'Gene', '6227;5717', (208, 213))	('RAF', 'Gene', (155, 158))	('ERK1', 'molecular_function', 'GO:0004707', ('182', '186'))	('PI3K pathway', 'Pathway', (88, 100))	('p70S6 kinase S371', 'Var', (215, 232))	('RAF', 'Gene', '22882', (41, 44))
130411	33826614	SM0025 (MU) also demonstrated activation of multiple pathways including PI3K/Akt (phosphorylation of Akt S473 and RSK3 T356/S360), Alk, cell cycle (cyclin D1), GSK3A/B (GSK3a/b S21/9 phosphorylation), PTEN (protein level and S380 phosphorylation), and insulin signaling (IRS-1 S612 phosphorylation).	('protein', 'cellular_component', 'GO:0003675', ('207', '214'))	('RSK3', 'Gene', (114, 118))	('GSK3A/B', 'Gene', '2931;2932', (160, 167))	('Akt', 'Gene', (77, 80))	('S473', 'Var', (105, 109))	('SM0025', 'Var', (0, 6))	('insulin signaling', 'CPA', (252, 269))	('Alk', 'Gene', '238', (131, 134))	('GSK3a/b', 'Gene', (169, 176))	('cell cycle', 'CPA', (136, 146))	('IRS-1', 'Gene', '3667', (271, 276))	('Akt', 'Gene', '207', (77, 80))	('PTEN', 'Gene', (201, 205))	('Akt', 'Gene', (101, 104))	('Alk', 'Gene', (131, 134))	('GSK', 'molecular_function', 'GO:0050321', ('169', '172'))	('GSK3A/B', 'Gene', (160, 167))	('PI3K', 'molecular_function', 'GO:0016303', ('72', '76'))	('cell cycle', 'biological_process', 'GO:0007049', ('136', '146'))	('RSK3', 'Gene', '6196', (114, 118))	('Akt', 'Gene', '207', (101, 104))	('insulin', 'molecular_function', 'GO:0016088', ('252', '259'))	('cyclin D1', 'Gene', (148, 157))	('PTEN', 'Gene', '5728', (201, 205))	('phosphorylation', 'biological_process', 'GO:0016310', ('82', '97'))	('cyclin', 'molecular_function', 'GO:0016538', ('148', '154'))	('cyclin D1', 'Gene', '595', (148, 157))	('S21/9', 'Gene', '6227;5717', (177, 182))	('phosphorylation', 'biological_process', 'GO:0016310', ('183', '198'))	('signaling', 'biological_process', 'GO:0023052', ('260', '269'))	('IRS-1', 'Gene', (271, 276))	('phosphorylation', 'biological_process', 'GO:0016310', ('282', '297'))	('S21/9', 'Gene', (177, 182))	('activation', 'PosReg', (30, 40))	('GSK', 'molecular_function', 'GO:0050321', ('160', '163'))	('phosphorylation', 'biological_process', 'GO:0016310', ('230', '245'))	('GSK3a/b', 'Gene', '2931', (169, 176))
130416	33826614	trial previously received and progressed on immunotherapy (Fig 1; S2 Table), clarifying the utility of immunotherapy for treatment of BRAF V600wt MMs is needed.	('RAF', 'Gene', '22882', (135, 138))	('MM', 'Phenotype', 'HP:0002861', (146, 148))	('V600wt MMs', 'Var', (139, 149))	('RAF', 'Gene', (135, 138))
130420	33826614	To investigate if individual tumors may be better or less able to evade the patient's immune system, we evaluated neo-antigen binding predictions between somatic mutations in each patient's tumor and his or her own MHC alleles, as compared against the entire cohort in both trial and available archival specimens.	('mutations', 'Var', (162, 171))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('antigen binding', 'molecular_function', 'GO:0003823', ('118', '133'))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('neo-antigen binding', 'MPA', (114, 133))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('patient', 'Species', '9606', (76, 83))	('patient', 'Species', '9606', (180, 187))
130426	33826614	Two tumors with elevated mutation burden (>150 mutations/Mb), and which were hypermutated, harbored somatic MSH6 missense mutations (S9 Table).	('MSH6', 'Gene', (108, 112))	('missense mutations', 'Var', (113, 131))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('MSH6', 'Gene', '2956', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
130427	33826614	The functional impact of the variants is not known but one (G409E) falls within the MutS DNA binding domain and may thus affect DNA repair.	('DNA repair', 'biological_process', 'GO:0006281', ('128', '138'))	('affect', 'Reg', (121, 127))	('falls', 'NegReg', (67, 72))	('G409E', 'Var', (60, 65))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('G409E', 'Mutation', 'p.G409E', (60, 65))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('DNA repair', 'MPA', (128, 138))	('falls', 'Phenotype', 'HP:0002527', (67, 72))	('DNA binding', 'molecular_function', 'GO:0003677', ('89', '100'))
130428	33826614	The remaining tumors did not harbor any MSH6 mutations.	('mutations', 'Var', (45, 54))	('MSH6', 'Gene', (40, 44))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('MSH6', 'Gene', '2956', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
130429	33826614	Missense mutations in other MMR genes (MLH1, MSH2, PMS2) were identified across four tumors, however these may represent passenger events.	('MMR', 'biological_process', 'GO:0006298', ('28', '31'))	('PMS2', 'Gene', (51, 55))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('MLH1', 'Gene', '4292', (39, 43))	('identified', 'Reg', (62, 72))	('MSH2', 'Gene', (45, 49))	('MLH1', 'Gene', (39, 43))	('Missense mutations', 'Var', (0, 18))	('MSH2', 'Gene', '4436', (45, 49))	('PMS2', 'Gene', '5395', (51, 55))	('MM', 'Phenotype', 'HP:0002861', (28, 30))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
130432	33826614	trial, comprehensive interrogation of the whole exome and transcriptome, in combination with a specific pharmacopeia, did not outperform physician's choice for treatment of BRAF V600wt MM patients.	('V600wt MM', 'Var', (178, 187))	('MM', 'Phenotype', 'HP:0002861', (185, 187))	('patients', 'Species', '9606', (188, 196))	('RAF', 'Gene', (174, 177))	('RAF', 'Gene', '22882', (174, 177))
130433	33826614	Based on genomic profiling and due to activating NRAS mutations, binimetinib was predominantly selected as the treatment strategy.	('NRAS', 'Gene', '4893', (49, 53))	('activating', 'PosReg', (38, 48))	('mutations', 'Var', (54, 63))	('NRAS', 'Gene', (49, 53))	('binimetinib', 'Chemical', 'MESH:C581313', (65, 76))
130441	33826614	Activation of key cancer pathways was found to be associated with specific genomic contexts including mutation of cell cycle genes, TERT expression, tumor mutation burden, and non-triple wt status of tumors and thus points to the need for development of novel drug classes to potentially inhibit activated pathways.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cell cycle genes', 'Gene', (114, 130))	('mutation', 'Var', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('cell cycle', 'biological_process', 'GO:0007049', ('114', '124'))	('tumor', 'Disease', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('Activation', 'PosReg', (0, 10))	('tumors', 'Disease', (200, 206))	('tumor', 'Disease', (149, 154))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('TERT', 'Gene', (132, 136))	('TERT', 'Gene', '7015', (132, 136))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
130451	33826614	Of note, while the effectiveness of combined MEK and CDK4/6 inhibitors has been demonstrated to some extent in both pre-clinically and clinically in NRAS codon 61 mutant melanoma, significant toxicities from this regimen have clinically been described.	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('NRAS', 'Gene', (149, 153))	('melanoma', 'Disease', (170, 178))	('CDK4/6', 'Gene', (53, 59))	('pre', 'molecular_function', 'GO:0003904', ('116', '119'))	('MEK', 'Gene', (45, 48))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('MEK', 'Gene', '5609', (45, 48))	('mutant', 'Var', (163, 169))	('NRAS', 'Gene', '4893', (149, 153))	('toxicities', 'Disease', 'MESH:D064420', (192, 202))	('CDK', 'molecular_function', 'GO:0004693', ('53', '56'))	('CDK4/6', 'Gene', '1019;1021', (53, 59))	('toxicities', 'Disease', (192, 202))
130459	33826614	Other criteria included life expectancy >=3 months; tumor accessible by interventional radiology or surgical intervention; measurable disease as defined by RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 criteria; Eastern Cooperative Oncology Group performance status of <=2; ability to tolerate oral medication; and adequate organ and marrow function, Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase <=5 x upper limit of normal (ULN) was allowed if liver metastases were present, Alanine aminotransferase (ALT) <= 2.5 x upper limit of normal (ULN) or <= 5 x ULN if liver metastases were present.	('tumor', 'Disease', (52, 57))	('Alanine aminotransferase', 'Gene', (534, 558))	('AST', 'Gene', (392, 395))	('Tumors', 'Disease', 'MESH:D009369', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('ALT', 'molecular_function', 'GO:0004021', ('560', '563'))	('Oncology', 'Phenotype', 'HP:0002664', (245, 253))	('phosphatase', 'molecular_function', 'GO:0016791', ('442', '453'))	('metastases', 'Disease', 'MESH:D009362', (509, 519))	('Alanine aminotransferase', 'Gene', '2875', (534, 558))	('metastases', 'Disease', (509, 519))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('alanine aminotransferase', 'Gene', (398, 422))	('alanine aminotransferase', 'Gene', '2875', (398, 422))	('Tumors', 'Phenotype', 'HP:0002664', (202, 208))	('AST', 'Gene', '26503', (392, 395))	('metastases', 'Disease', 'MESH:D009362', (625, 635))	('Tumor', 'Phenotype', 'HP:0002664', (202, 207))	('ALT', 'molecular_function', 'GO:0004021', ('424', '427'))	('<= 5 x', 'Var', (605, 611))	('Tumors', 'Disease', (202, 208))	('Aspartate aminotransferase', 'Gene', '26503', (364, 390))	('Aspartate aminotransferase', 'Gene', (364, 390))	('metastases', 'Disease', (625, 635))
130465	33826614	Pre-treatment tumor specimens underwent next generation sequencing and gene expression profiling identifying mutations, inserts and deletions, and copy number variations.	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('tumor', 'Disease', (14, 19))	('deletions', 'Var', (132, 141))	('inserts', 'Var', (120, 127))	('gene expression', 'biological_process', 'GO:0010467', ('71', '86'))	('mutations', 'Var', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('copy number variations', 'Var', (147, 169))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
130519	32976223	Laboratory values within the prespecified range for absolute neutrophil count (>=1500/mm3), platelets (>=100 000/mm3), hemoglobin (>=90 g/L), serum creatinine (<=1.5 X institutional ULN), serum total bilirubin (<=1.5 X institutional ULN), aspartate and alanine aminotransferases (<=3 x ULN or <=5 x ULN for patients with liver metastases), and fasting serum glucose (<120 mg/dL).	('serum creatinine', 'MPA', (142, 158))	('glucose', 'Chemical', 'MESH:D005947', (358, 365))	('>=100 000/mm3', 'Var', (103, 116))	('alanine', 'Enzyme', (253, 260))	('creatinine', 'Chemical', 'MESH:D003404', (148, 158))	('liver metastases', 'Disease', (321, 337))	('aspartate', 'MPA', (239, 248))	('rat', 'Species', '10116', (4, 7))	('patients', 'Species', '9606', (307, 315))	('liver metastases', 'Disease', 'MESH:D009362', (321, 337))
130546	32976223	When UM cell lines from this panel were treated with IMC-A12, complete inhibition of IGF-1R phosphorylation/activation was observed at 50 ug/mL IMC-A12 concentration and within 6-hour treatment period (Fig.	('IMC-A12', 'Var', (144, 151))	('IMC-A12', 'Chemical', 'MESH:C557414', (53, 60))	('phosphorylation/activation', 'MPA', (92, 118))	('phosphorylation', 'biological_process', 'GO:0016310', ('92', '107'))	('inhibition', 'NegReg', (71, 81))	('IGF-1R', 'Gene', (85, 91))	('IMC-A12', 'Chemical', 'MESH:C557414', (144, 151))	('rat', 'Species', '10116', (159, 162))
130577	31323388	Brief Report: Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations Inherited mutations are easily detected factors that influence the disease courses and optimal treatment strategies of some cancers.	('BAP1', 'Gene', '8314', (107, 111))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('cancers', 'Disease', (246, 253))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('mutations', 'Var', (132, 141))	('Mutations', 'Var', (112, 121))	('BAP1', 'Gene', (107, 111))	('influence', 'Reg', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))
130578	31323388	Germline mutations in BRCA associated protein-1 (BAP1) are associated with unique disease profiles in mesothelioma, atypical spitz nevi, and uveal melanoma (UM), but the patient characteristics of an unselected population of BAP1 carriers identified by an ascertainment prevalence study are unknown.	('Germline mutations', 'Var', (0, 18))	('uveal melanoma', 'Disease', 'MESH:C536494', (141, 155))	('mesothelioma', 'Disease', (102, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (141, 155))	('uveal melanoma', 'Disease', (141, 155))	('atypical spitz nevi', 'Phenotype', 'HP:0001062', (116, 135))	('BAP1', 'Gene', (49, 53))	('BAP1', 'Gene', '8314', (225, 229))	('nevi', 'Phenotype', 'HP:0003764', (131, 135))	('atypical spitz nevi', 'Disease', (116, 135))	('associated', 'Reg', (59, 69))	('patient', 'Species', '9606', (170, 177))	('mesothelioma', 'Disease', 'MESH:D008654', (102, 114))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('BAP1', 'Gene', (225, 229))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('UM', 'Phenotype', 'HP:0007716', (157, 159))	('BAP1', 'Gene', '8314', (49, 53))
130581	31323388	We tested screening criteria developed to identify patients with a possible germline BAP1 mutation.	('BAP1', 'Gene', (85, 89))	('mutation', 'Var', (90, 98))	('patients', 'Species', '9606', (51, 59))	('BAP1', 'Gene', '8314', (85, 89))
130582	31323388	Pathogenic or likely pathogenic germline BAP1 mutations were observed in 5 of 180 sequenced specimens and were exclusively found in patients identified by our screening criteria.	('mutations', 'Var', (46, 55))	('Pathogenic', 'Reg', (0, 10))	('BAP1', 'Gene', (41, 45))	('patients', 'Species', '9606', (132, 140))	('pathogenic', 'Reg', (21, 31))	('BAP1', 'Gene', '8314', (41, 45))
130583	31323388	Several patients with characteristics suspicious for a heritable deleterious mutation did not have a germline BAP1 mutation.	('mutation', 'Var', (115, 123))	('BAP1', 'Gene', '8314', (110, 114))	('patients', 'Species', '9606', (8, 16))	('BAP1', 'Gene', (110, 114))
130584	31323388	The prevalence of pathogenic germline BAP1 mutations in patients with mesothelioma was 4.4% (95% confidence interval 1.1-11.1).	('patients', 'Species', '9606', (56, 64))	('pathogenic', 'Reg', (18, 28))	('BAP1', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('mesothelioma', 'Disease', (70, 82))	('mesothelioma', 'Disease', 'MESH:D008654', (70, 82))	('BAP1', 'Gene', '8314', (38, 42))
130585	31323388	Results from the first unselected prevalence ascertainment study of germline BAP1 alterations suggest that the frequency of this mutation is low among patients with mesothelioma.	('mesothelioma', 'Disease', (165, 177))	('patients', 'Species', '9606', (151, 159))	('BAP1', 'Gene', '8314', (77, 81))	('mesothelioma', 'Disease', 'MESH:D008654', (165, 177))	('low', 'NegReg', (141, 144))	('alterations', 'Var', (82, 93))	('BAP1', 'Gene', (77, 81))
130590	31323388	In 2011, alterations in BRCA-associated protein 1 (BAP1) were identified as common oncogenic drivers in malignant pleural mesothelioma (MPM).	('BRCA-associated protein 1', 'Gene', '8314', (24, 49))	('BAP1', 'Gene', (51, 55))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('BRCA-associated protein 1', 'Gene', (24, 49))	('alterations', 'Var', (9, 20))	('malignant pleural mesothelioma', 'Disease', (104, 134))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (104, 134))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (114, 134))	('BAP1', 'Gene', '8314', (51, 55))
130591	31323388	Germline BAP1 mutations are also found in atypical Spitz nevi, uveal melanoma (UM), and a wide range of other cancers.	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('cancers', 'Disease', (110, 117))	('atypical Spitz nevi', 'Phenotype', 'HP:0001062', (42, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (63, 77))	('uveal melanoma', 'Disease', (63, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (63, 77))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('BAP1', 'Gene', '8314', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('found in', 'Reg', (33, 41))	('nevi', 'Phenotype', 'HP:0003764', (57, 61))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
130592	31323388	Pathogenic BAP1 alterations typically decrease or eliminate expression of the tumor suppressor and ubiquitin hydrolase protein, BAP1.	('expression', 'MPA', (60, 70))	('ubiquitin', 'molecular_function', 'GO:0031386', ('99', '108'))	('BAP1', 'Gene', '8314', (128, 132))	('BAP1', 'Gene', '8314', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('eliminate', 'NegReg', (50, 59))	('alterations', 'Var', (16, 27))	('tumor suppressor', 'biological_process', 'GO:0051726', ('78', '94'))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('decrease', 'NegReg', (38, 46))	('BAP1', 'Gene', (128, 132))	('BAP1', 'Gene', (11, 15))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('78', '94'))	('tumor', 'Disease', (78, 83))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))
130593	31323388	BAP1 tumor predisposition syndrome (BAP1-TPDS) is characterized by increased cancer risk in individuals with inherited BAP1 mutations.	('mutations', 'Var', (124, 133))	('BAP1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('BAP1', 'Gene', '8314', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('BAP1', 'Gene', '8314', (119, 123))	('tumor', 'Disease', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('BAP1', 'Gene', (36, 40))	('BAP1', 'Gene', '8314', (0, 4))	('BAP1', 'Gene', (119, 123))
130594	31323388	A recent review analyzed the history of cancer in families with germline BAP1 mutations and started to refine the phenotypes associated with these alterations.	('BAP1', 'Gene', '8314', (73, 77))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('BAP1', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('germline', 'Var', (64, 72))
130595	31323388	The prevalence of germline BAP1 alterations in unselected patients with metastatic UM ranges from 2 to 8%.	('metastatic UM', 'Disease', (72, 85))	('BAP1', 'Gene', (27, 31))	('UM', 'Phenotype', 'HP:0007716', (83, 85))	('alterations', 'Var', (32, 43))	('patients', 'Species', '9606', (58, 66))	('BAP1', 'Gene', '8314', (27, 31))
130598	31323388	BAP1 mutation status offers an easy way to identify patients at an increased risk of developing mesothelioma and other cancers and provides prognostic insight into management of these cases.	('BAP1', 'Gene', (0, 4))	('mesothelioma', 'Disease', (96, 108))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('BAP1', 'Gene', '8314', (0, 4))	('mutation', 'Var', (5, 13))	('patients', 'Species', '9606', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
130599	31323388	Cancer screening recommendations, based on a retrospective analysis of familial clusters, have been proposed for individuals with a germline BAP1 mutation.	('BAP1', 'Gene', '8314', (141, 145))	('BAP1', 'Gene', (141, 145))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutation', 'Var', (146, 154))
130601	31323388	Therefore, we developed and began to validate screening criteria to identify and determine the incidence of germline BAP1 mutations in patients with BAP1-associated diseases.	('patients', 'Species', '9606', (135, 143))	('BAP1', 'Gene', '8314', (117, 121))	('BAP1', 'Gene', '8314', (149, 153))	('BAP1', 'Gene', (117, 121))	('mutations', 'Var', (122, 131))	('BAP1', 'Gene', (149, 153))
130604	31323388	All patients receiving clinical care at MSK between March 2013 and October 2016 for disorders associated with germline BAP1 mutations (mesothelioma, UM, and choroidal nevus (CN)) were eligible and offered enrollment in this prospective clinical trial .	('mesothelioma', 'Disease', 'MESH:D008654', (135, 147))	('mutations', 'Var', (124, 133))	('choroidal nevus', 'Disease', (157, 172))	('UM', 'Phenotype', 'HP:0007716', (149, 151))	('nevus', 'Phenotype', 'HP:0003764', (167, 172))	('MSK', 'Gene', '150094', (40, 43))	('MSK', 'Gene', (40, 43))	('BAP1', 'Gene', '8314', (119, 123))	('mesothelioma', 'Disease', (135, 147))	('choroidal nevus', 'Phenotype', 'HP:0025314', (157, 172))	('patients', 'Species', '9606', (4, 12))	('BAP1', 'Gene', (119, 123))
130607	31323388	Germline DNA was extracted from blood samples, sequenced using a 410-gene next-generation sequencing assay (MSK-IMPACT; MSK-Integrated Mutation Profiling of Actionable Cancer Targets), and BAP1 alterations called as previously described.	('BAP1', 'Gene', '8314', (189, 193))	('MSK', 'Gene', '150094', (108, 111))	('MSK', 'Gene', (108, 111))	('BAP1', 'Gene', (189, 193))	('Cancer', 'Disease', (168, 174))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('alterations', 'Var', (194, 205))	('Cancer', 'Disease', 'MESH:D009369', (168, 174))	('Cancer', 'Phenotype', 'HP:0002664', (168, 174))	('MSK', 'Gene', '150094', (120, 123))	('MSK', 'Gene', (120, 123))
130609	31323388	Individuals matching screening criteria developed to identify potential carriers of pathogenic germline BAP1 mutations were offered additional genetic counseling and non-anonymous genetic testing.	('BAP1', 'Gene', '8314', (104, 108))	('mutations', 'Var', (109, 118))	('BAP1', 'Gene', (104, 108))
130611	31323388	Relatives of patients with a pathogenic BAP1 mutation were invited to participate in a family expansion phase of the study that is beyond the scope of this manuscript.	('pathogenic', 'Reg', (29, 39))	('patients', 'Species', '9606', (13, 21))	('BAP1', 'Gene', '8314', (40, 44))	('mutation', 'Var', (45, 53))	('BAP1', 'Gene', (40, 44))
130612	31323388	The prevalence of deleterious BAP1 mutations was estimated as the proportion of all tested specimens that were positive for any pathogenic or likely pathogenic BAP1 alteration and calculated separately for various patient groups.	('patient', 'Species', '9606', (214, 221))	('BAP1', 'Gene', (30, 34))	('BAP1', 'Gene', '8314', (160, 164))	('positive', 'Reg', (111, 119))	('BAP1', 'Gene', (160, 164))	('BAP1', 'Gene', '8314', (30, 34))	('mutations', 'Var', (35, 44))
130613	31323388	Patient demographics and disease characteristics were compared between patients with and without BAP1 mutations by the Fisher's exact test and Wilcoxon rank-sum test for categorical variables and continuous variables, respectively.	('BAP1', 'Gene', '8314', (97, 101))	('patients', 'Species', '9606', (71, 79))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('Patient', 'Species', '9606', (0, 7))
130614	31323388	The Fisher's exact test was also used to determine whether the screening criteria enriched for pathogenic BAP1 mutations by chance.	('mutations', 'Var', (111, 120))	('BAP1', 'Gene', '8314', (106, 110))	('pathogenic', 'Reg', (95, 105))	('BAP1', 'Gene', (106, 110))
130618	31323388	Ten of the 180 (5.6%) patient samples had a germline BAP1 mutation, with 5 of these mutations considered pathogenic or likely pathogenic (Supplemental Table 1).	('mutation', 'Var', (58, 66))	('BAP1', 'Gene', '8314', (53, 57))	('patient', 'Species', '9606', (22, 29))	('BAP1', 'Gene', (53, 57))
130619	31323388	BAP1 alterations included point mutations and frame shifts but not copy number variations.	('point mutations', 'Var', (26, 41))	('BAP1', 'Gene', (0, 4))	('frame shifts', 'Var', (46, 58))	('alterations', 'Reg', (5, 16))	('BAP1', 'Gene', '8314', (0, 4))
130620	31323388	Several patients without germline BAP1 mutations had characteristics suggestive of a heritable disorder: three patients had mesothelioma and a family history of mesothelioma, another patient had a personal history of both MPM and UM, and several other patients had a personal or family history that was suspicious for a germline mutation.	('patient', 'Species', '9606', (252, 259))	('mesothelioma', 'Disease', (161, 173))	('BAP1', 'Gene', (34, 38))	('patients', 'Species', '9606', (252, 260))	('mesothelioma', 'Disease', (124, 136))	('mutations', 'Var', (39, 48))	('patients', 'Species', '9606', (111, 119))	('mesothelioma', 'Disease', 'MESH:D008654', (161, 173))	('patient', 'Species', '9606', (183, 190))	('patient', 'Species', '9606', (8, 15))	('patient', 'Species', '9606', (111, 118))	('UM', 'Phenotype', 'HP:0007716', (230, 232))	('mesothelioma', 'Disease', 'MESH:D008654', (124, 136))	('BAP1', 'Gene', '8314', (34, 38))	('patients', 'Species', '9606', (8, 16))
130621	31323388	Pathogenic BAP1 mutations (depicted in a mutation diagram in Supplementary Fig.	('Pathogenic', 'Reg', (0, 10))	('mutations', 'Var', (16, 25))	('BAP1', 'Gene', '8314', (11, 15))	('BAP1', 'Gene', (11, 15))
130623	31323388	The prevalence of germline BAP1 mutations in the cohort of unselected patients with mesothelioma was 4.4%.	('patients', 'Species', '9606', (70, 78))	('mesothelioma', 'Disease', 'MESH:D008654', (84, 96))	('BAP1', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('mesothelioma', 'Disease', (84, 96))	('BAP1', 'Gene', '8314', (27, 31))
130624	31323388	Notably, all of the patients with pathogenic BAP1 alterations were positively identified by our screening criteria.	('BAP1', 'Gene', (45, 49))	('alterations', 'Var', (50, 61))	('patients', 'Species', '9606', (20, 28))	('pathogenic', 'Reg', (34, 44))	('BAP1', 'Gene', '8314', (45, 49))
130625	31323388	We examined the demographics and disease characteristics of patients with MPM with or without a germline BAP1 mutation (Table 3).	('MPM', 'Disease', (74, 77))	('patients', 'Species', '9606', (60, 68))	('BAP1', 'Gene', '8314', (105, 109))	('mutation', 'Var', (110, 118))	('BAP1', 'Gene', (105, 109))
130626	31323388	Patients with a germline BAP1 mutation were more likely to be diagnosed with stage IV disease and tended to be younger at diagnosis than patients without a germline BAP1 mutation.	('germline', 'Var', (16, 24))	('BAP1', 'Gene', (25, 29))	('BAP1', 'Gene', (165, 169))	('mutation', 'Var', (30, 38))	('patients', 'Species', '9606', (137, 145))	('stage IV disease', 'Disease', 'MESH:D058625', (77, 93))	('Patients', 'Species', '9606', (0, 8))	('BAP1', 'Gene', '8314', (25, 29))	('stage IV disease', 'Disease', (77, 93))	('BAP1', 'Gene', '8314', (165, 169))
130627	31323388	Despite having more advanced disease, patients with MPM and a germline BAP1 mutation had improved overall survival compared to patients without a germline BAP1 mutation, though this was not statistically significant (Supplementary Fig.	('improved', 'PosReg', (89, 97))	('BAP1', 'Gene', '8314', (155, 159))	('germline', 'Var', (62, 70))	('BAP1', 'Gene', (155, 159))	('BAP1', 'Gene', '8314', (71, 75))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (38, 46))	('overall survival', 'MPA', (98, 114))	('mutation', 'Var', (76, 84))	('BAP1', 'Gene', (71, 75))	('MPM', 'Disease', (52, 55))
130628	31323388	Early identification of patients with germline BAP1 mutations is important because of the unique disease courses and characteristics observed in cancers with this alteration.	('cancers', 'Disease', (145, 152))	('mutations', 'Var', (52, 61))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('BAP1', 'Gene', '8314', (47, 51))	('patients', 'Species', '9606', (24, 32))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('BAP1', 'Gene', (47, 51))
130630	31323388	Our cohort of patients with MPM and a germline BAP1 mutation, compared to patients without a germline BAP1 mutation, were more often diagnosed at an advanced disease stage, and tended to be younger at diagnosis and have better overall survival.	('BAP1', 'Gene', (102, 106))	('patients', 'Species', '9606', (74, 82))	('overall', 'MPA', (227, 234))	('better', 'PosReg', (220, 226))	('BAP1', 'Gene', '8314', (47, 51))	('mutation', 'Var', (52, 60))	('BAP1', 'Gene', '8314', (102, 106))	('patients', 'Species', '9606', (14, 22))	('BAP1', 'Gene', (47, 51))
130631	31323388	Improved survival in patients with mesothelioma and germline BAP1 mutations has been observed previously.	('mutations', 'Var', (66, 75))	('BAP1', 'Gene', (61, 65))	('mesothelioma', 'Disease', (35, 47))	('survival', 'MPA', (9, 17))	('patients', 'Species', '9606', (21, 29))	('mesothelioma', 'Disease', 'MESH:D008654', (35, 47))	('germline', 'Var', (52, 60))	('BAP1', 'Gene', '8314', (61, 65))	('Improved', 'PosReg', (0, 8))
130632	31323388	Importantly, our screening criteria identified all patients in the cohort with heritable BAP1 mutations, reducing the proportion of suspected carriers to 60% of the total population.	('BAP1', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('patients', 'Species', '9606', (51, 59))	('reducing', 'NegReg', (105, 113))	('BAP1', 'Gene', '8314', (89, 93))
130635	31323388	In our cohort of 113 analyzed samples from patients with mesothelioma (2 samples were lost due to technical issues), we identified 5 pathogenic BAP1 variants.	('mesothelioma', 'Disease', (57, 69))	('patients', 'Species', '9606', (43, 51))	('BAP1', 'Gene', (144, 148))	('mesothelioma', 'Disease', 'MESH:D008654', (57, 69))	('pathogenic', 'Reg', (133, 143))	('variants', 'Var', (149, 157))	('BAP1', 'Gene', '8314', (144, 148))
130636	31323388	The majority (80%) of patients with deleterious BAP1 variants had MPM, with only one pathogenic variant identified in patients with MPeM.	('BAP1', 'Gene', '8314', (48, 52))	('patients', 'Species', '9606', (22, 30))	('BAP1', 'Gene', (48, 52))	('MPM', 'Disease', (66, 69))	('patients', 'Species', '9606', (118, 126))	('variants', 'Var', (53, 61))
130645	31323388	There were numerous patients in our cohort with personal or family histories suspicious for a predisposition to cancer that did not have a germline BAP1 mutation.	('cancer', 'Disease', (112, 118))	('BAP1', 'Gene', '8314', (148, 152))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('BAP1', 'Gene', (148, 152))	('patients', 'Species', '9606', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutation', 'Var', (153, 161))
130667	31598164	Gene mutations and chromosome copy number variants strongly correlated with UM outcome.	('correlated with', 'Reg', (60, 75))	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('variants', 'Var', (42, 50))	('UM', 'Disease', 'MESH:C536494', (76, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('19', '29'))
130669	31598164	GNAQ and GNA11 mutations are reported to promote cell proliferation and metastasis.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('cell proliferation', 'biological_process', 'GO:0008283', ('49', '67'))	('mutations', 'Var', (15, 24))	('promote', 'PosReg', (41, 48))	('cell proliferation', 'CPA', (49, 67))	('GNAQ', 'Gene', (0, 4))	('GNA11', 'Gene', '2767', (9, 14))
130670	31598164	BAP1 mutations are related to metastasis and EIF1AX mutations are associated with favorable metastatic-free survival.	('mutations', 'Var', (52, 61))	('BAP1', 'Gene', (0, 4))	('related', 'Reg', (19, 26))	('mutations', 'Var', (5, 14))	('favorable', 'PosReg', (82, 91))	('BAP1', 'Gene', '8314', (0, 4))	('metastasis', 'CPA', (30, 40))	('EIF1AX', 'Gene', (45, 51))	('metastatic-free survival', 'CPA', (92, 116))	('EIF1AX', 'Gene', '1964', (45, 51))
130673	31598164	UM patients with chromosome 3 loss, 8q gain and 1p loss have reduced overall survival.	('1p loss', 'Var', (48, 55))	('UM', 'Disease', 'MESH:C536494', (0, 2))	('overall', 'MPA', (69, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('patients', 'Species', '9606', (3, 11))	('loss', 'NegReg', (30, 34))	('gain', 'PosReg', (39, 43))	('chromosome', 'Gene', (17, 27))	('reduced', 'NegReg', (61, 68))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
130677	31598164	Meantime, we also found the specific gene mutations and chromosome copy number variations involved in uveal melanoma associated with overall survival.	('associated', 'Reg', (117, 127))	('chromosome', 'cellular_component', 'GO:0005694', ('56', '66'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('chromosome copy number variations', 'Var', (56, 89))	('uveal melanoma', 'Disease', (102, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (102, 116))	('overall', 'MPA', (133, 140))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))
130678	31598164	By utilizing 18-gene prognostic model, gene mutations and copy number variations of UM may provide evidence for the selection and determination of an individualized and targeted therapeutic treatment for each patient.	('patient', 'Species', '9606', (209, 216))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('gene mutations', 'Var', (39, 53))	('UM', 'Disease', 'MESH:C536494', (84, 86))	('copy number variations', 'Var', (58, 80))
130681	31598164	Mutation data containing somatic variants was stored in the form of Mutation Annotation Format (MAF) and was downloaded from Genomic Data Commons (GDC) (https://portal.gdc.cancer.gov/).	('cancer', 'Disease', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('variants', 'Var', (33, 41))
130693	31598164	We selected the one with the highest frequency as our final prognosis gene model, including 18 genes, of which are S100A13, FAM189A2, ZBED1, RNF208, TCTN1, SIRT3, AC092821.1, AL137784.1, ZNF497, GRIN2A, AC010442.3, AC023790.2, FABP5P1, CA12, PARP8, MIR4655, MGLL, and MMP9 (Figure 1B, Table 1).	('CA12', 'Gene', (236, 240))	('PARP8', 'Gene', '79668', (242, 247))	('MIR4655', 'Gene', '100616160', (249, 256))	('SIRT3', 'Gene', '23410', (156, 161))	('SIRT3', 'Gene', (156, 161))	('AL137784.1', 'Var', (175, 185))	('CA12', 'Gene', '771', (236, 240))	('MMP9', 'Gene', (268, 272))	('FABP5P1', 'Gene', '387934', (227, 234))	('RNF208', 'Gene', '727800', (141, 147))	('MMP9', 'Gene', '4318', (268, 272))	('GRIN2A', 'Gene', (195, 201))	('FABP5P1', 'Gene', (227, 234))	('ZBED1', 'Gene', (134, 139))	('MIR4655', 'Gene', (249, 256))	('MGLL', 'Gene', (258, 262))	('ZBED1', 'Gene', '9189', (134, 139))	('TCTN1', 'Gene', (149, 154))	('MMP9', 'molecular_function', 'GO:0004229', ('268', '272'))	('MGLL', 'Gene', '11343', (258, 262))	('RNF208', 'Gene', (141, 147))	('TCTN1', 'Gene', '79600', (149, 154))	('ZNF497', 'Gene', (187, 193))	('PARP8', 'Gene', (242, 247))	('S100A13', 'Gene', (115, 122))	('FAM189A2', 'Gene', '9413', (124, 132))	('GRIN2A', 'Gene', '2903', (195, 201))	('FAM189A2', 'Gene', (124, 132))	('ZNF497', 'Gene', '162968', (187, 193))	('S100A13', 'Gene', '6284', (115, 122))
130703	31598164	The Kaplan-Meier curve demonstrated that uveal melanoma patients with high risk score had poorer survival than those with low risk score patients (log-rank test, p<0.001) (Figure 3B).	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('uveal melanoma', 'Disease', (41, 55))	('patients', 'Species', '9606', (56, 64))	('high risk score', 'Var', (70, 85))	('uveal melanoma', 'Disease', 'MESH:C536494', (41, 55))	('survival', 'MPA', (97, 105))	('poorer', 'NegReg', (90, 96))	('patients', 'Species', '9606', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))
130707	31598164	Uveal melanoma displays gene mutations and copy number variations that correlate strongly with clinical outcome which are not present in cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (137, 155))	('melanoma displays', 'Disease', 'MESH:D008545', (6, 23))	('copy number variations', 'Var', (43, 65))	('Uveal melanoma', 'Disease', 'MESH:C536494', (0, 14))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('cutaneous melanoma', 'Disease', (137, 155))	('Uveal melanoma', 'Disease', (0, 14))	('melanoma displays', 'Disease', (6, 23))
130709	31598164	As shown in Figure 4A, patients with SF3B1 mutations and EIF1AX mutation were mainly distributed in low-risk group, while patients with BAP1 mutations mainly emerged in high-risk group.	('BAP1', 'Gene', (136, 140))	('SF3B1', 'Gene', '23451', (37, 42))	('EIF1AX', 'Gene', '1964', (57, 63))	('EIF1AX', 'Gene', (57, 63))	('patients', 'Species', '9606', (23, 31))	('BAP1', 'Gene', '8314', (136, 140))	('mutations', 'Var', (43, 52))	('patients', 'Species', '9606', (122, 130))	('SF3B1', 'Gene', (37, 42))
130710	31598164	BAP1 mutations were identified in 28% uveal melanoma patients, and the types of mutations included frame shift deletion, missense mutation, nonsense mutation, splice site and frame shift insert.	('uveal melanoma', 'Disease', (38, 52))	('frame shift insert', 'Var', (175, 193))	('BAP1', 'Gene', (0, 4))	('patients', 'Species', '9606', (53, 61))	('missense mutation', 'Var', (121, 138))	('nonsense mutation', 'Var', (140, 157))	('uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('frame shift deletion', 'Var', (99, 119))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('mutations', 'Var', (5, 14))	('splice', 'Disease', (159, 165))	('uveal melanoma', 'Disease', 'MESH:C536494', (38, 52))	('BAP1', 'Gene', '8314', (0, 4))
130711	31598164	SF3B1 and EIF1AX mutations are mainly missense mutations.	('SF3B1', 'Gene', (0, 5))	('missense', 'Var', (38, 46))	('SF3B1', 'Gene', '23451', (0, 5))	('EIF1AX', 'Gene', '1964', (10, 16))	('EIF1AX', 'Gene', (10, 16))
130712	31598164	Patients with SF3B1 and EIF1AX wildtypes have higher risk score than patients with mutation types (Figure 4D, 4E).	('wildtypes', 'Var', (31, 40))	('risk score', 'MPA', (53, 63))	('higher', 'PosReg', (46, 52))	('SF3B1', 'Gene', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('EIF1AX', 'Gene', '1964', (24, 30))	('EIF1AX', 'Gene', (24, 30))	('SF3B1', 'Gene', '23451', (14, 19))	('patients', 'Species', '9606', (69, 77))
130713	31598164	The Kaplan-Meier curve showed that the overall survival in SF3B1 mutation group was significantly longer than in wildtype group (p=0.0071, Figure 4H), while the overall survival of EIF1AX in mutation cohort versus wildtype cohorts had no statistical difference (p=0.2547, Figure 4I).	('SF3B1', 'Gene', '23451', (59, 64))	('longer', 'PosReg', (98, 104))	('SF3B1', 'Gene', (59, 64))	('mutation', 'Var', (65, 73))	('EIF1AX', 'Gene', '1964', (181, 187))	('EIF1AX', 'Gene', (181, 187))	('4H', 'Chemical', 'MESH:D006859', (146, 148))
130714	31598164	BAP1 risk score was much higher in mutation group than in wildtype group (p=6x10-4, Figure 4C), adversely compared to GNAQ, SF3B1, and EIF1AX.	('EIF1AX', 'Gene', '1964', (135, 141))	('EIF1AX', 'Gene', (135, 141))	('GNAQ', 'Gene', (118, 122))	('BAP1', 'Gene', (0, 4))	('SF3B1', 'Gene', (124, 129))	('GNAQ', 'Gene', '2776', (118, 122))	('mutation', 'Var', (35, 43))	('higher', 'PosReg', (25, 31))	('BAP1', 'Gene', '8314', (0, 4))	('SF3B1', 'Gene', '23451', (124, 129))
130715	31598164	Notably, there was no significantly prognostic difference between BAP1 mutated group and wildtype group (p=0.0875, Figure 4G).	('BAP1', 'Gene', (66, 70))	('BAP1', 'Gene', '8314', (66, 70))	('mutated', 'Var', (71, 78))
130716	31598164	Meanwhile, we found that patients with GNAQ mutation have more favorable prognosis than patients in GNAQ wildtype group (p=0.0426, Figure 4B, 4F).	('4F', 'Chemical', 'MESH:C006011', (142, 144))	('GNAQ', 'Gene', '2776', (100, 104))	('mutation', 'Var', (44, 52))	('GNAQ', 'Gene', (39, 43))	('patients', 'Species', '9606', (88, 96))	('GNAQ', 'Gene', (100, 104))	('patients', 'Species', '9606', (25, 33))	('GNAQ', 'Gene', '2776', (39, 43))	('4B', 'Chemical', 'MESH:D001895', (138, 140))
130718	31598164	These specific gene mutations and chromosome copy number variations (CNVs) can also be a prognostic biomarker for uveal melanoma patients.	('chromosome', 'cellular_component', 'GO:0005694', ('34', '44'))	('patients', 'Species', '9606', (129, 137))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('uveal melanoma', 'Disease', (114, 128))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('mutations', 'Var', (20, 29))
130726	31598164	As a result, we identified an 18-gene prognostic model, including S100A13, FAM189A2, ZBED1, RNF208, TCTN1, SIRT3, AC092821.1, AL137784.1, ZNF497, GRIN2A, AC010442.3, AC023790.2, FABP5P1, CA12, PARP8, MIR4655, MGLL, and MMP9 (Figure 1B, Table 1).	('SIRT3', 'Gene', '23410', (107, 112))	('ZNF497', 'Gene', (138, 144))	('SIRT3', 'Gene', (107, 112))	('PARP8', 'Gene', (193, 198))	('TCTN1', 'Gene', '79600', (100, 105))	('ZNF497', 'Gene', '162968', (138, 144))	('FABP5P1', 'Gene', '387934', (178, 185))	('CA12', 'Gene', '771', (187, 191))	('FAM189A2', 'Gene', '9413', (75, 83))	('MMP9', 'molecular_function', 'GO:0004229', ('219', '223'))	('FABP5P1', 'Gene', (178, 185))	('GRIN2A', 'Gene', '2903', (146, 152))	('FAM189A2', 'Gene', (75, 83))	('MIR4655', 'Gene', '100616160', (200, 207))	('PARP8', 'Gene', '79668', (193, 198))	('RNF208', 'Gene', '727800', (92, 98))	('MMP9', 'Gene', '4318', (219, 223))	('MMP9', 'Gene', (219, 223))	('AL137784.1', 'Var', (126, 136))	('MGLL', 'Gene', (209, 213))	('ZBED1', 'Gene', (85, 90))	('MIR4655', 'Gene', (200, 207))	('GRIN2A', 'Gene', (146, 152))	('S100A13', 'Gene', (66, 73))	('TCTN1', 'Gene', (100, 105))	('RNF208', 'Gene', (92, 98))	('MGLL', 'Gene', '11343', (209, 213))	('ZBED1', 'Gene', '9189', (85, 90))	('S100A13', 'Gene', '6284', (66, 73))	('CA12', 'Gene', (187, 191))
130741	31598164	Uveal melanoma displays gene mutations and copy number variations that correlate strongly with clinical outcome.	('melanoma displays', 'Disease', 'MESH:D008545', (6, 23))	('Uveal melanoma', 'Disease', 'MESH:C536494', (0, 14))	('copy number variations', 'Var', (43, 65))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('Uveal melanoma', 'Disease', (0, 14))	('melanoma displays', 'Disease', (6, 23))
130744	31598164	In our study, most of uveal melanoma harbored mutations in GNAQ, GNA11 as previously reported.	('mutations', 'Var', (46, 55))	('uveal melanoma harbored', 'Disease', 'MESH:C536494', (22, 45))	('uveal melanoma', 'Phenotype', 'HP:0007716', (22, 36))	('uveal melanoma harbored', 'Disease', (22, 45))	('GNA11', 'Gene', '2767', (65, 70))	('GNA11', 'Gene', (65, 70))	('GNAQ', 'Gene', (59, 63))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('GNAQ', 'Gene', '2776', (59, 63))
130746	31598164	Mutations in GNAQ (50%) and GNA11 (44%) are early events that promote cell proliferation, suggesting that activated G-protein signaling plays a crucial role in early uveal melanoma development.	('uveal melanoma', 'Phenotype', 'HP:0007716', (166, 180))	('uveal melanoma', 'Disease', (166, 180))	('uveal melanoma', 'Disease', 'MESH:C536494', (166, 180))	('GNAQ', 'Gene', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('cell proliferation', 'biological_process', 'GO:0008283', ('70', '88'))	('cell proliferation', 'CPA', (70, 88))	('GNA11', 'Gene', (28, 33))	('Mutations', 'Var', (0, 9))	('promote', 'PosReg', (62, 69))	('signaling', 'biological_process', 'GO:0023052', ('126', '135'))	('GNA11', 'Gene', '2767', (28, 33))	('GNAQ', 'Gene', '2776', (13, 17))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))
130748	31598164	BAP1, SF3B1 and EIF1AX gene mutations in UM patients are related to poor, median and favorable prognosis, respectively.	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('SF3B1', 'Gene', (6, 11))	('BAP1', 'Gene', (0, 4))	('patients', 'Species', '9606', (44, 52))	('EIF1AX', 'Gene', '1964', (16, 22))	('EIF1AX', 'Gene', (16, 22))	('UM', 'Disease', 'MESH:C536494', (41, 43))	('SF3B1', 'Gene', '23451', (6, 11))	('BAP1', 'Gene', '8314', (0, 4))	('mutations', 'Var', (28, 37))
130749	31598164	While our study identified UM patients to have a favorable prognosis harboring GNAQ and SF3B1 mutations (Figure 4F, 4H).	('4H', 'Chemical', 'MESH:D006859', (116, 118))	('UM', 'Phenotype', 'HP:0007716', (27, 29))	('SF3B1', 'Gene', '23451', (88, 93))	('GNAQ', 'Gene', '2776', (79, 83))	('mutations', 'Var', (94, 103))	('UM', 'Disease', 'MESH:C536494', (27, 29))	('4F', 'Chemical', 'MESH:C006011', (112, 114))	('patients', 'Species', '9606', (30, 38))	('GNAQ', 'Gene', (79, 83))	('SF3B1', 'Gene', (88, 93))
130750	31598164	BAP1 inactivation being related to poor prognosis in uveal melanoma is well studied.	('BAP1', 'Gene', (0, 4))	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('uveal melanoma', 'Disease', (53, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (53, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('inactivation', 'Var', (5, 17))	('BAP1', 'Gene', '8314', (0, 4))
130751	31598164	However, In our Kaplan-Meier analysis, the difference in overall survival among patients with BAP1 mutation and patients without mutation was not statistically significant (P = 0.0875), indicating that BAP1 mutation was not significantly associated with OS (Figure 4G).	('BAP1', 'Gene', (202, 206))	('BAP1', 'Gene', '8314', (94, 98))	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (112, 120))	('mutation', 'Var', (99, 107))	('BAP1', 'Gene', (94, 98))	('associated', 'Reg', (238, 248))	('BAP1', 'Gene', '8314', (202, 206))
130764	31143514	This meta-analysis confirmed the favorable prognostic role of the CD3+, CD4+, CD8+, FOXP3+, and CD20+ TILs in the overall survival of melanoma patients and found an association between the TILs present and improved overall survival.	('TIL', 'Gene', (102, 105))	('CD4', 'Gene', (72, 75))	('overall survival', 'MPA', (215, 231))	('TIL', 'Gene', (189, 192))	('FOXP3', 'Gene', '50943', (84, 89))	('improved', 'PosReg', (206, 214))	('CD8', 'Gene', '925', (78, 81))	('CD20', 'Gene', (96, 100))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('CD3+', 'Var', (66, 70))	('CD20', 'Gene', '931', (96, 100))	('TIL', 'Gene', '7096', (102, 105))	('CD8', 'Gene', (78, 81))	('TIL', 'Gene', '7096', (189, 192))	('patients', 'Species', '9606', (143, 151))	('FOXP3', 'Gene', (84, 89))	('CD4', 'Gene', '920', (72, 75))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))
130776	31143514	Many studies have indicated that TILs are a favorable prognostic factor for melanoma patients, and the presence of TILs might lead to a better prognosis.	('melanoma', 'Disease', (76, 84))	('TIL', 'Gene', (115, 118))	('presence', 'Var', (103, 111))	('TIL', 'Gene', (33, 36))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('patients', 'Species', '9606', (85, 93))	('lead to', 'Reg', (126, 133))	('TIL', 'Gene', '7096', (115, 118))	('TIL', 'Gene', '7096', (33, 36))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
130788	31143514	Additionally, CD3+ T-cell infiltration into the primary tumor has also been observed as an excellent early predictor of longer survival in metastatic melanoma patients receiving DC-based immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('CD3+', 'Var', (14, 18))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('patients', 'Species', '9606', (159, 167))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
130815	31143514	Additionally, we assessed the prognostic roles of different TIL grades for the OS of melanoma patients, and the results indicated that an advantageous prognostic role for non-brisk TILs [HR: 0.71 (0.55-0.90)] and brisk TILs [HR: 0.61 (0.52-0.72)] but not moderate TILs [HR: 0.81 (0.32-2.07)] for OS (Figure 3).	('TIL', 'Gene', (60, 63))	('OS', 'Chemical', '-', (296, 298))	('advantageous', 'PosReg', (138, 150))	('TIL', 'Gene', '7096', (181, 184))	('OS', 'Chemical', '-', (79, 81))	('TIL', 'Gene', '7096', (219, 222))	('non-brisk', 'Var', (171, 180))	('TIL', 'Gene', '7096', (264, 267))	('patients', 'Species', '9606', (94, 102))	('TIL', 'Gene', (181, 184))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('TIL', 'Gene', '7096', (60, 63))	('melanoma', 'Disease', (85, 93))	('TIL', 'Gene', (219, 222))	('TIL', 'Gene', (264, 267))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))
130820	31143514	The prognostic value of brisk TILs was assessed in 3 studies, and the meta-analysis demonstrated brisk TILs to be a favorable prognostic factor for RFS [HR: 0.50 (0.27-0.94)] (Figure 5(b)).	('TIL', 'Gene', (30, 33))	('TIL', 'Gene', (103, 106))	('TIL', 'Gene', '7096', (103, 106))	('brisk', 'Var', (97, 102))	('TIL', 'Gene', '7096', (30, 33))	('RFS', 'Disease', (148, 151))	('RFS', 'Chemical', '-', (148, 151))
130845	31143514	The results indicated a better OS in melanoma patients with high FOXP3 TIL infiltration [HR: 0.57 (0.40-0.82)] (Table 3, Supplement Figure 8).	('TIL', 'Gene', (71, 74))	('OS', 'Chemical', '-', (31, 33))	('patients', 'Species', '9606', (46, 54))	('FOXP3', 'Gene', (65, 70))	('high', 'Var', (60, 64))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('FOXP3', 'Gene', '50943', (65, 70))	('TIL', 'Gene', '7096', (71, 74))
130850	31143514	The meta-analysis showed a markedly favorable prognostic value for patients with high CD20 TIL infiltration [HR: 0.49 (0.34-0.71)] (Table 3, Supplement Figure 9).	('TIL', 'Gene', (91, 94))	('patients', 'Species', '9606', (67, 75))	('high', 'Var', (81, 85))	('CD20', 'Gene', '931', (86, 90))	('TIL', 'Gene', '7096', (91, 94))	('CD20', 'Gene', (86, 90))
130868	31143514	This finding is consistent with the reports of Clemente et al and Clark et al, both of whom observed that the survival rate of melanoma patients with a brisk TIL response compared with those with a non-brisk response was higher, and the TIL response was an independent prognostic indicator.	('TIL', 'Gene', (158, 161))	('TIL', 'Gene', (237, 240))	('brisk', 'Var', (152, 157))	('TIL', 'Gene', '7096', (237, 240))	('patients', 'Species', '9606', (136, 144))	('survival', 'CPA', (110, 118))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('TIL', 'Gene', '7096', (158, 161))	('higher', 'PosReg', (221, 227))
130870	31143514	In addition, the presence of TILs would decrease the involvement of regional lymph nodes and distant metastasis to lead a positive outcome.	('TIL', 'Gene', (29, 32))	('decrease', 'NegReg', (40, 48))	('involvement', 'CPA', (53, 64))	('presence', 'Var', (17, 25))	('TIL', 'Gene', '7096', (29, 32))
130903	31143514	The specific mechanism of CD3+ TILs as favorable prognostic factor is unclear, and additional large-sample studies are needed to confirm the results due to the small number of enrolled studies.	('CD3+', 'Var', (26, 30))	('TIL', 'Gene', (31, 34))	('TIL', 'Gene', '7096', (31, 34))
130913	31143514	In conclusion, our meta-analysis confirmed the favorable prognostic role of CD3+, CD4+, CD8+, FOXP3+, and CD20+ TILs in the overall survival of melanoma patients.	('CD8', 'Gene', '925', (88, 91))	('CD4', 'Gene', '920', (82, 85))	('FOXP3', 'Gene', '50943', (94, 99))	('patients', 'Species', '9606', (153, 161))	('CD20', 'Gene', (106, 110))	('TIL', 'Gene', (112, 115))	('CD20', 'Gene', '931', (106, 110))	('FOXP3', 'Gene', (94, 99))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('TIL', 'Gene', '7096', (112, 115))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('CD4', 'Gene', (82, 85))	('CD3+', 'Var', (76, 80))	('CD8', 'Gene', (88, 91))
130920	30816227	Here, we show that CRMP2 is mostly dephosphorylated on T514 in PTP4A3 expressing cells.	('T514', 'Var', (55, 59))	('PTP4A3', 'Gene', (63, 69))	('CRMP2', 'Gene', (19, 24))	('PTP4A3', 'Gene', '11156', (63, 69))	('CRMP2', 'Gene', '1808', (19, 24))	('T514', 'Chemical', 'MESH:C075149', (55, 59))
130936	30816227	We found that CRMP2 is less phosphorylated on T514 after interaction with PTP4A3 in comparaison to the catalytically inactive mutant of the phosphatase, PTP4A3 (C104S).	('phosphorylated', 'MPA', (28, 42))	('PTP4A3', 'Gene', (153, 159))	('T514', 'Chemical', 'MESH:C075149', (46, 50))	('PTP4A3', 'Gene', '11156', (74, 80))	('T514', 'Var', (46, 50))	('less', 'NegReg', (23, 27))	('PTP4A3', 'Gene', (74, 80))	('C104S', 'Var', (161, 166))	('CRMP2', 'Gene', (14, 19))	('C104S', 'Mutation', 'p.C104S', (161, 166))	('phosphatase', 'molecular_function', 'GO:0016791', ('140', '151'))	('CRMP2', 'Gene', '1808', (14, 19))	('interaction', 'Interaction', (57, 68))	('PTP4A3', 'Gene', '11156', (153, 159))
130940	30816227	Modifications of the phosphorylation state of CRMP2 change its activity.	('CRMP2', 'Gene', '1808', (46, 51))	('activity', 'MPA', (63, 71))	('change', 'Reg', (52, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('21', '36'))	('Modifications', 'Var', (0, 13))	('CRMP2', 'Gene', (46, 51))
130941	30816227	Indeed, phosphorylated CRMP2 loses its affinity for microtubule heterodimers, thus reduces microtubule stability.	('CRMP2', 'Gene', (23, 28))	('microtubule', 'cellular_component', 'GO:0005874', ('52', '63'))	('CRMP2', 'Gene', '1808', (23, 28))	('microtubule', 'Protein', (52, 63))	('affinity', 'Interaction', (39, 47))	('reduces', 'NegReg', (83, 90))	('loses', 'NegReg', (29, 34))	('microtubule stability', 'MPA', (91, 112))	('phosphorylated', 'Var', (8, 22))	('microtubule', 'cellular_component', 'GO:0005874', ('91', '102'))
130948	30816227	Here, we identified phosphoproteins regulated by PTP4A3 by performing 2D phosphoprotein gel analysis between OCM-1 cells expressing wildtype PTP4A3 and those expressing the phosphatase inactive C104S mutant of PTP4A3, devoid of a pro-invasive effect.	('PTP4A3', 'Gene', (210, 216))	('PTP4A3', 'Gene', (49, 55))	('OCM-1', 'Species', '83984', (109, 114))	('C104S', 'Mutation', 'p.C104S', (194, 199))	('phosphatase', 'molecular_function', 'GO:0016791', ('173', '184'))	('C104S', 'Var', (194, 199))	('PTP4A3', 'Gene', '11156', (210, 216))	('PTP4A3', 'Gene', '11156', (141, 147))	('PTP4A3', 'Gene', '11156', (49, 55))	('PTP4A3', 'Gene', (141, 147))
130951	30816227	Figure 1A shows the profile of CRMP2 spots by 2D electrophoresis of OCM-1 cells expressing EGFP-PTP4A3 or EGFP-C104S using anti-CRMP2, anti-CRMP2 S522, and anti-CRMP2 T514 antibodies.	('C104S', 'Mutation', 'p.C104S', (111, 116))	('PTP4A3', 'Gene', (96, 102))	('CRMP2', 'Gene', '1808', (128, 133))	('OCM-1', 'Species', '83984', (68, 73))	('CRMP2', 'Gene', (161, 166))	('EGFP-C104S', 'Var', (106, 116))	('CRMP2', 'Gene', (140, 145))	('CRMP2', 'Gene', '1808', (161, 166))	('T514', 'Chemical', 'MESH:C075149', (167, 171))	('CRMP2', 'Gene', '1808', (140, 145))	('PTP4A3', 'Gene', '11156', (96, 102))	('CRMP2', 'Gene', (31, 36))	('CRMP2', 'Gene', '1808', (31, 36))	('CRMP2', 'Gene', (128, 133))
130956	30816227	Cell lysates were prepared from OCM-1 cells expressing EGFP-PTP4A3, EGFP-C104S, or EGFP, and GFP-Trap  beads were used for immunoprecipitation.	('OCM-1', 'Species', '83984', (32, 37))	('C104S', 'Mutation', 'p.C104S', (73, 78))	('EGFP-C104S', 'Var', (68, 78))	('PTP4A3', 'Gene', '11156', (60, 66))	('PTP4A3', 'Gene', (60, 66))
130958	30816227	CRMP2 was detected only in cells expressing either EGFP-PTP4A3 or the mutant EGFP-C104S after co-immunoprecipitation.	('PTP4A3', 'Gene', (56, 62))	('EGFP-C104S', 'Gene', (77, 87))	('mutant', 'Var', (70, 76))	('C104S', 'Mutation', 'p.C104S', (82, 87))	('CRMP2', 'Gene', (0, 5))	('CRMP2', 'Gene', '1808', (0, 5))	('PTP4A3', 'Gene', '11156', (56, 62))
130959	30816227	Much less CRMP2 was recovered from cells expressing wildtype PTP4A3 than that expressing the C104S mutant, yet the mutated phosphatase was designed to increase the retention time with interacting partners, suggesting that the interaction between CRMP2 and the phosphatase is direct.	('CRMP2', 'Gene', (246, 251))	('interaction', 'Interaction', (226, 237))	('C104S', 'Var', (93, 98))	('retention', 'biological_process', 'GO:0051235', ('164', '173'))	('CRMP2', 'Gene', '1808', (246, 251))	('PTP4A3', 'Gene', '11156', (61, 67))	('CRMP2', 'Gene', (10, 15))	('phosphatase', 'molecular_function', 'GO:0016791', ('123', '134'))	('PTP4A3', 'Gene', (61, 67))	('CRMP2', 'Gene', '1808', (10, 15))	('phosphatase', 'molecular_function', 'GO:0016791', ('260', '271'))	('increase', 'PosReg', (151, 159))	('C104S', 'Mutation', 'p.C104S', (93, 98))
130963	30816227	CRMP2 was immunoprecipitated from OCM-1 cell lysates, eluted in three successive fractions, and the presence of phosphorylated T514 CRMP2 analyzed by Western blotting (Fig.	('CRMP2', 'Gene', (132, 137))	('CRMP2', 'Gene', '1808', (132, 137))	('CRMP2', 'Gene', (0, 5))	('OCM-1', 'Species', '83984', (34, 39))	('CRMP2', 'Gene', '1808', (0, 5))	('T514', 'Var', (127, 131))	('T514', 'Chemical', 'MESH:C075149', (127, 131))
130964	30816227	Fractions F2 and F3, containing phosphorylated T514 CRMP2, were used for subsequent pull downs.	('T514', 'Chemical', 'MESH:C075149', (47, 51))	('CRMP2', 'Gene', '1808', (52, 57))	('T514', 'Var', (47, 51))	('CRMP2', 'Gene', (52, 57))
130973	30816227	The migration speed of PDX-MP41 cells increased significantly after CRMP2 knock-down (Fig.	('knock-down', 'Var', (74, 84))	('CRMP2', 'Gene', (68, 73))	('CRMP2', 'Gene', '1808', (68, 73))	('increased', 'PosReg', (38, 47))	('migration speed', 'CPA', (4, 19))
130977	30816227	Similar results of micronuclei increased after CRMP2 knockdow was observed with de PDX-MP41.	('micronuclei', 'CPA', (19, 30))	('CRMP2', 'Gene', (47, 52))	('increased', 'PosReg', (31, 40))	('CRMP2', 'Gene', '1808', (47, 52))	('knockdow', 'Var', (53, 61))
130981	30816227	The expression of PTP4A3 increased the quantity of MMP14 localized at the cell surface, as observed previously.	('PTP4A3', 'Gene', (18, 24))	('increased', 'PosReg', (25, 34))	('PTP4A3', 'Gene', '11156', (18, 24))	('cell surface', 'cellular_component', 'GO:0009986', ('74', '86'))	('MMP', 'molecular_function', 'GO:0004235', ('51', '54'))	('expression', 'Var', (4, 14))	('MMP14', 'Gene', '4323', (51, 56))	('MMP14', 'Gene', (51, 56))
130988	30816227	Therefore, we analyzed modifications of the actin network following CRMP2 knock-down in OCM-1 cells expressing EGFP-PTP4A3, EGFP-C104S, or EGFP.	('OCM-1', 'Species', '83984', (88, 93))	('knock-down', 'Var', (74, 84))	('PTP4A3', 'Gene', '11156', (116, 122))	('C104S', 'Mutation', 'p.C104S', (129, 134))	('CRMP2', 'Gene', (68, 73))	('PTP4A3', 'Gene', (116, 122))	('CRMP2', 'Gene', '1808', (68, 73))	('EGFP-C104S', 'Var', (124, 134))	('actin network', 'MPA', (44, 57))	('EGFP', 'Var', (139, 143))
130992	30816227	Cells treated with Y26732 had much fewer stress fibers compare to non-treated cells (Fig.	('stress fibers', 'CPA', (41, 54))	('Y26732', 'Chemical', '-', (19, 25))	('fewer', 'NegReg', (35, 40))	('Y26732', 'Var', (19, 25))
130994	30816227	Cells treated with Y27632 migrated faster in comparaison to non-treated cells, independently of CRMP2 expression (Fig.	('Y27632', 'Var', (19, 25))	('faster', 'PosReg', (35, 41))	('CRMP2', 'Gene', (96, 101))	('CRMP2', 'Gene', '1808', (96, 101))	('Y27632', 'Chemical', 'MESH:C108830', (19, 25))
130996	30816227	As Cofilin phosphorylation is regulated by ROCKII via LIMK, we also confirmed the dephosphorylation of Cofilin S9 in Y27632-treated cells by Western blotting (Supplementary Fig.	('Cofilin', 'Gene', '1072', (103, 110))	('Y27632', 'Chemical', 'MESH:C108830', (117, 123))	('Cofilin', 'Gene', (103, 110))	('dephosphorylation', 'biological_process', 'GO:0016311', ('82', '99'))	('phosphorylation', 'biological_process', 'GO:0016310', ('11', '26'))	('ROCKII', 'Gene', (43, 49))	('Y27632-treated', 'Var', (117, 131))	('Cofilin', 'Gene', (3, 10))	('ROCKII', 'Gene', '9475', (43, 49))	('Cofilin', 'Gene', '1072', (3, 10))	('LIMK', 'Gene', (54, 58))	('dephosphorylation', 'MPA', (82, 99))	('LIMK', 'Gene', '3984', (54, 58))
130998	30816227	We also analysed the effect of CRMP2 knock-down on microtubule dynamics in OCM-1 cells expressing EGFP-PTP4A3 or EGFP (Supplementary Fig.	('PTP4A3', 'Gene', (103, 109))	('OCM-1', 'Species', '83984', (75, 80))	('microtubule dynamics', 'biological_process', 'GO:0000226', ('51', '71'))	('microtubule dynamics', 'MPA', (51, 71))	('PTP4A3', 'Gene', '11156', (103, 109))	('microtubule', 'cellular_component', 'GO:0005874', ('51', '62'))	('analysed', 'Reg', (8, 16))	('CRMP2', 'Gene', (31, 36))	('knock-down', 'Var', (37, 47))	('EGFP', 'Var', (113, 117))	('CRMP2', 'Gene', '1808', (31, 36))
131002	30816227	Interestingly, the effect of CRMP2 knock-down on microtubules are PTP4A3 dependant in these cells.	('CRMP2', 'Gene', (29, 34))	('microtubules', 'MPA', (49, 61))	('CRMP2', 'Gene', '1808', (29, 34))	('knock-down', 'Var', (35, 45))	('PTP4A3', 'Gene', '11156', (66, 72))	('PTP4A3', 'Gene', (66, 72))
131004	30816227	Viscoelastic relaxation experiments showed that the rigidity of OCM-1 C104S cells increased after CRMP2 knock down to a level already obtained in OCM-1 PTP4A3 cells in the presence of CRMP2 (Fig.	('CRMP2', 'Gene', (184, 189))	('PTP4A3', 'Gene', '11156', (152, 158))	('CRMP2', 'Gene', '1808', (184, 189))	('CRMP2', 'Gene', (98, 103))	('knock down', 'Var', (104, 114))	('rigidity', 'Disease', (52, 60))	('PTP4A3', 'Gene', (152, 158))	('OCM-1', 'Species', '83984', (64, 69))	('CRMP2', 'Gene', '1808', (98, 103))	('rigidity', 'Phenotype', 'HP:0002063', (52, 60))	('OCM-1', 'Species', '83984', (146, 151))	('increased', 'PosReg', (82, 91))	('rigidity', 'Disease', 'MESH:D009127', (52, 60))	('C104S', 'Mutation', 'p.C104S', (70, 75))
131005	30816227	Quantification of the relaxation curves using a phenomenological model-independent approach showed a significant increase in the rigidity index and bead-step amplitude in OCM-1 C104S cells upon CRMP2 knock-down (Fig.	('CRMP2', 'Gene', '1808', (194, 199))	('rigidity', 'Disease', 'MESH:D009127', (129, 137))	('OCM-1', 'Species', '83984', (171, 176))	('C104S', 'Mutation', 'p.C104S', (177, 182))	('C104S', 'Var', (177, 182))	('increase', 'PosReg', (113, 121))	('bead-step amplitude', 'MPA', (148, 167))	('rigidity', 'Phenotype', 'HP:0002063', (129, 137))	('knock-down', 'Var', (200, 210))	('rigidity', 'Disease', (129, 137))	('CRMP2', 'Gene', (194, 199))
131006	30816227	In contrast, the knock-down of CRMP2 in OCM-1 PTP4A3 cells did not modify intracellular rigidity, suggesting that knocking down CRMP2 was equivalent to dephosphorylation of the protein by PTP4A3 for this property.	('OCM-1', 'Species', '83984', (40, 45))	('rigidity', 'Disease', 'MESH:D009127', (88, 96))	('CRMP2', 'Gene', '1808', (128, 133))	('PTP4A3', 'Gene', '11156', (46, 52))	('dephosphorylation', 'biological_process', 'GO:0016311', ('152', '169'))	('intracellular', 'cellular_component', 'GO:0005622', ('74', '87'))	('PTP4A3', 'Gene', '11156', (188, 194))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('PTP4A3', 'Gene', (46, 52))	('knocking down', 'Var', (114, 127))	('dephosphorylation', 'MPA', (152, 169))	('PTP4A3', 'Gene', (188, 194))	('rigidity', 'Disease', (88, 96))	('rigidity', 'Phenotype', 'HP:0002063', (88, 96))	('CRMP2', 'Gene', (31, 36))	('CRMP2', 'Gene', '1808', (31, 36))	('CRMP2', 'Gene', (128, 133))
131007	30816227	Consistent with these results, analysis of the relaxation curves using the Standard Liquid Linear (SLL) viscoelastic model showed that knocking down CRMP2 induced a significant increase in both elasticity and viscosity in OCM-1 C104S cells, but only a slight increase in elasticity in OCM-1 PTP4A3 cells (Fig.	('CRMP2', 'Gene', '1808', (149, 154))	('CRMP2', 'Gene', (149, 154))	('elasticity', 'MPA', (194, 204))	('C104S', 'Mutation', 'p.C104S', (228, 233))	('PTP4A3', 'Gene', '11156', (291, 297))	('increase', 'PosReg', (177, 185))	('knocking down', 'Var', (135, 148))	('PTP4A3', 'Gene', (291, 297))	('OCM-1', 'Species', '83984', (285, 290))	('viscosity', 'MPA', (209, 218))	('OCM-1', 'Species', '83984', (222, 227))
131013	30816227	Indeed, CRMP2 was less highly phosphorylated, especially on T514 (Fig.	('CRMP2', 'Gene', '1808', (8, 13))	('T514', 'Var', (60, 64))	('CRMP2', 'Gene', (8, 13))	('T514', 'Chemical', 'MESH:C075149', (60, 64))
131016	30816227	Thus, it is possible that PTP4A3 expression increases global CRMP2 phosphorylation, and more particularly those of tyrosine (CRMP2 has at least six tyrosine phosphorylation sites: Y32, Y251, Y275, Y431, Y479, and Y499) while locally decreasing CRMP2 phosphorylation of T514.	('T514', 'Chemical', 'MESH:C075149', (269, 273))	('Y275', 'Var', (191, 195))	('Y499', 'Var', (213, 217))	('increases', 'PosReg', (44, 53))	('phosphorylation', 'biological_process', 'GO:0016310', ('157', '172'))	('Y431', 'Var', (197, 201))	('tyrosine', 'Chemical', 'MESH:D014443', (148, 156))	('phosphorylation', 'biological_process', 'GO:0016310', ('67', '82'))	('CRMP2', 'Gene', (244, 249))	('decreasing', 'NegReg', (233, 243))	('Y479', 'Var', (203, 207))	('CRMP2', 'Gene', '1808', (244, 249))	('CRMP2', 'Gene', (125, 130))	('CRMP2', 'Gene', '1808', (125, 130))	('phosphorylation', 'biological_process', 'GO:0016310', ('250', '265'))	('CRMP2', 'Gene', (61, 66))	('expression', 'Var', (33, 43))	('PTP4A3', 'Gene', '11156', (26, 32))	('CRMP2', 'Gene', '1808', (61, 66))	('Y32', 'Var', (180, 183))	('Y431', 'CellLine', 'CVCL:0037', (197, 201))	('tyrosine', 'Chemical', 'MESH:D014443', (115, 123))	('Y251', 'Var', (185, 189))	('PTP4A3', 'Gene', (26, 32))
131018	30816227	Moreover, the greater recovery of CRMP2 from cells carrying the C104S mutant than those carrying wildtype PTP4A3 in GFP-trap experiment suggests a higher retention time of the mutated phosphatase, reinforcing this possibility.	('greater', 'PosReg', (14, 21))	('recovery', 'MPA', (22, 30))	('retention', 'biological_process', 'GO:0051235', ('154', '163'))	('phosphatase', 'molecular_function', 'GO:0016791', ('184', '195'))	('PTP4A3', 'Gene', '11156', (106, 112))	('CRMP2', 'Gene', (34, 39))	('C104S', 'Mutation', 'p.C104S', (64, 69))	('higher', 'PosReg', (147, 153))	('CRMP2', 'Gene', '1808', (34, 39))	('C104S', 'Var', (64, 69))	('PTP4A3', 'Gene', (106, 112))	('retention time', 'MPA', (154, 168))
131020	30816227	The phosphorylation of CRMP2 T514 by GSK-3beta inhibits CRMP2 activity, leading to microtubule depolymerization and destabilization.	('microtubule', 'cellular_component', 'GO:0005874', ('83', '94'))	('CRMP2', 'Gene', (23, 28))	('CRMP2', 'Gene', '1808', (23, 28))	('T514', 'Chemical', 'MESH:C075149', (29, 33))	('activity', 'MPA', (62, 70))	('T514', 'Var', (29, 33))	('phosphorylation', 'MPA', (4, 19))	('microtubule depolymerization', 'MPA', (83, 111))	('GSK', 'molecular_function', 'GO:0050321', ('37', '40'))	('microtubule depolymerization', 'biological_process', 'GO:0007019', ('83', '111'))	('destabilization', 'MPA', (116, 131))	('GSK-3beta', 'Gene', (37, 46))	('GSK-3beta', 'Gene', '2932', (37, 46))	('CRMP2', 'Gene', (56, 61))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))	('CRMP2', 'Gene', '1808', (56, 61))	('inhibits', 'NegReg', (47, 55))
131022	30816227	However, the increase in the speed of cells in which CRMP2 was knocked down was only observed in those expressing PTP4A3.	('CRMP2', 'Gene', (53, 58))	('PTP4A3', 'Gene', (114, 120))	('CRMP2', 'Gene', '1808', (53, 58))	('increase', 'PosReg', (13, 21))	('knocked', 'Var', (63, 70))	('PTP4A3', 'Gene', '11156', (114, 120))
131023	30816227	CRMP2 knockdown did not change the speed of migration of cells expressing the mutant (C104S) or GFP alone.	('CRMP2', 'Gene', '1808', (0, 5))	('C104S', 'Mutation', 'p.C104S', (86, 91))	('CRMP2', 'Gene', (0, 5))	('C104S', 'Var', (86, 91))
131024	30816227	Along this line, CRMP2 knockdown was shown to decrease the duration of closure in a scratch wound assay based on PDGF-induced cell migration.	('duration of closure in a scratch wound assay', 'CPA', (59, 103))	('knockdown', 'Var', (23, 32))	('PDGF', 'molecular_function', 'GO:0005161', ('113', '117'))	('cell migration', 'biological_process', 'GO:0016477', ('126', '140'))	('CRMP2', 'Gene', (17, 22))	('CRMP2', 'Gene', '1808', (17, 22))	('decrease', 'NegReg', (46, 54))
131028	30816227	Loss of CRMP2 increased the number of micronuclei in PTP4A3-expressing cells.	('increased', 'PosReg', (14, 23))	('CRMP2', 'Gene', (8, 13))	('PTP4A3', 'Gene', '11156', (53, 59))	('micronuclei', 'CPA', (38, 49))	('CRMP2', 'Gene', '1808', (8, 13))	('PTP4A3', 'Gene', (53, 59))	('Loss', 'Var', (0, 4))
131031	30816227	MMP14 membrane accumulation is also observed in cells expressing the mutant C104S, but the level reached in these cells is not sufficient to increase cell migration.	('membrane', 'cellular_component', 'GO:0016020', ('6', '14'))	('C104S', 'Mutation', 'p.C104S', (76, 81))	('C104S', 'Var', (76, 81))	('MMP14', 'Gene', '4323', (0, 5))	('cell migration', 'biological_process', 'GO:0016477', ('150', '164'))	('MMP14', 'Gene', (0, 5))	('MMP', 'molecular_function', 'GO:0004235', ('0', '3'))	('mutant C104S', 'Var', (69, 81))
131038	30816227	This observation was confirmed by the increase of migration capacity of cells treated with the ROCKII inhibitor, Y27632.	('increase', 'PosReg', (38, 46))	('Y27632', 'Var', (113, 119))	('ROCKII', 'Gene', (95, 101))	('ROCKII', 'Gene', '9475', (95, 101))	('Y27632', 'Chemical', 'MESH:C108830', (113, 119))	('migration capacity', 'CPA', (50, 68))
131040	30816227	The experiments on the microrheological properties of the cells show that knocking down CRMP2 is equivalent to the effect of PTP4A3 on the protein in controlling intracellular rigidity (Fig.	('CRMP2', 'Gene', (88, 93))	('CRMP2', 'Gene', '1808', (88, 93))	('rigidity', 'Disease', (176, 184))	('rigidity', 'Phenotype', 'HP:0002063', (176, 184))	('knocking down', 'Var', (74, 87))	('intracellular', 'cellular_component', 'GO:0005622', ('162', '175'))	('PTP4A3', 'Gene', '11156', (125, 131))	('rigidity', 'Disease', 'MESH:D009127', (176, 184))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('PTP4A3', 'Gene', (125, 131))
131041	30816227	The lower rigidity of the cytoplasm of C104S cells is consistent with the reported microtubule destabilization in these cells.	('microtubule', 'cellular_component', 'GO:0005874', ('83', '94'))	('rigidity', 'Disease', (10, 18))	('lower', 'NegReg', (4, 9))	('rigidity', 'Phenotype', 'HP:0002063', (10, 18))	('C104S', 'Mutation', 'p.C104S', (39, 44))	('cytoplasm', 'cellular_component', 'GO:0005737', ('26', '35'))	('C104S', 'Var', (39, 44))	('rigidity', 'Disease', 'MESH:D009127', (10, 18))	('microtubule destabilization', 'MPA', (83, 110))	('microtubule destabilization', 'biological_process', 'GO:0031117', ('83', '110'))
131042	30816227	However, these microrheological modifications do not explain the migration/invasion phenotype, as knocking down CRMP2 in C104S cells changed the elastic properties of the cells but had no effect on the motility properties, suggesting additional key properties of PTP4A3 in UM invasion.	('PTP4A3', 'Gene', '11156', (263, 269))	('C104S', 'Var', (121, 126))	('CRMP2', 'Gene', (112, 117))	('PTP4A3', 'Gene', (263, 269))	('CRMP2', 'Gene', '1808', (112, 117))	('UM', 'Phenotype', 'HP:0007716', (273, 275))	('elastic properties of', 'MPA', (145, 166))	('knocking down', 'Var', (98, 111))	('changed', 'Reg', (133, 140))	('C104S', 'Mutation', 'p.C104S', (121, 126))
131045	30816227	These modifications on cytoskeleton will affect cells micro-rheological properties and MMP14 membrane accumulation leading to an increase of both migration and invasion.	('cells micro-rheological properties', 'CPA', (48, 82))	('modifications', 'Var', (6, 19))	('migration', 'CPA', (146, 155))	('invasion', 'CPA', (160, 168))	('MMP14', 'Gene', '4323', (87, 92))	('increase', 'PosReg', (129, 137))	('membrane', 'cellular_component', 'GO:0016020', ('93', '101'))	('MMP', 'molecular_function', 'GO:0004235', ('87', '90'))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('23', '35'))	('MMP14', 'Gene', (87, 92))	('affect', 'Reg', (41, 47))
131048	30816227	A study carried out in breast cancer showed a lower level of CRMP2 in cancer cells than in healthy tissue, whereas there is greater phosphorylation of CRMP2 at T509, S518, and S522.	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('level', 'MPA', (52, 57))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('breast cancer', 'Disease', (23, 36))	('greater', 'PosReg', (124, 131))	('S522', 'Var', (176, 180))	('CRMP2', 'Gene', (151, 156))	('CRMP2', 'Gene', '1808', (151, 156))	('cancer', 'Disease', (70, 76))	('CRMP2', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CRMP2', 'Gene', '1808', (61, 66))	('cancer', 'Disease', (30, 36))	('lower', 'NegReg', (46, 51))	('T509', 'Var', (160, 164))	('S518', 'Var', (166, 170))	('phosphorylation', 'MPA', (132, 147))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('phosphorylation', 'biological_process', 'GO:0016310', ('132', '147'))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
131054	30816227	We previously established OCM-1 clones stably expressing EGFP-PTP4A3, EGFP-C104S, or EGFP.	('EGFP', 'Var', (85, 89))	('OCM-1', 'Species', '83984', (26, 31))	('EGFP-C104S', 'Var', (70, 80))	('C104S', 'Mutation', 'p.C104S', (75, 80))	('PTP4A3', 'Gene', '11156', (62, 68))	('PTP4A3', 'Gene', (62, 68))
131055	30816227	Human PDX-MP41 cells bearing the GNA11 mutation and wild-type BAP1, disomic for chromosome 3 were maintained in RPMI (Gibco) with 20% FBS (HyClone UK laboratories).	('Human', 'Species', '9606', (0, 5))	('BAP1', 'Gene', '8314', (62, 66))	('GNA11', 'Gene', (33, 38))	('mutation', 'Var', (39, 47))	('RPMI', 'Chemical', '-', (112, 116))	('GNA11', 'Gene', '2767', (33, 38))	('BAP1', 'Gene', (62, 66))	('chromosome', 'cellular_component', 'GO:0005694', ('80', '90'))
131064	30816227	The GST-tagged PTP4A3 and C104S were generated by PCR amplification and then ligated into the pGEX-4 T-2 expression vector.	('C104S', 'Mutation', 'p.C104S', (26, 31))	('PTP4A3', 'Gene', '11156', (15, 21))	('C104S', 'Var', (26, 31))	('PTP4A3', 'Gene', (15, 21))
131084	30816227	The inhibition of ROCKII in OCM-1 cells was achieved by Y27632 (Sigma-Aldrich) treatment at 10 muM for 24 h at 37  C. OCM-1 cells were seeded 24 h on glass-coverslips coated with 50 microg/mL collagen I.	('Y27632', 'Chemical', 'MESH:C108830', (56, 62))	('OCM-1', 'Species', '83984', (118, 123))	('collagen', 'molecular_function', 'GO:0005202', ('192', '200'))	('ROCKII', 'Gene', (18, 24))	('OCM-1', 'Species', '83984', (28, 33))	('ROCKII', 'Gene', '9475', (18, 24))	('Y27632', 'Var', (56, 62))	('inhibition', 'NegReg', (4, 14))
131105	29207628	To this regard, a recent report using the L1000CDS2 web-based utility was able to predict small molecules and drugs targeting uveal melanoma gene signature.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('L1000CDS2', 'Var', (42, 51))	('uveal melanoma', 'Disease', 'MESH:C536494', (126, 140))	('uveal melanoma', 'Phenotype', 'HP:0007716', (126, 140))	('uveal melanoma', 'Disease', (126, 140))
131118	29207628	By contrast, continuous cell proliferation analysis showed that (+)-pentazocine (Figure 2C) resulted in a dose dependent increase of cell proliferation when compared to control.	('cell proliferation', 'biological_process', 'GO:0008283', ('133', '151'))	('cell proliferation', 'CPA', (133, 151))	('(+)-pentazocine', 'Chemical', 'MESH:D010423', (64, 79))	('increase', 'PosReg', (121, 129))	('+)-pentazocine', 'Var', (65, 79))	('cell proliferation', 'biological_process', 'GO:0008283', ('24', '42'))
131121	29207628	These results were further confirmed in part by clonogenic assay (Figure 4A and 4B) showing that haloperidol was able to induce colonies formation at 1 muM whereas had an opposite effect at 10 and 25 muM (p < 0.05).	('haloperidol', 'Var', (97, 108))	('formation', 'biological_process', 'GO:0009058', ('137', '146'))	('induce', 'PosReg', (121, 127))	('muM', 'Gene', '56925', (152, 155))	('muM', 'Gene', '56925', (200, 203))	('haloperidol', 'Chemical', 'MESH:D006220', (97, 108))	('muM', 'Gene', (152, 155))	('muM', 'Gene', (200, 203))	('colonies formation', 'CPA', (128, 146))
131140	29207628	Our results are consistent with previous studies showing that sigma2 receptor ligands are associated with proliferation inhibition of cancer cells whereas under our experimental conditions sigma1 receptor ligand treatment resulted in an increased cell proliferation.	('sigma2 receptor', 'Protein', (62, 77))	('cell proliferation', 'biological_process', 'GO:0008283', ('247', '265'))	('receptor ligand', 'molecular_function', 'GO:0005102', ('196', '211'))	('cell proliferation', 'CPA', (247, 265))	('cancer', 'Disease', (134, 140))	('proliferation inhibition', 'CPA', (106, 130))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('ligands', 'Var', (78, 85))
131165	29184418	In vitro experiments showed that FGF2 treatment caused increased horizontal and vertical migration and F-actin cytoskeleton assembly as well as decreased adhesive activity of MUM2B cells, together with increased intracellular calcium concentration and expression of ORAI1 and STIM1 - two key regulatory proteins of store-operated calcium entry (SOCE).	('store-operated calcium entry', 'biological_process', 'GO:0002115', ('315', '343'))	('increased', 'PosReg', (55, 64))	('calcium', 'Chemical', 'MESH:D002118', (226, 233))	('FGF2', 'Gene', (33, 37))	('UM', 'Phenotype', 'HP:0007716', (176, 178))	('decreased', 'NegReg', (144, 153))	('F-actin cytoskeleton assembly', 'CPA', (103, 132))	('treatment', 'Var', (38, 47))	('increased intracellular calcium', 'Phenotype', 'HP:0003575', (202, 233))	('MUM2', 'Gene', (175, 179))	('intracellular', 'cellular_component', 'GO:0005622', ('212', '225'))	('increased', 'PosReg', (202, 211))	('MUM2', 'Gene', '9589', (175, 179))	('F-actin', 'cellular_component', 'GO:0031941', ('103', '110'))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('105', '123'))	('adhesive activity', 'CPA', (154, 171))	('ORAI1', 'Gene', (266, 271))	('intracellular calcium concentration', 'MPA', (212, 247))	('SOCE', 'biological_process', 'GO:0002115', ('345', '349'))	('calcium', 'Chemical', 'MESH:D002118', (330, 337))	('STIM1', 'Gene', (276, 281))
131176	29184418	Interferences with the FGF2/FGFR pathway resulted in impaired neovascularization and growth of human melanoma xenografts, demonstrating that FGF2 is essential in melanoma progression and may be an interesting target to explore for antitumor approaches.	('neovascularization', 'CPA', (62, 80))	('human', 'Species', '9606', (95, 100))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (162, 170))	('melanoma', 'Disease', (101, 109))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('FGFR', 'molecular_function', 'GO:0005007', ('28', '32'))	('impaired', 'NegReg', (53, 61))	('melanoma xenografts', 'Disease', 'MESH:D008545', (101, 120))	('Interferences', 'Var', (0, 13))	('melanoma xenografts', 'Disease', (101, 120))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('FGF2/FGFR', 'Gene', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', (235, 240))	('growth', 'CPA', (85, 91))
131178	29184418	In general, activation of IP3 evokes Ca2+ release from the endoplasmic reticulum (ER) store.	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('59', '80'))	('evokes', 'Reg', (30, 36))	('IP3', 'Chemical', 'MESH:D015544', (26, 29))	('activation', 'Var', (12, 22))	('IP3', 'Gene', (26, 29))	('Ca2+', 'Chemical', 'MESH:D000069285', (37, 41))
131229	29184418	Patients with positive FGF2 expression had a higher rate of metastasis (10/12, 83.3%) than those with negative FGF2 expression (2/14, 14.3%).	('Patients', 'Species', '9606', (0, 8))	('positive', 'Var', (14, 22))	('expression', 'Var', (28, 38))	('metastasis', 'CPA', (60, 70))	('FGF2', 'Gene', (23, 27))
131235	29184418	We found that both STIM1 and ORAI1 were significantly upregulated after FGF2 treatment in MUM2B cells (Figure 2B).	('MUM2', 'Gene', (90, 94))	('STIM1', 'Gene', (19, 24))	('upregulated', 'PosReg', (54, 65))	('treatment', 'Var', (77, 86))	('ORAI1', 'Gene', (29, 34))	('UM', 'Phenotype', 'HP:0007716', (91, 93))	('FGF2', 'Gene', (72, 76))	('MUM2', 'Gene', '9589', (90, 94))
131240	29184418	Structural and functional dysregulation of the actin cytoskeleton correlate with uncontrolled movement of tumor cells.	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('47', '65'))	('dysregulation', 'Var', (26, 39))	('uncontrolled movement', 'CPA', (81, 102))	('uncontrolled movement', 'Phenotype', 'HP:0007738', (81, 102))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
131241	29184418	By using phalloidin to dye fibrous actin (F-actin), we observed that FGF2 treatment caused cell polarization and pseudopodium protrusion in MUM2B cells (Figure 4).	('treatment', 'Var', (74, 83))	('UM', 'Phenotype', 'HP:0007716', (141, 143))	('pseudopodium protrusion', 'CPA', (113, 136))	('cell polarization', 'CPA', (91, 108))	('phalloidin', 'Chemical', 'MESH:D010590', (9, 19))	('FGF2', 'Gene', (69, 73))	('MUM2', 'Gene', '9589', (140, 144))	('cell polarization', 'biological_process', 'GO:0030010', ('91', '108'))	('MUM2', 'Gene', (140, 144))	('F-actin', 'cellular_component', 'GO:0031941', ('42', '49'))	('pseudopodium', 'cellular_component', 'GO:0031143', ('113', '125'))
131253	29184418	Coexpression of FGFR-1 and bFGF in melanoma cells was associated with increased microvessel density, and antisense oligonucleotides against FGF2 mRNA could effectively inhibit intratumoral angiogenesis and melanoma growth in nude mice.	('increased', 'PosReg', (70, 79))	('angiogenesis', 'biological_process', 'GO:0001525', ('189', '201'))	('antisense oligonucleotides', 'Var', (105, 131))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('melanoma', 'Disease', (206, 214))	('oligonucleotides', 'Chemical', 'MESH:D009841', (115, 131))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('FGFR', 'molecular_function', 'GO:0005007', ('16', '20'))	('bFGF', 'Gene', '14173', (27, 31))	('bFGF', 'Gene', (27, 31))	('melanoma growth', 'Disease', 'MESH:D008545', (206, 221))	('FGFR-1', 'Gene', '14182', (16, 22))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', 'MESH:D008545', (206, 214))	('melanoma', 'Disease', (35, 43))	('tumor', 'Disease', (181, 186))	('nude mice', 'Species', '10090', (225, 234))	('melanoma growth', 'Disease', (206, 221))	('FGF2', 'Gene', (140, 144))	('FGFR-1', 'Gene', (16, 22))	('microvessel density', 'CPA', (80, 99))	('inhibit', 'NegReg', (168, 175))	('tumor', 'Disease', 'MESH:D009369', (181, 186))
131254	29184418	Lefevre and colleagues reported that FGF2 was strongly expressed in UM, and that antisense oligonucleotide-mediated depletion of endogenous FGF2 could induce decreased proliferation of UM cells.	('UM', 'Phenotype', 'HP:0007716', (185, 187))	('proliferation', 'CPA', (168, 181))	('decreased', 'NegReg', (158, 167))	('FGF2', 'Gene', (140, 144))	('antisense oligonucleotide-mediated depletion', 'Var', (81, 125))	('oligonucleotide', 'Chemical', 'MESH:D009841', (91, 106))	('UM', 'Phenotype', 'HP:0007716', (68, 70))	('FGF2', 'Gene', (37, 41))
131266	29184418	Feldman et al showed that ORAI1 and STIM1 expressed in B16BL6 mouse melanoma cells control SOCE, and silencing of STIM1 caused a reduction in cell growth and increased cell death.	('cell growth', 'CPA', (142, 153))	('B16BL6', 'CellLine', 'CVCL:0157', (55, 61))	('STIM1', 'Gene', (114, 119))	('mouse', 'Species', '10090', (62, 67))	('silencing', 'Var', (101, 110))	('reduction', 'NegReg', (129, 138))	('SOCE', 'biological_process', 'GO:0002115', ('91', '95'))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('cell death', 'CPA', (168, 178))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('cell death', 'biological_process', 'GO:0008219', ('168', '178'))	('cell growth', 'biological_process', 'GO:0016049', ('142', '153'))	('increased', 'PosReg', (158, 167))
131273	29184418	Umemura et al reported that STIM1 knockdown significantly suppressed melanoma lung metastasis in a xenograft mouse model, implicating the importance of SOCE in metastatic dissemination.	('melanoma lung metastasis', 'Disease', (69, 93))	('suppressed', 'NegReg', (58, 68))	('melanoma lung metastasis', 'Disease', 'MESH:D009362', (69, 93))	('knockdown', 'Var', (34, 43))	('STIM1', 'Gene', (28, 33))	('SOCE', 'biological_process', 'GO:0002115', ('152', '156'))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('mouse', 'Species', '10090', (109, 114))
131275	29184418	The SOCE pharmacological inhibitor 2-APB could abrogate the pro-migration response to FGF2 in vitro, and restrain tumor metastasis in the mouse xenograft model.	('mouse', 'Species', '10090', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('2-APB', 'Var', (35, 40))	('2-APB', 'Chemical', 'MESH:C109986', (35, 40))	('restrain', 'NegReg', (105, 113))	('pro-migration response', 'MPA', (60, 82))	('tumor metastasis', 'Disease', 'MESH:D009362', (114, 130))	('abrogate', 'NegReg', (47, 55))	('FGF2', 'Gene', (86, 90))	('SOCE', 'biological_process', 'GO:0002115', ('4', '8'))	('tumor metastasis', 'Disease', (114, 130))
131276	29184418	Thus, FGF2-induced tumor metastasis correlates with enhancement of SOCE, and the antimotility effect caused by 2-APB in UM may be caused by its inhibitory effect on SOCE.	('tumor metastasis', 'Disease', (19, 35))	('SOCE', 'CPA', (67, 71))	('enhancement', 'PosReg', (52, 63))	('FGF2-induced', 'Gene', (6, 18))	('2-APB', 'Chemical', 'MESH:C109986', (111, 116))	('2-APB', 'Var', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('SOCE', 'biological_process', 'GO:0002115', ('67', '71'))	('UM', 'Phenotype', 'HP:0007716', (120, 122))	('SOCE', 'biological_process', 'GO:0002115', ('165', '169'))	('antimotility effect', 'MPA', (81, 100))	('tumor metastasis', 'Disease', 'MESH:D009362', (19, 35))
131281	29184418	Some researchers found disruption of the FGF2 gene could not affect tumor growth in an experimental model of hemangiomas, nor prevent tumor growth and angiogenesis in a transgenic mouse model for tumors of the retinal pigment epithelium.	('tumor', 'Disease', (196, 201))	('FGF2', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('angiogenesis', 'biological_process', 'GO:0001525', ('151', '163'))	('tumor', 'Disease', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('disruption', 'Var', (23, 33))	('mouse', 'Species', '10090', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('angiogenesis', 'CPA', (151, 163))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumors', 'Disease', (196, 202))	('hemangiomas', 'Disease', (109, 120))	('hemangiomas', 'Phenotype', 'HP:0001028', (109, 120))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', (134, 139))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('hemangiomas', 'Disease', 'MESH:D006391', (109, 120))
131282	29184418	Stanisz et al reported that silencing of ORAI1/STIM2 caused a decrease in intracellular Ca2+, which correlated with increased expression of microphthalmia-associated transcription factor and enhanced proliferation.	('intracellular Ca2+', 'MPA', (74, 92))	('transcription factor', 'molecular_function', 'GO:0000981', ('166', '186'))	('STIM2', 'Gene', (47, 52))	('intracellular', 'cellular_component', 'GO:0005622', ('74', '87'))	('expression', 'MPA', (126, 136))	('microphthalmia-associated transcription factor', 'Gene', (140, 186))	('proliferation', 'CPA', (200, 213))	('Ca2+', 'Chemical', 'MESH:D000069285', (88, 92))	('decrease', 'NegReg', (62, 70))	('microphthalmia', 'Phenotype', 'HP:0000568', (140, 154))	('enhanced', 'PosReg', (191, 199))	('increased', 'PosReg', (116, 125))	('microphthalmia-associated transcription factor', 'Gene', '4286', (140, 186))	('silencing', 'Var', (28, 37))	('STIM2', 'Gene', '57620', (47, 52))	('transcription', 'biological_process', 'GO:0006351', ('166', '179'))
131287	27187621	We observed less efficient repair when DNA damage was induced by heavy ions compared with X-rays and most of the irreparable damage was complex of single strand breaks and double strand breaks, while DNA damage induced by X-rays was mostly repaired in 24 hours and the remained damage was preferentially associated with telomeric DNA.	('rays', 'Species', '255564', (224, 228))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('DNA', 'cellular_component', 'GO:0005574', ('330', '333'))	('double strand breaks', 'Var', (172, 192))	('DNA', 'cellular_component', 'GO:0005574', ('200', '203'))	('single strand breaks', 'Var', (147, 167))	('rays', 'Species', '255564', (92, 96))
131292	27187621	gammaH2AX foci or 53BP1 foci represent the sites of double strand breaks (DSBs), both can be used as surrogate marker for DSBs.	('gammaH2AX', 'Var', (0, 9))	('DSBs', 'Chemical', '-', (122, 126))	('53BP1', 'Gene', (18, 23))	('DSBs', 'Chemical', '-', (74, 78))
131319	27187621	The antibodies employed in this study were anti-p53 (ab2433, Abcam), anti-p21 (sc-397, Santa Cruz), anti-pATM (ab81292, Abcam), anti-pRB (8516, Cell Signaling) anti-RB (554136, Becton Dickinson) and anti-GAPDH (sc-25778, Santa Cruz).	('p53', 'Gene', (48, 51))	('pRB', 'Gene', (133, 136))	('anti-GAPDH', 'Var', (199, 209))	('anti-p21', 'Var', (69, 77))	('p53', 'Gene', '7157', (48, 51))	('Signaling', 'biological_process', 'GO:0023052', ('149', '158'))	('pRB', 'Gene', '5925', (133, 136))	('anti-pATM', 'Var', (100, 109))
131324	27187621	However, we also determined that ionizing radiation treatment was unable to induce remarkable cellular senescence in cells with mutant type of p53 (S2 Fig).	('p53', 'Gene', '7157', (143, 146))	('cellular senescence', 'biological_process', 'GO:0090398', ('94', '113'))	('p53', 'Gene', (143, 146))	('mutant type', 'Var', (128, 139))
131333	27187621	Therefore, we further detected the protein levels of p53, p21, p16INK4a, RB and pRB in 92-1 cells exposed to 10 Gy of X-rays.	('p16INK4a', 'Var', (63, 71))	('pRB', 'Gene', '5925', (80, 83))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('p21', 'Var', (58, 61))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('detected', 'Reg', (22, 30))	('rays', 'Species', '255564', (120, 124))	('pRB', 'Gene', (80, 83))
131337	27187621	To explore the relationship between radiation dose and cellular senescence, 92-1 cells were treated with X-rays (LET 4 keV/mum), carbon ions (LET 80 keV/mum) and iron ions (LET 400 keV/mum) at different doses.	('carbon', 'Chemical', 'MESH:D002244', (129, 135))	('LET 400 keV/mum', 'Var', (173, 188))	('LET 80 keV/mum', 'Var', (142, 156))	('rays', 'Species', '255564', (107, 111))	('iron', 'Chemical', 'MESH:D007501', (162, 166))	('cellular senescence', 'biological_process', 'GO:0090398', ('55', '74'))
131368	27187621	Here, we demonstrated that heavy ions could induce senescence in 92-1 cells, though heavy ions were charged high atomic number particles while X-rays were uncharged photons.	('senescence', 'CPA', (51, 61))	('heavy ions', 'Var', (27, 37))	('rays', 'Species', '255564', (145, 149))	('senescence', 'biological_process', 'GO:0010149', ('51', '61'))
131379	27187621	While exogenous treatment with H2O2 can promote cellular senescence, endogenous ROS (such as superoxides and hydroxyl radicals) is also implicated in the establishment and maintenance of the irreversible growth arrest.	('promote', 'PosReg', (40, 47))	('H2O2', 'Chemical', 'MESH:D006861', (31, 35))	('H2O2', 'Var', (31, 35))	('hydroxyl radicals', 'Chemical', 'MESH:D017665', (109, 126))	('superoxides', 'Chemical', 'MESH:D013481', (93, 104))	('growth arrest', 'Phenotype', 'HP:0001510', (204, 217))	('cellular senescence', 'CPA', (48, 67))	('implicated', 'Reg', (136, 146))	('ROS', 'Chemical', '-', (80, 83))	('cellular senescence', 'biological_process', 'GO:0090398', ('48', '67'))
131390	24713608	The techniques for assessing prognosis in uveal melanoma have evolved from simple physical features, such as tumor size, location, and cell morphology, to the slightly more sophisticated counting of chromosomal gains and losses.	('losses', 'NegReg', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('chromosomal', 'Var', (199, 210))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('uveal melanoma', 'Disease', (42, 56))	('tumor', 'Disease', (109, 114))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
131391	24713608	Mutations in GNAQ and GNA11 are early events that promote cell proliferation, and these mutations are sensitive to MAPK kinase, PKC, and AKT inhibitors.	('GNA11', 'Gene', (22, 27))	('promote', 'PosReg', (50, 57))	('PKC', 'Gene', (128, 131))	('GNAQ', 'Gene', (13, 17))	('cell proliferation', 'CPA', (58, 76))	('GNA11', 'Gene', '2767', (22, 27))	('AKT', 'Gene', '207', (137, 140))	('PKC', 'Gene', '112476', (128, 131))	('MAPK', 'molecular_function', 'GO:0004707', ('115', '119'))	('Mutations', 'Var', (0, 9))	('AKT', 'Gene', (137, 140))	('PKC', 'molecular_function', 'GO:0004697', ('128', '131'))	('cell proliferation', 'biological_process', 'GO:0008283', ('58', '76'))
131392	24713608	Mutations in BAP1, SF3B1, and EIF1AX are later events that are largely mutually exclusive.	('BAP1', 'Gene', (13, 17))	('SF3B1', 'Gene', '23451', (19, 24))	('EIF1AX', 'Gene', '1964', (30, 36))	('EIF1AX', 'Gene', (30, 36))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (13, 17))	('SF3B1', 'Gene', (19, 24))
131393	24713608	Mutations in BAP1 are strongly associated with metastasis, whereas those in SF3B1 and EIF1AX are associated with good prognosis.	('BAP1', 'Gene', (13, 17))	('associated with', 'Reg', (31, 46))	('metastasis', 'CPA', (47, 57))	('SF3B1', 'Gene', (76, 81))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (13, 17))	('EIF1AX', 'Gene', '1964', (86, 92))	('EIF1AX', 'Gene', (86, 92))	('SF3B1', 'Gene', '23451', (76, 81))
131394	24713608	Uveal melanomas with BAP1 mutations demonstrate sensitivity to epigenetic modulators, such as histone deacetylase inhibitors.	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('BAP1', 'Gene', (21, 25))	('melanomas', 'Disease', (6, 15))	('sensitivity', 'MPA', (48, 59))	('histone deacetylase', 'Gene', '9734', (94, 113))	('mutations', 'Var', (26, 35))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('histone deacetylase', 'Gene', (94, 113))	('BAP1', 'Gene', '8314', (21, 25))
131405	24713608	For several decades, it was recognized that the copy number changes in certain chromosomes are associated with an increased risk for metastasis in uveal melanoma.	('uveal melanoma', 'Disease', (147, 161))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('uveal melanoma', 'Phenotype', 'HP:0007716', (147, 161))	('metastasis', 'CPA', (133, 143))	('copy number changes', 'Var', (48, 67))	('associated', 'Reg', (95, 105))	('uveal melanoma', 'Disease', 'MESH:C536494', (147, 161))
131410	24713608	Several key mutations in uveal melanoma have been identified from sequencing of primary tissue samples.	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('uveal melanoma', 'Disease', (25, 39))	('mutations', 'Var', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('uveal melanoma', 'Disease', 'MESH:C536494', (25, 39))
131413	24713608	Mutually exclusive mutations in GNAQ and GNA11, two closely-related G-coupled protein receptor subunits, have recently been found to occur in 85-91% of uveal melanomas.	('GNAQ', 'Gene', (32, 36))	('uveal melanomas', 'Disease', 'MESH:C536494', (152, 167))	('uveal melanoma', 'Phenotype', 'HP:0007716', (152, 166))	('mutations', 'Var', (19, 28))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('GNA11', 'Gene', (41, 46))	('melanomas', 'Phenotype', 'HP:0002861', (158, 167))	('uveal melanomas', 'Disease', (152, 167))	('uveal melanomas', 'Phenotype', 'HP:0007716', (152, 167))	('occur', 'Reg', (133, 138))	('GNA11', 'Gene', '2767', (41, 46))
131414	24713608	These mutations lead to constitutive activation of pathways involved in proliferation, differentiation, and apoptosis, including the protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) pathways.	('PKC', 'Gene', (151, 154))	('PKC', 'Gene', '112476', (151, 154))	('MAPK', 'molecular_function', 'GO:0004707', ('194', '198'))	('protein kinase C', 'Gene', (133, 149))	('differentiation', 'CPA', (87, 102))	('activation', 'PosReg', (37, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('PKC', 'molecular_function', 'GO:0004697', ('151', '154'))	('protein kinase C', 'Gene', '112476', (133, 149))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('apoptosis', 'CPA', (108, 117))	('mutations', 'Var', (6, 15))
131415	24713608	GNAQ and GNA11 mutations are thought to be early mutations or initiating events in uveal melanoma pathogenesis, as they are present in benign uveal nevi and almost all uveal melanomas regardless of cytogenetic status or GEP class, and do not correlate with patient survival.	('GNA11', 'Gene', (9, 14))	('uveal melanoma', 'Disease', 'MESH:C536494', (168, 182))	('uveal melanoma', 'Disease', (83, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('pathogenesis', 'biological_process', 'GO:0009405', ('98', '110'))	('nevi', 'Phenotype', 'HP:0003764', (148, 152))	('mutations', 'Var', (15, 24))	('patient', 'Species', '9606', (257, 264))	('uveal melanomas', 'Phenotype', 'HP:0007716', (168, 183))	('uveal melanomas regardless', 'Disease', 'MESH:C536494', (168, 194))	('GNAQ', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanomas', 'Phenotype', 'HP:0002861', (174, 183))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('uveal melanoma', 'Disease', 'MESH:C536494', (83, 97))	('uveal melanomas regardless', 'Disease', (168, 194))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('GNA11', 'Gene', '2767', (9, 14))
131417	24713608	In uveal melanoma cell lines and xenograft animal models with GNAQ or GNA11 mutations, combination treatment with PKC and MAPK inhibitors had a synergistic effect in reducing tumor progression, showing improved efficacy than treatment with either agent alone.	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('tumor', 'Disease', (175, 180))	('mutations', 'Var', (76, 85))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('MAPK', 'molecular_function', 'GO:0004707', ('122', '126'))	('PKC', 'Gene', (114, 117))	('PKC', 'Gene', '112476', (114, 117))	('PKC', 'molecular_function', 'GO:0004697', ('114', '117'))	('GNAQ', 'Gene', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('GNA11', 'Gene', '2767', (70, 75))	('reducing', 'NegReg', (166, 174))	('GNA11', 'Gene', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))	('combination', 'Interaction', (87, 98))
131418	24713608	Additionally, the phosphoinositide 3-kinase (PI3K)/AKT pathway has also been shown to be activated in uveal melanoma, and may be due to GNAQ mutations or loss of phosphatase and tensin homolog (PTEN) activity.	('PTEN) activity', 'molecular_function', 'GO:0051800', ('194', '208'))	('mutations', 'Var', (141, 150))	('AKT', 'Gene', (51, 54))	('phosphatase', 'molecular_function', 'GO:0016791', ('162', '173'))	('PTEN', 'Gene', (194, 198))	('GNAQ', 'Gene', (136, 140))	('PI3K', 'molecular_function', 'GO:0016303', ('45', '49'))	('PTEN', 'Gene', '5728', (194, 198))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('162', '192'))	('activity', 'MPA', (200, 208))	('activated', 'PosReg', (89, 98))	('uveal melanoma', 'Disease', (102, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (102, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('loss', 'NegReg', (154, 158))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('AKT', 'Gene', '207', (51, 54))
131422	24713608	As loss of one copy of chromosome 3 is known to be a poor prognostic indicator and is associated with uveal melanoma metastasis, we conducted exome sequencing of uveal melanoma samples with only one copy of chromosome 3 (monosomy 3) to look for DNA mutations on the remaining chromosome 3 that may occur on potential tumor suppressor genes important in uveal melanoma pathogenesis.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('melanoma', 'Phenotype', 'HP:0002861', (359, 367))	('uveal melanoma', 'Disease', (162, 176))	('uveal melanoma', 'Disease', 'MESH:C536494', (162, 176))	('uveal melanoma metastasis', 'Disease', (102, 127))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('uveal melanoma', 'Disease', 'MESH:C536494', (353, 367))	('uveal melanoma', 'Disease', (353, 367))	('DNA', 'cellular_component', 'GO:0005574', ('245', '248'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (162, 176))	('chromosome', 'cellular_component', 'GO:0005694', ('23', '33'))	('associated', 'Reg', (86, 96))	('pathogenesis', 'biological_process', 'GO:0009405', ('368', '380'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (353, 367))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('chromosome', 'cellular_component', 'GO:0005694', ('276', '286'))	('tumor', 'Disease', (317, 322))	('uveal melanoma metastasis', 'Disease', 'MESH:C536494', (102, 127))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('317', '333'))	('uveal melanoma', 'Disease', 'MESH:C536494', (102, 116))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('loss', 'Var', (3, 7))	('tumor suppressor', 'biological_process', 'GO:0051726', ('317', '333'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('chromosome', 'cellular_component', 'GO:0005694', ('207', '217'))
131423	24713608	These analyses led to the discovery that BRCA1-associated protein 1 (BAP1) had mutations on 3p21.1 in 85% of class 2 uveal melanomas and almost never in class 1 tumors.	('BRCA1-associated protein 1', 'Gene', '8314', (41, 67))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('BAP1', 'Gene', (69, 73))	('BRCA1-associated protein 1', 'Gene', (41, 67))	('uveal melanomas', 'Disease', (117, 132))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('uveal melanomas', 'Phenotype', 'HP:0007716', (117, 132))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('uveal melanomas', 'Disease', 'MESH:C536494', (117, 132))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('uveal melanoma', 'Phenotype', 'HP:0007716', (117, 131))	('mutations', 'Var', (79, 88))	('BAP1', 'Gene', '8314', (69, 73))
131427	24713608	One set of genes that are affected by loss of BAP1 is that involved in melanocyte differentiation and function; loss of BAP1 causes uveal melanoma cells to revert to a de-differentiated, stem cell-like state that possibly contributes to their prometastatic behavior.	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('BAP1', 'Gene', '8314', (46, 50))	('uveal melanoma', 'Phenotype', 'HP:0007716', (132, 146))	('uveal melanoma', 'Disease', (132, 146))	('uveal melanoma', 'Disease', 'MESH:C536494', (132, 146))	('causes', 'Reg', (125, 131))	('BAP1', 'Gene', '8314', (120, 124))	('BAP1', 'Gene', (46, 50))	('loss', 'Var', (112, 116))	('melanocyte differentiation', 'biological_process', 'GO:0030318', ('71', '97'))	('BAP1', 'Gene', (120, 124))
131430	24713608	In our original report of BAP1 mutations in uveal melanoma, we described a patient with a germ-line BAP1 mutation, thereby providing the first evidence that BAP1 represents a hereditary cancer susceptibility gene.	('BAP1', 'Gene', '8314', (100, 104))	('BAP1', 'Gene', (26, 30))	('hereditary cancer', 'Disease', (175, 192))	('mutations', 'Var', (31, 40))	('mutation', 'Var', (105, 113))	('BAP1', 'Gene', (157, 161))	('patient', 'Species', '9606', (75, 82))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('BAP1', 'Gene', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('BAP1', 'Gene', '8314', (26, 30))	('BAP1', 'Gene', '8314', (157, 161))	('uveal melanoma', 'Disease', (44, 58))	('hereditary cancer', 'Disease', 'MESH:D009369', (175, 192))
131432	24713608	We estimate that perhaps 2-3% of patients with uveal melanoma may have a germline BAP1 mutation.	('BAP1', 'Gene', (82, 86))	('patients', 'Species', '9606', (33, 41))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('uveal melanoma', 'Disease', (47, 61))	('BAP1', 'Gene', '8314', (82, 86))	('mutation', 'Var', (87, 95))
131433	24713608	Cognizance of the BAP1 familial cancer syndrome and identification of patients with germline BAP1 mutations are now critical for physicians taking care of patients with uveal melanoma, as these patients have increased risk of developing metastasis from their uveal melanoma and are at risk for multiple other types of cancer.	('cancer', 'Disease', (318, 324))	('uveal melanoma', 'Phenotype', 'HP:0007716', (259, 273))	('BAP1', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('familial cancer syndrome', 'Disease', 'MESH:D009386', (23, 47))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('patients', 'Species', '9606', (155, 163))	('patients', 'Species', '9606', (70, 78))	('BAP1', 'Gene', '8314', (93, 97))	('uveal melanoma', 'Disease', 'MESH:C536494', (169, 183))	('cancer', 'Disease', (32, 38))	('uveal melanoma', 'Disease', (169, 183))	('developing metastasis', 'CPA', (226, 247))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('patients', 'Species', '9606', (194, 202))	('uveal melanoma', 'Phenotype', 'HP:0007716', (169, 183))	('BAP1', 'Gene', (93, 97))	('familial cancer syndrome', 'Disease', (23, 47))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('BAP1', 'Gene', '8314', (18, 22))	('uveal melanoma', 'Disease', 'MESH:C536494', (259, 273))	('mutations', 'Var', (98, 107))	('uveal melanoma', 'Disease', (259, 273))
131434	24713608	In contrast to our findings with BAP1, we discovered that mutations in the splicing factor 3b subunit 1 (SF3B1) occurred in about 19% of uveal melanomas and were associated with a favorable prognosis.	('mutations', 'Var', (58, 67))	('SF3B1', 'Gene', (105, 110))	('splicing factor 3b subunit 1', 'Gene', (75, 103))	('uveal melanomas', 'Disease', (137, 152))	('uveal melanomas', 'Phenotype', 'HP:0007716', (137, 152))	('BAP1', 'Gene', '8314', (33, 37))	('SF3B1', 'Gene', '23451', (105, 110))	('associated', 'Reg', (162, 172))	('splicing factor 3b subunit 1', 'Gene', '23451', (75, 103))	('uveal melanomas', 'Disease', 'MESH:C536494', (137, 152))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('occurred', 'Reg', (112, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (137, 151))	('BAP1', 'Gene', (33, 37))	('splicing', 'biological_process', 'GO:0045292', ('75', '83'))	('melanomas', 'Phenotype', 'HP:0002861', (143, 152))
131436	24713608	Mutations in SF3B1 result in alternative splicing of a select group of mRNAs, and it is not clear how these mutations promote cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('splicing', 'biological_process', 'GO:0045292', ('41', '49'))	('SF3B1', 'Gene', (13, 18))	('result in', 'Reg', (19, 28))	('alternative splicing', 'MPA', (29, 49))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('Mutations', 'Var', (0, 9))	('SF3B1', 'Gene', '23451', (13, 18))	('promote', 'PosReg', (118, 125))
131437	24713608	Our findings have been verified by Martin et al., who also identified mutations in eukaryotic translation initiation factor 1A, X-linked (EIF1AX) in 24% of uveal melanomas, which were also associated with good prognosis.	('EIF1AX', 'Gene', '1964', (138, 144))	('EIF1AX', 'Gene', (138, 144))	('mutations', 'Var', (70, 79))	('translation initiation', 'biological_process', 'GO:0006413', ('94', '116'))	('uveal melanomas', 'Disease', 'MESH:C536494', (156, 171))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('uveal melanoma', 'Phenotype', 'HP:0007716', (156, 170))	('eukaryotic translation initiation factor 1A, X-linked', 'Gene', '1964', (83, 136))	('uveal melanomas', 'Disease', (156, 171))	('uveal melanomas', 'Phenotype', 'HP:0007716', (156, 171))	('melanomas', 'Phenotype', 'HP:0002861', (162, 171))
131439	24713608	Interestingly, mutations in BAP1, SF3B1, and EIF1AX are largely mutually exclusive with one another.	('BAP1', 'Gene', '8314', (28, 32))	('mutations', 'Var', (15, 24))	('BAP1', 'Gene', (28, 32))	('SF3B1', 'Gene', (34, 39))	('SF3B1', 'Gene', '23451', (34, 39))	('EIF1AX', 'Gene', (45, 51))	('EIF1AX', 'Gene', '1964', (45, 51))
131449	24713608	For example, pharmacologic inhibitors of MEK, AKT and/or PKC may be more effective in tumors with GNAQ/11 mutations, whereas HDAC inhibitors may play a role in tumors with BAP1 mutations.	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('AKT', 'Gene', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', (86, 92))	('BAP1', 'Gene', '8314', (172, 176))	('PKC', 'Gene', '112476', (57, 60))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('AKT', 'Gene', '207', (46, 49))	('MEK', 'Gene', '5609', (41, 44))	('HDAC', 'Gene', '9734', (125, 129))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('PKC', 'molecular_function', 'GO:0004697', ('57', '60'))	('GNAQ/11', 'Gene', (98, 105))	('PKC', 'Gene', (57, 60))	('HDAC', 'Gene', (125, 129))	('MEK', 'Gene', (41, 44))	('BAP1', 'Gene', (172, 176))	('mutations', 'Var', (106, 115))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
131458	24713608	In uveal melanoma patients who are assessed for DNA mutations in GNAQ, GNA11, and BAP1, the DNA mutations have been shown to turn on or off various cellular pathways.	('mutations', 'Var', (52, 61))	('BAP1', 'Gene', (82, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('GNA11', 'Gene', (71, 76))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('GNA11', 'Gene', '2767', (71, 76))	('GNAQ', 'Gene', (65, 69))	('turn on', 'Reg', (125, 132))	('BAP1', 'Gene', '8314', (82, 86))	('patients', 'Species', '9606', (18, 26))	('cellular pathways', 'Pathway', (148, 165))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))	('mutations', 'Var', (96, 105))
131462	24713608	Future studies that lead to better understanding of uveal melanoma pathogenesis and the effects of the DNA mutations will likely lead to better therapeutic strategies.	('uveal melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('uveal melanoma', 'Disease', (52, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (52, 66))	('lead', 'Reg', (129, 133))	('mutations', 'Var', (107, 116))	('DNA', 'Gene', (103, 106))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('pathogenesis', 'biological_process', 'GO:0009405', ('67', '79'))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
131464	24713608	GNAQ or GNA11 mutations are mutually exclusive and represent early events in the development of uveal melanoma.	('GNA11', 'Gene', (8, 13))	('uveal melanoma', 'Disease', (96, 110))	('GNA11', 'Gene', '2767', (8, 13))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('GNAQ', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('uveal melanoma', 'Disease', 'MESH:C536494', (96, 110))
131465	24713608	BAP1, SF3B1, and EIF1AX mutations appear to represent downstream mutations that are, for the most part, mutually exclusive with each other.	('SF3B1', 'Gene', (6, 11))	('BAP1', 'Gene', (0, 4))	('SF3B1', 'Gene', '23451', (6, 11))	('EIF1AX', 'Gene', '1964', (17, 23))	('EIF1AX', 'Gene', (17, 23))	('mutations', 'Var', (24, 33))	('BAP1', 'Gene', '8314', (0, 4))
131466	24713608	SF3B1 and EIF1AX mutations are associated with the class 1 gene expression profile and good prognosis, whereas BAP1 mutations are associated with the class 2 profile and poor prognosis.	('class 1 gene expression profile', 'MPA', (51, 82))	('SF3B1', 'Gene', (0, 5))	('BAP1', 'Gene', '8314', (111, 115))	('associated', 'Reg', (31, 41))	('SF3B1', 'Gene', '23451', (0, 5))	('BAP1', 'Gene', (111, 115))	('mutations', 'Var', (116, 125))	('gene expression', 'biological_process', 'GO:0010467', ('59', '74'))	('EIF1AX', 'Gene', '1964', (10, 16))	('EIF1AX', 'Gene', (10, 16))	('mutations', 'Var', (17, 26))
131467	24713608	An increasing number of clinical trials are becoming available for patients at high risk for metastasis (class 2) or with overt metastatic disease using targeted therapies based on GNAQ/11 and BAP1 mutations.	('GNAQ/11', 'Gene', (181, 188))	('patients', 'Species', '9606', (67, 75))	('metastasis', 'CPA', (93, 103))	('BAP1', 'Gene', '8314', (193, 197))	('mutations', 'Var', (198, 207))	('BAP1', 'Gene', (193, 197))
131732	25768983	Transcriptome Sequencing Reveals Potential Mechanism of Cryptic 3' Splice Site Selection in SF3B1-mutated Cancers Mutations in the splicing factor SF3B1 are found in several cancer types and have been associated with various splicing defects.	('SF3B1', 'Gene', (147, 152))	('SF3B1', 'Gene', '23451', (92, 97))	('splicing', 'biological_process', 'GO:0045292', ('225', '233'))	('Cryptic', 'Gene', (56, 63))	('Mutations', 'Var', (114, 123))	('Splice Site Selection', 'biological_process', 'GO:0000380', ('67', '88'))	('Cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Disease', (174, 180))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('SF3B1', 'Gene', '23451', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('found', 'Reg', (157, 162))	('SF3B1', 'Gene', (92, 97))	('splicing defects', 'MPA', (225, 241))	('Splice Site Selection', 'biological_process', 'GO:0000381', ('67', '88'))	('Cancers', 'Disease', (106, 113))	('splicing', 'biological_process', 'GO:0045292', ('131', '139'))	('Cryptic', 'Gene', '55997', (56, 63))	('Cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('associated', 'Reg', (201, 211))
131733	25768983	Using transcriptome sequencing data from chronic lymphocytic leukemia, breast cancer and uveal melanoma tumor samples, we show that hundreds of cryptic 3' splice sites (3'SSs) are used in cancers with SF3B1 mutations.	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (41, 69))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('chronic lymphocytic leukemia', 'Disease', (41, 69))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('uveal melanoma tumor', 'Disease', 'MESH:C536494', (89, 109))	('SF3B1', 'Gene', (201, 206))	('breast cancer', 'Disease', (71, 84))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (41, 69))	('mutations', 'Var', (207, 216))	('leukemia', 'Phenotype', 'HP:0001909', (61, 69))	('SF3B1', 'Gene', '23451', (201, 206))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancers', 'Disease', (188, 195))	('uveal melanoma', 'Phenotype', 'HP:0007716', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('uveal melanoma tumor', 'Disease', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cryptic', 'Gene', '55997', (144, 151))	('cryptic', 'Gene', (144, 151))
131734	25768983	We define the necessary sequence context for the observed cryptic 3' SSs and propose that cryptic 3'SS selection is a result of SF3B1 mutations causing a shift in the sterically protected region downstream of the branch point.	('causing', 'Reg', (144, 151))	('SF3B1', 'Gene', '23451', (128, 133))	('cryptic', 'Gene', '55997', (58, 65))	('cryptic', 'Gene', (58, 65))	('mutations', 'Var', (134, 143))	('SF3B1', 'Gene', (128, 133))	('cryptic', 'Gene', '55997', (90, 97))	('cryptic', 'Gene', (90, 97))
131736	25768983	We show that cancers with mutations in the SF3B1 HEAT 5-9 repeats use cryptic 3'SSs downstream of the branch point and provide both a mechanistic model consistent with published experimental data and affected targets that will guide further research into the oncogenic effects of SF3B1 mutation.	('SF3B1', 'Gene', (43, 48))	('SF3B1', 'Gene', (280, 285))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('SF3B1', 'Gene', '23451', (280, 285))	('SF3B1', 'Gene', '23451', (43, 48))	('mutations', 'Var', (26, 35))	('cancers', 'Disease', (13, 20))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cryptic', 'Gene', '55997', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('cryptic', 'Gene', (70, 77))
131738	25768983	Many such recurrently mutated genes have been identified over the last few years, but we often do not know the underlying mechanisms by which they contribute to cancer growth.	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('mutated', 'Var', (22, 29))
131739	25768983	Unexpectedly, several genes in the spliceosome, the collection of RNAs and proteins that remove introns from transcribed RNAs, are recurrently mutated in different cancers.	('spliceosome', 'cellular_component', 'GO:0005681', ('35', '46'))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Disease', (164, 171))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('mutated', 'Var', (143, 150))
131740	25768983	Here, we have examined mutations in the splicing factor SF3B1, a key component of the spliceosome, and identified a global splicing defect present in different cancers with SF3B1 mutations by comparing the expression of splice junctions using generalized linear models.	('SF3B1', 'Gene', '23451', (173, 178))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('splicing', 'MPA', (123, 131))	('cancers', 'Disease', (160, 167))	('splicing', 'biological_process', 'GO:0045292', ('40', '48'))	('defect', 'NegReg', (132, 138))	('mutations', 'Var', (23, 32))	('SF3B1', 'Gene', (56, 61))	('splicing', 'biological_process', 'GO:0045292', ('123', '131'))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('mutations', 'Var', (179, 188))	('SF3B1', 'Gene', (173, 178))	('SF3B1', 'Gene', '23451', (56, 61))	('spliceosome', 'cellular_component', 'GO:0005681', ('86', '97'))
131741	25768983	While prior studies have reported a limited number of aberrant splicing events in SF3B1-mutated cancers, we have established that SF3B1 mutations are associated with usage of hundreds of atypical splice sites at the 3' end of the intron.	('associated', 'Reg', (150, 160))	('SF3B1', 'Gene', (82, 87))	('SF3B1', 'Gene', (130, 135))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('SF3B1', 'Gene', '23451', (82, 87))	('SF3B1', 'Gene', '23451', (130, 135))	('mutations', 'Var', (136, 145))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))	('splicing', 'biological_process', 'GO:0045292', ('63', '71'))
131743	25768983	These findings greatly expand our understanding of the effect of SF3B1 mutations on splicing and provide new targets for determining the oncogenic effect of SF3B1 mutations.	('SF3B1', 'Gene', (157, 162))	('splicing', 'MPA', (84, 92))	('SF3B1', 'Gene', '23451', (157, 162))	('SF3B1', 'Gene', (65, 70))	('splicing', 'biological_process', 'GO:0045292', ('84', '92'))	('mutations', 'Var', (71, 80))	('SF3B1', 'Gene', '23451', (65, 70))
131744	25768983	One of the biggest surprises to emerge from the growing catalog of somatic mutations in various cancer types is the recurrent mutation of genes encoding the RNA spliceosome.	('RNA', 'cellular_component', 'GO:0005562', ('157', '160'))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutation', 'Var', (126, 134))	('spliceosome', 'cellular_component', 'GO:0005681', ('161', '172'))	('mutations', 'Var', (75, 84))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
131745	25768983	Recurrent mutations in the highly conserved HEAT 5-9 repeats of splicing factor 3B subunit 1 (SF3B1) have been reported in myelodysplastic syndrome, chronic lymphocytic leukemia (CLL), breast cancer (BRCA), uveal melanoma (UM), and pancreatic cancer.	('SF3B1', 'Gene', '23451', (94, 99))	('splicing', 'biological_process', 'GO:0045292', ('64', '72'))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (123, 147))	('splicing factor 3B subunit 1', 'Gene', (64, 92))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (123, 147))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (232, 249))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (149, 177))	('pancreatic cancer', 'Disease', (232, 249))	('chronic lymphocytic leukemia', 'Disease', (149, 177))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (149, 177))	('BRCA', 'Gene', '672', (200, 204))	('splicing factor 3B subunit 1', 'Gene', '23451', (64, 92))	('uveal melanoma', 'Disease', 'MESH:C536494', (207, 221))	('reported', 'Reg', (111, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('uveal melanoma', 'Disease', (207, 221))	('SF3B1', 'Gene', (94, 99))	('pancreatic cancer', 'Disease', 'MESH:D010190', (232, 249))	('myelodysplastic syndrome', 'Disease', (123, 147))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('uveal melanoma', 'Phenotype', 'HP:0007716', (207, 221))	('breast cancer', 'Disease', (185, 198))	('BRCA', 'Gene', (200, 204))	('leukemia', 'Phenotype', 'HP:0001909', (169, 177))	('mutations', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
131746	25768983	SF3B1 mutation is associated with poor prognosis in CLL but improved prognosis in myelodysplasia and UM.	('myelodysplasia', 'Phenotype', 'HP:0002863', (82, 96))	('SF3B1', 'Gene', (0, 5))	('prognosis', 'MPA', (69, 78))	('mutation', 'Var', (6, 14))	('CLL', 'Disease', (52, 55))	('myelodysplasia', 'Disease', 'MESH:D009190', (82, 96))	('SF3B1', 'Gene', '23451', (0, 5))	('myelodysplasia', 'Disease', (82, 96))	('improved', 'PosReg', (60, 68))
131747	25768983	Prior studies have shown that mutated SF3B1 CLL samples have differential exon inclusion and use some cryptic 3' splice sites (3'SSs) relative to wild-type SF3B1 CLL samples.	('differential', 'Reg', (61, 73))	('SF3B1', 'Gene', (38, 43))	('SF3B1', 'Gene', '23451', (156, 161))	('mutated', 'Var', (30, 37))	('cryptic', 'Gene', '55997', (102, 109))	('SF3B1', 'Gene', '23451', (38, 43))	('cryptic', 'Gene', (102, 109))	('exon inclusion', 'MPA', (74, 88))	('SF3B1', 'Gene', (156, 161))
131748	25768983	However, it is unknown whether SF3B1 mutation is associated with the same 3'SS selection defects in different cancers.	('cancers', 'Disease', (110, 117))	('mutation', 'Var', (37, 45))	('associated', 'Reg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('SF3B1', 'Gene', (31, 36))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('SF3B1', 'Gene', '23451', (31, 36))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
131753	25768983	The role of SF3B1 and the U2-snRNP in recognizing and binding the BP and the localization of mutations to HEAT 5-9 repeats suggest that SF3B1 mutations are dominant drivers that may alter 3'SS selection.	('SF3B1', 'Gene', (12, 17))	('localization', 'biological_process', 'GO:0051179', ('77', '89'))	('mutations', 'Var', (142, 151))	('SF3B1', 'Gene', (136, 141))	('binding', 'molecular_function', 'GO:0005488', ('54', '61'))	("3'SS selection", 'MPA', (188, 202))	('SF3B1', 'Gene', '23451', (12, 17))	('SF3B1', 'Gene', '23451', (136, 141))	('alter', 'Reg', (182, 187))	('snRNP', 'molecular_function', 'GO:0003734', ('29', '34'))	('U2-snRNP', 'cellular_component', 'GO:0005686', ('26', '34'))
131754	25768983	To test this, we examined splice site usage in transcriptome data from SF3B1 mutant and SF3B1 wild-type CLL, UM and BRCA cases.	('SF3B1', 'Gene', (71, 76))	('SF3B1', 'Gene', '23451', (88, 93))	('SF3B1', 'Gene', '23451', (71, 76))	('mutant', 'Var', (77, 83))	('SF3B1', 'Gene', (88, 93))	('BRCA', 'Gene', (116, 120))	('BRCA', 'Gene', '672', (116, 120))
131755	25768983	We identified 619 cryptic 3'SSs used more frequently in SF3B1 mutants and clustered 10-30 bp upstream of canonical 3'SSs.	('cryptic', 'Gene', (18, 25))	('mutants', 'Var', (62, 69))	('SF3B1', 'Gene', (56, 61))	('cryptic', 'Gene', '55997', (18, 25))	('SF3B1', 'Gene', '23451', (56, 61))
131756	25768983	The majority of these cryptic 3'SSs were observed in all three tumor types despite the divergent clinical implications of SF3B1 mutation.	('tumor', 'Disease', (63, 68))	('SF3B1', 'Gene', (122, 127))	('cryptic', 'Gene', '55997', (22, 29))	('cryptic', 'Gene', (22, 29))	('SF3B1', 'Gene', '23451', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mutation', 'Var', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
131757	25768983	Our analysis of tumors with SF3B1 mutations shows that cryptic 3'SS selection occurs only in samples with missense mutations at ~10 amino acid hotspots in the fifth to ninth HEAT repeats.	('cryptic', 'Gene', (55, 62))	('missense mutations', 'Var', (106, 124))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('SF3B1', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	("3'SS", 'MPA', (63, 67))	('SF3B1', 'Gene', '23451', (28, 33))	('tumors', 'Disease', (16, 22))	('mutations', 'Var', (34, 43))	('cryptic', 'Gene', '55997', (55, 62))
131758	25768983	We analyzed the organization of splicing motifs around the cryptic 3'SSs and found that only introns with an AG dinucleotide at the boundary of the sterically protected region downstream of the BP but >10 bp upstream of the canonical 3'SS are susceptible to cryptic 3'SS selection in SF3B1 mutants.	('SF3B1', 'Gene', (284, 289))	('splicing', 'biological_process', 'GO:0045292', ('32', '40'))	('SF3B1', 'Gene', '23451', (284, 289))	('cryptic', 'Gene', '55997', (59, 66))	('cryptic', 'Gene', '55997', (258, 265))	('mutants', 'Var', (290, 297))	('cryptic', 'Gene', (59, 66))	('cryptic', 'Gene', (258, 265))
131759	25768983	We assessed the functional impact of SF3B1 mutation and found that the cryptic 3'SSs are typically used at low frequency in the SF3B1 mutants (<10% relative to the canonical splice site) and are sometimes present in the SF3B1 wild-types but at an even lower frequency (<0.5% relative to the canonical splice site).	('SF3B1', 'Gene', '23451', (128, 133))	('cryptic', 'Gene', '55997', (71, 78))	('SF3B1', 'Gene', '23451', (37, 42))	('cryptic', 'Gene', (71, 78))	('SF3B1', 'Gene', (220, 225))	('mutants', 'Var', (134, 141))	('SF3B1', 'Gene', (37, 42))	('SF3B1', 'Gene', '23451', (220, 225))	('SF3B1', 'Gene', (128, 133))
131761	25768983	We used RNA-sequencing data from SF3B1 mutated and SF3B1 wild-type chronic lymphocytic leukemia (CLL; seven mutant, nine wild-type), breast cancer (BRCA; 14 mutant, 18 wild-type), and uveal melanoma (UM; four mutant, four wild-type) samples (S1 Fig., S1 File) to test 219,476 splice junctions present in the Gencode v14 gene annotation along with 87,941 novel splice junctions (not annotated in Gencode) for differential usage by comparing junction-spanning reads using a generalized linear model as implemented in DEXSeq.	('RNA', 'cellular_component', 'GO:0005562', ('8', '11'))	('BRCA', 'Gene', '672', (148, 152))	('v14', 'Gene', '28815', (316, 319))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('leukemia', 'Phenotype', 'HP:0001909', (87, 95))	('SF3B1', 'Gene', (51, 56))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('SF3B1', 'Gene', (33, 38))	('breast cancer', 'Disease', (133, 146))	('uveal melanoma', 'Disease', 'MESH:C536494', (184, 198))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('uveal melanoma', 'Disease', (184, 198))	('BRCA', 'Gene', (148, 152))	('v14', 'Gene', (316, 319))	('SF3B1', 'Gene', '23451', (51, 56))	('SF3B1', 'Gene', '23451', (33, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (184, 198))	('-type chronic lymphocytic leukemia', 'Phenotype', 'HP:0005539', (61, 95))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (67, 95))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('chronic lymphocytic leukemia', 'Disease', (67, 95))	('mutant', 'Var', (157, 163))	('mutant', 'Var', (108, 114))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (67, 95))	('DEXSeq', 'Chemical', '-', (515, 521))
131763	25768983	We identified 1,749 junctions that were significantly differentially used between the SF3B1 mutant and SF3B1 wild-type samples across the three tumor types including 1,330 novel junctions, of which 1,117 are novel 3'SSs (BH-adjusted p < 0.1, S2 File).	('tumor', 'Disease', (144, 149))	('SF3B1', 'Gene', (86, 91))	('SF3B1', 'Gene', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('mutant', 'Var', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('SF3B1', 'Gene', '23451', (86, 91))	('SF3B1', 'Gene', '23451', (103, 108))
131764	25768983	These 1,749 significant junctions were highly enriched for novel splice junctions compared to annotated junctions (Fisher exact, p < 10-200) and the novel junctions were enriched for novel 3'SSs (Fisher exact, p < 10-200) showing that SF3B1 mutations result in the usage of a large number of novel 3'SSs.	('SF3B1', 'Gene', (235, 240))	('SF3B1', 'Gene', '23451', (235, 240))	('splice junctions', 'MPA', (65, 81))	('mutations', 'Var', (241, 250))
131765	25768983	These 1,749 significant junctions include 61 of 79 splice sites recently reported as specific to CLL cases with SF3B1 mutations supporting the specificity of our approach while demonstrating an increased sensitivity that has allowed us to identify many more cryptic 3'SSs than previously reported.	('SF3B1', 'Gene', '23451', (112, 117))	('mutations', 'Var', (118, 127))	('cryptic', 'Gene', '55997', (258, 265))	('cryptic', 'Gene', (258, 265))	('SF3B1', 'Gene', (112, 117))
131767	25768983	All of the 619 proximal cryptic 3'SSs were used more often in the SF3B1 mutant samples compared to the wild-type samples and 58% were out-of-frame relative to the nearby canonical 3'SSs, suggesting that these are not canonical 3'SSs missing from Gencode.	('cryptic', 'Gene', (24, 31))	('mutant', 'Var', (72, 78))	('SF3B1', 'Gene', (66, 71))	('cryptic', 'Gene', '55997', (24, 31))	('SF3B1', 'Gene', '23451', (66, 71))
131768	25768983	417 of the 498 distal cryptic 3'SSs were also used more highly in the SF3B1 mutants (S4 File).	('cryptic', 'Gene', '55997', (22, 29))	('cryptic', 'Gene', (22, 29))	('mutants', 'Var', (76, 83))	('SF3B1', 'Gene', (70, 75))	('SF3B1', 'Gene', '23451', (70, 75))
131769	25768983	The distribution of the 1,117 significant novel 3'SSs is different from that of novel 3'SSs whose usage did not differ significantly between the SF3B1 mutants and wild-types (Fig.	('SF3B1', 'Gene', (145, 150))	('SF3B1', 'Gene', '23451', (145, 150))	('mutants', 'Var', (151, 158))
131770	25768983	1B,C), further demonstrating that the usage of proximal cryptic 3'SSs is a property of SF3B1 mutants.	('cryptic', 'Gene', '55997', (56, 63))	('cryptic', 'Gene', (56, 63))	('SF3B1', 'Gene', (87, 92))	('mutants', 'Var', (93, 100))	('SF3B1', 'Gene', '23451', (87, 92))
131774	25768983	The SF3B1 mutation for one of these BRCA samples was a nonsense mutation not located in the HEAT 5-9 repeats while another sample had a subclonal (8.4%) HEAT 5-9 mutation with attenuated cryptic 3'SS selection (S3 Fig.).	('cryptic', 'Gene', '55997', (187, 194))	('cryptic', 'Gene', (187, 194))	('SF3B1', 'Gene', (4, 9))	('mutation', 'Var', (10, 18))	('BRCA', 'Gene', '672', (36, 40))	('SF3B1', 'Gene', '23451', (4, 9))	('BRCA', 'Gene', (36, 40))
131775	25768983	We observed cryptic 3'SS selection in a TCGA lung adenocarcinoma sample with a hotspot mutation but not in lung cancer samples with SF3B1 mutations outside of the five hotspots (S4 Fig.).	('cryptic', 'Gene', '55997', (12, 19))	('cryptic', 'Gene', (12, 19))	('SF3B1', 'Gene', '23451', (132, 137))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (45, 64))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	("3'SS", 'MPA', (20, 24))	('mutation', 'Var', (87, 95))	('lung cancer', 'Disease', (107, 118))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (45, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('SF3B1', 'Gene', (132, 137))	('lung adenocarcinoma', 'Disease', (45, 64))
131776	25768983	These results show that cryptic 3'SS selection only occurs in tumors carrying mutations in one of the five ~10 amino acid hotspots in the HEAT 5-9 repeats and is not limited to cancers in which SF3B1 is recurrently mutated.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('SF3B1', 'Gene', '23451', (194, 199))	('tumors', 'Disease', (62, 68))	('cancers', 'Disease', (177, 184))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (78, 87))	('cryptic', 'Gene', '55997', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cryptic', 'Gene', (24, 31))	('SF3B1', 'Gene', (194, 199))
131779	25768983	Differences in cryptic 3'SS usage due to varying gene expression may contribute to the divergent prognostic implications of SF3B1 mutation in various cancers.	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cryptic', 'Gene', '55997', (15, 22))	('mutation', 'Var', (130, 138))	('cancers', 'Disease', (150, 157))	('cryptic', 'Gene', (15, 22))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('SF3B1', 'Gene', (124, 129))	('gene expression', 'biological_process', 'GO:0010467', ('49', '64'))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('SF3B1', 'Gene', '23451', (124, 129))
131780	25768983	To characterize the roles of the genes affected by cryptic 3'SS usage, we performed a gene set enrichment analysis for the 912 genes that contained the 619 proximal and 417 distal cryptic 3'SSs used significantly more often in the SF3B1 mutant samples (S5 File).	('SF3B1', 'Gene', '23451', (231, 236))	('mutant', 'Var', (237, 243))	('cryptic', 'Gene', '55997', (180, 187))	('more often', 'PosReg', (213, 223))	('cryptic', 'Gene', (180, 187))	('cryptic', 'Gene', '55997', (51, 58))	('SF3B1', 'Gene', (231, 236))	('cryptic', 'Gene', (51, 58))
131788	25768983	These results suggest that the increased usage of the 619 proximal and 417 distal cryptic 3'SSs in the SF3B1 mutants may result from the same mechanism.	('increased', 'PosReg', (31, 40))	('cryptic', 'Gene', (82, 89))	('cryptic', 'Gene', '55997', (82, 89))	('SF3B1', 'Gene', (103, 108))	('mutants', 'Var', (109, 116))	('usage', 'MPA', (41, 46))	('SF3B1', 'Gene', '23451', (103, 108))
131794	25768983	Our results suggest that AG dinucleotides serving as cryptic 3'SSs in SF3B1 mutants are located at the end of this sterically protected region downstream of the BP (Fig.	('cryptic', 'Gene', '55997', (53, 60))	('cryptic', 'Gene', (53, 60))	('mutants', 'Var', (76, 83))	('SF3B1', 'Gene', (70, 75))	('SF3B1', 'Gene', '23451', (70, 75))
131796	25768983	1A) indicates that cryptic 3'SSs used in SF3B1 mutants are located far enough upstream of the associated canonical 3'SSs to avoid competition for splicing.	('cryptic', 'Gene', (19, 26))	('cryptic', 'Gene', '55997', (19, 26))	('SF3B1', 'Gene', (41, 46))	('splicing', 'biological_process', 'GO:0045292', ('146', '154'))	('SF3B1', 'Gene', '23451', (41, 46))	('mutants', 'Var', (47, 54))
131799	25768983	providing further evidence that most cryptic 3'SSs (both proximal and distal) associated with SF3B1 mutations are located at the edge of the sterically protected region.	('SF3B1', 'Gene', '23451', (94, 99))	('mutations', 'Var', (100, 109))	("3'SSs", 'Disease', (45, 50))	('cryptic', 'Gene', '55997', (37, 44))	('cryptic', 'Gene', (37, 44))	('SF3B1', 'Gene', (94, 99))
131800	25768983	Our results suggest that the mechanism of cryptic 3'SS selection in SF3B1 mutants is not altered BP recognition because a more varied distribution of distances from the cryptic 3'SS to the canonical 3'SS BP would be expected if BP recognition was altered.	('cryptic', 'Gene', (169, 176))	('SF3B1', 'Gene', (68, 73))	('cryptic', 'Gene', (42, 49))	('SF3B1', 'Gene', '23451', (68, 73))	('cryptic', 'Gene', '55997', (42, 49))	('mutants', 'Var', (74, 81))	('cryptic', 'Gene', '55997', (169, 176))
131804	25768983	These published experimental results and the rigid distance between the BP and the cryptic 3'SSs observed in our study are consistent with a model of altered 3'SS selection in SF3B1 mutants due to a change in the size of the sterically hindered region downstream of the BP.	('size of the sterically hindered region', 'MPA', (213, 251))	('change', 'Reg', (199, 205))	('SF3B1', 'Gene', (176, 181))	('cryptic', 'Gene', (83, 90))	('SF3B1', 'Gene', '23451', (176, 181))	('cryptic', 'Gene', '55997', (83, 90))	('mutants', 'Var', (182, 189))
131806	25768983	For 900 of these introns, the potential cryptic 3'SSs also passed the coverage cutoff, of which 310 were used significantly more often in the SF3B1 mutants.	('cryptic', 'Gene', '55997', (40, 47))	('mutants', 'Var', (148, 155))	('cryptic', 'Gene', (40, 47))	('SF3B1', 'Gene', (142, 147))	('SF3B1', 'Gene', '23451', (142, 147))
131807	25768983	This analysis demonstrates that not every potential cryptic 3'SS is differentially used in the mutants, so the sequence requirements described here appear to be necessary for cryptic 3'SS usage but not sufficient.	('cryptic', 'Gene', (52, 59))	('cryptic', 'Gene', '55997', (175, 182))	('cryptic', 'Gene', (175, 182))	('mutants', 'Var', (95, 102))	('cryptic', 'Gene', '55997', (52, 59))
131808	25768983	Although the cryptic splice sites described here are used significantly more often in the SF3B1 mutants, the biological effects are likely dependent on the proportion of transcripts that use the cryptic 3'SSs relative to the canonical 3'SSs.	('cryptic', 'Gene', '55997', (13, 20))	('cryptic', 'Gene', '55997', (195, 202))	('SF3B1', 'Gene', (90, 95))	('cryptic', 'Gene', (13, 20))	('cryptic', 'Gene', (195, 202))	('SF3B1', 'Gene', '23451', (90, 95))	('mutants', 'Var', (96, 103))
131810	25768983	that allows for more accurate quantification of splicing and because the distribution of well-characterized low- and high-risk CLL prognostic factors was similar between the SF3B1 mutated and wild-type samples (Fig.	('SF3B1', 'Gene', '23451', (174, 179))	('splicing', 'biological_process', 'GO:0045292', ('48', '56'))	('mutated', 'Var', (180, 187))	('SF3B1', 'Gene', (174, 179))
131811	25768983	To calculate PSI for the 325 proximal cryptic 3'SSs used significantly more often in the SF3B1 mutants from the CLL-only analysis (S6-S7 Files), we divided the number of reads that span the cryptic 3'SS by the number of reads that span both the cryptic 3'SS and its associated canonical 3'SS.	('SF3B1', 'Gene', (89, 94))	('cryptic', 'Gene', '55997', (245, 252))	('cryptic', 'Gene', '55997', (190, 197))	('cryptic', 'Gene', (245, 252))	('cryptic', 'Gene', (190, 197))	('SF3B1', 'Gene', '23451', (89, 94))	('cryptic', 'Gene', '55997', (38, 45))	('mutants', 'Var', (95, 102))	('cryptic', 'Gene', (38, 45))
131812	25768983	We observed that some cryptic 3'SSs are used exclusively in SF3B1 mutants while others are also used in SF3B1 wild-type samples but at a lower frequency relative to the mutants (Fig.	('SF3B1', 'Gene', (60, 65))	('mutants', 'Var', (66, 73))	('cryptic', 'Gene', '55997', (22, 29))	('cryptic', 'Gene', (22, 29))	('SF3B1', 'Gene', '23451', (60, 65))	('SF3B1', 'Gene', (104, 109))	('SF3B1', 'Gene', '23451', (104, 109))
131814	25768983	These results suggest that the cryptic splice sites are either included rarely even in the SF3B1 mutants or that transcripts with cryptic splice sites are subject to a higher rate of nonsense-mediated decay (NMD).	('SF3B1', 'Gene', (91, 96))	('cryptic', 'Gene', '55997', (130, 137))	('SF3B1', 'Gene', '23451', (91, 96))	('cryptic', 'Gene', (130, 137))	('mutants', 'Var', (97, 104))	('nonsense-mediated decay', 'MPA', (183, 206))	('higher', 'PosReg', (168, 174))	('cryptic', 'Gene', (31, 38))	('cryptic', 'Gene', '55997', (31, 38))
131815	25768983	To investigate the potential role of NMD, we identified differentially expressed genes between the SF3B1 mutant and wild-type samples in a joint analysis of all three cancers and performed a gene set enrichment analysis.	('SF3B1', 'Gene', (99, 104))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cancers', 'Disease', (167, 174))	('SF3B1', 'Gene', '23451', (99, 104))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('mutant', 'Var', (105, 111))
131816	25768983	We found that genes in the "Reactome NMD enhanced by the exon junction complex" set were enriched (GSEA, q < 10-28) among the 272 differentially expressed genes (DESeq2, BH-adjusted p < 0.1, S8-S9 Files) suggesting that NMD may be different between the SF3B1 mutants and wild-types.	('SF3B1', 'Gene', '23451', (253, 258))	('GSEA', 'Chemical', '-', (99, 103))	('SF3B1', 'Gene', (253, 258))	('mutants', 'Var', (259, 266))
131817	25768983	33 of the 582 genes that contained the 619 proximal cryptic 3'SSs were differentially expressed with the expression of 29/33 of these genes lower in the SF3B1 mutants.	('cryptic', 'Gene', (52, 59))	('SF3B1', 'Gene', '23451', (153, 158))	('lower', 'NegReg', (140, 145))	('mutants', 'Var', (159, 166))	('SF3B1', 'Gene', (153, 158))	('expression', 'MPA', (105, 115))	('cryptic', 'Gene', '55997', (52, 59))
131818	25768983	Genes containing a proximal cryptic 3'SSs were more likely to be differentially expressed (Fisher exact, p < 10-8) and more likely to have lower expression in SF3B1 mutants (Fisher exact, p = 0.0009).	('mutants', 'Var', (165, 172))	('SF3B1', 'Gene', (159, 164))	('expression', 'MPA', (145, 155))	('differentially', 'Reg', (65, 79))	('lower', 'NegReg', (139, 144))	('cryptic', 'Gene', '55997', (28, 35))	('SF3B1', 'Gene', '23451', (159, 164))	('cryptic', 'Gene', (28, 35))
131822	25768983	To identify cryptic 3'SSs with relatively high PSI values in the SF3B1 mutant versus wild-type samples, we searched for cryptic 3'SSs that were 1) used more than 50% of the time in the CLL SF3B1 mutants; 2) used less than 20% of the time in wild-type samples; and 3) had an average coverage of at least 30 junction-spanning reads in the mutant samples.	('cryptic', 'Gene', '55997', (12, 19))	('mutants', 'Var', (195, 202))	('cryptic', 'Gene', (12, 19))	('mutant', 'Var', (337, 343))	('SF3B1', 'Gene', (189, 194))	('SF3B1', 'Gene', (65, 70))	('mutant', 'Var', (71, 77))	('cryptic', 'Gene', '55997', (120, 127))	('SF3B1', 'Gene', '23451', (189, 194))	('cryptic', 'Gene', (120, 127))	('SF3B1', 'Gene', '23451', (65, 70))
131823	25768983	Despite the generally low PSI values for the 325 cryptic 3'SSs from the CLL-only analysis, we identified four genes previously implicated in cancer (TTI1, MAP3K7, FXYD5, PFDN5) and six others (YIF1A, ORAI2, ZNF91, ZNF548, RP11-1280I22.1, RP11-532F12.5) with out-of-frame cryptic 3'SSs that were consistently preferred to the associated canonical 3'SS in the CLL SF3B1 mutant samples (Fig.	('YIF1A', 'Gene', '10897', (193, 198))	('mutant', 'Var', (368, 374))	('ZNF548', 'Gene', '147694', (214, 220))	('PFDN5', 'Gene', '5204', (170, 175))	('PFDN5', 'Gene', (170, 175))	('MAP3K', 'molecular_function', 'GO:0004709', ('155', '160'))	('FXYD5', 'Gene', '53827', (163, 168))	('SF3B1', 'Gene', '23451', (362, 367))	('RP11', 'Gene', '26121', (238, 242))	('RP11', 'Gene', '26121', (222, 226))	('MAP3K7', 'Gene', (155, 161))	('cancer', 'Disease', (141, 147))	('ZNF91', 'Gene', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('ORAI2', 'Gene', (200, 205))	('MAP3K7', 'Gene', '6885', (155, 161))	('FXYD5', 'Gene', (163, 168))	('ZNF548', 'Gene', (214, 220))	('cryptic', 'Gene', '55997', (271, 278))	('ZNF91', 'Gene', '7644', (207, 212))	('cryptic', 'Gene', '55997', (49, 56))	('implicated', 'Reg', (127, 137))	('cryptic', 'Gene', (271, 278))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cryptic', 'Gene', (49, 56))	('TTI1', 'Gene', (149, 153))	('ORAI2', 'Gene', '80228', (200, 205))	('RP11', 'Gene', (238, 242))	('RP11', 'Gene', (222, 226))	('YIF1A', 'Gene', (193, 198))	('SF3B1', 'Gene', (362, 367))	('TTI1', 'Gene', '9675', (149, 153))
131824	25768983	identified the junctions in ORAI2, ZNF91, and TTI1 in CLL SF3B1 mutants as well.	('TTI1', 'Gene', (46, 50))	('SF3B1', 'Gene', (58, 63))	('ZNF91', 'Gene', '7644', (35, 40))	('SF3B1', 'Gene', '23451', (58, 63))	('mutants', 'Var', (64, 71))	('ZNF91', 'Gene', (35, 40))	('ORAI2', 'Gene', '80228', (28, 33))	('TTI1', 'Gene', '9675', (46, 50))	('ORAI2', 'Gene', (28, 33))
131825	25768983	Nine of the ten junctions were significant in our BRCA-only analysis and showed high differences in relative inclusion (S6 Fig., S10-S11 Files).	('BRCA', 'Gene', (50, 54))	('BRCA', 'Gene', '672', (50, 54))	('S10-S11', 'Var', (129, 136))
131826	25768983	These genes are not differentially expressed between the CLL SF3B1 mutant and wild-type samples (S12 File) but the frequent inclusion of out-of-frame cryptic 3'SSs may affect their biological function.	('SF3B1', 'Gene', (61, 66))	('cryptic', 'Gene', '55997', (150, 157))	('cryptic', 'Gene', (150, 157))	('SF3B1', 'Gene', '23451', (61, 66))	('biological function', 'MPA', (181, 200))	('mutant', 'Var', (67, 73))	('affect', 'Reg', (168, 174))
131827	25768983	Here we have shown that a consequence of SF3B1 mutations in different cancer types is genome-wide selection of hundreds of cryptic 3'SSs.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cryptic', 'Gene', '55997', (123, 130))	('mutations', 'Var', (47, 56))	('SF3B1', 'Gene', (41, 46))	('cryptic', 'Gene', (123, 130))	('SF3B1', 'Gene', '23451', (41, 46))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
131828	25768983	We have shown the cryptic 3'SSs have specific sequence requirements; AG dinucleotides used as cryptic 3'SSs in SF3B1 mutants are located at the end of the sterically protected region ~13-17 bp downstream of the BP but are >10 bp upstream of nearby canonical 3'SSs allowing them to avoid competition for splicing.	('cryptic', 'Gene', (18, 25))	('SF3B1', 'Gene', '23451', (111, 116))	('mutants', 'Var', (117, 124))	('splicing', 'biological_process', 'GO:0045292', ('303', '311'))	('SF3B1', 'Gene', (111, 116))	('cryptic', 'Gene', (94, 101))	('cryptic', 'Gene', '55997', (18, 25))	('cryptic', 'Gene', '55997', (94, 101))
131832	25768983	Examining differential splice junction usage allowed us to identify many more cryptic 3'SSs than previous studies while still identifying 61 of 79 cryptic 3'SSs recently reported for CLL SF3B1 mutants using a method based on relative inclusion.	('SF3B1', 'Gene', '23451', (187, 192))	('cryptic', 'Gene', '55997', (78, 85))	('cryptic', 'Gene', (78, 85))	('cryptic', 'Gene', '55997', (147, 154))	('mutants', 'Var', (193, 200))	('cryptic', 'Gene', (147, 154))	('SF3B1', 'Gene', (187, 192))
131834	25768983	Additionally, examining cryptic 3'SSs expressed higher in the SF3B1 mutants but not significantly (Fig.	('higher', 'PosReg', (48, 54))	('SF3B1', 'Gene', (62, 67))	('cryptic', 'Gene', '55997', (24, 31))	('mutants', 'Var', (68, 75))	('cryptic', 'Gene', (24, 31))	('SF3B1', 'Gene', '23451', (62, 67))
131835	25768983	These observations suggest that deeper sequencing will continue to reveal proximal cryptic 3'SSs in SF3B1 mutants that are used very infrequently or are present in lowly expressed genes.	("3'SSs", 'MPA', (91, 96))	('SF3B1', 'Gene', '23451', (100, 105))	('SF3B1', 'Gene', (100, 105))	('cryptic', 'Gene', (83, 90))	('mutants', 'Var', (106, 113))	('cryptic', 'Gene', '55997', (83, 90))
131839	25768983	In these cases, a mutation in the PPT between the sterically protected and competitive regions has introduced a cryptic 3'SS (Fig.	('introduced', 'Reg', (99, 109))	('PPT', 'molecular_function', 'GO:0015121', ('34', '37'))	('cryptic', 'Gene', '55997', (112, 119))	('cryptic', 'Gene', (112, 119))	('PPT', 'molecular_function', 'GO:0043751', ('34', '37'))	('mutation', 'Var', (18, 26))	('PPT', 'Gene', (34, 37))	("3'SS", 'Disease', (120, 124))
131840	25768983	For cancers with SF3B1 mutations, we suspect that the size of the sterically protected region is slightly altered allowing for existing AG dinucleotides to be used as cryptic 3'SSs in hundreds of genes.	('altered', 'Reg', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('SF3B1', 'Gene', (17, 22))	('cryptic', 'Gene', '55997', (167, 174))	('cryptic', 'Gene', (167, 174))	('mutations', 'Var', (23, 32))	('SF3B1', 'Gene', '23451', (17, 22))	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('cancers', 'Disease', (4, 11))
131841	25768983	It is also possible SF3B1 mutations could cause destabilization of the U2 snRNP complex or alter interactions with U2AF2, affecting the ability to recognize the canonical 3'SS and leading to cryptic 3'SS selection.	('cryptic', 'Gene', '55997', (191, 198))	('U2AF', 'cellular_component', 'GO:0089701', ('115', '119'))	('SF3B1', 'Gene', (20, 25))	('snRNP', 'molecular_function', 'GO:0003734', ('74', '79'))	('alter', 'Reg', (91, 96))	('ability', 'MPA', (136, 143))	('U2AF2', 'Gene', (115, 120))	('affecting', 'Reg', (122, 131))	('destabilization', 'NegReg', (48, 63))	('cryptic', 'Gene', (191, 198))	('SF3B1', 'Gene', '23451', (20, 25))	('mutations', 'Var', (26, 35))	('U2AF2', 'Gene', '11338', (115, 120))	('interactions', 'Interaction', (97, 109))	('U2 snRNP complex', 'Protein', (71, 87))	('recognize', 'MPA', (147, 156))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('71', '79'))	('leading to', 'Reg', (180, 190))
131843	25768983	We found that cryptic 3'SS selection is limited to tumors with mutations in the five ~10 amino acid hotspots in the SF3B1 HEAT 5-9 repeats and that these mutations are associated with cryptic 3'SS selection across different cancer types and even in cancers in which SF3B1 is not recurrently mutated.	('SF3B1', 'Gene', (266, 271))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('SF3B1', 'Gene', '23451', (116, 121))	('cancer', 'Disease', (249, 255))	('cancers', 'Disease', (249, 256))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('cryptic', 'Gene', '55997', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('cancer', 'Disease', (224, 230))	('cryptic', 'Gene', (14, 21))	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('associated with', 'Reg', (168, 183))	('SF3B1', 'Gene', '23451', (266, 271))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('SF3B1', 'Gene', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cryptic', 'Gene', '55997', (184, 191))	('cryptic', 'Gene', (184, 191))	('tumors', 'Disease', (51, 57))	('mutations', 'Var', (154, 163))
131845	25768983	We found that while the cryptic 3'SSs are used more often in the SF3B1 mutated samples compared to wild-type samples, they are used relatively infrequently (<10%) compared to nearby canonical 3'SSs.	('mutated', 'Var', (71, 78))	('SF3B1', 'Gene', (65, 70))	('cryptic', 'Gene', '55997', (24, 31))	('SF3B1', 'Gene', '23451', (65, 70))	('cryptic', 'Gene', (24, 31))
131846	25768983	While the differentially expressed genes between the SF3B1 mutated and wild-type samples are enriched for genes in the NMD pathway, even in-frame cryptic 3'SSs are used at a low frequency indicating that the associated canonical 3'SS is mostly preferred to the cryptic 3'SS even in SF3B1 mutants.	('cryptic', 'Gene', '55997', (146, 153))	('SF3B1', 'Gene', (53, 58))	('SF3B1', 'Gene', '23451', (53, 58))	('SF3B1', 'Gene', '23451', (282, 287))	('SF3B1', 'Gene', (282, 287))	('cryptic', 'Gene', '55997', (261, 268))	('mutants', 'Var', (288, 295))	('cryptic', 'Gene', (261, 268))	('mutated', 'Var', (59, 66))	('cryptic', 'Gene', (146, 153))
131848	25768983	Further studies are required to determine whether low-frequency cryptic 3'SS selection in hundreds of genes, high-frequency cryptic 3'SS selection in a small group of genes, and/or other splicing alterations drive the oncogenic effect of SF3B1 mutation.	('cryptic', 'Gene', (124, 131))	('drive', 'PosReg', (208, 213))	('SF3B1', 'Gene', '23451', (238, 243))	('oncogenic effect', 'CPA', (218, 234))	('cryptic', 'Gene', '55997', (64, 71))	('cryptic', 'Gene', (64, 71))	('splicing', 'biological_process', 'GO:0045292', ('187', '195'))	('mutation', 'Var', (244, 252))	('SF3B1', 'Gene', (238, 243))	('cryptic', 'Gene', '55997', (124, 131))
131856	25768983	SF3B1 mutant samples were identified using the Broad GDAC TCGA analysis (http://gdac.broadinstitute.org/runs/analyses__2013_02_22/) in TCGA tumor types with no publication restrictions.	('mutant', 'Var', (6, 12))	('SF3B1', 'Gene', (0, 5))	('SF3B1', 'Gene', '23451', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('TCGA', 'Disease', (135, 139))	('tumor', 'Disease', (140, 145))
131857	25768983	Samples with SF3B1 mutations outside of Gencode version 14 exons were excluded.	('SF3B1', 'Gene', (13, 18))	('SF3B1', 'Gene', '23451', (13, 18))	('mutations', 'Var', (19, 28))
131858	25768983	We excluded any cancer types with less than four SF3B1 mutants or for which paired-end RNA-sequencing data was not available leaving breast cancer (BRCA), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC).	('lung adenocarcinoma', 'Disease', (155, 174))	('BRCA', 'Gene', '672', (148, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('RNA', 'cellular_component', 'GO:0005562', ('87', '90'))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('breast cancer', 'Disease', (133, 146))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (155, 174))	('cancer', 'Disease', (16, 22))	('BRCA', 'Gene', (148, 152))	('SF3B1', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (155, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('cancer', 'Disease', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('SF3B1', 'Gene', '23451', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('mutants', 'Var', (55, 62))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (187, 215))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))	('lung squamous cell carcinoma', 'Disease', (187, 215))
131861	25768983	As reported in Furney et al., four uveal melanoma samples had SF3B1 mutations in codon 625 and four had wild-type copies of SF3B1.	('uveal melanoma', 'Disease', 'MESH:C536494', (35, 49))	('uveal melanoma', 'Disease', (35, 49))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))	('mutations in', 'Var', (68, 80))	('SF3B1', 'Gene', (62, 67))	('SF3B1', 'Gene', (124, 129))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('SF3B1', 'Gene', '23451', (62, 67))	('SF3B1', 'Gene', '23451', (124, 129))
131880	25768983	COSMIC v66 complete export was downloaded and the number of mutations at each location in the SF3B1 heat domains 5-9 was plotted for locations with at least two observed mutations in COSMIC.	('SF3B1', 'Gene', '23451', (94, 99))	('mutations', 'Var', (170, 179))	('SF3B1', 'Gene', (94, 99))
131887	25768983	The ten 3'SSs with high PSI values in CLL were identified by identifying cryptic 3'SSs whose median PSI was greater than 50% in the CLL SF3B1 mutants but less than 20% in the wild-type samples and whose average coverage was at least 30 junction-spanning reads in the CLL mutant samples.	('SF3B1', 'Gene', (136, 141))	('mutants', 'Var', (142, 149))	('SF3B1', 'Gene', '23451', (136, 141))	('cryptic', 'Gene', '55997', (73, 80))	('cryptic', 'Gene', (73, 80))
131952	24652500	In the presence of an abnormal laminar beam microstructure, a ball-valve mechanism may develop, allowing a 1-way flow of the vitreous to the retrolaminar part of the optic nerve in the presence of glaucoma.	('glaucoma', 'Phenotype', 'HP:0000501', (197, 205))	('glaucoma', 'Disease', (197, 205))	('1-way flow of the vitreous to the', 'MPA', (107, 140))	('allowing', 'Reg', (96, 104))	('glaucoma', 'Disease', 'MESH:D005901', (197, 205))	('abnormal', 'Var', (22, 30))
131967	22065079	PI3K, AKT and the downstream mTOR are involved in cell growth and survival and are often found to be activated in mesothelioma.	('AKT', 'Gene', (6, 9))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('PI3K', 'Var', (0, 4))	('involved', 'Reg', (38, 46))	('mTOR', 'Gene', (29, 33))	('mTOR', 'Gene', '2475', (29, 33))	('mesothelioma', 'Disease', (114, 126))	('AKT', 'Gene', '207', (6, 9))	('mesothelioma', 'Disease', 'MESH:D008654', (114, 126))	('activated', 'PosReg', (101, 110))	('cell growth', 'biological_process', 'GO:0016049', ('50', '61'))
131974	22065079	The very recent discovery that germline BAP1 mutations cause a new cancer syndrome characterized by mesothelioma, uveal melanoma and melanocytic tumors provides researchers with a novel target for prevention and early detection.	('melanocytic tumors', 'Disease', 'MESH:D009508', (133, 151))	('mutations', 'Var', (45, 54))	('cancer syndrome', 'Disease', 'MESH:D009369', (67, 82))	('melanocytic tumors', 'Disease', (133, 151))	('cancer syndrome', 'Disease', (67, 82))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('mesothelioma', 'Disease', (100, 112))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))	('uveal melanoma', 'Disease', (114, 128))	('BAP1', 'Gene', '8314', (40, 44))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cause', 'Reg', (55, 60))	('BAP1', 'Gene', (40, 44))
131999	22065079	Germline mutations of the BAP1 gene have now been linked to the high incidence of MM in some US families.	('Germline mutations', 'Var', (0, 18))	('linked to', 'Reg', (50, 59))	('BAP1', 'Gene', (26, 30))	('BAP1', 'Gene', '8314', (26, 30))
132000	22065079	Individuals with heterozygous BAP1 germline mutations are affected by a novel cancer syndrome characterized by very high risk of developing mesothelioma, uveal melanoma, and possibly additional cancers.	('uveal melanoma', 'Disease', 'MESH:C536494', (154, 168))	('BAP1', 'Gene', (30, 34))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('mesothelioma', 'Disease', (140, 152))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mesothelioma', 'Disease', 'MESH:D008654', (140, 152))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('affected', 'Reg', (58, 66))	('cancers', 'Disease', (194, 201))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer syndrome', 'Disease', 'MESH:D009369', (78, 93))	('cancer syndrome', 'Disease', (78, 93))	('uveal melanoma', 'Phenotype', 'HP:0007716', (154, 168))	('uveal melanoma', 'Disease', (154, 168))	('BAP1', 'Gene', '8314', (30, 34))	('germline mutations', 'Var', (35, 53))
132002	22065079	The identification of BAP1 mutant carriers may be facilitated by the detection of melanocytic nevi as described by Wiesner et al and confirmed by genetic testing.	('mutant', 'Var', (27, 33))	('nevi', 'Phenotype', 'HP:0003764', (94, 98))	('melanocytic nevi', 'Disease', (82, 98))	('BAP1', 'Gene', '8314', (22, 26))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (82, 98))	('BAP1', 'Gene', (22, 26))
132006	22065079	Mutations that abolish the deubiquitinating activity of BAP1 and/or its nuclear localization abolish BAP1 tumor suppressor activity.	('localization', 'biological_process', 'GO:0051179', ('80', '92'))	('BAP1', 'Gene', '8314', (56, 60))	('nuclear localization', 'MPA', (72, 92))	('BAP1', 'Gene', '8314', (101, 105))	('abolish', 'NegReg', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('abolish', 'NegReg', (15, 22))	('BAP1', 'Gene', (56, 60))	('BAP1', 'Gene', (101, 105))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor suppressor', 'biological_process', 'GO:0051726', ('106', '122'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('106', '122'))	('tumor', 'Disease', (106, 111))	('deubiquitinating activity', 'MPA', (27, 52))
132008	22065079	Ventii et al proposed that expression of BAP1 induces early exit out of G1 causing an accumulation of DNA damage and cell death.	('BAP1', 'Gene', (41, 45))	('DNA damage', 'MPA', (102, 112))	('accumulation', 'MPA', (86, 98))	('cell death', 'biological_process', 'GO:0008219', ('117', '127'))	('expression', 'Var', (27, 37))	('induces', 'Reg', (46, 53))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))	('BAP1', 'Gene', '8314', (41, 45))
132019	22065079	P16INK4a and p14ARF are frequently inactivated in mesothelioma, and approximately 50% of mesotheliomas contain missense or nonsense mutations in the neurofibromatosis type 2 (NF2) gene.	('mesotheliomas', 'Disease', 'MESH:D008654', (89, 102))	('mesotheliomas', 'Disease', (89, 102))	('mesothelioma', 'Disease', (89, 101))	('neurofibromatosis type 2', 'Disease', (149, 173))	('P16INK4a', 'Gene', (0, 8))	('mesothelioma', 'Disease', 'MESH:D008654', (50, 62))	('p14ARF', 'Gene', '1029', (13, 19))	('p14ARF', 'Gene', (13, 19))	('NF2', 'Gene', '4771', (175, 178))	('missense', 'Var', (111, 119))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (149, 166))	('mesothelioma', 'Disease', 'MESH:D008654', (89, 101))	('mesothelioma', 'Disease', (50, 62))	('P16INK4a', 'Gene', '1029', (0, 8))	('NF2', 'Gene', (175, 178))	('neurofibromatosis type 2', 'Disease', 'MESH:C537392', (149, 173))	('nonsense mutations', 'Var', (123, 141))
132034	22065079	This allows HM that accumulated asbestos-induced genetic damage to survive, divide and propagate genetic aberrations in pre-malignant cells that can give rise to a malignant clone.	('asbestos', 'Chemical', 'MESH:D001194', (32, 40))	('genetic aberrations', 'Var', (97, 116))	('pre', 'molecular_function', 'GO:0003904', ('120', '123'))	('genetic damage', 'Disease', 'MESH:D030342', (49, 63))	('give rise to', 'Reg', (149, 161))	('genetic damage', 'Disease', (49, 63))	('malignant clone', 'CPA', (164, 179))
132045	22065079	Moreover, the disheveled proteins, also downstream of Wnt, are often over-expressed in mesothelioma and siRNA knockdown of disheveled suppressed mesothelioma growth.	('knockdown', 'Var', (110, 119))	('suppressed', 'NegReg', (134, 144))	('mesothelioma', 'Disease', (87, 99))	('over-expressed', 'PosReg', (69, 83))	('mesothelioma', 'Disease', (145, 157))	('mesothelioma growth', 'Disease', (145, 164))	('mesothelioma growth', 'Disease', 'MESH:D008654', (145, 164))	('mesothelioma', 'Disease', 'MESH:D008654', (87, 99))	('mesothelioma', 'Disease', 'MESH:D008654', (145, 157))
132049	22065079	PI3K, AKT and the downstream mTOR are often found to be activated in mesothelioma, and inhibition of mTOR using rapamycin enhances the apoptosis of mesothelioma cells in vitro, which suggest that mTOR may serve as a target for mesothelioma therapies (Figure 2).	('apoptosis', 'CPA', (135, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('mTOR', 'Gene', '2475', (101, 105))	('mesothelioma', 'Disease', (227, 239))	('enhances', 'PosReg', (122, 130))	('mTOR', 'Gene', '2475', (29, 33))	('mesothelioma', 'Disease', 'MESH:D008654', (227, 239))	('AKT', 'Gene', (6, 9))	('rapamycin', 'Chemical', 'MESH:D020123', (112, 121))	('AKT', 'Gene', '207', (6, 9))	('mTOR', 'Gene', (196, 200))	('activated', 'PosReg', (56, 65))	('inhibition', 'Var', (87, 97))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('mTOR', 'Gene', (101, 105))	('mTOR', 'Gene', (29, 33))	('mesothelioma', 'Disease', (69, 81))	('mesothelioma', 'Disease', (148, 160))	('mesothelioma', 'Disease', 'MESH:D008654', (69, 81))	('mTOR', 'Gene', '2475', (196, 200))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))	('mesothelioma', 'Disease', 'MESH:D008654', (148, 160))
132077	22065079	Moreover, genetic testing for BAP1 mutations should help us identify among exposed cohorts of those genetically susceptible individuals that have the highest risk of developing mesothelioma.	('BAP1', 'Gene', (30, 34))	('mesothelioma', 'Disease', 'MESH:D008654', (177, 189))	('BAP1', 'Gene', '8314', (30, 34))	('mesothelioma', 'Disease', (177, 189))	('mutations', 'Var', (35, 44))
132087	22267972	A pseudo-metastatic model of uveal melanoma to the liver was developed in NOD/SCID/IL2Rgamma null mice and the study of mda-9/syntenin expression in primary and metastatic lesions revealed higher mda-9/syntenin in metastases.	('mda-9/syntenin', 'Var', (196, 210))	('uveal melanoma to the liver', 'Disease', 'MESH:C536494', (29, 56))	('SCID', 'Gene', '19090', (78, 82))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('IL2', 'molecular_function', 'GO:0005134', ('83', '86'))	('metastases', 'Disease', (214, 224))	('SCID', 'Gene', (78, 82))	('metastases', 'Disease', 'MESH:D009362', (214, 224))	('higher', 'PosReg', (189, 195))	('uveal melanoma to the liver', 'Disease', (29, 56))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('mice', 'Species', '10090', (98, 102))
132089	22267972	Moreover, silencing of SDCBP in mda-9/syntenin-high uveal melanoma cells inhibited the hepatocyte growth factor (HGF)-triggered invasion of matrigel membranes and inhibited the activation of FAK, AKT and Src.	('uveal melanoma', 'Disease', (52, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (52, 66))	('HGF', 'Gene', '3082', (113, 116))	('SDCBP', 'Gene', '6386', (23, 28))	('inhibited', 'NegReg', (163, 172))	('HGF', 'Gene', (113, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('AKT', 'Gene', (196, 199))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('87', '111'))	('inhibited', 'NegReg', (73, 82))	('FAK', 'molecular_function', 'GO:0004717', ('191', '194'))	('Src', 'Gene', (204, 207))	('FAK', 'Gene', (191, 194))	('SDCBP', 'Gene', (23, 28))	('AKT', 'Gene', '207', (196, 199))	('hepatocyte growth factor', 'Gene', '3082', (87, 111))	('Src', 'Gene', '6714', (204, 207))	('silencing', 'Var', (10, 19))	('FAK', 'Gene', '5747', (191, 194))	('invasion of matrigel', 'CPA', (128, 148))	('hepatocyte growth factor', 'Gene', (87, 111))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
132102	22267972	high-risk) tumors, was later reported by the same authors as the top class discriminating gene, the loss of which causes an increase in the rate of liver metastasis in a transgenic mouse model of ocular melanoma.	('increase', 'PosReg', (124, 132))	('loss', 'Var', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('liver metastasis', 'CPA', (148, 164))	('ocular melanoma', 'Phenotype', 'HP:0007716', (196, 211))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('ocular melanoma', 'Disease', 'MESH:D008545', (196, 211))	('mouse', 'Species', '10090', (181, 186))	('ocular melanoma', 'Disease', (196, 211))
132111	22267972	This possibility is also supported by the finding that mda-9/syntenin is involved in cell migration of uveal melanoma cells in culture and in invasiveness and activation of focal adhesion kinase (FAK), AKT and Src triggered by HGF.	('focal adhesion kinase', 'Gene', (173, 194))	('cell migration', 'CPA', (85, 99))	('FAK', 'Gene', '5747', (196, 199))	('HGF', 'Gene', (227, 230))	('focal adhesion', 'cellular_component', 'GO:0005925', ('173', '187'))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('uveal melanoma', 'Disease', 'MESH:C536494', (103, 117))	('activation', 'PosReg', (159, 169))	('uveal melanoma', 'Disease', (103, 117))	('AKT', 'Gene', (202, 205))	('invasiveness', 'CPA', (142, 154))	('focal adhesion kinase', 'Gene', '5747', (173, 194))	('Src', 'Gene', (210, 213))	('FAK', 'molecular_function', 'GO:0004717', ('196', '199'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('mda-9/syntenin', 'Var', (55, 69))	('Src', 'Gene', '6714', (210, 213))	('FAK', 'Gene', (196, 199))	('cell migration', 'biological_process', 'GO:0016477', ('85', '99'))	('AKT', 'Gene', '207', (202, 205))	('HGF', 'Gene', '3082', (227, 230))
132133	22267972	Gel was then blotted to nitrocellulose membranes (Hybond-C Extra, Amersham GE Healthcare, Little Chalfont, UK) according to standard procedures and stained with antibodies to mda-9/syntenin, HDAC1, Actin (Sigma-Aldrich), anti-FAK(pY397), anti-Src (pY418) and anti-Src pan (Invitrogen), and anti-FAK (Cell Signaling), anti-phospho-AKT (Ser473), anti-AKT (pan), anti-phospho-MET (Tyr1234/1235) and anti-MET (L41G3) (Cell Signaling).	('HDAC1', 'Gene', (191, 196))	('FAK', 'Gene', (226, 229))	('Src', 'Gene', '6714', (264, 267))	('AKT', 'Gene', (330, 333))	('Tyr1234/1235', 'Var', (378, 390))	('FAK', 'molecular_function', 'GO:0004717', ('295', '298'))	('anti-MET (L41G3', 'Var', (396, 411))	('HDAC1', 'Gene', '3065', (191, 196))	('AKT', 'Gene', '207', (349, 352))	('FAK', 'Gene', '5747', (226, 229))	('anti-phospho-MET', 'Var', (360, 376))	('Src', 'Gene', (243, 246))	('FAK', 'Gene', (295, 298))	('Ser', 'cellular_component', 'GO:0005790', ('335', '338'))	('AKT', 'Gene', '207', (330, 333))	('Src', 'Gene', '6714', (243, 246))	('FAK', 'Gene', '5747', (295, 298))	('FAK', 'molecular_function', 'GO:0004717', ('226', '229'))	('Src', 'Gene', (264, 267))	('Signaling', 'biological_process', 'GO:0023052', ('419', '428'))	('Signaling', 'biological_process', 'GO:0023052', ('305', '314'))	('AKT', 'Gene', (349, 352))
132160	22267972	High SDCBP mRNA expression conferred a risk with Odds Ratio of 9.0 (p = 0.01, IC 95% 1.46-55.48) for recurrence, which was as strong as monosomy 3 (OR: 12.50, p = 0.01, IC 95% 1.31-119.33), in our cohort.	('SDCBP', 'Gene', (5, 10))	('mRNA', 'MPA', (11, 15))	('SDCBP', 'Gene', '6386', (5, 10))	('High', 'Var', (0, 4))
132166	22267972	Expression of SDCBP was significantly higher (p = 0.009) in class-2 (high risk) than in class-1 (low risk) cases (Fig.	('SDCBP', 'Gene', '6386', (14, 19))	('Expression', 'MPA', (0, 10))	('class-2', 'Var', (60, 67))	('higher', 'PosReg', (38, 44))	('SDCBP', 'Gene', (14, 19))
132183	22267972	Nine patients with high-mda-9/syntenin tumors developed metastatic progression, while among the fourteen patients of the mda-9/syntenin-low group only two developed metastasis.	('patients', 'Species', '9606', (105, 113))	('patients', 'Species', '9606', (5, 13))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('metastatic progression', 'CPA', (56, 78))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (39, 45))	('high-mda-9/syntenin', 'Var', (19, 38))
132204	22267972	The 92.1 cell line, which expresses high levels of mda-9/syntenin and the HGF receptor c-MET (Figure 8A) invaded the matrigel membrane in response to MG63 conditioned medium or to recombinant HGF (Figure 8B).	('c-MET', 'Gene', (87, 92))	('HGF', 'Gene', '3082', (74, 77))	('HGF', 'Gene', (192, 195))	('mda-9/syntenin', 'Var', (51, 65))	('c-MET', 'Gene', '4233', (87, 92))	('HGF', 'Gene', '3082', (192, 195))	('membrane', 'cellular_component', 'GO:0016020', ('126', '134'))	('MG63', 'Chemical', '-', (150, 154))	('HGF', 'Gene', (74, 77))
132205	22267972	SDCBP silencing significantly inhibited invasion triggered by both stimuli (Figure 8C).	('SDCBP', 'Gene', '6386', (0, 5))	('invasion', 'CPA', (40, 48))	('inhibited', 'NegReg', (30, 39))	('SDCBP', 'Gene', (0, 5))	('silencing', 'Var', (6, 15))
132211	22267972	Silencing the expression of SDCBP by siRNA strongly inhibited constitutive and HGF induced Fak phosphorylation (45 and 50% respectively) (Fig.	('SDCBP', 'Gene', '6386', (28, 33))	('Fak', 'Gene', (91, 94))	('constitutive', 'MPA', (62, 74))	('HGF', 'Gene', (79, 82))	('expression', 'MPA', (14, 24))	('phosphorylation', 'biological_process', 'GO:0016310', ('95', '110'))	('inhibited', 'NegReg', (52, 61))	('Fak', 'Gene', '5747', (91, 94))	('HGF', 'Gene', '3082', (79, 82))	('Silencing', 'Var', (0, 9))	('Fak', 'molecular_function', 'GO:0004717', ('91', '94'))	('SDCBP', 'Gene', (28, 33))
132212	22267972	In addition, mda-9/syntenin silencing also partially inhibited constitutive and/or HGF-promoted Src (15 and 30% respectively) and AKT phosphorylation (20%) in 92.1 cells (Fig.	('inhibited', 'NegReg', (53, 62))	('constitutive', 'MPA', (63, 75))	('Src', 'Gene', (96, 99))	('Src', 'Gene', '6714', (96, 99))	('AKT', 'Gene', '207', (130, 133))	('HGF', 'Gene', (83, 86))	('phosphorylation', 'biological_process', 'GO:0016310', ('134', '149'))	('silencing', 'Var', (28, 37))	('HGF', 'Gene', '3082', (83, 86))	('AKT', 'Gene', (130, 133))	('mda-9/syntenin', 'Gene', (13, 27))
132221	22267972	Our results provide the first evidence that mda-9/syntenin is expressed in human uveal melanoma and that high level of expression of mda-9/syntenin conferres a high risk of metastatic recurrence.	('mda-9/syntenin', 'Var', (133, 147))	('uveal melanoma', 'Disease', (81, 95))	('metastatic recurrence', 'CPA', (173, 194))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('uveal melanoma', 'Disease', 'MESH:C536494', (81, 95))	('human', 'Species', '9606', (75, 80))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
132224	22267972	The possible role of mda-9/syntenin expression and metastatic progression was demonstrated in cutaneous melanoma, where mda-9/syntenin, through interaction with c-Src/FAK, activates the p38 MAPK/NFkB pathway with subsequent induction of genes involved in migration and invasion.	('interaction', 'Interaction', (144, 155))	('activates', 'PosReg', (172, 181))	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('migration', 'CPA', (255, 264))	('MAPK', 'molecular_function', 'GO:0004707', ('190', '194'))	('FAK', 'molecular_function', 'GO:0004717', ('167', '170'))	('induction', 'PosReg', (224, 233))	('cutaneous melanoma', 'Disease', (94, 112))	('FAK', 'Gene', '5747', (167, 170))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (94, 112))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (94, 112))	('c-Src', 'Gene', (161, 166))	('FAK', 'Gene', (167, 170))	('genes', 'Gene', (237, 242))	('c-Src', 'Gene', '6714', (161, 166))	('p38 MAPK/NFkB pathway', 'Pathway', (186, 207))	('mda-9/syntenin', 'Var', (120, 134))
132225	22267972	In the present study, a correlation of high SDCBP gene expression with metastatic progression was suggested by the analysis of the gene expression profile of 29 primary uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (169, 184))	('high', 'Var', (39, 43))	('uveal melanoma', 'Phenotype', 'HP:0007716', (169, 183))	('uveal melanomas', 'Phenotype', 'HP:0007716', (169, 184))	('gene expression', 'biological_process', 'GO:0010467', ('131', '146'))	('melanomas', 'Phenotype', 'HP:0002861', (175, 184))	('gene expression', 'biological_process', 'GO:0010467', ('50', '65'))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('SDCBP', 'Gene', (44, 49))	('uveal melanomas', 'Disease', (169, 184))	('SDCBP', 'Gene', '6386', (44, 49))	('metastatic progression', 'CPA', (71, 93))
132226	22267972	Indeed we found that high SDCBP expression conferred a significantly increased risk of metastatic recurrence (Odds ratio of 11.70 p<0,005) in our cohort.	('SDCBP', 'Gene', '6386', (26, 31))	('SDCBP', 'Gene', (26, 31))	('high', 'Var', (21, 25))	('metastatic recurrence', 'CPA', (87, 108))
132234	22267972	It is of note that a high level of mda-9/syntenin protein in primary tumors was significantly related to earlier metastatic progression although, further studies involving larger groups of patients are needed to confirm this possibility.	('primary tumors', 'Disease', 'MESH:D009369', (61, 75))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('earlier metastatic progression although', 'CPA', (105, 144))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('mda-9/syntenin', 'Var', (35, 49))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('primary tumors', 'Disease', (61, 75))	('patients', 'Species', '9606', (189, 197))	('related', 'Reg', (94, 101))
132238	22267972	Though the possible role of mda-9/syntenin in nuclear functions has yet to be determined in uveal melanoma, recent findings indicated that mda-9/syntenin colocalizes with the SOX-4 transcription factor in the nucleus and stabilizes its expression in different tumor cells.	('tumor', 'Disease', (260, 265))	('colocalizes', 'Interaction', (154, 165))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('SOX-4', 'Gene', '6659', (175, 180))	('transcription factor', 'molecular_function', 'GO:0000981', ('181', '201'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (92, 106))	('mda-9/syntenin', 'Var', (139, 153))	('uveal melanoma', 'Disease', (92, 106))	('uveal melanoma', 'Disease', 'MESH:C536494', (92, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('transcription', 'biological_process', 'GO:0006351', ('181', '194'))	('SOX-4', 'Gene', (175, 180))	('expression', 'MPA', (236, 246))	('nucleus', 'cellular_component', 'GO:0005634', ('209', '216'))
132244	22267972	This hypothesis would corroborate the finding of a worse prognosis for those patients expressing high levels of mda-9/syntenin in the primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('high levels', 'Var', (97, 108))	('patients', 'Species', '9606', (77, 85))	('mda-9/syntenin', 'Var', (112, 126))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
132245	22267972	However, incubation of human uveal melanoma cell lines with mouse liver extracts did not increase mda-9/syntenin expression (data not shown) suggesting that high mda-9/syntenin expressing cells are more prone to metastasize.	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('prone', 'PosReg', (203, 208))	('mouse', 'Species', '10090', (60, 65))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('human', 'Species', '9606', (23, 28))	('metastasize', 'CPA', (212, 223))	('high mda-9/syntenin expressing', 'Var', (157, 187))
132246	22267972	In addition, our present observation that silencing of SDCBP by siRNA inhibits migration and invasiveness of uveal melanoma cells, suggests that mda-9/syntenin is involved in the metastatic dissemination.	('silencing', 'Var', (42, 51))	('SDCBP', 'Gene', (55, 60))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('inhibits', 'NegReg', (70, 78))	('SDCBP', 'Gene', '6386', (55, 60))	('invasiveness of uveal melanoma', 'Disease', 'MESH:C536494', (93, 123))	('invasiveness of uveal melanoma', 'Disease', (93, 123))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))
132250	22267972	Regarding the molecular mechanisms involved, we found that inhibition of mda-9/syntenin expression reduces the activation of FAK, Src and AKT mediated by HGF, whereas its overexpression has opposite effects.	('activation', 'PosReg', (111, 121))	('HGF', 'Gene', (154, 157))	('AKT', 'Gene', (138, 141))	('FAK', 'Gene', '5747', (125, 128))	('Src', 'Gene', (130, 133))	('Src', 'Gene', '6714', (130, 133))	('HGF', 'Gene', '3082', (154, 157))	('mda-9/syntenin', 'Gene', (73, 87))	('FAK', 'molecular_function', 'GO:0004717', ('125', '128'))	('inhibition', 'Var', (59, 69))	('reduces', 'NegReg', (99, 106))	('FAK', 'Gene', (125, 128))	('AKT', 'Gene', '207', (138, 141))
132255	19078957	Frequent somatic mutations of GNAQ in uveal melanoma and blue nevi BRAF and NRAS are common targets for somatic mutations in benign and malignant neoplasms that arise from melanocytes situated in epithelial structures and lead to constitutive activation of the MAP-kinase pathway.	('NRAS', 'Gene', (76, 80))	('activation', 'PosReg', (243, 253))	('mutations', 'Var', (112, 121))	('neoplasms', 'Phenotype', 'HP:0002664', (146, 155))	('mutations', 'Var', (17, 26))	('nevi', 'Phenotype', 'HP:0003764', (62, 66))	('malignant neoplasms', 'Disease', 'MESH:D009369', (136, 155))	('GNAQ', 'Gene', (30, 34))	('malignant neoplasms', 'Disease', (136, 155))	('neoplasm', 'Phenotype', 'HP:0002664', (146, 154))	('MAP-kinase pathway', 'Pathway', (261, 279))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('NRAS', 'Gene', '4893', (76, 80))	('blue nevi', 'Phenotype', 'HP:0100814', (57, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (38, 52))	('MAP', 'molecular_function', 'GO:0004239', ('261', '264'))	('uveal melanoma', 'Disease', (38, 52))	('BRAF', 'Gene', '673', (67, 71))	('BRAF', 'Gene', (67, 71))	('malignant neoplasms that arise from melanocytes', 'Phenotype', 'HP:0002861', (136, 183))	('uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))
132258	19078957	The mutations occur exclusively in codon 209 in the ras-like domain and result in constitutive activation, turning GNAQ into a dominant acting oncogene.	('mutations', 'Var', (4, 13))	('constitutive activation', 'MPA', (82, 105))	('GNAQ', 'Chemical', '-', (115, 119))
132261	19078957	The majority of nevi and melanomas show oncogenic mutations in signaling components of the MAP kinase pathway, in particular BRAF and NRAS.	('MAP kinase pathway', 'Pathway', (91, 109))	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('melanomas', 'Disease', 'MESH:D008545', (25, 34))	('mutations', 'Var', (50, 59))	('nevi', 'Disease', (16, 20))	('nevi', 'Phenotype', 'HP:0003764', (16, 20))	('NRAS', 'Gene', '4893', (134, 138))	('melanomas', 'Disease', (25, 34))	('BRAF', 'Gene', '673', (125, 129))	('NRAS', 'Gene', (134, 138))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('MAP', 'molecular_function', 'GO:0004239', ('91', '94'))	('BRAF', 'Gene', (125, 129))	('melanomas', 'Phenotype', 'HP:0002861', (25, 34))
132262	19078957	However, a subset of melanocytic neoplasms does not show mutations in BRAF and NRAS.	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (21, 42))	('neoplasms', 'Phenotype', 'HP:0002664', (33, 42))	('NRAS', 'Gene', '4893', (79, 83))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (21, 42))	('melanocytic neoplasms', 'Disease', (21, 42))	('mutations', 'Var', (57, 66))	('neoplasm', 'Phenotype', 'HP:0002664', (33, 41))	('BRAF', 'Gene', '673', (70, 74))	('NRAS', 'Gene', (79, 83))	('BRAF', 'Gene', (70, 74))
132269	19078957	We found mutations in GNAQ in 83% of blue nevi (n=29), 50% of "malignant blue nevi" (n=2), and 46% of uveal melanomas (n=48) (Table 1, Supplementary Information, Figure 1a).	('nevi', 'Phenotype', 'HP:0003764', (42, 46))	('melanomas', 'Phenotype', 'HP:0002861', (108, 117))	('uveal melanomas', 'Disease', (102, 117))	('uveal melanomas', 'Phenotype', 'HP:0007716', (102, 117))	('blue nevi', 'Phenotype', 'HP:0100814', (73, 82))	('mutations', 'Var', (9, 18))	('GNAQ', 'Gene', (22, 26))	('nevi', 'Phenotype', 'HP:0003764', (78, 82))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('blue nevi', 'Phenotype', 'HP:0100814', (37, 46))	('uveal melanomas', 'Disease', 'MESH:C536494', (102, 117))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('blue nevi', 'Disease', (37, 46))	('GNAQ', 'Chemical', '-', (22, 26))
132271	19078957	All mutations in GNAQ were somatically acquired as assessed by sequencing DNA from adjacent tissue, and occurred exclusively at codon 209 (Supplementary Information, Table 1).	('mutations', 'Var', (4, 13))	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('GNAQ', 'Gene', (17, 21))	('GNAQ', 'Chemical', '-', (17, 21))
132273	19078957	In RAS family members, mutations at this site, and at codon 12, cause loss of GTPase activity with constitutive activation.	('GTPase activity', 'molecular_function', 'GO:0003924', ('78', '93'))	('GTP', 'Chemical', 'MESH:D006160', (78, 81))	('loss', 'NegReg', (70, 74))	('GTPase', 'Protein', (78, 84))	('mutations', 'Var', (23, 32))	('codon 12', 'Chemical', '-', (54, 62))	('activity', 'MPA', (85, 93))
132275	19078957	In contrast to the findings in humans, the mutations found in the dark skinned mice occurred at I63, V179, and F335 in the mouse proteins and do not cause constitutive activation.	('mouse', 'Species', '10090', (123, 128))	('I63', 'Var', (96, 99))	('mice', 'Species', '10090', (79, 83))	('F335', 'Var', (111, 115))	('occurred', 'Reg', (84, 92))	('V179', 'Var', (101, 105))	('humans', 'Species', '9606', (31, 37))
132276	19078957	To date no mutations of GNAQ have been described in human neoplasia, but GNAQQ209L has been demonstrated to transform 3T3 cells.	('neoplasia', 'Phenotype', 'HP:0002664', (58, 67))	('3T3 cells', 'CPA', (118, 127))	('neoplasia', 'Disease', 'MESH:D009369', (58, 67))	('GNAQ', 'Chemical', '-', (24, 28))	('human', 'Species', '9606', (52, 57))	('GNAQ', 'Chemical', '-', (73, 77))	('GNAQQ209L', 'Chemical', '-', (73, 82))	('GNAQQ209L', 'Var', (73, 82))	('neoplasia', 'Disease', (58, 67))	('transform', 'Reg', (108, 117))
132277	19078957	In addition, mutations of the corresponding codon in G alpha S (GNAS) are found in human pituitary and thyroid tumors.	('GNAS', 'Gene', (64, 68))	('found', 'Reg', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('thyroid tumors', 'Disease', (103, 117))	('thyroid tumors', 'Disease', 'MESH:D013959', (103, 117))	('human', 'Species', '9606', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('GNAS', 'Gene', '2778', (64, 68))	('mutations', 'Var', (13, 22))	('pituitary', 'Disease', (89, 98))
132280	19078957	In contrast, transfection of GNAQQ209L into hTERT/CDK4R24C/p53DD melanocytes resulted in anchorage independent growth with efficiencies comparable or slightly greater than transfection with NRASQ61R (Figure 1a, Supplementary Information, Table 2).	('GNAQQ209L', 'Chemical', '-', (29, 38))	('p53', 'Gene', (59, 62))	('GNAQQ209L', 'Var', (29, 38))	('NRAS', 'Gene', (190, 194))	('p53', 'Gene', '7157', (59, 62))	('anchorage independent growth', 'CPA', (89, 117))	('CDK', 'molecular_function', 'GO:0004693', ('50', '53'))	('NRAS', 'Gene', '4893', (190, 194))	('greater', 'PosReg', (159, 166))	('hTERT', 'Gene', '7015', (44, 49))	('hTERT', 'Gene', (44, 49))
132281	19078957	Furthermore, GNAQQ209L but not GNAQwt induced abnormally enlarged nuclei with markedly irregular contours (Figure 1b, Supplementary Information, Table 3).	('enlarged', 'PosReg', (57, 65))	('GNAQ', 'Chemical', '-', (13, 17))	('GNAQ', 'Chemical', '-', (31, 35))	('GNAQQ209L', 'Chemical', '-', (13, 22))	('GNAQQ209L', 'Var', (13, 22))	('nuclei', 'CPA', (66, 72))
132283	19078957	GNAQQ209L, but not GNAQwt or vector control transfected melanocytes gave rise to heavily pigmented tumors at the injection site.	('GNAQ', 'Chemical', '-', (0, 4))	('GNAQQ209L', 'Chemical', '-', (0, 9))	('GNAQQ209L', 'Var', (0, 9))	('pigmented tumors', 'Disease', 'MESH:D010859', (89, 105))	('pigmented tumors', 'Disease', (89, 105))	('GNAQ', 'Chemical', '-', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
132286	19078957	Consistently, GNAQQ209L-transformed melanocytes grew in soft agar in the absence of TPA, a synthetic DAG analog (Figure 1a, Supplementary Information, Table 2).	('agar', 'Chemical', 'MESH:D000362', (61, 65))	('TPA', 'molecular_function', 'GO:0031299', ('84', '87'))	('GNAQQ209L-transformed', 'Var', (14, 35))	('TPA', 'Gene', (84, 87))	('GNAQQ209L', 'Chemical', '-', (14, 23))	('DAG', 'Chemical', 'MESH:D004075', (101, 104))	('TPA', 'Gene', '5327', (84, 87))
132288	19078957	Uveal melanomas display MAP-kinase activation, but none of the uveal melanomas we examined in our study showed mutations in BRAF or NRAS (Supplementary Information, Table 4), consistent with other studies.	('uveal melanoma', 'Phenotype', 'HP:0007716', (63, 77))	('Uveal melanoma', 'Disease', 'MESH:C536494', (0, 14))	('uveal melanomas', 'Disease', (63, 78))	('uveal melanomas', 'Phenotype', 'HP:0007716', (63, 78))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (69, 78))	('mutations', 'Var', (111, 120))	('NRAS', 'Gene', '4893', (132, 136))	('MAP-kinase', 'MPA', (24, 34))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('MAP', 'molecular_function', 'GO:0004239', ('24', '27'))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('BRAF', 'Gene', '673', (124, 128))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('BRAF', 'Gene', (124, 128))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('uveal melanomas', 'Disease', 'MESH:C536494', (63, 78))	('melanomas', 'Disease', 'MESH:D008545', (69, 78))	('NRAS', 'Gene', (132, 136))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))	('melanomas', 'Disease', (6, 15))	('melanomas', 'Disease', (69, 78))	('Uveal melanoma', 'Disease', (0, 14))
132289	19078957	We therefore tested whether GNAQQ209L would contribute to MAP-kinase pathway activation in human melanocytes and uveal melanoma cells.	('MAP-kinase pathway', 'Pathway', (58, 76))	('activation', 'PosReg', (77, 87))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('GNAQQ209L', 'Chemical', '-', (28, 37))	('tested', 'Reg', (13, 19))	('GNAQQ209L', 'Var', (28, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (113, 127))	('uveal melanoma', 'Phenotype', 'HP:0007716', (113, 127))	('uveal melanoma', 'Disease', (113, 127))	('MAP', 'molecular_function', 'GO:0004239', ('58', '61'))	('human', 'Species', '9606', (91, 96))
132290	19078957	As shown in Figure 2, GNAQQ209L transfection into hTERT/CDK4R24C/p53DD melanocytes caused increased levels of phospho-ERK compared to control cells transfected with wildtype GNAQ (GNAQWT) or an empty vector (Vector).	('p53', 'Gene', (65, 68))	('GNAQQ209L', 'Chemical', '-', (22, 31))	('p53', 'Gene', '7157', (65, 68))	('levels', 'MPA', (100, 106))	('CDK', 'molecular_function', 'GO:0004693', ('56', '59'))	('GNAQQ209L transfection', 'Var', (22, 44))	('increased', 'PosReg', (90, 99))	('phospho-ERK', 'MPA', (110, 121))	('GNAQ', 'Chemical', '-', (174, 178))	('GNAQ', 'Chemical', '-', (180, 184))	('hTERT', 'Gene', '7015', (50, 55))	('GNAQ', 'Chemical', '-', (22, 26))	('ERK', 'molecular_function', 'GO:0004707', ('118', '121'))	('transfection', 'Var', (32, 44))	('hTERT', 'Gene', (50, 55))
132292	19078957	Conversely, siRNA-mediated knock-down of GNAQ in the uveal melanoma cell line, OMM1.3, which harbors the GNAQ-Q209L mutation, resulted in a decrease of phospho-ERK levels (Figure 3a).	('ERK', 'molecular_function', 'GO:0004707', ('160', '163'))	('GNAQ', 'Chemical', '-', (41, 45))	('GNAQ-Q209L', 'Gene', (105, 115))	('knock-down', 'Var', (27, 37))	('phospho-ERK levels', 'MPA', (152, 170))	('Q209L', 'Mutation', 'rs1057519742', (110, 115))	('decrease', 'NegReg', (140, 148))	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('uveal melanoma', 'Disease', (53, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (53, 67))	('GNAQ', 'Chemical', '-', (105, 109))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))
132293	19078957	In addition, GNAQ knock-down in OMM1.3 cells causes a substantial decrease in cell number (Figure 3b), loss of anchorage independent growth (Figure 3c) and a marked increase in sub-G0/G1 population (Figure 3d) as compared to control cells.	('increase', 'PosReg', (165, 173))	('GNAQ', 'Chemical', '-', (13, 17))	('cell number', 'CPA', (78, 89))	('GNAQ', 'Gene', (13, 17))	('sub-G0/G1 population', 'CPA', (177, 197))	('decrease', 'NegReg', (66, 74))	('anchorage independent growth', 'CPA', (111, 139))	('knock-down', 'Var', (18, 28))	('loss', 'NegReg', (103, 107))
132301	19078957	The location of neoplastic melanocytes induced by somatic GNAQ mutation in humans is very similar to the location of melanocytes affected by germline GNAQ (and GNA11) mutations in mice.	('GNAQ', 'Chemical', '-', (150, 154))	('neoplastic melanocytes', 'Phenotype', 'HP:0002861', (16, 38))	('GNAQ', 'Chemical', '-', (58, 62))	('humans', 'Species', '9606', (75, 81))	('mutation', 'Var', (63, 71))	('mice', 'Species', '10090', (180, 184))	('GNAQ', 'Gene', (58, 62))
132303	19078957	However, our previous work in mice suggests that these mutations do not interfere with homing of melanocytes to epithelial structures, but instead lead to an increase of the total melanoblast pool.	('mice', 'Species', '10090', (30, 34))	('increase', 'PosReg', (158, 166))	('mutations', 'Var', (55, 64))
132304	19078957	In humans, it is not known whether the adult dermis contains any residual sparse populations of melanocytes in which GNAQ mutations could occur and induce intradermal melanocytic tumors.	('intradermal melanocytic tumors', 'Disease', (155, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('GNAQ', 'Chemical', '-', (117, 121))	('humans', 'Species', '9606', (3, 9))	('mutations', 'Var', (122, 131))	('induce', 'Reg', (148, 154))	('intradermal melanocytic tumors', 'Disease', 'MESH:D018330', (155, 185))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('GNAQ', 'Gene', (117, 121))
132305	19078957	By contrast, nevus of Ota involves different structures such as periorbital skin, conjunctiva, neurovascular bundles, ganglia, and uvea, suggesting these GNAQ mutations may arise early in a migrating melanoblast.	('nevus of Ota', 'Phenotype', 'HP:0009920', (13, 25))	('GNAQ', 'Chemical', '-', (154, 158))	('uvea', 'Disease', (131, 135))	('mutations', 'Var', (159, 168))	('GNAQ', 'Gene', (154, 158))	('uvea', 'Disease', 'MESH:C536494', (131, 135))	('nevus', 'Phenotype', 'HP:0003764', (13, 18))
132308	19078957	The risk is small, as only about 1 in 400 nevi of Ota progress to uveal melanoma and future studies will have to elucidate the role of GNAQ mutations in this risk.	('nevi', 'Phenotype', 'HP:0003764', (42, 46))	('uveal melanoma', 'Disease', (66, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('GNAQ', 'Gene', (135, 139))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('progress', 'Reg', (54, 62))	('nevi of Ota', 'Phenotype', 'HP:0009920', (42, 53))	('GNAQ', 'Chemical', '-', (135, 139))	('mutations', 'Var', (140, 149))
132310	19078957	Thus MAPK activation appears to be an early event in neoplasms with GNAQ mutations, as it is in neoplasms with BRAF and NRAS mutations.	('neoplasms', 'Disease', 'MESH:D009369', (96, 105))	('neoplasms', 'Phenotype', 'HP:0002664', (53, 62))	('neoplasm', 'Phenotype', 'HP:0002664', (53, 61))	('BRAF', 'Gene', (111, 115))	('BRAF', 'Gene', '673', (111, 115))	('MAPK', 'molecular_function', 'GO:0004707', ('5', '9'))	('GNAQ', 'Gene', (68, 72))	('neoplasms', 'Disease', (96, 105))	('NRAS', 'Gene', (120, 124))	('MAPK activation', 'biological_process', 'GO:0000187', ('5', '20'))	('neoplasms', 'Disease', 'MESH:D009369', (53, 62))	('activation', 'PosReg', (10, 20))	('MAPK', 'Gene', (5, 9))	('neoplasm', 'Phenotype', 'HP:0002664', (96, 104))	('neoplasms', 'Phenotype', 'HP:0002664', (96, 105))	('neoplasms', 'Disease', (53, 62))	('MAPK', 'Gene', '5595;5594;5595', (5, 9))	('NRAS', 'Gene', '4893', (120, 124))	('GNAQ', 'Chemical', '-', (68, 72))	('mutations', 'Var', (73, 82))
132311	19078957	Further studies are necessary to determine whether the difference in tissue involvement between melanocytic neoplasms with BRAF mutations and those with GNAQ mutations is a functional consequence of the mutations themselves, or indicates differences in the target cell populations in which these mutations occur.	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (96, 117))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (96, 117))	('mutations', 'Var', (128, 137))	('neoplasm', 'Phenotype', 'HP:0002664', (108, 116))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('melanocytic neoplasms', 'Disease', (96, 117))	('GNAQ', 'Chemical', '-', (153, 157))	('neoplasms', 'Phenotype', 'HP:0002664', (108, 117))
132316	19078957	Primary, hTERT/CDK4R24C/p53DD, and melan-a melanocytes were stably infected with FG12 lentiviral expression vectors expressing flag-tagged wildtype GNAQ or GNAQQ209L, empty vector or NRASQ61R.	('NRAS', 'Gene', (183, 187))	('expression vectors', 'Species', '29278', (97, 115))	('p53', 'Gene', (24, 27))	('hTERT', 'Gene', '7015', (9, 14))	('p53', 'Gene', '7157', (24, 27))	('NRAS', 'Gene', '4893', (183, 187))	('GNAQ', 'Chemical', '-', (148, 152))	('CDK', 'molecular_function', 'GO:0004693', ('15', '18'))	('GNAQ', 'Chemical', '-', (156, 160))	('hTERT', 'Gene', (9, 14))	('GNAQQ209L', 'Chemical', '-', (156, 165))	('GNAQQ209L', 'Var', (156, 165))
132321	19078957	Primary antibodies were: pERK, cyclin D1, GNAQ, Cyclophilin B (Abcam), anti-FLAG M2 (Sigma), Anti-ERK 1/2 pAb (Promega), and beta-actin (Sigma).	('cyclin', 'molecular_function', 'GO:0016538', ('31', '37'))	('Cyclophilin', 'molecular_function', 'GO:0004600', ('48', '59'))	('ERK 1/2', 'Gene', '5595;5594', (98, 105))	('pERK', 'Gene', '9451', (25, 29))	('pERK', 'Gene', (25, 29))	('GNAQ', 'Chemical', '-', (42, 46))	('beta-actin (Sigma)', 'Gene', '728378', (125, 143))	('ERK 1', 'molecular_function', 'GO:0004707', ('98', '103'))	('Cyclophilin', 'molecular_function', 'GO:0016018', ('48', '59'))	('ERK 1/2', 'Gene', (98, 105))	('anti-FLAG', 'Var', (71, 80))	('cyclin D1', 'Gene', '595', (31, 40))	('beta-actin (Sigma', 'Gene', (125, 142))	('cyclin D1', 'Gene', (31, 40))
132343	19078957	Human primary and hTERT/CDK4R24C/p53DD melanocytes were cultured on cover slips in 6 well plates and infected with lentiviral vectors containing either GNAQQ209L GNAQWT, or an empty vector as control.	('Human', 'Species', '9606', (0, 5))	('hTERT', 'Gene', '7015', (18, 23))	('CDK', 'molecular_function', 'GO:0004693', ('24', '27'))	('hTERT', 'Gene', (18, 23))	('GNAQ', 'Chemical', '-', (162, 166))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('GNAQQ209L', 'Var', (152, 161))	('GNAQ', 'Chemical', '-', (152, 156))	('GNAQQ209L', 'Chemical', '-', (152, 161))
132346	19078957	10x103 human primary melanocytes, hTERT/CDK4R24C/p53DD melanocytes stably expressing GNAQQ209L, GNAQWT, NRASQ61R or vector control and siRNA treated OMM1.3 and Mel202 cells were suspended in full media containing 0.35% agar and plated on a lower layer of 0.5% agar in 6 well plates.	('GNAQ', 'Chemical', '-', (85, 89))	('p53', 'Gene', (49, 52))	('NRAS', 'Gene', '4893', (104, 108))	('hTERT', 'Gene', (34, 39))	('GNAQQ209L', 'Chemical', '-', (85, 94))	('GNAQQ209L', 'Var', (85, 94))	('GNAQ', 'Chemical', '-', (96, 100))	('agar', 'Chemical', 'MESH:D000362', (260, 264))	('human', 'Species', '9606', (7, 12))	('agar', 'Chemical', 'MESH:D000362', (219, 223))	('p53', 'Gene', '7157', (49, 52))	('CDK', 'molecular_function', 'GO:0004693', ('40', '43'))	('NRAS', 'Gene', (104, 108))	('hTERT', 'Gene', '7015', (34, 39))
132360	33100043	The most promising hit was the quinoline derivative VS13, a nanomolar inhibitor of HDAC6, which exhibited a good antiproliferative effect on UM cell lines at micromolar concentration and a capability to modify the mRNA levels of HDAC target genes similar to that of SAHA.	('UM', 'Phenotype', 'HP:0007716', (141, 143))	('HDAC', 'Gene', (83, 87))	('HDAC', 'Gene', '9734', (83, 87))	('VS13', 'Var', (52, 56))	('HDAC', 'Gene', (229, 233))	('HDAC6', 'Gene', '10013', (83, 88))	('antiproliferative effect', 'MPA', (113, 137))	('mRNA levels', 'MPA', (214, 225))	('modify', 'Reg', (203, 209))	('HDAC6', 'Gene', (83, 88))	('HDAC', 'Gene', '9734', (229, 233))	('quinoline', 'Chemical', 'MESH:C037219', (31, 40))	('N', 'Chemical', 'MESH:D009584', (216, 217))
132385	33100043	Modifications of these four structural parts such as the CAP group, the linker, or the ZBG, have become important strategies that have led to the development of a large number of HDACIs.	('ZBG', 'Chemical', '-', (87, 90))	('led to', 'Reg', (135, 141))	('C', 'Chemical', 'MESH:D002244', (182, 183))	('C', 'Chemical', 'MESH:D002244', (57, 58))	('Modifications', 'Var', (0, 13))	('HDAC', 'Gene', (179, 183))	('HDAC', 'Gene', '9734', (179, 183))
132403	33100043	The length of the linker influences the HDAC inhibitory activity and a 4-carbon linear aliphatic chain appears nearly optimal: IC50 values of compounds with n = 1 are in the micromolar range while the IC50 values of compounds with n = 2 are in the nanomolar range.	('n = 1', 'Var', (157, 162))	('C', 'Chemical', 'MESH:D002244', (202, 203))	('influences', 'Reg', (25, 35))	('-c', 'Chemical', 'MESH:D002244', (72, 74))	('C', 'Chemical', 'MESH:D002244', (128, 129))	('C', 'Chemical', 'MESH:D002244', (43, 44))	('HDAC', 'Gene', (40, 44))	('carbon', 'Chemical', 'MESH:D002244', (73, 79))	('HDAC', 'Gene', '9734', (40, 44))	('IC50', 'MPA', (127, 131))
132406	33100043	The selected hydroxamates (SN2, VS16, LD10, and VS13) were tested for their inhibitory activity towards four human isolated HDACs: HDACs 1, 3, and 8 (Class I HDACs) and HDAC 6 (a Class II HDAC) to investigate how the different CAP groups could influence the HDAC activity.	('C', 'Chemical', 'MESH:D002244', (227, 228))	('HDAC', 'Gene', (258, 262))	('HDAC', 'Gene', (131, 135))	('HDAC', 'Gene', '9734', (169, 173))	('HDAC 6', 'Gene', (169, 175))	('C', 'Chemical', 'MESH:D002244', (161, 162))	('LD10', 'Var', (38, 42))	('VS13', 'Var', (48, 52))	('HDAC', 'Gene', (169, 173))	('influence', 'Reg', (244, 253))	('HDACs 1, 3, and 8', 'Gene', '3065;8841;55869', (131, 148))	('SN2', 'Gene', (27, 30))	('HDAC', 'Gene', '9734', (188, 192))	('hydroxamates', 'Chemical', '-', (13, 25))	('HDAC', 'Gene', '9734', (158, 162))	('HDAC', 'Gene', '9734', (124, 128))	('inhibitory activity', 'MPA', (76, 95))	('C', 'Chemical', 'MESH:D002244', (191, 192))	('HDAC 6', 'Gene', '10013', (169, 175))	('HDAC', 'Gene', (188, 192))	('C', 'Chemical', 'MESH:D002244', (150, 151))	('C', 'Chemical', 'MESH:D002244', (134, 135))	('C', 'Chemical', 'MESH:D002244', (127, 128))	('HDAC', 'Gene', (158, 162))	('human', 'Species', '9606', (109, 114))	('HDAC', 'Gene', (124, 128))	('C', 'Chemical', 'MESH:D002244', (261, 262))	('HDAC', 'Gene', '9734', (258, 262))	('VS16', 'Var', (32, 36))	('SN2', 'Gene', '92745', (27, 30))	('HDAC', 'Gene', '9734', (131, 135))	('C', 'Chemical', 'MESH:D002244', (179, 180))	('C', 'Chemical', 'MESH:D002244', (172, 173))
132410	33100043	Moreover, compounds SN2, VS16, and LD10 resulted in more active on HDAC3 than on the other isoforms.	('SN2', 'Gene', '92745', (20, 23))	('HDAC3', 'Gene', '8841', (67, 72))	('LD10', 'Var', (35, 39))	('active', 'MPA', (57, 63))	('more', 'PosReg', (52, 56))	('HDAC3', 'Gene', (67, 72))	('VS16', 'Var', (25, 29))	('SN2', 'Gene', (20, 23))
132412	33100043	Among the four selected compounds, the most active on all the HDACs considered in this work was the quinoline derivative VS13 that showed a stronger effect on HDAC6 than on the other isoforms.	('HDAC', 'Gene', (62, 66))	('HDAC', 'Gene', '9734', (62, 66))	('VS13', 'Var', (121, 125))	('HDAC', 'Gene', (159, 163))	('HDAC6', 'Gene', '10013', (159, 164))	('HDAC', 'Gene', '9734', (159, 163))	('HDAC6', 'Gene', (159, 164))	('quinoline', 'Chemical', 'MESH:C037219', (100, 109))
132413	33100043	In particular, VS13 was active at 10 nM on HDAC6, only 7 times less active than SAHA and ~900 times more selective for HDAC6 over HDAC8.	('HDAC6', 'Gene', '10013', (119, 124))	('HDAC6', 'Gene', (43, 48))	('active', 'MPA', (24, 30))	('HDAC8', 'Gene', '55869', (130, 135))	('HDAC6', 'Gene', (119, 124))	('HDAC8', 'Gene', (130, 135))	('VS13', 'Var', (15, 19))	('HDAC6', 'Gene', '10013', (43, 48))
132414	33100043	Compounds LD10, VS13, SN2, and VS16 were docked in HDAC1, HDAC3, HDAC6, and HDAC8.	('VS16', 'Var', (31, 35))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('HDAC3', 'Gene', (58, 63))	('HDAC8', 'Gene', (76, 81))	('HDAC6', 'Gene', '10013', (65, 70))	('SN2', 'Gene', (22, 25))	('LD10', 'Var', (10, 14))	('HDAC1', 'Gene', '3065', (51, 56))	('HDAC3', 'Gene', '8841', (58, 63))	('HDAC6', 'Gene', (65, 70))	('C', 'Chemical', 'MESH:D002244', (61, 62))	('C', 'Chemical', 'MESH:D002244', (54, 55))	('SN2', 'Gene', '92745', (22, 25))	('VS13', 'Var', (16, 20))	('HDAC1', 'Gene', (51, 56))	('C', 'Chemical', 'MESH:D002244', (79, 80))	('C', 'Chemical', 'MESH:D002244', (68, 69))	('HDAC8', 'Gene', '55869', (76, 81))
132415	33100043	The superposition between the docked-pose of two investigated compounds LD10 and VS13 and the PDB structures (human HDACs in complex with hydroxamate inhibitors) showed a quite different disposition of both ligands in the HDACs binding site.	('VS13', 'Var', (81, 85))	('binding', 'molecular_function', 'GO:0005488', ('228', '235'))	('hydroxamate', 'Chemical', '-', (138, 149))	('LD10', 'Var', (72, 76))	('human', 'Species', '9606', (110, 115))	('HDAC', 'Gene', (116, 120))	('HDAC', 'Gene', (222, 226))	('HDAC', 'Gene', '9734', (116, 120))	('HDAC', 'Gene', '9734', (222, 226))
132418	33100043	The different pose displayed by compounds LD10 and VS13 could be related to the substitution of the typical amidic connection unit, present in the HDAC inhibitors, with the methyloximino moiety.	('substitution', 'Var', (80, 92))	('VS13', 'Var', (51, 55))	('LD10', 'Var', (42, 46))	('methyloximino', 'Chemical', '-', (173, 186))	('HDAC', 'Gene', (147, 151))	('HDAC', 'Gene', '9734', (147, 151))
132421	33100043	The only exception was the different orientation displayed by Phe152, in HDAC8, with respect to Phe150 (HDAC1), Phe144 (HDAC3), and Phe620 (HDAC6) (Figure 4(a-d), Figure 5).	('Phe152', 'Var', (62, 68))	('HDAC6', 'Gene', '10013', (140, 145))	('HDAC1', 'Gene', '3065', (104, 109))	('HDAC6', 'Gene', (140, 145))	('Phe150', 'Chemical', '-', (96, 102))	('Phe620', 'Chemical', '-', (132, 138))	('HDAC8', 'Gene', (73, 78))	('Phe152', 'Chemical', '-', (62, 68))	('Phe144', 'Var', (112, 118))	('HDAC3', 'Gene', '8841', (120, 125))	('Phe144', 'Chemical', '-', (112, 118))	('HDAC8', 'Gene', '55869', (73, 78))	('HDAC1', 'Gene', (104, 109))	('HDAC3', 'Gene', (120, 125))	('Phe620', 'Var', (132, 138))
132424	33100043	Precisely, loop4 of HDAC8 opens the binding cavity outside, with respect to the arrangement of the same loop in HDAC1 and HDAC3 (see also the surface in Figure 4).	('HDAC1', 'Gene', (112, 117))	('binding', 'molecular_function', 'GO:0005488', ('36', '43'))	('loop4', 'Var', (11, 16))	('HDAC8', 'Gene', '55869', (20, 25))	('HDAC1', 'Gene', '3065', (112, 117))	('HDAC8', 'Gene', (20, 25))	('HDAC3', 'Gene', '8841', (122, 127))	('binding', 'Interaction', (36, 43))	('HDAC3', 'Gene', (122, 127))
132425	33100043	On the contrary, the arrangement of loop3 in HDAC8 (as in HDAC1) shrinks the binding channel.	('binding', 'molecular_function', 'GO:0005488', ('77', '84'))	('HDAC8', 'Gene', (45, 50))	('HDAC8', 'Gene', '55869', (45, 50))	('shrinks', 'NegReg', (65, 72))	('HDAC1', 'Gene', (58, 63))	('binding', 'Interaction', (77, 84))	('HDAC1', 'Gene', '3065', (58, 63))	('arrangement', 'Var', (21, 32))
132427	33100043	Regarding the CAP group orientation, the differences between loop3 and 4 regions among the HDAC subtypes can induce a different pose of the studied ligands.	('pose', 'MPA', (128, 132))	('C', 'Chemical', 'MESH:D002244', (14, 15))	('differences', 'Var', (41, 52))	('C', 'Chemical', 'MESH:D002244', (94, 95))	('HDAC', 'Gene', (91, 95))	('induce', 'Reg', (109, 115))	('HDAC', 'Gene', '9734', (91, 95))
132430	33100043	In HDAC8, both ligands LD10 and VS13 coordinated the catalytic zinc and established one polar interaction with the His143 of the second binding shell (Figure 4(d)).	('coordinated', 'MPA', (37, 48))	('binding', 'molecular_function', 'GO:0005488', ('136', '143'))	('VS13', 'Var', (32, 36))	('HDAC8', 'Gene', '55869', (3, 8))	('His143', 'Chemical', '-', (115, 121))	('HDAC8', 'Gene', (3, 8))	('catalytic zinc', 'MPA', (53, 67))	('polar interaction', 'MPA', (88, 105))	('LD10', 'Var', (23, 27))
132431	33100043	In HDAC1 core, the hydroxamic moiety of both inhibitors established two hydrogen bonds with His141 and Tyr303.	('His141', 'Protein', (92, 98))	('Tyr303', 'Var', (103, 109))	('hydrogen', 'Interaction', (72, 80))	('HDAC1', 'Gene', (3, 8))	('His141', 'Chemical', '-', (92, 98))	('hydrogen', 'Chemical', 'MESH:D006859', (72, 80))	('established', 'Reg', (56, 67))	('Tyr303', 'Chemical', '-', (103, 109))	('HDAC1', 'Gene', '3065', (3, 8))	('core', 'cellular_component', 'GO:0019013', ('9', '13'))
132433	33100043	In HDAC3, the LD10 and VS13 hydroxamate group was stabilised through two hydrogen interactions with His135 and Tyr298.	('Tyr298', 'Chemical', '-', (111, 117))	('HDAC3', 'Gene', (3, 8))	('His135', 'Var', (100, 106))	('LD10', 'Var', (14, 18))	('His135', 'Chemical', '-', (100, 106))	('hydroxamate', 'Chemical', '-', (28, 39))	('Tyr298', 'Var', (111, 117))	('VS13', 'Var', (23, 27))	('hydrogen', 'Chemical', 'MESH:D006859', (73, 81))	('HDAC3', 'Gene', '8841', (3, 8))
132434	33100043	Both aromatic CAP groups pointed towards loop3, in particular, the quinoline nitrogen of VS13 engaged a strong hydrogen bond with the loop3's backbone (Figure 4(b)).	('VS13', 'Var', (89, 93))	('C', 'Chemical', 'MESH:D002244', (14, 15))	('quinoline', 'Chemical', 'MESH:C037219', (67, 76))	('nitrogen', 'Chemical', 'MESH:D009584', (77, 85))	('hydrogen bond', 'MPA', (111, 124))	('hydrogen', 'Chemical', 'MESH:D006859', (111, 119))
132435	33100043	A similar ligands pose was calculated in HDAC6 where the hydroxamate group was further stabilised by the His610 of the second catalytic shell (Figure 4(c)).	('His610', 'Var', (105, 111))	('HDAC6', 'Gene', '10013', (41, 46))	('HDAC6', 'Gene', (41, 46))	('hydroxamate', 'Chemical', '-', (57, 68))	('His610', 'Chemical', '-', (105, 111))
132437	33100043	Analysing the VS13 binding pose, it can be hypothesised that a nitrogen atom in the aromatic CAP ring allows better interaction with loop3 and, therefore, enhances the inhibitory activity.	('C', 'Chemical', 'MESH:D002244', (93, 94))	('nitrogen', 'Var', (63, 71))	('binding', 'molecular_function', 'GO:0005488', ('19', '26'))	('nitrogen', 'Chemical', 'MESH:D009584', (63, 71))	('loop3', 'Protein', (133, 138))	('enhances', 'PosReg', (155, 163))	('better', 'PosReg', (109, 115))	('inhibitory activity', 'MPA', (168, 187))	('interaction', 'Interaction', (116, 127))
132440	33100043	As previously mentioned, the loop3 of HDAC8 shrinked the outer binding channel.	('outer binding channel', 'MPA', (57, 78))	('HDAC8', 'Gene', '55869', (38, 43))	('loop3', 'Var', (29, 34))	('HDAC8', 'Gene', (38, 43))	('shrinked', 'NegReg', (44, 52))	('binding', 'molecular_function', 'GO:0005488', ('63', '70'))
132444	33100043	For all investigated ligands (LD10, VS13, SN2 and VS16) the computational study showed tiny differences in the ligand-binding poses, principally due to the sequence and shape variations of loops3 and 4 among the four HDAC subtypes.	('HDAC', 'Gene', '9734', (217, 221))	('differences', 'Reg', (92, 103))	('SN2', 'Gene', '92745', (42, 45))	('VS16', 'Var', (50, 54))	('VS13', 'Var', (36, 40))	('ligand-binding', 'Interaction', (111, 125))	('ligand', 'molecular_function', 'GO:0005488', ('111', '117'))	('SN2', 'Gene', (42, 45))	('binding', 'molecular_function', 'GO:0005488', ('118', '125'))	('HDAC', 'Gene', (217, 221))
132445	33100043	The anti-proliferative effects of the most promising HDAC inhibitors, VS16, VS13, SN2, and LD10 were evaluated on human UM cell lines (92.1 and Mel270) and SAHA was used as a positive control.	('SN2', 'Gene', '92745', (82, 85))	('VS16', 'Var', (70, 74))	('SN2', 'Gene', (82, 85))	('anti-proliferative', 'MPA', (4, 22))	('HDAC', 'Gene', (53, 57))	('human', 'Species', '9606', (114, 119))	('UM', 'Phenotype', 'HP:0007716', (120, 122))	('HDAC', 'Gene', '9734', (53, 57))
132447	33100043	Figure 7 and Supplementary Figure S2 show that compounds VS16, VS13, and SN2 have a stronger effect on 92.1 and Mel270 cell viability than SAHA and LD10.	('SN2', 'Gene', (73, 76))	('SN2', 'Gene', '92745', (73, 76))	('92.1', 'CPA', (103, 107))	('VS13', 'Var', (63, 67))
132450	33100043	Flow cytometry analysis of cell cycle distribution in 92.1 and Mel270 cells after treatment with the different compounds or control DMSO, indeed showed that VS16, VS13, SN2, and SAHA efficiently block the cell cycle at the G0/G1 phase (Figure 8 and Supplementary Figure S3) while LD10 behaved like the control DMSO.	('SN2', 'Gene', (169, 172))	('cell cycle at the G0/G1 phase', 'CPA', (205, 234))	('cell cycle', 'biological_process', 'GO:0007049', ('27', '37'))	('VS13', 'Var', (163, 167))	('SAHA efficiently block', 'Disease', (178, 200))	('VS16', 'Var', (157, 161))	('SN2', 'Gene', '92745', (169, 172))	('SAHA efficiently block', 'Disease', 'MESH:D006327', (178, 200))	('DMSO', 'Chemical', 'MESH:D004121', (132, 136))	('cell cycle', 'biological_process', 'GO:0007049', ('205', '215'))	('G1 phase', 'biological_process', 'GO:0051318', ('226', '234'))	('DMSO', 'Chemical', 'MESH:D004121', (310, 314))
132453	33100043	Of note, VS13 shares with SAHA the high activity on HDAC6 (see Table 2), thus supporting the hypothesis that these modulatory effects on genes could be mainly mediated by HDAC6 inhibition on which the other compounds have a lower effect.	('HDAC6', 'Gene', (171, 176))	('inhibition', 'NegReg', (177, 187))	('HDAC6', 'Gene', '10013', (52, 57))	('HDAC6', 'Gene', (52, 57))	('VS13', 'Var', (9, 13))	('activity', 'MPA', (40, 48))	('HDAC6', 'Gene', '10013', (171, 176))
132524	33100043	(%) for C11H14N2O3S: C 51.95; H 5.55; N 11.02; found: C 52.02, H 5.61, N 11.25.	('C', 'Chemical', 'MESH:D002244', (21, 22))	('C11H14N2O3S: C 51.95', 'Var', (8, 28))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('C', 'Chemical', 'MESH:D002244', (8, 9))	('1H', 'Chemical', '-', (10, 12))	('C 52.02', 'Var', (54, 61))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('N', 'Chemical', 'MESH:D009584', (14, 15))	('C', 'Chemical', 'MESH:D002244', (54, 55))	('H14N2', 'Species', '1346489', (11, 16))
132622	33100043	The human UM cell lines 92.1 and Mel270 (kindly provided to RG by M. J. Jager) and the ovarian cancer cell lines SKOV3 (ATTC), A2780 (ICLC) and A2774 (IST Genoa) were grown in RPMI 1640, with 2 mM L-glutamine, 10% heat-inactivated foetal calf serum, and 100 mug/ml penicillin-streptomycin (Lonza) at 37  C in a 5% CO2 incubator.	('Lonza', 'Chemical', '-', (290, 295))	('C', 'Chemical', 'MESH:D002244', (314, 315))	('C', 'Chemical', 'MESH:D002244', (304, 305))	('C', 'Chemical', 'MESH:D002244', (123, 124))	('ovarian cancer', 'Disease', 'MESH:D010051', (87, 101))	('SKOV3', 'CellLine', 'CVCL:0532', (113, 118))	('L-glutamine', 'Chemical', 'MESH:D005973', (197, 208))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('C', 'Chemical', 'MESH:D002244', (137, 138))	('A2780', 'CellLine', 'CVCL:0134', (127, 132))	('UM', 'Phenotype', 'HP:0007716', (10, 12))	('A2780', 'Var', (127, 132))	('A2774', 'Var', (144, 149))	('C', 'Chemical', 'MESH:D002244', (135, 136))	('ovarian cancer', 'Disease', (87, 101))	('human', 'Species', '9606', (4, 9))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('streptomycin', 'Chemical', 'MESH:D013307', (276, 288))	('mug', 'molecular_function', 'GO:0043739', ('258', '261'))	('penicillin', 'Chemical', 'MESH:D010406', (265, 275))	('RPMI', 'Chemical', '-', (176, 180))	('CO2', 'Chemical', 'MESH:D002245', (314, 317))
132638	33092094	Novel Methylation Patterns Predict Outcome in Uveal Melanoma Uveal melanoma (UM) is the most common intraocular tumor in adults.	('Predict', 'Reg', (27, 34))	('intraocular tumor', 'Disease', (100, 117))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('Methylation', 'Var', (6, 17))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('Melanoma', 'Disease', 'MESH:D008545', (52, 60))	('Melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('ocular tumor', 'Phenotype', 'HP:0100012', (105, 117))	('Melanoma', 'Disease', (52, 60))	('Methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('intraocular tumor', 'Disease', 'MESH:D009798', (100, 117))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (46, 60))
132651	33092094	More than 80% of UMs harbour mutually exclusive mutations in GNAQ or GNA11, which lead to constitutive activation of signaling pathways such as the RAS-ERK and PI3K/AKT/mTOR pathways.	('ERK', 'Gene', '5594', (152, 155))	('AKT', 'Gene', (165, 168))	('ERK', 'molecular_function', 'GO:0004707', ('152', '155'))	('ERK', 'Gene', (152, 155))	('mTOR', 'Gene', '2475', (169, 173))	('GNAQ', 'Gene', (61, 65))	('signaling pathways', 'Pathway', (117, 135))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))	('mTOR', 'Gene', (169, 173))	('GNA11', 'Gene', '2767', (69, 74))	('AKT', 'Gene', '207', (165, 168))	('GNA11', 'Gene', (69, 74))	('PI3K', 'molecular_function', 'GO:0016303', ('160', '164'))	('activation', 'PosReg', (103, 113))	('mutations', 'Var', (48, 57))	('GNAQ', 'Gene', '2776', (61, 65))	('UM', 'Phenotype', 'HP:0007716', (17, 19))
132652	33092094	GNAQ and GNA11 mutations are initiating mutations in UM, and despite their presence in almost all of these tumors, the presence of these mutations is not generally related to the development of metastasis or to prognosis.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('mutations', 'Var', (15, 24))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('related', 'Reg', (164, 171))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('GNAQ', 'Gene', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (53, 55))	('GNA11', 'Gene', '2767', (9, 14))
132653	33092094	There are three mutations that have been shown to be associated with prognosis in UM; EIF1AX, SF3B1, and BAP1 mutations can be used to classify UMs into low, intermediate, and high-risk, respectively.	('SF3B1', 'Gene', '23451', (94, 99))	('mutations', 'Var', (110, 119))	('UM', 'Phenotype', 'HP:0007716', (144, 146))	('UMs', 'Disease', (144, 147))	('UM', 'Disease', (82, 84))	('BAP1', 'Gene', '8314', (105, 109))	('BAP1', 'Gene', (105, 109))	('associated', 'Reg', (53, 63))	('SF3B1', 'Gene', (94, 99))	('UM', 'Phenotype', 'HP:0007716', (82, 84))	('EIF1AX', 'Gene', '1964', (86, 92))	('EIF1AX', 'Gene', (86, 92))
132654	33092094	EIF1AX mutations are generally an indicator of good prognosis and are associated with low risk of metastasis.	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
132655	33092094	SF3B1 mutations have been associated with late metastases, while BAP1 mutations are associated with the development of early metastases.	('metastases', 'Disease', (125, 135))	('BAP1', 'Gene', '8314', (65, 69))	('SF3B1', 'Gene', (0, 5))	('metastases', 'Disease', 'MESH:D009362', (125, 135))	('metastases', 'Disease', (47, 57))	('BAP1', 'Gene', (65, 69))	('SF3B1', 'Gene', '23451', (0, 5))	('associated', 'Reg', (84, 94))	('metastases', 'Disease', 'MESH:D009362', (47, 57))	('associated', 'Reg', (26, 36))	('mutations', 'Var', (6, 15))
132657	33092094	DNA methylation is recognized as an important event in cancer, where a pattern of global hypomethylation leading to genomic instability is often seen.	('global hypomethylation', 'Var', (82, 104))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('genomic instability', 'MPA', (116, 135))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('leading to', 'Reg', (105, 115))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
132658	33092094	Along with this, many tumor types also show a specific pattern of hypermethylation at CpG islands which can be important in tumor progression, for example leading to the silencing of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('hypermethylation', 'Var', (66, 82))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('silencing', 'MPA', (170, 179))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', (22, 27))	('tumor suppressor', 'biological_process', 'GO:0051726', ('183', '199'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('183', '199'))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
132660	33092094	Because epigenetic processes such as DNA methylation are mitotically heritable, they can play similar roles as genetic alterations in the development of cancer, making them an important target in both prognostication and drug development.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('DNA methylation', 'biological_process', 'GO:0006306', ('37', '52'))	('methylation', 'Var', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))
132662	33092094	Additionally, a recent study has shown that BAP1 knockdown in UM cells is associated with methylomic reprogramming in these cells, pointing to a link between the genetic mutations seen in UM and large scale changes in methylation pattern.	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('knockdown', 'Var', (49, 58))	('methylation', 'biological_process', 'GO:0032259', ('218', '229'))	('associated', 'Reg', (74, 84))	('BAP1', 'Gene', '8314', (44, 48))	('UM', 'Phenotype', 'HP:0007716', (188, 190))	('BAP1', 'Gene', (44, 48))
132664	33092094	Given the promise that epigenetic-targeting agents have shown in many tumor types, either through targeting specific modifications directly or through targeting epigenetic regulators, the reversal of epigenetic alterations may be a promising avenue for preventing metastasis in UM.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('epigenetic alterations', 'Var', (200, 222))	('tumor', 'Disease', (70, 75))	('UM', 'Phenotype', 'HP:0007716', (278, 280))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('metastasis', 'CPA', (264, 274))
132671	33092094	The two groups were compared based on the sex and age of the individuals, survival and the development of metastatic UM, GNAQ, GNA11, and BAP1 mutations, and CNVs.	('BAP1', 'Gene', '8314', (138, 142))	('metastatic UM', 'CPA', (106, 119))	('GNAQ', 'Gene', '2776', (121, 125))	('BAP1', 'Gene', (138, 142))	('GNA11', 'Gene', '2767', (127, 132))	('GNA11', 'Gene', (127, 132))	('GNAQ', 'Gene', (121, 125))	('UM', 'Phenotype', 'HP:0007716', (117, 119))	('mutations', 'Var', (143, 152))
132691	33092094	The occurrence of GNAQ and GNA11 mutations, which are initiating events in UM and not generally believed to be prognostically significant, differed between the two groups, with more GNAQ mutations in the low risk group (25 vs. 15, p < 0.05) and slightly more GNA11 mutations in the high risk group (22 vs. 14, p = 0.07, Table 4).	('GNA11', 'Gene', '2767', (259, 264))	('GNA11', 'Gene', (259, 264))	('GNAQ', 'Gene', '2776', (182, 186))	('GNAQ', 'Gene', '2776', (18, 22))	('mutations', 'Var', (33, 42))	('mutations', 'Var', (187, 196))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('GNAQ', 'Gene', (182, 186))	('GNAQ', 'Gene', (18, 22))	('GNA11', 'Gene', (27, 32))	('GNA11', 'Gene', '2767', (27, 32))
132692	33092094	BAP1 mutations are the most prognostically significant genomic alteration in UM, and are associated with high risk of metastasis.	('associated', 'Reg', (89, 99))	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('BAP1', 'Gene', '8314', (0, 4))
132693	33092094	The presence of a BAP1 mutation was significantly associated with survival in this cohort (p = 0.00022, Figure 4B).	('associated with', 'Reg', (50, 65))	('BAP1', 'Gene', '8314', (18, 22))	('mutation', 'Var', (23, 31))	('BAP1', 'Gene', (18, 22))	('presence', 'Var', (4, 12))
132694	33092094	The two groups differed by the number of cases with presence/absence of a BAP1 mutation (p < 0.00001), with all confirmed BAP1 mutations (24/80) found in the high-risk group (Figure 4A).	('BAP1', 'Gene', (122, 126))	('BAP1', 'Gene', '8314', (74, 78))	('BAP1', 'Gene', '8314', (122, 126))	('mutation', 'Var', (79, 87))	('mutations', 'Var', (127, 136))	('BAP1', 'Gene', (74, 78))
132695	33092094	In addition to BAP1 mutations, chromosomal changes are significantly associated with risk of metastasis and survival in UM.	('chromosomal changes', 'Var', (31, 50))	('metastasis', 'CPA', (93, 103))	('associated', 'Reg', (69, 79))	('BAP1', 'Gene', '8314', (15, 19))	('UM', 'Phenotype', 'HP:0007716', (120, 122))	('survival', 'CPA', (108, 116))	('BAP1', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))
132696	33092094	Loss of chromosome 1p is not associated with decreased disease-free survival except in instances where this loss is combined with a loss of chromosome 3.	('decreased disease-free', 'Disease', (45, 67))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('decreased disease-free', 'Disease', 'MESH:D008569', (45, 67))	('chromosome', 'cellular_component', 'GO:0005694', ('140', '150'))	('Loss', 'Var', (0, 4))
132697	33092094	Importantly, all cases in the high-risk group had at least one important marker of poor outcome (either chromosome 3 loss, confirmed BAP1 mutation, and/or development of metastasis) (Figure 4A).	('chromosome', 'Gene', (104, 114))	('loss', 'NegReg', (117, 121))	('BAP1', 'Gene', '8314', (133, 137))	('mutation', 'Var', (138, 146))	('BAP1', 'Gene', (133, 137))	('chromosome', 'cellular_component', 'GO:0005694', ('104', '114'))
132698	33092094	Additionally, the methylation groupings were more accurate in predicting death from metastasis in this cohort than other known prognostic indicators of UM, including chromosome 3 loss, BAP1 mutations, and clinical features (Figure 4B).	('BAP1', 'Gene', (185, 189))	('mutations', 'Var', (190, 199))	('death', 'Disease', (73, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('166', '176'))	('UM', 'Phenotype', 'HP:0007716', (152, 154))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('loss', 'NegReg', (179, 183))	('death', 'Disease', 'MESH:D003643', (73, 78))	('BAP1', 'Gene', '8314', (185, 189))
132701	33092094	Along with this, the analysis showed hypermethylation of a number of genes involved in the negative regulation of ERK1/2 in the high-risk group, as seen by analysis of DAVID biological process GO (Table S6).	('ERK1', 'molecular_function', 'GO:0004707', ('114', '118'))	('ERK1/2', 'Gene', (114, 120))	('biological process', 'biological_process', 'GO:0008150', ('174', '192'))	('ERK1/2', 'Gene', '5595;5594', (114, 120))	('regulation', 'biological_process', 'GO:0065007', ('100', '110'))	('hypermethylation', 'Var', (37, 53))
132702	33092094	This category includes the hypermethylation of 10 probes associated with in the PTEN gene in the high-risk group (Table S7).	('PTEN', 'Gene', '5728', (80, 84))	('hypermethylation', 'Var', (27, 43))	('PTEN', 'Gene', (80, 84))
132703	33092094	Among the many DMPs, several tumor suppressor genes and transcriptional regulators appear to be methylated in the high-risk group.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor suppressor', 'biological_process', 'GO:0051726', ('29', '45'))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('29', '45'))	('methylated', 'Var', (96, 106))	('DMPs', 'Gene', (15, 19))	('tumor', 'Disease', (29, 34))	('DMPs', 'Chemical', '-', (15, 19))
132705	33092094	RASSF1, a gene known to be inactivated through methylation in UM, was also found to be highly differentially methylated at multiple probes between the high- and low-risk groups (Table S10).	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('S10', 'Gene', '6204', (184, 187))	('methylation', 'Var', (47, 58))	('RASSF1', 'Gene', '11186', (0, 6))	('methylation', 'biological_process', 'GO:0032259', ('47', '58'))	('S10', 'Gene', (184, 187))	('RASSF1', 'Gene', (0, 6))
132706	33092094	Similarly, hypermethylation in the high-risk group in multiple ZNF genes, especially in ZNF358 (three probes with a log FC > 1.5, range: 3.49-4.37, Figure 6B) and ZNF532 (nine probes with a log FC > 1.5, range: 1.63-4.04) was seen (Tables S11 and S12).	('ZNF358', 'Gene', (88, 94))	('ZNF358', 'Gene', '140467', (88, 94))	('hypermethylation', 'Var', (11, 27))	('S12', 'Gene', (247, 250))	('ZNF genes', 'Gene', (63, 72))	('ZNF532', 'Gene', (163, 169))	('S12', 'Gene', '6268', (247, 250))	('ZNF532', 'Gene', '55205', (163, 169))	('S11', 'Gene', '6267', (239, 242))	('S11', 'Gene', (239, 242))
132711	33092094	A loss of function mutation in BAP1 is a very strong predictor of metastasis, and was found in 24 cases of this cohort, all of which were placed into the high-risk group.	('mutation', 'Var', (19, 27))	('BAP1', 'Gene', '8314', (31, 35))	('loss of function', 'NegReg', (2, 18))	('BAP1', 'Gene', (31, 35))	('metastasis', 'CPA', (66, 76))
132712	33092094	All cases in the high-risk group had one or more important markers of poor outcome (either confirmed metastatic UM, chromosome 3 loss, and/or confirmed BAP1 mutation), suggesting that these cases all show high metastatic potential as compared to the cases designated into the low-risk group (Figure 4).	('BAP1', 'Gene', '8314', (152, 156))	('loss', 'NegReg', (129, 133))	('mutation', 'Var', (157, 165))	('chromosome', 'cellular_component', 'GO:0005694', ('116', '126'))	('UM', 'Phenotype', 'HP:0007716', (112, 114))	('BAP1', 'Gene', (152, 156))	('metastatic UM', 'CPA', (101, 114))
132713	33092094	Additionally, the methylation groupings were more accurate in predicting the development of metastasis in this cohort than other significant markers of UM progression, including chromosome 3 loss, BAP1 mutations, and tumor features used to predict prognosis (Figure 4B).	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('loss', 'NegReg', (191, 195))	('UM', 'Phenotype', 'HP:0007716', (152, 154))	('BAP1', 'Gene', '8314', (197, 201))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('chromosome', 'cellular_component', 'GO:0005694', ('178', '188'))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('BAP1', 'Gene', (197, 201))	('mutations', 'Var', (202, 211))
132714	33092094	BAP1 mutations are difficult to detect as they can occur on multiple locations in the gene, therefore requiring whole-gene sequencing.	('BAP1', 'Gene', '8314', (0, 4))	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
132723	33092094	For the remaining three patients in the low risk group who developed metastasis, two showed SF3B1 mutations, which have been associated with the development of late metastases, suggesting that methylation patterns are altered in patients who develop earlier metastases, but may be different in patients who will develop later metastases.	('patients', 'Species', '9606', (229, 237))	('metastases', 'Disease', 'MESH:D009362', (258, 268))	('metastases', 'Disease', 'MESH:D009362', (165, 175))	('patients', 'Species', '9606', (294, 302))	('SF3B1', 'Gene', '23451', (92, 97))	('methylation', 'biological_process', 'GO:0032259', ('193', '204'))	('metastases', 'Disease', (326, 336))	('mutations', 'Var', (98, 107))	('metastases', 'Disease', 'MESH:D009362', (326, 336))	('altered', 'Reg', (218, 225))	('patients', 'Species', '9606', (24, 32))	('metastases', 'Disease', (258, 268))	('metastases', 'Disease', (165, 175))	('SF3B1', 'Gene', (92, 97))
132724	33092094	Supporting this, 15 of the 18 patients with SF3B1 mutations were classified in the low-risk group.	('mutations', 'Var', (50, 59))	('patients', 'Species', '9606', (30, 38))	('SF3B1', 'Gene', (44, 49))	('SF3B1', 'Gene', '23451', (44, 49))
132725	33092094	As none of the patients in the low-risk group who developed metastasis showed BAP1 mutations or copy number alterations at chromosome 3, other factors may be contributing to metastasis in these patients and warrant further examination.	('mutations', 'Var', (83, 92))	('patients', 'Species', '9606', (15, 23))	('patients', 'Species', '9606', (194, 202))	('contributing', 'Reg', (158, 170))	('copy number alterations', 'Var', (96, 119))	('BAP1', 'Gene', '8314', (78, 82))	('chromosome', 'cellular_component', 'GO:0005694', ('123', '133'))	('BAP1', 'Gene', (78, 82))
132726	33092094	For the patients in the high-risk grouping, metastasis tended to occur early (average of 1.86 years), and was generally, but not always, associated with the presence of alterations in chromosome 3 or BAP1 mutations.	('associated', 'Reg', (137, 147))	('alterations', 'Var', (169, 180))	('patients', 'Species', '9606', (8, 16))	('mutations', 'Var', (205, 214))	('BAP1', 'Gene', '8314', (200, 204))	('metastasis', 'CPA', (44, 54))	('chromosome', 'cellular_component', 'GO:0005694', ('184', '194'))	('BAP1', 'Gene', (200, 204))	('chromosome', 'Gene', (184, 194))
132727	33092094	Additionally, as inactivating BAP1 mutations can occur across multiple regions of the gene, it is possible that not all BAP1 mutations have been detected in this study, and that changes in methylation in the high risk group may be related to changes in the BAP1 gene that were not discovered in the TCGA study.	('BAP1', 'Gene', (30, 34))	('BAP1', 'Gene', (257, 261))	('methylation', 'MPA', (189, 200))	('changes', 'Reg', (178, 185))	('mutations', 'Var', (35, 44))	('BAP1', 'Gene', '8314', (120, 124))	('methylation', 'biological_process', 'GO:0032259', ('189', '200'))	('BAP1', 'Gene', '8314', (30, 34))	('BAP1', 'Gene', '8314', (257, 261))	('BAP1', 'Gene', (120, 124))
132728	33092094	Differential methylation at a number of genes involved in cancer (KEGG pathways) and for tumor suppressors (Tables S1 and S2) may point to differential regulation of cell proliferation and tumor dissemination occurring through changes in methylation in UM in genes that are not mutated.	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('tumor', 'Disease', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('methylation', 'Var', (13, 24))	('methylation', 'biological_process', 'GO:0032259', ('238', '249'))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cell proliferation', 'CPA', (166, 184))	('methylation', 'MPA', (238, 249))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('regulation of cell proliferation', 'biological_process', 'GO:0042127', ('152', '184'))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('UM', 'Phenotype', 'HP:0007716', (253, 255))	('cancer', 'Disease', (58, 64))	('changes', 'Reg', (227, 234))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
132729	33092094	Our analysis revealed differential methylation in multiple signaling pathways that have specifically been involved in UM progression (Figure 5), including the PI3K-Akt signaling pathway (Figure 5A, KEGG pathways, Table S4), which has been implicated in UM.	('signaling pathway', 'biological_process', 'GO:0007165', ('168', '185'))	('UM progression', 'Disease', (118, 132))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('involved', 'Reg', (106, 114))	('Akt', 'Gene', '207', (164, 167))	('Akt signaling', 'biological_process', 'GO:0043491', ('164', '177'))	('UM', 'Phenotype', 'HP:0007716', (118, 120))	('signaling pathways', 'Pathway', (59, 77))	('methylation', 'Var', (35, 46))	('UM', 'Phenotype', 'HP:0007716', (253, 255))	('PI3K', 'molecular_function', 'GO:0016303', ('159', '163'))	('Akt', 'Gene', (164, 167))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))
132730	33092094	Particularly of interest was the hypermethylation of a number of genes involved in the negative regulation of ERK1/2 in the high-risk group (Figure 5), and the hypermethylation of 10 probes associated with the PTEN gene in the high-risk group (Table S7).	('PTEN', 'Gene', '5728', (210, 214))	('ERK1', 'molecular_function', 'GO:0004707', ('110', '114'))	('hypermethylation', 'MPA', (33, 49))	('ERK1/2', 'Gene', (110, 116))	('ERK1/2', 'Gene', '5595;5594', (110, 116))	('regulation', 'biological_process', 'GO:0065007', ('96', '106'))	('hypermethylation', 'Var', (160, 176))	('PTEN', 'Gene', (210, 214))
132734	33092094	In the same vein, the GNAQ/GNA11 mutations in UM lead to increased phosphorylation of ERK, driving growth in UM cells through the Ras/Raf/MEK/ERK pathway.	('mutations', 'Var', (33, 42))	('ERK', 'molecular_function', 'GO:0004707', ('142', '145'))	('GNAQ', 'Gene', '2776', (22, 26))	('GNA11', 'Gene', '2767', (27, 32))	('Raf', 'Gene', '673', (134, 137))	('GNAQ', 'Gene', (22, 26))	('phosphorylation', 'biological_process', 'GO:0016310', ('67', '82'))	('MEK', 'Gene', '5609', (138, 141))	('ERK', 'Gene', '5594', (86, 89))	('ERK', 'Gene', '5594', (142, 145))	('Raf', 'Gene', (134, 137))	('MEK', 'Gene', (138, 141))	('increased', 'PosReg', (57, 66))	('GNA11', 'Gene', (27, 32))	('phosphorylation', 'MPA', (67, 82))	('ERK', 'Gene', (86, 89))	('ERK', 'molecular_function', 'GO:0004707', ('86', '89'))	('ERK', 'Gene', (142, 145))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('UM', 'Phenotype', 'HP:0007716', (109, 111))
132735	33092094	The hypermethylation of multiple genes involved in the negative regulation of ERK1/2 signaling in the high-risk group implies the existence of alternative mechanisms that might also be working to increase ERK activation in UM.	('ERK', 'Gene', '5594', (205, 208))	('ERK1', 'molecular_function', 'GO:0004707', ('78', '82'))	('ERK1/2', 'Gene', '5595;5594', (78, 84))	('regulation', 'biological_process', 'GO:0065007', ('64', '74'))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('ERK', 'Gene', (205, 208))	('ERK', 'Gene', '5594', (78, 81))	('UM', 'Phenotype', 'HP:0007716', (223, 225))	('ERK', 'molecular_function', 'GO:0004707', ('205', '208'))	('ERK', 'Gene', (78, 81))	('activation', 'PosReg', (209, 219))	('ERK1/2', 'Gene', (78, 84))	('increase', 'PosReg', (196, 204))	('hypermethylation', 'Var', (4, 20))
132736	33092094	Along with this, UM cells show upregulation of PI3K/Akt/mTOR pathway, and the methylation of genes involved in mTOR and PI3K signaling (Figure 5A, Tables S3 and S4) points to yet another example of a signaling pathway known to be altered in UM potentially being epigenetically regulated to some extent.	('UM', 'Phenotype', 'HP:0007716', (241, 243))	('mTOR', 'Gene', (56, 60))	('methylation', 'Var', (78, 89))	('Akt', 'Gene', (52, 55))	('mTOR', 'Gene', '2475', (111, 115))	('mTOR', 'Gene', '2475', (56, 60))	('mTOR', 'Gene', (111, 115))	('PI3K', 'molecular_function', 'GO:0016303', ('120', '124'))	('signaling pathway', 'biological_process', 'GO:0007165', ('200', '217'))	('PI3K signaling', 'biological_process', 'GO:0014065', ('120', '134'))	('methylation', 'biological_process', 'GO:0032259', ('78', '89'))	('Akt', 'Gene', '207', (52, 55))	('UM', 'Phenotype', 'HP:0007716', (17, 19))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))	('upregulation', 'PosReg', (31, 43))
132740	33092094	Additionally, IL12RB2 knockout mice have been shown to develop spontaneous tumors (B cell and lung epithelial), and restoring the IL12RB2 leads to reduction of these tumors (in terms of proliferation, size, and microvessel formation).	('formation', 'biological_process', 'GO:0009058', ('223', '232'))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('IL12RB2', 'Gene', (14, 21))	('develop', 'PosReg', (55, 62))	('reduction', 'NegReg', (147, 156))	('mice', 'Species', '10090', (31, 35))	('IL12', 'molecular_function', 'GO:0005143', ('14', '18'))	('restoring', 'Var', (116, 125))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Disease', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('microvessel formation', 'CPA', (211, 232))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumors', 'Disease', (75, 81))	('IL12', 'molecular_function', 'GO:0005143', ('130', '134'))	('IL12RB2', 'Gene', (130, 137))
132741	33092094	Endogenous IL-12 was shown to exert antitumor effects only in IL12RB2+ tumors, suggesting that changes in gene expression associated with DNA methylation may also have an impact on host antitumor response mechanisms.	('gene expression', 'biological_process', 'GO:0010467', ('106', '121'))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (71, 77))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('DNA methylation', 'biological_process', 'GO:0006306', ('138', '153'))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumor', 'Disease', (190, 195))	('IL12', 'molecular_function', 'GO:0005143', ('62', '66'))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('impact', 'Reg', (171, 177))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('IL12RB2+', 'Var', (62, 70))	('IL-12', 'molecular_function', 'GO:0005143', ('11', '16'))
132742	33092094	While large-scale epigenetic changes have been documented in UM tumors, and these changes have been significantly related to prognosis, there are currently no approved treatments using these agents in UM.	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Disease', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('UM', 'Phenotype', 'HP:0007716', (201, 203))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('epigenetic changes', 'Var', (18, 36))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('related', 'Reg', (114, 121))
132743	33092094	In vitro, treatment with epigenetic modifying drugs has been shown to reduce growth and invasiveness in UM cell lines, and decitabine (a DNMT inhibitor) in combination with MEK inhibition has been shown to suppress growth in UM cells.	('UM', 'Phenotype', 'HP:0007716', (104, 106))	('reduce growth', 'Phenotype', 'HP:0001510', (70, 83))	('DNMT', 'Gene', '1786', (137, 141))	('epigenetic modifying drugs', 'Var', (25, 51))	('UM', 'Phenotype', 'HP:0007716', (225, 227))	('reduce', 'NegReg', (70, 76))	('invasiveness', 'Disease', 'MESH:D009361', (88, 100))	('MEK', 'Gene', (173, 176))	('DNMT', 'Gene', (137, 141))	('MEK', 'Gene', '5609', (173, 176))	('suppress', 'NegReg', (206, 214))	('decitabine', 'Chemical', 'MESH:D000077209', (123, 133))	('invasiveness', 'Disease', (88, 100))	('growth in UM cells', 'CPA', (215, 233))
132746	33092094	In our study, the specific DMPs associated with NFIA, HDAC4, and IL12RB2 correlated with the level of gene expression of these genes as seen on RNA sequencing data (Figure 7), with hypermethylation at these probes being associated with lower expression of transcripts for these genes.	('lower', 'NegReg', (236, 241))	('NFIA', 'Gene', (48, 52))	('gene expression', 'biological_process', 'GO:0010467', ('102', '117'))	('NFIA', 'Gene', '4774', (48, 52))	('DMPs', 'Chemical', '-', (27, 31))	('HDAC4', 'Gene', '9759', (54, 59))	('IL12RB2', 'Gene', (65, 72))	('RNA', 'cellular_component', 'GO:0005562', ('144', '147'))	('HDAC4', 'Gene', (54, 59))	('DMPs', 'MPA', (27, 31))	('hypermethylation', 'Var', (181, 197))	('expression', 'MPA', (242, 252))	('IL12', 'molecular_function', 'GO:0005143', ('65', '69'))
132748	33092094	This is consistent with the findings of Field et al., showing that many specific genes and functional pathways are altered through methylation in certain UM cases, and that this information may help in the future to find potential therapeutic avenues for UM patients that have a high risk of developing metastases.	('UM', 'Phenotype', 'HP:0007716', (255, 257))	('functional pathways', 'Pathway', (91, 110))	('specific genes', 'Gene', (72, 86))	('metastases', 'Disease', (303, 313))	('metastases', 'Disease', 'MESH:D009362', (303, 313))	('methylation', 'biological_process', 'GO:0032259', ('131', '142'))	('altered', 'Reg', (115, 122))	('patients', 'Species', '9606', (258, 266))	('UM', 'Phenotype', 'HP:0007716', (154, 156))	('methylation', 'Var', (131, 142))
132749	33092094	As suggested, BAP1 mutations seem to be importantly associated with the altered methylation patterns, though the lack of BAP1 mutations in some patients in the high-risk group implies that there are also potentially other events that can lead to the same downstream effects on methylation patterns.	('BAP1', 'Gene', '8314', (14, 18))	('BAP1', 'Gene', '8314', (121, 125))	('methylation patterns', 'MPA', (80, 100))	('methylation', 'biological_process', 'GO:0032259', ('277', '288'))	('altered', 'Reg', (72, 79))	('associated', 'Reg', (52, 62))	('BAP1', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('BAP1', 'Gene', (121, 125))	('methylation patterns', 'MPA', (277, 297))	('patients', 'Species', '9606', (144, 152))	('mutations', 'Var', (126, 135))	('methylation', 'biological_process', 'GO:0032259', ('80', '91'))
132751	33092094	We identified hypermethylation at CpG shores and islands along with hypomethylation at CpG shelves in the high-risk cases, suggesting that methylation may be impacting gene expression of NFIA (Figure 7A,D).	('gene expression', 'biological_process', 'GO:0010467', ('168', '183'))	('NFIA', 'Gene', (187, 191))	('gene expression', 'MPA', (168, 183))	('NFIA', 'Gene', '4774', (187, 191))	('impacting', 'Reg', (158, 167))	('methylation', 'biological_process', 'GO:0032259', ('139', '150'))	('methylation', 'Var', (139, 150))
132755	33092094	The high degree of differential methylation of this gene in the high-risk group suggests methylation of the NFIA gene as both a potential biomarker and therapeutic target in UM.	('NFIA', 'Gene', '4774', (108, 112))	('methylation', 'biological_process', 'GO:0032259', ('89', '100'))	('NFIA', 'Gene', (108, 112))	('methylation', 'Var', (89, 100))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('UM', 'Phenotype', 'HP:0007716', (174, 176))
132756	33092094	In this cohort, the most highly differentially methylated NFIA probes were also fully segregated based on risk group, highlighting that methylation of this single gene may be able to classify patients into high and low-risk groups (Figure 6A).	('NFIA', 'Gene', '4774', (58, 62))	('methylation', 'Var', (136, 147))	('NFIA', 'Gene', (58, 62))	('patients', 'Species', '9606', (192, 200))	('methylation', 'biological_process', 'GO:0032259', ('136', '147'))
132760	33092094	Previously, 5-aza-2-deoxycytidine was shown to reverse RASSF1 methylation in a UM cell line, suggesting that the presence of hypermethylation in this region is a potentially reversible change that increases tumorigenicity in UM.	('RASSF1', 'Gene', (55, 61))	('methylation', 'biological_process', 'GO:0032259', ('62', '73'))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('hypermethylation', 'Var', (125, 141))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('5-aza-2-deoxycytidine', 'Chemical', 'MESH:D000077209', (12, 33))	('UM', 'Phenotype', 'HP:0007716', (225, 227))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('increases', 'PosReg', (197, 206))	('RASSF1', 'Gene', '11186', (55, 61))	('tumor', 'Disease', (207, 212))
132763	33092094	ZNFs can function as tumor suppressors, and are inactivated in some tumor types through promoter hypermethylation.	('tumor', 'Disease', (68, 73))	('ZNFs', 'Protein', (0, 4))	('tumor', 'Disease', (21, 26))	('promoter hypermethylation', 'Var', (88, 113))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
132766	33092094	HDAC inhibitors are currently of strong clinical interest in UM due to their potential to reverse the phenotypic effects of loss of BAP1 expression, specifically inducing growth arrest and differentiation in UM.	('HDAC', 'Gene', (0, 4))	('BAP1', 'Gene', '8314', (132, 136))	('HDAC', 'Gene', '9734', (0, 4))	('inducing', 'PosReg', (162, 170))	('loss', 'Var', (124, 128))	('differentiation', 'CPA', (189, 204))	('growth arrest', 'Disease', (171, 184))	('UM', 'Phenotype', 'HP:0007716', (208, 210))	('BAP1', 'Gene', (132, 136))	('growth arrest', 'Disease', 'MESH:D006323', (171, 184))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('growth arrest', 'Phenotype', 'HP:0001510', (171, 184))
132767	33092094	noted a relationship between BAP1 loss and HDAC4, where BAP1 mutant UM cells showed a change in HDAC4 expression pattern from cytoplasmic to nuclear.	('expression pattern', 'MPA', (102, 120))	('BAP1', 'Gene', '8314', (56, 60))	('change', 'Reg', (86, 92))	('HDAC4', 'Gene', '9759', (43, 48))	('BAP1', 'Gene', '8314', (29, 33))	('HDAC4', 'Gene', (43, 48))	('BAP1', 'Gene', (56, 60))	('UM', 'Phenotype', 'HP:0007716', (68, 70))	('mutant', 'Var', (61, 67))	('HDAC4', 'Gene', '9759', (96, 101))	('BAP1', 'Gene', (29, 33))	('HDAC4', 'Gene', (96, 101))
132771	33092094	Of note, hypomethylation of several sites associated with HDAC4 was also seen.	('hypomethylation', 'Var', (9, 24))	('HDAC4', 'Gene', (58, 63))	('HDAC4', 'Gene', '9759', (58, 63))
132856	31635036	Potential intraoperative complications are the damage of the lens and the laceration of iris blood vessels and the ciliary body causing hyphema.	('hyphema', 'Phenotype', 'HP:0011886', (136, 143))	('laceration', 'Var', (74, 84))	('hyphema', 'Disease', (136, 143))	('hyphema', 'Disease', 'MESH:D006988', (136, 143))
132872	31635036	PCR and microdissection have also been used for the detection of the t(14:18) translocation (i.e., translocation between the genes for BCL-2 and IgH).	('translocation', 'Var', (99, 112))	('CR', 'Disease', 'MESH:D002825', (1, 3))	('BCL-2', 'Gene', '596', (135, 140))	('IgH', 'Gene', '3492', (145, 148))	('IgH', 'Gene', (145, 148))	('BCL-2', 'molecular_function', 'GO:0015283', ('135', '140'))	('BCL-2', 'Gene', (135, 140))
132881	31635036	In terms of a demonstration of the combination therapeutic and diagnostic effect of vitrectomy, the randomized multicenter clinical trial known as "The Endophthalmitis Vitrectomy Study (EVS)", has demonstrated that immediate PPV is of substantial benefit for the treatment of postoperative bacterial endophthalmitis in patients with visual acuity of light perception (LP).	('bacterial endophthalmitis', 'Disease', 'MESH:D009877', (290, 315))	('bacterial endophthalmitis', 'Disease', (290, 315))	('Endophthalmitis', 'Disease', 'MESH:D009877', (152, 167))	('patients', 'Species', '9606', (319, 327))	('Endophthalmitis', 'Disease', (152, 167))	('PPV', 'Var', (225, 228))
132940	31137687	However, when controlling for intra-ocular location and its relation to UV exposure, UV signature genetic changes have been found in posterior uveal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanomas', 'Phenotype', 'HP:0002861', (149, 158))	('uveal melanomas', 'Disease', (143, 158))	('uveal melanomas', 'Phenotype', 'HP:0007716', (143, 158))	('uveal melanomas', 'Disease', 'MESH:C536494', (143, 158))	('genetic changes', 'Var', (98, 113))	('uveal melanoma', 'Phenotype', 'HP:0007716', (143, 157))
133034	29844317	On the contrary, CD4+ T cells can also have protumoral effects through the immumodulatory capacity of Treg cells (Tregs).	('Treg', 'Chemical', '-', (114, 118))	('immumodulatory capacity', 'CPA', (75, 98))	('Treg', 'Chemical', '-', (102, 106))	('CD4+ T', 'Var', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
133036	29844317	In addition, systemic or local depletion of Tregs can enhance antitumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Tregs', 'Protein', (44, 49))	('Treg', 'Chemical', '-', (44, 48))	('tumor', 'Disease', (66, 71))	('enhance', 'PosReg', (54, 61))	('depletion', 'Var', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
133043	29844317	The expression of high level of FR4 and CD73 on FOXP3-CD44hi CD4+ T cell represents a positive definition of anergic T cells.	('CD73', 'Gene', '4907', (40, 44))	('FR4', 'Gene', (32, 35))	('FOXP3-CD44hi', 'Var', (48, 60))	('CD73', 'Gene', (40, 44))
133060	29844317	To reduce expression of DBY by APCs after virus inoculation, we inserted four tandem target sequences of the hematopoietic-specific mir142-3p after the Luciferase-DBY cassette to induce its degradation specifically in hematopoietic cells (Supplementary Fig.	('DBY', 'Gene', '26900', (163, 166))	('DBY', 'Gene', (24, 27))	('degradation', 'biological_process', 'GO:0009056', ('190', '201'))	('DBY', 'Gene', (163, 166))	('induce', 'PosReg', (179, 185))	('degradation', 'MPA', (190, 201))	('mir142-3p', 'Var', (132, 141))	('DBY', 'Gene', '26900', (24, 27))
133066	29844317	Thus, APCs having captured DBY Ag from transduced cells or expressing residual Ag in the absence of complete silencing by the mir142-3p generate inefficient priming that rapidly vanishes without giving rise to Treg or memory cells.	('memory', 'biological_process', 'GO:0007613', ('218', '224'))	('priming', 'MPA', (157, 164))	('Treg', 'Chemical', '-', (210, 214))	('mir142-3p', 'Var', (126, 135))	('DBY', 'Gene', '26900', (27, 30))	('rat', 'Species', '10116', (140, 143))	('vanishes', 'NegReg', (178, 186))	('DBY', 'Gene', (27, 30))
133122	29844317	Conversely, the expression of a high number of genes was increased in pTregs (515 and 440 for early and advanced stage, respectively) when compared to the anergic cells (Supplementary Fig.	('pTregs', 'Var', (70, 76))	('expression', 'MPA', (16, 26))	('increased', 'PosReg', (57, 66))	('pTregs', 'Chemical', '-', (70, 76))
133152	29844317	Tumor-bearing mice received DBY and CpG i.t., twice 5 days apart, before Marilyn transfer (Fig.	('DBY', 'Gene', '26900', (28, 31))	('CpG', 'Var', (36, 39))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('DBY', 'Gene', (28, 31))	('mice', 'Species', '10090', (14, 18))
133170	29844317	Host Treg depletion also significantly reduced the frequency and number of Marilyn pTregs in the TdLN (Fig.	('pTregs', 'Chemical', '-', (83, 89))	('Treg', 'Chemical', '-', (5, 9))	('Treg', 'Chemical', '-', (84, 88))	('depletion', 'Var', (10, 19))	('reduced', 'NegReg', (39, 46))
133199	29844317	Thus, in cancer, therapeutic manipulations targeting Tregs would not only release the brake from effector immune response but also impair generation of anergic T cells, further enhancing antitumor immune responses.	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('manipulations', 'Var', (29, 42))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('Treg', 'Chemical', '-', (53, 57))	('rat', 'Species', '10116', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('impair', 'NegReg', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('enhancing', 'PosReg', (177, 186))	('immune response', 'biological_process', 'GO:0006955', ('106', '121'))	('brake', 'MPA', (86, 91))	('release', 'PosReg', (74, 81))	('generation of anergic T cells', 'MPA', (138, 167))
133202	29844317	Induction of FOXP3 in Marilyn cells was only observed in CD44hi T cells, indicating that activation is a prerequisite for Treg conversion.	('FOXP3', 'Gene', (13, 18))	('Treg', 'Chemical', '-', (122, 126))	('CD44hi', 'Var', (57, 63))
133215	29844317	11d), suggesting that CD4+ T cells may also become anergic in tumor bearing patients including NSLC patients (Supplementary Fig.	('patients', 'Species', '9606', (76, 84))	('NSLC', 'Disease', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('NSLC', 'Disease', 'None', (95, 99))	('tumor', 'Disease', (62, 67))	('patients', 'Species', '9606', (100, 108))	('CD4+', 'Var', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('anergic', 'MPA', (51, 58))
133217	29844317	With regard to the mechanisms of anergy and pTreg induction, depletion of host Tregs inhibited conversion of naive tumor Ag-specific CD4+ T cells into pTregs and restored a typical effector phenotype, ultimately promoting their accumulation in the tumor bed.	('depletion', 'Var', (61, 70))	('tumor', 'Disease', (248, 253))	('Treg', 'Chemical', '-', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('inhibited', 'NegReg', (85, 94))	('effector phenotype', 'MPA', (181, 199))	('tumor', 'Disease', (115, 120))	('restored', 'PosReg', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('Treg', 'Chemical', '-', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('Treg', 'Chemical', '-', (79, 83))	('promoting', 'PosReg', (212, 221))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('pTregs', 'Chemical', '-', (151, 157))	('accumulation', 'PosReg', (228, 240))
133249	29844317	A second-generation LV was produced by transfection of HEK-293LTV cell line (Cell Biolabs, Inc) with psPAX2 (packaging plasmid, Addgene), pCMV-VSV-G (envelope plasmid, Addgene) and Luciferase and recombinase Cre-expressing plasmid.	('envelope', 'cellular_component', 'GO:0009274', ('150', '158'))	('HEK-293LTV', 'CellLine', 'CVCL:0045', (55, 65))	('psPAX2', 'Gene', (101, 107))	('envelope', 'cellular_component', 'GO:0031975', ('150', '158'))	('rat', 'Species', '10116', (13, 16))	('pCMV-VSV-G', 'Var', (138, 148))
133258	29844317	Early and advanced tumor stages corresponding to 10-12 weeks and 20-24 weeks after lentiviral infection, respectively were validated by IHC analysis.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('lentiviral', 'Var', (83, 93))	('tumor', 'Disease', (19, 24))
133276	29844317	To neutralize TGF-beta in vivo, tumor-bearing mice received 4 i.p.	('TGF-beta', 'Gene', '21803', (14, 22))	('TGF-beta', 'Gene', (14, 22))	('neutralize', 'Var', (3, 13))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mice', 'Species', '10090', (46, 50))	('tumor', 'Disease', (32, 37))
133307	29844317	A second data set (3 pools of 5 mice per condition) was generated with 3000 CD4+CD25hi host Tregs and FOXP3-GFPPos Marilyn pTregs or FOXP3-GFPNeg Marilyn anergic cells purified from TdLN of mice bearing early or advanced tumors.	('CD4+CD25hi', 'Var', (76, 86))	('Treg', 'Chemical', '-', (92, 96))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('rat', 'Species', '10116', (60, 63))	('FOXP3-GFPPos', 'Var', (102, 114))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('mice', 'Species', '10090', (32, 36))	('pTregs', 'Chemical', '-', (123, 129))	('tumors', 'Disease', (221, 227))	('mice', 'Species', '10090', (190, 194))	('FOXP3-GFPNeg', 'Var', (133, 145))	('Treg', 'Chemical', '-', (124, 128))
133316	29769598	Germline mutation in the TP53 gene in uveal melanoma We performed comprehensive molecular analysis of five cases of metastasizing uveal malignant melanoma (UM) (fresh-frozen samples) with an NGS panel of 73 genes.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('uveal melanoma', 'Disease', (38, 52))	('uveal malignant melanoma', 'Disease', (130, 154))	('TP53', 'Gene', (25, 29))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('TP53', 'Gene', '7157', (25, 29))	('malignant melanoma', 'Phenotype', 'HP:0002861', (136, 154))	('uveal melanoma', 'Disease', 'MESH:C536494', (38, 52))	('Germline mutation', 'Var', (0, 17))	('metastasizing', 'Disease', (116, 129))	('uveal malignant melanoma', 'Phenotype', 'HP:0007716', (130, 154))	('uveal malignant melanoma', 'Disease', 'MESH:C536494', (130, 154))
133317	29769598	A likely pathogenic germline TP53 mutation c.760A > G (p.I254V) was found in two tumor samples and matched nontumor tissue.	('pathogenic', 'Reg', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('c.760A > G', 'Mutation', 'rs746601313', (43, 53))	('TP53', 'Gene', '7157', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('TP53', 'Gene', (29, 33))	('c.760A > G', 'Var', (43, 53))	('p.I254V', 'Mutation', 'rs746601313', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
133318	29769598	In three cases, pathogenic BAP1 mutation was detected together with germline missense variants of uncertain significance in ATM.	('ATM', 'Gene', (124, 127))	('ATM', 'Gene', '472', (124, 127))	('BAP1', 'Gene', (27, 31))	('pathogenic', 'Reg', (16, 26))	('mutation', 'Var', (32, 40))	('BAP1', 'Gene', '8314', (27, 31))
133319	29769598	All cases carried recurrent activating GNAQ or GNA11 mutation.	('mutation', 'Var', (53, 61))	('GNAQ', 'Gene', (39, 43))	('GNA11', 'Gene', '2767', (47, 52))	('GNA11', 'Gene', (47, 52))	('activating', 'PosReg', (28, 38))	('GNAQ', 'Gene', '2776', (39, 43))
133322	29769598	Germline TP53 mutation, usually associated with Li-Fraumeni syndrome, is a rare event in UM.	('Li-Fraumeni syndrome', 'Disease', (48, 68))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('mutation', 'Var', (14, 22))	('associated', 'Reg', (32, 42))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (48, 68))
133324	29769598	In our study, we detected TP53 mutation in two patients without known family relationship.	('TP53', 'Gene', (26, 30))	('mutation', 'Var', (31, 39))	('patients', 'Species', '9606', (47, 55))	('TP53', 'Gene', '7157', (26, 30))	('detected', 'Reg', (17, 25))
133325	29769598	The identification of germline aberrations in TP53 or BAP1 is important to identify patients with Li-Fraumeni syndrome or BAP1 cancer syndrome, which is also crucial for proper genetic counseling.	('BAP1 cancer syndrome', 'Disease', 'MESH:D009369', (122, 142))	('BAP1', 'Gene', (122, 126))	('germline', 'Var', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('patients', 'Species', '9606', (84, 92))	('BAP1 cancer syndrome', 'Disease', (122, 142))	('TP53', 'Gene', '7157', (46, 50))	('BAP1', 'Gene', '8314', (54, 58))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (98, 118))	('TP53', 'Gene', (46, 50))	('BAP1', 'Gene', '8314', (122, 126))	('BAP1', 'Gene', (54, 58))	('Li-Fraumeni syndrome', 'Disease', (98, 118))
133334	29769598	Recurrent activating somatic mutation in GNA11 or GNAQ (NM_002067.2: c.626A > T, p.Q209L or NM_002072.3: c.626A > C, p.Q209P, respectively), a typical molecular sign of uveal melanoma, have been detected in all five cases.	('p.Q209P', 'Mutation', 'rs1057519742', (117, 124))	('uveal melanoma', 'Phenotype', 'HP:0007716', (169, 183))	('uveal melanoma', 'Disease', 'MESH:C536494', (169, 183))	('NM_002067.2: c.626A > T', 'Mutation', 'rs121913492', (56, 79))	('p.Q209L', 'Var', (81, 88))	('uveal melanoma', 'Disease', (169, 183))	('activating', 'PosReg', (10, 20))	('GNAQ', 'Gene', '2776', (50, 54))	('NM_002072.3: c.626A > C', 'Mutation', 'rs121913492', (92, 115))	('GNA11', 'Gene', (41, 46))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('p.Q209L', 'Mutation', 'rs1057519742', (81, 88))	('GNA11', 'Gene', '2767', (41, 46))	('NM_002072.3: c.626A > C', 'Var', (92, 115))	('GNAQ', 'Gene', (50, 54))
133335	29769598	In two of five patients with mUMs, identical germline TP53 mutation NM_001126112.2: c.760A > G, p.I254V was detected (representative visualization in IGV and confirmation by Sanger sequencing is in Supplementary Fig.	('mUMs', 'Species', '41568', (29, 33))	('patients', 'Species', '9606', (15, 23))	('p.I254V', 'Mutation', 'rs746601313', (96, 103))	('NM_001126112.2: c.760A > G', 'Mutation', 'rs746601313', (68, 94))	('TP53', 'Gene', '7157', (54, 58))	('p.I254V', 'Var', (96, 103))	('TP53', 'Gene', (54, 58))
133343	29769598	Both mUM samples with germline TP53 mutation did not have a deletion of chromosome 3 and carried a duplication of 8q (Supplementary Fig.	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('mutation', 'Var', (36, 44))
133344	29769598	One of them also carried a somatic mutation in SF3B1 (NM_012433.2: c.1874G > T, p.R625L).	('p.R625L', 'Var', (80, 87))	('SF3B1', 'Gene', (47, 52))	('SF3B1', 'Gene', '23451', (47, 52))	('p.R625L', 'Mutation', 'p.R625L', (80, 87))	('NM_012433.2: c.1874G > T', 'Mutation', 'c.1874G>T', (54, 78))
133347	29769598	A germline mutation of ATM and a somatic mutation in BAP1 were found in three patients.	('ATM', 'Gene', (23, 26))	('germline mutation', 'Var', (2, 19))	('patients', 'Species', '9606', (78, 86))	('ATM', 'Gene', '472', (23, 26))	('BAP1', 'Gene', '8314', (53, 57))	('found', 'Reg', (63, 68))	('BAP1', 'Gene', (53, 57))
133348	29769598	None of these patients have a mutation of TP53.	('TP53', 'Gene', '7157', (42, 46))	('mutation', 'Var', (30, 38))	('TP53', 'Gene', (42, 46))	('patients', 'Species', '9606', (14, 22))
133349	29769598	One patient carried a mutation in ATM (NM_000051.3:c.5975A > C, p.K1992T) and had a somatic frameshift mutation in BAP1 (NM_004656.2:c.79delG, p.V27Cfs*45, VAF 29.21%).	('NM_004656.2:c.79delG', 'Mutation', 'c.79delG', (121, 141))	('p.K1992T', 'Var', (64, 72))	('NM_004656.2', 'Var', (121, 132))	('NM_000051.3', 'Var', (39, 50))	('p.V27Cfs*45', 'Var', (143, 154))	('p.K1992T', 'Mutation', 'rs150757822', (64, 72))	('BAP1', 'Gene', '8314', (115, 119))	('patient', 'Species', '9606', (4, 11))	('NM_000051.3:c.5975A > C', 'Mutation', 'rs150757822', (39, 62))	('p.V27Cfs*45', 'Mutation', 'p.V27CfsX45', (143, 154))	('ATM', 'Gene', (34, 37))	('BAP1', 'Gene', (115, 119))	('ATM', 'Gene', '472', (34, 37))
133350	29769598	Other patient had a somatic mutation in the BAP1 first coding amino acid that leads to the change of methionine to lysine (c.2T > A, p.?, VAF 60.78%).	('methionine', 'Chemical', 'MESH:D008715', (101, 111))	('change', 'MPA', (91, 97))	('lysine', 'Chemical', 'MESH:D008239', (115, 121))	('patient', 'Species', '9606', (6, 13))	('c.2T > A', 'Var', (123, 131))	('methionine to lysine', 'MPA', (101, 121))	('c.2T > A', 'Mutation', 'c.2T>A', (123, 131))	('BAP1', 'Gene', '8314', (44, 48))	('BAP1', 'Gene', (44, 48))
133351	29769598	CNV analyses suggested a partial deletion of chromosome 3, and the patient carried a germline missense mutation in ATM (c.5558A > T, p.D1853V) and a germline tandem duplication of 56 bp in exon 48 of the ATM gene (c.7010_7065dup56, p.?)	('ATM', 'Gene', (115, 118))	('ATM', 'Gene', (204, 207))	('p.D1853V', 'Var', (133, 141))	('c.7010_7065dup56', 'Var', (214, 230))	('c.5558A > T', 'Var', (120, 131))	('c.5558A > T', 'Mutation', 'rs1801673', (120, 131))	('ATM', 'Gene', '472', (115, 118))	('p.D1853V', 'Mutation', 'rs1801673', (133, 141))	('ATM', 'Gene', '472', (204, 207))	('chromosome', 'cellular_component', 'GO:0005694', ('45', '55'))	('patient', 'Species', '9606', (67, 74))	('c.7010_7065dup56', 'Mutation', 'c.7010_7065dup56', (214, 230))
133354	29769598	The third patient without TP53 mutation carried germline mutation in the ATM gene (c.1522C > T, p.L508F), and somatic mutation in BAP1 (c.505_506insC, p.H169Pfs*13, VAF 77.59%) and CNV analyses suggested a partial deletion of chromosome 3.	('TP53', 'Gene', (26, 30))	('ATM', 'Gene', (73, 76))	('BAP1', 'Gene', (130, 134))	('chromosome', 'cellular_component', 'GO:0005694', ('226', '236'))	('ATM', 'Gene', '472', (73, 76))	('partial deletion', 'Var', (206, 222))	('p.L508F', 'Var', (96, 103))	('p.L508F', 'Mutation', 'rs1011518082', (96, 103))	('patient', 'Species', '9606', (10, 17))	('c.505_506insC', 'Mutation', 'c.505_506insC', (136, 149))	('c.505_506insC', 'Var', (136, 149))	('TP53', 'Gene', '7157', (26, 30))	('BAP1', 'Gene', '8314', (130, 134))	('c.1522C > T', 'Var', (83, 94))	('c.1522C > T', 'Mutation', 'rs1011518082', (83, 94))	('p.H169Pfs*13', 'Mutation', 'p.H169PfsX13', (151, 163))
133356	29769598	The most prevalent somatic mutations were GNAQ (guanine nucleotide-binding protein G(q) subunit alpha) (50%), GNA11 (guanine nucleotide-binding protein subunit alpha-11) (45%), BAP1 (BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase) (32.5%), SF3B1 (splicing factor 3b, subunit 1) (22.5%), and EIF1AX (Eukaryotic Translation Initiation Factor 1 A, X-Linked) (12.5%).	('mutations', 'Var', (27, 36))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('Eukaryotic Translation Initiation Factor 1 A, X-Linked', 'Gene', (317, 371))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('SF3B1', 'Gene', '23451', (258, 263))	('GNA11', 'Gene', (110, 115))	('BAP1', 'Gene', (177, 181))	('EIF1AX', 'Gene', (309, 315))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('125', '143'))	('BRCA1 associated protein-1', 'Gene', (183, 209))	('EIF1AX', 'Gene', '1964', (309, 315))	('Translation Initiation', 'biological_process', 'GO:0006413', ('328', '350'))	('guanine nucleotide-binding protein G(q) subunit alpha', 'Gene', '2776', (48, 101))	('GNAQ', 'Gene', '2776', (42, 46))	('ubiquitin', 'molecular_function', 'GO:0031386', ('211', '220'))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('56', '74'))	('GNAQ', 'Gene', (42, 46))	('protein', 'cellular_component', 'GO:0003675', ('200', '207'))	('GNA11', 'Gene', '2767', (110, 115))	('Eukaryotic Translation Initiation Factor 1 A, X-Linked)', 'Gene', '1964', (317, 372))	('BRCA1 associated protein-1', 'Gene', '8314', (183, 209))	('SF3B1', 'Gene', (258, 263))	('BAP1', 'Gene', '8314', (177, 181))	('splicing', 'biological_process', 'GO:0045292', ('265', '273'))	('guanine nucleotide-binding protein subunit alpha-11', 'Gene', '2767', (117, 168))
133357	29769598	Mutant GNAQ was shown to activate the MAPK pathway and it may also have important effects on other pathways such as the phosphatidylinositol-calcium second messenger system.	('activate', 'PosReg', (25, 33))	('phosphatidylinositol-calcium', 'Chemical', '-', (120, 148))	('GNAQ', 'Gene', '2776', (7, 11))	('GNAQ', 'Gene', (7, 11))	('effects', 'Reg', (82, 89))	('Mutant', 'Var', (0, 6))	('MAPK pathway', 'Pathway', (38, 50))	('MAPK', 'molecular_function', 'GO:0004707', ('38', '42'))
133358	29769598	Hot-spot mutations affecting amino acid Glutamine at codon 209 in GNAQ or its paralog GNA11 are mutually exclusive, they have also been detected in benign uveal nevi and are not sufficient for full malignant transformation to melanoma.	('melanoma', 'Disease', (226, 234))	('GNAQ', 'Gene', '2776', (66, 70))	('amino acid Glutamine at codon 209', 'Var', (29, 62))	('mutations', 'Var', (9, 18))	('Glutamine', 'Chemical', 'MESH:D005973', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('GNA11', 'Gene', (86, 91))	('benign uveal nevi', 'Disease', (148, 165))	('GNAQ', 'Gene', (66, 70))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('GNA11', 'Gene', '2767', (86, 91))	('detected', 'Reg', (136, 144))	('nevi', 'Phenotype', 'HP:0003764', (161, 165))
133360	29769598	Partial or complete monosomy of chromosome 3, where BAP1 (3p21.31-p21.2) is located, is a relatively common event in metastasizing uveal melanoma.	('p21', 'Gene', (66, 69))	('uveal melanoma', 'Disease', 'MESH:C536494', (131, 145))	('uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))	('p21', 'Gene', (59, 62))	('BAP1', 'Gene', '8314', (52, 56))	('p21', 'Gene', '644914', (59, 62))	('uveal melanoma', 'Disease', (131, 145))	('p21', 'Gene', '644914', (66, 69))	('Partial or complete monosomy', 'Var', (0, 28))	('common', 'Reg', (101, 107))	('BAP1', 'Gene', (52, 56))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('chromosome', 'cellular_component', 'GO:0005694', ('32', '42'))
133361	29769598	Monosomy of chromosome 3, gain of 8q, epithelioid-mixed cell type and/or larger tumor diameter were strongly associated with a poor prognosis and potential to metastasize.	('Monosomy', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('epithelioid-mixed cell type', 'CPA', (38, 65))	('tumor', 'Disease', (80, 85))	('gain', 'PosReg', (26, 30))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))
133363	29769598	We detected germline TP53 mutation in 2/5 patients and germline ATM mutation together with somatic BAP1 alteration in another 3/5 patients.	('TP53', 'Gene', (21, 25))	('BAP1', 'Gene', (99, 103))	('mutation', 'Var', (26, 34))	('ATM', 'Gene', (64, 67))	('patients', 'Species', '9606', (130, 138))	('BAP1', 'Gene', '8314', (99, 103))	('ATM', 'Gene', '472', (64, 67))	('TP53', 'Gene', '7157', (21, 25))	('patients', 'Species', '9606', (42, 50))	('detected', 'Reg', (3, 11))
133365	29769598	Further, somatic or germline variants were detected in BARD1, CDH1, MET, MMR genes, PARD3, SF3B1, SNAI3 (Table 1).	('SNAI3', 'Gene', (98, 103))	('BARD1', 'Gene', (55, 60))	('MET', 'Gene', (68, 71))	('SF3B1', 'Gene', (91, 96))	('CDH1', 'Gene', (62, 66))	('SNAI3', 'Gene', '333929', (98, 103))	('CDH1', 'Gene', '999', (62, 66))	('MMR', 'biological_process', 'GO:0006298', ('73', '76'))	('SF3B1', 'Gene', '23451', (91, 96))	('PARD3', 'Gene', '56288', (84, 89))	('variants', 'Var', (29, 37))	('PARD3', 'Gene', (84, 89))	('MMR genes', 'Gene', (73, 82))	('BARD1', 'Gene', '580', (55, 60))
133366	29769598	Based on the unexpected finding of germline TP53 mutation, we analyzed another 16 patients with UM focusing only on germline TP53 mutations.	('TP53', 'Gene', '7157', (125, 129))	('patients', 'Species', '9606', (82, 90))	('mutation', 'Var', (49, 57))	('TP53', 'Gene', (125, 129))	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))
133368	29769598	The TP53 gene is highly polymorphic in coding and noncoding regions and some of these polymorphisms have been shown to increase cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('TP53', 'Gene', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('increase', 'PosReg', (119, 127))	('polymorphisms', 'Var', (86, 99))	('TP53', 'Gene', '7157', (4, 8))	('cancer', 'Disease', (128, 134))
133369	29769598	The frequency of de novo TP53 germline mutation has been estimated up to 30%, which is very high compared with the frequency of mutations in other tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('TP53', 'Gene', (25, 29))	('tumor suppressor', 'biological_process', 'GO:0051726', ('147', '163'))	('germline mutation', 'Var', (30, 47))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('147', '163'))	('TP53', 'Gene', '7157', (25, 29))
133370	29769598	Germline mutations in TP53 are linked to Li-Fraumeni syndrome (LFS).	('Germline mutations', 'Var', (0, 18))	('Li-Fraumeni syndrome', 'Disease', (41, 61))	('linked', 'Reg', (31, 37))	('TP53', 'Gene', '7157', (22, 26))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (41, 61))	('TP53', 'Gene', (22, 26))
133371	29769598	Germline missense mutations are the most common TP53 variants, occurring in approximately 70% of cases and mainly altering residues within the DNA-binding domain.	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (48, 52))	('DNA-binding', 'molecular_function', 'GO:0003677', ('143', '154'))	('Germline missense mutations', 'Var', (0, 27))	('altering', 'Reg', (114, 122))	('residues', 'MPA', (123, 131))
133376	29769598	Somatic TP53 mutations were detected in 12-19% cases of cutaneous malignant melanoma and also described in melanocytic tumor originating in the central nervous system.	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (56, 84))	('cutaneous malignant melanoma', 'Disease', (56, 84))	('detected', 'Reg', (28, 36))	('malignant melanoma', 'Phenotype', 'HP:0002861', (66, 84))	('melanocytic tumor', 'Disease', (107, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (56, 84))	('mutations', 'Var', (13, 22))	('melanocytic tumor', 'Disease', 'MESH:D009508', (107, 124))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
133379	29769598	According to the dataset from IARC TP53 database, detected missense mutation show positive IHC results in 88% of cases.	('missense mutation', 'Var', (59, 76))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))
133380	29769598	Not only TP53 mutations but also a disturbed p53 pathway can result in abnormal p53 expression.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('p53', 'Gene', (80, 83))	('result in', 'Reg', (61, 70))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('p53', 'Gene', '7157', (80, 83))	('mutations', 'Var', (14, 23))
133381	29769598	On the contrary, germline TP53 mutations in UM is, according to the literature, exceedingly rare and has been described only once in a British family with four generations burdened with uveal melanoma.	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('uveal melanoma', 'Phenotype', 'HP:0007716', (186, 200))	('uveal melanoma', 'Disease', (186, 200))	('uveal melanoma', 'Disease', 'MESH:C536494', (186, 200))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('TP53', 'Gene', '7157', (26, 30))
133382	29769598	Here, we describe two other unrelated Czech patients with uveal melanoma that are carriers of germline TP53 p.I254V mutation.	('TP53', 'Gene', '7157', (103, 107))	('p.I254V', 'Var', (108, 115))	('patients', 'Species', '9606', (44, 52))	('TP53', 'Gene', (103, 107))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('uveal melanoma', 'Disease', 'MESH:C536494', (58, 72))	('p.I254V', 'Mutation', 'rs746601313', (108, 115))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('uveal melanoma', 'Disease', (58, 72))
133383	29769598	However, pathogenicity of the TP53 variant p.I254V is not fully elucidated.	('TP53', 'Gene', '7157', (30, 34))	('TP53', 'Gene', (30, 34))	('p.I254V', 'Var', (43, 50))	('p.I254V', 'Mutation', 'rs746601313', (43, 50))
133385	29769598	The result of functional analysis of p53 transactivation ability in yeast (FASAY) has confirmed that p.I254V is a fully inactivating mutation.	('transactivation', 'biological_process', 'GO:2000144', ('41', '56'))	('p.I254V', 'Var', (101, 108))	('yeast', 'Species', '4932', (68, 73))	('p53', 'Gene', '7157', (37, 40))	('p53', 'Gene', (37, 40))	('p.I254V', 'Mutation', 'rs746601313', (101, 108))	('transactivation', 'MPA', (41, 56))
133388	29769598	The ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/, accessed November 2017) contains data from two submitters and indicates uncertain significance of this germline TP53 variant.	('TP53', 'Gene', (173, 177))	('TP53', 'Gene', '7157', (173, 177))	('variant', 'Var', (178, 185))
133389	29769598	detected germline variant p.I254V in TP53 in 3 out of 394 patients with lung cancer and designated this variant as polymorphism.	('p.I254V', 'Mutation', 'rs746601313', (26, 33))	('p.I254V', 'Var', (26, 33))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('TP53', 'Gene', '7157', (37, 41))	('patients', 'Species', '9606', (58, 66))	('TP53', 'Gene', (37, 41))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
133390	29769598	On the other hand, in the same codon 254 another two missense variants p.I254T and p.I254L were described, either somatic or germline in LFS family, that were considered pathogenic throughout the databases and the literature.	('p.I254L', 'Mutation', 'rs879253984', (83, 90))	('p.I254T', 'Mutation', 'p.I254T', (71, 78))	('p.I254L', 'Var', (83, 90))	('p.I254T', 'Var', (71, 78))
133391	29769598	Somatic mutation p.I254V has been described according to the IARC TP53 database (http://p53.iarc.fr; assessed December 2017) in seven different tumors so far (Table 2).	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('TP53', 'Gene', '7157', (66, 70))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('TP53', 'Gene', (66, 70))	('p.I254V', 'Mutation', 'rs746601313', (17, 24))	('p53', 'Gene', (88, 91))	('p53', 'Gene', '7157', (88, 91))	('p.I254V', 'Var', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
133392	29769598	Inherited pathogenic ATM mutation is the cause of autosomal recessive disease ataxia-telangiectasia which predisposes the individuals for increased cancer risk.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('ataxia-telangiectasia', 'Disease', 'MESH:D001260', (78, 99))	('ataxia', 'Phenotype', 'HP:0001251', (78, 84))	('mutation', 'Var', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('telangiectasia', 'Phenotype', 'HP:0001009', (85, 99))	('cause', 'Reg', (41, 46))	('ATM', 'Gene', (21, 24))	('autosomal recessive disease', 'Disease', 'MESH:D030342', (50, 77))	('ataxia-telangiectasia', 'Disease', (78, 99))	('ATM', 'Gene', '472', (21, 24))	('autosomal recessive disease', 'Disease', (50, 77))
133394	29769598	In our study, we detected germline ATM variants in three patients with metastatic uveal melanoma.	('ATM', 'Gene', '472', (35, 38))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('patients', 'Species', '9606', (57, 65))	('uveal melanoma', 'Disease', 'MESH:C536494', (82, 96))	('ATM', 'Gene', (35, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('uveal melanoma', 'Disease', (82, 96))	('variants', 'Var', (39, 47))
133395	29769598	Three of them have been described previously and their population mutant allele frequency (MAF) is low: p.K1992T, MAF(gnomAD) = 0.0003; p.D1853V, MAF(gnomAD) = 0.004915, and p.L508F, which is only described in database FLOSSIES MAF = 0.0001.	('p.L508F', 'Var', (174, 181))	('p.L508F', 'Mutation', 'rs1011518082', (174, 181))	('p.D1853V', 'Var', (136, 144))	('p.K1992T', 'Var', (104, 112))	('p.D1853V', 'Mutation', 'rs1801673', (136, 144))	('p.K1992T', 'Mutation', 'rs150757822', (104, 112))
133396	29769598	In all three of our cases, ATM mutations cooccurred with pathogenic somatic variants in the BAP1 gene and two tumors have partial loss of chromosome 3, which are also relatively common event in metastasizing uveal melanoma, both associated with worse prognosis.	('mutations', 'Var', (31, 40))	('uveal melanoma', 'Disease', 'MESH:C536494', (208, 222))	('chromosome', 'cellular_component', 'GO:0005694', ('138', '148'))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('uveal melanoma', 'Phenotype', 'HP:0007716', (208, 222))	('uveal melanoma', 'Disease', (208, 222))	('tumors', 'Disease', (110, 116))	('variants', 'Var', (76, 84))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('BAP1', 'Gene', '8314', (92, 96))	('loss', 'NegReg', (130, 134))	('ATM', 'Gene', (27, 30))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('ATM', 'Gene', '472', (27, 30))	('BAP1', 'Gene', (92, 96))
133397	29769598	Not only somatic but also germline mutation of BAP1 gene may occur in UM and the majority of familial UM with germline BAP1 mutation is associated with BAP1-tumor predisposition syndrome, which also increases the risk of the atypical Spitz tumors, malignant mesothelioma, and cutaneous melanoma.	('associated', 'Reg', (136, 146))	('familial', 'Disease', (93, 101))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (248, 270))	('tumors', 'Disease', (240, 246))	('BAP1', 'Gene', '8314', (47, 51))	('BAP1', 'Gene', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('BAP1', 'Gene', (119, 123))	('melanoma', 'Phenotype', 'HP:0002861', (286, 294))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('cutaneous melanoma', 'Disease', (276, 294))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (276, 294))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (276, 294))	('BAP1', 'Gene', (47, 51))	('increases', 'Reg', (199, 208))	('BAP1-tumor', 'Disease', 'MESH:D009369', (152, 162))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (248, 270))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('BAP1-tumor', 'Disease', (152, 162))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('BAP1', 'Gene', '8314', (152, 156))	('BAP1', 'Gene', '8314', (119, 123))	('mutation', 'Var', (124, 132))	('malignant mesothelioma', 'Disease', (248, 270))
133398	29769598	In three tumors and/or metastases we detected pathogenic somatic mutations in BAP1, which is not an unexpected finding, but these mutations occur in all three patients together with the germline missense variant in ATM.	('metastases', 'Disease', 'MESH:D009362', (23, 33))	('ATM', 'Gene', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('metastases', 'Disease', (23, 33))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (130, 139))	('ATM', 'Gene', '472', (215, 218))	('BAP1', 'Gene', '8314', (78, 82))	('tumors', 'Disease', (9, 15))	('patients', 'Species', '9606', (159, 167))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('mutations', 'Var', (65, 74))	('BAP1', 'Gene', (78, 82))
133400	29769598	Moreover, we have found germline TP53 mutation in two patients.	('patients', 'Species', '9606', (54, 62))	('TP53', 'Gene', '7157', (33, 37))	('germline', 'Var', (24, 32))	('mutation', 'Var', (38, 46))	('TP53', 'Gene', (33, 37))
133402	29769598	However, the identification of germline TP53 or BAP1 mutations is important to be able to identify patients with Li-Fraumeni syndrome or BAP1 cancer syndrome and is the first step for proper genetic counseling and management of the patients and family members.	('BAP1', 'Gene', (137, 141))	('BAP1', 'Gene', '8314', (48, 52))	('BAP1 cancer syndrome', 'Disease', 'MESH:D009369', (137, 157))	('patients', 'Species', '9606', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('BAP1', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('patients', 'Species', '9606', (99, 107))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (113, 133))	('BAP1', 'Gene', '8314', (137, 141))	('Li-Fraumeni syndrome', 'Disease', (113, 133))	('BAP1 cancer syndrome', 'Disease', (137, 157))
133415	29769598	Nontumor tissue or genomic DNA from blood was used to determine germline or somatic state of detected variants.	('variants', 'Var', (102, 110))	('tumor', 'Disease', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))
133420	29769598	Additional IHC in the case mUM_2 (carrier of the mutation in MSH2 c.4G > A, p.A2T) was performed with antibodies against mismatch repair (MMR) proteins including MSH2 (clone FE 11, dilution 1:50, Zytomed Systems), MSH6 (clone 44, dilution 1:50, Zytomed Systems), MLH1 (clone G168-15, dilution 1:200, Spring Bioscience, Pleasanton, CA), PMS2 (EPR3947, ready-to-use, Zytomed Systems).	('PMS2', 'Gene', (336, 340))	('p.A2T', 'Mutation', 'rs63750466', (76, 81))	('MLH1', 'Gene', '4292', (263, 267))	('MLH1', 'Gene', (263, 267))	('PMS2', 'Gene', '5395', (336, 340))	('MSH2', 'Gene', (61, 65))	('MSH2', 'Gene', '4436', (61, 65))	('MSH6', 'Gene', (214, 218))	('mutation', 'Var', (49, 57))	('c.4G > A', 'Mutation', 'rs63750466', (66, 74))	('carrier', 'molecular_function', 'GO:0005215', ('34', '41'))	('MSH2', 'Gene', (162, 166))	('mismatch repair', 'biological_process', 'GO:0006298', ('121', '136'))	('MSH2', 'Gene', '4436', (162, 166))	('MMR', 'biological_process', 'GO:0006298', ('138', '141'))	('MSH6', 'Gene', '2956', (214, 218))
133426	29769598	Contribution of the patient material with clinical data: P.D., K.N., J.U., K.J., J.G.	('K.J.', 'Var', (75, 79))	('patient', 'Species', '9606', (20, 27))	('K.N.', 'Var', (63, 67))	('J.U.', 'Var', (69, 73))	('P.D.', 'Var', (57, 61))
133438	29441099	Other radionuclides traditionally used for ophthalmic brachytherapy include iodine-125 (125I) and palladium-103 (103Pd).	('palladium-103', 'Chemical', 'MESH:C000615531', (98, 111))	('125I', 'Var', (88, 92))	('iodine-125', 'Chemical', 'MESH:C000614960', (76, 86))	('103Pd', 'Var', (113, 118))
133441	29441099	However, the I-125 is gamma emitter and more likely to cause radiation side effects than Ru-106, if same-sized tumors are treated.	('I-125', 'Var', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Ru-106', 'Chemical', 'MESH:C000615522', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('cause', 'Reg', (55, 60))
133569	29326884	Several genetic signatures have been found for "type I" tumors:with monosomy 3, present in a half of uveal melanomas, being the most significant chromosomal aberration and strongly associated with metastasis and death.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('"type I" tumors', 'Disease', 'MESH:D005776', (47, 62))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('monosomy 3', 'Var', (68, 78))	('death', 'Disease', 'MESH:D003643', (212, 217))	('uveal melanomas', 'Disease', 'MESH:C536494', (101, 116))	('"type I" tumors', 'Disease', (47, 62))	('death', 'Disease', (212, 217))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (145, 167))	('uveal melanoma', 'Phenotype', 'HP:0007716', (101, 115))	('associated with', 'Reg', (181, 196))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('metastasis', 'CPA', (197, 207))	('uveal melanomas', 'Disease', (101, 116))	('uveal melanomas', 'Phenotype', 'HP:0007716', (101, 116))
133570	29326884	Monosomy 3 affects prognosis due to tumor haploinsufficiency of BAP1:an important BRCA1-associated tumor suppressor gene.	('BRCA1', 'Gene', (82, 87))	('Monosomy', 'Var', (0, 8))	('tumor', 'Disease', (99, 104))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('99', '115'))	('tumor haploinsufficiency', 'Disease', 'MESH:D058495', (36, 60))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor haploinsufficiency', 'Disease', (36, 60))	('prognosis', 'MPA', (19, 28))	('BAP1', 'Gene', '8314', (64, 68))	('BRCA1', 'Gene', '672', (82, 87))	('affects', 'Reg', (11, 18))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('tumor suppressor', 'biological_process', 'GO:0051726', ('99', '115'))	('BAP1', 'Gene', (64, 68))
133571	29326884	Other chromosomal abnormalities, such as loss of 6q and gain of 8q, have been associated with poor prognosis in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('chromosomal abnormalities', 'Disease', (6, 31))	('uveal melanoma', 'Disease', 'MESH:C536494', (112, 126))	('gain', 'PosReg', (56, 60))	('loss of 6q', 'Var', (41, 51))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (6, 31))	('uveal melanoma', 'Phenotype', 'HP:0007716', (112, 126))	('uveal melanoma', 'Disease', (112, 126))
133572	29326884	Point mutations in GNAQ and GNA11 have been identified in 80-90% of uveal melanomas and lead to activation of the MAPK/MEK/ERK pathway.	('MEK', 'Gene', (119, 122))	('identified', 'Reg', (44, 54))	('ERK', 'Gene', (123, 126))	('uveal melanomas', 'Disease', 'MESH:C536494', (68, 83))	('GNA11', 'Gene', (28, 33))	('MAPK', 'molecular_function', 'GO:0004707', ('114', '118'))	('ERK', 'molecular_function', 'GO:0004707', ('123', '126'))	('GNAQ', 'Gene', '2776', (19, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('Point mutations', 'Var', (0, 15))	('MAPK', 'Gene', (114, 118))	('activation', 'PosReg', (96, 106))	('uveal melanomas', 'Disease', (68, 83))	('GNAQ', 'Gene', (19, 23))	('uveal melanomas', 'Phenotype', 'HP:0007716', (68, 83))	('melanomas', 'Phenotype', 'HP:0002861', (74, 83))	('MAPK', 'Gene', '5594', (114, 118))	('MEK', 'Gene', '5609', (119, 122))	('ERK', 'Gene', '5594', (123, 126))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('GNA11', 'Gene', '2767', (28, 33))
133631	28690979	Furthermore, melanomas showing spontaneous regression contain more tumor-specific lymphocytes than those in non-regressing tumors, and the presence of these lymphocytes portends a better prognosis.	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumor', 'Disease', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('melanomas', 'Disease', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('presence', 'Var', (139, 147))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('tumor', 'Disease', (67, 72))	('melanomas', 'Disease', 'MESH:D008545', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
133632	28690979	High levels of immunosurveillance within the orbit might, therefore, maintain micro-metastases of primary tumor in remission for many years; later, mutations might occur in tumor-associated antigens, leading to loss of lymphocytic recognition and, thereby, loss of tumor control.	('mutations', 'Var', (148, 157))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('loss of tumor', 'Disease', (257, 270))	('metastases', 'Disease', (84, 94))	('loss', 'NegReg', (211, 215))	('tumor', 'Disease', (265, 270))	('metastases', 'Disease', 'MESH:D009362', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (173, 178))	('lymphocytic', 'CPA', (219, 230))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('loss of tumor', 'Disease', 'MESH:D009369', (257, 270))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('tumor', 'Disease', (106, 111))
133663	19800609	The most accurate molecular tests for predicting metastatic death in patients with uveal melanoma currently involve automated techniques for assessing deoxyribonucleic acid (DNA) copy number alterations and gene expression profiling.	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('uveal melanoma', 'Disease', (83, 97))	('death', 'Disease', 'MESH:D003643', (60, 65))	('death', 'Disease', (60, 65))	('copy number alterations', 'Var', (179, 202))	('deoxyribonucleic acid', 'MPA', (151, 172))	('DNA', 'cellular_component', 'GO:0005574', ('174', '177'))	('gene expression', 'biological_process', 'GO:0010467', ('207', '222'))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('patients', 'Species', '9606', (69, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (83, 97))
133676	19800609	Several cytogenetic or chromosomal abnormalities, including loss of 1p, loss of chromosome 3 (monosomy 3), gain of 6p, loss of 6q, loss of 8p, and gain of 8q, have been linked statistically to metastatic death in uveal melanoma.	('uveal melanoma', 'Disease', (213, 227))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (23, 48))	('gain', 'PosReg', (147, 151))	('loss of 6q', 'Var', (119, 129))	('gain', 'PosReg', (107, 111))	('loss', 'Var', (72, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('80', '90'))	('loss', 'Var', (60, 64))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('uveal melanoma', 'Phenotype', 'HP:0007716', (213, 227))	('uveal melanoma', 'Disease', 'MESH:C536494', (213, 227))	('death', 'Disease', 'MESH:D003643', (204, 209))	('loss of 8p', 'Var', (131, 141))	('death', 'Disease', (204, 209))	('chromosomal abnormalities', 'Disease', (23, 48))
133690	19800609	Most prognostic tests in uveal melanoma have been reported in the literature as if they yield simple, categorical answers, such as "disomy 3" vs "monosomy 3."	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('uveal melanoma', 'Disease', (25, 39))	('monosomy 3', 'Var', (146, 156))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('uveal melanoma', 'Disease', 'MESH:C536494', (25, 39))
133691	19800609	For example, what percentage of cells in a tumor must exhibit monosomy 3 before the tumor is "diagnosed" as monosomy 3?	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('monosomy 3', 'Var', (62, 72))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
133714	19800609	For example, it has been speculated that cytogenetic markers can be used to determine which small suspicious uveal melanocytic tumors should be treated; those with monosomy 3 would presumably be treated promptly, whereas those with disomy 3 would be observed.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('uveal melanocytic tumors', 'Disease', (109, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('uveal melanocytic tumors', 'Phenotype', 'HP:0007716', (109, 133))	('uveal melanocytic tumors', 'Disease', 'MESH:D014604', (109, 133))	('monosomy 3', 'Var', (164, 174))
133724	22935333	Germline BAP1 mutations have been recently associated with an increased risk of malignant mesothelioma, atypical melanocytic tumors and other neoplasms.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (80, 102))	('melanocytic tumors', 'Disease', (113, 131))	('neoplasms', 'Disease', (142, 151))	('malignant mesothelioma', 'Disease', (80, 102))	('neoplasms', 'Phenotype', 'HP:0002664', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('neoplasms', 'Disease', 'MESH:D009369', (142, 151))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('BAP1', 'Gene', '8314', (9, 13))	('associated', 'Reg', (43, 53))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (80, 102))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('melanocytic tumors', 'Disease', 'MESH:D009508', (113, 131))
133725	22935333	To answer the question if different germline BAP1 mutations may predispose to a single syndrome with a wide phenotypic range or to distinct syndromes, we investigated the presence of melanocytic tumors in two unrelated families (L and W) with germline BAP1 mutations and increased risk of malignant mesothelioma.	('BAP1', 'Gene', (252, 256))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('mutations', 'Var', (257, 266))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (289, 311))	('BAP1', 'Gene', (45, 49))	('malignant mesothelioma', 'Disease', (289, 311))	('mutations', 'Var', (50, 59))	('BAP1', 'Gene', '8314', (252, 256))	('melanocytic tumors', 'Disease', 'MESH:D009508', (183, 201))	('predispose', 'Reg', (64, 74))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (289, 311))	('melanocytic tumors', 'Disease', (183, 201))	('BAP1', 'Gene', '8314', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
133726	22935333	Suspicious cutaneous lesions were clinically and pathologically characterized and compared to those present in other families carrying BAP1 mutations.	('BAP1', 'Gene', '8314', (135, 139))	('BAP1', 'Gene', (135, 139))	('mutations', 'Var', (140, 149))
133727	22935333	We then conducted a meta-analysis of all the studies reporting BAP1-mutated families to survey cancer risk related to the germline BAP1 mutation (means were compared using t-test and proportions were compared with Pearson chi2 test or two-tailed Fisher's exact test).	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('BAP1', 'Gene', (63, 67))	('mutation', 'Var', (136, 144))	('cancer', 'Disease', (95, 101))	('BAP1', 'Gene', '8314', (131, 135))	('BAP1', 'Gene', (131, 135))	('BAP1', 'Gene', '8314', (63, 67))
133728	22935333	Melanocytic tumors: of the five members of the L family studied, four (80%) carried a germline BAP1 mutation (p.Gln684*) and also presented one or more atypical melanocytic tumors; of the seven members of W family studied, all carried a germline BAP1 mutation (p.Pro147fs*48) and four of them (57%) presented one or more atypical melanocytic tumors, that we propose to call "melanocytic BAP1-mutated atypical intradermal tumors" (MBAITs).	('melanocytic tumors', 'Disease', 'MESH:D009508', (161, 179))	('melanocytic tumors', 'Disease', (161, 179))	('tumor', 'Phenotype', 'HP:0002664', (421, 426))	('Melanocytic tumors', 'Disease', (0, 18))	('BAP1', 'Gene', '8314', (95, 99))	('BAP1', 'Gene', '8314', (246, 250))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('BAP1', 'Gene', '8314', (387, 391))	('p.Gln684*', 'Var', (110, 119))	('Melanocytic tumors', 'Disease', 'MESH:D009508', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('atypical', 'Disease', (321, 329))	('BAP1', 'Gene', (246, 250))	('BAP1', 'Gene', (387, 391))	('BAP1', 'Gene', (95, 99))	('melanocytic tumors', 'Disease', 'MESH:D009508', (330, 348))	('p.Gln684*', 'Mutation', 'p.Q684*', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('melanocytic tumors', 'Disease', (330, 348))	('p.Pro147fs*48', 'Mutation', 'p.P147fsX48', (261, 274))	('tumors', 'Phenotype', 'HP:0002664', (342, 348))	('p.Pro147fs*48', 'Var', (261, 274))	('intradermal tumors', 'Disease', 'MESH:D018330', (409, 427))	('intradermal tumors', 'Disease', (409, 427))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('tumors', 'Phenotype', 'HP:0002664', (421, 427))
133731	22935333	Germline BAP1 mutations are associated with a novel cancer syndrome characterized by malignant mesothelioma, uveal melanoma, cutaneous melanoma and MBAITs, and possibly by other cancers.	('cancer syndrome', 'Disease', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('BAP1', 'Gene', (9, 13))	('cutaneous melanoma', 'Disease', (125, 143))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (125, 143))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (125, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (85, 107))	('mutations', 'Var', (14, 23))	('MBAITs', 'Disease', (148, 154))	('associated', 'Reg', (28, 38))	('malignant mesothelioma', 'Disease', (85, 107))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer syndrome', 'Disease', 'MESH:D009369', (52, 67))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (85, 107))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('BAP1', 'Gene', '8314', (9, 13))	('uveal melanoma', 'Disease', 'MESH:C536494', (109, 123))	('cancers', 'Disease', (178, 185))	('uveal melanoma', 'Disease', (109, 123))
133732	22935333	MBAITs provide physicians with a marker to identify individuals who may carry germline BAP1 mutations and thus are at high risk of developing associated cancers.	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('BAP1', 'Gene', '8314', (87, 91))	('germline', 'Var', (78, 86))	('cancers', 'Disease', (153, 160))	('BAP1', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
133733	22935333	Hereditary cancer syndromes are caused by mutations in genes conferring high relative risks of cancer among carriers.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('Hereditary cancer', 'Disease', 'MESH:D009369', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('caused by', 'Reg', (32, 41))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer syndrome', 'Disease', 'MESH:D009369', (11, 26))	('cancer', 'Disease', (11, 17))	('cancer syndrome', 'Disease', (11, 26))	('mutations', 'Var', (42, 51))	('Hereditary cancer', 'Disease', (0, 17))
133738	22935333	We recently identified two unrelated families (L and W) with germline BAP1 mutations and increased risk of malignant mesothelioma (MM) and possibly other cancers.	('malignant mesothelioma', 'Disease', (107, 129))	('germline', 'Var', (61, 69))	('BAP1', 'Gene', '8314', (70, 74))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (107, 129))	('BAP1', 'Gene', (70, 74))	('cancers', 'Disease', (154, 161))	('mutations', 'Var', (75, 84))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (107, 129))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
133739	22935333	In parallel with our study, Wiesner and colleagues reported germline BAP1 mutations in two unrelated families with "atypical melanocytic tumors" and other cancers.	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('BAP1', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('melanocytic tumors', 'Disease', (125, 143))	('melanocytic tumors', 'Disease', 'MESH:D009508', (125, 143))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('cancers', 'Disease', (155, 162))	('BAP1', 'Gene', '8314', (69, 73))
133740	22935333	In a subsequent paper, Wiesner and colleagues called the same melanocytic lesions "atypical Spitz tumors" (ASTs), but noted that in contrast to ASTs these lesions had a different histology and were characterized by the presence of both BAP1 and BRAF mutations.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('BRAF', 'Gene', (245, 249))	('BRAF', 'Gene', '673', (245, 249))	('AST', 'Gene', (144, 147))	('presence', 'Reg', (219, 227))	('AST', 'Gene', (107, 110))	('AST', 'Gene', '26503', (144, 147))	('melanocytic lesions "atypical Spitz tumors', 'Disease', 'MESH:D018332', (62, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('BAP1', 'Gene', '8314', (236, 240))	('mutations', 'Var', (250, 259))	('melanocytic lesions "atypical Spitz tumors', 'Disease', (62, 104))	('AST', 'Gene', '26503', (107, 110))	('BAP1', 'Gene', (236, 240))
133741	22935333	BRAF mutations are indeed common in melanocytic nevi (80%) and in cutaneous melanomas (CMs) (65%) but are rare in ASTs.	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('nevi', 'Phenotype', 'HP:0003764', (48, 52))	('melanocytic nevi', 'Disease', (36, 52))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (66, 85))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (66, 85))	('CMs', 'Phenotype', 'HP:0012056', (87, 90))	('CM', 'Disease', 'MESH:D009202', (87, 89))	('AST', 'Gene', (114, 117))	('mutations', 'Var', (5, 14))	('common', 'Reg', (26, 32))	('cutaneous melanomas', 'Disease', (66, 85))	('BRAF', 'Gene', '673', (0, 4))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (36, 52))	('AST', 'Gene', '26503', (114, 117))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
133742	22935333	Other investigators independently confirmed the association of germline BAP1 mutations and other cancers in additional families.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('BAP1', 'Gene', '8314', (72, 76))	('association', 'Interaction', (48, 59))	('germline', 'Var', (63, 71))	('BAP1', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutations', 'Var', (77, 86))
133744	22935333	To verify if germline BAP1 mutations are associated with distinct syndromes or with a single syndrome exhibiting a wide phenotypic range, we first investigated the presence of melanocytic tumors in our two families and compared them to those published in the literature, and then conducted a pooled analysis of individuals from studies reporting BAP1-mutated families to compare cancer risk in the 63 mutated vs the 55 non-mutated individuals from those families.	('cancer', 'Disease', (379, 385))	('BAP1', 'Gene', (346, 350))	('mutations', 'Var', (27, 36))	('associated', 'Reg', (41, 51))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('melanocytic tumors', 'Disease', (176, 194))	('melanocytic tumors', 'Disease', 'MESH:D009508', (176, 194))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', '8314', (346, 350))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('cancer', 'Disease', 'MESH:D009369', (379, 385))	('BAP1', 'Gene', (22, 26))
133745	22935333	We demonstrate that germline BAP1 mutations are associated with a novel cancer syndrome characterized by MM, uveal melanoma (UVM), CM, MBAITs and possibly by other tumors.	('cancer syndrome', 'Disease', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('UVM', 'Phenotype', 'HP:0007716', (125, 128))	('tumors', 'Disease', (164, 170))	('associated', 'Reg', (48, 58))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('CM', 'Disease', 'MESH:D009202', (131, 133))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('BAP1', 'Gene', '8314', (29, 33))	('uveal melanoma', 'Disease', 'MESH:C536494', (109, 123))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('uveal melanoma', 'Disease', (109, 123))	('MBAITs', 'Disease', (135, 141))	('mutations', 'Var', (34, 43))	('BAP1', 'Gene', (29, 33))	('cancer syndrome', 'Disease', 'MESH:D009369', (72, 87))
133750	22935333	BRAF (exon15) mutations were detected by multiplex PCR amplification of tumor DNA, followed by automated fluorescent labeling, hybridization to a BioFilmChip Microarray, and signal detection using the AutoGenomics INFINITY Analyzer (AutoGenomics).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('mutations', 'Var', (14, 23))
133752	22935333	The inclusion criteria were: at least two generations and five members tested for germline BAP1 mutations, one positive germline BAP1 mutation found in at least one member of the family, and cancer status assessed for each of the tested members.	('germline', 'Var', (82, 90))	('cancer', 'Disease', (191, 197))	('tested', 'Reg', (71, 77))	('BAP1', 'Gene', (91, 95))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('BAP1', 'Gene', '8314', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('BAP1', 'Gene', '8314', (91, 95))	('BAP1', 'Gene', (129, 133))	('mutations', 'Var', (96, 105))
133753	22935333	We asked the authors of the four selected papers for additional data: we collected gender, age of death or age of last follow up, germline BAP1 mutation result, all diagnosed cancers, and age of each cancer diagnosis.	('death', 'Disease', 'MESH:D003643', (98, 103))	('death', 'Disease', (98, 103))	('BAP1', 'Gene', (139, 143))	('mutation result', 'Var', (144, 159))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('germline', 'Var', (130, 138))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('BAP1', 'Gene', '8314', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('cancer', 'Disease', (200, 206))
133754	22935333	To assess if germline BAP1 mutations were associated with an increased risk of cancer or MBAITs, we built two cohorts from these families: one cohort constituting 63 germline BAP1-mutated patients and the second cohort constituting 55 non-mutated patients.	('mutations', 'Var', (27, 36))	('BAP1', 'Gene', (175, 179))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (188, 196))	('patients', 'Species', '9606', (247, 255))	('BAP1', 'Gene', '8314', (22, 26))	('BAP1', 'Gene', '8314', (175, 179))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('BAP1', 'Gene', (22, 26))
133766	22935333	Of the five members of L family, four (80%) carried the germline BAP1 mutation (p.Gln684*).	('BAP1', 'Gene', '8314', (65, 69))	('p.Gln684*', 'Var', (80, 89))	('BAP1', 'Gene', (65, 69))	('p.Gln684*', 'Mutation', 'p.Q684*', (80, 89))
133768	22935333	All of the seven members of W family carried the germline BAP1 mutations (p.Pro147fs*48).	('BAP1', 'Gene', (58, 62))	('p.Pro147fs*48', 'Mutation', 'p.P147fsX48', (74, 87))	('p.Pro147fs*48', 'Var', (74, 87))	('BAP1', 'Gene', '8314', (58, 62))
133772	22935333	The mean ages of follow up were comparable in both cohorts (53.2 years, 95%CI: 49.0-57.4 in the BAP1 mutated cohort, 51.0 years, 95%CI: 46.3-55.8 in the non-mutated cohort).	('BAP1', 'Gene', (96, 100))	('mutated', 'Var', (101, 108))	('BAP1', 'Gene', '8314', (96, 100))
133774	22935333	At this time we do not have an explanation for this finding, although it appears possible that BAP1 mutation may carry a higher risk of lethality in utero for males.	('mutation', 'Var', (100, 108))	('BAP1', 'Gene', '8314', (95, 99))	('BAP1', 'Gene', (95, 99))	('lethality', 'MPA', (136, 145))
133777	22935333	The odds ratio (OR) of cancer risk in the germline BAP1-mutated cohort versus the non-mutated cohort was 17.39 (95% CI: 6.07-49.83).	('BAP1', 'Gene', (51, 55))	('germline', 'Var', (42, 50))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('BAP1', 'Gene', '8314', (51, 55))
133781	22935333	To avoid the overestimation of the cancer risks estimates usually due to publication bias in meta-analyses, we chose to compare BAP1 mutated vs non-mutated patients from the same families.	('patients', 'Species', '9606', (156, 164))	('BAP1', 'Gene', '8314', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('BAP1', 'Gene', (128, 132))	('mutated', 'Var', (133, 140))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
133782	22935333	We demonstrate that germline BAP1 mutations are associated with a significant increased overall risk of cancer and particularly of MM, UVM and CM (Table 2).	('CM', 'Disease', 'MESH:D009202', (143, 145))	('UVM', 'Phenotype', 'HP:0007716', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('BAP1', 'Gene', '8314', (29, 33))	('UVM', 'Disease', (135, 138))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('mutations', 'Var', (34, 43))	('BAP1', 'Gene', (29, 33))
133784	22935333	Our results reveal that germline BAP1 mutations cause a novel autosomal dominant hereditary cancer syndrome, the BAP1 cancer syndrome, characterized predominantly by MM, UVM, CM and by MBAITs and possibly by other cancers.	('CM', 'Disease', 'MESH:D009202', (175, 177))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('UVM', 'Phenotype', 'HP:0007716', (170, 173))	('cancers', 'Disease', (214, 221))	('BAP1', 'Gene', '8314', (33, 37))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cause', 'Reg', (48, 53))	('BAP1', 'Gene', '8314', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('autosomal dominant hereditary cancer syndrome, the BAP1 cancer syndrome', 'Disease', 'MESH:D009386', (62, 133))	('BAP1', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))	('BAP1', 'Gene', (113, 117))	('UVM', 'Disease', (170, 173))
133790	22935333	MBAITs provide physicians with a marker to identify individuals who may carry germline BAP1 mutations and thus are at high risk of developing CM, UVM and MM.	('BAP1', 'Gene', '8314', (87, 91))	('UVM', 'Phenotype', 'HP:0007716', (146, 149))	('germline', 'Var', (78, 86))	('developing', 'PosReg', (131, 141))	('BAP1', 'Gene', (87, 91))	('UVM', 'Disease', (146, 149))	('mutations', 'Var', (92, 101))	('CM', 'Disease', 'MESH:D009202', (142, 144))
133791	22935333	We identified MBAITs among the majority of germline BAP1 mutation carriers in the L and W families.	('BAP1', 'Gene', (52, 56))	('mutation', 'Var', (57, 65))	('BAP1', 'Gene', '8314', (52, 56))
133792	22935333	Our meta-analysis demonstrates that the prevalence of MBAITs is significantly higher in germline BAP1 mutation carriers compared to controls.	('BAP1', 'Gene', '8314', (97, 101))	('MBAITs', 'Disease', (54, 60))	('mutation', 'Var', (102, 110))	('higher', 'PosReg', (78, 84))	('BAP1', 'Gene', (97, 101))
133796	22935333	Instead, the tumors found in these BAP1 mutated patients show large epithelioid clonal cells (that resemble those found in Spitz nevus and in ASTs) but these cells are present only in the dermis (there is no epidermal component).	('tumors', 'Disease', (13, 19))	('AST', 'Gene', (142, 145))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('nevus', 'Phenotype', 'HP:0003764', (129, 134))	('BAP1', 'Gene', '8314', (35, 39))	('Spitz nevus', 'Disease', (123, 134))	('mutated', 'Var', (40, 47))	('AST', 'Gene', '26503', (142, 145))	('BAP1', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('patients', 'Species', '9606', (48, 56))
133801	22935333	At the molecular level, these lesions are characterized by BAP1 inactivation and almost always by concurrent BRAF mutation, features that are not found in Spitz and ASTs.	('AST', 'Gene', (165, 168))	('BRAF', 'Gene', (109, 113))	('BAP1', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (109, 113))	('AST', 'Gene', '26503', (165, 168))	('mutation', 'Var', (114, 122))	('BAP1', 'Gene', '8314', (59, 63))	('inactivation', 'NegReg', (64, 76))
133806	22935333	Therefore, we believe that if we continue to lump different melanocytic lesions (such as MBAITs) under the umbrella term of AST we will miss an opportunity to help pathologists to identify and classify this subgroup and to guide clinicians in selecting patients who may need testing for BAP1 mutations.	('mutations', 'Var', (292, 301))	('melanocytic lesions', 'Disease', 'MESH:D009508', (60, 79))	('melanocytic lesions', 'Disease', (60, 79))	('AST', 'Gene', (124, 127))	('patients', 'Species', '9606', (253, 261))	('AST', 'Gene', '26503', (124, 127))	('BAP1', 'Gene', '8314', (287, 291))	('BAP1', 'Gene', (287, 291))
133809	22935333	Along the guidelines used for FAMM-P families we advise families with hereditary BAP1 mutation to have family members tested for mutant gene carrier status at the age of ten and, if positive, to begin routine screening with a total body dermatological examination as family members may develop melanoma at an early age.	('carrier', 'molecular_function', 'GO:0005215', ('141', '148'))	('BAP1', 'Gene', (81, 85))	('melanoma', 'Disease', 'MESH:D008545', (294, 302))	('develop', 'PosReg', (286, 293))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('melanoma', 'Disease', (294, 302))	('mutation', 'Var', (86, 94))	('BAP1', 'Gene', '8314', (81, 85))
133814	22935333	Detection of BRAF mutations may help diagnose this condition in cases of inconclusive BAP1 staining.	('BAP1', 'Gene', '8314', (86, 90))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('BAP1', 'Gene', (86, 90))	('mutations', 'Var', (18, 27))
133815	22935333	Next, genetic counseling should be offered and germline DNA should be tested for BAP1 mutations to identify individuals and families at higher risk for one or more of the neoplasms associated with the BAP1 cancer syndrome.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('BAP1', 'Gene', (81, 85))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('neoplasms', 'Phenotype', 'HP:0002664', (171, 180))	('cancer syndrome', 'Disease', 'MESH:D009369', (206, 221))	('cancer syndrome', 'Disease', (206, 221))	('neoplasms', 'Disease', 'MESH:D009369', (171, 180))	('neoplasms', 'Disease', (171, 180))
133816	22935333	Germline BAP1 mutation carriers can be targeted for early detection and therapy that is associated with either a cure or improved prognosis.	('mutation', 'Var', (14, 22))	('BAP1', 'Gene', '8314', (9, 13))	('BAP1', 'Gene', (9, 13))
133836	22815634	In addition, cytogenetic modifications on chromosomes 1, 3, 6, and 8 are frequently observed in UM, and monosomy 3 and 8p loss are strongly associated to metastatic death.	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('associated', 'Reg', (140, 150))	('cytogenetic', 'Var', (13, 24))	('modifications', 'Var', (25, 38))	('death', 'Disease', 'MESH:D003643', (165, 170))	('death', 'Disease', (165, 170))	('monosomy 3', 'Var', (104, 114))
133837	22815634	Since chromosome 6p gain (non-metastasizing tumors) and monosomy chromosome 3 (metastasizing tumors) are mutually exclusive, these events can predict metastatic potential of UM tumors.	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('monosomy chromosome', 'Var', (56, 75))	('gain', 'PosReg', (20, 24))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('chromosome', 'cellular_component', 'GO:0005694', ('6', '16'))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('metastatic potential', 'CPA', (150, 170))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumors', 'Disease', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('UM', 'Phenotype', 'HP:0007716', (174, 176))	('tumors', 'Disease', (44, 50))	('predict', 'Reg', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Disease', (177, 183))	('chromosome', 'cellular_component', 'GO:0005694', ('65', '75'))
133839	22815634	More than 80% of UM tumors have mutations in guanine nucleotide binding protein q polypeptide (GNAQ) and guanine nucleotide binding protein alpha 11 (GNA11) G-proteins that lead to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway.	('activation', 'PosReg', (194, 204))	('GNA11', 'Gene', (150, 155))	('GNAQ', 'Gene', (95, 99))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('113', '131'))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('53', '71'))	('UM', 'Phenotype', 'HP:0007716', (17, 19))	('tumors', 'Disease', (20, 26))	('GNA11', 'Gene', '2767', (150, 155))	('MAPK', 'molecular_function', 'GO:0004707', ('246', '250'))	('guanine nucleotide binding protein alpha 11', 'Gene', (105, 148))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('protein', 'cellular_component', 'GO:0003675', ('230', '237'))	('guanine nucleotide binding protein alpha 11', 'Gene', '2767', (105, 148))	('GNAQ', 'Gene', '2776', (95, 99))
133882	22815634	There is little information in the literature on this monocarboxylate transporter, but a recent microarray study identified a repression of this gene in GNAQ/BRAF mutant UM cells following treatment with selumetinib, a MAPK/ERK kinase (MEK) inhibitor currently in clinical trial for UM.	('MAPK', 'molecular_function', 'GO:0004707', ('219', '223'))	('repression', 'NegReg', (126, 136))	('mutant', 'Var', (163, 169))	('selumetinib', 'Chemical', 'MESH:C517975', (204, 215))	('BRAF', 'Gene', '673', (158, 162))	('UM', 'Phenotype', 'HP:0007716', (283, 285))	('GNAQ', 'Gene', '2776', (153, 157))	('UM', 'Phenotype', 'HP:0007716', (170, 172))	('BRAF', 'Gene', (158, 162))	('MEK', 'Gene', (236, 239))	('ERK', 'molecular_function', 'GO:0004707', ('224', '227'))	('MEK', 'Gene', '5609', (236, 239))	('GNAQ', 'Gene', (153, 157))
133896	22815634	Interestingly, inhibition of MITF in malignant melanoma cells increases the expression of stem cell marker OCT4.	('OCT4', 'Protein', (107, 111))	('MITF', 'Gene', '4286', (29, 33))	('MITF', 'Gene', (29, 33))	('increases', 'PosReg', (62, 71))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('malignant melanoma', 'Phenotype', 'HP:0002861', (37, 55))	('expression of', 'MPA', (76, 89))	('malignant melanoma', 'Disease', 'MESH:D008545', (37, 55))	('inhibition', 'Var', (15, 25))	('malignant melanoma', 'Disease', (37, 55))
133975	20442802	With time, such changes could add up to transform a melanocyte precursor to a malignant melanoma stem cell.	('changes', 'Var', (16, 23))	('malignant melanoma', 'Disease', 'MESH:D008545', (78, 96))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('malignant melanoma', 'Disease', (78, 96))	('transform', 'Reg', (40, 49))	('melanocyte precursor', 'CPA', (52, 72))	('malignant melanoma', 'Phenotype', 'HP:0002861', (78, 96))
133990	20442802	Over the past five years, more than 50 genes in melanoma have been shown to be dysregulated through epigenetic changes.	('melanoma', 'Disease', (48, 56))	('epigenetic changes', 'Var', (100, 118))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
133991	20442802	Epigenetic changes and also mutations, could be augmented by ultraviolet radiation (UVR).	('Epigenetic changes', 'Var', (0, 18))	('mutations', 'Var', (28, 37))	('men', 'Species', '9606', (51, 54))
134007	20442802	Melanoma progression and metastasis is traditionally modeled as a stepwise process with the initial mutagenic event occurring in a melanocyte in the epidermis, with further mutation resulting in the proliferation passing through nevus and dysplastic nevus phases.	('dysplastic', 'Disease', (239, 249))	('resulting in', 'Reg', (182, 194))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('nevus', 'Phenotype', 'HP:0003764', (229, 234))	('Melanoma', 'Disease', (0, 8))	('nevus', 'Phenotype', 'HP:0003764', (250, 255))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (239, 255))	('dysplastic', 'Disease', 'MESH:D004416', (239, 249))	('mutation', 'Var', (173, 181))
134009	20442802	Only long-time residents of the dermis/epidermis, most likely stem cells, have the ability to accumulate the number of necessary genetic hits that will result in melanoma development.	('result in', 'Reg', (152, 161))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('genetic hits', 'Var', (129, 141))	('men', 'Species', '9606', (178, 181))
134010	20442802	When eventually, environmental signaling would activate the stem cell, due to these mutations, proliferation would not be appropriately controlled.	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('men', 'Species', '9606', (24, 27))	('activate', 'PosReg', (47, 55))	('stem cell', 'CPA', (60, 69))	('mutations', 'Var', (84, 93))
134017	20442802	These UVB-induced lesions give rise to DNA mutations hallmarked by CT T and CC TT transitions, the so-called "UVB signature mutations".	('DNA mutations', 'Disease', (39, 52))	('CC TT transitions', 'Disease', (76, 93))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('hal', 'Chemical', '-', (53, 56))	('lesions', 'Var', (18, 25))	('CT T', 'Disease', (67, 71))
134018	20442802	Definitive evidence for UVB signature mutations in melanoma genes has been surprisingly lacking in the literature.	('mutations', 'Var', (38, 47))	('UVB', 'Gene', (24, 27))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
134021	20442802	Studies have examined polymorphisms in genes associated with DNA repair and identified significant association with xeroderma pigmentosum complementating group D(XPD, locus 19q13.2-3) gene and suggested that XPD gene polymorphisms might predispose to melanoma in the general population.	('association', 'Interaction', (99, 110))	('men', 'Species', '9606', (144, 147))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('XPD', 'Gene', (162, 165))	('DNA repair', 'biological_process', 'GO:0006281', ('61', '71'))	('polymorphisms', 'Var', (217, 230))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('men', 'Species', '9606', (129, 132))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (116, 137))	('XPD', 'Gene', '2068', (162, 165))	('melanoma', 'Disease', 'MESH:D008545', (251, 259))	('XPD', 'Gene', (208, 211))	('melanoma', 'Disease', (251, 259))	('XPD', 'Gene', '2068', (208, 211))	('xeroderma pigmentosum', 'Disease', (116, 137))	('predispose', 'Reg', (237, 247))
134022	20442802	Recent studies have also provided evidence for the presence of several genes whose expression could be altered in melanoma by epigenetic modulations.	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('altered', 'Reg', (103, 110))	('epigenetic modulations', 'Var', (126, 148))	('expression', 'MPA', (83, 93))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
134024	20442802	In lung cancer, silencing of genes by hypermethylation has been thoroughly documented.	('hypermethylation', 'Var', (38, 54))	('men', 'Species', '9606', (79, 82))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('silencing', 'NegReg', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
134026	20442802	Thus a possible linkage between epigenetic silencing or gene amplification and UVB exposure already exists for melanoma.	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('gene amplification', 'Var', (56, 74))	('epigenetic silencing', 'Var', (32, 52))
134027	20442802	Aberrant proliferation of normal melanocytes, presumably in response to UVR, could result in the formation of benign or dysplastic nevi.	('dysplastic nevi', 'Phenotype', 'HP:0001062', (120, 135))	('Aberrant', 'Var', (0, 8))	('formation', 'biological_process', 'GO:0009058', ('97', '106'))	('benign', 'Disease', (110, 116))	('nevi', 'Phenotype', 'HP:0003764', (131, 135))	('dysplastic', 'Disease', (120, 130))	('result in', 'Reg', (83, 92))	('dysplastic', 'Disease', 'MESH:D004416', (120, 130))
134034	20442802	Subsequent studies validated the role of RAS in melanoma biology because activating NRAS mutations are relatively common(26%) in sporadic melanoma.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Disease', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('NRAS', 'Gene', (84, 88))	('activating', 'PosReg', (73, 83))	('mutations', 'Var', (89, 98))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
134035	20442802	NRAS is capable of inducing melanoma in CDKN2A-deficient mice and has been shown to play a key role in melanoma maintenance in murine models.	('melanoma', 'Disease', (28, 36))	('mice', 'Species', '10090', (57, 61))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('NRAS', 'Var', (0, 4))	('murine', 'Species', '10090', (127, 133))	('inducing', 'Reg', (19, 27))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('melanoma', 'Disease', (103, 111))
134038	20442802	However, NRAS mutations appear to be at least as common in congenital nevi as in melanomas signifying that sun exposure is not necessary to induce the commonest NRAS mutations.	('common', 'Reg', (49, 55))	('melanomas', 'Disease', (81, 90))	('nevi', 'Phenotype', 'HP:0003764', (70, 74))	('congenital nevi', 'Disease', (59, 74))	('NRAS', 'Gene', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanomas', 'Phenotype', 'HP:0002861', (81, 90))	('melanomas', 'Disease', 'MESH:D008545', (81, 90))	('mutations', 'Var', (14, 23))
134039	20442802	Given the sheer prevalence of RAS mutations in human cancer, direct and efficacious inhibition of RAS would be an ideal therapeutic goal.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('RAS', 'Gene', (30, 33))	('human', 'Species', '9606', (47, 52))	('mutations', 'Var', (34, 43))
134042	20442802	identified V-Raf Murine Sarcoma Viral Oncogene Homolog B1(BRAF; gene map locus 7q34) somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('Sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('malignant melanomas', 'Disease', (122, 141))	('V-Raf Murine Sarcoma Viral Oncogene Homolog B1', 'Gene', '673', (11, 57))	('cancers', 'Disease', (190, 197))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('melanomas', 'Phenotype', 'HP:0002861', (132, 141))	('missense mutations', 'Var', (93, 111))	('human', 'Species', '9606', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('V-Raf Murine Sarcoma Viral Oncogene Homolog B1', 'Gene', (11, 57))	('malignant melanomas', 'Phenotype', 'HP:0002861', (122, 141))	('malignant melanoma', 'Phenotype', 'HP:0002861', (122, 140))	('malignant melanomas', 'Disease', 'MESH:D008545', (122, 141))
134044	20442802	RAS function is not required for the growth of cancer cell lines with the V600E mutation.	('V600E', 'Mutation', 'rs113488022', (74, 79))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('V600E', 'Var', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
134046	20442802	Mutagenic activation of the mitogen-activated protein kinase(MAPK) pathway is observed in up to 90% of melanomas and is most commonly achieved via mutations in NRAS or BRAF.	('mutations', 'Var', (147, 156))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))	('NRAS', 'Gene', (160, 164))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('achieved', 'Reg', (134, 142))	('melanomas', 'Disease', (103, 112))	('MAPK', 'molecular_function', 'GO:0004707', ('61', '65'))	('BRAF', 'Gene', (168, 172))	('melanomas', 'Disease', 'MESH:D008545', (103, 112))	('activation', 'PosReg', (10, 20))
134047	20442802	A large series reported that in 57.5% of the tumors either BRAF or NRAS were mutated with a higher incidence in metastatic (66.3%) than in primary lesions (50.9%).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('metastatic', 'Disease', (112, 122))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('mutated', 'Var', (77, 84))	('NRAS', 'Gene', (67, 71))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('BRAF', 'Gene', (59, 63))
134048	20442802	As BRAF mutations occur at such a high rate in melanomas, targeted approaches against BRAF V600E represent an ideal approach.	('V600E', 'Mutation', 'rs113488022', (91, 96))	('mutations', 'Var', (8, 17))	('melanomas', 'Disease', 'MESH:D008545', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('V600E', 'Var', (91, 96))	('BRAF', 'Gene', (3, 7))	('BRAF', 'Gene', (86, 90))	('melanomas', 'Disease', (47, 56))
134052	20442802	More specifically, high VEGF -R2 expression is associated with response to sorafenib, carboplatin, and paclitaxel combination treatment in melanoma, whereas high MEK expression is associated with resistance [Figure 1].	('VEGF -R2', 'Gene', '3791', (24, 32))	('MEK', 'Gene', '5609', (162, 165))	('high', 'Var', (19, 23))	('paclitaxel', 'Chemical', 'MESH:D017239', (103, 113))	('associated with', 'Reg', (47, 62))	('response', 'MPA', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('men', 'Species', '9606', (131, 134))	('melanoma', 'Disease', (139, 147))	('carboplatin', 'Chemical', 'MESH:D016190', (86, 97))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('sorafenib', 'Chemical', 'MESH:D000077157', (75, 84))	('MEK', 'Gene', (162, 165))	('VEGF -R2', 'Gene', (24, 32))	('expression', 'MPA', (33, 43))
134057	20442802	Recently, melanoma cell lines harboring BRAF mutations were found to be markedly more sensitive to MEK inhibition than lines with NRAS mutations.	('MEK', 'Gene', '5609', (99, 102))	('melanoma cell', 'Disease', (10, 23))	('mutations', 'Var', (45, 54))	('BRAF', 'Gene', (40, 44))	('melanoma cell', 'Disease', 'MESH:D008545', (10, 23))	('more', 'PosReg', (81, 85))	('sensitive', 'MPA', (86, 95))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('MEK', 'Gene', (99, 102))
134058	20442802	GSK1120212 is a potent and highly selective inhibitor of MEK activation and kinase activity.	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('MEK', 'Gene', '5609', (57, 60))	('kinase activity', 'molecular_function', 'GO:0016301', ('76', '91'))	('GSK1120212', 'Var', (0, 10))	('GSK1120212', 'Chemical', 'MESH:C560077', (0, 10))	('kinase', 'MPA', (76, 82))	('MEK', 'Gene', (57, 60))
134059	20442802	The objective response rate, safety, and pharmacokinetics of GSK1120212 in BRAF mutation-positive melanoma subjects previously treated with a BRAF inhibitor is under investigation (NCT01037127).	('GSK1120212', 'Var', (61, 71))	('GSK', 'molecular_function', 'GO:0050321', ('61', '64'))	('GSK1120212', 'Chemical', 'MESH:C560077', (61, 71))	('mutation-positive', 'Reg', (80, 97))	('BRAF', 'Gene', (75, 79))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))
134061	20442802	One of the best characterized targets of PI3K lipid products is the protein kinase AKT(PKB; V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOG 1; PROTEIN KINASE B-ALPHA; gene map locus 14q32.3).	('PI3K', 'molecular_function', 'GO:0016303', ('41', '45'))	('PI3K', 'Var', (41, 45))	('PROTEIN KINASE B-ALPHA', 'Gene', '11651', (139, 161))	('THYMOMA', 'Phenotype', 'HP:0100522', (105, 112))	('PROTEIN KINASE B-ALPHA', 'Gene', (139, 161))	('lipid', 'Chemical', 'MESH:D008055', (46, 51))	('MURINE', 'Species', '10090', (98, 104))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('AKT(PKB; V-AKT', 'Gene', '11651', (83, 97))
134062	20442802	Aziz et al., studied PI3K protein expression in 548 melanomas and 540 benign nevi and demonstrated that PI3K expression was higher in melanomas when compared to nevi, while it was significantly higher in those specimens from patients with metastases.	('melanomas', 'Disease', 'MESH:D008545', (52, 61))	('melanomas', 'Disease', (52, 61))	('melanomas', 'Phenotype', 'HP:0002861', (134, 143))	('PI3K', 'Var', (104, 108))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('men', 'Species', '9606', (215, 218))	('nevi', 'Phenotype', 'HP:0003764', (77, 81))	('metastases', 'Disease', 'MESH:D009362', (239, 249))	('higher', 'PosReg', (124, 130))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))	('patients', 'Species', '9606', (225, 233))	('melanomas', 'Disease', 'MESH:D008545', (134, 143))	('metastases', 'Disease', (239, 249))	('nevi', 'Phenotype', 'HP:0003764', (161, 165))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanomas', 'Disease', (134, 143))	('PI3K', 'molecular_function', 'GO:0016303', ('104', '108'))	('PI3K', 'molecular_function', 'GO:0016303', ('21', '25'))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))
134074	20442802	Another ongoing trial, examines whether nilotinib (Tasigna ) is more efficacious than dacarbazine in the treatment of metastatic inoperable melanomas harboring c-KIT mutations [Figure 1].	('nilotinib', 'Chemical', 'MESH:C498826', (40, 49))	('c-KIT', 'Gene', '3815', (160, 165))	('mutations', 'Var', (166, 175))	('melanomas', 'Disease', (140, 149))	('men', 'Species', '9606', (110, 113))	('dacarbazine', 'Chemical', 'MESH:D003606', (86, 97))	('KIT', 'molecular_function', 'GO:0005020', ('162', '165'))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('c-KIT', 'Gene', (160, 165))	('melanomas', 'Disease', 'MESH:D008545', (140, 149))
134077	20442802	It appears that mutations in CDKN2A, CDK4 and RB1 occur in a mutually exclusive manner.	('CDKN2A', 'Gene', (29, 35))	('CDK', 'molecular_function', 'GO:0004693', ('37', '40'))	('RB1', 'Gene', (46, 49))	('CDK4', 'Gene', (37, 41))	('mutations', 'Var', (16, 25))	('CDK4', 'Gene', '1019', (37, 41))	('RB1', 'Gene', '5925', (46, 49))
134087	20442802	CDKN2A expression changes were identified in the vast majority of melanomas through mutation, deletion or promoter hypermethylation of CDKN2A gene.	('CDKN2A', 'Gene', (135, 141))	('melanomas', 'Disease', 'MESH:D008545', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('deletion', 'Var', (94, 102))	('melanomas', 'Disease', (66, 75))	('promoter hypermethylation', 'Var', (106, 131))	('CDKN2A', 'Gene', (0, 6))	('changes', 'Reg', (18, 25))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('mutation', 'Var', (84, 92))
134088	20442802	CDKN2A harbors mutations in melanoma at dipyrimidine sites but many of these genetic alterations are not UVB signature mutations.	('melanoma', 'Disease', (28, 36))	('mutations', 'Var', (15, 24))	('CDKN2A', 'Gene', (0, 6))	('dipyrimidine', 'Chemical', '-', (40, 52))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
134091	20442802	Notably, hypermethylation of the CDKN2A promoter region has been shown to lead to loss of p16 expression in 19% of primary and 33% metastatic melanomas.	('p16', 'Gene', '1029', (90, 93))	('CDKN2A', 'Gene', (33, 39))	('melanomas', 'Disease', 'MESH:D008545', (142, 151))	('hypermethylation', 'Var', (9, 25))	('melanomas', 'Disease', (142, 151))	('p16', 'Gene', (90, 93))	('loss', 'NegReg', (82, 86))	('expression', 'MPA', (94, 104))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanomas', 'Phenotype', 'HP:0002861', (142, 151))
134101	20442802	Given that p16INK4A needs to directly interact with the cyclin-CDK complex in order to inhibit its protein kinase activity, changes in CDK4 that render it resistant to p16INK4A mimic p16INK4A loss [Figure 1].	('CDK4', 'Gene', '1019', (135, 139))	('p16INK4A', 'Gene', (11, 19))	('changes', 'Var', (124, 131))	('p16INK4A', 'Gene', (183, 191))	('inhibit', 'NegReg', (87, 94))	('CDK', 'molecular_function', 'GO:0004693', ('135', '138'))	('cyclin', 'Gene', (56, 62))	('p16INK4A', 'Gene', '1029', (11, 19))	('cyclin', 'molecular_function', 'GO:0016538', ('56', '62'))	('p16INK4A', 'Gene', '1029', (183, 191))	('CDK', 'molecular_function', 'GO:0004693', ('63', '66'))	('p16INK4A', 'Gene', (168, 176))	('loss', 'NegReg', (192, 196))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('p16INK4A', 'Gene', '1029', (168, 176))	('protein kinase activity', 'MPA', (99, 122))	('CDK4', 'Gene', (135, 139))	('protein kinase activity', 'molecular_function', 'GO:0004672', ('99', '122'))	('cyclin', 'Gene', '5111', (56, 62))
134102	20442802	In fact, both somatic and germline mutations in CDK4 have been detected in melanoma cell lines.	('detected', 'Reg', (63, 71))	('CDK4', 'Gene', '1019', (48, 52))	('CDK', 'molecular_function', 'GO:0004693', ('48', '51'))	('germline', 'Var', (26, 34))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma cell', 'Disease', (75, 88))	('CDK4', 'Gene', (48, 52))	('melanoma cell', 'Disease', 'MESH:D008545', (75, 88))
134103	20442802	P276-00 is a flavone that inhibits cyclin-dependent kinases, and has been recently proposed as a novel antineoplastic agent.	('inhibits', 'NegReg', (26, 34))	('flavone', 'Chemical', 'MESH:C043562', (13, 20))	('P276-00', 'Var', (0, 7))	('cyclin', 'molecular_function', 'GO:0016538', ('35', '41'))	('cyclin', 'Gene', '5111', (35, 41))	('cyclin', 'Gene', (35, 41))
134104	20442802	ENVER is an ongoing trial that evaluates the efficacy of P276-00 in subjects with advanced malignant melanoma positive for CCND1 expression.	('malignant melanoma', 'Disease', 'MESH:D008545', (91, 109))	('P276-00', 'Var', (57, 64))	('CCND1', 'Gene', '595', (123, 128))	('malignant melanoma', 'Disease', (91, 109))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('CCND1', 'Gene', (123, 128))	('malignant melanoma', 'Phenotype', 'HP:0002861', (91, 109))
134109	20442802	Amplification or overexpression of CCND1 plays pivotal roles in the development of several human cancers, including parathyroid adenoma, breast cancer, colon cancer, lymphoma, melanoma, and prostate cancer.	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))	('parathyroid adenoma', 'Disease', (116, 135))	('CCND1', 'Gene', '595', (35, 40))	('colon cancer', 'Phenotype', 'HP:0003003', (152, 164))	('CCND1', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('parathyroid adenoma', 'Disease', 'MESH:D010282', (116, 135))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lymphoma', 'Phenotype', 'HP:0002665', (166, 174))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('colon cancer', 'Disease', 'MESH:D015179', (152, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('prostate cancer', 'Disease', 'MESH:D011471', (190, 205))	('overexpression', 'PosReg', (17, 31))	('prostate cancer', 'Phenotype', 'HP:0012125', (190, 205))	('roles', 'Reg', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('Amplification', 'Var', (0, 13))	('breast cancer', 'Disease', (137, 150))	('prostate cancer', 'Disease', (190, 205))	('colon cancer', 'Disease', (152, 164))	('men', 'Species', '9606', (75, 78))	('lymphoma', 'Disease', (166, 174))	('lymphoma', 'Disease', 'MESH:D008223', (166, 174))	('parathyroid adenoma', 'Phenotype', 'HP:0002897', (116, 135))	('human', 'Species', '9606', (91, 96))
134110	20442802	Oncogenic RAS has been shown to positively impact the cell cycle by upregulating CCND1 through MAPK signaling thereby serving as a link between the MAPK and p16-cyclin D/CDK4-RB pathways [Figure 1].	('upregulating', 'PosReg', (68, 80))	('impact', 'Reg', (43, 49))	('RB', 'Gene', '5925', (175, 177))	('CCND1', 'Gene', '595', (81, 86))	('cyclin', 'Gene', (161, 167))	('Oncogenic RAS', 'Var', (0, 13))	('CDK4', 'Gene', (170, 174))	('CCND1', 'Gene', (81, 86))	('MAPK signaling', 'MPA', (95, 109))	('CDK4', 'Gene', '1019', (170, 174))	('cell cycle', 'biological_process', 'GO:0007049', ('54', '64'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('95', '109'))	('MAPK', 'molecular_function', 'GO:0004707', ('95', '99'))	('cyclin', 'molecular_function', 'GO:0016538', ('161', '167'))	('CDK', 'molecular_function', 'GO:0004693', ('170', '173'))	('cell cycle', 'CPA', (54, 64))	('MAPK', 'molecular_function', 'GO:0004707', ('148', '152'))	('p16', 'Gene', (157, 160))	('cyclin', 'Gene', '5111', (161, 167))	('p16', 'Gene', '1029', (157, 160))
134111	20442802	CCND1 amplifications were noted to occur more frequently on melanomas that arose on skin with chronic sun-induced damage, a subtype that rarely possesses BRAF or NRAS mutations.	('melanomas', 'Disease', (60, 69))	('amplifications', 'Var', (6, 20))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanomas', 'Disease', 'MESH:D008545', (60, 69))	('CCND1', 'Gene', (0, 5))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('CCND1', 'Gene', '595', (0, 5))
134114	20442802	PTEN (PHOSPHATASE AND TENSIN HOMOLOG; gene map locus 10q23.31) was one of the putative TSGs on Chromosome 10 and had been shown to be mutated in gliomas, breast, prostate, and kidney cancers and melanomas.	('melanomas', 'Disease', (195, 204))	('PHOSPHATASE AND TENSIN HOMOLOG', 'Gene', (6, 36))	('kidney cancers', 'Disease', 'MESH:D007680', (176, 190))	('kidney cancers', 'Disease', (176, 190))	('Chromosome', 'cellular_component', 'GO:0005694', ('95', '105'))	('PHOSPHATASE AND TENSIN HOMOLOG', 'cellular_component', 'GO:1990455', ('6', '36'))	('PHOSPHATASE AND TENSIN HOMOLOG', 'Gene', '5728', (6, 36))	('gliomas', 'Disease', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('kidney cancers', 'Phenotype', 'HP:0009726', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('melanomas', 'Phenotype', 'HP:0002861', (195, 204))	('breast', 'Disease', (154, 160))	('gliomas', 'Disease', 'MESH:D005910', (145, 152))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('PTEN', 'Gene', (0, 4))	('prostate', 'Disease', (162, 170))	('gliomas', 'Phenotype', 'HP:0009733', (145, 152))	('mutated', 'Var', (134, 141))	('melanomas', 'Disease', 'MESH:D008545', (195, 204))	('PHOSPHATASE', 'molecular_function', 'GO:0016791', ('6', '17'))	('PTEN', 'Gene', '5728', (0, 4))
134115	20442802	PTEN mutations have been identified at overall frequencies of > 10% in uncultured melanomas and 30-50% in cell lines.	('melanomas', 'Disease', (82, 91))	('melanomas', 'Disease', 'MESH:D008545', (82, 91))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
134116	20442802	PTEN is a negative regulator of the PI3K signaling pathway and inactivation of PTEN by deletion or mutation leads to constitutive activation of this pathway [Figure 1].	('inactivation', 'NegReg', (63, 75))	('activation', 'PosReg', (130, 140))	('constitutive', 'MPA', (117, 129))	('mutation', 'Var', (99, 107))	('PTEN', 'Gene', (0, 4))	('signaling pathway', 'biological_process', 'GO:0007165', ('41', '58'))	('PI3K signaling', 'biological_process', 'GO:0014065', ('36', '50'))	('PI3K signaling pathway', 'Pathway', (36, 58))	('PI3K', 'molecular_function', 'GO:0016303', ('36', '40'))	('deletion', 'Var', (87, 95))	('PTEN', 'Gene', (79, 83))	('PTEN', 'Gene', '5728', (0, 4))	('PTEN', 'Gene', '5728', (79, 83))
134117	20442802	PTEN mutations are found only rarely in primary melanomas, suggesting that activation of the PI3K pathway may be responsible for the late processes in melanoma development, mainly invasion and metastasis.	('melanoma', 'Disease', (48, 56))	('PI3K pathway', 'Pathway', (93, 105))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('PI3K', 'molecular_function', 'GO:0016303', ('93', '97'))	('activation', 'PosReg', (75, 85))	('metastasis', 'CPA', (193, 203))	('mutations', 'Var', (5, 14))	('melanomas', 'Disease', (48, 57))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('men', 'Species', '9606', (167, 170))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))
134119	20442802	PTEN mutations were found in 56% of the melanomas, and 91% of the melanomas with mutations had one to four UVB-signature mutations.	('melanomas', 'Disease', 'MESH:D008545', (66, 75))	('melanomas', 'Disease', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('mutations', 'Var', (5, 14))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('melanomas', 'Disease', (66, 75))	('melanomas', 'Disease', 'MESH:D008545', (40, 49))	('PTEN', 'Gene', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('PTEN', 'Gene', '5728', (0, 4))
134121	20442802	PTEN has been identified as a likely target for epigenetic silencing, because its expression is lost or decreased in up to 50% of melanomas, even in the absence of demonstrable mutations.	('melanomas', 'Disease', (130, 139))	('expression', 'MPA', (82, 92))	('epigenetic silencing', 'Var', (48, 68))	('lost', 'NegReg', (96, 100))	('decreased', 'NegReg', (104, 113))	('melanomas', 'Phenotype', 'HP:0002861', (130, 139))	('melanomas', 'Disease', 'MESH:D008545', (130, 139))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
134122	20442802	DNMT inhibitors can be used to target this type of epigenetic silencing.	('DNMT', 'Gene', '1786', (0, 4))	('epigenetic silencing', 'Var', (51, 71))	('DNMT', 'Gene', (0, 4))
134126	20442802	Disruption of the canonical Wnt pathway abrogated growth of melanoma cells, and constitutive overexpression of MITF rescued the growth suppression.	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('canonical Wnt pathway', 'Pathway', (18, 39))	('abrogated', 'NegReg', (40, 49))	('melanoma cell', 'Disease', (60, 73))	('MITF', 'Gene', '4286', (111, 115))	('MITF', 'Gene', (111, 115))	('melanoma cell', 'Disease', 'MESH:D008545', (60, 73))	('growth', 'MPA', (128, 134))	('Disruption', 'Var', (0, 10))
134130	20442802	The frequency of p53 mutations in melanoma derived specimens is reported to be 5-25% which is relatively low compared with many other cancers, and may be explained by the frequent loss of p14ARF in melanoma through CDKN2A mutations and deletions.	('deletions', 'Var', (236, 245))	('loss', 'NegReg', (180, 184))	('p53', 'Gene', (17, 20))	('p14ARF', 'Gene', (188, 194))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('cancers', 'Disease', (134, 141))	('melanoma', 'Disease', (198, 206))	('melanoma', 'Disease', (34, 42))	('mutations', 'Var', (222, 231))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('CDKN2A', 'Gene', (215, 221))	('men', 'Species', '9606', (56, 59))	('mutations', 'Var', (21, 30))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('p14ARF', 'Gene', '1029', (188, 194))
134133	20442802	In the presence of cytochrome C and dATP, APAF1 assembles into an oligomeric apoptosome, which is responsible for activation of procaspase-9 and maintenance of the enzymatic activity of processed caspase-9.	('activation', 'PosReg', (114, 124))	('ATP', 'Chemical', 'MESH:D000255', (37, 40))	('APAF1', 'Gene', '317', (42, 47))	('caspase-9', 'Gene', (131, 140))	('cytochrome C', 'molecular_function', 'GO:0045155', ('19', '31'))	('apoptosome', 'cellular_component', 'GO:0043293', ('77', '87'))	('cytochrome C', 'Gene', (19, 31))	('caspase-9', 'Gene', '842', (196, 205))	('cytochrome C', 'molecular_function', 'GO:0009461', ('19', '31'))	('caspase-9', 'Gene', '842', (131, 140))	('cytochrome C', 'Gene', '54205', (19, 31))	('dATP', 'Var', (36, 40))	('caspase-9', 'Gene', (196, 205))	('APAF1', 'Gene', (42, 47))
134150	20442802	Experimental data have shown that antisense suppression of Bcl-2 led to decreased melanoma cell survival and increased sensitivity to chemotherapy.	('Bcl-2', 'molecular_function', 'GO:0015283', ('59', '64'))	('sensitivity to chemotherapy', 'MPA', (119, 146))	('increased', 'PosReg', (109, 118))	('melanoma cell', 'Disease', 'MESH:D008545', (82, 95))	('decreased', 'NegReg', (72, 81))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('Bcl-2', 'Gene', (59, 64))	('melanoma cell', 'Disease', (82, 95))	('Bcl-2', 'Gene', '596', (59, 64))	('antisense suppression', 'Var', (34, 55))	('men', 'Species', '9606', (6, 9))
134157	20442802	Alternative splicing resulted in two distinct Bcl-X mRNAs.	('resulted in', 'Reg', (21, 32))	('Bcl-X', 'Gene', (46, 51))	('Bcl-X', 'Gene', '598', (46, 51))	('Alternative splicing', 'Var', (0, 20))	('splicing', 'biological_process', 'GO:0045292', ('12', '20'))
134171	20442802	Although Mcl-1 inhibitors may generally increase tumor-cell sensitivity to a variety of traditional chemotherapeutic agents, their unique relationship with the proteasome inhibitor class of chemotherapeutic agents may prove especially beneficial.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('increase', 'PosReg', (40, 48))	('tumor', 'Disease', (49, 54))	('Mcl-1', 'Gene', '4170', (9, 14))	('proteasome', 'cellular_component', 'GO:0000502', ('160', '170'))	('inhibitors', 'Var', (15, 25))	('proteasome', 'molecular_function', 'GO:0004299', ('160', '170'))	('Mcl-1', 'Gene', (9, 14))
134177	20442802	Similarly, transduction of ectopic c-Myc into melanoma cells led to increased response to lower doses of bortezomib and enhanced the extent of cell death by twofold.	('bortezomib', 'Chemical', 'MESH:D000069286', (105, 115))	('cell death', 'biological_process', 'GO:0008219', ('143', '153'))	('c-Myc', 'Gene', '4609', (35, 40))	('transduction', 'biological_process', 'GO:0009293', ('11', '23'))	('enhanced', 'PosReg', (120, 128))	('response to lower doses of', 'MPA', (78, 104))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma cell', 'Disease', (46, 59))	('cell death', 'CPA', (143, 153))	('c-Myc', 'Gene', (35, 40))	('ectopic', 'Var', (27, 34))	('transduction', 'Var', (11, 23))	('melanoma cell', 'Disease', 'MESH:D008545', (46, 59))	('increased', 'PosReg', (68, 77))
134199	20442802	Deregulated expression of MYC caused by gene amplification, retroviral insertion or chromosomal translocation is associated with carcinogenesis.	('Deregulated', 'Var', (0, 11))	('associated', 'Reg', (113, 123))	('MYC', 'Gene', '4609', (26, 29))	('carcinogenesis', 'Disease', 'MESH:D063646', (129, 143))	('gene amplification', 'Var', (40, 58))	('carcinogenesis', 'Disease', (129, 143))	('MYC', 'Gene', (26, 29))	('retroviral insertion', 'Var', (60, 80))	('expression', 'MPA', (12, 22))	('chromosomal translocation', 'Var', (84, 109))
134232	20442802	The unambiguous importance of the MC1R variants towards the population burden of melanoma which have been reported to differ among the investigated populations have motivated an ongoing clinical trial.	('MC1R', 'Gene', (34, 38))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('variants', 'Var', (39, 47))
134233	20442802	Based on the finding that genetic variants of the melanocortin-1 receptor(MC1R) gene, associated with red hair and fair skin, have been shown to be associated with increased risk for melanoma, particularly those harboring BRAF mutations, the investigators intend to focus on the study of recently discovered genetic variants associated with pigmentation.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanocortin-1 receptor', 'Gene', '4157', (50, 73))	('melanoma', 'Disease', (183, 191))	('variants', 'Var', (34, 42))	('fair skin', 'Phenotype', 'HP:0007513', (115, 124))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('pigmentation', 'biological_process', 'GO:0043473', ('341', '353'))	('fair skin', 'Disease', (115, 124))	('associated', 'Reg', (86, 96))	('pigmentation', 'Disease', 'MESH:D010859', (341, 353))	('red hair', 'Disease', (102, 110))	('pigmentation', 'Disease', (341, 353))	('associated', 'Reg', (148, 158))	('red hair', 'Phenotype', 'HP:0002297', (102, 110))	('red hair', 'Disease', 'MESH:C567091', (102, 110))	('melanocortin-1 receptor', 'Gene', (50, 73))
134234	20442802	Furthermore, the investigators will study the relation of these variants with oncogenic mutations of melanoma in BRAF, RAS and KIT.	('KIT', 'molecular_function', 'GO:0005020', ('127', '130'))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('variants', 'Var', (64, 72))
134248	20442802	Gudbjartson et al., reported an SNP located near the TYRP1 (TYROSINASE-RELATED PROTEIN 1; TYRP; gene map locus 9p23) gene locus to be associated with an increased risk for melanoma.	('associated with', 'Reg', (134, 149))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('TYROSINASE-RELATED PROTEIN 1', 'Gene', (60, 88))	('TYRP1', 'Gene', (53, 58))	('TYRP1', 'Gene', '7306', (53, 58))	('TYRP', 'Gene', '7306', (53, 57))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('TYROSINASE-RELATED PROTEIN 1', 'Gene', '7306', (60, 88))	('TYRP', 'Gene', (90, 94))	('SNP located', 'Var', (32, 43))	('TYRP', 'Gene', (53, 57))	('melanoma', 'Disease', (172, 180))	('TYRP', 'Gene', '7306', (90, 94))
134250	20442802	The variants in MC1R, ASIP, TYR and TYRP1 have been identified as independent low-penetrance susceptibility factors, but little is known about the combined risk of two or more factors.	('variants', 'Var', (4, 12))	('TYR', 'Chemical', 'MESH:D014443', (36, 39))	('ASIP', 'Gene', '434', (22, 26))	('TYRP1', 'Gene', (36, 41))	('TYRP1', 'Gene', '7306', (36, 41))	('ASIP', 'Gene', (22, 26))	('MC1R', 'Gene', (16, 20))	('TYR', 'Chemical', 'MESH:D014443', (28, 31))	('TYR', 'Var', (28, 31))
134251	20442802	Low-penetrance genes are associated with only a small increase in risk but contribute to the complex interrelation between pigmentation and sun-sensitivity phenotypes that interact with exposure to UV light to affect predisposition to melanoma.	('genes', 'Var', (15, 20))	('affect', 'Reg', (210, 216))	('pigmentation', 'Disease', (123, 135))	('pigmentation', 'biological_process', 'GO:0043473', ('123', '135'))	('predisposition', 'MPA', (217, 231))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('melanoma', 'Disease', (235, 243))	('melanoma', 'Disease', 'MESH:D008545', (235, 243))	('Low-penetrance genes', 'Var', (0, 20))	('pigmentation', 'Disease', 'MESH:D010859', (123, 135))	('sun-sensitivity', 'Phenotype', 'HP:0000992', (140, 155))
134253	20442802	As time passes, such changes could add up to transform melanocyte precursors to malignant melanoma stem cells [Figure 2].	('malignant melanoma', 'Phenotype', 'HP:0002861', (80, 98))	('changes', 'Var', (21, 28))	('malignant melanoma', 'Disease', (80, 98))	('transform', 'Reg', (45, 54))	('melanocyte precursors', 'CPA', (55, 76))	('malignant melanoma', 'Disease', 'MESH:D008545', (80, 98))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
134328	18042295	It was also used to compare results of 28SC incubated with conditioned medium from COX-2 transfected versus non-COX-2 transfected melanoma cell lines as well as 28SC incubated with conditioned medium from these cell lines with and without amfenac.	('amfenac', 'Chemical', 'MESH:C014285', (239, 246))	('COX-2', 'Gene', '5743', (83, 88))	('transfected', 'Var', (89, 100))	('COX-2', 'Gene', (112, 117))	('COX-2', 'Gene', '5743', (112, 117))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Disease', (130, 138))	('COX-2', 'Gene', (83, 88))
134330	18042295	All uveal melanoma cell lines were positive for COX-2 expression following transfection, with no apparent difference in expression between the five transfected cell lines.	('expression', 'MPA', (54, 64))	('uveal melanoma cell lines', 'Disease', 'MESH:C536494', (4, 29))	('COX-2', 'Gene', '5743', (48, 53))	('uveal melanoma cell lines', 'Disease', (4, 29))	('uveal melanoma', 'Phenotype', 'HP:0007716', (4, 18))	('transfection', 'Var', (75, 87))	('positive', 'Reg', (35, 43))	('COX-2', 'Gene', (48, 53))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))
134342	18042295	The addition of conditioned medium from the COX-2 transfected UW-1 cell line also yielded a significant decrease in NO production (P < 0.0006) as compared to MCM from the non-transfected UW-1 cell line.	('NO production', 'MPA', (116, 129))	('COX-2', 'Gene', (44, 49))	('decrease', 'NegReg', (104, 112))	('transfected', 'Var', (50, 61))	('COX-2', 'Gene', '5743', (44, 49))
134353	18042295	The present study showed that COX-2 transfected human uveal melanoma cell lines had a higher proliferation rate compared to their non-transfected counterparts with the exception of OCM-1.	('proliferation rate', 'CPA', (93, 111))	('human', 'Species', '9606', (48, 53))	('OCM-1', 'Species', '83984', (181, 186))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('COX-2', 'Gene', (30, 35))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('uveal melanoma cell lines', 'Disease', 'MESH:C536494', (54, 79))	('uveal melanoma cell lines', 'Disease', (54, 79))	('transfected', 'Var', (36, 47))	('higher', 'PosReg', (86, 92))	('COX-2', 'Gene', '5743', (30, 35))
134356	18042295	It is interesting to note that using the Sulforhodamine-B assay a decrease in proliferation was seen for OCM-1 transfected with COX-2, however a small increase in SPF% was seen when analyzed by flow cytometry.	('OCM-1', 'Species', '83984', (105, 110))	('Sulforhodamine-B', 'Chemical', 'MESH:C022027', (41, 57))	('COX-2', 'Gene', (128, 133))	('COX-2', 'Gene', '5743', (128, 133))	('transfected', 'Var', (111, 122))	('SPF%', 'Gene', (163, 167))	('proliferation', 'CPA', (78, 91))	('OCM-1', 'Gene', (105, 110))	('decrease', 'NegReg', (66, 74))	('SPF%', 'Gene', '23541', (163, 167))
134377	18042295	The addition of amfenac not only affected macrophages exposed to medium from COX-2 transfected cells, but also macrophages exposed to medium from non-transfected cells.	('affected', 'Reg', (33, 41))	('transfected', 'Var', (83, 94))	('COX-2', 'Gene', (77, 82))	('COX-2', 'Gene', '5743', (77, 82))	('amfenac', 'Chemical', 'MESH:C014285', (16, 23))
134379	18042295	COX-2 inhibitors show promise for use as an adjuvant therapy in many tumor types.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('inhibitors', 'Var', (6, 16))	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
134385	18042295	In addition, amfenac partially overcame the suppression of macrophage function by conditioned medium from both COX-2 transfected and non-transfected uveal melanoma cell lines.	('transfected', 'Var', (117, 128))	('COX-2', 'Gene', (111, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (149, 163))	('amfenac', 'Chemical', 'MESH:C014285', (13, 20))	('COX-2', 'Gene', '5743', (111, 116))	('uveal melanoma cell lines', 'Disease', (149, 174))	('uveal melanoma cell lines', 'Disease', 'MESH:C536494', (149, 174))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))
134387	33076392	Genetic Alterations in the INK4a/ARF Locus: Effects on Melanoma Development and Progression Genetic alterations in the INK4a/ARF (or CDKN2A) locus have been reported in many cancer types, including melanoma; head and neck squamous cell carcinomas; lung, breast, and pancreatic cancers.	('Melanoma', 'Disease', 'MESH:D008545', (55, 63))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (222, 246))	('lung', 'Disease', (248, 252))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (266, 283))	('INK4a/ARF', 'Gene', '1029', (27, 36))	('cancer', 'Disease', (277, 283))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('cancer', 'Disease', (174, 180))	('Melanoma', 'Disease', (55, 63))	('neck', 'cellular_component', 'GO:0044326', ('217', '221'))	('INK4a/ARF', 'Gene', (27, 36))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (208, 246))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (266, 284))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('neck squamous cell carcinomas', 'Disease', (217, 246))	('INK4a/ARF', 'Gene', '1029', (119, 128))	('Melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('pancreatic cancers', 'Disease', (266, 284))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('carcinomas', 'Phenotype', 'HP:0030731', (236, 246))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (217, 246))	('breast', 'Disease', (254, 260))	('reported', 'Reg', (157, 165))	('pancreatic cancers', 'Disease', 'MESH:D010190', (266, 284))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('INK4a/ARF', 'Gene', (119, 128))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('Effects', 'Reg', (44, 51))	('alterations', 'Var', (100, 111))
134388	33076392	In melanoma, loss of function CDKN2A alterations have been identified in approximately 50% of primary melanomas, in over 75% of metastatic melanomas, and in the germline of 40% of families with a predisposition to cutaneous melanoma.	('melanomas', 'Disease', 'MESH:D008545', (139, 148))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('cutaneous melanoma', 'Disease', (214, 232))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (214, 232))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (214, 232))	('alterations', 'Var', (37, 48))	('melanomas', 'Disease', (139, 148))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('melanoma', 'Disease', 'MESH:D008545', (224, 232))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('melanomas', 'Phenotype', 'HP:0002861', (139, 148))	('melanomas', 'Disease', 'MESH:D008545', (102, 111))	('loss of function', 'NegReg', (13, 29))	('melanomas', 'Disease', (102, 111))	('CDKN2A', 'Gene', (30, 36))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('melanoma', 'Disease', (224, 232))
134390	33076392	The majority of CDKN2A alterations in melanoma selectively target p16INK4a or affect the coding sequence of both p16INK4a and p14ARF.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('p14ARF', 'Gene', (126, 132))	('CDKN2A', 'Gene', (16, 22))	('affect', 'Reg', (78, 84))	('alterations', 'Var', (23, 34))	('coding sequence', 'MPA', (89, 104))	('p14ARF', 'Gene', '1029', (126, 132))	('target', 'Reg', (59, 65))	('p16INK4a', 'Var', (113, 121))	('melanoma', 'Disease', (38, 46))	('p16INK4a', 'Protein', (66, 74))
134391	33076392	There is also a subset of less common somatic and germline INK4a/ARF alterations that affect p14ARF, while not altering the syntenic p16INK4a coding regions.	('affect', 'Reg', (86, 92))	('alterations', 'Var', (69, 80))	('INK4a/ARF', 'Gene', '1029', (59, 68))	('p14ARF', 'Gene', '1029', (93, 99))	('INK4a/ARF', 'Gene', (59, 68))	('p14ARF', 'Gene', (93, 99))
134392	33076392	In this review, we describe the frequency and types of somatic alterations affecting the CDKN2A locus in melanoma and germline CDKN2A alterations in familial melanoma, and their functional consequences in melanoma development.	('alterations', 'Var', (63, 74))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (205, 213))	('melanoma', 'Disease', (105, 113))	('familial melanoma', 'Disease', (149, 166))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('familial melanoma', 'Disease', 'MESH:C562393', (149, 166))	('CDKN2A', 'Gene', (89, 95))	('alterations', 'Var', (134, 145))	('CDKN2A', 'Gene', (127, 133))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (158, 166))
134395	33076392	The transformation of melanocytes into melanoma, termed melanomagenesis, involves the sequential selection of genetic and epigenetic alterations that promote proliferation, invasion, and immune escape.	('invasion', 'CPA', (173, 181))	('promote', 'PosReg', (150, 157))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('transformation of melanocytes', 'Phenotype', 'HP:0002861', (4, 33))	('immune escape', 'CPA', (187, 200))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('epigenetic alterations', 'Var', (122, 144))	('proliferation', 'CPA', (158, 171))
134396	33076392	Cutaneous melanoma has the highest median coding mutation rate of any cancer type (14.4 coding mutations per megabase) and this reflects the high proportion of ultraviolet (UV)-induced C>T substitutions that occur at pyrimidines.	('pyrimidines', 'Chemical', 'MESH:D011743', (217, 228))	('C>T substitutions', 'Var', (185, 202))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('coding mutation', 'MPA', (42, 57))	('Cutaneous melanoma', 'Disease', (0, 18))
134400	33076392	This is one of the most commonly altered sequences in cancer and is mutated, deleted, or methylated in 40-70% of sporadic melanomas.	('sporadic melanomas', 'Disease', (113, 131))	('methylated', 'Var', (89, 99))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('deleted', 'Var', (77, 84))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('sporadic melanomas', 'Disease', 'MESH:D008545', (113, 131))
134403	33076392	p16INK4a forms binary complexes with the cyclin-dependent kinases 4 and 6 (CDK4/6) to inhibit cyclin D-CDK4/6-mediated phosphorylation of the retinoblastoma protein and, thus, prevents G1 to S phase cell cycle transition.	('p16INK4a', 'Var', (0, 8))	('cyclin', 'molecular_function', 'GO:0016538', ('41', '47'))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('S phase', 'biological_process', 'GO:0051320', ('191', '198'))	('inhibit', 'NegReg', (86, 93))	('cyclin', 'Gene', (41, 47))	('retinoblastoma', 'Phenotype', 'HP:0009919', (142, 156))	('cell cycle transition', 'biological_process', 'GO:0044771', ('199', '220'))	('cyclin', 'Gene', '5111', (94, 100))	('G1 to S phase cell cycle transition', 'CPA', (185, 220))	('retinoblastoma', 'Disease', (142, 156))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('cyclin', 'Gene', (94, 100))	('CDK', 'molecular_function', 'GO:0004693', ('75', '78'))	('CDK', 'molecular_function', 'GO:0004693', ('103', '106'))	('prevents', 'NegReg', (176, 184))	('complexes', 'Interaction', (22, 31))	('retinoblastoma', 'Disease', 'MESH:D012175', (142, 156))	('cyclin-dependent kinases 4 and 6', 'Gene', '1019;1021', (41, 73))	('cell cycle transition', 'biological_process', 'GO:0044770', ('199', '220'))	('cyclin', 'Gene', '5111', (41, 47))	('cyclin', 'molecular_function', 'GO:0016538', ('94', '100'))
134405	33076392	In this review, we examine genetic alterations affecting the CDKN2A locus in melanoma, the functional impact of altered CDKN2A, and the contribution of this locus to melanoma development and progression.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('CDKN2A', 'Gene', (61, 67))	('CDKN2A', 'Gene', (120, 126))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('altered', 'Var', (112, 119))
134407	33076392	Inactivation of the CDKN2A locus has been detected in approximately 50% of primary melanomas and over 75% of metastatic melanomas.	('melanomas', 'Disease', (120, 129))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('melanomas', 'Disease', 'MESH:D008545', (120, 129))	('melanomas', 'Disease', (83, 92))	('CDKN2A', 'Gene', (20, 26))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanomas', 'Phenotype', 'HP:0002861', (120, 129))	('melanomas', 'Disease', 'MESH:D008545', (83, 92))	('Inactivation', 'Var', (0, 12))	('detected', 'Reg', (42, 50))
134408	33076392	The majority of CDKN2A alterations in melanoma selectively target p16INK4a or affect the coding sequences of both p16INK4a and p14ARF.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('p14ARF', 'Gene', '1029', (127, 133))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('CDKN2A', 'Gene', (16, 22))	('coding sequences', 'MPA', (89, 105))	('p14ARF', 'Gene', (127, 133))	('p16INK4a', 'Var', (114, 122))	('affect', 'Reg', (78, 84))	('alterations', 'Var', (23, 34))	('target', 'Reg', (59, 65))	('melanoma', 'Disease', (38, 46))	('p16INK4a', 'Protein', (66, 74))
134409	33076392	Somatic CDKN2A alterations that solely affect p14ARF without compromising the syntenic p16INK4a coding region are rare.	('p14ARF', 'Gene', (46, 52))	('CDKN2A', 'Gene', (8, 14))	('affect', 'Reg', (39, 45))	('p14ARF', 'Gene', '1029', (46, 52))	('alterations', 'Var', (15, 26))
134410	33076392	For example, analysis of the mutation spectrum of primary and metastatic cutaneous melanoma in The Cancer Genome Atlas (TCGA) (n = 363, data derived through the Memorial Sloan Kettering Cancer Center cBioPortal for Cancer Genomics identified CDKN2A genetic alterations in approximately 45% (162/363) of melanoma cases; these included missense mutations (21/363, 5.8%), truncating mutations (34/363, 9.4%), in-frame deletions (2/363, 0.6%), amplifications (1/363, 0.3%), and homozygous deletions (112/363, 30.8%).	('melanoma', 'Phenotype', 'HP:0002861', (303, 311))	('melanoma', 'Disease', 'MESH:D008545', (303, 311))	('CDKN2A', 'Gene', (242, 248))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('Cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cutaneous melanoma', 'Disease', (73, 91))	('truncating', 'MPA', (369, 379))	('in-frame deletions', 'Var', (406, 424))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('amplifications', 'Var', (440, 454))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (73, 91))	('melanoma', 'Disease', (303, 311))	('missense mutations', 'Var', (334, 352))	('Cancer', 'Phenotype', 'HP:0002664', (186, 192))	('alterations', 'Reg', (257, 268))	('melanoma', 'Disease', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
134411	33076392	Almost 43% of the missense, truncating, and in-frame mutations specifically affected p16INK4a, 57% affected both p14ARF and p16INK4a, and mutations that altered p14ARF alone were not observed.	('p14ARF', 'Gene', (113, 119))	('p14ARF', 'Gene', (161, 167))	('missense', 'Var', (18, 26))	('mutations', 'Var', (53, 62))	('affected', 'Reg', (99, 107))	('p16INK4a', 'Gene', (85, 93))	('truncating', 'MPA', (28, 38))	('affected', 'Reg', (76, 84))	('p14ARF', 'Gene', '1029', (113, 119))	('p14ARF', 'Gene', '1029', (161, 167))
134412	33076392	It is worth noting that alterations that appear to specifically alter one of the CDKN2A-encoded proteins may impact the co-ordinated regulation of p14ARF and/or p16INK4a.	('alterations', 'Var', (24, 35))	('p16INK4a', 'Var', (161, 169))	('impact', 'Reg', (109, 115))	('CDKN2A-encoded', 'Gene', (81, 95))	('alter', 'Reg', (64, 69))	('p14ARF', 'Gene', (147, 153))	('regulation', 'biological_process', 'GO:0065007', ('133', '143'))	('co-ordinated regulation', 'MPA', (120, 143))	('p14ARF', 'Gene', '1029', (147, 153))
134413	33076392	These mutation frequencies are consistent with previous reports and confirm that homozygous CDKN2A deletions are the most common alterations affecting this locus in melanoma (reviewed in reference).	('CDKN2A', 'Gene', (92, 98))	('deletions', 'Var', (99, 108))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
134414	33076392	Promoter hypermethylation of CDKN2A leading to transcription silencing and loss of protein expression increases during melanoma progression and has been identified in approximately 19-60% of vertical-growth-phase melanomas, 40% of radial-growth-phase melanomas, and 25-33% of melanoma metastases.	('protein expression', 'MPA', (83, 101))	('identified', 'Reg', (153, 163))	('melanomas', 'Disease', (251, 260))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('melanomas', 'Phenotype', 'HP:0002861', (213, 222))	('Promoter hypermethylation', 'Var', (0, 25))	('transcription', 'MPA', (47, 60))	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('melanoma', 'Disease', (276, 284))	('vertical-growth-phase', 'CPA', (191, 212))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('loss', 'NegReg', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('melanoma', 'Disease', (251, 259))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('melanoma', 'Disease', (213, 221))	('melanomas', 'Phenotype', 'HP:0002861', (251, 260))	('melanoma metastases', 'Disease', 'MESH:D009362', (276, 295))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('transcription', 'biological_process', 'GO:0006351', ('47', '60'))	('melanomas', 'Disease', 'MESH:D008545', (213, 222))	('increases', 'PosReg', (102, 111))	('melanoma metastases', 'Disease', (276, 295))	('CDKN2A', 'Gene', (29, 35))	('melanomas', 'Disease', (213, 222))	('melanoma', 'Disease', 'MESH:D008545', (276, 284))	('melanoma', 'Disease', 'MESH:D008545', (251, 259))	('melanoma', 'Disease', 'MESH:D008545', (213, 221))	('melanomas', 'Disease', 'MESH:D008545', (251, 260))
134416	33076392	In this study, only 16/60 (27%) metastases displayed p16INK4a promoter methylation and seven of these tumors showed concurrent methylation on both the p16INK4a and p14ARF promoters.	('methylation', 'Var', (71, 82))	('p16INK4a', 'Gene', (53, 61))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('metastases', 'Disease', (32, 42))	('p14ARF', 'Gene', (164, 170))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('methylation', 'biological_process', 'GO:0032259', ('127', '138'))	('metastases', 'Disease', 'MESH:D009362', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('p14ARF', 'Gene', '1029', (164, 170))
134417	33076392	Intriguingly, the epigenetic modifications affecting p14ARF and p16INK4a may vary in melanoma, with 5' CpG promoter hypermethylation reported to be predominant in p16INK4a gene inactivation, whereas histone hypoacetylation is more commonly associated with p14ARF gene silencing.	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('p14ARF', 'Gene', '1029', (256, 262))	('p14ARF', 'Gene', '1029', (53, 59))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('p16INK4a', 'Var', (163, 171))	('melanoma', 'Disease', (85, 93))	('gene silencing', 'biological_process', 'GO:0016458', ('263', '277'))	('inactivation', 'NegReg', (177, 189))	('p14ARF', 'Gene', (256, 262))	('p14ARF', 'Gene', (53, 59))
134418	33076392	In the TCGA cohort, methylation of three CpG islands in the p16INK4a exon 1alpha [cg12840719, cg13601799, cg04026675] and five CpG islands in p14ARF exon 1beta [cg03079681, cg07562918, cg00718440, cg10848754, cg14430974] were analyzed.	('p14ARF exon 1beta', 'Gene', '1029', (142, 159))	('[cg12840719', 'Var', (81, 92))	('p14ARF exon 1beta', 'Gene', (142, 159))	('cg04026675]', 'Var', (106, 117))	('cg14430974]', 'Var', (209, 220))	('[cg03079681', 'Var', (160, 171))	('cg07562918', 'Var', (173, 183))	('cg00718440', 'Var', (185, 195))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('cg10848754', 'Var', (197, 207))
134420	33076392	The co-operative binding of PRC1 (including the BMI1 subunit) and the long noncoding RNA ANRIL to H3K27me3 compacts the CDKN2A genomic locus and represses transcription, in particular the transcription of p16INK4a.	('transcription', 'MPA', (188, 201))	('p16INK4a', 'Gene', (205, 213))	('ANRIL', 'Gene', '100048912', (89, 94))	('binding', 'Interaction', (17, 24))	('PRC1', 'Gene', (28, 32))	('CDKN2A', 'Gene', (120, 126))	('BMI1', 'Gene', '648', (48, 52))	('PRC1', 'Gene', '9055', (28, 32))	('H3K27me3', 'Var', (98, 106))	('represses', 'NegReg', (145, 154))	('transcription', 'biological_process', 'GO:0006351', ('188', '201'))	('binding', 'molecular_function', 'GO:0005488', ('17', '24'))	('RNA', 'cellular_component', 'GO:0005562', ('85', '88'))	('ANRIL', 'Gene', (89, 94))	('transcription', 'MPA', (155, 168))	('BMI1', 'Gene', (48, 52))	('transcription', 'biological_process', 'GO:0006351', ('155', '168'))
134421	33076392	In line with these data, the levels of H3K27me3 increase from primary to metastatic melanoma, and high H3K27me3 is an independent poor prognostic marker in melanoma.	('H3K27me3', 'Protein', (39, 47))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('levels', 'MPA', (29, 35))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('primary', 'Disease', (62, 69))	('high H3K27me3', 'Var', (98, 111))	('increase', 'PosReg', (48, 56))
134422	33076392	Mutations in the BRAF, NRAS, and NF1 genes are the predominant drivers in cutaneous melanoma, and CDKN2A genetic alterations are distributed evenly amongst these genetic melanoma subtypes, with CDKN2A genetic alterations detected in 48.9% (92/188) of BRAF-mutant, 44.7% (51/114) of NRAS-mutant, and 50% (33/66) of NF1-mutant cutaneous melanomas (Table 1).	('NF1', 'Gene', (33, 36))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (325, 344))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (325, 344))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (325, 343))	('NRAS', 'Gene', '4893', (23, 27))	('melanoma', 'Disease', (335, 343))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (325, 343))	('melanoma', 'Phenotype', 'HP:0002861', (335, 343))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('BRAF', 'Gene', (251, 255))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', '673', (251, 255))	('cutaneous melanomas', 'Disease', (325, 344))	('NRAS', 'Gene', '4893', (282, 286))	('NRAS', 'Gene', (23, 27))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('NF1', 'Gene', '4763', (314, 317))	('melanoma', 'Disease', 'MESH:D008545', (335, 343))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('NF1', 'Gene', (314, 317))	('BRAF', 'Gene', '673', (17, 21))	('NF1', 'Gene', '4763', (33, 36))	('BRAF', 'Gene', (17, 21))	('melanomas', 'Phenotype', 'HP:0002861', (335, 344))	('cutaneous melanoma', 'Disease', (74, 92))	('NRAS', 'Gene', (282, 286))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (74, 92))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (74, 92))
134425	33076392	Interestingly CDKN2A methylation was rarely detected in sporadic primary melanoma and has not been identified in melanocytic nevi.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('nevi', 'Phenotype', 'HP:0003764', (125, 129))	('methylation', 'biological_process', 'GO:0032259', ('21', '32'))	('methylation', 'Var', (21, 32))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (113, 129))	('CDKN2A', 'Gene', (14, 20))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
134426	33076392	Altogether, CDKN2A alterations (including mutation, deletion, and promoter hypermethylation) appear to be differentially distributed across the cutaneous melanoma genomic subtypes, and have been identified in 58% of BRAF-mutant, 72% of NRAS-mutant, and 71% of NF1-mutant melanoma but only in 37% of triple wild-type melanomas.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (144, 162))	('CDKN2A', 'Gene', (12, 18))	('melanoma', 'Disease', 'MESH:D008545', (316, 324))	('NF1', 'Gene', '4763', (260, 263))	('melanomas', 'Phenotype', 'HP:0002861', (316, 325))	('NF1', 'Gene', (260, 263))	('mutation', 'Var', (42, 50))	('alterations', 'Var', (19, 30))	('NRAS', 'Gene', '4893', (236, 240))	('melanoma', 'Disease', 'MESH:D008545', (271, 279))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (316, 324))	('melanoma', 'Disease', (316, 324))	('promoter hypermethylation', 'MPA', (66, 91))	('deletion', 'Var', (52, 60))	('identified', 'Reg', (195, 205))	('melanomas', 'Disease', 'MESH:D008545', (316, 325))	('NRAS', 'Gene', (236, 240))	('BRAF', 'Gene', '673', (216, 220))	('melanoma', 'Phenotype', 'HP:0002861', (271, 279))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('melanoma', 'Disease', (271, 279))	('BRAF', 'Gene', (216, 220))	('melanomas', 'Disease', (316, 325))	('cutaneous melanoma', 'Disease', (144, 162))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (144, 162))
134429	33076392	In particular, 50% of melanoma patients aged 31-50, 41% of patients aged 51-70, and 36% of patients aged > 71 had somatic CDKN2A genetic changes.	('patients', 'Species', '9606', (91, 99))	('CDKN2A', 'Gene', (122, 128))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma', 'Disease', (22, 30))	('patients', 'Species', '9606', (59, 67))	('patients', 'Species', '9606', (31, 39))	('genetic changes', 'Var', (129, 144))
134430	33076392	Further, CDKN2A mutation status is not associated with overall survival in melanoma; melanoma patients with somatic CDKN2A alterations had a median overall survival of 112 months compared to a median overall survival of 79 months in patients with wild-type CDKN2A (Figure 2).	('patients', 'Species', '9606', (94, 102))	('CDKN2A', 'Gene', (116, 122))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('patients', 'Species', '9606', (233, 241))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('alterations', 'Var', (123, 134))
134432	33076392	For instance, CDKN2A mutations are present in 20% (4 out of 20 cases; 3 truncating mutations and one missense mutation) of desmoplastic melanoma, and these alterations predominantly affected either p16INK4a alone or p16INK4a along with p14ARF.	('p14ARF', 'Gene', (236, 242))	('p16INK4a', 'Var', (216, 224))	('p14ARF', 'Gene', '1029', (236, 242))	('affected', 'Reg', (182, 190))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('p16INK4a', 'Var', (198, 206))	('desmoplastic melanoma', 'Disease', 'MESH:D008545', (123, 144))	('desmoplastic melanoma', 'Disease', (123, 144))	('CDKN2A', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
134433	33076392	CDKN2A mutations are less common in acral melanoma, with only 9-18% of acral melanomas showing somatic CDKN2A alterations, and these alterations were predominantly homozygous deletions.	('acral melanomas', 'Disease', 'MESH:D008545', (71, 86))	('alterations', 'Var', (110, 121))	('acral melanoma', 'Phenotype', 'HP:0012060', (71, 85))	('acral melanoma', 'Phenotype', 'HP:0012060', (36, 50))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('acral melanoma', 'Disease', (36, 50))	('acral melanomas', 'Disease', (71, 86))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('acral melanomas', 'Phenotype', 'HP:0012060', (71, 86))	('CDKN2A', 'Gene', (103, 109))	('acral melanoma', 'Disease', 'MESH:D008545', (71, 85))	('acral melanoma', 'Disease', 'MESH:D008545', (36, 50))	('CDKN2A', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
134434	33076392	CDKN2A mutation rates were similarly low in uveal melanoma, with only one missense mutation (V28G within exon 1alpha) detected in the 80 uveal melanomas included in TCGA uveal melanoma cohort.	('uveal melanoma', 'Disease', 'MESH:C536494', (170, 184))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('V28G', 'Mutation', 'rs775176191', (93, 97))	('uveal melanoma', 'Disease', (170, 184))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('melanomas', 'Phenotype', 'HP:0002861', (143, 152))	('uveal melanoma', 'Disease', (44, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (170, 184))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (137, 151))	('uveal melanoma', 'Disease', (137, 151))	('uveal melanoma', 'Phenotype', 'HP:0007716', (137, 151))	('CDKN2A', 'Gene', (0, 6))	('melanomas', 'Disease', 'MESH:D008545', (143, 152))	('uveal melanomas', 'Phenotype', 'HP:0007716', (137, 152))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanomas', 'Disease', (143, 152))	('mutation', 'Var', (7, 15))
134436	33076392	Loss of function alterations affecting the CDKN2A locus have been identified in the germline of multiple-case melanoma kindreds around the world.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('CDKN2A', 'Gene', (43, 49))	('Loss of function', 'NegReg', (0, 16))	('alterations', 'Var', (17, 28))
134438	33076392	The systematic analysis of 80 melanoma-prone families identified 37 distinct mutations affecting the CDKN2A locus.	('CDKN2A', 'Gene', (101, 107))	('mutations', 'Var', (77, 86))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Disease', (30, 38))
134439	33076392	Half of these mutations were in exon 1alpha (these will not affect the p14ARF coding sequence) and half were in exon 2.	('p14ARF', 'Gene', (71, 77))	('mutations', 'Var', (14, 23))	('p14ARF', 'Gene', '1029', (71, 77))
134440	33076392	Whereas all exon 2 mutations altered the p16INK4a protein, only 14/20 of these exon 2 mutations also impacted the p14ARF protein sequence.	('mutations', 'Var', (86, 95))	('p14ARF', 'Gene', '1029', (114, 120))	('p16INK4a protein', 'Protein', (41, 57))	('mutations', 'Var', (19, 28))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('impacted', 'Reg', (101, 109))	('altered', 'Reg', (29, 36))	('p14ARF', 'Gene', (114, 120))
134442	33076392	Germline inactivation of p14ARF is mostly due to whole gene deletions, insertions, or splice mutations.	('p14ARF', 'Gene', (25, 31))	('insertions', 'Var', (71, 81))	('p14ARF', 'Gene', '1029', (25, 31))	('splice mutations', 'Var', (86, 102))
134443	33076392	For instance, a germline deletion of p14ARF exon 1beta coding sequence and a germline mutation (Gly16Asp) in exon 1beta were identified in families with melanoma-neural system tumor syndrome; a frameshift mutation (16 base pair insertion) was detected in a Spanish female who developed multiple primary melanomas at a young age; a splice mutation resulting in haploinsufficiency was associated with melanoma in a single family; and a mutation coding for the missense Arg54His mutation in p14ARF was found in an Italian melanoma family.	('Gly16Asp', 'Mutation', 'rs1444669684', (96, 104))	('haploinsufficiency', 'Disease', 'MESH:D058495', (360, 378))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('p14ARF exon 1beta', 'Gene', (37, 54))	('melanoma', 'Disease', (153, 161))	('melanoma', 'Phenotype', 'HP:0002861', (399, 407))	('melanoma', 'Disease', (399, 407))	('haploinsufficiency', 'Disease', (360, 378))	('melanomas', 'Disease', 'MESH:D008545', (303, 312))	('missense Arg54His', 'Var', (458, 475))	('p14ARF', 'Gene', (37, 43))	('melanoma', 'Disease', 'MESH:D008545', (519, 527))	('p14ARF', 'Gene', (488, 494))	('melanomas', 'Disease', (303, 312))	('neural system tumor', 'Phenotype', 'HP:0004375', (162, 181))	('melanoma', 'Disease', 'MESH:D008545', (303, 311))	('Arg54His', 'Mutation', 'p.R54H', (467, 475))	('melanoma', 'Disease', 'MESH:D008545', (399, 407))	('melanoma-neural system tumor syndrome', 'Disease', (153, 190))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('melanoma-neural system tumor syndrome', 'Disease', 'MESH:C536149', (153, 190))	('melanomas', 'Phenotype', 'HP:0002861', (303, 312))	('melanoma', 'Phenotype', 'HP:0002861', (519, 527))	('melanoma', 'Disease', (519, 527))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('p14ARF', 'Gene', '1029', (37, 43))	('p14ARF exon 1beta', 'Gene', '1029', (37, 54))	('melanoma', 'Phenotype', 'HP:0002861', (303, 311))	('melanoma', 'Disease', (303, 311))	('p14ARF', 'Gene', '1029', (488, 494))
134444	33076392	Large germline CDKN2A deletions encompassing exon 1alpha, 2, and/or 3 which affect both p14ARF and p16INK4a have also been identified in melanoma-prone kindreds, although these are uncommon and account for only 2% of germline CDKN2A alterations.	('affect', 'Reg', (76, 82))	('deletions', 'Var', (22, 31))	('CDKN2A', 'Gene', (15, 21))	('p14ARF', 'Gene', '1029', (88, 94))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('p14ARF', 'Gene', (88, 94))
134445	33076392	A germline splice site mutation removing exon 2 of CDKN2A was identified in a family with melanoma and multiple dysplastic nevi.	('melanoma and multiple dysplastic', 'Disease', 'MESH:D008545', (90, 122))	('multiple dysplastic nevi', 'Phenotype', 'HP:0001054', (103, 127))	('mutation removing', 'Var', (23, 40))	('nevi', 'Phenotype', 'HP:0003764', (123, 127))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (112, 127))	('CDKN2A', 'Gene', (51, 57))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
134446	33076392	The penetrance of germline CDKN2A mutations for melanoma also varies according to geographical locations, with penetrance increasing with higher baseline melanoma incidence rates.	('melanoma', 'Disease', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('CDKN2A', 'Gene', (27, 33))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('mutations', 'Var', (34, 43))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
134448	33076392	A GenoMEL study that screened for CDKN2A mutations in Australian, European, and North American families reported increased mutation frequency in families with melanoma and pancreatic cancer.	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('CDKN2A', 'Gene', (34, 40))	('melanoma and pancreatic cancer', 'Disease', 'MESH:C563985', (159, 189))	('increased', 'PosReg', (113, 122))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (172, 189))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
134449	33076392	A prospective study examining cancer diagnoses in Swedish carriers of the Arg112dup alteration in CDKN2A concluded that mutation carriers had a significantly elevated risk of developing pancreatic, lung, head and neck, and gastro-oesophageal carcinomas.	('gastro-oesophageal carcinomas', 'Disease', (223, 252))	('neck', 'cellular_component', 'GO:0044326', ('213', '217'))	('pancreatic', 'Disease', (186, 196))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('Arg112dup', 'Var', (74, 83))	('CDKN2A', 'Gene', (98, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (242, 252))	('developing', 'PosReg', (175, 185))	('lung', 'Disease', (198, 202))	('gastro-oesophageal carcinomas', 'Disease', 'MESH:D005764', (223, 252))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('pancreatic', 'Disease', 'MESH:D010195', (186, 196))
134451	33076392	developed the CDKN2A Mutation (CM) score to predict CDKN2A germline mutation status among melanoma prone families; a CM score > 35 out of 49 possible points was associated with a > 90% probability of a melanoma-prone family sharing a CDKN2A mutation.	('melanoma', 'Disease', (90, 98))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', (202, 210))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('CM score', 'Var', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
134452	33076392	Importantly, CDKN2A mutation carriers have been reported to be at increased risk of developing other cancers, including breast, lung, and non-melanoma skin cancers.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (156, 163))	('skin cancer', 'Phenotype', 'HP:0008069', (151, 162))	('cancers', 'Disease', (101, 108))	('lung', 'Disease', (128, 132))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('mutation', 'Var', (20, 28))	('skin cancers', 'Phenotype', 'HP:0008069', (151, 163))	('CDKN2A', 'Gene', (13, 19))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('non-melanoma skin cancers', 'Disease', 'MESH:D012878', (138, 163))	('breast', 'Disease', (120, 126))	('non-melanoma skin cancers', 'Disease', (138, 163))
134453	33076392	These additional cancer risks are not consistently observed, however, and this may indicate that the risk of other cancer types reflects the specific germline CDKN2A mutation.	('cancer', 'Disease', (115, 121))	('germline', 'Var', (150, 158))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('CDKN2A', 'Gene', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
134454	33076392	For instance, whereas 25-36% of melanoma-prone families with Arg24Pro, c.34G>T, or Gly101Trp had pancreatic cancer, none of the 30 families with Met53Ile, c.IVS2-104A>G, or c.32_33ins9-32 developed pancreatic cancer.	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('Met53Ile', 'Var', (145, 153))	('pancreatic cancer', 'Disease', (198, 215))	('c.34G>T', 'Mutation', 'rs121913250', (71, 78))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (97, 114))	('c.IVS2-104A>G', 'Var', (155, 168))	('Gly101Trp', 'Var', (83, 92))	('c.IVS2-104A>G', 'Mutation', 'c.IVS2-104A>G', (155, 168))	('Arg24Pro', 'SUBSTITUTION', 'None', (61, 69))	('Arg24Pro', 'Var', (61, 69))	('c.32_33ins9-32', 'Var', (173, 187))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('c.32_33ins9', 'Mutation', 'c.32_33ins9', (173, 184))	('Gly101Trp', 'SUBSTITUTION', 'None', (83, 92))	('c.34G>T', 'Var', (71, 78))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (198, 215))	('pancreatic cancer', 'Disease', 'MESH:D010190', (97, 114))	('pancreatic cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('pancreatic cancer', 'Disease', 'MESH:D010190', (198, 215))	('Met53Ile', 'Mutation', 'rs104894095', (145, 153))
134455	33076392	Finally, a CDKN2A germline deletion of the p14ARF-specific exon 1ss was associated with excess risk for melanoma, astrocytoma, neurofibromas, and schwannomas.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('p14ARF', 'Gene', (43, 49))	('melanoma', 'Disease', (104, 112))	('schwannomas', 'Disease', (146, 157))	('astrocytoma', 'Disease', 'MESH:D001254', (114, 125))	('associated', 'Reg', (72, 82))	('p14ARF', 'Gene', '1029', (43, 49))	('germline deletion', 'Var', (18, 35))	('neurofibromas', 'Phenotype', 'HP:0001067', (127, 140))	('astrocytoma', 'Disease', (114, 125))	('schwannomas', 'Disease', 'MESH:D009442', (146, 157))	('astrocytoma', 'Phenotype', 'HP:0009592', (114, 125))	('CDKN2A', 'Gene', (11, 17))	('neurofibromas', 'Disease', (127, 140))	('neurofibromas', 'Disease', 'MESH:D009455', (127, 140))	('schwannomas', 'Phenotype', 'HP:0100008', (146, 157))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
134456	33076392	Modifier genes for melanoma kindreds carrying CDKN2A mutations have also been reported.	('CDKN2A', 'Gene', (46, 52))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('mutations', 'Var', (53, 62))
134457	33076392	In an early study on Dutch melanoma families, the melanocortin-1 receptor (MC1R) variant Arg151Cys increased the risk of melanoma in carriers of a p16INK4a-inactivating deletion (known as p16-Leiden).	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', (121, 129))	('melanocortin-1 receptor', 'Gene', '4157', (50, 73))	('MC1R', 'Gene', (75, 79))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('p16', 'Gene', (188, 191))	('p16', 'Gene', (147, 150))	('Arg151Cys', 'SUBSTITUTION', 'None', (89, 98))	('p16', 'Gene', '1029', (147, 150))	('Arg151Cys', 'Var', (89, 98))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('increased', 'PosReg', (99, 108))	('melanoma', 'Disease', (27, 35))	('p16', 'Gene', '1029', (188, 191))	('MC1R', 'Gene', '4157', (75, 79))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('melanocortin-1 receptor', 'Gene', (50, 73))
134458	33076392	This increased risk of melanoma was not wholly attributed to the fair skin type associated with this MC1R variant.	('fair skin', 'Phenotype', 'HP:0007513', (65, 74))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('MC1R', 'Gene', '4157', (101, 105))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('MC1R', 'Gene', (101, 105))	('variant', 'Var', (106, 113))
134459	33076392	A later study confirmed that four frequent MC1R variants (Val60Leu, Val92Met, Arg151Cys, Arg160Tro) were associated with an increased melanoma risk in CDKN2A mutation carriers.	('MC1R', 'Gene', (43, 47))	('MC1R', 'Gene', '4157', (43, 47))	('Arg151Cys', 'SUBSTITUTION', 'None', (78, 87))	('Val92Met', 'SUBSTITUTION', 'None', (68, 76))	('Arg160Tro', 'Var', (89, 98))	('Arg151Cys', 'Var', (78, 87))	('Val60Leu', 'SUBSTITUTION', 'None', (58, 66))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('CDKN2A', 'Gene', (151, 157))	('melanoma', 'Disease', (134, 142))	('Val60Leu', 'Var', (58, 66))	('associated', 'Reg', (105, 115))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('Val92Met', 'Var', (68, 76))
134460	33076392	Polymorphisms in genes involved in DNA repair (POLN, PRKDC), immune regulation (IL9), and apoptosis (BCL7A, BCL2L1) have also been associated with increased melanoma risk, and in some instances, these polymorphisms (IL9 and BCL7A) have stronger risks in CDKN2A-positive families.	('IL9', 'molecular_function', 'GO:0005140', ('216', '219'))	('POLN', 'Gene', '353497', (47, 51))	('BCL7A', 'Gene', (224, 229))	('IL9', 'Gene', '3578', (216, 219))	('BCL2L1', 'Gene', '598', (108, 114))	('regulation', 'biological_process', 'GO:0065007', ('68', '78'))	('apoptosis', 'biological_process', 'GO:0097194', ('90', '99'))	('Polymorphisms', 'Var', (0, 13))	('apoptosis', 'biological_process', 'GO:0006915', ('90', '99'))	('BCL7A', 'Gene', (101, 106))	('IL9', 'Gene', (216, 219))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('IL9', 'molecular_function', 'GO:0005140', ('80', '83'))	('IL9', 'Gene', '3578', (80, 83))	('PRKDC', 'Gene', '5591', (53, 58))	('POLN', 'Gene', (47, 51))	('associated', 'Reg', (131, 141))	('BCL7A', 'Gene', '605', (224, 229))	('PRKDC', 'Gene', (53, 58))	('IL9', 'Gene', (80, 83))	('BCL2L1', 'Gene', (108, 114))	('DNA repair', 'biological_process', 'GO:0006281', ('35', '45'))	('BCL7A', 'Gene', '605', (101, 106))	('BCL2', 'molecular_function', 'GO:0015283', ('108', '112'))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))
134461	33076392	Melanoma-associated CDKN2A missense mutations commonly diminish the capacity of p16INK4a to bind and inhibit CDK4/6.	('diminish', 'NegReg', (55, 63))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('inhibit', 'NegReg', (101, 108))	('p16INK4a', 'Protein', (80, 88))	('CDK', 'molecular_function', 'GO:0004693', ('109', '112'))	('Melanoma', 'Disease', (0, 8))	('bind', 'Interaction', (92, 96))	('CDK4/6', 'Protein', (109, 115))	('missense mutations', 'Var', (27, 45))	('CDKN2A', 'Gene', (20, 26))
134462	33076392	described germline CDKN2A substitutions that impaired the ability of p16INK4a to inhibit the catalytic activity of cyclin D1/CDK4 and cyclin D1/CDK6 complexes.	('cyclin', 'molecular_function', 'GO:0016538', ('115', '121'))	('CDK4', 'Gene', (125, 129))	('cyclin D1', 'Gene', '595', (115, 124))	('cyclin D1', 'Gene', (115, 124))	('CDK4', 'Gene', '1019', (125, 129))	('CDKN2A', 'Gene', (19, 25))	('catalytic activity', 'molecular_function', 'GO:0003824', ('93', '111'))	('inhibit', 'NegReg', (81, 88))	('CDK6', 'Gene', (144, 148))	('cyclin D1', 'Gene', '595', (134, 143))	('CDK6', 'Gene', '1021', (144, 148))	('cyclin D1', 'Gene', (134, 143))	('cyclin', 'molecular_function', 'GO:0016538', ('134', '140'))	('substitutions', 'Var', (26, 39))	('CDK', 'molecular_function', 'GO:0004693', ('144', '147'))	('CDK', 'molecular_function', 'GO:0004693', ('125', '128'))	('impaired', 'NegReg', (45, 53))	('catalytic activity', 'MPA', (93, 111))
134463	33076392	The Met53Ile and Arg24Pro germline mutants of p16INK4a have diminished capacity to bind CDK4 compared to wild-type p16INK4a.	('Met53Ile', 'Var', (4, 12))	('bind', 'Interaction', (83, 87))	('p16INK4a', 'Gene', (46, 54))	('diminished', 'NegReg', (60, 70))	('CDK', 'molecular_function', 'GO:0004693', ('88', '91'))	('CDK4', 'Gene', '1019', (88, 92))	('CDK4', 'Gene', (88, 92))	('Arg24Pro', 'Var', (17, 25))	('Met53Ile', 'Mutation', 'rs104894095', (4, 12))	('Arg24Pro', 'SUBSTITUTION', 'None', (17, 25))	('capacity', 'MPA', (71, 79))
134464	33076392	Although, it is worth noting that the CDK4-binding affinity of the Arg24Pro mutation is controversial.	('Arg24Pro', 'SUBSTITUTION', 'None', (67, 75))	('Arg24Pro', 'Var', (67, 75))	('CDK', 'molecular_function', 'GO:0004693', ('38', '41'))	('CDK4', 'Gene', '1019', (38, 42))	('CDK4', 'Gene', (38, 42))	('binding', 'molecular_function', 'GO:0005488', ('43', '50'))
134465	33076392	The somatic missense p16INK4a mutation (Pro48Leu) decreased the ability of the protein to bind and inhibit CDK6 kinase activity, thus, failing to arrest melanoma cell growth.	('p16INK4a', 'Var', (21, 29))	('arrest melanoma', 'Disease', (146, 161))	('bind', 'Interaction', (90, 94))	('missense p16INK4a', 'Var', (12, 29))	('kinase activity', 'molecular_function', 'GO:0016301', ('112', '127'))	('ability', 'MPA', (64, 71))	('cell growth', 'biological_process', 'GO:0016049', ('162', '173'))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('inhibit', 'NegReg', (99, 106))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('decreased', 'NegReg', (50, 59))	('arrest melanoma', 'Disease', 'MESH:D006323', (146, 161))	('CDK6', 'Gene', (107, 111))	('CDK6', 'Gene', '1021', (107, 111))	('CDK', 'molecular_function', 'GO:0004693', ('107', '110'))	('Pro48Leu', 'Mutation', 'p.P48L', (40, 48))
134466	33076392	Melanoma cell lines with a Pro81Leu missense mutation in p16INK4a also showed defective binding ability to CDK4, and these cells had more aggressive cell growth compared to the wild-type cells.	('Pro81Leu missense mutation', 'Var', (27, 53))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('CDK4', 'Gene', '1019', (107, 111))	('defective', 'NegReg', (78, 87))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('p16INK4a', 'Gene', (57, 65))	('binding', 'molecular_function', 'GO:0005488', ('88', '95'))	('more', 'PosReg', (133, 137))	('Melanoma', 'Disease', (0, 8))	('Pro81Leu', 'Mutation', 'rs11552823', (27, 35))	('cell growth', 'biological_process', 'GO:0016049', ('149', '160'))	('CDK', 'molecular_function', 'GO:0004693', ('107', '110'))	('aggressive cell growth', 'CPA', (138, 160))	('binding', 'Interaction', (88, 95))	('CDK4', 'Gene', (107, 111))
134467	33076392	There is some evidence that CDKN2A mutations do not only impact the binding affinity of p16INK4a for CDK4 or CDK6.	('CDK6', 'Gene', (109, 113))	('impact', 'Reg', (57, 63))	('CDK4', 'Gene', (101, 105))	('CDK4', 'Gene', '1019', (101, 105))	('CDK6', 'Gene', '1021', (109, 113))	('CDK', 'molecular_function', 'GO:0004693', ('109', '112'))	('CDK', 'molecular_function', 'GO:0004693', ('101', '104'))	('CDKN2A', 'Gene', (28, 34))	('binding affinity', 'Interaction', (68, 84))	('binding', 'molecular_function', 'GO:0005488', ('68', '75'))	('mutations', 'Var', (35, 44))
134468	33076392	Indeed, several melanoma-associated mutations (e.g., N-terminal 24bp p16INK4a duplication, Arg24Pro, Leu117Pro) retained CDK4 and/or CDK6 binding activity even though they displayed diminished cell cycle inhibitory activity, suggesting that other p16INK4a binding interactions may be important in melanoma susceptibility.	('Leu117Pro', 'Var', (101, 110))	('p16INK4a', 'Gene', (69, 77))	('binding', 'molecular_function', 'GO:0005488', ('256', '263'))	('Arg24Pro', 'SUBSTITUTION', 'None', (91, 99))	('Arg24Pro', 'Var', (91, 99))	('CDK6', 'Gene', '1021', (133, 137))	('melanoma', 'Disease', 'MESH:D008545', (297, 305))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('binding', 'Interaction', (138, 145))	('melanoma', 'Disease', (16, 24))	('CDK4', 'Gene', (121, 125))	('CDK', 'molecular_function', 'GO:0004693', ('121', '124'))	('CDK6', 'Gene', (133, 137))	('Leu117Pro', 'SUBSTITUTION', 'None', (101, 110))	('cell cycle', 'biological_process', 'GO:0007049', ('193', '203'))	('CDK', 'molecular_function', 'GO:0004693', ('133', '136'))	('CDK4', 'Gene', '1019', (121, 125))	('activity', 'MPA', (146, 154))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (297, 305))	('melanoma', 'Disease', (297, 305))	('binding', 'molecular_function', 'GO:0005488', ('138', '145'))
134470	33076392	Various p16INK4a mutants, including the melanoma-associated germline mutations Ala36Pro and Ala57Val, were also associated with impaired oxidative regulatory functions, and intracellular oxidative dysregulation in melanocytes can lead to genetic damage that contributes to increased melanoma susceptibility.	('genetic damage', 'Disease', 'MESH:D030342', (238, 252))	('Ala57Val', 'Var', (92, 100))	('genetic damage', 'Disease', (238, 252))	('Ala36Pro', 'SUBSTITUTION', 'None', (79, 87))	('intracellular', 'cellular_component', 'GO:0005622', ('173', '186'))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('lead to', 'Reg', (230, 237))	('Ala57Val', 'SUBSTITUTION', 'None', (92, 100))	('melanoma', 'Disease', (40, 48))	('melanoma', 'Disease', (283, 291))	('intracellular oxidative dysregulation', 'MPA', (173, 210))	('oxidative regulatory functions', 'MPA', (137, 167))	('melanoma', 'Disease', 'MESH:D008545', (283, 291))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (283, 291))	('p16INK4a', 'Gene', (8, 16))	('Ala36Pro', 'Var', (79, 87))	('impaired', 'NegReg', (128, 136))
134471	33076392	Inactivation of p16INK4a has been shown to contribute to the failure of senescence and progression from normal melanocytes to malignant melanoma via benign nevi, dysplastic nevi, radial growth phase, and vertical growth phase stages.	('malignant melanoma', 'Disease', 'MESH:D008545', (126, 144))	('p16INK4a', 'Gene', (16, 24))	('malignant melanoma', 'Disease', (126, 144))	('senescence', 'CPA', (72, 82))	('dysplastic', 'Disease', 'MESH:D004416', (162, 172))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (162, 177))	('dysplastic', 'Disease', (162, 172))	('nevi', 'Phenotype', 'HP:0003764', (156, 160))	('senescence', 'biological_process', 'GO:0010149', ('72', '82'))	('nevi', 'Phenotype', 'HP:0003764', (173, 177))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('malignant melanoma', 'Phenotype', 'HP:0002861', (126, 144))	('vertical growth phase', 'CPA', (204, 225))	('radial growth phase', 'CPA', (179, 198))	('progression', 'CPA', (87, 98))	('Inactivation', 'Var', (0, 12))	('benign nevi', 'Disease', (149, 160))
134472	33076392	Loss of p16INK4a as a single event is not sufficient to induce melanomagenesis but does predispose one to melanoma development, especially in the presence of other driver mutations.	('p16INK4a', 'Protein', (8, 16))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('predispose', 'Reg', (88, 98))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('Loss', 'Var', (0, 4))	('melanoma', 'Disease', (63, 71))
134473	33076392	For instance, loss of p16INK4a cooperates with BRAFV600E oncogenic mutation to promote melanoma progression in genetic mouse models.	('melanoma', 'Disease', (87, 95))	('mouse', 'Species', '10090', (119, 124))	('loss', 'Var', (14, 18))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('p16INK4a', 'Protein', (22, 30))	('promote', 'PosReg', (79, 86))	('BRAFV600E', 'Mutation', 'rs113488022', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
134477	33076392	A 16 base pair insertion (60ins16) caused by a duplication of a CG-rich region within exon 1beta was detected in a Spanish female who had multiple primary melanomas.	('melanomas', 'Disease', 'MESH:D008545', (155, 164))	('60ins16', 'Var', (26, 33))	('CG-rich region', 'Gene', (64, 78))	('melanomas', 'Phenotype', 'HP:0002861', (155, 164))	('duplication', 'Var', (47, 58))	('60ins16', 'Mutation', 'c.60ins16', (26, 33))	('melanomas', 'Disease', (155, 164))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))
134479	33076392	In contrast, another p14ARF variant (Gly16Asp) in exon 1beta retained its ability to bind HDM2 and stabilize p53.	('p14ARF', 'Gene', '1029', (21, 27))	('ability', 'MPA', (74, 81))	('p14ARF', 'Gene', (21, 27))	('HDM2', 'Gene', (90, 94))	('p53', 'Gene', (109, 112))	('p53', 'Gene', '7157', (109, 112))	('Gly16Asp', 'Var', (37, 45))	('Gly16Asp', 'Mutation', 'rs1444669684', (37, 45))	('bind', 'Interaction', (85, 89))	('HDM2', 'Gene', '4193', (90, 94))
134480	33076392	A splice site mutation in exon 1beta was shown to cause p14ARF haploinsufficiency and was associated with melanoma susceptibility.	('cause', 'Reg', (50, 55))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('haploinsufficiency', 'Disease', (63, 81))	('p14ARF', 'Gene', '1029', (56, 62))	('associated with', 'Reg', (90, 105))	('p14ARF', 'Gene', (56, 62))	('haploinsufficiency', 'Disease', 'MESH:D058495', (63, 81))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('splice site mutation', 'Var', (2, 22))
134481	33076392	There have been several studies investigating the role of CDKN2A exon 2 mutations that impact the p14ARF coding sequence.	('p14ARF', 'Gene', '1029', (98, 104))	('mutations', 'Var', (72, 81))	('CDKN2A', 'Gene', (58, 64))	('p14ARF', 'Gene', (98, 104))
134482	33076392	In one study, 3/7 p14ARF mutations, encoded by CDKN2A exon 2 mutations, altered the subcellular distribution of p14ARF and diminished its ability to stabilize p53.	('p14ARF', 'Gene', (112, 118))	('mutations', 'Var', (25, 34))	('altered', 'Reg', (72, 79))	('p53', 'Gene', (159, 162))	('p53', 'Gene', '7157', (159, 162))	('diminished', 'NegReg', (123, 133))	('CDKN2A', 'Gene', (47, 53))	('p14ARF', 'Gene', '1029', (18, 24))	('subcellular distribution', 'MPA', (84, 108))	('mutations', 'Var', (61, 70))	('p14ARF', 'Gene', '1029', (112, 118))	('p14ARF', 'Gene', (18, 24))	('ability', 'MPA', (138, 145))
134483	33076392	The restoration of p14ARF and/or p16INK4a functions has not yet been possible, and most therapeutic strategies involve modulating downstream cell cycle regulators or pathways to overcome the loss of CDKN2A-encoded functions.	('p14ARF', 'Gene', (19, 25))	('modulating', 'Reg', (119, 129))	('cell cycle', 'biological_process', 'GO:0007049', ('141', '151'))	('p14ARF', 'Gene', '1029', (19, 25))	('p16INK4a', 'Var', (33, 41))
134496	33076392	The combination of ribociclib and MDM2 inhibition also enhanced tumor regression and overcame resistance to CDK4/6 inhibitors in a melanoma xenograft model.	('inhibition', 'Var', (39, 49))	('tumor', 'Disease', (64, 69))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('CDK', 'molecular_function', 'GO:0004693', ('108', '111'))	('enhanced', 'PosReg', (55, 63))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('MDM2', 'Gene', '4193', (34, 38))	('ribociclib', 'Chemical', 'MESH:C000589651', (19, 29))	('MDM2', 'Gene', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
134502	33076392	The presence of an activating Arg24Cys CDK4 mutation, which abolishes the ability of CDK4 to bind to p16INK4 was also associated with melanoma cell sensitivity to CDK4/6 inhibition.	('CDK', 'molecular_function', 'GO:0004693', ('39', '42'))	('Arg24Cys', 'SUBSTITUTION', 'None', (30, 38))	('activating', 'PosReg', (19, 29))	('CDK4', 'Gene', (163, 167))	('CDK4', 'Gene', '1019', (163, 167))	('CDK4', 'Gene', '1019', (39, 43))	('CDK4', 'Gene', (39, 43))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('CDK4', 'Gene', (85, 89))	('melanoma', 'Disease', (134, 142))	('p16INK4', 'Gene', '1029', (101, 108))	('p16INK4', 'Gene', (101, 108))	('associated', 'Reg', (118, 128))	('CDK4', 'Gene', '1019', (85, 89))	('Arg24Cys', 'Var', (30, 38))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('CDK', 'molecular_function', 'GO:0004693', ('163', '166'))	('CDK', 'molecular_function', 'GO:0004693', ('85', '88'))
134504	33076392	Considering that CDKN2A methylation can lead to p14ARF and p16INK4a loss, epigenetic reactivation of CDKN2A has also been attempted with inhibitors of DNA methyltransferase (DNMT), histone deacetylase (HDAC), histone methyltransferase, and histone acetyltransferase.	('DNA methyltransferase', 'Gene', (151, 172))	('p14ARF', 'Gene', (48, 54))	('methylation', 'Var', (24, 35))	('CDKN2A', 'Gene', (17, 23))	('DNA methyltransferase', 'Gene', '1786', (151, 172))	('p16INK4a', 'Gene', (59, 67))	('DNMT', 'Gene', '1786', (174, 178))	('loss', 'NegReg', (68, 72))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('DNMT', 'Gene', (174, 178))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))	('p14ARF', 'Gene', '1029', (48, 54))
134505	33076392	These inhibitors have been shown to induce p14ARF and p16INK4a expression in cancer cell lines and preclinical models (reviewed in reference).	('p14ARF', 'Gene', (43, 49))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('p14ARF', 'Gene', '1029', (43, 49))	('expression', 'MPA', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('p16INK4a', 'Var', (54, 62))	('induce', 'PosReg', (36, 42))
134507	33076392	However, given that these epigenetic modulators have promiscuous effects, it is difficult to attribute the consequent melanoma control on modulation of p14ARF and p16INK4a function alone.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('p14ARF', 'Gene', '1029', (152, 158))	('p16INK4a', 'Var', (163, 171))	('p14ARF', 'Gene', (152, 158))
134511	33076392	Despite the high frequency of CDKN2A alterations in melanomas, the impact of CDKN2A mutations on patient responses to BRAF/MEK inhibitors is not well established.	('BRAF', 'Gene', '673', (118, 122))	('melanomas', 'Disease', 'MESH:D008545', (52, 61))	('MEK', 'Gene', (123, 126))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('MEK', 'Gene', '5609', (123, 126))	('BRAF', 'Gene', (118, 122))	('CDKN2A', 'Gene', (77, 83))	('CDKN2A', 'Gene', (30, 36))	('melanomas', 'Disease', (52, 61))	('alterations', 'Var', (37, 48))	('patient', 'Species', '9606', (97, 104))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))
134512	33076392	For instance, in melanoma cell studies, the presence of p16INK4a-resistant CDK4 mutations (including the melanoma-associated germline CDK4 Arg24Cys mutation) did not alter cell sensitivity to BRAF inhibitors.	('CDK', 'molecular_function', 'GO:0004693', ('134', '137'))	('mutations', 'Var', (80, 89))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('CDK', 'molecular_function', 'GO:0004693', ('75', '78'))	('melanoma', 'Disease', (105, 113))	('BRAF', 'Gene', '673', (192, 196))	('CDK4', 'Gene', (75, 79))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('BRAF', 'Gene', (192, 196))	('Arg24Cys', 'Var', (139, 147))	('melanoma', 'Disease', (17, 25))	('CDK4', 'Gene', '1019', (75, 79))	('CDK4', 'Gene', '1019', (134, 138))	('CDK4', 'Gene', (134, 138))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('Arg24Cys', 'SUBSTITUTION', 'None', (139, 147))	('p16INK4a-resistant', 'Var', (56, 74))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))
134513	33076392	Conversely, the overexpression of cyclin D1 was associated with BRAF inhibitor resistance and resistance was enhanced when cyclin D1 overexpression was combined with the CDK4 Arg24Cys mutation.	('resistance', 'MPA', (94, 104))	('cyclin D1', 'Gene', (34, 43))	('CDK4', 'Gene', (170, 174))	('Arg24Cys', 'SUBSTITUTION', 'None', (175, 183))	('BRAF', 'Gene', '673', (64, 68))	('cyclin', 'molecular_function', 'GO:0016538', ('123', '129'))	('overexpression', 'PosReg', (16, 30))	('CDK4', 'Gene', '1019', (170, 174))	('associated', 'Reg', (48, 58))	('CDK', 'molecular_function', 'GO:0004693', ('170', '173'))	('BRAF', 'Gene', (64, 68))	('enhanced', 'PosReg', (109, 117))	('cyclin', 'molecular_function', 'GO:0016538', ('34', '40'))	('cyclin D1', 'Gene', '595', (123, 132))	('cyclin D1', 'Gene', '595', (34, 43))	('Arg24Cys', 'Var', (175, 183))	('cyclin D1', 'Gene', (123, 132))
134514	33076392	Recurrent CDKN2A loss has been implicated in BRAF inhibitor resistance, although CDKN2A alterations have been found to be pre-existing in responding patients, and CDKN2A alterations commonly co-occur with other mechanisms of BRAF inhibitor resistance (i.e., PTEN loss, N-RAS mutations).	('mutations', 'Var', (275, 284))	('implicated', 'Reg', (31, 41))	('N-RAS', 'Gene', (269, 274))	('BRAF', 'Gene', (225, 229))	('patients', 'Species', '9606', (149, 157))	('BRAF', 'Gene', '673', (225, 229))	('PTEN loss', 'Disease', (258, 267))	('N-RAS', 'Gene', '4893', (269, 274))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('PTEN loss', 'Disease', 'MESH:D006223', (258, 267))	('pre', 'molecular_function', 'GO:0003904', ('122', '125'))	('loss', 'NegReg', (17, 21))	('CDKN2A', 'Gene', (10, 16))
134516	33076392	It is important to mention that 15-40% of mucosal and acral melanomas show activating mutations or amplification of the receptor tyrosine kinase KIT, and the kinase inhibitor imatinib has shown efficacy in KIT-mutant melanoma with an overall response rate of 54%.	('KIT', 'molecular_function', 'GO:0005020', ('206', '209'))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('acral melanoma', 'Phenotype', 'HP:0012060', (54, 68))	('KIT', 'Gene', '3815', (206, 209))	('KIT', 'Gene', (145, 148))	('amplification', 'Var', (99, 112))	('acral melanomas', 'Disease', 'MESH:D008545', (54, 69))	('mutations', 'Var', (86, 95))	('melanoma', 'Disease', 'MESH:D008545', (217, 225))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('acral melanomas', 'Phenotype', 'HP:0012060', (54, 69))	('melanoma', 'Disease', (60, 68))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('KIT', 'Gene', '3815', (145, 148))	('KIT', 'Gene', (206, 209))	('activating', 'PosReg', (75, 85))	('KIT', 'molecular_function', 'GO:0005020', ('145', '148'))	('acral melanomas', 'Disease', (54, 69))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('158', '174'))	('imatinib', 'Chemical', 'MESH:D000068877', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('melanoma', 'Disease', (217, 225))
134517	33076392	Imatinib is also used commonly in the treatment of BCR-ABL chronic myelogenous leukemia but has not been as successful in BCR-ABL positive acute lymphoblastic leukemia showing deletion in the CDKN2A gene, suggesting that expression of p14ARF and/or p16INK4a may sensitize cancer cells to imatinib treatment.	('deletion', 'Var', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('p14ARF', 'Gene', '1029', (235, 241))	('BCR-ABL', 'Gene', (51, 58))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (145, 167))	('BCR-ABL', 'Gene', (122, 129))	('CDKN2A', 'Gene', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (67, 87))	('lymphoblastic leukemia', 'Disease', (145, 167))	('sensitize', 'Reg', (262, 271))	('p14ARF', 'Gene', (235, 241))	('myelogenous leukemia', 'Disease', (67, 87))	('positive acute lymphoblastic leukemia', 'Phenotype', 'HP:0004848', (130, 167))	('imatinib', 'Chemical', 'MESH:D000068877', (288, 296))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (139, 167))	('BCR-ABL', 'Gene', '25', (51, 58))	('p16INK4a', 'Var', (249, 257))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (145, 167))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (59, 87))	('leukemia', 'Phenotype', 'HP:0001909', (159, 167))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (67, 87))	('BCR-ABL', 'Gene', '25', (122, 129))	('cancer', 'Disease', (272, 278))
134518	33076392	Thus, it is tempting to speculate that CDKN2A inactivation in melanoma may analogously diminish sensitivity to imatinib in melanoma.	('melanoma', 'Disease', (62, 70))	('diminish', 'NegReg', (87, 95))	('CDKN2A', 'Gene', (39, 45))	('imatinib', 'Chemical', 'MESH:D000068877', (111, 119))	('sensitivity to imatinib', 'MPA', (96, 119))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('inactivation', 'Var', (46, 58))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
134521	33076392	Response rates are higher with PD-1 inhibitors (up to 45%) and the combination of CTLA-4 and PD-1 inhibitors further enhances the response rate to 60%.	('combination', 'Interaction', (67, 78))	('inhibitors', 'Var', (36, 46))	('inhibitors', 'Var', (98, 108))	('higher', 'PosReg', (19, 25))	('Response', 'MPA', (0, 8))	('CTLA-4', 'Gene', '1493', (82, 88))	('PD-1', 'Gene', (31, 35))	('PD-1', 'Gene', (93, 97))	('PD-1', 'Gene', '5133', (31, 35))	('PD-1', 'Gene', '5133', (93, 97))	('CTLA-4', 'Gene', (82, 88))	('enhances', 'PosReg', (117, 125))
134523	33076392	In this context, knockout of the CDKN2A gene in mice resulted in increased inflammatory cytokine expression in the skin following chronic UVB irradiation.	('increased', 'PosReg', (65, 74))	('CDKN2A', 'Gene', (33, 39))	('mice', 'Species', '10090', (48, 52))	('inflammatory cytokine expression in', 'MPA', (75, 110))	('knockout', 'Var', (17, 25))	('increased inflammatory cytokine expression', 'Phenotype', 'HP:0012649', (65, 107))
134526	33076392	JAK2 is a critical transcription factor in IFNgamma signaling, and the loss of JAK2 is associated with PD-1 inhibitor resistance.	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('IFNgamma', 'Gene', (43, 51))	('JAK', 'molecular_function', 'GO:0004713', ('79', '82'))	('JAK2', 'Gene', '3717', (0, 4))	('JAK2', 'Gene', '3717', (79, 83))	('PD-1', 'Gene', (103, 107))	('IFNgamma', 'Gene', '3458', (43, 51))	('associated', 'Reg', (87, 97))	('PD-1', 'Gene', '5133', (103, 107))	('transcription factor', 'molecular_function', 'GO:0000981', ('19', '39'))	('JAK2', 'Gene', (0, 4))	('JAK', 'molecular_function', 'GO:0004713', ('0', '3'))	('transcription', 'biological_process', 'GO:0006351', ('19', '32'))	('loss', 'Var', (71, 75))	('JAK2', 'Gene', (79, 83))
134528	33076392	Hence, loss of CDKN2A may increase inflammatory responses, which may augment response to immune checkpoint blockade, but also confer susceptibility to immunotherapy resistance through IFNgamma suppression.	('inflammatory responses', 'CPA', (35, 57))	('response to immune checkpoint blockade', 'MPA', (77, 115))	('CDKN2A', 'Gene', (15, 21))	('IFNgamma', 'Gene', (184, 192))	('loss', 'Var', (7, 11))	('increase inflammatory responses', 'Phenotype', 'HP:0012649', (26, 57))	('susceptibility', 'Reg', (133, 147))	('IFNgamma', 'Gene', '3458', (184, 192))	('augment', 'PosReg', (69, 76))	('increase', 'PosReg', (26, 34))
134529	33076392	Given the complexity of the immune response and the heterogeneity of immune cell subsets, it is unclear if and how p14ARF and/or p16INK4a regulate melanoma response to immunotherapy.	('p14ARF', 'Gene', '1029', (115, 121))	('regulate', 'Reg', (138, 146))	('p14ARF', 'Gene', (115, 121))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('immune response', 'biological_process', 'GO:0006955', ('28', '43'))	('p16INK4a', 'Var', (129, 137))
134530	33076392	CDKN2A mutations were not significantly associated with clinical outcomes such as median time to progression, overall survival, and disease control rate in a cohort of 102 cutaneous melanoma patients treated with immune checkpoint inhibitors.	('patients', 'Species', '9606', (191, 199))	('cutaneous melanoma', 'Disease', (172, 190))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (172, 190))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (172, 190))	('CDKN2A', 'Gene', (0, 6))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('mutations', 'Var', (7, 16))
134531	33076392	However, this study did report a trend towards improved time to progression and disease control rate in patients with CDKN2A mutations.	('CDKN2A', 'Gene', (118, 124))	('mutations', 'Var', (125, 134))	('improved', 'PosReg', (47, 55))	('disease control rate', 'CPA', (80, 100))	('patients', 'Species', '9606', (104, 112))	('time to progression', 'MPA', (56, 75))
134532	33076392	Similarly, melanoma patients with CDKN2A germline mutations also showed improved response to immune checkpoint blockade; approximately 58% of carriers responded to therapy, with 32% showing complete response, suggesting that CDKN2A mutation may be associated with better immunotherapy response rates.	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('immunotherapy response', 'CPA', (271, 293))	('mutation', 'Var', (232, 240))	('CDKN2A', 'Gene', (225, 231))	('CDKN2A', 'Gene', (34, 40))	('patients', 'Species', '9606', (20, 28))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
134533	33076392	Although the mechanism for improved immunotherapy responsiveness in CDKN2A mutation carriers remains unclear, melanomas with somatic CDKN2A mutations have an increased mutational burden, and this may result in more neoantigens and stronger immune responses.	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('immune responses', 'CPA', (240, 256))	('melanomas', 'Disease', 'MESH:D008545', (110, 119))	('mutation', 'Var', (75, 83))	('neoantigens', 'MPA', (215, 226))	('CDKN2A', 'Gene', (68, 74))	('CDKN2A', 'Gene', (133, 139))	('more', 'PosReg', (210, 214))	('mutational burden', 'MPA', (168, 185))	('melanomas', 'Disease', (110, 119))	('mutations', 'Var', (140, 149))	('stronger', 'PosReg', (231, 239))	('increased', 'PosReg', (158, 167))
134540	33076392	Similar to p14ARF, ectopic expression of p16INK4a in glioma cell lines also sensitized cells to the chemotherapy drug vincristine.	('p16INK4a', 'Var', (41, 49))	('p14ARF', 'Gene', '1029', (11, 17))	('ectopic expression', 'Var', (19, 37))	('glioma', 'Disease', (53, 59))	('sensitized', 'Reg', (76, 86))	('p14ARF', 'Gene', (11, 17))	('vincristine', 'Chemical', 'MESH:D014750', (118, 129))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))
134541	33076392	In melanoma cells, CDKN2A expression was associated with better response to chemotherapy in the form of melphalan or actinomycin-D, and enforced accumulation of p16INK4a induced cell death by augmenting response to these cytotoxic drugs.	('death', 'Disease', (183, 188))	('better', 'PosReg', (57, 63))	('p16INK4a', 'Var', (161, 169))	('response to these cytotoxic drugs', 'MPA', (203, 236))	('CDKN2A', 'Gene', (19, 25))	('actinomycin', 'Chemical', 'MESH:D003609', (117, 128))	('melphalan', 'Chemical', 'MESH:D008558', (104, 113))	('cell death', 'biological_process', 'GO:0008219', ('178', '188'))	('response to chemotherapy', 'MPA', (64, 88))	('accumulation', 'PosReg', (145, 157))	('induced', 'PosReg', (170, 177))	('augmenting', 'PosReg', (192, 202))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('death', 'Disease', 'MESH:D003643', (183, 188))
134543	33076392	Many CDKN2A genetic and epigenetic changes impact both the p16INK4a and p14ARF protein products encoded by this locus, and although early studies confirmed the major contribution of p16INK4a in CDKN2A-associated melanoma, there is now significant evidence that p14ARF plays an important and additional role in melanomagenesis.	('p14ARF', 'Gene', '1029', (261, 267))	('impact', 'Reg', (43, 49))	('p14ARF', 'Gene', '1029', (72, 78))	('melanoma', 'Phenotype', 'HP:0002861', (310, 318))	('p16INK4a', 'Var', (182, 190))	('melanoma', 'Disease', (310, 318))	('CDKN2A', 'Gene', (5, 11))	('melanoma', 'Disease', 'MESH:D008545', (310, 318))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('CDKN2A-associated', 'Gene', (194, 211))	('p14ARF', 'Gene', (261, 267))	('p14ARF', 'Gene', (72, 78))	('melanoma', 'Disease', (212, 220))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))	('changes', 'Var', (35, 42))
134544	33076392	CDKN2A loss is associated with histological features predictive of poor prognosis in melanoma and also correlates with diminished patient response to treatment, with loss of CDKN2A associated with poor response to BRAF/MEK inhibitors and chemotherapy but potentially improved responses to immune checkpoint inhibitors.	('associated', 'Reg', (181, 191))	('loss', 'NegReg', (7, 11))	('patient', 'Species', '9606', (130, 137))	('BRAF', 'Gene', '673', (214, 218))	('BRAF', 'Gene', (214, 218))	('MEK', 'Gene', (219, 222))	('loss', 'Var', (166, 170))	('CDKN2A', 'Gene', (174, 180))	('diminished', 'NegReg', (119, 129))	('MEK', 'Gene', '5609', (219, 222))	('patient response to', 'MPA', (130, 149))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('CDKN2A', 'Gene', (0, 6))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))
134545	33076392	The loss of the CDKN2A sequence also co-operates with the BRAF and NRAS oncogenes to promote melanoma development.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('promote', 'PosReg', (85, 92))	('CDKN2A', 'Gene', (16, 22))	('NRAS', 'Gene', (67, 71))	('BRAF', 'Gene', '673', (58, 62))	('NRAS', 'Gene', '4893', (67, 71))	('BRAF', 'Gene', (58, 62))	('loss', 'Var', (4, 8))
134546	33076392	Thus, there is renewed interest in restoring the functional loss of p16INK4a and p14ARF in melanoma, and the frequent loss of this locus in melanoma may provide unique therapeutic opportunities, as the downstream targets retinoblastoma protein and p53 are often retained.	('retinoblastoma', 'Phenotype', 'HP:0009919', (221, 235))	('p16INK4a', 'Var', (68, 76))	('p14ARF', 'Gene', (81, 87))	('p53', 'Gene', (248, 251))	('p53', 'Gene', '7157', (248, 251))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('loss', 'NegReg', (118, 122))	('loss', 'NegReg', (60, 64))	('retinoblastoma', 'Disease', (221, 235))	('retinoblastoma', 'Disease', 'MESH:D012175', (221, 235))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('protein', 'cellular_component', 'GO:0003675', ('236', '243'))	('p14ARF', 'Gene', '1029', (81, 87))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))
134549	31580399	Intraocular Metastasis in Unilateral Multifocal Uveal Melanoma Without Melanocytosis or Germline BAP1 Mutations There has been speculation on the pathogenesis of unilateral multifocal uveal melanoma, but there remains no convincing explanation.	('unilateral multifocal uveal melanoma', 'Disease', 'MESH:C536494', (162, 198))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('BAP1', 'Gene', '8314', (97, 101))	('Melanoma Without Melanocytosis', 'Disease', (54, 84))	('uveal melanoma', 'Phenotype', 'HP:0007716', (184, 198))	('unilateral multifocal uveal melanoma', 'Disease', (162, 198))	('Mutations', 'Var', (102, 111))	('BAP1', 'Gene', (97, 101))	('Melanoma Without Melanocytosis', 'Disease', 'MESH:D008545', (54, 84))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('Melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('pathogenesis', 'biological_process', 'GO:0009405', ('146', '158'))
134558	31580399	Unilateral multifocal uveal melanoma in the absence of ocular melanocytosis appears to occur preferentially in tumors with the class 2 gene expression profile and a BRCA1-associated protein 1 gene (BAP1) mutation.	('mutation', 'Var', (204, 212))	('ocular melanocytosis', 'Disease', (55, 75))	('BRCA1-associated protein 1', 'Gene', (165, 191))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('gene expression', 'biological_process', 'GO:0010467', ('135', '150'))	('tumors', 'Disease', (111, 117))	('BAP1', 'Gene', '8314', (198, 202))	('uveal melanoma', 'Phenotype', 'HP:0007716', (22, 36))	('absence of ocular', 'Phenotype', 'HP:0000528', (44, 61))	('ocular melanocytosis', 'Disease', 'MESH:C535835', (55, 75))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('protein', 'cellular_component', 'GO:0003675', ('182', '189'))	('BAP1', 'Gene', (198, 202))	('ocular melanocytosis', 'Phenotype', 'HP:0025534', (55, 75))	('BRCA1-associated protein 1', 'Gene', '8314', (165, 191))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('uveal melanoma', 'Disease', 'MESH:C536494', (22, 36))	('uveal melanoma', 'Disease', (22, 36))
134559	31580399	The presence of identical BAP1 mutations in multiple tumors in the same eye in the absence of a germline BAP1 mutation suggests intraocular metastasis rather than independent primary tumors.	('BAP1', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('intraocular', 'Disease', 'MESH:D009798', (128, 139))	('intraocular', 'Disease', (128, 139))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('BAP1', 'Gene', '8314', (105, 109))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('BAP1', 'Gene', '8314', (26, 30))	('tumors', 'Disease', (183, 189))	('tumors', 'Disease', (53, 59))	('BAP1', 'Gene', (105, 109))
134576	31580399	Sequencing revealed an oncogenic mutation in the G protein subunit alpha Q gene (GNAQ) p.Q209L and a deletion in the BAP1 p.R207fs (Table and Figure 2).	('p.R207fs', 'Var', (122, 130))	('deletion', 'Var', (101, 109))	('BAP1', 'Gene', '8314', (117, 121))	('p.Q209L', 'Mutation', 'rs121913492', (87, 94))	('GNAQ', 'Gene', (81, 85))	('p.R207fs', 'Mutation', 'p.R207fsX', (122, 130))	('BAP1', 'Gene', (117, 121))	('p.Q209L', 'Var', (87, 94))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))	('GNAQ', 'Gene', '2776', (81, 85))
134579	31580399	One of the subsequent tumors revealed GNAQ and BAP1 mutations identical to the initial tumor.	('mutations', 'Var', (52, 61))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('GNAQ', 'Gene', '2776', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('GNAQ', 'Gene', (38, 42))	('BAP1', 'Gene', '8314', (47, 51))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumors', 'Disease', (22, 28))	('BAP1', 'Gene', (47, 51))
134583	31580399	Fine-needle aspiration biopsy revealed a mixed spindle and epithelioid cell melanoma with a class 2 GEP, the guanine nucleotide-binding protein subunit alpha-11 gene (GNA11) mutation (p.Q209L), and no detectable BAP1 mutation (Table and Figure 2).	('melanoma', 'Disease', (76, 84))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('117', '135'))	('p.Q209L', 'Var', (184, 191))	('BAP1', 'Gene', (212, 216))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('guanine nucleotide-binding protein subunit alpha-11', 'Gene', '2767', (109, 160))	('GNA11', 'Gene', (167, 172))	('GNA11', 'Gene', '2767', (167, 172))	('p.Q209L', 'Mutation', 'rs121913492', (184, 191))	('aspiration', 'Phenotype', 'HP:0002835', (12, 22))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('BAP1', 'Gene', '8314', (212, 216))	('spindle', 'cellular_component', 'GO:0005819', ('47', '54'))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
134587	31580399	The second tumor was class 2, with a GNA11 mutation identical to the first tumor (Table and Figure 2) and no detectable BAP1 mutation.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('GNA11', 'Gene', '2767', (37, 42))	('GNA11', 'Gene', (37, 42))	('mutation', 'Var', (43, 51))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('BAP1', 'Gene', '8314', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', (75, 80))	('BAP1', 'Gene', (120, 124))
134590	31580399	Treatment with iodine 125 plaque radio-therapy and FNAB revealed spindle-epithelioid melanoma, a class 2 GEP, a GNA11 mutation (p.Q209L), and a BAP1 mutation (p.R244fs) (Table and Figure 2).	('spindle', 'cellular_component', 'GO:0005819', ('65', '72'))	('p.R244fs', 'Mutation', 'p.R244fsX', (159, 167))	('GNA11', 'Gene', (112, 117))	('p.R244fs', 'Var', (159, 167))	('BAP1', 'Gene', (144, 148))	('iodine', 'Chemical', 'MESH:D007455', (15, 21))	('GNA11', 'Gene', '2767', (112, 117))	('p.Q209L', 'Mutation', 'rs121913492', (128, 135))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('p.Q209L', 'Var', (128, 135))	('BAP1', 'Gene', '8314', (144, 148))
134593	31580399	Fine-needle aspiration biopsy revealed spindle-epithelioid melanoma, class 2 GEP, and GNA11 and BAP1 mutations identical to the first tumor.	('GNA11', 'Gene', '2767', (86, 91))	('mutations', 'Var', (101, 110))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('BAP1', 'Gene', (96, 100))	('aspiration', 'Phenotype', 'HP:0002835', (12, 22))	('spindle', 'cellular_component', 'GO:0005819', ('39', '46'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('GNA11', 'Gene', (86, 91))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('BAP1', 'Gene', '8314', (96, 100))	('tumor', 'Disease', (134, 139))
134596	31580399	Afterundergoingiodine125plaqueradiotherapyandFNAB, which revealed class 2 GEP, GNA11 mutation (p.Q209L), and BAP1 mutation (p.E198fs) (Table and Figure 2), the patient underwent vitrectomy to remove pigmented vitreous cells, which were found to be melanoma cells on cytopathologic examination.	('melanoma', 'Disease', (248, 256))	('pigmented', 'Disease', 'MESH:D010859', (199, 208))	('patient', 'Species', '9606', (160, 167))	('p.Q209L', 'Var', (95, 102))	('BAP1', 'Gene', '8314', (109, 113))	('GNA11', 'Gene', '2767', (79, 84))	('GNA11', 'Gene', (79, 84))	('p.Q209L', 'Mutation', 'rs121913492', (95, 102))	('p.E198fs', 'Var', (124, 132))	('p.E198fs', 'Mutation', 'rs1205668341', (124, 132))	('BAP1', 'Gene', (109, 113))	('iodine', 'Chemical', 'MESH:D007455', (15, 21))	('pigmented', 'Disease', (199, 208))	('melanoma', 'Disease', 'MESH:D008545', (248, 256))	('melanoma', 'Phenotype', 'HP:0002861', (248, 256))
134600	31580399	The second tumor was class 2 and harbored GNA11 and BAP1 mutations identical to those of the original tumor.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('BAP1', 'Gene', '8314', (52, 56))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('BAP1', 'Gene', (52, 56))	('GNA11', 'Gene', (42, 47))	('mutations', 'Var', (57, 66))	('GNA11', 'Gene', '2767', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
134605	31580399	In the cases in this study that lacked an identifiable predisposing condition, mutational analysis provided evidence for intraocular metastasis from a primary tumor to a second noncontiguous intraocular location.	('intraocular', 'Disease', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('intraocular', 'Disease', 'MESH:D009798', (191, 202))	('intraocular', 'Disease', (191, 202))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('mutational', 'Var', (79, 89))	('intraocular', 'Disease', 'MESH:D009798', (121, 132))
134607	31580399	Considering the relative frequency of each specific GNAQ11 mutation in primary uveal melanoma, the odds of any 1 of them arising twice in the same eye ranged from 1 in 5 to 1 in 47.	('GNAQ', 'Gene', '2776', (52, 56))	('mutation', 'Var', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('GNAQ', 'Gene', (52, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('uveal melanoma', 'Disease', (79, 93))
134608	31580399	Even more improbable would be the same BAP1 mutation arising independently in the same eye, since these mutations are mostly unique.	('BAP1', 'Gene', '8314', (39, 43))	('mutation', 'Var', (44, 52))	('BAP1', 'Gene', (39, 43))
134624	30518599	Accordingly, parabiosis experiments demonstrated that MAIT and NKT cells are resident in the spleen, liver, and lungs, with LFA1/ICAM1 interactions controlling MAIT1 and NKT1 retention in spleen and liver.	('LFA1', 'Gene', (124, 128))	('NKT1', 'Gene', (170, 174))	('ICAM1', 'Gene', (129, 134))	('ICAM1', 'Gene', '15894', (129, 134))	('rat', 'Species', '10116', (43, 46))	('retention', 'biological_process', 'GO:0051235', ('175', '184'))	('NKT1', 'Gene', '493025', (170, 174))	('interactions', 'Var', (135, 147))	('LFA1', 'Gene', '16408', (124, 128))
134641	30518599	In C57BL/6, NKT1 cells are far more numerous than any other NKT subset, while MAIT17 cells are more abundant than MAIT1 cells both in the thymus and the periphery.	('NKT1', 'Gene', (12, 16))	('C57BL/6', 'Var', (3, 10))	('NKT1', 'Gene', '493025', (12, 16))
134672	30518599	Finally, some calcium-binding proteins (S100a8 and S100a9), as well as Lyz2, show a tissue-specific expression pattern.	('S100a9', 'Var', (51, 57))	('binding', 'molecular_function', 'GO:0005488', ('22', '29'))	('Lyz2', 'Gene', '17105', (71, 75))	('S100a8', 'Var', (40, 46))	('calcium', 'Chemical', 'MESH:D002118', (14, 21))	('calcium-binding proteins', 'Protein', (14, 38))	('Lyz2', 'Gene', (71, 75))
134744	30518599	In contrast, despite similar residency transcriptional program and intra-/extravascular location, liver and spleen preset-17 subsets are not released upon ICAM1/LFA1 interaction blockade.	('ICAM1', 'Gene', '15894', (155, 160))	('blockade', 'Var', (178, 186))	('LFA1', 'Gene', '16408', (161, 165))	('interaction', 'Interaction', (166, 177))	('LFA1', 'Gene', (161, 165))	('ICAM1', 'Gene', (155, 160))
134824	30518599	S2 shows the absence of Vbeta6 and Vbeta8 TCR bias in MAIT1 and MAIT17 subsets.	('TCR', 'Gene', (42, 45))	('TCR', 'Gene', '328483', (42, 45))	('Vbeta6', 'Var', (24, 30))	('TCR', 'cellular_component', 'GO:0042101', ('42', '45'))	('MAIT1', 'CPA', (54, 59))	('Vbeta8', 'Var', (35, 41))	('TCR', 'biological_process', 'GO:0006283', ('42', '45'))
134865	29141225	The genes included in this panel were selected based on previously described mutations and copy number variations in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('copy number variations', 'Var', (91, 113))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
134869	29141225	Half (55%) of all samples analyzed were BRAF hotspot mutant, 20% NRAS mutant, 7% NF1 mutant, 2% KIT, 1.4% GNAQ/GNA11, and 18% wild-type (WT) (Figure 3A and Supplementary File S2).	('NRAS', 'Gene', '4893', (65, 69))	('NF1', 'Gene', (81, 84))	('mutant', 'Var', (70, 76))	('GNAQ', 'Gene', (106, 110))	('NF1', 'Gene', '4763', (81, 84))	('GNA11', 'Gene', (111, 116))	('KIT', 'molecular_function', 'GO:0005020', ('96', '99'))	('mutant', 'Var', (53, 59))	('mutant', 'Var', (85, 91))	('GNA11', 'Gene', '2767', (111, 116))	('NRAS', 'Gene', (65, 69))	('GNAQ', 'Gene', '2776', (106, 110))
134871	29141225	Thirty-seven of the BRAF hotspot mutation PDX were from patients progressed on a BRAF inhibitor (12 previously published in and 44 progressed on BRAF/MEK inhibitor combination therapy.	('patients', 'Species', '9606', (56, 64))	('PDX', 'Chemical', '-', (42, 45))	('mutation', 'Var', (33, 41))	('MEK', 'Gene', '5609', (150, 153))	('BRAF', 'Gene', (20, 24))	('MEK', 'Gene', (150, 153))
134877	29141225	Further, the cell lines include seven from brain metastasis, two acral melanoma (WM4324: V600E, WM4235: Q61R) and one mucosal (WM4173: WT/WT).	('WM4235: Q61R', 'Var', (96, 108))	('acral melanoma', 'Disease', 'MESH:D008545', (65, 79))	('brain metastasis', 'Disease', 'MESH:D009362', (43, 59))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('Q61R', 'Mutation', 'rs11554290', (104, 108))	('V600E', 'Mutation', 'rs113488022', (89, 94))	('brain metastasis', 'Disease', (43, 59))	('WM4324: V600E', 'Var', (81, 94))	('acral melanoma', 'Phenotype', 'HP:0012060', (65, 79))	('acral melanoma', 'Disease', (65, 79))
134885	29141225	Targeted sequencing of resistant PDX tumors using our 108-gene panel confirmed a BRAFV600 hotspot mutation in all but two of the models.	('BRAFV600', 'Gene', (81, 89))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('mutation', 'Var', (98, 106))	('PDX', 'Chemical', '-', (33, 36))	('hotspot', 'PosReg', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
134886	29141225	These two PDX models were established from patients with clinical BRAFV600E positive tumors.	('PDX', 'Chemical', '-', (10, 13))	('BRAFV600E', 'Mutation', 'rs113488022', (66, 75))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('patients', 'Species', '9606', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('BRAFV600E positive', 'Var', (66, 84))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
134887	29141225	However, the patient material tested for WM4323 was the primary cutaneous melanoma diagnostic biopsy accessioned 5 years prior to the specimen sent for PDX.	('PDX', 'Chemical', '-', (152, 155))	('patient', 'Species', '9606', (13, 20))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (64, 82))	('WM4323', 'Var', (41, 47))
134889	29141225	We found concomitant RAS (n=7/47 patients) and MAP2K1/2 (n=9/47 patients) mutations.	('patients', 'Species', '9606', (33, 41))	('patients', 'Species', '9606', (64, 72))	('MAP2K1/2', 'Gene', '5604;5605', (47, 55))	('MAP2K', 'molecular_function', 'GO:0004708', ('47', '52'))	('mutations', 'Var', (74, 83))	('MAP2K1/2', 'Gene', (47, 55))	('RAS', 'Disease', (21, 24))
134891	29141225	PDX from 15 patients had alterations in the PI3K signaling pathway (13 PTEN deletion, 3 deleterious PTEN mutation, 5 likely deleterious PTEN mutation, 1 deleterious PIK3CA mutation) although these were not mutually exclusive with the other genomic changes observed.	('PTEN', 'Gene', (100, 104))	('deletion', 'Var', (76, 84))	('patients', 'Species', '9606', (12, 20))	('PTEN', 'Gene', '5728', (100, 104))	('signaling pathway', 'biological_process', 'GO:0007165', ('49', '66'))	('PIK3CA', 'Gene', (165, 171))	('PI3K signaling', 'biological_process', 'GO:0014065', ('44', '58'))	('PTEN', 'Gene', (71, 75))	('PTEN', 'Gene', '5728', (71, 75))	('PDX', 'Chemical', '-', (0, 3))	('PIK3CA', 'Gene', '5290', (165, 171))	('PTEN', 'Gene', (136, 140))	('alterations', 'Reg', (25, 36))	('PTEN', 'Gene', '5728', (136, 140))	('PI3K signaling pathway', 'Pathway', (44, 66))	('PI3K', 'molecular_function', 'GO:0016303', ('44', '48'))
134893	29141225	Of these, two (WM4298, WM4351) had acquired NRAS mutations on dabrafenib-trametinib combination therapy (D/T) and progressed after 406 and 161 days respectively.	('mutations', 'Var', (49, 58))	('NRAS', 'Gene', (44, 48))	('WM4298', 'CellLine', 'CVCL:6806', (15, 21))	('WM4351', 'Var', (23, 29))	('NRAS', 'Gene', '4893', (44, 48))	('dabrafenib', 'Chemical', 'MESH:C561627', (62, 72))	('trametinib', 'Chemical', 'MESH:C560077', (73, 83))
134894	29141225	WM4264 had PFS of 120 days and an acquired MEK2K61E heterozygous mutation in the relapse PDX.	('MEK', 'Gene', '5609', (43, 46))	('WM4264', 'Var', (0, 6))	('PDX', 'Chemical', '-', (89, 92))	('MEK2', 'molecular_function', 'GO:0004708', ('43', '47'))	('MEK', 'Gene', (43, 46))
134896	29141225	WM4070 PDX were established from the patient with the shortest PFS (60 days) and we found a pre-existing MEK1 mutation in both pre-and post- therapy PDX.	('pre', 'molecular_function', 'GO:0003904', ('127', '130'))	('MEK1', 'Gene', '5604', (105, 109))	('MEK1', 'molecular_function', 'GO:0004708', ('105', '109'))	('patient', 'Species', '9606', (37, 44))	('MEK1', 'Gene', (105, 109))	('pre', 'molecular_function', 'GO:0003904', ('92', '95'))	('mutation', 'Var', (110, 118))	('PDX', 'Chemical', '-', (7, 10))	('PDX', 'Chemical', '-', (149, 152))
134897	29141225	The remaining two models (WM4276, WM4237) had pre-existing loss of PTEN and amplification of MET respectively as possible contributors to resistance (Figure 3C).	('WM4237', 'Var', (34, 40))	('PTEN', 'Gene', (67, 71))	('amplification', 'MPA', (76, 89))	('PTEN', 'Gene', '5728', (67, 71))	('loss', 'NegReg', (59, 63))	('pre', 'molecular_function', 'GO:0003904', ('46', '49'))	('WM4276', 'Var', (26, 32))	('MET', 'MPA', (93, 96))
134902	29141225	Remarkably, four brain metastases were collected from the same patient (WM4237-1 to -4) at 2- to 4-month intervals.	('metastases', 'Disease', (23, 33))	('metastases', 'Disease', 'MESH:D009362', (23, 33))	('patient', 'Species', '9606', (63, 70))	('WM4237-1', 'Var', (72, 80))
134905	29141225	Another BRAF non-hotspot mutation was co-occurring with an NF1 mutation.	('BRAF', 'Gene', (8, 12))	('mutation', 'Var', (25, 33))	('mutation', 'Var', (63, 71))	('NF1', 'Gene', (59, 62))	('NF1', 'Gene', '4763', (59, 62))
134907	29141225	We found PTEN deletion or deleterious mutation in four of 7 patients with BRAF hotspot mutation which has been shown to be associated with MBM.	('deleterious mutation', 'Var', (26, 46))	('associated', 'Reg', (123, 133))	('BRAF', 'Gene', (74, 78))	('PTEN', 'Gene', (9, 13))	('patients', 'Species', '9606', (60, 68))	('PTEN', 'Gene', '5728', (9, 13))	('MBM', 'Disease', (139, 142))	('deletion', 'Var', (14, 22))	('mutation', 'Var', (87, 95))
134908	29141225	On the protein expression level, both patients with deleterious PTEN mutations had evidence of PI3K pathway activation by relative increased phospho AKT compared to WT PTEN samples.	('mutations', 'Var', (69, 78))	('PTEN', 'Gene', (168, 172))	('protein', 'cellular_component', 'GO:0003675', ('7', '14'))	('increased', 'PosReg', (131, 140))	('PTEN', 'Gene', '5728', (168, 172))	('PTEN', 'Gene', '5728', (64, 68))	('AKT', 'Gene', (149, 152))	('PI3K pathway', 'Pathway', (95, 107))	('PTEN', 'Gene', (64, 68))	('patients', 'Species', '9606', (38, 46))	('PI3K', 'molecular_function', 'GO:0016303', ('95', '99'))	('AKT', 'Gene', '207', (149, 152))	('activation', 'PosReg', (108, 118))
134911	29141225	Three of these had mutations in GNAQ or GNA11, one was WT, and one failed genomic analysis.	('GNAQ', 'Gene', (32, 36))	('GNA11', 'Gene', (40, 45))	('GNA11', 'Gene', '2767', (40, 45))	('GNAQ', 'Gene', '2776', (32, 36))	('mutations', 'Var', (19, 28))
134920	29141225	There was a significant increase in metastatic ability of BRAF hotspot mutant PDX and a decreased metastatic rate in triple WT PDX (Figure 4F).	('PDX', 'Gene', (78, 81))	('increase', 'PosReg', (24, 32))	('metastatic rate', 'CPA', (98, 113))	('metastatic ability', 'CPA', (36, 54))	('mutant', 'Var', (71, 77))	('decreased', 'NegReg', (88, 97))	('PDX', 'Chemical', '-', (78, 81))	('PDX', 'Chemical', '-', (127, 130))	('BRAF', 'Gene', (58, 62))
134925	29141225	However, tumors derived from targeted therapy progressed patients had significantly higher levels of IGF-1R than tumors from therapy naive patients (Figure 4I).	('IGF-1R', 'Gene', '3480', (101, 107))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('patients', 'Species', '9606', (139, 147))	('patients', 'Species', '9606', (57, 65))	('IGF-1R', 'Gene', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('levels', 'MPA', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('targeted', 'Var', (29, 37))	('tumors', 'Disease', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('higher', 'PosReg', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
134934	29141225	Two had homozygous PTEN deletion and one had an activating NRASQ61K mutation; all showed activation of both MAPK and PI3K pathways on the protein level.	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('PTEN', 'Gene', (19, 23))	('PTEN', 'Gene', '5728', (19, 23))	('PI3K', 'molecular_function', 'GO:0016303', ('117', '121'))	('activation', 'PosReg', (89, 99))	('deletion', 'Var', (24, 32))	('NRAS', 'Gene', (59, 63))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('NRAS', 'Gene', '4893', (59, 63))
134935	29141225	The MEK inhibitor trametinib and the PI3K beta/delta isoform-specific inhibitor GSK418 (an analog of GSK2636771 (Rivero and Hardwicke) significantly decreased tumor growth in the two PDX models with PTEN deletion without evident toxicity (Figure 5D), but not in the PDX with concurrent BRAF and NRAS mutation.	('PTEN', 'Gene', '5728', (199, 203))	('PDX', 'Chemical', '-', (183, 186))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('toxicity', 'Disease', 'MESH:D064420', (229, 237))	('GSK', 'molecular_function', 'GO:0050321', ('101', '104'))	('PI3K beta', 'Gene', (37, 46))	('MEK', 'Gene', '5609', (4, 7))	('PI3K beta', 'Gene', '5291', (37, 46))	('PI3K', 'molecular_function', 'GO:0016303', ('37', '41'))	('NRAS', 'Gene', (295, 299))	('toxicity', 'Disease', (229, 237))	('GSK418', 'Gene', (80, 86))	('GSK418', 'Chemical', '-', (80, 86))	('deletion', 'Var', (204, 212))	('GSK', 'molecular_function', 'GO:0050321', ('80', '83'))	('MEK', 'Gene', (4, 7))	('PDX', 'Chemical', '-', (266, 269))	('GSK2636771', 'Chemical', 'MESH:C000627739', (101, 111))	('tumor', 'Disease', (159, 164))	('decreased', 'NegReg', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('PTEN', 'Gene', (199, 203))	('trametinib', 'Chemical', 'MESH:C560077', (18, 28))	('NRAS', 'Gene', '4893', (295, 299))
134936	29141225	WM3973 was derived from a patient progressed on vemurafenib with MAPK pathway reactivation via an activating MAP2K1 (MEK1) mutation as a potential resistance mechanism.	('patient', 'Species', '9606', (26, 33))	('MAPK pathway', 'Pathway', (65, 77))	('mutation', 'Var', (123, 131))	('MEK1', 'Gene', '5604', (117, 121))	('vemurafenib', 'Chemical', 'MESH:D000077484', (48, 59))	('MAP2K1', 'Gene', '5604', (109, 115))	('MAPK', 'molecular_function', 'GO:0004707', ('65', '69'))	('MAP2K1', 'Gene', (109, 115))	('reactivation', 'PosReg', (78, 90))	('MAP2K', 'molecular_function', 'GO:0004708', ('109', '114'))	('MEK1', 'molecular_function', 'GO:0004708', ('117', '121'))	('MEK1', 'Gene', (117, 121))	('activating', 'PosReg', (98, 108))
134955	29141225	We identified eight PDX with the canonical IDH1 mutation R132C.	('R132C', 'Mutation', 'rs121913499', (57, 62))	('R132C', 'Var', (57, 62))	('IDH1', 'Gene', (43, 47))	('IDH1', 'Gene', '3417', (43, 47))	('PDX', 'Chemical', '-', (20, 23))
134966	29141225	Established melanoma cell lines have significant bias toward BRAF, TP53 mutations, and CDKN2A loss since these adapt well to in vitro growth.	('mutations', 'Var', (72, 81))	('CDKN2A', 'Gene', '1029', (87, 93))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', (12, 20))	('loss', 'NegReg', (94, 98))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('CDKN2A', 'Gene', (87, 93))
134972	29141225	established 89 PDX, but focused on BRAF mutant patients with only 10 NRAS and 6 WT/WT samples.	('NRAS', 'Gene', '4893', (69, 73))	('BRAF', 'Gene', (35, 39))	('PDX', 'Chemical', '-', (15, 18))	('patients', 'Species', '9606', (47, 55))	('mutant', 'Var', (40, 46))	('NRAS', 'Gene', (69, 73))
134975	29141225	Pre-clinical data by several groups have suggested that combining BRAF/MEK inhibitors with PI3K/mTOR inhibitors may overcome resistance in BRAF mutant melanomas.	('resistance', 'MPA', (125, 135))	('mTOR', 'Gene', (96, 100))	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('BRAF', 'Gene', (139, 143))	('melanomas', 'Disease', (151, 160))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('PI3K', 'molecular_function', 'GO:0016303', ('91', '95'))	('MEK', 'Gene', (71, 74))	('melanomas', 'Phenotype', 'HP:0002861', (151, 160))	('mutant', 'Var', (144, 150))	('mTOR', 'Gene', '2475', (96, 100))	('MEK', 'Gene', '5609', (71, 74))	('melanomas', 'Disease', 'MESH:D008545', (151, 160))
134976	29141225	On the other hand, a Phase I trial testing the combination of pan-PI3K/mTORC1/2 inhibitor GSK2126458 with trametinib was terminated due to a lack of tolerability and efficacy (NCT01248858), suggesting a narrower targeting profile might be advantageous.	('GSK', 'molecular_function', 'GO:0050321', ('90', '93'))	('mTORC1/2', 'Gene', (71, 79))	('GSK2126458', 'Chemical', 'MESH:C561454', (90, 100))	('mTORC1', 'cellular_component', 'GO:0031931', ('71', '77'))	('PI3K', 'molecular_function', 'GO:0016303', ('66', '70'))	('trametinib', 'Chemical', 'MESH:C560077', (106, 116))	('GSK2126458', 'Var', (90, 100))	('mTORC1/2', 'Gene', '74343;382056', (71, 79))
134984	29141225	IDH1 is a rarely mutated oncogene in melanoma, representing about 6% of driver mutations and has been described as a viable target in other cancers.	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('IDH1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutations', 'Var', (79, 88))	('IDH1', 'Gene', '3417', (0, 4))
135003	29141225	PDX tumors from patients progressed on BRAF or BRAF/MEK inhibitor therapy were expanded on continuous PLX4720 200ppm or PLX4720 200ppm + PD-0325901 7ppm chemical additive diet (Research Diets, New Brunswick, NJ).	('PLX4720 200ppm', 'Var', (120, 134))	('tumors', 'Disease', (4, 10))	('patients', 'Species', '9606', (16, 24))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('MEK', 'Gene', (52, 55))	('MEK', 'Gene', '5609', (52, 55))	('PD-0325901', 'Chemical', 'MESH:C506614', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('PDX', 'Chemical', '-', (0, 3))
135020	29141225	For surface staining, cells were incubated at 4 C for 30 minutes with anti-human PeCy7 CD146 (M-CAM), anti-mouse FITC- CD45, H2Kb and H2Kd and anti-human PE IGFR1 from BD Biosciences (San Jose, CA).	('anti-mouse', 'Var', (102, 112))	('CD45', 'Gene', '5788', (119, 123))	('CD146', 'Gene', (87, 92))	('mouse', 'Species', '10090', (107, 112))	('IGFR1', 'Gene', '100132417', (157, 162))	('FITC', 'Chemical', 'MESH:D016650', (113, 117))	('human', 'Species', '9606', (148, 153))	('CAM', 'Gene', '808', (96, 99))	('IGFR1', 'Gene', (157, 162))	('CD45', 'Gene', (119, 123))	('human', 'Species', '9606', (75, 80))	('CAM', 'Gene', (96, 99))	('CD146', 'Gene', '84004', (87, 92))
135041	29069806	From the aforementioned results, BAP1 inactivation is expected to affect transcription regulation, either through direct gene expression dysregulation or chromatin structure perturbation.	('transcription regulation', 'MPA', (73, 97))	('affect', 'Reg', (66, 72))	('regulation', 'biological_process', 'GO:0065007', ('87', '97'))	('inactivation', 'Var', (38, 50))	('BAP1', 'Gene', '8314', (33, 37))	('transcription', 'biological_process', 'GO:0006351', ('73', '86'))	('BAP1', 'Gene', (33, 37))	('chromatin', 'cellular_component', 'GO:0000785', ('154', '163'))	('gene expression', 'biological_process', 'GO:0010467', ('121', '136'))
135065	29069806	In order to confirm the phenotypes predicted by IPA on the SILAC-based proteomics data and to determine the involvement of BAP1 catalytic activity, NCI-H226 and QR (also known as MPM_33) mesothelioma cell lines were complemented with pBABE retroviral vector alone (EV), pBABE expressing a wild-type BAP1 protein (BAP1wt), or the same vector expressing a catalytically dead BAP1 protein carrying the C91S point mutation (BAP1C91S) (Supplementary Figure 3A&3B).This mutation specifically affects the catalytic cysteine and prevents BAP1 deubiquitinase activity.	('EV', 'Chemical', '-', (265, 267))	('protein', 'cellular_component', 'GO:0003675', ('378', '385'))	('BAP1', 'Gene', '8314', (420, 424))	('C91S', 'Mutation', 'p.C91S', (424, 428))	('catalytic activity', 'molecular_function', 'GO:0003824', ('128', '146'))	('BAP1', 'Gene', (373, 377))	('prevents', 'Enzyme', (521, 529))	('BAP1', 'Gene', '8314', (299, 303))	('NCI-H226', 'CellLine', 'CVCL:1544', (148, 156))	('C91S', 'Mutation', 'p.C91S', (399, 403))	('BAP1', 'Gene', '8314', (530, 534))	('the catalytic', 'MPA', (494, 507))	('BAP1', 'Gene', '8314', (123, 127))	('BAP1', 'Gene', (420, 424))	('deubiquitinase activity', 'molecular_function', 'GO:0004843', ('535', '558'))	('BAP1', 'Gene', '8314', (313, 317))	('protein', 'cellular_component', 'GO:0003675', ('304', '311'))	('BAP1', 'Gene', (299, 303))	('BAP1', 'Gene', (530, 534))	('deubiquitinase activity', 'molecular_function', 'GO:0101005', ('535', '558'))	('specifically', 'Reg', (473, 485))	('BAP1', 'Gene', (123, 127))	('and', 'NegReg', (517, 520))	('BAP1', 'Gene', (313, 317))	('BAP1wt', 'Gene', '8314', (313, 319))	('mesothelioma', 'Disease', (187, 199))	('BAP1', 'Gene', '8314', (373, 377))	('.This', 'Var', (458, 463))	('BAP1wt', 'Gene', (313, 319))	('mesothelioma', 'Disease', 'MESH:D008654', (187, 199))
135069	29069806	Immunofluorescence revealed an expected CDH2 membrane localization in control EV cells and upon expression of BAP1C91S.	('localization', 'biological_process', 'GO:0051179', ('54', '66'))	('CDH2', 'Gene', (40, 44))	('CDH2', 'Gene', '1000', (40, 44))	('BAP1C91S', 'Var', (110, 118))	('membrane', 'cellular_component', 'GO:0016020', ('45', '53'))	('EV', 'Chemical', '-', (78, 80))
135083	29069806	Of note, the expression of BAP1C91S resulted in a decrease of respiratory capacities in NCI-H226 cell line compared to the empty vector, Figure 3E, p<0.05), while EV and BAP1C91S have similar respiratory capacities in QR cell line (Figure 3F).	('respiratory capacities', 'MPA', (62, 84))	('EV', 'Chemical', '-', (163, 165))	('BAP1C91S', 'Var', (27, 35))	('NCI-H226', 'CellLine', 'CVCL:1544', (88, 96))	('decrease', 'NegReg', (50, 58))
135088	29069806	Of note, the expression of BAP1C91S resulted in a significant increase of ROS level in NCI-H226 cell line compared to the empty vector (p<0.05; Figure 4B) while EV and BAP1C91S have similar ROS levels in QR cell line (Figure 4A&4B).	('BAP1C91S', 'Var', (27, 35))	('increase of ROS level', 'Phenotype', 'HP:0025464', (62, 83))	('NCI-H226', 'CellLine', 'CVCL:1544', (87, 95))	('EV', 'Chemical', '-', (161, 163))	('ROS', 'Chemical', 'MESH:D017382', (190, 193))	('ROS', 'Chemical', 'MESH:D017382', (74, 77))	('ROS level', 'MPA', (74, 83))	('increase', 'PosReg', (62, 70))
135090	29069806	CAT expression measured by qPCR confirmed a 1.5-fold and 3-fold increased expression level associated with BAP1wt expression compared to either EV or mutant BAP1C91S expressing cells in NCI-H226 and QR, respectively (Figure 4C).	('CAT', 'molecular_function', 'GO:0004096', ('0', '3'))	('NCI-H226', 'CellLine', 'CVCL:1544', (186, 194))	('BAP1C91S', 'Gene', (157, 165))	('BAP1wt', 'Gene', '8314', (107, 113))	('BAP1wt', 'Gene', (107, 113))	('expression level', 'MPA', (74, 90))	('EV', 'Chemical', '-', (144, 146))	('increased', 'PosReg', (64, 73))	('mutant', 'Var', (150, 156))
135092	29069806	NCI-H226 expressing EV or mutant BAP1C91S showed significantly lower intracellular ROS levels compared to BAP1wt (p<0.05; Figure 4B), and ROS levels did not fluctuate under antioxidant treatment (Supplementary Figure 7), and EV and mutant BAP1C91S expressing NCI-H226 show similar level of ROS management proteins.	('intracellular ROS levels', 'MPA', (69, 93))	('BAP1C91S', 'Gene', (33, 41))	('lower', 'NegReg', (63, 68))	('BAP1wt', 'Gene', '8314', (106, 112))	('ROS management proteins', 'MPA', (290, 313))	('EV', 'Chemical', '-', (225, 227))	('NCI-H226', 'CellLine', 'CVCL:1544', (259, 267))	('NCI-H226', 'Gene', (259, 267))	('BAP1wt', 'Gene', (106, 112))	('ROS', 'Chemical', 'MESH:D017382', (138, 141))	('EV', 'Chemical', '-', (20, 22))	('ROS', 'Chemical', 'MESH:D017382', (83, 86))	('intracellular', 'cellular_component', 'GO:0005622', ('69', '82'))	('NCI-H226', 'CellLine', 'CVCL:1544', (0, 8))	('mutant', 'Var', (26, 32))	('ROS', 'Chemical', 'MESH:D017382', (290, 293))
135100	29069806	Importantly, BAP1wt expressing cells were significantly more affected by H2O2 treatment than control EV cells (p<0.05, Figure 4E).	('BAP1wt', 'Gene', '8314', (13, 19))	('H2O2', 'Var', (73, 77))	('H2O2', 'Chemical', 'MESH:D006861', (73, 77))	('EV', 'Chemical', '-', (101, 103))	('affected', 'Reg', (61, 69))	('BAP1wt', 'Gene', (13, 19))
135102	29069806	After 400muM H2O2, BAP1wt cells had a 50% survival rate and EV cells had 15% survival rate, which is a 3-fold difference (p<0.01, Figure 4F).	('BAP1wt', 'Gene', (19, 25))	('EV', 'Chemical', '-', (60, 62))	('muM', 'Gene', '56925', (9, 12))	('H2O2', 'Chemical', 'MESH:D006861', (13, 17))	('H2O2', 'Var', (13, 17))	('BAP1wt', 'Gene', '8314', (19, 25))	('muM', 'Gene', (9, 12))
135114	29069806	Hence, no consistent transcriptional signature has been associated to BAP1 inactivation among the BAP1-associated tumors, although histone H2A deubiquitination and interactions with numerous transcriptomic factors are strongly supported by an abundant literature.	('inactivation', 'Var', (75, 87))	('BAP1', 'Gene', (98, 102))	('histone H2A', 'Protein', (131, 142))	('deubiquitination', 'biological_process', 'GO:0016579', ('143', '159'))	('BAP1', 'Gene', '8314', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('interactions', 'Interaction', (164, 176))	('BAP1', 'Gene', (70, 74))	('tumors', 'Disease', (114, 120))	('deubiquitination', 'MPA', (143, 159))	('BAP1', 'Gene', '8314', (98, 102))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
135116	29069806	Parallel investigation of transcriptomic and proteomic consequences of BAP1 expression modulation revealed major protein dysregulations.	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('modulation', 'Var', (87, 97))	('BAP1', 'Gene', '8314', (71, 75))	('protein dysregulations', 'MPA', (113, 135))	('BAP1', 'Gene', (71, 75))
135121	29069806	However, mutant BAP1 expression led to some phenotypic differences, suggesting that the catalytically inactive BAP1 may maintain some biological activities - possibly a scaffold or a dominant negative protein.	('BAP1', 'Gene', '8314', (111, 115))	('protein', 'cellular_component', 'GO:0003675', ('201', '208'))	('mutant', 'Var', (9, 15))	('BAP1', 'Gene', (111, 115))	('BAP1', 'Gene', '8314', (16, 20))	('biological activities', 'MPA', (134, 155))	('BAP1', 'Gene', (16, 20))
135130	29069806	Interestingly, our results suggest that mesothelioma cells expressing wild-type BAP1 are more aggressive, which is consistent with clinical studies associating BAP1 expression with worse prognosis in mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (200, 212))	('mesothelioma', 'Disease', 'MESH:D008654', (40, 52))	('aggressive', 'CPA', (94, 104))	('BAP1', 'Gene', '8314', (160, 164))	('BAP1', 'Gene', '8314', (80, 84))	('BAP1', 'Gene', (160, 164))	('mesothelioma', 'Disease', (200, 212))	('BAP1', 'Gene', (80, 84))	('mesothelioma', 'Disease', (40, 52))	('wild-type', 'Var', (70, 79))
135132	29069806	Interestingly, morphologic changes were also observed after BAP1 expression modulation in uveal melanoma cell lines, although no loss of cellular identity was observed in our study.	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('modulation', 'Var', (76, 86))	('uveal melanoma', 'Disease', (90, 104))	('uveal melanoma', 'Disease', 'MESH:C536494', (90, 104))	('expression modulation', 'Var', (65, 86))	('BAP1', 'Gene', '8314', (60, 64))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('BAP1', 'Gene', (60, 64))
135149	29069806	In uveal melanoma, BAP1 inactivation is associated with metastasis development and worse prognosis.	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('inactivation', 'Var', (24, 36))	('BAP1', 'Gene', '8314', (19, 23))	('BAP1', 'Gene', (19, 23))	('associated', 'Reg', (40, 50))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))	('metastasis development', 'CPA', (56, 78))
135150	29069806	In clear cell renal cell carcinoma, BAP1 inactivation defines a specific subtype of cancer of worse prognosis.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (3, 34))	('cancer', 'Disease', (84, 90))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (14, 34))	('inactivation', 'Var', (41, 53))	('BAP1', 'Gene', '8314', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 34))	('BAP1', 'Gene', (36, 40))	('clear cell renal cell carcinoma', 'Disease', (3, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
135151	29069806	Interestingly, in mesothelioma, BAP1 inactivation is associated with less aggressive tumors and a better outcome.	('aggressive tumors', 'Disease', 'MESH:D001523', (74, 91))	('BAP1', 'Gene', '8314', (32, 36))	('aggressive tumors', 'Disease', (74, 91))	('mesothelioma', 'Disease', (18, 30))	('mesothelioma', 'Disease', 'MESH:D008654', (18, 30))	('BAP1', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('inactivation', 'Var', (37, 49))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
135154	29069806	Antioxidant treatment partially abrogated the phenotypes, supporting the sensing and/or management of ROS as the most direct function altered by BAP1 expression modulation, cellular morphology and respiration defects most likely being at least in part consequence of increased intracellular oxidative stress.	('modulation', 'Var', (161, 171))	('intracellular', 'cellular_component', 'GO:0005622', ('277', '290'))	('expression modulation', 'Var', (150, 171))	('ROS', 'Chemical', 'MESH:D017382', (102, 105))	('oxidative stress', 'Phenotype', 'HP:0025464', (291, 307))	('respiration', 'biological_process', 'GO:0045333', ('197', '208'))	('respiration', 'MPA', (197, 208))	('BAP1', 'Gene', '8314', (145, 149))	('altered', 'Reg', (134, 141))	('BAP1', 'Gene', (145, 149))	('respiration', 'biological_process', 'GO:0007585', ('197', '208'))
135181	29069806	We set carbamidomethyl cysteine, oxidation of methionine, N-terminal acetylation, heavy 13C615N2-Lysine (Lys8) and 13C615N4-Arginine (Arg10) as variable modifications.	('methionine', 'Chemical', 'MESH:D008715', (46, 56))	('N-terminal acetylation', 'MPA', (58, 80))	('Lys8', 'Chemical', '-', (105, 109))	('carbamidomethyl cysteine', 'Chemical', 'MESH:C034636', (7, 31))	('oxidation', 'MPA', (33, 42))	('13C615N2-Lysine', 'Chemical', '-', (88, 103))	('13C615N2-Lysine', 'Var', (88, 103))	('13C615N4-Arginine', 'Var', (115, 132))	('13C615N4-Arginine', 'Chemical', '-', (115, 132))	('Arg10', 'Chemical', '-', (134, 139))
135221	26744134	Similar to uveal melanoma and blue nevi, they frequently harbor activating GNAQ or GNA11 mutations.	('uveal melanoma', 'Phenotype', 'HP:0007716', (11, 25))	('uveal melanoma', 'Disease', (11, 25))	('activating', 'PosReg', (64, 74))	('uveal melanoma', 'Disease', 'MESH:C536494', (11, 25))	('nevi', 'Phenotype', 'HP:0003764', (35, 39))	('GNAQ', 'Gene', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('mutations', 'Var', (89, 98))	('GNA11', 'Gene', (83, 88))	('GNA11', 'Gene', '2767', (83, 88))	('GNAQ', 'Gene', '2776', (75, 79))	('blue nevi', 'Phenotype', 'HP:0100814', (30, 39))
135222	26744134	Rare NRAS mutations have also been reported.	('mutations', 'Var', (10, 19))	('NRAS', 'Gene', '4893', (5, 9))	('NRAS', 'Gene', (5, 9))
135224	26744134	In concordance with previous studies, cutaneous melanoma samples showed frequent NRAS or BRAF mutations, as well as mutations in other genes (e.g.	('mutations', 'Var', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('NRAS', 'Gene', (81, 85))	('BRAF', 'Gene', '673', (89, 93))	('BRAF', 'Gene', (89, 93))	('cutaneous melanoma', 'Disease', (38, 56))	('NRAS', 'Gene', '4893', (81, 85))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (38, 56))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (38, 56))
135226	26744134	Metastasized uveal melanomas exhibited mutations in GNAQ, GNA11 and BAP1.	('uveal melanomas', 'Phenotype', 'HP:0007716', (13, 28))	('Metastasized uveal melanomas', 'Disease', (0, 28))	('GNAQ', 'Gene', '2776', (52, 56))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('exhibited', 'Reg', (29, 38))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('mutations', 'Var', (39, 48))	('BAP1', 'Gene', '8314', (68, 72))	('Metastasized uveal melanomas', 'Disease', 'MESH:D009362', (0, 28))	('GNA11', 'Gene', (58, 63))	('GNA11', 'Gene', '2767', (58, 63))	('GNAQ', 'Gene', (52, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (13, 27))	('BAP1', 'Gene', (68, 72))
135227	26744134	In contrast, MT-CNS almost exclusively demonstrated mutations in GNAQ (71 %) or GNA11 (12 %).	('mutations', 'Var', (52, 61))	('GNA11', 'Gene', '2767', (80, 85))	('GNAQ', 'Gene', '2776', (65, 69))	('demonstrated', 'Reg', (39, 51))	('GNAQ', 'Gene', (65, 69))	('GNA11', 'Gene', (80, 85))
135228	26744134	Interestingly both GNA11 mutations identified were detected in MT-CNS diagnosed as intermediate grade melanocytomas which also recurred.	('detected', 'Reg', (51, 59))	('mutations', 'Var', (25, 34))	('GNA11', 'Gene', (19, 24))	('melanocytomas', 'Disease', (102, 115))	('GNA11', 'Gene', '2767', (19, 24))	('melanocytomas', 'Disease', 'None', (102, 115))
135229	26744134	One of these recurrent cases also harbored an inactivating BAP1 mutation and was found to have lost one copy of chromosome 3.	('lost', 'NegReg', (95, 99))	('inactivating', 'Var', (46, 58))	('mutation', 'Var', (64, 72))	('BAP1', 'Gene', (59, 63))	('harbored', 'Reg', (34, 42))	('BAP1', 'Gene', '8314', (59, 63))	('chromosome', 'cellular_component', 'GO:0005694', ('112', '122'))
135230	26744134	Our findings show that while MT-CNS do have GNAQ or GNA11 mutations, they rarely harbor other recurrent mutations found in uveal or cutaneous melanomas.	('mutations', 'Var', (58, 67))	('uveal or cutaneous melanomas', 'Phenotype', 'HP:0007716', (123, 151))	('GNAQ', 'Gene', (44, 48))	('uveal or cutaneous melanomas', 'Disease', (123, 151))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (132, 151))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (132, 150))	('GNA11', 'Gene', (52, 57))	('GNAQ', 'Gene', '2776', (44, 48))	('GNA11', 'Gene', '2767', (52, 57))	('uveal or cutaneous melanomas', 'Disease', 'MESH:C536494', (123, 151))	('melanomas', 'Phenotype', 'HP:0002861', (142, 151))
135240	26744134	In uveal melanoma, activating mutations in GNAQ and GNA11 were identified, as well as mutations in BAP1 , SF3B1  and EIF1AX .	('mutations', 'Var', (86, 95))	('BAP1', 'Gene', (99, 103))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('SF3B1', 'Gene', (106, 111))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('GNAQ', 'Gene', (43, 47))	('SF3B1', 'Gene', '23451', (106, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('EIF1AX', 'Gene', '1964', (117, 123))	('mutations', 'Var', (30, 39))	('GNA11', 'Gene', (52, 57))	('BAP1', 'Gene', '8314', (99, 103))	('GNAQ', 'Gene', '2776', (43, 47))	('GNA11', 'Gene', '2767', (52, 57))	('uveal melanoma', 'Disease', (3, 17))	('EIF1AX', 'Gene', (117, 123))
135241	26744134	Inactivating BAP1 mutations are associated with poor prognosis, whereas SF3B1 and EIF1AX mutations primarily occur in tumors which do not metastasize.	('BAP1', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Inactivating', 'Var', (0, 12))	('SF3B1', 'Gene', (72, 77))	('BAP1', 'Gene', '8314', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('EIF1AX', 'Gene', '1964', (82, 88))	('EIF1AX', 'Gene', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('SF3B1', 'Gene', '23451', (72, 77))	('mutations', 'Var', (18, 27))
135242	26744134	In MT-CNS, the occurrence of activating GNAQ and GNA11 mutations has been well documented.	('GNAQ', 'Gene', (40, 44))	('mutations', 'Var', (55, 64))	('GNAQ', 'Gene', '2776', (40, 44))	('activating', 'PosReg', (29, 39))	('GNA11', 'Gene', '2767', (49, 54))	('GNA11', 'Gene', (49, 54))
135243	26744134	The common occurrence of these mutations in uveal melanoma and their rarity in cutaneous melanoma points toward a pathogenetic relationship of MT-CNS with uveal melanomas.	('uveal melanoma', 'Disease', 'MESH:C536494', (155, 169))	('cutaneous melanoma', 'Disease', (79, 97))	('mutations', 'Var', (31, 40))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (79, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (155, 169))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('uveal melanomas', 'Disease', 'MESH:C536494', (155, 170))	('uveal melanomas', 'Disease', (155, 170))	('uveal melanomas', 'Phenotype', 'HP:0007716', (155, 170))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanomas', 'Phenotype', 'HP:0002861', (161, 170))	('uveal melanoma', 'Disease', (44, 58))
135245	26744134	In rare, mainly pediatric MT-CNS cases, NRAS mutations have been reported.	('NRAS', 'Gene', '4893', (40, 44))	('mutations', 'Var', (45, 54))	('NRAS', 'Gene', (40, 44))	('MT-CNS', 'Disease', (26, 32))
135246	26744134	Recent work by Kusters-Vandevelde et al.. demonstrated GNAQ and GNA11 mutations in CNS melanocytomas and found at least one tumor to have copy number alterations similar to uveal melanoma (loss of chromosome 3 and gains of chromosome 8q).	('uveal melanoma', 'Phenotype', 'HP:0007716', (173, 187))	('copy', 'MPA', (138, 142))	('tumor', 'Disease', (124, 129))	('gains', 'PosReg', (214, 219))	('GNA11', 'Gene', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('chromosome', 'cellular_component', 'GO:0005694', ('197', '207'))	('CNS melanocytomas', 'Disease', 'MESH:D002493', (83, 100))	('CNS melanocytomas', 'Disease', (83, 100))	('mutations', 'Var', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('GNA11', 'Gene', '2767', (64, 69))	('chromosome', 'cellular_component', 'GO:0005694', ('223', '233'))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('uveal melanoma', 'Disease', (173, 187))	('uveal melanoma', 'Disease', 'MESH:C536494', (173, 187))	('GNAQ', 'Gene', '2776', (55, 59))	('GNAQ', 'Gene', (55, 59))	('loss', 'NegReg', (189, 193))
135248	26744134	analyzed copy number alterations, methylation profiles and individual activating gene mutations in melanocytomas, schwannomas and melanomas.	('mutations', 'Var', (86, 95))	('schwannomas', 'Phenotype', 'HP:0100008', (114, 125))	('activating', 'PosReg', (70, 80))	('melanocytomas, schwannomas and melanomas', 'Disease', 'MESH:D009442', (99, 139))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('melanomas', 'Phenotype', 'HP:0002861', (130, 139))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('copy number alterations', 'Var', (9, 32))
135251	26744134	The aim of our study was to analyze the occurrence of gene mutations known to be frequent in cutaneous or uveal melanoma in a cohort of MT-CNS using a next generation targeted sequencing approach.	('frequent', 'Reg', (81, 89))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('mutations', 'Var', (59, 68))	('uveal melanoma', 'Disease', (106, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))
135279	26744134	The sequencing of all samples with the 29 gene assay identified recurrent activating Q209 mutations in GNAQ and GNA11 in the MT-CNS (Table 1; Fig.	('activating', 'PosReg', (74, 84))	('GNAQ', 'Gene', '2776', (103, 107))	('GNA11', 'Gene', (112, 117))	('Q209 mutations', 'Var', (85, 99))	('GNA11', 'Gene', '2767', (112, 117))	('GNAQ', 'Gene', (103, 107))
135280	26744134	Mutations in GNAQ were identified in 13 samples from 12 patients (12 of 17 = 71 %).	('patients', 'Species', '9606', (56, 64))	('GNAQ', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (23, 33))	('GNAQ', 'Gene', '2776', (13, 17))
135281	26744134	Mutations in GNA11 were found in three samples from two patients (2 of 17 = 12 %).	('patients', 'Species', '9606', (56, 64))	('GNA11', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('GNA11', 'Gene', '2767', (13, 18))	('found', 'Reg', (24, 29))
135282	26744134	An inactivating BAP1 mutation leading to the formation of a stop codon at residue 60 (R60*) was identified in two samples of the same patient (the primary tumor and a recurrence, shown in Fig.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('R60*', 'SUBSTITUTION', 'None', (86, 90))	('tumor', 'Disease', (155, 160))	('BAP1', 'Gene', '8314', (16, 20))	('formation', 'biological_process', 'GO:0009058', ('45', '54'))	('BAP1', 'Gene', (16, 20))	('patient', 'Species', '9606', (134, 141))	('R60*', 'Var', (86, 90))
135284	26744134	The uveal melanoma samples harbored recurrent GNAQ (n = 2, 29 %) and GNA11 mutations (n = 4, 57 %).	('GNAQ', 'Gene', (46, 50))	('uveal melanoma', 'Phenotype', 'HP:0007716', (4, 18))	('uveal melanoma', 'Disease', (4, 18))	('GNAQ', 'Gene', '2776', (46, 50))	('mutations', 'Var', (75, 84))	('GNA11', 'Gene', (69, 74))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('GNA11', 'Gene', '2767', (69, 74))	('uveal melanoma', 'Disease', 'MESH:C536494', (4, 18))
135285	26744134	BAP1 mutations were identified in 4 samples (57 %), of which 3 (75 %) were clearly inactivating, leading to loss of the functional protein (Supplemental Fig.	('loss', 'NegReg', (108, 112))	('BAP1', 'Gene', (0, 4))	('functional protein', 'MPA', (120, 138))	('mutations', 'Var', (5, 14))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('BAP1', 'Gene', '8314', (0, 4))
135286	26744134	BRAF V600 mutations were detected in 10 of 19 (53 %) samples, including 7 V600E, 2 V600K and 1 T599_V600insT alterations.	('V600K', 'Var', (83, 88))	('V600E', 'Mutation', 'rs113488022', (74, 79))	('V600K', 'Mutation', 'rs121913227', (83, 88))	('T599_V600insT', 'Var', (95, 108))	('BRAF', 'Gene', '673', (0, 4))	('V600E', 'Var', (74, 79))	('BRAF', 'Gene', (0, 4))	('V600insT', 'Mutation', 'c.600insV,T', (100, 108))	('detected', 'Reg', (25, 33))
135287	26744134	Another two samples carried N581S and P239L mutations of unclear functional significance.	('N581S', 'Mutation', 'rs121913370', (28, 33))	('P239L', 'Var', (38, 43))	('P239L', 'Mutation', 'rs1471878830', (38, 43))	('N581S', 'Var', (28, 33))
135288	26744134	NRAS mutations were found mutually exclusively with BRAF mutations in 5 (26 %) samples and included 4 Q61K and 1 Q61R alterations.	('Q61R', 'Var', (113, 117))	('NRAS', 'Gene', '4893', (0, 4))	('Q61R', 'Mutation', 'rs11554290', (113, 117))	('Q61K', 'Var', (102, 106))	('mutations', 'Var', (5, 14))	('Q61K', 'Mutation', 'rs121913254', (102, 106))	('mutations', 'Var', (57, 66))	('NRAS', 'Gene', (0, 4))	('found', 'Reg', (20, 25))	('BRAF', 'Gene', '673', (52, 56))	('BRAF', 'Gene', (52, 56))
135289	26744134	Other rarer mutations were identified, including NF1, PTEN, ARID1A, RAC1, KIT, SF3B1 and other mutations (see Table 1; Supplemental Table 3 reporting mutations with an allelic frequency >=15 %).	('ARID1A', 'Gene', (60, 66))	('KIT', 'molecular_function', 'GO:0005020', ('74', '77'))	('NF1', 'Gene', '4763', (49, 52))	('RAC1', 'Gene', '5879', (68, 72))	('SF3B1', 'Gene', (79, 84))	('PTEN', 'Gene', (54, 58))	('RAC1', 'Gene', (68, 72))	('KIT', 'Gene', (74, 77))	('PTEN', 'Gene', '5728', (54, 58))	('mutations', 'Var', (150, 159))	('mutations', 'Var', (95, 104))	('SF3B1', 'Gene', '23451', (79, 84))	('NF1', 'Gene', (49, 52))	('ARID1A', 'Gene', '8289', (60, 66))
135290	26744134	In 14 of the MT-CNS samples, exon 1 of the gene EIF1AX, which was not covered in the next gen sequencing panel, was sequenced by Sanger-sequencing, in search of recurrent mutations which are frequently seen in primary uveal melanoma samples; no EIF1AX mutations were identified.	('EIF1AX', 'Gene', '1964', (245, 251))	('EIF1AX', 'Gene', (245, 251))	('uveal melanoma', 'Disease', 'MESH:C536494', (218, 232))	('uveal melanoma', 'Phenotype', 'HP:0007716', (218, 232))	('uveal melanoma', 'Disease', (218, 232))	('mutations', 'Var', (171, 180))	('EIF1AX', 'Gene', (48, 54))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('EIF1AX', 'Gene', '1964', (48, 54))
135293	26744134	In two samples, the primary and recurrent tumor from the same patient harboring the BAP1 R60* mutations, BAP1 IHC showed absent nuclear expression (Fig.	('R60*', 'SUBSTITUTION', 'None', (89, 93))	('tumor', 'Disease', (42, 47))	('absent', 'NegReg', (121, 127))	('BAP1', 'Gene', '8314', (105, 109))	('patient', 'Species', '9606', (62, 69))	('BAP1', 'Gene', '8314', (84, 88))	('R60*', 'Var', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('BAP1', 'Gene', (84, 88))	('nuclear expression', 'MPA', (128, 146))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('BAP1', 'Gene', (105, 109))
135294	26744134	Genome wide chromosomal copy number analysis was performed on both samples identified as having inactivating BAP1 c.178C > T, p.R60* mutations as well as two other MT-CNS (also intermediate-grade melanocytoma) samples, both harboring GNAQ c.626A > T, p.Q209L mutations.	('melanocytoma', 'Disease', (196, 208))	('p.R60*', 'Mutation', 'p.R60*', (126, 132))	('GNAQ', 'Gene', '2776', (234, 238))	('c.178C > T', 'Var', (114, 124))	('BAP1', 'Gene', '8314', (109, 113))	('melanocytoma', 'Disease', 'None', (196, 208))	('p.Q209L', 'Var', (251, 258))	('GNAQ', 'Gene', (234, 238))	('p.R60*', 'Var', (126, 132))	('c.178C > T', 'Mutation', 'rs587777021', (114, 124))	('inactivating', 'Var', (96, 108))	('BAP1', 'Gene', (109, 113))	('p.Q209L', 'Mutation', 'rs121913492', (251, 258))	('c.626A > T', 'Mutation', 'rs121913492', (239, 249))
135297	26744134	In our study, a larger cohort of MT-CNS was screened for mutations in a range of genes known to be recurrently mutated in other melanocytic tumors, in particular cutaneous and uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (176, 190))	('uveal melanoma', 'Disease', (176, 190))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('mutations', 'Var', (57, 66))	('melanocytic tumors', 'Disease', 'MESH:D009508', (128, 146))	('melanocytic tumors', 'Disease', (128, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('uveal melanoma', 'Disease', 'MESH:C536494', (176, 190))
135298	26744134	Other than the known mutations in GNAQ and GNA11, none of the other genes analyzed were found to harbor recurrent mutations in MT-CNS from different patients.	('patients', 'Species', '9606', (149, 157))	('GNA11', 'Gene', (43, 48))	('mutations', 'Var', (114, 123))	('GNA11', 'Gene', '2767', (43, 48))	('MT-CNS', 'Gene', (127, 133))	('GNAQ', 'Gene', (34, 38))	('GNAQ', 'Gene', '2776', (34, 38))
135300	26744134	In the uveal melanoma samples analyzed, 4 out of 7 (57 %) had mutations in BAP1.	('uveal melanoma', 'Disease', (7, 21))	('BAP1', 'Gene', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('uveal melanoma', 'Disease', 'MESH:C536494', (7, 21))	('BAP1', 'Gene', '8314', (75, 79))	('mutations', 'Var', (62, 71))	('uveal melanoma', 'Phenotype', 'HP:0007716', (7, 21))
135301	26744134	Potentially events inactivating BAP1, such as promoter methylation or homozygous deletions, not detected by our sequencing approach, may have taken place in some of the remaining samples.	('deletions', 'Var', (81, 90))	('BAP1', 'Gene', '8314', (32, 36))	('promoter', 'MPA', (46, 54))	('BAP1', 'Gene', (32, 36))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))
135303	26744134	The mutations identified in cutaneous melanomas reflect those described in previous studies with activating BRAF and NRAS mutations in 53 and 26 % of samples, respectively.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('NRAS', 'Gene', (117, 121))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (28, 47))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (28, 47))	('NRAS', 'Gene', '4893', (117, 121))	('cutaneous melanomas', 'Disease', (28, 47))	('mutations', 'Var', (122, 131))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('activating', 'PosReg', (97, 107))	('BRAF', 'Gene', '673', (108, 112))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('BRAF', 'Gene', (108, 112))
135304	26744134	Additionally, our screen identified a number of other recently described mutations such as two hotspot R29 RAC1 mutations, 3 inactivating NF1 mutations, 2 inactivating ARID1A mutations and 2 KIT mutations.	('mutations', 'Var', (142, 151))	('inactivating', 'NegReg', (125, 137))	('RAC1', 'Gene', (107, 111))	('KIT', 'molecular_function', 'GO:0005020', ('191', '194'))	('ARID1A', 'Gene', '8289', (168, 174))	('ARID1A', 'Gene', (168, 174))	('mutations', 'Var', (112, 121))	('mutations', 'Var', (175, 184))	('NF1', 'Gene', (138, 141))	('inactivating', 'NegReg', (155, 167))	('mutations', 'Var', (73, 82))	('NF1', 'Gene', '4763', (138, 141))	('RAC1', 'Gene', '5879', (107, 111))
135305	26744134	One KIT mutation, K642E, is clearly activating and was identified in an NRAS and BRAF wild-type sample.	('NRAS', 'Gene', (72, 76))	('KIT', 'molecular_function', 'GO:0005020', ('4', '7'))	('NRAS', 'Gene', '4893', (72, 76))	('BRAF', 'Gene', '673', (81, 85))	('K642E', 'Var', (18, 23))	('BRAF', 'Gene', (81, 85))	('K642E', 'Mutation', 'rs121913512', (18, 23))	('activating', 'MPA', (36, 46))
135307	26744134	The high mutation frequency of GNAQ and GNA11 mutations detected in MT-CNS is intriguing.	('mutations', 'Var', (46, 55))	('GNA11', 'Gene', (40, 45))	('GNAQ', 'Gene', '2776', (31, 35))	('GNA11', 'Gene', '2767', (40, 45))	('GNAQ', 'Gene', (31, 35))
135308	26744134	As we previously reported, in contrast to uveal melanomas, MT-CNS samples much more commonly harbor GNAQ mutations than GNA11 mutations.	('GNAQ', 'Gene', '2776', (100, 104))	('harbor', 'Reg', (93, 99))	('uveal melanomas', 'Disease', (42, 57))	('uveal melanomas', 'Phenotype', 'HP:0007716', (42, 57))	('GNA11', 'Gene', (120, 125))	('GNAQ', 'Gene', (100, 104))	('mutations', 'Var', (105, 114))	('GNA11', 'Gene', '2767', (120, 125))	('uveal melanomas', 'Disease', 'MESH:C536494', (42, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
135309	26744134	Concordant with our previous study, our targeted next generation sequencing in the current study identified 71 % GNAQ and 12 % GNA11 mutations.	('GNAQ', 'Gene', (113, 117))	('mutations', 'Var', (133, 142))	('GNA11', 'Gene', '2767', (127, 132))	('GNA11', 'Gene', (127, 132))	('GNAQ', 'Gene', '2776', (113, 117))
135310	26744134	also recently reported more frequent GNAQ mutations (37 %) than GNA11 mutations (10 %) in MT-CNS.	('GNAQ', 'Gene', (37, 41))	('MT-CNS', 'Disease', (90, 96))	('GNA11', 'Gene', '2767', (64, 69))	('GNA11', 'Gene', (64, 69))	('GNAQ', 'Gene', '2776', (37, 41))	('mutations', 'Var', (42, 51))
135311	26744134	Blue nevi, benign melanocytic proliferations of the skin, also show a similar distribution with 55 % GNAQ and 7 % GNA11 mutations reported in one study.	('GNA11', 'Gene', '2767', (114, 119))	('melanocytic', 'Disease', (18, 29))	('GNAQ', 'Gene', '2776', (101, 105))	('Blue nevi', 'Disease', (0, 9))	('melanocytic', 'Disease', 'MESH:D009508', (18, 29))	('Blue nevi', 'Phenotype', 'HP:0100814', (0, 9))	('nevi', 'Phenotype', 'HP:0003764', (5, 9))	('mutations', 'Var', (120, 129))	('GNAQ', 'Gene', (101, 105))	('GNA11', 'Gene', (114, 119))
135312	26744134	The distribution of mutations in primary uveal melanoma samples is more evenly distributed, however still shows slightly more GNAQ (45-47 %) than GNA11 (32-44 %) mutations .	('GNAQ', 'Gene', '2776', (126, 130))	('uveal melanoma', 'Disease', 'MESH:C536494', (41, 55))	('uveal melanoma', 'Disease', (41, 55))	('mutations', 'Var', (162, 171))	('GNA11', 'Gene', '2767', (146, 151))	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('GNAQ', 'Gene', (126, 130))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('GNA11', 'Gene', (146, 151))
135313	26744134	In contrast, a higher frequency of GNA11 (57-60 %) to GNAQ (20-22 %) mutations has been reported in uveal melanoma metastases .	('mutations', 'Var', (69, 78))	('GNAQ', 'Gene', (54, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('uveal melanoma metastases', 'Disease', (100, 125))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (100, 125))	('GNAQ', 'Gene', '2776', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('GNA11', 'Gene', '2767', (35, 40))	('GNA11', 'Gene', (35, 40))
135314	26744134	The shift in mutation frequencies from GNAQ to GNA11 from benign to increasingly malignant tumors may indicate GNA11 mutations are associated with a more malignant phenotype in this entity.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (117, 126))	('GNAQ', 'Gene', (39, 43))	('malignant tumors', 'Disease', (81, 97))	('GNA11', 'Gene', '2767', (47, 52))	('GNA11', 'Gene', (47, 52))	('associated', 'Reg', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('malignant tumors', 'Disease', 'MESH:D018198', (81, 97))	('GNAQ', 'Gene', '2776', (39, 43))	('GNA11', 'Gene', '2767', (111, 116))	('GNA11', 'Gene', (111, 116))
135315	26744134	Interestingly, both of the two mutant GNA11 cases (three samples from two patients) we observed in MT-CNS were rated intermediate grade melanocytomas.	('mutant', 'Var', (31, 37))	('melanocytomas', 'Disease', (136, 149))	('patients', 'Species', '9606', (74, 82))	('GNA11', 'Gene', '2767', (38, 43))	('GNA11', 'Gene', (38, 43))	('melanocytomas', 'Disease', 'None', (136, 149))
135316	26744134	Furthermore, both mutant GNA11 MT-CNS cases were tumors that recurred.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mutant', 'Var', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('GNA11', 'Gene', (25, 30))	('GNA11', 'Gene', '2767', (25, 30))
135317	26744134	One of these cases also harbored an inactivating BAP1 mutation.	('mutation', 'Var', (54, 62))	('inactivating', 'Var', (36, 48))	('BAP1', 'Gene', '8314', (49, 53))	('BAP1', 'Gene', (49, 53))
135318	26744134	also reported that all melanocytomas in their cohort with GNA11 mutations were of intermediate grade.	('melanocytomas', 'Disease', (23, 36))	('melanocytomas', 'Disease', 'None', (23, 36))	('mutations', 'Var', (64, 73))	('GNA11', 'Gene', '2767', (58, 63))	('GNA11', 'Gene', (58, 63))
135319	26744134	If future studies with larger case numbers report similar findings to our study, this could signify GNA11 mutations are also associated with a more aggressive phenotype in MT-CNS.	('MT-CNS', 'Disease', (172, 178))	('associated with', 'Reg', (125, 140))	('mutations', 'Var', (106, 115))	('GNA11', 'Gene', (100, 105))	('GNA11', 'Gene', '2767', (100, 105))
135320	26744134	Considering the similar occurrence of GNAQ and GNA11 mutations in a high frequency of MT-CNS and uveal melanomas, it would seem likely that MT-CNS could potentially also harbor mutations in other genes known to be relevant in uveal melanoma, in particular the recently identified mutations in SF3B1, EIF1AX and BAP1.	('GNAQ', 'Gene', '2776', (38, 42))	('SF3B1', 'Gene', '23451', (293, 298))	('GNA11', 'Gene', (47, 52))	('mutations', 'Var', (177, 186))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('GNAQ', 'Gene', (38, 42))	('uveal melanoma', 'Phenotype', 'HP:0007716', (226, 240))	('EIF1AX', 'Gene', (300, 306))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('BAP1', 'Gene', (311, 315))	('EIF1AX', 'Gene', '1964', (300, 306))	('uveal melanomas', 'Disease', 'MESH:C536494', (97, 112))	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('GNA11', 'Gene', '2767', (47, 52))	('mutations', 'Var', (53, 62))	('SF3B1', 'Gene', (293, 298))	('harbor', 'Reg', (170, 176))	('mutations', 'Var', (280, 289))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('uveal melanoma', 'Disease', 'MESH:C536494', (226, 240))	('uveal melanoma', 'Disease', (226, 240))	('BAP1', 'Gene', '8314', (311, 315))	('uveal melanomas', 'Disease', (97, 112))	('uveal melanomas', 'Phenotype', 'HP:0007716', (97, 112))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))
135321	26744134	Mutations in these genes are found in most uveal melanoma samples and with rare exceptions are mutually exclusive.	('found', 'Reg', (29, 34))	('uveal melanoma', 'Disease', 'MESH:C536494', (43, 57))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Disease', (43, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
135322	26744134	BAP1 mutations are associated with metastasis and poor prognosis, whereas SF3B1 and EIF1AX mutations primarily occur in tumors with a favorable prognosis.	('associated', 'Reg', (19, 29))	('metastasis', 'Disease', 'MESH:D009362', (35, 45))	('tumors', 'Disease', (120, 126))	('EIF1AX', 'Gene', '1964', (84, 90))	('BAP1', 'Gene', (0, 4))	('EIF1AX', 'Gene', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('metastasis', 'Disease', (35, 45))	('SF3B1', 'Gene', '23451', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('BAP1', 'Gene', '8314', (0, 4))	('SF3B1', 'Gene', (74, 79))
135323	26744134	As MT-CNS are mostly benign tumors with a favorable prognosis, it would seem likely that they could also harbor SF3B1 or EIF1AX mutations.	('MT-CNS', 'Disease', (3, 9))	('mutations', 'Var', (128, 137))	('tumors', 'Disease', (28, 34))	('SF3B1', 'Gene', '23451', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('EIF1AX', 'Gene', '1964', (121, 127))	('EIF1AX', 'Gene', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('SF3B1', 'Gene', (112, 117))
135325	26744134	These results suggest that mutations in uveal melanoma genes other than GNAQ and GNA11 are rare in MT-CNS.	('mutations', 'Var', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('GNAQ', 'Gene', '2776', (72, 76))	('GNA11', 'Gene', '2767', (81, 86))	('GNA11', 'Gene', (81, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))	('uveal melanoma', 'Disease', (40, 54))	('uveal melanoma', 'Disease', 'MESH:C536494', (40, 54))	('GNAQ', 'Gene', (72, 76))
135326	26744134	Although only identified in one MT-CNS case (1 of 17 = 6 %), the case with BAP1 inactivation and Chr.	('inactivation', 'Var', (80, 92))	('BAP1', 'Gene', '8314', (75, 79))	('BAP1', 'Gene', (75, 79))
135327	26744134	Similar to our findings, the chromosomal alterations in these cases are highly reminiscent of uveal melanomas with a poor prognosis.	('uveal melanomas', 'Disease', 'MESH:C536494', (94, 109))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('chromosomal alterations', 'Var', (29, 52))	('uveal melanomas', 'Disease', (94, 109))	('uveal melanomas', 'Phenotype', 'HP:0007716', (94, 109))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))
135328	26744134	As such, screening for inactivating BAP1 mutations and/or Chr.	('BAP1', 'Gene', (36, 40))	('BAP1', 'Gene', '8314', (36, 40))	('mutations', 'Var', (41, 50))	('inactivating', 'Var', (23, 35))
135329	26744134	3 and an inactivating BAP1 mutation, both patient history and MRI scans showed no sign of uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('uveal melanoma', 'Disease', (90, 104))	('uveal melanoma', 'Disease', 'MESH:C536494', (90, 104))	('inactivating', 'Var', (9, 21))	('mutation', 'Var', (27, 35))	('patient', 'Species', '9606', (42, 49))	('BAP1', 'Gene', '8314', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('BAP1', 'Gene', (22, 26))
135333	26744134	Our study screened for the presence of mutations in many genes known to be recurrently mutated in cutaneous and uveal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanomas', 'Phenotype', 'HP:0002861', (118, 127))	('uveal melanomas', 'Disease', (112, 127))	('uveal melanomas', 'Phenotype', 'HP:0007716', (112, 127))	('mutations', 'Var', (39, 48))	('uveal melanoma', 'Phenotype', 'HP:0007716', (112, 126))	('uveal melanomas', 'Disease', 'MESH:C536494', (112, 127))
135335	26744134	Although MT-CNS share frequent GNAQ and GNA11 mutations with uveal melanomas, mutations in other uveal melanoma genes were very rare.	('uveal melanomas', 'Disease', (61, 76))	('uveal melanomas', 'Phenotype', 'HP:0007716', (61, 76))	('mutations', 'Var', (46, 55))	('GNA11', 'Gene', (40, 45))	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('uveal melanomas', 'Disease', 'MESH:C536494', (61, 76))	('GNAQ', 'Gene', '2776', (31, 35))	('GNA11', 'Gene', '2767', (40, 45))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('uveal melanoma', 'Disease', (97, 111))	('uveal melanoma', 'Disease', 'MESH:C536494', (61, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('GNAQ', 'Gene', (31, 35))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
135337	26744134	The identification of novel gene mutations unique to MT-CNS would be a valuable diagnostic tool to help distinguish MT-CNS from metastases of melanocytic tumors from other sites.	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('metastases of melanocytic tumors', 'Disease', 'MESH:D009362', (128, 160))	('mutations', 'Var', (33, 42))	('metastases of melanocytic tumors', 'Disease', (128, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))
135338	28350340	Function and Clinical Implications of Long Non-Coding RNAs in Melanoma Metastatic melanoma is the most deadly type of skin cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('Melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('Long Non-Coding RNAs', 'Var', (38, 58))	('Metastatic melanoma', 'Disease', 'MESH:D008545', (71, 90))	('Metastatic melanoma', 'Disease', (71, 90))	('Melanoma', 'Disease', (62, 70))	('skin cancer', 'Phenotype', 'HP:0008069', (118, 129))	('skin cancer', 'Disease', (118, 129))	('skin cancer', 'Disease', 'MESH:D012878', (118, 129))
135341	28350340	In this review, we will summarize the growing evidence of deregulated lncRNA expression in melanoma, which is linked to tumor growth and progression.	('lncRNA expression', 'Protein', (70, 87))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('deregulated', 'Var', (58, 69))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
135347	28350340	Effectively mutational rate in melanoma is the highest within all cancer types and considered responsible for the success of immunotherapy.	('highest', 'Reg', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('rat', 'Species', '10116', (23, 26))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('mutational', 'Var', (12, 22))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('melanoma', 'Disease', (31, 39))	('cancer', 'Disease', (66, 72))
135351	28350340	The majority of BRAF mutations lead to a hyper-activation of the MAPK pathway, resulting in enhanced cell growth and survival.	('MAPK pathway', 'Pathway', (65, 77))	('BRAF', 'Gene', (16, 20))	('cell growth', 'CPA', (101, 112))	('BRAF', 'Gene', '673', (16, 20))	('cell growth', 'biological_process', 'GO:0016049', ('101', '112'))	('enhanced', 'PosReg', (92, 100))	('MAPK', 'molecular_function', 'GO:0004707', ('65', '69'))	('mutations', 'Var', (21, 30))
135353	28350340	When a high-kinase activity mutation in BRAF occurs, it can independently activate the MAPK pathway and in fact BRAFV600E has a ~500-fold increased activity compared to BRAFwt.	('BRAF', 'Gene', '673', (40, 44))	('BRAF', 'Gene', (169, 173))	('increased', 'PosReg', (138, 147))	('BRAF', 'Gene', '673', (169, 173))	('MAPK', 'molecular_function', 'GO:0004707', ('87', '91'))	('BRAF', 'Gene', (40, 44))	('high-kinase', 'PosReg', (7, 18))	('MAPK pathway', 'Pathway', (87, 99))	('BRAF', 'Gene', (112, 116))	('activity', 'MPA', (148, 156))	('BRAF', 'Gene', '673', (112, 116))	('mutation', 'Var', (28, 36))	('BRAFV600E', 'Mutation', 'rs113488022', (112, 121))	('activate', 'PosReg', (74, 82))	('kinase activity', 'molecular_function', 'GO:0016301', ('12', '27'))
135354	28350340	The second most common mutation found in melanoma is affecting the NRAS proto-oncogene, GTPase (NRAS) gene with a frequency of ~20%.	('mutation', 'Var', (23, 31))	('GTPase', 'Gene', (88, 94))	('NRAS', 'Gene', (67, 71))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('NRAS', 'Gene', '4893', (67, 71))	('melanoma', 'Disease', (41, 49))	('NRAS', 'Gene', (96, 100))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('NRAS', 'Gene', '4893', (96, 100))
135356	28350340	However, recent studies revealed additional mutations involved in growth and progression of malignant melanoma, e.g., KIT proto-oncogene receptor tyrosine kinase (KIT) gene in mucosal melanoma, telomerase reverse transcriptase (TERT) gene, germline cyclin dependent kinase inhibitor 2A (CDKN2A) gene, tumor protein p53 (TP53) gene, neurofibromin 1 (NF1) gene and others.	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('KIT proto-oncogene receptor tyrosine kinase', 'Gene', (118, 161))	('KIT', 'Gene', (163, 166))	('TP53', 'Gene', '7157', (320, 324))	('NF1', 'Gene', (349, 352))	('neurofibromin 1', 'Gene', '4763', (332, 347))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('mucosal melanoma', 'Disease', 'MESH:D008545', (176, 192))	('malignant melanoma', 'Disease', (92, 110))	('KIT proto-oncogene receptor tyrosine kinase', 'Gene', '3815', (118, 161))	('TERT', 'Gene', (228, 232))	('neurofibromin 1', 'Gene', (332, 347))	('CDKN2A', 'Gene', (287, 293))	('cyclin dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('249', '282'))	('transcriptase', 'molecular_function', 'GO:0003899', ('213', '226'))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('mucosal melanoma', 'Disease', (176, 192))	('KIT', 'molecular_function', 'GO:0005020', ('163', '166'))	('cyclin dependent kinase inhibitor 2A', 'Gene', (249, 285))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('266', '282'))	('CDKN2A', 'Gene', '1029', (287, 293))	('TP53', 'Gene', (320, 324))	('malignant melanoma', 'Phenotype', 'HP:0002861', (92, 110))	('tumor', 'Disease', (301, 306))	('malignant melanoma', 'Disease', 'MESH:D008545', (92, 110))	('KIT', 'molecular_function', 'GO:0005020', ('118', '121'))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('NF1', 'Gene', '4763', (349, 352))	('transcriptase', 'molecular_function', 'GO:0003968', ('213', '226'))	('mutations', 'Var', (44, 53))	('transcriptase', 'molecular_function', 'GO:0034062', ('213', '226'))	('cyclin dependent kinase inhibitor 2A', 'Gene', '1029', (249, 285))	('protein', 'cellular_component', 'GO:0003675', ('307', '314'))
135360	28350340	In the BRAF Inhibitor in Melanoma 3 (BRIM-3) study, vemurafenib was more effective in BRAFV600E mutated melanoma compared to conventional chemotherapy (dacarbazine and DTIC).	('mutated', 'Var', (96, 103))	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('Melanoma', 'Disease', 'MESH:D008545', (25, 33))	('dacarbazine', 'Chemical', 'MESH:D003606', (152, 163))	('Melanoma', 'Disease', (25, 33))	('BRAFV600E', 'Mutation', 'rs113488022', (86, 95))	('Melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('BRAF', 'Gene', '673', (86, 90))	('vemurafenib', 'Chemical', 'MESH:D000077484', (52, 63))	('BRAF', 'Gene', '673', (7, 11))	('BRAF', 'Gene', (7, 11))	('DTIC', 'Chemical', 'MESH:D003606', (168, 172))	('BRAF', 'Gene', (86, 90))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
135362	28350340	However, a major problem of targeted therapy is the emergence of receptor tyrosine kinase (RTK) mutations upon treatment with BRAF inhibitors.	('receptor tyrosine kinase', 'Gene', (65, 89))	('RTK', 'Gene', (91, 94))	('receptor tyrosine kinase', 'Gene', '5979', (65, 89))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('RTK', 'Gene', '5979', (91, 94))	('mutations', 'Var', (96, 105))
135363	28350340	Another common side effect of BRAF inhibitors is the development of new BRAFwt and RASmt melanoma, which may be explained by a paradoxical activation of the MAPK pathway in BRAFwt melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (173, 177))	('MAPK', 'molecular_function', 'GO:0004707', ('157', '161'))	('activation', 'PosReg', (139, 149))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('BRAF', 'Gene', (173, 177))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('BRAF', 'Gene', '673', (72, 76))	('inhibitors', 'Var', (35, 45))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('MAPK pathway', 'Pathway', (157, 169))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
135366	28350340	Therefore, dual inhibition is now considered the standard of care in BRAFV600 mutated melanoma.	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('BRAF', 'Gene', '673', (69, 73))	('mutated', 'Var', (78, 85))	('dual', 'MPA', (11, 15))	('BRAF', 'Gene', (69, 73))
135368	28350340	Due to its downstream signaling to the MAPK pathway and the knowledge that BRAF inhibitors lead to enhanced growth of BRAFwt melanomas, several trials investigated the efficiency of MEK inhibition in this subset of melanoma.	('MEK', 'Gene', (182, 185))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('melanoma', 'Disease', (215, 223))	('enhanced', 'PosReg', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('MAPK', 'molecular_function', 'GO:0004707', ('39', '43'))	('melanomas', 'Phenotype', 'HP:0002861', (125, 134))	('growth', 'MPA', (108, 114))	('inhibitors', 'Var', (80, 90))	('BRAFwt melanomas', 'Disease', 'MESH:D008545', (118, 134))	('BRAF', 'Gene', '673', (118, 122))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('BRAF', 'Gene', (118, 122))	('melanoma', 'Disease', 'MESH:D008545', (215, 223))	('MAPK pathway', 'Pathway', (39, 51))	('BRAFwt melanomas', 'Disease', (118, 134))	('MEK', 'Gene', '5609', (182, 185))	('BRAF', 'Gene', '673', (75, 79))	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('BRAF', 'Gene', (75, 79))
135370	28350340	In the literature, new mutations in the MAPK pathway and other pathways involved in proliferation and growth have been suggested as putative escape mechanism, but it might also be possible that there are some epigenetic modifications involved.	('rat', 'Species', '10116', (91, 94))	('MAPK', 'molecular_function', 'GO:0004707', ('40', '44'))	('mutations', 'Var', (23, 32))	('rat', 'Species', '10116', (11, 14))	('MAPK', 'Gene', (40, 44))
135371	28350340	The Cancer Genome Atlas proposed that NF1 mutations should be included for classification in BRAFwt/NRASwt melanoma, since reports were available showing that mutations in NF1 led to hyper-activation of the MAPK pathway and were responsive to MEK inhibition.	('NF1', 'Gene', '4763', (38, 41))	('BRAF', 'Gene', (93, 97))	('melanoma', 'Disease', (107, 115))	('hyper-activation', 'PosReg', (183, 199))	('NRAS', 'Gene', '4893', (100, 104))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('NF1', 'Gene', '4763', (172, 175))	('MAPK', 'molecular_function', 'GO:0004707', ('207', '211'))	('mutations', 'Var', (159, 168))	('BRAF', 'Gene', '673', (93, 97))	('MAPK pathway', 'Pathway', (207, 219))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('NF1', 'Gene', (172, 175))	('NF1', 'Gene', (38, 41))	('NRAS', 'Gene', (100, 104))	('MEK', 'Gene', (243, 246))	('MEK', 'Gene', '5609', (243, 246))
135373	28350340	However, Krauthammer and colleagues showed that not all NF1 mutated melanoma were responsive to MEK inhibition and that many NF1 mutated melanoma had concurrent mutations in RAS related genes.	('NF1', 'Gene', (125, 128))	('NF1', 'Gene', '4763', (56, 59))	('NF1', 'Gene', '4763', (125, 128))	('MEK', 'Gene', (96, 99))	('MEK', 'Gene', '5609', (96, 99))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('mutated', 'Var', (129, 136))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('melanoma', 'Disease', (137, 145))	('mutated', 'Var', (60, 67))	('mutations', 'Reg', (161, 170))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('NF1', 'Gene', (56, 59))
135375	28350340	The KIT proto-oncogene receptor tyrosine kinase gene is frequently mutated in acral and mucosal melanoma as well as in melanomas of chronically sun-damaged skin.	('KIT', 'molecular_function', 'GO:0005020', ('4', '7'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (88, 104))	('melanomas', 'Disease', (119, 128))	('KIT proto-oncogene receptor tyrosine kinase', 'Gene', (4, 47))	('KIT proto-oncogene receptor tyrosine kinase', 'Gene', '3815', (4, 47))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('mutated', 'Var', (67, 74))	('sun-damaged', 'Phenotype', 'HP:0000992', (144, 155))	('melanomas', 'Phenotype', 'HP:0002861', (119, 128))	('mucosal melanoma', 'Disease', (88, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanomas', 'Disease', 'MESH:D008545', (119, 128))
135377	28350340	Imatinib-a receptor tyrosine kinase inhibitor-showed high response rates and beneficial effects in patients harboring a melanoma with mutations in the exons 11 and 13 of the KIT gene.	('receptor tyrosine kinase', 'Gene', '5979', (11, 35))	('rat', 'Species', '10116', (67, 70))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('patients', 'Species', '9606', (99, 107))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('mutations in', 'Var', (134, 146))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('29', '45'))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('KIT', 'Gene', (174, 177))	('KIT', 'molecular_function', 'GO:0005020', ('174', '177'))	('receptor tyrosine kinase', 'Gene', (11, 35))
135378	28350340	In addition, nilotinib, a tyrosine kinase inhibitor used in imatinib-resistant chronic myeloid leukaemia, as well as sunitinib, provided promising results in the treatment of KIT mutated metastatic melanoma.	('kinase inhibitor', 'biological_process', 'GO:0033673', ('35', '51'))	('KIT mutated', 'Var', (175, 186))	('nilotinib', 'Chemical', 'MESH:C498826', (13, 22))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('sunitinib', 'Chemical', 'MESH:D000077210', (117, 126))	('melanoma', 'Disease', (198, 206))	('myeloid leukaemia', 'Disease', (87, 104))	('imatinib', 'Chemical', 'MESH:D000068877', (60, 68))	('chronic myeloid leukaemia', 'Phenotype', 'HP:0005506', (79, 104))	('KIT', 'molecular_function', 'GO:0005020', ('175', '178'))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (87, 104))	('myeloid leukaemia', 'Disease', 'MESH:D007938', (87, 104))
135400	28350340	One scaffold lncRNA is the antisense lncRNA in INK4 locus (ANRIL), which directly interacts with polycomb repressive complexes (PRC1 and PRC2).	('ANRIL', 'Gene', '100048912', (59, 64))	('PRC1', 'Gene', (128, 132))	('PRC1', 'Gene', '9055', (128, 132))	('ANRIL', 'Gene', (59, 64))	('antisense', 'Var', (27, 36))	('INK4', 'Gene', '1029', (47, 51))	('INK4', 'Gene', (47, 51))
135403	28350340	HOX transcript antisense RNA (HOTAIR) is also a multifunctional lncRNA transcribed in distal and posterior cells, thus being an anatomically specific signal, which is also involved in both PRC2 and Lysine-specific histone demethylase 1 (LSD1) complex assembly, therefore fitting the scaffold category and the localization of PRC2 as a guide.	('LSD1', 'Gene', (237, 241))	('antisense', 'Var', (15, 24))	('LSD1', 'Gene', '23028', (237, 241))	('RNA', 'cellular_component', 'GO:0005562', ('25', '28'))	('HOTAIR', 'Gene', (30, 36))	('antisense RNA', 'molecular_function', 'GO:0009388', ('15', '28'))	('localization', 'biological_process', 'GO:0051179', ('309', '321'))	('HOTAIR', 'Gene', '100124700', (30, 36))	('Lysine-specific histone demethylase 1', 'Gene', (198, 235))	('Lysine-specific histone demethylase 1', 'Gene', '23028', (198, 235))
135405	28350340	Furthermore, NBR2 depletion led to altered apoptosis/autophagy and unchecked cell cycling with increased tumor development in vivo.	('autophagy', 'biological_process', 'GO:0016236', ('53', '62'))	('altered', 'Reg', (35, 42))	('NBR2', 'Gene', '10230', (13, 17))	('autophagy', 'biological_process', 'GO:0006914', ('53', '62'))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('apoptosis/autophagy', 'CPA', (43, 62))	('depletion', 'Var', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('increased', 'PosReg', (95, 104))	('tumor', 'Disease', (105, 110))	('unchecked cell cycling', 'CPA', (67, 89))	('NBR2', 'Gene', (13, 17))
135406	28350340	Consequently, lncRNA deregulation can have a severe impact on cellular behavior and is often found in human diseases, especially cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('deregulation', 'Var', (21, 33))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('impact', 'Reg', (52, 58))	('lncRNA', 'Protein', (14, 20))	('cellular behavior', 'CPA', (62, 79))	('human', 'Species', '9606', (102, 107))
135427	28350340	It was frequently expressed in metastatic melanoma cell lines independent of their BRAF mutational status and was absent in normal melanocytes.	('melanoma', 'Disease', (42, 50))	('BRAF', 'Gene', (83, 87))	('mutational', 'Var', (88, 98))	('BRAF', 'Gene', '673', (83, 87))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
135430	28350340	Analysis of the 10-year disease-free survival rates and CASC15 expression in stage III melanoma lymph node metastases revealed that patients with high CASC15 expression had a significantly reduced DFS.	('rat', 'Species', '10116', (46, 49))	('melanoma lymph node metastases', 'Disease', 'MESH:D009362', (87, 117))	('expression', 'MPA', (158, 168))	('reduced', 'NegReg', (189, 196))	('CASC15', 'Gene', (151, 157))	('melanoma lymph node metastases', 'Disease', (87, 117))	('CASC15', 'Gene', '401237', (151, 157))	('high', 'Var', (146, 150))	('CASC15', 'Gene', (56, 62))	('CASC15', 'Gene', '401237', (56, 62))	('patients', 'Species', '9606', (132, 140))	('DFS', 'MPA', (197, 200))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
135438	28350340	In fact, HOTAIR knockdown experiments led to a decreased melanoma cell motility and invasiveness in conjunction with a reduced capability to degrade the extracellular matrix.	('HOTAIR', 'Gene', (9, 15))	('HOTAIR', 'Gene', '100124700', (9, 15))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('knockdown', 'Var', (16, 25))	('invasiveness', 'CPA', (84, 96))	('decreased melanoma cell motility', 'Disease', (47, 79))	('cell motility', 'biological_process', 'GO:0048870', ('66', '79'))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('153', '173'))	('degrade', 'NegReg', (141, 148))	('decreased melanoma cell motility', 'Disease', 'MESH:D008545', (47, 79))
135439	28350340	Mechanistically, HOTAIR acts as a guide lncRNA in trans by recruiting PRC2 to its target genes, which in turn results in H3K27 tri-methylation and an epigenetic silencing of metastasis suppressor genes (Figure 1B and Table 1).	('H3K27', 'Protein', (121, 126))	('PRC2', 'Gene', (70, 74))	('methylation', 'biological_process', 'GO:0032259', ('131', '142'))	('recruiting', 'PosReg', (59, 69))	('HOTAIR', 'Gene', (17, 23))	('metastasis suppressor genes', 'Gene', (174, 201))	('tri-methylation', 'Var', (127, 142))	('epigenetic silencing', 'Var', (150, 170))	('HOTAIR', 'Gene', '100124700', (17, 23))	('results in', 'Reg', (110, 120))
135445	28350340	MALAT1 knockdown resulted in impaired melanoma migration, implying possible effects on tumor dissemination.	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('impaired melanoma migration', 'Disease', 'MESH:D054081', (29, 56))	('MALAT1', 'Gene', '378938', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('MALAT1', 'Gene', (0, 6))	('effects', 'Reg', (76, 83))	('tumor dissemination', 'Disease', 'MESH:D009103', (87, 106))	('knockdown', 'Var', (7, 16))	('tumor dissemination', 'Disease', (87, 106))	('impaired melanoma migration', 'Disease', (29, 56))
135460	28350340	Because RMEL3 depletion decrease cell survival and proliferation in BRAFV600E melanoma cell lines, it might represent a potential therapeutic target gene in this subset of melanomas (summarized in Table 1).	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('decrease', 'NegReg', (24, 32))	('depletion', 'Var', (14, 23))	('melanomas', 'Disease', (172, 181))	('melanoma', 'Disease', (78, 86))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('rat', 'Species', '10116', (58, 61))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('cell survival', 'CPA', (33, 46))	('BRAFV600E', 'Mutation', 'rs113488022', (68, 77))	('melanomas', 'Disease', 'MESH:D008545', (172, 181))	('melanomas', 'Phenotype', 'HP:0002861', (172, 181))	('melanoma', 'Disease', (172, 180))	('RMEL3', 'Gene', (8, 13))
135473	28350340	Furthermore, SPRY4-IT1 reduces the abundance of the lipid phosphatase lipin 2.	('phosphatase', 'molecular_function', 'GO:0016791', ('58', '69'))	('lipin 2', 'Gene', '9663', (70, 77))	('SPRY4-IT1', 'Var', (13, 22))	('lipid', 'Chemical', 'MESH:D008055', (52, 57))	('lipin 2', 'Gene', (70, 77))	('reduces', 'NegReg', (23, 30))
135477	28350340	Interestingly, one month after ectopic overexpression of SPRY4-IT1 in melanocytes induced dendritic-like cell morphologies together with enlarged nuclei in 25% of the cells.	('overexpression', 'PosReg', (39, 53))	('SPRY4-IT1', 'Var', (57, 66))	('dendritic', 'Disease', 'MESH:D007635', (90, 99))	('dendritic', 'Disease', (90, 99))	('induced', 'PosReg', (82, 89))
135484	28350340	Depletion of UCA1 increased the levels of miR-507 and reduced FoxM1 levels which led to cell cycle progression defects.	('miR-507', 'Gene', (42, 49))	('increased', 'PosReg', (18, 27))	('defects', 'NegReg', (111, 118))	('miR-507', 'Gene', '574512', (42, 49))	('Depletion', 'Var', (0, 9))	('levels', 'MPA', (32, 38))	('cell cycle progression', 'CPA', (88, 110))	('reduced', 'NegReg', (54, 61))	('UCA1', 'Gene', '652995', (13, 17))	('FoxM1', 'Gene', '2305', (62, 67))	('UCA1', 'Gene', (13, 17))	('FoxM1', 'Gene', (62, 67))	('cell cycle', 'biological_process', 'GO:0007049', ('88', '98'))
135486	28350340	Long noncoding RNAs are now widely recognized as contributing factors which play diverse and complex roles in cancer.	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('Long noncoding RNAs', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))
135498	26818117	Furthermore, the possibility of an association between TRP mutations and disease is considered.	('TRP', 'Chemical', '-', (55, 58))	('mutations', 'Var', (59, 68))	('disease', 'Disease', (73, 80))	('TRP', 'Gene', (55, 58))
135502	26818117	About 20 years later, this aberrant behavior was attributed to a mutant TRP gene.	('TRP gene', 'Gene', (72, 80))	('mutant', 'Var', (65, 71))	('TRP', 'Chemical', '-', (72, 75))	('attributed', 'Reg', (49, 59))
135515	26818117	It is our intent that the reader will a) more fully appreciate their importance in maintaining ocular function; b) realize that changes in TRP functional expression can underlie ocular disease.	('ocular disease', 'Phenotype', 'HP:0000478', (178, 192))	('underlie', 'Reg', (169, 177))	('TRP', 'Chemical', '-', (139, 142))	('ocular disease', 'Disease', 'MESH:D005128', (178, 192))	('ocular disease', 'Disease', (178, 192))	('TRP', 'Protein', (139, 142))	('changes', 'Var', (128, 135))
135517	26818117	Changes in their function due to mutation [so-called (TRP) channelopathies] are associated with human diseases such as cancer.	('mutation', 'Var', (33, 41))	('function', 'MPA', (17, 25))	('human', 'Species', '9606', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('channelopathies', 'Disease', (59, 74))	('channelopathies', 'Disease', 'MESH:D053447', (59, 74))	('TRP', 'Chemical', '-', (54, 57))	('cancer', 'Disease', (119, 125))	('associated', 'Reg', (80, 90))	('Changes', 'Reg', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
135518	26818117	There are strong indications that variant TRP expression is also involved in many diseases (e.g.	('TRP', 'Chemical', '-', (42, 45))	('diseases', 'Disease', (82, 90))	('involved', 'Reg', (65, 73))	('variant', 'Var', (34, 41))	('TRP', 'Gene', (42, 45))
135519	26818117	mutations in TRPs are responsible for various kidney diseases), or cancer (e.g.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('responsible', 'Reg', (22, 33))	('various kidney diseases', 'Disease', 'MESH:D007674', (38, 61))	('cancer', 'Disease', (67, 73))	('kidney diseases', 'Phenotype', 'HP:0000112', (46, 61))	('TRPs', 'Gene', (13, 17))	('TRPs', 'Chemical', 'MESH:D014364', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('various kidney diseases', 'Disease', (38, 61))	('mutations', 'Var', (0, 9))
135528	26818117	Modulation of TRP channel activity contributes to the control of cell growth, differentiation, proliferation or secretion through changes in intracellular Ca2+ levels.	('Modulation', 'Var', (0, 10))	('TRP', 'Chemical', '-', (14, 17))	('cell growth', 'CPA', (65, 76))	('intracellular', 'cellular_component', 'GO:0005622', ('141', '154'))	('secretion', 'biological_process', 'GO:0046903', ('112', '121'))	('differentiation', 'CPA', (78, 93))	('changes', 'Reg', (130, 137))	('TRP', 'Protein', (14, 17))	('cell growth', 'biological_process', 'GO:0016049', ('65', '76'))	('secretion', 'CPA', (112, 121))	('rat', 'Species', '10116', (102, 105))	('proliferation', 'CPA', (95, 108))	('activity', 'MPA', (26, 34))	('intracellular Ca2+ levels', 'MPA', (141, 166))	('channel activity', 'molecular_function', 'GO:0015267', ('18', '34'))
135529	26818117	On the other hand, aberrant enhanced TRP channel activation leading to non-physiological rises in extracellular calcium influx or intracellular calcium release from stores (e.g.	('extracellular calcium influx', 'biological_process', 'GO:0035585', ('98', '126'))	('enhanced', 'PosReg', (28, 36))	('calcium', 'Chemical', 'MESH:D002118', (112, 119))	('TRP', 'Chemical', '-', (37, 40))	('intracellular calcium release from stores', 'MPA', (130, 171))	('intracellular', 'cellular_component', 'GO:0005622', ('130', '143'))	('calcium', 'Chemical', 'MESH:D002118', (144, 151))	('aberrant', 'Var', (19, 27))	('TRP channel', 'Protein', (37, 48))	('extracellular calcium influx', 'MPA', (98, 126))	('extracellular', 'cellular_component', 'GO:0005576', ('98', '111'))	('activation', 'PosReg', (49, 59))
135531	26818117	found that there is an extremely rapid photoreceptor cell death when a TRP channel is constitutively active due to mutations.	('mutations', 'Var', (115, 124))	('photoreceptor cell death', 'CPA', (39, 63))	('TRP', 'Gene', (71, 74))	('TRP', 'Chemical', '-', (71, 74))	('cell death', 'biological_process', 'GO:0008219', ('53', '63'))
135532	26818117	In the corneal endothelium, changes in TRP channel activity affect its role in maintaining tissue transparency (barrier and pump function).	('TRP channel', 'Protein', (39, 50))	('activity', 'MPA', (51, 59))	('channel activity', 'molecular_function', 'GO:0015267', ('43', '59'))	('tissue transparency', 'CPA', (91, 110))	('TRP', 'Chemical', '-', (39, 42))	('changes', 'Var', (28, 35))	('affect', 'Reg', (60, 66))
50781	26818117	However, it is not yet known if the TRP conformational changes induced by Ca2+ or Mg2+ are the same as those induced by a thermal transition known to activate these different TRP channel subtypes.	('TRP', 'Chemical', '-', (36, 39))	('Mg2', 'Gene', '57192', (82, 85))	('TRP', 'Protein', (36, 39))	('Ca2+', 'Var', (74, 78))	('TRP', 'Chemical', '-', (175, 178))	('Mg2', 'Gene', (82, 85))
135567	26818117	Many human mutations affected this system.	('mutations', 'Var', (11, 20))	('human', 'Species', '9606', (5, 10))	('affected', 'Reg', (21, 29))
135576	26818117	Activation by epidermal growth factor of its cognate receptor, EGFR, transactivates TRPC4.	('transactivates', 'Var', (69, 83))	('EGFR', 'Gene', '1956', (63, 67))	('TRPC4', 'Gene', (84, 89))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('14', '37'))	('EGFR', 'Gene', (63, 67))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))
135601	26818117	suggested that other TRP subtypes may be also expressed in human corneal endothelium since H2O2 induced significant rises in [Ca2+]I levels.	('human', 'Species', '9606', (59, 64))	('H2O2', 'Var', (91, 95))	('[Ca2+]I levels', 'MPA', (125, 139))	('TRP', 'Chemical', '-', (21, 24))	('H2O2', 'Chemical', 'MESH:D006861', (91, 95))	('rises', 'PosReg', (116, 121))
135607	26818117	TRPM3 variants are associated with cataractogenesis.	('associated', 'Reg', (19, 29))	('cataractogenesis', 'Disease', (35, 51))	('variants', 'Var', (6, 14))	('TRPM3', 'Gene', (0, 5))	('cataractogenesis', 'Disease', 'None', (35, 51))	('TRPM3', 'Gene', '80036', (0, 5))	('cataract', 'Phenotype', 'HP:0000518', (35, 43))
135626	26818117	One of the realizations sparking such interest is that TRP gene mutations underlie numerous inherited diseases in humans including the eye.	('numerous inherited diseases', 'Disease', 'MESH:D030342', (83, 110))	('eye', 'Disease', (135, 138))	('underlie', 'Reg', (74, 82))	('TRP gene', 'Gene', (55, 63))	('numerous inherited diseases', 'Disease', (83, 110))	('mutations', 'Var', (64, 73))	('TRP', 'Chemical', '-', (55, 58))	('humans', 'Species', '9606', (114, 120))
135628	26818117	Regarding the eye, one of them deals with mucolipidosis type IV (MLIV) and another indicates that mutant TRPM3 expression is associated with cataractogenesis and glaucoma.	('cataract', 'Phenotype', 'HP:0000518', (141, 149))	('TRPM3', 'Gene', (105, 110))	('glaucoma', 'Phenotype', 'HP:0000501', (162, 170))	('cataractogenesis and glaucoma', 'Disease', 'MESH:D005901', (141, 170))	('mucolipidosis type IV', 'Disease', (42, 63))	('associated', 'Reg', (125, 135))	('mucolipidosis type IV', 'Disease', 'MESH:D009081', (42, 63))	('TRPM3', 'Gene', '80036', (105, 110))	('MLIV', 'Disease', 'None', (65, 69))	('MLIV', 'Disease', (65, 69))	('mutant', 'Var', (98, 104))
135629	26818117	MLIV is an autosomal recessive, neurodegenerative lysosomal storage disorder, which is due to mutations in the gene MCOLN1.	('mutations', 'Var', (94, 103))	('MCOLN1', 'Gene', '57192', (116, 122))	('neurodegenerative lysosomal storage disorder', 'Disease', 'MESH:D016464', (32, 76))	('MLIV', 'Disease', 'None', (0, 4))	('storage', 'biological_process', 'GO:0051235', ('60', '67'))	('due to', 'Reg', (87, 93))	('MCOLN1', 'Gene', (116, 122))	('MLIV', 'Disease', (0, 4))	('neurodegenerative lysosomal storage disorder', 'Disease', (32, 76))
50877	26818117	In addition, human TRPM1 mutations are associated with congenital stationary night blindness (CSNB), whose patients lack rod function and suffer from night blindness starting in early childhood.	('blindness', 'Disease', (83, 92))	('blindness', 'Disease', 'MESH:D001766', (83, 92))	('mutations', 'Var', (25, 34))	('congenital stationary night blindness', 'Disease', 'MESH:C536122', (55, 92))	('human', 'Species', '9606', (13, 18))	('TRPM1', 'Gene', (19, 24))	('blindness', 'Disease', (156, 165))	('blindness', 'Disease', 'MESH:D001766', (156, 165))	('blindness', 'Phenotype', 'HP:0000618', (83, 92))	('night blindness', 'Phenotype', 'HP:0000662', (77, 92))	('associated', 'Reg', (39, 49))	('congenital stationary night blindness', 'Disease', (55, 92))	('night blindness', 'Phenotype', 'HP:0000662', (150, 165))	('blindness', 'Phenotype', 'HP:0000618', (156, 165))	('patients', 'Species', '9606', (107, 115))	('congenital stationary night blindness', 'Phenotype', 'HP:0007642', (55, 92))
135644	26818117	This subtype is implicated in how the eye senses such variations to maintain normostensive aqueous humor outflow Its regulatory role suggests that TRPV4 is an attractive therapeutic target for the treatment of hypertensive glaucoma.	('normostensive aqueous humor outflow', 'MPA', (77, 112))	('variations', 'Var', (54, 64))	('hypertensive glaucoma', 'Disease', 'MESH:D005901', (210, 231))	('hypertensive glaucoma', 'Disease', (210, 231))	('glaucoma', 'Phenotype', 'HP:0000501', (223, 231))	('TRPV4', 'Gene', (147, 152))
135655	26818117	One study showed that blockage of Ca2+ activated K+ channels inhibited angiogenesis induced by epidermal growth factor (EGF).	('angiogenesis', 'biological_process', 'GO:0001525', ('71', '83'))	('inhibited', 'NegReg', (61, 70))	('Ca2+ activated', 'Protein', (34, 48))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('95', '118'))	('EGF', 'Gene', (120, 123))	('angiogenesis', 'CPA', (71, 83))	('EGF', 'molecular_function', 'GO:0005154', ('120', '123'))	('blockage', 'Var', (22, 30))	('EGF', 'Gene', '1950', (120, 123))
135670	26818117	Its incidence is low, but is the most common ocular tumor of the eye in children and is associated with a RB mutation.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('RB', 'Gene', '5925', (106, 108))	('ocular tumor', 'Phenotype', 'HP:0100012', (45, 57))	('children', 'Species', '9606', (72, 80))	('associated', 'Reg', (88, 98))	('ocular tumor', 'Disease', 'MESH:D009369', (45, 57))	('ocular tumor', 'Disease', (45, 57))	('mutation', 'Var', (109, 117))
135678	26818117	Therefore, modulation of TRP expression and/or function could provide a badly needed therapeutic option.	('modulation', 'Var', (11, 21))	('function', 'MPA', (47, 55))	('TRP', 'Protein', (25, 28))	('TRP', 'Chemical', '-', (25, 28))	('expression', 'MPA', (29, 39))
135684	26818117	Verification of this possibility requires generating site specific TRP mutants to determine if such alterations correspond with any of the pathophysiological responses by cells expressing TRPs.	('TRP', 'Chemical', '-', (67, 70))	('rat', 'Species', '10116', (46, 49))	('TRP', 'Gene', (67, 70))	('TRPs', 'Chemical', 'MESH:D014364', (188, 192))	('mutants', 'Var', (71, 78))	('TRP', 'Chemical', '-', (188, 191))	('rat', 'Species', '10116', (104, 107))
135685	26818117	One example of such an approach would entail delineating why capsazepine interaction with TRPV1 in one setting suppresses injury-induced inflammation, but in another setting it instead elevates body temperature.	('capsazepine', 'Chemical', 'MESH:C071423', (61, 72))	('injury-induced inflammation', 'Disease', 'MESH:D007249', (122, 149))	('body temperature', 'MPA', (194, 210))	('elevates', 'PosReg', (185, 193))	('interaction', 'Interaction', (73, 84))	('inflammation', 'biological_process', 'GO:0006954', ('137', '149'))	('rat', 'Species', '10116', (204, 207))	('capsazepine', 'Var', (61, 72))	('injury-induced inflammation', 'Disease', (122, 149))	('TRPV1', 'Protein', (90, 95))	('suppresses', 'NegReg', (111, 121))	('elevates body temperature', 'Phenotype', 'HP:0004370', (185, 210))
135687	26818117	This appears to be tenable since there are indications that there is an association between aberrant TRP expression and disease.	('TRP expression', 'Protein', (101, 115))	('aberrant', 'Var', (92, 100))	('TRP', 'Chemical', '-', (101, 104))	('disease', 'Disease', (120, 127))
135688	26818117	In any case, much effort must still be committed to determine if there is a cause and effect relationship between specific TRP malfunctions and a pathophysiological condition underlying a eye disease.	('TRP', 'Gene', (123, 126))	('malfunctions', 'Var', (127, 139))	('eye disease', 'Disease', 'MESH:D005128', (188, 199))	('TRP', 'Chemical', '-', (123, 126))	('eye disease', 'Disease', (188, 199))	('eye disease', 'Phenotype', 'HP:0000478', (188, 199))
135690	24563540	The Phosphoinositide 3-Kinasealpha Selective Inhibitor, BYL719, Enhances the Effect of the Protein Kinase C Inhibitor, AEB071, in GNAQ/GNA11 Mutant Uveal Melanoma Cells G-protein mutations are one of the most common mutations occurring in uveal melanoma activating the protein kinase C (PKC)/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-Kinase (PI3K)/AKT pathways.	('phosphoinositide 3-Kinase', 'Gene', (336, 361))	('protein kinase C', 'Gene', '112476', (269, 285))	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('Protein Kinase C', 'Gene', (91, 107))	('Melanoma', 'Disease', (154, 162))	('activating', 'PosReg', (254, 264))	('AKT', 'Gene', '207', (369, 372))	('PI3K', 'molecular_function', 'GO:0016303', ('363', '367'))	('phosphoinositide 3-Kinase', 'Gene', '5290', (336, 361))	('protein kinase C', 'Gene', (269, 285))	('Protein Kinase C', 'Gene', '112476', (91, 107))	('MAPK', 'Gene', '5595;5594;5595', (326, 330))	('Melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('PKC', 'Gene', '112476', (287, 290))	('GNAQ', 'Gene', '2776', (130, 134))	('GNA11', 'Gene', '2767', (135, 140))	('MAPK', 'Gene', (326, 330))	('GNAQ', 'Gene', (130, 134))	('protein', 'cellular_component', 'GO:0003675', ('269', '276'))	('uveal melanoma', 'Disease', (239, 253))	('uveal melanoma', 'Disease', 'MESH:C536494', (239, 253))	('mutations', 'Var', (179, 188))	('AKT', 'Gene', (369, 372))	('PKC', 'molecular_function', 'GO:0004697', ('287', '290'))	('PKC', 'Gene', (287, 290))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (148, 162))	('Melanoma', 'Disease', 'MESH:D008545', (154, 162))	('protein', 'cellular_component', 'GO:0003675', ('310', '317'))	('Enhances', 'PosReg', (64, 72))	('MAPK', 'molecular_function', 'GO:0004707', ('326', '330'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (239, 253))	('mutations', 'Var', (216, 225))	('GNA11', 'Gene', (135, 140))
135691	24563540	In this study, we described the effect of dual pathway inhibition in uveal melanoma harboring GNAQ and GNA11 mutations via PKC inhibition with AEB071 (Sotrastaurin) and PI3k/AKT inhibition with BYL719, a selective PI3Kalpha inhibitor.	('uveal melanoma', 'Disease', (69, 83))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('Sotrastaurin', 'Chemical', 'MESH:C543528', (151, 163))	('inhibition', 'NegReg', (127, 137))	('PI3Kalpha', 'Gene', (214, 223))	('PKC', 'Gene', (123, 126))	('inhibition', 'NegReg', (55, 65))	('GNAQ', 'Gene', (94, 98))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('AEB071', 'Chemical', 'MESH:C543528', (143, 149))	('PKC', 'Gene', '112476', (123, 126))	('AKT', 'Gene', '207', (174, 177))	('PI3k', 'molecular_function', 'GO:0016303', ('169', '173'))	('dual pathway', 'Pathway', (42, 54))	('BYL719', 'Chemical', 'MESH:C585539', (194, 200))	('PKC', 'molecular_function', 'GO:0004697', ('123', '126'))	('mutations', 'Var', (109, 118))	('PI3Kalpha', 'Gene', '5290', (214, 223))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('GNA11', 'Gene', (103, 108))	('AKT', 'Gene', (174, 177))
135692	24563540	Growth inhibition was observed in GNAQ/GNA11 mutant cells with AEB071 versus no activity in WT cells.	('mutant', 'Var', (45, 51))	('AEB071', 'Chemical', 'MESH:C543528', (63, 69))	('GNAQ/GNA11', 'Gene', (34, 44))	('Growth', 'MPA', (0, 6))	('AEB071', 'Var', (63, 69))
135693	24563540	In the GNAQ-mutant cells, AEB071 decreased phosphorylation of MARCKS, a substrate of PKC, along with ERK1/2 and ribosomal S6, but persistent AKT activation was present.	('MARCKS', 'Gene', '4082', (62, 68))	('phosphorylation', 'MPA', (43, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('43', '58'))	('AEB071', 'Var', (26, 32))	('AKT', 'Gene', (141, 144))	('PKC', 'Gene', '112476', (85, 88))	('AEB071', 'Chemical', 'MESH:C543528', (26, 32))	('PKC', 'molecular_function', 'GO:0004697', ('85', '88'))	('MARCKS', 'Gene', (62, 68))	('ERK1/2', 'Gene', (101, 107))	('ERK1/2', 'Gene', '5595;5594', (101, 107))	('PKC', 'Gene', (85, 88))	('AKT', 'Gene', '207', (141, 144))	('ERK1', 'molecular_function', 'GO:0004707', ('101', '105'))	('decreased', 'NegReg', (33, 42))
135694	24563540	BYL719 had minimal anti-proliferative activity in all uveal melanoma cell lines, and inhibited phosphorylation of AKT in most cell lines.	('AKT', 'Gene', '207', (114, 117))	('BYL719', 'Chemical', 'MESH:C585539', (0, 6))	('inhibited', 'NegReg', (85, 94))	('AKT', 'Gene', (114, 117))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('uveal melanoma', 'Disease', (54, 68))	('uveal melanoma', 'Disease', 'MESH:C536494', (54, 68))	('phosphorylation', 'biological_process', 'GO:0016310', ('95', '110'))	('anti-proliferative activity', 'MPA', (19, 46))	('minimal', 'NegReg', (11, 18))	('BYL719', 'Var', (0, 6))	('phosphorylation', 'MPA', (95, 110))
135696	24563540	In vivo studies correlated with in vitro findings showing reduced xenograft tumor growth with the combination therapy in a GNAQ mutant model.	('GNAQ', 'Gene', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('mutant', 'Var', (128, 134))	('reduced', 'NegReg', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
135697	24563540	These findings suggest a new therapy treatment option for G-protein mutant uveal melanoma with a focus on specific targeting of multiple downstream pathways as part of combination therapy.	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (75, 89))	('uveal melanoma', 'Disease', 'MESH:C536494', (75, 89))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('uveal melanoma', 'Disease', (75, 89))	('G-protein', 'Protein', (58, 67))	('mutant', 'Var', (68, 74))
135702	24563540	Activation of MAPK in uveal melanoma can be attributed to mutations in GNA11 or GNAQ, an early event of malignant transformation.	('mutations', 'Var', (58, 67))	('GNA11', 'Gene', (71, 76))	('MAPK', 'Gene', (14, 18))	('MAPK', 'Gene', '5595;5594;5595', (14, 18))	('MAPK', 'molecular_function', 'GO:0004707', ('14', '18'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (22, 36))	('uveal melanoma', 'Disease', 'MESH:C536494', (22, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('Activation', 'PosReg', (0, 10))	('uveal melanoma', 'Disease', (22, 36))	('GNAQ', 'Gene', (80, 84))
135704	24563540	To date, most experimental therapies used to treat GNAQ and GNA11 mutant uveal melanoma have focused on the targeting of the MEK/ERK pathway.	('ERK', 'molecular_function', 'GO:0004707', ('129', '132'))	('uveal melanoma', 'Disease', 'MESH:C536494', (73, 87))	('mutant', 'Var', (66, 72))	('GNA11', 'Gene', (60, 65))	('uveal melanoma', 'Phenotype', 'HP:0007716', (73, 87))	('uveal melanoma', 'Disease', (73, 87))	('ERK', 'Gene', '5594', (129, 132))	('MEK', 'Gene', (125, 128))	('ERK', 'Gene', (129, 132))	('MEK', 'Gene', '5609', (125, 128))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))
135705	24563540	However, these mutations have been shown to activate other signaling pathways upstream of MEK including protein kinase C (PKC) family members which are involved in cell proliferation and apoptosis.	('PKC', 'Gene', (122, 125))	('PKC', 'Gene', '112476', (122, 125))	('protein kinase C', 'Gene', '112476', (104, 120))	('apoptosis', 'biological_process', 'GO:0006915', ('187', '196'))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('apoptosis', 'biological_process', 'GO:0097194', ('187', '196'))	('mutations', 'Var', (15, 24))	('PKC', 'molecular_function', 'GO:0004697', ('122', '125'))	('MEK', 'Gene', (90, 93))	('protein kinase C', 'Gene', (104, 120))	('MEK', 'Gene', '5609', (90, 93))	('signaling pathways', 'Pathway', (59, 77))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('cell proliferation', 'biological_process', 'GO:0008283', ('164', '182'))	('activate', 'PosReg', (44, 52))
135709	24563540	PI3K/AKT signaling pathways are also activated in the setting of G-protein mutations in uveal melanoma.	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('AKT signaling', 'biological_process', 'GO:0043491', ('5', '18'))	('activated', 'PosReg', (37, 46))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('AKT', 'Gene', '207', (5, 8))	('uveal melanoma', 'Disease', 'MESH:C536494', (88, 102))	('uveal melanoma', 'Disease', (88, 102))	('mutations', 'Var', (75, 84))	('G-protein', 'Protein', (65, 74))	('AKT', 'Gene', (5, 8))
135711	24563540	PI3K mediates phosphorylation of PIP2 to PIP3 [phosphatidylinositol -tris-phosphate], which activates AKT to promote tumor growth and proliferation.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('PI3K', 'Var', (0, 4))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('promote', 'PosReg', (109, 116))	('tumor', 'Disease', (117, 122))	('activates', 'PosReg', (92, 101))	('PIP2', 'Chemical', 'MESH:D019269', (33, 37))	('PIP3', 'Chemical', '-', (41, 45))	('phosphorylation', 'biological_process', 'GO:0016310', ('14', '29'))	('AKT', 'Gene', '207', (102, 105))	('phosphatidylinositol -tris-phosphate', 'Chemical', '-', (47, 83))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('AKT', 'Gene', (102, 105))
135720	24563540	Toward this end, we elected to evaluate dual target inhibition of PI3kalpha and PKC in GNAQ and GNA11 mutant uveal melanoma cells.	('mutant', 'Var', (102, 108))	('PKC', 'molecular_function', 'GO:0004697', ('80', '83'))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('uveal melanoma', 'Disease', 'MESH:C536494', (109, 123))	('PKC', 'Gene', (80, 83))	('PKC', 'Gene', '112476', (80, 83))	('PI3kalpha', 'Gene', (66, 75))	('uveal melanoma', 'Disease', (109, 123))	('PI3kalpha', 'Gene', '5290', (66, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('GNA11', 'Gene', (96, 101))
135722	24563540	AEB071 (sotrastaurin) is a potent inhibitor of many forms of PKC shown to have anti-proliferative activity in other cell types as well.	('sotrastaurin', 'Chemical', 'MESH:C543528', (8, 20))	('AEB071', 'Chemical', 'MESH:C543528', (0, 6))	('PKC', 'Gene', '112476', (61, 64))	('PKC', 'molecular_function', 'GO:0004697', ('61', '64'))	('anti-proliferative activity', 'MPA', (79, 106))	('PKC', 'Gene', (61, 64))	('AEB071', 'Var', (0, 6))
135725	24563540	We now show that the combination of the PKC inhibitor AEB071 with BYL719, a selective PI3kalpha inhibitor, results in an enhanced anti-tumor effect due to inhibition of both PKC and PI3K/AKT signaling in G-protein mutant uveal melanoma cells in vitro as well as in vivo.	('G-protein', 'Protein', (204, 213))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('uveal melanoma', 'Phenotype', 'HP:0007716', (221, 235))	('PI3K', 'molecular_function', 'GO:0016303', ('182', '186'))	('enhanced', 'PosReg', (121, 129))	('AEB071', 'Chemical', 'MESH:C543528', (54, 60))	('combination', 'Interaction', (21, 32))	('PKC', 'molecular_function', 'GO:0004697', ('40', '43'))	('protein', 'cellular_component', 'GO:0003675', ('206', '213'))	('AEB071', 'Var', (54, 60))	('mutant', 'Var', (214, 220))	('AKT', 'Gene', (187, 190))	('PKC', 'Gene', '112476', (40, 43))	('PKC', 'Gene', '112476', (174, 177))	('inhibition', 'NegReg', (155, 165))	('tumor', 'Disease', (135, 140))	('PKC', 'Gene', (40, 43))	('PKC', 'Gene', (174, 177))	('PI3kalpha', 'Gene', '5290', (86, 95))	('PI3kalpha', 'Gene', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('AKT', 'Gene', '207', (187, 190))	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('BYL719', 'Chemical', 'MESH:C585539', (66, 72))	('uveal melanoma', 'Disease', 'MESH:C536494', (221, 235))	('PKC', 'molecular_function', 'GO:0004697', ('174', '177'))	('uveal melanoma', 'Disease', (221, 235))	('AKT signaling', 'biological_process', 'GO:0043491', ('187', '200'))
135729	24563540	As previously reported, uveal melanoma cell lines have been sequenced for the presence of activating mutations in codons 209 (exon 5) and 183 (exon 4) of GNAQ and GNA11.	('uveal melanoma', 'Disease', (24, 38))	('GNA11', 'Gene', (163, 168))	('mutations in', 'Var', (101, 113))	('GNAQ', 'Gene', (154, 158))	('activating', 'PosReg', (90, 100))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (24, 38))	('uveal melanoma', 'Disease', 'MESH:C536494', (24, 38))
135730	24563540	Two cell lines had Q209L mutation (92.1, Mel202), whereas Omm1.3 and Mel270 had Q209P mutation.	('Q209L', 'Var', (19, 24))	('Q209L', 'Mutation', 'rs1057519742', (19, 24))	('Q209P', 'Mutation', 'rs1057519742', (80, 85))	('Q209P', 'Var', (80, 85))
135736	24563540	Antibodies used to probe were pAKT (Ser473), Pan AKT, pS6 (S240/244), S6 ribosomal protein, pMARCKS (S152/156), MARCKS, alpha-Tubulin, ERK1/2, Cleaved PARP (Cell Signaling) and pERK1/2 (Y204) (Santa Cruz Biotechnology).	('alpha-Tubulin', 'Gene', '10376', (120, 133))	('Ser473', 'Var', (36, 42))	('AKT', 'Gene', (31, 34))	('Ser473', 'Chemical', '-', (36, 42))	('AKT', 'Gene', '207', (49, 52))	('pS6', 'Gene', (54, 57))	('MARCKS', 'Gene', (93, 99))	('ERK1/2', 'Gene', (135, 141))	('Signaling', 'biological_process', 'GO:0023052', ('162', '171'))	('ERK1/2', 'Gene', '5595;5594', (135, 141))	('ERK1', 'molecular_function', 'GO:0004707', ('135', '139'))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('pERK', 'Gene', (177, 181))	('AKT', 'Gene', '207', (31, 34))	('alpha-Tubulin', 'Gene', (120, 133))	('pERK', 'Gene', '9451', (177, 181))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('73', '90'))	('pS6', 'Gene', '338413', (54, 57))	('MARCKS', 'Gene', (112, 118))	('ERK1/2', 'Gene', (178, 184))	('MARCKS', 'Gene', '4082', (93, 99))	('PARP', 'Gene', '142', (151, 155))	('AKT', 'Gene', (49, 52))	('PARP', 'Gene', (151, 155))	('Ser', 'cellular_component', 'GO:0005790', ('36', '39'))	('MARCKS', 'Gene', '4082', (112, 118))	('ERK1/2', 'Gene', '5595;5594', (178, 184))
135751	24563540	AEB071 inhibited p-MARCKS, a PKC substrate, and pS6 in all the cell lines, independently of the mutational status.	('AEB071', 'Chemical', 'MESH:C543528', (0, 6))	('pS6', 'Gene', (48, 51))	('MARCKS', 'Gene', (19, 25))	('PKC', 'molecular_function', 'GO:0004697', ('29', '32'))	('inhibited', 'NegReg', (7, 16))	('pS6', 'Gene', '338413', (48, 51))	('PKC', 'Gene', (29, 32))	('PKC', 'Gene', '112476', (29, 32))	('MARCKS', 'Gene', '4082', (19, 25))	('AEB071', 'Var', (0, 6))
135752	24563540	We also found an inhibition of ERK phosphorylation only in the GNAQ mutant cells.	('ERK', 'Gene', (31, 34))	('phosphorylation', 'biological_process', 'GO:0016310', ('35', '50'))	('ERK', 'molecular_function', 'GO:0004707', ('31', '34'))	('phosphorylation', 'MPA', (35, 50))	('GNAQ', 'Gene', (63, 67))	('ERK', 'Gene', '5594', (31, 34))	('inhibition', 'NegReg', (17, 27))	('mutant', 'Var', (68, 74))
135753	24563540	There was a slight inhibition of pERK at lower doses also in the GNA11 mutant cells, but not in the WT cells at any concentrations.	('inhibition', 'NegReg', (19, 29))	('mutant', 'Var', (71, 77))	('GNA11', 'Gene', (65, 70))	('pERK', 'Gene', '9451', (33, 37))	('pERK', 'Gene', (33, 37))
135754	24563540	This is consistent with previous reports indicating that AEB071 inhibits ERK1/2 phosphorylation in GNAQ mutant cell lines.	('AEB071', 'Var', (57, 63))	('ERK1', 'molecular_function', 'GO:0004707', ('73', '77'))	('phosphorylation', 'biological_process', 'GO:0016310', ('80', '95'))	('AEB071', 'Chemical', 'MESH:C543528', (57, 63))	('mutant', 'Var', (104, 110))	('ERK1/2', 'Gene', (73, 79))	('ERK1/2', 'Gene', '5595;5594', (73, 79))	('phosphorylation', 'MPA', (80, 95))	('inhibits', 'NegReg', (64, 72))
135755	24563540	Phosphorylation of AKT at Ser473 was minimally affected in the GNAQ mutant cells, while it increased in the GNA11-mutant and WT cells.	('Ser473', 'Var', (26, 32))	('AKT', 'Gene', '207', (19, 22))	('Phosphorylation', 'MPA', (0, 15))	('Ser473', 'Chemical', '-', (26, 32))	('increased', 'PosReg', (91, 100))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('GNAQ', 'Gene', (63, 67))	('AKT', 'Gene', (19, 22))	('Ser', 'cellular_component', 'GO:0005790', ('26', '29'))	('mutant', 'Var', (68, 74))
135756	24563540	In Mel290 (WT), the activation of AKT in response to AEB071 was particularly evident, indicating a feedback mechanism, possibly dependent on EGFR, which has been reported to be overexpressed in this cell line.	('AKT', 'Gene', (34, 37))	('EGFR', 'Gene', '1956', (141, 145))	('AEB071', 'Var', (53, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('141', '145'))	('AEB071', 'Chemical', 'MESH:C543528', (53, 59))	('EGFR', 'Gene', (141, 145))	('activation', 'PosReg', (20, 30))	('AKT', 'Gene', '207', (34, 37))
135757	24563540	To explore whether selective PI3kalpha inhibition contributes to the PKC inhibitory effects in uveal melanoma, we performed gene silencing of p110alpha with or without the presence of AEB071 (Figure 2A).	('PI3kalpha', 'Gene', (29, 38))	('p110alpha', 'Gene', (142, 151))	('PI3kalpha', 'Gene', '5290', (29, 38))	('AEB071', 'Chemical', 'MESH:C543528', (184, 190))	('PKC', 'Gene', (69, 72))	('PKC', 'Gene', '112476', (69, 72))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('gene silencing', 'biological_process', 'GO:0016458', ('124', '138'))	('uveal melanoma', 'Disease', 'MESH:C536494', (95, 109))	('uveal melanoma', 'Phenotype', 'HP:0007716', (95, 109))	('uveal melanoma', 'Disease', (95, 109))	('gene silencing', 'Var', (124, 138))	('PKC', 'molecular_function', 'GO:0004697', ('69', '72'))	('p110alpha', 'Gene', '5290', (142, 151))
135758	24563540	Depletion of p110alpha inhibited AKT phosphorylation in the GNAQ mutant (92.1, Omm1.3) and WT (C918) cells.	('GNAQ', 'Gene', (60, 64))	('inhibited', 'NegReg', (23, 32))	('mutant', 'Var', (65, 71))	('AKT', 'Gene', '207', (33, 36))	('C918', 'CellLine', 'CVCL:8471', (95, 99))	('phosphorylation', 'biological_process', 'GO:0016310', ('37', '52'))	('p110alpha', 'Gene', (13, 22))	('AKT', 'Gene', (33, 36))	('p110alpha', 'Gene', '5290', (13, 22))
135760	24563540	However, treatment with AEB071 in the presence of p110alpha siRNA suppression induced PARP cleavage only in the mutant cells, under which condition p-MARCKS, p-ERK, p-AKT and p-S6 were inhibited (Figure 2A).	('AKT', 'Gene', (167, 170))	('ERK', 'molecular_function', 'GO:0004707', ('160', '163'))	('p110alpha', 'Gene', (50, 59))	('PARP', 'Gene', '142', (86, 90))	('p110alpha', 'Gene', '5290', (50, 59))	('p-S6', 'Gene', '338413', (175, 179))	('inhibited', 'NegReg', (185, 194))	('MARCKS', 'Gene', (150, 156))	('PARP', 'Gene', (86, 90))	('AKT', 'Gene', '207', (167, 170))	('mutant', 'Var', (112, 118))	('AEB071', 'Chemical', 'MESH:C543528', (24, 30))	('MARCKS', 'Gene', '4082', (150, 156))	('p-S6', 'Gene', (175, 179))	('p-ERK', 'Gene', '9451', (158, 163))	('p-ERK', 'Gene', (158, 163))
135764	24563540	We observed inhibition of phosphorylation of AKT (Ser473) up to 1 muM in most cell lines (Figure 2D), even though there was reactivation at higher doses in Omm1.3, Mel270 and Mel290.	('inhibition of phosphorylation', 'biological_process', 'GO:0042326', ('12', '41'))	('Ser473', 'Var', (50, 56))	('inhibition', 'NegReg', (12, 22))	('AKT', 'Gene', (45, 48))	('Ser473', 'Chemical', '-', (50, 56))	('Ser', 'cellular_component', 'GO:0005790', ('50', '53'))	('AKT', 'Gene', '207', (45, 48))	('phosphorylation', 'MPA', (26, 41))
135770	24563540	The combination of AEB071 and BYL719 at different doses exhibited a combination index (CI) < 1, indicative of synergy and a fractional activity of more than 50% ((Fa)>0.5) in all GNAQ/GNA11 mutant cell lines (Supplementary Figure 1).	('combination', 'MPA', (68, 79))	('GNAQ/GNA11', 'Gene', (179, 189))	('AEB071', 'Var', (19, 25))	('AEB071', 'Chemical', 'MESH:C543528', (19, 25))	('BYL719', 'Var', (30, 36))	('synergy', 'MPA', (110, 117))	('BYL719', 'Chemical', 'MESH:C585539', (30, 36))
135774	24563540	Single agent BYL719 caused a slight activation of p-ERK that was detectable as early as 2 hours after drug exposure, especially in the 92.1 cells, but this activation was suppressed with the combination treatment.	('ERK', 'molecular_function', 'GO:0004707', ('52', '55'))	('BYL719', 'Chemical', 'MESH:C585539', (13, 19))	('activation', 'PosReg', (36, 46))	('p-ERK', 'Gene', '9451', (50, 55))	('BYL719', 'Var', (13, 19))	('p-ERK', 'Gene', (50, 55))
135777	24563540	In the Mel290 WT cell line, there was activation of AKT to both AEB071 and BYL719 along with reactivation of p-MARCKS at later time points suggesting that this cell line may have a dependency on other survival pathways such as EGFR.	('MARCKS', 'Gene', '4082', (111, 117))	('EGFR', 'Gene', '1956', (227, 231))	('EGFR', 'molecular_function', 'GO:0005006', ('227', '231'))	('AKT', 'Gene', (52, 55))	('BYL719', 'Var', (75, 81))	('EGFR', 'Gene', (227, 231))	('BYL719', 'Chemical', 'MESH:C585539', (75, 81))	('AEB071', 'Chemical', 'MESH:C543528', (64, 70))	('activation', 'PosReg', (38, 48))	('MARCKS', 'Gene', (111, 117))	('AKT', 'Gene', '207', (52, 55))
135779	24563540	In these cells AEB071 inhibited p-MARCKS and p-S6 but induced activation of p-AKT over time, which was inhibited by BYL719 in the combination therapy.	('inhibited', 'NegReg', (22, 31))	('AEB071', 'Var', (15, 21))	('AKT', 'Gene', '207', (78, 81))	('AEB071', 'Chemical', 'MESH:C543528', (15, 21))	('MARCKS', 'Gene', (34, 40))	('BYL719', 'Chemical', 'MESH:C585539', (116, 122))	('p-S6', 'Gene', '338413', (45, 49))	('AKT', 'Gene', (78, 81))	('MARCKS', 'Gene', '4082', (34, 40))	('activation', 'PosReg', (62, 72))	('p-S6', 'Gene', (45, 49))
135780	24563540	Interestingly, BYL719 also inhibited pERK in this cell line.	('BYL719', 'Var', (15, 21))	('BYL719', 'Chemical', 'MESH:C585539', (15, 21))	('inhibited', 'NegReg', (27, 36))	('pERK', 'Gene', '9451', (37, 41))	('pERK', 'Gene', (37, 41))
135781	24563540	Thus, these results indicate that inhibition of PKC and PI3kalpha together achieves a synergistic effect in GNAQ and GNA11 cells with inhibition of downstream survival pathways that is not achievable with single agent therapy alone.	('PKC', 'molecular_function', 'GO:0004697', ('48', '51'))	('synergistic effect', 'MPA', (86, 104))	('inhibition', 'Var', (34, 44))	('PKC', 'Gene', (48, 51))	('PKC', 'Gene', '112476', (48, 51))	('PI3kalpha', 'Gene', '5290', (56, 65))	('inhibition', 'NegReg', (134, 144))	('downstream survival pathways', 'Pathway', (148, 176))	('PI3kalpha', 'Gene', (56, 65))
135786	24563540	Furthermore, the combination treatment induced PARP cleavage, an early apoptotic marker, in GNAQ mutant cells, while there was no evidence of PARP cleavage in the WT cell lines (Figure 4B).	('PARP', 'Gene', (47, 51))	('PARP', 'Gene', '142', (142, 146))	('GNAQ', 'Gene', (92, 96))	('induced', 'Reg', (39, 46))	('mutant', 'Var', (97, 103))	('PARP', 'Gene', '142', (47, 51))	('PARP', 'Gene', (142, 146))
135787	24563540	In view of the synergistic effects of the combination therapy observed in vitro, we elected to determine whether the combination therapy would be superior to single agent therapy in a GNAQ mutant xenograft mouse model.	('GNAQ', 'Gene', (184, 188))	('mouse', 'Species', '10090', (206, 211))	('mutant', 'Var', (189, 195))
135792	24563540	The Omm1(GNA11) mutant xenograft mouse model was also performed with both single agents having an effect on inhibiting tumor growth at their respective single agent MTDs, which appeared greater than that observed in the GNAQ xenograft.	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('mutant', 'Var', (16, 22))	('inhibiting', 'NegReg', (108, 118))	('mouse', 'Species', '10090', (33, 38))	('Omm1(GNA11', 'Gene', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
135797	24563540	Previous studies have focused on combining inhibitors of MEK with mTOR and PI3K/AKT pathways.	('mTOR', 'Gene', (66, 70))	('inhibitors', 'Var', (43, 53))	('mTOR', 'Gene', '2475', (66, 70))	('AKT', 'Gene', '207', (80, 83))	('MEK', 'Gene', '5609', (57, 60))	('AKT', 'Gene', (80, 83))	('PI3K', 'molecular_function', 'GO:0016303', ('75', '79'))	('MEK', 'Gene', (57, 60))
135798	24563540	Targeted therapy directed against PI3K isoforms has usually been effective in cancers harboring mutations of the isoform but PI3K mutations have not been reported in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (166, 180))	('uveal melanoma', 'Disease', 'MESH:C536494', (166, 180))	('uveal melanoma', 'Disease', (166, 180))	('PI3K', 'molecular_function', 'GO:0016303', ('125', '129'))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('PI3K', 'molecular_function', 'GO:0016303', ('34', '38'))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('mutations', 'Var', (96, 105))
135802	24563540	The G-protein oncogenic mutations have been shown to activate PKC.	('PKC', 'molecular_function', 'GO:0004697', ('62', '65'))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('PKC', 'Gene', '112476', (62, 65))	('G-protein', 'Protein', (4, 13))	('mutations', 'Var', (24, 33))	('PKC', 'Gene', (62, 65))	('activate', 'PosReg', (53, 61))
135803	24563540	In fact, GNAQ mutations rely mostly on PKC and MAPK pathways for survival.	('GNAQ', 'Gene', (9, 13))	('MAPK', 'Gene', (47, 51))	('MAPK', 'molecular_function', 'GO:0004707', ('47', '51'))	('PKC', 'Gene', (39, 42))	('PKC', 'Gene', '112476', (39, 42))	('mutations', 'Var', (14, 23))	('PKC', 'molecular_function', 'GO:0004697', ('39', '42'))	('MAPK', 'Gene', '5595;5594;5595', (47, 51))
135804	24563540	This present study demonstrates that inhibiting PKC and ERK1/2 signaling with AEB071 together with the PI3kalpha inhibitor, BYL179, results in a synergistic anti-tumor effect in uveal melanoma harboring GNAQ and GNA11 mutations in vitro.	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('tumor', 'Disease', (162, 167))	('GNA11', 'Gene', (212, 217))	('AEB071', 'Chemical', 'MESH:C543528', (78, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (178, 192))	('AEB071', 'Gene', (78, 84))	('uveal melanoma', 'Disease', (178, 192))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('PKC', 'molecular_function', 'GO:0004697', ('48', '51'))	('ERK1/2', 'Gene', (56, 62))	('ERK1/2', 'Gene', '5595;5594', (56, 62))	('GNAQ', 'Gene', (203, 207))	('PI3kalpha', 'Gene', '5290', (103, 112))	('PI3kalpha', 'Gene', (103, 112))	('uveal melanoma', 'Phenotype', 'HP:0007716', (178, 192))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('PKC', 'Gene', '112476', (48, 51))	('PKC', 'Gene', (48, 51))	('mutations', 'Var', (218, 227))	('ERK1', 'molecular_function', 'GO:0004707', ('56', '60'))	('inhibiting', 'NegReg', (37, 47))
135806	24563540	This may explain the minimal single agent effect of AEB071 on inhibiting pAKT in the GNAQ and GNA11 mutant cell lines.	('mutant', 'Var', (100, 106))	('AKT', 'Gene', '207', (74, 77))	('inhibiting', 'MPA', (62, 72))	('AKT', 'Gene', (74, 77))	('AEB071', 'Chemical', 'MESH:C543528', (52, 58))
135809	24563540	This could explain why inhibition of this pathway also enhances the anti-tumor effect we have observed in these cells.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('inhibition', 'Var', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('enhances', 'PosReg', (55, 63))
135810	24563540	In the setting of GNAQ/GNA11 mutations, the inhibition of MARCKS, ERK, AKT and S6 phosphorylation results in apoptosis by the combination treatment.	('ERK', 'molecular_function', 'GO:0004707', ('66', '69'))	('AKT', 'Gene', '207', (71, 74))	('MARCKS', 'Gene', '4082', (58, 64))	('GNAQ/GNA11', 'Gene', (18, 28))	('apoptosis', 'CPA', (109, 118))	('mutations', 'Var', (29, 38))	('inhibition', 'NegReg', (44, 54))	('ERK', 'Gene', '5594', (66, 69))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('AKT', 'Gene', (71, 74))	('phosphorylation', 'biological_process', 'GO:0016310', ('82', '97'))	('MARCKS', 'Gene', (58, 64))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))	('ERK', 'Gene', (66, 69))
135814	24563540	For example, we previously reported that blockade of Torc1 and Torc2 with AZD8055 in combination with the MEK inhibitor selumetinib (AZD6244) in GNAQ mutant cells is insufficient to suppress tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('AZD8055', 'Var', (74, 81))	('Torc1', 'Gene', '23373', (53, 58))	('insufficient', 'Disease', 'MESH:D000309', (166, 178))	('mutant', 'Var', (150, 156))	('AZD8055', 'Chemical', 'MESH:C546624', (74, 81))	('MEK', 'Gene', '5609', (106, 109))	('Torc2', 'cellular_component', 'GO:0031932', ('63', '68'))	('tumor', 'Disease', (191, 196))	('Torc1', 'cellular_component', 'GO:0031931', ('53', '58'))	('AZD6244', 'Chemical', 'MESH:C517975', (133, 140))	('suppress', 'NegReg', (182, 190))	('Torc2', 'Gene', (63, 68))	('selumetinib', 'Chemical', 'MESH:C517975', (120, 131))	('Torc1', 'Gene', (53, 58))	('Torc2', 'Gene', '200186', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('MEK', 'Gene', (106, 109))	('insufficient', 'Disease', (166, 178))
135815	24563540	In contrast, we have shown that inhibition of p-AKT with MK2206, an allosteric inhibitor of AKT, in combination with selumetinib results in enhanced anti-tumor effects.	('selumetinib', 'Chemical', 'MESH:C517975', (117, 128))	('enhanced', 'PosReg', (140, 148))	('AKT', 'Gene', (48, 51))	('MK2206', 'Var', (57, 63))	('inhibition', 'NegReg', (32, 42))	('AKT', 'Gene', '207', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('MK2206', 'Chemical', 'MESH:C548887', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('AKT', 'Gene', (92, 95))	('AKT', 'Gene', '207', (48, 51))	('tumor', 'Disease', (154, 159))
135817	24563540	Based on our MK2206 and selumetinib data, inhibition of p-ERK in combination with inhibition of p-AKT appears to be the minimal requirement necessary to promote an anti-tumor effect with combination therapy.	('selumetinib', 'Chemical', 'MESH:C517975', (24, 35))	('ERK', 'molecular_function', 'GO:0004707', ('58', '61'))	('MK2206', 'Chemical', 'MESH:C548887', (13, 19))	('p-ERK', 'Gene', '9451', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('p-ERK', 'Gene', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('inhibition', 'Var', (42, 52))	('AKT', 'Gene', '207', (98, 101))	('tumor', 'Disease', (169, 174))	('AKT', 'Gene', (98, 101))
135818	24563540	As AEB071 results in inhibition of PKC as well as p-ERK, this dual pathway inhibition, when combined with inhibition of PI3kalpha/AKT by BYL719, appears to provide a means to broaden pathway inhibition above and beyond MEK and AKT alone for cell growth inhibition of GNAQ/GNA11 mutant cells.	('pathway inhibition', 'Pathway', (183, 201))	('BYL719', 'Chemical', 'MESH:C585539', (137, 143))	('ERK', 'molecular_function', 'GO:0004707', ('52', '55'))	('PKC', 'Gene', '112476', (35, 38))	('p-ERK', 'Gene', '9451', (50, 55))	('AKT', 'Gene', '207', (130, 133))	('p-ERK', 'Gene', (50, 55))	('mutant', 'Var', (278, 284))	('PKC', 'Gene', (35, 38))	('PI3kalpha', 'Gene', (120, 129))	('PI3kalpha', 'Gene', '5290', (120, 129))	('MEK', 'Gene', '5609', (219, 222))	('AEB071', 'Chemical', 'MESH:C543528', (3, 9))	('GNAQ/GNA11', 'Gene', (267, 277))	('PKC', 'molecular_function', 'GO:0004697', ('35', '38'))	('AKT', 'Gene', (227, 230))	('MEK', 'Gene', (219, 222))	('cell growth', 'biological_process', 'GO:0016049', ('241', '252'))	('AKT', 'Gene', (130, 133))	('AKT', 'Gene', '207', (227, 230))
135819	24563540	All together our findings indicate that the targeting of PKC/ERK, along with a selective PI3kalpha isoform inhibitor, cooperates in inhibiting growth in GNAQ mutant uveal melanoma cells.	('uveal melanoma', 'Disease', (165, 179))	('PI3kalpha', 'Gene', (89, 98))	('ERK', 'molecular_function', 'GO:0004707', ('61', '64'))	('inhibiting', 'NegReg', (132, 142))	('uveal melanoma', 'Disease', 'MESH:C536494', (165, 179))	('ERK', 'Gene', '5594', (61, 64))	('PI3kalpha', 'Gene', '5290', (89, 98))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('growth', 'MPA', (143, 149))	('PKC', 'Gene', '112476', (57, 60))	('PKC', 'molecular_function', 'GO:0004697', ('57', '60'))	('ERK', 'Gene', (61, 64))	('mutant', 'Var', (158, 164))	('uveal melanoma', 'Phenotype', 'HP:0007716', (165, 179))	('PKC', 'Gene', (57, 60))	('GNAQ', 'Gene', (153, 157))
135824	24563540	Our studies indicate that both AEB071 and BYL719 can inhibit p-ERK as single agents or as part of combination therapy.	('inhibit', 'NegReg', (53, 60))	('BYL719', 'Chemical', 'MESH:C585539', (42, 48))	('ERK', 'molecular_function', 'GO:0004707', ('63', '66'))	('p-ERK', 'Gene', '9451', (61, 66))	('p-ERK', 'Gene', (61, 66))	('AEB071', 'Chemical', 'MESH:C543528', (31, 37))	('BYL719', 'Var', (42, 48))
135828	23443086	The Pharmacological NF-kappaB Inhibitor BAY11-7082 Induces Cell Apoptosis and Inhibits the Migration of Human Uveal Melanoma Cells Uveal melanomas are highly metastatic and have high rate of recurrence due to the lack of effective systemic therapy.	('Uveal melanomas', 'Phenotype', 'HP:0007716', (131, 146))	('BAY11-7082', 'Var', (40, 50))	('Human', 'Species', '9606', (104, 109))	('melanomas', 'Disease', 'MESH:D008545', (137, 146))	('Induces', 'Reg', (51, 58))	('NF-kappaB Inhibitor', 'biological_process', 'GO:0032088', ('20', '39'))	('melanomas', 'Disease', (137, 146))	('BAY11-7082', 'Chemical', 'MESH:C434003', (40, 50))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (110, 124))	('Melanoma', 'Disease', 'MESH:D008545', (116, 124))	('melanomas', 'Phenotype', 'HP:0002861', (137, 146))	('Inhibits', 'NegReg', (78, 86))	('NF-kappaB', 'Gene', (20, 29))	('Migration', 'CPA', (91, 100))	('Melanoma', 'Disease', (116, 124))	('NF-kappaB', 'Gene', '4790', (20, 29))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('Cell Apoptosis', 'CPA', (59, 73))	('Melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))
135831	23443086	Treatment with the pharmacological NF-kappaB specific inhibitor BAY11-7082 markedly decreased the nuclear translocation of NF-kappaB.	('nuclear translocation', 'MPA', (98, 119))	('BAY11-7082', 'Chemical', 'MESH:C434003', (64, 74))	('BAY11-7082', 'Var', (64, 74))	('decreased', 'NegReg', (84, 93))	('NF-kappaB', 'Protein', (123, 132))
135832	23443086	In a dose-dependent setting, BAY11-7082 inhibited the proliferation and growth of uveal melanoma cells by inducing apoptosis without effect on cell cycle.	('BAY11-7082', 'Chemical', 'MESH:C434003', (29, 39))	('growth', 'CPA', (72, 78))	('inhibited', 'NegReg', (40, 49))	('BAY11-7082', 'Var', (29, 39))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('apoptosis', 'biological_process', 'GO:0097194', ('115', '124'))	('apoptosis', 'biological_process', 'GO:0006915', ('115', '124'))	('apoptosis', 'CPA', (115, 124))	('uveal melanoma', 'Disease', 'MESH:C536494', (82, 96))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('uveal melanoma', 'Disease', (82, 96))	('cell cycle', 'biological_process', 'GO:0007049', ('143', '153'))	('inducing', 'NegReg', (106, 114))
135833	23443086	The migration capacity of uveal melanoma cells was also significantly suppressed by BAY11-7082 treatment.	('BAY11-7082', 'Var', (84, 94))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('suppressed', 'NegReg', (70, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (26, 40))	('uveal melanoma', 'Disease', (26, 40))	('uveal melanoma', 'Disease', 'MESH:C536494', (26, 40))	('BAY11-7082', 'Chemical', 'MESH:C434003', (84, 94))
135834	23443086	Mechanistically, BAY11-7082 increased the activity of caspase 3 and reduced the expression of anti-apoptotic protein Bcl-2, but did not influence the expression of pro-apoptotic protein Bax.	('increased', 'PosReg', (28, 37))	('Bcl-2', 'Gene', '596', (117, 122))	('Bax', 'Gene', (186, 189))	('Bcl-2', 'molecular_function', 'GO:0015283', ('117', '122'))	('activity', 'MPA', (42, 50))	('caspase 3', 'Gene', (54, 63))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('BAY11-7082', 'Chemical', 'MESH:C434003', (17, 27))	('caspase 3', 'Gene', '836', (54, 63))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('reduced', 'NegReg', (68, 75))	('expression', 'MPA', (80, 90))	('Bax', 'Gene', '581', (186, 189))	('BAY11-7082', 'Var', (17, 27))	('Bcl-2', 'Gene', (117, 122))
135835	23443086	Furthermore, BAY11-7082 induced uveal melanoma cell apoptosis and inhibited xenograft tumor growth in vivo.	('uveal melanoma cell apoptosis', 'Disease', 'MESH:C536494', (32, 61))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('induced', 'PosReg', (24, 31))	('BAY11-7082', 'Chemical', 'MESH:C434003', (13, 23))	('tumor', 'Disease', (86, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (32, 46))	('uveal melanoma cell apoptosis', 'Disease', (32, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('52', '61'))	('inhibited', 'NegReg', (66, 75))	('BAY11-7082', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('apoptosis', 'biological_process', 'GO:0006915', ('52', '61'))
135836	23443086	Collectively, the present study identified NF-kappaB as an important survival signal for uveal melanoma cells and suggested that administration of specific NF-kappaB inhibitor BAY11-7082 could serve as an effective treatment for patients with uveal melanoma.	('BAY11-7082', 'Var', (176, 186))	('patients', 'Species', '9606', (229, 237))	('uveal melanoma', 'Disease', 'MESH:C536494', (243, 257))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (249, 257))	('BAY11-7082', 'Chemical', 'MESH:C434003', (176, 186))	('uveal melanoma', 'Phenotype', 'HP:0007716', (243, 257))	('uveal melanoma', 'Disease', 'MESH:C536494', (89, 103))	('uveal melanoma', 'Disease', (89, 103))	('uveal melanoma', 'Disease', (243, 257))	('uveal melanoma', 'Phenotype', 'HP:0007716', (89, 103))	('NF-kappaB inhibitor', 'biological_process', 'GO:0032088', ('156', '175'))
135849	23443086	A growing body of evidence has suggested that aberrant NF-kappaB activation correlates with many characteristics and hallmarks of cancer development.	('NF-kappaB', 'Protein', (55, 64))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (117, 136))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('55', '75'))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('aberrant', 'Var', (46, 54))	('hallmarks of cancer', 'Disease', (117, 136))	('activation', 'PosReg', (65, 75))
135850	23443086	Hyperactivation of NF-kappaB not only contributes to inappropriate local tumor cell survival, growth and proliferation, but also promotes distant metastasis.	('distant metastasis', 'CPA', (138, 156))	('promotes', 'PosReg', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('growth', 'CPA', (94, 100))	('NF-kappaB', 'Protein', (19, 28))	('Hyperactivation', 'Var', (0, 15))	('proliferation', 'CPA', (105, 118))	('inappropriate local tumor', 'Disease', (53, 78))	('inappropriate local tumor', 'Disease', 'MESH:D009364', (53, 78))
135851	23443086	Given the central role of aberrant NF-kappaB activation in controlling cancer development and progression, the functional significance of the NF-kappaB signaling pathway has been intensively investigated and its therapeutic values as a target for cancer therapy have been studied in many types of human cancers.	('cancers', 'Disease', 'MESH:D009369', (303, 310))	('signaling pathway', 'biological_process', 'GO:0007165', ('152', '169'))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('aberrant', 'Var', (26, 34))	('NF-kappaB', 'Protein', (35, 44))	('cancer', 'Disease', (303, 309))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Disease', (71, 77))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('35', '55'))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('human', 'Species', '9606', (297, 302))	('cancers', 'Phenotype', 'HP:0002664', (303, 310))	('activation', 'PosReg', (45, 55))	('cancers', 'Disease', (303, 310))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
135862	23443086	However, with the treatment of NF-kappaB specific inhibitor BAY11-7082 for 2 h, translocation of p65 in the nucleus decreased significantly as shown by the reduced staining in the nucleus, and relocated in the cytoplasm (Figure 1B).	('nucleus', 'cellular_component', 'GO:0005634', ('180', '187'))	('nucleus', 'cellular_component', 'GO:0005634', ('108', '115'))	('p65', 'Gene', '5970', (97, 100))	('BAY11-7082', 'Chemical', 'MESH:C434003', (60, 70))	('BAY11-7082', 'Var', (60, 70))	('reduced', 'NegReg', (156, 163))	('translocation', 'MPA', (80, 93))	('staining', 'MPA', (164, 172))	('p65', 'Gene', (97, 100))	('cytoplasm', 'cellular_component', 'GO:0005737', ('210', '219'))	('decreased', 'NegReg', (116, 125))
135865	23443086	As shown in Figure 2A, BAY11-7082 exhibited strong anti-proliferative effects in all four uveal melanoma cell lines in a dose-dependent manner, with approximately 50% inhibition of cell proliferation at the concentration of 5 muM.	('muM', 'Gene', '56925', (226, 229))	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('uveal melanoma', 'Disease', (90, 104))	('cell proliferation', 'CPA', (181, 199))	('uveal melanoma', 'Disease', 'MESH:C536494', (90, 104))	('BAY11-7082', 'Chemical', 'MESH:C434003', (23, 33))	('inhibition', 'NegReg', (167, 177))	('muM', 'Gene', (226, 229))	('BAY11-7082', 'Var', (23, 33))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('167', '199'))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('anti-proliferative effects', 'CPA', (51, 77))
135866	23443086	Furthermore, BAY11-7082 treatment also significantly inhibited the colony formation capacity of the uveal melanoma cells at the concentration of 2.5 muM (Figure 2B).	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('inhibited', 'NegReg', (53, 62))	('BAY11-7082', 'Chemical', 'MESH:C434003', (13, 23))	('uveal melanoma', 'Disease', (100, 114))	('muM', 'Gene', '56925', (149, 152))	('muM', 'Gene', (149, 152))	('BAY11-7082', 'Var', (13, 23))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('formation', 'biological_process', 'GO:0009058', ('74', '83'))
135867	23443086	The number of colonies was reduced in a dose-dependent manner and fewer colonies were formed following treatment with 5 muM BAY11-7082 (Figure 2B,C).	('muM', 'Gene', '56925', (120, 123))	('reduced', 'NegReg', (27, 34))	('BAY11-7082', 'Var', (124, 134))	('fewer', 'NegReg', (66, 71))	('muM', 'Gene', (120, 123))	('BAY11-7082', 'Chemical', 'MESH:C434003', (124, 134))
135870	23443086	A significant increase in Annexin V positive cells was determined by flow cytometry when cells were treated with BAY11-7082 (Figure 3A,B).	('Annexin V', 'Gene', (26, 35))	('BAY11-7082', 'Chemical', 'MESH:C434003', (113, 123))	('increase', 'PosReg', (14, 22))	('BAY11-7082', 'Var', (113, 123))	('Annexin V', 'Gene', '308', (26, 35))
135874	23443086	Thus, Bcl-2 was decreased by BAY11-7082 treatment and could help to explain why NF-kappaB blockade induced apoptosis in uveal melanoma cells.	('BAY11-7082', 'Chemical', 'MESH:C434003', (29, 39))	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('6', '11'))	('NF-kappaB', 'Protein', (80, 89))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('BAY11-7082', 'Var', (29, 39))	('apoptosis', 'CPA', (107, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (120, 134))	('uveal melanoma', 'Phenotype', 'HP:0007716', (120, 134))	('uveal melanoma', 'Disease', (120, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('Bcl-2', 'Gene', (6, 11))	('Bcl-2', 'Gene', '596', (6, 11))	('decreased', 'NegReg', (16, 25))
135877	23443086	Thus, these data together suggested that BAY11-7082 inhibited the proliferation of uveal melanoma cells by inducing cell apoptosis, but not cell cycle arrest.	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('uveal melanoma', 'Disease', (83, 97))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (140, 157))	('cell apoptosis', 'CPA', (116, 130))	('inducing', 'NegReg', (107, 115))	('BAY11-7082', 'Chemical', 'MESH:C434003', (41, 51))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('140', '157'))	('inhibited', 'NegReg', (52, 61))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('apoptosis', 'biological_process', 'GO:0097194', ('121', '130'))	('uveal melanoma', 'Disease', 'MESH:C536494', (83, 97))	('BAY11-7082', 'Var', (41, 51))	('apoptosis', 'biological_process', 'GO:0006915', ('121', '130'))
135883	23443086	Treatment of BAY11-7082 at 5 muM significantly suppressed the migration of all four uveal melanoma cell lines to either high concentration FBS or HGF (Figure 4), suggesting that NF-kappaB pathway was also involved in the regulation of migration and may functionally contribute to liver metastasis of uveal melanoma patients.	('muM', 'Gene', (29, 32))	('liver metastasis of uveal melanoma', 'Disease', (280, 314))	('uveal melanoma', 'Phenotype', 'HP:0007716', (300, 314))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('FBS', 'Disease', (139, 142))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('HGF', 'Gene', (146, 149))	('FBS', 'Disease', 'MESH:D005198', (139, 142))	('migration', 'CPA', (62, 71))	('suppressed', 'NegReg', (47, 57))	('regulation', 'biological_process', 'GO:0065007', ('221', '231'))	('contribute', 'Reg', (266, 276))	('patients', 'Species', '9606', (315, 323))	('BAY11-7082', 'Var', (13, 23))	('involved', 'Reg', (205, 213))	('BAY11-7082', 'Chemical', 'MESH:C434003', (13, 23))	('uveal melanoma', 'Disease', 'MESH:C536494', (300, 314))	('melanoma', 'Phenotype', 'HP:0002861', (306, 314))	('uveal melanoma', 'Disease', (84, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('liver metastasis of uveal melanoma', 'Disease', 'MESH:C536494', (280, 314))	('muM', 'Gene', '56925', (29, 32))	('HGF', 'Gene', '3082', (146, 149))
135884	23443086	To study the therapeutic potential of the NF-kappaB inhibitor BAY11-7082 in the treatment of uveal melanoma in vivo, a xenograft nude mouse model with subcutaneous inoculation of OCM1 cells was established.	('BAY11-7082', 'Var', (62, 72))	('uveal melanoma', 'Phenotype', 'HP:0007716', (93, 107))	('uveal melanoma', 'Disease', 'MESH:C536494', (93, 107))	('uveal melanoma', 'Disease', (93, 107))	('OCM1', 'Species', '83984', (179, 183))	('NF-kappaB inhibitor', 'biological_process', 'GO:0032088', ('42', '61'))	('BAY11-7082', 'Chemical', 'MESH:C434003', (62, 72))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('mouse', 'Species', '10090', (134, 139))
135885	23443086	After solid tumors were established and palpable, mice were randomly grouped and 1 muM BAY11-7082 was syringed subcutaneously peri-tumor every day for 14 days.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('BAY11-7082', 'Var', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('muM', 'Gene', '56925', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('muM', 'Gene', (83, 86))	('tumors', 'Disease', (12, 18))	('BAY11-7082', 'Chemical', 'MESH:C434003', (87, 97))	('tumor', 'Disease', (12, 17))	('mice', 'Species', '10090', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
135887	23443086	BAY11-7082 treatment significantly suppressed OCM1 tumor growth and tumor volume in vivo (Figure 5A,B).	('tumor', 'Disease', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('BAY11-7082', 'Chemical', 'MESH:C434003', (0, 10))	('OCM1', 'Gene', (46, 50))	('suppressed', 'NegReg', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('OCM1', 'Species', '83984', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('BAY11-7082', 'Var', (0, 10))
135888	23443086	Reduced tumor weight was also observed in the BAY11-7082 treated group compared with that of control mice (Figure 5C).	('BAY11-7082', 'Chemical', 'MESH:C434003', (46, 56))	('BAY11-7082', 'Var', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('Reduced', 'NegReg', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mice', 'Species', '10090', (101, 105))	('tumor', 'Disease', (8, 13))
135890	23443086	Remarkably, there were more apoptotic tumor cells in BAY11-7082-treated mice group, as indicated by the increased brown nuclear staining (Figure 5D,E).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('increased', 'PosReg', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('brown nuclear staining', 'MPA', (114, 136))	('mice', 'Species', '10090', (72, 76))	('BAY11-7082-treated', 'Var', (53, 71))	('BAY11-7082', 'Chemical', 'MESH:C434003', (53, 63))
135891	23443086	Therefore, blockade of NF-kappaB signaling pathway not only suppressed uveal melanoma tumor cell growth and survival in vitro, but also induced apoptosis and inhibited tumor growth in vivo.	('cell growth', 'biological_process', 'GO:0016049', ('92', '103'))	('induced', 'Reg', (136, 143))	('uveal melanoma tumor', 'Disease', 'MESH:C536494', (71, 91))	('apoptosis', 'biological_process', 'GO:0097194', ('144', '153'))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('apoptosis', 'biological_process', 'GO:0006915', ('144', '153'))	('NF-kappaB signaling pathway', 'Pathway', (23, 50))	('survival', 'CPA', (108, 116))	('blockade', 'Var', (11, 19))	('tumor', 'Disease', (168, 173))	('uveal melanoma tumor', 'Disease', (71, 91))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('suppressed', 'NegReg', (60, 70))	('tumor', 'Disease', (86, 91))	('signaling pathway', 'biological_process', 'GO:0007165', ('33', '50'))	('apoptosis', 'CPA', (144, 153))	('inhibited', 'NegReg', (158, 167))	('uveal melanoma', 'Phenotype', 'HP:0007716', (71, 85))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
135896	23443086	We further provided for the first time that NF-kappaB specific inhibitor BAY11-7082, an irreversible inhibitor for IkappaBalpha phosphorylation and subsequent proteasome degradation, could block the translocation of NF-kappaB p65 subunit into the nucleus of uveal melanoma cells and markedly inhibit tumor growth by directly inducing uveal melanoma cells apoptosis both in vitro and in vivo.	('uveal melanoma', 'Disease', (258, 272))	('block', 'NegReg', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('BAY11-7082', 'Var', (73, 83))	('inducing', 'Reg', (325, 333))	('inhibit', 'NegReg', (292, 299))	('BAY11-7082', 'Chemical', 'MESH:C434003', (73, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (258, 272))	('NF-kappaB p65', 'Gene', (216, 229))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('NF-kappaB p65', 'Gene', '5970', (216, 229))	('melanoma', 'Phenotype', 'HP:0002861', (340, 348))	('uveal melanoma', 'Disease', 'MESH:C536494', (334, 348))	('proteasome degradation', 'biological_process', 'GO:1903009', ('159', '181'))	('uveal melanoma', 'Disease', (334, 348))	('translocation', 'MPA', (199, 212))	('IkappaBalpha', 'Gene', (115, 127))	('proteasome', 'molecular_function', 'GO:0004299', ('159', '169'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (334, 348))	('IkappaBalpha', 'Gene', '4792', (115, 127))	('phosphorylation', 'biological_process', 'GO:0016310', ('128', '143'))	('nucleus', 'cellular_component', 'GO:0005634', ('247', '254'))	('tumor', 'Disease', (300, 305))	('apoptosis', 'biological_process', 'GO:0097194', ('355', '364'))	('apoptosis', 'biological_process', 'GO:0006915', ('355', '364'))	('uveal melanoma', 'Disease', 'MESH:C536494', (258, 272))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))	('proteasome', 'cellular_component', 'GO:0000502', ('159', '169'))
135897	23443086	BAY11-7082 also inhibited the migration of uveal melanoma cells towards high concentrations of FBS and the uveal melanoma cell specific chemoattractant HGF.	('HGF', 'Gene', '3082', (152, 155))	('FBS', 'Disease', 'MESH:D005198', (95, 98))	('inhibited', 'NegReg', (16, 25))	('uveal melanoma', 'Disease', 'MESH:C536494', (107, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('uveal melanoma', 'Disease', (107, 121))	('uveal melanoma', 'Disease', 'MESH:C536494', (43, 57))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('BAY11-7082', 'Chemical', 'MESH:C434003', (0, 10))	('FBS', 'Disease', (95, 98))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('uveal melanoma', 'Disease', (43, 57))	('migration', 'CPA', (30, 39))	('HGF', 'Gene', (152, 155))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('BAY11-7082', 'Var', (0, 10))
135898	23443086	In a xenograft nude mouse model, we proved that BAY11-7082 effectively inhibited tumor growth by inducing apoptosis of uveal melanoma cells in vivo.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('inhibited', 'NegReg', (71, 80))	('inducing', 'NegReg', (97, 105))	('apoptosis', 'CPA', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('BAY11-7082', 'Chemical', 'MESH:C434003', (48, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (119, 133))	('uveal melanoma', 'Disease', 'MESH:C536494', (119, 133))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('BAY11-7082', 'Var', (48, 58))	('uveal melanoma', 'Disease', (119, 133))	('tumor', 'Disease', (81, 86))	('mouse', 'Species', '10090', (20, 25))
135907	23443086	Nonetheless, the inhibition of anti-apoptotic Bcl-2 by BAY11-7082 may contribute to its effects to induce apoptosis of uveal melanoma cells.	('induce', 'PosReg', (99, 105))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('BAY11-7082', 'Var', (55, 65))	('Bcl-2', 'Gene', (46, 51))	('apoptosis', 'CPA', (106, 115))	('Bcl-2', 'Gene', '596', (46, 51))	('Bcl-2', 'molecular_function', 'GO:0015283', ('46', '51'))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (119, 133))	('uveal melanoma', 'Disease', 'MESH:C536494', (119, 133))	('BAY11-7082', 'Chemical', 'MESH:C434003', (55, 65))	('inhibition', 'NegReg', (17, 27))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('uveal melanoma', 'Disease', (119, 133))
135921	23443086	The Notch signaling pathway was also reported to be active in some but not all uveal melanoma cells, and blockage of Notch signaling reduced uveal melanoma growth and invasion.	('uveal melanoma', 'Disease', 'MESH:C536494', (141, 155))	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('Notch signaling', 'Gene', (117, 132))	('uveal melanoma', 'Phenotype', 'HP:0007716', (141, 155))	('uveal melanoma growth', 'Disease', (141, 162))	('blockage', 'Var', (105, 113))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('4', '27'))	('invasion', 'CPA', (167, 175))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('uveal melanoma growth', 'Disease', 'MESH:C536494', (141, 162))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('reduced', 'NegReg', (133, 140))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('uveal melanoma', 'Disease', (79, 93))
135951	23443086	After 24 h, cultures were replaced with fresh medium containing 0.5% FBS (control) or the same medium containing 2.5 muM or 5 muM BAY11-7082 in a 37  C humidified atmosphere containing 95% air and 5% CO2 and grown for three weeks.	('muM', 'Gene', '56925', (126, 129))	('FBS', 'Disease', (69, 72))	('CO2', 'Chemical', '-', (200, 203))	('BAY11-7082', 'Chemical', 'MESH:C434003', (130, 140))	('muM', 'Gene', (126, 129))	('muM', 'Gene', '56925', (117, 120))	('BAY11-7082', 'Var', (130, 140))	('FBS', 'Disease', 'MESH:D005198', (69, 72))	('muM', 'Gene', (117, 120))
135954	23443086	The upper chamber contained cells in DMEM plus 1% FBS with or without 5 muM BAY11-7082, and the lower chamber contained DMEM plus 20% FBS or recombinant human hepatocyte growth factor (HGF) (20 ng/mL; R & D Systems, Minneapolis, MN, USA) in DMEM containing 1% FBS.	('FBS', 'Disease', (50, 53))	('HGF', 'Gene', '3082', (185, 188))	('human', 'Species', '9606', (153, 158))	('FBS', 'Disease', 'MESH:D005198', (50, 53))	('HGF', 'Gene', (185, 188))	('DMEM', 'Chemical', '-', (241, 245))	('MN', 'CellLine', 'CVCL:U508', (229, 231))	('hepatocyte growth factor', 'Gene', '3082', (159, 183))	('DMEM', 'Chemical', '-', (120, 124))	('BAY11-7082', 'Var', (76, 86))	('hepatocyte growth factor', 'Gene', (159, 183))	('muM', 'Gene', '56925', (72, 75))	('BAY11-7082', 'Chemical', 'MESH:C434003', (76, 86))	('FBS', 'Disease', (260, 263))	('muM', 'Gene', (72, 75))	('FBS', 'Disease', (134, 137))	('FBS', 'Disease', 'MESH:D005198', (260, 263))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('159', '183'))	('FBS', 'Disease', 'MESH:D005198', (134, 137))	('DMEM', 'Chemical', '-', (37, 41))
135988	20706624	In cancer medicine, tumor-specific molecular derangements (e.g., gene mutation or protein overactivation), are the ideal targets for therapeutic strategies aimed to kill malignant cells while sparing normal cells.	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('men', 'Species', '9606', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('gene mutation', 'Var', (65, 78))	('cancer', 'Disease', (3, 9))	('overactivation', 'PosReg', (90, 104))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))	('protein', 'Protein', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
135989	20706624	Furthermore, patient-specific molecular features such as polymorphisms of detoxifying enzymes can affect the metabolism of anticancer drugs and thus can play a role in both efficacy and toxicity profiles.	('polymorphisms', 'Var', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('play', 'Reg', (153, 157))	('role', 'Reg', (160, 164))	('patient', 'Species', '9606', (13, 20))	('detoxifying enzymes', 'Enzyme', (74, 93))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('metabolism', 'MPA', (109, 119))	('toxicity', 'Disease', 'MESH:D064420', (186, 194))	('toxicity', 'Disease', (186, 194))	('cancer', 'Disease', (127, 133))	('metabolism', 'biological_process', 'GO:0008152', ('109', '119'))	('affect', 'Reg', (98, 104))
136030	20706624	For instance, the expression "mut V600E" for the protein BRAF refers to its V600E mutation (as opposed to the wild type protein or any other mutational status).	('V600E', 'Mutation', 'rs113488022', (76, 81))	('BRAF', 'Gene', '673', (57, 61))	('V600E', 'Var', (76, 81))	('BRAF', 'Gene', (57, 61))	('V600E', 'Mutation', 'rs113488022', (34, 39))
136032	20706624	small interfering RNA) can downregulate the expression of a gene of interest which may ultimately impact on the melanoma sensitivity to a given treatment.	('expression', 'MPA', (44, 54))	('sensitivity to a given treatment', 'MPA', (121, 153))	('men', 'Species', '9606', (149, 152))	('small interfering', 'Var', (0, 17))	('RNA', 'cellular_component', 'GO:0005562', ('18', '21'))	('downregulate', 'NegReg', (27, 39))	('impact', 'Reg', (98, 104))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))
136035	20706624	Three main types of relationships are considered: A) Efficacy: the molecule under investigation can be associated with either sensitivity or resistance to a therapeutic agent; B) Synergism: the modulation of a molecule activity by a modifier (see "Modifier" column) can be associated with an increased (synergism) or decreased (antagonism) therapeutic activity of a given drug/treatment; C) Toxicity: the molecule under investigation can be associated with either increased or decreased toxicity of a given drug/treatment.	('activity', 'MPA', (219, 227))	('toxicity', 'Disease', (487, 495))	('decreased', 'NegReg', (317, 326))	('therapeutic activity', 'MPA', (340, 360))	('men', 'Species', '9606', (382, 385))	('modulation', 'Var', (194, 204))	('toxicity', 'Disease', 'MESH:D064420', (487, 495))	('men', 'Species', '9606', (517, 520))
136054	20706624	When more than one record (i.e., one row of the database) exists for a given hypothesis (e.g., BRAF mutation V600E modulates the efficacy of small molecule inhibitor sorafenib), we propose a score-based approach to make a summary of the available evidence.	('mutation V600E', 'Var', (100, 114))	('efficacy', 'MPA', (129, 137))	('sorafenib', 'Chemical', 'MESH:D000077157', (166, 175))	('BRAF', 'Gene', '673', (95, 99))	('V600E', 'Mutation', 'rs113488022', (109, 114))	('BRAF', 'Gene', (95, 99))	('modulates', 'Reg', (115, 124))	('V600E', 'Var', (109, 114))
136056	20706624	mutation V600E) is associated with increased efficacy of a drug, synergism between drugs or decreased toxicity of a drug.	('toxicity', 'Disease', 'MESH:D064420', (102, 110))	('V600E', 'Mutation', 'rs113488022', (9, 14))	('toxicity', 'Disease', (102, 110))	('increased', 'PosReg', (35, 44))	('V600E', 'Var', (9, 14))	('efficacy', 'MPA', (45, 53))	('decreased', 'NegReg', (92, 101))	('synergism', 'Interaction', (65, 74))
136075	20706624	BRAF mutation V600E increases the efficacy of drug Sorafenib), whereas molecules associated with resistance to treatment are assigned a "-" sign (e.g.	('Sorafenib', 'Chemical', 'MESH:D000077157', (51, 60))	('V600E', 'Var', (14, 19))	('BRAF', 'Gene', '673', (0, 4))	('efficacy', 'MPA', (34, 42))	('BRAF', 'Gene', (0, 4))	('V600E', 'Mutation', 'rs113488022', (14, 19))	('men', 'Species', '9606', (116, 119))	('increases', 'PosReg', (20, 29))
136076	20706624	BRAF mutation V600E decreases the efficacy of drug Sorafenib).	('Sorafenib', 'Chemical', 'MESH:D000077157', (51, 60))	('decreases', 'NegReg', (20, 29))	('V600E', 'Var', (14, 19))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('V600E', 'Mutation', 'rs113488022', (14, 19))	('efficacy of', 'MPA', (34, 45))
136079	20706624	BRAF mutation V600E); in contrast, if the patient carries the "opposite" molecular state (e.g.	('patient', 'Species', '9606', (42, 49))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('V600E', 'Mutation', 'rs113488022', (14, 19))	('V600E)', 'Var', (14, 20))
136174	33964953	The BRAF/RAS/RAF/MEK/ERK signalling pathway is frequently altered in CM, with 40-50% of CM presenting BRAF mutations, 20-30% NRAS mutations, 10-15% NF1 mutations and 1-3% KIT mutations.	('ERK', 'molecular_function', 'GO:0004707', ('21', '24'))	('mutations', 'Var', (152, 161))	('signalling pathway', 'biological_process', 'GO:0007165', ('25', '43'))	('CM', 'Chemical', 'MESH:D003476', (69, 71))	('KIT', 'Gene', (171, 174))	('RAF', 'Gene', '22882', (103, 106))	('BRAF', 'Gene', '673', (102, 106))	('NF1', 'Gene', '4763', (148, 151))	('NRAS', 'Gene', '4893', (125, 129))	('BRAF', 'Gene', (102, 106))	('KIT', 'molecular_function', 'GO:0005020', ('171', '174'))	('RAF', 'Gene', '22882', (13, 16))	('NF1', 'Gene', (148, 151))	('RAF', 'Gene', (103, 106))	('MEK', 'Gene', '5609', (17, 20))	('KIT', 'Gene', '3815', (171, 174))	('RAF', 'Gene', '22882', (5, 8))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('CM', 'Chemical', 'MESH:D003476', (88, 90))	('ERK', 'Gene', '5594', (21, 24))	('RAF', 'Gene', (13, 16))	('altered', 'Reg', (58, 65))	('NRAS', 'Gene', (125, 129))	('MEK', 'Gene', (17, 20))	('mutations', 'Var', (107, 116))	('mutations', 'Var', (130, 139))	('RAF', 'Gene', (5, 8))	('ERK', 'Gene', (21, 24))
136175	33964953	Approximately 80-90% of BRAF mutations are V600E (valine to glutamic acid), while 5-12% are V600K (valine to lysine) and <= 5% are V600D (valine to aspartic acid) or V600R (valine to arginine).	('valine', 'Chemical', 'MESH:D014633', (138, 144))	('valine', 'Chemical', 'MESH:D014633', (173, 179))	('V600E', 'Mutation', 'rs113488022', (43, 48))	('V600R', 'Var', (166, 171))	('mutations', 'Var', (29, 38))	('glutamic acid', 'Chemical', 'MESH:D018698', (60, 73))	('valine', 'Chemical', 'MESH:D014633', (50, 56))	('V600K', 'Var', (92, 97))	('V600D', 'Mutation', 'rs121913377', (131, 136))	('valine', 'Chemical', 'MESH:D014633', (99, 105))	('aspartic acid', 'Chemical', 'MESH:D001224', (148, 161))	('lysine', 'Chemical', 'MESH:D008239', (109, 115))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('arginine', 'Chemical', 'MESH:D001120', (183, 191))	('V600K', 'Mutation', 'rs121913227', (92, 97))	('V600E', 'Var', (43, 48))	('V600R', 'Mutation', 'rs121913227', (166, 171))
136194	33964953	BRAFV600E mutation was found to directly regulate HIF-1alpha expression in CM.	('HIF-1alpha', 'Protein', (50, 60))	('regulate', 'Reg', (41, 49))	('CM', 'Chemical', 'MESH:D003476', (75, 77))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('BRAFV600E mutation', 'Var', (0, 18))	('expression', 'MPA', (61, 71))
136195	33964953	Increased HIF-1alpha promoted by BRAFV600E could contribute to intensify and foster melanoma genesis in association to PI3K-Akt pathway, which is known to play a relevant role in early melanoma.	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('foster', 'PosReg', (77, 83))	('Akt', 'Gene', (124, 127))	('HIF-1alpha', 'Protein', (10, 20))	('melanoma genesis', 'Disease', 'MESH:D008545', (84, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('119', '123'))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('BRAFV600E', 'Var', (33, 42))	('melanoma genesis', 'Disease', (84, 100))	('BRAFV600E', 'Mutation', 'rs113488022', (33, 42))	('intensify', 'PosReg', (63, 72))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('Akt', 'Gene', '207', (124, 127))	('melanoma', 'Disease', (185, 193))
136196	33964953	In line with these evidences, decreased HIF-1alpha expression was observed after pharmacologic inhibition of BRAF by using sorafenib, a dual inhibitor targeting RAF/MEK/ERK pathway in CM cells, and tyrosine kinase VEGFR and platelet-derived growth factor receptor (PDGFR) in tumor vessels.	('RAF', 'Gene', '22882', (161, 164))	('PDGFR', 'Gene', (265, 270))	('ERK', 'Gene', '5594', (169, 172))	('PDGFR', 'Gene', '5159', (265, 270))	('tumor', 'Disease', (275, 280))	('VEGFR', 'Gene', (214, 219))	('MEK', 'Gene', '5609', (165, 168))	('platelet-derived growth factor receptor', 'Gene', '5159', (224, 263))	('expression', 'MPA', (51, 61))	('platelet-derived growth factor receptor', 'Gene', (224, 263))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('RAF', 'Gene', (161, 164))	('ERK', 'Gene', (169, 172))	('BRAF', 'Gene', (109, 113))	('CM', 'Chemical', 'MESH:D003476', (184, 186))	('BRAF', 'Gene', '673', (109, 113))	('ERK', 'molecular_function', 'GO:0004707', ('169', '172'))	('MEK', 'Gene', (165, 168))	('RAF', 'Gene', '22882', (110, 113))	('sorafenib', 'Chemical', 'MESH:D000077157', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('inhibition', 'Var', (95, 105))	('RAF', 'Gene', (110, 113))	('decreased', 'NegReg', (30, 39))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('224', '254'))	('HIF-1alpha', 'Gene', (40, 50))	('VEGFR', 'Gene', '3791', (214, 219))
136208	33964953	VEGF-A, commonly referred to as VEGF, can be processed by alternative gene splicing into at least five isoforms, including isoforms of 121, 143, 165, 189 and 206 amino acid length.	('splicing', 'biological_process', 'GO:0045292', ('75', '83'))	('VEGF-A', 'Gene', '7422', (0, 6))	('VEGF-A', 'Gene', (0, 6))	('121', 'Var', (135, 138))
136224	33964953	Silencing of HIF-1alpha and HIF-2alpha was found to completely inhibit melanoma capillary-like structure formation, indicating that vasculogenic mimicry in melanoma cells is controlled by HIF-dependent transcriptional mechanism.	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma capillary', 'Disease', 'MESH:D008545', (71, 89))	('melanoma', 'Disease', (156, 164))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('formation', 'biological_process', 'GO:0009058', ('105', '114'))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('Silencing', 'Var', (0, 9))	('inhibit', 'NegReg', (63, 70))	('melanoma capillary', 'Disease', (71, 89))	('HIF-1alpha', 'Gene', (13, 23))	('HIF-2alpha', 'Gene', (28, 38))
136225	33964953	Hypoxia-related HIF-1alpha stabilization has been also reported to enhance expression/activation of the Met proto-oncogene in melanoma cells, which in turn promotes formation of capillary-like structures by vasculogenic mimicry.	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('Hypoxia', 'Disease', (0, 7))	('Met', 'Gene', '79811', (104, 107))	('expression/activation', 'MPA', (75, 96))	('Met', 'Gene', (104, 107))	('HIF-1alpha', 'Protein', (16, 26))	('formation', 'biological_process', 'GO:0009058', ('165', '174'))	('enhance', 'PosReg', (67, 74))	('stabilization', 'Var', (27, 40))	('formation of', 'CPA', (165, 177))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))	('promotes', 'PosReg', (156, 164))
136234	33964953	A recent paper reported high uPAR expression and vascular proliferation index as novel markers of reduced cancer specific survival in primary melanoma, and confirmed an association between uPAR and angiogenesis.	('expression', 'MPA', (34, 44))	('cancer', 'Disease', (106, 112))	('high', 'Var', (24, 28))	('uPAR', 'molecular_function', 'GO:0030377', ('189', '193'))	('reduced', 'NegReg', (98, 105))	('angiogenesis', 'biological_process', 'GO:0001525', ('198', '210'))	('uPAR', 'molecular_function', 'GO:0030377', ('29', '33'))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma', 'Disease', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('uPAR', 'Gene', (189, 193))	('uPAR', 'Gene', (29, 33))	('angiogenesis', 'CPA', (198, 210))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('uPAR', 'Gene', '5329', (189, 193))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('uPAR', 'Gene', '5329', (29, 33))	('vascular proliferation index', 'CPA', (49, 77))	('rat', 'Species', '10116', (65, 68))
136245	33964953	Intriguingly, selective stabilization of HIF-2alpha was found to reduce tumor growth and angiogenesis by promoting secretion of a soluble form of the VEGF receptor (sVEGFR-1) from tumor-associated macrophages, which can inhibit VEGF biological activity, as evaluated in a murine melanoma model.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('secretion', 'biological_process', 'GO:0046903', ('115', '124'))	('VEGFR-1', 'Gene', '2321', (166, 173))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('angiogenesis', 'biological_process', 'GO:0001525', ('89', '101'))	('angiogenesis', 'CPA', (89, 101))	('melanoma', 'Disease', 'MESH:D008545', (279, 287))	('tumor', 'Disease', (72, 77))	('stabilization', 'Var', (24, 37))	('promoting', 'PosReg', (105, 114))	('murine', 'Species', '10090', (272, 278))	('secretion', 'MPA', (115, 124))	('VEGFR-1', 'Gene', (166, 173))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('HIF-2alpha', 'Gene', (41, 51))	('tumor', 'Disease', (180, 185))	('reduce', 'NegReg', (65, 71))	('melanoma', 'Phenotype', 'HP:0002861', (279, 287))	('melanoma', 'Disease', (279, 287))	('soluble', 'cellular_component', 'GO:0005625', ('130', '137'))
136251	33964953	On the other hand, miR-199a-5p, miR-18b, miR-138 and miR-33a/b have been reported to inhibit proliferation, tumor growth, and invasion in melanoma by targeting HIF-1alpha.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('miR-33a/b', 'Gene', '407039', (53, 62))	('miR-18b', 'Gene', '574033', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('targeting', 'Reg', (150, 159))	('miR-33a/b', 'Gene', (53, 62))	('proliferation', 'CPA', (93, 106))	('inhibit', 'NegReg', (85, 92))	('tumor', 'Disease', (108, 113))	('HIF-1alpha', 'Protein', (160, 170))	('invasion', 'CPA', (126, 134))	('miR-138', 'Var', (41, 48))	('miR-18b', 'Gene', (32, 39))	('rat', 'Species', '10116', (100, 103))	('miR-199a-5p', 'Var', (19, 30))
136255	33964953	The HIF-1alpha target gene GLUT1, was found to be elevated in metastatic and BRAFV600E mutated melanoma cell lines under hypoxic conditions.	('metastatic', 'CPA', (62, 72))	('mutated', 'Var', (87, 94))	('elevated', 'PosReg', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('GLUT1', 'Gene', (27, 32))	('GLUT1', 'Gene', '6513', (27, 32))	('BRAFV600E', 'Var', (77, 86))	('BRAFV600E', 'Mutation', 'rs113488022', (77, 86))
136271	33964953	Inhibition of HIF-1alpha has been reported to reduce metastasization of cancers from different origin, such as lung and breast carcinoma.	('HIF-1alpha', 'Protein', (14, 24))	('metastasization of cancers', 'Disease', (53, 79))	('breast carcinoma', 'Disease', (120, 136))	('reduce', 'NegReg', (46, 52))	('metastasization of cancers', 'Disease', 'MESH:D009362', (53, 79))	('breast carcinoma', 'Disease', 'MESH:D001943', (120, 136))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung', 'Disease', (111, 115))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('Inhibition', 'Var', (0, 10))	('breast carcinoma', 'Phenotype', 'HP:0003002', (120, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
136281	33964953	Inhibition of angiogenesis, tumor infiltration by myeloid cells, myeloid progenitors mobilization, tumor cell chemotaxis, ECM, bone marrow invasion and endothelial cell migration have been also observed after exposure to D16F7.	('tumor', 'Disease', (28, 33))	('Inhibition', 'NegReg', (0, 10))	('rat', 'Species', '10116', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('CM', 'Chemical', 'MESH:D003476', (123, 125))	('endothelial cell migration', 'CPA', (152, 178))	('tumor', 'Disease', (99, 104))	('bone marrow invasion', 'Disease', (127, 147))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('rat', 'Species', '10116', (172, 175))	('bone marrow invasion', 'Disease', 'MESH:D001855', (127, 147))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('cell chemotaxis', 'biological_process', 'GO:0060326', ('105', '120'))	('Inhibition of angiogenesis', 'biological_process', 'GO:0016525', ('0', '26'))	('endothelial cell migration', 'biological_process', 'GO:0043542', ('152', '178'))	('angiogenesis', 'CPA', (14, 26))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('D16F7', 'Var', (221, 226))	('myeloid progenitors mobilization', 'CPA', (65, 97))	('ECM', 'CPA', (122, 125))	('D16F7', 'Chemical', 'MESH:C000627505', (221, 226))
136282	33964953	In vivo treatment of CM murine syngeneic model with D16F7 also inhibited tumor growth and increased the activity of immune checkpoint inhibitors.	('CM', 'Chemical', 'MESH:D003476', (21, 23))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('activity', 'MPA', (104, 112))	('increased', 'PosReg', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('murine', 'Species', '10090', (24, 30))	('tumor', 'Disease', (73, 78))	('immune', 'Protein', (116, 122))	('D16F7', 'Var', (52, 57))	('inhibited', 'NegReg', (63, 72))	('D16F7', 'Chemical', 'MESH:C000627505', (52, 57))	('men', 'Species', '9606', (13, 16))
136294	33964953	Also VEGFR-1 blocking has been found to induce vasculogenic mimicry inhibition.	('vasculogenic mimicry inhibition', 'MPA', (47, 78))	('VEGFR-1', 'Gene', (5, 12))	('blocking', 'Var', (13, 21))	('VEGFR-1', 'Gene', '2321', (5, 12))
136300	33964953	Also lycorine hydrochloride has been reported to reduce vasculogenic mimicry by decreasing VE-cadherin gene expression and diminishing its exposure at the cell surface.	('decreasing', 'NegReg', (80, 90))	('exposure at the cell surface', 'MPA', (139, 167))	('lycorine hydrochloride', 'Var', (5, 27))	('cell surface', 'cellular_component', 'GO:0009986', ('155', '167'))	('lycorine hydrochloride', 'Chemical', '-', (5, 27))	('vasculogenic mimicry', 'CPA', (56, 76))	('VE-cadherin', 'Protein', (91, 102))	('cadherin', 'molecular_function', 'GO:0008014', ('94', '102'))	('reduce', 'NegReg', (49, 55))	('gene expression', 'biological_process', 'GO:0010467', ('103', '118'))	('diminishing', 'NegReg', (123, 134))
136323	33964953	However, single-agent activity of imatinib was reported in melanoma patients whose tumors harboured activating KIT mutations, warranting further investigation in this subset of patients.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mutations', 'Var', (115, 124))	('KIT', 'Gene', (111, 114))	('patients', 'Species', '9606', (177, 185))	('KIT', 'molecular_function', 'GO:0005020', ('111', '114'))	('tumors', 'Disease', (83, 89))	('imatinib', 'Chemical', 'MESH:D000068877', (34, 42))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('activating', 'PosReg', (100, 110))	('patients', 'Species', '9606', (68, 76))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('KIT', 'Gene', '3815', (111, 114))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
136354	33964953	Studies on molecular profiling identified mutations in the GNAQ and GNA11 genes, encoding for Galpha subunits of G-proteins, in about 80% of UM patients.	('GNA11', 'Gene', (68, 73))	('patients', 'Species', '9606', (144, 152))	('Galpha', 'Gene', '8802', (94, 100))	('GNA11', 'Gene', '2767', (68, 73))	('GNAQ', 'Gene', (59, 63))	('Galpha', 'Gene', (94, 100))	('mutations', 'Var', (42, 51))	('GNAQ', 'Gene', '2776', (59, 63))
136356	33964953	The main risk factors for UM development include the presence of dysplastic nevus syndrome, choroidal nevi, ocular or oculodermal melanocytosis, familial syndromes including germline BRCA1-associated protein 1 (BAP1) mutations and neurofibromatosis.	('oculodermal melanocytosis', 'Phenotype', 'HP:0009920', (118, 143))	('neurofibromatosis', 'Disease', 'MESH:C537392', (231, 248))	('choroidal nevi', 'Phenotype', 'HP:0025314', (92, 106))	('nevi', 'Phenotype', 'HP:0003764', (102, 106))	('UM development', 'Disease', (26, 40))	('choroidal', 'Disease', (92, 101))	('neurofibromatosis', 'Disease', (231, 248))	('BAP1', 'Gene', '8314', (211, 215))	('melanocytosis', 'Disease', 'MESH:C535835', (130, 143))	('familial syndromes', 'Disease', (145, 163))	('BRCA1-associated protein 1', 'Gene', '8314', (183, 209))	('protein', 'cellular_component', 'GO:0003675', ('200', '207'))	('BAP1', 'Gene', (211, 215))	('dysplastic nevus syndrome', 'Disease', (65, 90))	('choroidal', 'Disease', 'MESH:D002833', (92, 101))	('nevus', 'Phenotype', 'HP:0003764', (76, 81))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (65, 81))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (231, 248))	('dysplastic nevus syndrome', 'Disease', 'MESH:D004416', (65, 90))	('men', 'Species', '9606', (36, 39))	('BRCA1-associated protein 1', 'Gene', (183, 209))	('melanocytosis', 'Disease', (130, 143))	('mutations', 'Var', (217, 226))
136435	33964953	Recently, systemic administration of the small molecule arylsulfonamide 64B, a chemically stable and lipophilic inhibitor of HIF pathway, has been reported to reduce in vivo UM growth and metastasization in orthotopic UM syngeneic and xenogeneic mouse models with minimal toxicity.	('arylsulfonamide 64B', 'Var', (56, 75))	('toxicity', 'Disease', 'MESH:D064420', (272, 280))	('toxicity', 'Disease', (272, 280))	('mouse', 'Species', '10090', (246, 251))	('rat', 'Species', '10116', (27, 30))	('arylsulfonamide 64B', 'Chemical', '-', (56, 75))	('reduce', 'NegReg', (159, 165))
136438	33964953	By using both primary and metastatic cell lines the group of Frenkel demonstrated that UM cell lines are insensitive to hypoxia, and knockdown of CREB through retroviral vectors sensitized UM cells to doxorubicin and DTIC both under normoxia and hypoxia.	('DTIC', 'Chemical', 'MESH:D003606', (217, 221))	('sensitized', 'Reg', (178, 188))	('hypoxia', 'Disease', (246, 253))	('hypoxia', 'Disease', 'MESH:D000860', (246, 253))	('rat', 'Species', '10116', (76, 79))	('hypoxia', 'Disease', (120, 127))	('knockdown', 'Var', (133, 142))	('hypoxia', 'Disease', 'MESH:D000860', (120, 127))	('DTIC', 'MPA', (217, 221))	('doxorubicin', 'Chemical', 'MESH:D004317', (201, 212))
136439	33964953	Silencing of CREB under hypoxia also enhanced apoptosis and reduced the expression of VEGF, thus indicating involvement of CREB in the UM cell resistance to hypoxia.	('CREB', 'Gene', (13, 17))	('apoptosis', 'CPA', (46, 55))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))	('hypoxia', 'Disease', 'MESH:D000860', (157, 164))	('VEGF', 'Protein', (86, 90))	('Silencing', 'Var', (0, 9))	('men', 'Species', '9606', (115, 118))	('hypoxia', 'Disease', (157, 164))	('expression', 'MPA', (72, 82))	('hypoxia', 'Disease', 'MESH:D000860', (24, 31))	('reduced', 'NegReg', (60, 67))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('hypoxia', 'Disease', (24, 31))	('enhanced', 'PosReg', (37, 45))	('involvement', 'Reg', (108, 119))
136440	33964953	In vivo experiments in mouse models performed by the same group using vectors targeting HIF-1 and CREB blocked tumor growth, thus demonstrating the relevance of the two transcription factors in UM progression and indicated the dependence on glycolysis for the progression of UM.	('glycolysis', 'biological_process', 'GO:0006096', ('241', '251'))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('CREB', 'Gene', (98, 102))	('men', 'Species', '9606', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('HIF-1', 'Gene', '3091', (88, 93))	('tumor', 'Disease', (111, 116))	('rat', 'Species', '10116', (137, 140))	('vectors', 'Var', (70, 77))	('mouse', 'Species', '10090', (23, 28))	('transcription', 'biological_process', 'GO:0006351', ('169', '182'))	('HIF-1', 'Gene', (88, 93))	('blocked', 'NegReg', (103, 110))
136465	33964953	Inhibition of neddylation in UM cells expressing components of neddylation machinery, such as NEDD8-activating enzyme (NAE), also impaired maintenance of cancer stem cells and, more importantly, inhibited liver metastasis in UM cells xenografted in immunodepressed mouse models.	('liver metastasis', 'CPA', (205, 221))	('inhibited', 'NegReg', (195, 204))	('mouse', 'Species', '10090', (265, 270))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('NEDD8', 'Gene', '18002', (94, 99))	('Inhibition', 'Var', (0, 10))	('impaired', 'NegReg', (130, 138))	('neddylation', 'Protein', (14, 25))	('NEDD8', 'Gene', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
136475	33964953	Starting from 2007, several pilot or phase II clinical trials have been carried out with several antiangiogenic agents, including inhibitors of VEGFR - 1, - 2, and - 3, PDGFR-alpha and -beta, for the treatment of metastatic UM, but disappointing results were obtained, probably due to the small cohort of the recruited patients invalidating the reliability of results.	('inhibitors', 'Var', (130, 140))	('men', 'Species', '9606', (205, 208))	('patients', 'Species', '9606', (319, 327))	('PDGFR-alpha and -beta', 'Gene', '5156', (169, 190))	('metastatic UM', 'Disease', (213, 226))	('VEGFR - 1, - 2, and - 3', 'Gene', '2321;3791;2324', (144, 167))
136500	33964953	Specifically, KIT mutation has been identified in over 20% of all MM.	('KIT', 'Gene', (14, 17))	('mutation', 'Var', (18, 26))	('KIT', 'Gene', '3815', (14, 17))	('identified', 'Reg', (36, 46))	('KIT', 'molecular_function', 'GO:0005020', ('14', '17'))
136501	33964953	However, recent genetic studies and molecular profiling indicated the presence of BRAF mutation in approximately 30% of conjunctival melanoma.	('conjunctival melanoma', 'Disease', (120, 141))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (120, 141))	('BRAF', 'Gene', '673', (82, 86))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (120, 141))	('BRAF', 'Gene', (82, 86))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('presence', 'Reg', (70, 78))	('mutation', 'Var', (87, 95))
136503	33964953	However, it is genetically similar to CM based on associated BRAF and NRAS mutations, thus therapies effective at treating CM appear to have clinical benefits in conjunctival melanoma.	('NRAS', 'Gene', (70, 74))	('BRAF', 'Gene', '673', (61, 65))	('NRAS', 'Gene', '4893', (70, 74))	('BRAF', 'Gene', (61, 65))	('benefits', 'PosReg', (150, 158))	('conjunctival melanoma', 'Disease', (162, 183))	('mutations', 'Var', (75, 84))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (162, 183))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (162, 183))	('CM', 'Chemical', 'MESH:D003476', (123, 125))	('CM', 'Chemical', 'MESH:D003476', (38, 40))
136510	33964953	In detail, the presence of PAS-positive loops, indicative of vasculogenic mimicry and networks, was a strong independent prognostic factor of OS, and it was also associated with lymphogenous and hematogenous metastasis.	('OS', 'Gene', '17451', (142, 144))	('presence', 'Var', (15, 23))	('associated', 'Reg', (162, 172))	('PAS-positive', 'Protein', (27, 39))	('PAS', 'cellular_component', 'GO:0000407', ('27', '30'))
136518	33964953	However, the therapy of choice for patients with KIT mutation is still represented by imatinib based on significant activity resulting from phase II clinical trials.	('mutation', 'Var', (53, 61))	('imatinib', 'Chemical', 'MESH:D000068877', (86, 94))	('KIT', 'molecular_function', 'GO:0005020', ('49', '52'))	('KIT', 'Gene', '3815', (49, 52))	('patients', 'Species', '9606', (35, 43))	('KIT', 'Gene', (49, 52))
136546	33219855	Risk for metastases strongly depends on monosomy 3 (Shields et al.).	('metastases', 'Disease', (9, 19))	('monosomy 3', 'Var', (40, 50))	('metastases', 'Disease', 'MESH:D009362', (9, 19))
136622	33923737	Both anticancer drugs and radiotherapy can lead to ocular surface morbidities, ranging from transient dry eye disease or keratitis up to corneal melting and perforation.	('eye disease', 'Phenotype', 'HP:0000478', (106, 117))	('dry eye disease', 'Disease', 'MESH:D015352', (102, 117))	('corneal melting', 'Disease', (137, 152))	('dry eye disease', 'Disease', (102, 117))	('ocular surface morbidities', 'Disease', (51, 77))	('perforation', 'Disease', (157, 168))	('lead to', 'Reg', (43, 50))	('radiotherapy', 'Var', (26, 38))	('keratitis', 'Disease', (121, 130))	('keratitis', 'Disease', 'MESH:D007634', (121, 130))	('dry eye', 'Phenotype', 'HP:0001097', (102, 109))	('keratitis', 'Phenotype', 'HP:0000491', (121, 130))
136638	33923737	Less commonly, MMC may cause lid toxicity resulting in lid edema, ectropion or ptosis due to levator disinsertion.	('lid edema', 'Disease', (55, 64))	('MMC', 'Chemical', 'MESH:D016685', (15, 18))	('toxicity', 'Disease', 'MESH:D064420', (33, 41))	('ptosis', 'Disease', 'MESH:C564553', (79, 85))	('lid edema', 'Phenotype', 'HP:0100540', (55, 64))	('ptosis', 'Disease', (79, 85))	('MMC', 'Var', (15, 18))	('lid edema', 'Disease', 'MESH:D004487', (55, 64))	('ectropion', 'Phenotype', 'HP:0000656', (66, 75))	('ptosis', 'Phenotype', 'HP:0000508', (79, 85))	('edema', 'Phenotype', 'HP:0000969', (59, 64))	('ectropion', 'Disease', (66, 75))	('cause', 'Reg', (23, 28))	('toxicity', 'Disease', (33, 41))
136653	33923737	These cells are responsible for the production of mucins contained in the tear film and their deficiency represents one of the mechanisms underlying the vicious cycle of dry eye disease.	('dry eye', 'Phenotype', 'HP:0001097', (170, 177))	('dry eye disease', 'Disease', (170, 185))	('deficiency', 'Var', (94, 104))	('dry eye disease', 'Disease', 'MESH:D015352', (170, 185))	('eye disease', 'Phenotype', 'HP:0000478', (174, 185))	('tear', 'Phenotype', 'HP:0009926', (74, 78))
136659	33923737	Although studies in the literature report conflicting results regarding corneal epithelial toxicity, 5-FU seems to be better tolerated than MMC.	('5-FU', 'Var', (101, 105))	('MMC', 'Chemical', 'MESH:D016685', (140, 143))	('corneal epithelial toxicity', 'Disease', 'MESH:D003316', (72, 99))	('5-FU', 'Chemical', 'MESH:D005472', (101, 105))	('corneal epithelial toxicity', 'Disease', (72, 99))
136660	33923737	reported an incidence of epithelial defects in 8% of eyes treated with 5-FU compared to 18% of eyes treated with MMC.	('5-FU', 'Chemical', 'MESH:D005472', (71, 75))	('MMC', 'Chemical', 'MESH:D016685', (113, 116))	('epithelial defects', 'Disease', 'MESH:D053559', (25, 43))	('5-FU', 'Var', (71, 75))	('epithelial defects', 'Disease', (25, 43))
136666	33923737	Epiphora may be a common complication of 5-FU, with 49% of eyes treated with 5-FU presenting this symptom after 1 month in a randomized controlled trial comparing 5-FU with placebo.	('5-FU', 'Chemical', 'MESH:D005472', (77, 81))	('5-FU', 'Chemical', 'MESH:D005472', (41, 45))	('Epiphora', 'Phenotype', 'HP:0009926', (0, 8))	('Epiphora', 'Disease', 'MESH:D007766', (0, 8))	('5-FU', 'Chemical', 'MESH:D005472', (163, 167))	('5-FU', 'Var', (77, 81))	('Epiphora', 'Disease', (0, 8))
136667	33923737	Although several studies reported the occurrence of epiphora due to stenosis of the lacrimal punctum, it must be taken into account that epiphora may also occur due to other causes such as reflex tearing due to ocular surface irritation from local chemotherapy.	('irritation', 'Disease', 'MESH:D001523', (226, 236))	('tear', 'Phenotype', 'HP:0009926', (196, 200))	('epiphora', 'Disease', 'MESH:D007766', (52, 60))	('stenosis', 'Var', (68, 76))	('reflex', 'biological_process', 'GO:0060004', ('189', '195'))	('stenosis of the lacrimal punctum', 'Phenotype', 'HP:0025572', (68, 100))	('epiphora', 'Disease', (52, 60))	('epiphora', 'Phenotype', 'HP:0009926', (52, 60))	('lacrimal punctum', 'Phenotype', 'HP:0032514', (84, 100))	('irritation', 'Disease', (226, 236))	('reflex tearing', 'Disease', (189, 203))	('epiphora', 'Disease', 'MESH:D007766', (137, 145))	('reflex tearing', 'Phenotype', 'HP:0031733', (189, 203))	('epiphora', 'Phenotype', 'HP:0009926', (137, 145))	('epiphora', 'Disease', (137, 145))	('tearing', 'Phenotype', 'HP:0009926', (196, 203))
136699	33923737	Other studies reported no relevant alterations of the ocular surface after brachytherapy Iodine-125, Palladium-103, Ruthenium-106, and Strontium-90.	('Ruthenium-106', 'Var', (116, 129))	('Palladium-103', 'Var', (101, 114))	('Iodine-125', 'Var', (89, 99))	('Palladium-103', 'Chemical', 'MESH:C000615531', (101, 114))	('Strontium-90', 'Chemical', 'MESH:C000615490', (135, 147))	('Iodine-125', 'Chemical', 'MESH:C000614960', (89, 99))	('Ruthenium-106', 'Chemical', 'MESH:C000615522', (116, 129))
136716	33923737	Furthermore, the damage of the sub-basal nerve plexus can lead to a reduced nervous trophism of the cornea, which determines the onset of neurotrophic keratopathy.	('damage', 'Var', (17, 23))	('nervous trophism of the cornea', 'CPA', (76, 106))	('neurotrophic keratopathy', 'Disease', 'MESH:C562399', (138, 162))	('neurotrophic keratopathy', 'Disease', (138, 162))	('reduced', 'NegReg', (68, 75))
136718	33923737	In particular, the treatment of a lesion at the corneal level will lead to complications such as persistent epithelial defect or corneal ulceration.	('corneal ulceration', 'Disease', 'MESH:D003320', (129, 147))	('lead to', 'Reg', (67, 74))	('lesion', 'Var', (34, 40))	('corneal ulceration', 'Phenotype', 'HP:0012804', (129, 147))	('corneal ulceration', 'Disease', (129, 147))	('corneal ulcer', 'Phenotype', 'HP:0012804', (129, 142))	('epithelial defect', 'Disease', (108, 125))	('epithelial defect', 'Disease', 'MESH:D053559', (108, 125))
136722	33923737	treated 19 patients with Iodine-125 and reported corneal ulceration in six of them (32%).	('Iodine-125', 'Chemical', 'MESH:C000614960', (25, 35))	('corneal ulcer', 'Phenotype', 'HP:0012804', (49, 62))	('corneal ulceration', 'Disease', 'MESH:D003320', (49, 67))	('Iodine-125', 'Var', (25, 35))	('patients', 'Species', '9606', (11, 19))	('corneal ulceration', 'Phenotype', 'HP:0012804', (49, 67))	('corneal ulceration', 'Disease', (49, 67))
136765	32127952	Previously, we performed gain- and loss-of-function experiments in liver cancer cells, demonstrating that YWHAZ silencing decreased cell proliferation, clonogenicity, migration/invasion and induced G2 arrest and apoptosis, while YWHAZ up-regulation led to the opposite.	('G2 arrest', 'CPA', (198, 207))	('apoptosis', 'CPA', (212, 221))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('clonogenicity', 'CPA', (152, 165))	('liver cancer', 'Disease', 'MESH:D006528', (67, 79))	('si', 'Chemical', 'MESH:D012825', (264, 266))	('migration/invasion', 'CPA', (167, 185))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('liver cancer', 'Phenotype', 'HP:0002896', (67, 79))	('liver cancer', 'Disease', (67, 79))	('induced', 'Reg', (190, 197))	('YWHAZ', 'Gene', (106, 111))	('apoptosis', 'biological_process', 'GO:0097194', ('212', '221'))	('si', 'Chemical', 'MESH:D012825', (181, 183))	('apoptosis', 'biological_process', 'GO:0006915', ('212', '221'))	('si', 'Chemical', 'MESH:D012825', (218, 220))	('regulation', 'biological_process', 'GO:0065007', ('238', '248'))	('silencing', 'Var', (112, 121))	('cell proliferation', 'CPA', (132, 150))	('cell proliferation', 'biological_process', 'GO:0008283', ('132', '150'))	('decreased', 'NegReg', (122, 131))
136766	32127952	showed that YWHAZ knockdown increased the chemotherapeutic effect of cis-diammined dichloridoplatium through phosphorylation of JNK and p38.	('increased', 'PosReg', (28, 37))	('knockdown', 'Var', (18, 27))	('phosphorylation', 'biological_process', 'GO:0016310', ('109', '124'))	('JNK', 'Gene', '5599', (128, 131))	('p38', 'Gene', '1432', (136, 139))	('chemotherapeutic effect', 'MPA', (42, 65))	('p38', 'Gene', (136, 139))	('JNK', 'molecular_function', 'GO:0004705', ('128', '131'))	('phosphorylation', 'MPA', (109, 124))	('JNK', 'Gene', (128, 131))
136767	32127952	revealed that YWHAZ silencing in liver cancer stem-like cells reduced radio-resistance, leading to decreased cell viability and enhanced apoptosis following gamma-irradiation.	('liver cancer', 'Disease', (33, 45))	('decreased', 'NegReg', (99, 108))	('apoptosis', 'CPA', (137, 146))	('radio-resistance', 'MPA', (70, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('137', '146'))	('apoptosis', 'biological_process', 'GO:0006915', ('137', '146'))	('enhanced', 'PosReg', (128, 136))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('si', 'Chemical', 'MESH:D012825', (143, 145))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('liver cancer', 'Phenotype', 'HP:0002896', (33, 45))	('silencing', 'Var', (20, 29))	('liver cancer', 'Disease', 'MESH:D006528', (33, 45))	('reduced', 'NegReg', (62, 69))	('cell viability', 'CPA', (109, 123))
136772	32127952	However, YWHAZ interference dismissed the mesenchymal phenotype conferred by Cryab overexpression and decreased Gas6/Axl-dependent migration and invasion.	('si', 'Chemical', 'MESH:D012825', (93, 95))	('Cryab', 'Gene', '1410', (77, 82))	('si', 'Chemical', 'MESH:D012825', (149, 151))	('Gas6', 'Gene', '2621', (112, 116))	('Axl', 'Gene', '558', (117, 120))	('mesenchymal phenotype', 'CPA', (42, 63))	('Cryab', 'Gene', (77, 82))	('dismissed', 'NegReg', (28, 37))	('overexpression', 'PosReg', (83, 97))	('invasion', 'CPA', (145, 153))	('Gas6', 'Gene', (112, 116))	('Axl', 'Gene', (117, 120))	('YWHAZ', 'Var', (9, 14))	('decreased', 'NegReg', (102, 111))
136776	32127952	observed that the mRNA and protein levels of YWHAZ were both increased in 46 colorectal cancer (CRC) tissues by qRT-PCR and IHC.	('colorectal cancer', 'Disease', (77, 94))	('CRC', 'Disease', 'MESH:D015179', (96, 99))	('IHC', 'Var', (124, 127))	('qRT-PCR', 'Var', (112, 119))	('increased', 'PosReg', (61, 70))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('CRC', 'Disease', (96, 99))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))
136785	32127952	Silencing of YWHAZ accelerated miR-375-induced apoptosis by caspase-3/ caspase-7 activation and promoted autophagy by PI3K/AKT/mTOR signaling pathway, as well as inhibiting cell proliferation, migration/invasion and EMT in GC.	('apoptosis', 'biological_process', 'GO:0097194', ('47', '56'))	('apoptosis', 'biological_process', 'GO:0006915', ('47', '56'))	('apoptosis', 'CPA', (47, 56))	('autophagy', 'biological_process', 'GO:0016236', ('105', '114'))	('inhibiting', 'NegReg', (162, 172))	('miR-375', 'Gene', '494324', (31, 38))	('Silencing', 'Var', (0, 9))	('caspase-7', 'Gene', (71, 80))	('autophagy', 'biological_process', 'GO:0006914', ('105', '114'))	('miR-375', 'Gene', (31, 38))	('si', 'Chemical', 'MESH:D012825', (207, 209))	('EMT', 'biological_process', 'GO:0001837', ('216', '219'))	('migration/invasion', 'CPA', (193, 211))	('signaling pathway', 'biological_process', 'GO:0007165', ('132', '149'))	('mTOR', 'Gene', (127, 131))	('YWHAZ', 'Gene', (13, 18))	('AKT', 'Gene', (123, 126))	('PI3K', 'molecular_function', 'GO:0016303', ('118', '122'))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('cell proliferation', 'biological_process', 'GO:0008283', ('173', '191'))	('mTOR', 'Gene', '2475', (127, 131))	('GC', 'Disease', 'MESH:D013274', (223, 225))	('cell proliferation', 'CPA', (173, 191))	('caspase-3', 'Gene', '836', (60, 69))	('si', 'Chemical', 'MESH:D012825', (132, 134))	('caspase-7', 'Gene', '840', (71, 80))	('accelerated', 'PosReg', (19, 30))	('AKT', 'Gene', '207', (123, 126))	('promoted', 'PosReg', (96, 104))	('caspase-3', 'Gene', (60, 69))	('autophagy', 'CPA', (105, 114))
136789	32127952	observed that YWHAZ copy number, mRNA and protein expression were all higher in highly invasive lung cancer cell line than less invasive lung cancer cell line.	('invasive lung cancer', 'Disease', (128, 148))	('si', 'Chemical', 'MESH:D012825', (132, 134))	('invasive lung cancer', 'Disease', (87, 107))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('YWHAZ', 'Var', (14, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('invasive lung cancer', 'Disease', 'MESH:D008175', (128, 148))	('higher', 'PosReg', (70, 76))	('invasive lung cancer', 'Disease', 'MESH:D008175', (87, 107))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))
136791	32127952	In vitro, proliferation, migration/invasion and EMT were enhanced in lung cancer cells overexpressing YWHAZ, while silence of YWHAZ led to the opposite.	('migration/invasion', 'CPA', (25, 43))	('proliferation', 'CPA', (10, 23))	('YWHAZ', 'Var', (102, 107))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('si', 'Chemical', 'MESH:D012825', (97, 99))	('EMT', 'CPA', (48, 51))	('si', 'Chemical', 'MESH:D012825', (115, 117))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('EMT', 'biological_process', 'GO:0001837', ('48', '51'))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('overexpressing', 'Var', (87, 101))	('si', 'Chemical', 'MESH:D012825', (147, 149))	('enhanced', 'PosReg', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
136794	32127952	Additionally, YWHAZ bound with partitioning defective protein 3 (Par3) in lung cancer and loss of Par3 enhanced the interaction of YWHAZ and Tiam1, subsequently activating Rac1 and promoting cancer cell metastasis.	('activating', 'PosReg', (161, 171))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('Par3', 'Gene', (98, 102))	('Par3', 'Gene', (65, 69))	('cancer', 'Disease', (191, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('Tiam1', 'Gene', (141, 146))	('enhanced', 'PosReg', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('Rac1', 'Gene', (172, 176))	('cancer', 'Disease', (79, 85))	('Par3', 'Gene', '56288', (98, 102))	('interaction', 'Interaction', (116, 127))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Tiam1', 'Gene', '7074', (141, 146))	('Par3', 'Gene', '56288', (65, 69))	('si', 'Chemical', 'MESH:D012825', (210, 212))	('lung cancer', 'Disease', (74, 85))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('loss', 'Var', (90, 94))	('Rac1', 'Gene', '5879', (172, 176))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('promoting', 'PosReg', (181, 190))
136804	32127952	However, Knockdown of YWHAZ greatly decreased cell growth, proliferation, invasion capacity, as well as enhancing tamoxifen-induced inhibition of cell viability and apoptosis promotion.	('apoptosis', 'biological_process', 'GO:0097194', ('165', '174'))	('apoptosis', 'biological_process', 'GO:0006915', ('165', '174'))	('tamoxifen', 'Chemical', 'MESH:D013629', (114, 123))	('cell growth', 'CPA', (46, 57))	('YWHAZ', 'Gene', (22, 27))	('tamoxifen-induced inhibition', 'MPA', (114, 142))	('apoptosis promotion', 'CPA', (165, 184))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('enhancing', 'PosReg', (104, 113))	('invasion capacity', 'CPA', (74, 91))	('si', 'Chemical', 'MESH:D012825', (171, 173))	('cell growth', 'biological_process', 'GO:0016049', ('46', '57'))	('Knockdown', 'Var', (9, 18))	('decreased', 'NegReg', (36, 45))
136806	32127952	Inhibition of YWHAZ binding to p85 was found to reduce cell proliferation and promote apoptosis.	('p85', 'Gene', '5296', (31, 34))	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('promote', 'PosReg', (78, 85))	('binding', 'Interaction', (20, 27))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('p85', 'Gene', (31, 34))	('cell proliferation', 'biological_process', 'GO:0008283', ('55', '73'))	('cell proliferation', 'CPA', (55, 73))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('Inhibition', 'Var', (0, 10))	('reduce', 'NegReg', (48, 54))	('binding', 'molecular_function', 'GO:0005488', ('20', '27'))	('apoptosis', 'CPA', (86, 95))
136808	32127952	Conversely, delayed tumor onset and reduced tumor growth were observed in mice injected with YWHAZ siRNA-treated cells compared with siRNA-control cells.	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('YWHAZ siRNA-treated', 'Var', (93, 112))	('si', 'Chemical', 'MESH:D012825', (133, 135))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('reduced', 'NegReg', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mice', 'Species', '10090', (74, 78))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', (20, 25))
136820	32127952	Moreover, YWHAZ was associated with the androgen receptor (AR) in the nucleus, promoting AR transcriptional activity.	('promoting', 'PosReg', (79, 88))	('androgen receptor', 'Gene', '367', (40, 57))	('AR', 'Gene', '367', (89, 91))	('nucleus', 'cellular_component', 'GO:0005634', ('70', '77'))	('YWHAZ', 'Var', (10, 15))	('androgen receptor', 'Gene', (40, 57))	('AR', 'Gene', '367', (59, 61))
136823	32127952	Dimerization of increased YWHAZ was found to significantly enhance cell proliferation, viability, and colony formation, while YWHAZ/rac1 complex promoted cell-matrix interactions, lamellipodia formation, cell migration in prostate cancer cell lines.	('viability', 'CPA', (87, 96))	('cell-matrix interactions', 'CPA', (154, 178))	('colony formation', 'CPA', (102, 118))	('formation', 'biological_process', 'GO:0009058', ('193', '202'))	('cell migration', 'biological_process', 'GO:0016477', ('204', '218'))	('lamellipodia formation', 'CPA', (180, 202))	('rac1', 'Gene', '5879', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('Dimerization', 'Var', (0, 12))	('enhance', 'PosReg', (59, 66))	('rac1', 'Gene', (132, 136))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('prostate cancer', 'Disease', 'MESH:D011471', (222, 237))	('prostate cancer', 'Phenotype', 'HP:0012125', (222, 237))	('prostate cancer', 'Disease', (222, 237))	('cell migration', 'CPA', (204, 218))	('cell proliferation', 'CPA', (67, 85))	('formation', 'biological_process', 'GO:0009058', ('109', '118'))	('promoted', 'PosReg', (145, 153))
136826	32127952	Knockdown of YWHAZ by siRNA effectively reduced cell growth and proportion of cells in the S/G2 phases, while increasing the proportion of cells in the G0/G1 phase and enhancing sensitivity to topotecan in both drug-resistant and sensitive AML cells.	('cell growth', 'CPA', (48, 59))	('AML', 'Disease', (240, 243))	('si', 'Chemical', 'MESH:D012825', (218, 220))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('enhancing', 'PosReg', (168, 177))	('G1 phase', 'biological_process', 'GO:0051318', ('155', '163'))	('reduced', 'NegReg', (40, 47))	('S/G2', 'Var', (91, 95))	('AML', 'Disease', 'MESH:D015470', (240, 243))	('S/G2', 'SUBSTITUTION', 'None', (91, 95))	('si', 'Chemical', 'MESH:D012825', (233, 235))	('topotecan', 'Chemical', 'MESH:D019772', (193, 202))	('si', 'Chemical', 'MESH:D012825', (181, 183))	('sensitivity to topotecan', 'MPA', (178, 202))	('cell growth', 'biological_process', 'GO:0016049', ('48', '59'))	('increasing', 'PosReg', (110, 120))
136828	32127952	Overexpression of YWHAZ was positively related with lymphatic metastasis, tumor-node-metastasis stage, recurrence and the expression of EMT-related markers in ICC.	('expression', 'MPA', (122, 132))	('EMT', 'biological_process', 'GO:0001837', ('136', '139'))	('lymphatic metastasis', 'CPA', (52, 72))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('ICC', 'Disease', 'MESH:C535533', (159, 162))	('related', 'Reg', (39, 46))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('YWHAZ', 'Var', (18, 23))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('tumor', 'Disease', (74, 79))	('recurrence', 'CPA', (103, 113))	('ICC', 'Disease', (159, 162))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('si', 'Chemical', 'MESH:D012825', (69, 71))
136829	32127952	Reversely, silence of YWHAZ impaired the invasion, migration, and proliferation of ICC cells.	('ICC', 'Disease', (83, 86))	('ICC', 'Disease', 'MESH:C535533', (83, 86))	('silence', 'Var', (11, 18))	('migration', 'CPA', (51, 60))	('proliferation', 'CPA', (66, 79))	('invasion', 'CPA', (41, 49))	('YWHAZ', 'Gene', (22, 27))	('si', 'Chemical', 'MESH:D012825', (11, 13))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('impaired', 'NegReg', (28, 36))
136830	32127952	In diffuse large B cell lymphoma (DLBCL), 20 of 35 DLBCL cases showed positive expression of YWHAZ and higher YWHAZ was also found in the metastatic T1 DLBCL lymph node tissue compared with the non-metastatic DLBCL tissue and a normal lymph node.	('B cell lymphoma', 'Disease', 'MESH:D016393', (17, 32))	('B cell lymphoma', 'Disease', (17, 32))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (17, 32))	('large B cell', 'Phenotype', 'HP:0005404', (11, 23))	('YWHAZ', 'Var', (93, 98))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('lymphoma', 'Phenotype', 'HP:0002665', (24, 32))
136832	32127952	Further study demonstrated that blockade of YWHAZ inhibited DLBCL cell growth, leading to the accumulation of cells in the G2/M phase and restoring the sensitivity of resistant DLBCL to CHOP-induced apoptosis.	('cell growth', 'biological_process', 'GO:0016049', ('66', '77'))	('si', 'Chemical', 'MESH:D012825', (169, 171))	('restoring', 'PosReg', (138, 147))	('CHOP', 'Gene', (186, 190))	('si', 'Chemical', 'MESH:D012825', (205, 207))	('M phase', 'biological_process', 'GO:0000279', ('126', '133'))	('apoptosis', 'biological_process', 'GO:0097194', ('199', '208'))	('YWHAZ', 'Gene', (44, 49))	('accumulation', 'PosReg', (94, 106))	('sensitivity', 'MPA', (152, 163))	('apoptosis', 'biological_process', 'GO:0006915', ('199', '208'))	('blockade', 'Var', (32, 40))	('CHOP', 'Gene', '1649', (186, 190))	('si', 'Chemical', 'MESH:D012825', (155, 157))	('inhibited', 'NegReg', (50, 59))
136835	32127952	Alterations and dysregulation of miRNAs are often implicated in the initiation and progression of human cancers and are essential for maintaining the malignant phenotype of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('si', 'Chemical', 'MESH:D012825', (90, 92))	('cancer', 'Disease', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Alterations', 'Var', (0, 11))	('implicated', 'Reg', (50, 60))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('human', 'Species', '9606', (98, 103))	('cancer', 'Disease', (104, 110))	('cancers', 'Disease', (104, 111))	('miRNAs', 'Protein', (33, 39))	('dysregulation', 'Var', (16, 29))
136840	32127952	Conversely, negative regulation of YWHAZ via high miR-451 expression greatly reduced cell proliferation and growth and induced cell-cycle arrest alongside apoptotic cascade in breast cancer.	('cell proliferation', 'CPA', (85, 103))	('cell proliferation', 'biological_process', 'GO:0008283', ('85', '103'))	('induced', 'Reg', (119, 126))	('si', 'Chemical', 'MESH:D012825', (150, 152))	('growth', 'CPA', (108, 114))	('regulation', 'biological_process', 'GO:0065007', ('21', '31'))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('127', '144'))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('high', 'Var', (45, 49))	('miR-451', 'Gene', (50, 57))	('reduced', 'NegReg', (77, 84))	('cell-cycle arrest', 'CPA', (127, 144))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('negative regulation', 'NegReg', (12, 31))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('breast cancer', 'Disease', (176, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('miR-451', 'Gene', '574411', (50, 57))
136845	32127952	In gastric cancer, long non-coding RNA LUCAT1 was negatively correlated with miR-134-5p and miR-134-5p was negatively related with YWHAZ .	('related', 'Reg', (118, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('LUCAT1', 'Gene', '100505994', (39, 45))	('negatively', 'NegReg', (107, 117))	('LUCAT1', 'Gene', (39, 45))	('RNA', 'cellular_component', 'GO:0005562', ('35', '38'))	('YWHAZ', 'Disease', (131, 136))	('miR-134-5p', 'Var', (92, 102))	('miR-134-5p', 'Var', (77, 87))	('miR-134-5p', 'Chemical', '-', (77, 87))	('miR-134-5p', 'Chemical', '-', (92, 102))	('gastric cancer', 'Disease', (3, 17))	('negatively', 'NegReg', (50, 60))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('long non-coding RNA', 'Var', (19, 38))
136853	32127952	Cdc2 phosphorylation had been observed after YWHAZ reduction, subsequently sensitizing lung cancer cells to cisplatin-induced G2-M arrest.	('phosphorylation', 'MPA', (5, 20))	('Cdc2', 'Gene', (0, 4))	('cisplatin-induced', 'MPA', (108, 125))	('sensitizing lung cancer', 'Disease', (75, 98))	('sensitizing lung cancer', 'Disease', 'MESH:D008175', (75, 98))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('YWHAZ', 'Var', (45, 50))	('Cdc2', 'Gene', '983', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
136855	32127952	Conversely, a dramatic loss of Bax and caspase-3 were observed in breast cancer cells overexpressing YWHAZ.	('Bax', 'Gene', '581', (31, 34))	('caspase-3', 'Gene', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('loss', 'NegReg', (23, 27))	('YWHAZ', 'Var', (101, 106))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('Bax', 'Gene', (31, 34))	('caspase-3', 'Gene', '836', (39, 48))	('si', 'Chemical', 'MESH:D012825', (96, 98))
136856	32127952	also found that decreased YWHAZ sensitized breast cancer cells to apoptosis in low serum conditions by increasing cytochrome C release, subsequently reducing procaspase 9 expression and caspase substrate cleavage.	('YWHAZ', 'Var', (26, 31))	('si', 'Chemical', 'MESH:D012825', (177, 179))	('caspase substrate cleavage', 'MPA', (186, 212))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('cytochrome C', 'molecular_function', 'GO:0009461', ('114', '126'))	('procaspase', 'Protein', (158, 168))	('cytochrome C', 'Gene', (114, 126))	('apoptosis', 'biological_process', 'GO:0097194', ('66', '75'))	('apoptosis', 'biological_process', 'GO:0006915', ('66', '75'))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('reducing', 'NegReg', (149, 157))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('expression', 'MPA', (171, 181))	('breast cancer', 'Disease', (43, 56))	('cytochrome C', 'Gene', '54205', (114, 126))	('increasing', 'PosReg', (103, 113))	('cytochrome C', 'molecular_function', 'GO:0045155', ('114', '126'))	('si', 'Chemical', 'MESH:D012825', (35, 37))
136857	32127952	These studies demonstrated that YWHAZ may induce apoptosis resistance by modulating mitochondrial apoptosis pathways.	('YWHAZ', 'Var', (32, 37))	('induce', 'PosReg', (42, 48))	('mitochondrial apoptosis pathways', 'Pathway', (84, 116))	('si', 'Chemical', 'MESH:D012825', (61, 63))	('apoptosis resistance', 'CPA', (49, 69))	('modulating', 'Reg', (73, 83))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0097194', ('49', '58'))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0006915', ('49', '58'))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('si', 'Chemical', 'MESH:D012825', (55, 57))
136859	32127952	Co-overexpression of YWHAZ and ErbB2 in ductal CIS conferred an increased risk of progression to invasive BRCA than those overexpressed one molecule alone.	('si', 'Chemical', 'MESH:D012825', (101, 103))	('BRCA', 'Disease', (106, 110))	('YWHAZ', 'Var', (21, 26))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('ErbB2', 'Gene', (31, 36))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('BRCA', 'Disease', 'MESH:D001943', (106, 110))	('ErbB2', 'Gene', '2064', (31, 36))
136863	32127952	In breast cancer cells, YWHAZ destabilized p53 and stabilizes Gli2, promoting TGF-beta-induced bone metastasis.	('bone metastasis', 'CPA', (95, 110))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('TGF-beta', 'Gene', '7039', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('Gli2', 'Gene', '2736', (62, 66))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('destabilized', 'NegReg', (30, 42))	('Gli2', 'Gene', (62, 66))	('YWHAZ', 'Var', (24, 29))	('p53', 'Gene', (43, 46))	('stabilizes', 'Var', (51, 61))	('p53', 'Gene', '7157', (43, 46))	('TGF-beta', 'Gene', (78, 86))	('promoting', 'PosReg', (68, 77))	('si', 'Chemical', 'MESH:D012825', (107, 109))
136868	32127952	Importantly, three HCC RNA-seq datasets (GSE69164, GSE63863, and GSE55758) from Gene Expression Omnibus (GEO) indicated that YWHAZ is a hub gene in HCC.	('Gene Expression', 'biological_process', 'GO:0010467', ('80', '95'))	('HCC', 'Disease', (148, 151))	('HCC', 'Disease', (19, 22))	('HCC', 'Disease', 'MESH:D006528', (19, 22))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('RNA', 'cellular_component', 'GO:0005562', ('23', '26'))	('GSE69164', 'Var', (41, 49))	('GSE55758', 'Var', (65, 73))	('HCC', 'Disease', 'MESH:D006528', (148, 151))
136873	32127952	Moreover, YWHAZ autoantibody combined with diagnosis biomarkers of gastric cancer (CEA, CA199, CA724), increasing the diagnostic sensitivity to 52.7%.	('si', 'Chemical', 'MESH:D012825', (132, 134))	('gastric cancer', 'Disease', (67, 81))	('CA724', 'Chemical', '-', (95, 100))	('gastric cancer', 'Disease', 'MESH:D013274', (67, 81))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('combined', 'Interaction', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('increasing', 'PosReg', (103, 113))	('YWHAZ', 'Var', (10, 15))	('gastric cancer', 'Phenotype', 'HP:0012126', (67, 81))	('si', 'Chemical', 'MESH:D012825', (49, 51))	('CA724', 'Var', (95, 100))
136879	32127952	As can be seen in Figure 3A and Figure 4A, YWHAZ expression was significantly correlated with overall survival at 60 months in LIHC (p = 0.0197) and LUAD (p = 0.016), and with disease-free survival at 60 months in BRCA (p = 0.0279) and LUAD (p = 0.016).	('correlated with', 'Reg', (78, 93))	('BRCA', 'Disease', (214, 218))	('BRCA', 'Disease', 'MESH:D001943', (214, 218))	('LUAD', 'Disease', (149, 153))	('LIHC', 'Disease', (127, 131))	('YWHAZ expression', 'Var', (43, 59))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('LUAD', 'Disease', 'MESH:C538231', (149, 153))	('LIHC', 'Disease', 'MESH:D006528', (127, 131))	('LUAD', 'Disease', (236, 240))	('LUAD', 'Disease', 'MESH:C538231', (236, 240))	('si', 'Chemical', 'MESH:D012825', (55, 57))
136884	32127952	reported that overall survival at 5 years after surgery and cancer-specific survival in stage I NSCLC YWHAZ-positive patients were 0.36 and 0.60, compared with 0.68 and 0.95 in YWHAZ-negative patients.	('si', 'Chemical', 'MESH:D012825', (110, 112))	('NSCLC', 'Disease', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('patients', 'Species', '9606', (192, 200))	('cancer', 'Disease', (60, 66))	('YWHAZ-positive', 'Var', (102, 116))	('patients', 'Species', '9606', (117, 125))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
136885	32127952	LUSC patients with high YWHAZ/ TGFbeta receptor types 1 (TGFbetaR1) have shorter overall survival than patients with low YWHAZ/TGFbetaR1.	('TGFbeta', 'Disease', (31, 38))	('TGFbeta', 'Disease', 'None', (31, 38))	('patients', 'Species', '9606', (5, 13))	('high YWHAZ/', 'Var', (19, 30))	('shorter', 'NegReg', (73, 80))	('TGFbetaR', 'molecular_function', 'GO:0005024', ('57', '65'))	('TGFbeta', 'Disease', (57, 64))	('TGFbeta', 'Disease', (127, 134))	('overall survival', 'MPA', (81, 97))	('patients', 'Species', '9606', (103, 111))	('TGFbeta', 'Disease', 'None', (127, 134))	('TGFbetaR', 'molecular_function', 'GO:0005024', ('127', '135'))	('TGFbeta', 'Disease', 'None', (57, 64))	('LUSC', 'Disease', 'MESH:D002294', (0, 4))	('LUSC', 'Disease', (0, 4))
136886	32127952	Similarly, YWHAZ overexpression was significantly associated with reduced disease-free survival/overall survival and earlier time to disease recurrence, and death in breast cancer by combining with elevated levels of Akt, FOXM1, ErbB2, LOC441453 and LAPTM4B.	('reduced', 'NegReg', (66, 73))	('survival/overall survival', 'CPA', (87, 112))	('LAPTM4B', 'Gene', (250, 257))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('LOC441453', 'Var', (236, 245))	('breast cancer', 'Disease', (166, 179))	('ErbB2', 'Gene', '2064', (229, 234))	('death', 'Disease', (157, 162))	('FOXM1', 'Gene', '2305', (222, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('overexpression', 'PosReg', (17, 31))	('ErbB2', 'Gene', (229, 234))	('Akt', 'Gene', (217, 220))	('death', 'Disease', 'MESH:D003643', (157, 162))	('elevated', 'PosReg', (198, 206))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('FOXM1', 'Gene', (222, 227))	('Akt', 'Gene', '207', (217, 220))	('disease-free survival/overall', 'CPA', (74, 103))	('LAPTM4B', 'Gene', '55353', (250, 257))	('si', 'Chemical', 'MESH:D012825', (27, 29))
136887	32127952	In particular, YWHAZ overexpression, ErbB2 overexpression, and positive lymph node status were seen to be independent prognostic factors in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('ErbB2', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('ErbB2', 'Gene', '2064', (37, 42))	('YWHAZ overexpression', 'Var', (15, 35))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('si', 'Chemical', 'MESH:D012825', (65, 67))
136889	32127952	In glioblastoma, 2-year overall survival and median survival time in the YWHAZ-positive group were 8.6% and 12.9 months, compared with 16.7% and 17.9 months in the YWHAZ-negative group.	('si', 'Chemical', 'MESH:D012825', (81, 83))	('YWHAZ-positive', 'Var', (73, 87))	('glioblastoma', 'Disease', (3, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))
136892	32127952	The anti-apoptosis ability exerted by YWHAZ may be responsible for chemoresistance.	('si', 'Chemical', 'MESH:D012825', (57, 59))	('chemoresistance', 'CPA', (67, 82))	('YWHAZ', 'Var', (38, 43))	('anti-apoptosis ability', 'CPA', (4, 26))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('anti-apoptosis', 'biological_process', 'GO:0043066', ('4', '18'))
136894	32127952	Intriguingly, YWHAZ knockdown had been shown to restore the sensitivity of resistant cells to apoptosis induced by chemotherapeutic agents including CHOP, 9-nitrocamptothecin, CDDP, cisplatin and TPT.	('cisplatin', 'Chemical', 'MESH:D002945', (182, 191))	('CHOP', 'Gene', (149, 153))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('TPT', 'molecular_function', 'GO:0009670', ('196', '199'))	('CDDP', 'Chemical', 'MESH:D002945', (176, 180))	('9-nitrocamptothecin', 'Chemical', 'MESH:C079905', (155, 174))	('TPT', 'Chemical', 'MESH:C026677', (196, 199))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))	('restore', 'PosReg', (48, 55))	('knockdown', 'Var', (20, 29))	('CHOP', 'Gene', '1649', (149, 153))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('sensitivity', 'MPA', (60, 71))	('si', 'Chemical', 'MESH:D012825', (100, 102))
136895	32127952	In breast cancer, silencing of LAPTM4B and YWHAZ gene sensitized tumor cells to anthracyclines, while overexpression of these genes induced drug resistance.	('drug resistance', 'Phenotype', 'HP:0020174', (140, 155))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('tumor', 'Disease', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('drug resistance', 'biological_process', 'GO:0009315', ('140', '155'))	('drug resistance', 'biological_process', 'GO:0042493', ('140', '155'))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('LAPTM4B', 'Gene', '55353', (31, 38))	('YWHAZ', 'Gene', (43, 48))	('LAPTM4B', 'Gene', (31, 38))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('sensitized', 'Reg', (54, 64))	('induced', 'Reg', (132, 139))	('silencing', 'Var', (18, 27))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('drug resistance', 'MPA', (140, 155))	('breast cancer', 'Disease', (3, 16))	('si', 'Chemical', 'MESH:D012825', (147, 149))	('anthracyclines', 'Chemical', 'MESH:D018943', (80, 94))
136896	32127952	Moreover, YWHAZ knockdown enhanced the growth inhibitory effects of SERMs in endocrine-resistant breast cancer cells, restoring sensitivity to endocrine treatments.	('si', 'Chemical', 'MESH:D012825', (131, 133))	('enhanced', 'PosReg', (26, 34))	('sensitivity to endocrine treatments', 'MPA', (128, 163))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('restoring', 'PosReg', (118, 127))	('growth inhibitory effects', 'MPA', (39, 64))	('knockdown', 'Var', (16, 25))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('YWHAZ', 'Var', (10, 15))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))
136913	32127952	To date, YWHAZ has been shown to be frequently up-regulated and function as an oncogene by regulating multiple signaling pathways in cancers (Table 1).	('si', 'Chemical', 'MESH:D012825', (111, 113))	('regulating', 'Reg', (91, 101))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('signaling', 'biological_process', 'GO:0023052', ('111', '120'))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('up-regulated', 'PosReg', (47, 59))	('YWHAZ', 'Var', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
136914	32127952	YWHAZ overexpression is regulated by miRNAs or long non-coding RNAs and activates downstream molecules, including protein kinases, apoptosis proteins, and metastasis-related molecules, to facilitate the malignant potential of cancer cells.	('facilitate', 'PosReg', (188, 198))	('activates', 'PosReg', (72, 81))	('miRNAs', 'Var', (37, 43))	('si', 'Chemical', 'MESH:D012825', (162, 164))	('apoptosis', 'Protein', (131, 140))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('apoptosis', 'biological_process', 'GO:0097194', ('131', '140'))	('protein', 'Protein', (114, 121))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('si', 'Chemical', 'MESH:D012825', (137, 139))	('apoptosis', 'biological_process', 'GO:0006915', ('131', '140'))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
136928	32005108	Additional bioinformatic analyses would reveal that these methylation markers are independent of patient race and age, and positively associated with signaling pathways associated with BrCa progression (such as those related to retinoid nuclear receptor, PTEN, p53, pRB, and p27).	('retinoid', 'Protein', (228, 236))	('associated', 'Reg', (134, 144))	('BrCa', 'Gene', (185, 189))	('p53', 'Gene', (261, 264))	('signaling pathways', 'Pathway', (150, 168))	('p53', 'Gene', '7157', (261, 264))	('signaling', 'biological_process', 'GO:0023052', ('150', '159'))	('p27', 'Gene', '3429', (275, 278))	('p27', 'Gene', (275, 278))	('BrCa', 'Gene', '672', (185, 189))	('pRB', 'Gene', '5925', (266, 269))	('methylation', 'Var', (58, 69))	('methylation', 'biological_process', 'GO:0032259', ('58', '69'))	('patient', 'Species', '9606', (97, 104))	('PTEN', 'Gene', (255, 259))	('PTEN', 'Gene', '5728', (255, 259))	('pRB', 'Gene', (266, 269))	('methyl', 'Chemical', 'MESH:C031105', (58, 64))
136932	32005108	BRCA1/2 mutations) is an important contributing factor (5-10%), most BrCa cases are those without clear genetic link (it may still be due to unknown genetic risk, thus considered familial).	('BRCA1', 'Gene', (0, 5))	('BrCa', 'Gene', (69, 73))	('BrCa', 'Gene', '672', (69, 73))	('mutations', 'Var', (8, 17))	('BRCA1', 'Gene', '672', (0, 5))
136941	32005108	mutation, copy number variation, CpG methylation) found in cancer tissues are largely concordant with those identified in ctDNAs.	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('mutation', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('methyl', 'Chemical', 'MESH:C031105', (37, 43))	('copy number variation', 'Var', (10, 31))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
136942	32005108	Already marketed are early cancer diagnostic tests based on interrogating site-specific CpG hypermethylation in ctDNAs isolated from patient plasma.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('CpG', 'Var', (88, 91))	('patient', 'Species', '9606', (133, 140))	('methyl', 'Chemical', 'MESH:C031105', (97, 103))	('hypermethylation', 'Var', (92, 108))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
136943	32005108	These include: a) Epi proColon, ColoVantage, Realtime mS9, all of which detect methylation in the SEPT9 gene for colon cancer detection; b) Epi proLung which detects methylation of SHOX2 for lung cancer detection, and c) Colvera, which detects methylation at BCAT1 and IKZF1 for colon cancer recurrence.	('methyl', 'Chemical', 'MESH:C031105', (79, 85))	('colon cancer', 'Phenotype', 'HP:0003003', (113, 125))	('methyl', 'Chemical', 'MESH:C031105', (166, 172))	('mS9', 'Gene', '69077', (54, 57))	('BCAT1', 'Gene', '586', (259, 264))	('colon cancer', 'Phenotype', 'HP:0003003', (279, 291))	('methylation', 'Var', (166, 177))	('BCAT1', 'Gene', (259, 264))	('methyl', 'Chemical', 'MESH:C031105', (244, 250))	('methylation', 'biological_process', 'GO:0032259', ('244', '255'))	('lung cancer', 'Disease', 'MESH:D008175', (191, 202))	('colon cancer', 'Disease', 'MESH:D015179', (113, 125))	('IKZF1', 'Gene', '10320', (269, 274))	('mS9', 'Gene', (54, 57))	('methylation', 'Var', (244, 255))	('colon cancer', 'Disease', 'MESH:D015179', (279, 291))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('methylation', 'biological_process', 'GO:0032259', ('166', '177'))	('SEPT9', 'Gene', (98, 103))	('SHOX2', 'Gene', (181, 186))	('SHOX2', 'Gene', '6474', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('colon cancer', 'Disease', (113, 125))	('colon cancer', 'Disease', (279, 291))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('lung cancer', 'Disease', (191, 202))	('methylation', 'biological_process', 'GO:0032259', ('79', '90'))	('BCAT', 'molecular_function', 'GO:0043840', ('259', '263'))	('SEPT9', 'Gene', '10801', (98, 103))	('IKZF1', 'Gene', (269, 274))
136948	32005108	In this report, we demonstrate a new and more sensitive assay for methylated CpG detection (incorporating various steps including ligase detection reaction), and a comprehensive approach to biomarker discovery using integrated public genomic datasets.	('CpG', 'Gene', (77, 80))	('methylated', 'Var', (66, 76))	('methyl', 'Chemical', 'MESH:C031105', (66, 72))
136952	32005108	Also crucial to our biomarker identification is the integration of various GEO datasets such as: GSE65820 (ovarian cancer PTs and matching normals), GSE46306 (normal tissues of the cervix), GSE99553 (gastric mucosa), GSE74104 (testis), GSE77871 (adrenal tissues), GSE51954 (dermis and epidermis), GSE64509 (various brain tissues), GSE42861 (peripheral blood), and GSE59250 (various immune cells from healthy individuals).	('GSE59250', 'Var', (364, 372))	('GSE99553', 'Var', (190, 198))	('GSE42861', 'Var', (331, 339))	('GSE51954', 'Var', (264, 272))	('GSE64509', 'Var', (297, 305))	('ovarian cancer', 'Disease', 'MESH:D010051', (107, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ovarian cancer', 'Phenotype', 'HP:0100615', (107, 121))	('GSE74104', 'Var', (217, 225))	('gastric mucosa', 'Disease', (200, 214))	('GSE65820', 'Var', (97, 105))	('GSE46306', 'Var', (149, 157))	('gastric mucosa', 'Disease', 'MESH:D013274', (200, 214))	('GSE77871', 'Var', (236, 244))	('ovarian cancer', 'Disease', (107, 121))
136953	32005108	The methylation data for BrCa cell lines were extracted from the GEO datasets GSE57342, GSE68379, GSE78875, and GSE94943.	('GSE57342', 'Var', (78, 86))	('BrCa', 'Gene', (25, 29))	('methyl', 'Chemical', 'MESH:C031105', (4, 10))	('BrCa', 'Gene', '672', (25, 29))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))
136958	32005108	First, the combined transcriptional and methylation data enabled us to predict if the CpG sites can potentially influence the transcription of their respective genes.	('transcription', 'MPA', (126, 139))	('CpG sites', 'Var', (86, 95))	('transcription', 'biological_process', 'GO:0006351', ('126', '139'))	('influence', 'Reg', (112, 121))	('methyl', 'Chemical', 'MESH:C031105', (40, 46))	('methylation', 'biological_process', 'GO:0032259', ('40', '51'))	('sites', 'Var', (90, 95))
136987	32005108	Among the major cancer types, the marker m_PRKCB exhibits the highest degree of methylation ( PT equals 0.561).	('methyl', 'Chemical', 'MESH:C031105', (80, 86))	('methylation', 'MPA', (80, 91))	('cancer type', 'Disease', 'MESH:D009369', (16, 27))	('cancer type', 'Disease', (16, 27))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('methylation', 'biological_process', 'GO:0032259', ('80', '91'))	('m_PRKCB', 'Var', (41, 48))
136994	32005108	The methylation level of either m_NR5A2 or m_PRKCB, apparently does not correlate with its transcript level (the respective R values are - 0.198 and - 0.123) (Additional file 1: Supplement 10).	('m_NR5A2', 'Var', (32, 39))	('m_PRKCB', 'Gene', (43, 50))	('methyl', 'Chemical', 'MESH:C031105', (4, 10))	('methylation', 'MPA', (4, 15))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))
137001	32005108	ERBB3 expression, which is positively correlated with methylation at m_PRKCB and m_NR5A2 (Fig.	('ERBB3', 'Gene', (0, 5))	('ERBB3', 'Gene', '2065', (0, 5))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('methylation', 'Var', (54, 65))	('expression', 'MPA', (6, 16))	('m_PRKCB', 'Gene', (69, 76))	('m_NR5A2', 'Gene', (81, 88))	('methyl', 'Chemical', 'MESH:C031105', (54, 60))	('correlated', 'Reg', (38, 48))
137015	32005108	The positive association between the methylation markers and CARM1 pathway is consistent with previous studies indicating that CARM1 (which codes for arginine methyltransferase) is involved in epigenetic transactivation of many nuclear receptors (NRs) including ERalpha.	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('CARM1', 'Gene', '10498', (127, 132))	('methyl', 'Chemical', 'MESH:C031105', (159, 165))	('transactivation', 'biological_process', 'GO:2000144', ('204', '219'))	('arginine', 'Chemical', 'MESH:D001127', (150, 158))	('epigenetic', 'Var', (193, 203))	('ERalpha', 'Gene', (262, 269))	('involved', 'Reg', (181, 189))	('methyl', 'Chemical', 'MESH:C031105', (37, 43))	('CARM1', 'Gene', (61, 66))	('ERalpha', 'Gene', '2099', (262, 269))	('CARM1', 'Gene', '10498', (61, 66))	('CARM1', 'Gene', (127, 132))
137027	32005108	According to the datasets GSE57342, GSE68379, GSE78875, and GSE94943, the average beta values for the CpG markers m_NR5A2, m_PRKCB, and m_ncr1 in the BrCa cell line MCF7 are 0.96, 0.97, and 0.98 respectively (Fig.	('BrCa', 'Gene', (150, 154))	('GSE57342', 'Var', (26, 34))	('BrCa', 'Gene', '672', (150, 154))	('GSE68379', 'Var', (36, 44))	('GSE94943', 'Var', (60, 68))	('GSE78875', 'Var', (46, 54))	('MCF7', 'CellLine', 'CVCL:0031', (165, 169))	('m_NR5A2', 'Var', (114, 121))
137036	32005108	For this experiment, we performed the 2-step PCR and LDR reactions as described above, using the primers for the detection of methylation at the CpG site located in the promoter region of the gene GRK7 (m_GRK7 or cg18768784; Chr3:_141516271-141,516,272), although highly methylated in the BrCa cohort, has low BRCA-specificity.	('GRK7', 'molecular_function', 'GO:0050254', ('197', '201'))	('GRK7', 'Gene', (197, 201))	('methyl', 'Chemical', 'MESH:C031105', (271, 277))	('methylation', 'biological_process', 'GO:0032259', ('126', '137'))	('BrCa', 'Gene', (289, 293))	('GRK7', 'Gene', '131890', (205, 209))	('BrCa', 'Gene', '672', (289, 293))	('BRCA', 'Gene', '672', (310, 314))	('GRK7', 'Gene', '131890', (197, 201))	('cg18768784', 'Var', (213, 223))	('BRCA', 'Gene', (310, 314))	('methyl', 'Chemical', 'MESH:C031105', (126, 132))	('GRK7', 'molecular_function', 'GO:0050254', ('205', '209'))	('GRK7', 'Gene', (205, 209))
137038	32005108	In the digital PCR detection system, the corresponding readings are 8164, 4986, and 805 for the MCF7, MDA-MB-134VI, and control (peripheral blood only) respectively.	('MDA-MB-134', 'CellLine', 'CVCL:0617', (102, 112))	('MDA-MB-134VI', 'Var', (102, 114))	('MCF7', 'Var', (96, 100))	('MCF7', 'CellLine', 'CVCL:0031', (96, 100))
137042	32005108	As expected, ctDNA fragments possess the same molecular signatures (somatic mutations, methylation, copy number variation/aberration, SNPs) present in gDNAs isolated from the tumor tissue samples.	('tumor', 'Disease', (175, 180))	('methyl', 'Chemical', 'MESH:C031105', (87, 93))	('methylation', 'biological_process', 'GO:0032259', ('87', '98'))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('methylation', 'Var', (87, 98))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('copy number variation/aberration', 'Var', (100, 132))
137072	32005108	However, bisulfite conversion can cause the degradation of around 84-96% of the input cfDNA, and is thus a significant contributing factor to MSP's limitations in liquid biopsy.	('degradation', 'MPA', (44, 55))	('bisulfite', 'Chemical', 'MESH:C042345', (9, 18))	('bisulfite conversion', 'Var', (9, 29))	('degradation', 'biological_process', 'GO:0009056', ('44', '55'))
137090	29284740	Familial and Somatic BAP1 Mutations Inactivate ASXL1/2-Mediated Allosteric Regulation of BAP1 Deubiquitinase by Targeting Multiple Independent Domains Deleterious mutations of the ubiquitin carboxy-terminal hydrolase BAP1 found in cancers are predicted to encode inactive truncated proteins, suggesting that loss of enzyme function is a primary tumorigenic mechanism.	('BAP1', 'Gene', (217, 221))	('tumor', 'Disease', (345, 350))	('ubiquitin', 'molecular_function', 'GO:0031386', ('180', '189'))	('ASXL1', 'Gene', (47, 52))	('BAP1', 'Gene', '8314', (21, 25))	('Inactivate', 'NegReg', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (345, 350))	('BAP1', 'Gene', (89, 93))	('Deubiquitinase', 'molecular_function', 'GO:0004843', ('94', '108'))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('cancers', 'Disease', (231, 238))	('Mutations', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (345, 350))	('BAP1', 'Gene', (21, 25))	('BAP1', 'Gene', '8314', (217, 221))	('mutations', 'Var', (163, 172))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('ASXL1', 'Gene', '171023', (47, 52))	('BAP1', 'Gene', '8314', (89, 93))
137091	29284740	However, many tumors exhibit missense mutations or in-frame deletions or insertions, often outside the functionally critical UCH domain in this tumor suppressor protein.	('tumor', 'Disease', (144, 149))	('in-frame deletions', 'Var', (51, 69))	('tumor', 'Disease', (14, 19))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('144', '160'))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('insertions', 'Var', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('missense mutations', 'Var', (29, 47))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor suppressor', 'biological_process', 'GO:0051726', ('144', '160'))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))
137093	29284740	The ASXH domain was the minimal domain for binding the BAP1 ULD domain, and mutations on the surfaces of predicted helices of ASXH abolished BAP1 association and stimulation of BAP1 enzymatic activity.	('enzymatic activity', 'MPA', (182, 200))	('mutations', 'Var', (76, 85))	('BAP1', 'Protein', (141, 145))	('abolished', 'NegReg', (131, 140))	('association', 'Interaction', (146, 157))	('BAP1', 'Protein', (177, 181))	('stimulation', 'PosReg', (162, 173))	('ASX', 'Gene', (126, 129))	('ASX', 'Gene', (4, 7))	('binding', 'molecular_function', 'GO:0005488', ('43', '50'))	('ASX', 'Gene', '36612', (126, 129))	('ASX', 'Gene', '36612', (4, 7))
137095	29284740	We defined four classes of alterations in BAP1 outside the UCH domain, each failing to productively recruit ASXH to the wild-type BAP1 catalytic site via the ULD, resulting in loss of BAP1 ubiquitin hydrolase activity.	('ubiquitin hydrolase activity', 'molecular_function', 'GO:0004843', ('189', '217'))	('loss', 'NegReg', (176, 180))	('ASX', 'Gene', '36612', (108, 111))	('BAP1 ubiquitin hydrolase activity', 'MPA', (184, 217))	('BAP1', 'Gene', (42, 46))	('ASX', 'Gene', (108, 111))	('alterations', 'Var', (27, 38))
137096	29284740	Our results indicate that many BAP1 mutations act allosterically to inhibit ASXH binding, thereby leading to loss of enzyme activity.	('enzyme activity', 'MPA', (117, 132))	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('ASX', 'Gene', (76, 79))	('ASX', 'Gene', '36612', (76, 79))	('loss', 'NegReg', (109, 113))	('inhibit', 'NegReg', (68, 75))	('mutations', 'Var', (36, 45))	('BAP1', 'Gene', (31, 35))	('enzyme activity', 'molecular_function', 'GO:0003824', ('117', '132'))
137104	29284740	Families with heritable mutations of BAP1 were first published simultaneously in two papers in Nature Genetics; one reported two families with a high incidence of mesothelioma, uveal melanoma, and several types of epithelial cancer, such as renal carcinoma; the second reported two families with numerous cases of atypical melanocytic tumors and occasional uveal and cutaneous melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('mutations', 'Var', (24, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('renal carcinoma', 'Disease', 'MESH:C538614', (241, 256))	('cutaneous melanomas', 'Disease', (367, 386))	('uveal melanoma', 'Disease', 'MESH:C536494', (177, 191))	('melanocytic tumors', 'Disease', (323, 341))	('melanocytic tumors', 'Disease', 'MESH:D009508', (323, 341))	('renal carcinoma', 'Disease', (241, 256))	('uveal melanoma', 'Disease', (177, 191))	('renal carcinoma', 'Phenotype', 'HP:0005584', (241, 256))	('uveal', 'Disease', (357, 362))	('uveal melanoma', 'Phenotype', 'HP:0007716', (177, 191))	('melanoma', 'Phenotype', 'HP:0002861', (377, 385))	('BAP1', 'Gene', (37, 41))	('melanomas', 'Phenotype', 'HP:0002861', (377, 386))	('tumors', 'Phenotype', 'HP:0002664', (335, 341))	('epithelial cancer', 'Phenotype', 'HP:0031492', (214, 231))	('mesothelioma', 'Disease', (163, 175))	('epithelial cancer', 'Disease', (214, 231))	('epithelial cancer', 'Disease', 'MESH:D000077216', (214, 231))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('mesothelioma', 'Disease', 'MESH:D008654', (163, 175))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (367, 386))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (367, 386))
137105	29284740	Contemporaneously, a third group independently reported a family with a germline BAP1 mutation associated with uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('uveal melanoma', 'Disease', 'MESH:C536494', (111, 125))	('uveal melanoma', 'Phenotype', 'HP:0007716', (111, 125))	('meningioma', 'Phenotype', 'HP:0002858', (148, 158))	('cancers', 'Disease', (170, 177))	('BAP1', 'Gene', (81, 85))	('associated', 'Reg', (95, 105))	('uveal melanoma', 'Disease', (111, 125))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (127, 146))	('meningioma', 'Disease', 'MESH:D008577', (148, 158))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('mutation', 'Var', (86, 94))	('lung adenocarcinoma', 'Disease', (127, 146))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('meningioma', 'Disease', (148, 158))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (127, 146))
137106	29284740	Subsequently, numerous reports have expanded on the discovery of germline BAP1 mutations in families with these and other cancers, now defined as the BAP1 tumor predisposition syndrome.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('germline', 'Var', (65, 73))	('tumor', 'Disease', (155, 160))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('BAP1', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))
137115	29284740	Similar to Drosophila Asx, human ASXL1/2 complexes with BAP1 to deubiquitinate H2A ub1, thus providing evidence that an epigenetic modifier and associated proteins play a special role in modifying chromatin.	('chromatin', 'MPA', (197, 206))	('Asx', 'Gene', '36612', (22, 25))	('ASXL1/2', 'Gene', '171023;55252', (33, 40))	('ASXL1/2', 'Gene', (33, 40))	('human', 'Species', '9606', (27, 32))	('H2A', 'Gene', (79, 82))	('modifying', 'Reg', (187, 196))	('epigenetic', 'Var', (120, 130))	('Asx', 'Gene', (22, 25))	('Drosophila', 'Species', '7227', (11, 21))	('chromatin', 'cellular_component', 'GO:0000785', ('197', '206'))
137116	29284740	However, the mechanism by which cancer-related mutations in BAP1 and other PR-DUB genes and their encoded proteins/protein complexes has not been determined.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('mutations', 'Var', (47, 56))	('PR-DUB genes', 'Gene', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('BAP1', 'Gene', (60, 64))
137117	29284740	Mutations of ASXL1/2/3 genes leading to protein truncations have been found to associate with human cancers and other diseases.	('associate', 'Reg', (79, 88))	('ASXL1/2/3', 'Gene', (13, 22))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('Mutations', 'Var', (0, 9))	('human', 'Species', '9606', (94, 99))	('ASXL1/2/3', 'Gene', '171023;55252;80816', (13, 22))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('protein truncations', 'MPA', (40, 59))	('cancers', 'Disease', (100, 107))
137118	29284740	De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome, a severe malformation disorder, and de novo truncating mutations in ASXL3 result in a clinical phenotype with some similarities.	('ASXL3', 'Gene', (134, 139))	('malformation disorder', 'Disease', 'MESH:D000014', (75, 96))	('cause', 'Reg', (36, 41))	('malformation disorder', 'Disease', (75, 96))	('nonsense mutations', 'Var', (8, 26))	('Bohring-Opitz syndrome', 'Disease', 'MESH:C537419', (42, 64))	('Bohring-Opitz syndrome', 'Disease', (42, 64))	('ASXL1', 'Gene', (30, 35))	('truncating mutations', 'Var', (110, 130))	('ASXL3', 'Gene', '80816', (134, 139))
137119	29284740	Somatic mutations in ASXL1 in patients with myeloid disorders/leukemias are associated with adverse outcome.	('myeloid disorders', 'Disease', (44, 61))	('leukemias', 'Disease', 'MESH:D007938', (62, 71))	('leukemia', 'Phenotype', 'HP:0001909', (62, 70))	('leukemias', 'Phenotype', 'HP:0001909', (62, 71))	('associated', 'Reg', (76, 86))	('patients', 'Species', '9606', (30, 38))	('myeloid disorders', 'Disease', 'MESH:D007951', (44, 61))	('Somatic mutations', 'Var', (0, 17))	('leukemias', 'Disease', (62, 71))	('ASXL1', 'Gene', (21, 26))
137120	29284740	ASXL1 is an epigenetic modifier that plays a role in polycomb repressive complex 2 (PRC2)-mediated transcriptional repression in hematopoietic cells, and ASXL1 loss-of-function mutants in myeloid malignancies result in loss of PRC2-mediated gene repression of leukemogenic target genes.	('PRC2-mediated gene repression', 'MPA', (227, 256))	('mutants', 'Var', (177, 184))	('myeloid malignancies', 'Disease', 'MESH:D009369', (188, 208))	('loss', 'NegReg', (219, 223))	('ASXL1', 'Gene', (154, 159))	('loss-of-function', 'NegReg', (160, 176))	('myeloid malignancies', 'Disease', (188, 208))
137121	29284740	In this study, we define molecular mechanisms whereby tumor-derived, discrete in-frame deletions and insertions outside of the BAP1 catalytic domain perturb BAP1-ASXL2 interactions leading to tumor-related loss of BAP1 catalytic activity.	('tumor', 'Disease', (192, 197))	('catalytic activity', 'molecular_function', 'GO:0003824', ('219', '237'))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('perturb', 'NegReg', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('deletions', 'Var', (87, 96))	('BAP1', 'Enzyme', (214, 218))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', (54, 59))	('insertions', 'Var', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('BAP1-ASXL2 interactions', 'MPA', (157, 180))	('loss', 'NegReg', (206, 210))
137122	29284740	The pC3-BAP1-FL(6His), pC3-BAP1-FL,C91S(6His), pC3.1-Myc-BAP1, FL wild type (WT), and patient-related BAP1 mutations/deletions [C91W, S172R, D672G,  E283-S285,  E631-A634,  K637-C638(sub of N),  R666-H669] plasmids were constructed through PCR-based cloning.	('D672G', 'Var', (141, 146))	('K637-C638', 'Var', (173, 182))	('pC3', 'Gene', '57332', (23, 26))	('pC3', 'Gene', '57332', (47, 50))	('C91W', 'Var', (128, 132))	('pC3', 'Gene', (4, 7))	('C91S', 'Mutation', 'p.C91S', (35, 39))	('D672G', 'Mutation', 'p.D672G', (141, 146))	('patient', 'Species', '9606', (86, 93))	('S172R', 'Var', (134, 139))	('S172R', 'Mutation', 'p.S172R', (134, 139))	('Myc', 'Gene', (53, 56))	('R666-H669]', 'Var', (195, 205))	('BAP1', 'Gene', (102, 106))	('His', 'Chemical', 'MESH:D006639', (41, 44))	('pC3', 'Gene', '57332', (4, 7))	('His', 'Chemical', 'MESH:D006639', (17, 20))	('E631-A634', 'Var', (161, 170))	('C91W', 'SUBSTITUTION', 'None', (128, 132))	('E283-S285', 'Var', (149, 158))	('pC3', 'Gene', (23, 26))	('Myc', 'Gene', '4609', (53, 56))	('pC3', 'Gene', (47, 50))
137123	29284740	The nucleotide locations for these mutations, corresponding to those observed in uveal melanoma patients, are as follows: C91W(NT: T388G); S172R(NT: C631G); D672G(NT: A2130G); DeltaE283-S285(NT: 960-968 del); DeltaE631-A634(NT: 2006-2017 del); DeltaK637-C638 sub of N(NT: 2026-2028 del); and DeltaR666-H669(NT: 2112-2120 del).	('C91W', 'Var', (122, 126))	('DeltaR666', 'Var', (292, 301))	('D672G', 'Mutation', 'p.D672G', (157, 162))	('DeltaK637', 'Var', (244, 253))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('960-968 del', 'Mutation', 'c.960_968del', (195, 206))	('2006-2017 del', 'Mutation', 'c.2006_2017del', (228, 241))	('uveal melanoma', 'Disease', 'MESH:C536494', (81, 95))	('uveal melanoma', 'Disease', (81, 95))	('2112-2120 del', 'Mutation', 'c.2112_2120del', (311, 324))	('DeltaE631', 'DELETION', 'None', (209, 218))	('2026-2028 del', 'Mutation', 'c.2026_2028del', (272, 285))	('DeltaR666', 'DELETION', 'None', (292, 301))	('patients', 'Species', '9606', (96, 104))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('DeltaE631', 'Var', (209, 218))	('A2130G', 'Mutation', 'c.2130A>G', (167, 173))	('T388G', 'Mutation', 'rs758414333', (131, 136))	('S172R', 'Mutation', 'p.S172R', (139, 144))	('DeltaE283', 'Mutation', 'p.283delE', (176, 185))	('C631G', 'Mutation', 'rs1476052732', (149, 154))	('DeltaK637', 'DELETION', 'None', (244, 253))
137124	29284740	Note that the C91W mutation was originally reported as C91G, but was later corrected following discussions with staff affiliated with the COSMIC cancer database.	('cancer', 'Disease', (145, 151))	('C91G', 'Mutation', 'rs867696559', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('C91W', 'Var', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('C91W', 'SUBSTITUTION', 'None', (14, 18))
137125	29284740	The pEZ-M12-BAP1-WT and mutation/deletion plasmids were from AMB.	('mutation/deletion', 'Var', (24, 41))	('pEZ', 'Gene', (4, 7))	('pEZ', 'Gene', '5784', (4, 7))
137127	29284740	The pFastBacHTa-BAP1, FL WT, and mutations/deletions from patients [C91W, S172R, D672G,  E283-S285,  E631-A634,  K637-C638(sub of N),  R666-H669] constructs were sub-cloned from pC3.1-Myc-BAP1, FL WT, and mutations/deletions plasmids.	('D672G', 'Var', (81, 86))	('E631-A634', 'Var', (101, 110))	('C91W', 'Var', (68, 72))	('pC3', 'Gene', '57332', (178, 181))	('C91W', 'SUBSTITUTION', 'None', (68, 72))	('Myc', 'Gene', '4609', (184, 187))	('D672G', 'Mutation', 'p.D672G', (81, 86))	('S172R', 'Mutation', 'p.S172R', (74, 79))	('patients', 'Species', '9606', (58, 66))	('pC3', 'Gene', (178, 181))	('Myc', 'Gene', (184, 187))	('E283-S285', 'Var', (89, 98))
137131	29284740	Plasmids with the mutations pQE30-BAP1-ULD, L650P, or F660P were introduced using Quikchange site-directed mutagenesis (Stratagene).	('L650P', 'Mutation', 'p.L650P', (44, 49))	('F660P', 'Var', (54, 59))	('pQE30-BAP1-ULD', 'Var', (28, 42))	('F660P', 'Mutation', 'p.F660P', (54, 59))	('L650P', 'Var', (44, 49))	('mutagenesis', 'biological_process', 'GO:0006280', ('107', '118'))
137132	29284740	The pQE30-BAP1-ULD plasmids with mutations or deletions D72G,  E283-S285,  E631-A634,  K637-C638 (sub of N), or  R666-H669 were constructed via PCR-based cloning.	('E283-S285', 'Var', (63, 72))	('K637-C638', 'Var', (87, 96))	('D72G', 'Mutation', 'p.D72G', (56, 60))	('E631-A634', 'Var', (75, 84))	('R666-H669', 'Var', (113, 122))	('D72G', 'Var', (56, 60))
137134	29284740	The pQE30-ASXL2-AB mutations (R284P, VDR-AAA, NEF-AAA, ERL-AAA, EKE-AAA) were introduced by Quikchange site-directed mutagenesis (Stratagene).	('pQE30-ASXL2-AB', 'Gene', (4, 18))	('NEF', 'Gene', '6285', (46, 49))	('mutagenesis', 'biological_process', 'GO:0006280', ('117', '128'))	('VDR', 'Gene', (37, 40))	('R284P', 'Mutation', 'p.R284P', (30, 35))	('R284P', 'Var', (30, 35))	('VDR', 'Gene', '7421', (37, 40))	('NEF', 'Gene', (46, 49))
137135	29284740	The 35S-labeled BAP1-FL, ASXL2 (261-1435 aa), and ASXL2 (261-469aa) probes were produced by coupled in vitro transcription and translation (IVT) using TNT@T7 quick coupled transcription/translation system (Promega).	('BAP1-FL', 'Gene', (16, 23))	('261-469aa', 'Var', (57, 66))	('transcription', 'biological_process', 'GO:0006351', ('172', '185'))	('transcription', 'biological_process', 'GO:0006351', ('109', '122'))	('35S', 'Chemical', 'MESH:C000615320', (4, 7))	('translation', 'biological_process', 'GO:0006412', ('186', '197'))	('translation', 'biological_process', 'GO:0006412', ('127', '138'))
137141	29284740	Cleavage of Ub-AMC by wild type or BAP1 mutants or by co-expressed proteins, e.g., BAP1-ASXL2-AB (wild type and mutant forms) was assayed in reactions containing 5 nmol Ub-AMC and the indicated proteins or complexes.	('AMC', 'Chemical', '-', (172, 175))	('mutants', 'Var', (40, 47))	('Ub', 'Chemical', '-', (169, 171))	('AMC', 'Chemical', '-', (15, 18))	('Ub', 'Chemical', '-', (12, 14))	('BAP1', 'Gene', (35, 39))	('Cleavage', 'MPA', (0, 8))
137154	29284740	The sequence of the UCH domain of human BAP1 (Q92560) was blasted against the Protein Data Bank (pdb), which revealed structure 3a7s (of UCH-L5/UCH37) as the most homologous.	('human', 'Species', '9606', (34, 39))	('UCH-L5', 'Gene', '51377', (137, 143))	('UCH37', 'Gene', (144, 149))	('UCH37', 'Gene', '51377', (144, 149))	('UCH-L5', 'Gene', (137, 143))	('Q92560', 'Var', (46, 52))
137163	29284740	Mutations C91W and H169Q in the catalytic site of UCH were identified in uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (73, 88))	('C91W', 'SUBSTITUTION', 'None', (10, 14))	('uveal melanomas', 'Phenotype', 'HP:0007716', (73, 88))	('UCH', 'Gene', (50, 53))	('identified', 'Reg', (59, 69))	('uveal melanoma', 'Phenotype', 'HP:0007716', (73, 87))	('H169Q', 'Var', (19, 24))	('C91W', 'Var', (10, 14))	('uveal melanomas', 'Disease', (73, 88))	('H169Q', 'Mutation', 'p.H169Q', (19, 24))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))
137164	29284740	Other mutations/deletions/truncations in BAP1-UCH were found in uveal melanomas, mesothelioma and breast cancer, and were confirmed as loss-of-function changes leading to loss of enzymatic activity.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('BAP1-UCH', 'Gene', (41, 49))	('uveal melanomas', 'Disease', (64, 79))	('mutations/deletions/truncations', 'Var', (6, 37))	('uveal melanomas', 'Phenotype', 'HP:0007716', (64, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('mesothelioma', 'Disease', 'MESH:D008654', (81, 93))	('loss', 'NegReg', (171, 175))	('uveal melanomas', 'Disease', 'MESH:C536494', (64, 79))	('uveal melanoma', 'Phenotype', 'HP:0007716', (64, 78))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('enzymatic activity', 'MPA', (179, 197))	('loss-of-function', 'NegReg', (135, 151))	('mesothelioma', 'Disease', (81, 93))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))
137170	29284740	Many mutations/deletions/truncations in the ULD domain were identified in human cancers (Figure 1A).	('ULD', 'Gene', (44, 47))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('identified', 'Reg', (60, 70))	('human', 'Species', '9606', (74, 79))	('mutations/deletions/truncations', 'Var', (5, 36))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
137176	29284740	Several mutations in ASXL proteins have been found in myeloid leukemia and other disorders.	('ASXL', 'Chemical', '-', (21, 25))	('mutations', 'Var', (8, 17))	('leukemia', 'Phenotype', 'HP:0001909', (62, 70))	('myeloid leukemia', 'Disease', (54, 70))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (54, 70))	('ASXL', 'Gene', (21, 25))	('found', 'Reg', (45, 50))	('myeloid leukemia', 'Disease', 'MESH:D007951', (54, 70))
137177	29284740	However, the mechanism by which such mutations cause cancer and other diseases remains unclear.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cause', 'Reg', (47, 52))	('mutations', 'Var', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
137178	29284740	We investigated the molecular mechanism for the mutations/deletions occurring in either the N-terminus of UCH or in the C-terminus of ULD domain for inactivating BAP1 in cancer, as well as for mutations occurring in ASXL proteins (Figure 1A, 1B).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('inactivating', 'NegReg', (149, 161))	('mutations/deletions', 'Var', (48, 67))	('BAP1', 'Gene', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('ASXL', 'Chemical', '-', (216, 220))
137183	29284740	To test this hypothesis and to explain how mutations/deletions/truncations occurring in either ULD or UCH domains inactivate BAP1 in cancer, we used computer predicted molecular modeling of these proteins as a guide and biochemically characterized the protein-protein and/or domain-domain interactions of BAP1 and ASXL2 in vivo and in vitro using highly purified recombinant proteins, in coordination with BAP1 ubiquitin enzymatic activity.	('inactivate', 'NegReg', (114, 124))	('protein', 'cellular_component', 'GO:0003675', ('260', '267'))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('mutations/deletions/truncations', 'Var', (43, 74))	('BAP1', 'Gene', (125, 129))	('cancer', 'Disease', (133, 139))	('protein', 'cellular_component', 'GO:0003675', ('252', '259'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('411', '420'))	('protein-protein', 'Protein', (252, 267))	('domain-domain interactions', 'MPA', (275, 301))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
137185	29284740	Single-expressed BAP1 WT, C91S mutant, and ASXL2 proteins were soluble and easily affinity-purified either with Ni-NTA or ANTI-FLAG M2 Affinity Gels (Figure 2B).	('C91S mutant', 'Var', (26, 37))	('C91S', 'Mutation', 'p.C91S', (26, 30))	('soluble', 'cellular_component', 'GO:0005625', ('63', '70'))	('Ni-NTA', 'Chemical', '-', (112, 118))	('BAP1', 'Gene', (17, 21))
137196	29284740	We made mutations for these amino acids by either disrupting the helix structure (R284P in Helix 1) or by changing conserved amino acids to alanines on surfaces of helices (VDR-AAA, NEF-AAA, ERL-AAA, EKE-AAA in Helices 2, 3 and 4, respectively) (Figure 4A, B).	('VDR', 'Gene', (173, 176))	('disrupting', 'NegReg', (50, 60))	('R284P', 'Mutation', 'p.R284P', (82, 87))	('mutations', 'Var', (8, 17))	('helix structure', 'MPA', (65, 80))	('R284P', 'Var', (82, 87))	('NEF', 'Gene', (182, 185))	('changing', 'Reg', (106, 114))	('VDR', 'Gene', '7421', (173, 176))	('NEF', 'Gene', '6285', (182, 185))	('conserved', 'MPA', (115, 124))	('alanines', 'Chemical', 'MESH:D000409', (140, 148))
137197	29284740	Mutant AB box proteins (R284P: Helix 1; EKE-AAA: Helix 4) had intermediate effects on BAP1 binding, whereas VDR-AAA, NEF-AAA, and ERL-AAA (located in Helices 2 and 3) caused marked defects in BAP1 binding (Figure 4C, right), suggesting these conserved amino acids in helices of the AB box make direct contact with BAP1 and that mutations of these amino acids disrupt its interaction with BAP1.	('binding', 'molecular_function', 'GO:0005488', ('91', '98'))	('VDR', 'Gene', '7421', (108, 111))	('binding', 'Interaction', (91, 98))	('NEF', 'Gene', (117, 120))	('BAP1', 'Protein', (388, 392))	('interaction', 'Interaction', (371, 382))	('BAP1', 'Protein', (86, 90))	('R284P', 'Mutation', 'p.R284P', (24, 29))	('defects', 'NegReg', (181, 188))	('contact', 'Interaction', (301, 308))	('R284P', 'Var', (24, 29))	('NEF', 'Gene', '6285', (117, 120))	('disrupt', 'NegReg', (359, 366))	('Mutant', 'Var', (0, 6))	('BAP1', 'Protein', (192, 196))	('VDR', 'Gene', (108, 111))	('Helices 2 and 3', 'Phenotype', 'HP:0004691', (150, 165))	('mutations', 'Var', (328, 337))	('BAP1', 'Gene', (314, 318))	('binding', 'Interaction', (197, 204))	('binding', 'molecular_function', 'GO:0005488', ('197', '204'))
137199	29284740	However, mutations (VDR-AAA) and (NEF-AAA) of the AB box that failed to bind BAP1 coordinately lost the ability to stimulate BAP1 activity (Figure 4C, D).	('lost', 'NegReg', (95, 99))	('VDR', 'Gene', '7421', (20, 23))	('mutations', 'Var', (9, 18))	('BAP1 activity', 'MPA', (125, 138))	('NEF', 'Gene', (34, 37))	('VDR', 'Gene', (20, 23))	('NEF', 'Gene', '6285', (34, 37))	('stimulate', 'PosReg', (115, 124))
137201	29284740	To investigate how cancer-related mutations/deletions of BAP1 affect ASXL2 binding and BAP1 ubiquitin hydrolase activity, WT and mutant BAP1 proteins were produced in Bv and purified for ASXL2 binding in vitro.	('affect', 'Reg', (62, 68))	('binding', 'molecular_function', 'GO:0005488', ('193', '200'))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('ASXL2', 'MPA', (69, 74))	('cancer', 'Disease', (19, 25))	('mutations/deletions', 'Var', (34, 53))	('binding', 'molecular_function', 'GO:0005488', ('75', '82'))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('ubiquitin hydrolase activity', 'molecular_function', 'GO:0004843', ('92', '120'))	('activity', 'MPA', (112, 120))	('BAP1', 'Gene', (57, 61))
137202	29284740	BAP1 mutant S172R and BAP1 DeltaE631-A634, DeltaK637-C638, DeltaR666-H669 significant abolished ASXL2 protein binding in vitro (Figure 5A, B; Supplemental Figure 1), indicating that BAP1 harboring in-frame deletions in the ULD domain abolished ASXL binding.	('ASXL', 'Chemical', '-', (96, 100))	('mutant S172R', 'Var', (5, 17))	('ASXL', 'MPA', (244, 248))	('BAP1', 'Gene', (0, 4))	('DeltaR666', 'Var', (59, 68))	('DeltaK637', 'DELETION', 'None', (43, 52))	('ASXL', 'Chemical', '-', (244, 248))	('DeltaK637', 'Var', (43, 52))	('BAP1', 'Gene', (182, 186))	('DeltaE631', 'DELETION', 'None', (27, 36))	('protein binding', 'molecular_function', 'GO:0005515', ('102', '117'))	('abolished', 'NegReg', (86, 95))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('ASXL2 protein', 'MPA', (96, 109))	('BAP1', 'Gene', (22, 26))	('binding', 'molecular_function', 'GO:0005488', ('249', '256'))	('abolished', 'NegReg', (234, 243))	('DeltaE631', 'Var', (27, 36))	('DeltaR666', 'DELETION', 'None', (59, 68))	('S172R', 'Mutation', 'p.S172R', (12, 17))	('deletions', 'Var', (206, 215))
137204	29284740	Although the catalytically dead BAP1 mutant C91W could bind to ASXL2, it showed no enzymatic activity.	('bind', 'Interaction', (55, 59))	('C91W', 'Var', (44, 48))	('BAP1', 'Gene', (32, 36))	('C91W', 'SUBSTITUTION', 'None', (44, 48))
137210	29284740	To test this hypothesis, two mutations (L650P, F660P) located in the middle of the long helix were individually introduced into the ULD motif.	('L650P', 'Mutation', 'p.L650P', (40, 45))	('F660P', 'Var', (47, 52))	('L650P', 'Var', (40, 45))	('F660P', 'Mutation', 'p.F660P', (47, 52))
137211	29284740	Surprisingly, L650P and F660P mutants did not affect UCH binding; however, they did abolish AB box binding (Supplemental Figure 3), suggesting that the interface of the AB box is on the long helix of ULD and that disruption of this helix disassociates binding to the AB box.	('binding', 'molecular_function', 'GO:0005488', ('99', '106'))	('F660P', 'Mutation', 'p.F660P', (24, 29))	('L650P', 'Var', (14, 19))	('disruption', 'Var', (213, 223))	('disassociates', 'NegReg', (238, 251))	('AB box', 'Protein', (92, 98))	('abolish', 'NegReg', (84, 91))	('binding', 'molecular_function', 'GO:0005488', ('252', '259'))	('L650P', 'Mutation', 'p.L650P', (14, 19))	('F660P', 'Var', (24, 29))	('binding', 'Interaction', (99, 106))	('binding', 'molecular_function', 'GO:0005488', ('57', '64'))	('binding', 'Interaction', (252, 259))
137214	29284740	Therefore, GST-UCH association assays were carried out with purified BAP1 ULD WT and mutant proteins and ASXL2-AB.	('mutant', 'Var', (85, 91))	('BAP1', 'Gene', (69, 73))	('ULD WT', 'Disease', 'MESH:D020194', (74, 80))	('ULD WT', 'Disease', (74, 80))
137215	29284740	BAP1 ULD mutants D672G and K637-C638 slightly decreased UCH binding but significantly decreased AB box association.	('D672G', 'Mutation', 'p.D672G', (17, 22))	('AB box', 'Protein', (96, 102))	('UCH', 'Protein', (56, 59))	('BAP1', 'Gene', (0, 4))	('binding', 'molecular_function', 'GO:0005488', ('60', '67'))	('D672G', 'Var', (17, 22))	('K637-C638', 'Var', (27, 36))	('decreased', 'NegReg', (86, 95))	('decreased', 'NegReg', (46, 55))
137216	29284740	We also investigated the molecular mechanism underlying loss-of-function mutations/deletions affecting BAP1 and the BAP1-ASXL2 complex that contribute to tumor susceptibility and progression in patients with mesothelioma, uveal melanoma, and other cancers.	('cancers', 'Disease', (248, 255))	('cancers', 'Disease', 'MESH:D009369', (248, 255))	('patients', 'Species', '9606', (194, 202))	('mesothelioma', 'Disease', 'MESH:D008654', (208, 220))	('BAP1', 'Gene', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('uveal melanoma', 'Disease', 'MESH:C536494', (222, 236))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('loss-of-function', 'NegReg', (56, 72))	('mutations/deletions', 'Var', (73, 92))	('uveal melanoma', 'Disease', (222, 236))	('uveal melanoma', 'Phenotype', 'HP:0007716', (222, 236))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('mesothelioma', 'Disease', (208, 220))	('tumor', 'Disease', (154, 159))
137217	29284740	Third, cancer-derived mutations/deletions in the BAP1-ULD abolish ASXL2 binding and thereby result in loss of ASXL2's ability to stimulate BAP1 activity.	('stimulate', 'PosReg', (129, 138))	('mutations/deletions', 'Var', (22, 41))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('ASXL2', 'MPA', (110, 115))	('BAP1 activity', 'MPA', (139, 152))	('ASXL2', 'Protein', (66, 71))	('binding', 'Interaction', (72, 79))	('binding', 'molecular_function', 'GO:0005488', ('72', '79'))	('loss', 'NegReg', (102, 106))	('cancer', 'Disease', (7, 13))	('BAP1-ULD', 'Gene', (49, 57))	('abolish', 'NegReg', (58, 65))	('ability', 'MPA', (118, 125))
137220	29284740	Alterations in the ULD domain of BAP1 occurring in cancers failed to recruit the ASXL2-AB box to the UCH catalytic site, such that BAP1 deubiquitin hydrolase activity was dramatically reduced.	('hydrolase activity', 'molecular_function', 'GO:0016787', ('148', '166'))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('reduced', 'NegReg', (184, 191))	('BAP1 deubiquitin hydrolase activity', 'MPA', (131, 166))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('BAP1', 'Gene', (33, 37))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('failed', 'NegReg', (59, 65))
137226	29284740	Surprisingly, BAP1 mutations L650P and F660P, within the long helix of ULD (Figure 6A-C), did not interfere with UCH binding, but did abolish association with the AB box.	('AB box', 'Protein', (163, 169))	('L650P', 'Mutation', 'p.L650P', (29, 34))	('interfere', 'NegReg', (98, 107))	('F660P', 'Var', (39, 44))	('BAP1', 'Gene', (14, 18))	('mutations L650P', 'Var', (19, 34))	('association', 'Interaction', (142, 153))	('UCH', 'Protein', (113, 116))	('binding', 'molecular_function', 'GO:0005488', ('117', '124'))	('abolish', 'NegReg', (134, 141))	('L650P', 'Var', (29, 34))	('F660P', 'Mutation', 'p.F660P', (39, 44))
137227	29284740	Both mutations (L650P, F660P) were predicted to kink the long helix of ULD and disrupt UCH binding.	('L650P', 'Mutation', 'p.L650P', (16, 21))	('F660P', 'Var', (23, 28))	('UCH', 'Protein', (87, 90))	('disrupt', 'NegReg', (79, 86))	('kink', 'NegReg', (48, 52))	('binding', 'molecular_function', 'GO:0005488', ('91', '98'))	('long helix', 'MPA', (57, 67))	('F660P', 'Mutation', 'p.F660P', (23, 28))	('L650P', 'Var', (16, 21))
137228	29284740	Furthermore, we discovered a novel loss-of-function mechanism by which BAP1 mutations/deletions occur in cancer.	('loss-of-function', 'NegReg', (35, 51))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mutations/deletions', 'Var', (76, 95))	('BAP1', 'Gene', (71, 75))
137229	29284740	These mutations/deletions affect the interface of BAP1 with either ASXL-AB or UCH.	('interface', 'MPA', (37, 46))	('affect', 'Reg', (26, 32))	('mutations/deletions', 'Var', (6, 25))	('ASXL-AB', 'Chemical', '-', (67, 74))	('BAP1', 'Gene', (50, 54))
137235	29284740	Based on our studies, we propose a working model for the mechanism of germline and/or somatic loss of BAP1 that increases susceptibility to various cancers.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('BAP1', 'Gene', (102, 106))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('loss', 'Var', (94, 98))	('increases', 'PosReg', (112, 121))	('susceptibility', 'MPA', (122, 136))
137238	29284740	When mutations/deletions occur in BAP1, either they cause enzymatic loss-of-function of BAP1 or abolish BAP1's association with ASXL.	('loss-of-function', 'NegReg', (68, 84))	('BAP1', 'Gene', (34, 38))	('mutations/deletions', 'Var', (5, 24))	('ASXL', 'Chemical', '-', (128, 132))	('BAP1', 'Gene', (104, 108))	('association', 'Interaction', (111, 122))	('ASXL', 'MPA', (128, 132))	('BAP1', 'Gene', (88, 92))	('abolish', 'NegReg', (96, 103))
137239	29284740	Loss of binding to ASXL would dramatically decrease BAP1 deubiquitination activity, because of inability to bring ASXL to BAP1's catalytic site (e.g., deletions in the ULD domain: E631-A634 del and K637-C638 del).	('C638 del', 'Mutation', 'c.638delC', (203, 211))	('binding', 'molecular_function', 'GO:0005488', ('8', '15'))	('decrease', 'NegReg', (43, 51))	('deubiquitination', 'biological_process', 'GO:0016579', ('57', '73'))	('E631-A634 del', 'Mutation', 'p.631,634delA', (180, 193))	('K637-C638 del', 'Var', (198, 211))	('Loss', 'NegReg', (0, 4))	('ASXL', 'Chemical', '-', (19, 23))	('binding', 'Interaction', (8, 15))	('ASXL', 'Chemical', '-', (114, 118))	('BAP1 deubiquitination activity', 'MPA', (52, 82))	('E631-A634 del', 'Var', (180, 193))
137240	29284740	On the other hand, products of ASXL gene mutations that lose association with BAP1 also lead to BAP1 loss-of-function.	('mutations', 'Var', (41, 50))	('ASXL', 'Gene', (31, 35))	('BAP1', 'Gene', (96, 100))	('ASXL', 'Chemical', '-', (31, 35))	('loss-of-function', 'NegReg', (101, 117))	('BAP1', 'Gene', (78, 82))
137241	29284740	These mutations occur in highly conserved amino acids of the ASXL-AB box, the minimal domain required for BAP1 interaction.	('ASXL-AB', 'Chemical', '-', (61, 68))	('occur', 'Reg', (16, 21))	('mutations', 'Var', (6, 15))
137243	29284740	We have also elucidated a molecular mechanism for certain naturally occurring loss-of-function BAP1 mutations/deletions in cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('BAP1', 'Gene', (95, 99))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('mutations/deletions', 'Var', (100, 119))	('loss-of-function', 'NegReg', (78, 94))
137244	29284740	Drosophila Calypso-Asx and human BAP1-ASXL2 complexes deubiquitinate H2A ub1, and mutations in chromatin modifying enzymes such as BAP1 are implicated in the epigenetic deregulation that occurs commonly in human cancers.	('BAP1', 'Gene', (131, 135))	('epigenetic deregulation', 'MPA', (158, 181))	('H2A ub1', 'Protein', (69, 76))	('chromatin', 'cellular_component', 'GO:0000785', ('95', '104'))	('human', 'Species', '9606', (206, 211))	('Asx', 'Gene', '36612', (19, 22))	('human', 'Species', '9606', (27, 32))	('deubiquitinate', 'MPA', (54, 68))	('implicated', 'Reg', (140, 150))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('mutations', 'Var', (82, 91))	('Drosophila Calypso', 'Disease', 'None', (0, 18))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('Drosophila Calypso', 'Disease', (0, 18))	('cancers', 'Disease', (212, 219))	('Asx', 'Gene', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
137247	29284740	Further epigenomic studies of human malignancies will likely uncover novel routes to malignant transformation, and therapeutic strategies that reverse epigenetic changes might be of benefit in patients with mutations in epigenetic regulators.	('human', 'Species', '9606', (30, 35))	('patients', 'Species', '9606', (193, 201))	('malignancies', 'Disease', (36, 48))	('mutations', 'Var', (207, 216))	('malignancies', 'Disease', 'MESH:D009369', (36, 48))	('malignant transformation', 'CPA', (85, 109))
137248	29464063	Combined inhibition of CDK and HDAC as a promising therapeutic strategy for both cutaneous and uveal metastatic melanoma Very little to no improvement in overall survival has been seen in patients with advanced non-resectable cutaneous melanoma or metastatic uveal melanoma in decades, highlighting the need for novel therapeutic options.	('uveal melanoma', 'Phenotype', 'HP:0007716', (259, 273))	('patients', 'Species', '9606', (188, 196))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('melanoma', 'Disease', 'MESH:D008545', (236, 244))	('inhibition', 'Var', (9, 19))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('cutaneous', 'Disease', (81, 90))	('cutaneous melanoma', 'Disease', (226, 244))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (226, 244))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (226, 244))	('CDK', 'Gene', (23, 26))	('HDAC', 'Gene', '9734', (31, 35))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('uveal metastatic melanoma', 'Phenotype', 'HP:0007716', (95, 120))	('melanoma', 'Disease', (236, 244))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('melanoma', 'Disease', (265, 273))	('HDAC', 'Gene', (31, 35))	('uveal melanoma', 'Disease', 'MESH:C536494', (259, 273))	('uveal melanoma', 'Disease', (259, 273))	('CDK', 'molecular_function', 'GO:0004693', ('23', '26'))
137251	29464063	This synergism was also observed in BRAFV600E mutant melanoma that had acquired resistance to BRAF inhibition.	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('BRAFV600E', 'Var', (36, 45))	('BRAFV600E', 'Mutation', 'rs113488022', (36, 45))
137252	29464063	The combination was also effectively inducing tumor regression in a preclinical setting, namely a patient-derived tumor xenograft (PDX) model of cutaneous melanoma, without increasing adverse effects.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('patient', 'Species', '9606', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('combination', 'Var', (4, 15))	('cutaneous melanoma', 'Disease', (145, 163))	('tumor', 'Disease', (46, 51))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (145, 163))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (145, 163))	('tumor', 'Disease', (114, 119))	('inducing', 'Reg', (37, 45))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
137257	29464063	CM is most commonly driven by oncogenic mutations in NRAS or BRAF; the latter spurred the development of mutant-specific BRAF inhibitors.	('CM', 'Phenotype', 'HP:0012056', (0, 2))	('NRAS', 'Gene', (53, 57))	('BRAF', 'Gene', (61, 65))	('mutations', 'Var', (40, 49))	('driven', 'Reg', (20, 26))	('NRAS', 'Gene', '4893', (53, 57))
137258	29464063	Although most patients with BRAF mutations initially respond well to BRAF inhibition, resistance and relapse inevitably occurs within 6 to 8 months.	('BRAF', 'Gene', (28, 32))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (33, 42))
137290	29464063	The flavopiridol-mediated increase in c-Myc is largely reversed by the addition of quisinostat in most cell lines, as indeed quisinostat in most cases reduces c-Myc levels.	('c-Myc', 'Gene', (38, 43))	('reduces', 'NegReg', (151, 158))	('c-Myc', 'Gene', '4609', (159, 164))	('c-Myc', 'Gene', (159, 164))	('quisinostat', 'Chemical', 'MESH:C541788', (125, 136))	('quisinostat', 'Chemical', 'MESH:C541788', (83, 94))	('c-Myc', 'Gene', '4609', (38, 43))	('flavopiridol', 'Chemical', 'MESH:C077990', (4, 16))	('quisinostat', 'Var', (125, 136))
137296	29464063	We observed no obvious changes in the cell cycle profiles of MM66, OMM1 and MEL202 upon flavopiridol treatment, whereas in OMM2.3 cells flavopiridol treatment resulted in a G1 cell cycle arrest and in MEL270 cells in a G2/M cell cycle arrest (Figure 2A and Supplementary Figure 3).	('flavopiridol', 'Chemical', 'MESH:C077990', (136, 148))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (176, 193))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('176', '193'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('224', '241'))	('G1 cell cycle arrest', 'CPA', (173, 193))	('cell cycle', 'biological_process', 'GO:0007049', ('38', '48'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (224, 241))	('flavopiridol', 'Chemical', 'MESH:C077990', (88, 100))	('flavopiridol', 'Var', (136, 148))	('G2/M cell cycle arrest', 'CPA', (219, 241))
137310	29464063	As observed in UM cell lines, in some CM cell lines concurrent HDAC and CDK inhibition could affect the molecular responses; reversal of flavopiridol induced c-Myc increase, more pronounced drop of RNA pol2-S2 and further increase of acetylated histone 3.	('reversal', 'Var', (125, 133))	('CDK', 'molecular_function', 'GO:0004693', ('72', '75'))	('RNA pol2-S2', 'MPA', (198, 209))	('c-Myc', 'Gene', (158, 163))	('flavopiridol', 'Gene', (137, 149))	('HDAC', 'Gene', (63, 67))	('CM', 'Phenotype', 'HP:0012056', (38, 40))	('affect', 'Reg', (93, 99))	('HDAC', 'Gene', '9734', (63, 67))	('acetylated histone 3', 'MPA', (234, 254))	('molecular responses', 'MPA', (104, 123))	('drop', 'NegReg', (190, 194))	('UM', 'Phenotype', 'HP:0007716', (15, 17))	('increase', 'PosReg', (222, 230))	('c-Myc', 'Gene', '4609', (158, 163))	('flavopiridol', 'Chemical', 'MESH:C077990', (137, 149))	('increase', 'PosReg', (164, 172))	('RNA', 'cellular_component', 'GO:0005562', ('198', '201'))
137327	29464063	Given that these cell lines carry different driver mutations, these data show that the induction of apoptosis in response to this combination is independent on the BRAF or NRAS mutational status.	('NRAS', 'Gene', '4893', (172, 176))	('NRAS', 'Gene', (172, 176))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('87', '109'))	('mutations', 'Var', (51, 60))
137343	29464063	For CM, advances have been made with respect to the optimization of mutated BRAF-targeting therapies, with or without MEK inhibitors, and immunotherapy has made it in some cases to first-line treatment.	('BRAF-targeting', 'Gene', (76, 90))	('CM', 'Phenotype', 'HP:0012056', (4, 6))	('MEK', 'Gene', (118, 121))	('mutated', 'Var', (68, 75))	('MEK', 'Gene', '5609', (118, 121))
137349	29464063	Quisinostat induces a G1 cell cycle arrest in tested UM cell lines, consistent with previous published results from Landreville et al..	('cell cycle arrest', 'biological_process', 'GO:0007050', ('25', '42'))	('Quisinostat', 'Chemical', 'MESH:C541788', (0, 11))	('UM', 'Phenotype', 'HP:0007716', (53, 55))	('G1 cell cycle arrest', 'CPA', (22, 42))	('Quisinostat', 'Var', (0, 11))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (25, 42))
137362	29464063	Based upon literature showing that both CDK9 and HDAC inhibition decrease expression of the anti-apoptotic protein MCL-1 and thereby stimulate apoptosis one could propose that the combination treatment further reduces MCL-1 levels.	('inhibition', 'Var', (54, 64))	('HDAC', 'Gene', (49, 53))	('stimulate', 'PosReg', (133, 142))	('CDK9', 'Gene', (40, 44))	('HDAC', 'Gene', '9734', (49, 53))	('MCL-1', 'Gene', '4170', (115, 120))	('MCL-1', 'Gene', (115, 120))	('reduces', 'NegReg', (210, 217))	('CDK', 'molecular_function', 'GO:0004693', ('40', '43'))	('CDK9', 'Gene', '1025', (40, 44))	('MCL-1', 'Gene', (218, 223))	('apoptosis', 'CPA', (143, 152))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('decrease', 'NegReg', (65, 73))	('MCL-1', 'Gene', '4170', (218, 223))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
137377	29464063	It seems unlikely that one mutation or epigenetic change is able to induce resistance to this combination, since quisinostat and flavopiridol inhibits multiple HDACs and CDKs.	('epigenetic change', 'Var', (39, 56))	('HDAC', 'Gene', (160, 164))	('inhibits', 'NegReg', (142, 150))	('quisinostat', 'Chemical', 'MESH:C541788', (113, 124))	('HDAC', 'Gene', '9734', (160, 164))	('CDKs', 'Gene', '983;1017;1019;1021;1022;1025;107951;51755', (170, 174))	('flavopiridol', 'Chemical', 'MESH:C077990', (129, 141))	('CDKs', 'Gene', (170, 174))
137418	29292745	The risk of metastasis correlates with certain chromosomal abnormalities within the tumour principally monosomy 3 and multiple copies of chromosome 8.	('chromosomal abnormalities within the tumour', 'Disease', (47, 90))	('metastasis', 'CPA', (12, 22))	('monosomy 3', 'Var', (103, 113))	('chromosomal abnormalities within the tumour', 'Disease', 'MESH:D001929', (47, 90))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('chromosome', 'cellular_component', 'GO:0005694', ('137', '147'))	('multiple copies of chromosome 8', 'Var', (118, 149))
137459	29292745	It is interesting to note that none of the patients reported developed significant pain or scleritis following PDT.	('pain', 'Disease', 'MESH:D010146', (83, 87))	('pain', 'Disease', (83, 87))	('scleritis', 'Disease', 'MESH:D015423', (91, 100))	('patients', 'Species', '9606', (43, 51))	('scleritis', 'Disease', (91, 100))	('PDT', 'Var', (111, 114))	('scleritis', 'Phenotype', 'HP:0100532', (91, 100))	('pain', 'Phenotype', 'HP:0012531', (83, 87))
137478	26940009	Instead of common occurence of BRAF or NRAS mutations in cutaneous melanoma, few cases of UM harbor BRAF and NRAS mutations.	('UM', 'Phenotype', 'HP:0007716', (90, 92))	('NRAS', 'Gene', (109, 113))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('NRAS', 'Gene', (39, 43))	('BRAF', 'Gene', '673', (100, 104))	('NRAS', 'Gene', '4893', (109, 113))	('mutations', 'Var', (44, 53))	('cutaneous melanoma', 'Disease', (57, 75))	('BRAF', 'Gene', '673', (31, 35))	('BRAF', 'Gene', (100, 104))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (57, 75))	('NRAS', 'Gene', '4893', (39, 43))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (57, 75))	('BRAF', 'Gene', (31, 35))
137479	26940009	Mutations in SF3B1 encoding subunit 1 of the splicing factor 3b protein which is a component of the U2 small nuclear ribonucleoprotein complex (snRNP) were observed to be associated with good prognosis and were rarely coexist with BAP1 mutations.	('small nuclear ribonucleoprotein', 'molecular_function', 'GO:0003734', ('103', '134'))	('snRNP', 'molecular_function', 'GO:0003734', ('144', '149'))	('SF3B1', 'Gene', (13, 18))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('small nuclear ribonucleoprotein complex', 'cellular_component', 'GO:0030532', ('103', '142'))	('BAP1', 'Gene', '8314', (231, 235))	('splicing', 'biological_process', 'GO:0045292', ('45', '53'))	('Mutations', 'Var', (0, 9))	('SF3B1', 'Gene', '23451', (13, 18))	('snRNP', 'cellular_component', 'GO:0030532', ('144', '149'))	('BAP1', 'Gene', (231, 235))	('associated', 'Reg', (171, 181))
137481	26940009	Recent mutational profiling studies of UM have identified mutually exclusive activating mutations (e.g., Q209 and R183) in the two G protein coupled receptor (GPCR) alpha subunits, GNAQ and GNA11, and these are driver mutations in more than 80% of profiled UM tumors.	('GNA11', 'Gene', (190, 195))	('R183', 'Var', (114, 118))	('Q209', 'Var', (105, 109))	('G protein coupled receptor', 'Gene', '151', (131, 157))	('GNAQ', 'Gene', '2776', (181, 185))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('GNA11', 'Gene', '2767', (190, 195))	('UM', 'Phenotype', 'HP:0007716', (257, 259))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('GNAQ', 'Gene', (181, 185))	('GPCR', 'Gene', '151', (159, 163))	('UM', 'Phenotype', 'HP:0007716', (39, 41))	('G protein coupled receptor', 'Gene', (131, 157))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('activating', 'PosReg', (77, 87))	('tumors', 'Disease', (260, 266))	('GPCR', 'Gene', (159, 163))
137484	26940009	Recently, it has been demonstrated that the activating mutations in GPCR can inhibit large tumor suppressor kinases LATS1/2 and promote actin polymerization, both of which can eventually trigger accumulation of dephosphorylated (active) YAP in the nucleus and YAP-dependent transcription.	('dephosphorylated', 'MPA', (211, 227))	('accumulation', 'PosReg', (195, 207))	('YAP', 'Gene', (237, 240))	('transcription', 'biological_process', 'GO:0006351', ('274', '287'))	('promote', 'PosReg', (128, 135))	('YAP', 'Gene', (260, 263))	('tumor', 'Disease', (91, 96))	('trigger', 'Reg', (187, 194))	('LATS1/2', 'Gene', '9113;26524', (116, 123))	('inhibit', 'NegReg', (77, 84))	('GPCR', 'Gene', (68, 72))	('actin polymerization', 'biological_process', 'GO:0030041', ('136', '156'))	('nucleus', 'cellular_component', 'GO:0005634', ('248', '255'))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('LATS1/2', 'Gene', (116, 123))	('YAP', 'Gene', '10413', (237, 240))	('actin polymerization', 'MPA', (136, 156))	('mutations', 'Var', (55, 64))	('YAP', 'Gene', '10413', (260, 263))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('activating', 'PosReg', (44, 54))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('91', '107'))	('GPCR', 'Gene', '151', (68, 72))	('tumor suppressor', 'biological_process', 'GO:0051726', ('91', '107'))
137487	26940009	Pan-HDAC inhibitors (HDACis) (e.g., Valproic acid, trichostatin A, LBH589), and Class II-specific HDACis (e.g., MC1586, MC1575) have showed potent antitumor activity in UM.	('HDAC', 'Gene', '9734', (4, 8))	('HDAC', 'Gene', '9734', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('UM', 'Phenotype', 'HP:0007716', (169, 171))	('tumor', 'Disease', (151, 156))	('LBH589', 'Chemical', 'MESH:D000077767', (67, 73))	('Valproic acid', 'Chemical', 'MESH:D014635', (36, 49))	('HDAC', 'Gene', (98, 102))	('HDAC', 'Gene', '9734', (98, 102))	('trichostatin A', 'Chemical', 'MESH:C012589', (51, 65))	('HDAC', 'Gene', (4, 8))	('HDAC', 'Gene', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('MC1575', 'Var', (120, 126))
137489	26940009	Overexpression of SIRT1/2 has been shown to predict poor prognosis in a wide variety of solid tumors such as pancreatic cancer, non-small cell lung cancer, and malignant hematological diseases such as chronic myeloid leukemia and acute lymphoblastic leukemia.	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (230, 258))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (132, 154))	('solid tumors', 'Disease', 'MESH:D009369', (88, 100))	('malignant hematological diseases', 'Disease', 'MESH:D019337', (160, 192))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('SIRT1/2', 'Gene', (18, 25))	('Overexpression', 'Var', (0, 14))	('pancreatic cancer', 'Disease', (109, 126))	('chronic myeloid leukemia', 'Disease', (201, 225))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (128, 154))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (236, 258))	('non-small cell lung cancer', 'Disease', (128, 154))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (109, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (201, 225))	('solid tumors', 'Disease', (88, 100))	('leukemia', 'Phenotype', 'HP:0001909', (250, 258))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (201, 225))	('SIRT1/2', 'Gene', '23411;22933', (18, 25))	('acute lymphoblastic leukemia', 'Disease', (230, 258))	('malignant hematological diseases', 'Disease', (160, 192))	('leukemia', 'Phenotype', 'HP:0001909', (217, 225))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (209, 225))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (128, 154))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (230, 258))	('pancreatic cancer', 'Disease', 'MESH:D010190', (109, 126))
137492	26940009	In the present study, we hypothesized that SIRT1/2 was critical in controlling the destiny of bulk tumor cells and cancer stem cells (CSCs) of UM, and that inhibiting SIRT1/2 by Tenovin-6 might result in apoptosis in UM cells by releasing expression of tumor suppressor genes such as p53 and elevating reactive oxygen species (ROS).	('SIRT1/2', 'Gene', (43, 50))	('elevating', 'PosReg', (292, 301))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('apoptosis', 'biological_process', 'GO:0097194', ('204', '213'))	('apoptosis', 'biological_process', 'GO:0006915', ('204', '213'))	('elevating reactive oxygen species', 'Phenotype', 'HP:0025464', (292, 325))	('ROS', 'Chemical', 'MESH:D017382', (327, 330))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (302, 325))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('UM', 'Phenotype', 'HP:0007716', (217, 219))	('apoptosis', 'CPA', (204, 213))	('tumor', 'Disease', (99, 104))	('SIRT1/2', 'Gene', (167, 174))	('result in', 'Reg', (194, 203))	('releasing', 'PosReg', (229, 238))	('p53', 'Gene', '7157', (284, 287))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('253', '269'))	('expression', 'MPA', (239, 249))	('inhibiting', 'Var', (156, 166))	('p53', 'Gene', (284, 287))	('tumor', 'Disease', (253, 258))	('SIRT1/2', 'Gene', '23411;22933', (43, 50))	('tumor suppressor', 'biological_process', 'GO:0051726', ('253', '269'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('UM', 'Phenotype', 'HP:0007716', (143, 145))	('cancer', 'Disease', (115, 121))	('Tenovin-6', 'Chemical', 'MESH:C574854', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('reactive oxygen species', 'MPA', (302, 325))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('SIRT1/2', 'Gene', '23411;22933', (167, 174))
137554	26940009	7D) were strikingly lower in 92.1and Mel 270 cells treated with Tenovin-6 compared with those in the untreated control cells.	('Tenovin-6', 'Chemical', 'MESH:C574854', (64, 73))	('lower', 'NegReg', (20, 25))	('Tenovin-6', 'Var', (64, 73))
137563	26940009	In contrast to other tumor types, mutation of tumor suppress gene p53 is not common in UM.	('p53', 'Gene', '7157', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (21, 26))	('UM', 'Phenotype', 'HP:0007716', (87, 89))	('mutation', 'Var', (34, 42))	('tumor', 'Disease', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('p53', 'Gene', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
137620	24039721	Membrane disruption and loss of cellular capacitance were also associated with significant reduction in total tumor impedance and loss of impedance frequency dependence.	('impedance frequency dependence', 'MPA', (138, 168))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('loss', 'NegReg', (24, 28))	('reduction', 'NegReg', (91, 100))	('loss', 'NegReg', (130, 134))	('cellular capacitance', 'MPA', (32, 52))	('Membrane disruption', 'Var', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
137625	24039721	Brachytherapy, the most common globe sparing treatment modality for uveal melanoma, is delivered via radioactive plaques, mostly Ruthenium-106 (Europe) or Iodine-125 (USA).	('Ruthenium-106', 'Var', (129, 142))	('Iodine-125', 'Chemical', 'MESH:C000614960', (155, 165))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('uveal melanoma', 'Disease', 'MESH:C536494', (68, 82))	('Ruthenium-106', 'Chemical', 'MESH:C000615522', (129, 142))	('uveal melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('uveal melanoma', 'Disease', (68, 82))	('Iodine-125', 'Var', (155, 165))
137656	24039721	Ablation caused distinct histopathological features suggestive of cell membrane permeation and rupture.	('cell membrane', 'cellular_component', 'GO:0005886', ('66', '79'))	('Ablation', 'Var', (0, 8))	('rupture', 'Disease', 'MESH:D012421', (95, 102))	('rupture', 'Disease', (95, 102))	('cell membrane permeation', 'CPA', (66, 90))
137701	21730846	Novel pathogenic mitochondrial DNA mutations continue to be detected in diverse ethnic populations for primary mitochondrial ophthalmologic disorders that common affect the optic nerve, retina, and extraocular muscles.	('mitochondrial DNA', 'Gene', (17, 34))	('mitochondrial ophthalmologic disorders', 'Disease', 'MESH:D028361', (111, 149))	('pathogenic', 'Reg', (6, 16))	('mitochondrial ophthalmologic disorders', 'Disease', (111, 149))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('17', '34'))	('mutations', 'Var', (35, 44))
137712	21730846	Primary mitochondrial diseases result from direct impairment of mitochondrial functions by genes located in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA).	('nuclear', 'Disease', (144, 151))	('mitochondrial functions', 'MPA', (64, 87))	('mtDNA', 'cellular_component', 'GO:0000262', ('134', '139'))	('Primary mitochondrial diseases', 'Disease', 'MESH:D028361', (0, 30))	('mitochondrial DNA', 'Disease', (115, 132))	('Primary mitochondrial diseases', 'Disease', (0, 30))	('men', 'Species', '9606', (56, 59))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('115', '132'))	('genes located', 'Var', (91, 104))	('DNA', 'cellular_component', 'GO:0005574', ('152', '155'))	('impairment', 'NegReg', (50, 60))
137717	21730846	To further complicate matters, mutations in a given mitochondrial disease gene may be associated with a spectrum of different clinical phenotypes.	('mutations', 'Var', (31, 40))	('mitochondrial disease', 'Disease', 'MESH:D028361', (52, 73))	('associated', 'Reg', (86, 96))	('mitochondrial disease', 'Disease', (52, 73))
137719	21730846	Thinning of the neuroretinal rim appears to be a universal finding in DOA, with occasional findings including "saucerization" of the disc, a cup to disc ratio exceeding 0.5, and peripapillary atrophy.	('neuroretinal rim', 'Disease', 'MESH:D012173', (16, 32))	('neuroretinal rim', 'Disease', (16, 32))	('peripapillary atrophy', 'Disease', (178, 199))	('rat', 'Species', '10116', (153, 156))	('peripapillary atrophy', 'Phenotype', 'HP:0500087', (178, 199))	('peripapillary atrophy', 'Disease', 'MESH:C566898', (178, 199))	('DOA', 'Disease', (70, 73))	('Thinning', 'Var', (0, 8))
137720	21730846	In contrast, mutations in a mitochondrial-localized gene of unknown function, OPA3, have been identified in only two kindreds with familial optic atrophy, premature cataracts, and 3-methylglutaconic aciduria.	('aciduria', 'Phenotype', 'HP:0012072', (199, 207))	('familial optic atrophy', 'Disease', 'MESH:D015418', (131, 153))	('OPA3', 'Gene', (78, 82))	('OPA3', 'Gene', '80207', (78, 82))	('optic atrophy', 'Phenotype', 'HP:0000648', (140, 153))	('cataracts', 'Phenotype', 'HP:0000518', (165, 174))	('identified', 'Reg', (94, 104))	('premature cataracts', 'Disease', 'MESH:D002386', (155, 174))	('3-methylglutaconic aciduria', 'Phenotype', 'HP:0003535', (180, 207))	('mutations', 'Var', (13, 22))	('premature cataracts', 'Disease', (155, 174))	('3-methylglutaconic', 'MPA', (180, 198))	('familial optic atrophy', 'Disease', (131, 153))
137722	21730846	OPA1 mutations can cause mitochondrial disease even in the absence of optic atrophy.	('cause', 'Reg', (19, 24))	('mitochondrial disease', 'Disease', 'MESH:D028361', (25, 46))	('optic atrophy', 'Phenotype', 'HP:0000648', (70, 83))	('mutations', 'Var', (5, 14))	('OPA1', 'Gene', (0, 4))	('optic atrophy', 'Disease', (70, 83))	('mitochondrial disease', 'Disease', (25, 46))	('optic atrophy', 'Disease', 'MESH:D009896', (70, 83))
137723	21730846	A recent retrospective study that evaluated the efficacy of genetic diagnostic testing among 38 individuals with an autosomal dominant family history of optic atrophy and 150 sporadic cases of bilateral optic atrophy identified OPA1 mutations in approximately 14% of the patient cohort, whereas OPA3 mutations were not found in any cases of isolated optic atrophy.	('bilateral optic atrophy', 'Disease', (193, 216))	('optic atrophy', 'Disease', (153, 166))	('OPA1', 'Gene', (228, 232))	('optic atrophy', 'Disease', 'MESH:D009896', (153, 166))	('OPA3', 'Gene', '80207', (295, 299))	('OPA3', 'Gene', (295, 299))	('patient', 'Species', '9606', (271, 278))	('optic atrophy', 'Phenotype', 'HP:0000648', (153, 166))	('optic atrophy', 'Disease', (350, 363))	('optic atrophy', 'Disease', 'MESH:D009896', (350, 363))	('optic atrophy', 'Disease', 'MESH:D009896', (203, 216))	('bilateral optic atrophy', 'Disease', 'MESH:D009896', (193, 216))	('optic atrophy', 'Phenotype', 'HP:0000648', (350, 363))	('mutations', 'Var', (233, 242))	('optic atrophy', 'Phenotype', 'HP:0000648', (203, 216))
137724	21730846	The rate of detecting OPA1 mutations was 50% among individuals with a family history of visual failure compared to 5.3% of sporadic cases.	('mutations', 'Var', (27, 36))	('OPA1', 'Gene', (22, 26))	('visual failure', 'Disease', (88, 102))	('visual failure', 'Disease', 'MESH:D014786', (88, 102))	('rat', 'Species', '10116', (4, 7))	('visual failure', 'Phenotype', 'HP:0000505', (88, 102))
137725	21730846	These studies highlight the particular utility of testing for OPA1 mutations in individuals with a family history of optic atrophy.	('testing', 'Reg', (50, 57))	('mutations', 'Var', (67, 76))	('optic atrophy', 'Disease', (117, 130))	('OPA1', 'Gene', (62, 66))	('optic atrophy', 'Phenotype', 'HP:0000648', (117, 130))	('optic atrophy', 'Disease', 'MESH:D009896', (117, 130))
137726	21730846	The mechanism by which OPA1 causes ophthalmologic disease was explored in a heterozygous Opa1 mutant mouse model that develops visual dysfunction and structural changes in the retina and optic nerve.	('ophthalmologic disease', 'Disease', 'MESH:C536647', (35, 57))	('structural changes', 'CPA', (150, 168))	('ophthalmologic disease', 'Disease', (35, 57))	('visual dysfunction', 'Disease', 'MESH:D014786', (127, 145))	('mouse', 'Species', '10090', (101, 106))	('visual dysfunction', 'Disease', (127, 145))	('mutant', 'Var', (94, 100))	('develops', 'Reg', (118, 126))	('Opa1', 'Gene', (89, 93))	('Opa1', 'Gene', '74143', (89, 93))
137728	21730846	Characterized by acute and painless central vision loss of both eyes in a sequential fashion over a period of days to months, LHON was the first maternally-inherited ophthalmologic disorder to be linked to a point mutation in mitochondrial DNA.	('linked', 'Reg', (196, 202))	('acute and painless central vision loss', 'Phenotype', 'HP:0001117', (17, 55))	('painless central vision loss of both eyes', 'Disease', 'MESH:D054062', (27, 68))	('vision loss', 'Phenotype', 'HP:0000572', (44, 55))	('LHON', 'Disease', (126, 130))	('painless central vision', 'Phenotype', 'HP:0007994', (27, 50))	('painless central vision loss of both eyes', 'Disease', (27, 68))	('vision', 'biological_process', 'GO:0007601', ('44', '50'))	('inherited ophthalmologic disorder', 'Disease', 'MESH:D030342', (156, 189))	('point mutation', 'Var', (208, 222))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('226', '243'))	('inherited ophthalmologic disorder', 'Disease', (156, 189))	('mitochondrial DNA', 'Gene', (226, 243))
137729	21730846	Three mtDNA point mutations within mitochondrial respiratory chain complex I subunit genes (G11778A in ND4, G3460A in ND1, and T14484C in ND6) collectively cause 95% of LHON cases.	('mtDNA', 'cellular_component', 'GO:0000262', ('6', '11'))	('cause', 'Reg', (156, 161))	('ND4', 'Gene', (103, 106))	('G3460A', 'Var', (108, 114))	('ND1', 'Gene', '4535', (118, 121))	('T14484C', 'Mutation', 'g.14484T>C', (127, 134))	('ND6', 'Gene', (138, 141))	('mitochondrial respiratory chain complex I', 'cellular_component', 'GO:0005747', ('35', '76'))	('T14484C', 'Var', (127, 134))	('G11778A', 'Var', (92, 99))	('ND1', 'Gene', (118, 121))	('rat', 'Species', '10116', (54, 57))	('ND6', 'Gene', '4541', (138, 141))	('LHON cases', 'Disease', (169, 179))	('G3460A', 'Mutation', 'rs1249252076', (108, 114))	('G11778A', 'Mutation', 'g.11778G>A', (92, 99))	('ND4', 'Gene', '4538', (103, 106))
137730	21730846	Other pathogenic mtDNA mutations continue to be identified, particularly among non-Caucasian ethnic groups, such as the recently identified mtDNA T12338C mutation in ND5 that appears to be common in Han Chinese.	('T12338C', 'Mutation', 'g.12338T>C', (146, 153))	('mtDNA', 'cellular_component', 'GO:0000262', ('140', '145'))	('T12338C', 'Var', (146, 153))	('ND5', 'Gene', '4540', (166, 169))	('mtDNA', 'cellular_component', 'GO:0000262', ('17', '22'))	('ND5', 'Gene', (166, 169))	('pathogenic', 'Reg', (6, 16))
137732	21730846	A recent genome-wide expression profiling study in LHON patient leukocytes found that the G11778A mutation downregulates OPA1 expression, which the authors postulated might result in a fragmented mitochondrial network, dissipation of the mitochondrial membrane potential, and disorganization of the cristae structure of optic nerve mitochondria.	('fragmented', 'NegReg', (185, 195))	('mitochondrial network', 'CPA', (196, 217))	('men', 'Species', '9606', (189, 192))	('cristae', 'cellular_component', 'GO:0030061', ('299', '306'))	('expression', 'MPA', (126, 136))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('238', '260'))	('G11778A', 'Mutation', 'g.11778G>A', (90, 97))	('mitochondria', 'cellular_component', 'GO:0005739', ('332', '344'))	('disorganization', 'NegReg', (276, 291))	('downregulates', 'NegReg', (107, 120))	('patient', 'Species', '9606', (56, 63))	('OPA1', 'Gene', (121, 125))	('G11778A', 'Var', (90, 97))	('dissipation', 'MPA', (219, 230))
137734	21730846	It has been known for some time that the T14484C mutation in ND6 is associated with a more favorable prognosis and spontaneous recovery of vision in some individuals.	('T14484C', 'Var', (41, 48))	('T14484C', 'Mutation', 'g.14484T>C', (41, 48))	('ND6', 'Gene', '4541', (61, 64))	('vision', 'biological_process', 'GO:0007601', ('139', '145'))	('ND6', 'Gene', (61, 64))
137735	21730846	In the Han Chinese population, a mtDNA T14502C variant in ND6 increases the clinical penetrance of LHON in patients who have the classic mtDNA G11778A mutation in ND4.	('LHON', 'Disease', (99, 103))	('ND4', 'Gene', (163, 166))	('ND4', 'Gene', '4538', (163, 166))	('G11778A', 'Mutation', 'g.11778G>A', (143, 150))	('increases', 'PosReg', (62, 71))	('T14502C', 'Var', (39, 46))	('clinical penetrance', 'MPA', (76, 95))	('ND6', 'Gene', '4541', (58, 61))	('mtDNA', 'cellular_component', 'GO:0000262', ('137', '142'))	('mtDNA', 'cellular_component', 'GO:0000262', ('33', '38'))	('T14502C', 'Mutation', 'g.14502T>C', (39, 46))	('patients', 'Species', '9606', (107, 115))	('ND6', 'Gene', (58, 61))
137736	21730846	A recent epidemiological study of 196 affected and 206 unaffected carriers from 125 LHON pedigrees that carry one of the three LHON primary mtDNA mutations, found a strong association between visual loss and smoking that was independent of gender and alcohol intake, with a clinical penetrance of LHON in 93% of men who smoked.	('smoking', 'Disease', (208, 215))	('mutations', 'Var', (146, 155))	('LHON', 'Gene', (127, 131))	('alcohol', 'Chemical', 'MESH:D000438', (251, 258))	('visual loss', 'Disease', 'MESH:C531604', (192, 203))	('mtDNA', 'Gene', (140, 145))	('visual loss', 'Phenotype', 'HP:0000572', (192, 203))	('men', 'Species', '9606', (312, 315))	('mtDNA', 'cellular_component', 'GO:0000262', ('140', '145'))	('visual loss', 'Disease', (192, 203))
137738	21730846	Based on these findings, the authors suggested that asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to smoke and to moderate their alcohol intake.	('mtDNA', 'cellular_component', 'GO:0000262', ('84', '89'))	('mtDNA', 'Gene', (84, 89))	('rat', 'Species', '10116', (150, 153))	('alcohol', 'Chemical', 'MESH:D000438', (161, 168))	('LHON mtDNA', 'Gene', (79, 89))	('mutation', 'Var', (90, 98))
137745	21730846	Other structural rearrangements or point mutations in mtDNA that may also result in CPEO that can be transmitted in a maternal fashion.	('result in', 'Reg', (74, 83))	('CPEO', 'Disease', (84, 88))	('point mutations', 'Var', (35, 50))	('men', 'Species', '9606', (26, 29))	('mtDNA', 'Gene', (54, 59))	('mtDNA', 'cellular_component', 'GO:0000262', ('54', '59'))
137747	21730846	A clinical diagnosis of CPEO is typically confirmed by the finding of mtDNA deletion(s) on skeletal muscle biopsy, with muscle histology revealing classic "ragged red fibers", that are characteristic of secondary mitochondrial proliferation, as well as cytochrome oxidase-negative fibers, that are consistent with secondary deficiency of mitochondrial complex IV.	('mtDNA', 'Gene', (70, 75))	('deletion', 'Var', (76, 84))	('secondary deficiency', 'Disease', (314, 334))	('secondary deficiency', 'Disease', 'MESH:D060085', (314, 334))	('deficiency of mitochondrial complex IV', 'Phenotype', 'HP:0008347', (324, 362))	('cytochrome oxidase-negative fibers', 'Phenotype', 'HP:0003688', (253, 287))	('mtDNA', 'cellular_component', 'GO:0000262', ('70', '75'))	('rat', 'Species', '10116', (234, 237))	('ragged red fibers', 'Phenotype', 'HP:0003200', (156, 173))
137755	21730846	The best described primary mtDNA disease in which pigmentary retinopathy may be seen is Neurogenic weakness, Ataxia, and Retinitis Pigmentosa (NARP), which results from a T8993C mtDNA mutation in the mitochondrial complex V subunit gene, ATPase 6.	('pigmentary retinopathy', 'Disease', 'MESH:C538365', (50, 72))	('ATPase 6', 'Gene', '4508', (238, 246))	('Retinitis Pigmentosa', 'Phenotype', 'HP:0000510', (121, 141))	('Retinitis Pigmentosa', 'Disease', (121, 141))	('T8993C', 'Mutation', 'rs1438399652', (171, 177))	('Neurogenic weakness', 'Disease', 'MESH:D018908', (88, 107))	('Retinitis', 'Phenotype', 'HP:0032118', (121, 130))	('Ataxia', 'Disease', (109, 115))	('retinopathy', 'Phenotype', 'HP:0000488', (61, 72))	('Ataxia', 'Phenotype', 'HP:0001251', (109, 115))	('Neurogenic weakness', 'Phenotype', 'HP:0001324', (88, 107))	('pigmentary retinopathy', 'Phenotype', 'HP:0000580', (50, 72))	('ATPase 6', 'Gene', (238, 246))	('mtDNA', 'cellular_component', 'GO:0000262', ('27', '32'))	('mtDNA', 'Gene', (178, 183))	('Retinitis Pigmentosa', 'Disease', 'MESH:C538365', (121, 141))	('T8993C', 'Var', (171, 177))	('results from', 'Reg', (156, 168))	('mtDNA', 'cellular_component', 'GO:0000262', ('178', '183'))	('pigmentary retinopathy', 'Disease', (50, 72))	('primary', 'Disease', (19, 26))	('Ataxia', 'Disease', 'MESH:D001259', (109, 115))	('Neurogenic weakness', 'Disease', (88, 107))
137767	21730846	Activated MMP2 causes mitochondrial membrane degradation through modulation of Hsp60 (heat shock protein 60) and damage to connexin 43, which activates the apoptotic machinery.	('activates', 'PosReg', (142, 151))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('mitochondrial membrane degradation', 'MPA', (22, 56))	('Hsp60', 'Gene', '3329', (79, 84))	('apoptotic', 'CPA', (156, 165))	('Hsp60', 'Gene', (79, 84))	('connexin 43', 'Gene', '2697', (123, 134))	('MMP2', 'Gene', (10, 14))	('damage', 'Var', (113, 119))	('connexin', 'molecular_function', 'GO:0005243', ('123', '131'))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('22', '44'))	('modulation', 'Var', (65, 75))	('heat shock protein 60', 'Gene', (86, 107))	('MMP2', 'Gene', '4313', (10, 14))	('shock', 'Phenotype', 'HP:0031273', (91, 96))	('heat shock protein 60', 'Gene', '3329', (86, 107))	('connexin 43', 'Gene', (123, 134))	('MMP2', 'molecular_function', 'GO:0004228', ('10', '14'))	('membrane degradation', 'biological_process', 'GO:0030397', ('36', '56'))
137775	21730846	In another study, a novel antioxidant agent, SS31, was found to attenuate glucose-induced injury in human diabetic retinal cells, where significantly decreased mitochondrial oxidant species generation, decreased cell destruction, and reduced cytochrome c release was seen following treatment of cells in high glucose media with SS31.	('attenuate', 'NegReg', (64, 73))	('reduced', 'NegReg', (234, 241))	('glucose', 'Chemical', 'MESH:D005947', (309, 316))	('cytochrome c', 'Gene', (242, 254))	('decreased', 'NegReg', (202, 211))	('glucose-induced injury', 'Disease', 'MESH:D056486', (74, 96))	('diabetic retinal', 'Disease', 'MESH:D012173', (106, 122))	('cell destruction', 'CPA', (212, 228))	('cytochrome c', 'molecular_function', 'GO:0045155', ('242', '254'))	('men', 'Species', '9606', (287, 290))	('glucose-induced injury', 'Disease', (74, 96))	('decreased', 'NegReg', (150, 159))	('mitochondrial oxidant species generation', 'MPA', (160, 200))	('diabetic retinal', 'Disease', (106, 122))	('glucose', 'Chemical', 'MESH:D005947', (74, 81))	('cytochrome c', 'Gene', '54205', (242, 254))	('cytochrome c', 'molecular_function', 'GO:0009461', ('242', '254'))	('SS31', 'Var', (45, 49))	('rat', 'Species', '10116', (194, 197))	('human', 'Species', '9606', (100, 105))	('high glucose', 'Phenotype', 'HP:0003074', (304, 316))
137781	21730846	To determine whether pathogenic mtDNA variants also occur in patients with AMD, retinal and blood mtDNA were compared between AMD patients and age-matched controls.	('AMD', 'Disease', 'MESH:D006009', (75, 78))	('variants', 'Var', (38, 46))	('mtDNA', 'cellular_component', 'GO:0000262', ('98', '103'))	('patients', 'Species', '9606', (61, 69))	('mtDNA', 'cellular_component', 'GO:0000262', ('32', '37'))	('AMD', 'Disease', (75, 78))	('patients', 'Species', '9606', (130, 138))	('AMD', 'Disease', 'MESH:D006009', (126, 129))	('AMD', 'Disease', (126, 129))
137782	21730846	The authors found that retinal cells had more mtDNA rearrangements and deletions than did blood, with a greater number of non-synonymous gene variants of potential pathogenic significance occurring in AMD patients.	('AMD', 'Disease', 'MESH:D006009', (201, 204))	('deletions', 'Var', (71, 80))	('AMD', 'Disease', (201, 204))	('patients', 'Species', '9606', (205, 213))	('mtDNA', 'Gene', (46, 51))	('rearrangements', 'Var', (52, 66))	('occurring', 'Reg', (188, 197))	('mtDNA', 'cellular_component', 'GO:0000262', ('46', '51'))	('men', 'Species', '9606', (61, 64))
137783	21730846	These mtDNA genome alterations seem to accumulate over time in the diseased retinal ganglion cells both as a consequence from, and likely ongoing cause of, oxidative stress that exacerbates mitochondrial dysfunction in the retina.	('mtDNA', 'cellular_component', 'GO:0000262', ('6', '11'))	('rat', 'Species', '10116', (23, 26))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (190, 215))	('alterations', 'Var', (19, 30))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (190, 215))	('mitochondrial dysfunction', 'Disease', (190, 215))	('oxidative stress', 'Phenotype', 'HP:0025464', (156, 172))	('exacerbates', 'PosReg', (178, 189))
137786	21730846	The optic nerve is packed with mitochondria, making it particularly susceptible to impairment of mitochondrial respiratory capacity that can selectively damage RGCs.	('impairment', 'Var', (83, 93))	('damage', 'Reg', (153, 159))	('rat', 'Species', '10116', (116, 119))	('men', 'Species', '9606', (89, 92))	('mitochondria', 'cellular_component', 'GO:0005739', ('31', '43'))
137787	21730846	Mitochondrial function may be impaired by mutations in either nuclear or mtDNA genes, mechanical stress or chronic hypoperfusion caused by increased intraocular pressure, toxic xenobiotics, or even light-induced oxidative stress.	('increased intraocular pressure', 'Phenotype', 'HP:0007906', (139, 169))	('Mitochondrial function', 'MPA', (0, 22))	('oxidative stress', 'Phenotype', 'HP:0025464', (212, 228))	('chronic hypoperfusion', 'Disease', (107, 128))	('mtDNA', 'cellular_component', 'GO:0000262', ('73', '78'))	('impaired', 'NegReg', (30, 38))	('mtDNA genes', 'Gene', (73, 84))	('chronic hypoperfusion', 'Disease', 'MESH:D006505', (107, 128))	('mutations', 'Var', (42, 51))
137791	21730846	A recent study found an increased burden of potentially pathogenic mtDNA mutations among 35 congenital glaucoma patients relative to controls, which the authors postulated may impair mitochondrial function within the trabecular meshwork.	('pathogenic', 'Reg', (56, 66))	('glaucoma', 'Phenotype', 'HP:0000501', (103, 111))	('congenital glaucoma', 'Disease', 'MESH:C565547', (92, 111))	('mtDNA', 'cellular_component', 'GO:0000262', ('67', '72'))	('patients', 'Species', '9606', (112, 120))	('impair', 'NegReg', (176, 182))	('mtDNA', 'Gene', (67, 72))	('congenital glaucoma', 'Disease', (92, 111))	('mutations', 'Var', (73, 82))	('mitochondrial function', 'MPA', (183, 205))
137794	21730846	While the origin of these cancers is not typically considered to be mitochondrial, some recent investigational therapies have been targeted at disruption of mitochondrial function in tumor cells to specifically induce their apoptosis.	('ptosis', 'Disease', 'MESH:C564553', (227, 233))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('apoptosis', 'biological_process', 'GO:0097194', ('224', '233'))	('mitochondrial function', 'MPA', (157, 179))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cancers', 'Disease', (26, 33))	('disruption', 'Var', (143, 153))	('ptosis', 'Disease', (227, 233))	('ptosis', 'Phenotype', 'HP:0000508', (227, 233))	('apoptosis', 'biological_process', 'GO:0006915', ('224', '233'))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', (183, 188))	('induce', 'PosReg', (211, 217))
137806	21730846	Primary mitochondrial diseases that are caused by mutations in either the nuclear genome or mitochondrial genome frequently involve clinically significant ophthalmologic disease that most commonly involves the optic nerve, retina, extraocular eye muscles, and eyelids.	('ophthalmologic disease', 'Disease', 'MESH:C536647', (155, 177))	('ophthalmologic disease', 'Disease', (155, 177))	('Primary mitochondrial diseases', 'Disease', 'MESH:D028361', (0, 30))	('mutations', 'Var', (50, 59))	('mitochondrial', 'Gene', (92, 105))	('Primary mitochondrial diseases', 'Disease', (0, 30))	('caused by', 'Reg', (40, 49))	('mitochondrial genome', 'cellular_component', 'GO:0000262', ('92', '112'))	('involve', 'Reg', (124, 131))
137830	22557869	Nevi on the skin have been shown in several studies to increase the risk of cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('cutaneous melanoma', 'Disease', (76, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (76, 94))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (76, 94))	('Nevi', 'Var', (0, 4))	('Nevi', 'Phenotype', 'HP:0003764', (0, 4))
137840	22557869	Recurrent aberrations in uveal melanomas concern loss of 1p, monosomy of chromosome 3, loss of 6q and 8p, and gain of 6p and 8q.	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('loss', 'Var', (87, 91))	('gain', 'PosReg', (110, 114))	('monosomy', 'Var', (61, 69))	('uveal melanomas', 'Phenotype', 'HP:0007716', (25, 40))	('uveal melanomas concern loss', 'Disease', 'MESH:C536494', (25, 53))	('uveal melanomas concern loss', 'Disease', (25, 53))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))
137882	22557869	One of the two clinical trials of the collaborative ocular melanoma study(COMS) compared preoperative external been radiation therapy plus enucleation to enucleation alone in patients with large choroidal tumors to address the concern that enucleation might precipitate tumor metastasis and shorten survival.	('choroidal tumors', 'Disease', (195, 211))	('enucleation', 'biological_process', 'GO:0090601', ('154', '165'))	('ocular melanoma', 'Disease', (52, 67))	('enucleation', 'Var', (240, 251))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('choroidal tumors', 'Disease', 'MESH:D002833', (195, 211))	('enucleation', 'biological_process', 'GO:0090601', ('240', '251'))	('survival', 'CPA', (299, 307))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('ocular melanoma', 'Phenotype', 'HP:0007716', (52, 67))	('tumor metastasis', 'Disease', 'MESH:D009362', (270, 286))	('precipitate', 'PosReg', (258, 269))	('ocular melanoma', 'Disease', 'MESH:D008545', (52, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('tumor metastasis', 'Disease', (270, 286))	('shorten', 'NegReg', (291, 298))	('enucleation', 'biological_process', 'GO:0090601', ('139', '150'))	('patients', 'Species', '9606', (175, 183))	('large choroidal tumors', 'Phenotype', 'HP:0030979', (189, 211))
137895	22557869	Results from the second COMS clinical trial, which compared 125-I plaque brachytherapy to enucleation in patients with medium-sized choroidal tumors, revealed no significant difference in cumulative all-cause mortality between the two study arms at 12 years of follow-up (43% for 125-I plaque brachytherapy vs. 41% for enucleation; risk ratio=1.04; 95% CI, 0.86-1.24).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('patients', 'Species', '9606', (105, 113))	('choroidal tumors', 'Disease', 'MESH:D002833', (132, 148))	('enucleation', 'biological_process', 'GO:0090601', ('319', '330'))	('choroidal tumors', 'Disease', (132, 148))	('enucleation', 'biological_process', 'GO:0090601', ('90', '101'))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('125-I', 'Var', (280, 285))
137920	22557869	Patients treated with brachytherapy reported significantly better visual function than patients treated with enucleation with respect to driving and peripheral vision for up to 2 years following treatment.	('vision', 'biological_process', 'GO:0007601', ('160', '166'))	('enucleation', 'biological_process', 'GO:0090601', ('109', '120'))	('men', 'Species', '9606', (200, 203))	('better', 'PosReg', (59, 65))	('visual', 'CPA', (66, 72))	('Patients', 'Species', '9606', (0, 8))	('brachytherapy', 'Var', (22, 35))	('patients', 'Species', '9606', (87, 95))
137922	22557869	Patients treated with brachytherapy were more likely to have symptoms of anxiety during follow-up than patients treated with enucleation.	('anxiety', 'Disease', (73, 80))	('anxiety', 'Phenotype', 'HP:0000739', (73, 80))	('Patients', 'Species', '9606', (0, 8))	('brachytherapy', 'Var', (22, 35))	('patients', 'Species', '9606', (103, 111))	('anxiety', 'Disease', 'MESH:D001008', (73, 80))	('enucleation', 'biological_process', 'GO:0090601', ('125', '136'))
137925	22557869	included genetic testing in their analysis for factors predictive of metastatic death and found the most important independent predictors to be basal tumor diameter, chromosome 3 loss, and epithelioid cell histopathology.	('death', 'Disease', (80, 85))	('chromosome', 'Var', (166, 176))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('chromosome', 'cellular_component', 'GO:0005694', ('166', '176'))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('basal tumor', 'Phenotype', 'HP:0002671', (144, 155))	('death', 'Disease', 'MESH:D003643', (80, 85))	('loss', 'NegReg', (179, 183))	('tumor', 'Disease', (150, 155))
137941	32022332	Therefore, the modulation of PRAME might be useful for the treatment of patients with cancer.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('modulation', 'Var', (15, 25))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))	('patients', 'Species', '9606', (72, 80))
137956	32022332	Haematological malignancies such as CML and AML as well as lymphomas could be vulnerable to control by the immune system, and effector T cells, which recognize minor histocompatibility antigens and tumour-associated antigens (TAAs) that are overexpressed in tumour cells, play a key role in this process.49, 50, 51, 52, 53 PRAME is overexpressed in many haematological malignancies but is absent in normal tissues.	('tumour', 'Phenotype', 'HP:0002664', (258, 264))	('tumour', 'Disease', 'MESH:D009369', (258, 264))	('Haematological malignancies', 'Disease', 'MESH:D019337', (0, 27))	('tumour', 'Disease', (258, 264))	('lymphomas', 'Disease', 'MESH:D008223', (59, 68))	('CML', 'Phenotype', 'HP:0005506', (36, 39))	('TAAs', 'Disease', 'None', (226, 230))	('lymphomas', 'Phenotype', 'HP:0002665', (59, 68))	('haematological malignancies', 'Disease', 'MESH:D019337', (354, 381))	('process.49', 'Var', (296, 306))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('Haematological malignancies', 'Disease', (0, 27))	('overexpressed', 'PosReg', (332, 345))	('tumour', 'Disease', 'MESH:D009369', (198, 204))	('lymphomas', 'Disease', (59, 68))	('TAAs', 'Disease', (226, 230))	('tumour', 'Disease', (198, 204))	('AML', 'Disease', 'MESH:D015470', (44, 47))	('haematological malignancies', 'Disease', (354, 381))	('AML', 'Disease', (44, 47))	('lymphoma', 'Phenotype', 'HP:0002665', (59, 67))	('AML', 'Phenotype', 'HP:0004808', (44, 47))
137986	31344948	In summary, PBR for T1UM yields excellent tumor control and good long-term visual outcomes for tumors located >=3 mm from fovea-optic disc.	('T1UM', 'Gene', (20, 24))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('T1UM', 'Gene', '9173', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('UM', 'Phenotype', 'HP:0007716', (22, 24))	('PBR', 'Var', (12, 15))	('PBR', 'Chemical', '-', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('tumor', 'Disease', (95, 100))
138148	29755268	In that large cohort, theclinical features significantly (p < 0.05) related to any cytogenetic abnormality in chromosomes 3, 6, or 8 (versus [vs.] no abnormality) included older mean age (55 vs. 58 years old), presence of ocular melanocytosis (1% vs. 5%), reduced visual acuity (VA) (20/30 vs. 20/50), ciliary body location (5% vs. 11%), extramacular tumor location (73% vs. 87%), increased mean distance to optic disc (3.3 vs. 5.0 mm) and foveola (3.1 vs. 4.7 mm), and increased mean basal diameter (9.8 vs. 12.6 mm) and thickness 2(3.8 vs. 5.9 mm).	('presence', 'Var', (210, 218))	('ciliary body location', 'CPA', (302, 323))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('increased', 'PosReg', (381, 390))	('tumor', 'Disease', (351, 356))	('ocular melanocytosis', 'Disease', 'MESH:C535835', (222, 242))	('ocular melanocytosis', 'Phenotype', 'HP:0025534', (222, 242))	('reduced visual acuity', 'Phenotype', 'HP:0007663', (256, 277))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('ocular melanocytosis', 'Disease', (222, 242))	('reduced', 'NegReg', (256, 263))	('visual acuity', 'CPA', (264, 277))	('thickness 2', 'CPA', (522, 533))	('increased', 'PosReg', (470, 479))
138149	29755268	Further comparison of small vs large melanoma revealed abnormalities in chromosome 3 (35% vs. 65%), chromosome 6 (15% vs. 51%), and chromosome 8 (19% vs. 69%).	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('abnormalities', 'Var', (55, 68))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('chromosome', 'cellular_component', 'GO:0005694', ('100', '110'))	('chromosome', 'cellular_component', 'GO:0005694', ('132', '142'))
138154	29755268	(Table 2) A previously-mentioned comprehensive study on cytogenetics of choroidal melanoma in 1059 cases was the first to recognize that choroidal melanoma that arose from previously documented nevus showed reduced risk for any chromosomal abnormality, particularly chromosome 3 (p < 0.001).	('nevus', 'Phenotype', 'HP:0003764', (194, 199))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (72, 90))	('choroidal melanoma', 'Disease', 'MESH:D008545', (137, 155))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('chromosome', 'Var', (266, 276))	('chromosomal abnormality', 'Disease', (228, 251))	('reduced', 'NegReg', (207, 214))	('chromosome', 'cellular_component', 'GO:0005694', ('266', '276'))	('choroidal melanoma', 'Disease', (137, 155))	('choroidal melanoma', 'Disease', 'MESH:D008545', (72, 90))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('chromosomal abnormality', 'Disease', 'MESH:D002869', (228, 251))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (137, 155))	('choroidal melanoma', 'Disease', (72, 90))
138165	27211273	Our analysis unveiled aberrant ABCB7 splicing, due to usage of an alternative 3' splice site in MDS patient samples, giving rise to a premature termination codon in the ABCB7 mRNA.	('MDS', 'Disease', 'MESH:D009190', (96, 99))	('aberrant', 'Var', (22, 30))	('ABCB7', 'Gene', (31, 36))	('patient', 'Species', '9606', (100, 107))	('ABCB7', 'Gene', (169, 174))	('splicing', 'biological_process', 'GO:0045292', ('37', '45'))	('MDS', 'Phenotype', 'HP:0002863', (96, 99))	('MDS', 'Disease', (96, 99))
138167	27211273	We describe cryptic splicing events in the HSCs of SF3B1-mutant MDS, and our data support a model in which NMD-induced downregulation of the iron exporter ABCB7 mRNA transcript resulting from aberrant splicing caused by mutant SF3B1 underlies the increased mitochondrial iron accumulation found in MDS patients with RS.	('downregulation', 'NegReg', (119, 133))	('SF3B1', 'Gene', (51, 56))	('MDS', 'Disease', (298, 301))	('MDS', 'Phenotype', 'HP:0002863', (64, 67))	('SF3B1', 'Gene', '23451', (227, 232))	('cryptic', 'Gene', '55997', (12, 19))	('cryptic', 'Gene', (12, 19))	('aberrant splicing', 'Var', (192, 209))	('iron', 'Chemical', 'MESH:D007501', (141, 145))	('increased mitochondrial iron accumulation', 'Phenotype', 'HP:0012465', (247, 288))	('RS', 'Chemical', '-', (316, 318))	('MDS', 'Disease', 'MESH:D009190', (64, 67))	('SF3B1', 'Gene', '23451', (51, 56))	('splicing', 'biological_process', 'GO:0045292', ('201', '209'))	('splicing', 'biological_process', 'GO:0045292', ('20', '28'))	('MDS', 'Disease', (64, 67))	('MDS', 'Phenotype', 'HP:0002863', (298, 301))	('increased', 'PosReg', (247, 256))	('iron', 'Chemical', 'MESH:D007501', (271, 275))	('mutant', 'Var', (220, 226))	('SF3B1', 'Gene', (227, 232))	('mitochondrial iron accumulation', 'MPA', (257, 288))	('mRNA transcript', 'MPA', (161, 176))	('MDS', 'Disease', 'MESH:D009190', (298, 301))	('patients', 'Species', '9606', (302, 310))
138170	27211273	Several genes involved in pre-messenger RNA splicing, including SF3B1, U2AF1, SRSF2 and ZRSR2, have been shown to be mutated in over 50% of MDS patients, revealing a new leukemogenic pathway involving spliceosomal dysfunction.	('SRSF2', 'Gene', (78, 83))	('mutated', 'Var', (117, 124))	('SF3B1', 'Gene', (64, 69))	('U2AF', 'cellular_component', 'GO:0089701', ('71', '75'))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('pre', 'molecular_function', 'GO:0003904', ('26', '29'))	('RNA splicing', 'biological_process', 'GO:0008380', ('40', '52'))	('SRSF2', 'Gene', '6427', (78, 83))	('ZRSR2', 'Gene', (88, 93))	('patients', 'Species', '9606', (144, 152))	('leukemogenic', 'Disease', (170, 182))	('U2AF1', 'Gene', (71, 76))	('U2AF1', 'Gene', '7307', (71, 76))	('ZRSR2', 'Gene', '8233', (88, 93))	('SF3B1', 'Gene', '23451', (64, 69))	('MDS', 'Phenotype', 'HP:0002863', (140, 143))	('MDS', 'Disease', (140, 143))	('MDS', 'Disease', 'MESH:D009190', (140, 143))
138172	27211273	Mutations of SF3B1 occur in a high proportion (>80%) of MDS patients in whom the presence of ring sideroblasts (RS) is a characteristic disease feature, namely the refractory anemia with RS (RARS) and refractory cytopenia with multilineage dysplasia and RS (RCMD-RS) subtypes.	('multilineage dysplasia', 'Disease', 'MESH:D004476', (227, 249))	('anemia', 'Disease', (175, 181))	('RCMD-RS', 'Disease', (258, 265))	('SF3B1', 'Gene', '23451', (13, 18))	('MDS', 'Phenotype', 'HP:0002863', (56, 59))	('patients', 'Species', '9606', (60, 68))	('Mutations', 'Var', (0, 9))	('RS', 'Chemical', '-', (254, 256))	('multilineage dysplasia', 'Disease', (227, 249))	('presence of ring sideroblasts', 'Phenotype', 'HP:0004828', (81, 110))	('MDS', 'Disease', 'MESH:D009190', (56, 59))	('anemia', 'Disease', 'MESH:D000740', (175, 181))	('RS', 'Chemical', '-', (187, 189))	('cytopenia', 'Disease', 'MESH:D006402', (212, 221))	('cytopenia', 'Disease', (212, 221))	('SF3B1', 'Gene', (13, 18))	('RCMD-RS', 'Disease', 'MESH:D041441', (258, 265))	('MDS', 'Disease', (56, 59))	('refractory anemia', 'Phenotype', 'HP:0005505', (164, 181))	('RS', 'Chemical', '-', (193, 195))	('RS', 'Chemical', '-', (263, 265))	('anemia', 'Phenotype', 'HP:0001903', (175, 181))	('RS', 'Chemical', '-', (112, 114))
138173	27211273	In the recent 2016 revision of the World Health Organization (WHO) classification for MDS, if a patient harbors an SF3B1 mutation, a diagnosis of MDS with RS (MDS-RS) may be made if 5-14% RS are present in the bone marrow.	('MDS', 'Disease', (86, 89))	('MDS', 'Disease', (159, 162))	('MDS', 'Disease', 'MESH:D009190', (86, 89))	('MDS', 'Disease', 'MESH:D009190', (159, 162))	('MDS', 'Disease', 'MESH:D009190', (146, 149))	('RS', 'Chemical', '-', (188, 190))	('MDS', 'Phenotype', 'HP:0002863', (146, 149))	('MDS', 'Phenotype', 'HP:0002863', (159, 162))	('MDS-RS', 'Disease', 'MESH:D009190', (159, 165))	('MDS', 'Disease', (146, 149))	('MDS-RS', 'Disease', (159, 165))	('patient', 'Species', '9606', (96, 103))	('RS', 'Chemical', '-', (155, 157))	('SF3B1', 'Gene', (115, 120))	('mutation', 'Var', (121, 129))	('RS', 'Chemical', '-', (163, 165))	('MDS', 'Phenotype', 'HP:0002863', (86, 89))	('SF3B1', 'Gene', '23451', (115, 120))
138174	27211273	SF3B1 mutations are closely associated with the presence of RS, suggesting a causal relationship and making SF3B1 the first gene showing a strong association with a particular morphological feature in MDS.	('SF3B1', 'Gene', '23451', (108, 113))	('RS', 'Chemical', '-', (60, 62))	('MDS', 'Phenotype', 'HP:0002863', (201, 204))	('SF3B1', 'Gene', (0, 5))	('associated', 'Reg', (28, 38))	('MDS', 'Disease', (201, 204))	('MDS', 'Disease', 'MESH:D009190', (201, 204))	('SF3B1', 'Gene', '23451', (0, 5))	('SF3B1', 'Gene', (108, 113))	('mutations', 'Var', (6, 15))
138175	27211273	RS are erythroblasts with excessive mitochondrial iron accumulation, and RARS patients with SF3B1 mutation have altered iron distribution characterized by coarse iron deposits in comparison with RARS patients without SF3B1 mutation.	('iron distribution', 'MPA', (120, 137))	('patients', 'Species', '9606', (200, 208))	('mutation', 'Var', (98, 106))	('mitochondrial iron accumulation', 'MPA', (36, 67))	('SF3B1', 'Gene', '23451', (92, 97))	('SF3B1', 'Gene', (217, 222))	('RS', 'Chemical', '-', (0, 2))	('patients', 'Species', '9606', (78, 86))	('iron', 'Chemical', 'MESH:D007501', (162, 166))	('iron', 'Chemical', 'MESH:D007501', (50, 54))	('SF3B1', 'Gene', '23451', (217, 222))	('iron deposits', 'Phenotype', 'HP:0012675', (162, 175))	('coarse iron deposits', 'MPA', (155, 175))	('iron', 'Chemical', 'MESH:D007501', (120, 124))	('altered', 'Reg', (112, 119))	('RS', 'Chemical', '-', (197, 199))	('RS', 'Chemical', '-', (75, 77))	('SF3B1', 'Gene', (92, 97))
138176	27211273	SF3B1 mutations occur more frequently in low-risk MDS cases and are independent predictors of favorable survival in MDS.	('SF3B1', 'Gene', (0, 5))	('MDS', 'Phenotype', 'HP:0002863', (116, 119))	('SF3B1', 'Gene', '23451', (0, 5))	('MDS', 'Disease', (50, 53))	('MDS', 'Disease', 'MESH:D009190', (50, 53))	('MDS', 'Phenotype', 'HP:0002863', (50, 53))	('MDS', 'Disease', (116, 119))	('MDS', 'Disease', 'MESH:D009190', (116, 119))	('mutations', 'Var', (6, 15))
138177	27211273	The clinical consequences of mutations in SF3B1 are well documented in MDS, however the functional consequences of SF3B1 mutations in human hematopoietic cells are not fully understood.	('human', 'Species', '9606', (134, 139))	('SF3B1', 'Gene', (42, 47))	('mutations', 'Var', (29, 38))	('MDS', 'Disease', (71, 74))	('MDS', 'Disease', 'MESH:D009190', (71, 74))	('MDS', 'Phenotype', 'HP:0002863', (71, 74))	('SF3B1', 'Gene', (115, 120))	('SF3B1', 'Gene', '23451', (42, 47))	('SF3B1', 'Gene', '23451', (115, 120))
138180	27211273	Hereditary X-linked sideroblastic anemia with ataxia is caused by partial loss-of-function mutations of ABCB7, which inhibit heme biosynthesis.	('X-linked sideroblastic anemia', 'Disease', 'MESH:C536761', (11, 40))	('sideroblastic anemia', 'Phenotype', 'HP:0001924', (20, 40))	('X-linked sideroblastic anemia', 'Disease', (11, 40))	('heme biosynthesis', 'biological_process', 'GO:0006783', ('125', '142'))	('heme', 'Chemical', 'MESH:D006418', (125, 129))	('ABCB7', 'Gene', (104, 109))	('mutations', 'Var', (91, 100))	('heme biosynthesis', 'MPA', (125, 142))	('linked sideroblastic anemia', 'Phenotype', 'HP:0004828', (13, 40))	('ataxia', 'Phenotype', 'HP:0001251', (46, 52))	('ataxia', 'Disease', 'MESH:D001259', (46, 52))	('loss-of-function', 'NegReg', (74, 90))	('inhibit', 'NegReg', (117, 124))	('anemia', 'Phenotype', 'HP:0001903', (34, 40))	('ataxia', 'Disease', (46, 52))
138181	27211273	Moreover, knockdown of ABCB7 in HeLa cells resulted in an iron-deficient phenotype with mitochondrial iron accumulation.	('iron', 'Chemical', 'MESH:D007501', (58, 62))	('mitochondrial iron accumulation', 'MPA', (88, 119))	('resulted in', 'Reg', (43, 54))	('HeLa', 'CellLine', 'CVCL:0030', (32, 36))	('iron-deficient', 'Disease', 'MESH:C562385', (58, 72))	('ABCB7', 'Gene', (23, 28))	('iron-deficient', 'Disease', (58, 72))	('knockdown', 'Var', (10, 19))	('iron', 'Chemical', 'MESH:D007501', (102, 106))
138186	27211273	The role of SF3B1 and the U2-small nuclear ribonucleoprotein in recognizing and binding the BP suggest that SF3B1 mutations may alter BP and/or 3' splice site selection.	('SF3B1', 'Gene', (12, 17))	('SF3B1', 'Gene', '23451', (108, 113))	('splice site selection', 'biological_process', 'GO:0000380', ('147', '168'))	('alter', 'Reg', (128, 133))	('BP and/or', 'MPA', (134, 143))	('splice site selection', 'biological_process', 'GO:0000381', ('147', '168'))	('mutations', 'Var', (114, 123))	('small nuclear ribonucleoprotein', 'molecular_function', 'GO:0003734', ('29', '60'))	('small nuclear ribonucleoprotein', 'cellular_component', 'GO:0030532', ('29', '60'))	('SF3B1', 'Gene', '23451', (12, 17))	('binding', 'molecular_function', 'GO:0005488', ('80', '87'))	('SF3B1', 'Gene', (108, 113))	('BP', 'Chemical', '-', (134, 136))	('BP', 'Chemical', '-', (92, 94))
138187	27211273	The splicing factor genes found to be mutated in MDS code for proteins that have a role in the recognition of 3' splice sites during processing of pre-messenger RNAs.	('MDS', 'Disease', (49, 52))	('mutated', 'Var', (38, 45))	('MDS', 'Disease', 'MESH:D009190', (49, 52))	('splicing factor', 'Gene', (4, 19))	('MDS', 'Phenotype', 'HP:0002863', (49, 52))	('pre', 'molecular_function', 'GO:0003904', ('147', '150'))	('splicing factor', 'Gene', '10569', (4, 19))	('splicing', 'biological_process', 'GO:0045292', ('4', '12'))
138188	27211273	Altered RNA splicing has been suggested as the mechanism underlying the observed phenotypic changes concomitant to splicing factor gene mutations, including SF3B1, and the identification of aberrantly spliced target genes in the hematopoietic cells of SF3B1-mutant MDS cases is important.	('SF3B1', 'Gene', (157, 162))	('SF3B1', 'Gene', (252, 257))	('RNA', 'cellular_component', 'GO:0005562', ('8', '11'))	('MDS', 'Disease', (265, 268))	('MDS', 'Disease', 'MESH:D009190', (265, 268))	('SF3B1', 'Gene', '23451', (157, 162))	('splicing factor', 'Gene', (115, 130))	('SF3B1', 'Gene', '23451', (252, 257))	('splicing', 'biological_process', 'GO:0045292', ('115', '123'))	('mutations', 'Var', (136, 145))	('RNA splicing', 'biological_process', 'GO:0008380', ('8', '20'))	('MDS', 'Phenotype', 'HP:0002863', (265, 268))	('splicing factor', 'Gene', '10569', (115, 130))
138190	27211273	MDS is a disorder of the HSC and we thus studied the transcriptome of CD34+ cells from MDS patients with SF3B1 mutations using RNA-Seq.	('mutations', 'Var', (111, 120))	('SF3B1', 'Gene', (105, 110))	('MDS', 'Disease', (87, 90))	('MDS', 'Disease', 'MESH:D009190', (87, 90))	('patients', 'Species', '9606', (91, 99))	('MDS', 'Phenotype', 'HP:0002863', (87, 90))	('SF3B1', 'Gene', '23451', (105, 110))	('MDS', 'Phenotype', 'HP:0002863', (0, 3))	('RNA', 'cellular_component', 'GO:0005562', ('127', '130'))	('MDS', 'Disease', 'MESH:D009190', (0, 3))	('CD34', 'Gene', '947', (70, 74))	('MDS', 'Disease', (0, 3))	('CD34', 'Gene', (70, 74))	('HSC', 'cellular_component', 'GO:0035301', ('25', '28'))
138192	27211273	Recently, SF3B1 mutations have been identified in various tumor types, suggesting that somatic mutations in spliceosome genes have an important role in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutations', 'Var', (16, 25))	('tumor', 'Disease', (152, 157))	('SF3B1', 'Gene', (10, 15))	('spliceosome', 'cellular_component', 'GO:0005681', ('108', '119'))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('SF3B1', 'Gene', '23451', (10, 15))
138193	27211273	SF3B1 mutations have been shown to occur in chronic lymphocytic leukemia, uveal melanoma, breast cancer and pancreatic cancer.	('occur', 'Reg', (35, 40))	('SF3B1', 'Gene', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('pancreatic cancer', 'Disease', 'MESH:D010190', (108, 125))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('uveal melanoma', 'Disease', (74, 88))	('mutations', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('pancreatic cancer', 'Disease', (108, 125))	('SF3B1', 'Gene', '23451', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (44, 72))	('chronic lymphocytic leukemia', 'Disease', (44, 72))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('breast cancer', 'Disease', (90, 103))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (44, 72))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (108, 125))
138194	27211273	SF3B1 mutations have clear mutational hotspots and are considered to be gain-of-function/neomorphic mutations.	('SF3B1', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('SF3B1', 'Gene', '23451', (0, 5))
138195	27211273	The codons most commonly affected by SF3B1 mutations in other cancers that harbor this mutation, including chronic lymphocytic leukemia, uveal melanoma, breast cancer and pancreatic cancer, are the same as the ones affected in MDS (K700, R625 and K666).	('SF3B1', 'Gene', '23451', (37, 42))	('leukemia', 'Phenotype', 'HP:0001909', (127, 135))	('MDS', 'Disease', 'MESH:D009190', (227, 230))	('R625', 'Var', (238, 242))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (107, 135))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('pancreatic cancer', 'Disease', 'MESH:D010190', (171, 188))	('MDS', 'Disease', (227, 230))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('uveal melanoma', 'Disease', 'MESH:C536494', (137, 151))	('pancreatic cancer', 'Disease', (171, 188))	('cancers', 'Disease', (62, 69))	('uveal melanoma', 'Disease', (137, 151))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (137, 151))	('SF3B1', 'Gene', (37, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('K666', 'Var', (247, 251))	('MDS', 'Phenotype', 'HP:0002863', (227, 230))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (171, 188))	('mutations', 'Var', (43, 52))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (107, 135))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('K700', 'Var', (232, 236))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('chronic lymphocytic leukemia', 'Disease', (107, 135))	('breast cancer', 'Disease', (153, 166))
138196	27211273	Recent studies of chronic lymphocytic leukemia, breast cancer and uveal melanoma using RNA-Seq have shown that SF3B1 mutations are associated with differential exon usage and induce cryptic alternative 3' splice site selection in these cancers.	('cancers', 'Disease', 'MESH:D009369', (236, 243))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (18, 46))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Disease', (48, 61))	('chronic lymphocytic leukemia', 'Disease', (18, 46))	('splice site selection', 'biological_process', 'GO:0000380', ('205', '226'))	('RNA', 'cellular_component', 'GO:0005562', ('87', '90'))	('uveal melanoma', 'Disease', (66, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (18, 46))	('leukemia', 'Phenotype', 'HP:0001909', (38, 46))	('SF3B1', 'Gene', (111, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('mutations', 'Var', (117, 126))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancers', 'Disease', (236, 243))	('associated', 'Reg', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('SF3B1', 'Gene', '23451', (111, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('cryptic', 'Gene', '55997', (182, 189))	('splice site selection', 'biological_process', 'GO:0000381', ('205', '226'))	('cryptic', 'Gene', (182, 189))
138199	27211273	The identification of the splicing aberrations induced by SF3B1 mutation in the HSCs of MDS patients will shed light on the downstream effects that lead to the MDS phenotype and may allow for the identification of new therapeutic targets in this disease.	('mutation', 'Var', (64, 72))	('SF3B1', 'Gene', (58, 63))	('MDS', 'Disease', (160, 163))	('MDS', 'Disease', 'MESH:D009190', (160, 163))	('patients', 'Species', '9606', (92, 100))	('MDS', 'Phenotype', 'HP:0002863', (88, 91))	('HSCs', 'Disease', (80, 84))	('MDS', 'Phenotype', 'HP:0002863', (160, 163))	('splicing', 'biological_process', 'GO:0045292', ('26', '34'))	('MDS', 'Disease', (88, 91))	('SF3B1', 'Gene', '23451', (58, 63))	('MDS', 'Disease', 'MESH:D009190', (88, 91))
138200	27211273	RNA-Seq data were obtained from CD34+ cells isolated from bone marrow samples of eight MDS patients (four RARS and four RCMD-RS) with SF3B1 mutation (four K700E, one E622D, one R625L, one H662Q and one K666R; 45-52% SF3B1-mutant allele expression range), four MDS cases (all refractory cytopenia with multilineage dysplasia) without mutations in the splicing factor genes SF3B1, SRSF2, U2AF1 and ZRSR2, and five healthy individuals.	('H662Q', 'Mutation', 'rs778467242', (188, 193))	('SF3B1', 'Gene', (216, 221))	('SRSF2', 'Gene', '6427', (379, 384))	('multilineage dysplasia', 'Disease', (301, 323))	('RS', 'Chemical', '-', (397, 399))	('U2AF1', 'Gene', (386, 391))	('splicing factor', 'Gene', (350, 365))	('SRSF2', 'Gene', (379, 384))	('RCMD-RS', 'Disease', 'MESH:D041441', (120, 127))	('RS', 'Chemical', '-', (380, 382))	('patients', 'Species', '9606', (91, 99))	('MDS', 'Phenotype', 'HP:0002863', (87, 90))	('CD34', 'Gene', (32, 36))	('ZRSR2', 'Gene', '8233', (396, 401))	('RS', 'Chemical', '-', (125, 127))	('E622D', 'Var', (166, 171))	('MDS', 'Phenotype', 'HP:0002863', (260, 263))	('SF3B1', 'Gene', '23451', (216, 221))	('SF3B1', 'Gene', (372, 377))	('U2AF1', 'Gene', '7307', (386, 391))	('RCMD-RS', 'Disease', (120, 127))	('SF3B1', 'Gene', (134, 139))	('MDS', 'Disease', 'MESH:D009190', (87, 90))	('cytopenia', 'Disease', (286, 295))	('cytopenia', 'Disease', 'MESH:D006402', (286, 295))	('R625L', 'Mutation', 'p.R625L', (177, 182))	('splicing factor', 'Gene', '10569', (350, 365))	('E622D', 'Mutation', 'rs763149798', (166, 171))	('MDS', 'Disease', 'MESH:D009190', (260, 263))	('multilineage dysplasia', 'Disease', 'MESH:D004476', (301, 323))	('RS', 'Chemical', '-', (108, 110))	('K666R', 'Mutation', 'rs374250186', (202, 207))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('K700E', 'Mutation', 'rs559063155', (155, 160))	('CD34', 'Gene', '947', (32, 36))	('SF3B1', 'Gene', '23451', (372, 377))	('MDS', 'Disease', (87, 90))	('ZRSR2', 'Gene', (396, 401))	('splicing', 'biological_process', 'GO:0045292', ('350', '358'))	('SF3B1', 'Gene', '23451', (134, 139))	('MDS', 'Disease', (260, 263))	('U2AF', 'cellular_component', 'GO:0089701', ('386', '390'))
138205	27211273	Bone marrow samples were obtained and CD34+ cells were isolated from two MDS patients with SF3B1 K700E mutation.	('SF3B1', 'Gene', (91, 96))	('MDS', 'Disease', (73, 76))	('MDS', 'Disease', 'MESH:D009190', (73, 76))	('K700E', 'Var', (97, 102))	('MDS', 'Phenotype', 'HP:0002863', (73, 76))	('SF3B1', 'Gene', '23451', (91, 96))	('patients', 'Species', '9606', (77, 85))	('CD34', 'Gene', (38, 42))	('CD34', 'Gene', '947', (38, 42))	('K700E', 'Mutation', 'rs559063155', (97, 102))
138208	27211273	We have analyzed RNA-Seq data obtained from the CD34+ cells from eight MDS cases harboring SF3B1 mutations (SF3B1-mutant, all with >15% RS), four MDS patients without splicing factor gene mutations (wild type) and five healthy individuals (control) using rMATS, a bioinformatics pipeline designed to detect alternative (including cryptic) splicing events involving two isoforms from an alternatively spliced region.	('mutations', 'Var', (97, 106))	('SF3B1', 'Gene', (91, 96))	('RS', 'Chemical', '-', (136, 138))	('MDS', 'Disease', 'MESH:D009190', (146, 149))	('MDS', 'Phenotype', 'HP:0002863', (71, 74))	('patients', 'Species', '9606', (150, 158))	('cryptic', 'Gene', (330, 337))	('cryptic', 'Gene', '55997', (330, 337))	('splicing factor', 'Gene', (167, 182))	('SF3B1', 'Gene', '23451', (108, 113))	('RNA', 'cellular_component', 'GO:0005562', ('17', '20'))	('MDS', 'Disease', (146, 149))	('MDS', 'Disease', 'MESH:D009190', (71, 74))	('SF3B1', 'Gene', '23451', (91, 96))	('CD34', 'Gene', (48, 52))	('splicing', 'biological_process', 'GO:0045292', ('339', '347'))	('splicing factor', 'Gene', '10569', (167, 182))	('MDS', 'Disease', (71, 74))	('splicing', 'biological_process', 'GO:0045292', ('167', '175'))	('MDS', 'Phenotype', 'HP:0002863', (146, 149))	('SF3B1', 'Gene', (108, 113))	('CD34', 'Gene', '947', (48, 52))
138209	27211273	When comparing SF3B1-mutant to wild type, we identified 126 significant splicing events (92 genes), of which 42 were A3SS, 6 A5SS, 8 mutually exclusive exons, 13 skipped exons and 57 retained introns (Tables 1 and 2, Supplementary Table S1).	('A3SS', 'Var', (117, 121))	('SF3B1', 'Gene', '23451', (15, 20))	('splicing', 'MPA', (72, 80))	('SF3B1', 'Gene', (15, 20))	('splicing', 'biological_process', 'GO:0045292', ('72', '80'))
138210	27211273	When comparing SF3B1-mutant with controls, 213 significant splicing events (164 genes) were identified, of which 62 were A3SS, 10 A5SS, 12 mutually exclusive exon, 12 skipped exons and 117 retained intron (Tables 1 and 3, Supplementary Table S2).	('A3SS', 'Var', (121, 125))	('SF3B1', 'Gene', '23451', (15, 20))	('splicing', 'biological_process', 'GO:0045292', ('59', '67'))	('splicing', 'MPA', (59, 67))	('SF3B1', 'Gene', (15, 20))
138221	27211273	In contrast, downstream cryptic 3' splice sites and A3SS unregulated by the SF3B1 mutation showed a much broader distribution of spacing with most pairs of A3SS being much more widely spaced (red and green traces in Figure 1b and Supplementary Figure S1B).	('mutation', 'Var', (82, 90))	('SF3B1', 'Gene', (76, 81))	('cryptic', 'Gene', '55997', (24, 31))	('more', 'PosReg', (172, 176))	('cryptic', 'Gene', (24, 31))	('SF3B1', 'Gene', '23451', (76, 81))
138222	27211273	One interesting exception was a peak at 3 nt (1.6 on log2 scale) for the unregulated A3SS, which corresponds to the so-called NAGNAG class of A3SS, selection of which occurs at step 2 of splicing consistent with a lack of effect of SF3B1 mutation.	('SF3B1', 'Gene', (232, 237))	('SF3B1', 'Gene', '23451', (232, 237))	('mutation', 'Var', (238, 246))	('splicing', 'biological_process', 'GO:0045292', ('187', '195'))
138227	27211273	Taken together, our data show that MDS-associated SF3B1 mutations result in widespread use of cryptic 3' splice sites a short distance upstream of canonical sites and could be consistent either with use of a common BP in association with upstream cryptic and canonical splice site pairs or, more likely, with shifted use of both BP and consequently 3' splice site in the SF3B1-mutant, as shown in recent reports in other cancers.	('MDS', 'Disease', (35, 38))	('BP', 'Chemical', '-', (329, 331))	('MDS', 'Disease', 'MESH:D009190', (35, 38))	('mutations', 'Var', (56, 65))	('SF3B1', 'Gene', (50, 55))	('cancers', 'Disease', 'MESH:D009369', (421, 428))	('cancers', 'Phenotype', 'HP:0002664', (421, 428))	('cancers', 'Disease', (421, 428))	('MDS', 'Phenotype', 'HP:0002863', (35, 38))	('SF3B1', 'Gene', (371, 376))	('SF3B1', 'Gene', '23451', (50, 55))	('cryptic', 'Gene', '55997', (247, 254))	('cancer', 'Phenotype', 'HP:0002664', (421, 427))	('cryptic', 'Gene', (247, 254))	('SF3B1', 'Gene', '23451', (371, 376))	('BP', 'Chemical', '-', (215, 217))	('cryptic', 'Gene', (94, 101))	('cryptic', 'Gene', '55997', (94, 101))
138231	27211273	Aberrant splicing of TMEM14C and DYNLL1 introduces an addition of 14 base pairs in the 5'UTR region of these genes.	('TMEM14C', 'Gene', '51522', (21, 28))	('DYNLL1', 'Gene', (33, 39))	('TMEM14C', 'Gene', (21, 28))	('splicing', 'biological_process', 'GO:0045292', ('9', '17'))	('Aberrant splicing', 'Var', (0, 17))	('DYNLL1', 'Gene', '8655', (33, 39))
138233	27211273	Aberrant splicing of SEPT6 and HINT2 introduces an addition of 17 and 11 base pairs, respectively, leading to a frameshift in SEPT6 and to the rise of a premature termination codon in the first 3 base pairs of exon 5 in HINT2.	('SEPT6', 'Gene', '23157', (21, 26))	('SEPT6', 'Gene', (126, 131))	('Aberrant', 'Var', (0, 8))	('SEPT6', 'Gene', '23157', (126, 131))	('SEPT6', 'Gene', (21, 26))	('splicing', 'biological_process', 'GO:0045292', ('9', '17'))	('frameshift', 'Var', (112, 122))	('HINT2', 'Gene', (220, 225))	('HINT2', 'Gene', '84681', (220, 225))	('HINT2', 'Gene', '84681', (31, 36))	('HINT2', 'Gene', (31, 36))	('premature termination codon', 'MPA', (153, 180))	('rise', 'PosReg', (143, 147))
138234	27211273	The RT-PCR results confirmed the cryptic splicing events identified by RNA-Seq in these five genes in MDS patient samples with SF3B1 mutation (Figures 2a and b).	('splicing', 'biological_process', 'GO:0045292', ('41', '49'))	('mutation', 'Var', (133, 141))	('cryptic', 'Gene', (33, 40))	('SF3B1', 'Gene', (127, 132))	('patient', 'Species', '9606', (106, 113))	('cryptic', 'Gene', '55997', (33, 40))	('RNA', 'cellular_component', 'GO:0005562', ('71', '74'))	('MDS', 'Phenotype', 'HP:0002863', (102, 105))	('MDS', 'Disease', 'MESH:D009190', (102, 105))	('SF3B1', 'Gene', '23451', (127, 132))	('MDS', 'Disease', (102, 105))
138238	27211273	These data demonstrate that aberrant splicing of ABCB7 observed is specific to MDS cases carrying mutation of SF3B1.	('mutation', 'Var', (98, 106))	('SF3B1', 'Gene', '23451', (110, 115))	('ABCB7', 'Gene', (49, 54))	('aberrant splicing', 'Var', (28, 45))	('MDS', 'Phenotype', 'HP:0002863', (79, 82))	('SF3B1', 'Gene', (110, 115))	('splicing', 'biological_process', 'GO:0045292', ('37', '45'))	('MDS', 'Disease', (79, 82))	('MDS', 'Disease', 'MESH:D009190', (79, 82))
138243	27211273	In addition, we performed RT-PCR for ABCB7 in K562-SF3B1K700E and SF3B1WT isogenic cells obtained using CRISPR/Cas9 gene editing and the pancreatic cell line Panc 05.04, which has a heterozygous SF3B1 K700E mutation, and we observed the same ABCB7 cryptic 3' splice site event (Figures 4c and d), which introduces a stop codon as identified in the CD34+ cells and cultured erythroblasts of SF3B1-mutant MDS patients.	('K700E', 'Mutation', 'rs559063155', (201, 206))	('SF3B1', 'Gene', (66, 71))	('SF3B1', 'Gene', (51, 56))	('K562', 'CellLine', 'CVCL:0004', (46, 50))	('SF3B1', 'Gene', '23451', (195, 200))	('K700E', 'Mutation', 'rs559063155', (56, 61))	('CD34', 'Gene', '947', (348, 352))	('MDS', 'Phenotype', 'HP:0002863', (403, 406))	('pancreatic', 'Disease', 'MESH:D010195', (137, 147))	('SF3B1', 'Gene', '23451', (66, 71))	('SF3B1', 'Gene', '23451', (51, 56))	('SF3B1', 'Gene', (390, 395))	('Cas', 'cellular_component', 'GO:0005650', ('111', '114'))	('MDS', 'Disease', 'MESH:D009190', (403, 406))	('K700E', 'Var', (201, 206))	('pancreatic', 'Disease', (137, 147))	('cryptic', 'Gene', (248, 255))	('cryptic', 'Gene', '55997', (248, 255))	('CD34', 'Gene', (348, 352))	('MDS', 'Disease', (403, 406))	('patients', 'Species', '9606', (407, 415))	('SF3B1', 'Gene', '23451', (390, 395))	('SF3B1', 'Gene', (195, 200))	('Panc 05.04', 'CellLine', 'CVCL:1637', (158, 168))
138244	27211273	Treatment of K562-SF3B1K700E and Panc 05.04 cells with cycloheximide resulted in an increase of the aberrantly spliced form of the ABCB7 transcript (Figures 4c and d).	('K562', 'CellLine', 'CVCL:0004', (13, 17))	('Panc 05.04', 'CellLine', 'CVCL:1637', (33, 43))	('cycloheximide', 'Chemical', 'MESH:D003513', (55, 68))	('K562-SF3B1K700E', 'Var', (13, 28))	('ABCB7', 'Gene', (131, 136))	('increase', 'PosReg', (84, 92))	('aberrantly spliced form', 'MPA', (100, 123))
138246	27211273	It is still unknown how SF3B1 mutations lead to the formation of RS in MDS.	('formation', 'biological_process', 'GO:0009058', ('52', '61'))	('lead to', 'Reg', (40, 47))	('SF3B1', 'Gene', (24, 29))	('MDS', 'Disease', (71, 74))	('MDS', 'Disease', 'MESH:D009190', (71, 74))	('MDS', 'Phenotype', 'HP:0002863', (71, 74))	('RS', 'Chemical', '-', (65, 67))	('mutations', 'Var', (30, 39))	('SF3B1', 'Gene', '23451', (24, 29))
138247	27211273	Given the critical functions of SF3B1 on 3' splice site recognition, the probable consequence of this spliceosome mutation is aberrant splicing of various downstream target genes in MDS.	('MDS', 'Phenotype', 'HP:0002863', (182, 185))	('mutation', 'Var', (114, 122))	('spliceosome', 'cellular_component', 'GO:0005681', ('102', '113'))	('SF3B1', 'Gene', '23451', (32, 37))	('splicing', 'biological_process', 'GO:0045292', ('135', '143'))	('MDS', 'Disease', (182, 185))	('MDS', 'Disease', 'MESH:D009190', (182, 185))	('SF3B1', 'Gene', (32, 37))	('splicing', 'MPA', (135, 143))
138249	27211273	It is important to study the impact of SF3B1 mutation on the transcriptome in the cell of origin.	('SF3B1', 'Gene', '23451', (39, 44))	('mutation', 'Var', (45, 53))	('SF3B1', 'Gene', (39, 44))
138250	27211273	We sought to identify the aberrant/cryptic mRNA splicing events associated with the SF3B1 mutation in the HSCs of MDS patients.	('mRNA splicing', 'biological_process', 'GO:0000398', ('43', '56'))	('MDS', 'Disease', (114, 117))	('MDS', 'Disease', 'MESH:D009190', (114, 117))	('SF3B1', 'Gene', '23451', (84, 89))	('MDS', 'Phenotype', 'HP:0002863', (114, 117))	('mRNA splicing', 'biological_process', 'GO:0000394', ('43', '56'))	('mRNA splicing', 'MPA', (43, 56))	('mRNA splicing', 'biological_process', 'GO:0000372', ('43', '56'))	('cryptic', 'Gene', (35, 42))	('mRNA splicing', 'biological_process', 'GO:0000374', ('43', '56'))	('mRNA splicing', 'biological_process', 'GO:0006371', ('43', '56'))	('cryptic', 'Gene', '55997', (35, 42))	('SF3B1', 'Gene', (84, 89))	('mutation', 'Var', (90, 98))	('patients', 'Species', '9606', (118, 126))	('mRNA splicing', 'biological_process', 'GO:0000373', ('43', '56'))	('HSCs', 'Disease', (106, 110))
138252	27211273	The recent identification of A3SS usage in other malignancies with SF3B1 mutation highlights the importance of interrogating RNA-seq data using a method that allows the identification of not only annotated alternative splicing events, but also of de novo cryptic splicing events.	('splicing', 'biological_process', 'GO:0045292', ('218', '226'))	('splicing', 'biological_process', 'GO:0045292', ('263', '271'))	('SF3B1', 'Gene', '23451', (67, 72))	('RNA', 'cellular_component', 'GO:0005562', ('125', '128'))	('malignancies', 'Disease', 'MESH:D009369', (49, 61))	('cryptic', 'Gene', '55997', (255, 262))	('malignancies', 'Disease', (49, 61))	('cryptic', 'Gene', (255, 262))	('mutation', 'Var', (73, 81))	('SF3B1', 'Gene', (67, 72))
138253	27211273	We have found that SF3B1 mutations are associated with various aberrant splicing events in the HSCs of MDS patients.	('mutations', 'Var', (25, 34))	('MDS', 'Disease', 'MESH:D009190', (103, 106))	('MDS', 'Phenotype', 'HP:0002863', (103, 106))	('SF3B1', 'Gene', '23451', (19, 24))	('MDS', 'Disease', (103, 106))	('associated', 'Reg', (39, 49))	('aberrant splicing events', 'MPA', (63, 87))	('splicing', 'biological_process', 'GO:0045292', ('72', '80'))	('patients', 'Species', '9606', (107, 115))	('SF3B1', 'Gene', (19, 24))	('HSCs', 'Disease', (95, 99))
138255	27211273	Indeed, the majority (65-75%) of the most significant aberrant splicing events in the comparison of SF3B1-mutant with both wild type and controls were A3SS.	('SF3B1', 'Gene', (100, 105))	('splicing', 'MPA', (63, 71))	('SF3B1', 'Gene', '23451', (100, 105))	('A3SS', 'Var', (151, 155))	('splicing', 'biological_process', 'GO:0045292', ('63', '71'))
138256	27211273	These data show that aberrant 3' splice site selection is a frequent and important event associated with SF3B1 mutations in the HSCs of MDS patients.	('mutations', 'Var', (111, 120))	('SF3B1', 'Gene', (105, 110))	('splice site selection', 'biological_process', 'GO:0000381', ('33', '54'))	('MDS', 'Phenotype', 'HP:0002863', (136, 139))	('aberrant', 'Var', (21, 29))	('HSCs', 'Disease', (128, 132))	('SF3B1', 'Gene', '23451', (105, 110))	("3' splice site selection", 'MPA', (30, 54))	('splice site selection', 'biological_process', 'GO:0000380', ('33', '54'))	('patients', 'Species', '9606', (140, 148))	('MDS', 'Disease', (136, 139))	('MDS', 'Disease', 'MESH:D009190', (136, 139))
138260	27211273	Alternatively, SF3B1 mutations could lead to a shift in BP selection a short distance upstream leading to altered 3' splice site selection.	('altered', 'Reg', (106, 113))	('BP', 'Chemical', '-', (56, 58))	("3' splice site selection", 'MPA', (114, 138))	('shift', 'Reg', (47, 52))	('SF3B1', 'Gene', '23451', (15, 20))	('BP selection a short distance upstream', 'MPA', (56, 94))	('lead to', 'Reg', (37, 44))	('splice site selection', 'biological_process', 'GO:0000381', ('117', '138'))	('splice site selection', 'biological_process', 'GO:0000380', ('117', '138'))	('SF3B1', 'Gene', (15, 20))	('mutations', 'Var', (21, 30))
138263	27211273	Emerging data suggest that myeloid malignancies with splicing factor gene mutations are preferentially susceptible to additional splicing perturbations induced by splicing factor inhibitors and this may also represent a therapeutic approach in SF3B1-mutant MDS.	('splicing', 'biological_process', 'GO:0045292', ('53', '61'))	('myeloid malignancies', 'Disease', (27, 47))	('splicing factor', 'Gene', (163, 178))	('splicing', 'biological_process', 'GO:0045292', ('129', '137'))	('mutations', 'Var', (74, 83))	('SF3B1', 'Gene', (244, 249))	('splicing factor', 'Gene', (53, 68))	('splicing perturbations', 'MPA', (129, 151))	('MDS', 'Phenotype', 'HP:0002863', (257, 260))	('splicing', 'biological_process', 'GO:0045292', ('163', '171'))	('myeloid malignancies', 'Disease', 'MESH:D009369', (27, 47))	('splicing factor', 'Gene', '10569', (163, 178))	('SF3B1', 'Gene', '23451', (244, 249))	('splicing factor', 'Gene', '10569', (53, 68))	('MDS', 'Disease', (257, 260))	('MDS', 'Disease', 'MESH:D009190', (257, 260))
138265	27211273	Importantly, cryptic splicing events affecting TMEM14C, ENOSF1, DYNLL1 and HINT2 have been associated with SF3B1 mutation in other cancers such as chronic lymphocytic leukemia, uveal melanoma and breast cancer.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (147, 175))	('cancers', 'Disease', (131, 138))	('ENOSF1', 'Gene', (56, 62))	('DYNLL1', 'Gene', (64, 70))	('cryptic', 'Gene', '55997', (13, 20))	('cryptic', 'Gene', (13, 20))	('SF3B1', 'Gene', '23451', (107, 112))	('DYNLL1', 'Gene', '8655', (64, 70))	('mutation', 'Var', (113, 121))	('ENOSF1', 'Gene', '55556', (56, 62))	('TMEM14C', 'Gene', (47, 54))	('uveal melanoma', 'Disease', 'MESH:C536494', (177, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('uveal melanoma', 'Disease', (177, 191))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('HINT2', 'Gene', (75, 80))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('uveal melanoma', 'Phenotype', 'HP:0007716', (177, 191))	('breast cancer', 'Disease', (196, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('associated', 'Reg', (91, 101))	('TMEM14C', 'Gene', '51522', (47, 54))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (147, 175))	('HINT2', 'Gene', '84681', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('SF3B1', 'Gene', (107, 112))	('splicing', 'biological_process', 'GO:0045292', ('21', '29'))	('chronic lymphocytic leukemia', 'Disease', (147, 175))	('leukemia', 'Phenotype', 'HP:0001909', (167, 175))
138267	27211273	It is most probable that several target genes showing cryptic splicing contribute to the phenotype observed in MDS patients with the SF3B1 mutation.	('patients', 'Species', '9606', (115, 123))	('mutation', 'Var', (139, 147))	('splicing', 'biological_process', 'GO:0045292', ('62', '70'))	('SF3B1', 'Gene', '23451', (133, 138))	('MDS', 'Disease', (111, 114))	('MDS', 'Disease', 'MESH:D009190', (111, 114))	('cryptic', 'Gene', '55997', (54, 61))	('MDS', 'Phenotype', 'HP:0002863', (111, 114))	('cryptic', 'Gene', (54, 61))	('SF3B1', 'Gene', (133, 138))
138271	27211273	The close association between SF3B1 mutations and RS is consistent with a causal relationship, and makes this the first gene to be strongly associated with a specific feature of MDS.	('associated', 'Reg', (140, 150))	('SF3B1', 'Gene', (30, 35))	('mutations', 'Var', (36, 45))	('SF3B1', 'Gene', '23451', (30, 35))	('MDS', 'Disease', (178, 181))	('MDS', 'Disease', 'MESH:D009190', (178, 181))	('MDS', 'Phenotype', 'HP:0002863', (178, 181))	('RS', 'Chemical', '-', (50, 52))
138272	27211273	How SF3B1 mutations affect formation of RS is still unknown.	('RS', 'Chemical', '-', (40, 42))	('SF3B1', 'Gene', (4, 9))	('SF3B1', 'Gene', '23451', (4, 9))	('mutations', 'Var', (10, 19))	('affect', 'Reg', (20, 26))	('formation', 'biological_process', 'GO:0009058', ('27', '36'))
138273	27211273	Cryptic splicing of genes involved in iron homeostasis and/or hemoglobin synthesis could have a role in the ineffective erythropoiesis observed in MDS patients with SF3B1 mutation and RS.	('iron', 'Chemical', 'MESH:D007501', (38, 42))	('iron homeostasis', 'biological_process', 'GO:0006879', ('38', '54'))	('SF3B1', 'Gene', (165, 170))	('mutation', 'Var', (171, 179))	('splicing', 'biological_process', 'GO:0045292', ('8', '16'))	('patients', 'Species', '9606', (151, 159))	('MDS', 'Phenotype', 'HP:0002863', (147, 150))	('ineffective erythropoiesis', 'Phenotype', 'HP:0010972', (108, 134))	('SF3B1', 'Gene', '23451', (165, 170))	('iron homeostasis', 'biological_process', 'GO:0055072', ('38', '54'))	('MDS', 'Disease', 'MESH:D009190', (147, 150))	('erythropoiesis', 'biological_process', 'GO:0030218', ('120', '134'))	('RS', 'Chemical', '-', (184, 186))	('hemoglobin synthesis', 'biological_process', 'GO:0042541', ('62', '82'))	('MDS', 'Disease', (147, 150))	('Cryptic', 'Gene', '55997', (0, 7))	('Cryptic', 'Gene', (0, 7))
138277	27211273	In a recent study, we performed an integrative analysis in MDS and the strongest association found was between the presence of SF3B1 mutations and marked downregulation of ABCB7.	('ABCB7', 'Gene', (172, 177))	('SF3B1', 'Gene', (127, 132))	('downregulation', 'NegReg', (154, 168))	('mutations', 'Var', (133, 142))	('SF3B1', 'Gene', '23451', (127, 132))	('MDS', 'Phenotype', 'HP:0002863', (59, 62))	('MDS', 'Disease', (59, 62))	('MDS', 'Disease', 'MESH:D009190', (59, 62))
138278	27211273	Given the strong correlation between SF3B1 mutations and the presence of RS, our data suggested a three-way association among SF3B1 mutation, ABCB7 downregulation and the occurrence of RS.	('SF3B1', 'Gene', '23451', (37, 42))	('SF3B1', 'Gene', (126, 131))	('RS', 'Chemical', '-', (185, 187))	('ABCB7', 'Gene', (142, 147))	('SF3B1', 'Gene', '23451', (126, 131))	('RS', 'Chemical', '-', (73, 75))	('SF3B1', 'Gene', (37, 42))	('mutation', 'Var', (132, 140))	('downregulation', 'NegReg', (148, 162))
138284	27211273	Importantly, we next showed that the aberrantly spliced ABCB7 transcript was present in the myeloid cell line K562 in which the SF3B1 mutation was introduced using CRISPR/Cas9 gene editing, and in the pancreatic cell line Panc 05.04 (which is mutant for SF3B1).	('pancreatic', 'Disease', 'MESH:D010195', (201, 211))	('SF3B1', 'Gene', '23451', (128, 133))	('Panc 05.04', 'CellLine', 'CVCL:1637', (222, 232))	('ABCB7', 'Gene', (56, 61))	('pancreatic', 'Disease', (201, 211))	('mutation', 'Var', (134, 142))	('SF3B1', 'Gene', (254, 259))	('SF3B1', 'Gene', '23451', (254, 259))	('K562', 'CellLine', 'CVCL:0004', (110, 114))	('Cas', 'cellular_component', 'GO:0005650', ('171', '174'))	('SF3B1', 'Gene', (128, 133))
138286	27211273	These data provide strong evidence that the SF3B1 mutation leads to aberrant ABCB7 splicing and downregulation via NMD in human myeloid cells and other cancer cells.	('human', 'Species', '9606', (122, 127))	('SF3B1', 'Gene', (44, 49))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('SF3B1', 'Gene', '23451', (44, 49))	('mutation', 'Var', (50, 58))	('splicing', 'MPA', (83, 91))	('downregulation', 'NegReg', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('ABCB7', 'Gene', (77, 82))	('splicing', 'biological_process', 'GO:0045292', ('83', '91'))	('aberrant', 'Var', (68, 76))
138287	27211273	Aberrant splicing of ABCB7 has been reported recently in an isogenic SF3B1-mutant pre-B ALL cell line in another study.	('ABCB7', 'Gene', (21, 26))	('pre', 'molecular_function', 'GO:0003904', ('82', '85'))	('splicing', 'biological_process', 'GO:0045292', ('9', '17'))	('SF3B1', 'Gene', (69, 74))	('reported', 'Reg', (36, 44))	('Aberrant splicing', 'Var', (0, 17))	('SF3B1', 'Gene', '23451', (69, 74))
138288	27211273	We suggest that downregulation of the iron exporter ABCB7 resulting from aberrant splicing of the mRNA transcript leading to NMD underlies the increased mitochondrial iron accumulation found in MDS patients with RS.	('leading to', 'Reg', (114, 124))	('increased', 'PosReg', (143, 152))	('downregulation', 'NegReg', (16, 30))	('iron', 'Chemical', 'MESH:D007501', (38, 42))	('patients', 'Species', '9606', (198, 206))	('splicing', 'biological_process', 'GO:0045292', ('82', '90'))	('RS', 'Chemical', '-', (212, 214))	('increased mitochondrial iron accumulation', 'Phenotype', 'HP:0012465', (143, 184))	('MDS', 'Disease', (194, 197))	('ABCB7', 'Gene', (52, 57))	('MDS', 'Disease', 'MESH:D009190', (194, 197))	('MDS', 'Phenotype', 'HP:0002863', (194, 197))	('NMD', 'Disease', (125, 128))	('aberrant splicing', 'Var', (73, 90))	('iron', 'Chemical', 'MESH:D007501', (167, 171))	('mitochondrial iron accumulation', 'MPA', (153, 184))
138292	27211273	These data illuminate the downstream target genes that may have a role in the development of the MDS phenotype, and further our understanding of the effect of SF3B1 mutations on splicing in malignancy.	('splicing', 'biological_process', 'GO:0045292', ('178', '186'))	('MDS', 'Disease', (97, 100))	('MDS', 'Disease', 'MESH:D009190', (97, 100))	('MDS', 'Phenotype', 'HP:0002863', (97, 100))	('malignancy', 'Disease', 'MESH:D009369', (190, 200))	('splicing', 'MPA', (178, 186))	('SF3B1', 'Gene', (159, 164))	('mutations', 'Var', (165, 174))	('malignancy', 'Disease', (190, 200))	('SF3B1', 'Gene', '23451', (159, 164))
138293	27211273	We demonstrate a mechanism linking the presence of SF3B1 mutation in MDS RARS patients and the NMD-induced marked downregulation of the iron transporter ABCB7, and provide strong evidence supporting a critical role of ABCB7 in the development of the RS phenotype.	('mutation', 'Var', (57, 65))	('MDS', 'Phenotype', 'HP:0002863', (69, 72))	('iron transporter ABCB7', 'MPA', (136, 158))	('MDS RARS', 'Disease', (69, 77))	('patients', 'Species', '9606', (78, 86))	('MDS RARS', 'Disease', 'MESH:D009190', (69, 77))	('SF3B1', 'Gene', (51, 56))	('SF3B1', 'Gene', '23451', (51, 56))	('RS', 'Chemical', '-', (250, 252))	('RS', 'Chemical', '-', (75, 77))	('downregulation', 'NegReg', (114, 128))	('iron', 'Chemical', 'MESH:D007501', (136, 140))
138298	25592648	The Hippo pathway was initially identified and named through screenings for mutant tumour suppressors in flies, in which loss-of-function mutations of components of the Hippo pathway revealed robust overgrowth as a result of increased cell proliferation and decreased cell death.	('tumour', 'Disease', (83, 89))	('cell proliferation', 'CPA', (235, 253))	('overgrowth', 'CPA', (199, 209))	('overgrowth', 'Phenotype', 'HP:0001548', (199, 209))	('cell death', 'biological_process', 'GO:0008219', ('268', '278'))	('decreased cell death', 'Disease', 'MESH:D003643', (258, 278))	('increased', 'PosReg', (225, 234))	('decreased cell death', 'Disease', (258, 278))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('cell proliferation', 'biological_process', 'GO:0008283', ('235', '253'))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('loss-of-function', 'NegReg', (121, 137))	('mutations', 'Var', (138, 147))
138334	25592648	Intriguingly, separate YAP and TAZ ablation in the mouse kidney yields distinct phenotypes; YAP loss leads to the development of dysplastic kidneys, whereas depletion of TAZ results in cystic kidneys.	('dysplastic kidneys', 'Disease', (129, 147))	('cystic kidneys', 'Phenotype', 'HP:0000107', (185, 199))	('mouse', 'Species', '10090', (51, 56))	('cystic kidneys', 'Disease', (185, 199))	('depletion', 'MPA', (157, 166))	('cystic kidneys', 'Disease', 'MESH:D052177', (185, 199))	('dysplastic kidneys', 'Disease', 'MESH:D021782', (129, 147))	('dysplastic kidneys', 'Phenotype', 'HP:0000110', (129, 147))	('loss', 'NegReg', (96, 100))	('ablation', 'Var', (35, 43))	('YAP', 'Gene', (92, 95))
138335	25592648	Importantly, additional ablation of TAZ shows no exacerbation of the glomeruli phenotype in YAP-mutant kidneys, indicating their distinct roles during nephrogenesis.	('TAZ', 'Gene', (36, 39))	('nephrogenesis', 'Disease', 'None', (151, 164))	('nephrogenesis', 'Disease', (151, 164))	('nephrogenesis', 'biological_process', 'GO:0001822', ('151', '164'))	('nephrogenesis', 'biological_process', 'GO:0072006', ('151', '164'))	('ablation', 'Var', (24, 32))	('YAP-mutant', 'Gene', (92, 102))
138337	25592648	Importantly, predisposition for neoplasia by NF2 loss is mediated by the activation of YAP, as genetic and pharmacological inhibition of YAP prevents the neoplastic phenotype in Nf2-mutant mice.	('loss', 'NegReg', (49, 53))	('NF2', 'Gene', (45, 48))	('inhibition', 'Var', (123, 133))	('Nf2', 'Gene', (178, 181))	('neoplasia', 'Disease', (32, 41))	('mice', 'Species', '10090', (189, 193))	('Nf2', 'Gene', '18016', (178, 181))	('neoplasia', 'Phenotype', 'HP:0002664', (32, 41))	('neoplasia', 'Disease', 'MESH:D009369', (32, 41))
138338	25592648	Activating mutations in KRAS frequently occur in diverse human carcinomas and are particularly prominent in those of the pancreas, lung and colon.	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('carcinomas', 'Disease', 'MESH:D002277', (63, 73))	('human', 'Species', '9606', (57, 62))	('Activating mutations', 'Var', (0, 20))	('carcinomas', 'Disease', (63, 73))	('lung', 'Disease', (131, 135))	('pancreas', 'Disease', (121, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('occur', 'Reg', (40, 45))	('KRAS', 'Gene', (24, 28))
138339	25592648	Recent data revealed that YAP is essential for the neoplastic progression of pancreatic ductal adenocarcinoma (PDAC) in Kras-mutant mice.	('Kras-mutant', 'Var', (120, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('pancreatic ductal adenocarcinoma', 'Disease', (77, 109))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (77, 109))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (77, 109))	('mice', 'Species', '10090', (132, 136))	('PDAC', 'Phenotype', 'HP:0006725', (111, 115))
138343	25592648	LKB1 is also mutated in 15-35% of non-small-cell lung carcinomas and 20% of cervical carcinomas.	('cervical carcinomas', 'Disease', (76, 95))	('lung carcinomas', 'Disease', (49, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('LKB1', 'Gene', (0, 4))	('cervical carcinomas', 'Disease', 'MESH:D002575', (76, 95))	('LKB1', 'Gene', '6794', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (54, 64))	('lung carcinomas', 'Disease', 'MESH:D008175', (49, 64))	('mutated', 'Var', (13, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))
138350	25592648	Deep sequencing studies revealed a high rate of mutations in GPCRs and G proteins across a wide range of human cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('GPCR', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('GPCR', 'Gene', '441931', (61, 65))	('G proteins', 'Protein', (71, 81))	('human', 'Species', '9606', (105, 110))	('mutations', 'Var', (48, 57))
138351	25592648	Strikingly, somatic mutations in GNAQ or GNA11 (which encode Galphaq and Galpha11, respectively) have been observed in more than 80% of uveal melanomas, which is the most common intraocular tumour in adults and accounts for ~5% of all melanomas.	('Galpha11', 'Gene', (73, 81))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanomas', 'Phenotype', 'HP:0002861', (235, 244))	('uveal melanomas', 'Disease', 'MESH:C536494', (136, 151))	('intraocular tumour', 'Disease', (178, 196))	('GNA11', 'Gene', '2767', (41, 46))	('melanomas', 'Disease', 'MESH:D008545', (142, 151))	('intraocular tumour', 'Disease', 'MESH:D064090', (178, 196))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('GNAQ', 'Gene', '2776', (33, 37))	('melanomas', 'Disease', (142, 151))	('uveal melanoma', 'Phenotype', 'HP:0007716', (136, 150))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('mutations', 'Var', (20, 29))	('Galphaq', 'Gene', (61, 68))	('observed', 'Reg', (107, 115))	('uveal melanomas', 'Phenotype', 'HP:0007716', (136, 151))	('GNAQ', 'Gene', (33, 37))	('uveal melanomas', 'Disease', (136, 151))	('Galpha11', 'Gene', '2767', (73, 81))	('melanomas', 'Disease', 'MESH:D008545', (235, 244))	('GNA11', 'Gene', (41, 46))	('melanomas', 'Disease', (235, 244))	('melanomas', 'Phenotype', 'HP:0002861', (142, 151))	('Galphaq', 'Gene', '2776', (61, 68))
138352	25592648	Recently, two independent studies have revealed that cancer-associated Galphaq and Galpha11 mutants activate YAP, mediating the oncogenic activity of mutant Galphaq and Galpha11 in uveal melanoma development (FIG.	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('activate', 'PosReg', (100, 108))	('Galphaq', 'Gene', (71, 78))	('mutants', 'Var', (92, 99))	('Galpha11', 'Gene', (169, 177))	('Galphaq', 'Gene', '2776', (71, 78))	('mutant', 'Var', (150, 156))	('Galphaq', 'Gene', (157, 164))	('Galpha11', 'Gene', '2767', (83, 91))	('cancer', 'Disease', (53, 59))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('uveal melanoma', 'Disease', 'MESH:C536494', (181, 195))	('uveal melanoma', 'Disease', (181, 195))	('YAP', 'Protein', (109, 112))	('Galphaq', 'Gene', '2776', (157, 164))	('Galpha11', 'Gene', '2767', (169, 177))	('uveal melanoma', 'Phenotype', 'HP:0007716', (181, 195))	('Galpha11', 'Gene', (83, 91))
138353	25592648	showed that cancer-associated Galphaq and Galpha11 mutants inhibit LATS, resulting in dephosphorylation and activation of YAP; on the other hand, Feng et al.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('mutants', 'Var', (51, 58))	('Galpha11', 'Gene', '2767', (42, 50))	('cancer', 'Disease', (12, 18))	('Galphaq', 'Gene', '2776', (30, 37))	('LATS', 'MPA', (67, 71))	('dephosphorylation', 'MPA', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('dephosphorylation', 'biological_process', 'GO:0016311', ('86', '103'))	('inhibit', 'NegReg', (59, 66))	('Galpha11', 'Gene', (42, 50))	('YAP', 'MPA', (122, 125))	('Galphaq', 'Gene', (30, 37))	('activation', 'PosReg', (108, 118))
138355	25592648	Although the mechanisms linking the actin cytoskeleton to YAP activation are poorly understood, both groups showed that YAP is essential in transducing the oncogenic activity of mutant Galphaq and Galpha11 to induce uveal melanoma.	('uveal melanoma', 'Disease', (216, 230))	('mutant', 'Var', (178, 184))	('induce', 'PosReg', (209, 215))	('Galpha11', 'Gene', (197, 205))	('Galphaq', 'Gene', (185, 192))	('Galphaq', 'Gene', '2776', (185, 192))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('oncogenic activity', 'MPA', (156, 174))	('Galpha11', 'Gene', '2767', (197, 205))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('36', '54'))	('uveal melanoma', 'Disease', 'MESH:C536494', (216, 230))	('uveal melanoma', 'Phenotype', 'HP:0007716', (216, 230))
138356	25592648	In addition, both groups successfully used the YAP and TAZ inhibitor verteporfin to block tumour growth of uveal melanoma cells containing Galphaq and Galpha11 mutations, suggesting that YAP could be a therapeutic target in these tumours.	('Galphaq', 'Gene', '2776', (139, 146))	('mutations', 'Var', (160, 169))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('tumours', 'Phenotype', 'HP:0002664', (230, 237))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('verteporfin', 'Chemical', 'MESH:D000077362', (69, 80))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('tumours', 'Disease', 'MESH:D009369', (230, 237))	('block tumour growth of uveal melanoma', 'Disease', 'MESH:C536494', (84, 121))	('Galpha11', 'Gene', (151, 159))	('Galphaq', 'Gene', (139, 146))	('tumours', 'Disease', (230, 237))	('Galpha11', 'Gene', '2767', (151, 159))	('block tumour growth of uveal melanoma', 'Disease', (84, 121))
138361	25592648	Moreover, these findings are clinically relevant as YAP and TAZ have been revealed to be independent predictors of colorectal cancer progression.	('YAP', 'Var', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (115, 132))	('colorectal cancer', 'Phenotype', 'HP:0003003', (115, 132))	('colorectal cancer', 'Disease', (115, 132))
138368	25592648	found that loss of YAP can lead to WNT hypersensitivity with subsequent stem cell expansion and hyperplasia during mouse intestinal regeneration, whereas transgenic overexpression of YAP restricts WNT signals.	('hypersensitivity', 'Disease', 'MESH:D004342', (39, 55))	('stem cell expansion', 'CPA', (72, 91))	('loss', 'Var', (11, 15))	('regeneration', 'biological_process', 'GO:0031099', ('132', '144'))	('hyperplasia', 'Disease', 'MESH:D006965', (96, 107))	('mouse', 'Species', '10090', (115, 120))	('YAP', 'Gene', (19, 22))	('lead to', 'Reg', (27, 34))	('hypersensitivity', 'Disease', (39, 55))	('hypersensitivity', 'biological_process', 'GO:0002524', ('39', '55'))	('cell expansion', 'biological_process', 'GO:0016049', ('77', '91'))	('hyperplasia', 'Disease', (96, 107))
138369	25592648	Furthermore, YAP is silenced in a subset of highly aggressive and undifferentiated human colorectal cancers, and its re-expression can restrict the growth of colorectal carcinoma xenografts, suggesting a potential tumour suppressor role for YAP in this tissue.	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('colorectal carcinoma xenografts', 'Disease', 'MESH:D015179', (158, 189))	('colorectal cancers', 'Disease', 'MESH:D015179', (89, 107))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('tumour', 'Disease', (214, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('human', 'Species', '9606', (83, 88))	('growth', 'CPA', (148, 154))	('colorectal cancers', 'Disease', (89, 107))	('restrict', 'NegReg', (135, 143))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('silenced', 'NegReg', (20, 28))	('re-expression', 'Var', (117, 130))	('YAP', 'Gene', (13, 16))	('tumour', 'Disease', 'MESH:D009369', (214, 220))	('colorectal carcinoma xenografts', 'Disease', (158, 189))
138375	25592648	Re-expression of YAP in multiple myeloma cells with YAP deletion or knockdown of MST1 in multiple myeloma cells with wild-type YAP, promoted apoptosis and growth arrest.	('deletion', 'Var', (56, 64))	('multiple myeloma', 'Disease', (89, 105))	('multiple myeloma', 'Disease', 'MESH:D009101', (24, 40))	('multiple myeloma', 'Phenotype', 'HP:0006775', (89, 105))	('multiple myeloma', 'Disease', (24, 40))	('MST1', 'Gene', '6789', (81, 85))	('apoptosis', 'biological_process', 'GO:0097194', ('141', '150'))	('growth arrest', 'Disease', 'MESH:D006323', (155, 168))	('apoptosis', 'biological_process', 'GO:0006915', ('141', '150'))	('growth arrest', 'Phenotype', 'HP:0001510', (155, 168))	('YAP', 'Gene', (52, 55))	('promoted', 'PosReg', (132, 140))	('apoptosis', 'CPA', (141, 150))	('MST1', 'Gene', (81, 85))	('multiple myeloma', 'Disease', 'MESH:D009101', (89, 105))	('growth arrest', 'Disease', (155, 168))	('multiple myeloma', 'Phenotype', 'HP:0006775', (24, 40))
138377	25592648	Of note, in contrast to YAP, focal deletions affecting the TAZ locus were not detected in multiple myeloma, suggesting that haematological cancers preferentially inactivate YAP.	('multiple myeloma', 'Phenotype', 'HP:0006775', (90, 106))	('multiple myeloma', 'Disease', 'MESH:D009101', (90, 106))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('haematological cancers', 'Disease', (124, 146))	('multiple myeloma', 'Disease', (90, 106))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('YAP', 'Gene', (173, 176))	('deletions', 'Var', (35, 44))	('haematological cancers', 'Disease', 'MESH:D009369', (124, 146))	('inactivate', 'NegReg', (162, 172))
138378	25592648	Interestingly, a recurrent inactivating mutation encoding a G17V substitution in the GTP-binding domain of RHOA GTPase was observed in T cell lymphoma.	('G17V', 'Mutation', 'p.G17V', (60, 64))	('T cell lymphoma', 'Disease', (135, 150))	('RHOA', 'Gene', '387', (107, 111))	('GTP', 'Chemical', 'MESH:D006160', (85, 88))	('G17V', 'Var', (60, 64))	('RHOA', 'Gene', (107, 111))	('GTPase', 'Gene', (112, 118))	('T cell lymphoma', 'Disease', 'MESH:D016399', (135, 150))	('lymphoma', 'Phenotype', 'HP:0002665', (142, 150))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (135, 150))	('cell lymphoma', 'Phenotype', 'HP:0012191', (137, 150))	('GTP-binding', 'molecular_function', 'GO:0005525', ('85', '96'))	('GTP', 'Chemical', 'MESH:D006160', (112, 115))
138380	25592648	2), it is possible that the RHOA mutation could inactivate YAP and thus inhibit YAP-TP73-mediated apoptosis in T cell lymphoma, although this awaits formal examination.	('RHOA', 'Gene', (28, 32))	('YAP', 'Gene', (59, 62))	('mutation', 'Var', (33, 41))	('cell lymphoma', 'Phenotype', 'HP:0012191', (113, 126))	('T cell lymphoma', 'Disease', 'MESH:D016399', (111, 126))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('TP73', 'Gene', '7161', (84, 88))	('inactivate', 'NegReg', (48, 58))	('TP73', 'Gene', (84, 88))	('inhibit', 'NegReg', (72, 79))	('RHOA', 'Gene', '387', (28, 32))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (111, 126))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))	('T cell lymphoma', 'Disease', (111, 126))
138397	25592648	Inhibition of the mevalonate pathway had antiproliferative and apoptotic effects in breast cancer cells and prevented the transcriptional co-activator Yorkie (the fly homologue of YAP and TAZ) from inducing eye overgrowth in D. melanogaster.	('antiproliferative', 'CPA', (41, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('Yorkie', 'Gene', '37851', (151, 157))	('apoptotic effects', 'CPA', (63, 80))	('eye overgrowth', 'CPA', (207, 221))	('prevented', 'NegReg', (108, 117))	('mevalonate pathway', 'Pathway', (18, 36))	('Inhibition', 'Var', (0, 10))	('D. melanogaster', 'Species', '7227', (225, 240))	('inducing', 'Reg', (198, 206))	('Yorkie', 'Gene', (151, 157))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('mevalonate', 'Chemical', 'MESH:D008798', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('overgrowth', 'Phenotype', 'HP:0001548', (211, 221))	('breast cancer', 'Disease', (84, 97))
138400	25592648	An additional plausible scenario is that mutations in components of the Hippo pathway might be identified in rare types of cancers, as the recent finding of LATS2 loss-of-function mutations in malignant mesothelioma-derived cell lines implies.	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('LATS2', 'Gene', (157, 162))	('mutations', 'Var', (180, 189))	('LATS2', 'Gene', '26524', (157, 162))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (193, 215))	('malignant mesothelioma', 'Disease', (193, 215))	('loss-of-function', 'NegReg', (163, 179))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (193, 215))
138401	25592648	In addition, it is clear that some of the proteins that are implicated in regulation of the Hippo pathway are 'derailed' and mutated in cancers, such as the junctional protein E-cadherin (in breast adenocarcinomas), the LIM domain-containing protein AJUBA (in head and neck squamous carcinoma), LKB1 (REFS), RHOA, and GPCRs and their cognate G proteins.	('cadherin', 'molecular_function', 'GO:0008014', ('178', '186'))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('breast adenocarcinomas', 'Disease', 'MESH:D000230', (191, 213))	('cancers', 'Disease', (136, 143))	('Hippo pathway', 'Pathway', (92, 105))	('GPCR', 'Gene', '441931', (318, 322))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('LKB1', 'Gene', '6794', (295, 299))	('mutated', 'Var', (125, 132))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (274, 292))	('neck squamous carcinoma', 'Disease', (269, 292))	('breast adenocarcinomas', 'Disease', (191, 213))	('E-cadherin', 'Gene', (176, 186))	('E-cadherin', 'Gene', '999', (176, 186))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('protein', 'cellular_component', 'GO:0003675', ('242', '249'))	("'derailed", 'PosReg', (110, 119))	('regulation', 'biological_process', 'GO:0065007', ('74', '84'))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('neck squamous carcinoma', 'Disease', 'MESH:D000077195', (269, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('carcinomas', 'Phenotype', 'HP:0030731', (203, 213))	('LKB1', 'Gene', (295, 299))	('GPCR', 'Gene', (318, 322))	('RHOA', 'Gene', '387', (308, 312))	('RHOA', 'Gene', (308, 312))	('neck', 'cellular_component', 'GO:0044326', ('269', '273'))
138407	25526026	Uveal melanoma growth is driven by gain-of-function mutations in GNAQ or GNA11 oncogenes, encoding persistently active G protein alpha subunits of the Gq family.	('GNA11', 'Gene', (73, 78))	('mutations', 'Var', (52, 61))	('GNA11', 'Gene', '2767', (73, 78))	('GNAQ', 'Gene', '2776', (65, 69))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('gain-of-function', 'PosReg', (35, 51))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('GNAQ', 'Gene', (65, 69))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
138411	25526026	The latter mimics the impact of B-RAF or N-RAS oncogene mutations in cutaneous melanomas.	('mutations', 'Var', (56, 65))	('B-RAF', 'Gene', (32, 37))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (69, 88))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (69, 88))	('cutaneous melanomas', 'Disease', (69, 88))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))	('B-RAF', 'Gene', '673', (32, 37))
138412	25526026	However, inhibitors of the ERK pathway increase progression free survival but has a limited impact in overall survival of uveal melanoma patients, suggesting that GNAQ can activate oncogenic signaling circuitries circumventing ERK inhibition.	('increase', 'PosReg', (39, 47))	('uveal melanoma', 'Disease', (122, 136))	('uveal melanoma', 'Disease', 'MESH:C536494', (122, 136))	('ERK', 'Gene', (27, 30))	('ERK', 'Gene', (227, 230))	('activate', 'PosReg', (172, 180))	('GNAQ', 'Gene', '2776', (163, 167))	('uveal melanoma', 'Phenotype', 'HP:0007716', (122, 136))	('ERK', 'molecular_function', 'GO:0004707', ('227', '230'))	('GNAQ', 'Gene', (163, 167))	('ERK', 'molecular_function', 'GO:0004707', ('27', '30'))	('patients', 'Species', '9606', (137, 145))	('oncogenic signaling circuitries', 'Pathway', (181, 212))	('signaling', 'biological_process', 'GO:0023052', ('191', '200'))	('ERK', 'Gene', '5594', (27, 30))	('progression', 'MPA', (48, 59))	('ERK', 'Gene', '5594', (227, 230))	('inhibitors', 'Var', (9, 19))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))
138423	25526026	As AMOT's PPxY motifs are adjacent to its F-actin binding region, polymerized actin competes for YAP binding thereby increasing free YAP, while actin depolymerization and increase in G-actin will result in the accumulation of inactive, AMOT-bound YAP protein complexes (Fig.	('accumulation', 'PosReg', (210, 222))	('increasing', 'PosReg', (117, 127))	('YAP', 'Gene', '10413', (247, 250))	('actin depolymerization', 'biological_process', 'GO:0030042', ('144', '166'))	('protein', 'cellular_component', 'GO:0003675', ('251', '258'))	('YAP', 'Gene', (133, 136))	('YAP', 'Gene', '10413', (97, 100))	('depolymerization', 'Var', (150, 166))	('increase', 'PosReg', (171, 179))	('AMOT', 'Gene', (236, 240))	('YAP', 'Gene', '10413', (133, 136))	('AMOT', 'Gene', '51421', (236, 240))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))	('F-actin binding', 'molecular_function', 'GO:0051015', ('42', '57'))	('F-actin', 'cellular_component', 'GO:0031941', ('42', '49'))	('YAP', 'Gene', (247, 250))	('YAP', 'Gene', (97, 100))	('AMOT', 'Gene', (3, 7))	('AMOT', 'Gene', '51421', (3, 7))
138539	32906203	Aberrant DNA methylation of these islands may cause downregulation of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Aberrant DNA methylation', 'Var', (0, 24))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', (70, 75))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('downregulation', 'NegReg', (52, 66))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
138542	32906203	Mutations, copy number alterations, and cell type-specific DNA markers have been quantified successfully to gain insight into the content and the evolutionary history of tumors (de Lange et al., 2015; Versluis et al., 2015; Zoutman et al., 2017).	('tumors', 'Disease', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))
138543	32906203	Whereas most analog methylation analysis methods depend on the chemical conversion of the input DNA with sodium bisulfite, MSREs can differentiate between methylated and unmethylated alleles independently of this conversion.	('sodium bisulfite', 'Chemical', 'MESH:C009279', (105, 121))	('differentiate', 'Reg', (133, 146))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('methylated', 'Var', (155, 165))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))
138545	32906203	Instead, our experimental setup provides a complete quantification of DNA methylation with confidence intervals in the whole range from 0% to 100%, and can be applied in copy number unstable specimens, such as malignancies.	('methylation', 'Var', (74, 85))	('DNA methylation', 'biological_process', 'GO:0006306', ('70', '85'))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('malignancies', 'Disease', 'MESH:D009369', (210, 222))	('malignancies', 'Disease', (210, 222))
138548	32906203	Epigenetic silencing in the form of DNA promoter methylation of this gene has been demonstrated in a wide variety of human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (123, 135))	('human', 'Species', '9606', (117, 122))	('malignancies', 'Disease', (123, 135))	('Epigenetic silencing', 'Var', (0, 20))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('methylation', 'biological_process', 'GO:0032259', ('49', '60'))	('DNA promoter', 'MPA', (36, 48))
138559	32906203	In copy number unstable samples, TERT might be involved in genetic alterations.	('involved', 'Reg', (47, 55))	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('copy number unstable', 'Var', (3, 23))
138575	32906203	In four out of the five uveal melanoma cell lines, in which previously extensive RASSF1 methylation was observed, only completely methylated alleles were detected (Figure 4b; Maat et al., 2007).	('uveal melanoma', 'Disease', (24, 38))	('methylation', 'Var', (88, 99))	('RASSF1', 'Gene', '11186', (81, 87))	('RASSF1', 'Gene', (81, 87))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (24, 38))	('uveal melanoma', 'Disease', 'MESH:C536494', (24, 38))
138576	32906203	In placental tissue, both fetal and maternal cells are present, with hypo- and hypermethylated RASSF1 in distinct cell types (Chiu et al., 2007).	('RASSF1', 'Gene', (95, 101))	('RASSF1', 'Gene', '11186', (95, 101))	('hypo-', 'Var', (69, 74))	('hypermethylated', 'Var', (79, 94))
138584	32906203	As thymines bind to adenine via two hydrogen bonds, and cytosines to guanines via three hydrogen bonds, methylated and unmethylated alleles ultimately lead to distinct melting profiles when subjected to thermal denaturation (MS-MCA; Wojdacz, Dobrovic, & Hansen, 2008).	('hydrogen', 'Chemical', 'MESH:D006859', (36, 44))	('adenine', 'Chemical', 'MESH:D000225', (20, 27))	('cytosines', 'Var', (56, 65))	('melting profiles', 'MPA', (168, 184))	('cytosines', 'Chemical', 'MESH:D003596', (56, 65))	('guanines', 'Chemical', 'MESH:D006147', (69, 77))	('hydrogen', 'Chemical', 'MESH:D006859', (88, 96))	('thymines', 'Chemical', 'MESH:D013941', (3, 11))	('bind', 'Interaction', (12, 16))	('lead to', 'Reg', (151, 158))
138585	32906203	The placenta samples and two of the three commercially available methylation control samples (the methylated control and unmethylated control A) were all characterized by heterogeneous RASSF1 methylation, in which both methylated and unmethylated alleles were present.	('RASSF1', 'Gene', (185, 191))	('methylation', 'Var', (192, 203))	('methylation', 'biological_process', 'GO:0032259', ('192', '203'))	('RASSF1', 'Gene', '11186', (185, 191))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))
138587	32906203	In addition, the genotype status of single-nucleotide polymorphism (SNP) rs1989839 was quantified in all mixtures.	('rs1989839', 'Var', (73, 82))	('rs1989839', 'Mutation', 'rs1989839', (73, 82))	('single-nucleotide polymorphism', 'Var', (36, 66))
138590	32906203	Especially in cancer, aberrant methylation plays a role in the initiation and progression of the disease (Jones & Baylin, 2002, 2007).	('cancer', 'Disease', (14, 20))	('aberrant methylation', 'Var', (22, 42))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
138591	32906203	Along with genetic alterations, also epigenetic changes diversify tumor cell populations ("intratumor heterogeneity").	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('epigenetic changes', 'Var', (37, 55))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('diversify', 'Reg', (56, 65))
138596	32906203	Similarly, uveal melanoma cell line Mel-290 presented with a small fraction of 6% methylated alleles using digital PCR, which was again undetectable with MS-MCA and BS (Figure 5c; Maat et al., 2007).	('uveal melanoma', 'Phenotype', 'HP:0007716', (11, 25))	('uveal melanoma', 'Disease', 'MESH:C536494', (11, 25))	('uveal melanoma', 'Disease', (11, 25))	('methylated', 'Var', (82, 92))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))
138600	32906203	However, here we showed that absolute quantification with digital PCR indicated the presence of both methylated and unmethylated RASSF1 alleles in two of these commercial control samples (Figures 4E and S1).	('RASSF1', 'Gene', '11186', (129, 135))	('RASSF1', 'Gene', (129, 135))	('methylated', 'Var', (101, 111))	('presence', 'Reg', (84, 92))
138706	32434572	In mice with 0.5 and 0.25x106 cells injection, one of 5 mice in each group showed a continuous increase in fluorescent intensity that was similar to mice with 2.0 and 1.0x106 injection (Fig.	('0.25x106 cells injection', 'Var', (21, 45))	('mice', 'Species', '10090', (3, 7))	('increase', 'PosReg', (95, 103))	('mice', 'Species', '10090', (56, 60))	('mice', 'Species', '10090', (149, 153))	('fluorescent intensity', 'MPA', (107, 128))
138708	32434572	All mice with less than 0.5x106 cells injection also developed diffuse hepatic tumors, and one mouse with 0.25x106 cells injection survived over 16 weeks after injection (Fig.	('hepatic tumors', 'Disease', (71, 85))	('mice', 'Species', '10090', (4, 8))	('hepatic tumor', 'Phenotype', 'HP:0002896', (71, 84))	('less', 'Var', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('hepatic tumors', 'Disease', 'MESH:D056486', (71, 85))	('developed', 'PosReg', (53, 62))	('diffuse', 'CPA', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('mouse', 'Species', '10090', (95, 100))
138830	31755472	Recent data have suggested that ocular melanocytosis, a sporadic condition, is related to a somatic mutation of GNAQ, a heterotrimeric G protein alpha subunit.	('ocular melanocytosis', 'Disease', 'MESH:C535835', (32, 52))	('ocular melanocytosis', 'Phenotype', 'HP:0025534', (32, 52))	('ocular melanocytosis', 'Disease', (32, 52))	('GNAQ', 'Gene', (112, 116))	('GNAQ', 'Gene', '2776', (112, 116))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('120', '144'))	('mutation', 'Var', (100, 108))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('related', 'Reg', (79, 86))
138832	31755472	studied skin biopsies of cutaneous melanocytosis in six cases and found GNAQ/GNA11 mutations in three (50%).	('mutations', 'Var', (83, 92))	('GNA11', 'Gene', (77, 82))	('GNAQ', 'Gene', '2776', (72, 76))	('cutaneous melanocytosis', 'Disease', (25, 48))	('GNA11', 'Gene', '2767', (77, 82))	('cutaneous melanocytosis', 'Disease', 'MESH:C535835', (25, 48))	('GNAQ', 'Gene', (72, 76))
138833	31755472	reported transformation of dermal melanocytosis into melanoma and documented both GNAQ and BAP-1 mutations.	('mutations', 'Var', (97, 106))	('dermal melanocytosis', 'Disease', 'MESH:C535835', (27, 47))	('BAP-1', 'Gene', '8314', (91, 96))	('GNAQ', 'Gene', (82, 86))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('BAP-1', 'Gene', (91, 96))	('dermal melanocytosis', 'Phenotype', 'HP:0100814', (27, 47))	('GNAQ', 'Gene', '2776', (82, 86))	('dermal melanocytosis', 'Disease', (27, 47))
138859	31722735	Molecular biomarkers associated with a higher risk of metastasis are monosomy 3 or genomic alterations of BAP-1.	('genomic alterations', 'Var', (83, 102))	('monosomy 3', 'Var', (69, 79))	('BAP-1', 'Gene', '8314', (106, 111))	('BAP-1', 'Gene', (106, 111))
138884	31722735	Mutations and inactivations of MBD4 which were previously linked to a hypermutator profile with high sensitivity to PD-1 inhibition were not investigated in any case.	('PD-1', 'Gene', (116, 120))	('inactivations', 'Var', (14, 27))	('PD-1', 'Gene', '9825', (116, 120))	('Mutations', 'Var', (0, 9))	('MBD4', 'Gene', '8930', (31, 35))	('MBD4', 'Gene', (31, 35))
138948	31234340	In this setting, a monosomy of chromosome 3 and chromosome 8q gain (M3/8g) has been reported to be a prominent risk factor for metastases.	('chromosome', 'cellular_component', 'GO:0005694', ('31', '41'))	('metastases', 'Disease', 'MESH:D009362', (127, 137))	('gain', 'PosReg', (62, 66))	('monosomy', 'Var', (19, 27))	('chromosome', 'cellular_component', 'GO:0005694', ('48', '58'))	('metastases', 'Disease', (127, 137))
139013	31234340	Seventh, only a few studies have compared the genomic profiles of the primary tumor and metastases, and only one study showed the negative impact of GNA11 mutation on the disease specific survival and the overall survival of the 30 metastatic patients studied.	('GNA11', 'Gene', '2767', (149, 154))	('GNA11', 'Gene', (149, 154))	('metastases', 'Disease', (88, 98))	('patients', 'Species', '9606', (243, 251))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('metastases', 'Disease', 'MESH:D009362', (88, 98))	('mutation', 'Var', (155, 163))	('tumor', 'Disease', (78, 83))
139090	31191996	The lack of oxygen induces an anaerobic metabolism which probably causes the accumulation of vasoactive metabolites or the release of vasoactive substances from mast cells that abound in the sclera and conjunctiva.	('accumulation', 'PosReg', (77, 89))	('anaerobic metabolism', 'MPA', (30, 50))	('vasoactive metabolites', 'MPA', (93, 115))	('release of vasoactive substances', 'MPA', (123, 155))	('metabolism', 'biological_process', 'GO:0008152', ('40', '50'))	('lack', 'Var', (4, 8))	('oxygen', 'Chemical', 'MESH:D010100', (12, 18))	('induces', 'Reg', (19, 26))
139105	30911311	The two most widely used forms of interventional radiation therapy, Iodine-125 and Ruthenium-106 brachytherapy, were associated with a weighted average of local recurrence rate of 9.6%.	('Ruthenium-106 brachytherapy', 'Var', (83, 110))	('local recurrence', 'CPA', (155, 171))	('Iodine-125', 'Var', (68, 78))	('Iodine-125', 'Chemical', 'MESH:C000614960', (68, 78))	('Ruthenium-106', 'Chemical', 'MESH:C000615522', (83, 96))
139133	30911311	Important tumor and treatment features as well as the total dose of treatment may influence the outcomes (as reported in literature) of both Iodine-125 and Ruthenium-106.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('influence', 'Reg', (82, 91))	('Iodine-125', 'Chemical', 'MESH:C000614960', (141, 151))	('tumor', 'Disease', (10, 15))	('Ruthenium-106', 'Chemical', 'MESH:C000615522', (156, 169))	('outcomes', 'MPA', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('Iodine-125', 'Var', (141, 151))
139251	30122854	However, none of the second cancers found on our cohort were typical tumors seen in the described germline BAP1 mutation.	('cancers', 'Disease', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('BAP1', 'Gene', '8314', (107, 111))	('mutation', 'Var', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('BAP1', 'Gene', (107, 111))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('cancers', 'Disease', 'MESH:D009369', (28, 35))
139322	29789761	VA on presentation was 20/12.5 to 20/20 in 54 patients (29%), 20/20 to 20/32 in 44 patients (24%), 20/32 to 20/50 in 44 patients (24%), 20/50 to 20/80 in 21 patients (11%), 20/80 to 20/200 in 22 patients (12%), and 20/200 to 20/125 in 1 patients (1%).	('patients', 'Species', '9606', (46, 54))	('20/32 to 20/50', 'Var', (99, 113))	('20/50 to 20/80', 'Var', (136, 150))	('patients', 'Species', '9606', (157, 165))	('20/20 to 20/32', 'Var', (62, 76))	('patients', 'Species', '9606', (195, 203))	('patients', 'Species', '9606', (120, 128))	('20/80 to 20/200', 'Var', (173, 188))	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (237, 245))
139356	29317634	Uveal melanoma (UM) is the most common primary eye cancer and frequently leads to metastatic death, which is strongly linked to BAP1 mutations.	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('BAP1', 'Gene', '8314', (128, 132))	('eye cancer', 'Phenotype', 'HP:0100012', (47, 57))	('death', 'Disease', 'MESH:D003643', (93, 98))	('leads to', 'Reg', (73, 81))	('primary eye cancer', 'Disease', (39, 57))	('BAP1', 'Gene', (128, 132))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('mutations', 'Var', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('UM', 'Phenotype', 'HP:0007716', (16, 18))	('death', 'Disease', (93, 98))	('melanoma', 'Disease', (6, 14))	('primary eye cancer', 'Disease', 'MESH:D005134', (39, 57))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
139357	29317634	Here we analyze sequencing data from 151 primary UM samples using a customized bioinformatic pipeline, to improve detection of BAP1 mutations and infer the clonal relationships among genomic aberrations.	('BAP1', 'Gene', (127, 131))	('improve', 'PosReg', (106, 113))	('UM', 'Phenotype', 'HP:0007716', (49, 51))	('mutations', 'Var', (132, 141))	('BAP1', 'Gene', '8314', (127, 131))
139358	29317634	Strikingly, we find BAP1 mutations and other canonical genomic aberrations usually arise in an early punctuated burst, followed by neutral evolution extending to the time of clinical detection.	('mutations', 'Var', (25, 34))	('BAP1', 'Gene', (20, 24))	('arise', 'Reg', (83, 88))	('clinical', 'Species', '191496', (174, 182))	('BAP1', 'Gene', '8314', (20, 24))
139360	29317634	Uveal melanoma (UM), the most common primary eye cancer, is strongly linked to mutations in the tumor suppressor BAP1.	('melanoma', 'Disease', 'MESH:D008545', (6, 14))	('tumor suppressor', 'biological_process', 'GO:0051726', ('96', '112'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('96', '112'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('linked', 'Reg', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('primary eye cancer', 'Disease', (37, 55))	('tumor', 'Disease', (96, 101))	('eye cancer', 'Phenotype', 'HP:0100012', (45, 55))	('primary eye cancer', 'Disease', 'MESH:D005134', (37, 55))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('BAP1', 'Gene', '8314', (113, 117))	('UM', 'Phenotype', 'HP:0007716', (16, 18))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('melanoma', 'Disease', (6, 14))	('BAP1', 'Gene', (113, 117))	('mutations', 'Var', (79, 88))
139363	29317634	One group consists of mutually exclusive gain-of-function mutations in members of the Gq signaling pathway:GNAQ, GNA11, CYSLTR2, or PLCB4.	('mutations', 'Var', (58, 67))	('PLCB4', 'Gene', (132, 137))	('Gq signaling pathway', 'Pathway', (86, 106))	('CYSLTR2', 'Gene', (120, 127))	('signaling pathway', 'biological_process', 'GO:0007165', ('89', '106'))	('GNAQ', 'Gene', '2776', (107, 111))	('GNA11', 'Gene', (113, 118))	('GNA11', 'Gene', '2767', (113, 118))	('gain-of-function', 'PosReg', (41, 57))	('PLCB4', 'Gene', '5332', (132, 137))	('GNAQ', 'Gene', (107, 111))	('CYSLTR2', 'Gene', '57105', (120, 127))
139364	29317634	These "Gq mutations" are present in virtually all UMs, are not prognostically significant, are insufficient alone to induce malignant transformation, but are seemingly required to initiate tumorigenesis.	('insufficient', 'Disease', (95, 107))	('insufficient', 'Disease', 'MESH:D000309', (95, 107))	('tumor', 'Disease', (189, 194))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('mutations', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
139365	29317634	The other group consists of near-mutually exclusive mutations in BAP1, SF3B1, and EIF1AX ("BSE" mutations), which are strongly prognostic of metastatic risk.	('mutations', 'Var', (52, 61))	('SF3B1', 'Gene', (71, 76))	('BAP1', 'Gene', '8314', (65, 69))	('SF3B1', 'Gene', '23451', (71, 76))	('BAP1', 'Gene', (65, 69))	('prognostic', 'Reg', (127, 137))	('EIF1AX', 'Gene', '1964', (82, 88))	('EIF1AX', 'Gene', (82, 88))
139366	29317634	Inactivating mutations in the tumor suppressor BAP1 are associated with the class 2 GEP and high metastatic risk, whereas single nucleotide substitutions in SF3B1 and EIF1AX are found mainly in class 1 tumors and are associated with intermediate and low metastatic risk, respectively.	('EIF1AX', 'Gene', '1964', (167, 173))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('associated', 'Reg', (56, 66))	('BAP1', 'Gene', '8314', (47, 51))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('tumor', 'Disease', (202, 207))	('Inactivating mutations', 'Var', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('single nucleotide substitutions', 'Var', (122, 153))	('BAP1', 'Gene', (47, 51))	('SF3B1', 'Gene', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('class 2 GEP', 'Disease', (76, 87))	('EIF1AX', 'Gene', (167, 173))	('SF3B1', 'Gene', '23451', (157, 162))	('tumors', 'Disease', (202, 208))	('tumor', 'Disease', (30, 35))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))
139368	29317634	6p Gain (6p+) is often found in class 1 tumors harboring SF3B1 and EIF1AX mutations, whereas 8q gain (8q+) can be found in both class 1 and class 2 tumors, and is associated with BAP1 and SF3B1 mutations.	('SF3B1', 'Gene', '23451', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('8q+', 'Chemical', '-', (102, 105))	('tumors', 'Disease', (40, 46))	('SF3B1', 'Gene', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('BAP1', 'Gene', '8314', (179, 183))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('EIF1AX', 'Gene', (67, 73))	('Gain', 'PosReg', (3, 7))	('SF3B1', 'Gene', '23451', (57, 62))	('tumors', 'Disease', (148, 154))	('SF3B1', 'Gene', (188, 193))	('BAP1', 'Gene', (179, 183))	('EIF1AX', 'Gene', '1964', (67, 73))	('mutations', 'Var', (74, 83))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
139371	29317634	An obstacle to performing reliable genomic clonality analysis in UM has been an inability to detect the wide diversity of BAP1 mutations using standard bioinformatic methods.	('BAP1', 'Gene', '8314', (122, 126))	('mutations', 'Var', (127, 136))	('UM', 'Phenotype', 'HP:0007716', (65, 67))	('BAP1', 'Gene', (122, 126))
139372	29317634	Here we analyze next generation sequencing (NGS) data from 151 primary UMs using a wide range of bioinformatic tools and techniques to optimize our detection of BAP1 and other mutations and CNAs, to explore their clonal relationships.	('BAP1', 'Gene', '8314', (161, 165))	('mutations', 'Var', (176, 185))	('BAP1', 'Gene', (161, 165))	('UM', 'Phenotype', 'HP:0007716', (71, 73))
139373	29317634	This approach reveals many previously undetected BAP1 and spliceosome mutations, and uncovers strong evidence that the canonical genomic aberrations in UM usually arise in an early, punctuated burst followed by clonal stasis.	('mutations', 'Var', (70, 79))	('BAP1', 'Gene', (49, 53))	('UM usually', 'Gene', (152, 162))	('UM', 'Phenotype', 'HP:0007716', (152, 154))	('spliceosome', 'cellular_component', 'GO:0005681', ('58', '69'))	('BAP1', 'Gene', '8314', (49, 53))
139375	29317634	), 80 from the The Cancer Genome Atlas (TCGA), and 22 from a publicly available data set (UNI-UDE) to identify driver mutations and CNAs (Fig.	('Cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (19, 38))	('mutations', 'Var', (118, 127))	('Cancer Genome Atlas', 'Disease', (19, 38))
139376	29317634	Recent analyses have found BAP1 mutations in only about 20% of UMs, yet ~ 40% of UMs are expected to harbor these mutations.	('UM', 'Phenotype', 'HP:0007716', (63, 65))	('BAP1', 'Gene', (27, 31))	('UMs', 'Disease', (63, 66))	('mutations', 'Var', (32, 41))	('UM', 'Phenotype', 'HP:0007716', (81, 83))	('BAP1', 'Gene', '8314', (27, 31))
139377	29317634	Thus, we suspected that BAP1 mutations may frequently be missed when they comprise large insertions/deletions (indels), intronic/splicing alterations, and other complex rearrangements of the BAP1 locus.	('insertions/deletions', 'Var', (89, 109))	('BAP1', 'Gene', (24, 28))	('splicing', 'biological_process', 'GO:0045292', ('129', '137'))	('mutations', 'Var', (29, 38))	('BAP1', 'Gene', '8314', (191, 195))	('BAP1', 'Gene', (191, 195))	('BAP1', 'Gene', '8314', (24, 28))
139378	29317634	In comparison with the Firehose analysis, which detected BAP1 mutations in 17 (21%) of the 80 TCGA samples using the GATK pipeline (Supplementary Fig.	('BAP1', 'Gene', '8314', (57, 61))	('BAP1', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
139379	29317634	2), our pipeline detected BAP1 mutations in 36/80 (45%) of the same samples (Supplementary Data 1).	('detected', 'Reg', (17, 25))	('BAP1', 'Gene', '8314', (26, 30))	('mutations', 'Var', (31, 40))	('BAP1', 'Gene', (26, 30))
139380	29317634	identified BAP1 mutations in 4 (18%) of 22 samples, whereas we identified BAP1 mutations in 9 (41%) of the same samples (Supplementary Data 1).	('BAP1', 'Gene', '8314', (11, 15))	('mutations', 'Var', (16, 25))	('BAP1', 'Gene', '8314', (74, 78))	('BAP1', 'Gene', (11, 15))	('BAP1', 'Gene', (74, 78))
139381	29317634	Overall, BAP1 mutations were detected in 62 (45%) of the 139 WES samples queried in this study, including 9 non-synonymous single-nucleotide polymorphisms (SNPs), 10 stopgain/stoploss SNPs, 2 intronic/splice SNPs, and 41 indels (Fig.	('indels', 'Var', (221, 227))	('detected', 'Reg', (29, 37))	('BAP1', 'Gene', '8314', (9, 13))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
139382	29317634	The use of two different mutation callers (MuTect2 and Varscan2) improved detection of BAP1 mutations, 17 of which were only called by one algorithm or the other.	('BAP1', 'Gene', '8314', (87, 91))	('improved', 'PosReg', (65, 73))	('BAP1', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('detection', 'MPA', (74, 83))
139383	29317634	Using ABRA to re-align around large indels, we detected BAP1 deletions of > 20 base pairs in 10 samples that were not previously detected by other methods (Fig.	('deletions', 'Var', (61, 70))	('BAP1', 'Gene', '8314', (56, 60))	('ABRA', 'Gene', (6, 10))	('BAP1', 'Gene', (56, 60))	('ABRA', 'Gene', '137735', (6, 10))
139384	29317634	In one sample (A8KF), we detected a BAP1 mutation that was initially filtered out due to low exome coverage but was "rescued" with matched RNA-Seq data using UNCeqR (Fig.	('mutation', 'Var', (41, 49))	('RNA', 'cellular_component', 'GO:0005562', ('137', '140'))	('BAP1', 'Gene', (36, 40))	('BAP1', 'Gene', '8314', (36, 40))
139386	29317634	In two samples (E21 and AA8O), we identified homozygous deletions of the BAP1 locus using CNVkit that would be missed by most mutation-calling algorithms (Fig.	('deletions', 'Var', (56, 65))	('BAP1', 'Gene', (73, 77))	('BAP1', 'Gene', '8314', (73, 77))
139387	29317634	In two samples that were initially filtered out by our pipeline due to low coverage (A9EQ and E22), BAP1 mutations were identified by visual inspection using the Integrative Genomics Viewer (IGV).	('BAP1', 'Gene', '8314', (100, 104))	('A9EQ', 'Var', (85, 89))	('mutations', 'Var', (105, 114))	('BAP1', 'Gene', (100, 104))
139389	29317634	However, as BAP1 mutations are known to occur in the germline in some cases, we analyzed all blood samples independently of their matched tumor using MuTect2, with which we identified two cases with germline BAP1 mutations (MM87 and A8KN) (Fig.	('A8KN', 'Var', (233, 237))	('tumor', 'Disease', (138, 143))	('BAP1', 'Gene', '8314', (208, 212))	('MM87', 'Var', (224, 228))	('BAP1', 'Gene', '8314', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('BAP1', 'Gene', (12, 16))	('BAP1', 'Gene', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
139390	29317634	Even with our optimized pipeline, we did not identify a BAP1 mutation in 10 of the class 2 samples; thus, we suspected that some BAP1 mutations are not detectable with WES or RNA-seq data, because they span multiple exons or start in untranscribed regions.	('BAP1', 'Gene', '8314', (56, 60))	('BAP1', 'Gene', '8314', (129, 133))	('span', 'Reg', (202, 206))	('RNA', 'cellular_component', 'GO:0005562', ('175', '178'))	('BAP1', 'Gene', (56, 60))	('mutations', 'Var', (134, 143))	('BAP1', 'Gene', (129, 133))
139391	29317634	using our "SpliceDel" technique, we identified 2 samples containing multi-exonic BAP1 deletions that started in the 5'-untranslated region and intronic regions (Fig.	('BAP1', 'Gene', '8314', (81, 85))	('BAP1', 'Gene', (81, 85))	('deletions', 'Var', (86, 95))
139392	29317634	Hence, a complimentary repertoire of sequencing and analytical techniques will be required to detect all BAP1 mutations.	('BAP1', 'Gene', '8314', (105, 109))	('mutations', 'Var', (110, 119))	('BAP1', 'Gene', (105, 109))
139393	29317634	SF3B1 mutations were present in 31 (22%) samples and EIF1AX mutations were present in 20 (14%) samples (Supplementary Data 1 and Supplementary Fig.	('SF3B1', 'Gene', (0, 5))	('EIF1AX', 'Gene', '1964', (53, 59))	('EIF1AX', 'Gene', (53, 59))	('SF3B1', 'Gene', '23451', (0, 5))	('mutations', 'Var', (6, 15))
139394	29317634	Among samples without a detectable BSE mutation, five were found to harbor mutations in additional spliceosome factors, including RBM10 (two samples), SRSF2 (two samples), and SF3A1 (one sample) (Supplementary Fig.	('SF3A1', 'Gene', (176, 181))	('SRSF2', 'Gene', '6427', (151, 156))	('SF3A1', 'Gene', '10291', (176, 181))	('spliceosome', 'cellular_component', 'GO:0005681', ('99', '110'))	('harbor', 'Reg', (68, 74))	('mutations', 'Var', (75, 84))	('RBM10', 'Gene', '8241', (130, 135))	('SRSF2', 'Gene', (151, 156))	('RBM10', 'Gene', (130, 135))
139395	29317634	The SRSF2 mutations consisted of deletions encompassing the P95-R102 region previously reported to disrupt splicing in myelodysplastic syndrome.	('splicing', 'biological_process', 'GO:0045292', ('107', '115'))	('consisted', 'Reg', (20, 29))	('SRSF2', 'Gene', (4, 9))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (119, 143))	('SRSF2', 'Gene', '6427', (4, 9))	('disrupt splicing', 'MPA', (99, 115))	('mutations', 'Var', (10, 19))	('myelodysplastic syndrome', 'Disease', (119, 143))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (119, 143))	('deletions', 'Var', (33, 42))
139396	29317634	We then reviewed the BSE-mutant samples and found additional mutations in RBM10 (two samples), SRSF2 (one sample), and SRSF7 (one sample).	('SRSF7', 'Gene', (119, 124))	('SRSF7', 'Gene', '6432', (119, 124))	('SRSF2', 'Gene', (95, 100))	('RBM10', 'Gene', '8241', (74, 79))	('mutations', 'Var', (61, 70))	('RBM10', 'Gene', (74, 79))	('SRSF2', 'Gene', '6427', (95, 100))
139397	29317634	Although the functional consequences of the SF3A1 and SRSF7 mutations are not known, the tumors containing these mutations cluster with the SF3B1-mutant tumors (Fig.	('SRSF7', 'Gene', (54, 59))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('SRSF7', 'Gene', '6432', (54, 59))	('SF3B1', 'Gene', (140, 145))	('SF3A1', 'Gene', '10291', (44, 49))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('SF3A1', 'Gene', (44, 49))	('mutations', 'Var', (113, 122))	('SF3B1', 'Gene', '23451', (140, 145))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
139398	29317634	3), suggesting that they may confer similar functional consequences as SF3B1 mutations.	('SF3B1', 'Gene', (71, 76))	('mutations', 'Var', (77, 86))	('SF3B1', 'Gene', '23451', (71, 76))
139399	29317634	Indeed, all of these spliceosome factors have been shown to be mutated in other cancers, and they interact functionally with each other and with SF3B1, which may explain the tendency for these mutations to be mutually exclusive with SF3B1 mutations.	('SF3B1', 'Gene', '23451', (145, 150))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('mutations', 'Var', (239, 248))	('SF3B1', 'Gene', (233, 238))	('spliceosome', 'cellular_component', 'GO:0005681', ('21', '32'))	('SF3B1', 'Gene', (145, 150))	('mutations', 'Var', (193, 202))	('interact', 'Interaction', (98, 106))	('SF3B1', 'Gene', '23451', (233, 238))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
139400	29317634	Although cancer-associated alterations in SF3B1 are mostly change-of-function hotspot mutations, this is not the case for all splicing factors.	('cancer', 'Disease', (9, 15))	('SF3B1', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('SF3B1', 'Gene', '23451', (42, 47))	('splicing', 'biological_process', 'GO:0045292', ('126', '134'))	('change-of-function', 'Reg', (59, 77))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('alterations', 'Var', (27, 38))
139401	29317634	For example, RBM10 undergoes frameshifts, truncations, and indels in lung cancer similar to our findings in UM, suggesting that oncogenic mechanisms may vary among different splicing factor mutations.	('truncations', 'Var', (42, 53))	('RBM10', 'Gene', (13, 18))	('UM', 'Phenotype', 'HP:0007716', (108, 110))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('undergoes', 'Reg', (19, 28))	('lung cancer', 'Disease', (69, 80))	('RBM10', 'Gene', '8241', (13, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('splicing', 'biological_process', 'GO:0045292', ('174', '182'))	('frameshifts', 'Var', (29, 40))	('indels', 'Var', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
139405	29317634	Interestingly, when samples were analyzed separately based on their BSE mutation, this signature was enriched only in SF3B1 mutant tumors.	('SF3B1', 'Gene', '23451', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('mutant', 'Var', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))	('SF3B1', 'Gene', (118, 123))
139409	29317634	Thus, most UMs evolve along one of three canonical trajectories toward fitness maximums denoted by BAP1, SF3B1, or EIF1AX mutations.	('EIF1AX', 'Gene', (115, 121))	('SF3B1', 'Gene', (105, 110))	('BAP1', 'Gene', (99, 103))	('fitness maximums', 'Disease', 'MESH:D012640', (71, 87))	('UM', 'Phenotype', 'HP:0007716', (11, 13))	('evolve', 'Reg', (15, 21))	('SF3B1', 'Gene', '23451', (105, 110))	('mutations', 'Var', (122, 131))	('BAP1', 'Gene', '8314', (99, 103))	('EIF1AX', 'Gene', '1964', (115, 121))	('fitness maximums', 'Disease', (71, 87))
139410	29317634	Most tumors containing alternative spliceosome mutations (RBM10, SRSF2, SF3A1, and SRSF7) lie between the SF3B1 and BAP1 clusters and may therefore represent intermediate transitional cases or uncommon non-canonical trajectories.	('tumors', 'Disease', (5, 11))	('RBM10', 'Gene', (58, 63))	('BAP1', 'Gene', (116, 120))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('SF3B1', 'Gene', (106, 111))	('spliceosome', 'cellular_component', 'GO:0005681', ('35', '46'))	('SRSF7', 'Gene', (83, 88))	('mutations', 'Var', (47, 56))	('SRSF7', 'Gene', '6432', (83, 88))	('SF3B1', 'Gene', '23451', (106, 111))	('SRSF2', 'Gene', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('SF3A1', 'Gene', '10291', (72, 77))	('BAP1', 'Gene', '8314', (116, 120))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('RBM10', 'Gene', '8241', (58, 63))	('SF3A1', 'Gene', (72, 77))	('SRSF2', 'Gene', '6427', (65, 70))
139412	29317634	As expected, in almost all samples, an initiating Gq pathway mutation was present in 100% of tumor cells, indicating that it occurred before the appearance of the most recent common ancestor (MRCA).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mutation', 'Var', (61, 69))	('tumor', 'Disease', (93, 98))	('Gq pathway', 'Pathway', (50, 60))	('initiating', 'Reg', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
139415	29317634	Similarly, LOH3 was always present in 100% of tumor cells, whereas the associated BAP1 mutations were occasionally found in a subclone.	('BAP1', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('BAP1', 'Gene', '8314', (82, 86))	('mutations', 'Var', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
139416	29317634	In addition, most alternative spliceosome mutations (RBM10, SRSF2, SF3A1, and SRSF7) mapped to subclones.	('SRSF7', 'Gene', (78, 83))	('SF3A1', 'Gene', '10291', (67, 72))	('SRSF7', 'Gene', '6432', (78, 83))	('SRSF2', 'Gene', (60, 65))	('SF3A1', 'Gene', (67, 72))	('RBM10', 'Gene', '8241', (53, 58))	('SRSF2', 'Gene', '6427', (60, 65))	('spliceosome', 'cellular_component', 'GO:0005681', ('30', '41'))	('RBM10', 'Gene', (53, 58))	('mutations', 'Var', (42, 51))
139421	29317634	Historically, cancer has been thought to develop through the gradual accumulation of numerous mutations over long periods of time, with occasional "driver mutations" giving rise to new subclones that evolve under ongoing selective pressure.	('cancer', 'Disease', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (155, 164))
139424	29317634	As most UMs cease to accrue subsequent driver mutations once they acquire a BSE mutation, these mutually exclusive aberrations appear to represent alternative fitness maximums, with mutation of one gene relieving selective pressure to mutate the others.	('mutations', 'Var', (46, 55))	('fitness maximums', 'Disease', (159, 175))	('UM', 'Phenotype', 'HP:0007716', (8, 10))	('BSE', 'Gene', (76, 79))	('fitness maximums', 'Disease', 'MESH:D012640', (159, 175))	('mutation', 'Var', (182, 190))	('mutation', 'Var', (80, 88))
139425	29317634	Taken together, these findings imply that the metastatic proclivity of a given tumor, which is strongly associated with its respective BSE mutation, may be "set in stone" early in tumor evolution, often before detection of the primary mass, which may explain the lack of improvement in survival rates despite advances in diagnosis and treatment.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('mutation', 'Var', (139, 147))	('tumor', 'Disease', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('metastatic proclivity', 'CPA', (46, 67))	('tumor', 'Disease', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
139426	29317634	Our findings, taken together with previous work suggest that Gq pathway mutations are early events required to initiate tumorigenesis but insufficient alone for malignant transformation, whereas BSE mutations confer malignant potential but are unable to trigger clonal expansion without a Gq mutation.	('mutations', 'Var', (72, 81))	('malignant potential', 'CPA', (216, 235))	('insufficient', 'Disease', (138, 150))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('insufficient', 'Disease', 'MESH:D000309', (138, 150))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Gq pathway', 'Gene', (61, 71))	('tumor', 'Disease', (120, 125))
139428	29317634	In both cases, a Gq mutation was present in 100% of tumor cells but was absent in the germline.	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('Gq mutation', 'Var', (17, 28))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))
139429	29317634	Hence, a preexistent BAP1 mutation was present in all uveal melanocytes but clonal expansion only occurred after one of these cells acquired a Gq mutation.	('BAP1', 'Gene', (21, 25))	('BAP1', 'Gene', '8314', (21, 25))	('mutation', 'Var', (26, 34))
139430	29317634	This need for a tumor-initiating Gq mutation could explain why only a minority of individuals with germline BAP1 mutations develop UM.	('UM', 'Phenotype', 'HP:0007716', (131, 133))	('BAP1', 'Gene', '8314', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('BAP1', 'Gene', (108, 112))	('mutations', 'Var', (113, 122))	('tumor', 'Disease', (16, 21))	('develop', 'PosReg', (123, 130))
139431	29317634	AA9A, A985 and T11 contained BAP1 and SF3B1 mutations, whereas A9EC contained SF3B1 and EIF1AX mutations.	('EIF1AX', 'Gene', '1964', (88, 94))	('SF3B1', 'Gene', (38, 43))	('EIF1AX', 'Gene', (88, 94))	('SF3B1', 'Gene', '23451', (78, 83))	('BAP1', 'Gene', '8314', (29, 33))	('SF3B1', 'Gene', '23451', (38, 43))	('mutations', 'Var', (44, 53))	('AA9A', 'Mutation', 'c.9AA>A', (0, 4))	('BAP1', 'Gene', (29, 33))	('SF3B1', 'Gene', (78, 83))
139432	29317634	As all of these BSE mutations were present in the MRCA, they most likely coexisted in the same tumor cells rather than in different tumor subclones.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('BSE', 'Gene', (16, 19))	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutations', 'Var', (20, 29))	('tumor', 'Disease', (95, 100))
139433	29317634	Although most class 2 tumors contained a BAP1 mutation and LOH3 in the MRCA, the BAP1 mutation (but not LOH3) was occasionally present in a subclone, suggesting that LOH3 can precede mutation of BAP1 on the other chromosome 3.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('BAP1', 'Gene', '8314', (81, 85))	('BAP1', 'Gene', (195, 199))	('BAP1', 'Gene', (81, 85))	('BAP1', 'Gene', (41, 45))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('chromosome', 'cellular_component', 'GO:0005694', ('213', '223'))	('BAP1', 'Gene', '8314', (195, 199))	('mutation', 'Var', (46, 54))	('tumors', 'Disease', (22, 28))	('LOH3', 'Var', (166, 170))	('BAP1', 'Gene', '8314', (41, 45))
139436	29317634	Of all the canonical aberrations in UM, the single most prognostically significant is the bi-allelic inactivation of BAP1, which is tightly linked to the class 2 GEP prognostic signature and high metastatic risk.	('BAP1', 'Gene', '8314', (117, 121))	('BAP1', 'Gene', (117, 121))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('bi-allelic inactivation', 'Var', (90, 113))
139437	29317634	As such, we developed an enhanced bioinformatic pipeline to discover additional BAP1 mutations.	('mutations', 'Var', (85, 94))	('BAP1', 'Gene', '8314', (80, 84))	('BAP1', 'Gene', (80, 84))
139438	29317634	We show here that optimal detection of BAP1 mutations requires a variety of different bioinformatic techniques, including special re-alignment of reads around large indels, use of multiple mutation callers, detection of homozygous deletions, and "SpliceDel" analysis of RNA-Seq and WGS data, to detect deletions spanning multiple exons or encompassing untranscribed regions.	('RNA', 'cellular_component', 'GO:0005562', ('268', '271'))	('mutations', 'Var', (44, 53))	('BAP1', 'Gene', '8314', (39, 43))	('deletions', 'Var', (302, 311))	('BAP1', 'Gene', (39, 43))
139439	29317634	These findings indicate that the frequency of BAP1 mutations in UM and other cancer types may be considerably underestimated.	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('BAP1', 'Gene', '8314', (46, 50))	('BAP1', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('UM', 'Phenotype', 'HP:0007716', (64, 66))
139440	29317634	This study discloses a wide variety of previously unreported BAP1 and spliceosome mutations, and identifies punctuated evolution as an organizing principle behind the genetic, genomic, and transcriptomic landscape of UM.	('spliceosome', 'Gene', (70, 81))	('BAP1', 'Gene', (61, 65))	('ape', 'Gene', (210, 213))	('spliceosome', 'cellular_component', 'GO:0005681', ('70', '81'))	('mutations', 'Var', (82, 91))	('ape', 'Gene', '328', (210, 213))	('BAP1', 'Gene', '8314', (61, 65))	('UM', 'Phenotype', 'HP:0007716', (217, 219))
139441	29317634	The early emergence of prognostically significant BSE mutations could explain why micrometastasis frequently occurs before diagnosis, and why more aggressive primary tumor treatment has not resulted in improved survival.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', (166, 171))	('BSE', 'Gene', (50, 53))
139454	29317634	MuTect2 has its own incorporated local realignment that adjusts for tumors with purity less than 100%, multiple subclones, and/or copy number variation (either local or aneuploidy).	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('copy number variation', 'Var', (130, 151))	('aneuploidy', 'Disease', (169, 179))	('aneuploidy', 'Disease', 'MESH:D000782', (169, 179))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('less', 'NegReg', (87, 91))
139455	29317634	For tumors without matched blood samples, MuTect2 was used for variant calling with a panel of normals and a high coverage blood sample to filter out likely germline mutations.	('variant', 'Var', (63, 70))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
139457	29317634	In addition to the default settings for UNCeqR, mutations were filtered if both DNA and RNA alternate tumor read counts were < 3, < 20% of the total tumor read count, or the gene fell within the blacklist suggested by Radia.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('RNA', 'cellular_component', 'GO:0005562', ('88', '91'))	('tumor', 'Disease', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('mutations', 'Var', (48, 57))
139460	29317634	STAR-aligned RNA-seq data from the TCGA samples was also evaluated for "alternative splicing" within BAP1 exons, indicative of deletions not detected in the corresponding WES data due to the design baits for exome capture.	('BAP1', 'Gene', '8314', (101, 105))	('STAR', 'Gene', '6770', (0, 4))	('deletions', 'Var', (127, 136))	('STAR', 'Gene', (0, 4))	('BAP1', 'Gene', (101, 105))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))
139461	29317634	Following annotation, mutations were filtered out if the MAF was 1% or greater in the population according to 1000 Genomes Project (2015 August) or Exome Sequencing Project (2015 March), and mutations listed in dbSNP (v138) were filtered out, with the exception of SNPs with a MAF < 1% (or unknown) in the population, a single mapping to reference assembly, or with a "clinically associated" tag.	('mutations', 'Var', (191, 200))	('clinical', 'Species', '191496', (369, 377))	('MAF < 1', 'Gene', '84232', (277, 284))	('dbSNP (v138', 'Gene', (211, 222))	('mutations', 'Var', (22, 31))	('MAF < 1', 'Gene', (277, 284))
139462	29317634	A summary of the driver mutations, GEP status (class 1 versus class 2), source of tumor sample, and availability of matched normal DNA were mapped in a co-occurrence of mutations plot using ComplexHeatmap.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('DNA', 'cellular_component', 'GO:0005574', ('131', '134'))	('mutations', 'Var', (24, 33))	('tumor', 'Disease', (82, 87))
139472	23861464	SF3B1 mutations are associated with alternative splicing in uveal melanoma Uveal melanoma, the most common eye malignancy causes severe visual morbidity and is fatal in about 50% of patients.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('splicing', 'biological_process', 'GO:0045292', ('48', '56'))	('alternative splicing', 'Var', (36, 56))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (75, 89))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('visual morbidity', 'Disease', 'MESH:D014786', (136, 152))	('melanoma', 'Disease', (81, 89))	('uveal melanoma', 'Disease', 'MESH:C536494', (60, 74))	('patients', 'Species', '9606', (182, 190))	('uveal melanoma', 'Disease', (60, 74))	('SF3B1', 'Gene', (0, 5))	('eye malignancy', 'Disease', (107, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('mutations', 'Var', (6, 15))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('SF3B1', 'Gene', '23451', (0, 5))	('visual morbidity', 'Disease', (136, 152))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('causes', 'Reg', (122, 128))	('eye malignancy', 'Disease', 'MESH:D009369', (107, 121))	('eye malignancy', 'Phenotype', 'HP:0100012', (107, 121))	('severe visual morbidity', 'Phenotype', 'HP:0001141', (129, 152))
139475	23861464	We observed only ~2000 predicted somatic single nucleotide variants per tumor and low levels of aneuploidy.	('single nucleotide variants', 'Var', (41, 67))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('aneuploidy', 'Disease', (96, 106))	('tumor', 'Disease', (72, 77))	('aneuploidy', 'Disease', 'MESH:D000782', (96, 106))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
139476	23861464	We did not observe an ultraviolet radiation DNA-damage signature, but identified SF3B1 mutations in three samples and a further 15 mutations in an extension cohort of 105 samples.	('SF3B1', 'Gene', '23451', (81, 86))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('SF3B1', 'Gene', (81, 86))	('mutations', 'Var', (87, 96))
139477	23861464	SF3B1 mutations were associated with good prognosis and were rarely coincident with BAP1 mutations.	('SF3B1', 'Gene', (0, 5))	('BAP1', 'Gene', '8314', (84, 88))	('SF3B1', 'Gene', '23451', (0, 5))	('BAP1', 'Gene', (84, 88))	('mutations', 'Var', (6, 15))
139478	23861464	SF3B1 encodes a component of the spliceosome and RNA sequencing revealed that SF3B1 mutations were associated with differential alternative splicing of protein coding genes including ABCC5 and UQCC, and of the long non-coding RNA (lncRNA) CRNDE.	('SF3B1', 'Gene', (78, 83))	('UQCC', 'Gene', (193, 197))	('SF3B1', 'Gene', (0, 5))	('CRNDE', 'Gene', '643911', (239, 244))	('RNA', 'cellular_component', 'GO:0005562', ('49', '52'))	('CRNDE', 'Gene', (239, 244))	('splicing', 'biological_process', 'GO:0045292', ('140', '148'))	('SF3B1', 'Gene', '23451', (78, 83))	('RNA', 'cellular_component', 'GO:0005562', ('226', '229'))	('spliceosome', 'cellular_component', 'GO:0005681', ('33', '44'))	('ABCC5', 'Gene', (183, 188))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('SF3B1', 'Gene', '23451', (0, 5))	('mutations', 'Var', (84, 93))	('ABCC5', 'Gene', '10057', (183, 188))	('UQCC', 'Gene', '55245', (193, 197))	('associated', 'Reg', (99, 109))	('alternative splicing', 'MPA', (128, 148))
139482	23861464	Class 1 uveal melanomas present a low risk of metastasis, whereas class 2 tumors are highly metastatic and are characterized by monosomy of chromosome 3 and gain of 8q.	('gain', 'PosReg', (157, 161))	('uveal melanomas', 'Disease', 'MESH:C536494', (8, 23))	('monosomy', 'Var', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('metastatic', 'CPA', (92, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (8, 22))	('chromosome', 'cellular_component', 'GO:0005694', ('140', '150'))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('melanomas', 'Phenotype', 'HP:0002861', (14, 23))	('uveal melanomas', 'Disease', (8, 23))	('uveal melanomas', 'Phenotype', 'HP:0007716', (8, 23))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('tumors', 'Disease', (74, 80))
139483	23861464	Mutually exclusive mutations in GNAQ or GNA11, the principal driver oncogenes in uveal melanoma, occur in ~85% of cases, and inactivating mutations in the tumor suppressor BAP1 occur in ~85% of metastatic tumors and are associated with disease dissemination.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('GNA11', 'Gene', (40, 45))	('tumor', 'Disease', (155, 160))	('occur', 'Reg', (177, 182))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('uveal melanoma', 'Disease', 'MESH:C536494', (81, 95))	('uveal melanoma', 'Disease', (81, 95))	('tumors', 'Disease', (205, 211))	('BAP1', 'Gene', '8314', (172, 176))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('155', '171'))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('GNA11', 'Gene', '2767', (40, 45))	('GNAQ', 'Gene', '2776', (32, 36))	('tumor suppressor', 'biological_process', 'GO:0051726', ('155', '171'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('GNAQ', 'Gene', (32, 36))	('inactivating mutations', 'Var', (125, 147))	('BAP1', 'Gene', (172, 176))	('associated with', 'Reg', (220, 235))	('mutations', 'Var', (19, 28))	('tumor', 'Disease', (205, 210))
139484	23861464	Recently, exome sequencing of uveal melanomas has identified recurrent mutations in EIF1AX and SF3B1, predominantly in low grade tumors.	('uveal melanomas', 'Disease', (30, 45))	('uveal melanomas', 'Phenotype', 'HP:0007716', (30, 45))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('tumors', 'Disease', (129, 135))	('EIF1AX', 'Gene', (84, 90))	('SF3B1', 'Gene', (95, 100))	('EIF1AX', 'Gene', '1964', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('SF3B1', 'Gene', '23451', (95, 100))	('uveal melanomas', 'Disease', 'MESH:C536494', (30, 45))	('mutations', 'Var', (71, 80))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('low', 'Disease', (119, 122))
139486	23861464	Mutant SF3B1 is associated with differential gene splicing in chronic lymphocytic leukemia, but aberrant splicing in SF3B1 mutant uveal melanoma has not been reported.	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (62, 90))	('splicing', 'biological_process', 'GO:0045292', ('105', '113'))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (62, 90))	('splicing', 'biological_process', 'GO:0045292', ('50', '58'))	('SF3B1', 'Gene', (7, 12))	('chronic lymphocytic leukemia', 'Disease', (62, 90))	('SF3B1', 'Gene', (117, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (130, 144))	('uveal melanoma', 'Disease', (130, 144))	('uveal melanoma', 'Disease', 'MESH:C536494', (130, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('leukemia', 'Phenotype', 'HP:0001909', (82, 90))	('Mutant', 'Var', (0, 6))	('SF3B1', 'Gene', '23451', (7, 12))	('SF3B1', 'Gene', '23451', (117, 122))
139489	23861464	However, we found recurrent mutations in SF3B1 that were associated with differential alternative splicing of both coding and non-coding genes that may play a role in the etiology of this disease.	('play', 'Reg', (152, 156))	('role', 'Reg', (159, 163))	('splicing', 'biological_process', 'GO:0045292', ('98', '106'))	('SF3B1', 'Gene', (41, 46))	('SF3B1', 'Gene', '23451', (41, 46))	('mutations', 'Var', (28, 37))	('differential alternative splicing of', 'MPA', (73, 109))	('associated', 'Reg', (57, 67))
139493	23861464	The SNP arrays revealed low levels of aneuploidy in 11 of the tumors and tetraploidy in tumor #7 (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tetraploidy', 'Var', (73, 84))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Disease', (62, 67))	('aneuploidy', 'Disease', 'MESH:D000782', (38, 48))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('aneuploidy', 'Disease', (38, 48))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
139494	23861464	The diploid tumors presented recurrent chromosome 3 monosomy (9 tumors), losses of 1p (5 tumors), 6q (3 tumors) and 8p (5 tumors), and gains in 6p (4 tumors) and 8q (7 tumors; Supplementary Figs.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('diploid tumors', 'Disease', 'MESH:C548012', (4, 18))	('gains', 'PosReg', (135, 140))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('losses', 'NegReg', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Disease', (12, 18))	('monosomy', 'Var', (52, 60))	('tumors', 'Disease', (122, 128))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('chromosome', 'Var', (39, 49))	('diploid tumors', 'Disease', (4, 18))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
139495	23861464	These aberrations are characteristic of uveal melanoma, but we also observed loss of 16q in three tumors and gain of chromosome 11 in two (Supplementary Figs.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('chromosome', 'cellular_component', 'GO:0005694', ('117', '127'))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))	('uveal melanoma', 'Disease', (40, 54))	('uveal melanoma', 'Disease', 'MESH:C536494', (40, 54))	('gain', 'PosReg', (109, 113))	('loss', 'Var', (77, 81))
139496	23861464	The presence of two identical copies of chromosome 3 in tumor #7 suggested that chromosome 3 monosomy preceded acquisition of the tetraploid state.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('chromosome', 'cellular_component', 'GO:0005694', ('40', '50'))	('tumor', 'Disease', (56, 61))	('monosomy', 'Var', (93, 101))	('chromosome', 'cellular_component', 'GO:0005694', ('80', '90'))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
139501	23861464	UVR-induced DNA damage is characterized by C>T transitions at the 3' end of pyrimidine dinucleotides, a "signature" that accounts for 80-90% of mutations in cutaneous melanoma, and up to 60% of the mutations in acral melanoma.	('cutaneous melanoma', 'Disease', (157, 175))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (157, 175))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (157, 175))	('acral melanoma', 'Disease', (211, 225))	('acral melanoma', 'Phenotype', 'HP:0012060', (211, 225))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('C>T transitions', 'Var', (43, 58))	('pyrimidine dinucleotides', 'Chemical', '-', (76, 100))	('DNA', 'cellular_component', 'GO:0005574', ('12', '15'))	('mutations', 'Var', (144, 153))	('acral melanoma', 'Disease', 'MESH:D008545', (211, 225))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))
139502	23861464	Although C to T (G to A) transitions were the commonest mutation in uveal melanoma, they accounted for only ~35% of the lesions (Fig.	('uveal melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('C to T (G to A) transitions', 'Var', (9, 36))	('uveal melanoma', 'Disease', 'MESH:C536494', (68, 82))	('transitions', 'Var', (25, 36))	('uveal melanoma', 'Disease', (68, 82))
139505	23861464	In line with the generally low level of mutations, we observed very few coding region mutations, predicting only 4-19 non-synonymous SNVs per tumor; of which 92% of those tested were validated by Sanger sequencing (Supplementary Table 5).	('mutations', 'Var', (86, 95))	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
139507	23861464	The only recurrent mutations were A>T, p.209L mutations in GNA11 (7 tumors) and T>A/T>G, p.209L mutations in GNAQ (3 tumors; Supplementary Table 6).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('T>A/T>G', 'Var', (80, 87))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('GNAQ', 'Gene', (109, 113))	('A>T', 'Var', (34, 37))	('p.209L', 'Var', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('p.209L mutations', 'Var', (39, 55))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('GNAQ', 'Gene', '2776', (109, 113))	('GNA11', 'Gene', (59, 64))	('GNA11', 'Gene', '2767', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
139508	23861464	We did, however, observe a small number of non-recurrent mutations in individual genes with possible functional significance, including C>T p.P107L in GNA15 that was coincident with A>T, p.209L GNA11 in tumor #10, C>T p.G8R in EIF1AX in tumor #8, and BAP1 mutations in 7 tumors (Supplementary Table 6).	('GNA11', 'Gene', '2767', (194, 199))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumors', 'Disease', (271, 277))	('C>T p.G8R', 'Var', (214, 223))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('BAP1', 'Gene', '8314', (251, 255))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('A>T', 'Var', (182, 185))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('C>T p.P107L', 'Var', (136, 147))	('EIF1AX', 'Gene', (227, 233))	('p.209L', 'Var', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('GNA11', 'Gene', (194, 199))	('BAP1', 'Gene', (251, 255))	('p.G8R', 'Mutation', 'p.G8R', (218, 223))	('tumor', 'Disease', (271, 276))	('GNA15', 'Gene', (151, 156))	('GNA15', 'Gene', '2769', (151, 156))	('EIF1AX', 'Gene', '1964', (227, 233))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('tumor', 'Disease', (237, 242))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('p.P107L', 'Mutation', 'p.P107L', (140, 147))	('tumor', 'Disease', 'MESH:D009369', (237, 242))
139509	23861464	Critically, we also observed non-recurrent mutations in SF3B1 in three tumors (T>G, p.K666T: tumor #6; T>C, p.K700E: tumor #11; C>T, p.R625H: tumor #12) and although there were no chromosome losses or gains in the region encoding SF3B1 (2q33.1) these data suggested a role for SF3B1 in uveal melanoma.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('T>G', 'Var', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('SF3B1', 'Gene', (230, 235))	('p.K666T', 'Mutation', 'rs374250186', (84, 91))	('chromosome', 'cellular_component', 'GO:0005694', ('180', '190'))	('SF3B1', 'Gene', (56, 61))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('melanoma', 'Phenotype', 'HP:0002861', (292, 300))	('uveal melanoma', 'Disease', (286, 300))	('SF3B1', 'Gene', (277, 282))	('uveal melanoma', 'Disease', 'MESH:C536494', (286, 300))	('tumor', 'Disease', (142, 147))	('SF3B1', 'Gene', '23451', (230, 235))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('SF3B1', 'Gene', '23451', (56, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (286, 300))	('p.K700E', 'Mutation', 'rs559063155', (108, 115))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', (93, 98))	('SF3B1', 'Gene', '23451', (277, 282))	('p.R625H', 'Mutation', 'rs1057519961', (133, 140))	('mutations', 'Var', (43, 52))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
139510	23861464	We screened SF3B1 in 105 additional consecutive archival primary uveal melanomas and detected 15 additional mutations (8 p.R625H, 4 p.R625C, 1 p.R625P, 1 p.R625L, 1 p.K666T; Supplementary Table 7).	('SF3B1', 'Gene', (12, 17))	('p.R625H', 'Mutation', 'rs1057519961', (121, 128))	('uveal melanomas', 'Disease', 'MESH:C536494', (65, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('p.R625P', 'Var', (143, 150))	('p.R625H', 'Var', (121, 128))	('p.R625L', 'Var', (154, 161))	('SF3B1', 'Gene', '23451', (12, 17))	('p.R625P', 'Mutation', 'p.R625P', (143, 150))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('uveal melanomas', 'Disease', (65, 80))	('p.R625L', 'Mutation', 'p.R625L', (154, 161))	('p.R625C', 'Mutation', 'rs775623976', (132, 139))	('uveal melanomas', 'Phenotype', 'HP:0007716', (65, 80))	('p.R625C', 'Var', (132, 139))	('p.K666T', 'Mutation', 'rs374250186', (165, 172))	('p.K666T', 'Var', (165, 172))
139511	23861464	Our overall mutation rate of 15% (18/119) is similar to the rate (18.6%) recently reported for SF3B1 mutations in uveal melanoma by whole exome sequencing, but note that in addition to the R625 codon mutations reported therein, we also observed K666 and K700 codon mutations (Supplementary Fig.	('SF3B1', 'Gene', (95, 100))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('uveal melanoma', 'Disease', 'MESH:C536494', (114, 128))	('K700 codon', 'Var', (254, 264))	('uveal melanoma', 'Disease', (114, 128))	('SF3B1', 'Gene', '23451', (95, 100))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('K666', 'Var', (245, 249))
139512	23861464	The SF3B1 mutations are inversely associated with chromosome 3 monosomy and notably, they are associated with improved progression-free and cancer survival (Supplementary Table 7, Supplementary Fig.	('SF3B1', 'Gene', (4, 9))	('improved', 'PosReg', (110, 118))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('chromosome 3 monosomy', 'Disease', (50, 71))	('SF3B1', 'Gene', '23451', (4, 9))	('chromosome', 'cellular_component', 'GO:0005694', ('50', '60'))	('mutations', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
139513	23861464	SF3B1 encodes subunit 1 of splicing factor 3b, a component of the spliceosome, so to evaluate the effects of SF3B1 mutations on uveal melanoma transcripts, we hybridized three SF3B1 mutated tumors and three SF3B1 wild-type tumors to Affymetrix Human Transcriptome Arrays (HTA2), which contain both exon and exon-exon junction probes.	('mutated', 'Var', (182, 189))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('SF3B1', 'Gene', '23451', (109, 114))	('SF3B1', 'Gene', (176, 181))	('tumors', 'Disease', (190, 196))	('SF3B1', 'Gene', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('Human', 'Species', '9606', (244, 249))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('SF3B1', 'Gene', '23451', (176, 181))	('SF3B1', 'Gene', (207, 212))	('uveal melanoma', 'Disease', 'MESH:C536494', (128, 142))	('SF3B1', 'Gene', '23451', (0, 5))	('uveal melanoma', 'Disease', (128, 142))	('spliceosome', 'cellular_component', 'GO:0005681', ('66', '77'))	('splicing', 'biological_process', 'GO:0045292', ('27', '35'))	('SF3B1', 'Gene', (109, 114))	('uveal melanoma', 'Phenotype', 'HP:0007716', (128, 142))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('SF3B1', 'Gene', '23451', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
139514	23861464	325 genes were predicted to be differentially expressed, with 46 genes up-regulated and 279 genes down-regulated in the SF3B1 mutant compared to the SF3B1 wild-type tumors (Supplementary Table 8).	('SF3B1', 'Gene', (120, 125))	('SF3B1', 'Gene', '23451', (149, 154))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('SF3B1', 'Gene', '23451', (120, 125))	('down-regulated', 'NegReg', (98, 112))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('up-regulated', 'PosReg', (71, 83))	('SF3B1', 'Gene', (149, 154))	('mutant', 'Var', (126, 132))
139516	23861464	Next, we compared the RNA-seq data from our three SF3B1 mutant to our nine SF3B1 wildtype tumors.	('RNA', 'cellular_component', 'GO:0005562', ('22', '25'))	('SF3B1', 'Gene', (50, 55))	('mutant', 'Var', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('SF3B1', 'Gene', '23451', (75, 80))	('SF3B1', 'Gene', '23451', (50, 55))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Disease', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('SF3B1', 'Gene', (75, 80))
139519	23861464	These data suggest that CRNDE, ABCC5 and UQCC are strong candidates for alternative splicing in SF3B1 mutant tumors, hence we examined the sequencing profiles for three genes in our RNA-seq data.	('mutant', 'Var', (102, 108))	('ABCC5', 'Gene', (31, 36))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('SF3B1', 'Gene', (96, 101))	('RNA', 'cellular_component', 'GO:0005562', ('182', '185'))	('ABCC5', 'Gene', '10057', (31, 36))	('UQCC', 'Gene', '55245', (41, 45))	('splicing', 'biological_process', 'GO:0045292', ('84', '92'))	('UQCC', 'Gene', (41, 45))	('CRNDE', 'Gene', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('CRNDE', 'Gene', '643911', (24, 29))	('SF3B1', 'Gene', '23451', (96, 101))	('tumors', 'Disease', (109, 115))
139520	23861464	We normalized the number of mapped bases for these genes and compared nucleotide coverage at each base in SF3B1 mutant and wild-type tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('SF3B1', 'Gene', (106, 111))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('SF3B1', 'Gene', '23451', (106, 111))	('mutant', 'Var', (112, 118))
139521	23861464	The profiles for UQCC, revealed clear evidence of alternative terminal exon use in the SF3B1 wild-type and SF3B1 mutant tumors (Fig.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('SF3B1', 'Gene', (87, 92))	('SF3B1', 'Gene', (107, 112))	('UQCC', 'Gene', (17, 21))	('UQCC', 'Gene', '55245', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('SF3B1', 'Gene', '23451', (87, 92))	('SF3B1', 'Gene', '23451', (107, 112))	('mutant', 'Var', (113, 119))
139522	23861464	For CRNDE we observed near uniform representation of all bases of exon 4 in the SF3B1 wild-type tumors, but an enrichment of the reads at the 3' end of this exon in the SF3B1 mutant tumors (Fig.	('SF3B1', 'Gene', '23451', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('SF3B1', 'Gene', '23451', (169, 174))	('tumors', 'Disease', (96, 102))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('CRNDE', 'Gene', '643911', (4, 9))	('CRNDE', 'Gene', (4, 9))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('SF3B1', 'Gene', (80, 85))	('mutant', 'Var', (175, 181))	('SF3B1', 'Gene', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
139524	23861464	Finally, to further validate our findings, we assessed alternative splicing of GUSBP11, UQCC, ANKHD1, GAS8, F8, ADAM12, CRNDE and ABCC5 - the eight genes that provided the strongest evidence of splicing - by qRT-PCR in 74 independent uveal melanomas comprising 58 SF3B1 wild-type and 16 SF3B1 mutant tumors.	('UQCC', 'Gene', '55245', (88, 92))	('UQCC', 'Gene', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (300, 306))	('splicing', 'biological_process', 'GO:0045292', ('67', '75'))	('SF3B1', 'Gene', (264, 269))	('ABCC5', 'Gene', (130, 135))	('uveal melanomas', 'Disease', 'MESH:C536494', (234, 249))	('GUSBP11', 'Gene', '91316', (79, 86))	('ANKHD1', 'Gene', '54882', (94, 100))	('SF3B1', 'Gene', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('tumors', 'Disease', (300, 306))	('CRNDE', 'Gene', '643911', (120, 125))	('CRNDE', 'Gene', (120, 125))	('GAS8', 'Gene', (102, 106))	('SF3B1', 'Gene', '23451', (264, 269))	('ANKHD1', 'Gene', (94, 100))	('uveal melanoma', 'Phenotype', 'HP:0007716', (234, 248))	('GAS8', 'Gene', '2622', (102, 106))	('splicing - by', 'Var', (194, 207))	('SF3B1', 'Gene', '23451', (287, 292))	('tumors', 'Disease', 'MESH:D009369', (300, 306))	('uveal melanomas', 'Disease', (234, 249))	('uveal melanomas', 'Phenotype', 'HP:0007716', (234, 249))	('GAS', 'molecular_function', 'GO:0034005', ('102', '105'))	('mutant', 'Var', (293, 299))	('ADAM12', 'Gene', '8038', (112, 118))	('ADAM12', 'Gene', (112, 118))	('GUSBP11', 'Gene', (79, 86))	('melanomas', 'Phenotype', 'HP:0002861', (240, 249))	('splicing', 'biological_process', 'GO:0045292', ('194', '202'))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('ABCC5', 'Gene', '10057', (130, 135))
139525	23861464	This analysis confirmed that all eight genes were alternatively spliced in SF3B1 mutant compared to SF3B1 wild-type tumors (Fig.	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumors', 'Disease', (116, 122))	('SF3B1', 'Gene', '23451', (75, 80))	('SF3B1', 'Gene', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutant', 'Var', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('SF3B1', 'Gene', '23451', (100, 105))	('SF3B1', 'Gene', (75, 80))
139530	23861464	SF3B1 mutations have been reported in hematological, breast and pancreatic cancers.	('reported', 'Reg', (26, 34))	('SF3B1', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('hematological', 'Disease', (38, 51))	('SF3B1', 'Gene', '23451', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('breast and pancreatic cancers', 'Disease', 'MESH:D010190', (53, 82))	('mutations', 'Var', (6, 15))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (64, 82))
139531	23861464	Intriguingly, in those cancers codon K700 mutations predominate whereas in uveal melanoma R625 codon mutations predominate.	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('uveal melanoma', 'Disease', 'MESH:C536494', (75, 89))	('uveal melanoma', 'Phenotype', 'HP:0007716', (75, 89))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('uveal melanoma', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('codon K700 mutations', 'Var', (31, 51))
139532	23861464	Notably, in common with previous studies, we confirm that in uveal melanoma SF3B1 mutations are associated with better prognosis.	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('uveal melanoma', 'Disease', 'MESH:C536494', (61, 75))	('mutations', 'Var', (82, 91))	('SF3B1', 'Gene', (76, 81))	('uveal melanoma', 'Disease', (61, 75))	('SF3B1', 'Gene', '23451', (76, 81))
139533	23861464	Thus, in uveal melanoma and myelodysplastic syndrome SF3B1 mutations are associated with improved outcome, whereas in chronic lymphocytic leukemia (CLL), SF3B1 mutations are associated with poorer prognosis.	('improved', 'PosReg', (89, 97))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (28, 52))	('SF3B1', 'Gene', (154, 159))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('myelodysplastic syndrome', 'Disease', (28, 52))	('SF3B1', 'Gene', '23451', (53, 58))	('uveal melanoma', 'Disease', (9, 23))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (28, 52))	('uveal melanoma', 'Disease', 'MESH:C536494', (9, 23))	('CLL', 'Phenotype', 'HP:0005550', (148, 151))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (118, 146))	('leukemia', 'Phenotype', 'HP:0001909', (138, 146))	('SF3B1', 'Gene', '23451', (154, 159))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (118, 146))	('uveal melanoma', 'Phenotype', 'HP:0007716', (9, 23))	('mutations', 'Var', (59, 68))	('chronic lymphocytic leukemia', 'Disease', (118, 146))	('SF3B1', 'Gene', (53, 58))
139535	23861464	In CLL, SF3B1 mutations are associated with alternative splicing at the 3' ends of genes to generate truncated variants of the vitamin C transporter SLC23A2, the T-cell regulator TC1RG1, and the forkhead transcription factor FOXP1.	('FOXP1', 'Gene', (225, 230))	('CLL', 'Phenotype', 'HP:0005550', (3, 6))	('SLC23A2', 'Gene', '9962', (149, 156))	('SF3B1', 'Gene', '23451', (8, 13))	('CLL', 'Gene', (3, 6))	('splicing', 'biological_process', 'GO:0045292', ('56', '64'))	('variants', 'Var', (111, 119))	('TC1RG1', 'CellLine', 'CVCL:1F93', (179, 185))	('transcription', 'biological_process', 'GO:0006351', ('204', '217'))	('FOXP1', 'Gene', '27086', (225, 230))	('SLC23A2', 'Gene', (149, 156))	('mutations', 'Var', (14, 23))	('SF3B1', 'Gene', (8, 13))	('transcription factor', 'molecular_function', 'GO:0000981', ('204', '224'))
139536	23861464	We show that in uveal melanoma SF3B1 mutations are also associated with alternative splicing (Fig.	('alternative splicing', 'MPA', (72, 92))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('uveal melanoma', 'Disease', (16, 30))	('associated', 'Reg', (56, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (16, 30))	('mutations', 'Var', (37, 46))	('SF3B1', 'Gene', (31, 36))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('splicing', 'biological_process', 'GO:0045292', ('84', '92'))	('SF3B1', 'Gene', '23451', (31, 36))
139537	23861464	We show that in common with CLL, SF3B1 mutations in uveal melanoma are associated with alternative splicing of the 3' end of transcripts, for example in UQCC, which encodes the ubiquinol-cytochrome c reductase complex chaperone, a protein implicated in bone development and stature.	('uveal melanoma', 'Disease', (52, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (52, 66))	('ubiquinol-cytochrome c reductase complex', 'cellular_component', 'GO:0045275', ('177', '217'))	('UQCC', 'Gene', (153, 157))	('SF3B1', 'Gene', (33, 38))	('associated', 'Reg', (71, 81))	('uveal melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('cytochrome c', 'molecular_function', 'GO:0009461', ('187', '199'))	('CLL', 'Phenotype', 'HP:0005550', (28, 31))	('mutations', 'Var', (39, 48))	("alternative splicing of the 3' end", 'MPA', (87, 121))	('bone development', 'biological_process', 'GO:0060348', ('253', '269'))	('ubiquinol-cytochrome c reductase complex', 'cellular_component', 'GO:0045276', ('177', '217'))	('SF3B1', 'Gene', '23451', (33, 38))	('splicing', 'biological_process', 'GO:0045292', ('99', '107'))	('protein', 'cellular_component', 'GO:0003675', ('231', '238'))	('cytochrome c', 'molecular_function', 'GO:0045155', ('187', '199'))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('UQCC', 'Gene', '55245', (153, 157))
139539	23861464	Interestingly, in uveal melanoma, we observe evidence of intron retention in ABCC5 in the SF3B1 wild type samples compared to the mutant samples, suggesting that this gene is more efficiently spliced in the SF3B1 mutant than wild-type tumors.	('SF3B1', 'Gene', (207, 212))	('retention', 'biological_process', 'GO:0051235', ('64', '73'))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('uveal melanoma', 'Phenotype', 'HP:0007716', (18, 32))	('uveal melanoma', 'Disease', 'MESH:C536494', (18, 32))	('intron retention', 'MPA', (57, 73))	('SF3B1', 'Gene', '23451', (207, 212))	('uveal melanoma', 'Disease', (18, 32))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('SF3B1', 'Gene', '23451', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('SF3B1', 'Gene', (90, 95))	('ABCC5', 'Gene', (77, 82))	('mutant', 'Var', (130, 136))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('tumors', 'Disease', (235, 241))	('ABCC5', 'Gene', '10057', (77, 82))
139540	23861464	More intriguing, we show that SF3B1 mutations are associated with cryptic alternative splicing of exon 4 of CRNDE.	('CRNDE', 'Gene', (108, 113))	('SF3B1', 'Gene', (30, 35))	('mutations', 'Var', (36, 45))	('cryptic alternative splicing of', 'MPA', (66, 97))	('SF3B1', 'Gene', '23451', (30, 35))	('splicing', 'biological_process', 'GO:0045292', ('86', '94'))	('associated', 'Reg', (50, 60))	('CRNDE', 'Gene', '643911', (108, 113))
139543	23861464	We show that in uveal melanoma, mutations in SF3B1 are associated with cryptic alternative splicing within exon 4 of CRNDE, and considering the comparatively simple genetics of uveal melanoma, it will be important to determine how alternative splicing of this non-coding gene affects cellular function.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('affects', 'Reg', (276, 283))	('cellular function', 'MPA', (284, 301))	('splicing', 'biological_process', 'GO:0045292', ('243', '251'))	('associated', 'Reg', (55, 65))	('uveal melanoma', 'Disease', 'MESH:C536494', (177, 191))	('uveal melanoma', 'Disease', (16, 30))	('uveal melanoma', 'Disease', 'MESH:C536494', (16, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('mutations', 'Var', (32, 41))	('SF3B1', 'Gene', (45, 50))	('uveal melanoma', 'Disease', (177, 191))	('uveal melanoma', 'Phenotype', 'HP:0007716', (177, 191))	('CRNDE', 'Gene', '643911', (117, 122))	('CRNDE', 'Gene', (117, 122))	('SF3B1', 'Gene', '23451', (45, 50))	('splicing', 'biological_process', 'GO:0045292', ('91', '99'))
139544	23861464	In conclusion, we show that despite its appalling prognosis, uveal melanoma is a relatively simple genetic disease characterized by recurrent chromosomal losses and gains, and a low mutational burden.	('genetic disease', 'Disease', 'MESH:D030342', (99, 114))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('uveal melanoma', 'Disease', 'MESH:C536494', (61, 75))	('chromosomal losses', 'Var', (142, 160))	('uveal melanoma', 'Disease', (61, 75))	('gains', 'PosReg', (165, 170))	('genetic disease', 'Disease', (99, 114))
139546	23861464	We identify SF3B1 mutations in ~15% of cases and show these are associated with better prognosis, which will guide clinical management of this disease.	('SF3B1', 'Gene', (12, 17))	('SF3B1', 'Gene', '23451', (12, 17))	('mutations', 'Var', (18, 27))
139547	23861464	Intriguingly, we show that SF3B1 mutations are associated with diverse alternative splicing events, including alternative terminal exon usage, intron retention and cryptic splicing within exons of both protein coding and non-coding genes.	('SF3B1', 'Gene', '23451', (27, 32))	('cryptic splicing', 'MPA', (164, 180))	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('alternative splicing', 'MPA', (71, 91))	('mutations', 'Var', (33, 42))	('SF3B1', 'Gene', (27, 32))	('intron retention', 'MPA', (143, 159))	('alternative terminal exon usage', 'MPA', (110, 141))	('splicing', 'biological_process', 'GO:0045292', ('172', '180'))	('associated', 'Reg', (47, 57))	('splicing', 'biological_process', 'GO:0045292', ('83', '91'))	('retention', 'biological_process', 'GO:0051235', ('150', '159'))
139562	23861464	We performed an unpaired Student's t-test to compare gene intensities between SF3B1 wild-type and SF3B1 mutated tumors.	('mutated', 'Var', (104, 111))	('SF3B1', 'Gene', '23451', (78, 83))	('SF3B1', 'Gene', '23451', (98, 103))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))	('SF3B1', 'Gene', (78, 83))	('SF3B1', 'Gene', (98, 103))
139564	23861464	Differential splicing analysis between the mutant (n=3) and wild-type SF3B1 (n=9) samples was conducted using DEXseq and events with an FDR <0.1 were regarded as significant.	('splicing', 'biological_process', 'GO:0045292', ('13', '21'))	('SF3B1', 'Gene', (70, 75))	('SF3B1', 'Gene', '23451', (70, 75))	('mutant', 'Var', (43, 49))
139566	23861464	One of the samples described as wild-type SF3B1 was predicted to have an SF3B1 R625C mutation (Supplementary Figure S7) and was designated SF3B1 mutant for the differential splicing analysis.	('SF3B1', 'Gene', '23451', (139, 144))	('SF3B1', 'Gene', '23451', (73, 78))	('splicing', 'biological_process', 'GO:0045292', ('173', '181'))	('SF3B1', 'Gene', (42, 47))	('R625C', 'Mutation', 'rs775623976', (79, 84))	('SF3B1', 'Gene', '23451', (42, 47))	('SF3B1', 'Gene', (139, 144))	('SF3B1', 'Gene', (73, 78))	('R625C', 'Var', (79, 84))
139568	23861464	Finally, for each splicing event, a Mann-Whitney U test was applied between SF3B1 mutated and wildtype cases.	('SF3B1', 'Gene', (76, 81))	('mutated', 'Var', (82, 89))	('splicing', 'biological_process', 'GO:0045292', ('18', '26'))	('SF3B1', 'Gene', '23451', (76, 81))
139570	23861464	Our data show that despite its dismal prognosis, uveal melanoma is a relatively simple genetic disease characterized by recurrent chromosomal losses and gains and a low mutational burden.	('uveal melanoma', 'Disease', 'MESH:C536494', (49, 63))	('uveal melanoma', 'Disease', (49, 63))	('gains', 'PosReg', (153, 158))	('uveal melanoma', 'Phenotype', 'HP:0007716', (49, 63))	('genetic disease', 'Disease', 'MESH:D030342', (87, 102))	('genetic disease', 'Disease', (87, 102))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('chromosomal losses', 'Var', (130, 148))
139579	27877085	Imbalances in autophagy can promote many neurodegenerative disorders, such as Huntington's disease, Parkinson's disease (PD), and Alzheimer's disease (AD).	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (41, 68))	('autophagy', 'biological_process', 'GO:0006914', ('14', '23'))	("Parkinson's disease", 'Disease', (100, 119))	('AD', 'Disease', (151, 153))	('AD', 'Phenotype', 'HP:0002511', (151, 153))	('neurodegenerative disorder', 'Phenotype', 'HP:0002180', (41, 67))	('autophagy', 'CPA', (14, 23))	('neurodegenerative disorders', 'Disease', (41, 68))	('AD', 'Disease', 'MESH:D000544', (151, 153))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (130, 149))	("Alzheimer's disease", 'Disease', (130, 149))	("Huntington's disease", 'Disease', 'MESH:D006816', (78, 98))	("Parkinson's disease", 'Disease', 'MESH:D010300', (100, 119))	("Huntington's disease", 'Disease', (78, 98))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (130, 149))	('autophagy', 'biological_process', 'GO:0016236', ('14', '23'))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (41, 68))	('Imbalances', 'Phenotype', 'HP:0002172', (0, 10))	('Imbalances', 'Var', (0, 10))	('PD', 'Disease', 'MESH:D010300', (121, 123))	('promote', 'PosReg', (28, 35))
139589	27877085	Autophagy is responsible for degrading cellular components, and any autophagic defects will disrupt intracellular homeostasis and can cause specific retinal diseases.	('retinal diseases', 'Phenotype', 'HP:0000479', (149, 165))	('retinal diseases', 'Disease', (149, 165))	('Autophagy', 'biological_process', 'GO:0006914', ('0', '9'))	('defects', 'Var', (79, 86))	('intracellular', 'cellular_component', 'GO:0005622', ('100', '113'))	('cellular components', 'MPA', (39, 58))	('degrading', 'NegReg', (29, 38))	('cause', 'Reg', (134, 139))	('Autophagy', 'biological_process', 'GO:0016236', ('0', '9'))	('homeostasis', 'biological_process', 'GO:0042592', ('114', '125'))	('retinal diseases', 'Disease', 'MESH:D012164', (149, 165))	('autophagic', 'CPA', (68, 78))	('intracellular', 'MPA', (100, 113))	('Autophagy', 'CPA', (0, 9))	('disrupt', 'NegReg', (92, 99))
139595	27877085	The pathology of ARMD is related to inflammation, oxidative stress, and defective lysosomal or proteasomal function, leading to the accumulation of abnormal intra- and extracellular products.	('inflammation', 'biological_process', 'GO:0006954', ('36', '48'))	('inflammation', 'Disease', 'MESH:D007249', (36, 48))	('ARMD', 'Disease', 'None', (17, 21))	('extracellular', 'cellular_component', 'GO:0005576', ('168', '181'))	('defective', 'Var', (72, 81))	('inflammation', 'Disease', (36, 48))	('lysosomal', 'Enzyme', (82, 91))	('accumulation', 'PosReg', (132, 144))	('ARMD', 'Disease', (17, 21))	('oxidative stress', 'Phenotype', 'HP:0025464', (50, 66))
139605	27877085	found that A2E triggers autophagy in RPE cells during the early stages of ARMD.	('triggers', 'Reg', (15, 23))	('autophagy', 'biological_process', 'GO:0006914', ('24', '33'))	('ARMD', 'Disease', 'None', (74, 78))	('ARMD', 'Disease', (74, 78))	('A2E', 'Chemical', '-', (11, 14))	('A2E', 'Var', (11, 14))	('autophagy', 'biological_process', 'GO:0016236', ('24', '33'))	('autophagy', 'CPA', (24, 33))
139607	27877085	Defective lysosomal degradation is the major cause of lipofuscinogenesis.	('lipofuscinogenesis', 'Disease', (54, 72))	('lipofuscin', 'Chemical', 'MESH:D008062', (54, 64))	('lysosomal degradation', 'MPA', (10, 31))	('cause', 'Reg', (45, 50))	('Defective', 'Var', (0, 9))	('degradation', 'biological_process', 'GO:0009056', ('20', '31'))
139608	27877085	Animal models deficient in bA3/A1-crystallin, which is encoded by the Cryba1 gene, exhibit insufficient lysosomal clearance in RPE cells, the same pathological sign seen in AMD patients.bA3/A1-crystallin regulates lysosome-mediated degradation in the RPE by modulating the activity of V-ATPase, the proton pump that acidifies the lysosomal lumen, through the AKT/mTORC1 signalling pathway.Deficient lysosomal function will disrupt the autophagic degradation of toxic components and misfolded proteins.	('V-ATPase', 'cellular_component', 'GO:0000219', ('285', '293'))	('Cryba1', 'Gene', (70, 76))	('mTORC1', 'Gene', '382056', (363, 369))	('mTORC1', 'cellular_component', 'GO:0031931', ('363', '369'))	('degradation', 'biological_process', 'GO:0009056', ('232', '243'))	('Cryba1', 'Gene', '1411', (70, 76))	('AMD', 'Gene', '262', (173, 176))	('AKT', 'Gene', '207', (359, 362))	('pathway.Deficient', 'Var', (381, 398))	('signalling pathway', 'biological_process', 'GO:0007165', ('370', '388'))	('AMD', 'Gene', (173, 176))	('disrupt', 'NegReg', (423, 430))	('degradation', 'biological_process', 'GO:0009056', ('446', '457'))	('proton pump', 'cellular_component', 'GO:0005889', ('299', '310'))	('autophagic degradation', 'CPA', (435, 457))	('lysosomal function', 'CPA', (399, 417))	('lysosome', 'cellular_component', 'GO:0005764', ('214', '222'))	('patients', 'Species', '9606', (177, 185))	('mTORC1', 'Gene', (363, 369))	('lysosomal lumen', 'cellular_component', 'GO:0043202', ('330', '345'))	('AKT', 'Gene', (359, 362))	('V-ATPase', 'cellular_component', 'GO:0008245', ('285', '293'))
139623	27877085	In addition, treatment with CQ and/or HCQ also increases the mRNA expression levels of transcription factor EB (TFEB) and the proton pump v-(H+)ATPase.	('TFEB', 'Gene', '7942', (112, 116))	('transcription factor EB', 'Gene', '7942', (87, 110))	('mRNA expression levels', 'MPA', (61, 83))	('v-(H+)ATPase', 'Gene', (138, 150))	('TFEB', 'Gene', (112, 116))	('CQ', 'Chemical', 'MESH:D002738', (28, 30))	('proton pump', 'cellular_component', 'GO:0005889', ('126', '137'))	('HCQ', 'Var', (38, 41))	('CQ', 'Chemical', 'MESH:D002738', (39, 41))	('transcription factor EB', 'Gene', (87, 110))	('transcription factor', 'molecular_function', 'GO:0000981', ('87', '107'))	('increases', 'PosReg', (47, 56))	('v-(H+)ATPase', 'Gene', '1769', (138, 150))	('HCQ', 'Chemical', 'MESH:D006886', (38, 41))	('transcription', 'biological_process', 'GO:0006351', ('87', '100'))
139624	27877085	Similar features are observed in AD patients with fibroblasts with mutant presenilin 1 (PS1), suggesting a potential link between ARMD and AD.	('AD', 'Disease', 'MESH:D000544', (33, 35))	('AD', 'Disease', 'MESH:D000544', (139, 141))	('AD', 'Disease', (33, 35))	('AD', 'Disease', (139, 141))	('PS1', 'Gene', '5663', (88, 91))	('ARMD', 'Disease', 'None', (130, 134))	('patients', 'Species', '9606', (36, 44))	('AD', 'Phenotype', 'HP:0002511', (139, 141))	('AD', 'Phenotype', 'HP:0002511', (33, 35))	('presenilin 1', 'Gene', '5663', (74, 86))	('PS1', 'Gene', (88, 91))	('ARMD', 'Disease', (130, 134))	('mutant', 'Var', (67, 73))	('presenilin 1', 'Gene', (74, 86))	('link', 'Reg', (117, 121))
139637	27877085	For example, in mice, a mutation in Atg5, an autophagy gene, interfered with chronic liver fibrosis.	('autophagy', 'biological_process', 'GO:0006914', ('45', '54'))	('liver fibrosis', 'Disease', (85, 99))	('liver fibrosis', 'Disease', 'MESH:D008103', (85, 99))	('interfered', 'NegReg', (61, 71))	('mutation', 'Var', (24, 32))	('Atg5', 'Gene', (36, 40))	('mice', 'Species', '10090', (16, 20))	('liver fibrosis', 'Phenotype', 'HP:0001395', (85, 99))	('autophagy', 'biological_process', 'GO:0016236', ('45', '54'))
139650	27877085	Elevated IOP can activate autophagy, up-regulating the levels of autophagic markers such as LC3-II/LC3-I and beclin-1 and inducing cell death.	('autophagy', 'biological_process', 'GO:0006914', ('26', '35'))	('inducing', 'Reg', (122, 130))	('activate', 'PosReg', (17, 25))	('up-regulating', 'PosReg', (37, 50))	('LC3-II/LC3-I', 'MPA', (92, 104))	('autophagy', 'CPA', (26, 35))	('beclin-1', 'Gene', (109, 117))	('IOP', 'Var', (9, 12))	('beclin-1', 'Gene', '8678', (109, 117))	('cell death', 'CPA', (131, 141))	('Elevated IOP', 'Phenotype', 'HP:0007906', (0, 12))	('levels of', 'MPA', (55, 64))	('autophagy', 'biological_process', 'GO:0016236', ('26', '35'))	('cell death', 'biological_process', 'GO:0008219', ('131', '141'))
139657	27877085	Congenital cataracts are directly linked to mutations in the FYCO1 gene.	('FYCO1', 'Gene', '79443', (61, 66))	('cataracts', 'Phenotype', 'HP:0000518', (11, 20))	('FYCO1', 'Gene', (61, 66))	('mutations', 'Var', (44, 53))	('Congenital cataracts', 'Disease', (0, 20))	('Congenital cataracts', 'Phenotype', 'HP:0000519', (0, 20))	('Congenital cataracts', 'Disease', 'MESH:D002386', (0, 20))	('cataract', 'Phenotype', 'HP:0000518', (11, 19))	('linked', 'Reg', (34, 40))
139659	27877085	Mutation of the FYCO1 gene can lead to an autosomal-recessive form of congenital cataracts.	('cataracts', 'Phenotype', 'HP:0000518', (81, 90))	('congenital cataracts', 'Disease', (70, 90))	('Mutation', 'Var', (0, 8))	('FYCO1', 'Gene', '79443', (16, 21))	('congenital cataracts', 'Disease', 'MESH:D002386', (70, 90))	('cataract', 'Phenotype', 'HP:0000518', (81, 89))	('lead to', 'Reg', (31, 38))	('FYCO1', 'Gene', (16, 21))	('congenital cataracts', 'Phenotype', 'HP:0000519', (70, 90))
139660	27877085	Additionally, Vps34is involved in Atg5-independent autophagy, and a mutation in Vps34can also lead to the formation of congenital cataracts.	('Vps34', 'Gene', '5289', (80, 85))	('congenital cataracts', 'Disease', 'MESH:D002386', (119, 139))	('cataracts', 'Phenotype', 'HP:0000518', (130, 139))	('autophagy', 'biological_process', 'GO:0006914', ('51', '60'))	('mutation', 'Var', (68, 76))	('Vps34', 'Gene', (80, 85))	('congenital cataracts', 'Phenotype', 'HP:0000519', (119, 139))	('cataract', 'Phenotype', 'HP:0000518', (130, 138))	('autophagy', 'biological_process', 'GO:0016236', ('51', '60'))	('congenital cataracts', 'Disease', (119, 139))	('lead to', 'Reg', (94, 101))	('Vps34', 'Gene', '5289', (14, 19))	('formation', 'biological_process', 'GO:0009058', ('106', '115'))	('Vps34', 'Gene', (14, 19))
139661	27877085	The R120G mutation in alphaB-crystallin increases the levels of LC3-II and p62 and the size of the APs in lens fibre and epithelial cells in a hereditary cataract model.	('R120G', 'Var', (4, 9))	('hereditary cataract', 'Phenotype', 'HP:0000519', (143, 162))	('levels of LC3-II', 'MPA', (54, 70))	('hereditary cataract', 'Disease', 'MESH:D002386', (143, 162))	('hereditary cataract', 'Disease', (143, 162))	('cataract', 'Phenotype', 'HP:0000518', (154, 162))	('p62', 'Gene', (75, 78))	('R120G', 'Mutation', 'rs1028525078', (4, 9))	('p62', 'Gene', '23636', (75, 78))	('increases', 'PosReg', (40, 49))	('alphaB-crystallin', 'Protein', (22, 39))
139662	27877085	In conclusion, the disruption of autophagy in lens cells results in a loss of stress resistance and inhibits differentiation, finally resulting in cataract formation.	('resulting in', 'Reg', (134, 146))	('inhibits', 'NegReg', (100, 108))	('disruption', 'Var', (19, 29))	('loss', 'NegReg', (70, 74))	('cataract', 'Disease', 'MESH:D002386', (147, 155))	('cataract', 'Disease', (147, 155))	('cataract', 'Phenotype', 'HP:0000518', (147, 155))	('autophagy', 'CPA', (33, 42))	('autophagy', 'biological_process', 'GO:0016236', ('33', '42'))	('differentiation', 'CPA', (109, 124))	('formation', 'biological_process', 'GO:0009058', ('156', '165'))	('autophagy', 'biological_process', 'GO:0006914', ('33', '42'))	('stress', 'MPA', (78, 84))
139664	27877085	After the anatomical barriers of the eye are breached, humans do not mount a sufficient immune response to prevent the infection from spreading because of a specific ocular immune-tolerance area, and such infections can eventually result in blindness.	('blindness', 'Disease', 'MESH:D001766', (241, 250))	('humans', 'Species', '9606', (55, 61))	('result in', 'Reg', (231, 240))	('blindness', 'Phenotype', 'HP:0000618', (241, 250))	('infections', 'Var', (205, 215))	('immune response', 'biological_process', 'GO:0006955', ('88', '103'))	('blindness', 'Disease', (241, 250))
139668	27877085	Patients with defective CD40 generally develop ocular toxoplasmosis.	('develop', 'Reg', (39, 46))	('defective', 'Var', (14, 23))	('ocular toxoplasmosis', 'Disease', 'MESH:D014126', (47, 67))	('Patients', 'Species', '9606', (0, 8))	('ocular toxoplasmosis', 'Disease', (47, 67))	('CD40', 'Gene', '958', (24, 28))	('CD40', 'Gene', (24, 28))
139683	27877085	Moreover, AKT and MEK inhibition can also induce AMPK-dependent autophagic cell death, making this pathway a promising target for the treatment of uveal melanoma.	('inhibition', 'Var', (22, 32))	('uveal melanoma', 'Disease', (147, 161))	('AKT', 'Gene', (10, 13))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('AMPK-dependent autophagic cell death', 'CPA', (49, 85))	('MEK', 'Gene', (18, 21))	('AMPK', 'molecular_function', 'GO:0047322', ('49', '53'))	('autophagic cell death', 'biological_process', 'GO:0048102', ('64', '85'))	('MEK', 'Gene', '5609', (18, 21))	('AMPK', 'molecular_function', 'GO:0050405', ('49', '53'))	('AKT', 'Gene', '207', (10, 13))	('uveal melanoma', 'Phenotype', 'HP:0007716', (147, 161))	('uveal melanoma', 'Disease', 'MESH:C536494', (147, 161))	('AMPK', 'molecular_function', 'GO:0004691', ('49', '53'))
139849	26915081	As small millimetre-size differences in tumour prominence can result in significant changes in the treatment, accurate length measurements are essential to assess the optimal treatment.	('differences', 'Var', (25, 36))	('changes', 'Reg', (84, 91))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('tumour', 'Disease', (40, 46))	('treatment', 'MPA', (99, 108))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('result in', 'Reg', (62, 71))
139868	26812476	Differential expression of 8 miRNAs: miR-214, miR-149*, miR-143, miR-146b, miR-199a, let7b, miR-1238 and miR-134 were studied.	('miR-143', 'Var', (56, 63))	('miR-1238', 'Gene', (92, 100))	('miR-149', 'Gene', '406941', (46, 53))	('miR-199a', 'Gene', '100314245', (75, 83))	('miR-1238', 'Gene', '100302226', (92, 100))	('miR-134', 'Gene', '406924', (105, 112))	('miR-199a', 'Gene', (75, 83))	('miR-134', 'Gene', (105, 112))	('miR-214', 'Var', (37, 44))	('let7b', 'Gene', '406884', (85, 90))	('miR-146b', 'Var', (65, 73))	('miR-149', 'Gene', (46, 53))	('let7b', 'Gene', (85, 90))
139869	26812476	Gene target prediction revealed SMAD4, WISP1, HIPK1, HDAC8 and C-KIT as the post-transcriptional regulators of miR-146b, miR-199a, miR-1238 and miR-134.	('WISP1', 'Gene', '8840', (39, 44))	('HIPK1', 'Gene', (46, 51))	('WISP1', 'Gene', (39, 44))	('HIPK1', 'Gene', '204851', (46, 51))	('C-KIT', 'Gene', '3815', (63, 68))	('miR-199a', 'Gene', (121, 129))	('HDAC8', 'Gene', (53, 58))	('miR-1238', 'Gene', '100302226', (131, 139))	('miR-1238', 'Gene', (131, 139))	('KIT', 'molecular_function', 'GO:0005020', ('65', '68'))	('C-KIT', 'Gene', (63, 68))	('miR-134', 'Gene', '406924', (144, 151))	('miR-199a', 'Gene', '100314245', (121, 129))	('HDAC8', 'Gene', '55869', (53, 58))	('miR-134', 'Gene', (144, 151))	('miR-146b', 'Var', (111, 119))
139870	26812476	Five miRNAs (miR-214, miR146b, miR-143, miR-199a and miR-134) were found to be differentially expressed in M3/ D3 UM tumors.	('miR146b', 'Gene', (22, 29))	('miR146b', 'Gene', '574447', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('miR-199a', 'Gene', '100314245', (40, 48))	('miR-134', 'Gene', '406924', (53, 60))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('miR-143', 'Var', (31, 38))	('UM', 'Phenotype', 'HP:0007716', (114, 116))	('miR-134', 'Gene', (53, 60))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('miR-214', 'Var', (13, 20))	('miR-199a', 'Gene', (40, 48))
139879	26812476	Extensive molecular studies using gene expression and chromosomal aberration analysis have helped to stratify UM into 2 classes:class 1 tumors with low risk of liver metastasis, associated with disomy3 (D3), and class 2 tumors with high risk of liver metastasis associated with monosomy3 (M3).	('tumors', 'Disease', (136, 142))	('disomy', 'Disease', (194, 200))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (54, 76))	('liver metastasis', 'Disease', 'MESH:D009362', (160, 176))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('rat', 'Species', '10116', (103, 106))	('gene expression', 'biological_process', 'GO:0010467', ('34', '49'))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('liver metastasis', 'Disease', 'MESH:D009362', (245, 261))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('rat', 'Species', '10116', (70, 73))	('disomy', 'Disease', 'MESH:D024182', (194, 200))	('tumors', 'Disease', (220, 226))	('liver metastasis', 'Disease', (160, 176))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('associated', 'Reg', (178, 188))	('UM', 'Phenotype', 'HP:0007716', (110, 112))	('monosomy3', 'Var', (278, 287))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('liver metastasis', 'Disease', (245, 261))
139880	26812476	Unfortunately, there is a lack of accuracy in the molecular genetic testing due to intra-tumoral heterogeneity and micro-deletions of genes prevailing in UM tumors decreasing the precision in identifying micro-metastases.	('intra-tumoral', 'Disease', (83, 96))	('micro-deletions', 'Var', (115, 130))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('metastases', 'Disease', 'MESH:D009362', (210, 220))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('decreasing', 'NegReg', (164, 174))	('intra-tumoral', 'Disease', 'MESH:D009369', (83, 96))	('UM', 'Phenotype', 'HP:0007716', (154, 156))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('metastases', 'Disease', (210, 220))
139884	26812476	In the second study, 6 miRNAs (let-7b, miR-199a, miR-199a*, miR-143, miR-193b, and miR-652) were identified to differentiate class 1 and class 2 UM tumors.	('miR-199a', 'Gene', '100314245', (39, 47))	('differentiate', 'Reg', (111, 124))	('miR-193b', 'Gene', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('miR-199a', 'Gene', (49, 57))	('miR-143', 'Var', (60, 67))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('let-7b', 'Gene', '406884', (31, 37))	('let-7b', 'Gene', (31, 37))	('miR-652', 'Gene', '724022', (83, 90))	('miR-199a', 'Gene', '100314245', (49, 57))	('tumors', 'Disease', (148, 154))	('miR-199a', 'Gene', (39, 47))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('miR-193b', 'Gene', '574455', (69, 77))	('miR-652', 'Gene', (83, 90))
139901	26812476	Centromeric probes (Invitrogen, USA) were used to detect chromosome 3 aberrations and disomy 18 (control).	('aberrations', 'Var', (70, 81))	('disomy', 'Disease', 'MESH:D024182', (86, 92))	('chromosome', 'Gene', (57, 67))	('disomy', 'Disease', (86, 92))	('rat', 'Species', '10116', (74, 77))	('chromosome', 'cellular_component', 'GO:0005694', ('57', '67'))
139927	26812476	Top 10 up-regulated miRNAs with maximum score and high fold change were: miR-317-5p, miR-373, miR-1268, miR-191*, miR-150, miR-1275, miR-188-5p, miR-1238, miR-134 and miR-296-5p.	('miR-150', 'Gene', '406942', (114, 121))	('miR-134', 'Gene', (155, 162))	('miR-1268', 'Gene', (94, 102))	('up-regulated', 'PosReg', (7, 19))	('miR-296-5p', 'Var', (167, 177))	('miR-191', 'Gene', '406966', (104, 111))	('miR-1268', 'Gene', '100302233', (94, 102))	('miR-373', 'Gene', (85, 92))	('miR-317-5p', 'Var', (73, 83))	('miR-1275', 'Gene', (123, 131))	('miR-373', 'Gene', '442918', (85, 92))	('miR-191', 'Gene', (104, 111))	('miR-1275', 'Gene', '100302123', (123, 131))	('miR-1238', 'Gene', '100302226', (145, 153))	('miR-1238', 'Gene', (145, 153))	('miR-188-5p', 'Var', (133, 143))	('miR-150', 'Gene', (114, 121))	('miR-134', 'Gene', '406924', (155, 162))
139931	26812476	Since, dys-regulation of p53 pathway has been reported in UM earlier, we explored the miRNAs and their targets and subjected to regulatory network modeling to understand the differential regulation of p53 pathway in M3 and D3 UM tumors.	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('UM', 'Phenotype', 'HP:0007716', (58, 60))	('p53', 'Gene', (201, 204))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('dys-regulation', 'Var', (7, 21))	('regulation', 'biological_process', 'GO:0065007', ('187', '197'))	('regulation', 'biological_process', 'GO:0065007', ('11', '21'))	('p53', 'Gene', '7157', (201, 204))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('tumors', 'Disease', (229, 235))	('UM', 'Phenotype', 'HP:0007716', (226, 228))
139932	26812476	Three miRNAs: miR-149*, miR-1238 and miR-134 (which were in common with supervised and unsupervised data analysis; Fig 1C) and 5 miRNAs: miR-214, miR-143, miR146b, miR-199a and let7b (earlier shown as class 1/ class 2 discriminators) were selected for validation.	('miR-143', 'Var', (146, 153))	('miR-1238', 'Gene', '100302226', (24, 32))	('miR-1238', 'Gene', (24, 32))	('miR-199a', 'Gene', (164, 172))	('miR-134', 'Gene', '406924', (37, 44))	('miR146b', 'Gene', (155, 162))	('let7b', 'Gene', (177, 182))	('let7b', 'Gene', '406884', (177, 182))	('miR-149', 'Gene', (14, 21))	('miR-134', 'Gene', (37, 44))	('miR-214', 'Var', (137, 144))	('miR-199a', 'Gene', '100314245', (164, 172))	('miR146b', 'Gene', '574447', (155, 162))	('miR-149', 'Gene', '406941', (14, 21))
139934	26812476	Among M3 UM with liver metastasis (n = 11), higher expressions of miR-149* (72.72%), miR-1238 (100%), miR-134 (100%), miR-214 (54.54%), miR-146b (54.54%), miR-199a (100%) while moderate expression of miR-143 (45.45%) and negative expression of let-7b (100%) was observed.	('liver metastasis', 'Disease', 'MESH:D009362', (17, 33))	('liver metastasis', 'Disease', (17, 33))	('miR-214', 'Var', (118, 125))	('miR-1238', 'Gene', (85, 93))	('miR-199a', 'Gene', (155, 163))	('higher', 'PosReg', (44, 50))	('miR-1238', 'Gene', '100302226', (85, 93))	('miR-149', 'Gene', (66, 73))	('let-7b', 'Gene', '406884', (244, 250))	('miR-134', 'Gene', '406924', (102, 109))	('miR-146b', 'Var', (136, 144))	('expressions', 'MPA', (51, 62))	('miR-149', 'Gene', '406941', (66, 73))	('miR-199a', 'Gene', '100314245', (155, 163))	('miR-134', 'Gene', (102, 109))	('rat', 'Species', '10116', (181, 184))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('let-7b', 'Gene', (244, 250))
139935	26812476	Among M3 UM with no history of liver metastasis (n = 40), higher expressions of miR-149* (90.0%), miR-1238 (97.5%) and miR-134 (57.5%), miR-214 (62.5%), miR-146b (67.5%), miR-143 (65.0%), miR-199a (90.0%) and lower expression of let-7b (30.0%) were observed.	('miR-1238', 'Gene', (98, 106))	('let-7b', 'Gene', (229, 235))	('miR-143', 'Var', (171, 178))	('miR-199a', 'Gene', (188, 196))	('liver metastasis', 'Disease', 'MESH:D009362', (31, 47))	('lower', 'NegReg', (209, 214))	('expression', 'MPA', (215, 225))	('miR-149', 'Gene', (80, 87))	('miR-199a', 'Gene', '100314245', (188, 196))	('miR-214', 'Var', (136, 143))	('miR-134', 'Gene', (119, 126))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('higher', 'PosReg', (58, 64))	('miR-1238', 'Gene', '100302226', (98, 106))	('let-7b', 'Gene', '406884', (229, 235))	('miR-149', 'Gene', '406941', (80, 87))	('liver metastasis', 'Disease', (31, 47))	('miR-146b', 'Var', (153, 161))	('miR-134', 'Gene', '406924', (119, 126))	('expressions', 'MPA', (65, 76))
139936	26812476	Among D3 UM with liver metastasis (n = 6), higher expressions of miR-149* (83.3%), miR-1238 (83.3%), miR-199a (100%); moderate expressions in miR-134 (50%), miR-214 (50.0%), while lower expressions of miR-146b (33.33%) and let-7b (25%) and negative expression in miR-143 (100%) were observed.	('liver metastasis', 'Disease', 'MESH:D009362', (17, 33))	('liver metastasis', 'Disease', (17, 33))	('miR-134', 'Gene', (142, 149))	('higher', 'PosReg', (43, 49))	('miR-1238', 'Gene', '100302226', (83, 91))	('miR-1238', 'Gene', (83, 91))	('let-7b', 'Gene', '406884', (223, 229))	('miR-149', 'Gene', (65, 72))	('let-7b', 'Gene', (223, 229))	('miR-199a', 'Gene', (101, 109))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('rat', 'Species', '10116', (122, 125))	('miR-214', 'Var', (157, 164))	('miR-149', 'Gene', '406941', (65, 72))	('miR-199a', 'Gene', '100314245', (101, 109))	('miR-134', 'Gene', '406924', (142, 149))
139937	26812476	Among D3 UM with no liver metastasis (n = 29), higher expressions of miR-149* (72.41%), miR-1238 (86.2%), miR-199a (82.75%), miR-134 (41.37%), miR-214 (41.37%) and miR-146b (58.62%), while lower expression of miR-143 (37.93%), let-7b (13.79%) were observed (S6 Table and Fig 3).	('expressions', 'MPA', (54, 65))	('miR-199a', 'Gene', (106, 114))	('miR-134', 'Gene', '406924', (125, 132))	('liver metastasis', 'Disease', 'MESH:D009362', (20, 36))	('miR-199a', 'Gene', '100314245', (106, 114))	('liver metastasis', 'Disease', (20, 36))	('miR-134', 'Gene', (125, 132))	('higher', 'PosReg', (47, 53))	('let-7b', 'Gene', '406884', (227, 233))	('miR-149', 'Gene', (69, 76))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('let-7b', 'Gene', (227, 233))	('miR-1238', 'Gene', (88, 96))	('miR-214', 'Var', (143, 150))	('miR-146b', 'Var', (164, 172))	('miR-149', 'Gene', '406941', (69, 76))	('miR-1238', 'Gene', '100302226', (88, 96))
139944	26812476	Among the five miRNAs previously shown as class 2 tumor discriminators, four up-regulated miRNAs (miR-214, miR-143, miR-146b and miR-199a) showed a significant association with M3 tumors while the other miRNA, let-7b did not show any significant association with M3 UM (Fig 3).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('miR-143', 'Var', (107, 114))	('miR-199a', 'Gene', '100314245', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Disease', (180, 185))	('let-7b', 'Gene', '406884', (210, 216))	('miR-146b', 'Var', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('let-7b', 'Gene', (210, 216))	('M3 tumors', 'Disease', 'MESH:D015473', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('miR-214', 'Var', (98, 105))	('up-regulated', 'PosReg', (77, 89))	('UM', 'Phenotype', 'HP:0007716', (266, 268))	('miR-199a', 'Gene', (129, 137))	('M3 tumors', 'Disease', (177, 186))	('tumor', 'Disease', (50, 55))
139948	26812476	Deregulation of NF-kB pathways is known to regulate UM metastasis.	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('Deregulation', 'Var', (0, 12))	('NF-kB', 'Gene', (16, 21))	('UM metastasis', 'CPA', (52, 65))	('NF-kB', 'Gene', '309165', (16, 21))
139952	26812476	Restoration of let-7b is considered as a potential therapeutic option in cancers.	('cancers', 'Disease', (73, 80))	('let-7b', 'Gene', '406884', (15, 21))	('let-7b', 'Gene', (15, 21))	('Restoration', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('rat', 'Species', '10116', (5, 8))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
139956	26812476	However, the additional prognostic factors specific to UM tumors such as cytogenetic analysis and miRNA expressions would confirm the uveal melanoma risk stratification.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('rat', 'Species', '10116', (156, 159))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('uveal melanoma', 'Disease', 'MESH:C536494', (134, 148))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('miRNA', 'Var', (98, 103))	('uveal melanoma', 'Disease', (134, 148))	('uveal melanoma', 'Phenotype', 'HP:0007716', (134, 148))
139957	26812476	Further, gene targets prediction of the differentially expressed miRNAs revealed the negative regulation of gene lists namely (i) SMAD4, WISP1, HDAC8 and C-KIT by miR-146b, (ii) WISP1 by miR-1238, miR-134 and (iii) SMAD4 by miR-199a (Fig 4).	('miR-146b', 'Var', (163, 171))	('C-KIT', 'Gene', '3815', (154, 159))	('regulation', 'biological_process', 'GO:0065007', ('94', '104'))	('miR-199a', 'Gene', (224, 232))	('miR-134', 'Gene', (197, 204))	('miR-134', 'Gene', '406924', (197, 204))	('WISP1', 'Gene', '8840', (178, 183))	('C-KIT', 'Gene', (154, 159))	('miR-1238', 'Gene', (187, 195))	('HDAC8', 'Gene', '55869', (144, 149))	('WISP1', 'Gene', '8840', (137, 142))	('KIT', 'molecular_function', 'GO:0005020', ('156', '159'))	('miR-199a', 'Gene', '100314245', (224, 232))	('miR-1238', 'Gene', '100302226', (187, 195))	('WISP1', 'Gene', (178, 183))	('WISP1', 'Gene', (137, 142))	('HDAC8', 'Gene', (144, 149))	('negative regulation', 'NegReg', (85, 104))
139962	26812476	Here, inactivation of p53 pathway in UM was supported by the over-expression of HIPK1 gene (S9 Table) which corroborates with an earlier report in other cancer (colorectal cancer).	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('colorectal cancer', 'Disease', (161, 178))	('rat', 'Species', '10116', (115, 118))	('cancer', 'Disease', (153, 159))	('HIPK1', 'Gene', (80, 85))	('inactivation', 'Var', (6, 18))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('HIPK1', 'Gene', '204851', (80, 85))	('p53', 'Gene', (22, 25))	('UM', 'Phenotype', 'HP:0007716', (37, 39))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('colorectal cancer', 'Disease', 'MESH:D015179', (161, 178))	('p53', 'Gene', '7157', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (172, 178))	('colorectal cancer', 'Phenotype', 'HP:0003003', (161, 178))	('over-expression', 'PosReg', (61, 76))
139965	26812476	These results indicate that the expression of miR-214, miR-149*, miR-146b, miR-199a, miR-1238 and miR-134 can be used to evaluate the metastasis-free survival in UM patients.	('miR-1238', 'Gene', (85, 93))	('metastasis-free survival', 'CPA', (134, 158))	('miR-149', 'Gene', '406941', (55, 62))	('miR-199a', 'Gene', '100314245', (75, 83))	('miR-1238', 'Gene', '100302226', (85, 93))	('miR-214', 'Var', (46, 53))	('UM', 'Phenotype', 'HP:0007716', (162, 164))	('miR-134', 'Gene', '406924', (98, 105))	('evaluate', 'Reg', (121, 129))	('miR-149', 'Gene', (55, 62))	('miR-134', 'Gene', (98, 105))	('patients', 'Species', '9606', (165, 173))	('miR-146b', 'Var', (65, 73))	('miR-199a', 'Gene', (75, 83))
139969	26765459	Double hit BAP1 inactivation has been reported in a range of tumor types, including intrahepatic cholangiocarcinoma (ICC), sometimes in association with germline mutation.	('BAP1', 'Gene', '8314', (11, 15))	('reported', 'Reg', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('inactivation', 'Var', (16, 28))	('BAP1', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('intrahepatic cholangiocarcinoma', 'Disease', (84, 115))	('tumor', 'Disease', (61, 66))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (97, 115))
139980	26765459	That is, germline BAP1 mutation is associated with a newly recognized autosomal-dominant hereditary cancer syndrome, (OMIM #6143), characterized by uveal melanoma, mesothelioma, cutaneous melanocytic lesions, renal cell carcinoma, basal cell carcinoma, and intrahepatic cholangiocarcinoma (ICC); while biallelic inactivations including somatic mutations or deletions have also been reported in a range of tumors including uveal melanoma, mesothelioma, cutaneous melanocytic neoplasms, and clear cell renal carcinoma.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (209, 229))	('uveal melanoma', 'Disease', 'MESH:C536494', (148, 162))	('mesothelioma', 'Disease', (164, 176))	('autosomal-dominant hereditary cancer syndrome', 'Disease', (70, 115))	('BAP1', 'Gene', (18, 22))	('uveal melanoma', 'Disease', (148, 162))	('basal cell carcinoma', 'Disease', (231, 251))	('mesothelioma', 'Disease', 'MESH:D008654', (164, 176))	('clear cell renal carcinoma', 'Disease', (489, 515))	('germline', 'Var', (9, 17))	('cutaneous melanocytic lesions', 'Disease', 'MESH:D009508', (178, 207))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (462, 483))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (257, 288))	('tumors', 'Disease', 'MESH:D009369', (405, 411))	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('uveal melanoma', 'Phenotype', 'HP:0007716', (148, 162))	('intrahepatic cholangiocarcinoma', 'Disease', (257, 288))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (489, 515))	('melanoma', 'Phenotype', 'HP:0002861', (428, 436))	('cutaneous melanocytic neoplasms', 'Disease', (452, 483))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('mesothelioma', 'Disease', (438, 450))	('renal cell carcinoma', 'Disease', (209, 229))	('uveal melanoma', 'Disease', 'MESH:C536494', (422, 436))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (209, 229))	('uveal melanoma', 'Disease', (422, 436))	('carcinoma', 'Phenotype', 'HP:0030731', (506, 515))	('mesothelioma', 'Disease', 'MESH:D008654', (438, 450))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (270, 288))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (231, 251))	('autosomal-dominant hereditary cancer syndrome', 'Disease', 'MESH:D009386', (70, 115))	('cutaneous melanocytic neoplasms', 'Disease', 'MESH:D009508', (452, 483))	('tumors', 'Phenotype', 'HP:0002664', (405, 411))	('uveal melanoma', 'Phenotype', 'HP:0007716', (422, 436))	('BAP1', 'Gene', '8314', (18, 22))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (489, 515))	('mutation', 'Var', (23, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('associated', 'Reg', (35, 45))	('deletions', 'Var', (357, 366))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('renal carcinoma', 'Phenotype', 'HP:0005584', (500, 515))	('cutaneous melanocytic lesions', 'Disease', (178, 207))	('neoplasms', 'Phenotype', 'HP:0002664', (474, 483))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (231, 251))	('tumor', 'Phenotype', 'HP:0002664', (405, 410))	('tumors', 'Disease', (405, 411))
139987	26765459	It has recently been suggested that germline BAP1 mutations predispose to intrahepatic cholangiocarcinoma and somatic biallelic inactivating BAP1 mutations have been reported in up to 25% of intrahepatic cholangiocarcinomas (ICC).	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (204, 222))	('intrahepatic cholangiocarcinomas', 'Disease', (191, 223))	('mutations', 'Var', (146, 155))	('BAP1', 'Gene', (45, 49))	('BAP1', 'Gene', '8314', (141, 145))	('mutations', 'Var', (50, 59))	('intrahepatic cholangiocarcinomas', 'Disease', 'MESH:D018281', (191, 223))	('reported', 'Reg', (166, 174))	('BAP1', 'Gene', (141, 145))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (191, 222))	('predispose', 'Reg', (60, 70))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (87, 105))	('biallelic inactivating', 'Var', (118, 140))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (74, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('BAP1', 'Gene', '8314', (45, 49))	('intrahepatic cholangiocarcinoma', 'Disease', (74, 105))
140018	26765459	Although our study was not intended or designed to assess the sensitivity and specificity of BAP1 IHC for BAP1 mutation, our incidence of negative staining for BAP1 is very similar to the rate of inactivating mutations reported by Jiao et al (25%) and Chan-On et al (22.2%), suggesting that loss of IHC staining for BAP1 is likely to correlate strongly with BAP1 mutation in ICC as it has been proven to do in mesothelioma and uveal melanoma.	('BAP1', 'Gene', '8314', (93, 97))	('BAP1', 'Gene', '8314', (358, 362))	('BAP1', 'Gene', (106, 110))	('mutation', 'Var', (363, 371))	('melanoma', 'Phenotype', 'HP:0002861', (433, 441))	('BAP1', 'Gene', '8314', (316, 320))	('BAP1', 'Gene', '8314', (160, 164))	('BAP1', 'Gene', (358, 362))	('uveal melanoma', 'Phenotype', 'HP:0007716', (427, 441))	('BAP1', 'Gene', '8314', (106, 110))	('BAP1', 'Gene', (93, 97))	('BAP1', 'Gene', (316, 320))	('BAP1', 'Gene', (160, 164))	('mesothelioma and uveal melanoma', 'Disease', 'MESH:C536494', (410, 441))
140024	26765459	Presumably this indicates that pathways other than those associated with BAP1 mutation are more lethal in mesothelioma but less lethal that BAP1 associated pathways in uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (168, 182))	('BAP1', 'Gene', '8314', (73, 77))	('mutation', 'Var', (78, 86))	('mesothelioma', 'Disease', (106, 118))	('BAP1', 'Gene', (140, 144))	('BAP1', 'Gene', (73, 77))	('mesothelioma', 'Disease', 'MESH:D008654', (106, 118))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('BAP1', 'Gene', '8314', (140, 144))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('uveal melanoma', 'Disease', (168, 182))
140033	26765459	It has been suggested that ICC may be a component of the hereditary cancer syndrome associated with germline BAP1 mutations.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutations', 'Var', (114, 123))	('BAP1', 'Gene', '8314', (109, 113))	('component of the hereditary cancer syndrome', 'Disease', (40, 83))	('associated', 'Reg', (84, 94))	('BAP1', 'Gene', (109, 113))	('ICC', 'Disease', (27, 30))	('component of the hereditary cancer syndrome', 'Disease', 'MESH:D009386', (40, 83))
140034	26765459	Therefore, it is possible that IHC for BAP1 may play a role in triaging formal genetic testing for germline BAP1 mutation in patients presenting with cholangiocarcinoma.	('patients', 'Species', '9606', (125, 133))	('mutation', 'Var', (113, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('BAP1', 'Gene', '8314', (108, 112))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (150, 168))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (150, 168))	('BAP1', 'Gene', (108, 112))	('BAP1', 'Gene', '8314', (39, 43))	('cholangiocarcinoma', 'Disease', (150, 168))	('BAP1', 'Gene', (39, 43))
140035	26765459	That is, if a tumor shows positive staining for BAP1 then germline BAP1 mutation can be considered unlikely, whereas if a tumor shows negative staining for BAP1 then BAP1 mutation is not excluded and formal counselling and genetic testing may be warranted in patients considered at high risk for hereditary disease for example due to onset at a young age or a family history of BAP1-associated malignancy such as mesothelioma, uveal melanoma, or cholangiocarcinoma.	('BAP1', 'Gene', '8314', (48, 52))	('BAP1', 'Gene', '8314', (166, 170))	('uveal melanoma', 'Phenotype', 'HP:0007716', (427, 441))	('tumor', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('malignancy', 'Disease', 'MESH:D009369', (394, 404))	('patients', 'Species', '9606', (259, 267))	('BAP1', 'Gene', '8314', (156, 160))	('BAP1', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mesothelioma', 'Disease', (413, 425))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (446, 464))	('BAP1', 'Gene', (166, 170))	('mesothelioma', 'Disease', 'MESH:D008654', (413, 425))	('BAP1', 'Gene', '8314', (378, 382))	('malignancy', 'Disease', (394, 404))	('hereditary disease', 'Disease', (296, 314))	('cholangiocarcinoma', 'Disease', (446, 464))	('hereditary disease', 'Disease', 'MESH:D030342', (296, 314))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (446, 464))	('BAP1', 'Gene', '8314', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mutation', 'Var', (72, 80))	('BAP1', 'Gene', (156, 160))	('melanoma', 'Phenotype', 'HP:0002861', (433, 441))	('tumor', 'Disease', (14, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (455, 464))	('BAP1', 'Gene', (378, 382))	('uveal melanoma', 'Disease', 'MESH:C536494', (427, 441))	('uveal melanoma', 'Disease', (427, 441))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('BAP1', 'Gene', (67, 71))
140036	26765459	The incidence of germline BAP1 mutations in cholangiocarcinoma is not currently known; however, the incidence of germline BAP1 mutations in malignancies such as mesothelioma and metastasising uveal melanoma has been estimated at 1 to 2% or less.	('BAP1', 'Gene', (26, 30))	('malignancies', 'Disease', 'MESH:D009369', (140, 152))	('mesothelioma', 'Disease', (161, 173))	('uveal melanoma', 'Disease', (192, 206))	('BAP1', 'Gene', (122, 126))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (44, 62))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (44, 62))	('malignancies', 'Disease', (140, 152))	('mesothelioma', 'Disease', 'MESH:D008654', (161, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('BAP1', 'Gene', '8314', (122, 126))	('BAP1', 'Gene', '8314', (26, 30))	('mutations', 'Var', (127, 136))	('cholangiocarcinoma', 'Disease', (44, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (192, 206))	('uveal melanoma', 'Phenotype', 'HP:0007716', (192, 206))
140037	26765459	It is likely that the rate of germline BAP1 mutations to be lower in cholangiocarcinoma than that found in mesothelioma and uveal melanoma, given that somatic mutations resulting in BAP1 loss occur in approximately half of mesotheliomas and in up to 84% of uveal melanomas, which is higher than the rate of BAP1 loss so far reported in cholangiocarcinoma.	('loss', 'NegReg', (187, 191))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (336, 354))	('melanoma', 'Phenotype', 'HP:0002861', (263, 271))	('cholangiocarcinoma', 'Disease', (69, 87))	('BAP1', 'Gene', '8314', (39, 43))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (69, 87))	('cholangiocarcinoma', 'Disease', (336, 354))	('uveal melanomas', 'Disease', 'MESH:C536494', (257, 272))	('lower', 'NegReg', (60, 65))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (336, 354))	('BAP1', 'Gene', '8314', (182, 186))	('uveal melanoma', 'Phenotype', 'HP:0007716', (124, 138))	('mesothelioma and uveal melanoma', 'Disease', 'MESH:C536494', (107, 138))	('BAP1', 'Gene', '8314', (307, 311))	('mesotheliomas', 'Disease', (223, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('BAP1', 'Gene', (39, 43))	('uveal melanoma', 'Phenotype', 'HP:0007716', (257, 271))	('mesotheliomas', 'Disease', 'MESH:D008654', (223, 236))	('BAP1', 'Gene', (182, 186))	('uveal melanomas', 'Disease', (257, 272))	('uveal melanomas', 'Phenotype', 'HP:0007716', (257, 272))	('BAP1', 'Gene', (307, 311))	('melanomas', 'Phenotype', 'HP:0002861', (263, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (345, 354))	('mutations', 'Var', (44, 53))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (69, 87))
140038	26765459	Given that real rate of germline BAP1 mutations is likely to be less than 1%, it is reasonable that formal genetic testing for BAP1 mutation be reserved for those patients who are considered high-risk based on family and personal history and demonstrate loss of BAP1 expression by IHC.	('loss', 'NegReg', (254, 258))	('BAP1', 'Gene', '8314', (262, 266))	('BAP1', 'Gene', (127, 131))	('patients', 'Species', '9606', (163, 171))	('BAP1', 'Gene', (262, 266))	('BAP1', 'Gene', '8314', (33, 37))	('BAP1', 'Gene', (33, 37))	('BAP1', 'Gene', '8314', (127, 131))	('mutation', 'Var', (132, 140))	('expression', 'MPA', (267, 277))
140050	26087189	Inhibitors of HDAC and BET proteins have individually been shown to cause apoptosis and reduce growth of melanoma cells.	('HDAC', 'Gene', (14, 18))	('apoptosis', 'CPA', (74, 83))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('cause', 'Reg', (68, 73))	('melanoma', 'Disease', (105, 113))	('Inhibitors', 'Var', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('reduce growth', 'Phenotype', 'HP:0001510', (88, 101))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('BET proteins', 'Protein', (23, 35))	('reduce', 'NegReg', (88, 94))
140051	26087189	Here we show that combining the HDAC inhibitor LBH589 and BET inhibitor I-BET151 synergistically induce apoptosis of melanoma cells but not of melanocytes.	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('LBH589', 'Var', (47, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('104', '113'))	('I-BET151', 'Chemical', 'MESH:C568713', (72, 80))	('induce', 'PosReg', (97, 103))	('LBH589', 'Chemical', 'MESH:D000077767', (47, 53))	('apoptosis', 'CPA', (104, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('104', '113'))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
140055	26087189	Dysregulation of chromatin structure is a frequent event in melanoma and underlies many aspects of melanoma biology including resistance to targeted therapies and melanoma invasiveness.	('melanoma invasiveness', 'Disease', (163, 184))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('Dysregulation', 'Var', (0, 13))	('melanoma', 'Disease', (163, 171))	('chromatin', 'cellular_component', 'GO:0000785', ('17', '26'))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma invasiveness', 'Disease', 'MESH:D008545', (163, 184))	('chromatin', 'MPA', (17, 26))	('melanoma', 'Disease', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))
140058	26087189	Members of the BET family, which consists of BRD2, BRD3, BRD4 and the testis specific BRDT, have two bromodomains in the N-terminal region which bind to acetylated lysines in histones and a C-terminal (CT) region which binds to transcription elongation factors (TEFs).	('TEFs', 'Species', '110835', (262, 266))	('binds', 'Interaction', (219, 224))	('lysines', 'Chemical', 'MESH:D008239', (164, 171))	('bind', 'Interaction', (145, 149))	('BRD4', 'Gene', (57, 61))	('acetylated lysines', 'MPA', (153, 171))	('transcription', 'biological_process', 'GO:0006351', ('228', '241'))	('BRD3', 'Var', (51, 55))	('BRD4', 'Gene', '23476', (57, 61))	('BRD2', 'Var', (45, 49))
140061	26087189	Additionally I-BET151 has strong inhibitory effects on activation of NF-kB.	('I-BET151', 'Chemical', 'MESH:C568713', (13, 21))	('inhibitory effects', 'MPA', (33, 51))	('I-BET151', 'Var', (13, 21))	('NF-kB', 'Protein', (69, 74))	('activation', 'PosReg', (55, 65))
140065	26087189	To determine whether combined treatment of I-BET151 and LBH589 can potentiate sensitivity of melanoma cells to apoptosis we examined the cytotoxic capacity of both inhibitors in a panel of melanoma cell lines.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('I-BET151', 'Chemical', 'MESH:C568713', (43, 51))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('melanoma', 'Disease', (189, 197))	('LBH589', 'Chemical', 'MESH:D000077767', (56, 62))	('LBH589', 'Gene', (56, 62))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('potentiate', 'PosReg', (67, 77))	('I-BET151', 'Var', (43, 51))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))
140069	26087189	As shown in Figure 1A single drug treatment of Me1007 cells with I-BET151 or LBH589 showed slight induction of Annexin-V/PI positive cells when compared to DMSO treated cells.	('Annexin-V', 'Gene', '308', (111, 120))	('Annexin-V', 'Gene', (111, 120))	('LBH589', 'Gene', (77, 83))	('I-BET151', 'Var', (65, 73))	('I-BET151', 'Chemical', 'MESH:C568713', (65, 73))	('Me1007', 'Chemical', '-', (47, 53))	('LBH589', 'Chemical', 'MESH:D000077767', (77, 83))	('DMSO', 'Chemical', 'MESH:D004121', (156, 160))
140072	26087189	Studies on the melanoma cell growth showed that the combination of I-BET151 and LBH589 inhibited cell growth and resulted in changes in cell morphology characterized by enlarged and flattened cell bodies (Supplementary Figure 2A).	('cell morphology', 'CPA', (136, 151))	('cell growth', 'CPA', (97, 108))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('LBH589', 'Chemical', 'MESH:D000077767', (80, 86))	('cell growth', 'biological_process', 'GO:0016049', ('97', '108'))	('cell growth', 'biological_process', 'GO:0016049', ('24', '35'))	('combination', 'Var', (52, 63))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('inhibited', 'NegReg', (87, 96))	('I-BET151', 'Chemical', 'MESH:C568713', (67, 75))	('LBH589', 'Gene', (80, 86))	('I-BET151', 'Var', (67, 75))	('changes', 'Reg', (125, 132))	('enlarged', 'PosReg', (169, 177))
140078	26087189	Taken together, these results indicate that the combination of I-BET151 and LBH589 synergistically induces apoptosis and cell cycle arrest in melanoma, even in cells with acquired resistance to BRAF inhibitors.	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('BRAF', 'Gene', '673', (194, 198))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('I-BET151', 'Chemical', 'MESH:C568713', (63, 71))	('BRAF', 'Gene', (194, 198))	('I-BET151', 'Var', (63, 71))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('121', '138'))	('cell cycle arrest', 'CPA', (121, 138))	('LBH589', 'Chemical', 'MESH:D000077767', (76, 82))	('LBH589', 'Gene', (76, 82))	('induces', 'PosReg', (99, 106))	('apoptosis', 'CPA', (107, 116))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (121, 138))	('melanoma', 'Disease', (142, 150))
140086	26087189	In contrast, Q-VD-OPh treatment did not prevent mitochondrial depolarization in either cell line, indicating that combination of I-BET151 and LBH589 induces an initial caspase-independent loss of mitochondrial depolarization (Figure 2D) followed by caspase dependent apoptosis.	('I-BET151', 'Chemical', 'MESH:C568713', (129, 137))	('apoptosis', 'CPA', (267, 276))	('mitochondrial depolarization', 'biological_process', 'GO:0051882', ('48', '76'))	('combination', 'Var', (114, 125))	('caspase', 'CPA', (249, 256))	('Q-VD-OPh', 'Chemical', 'MESH:C468548', (13, 21))	('LBH589', 'Chemical', 'MESH:D000077767', (142, 148))	('apoptosis', 'biological_process', 'GO:0097194', ('267', '276'))	('OPh', 'molecular_function', 'GO:0004063', ('18', '21'))	('mitochondrial depolarization', 'biological_process', 'GO:0051882', ('196', '224'))	('loss', 'NegReg', (188, 192))	('apoptosis', 'biological_process', 'GO:0006915', ('267', '276'))	('LBH589', 'Gene', (142, 148))	('I-BET151', 'Var', (129, 137))	('mitochondrial depolarization', 'MPA', (196, 224))
140093	26087189	Knockdown of FOXO3a also inhibited apoptosis in combination-treated Me1007 cells as shown by the results in Figure 3E.	('apoptosis', 'biological_process', 'GO:0006915', ('35', '44'))	('Knockdown', 'Var', (0, 9))	('FOXO3a', 'Gene', '2309', (13, 19))	('FOXO3a', 'Gene', (13, 19))	('inhibited', 'NegReg', (25, 34))	('Me1007', 'Chemical', '-', (68, 74))	('apoptosis', 'CPA', (35, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('35', '44'))
140104	26087189	To give these findings wider relevance we examined The Cancer Genome Atlas (TCGA) data (http://cancergenome.nih.gov/) for the prognostic significance of BIM and cleaved caspase 7 expression.	('caspase 7', 'Gene', (169, 178))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (55, 74))	('Cancer Genome Atlas', 'Disease', (55, 74))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cleaved', 'Var', (161, 168))	('caspase 7', 'Gene', '840', (169, 178))
140109	26087189	This revealed a consistent downregulation of YAP1 mRNA expression both in melanoma cell lines Patient-1-post and Me1007 cells, indicating that the combination of I-BET151 and LBH589 reduces YAP1 expression at the transcriptional level (Figure 5B).	('Patient', 'Species', '9606', (94, 101))	('mRNA expression', 'MPA', (50, 65))	('expression', 'MPA', (195, 205))	('reduces', 'NegReg', (182, 189))	('YAP1', 'Gene', (45, 49))	('YAP1', 'Gene', '10413', (45, 49))	('LBH589', 'Var', (175, 181))	('I-BET151', 'Var', (162, 170))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('I-BET151', 'Chemical', 'MESH:C568713', (162, 170))	('YAP1', 'Gene', (190, 194))	('YAP1', 'Gene', '10413', (190, 194))	('downregulation', 'NegReg', (27, 41))	('Me1007', 'Chemical', '-', (113, 119))	('LBH589', 'Chemical', 'MESH:D000077767', (175, 181))
140112	26087189	As shown in Figure 6A, treatment with I-BET151 or LBH589 alone inhibited tumor growth by 44.3% (p < 0.01, ANOVA, Dunnett's post-hoc test) and 22.3% (ns), respectively on day 15 when compared to vehicle treated tumors.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('LBH589', 'Gene', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('I-BET151', 'Chemical', 'MESH:C568713', (38, 46))	('I-BET151', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Disease', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', (73, 78))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('inhibited', 'NegReg', (63, 72))	('LBH589', 'Chemical', 'MESH:D000077767', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
140113	26087189	Combined treatment with I-BET151 and LBH589 reduced tumor growth further by 65.4% (p < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('LBH589', 'Gene', (37, 43))	('tumor', 'Disease', (52, 57))	('I-BET151', 'Var', (24, 32))	('I-BET151', 'Chemical', 'MESH:C568713', (24, 32))	('LBH589', 'Chemical', 'MESH:D000077767', (37, 43))	('reduced', 'NegReg', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
140114	26087189	Kaplan-Meier analysis of survival of the mice revealed that, as compared to vehicle control, treatment with I-BET151 (p < 0.01, Mantel Cox log rank test) but not LBH589, prolonged the survival (as defined by time to an ethical tumor volume endpoint) of mice.	('tumor', 'Disease', (227, 232))	('mice', 'Species', '10090', (41, 45))	('I-BET151', 'Var', (108, 116))	('I-BET151', 'Chemical', 'MESH:C568713', (108, 116))	('prolonged', 'PosReg', (170, 179))	('LBH589', 'Chemical', 'MESH:D000077767', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('mice', 'Species', '10090', (253, 257))	('survival', 'CPA', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
140115	26087189	Combined treatment with I-BET151 and LBH589 further prolonged survival as compared with I-BET151 alone (Figure 6B) (p-value < 0.05).	('LBH589', 'Gene', (37, 43))	('I-BET151', 'Var', (24, 32))	('I-BET151', 'Chemical', 'MESH:C568713', (24, 32))	('prolonged', 'PosReg', (52, 61))	('survival', 'CPA', (62, 70))	('LBH589', 'Chemical', 'MESH:D000077767', (37, 43))	('I-BET151', 'Chemical', 'MESH:C568713', (88, 96))
140119	26087189	Taken together, these findings indicate that combined treatment with I-BET151 and LBH589 inhibits tumor growth in vivo and prolongs survival of mice with melanoma xenografts.	('LBH589', 'Chemical', 'MESH:D000077767', (82, 88))	('inhibits', 'NegReg', (89, 97))	('mice', 'Species', '10090', (144, 148))	('I-BET151', 'Chemical', 'MESH:C568713', (69, 77))	('I-BET151', 'Var', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('LBH589', 'Gene', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('prolongs', 'PosReg', (123, 131))	('melanoma xenografts', 'Disease', 'MESH:D008545', (154, 173))	('melanoma xenografts', 'Disease', (154, 173))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('tumor', 'Disease', (98, 103))	('survival', 'CPA', (132, 140))
140123	26087189	These results are consistent with our previous studies on the individual inhibitors which showed that HDAC inhibitors resulted in upregulation of several pro-apoptotic proteins and downregulation of Bcl-XL and XIAP.	('downregulation', 'NegReg', (181, 195))	('Bcl-XL', 'Gene', '598', (199, 205))	('pro-apoptotic proteins', 'MPA', (154, 176))	('upregulation', 'PosReg', (130, 142))	('Bcl-XL', 'Gene', (199, 205))	('inhibitors', 'Var', (107, 117))	('HDAC', 'Gene', (102, 106))
140124	26087189	Similarly we found that I-BET151 induced BIM expression (but not NOXA or PUMA) as well as downregulation of Bcl-2, Bcl-XL and XIAP.	('Bcl-XL', 'Gene', (115, 121))	('I-BET151', 'Var', (24, 32))	('Bcl-2', 'Gene', (108, 113))	('Bcl-2', 'Gene', '596', (108, 113))	('BIM expression', 'MPA', (41, 55))	('I-BET151', 'Chemical', 'MESH:C568713', (24, 32))	('Bcl-2', 'molecular_function', 'GO:0015283', ('108', '113'))	('Bcl-XL', 'Gene', '598', (115, 121))	('downregulation', 'NegReg', (90, 104))
140127	26087189	In the present studies the combination of LBH589 and I-BET151 caused enhanced expression of p21 compared to each drug alone and an increase in the number of cells with 4N DNA content, suggestive of arrest predominantly in the G2-M phase.	('p21', 'Gene', '644914', (92, 95))	('expression', 'MPA', (78, 88))	('LBH589', 'Chemical', 'MESH:D000077767', (42, 48))	('enhanced', 'PosReg', (69, 77))	('increase', 'PosReg', (131, 139))	('M phase', 'biological_process', 'GO:0000279', ('229', '236'))	('LBH589', 'Var', (42, 48))	('DNA', 'cellular_component', 'GO:0005574', ('171', '174'))	('I-BET151', 'Var', (53, 61))	('I-BET151', 'Chemical', 'MESH:C568713', (53, 61))	('p21', 'Gene', (92, 95))
140133	26087189	Our data showing upregulation of BIM is consistent with this and further supported by studies showing that knockdown of FOXO3a prevented upregulation of mRNA for BIM by the drug combination.	('knockdown', 'Var', (107, 116))	('FOXO3a', 'Gene', '2309', (120, 126))	('FOXO3a', 'Gene', (120, 126))	('prevented', 'NegReg', (127, 136))	('upregulation', 'PosReg', (137, 149))	('mRNA for BIM', 'MPA', (153, 165))
140140	26087189	Dephosphorylation of YAP by the mutant Gq11 component of G protein coupled receptors allows its entry into the nucleus.	('YAP', 'Gene', (21, 24))	('G protein coupled', 'Protein', (57, 74))	('mutant', 'Var', (32, 38))	('YAP', 'Gene', '10413', (21, 24))	('nucleus', 'cellular_component', 'GO:0005634', ('111', '118'))	('Dephosphorylation', 'MPA', (0, 17))	('Dephosphorylation', 'biological_process', 'GO:0016311', ('0', '17'))	('entry into the nucleus', 'MPA', (96, 118))	('Gq11', 'Gene', (39, 43))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
140149	26087189	This showed that high levels of BIM and cleaved caspase 7 were highly associated with improved survival, implying that changes induced by the combined drugs may have beneficial effects on survival.	('improved', 'PosReg', (86, 94))	('caspase 7', 'Gene', (48, 57))	('BIM', 'MPA', (32, 35))	('cleaved', 'Var', (40, 47))	('caspase 7', 'Gene', '840', (48, 57))	('survival', 'CPA', (95, 103))
140150	26087189	These conclusions were supported by the results of the studies on melanoma xenografts in NOD/SCID mice which showed that the combination of I-BET151 and LBH589 significantly improved survival of the mice challenged with the vemurafenib-resistant Patient-1-post melanoma cell line compared to either drug alone.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('NOD', 'Gene', '1822', (89, 92))	('melanoma xenografts', 'Disease', 'MESH:D008545', (66, 85))	('SCID', 'Disease', (93, 97))	('improved', 'PosReg', (174, 182))	('melanoma', 'Disease', (261, 269))	('NOD', 'Gene', (89, 92))	('melanoma', 'Phenotype', 'HP:0002861', (261, 269))	('vemurafenib', 'Chemical', 'MESH:D000077484', (224, 235))	('LBH589', 'Chemical', 'MESH:D000077767', (153, 159))	('mice', 'Species', '10090', (98, 102))	('LBH589', 'Gene', (153, 159))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Disease', 'MESH:D008545', (261, 269))	('melanoma xenografts', 'Disease', (66, 85))	('I-BET151', 'Var', (140, 148))	('mice', 'Species', '10090', (199, 203))	('I-BET151', 'Chemical', 'MESH:C568713', (140, 148))	('Patient', 'Species', '9606', (246, 253))	('survival', 'CPA', (183, 191))	('SCID', 'Disease', 'MESH:D053632', (93, 97))
140154	26087189	These preclinical studies provide a basis for considering combinations of these epigenetic inhibitors in new treatments for melanoma particularly those resistant to BRAFi.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('epigenetic', 'Var', (80, 90))	('melanoma', 'Disease', (124, 132))	('BRAF', 'Gene', '673', (165, 169))	('BRAF', 'Gene', (165, 169))
140161	26087189	Cells were treated with either with 2 muM I-BET151, 30 nM LBH589 or combination and control cells were treated with DMSO.	('LBH589', 'Chemical', 'MESH:D000077767', (58, 64))	('I-BET151', 'Var', (42, 50))	('I-BET151', 'Chemical', 'MESH:C568713', (42, 50))	('DMSO', 'Chemical', 'MESH:D004121', (116, 120))	('LBH589', 'Gene', (58, 64))
140163	26087189	For gene knockdown studies, cells were transiently transfected with siRNA of BCL2L11 (siRNA#1: SI04951968; siRNA #2: SI02655359 Qiagen, Venlo, Netherlands), FOXO3a (siRNA #1: SI04916366, siRNA #2: SI04916387) or a non-silencing control (1027281, Qiagen) using Lipofectamine RNAiMax (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's protocol.	('BCL2', 'molecular_function', 'GO:0015283', ('77', '81'))	('FOXO3a', 'Gene', '2309', (157, 163))	('siRNA', 'Var', (165, 170))	('BCL2L11', 'Gene', '10018', (77, 84))	('FOXO3a', 'Gene', (157, 163))	('BCL2L11', 'Gene', (77, 84))	('siRNA', 'Var', (86, 91))
140170	26087189	Proteins were separated by SDS-PAGE, electroblotted onto nitrocellulose membranes and probed with the following primary anti-human antibodies: BIM (C34C5), Bax (2772), PUMA (4976), caspase 7 (9492), caspase 9 (9502), AKT (9272) and phospho AKT (pS473, 9271), pPRAS40 (pThr 246, 2997) all from Cell Signaling Technology (Cambridge, UK), Bcl-2 (C-2, sc-7382), Bcl-XL (H-5, sc-8392), Bak (G-23, sc-832), caspase 3 (sc-7148), PARP (F-2, sc-8007), GAPDH (sc-32233), YAP1 (sc-15407) from Santa Cruz (Santa Cruz, CA, USA), anti-MCL-1 (559027) and anti-XIAP, (610716), BAD (610392) from BD Bioscience (San Jose, CA, USA), NOXA (114C307.1) from Imgenex (Littleton, CO, USA), pYAP1 (pS127, ab76252) from abcam (Cambridge, UK), cIAP/HIAP-2 (AF 8181) from R&D (Minneapolis, MN, USA) and alpha-Tubulin (B-5-1-2) from Sigma (St. Louis, MO, USA).	('YAP1', 'Gene', '10413', (667, 671))	('caspase 7', 'Gene', (181, 190))	('YAP1', 'Gene', '10413', (461, 465))	('Signaling', 'biological_process', 'GO:0023052', ('298', '307'))	('Bcl-XL', 'Gene', '598', (358, 364))	('AKT', 'Gene', '207', (217, 220))	('AKT', 'Gene', '207', (240, 243))	('MN', 'CellLine', 'CVCL:U508', (762, 764))	('Bcl-XL', 'Gene', (358, 364))	('YAP1', 'Gene', (667, 671))	('YAP1', 'Gene', (461, 465))	('PRAS40', 'Gene', (260, 266))	('caspase 7', 'Gene', '840', (181, 190))	('MCL-1', 'Gene', '4170', (521, 526))	('Bcl-2', 'Gene', (336, 341))	('610716', 'Var', (552, 558))	('GAPDH', 'Gene', '2597', (443, 448))	('Bcl-2', 'molecular_function', 'GO:0015283', ('336', '341'))	('alpha-Tubulin', 'Gene', '10376', (775, 788))	('HIAP-2', 'Disease', (722, 728))	('human', 'Species', '9606', (125, 130))	('MCL-1', 'Gene', (521, 526))	('Bcl-2', 'Gene', '596', (336, 341))	('HIAP-2', 'Disease', 'MESH:D014923', (722, 728))	('PRAS40', 'Gene', '84335', (260, 266))	('Bax', 'Gene', (156, 159))	('AKT', 'Gene', (217, 220))	('AKT', 'Gene', (240, 243))	('GAPDH', 'Gene', (443, 448))	('Bax', 'Gene', '581', (156, 159))	('alpha-Tubulin', 'Gene', (775, 788))
140173	26087189	cDNA was amplified on AB7900 (Applied Biosystems, Mulgrave, VIC) using Universal PCR Master Mix and Taqman probes specific for BIM (Hs00708019_s1), YAP (Hs00371735_m1), Foxo3a (Hs00818121_m1) and normalized to levels of endogenous 18S (Hs99999901_s1) (Applied Biosystems).	('Hs00818121_m1', 'Var', (177, 190))	('YAP', 'Gene', '10413', (148, 151))	('Hs00708019_s1', 'Var', (132, 145))	('Hs00371735_m1', 'Var', (153, 166))	('YAP', 'Gene', (148, 151))	('Foxo3a', 'Gene', '2309', (169, 175))	('Foxo3a', 'Gene', (169, 175))
140183	26087189	Sections were incubated with the respective primary antibodies at the following dilutions: BIM (1:100, CS2933), cPARP (1:100, CS9541), XIAP (1:200, BD610716).	('CS2933', 'CellLine', 'CVCL:S510', (103, 109))	('CS2933', 'Var', (103, 109))	('1:100', 'Var', (119, 124))	('BD610716', 'Var', (148, 156))	('1:100', 'Var', (96, 101))	('1:200', 'Var', (141, 146))
140185	24141786	Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations Uveal melanoma (UM) is a genetically and biologically distinct type of melanoma, and once metastatic there is no effective treatment currently available.	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('PKC', 'molecular_function', 'GO:0004697', ('9', '12'))	('GNA11', 'Gene', (64, 69))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('uveal melanoma', 'Disease', 'MESH:C536494', (35, 49))	('uveal melanoma', 'Disease', (35, 49))	('PKC', 'Gene', '112476', (9, 12))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('inhibition', 'NegReg', (21, 31))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))	('mutations', 'Var', (70, 79))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('MEK', 'Gene', '5609', (17, 20))	('PKC', 'Gene', (9, 12))	('GNA11', 'Gene', '2767', (64, 69))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('MEK', 'Gene', (17, 20))	('GNAQ', 'Gene', '2776', (55, 59))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('GNAQ', 'Gene', (55, 59))
140186	24141786	80% of UMs harbor mutations in the Galphaq family members GNAQ and GNA11.	('Galphaq', 'Gene', '2776;14682;2767;14672', (35, 42))	('GNA11', 'Gene', (67, 72))	('Galphaq', 'Gene', (35, 42))	('UMs', 'Disease', (7, 10))	('GNAQ', 'Gene', (58, 62))	('mutations', 'Var', (18, 27))
140187	24141786	We report consistent activation of the protein kinase C (PKC) and MAPK pathways as a consequence of GNAQ or GNA11 mutation.	('protein kinase C', 'Gene', (39, 55))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('MAPK pathways', 'Pathway', (66, 79))	('GNAQ', 'Gene', (100, 104))	('protein kinase C', 'Gene', '112476', (39, 55))	('PKC', 'molecular_function', 'GO:0004697', ('57', '60'))	('MAPK', 'molecular_function', 'GO:0004707', ('66', '70'))	('activation', 'PosReg', (21, 31))	('mutation', 'Var', (114, 122))	('GNA11', 'Gene', (108, 113))	('PKC', 'Gene', (57, 60))	('PKC', 'Gene', '112476', (57, 60))
140188	24141786	PKC inhibition with AEB071 or AHT956 suppressed PKC and MAPK signalling and induced G1 arrest selectively in melanoma cell lines carrying GNAQ or GNA11 mutations.	('PKC', 'Gene', (0, 3))	('PKC', 'Gene', '112476', (0, 3))	('G1 arrest', 'MPA', (84, 93))	('PKC', 'molecular_function', 'GO:0004697', ('48', '51'))	('mutations', 'Var', (152, 161))	('MAPK signalling', 'biological_process', 'GO:0000165', ('56', '71'))	('PKC', 'Gene', (48, 51))	('induced', 'Reg', (76, 83))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('PKC', 'Gene', '112476', (48, 51))	('melanoma', 'Disease', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('MAPK', 'molecular_function', 'GO:0004707', ('56', '60'))	('AHT956', 'Gene', (30, 36))	('MAPK signalling', 'Pathway', (56, 71))	('suppressed', 'NegReg', (37, 47))	('PKC', 'molecular_function', 'GO:0004697', ('0', '3'))
140189	24141786	In contrast, treatment with two different MEK inhibitors, PD0325901 and MEK162, inhibited the proliferation of melanoma cell lines irrespective of their mutation status, indicating that in the context of GNAQ or GNA11 mutation, MAPK activation can be attributed to activated PKC.	('GNAQ', 'Gene', (204, 208))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('PKC', 'Gene', (275, 278))	('mutation', 'Var', (218, 226))	('PKC', 'Gene', '112476', (275, 278))	('PKC', 'molecular_function', 'GO:0004697', ('275', '278'))	('GNA11', 'Gene', (212, 217))	('PD0325901', 'Var', (58, 67))	('MAPK', 'Enzyme', (228, 232))	('MAPK activation', 'biological_process', 'GO:0000187', ('228', '243'))	('proliferation', 'CPA', (94, 107))	('activation', 'PosReg', (233, 243))	('PD0325901', 'Chemical', 'MESH:C506614', (58, 67))	('inhibited', 'NegReg', (80, 89))	('MAPK', 'molecular_function', 'GO:0004707', ('228', '232'))
140190	24141786	AEB071 significantly slowed the growth of tumors in an allograft model of GNAQQ209L transduced melanocytes, but did not induce tumor shrinkage.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('growth', 'MPA', (32, 38))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', (127, 132))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('slowed', 'NegReg', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('AEB071', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
140192	24141786	However, combinations of PKC and MEK inhibition, using either PD0325901 or MEK162, led to sustained MAP-kinase pathway inhibition and showed a strong synergistic effect in halting proliferation and in inducing apoptosis in vitro.	('PKC', 'Gene', (25, 28))	('PKC', 'Gene', '112476', (25, 28))	('apoptosis', 'biological_process', 'GO:0097194', ('210', '219'))	('MAP-kinase pathway', 'Pathway', (100, 118))	('PKC', 'molecular_function', 'GO:0004697', ('25', '28'))	('inhibition', 'NegReg', (119, 129))	('inducing', 'Reg', (201, 209))	('PD0325901', 'Var', (62, 71))	('halting', 'NegReg', (172, 179))	('PD0325901', 'Chemical', 'MESH:C506614', (62, 71))	('MAP', 'molecular_function', 'GO:0004239', ('100', '103'))	('apoptosis', 'biological_process', 'GO:0006915', ('210', '219'))	('apoptosis', 'CPA', (210, 219))	('MEK162', 'Var', (75, 81))
140194	24141786	Our data identifies PKC as a rational therapeutic target for melanoma patients with GNAQ or GNA11 mutations, and demonstrates combined MEK and PKC inhibition is synergistic, with superior efficacy compared to treatment with either approach alone.	('patients', 'Species', '9606', (70, 78))	('PKC', 'Gene', (20, 23))	('PKC', 'Gene', '112476', (20, 23))	('GNA11', 'Gene', (92, 97))	('PKC', 'Gene', '112476', (143, 146))	('GNAQ', 'Gene', (84, 88))	('mutations', 'Var', (98, 107))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('PKC', 'molecular_function', 'GO:0004697', ('20', '23'))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('inhibition', 'NegReg', (147, 157))	('PKC', 'molecular_function', 'GO:0004697', ('143', '146'))	('PKC', 'Gene', (143, 146))	('MEK', 'Enzyme', (135, 138))
140198	24141786	Different from melanomas originating from the skin, UM does not harbor mutations in BRAF, NRAS or KIT, but instead shows mutations in GNAQ or GNA11.	('NRAS', 'Gene', (90, 94))	('mutations', 'Var', (121, 130))	('BRAF', 'Gene', '673', (84, 88))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('NRAS', 'Gene', '4893', (90, 94))	('BRAF', 'Gene', (84, 88))	('GNAQ', 'Gene', (134, 138))	('melanomas', 'Disease', 'MESH:D008545', (15, 24))	('KIT', 'Gene', (98, 101))	('GNA11', 'Gene', (142, 147))	('KIT', 'molecular_function', 'GO:0005020', ('98', '101'))	('melanomas', 'Disease', (15, 24))
140199	24141786	Over 80% of uveal melanomas harbor mutations in these genes in a mutually exclusive pattern.	('uveal melanomas', 'Disease', 'MESH:C536494', (12, 27))	('uveal melanoma', 'Phenotype', 'HP:0007716', (12, 26))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))	('uveal melanomas', 'Disease', (12, 27))	('uveal melanomas', 'Phenotype', 'HP:0007716', (12, 27))	('mutations', 'Var', (35, 44))
140205	24141786	GNAQ and GNA11 mutations in melanoma affect codons 209 (approximately 95%) or 183 (5%) and result in complete or partial loss of GTPase activity, respectively, thereby leading to constitutive activation of downstream effector pathways.	('melanoma', 'Disease', (28, 36))	('constitutive', 'MPA', (179, 191))	('GNA11', 'Gene', (9, 14))	('downstream effector pathways', 'Pathway', (206, 234))	('GTPase activity', 'molecular_function', 'GO:0003924', ('129', '144'))	('loss', 'NegReg', (121, 125))	('mutations', 'Var', (15, 24))	('affect', 'Reg', (37, 43))	('GTPase', 'Protein', (129, 135))	('codons 209', 'Var', (44, 54))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('GNAQ', 'Gene', (0, 4))	('activation', 'PosReg', (192, 202))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('activity', 'MPA', (136, 144))	('GTP', 'Chemical', 'MESH:D006160', (129, 132))
140216	24141786	While aberrant PKC activity and expression have been reported in multiple cancers, no specific genetic alterations leading to constitutive activation of the PKC pathway have been found, and clinical trials with PKC inhibitors in cancer have not shown impressive results.	('PKC', 'molecular_function', 'GO:0004697', ('211', '214'))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('multiple cancers', 'Disease', 'MESH:D009369', (65, 81))	('cancer', 'Disease', (74, 80))	('PKC', 'Gene', (211, 214))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('PKC', 'molecular_function', 'GO:0004697', ('157', '160'))	('PKC activity', 'molecular_function', 'GO:0004697', ('15', '27'))	('expression', 'MPA', (32, 42))	('multiple cancers', 'Disease', (65, 81))	('cancer', 'Disease', (229, 235))	('aberrant', 'Var', (6, 14))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('PKC', 'Gene', '112476', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('PKC', 'Gene', '112476', (157, 160))	('PKC', 'Gene', (15, 18))	('activity', 'MPA', (19, 27))	('PKC', 'Gene', '112476', (211, 214))	('reported', 'Reg', (53, 61))	('PKC', 'Gene', (157, 160))
140218	24141786	Previous studies have shown that uveal melanoma cell lines with GNAQ mutations have an increased sensitivity to PKC inhibition in vitro.	('mutations', 'Var', (69, 78))	('GNAQ', 'Gene', (64, 68))	('uveal melanoma', 'Disease', 'MESH:C536494', (33, 47))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('uveal melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('uveal melanoma', 'Disease', (33, 47))	('PKC', 'molecular_function', 'GO:0004697', ('112', '115'))	('sensitivity', 'MPA', (97, 108))	('PKC', 'Gene', (112, 115))	('PKC', 'Gene', '112476', (112, 115))
140219	24141786	However, the relationship between PKC and MAP-kinase pathway activation in the setting of GNAQ or GNA11 mutations is not fully resolved.	('PKC', 'Gene', (34, 37))	('MAP-kinase pathway', 'Pathway', (42, 60))	('mutations', 'Var', (104, 113))	('PKC', 'Gene', '112476', (34, 37))	('GNA11', 'Gene', (98, 103))	('PKC', 'molecular_function', 'GO:0004697', ('34', '37'))	('MAP', 'molecular_function', 'GO:0004239', ('42', '45'))	('GNAQ', 'Gene', (90, 94))
140221	24141786	Here we demonstrate that the activation of PKC is a direct consequence of activating mutations in GNAQ and GNA11 and confirm that inhibition of PKC lead to selective growth arrest in uveal melanoma cell lines with mutations in GNAQ and demonstrate that these findings extend to cell lines with mutant GNA11.	('activating', 'PosReg', (74, 84))	('GNA11', 'Gene', (301, 306))	('PKC', 'molecular_function', 'GO:0004697', ('144', '147'))	('PKC', 'molecular_function', 'GO:0004697', ('43', '46'))	('PKC', 'Gene', '112476', (43, 46))	('growth arrest', 'Phenotype', 'HP:0001510', (166, 179))	('growth arrest', 'CPA', (166, 179))	('mutations', 'Var', (214, 223))	('GNAQ', 'Gene', (227, 231))	('PKC', 'Gene', (43, 46))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('mutant', 'Var', (294, 300))	('GNA11', 'Gene', (107, 112))	('uveal melanoma', 'Disease', 'MESH:C536494', (183, 197))	('PKC', 'Gene', '112476', (144, 147))	('GNAQ', 'Gene', (98, 102))	('uveal melanoma', 'Disease', (183, 197))	('inhibition', 'NegReg', (130, 140))	('mutations', 'Var', (85, 94))	('activation', 'PosReg', (29, 39))	('PKC', 'Gene', (144, 147))	('uveal melanoma', 'Phenotype', 'HP:0007716', (183, 197))
140223	24141786	However, a significantly improved response can be obtained by combined PKC and MEK inhibition, which synergistically result in sustained growth inhibition and apoptosis in vitro, a markedly enhanced anti-tumoral response in vivo.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('apoptosis', 'biological_process', 'GO:0097194', ('159', '168'))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('growth inhibition', 'CPA', (137, 154))	('apoptosis', 'biological_process', 'GO:0006915', ('159', '168'))	('PKC', 'Gene', (71, 74))	('tumor', 'Disease', (204, 209))	('PKC', 'molecular_function', 'GO:0004697', ('71', '74'))	('MEK', 'Enzyme', (79, 82))	('inhibition', 'Var', (83, 93))	('enhanced', 'PosReg', (190, 198))	('PKC', 'Gene', '112476', (71, 74))	('apoptosis', 'CPA', (159, 168))
140224	24141786	We propose combinatorial inhibition of PKC and MAP-kinase signaling as a rational therapeutic approach for treating melanomas with GNAQ or GNA11 mutations.	('GNAQ', 'Gene', (131, 135))	('GNA11', 'Gene', (139, 144))	('treating melanomas', 'Disease', 'MESH:D008545', (107, 125))	('mutations', 'Var', (145, 154))	('treating melanomas', 'Disease', (107, 125))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('MAP', 'molecular_function', 'GO:0004239', ('47', '50'))	('PKC', 'Gene', (39, 42))	('PKC', 'Gene', '112476', (39, 42))	('PKC', 'molecular_function', 'GO:0004697', ('39', '42'))	('signaling', 'biological_process', 'GO:0023052', ('58', '67'))
140225	24141786	To explore the role of PKC as a mediator of the oncogenic output downstream of mutant GNAQ or GNA11, we examined PKC signaling in a panel of melanoma cell lines, with or without activating mutations in GNAQ or GNA11.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('PKC', 'molecular_function', 'GO:0004697', ('113', '116'))	('mutant', 'Var', (79, 85))	('GNAQ', 'Gene', (202, 206))	('examined', 'Reg', (104, 112))	('PKC', 'Gene', (23, 26))	('signaling', 'biological_process', 'GO:0023052', ('117', '126'))	('PKC', 'Gene', (113, 116))	('PKC', 'Gene', '112476', (113, 116))	('PKC', 'molecular_function', 'GO:0004697', ('23', '26'))	('GNA11', 'Gene', (94, 99))	('PKC', 'Gene', '112476', (23, 26))	('GNAQ', 'Gene', (86, 90))
140227	24141786	All six melanoma cell lines with oncogenic GNAQ or GNA11 mutations (GNA11: UPMD-1; OMM-GN11; GNAQ: Mel270; OMM1.3; 92-1; Mel202) expressed p-MARCKS levels, whereas three of four uveal melanoma cell lines without mutations in GNAQ and GNA11 (Mel290, MUM2C, Mel285) showed no expression and the fourth (C918) expressed only trace levels.	('melanoma', 'Disease', 'MESH:D008545', (8, 16))	('p-MARCKS levels', 'MPA', (139, 154))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('melanoma', 'Disease', (8, 16))	('melanoma', 'Disease', (184, 192))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('GNAQ', 'Gene', (43, 47))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('mutations', 'Var', (57, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (178, 192))	('GNA11', 'Gene', (51, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (178, 192))	('uveal melanoma', 'Disease', (178, 192))
140229	24141786	We performed the following experiments to determine whether the PKC activation in the uveal melanoma cell lines with oncogenic GNAQ or GNA11 was a consequence of these mutations.	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('uveal melanoma', 'Disease', 'MESH:C536494', (86, 100))	('uveal melanoma', 'Disease', (86, 100))	('PKC activation', 'biological_process', 'GO:1990051', ('64', '78'))	('activation', 'PosReg', (68, 78))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('PKC', 'Gene', (64, 67))	('PKC', 'Gene', '112476', (64, 67))	('mutations', 'Var', (168, 177))	('PKC', 'molecular_function', 'GO:0004697', ('64', '67'))
140230	24141786	First we introduced Glu-Glu epitope tagged GNAQQ209L or GNA11Q209L into three different cell types, 293T cells, immortalized mouse (melan-a) and human (IHM) melanocytes, and determined the effects on p-MARCKS compared to control cells expressing either GFP, Glu-Glu tagged GNAQwt, Glu-Glu tagged GNA11wt, BRAFV600E or myc-tagged NRASG12V.	('Glu', 'Chemical', 'MESH:D018698', (281, 284))	('Glu', 'Chemical', 'MESH:D018698', (20, 23))	('Glu', 'Chemical', 'MESH:D018698', (285, 288))	('Glu', 'Chemical', 'MESH:D018698', (24, 27))	('Glu', 'Chemical', 'MESH:D018698', (258, 261))	('293T', 'CellLine', 'CVCL:0063', (100, 104))	('Glu', 'Chemical', 'MESH:D018698', (262, 265))	('mouse', 'Species', '10090', (125, 130))	('human', 'Species', '9606', (145, 150))	('NRAS', 'Gene', (329, 333))	('GNA11Q209L', 'Var', (56, 66))	('BRAFV600E', 'Var', (305, 314))	('BRAFV600E', 'Mutation', 'rs113488022', (305, 314))	('NRAS', 'Gene', '4893', (329, 333))
140231	24141786	By contrast wild type GNAQ or GNA11 had weak effects, whereas mutant BRAF or NRAS, or the GFP control had no effect on p-MARCKS.	('mutant', 'Var', (62, 68))	('NRAS', 'Gene', (77, 81))	('NRAS', 'Gene', '4893', (77, 81))	('BRAF', 'Gene', '673', (69, 73))	('BRAF', 'Gene', (69, 73))
140233	24141786	To confirm that p-MARCKS induction indeed reflected PKC activation by mutant GNAQ or GNA11, we also used an antibody that detects specific phosphorylation motifs of PKC (Arg/Lys-X-Serphos-Hyd-Arg/Lys, where Hyd represents a hydrophobic residue).	('PKC', 'Gene', (165, 168))	('antibody', 'cellular_component', 'GO:0019815', ('108', '116'))	('PKC', 'Gene', '112476', (52, 55))	('Arg', 'Chemical', 'MESH:D001120', (170, 173))	('Arg', 'Chemical', 'MESH:D001120', (192, 195))	('GNAQ', 'Gene', (77, 81))	('PKC', 'Gene', (52, 55))	('antibody', 'cellular_component', 'GO:0019814', ('108', '116'))	('PKC activation', 'biological_process', 'GO:1990051', ('52', '66'))	('GNA11', 'Gene', (85, 90))	('Lys', 'Chemical', 'MESH:D008239', (174, 177))	('activation', 'PosReg', (56, 66))	('PKC', 'molecular_function', 'GO:0004697', ('52', '55'))	('mutant', 'Var', (70, 76))	('PKC', 'molecular_function', 'GO:0004697', ('165', '168'))	('antibody', 'molecular_function', 'GO:0003823', ('108', '116'))	('phosphorylation', 'biological_process', 'GO:0016310', ('139', '154'))	('Lys', 'Chemical', 'MESH:D008239', (196, 199))	('antibody', 'cellular_component', 'GO:0042571', ('108', '116'))	('PKC', 'Gene', '112476', (165, 168))
140234	24141786	Mutant BRAF or NRAS also led to the appearance of certain bands, but their pattern was distinct and not consistent between the three cells.	('bands', 'MPA', (58, 63))	('led to', 'Reg', (25, 31))	('NRAS', 'Gene', (15, 19))	('NRAS', 'Gene', '4893', (15, 19))	('BRAF', 'Gene', '673', (7, 11))	('Mutant', 'Var', (0, 6))	('BRAF', 'Gene', (7, 11))
140235	24141786	Taken together, these experiments indicate consistent activation of PKC in uveal melanoma cell lines, and that this activation is due to mutations in GNAQ and GNA11.	('uveal melanoma', 'Phenotype', 'HP:0007716', (75, 89))	('uveal melanoma', 'Disease', 'MESH:C536494', (75, 89))	('activation', 'PosReg', (54, 64))	('mutations', 'Var', (137, 146))	('GNAQ', 'Gene', (150, 154))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('due', 'Reg', (130, 133))	('PKC', 'molecular_function', 'GO:0004697', ('68', '71'))	('uveal melanoma', 'Disease', (75, 89))	('PKC', 'Gene', '112476', (68, 71))	('PKC', 'Gene', (68, 71))	('GNA11', 'Gene', (159, 164))
140236	24141786	The experiments in Figure 1B also showed a concomitant increase in pERK and p-p90RSK levels in all three cell lines expressing GNAQQ209Land GNA11Q209L, indicative of MAPK pathway activation in response to GNAQ or GNA11 mutation, consistent with prior reports.	('pERK', 'Gene', '9451', (67, 71))	('increase', 'PosReg', (55, 63))	('GNA11Q209L', 'Var', (140, 150))	('GNAQQ209Land GNA11Q209L', 'Var', (127, 150))	('MAPK pathway', 'Pathway', (166, 178))	('p90RSK', 'Gene', '6195', (78, 84))	('GNA11', 'Gene', (213, 218))	('p90RSK', 'Gene', (78, 84))	('activation', 'PosReg', (179, 189))	('MAPK', 'molecular_function', 'GO:0004707', ('166', '170'))	('pERK', 'Gene', (67, 71))
140237	24141786	As expected, BRAFV600E and NRASG12V also resulted in an increase pERK and p-p90RSK, but did not affect the levels of p-MARCKS.	('NRAS', 'Gene', '4893', (27, 31))	('BRAFV600E', 'Var', (13, 22))	('BRAFV600E', 'Mutation', 'rs113488022', (13, 22))	('p90RSK', 'Gene', (76, 82))	('increase', 'PosReg', (56, 64))	('pERK', 'Gene', (65, 69))	('pERK', 'Gene', '9451', (65, 69))	('NRAS', 'Gene', (27, 31))	('p90RSK', 'Gene', '6195', (76, 82))
140238	24141786	Similar results were also obtained with melan-a cell lines generated to stably express GFP, GNAQWT, GNA11WT, GNAQQ209L, GNA11Q209L or BRAFV600E, respectively (Supplemental Figure 2, A and B).	('GNA11Q209L', 'Var', (120, 130))	('GNA11WT', 'Var', (100, 107))	('GNAQQ209L', 'Var', (109, 118))	('BRAFV600E', 'Var', (134, 143))	('BRAFV600E', 'Mutation', 'rs113488022', (134, 143))
140239	24141786	This constellation raised the possibility that in the context of mutant GNAQ and GNA11 the MAP-kinase pathway activation is significantly mediated by PKC activation.	('activation', 'PosReg', (110, 120))	('PKC activation', 'biological_process', 'GO:1990051', ('150', '164'))	('PKC', 'molecular_function', 'GO:0004697', ('150', '153'))	('mutant', 'Var', (65, 71))	('MAP-kinase pathway', 'Pathway', (91, 109))	('mediated', 'Reg', (138, 146))	('MAP', 'molecular_function', 'GO:0004239', ('91', '94'))	('PKC', 'Gene', (150, 153))	('PKC', 'Gene', '112476', (150, 153))
140240	24141786	To confirm this notion and to further corroborate the role of PKC signaling as an effector of mutant GNAQ or GNA11 we performed a series of experiments in uveal melanoma cell lines that harbored GNAQ or GNA11 mutations.	('uveal melanoma', 'Disease', 'MESH:C536494', (155, 169))	('PKC', 'molecular_function', 'GO:0004697', ('62', '65'))	('PKC', 'Gene', '112476', (62, 65))	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (155, 169))	('uveal melanoma', 'Disease', (155, 169))	('GNA11', 'Gene', (109, 114))	('GNAQ', 'Gene', (195, 199))	('mutant', 'Var', (94, 100))	('ser', 'Chemical', 'MESH:D012694', (130, 133))	('mutations', 'Var', (209, 218))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('GNA11', 'Gene', (203, 208))	('GNAQ', 'Gene', (101, 105))	('PKC', 'Gene', (62, 65))
140241	24141786	We knocked down the expression of GNAQ with small interfering RNA (siRNAs) in three different melanoma cells (OMM1.3, 92-1 and Mel202) with GNAQ mutation, and found PKC and MAPK signaling to be suppressed 72hr after knock-down.	('PKC', 'Gene', (165, 168))	('knocked', 'Reg', (3, 10))	('expression', 'MPA', (20, 30))	('PKC', 'Gene', '112476', (165, 168))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('MAPK signaling', 'biological_process', 'GO:0000165', ('173', '187'))	('melanoma', 'Disease', (94, 102))	('MAPK signaling', 'Pathway', (173, 187))	('GNAQ', 'Gene', (140, 144))	('MAPK', 'molecular_function', 'GO:0004707', ('173', '177'))	('PKC', 'molecular_function', 'GO:0004697', ('165', '168'))	('suppressed', 'NegReg', (194, 204))	('RNA', 'cellular_component', 'GO:0005562', ('62', '65'))	('mutation', 'Var', (145, 153))
140242	24141786	As shown in Figure 1C, knock-down of GNAQ inhibited the expression of pMEK, pERK, pMARCKS and p-(ser) PKC substrate compared to non-target siRNA control in all three cell lines.	('PKC', 'Gene', '112476', (102, 105))	('ser', 'Chemical', 'MESH:D012694', (97, 100))	('knock-down', 'Var', (23, 33))	('pMARCKS', 'Gene', (82, 89))	('pMEK', 'Gene', (70, 74))	('pERK', 'Gene', (76, 80))	('inhibited', 'NegReg', (42, 51))	('expression', 'MPA', (56, 66))	('GNAQ', 'Protein', (37, 41))	('PKC', 'molecular_function', 'GO:0004697', ('102', '105'))	('pERK', 'Gene', '9451', (76, 80))	('ser', 'cellular_component', 'GO:0005790', ('97', '100'))	('PKC', 'Gene', (102, 105))
140243	24141786	Similar results were also observed with shRNA-mediated knock-down of GNAQ.	('GNAQ', 'Protein', (69, 73))	('knock-down', 'Var', (55, 65))	('ser', 'Chemical', 'MESH:D012694', (28, 31))
140246	24141786	Similar results were obtained when melan-a cells, stably expressing GNAQQ209L, were transduced with lentiviruses encoding GNAQ shRNA 1 and GNAQ shRNA3 (Supplemental Figure 3, right panel).	('GNAQ shRNA3', 'Gene', '2776', (139, 150))	('GNAQ shRNA3', 'Gene', (139, 150))	('GNAQQ209L', 'Var', (68, 77))	('GNAQ shRNA 1', 'Gene', '2776', (122, 134))	('GNAQ shRNA 1', 'Gene', (122, 134))
140247	24141786	To investigate whether PKC inhibition could inhibit growth in melanoma cell lines with GNAQ or GNA11 mutations, we evaluated the anti-proliferative effect of two distinct ATP-competitive PKC inhibitors, AEB071 and AHT956.	('PKC', 'molecular_function', 'GO:0004697', ('187', '190'))	('melanoma', 'Disease', (62, 70))	('mutations', 'Var', (101, 110))	('ATP', 'Chemical', 'MESH:D000255', (171, 174))	('inhibit', 'NegReg', (44, 51))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('GNA11', 'Gene', (95, 100))	('anti-proliferative effect', 'MPA', (129, 154))	('PKC', 'Gene', (187, 190))	('PKC', 'Gene', '112476', (187, 190))	('GNAQ', 'Gene', (87, 91))	('PKC', 'Gene', (23, 26))	('PKC', 'molecular_function', 'GO:0004697', ('23', '26'))	('PKC', 'Gene', '112476', (23, 26))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
140248	24141786	We used two panels of six human melanoma cell lines with and without GNAQ or GNA11 mutations, respectively, and three mouse melan-a cell lines stably expressing GNAQQ209L, GNA11Q209L or BRAFV600E.	('mutations', 'Var', (83, 92))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('BRAFV600E', 'Var', (186, 195))	('GNA11', 'Gene', (77, 82))	('melanoma', 'Disease', (32, 40))	('GNAQQ209L', 'Var', (161, 170))	('BRAFV600E', 'Mutation', 'rs113488022', (186, 195))	('GNA11Q209L', 'Var', (172, 182))	('mouse', 'Species', '10090', (118, 123))	('GNAQ', 'Gene', (69, 73))	('human', 'Species', '9606', (26, 31))
140249	24141786	Without exception, human and mouse melanoma cell lines carrying mutations of GNAQ or GNA11 expressed a significantly higher sensitivity to both AEB071 (Figure 2A and Supplemental Figure 4A and 4B, top panel) and AHT956 (Figure 2B and Supplemental Figure 4A and 4B, lower panel), compared to melanoma cell lines without these mutations.	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('GNAQ', 'Gene', (77, 81))	('GNA11', 'Gene', (85, 90))	('sensitivity', 'MPA', (124, 135))	('melanoma', 'Disease', 'MESH:D008545', (291, 299))	('mouse', 'Species', '10090', (29, 34))	('mutations', 'Var', (64, 73))	('melanoma', 'Disease', (291, 299))	('higher', 'PosReg', (117, 123))	('melanoma', 'Phenotype', 'HP:0002861', (291, 299))	('human', 'Species', '9606', (19, 24))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))
140250	24141786	By contrast, the cell lines without GNAQ or GNA11 mutations invariably were insensitive to both compounds at doses up to 1 muM.	('mutations', 'Var', (50, 59))	('GNA11', 'Gene', (44, 49))	('muM', 'Gene', (123, 126))	('muM', 'Gene', '56925', (123, 126))
140251	24141786	In contrast to the selective effect of PKC inhibitors on GNAQ/11 mutant melanoma cell lines, the MEK inhibitor PD0325901 inhibited melanoma cell lines independent of mutation status (Supplemental Figure 5 and Figure 2C).	('PD0325901', 'Chemical', 'MESH:C506614', (111, 120))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (72, 80))	('melanoma', 'Disease', (131, 139))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('PKC', 'Gene', (39, 42))	('PD0325901', 'Var', (111, 120))	('inhibited', 'NegReg', (121, 130))	('PKC', 'Gene', '112476', (39, 42))	('PKC', 'molecular_function', 'GO:0004697', ('39', '42'))
140252	24141786	To explore the mechanism of the selective growth inhibitory effects in response to PKC inhibition we treated GNAQ mutant uveal melanoma cell lines with 500nM AEB071 or 100nM AHT956 and analyzed the effect on cell proliferation and death.	('uveal melanoma', 'Phenotype', 'HP:0007716', (121, 135))	('uveal melanoma', 'Disease', (121, 135))	('PKC', 'Gene', (83, 86))	('GNAQ', 'Gene', (109, 113))	('PKC', 'molecular_function', 'GO:0004697', ('83', '86'))	('PKC', 'Gene', '112476', (83, 86))	('mutant', 'Var', (114, 120))	('cell proliferation', 'biological_process', 'GO:0008283', ('208', '226'))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('uveal melanoma', 'Disease', 'MESH:C536494', (121, 135))
140253	24141786	The G1 arrest in the GNAQ-mutant cell lines was accompanied by a decrease of phospho- and total RB, down regulation of cyclinD1, and induction of p27, all supporting G1 cell cycle arrest in response to treatment, whereas the level of these proteins remained unaffected in the GNAQ wild type cell lines (Supplemental Figure 6C).	('GNAQ-mutant', 'Var', (21, 32))	('cyclinD1', 'Gene', '595', (119, 127))	('down regulation', 'NegReg', (100, 115))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (169, 186))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('169', '186'))	('G1 arrest', 'CPA', (4, 13))	('G1 cell cycle arrest', 'CPA', (166, 186))	('decrease', 'NegReg', (65, 73))	('cyclinD1', 'Gene', (119, 127))	('p27', 'Gene', (146, 149))	('p27', 'Gene', '3429', (146, 149))	('induction', 'Reg', (133, 142))	('phospho-', 'MPA', (77, 85))	('regulation', 'biological_process', 'GO:0065007', ('105', '115'))
140255	24141786	The results above indicate that mutations in GNAQ and GNA11 may result in a selective dependency on PKC activation, which could be of therapeutic relevance to treat cancers with these mutations.	('PKC activation', 'biological_process', 'GO:1990051', ('100', '114'))	('activation', 'PosReg', (104, 114))	('PKC', 'Gene', (100, 103))	('GNA11', 'Gene', (54, 59))	('dependency', 'MPA', (86, 96))	('PKC', 'Gene', '112476', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('result in', 'Reg', (64, 73))	('mutations', 'Var', (32, 41))	('GNAQ', 'Gene', (45, 49))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))	('PKC', 'molecular_function', 'GO:0004697', ('100', '103'))
140256	24141786	We performed dose-response studies of two panels of four melanoma cell lines with and without GNAQ or GNA11 mutation exposing them to increasing doses (0-1muM) of AEB071 or AHT956 for 24h.	('GNA11', 'Gene', (102, 107))	('muM', 'Gene', '56925', (155, 158))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('muM', 'Gene', (155, 158))	('melanoma', 'Disease', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('mutation', 'Var', (108, 116))	('GNAQ', 'Gene', (94, 98))
140258	24141786	When we treated two of the GNAQ mutant cells (mel202 and 92-1) with the MEK inhibitor PD0325901 we observed the expected dose-dependent inhibitor of MAPK signaling, but no effect on p-MARCKS levels, even at higher concentrations (Figure 3C).	('MAPK signaling', 'MPA', (149, 163))	('PD0325901', 'Chemical', 'MESH:C506614', (86, 95))	('ser', 'Chemical', 'MESH:D012694', (101, 104))	('MAPK', 'molecular_function', 'GO:0004707', ('149', '153'))	('PD0325901', 'Var', (86, 95))	('inhibitor', 'NegReg', (136, 145))	('MAPK signaling', 'biological_process', 'GO:0000165', ('149', '163'))
140259	24141786	In aggregate, our findings indicate that in melanoma cell lines with GNAQ or GNA11 mutations, MAPK pathway activation occurs downstream of PKC.	('mutations', 'Var', (83, 92))	('MAPK', 'molecular_function', 'GO:0004707', ('94', '98'))	('GNA11', 'Gene', (77, 82))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('MAPK pathway', 'Pathway', (94, 106))	('PKC', 'molecular_function', 'GO:0004697', ('139', '142'))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('PKC', 'Gene', (139, 142))	('PKC', 'Gene', '112476', (139, 142))	('activation', 'PosReg', (107, 117))
140262	24141786	Melan-a cells were originally derived from c57BL/6 mice and GNAQQ209L transduced melan-a cells cause rapidly growing tumors in syngeneic mice, with histopathological features recapitulating human melanocytic neoplasms with GNAQ mutations.	('neoplasms', 'Phenotype', 'HP:0002664', (208, 217))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (196, 217))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mice', 'Species', '10090', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('melanocytic neoplasms', 'Disease', (196, 217))	('mutations', 'Var', (228, 237))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('transduced', 'Var', (70, 80))	('tumors', 'Disease', (117, 123))	('human', 'Species', '9606', (190, 195))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (196, 217))	('mice', 'Species', '10090', (137, 141))
140271	24141786	These results indicate that AEB071 inhibits PKC signaling in vivo, but that compensatory mechanisms prevent the suppression of the MAP-kinase pathway and that the treatment is not sufficient to completely stop cell proliferation or kill cells.	('MAP', 'molecular_function', 'GO:0004239', ('131', '134'))	('MAP-kinase pathway', 'Pathway', (131, 149))	('cell proliferation', 'biological_process', 'GO:0008283', ('210', '228'))	('inhibits', 'NegReg', (35, 43))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('PKC', 'molecular_function', 'GO:0004697', ('44', '47'))	('PKC', 'Gene', (44, 47))	('AEB071', 'Var', (28, 34))	('prevent', 'NegReg', (100, 107))	('PKC', 'Gene', '112476', (44, 47))
140272	24141786	Incomplete suppression or reactivation of the MAPK pathway under treatment is a well-studied phenomenon in melanomas with BRAF mutations following administration of BRAF inhibitors and can occur by several mechanisms linked to resistance.	('melanomas', 'Disease', 'MESH:D008545', (107, 116))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('MAPK pathway', 'Pathway', (46, 58))	('BRAF', 'Gene', '673', (122, 126))	('BRAF', 'Gene', '673', (165, 169))	('BRAF', 'Gene', (122, 126))	('MAPK', 'molecular_function', 'GO:0004707', ('46', '50'))	('BRAF', 'Gene', (165, 169))	('reactivation', 'MPA', (26, 38))	('melanomas', 'Disease', (107, 116))	('mutations', 'Var', (127, 136))
140278	24141786	We exposed two GNAQ mutants, one GNA11 mutant, and two melanoma cell lines without either mutation to combinations of AEB071 and PD0325901 at doses ranging from 0 to 5muM and 0 to 0.5muM, respectively and determined the effect on cell viability after four days.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('muM', 'Gene', '56925', (167, 170))	('combinations', 'Var', (102, 114))	('PD0325901', 'Chemical', 'MESH:C506614', (129, 138))	('muM', 'Gene', (167, 170))	('AEB071', 'Gene', (118, 124))	('muM', 'Gene', '56925', (183, 186))	('muM', 'Gene', (183, 186))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))	('PD0325901', 'Var', (129, 138))
140279	24141786	We observed an improved growth inhibition of the combinations in all three melanoma cells with GNAQ/11 mutation (92-1, OMM1.3 and OMM-GN11) compared to treatments with either compound alone.	('ser', 'Chemical', 'MESH:D012694', (5, 8))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('improved', 'PosReg', (15, 23))	('growth inhibition', 'CPA', (24, 41))	('GNAQ/11', 'Gene', (95, 102))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('mutation', 'Var', (103, 111))
140280	24141786	Isobologram analysis (Figure 6B) and Combination Index (Supplemental Figure 7) revealed that the effects of AEB071 and PD0325901 were strongly synergistic.	('PD0325901', 'Chemical', 'MESH:C506614', (119, 128))	('AEB071', 'Gene', (108, 114))	('PD0325901', 'Var', (119, 128))
140282	24141786	A combination of 250nM AEB071 and 20nM PD0325901 inhibited proliferation of 92-1 and OMM1.3 to a greater extent, compared to the individual compounds at these concentrations (Figure 6C).	('proliferation', 'CPA', (59, 72))	('PD0325901', 'Var', (39, 48))	('PD0325901', 'Chemical', 'MESH:C506614', (39, 48))	('AEB071', 'Var', (23, 29))	('inhibited', 'NegReg', (49, 58))
140284	24141786	As shown in Figure 6D, the combination of AEB071 and PD0325901 resulted in a significant increase in cleaved PARP level, supporting this notion.	('PD0325901', 'Var', (53, 62))	('PD0325901', 'Chemical', 'MESH:C506614', (53, 62))	('AEB071', 'Var', (42, 48))	('PARP', 'Gene', '1302', (109, 113))	('PARP', 'Gene', (109, 113))	('increase', 'PosReg', (89, 97))
140285	24141786	The combination treatment resulted in near complete extinction of pMEK and pERK expression in all three melanoma cells with GNAQ or GNA11 mutation, compared to treatment with the individual inhibitors alone.	('pERK', 'Gene', '9451', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('pERK', 'Gene', (75, 79))	('melanoma', 'Disease', (104, 112))	('pMEK', 'Gene', (66, 70))	('extinction', 'NegReg', (52, 62))	('mutation', 'Var', (138, 146))	('GNAQ', 'Gene', (124, 128))	('expression', 'MPA', (80, 90))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
140286	24141786	In contrast, the combination did not increase levels of cleaved PARP or reduce pMEK and pERK levels in the three control cell lines without GNAQ and GNA11 mutations.	('PARP', 'Gene', (64, 68))	('mutations', 'Var', (155, 164))	('reduce', 'NegReg', (72, 78))	('PARP', 'Gene', '1302', (64, 68))	('pERK', 'Gene', (88, 92))	('pERK', 'Gene', '9451', (88, 92))
140288	24141786	Only the combination of AEB071 and MEK162 yielded sustained suppression of pMEK and pERK in uveal melanoma cell lines with GNAQ or GNA11 mutations (Supplemental Figure 9).	('GNAQ', 'Gene', (123, 127))	('uveal melanoma', 'Phenotype', 'HP:0007716', (92, 106))	('mutations', 'Var', (137, 146))	('uveal melanoma', 'Disease', (92, 106))	('uveal melanoma', 'Disease', 'MESH:C536494', (92, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('MEK162', 'Var', (35, 41))	('suppression', 'NegReg', (60, 71))	('pERK', 'Gene', '9451', (84, 88))	('pERK', 'Gene', (84, 88))	('pMEK', 'Protein', (75, 79))	('GNA11', 'Gene', (131, 136))
140289	24141786	Interestingly we observed that single agent treatment with one of two different MEK inhibitors (PD0325901 or MEK162) resulted in the accumulation of pMEK in GNAQ and GNA11 mutant melanoma cells due to relieved negative feedback on the MAPK pathway (Figure 6D and Supplemental Figure 9).	('mutant', 'Var', (172, 178))	('PD0325901', 'Chemical', 'MESH:C506614', (96, 105))	('pMEK', 'Gene', (149, 153))	('negative', 'NegReg', (210, 218))	('ser', 'Chemical', 'MESH:D012694', (19, 22))	('MAPK pathway', 'Pathway', (235, 247))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('PD0325901', 'Var', (96, 105))	('MAPK', 'molecular_function', 'GO:0004707', ('235', '239'))	('accumulation', 'PosReg', (133, 145))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanoma', 'Disease', (179, 187))	('MEK162', 'Var', (109, 115))
140291	24141786	Taken together, these results suggest that a combination of PKC and MEK inhibition leads to sustained blockade of MAP-kinase signaling and induction of cell death in melanoma cell lines with GNAQ or GNA11 mutations.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('MEK', 'Enzyme', (68, 71))	('mutations', 'Var', (205, 214))	('GNA11', 'Gene', (199, 204))	('MAP', 'molecular_function', 'GO:0004239', ('114', '117'))	('PKC', 'molecular_function', 'GO:0004697', ('60', '63'))	('MAP-kinase signaling', 'MPA', (114, 134))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('cell death', 'biological_process', 'GO:0008219', ('152', '162'))	('PKC', 'Gene', (60, 63))	('PKC', 'Gene', '112476', (60, 63))	('blockade', 'NegReg', (102, 110))	('cell death', 'CPA', (152, 162))	('GNAQ', 'Gene', (191, 195))	('inhibition', 'NegReg', (72, 82))
140292	24141786	To determine whether the synergistic effects of combined MEK and PKC inhibition translates into improved in vivo efficacy, we used a mouse xenograft model in which subcutaneous tumors are generated by injecting the GNAQ-mutant human uveal melanoma cell line 92-1 into nude mice.	('uveal melanoma', 'Disease', (233, 247))	('PKC', 'Gene', (65, 68))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('PKC', 'molecular_function', 'GO:0004697', ('65', '68'))	('PKC', 'Gene', '112476', (65, 68))	('human', 'Species', '9606', (227, 232))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (164, 183))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('GNAQ-mutant', 'Var', (215, 226))	('uveal melanoma', 'Phenotype', 'HP:0007716', (233, 247))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('mouse', 'Species', '10090', (133, 138))	('tumors', 'Disease', (177, 183))	('uveal melanoma', 'Disease', 'MESH:C536494', (233, 247))	('nude mice', 'Species', '10090', (268, 277))
140294	24141786	As shown in Figure 7, AEB071 monotherapy results in slow growth of tumors compared to vehicle control in a dosage dependent manner.	('monotherapy', 'Var', (29, 40))	('slow growth', 'Phenotype', 'HP:0001510', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('AEB071', 'Gene', (22, 28))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('slow', 'NegReg', (52, 56))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
140300	24141786	Our study highlights PKC signaling as a critical oncogenic effector pathway in melanomas with oncogenic GNAQ and GNA11 mutations and as a potential therapeutic target for UM.	('melanomas', 'Disease', 'MESH:D008545', (79, 88))	('PKC', 'molecular_function', 'GO:0004697', ('21', '24'))	('PKC', 'Gene', '112476', (21, 24))	('melanomas', 'Disease', (79, 88))	('GNA11', 'Gene', (113, 118))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))	('GNAQ', 'Gene', (104, 108))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('mutations', 'Var', (119, 128))	('signaling', 'biological_process', 'GO:0023052', ('25', '34'))	('PKC', 'Gene', (21, 24))
140301	24141786	The importance of PKC is indicated by several lines of evidence: 1) we found a consistent increase in PKC activation across a panel of uveal melanoma cell lines with GNAQ or GNA11 mutations; 2) depletion of mutant GNAQ in these lines abrogates PKC activation, whereas 3) introduction of mutant GNAQ or GNA11 into human and murine melanocytes activated PKC.	('PKC', 'Gene', (244, 247))	('GNAQ', 'Gene', (214, 218))	('depletion', 'MPA', (194, 203))	('GNA11', 'Gene', (174, 179))	('PKC', 'Gene', '112476', (352, 355))	('PKC activation', 'biological_process', 'GO:1990051', ('244', '258'))	('mutant', 'Var', (287, 293))	('abrogates', 'NegReg', (234, 243))	('PKC', 'molecular_function', 'GO:0004697', ('352', '355'))	('PKC', 'Gene', '112476', (18, 21))	('mutant', 'Var', (207, 213))	('PKC', 'Gene', (352, 355))	('murine', 'Species', '10090', (323, 329))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('mutations', 'Var', (180, 189))	('uveal melanoma', 'Disease', 'MESH:C536494', (135, 149))	('PKC', 'molecular_function', 'GO:0004697', ('244', '247'))	('PKC', 'Gene', (18, 21))	('activated', 'PosReg', (342, 351))	('uveal melanoma', 'Disease', (135, 149))	('PKC', 'Gene', '112476', (102, 105))	('human', 'Species', '9606', (313, 318))	('uveal melanoma', 'Phenotype', 'HP:0007716', (135, 149))	('PKC', 'Gene', '112476', (244, 247))	('PKC', 'molecular_function', 'GO:0004697', ('18', '21'))	('activation', 'MPA', (248, 258))	('PKC', 'molecular_function', 'GO:0004697', ('102', '105'))	('PKC', 'Gene', (102, 105))	('PKC activation', 'biological_process', 'GO:1990051', ('102', '116'))	('GNAQ', 'Gene', (166, 170))
140304	24141786	Our results indicate that melanoma cells with GNAQ or GNA11 mutations are selectively sensitive to PKC inhibition, consistent with the findings from other groups.	('GNAQ', 'Gene', (46, 50))	('GNA11', 'Gene', (54, 59))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))	('PKC', 'Gene', '112476', (99, 102))	('PKC', 'molecular_function', 'GO:0004697', ('99', '102'))	('sensitive', 'Reg', (86, 95))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (26, 34))	('PKC', 'Gene', (99, 102))	('mutations', 'Var', (60, 69))
140305	24141786	We show here that these findings extend to melanoma cell lines with GNA11 mutations, but that neither cells do express selective sensitivity to MEK inhibitors, compared to melanoma cell lines without these mutations.	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('mutations', 'Var', (74, 83))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('GNA11', 'Gene', (68, 73))	('melanoma', 'Disease', (43, 51))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanoma', 'Disease', (172, 180))
140306	24141786	Using two different PKC inhibitors across a panel of six different UM cell lines with GNAQ or GNA11 mutations and two melanocyte lines stably expressing GNAQ or GNA11, the inhibitors reduced growth at IC50s ranging from 56nM to 467nM for AEB071 and from 4nM to 159nM for AHT956, whereas melanoma cell lines with other mutations, irrespective of whether they were derived from uveal or cutaneous melanoma, were not sensitive.	('50s', 'Species', '1214577', (203, 206))	('PKC', 'Gene', '112476', (20, 23))	('melanoma', 'Phenotype', 'HP:0002861', (287, 295))	('melanoma', 'Disease', (287, 295))	('GNA11', 'Gene', (94, 99))	('GNAQ', 'Gene', (86, 90))	('PKC', 'Gene', (20, 23))	('reduced', 'NegReg', (183, 190))	('melanoma', 'Phenotype', 'HP:0002861', (395, 403))	('melanoma', 'Disease', (395, 403))	('uveal or cutaneous melanoma', 'Phenotype', 'HP:0007716', (376, 403))	('PKC', 'molecular_function', 'GO:0004697', ('20', '23'))	('melanoma', 'Disease', 'MESH:D008545', (287, 295))	('mutations', 'Var', (100, 109))	('growth', 'MPA', (191, 197))	('cutaneous melanoma', 'Disease', (385, 403))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (385, 403))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (385, 403))	('melanoma', 'Disease', 'MESH:D008545', (395, 403))
140307	24141786	Interestingly, two of the latter cell lines also showed PKC activation as evidenced by expression of phospho-MARCKS (Figure 1).	('phospho-MARCKS', 'Var', (101, 115))	('PKC', 'molecular_function', 'GO:0004697', ('56', '59'))	('PKC', 'Gene', (56, 59))	('PKC', 'Gene', '112476', (56, 59))	('activation', 'PosReg', (60, 70))	('PKC activation', 'biological_process', 'GO:1990051', ('56', '70'))
140308	24141786	This indicates that in contrast to other cell lines, GNAQ or GNA11 mutant cell lines are dependent on PKC activation to initiate critical growth pathways.	('PKC', 'Gene', '112476', (102, 105))	('GNAQ', 'Gene', (53, 57))	('GNA11', 'Gene', (61, 66))	('PKC', 'molecular_function', 'GO:0004697', ('102', '105'))	('mutant', 'Var', (67, 73))	('PKC', 'Gene', (102, 105))	('PKC activation', 'biological_process', 'GO:1990051', ('102', '116'))	('critical growth pathways', 'Pathway', (129, 153))
140313	24141786	In contrast to normal melan-a cells, melan-a cell lines stably expressing GNAQQ209L or GNA11Q209L proliferate independently of TPA (Supplemental Figure 10).	('TPA', 'molecular_function', 'GO:0031299', ('127', '130'))	('GNA11Q209L', 'Var', (87, 97))	('TPA', 'Chemical', 'MESH:D013755', (127, 130))	('proliferate', 'CPA', (98, 109))
140315	24141786	Our results and published data indicate that MAP-kinase pathway activation is a critical component of oncogenic signaling in the context of mutant GNAQ or GNA11 and occurs down-stream of PKC.	('PKC', 'molecular_function', 'GO:0004697', ('187', '190'))	('MAP', 'molecular_function', 'GO:0004239', ('45', '48'))	('MAP-kinase pathway', 'Pathway', (45, 63))	('PKC', 'Gene', (187, 190))	('PKC', 'Gene', '112476', (187, 190))	('signaling', 'biological_process', 'GO:0023052', ('112', '121'))	('GNAQ', 'Gene', (147, 151))	('activation', 'PosReg', (64, 74))	('GNA11', 'Gene', (155, 160))	('mutant', 'Var', (140, 146))
140316	24141786	Prior studies have shown that GalphaqQ209L can stimulate MAPK pathway via PLC-DAG-PKC, presumably by PKC-mediated phosphorylation of Raf-1.	('PKC', 'molecular_function', 'GO:0004697', ('101', '104'))	('PLC', 'cellular_component', 'GO:0042824', ('74', '77'))	('PKC', 'molecular_function', 'GO:0004697', ('82', '85'))	('DAG', 'Chemical', 'MESH:D004075', (78, 81))	('stimulate', 'PosReg', (47, 56))	('MAPK', 'molecular_function', 'GO:0004707', ('57', '61'))	('Raf-1', 'Gene', (133, 138))	('PKC', 'Gene', (101, 104))	('PKC', 'Gene', '112476', (101, 104))	('GalphaqQ209L', 'Chemical', '-', (30, 42))	('Raf-1', 'Gene', '5894', (133, 138))	('MAPK pathway', 'Pathway', (57, 69))	('phosphorylation', 'biological_process', 'GO:0016310', ('114', '129'))	('GalphaqQ209L', 'Var', (30, 42))	('PKC', 'Gene', (82, 85))	('PKC', 'Gene', '112476', (82, 85))
140317	24141786	MAP-kinase pathway activation has also been demonstrated via PLC-IP3-Ca2+-Pyk2-Src-Ras signaling, and the precise conduit of signaling in the context of mutant GNAQ or GNA11 remains to be determined.	('IP3', 'Chemical', 'MESH:D015544', (65, 68))	('signaling', 'biological_process', 'GO:0023052', ('87', '96'))	('activation', 'PosReg', (19, 29))	('mutant', 'Var', (153, 159))	('PLC', 'cellular_component', 'GO:0042824', ('61', '64'))	('PLC-IP3-Ca2+-Pyk2-Src-Ras signaling', 'MPA', (61, 96))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('MAP', 'molecular_function', 'GO:0004239', ('0', '3'))	('MAP-kinase pathway', 'Pathway', (0, 18))
140318	24141786	In our study with two different PKC inhibitors, PKC inhibition attenuated MAPK phosphorylation in the context of GNAQ or GNA11 mutation, whereas MEK inhibition only blocked MAPK phosphorylation, with no effect on PKC activation in GNAQ or GNA11 mutant cells (Figure 3).	('PKC', 'molecular_function', 'GO:0004697', ('213', '216'))	('MAPK', 'molecular_function', 'GO:0004707', ('173', '177'))	('phosphorylation', 'biological_process', 'GO:0016310', ('178', '193'))	('PKC', 'molecular_function', 'GO:0004697', ('48', '51'))	('PKC activation', 'biological_process', 'GO:1990051', ('213', '227'))	('phosphorylation', 'biological_process', 'GO:0016310', ('79', '94'))	('PKC', 'Gene', '112476', (32, 35))	('PKC', 'Gene', '112476', (213, 216))	('GNAQ', 'Gene', (113, 117))	('attenuated', 'NegReg', (63, 73))	('mutation', 'Var', (127, 135))	('PKC', 'Gene', '112476', (48, 51))	('PKC', 'Gene', (32, 35))	('GNA11', 'Gene', (121, 126))	('PKC', 'Gene', (213, 216))	('MAPK', 'molecular_function', 'GO:0004707', ('74', '78'))	('PKC', 'Gene', (48, 51))	('MAPK', 'Enzyme', (74, 78))	('PKC', 'molecular_function', 'GO:0004697', ('32', '35'))
140319	24141786	The experiments using the PKC substrate motif antibody revealed that introduction of mutant BRAF or NRAS also results in PKC activation, but with a different spectrum of phosphorylation targets than GalphaqQ209L (Supplemental Figure 1).	('phosphorylation', 'biological_process', 'GO:0016310', ('170', '185'))	('antibody', 'molecular_function', 'GO:0003823', ('46', '54'))	('GalphaqQ209L', 'Chemical', '-', (199, 211))	('PKC', 'molecular_function', 'GO:0004697', ('121', '124'))	('PKC', 'Gene', '112476', (26, 29))	('antibody', 'cellular_component', 'GO:0042571', ('46', '54'))	('NRAS', 'Gene', '4893', (100, 104))	('PKC', 'Gene', '112476', (121, 124))	('PKC', 'Gene', (26, 29))	('BRAF', 'Gene', '673', (92, 96))	('antibody', 'cellular_component', 'GO:0019815', ('46', '54'))	('PKC', 'Gene', (121, 124))	('BRAF', 'Gene', (92, 96))	('PKC activation', 'biological_process', 'GO:1990051', ('121', '135'))	('mutant', 'Var', (85, 91))	('NRAS', 'Gene', (100, 104))	('PKC', 'molecular_function', 'GO:0004697', ('26', '29'))	('activation', 'PosReg', (125, 135))	('antibody', 'cellular_component', 'GO:0019814', ('46', '54'))
140320	24141786	As BRAF signals predominantly through the MAP-kinase pathway, in melanoma cells with BRAF mutations PKC most likely becomes activated as a consequence of MAP-kinase pathway activation, contrary to the context of mutant GNAQ or GNA11 where the MAP-kinase pathway operates down-stream of PKC.	('MAP-kinase pathway', 'Pathway', (42, 60))	('mutations', 'Var', (90, 99))	('PKC', 'Gene', (100, 103))	('MAP', 'molecular_function', 'GO:0004239', ('154', '157'))	('PKC', 'molecular_function', 'GO:0004697', ('286', '289'))	('activated', 'PosReg', (124, 133))	('PKC', 'molecular_function', 'GO:0004697', ('100', '103'))	('MAP', 'molecular_function', 'GO:0004239', ('243', '246'))	('MAP', 'molecular_function', 'GO:0004239', ('42', '45'))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))	('PKC', 'Gene', '112476', (286, 289))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('PKC', 'Gene', '112476', (100, 103))	('PKC', 'Gene', (286, 289))	('BRAF', 'Gene', '673', (3, 7))	('MAP-kinase pathway', 'Pathway', (154, 172))	('BRAF', 'Gene', (3, 7))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))
140321	24141786	MAP-kinase pathway activation via PKC appears to represent a major proliferative stimulus in the context of GNAQ or GNA11 mutations, as both PKC or MEK inhibition led to G1 arrest with loss of phospho-RB, reduction of cyclin D1 and upregulation of the negative cell cycle regulator p27kip1.	('cell cycle regulator', 'biological_process', 'GO:0051726', ('261', '281'))	('cyclin D1', 'Gene', '595', (218, 227))	('inhibition', 'NegReg', (152, 162))	('reduction', 'NegReg', (205, 214))	('upregulation', 'PosReg', (232, 244))	('phospho-RB', 'Protein', (193, 203))	('GNAQ', 'Gene', (108, 112))	('PKC', 'Gene', '112476', (34, 37))	('GNA11', 'Gene', (116, 121))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('261', '281'))	('loss', 'NegReg', (185, 189))	('PKC', 'Gene', (34, 37))	('PKC', 'molecular_function', 'GO:0004697', ('34', '37'))	('PKC', 'Gene', '112476', (141, 144))	('G1 arrest', 'CPA', (170, 179))	('MAP', 'molecular_function', 'GO:0004239', ('0', '3'))	('MAP-kinase', 'Enzyme', (0, 10))	('cyclin', 'molecular_function', 'GO:0016538', ('218', '224'))	('PKC', 'Gene', (141, 144))	('p27kip1', 'Gene', '1027', (282, 289))	('cyclin D1', 'Gene', (218, 227))	('mutations', 'Var', (122, 131))	('PKC', 'molecular_function', 'GO:0004697', ('141', '144'))	('p27kip1', 'Gene', (282, 289))
140322	24141786	The findings are consistent with the effects of MEK inhibition in BRAF mutant melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('mutant', 'Var', (71, 77))	('melanoma', 'Disease', (78, 86))	('BRAF', 'Gene', '673', (66, 70))	('BRAF', 'Gene', (66, 70))
140323	24141786	PKC inhibition with either PKC inhibitor alone did not result in cell death in uveal melanoma cell lines with GNAQ or GNA11 mutations at doses used in our study.	('PKC', 'Gene', (0, 3))	('GNA11', 'Gene', (118, 123))	('PKC', 'Gene', '112476', (0, 3))	('mutations', 'Var', (124, 133))	('PKC', 'Gene', '112476', (27, 30))	('PKC', 'molecular_function', 'GO:0004697', ('27', '30'))	('cell death', 'biological_process', 'GO:0008219', ('65', '75'))	('PKC', 'molecular_function', 'GO:0004697', ('0', '3'))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Disease', (79, 93))	('GNAQ', 'Gene', (110, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('PKC', 'Gene', (27, 30))
140324	24141786	et al found that AEB071 at high doses (5muM) induced apoptosis in 92-1, mel202 and omm1.3 uveal melanoma cell lines, which harbor GNAQ mutations.	('muM', 'Gene', (40, 43))	('apoptosis', 'CPA', (53, 62))	('uveal melanoma', 'Disease', (90, 104))	('uveal melanoma', 'Disease', 'MESH:C536494', (90, 104))	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('mutations', 'Var', (135, 144))	('muM', 'Gene', '56925', (40, 43))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))
140325	24141786	In the allograft experiment with melan-a cells transduced with GNAQQ209L, AEB071 slowed tumor growth at the maximally tolerated dose level, but did not result in tumor regression or apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('slowed', 'NegReg', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (162, 167))	('AEB071', 'Var', (74, 80))	('GNAQQ209L', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('182', '191'))	('apoptosis', 'biological_process', 'GO:0006915', ('182', '191'))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
140327	24141786	A clinical trial with AEB071 is currently underway in patients with UM with GNAQ or GNA11 mutations.	('patients', 'Species', '9606', (54, 62))	('GNAQ', 'Gene', (76, 80))	('mutations', 'Var', (90, 99))	('GNA11', 'Gene', (84, 89))
140329	24141786	The finding that the treated tumors in our allograft experiment continued to express pERK while PKC output continued to be suppressed points to additional complexity in the activation of the MAP-kinase pathway in the context of GNAQ or GNA11 mutation.	('PKC', 'Gene', (96, 99))	('GNAQ', 'Gene', (228, 232))	('pERK', 'Gene', (85, 89))	('PKC', 'Gene', '112476', (96, 99))	('activation', 'PosReg', (173, 183))	('pERK', 'Gene', '9451', (85, 89))	('GNA11', 'Gene', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('PKC', 'molecular_function', 'GO:0004697', ('96', '99'))	('MAP', 'molecular_function', 'GO:0004239', ('191', '194'))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('MAP-kinase pathway', 'Pathway', (191, 209))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('mutation', 'Var', (242, 250))
140331	24141786	A similar phenomenon has been observed with the use of BRAF inhibitors in melanoma cells with BRAF mutations, in which the MAP-kinase pathway becomes re-activated after 24 hours of treatment.	('BRAF', 'Gene', (94, 98))	('ser', 'Chemical', 'MESH:D012694', (32, 35))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('mutations', 'Var', (99, 108))	('BRAF', 'Gene', '673', (94, 98))	('MAP', 'molecular_function', 'GO:0004239', ('123', '126'))	('BRAF', 'Gene', '673', (55, 59))	('MAP-kinase pathway', 'Pathway', (123, 141))	('BRAF', 'Gene', (55, 59))
140332	24141786	The intriguing synergy between compounds targeting the same pathway in a seemingly redundant fashion has now been shown to have clinical benefits in patients with BRAF mutant melanomas.	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('patients', 'Species', '9606', (149, 157))	('mutant', 'Var', (168, 174))	('melanomas', 'Disease', (175, 184))	('benefits', 'PosReg', (137, 145))	('melanomas', 'Phenotype', 'HP:0002861', (175, 184))	('melanomas', 'Disease', 'MESH:D008545', (175, 184))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))
140333	24141786	These findings motivated us to investigate a combination of PKC inhibition and MEK inhibition and we also found a strong synergistic effect of the two approaches both in vitro and in vivo (Figure 6, Figure 7 and Supplemental Figure 8 and 9) associated with nearly full suppression of pMEK and pERK levels in melanomas with GNAQ and GNA11 mutation.	('suppression', 'NegReg', (269, 280))	('melanomas', 'Phenotype', 'HP:0002861', (308, 317))	('GNA11', 'Gene', (332, 337))	('melanomas', 'Disease', 'MESH:D008545', (308, 317))	('melanoma', 'Phenotype', 'HP:0002861', (308, 316))	('PKC', 'molecular_function', 'GO:0004697', ('60', '63'))	('pERK', 'Gene', (293, 297))	('PKC', 'Gene', '112476', (60, 63))	('mutation', 'Var', (338, 346))	('pERK', 'Gene', '9451', (293, 297))	('PKC', 'Gene', (60, 63))	('GNAQ', 'Gene', (323, 327))	('melanomas', 'Disease', (308, 317))
140335	24141786	However, MEK inhibitors inhibit ERK signaling in all cells including normal tissues, resulting in a reduced therapeutic index.	('ERK', 'Gene', '5594', (32, 35))	('reduced', 'NegReg', (100, 107))	('inhibitors', 'Var', (13, 23))	('ERK', 'Gene', (32, 35))	('signaling', 'biological_process', 'GO:0023052', ('36', '45'))	('MEK', 'Gene', (9, 12))	('therapeutic index', 'MPA', (108, 125))	('ERK', 'molecular_function', 'GO:0004707', ('32', '35'))	('inhibit', 'NegReg', (24, 31))
140336	24141786	The accumulation of pMEK induced by MEK inhibition in GNAQ and GNA11 mutant cells is consistent with the findings in BRAF wild type melanoma cells and has been explained by the abrogation of negative feedback pathways as a consequence of MEK inhibition.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('mutant', 'Var', (69, 75))	('accumulation', 'PosReg', (4, 16))	('inhibition', 'NegReg', (40, 50))	('GNA11', 'Gene', (63, 68))	('MEK', 'Gene', (36, 39))	('BRAF', 'Gene', '673', (117, 121))	('pMEK', 'Gene', (20, 24))	('BRAF', 'Gene', (117, 121))	('negative feedback pathways', 'Pathway', (191, 217))
140337	24141786	Using two different MEK inhibitors, we found that pMEK accumulation in response to MEK inhibition can be abrogated by the addition of the PKC inhibitor AEB071 (Figure 6D and Supplemental Figure 9) in the GNAQ/11 mutant cells, but not melanoma cell lines without GNAQ/11 mutations.	('inhibition', 'NegReg', (87, 97))	('mutant', 'Var', (212, 218))	('accumulation', 'PosReg', (55, 67))	('PKC', 'Gene', (138, 141))	('PKC', 'Gene', '112476', (138, 141))	('pMEK', 'Gene', (50, 54))	('GNAQ/11', 'Gene', (204, 211))	('abrogated', 'NegReg', (105, 114))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('PKC', 'molecular_function', 'GO:0004697', ('138', '141'))	('melanoma', 'Disease', (234, 242))	('MEK', 'Enzyme', (83, 86))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))
140338	24141786	While this could point to a role of PKC in the negative feedback loop, a simpler explanation is that PKC inhibition reduces some of the pathway flux upstream of MEK, coming from mutant GNAQ or GNA11.	('inhibition reduces', 'NegReg', (105, 123))	('mutant', 'Var', (178, 184))	('PKC', 'molecular_function', 'GO:0004697', ('101', '104'))	('MEK', 'Gene', (161, 164))	('pathway', 'Pathway', (136, 143))	('PKC', 'molecular_function', 'GO:0004697', ('36', '39'))	('PKC', 'Gene', (101, 104))	('PKC', 'Gene', '112476', (101, 104))	('PKC', 'Gene', (36, 39))	('PKC', 'Gene', '112476', (36, 39))
140340	24141786	We conclude that in the setting of GNAQ or GNA11 mutation, the combined treatment with PKC and MEK inhibitors may improve treatment responses in patients with metastatic uveal melanoma compared to either of the two compounds alone.	('patients', 'Species', '9606', (145, 153))	('MEK', 'Enzyme', (95, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (170, 184))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('GNA11', 'Gene', (43, 48))	('PKC', 'Gene', (87, 90))	('uveal melanoma', 'Disease', (170, 184))	('PKC', 'Gene', '112476', (87, 90))	('uveal melanoma', 'Phenotype', 'HP:0007716', (170, 184))	('mutation', 'Var', (49, 57))	('improve', 'PosReg', (114, 121))	('PKC', 'molecular_function', 'GO:0004697', ('87', '90'))	('treatment responses', 'CPA', (122, 141))	('GNAQ', 'Gene', (35, 39))
140343	24141786	PD0325901 was obtained from Chemie Tek (Indianapolis, IN).	('Tek', 'Gene', '7010', (35, 38))	('PD0325901', 'Var', (0, 9))	('PD0325901', 'Chemical', 'MESH:C506614', (0, 9))	('Tek', 'Gene', (35, 38))
140349	24141786	For generation of stable melan-a cells expressing various proteins, melan-a cells were transduced with lentiviruses expressing GFP, GNAQ wt, GNA11wt, GNAQQ209L, GNA11Q209L or Braf V600E, respectively.	('GNA11wt', 'Var', (141, 148))	('GNA11Q209L', 'Var', (161, 171))	('GNAQQ209L', 'Var', (150, 159))	('Braf', 'Gene', (175, 179))	('Braf', 'Gene', '673', (175, 179))	('V600E', 'Mutation', 'rs113488022', (180, 185))
140350	24141786	200nM TPA was added to media for cells transduced with lentivirus expressing GFP, GNAQwt or GNA11wt, but not to cells infected with lentivirus expressing GNAQQ209L, GNA11Q209L or BrafV600E.	('TPA', 'Chemical', 'MESH:D013755', (6, 9))	('TPA', 'molecular_function', 'GO:0031299', ('6', '9'))	('GNAQwt', 'Var', (82, 88))	('GNA11wt', 'Var', (92, 99))	('GFP', 'Var', (77, 80))
140362	24141786	1x106 melan-a cells stably expressing GNAQQ209L were injected into the flanks of c57/Bl6 mouse, and allowed 10 to 14 days to reach a tumor volume of about 100 mm3.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('GNAQQ209L', 'Var', (38, 47))	('tumor', 'Disease', (133, 138))	('mouse', 'Species', '10090', (89, 94))
140377	25646071	We review evidence for a link between cadmium-induced epigenetic changes and cell transformation, with special emphasis on melanoma.	('cadmium', 'Chemical', 'MESH:D002104', (38, 45))	('epigenetic changes', 'Var', (54, 72))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('cell transformation', 'CPA', (77, 96))
140378	25646071	DNA methylation, with reduced expression of key genes that regulate cell proliferation and apoptosis, has emerged as a possible cadmium-induced epigenetic mechanism in melanoma.	('expression', 'MPA', (30, 40))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('rat', 'Species', '10116', (80, 83))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cadmium', 'Chemical', 'MESH:D002104', (128, 135))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('methylation', 'Var', (4, 15))	('reduced', 'NegReg', (22, 29))	('cell proliferation', 'biological_process', 'GO:0008283', ('68', '86'))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', (168, 176))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
140398	25646071	Liver is the first organ to be reached and there cadmium activates MT production.	('cadmium', 'Chemical', 'MESH:D002104', (49, 56))	('activates', 'PosReg', (57, 66))	('cadmium', 'Var', (49, 56))	('MT production', 'MPA', (67, 80))
140414	25646071	Foulkes showed that, in rat jejunum, cadmium uptake was depressed by high concentrations of polyvalent cations, including Pb, Ni, Cr3+, Sr, and Mg .	('cadmium', 'Chemical', 'MESH:D002104', (37, 44))	('depressed', 'NegReg', (56, 65))	('rat', 'Species', '10116', (81, 84))	('uptake', 'biological_process', 'GO:0098739', ('45', '51'))	('cadmium uptake', 'MPA', (37, 51))	('Pb', 'Chemical', 'MESH:D007854', (122, 124))	('Sr', 'Chemical', 'MESH:D013324', (136, 138))	('uptake', 'biological_process', 'GO:0098657', ('45', '51'))	('Mg', 'Chemical', 'MESH:D008274', (144, 146))	('Cr3+', 'Var', (130, 134))	('rat', 'Species', '10116', (24, 27))
140461	25646071	Early signs of glomerular damage provoked by cadmium are increased excretion of albumin and transferrin.	('glomerular damage', 'Disease', (15, 32))	('cadmium', 'Chemical', 'MESH:D002104', (45, 52))	('glomerular damage', 'Disease', 'MESH:D007674', (15, 32))	('excretion', 'biological_process', 'GO:0007588', ('67', '76'))	('excretion of albumin', 'MPA', (67, 87))	('increased', 'PosReg', (57, 66))	('transferrin', 'Gene', '7018', (92, 103))	('transferrin', 'Gene', (92, 103))	('cadmium', 'Var', (45, 52))
140463	25646071	Glomerular filtration rate (GFR) decreases slowly but progressively and it's possible that cadmium accelerates the normal age-related decline in kidney function.	('Glomerular filtration', 'biological_process', 'GO:0003094', ('0', '21'))	('rat', 'Species', '10116', (15, 18))	('rat', 'Species', '10116', (105, 108))	('rat', 'Species', '10116', (22, 25))	('kidney function', 'MPA', (145, 160))	('cadmium', 'Var', (91, 98))	('Glomerular filtration rate', 'MPA', (0, 26))	('cadmium', 'Chemical', 'MESH:D002104', (91, 98))
140478	25646071	When animals are pregnant, cadmium crosses the placenta inducing malformations in the newborns.	('cadmium', 'Chemical', 'MESH:D002104', (27, 34))	('cadmium', 'Var', (27, 34))	('malformations', 'Disease', 'MESH:D000014', (65, 78))	('malformations', 'Disease', (65, 78))	('inducing', 'Reg', (56, 64))
140493	25646071	Recent studies have indicated that cadmium, even at non-toxic concentrations, can induce inflammatory changes in the airways and in the vascular bed, and that these effects might be mediated by its ability to induce CXCL1 and CXCL2 chemokines.	('induce', 'Reg', (209, 215))	('cadmium', 'Var', (35, 42))	('induce', 'Reg', (82, 88))	('CXCL2', 'Gene', (226, 231))	('CXCL1', 'Gene', '2919', (216, 221))	('cadmium', 'Chemical', 'MESH:D002104', (35, 42))	('CXCL2', 'Gene', '2920', (226, 231))	('CXCL1', 'Gene', (216, 221))	('rat', 'Species', '10116', (69, 72))	('inflammatory changes', 'CPA', (89, 109))
140495	25646071	Further studies will be needed to ascertain whether cadmium can directly potentiate the activation of receptors of the innate immune system, including the Toll-like receptors and Nod-like receptors, leading to the induction of proinflammatory cytokines.	('activation', 'PosReg', (88, 98))	('cadmium', 'Var', (52, 59))	('cadmium', 'Chemical', 'MESH:D002104', (52, 59))	('induction', 'Reg', (214, 223))	('potentiate', 'PosReg', (73, 83))	('proinflammatory cytokines', 'MPA', (227, 252))
140502	25646071	Cadmium can activate oncogenes or genes associated with cell proliferation, such as c-myc, c-jun or c-fos, both in vivo and in vitro and it can also induce up-regulation of signal pathways resulting in increased mitogenesis, such as, for example, the AP-1 and MAP kinase pathways.	('regulation', 'biological_process', 'GO:0065007', ('159', '169'))	('activate', 'PosReg', (12, 20))	('c-fos', 'Gene', (100, 105))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))	('AP-1', 'Gene', '2353', (251, 255))	('genes', 'Gene', (34, 39))	('MAP', 'molecular_function', 'GO:0004239', ('260', '263'))	('cell proliferation', 'CPA', (56, 74))	('c-myc', 'Gene', (84, 89))	('signal pathways', 'Pathway', (173, 188))	('c-jun', 'Gene', '3725', (91, 96))	('c-jun', 'Gene', (91, 96))	('increased', 'PosReg', (202, 211))	('Cadmium', 'Var', (0, 7))	('up-regulation', 'PosReg', (156, 169))	('AP-1', 'Gene', (251, 255))	('rat', 'Species', '10116', (68, 71))	('Cadmium', 'Chemical', 'MESH:D002104', (0, 7))	('MAP kinase pathways', 'Pathway', (260, 279))	('AP-1', 'cellular_component', 'GO:0005907', ('251', '255'))	('c-fos', 'Gene', '2353', (100, 105))	('mitogenesis', 'MPA', (212, 223))	('oncogenes', 'Gene', (21, 30))	('c-myc', 'Gene', '4609', (84, 89))
140503	25646071	A direct action of cadmium on the expression of E-cadherin, a transmembrane Ca(II)-binding glycoprotein, has not been demonstrated yet, but the few available data indicate that cadmium may disrupt E- cadherin-dependent cell communication and promote cell division.	('transmembrane', 'cellular_component', 'GO:0016021', ('62', '75'))	('rat', 'Species', '10116', (125, 128))	('cell division', 'biological_process', 'GO:0051301', ('250', '263'))	('disrupt', 'NegReg', (189, 196))	('cadherin', 'molecular_function', 'GO:0008014', ('200', '208'))	('cell division', 'CPA', (250, 263))	('cadherin', 'molecular_function', 'GO:0008014', ('50', '58'))	('cadmium', 'Var', (177, 184))	('cell communication', 'biological_process', 'GO:0007154', ('219', '237'))	('binding', 'molecular_function', 'GO:0005488', ('83', '90'))	('cadmium', 'Chemical', 'MESH:D002104', (177, 184))	('E-cadherin', 'Gene', (48, 58))	('E- cadherin', 'Gene', '999', (197, 208))	('E- cadherin', 'Gene', (197, 208))	('cadmium', 'Chemical', 'MESH:D002104', (19, 26))	('E-cadherin', 'Gene', '999', (48, 58))	('transmembrane', 'cellular_component', 'GO:0044214', ('62', '75'))	('promote', 'PosReg', (242, 249))
140510	25646071	But, nevertheless, the IARC (International Agency for Research on Cancer) classified cadmium as a group I carcinogen by virtue of its effect in inducing renal cancer.	('inducing', 'Reg', (144, 152))	('renal cancer', 'Disease', 'MESH:D007680', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('IARC', 'Disease', 'None', (23, 27))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cadmium', 'Var', (85, 92))	('renal cancer', 'Disease', (153, 165))	('IARC', 'Disease', (23, 27))	('cadmium', 'Chemical', 'MESH:D002104', (85, 92))	('renal cancer', 'Phenotype', 'HP:0009726', (153, 165))
140511	25646071	Some evidences indicate that cadmium may be tumorigenic only when it is absorbed through the respiratory tract.	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('rat', 'Species', '10116', (98, 101))	('cadmium', 'Chemical', 'MESH:D002104', (29, 36))	('cadmium', 'Var', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
140514	25646071	Alterations in DNA mismatch repair genes have also been described.	('mismatch repair', 'biological_process', 'GO:0006298', ('19', '34'))	('Alterations', 'Var', (0, 11))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('rat', 'Species', '10116', (4, 7))	('DNA mismatch repair genes', 'Gene', (15, 40))
140515	25646071	Moreover, cadmium was shown to interfere with the transcriptional machinery by substituting for zinc in some transcriptional factors .	('transcriptional', 'MPA', (50, 65))	('cadmium', 'Chemical', 'MESH:D002104', (10, 17))	('interfere', 'NegReg', (31, 40))	('substituting', 'Var', (79, 91))
140516	25646071	Epidemiological studies have provided further evidence that in addition to lung cancer, other cancers can be induced by cadmium.	('lung cancer', 'Disease', (75, 86))	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('induced', 'Reg', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cadmium', 'Chemical', 'MESH:D002104', (120, 127))	('cadmium', 'Var', (120, 127))
140520	25646071	However cadmium can induce perturbations of genome stability through several indirect mechanisms, such as the production of reactive oxygen species (ROS), the disturbance of cellular signalling processes, DNA repair, mitotic cycle regulation, induction of apoptosis as well as epigenetic alterations, which may act together and lead to carcinogenesis.	('cadmium', 'Var', (8, 15))	('mitotic cycle regulation', 'CPA', (217, 241))	('rat', 'Species', '10116', (292, 295))	('DNA repair', 'CPA', (205, 215))	('cellular signalling processes', 'CPA', (174, 203))	('carcinogenesis', 'Disease', (336, 350))	('DNA repair', 'biological_process', 'GO:0006281', ('205', '215'))	('genome stability', 'CPA', (44, 60))	('ROS', 'Chemical', 'MESH:D017382', (149, 152))	('cadmium', 'Chemical', 'MESH:D002104', (8, 15))	('disturbance', 'Reg', (159, 170))	('signalling', 'biological_process', 'GO:0023052', ('183', '193'))	('carcinogenesis', 'Disease', 'MESH:D063646', (336, 350))	('lead to', 'Reg', (328, 335))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('243', '265'))	('DNA', 'cellular_component', 'GO:0005574', ('205', '208'))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (124, 147))	('apoptosis', 'CPA', (256, 265))	('epigenetic alterations', 'Var', (277, 299))	('regulation', 'biological_process', 'GO:0065007', ('231', '241'))
140531	25646071	Decreased antioxidant activities induce apoptosis and overproduction of ROS leads to inhibition of apoptosis.	('antioxidant activities', 'MPA', (10, 32))	('apoptosis', 'CPA', (40, 49))	('overproduction', 'Var', (54, 68))	('Decreased', 'NegReg', (0, 9))	('apoptosis', 'biological_process', 'GO:0097194', ('40', '49'))	('apoptosis', 'biological_process', 'GO:0006915', ('40', '49'))	('apoptosis', 'CPA', (99, 108))	('inhibition', 'NegReg', (85, 95))	('ROS', 'Chemical', 'MESH:D017382', (72, 75))	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('85', '108'))	('ROS', 'Gene', (72, 75))
140536	25646071	Recently, it has been shown that cadmium is able to induce apoptosis in naive alveolar epithelial cells, likely by a mechanism of oxidative stress.	('apoptosis', 'biological_process', 'GO:0097194', ('59', '68'))	('apoptosis', 'biological_process', 'GO:0006915', ('59', '68'))	('oxidative stress', 'Phenotype', 'HP:0025464', (130, 146))	('cadmium', 'Var', (33, 40))	('apoptosis', 'CPA', (59, 68))	('cadmium', 'Chemical', 'MESH:D002104', (33, 40))
140537	25646071	Indeed, cadmium may also affect antioxidative proteins, such as catalase and glutathione reductase, which have a crucial role in ROS elimination and induce, thereby, a reduction in cellular antioxidants and release of ROS by mitochondria.	('release of ROS by mitochondria', 'MPA', (207, 237))	('cellular antioxidants', 'MPA', (181, 202))	('ROS', 'Chemical', 'MESH:D017382', (218, 221))	('cadmium', 'Var', (8, 15))	('mitochondria', 'cellular_component', 'GO:0005739', ('225', '237'))	('antioxidative proteins', 'Enzyme', (32, 54))	('glutathione reductase', 'Gene', (77, 98))	('glutathione reductase', 'Gene', '2936', (77, 98))	('catalase', 'Gene', '847', (64, 72))	('cadmium', 'Chemical', 'MESH:D002104', (8, 15))	('catalase', 'Gene', (64, 72))	('ROS', 'Chemical', 'MESH:D017382', (129, 132))	('reduction', 'NegReg', (168, 177))	('affect', 'Reg', (25, 31))
140538	25646071	Cadmium is believed to impair not only the repair of DNA damage caused by oxidative stress but also the repair of DNA double-strand breaks and DNA interstrand crosslinks.	('impair', 'NegReg', (23, 29))	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('Cadmium', 'Var', (0, 7))	('repair', 'MPA', (43, 49))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('Cadmium', 'Chemical', 'MESH:D002104', (0, 7))	('oxidative stress', 'Phenotype', 'HP:0025464', (74, 90))
140539	25646071	It is noteworthy that cadmium has been shown to act as a tumour "progressor" in mouse models of sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('tumour', 'Disease', (57, 63))	('sarcomas', 'Disease', (96, 104))	('mouse', 'Species', '10090', (80, 85))	('cadmium', 'Var', (22, 29))	('cadmium', 'Chemical', 'MESH:D002104', (22, 29))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('sarcomas', 'Disease', 'MESH:D012509', (96, 104))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
140543	25646071	Cadmium exposure has been associated with tumors of the lung, testes, injection site, prostate, hematopoietic system, pancreas, adrenals, liver, kidney and pituitary and several of these sites concur with potential target sites of cadmium carcinogenesis in humans.	('carcinogenesis', 'Disease', 'MESH:D063646', (239, 253))	('Cadmium', 'Var', (0, 7))	('tumors of the lung', 'Disease', (42, 60))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('carcinogenesis', 'Disease', (239, 253))	('tumors of the lung', 'Disease', 'MESH:D008175', (42, 60))	('pancreas', 'Disease', (118, 126))	('cadmium', 'Chemical', 'MESH:D002104', (231, 238))	('humans', 'Species', '9606', (257, 263))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('associated', 'Reg', (26, 36))	('Cadmium', 'Chemical', 'MESH:D002104', (0, 7))	('pancreas', 'Disease', 'MESH:D010190', (118, 126))
140548	25646071	Instead, epigenetic events appear to be involved in the starting phase of heavy metal carcinogenesis by "writing" and "erasing" epigenetic signals at the promoter regions of several cancerous genes.	('carcinogenesis', 'Disease', (86, 100))	('epigenetic events', 'Var', (9, 26))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancerous', 'Disease', 'MESH:D009369', (182, 191))	('erasing', 'NegReg', (119, 126))	('metal', 'Chemical', 'MESH:D008670', (80, 85))	('carcinogenesis', 'Disease', 'MESH:D063646', (86, 100))	('cancerous', 'Disease', (182, 191))	('involved', 'Reg', (40, 48))
140549	25646071	Epigenetic alterations regulate key events in cellular homeostasis, including transcriptional and translational regulation of gene expression.	('Epigenetic alterations', 'Var', (0, 22))	('regulate', 'Reg', (23, 31))	('rat', 'Species', '10116', (15, 18))	('cellular homeostasis', 'biological_process', 'GO:0019725', ('46', '66'))	('regulation of gene expression', 'biological_process', 'GO:0010468', ('112', '141'))	('transcriptional', 'MPA', (78, 93))	('cellular homeostasis', 'MPA', (46, 66))	('translational regulation', 'MPA', (98, 122))
140550	25646071	The most well studied epigenetic alterations are DNA methylation, the covalent, post-translational modification of histones, and non-coding small RNAs (miRNAs).	('post-translational modification', 'MPA', (80, 111))	('DNA methylation', 'biological_process', 'GO:0006306', ('49', '64'))	('histones', 'Protein', (115, 123))	('rat', 'Species', '10116', (37, 40))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('covalent', 'MPA', (70, 78))	('non-coding small RNAs', 'Var', (129, 150))	('post-translational modification', 'biological_process', 'GO:0043687', ('80', '111'))	('DNA methylation', 'Var', (49, 64))	('methylation', 'Var', (53, 64))
140555	25646071	The carcinogenic potential of cadmium through epigenetic changes includes silencing of DNA repair and tumor-suppressor genes.	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('102', '118'))	('DNA repair', 'biological_process', 'GO:0006281', ('87', '97'))	('epigenetic changes', 'Var', (46, 64))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('carcinogenic', 'Disease', 'MESH:D063646', (4, 16))	('DNA repair', 'Protein', (87, 97))	('silencing', 'NegReg', (74, 83))	('carcinogenic', 'Disease', (4, 16))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('102', '118'))	('cadmium', 'Chemical', 'MESH:D002104', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
140562	25646071	These data are of concern, since genome-wide methylation loss from LINE-1 promoter sites, which are normally heavily methylated at CpG sites, is considered as a frequent epigenetic change in malignancies and may play a role in carcinogenesis.	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('LINE-1', 'Gene', (67, 73))	('carcinogenesis', 'Disease', 'MESH:D063646', (227, 241))	('malignancies', 'Disease', 'MESH:D009369', (191, 203))	('methylation', 'Var', (45, 56))	('loss', 'NegReg', (57, 61))	('play', 'Reg', (212, 216))	('carcinogenesis', 'Disease', (227, 241))	('role', 'Reg', (219, 223))	('malignancies', 'Disease', (191, 203))
140564	25646071	The association between urinary cadmium and decreased LINE-1 methylation was stronger among carriers of the rare alleles of DNMT1 rs10854076 and rs2228611, indicating that cadmium effects can vary according to DNMT1 polymorphisms.	('cadmium', 'Chemical', 'MESH:D002104', (172, 179))	('DNMT1', 'Gene', (124, 129))	('stronger', 'PosReg', (77, 85))	('DNMT1', 'Gene', '1786', (124, 129))	('DNMT1', 'Gene', '1786', (210, 215))	('rs10854076', 'Var', (130, 140))	('rs10854076', 'Mutation', 'rs10854076', (130, 140))	('cadmium', 'Chemical', 'MESH:D002104', (32, 39))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('decreased', 'NegReg', (44, 53))	('LINE-1 methylation', 'MPA', (54, 72))	('rs2228611', 'Mutation', 'rs2228611', (145, 154))	('rs2228611', 'Var', (145, 154))	('DNMT1', 'Gene', (210, 215))
140568	25646071	Agglomerative DNA hypermethylation has been observed in different kinds of human tumors in association with a reduction in plasticity-associated gene transcription of consecutive genes.	('transcription', 'biological_process', 'GO:0006351', ('150', '163'))	('tumors', 'Disease', (81, 87))	('reduction', 'NegReg', (110, 119))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('hypermethylation', 'Var', (18, 34))	('rat', 'Species', '10116', (7, 10))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('14', '34'))	('plasticity-associated gene transcription', 'MPA', (123, 163))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('DNA', 'cellular_component', 'GO:0005574', ('14', '17'))	('human', 'Species', '9606', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
140571	25646071	Moreover, four key genes related to DNA repair, hMSH2, ERCC1, XRCC1, and hOGG1, were hypermethylated at the promoter and suppressed at the mRNA and protein levels in cadmium-transformed cells compared to controls.	('hOGG1', 'Gene', (73, 78))	('hMSH', 'molecular_function', 'GO:0018775', ('48', '52'))	('XRCC1', 'Gene', '7515', (62, 67))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('hypermethylated', 'Var', (85, 100))	('ERCC1', 'Gene', (55, 60))	('hOGG1', 'Gene', '4968', (73, 78))	('cadmium', 'Chemical', 'MESH:D002104', (166, 173))	('hMSH2', 'Gene', '4436', (48, 53))	('XRCC1', 'Gene', (62, 67))	('suppressed', 'NegReg', (121, 131))	('ERCC1', 'Gene', '2067', (55, 60))	('hMSH2', 'Gene', (48, 53))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('DNA repair', 'biological_process', 'GO:0006281', ('36', '46'))
140573	25646071	Hypermethylation and repression of DNA repair genes, therefore, appear to be an early signature for cadmium-induced cancer and may also constitute part of the mechanism by which the toxicant induces tumorigenesis.	('tumor', 'Disease', (199, 204))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Disease', (116, 122))	('cadmium', 'Chemical', 'MESH:D002104', (100, 107))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('DNA repair genes', 'Gene', (35, 51))	('DNA repair', 'biological_process', 'GO:0006281', ('35', '45'))	('repression', 'NegReg', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('induces', 'Reg', (191, 198))
140575	25646071	A study using human prostate cells was in line with these results by showing that a 10-week exposure to cadmium led to malignant transformation in association with DNA hypermethylation at the global level, overexpression of DNMT3b and increased DNMT activity, promoter hypermethylation and decreased expression of the tumor suppressor genes RASSF1A and p16INK4A.	('decreased', 'NegReg', (290, 299))	('tumor suppressor', 'Gene', (318, 334))	('increased', 'PosReg', (235, 244))	('DNA', 'cellular_component', 'GO:0005574', ('164', '167'))	('cadmium', 'Chemical', 'MESH:D002104', (104, 111))	('DNMT', 'Gene', '1786', (224, 228))	('tumor suppressor', 'Gene', '7248', (318, 334))	('promoter', 'MPA', (260, 268))	('DNMT', 'Gene', (224, 228))	('DNMT3b', 'Gene', '1789', (224, 230))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('164', '184'))	('human', 'Species', '9606', (14, 19))	('expression', 'MPA', (300, 310))	('DNMT3b', 'Gene', (224, 230))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('318', '334'))	('malignant transformation', 'CPA', (119, 143))	('RASSF1A', 'Gene', '11186', (341, 348))	('DNMT', 'Gene', '1786', (245, 249))	('p16INK4A', 'Gene', (353, 361))	('tumor suppressor', 'biological_process', 'GO:0051726', ('318', '334'))	('DNMT', 'Gene', (245, 249))	('DNA hypermethylation', 'Var', (164, 184))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('RASSF1A', 'Gene', (341, 348))	('p16INK4A', 'Gene', '1029', (353, 361))	('overexpression', 'PosReg', (206, 220))
140581	25646071	Recently, a causal association was demonstrated between caspase 8 promoter hypermethylation, pathological changes in the liver of rats and mice exposed to cadmium, and loss of the apoptotic pathway.	('loss', 'NegReg', (168, 172))	('promoter hypermethylation', 'Var', (66, 91))	('caspase 8', 'Protein', (56, 65))	('rats', 'Species', '10116', (130, 134))	('apoptotic pathway', 'Pathway', (180, 197))	('cadmium', 'Chemical', 'MESH:D002104', (155, 162))	('rat', 'Species', '10116', (130, 133))	('mice', 'Species', '10090', (139, 143))	('rat', 'Species', '10116', (42, 45))
140583	25646071	In addition, caspase 8 promoter was aberrantly methylated in all liver tissues from patients with hepatic cell carcinoma (HCC) while it was unmethylated in all the normal liver tissues.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('hepatic cell carcinoma', 'Disease', (98, 120))	('aberrantly methylated', 'Var', (36, 57))	('patients', 'Species', '9606', (84, 92))	('caspase', 'Protein', (13, 20))	('hepatic cell carcinoma', 'Disease', 'MESH:D006528', (98, 120))	('hepatic cell carcinoma', 'Phenotype', 'HP:0001402', (98, 120))
140584	25646071	Moreover, it has been shown that the hypermethylation of caspase 8 promoter is a common feature of relapsed glioblastoma multiforme.	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (108, 131))	('hypermethylation', 'Var', (37, 53))	('caspase 8', 'Gene', (57, 66))	('glioblastoma multiforme', 'Disease', (108, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))
140594	25646071	Further studies are recommended to explore whether cadmium can alter gene expression by inducing histone changes at a global or gene-specific level.	('cadmium', 'Var', (51, 58))	('histone changes', 'MPA', (97, 112))	('cadmium', 'Chemical', 'MESH:D002104', (51, 58))	('gene expression', 'biological_process', 'GO:0010467', ('69', '84'))	('gene expression', 'MPA', (69, 84))	('inducing', 'Reg', (88, 96))	('men', 'Species', '9606', (25, 28))
140597	25646071	Aberrant expression of miRNAs has been associated with several human disease states, including cancer, cardiovascular disease, and genetic disorders.	('Aberrant expression', 'Var', (0, 19))	('cardiovascular disease', 'Disease', (103, 125))	('human', 'Species', '9606', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('genetic disorders', 'Disease', (131, 148))	('miRNAs', 'Gene', (23, 29))	('cancer', 'Disease', (95, 101))	('genetic disorders', 'Disease', 'MESH:D030342', (131, 148))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (103, 125))	('associated', 'Reg', (39, 49))	('cardiovascular disease', 'Disease', 'MESH:D002318', (103, 125))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
140599	25646071	Cadmium has been shown to alter miRNA levels in vitro.	('Cadmium', 'Var', (0, 7))	('alter', 'Reg', (26, 31))	('Cadmium', 'Chemical', 'MESH:D002104', (0, 7))	('miRNA levels', 'MPA', (32, 44))
140605	25646071	Focal adhesion (hsa04510) and the MAPK signaling pathway (hsa04010) were the two top pathways in the analysis of enrichment in KEGG pathways of the downregulated miRNAs targets.	('MAPK', 'molecular_function', 'GO:0004707', ('34', '38'))	('hsa04010', 'Var', (58, 66))	('MAPK', 'Gene', '5595;5594;5595', (34, 38))	('hsa04510', 'Var', (16, 24))	('MAPK', 'Gene', (34, 38))	('MAPK signaling', 'biological_process', 'GO:0000165', ('34', '48'))	('Focal adhesion', 'cellular_component', 'GO:0005925', ('0', '14'))	('signaling pathway', 'biological_process', 'GO:0007165', ('39', '56'))	('men', 'Species', '9606', (119, 122))
140615	25646071	showed that cadmium reduced the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in human bronchial epithelial cells through upregulation of miR-101 and miR-144.	('CFTR', 'Gene', '1080', (103, 107))	('reduced', 'NegReg', (20, 27))	('cystic fibrosis transmembrane conductance regulator', 'molecular_function', 'GO:0005260', ('50', '101'))	('miR-101', 'Chemical', '-', (169, 176))	('miR-144', 'Gene', (181, 188))	('upregulation', 'PosReg', (153, 165))	('transmembrane', 'cellular_component', 'GO:0044214', ('66', '79'))	('miR-101', 'Var', (169, 176))	('CFTR', 'Gene', (103, 107))	('cadmium', 'Chemical', 'MESH:D002104', (12, 19))	('miR-144', 'Gene', '406936', (181, 188))	('transmembrane', 'cellular_component', 'GO:0016021', ('66', '79'))	('cystic fibrosis transmembrane conductance regulator', 'Gene', '1080', (50, 101))	('expression', 'MPA', (32, 42))	('human', 'Species', '9606', (112, 117))
140616	25646071	Notably, miR-101 might promote inflammation by downregulating the expression of MAPK phosphatase-1 (MKP-1).	('MKP-1', 'Gene', (100, 105))	('inflammation', 'Disease', (31, 43))	('phosphatase', 'molecular_function', 'GO:0016791', ('85', '96'))	('promote', 'PosReg', (23, 30))	('miR-101', 'Chemical', '-', (9, 16))	('MKP-1', 'Gene', '1843', (100, 105))	('MAPK phosphatase-1', 'Gene', '1843', (80, 98))	('MAPK', 'molecular_function', 'GO:0004707', ('80', '84'))	('expression', 'MPA', (66, 76))	('inflammation', 'biological_process', 'GO:0006954', ('31', '43'))	('miR-101', 'Var', (9, 16))	('downregulating', 'NegReg', (47, 61))	('MAPK phosphatase-1', 'Gene', (80, 98))	('inflammation', 'Disease', 'MESH:D007249', (31, 43))
140635	25646071	For example, a tendency towards disease progression is associated with MT overexpression in primary melanoma.	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('MT overexpression', 'Var', (71, 88))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))
140645	25646071	Interestingly, however, VM-forming tumour cells showed increased survival following cadmium exposure relative to other subpopulations in 3D cultures or cells cultured in 2D.	('increased', 'PosReg', (55, 64))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('cadmium', 'Var', (84, 91))	('survival', 'CPA', (65, 73))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('cadmium', 'Chemical', 'MESH:D002104', (84, 91))	('tumour', 'Disease', (35, 41))
140655	25646071	For example, as previously indicated, cadmium interferes with nucleotide excision repair by interfering with the removal of thymine dimers after UV irradiation.	('cadmium', 'Var', (38, 45))	('cadmium', 'Chemical', 'MESH:D002104', (38, 45))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('62', '88'))	('nucleotide excision repair', 'MPA', (62, 88))	('interferes', 'NegReg', (46, 56))	('interfering', 'NegReg', (92, 103))	('thymine', 'Chemical', 'MESH:D013941', (124, 131))	('removal of thymine dimers', 'MPA', (113, 138))
140660	25646071	Similarly, we could document that short-term cadmium exposure had a critical impact on the behavior of melanoma cells through epigenetic modifications of p16INK4A and caspase 8, resulting in their altered expression and in aberrant cell proliferation and apoptosis.	('cell proliferation', 'biological_process', 'GO:0008283', ('232', '250'))	('p16INK4A', 'Gene', (154, 162))	('p16INK4A', 'Gene', '1029', (154, 162))	('aberrant cell proliferation', 'Phenotype', 'HP:0031377', (223, 250))	('cell proliferation', 'CPA', (232, 250))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))	('epigenetic modifications', 'Var', (126, 150))	('altered', 'Reg', (197, 204))	('rat', 'Species', '10116', (244, 247))	('apoptosis', 'biological_process', 'GO:0097194', ('255', '264'))	('men', 'Species', '9606', (24, 27))	('apoptosis', 'biological_process', 'GO:0006915', ('255', '264'))	('expression', 'MPA', (205, 215))	('caspase 8', 'Gene', (167, 176))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('cadmium', 'Chemical', 'MESH:D002104', (45, 52))	('impact', 'Reg', (77, 83))	('apoptosis', 'CPA', (255, 264))
140662	25646071	In skin melanoma the extrinsic pathway of apoptosis was affected and caspase 8 hypermethylation and inactivation was indicated as the main pathogenic mechanism.	('caspase 8', 'Protein', (69, 78))	('extrinsic pathway of apoptosis', 'Pathway', (21, 51))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('hypermethylation', 'Var', (79, 95))	('skin melanoma', 'Disease', 'MESH:D008545', (3, 16))	('skin melanoma', 'Disease', (3, 16))	('apoptosis', 'biological_process', 'GO:0097194', ('42', '51'))	('apoptosis', 'biological_process', 'GO:0006915', ('42', '51'))	('affected', 'Reg', (56, 64))	('inactivation', 'MPA', (100, 112))
140663	25646071	In uveal melanoma, instead, p16INK4A aberrant methylation and silencing was called as the determinant cause.	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('uveal melanoma', 'Disease', (3, 17))	('p16INK4A', 'Gene', '1029', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('aberrant methylation', 'Var', (37, 57))	('silencing', 'MPA', (62, 71))	('p16INK4A', 'Gene', (28, 36))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))
140666	25646071	Our results show that cadmium-treated uveal melanoma cell lines have >80% methylated clones (i.e., severe hypermethylation and complete methylation) in the p16 INK4A promoter versus >60% unmethylated clones (i.e., severe hypomethylation and complete unmethylation) in the same gene region of the corresponding untreated cells.	('uveal melanoma', 'Disease', (38, 52))	('p16 INK4A', 'Gene', (156, 165))	('severe hypermethylation', 'Var', (99, 122))	('cadmium', 'Chemical', 'MESH:D002104', (22, 29))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('methylation', 'biological_process', 'GO:0032259', ('136', '147'))	('p16 INK4A', 'Gene', '1029', (156, 165))	('uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('uveal melanoma', 'Disease', 'MESH:C536494', (38, 52))	('methylation', 'MPA', (136, 147))	('methylated', 'Var', (74, 84))
140668	25646071	Integrative analysis of DNA methylation and RNA expression data revealed a positive association between DNA methylation and transcript expression of p16INK4A and caspase 8 either before or after treatment with cadmium.	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('cadmium', 'Chemical', 'MESH:D002104', (210, 217))	('caspase 8', 'Gene', (162, 171))	('positive', 'PosReg', (75, 83))	('p16INK4A', 'Gene', '1029', (149, 157))	('transcript expression', 'MPA', (124, 145))	('RNA', 'cellular_component', 'GO:0005562', ('44', '47'))	('rat', 'Species', '10116', (5, 8))	('men', 'Species', '9606', (200, 203))	('DNA methylation', 'biological_process', 'GO:0006306', ('24', '39'))	('methylation', 'Var', (108, 119))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('DNA methylation', 'biological_process', 'GO:0006306', ('104', '119'))	('p16INK4A', 'Gene', (149, 157))
140672	25646071	The silencing of p16INK4A and caspase 8 by cadmium in melanoma cells is of particular importance in light of the negligible role played by constitutional epimutations of CDKN2A (p16INK4A and p14ARF) genes in melanoma families, whereby it was concluded that it is unlikely that they play a role in susceptibility to the disease in families without CDKN2A mutations.	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma', 'Disease', (208, 216))	('p16INK4A', 'Gene', (17, 25))	('silencing', 'NegReg', (4, 13))	('cadmium', 'Chemical', 'MESH:D002104', (43, 50))	('p16INK4A', 'Gene', '1029', (17, 25))	('CDKN2A', 'Gene', (170, 176))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('CDKN2A', 'Gene', '1029', (170, 176))	('p14ARF', 'Gene', '1029', (191, 197))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('CDKN2A', 'Gene', (347, 353))	('caspase', 'Enzyme', (30, 37))	('epimutations', 'Var', (154, 166))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('p16INK4A', 'Gene', (178, 186))	('p16INK4A', 'Gene', '1029', (178, 186))	('CDKN2A', 'Gene', '1029', (347, 353))	('p14ARF', 'Gene', (191, 197))
140675	25646071	These data confirm the ones presented in this study, and highlight a crucial role of the environment in inducing epigenetic changes in a key gene in melanoma development, such as p16INK4A, in absence of inherited mutations.	('men', 'Species', '9606', (165, 168))	('men', 'Species', '9606', (96, 99))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('epigenetic changes', 'Var', (113, 131))	('inducing', 'Reg', (104, 112))	('p16INK4A', 'Gene', (179, 187))	('p16INK4A', 'Gene', '1029', (179, 187))
140677	25646071	Notably, p16INK4A methylation well correlated with increased melanoma thickness and marginally with increased Clark level.	('p16INK4A', 'Gene', '1029', (9, 17))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('methylation', 'Var', (18, 29))	('increased melanoma thickness', 'Disease', 'MESH:D008545', (51, 79))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('increased melanoma thickness', 'Disease', (51, 79))	('p16INK4A', 'Gene', (9, 17))
140682	25646071	Several studies have demonstrated that expression of caspase 8 may be controlled by epigenetic modifications, which differ according to the type of cancer cells.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('controlled', 'Reg', (70, 80))	('expression', 'MPA', (39, 49))	('epigenetic modifications', 'Var', (84, 108))	('rat', 'Species', '10116', (28, 31))	('caspase', 'Protein', (53, 60))
140683	25646071	However, although an association between aberrant DNA methylation of caspase 8 and carcinogenesis has been demonstrated in several studies, the functional relevance of this epigenetic trait in melanomagenesis has not yet been fully understood.	('rat', 'Species', '10116', (114, 117))	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('melanoma', 'Disease', (193, 201))	('carcinogenesis', 'Disease', 'MESH:D063646', (83, 97))	('DNA methylation', 'biological_process', 'GO:0006306', ('50', '65'))	('caspase', 'Protein', (69, 76))	('aberrant DNA methylation', 'Var', (41, 65))	('carcinogenesis', 'Disease', (83, 97))
140684	25646071	Our findings, showing for the first time that caspase 8 expression is impaired by DNA hypermethylation following cadmium treatment in cutaneous melanoma cell lines, highlight the potential relevance of such a mechanism in the context of this tumor and extend earlier in vitro and in vivo observations linking exposure to cadmium with decreased expression of caspase 8 in tumours different from melanoma.	('tumour', 'Phenotype', 'HP:0002664', (371, 377))	('expression', 'MPA', (344, 354))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('tumor', 'Disease', (242, 247))	('melanoma', 'Disease', (144, 152))	('cutaneous melanoma', 'Disease', (134, 152))	('cadmium', 'Chemical', 'MESH:D002104', (113, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (134, 152))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (134, 152))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('82', '102'))	('melanoma', 'Disease', 'MESH:D008545', (394, 402))	('hypermethylation', 'Var', (86, 102))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('expression', 'MPA', (56, 66))	('caspase', 'Protein', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumours', 'Disease', (371, 378))	('melanoma', 'Phenotype', 'HP:0002861', (394, 402))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('melanoma', 'Disease', (394, 402))	('men', 'Species', '9606', (126, 129))	('tumours', 'Phenotype', 'HP:0002664', (371, 378))	('tumours', 'Disease', 'MESH:D009369', (371, 378))	('cadmium', 'Chemical', 'MESH:D002104', (321, 328))	('impaired', 'NegReg', (70, 78))
140686	25646071	Based on evidence that both the programmed re-expression of caspase 8 by demethylation and caspase 8 gene transfer can sensitize tumour cell lines for drug-induced apoptosis, it is possible to hypothesize that this pollutant may prevent drug-induced apoptosis and interfere with therapeutic strategies targeting cutaneous melanoma.	('caspase', 'Gene', (91, 98))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (312, 330))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (312, 330))	('apoptosis', 'biological_process', 'GO:0097194', ('250', '259'))	('rat', 'Species', '10116', (293, 296))	('prevent', 'NegReg', (229, 236))	('apoptosis', 'biological_process', 'GO:0006915', ('250', '259'))	('drug-induced apoptosis', 'CPA', (237, 259))	('gene transfer', 'Var', (101, 114))	('demethylation', 'biological_process', 'GO:0070988', ('73', '86'))	('apoptosis', 'biological_process', 'GO:0097194', ('164', '173'))	('apoptosis', 'biological_process', 'GO:0006915', ('164', '173'))	('caspase 8', 'Gene', (60, 69))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('melanoma', 'Phenotype', 'HP:0002861', (322, 330))	('tumour', 'Disease', (129, 135))	('sensitize', 'Reg', (119, 128))	('interfere', 'NegReg', (264, 273))	('demethylation', 'Var', (73, 86))	('cutaneous melanoma', 'Disease', (312, 330))
140687	25646071	Therefore, these findings may be of interest because they: i) highlight the crucial role of acute cadmium exposure in silencing key genes involved in the control of cell cycle and apoptosis in melanoma; ii) discriminate between cutaneous and uveal melanoma on the basis of the genes epigenetically modified by cadmium; iii) indicate cadmium pollution as one of the potential causes of inactivation of p16INK4A, a previously recognized biomarker of malignant melanoma; iv) show for the first time the significance of caspase 8 methylation and silencing in cutaneous melanoma and the role of cadmium in this effect.	('melanoma', 'Disease', (248, 256))	('melanoma', 'Phenotype', 'HP:0002861', (565, 573))	('melanoma', 'Disease', (565, 573))	('uveal melanoma', 'Disease', 'MESH:C536494', (242, 256))	('cell cycle', 'biological_process', 'GO:0007049', ('165', '175'))	('uveal melanoma', 'Disease', (242, 256))	('cutaneous melanoma', 'Disease', (555, 573))	('melanoma', 'Disease', 'MESH:D008545', (458, 466))	('cadmium', 'Chemical', 'MESH:D002104', (98, 105))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (555, 573))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (555, 573))	('cadmium', 'Chemical', 'MESH:D002104', (590, 597))	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('apoptosis', 'biological_process', 'GO:0097194', ('180', '189'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (242, 256))	('apoptosis', 'biological_process', 'GO:0006915', ('180', '189'))	('caspase', 'Protein', (516, 523))	('silencing', 'MPA', (542, 551))	('cadmium', 'Chemical', 'MESH:D002104', (333, 340))	('melanoma', 'Disease', 'MESH:D008545', (248, 256))	('melanoma', 'Phenotype', 'HP:0002861', (248, 256))	('malignant melanoma', 'Disease', (448, 466))	('melanoma', 'Disease', 'MESH:D008545', (565, 573))	('melanoma', 'Phenotype', 'HP:0002861', (458, 466))	('melanoma', 'Disease', (458, 466))	('methylation', 'Var', (526, 537))	('cadmium', 'Chemical', 'MESH:D002104', (310, 317))	('methylation', 'biological_process', 'GO:0032259', ('526', '537'))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('melanoma', 'Disease', (193, 201))	('p16INK4A', 'Gene', (401, 409))	('p16INK4A', 'Gene', '1029', (401, 409))	('malignant melanoma', 'Phenotype', 'HP:0002861', (448, 466))	('malignant melanoma', 'Disease', 'MESH:D008545', (448, 466))
140688	25646071	In conclusion, our data suggest that aberrant DNA methylation of p16INK4A and caspase 8 gene promoters is associated with single-phenotype defects in melanoma cells after acute exposure to low non cytotoxic doses of cadmium.	('DNA methylation', 'MPA', (46, 61))	('cadmium', 'Chemical', 'MESH:D002104', (216, 223))	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('associated', 'Reg', (106, 116))	('caspase 8', 'Gene', (78, 87))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('p16INK4A', 'Gene', (65, 73))	('melanoma', 'Disease', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('DNA methylation', 'biological_process', 'GO:0006306', ('46', '61'))	('aberrant', 'Var', (37, 45))	('p16INK4A', 'Gene', '1029', (65, 73))
140689	25646071	Further studies are warranted to address the role of epigenetic mechanisms induced by environmental pollutants in worsening the melanoma progression.	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('epigenetic', 'Var', (53, 63))	('worsening', 'PosReg', (114, 123))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
140694	25646071	Relying on available evidence, cadmium apparently has little direct genotoxic activity and acts apparently through various indirect mechanisms, including ROS generation, DNA repair inhibition, impairment of the cellular antioxidant defence system, interference with signal transduction, and possibly the disruption of cell-cell adhesion with the consequent initiation of cancer.	('DNA repair', 'biological_process', 'GO:0006281', ('170', '180'))	('inhibition', 'NegReg', (181, 191))	('cadmium', 'Var', (31, 38))	('DNA repair', 'MPA', (170, 180))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('318', '336'))	('ROS generation', 'MPA', (154, 168))	('impairment', 'NegReg', (193, 203))	('interference', 'NegReg', (248, 260))	('signal transduction', 'biological_process', 'GO:0007165', ('266', '285'))	('men', 'Species', '9606', (199, 202))	('cadmium', 'Chemical', 'MESH:D002104', (31, 38))	('signal transduction', 'MPA', (266, 285))	('ROS generation', 'biological_process', 'GO:1903409', ('154', '168'))	('initiation of cancer', 'Disease', 'MESH:D009369', (357, 377))	('ROS', 'Chemical', 'MESH:D017382', (154, 157))	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))	('cancer', 'Phenotype', 'HP:0002664', (371, 377))	('rat', 'Species', '10116', (162, 165))	('initiation of cancer', 'Disease', (357, 377))	('cellular antioxidant defence system', 'MPA', (211, 246))
140698	25646071	Moreover, they highlight the role of epigenetics in melanoma progression following exposure to cadmium.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('cadmium', 'Chemical', 'MESH:D002104', (95, 102))	('epigenetics', 'Var', (37, 48))
140699	25646071	It is speculated that in cutaneous melanoma cadmium affects the extrinsic apoptotic pathway, that is prevalent in this kind of tumor, through methylation and inactivation of caspase 8, while in uveal melanoma the metal alters the cell cycle through methylation and silencing of p16INK4A.	('cutaneous melanoma', 'Disease', (25, 43))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (25, 43))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (25, 43))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('alters', 'Reg', (219, 225))	('uveal melanoma', 'Disease', (194, 208))	('uveal melanoma', 'Disease', 'MESH:C536494', (194, 208))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('metal', 'Chemical', 'MESH:D008670', (213, 218))	('uveal melanoma', 'Phenotype', 'HP:0007716', (194, 208))	('p16INK4A', 'Gene', (278, 286))	('affects', 'Reg', (52, 59))	('silencing', 'NegReg', (265, 274))	('p16INK4A', 'Gene', '1029', (278, 286))	('methylation', 'biological_process', 'GO:0032259', ('142', '153'))	('cell cycle', 'CPA', (230, 240))	('extrinsic apoptotic pathway', 'Pathway', (64, 91))	('cell cycle', 'biological_process', 'GO:0007049', ('230', '240'))	('caspase 8', 'Protein', (174, 183))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('methylation', 'biological_process', 'GO:0032259', ('249', '260'))	('methylation', 'Var', (249, 260))	('inactivation', 'NegReg', (158, 170))	('extrinsic apoptotic pathway', 'biological_process', 'GO:0097191', ('64', '91'))	('tumor', 'Disease', (127, 132))	('methylation', 'MPA', (142, 153))	('cadmium', 'Chemical', 'MESH:D002104', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
140700	25646071	It's possible that in a near future well characterized epigenetic modifications will aid in the molecular diagnosis and treatment of a variety of cancers and other disorders induced by cadmium.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cadmium', 'Chemical', 'MESH:D002104', (185, 192))	('men', 'Species', '9606', (125, 128))	('induced', 'Reg', (174, 181))	('epigenetic modifications', 'Var', (55, 79))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('aid', 'Reg', (85, 88))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
140764	23724856	demonstrated elevated CXCL11, CCL19, IL-18, and IL-23, as well as high IL-17, in granulomatous infiltrates of sympathetic ophthalmia, and increased IFN-gamma and CCL17 levels in non-granulomatous inflammatory infiltrates.	('IL-17', 'molecular_function', 'GO:0030367', ('71', '76'))	('IL-17', 'Gene', (71, 76))	('IL-17', 'Gene', '3605', (71, 76))	('CCL', 'molecular_function', 'GO:0044101', ('30', '33'))	('CCL', 'molecular_function', 'GO:0044101', ('162', '165'))	('IL-23', 'molecular_function', 'GO:0045519', ('48', '53'))	('increased', 'PosReg', (138, 147))	('CCL17', 'Gene', (162, 167))	('granulomatous infiltrates of sympathetic ophthalmia', 'Disease', 'MESH:D009879', (81, 132))	('IFN-gamma', 'Gene', '3458', (148, 157))	('IFN-gamma', 'Gene', (148, 157))	('IL-18', 'Gene', (37, 42))	('CCL19', 'Gene', '6363', (30, 35))	('IL-23', 'Gene', '51561', (48, 53))	('IL-23', 'Gene', (48, 53))	('IL-18', 'molecular_function', 'GO:0045515', ('37', '42'))	('CXCL11', 'Gene', (22, 28))	('CXCL11', 'Gene', '6373', (22, 28))	('IL-18', 'Gene', '3606', (37, 42))	('CCL19', 'Gene', (30, 35))	('elevated', 'PosReg', (13, 21))	('high', 'Var', (66, 70))	('CCL17', 'Gene', '6361', (162, 167))
140767	23724856	The report suggests that HIV-mediated CD4+ T cell deficiency impairs inflammatory response, halting development of sympathetic ophthalmia, an effect that is reversed by antiretroviral therapy.	('HIV', 'Disease', 'MESH:D015658', (25, 28))	('CD4', 'Gene', (38, 41))	('inflammatory response', 'CPA', (69, 90))	('impairs', 'NegReg', (61, 68))	('T cell deficiency', 'Phenotype', 'HP:0005403', (43, 60))	('CD4', 'Gene', '920', (38, 41))	('inflammatory response', 'biological_process', 'GO:0006954', ('69', '90'))	('halting', 'NegReg', (92, 99))	('sympathetic ophthalmia', 'Disease', (115, 137))	('sympathetic ophthalmia', 'Disease', 'MESH:D009879', (115, 137))	('HIV', 'Disease', (25, 28))	('CD4+ T cell deficiency', 'Phenotype', 'HP:0005407', (38, 60))	('T cell deficiency impairs', 'Phenotype', 'HP:0005435', (43, 68))	('deficiency', 'Var', (50, 60))
140794	23724856	The use of laser cyclodestructive procedures for the treatment of glaucoma, particularly neodymium:YAG cyclodestruction has also been reported to cause sympathetic ophthalmia.	('glaucoma', 'Phenotype', 'HP:0000501', (66, 74))	('glaucoma', 'Disease', (66, 74))	('cyclodestruction', 'Var', (103, 119))	('sympathetic ophthalmia', 'Disease', 'MESH:D009879', (152, 174))	('glaucoma', 'Disease', 'MESH:D005901', (66, 74))	('sympathetic ophthalmia', 'Disease', (152, 174))	('cause', 'Reg', (146, 151))
140824	23724856	Elevated CXCL11, CCL19, IL-18, and IL-23, and high IL-17 in sympathetic ophthalmia suggest targeting M1 macrophages and their cytokines and chemokines, Th17, or Th1 lymphocytes.	('IL-18', 'Gene', (24, 29))	('Th1', 'Gene', '51497', (152, 155))	('CCL19', 'Gene', '6363', (17, 22))	('IL-23', 'molecular_function', 'GO:0045519', ('35', '40'))	('Elevated', 'PosReg', (0, 8))	('CXCL11', 'Gene', (9, 15))	('high', 'Var', (46, 50))	('CXCL11', 'Gene', '6373', (9, 15))	('IL-18', 'molecular_function', 'GO:0045515', ('24', '29'))	('CCL', 'molecular_function', 'GO:0044101', ('17', '20'))	('CCL19', 'Gene', (17, 22))	('IL-23', 'Gene', '51561', (35, 40))	('IL-18', 'Gene', '3606', (24, 29))	('IL-23', 'Gene', (35, 40))	('sympathetic ophthalmia', 'Disease', 'MESH:D009879', (60, 82))	('sympathetic ophthalmia', 'Disease', (60, 82))	('Th1', 'Gene', (161, 164))	('IL-17', 'Gene', (51, 56))	('IL-17', 'Gene', '3605', (51, 56))	('Th1', 'Gene', (152, 155))	('Th1', 'Gene', '51497', (161, 164))	('IL-17', 'molecular_function', 'GO:0030367', ('51', '56'))
140830	23724856	found an association between cytokine gene polymorphisms and the severity of sympathetic ophthalmia, specifically that the IL-10 1082 SNP was associated with disease recurrence and level of steroid treatment required for management and that the GCC IL-10 promoter haplotype was protective against disease recurrence.	('IL-10', 'Gene', (249, 254))	('IL-10', 'Gene', '3586', (123, 128))	('IL-10', 'molecular_function', 'GO:0005141', ('249', '254'))	('1082 SNP', 'Var', (129, 137))	('associated with', 'Reg', (142, 157))	('IL-10', 'Gene', '3586', (249, 254))	('IL-10', 'Gene', (123, 128))	('disease', 'Disease', (158, 165))	('sympathetic ophthalmia', 'Disease', 'MESH:D009879', (77, 99))	('association', 'Interaction', (9, 20))	('steroid', 'Chemical', 'MESH:D013256', (190, 197))	('IL-10', 'molecular_function', 'GO:0005141', ('123', '128'))	('sympathetic ophthalmia', 'Disease', (77, 99))
140834	23555837	Genetic Interactions between Neurofibromin and Endothelin Receptor B in Mice When mutations in two different genes produce the same mutant phenotype, it suggests that the encoded proteins either interact with each other, or act in parallel to fulfill a similar purpose.	('interact', 'Interaction', (195, 203))	('Neurofibromin', 'Gene', (29, 42))	('Interactions', 'Interaction', (8, 20))	('Neurofibromin', 'Gene', '18015', (29, 42))	('Endothelin Receptor B', 'Gene', '1910', (47, 68))	('Endothelin Receptor B', 'Gene', (47, 68))	('mutations', 'Var', (82, 91))
140841	23555837	We also found an oncogenic mutation in the G protein alpha subunit, GNAQ, which couples to Endothelin receptor B, in a uveal melanoma from a patient with neurofibromatosis type 1.	('neurofibromatosis type 1', 'Gene', '4763', (154, 178))	('neurofibromatosis type 1', 'Gene', (154, 178))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('GNAQ', 'Gene', (68, 72))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('patient', 'Species', '9606', (141, 148))	('mutation', 'Var', (27, 35))	('GNAQ', 'Chemical', '-', (68, 72))	('uveal melanoma', 'Disease', 'MESH:C536494', (119, 133))	('Endothelin receptor B', 'Gene', '1910', (91, 112))	('Endothelin receptor B', 'Gene', (91, 112))	('uveal melanoma', 'Phenotype', 'HP:0007716', (119, 133))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (154, 171))	('uveal melanoma', 'Disease', (119, 133))
140851	23555837	Second, there are no white coat patches when Ednrb knockout occurs after E12.5, when melanoblasts, immature melanocytes, first migrate into the epidermis.	('white coat patches', 'Phenotype', 'HP:0002290', (21, 39))	('knockout', 'Var', (51, 59))	('Ednrb', 'Chemical', '-', (45, 50))	('Ednrb', 'Gene', (45, 50))
140854	23555837	In humans, inherited heterozygous mutations in NF1 cause neurofibromatosis type 1, which is characterized by skin hyper-pigmentation and Schwann cell based tumors.	('neurofibromatosis type 1', 'Gene', '4763', (57, 81))	('neurofibromatosis type 1', 'Gene', (57, 81))	('heterozygous mutations', 'Var', (21, 43))	('skin hyper-pigmentation', 'Phenotype', 'HP:0000953', (109, 132))	('hyper-pigmentation', 'Phenotype', 'HP:0000953', (114, 132))	('NF1', 'Gene', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('pigmentation', 'biological_process', 'GO:0043473', ('120', '132'))	('skin hyper-pigmentation', 'Disease', (109, 132))	('humans', 'Species', '9606', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('cause', 'Reg', (51, 56))	('skin hyper-pigmentation', 'Disease', 'MESH:D010859', (109, 132))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('skin hyper-', 'Phenotype', 'HP:0000974', (109, 120))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (57, 74))	('tumors', 'Disease', (156, 162))
140856	23555837	Nf1 mutant mice exhibit a darker dermis and epidermis.	('mutant', 'Var', (4, 10))	('Nf1', 'Gene', (0, 3))	('mice', 'Species', '10090', (11, 15))	('Nf1', 'Gene', '18015', (0, 3))	('darker dermis', 'Phenotype', 'HP:0000953', (26, 39))	('darker', 'PosReg', (26, 32))
140863	23555837	To be able to use this allele in our crosses, we needed to determine the location of the Ednrbs-l deletion breakpoints, in order to verify that no other genes are included in the deletion and to permit genotyping by PCR (polymerase chain reaction).	('Ednrbs-l', 'Gene', (89, 97))	('Ednrbs', 'Chemical', '-', (89, 95))	('deletion', 'Var', (98, 106))
140868	23555837	The Ednrbs-l deletion encompasses 97,637 base pairs of chromosome 14 (Figure 1a).	('deletion', 'Var', (13, 21))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))	('Ednrbs', 'Chemical', '-', (4, 10))	('Ednrbs-l', 'Gene', (4, 12))
140871	23555837	The Dsk9 mutation is a missense in the GTPase accelerating protein related domain (GRD) of neurofibromin.	('mutation', 'Var', (9, 17))	('neurofibromin', 'Gene', (91, 104))	('GRD', 'Disease', 'MESH:D006111', (83, 86))	('accelerating', 'PosReg', (46, 58))	('neurofibromin', 'Gene', '18015', (91, 104))	('GRD', 'Disease', (83, 86))	('Dsk9', 'Gene', (4, 8))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
140875	23555837	The mean pixel intensity of +/+; Nf1Dsk9/+ dermis is greater than +/+; +/+ dermis and Ednrbs-l/+; +/+ dermis (Figure 2a-b, p = 0.0328 and p = 0.00748, respectively, student's ttest), while the mean pixel intensity of Ednrbs-l/+; Nf1Dsk9/+ dermis is not significantly different than +/+; +/+.	('Nf1', 'Gene', '18015', (229, 232))	('pixel intensity', 'MPA', (9, 24))	('+/+', 'Var', (28, 31))	('Nf1', 'Gene', '18015', (33, 36))	('Ednrbs', 'Chemical', '-', (217, 223))	('greater', 'PosReg', (53, 60))	('Ednrbs', 'Chemical', '-', (86, 92))	('Nf1', 'Gene', (229, 232))	('Nf1', 'Gene', (33, 36))
140881	23555837	Spots of coat pigmentation in both Ednrbs-l/Ednrbs-l; Nf1Dsk9/+ and Ednrbs-l/Ednrbs-l; +/+ mice were restricted to the head and rump regions.	('mice', 'Species', '10090', (91, 95))	('Ednrbs', 'Chemical', '-', (77, 83))	('Ednrbs', 'Chemical', '-', (44, 50))	('Nf1', 'Gene', '18015', (54, 57))	('coat pigmentation', 'Disease', 'MESH:D058456', (9, 26))	('Ednrbs', 'Chemical', '-', (68, 74))	('coat pigmentation', 'Disease', (9, 26))	('Ednrbs', 'Chemical', '-', (35, 41))	('Ednrbs-l/Ednrbs-l', 'Var', (35, 52))	('Nf1', 'Gene', (54, 57))	('pigmentation', 'biological_process', 'GO:0043473', ('14', '26'))
140884	23555837	In addition, constitutively active, oncogenic mutations in either GNAQ or GNA11 are found in ~75% of common nevi of the dermis and in ~83% of uveal melanomas.	('GNA11', 'Gene', (74, 79))	('mutations', 'Var', (46, 55))	('uveal melanomas', 'Disease', 'MESH:C536494', (142, 157))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('nevi', 'Phenotype', 'HP:0003764', (108, 112))	('found', 'Reg', (84, 89))	('GNAQ', 'Chemical', '-', (66, 70))	('uveal melanoma', 'Phenotype', 'HP:0007716', (142, 156))	('uveal melanomas', 'Disease', (142, 157))	('common nevi of the dermis', 'Disease', (101, 126))	('uveal melanomas', 'Phenotype', 'HP:0007716', (142, 157))	('GNAQ', 'Gene', (66, 70))	('melanomas', 'Phenotype', 'HP:0002861', (148, 157))
140885	23555837	Furthermore, constitutively active mutations in GNAQ/GNA11 and loss of function mutations in NF1 both lead to hyper-active MAP kinase signaling.	('hyper-active', 'Phenotype', 'HP:0000752', (110, 122))	('mutations', 'Var', (80, 89))	('hyper-active MAP', 'Disease', (110, 126))	('hyper-active MAP', 'Disease', 'OMIM:612348', (110, 126))	('GNAQ', 'Chemical', '-', (48, 52))	('signaling', 'biological_process', 'GO:0023052', ('134', '143'))	('GNAQ/GNA11', 'Gene', (48, 58))	('loss of function', 'NegReg', (63, 79))	('mutations', 'Var', (35, 44))	('MAP', 'molecular_function', 'GO:0004239', ('123', '126'))	('NF1', 'Gene', (93, 96))
140886	23555837	To examine whether oncogenic GNAQ or GNA11 mutations are required in uveal melanomas bearing NF1 mutations, we examined a uveal melanoma tumor from a patient with neurofibromatosis type 1, which is known to be caused by inherited heterozygous mutations in NF1 .	('mutations', 'Var', (97, 106))	('uveal melanomas', 'Disease', 'MESH:C536494', (69, 84))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('neurofibromatosis type 1', 'Gene', (163, 187))	('patient', 'Species', '9606', (150, 157))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('uveal melanomas', 'Disease', (69, 84))	('uveal melanomas', 'Phenotype', 'HP:0007716', (69, 84))	('uveal melanoma', 'Phenotype', 'HP:0007716', (122, 136))	('uveal melanoma tumor', 'Disease', (122, 142))	('NF1', 'Gene', (93, 96))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (163, 180))	('neurofibromatosis type 1', 'Gene', '4763', (163, 187))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('NF1', 'Gene', (256, 259))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('GNAQ', 'Chemical', '-', (29, 33))	('uveal melanoma tumor', 'Disease', 'MESH:C536494', (122, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
140890	23555837	We found that this tumor bears a somatic glutamine 209 to proline substitution in GNAQ (GNAQQ209P), which is known to cause constitutive activity (Figure 3a-b).	('GNAQ', 'Chemical', '-', (82, 86))	('glutamine 209 to proline', 'Mutation', 'rs1057519742', (41, 65))	('constitutive', 'MPA', (124, 136))	('GNAQ', 'Gene', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('GNAQQ209P', 'Mutation', 'rs121913492', (88, 97))	('tumor', 'Disease', (19, 24))	('glutamine 209 to proline', 'Var', (41, 65))	('GNAQ', 'Chemical', '-', (88, 92))	('cause', 'Reg', (118, 123))
140892	23555837	We have studied the genetic interactions between Ednrb and Nf1 in pigmentation, examining the result of bringing loss of function mutations in Ednrb and Nf1 together in mice.	('Ednrb', 'Chemical', '-', (143, 148))	('Nf1', 'Gene', '18015', (153, 156))	('Ednrb', 'Gene', (143, 148))	('Nf1', 'Gene', (59, 62))	('Ednrb', 'Chemical', '-', (49, 54))	('pigmentation', 'biological_process', 'GO:0043473', ('66', '78'))	('mutations', 'Var', (130, 139))	('mice', 'Species', '10090', (169, 173))	('Nf1', 'Gene', '18015', (59, 62))	('Nf1', 'Gene', (153, 156))	('loss of function', 'NegReg', (113, 129))
140895	23555837	Since the dermis of Ednrbs-l/Ednrbs-l mice is completely albino, this suggests that endothelin signaling is required prior to or in parallel with Nf1 to support melanoblast formation/survival/proliferation in the dermis during development.	('support', 'PosReg', (153, 160))	('mice', 'Species', '10090', (38, 42))	('Ednrbs', 'Chemical', '-', (20, 26))	('Ednrbs-l/Ednrbs-l', 'Var', (20, 37))	('melanoblast formation/survival/proliferation', 'CPA', (161, 205))	('signaling', 'biological_process', 'GO:0023052', ('95', '104'))	('formation', 'biological_process', 'GO:0009058', ('173', '182'))	('Nf1', 'Gene', (146, 149))	('Ednrbs', 'Chemical', '-', (29, 35))	('Nf1', 'Gene', '18015', (146, 149))
140898	23555837	This is supported by the finding of a constitutively active GNAQ mutation in an NF1+/- uveal melanoma, which otherwise might be redundant, if EDNRB/GNAQ signaling completely overlapped with NF1.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('signaling', 'biological_process', 'GO:0023052', ('153', '162'))	('GNAQ', 'Gene', (60, 64))	('uveal melanoma', 'Disease', (87, 101))	('NF1+/-', 'Gene', (80, 86))	('GNAQ', 'Chemical', '-', (148, 152))	('mutation', 'Var', (65, 73))	('GNAQ', 'Chemical', '-', (60, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (87, 101))	('uveal melanoma', 'Disease', 'MESH:C536494', (87, 101))
140901	23555837	During embryogenesis, Ednrbs-l/Ednrbs-l embryos exhibit greatly reduced numbers of melanoblasts, at or before embryonic day (E) 10.5.	('Ednrbs', 'Chemical', '-', (22, 28))	('embryogenesis', 'biological_process', 'GO:0009792', ('7', '20'))	('Ednrbs-l/Ednrbs-l', 'Var', (22, 39))	('embryogenesis', 'biological_process', 'GO:0009793', ('7', '20'))	('Ednrbs', 'Chemical', '-', (31, 37))	('reduced', 'NegReg', (64, 71))	('embryogenesis', 'biological_process', 'GO:0009790', ('7', '20'))
140905	23555837	Newly formed melanoblasts located close to cranial nerves exhibit a greater reduction in number in Ednrbtm1Nrd/Ednrbtm1Nrd embryos compared to the other melanoblasts in the head, suggesting that the non-Schwann cell derived melanocytes have a reduced requirement for Ednrb.	('Nrd', 'biological_process', 'GO:0070651', ('119', '122'))	('Ednrb', 'Chemical', '-', (99, 104))	('reduction', 'NegReg', (76, 85))	('Ednrbtm1Nrd/Ednrbtm1Nrd', 'Var', (99, 122))	('number', 'CPA', (89, 95))	('Ednrb', 'Chemical', '-', (111, 116))	('close to cranial nerves', 'Phenotype', 'HP:0001291', (34, 57))	('Nrd', 'biological_process', 'GO:0070651', ('107', '110'))	('Ednrb', 'Chemical', '-', (267, 272))
140910	23555837	If one copy of Nf1 is lost, more melanoblasts are produced from Schwann cell precursors, which darkens the dermis.	('darkens the dermis', 'Phenotype', 'HP:0000953', (95, 113))	('Nf1', 'Gene', '18015', (15, 18))	('lost', 'Var', (22, 26))	('darkens', 'NegReg', (95, 102))	('more', 'PosReg', (28, 32))	('Nf1', 'Gene', (15, 18))
140937	23087781	Also, mice treated with repeated intravenous injections of taxol-loaded nanoparticles showed a substantial accumulation of nanoparticles in B16F10 murine melanoma tissues, significant tumor regression and higher survival rates than mice treated with free taxol.	('taxol', 'Chemical', 'MESH:D017239', (59, 64))	('taxol', 'Chemical', 'MESH:D017239', (255, 260))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('higher', 'PosReg', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('melanoma tissues', 'Disease', 'MESH:D008545', (154, 170))	('mice', 'Species', '10090', (6, 10))	('accumulation', 'PosReg', (107, 119))	('tumor', 'Disease', (184, 189))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('nanoparticles', 'Var', (123, 136))	('melanoma tissues', 'Disease', (154, 170))	('murine', 'Species', '10090', (147, 153))	('survival rates', 'CPA', (212, 226))	('mice', 'Species', '10090', (232, 236))
140939	23087781	Our recent work assessed the in vivo tissue compatibility of hydrogels and found that poly(N-isopropylacrylamide) (PNIPAM) nanoparticles elicited the least inflammatory response when compared to FDA approved Poly-L-Lactic acid (PLA) and poly-L-glycolic acid (PLGA) particles.	('inflammatory response', 'CPA', (156, 177))	('poly', 'Var', (86, 90))	('least', 'NegReg', (150, 155))	('poly(N-isopropylacrylamide)', 'Chemical', 'MESH:C052970', (86, 113))	('PNIPAM', 'Chemical', 'MESH:C052970', (115, 121))	('poly-L-glycolic acid', 'Chemical', '-', (237, 257))	('Poly-L-Lactic acid', 'Chemical', 'MESH:C033616', (208, 226))	('elicited', 'Reg', (137, 145))	('inflammatory response', 'biological_process', 'GO:0006954', ('156', '177'))
140953	23087781	In our earlier study we had determined that NIPAM nanoparticles elicited the weakest foreign body reaction as compared to the commonly used polymers like PLLA and polystyrene.	('foreign body reaction', 'CPA', (85, 106))	('polymers', 'Chemical', 'MESH:D011108', (140, 148))	('PLLA', 'Chemical', 'MESH:C033616', (154, 158))	('polystyrene', 'Chemical', 'MESH:D011137', (163, 174))	('nanoparticles', 'Var', (50, 63))	('weakest', 'NegReg', (77, 84))	('NIPAM', 'Var', (44, 49))	('NIPAM', 'Chemical', '-', (44, 49))	('elicited', 'Reg', (64, 72))
140973	23087781	To summarize, both micro- and nano- particles circulate in the blood, however, nanoparticles can escape through the uveal and leaky tumor vasculature in to the uveal and melanoma tissue.	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('leaky tumor', 'Disease', (126, 137))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('leaky tumor', 'Disease', 'MESH:C535298', (126, 137))	('nanoparticles', 'Var', (79, 92))
140982	32036455	Instead, more than 80% harbour mutations in the guanine nucleotide binding protein Q polypeptide (GNAQ) and alpha-11 (GNA11) genes (Onken et al.	('alpha-11', 'Gene', (108, 116))	('GNA11', 'Gene', (118, 123))	('mutations', 'Var', (31, 40))	('alpha-11', 'Gene', '8248', (108, 116))	('GNA11', 'Gene', '2767', (118, 123))	('GNAQ', 'Gene', (98, 102))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('GNAQ', 'Gene', '2776', (98, 102))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('56', '74'))
141027	31892603	Furthermore, molecular and clinicopathological studies have demonstrated a correlation between defects in vitamin D signaling and progression of melanoma and disease outcome.	('vitamin D signaling', 'MPA', (106, 125))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('defects in vitamin D', 'Phenotype', 'HP:0100512', (95, 115))	('defects', 'Var', (95, 102))	('vitamin D', 'Chemical', 'MESH:D014807', (106, 115))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))
141032	31892603	We also present the association of vitamin D and melanoma based on epidemiological, experimental and clinical evidence, showing that defects in vitamin D signaling correlate with progression of melanoma and disease outcome.	('vitamin D signaling', 'MPA', (144, 163))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('defects in vitamin D', 'Phenotype', 'HP:0100512', (133, 153))	('men', 'Species', '9606', (90, 93))	('vitamin D', 'Chemical', 'MESH:D014807', (35, 44))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Disease', (194, 202))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('defects', 'Var', (133, 140))	('vitamin D', 'Chemical', 'MESH:D014807', (144, 153))	('melanoma', 'Disease', (49, 57))
141039	31892603	Inactivation of both 25(OH)D3 and 1,25(OH)2D3 is catalyzed by cytochrome P450 family 24 subfamily A member 1 (CYP24A1) via hydroxylation.	('cytochrome P450', 'molecular_function', 'GO:0019825', ('62', '77'))	('CYP24A1', 'Gene', (110, 117))	('CYP24A1', 'Gene', '1591', (110, 117))	('1,25(OH)2D3', 'Var', (34, 45))	('cytochrome P450 family 24 subfamily A member 1', 'Gene', '1591', (62, 108))	('cytochrome P450', 'molecular_function', 'GO:0005490', ('62', '77'))	('25(OH)D3', 'Chemical', 'MESH:D002112', (21, 29))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (34, 45))	('cytochrome P450 family 24 subfamily A member 1', 'Gene', (62, 108))	('25(OH)D3', 'Var', (21, 29))	('hydroxylation', 'MPA', (123, 136))
141043	31892603	In the non-canonical pathway, vitamin D3 is activated by the action of steroidogenic enzyme CYP11A1 with initial production 20(OH)D3 and 22(OH)2D3, and further hydroxylation of the side chain by the same enzyme (Figure 1).	('20(OH)D3', 'Chemical', 'MESH:C480634', (124, 132))	('vitamin D3', 'Chemical', 'MESH:D002762', (30, 40))	('CYP11A1', 'Gene', '1583', (92, 99))	('CYP11A1', 'molecular_function', 'GO:0008386', ('92', '99'))	('20(OH)D3', 'Var', (124, 132))	('hydroxylation of the', 'MPA', (160, 180))	('activated', 'PosReg', (44, 53))	('CYP11A1', 'Gene', (92, 99))	('(OH)2D3', 'Chemical', '-', (139, 146))	('non-canonical pathway', 'Pathway', (7, 28))
141053	31892603	Individuals with genetically conditioned disease, such as xeroderma pigmentosum, related to mutations in XP and XPV genes, encoding proteins crucial for nucleotide excision repair whereby they are unable to repair UV-induced DNA damage, are more susceptible to both melanoma (more than 2,000-fold increased risk in comparison to the general population) and non-melanoma skin cancer (more than a 10,000-fold increased incidence in comparison to the general population).	('xeroderma pigmentosum', 'Disease', (58, 79))	('non-melanoma skin cancer', 'Disease', (357, 381))	('melanoma', 'Disease', 'MESH:D008545', (266, 274))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('melanoma', 'Disease', 'MESH:D008545', (361, 369))	('increased', 'PosReg', (297, 306))	('XPV genes', 'Gene', (112, 121))	('DNA', 'cellular_component', 'GO:0005574', ('225', '228'))	('unable', 'NegReg', (197, 203))	('susceptible', 'Reg', (246, 257))	('melanoma', 'Phenotype', 'HP:0002861', (266, 274))	('melanoma', 'Disease', (266, 274))	('mutations', 'Var', (92, 101))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('153', '179'))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (58, 79))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (357, 381))	('melanoma', 'Phenotype', 'HP:0002861', (361, 369))	('melanoma', 'Disease', (361, 369))	('skin cancer', 'Phenotype', 'HP:0008069', (370, 381))
141056	31892603	The mechanism involved in UV-induced carcinogenesis is complex and is related to such processes as immunosuppression, induction of mutations in a broad range of genes, stimulation of growth via altered expression of growth factors, cytokines, neuropetides and their receptors, and which can affect keratinocytes and melanocytes, and promote melanocyte-fibroblast interactions, and modify cadherins, integrins, melanoma inhibitory activity and expression of other genes (Figure 1).	('mutations', 'Var', (131, 140))	('cadherins', 'Protein', (388, 397))	('expression', 'MPA', (443, 453))	('carcinogenesis', 'Disease', 'MESH:D063646', (37, 51))	('carcinogenesis', 'Disease', (37, 51))	('promote', 'PosReg', (333, 340))	('melanoma', 'Disease', 'MESH:D008545', (410, 418))	('melanoma', 'Phenotype', 'HP:0002861', (410, 418))	('melanoma', 'Disease', (410, 418))	('stimulation of growth', 'biological_process', 'GO:0045927', ('168', '189'))	('integrins', 'Protein', (399, 408))	('affect', 'Reg', (291, 297))	('modify', 'Reg', (381, 387))	('melanocyte-fibroblast interactions', 'CPA', (341, 375))
141057	31892603	Although UV fingerprint mutations have been identified in genes p53 and cyclin-dependent kinase inhibitor 2A (CDKN2A) in BCC and SCC, the role of p53 in melanomagenesis is not defined [reviewed in ].	('CDKN2A', 'Gene', (110, 116))	('SCC', 'Disease', (129, 132))	('CDKN2A', 'Gene', '1029', (110, 116))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', (153, 161))	('p53', 'Gene', (64, 67))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('72', '105'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('89', '105'))	('mutations', 'Var', (24, 33))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (72, 108))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (72, 108))	('BCC', 'Disease', (121, 124))	('p53', 'Gene', '7157', (64, 67))
141074	31892603	The involvement of UV in melanoma development is, in part, related to genetic factors, such as germline mutations, pigmentation, UV-induced mutations or inability to repair UV-induced DNA damages.	('DNA', 'cellular_component', 'GO:0005574', ('184', '187'))	('men', 'Species', '9606', (11, 14))	('pigmentation', 'Disease', 'MESH:D010859', (115, 127))	('men', 'Species', '9606', (118, 121))	('pigmentation', 'Disease', (115, 127))	('inability', 'Disease', 'MESH:D007319', (153, 162))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('men', 'Species', '9606', (41, 44))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('mutations', 'Var', (140, 149))	('pigmentation', 'biological_process', 'GO:0043473', ('115', '127'))	('melanoma', 'Disease', (25, 33))	('involvement', 'Reg', (4, 15))	('inability', 'Disease', (153, 162))
141077	31892603	About 20% of patients with susceptibility to melanoma are carriers of a CDKN2A (called also INK4a/ARF) gene mutation, coding two structurally distinct proteins, p14ARF and p16INK4a, involved in cell-cycle regulation, with mutations in p16INK4a.	('p16INK4a', 'Gene', '1029', (172, 180))	('INK4a/ARF', 'Gene', (92, 101))	('INK4a/ARF', 'Gene', '1029', (92, 101))	('cell-cycle regulation', 'biological_process', 'GO:0051726', ('194', '215'))	('p16INK4a', 'Gene', (235, 243))	('p16INK4a', 'Gene', (172, 180))	('p14ARF', 'Gene', (161, 167))	('patients', 'Species', '9606', (13, 21))	('CDKN2A', 'Gene', '1029', (72, 78))	('p16INK4a', 'Gene', '1029', (235, 243))	('mutations', 'Var', (222, 231))	('mutation', 'Var', (108, 116))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('p14ARF', 'Gene', '1029', (161, 167))	('CDKN2A', 'Gene', (72, 78))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
141078	31892603	Mutations in the cyclin-dependent kinase-4 (CDK4) gene confer susceptibility to cutaneous melanoma, but mutations in CDK4 are not as frequent as those in CDKN2A.	('CDK4', 'Gene', '1019', (117, 121))	('cyclin', 'molecular_function', 'GO:0016538', ('17', '23'))	('CDK', 'molecular_function', 'GO:0004693', ('117', '120'))	('cutaneous melanoma', 'Disease', (80, 98))	('CDKN2A', 'Gene', (154, 160))	('CDK4', 'Gene', '1019', (44, 48))	('susceptibility', 'Reg', (62, 76))	('CDK4', 'Gene', (44, 48))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (80, 98))	('cyclin-dependent kinase-4', 'Gene', (17, 42))	('Mutations', 'Var', (0, 9))	('CDKN2A', 'Gene', '1029', (154, 160))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (80, 98))	('cyclin-dependent kinase-4', 'Gene', '1019', (17, 42))	('CDK4', 'Gene', (117, 121))	('CDK', 'molecular_function', 'GO:0004693', ('44', '47'))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
141079	31892603	in addition, germline mutations in the tumor-suppressor BRCA-associated protein-1 (BAP1) gene, ubiquitin C-terminal hydrolase, encoding the protein interacting with BRCA1, have been identified in fewer than 1% of cutaneous melanomas.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('ubiquitin C-terminal hydrolase', 'Gene', '7345', (95, 125))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (213, 232))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (213, 231))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (213, 232))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('ubiquitin C-terminal hydrolase', 'molecular_function', 'GO:0036459', ('95', '125'))	('BRCA-associated protein-1', 'Gene', '8314', (56, 81))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('39', '55'))	('BAP1', 'Gene', '8314', (83, 87))	('identified', 'Reg', (182, 192))	('germline', 'Var', (13, 21))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('39', '55'))	('cutaneous melanomas', 'Disease', (213, 232))	('BRCA-associated protein-1', 'Gene', (56, 81))	('tumor', 'Disease', (39, 44))	('BRCA1', 'Gene', '672', (165, 170))	('ubiquitin C-terminal hydrolase', 'Gene', (95, 125))	('BRCA1', 'Gene', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('BAP1', 'Gene', (83, 87))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('melanomas', 'Phenotype', 'HP:0002861', (223, 232))
141080	31892603	Melanocortin 1 receptor (MC1R) mutations increase susceptibility to melanoma in general population.	('MC1R', 'Gene', '4157', (25, 29))	('mutations', 'Var', (31, 40))	('MC1R', 'Gene', (25, 29))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('Melanocortin 1 receptor', 'Gene', (0, 23))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('susceptibility', 'MPA', (50, 64))	('Melanocortin 1 receptor', 'Gene', '4157', (0, 23))
141084	31892603	However recently mutations in BAP1 were found to be related to younger age (39-50 years) at diagnosis, and higher risk of second tumors (cutaneous melanoma, renal cell carcinoma) has been identified.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (157, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (137, 155))	('tumors', 'Disease', (129, 135))	('BAP1', 'Gene', (30, 34))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('BAP1', 'Gene', '8314', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('renal cell carcinoma', 'Disease', (157, 177))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('cutaneous melanoma', 'Disease', (137, 155))	('mutations', 'Var', (17, 26))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (157, 177))
141107	31892603	1,25(OH)2D3 has antitumor properties affecting molecular pathways involved in proliferation, apoptosis and differentiation, but can also improve effectiveness of classical anticancer therapies.	('molecular pathways', 'Pathway', (47, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('improve', 'PosReg', (137, 144))	('differentiation', 'CPA', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('1,25(OH)2D3', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('proliferation', 'CPA', (78, 91))	('apoptosis', 'CPA', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (0, 11))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('tumor', 'Disease', (20, 25))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))
141112	31892603	Colston and co-workers showed VDR-expressing melanoma cells were inhibited by 1,25(OH)2D3.	('1,25(OH)2D3', 'Var', (78, 89))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (78, 89))	('inhibited', 'NegReg', (65, 74))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
141118	31892603	1,25(OH)2D3 also inhibited colony formation by SkMel-188 cells.	('1,25(OH)2D3', 'Var', (0, 11))	('inhibited', 'NegReg', (17, 26))	('colony formation', 'CPA', (27, 43))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (0, 11))	('formation', 'biological_process', 'GO:0009058', ('34', '43'))
141119	31892603	The antiproliferative activity of 1,25(OH)2D3l, calcipotriol and 25(OH)D3 are related to the expression VDR and CYP27B1.	('calcipotriol', 'Chemical', 'MESH:C055085', (48, 60))	('CYP27B1', 'Gene', '1594', (112, 119))	('25(OH)D3', 'Var', (65, 73))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (34, 45))	('CYP27B1', 'Gene', (112, 119))	('25(OH)D3', 'Chemical', 'MESH:D002112', (65, 73))	('antiproliferative', 'CPA', (4, 21))	('VDR', 'Gene', (104, 107))
141127	31892603	20,23(OH)2D3, and 1,20(OH)2D3 also inhibited proliferation and colony formation of melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('formation', 'biological_process', 'GO:0009058', ('70', '79'))	('inhibited', 'NegReg', (35, 44))	('(OH)2D3', 'Chemical', '-', (22, 29))	('(OH)2D3', 'Chemical', '-', (5, 12))	('1,20(OH)2D3', 'Var', (18, 29))	('melanoma', 'Disease', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
141131	31892603	The antitumorigenic activity of 1,25(OH)2D3 in an animal model was reported for the first time by Eisman and coworkers, demonstrating the inhibition by 1,25(OH)2D3 of the growth of human melanoma cells COLO 239F expressing VDR, which were injected into immunosuppressed mice.	('human', 'Species', '9606', (181, 186))	('inhibition', 'NegReg', (138, 148))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('growth', 'MPA', (171, 177))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (152, 163))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('COLO', 'Species', '307630', (202, 206))	('tumor', 'Disease', (8, 13))	('mice', 'Species', '10090', (270, 274))	('VDR', 'Gene', (223, 226))	('1,25(OH)2D3', 'Var', (152, 163))
141133	31892603	The VDR-positive SKMel-188 melanoma cell line, injected into immunocompromised mice, was inhibited by 20(OH)D3.	('inhibited', 'NegReg', (89, 98))	('mice', 'Species', '10090', (79, 83))	('melanoma', 'Disease', (27, 35))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('20(OH)D3', 'Chemical', 'MESH:C480634', (102, 110))	('20(OH)D3', 'Var', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('SKMel-188', 'CellLine', 'CVCL:6098', (17, 26))
141134	31892603	1,25(OH)2D3 reduced lung metastasis of B16 melanoma cells injected into mouse by affecting the extracellular matrix, and 1(OH)D2 reduced tumor growth in Tyr-Tag transgenic mice, which develop pigmented ocular tumors, similar to human choroidal melanoma.	('melanoma', 'Disease', 'MESH:D008545', (244, 252))	('choroidal melanoma', 'Disease', 'MESH:D008545', (234, 252))	('mouse', 'Species', '10090', (72, 77))	('reduced', 'NegReg', (129, 136))	('tumor', 'Disease', (209, 214))	('ocular tumors', 'Phenotype', 'HP:0100012', (202, 215))	('pigmented ocular tumors', 'Disease', 'MESH:D010859', (192, 215))	('choroidal melanoma', 'Disease', (234, 252))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('lung metastasis', 'CPA', (20, 35))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('melanoma', 'Disease', (244, 252))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (234, 252))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('95', '115'))	('tumor', 'Disease', (137, 142))	('extracellular matrix', 'MPA', (95, 115))	('pigmented ocular tumors', 'Disease', (192, 215))	('Tyr', 'Chemical', 'MESH:D014443', (153, 156))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('human', 'Species', '9606', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('affecting', 'Reg', (81, 90))	('1(OH)D2', 'Var', (121, 128))	('reduced', 'NegReg', (12, 19))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('transgenic mice', 'Species', '10090', (161, 176))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
141137	31892603	Garland and Garland suggested that low-sun-exposure-related vitamin D insufficiency was correlated with higher colon cancer mortality rates.	('colon cancer', 'Disease', 'MESH:D015179', (111, 123))	('mortality', 'Disease', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('colon cancer', 'Phenotype', 'HP:0003003', (111, 123))	('colon cancer', 'Disease', (111, 123))	('mortality', 'Disease', 'MESH:D003643', (124, 133))	('low-sun-exposure-related', 'Var', (35, 59))	('insufficiency', 'Disease', 'MESH:D000309', (70, 83))	('higher', 'PosReg', (104, 110))	('vitamin D', 'Chemical', 'MESH:D014807', (60, 69))	('insufficiency', 'Disease', (70, 83))	('vitamin D insufficiency', 'Phenotype', 'HP:0100512', (60, 83))
141142	31892603	Subsequent studies confirmed that a lower vitamin D level was related to greater progression of melanoma (Breslow thickness, Clark level, the American Joint Committee on Cancer stage), the presences of poor prognostic markers (ulceration, higher mitotic index), shorter overall survival and increased risk for melanoma-specific death.	('lower', 'NegReg', (36, 41))	('Cancer', 'Disease', 'MESH:D009369', (170, 176))	('Clark level', 'MPA', (125, 136))	('vitamin D', 'Chemical', 'MESH:D014807', (42, 51))	('melanoma', 'Phenotype', 'HP:0002861', (310, 318))	('lower vitamin D', 'Phenotype', 'HP:0100512', (36, 51))	('melanoma', 'Disease', (310, 318))	('vitamin D level', 'MPA', (42, 57))	('higher', 'PosReg', (239, 245))	('Cancer', 'Phenotype', 'HP:0002664', (170, 176))	('melanoma', 'Disease', 'MESH:D008545', (310, 318))	('shorter', 'NegReg', (262, 269))	('overall', 'MPA', (270, 277))	('presences', 'Var', (189, 198))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))	('Cancer', 'Disease', (170, 176))
141145	31892603	These authors suggested that melanomas associated with a low vitamin D level might be a different type from those associated with a higher nevi count, thus further studies are required to explain the association between nevi, melanoma and vitamin D level.	('nevi', 'Phenotype', 'HP:0003764', (220, 224))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanomas', 'Phenotype', 'HP:0002861', (29, 38))	('melanoma', 'Disease', (29, 37))	('low vitamin D', 'Phenotype', 'HP:0100512', (57, 70))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('melanomas', 'Disease', 'MESH:D008545', (29, 38))	('nevi', 'Phenotype', 'HP:0003764', (139, 143))	('vitamin D', 'Chemical', 'MESH:D014807', (239, 248))	('low', 'Var', (57, 60))	('vitamin D', 'Chemical', 'MESH:D014807', (61, 70))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('melanoma', 'Disease', (226, 234))	('vitamin D level', 'MPA', (61, 76))	('melanomas', 'Disease', (29, 38))
141159	31892603	Additionally, patients with melanoma showing poor prognostic markers such as nodular type, high mitotic index, ulceration and necrosis had low CYP24A1 expression.	('melanoma', 'Disease', (28, 36))	('necrosis', 'biological_process', 'GO:0001906', ('126', '134'))	('necrosis', 'Disease', (126, 134))	('low', 'NegReg', (139, 142))	('necrosis', 'biological_process', 'GO:0019835', ('126', '134'))	('necrosis', 'biological_process', 'GO:0008220', ('126', '134'))	('high', 'Var', (91, 95))	('necrosis', 'Disease', 'MESH:D009336', (126, 134))	('expression', 'MPA', (151, 161))	('necrosis', 'biological_process', 'GO:0070265', ('126', '134'))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('necrosis', 'biological_process', 'GO:0008219', ('126', '134'))	('patients', 'Species', '9606', (14, 22))	('CYP24A1', 'Gene', (143, 150))	('CYP24A1', 'Gene', '1591', (143, 150))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
141167	31892603	In summary, alterations in vitamin D activation, its local and systemic levels, and vitamin D-regulated signaling pathways can result in loss of anticancer protection provided by vitamin D and promote melanoma development.	('melanoma', 'Disease', (201, 209))	('promote', 'PosReg', (193, 200))	('cancer', 'Disease', (149, 155))	('men', 'Species', '9606', (217, 220))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('alterations', 'Var', (12, 23))	('activation', 'PosReg', (37, 47))	('vitamin D', 'Chemical', 'MESH:D014807', (27, 36))	('vitamin D', 'Gene', (27, 36))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('vitamin D', 'Chemical', 'MESH:D014807', (84, 93))	('loss', 'NegReg', (137, 141))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('vitamin D', 'Chemical', 'MESH:D014807', (179, 188))
141177	31892603	However, both experimental- and clinical-based studies clearly suggest that disturbances in vitamin D signaling may be related to melanoma development, progression and disease-free and overall survival of patients.	('disturbances', 'Var', (76, 88))	('patients', 'Species', '9606', (205, 213))	('related', 'Reg', (119, 126))	('men', 'Species', '9606', (146, 149))	('vitamin D', 'Chemical', 'MESH:D014807', (92, 101))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('melanoma', 'Disease', (130, 138))	('vitamin D signaling', 'MPA', (92, 111))	('men', 'Species', '9606', (20, 23))
141180	31892603	Since VDR, CYP27B1, CYP24A and ROR expression are related to the prognosis of patients with melanoma, they can be considered as potential biomarkers, similar to the serum vitamin D level.	('CYP24A', 'Var', (20, 26))	('ROR', 'Gene', (31, 34))	('CYP27B1', 'Gene', (11, 18))	('related', 'Reg', (50, 57))	('patients', 'Species', '9606', (78, 86))	('CYP27B1', 'Gene', '1594', (11, 18))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('VDR', 'Gene', (6, 9))	('vitamin D', 'Chemical', 'MESH:D014807', (171, 180))
141184	31526394	We hypothesized that inhibition of transcription by cyclin-dependent kinase 7/9 (CDK7/9) inhibitor SNS-032 diminished liver metastasis by abrogating the putative oncogenes in charge of colonization, stemness, cell motility of UM cells in host liver microenvironment.	('cyclin-dependent kinase 7/9', 'Gene', (52, 79))	('inhibitor', 'Var', (89, 98))	('oncogenes', 'Gene', (162, 171))	('UM', 'Phenotype', 'HP:0007716', (226, 228))	('abrogating', 'NegReg', (138, 148))	('inhibition', 'NegReg', (21, 31))	('diminished liver', 'Phenotype', 'HP:0001410', (107, 123))	('cell motility', 'biological_process', 'GO:0048870', ('209', '222'))	('liver metastasis', 'CPA', (118, 134))	('colonization', 'CPA', (185, 197))	('cell motility', 'CPA', (209, 222))	('SNS-032', 'Gene', (99, 106))	('transcription', 'biological_process', 'GO:0006351', ('35', '48'))	('CDK7/9', 'Gene', (81, 87))	('SNS-032', 'Chemical', 'MESH:C484864', (99, 106))	('CDK', 'molecular_function', 'GO:0004693', ('81', '84'))	('diminished', 'NegReg', (107, 117))	('transcription', 'MPA', (35, 48))	('cyclin-dependent kinase 7/9', 'Gene', '1022;1025', (52, 79))	('cyclin', 'molecular_function', 'GO:0016538', ('52', '58'))
141195	31526394	UM is biologically and clinically different from cutaneous melanoma which commonly harbors the activating mutations in BRAF or NRAS.	('cutaneous melanoma', 'Disease', (49, 67))	('BRAF', 'Gene', '673', (119, 123))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (49, 67))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (49, 67))	('BRAF', 'Gene', (119, 123))	('NRAS', 'Gene', (127, 131))	('mutations', 'Var', (106, 115))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('NRAS', 'Gene', '4893', (127, 131))	('activating', 'PosReg', (95, 105))
141199	31526394	Whole-genome sequencing has demonstrated that mutually exclusive gain of function mutations in GNAQ (Galphaq) or GNA11 (Galpha11), which encodes the alpha subunit of heterotrimeric G protein, are found in ~ 80% of patients with UM.	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('patients', 'Species', '9606', (214, 222))	('heterotrimeric G protein', 'molecular_function', 'GO:0005065', ('166', '190'))	('UM', 'Phenotype', 'HP:0007716', (228, 230))	('GNAQ', 'Gene', (95, 99))	('GNA11', 'Gene', (113, 118))	('mutations', 'Var', (82, 91))	('Galphaq', 'Gene', (101, 108))	('Galpha11', 'Gene', (120, 128))	('gain of function', 'PosReg', (65, 81))	('Galphaq', 'Gene', '2776', (101, 108))	('Galpha11', 'Gene', '2767', (120, 128))	('GNAQ', 'Gene', '2776', (95, 99))
141200	31526394	Gain-of-function mutations in GNAQ (Galphaq) or GNA11 (Galpha11), leading to activation of the protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) pathway via phospholipase C-beta (PLCbeta), are presumably believed to be drive tumorigenecity of UM.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('MAPK', 'molecular_function', 'GO:0004707', ('156', '160'))	('Galpha11', 'Gene', '2767', (55, 63))	('C-beta', 'Species', '10703', (188, 194))	('Gain-of-function', 'PosReg', (0, 16))	('tumor', 'Disease', (242, 247))	('PKC', 'Gene', '112476', (113, 116))	('PKC', 'molecular_function', 'GO:0004697', ('113', '116'))	('mutations', 'Var', (17, 26))	('GNAQ', 'Gene', '2776', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('GNAQ', 'Gene', (30, 34))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('PKC', 'Gene', (113, 116))	('Galpha11', 'Gene', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('Galphaq', 'Gene', (36, 43))	('activation', 'PosReg', (77, 87))	('GNA11', 'Gene', (48, 53))	('UM', 'Phenotype', 'HP:0007716', (260, 262))	('Galphaq', 'Gene', '2776', (36, 43))
141201	31526394	Combinational treatment with PKC and MEK inhibitors showed modest effective in UM cells with Galphaq/11 mutations.	('mutations', 'Var', (104, 113))	('UM', 'Phenotype', 'HP:0007716', (79, 81))	('Galphaq', 'Gene', (93, 100))	('Galphaq', 'Gene', '2776', (93, 100))	('PKC', 'Gene', (29, 32))	('PKC', 'Gene', '112476', (29, 32))	('PKC', 'molecular_function', 'GO:0004697', ('29', '32'))	('MEK', 'Gene', (37, 40))	('MEK', 'Gene', '5609', (37, 40))
141203	31526394	Recent studies showed that activation of the transcriptional cofactor YAP by mutated GNAQ or GNA11 through Trio-Rho/Rac signaling was required for this mutation-induced tumorigenesis in UM.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('UM', 'Phenotype', 'HP:0007716', (186, 188))	('Trio', 'Gene', '7204', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('mutated', 'Var', (77, 84))	('GNAQ', 'Gene', (85, 89))	('GNAQ', 'Gene', '2776', (85, 89))	('tumor', 'Disease', (169, 174))	('Rac', 'Gene', '5879', (116, 119))	('activation', 'PosReg', (27, 37))	('GNA11', 'Gene', (93, 98))	('Trio', 'Gene', (107, 111))	('Rac', 'Gene', (116, 119))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))
141204	31526394	The YAP-inhibitory drug Verteporfin selectively suppresses tumorigenesis in UM with Galphaq/11 mutations.	('tumor', 'Disease', (59, 64))	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('Verteporfin', 'Chemical', 'MESH:D000077362', (24, 35))	('suppresses', 'NegReg', (48, 58))	('mutations', 'Var', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('Galphaq', 'Gene', (84, 91))	('Galphaq', 'Gene', '2776', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
141207	31526394	Highly metastatic UM patients are characterized by monosomy of chromosome 3 and gain of 8q.	('UM', 'Phenotype', 'HP:0007716', (18, 20))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('gain', 'PosReg', (80, 84))	('patients', 'Species', '9606', (21, 29))	('monosomy', 'Var', (51, 59))
141208	31526394	Recurrent somatic mutations in BRCA1-associated protein 1 (BAP1), splicing factor 3B subunit 1 (SF3B1), and eukaryotic translation initiation factor 1A (EIF1AX) are found in metastatic UM.	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('UM', 'Phenotype', 'HP:0007716', (185, 187))	('splicing factor 3B subunit 1', 'Gene', (66, 94))	('EIF1AX', 'Gene', (153, 159))	('EIF1AX', 'Gene', '1964', (153, 159))	('BAP1', 'Gene', (59, 63))	('BRCA1-associated protein 1', 'Gene', '8314', (31, 57))	('SF3B1', 'Gene', (96, 101))	('translation initiation', 'biological_process', 'GO:0006413', ('119', '141'))	('BRCA1-associated protein 1', 'Gene', (31, 57))	('splicing factor 3B subunit 1', 'Gene', '23451', (66, 94))	('found', 'Reg', (165, 170))	('SF3B1', 'Gene', '23451', (96, 101))	('metastatic UM', 'Disease', (174, 187))	('splicing', 'biological_process', 'GO:0045292', ('66', '74'))	('mutations', 'Var', (18, 27))
141216	31526394	For example, targeting bromodomain 4 (BRD4) with JQ1 potently inhibits the growth and metastasis in certain cancers which addiction to the transcription.	('BRD4', 'Gene', '23476', (38, 42))	('JQ1', 'Gene', (49, 52))	('bromodomain 4', 'Gene', (23, 36))	('inhibits', 'NegReg', (62, 70))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('transcription', 'biological_process', 'GO:0006351', ('139', '152'))	('BRD4', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('targeting', 'Var', (13, 22))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('bromodomain 4', 'Gene', '23476', (23, 36))	('cancers', 'Disease', (108, 115))
141221	31526394	SNS-032 (BMS-387032) is a potent and selective CDK7/9 inhibitor.	('SNS-032 (BMS-387032', 'Var', (0, 19))	('CDK7/9', 'Enzyme', (47, 53))	('SNS-032', 'Chemical', 'MESH:C484864', (0, 7))	('CDK', 'molecular_function', 'GO:0004693', ('47', '50'))
141256	31526394	Because the addiction of transcription coactivator YAP oncogene-driven by mutant Galphaq/11 is required for tumorigenesis of UM, we next examined the effect of SNS-032 on YAP signaling.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('UM', 'Phenotype', 'HP:0007716', (125, 127))	('SNS-032', 'Chemical', 'MESH:C484864', (160, 167))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('transcription', 'biological_process', 'GO:0006351', ('25', '38'))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('tumor', 'Disease', (108, 113))	('mutant', 'Var', (74, 80))	('Galphaq', 'Gene', '2776', (81, 88))	('Galphaq', 'Gene', (81, 88))
141258	31526394	Using qRT-PCR assay, we found that SNS-032 inhibited the expression of YAP at the transcriptional level (Fig.	('expression', 'MPA', (57, 67))	('inhibited', 'NegReg', (43, 52))	('YAP', 'Gene', (71, 74))	('SNS-032', 'Var', (35, 42))	('SNS-032', 'Chemical', 'MESH:C484864', (35, 42))
141261	31526394	The results indicated that SNS-032 significantly reduced YAP-mediated transcriptional activities (Fig.	('reduced', 'NegReg', (49, 56))	('SNS-032', 'Chemical', 'MESH:C484864', (27, 34))	('YAP-mediated transcriptional activities', 'MPA', (57, 96))	('SNS-032', 'Var', (27, 34))
141262	31526394	Consistently, the mRNA levels of CTGF and CYR61 genes were significantly decreased in the SNS-032-treated UM cells (Fig.	('mRNA levels', 'MPA', (18, 29))	('SNS-032-treated', 'Var', (90, 105))	('decreased', 'NegReg', (73, 82))	('CTGF', 'Gene', '1490', (33, 37))	('CTGF', 'Gene', (33, 37))	('SNS-032', 'Chemical', 'MESH:C484864', (90, 97))	('CYR61', 'Gene', (42, 47))	('CYR61', 'Gene', '3491', (42, 47))	('UM', 'Phenotype', 'HP:0007716', (106, 108))
141265	31526394	Consistently, SNS-032 dose-dependently inhibited the colony-formation ability of UM cells in soft agar (IC50 values rang: 0.12~0.82 muM) (Fig.	('agar', 'Chemical', 'MESH:D000362', (98, 102))	('inhibited', 'NegReg', (39, 48))	('muM', 'Gene', '56925', (132, 135))	('SNS-032', 'Var', (14, 21))	('SNS-032', 'Chemical', 'MESH:C484864', (14, 21))	('UM', 'Phenotype', 'HP:0007716', (81, 83))	('muM', 'Gene', (132, 135))	('formation', 'biological_process', 'GO:0009058', ('60', '69'))	('colony-formation ability of UM cells in soft agar', 'CPA', (53, 102))
141268	31526394	Ectopic expression of YAP rescued SNS-032-induced decrease in cell growth (Fig.	('SNS-032-induced', 'Gene', (34, 49))	('Ectopic expression', 'Var', (0, 18))	('YAP', 'Gene', (22, 25))	('SNS-032', 'Chemical', 'MESH:C484864', (34, 41))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))	('cell growth', 'CPA', (62, 73))	('decrease', 'NegReg', (50, 58))
141269	31526394	Taken together, these results demonstrate that SNS-032 potently inhibits proliferation of UM cells through blocking YAP signaling.	('proliferation of UM cells', 'CPA', (73, 98))	('blocking', 'NegReg', (107, 115))	('UM', 'Phenotype', 'HP:0007716', (90, 92))	('SNS-032', 'Var', (47, 54))	('SNS-032', 'Chemical', 'MESH:C484864', (47, 54))	('YAP signaling', 'MPA', (116, 129))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('inhibits', 'NegReg', (64, 72))
141274	31526394	Additionally, the protein levels of cytochrome c in the cytosolic fractionations were dramatically elevated in UM cells treated with SNS-032 (Fig.	('cytochrome c', 'molecular_function', 'GO:0045155', ('36', '48'))	('SNS-032', 'Var', (133, 140))	('UM', 'Phenotype', 'HP:0007716', (111, 113))	('SNS-032', 'Chemical', 'MESH:C484864', (133, 140))	('cytochrome c', 'Gene', (36, 48))	('cytochrome c', 'molecular_function', 'GO:0009461', ('36', '48'))	('elevated', 'PosReg', (99, 107))	('cytochrome c', 'Gene', '54205', (36, 48))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))
141281	31526394	Ectopic expression of survivin in Omm1 cells by lentiviral construct encoding survivin attenuated SNS-032-induced apoptosis as reflected by cleavage of PARP and dead cells with trypan blue staining (Fig.	('SNS-032-induced', 'Gene', (98, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('114', '123'))	('cleavage', 'MPA', (140, 148))	('SNS-032', 'Chemical', 'MESH:C484864', (98, 105))	('attenuated', 'NegReg', (87, 97))	('Ectopic expression', 'Var', (0, 18))	('trypan blue', 'Chemical', 'MESH:D014343', (177, 188))	('PARP', 'Gene', '1302', (152, 156))	('PARP', 'Gene', (152, 156))	('apoptosis', 'biological_process', 'GO:0006915', ('114', '123'))	('apoptosis', 'CPA', (114, 123))	('survivin', 'Gene', (78, 86))
141285	31526394	The results showed that combinational treatment with SNS-032 and vinblastine induced enhanced cell apoptosis as reflected by increase of activated caspase-3 (Additional file 3: Figure S1C) and trypan blue staining cells (Additional file 3: Figure S1D).	('vinblastine', 'Chemical', 'MESH:D014747', (65, 76))	('SNS-032', 'Chemical', 'MESH:C484864', (53, 60))	('caspase-3', 'Gene', '836', (147, 156))	('enhanced', 'PosReg', (85, 93))	('increase', 'PosReg', (125, 133))	('combinational', 'Interaction', (24, 37))	('trypan blue', 'Chemical', 'MESH:D014343', (193, 204))	('trypan blue staining cells', 'CPA', (193, 219))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('activated', 'MPA', (137, 146))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('caspase-3', 'Gene', (147, 156))	('cell apoptosis', 'CPA', (94, 108))	('SNS-032', 'Var', (53, 60))
141290	31526394	In addition, the tumor weight was lighter in SNS-032-treated mice than vehicle-treated control ones (Fig.	('SNS-032-treated', 'Var', (45, 60))	('tumor', 'Disease', (17, 22))	('mice', 'Species', '10090', (61, 65))	('lighter', 'NegReg', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('SNS-032', 'Chemical', 'MESH:C484864', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
141294	31526394	The results showed that SNS-032 inhibited the CTD phosphorylation of RNA Pol II at Ser2, 5 and 7 sites; the expression and phosphorylation at Ser127 of YAP; as well as the expression of apoptosis-related protein survivin in tumor tissues (Fig.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('Ser2', 'Gene', '3714', (83, 87))	('protein', 'cellular_component', 'GO:0003675', ('204', '211'))	('RNA Pol II', 'Protein', (69, 79))	('Ser', 'cellular_component', 'GO:0005790', ('142', '145'))	('Ser', 'cellular_component', 'GO:0005790', ('83', '86'))	('Ser2', 'Gene', (83, 87))	('phosphorylation', 'biological_process', 'GO:0016310', ('50', '65'))	('SNS-032', 'Var', (24, 31))	('SNS-032', 'Chemical', 'MESH:C484864', (24, 31))	('tumor', 'Disease', (224, 229))	('Ser127', 'Chemical', '-', (142, 148))	('phosphorylation', 'biological_process', 'GO:0016310', ('123', '138'))	('apoptosis', 'biological_process', 'GO:0097194', ('186', '195'))	('apoptosis', 'biological_process', 'GO:0006915', ('186', '195'))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('phosphorylation', 'MPA', (123, 138))	('inhibited', 'NegReg', (32, 41))	('YAP', 'Gene', (152, 155))	('expression', 'MPA', (172, 182))	('RNA', 'cellular_component', 'GO:0005562', ('69', '72'))	('expression', 'MPA', (108, 118))	('CTD phosphorylation', 'MPA', (46, 65))
141296	31526394	These results demonstrate that SNS-032 inhibits the growth of UM cells in vivo.	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('growth of UM cells', 'CPA', (52, 70))	('SNS-032', 'Var', (31, 38))	('SNS-032', 'Chemical', 'MESH:C484864', (31, 38))	('inhibits', 'NegReg', (39, 47))
141303	31526394	The results showed that SNS-032 dramatically decreased the frequency of CSCs in UM (Fig.	('CSCs', 'Disease', (72, 76))	('UM', 'Phenotype', 'HP:0007716', (80, 82))	('decreased', 'NegReg', (45, 54))	('SNS-032', 'Var', (24, 31))	('SNS-032', 'Chemical', 'MESH:C484864', (24, 31))
141304	31526394	To elucidate the underlying mechanism that SNS-032 eliminates CSCs in UM, we detected the expression of stemness-related transcription factors.	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('SNS-032', 'Var', (43, 50))	('SNS-032', 'Chemical', 'MESH:C484864', (43, 50))	('transcription', 'biological_process', 'GO:0006351', ('121', '134'))	('eliminates', 'NegReg', (51, 61))	('CSCs', 'Disease', (62, 66))
141306	31526394	Consistently, the levels of KLF4 and Slug in tumor tissues from the mice administrated by SNS-032 were also appreciably reduced than those from the mice treated with vehicle (Fig.	('mice', 'Species', '10090', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('levels', 'MPA', (18, 24))	('tumor', 'Disease', (45, 50))	('Slug', 'MPA', (37, 41))	('mice', 'Species', '10090', (148, 152))	('SNS-032', 'Var', (90, 97))	('SNS-032', 'Chemical', 'MESH:C484864', (90, 97))	('reduced', 'NegReg', (120, 127))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('KLF4', 'MPA', (28, 32))
141314	31526394	In contrast, silencing KLF4 by lentiviral shRNAs enhanced the SNS-032-mediated decrease in capacity of serially melanosphere formation as well as the percentage of ALDH+ cells (Fig.	('KLF4', 'Gene', (23, 27))	('ALDH', 'Gene', '11670', (164, 168))	('decrease', 'NegReg', (79, 87))	('formation', 'biological_process', 'GO:0009058', ('125', '134'))	('ALDH', 'molecular_function', 'GO:0004030', ('164', '168'))	('ALDH', 'Gene', (164, 168))	('SNS-032', 'Chemical', 'MESH:C484864', (62, 69))	('silencing', 'Var', (13, 22))
141322	31526394	Using qRT-PCR analysis, we found that SNS-032 inhibited the expression of MMP9 at the transcriptional level (Fig.	('expression', 'MPA', (60, 70))	('MMP9', 'molecular_function', 'GO:0004229', ('74', '78'))	('SNS-032', 'Var', (38, 45))	('SNS-032', 'Chemical', 'MESH:C484864', (38, 45))	('inhibited', 'NegReg', (46, 55))	('MMP9', 'Gene', (74, 78))
141324	31526394	Because the promoter of MMP9 gene contains YAP binding sites, we hypothesized that SNS-032 may diminish the transcription of MMP9 gene via inhibiting YAP.	('MMP9', 'molecular_function', 'GO:0004229', ('24', '28'))	('diminish', 'NegReg', (95, 103))	('transcription', 'biological_process', 'GO:0006351', ('108', '121'))	('YAP', 'MPA', (150, 153))	('MMP9', 'Gene', (125, 129))	('binding', 'molecular_function', 'GO:0005488', ('47', '54'))	('MMP9', 'molecular_function', 'GO:0004229', ('125', '129'))	('transcription', 'MPA', (108, 121))	('SNS-032', 'Var', (83, 90))	('SNS-032', 'Chemical', 'MESH:C484864', (83, 90))	('inhibiting', 'NegReg', (139, 149))	('MMP9', 'Gene', (24, 28))
141335	31526394	The results showed that SNS-032 significantly decreased the fluorescence signals of actin polymerization (F-actin) and the formation of invadopodia (Fig.	('F-actin', 'cellular_component', 'GO:0031941', ('106', '113'))	('fluorescence signals', 'MPA', (60, 80))	('formation', 'CPA', (123, 132))	('actin polymerization', 'biological_process', 'GO:0030041', ('84', '104'))	('SNS-032', 'Var', (24, 31))	('decreased', 'NegReg', (46, 55))	('SNS-032', 'Chemical', 'MESH:C484864', (24, 31))	('actin polymerization', 'MPA', (84, 104))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))
141336	31526394	These data demonstrate that SNS-032 decreases RhoA activity, the actin polymerization and the formation of invadopodia, and thereby inhibits the abilities of migration and invasion in UM cells.	('formation', 'biological_process', 'GO:0009058', ('94', '103'))	('actin polymerization', 'biological_process', 'GO:0030041', ('65', '85'))	('RhoA', 'Gene', (46, 50))	('UM', 'Phenotype', 'HP:0007716', (184, 186))	('formation of', 'CPA', (94, 106))	('RhoA', 'Gene', '387', (46, 50))	('inhibits', 'NegReg', (132, 140))	('SNS-032', 'Var', (28, 35))	('SNS-032', 'Chemical', 'MESH:C484864', (28, 35))	('decreases', 'NegReg', (36, 45))	('actin polymerization', 'CPA', (65, 85))
141339	31526394	The ChIP assay indicated that SNS-032 attenuated c-Myc binding capacity to the RhoA promoter region surrounding non-canonical E-box 5 and 6 (Fig.	('attenuated', 'NegReg', (38, 48))	('SNS-032', 'Var', (30, 37))	('c-Myc', 'Gene', '4609', (49, 54))	('RhoA', 'Gene', '387', (79, 83))	('SNS-032', 'Chemical', 'MESH:C484864', (30, 37))	('c-Myc', 'Gene', (49, 54))	('binding', 'Interaction', (55, 62))	('binding', 'molecular_function', 'GO:0005488', ('55', '62'))	('RhoA', 'Gene', (79, 83))
141341	31526394	The results showed that overexpression of c-Myc partially rescued the RhoA decrease induced by SNS-032 (Fig.	('RhoA', 'Gene', (70, 74))	('decrease', 'NegReg', (75, 83))	('SNS-032', 'Var', (95, 102))	('c-Myc', 'Gene', (42, 47))	('SNS-032', 'Chemical', 'MESH:C484864', (95, 102))	('RhoA', 'Gene', '387', (70, 74))	('c-Myc', 'Gene', '4609', (42, 47))
141349	31526394	Histologic examination indicated a remarkable decrease in number and size of the metastatic nodules in the livers in SNS-032-treated mice, compared with those in vehicle-treated mice (Fig.	('SNS-032-treated', 'Var', (117, 132))	('mice', 'Species', '10090', (133, 137))	('mice', 'Species', '10090', (178, 182))	('SNS-032', 'Chemical', 'MESH:C484864', (117, 124))	('decrease', 'NegReg', (46, 54))	('metastatic nodules', 'CPA', (81, 99))
141350	31526394	These results demonstrate that SNS-032 suppresses liver metastasis in UM.	('suppresses', 'NegReg', (39, 49))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('liver metastasis', 'CPA', (50, 66))	('SNS-032', 'Var', (31, 38))	('SNS-032', 'Chemical', 'MESH:C484864', (31, 38))
141356	31526394	Most importantly, SNS-032 profoundly suppressed liver metastasis in UM (Fig.	('liver metastasis', 'CPA', (48, 64))	('SNS-032', 'Var', (18, 25))	('UM', 'Phenotype', 'HP:0007716', (68, 70))	('suppressed', 'NegReg', (37, 47))	('SNS-032', 'Chemical', 'MESH:C484864', (18, 25))
141358	31526394	It has been reported that transcriptional coactivator YAP is required for mutant Galphaq/11-driven tumorigenesis in UM.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('UM', 'Phenotype', 'HP:0007716', (116, 118))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mutant', 'Var', (74, 80))	('Galphaq', 'Gene', '2776', (81, 88))	('Galphaq', 'Gene', (81, 88))
141359	31526394	Our results showed that SNS-032 inhibited YAP signaling at the transcriptional level and YAP is critical in SNS-032-mediated growth inhibition in UM cells, further supporting the critical role of Galphaq/11-YAP pathway in UM growth.	('Galphaq', 'Gene', '2776', (196, 203))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('Galphaq', 'Gene', (196, 203))	('inhibited', 'NegReg', (32, 41))	('UM', 'Phenotype', 'HP:0007716', (146, 148))	('UM', 'Phenotype', 'HP:0007716', (222, 224))	('SNS-032', 'Var', (24, 31))	('YAP signaling', 'MPA', (42, 55))	('SNS-032', 'Chemical', 'MESH:C484864', (108, 115))	('SNS-032', 'Chemical', 'MESH:C484864', (24, 31))
141364	31526394	Consistent with our findings, it was reported that manipulation of survivin affects the efficacy of therapeutic cytotoxic-inducing agent cisplatin.	('manipulation', 'Var', (51, 63))	('survivin', 'Protein', (67, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (137, 146))	('affects', 'Reg', (76, 83))
141368	31526394	It is the first report that SNS-032 eliminated CSCs in UM cells.	('SNS-032', 'Var', (28, 35))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('SNS-032', 'Chemical', 'MESH:C484864', (28, 35))	('CSCs', 'Disease', (47, 51))
141374	31526394	A decreased Slug protein was observed in UM cells treated by neddylation modification inhibitor MLN4924, which was at least partially explained by induction in E3 ligase FBXO11 of Slug protein.	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('MLN4924', 'Var', (96, 103))	('FBXO11', 'Gene', (170, 176))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('Slug protein', 'Protein', (12, 24))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('decreased', 'NegReg', (2, 11))	('neddylation', 'MPA', (61, 72))	('FBXO11', 'Gene', '80204', (170, 176))
141380	31526394	In our study, we found that SNS-032 inhibited the activated form of RhoA and its downstream signaling, subsequently decreased actin polymerization and the formation of invadopodia.	('actin polymerization', 'biological_process', 'GO:0030041', ('126', '146'))	('inhibited', 'NegReg', (36, 45))	('formation of invadopodia', 'CPA', (155, 179))	('actin polymerization', 'MPA', (126, 146))	('formation', 'biological_process', 'GO:0009058', ('155', '164'))	('signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('SNS-032', 'Var', (28, 35))	('RhoA', 'Gene', (68, 72))	('activated', 'MPA', (50, 59))	('SNS-032', 'Chemical', 'MESH:C484864', (28, 35))	('RhoA', 'Gene', '387', (68, 72))	('decreased', 'NegReg', (116, 125))
141381	31526394	Ectopic expression of RhoA promoted migration and invasion, and partially rescued the effect of SNS-032 in UM cells.	('UM', 'Phenotype', 'HP:0007716', (107, 109))	('invasion', 'CPA', (50, 58))	('Ectopic expression', 'Var', (0, 18))	('promoted', 'PosReg', (27, 35))	('SNS-032', 'Chemical', 'MESH:C484864', (96, 103))	('migration', 'CPA', (36, 45))	('RhoA', 'Gene', (22, 26))	('RhoA', 'Gene', '387', (22, 26))
141383	31526394	Our results showed that SNS-032 has no effect on the expression of Galphaq/11 (data not shown), suggesting that SNS-032 inhibits RhoA activation and actin polymerization may not through Galphaq/11.	('inhibits', 'NegReg', (120, 128))	('SNS-032', 'Var', (112, 119))	('actin polymerization', 'CPA', (149, 169))	('actin polymerization', 'biological_process', 'GO:0030041', ('149', '169'))	('SNS-032', 'Chemical', 'MESH:C484864', (112, 119))	('RhoA', 'Gene', (129, 133))	('Galphaq', 'Gene', '2776', (186, 193))	('RhoA', 'Gene', '387', (129, 133))	('Galphaq', 'Gene', (186, 193))	('Galphaq', 'Gene', (67, 74))	('SNS-032', 'Chemical', 'MESH:C484864', (24, 31))	('Galphaq', 'Gene', '2776', (67, 74))
141393	31526394	We discovered that CDK7/9 is highly expressed in UM cells, transcriptional inhibition by a potent and selective CDK7/9 inhibitor SNS-032 remarkably suppressed the cellular growth in vitro and in xenograft NOD-SCID mice, induced apoptotic cell death, eradicates CSCs in UM cells.	('CDK', 'molecular_function', 'GO:0004693', ('19', '22'))	('cellular growth', 'biological_process', 'GO:0016049', ('163', '178'))	('apoptotic cell death', 'CPA', (228, 248))	('SNS-032', 'Chemical', 'MESH:C484864', (129, 136))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('228', '248'))	('CDK', 'molecular_function', 'GO:0004693', ('112', '115'))	('inhibitor', 'Var', (119, 128))	('NOD', 'Gene', '1822', (205, 208))	('UM', 'Phenotype', 'HP:0007716', (49, 51))	('CDK7/9', 'Gene', (112, 118))	('induced', 'Reg', (220, 227))	('NOD', 'Gene', (205, 208))	('cellular growth', 'CPA', (163, 178))	('suppressed', 'NegReg', (148, 158))	('transcriptional', 'MPA', (59, 74))	('CSCs', 'Disease', (261, 265))	('UM', 'Phenotype', 'HP:0007716', (269, 271))	('SNS-032', 'Gene', (129, 136))	('eradicates', 'NegReg', (250, 260))	('mice', 'Species', '10090', (214, 218))
141394	31526394	Strikingly, SNS-032 dramatically inhibited the activation of RhoA GTPase and actin polymerization, and subsequently reduced the invasive phenotypes (e.g., migration and invasion) and liver metastasis in UM.	('activation', 'MPA', (47, 57))	('liver metastasis', 'CPA', (183, 199))	('SNS-032', 'Chemical', 'MESH:C484864', (12, 19))	('GTP', 'Chemical', 'MESH:D006160', (66, 69))	('actin polymerization', 'CPA', (77, 97))	('RhoA', 'Gene', (61, 65))	('SNS-032', 'Var', (12, 19))	('reduced', 'NegReg', (116, 123))	('actin polymerization', 'biological_process', 'GO:0030041', ('77', '97'))	('invasive phenotypes', 'CPA', (128, 147))	('inhibited', 'NegReg', (33, 42))	('UM', 'Phenotype', 'HP:0007716', (203, 205))	('RhoA', 'Gene', '387', (61, 65))
141414	31323773	Genetic predictors for metastatic tumour behaviour are monosomy 3, gain of chromosome 8q, loss of BRCA1-associated protein 1 (BAP1) expression and a Class II gene expression profile.	('behaviour', 'biological_process', 'GO:0007610', ('41', '50'))	('loss', 'NegReg', (90, 94))	('BAP1', 'Gene', (126, 130))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour', 'Disease', (34, 40))	('monosomy 3', 'Var', (55, 65))	('BAP1', 'Gene', '8314', (126, 130))	('BRCA1-associated protein 1', 'Gene', '8314', (98, 124))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('gain', 'PosReg', (67, 71))	('expression', 'MPA', (132, 142))	('gene expression', 'biological_process', 'GO:0010467', ('158', '173'))	('BRCA1-associated protein 1', 'Gene', (98, 124))	('chromosome', 'cellular_component', 'GO:0005694', ('75', '85'))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
141421	31323773	VHL is mainly known for its role in the VHL syndrome, a disease caused by a mutation in the VHL gene on the short arm of chromosome 3, and this syndrome is associated with the development of various malignant diseases, including hemangioblastoma of the retina and of the central nervous system, and with tumours as renal cell carcinoma (RCC) and pheochromocytoma.	('hemangioblastoma of the retina', 'Disease', 'MESH:D018325', (229, 259))	('VHL', 'Gene', '7428', (40, 43))	('tumours', 'Disease', (304, 311))	('carcinoma', 'Phenotype', 'HP:0030731', (326, 335))	('renal cell carcinoma', 'Disease', (315, 335))	('pheochromocytoma', 'Disease', 'MESH:D010673', (346, 362))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (315, 335))	('VHL', 'Gene', '7428', (0, 3))	('mutation', 'Var', (76, 84))	('short arm', 'Phenotype', 'HP:0009824', (108, 117))	('RCC', 'Disease', (337, 340))	('RCC', 'Phenotype', 'HP:0005584', (337, 340))	('tumours', 'Phenotype', 'HP:0002664', (304, 311))	('chromosome', 'cellular_component', 'GO:0005694', ('121', '131'))	('VHL', 'Gene', (92, 95))	('tumours', 'Disease', 'MESH:D009369', (304, 311))	('pheochromocytoma', 'Disease', (346, 362))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (346, 362))	('tumour', 'Phenotype', 'HP:0002664', (304, 310))	('RCC', 'Disease', 'MESH:C538614', (337, 340))	('hemangioblastoma of the retina', 'Disease', (229, 259))	('VHL syndrome', 'Disease', (40, 52))	('caused by', 'Reg', (64, 73))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (229, 245))	('VHL', 'Gene', '7428', (92, 95))	('malignant diseases', 'Disease', (199, 217))	('associated', 'Reg', (156, 166))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (315, 335))	('VHL', 'Gene', (40, 43))	('a disease', 'Disease', 'MESH:D004194', (54, 63))	('malignant diseases', 'Disease', 'MESH:D009369', (199, 217))	('VHL', 'Gene', (0, 3))	('a disease', 'Disease', (54, 63))	('VHL syndrome', 'Disease', 'MESH:D006623', (40, 52))
141422	31323773	In several solid organ malignancies, a high HIF1a expression is related to a poor clinical outcome.	('high', 'Var', (39, 43))	('malignancies', 'Disease', (23, 35))	('HIF1a', 'Gene', (44, 49))	('related', 'Reg', (64, 71))	('HIF1a', 'Gene', '3091', (44, 49))	('malignancies', 'Disease', 'MESH:D009369', (23, 35))	('expression', 'MPA', (50, 60))
141440	31323773	However, a high HIF1a expression was related to worse survival in a Kaplan-Meier analysis (Figure 1).	('HIF1a', 'Gene', (16, 21))	('HIF1a', 'Gene', '3091', (16, 21))	('expression', 'MPA', (22, 32))	('high', 'Var', (11, 15))
141451	31323773	Tumour genetics influence inflammation, as tumours with an extra copy of chromosome 8q are known to have more macrophages, while loss of one chromosome 3 is associated with a complete inflammatory phenotype, containing a mixture of T cells and macrophages.	('chromosome', 'cellular_component', 'GO:0005694', ('73', '83'))	('more', 'PosReg', (105, 109))	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('influence', 'Reg', (16, 25))	('associated with', 'Reg', (157, 172))	('inflammation', 'Disease', 'MESH:D007249', (26, 38))	('chromosome', 'cellular_component', 'GO:0005694', ('141', '151'))	('tumours', 'Disease', 'MESH:D009369', (43, 50))	('loss', 'Var', (129, 133))	('tumours', 'Disease', (43, 50))	('extra copy', 'Var', (59, 69))	('inflammation', 'Disease', (26, 38))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('macrophages', 'MPA', (110, 121))	('inflammation', 'biological_process', 'GO:0006954', ('26', '38'))
141455	31323773	Tumours with monosomy 3 (M3) (n = 34) had a higher expression of HIF1a (p = 0.001) and a lower expression of VHL (p < 0.001) compared to tumours with disomy 3 (D3) (n = 20) (Table 3).	('lower', 'NegReg', (89, 94))	('monosomy 3', 'Var', (13, 23))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('higher', 'PosReg', (44, 50))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('VHL', 'Gene', (109, 112))	('HIF1a', 'Gene', (65, 70))	('tumours', 'Disease', 'MESH:D009369', (137, 144))	('HIF1a', 'Gene', '3091', (65, 70))	('expression', 'MPA', (51, 61))	('VHL', 'Gene', '7428', (109, 112))	('tumours', 'Disease', (137, 144))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('expression', 'MPA', (95, 105))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
141465	31323773	While loss of BAP1 (or M3) is considered a late event during UM tumour evolution, gain of 8q is considered an early event.	('BAP1', 'Gene', '8314', (14, 18))	('loss', 'Var', (6, 10))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('BAP1', 'Gene', (14, 18))	('tumour', 'Disease', (64, 70))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
141466	31323773	When analysing all cases, gain of chromosome 8q was associated with an increased expression of HIF1a (p = 0.003) and a decreased expression of VHL (p = 0.001); however, 8q gain itself was associated with BAP1 loss/M3.	('chromosome 8q', 'Var', (34, 47))	('decreased', 'NegReg', (119, 128))	('expression', 'MPA', (129, 139))	('loss/M3', 'NegReg', (209, 216))	('chromosome', 'cellular_component', 'GO:0005694', ('34', '44'))	('gain', 'PosReg', (172, 176))	('HIF1a', 'Gene', (95, 100))	('BAP1', 'Gene', (204, 208))	('BAP1', 'Gene', '8314', (204, 208))	('VHL', 'Gene', (143, 146))	('increased', 'PosReg', (71, 80))	('gain', 'PosReg', (26, 30))	('VHL', 'Gene', '7428', (143, 146))	('HIF1a', 'Gene', '3091', (95, 100))	('expression', 'MPA', (81, 91))
141467	31323773	Within the group of D3 lesions (and also within lesions with both D3 and BAP1 expression), 8q gain was no longer associated with either HIF1a or VHL (all p > 0.10) (Table 3) (Figure 2c,d).	('BAP1', 'Gene', '8314', (73, 77))	('HIF1a', 'Gene', (136, 141))	('BAP1', 'Gene', (73, 77))	('D3 lesions', 'Var', (20, 30))	('gain', 'PosReg', (94, 98))	('VHL', 'Gene', (145, 148))	('HIF1a', 'Gene', '3091', (136, 141))	('VHL', 'Gene', '7428', (145, 148))
141476	31323773	Within D3 lesions (n = 20), a significant relationship was found between LBD and lower VHL (univariate regression analysis, p = 0.033), indicating that tumour size may have an initial role in VHL expression, but is overshadowed by the effect of M3 as soon as this event occurs.	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('VHL', 'Gene', '7428', (87, 90))	('lower', 'NegReg', (81, 86))	('tumour', 'Disease', (152, 158))	('expression', 'MPA', (196, 206))	('VHL', 'Gene', (192, 195))	('lesions', 'Var', (10, 17))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('D3 lesions', 'Var', (7, 17))	('VHL', 'Gene', (87, 90))	('VHL', 'Gene', '7428', (192, 195))
141534	31323773	Expression of HIF1a is increased in tumours with monosomy 3 and BAP1 loss, but not with gain of chromosome 8q.	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('HIF1a', 'Gene', '3091', (14, 19))	('loss', 'NegReg', (69, 73))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('Expression', 'MPA', (0, 10))	('tumours', 'Disease', (36, 43))	('HIF1a', 'Gene', (14, 19))	('monosomy 3', 'Var', (49, 59))	('BAP1', 'Gene', '8314', (64, 68))	('increased', 'PosReg', (23, 32))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('BAP1', 'Gene', (64, 68))
141539	30477459	Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma Germline mutations in BAP1 have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a predisposition to multiple tumors within a family that includes uveal melanoma (UM), cutaneous melanoma, malignant mesothelioma and renal cell carcinoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (261, 275))	('Melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('BAP1', 'Gene', (183, 187))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (329, 349))	('Metastasis in Uveal Melanoma', 'Disease', (65, 93))	('TPDS', 'Chemical', '-', (188, 192))	('BAP1', 'Gene', '8314', (38, 42))	('mutations', 'Var', (103, 112))	('malignant mesothelioma and renal cell carcinoma', 'Disease', 'MESH:C562839', (302, 349))	('BAP1', 'Gene', '8314', (116, 120))	('BAP1', 'Gene', '8314', (147, 151))	('multiple tumors', 'Disease', (215, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (340, 349))	('melanoma', 'Phenotype', 'HP:0002861', (292, 300))	('cutaneous melanoma', 'Disease', (282, 300))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (282, 300))	('BAP1', 'Gene', (38, 42))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (282, 300))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('associated', 'Reg', (131, 141))	('uveal melanoma', 'Disease', 'MESH:C536494', (261, 275))	('BAP1', 'Gene', (116, 120))	('BAP1', 'Gene', (147, 151))	('BAP1', 'Gene', '8314', (183, 187))	('uveal melanoma', 'Disease', (261, 275))	('Metastasis in Uveal Melanoma', 'Disease', 'MESH:C536494', (65, 93))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('Tumor', 'Phenotype', 'HP:0002664', (152, 157))	('multiple tumors', 'Disease', 'MESH:D009369', (215, 230))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (302, 324))	('UM', 'Phenotype', 'HP:0007716', (277, 279))
141540	30477459	Alternatively, somatic mutations in BAP1 in UM have been associated with high risk for metastasis.	('metastasis', 'CPA', (87, 97))	('BAP1', 'Gene', '8314', (36, 40))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('BAP1', 'Gene', (36, 40))	('associated', 'Reg', (57, 67))	('somatic mutations', 'Var', (15, 32))
141541	30477459	In this study, we compare the risk of metastasis in UM that carry germline versus somatic BAP1 mutations and mutation-negative tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('BAP1', 'Gene', '8314', (90, 94))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('BAP1', 'Gene', (90, 94))	('mutations', 'Var', (95, 104))	('metastasis', 'CPA', (38, 48))
141542	30477459	DNA extracted from 142 UM and matched blood samples was sequenced using Sanger or next generation sequencing to identify BAP1 gene mutations.	('mutations', 'Var', (131, 140))	('BAP1', 'Gene', '8314', (121, 125))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('BAP1', 'Gene', (121, 125))	('UM', 'Phenotype', 'HP:0007716', (23, 25))
141543	30477459	Eleven of 142 UM (8%) carried germline BAP1 mutations, 43 (30%) had somatic mutations, and 88 (62%) were mutation-negative.	('BAP1', 'Gene', '8314', (39, 43))	('mutations', 'Var', (44, 53))	('UM', 'Phenotype', 'HP:0007716', (14, 16))	('BAP1', 'Gene', (39, 43))
141544	30477459	All BAP1 mutations identified in blood samples were also present in the matched UM.	('BAP1', 'Gene', (4, 8))	('mutations', 'Var', (9, 18))	('UM', 'Phenotype', 'HP:0007716', (80, 82))	('BAP1', 'Gene', '8314', (4, 8))
141545	30477459	There were 52 unique mutations in 54 tumors.	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('mutations', 'Var', (21, 30))
141547	30477459	Tumors with a somatic mutation compared to mutation-negative had an older age of diagnosis of (61.8 vs. 52.2 years, P=0.002), and shorter time to metastasis (16 vs. 26 months, P=0.04).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('somatic mutation', 'Var', (14, 30))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
141548	30477459	Kaplan-Meier analysis further showed that tumors with somatic (vs. germline) mutations demonstrated a greater metastatic risk (P=0.03).	('tumors', 'Disease', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('metastatic', 'CPA', (110, 120))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('mutations', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
141549	30477459	Cox multivariate analysis showed in addition to chromosome-3 monosomy and larger tumor diameter, the presence of BAP1 somatic, but not germline mutations, was significantly associated with risk of metastasis(P=0.02).	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('presence', 'Var', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('metastasis', 'CPA', (197, 207))	('BAP1', 'Gene', '8314', (113, 117))	('associated', 'Reg', (173, 183))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('chromosome', 'cellular_component', 'GO:0005694', ('48', '58'))	('BAP1', 'Gene', (113, 117))	('tumor', 'Disease', (81, 86))
141551	30477459	All eight cases with germline mutations reported a history of BAP1-TPDS, which was significantly greater than what was observed in cases with somatic mutations (10 of 23, P=0.009) or mutation-negative cases (11 of 48, P<0.001).	('BAP1', 'Gene', '8314', (62, 66))	('BAP1', 'Gene', (62, 66))	('germline mutations', 'Var', (21, 39))	('greater', 'PosReg', (97, 104))	('TPDS', 'Chemical', '-', (67, 71))
141552	30477459	Defining germline vs. somatic nature of BAP1 mutations in UM can inform the individual about both the risk of metastasis, and the time to metastasis, which are critically important outcomes for the individual.	('mutations', 'Var', (45, 54))	('inform', 'Reg', (65, 71))	('BAP1', 'Gene', '8314', (40, 44))	('BAP1', 'Gene', (40, 44))	('UM', 'Phenotype', 'HP:0007716', (58, 60))
141555	30477459	Germline BAP1 mutations have been associated with hereditary predisposition to multiple different cancers that include uveal and cutaneous melanoma, malignant mesothelioma on exposure to asbestos, renal cell carcinoma and other cancer types, such as lung adenocarcinoma and meningioma, that are collectively referred to as BAP1 Tumor Predisposition Syndrome (BAP1-TPDS, OMIM #614327).	('meningioma', 'Disease', (274, 284))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('asbestos', 'Chemical', 'MESH:D001194', (187, 195))	('meningioma', 'Phenotype', 'HP:0002858', (274, 284))	('lung adenocarcinoma', 'Disease', (250, 269))	('cancer', 'Disease', (98, 104))	('cancers', 'Disease', (98, 105))	('BAP1', 'Gene', (359, 363))	('BAP1', 'Gene', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (149, 171))	('TPDS', 'Chemical', '-', (364, 368))	('BAP1', 'Gene', '8314', (323, 327))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (250, 269))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (197, 217))	('meningioma', 'Disease', 'MESH:D008577', (274, 284))	('mutations', 'Var', (14, 23))	('uveal', 'Disease', (119, 124))	('malignant mesothelioma', 'Disease', (149, 171))	('cancer', 'Disease', (228, 234))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (250, 269))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('BAP1', 'Gene', (323, 327))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (149, 171))	('Tumor', 'Phenotype', 'HP:0002664', (328, 333))	('associated', 'Reg', (34, 44))	('renal cell carcinoma', 'Disease', (197, 217))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (197, 217))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('BAP1', 'Gene', '8314', (359, 363))	('BAP1', 'Gene', '8314', (9, 13))	('cutaneous melanoma', 'Disease', (129, 147))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (129, 147))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (129, 147))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
141559	30477459	Factors such as large tumor size, location and chromosome 3 monosomy, as well as a specific 12-gene expression pattern have all been associated with an increased risk of metastasis.	('monosomy', 'Var', (60, 68))	('chromosome 3 monosomy', 'Var', (47, 68))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('metastasis', 'CPA', (170, 180))	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('gene expression', 'biological_process', 'GO:0010467', ('95', '110'))	('tumor', 'Disease', (22, 27))	('associated', 'Reg', (133, 143))
141560	30477459	In addition, the presence of inactivating somatic or germline BAP1 mutations often in conjunction with chromosome 3 monosomy, loss of BAP1 expression, or lack of immunohistochemical staining, have all been associated with metastasizing UM.	('chromosome', 'cellular_component', 'GO:0005694', ('103', '113'))	('BAP1', 'Gene', '8314', (62, 66))	('BAP1', 'Gene', (134, 138))	('associated', 'Reg', (206, 216))	('inactivating', 'Var', (29, 41))	('BAP1', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))	('UM', 'Phenotype', 'HP:0007716', (236, 238))	('metastasizing UM', 'Disease', (222, 238))	('loss', 'NegReg', (126, 130))	('BAP1', 'Gene', '8314', (134, 138))
141561	30477459	Germline BAP1 mutations have been identified in approximately 2-5% of UM unselected for the presence of any high risk of hereditary cancers.	('hereditary cancers', 'Disease', 'MESH:D009369', (121, 139))	('BAP1', 'Gene', (9, 13))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('BAP1', 'Gene', '8314', (9, 13))	('hereditary cancers', 'Disease', (121, 139))	('identified', 'Reg', (34, 44))	('mutations', 'Var', (14, 23))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
141562	30477459	These studies reported that metastasis occurred more frequently in UM carrying germline mutations in the blood compared to BAP1 mutation-negative controls, but the differences were significant only in one study, possibly due to the small number of tumors with germline mutations.	('BAP1', 'Gene', (123, 127))	('tumors', 'Disease', (248, 254))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('germline mutations', 'Var', (79, 97))	('UM', 'Phenotype', 'HP:0007716', (67, 69))	('BAP1', 'Gene', '8314', (123, 127))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('metastasis', 'CPA', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
141563	30477459	In studies where DNA from both tumor tissue and blood was sequenced to rule out the presence of germline mutations, the frequency of somatic BAP1 mutations was considerably higher than that observed in tumors with germline mutations, approaching 50%.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('BAP1', 'Gene', '8314', (141, 145))	('mutations', 'Var', (146, 155))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', (31, 36))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('BAP1', 'Gene', (141, 145))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
141564	30477459	In other studies where somatic mutations were detected by BAP1 expression assays and/or negative immunohistochemical staining methods, as well as sequencing, the lack of BAP1 expression was also significantly associated with the risk of metastasis.	('metastasis', 'CPA', (237, 247))	('associated', 'Reg', (209, 219))	('expression', 'MPA', (175, 185))	('BAP1', 'Gene', '8314', (170, 174))	('BAP1', 'Gene', (58, 62))	('BAP1', 'Gene', (170, 174))	('lack', 'Var', (162, 166))	('BAP1', 'Gene', '8314', (58, 62))
141565	30477459	While these studies show a strong association between somatic BAP1 mutations and metastasis, the effect of germline changes remains unclear.	('BAP1', 'Gene', '8314', (62, 66))	('metastasis', 'CPA', (81, 91))	('BAP1', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))
141567	30477459	In this study of BAP1 mutations in UM, the presence of germline or somatic mutations was determined using sequence analysis of DNA extracted from biopsies of both enucleated globes and fine needle aspirations (FNA) and from matched blood samples.	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('aspirations', 'Phenotype', 'HP:0002835', (197, 208))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))	('BAP1', 'Gene', (17, 21))
141568	30477459	Demographic and clinical characteristics of the tumors and the frequency of metastasis were compared among tumors with germline or somatic BAP1 mutations and mutation-negative UM.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('BAP1', 'Gene', '8314', (139, 143))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('BAP1', 'Gene', (139, 143))	('mutations', 'Var', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('UM', 'Phenotype', 'HP:0007716', (176, 178))
141569	30477459	A total of 142 UM cases managed by the Ocular Oncology Service at Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA between 1998 and 2016 were evaluated in this study of somatic and germline BAP1 mutations.	('BAP1', 'Gene', '8314', (212, 216))	('BAP1', 'Gene', (212, 216))	('Ocular Oncology', 'Phenotype', 'HP:0100012', (39, 54))	('UM', 'Phenotype', 'HP:0007716', (15, 17))	('mutations', 'Var', (217, 226))	('Oncology', 'Phenotype', 'HP:0002664', (46, 54))
141575	30477459	In addition, there was no significant difference between the two cohorts in the relative number of tumors carrying germline or somatic BAP1 mutations and mutation-negative tumors (P= 0.76), or in the number of cases with personal or family history of BAP1-TPDS cancers (P=0.35, see below and Additional file 1: Table S1).	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('BAP1', 'Gene', (251, 255))	('tumors', 'Disease', (172, 178))	('BAP1-TPDS cancers', 'Disease', 'OMIM:614327', (251, 268))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('BAP1', 'Gene', '8314', (135, 139))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('BAP1', 'Gene', (135, 139))	('mutations', 'Var', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('BAP1-TPDS cancers', 'Disease', (251, 268))	('BAP1', 'Gene', '8314', (251, 255))	('tumors', 'Disease', (99, 105))
141580	30477459	DNA from enucleated tumor or FNA biopsies was sequenced to identify BAP1 mutations using either Sanger or next generation sequencing of all coding exons and adjacent intronic regions.	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('BAP1', 'Gene', '8314', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('BAP1', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))	('tumor', 'Disease', (20, 25))
141582	30477459	Tumors were categorized as either disomy-3 (N=63) or monosomy (N=79) that included 72 tumors with complete monosomy-3, two with partial monosomy and five with a mosaic monosomy 3 indicating tumor heterogeneity of cells with chromosome-3 disomy and monosomy.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('disomy-3', 'Disease', (34, 42))	('tumors', 'Disease', (86, 92))	('complete monosomy-3', 'Var', (98, 117))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('Tumors', 'Disease', (0, 6))	('tumor', 'Disease', (190, 195))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('disomy-3', 'Disease', 'MESH:D024182', (34, 42))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('chromosome', 'cellular_component', 'GO:0005694', ('224', '234'))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
141585	30477459	Of the 142 UM characterized in this study, 54 (38%) carried a BAP1 gene mutation.	('UM', 'Phenotype', 'HP:0007716', (11, 13))	('BAP1', 'Gene', '8314', (62, 66))	('BAP1', 'Gene', (62, 66))	('mutation', 'Var', (72, 80))
141589	30477459	Overall, 63 (44%) of the tumors carried two copies of chromosome 3 (disomy), and 79 (56%) carried one copy of chromosome 3 (monosomy), partial monosomy or mosaic.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('chromosome', 'cellular_component', 'GO:0005694', ('54', '64'))	('partial monosomy', 'Var', (135, 151))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('mosaic', 'Var', (155, 161))
141594	30477459	Thirty-six of 54 tumors with BAP1 mutations metastasized (67%) compared to only 23 of 88 (26%) mutation-negative tumors (P<0.001) within 2-107 months.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('metastasized', 'CPA', (44, 56))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('BAP1', 'Gene', '8314', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('BAP1', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mutations', 'Var', (34, 43))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
141599	30477459	Importantly, there was no difference in the number of tumors carrying a germline or somatic mutation or mutation-negative tumors in enucleated tumors compared to FNA samples (P=0.79, Table 1 footnotea).	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('germline', 'Var', (72, 80))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
141600	30477459	In a Cox univariate analysis, the presence of a somatic, but not a germline BAP1 mutation (hazard ratio (HR) =4.81, P<0.0001; HR=1.7, P=0.33, respectively, Table 1) was significantly associated with metastasis.	('Cox', 'Gene', (5, 8))	('BAP1', 'Gene', '8314', (76, 80))	('mutation', 'Var', (81, 89))	('BAP1', 'Gene', (76, 80))	('metastasis', 'CPA', (199, 209))	('associated with', 'Reg', (183, 198))	('Cox', 'Gene', '1351', (5, 8))	('presence', 'Var', (34, 42))
141601	30477459	Other tumor variables that were significant in the univariate regression analysis included tumor source (FNA or enucleated tumor, HR= 2.12; P=0.01), age HR=1.02, P=0.04), chromosome 3 monosomy, larger tumor diameter and thickness, and ciliary body involvement (HR=4.64, 1.25 and 1.22, respectively; all P<=0.001).	('chromosome', 'cellular_component', 'GO:0005694', ('171', '181'))	('tumor', 'Disease', (123, 128))	('ciliary body involvement', 'CPA', (235, 259))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('chromosome', 'Var', (171, 181))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', (6, 11))
141602	30477459	Considering all variables in a multivariate analysis, the presence of a somatic BAP1 mutation (HR=2.20, P=0.02), age (HR=1.02, P=0.03) tumor diameter (HR=1.20, P<0.001), and chromosome 3 monosomy (HR=2.99, P=0.008) remained significant, while the presence of a germline mutation was not significant (HR=0.87, P=0.81).	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('BAP1', 'Gene', '8314', (80, 84))	('tumor', 'Disease', (135, 140))	('mutation', 'Var', (85, 93))	('chromosome', 'cellular_component', 'GO:0005694', ('174', '184'))	('BAP1', 'Gene', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
141603	30477459	Fifty-two unique BAP1 mutations were identified in 54 tumors: 43 tumors (30%) carried somatic mutations, while 11 tumors (8%) carried germline mutations (Table 3).	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('BAP1', 'Gene', '8314', (17, 21))	('tumors', 'Disease', (114, 120))	('mutations', 'Var', (22, 31))	('carried', 'Reg', (78, 85))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))	('BAP1', 'Gene', (17, 21))
141605	30477459	One splice-site mutation, c.438-1A>G was present as a germline mutation in one tumor (UM-23) and as a somatic mutation in two tumors (UM-11 and UM-27).	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Disease', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('UM', 'Phenotype', 'HP:0007716', (86, 88))	('c.438-1A>G', 'Var', (26, 36))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('c.438-1A>G', 'Mutation', 'c.438-1A>G', (26, 36))	('UM', 'Phenotype', 'HP:0007716', (134, 136))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('UM', 'Phenotype', 'HP:0007716', (144, 146))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (126, 131))
141606	30477459	Clinical and tumor characteristics of UM carrying BAP1 germline or somatic mutations and mutation-negative tumors, as well as pairwise comparisons of the three groups are presented in Table 2.	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('BAP1', 'Gene', '8314', (50, 54))	('germline', 'Var', (55, 63))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('BAP1', 'Gene', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('UM', 'Phenotype', 'HP:0007716', (38, 40))
141607	30477459	The age at diagnosis of individuals with somatic mutations was significantly older (61.8 years, range=28-88) than individuals with mutation-negative tumors (median=52.2 years, range=14-84 years, P=0.002) and approached significance compared to individuals with a tumor carrying a germline mutation (median=59.0 years, range=22-67, P=0.07).	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('mutations', 'Var', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('tumor', 'Disease', (263, 268))	('tumor', 'Disease', (149, 154))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))
141608	30477459	There was a significant difference in the comparison of chromosome 3 monosomy in mutation-negative tumors compared to tumors with either germline or somatic mutations.	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('monosomy', 'Var', (69, 77))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('chromosome', 'cellular_component', 'GO:0005694', ('56', '66'))	('tumors', 'Disease', (99, 105))	('tumors', 'Disease', (118, 124))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('mutation-negative', 'Reg', (81, 98))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
141609	30477459	Only 26 (33%) mutation-negative tumors carried monosomy 3, while ten (91%) tumors with germline mutations and 40 (93%) with somatic mutations were chromosome 3 monosomy (P<0.001 in both cases).	('monosomy 3', 'Var', (47, 57))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', (75, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('147', '157'))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
141611	30477459	There were four tumors with BAP1 mutations and chromosome 3 disomy (marked with superscript b in Table 3).	('BAP1', 'Gene', '8314', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('chromosome', 'Gene', (47, 57))	('BAP1', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutations', 'Var', (33, 42))	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (16, 22))	('disomy', 'Var', (60, 66))
141614	30477459	The three somatic mutations included one splice-site mutation (intron 6, c.438-2A>G) and two truncating mutations: exon 4, c.178C>T (p.Arg60X) and a large deletion of exons 15-17 and the intervening introns.	('p.Arg60X', 'Mutation', 'rs1253151209', (133, 141))	('c.438-2A>G', 'Mutation', 'rs587776879', (73, 83))	('deletion', 'Var', (155, 163))	('c.178C>T (p.Arg60X', 'Var', (123, 141))	('c.178C>T', 'Mutation', 'rs1253151209', (123, 131))
141620	30477459	However, there was no significant difference in the frequency of metastasis between tumors with germline mutations and BAP1-negative tumors (P=0.72).	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('metastasis', 'CPA', (65, 75))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('BAP1', 'Gene', '8314', (119, 123))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('germline mutations', 'Var', (96, 114))	('BAP1', 'Gene', (119, 123))
141622	30477459	Kaplan-Meier analysis (Figure 1) also showed that tumors with a BAP1 somatic mutation had a significantly poorer metastatic outcome compared to those with germline mutations (P=0.03) or mutation-negative tumors (P<0.001), but the difference between tumors with germline mutations and BAP1 mutation-negative tumors was not significant (P=0.23).	('mutation', 'Var', (77, 85))	('BAP1', 'Gene', '8314', (284, 288))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('BAP1', 'Gene', (64, 68))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('metastatic outcome', 'CPA', (113, 131))	('tumors', 'Phenotype', 'HP:0002664', (307, 313))	('tumors', 'Disease', (204, 210))	('BAP1', 'Gene', (284, 288))	('poorer', 'NegReg', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumors', 'Disease', (307, 313))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('BAP1', 'Gene', '8314', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', 'MESH:D009369', (307, 313))	('tumors', 'Disease', (50, 56))	('tumors', 'Disease', (249, 255))
141625	30477459	There were eight cases that carried a germline mutation with information on personal or familial cancers; all had a positive history of BAP1-TPDS.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('BAP1', 'Gene', (136, 140))	('familial cancers', 'Disease', 'MESH:D009369', (88, 104))	('TPDS', 'Chemical', '-', (141, 145))	('familial cancers', 'Disease', (88, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('germline mutation', 'Var', (38, 55))	('BAP1', 'Gene', '8314', (136, 140))
141626	30477459	Comparisons of BAP1-TPDS tumors in UM cases with a germline (8, 100%) vs. somatic mutation (10, 44%) or germline vs. mutation-negative (11, 23%) were significant (P=0.009 and P<0.001, respectively), while a comparison of those with somatic mutations was not significantly different from those with mutation-negative tumors (P=0.10) Inactivating somatic mutations in the BAP1 gene in UM were first identified and associated with metastatic disease in 2010.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (316, 322))	('BAP1', 'Gene', '8314', (15, 19))	('BAP1-TPDS tumors', 'Disease', 'OMIM:614327', (15, 31))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('associated', 'Reg', (412, 422))	('UM', 'Phenotype', 'HP:0007716', (383, 385))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('tumors', 'Disease', (316, 322))	('BAP1', 'Gene', '8314', (370, 374))	('BAP1', 'Gene', (15, 19))	('metastatic disease', 'Disease', (428, 446))	('tumors', 'Disease', 'MESH:D009369', (316, 322))	('Inactivating somatic mutations', 'Var', (332, 362))	('BAP1-TPDS tumors', 'Disease', (15, 31))	('BAP1', 'Gene', (370, 374))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))
141628	30477459	However, to our knowledge, this is the first report directly comparing risk of metastasis in tumors carrying germline or somatic BAP1 mutations and mutation-negative tumors.	('metastasis in tumors', 'Disease', 'MESH:D009362', (79, 99))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('BAP1', 'Gene', '8314', (129, 133))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('mutations', 'Var', (134, 143))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumors', 'Disease', (93, 99))	('tumors', 'Disease', (166, 172))	('metastasis in tumors', 'Disease', (79, 99))	('BAP1', 'Gene', (129, 133))
141630	30477459	A second important difference in this study is that, compared to most other reports where UM tumors analyzed for BAP1 mutations were comprised primarily of samples biopsied from larger, enucleated tumors, 84% of the samples analyzed in this study were from FNA biopsies.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('UM', 'Phenotype', 'HP:0007716', (90, 92))	('mutations', 'Var', (118, 127))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('BAP1', 'Gene', '8314', (113, 117))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (93, 99))	('tumors', 'Disease', (197, 203))	('BAP1', 'Gene', (113, 117))
141631	30477459	We found no significant difference in the frequency of somatic and germline mutations in biopsies from FNAs compared to enucleated tumors.	('germline mutations', 'Var', (67, 85))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('FNAs', 'Disease', (103, 107))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))
141632	30477459	Since the majority of UM are currently being treated by globe sparing procedures, it was important to determine whether the consequences of carrying a BAP1 mutation identified in larger enucleated tumors could be applied to smaller UM biopsied by FNA sampling.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('BAP1', 'Gene', (151, 155))	('UM', 'Phenotype', 'HP:0007716', (232, 234))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('UM', 'Phenotype', 'HP:0007716', (22, 24))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))	('BAP1', 'Gene', '8314', (151, 155))	('mutation', 'Var', (156, 164))
141633	30477459	It is well established that tumor characteristics such as tumor diameter, ciliary body involvement and chromosome 3 monosomy are all associated with poor prognosis as measured by the development of metastases within 48 months after the primary is treated.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('chromosome', 'cellular_component', 'GO:0005694', ('103', '113'))	('tumor', 'Disease', (28, 33))	('metastases', 'Disease', (198, 208))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('monosomy', 'Var', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('metastases', 'Disease', 'MESH:D009362', (198, 208))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('chromosome 3', 'Gene', (103, 115))
141634	30477459	It has also been shown that that these same variables are significantly associated with BAP1 mutation status in tumors with somatic or germline mutations.	('associated', 'Reg', (72, 82))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('BAP1', 'Gene', '8314', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('mutation', 'Var', (93, 101))	('BAP1', 'Gene', (88, 92))	('tumors', 'Disease', (112, 118))
141635	30477459	In this study, multivariate regression analysis showed that in addition to these classic tumor variables, the presence of somatic, but not germline, BAP1 mutations was significantly associated with metastasis (HR=2.20, P=0.02; HR=0.87, P=0.81, respectively).	('associated with', 'Reg', (182, 197))	('BAP1', 'Gene', '8314', (149, 153))	('metastasis', 'CPA', (198, 208))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('BAP1', 'Gene', (149, 153))	('mutations', 'Var', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
141638	30477459	Thus, in a previous publication we showed that tumors with any mutation in the BAP1 gene, in combination with chromosome 3-monosomy, have the highest risk of metastasis (HR=11.5).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('BAP1', 'Gene', '8314', (79, 83))	('BAP1', 'Gene', (79, 83))	('mutation', 'Var', (63, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('metastasis', 'CPA', (158, 168))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
141640	30477459	Given that somatic BAP1 mutations appear to have a highly significant association with poor metastatic prognosis, it is surprising that the age of diagnosis of the individuals whose tumors carried somatic mutations was significantly older (median=61.8 years) compared to those with mutation-negative tumors (median=52.2 years, P=0.002).	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('poor metastatic prognosis', 'CPA', (87, 112))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', (300, 306))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (300, 306))	('BAP1', 'Gene', '8314', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (300, 306))	('BAP1', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('association', 'Reg', (70, 81))
141642	30477459	Among the 54 tumors with BAP1 mutations, there were four with chromosome 3 disomy.	('BAP1', 'Gene', (25, 29))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('chromosome', 'cellular_component', 'GO:0005694', ('62', '72'))	('mutations', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('BAP1', 'Gene', '8314', (25, 29))
141643	30477459	It cannot be ruled out that although these tumors appeared to be disomy-3, small deletions not detectable on the SNP arrays leading to partial monosomy or heterogeneity of the tumor sample could be responsible for this finding.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('deletions', 'Var', (81, 90))	('partial monosomy', 'Var', (135, 151))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('disomy-3', 'Disease', (65, 73))	('tumors', 'Disease', (43, 49))	('disomy-3', 'Disease', 'MESH:D024182', (65, 73))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
141644	30477459	Alternatively, in some cases it is possible the during tumor evolution, BAP1 mutation on one copy of chromosome 3 could precede the loss of the other copy of chromosome 3.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('chromosome', 'cellular_component', 'GO:0005694', ('101', '111'))	('chromosome', 'cellular_component', 'GO:0005694', ('158', '168'))	('BAP1', 'Gene', '8314', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('mutation', 'Var', (77, 85))	('tumor', 'Disease', (55, 60))	('BAP1', 'Gene', (72, 76))
141645	30477459	While several studies have found total concordance between the presence BAP1 mutations and monosomy 3, others using sequencing, gene expression, and/or immunostaining methods have identified BAP1 mutations in a small number of tumors with disomy 3.	('BAP1', 'Gene', '8314', (72, 76))	('identified', 'Reg', (180, 190))	('disomy 3', 'Disease', (239, 247))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('BAP1', 'Gene', '8314', (191, 195))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('BAP1', 'Gene', (72, 76))	('monosomy 3', 'Disease', (91, 101))	('mutations', 'Var', (77, 86))	('BAP1', 'Gene', (191, 195))	('gene expression', 'biological_process', 'GO:0010467', ('128', '143'))	('mutations', 'Var', (196, 205))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
141650	30477459	While the presence of germline BAP1 mutations in cancers associated with BAP1-TPSD is well documented, the role of somatic mutations in this syndrome is not well studied.	('BAP1', 'Gene', '8314', (73, 77))	('BAP1', 'Gene', '8314', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('BAP1', 'Gene', (73, 77))	('mutations', 'Var', (36, 45))	('BAP1', 'Gene', (31, 35))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))
141651	30477459	It is possible that the presence of TPDS in our cohort of UM cases that have a somatic BAP1 mutation or are mutation-negative could be interpreted as evidence for the existence of a second type of the syndrome associated with mutations in a second gene different from BAP1.	('BAP1', 'Gene', '8314', (87, 91))	('BAP1', 'Gene', '8314', (268, 272))	('mutation', 'Var', (92, 100))	('associated', 'Reg', (210, 220))	('type of the syndrome', 'Disease', 'MESH:D017827', (189, 209))	('BAP1', 'Gene', (268, 272))	('BAP1', 'Gene', (87, 91))	('TPDS', 'Chemical', '-', (36, 40))	('mutations', 'Var', (226, 235))	('type of the syndrome', 'Disease', (189, 209))	('UM', 'Phenotype', 'HP:0007716', (58, 60))
141652	30477459	A major strength of this study is that it includes UM sampled from enucleated tumors and FNAs with both somatic and germline BAP1 mutations.	('UM', 'Phenotype', 'HP:0007716', (51, 53))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('BAP1', 'Gene', '8314', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('BAP1', 'Gene', (125, 129))	('mutations', 'Var', (130, 139))
141654	30477459	This study identified significant differences in the risk of metastasis for individuals whose tumors carry somatic vs. germline BAP1 mutations.	('BAP1', 'Gene', '8314', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('BAP1', 'Gene', (128, 132))	('metastasis', 'CPA', (61, 71))	('tumors', 'Disease', (94, 100))	('mutations', 'Var', (133, 142))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
141655	30477459	While overall 36 of 59 (61%) metastasizing tumors carried a BAP1 mutation, only 7% carried germline mutations, compared to 54% with somatic mutations.	('metastasizing', 'CPA', (29, 42))	('BAP1', 'Gene', '8314', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutation', 'Var', (65, 73))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('BAP1', 'Gene', (60, 64))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
141656	30477459	The presence of germline mutations can provide the individual with information concerning the risk of development of other cancers themselves or in other family members, while information about the presence of somatic mutations is relevant to their individual risk of developing metastases within a shorter time period.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('germline mutations', 'Var', (16, 34))	('metastases', 'Disease', 'MESH:D009362', (279, 289))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('presence', 'Var', (4, 12))	('metastases', 'Disease', (279, 289))
141657	30477459	Thus it is important to determine whether a tumor carries a BAP1 mutation, and if positive, to also evaluate a matched blood sample to establish whether the mutation is germline or somatic.	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('BAP1', 'Gene', '8314', (60, 64))	('mutation', 'Var', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('BAP1', 'Gene', (60, 64))	('tumor', 'Disease', (44, 49))
141667	30373609	In two patients we identified resistance-associated variants explaining lack of therapy response.	('resistance-associated', 'Reg', (30, 51))	('patients', 'Species', '9606', (7, 15))	('variants', 'Var', (52, 60))
141675	30373609	Prominent examples are BRAF mutations in metastatic melanoma and HER2 overexpression in breast cancer, which can be targeted by specific kinase inhibitors or monoclonal antibodies, e.g.	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('HER2', 'Gene', '2064', (65, 69))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('BRAF', 'Gene', '673', (23, 27))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('BRAF', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('overexpression', 'PosReg', (70, 84))	('HER2', 'Gene', (65, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('mutations', 'Var', (28, 37))
141679	30373609	This allows us to detect not only cancer type specific alterations, but also mutations common in other cancer types, or mutations with associated therapies that are currently in clinical development.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('alterations', 'Var', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', (34, 40))	('mutations', 'Var', (120, 129))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
141722	30373609	These types of information help to prioritize variants with respect to their significance for tumor development or treatment resistance.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('treatment resistance', 'CPA', (115, 135))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('variants', 'Var', (46, 54))
141723	30373609	For instance, in colorectal cancer new mutations in the MAPK signaling pathway can confer resistance against combined RAF/MEK therapy by sustaining the activity of the pathway.	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('MEK', 'Gene', (122, 125))	('activity', 'MPA', (152, 160))	('MEK', 'Gene', '5609', (122, 125))	('RAF', 'Gene', '22882', (118, 121))	('colorectal cancer', 'Disease', (17, 34))	('MAPK', 'molecular_function', 'GO:0004707', ('56', '60'))	('RAF', 'Gene', (118, 121))	('mutations', 'Var', (39, 48))	('signaling pathway', 'biological_process', 'GO:0007165', ('61', '78'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('56', '70'))	('MAPK', 'Gene', (56, 60))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))	('sustaining', 'PosReg', (137, 147))
141728	30373609	The clinical report is intended to only present the relevant subset of variants found in a tumor.	('variants', 'Var', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
141732	30373609	For instance, the status of BRAF in melanoma (mutations prevalent in 40-50% of all cases) or ALK in lung cancer (rearrangements prevalent in 4-5% of all non-small cell lung cancers) influences eligibility for clinical trials.	('ALK', 'Gene', '238', (93, 96))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (157, 180))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('ALK', 'Gene', (93, 96))	('mutations', 'Var', (46, 55))	('influences', 'Reg', (182, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('lung cancer', 'Disease', (100, 111))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (153, 180))	('cell lung cancers', 'Disease', 'MESH:D008175', (163, 180))	('lung cancers', 'Phenotype', 'HP:0100526', (168, 180))	('BRAF', 'Gene', '673', (28, 32))	('BRAF', 'Gene', (28, 32))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('cell lung cancers', 'Disease', (163, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))
141734	30373609	For instance, various TP53 mutations have been reported to confer resistance to platinum-based chemotherapy in ovarian cancer.	('mutations', 'Var', (27, 36))	('ovarian cancer', 'Disease', (111, 125))	('platinum', 'Chemical', 'MESH:D010984', (80, 88))	('ovarian cancer', 'Phenotype', 'HP:0100615', (111, 125))	('ovarian cancer', 'Disease', 'MESH:D010051', (111, 125))	('TP53', 'Gene', '7157', (22, 26))	('resistance to platinum-based chemotherapy', 'MPA', (66, 107))	('TP53', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
141740	30373609	The BRAF mutation observed in our example patient illustrates how the clinical report can be utilized to facilitate clinical decision making.	('mutation', 'Var', (9, 17))	('patient', 'Species', '9606', (42, 49))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))
141741	30373609	BRAF V600E is a well-known therapy target in melanoma and thus assigned the highest confidence.	('V600E', 'Mutation', 'rs113488022', (5, 10))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
141759	30373609	A high mutational load above 100 non-synonymous coding mutations has been shown to be predictive of positive response to ipilimumab therapy in melanoma.	('ipilimumab', 'Chemical', 'MESH:D000074324', (121, 131))	('mutational load', 'Var', (7, 22))	('positive', 'PosReg', (100, 108))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))
141762	30373609	Furthermore, the patient's tumor harbored amplifications of BRAF, EGFR, MET, and CDK6, which provides a rationale for this tumor's acquired resistance to the triple BRAF/MEK/CDK4&6 inhibitor treatment applied before sequencing.	('CDK6', 'Gene', '1021', (81, 85))	('patient', 'Species', '9606', (17, 24))	('CDK', 'molecular_function', 'GO:0004693', ('174', '177'))	('tumor', 'Disease', (123, 128))	('CDK6', 'Gene', (81, 85))	('tumor', 'Disease', (27, 32))	('EGFR', 'Gene', (66, 70))	('BRAF', 'Gene', '673', (165, 169))	('BRAF', 'Gene', (165, 169))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('MET', 'Gene', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('MEK', 'Gene', '5609', (170, 173))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('MEK', 'Gene', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('EGFR', 'Gene', '1956', (66, 70))	('amplifications', 'Var', (42, 56))	('CDK', 'molecular_function', 'GO:0004693', ('81', '84'))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
141771	30373609	PXR knockdown in cancer cells induces increased paclitaxel sensitivity and apoptotic cell death.	('paclitaxel sensitivity', 'MPA', (48, 70))	('apoptotic cell death', 'CPA', (75, 95))	('PXR', 'Gene', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('75', '95'))	('cancer', 'Disease', (17, 23))	('PXR', 'Gene', '8856', (0, 3))	('knockdown', 'Var', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('increased', 'PosReg', (38, 47))	('paclitaxel', 'Chemical', 'MESH:D017239', (48, 58))
141797	30373609	For patient 13 several damaging variants were identified in genes associated with the MAPK signaling pathway.	('MAPK signaling pathway', 'Pathway', (86, 108))	('MAPK', 'molecular_function', 'GO:0004707', ('86', '90'))	('patient', 'Species', '9606', (4, 11))	('MAPK signaling', 'biological_process', 'GO:0000165', ('86', '100'))	('variants', 'Var', (32, 40))	('signaling pathway', 'biological_process', 'GO:0007165', ('91', '108'))
141801	30373609	For patient 14 the SwissMTB molecular diagnostic identified a variant in the WD40 domain of the tumor suppressor gene FBXW7.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('96', '112'))	('FBXW7', 'Gene', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('FBXW7', 'Gene', '55294', (118, 123))	('tumor', 'Disease', (96, 101))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor suppressor', 'biological_process', 'GO:0051726', ('96', '112'))	('variant in the WD40 domain', 'Var', (62, 88))
141804	30373609	Since in the panel-based analysis the observed FBXW7 variant appeared as the only mutation, a therapy with mTOR inhibitors such as everolimus might be justified.	('everolimus', 'Chemical', 'MESH:D000068338', (131, 141))	('FBXW7', 'Gene', (47, 52))	('mTOR', 'Gene', (107, 111))	('variant', 'Var', (53, 60))	('mTOR', 'Gene', '2475', (107, 111))	('FBXW7', 'Gene', '55294', (47, 52))
141810	30373609	In case of disease progression the SwissMTB report recommends off-label treatment with palbociclib to target the observed loss-of-function variant R80* in CDKN2A.	('CDKN2A', 'Gene', '1029', (155, 161))	('R80*', 'Var', (147, 151))	('loss-of-function', 'NegReg', (122, 138))	('R80*', 'SUBSTITUTION', 'None', (147, 151))	('CDKN2A', 'Gene', (155, 161))
141811	30373609	Patient 17 presented four different resistance mutations, namely ALK G1202R, KRAS S65 N, TP53 C275Y, and TP53 G245D.	('C275Y', 'Var', (94, 99))	('TP53', 'Gene', '7157', (89, 93))	('ALK', 'Gene', '238', (65, 68))	('TP53', 'Gene', (89, 93))	('C275Y', 'Mutation', 'rs863224451', (94, 99))	('KRAS', 'Gene', (77, 81))	('TP53', 'Gene', '7157', (105, 109))	('ALK', 'Gene', (65, 68))	('TP53', 'Gene', (105, 109))	('KRAS', 'Gene', '3845', (77, 81))	('S65 N', 'Mutation', 'p.S65N', (82, 87))	('G1202R', 'Mutation', 'rs1057519783', (69, 75))	('G245D', 'Var', (110, 115))	('Patient', 'Species', '9606', (0, 7))	('G245D', 'Mutation', 'rs121912656', (110, 115))
141813	30373609	Instead, we recommended treatment with tyrosine kinase and mTOR inhibitors such as pazopanib and everolimus based on several variants in genes associated to the MAPK signaling pathway and mTOR signaling pathway.	('MAPK signaling', 'biological_process', 'GO:0000165', ('161', '175'))	('tyrosine kinase', 'Gene', (39, 54))	('mTOR', 'Gene', '2475', (59, 63))	('everolimus', 'Chemical', 'MESH:D000068338', (97, 107))	('pazopanib', 'Chemical', 'MESH:C516667', (83, 92))	('signaling pathway', 'biological_process', 'GO:0007165', ('166', '183'))	('variants', 'Var', (125, 133))	('signaling pathway', 'biological_process', 'GO:0007165', ('193', '210'))	('mTOR', 'Gene', (188, 192))	('MAPK', 'molecular_function', 'GO:0004707', ('161', '165'))	('mTOR', 'Gene', '2475', (188, 192))	('tyrosine kinase', 'Gene', '7294', (39, 54))	('mTOR', 'Gene', (59, 63))
141815	30373609	Patient 19 presented a lung adenocarcinoma with an ALK G1202R variant, a mutation associated with general resistance against ALK inhibition.	('ALK', 'Gene', '238', (51, 54))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (23, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('ALK', 'Gene', '238', (125, 128))	('lung adenocarcinoma', 'Disease', (23, 42))	('ALK', 'Gene', (51, 54))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (23, 42))	('Patient', 'Species', '9606', (0, 7))	('G1202R', 'Mutation', 'rs1057519783', (55, 61))	('G1202R', 'Var', (55, 61))	('ALK', 'Gene', (125, 128))
141818	30373609	Here, the only two identified variants were TP53 R342* and TP53 R248Q.	('R248Q', 'Var', (64, 69))	('TP53', 'Gene', (59, 63))	('R248Q', 'Mutation', 'rs11540652', (64, 69))	('R342*', 'SUBSTITUTION', 'None', (49, 54))	('TP53', 'Gene', '7157', (44, 48))	('R342*', 'Var', (49, 54))	('TP53', 'Gene', '7157', (59, 63))	('TP53', 'Gene', (44, 48))
141821	30373609	For patient 22 we identified TP53 R273S, a variant associated to cisplatin therapy resistance in a variety of cancer types.	('R273S', 'Mutation', 'rs121913343', (34, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('cancer', 'Disease', (110, 116))	('R273S', 'Var', (34, 39))	('patient', 'Species', '9606', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('associated', 'Reg', (51, 61))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
141824	30373609	with sunitinib or regorafenib, based on multiple variants in the MAPK signaling pathway and a KIT exon11 variant.	('KIT', 'molecular_function', 'GO:0005020', ('94', '97'))	('signaling pathway', 'biological_process', 'GO:0007165', ('70', '87'))	('variants', 'Var', (49, 57))	('MAPK signaling pathway', 'Pathway', (65, 87))	('variant', 'Var', (105, 112))	('sunitinib', 'Chemical', 'MESH:D000077210', (5, 14))	('regorafenib', 'Chemical', 'MESH:C559147', (18, 29))	('MAPK', 'molecular_function', 'GO:0004707', ('65', '69'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('65', '79'))
141872	30373609	We identified actionable targets in 86% of the patients, and in addition identified several resistance-causing variants.	('resistance-causing', 'Reg', (92, 110))	('patients', 'Species', '9606', (47, 55))	('variants', 'Var', (111, 119))
141876	30373609	Proteomic analysis would provide information on the translated proteins in the tumor, thereby verifying variants identified on the genomic and transcriptomic level and additionally detecting post-translational modifications.	('tumor', 'Disease', (79, 84))	('variants', 'Var', (104, 112))	('detecting', 'Reg', (181, 190))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
141877	30373609	Post-translational modifications, such as phosphorylation or histone modifications, have been shown to play a critical role in the development of a variety of cancer types and in drug resistance development.	('cancer', 'Disease', (159, 165))	('drug resistance', 'Phenotype', 'HP:0020174', (179, 194))	('drug resistance', 'biological_process', 'GO:0009315', ('179', '194'))	('drug resistance', 'biological_process', 'GO:0042493', ('179', '194'))	('histone', 'Protein', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('phosphorylation', 'Var', (42, 57))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('role', 'Reg', (119, 123))	('play', 'Reg', (103, 107))
141889	30373609	Given the appropriate consent, variants found in a certain tumor type, as well as chosen therapies and their outcomes, can form a resource which facilitates and improves therapy recommendations for new patients.	('variants', 'Var', (31, 39))	('tumor', 'Disease', (59, 64))	('improves', 'PosReg', (161, 169))	('patients', 'Species', '9606', (202, 210))	('facilitates', 'PosReg', (145, 156))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
141896	30373609	CNV Copy number variant DKFZ Deutsches Krebsforschungszentrum DNA Deoxyribonucleic acid FFPE Formalin-fixed paraffin embedded HLA Human leukocyte antigen InDel Insertion and deletion IRB Institutional review board NCT Nationales Centrum fur Tumorerkrankungen NGS Next-generation sequencing RNA Ribonucleic acid RNA-seq RNA sequencing SKCM Skin cutaneous melanoma SNV Single nucleotide variant SwissMTB Swiss Molecular Tumor Board TCGA The Cancer Genome Atlas UNC Uniform naming convention UVM Uveal melanoma WES Whole exome sequencing WGS Whole genome sequening FS developed the WES/WGS pipeline, contributed to report design, and analyzed patient samples.	('RNA', 'cellular_component', 'GO:0005562', ('311', '314'))	('melanoma', 'Disease', 'MESH:D008545', (354, 362))	('melanoma', 'Disease', 'MESH:D008545', (499, 507))	('paraffin', 'Chemical', 'MESH:D010232', (108, 116))	('Skin cutaneous melanoma', 'Disease', (339, 362))	('Cancer', 'Phenotype', 'HP:0002664', (439, 445))	('Skin cutaneous melanoma', 'Disease', 'MESH:C562393', (339, 362))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (493, 507))	('InDel', 'Chemical', '-', (154, 159))	('variant', 'Var', (16, 23))	('Cancer', 'Disease', (439, 445))	('RNA', 'cellular_component', 'GO:0005562', ('319', '322'))	('melanoma', 'Phenotype', 'HP:0002861', (354, 362))	('melanoma', 'Disease', (354, 362))	('Tumor', 'Phenotype', 'HP:0002664', (418, 423))	('melanoma', 'Phenotype', 'HP:0002861', (499, 507))	('melanoma', 'Disease', (499, 507))	('Cancer', 'Disease', 'MESH:D009369', (439, 445))	('Human', 'Species', '9606', (130, 135))	('patient', 'Species', '9606', (640, 647))	('Tumor', 'Phenotype', 'HP:0002664', (241, 246))	('RNA', 'cellular_component', 'GO:0005562', ('290', '293'))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('UVM', 'Phenotype', 'HP:0007716', (489, 492))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (344, 362))	('Formalin', 'Chemical', 'MESH:D005557', (93, 101))	('variant', 'Var', (385, 392))
141909	29726589	Recurrent mutations in GNAQ, GNA11, CYSLTR2, PLCB4, BAP1, EIF1AX, and SF3B1 are described as well as non-random chromosomal aberrations.	('GNA11', 'Gene', (29, 34))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (112, 135))	('BAP1', 'Gene', '8314', (52, 56))	('GNA11', 'Gene', '2767', (29, 34))	('GNAQ', 'Gene', (23, 27))	('PLCB4', 'Gene', '5332', (45, 50))	('BAP1', 'Gene', (52, 56))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (112, 134))	('SF3B1', 'Gene', (70, 75))	('EIF1AX', 'Gene', '1964', (58, 64))	('EIF1AX', 'Gene', (58, 64))	('CYSLTR2', 'Gene', '57105', (36, 43))	('mutations', 'Var', (10, 19))	('GNAQ', 'Gene', '2776', (23, 27))	('PLCB4', 'Gene', (45, 50))	('SF3B1', 'Gene', '23451', (70, 75))	('CYSLTR2', 'Gene', (36, 43))
141910	29726589	Chromothripsis is a rare event in which chromosomes are shattered and rearranged and has been reported in a variety of cancers including UM.	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('reported', 'Reg', (94, 102))	('rearranged', 'Var', (70, 80))	('UM', 'Phenotype', 'HP:0007716', (137, 139))	('Chromothripsis', 'Disease', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
141916	29726589	GNAQ, GNA11 or CYSLTR2 mutations were present in 6 of these tumors and 5 tumors harbored a BAP1 mutation and/or lacked BAP1 protein expression by immunohistochemistry.	('BAP1', 'Gene', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('GNA11', 'Gene', (6, 11))	('tumors', 'Disease', (73, 79))	('CYSLTR2', 'Gene', (15, 22))	('BAP1', 'Gene', (119, 123))	('lacked', 'NegReg', (112, 118))	('mutation', 'Var', (96, 104))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('protein', 'Protein', (124, 131))	('GNA11', 'Gene', '2767', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('BAP1', 'Gene', '8314', (91, 95))	('tumors', 'Disease', (60, 66))	('GNAQ', 'Gene', '2776', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('BAP1', 'Gene', '8314', (119, 123))	('GNAQ', 'Gene', (0, 4))	('CYSLTR2', 'Gene', '57105', (15, 22))	('expression', 'MPA', (132, 142))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
141918	29726589	One of these metastatic tumors harbored an SF3B1 mutation.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('SF3B1', 'Gene', (43, 48))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('SF3B1', 'Gene', '23451', (43, 48))	('mutation', 'Var', (49, 57))
141920	29726589	Uveal melanoma (UM) is a relative rare disease and has a high mortality rate due to metastasis in about half of all patients within 15 y after diagnosis.1, 2, 3 It is the most common primary intra-ocular malignancy in adults in the Western world.4 UM specific mutations in the alpha subunit genes GNAQ and GNA11 are described as well as mutations in BAP1, SF3B1, and EIF1AX.5, 6, 7 Mutations in the latter 3 genes are found in ~75% of all UM and are useful for prognostication of patients.8, 9, 10 BAP1-mutated UM gives rise to early-onset metastasis whereas SF3B1-mutated UM gives rise to late-onset metastasis and EIF1AX-mutated UM hardly metastasizes.8 Mutations in PLCB4 and CYSLTR2 are described in UM in a mutually exclusive manner to GNAQ or GNA11 mutations but so far have not been associated with prognosis.11, 12 Copy number alterations in chromosomes 1, 3, 6, and 8 are correlated with prognosis of the UM patient.13, 14 UM with EIF1AX, SF3B1 and BAP1 mutations are associated with unique chromosomal patterns, suggesting distinct UM subclasses.	('SF3B1', 'Gene', (559, 564))	('GNA11', 'Gene', '2767', (306, 311))	('PLCB4', 'Gene', '5332', (669, 674))	('mutations', 'Var', (963, 972))	('EIF1AX', 'Gene', '1964', (367, 373))	('CYSLTR2', 'Gene', '57105', (679, 686))	('UM', 'Phenotype', 'HP:0007716', (439, 441))	('SF3B1', 'Gene', '23451', (948, 953))	('rare disease', 'Disease', (34, 46))	('intra-ocular malignancy', 'Disease', (191, 214))	('BAP1', 'Gene', '8314', (958, 962))	('BAP1', 'Gene', (350, 354))	('GNA11', 'Gene', '2767', (749, 754))	('BAP1', 'Gene', '8314', (498, 502))	('patients', 'Species', '9606', (116, 124))	('SF3B1', 'Gene', '23451', (559, 564))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('GNAQ', 'Gene', '2776', (297, 301))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('UM', 'Phenotype', 'HP:0007716', (511, 513))	('rare disease', 'Disease', 'MESH:D035583', (34, 46))	('UM', 'Phenotype', 'HP:0007716', (573, 575))	('GNA11', 'Gene', (306, 311))	('CYSLTR2', 'Gene', (679, 686))	('GNAQ', 'Gene', '2776', (741, 745))	('SF3B1', 'Gene', (356, 361))	('GNAQ', 'Gene', (297, 301))	('EIF1AX', 'Gene', (616, 622))	('UM', 'Phenotype', 'HP:0007716', (248, 250))	('ocular malignancy', 'Phenotype', 'HP:0100012', (197, 214))	('BAP1', 'Gene', (958, 962))	('GNAQ', 'Gene', (741, 745))	('EIF1AX', 'Gene', (940, 946))	('patients', 'Species', '9606', (480, 488))	('intra-ocular malignancy', 'Disease', 'MESH:D009369', (191, 214))	('BAP1', 'Gene', (498, 502))	('UM', 'Phenotype', 'HP:0007716', (16, 18))	('PLCB4', 'Gene', (669, 674))	('GNA11', 'Gene', (749, 754))	('patient', 'Species', '9606', (480, 487))	('patient', 'Species', '9606', (116, 123))	('EIF1AX', 'Gene', '1964', (616, 622))	('SF3B1', 'Gene', (948, 953))	('EIF1AX', 'Gene', '1964', (940, 946))	('SF3B1', 'Gene', '23451', (356, 361))	('EIF1AX', 'Gene', (367, 373))	('BAP1', 'Gene', '8314', (350, 354))	('patient', 'Species', '9606', (917, 924))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
141931	29726589	Mutation analysis of GNAQ, GNA11, EIF1AX, SF3B1, and BAP1 was performed with Sanger sequencing and Ion Torrent next-generation sequencing (NGS; Thermo Fisher Scientific, Waltham, MA) as described before.32 UM without a GNAQ or GNA11 mutation were sequenced for PLCB4 and CYSLTR2.	('GNAQ', 'Gene', '2776', (21, 25))	('SF3B1', 'Gene', (42, 47))	('GNAQ', 'Gene', (21, 25))	('GNA11', 'Gene', '2767', (27, 32))	('PLCB4', 'Gene', (261, 266))	('GNAQ', 'Gene', '2776', (219, 223))	('mutation', 'Var', (233, 241))	('BAP1', 'Gene', '8314', (53, 57))	('GNA11', 'Gene', (227, 232))	('SF3B1', 'Gene', '23451', (42, 47))	('GNAQ', 'Gene', (219, 223))	('CYSLTR2', 'Gene', '57105', (271, 278))	('PLCB4', 'Gene', '5332', (261, 266))	('EIF1AX', 'Gene', (34, 40))	('GNA11', 'Gene', (27, 32))	('UM', 'Phenotype', 'HP:0007716', (206, 208))	('BAP1', 'Gene', (53, 57))	('CYSLTR2', 'Gene', (271, 278))	('EIF1AX', 'Gene', '1964', (34, 40))	('GNA11', 'Gene', '2767', (227, 232))
141932	29726589	If the tumor did not harbor a mutation in EIF1AX, SF3B1 or BAP1, mutation analysis for SRSF2 was performed.	('EIF1AX', 'Gene', '1964', (42, 48))	('SF3B1', 'Gene', (50, 55))	('SRSF2', 'Gene', '6427', (87, 92))	('BAP1', 'Gene', (59, 63))	('tumor', 'Disease', (7, 12))	('mutation', 'Var', (30, 38))	('SF3B1', 'Gene', '23451', (50, 55))	('SRSF2', 'Gene', (87, 92))	('EIF1AX', 'Gene', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('BAP1', 'Gene', '8314', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
141952	29726589	A mutation in GNAQ,c.626A > C:p.(Gln209Pro), was detected in 2 tumors.	('GNAQ', 'Gene', '2776', (14, 18))	('C:p.(Gln209Pro', 'Var', (28, 42))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('GNAQ', 'Gene', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('C:p.(Gln209Pro)', 'SUBSTITUTION', 'None', (28, 43))
141953	29726589	A GNA11 c.626A > T:p.(Gln209Leu) mutation was detected in the UM of 3 patients.	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('patients', 'Species', '9606', (70, 78))	('GNA11', 'Gene', (2, 7))	('GNA11', 'Gene', '2767', (2, 7))	('T:p.(Gln209Leu', 'Var', (17, 31))	('T:p.(Gln209Leu)', 'SUBSTITUTION', 'None', (17, 32))
141954	29726589	The 2 UM without a GNAQ or GNA11 mutation did not harbor a mutation in PLCB4 but in 1 tumor a c.386T > A:p(Leu129Gln) in CYSLTR2 was detected (UM 6) .	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('GNAQ', 'Gene', (19, 23))	('UM', 'Phenotype', 'HP:0007716', (6, 8))	('Leu129Gln', 'SUBSTITUTION', 'None', (107, 116))	('tumor', 'Disease', (86, 91))	('PLCB4', 'Gene', (71, 76))	('CYSLTR2', 'Gene', '57105', (121, 128))	('c.386T > A', 'Mutation', 'c.386T>A', (94, 104))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('CYSLTR2', 'Gene', (121, 128))	('GNA11', 'Gene', (27, 32))	('GNAQ', 'Gene', '2776', (19, 23))	('UM', 'Phenotype', 'HP:0007716', (143, 145))	('PLCB4', 'Gene', '5332', (71, 76))	('GNA11', 'Gene', '2767', (27, 32))	('Leu129Gln', 'Var', (107, 116))
141955	29726589	One c.1873C > T:p.(Arg625Cys) mutation in SF3B1 was found (UM 1) but all tumors were wildtype for EIF1AX.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('SF3B1', 'Gene', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('EIF1AX', 'Gene', '1964', (98, 104))	('EIF1AX', 'Gene', (98, 104))	('tumors', 'Disease', (73, 79))	('SF3B1', 'Gene', '23451', (42, 47))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('T:p.(Arg625Cys', 'Var', (14, 28))	('T:p.(Arg625Cys)', 'SUBSTITUTION', 'None', (14, 29))	('UM', 'Phenotype', 'HP:0007716', (59, 61))
141956	29726589	BAP1 mutations were detected in 4 patients: a c.89A > G:p.(Glu31Gly; UM 2), a c.172_173del:p.(Ser58Profs*10) (UM 6), a c.206_207insA:p.(Thr69Asnfs*5; UM 7) and a mutation 2 base pairs after exon 5 (c.375 + 2T > C; UM 4) resulting in alternative splicing with a premature stop before the next predicted splice site (prediction in Alamut Visual, Interactive Biosoftware, Rouen, France).	('p.(Ser58Profs*10', 'Var', (91, 107))	('c.206_207insA', 'Mutation', 'c.206_207insA', (119, 132))	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('splicing', 'biological_process', 'GO:0045292', ('245', '253'))	('BAP1', 'Gene', (0, 4))	('premature stop', 'MPA', (261, 275))	('c.172_173del', 'Var', (78, 90))	('Ser', 'cellular_component', 'GO:0005790', ('94', '97'))	('p.(Ser58Profs*10)', 'FRAMESHIFT', 'None', (91, 108))	('mutations', 'Var', (5, 14))	('alternative splicing', 'MPA', (233, 253))	('UM', 'Phenotype', 'HP:0007716', (214, 216))	('patients', 'Species', '9606', (34, 42))	('G:p.(Glu31Gly', 'SUBSTITUTION', 'None', (54, 67))	('UM', 'Phenotype', 'HP:0007716', (150, 152))	('p.(Thr69Asnfs*5', 'FRAMESHIFT', 'None', (133, 148))	('UM', 'Phenotype', 'HP:0007716', (110, 112))	('c.206_207insA', 'Var', (119, 132))	('c.172_173del', 'Mutation', 'c.172_173del', (78, 90))	('c.375 + 2T > C', 'Mutation', 'c.375+2T>C', (198, 212))	('BAP1', 'Gene', '8314', (0, 4))
141959	29726589	The 2 UM without a mutation in EIF1AX, SF3B1 and BAP1 were wildtype for SRSF2 as well.	('SRSF2', 'Gene', '6427', (72, 77))	('mutation', 'Var', (19, 27))	('UM', 'Phenotype', 'HP:0007716', (6, 8))	('BAP1', 'Gene', (49, 53))	('SF3B1', 'Gene', '23451', (39, 44))	('BAP1', 'Gene', '8314', (49, 53))	('EIF1AX', 'Gene', '1964', (31, 37))	('EIF1AX', 'Gene', (31, 37))	('SRSF2', 'Gene', (72, 77))	('SF3B1', 'Gene', (39, 44))
141962	29726589	One tumor harbored chromothripsis in 2 separate chromosomes (UM 5; Figure 3).	('tumor', 'Disease', (4, 9))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('chromothripsis', 'Var', (19, 33))
141974	29726589	Four of the metastasizing tumors harbored a BAP1 mutation and or lacked BAP1 expression and in 1 tumor an SF3B1 mutation was present.	('expression', 'MPA', (77, 87))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('SF3B1', 'Gene', (106, 111))	('BAP1', 'Gene', '8314', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('mutation', 'Var', (49, 57))	('tumor', 'Disease', (97, 102))	('lacked', 'NegReg', (65, 71))	('BAP1', 'Gene', (72, 76))	('BAP1', 'Gene', '8314', (44, 48))	('SF3B1', 'Gene', '23451', (106, 111))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('BAP1', 'Gene', (44, 48))
141975	29726589	One of the 2 patients without metastatic disease did not harbor a BAP1 or SF3B1 mutation in the tumor and the IHC showed a positive BAP1 expression while from the other patient (harboring a BAP1 mutation in the tumor) only short follow-up data were available (16 mo).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('BAP1', 'Gene', '8314', (190, 194))	('patients', 'Species', '9606', (13, 21))	('BAP1', 'Gene', (66, 70))	('tumor', 'Disease', (211, 216))	('BAP1', 'Gene', '8314', (132, 136))	('expression', 'MPA', (137, 147))	('SF3B1', 'Gene', '23451', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('BAP1', 'Gene', (190, 194))	('patient', 'Species', '9606', (13, 20))	('tumor', 'Disease', (96, 101))	('BAP1', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('mutation', 'Var', (80, 88))	('BAP1', 'Gene', '8314', (66, 70))	('patient', 'Species', '9606', (169, 176))	('SF3B1', 'Gene', (74, 79))
141976	29726589	The overall poor prognosis of this cohort could be explained by the mutations in BAP1 and SF3B1 since it is known that mutations in these genes are correlated with a high risk of metastasis.8, 10 Therefore, there is no indication that chromothripsis itself causes metastatic disease, but it is possible that the rate of SF3B1 and BAP1 mutations is higher in UM with chromothripsis.	('SF3B1', 'Gene', '23451', (320, 325))	('BAP1', 'Gene', (81, 85))	('BAP1', 'Gene', (330, 334))	('UM', 'Phenotype', 'HP:0007716', (358, 360))	('SF3B1', 'Gene', (90, 95))	('mutations', 'Var', (335, 344))	('chromothripsis', 'Disease', (366, 380))	('BAP1', 'Gene', '8314', (81, 85))	('SF3B1', 'Gene', (320, 325))	('BAP1', 'Gene', '8314', (330, 334))	('SF3B1', 'Gene', '23451', (90, 95))
141979	29726589	The tumor with extensive inflammation was the UM with a BAP1 mutation but without metastatic disease.	('tumor', 'Disease', (4, 9))	('inflammation', 'Disease', (25, 37))	('BAP1', 'Gene', '8314', (56, 60))	('mutation', 'Var', (61, 69))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('BAP1', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('inflammation', 'Disease', 'MESH:D007249', (25, 37))	('inflammation', 'biological_process', 'GO:0006954', ('25', '37'))
142024	29844657	COMS and other recent trials have demonstrated that 125I brachytherapy provides survival rates that are equal to enucleation.	('enucleation', 'biological_process', 'GO:0090601', ('113', '124'))	('125I brachytherapy', 'Var', (52, 70))	('survival', 'CPA', (80, 88))	('125I', 'Chemical', 'MESH:C000614960', (52, 56))
142033	29844657	However, 103Pd photons are more rapidly absorbed by the vitreous, and thus decrease the risk of macular retinopathy.	('decrease', 'NegReg', (75, 83))	('macular retinopathy', 'Disease', (96, 115))	('retinopathy', 'Phenotype', 'HP:0000488', (104, 115))	('103Pd', 'Chemical', 'MESH:C000615531', (9, 14))	('103Pd photons', 'Var', (9, 22))	('macular retinopathy', 'Phenotype', 'HP:0000608', (96, 115))	('macular retinopathy', 'Disease', 'MESH:C562746', (96, 115))
142058	29844657	The most basic somatic tumor DNA change associated with UM prognosis is chromosomal copy-number aberration, where monosomy of chromosome 3 and gain of 8q are predictors of poor prognosis (Table 2).	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('monosomy', 'Var', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('chromosome', 'cellular_component', 'GO:0005694', ('126', '136'))	('chromosomal copy-number aberration', 'Var', (72, 106))	('tumor', 'Disease', (23, 28))	('gain', 'PosReg', (143, 147))	('associated', 'Reg', (40, 50))	('UM', 'Phenotype', 'HP:0007716', (56, 58))
142059	29844657	Patients with monosomy 3 have significantly worse relapse-free and overall survival.	('worse', 'NegReg', (44, 49))	('overall survival', 'CPA', (67, 83))	('monosomy 3', 'Var', (14, 24))	('Patients', 'Species', '9606', (0, 8))	('relapse-free', 'CPA', (50, 62))
142060	29844657	Tumors with >33% of cells positive for monosomy 3 have a greater risk of metastatic death than those with 1%-33% of cells positive for monosomy 3.	('metastatic death', 'CPA', (73, 89))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('monosomy 3', 'Var', (39, 49))
142061	29844657	Research suggests that there is no significant difference in prognosis in tumors with disomy 3 compared with partial change in chromosome 3.	('disomy 3', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('chromosome', 'cellular_component', 'GO:0005694', ('127', '137'))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
142063	29844657	Chromosome 3 and 8 abnormalities correlate with traditional factors of poor prognosis, such as largest-tumor basal diameter and ciliary body involvement.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('ciliary', 'Disease', (128, 135))	('tumor', 'Disease', (103, 108))	('abnormalities', 'Var', (19, 32))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
142067	29844657	Microsatellite analysis is used to assess copy loss and isodisomy of chromosome 3.	('isodisomy', 'Disease', (56, 65))	('copy loss', 'Var', (42, 51))	('chromosome', 'cellular_component', 'GO:0005694', ('69', '79'))	('isodisomy', 'Disease', 'MESH:D024182', (56, 65))
142068	29844657	If findings are negative for monosomy 3 or gain of 8q, GNAQ/GNA11 mutations, which are common in UM, are evaluated to assess for presence of tumors within the FNAB sample to limit false-negative results.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('GNA11', 'Gene', (60, 65))	('false', 'biological_process', 'GO:0071878', ('180', '185'))	('GNAQ', 'Gene', '2776', (55, 59))	('UM', 'Phenotype', 'HP:0007716', (97, 99))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('GNA11', 'Gene', '2767', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('GNAQ', 'Gene', (55, 59))	('false', 'biological_process', 'GO:0071877', ('180', '185'))	('gain', 'PosReg', (43, 47))
142069	29844657	Mutations in SF3B1 and EIF1AX are evaluated in disomy 3 specimens.	('SF3B1', 'Gene', (13, 18))	('EIF1AX', 'Gene', '1964', (23, 29))	('Mutations', 'Var', (0, 9))	('EIF1AX', 'Gene', (23, 29))	('SF3B1', 'Gene', '23451', (13, 18))
142071	29844657	Somatic mutation in the BAP1 gene was found in 84% of early-metastasizing (class 2) tumors.	('BAP1', 'Gene', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('found', 'Reg', (38, 43))	('Somatic mutation', 'Var', (0, 16))	('BAP1', 'Gene', '8314', (24, 28))
142072	29844657	Subsequently, germ-line mutation in BAP1 has been shown to be part of a cancer syndrome leading to UM, cutaneous melanoma, renal cell carcinoma, and other cancers.	('cutaneous melanoma', 'Disease', (103, 121))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (103, 121))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (103, 121))	('germ-line mutation', 'Var', (14, 32))	('renal cell carcinoma', 'Disease', (123, 143))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (123, 143))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('leading', 'Reg', (88, 95))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('cancer syndrome', 'Disease', (72, 87))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('BAP1', 'Gene', '8314', (36, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (123, 143))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('BAP1', 'Gene', (36, 40))	('cancers', 'Disease', (155, 162))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('cancer syndrome', 'Disease', 'MESH:D009369', (72, 87))
142073	29844657	UM patients with germ-line BAP1 mutations have significantly larger tumor diameters and a higher rate of ciliary body involvement.	('tumor', 'Disease', (68, 73))	('ciliary body involvement', 'CPA', (105, 129))	('BAP1', 'Gene', (27, 31))	('larger', 'PosReg', (61, 67))	('mutations', 'Var', (32, 41))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('BAP1', 'Gene', '8314', (27, 31))
142074	29844657	The rate of germ-line BAP1 mutation is significantly higher in metastatic UM compared to nonmetastatic UM.	('UM', 'Phenotype', 'HP:0007716', (103, 105))	('higher', 'Reg', (53, 59))	('mutation', 'Var', (27, 35))	('BAP1', 'Gene', '8314', (22, 26))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('metastatic UM', 'Disease', (63, 76))	('BAP1', 'Gene', (22, 26))
142075	29844657	The rate of germ-line BAP1 mutation is estimated to be 22% in patients with familial UM compared to 1.6%-4% of nonfamilial UM.	('mutation', 'Var', (27, 35))	('BAP1', 'Gene', '8314', (22, 26))	('familial UM', 'Disease', (76, 87))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('UM', 'Phenotype', 'HP:0007716', (123, 125))	('patients', 'Species', '9606', (62, 70))	('BAP1', 'Gene', (22, 26))
142076	29844657	In patients with a family history of BAP1-related tumors, the rate of germ-line BAP1 mutation can range up to 50%.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('BAP1', 'Gene', '8314', (80, 84))	('mutation', 'Var', (85, 93))	('BAP1', 'Gene', '8314', (37, 41))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('BAP1', 'Gene', (80, 84))	('BAP1', 'Gene', (37, 41))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
142077	29844657	As such, SF3B1 mutation is associated with intermediate risk of metastasis and EIF1AX mutation with lowest risk of metastasis (Table 2).	('EIF1AX', 'Gene', (79, 85))	('mutation', 'Var', (15, 23))	('SF3B1', 'Gene', '23451', (9, 14))	('SF3B1', 'Gene', (9, 14))	('metastasis', 'CPA', (64, 74))	('EIF1AX', 'Gene', '1964', (79, 85))
142078	29844657	In patients with disomy 3, SF3B1 mutation is associated with late development of metastasis.	('mutation', 'Var', (33, 41))	('late development', 'Phenotype', 'HP:0001263', (61, 77))	('SF3B1', 'Gene', (27, 32))	('associated', 'Reg', (45, 55))	('patients', 'Species', '9606', (3, 11))	('SF3B1', 'Gene', '23451', (27, 32))	('late development of metastasis', 'CPA', (61, 91))
142083	29844657	In patients with chromosome 3 and 8q abnormality, epithelioid histology, high mitotic rate, and closed loops correlate with worse survival, and these pathologic predictors have a cumulative effect on survival.	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('chromosome 3', 'Var', (17, 29))	('worse', 'NegReg', (124, 129))	('patients', 'Species', '9606', (3, 11))	('closed loops', 'CPA', (96, 108))
142088	29844657	However, variability in monosomy 3 status does exist within the same tumor, and variations in chromosomal copy number between the intraocular and extraocular portions of UM tumors have been reported.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('UM', 'Phenotype', 'HP:0007716', (170, 172))	('tumors', 'Disease', (173, 179))	('chromosomal copy number', 'Var', (94, 117))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('variations', 'Reg', (80, 90))
142104	29844657	Now, genetic testing via FNAB has allowed for prognostication for patients with ocular melanoma receiving globe-sparing brachytherapy in clinical practice.	('genetic', 'Var', (5, 12))	('allowed', 'Reg', (34, 41))	('ocular melanoma', 'Disease', 'MESH:D008545', (80, 95))	('FNAB', 'Gene', (25, 29))	('ocular melanoma', 'Disease', (80, 95))	('ocular melanoma', 'Phenotype', 'HP:0007716', (80, 95))	('patients', 'Species', '9606', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
142185	29578129	Our review reveals the complex mechanisms underlying the tumorigenesis of UM and highlights the great needs of future studies to discover more genes/5'-C-phosphate-G-3' sites contributing to the development/metastasis of UM and explore the mechanisms through which epigenetic changes exert their function in UM.	('contributing', 'Reg', (175, 187))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('UM', 'Phenotype', 'HP:0007716', (221, 223))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('epigenetic changes', 'Var', (265, 283))	('UM', 'Phenotype', 'HP:0007716', (308, 310))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('tumor', 'Disease', (57, 62))
142186	29578129	It is catalyzed by methyltransferase enzymes using a S-adenosyl methionine donor and can lead to the mitotic propagation of the modified sequence with consequences for the binding of regulatory proteins such as transcription factors.	('mitotic propagation', 'CPA', (101, 120))	('binding', 'Interaction', (172, 179))	('lead to', 'Reg', (89, 96))	('binding', 'molecular_function', 'GO:0005488', ('172', '179'))	('adenosyl methionine', 'Chemical', 'MESH:D012436', (55, 74))	('transcription', 'biological_process', 'GO:0006351', ('211', '224'))	('donor', 'Species', '9606', (75, 80))	('S', 'Chemical', 'MESH:D013455', (53, 54))	('modified', 'Var', (128, 136))
142188	29578129	Second, and likely more importantly, methylated DNA may be bound by proteins known as methyl-CpG-binding domain proteins (MBDs).	('MBD', 'Disease', 'MESH:D012080', (122, 125))	('bound', 'Interaction', (59, 64))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('methyl-CpG-binding', 'molecular_function', 'GO:0008327', ('86', '104'))	('MBD', 'Disease', (122, 125))	('methylated', 'Var', (37, 47))	('S', 'Chemical', 'MESH:D013455', (0, 1))
142196	29578129	Specifically, BAP1, EIF1AX, and SF3B1 mutations are mutually exclusive during UM progression, and BAP1 mutations showed the most significant association with UM metastasis.	('BAP1', 'Gene', (98, 102))	('BAP1', 'Gene', '8314', (14, 18))	('mutations', 'Var', (103, 112))	('UM metastasis', 'CPA', (158, 171))	('association', 'Interaction', (141, 152))	('BAP1', 'Gene', (14, 18))	('SF3B1', 'Gene', '23451', (32, 37))	('EIF1AX', 'Gene', '1964', (20, 26))	('EIF1AX', 'Gene', (20, 26))	('S', 'Chemical', 'MESH:D013455', (32, 33))	('BAP1', 'Gene', '8314', (98, 102))	('UM', 'Phenotype', 'HP:0007716', (158, 160))	('UM', 'Phenotype', 'HP:0007716', (78, 80))	('mutations', 'Var', (38, 47))	('SF3B1', 'Gene', (32, 37))	('S', 'Chemical', 'MESH:D013455', (0, 1))
142197	29578129	Although previous studies indicated that both genetic and epigenetic alterations may affect the biology of melanoma cells by simultaneously affecting multiple proteins/pathways, the role of epigenetics in general and DNA methylation in particular in the carcinogenesis and metastasis of UM is less well studied, compared with the genetic mechanisms involved in UM.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('UM', 'Phenotype', 'HP:0007716', (361, 363))	('alterations', 'Var', (69, 80))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('DNA', 'cellular_component', 'GO:0005574', ('217', '220'))	('affecting', 'Reg', (140, 149))	('carcinogenesis', 'Disease', 'MESH:D063646', (254, 268))	('proteins/pathways', 'Protein', (159, 176))	('UM', 'Phenotype', 'HP:0007716', (287, 289))	('DNA methylation', 'biological_process', 'GO:0006306', ('217', '232'))	('carcinogenesis', 'Disease', (254, 268))	('affect', 'Reg', (85, 91))	('epigenetic alterations', 'Var', (58, 80))
142205	29578129	These findings suggest that RASSF1A expression can suppress UM tumorigenesis, and epigenetic modification of gene expression might be a feasible approach for the future treatment of UM.	('tumor', 'Disease', (63, 68))	('suppress', 'NegReg', (51, 59))	('UM', 'Phenotype', 'HP:0007716', (182, 184))	('gene expression', 'biological_process', 'GO:0010467', ('109', '124'))	('RASSF1A', 'Gene', (28, 35))	('epigenetic modification', 'Var', (82, 105))	('expression', 'Var', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
142207	29578129	A pervious near-genome-wide RNAi screening found RASEF to be hypermethylated in primary cutaneous melanomas but not nevi, indicating that it is a potential melanoma suppressor gene.	('cutaneous melanomas', 'Disease', (88, 107))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('hypermethylated', 'Var', (61, 76))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('nevi', 'Phenotype', 'HP:0003764', (116, 120))	('RASEF', 'Gene', (49, 54))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('RASEF', 'Gene', '158158', (49, 54))	('melanoma', 'Disease', (98, 106))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (88, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (88, 107))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (88, 107))	('RNAi', 'biological_process', 'GO:0016246', ('28', '32'))
142209	29578129	Promoter methylation of RASEF was associated with increased risk of death due to metastasis, and patients with a homozygous genotype and methylation of RASEF had a significantly higher risk of metastasis than those with a heterozygous genotype and no methylation.	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('methylation', 'Var', (137, 148))	('death', 'Disease', 'MESH:D003643', (68, 73))	('RASEF', 'Gene', (24, 29))	('death', 'Disease', (68, 73))	('RASEF', 'Gene', '158158', (24, 29))	('metastasis', 'CPA', (193, 203))	('methylation', 'biological_process', 'GO:0032259', ('251', '262'))	('higher', 'PosReg', (178, 184))	('RASEF', 'Gene', (152, 157))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('Promoter', 'MPA', (0, 8))	('RASEF', 'Gene', '158158', (152, 157))	('patients', 'Species', '9606', (97, 105))
142212	29578129	A previous study found inactivating somatic mutations in more than 80% of metastasizing tumors, implicating the involvement of loss of BAP1 in UM metastasis.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('BAP1', 'Gene', '8314', (135, 139))	('UM', 'Phenotype', 'HP:0007716', (143, 145))	('inactivating', 'Var', (23, 35))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('BAP1', 'Gene', (135, 139))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('loss', 'Var', (127, 131))
142213	29578129	For the poor-prognosis UM, M3 developed initially followed by alterations of BAP1 which has distinct global DNA methylation from that observed in D3.	('DNA methylation', 'biological_process', 'GO:0006306', ('108', '123'))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('BAP1', 'Gene', '8314', (77, 81))	('UM', 'Phenotype', 'HP:0007716', (23, 25))	('alterations', 'Var', (62, 73))	('BAP1', 'Gene', (77, 81))
142214	29578129	For the better-prognosis D3, those with EIF1AX mutations had different DNA methylation patterns compared with those with SF3B1/SRFR2 mutations.	('S', 'Chemical', 'MESH:D013455', (127, 128))	('DNA methylation', 'biological_process', 'GO:0006306', ('71', '86'))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('S', 'Chemical', 'MESH:D013455', (121, 122))	('EIF1AX', 'Gene', '1964', (40, 46))	('EIF1AX', 'Gene', (40, 46))	('mutations', 'Var', (47, 56))	('DNA methylation patterns', 'MPA', (71, 95))	('SF3B1', 'Gene', (121, 126))	('different', 'Reg', (61, 70))	('SF3B1', 'Gene', '23451', (121, 126))
142215	29578129	These findings suggest that BAP1 mutations may lead to metastasis-prone DNA methylation states.	('BAP1', 'Gene', '8314', (28, 32))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('lead to', 'Reg', (47, 54))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('DNA methylation', 'biological_process', 'GO:0006306', ('72', '87'))	('metastasis-prone DNA methylation states', 'MPA', (55, 94))
142219	29578129	Because VHL and FHIT are known to be inactivated by promoter methylation in various cancer entities, these findings imply that epigenetic changes in these genes are unlikely to play a pivotal role in the tumorigenesis of UM.	('promoter methylation', 'Var', (52, 72))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('FHIT', 'Gene', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('cancer', 'Disease', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('FHIT', 'Gene', '2272', (16, 20))	('UM', 'Phenotype', 'HP:0007716', (221, 223))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('VHL', 'Disease', (8, 11))	('tumor', 'Disease', (204, 209))	('VHL', 'Disease', 'MESH:D006623', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
142229	29578129	UM patients with promoter hypermethylation also had a higher death rate due to metastasis, compared with those with nonmethylated primary tumor (71% vs. 13%).	('death', 'Disease', 'MESH:D003643', (61, 66))	('tumor', 'Disease', (138, 143))	('death', 'Disease', (61, 66))	('promoter hypermethylation', 'Var', (17, 42))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('metastasis', 'CPA', (79, 89))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
142234	29578129	Another study of 23 primary UMs, however, found only one case (4%) with promoter methylation in p16INK4a.	('methylation', 'biological_process', 'GO:0032259', ('81', '92'))	('UM', 'Phenotype', 'HP:0007716', (28, 30))	('promoter methylation', 'Var', (72, 92))	('p16INK4a', 'Gene', (96, 104))	('p16INK4a', 'Gene', '1029', (96, 104))
142235	29578129	As revealed, often less than 10% of tumor DNA are methylated.	('methylated', 'Var', (50, 60))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
142237	29578129	TIMP3 is generally expressed by the RPE, and mutations in TIMP3 can cause hereditary blindness.	('mutations', 'Var', (45, 54))	('blindness', 'Phenotype', 'HP:0000618', (85, 94))	('cause', 'Reg', (68, 73))	('TIMP3', 'Gene', (0, 5))	('TIMP3', 'Gene', '7078', (0, 5))	('TIMP3', 'Gene', (58, 63))	('hereditary blindness', 'Disease', 'MESH:D001766', (74, 94))	('hereditary blindness', 'Disease', (74, 94))	('TIMP3', 'Gene', '7078', (58, 63))
142239	29578129	These findings suggest that methylation of TIMP3 likely is involved in the development of UM.	('UM', 'Phenotype', 'HP:0007716', (90, 92))	('TIMP3', 'Gene', '7078', (43, 48))	('TIMP3', 'Gene', (43, 48))	('involved', 'Reg', (59, 67))	('methylation', 'Var', (28, 39))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))
142241	29578129	A study of 678 UM patients found that 12 CpG sites within and near the PRAME promoter region were hypomethylated in PRAME+ tumors, compared to PRAME- tumors.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('PRAME', 'Gene', '23532', (143, 148))	('PRAME', 'Gene', (143, 148))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('hypomethylated', 'Var', (98, 112))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('UM', 'Phenotype', 'HP:0007716', (15, 17))	('PRAME', 'Gene', '23532', (71, 76))	('PRAME', 'Gene', '23532', (116, 121))	('patients', 'Species', '9606', (18, 26))	('PRAME', 'Gene', (71, 76))	('PRAME', 'Gene', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
142242	29578129	Aberrantly hypomethylation of PRAME is associated with increased UM metastasis.	('UM', 'Phenotype', 'HP:0007716', (65, 67))	('increased', 'PosReg', (55, 64))	('Aberrantly hypomethylation', 'Var', (0, 26))	('UM metastasis', 'CPA', (65, 78))	('PRAME', 'Gene', '23532', (30, 35))	('PRAME', 'Gene', (30, 35))
142246	29578129	Full or partial methylation of EFS CpG island was observed in 81% of UMs.	('EFS', 'Gene', (31, 34))	('methylation', 'biological_process', 'GO:0032259', ('16', '27'))	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('partial methylation', 'Var', (8, 27))	('EFS', 'Gene', '10278', (31, 34))
142247	29578129	EFS methylation was only observed in UM with metastases and is associated with a higher risk of metastatic progression.	('metastases', 'Disease', 'MESH:D009362', (45, 55))	('metastatic progression', 'CPA', (96, 118))	('associated', 'Reg', (63, 73))	('UM', 'Phenotype', 'HP:0007716', (37, 39))	('methylation', 'Var', (4, 15))	('EFS', 'Gene', '10278', (0, 3))	('EFS', 'Gene', (0, 3))	('metastases', 'Disease', (45, 55))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))
142249	29578129	These findings suggest that there are methylated and unmethylated precursor cells, and EFS methylation in UM may depend on the type of precursor cells from which the tumor originated.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('methylation', 'Var', (91, 102))	('EFS', 'Gene', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('UM', 'Phenotype', 'HP:0007716', (106, 108))	('tumor', 'Disease', (166, 171))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('EFS', 'Gene', '10278', (87, 90))
142251	29578129	A recent study found that DSS1 hypomethylation led to elevated mRNA expression, which is associated with metastasis of UM, shorter overall survival (average 12.5 months vs. 18.5 months), and shorter disease-free survival (11.1 months vs. 22.3 months) of patients with UM.	('associated', 'Reg', (89, 99))	('shorter', 'NegReg', (123, 130))	('DSS1', 'Gene', (26, 30))	('UM', 'Phenotype', 'HP:0007716', (268, 270))	('elevated', 'PosReg', (54, 62))	('hypomethylation', 'Var', (31, 46))	('disease-free survival', 'CPA', (199, 220))	('overall', 'MPA', (131, 138))	('shorter', 'NegReg', (191, 198))	('mRNA expression', 'MPA', (63, 78))	('DSS1', 'Gene', '7979', (26, 30))	('patients', 'Species', '9606', (254, 262))	('UM', 'Phenotype', 'HP:0007716', (119, 121))
142252	29578129	These findings suggested a potentially important role that epigenetic changes of DSS1 could play in the tumorigenesis of UM.	('UM', 'Phenotype', 'HP:0007716', (121, 123))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('play', 'Reg', (92, 96))	('DSS1', 'Gene', (81, 85))	('tumor', 'Disease', (104, 109))	('epigenetic changes', 'Var', (59, 77))	('DSS1', 'Gene', '7979', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
142254	29578129	More studies are also needed on the potential role of DNA methylation of other genes which harbor major identified mutations for UM such as GNA11, GNAQ, EIF1AX, and SF3B1.	('EIF1AX', 'Gene', '1964', (153, 159))	('EIF1AX', 'Gene', (153, 159))	('mutations', 'Var', (115, 124))	('SF3B1', 'Gene', (165, 170))	('GNA11', 'Gene', (140, 145))	('DNA methylation', 'biological_process', 'GO:0006306', ('54', '69'))	('SF3B1', 'Gene', '23451', (165, 170))	('GNAQ', 'Gene', (147, 151))	('GNA11', 'Gene', '2767', (140, 145))	('UM', 'Phenotype', 'HP:0007716', (129, 131))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('GNAQ', 'Gene', '2776', (147, 151))
142258	27718540	Germline BAP1 Alterations in Familial Uveal Melanoma Uveal melanoma (UM) is the most commonly diagnosed primary intraocular tumor in adults.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('BAP1', 'Gene', (9, 13))	('Familial Uveal Melanoma', 'Disease', 'MESH:C536494', (29, 52))	('Alterations', 'Var', (14, 25))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('BAP1', 'Gene', '8314', (9, 13))	('intraocular tumor', 'Disease', (112, 129))	('intraocular tumor', 'Disease', 'MESH:D064090', (112, 129))	('Melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('Familial Uveal Melanoma', 'Disease', (29, 52))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
142260	27718540	In this study we aimed to estimate the frequency of BAP1 mutation in FUM and to characterize the family and personal histories of other cancers in these families.	('mutation', 'Var', (57, 65))	('BAP1', 'Gene', '8314', (52, 56))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('BAP1', 'Gene', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
142262	27718540	Germline deletion and duplication analysis of BAP1 was assessed by multiplex ligation-dependent probe amplification (MLPA).	('BAP1', 'Gene', '8314', (46, 50))	('duplication', 'Var', (22, 33))	('BAP1', 'Gene', (46, 50))
142263	27718540	Germline BAP1 mutations were found in 6/32 (19%) families.	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('BAP1', 'Gene', '8314', (9, 13))
142264	27718540	Combined with published studies, the frequency of BAP1 mutations was 14/64 (22%) in FUM.	('mutations', 'Var', (55, 64))	('BAP1', 'Gene', '8314', (50, 54))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('FUM', 'Disease', (84, 87))	('BAP1', 'Gene', (50, 54))
142265	27718540	FUM families without BAP1 mutations have distinct family histories with high rates of prostate cancer in first- and second-degree relatives.	('prostate cancer', 'Disease', 'MESH:D011471', (86, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (86, 101))	('BAP1', 'Gene', (21, 25))	('mutations', 'Var', (26, 35))	('UM', 'Phenotype', 'HP:0007716', (1, 3))	('prostate cancer', 'Disease', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('BAP1', 'Gene', '8314', (21, 25))
142272	27718540	The frequency of BAP1 mutations in FUM is currently unknown, however, complicating genetic testing decisions in high-risk families.	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('BAP1', 'Gene', (17, 21))
142274	27718540	Thus, the aims of this study were to estimate the prevalence of BAP1 mutations and deletions or duplications in FUM, and to demonstrate features of these families that may aid in the discovery of new genes predisposing to UM and other cancers.	('mutations', 'Var', (69, 78))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('cancers', 'Disease', (235, 242))	('duplications', 'Var', (96, 108))	('deletions', 'Var', (83, 92))	('UM', 'Phenotype', 'HP:0007716', (222, 224))	('BAP1', 'Gene', '8314', (64, 68))	('UM', 'Phenotype', 'HP:0007716', (113, 115))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('FUM', 'Disease', (112, 115))	('BAP1', 'Gene', (64, 68))
142277	27718540	Deletions and duplications were assessed in 24 patients with no detected germline BAP1 sequence mutation utilizing multiplex ligation-dependent probe amplification analysis (SALSA MLPA P417 BAP1 probemix, MRC-Holland) according to the manufacturer's protocol.	('BAP1', 'Gene', (82, 86))	('MRC', 'CellLine', 'CVCL:0440', (205, 208))	('BAP1', 'Gene', '8314', (190, 194))	('patients', 'Species', '9606', (47, 55))	('BAP1', 'Gene', (190, 194))	('BAP1', 'Gene', '8314', (82, 86))	('Deletions', 'Var', (0, 9))
142280	27718540	Single case reports were excluded from our assessment of the frequency of BAP1 mutation in familial cases to avoid introducing selection and testing bias.	('BAP1', 'Gene', '8314', (74, 78))	('familial cases', 'Disease', (91, 105))	('BAP1', 'Gene', (74, 78))	('mutation', 'Var', (79, 87))
142281	27718540	Thus, 32 FUM families with known BAP1 mutation status, from three published series of unselected families, were combined with our series for a meta-analysis to estimate the frequency of BAP1 mutation in FUM.	('UM', 'Phenotype', 'HP:0007716', (10, 12))	('UM', 'Phenotype', 'HP:0007716', (204, 206))	('BAP1', 'Gene', '8314', (186, 190))	('BAP1', 'Gene', '8314', (33, 37))	('BAP1', 'Gene', (33, 37))	('BAP1', 'Gene', (186, 190))	('mutation', 'Var', (191, 199))
142283	27718540	In one familial case a mutation in TP53 was suggested based on immunohistochemistry assessment.	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('mutation', 'Var', (23, 31))
142284	27718540	To evaluate the frequency of other cancers in FUM and effect of BAP1 mutation status, we combined data from our series with that from the literature.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('mutation', 'Var', (69, 77))	('BAP1', 'Gene', '8314', (64, 68))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))	('BAP1', 'Gene', (64, 68))
142285	27718540	We excluded the family with putative TP53 mutation as well as those missing full reports of family histories.	('TP53', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('TP53', 'Gene', '7157', (37, 41))
142290	27718540	Out of the 25 unreported FUM we identified two patients FUM327 and FUM340 with germline truncating mutation in BAP1 (Table 1).	('BAP1', 'Gene', '8314', (111, 115))	('patients', 'Species', '9606', (47, 55))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('BAP1', 'Gene', (111, 115))	('germline truncating mutation', 'Var', (79, 107))	('UM', 'Phenotype', 'HP:0007716', (26, 28))	('UM', 'Phenotype', 'HP:0007716', (68, 70))
142291	27718540	Combined with our previously published families the overall BAP1 mutations frequency in our cohort was 6/32 (19%; Table 1).	('BAP1', 'Gene', '8314', (60, 64))	('BAP1', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
142292	27718540	Deletions and duplications were successfully assessed by MLPA in 24 patients, with no such alterations detected in BAP1.	('BAP1', 'Gene', '8314', (115, 119))	('patients', 'Species', '9606', (68, 76))	('duplications', 'Var', (14, 26))	('BAP1', 'Gene', (115, 119))	('Deletions', 'Var', (0, 9))
142294	27718540	The BAP1 mutation frequency in our cohort is similar to the frequency of BAP1 mutations in FUM (20-29%) found by other groups in smaller cohorts.	('mutation', 'Var', (9, 17))	('BAP1', 'Gene', '8314', (73, 77))	('BAP1', 'Gene', (4, 8))	('BAP1', 'Gene', (73, 77))	('UM', 'Phenotype', 'HP:0007716', (92, 94))	('BAP1', 'Gene', '8314', (4, 8))
142295	27718540	found a BAP1 mutation frequency of 29% in a cohort of 14 families, while Gupta et al.	('mutation', 'Var', (13, 21))	('BAP1', 'Gene', '8314', (8, 12))	('BAP1', 'Gene', (8, 12))
142297	27718540	When our data are combined with these previous reports the frequency of BAP1 mutation in FUM is estimated to be approximately 22% (95% CI 21-23%).	('mutation', 'Var', (77, 85))	('BAP1', 'Gene', (72, 76))	('BAP1', 'Gene', '8314', (72, 76))	('UM', 'Phenotype', 'HP:0007716', (90, 92))
142299	27718540	Fifteen of the 53 FUM families in the literature with adequate family cancer history information had a BAP1 mutation, 10 families tested negative, and 28 families were untested.	('BAP1', 'Gene', '8314', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('BAP1', 'Gene', (103, 107))	('UM', 'Phenotype', 'HP:0007716', (19, 21))	('mutation', 'Var', (108, 116))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
142300	27718540	Table 2 summarizes the cancer family histories reported in families with and without BAP1 mutations, in our cohort and in the literature.	('BAP1', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('BAP1', 'Gene', '8314', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
142301	27718540	As expected, families with BAP1 mutations have significantly higher rates of malignant mesothelioma (MMe, p = 0.0001) and renal cell carcinoma (RCC, p = 0.0003).	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (122, 142))	('BAP1', 'Gene', (27, 31))	('higher', 'PosReg', (61, 67))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (77, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('malignant mesothelioma', 'Disease', (77, 99))	('mutations', 'Var', (32, 41))	('renal cell carcinoma', 'Disease', (122, 142))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (122, 142))	('RCC', 'Disease', (144, 147))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (77, 99))	('BAP1', 'Gene', '8314', (27, 31))
142302	27718540	Interestingly, higher rates of lung cancer approached significance (p = 0.09) in families with BAP1 mutation while higher rates of CM, a cancer with known predisposition conferred by BAP1, did not reach statistical significance (p = 0.2114).	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('BAP1', 'Gene', '8314', (183, 187))	('BAP1', 'Gene', (95, 99))	('higher', 'PosReg', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('CM', 'Disease', 'MESH:D009202', (131, 133))	('lung cancer', 'Disease', (31, 42))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('BAP1', 'Gene', (183, 187))	('mutation', 'Var', (100, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('CM', 'Phenotype', 'HP:0012056', (131, 133))	('cancer', 'Disease', (137, 143))	('BAP1', 'Gene', '8314', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
142303	27718540	In FUM families without BAP1 mutation, the family history rates of MMe and RCC are significantly lower.	('mutation', 'Var', (29, 37))	('UM', 'Phenotype', 'HP:0007716', (4, 6))	('BAP1', 'Gene', (24, 28))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('MMe', 'Disease', (67, 70))	('lower', 'NegReg', (97, 102))	('BAP1', 'Gene', '8314', (24, 28))
142305	27718540	However, until now there have been few estimates as to the prevalence of germline BAP1 mutations in FUM.	('BAP1', 'Gene', (82, 86))	('mutations', 'Var', (87, 96))	('UM', 'Phenotype', 'HP:0007716', (101, 103))	('BAP1', 'Gene', '8314', (82, 86))
142306	27718540	We estimate that BAP1 mutations are present in approximately 22% of FUM families overall, compared with 2-4% in unselected UM.	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('UM', 'Phenotype', 'HP:0007716', (123, 125))	('BAP1', 'Gene', (17, 21))
142307	27718540	However, the history of other cancers in the family can significantly alter the chance of finding a BAP1 mutation.	('BAP1', 'Gene', '8314', (100, 104))	('mutation', 'Var', (105, 113))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('cancers', 'Disease', (30, 37))	('BAP1', 'Gene', (100, 104))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('alter', 'Reg', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
142308	27718540	In FUM families with no other history of BAP1-associated cancers, the chance of BAP1 mutation may be as low as 8%.	('UM', 'Phenotype', 'HP:0007716', (4, 6))	('BAP1', 'Gene', (41, 45))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('BAP1', 'Gene', '8314', (80, 84))	('mutation', 'Var', (85, 93))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('BAP1', 'Gene', (80, 84))	('BAP1', 'Gene', '8314', (41, 45))
142309	27718540	Conversely, the chance of BAP1 mutation in FUM families with additional family history of CM, MMe, and/or RCC can be as high as 50%.	('BAP1', 'Gene', (26, 30))	('MMe', 'Disease', (94, 97))	('mutation', 'Var', (31, 39))	('CM', 'Disease', 'MESH:D009202', (90, 92))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('CM', 'Phenotype', 'HP:0012056', (90, 92))	('BAP1', 'Gene', '8314', (26, 30))	('RCC', 'Disease', (106, 109))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
142316	27718540	The tumor spectrum reported in the family histories is distinct between those that have germline BAP1 mutations and those that do not.	('tumor', 'Disease', (4, 9))	('BAP1', 'Gene', '8314', (97, 101))	('BAP1', 'Gene', (97, 101))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('mutations', 'Var', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('germline', 'Var', (88, 96))
142317	27718540	Specifically, families without BAP1 mutations have lower rates of MMe and RCC as compared to those with BAP1 mutations.	('BAP1', 'Gene', '8314', (104, 108))	('BAP1', 'Gene', '8314', (31, 35))	('MMe', 'Disease', (66, 69))	('RCC', 'Disease', (74, 77))	('mutations', 'Var', (36, 45))	('BAP1', 'Gene', (104, 108))	('lower', 'NegReg', (51, 56))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('BAP1', 'Gene', (31, 35))
142323	27718540	In one of the FUM families we confirmed BAP1 mutation in two family members (FUM036).	('confirmed', 'Reg', (30, 39))	('BAP1', 'Gene', '8314', (40, 44))	('mutation', 'Var', (45, 53))	('UM', 'Phenotype', 'HP:0007716', (15, 17))	('UM', 'Phenotype', 'HP:0007716', (78, 80))	('BAP1', 'Gene', (40, 44))
142324	27718540	In other families another family member with UM was not available for testing; however in several we confirmed BAP1 mutations in family members with other cancers.	('BAP1', 'Gene', '8314', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('BAP1', 'Gene', (111, 115))	('mutations', 'Var', (116, 125))	('confirmed', 'Reg', (101, 110))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('cancers', 'Disease', (155, 162))	('UM', 'Phenotype', 'HP:0007716', (45, 47))
142325	27718540	One of the mutations identified c.1717_1717delC, p.Leu573fs_3 (FUM152) was recently reported as a founder mutation in several families in North America.	('c.1717_1717delC', 'Var', (32, 47))	('c.1717_1717delC', 'Mutation', 'c.1717_1717delC', (32, 47))	('UM', 'Phenotype', 'HP:0007716', (64, 66))	('p.Leu573fs_3', 'Var', (49, 61))	('p.Leu573fs', 'Mutation', 'rs869025212', (49, 59))
142327	27718540	We should note that we recently identified another family with the same founder mutation and the rs71651686 variant (unpublished data) and the family presented with UM and other cancers linked to the BAP1-tumor predisposition syndrome.	('rs71651686', 'Var', (97, 107))	('rs71651686', 'Mutation', 'rs71651686', (97, 107))	('UM', 'Phenotype', 'HP:0007716', (165, 167))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('cancers linked to the BAP1-tumor', 'Disease', 'MESH:D009369', (178, 210))	('cancers linked to the BAP1-tumor', 'Disease', (178, 210))
142330	27718540	Interestingly, although UM was the first cancer-type associated with the gene, several other cancers were found to be associated with the syndrome upon further research.	('cancers', 'Disease', (93, 100))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('UM', 'Phenotype', 'HP:0007716', (24, 26))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('gene', 'Var', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
142336	27718540	In conclusion, the overall frequency of BAP1 mutation in FUM is estimated at 22%, although this can vary between 8% and 50% depending on additional family history of CM, MMe, and/or RCC.	('CM', 'Phenotype', 'HP:0012056', (166, 168))	('BAP1', 'Gene', '8314', (40, 44))	('mutation', 'Var', (45, 53))	('CM', 'Disease', 'MESH:D009202', (166, 168))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Disease', (182, 185))	('BAP1', 'Gene', (40, 44))	('UM', 'Phenotype', 'HP:0007716', (58, 60))
142365	26985199	In contrast, multiple clinical studies have shown that 106Ru brachytherapy can result in a favorable clinical outcome and complete regression even in large tumors.	('tumors', 'Disease', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('106Ru', 'Var', (55, 60))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
142382	26985199	The off-label use of 106Ru brachytherapy for a tumor height >= 7 mm and the safety concerns were discussed extensively with the patient and family, and an informed consent was obtained.	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('106Ru', 'Var', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('patient', 'Species', '9606', (128, 135))	('tumor', 'Disease', (47, 52))
142416	26985199	History of hypertension and notched plaque shape were predictors for tumor recurrence in univariate analysis.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('hypertension', 'Disease', 'MESH:D006973', (11, 23))	('notched', 'Var', (28, 35))	('hypertension', 'Disease', (11, 23))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('hypertension', 'Phenotype', 'HP:0000822', (11, 23))
142432	26985199	Our study showed that 106Ru brachytherapy in selected eyes with thick uveal malignant melanomas (7 mm <= thickness < 11 mm) that would otherwise be managed with enucleation could result in a high local tumor control rate in spite of the less than recommended radiation dose and dose rate to the apex in the majority of our cases.	('106Ru', 'Var', (22, 27))	('malignant melanomas', 'Phenotype', 'HP:0002861', (76, 95))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('thick uveal malignant melanomas', 'Disease', 'MESH:C536494', (64, 95))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('enucleation', 'biological_process', 'GO:0090601', ('161', '172'))	('thick uveal malignant melanomas', 'Disease', (64, 95))	('apex', 'cellular_component', 'GO:0097683', ('295', '299'))	('men', 'Species', '9606', (252, 255))	('local tumor', 'Disease', (196, 207))	('uveal malignant melanomas', 'Phenotype', 'HP:0007716', (70, 95))	('local tumor', 'Disease', 'MESH:D009364', (196, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
142458	26985199	Wilson and Hungerford reported a 5-year tumor recurrence of 4%, 11%, and 5% following 125I brachytherapy, 106Ru brachytherapy, and proton beam radiotherapy, respectively.	('125I brachytherapy', 'Var', (86, 104))	('106Ru', 'Var', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Wilson', 'Disease', 'MESH:D006527', (0, 6))	('Wilson', 'Disease', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
142468	26985199	In summary, 106Ru brachytherapy is a successful alternative for enucleation for thick uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('thick uveal melanoma', 'Disease', (80, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('thick uveal melanoma', 'Disease', 'MESH:C536494', (80, 100))	('enucleation', 'biological_process', 'GO:0090601', ('64', '75'))	('106Ru', 'Var', (12, 17))
142471	24938562	Effect of Selumetinib versus Chemotherapy on Progression-Free Survival in Uveal Melanoma: A Randomized Clinical Trial Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in MAPK pathway activation.	('MAPK pathway', 'Pathway', (195, 207))	('Uveal melanoma', 'Disease', 'MESH:C536494', (118, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('MAPK', 'molecular_function', 'GO:0004707', ('195', '199'))	('activation', 'PosReg', (208, 218))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('Uveal Melanoma', 'Disease', 'MESH:C536494', (74, 88))	('mutations', 'Var', (153, 162))	('GNAQ', 'Gene', '2776', (166, 170))	('Uveal melanoma', 'Disease', (118, 132))	('GNA11', 'Gene', (175, 180))	('GNA11', 'Gene', '2767', (175, 180))	('Melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('Uveal Melanoma', 'Disease', (74, 88))	('GNAQ', 'Gene', (166, 170))	('Selumetinib', 'Chemical', 'MESH:C517975', (10, 21))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (118, 132))
142488	24938562	Oncogenic mutations in GNAQ or GNA11, genes encoding for widely expressed G-protein alpha subunits, are observed in more than 80% of primary uveal melanomas and activate signaling pathways including the MAPK pathway.	('activate', 'PosReg', (161, 169))	('MAPK pathway', 'Pathway', (203, 215))	('uveal melanomas', 'Disease', 'MESH:C536494', (141, 156))	('uveal melanoma', 'Phenotype', 'HP:0007716', (141, 155))	('MAPK', 'molecular_function', 'GO:0004707', ('203', '207'))	('GNAQ', 'Gene', (23, 27))	('signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('GNA11', 'Gene', (31, 36))	('uveal melanomas', 'Disease', (141, 156))	('signaling pathways', 'Pathway', (170, 188))	('GNA11', 'Gene', '2767', (31, 36))	('uveal melanomas', 'Phenotype', 'HP:0007716', (141, 156))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('mutations', 'Var', (10, 19))	('GNAQ', 'Gene', '2776', (23, 27))	('melanomas', 'Phenotype', 'HP:0002861', (147, 156))	('observed', 'Reg', (104, 112))
142494	24938562	Tumor samples from all patients were prospectively genotyped for mutations in exon 5 of GNAQ and GNA11.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('GNAQ', 'Gene', (88, 92))	('patients', 'Species', '9606', (23, 31))	('mutations in', 'Var', (65, 77))	('GNAQ', 'Gene', '2776', (88, 92))	('GNA11', 'Gene', '2767', (97, 102))	('GNA11', 'Gene', (97, 102))
142496	24938562	Randomization was stratified by mutation status (GNAQ mutant versus GNA11 mutant versus GNAQ and GNA11 wild-type), American Joint Committee on Cancer cutaneous melanoma staging criteria M stage (M1a/b versus M1c), and number of prior systemic therapies for metastatic disease (0 versus >=1).	('GNAQ', 'Gene', (88, 92))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('GNAQ', 'Gene', '2776', (49, 53))	('Cancer cutaneous melanoma', 'Disease', 'MESH:C562393', (143, 168))	('GNA11', 'Gene', (68, 73))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (150, 168))	('Cancer', 'Phenotype', 'HP:0002664', (143, 149))	('GNA11', 'Gene', '2767', (68, 73))	('GNAQ', 'Gene', '2776', (88, 92))	('GNAQ', 'Gene', (49, 53))	('mutant', 'Var', (54, 60))	('mutant', 'Var', (74, 80))	('GNA11', 'Gene', '2767', (97, 102))	('GNA11', 'Gene', (97, 102))	('Cancer cutaneous melanoma', 'Disease', (143, 168))
142513	24938562	Final analysis was pre-specified to occur after >=68 progression events were observed in patients with tumor harboring a GNAQ or GNA11 mutation.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('GNA11', 'Gene', '2767', (129, 134))	('GNA11', 'Gene', (129, 134))	('tumor', 'Disease', (103, 108))	('GNAQ', 'Gene', '2776', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('patients', 'Species', '9606', (89, 97))	('pre', 'molecular_function', 'GO:0003904', ('19', '22'))	('mutation', 'Var', (135, 143))	('GNAQ', 'Gene', (121, 125))
142514	24938562	Randomization of >=80 patients with tumor harboring GNAQ or GNA11 mutation was planned.	('GNA11', 'Gene', (60, 65))	('GNAQ', 'Gene', '2776', (52, 56))	('patients', 'Species', '9606', (22, 30))	('GNA11', 'Gene', '2767', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mutation', 'Var', (66, 74))	('GNAQ', 'Gene', (52, 56))	('tumor', 'Disease', (36, 41))
142529	24938562	Mutational testing was performed on 117 metastatic and 3 primary specimens, with 37% harboring mutations in exon 5 of GNAQ (13-Q209L, 26-209P, 4-Q209H, and 1-Q209R) and 45% harboring mutations in exon 5 of GNA11 (53-Q209L and 1-Q209P).	('26-209P', 'Var', (134, 141))	('Q209L', 'Mutation', 'rs121913492', (127, 132))	('53-Q209L', 'Var', (213, 221))	('GNAQ', 'Gene', (118, 122))	('Q209P', 'Mutation', 'rs1057519742', (228, 233))	('4-Q209H', 'Var', (143, 150))	('1-Q209P', 'Var', (226, 233))	('men', 'Species', '9606', (70, 73))	('Q209H', 'Mutation', 'p.Q209H', (145, 150))	('1-Q209R', 'Var', (156, 163))	('Q209R', 'Mutation', 'rs121913492', (158, 163))	('13-Q209L', 'Var', (124, 132))	('GNAQ', 'Gene', '2776', (118, 122))	('GNA11', 'Gene', (206, 211))	('Q209L', 'Mutation', 'rs121913492', (216, 221))	('GNA11', 'Gene', '2767', (206, 211))
142533	24938562	Similar improvement was observed when limiting analysis to patients with tumor harboring a GNAQ or GNA11 mutation (n=80; Figure 2b).	('mutation', 'Var', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('GNAQ', 'Gene', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('men', 'Species', '9606', (15, 18))	('GNA11', 'Gene', '2767', (99, 104))	('GNA11', 'Gene', (99, 104))	('tumor', 'Disease', (73, 78))	('patients', 'Species', '9606', (59, 67))	('GNAQ', 'Gene', '2776', (91, 95))
142543	24938562	No difference in overall survival was observed when limiting analysis to patients with tumor harboring a GNAQ or GNA11 mutation (n=83; eFigure 4b).	('mutation', 'Var', (119, 127))	('GNAQ', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('GNA11', 'Gene', '2767', (113, 118))	('GNA11', 'Gene', (113, 118))	('GNAQ', 'Gene', '2776', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('patients', 'Species', '9606', (73, 81))
142570	24938562	The efficacy of MEK inhibition in uveal melanoma is predicted by the frequent activation of the MAPK pathway by functionally activating mutations in GNAQ or GNA11.	('GNAQ', 'Gene', (149, 153))	('GNA11', 'Gene', '2767', (157, 162))	('GNA11', 'Gene', (157, 162))	('GNAQ', 'Gene', '2776', (149, 153))	('activating', 'PosReg', (125, 135))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('MAPK', 'molecular_function', 'GO:0004707', ('96', '100'))	('MEK', 'Gene', (16, 19))	('mutations', 'Var', (136, 145))	('activation', 'PosReg', (78, 88))	('inhibition', 'NegReg', (20, 30))	('uveal melanoma', 'Disease', 'MESH:C536494', (34, 48))	('uveal melanoma', 'Phenotype', 'HP:0007716', (34, 48))	('MEK', 'Gene', '5609', (16, 19))	('MAPK pathway', 'Pathway', (96, 108))	('uveal melanoma', 'Disease', (34, 48))
142571	24938562	This strategy may be applicable to other tumors characterized by MAPK pathway activation via additional mechanisms including receptor tyrosine kinase activation, RAS mutation, NF1 loss, and others.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('NF1', 'Gene', '4763', (176, 179))	('NF1', 'Gene', (176, 179))	('receptor tyrosine kinase', 'MPA', (125, 149))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('loss', 'NegReg', (180, 184))	('activation', 'PosReg', (150, 160))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('RAS', 'Gene', (162, 165))	('activation', 'PosReg', (78, 88))	('MAPK', 'molecular_function', 'GO:0004707', ('65', '69'))	('mutation', 'Var', (166, 174))
142576	24938562	This observation may be explained by the presence of other mechanisms of MAPK pathway activation in exon 5 GNAQ or GNA11 wild-type tumors.	('GNA11', 'Gene', '2767', (115, 120))	('MAPK pathway', 'Pathway', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('GNAQ', 'Gene', '2776', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('exon 5', 'Var', (100, 106))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('MAPK', 'molecular_function', 'GO:0004707', ('73', '77'))	('activation', 'PosReg', (86, 96))	('GNA11', 'Gene', (115, 120))	('GNAQ', 'Gene', (107, 111))
142578	24938562	Thus, it is likely that the majority of the patients classified as wild-type in this study had tumors harboring exon 4 GNAQ or GNA11 mutations.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('patients', 'Species', '9606', (44, 52))	('GNAQ', 'Gene', (119, 123))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('mutations', 'Var', (133, 142))	('GNA11', 'Gene', '2767', (127, 132))	('GNA11', 'Gene', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('GNAQ', 'Gene', '2776', (119, 123))
142579	24938562	Of the five exon 5 wild-type cases with sufficient remaining tumor material, we identified exon 4 mutations in three, one of whom achieved a major response to selumetinib.	('selumetinib', 'Chemical', 'MESH:C517975', (159, 170))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mutations', 'Var', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('exon', 'Var', (91, 95))
142590	24938562	Additionally, this trial was designed before activating mutations in exon 4 of GNAQ and GNA11 were reported, thus prospective assessment for these alterations was not performed.	('mutations', 'Var', (56, 65))	('GNAQ', 'Gene', '2776', (79, 83))	('GNA11', 'Gene', '2767', (88, 93))	('GNA11', 'Gene', (88, 93))	('men', 'Species', '9606', (132, 135))	('GNAQ', 'Gene', (79, 83))
142640	22570544	In contrast, in Phase III clinical trials of topical bromfenac, safety assessments for subjects treated with bromfenac were generally equivalent to or better than those for subjects treated with a vehicle.	('bromfenac', 'Chemical', 'MESH:C053083', (109, 118))	('bromfenac', 'Var', (109, 118))	('better', 'PosReg', (151, 157))	('bromfenac', 'Chemical', 'MESH:C053083', (53, 62))	('topical', 'molecular_function', 'GO:0003809', ('45', '52'))
142655	22570544	Although studies comparing NSAIDs to corticosteroids have not revealed differences in the reduction of intraocular inflammation after cataract surgery, NSAIDs appear to be more effective at reestablishing the blood-aqueous barrier, as revealed by flare on slit-lamp examination and as quantitatively measured using ocular fluorophotometry.	('inflammation', 'biological_process', 'GO:0006954', ('115', '127'))	('ocular inflammation', 'Phenotype', 'HP:0100533', (108, 127))	('NSAIDs', 'Var', (152, 158))	('intraocular inflammation', 'Disease', 'MESH:D007249', (103, 127))	('cataract', 'Disease', 'MESH:D002386', (134, 142))	('cataract', 'Disease', (134, 142))	('intraocular inflammation', 'Disease', (103, 127))	('cataract', 'Phenotype', 'HP:0000518', (134, 142))	('steroids', 'Chemical', 'MESH:D013256', (44, 52))
142667	22570544	Among subjects who experienced ocular pain after surgery, the median time for resolution of pain was 2 days for those treated with bromfenac compared with 5 days for those treated with a vehicle.	('pain', 'Disease', 'MESH:D010146', (38, 42))	('pain', 'Disease', (38, 42))	('ocular pain', 'Disease', 'MESH:D058447', (31, 42))	('pain', 'Phenotype', 'HP:0012531', (92, 96))	('bromfenac', 'Chemical', 'MESH:C053083', (131, 140))	('ocular pain', 'Disease', (31, 42))	('ocular pain', 'Phenotype', 'HP:0200026', (31, 42))	('pain', 'Disease', 'MESH:D010146', (92, 96))	('pain', 'Disease', (92, 96))	('pain', 'Phenotype', 'HP:0012531', (38, 42))	('bromfenac', 'Var', (131, 140))
142676	22570544	Among them, PGE1 and PGE2 diminish the threshold of itching and become NSAIDs in potential therapy for allergic conjunctivitis.	('itching', 'Disease', 'MESH:D011537', (52, 59))	('itching', 'Disease', (52, 59))	('itching', 'Phenotype', 'HP:0000989', (52, 59))	('PGE2', 'Chemical', 'MESH:D015232', (21, 25))	('itch', 'Phenotype', 'HP:0000989', (52, 56))	('allergic conjunctivitis', 'Disease', (103, 126))	('PGE2', 'Gene', (21, 25))	('allergic conjunctivitis', 'Disease', 'MESH:D004342', (103, 126))	('conjunctivitis', 'Phenotype', 'HP:0000509', (112, 126))	('allergic conjunctivitis', 'Phenotype', 'HP:0007879', (103, 126))	('diminish', 'NegReg', (26, 34))	('PGE1', 'Chemical', 'MESH:D000527', (12, 16))	('PGE1', 'Var', (12, 16))
142697	22570544	However, Wang et al found there was less pain in eyes treated with bromfenac 0.09% than in those treated with ketorolac 0.5% following LASEK or epi-LASEK surgery.	('pain', 'Disease', 'MESH:D010146', (41, 45))	('pain', 'Disease', (41, 45))	('less', 'NegReg', (36, 40))	('bromfenac', 'Var', (67, 76))	('ketorolac', 'Chemical', 'MESH:D020910', (110, 119))	('pain in eyes', 'Phenotype', 'HP:0200026', (41, 53))	('pain', 'Phenotype', 'HP:0012531', (41, 45))	('bromfenac', 'Chemical', 'MESH:C053083', (67, 76))
142706	22570544	Thus, the inhibition of COX-2 by NSAIDs reduces vascular endothelial growth factor production and directly inhibits choroidal neovascularization in both trauma-induced and ischemia-induced animal models.	('choroidal neovascular', 'Disease', (116, 137))	('trauma', 'Disease', 'MESH:D014947', (153, 159))	('ischemia', 'Disease', 'MESH:D007511', (172, 180))	('inhibition', 'NegReg', (10, 20))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('48', '82'))	('vascular endothelial growth factor production', 'biological_process', 'GO:0010573', ('48', '93'))	('trauma', 'Disease', (153, 159))	('vascular endothelial growth factor', 'Gene', (48, 82))	('NSAIDs', 'Var', (33, 39))	('ischemia', 'Disease', (172, 180))	('inhibits', 'NegReg', (107, 115))	('choroidal neovascular', 'Disease', 'MESH:D020256', (116, 137))	('vascular endothelial growth factor', 'Gene', '7422', (48, 82))	('reduces', 'NegReg', (40, 47))	('choroidal neovascularization', 'Phenotype', 'HP:0011506', (116, 144))	('COX-2', 'Gene', (24, 29))	('COX-2', 'Gene', '5743', (24, 29))
142714	22570544	Some COX-2 inhibitors have been demonstrated in experimental studies to inhibit the proliferation of human retinoblastoma cell lines, limit the progression of uveal melanoma, and increase the radiosensitivity of uveal melanoma.	('retinoblastoma', 'Disease', 'MESH:D012175', (107, 121))	('progression', 'CPA', (144, 155))	('uveal melanoma', 'Phenotype', 'HP:0007716', (212, 226))	('uveal melanoma', 'Disease', (212, 226))	('COX-2', 'Gene', (5, 10))	('proliferation', 'CPA', (84, 97))	('retinoblastoma', 'Phenotype', 'HP:0009919', (107, 121))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('increase', 'PosReg', (179, 187))	('uveal melanoma', 'Disease', 'MESH:C536494', (159, 173))	('retinoblastoma', 'Disease', (107, 121))	('uveal melanoma', 'Disease', (159, 173))	('human', 'Species', '9606', (101, 106))	('COX-2', 'Gene', '5743', (5, 10))	('limit', 'NegReg', (134, 139))	('uveal melanoma', 'Phenotype', 'HP:0007716', (159, 173))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('inhibitors', 'Var', (11, 21))	('inhibit', 'NegReg', (72, 79))	('uveal melanoma', 'Disease', 'MESH:C536494', (212, 226))	('radiosensitivity', 'CPA', (192, 208))
142724	22363447	All three lines showed Mn2+-induced increases in R1 compared to cells not exposed to Mn2+.	('increases', 'PosReg', (36, 45))	('Mn2+', 'Chemical', '-', (23, 27))	('Mn2+', 'Chemical', '-', (85, 89))	('Mn2+-induced', 'Var', (23, 35))
142738	22363447	Importantly, Mn2+ accumulates intracellularly due to a slow rate of efflux and acts as an MRI contrast agent by increasing the tissue longitudinal relaxation rate (R1 = 1/T1) in proportion to manganese concentration.	('tissue longitudinal relaxation rate', 'MPA', (127, 162))	('Mn2+', 'Var', (13, 17))	('increasing', 'PosReg', (112, 122))	('slow rate', 'MPA', (55, 64))	('Mn2+', 'Chemical', '-', (13, 17))	('rat', 'Species', '10116', (60, 63))	('manganese', 'Chemical', 'MESH:D008345', (192, 201))	('efflux', 'biological_process', 'GO:0140115', ('68', '74'))	('efflux', 'MPA', (68, 74))	('rat', 'Species', '10116', (209, 212))	('efflux', 'biological_process', 'GO:0140352', ('68', '74'))	('rat', 'Species', '10116', (158, 161))
142746	22363447	The human uveal melanoma cell lines C918 and OCM-1 were used, because we had previously shown that C918 cells took up Mn2+ in vitro and in vivo , and we wished to further investigate this class of tumor.	('uveal melanoma', 'Disease', 'MESH:C536494', (10, 24))	('human', 'Species', '9606', (4, 9))	('uveal melanoma', 'Phenotype', 'HP:0007716', (10, 24))	('uveal melanoma', 'Disease', (10, 24))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('C918', 'CellLine', 'CVCL:8471', (36, 40))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('took up Mn2+', 'MPA', (110, 122))	('OCM-1', 'Species', '83984', (45, 50))	('C918', 'CellLine', 'CVCL:8471', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('C918', 'Var', (99, 103))	('Mn2+', 'Chemical', '-', (118, 122))
142754	22363447	Since the Weibull model best described the growth of the cells, we used the corresponding equation to describe the number of cell divisions as a function of time:where Cmax = maximum cell density (cells/mm2), kappa = the inverse of the time constant (1/daysnu), and nu = dimensionless constant.	('mm2', 'Gene', '10687', (203, 206))	('Cmax', 'Var', (168, 172))	('mm2', 'Gene', (203, 206))
142792	22363447	Post-hoc analysis demonstrated that, as expected, for each cell line, the R1 of cells exposed to Mn2+ for one hour and then rinsed was significantly greater than the R1 of corresponding cells not exposed to Mn2+ (p<0.0001, Tukey's HSD test, Figure 2).	('HSD', 'Disease', (231, 234))	('greater', 'PosReg', (149, 156))	('HSD', 'Disease', 'OMIM:143095', (231, 234))	('Mn2+', 'Chemical', '-', (97, 101))	('Mn2+', 'Var', (97, 101))	('rat', 'Species', '10116', (25, 28))	('Mn2+', 'Chemical', '-', (207, 211))
142798	22363447	In PC-3 prostate cancer cells, the Mn2+-enhanced R1 values for the cell pellets were positively correlated with proliferation rate (Figure 3A, r2 = 0.284, p = 0.005, n = 26), while the R1 values of cell pellets in the absence of Mn2+ were not correlated with proliferation rate (r2 = 0.146, p = 0.618, n = 4).	('PC-3', 'Gene', '3853', (3, 7))	('prostate cancer', 'Disease', 'MESH:D011471', (8, 23))	('rat', 'Species', '10116', (266, 269))	('Mn2+-enhanced', 'PosReg', (35, 48))	('rat', 'Species', '10116', (119, 122))	('rat', 'Species', '10116', (273, 276))	('proliferation rate', 'CPA', (112, 130))	('prostate cancer', 'Phenotype', 'HP:0012125', (8, 23))	('PC-3', 'Gene', (3, 7))	('rat', 'Species', '10116', (126, 129))	('Mn2+', 'Chemical', '-', (35, 39))	('Mn2+-enhanced', 'Var', (35, 48))	('prostate cancer', 'Disease', (8, 23))	('Mn2+', 'Chemical', '-', (229, 233))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
142801	22363447	The OCM-1 cells showed no correlation between Mn2+-dependent R1 and proliferation rate (Figure 3C, r2 = 4.94x10-5, p = 0.975, n = 22) or between R1 and proliferation rate in the absence of Mn2+ (r2 = 0.040, p = 0.799, n = 4).	('Mn2+-dependent', 'Var', (46, 60))	('rat', 'Species', '10116', (166, 169))	('OCM-1', 'Species', '83984', (4, 9))	('rat', 'Species', '10116', (75, 78))	('Mn2+', 'Chemical', '-', (189, 193))	('proliferation rate', 'CPA', (152, 170))	('rat', 'Species', '10116', (82, 85))	('Mn2+', 'Chemical', '-', (46, 50))	('proliferation rate', 'CPA', (68, 86))	('rat', 'Species', '10116', (159, 162))
142807	22363447	It is possible to derive a simple, general model to describe the positive correlation between Mn2+-induced changes in R1 and proliferation rate in the PC-3 and C918 cell lines (Figure 3).	('PC-3', 'Gene', '3853', (151, 155))	('Mn2+-induced', 'Var', (94, 106))	('proliferation rate', 'CPA', (125, 143))	('rat', 'Species', '10116', (132, 135))	('C918', 'CellLine', 'CVCL:8471', (160, 164))	('rat', 'Species', '10116', (139, 142))	('PC-3', 'Gene', (151, 155))	('Mn2+', 'Chemical', '-', (94, 98))	('changes', 'Var', (107, 114))
142809	22363447	If each subpopulation takes up a different amount of Mn2+, each subpopulation would have its own R1 value, and the average R1 of any mixed cell population would be the weighted average of these individual cell cycle-specific values.	('Mn2+', 'Var', (53, 57))	('cell cycle', 'biological_process', 'GO:0007049', ('205', '215'))	('R1 value', 'MPA', (97, 105))	('Mn2+', 'Chemical', '-', (53, 57))
142810	22363447	Thus, the overall R1 of the pellet is described by the following weighted average:where (R1)pellet = R1 value of cell pellet (sec-1), RS = R1 value of a cell in S phase (sec-1), R01 = R1 value of a cell in G0/G1 phase (sec-1), and RM = R1 value of a cell in G2/M phase (sec-1).	('sec-1', 'Gene', (270, 275))	('sec-1', 'Gene', '653677', (270, 275))	('sec-1', 'Gene', (126, 131))	('sec-1', 'Gene', '653677', (126, 131))	('S phase', 'biological_process', 'GO:0051320', ('161', '168'))	('R01 = R1', 'Var', (178, 186))	('M phase', 'biological_process', 'GO:0000279', ('261', '268'))	('G1 phase', 'biological_process', 'GO:0051318', ('209', '217'))	('sec-1', 'Gene', (219, 224))	('sec-1', 'Gene', '653677', (219, 224))	('sec-1', 'Gene', (170, 175))	('RS = R1', 'Var', (134, 141))	('sec-1', 'Gene', '653677', (170, 175))
142815	22363447	With the available data, it is possible to directly test the first possibility, i.e., that the three subpopulations demonstrate unique amounts of ion flux (R01, RS, and RM), but these amounts are not affected by proliferation rate.	('ion flux', 'MPA', (146, 154))	('R01', 'Var', (156, 159))	('rat', 'Species', '10116', (123, 126))	('rat', 'Species', '10116', (226, 229))	('rat', 'Species', '10116', (219, 222))
142821	22363447	The best-fit values of R01, RS, and RM with the 95% confidence intervals (95% CI) were 1.16 (95% CI: 0.82 to 1.51) sec-1, 1.86 (95% CI: 0.66 to 3.07) sec-1, and 2.02 (95% CI: -1.87 to 5.91) sec-1, respectively.	('sec-1', 'Gene', (150, 155))	('sec-1', 'Gene', '653677', (150, 155))	('sec-1', 'Gene', (115, 120))	('sec-1', 'Gene', '653677', (115, 120))	('sec-1', 'Gene', (190, 195))	('R01', 'Var', (23, 26))	('sec-1', 'Gene', '653677', (190, 195))
142822	22363447	Despite the wide confidence intervals (a consequence of uncertainty in RM), if the value for R01 is fixed within its 95% CI (between 0.82 and 1.51 sec-1), all solutions yield fits in which R01<RS.	('sec-1', 'Gene', '653677', (147, 152))	('sec-1', 'Gene', (147, 152))	('fits', 'Disease', (175, 179))	('R01<RS', 'Var', (189, 195))	('fits', 'Disease', 'MESH:D012640', (175, 179))
142825	22363447	The best-fit values of R01, RS, and RM with the 95% confidence intervals (95% CI) were 0.67 (95% CI: 0.48 to 0.86) sec-1, 1.57 (95% CI: 1.17 to 1.97) sec-1, and 1.07 (95% CI: -0.20 to 2.33) sec-1, respectively.	('sec-1', 'Gene', (150, 155))	('sec-1', 'Gene', '653677', (150, 155))	('sec-1', 'Gene', (115, 120))	('sec-1', 'Gene', '653677', (115, 120))	('sec-1', 'Gene', (190, 195))	('R01', 'Var', (23, 26))	('sec-1', 'Gene', '653677', (190, 195))
142831	22363447	Although we and others have shown that tumor cells accumulate Mn2+ when exposed to MnCl2 and that Mn2+ changes the cellular MEMRI R1 values, this is the first time that the Mn2+-induced R1 changes have been correlated with changes in proliferation rate.	('Mn2+', 'Var', (98, 102))	('MnCl2', 'Chemical', 'MESH:C025340', (83, 88))	('Mn2+', 'Chemical', '-', (173, 177))	('Mn2+', 'Chemical', '-', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Mn2+', 'Chemical', '-', (62, 66))	('changes', 'Reg', (103, 110))	('tumor', 'Disease', (39, 44))	('rat', 'Species', '10116', (241, 244))	('cellular MEMRI R1 values', 'MPA', (115, 139))	('rat', 'Species', '10116', (248, 251))
142857	22363447	As presented in the Results section, the simple weighted-average model (Equation 10) assumes that the changes in pellet R1 can be fully explained by changes in the relative distribution of cells in different phases of the cell cycle (each with a cell-cycle specific constant R1) as proliferation rate changes.	('rat', 'Species', '10116', (289, 292))	('proliferation', 'CPA', (282, 295))	('cell cycle', 'biological_process', 'GO:0007049', ('222', '232'))	('changes', 'Var', (102, 109))	('cell-cycle', 'biological_process', 'GO:0007049', ('246', '256'))	('rat', 'Species', '10116', (296, 299))	('changes', 'Reg', (149, 156))
142934	19735546	After treatment for up to 48 h with various concentrations of Genistein (10, 25, 50, 100, 200 muM), the result displayed Genistein significantly decreased the cell survival in a dose-dependent manner (Figure 2).	('Genistein', 'Chemical', 'MESH:D019833', (62, 71))	('Genistein', 'Chemical', 'MESH:D019833', (121, 130))	('muM', 'Gene', '56925', (94, 97))	('Genistein', 'Var', (121, 130))	('cell survival', 'CPA', (159, 172))	('decreased', 'NegReg', (145, 154))	('muM', 'Gene', (94, 97))
142974	19735546	This study shows that Genistein could effectively inhibit the VM formation of C918 human uveal melanoma in vivo and in vitro.	('VM formation', 'CPA', (62, 74))	('inhibit', 'NegReg', (50, 57))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('human', 'Species', '9606', (83, 88))	('C918', 'CellLine', 'CVCL:8471', (78, 82))	('C918', 'Var', (78, 82))	('Genistein', 'Chemical', 'MESH:D019833', (22, 31))	('uveal melanoma', 'Disease', 'MESH:C536494', (89, 103))	('uveal melanoma', 'Disease', (89, 103))	('uveal melanoma', 'Phenotype', 'HP:0007716', (89, 103))	('formation', 'biological_process', 'GO:0009058', ('65', '74'))
142975	19735546	One of the mechanisms that Genistein inhibits VM is associated with down regulation of VE-cadherin.	('cadherin', 'molecular_function', 'GO:0008014', ('90', '98'))	('VE-cadherin', 'Gene', (87, 98))	('Genistein', 'Chemical', 'MESH:D019833', (27, 36))	('VE-cadherin', 'Gene', '1003', (87, 98))	('Genistein', 'Var', (27, 36))	('inhibits', 'NegReg', (37, 45))	('down regulation', 'NegReg', (68, 83))	('regulation', 'biological_process', 'GO:0065007', ('73', '83'))
142977	18719078	Oncogenic mutations in GNAQ occur early in uveal melanoma Early/initiating oncogenic mutations have been identified for many cancers, but such mutations remain unidentified in uveal melanoma (UM).	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('uveal melanoma', 'Phenotype', 'HP:0007716', (176, 190))	('uveal melanoma', 'Disease', (176, 190))	('cancers', 'Disease', (125, 132))	('GNAQ', 'Gene', (23, 27))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('uveal melanoma', 'Disease', 'MESH:C536494', (43, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('uveal melanoma', 'Disease', (43, 57))	('mutations', 'Var', (10, 19))	('GNAQ', 'Gene', '2776', (23, 27))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('uveal melanoma', 'Disease', 'MESH:C536494', (176, 190))	('UM', 'Phenotype', 'HP:0007716', (192, 194))
142979	18719078	DNA samples from primary UMs were analyzed for mutations in 24 potential oncogenes that affect the RAF/MEK/ERK pathway.	('ERK', 'Gene', '5594', (107, 110))	('ERK', 'Gene', (107, 110))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('affect', 'Reg', (88, 94))	('RAF', 'Gene', '2889', (99, 102))	('mutations', 'Var', (47, 56))	('MEK', 'Gene', (103, 106))	('MEK', 'Gene', '5609', (103, 106))	('ERK', 'molecular_function', 'GO:0004707', ('107', '110'))	('RAF', 'Gene', (99, 102))	('UM', 'Phenotype', 'HP:0007716', (25, 27))
142983	18719078	GNAQ mutations occur in about half of UMs, representing the most common known oncogenic mutation in this cancer.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('mutations', 'Var', (5, 14))	('UMs', 'Disease', (38, 41))	('GNAQ', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('occur', 'Reg', (15, 20))	('UM', 'Phenotype', 'HP:0007716', (38, 40))
142985	18719078	Several of the late genetic events in tumor progression and metastasis have been identified in UM, such as the loss of chromosome 3 and the switch from class 1 (low metastatic risk) to class 2 (high metastatic risk) gene expression profile.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('chromosome', 'cellular_component', 'GO:0005694', ('119', '129'))	('gene expression', 'biological_process', 'GO:0010467', ('216', '231'))	('loss', 'Var', (111, 115))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('metastasis', 'CPA', (60, 70))
142988	18719078	Perhaps the most common signaling pathway affected by early oncogenic mutations is the RAF/MEK/ERK pathway, where mutations in BRAF, NRAS, HRAS and KIT lead to constitutive activation of the RAF/MEK/ERK pathway, which in turn stimulates the transcription of pro-proliferative genes such as CCND1, JUN and MYC.	('mutations', 'Var', (114, 123))	('KIT', 'Gene', (148, 151))	('BRAF', 'Gene', '673', (127, 131))	('CCND1', 'Gene', (290, 295))	('stimulates', 'PosReg', (226, 236))	('BRAF', 'Gene', (127, 131))	('NRAS', 'Gene', '4893', (133, 137))	('signaling pathway', 'biological_process', 'GO:0007165', ('24', '41'))	('MEK', 'Gene', '5609', (91, 94))	('ERK', 'molecular_function', 'GO:0004707', ('95', '98'))	('RAF', 'Gene', '2889', (128, 131))	('JUN', 'Gene', (297, 300))	('RAF', 'Gene', '2889', (191, 194))	('ERK', 'Gene', '5594', (95, 98))	('MYC', 'Gene', '4609', (305, 308))	('ERK', 'molecular_function', 'GO:0004707', ('199', '202'))	('MEK', 'Gene', '5609', (195, 198))	('RAF', 'Gene', (128, 131))	('HRAS', 'Gene', '3265', (139, 143))	('RAF', 'Gene', (191, 194))	('ERK', 'Gene', '5594', (199, 202))	('HRAS', 'Gene', (139, 143))	('MEK', 'Gene', (91, 94))	('RAF', 'Gene', '2889', (87, 90))	('mutations', 'Var', (70, 79))	('MEK', 'Gene', (195, 198))	('RAF', 'Gene', (87, 90))	('NRAS', 'Gene', (133, 137))	('ERK', 'Gene', (95, 98))	('ERK', 'Gene', (199, 202))	('transcription', 'biological_process', 'GO:0006351', ('241', '254'))	('KIT', 'molecular_function', 'GO:0005020', ('148', '151'))	('activation', 'PosReg', (173, 183))	('transcription', 'MPA', (241, 254))	('MYC', 'Gene', (305, 308))	('CCND1', 'Gene', '595', (290, 295))
142989	18719078	Nevertheless, there is strong evidence that mutations affecting the RAF/MEK/ERK pathway are present in UM, since MEK, ERK and ELK are constitutively activated in these tumors.	('ELK', 'Gene', '2047', (126, 129))	('tumors', 'Disease', (168, 174))	('MEK', 'Gene', (72, 75))	('ERK', 'Gene', (76, 79))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('UM', 'Phenotype', 'HP:0007716', (103, 105))	('ERK', 'Gene', '5594', (118, 121))	('MEK', 'Gene', '5609', (113, 116))	('ELK', 'Gene', (126, 129))	('ERK', 'molecular_function', 'GO:0004707', ('118', '121'))	('MEK', 'Gene', (113, 116))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('ERK', 'molecular_function', 'GO:0004707', ('76', '79'))	('ERK', 'Gene', (118, 121))	('RAF', 'Gene', '2889', (68, 71))	('mutations', 'Var', (44, 53))	('MEK', 'Gene', '5609', (72, 75))	('RAF', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('ERK', 'Gene', '5594', (76, 79))
142992	18719078	These lines of evidence implicating the RAF/MEK/ERK pathway as a likely location of early or initiating oncogenic mutations in UM prompted us to screen a large number of potential oncogenes in this pathway.	('ERK', 'Gene', (48, 51))	('UM', 'Phenotype', 'HP:0007716', (127, 129))	('mutations', 'Var', (114, 123))	('RAF', 'Gene', '2889', (40, 43))	('ERK', 'molecular_function', 'GO:0004707', ('48', '51'))	('RAF', 'Gene', (40, 43))	('ERK', 'Gene', '5594', (48, 51))	('MEK', 'Gene', (44, 47))	('MEK', 'Gene', '5609', (44, 47))
142993	18719078	Mutations in GNAQ, a stimulatory alphaq subunit of heterotrimeric G-proteins that was recently found to be mutated in UM, were found in half of the tumor samples, and the spectrum of GNAQ mutations suggested that this may be an early event in UM pathogenesis.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('GNAQ', 'Gene', (13, 17))	('tumor', 'Disease', (148, 153))	('pathogenesis', 'biological_process', 'GO:0009405', ('246', '258'))	('UM', 'Phenotype', 'HP:0007716', (118, 120))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', (183, 187))	('mutations', 'Var', (188, 197))	('UM', 'Phenotype', 'HP:0007716', (243, 245))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
142997	18719078	Normal uveal melanocytes were available in two patients with GNAQ-mutant tumors (MM86 and MM101) who had undergone enucleation.	('MM101', 'Var', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('patients', 'Species', '9606', (47, 55))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('GNAQ-mutant', 'Gene', (61, 72))	('enucleation', 'biological_process', 'GO:0090601', ('115', '126'))
143005	18719078	Factors used to choose regions to be re-sequenced included: (1) the locations of reported cancer-related mutations in the Sanger Institute Catalogue of Somatic Mutations (http://www.sanger.ac.uk/genetics/CGP/cosmic), and (2) the locations of catalytic or regulatory domains in the Swiss-Prot Database (http://www.expasy.org/sprot/).	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutations', 'Var', (105, 114))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))
143013	18719078	Chromosome 3 status was available on 42 of the tumors from a previous study using single nucleotide polymorphisms to detect loss of heterozygosity across the entire chromosome.	('tumors', 'Disease', (47, 53))	('single', 'Var', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('loss', 'NegReg', (124, 128))	('chromosome', 'cellular_component', 'GO:0005694', ('165', '175'))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
143021	18719078	Amplification of an oncogene in a subset of tumors has commonly been used as a means of identifying activating mutations in that oncogene in other, non-amplified, tumor samples.	('mutations', 'Var', (111, 120))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('activating', 'PosReg', (100, 110))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
143027	18719078	Mutations were found in GNAQ, but not in EDG5, GRM1 or PTPN11 (Figure 2).	('EDG5', 'Gene', '9294', (41, 45))	('EDG5', 'Gene', (41, 45))	('PTPN11', 'Gene', '5781', (55, 61))	('GRM1', 'Gene', '2911', (47, 51))	('PTPN11', 'Gene', (55, 61))	('Mutations', 'Var', (0, 9))	('GRM1', 'Gene', (47, 51))
143028	18719078	GNAQ mutations were found in 49% (33/67) of tumors, including 22% (2/9) iris UMs and 54% (31/58) of posterior UMs.	('tumors', 'Disease', (44, 50))	('posterior UMs', 'Disease', (100, 113))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('iris UMs', 'Disease', (72, 80))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('UM', 'Phenotype', 'HP:0007716', (110, 112))	('mutations', 'Var', (5, 14))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('GNAQ', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('found', 'Reg', (20, 25))
143029	18719078	Normal DNA samples from peripheral blood were available from 22 patients with GNAQ-mutant primary tumors, and none of these harbored GNAQ mutations.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('patients', 'Species', '9606', (64, 72))	('primary tumors', 'Disease', (90, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))	('primary tumors', 'Disease', 'MESH:D009369', (90, 104))	('GNAQ-mutant', 'Var', (78, 89))	('GNAQ-mutant', 'Gene', (78, 89))
143030	18719078	Normal uveal melanocytes surrounding the primary tumor were available in two patients with GNAQ-mutant tumors (MM86 and MM101), and neither melanocyte samples showed GNAQ mutations.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (49, 54))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('patients', 'Species', '9606', (77, 85))	('GNAQ-mutant', 'Var', (91, 102))	('GNAQ-mutant', 'Gene', (91, 102))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
143031	18719078	First, GNAQ mutations did not occur preferentially in tumors with clinical, pathologic or immunohistochemical features indicative of advanced tumor progression (Supplementary Table 2).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('mutations', 'Var', (12, 21))	('advanced tumor', 'Disease', (133, 147))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('GNAQ', 'Gene', (7, 11))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('advanced tumor', 'Disease', 'MESH:D020178', (133, 147))	('tumors', 'Disease', (54, 60))
143032	18719078	Second, GNAQ mutations did not correlate with the degree of chromosomal aneuploidy, which is often used as a surrogate measure of temporal tumor progression (P=0.498)(Supplementary Figure 1).	('temporal tumor', 'Disease', (130, 144))	('GNAQ', 'Gene', (8, 12))	('chromosomal aneuploidy', 'Disease', (60, 82))	('chromosomal aneuploidy', 'Disease', 'MESH:D000782', (60, 82))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('temporal tumor', 'Disease', 'MESH:C536956', (130, 144))	('mutations', 'Var', (13, 22))
143036	18719078	SAM was used to identify genes that were differentially expressed in tumors harboring GNAQ mutations.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (91, 100))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('GNAQ', 'Gene', (86, 90))
143037	18719078	Consistent with the PCA results, SAM revealed no genes that were consistently differentially expressed between tumors with and without GNAQ mutations (Supplementary Figure 1).	('GNAQ', 'Gene', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (140, 149))
143038	18719078	Activating oncogenic mutations affecting the RAF/MEK/ERK pathway are pervasive in cutaneous melanomas and other forms of cancer, but have rarely been found in UM.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (82, 101))	('UM', 'Phenotype', 'HP:0007716', (159, 161))	('RAF', 'Gene', (45, 48))	('cutaneous melanomas', 'Disease', (82, 101))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ERK', 'Gene', '5594', (53, 56))	('melanomas', 'Phenotype', 'HP:0002861', (92, 101))	('MEK', 'Gene', (49, 52))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (82, 100))	('MEK', 'Gene', '5609', (49, 52))	('ERK', 'molecular_function', 'GO:0004707', ('53', '56'))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('ERK', 'Gene', (53, 56))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('RAF', 'Gene', '2889', (45, 48))	('cancer', 'Disease', (121, 127))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (82, 101))	('mutations', 'Var', (21, 30))
143041	18719078	Mutation of this codon inactivates the catalytic domain, preventing hydrolysis of GTP and locking GNAQ in its active, GTP-bound state.	('GTP', 'Chemical', 'MESH:D006160', (82, 85))	('hydrolysis', 'MPA', (68, 78))	('catalytic domain', 'MPA', (39, 55))	('Mutation', 'Var', (0, 8))	('preventing', 'NegReg', (57, 67))	('GTP', 'Chemical', 'MESH:D006160', (118, 121))	('inactivates', 'NegReg', (23, 34))
143042	18719078	This mutation leads to melanocyte proliferation in mice, and can cooperate with other oncogenes to transform melanocytes.	('mice', 'Species', '10090', (51, 55))	('melanocyte proliferation', 'CPA', (23, 47))	('leads to', 'Reg', (14, 22))	('melanocyte proliferation', 'biological_process', 'GO:0097325', ('23', '47'))	('mutation', 'Var', (5, 13))
143045	18719078	In many cancers, mutations in the RAF/MEK/ERK pathway are thought to be early or initiating events in tumorigenesis.	('ERK', 'Gene', (42, 45))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('ERK', 'molecular_function', 'GO:0004707', ('42', '45'))	('MEK', 'Gene', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('MEK', 'Gene', '5609', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('RAF', 'Gene', '2889', (34, 37))	('ERK', 'Gene', '5594', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('mutations', 'Var', (17, 26))	('RAF', 'Gene', (34, 37))
143046	18719078	For example, BRAF mutations occur very early in cutaneous melanoma, and are even present in benign and pre-malignant nevi.	('cutaneous melanoma', 'Disease', (48, 66))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (48, 66))	('nevi', 'Phenotype', 'HP:0003764', (117, 121))	('BRAF', 'Gene', '673', (13, 17))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 66))	('pre', 'molecular_function', 'GO:0003904', ('103', '106'))	('BRAF', 'Gene', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('mutations', 'Var', (18, 27))
143048	18719078	GNAQ mutations were not found in normal DNA from patients bearing GNAQ-mutant tumors.	('GNAQ-mutant', 'Var', (66, 77))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('GNAQ', 'Gene', (0, 4))	('patients', 'Species', '9606', (49, 57))
143049	18719078	A potential effect of GNAQ mutations could be the creation of an expanded pool of morphologically normal but abnormally proliferating melanocytes, as occurred in the mouse model of GNAQ mutation.	('mutations', 'Var', (27, 36))	('GNAQ', 'Gene', (22, 26))	('mouse', 'Species', '10090', (166, 171))
143050	18719078	As a result, one might expect to find GNAQ mutations in uveal melanocytes of tumor-bearing eyes.	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('GNAQ', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
143052	18719078	Conversely, BRAF mutations are found in some iris UMs, but not in posterior UMs.	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', (12, 16))	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('iris UMs', 'Disease', (45, 53))	('mutations', 'Var', (17, 26))
143146	33577798	A novel therapeutic approach has been suggested by the discovery that UM cell lines driven by mutant constitutively active Gq or G11 can be targeted by FR900359 (FR) or YM-254890, which are bioavailable, selective inhibitors of the Gq/11/14 subfamily of heterotrimeric G proteins.	('heterotrimeric G proteins', 'Protein', (254, 279))	('YM-254890', 'Chemical', 'MESH:C475455', (169, 178))	('Gq/11/14', 'Protein', (232, 240))	('mutant', 'Var', (94, 100))	('FR900359', 'Gene', '233016', (152, 160))	('YM-254890', 'Var', (169, 178))	('FR', 'Gene', '233016', (152, 154))	('FR900359', 'Gene', (152, 160))	('G11', 'Gene', (129, 132))	('FR', 'Gene', '233016', (162, 164))
143148	33577798	We found that FR inhibited all oncogenic Gq/11 mutants reported in UM.	('FR', 'Gene', '233016', (14, 16))	('inhibited', 'NegReg', (17, 26))	('mutants', 'Var', (47, 54))	('oncogenic Gq/11', 'Gene', (31, 46))
143155	33577798	Mutant constitutively active forms of Gq or G11 (Gq/11) alpha-subunits of heterotrimeric G proteins cause uveal melanoma (UM) and several other diseases and disorders.	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('cause', 'Reg', (100, 105))	('melanoma', 'Disease', (112, 120))	('heterotrimeric G proteins', 'Protein', (74, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('Mutant', 'Var', (0, 6))
143159	33577798	Nevertheless, oncogenic Gq/11 can be inhibited by FR900359 (FR) or YM-254890 (YM), a pair of closely related, bioavailable cyclic depsipeptides that allosterically inhibit GDP release by the Gq/11/14 subfamily.	('YM-254890', 'Var', (67, 76))	('oncogenic', 'CPA', (14, 23))	('FR', 'Gene', '233016', (50, 52))	('FR900359', 'Gene', (50, 58))	('Gq/11', 'Gene', (24, 29))	('inhibited', 'NegReg', (37, 46))	('FR', 'Gene', '233016', (60, 62))	('YM-254890', 'Chemical', 'MESH:C475455', (67, 76))	('GDP', 'Chemical', 'MESH:D006153', (172, 175))	('GDP release', 'MPA', (172, 183))	('inhibit', 'NegReg', (164, 171))	('depsipeptides', 'Disease', 'None', (130, 143))	('FR900359', 'Gene', '233016', (50, 58))	('depsipeptides', 'Disease', (130, 143))
143161	33577798	In response to YM/FR, UM cell lines driven by oncogenic Gq/11 arrest the cell cycle and can undergo apoptosis and/or redifferentiation into melanocytic-like cells.	('arrest', 'Disease', 'MESH:D006323', (62, 68))	('undergo', 'Reg', (92, 99))	('arrest', 'Disease', (62, 68))	('cell cycle', 'biological_process', 'GO:0007049', ('73', '83'))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('FR', 'Gene', '233016', (18, 20))	('redifferentiation', 'CPA', (117, 134))	('Gq/11', 'Gene', (56, 61))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('cell cycle', 'CPA', (73, 83))	('oncogenic', 'Var', (46, 55))	('apoptosis', 'CPA', (100, 109))
143167	33577798	Furthermore, although recent studies have shown that YM/FR can inhibit growth of UM tumors in mouse xenograft models, questions left unanswered are whether YM/FR can target primary and/or metastatic UM tumor cells from patients, whether YM/FR responsiveness is affected by tumor-intrinsic factors, including the type of oncogenic Gq/11 mutation, tumor class or metastatic potential, or whether systemic administration of YM/FR at levels sufficient to target UM tumor xenografts has serious deleterious effects on viability or host physiological systems.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (461, 466))	('affected', 'Reg', (261, 269))	('tumor', 'Disease', 'MESH:D009369', (346, 351))	('UM tumors', 'Disease', (81, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', (273, 278))	('UM tumors', 'Disease', 'MESH:D009369', (81, 90))	('inhibit', 'NegReg', (63, 70))	('tumor', 'Disease', (202, 207))	('mutation', 'Var', (336, 344))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('mouse', 'Species', '10090', (94, 99))	('Gq/11', 'Gene', (330, 335))	('patients', 'Species', '9606', (219, 227))	('tumor', 'Phenotype', 'HP:0002664', (346, 351))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', (461, 466))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (461, 466))	('FR', 'Gene', '233016', (424, 426))	('tumor', 'Disease', (84, 89))	('FR', 'Gene', '233016', (56, 58))	('FR', 'Gene', '233016', (240, 242))	('FR', 'Gene', '233016', (159, 161))	('tumor', 'Disease', (346, 351))
143170	33577798	We found that each mutant G protein induced reporter expression and was inhibited by FR with similar potency (IC50 1.9-3.8 nM) and efficacy (Fig.	('FR', 'Gene', '233016', (85, 87))	('G protein', 'Protein', (26, 35))	('induced', 'PosReg', (36, 43))	('mutant', 'Var', (19, 25))	('reporter expression', 'MPA', (44, 63))	('inhibited', 'NegReg', (72, 81))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
143171	33577798	1B) driven by three different oncogenic Gq/11 mutants responded to FR in quantitatively or qualitatively different ways.	('Gq/11', 'Gene', (40, 45))	('mutants', 'Var', (46, 53))	('FR', 'Gene', '233016', (67, 69))	('responded', 'Reg', (54, 63))
143184	33577798	We defined this cluster as genes with log2 fold change in MP41 cells < -2.5 in response to FR, which identified 365 genes that were more significantly downregulated in MP41 cells (mean p = 0.04) than MP46 cells (mean p = 0.17).	('downregulated', 'NegReg', (151, 164))	('FR', 'Gene', '233016', (91, 93))	('MP41', 'Var', (168, 172))
143185	33577798	Many genes in this cluster are targets of epigenetic regulation by polycomb repressive complex 2 (PRC2), based on gene set analysis (H3K27trimethylation, EZH2; Fig.	('EZH2', 'Gene', (154, 158))	('EZH2', 'Gene', '2146', (154, 158))	('regulation', 'biological_process', 'GO:0065007', ('53', '63'))	('H3K27trimethylation', 'Var', (133, 152))	('PRC2', 'Gene', (98, 102))
143187	33577798	Consistent with these distinctions, FR induced pigmentation, a hallmark of melanocytic differentiation, of MP41 but not MP46 cells (Fig.	('pigmentation', 'Disease', (47, 59))	('FR', 'Gene', '233016', (36, 38))	('MP41', 'Var', (107, 111))	('pigmentation', 'biological_process', 'GO:0043473', ('47', '59'))	('pigmentation', 'Disease', 'MESH:D010859', (47, 59))
143202	33577798	Together, these results demonstrated that, regardless of tumor class, primary and metastatic UM tumor samples driven by mutant Gq/11 responded ex vivo to FR.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Gq/11', 'Gene', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (96, 101))	('FR', 'Gene', '233016', (154, 156))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (57, 62))	('mutant', 'Var', (120, 126))	('responded', 'Reg', (133, 142))
143205	33577798	Dissociated UM tumor and stromal cells were treated 7 days with FR at a concentration (100 nM) that strongly inhibited all oncogenic Gq/11 mutants (Fig.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('FR', 'Gene', '233016', (64, 66))	('inhibited', 'NegReg', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('mutants', 'Var', (139, 146))	('Gq/11', 'Gene', (133, 138))
143218	33577798	In sum, inhibition of oncogenic Gq/11 by FR upregulated Rb expression and downregulated E2F expression, thereby contributing to inhibition of UM cell cycle progression (Fig.	('cell cycle', 'biological_process', 'GO:0007049', ('145', '155'))	('inhibition', 'NegReg', (128, 138))	('UM cell cycle progression', 'CPA', (142, 167))	('upregulated', 'PosReg', (44, 55))	('inhibition', 'Var', (8, 18))	('FR', 'Gene', '233016', (41, 43))	('expression', 'MPA', (59, 69))	('E2F expression', 'MPA', (88, 102))	('downregulated', 'NegReg', (74, 87))
143239	33577798	Next, we determined whether FR delivered systemically at physiologically tolerated doses could inhibit growth of xenografted UM tumors driven specifically by oncogenic Gq/11.	('Gq/11', 'Gene', (168, 173))	('UM tumors', 'Disease', (125, 134))	('FR', 'Gene', '233016', (28, 30))	('oncogenic', 'Var', (158, 167))	('inhibit', 'NegReg', (95, 102))	('UM tumors', 'Disease', 'MESH:D009369', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('growth', 'MPA', (103, 109))
143253	33577798	At concentration of FR (1 muM) that maximally suppressed reporter activity driven by oncogenic Gq or G11 (Fig.	('reporter activity', 'MPA', (57, 74))	('FR', 'Gene', '233016', (20, 22))	('G11', 'Var', (101, 104))	('suppressed', 'NegReg', (46, 56))
143256	33577798	Thus, modulation rather than complete suppression of oncogenic G protein signaling in MP41 tumor xenografts was sufficient for FR to have therapeutic effect.	('modulation', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('signaling', 'biological_process', 'GO:0023052', ('73', '82'))	('FR', 'Gene', '233016', (127, 129))	('oncogenic G protein signaling', 'MPA', (53, 82))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('tumor', 'Disease', (91, 96))
143258	33577798	In this experiment, mice were implanted with MP41 cells and allowed to form tumors.	('MP41', 'Var', (45, 49))	('mice', 'Species', '10090', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
143265	33577798	Here we have provided several new lines of evidence that support the therapeutic potential of Gq/11 inhibitors such as FR for .	('inhibitors', 'Var', (100, 110))	('FR', 'Gene', '233016', (119, 121))	('Gq/11', 'Gene', (94, 99))
143267	33577798	We found that all constitutively active mutant forms of Gq/11 found in UM, which collectively drive tumorigenesis in >90% of patients, are sensitive to FR.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('sensitive', 'Reg', (139, 148))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('Gq/11', 'Gene', (56, 61))	('mutant', 'Var', (40, 46))	('FR', 'Gene', '233016', (152, 154))	('patients', 'Species', '9606', (125, 133))
143271	33577798	The vulnerability of UM tumors to FR may occur because the signaling networks downstream of oncogenic Gq/11 must be maintained above a high threshold.	('Gq/11', 'Gene', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('UM tumors', 'Disease', 'MESH:D009369', (21, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('FR', 'Gene', '233016', (34, 36))	('UM tumors', 'Disease', (21, 30))	('oncogenic', 'Var', (92, 101))
143283	33577798	Constitutively active mutant forms of Gq/11 occur in ~5% of all cancers, including melanocytic neoplasms of the central nervous system, mucosal melanoma, choroidal hemangiomas, and hepatic small vessel neoplasms, as well as in Sturge-Weber syndrome, certain forms of hypercalcemia and hypocalcemia, and autosomal dominant hypoparathyroidism.	('occur', 'Reg', (44, 49))	('Gq/11', 'Gene', (38, 43))	('choroidal hemangiomas', 'Phenotype', 'HP:0007872', (154, 175))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('hypercalcemia', 'Disease', 'MESH:D006934', (267, 280))	('mucosal melanoma', 'Disease', 'MESH:D008545', (136, 152))	('hypocalcemia', 'Disease', 'MESH:D006996', (285, 297))	('autosomal dominant hypoparathyroidism', 'Disease', (303, 340))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('neoplasms', 'Phenotype', 'HP:0002664', (202, 211))	('hypercalcemia', 'Disease', (267, 280))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('mucosal melanoma', 'Disease', (136, 152))	('autosomal dominant hypoparathyroidism', 'Disease', 'MESH:C562783', (303, 340))	('hypoparathyroidism', 'Phenotype', 'HP:0000829', (322, 340))	('mutant', 'Var', (22, 28))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (227, 248))	('hemangiomas', 'Phenotype', 'HP:0001028', (164, 175))	('neoplasms of the central nervous system', 'Phenotype', 'HP:0100006', (95, 134))	('Sturge-Weber syndrome', 'Disease', (227, 248))	('choroidal hemangiomas', 'Disease', (154, 175))	('vessel neoplasms', 'Phenotype', 'HP:0100742', (195, 211))	('hypocalcemia', 'Disease', (285, 297))	('neoplasms', 'Phenotype', 'HP:0002664', (95, 104))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (83, 104))	('hypocalcemia', 'Phenotype', 'HP:0002901', (285, 297))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('hypercalcemia', 'Phenotype', 'HP:0003072', (267, 280))	('hepatic small vessel neoplasms', 'Disease', 'MESH:D056486', (181, 211))	('choroidal hemangiomas', 'Disease', 'MESH:D006391', (154, 175))	('melanocytic neoplasms of the central nervous system', 'Disease', 'MESH:D016543', (83, 134))	('hepatic small vessel neoplasms', 'Disease', (181, 211))	('Weber syndrome', 'Phenotype', 'HP:0002277', (234, 248))
143315	33577798	Membranes were washed with TBST at least three times and incubated with IRDye 680-coupled goat anti-rabbit (LI-COR, catalog# 926-68,071, lot# C90618-09) and IRDye 800 goat anti-mouse (LI-COR, catalog# 926-32,210, lot# C91210-09 antibodies (LI-COR Biosciences).	('COR', 'Gene', '108031', (243, 246))	('COR', 'Gene', (111, 114))	('COR', 'Gene', (187, 190))	('COR', 'Gene', (243, 246))	('TBST', 'Chemical', '-', (27, 31))	('COR', 'Gene', '108031', (187, 190))	('mouse', 'Species', '10090', (177, 182))	('COR', 'Gene', '108031', (111, 114))	('lot# C91210-09', 'Var', (213, 227))
143329	33426053	The expression of RHPN1-AS1, miR-3133, (JAK2), and signal transducer and activator of transcription 3 (STAT3) was detected by qRT-PCR.	('STAT3', 'Gene', (103, 108))	('transcription', 'biological_process', 'GO:0006351', ('86', '99'))	('miR-3133', 'Var', (29, 37))	('RHPN1-AS1', 'Gene', (18, 27))	('STAT3', 'Gene', '6774', (103, 108))	('signal transducer and activator of transcription 3', 'Gene', '6774', (51, 101))	('JAK', 'molecular_function', 'GO:0004713', ('40', '43'))
143331	33426053	Double fluorescein and RNA immunoprecipitation assays were performed to detect the interaction between RHPN1-AS1 and miR-3133 or miR-3133 and JAK2.	('miR-3133', 'Var', (117, 125))	('fluorescein', 'Chemical', 'MESH:D019793', (7, 18))	('JAK', 'molecular_function', 'GO:0004713', ('142', '145'))	('interaction', 'Interaction', (83, 94))	('RHPN1-AS1', 'Gene', (103, 112))	('miR-3133', 'Var', (129, 137))	('RNA', 'cellular_component', 'GO:0005562', ('23', '26'))
143339	33426053	Herein, our results demonstrated an increased expression of RHPN1-AS1 in Y79 and WERI-Rb1, whereas silencing RHPN1-AS1 promoted Y79 and WERI-Rb1 apoptosis.	('Rb1', 'Gene', (141, 144))	('RHPN1-AS1', 'Gene', (109, 118))	('RHPN1-AS1', 'Gene', (60, 69))	('promoted', 'PosReg', (119, 127))	('Rb1', 'Gene', '5925', (86, 89))	('Rb1', 'Gene', '5925', (141, 144))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('increased', 'PosReg', (36, 45))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('silencing', 'Var', (99, 108))	('expression', 'MPA', (46, 56))	('Rb1', 'Gene', (86, 89))	('apoptosis', 'CPA', (145, 154))
143352	33426053	To further investigate the role of JAK2 on RB, Y79 and WERI-Rb1 cells were then transfected with siJAK2 or siNC and we found that there was a decreased expression of JAK2 in the siJAK2 group when compared with the siNC group (Figure 6(b)).	('siJAK2', 'Chemical', '-', (178, 184))	('RB', 'Phenotype', 'HP:0009919', (43, 45))	('JAK2', 'Gene', (166, 170))	('siJAK2', 'Var', (178, 184))	('siJAK2', 'Chemical', '-', (97, 103))	('decreased', 'NegReg', (142, 151))	('JAK', 'molecular_function', 'GO:0004713', ('166', '169'))	('expression', 'MPA', (152, 162))	('JAK', 'molecular_function', 'GO:0004713', ('35', '38'))
143353	33426053	Early studies have reported that RHPN1-AS1 is highly expressed in uveal melanoma cancer tissues and cell lines, and RHPN1-AS1, an oncogene, promotes the progression of uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('promotes', 'PosReg', (140, 148))	('melanoma cancer', 'Disease', 'MESH:D009369', (72, 87))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('progression', 'CPA', (153, 164))	('melanoma cancer', 'Disease', (72, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('RHPN1-AS1', 'Var', (116, 125))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('uveal melanoma', 'Disease', (168, 182))
143376	33317028	80-90% of uveal melanoma harbor mutations in the genes coding for G-protein-coupled receptor proteins GNAQ and GNA11.	('uveal melanoma', 'Phenotype', 'HP:0007716', (10, 24))	('GNAQ', 'Gene', (102, 106))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('mutations', 'Var', (32, 41))	('uveal melanoma harbor', 'Disease', (10, 31))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('GNAQ', 'Gene', '2776', (102, 106))	('GNA11', 'Gene', '2767', (111, 116))	('GNA11', 'Gene', (111, 116))	('uveal melanoma harbor', 'Disease', 'MESH:C536494', (10, 31))
143377	33317028	A small subset of cases harbor mutations in PLCB4 and CYSLTR2 genes.	('mutations', 'Var', (31, 40))	('PLCB4', 'Gene', (44, 49))	('CYSLTR2', 'Gene', '57105', (54, 61))	('CYSLTR2', 'Gene', (54, 61))	('PLCB4', 'Gene', '5332', (44, 49))
143378	33317028	Subsequent chromosomal and genetic alterations broadly divide uveal melanoma into three metastatic-risk groups: (1) High-risk: Characterized by loss of one copy of chromosome 3 (Monosomy 3), gain of chromosome 8q and BRCA Associated Protein-1 (BAP-1) gene mutation leading to a loss of BAP-1 expression; (2) Medium risk: Involving disomy 3, gain of chromosome 6p and SF3B1 or SRSF2 mutations; (3) Low-risk: Involving disomy 3, gain of chromosome 6p and EIF1AX mutation.	('mutations', 'Var', (382, 391))	('EIF1AX', 'Gene', '1964', (453, 459))	('BRCA Associated Protein-1', 'Gene', (217, 242))	('SRSF2', 'Gene', '6427', (376, 381))	('SF3B1', 'Gene', (367, 372))	('gain', 'PosReg', (191, 195))	('SRSF2', 'Gene', (376, 381))	('chromosome', 'cellular_component', 'GO:0005694', ('349', '359'))	('chromosome', 'cellular_component', 'GO:0005694', ('435', '445'))	('mutation', 'Var', (256, 264))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('gain', 'PosReg', (341, 345))	('expression', 'MPA', (292, 302))	('SF3B1', 'Gene', '23451', (367, 372))	('BAP-1', 'Gene', '8314', (286, 291))	('chromosome', 'cellular_component', 'GO:0005694', ('164', '174'))	('chromosome', 'cellular_component', 'GO:0005694', ('199', '209'))	('uveal melanoma', 'Disease', 'MESH:C536494', (62, 76))	('BAP-1', 'Gene', (286, 291))	('loss', 'NegReg', (278, 282))	('uveal melanoma', 'Disease', (62, 76))	('BRCA Associated Protein-1', 'Gene', '8314', (217, 242))	('BAP-1', 'Gene', '8314', (244, 249))	('BAP-1', 'Gene', (244, 249))	('EIF1AX', 'Gene', (453, 459))	('uveal melanoma', 'Phenotype', 'HP:0007716', (62, 76))
143418	33317028	Recent studies have highlighted the association of loss of BAP-1 with upregulation of immunosuppressive genes in primary and MUM.	('loss', 'Var', (51, 55))	('upregulation', 'PosReg', (70, 82))	('BAP-1', 'Gene', '8314', (59, 64))	('BAP-1', 'Gene', (59, 64))	('immunosuppressive genes', 'Gene', (86, 109))
143424	33317028	Blockade of TIGIT reverses NK cell exhaustion and promotes anti-tumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('NK cell exhaustion', 'CPA', (27, 45))	('Blockade', 'Var', (0, 8))	('TIGIT', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('promotes', 'PosReg', (50, 58))
143463	33317028	Metastasizing cells typically originate from high-risk tumors (with Monosomy 3, BAP-1 loss), that are associated with tumor infiltrating immune cells.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('loss', 'NegReg', (86, 90))	('Metastasizing', 'Disease', 'MESH:D009362', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('BAP-1', 'Gene', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', (55, 60))	('Metastasizing', 'Disease', (0, 13))	('tumor', 'Disease', (118, 123))	('tumors', 'Disease', (55, 61))	('Monosomy 3', 'Var', (68, 78))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('BAP-1', 'Gene', '8314', (80, 85))
143498	33317028	Interestingly, in primary uveal melanoma patients, the presence of homozygosity for HLA-C1 (ligand for iKIR KIR2DL2-3) and HLA-C2 (ligand for iKIR KIR2DL1) was associated with a worse melanoma related mortality as compared to patients who were heterozygous for HLA-C1/C2.	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('ligand', 'molecular_function', 'GO:0005488', ('131', '137'))	('melanoma', 'Disease', (184, 192))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('KIR', 'Gene', '3811', (143, 146))	('DL2', 'molecular_function', 'GO:0033904', ('112', '115'))	('KIR', 'Gene', (104, 107))	('mortality', 'Disease', (201, 210))	('presence', 'Var', (55, 63))	('KIR2DL2-3', 'Gene', '3803;3804', (108, 117))	('KIR2DL1', 'Gene', '3802', (147, 154))	('HLA-C1', 'Gene', (84, 90))	('ligand', 'molecular_function', 'GO:0005488', ('92', '98'))	('KIR', 'Gene', (143, 146))	('KIR2DL2-3', 'Gene', (108, 117))	('uveal melanoma', 'Disease', (26, 40))	('uveal melanoma', 'Disease', 'MESH:C536494', (26, 40))	('patients', 'Species', '9606', (226, 234))	('KIR', 'Gene', '3811', (108, 111))	('HLA-C2', 'Var', (123, 129))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('patients', 'Species', '9606', (41, 49))	('mortality', 'Disease', 'MESH:D003643', (201, 210))	('uveal melanoma', 'Phenotype', 'HP:0007716', (26, 40))	('KIR2DL1', 'Gene', (147, 154))	('KIR', 'Gene', (108, 111))	('KIR', 'Gene', '3811', (147, 150))	('KIR', 'Gene', (147, 150))	('KIR', 'Gene', '3811', (104, 107))
143499	33317028	A possible mechanism for NK cell protection from metastasis was proposed by the authors, suggesting that in the case of heterozygous HLA-C expression (C1/C2), loss of one HLA-C allele (C1 or C2) by the tumor will potentially lead to loss of cell surface expression of a ligand that will no longer be recognized by its respective NK cell iKIR.	('tumor', 'Disease', (202, 207))	('cell surface', 'cellular_component', 'GO:0009986', ('241', '253'))	('loss', 'Var', (159, 163))	('ligand', 'molecular_function', 'GO:0005488', ('270', '276'))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('cell surface expression of a', 'MPA', (241, 269))	('loss', 'NegReg', (233, 237))	('KIR', 'Gene', (338, 341))	('KIR', 'Gene', '3811', (338, 341))
143501	33317028	The net cytotoxic effect of such a mismatch between NK cell inhibitory KIRs and their ligands has been clinically utilized in high risk Acute Myeloid Leukemia patients utilizing haploidentical KIR ligand-mismatched NK cells.	('Myeloid Leukemia', 'Disease', 'MESH:D007951', (142, 158))	('KIR', 'Gene', (193, 196))	('KIR', 'Gene', (71, 74))	('KIR', 'Gene', '3811', (193, 196))	('mismatch', 'Var', (35, 43))	('Myeloid Leukemia', 'Disease', (142, 158))	('ligand', 'molecular_function', 'GO:0005488', ('197', '203'))	('KIR', 'Gene', '3811', (71, 74))	('Myeloid Leukemia', 'Phenotype', 'HP:0012324', (142, 158))	('Leukemia', 'Phenotype', 'HP:0001909', (150, 158))	('Acute Myeloid Leukemia', 'Phenotype', 'HP:0004808', (136, 158))	('patients', 'Species', '9606', (159, 167))
143503	33317028	Specific to uveal melanoma, aberrations in chromosome 6 are a frequent occurrence in primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('aberrations', 'Var', (28, 39))	('uveal melanoma', 'Phenotype', 'HP:0007716', (12, 26))	('uveal melanoma', 'Disease', 'MESH:C536494', (12, 26))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('uveal melanoma', 'Disease', (12, 26))	('tumors', 'Disease', (93, 99))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))
143504	33317028	Several studies have shown improved survival in uveal melanoma patients with gain of 6p as compared to monosomy 3.	('uveal melanoma', 'Disease', (48, 62))	('improved', 'PosReg', (27, 35))	('survival', 'MPA', (36, 44))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('gain', 'Var', (77, 81))	('patients', 'Species', '9606', (63, 71))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (48, 62))
143505	33317028	Gain of 6p and monosomy 3 are typically mutually exclusive occurrences in uveal melanoma.	('Gain of 6p', 'Var', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('monosomy 3', 'Var', (15, 25))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('uveal melanoma', 'Disease', (74, 88))
143506	33317028	Evidence suggests that 6p gain does not lead to over expression of HLA, and that the protective effect from metastasis seen in patients with 6p gain could be instead due to the lack of presence of monosomy 3 (which is associated with intra-tumoral inflammatory infiltrate, increased HLA expression and poor survival).	('6p gain', 'Var', (141, 148))	('patients', 'Species', '9606', (127, 135))	('increased', 'PosReg', (273, 282))	('intra-tumoral', 'Disease', 'MESH:D009369', (234, 247))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('monosomy 3', 'Var', (197, 207))	('protective effect', 'CPA', (85, 102))	('intra-tumoral', 'Disease', (234, 247))
143540	33317028	Abrogation of NK cell activity led to an increase in number of liver metastasis as well as an increase in the proportion of larger metastatic deposits.	('liver metastasis', 'CPA', (63, 79))	('Abrogation', 'Var', (0, 10))	('increase', 'PosReg', (94, 102))	('deposits', 'Disease', (142, 150))	('increase', 'PosReg', (41, 49))	('deposits', 'Disease', 'MESH:D000079822', (142, 150))
143586	33317028	In peripheral blood, a vast majority (>90%) of NK cells are characterized as CD3- CD16+ CD56Dim with high cytotoxicity potential.	('cytotoxicity', 'Disease', 'MESH:D064420', (106, 118))	('cytotoxicity', 'Disease', (106, 118))	('CD3- CD16+ CD56Dim', 'Var', (77, 95))
143587	33317028	CD56Bright NK cells in peripheral blood have poor cytotoxic potential but are efficient at cytokine production such as IFN-gamma.	('IFN-gamma', 'Gene', '3458', (119, 128))	('IFN-gamma', 'Gene', (119, 128))	('cytokine production', 'biological_process', 'GO:0001816', ('91', '110'))	('cytokine production', 'MPA', (91, 110))	('CD56Bright', 'Var', (0, 10))
143593	33317028	They lack markers of tissue residency and likely perform functions like their circulating counterparts; (2) CD56Bright CD49a-, non-circulating, liver resident (lr) NK cells.	('CD56Bright', 'Var', (108, 118))	('lr', 'Chemical', '-', (160, 162))	('CD49a', 'Gene', '3672', (119, 124))	('CD49a', 'Gene', (119, 124))
143625	33317028	Both liver cNK and peripheral blood CD16+CD56Dim NK cells had similar expression of activating NK cell receptors and similar quantities of intracellular perforin and granzyme B.	('liver cNK', 'Disease', (5, 14))	('granzyme B', 'Gene', '3002', (166, 176))	('CD16+CD56Dim', 'Var', (36, 48))	('liver cNK', 'Disease', 'MESH:D017093', (5, 14))	('granzyme B', 'Gene', (166, 176))	('activating', 'MPA', (84, 94))	('NK cell receptors', 'Protein', (95, 112))	('intracellular', 'cellular_component', 'GO:0005622', ('139', '152'))
143628	33317028	The factor of low expression iKIR expression by lr-NK cells is especially highlighted in the case of CD56Bright lr-NK cells that seem to completely lack KIR expression.	('lr', 'Chemical', '-', (112, 114))	('KIR', 'Gene', (30, 33))	('KIR', 'Gene', (153, 156))	('CD56Bright', 'Var', (101, 111))	('KIR', 'Gene', '3811', (30, 33))	('KIR', 'Gene', '3811', (153, 156))	('lack', 'NegReg', (148, 152))	('lr', 'Chemical', '-', (48, 50))
143658	33330070	Deregulation of cell death programs is a hallmark of cancer development, progression, and resistance to therapies.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('Deregulation', 'Var', (0, 12))	('cell death', 'biological_process', 'GO:0008219', ('16', '26'))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cell death programs', 'CPA', (16, 35))
143718	33330070	Figure 8  shows the results of Kaplan-Meier survival analyses in patients with uveal melanomas with low and high beclin-1 expression.	('uveal melanomas', 'Disease', 'MESH:C536494', (79, 94))	('expression', 'MPA', (122, 132))	('uveal melanomas', 'Disease', (79, 94))	('uveal melanomas', 'Phenotype', 'HP:0007716', (79, 94))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('patients', 'Species', '9606', (65, 73))	('high', 'Var', (108, 112))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('beclin-1', 'Gene', (113, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('beclin-1', 'Gene', '8678', (113, 121))
143720	33330070	Figure 9  shows the results of Kaplan-Meier survival analyses in patients with uveal melanomas with low and high p62 expression.	('uveal melanomas', 'Disease', 'MESH:C536494', (79, 94))	('p62', 'Gene', (113, 116))	('uveal melanomas', 'Disease', (79, 94))	('uveal melanomas', 'Phenotype', 'HP:0007716', (79, 94))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('patients', 'Species', '9606', (65, 73))	('high', 'Var', (108, 112))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('p62', 'Gene', '23636', (113, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))
143722	33330070	Figure 10  shows the results of Kaplan-Meier survival analyses in patients with uveal melanomas with low and high ATG7 expression.	('low', 'Var', (101, 104))	('uveal melanomas', 'Disease', 'MESH:C536494', (80, 95))	('high', 'Var', (109, 113))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('uveal melanoma', 'Phenotype', 'HP:0007716', (80, 94))	('ATG7', 'Gene', (114, 118))	('patients', 'Species', '9606', (66, 74))	('uveal melanomas', 'Disease', (80, 95))	('uveal melanomas', 'Phenotype', 'HP:0007716', (80, 95))	('ATG7', 'Gene', '10533', (114, 118))
143730	33330070	As well, tumor infiltrating lymphocytes and/or histiocytes and cytogenetic factors including monosomy 3, chromosome 8q-gain or 8p-loss, chromosome 1p-loss, chromosome 6q-loss, and high expression of insulin-like growth factor-1 receptor (IGF-1R), also contribute to the definition of the class risk of each case of UM.	('chromosome', 'cellular_component', 'GO:0005694', ('156', '166'))	('chromosome 8q-gain', 'Var', (105, 123))	('chromosome 1p-loss', 'Var', (136, 154))	('IGF-1R', 'Gene', (238, 244))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('chromosome', 'cellular_component', 'GO:0005694', ('105', '115'))	('insulin-like growth factor-1 receptor', 'Gene', (199, 236))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('chromosome', 'cellular_component', 'GO:0005694', ('136', '146'))	('insulin-like growth factor-1 receptor', 'Gene', '3480', (199, 236))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('199', '225'))	('monosomy 3', 'Var', (93, 103))	('chromosome 6q-loss', 'Var', (156, 174))	('IGF-1R', 'Gene', '3480', (238, 244))
143731	33330070	In particular, the reduction/loss of the nuclear immunostaining for the BRCA1 associated protein-1 (BAP-1), reflecting the presence of inactivating mutations of the corresponding gene, represents a poor prognostic factor for of UM.	('BAP-1', 'Gene', (100, 105))	('BRCA1 associated protein-1', 'Gene', '8314', (72, 98))	('inactivating mutations', 'Var', (135, 157))	('BRCA1 associated protein-1', 'Gene', (72, 98))	('reduction/loss', 'NegReg', (19, 33))	('BAP-1', 'Gene', '8314', (100, 105))	('of UM', 'Disease', (225, 230))	('nuclear immunostaining', 'MPA', (41, 63))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
143748	33330070	Moreover, controversies remain regarding whether to inhibit or enhance autophagy in cancer, considering that, besides activation of endocytosis, the deregulation of autophagy-related genes has been associated also with cell death pathways and DNA repair responses (non-autophagy functions).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('autophagy', 'biological_process', 'GO:0016236', ('269', '278'))	('cell death pathways', 'CPA', (219, 238))	('cell death', 'biological_process', 'GO:0008219', ('219', '229'))	('autophagy', 'biological_process', 'GO:0006914', ('71', '80'))	('cancer', 'Disease', (84, 90))	('autophagy', 'biological_process', 'GO:0006914', ('269', '278'))	('activation of endocytosis', 'biological_process', 'GO:0045807', ('118', '143'))	('autophagy', 'biological_process', 'GO:0016236', ('165', '174'))	('DNA repair responses', 'CPA', (243, 263))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('deregulation', 'Var', (149, 161))	('associated', 'Reg', (198, 208))	('DNA repair', 'biological_process', 'GO:0006281', ('243', '253'))	('autophagy-related genes', 'Gene', (165, 188))	('DNA', 'cellular_component', 'GO:0005574', ('243', '246'))	('autophagy', 'biological_process', 'GO:0006914', ('165', '174'))	('autophagy', 'biological_process', 'GO:0016236', ('71', '80'))
143749	33330070	Nevertheless, our finding of a strict correlation between Beclin-1 expression and the clinical outcome of UM support the idea that alteration in autophagy may be a particularly attracting targetable way to treat UM progression, as it has been proposed for skin melanoma.	('skin melanoma', 'Disease', (256, 269))	('autophagy', 'biological_process', 'GO:0006914', ('145', '154'))	('autophagy', 'biological_process', 'GO:0016236', ('145', '154'))	('Beclin-1', 'Gene', (58, 66))	('autophagy', 'CPA', (145, 154))	('Beclin-1', 'Gene', '8678', (58, 66))	('alteration', 'Var', (131, 141))	('melanoma', 'Phenotype', 'HP:0002861', (261, 269))	('skin melanoma', 'Disease', 'MESH:D008545', (256, 269))
143751	33330070	In addition, the finding of an altered expression of Beclin-1 in our study population sounds particularly attractive, if we consider that recent evidence suggests that alterations in autophagy may be a major mechanism of tumor escape from immune surveillance also by interfering with signaling pathways in tumor and immune cells and autophagy-associated cell death has emerged as a key immunogenic mechanism able to potentiate tumor response to therapy in several human malignancies and in skin melanoma.	('skin melanoma', 'Disease', (490, 503))	('Beclin-1', 'Gene', '8678', (53, 61))	('signaling', 'biological_process', 'GO:0023052', ('284', '293'))	('tumor', 'Disease', 'MESH:D009369', (427, 432))	('malignancies', 'Disease', 'MESH:D009369', (470, 482))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('potentiate', 'PosReg', (416, 426))	('cell death', 'biological_process', 'GO:0008219', ('354', '364'))	('tumor', 'Disease', (306, 311))	('malignancies', 'Disease', (470, 482))	('population sounds', 'Phenotype', 'HP:0008765', (75, 92))	('Beclin-1', 'Gene', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('autophagy', 'biological_process', 'GO:0006914', ('333', '342'))	('tumor', 'Phenotype', 'HP:0002664', (427, 432))	('alterations', 'Var', (168, 179))	('interfering', 'NegReg', (267, 278))	('signaling pathways', 'Pathway', (284, 302))	('autophagy', 'biological_process', 'GO:0016236', ('183', '192'))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('tumor', 'Disease', (221, 226))	('melanoma', 'Phenotype', 'HP:0002861', (495, 503))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('skin melanoma', 'Disease', 'MESH:D008545', (490, 503))	('human', 'Species', '9606', (464, 469))	('autophagy', 'biological_process', 'GO:0006914', ('183', '192'))	('tumor', 'Disease', (427, 432))	('autophagy', 'biological_process', 'GO:0016236', ('333', '342'))
143877	32333081	Various mechanisms of local immune tolerance in the liver have been proposed, including the elevated expression of anti-inflammatory molecules such as IL-10 induced by pathogen-derived molecules, direct cell-cell contact between liver sinusoidal endothelial cells (LSECs) and liver DCs in the microenvironment, expansion of regulatory T cells and trapping and deletion of activated CD8 + cells.	('CD8', 'Gene', '925', (382, 385))	('regulatory T cells', 'CPA', (324, 342))	('elevated', 'PosReg', (92, 100))	('IL-10', 'Gene', '3586', (151, 156))	('deletion', 'Var', (360, 368))	('CD8', 'Gene', (382, 385))	('expression', 'MPA', (101, 111))	('IL-10', 'molecular_function', 'GO:0005141', ('151', '156'))	('IL-10', 'Gene', (151, 156))
143880	32333081	Of all the ablative modalities available, cryoablation is believed to have the capability of generating the strongest antitumor immune responses.	('cryoablation', 'Var', (42, 54))	('rat', 'Species', '10116', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
143886	32333081	Hepatic arterial infusion of bevacizumab can achieve significantly more reduction in tumor volume and decreasement in cell proliferation than systemic administration of bevacizumab for colorectal liver metastasis in rat model.Theoretically, arterial infusion of anti-PD-1 antibody for hepatic metastases has the potential to achieve higher drug concentration for tumoral infiltrative lymphocytes (TILs) than the intravenous route, which may be translated into improved anti-tumor immune response.	('tumor', 'Disease', (85, 90))	('colorectal liver metastasis', 'Disease', (185, 212))	('antibody', 'molecular_function', 'GO:0003823', ('272', '280'))	('higher', 'PosReg', (333, 339))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cell proliferation', 'biological_process', 'GO:0008283', ('118', '136'))	('antibody', 'cellular_component', 'GO:0042571', ('272', '280'))	('hepatic metastases', 'Disease', (285, 303))	('tumor', 'Phenotype', 'HP:0002664', (474, 479))	('immune response', 'biological_process', 'GO:0006955', ('480', '495'))	('improved', 'PosReg', (460, 468))	('tumoral', 'Disease', (363, 370))	('tumoral', 'Disease', 'MESH:D009369', (363, 370))	('bevacizumab', 'Chemical', 'MESH:D000068258', (29, 40))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('drug concentration', 'MPA', (340, 358))	('bevacizumab', 'Chemical', 'MESH:D000068258', (169, 180))	('antibody', 'cellular_component', 'GO:0019815', ('272', '280'))	('anti-PD-1', 'Var', (262, 271))	('rat', 'Species', '10116', (377, 380))	('tumor', 'Disease', (363, 368))	('tumor', 'Disease', (474, 479))	('rat', 'Species', '10116', (352, 355))	('antibody', 'cellular_component', 'GO:0019814', ('272', '280'))	('tumor', 'Disease', 'MESH:D009369', (363, 368))	('rat', 'Species', '10116', (130, 133))	('tumor', 'Disease', 'MESH:D009369', (474, 479))	('colorectal liver metastasis', 'Disease', 'MESH:D015179', (185, 212))	('rat', 'Species', '10116', (216, 219))	('hepatic metastases', 'Disease', 'MESH:D009362', (285, 303))	('rat', 'Species', '10116', (159, 162))
143925	32333081	Technical success of cryoablation was achieved for all targeted intrahepatic lesions (51/51; 100.0%), and technical success of arterial catheter placement was achieved in 15/15 (100.0%) patients.	('patients', 'Species', '9606', (186, 194))	('intrahepatic lesions', 'Disease', 'MESH:D002780', (64, 84))	('cryoablation', 'Var', (21, 33))	('intrahepatic lesions', 'Disease', (64, 84))
143927	32333081	Regarding cryoablation, no early major complications requiring transfusion or embolization occurred; late major complications including abscess, infarction, tumor seeding and biloma were not observed during follow-up.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('abscess', 'Phenotype', 'HP:0025615', (136, 143))	('infarction', 'Disease', 'MESH:D007238', (145, 155))	('biloma', 'Disease', 'None', (175, 181))	('infarction', 'Disease', (145, 155))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('biloma', 'Disease', (175, 181))	('cryoablation', 'Var', (10, 22))
143942	32333081	All patients had microsatellite stable (MSS) tumors.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('patients', 'Species', '9606', (4, 12))	('microsatellite', 'Var', (17, 31))
143944	32333081	Based on the results of 295 cancer-related gene panel, the mutations of melanoma signature genes and PD-1 blockade-associated genes are displayed in Fig.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('mutations', 'Var', (59, 68))	('PD-1', 'Gene', (101, 105))	('cancer', 'Disease', (28, 34))
143945	32333081	One patient contained mutation in JAK2 was non-responder.	('mutation', 'Var', (22, 30))	('JAK2', 'Gene', '3717', (34, 38))	('patient', 'Species', '9606', (4, 11))	('JAK2', 'Gene', (34, 38))	('JAK', 'molecular_function', 'GO:0004713', ('34', '37'))
143946	32333081	No patients had MDM2 amplification, PTEN, BRCA2 or JAK1 mutation.	('MDM2', 'Gene', '4193', (16, 20))	('MDM2', 'Gene', (16, 20))	('BRCA2', 'Gene', '675', (42, 47))	('JAK', 'molecular_function', 'GO:0004713', ('51', '54'))	('PTEN', 'Gene', (36, 40))	('PTEN', 'Gene', '5728', (36, 40))	('patients', 'Species', '9606', (3, 11))	('JAK1', 'Gene', (51, 55))	('JAK1', 'Gene', '3716', (51, 55))	('amplification', 'Var', (21, 34))	('BRCA2', 'Gene', (42, 47))
143972	32333081	Certain genetic mutations in melanoma, including JAK1, JAK2, B2M and PTEN, etc., correlate with negative treatment response of PD-1 blockade therapy, while BRCA2 mutations were reported enriched in melanomas responsive to this treatment.	('B2M', 'Gene', '567', (61, 64))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('melanomas', 'Phenotype', 'HP:0002861', (198, 207))	('JAK2', 'Gene', '3717', (55, 59))	('BRCA2', 'Gene', '675', (156, 161))	('PTEN', 'Gene', '5728', (69, 73))	('JAK', 'molecular_function', 'GO:0004713', ('55', '58'))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('JAK2', 'Gene', (55, 59))	('JAK1', 'Gene', '3716', (49, 53))	('PD-1', 'Gene', (127, 131))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('melanomas', 'Disease', 'MESH:D008545', (198, 207))	('negative', 'NegReg', (96, 104))	('melanomas', 'Disease', (198, 207))	('mutations', 'Var', (162, 171))	('B2M', 'Gene', (61, 64))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('BRCA2', 'Gene', (156, 161))	('treatment response', 'MPA', (105, 123))	('JAK', 'molecular_function', 'GO:0004713', ('49', '52'))	('JAK1', 'Gene', (49, 53))	('PTEN', 'Gene', (69, 73))
143973	32333081	In our series, one patient with JAK2 mutation was non-responder, which is consistent with previous studies.	('patient', 'Species', '9606', (19, 26))	('JAK2', 'Gene', (32, 36))	('mutation', 'Var', (37, 45))	('JAK', 'molecular_function', 'GO:0004713', ('32', '35'))	('JAK2', 'Gene', '3717', (32, 36))
143979	32333081	In KEYNOTE-006, it is reported that grade 3-5 AEs occurred in 17% of patients receiving pembrolizumab, and the most common AEs were diarrhea (1-3%), colitis (1.4-2.5%) and hepatitis (1.1-1.8%).	('hepatitis', 'Phenotype', 'HP:0012115', (172, 181))	('colitis', 'Disease', 'MESH:D003092', (149, 156))	('hepatitis', 'Disease', (172, 181))	('colitis', 'Disease', (149, 156))	('pembrolizumab', 'Var', (88, 101))	('pembrolizumab', 'Chemical', 'MESH:C582435', (88, 101))	('diarrhea', 'Phenotype', 'HP:0002014', (132, 140))	('hepatitis', 'Disease', 'MESH:D056486', (172, 181))	('diarrhea', 'Disease', (132, 140))	('colitis', 'Phenotype', 'HP:0002583', (149, 156))	('patients', 'Species', '9606', (69, 77))	('diarrhea', 'Disease', 'MESH:D003967', (132, 140))
143988	32333081	AEs Adverse events AST Aspartate transaminase ALT Alanine transaminase CATAP Combined cryoablation and transarterial infusion of pembrolizumab treatment strategy CTLA-4 Cytotoxic T-lymphocyte antigen-4 ECOG Eastern cooperative oncology group LSECs Liver sinusoidal endothelial cells PD-1 Programmed cell death protein 1 TILs Tumoral infiltrative lymphocytes TMB Tumor mutation burden This study was conceived, designed, or planned by LS, XZ, and WF.	('mutation', 'Var', (368, 376))	('oncology', 'Phenotype', 'HP:0002664', (227, 235))	('AST', 'Gene', (19, 22))	('Programmed cell death', 'biological_process', 'GO:0012501', ('288', '309'))	('CTLA-4', 'Gene', '1493', (162, 168))	('death', 'Disease', 'MESH:D003643', (304, 309))	('Tumor', 'Phenotype', 'HP:0002664', (325, 330))	('CTLA-4', 'Gene', (162, 168))	('rat', 'Species', '10116', (339, 342))	('rat', 'Species', '10116', (220, 223))	('rat', 'Species', '10116', (155, 158))	('ALT', 'molecular_function', 'GO:0004021', ('46', '49'))	('TMB', 'Chemical', '-', (358, 361))	('CATAP', 'Chemical', '-', (71, 76))	('Tumor', 'Phenotype', 'HP:0002664', (362, 367))	('lymphocyte antigen', 'molecular_function', 'GO:0005557', ('181', '199'))	('AST', 'Gene', '26503', (19, 22))	('death', 'Disease', (304, 309))	('protein', 'cellular_component', 'GO:0003675', ('310', '317'))	('pembrolizumab', 'Chemical', 'MESH:C582435', (129, 142))
143992	31202631	Here we present CHASMplus, a computational method, that is uniquely capable of identifying driver missense mutations, including those specific to a cancer type, as evidenced by significantly superior performance on diverse benchmarks.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('missense mutations', 'Var', (98, 116))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('CHASMplus', 'Disease', (16, 25))	('CHASMplus', 'Disease', 'None', (16, 25))
143993	31202631	Applied to 8,657 tumor samples across 32 cancer types in The Cancer Genome Atlas, CHASMplus identifies over 4,000 unique driver missense mutations in 240 genes, supporting a prominent role for rare driver mutations.	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Cancer', 'Disease', (61, 67))	('tumor', 'Disease', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (41, 47))	('CHASMplus', 'Disease', (82, 91))	('missense mutations', 'Var', (128, 146))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('CHASMplus', 'Disease', 'None', (82, 91))
143996	31202631	Their analysis revealed that most driver mutations occur only in a few patients, presenting a challenge for precision medicine, and several cancer types will benefit from additional sequencing to identify these rare driver mutations.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (71, 79))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
143997	31202631	Cancer is a disease of the genome where certain somatic mutations drive the neoplastic process of cancer, while the majority of mutations are benign passengers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (56, 65))	('neoplastic process', 'CPA', (76, 94))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancer', 'Disease', (98, 104))	('drive', 'PosReg', (66, 71))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
143998	31202631	Missense mutations are the most common protein-coding mutation found in cancer genomes.	('cancer', 'Disease', (72, 78))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('Missense mutations', 'Var', (0, 18))
143999	31202631	However, due to the large number of somatic mutations identified in DNA sequencing of human tumors, it has been logistically impossible to experimentally validate driver mutations at sufficiently large scale.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('human', 'Species', '9606', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mutations', 'Var', (44, 53))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
144000	31202631	The task of identifying putative drivers from cancer sequencing studies has therefore depended on statistical models to identify genes with an excess number of mutations over expectation.	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('mutations', 'Var', (160, 169))
144001	31202631	The rationale is that because driver mutations provide a fitness advantage to cancer cells, they will be observed more often than expected by chance due to their contribution to carcinogenesis and, as such, leave a statistically detectable signal.	('cancer', 'Disease', (78, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (178, 192))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('mutations', 'Var', (37, 46))	('fitness', 'Disease', (57, 64))	('carcinogenesis', 'Disease', (178, 192))	('fitness', 'Disease', 'MESH:D012640', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
144002	31202631	Based on such gene-level analyses, it has been hypothesized that cancer driver mutations exhibit a long tail phenomenon with few common drivers and many rare drivers, suggesting that numerous rare drivers remain to be discovered.	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('long tail', 'Phenotype', 'HP:0002831', (99, 108))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('mutations', 'Var', (79, 88))
144005	31202631	Overall, this highlights the critical importance of new methods that can identify putative driver missense mutations and separate them from passenger mutations even within known cancer genes, which could spur effective experimental validation.	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('missense mutations', 'Var', (98, 116))
144006	31202631	While many computational methods have been developed to predict whether a missense mutation is generally deleterious or pathogenic, there has not previously been a method to score the oncogenic impact of a missense mutation specifically by cancer type.	('missense mutation', 'Var', (206, 223))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('missense mutation', 'Var', (74, 91))	('cancer', 'Disease', (240, 246))
144007	31202631	Although it is well known that missense mutations have different impacts in different cancer types, currently available computational methods either do not take it into consideration or fail at the task of distinguishing the differences.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('missense mutations', 'Var', (31, 49))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('impacts', 'Reg', (65, 72))	('cancer', 'Disease', (86, 92))
144008	31202631	This indicates an unmet need, given the clinical relevance of mutations is increasingly understood to depend both on the particular mutation and cancer type.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('mutations', 'Var', (62, 71))
144009	31202631	In this work, we introduce a machine learning method, CHASMplus, to predict the driver status of missense mutations in a cancer type-specific manner.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('CHASMplus', 'Disease', (54, 63))	('CHASMplus', 'Disease', 'None', (54, 63))	('cancer', 'Disease', (121, 127))	('missense mutations', 'Var', (97, 115))
144011	31202631	We explore the emerging role for rare driver missense mutations in cancer and, when possible, relate predictions to supporting functional evidence.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('missense mutations', 'Var', (45, 63))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
144012	31202631	We provide an interactive resource for exploring driver missense mutations identified from the TCGA (http://karchinlab.github.io/CHASMplus) and a user-friendly tool (http://chasmplus.readthedocs.io/) to predict whether newly observed mutations from further sequencing are likely cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('CHASMplus', 'Disease', (129, 138))	('CHASMplus', 'Disease', 'None', (129, 138))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('mutations', 'Var', (234, 243))
144013	31202631	Lastly, we examine the diversity of driver missense mutations across various types of cancer, which leads to a refined understanding of the likely trajectory of driver missense mutation discovery with further sequencing.	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('missense mutations', 'Var', (43, 61))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (86, 92))
144014	31202631	We have developed a method named CHASMplus that uses machine learning to discriminate somatic missense mutations (referred to hereafter as missense mutations) as either cancer drivers or passengers (Figure 1a, Methods).	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('CHASMplus', 'Disease', (33, 42))	('CHASMplus', 'Disease', 'None', (33, 42))	('missense mutations', 'Var', (94, 112))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
144019	31202631	In contrast, most previous methods provide a single impact score for each missense mutation, regardless of cancer type.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('missense mutation', 'Var', (74, 91))
144022	31202631	First, a cancer type-specific model should accurately predict oncogenic effects of missense mutations in an appropriate cell line.	('missense mutations', 'Var', (83, 101))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
144023	31202631	We therefore compared predictions of breast cancer-specific CHASMplus, CHASM, and CanDrA models in known breast cancer driver genes to a previous large-scale validation of 698 missense mutations in MCF10A (breast epithelium) cells that measured cell viability (Figure 2a, Methods).	('breast cancer', 'Disease', (37, 50))	('CHASM', 'Gene', '219537', (60, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('CHASMplus', 'Disease', 'None', (60, 69))	('MCF10A', 'CellLine', 'CVCL:0598', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('CHASM', 'Gene', (71, 76))	('CHASM', 'Gene', (60, 65))	('MCF10A', 'Gene', (198, 204))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('CHASM', 'Gene', '219537', (71, 76))	('missense mutations', 'Var', (176, 194))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('breast cancer', 'Disease', (105, 118))	('CHASMplus', 'Disease', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
144032	31202631	Lastly, we reasoned that distinguishing cancer type-specificity of driver mutations within the same gene would be an even harder task to accomplish.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('mutations', 'Var', (74, 83))	('cancer', 'Disease', (40, 46))
144033	31202631	It has been previously documented that lung adenocarcinoma (LUAD) missense mutations in EGFR appear predominantly in its kinase domain, while GBM missense mutations appear in its extracellular domain.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('extracellular', 'cellular_component', 'GO:0005576', ('179', '192'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (39, 58))	('missense mutations', 'Var', (66, 84))	('EGFR', 'Gene', '1956', (88, 92))	('lung adenocarcinoma', 'Disease', (39, 58))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (39, 58))	('EGFR', 'Gene', (88, 92))
144034	31202631	We therefore scored TCGA missense mutations in the gene EGFR from LUAD patients and from GBM patients with CHASMplus, CanDrA, and CHASM (Figure 2c).	('CHASM', 'Gene', (107, 112))	('CHASM', 'Gene', '219537', (130, 135))	('CHASMplus', 'Disease', (107, 116))	('patients', 'Species', '9606', (71, 79))	('EGFR', 'Gene', '1956', (56, 60))	('CHASM', 'Gene', '219537', (107, 112))	('missense mutations', 'Var', (25, 43))	('CHASMplus', 'Disease', 'None', (107, 116))	('EGFR', 'Gene', (56, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('CHASM', 'Gene', (130, 135))	('patients', 'Species', '9606', (93, 101))
144035	31202631	The CHASMplus GBM model correctly scores the missense mutations from GBM patients significantly higher than those from LUAD patients (p=0.004, two-sided t-test), and vice versa for the CHASMplus LUAD model (p=0.003, two-sided t-test).	('CHASMplus', 'Disease', (185, 194))	('CHASMplus', 'Disease', (4, 13))	('GBM', 'Disease', (69, 72))	('CHASMplus LUAD', 'Disease', 'None', (185, 199))	('CHASMplus', 'Disease', 'None', (185, 194))	('CHASMplus', 'Disease', 'None', (4, 13))	('CHASMplus LUAD', 'Disease', (185, 199))	('missense mutations', 'Var', (45, 63))	('higher', 'PosReg', (96, 102))	('patients', 'Species', '9606', (73, 81))	('patients', 'Species', '9606', (124, 132))
144036	31202631	In contrast, the CHASM GBM model and the CHASM LUAD model both score the mutations from LUAD patients higher than those from GBM patients (p=1e-5 and 5e-5, respectively, two-sided t-test).	('CHASM', 'Gene', (41, 46))	('score', 'PosReg', (63, 68))	('patients', 'Species', '9606', (129, 137))	('CHASM', 'Gene', '219537', (17, 22))	('higher', 'PosReg', (102, 108))	('CHASM', 'Gene', '219537', (41, 46))	('patients', 'Species', '9606', (93, 101))	('mutations', 'Var', (73, 82))	('CHASM', 'Gene', (17, 22))
144037	31202631	CanDrA does not have a LUAD model, but its GBM model scores mutations from LUAD patients higher than those from GBM patients (p=0.0002, two-sided t-test), which is significant in the wrong direction.	('mutations', 'Var', (60, 69))	('higher', 'PosReg', (89, 95))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (80, 88))
144038	31202631	In summary, several lines of evidence suggest that CHASMplus, relative to other methods, has a substantial advantage in distinguishing between driver and passenger missense mutations, specifically by cancer type.	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('CHASMplus', 'Disease', (51, 60))	('CHASMplus', 'Disease', 'None', (51, 60))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))	('driver', 'Var', (143, 149))
144040	31202631	This approach is useful because some cancer driver mutations do occur in many cancer types.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
144041	31202631	The power to detect these mutations, particularly when they occur at low frequency in many cancer types, is increased when many cancer types are aggregated, known as a pan-cancer analysis.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (91, 97))	('increased', 'PosReg', (108, 117))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (128, 134))
144044	31202631	A range of benchmarks was critical because missense mutations with the most established experimental support for a driver role tend to be in a few well-understood cancer driver genes.	('missense mutations', 'Var', (43, 61))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
144046	31202631	These results suggest that CHASMplus improves on previous methods to predict driver missense mutations in a pan-cancer setting, as well as in a cancer type-specific manner.	('driver missense mutations', 'Var', (77, 102))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('CHASMplus', 'Disease', (27, 36))	('CHASMplus', 'Disease', 'None', (27, 36))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
144049	31202631	Using cancer type-specific models, we found a wide range of putative driver missense mutations in various cancer types.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('missense mutations', 'Var', (76, 94))	('cancer', 'Disease', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
144051	31202631	In total, 479 unique driver missense mutations were identified by the cancer type-specific analyses but missed by pan-cancer analysis.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('missense mutations', 'Var', (28, 46))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
144052	31202631	The pan-cancer analysis identified 3,527 unique missense mutations as putative drivers (Table S3) and had substantial overlap with our earlier pan-cancer analysis (p<2.2e-16, one-sided Fisher's exact test).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('missense mutations', 'Var', (48, 66))	('cancer', 'Disease', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
144053	31202631	Given the substantially different methodology, the overlap suggests the CHASMplus pan-cancer analysis identifies a core set of driver mutations with multiple distinct sources of evidence.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CHASMplus pan-cancer', 'Disease', 'MESH:D009369', (72, 92))	('core', 'cellular_component', 'GO:0019013', ('115', '119'))	('mutations', 'Var', (134, 143))	('CHASMplus pan-cancer', 'Disease', (72, 92))
144055	31202631	Notably, the cancer type-specific analysis identified a substantial number of putative driver mutations not previously characterized in OncoKB (median overlap 53%).	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (94, 103))
144056	31202631	Altogether across the pan-cancer and cancer type-specific analyses, 4,006 unique driver missense mutations were identified by CHASMplus, of which 2,037 were neither found by OncoKB nor our earlier pan-cancer analysis, indicating a potentially expanded landscape of putative driver missense mutations of interest for further examination.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('CHASMplus', 'Disease', (126, 135))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('CHASMplus', 'Disease', 'None', (126, 135))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('missense mutations', 'Var', (88, 106))
144061	31202631	These results suggest that CHASMplus has potential to discriminate driver and passenger mutations in both well-known and putative cancer driver genes, although follow up experiments are required for confirmation.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('CHASMplus', 'Disease', (27, 36))	('mutations', 'Var', (88, 97))	('CHASMplus', 'Disease', 'None', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
144062	31202631	Based on our mutation-level analysis, we observed that the spectrum of rare (<1% of cancer samples), intermediate (1-5%), and common (>5%) frequency driver missense mutations varied substantially among cancer types (Figure 3a).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (202, 208))	('missense mutations', 'Var', (156, 174))
144063	31202631	For example, uveal melanoma was dominated by common driver missense mutations (88%), while head and neck squamous cell carcinoma (HNSC) was dominated by rare driver missense mutations (63%).	('uveal melanoma', 'Disease', (13, 27))	('neck squamous cell carcinoma', 'Disease', (100, 128))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('missense mutations', 'Var', (59, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (100, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('neck', 'cellular_component', 'GO:0044326', ('100', '104'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (13, 27))	('uveal melanoma', 'Disease', 'MESH:C536494', (13, 27))
144064	31202631	However, when we considered all cancer types together (pan-cancer), the overall proportion of rare driver missense mutations considered rare was slightly greater than for common (35.5% and 35.4%, respectively) and 4-fold greater than found by the cancer hotspots method (8%, P<2.2e-16, Fisher's exact test).	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('missense mutations', 'Var', (106, 124))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
144065	31202631	These results suggest that rare driver missense mutations have a greater role in many cancer types than previously suggested, but that this might not be the case for every cancer type.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('missense mutations', 'Var', (39, 57))	('cancer', 'Disease', (86, 92))
144066	31202631	We observed, after adjusting for sample size, that the average tumor mutation burden for a cancer type positively correlated with the prevalence of rare (but not common) driver missense mutations (R=0.63, P=4.7e-5, likelihood ratio test, Figure 3b).	('tumor', 'Disease', (63, 68))	('missense mutations', 'Var', (177, 195))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
144067	31202631	While cancer types appear to have different proportions of rare, intermediate and common driver missense mutations across cancer types, this result could be confounded by differences in subtypes or cell-of-origin.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('missense mutations', 'Var', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (6, 12))
144070	31202631	Fifty-five out of 223 genes (24.7%) contained putative driver missense mutations that were enriched in particular cancer subtypes (q-value<=0.1, chi-squared test, Figure 3c, Table S5, Figure S4).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('missense mutations', 'Var', (62, 80))	('cancer', 'Disease', (114, 120))
144071	31202631	Several genes showed strong specificity, consistent with prior literature, such as NFE2L2 mutations in esophageal cancers of squamous cell-of-origin, TP53 mutations in Human Papillomavirus-negative tumors in head and neck cancer, KIT mutations in testicular seminomas and PIK3CA mutations in the Luminal A subtype of breast cancer.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('TP53', 'Gene', (150, 154))	('mutations', 'Var', (90, 99))	('cancers', 'Disease', (114, 121))	('breast cancer', 'Disease', 'MESH:D001943', (317, 330))	('breast cancer', 'Disease', (317, 330))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('KIT', 'Gene', '3815', (230, 233))	('testicular seminomas', 'Phenotype', 'HP:0100617', (247, 267))	('Papillomavirus-negative tumors', 'Disease', 'MESH:D030361', (174, 204))	('KIT', 'molecular_function', 'GO:0005020', ('230', '233'))	('mutations', 'Var', (279, 288))	('Papillomavirus-negative tumors', 'Disease', (174, 204))	('PIK3CA', 'Gene', (272, 278))	('NFE2L2', 'Gene', '4780', (83, 89))	('neck', 'cellular_component', 'GO:0044326', ('217', '221'))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('neck cancer', 'Disease', 'MESH:D006258', (217, 228))	('TP53', 'Gene', '7157', (150, 154))	('neck cancer', 'Disease', (217, 228))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('seminomas', 'Disease', 'MESH:D018239', (258, 267))	('seminomas', 'Disease', (258, 267))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('head and neck cancer', 'Phenotype', 'HP:0012288', (208, 228))	('NFE2L2', 'Gene', (83, 89))	('mutations', 'Var', (234, 243))	('KIT', 'Gene', (230, 233))	('mutations', 'Var', (155, 164))	('PIK3CA', 'Gene', '5290', (272, 278))	('breast cancer', 'Phenotype', 'HP:0003002', (317, 330))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
144072	31202631	It should be noted that in some cases these differences are confounded by the fact that subtypes were originally defined by mutation status (GBM or LGG with IDH1/IDH2 mutations).	('IDH2', 'Gene', '3418', (162, 166))	('IDH2', 'Gene', (162, 166))	('mutations', 'Var', (167, 176))	('IDH1', 'Gene', (157, 161))	('IDH1', 'Gene', '3417', (157, 161))
144073	31202631	For example, the protein phosphatase PPP2R1A, which has been implicated as a tumor suppressor gene in many tumor types, contained common driver missense mutations in our pan-cancer analysis at residue positions 179 and 183, which is located at the protein interface composing the phosphatase 2A complex (Figure 3d).	('PPP2R1A', 'Gene', '5518', (37, 44))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('77', '93'))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('protein', 'cellular_component', 'GO:0003675', ('248', '255'))	('phosphatase 2A', 'molecular_function', 'GO:0004722', ('280', '294'))	('missense mutations', 'Var', (144, 162))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('phosphatase', 'molecular_function', 'GO:0016791', ('25', '36'))	('PPP2R1A', 'Gene', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (77, 82))	('tumor suppressor', 'biological_process', 'GO:0051726', ('77', '93'))
144074	31202631	It also had a much broader set of rare driver mutations throughout the protein interface, such as R105Q and R459C.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('R105Q', 'Mutation', 'rs1489963266', (98, 103))	('R105Q', 'Var', (98, 103))	('R459C', 'Var', (108, 113))	('R459C', 'Mutation', 'p.R459C', (108, 113))
144075	31202631	Similarly, CHASMplus identified common driver missense mutations (S310A/F/Y) in the extracellular domain of the well-known oncogene ERBB2, but also finds rare driver missense mutations in both the extracellular and kinase domain (e.g., L313V and R678Q) (Figure 3e).	('R678Q', 'Var', (246, 251))	('ERBB2', 'Gene', (132, 137))	('S310A/F/Y', 'Var', (66, 75))	('S310A/F/Y', 'Mutation', 'rs1057519816', (66, 75))	('L313V', 'Mutation', 'p.L313V', (236, 241))	('extracellular', 'cellular_component', 'GO:0005576', ('197', '210'))	('CHASMplus', 'Disease', (11, 20))	('CHASMplus', 'Disease', 'None', (11, 20))	('L313V', 'Var', (236, 241))	('extracellular', 'cellular_component', 'GO:0005576', ('84', '97'))	('ERBB2', 'Gene', '2064', (132, 137))	('R678Q', 'Mutation', 'rs1057519862', (246, 251))
144076	31202631	This is supportive of previous experimental work implicating rare cancer driver mutations in commonly mutated cancer driver genes.	('cancer', 'Disease', (110, 116))	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (66, 72))
144077	31202631	Truncating or likely loss-of-function mutations are typical hallmarks of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('loss-of-function', 'NegReg', (21, 37))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor suppressor', 'biological_process', 'GO:0051726', ('73', '89'))	('tumor', 'Disease', (73, 78))	('Truncating', 'Var', (0, 10))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('73', '89'))	('mutations', 'Var', (38, 47))
144078	31202631	However, the role of driver missense mutations may be under-characterized in tumor suppressor genes, since these mutations are more diverse and occur over a larger region than in oncogenes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('77', '93'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('missense mutations', 'Var', (28, 46))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('tumor suppressor', 'biological_process', 'GO:0051726', ('77', '93'))
144079	31202631	As a case in point, the tumor suppressor gene CASP8 contains many truncating variants, while all of the putative driver missense mutations identified by CHASMplus were considered rare (Figure 3f).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('variants', 'Var', (77, 85))	('tumor suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('CHASMplus', 'Disease', (153, 162))	('CASP8', 'Gene', (46, 51))	('CHASMplus', 'Disease', 'None', (153, 162))	('CASP8', 'Gene', '841', (46, 51))	('truncating', 'MPA', (66, 76))
144081	31202631	We explored functional evidence to support whether the rare driver missense mutations in CASP8, predicted by CHASMplus, behaved similarly to truncating variants.	('CHASMplus', 'Disease', 'None', (109, 118))	('CASP8', 'Gene', (89, 94))	('CASP8', 'Gene', '841', (89, 94))	('CHASMplus', 'Disease', (109, 118))	('missense mutations', 'Var', (67, 85))
144083	31202631	For 12 immune-related markers, we compared tumor samples with driver missense mutations or truncating mutations in CASP8 to control samples with no mutations in CASP8.	('CASP8', 'Gene', (161, 166))	('truncating mutations', 'Var', (91, 111))	('CASP8', 'Gene', '841', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('CASP8', 'Gene', (115, 120))	('CASP8', 'Gene', '841', (115, 120))	('missense mutations', 'Var', (69, 87))	('tumor', 'Disease', (43, 48))
144085	31202631	Conventional wisdom has suggested that because rare missense mutations in tumor suppressor genes do not tend to cluster in protein sequence, they are solely passenger events.	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('missense mutations', 'Var', (52, 70))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('tumor', 'Disease', (74, 79))
144086	31202631	However, our work suggests that rare driver missense mutations in CASP8 and perhaps in other tumor suppressor genes may be relevant to tumor immune-related phenotypes.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('missense mutations', 'Var', (44, 62))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', (93, 98))	('CASP8', 'Gene', (66, 71))	('CASP8', 'Gene', '841', (66, 71))	('tumor suppressor', 'biological_process', 'GO:0051726', ('93', '109'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('93', '109'))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
144091	31202631	Because PTEN mutations are found in many cancer types, we used CHASMplus pan-cancer predictions.	('CHASMplus pan-cancer', 'Disease', 'MESH:D009369', (63, 83))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('PTEN', 'Gene', (8, 12))	('PTEN', 'Gene', '5728', (8, 12))	('CHASMplus pan-cancer', 'Disease', (63, 83))	('found', 'Reg', (27, 32))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('mutations', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
144095	31202631	Next, we examined the lipid phosphatase activity and protein abundance for the PTEN mutations that we predicted as drivers in the TCGA.	('lipid phosphatase activity', 'molecular_function', 'GO:0042577', ('22', '48'))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('mutations', 'Var', (84, 93))	('PTEN', 'Gene', (79, 83))	('PTEN', 'Gene', '5728', (79, 83))
144096	31202631	We observed that these driver missense mutations, regardless of frequency, had significantly lower lipid phosphatase activity than other missense mutations in PTEN (common: p=0.008; intermediate: p=1.9e-9; rare: p=1.6e-18; Mann-Whitney U test, Figure 5e).	('lipid phosphatase activity', 'molecular_function', 'GO:0042577', ('99', '125'))	('PTEN', 'Gene', (159, 163))	('PTEN', 'Gene', '5728', (159, 163))	('missense mutations', 'Var', (30, 48))	('lipid phosphatase activity', 'MPA', (99, 125))	('lower', 'NegReg', (93, 98))
144097	31202631	A likely explanation is that greater decreases in PTEN lipid phosphatase activity may promote tumor growth and tumor clones with these mutations are positively selected in many patients.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('activity', 'MPA', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('patients', 'Species', '9606', (177, 185))	('mutations', 'Var', (135, 144))	('PTEN', 'Gene', (50, 54))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (111, 116))	('promote', 'PosReg', (86, 93))	('PTEN', 'Gene', '5728', (50, 54))	('lipid phosphatase activity', 'molecular_function', 'GO:0042577', ('55', '81'))	('decreases', 'NegReg', (37, 46))
144105	31202631	Based on our cancer type-specific models from CHASMplus, we found that the diversity and prevalence of driver missense mutations varied considerably across TCGA cancer types (Figure 6a, Methods).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', (13, 19))	('CHASMplus', 'Disease', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('CHASMplus', 'Disease', 'None', (46, 55))	('cancer', 'Disease', (161, 167))	('missense mutations', 'Var', (110, 128))	('TCGA', 'Disease', (156, 160))
144110	31202631	Are there substantially more cancer driver missense mutations yet to be discovered?	('missense mutations', 'Var', (43, 61))	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))
144113	31202631	Subsampling analysis showed all cancer types had a linear increase in the number of unique driver missense mutations identified (R2 > 0.5) with no evidence of saturation at current sample sizes (Figure S7a).	('S7', 'Gene', '6264', (202, 204))	('increase', 'PosReg', (58, 66))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('missense mutations', 'Var', (98, 116))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
144114	31202631	However, discovery of driver missense mutations, which occur in aggregate at a given prevalence (average number per cancer sample), varied substantially among cancer types (Figure 6b).	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('missense mutations', 'Var', (29, 47))
144116	31202631	This resulted in only marginal increases in the overall prevalence of identified driver missense mutations, consistent with our predicted trajectory based only on TCGA samples (Methods, Table S7, Figure S7b).	('S7', 'Gene', '6264', (203, 205))	('missense mutations', 'Var', (88, 106))	('increases', 'PosReg', (31, 40))	('S7', 'Gene', '6264', (192, 194))
144117	31202631	In contrast, thymoma (THYM), uveal melanoma (UVM), and pancreatic ductal adenocarcinoma (PAAD) contained common driver missense mutations that could be detected based on only a few samples from the cohort, e.g., GTF2I L424H in THYM.	('thymoma', 'Gene', (13, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('GTF2I', 'Gene', (212, 217))	('thymoma', 'Gene', '7063', (13, 20))	('thymoma', 'Phenotype', 'HP:0100522', (13, 20))	('GTF2I', 'Gene', '2969', (212, 217))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (55, 87))	('missense', 'Var', (119, 127))	('L424H', 'Mutation', 'p.L424H', (218, 223))	('pancreatic ductal adenocarcinoma', 'Disease', (55, 87))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (55, 87))
144118	31202631	In contrast, the prevalence of rare driver missense mutations increased substantially with sample size in breast cancer (BRCA), head and neck squamous cell carcinoma (HNSC), and colon adenocarcinoma (COAD).	('missense mutations', 'Var', (43, 61))	('neck', 'cellular_component', 'GO:0044326', ('137', '141'))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (137, 165))	('colon adenocarcinoma', 'Disease', (178, 198))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (178, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('neck squamous cell carcinoma', 'Disease', (137, 165))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
144119	31202631	These results suggest cancer types can be clustered by patterns of driver missense mutation diversity and prevalence (Figure 6a), in addition to well-established approaches to define cancer subtypes, such as by cell-of-origin.	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('driver missense mutation', 'Var', (67, 91))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
144121	31202631	Future insights into cancer evolution and its relevance for clinical care will increasingly rely on the precise interpretation of whether individual mutations are cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('mutations', 'Var', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
144123	31202631	The long tail hypothesis posits that there are many rare driver mutations in human cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('long tail', 'Phenotype', 'HP:0002831', (4, 13))	('mutations', 'Var', (64, 73))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))
144126	31202631	The observed diversity of driver mutations across patients' tumors may be influenced by tumor mutation burden, the type of gene (i.e., tumor suppressor genes), the functional strength of the mutation, and the mutation's subtype specificity.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('135', '151'))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('patients', 'Species', '9606', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('influenced', 'Reg', (74, 84))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor suppressor', 'biological_process', 'GO:0051726', ('135', '151'))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (88, 93))	('tumors', 'Disease', (60, 66))
144127	31202631	The diversity of driver missense mutations supports the critical role of understanding the origins and overall contribution of rare driver mutations -- failure to capture and identify rare driver mutations, which occur in aggregate at reasonable prevalence, may result in crucial missed opportunities for interpreting a patient's cancer.	('missense mutations', 'Var', (24, 42))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('patient', 'Species', '9606', (320, 327))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('cancer', 'Disease', (330, 336))
144129	31202631	We therefore have precomputed the score of every possible missense mutation across the genome, effectively an in silico saturation mutagenesis across all genes to score as of yet unobserved mutations that are potential cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('missense mutation', 'Var', (58, 75))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', (219, 225))	('mutagenesis', 'biological_process', 'GO:0006280', ('131', '142'))
144130	31202631	Although missense mutations are the most frequent protein-coding somatic alteration in cancer, CHASMplus only predicts missense mutations; but, in principle, our approach could be extended to other types of alterations.	('cancer', 'Disease', (87, 93))	('CHASMplus', 'Disease', (95, 104))	('CHASMplus', 'Disease', 'None', (95, 104))	('missense mutations', 'Var', (119, 137))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('missense mutations', 'Var', (9, 27))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
144131	31202631	Lastly, while our study leverages the large sized TCGA cohorts to make informed judgements about driver missense mutations, inevitably these tumors may still miss important contexts for understanding cancer.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('missense mutations', 'Var', (104, 122))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))
144133	31202631	For example, it is well known EGFR mutations in lung adenocarcinoma are more highly prevalent in Asian compared to Caucasian populations.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (48, 67))	('EGFR', 'Gene', (30, 34))	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('prevalent', 'Reg', (84, 93))	('mutations', 'Var', (35, 44))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('EGFR', 'Gene', '1956', (30, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('lung adenocarcinoma', 'Disease', (48, 67))
144135	31202631	We expect that an increasingly complete catalog of driver missense mutations will be generated by a combination of improved computational methods and cumulative growth of available samples from cancer sequencing studies.	('missense mutations', 'Var', (58, 76))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
144136	31202631	However, for some cancer types in some populations, discovery of driver missense mutations may already be effectively saturated.	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('missense mutations', 'Var', (72, 90))
144137	31202631	By analyzing the trajectory of discovery at the level of driver missense mutations, we identified a more complicated pattern which depends on the cancer type.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('missense mutations', 'Var', (64, 82))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
144138	31202631	Future work will further elucidate a broader range of driver mutations, including those within non-coding regions of the genome, at different stages of carcinogenesis, such as in pre-cancerous lesions, and in response to therapeutic treatment.	('carcinogenesis', 'Disease', (152, 166))	('cancerous lesions', 'Disease', 'MESH:D009369', (183, 200))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancerous lesions', 'Disease', (183, 200))	('pre', 'molecular_function', 'GO:0003904', ('179', '182'))	('carcinogenesis', 'Disease', 'MESH:D063646', (152, 166))
144141	31202631	We collected a set of 1,225,917 somatic mutations in 8,657 samples from The Cancer Genome Atlas (TCGA) somatic mutation calls from whole-exome sequencing (v0.2.8, https://synapse.org/MC3).	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('MC3', 'Gene', (183, 186))	('MC3', 'Gene', '4159', (183, 186))	('mutations', 'Var', (40, 49))	('Cancer', 'Disease', (76, 82))	('synapse', 'cellular_component', 'GO:0045202', ('171', '178'))	('Cancer', 'Disease', 'MESH:D009369', (76, 82))
144143	31202631	We identified hypermutated samples as having more mutations than 1.5 times the interquartile range above the third quartile (Tukey's condition) of samples within the same cancer type.	('mutations', 'Var', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (171, 177))
144146	31202631	Previous machine learning approaches for predicting driver mutations have been trained on a small positive class of bona fide driver missense mutations, which are highly prevalent in many cancer types.	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('missense mutations', 'Var', (133, 151))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', (188, 194))
144148	31202631	Driver genes have been labeled but the labels of missense mutations are inferred by cluster assumptions, e.g., driver missense mutations may occur together in known driver genes and in significantly mutated genes for a particular cancer type.	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('occur', 'Reg', (141, 146))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('missense mutations', 'Var', (118, 136))
144149	31202631	Mutations are assigned to the 'positive' class (driver-like) for a cancer type based on these assumptions, and all other mutations are assigned to the 'negative' class (passenger-like).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
144150	31202631	To extend this approach to a pan-cancer prediction, all mutations from the positive class were merged into one group and a single classifier was trained.	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (56, 65))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))
144152	31202631	To test the assumptions of our training procedure, we rigorously evaluated CHASMplus on orthogonally labeled mutations based on in vitro experiments, in vivo experiments, and literature curation.	('CHASMplus', 'Disease', (75, 84))	('CHASMplus', 'Disease', 'None', (75, 84))	('mutations', 'Var', (109, 118))
144155	31202631	The positive class (likely-driver missense mutations) was selected by the following criteria: 1) missense mutations had to occur in a curated set of 125 pan-cancer driver genes; 2) for each of the 32 TCGA cancer types, missense mutations found in that cancer type had to occur in a significantly mutated gene for that cancer type according to MutSigCV v1.4.	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (318, 324))	('v1.4', 'Gene', '28815', (352, 356))	('cancer', 'Disease', (252, 258))	('cancer', 'Disease', (205, 211))	('missense mutations', 'Var', (219, 237))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('v1.4', 'Gene', (352, 356))
144157	31202631	Notably, MutSigCV v1.4 only assess the total number of mutations in a gene, and not any characteristics of those mutations; thus, we avoid making strong assumptions about the properties of a particular driver mutation; 3) missense mutations had to occur in samples with relatively low mutation rate (less than 500 mutations, half the minimum hypermutator threshold as defined above).	('missense mutations', 'Var', (222, 240))	('v1.4', 'Gene', '28815', (18, 22))	('v1.4', 'Gene', (18, 22))
144167	31202631	We used random forests, a machine learning technique, to predict whether a missense mutation is a cancer driver.	('missense mutation', 'Var', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))
144169	31202631	Since missense mutations in the same gene may have overlapping feature representations which result in classifier overfitting, we performed prediction using a 10-fold gene hold-out cross-validation procedure for both CHASMplus and 20/20+.	('overfitting', 'PosReg', (114, 125))	('CHASMplus', 'Disease', (217, 226))	('CHASMplus', 'Disease', 'None', (217, 226))	('missense mutations', 'Var', (6, 24))	('result in', 'Reg', (93, 102))
144171	31202631	The CHASMplus score represents the fraction of decision trees which vote for the mutation being a driver.	('CHASMplus', 'Disease', (4, 13))	('mutation', 'Var', (81, 89))	('CHASMplus', 'Disease', 'None', (4, 13))
144176	31202631	Next, each simulated missense mutation and gene was scored with the CHASMplus and 20/20+ models that were previously trained on the observed data.	('missense mutation', 'Var', (21, 38))	('CHASMplus', 'Disease', (68, 77))	('CHASMplus', 'Disease', 'None', (68, 77))
144178	31202631	We compared CHASMplus to 12 other methods that were designed to prioritize likely cancer driver missense mutations or have been used for that purpose (VEST, CADD, FATHMM cancer, SIFT, MutationAssessor, REVEL, MCAP, ParsSNP, CHASM, Polyphen2, transFIC and CanDrA).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MCAP', 'Gene', (209, 213))	('cancer', 'Disease', (170, 176))	('CHASM', 'Gene', (224, 229))	('CHASM', 'Gene', (12, 17))	('CHASM', 'Gene', '219537', (224, 229))	('cancer', 'Disease', (82, 88))	('CADD', 'Disease', (157, 161))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('missense mutations', 'Var', (96, 114))	('CHASMplus', 'Disease', (12, 21))	('CHASMplus', 'Disease', 'None', (12, 21))	('CHASM', 'Gene', '219537', (12, 17))	('MCAP', 'Gene', '23476', (209, 213))
144189	31202631	Mutations were scored using the corresponding cancer type models of CHASMplus, CanDrA, and CHASM, along with two high-performing methods which are not cancer type-specific (ParsSNP and REVEL).	('CHASMplus', 'Disease', (68, 77))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('CHASMplus', 'Disease', 'None', (68, 77))	('CHASM', 'Gene', '219537', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (46, 52))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (151, 157))	('CHASM', 'Gene', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('CHASM', 'Gene', (68, 73))	('CHASM', 'Gene', '219537', (91, 96))
144191	31202631	To assess each method's ability to distinguish breast cancer-specific driver mutations, mutations that increased cell viability in known breast cancer driver genes were labeled as positive class.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (47, 60))	('increased', 'PosReg', (103, 112))	('breast cancer', 'Disease', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('mutations', 'Var', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cell viability', 'CPA', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
144192	31202631	Mutations that did not increase cell viability or increased cell viability but were not found in breast cancer-specific genes were labeled as negative class.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('Mutations', 'Var', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))
144194	31202631	Breast cancer-specific genes were labeled based on the Cancer Gene Census (CGC, genes marked as relevant to "breast" cancer and somatic missense mutations, COSMIC v79) or The Cancer Genome Atlas (TCGA).	('Cancer', 'Disease', (175, 181))	('missense mutations', 'Var', (136, 154))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Cancer', 'Disease', 'MESH:D009369', (175, 181))	('Cancer', 'Phenotype', 'HP:0002664', (175, 181))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('Cancer', 'Disease', (55, 61))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Disease', (117, 123))	('Breast cancer', 'Disease', (0, 13))	('Cancer', 'Disease', 'MESH:D009369', (55, 61))
144196	31202631	We obtained all missense mutations from targeted sequencing with the MSK-IMPACT gene panel of 414 cancer-related genes originating from approximately 10,000 patients' tumors.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('missense mutations', 'Var', (16, 34))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('patients', 'Species', '9606', (157, 165))	('cancer', 'Disease', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
144198	31202631	For each cancer type, mutations were labeled as 'positive' class if they occurred in a cancer driver gene implicated for that cancer type and also a tumor of the same type.	('cancer', 'Disease', (87, 93))	('occurred', 'Reg', (73, 81))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', (149, 154))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
144205	31202631	We obtained all missense mutations from targeted sequencing with the MSK-IMPACT gene panel of 414 cancer-related genes, originating from approximately 10,000 patients' tumors.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('missense mutations', 'Var', (16, 34))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('patients', 'Species', '9606', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
144207	31202631	The study selected mutations based on their presence in sequenced human tumors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('human', 'Species', '9606', (66, 71))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('mutations', 'Var', (19, 28))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Disease', (72, 78))
144210	31202631	We assessed each method's ability to distinguish TP53 mutations with low transactivation (positive class) versus all other TP53 mutations (negative class).	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('transactivation', 'MPA', (73, 88))	('mutations', 'Var', (54, 63))	('transactivation', 'biological_process', 'GO:2000144', ('73', '88'))	('low', 'NegReg', (69, 72))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (123, 127))
144211	31202631	We evaluated all missense mutations (n=2,314) for TP53 from the IARC TP53 database.	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('missense mutations', 'Var', (17, 35))	('TP53', 'Gene', '7157', (50, 54))	('TP53', 'Gene', (50, 54))
144212	31202631	Low transactivation was considered as less than 50% wildtype, as indicated by the median of 8 different targets (WAF1, MDM2, BAX, h1433s, AIP1, GADD45, NOXA, and P53R2).	('WAF1', 'Gene', (113, 117))	('transactivation', 'MPA', (4, 19))	('MDM2', 'Gene', '4193', (119, 123))	('NOXA', 'Gene', (152, 156))	('GADD45', 'Gene', (144, 150))	('MDM2', 'Gene', (119, 123))	('h1433s', 'Var', (130, 136))	('AIP1', 'Gene', '23204', (138, 142))	('NOXA', 'Gene', '5366', (152, 156))	('P53R2', 'Gene', '50484', (162, 167))	('BAX', 'Gene', (125, 128))	('transactivation', 'biological_process', 'GO:2000144', ('4', '19'))	('WAF1', 'Gene', '1026', (113, 117))	('BAX', 'Gene', '581', (125, 128))	('GADD45', 'Gene', '1647', (144, 150))	('P53R2', 'Gene', (162, 167))	('AIP1', 'Gene', (138, 142))
144214	31202631	The experiment assumes that mutations that provide a growth advantage to cells with growth factors withdrawn reflect cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('growth', 'MPA', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('mutations', 'Var', (28, 37))
144215	31202631	We compared (pan-cancer) CHASMplus to the cancer hotspots method (v0.6), with respect to its sensitivity to identify driver missense mutations.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('CHASMplus', 'Disease', (25, 34))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('CHASMplus', 'Disease', 'None', (25, 34))	('cancer', 'Disease', (17, 23))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('missense mutations', 'Var', (124, 142))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
144217	31202631	The sensitivity of CHASMplus to detect the OncoKB-labeled mutations was 0.83, which was significantly higher than the hotspot method (0.46, p<2.2e-16, McNemar's test, n=896).	('mutations', 'Var', (58, 67))	('CHASMplus', 'Disease', (19, 28))	('CHASMplus', 'Disease', 'None', (19, 28))	('higher', 'PosReg', (102, 108))
144218	31202631	To minimize potential gene bias, we also repeated the analysis after excluding all 389 TP53 mutations, yielding sensitivity of 0.76 for CHASMplus and 0.49 for hotspot detection, a difference which is still statistically significant (p<2.2e-16, McNemar's test, n=507) (Figure 7b).	('CHASMplus', 'Disease', 'None', (136, 145))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('CHASMplus', 'Disease', (136, 145))
144225	31202631	We performed gene ontology analysis on the set of 75 genes (Table S4) containing at least one driver missense mutation from CHASMplus that did not overlap with previous genes from the Cancer Gene Census (COSMIC v79, annotated with somatic missense) or any driver genes from the TCGA PancanAtlas analysis.	('gene ontology', 'biological_process', 'GO:0003673', ('13', '26'))	('CHASMplus', 'Disease', (124, 133))	('CHASMplus', 'Disease', 'None', (124, 133))	('mutation', 'Var', (110, 118))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Cancer', 'Disease', (184, 190))	('Cancer', 'Disease', 'MESH:D009369', (184, 190))
144226	31202631	Mutation frequency was calculated based on the fraction of cancer samples that contained a driver mutation in a particular cancer type.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutation', 'Var', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
144228	31202631	All mutations within a codon are then classified as rare (<1% of cancer samples), intermediate (1-5%), or common (>5%).	('mutations', 'Var', (4, 13))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))
144234	31202631	gwCHASMplus scores were computed for each of these missense mutations.	('missense mutations', 'Var', (51, 69))	('gwCHASMplus', 'Disease', 'None', (0, 11))	('gwCHASMplus', 'Disease', (0, 11))
144237	31202631	We extended our comparison of the PTEN saturation mutagenesis experiment of lipid phosphatase activity to the two "runner-up" methods (CanDrA and ParsSNP), assessed in the five benchmarks in Figure 2d.	('lipid phosphatase activity', 'molecular_function', 'GO:0042577', ('76', '102'))	('activity', 'MPA', (94, 102))	('mutagenesis', 'Var', (50, 61))	('mutagenesis', 'biological_process', 'GO:0006280', ('50', '61'))	('PTEN', 'Gene', (34, 38))	('PTEN', 'Gene', '5728', (34, 38))
144238	31202631	CHASMplus, CanDrA and ParsSNP were then compared to each other based on their specificity, sensitivity, precision and F1 score to identify mutations damaging to lipid phosphatase activity in PTEN.	('CHASMplus', 'Disease', (0, 9))	('CHASMplus', 'Disease', 'None', (0, 9))	('lipid phosphatase activity', 'molecular_function', 'GO:0042577', ('161', '187'))	('damaging', 'Reg', (149, 157))	('mutations', 'Var', (139, 148))	('PTEN', 'Gene', (191, 195))	('PTEN', 'Gene', '5728', (191, 195))	('lipid phosphatase activity', 'MPA', (161, 187))
144239	31202631	Most driver missense mutation prediction methods do not report p-values, but CHASMplus does compute a p-value.	('CHASMplus', 'Disease', 'None', (77, 86))	('missense mutation', 'Var', (12, 29))	('CHASMplus', 'Disease', (77, 86))
144242	31202631	We clustered TCGA cancer types according to two features, prevalence (fraction of samples mutated) and normalized diversity (normalized entropy) among predicted missense mutation drivers (q <= 0.01).	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('missense mutation', 'Var', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))
144244	31202631	To evaluate this possibility, we correlated the mean Variant Allele Fraction (VAF) for mutations in tumor samples in each cancer type with a variety of metrics summarizing our results.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mutations', 'Var', (87, 96))
144246	31202631	We found no significant correlation between mean VAF for cancer types with: average number of predicted driver mutations per sample (Pearson r=0.26, p=0.14, correlation test), fraction of samples with predicted driver mutations (Pearson r=0.2, p=0.28, correlation test), unique number of significant mutations (Pearson r=0.04, p=0.82, correlation test), and normalized driver diversity (Pearson r=0.33, p=0.07, correlation test).	('mutations', 'Var', (111, 120))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
144247	31202631	We performed driver missense mutation predictions on random subsamples of each of 9 representative cancer types (ACC, SARC, PRAD, THYM, UVM, PAAD, BRCA, HNSC, and COAD), using CHASMplus.	('missense mutation', 'Var', (20, 37))	('UVM', 'Disease', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('HNSC', 'Disease', (153, 157))	('CHASMplus', 'Disease', (176, 185))	('cancer', 'Disease', (99, 105))	('PRAD', 'Disease', (124, 128))	('BRCA', 'Disease', (147, 151))	('THYM', 'Disease', (130, 134))	('CHASMplus', 'Disease', 'None', (176, 185))	('ACC', 'Disease', (113, 116))	('SARC', 'Disease', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('PAAD', 'Disease', (141, 145))
144250	31202631	The number of unique driver missense mutations and overall driver prevalence (average number of driver missense mutations per cancer sample) were then calculated based on significant CHASMplus predictions (q<=0.01).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('CHASMplus', 'Disease', (183, 192))	('missense mutations', 'Var', (28, 46))	('CHASMplus', 'Disease', 'None', (183, 192))
144251	31202631	Results were then ordered by increasing sample size to observe trends in the identification of driver missense mutations by CHASMplus.	('CHASMplus', 'Disease', (124, 133))	('CHASMplus', 'Disease', 'None', (124, 133))	('driver missense mutations', 'Var', (95, 120))
144254	31202631	Similar to statistical methods for driver gene detection, hotspot detection identifies an excess number of mutations compared to expectation using a large number of cancer samples.	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', (165, 171))	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))
144255	31202631	We assessed the number of samples required to detect driver missense mutations across a range of frequencies (proportion of tumor samples in which a mutation occurs) and somatic background mutation rates.	('missense mutations', 'Var', (60, 78))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
144256	31202631	In Figure 7a, each of the 32 TCGA cancer types is placed according to its sample size and background mutation rate, relative to six curves which represent the required sample size to detect driver missense mutations of a certain frequency, with 90% power, using hotspot detection (see Statistical Power Analysis).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('missense mutations', 'Var', (197, 215))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (34, 40))
144258	31202631	At current TCGA sample sizes, we found codon-based hotspot detection approaches were not well powered to identify driver missense mutations that occurred at less than 1% frequency in most cancer types.	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('missense mutations', 'Var', (121, 139))	('cancer', 'Disease', (188, 194))
144261	31202631	For these mutations, pan-cancer analysis using ~10,000 TCGA samples should enable detection of driver mutations at frequency as low as 0.1%.	('mutations', 'Var', (10, 19))	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))
144263	31202631	Interactive portal for exploring driver missense mutations in TCGA: https://karchinlab.github.io/CHASMplus.	('missense mutations', 'Var', (40, 58))	('CHASMplus', 'Disease', (97, 106))	('CHASMplus', 'Disease', 'None', (97, 106))
144264	31202631	Missense mutations are the most frequent type of protein-coding alteration in cancers and the most difficult to interpret.	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Missense mutations', 'Var', (0, 18))
144265	31202631	While many computational methods have been developed to predict whether genes are cancer drivers or whether missense mutations are generally deleterious or pathogenic, there has not previously been a method to score the oncogenic impact of a missense mutation specifically by cancer type, limiting adoption of computational missense mutation predictors in the clinic.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('missense', 'Var', (242, 250))
144268	31202631	We introduce a machine learning method honed for each cancer type, and a resource for fast lookup of the cancer-specific driver propensity of every possible missense mutation in the human exome.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('human', 'Species', '9606', (182, 187))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('missense mutation', 'Var', (157, 174))
144269	31202631	CHASMplus identifies driver missense mutations in a cancer type-specific manner Rare driver mutations are common in cancer when considered as a group In some cancers, further sequencing will yield insight into rare driver mutations Comprehensive resource of driver propensity for all possible missense mutations	('CHASMplus', 'Disease', (0, 9))	('CHASMplus', 'Disease', 'None', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('cancer', 'Disease', (158, 164))	('missense mutations', 'Var', (28, 46))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
144287	30347896	Meanwhile, no survey has ever explored the mechanistic of the deregulated HTR2B gene expression at the transcription level in the class 2 tumors at risk of progressing towards the metastatic liver disease.	('HTR2B', 'Gene', '3357', (74, 79))	('transcription', 'biological_process', 'GO:0006351', ('103', '116'))	('liver disease', 'Phenotype', 'HP:0001392', (191, 204))	('gene expression', 'biological_process', 'GO:0010467', ('80', '95'))	('liver disease', 'Disease', (191, 204))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Disease', (138, 144))	('deregulated', 'Var', (62, 73))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('HTR2B', 'Gene', (74, 79))	('liver disease', 'Disease', 'MESH:D008107', (191, 204))	('expression', 'Species', '29278', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
144303	30347896	Transfection of the plasmid HTR2B/-138 that contains the HTR2B promoter sequence from 3' position +96 to 5' position -138 relative to the transcriptional start site into UM cell lines that express either very low (T97, T108 and T143) or intermediate (T142) levels of HTR2B, respectively (Figure 3A), yielded easily detectable CAT activities in all UM cell lines (Figure 3C).	('T108', 'Var', (219, 223))	('T97', 'Var', (214, 217))	('HTR2B', 'Gene', (28, 33))	('HTR2B', 'Gene', '3357', (28, 33))	('T143', 'Var', (228, 232))	('CAT activities', 'MPA', (326, 340))	('CAT', 'molecular_function', 'GO:0004096', ('326', '329'))	('HTR2B', 'Gene', (267, 272))	('HTR2B', 'Gene', '3357', (267, 272))	('HTR2B', 'Gene', (57, 62))	('T142', 'Var', (251, 255))	('HTR2B', 'Gene', '3357', (57, 62))
144318	30347896	The multiple bands detected for some of the NFI isoforms (particularly noticeable for both NFIA and NFIC) are most likely indicative of post-translational modifications occurring in some UM cell lines (for instance, T97 and T108 for NFIA and T142 and T143 for NFIC).	('NFI', 'Gene', '4782', (91, 94))	('NFIC', 'Gene', (100, 104))	('NFI', 'Gene', '4782', (44, 47))	('T97', 'Var', (216, 219))	('NFI', 'Gene', (260, 263))	('NFI', 'Gene', '4782', (233, 236))	('T143', 'Var', (251, 255))	('NFIA', 'Gene', '4774', (91, 95))	('NFIA', 'Gene', (91, 95))	('NFIC', 'Gene', '4782', (260, 264))	('NFI', 'Gene', (100, 103))	('NFIA', 'Gene', (233, 237))	('NFIC', 'Gene', (260, 264))	('NFIA', 'Gene', '4774', (233, 237))	('NFI', 'Gene', (91, 94))	('NFI', 'Gene', (44, 47))	('NFI', 'Gene', (233, 236))	('T108', 'Var', (224, 228))	('NFI', 'Gene', '4782', (260, 263))	('T142', 'Var', (242, 246))	('NFI', 'Gene', '4782', (100, 103))	('NFIC', 'Gene', '4782', (100, 104))
144327	30347896	Each of these NFI sites was mutated in the HTR2B promoter-bearing plasmids, either individually or in combination, and the derivative constructs transfected in T108 UM cells.	('mutated', 'Var', (28, 35))	('NFI', 'Gene', '4782', (14, 17))	('HTR2B', 'Gene', (43, 48))	('NFI', 'Gene', (14, 17))	('HTR2B', 'Gene', '3357', (43, 48))
144328	30347896	As indicated in Figure 6C, mutation of the -9 NFI site in the plasmid -2000/NFIm(-9) yielded a near 7-fold reduction in T108 cells when compared to its parental vector HTR2B/-2000 (considered as 100%).	('T108 cells', 'CPA', (120, 130))	('NFI', 'Gene', (76, 79))	('NFI', 'Gene', (46, 49))	('HTR2B', 'Gene', (168, 173))	('HTR2B', 'Gene', '3357', (168, 173))	('mutation', 'Var', (27, 35))	('NFI', 'Gene', '4782', (76, 79))	('NFI', 'Gene', '4782', (46, 49))	('reduction', 'NegReg', (107, 116))
144329	30347896	On the other hand, mutating either the -210 (in -2000/NFIm(-210)) or the -1249 (in -2000/NFIm(-1249)) NFI site reduced CAT activity by only 40% and 27% in these cells, respectively.	('NFI', 'Gene', '4782', (54, 57))	('CAT', 'molecular_function', 'GO:0004096', ('119', '122'))	('NFI', 'Gene', '4782', (89, 92))	('NFI', 'Gene', '4782', (102, 105))	('NFI', 'Gene', (54, 57))	('reduced', 'NegReg', (111, 118))	('mutating', 'Var', (19, 27))	('NFI', 'Gene', (89, 92))	('CAT activity', 'MPA', (119, 131))	('NFI', 'Gene', (102, 105))
144330	30347896	Interestingly, mutation of both the -9 and -210 NFI sites in the plasmid -2000/NFIm(-9, -210) caused a dramatic reduction of the CAT activity to only 6% (17-fold repression) relative to the level driven by the parental plasmid -2000/HTR2B.	('NFI', 'Gene', (79, 82))	('mutation', 'Var', (15, 23))	('CAT', 'molecular_function', 'GO:0004096', ('129', '132'))	('HTR2B', 'Gene', (233, 238))	('HTR2B', 'Gene', '3357', (233, 238))	('reduction', 'NegReg', (112, 121))	('CAT activity', 'MPA', (129, 141))	('NFI', 'Gene', '4782', (48, 51))	('NFI', 'Gene', '4782', (79, 82))	('NFI', 'Gene', (48, 51))
144331	30347896	Mutating both the -1279 and -9 sites in -2000/NFIm(-9, -1249) did not reduce promoter activity beyond the level of the -9 NFI mutant alone (18% vs. 15%, respectively) suggesting that the regulatory impact of the -1275 NFI site is negligible.	('Mutating', 'Var', (0, 8))	('NFI', 'Gene', (46, 49))	('NFI', 'Gene', '4782', (218, 221))	('promoter activity', 'MPA', (77, 94))	('NFI', 'Gene', '4782', (122, 125))	('NFI', 'Gene', (218, 221))	('reduce', 'NegReg', (70, 76))	('NFI', 'Gene', (122, 125))	('NFI', 'Gene', '4782', (46, 49))
144332	30347896	Similarly, mutating the -1275 NFI site along with both the -9 and -210 sites in plasmid -2000/NFIm(-9,-210,-1275) did not reduce further the CAT activity (5% of the level directed by the parental plasmid -2000/HTR2B) than the level observed with the plasmid -2000/NFIm(-9,-210).	('NFI', 'Gene', (264, 267))	('mutating', 'Var', (11, 19))	('reduce', 'NegReg', (122, 128))	('NFI', 'Gene', (94, 97))	('NFI', 'Gene', '4782', (30, 33))	('CAT activity', 'MPA', (141, 153))	('NFI', 'Gene', '4782', (94, 97))	('NFI', 'Gene', (30, 33))	('HTR2B', 'Gene', (210, 215))	('HTR2B', 'Gene', '3357', (210, 215))	('NFI', 'Gene', '4782', (264, 267))	('CAT', 'molecular_function', 'GO:0004096', ('141', '144'))
144333	30347896	Mutation of all four NFI sites in -2000/NFIm(-9,-210,-1249,-1275) reduced CAT activity to very much the same level (9%) as that yielded by the -9/-210 double mutant (6%).	('reduced', 'NegReg', (66, 73))	('NFI', 'Gene', '4782', (40, 43))	('NFI', 'Gene', (40, 43))	('NFI', 'Gene', '4782', (21, 24))	('-9', 'Var', (45, 47))	('CAT activity', 'MPA', (74, 86))	('NFI', 'Gene', (21, 24))	('CAT', 'molecular_function', 'GO:0004096', ('74', '77'))
144346	30347896	Consistent with the EMSA results from Figure 7A, nuclear extracts from T97, T108, T142 and T143 cells all yielded multiple DNA-protein complexes when incubated with the RUNX1 labeled probe, although much weaker signals were observed with the extract from T108 cells (C+; Figure 8A).	('RUNX1', 'Gene', (169, 174))	('DNA', 'cellular_component', 'GO:0005574', ('123', '126'))	('RUNX1', 'Gene', '861', (169, 174))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('T143', 'Var', (91, 95))	('yielded', 'Reg', (106, 113))	('DNA-protein complexes', 'MPA', (123, 144))
144353	30347896	Analysis of RUNX1 mRNA expression by microarray (Figure 8C) and qPCR (Figure 8D) confirmed that T97 and T108 UM cells express the highest and lowest level of the RUNX1 transcript, respectively.	('RUNX1', 'Gene', (162, 167))	('RUNX1', 'Gene', '861', (162, 167))	('RUNX1', 'Gene', (12, 17))	('T108 UM', 'Var', (104, 111))	('T97', 'Var', (96, 99))	('RUNX1', 'Gene', '861', (12, 17))	('lowest', 'NegReg', (142, 148))	('expression', 'Species', '29278', (23, 33))
144356	30347896	Disruption of the RUNX1 site resulted in a 2.8- and 2.7-fold increase in CAT activity in both T108 and T143 UM cells, respectively, relative to the level directed by the wild-type parental construct (Figure 8F) suggesting that RUNX1 functions as a repressor of HTR2B gene transcription in these cells.	('RUNX1', 'Gene', (227, 232))	('RUNX1', 'Gene', '861', (227, 232))	('RUNX1', 'Gene', '861', (18, 23))	('CAT activity', 'MPA', (73, 85))	('HTR2B', 'Gene', '3357', (261, 266))	('HTR2B', 'Gene', (261, 266))	('CAT', 'molecular_function', 'GO:0004096', ('73', '76'))	('increase', 'PosReg', (61, 69))	('RUNX1', 'Gene', (18, 23))	('transcription', 'biological_process', 'GO:0006351', ('272', '285'))	('Disruption', 'Var', (0, 10))
144361	30347896	Indeed, the basal promoter area bearing the -9 NFI site was occupied by NFI in all four UM cell lines (enrichment of the amplified region in T97, T108, T142 and T143 was defined as "strong", "weak", "weak" and "very strong", respectively).	('NFI', 'Gene', (72, 75))	('T108', 'Var', (146, 150))	('NFI', 'Gene', '4782', (47, 50))	('T142', 'Var', (152, 156))	('T143', 'Var', (161, 165))	('NFI', 'Gene', (47, 50))	('NFI', 'Gene', '4782', (72, 75))
144362	30347896	A similar scenario was also observed for the -210 NFI site ("weak", "very strong", "weak" and "strong" enrichment of the amplified region in T97, T108, T142 and T143, respectively; Table 1).	('NFI', 'Gene', '4782', (50, 53))	('T108', 'Var', (146, 150))	('NFI', 'Gene', (50, 53))	('T142', 'Var', (152, 156))	('T97', 'Var', (141, 144))	('T143', 'Var', (161, 165))
144365	30347896	Finally, binding of RUNX1 ranging from strong (in T142 and T143) to very strong (in T97) were observed in all but T108 UM cells when the area bearing the footprinted -1127 RUNX1 site was amplified using the -1234/-1022 specific primers (Table 1).	('RUNX1', 'Gene', '861', (172, 177))	('T142', 'Var', (50, 54))	('T108', 'Var', (114, 118))	('binding', 'molecular_function', 'GO:0005488', ('9', '16'))	('T143', 'Var', (59, 63))	('binding', 'Interaction', (9, 16))	('RUNX1', 'Gene', (20, 25))	('RUNX1', 'Gene', (172, 177))	('RUNX1', 'Gene', '861', (20, 25))
144379	30347896	However, in the case of HTR2B, the members of this family clearly turned out to be activators of that gene, as site-directed mutation of both the -9 and -210 NFI sites almost completely abolishes transcription directed by the HTR2B promoter.	('HTR2B', 'Gene', (226, 231))	('abolishes', 'NegReg', (186, 195))	('HTR2B', 'Gene', '3357', (226, 231))	('transcription', 'MPA', (196, 209))	('HTR2B', 'Gene', '3357', (24, 29))	('NFI', 'Gene', '4782', (158, 161))	('HTR2B', 'Gene', (24, 29))	('transcription', 'biological_process', 'GO:0006351', ('196', '209'))	('NFI', 'Gene', (158, 161))	('mutation', 'Var', (125, 133))
144382	30347896	As stated above, T108 UM cells distinguishes themselves from the other cell lines by their clearly-reduced NFI binding capacity in EMSA (Figure 4A), which likely results from the absence of both the NFIB and NFIC isoforms (Figure 4C).	('NFIB', 'Gene', '4781', (199, 203))	('NFI', 'Gene', '4782', (208, 211))	('NFI', 'Gene', (107, 110))	('T108 UM', 'Var', (17, 24))	('clearly-reduced', 'NegReg', (91, 106))	('NFI', 'Gene', '4782', (199, 202))	('NFI', 'Gene', (208, 211))	('NFIC', 'Gene', '4782', (208, 212))	('binding', 'molecular_function', 'GO:0005488', ('111', '118'))	('absence', 'NegReg', (179, 186))	('NFIC', 'Gene', (208, 212))	('NFI', 'Gene', (199, 202))	('NFI', 'Gene', '4782', (107, 110))	('NFIB', 'Gene', (199, 203))
144383	30347896	However, the lack of NFIB and NFIC proteins in T108 UM cells does not correlate with their corresponding mRNA, which are abundantly expressed in these cells (Figure 2B).	('T108 UM', 'Var', (47, 54))	('NFIB', 'Gene', (21, 25))	('NFIC', 'Gene', '4782', (30, 34))	('NFIB', 'Gene', '4781', (21, 25))	('NFIC', 'Gene', (30, 34))
144386	30347896	In addition, glycosylation of NFI has been postulated to delay its degradation by the proteasome in human skin keratinocytes.	('proteasome', 'molecular_function', 'GO:0004299', ('86', '96'))	('NFI', 'Gene', '4782', (30, 33))	('glycosylation', 'Var', (13, 26))	('degradation by the proteasome', 'MPA', (67, 96))	('degradation', 'biological_process', 'GO:0009056', ('67', '78'))	('human', 'Species', '9606', (100, 105))	('NFI', 'Gene', (30, 33))	('glycosylation', 'biological_process', 'GO:0070085', ('13', '26'))	('proteasome', 'cellular_component', 'GO:0000502', ('86', '96'))	('delay', 'NegReg', (57, 62))
144406	30347896	Identifying RUNX1 as a regulator of HTR2B gene expression in UM cancer cells is particularly relevant to our study in that deregulation of this TFs appears to be a characteristic of many types of cancers, including acute leukemia (reviewed in), human colorectal, prostate, endometrial, ovarian, and human skin and oral squamous cell carcinomas.	('HTR2B', 'Gene', (36, 41))	('prostate', 'Disease', (263, 271))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('endometrial', 'Disease', (273, 284))	('leukemia', 'Phenotype', 'HP:0001909', (221, 229))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('human colorectal', 'Disease', (245, 261))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (314, 343))	('RUNX1', 'Gene', (12, 17))	('cancer', 'Disease', (64, 70))	('RUNX1', 'Gene', '861', (12, 17))	('human', 'Species', '9606', (245, 250))	('acute leukemia', 'Disease', (215, 229))	('gene expression', 'biological_process', 'GO:0010467', ('42', '57'))	('carcinomas', 'Phenotype', 'HP:0030731', (333, 343))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('deregulation', 'Var', (123, 135))	('oral squamous cell carcinomas', 'Disease', (314, 343))	('human', 'Species', '9606', (299, 304))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('cancers', 'Disease', (196, 203))	('cancer', 'Disease', (196, 202))	('acute leukemia', 'Disease', 'MESH:D015470', (215, 229))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('HTR2B', 'Gene', '3357', (36, 41))	('ovarian', 'Disease', (286, 293))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (319, 343))	('acute leukemia', 'Phenotype', 'HP:0002488', (215, 229))	('expression', 'Species', '29278', (47, 57))
144407	30347896	have recently demonstrated a physical interaction between the tumor suppressor Foxp3 and RUNX1 that suppresses the trans-activating properties of RUNX1 and suggested that any disruption in this equilibrium in favor of RUNX1 (which is viewed as a tumor enhancer based on their results) may contribute to breast cancer development.	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('RUNX1', 'Gene', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('RUNX1', 'Gene', '861', (146, 151))	('RUNX1', 'Gene', (218, 223))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('RUNX1', 'Gene', '861', (218, 223))	('contribute', 'Reg', (289, 299))	('Foxp3', 'Gene', (79, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (303, 316))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('62', '78'))	('RUNX1', 'Gene', (89, 94))	('tumor', 'Disease', (246, 251))	('RUNX1', 'Gene', '861', (89, 94))	('disruption', 'Var', (175, 185))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Disease', (62, 67))	('tumor suppressor', 'biological_process', 'GO:0051726', ('62', '78'))	('breast cancer', 'Disease', (303, 316))	('breast cancer', 'Disease', 'MESH:D001943', (303, 316))	('trans-activating properties', 'MPA', (115, 142))	('suppresses', 'NegReg', (100, 110))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('interaction', 'Interaction', (38, 49))
144427	30347896	Western blots were conducted as described using antibodies directed against the following proteins: total NFI (sc-5567 (polyclonal), 1:2000; Santa Cruz Biotechnology), NFI-A (ab11988 (polyclonal), 1:500; Abcam, Toronto, ON, Canada), NFI-B (ab51352-100 (monoclonal), 1:100; Abcam), NFI-C (ab89516 (monoclonal), 1:500; Abcam), NFI-X (ab67169 (polyclonal), 1:100; Abcam), RUNX1 (ab23980, 1:1000; Abcam) and a peroxidase-conjugated AffiniPure Goat secondary antibody against mouse IgG (1:2500 dilution; Jackson ImmunoResearch Laboratories, West Grove, PA, USA).	('antibody', 'cellular_component', 'GO:0019815', ('454', '462'))	('poly', 'Chemical', '-', (341, 345))	('IgG (1', 'cellular_component', 'GO:0071735', ('477', '483'))	('Goat', 'Species', '9925', (439, 443))	('NFI', 'Gene', '4782', (233, 236))	('RUNX1', 'Gene', (369, 374))	('antibody', 'cellular_component', 'GO:0019814', ('454', '462'))	('NFI', 'Gene', '4782', (281, 284))	('NFI', 'Gene', '4782', (106, 109))	('RUNX1', 'Gene', '861', (369, 374))	('NFI', 'Gene', '4782', (168, 171))	('NFI', 'Gene', (233, 236))	('ab23980', 'Var', (376, 383))	('NFI', 'Gene', '4782', (325, 328))	('antibody', 'molecular_function', 'GO:0003823', ('454', '462'))	('NFI', 'Gene', (281, 284))	('NFI', 'Gene', (106, 109))	('NFI', 'Gene', (168, 171))	('antibody', 'cellular_component', 'GO:0042571', ('454', '462'))	('mouse', 'Species', '10090', (471, 476))	('poly', 'Chemical', '-', (184, 188))	('NFI', 'Gene', (325, 328))	('poly', 'Chemical', '-', (120, 124))
144437	30186714	NGS is important for personalizing tumor therapies to an individual's genome, allowing for both the targeting of specific tumor mutations as well as gaining an understanding of what the side effect profile will be for a specific patient.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('mutations', 'Var', (128, 137))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))	('patient', 'Species', '9606', (229, 236))
144444	30186714	Integrating KRAS mutation data with cachexia Murine models have displayed the presence of KRAS inducing Src-dependent expression of the PEAK1 protein.	('Src-dependent expression', 'MPA', (104, 128))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('cachexia', 'Disease', (36, 44))	('cachexia', 'Disease', 'MESH:D002100', (36, 44))	('KRAS', 'Var', (90, 94))	('mutation', 'Var', (17, 25))	('PEAK1', 'Gene', (136, 141))	('Murine', 'Species', '10090', (45, 51))	('inducing', 'Reg', (95, 103))	('cachexia', 'Phenotype', 'HP:0004326', (36, 44))	('PEAK1', 'Gene', '79834', (136, 141))
144445	30186714	In-vivo mouse models expressing KRAS G12D constitutively have activated KRAS/Src signaling through Src kinase activation.	('activation', 'PosReg', (110, 120))	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('Src kinase', 'MPA', (99, 109))	('KRAS G12D', 'Var', (32, 41))	('G12D', 'Mutation', 'rs121913529', (37, 41))	('KRAS/Src signaling', 'MPA', (72, 90))	('mouse', 'Species', '10090', (8, 13))	('activated', 'PosReg', (62, 71))
144451	30186714	From a clinical perspective, the loss of defined skeletal muscle can increase fall risk and decrease ambulation, which may contribute to higher risk of intracranial bleed and thrombosis, respectively.	('increase', 'PosReg', (69, 77))	('intracranial bleed', 'Disease', 'MESH:D020300', (152, 170))	('thrombosis', 'Disease', 'MESH:D013927', (175, 185))	('decrease', 'NegReg', (92, 100))	('intracranial bleed', 'Disease', (152, 170))	('ambulation', 'CPA', (101, 111))	('fall', 'Phenotype', 'HP:0002527', (78, 82))	('intracranial bleed', 'Phenotype', 'HP:0002170', (152, 170))	('fall', 'CPA', (78, 82))	('loss', 'Var', (33, 37))	('thrombosis', 'Disease', (175, 185))
144457	30186714	Determination of BRAF V600E mutations in ocular melanoma allows for greater therapeutic efficacy for BRAF inhibitors such as vemurafinib and dabrafenib.	('therapeutic efficacy', 'MPA', (76, 96))	('BRAF', 'Gene', (101, 105))	('ocular melanoma', 'Disease', (41, 56))	('dabrafenib', 'Chemical', 'MESH:C561627', (141, 151))	('ocular melanoma', 'Disease', 'MESH:D008545', (41, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('ocular melanoma', 'Phenotype', 'HP:0007716', (41, 56))	('BRAF', 'Gene', '673', (17, 21))	('V600E', 'Mutation', 'rs113488022', (22, 27))	('BRAF', 'Gene', (17, 21))	('vemurafinib', 'Chemical', '-', (125, 136))	('V600E', 'Var', (22, 27))	('BRAF', 'Gene', '673', (101, 105))	('greater', 'PosReg', (68, 75))
144462	30186714	Uveal melanomas, unlike cutaneous melanomas, rarely contain NRAS, NF1, or BRAF mutations and are more frequently characterized by point mutations in the G-protein alpha-subunit.	('melanomas', 'Disease', 'MESH:D008545', (34, 43))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('mutations', 'Var', (79, 88))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (24, 43))	('point mutations', 'Var', (130, 145))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (24, 43))	('melanomas', 'Disease', (34, 43))	('G-protein alpha-subunit', 'Protein', (153, 176))	('NRAS', 'Gene', '4893', (60, 64))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('NF1', 'Gene', '4763', (66, 69))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('cutaneous melanomas', 'Disease', (24, 43))	('NF1', 'Gene', (66, 69))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('NRAS', 'Gene', (60, 64))	('melanomas', 'Disease', (6, 15))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))
144464	30186714	Mutations in genes associated with GNAQ or GNA11 are reported in over 80% of primary uveal melanomas and are associated with constitutive activation of signaling pathways including the central oncogenic RAS/RAF/MEK/ERK (RAS-ERK) pathway, thereby driving cell proliferation.	('GNA11', 'Gene', '2767', (43, 48))	('RAF', 'Gene', '22882', (207, 210))	('uveal melanoma', 'Phenotype', 'HP:0007716', (85, 99))	('signaling', 'biological_process', 'GO:0023052', ('152', '161'))	('ERK', 'Gene', '5594', (224, 227))	('MEK', 'Gene', '5609', (211, 214))	('activation', 'PosReg', (138, 148))	('signaling pathways', 'Pathway', (152, 170))	('cell proliferation', 'biological_process', 'GO:0008283', ('254', '272'))	('uveal melanomas', 'Disease', (85, 100))	('ERK', 'Gene', '5594', (215, 218))	('cell proliferation', 'CPA', (254, 272))	('uveal melanomas', 'Phenotype', 'HP:0007716', (85, 100))	('Mutations', 'Var', (0, 9))	('RAF', 'Gene', (207, 210))	('MEK', 'Gene', (211, 214))	('associated', 'Reg', (109, 119))	('ERK', 'Gene', (224, 227))	('GNA11', 'Gene', (43, 48))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('ERK', 'Gene', (215, 218))	('GNAQ', 'Gene', '2776', (35, 39))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('GNAQ', 'Gene', (35, 39))	('driving', 'PosReg', (246, 253))	('ERK', 'molecular_function', 'GO:0004707', ('215', '218'))	('uveal melanomas', 'Disease', 'MESH:C536494', (85, 100))	('ERK', 'molecular_function', 'GO:0004707', ('224', '227'))
144501	27533448	While oncogenic BRAF and NRAS mutations are seen in 50% and 15% of cutaneous melanomas respectively, these mutations are rare in uveal melanoma tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('uveal melanoma tumors', 'Disease', (129, 150))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (67, 86))	('mutations', 'Var', (30, 39))	('NRAS', 'Gene', (25, 29))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (129, 150))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (67, 86))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (67, 85))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('NRAS', 'Gene', '4893', (25, 29))	('cutaneous melanomas', 'Disease', (67, 86))
144502	27533448	Instead, 90% harbor mutations in either the GNAQ or GNA11 components of the guanine nucleotide binding protein subunit alpha.	('GNAQ', 'Gene', (44, 48))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('84', '102'))	('GNA11', 'Gene', (52, 57))	('GNAQ', 'Gene', '2776', (44, 48))	('GNA11', 'Gene', '2767', (52, 57))	('mutations', 'Var', (20, 29))
144518	27533448	Uveal melanoma patients were included in several of the initial studies of PD-1 antibodies, but data are limited because these patients were excluded from most subsequent clinical trials.	('patients', 'Species', '9606', (15, 23))	('PD-1', 'Gene', (75, 79))	('PD-1', 'Gene', '5133', (75, 79))	('Uveal melanoma', 'Disease', 'MESH:C536494', (0, 14))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('patients', 'Species', '9606', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('Uveal melanoma', 'Disease', (0, 14))	('antibodies', 'Var', (80, 90))
144594	27533448	One patient had no detectable exon 5 GNAQ or GNA11 mutations, and an additional patient was found to be negative for GNAQ mutations with no record of GNA11 mutation analysis.	('mutations', 'Var', (51, 60))	('GNAQ', 'Gene', (37, 41))	('GNA11', 'Gene', (150, 155))	('GNAQ', 'Gene', '2776', (117, 121))	('patient', 'Species', '9606', (4, 11))	('GNA11', 'Gene', (45, 50))	('GNA11', 'Gene', '2767', (150, 155))	('GNAQ', 'Gene', (117, 121))	('GNAQ', 'Gene', '2776', (37, 41))	('patient', 'Species', '9606', (80, 87))	('GNA11', 'Gene', '2767', (45, 50))
144595	27533448	None of the patients with PD or SD after treatment with PD-1 or PD-L1 antibodies were tested for GNAQ or GNA11 mutations.	('mutations', 'Var', (111, 120))	('patients', 'Species', '9606', (12, 20))	('GNA11', 'Gene', (105, 110))	('GNAQ', 'Gene', '2776', (97, 101))	('men', 'Species', '9606', (46, 49))	('GNA11', 'Gene', '2767', (105, 110))	('PD-L1', 'Gene', (64, 69))	('PD-1', 'Gene', (56, 60))	('SD', 'Disease', 'MESH:D029461', (32, 34))	('PD-1', 'Gene', '5133', (56, 60))	('PD-L1', 'Gene', '29126', (64, 69))	('GNAQ', 'Gene', (97, 101))
144604	27533448	As described in cutaneous melanoma, there did not seem to be a clear association between clinical benefit from PD-1 or PD-L1 antibodies and benefit from prior treatment with other immune therapies, including ipilimumab.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (16, 34))	('ipilimumab', 'Chemical', 'MESH:D000074324', (208, 218))	('PD-L1', 'Gene', (119, 124))	('cutaneous melanoma', 'Disease', (16, 34))	('PD-1', 'Gene', (111, 115))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('PD-1', 'Gene', '5133', (111, 115))	('antibodies', 'Var', (125, 135))	('PD-L1', 'Gene', '29126', (119, 124))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (16, 34))	('men', 'Species', '9606', (164, 167))
144619	27533448	In patients with metastatic cutaneous melanoma and other advanced malignancies, tumors expressing high levels of PD-L1 (i.e., "PD-L1 positive") are more likely to respond to anti-PD-1 monotherapy than those with low expression (i.e., "PD-L1 negative").	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PD-1', 'Gene', (179, 183))	('PD-1', 'Gene', '5133', (179, 183))	('PD-L1', 'Gene', (113, 118))	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('tumors', 'Disease', (80, 86))	('malignancies', 'Disease', (66, 78))	('PD-L1', 'Gene', '29126', (113, 118))	('PD-L1', 'Gene', (127, 132))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('PD-L1', 'Gene', '29126', (127, 132))	('cutaneous melanoma', 'Disease', (28, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('PD-L1', 'Gene', (235, 240))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (28, 46))	('PD-L1', 'Gene', '29126', (235, 240))	('patients', 'Species', '9606', (3, 11))	('respond', 'MPA', (163, 170))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('high levels', 'Var', (98, 109))
144686	29056717	Genetic and epigenetic modifications in melanocytes that lead to alterations in expression or function of genes and proteins involved in cell cycle control and apoptosis are certainly involved in the development of melanomas.	('melanomas', 'Disease', (215, 224))	('cell cycle control', 'biological_process', 'GO:1901987', ('137', '155'))	('alterations', 'Reg', (65, 76))	('proteins', 'Protein', (116, 124))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('melanomas', 'Phenotype', 'HP:0002861', (215, 224))	('men', 'Species', '9606', (207, 210))	('melanomas', 'Disease', 'MESH:D008545', (215, 224))	('function', 'MPA', (94, 102))	('expression', 'MPA', (80, 90))	('epigenetic modifications', 'Var', (12, 36))	('involved', 'Reg', (184, 192))
144707	29056717	CDKN2A Locus:about 70% of melanomas harbor mutations or deletions in this locus on chromosome 9p21.	('melanomas', 'Disease', (26, 35))	('melanomas', 'Phenotype', 'HP:0002861', (26, 35))	('chromosome', 'cellular_component', 'GO:0005694', ('83', '93'))	('deletions', 'Var', (56, 65))	('mutations', 'Var', (43, 52))	('melanomas', 'Disease', 'MESH:D008545', (26, 35))	('CDKN2A', 'Gene', '100271861', (0, 6))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('CDKN2A', 'Gene', (0, 6))
144717	29056717	Mutations in exon 15 of BRAF are not found, similar to human mucosal malignant melanoma.	('mucosal malignant melanoma', 'Disease', (61, 87))	('mucosal malignant melanoma', 'Disease', 'MESH:D008545', (61, 87))	('human', 'Species', '9606', (55, 60))	('malignant melanoma', 'Phenotype', 'HP:0002861', (69, 87))	('Mutations in exon', 'Var', (0, 17))	('BRAF', 'Gene', (24, 28))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))
144723	29056717	BRAF mutations were seen in 57% of human cutaneous melanomas and NRAS was mutated in 17% of samples.	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (41, 60))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (41, 60))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (41, 59))	('human', 'Species', '9606', (35, 40))	('mutations', 'Var', (5, 14))	('cutaneous melanomas', 'Disease', (41, 60))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))
144724	29056717	The low frequency of BRAF mutations associated with UV-independent carcinogenesis and oral anatomical distribution of canine melanomas supports the dog as a spontaneous model for investigation of non-UV-associated human melanomas.	('carcinogenesis', 'Disease', 'MESH:D063646', (67, 81))	('melanomas', 'Disease', 'MESH:D008545', (125, 134))	('dog', 'Species', '9615', (148, 151))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanomas', 'Phenotype', 'HP:0002861', (220, 229))	('carcinogenesis', 'Disease', (67, 81))	('canine', 'Species', '9615', (118, 124))	('melanomas', 'Disease', (220, 229))	('mutations', 'Var', (26, 35))	('melanomas', 'Disease', (125, 134))	('BRAF', 'Gene', (21, 25))	('distribution of canine', 'Phenotype', 'HP:0012738', (102, 124))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('human', 'Species', '9606', (214, 219))	('associated', 'Reg', (36, 46))	('melanomas', 'Phenotype', 'HP:0002861', (125, 134))	('melanomas', 'Disease', 'MESH:D008545', (220, 229))
144859	29056717	Bianco et al., demonstrated that peripheral blood mononuclear cells with apoptotic melanoma cells significantly increased the antitumor immune response, leading to a reduction of the melanoma in three out of five dogs treated intralesionally with FasL-DNA.	('FasL', 'Gene', (247, 251))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('melanoma', 'Disease', (183, 191))	('reduction', 'NegReg', (166, 175))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('dogs', 'Species', '9615', (213, 217))	('apoptotic', 'Var', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('immune response', 'biological_process', 'GO:0006955', ('136', '151'))	('DNA', 'cellular_component', 'GO:0005574', ('252', '255'))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('increased', 'PosReg', (112, 121))	('FasL', 'Gene', '442968', (247, 251))	('tumor', 'Disease', (130, 135))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))
144867	29056717	The review found that dogs that received the vaccine did not achieve a greater progression-free survival, disease-free interval, or median survival time than dogs that did not receive the vaccine.	('dogs', 'Species', '9615', (158, 162))	('disease-free interval', 'CPA', (106, 127))	('progression-free survival', 'CPA', (79, 104))	('vaccine', 'Var', (45, 52))	('dogs', 'Species', '9615', (22, 26))
144904	28465248	MVEs carrying the lysosomal-associated membrane proteins LAMP1 and LAMP2, the tetraspanin CD63, and other molecules in late endosomes, can however also fuse with the plasma membrane and disseminate their content into the extracellular space (Jaiswal et al.	('CD63', 'Gene', '967', (90, 94))	('membrane', 'cellular_component', 'GO:0016020', ('39', '47'))	('LAMP1', 'Gene', (57, 62))	('extracellular space', 'cellular_component', 'GO:0005615', ('221', '240'))	('LAMP2', 'Gene', (67, 72))	('CD63', 'Gene', (90, 94))	('LAMP2', 'Gene', '3920', (67, 72))	('LAMP1', 'Gene', '3916', (57, 62))	('fuse', 'Var', (152, 156))	('disseminate', 'Reg', (186, 197))	('plasma membrane', 'cellular_component', 'GO:0005886', ('166', '181'))	('content', 'MPA', (204, 211))
144913	28465248	Recent adaptations of PEG precipitation for isolation of EVs have shown that the most efficient protocols for exosome precipitation utilize PEG polymers with average molecular weights of 6,000 or 8,000 Da (PEG-6000 and PEG-8000).	('PEG-8000', 'Var', (219, 227))	('PEG', 'Chemical', 'MESH:D011092', (22, 25))	('exosome', 'cellular_component', 'GO:0070062', ('110', '117'))	('PEG polymers', 'Protein', (140, 152))	('PEG-8000', 'Chemical', 'MESH:C000595216', (219, 227))	('PEG polymers', 'Chemical', '-', (140, 152))	('PEG-6000', 'Chemical', 'MESH:C000595215', (206, 214))	('PEG', 'Chemical', 'MESH:D011092', (140, 143))	('PEG', 'Chemical', 'MESH:D011092', (219, 222))	('PEG', 'Chemical', 'MESH:D011092', (206, 209))
144942	28465248	This is particularly relevant to the AMD disease process since genetic, immunohistochemical, and proteomic studies have identified dysregulation of the alternative complement pathway as an important driver of AMD (please see, for review).	('AMD disease', 'Disease', (37, 48))	('AMD disease', 'Disease', 'MESH:D006009', (37, 48))	('AMD', 'Disease', 'MESH:D006009', (37, 40))	('AMD', 'Disease', 'MESH:D006009', (209, 212))	('AMD', 'Disease', (37, 40))	('AMD', 'Disease', (209, 212))	('alternative complement pathway', 'Pathway', (152, 182))	('dysregulation', 'Var', (131, 144))
144945	28465248	Thus, the placental expression of FasL has been implicated as the basis of placental immune privilege, triggering local deletion of activated maternal lymphocytes that recognize placental paternal antigens and express the FasL receptor (Fas, CD95) .	('FasL', 'Gene', '356', (222, 226))	('CD95', 'Gene', (242, 246))	('FasL', 'Gene', (34, 38))	('FasL', 'Gene', '356', (34, 38))	('CD95', 'Gene', '355', (242, 246))	('deletion', 'Var', (120, 128))	('FasL', 'Gene', (222, 226))
144973	28465248	Taken together, changes in the ECM of the LC and TM are fundamental to the permanent vision loss in glaucoma.	('changes', 'Var', (16, 23))	('vision loss', 'Phenotype', 'HP:0000572', (85, 96))	('vision loss in glaucoma', 'Disease', 'MESH:D005901', (85, 108))	('vision', 'biological_process', 'GO:0007601', ('85', '91'))	('vision loss in glaucoma', 'Disease', (85, 108))	('glaucoma', 'Phenotype', 'HP:0000501', (100, 108))
144975	28465248	The first gene variant to be linked to glaucoma was MYOC which codes for the protein myocilin.	('MYOC', 'Gene', (52, 56))	('glaucoma', 'Disease', 'MESH:D005901', (39, 47))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('variant', 'Var', (15, 22))	('myocilin', 'Gene', (85, 93))	('linked', 'Reg', (29, 35))	('MYOC', 'Gene', '4653', (52, 56))	('glaucoma', 'Phenotype', 'HP:0000501', (39, 47))	('glaucoma', 'Disease', (39, 47))	('myocilin', 'Gene', '4653', (85, 93))
144976	28465248	Currently there are over 70 amino acid substitutions in the myocilin protein that are linked to high pressure glaucoma and many of these mutations result in early onset glaucoma.	('glaucoma', 'Phenotype', 'HP:0000501', (110, 118))	('glaucoma', 'Disease', 'MESH:D005901', (169, 177))	('glaucoma', 'Disease', (110, 118))	('linked', 'Reg', (86, 92))	('myocilin', 'Gene', '4653', (60, 68))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('glaucoma', 'Phenotype', 'HP:0000501', (169, 177))	('mutations', 'Var', (137, 146))	('glaucoma', 'Disease', (169, 177))	('glaucoma', 'Disease', 'MESH:D005901', (110, 118))	('result in', 'Reg', (147, 156))	('myocilin', 'Gene', (60, 68))
144987	28465248	The majority of myocilin mutations are located in the C-terminal olfactomedin domain; a 5-blade, beta-propeller.	('myocilin', 'Gene', (16, 24))	('mutations', 'Var', (25, 34))	('myocilin', 'Gene', '4653', (16, 24))
144989	28465248	Thus, myocilin mutations likely do not affect the proteins ability to associate with exosomal membranes but may disrupt other protein-protein interactions, such as those required for biogenesis, targeting or release.	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('protein-protein interactions', 'MPA', (126, 154))	('myocilin', 'Gene', (6, 14))	('mutations', 'Var', (15, 24))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('myocilin', 'Gene', '4653', (6, 14))	('disrupt', 'NegReg', (112, 119))
144995	28465248	One of the more common AMD risk-associated single nucleotide polymorphisms, which was identified in genome-wide association studies, is in the promoter region of a gene coding for High-Temperature Requirement A Serine Peptidase 1 (HTRA1).	('AMD', 'Disease', 'MESH:D006009', (23, 26))	('HTRA1', 'Gene', (231, 236))	('High-Temperature Requirement A Serine Peptidase 1', 'Gene', '5654', (180, 229))	('AMD', 'Disease', (23, 26))	('single nucleotide polymorphisms', 'Var', (43, 74))	('High-Temperature Requirement A Serine Peptidase 1', 'Gene', (180, 229))
144996	28465248	Experimental studies that over-expressed or deleted HTRA1 in mice, suggest that ECM remodeling in BrM plays an important role in the AMD disease process.	('BrM', 'Disease', (98, 101))	('HTRA1', 'Gene', (52, 57))	('mice', 'Species', '10090', (61, 65))	('AMD disease', 'Disease', (133, 144))	('AMD disease', 'Disease', 'MESH:D006009', (133, 144))	('deleted', 'Var', (44, 51))	('over-expressed', 'PosReg', (26, 40))
145011	28465248	The next step in these studies will be to study potential changes in the protein cargo in exosomes derived from RPE cells under conditions of stress relevant to the AMD disease process, such as photo-oxidative stress and dysregulation of lipid metabolism, to mention a few.	('AMD disease', 'Disease', (165, 176))	('cargo', 'molecular_function', 'GO:0140355', ('81', '86'))	('AMD disease', 'Disease', 'MESH:D006009', (165, 176))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('oxidative stress', 'Phenotype', 'HP:0025464', (200, 216))	('lipid', 'Chemical', 'MESH:D008055', (238, 243))	('dysregulation', 'Var', (221, 234))	('lipid metabolism', 'biological_process', 'GO:0006629', ('238', '254'))
145051	28465248	Furthermore, a recent study by Gangalum and colleagues reported that shRNA knockdown of alphaB-Crystallin in ARPE-19 cells severely inhibits both apical and basolateral exosome and/or small EV release.	('alphaB-Crystallin', 'Protein', (88, 105))	('ARPE-19', 'CellLine', 'CVCL:0145', (109, 116))	('small EV release', 'MPA', (184, 200))	('inhibits', 'NegReg', (132, 140))	('knockdown', 'Var', (75, 84))	('exosome', 'cellular_component', 'GO:0070062', ('169', '176'))
145208	23559860	Increasing evidence shows that epigenetic alterations influence common pathologic responses including inflammation, ischemia, neoplasia, aging, and neurodegeneration.	('neoplasia', 'Disease', 'MESH:D009369', (126, 135))	('neoplasia', 'Phenotype', 'HP:0002664', (126, 135))	('rat', 'Species', '10116', (46, 49))	('neurodegeneration', 'Disease', (148, 165))	('neurodegeneration', 'Disease', 'MESH:D019636', (148, 165))	('ischemia', 'Disease', (116, 124))	('aging', 'biological_process', 'GO:0007568', ('137', '142'))	('aging', 'Disease', (137, 142))	('inflammation', 'Disease', 'MESH:D007249', (102, 114))	('ischemia', 'Disease', 'MESH:D007511', (116, 124))	('neoplasia', 'Disease', (126, 135))	('inflammation', 'Disease', (102, 114))	('inflammation', 'biological_process', 'GO:0006954', ('102', '114'))	('epigenetic alterations', 'Var', (31, 53))	('rat', 'Species', '10116', (159, 162))	('neurodegeneration', 'Phenotype', 'HP:0002180', (148, 165))	('influence', 'Reg', (54, 63))
145209	23559860	Importantly, epigenetic mechanisms may have a pathogenic role in many complex eye diseases such as corneal dystrophy, cataract, glaucoma, diabetic retinopathy, ocular neoplasia, uveitis, and age-related macular degeneration.	('ocular neoplasia', 'Disease', (160, 176))	('uveitis', 'Disease', 'MESH:D014605', (178, 185))	('age-related macular degeneration', 'Disease', (191, 223))	('uveitis', 'Disease', (178, 185))	('corneal dystrophy', 'Disease', 'MESH:D003317', (99, 116))	('pathogenic role', 'Reg', (46, 61))	('diabetic retinopathy', 'Disease', 'MESH:D003920', (138, 158))	('eye diseases', 'Phenotype', 'HP:0000478', (78, 90))	('macular degeneration', 'Phenotype', 'HP:0000608', (203, 223))	('eye diseases', 'Disease', (78, 90))	('ocular neoplasia', 'Disease', 'MESH:D009369', (160, 176))	('neoplasia', 'Phenotype', 'HP:0002664', (167, 176))	('cataract', 'Phenotype', 'HP:0000518', (118, 126))	('uveitis', 'Phenotype', 'HP:0000554', (178, 185))	('ocular neoplasia', 'Phenotype', 'HP:0100012', (160, 176))	('glaucoma', 'Phenotype', 'HP:0000501', (128, 136))	('glaucoma', 'Disease', (128, 136))	('corneal dystrophy', 'Phenotype', 'HP:0001131', (99, 116))	('epigenetic mechanisms', 'Var', (13, 34))	('glaucoma', 'Disease', 'MESH:D005901', (128, 136))	('cataract', 'Disease', (118, 126))	('retinopathy', 'Phenotype', 'HP:0000488', (147, 158))	('eye disease', 'Phenotype', 'HP:0000478', (78, 89))	('eye diseases', 'Disease', 'MESH:D005128', (78, 90))	('corneal dystrophy', 'Disease', (99, 116))	('cataract', 'Disease', 'MESH:D002386', (118, 126))	('diabetic retinopathy', 'Disease', (138, 158))	('rat', 'Species', '10116', (217, 220))
145211	23559860	Epigenetic mechanisms play a role in the pathogenesis of major human diseases such as cardiovascular disease, diabetes, neurodegenerative disease, and cancer.	('cardiovascular disease', 'Disease', (86, 108))	('human', 'Species', '9606', (63, 68))	('neurodegenerative disease', 'Disease', (120, 145))	('neurodegenerative disease', 'Disease', 'MESH:D019636', (120, 145))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('pathogenesis', 'biological_process', 'GO:0009405', ('41', '53'))	('diabetes', 'Disease', (110, 118))	('role', 'Reg', (29, 33))	('diabetes', 'Disease', 'MESH:D003920', (110, 118))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (86, 108))	('cardiovascular disease', 'Disease', 'MESH:D002318', (86, 108))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (120, 145))	('Epigenetic mechanisms', 'Var', (0, 21))
145214	23559860	Ultimately, these basic studies will be translated into novel therapies; epigenetic drugs are currently in clinical trials, most notably in treating cancer.	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('epigenetic drugs', 'Var', (73, 89))
145235	23559860	During latent infection, H3K9 and K27 methylation is the major event of histone modifications; in the transition from latency to active infection, H3K9/14ac and H3K4me are the dominant histone modifications.	('infection', 'Disease', (136, 145))	('H3K9', 'Var', (25, 29))	('infection', 'Disease', 'MESH:D007239', (136, 145))	('infection', 'Disease', (14, 23))	('infection', 'Disease', 'MESH:D007239', (14, 23))	('H3K9/14ac', 'Var', (147, 156))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))	('H3K4me', 'Var', (161, 167))
145236	23559860	The latency-associated transcript increases deposition of heterochromatic H3K9me2, H3K9me3, and H3K27me3 and reduces the formation of H3K4me3 on lytic gene promoters, which indicates that histone methylation is important in maintaining HSV1 latency.	('formation of H3K4me3', 'MPA', (121, 141))	('histone methylation', 'biological_process', 'GO:0016571', ('188', '207'))	('increases', 'PosReg', (34, 43))	('deposition', 'MPA', (44, 54))	('H3K27me3', 'Var', (96, 104))	('H3K9me3', 'Var', (83, 90))	('formation', 'biological_process', 'GO:0009058', ('121', '130'))	('reduces', 'NegReg', (109, 116))	('HSV1', 'Species', '10298', (236, 240))	('heterochromatic', 'MPA', (58, 73))
145245	23559860	The result demonstrates that epigenetic factors are involved in the development of experimental form deprivation amblyopia, and suggests that inhibition of histone deacetylation might help to prevent visual loss in this disorder.	('rat', 'Species', '10116', (18, 21))	('visual loss', 'Phenotype', 'HP:0000572', (200, 211))	('inhibition of histone deacetylation', 'biological_process', 'GO:0031064', ('142', '177'))	('visual loss', 'Disease', (200, 211))	('deprivation amblyopia', 'Disease', 'MESH:D000550', (101, 122))	('amblyopia', 'Phenotype', 'HP:0000646', (113, 122))	('deprivation amblyopia', 'Disease', (101, 122))	('involved', 'Reg', (52, 60))	('inhibition', 'Var', (142, 152))	('visual loss', 'Disease', 'MESH:C531604', (200, 211))
145247	23559860	The results indicate that higher levels of DNA methylation in the COL1A1 promoter may inhibit scleral collagen synthesis and contribute to the development of myopia.	('myopia', 'Disease', 'MESH:D009216', (158, 164))	('COL1A1', 'Gene', (66, 72))	('myopia', 'Phenotype', 'HP:0000545', (158, 164))	('DNA', 'MPA', (43, 46))	('methylation', 'Var', (47, 58))	('collagen synthesis', 'biological_process', 'GO:0032964', ('102', '120'))	('collagen', 'molecular_function', 'GO:0005202', ('102', '110'))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('myopia', 'Disease', (158, 164))	('inhibit', 'NegReg', (86, 93))	('DNA methylation', 'biological_process', 'GO:0006306', ('43', '58'))	('contribute', 'Reg', (125, 135))	('scleral collagen synthesis', 'MPA', (94, 120))
145249	23559860	Epigenetic factors may also be involved in cataract formation.	('formation', 'biological_process', 'GO:0009058', ('52', '61'))	('Epigenetic factors', 'Var', (0, 18))	('cataract', 'Disease', 'MESH:D002386', (43, 51))	('involved', 'Reg', (31, 39))	('cataract', 'Disease', (43, 51))	('cataract', 'Phenotype', 'HP:0000518', (43, 51))
145252	23559860	showed that the transgenic mice developed cataract, while the lenses in the control group were transparent.	('transgenic mice', 'Species', '10090', (16, 31))	('transgenic', 'Var', (16, 26))	('cataract', 'Disease', 'MESH:D002386', (42, 50))	('cataract', 'Disease', (42, 50))	('cataract', 'Phenotype', 'HP:0000518', (42, 50))
145258	23559860	In addition, Fem1cR is expressed in the early stage of neuronal cell apoptosis; the death of retinal ganglion cells is closely related to the silenced Fem1cR gene and increased HDAC3 activity in mice.	('mice', 'Species', '10090', (195, 199))	('Fem1cR', 'Gene', (151, 157))	('neuronal cell apoptosis', 'biological_process', 'GO:0051402', ('55', '78'))	('silenced', 'Var', (142, 150))	('increased', 'PosReg', (167, 176))
145270	23559860	Many RP gene mutations have been identified, but the mechanism leading to photoreceptor death is still unclear, and no treatment is available for most patients.	('RP gene', 'Gene', (5, 12))	('mutations', 'Var', (13, 22))	('RP', 'Phenotype', 'HP:0000510', (5, 7))	('patients', 'Species', '9606', (151, 159))
145272	23559860	miRNA have also been implicated in photoreceptor degeneration.	('rat', 'Species', '10116', (55, 58))	('photoreceptor degeneration', 'Disease', (35, 61))	('implicated', 'Reg', (21, 31))	('miRNA', 'Var', (0, 5))
145273	23559860	Notably, if the retinal DICER enzyme is specifically knocked down in mice, a reduced electroretinography response is observed in degenerated retinal cells.	('DICER', 'Gene', (24, 29))	('rat', 'Species', '10116', (135, 138))	('mice', 'Species', '10090', (69, 73))	('electroretinography response', 'MPA', (85, 113))	('reduced', 'NegReg', (77, 84))	('reduced electroretinography', 'Phenotype', 'HP:0000654', (77, 104))	('knocked down', 'Var', (53, 65))
145274	23559860	In addition, reduced expression of miR-96, miR-182, and miR-183 is found in rd1 mice compared with normal mouse retinas, and the expression of miR-96, miR-183, miR-1, and miR-133 is aberrant in transgenic mice with the Pro347Ser mutation in rhodopsin compared with wild-type mice.	('miR-96', 'Gene', (35, 41))	('mice', 'Species', '10090', (275, 279))	('rhodopsin', 'Gene', (241, 250))	('miR-1', 'Gene', (160, 165))	('miR-182', 'Gene', '387177', (43, 50))	('miR-133', 'Gene', (171, 178))	('expression', 'MPA', (129, 139))	('rd1', 'Gene', (76, 79))	('miR-183', 'Gene', '387178', (151, 158))	('miR-96', 'Gene', (143, 149))	('Pro347Ser', 'SUBSTITUTION', 'None', (219, 228))	('miR-183', 'Gene', '387178', (56, 63))	('miR-96', 'Gene', '723886', (35, 41))	('Ser', 'cellular_component', 'GO:0005790', ('225', '228'))	('reduced', 'NegReg', (13, 20))	('miR-183', 'Gene', (151, 158))	('mouse', 'Species', '10090', (106, 111))	('miR-183', 'Gene', (56, 63))	('rhodopsin', 'Gene', '212541', (241, 250))	('rd1', 'Gene', '18587', (76, 79))	('miR-182', 'Gene', (43, 50))	('expression', 'MPA', (21, 31))	('transgenic mice', 'Species', '10090', (194, 209))	('mice', 'Species', '10090', (205, 209))	('mice', 'Species', '10090', (80, 84))	('miR-96', 'Gene', '723886', (143, 149))	('Pro347Ser', 'Var', (219, 228))
145277	23559860	Recently, a role for epigenetics in the pathogenesis of diabetic complications has been proposed.	('diabetic complications', 'Disease', 'MESH:D003925', (56, 78))	('diabetic complications', 'Disease', (56, 78))	('epigenetics', 'Var', (21, 32))	('pathogenesis', 'biological_process', 'GO:0009405', ('40', '52'))
145284	23559860	In another study, VEGF-induced miR-17-5p, miR-18a, miR-20a, miR-21, miR-31, and miR-133 expression was observed in the RECs of STZ-treated rats.	('miR-18a', 'Gene', (42, 49))	('miR-20a', 'Gene', '100314222', (51, 58))	('miR-133', 'Var', (80, 87))	('miR-20a', 'Gene', (51, 58))	('miR-17-5p', 'Var', (31, 40))	('miR-18a', 'Gene', '100314227', (42, 49))	('miR-31', 'Var', (68, 74))	('rats', 'Species', '10116', (139, 143))	('STZ', 'Chemical', 'MESH:D013311', (127, 130))	('miR-21', 'Var', (60, 66))
145287	23559860	Further, knocking down miR-200b inhibits the diabetes-induced upregulation of p300 in the retina, implying crosstalk between two epigenetic mechanisms in diabetic retinopathy.	('miR-200b', 'Gene', (23, 31))	('diabetes', 'Disease', (45, 53))	('diabetic retinopathy', 'Disease', (154, 174))	('p300', 'Gene', '2033', (78, 82))	('retinopathy', 'Phenotype', 'HP:0000488', (163, 174))	('knocking down', 'Var', (9, 22))	('diabetes', 'Disease', 'MESH:D003920', (45, 53))	('diabetic retinopathy', 'Disease', 'MESH:D003920', (154, 174))	('crosstalk', 'Reg', (107, 116))	('inhibits', 'NegReg', (32, 40))	('p300', 'Gene', (78, 82))	('upregulation', 'PosReg', (62, 74))
145289	23559860	Recently, epigenetic mechanisms have been implicated in the pathogenesis of AMD.	('epigenetic mechanisms', 'Var', (10, 31))	('AMD', 'Disease', 'MESH:D006009', (76, 79))	('AMD', 'Disease', (76, 79))	('pathogenesis', 'biological_process', 'GO:0009405', ('60', '72'))	('implicated', 'Reg', (42, 52))
145291	23559860	Epigenetic regulation of HIF-1alpha has been evaluated in cell culture and cancer models.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('regulation', 'biological_process', 'GO:0065007', ('11', '21'))	('cancer', 'Disease', (75, 81))	('HIF-1alpha', 'Gene', '3091', (25, 35))	('Epigenetic', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('HIF-1alpha', 'Gene', (25, 35))
145295	23559860	In a retinal ischemic rat model, TSA not only protected the retina from ischemic damage but also inhibited the TNF-alpha induction of matrix metalloproteinase-1 and matrix metalloproteinase-3.	('matrix metalloproteinase-1 and matrix metalloproteinase-3', 'Gene', '300339;171045', (134, 191))	('TSA', 'molecular_function', 'GO:0033984', ('33', '36'))	('retinal ischemic', 'Disease', 'MESH:D012173', (5, 21))	('retinal ischemic', 'Disease', (5, 21))	('TSA', 'Chemical', 'MESH:C012589', (33, 36))	('TNF-alpha', 'Protein', (111, 120))	('rat', 'Species', '10116', (22, 25))	('TSA', 'Var', (33, 36))	('matrix metalloproteinase-1', 'molecular_function', 'GO:0004232', ('134', '160'))	('inhibited', 'NegReg', (97, 106))	('matrix metalloproteinase-1', 'molecular_function', 'GO:0051405', ('134', '160'))	('induction', 'MPA', (121, 130))	('ischemic damage', 'Disease', (72, 87))	('ischemic damage', 'Disease', 'MESH:D003324', (72, 87))
145301	23559860	Hypomethylation of the interleukin-17 receptor C (IL17RC) promoter has recently been identified in peripheral blood cells from patients with AMD and was associated with increased expression of IL17RC in their peripheral blood and affected retina and choroid.	('AMD', 'Disease', (141, 144))	('interleukin-17 receptor C', 'Gene', '84818', (23, 48))	('IL17', 'molecular_function', 'GO:0030367', ('50', '54'))	('IL17', 'molecular_function', 'GO:0030367', ('193', '197'))	('expression', 'MPA', (179, 189))	('interleukin-17 receptor C', 'Gene', (23, 48))	('IL17RC', 'Gene', '84818', (193, 199))	('Hypomethylation', 'Var', (0, 15))	('increased', 'PosReg', (169, 178))	('IL17RC', 'Gene', '84818', (50, 56))	('patients', 'Species', '9606', (127, 135))	('IL17RC', 'Gene', (193, 199))	('AMD', 'Disease', 'MESH:D006009', (141, 144))	('IL17RC', 'Gene', (50, 56))
145302	23559860	These results suggest that epigenetic regulation of IL17RC may play a role in the pathogenesis of AMD.	('epigenetic regulation', 'Var', (27, 48))	('IL17RC', 'Gene', (52, 58))	('pathogenesis', 'biological_process', 'GO:0009405', ('82', '94'))	('role', 'Reg', (70, 74))	('regulation', 'biological_process', 'GO:0065007', ('38', '48'))	('AMD', 'Disease', 'MESH:D006009', (98, 101))	('IL17', 'molecular_function', 'GO:0030367', ('52', '56'))	('AMD', 'Disease', (98, 101))	('play', 'Reg', (63, 67))	('IL17RC', 'Gene', '84818', (52, 58))
145303	23559860	In a laser-induced murine CNV model, the intravitreal injection of pre-miR-21 significantly diminished CNV volume.	('diminished', 'NegReg', (92, 102))	('pre-miR-21', 'Var', (67, 77))	('murine', 'Species', '10090', (19, 25))	('pre', 'molecular_function', 'GO:0003904', ('67', '70'))	('CNV', 'Phenotype', 'HP:0011506', (103, 106))	('CNV', 'Phenotype', 'HP:0011506', (26, 29))	('CNV volume', 'MPA', (103, 113))
145304	23559860	When mice were put under ischemic stress, the injection of pre-miR-31 or -150 caused significant downregulation of VEGF in the retina, while premiR-31 also reduced the expression of retinal HIF-1alpha and platelet-derived growth factor B.	('platelet-derived', 'Protein', (205, 221))	('expression', 'MPA', (168, 178))	('retinal HIF-1alpha', 'Disease', (182, 200))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('205', '235'))	('VEGF', 'Protein', (115, 119))	('pre-miR-31', 'Var', (59, 69))	('reduced', 'NegReg', (156, 163))	('retinal HIF-1alpha', 'Disease', 'MESH:D012173', (182, 200))	('pre', 'molecular_function', 'GO:0003904', ('59', '62'))	('mice', 'Species', '10090', (5, 9))	('downregulation', 'NegReg', (97, 111))
145305	23559860	The injection of all three of the same pre-miRs, or of pre-miR-31 or -150 by itself reduced CNV lesion sizes in a laser-induced CNV mouse model, while the levels of these three miRNAs were significantly reduced in CNV lesions.	('CNV', 'Phenotype', 'HP:0011506', (214, 217))	('CNV', 'Phenotype', 'HP:0011506', (92, 95))	('pre', 'molecular_function', 'GO:0003904', ('39', '42'))	('pre-miR-31 or -150', 'Var', (55, 73))	('CNV lesion', 'Disease', 'MESH:D051437', (92, 102))	('reduced', 'NegReg', (203, 210))	('CNV lesion', 'Disease', 'MESH:D051437', (214, 224))	('reduced', 'NegReg', (84, 91))	('mouse', 'Species', '10090', (132, 137))	('CNV', 'Phenotype', 'HP:0011506', (128, 131))	('pre', 'molecular_function', 'GO:0003904', ('55', '58'))	('CNV lesions', 'Disease', 'MESH:D051437', (214, 225))	('CNV lesion', 'Disease', (92, 102))	('CNV lesions', 'Disease', (214, 225))
145310	23559860	In animal and cell culture experiments, the depletion of DICER1 reduces RPE cell viability by causing the accumulation of Alu RNA, which is toxic to RPE cells.	('RPE cell viability', 'CPA', (72, 90))	('RNA', 'cellular_component', 'GO:0005562', ('126', '129'))	('RP', 'Phenotype', 'HP:0000510', (149, 151))	('accumulation', 'PosReg', (106, 118))	('depletion', 'Var', (44, 53))	('DICER1', 'Gene', (57, 63))	('DICER1', 'Gene', '23405', (57, 63))	('RP', 'Phenotype', 'HP:0000510', (72, 74))	('Alu RNA', 'MPA', (122, 129))	('reduces', 'NegReg', (64, 71))
145312	23559860	Recent studies indicate that in addition to RB1 gene mutation, tumor development also involves promoter DNA methylation of other tumor suppressor genes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('129', '145'))	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mutation', 'Var', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('RB', 'Phenotype', 'HP:0009919', (44, 46))	('promoter DNA methylation', 'MPA', (95, 119))	('tumor suppressor', 'biological_process', 'GO:0051726', ('129', '145'))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('RB1', 'Gene', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', (129, 134))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('DNA methylation', 'biological_process', 'GO:0006306', ('104', '119'))	('RB1', 'Gene', '5925', (44, 47))
145313	23559860	Whole-genome sequencing analysis from samples of patients with RB and normal controls showed that the tumors contained a small number of mutations or chromosomal rearrangements; more likely, RB1 mutation causes epigenetic abnormalities in cancer-related genes, namely, the high expression of spleen tyrosine kinase (SYK), suggesting the regulation of RB and SYK is closely related.	('epigenetic abnormalities', 'MPA', (211, 235))	('mutation', 'Var', (195, 203))	('RB', 'Phenotype', 'HP:0009919', (351, 353))	('RB1', 'Gene', '5925', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (239, 245))	('SYK', 'Gene', (358, 361))	('causes', 'Reg', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('RB', 'Phenotype', 'HP:0009919', (191, 193))	('tumors', 'Disease', (102, 108))	('regulation', 'biological_process', 'GO:0065007', ('337', '347'))	('SYK', 'Gene', (316, 319))	('RB', 'Phenotype', 'HP:0009919', (63, 65))	('patients', 'Species', '9606', (49, 57))	('SYK', 'Gene', '6850', (358, 361))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('RB1', 'Gene', (191, 194))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('SYK', 'Gene', '6850', (316, 319))
145314	23559860	In addition, an association between RB and hypermethylation of the RAS association domain family 1A gene (RASSF1A) promoter has been demonstrated.	('RASSF1A', 'Gene', (106, 113))	('RB', 'Phenotype', 'HP:0009919', (36, 38))	('RASSF1A', 'Gene', '11186', (106, 113))	('association', 'Interaction', (16, 27))	('rat', 'Species', '10116', (140, 143))	('hypermethylation', 'Var', (43, 59))
145315	23559860	:  :  Previous studies showed that methylation of RASSF1A promoter CpG island is a common event in uveal melanoma; and importantly, hypermethylation of RASSF1A is related to the development of metastatic disease.	('RASSF1A', 'Gene', '11186', (50, 57))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('hypermethylation', 'Var', (132, 148))	('related to', 'Reg', (163, 173))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('RASSF1A', 'Gene', (152, 159))	('uveal melanoma', 'Disease', 'MESH:C536494', (99, 113))	('RASSF1A', 'Gene', (50, 57))	('uveal melanoma', 'Disease', (99, 113))	('RASSF1A', 'Gene', '11186', (152, 159))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))	('metastatic disease', 'Disease', (193, 211))
145316	23559860	However, a recent study demonstrated that the human telomerase reverse transcriptase gene was methylated, but not on RASSF1A, in uveal melanoma.	('transcriptase', 'molecular_function', 'GO:0003968', ('71', '84'))	('transcriptase', 'molecular_function', 'GO:0003899', ('71', '84'))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('telomerase reverse transcriptase', 'Gene', (52, 84))	('telomerase reverse transcriptase', 'Gene', '7015', (52, 84))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('RASSF1A', 'Gene', (117, 124))	('transcriptase', 'molecular_function', 'GO:0034062', ('71', '84'))	('human', 'Species', '9606', (46, 51))	('uveal melanoma', 'Disease', 'MESH:C536494', (129, 143))	('methylated', 'Var', (94, 104))	('RASSF1A', 'Gene', '11186', (117, 124))	('uveal melanoma', 'Disease', (129, 143))	('rat', 'Species', '10116', (31, 34))
145327	23559860	The rapid increase in epigenetic research in the past decade has increased our understanding of the role of epigenetic mechanisms in human physiology and disease.	('human', 'Species', '9606', (133, 138))	('epigenetic', 'Var', (22, 32))	('increased', 'PosReg', (65, 74))
145331	23559860	How do epigenetic factors regulate ocular stem cells and tissue regeneration?	('rat', 'Species', '10116', (70, 73))	('regulate', 'Reg', (26, 34))	('tissue regeneration', 'CPA', (57, 76))	('ocular stem cells', 'CPA', (35, 52))	('epigenetic factors', 'Var', (7, 25))	('tissue regeneration', 'biological_process', 'GO:0042246', ('57', '76'))
145335	23559860	Consideration should be given to the development of small molecules that specifically target epigenetic alterations related to specific eye diseases.	('rat', 'Species', '10116', (108, 111))	('eye diseases', 'Phenotype', 'HP:0000478', (136, 148))	('eye diseases', 'Disease', 'MESH:D005128', (136, 148))	('rat', 'Species', '10116', (7, 10))	('eye diseases', 'Disease', (136, 148))	('eye disease', 'Phenotype', 'HP:0000478', (136, 147))	('epigenetic alterations', 'Var', (93, 115))
145356	23206928	Additionally, there is a correlation between uveal melanomas with a monosomy 3 karyotype and an inflammatory phenotype including the presence of TAMs.	('uveal melanomas', 'Disease', 'MESH:C536494', (45, 60))	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('monosomy 3 karyotype', 'Var', (68, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('uveal melanomas', 'Disease', (45, 60))	('TAMs', 'Disease', (145, 149))	('uveal melanomas', 'Phenotype', 'HP:0007716', (45, 60))	('TAMs', 'Chemical', '-', (145, 149))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))
145357	23206928	TAMs in uveal melanomas with a monosomy 3 karyotype are predominantly pro-angiogenic M2 polarized macrophages.	('TAMs', 'Chemical', '-', (0, 4))	('uveal melanomas', 'Disease', 'MESH:C536494', (8, 23))	('monosomy 3 karyotype', 'Var', (31, 51))	('uveal melanoma', 'Phenotype', 'HP:0007716', (8, 22))	('melanomas', 'Phenotype', 'HP:0002861', (14, 23))	('uveal melanomas', 'Disease', (8, 23))	('uveal melanomas', 'Phenotype', 'HP:0007716', (8, 23))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
145398	23206928	A larger basal diameter was found in tumors with a high M2/M1 ratio as seen by a regression line (R2 Linear = 0.191).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('basal diameter', 'CPA', (9, 23))	('larger', 'PosReg', (2, 8))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('high', 'Var', (51, 55))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
145409	23206928	Our hypothesis was based on a previous study that detected more M2 macrophages in uveal melanomas with monosomy 3 than in uveal melanomas with disomy 3 and the finding that the RNA profile can predict prognosis in analogy to chromosome 3 status.	('RNA', 'cellular_component', 'GO:0005562', ('177', '180'))	('M2 macrophages', 'CPA', (64, 78))	('uveal melanomas', 'Disease', (82, 97))	('uveal melanomas', 'Phenotype', 'HP:0007716', (82, 97))	('melanomas', 'Phenotype', 'HP:0002861', (128, 137))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('more', 'PosReg', (59, 63))	('uveal melanomas', 'Disease', (122, 137))	('monosomy 3', 'Var', (103, 113))	('uveal melanomas', 'Phenotype', 'HP:0007716', (122, 137))	('uveal melanoma', 'Phenotype', 'HP:0007716', (122, 136))	('uveal melanomas', 'Disease', 'MESH:C536494', (82, 97))	('chromosome', 'cellular_component', 'GO:0005694', ('225', '235'))	('uveal melanomas', 'Disease', 'MESH:C536494', (122, 137))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))
145414	23206928	In our study, areas in the tumor that were infiltrated by macrophages were counted to assess their polarization in order to build ratios of M2/M1 MPhi.	('tumor', 'Disease', (27, 32))	('M2/M1', 'Var', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))
145423	23206928	Activation of the MAPK pathway, that is itself activated by GNAQ mutations, has been found to be commonly involved in the development of uveal melanoma.	('GNAQ', 'Gene', (60, 64))	('MAPK', 'Gene', '5594', (18, 22))	('involved', 'Reg', (106, 114))	('MAPK', 'Gene', (18, 22))	('uveal melanoma', 'Disease', (137, 151))	('Activation', 'PosReg', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('GNAQ', 'Gene', '2776', (60, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (137, 151))	('uveal melanoma', 'Disease', 'MESH:C536494', (137, 151))	('mutations', 'Var', (65, 74))	('MAPK', 'molecular_function', 'GO:0004707', ('18', '22'))
145426	23206928	Metastases from skin melanoma with a high PPAR-gamma expression were associated with a longer progression-free survival and a better response to biomodulatory therapy compared to metastases with a lower PPAR-gamma expression.	('PPAR-gamma', 'Gene', (42, 52))	('skin melanoma', 'Disease', 'MESH:D008545', (16, 29))	('PPAR-gamma', 'Gene', '5468', (42, 52))	('high', 'Var', (37, 41))	('PPAR-gamma', 'Gene', '5468', (203, 213))	('Metastases', 'Disease', 'MESH:D009362', (0, 10))	('progression-free survival', 'CPA', (94, 119))	('Metastases', 'Disease', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('metastases', 'Disease', (179, 189))	('longer', 'PosReg', (87, 93))	('skin melanoma', 'Disease', (16, 29))	('metastases', 'Disease', 'MESH:D009362', (179, 189))	('PPAR-gamma', 'Gene', (203, 213))
145449	33007931	The aim of the study was to evaluate the expression of ephrin receptors EphA1, EphA5, and EphA7 in uveal melanoma and its associations with clinicopathological parameters, overall survival, and disease-free survival.	('associations', 'Interaction', (122, 134))	('ephrin', 'molecular_function', 'GO:0005106', ('55', '61'))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('EphA1', 'Gene', '2041', (72, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (99, 113))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('EphA7', 'Var', (90, 95))	('EphA1', 'Gene', (72, 77))	('ephrin', 'molecular_function', 'GO:0046875', ('55', '61'))	('uveal melanoma', 'Disease', (99, 113))	('EphA5', 'Gene', (79, 84))	('EphA5', 'Gene', '2044', (79, 84))
145453	33007931	High expression of EphA7 was associated with a more frequent primary tumor location in the posterior pole.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('EphA7', 'Gene', (19, 24))	('High', 'Var', (0, 4))	('tumor', 'Disease', (69, 74))	('associated', 'Reg', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
145469	33007931	The present study aimed to assess EphA1, EphA5, and EphA7 expression in uveal melanoma, combined with clinicopathological parameters, overall survival, and disease-free survival.	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('uveal melanoma', 'Disease', (72, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('EphA1', 'Gene', '2041', (34, 39))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('EphA1', 'Gene', (34, 39))	('EphA7', 'Var', (52, 57))	('EphA5', 'Gene', (41, 46))	('EphA5', 'Gene', '2044', (41, 46))
145471	33007931	High EphA1, EphA5, and EphA7 expression was noted in 26 (29.5%), 13 (14.3%), and 14 (15.6%) cases, respectively.	('EphA1', 'Gene', (5, 10))	('EphA5', 'Gene', (12, 17))	('EphA5', 'Gene', '2044', (12, 17))	('EphA7', 'Var', (23, 28))	('EphA1', 'Gene', '2041', (5, 10))
145473	33007931	The total high expression of EphA1 (Table 2) was statistically associated with smaller tumor size (p = 0.048), less frequently occurring extra-scleral infiltration (p = 0.030), lower mitotic activity (p = 0.042), and more frequent presence of hemorrhage in the vitreous chamber (p = 0.014).	('lower', 'NegReg', (177, 182))	('EphA1', 'Gene', (29, 34))	('vitreous chamber', 'Phenotype', 'HP:0100832', (261, 277))	('hemorrhage', 'Disease', 'MESH:D006470', (243, 253))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('smaller', 'NegReg', (79, 86))	('hemorrhage in the vitreous', 'Phenotype', 'HP:0007902', (243, 269))	('high expression', 'Var', (10, 25))	('mitotic activity', 'CPA', (183, 199))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('hemorrhage', 'Disease', (243, 253))	('EphA1', 'Gene', '2041', (29, 34))
145475	33007931	Moreover, high reaction intensity showed significant associations with absence of distant metastases (p = 0.045).	('absence', 'NegReg', (71, 78))	('metastases', 'Disease', (90, 100))	('high', 'Var', (10, 14))	('metastases', 'Disease', 'MESH:D009362', (90, 100))
145476	33007931	Total high EphA5 expression (Table 3) was associated with less frequent loss of chromosome 3 (p < 0.001), absence of distant metastases (p = 0.010), and more frequent occurrence of vitreous hemorrhage (p = 0.013).	('metastases', 'Disease', (125, 135))	('loss', 'NegReg', (72, 76))	('vitreous hemorrhage', 'Phenotype', 'HP:0007902', (181, 200))	('frequent occurrence of vitreous', 'Phenotype', 'HP:0100832', (158, 189))	('metastases', 'Disease', 'MESH:D009362', (125, 135))	('vitreous hemorrhage', 'Disease', (181, 200))	('vitreous hemorrhage', 'Disease', 'MESH:D014823', (181, 200))	('chromosome', 'cellular_component', 'GO:0005694', ('80', '90'))	('high', 'Var', (6, 10))	('EphA5', 'Gene', (11, 16))	('EphA5', 'Gene', '2044', (11, 16))
145477	33007931	A trend of correlation between total EphA5 expression and lower mitotic activity was observed (p = 0.075), but high reaction intensity was statistically significant associated with lower mitotic activity (p = 0.023).	('mitotic activity', 'CPA', (64, 80))	('EphA5', 'Gene', (37, 42))	('EphA5', 'Gene', '2044', (37, 42))	('lower', 'NegReg', (58, 63))	('high reaction', 'Var', (111, 124))	('lower', 'NegReg', (181, 186))	('mitotic activity', 'CPA', (187, 203))
145479	33007931	Kaplan-Meier survival curves indicated that uveal melanoma patients with high EphA5 expression presented significantly longer overall survival periods compared to those presenting low EphA5 expression (Figure 1, p = 0.031).	('EphA5', 'Gene', (184, 189))	('EphA5', 'Gene', '2044', (184, 189))	('EphA5', 'Gene', (78, 83))	('longer', 'PosReg', (119, 125))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('EphA5', 'Gene', '2044', (78, 83))	('patients', 'Species', '9606', (59, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('overall survival periods', 'CPA', (126, 150))	('high', 'Var', (73, 77))	('uveal melanoma', 'Disease', (44, 58))
145480	33007931	Also, high EphA5 expression showed a trend of correlation with higher probability of longer disease-free survival (Figure 2, p = 0.083).	('expression', 'MPA', (17, 27))	('high', 'Var', (6, 10))	('EphA5', 'Gene', (11, 16))	('EphA5', 'Gene', '2044', (11, 16))	('disease-free survival', 'CPA', (92, 113))
145493	33007931	In clear-cell renal cell carcinoma, high expression of EphA1 is significantly associated with young age, sex, and higher histopathological grade.	('associated', 'Reg', (78, 88))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (14, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (3, 34))	('clear-cell renal cell carcinoma', 'Disease', (3, 34))	('EphA1', 'Gene', '2041', (55, 60))	('EphA1', 'Gene', (55, 60))	('high', 'Var', (36, 40))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 34))
145494	33007931	In gastric cancer, high expression of EphA1 is associated with lower tumor histological differentiation, the presence of lymph node and distant metastasis.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('high', 'Var', (19, 23))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('lower', 'NegReg', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', (69, 74))	('EphA1', 'Gene', '2041', (38, 43))	('EphA1', 'Gene', (38, 43))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
145496	33007931	In gastric cancers, high expression of EphA1 is an independent prognostic factor.	('EphA1', 'Gene', '2041', (39, 44))	('EphA1', 'Gene', (39, 44))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('gastric cancers', 'Disease', 'MESH:D013274', (3, 18))	('gastric cancers', 'Disease', (3, 18))	('gastric cancers', 'Phenotype', 'HP:0012126', (3, 18))	('high', 'Var', (20, 24))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))
145498	33007931	In squamous cell carcinoma of the tongue, high expression of EphA1 is associated with poorer tumor vasculature and less frequent lymph node metastasis.	('squamous cell carcinoma', 'Disease', (3, 26))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 26))	('squamous cell carcinoma of the tongue', 'Phenotype', 'HP:0030413', (3, 40))	('EphA1', 'Gene', '2041', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('EphA1', 'Gene', (61, 66))	('tumor', 'Disease', (93, 98))	('high expression', 'Var', (42, 57))	('cell carcinoma of the tongue', 'Phenotype', 'HP:0030415', (12, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (3, 26))	('frequent lymph node', 'Phenotype', 'HP:0032536', (120, 139))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
145499	33007931	Analysis of the results of this study showed that in uveal melanomas, high expression of EphA1 is associated with lower mitotic activity, smaller tumor size, less frequent extra-scleral infiltration, and less frequent loss of chromosome 3.	('extra-scleral infiltration', 'CPA', (172, 198))	('chromosome', 'cellular_component', 'GO:0005694', ('226', '236'))	('uveal melanomas', 'Disease', 'MESH:C536494', (53, 68))	('EphA1', 'Gene', '2041', (89, 94))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mitotic activity', 'CPA', (120, 136))	('loss', 'NegReg', (218, 222))	('tumor', 'Disease', (146, 151))	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('EphA1', 'Gene', (89, 94))	('lower', 'NegReg', (114, 119))	('high', 'Var', (70, 74))	('melanomas', 'Phenotype', 'HP:0002861', (59, 68))	('uveal melanomas', 'Disease', (53, 68))	('uveal melanomas', 'Phenotype', 'HP:0007716', (53, 68))	('expression', 'MPA', (75, 85))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
145501	33007931	In pancreatic adenocarcinomas, patients with moderate or high EphA5 and EphA7 expression had shorter survival times compared to the low-expression group.	('EphA5', 'Gene', '2044', (62, 67))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D000230', (3, 29))	('pancreatic adenocarcinomas', 'Disease', (3, 29))	('high', 'Var', (57, 61))	('EphA7', 'Protein', (72, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('survival times', 'CPA', (101, 115))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (3, 29))	('shorter', 'NegReg', (93, 100))	('patients', 'Species', '9606', (31, 39))	('EphA5', 'Gene', (62, 67))
145507	33007931	In uveal melanoma, as with EphA1, high EphA5 expression is also a favorable prognostic factor.	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('EphA5', 'Gene', (39, 44))	('EphA5', 'Gene', '2044', (39, 44))	('EphA1', 'Gene', '2041', (27, 32))	('high', 'Var', (34, 38))	('EphA1', 'Gene', (27, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
145508	33007931	High expression has been shown to be associated with less frequent chromosome 3 loss, lower mitotic activity, and less frequent distant metastases.	('chromosome', 'cellular_component', 'GO:0005694', ('67', '77'))	('mitotic activity', 'CPA', (92, 108))	('High', 'Var', (0, 4))	('loss', 'NegReg', (80, 84))	('lower', 'NegReg', (86, 91))	('chromosome 3', 'Protein', (67, 79))	('metastases', 'Disease', (136, 146))	('metastases', 'Disease', 'MESH:D009362', (136, 146))
145509	33007931	A tendency to lower histopathological grade was also observed in tumors with high EphA5 expression.	('high', 'Var', (77, 81))	('lower', 'NegReg', (14, 19))	('EphA5', 'Gene', (82, 87))	('EphA5', 'Gene', '2044', (82, 87))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('histopathological grade', 'CPA', (20, 43))
145516	33007931	In turn, studies on glioblastoma have shown that patients with tumors expressing EphA7 have shorter survival times compared to the non-expressed group, and the degree of expression inversely correlates with survival.	('EphA7', 'Var', (81, 86))	('survival times', 'CPA', (100, 114))	('glioblastoma', 'Disease', (20, 32))	('glioblastoma', 'Disease', 'MESH:D005909', (20, 32))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (20, 32))	('patients', 'Species', '9606', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('shorter', 'NegReg', (92, 99))
145518	33007931	These observations confirm the role of high EphA5 expression as a favorable prognostic factor.	('EphA5', 'Gene', '2044', (44, 49))	('EphA5', 'Gene', (44, 49))	('high', 'Var', (39, 43))	('expression', 'MPA', (50, 60))
145556	31474574	Disease-Causing Mutations in SF3B1 Alter Splicing by Disrupting Interaction with SUGP1 SF3B1, which encodes an essential spliceosomal protein, is frequently mutated in myelodysplastic syndromes (MDS) and many cancers.	('Disrupting', 'NegReg', (53, 63))	('SF3B1', 'Gene', '23451', (29, 34))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (168, 193))	('spliceosomal protein', 'Gene', '10262', (121, 141))	('MDS', 'Disease', (195, 198))	('SF3B1', 'Gene', (87, 92))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('Interaction', 'Interaction', (64, 75))	('Alter', 'Reg', (35, 40))	('Mutations', 'Var', (16, 25))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('SF3B1', 'Gene', '23451', (87, 92))	('SF3B1', 'Gene', (29, 34))	('Splicing', 'biological_process', 'GO:0045292', ('41', '49'))	('spliceosomal protein', 'Gene', (121, 141))	('Splicing', 'MPA', (41, 49))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (168, 193))	('cancers', 'Disease', (209, 216))	('myelodysplastic syndromes', 'Disease', (168, 193))	('MDS', 'Disease', 'MESH:D009190', (195, 198))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
145557	31474574	However, the defect of mutant SF3B1 is unknown.	('SF3B1', 'Gene', (30, 35))	('SF3B1', 'Gene', '23451', (30, 35))	('mutant', 'Var', (23, 29))
145558	31474574	Here, we analyzed RNA-sequencing data from MDS patients and confirmed that SF3B1 mutants use aberrant 3' splice sites.	('RNA', 'cellular_component', 'GO:0005562', ('18', '21'))	('patients', 'Species', '9606', (47, 55))	('SF3B1', 'Gene', '23451', (75, 80))	('MDS', 'Disease', (43, 46))	('MDS', 'Disease', 'MESH:D009190', (43, 46))	('mutants', 'Var', (81, 88))	('SF3B1', 'Gene', (75, 80))
145559	31474574	To elucidate the underlying mechanism, we purified complexes containing either wild-type or the hotspot K700E mutant SF3B1, and found that levels of a poorly studied spliceosomal protein, SUGP1, were reduced in mutant spliceosomes.	('K700E', 'Var', (104, 109))	('K700E', 'Mutation', 'rs559063155', (104, 109))	('levels', 'MPA', (139, 145))	('spliceosomal protein', 'Gene', (166, 186))	('reduced', 'NegReg', (200, 207))	('SF3B1', 'Gene', (117, 122))	('mutant', 'Var', (211, 217))	('spliceosomal protein', 'Gene', '10262', (166, 186))	('SF3B1', 'Gene', '23451', (117, 122))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))
145561	31474574	Other hotspot SF3B1 mutants showed similar altered splicing and diminished interaction with SUGP1.	('mutants', 'Var', (20, 27))	('diminished', 'NegReg', (64, 74))	('SF3B1', 'Gene', (14, 19))	('splicing', 'biological_process', 'GO:0045292', ('51', '59'))	('splicing', 'MPA', (51, 59))	('SF3B1', 'Gene', '23451', (14, 19))	('interaction', 'Interaction', (75, 86))	('altered', 'Reg', (43, 50))
145562	31474574	Our study demonstrates that SUGP1 loss is a common defect of spliceosomes with disease-causing SF3B1 mutations and, since this defect can be rescued, suggests possibilities for therapeutic intervention.	('mutations', 'Var', (101, 110))	('SF3B1', 'Gene', (95, 100))	('SF3B1', 'Gene', '23451', (95, 100))	('SUGP1', 'Gene', (28, 33))	('loss', 'NegReg', (34, 38))
145563	31474574	report that SF3B1 mutations found in myelodysplastic syndromes and many cancers disrupt interaction with splicing factor SUGP1 during branchsite recognition, leading to aberrant use of upstream branch points and cryptic 3' splice sites during RNA splicing.	('SF3B1', 'Gene', (12, 17))	('splicing', 'biological_process', 'GO:0045292', ('105', '113'))	('cryptic', 'Gene', '55997', (212, 219))	('branchsite', 'Disease', 'None', (134, 144))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('RNA splicing', 'biological_process', 'GO:0008380', ('243', '255'))	('cryptic', 'Gene', (212, 219))	('cancers', 'Disease', (72, 79))	('splicing factor', 'Gene', '10569', (105, 120))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (37, 62))	('myelodysplastic syndromes', 'Disease', (37, 62))	('RNA', 'cellular_component', 'GO:0005562', ('243', '246'))	('SF3B1', 'Gene', '23451', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('branchsite', 'Disease', (134, 144))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (37, 62))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('upstream branch points', 'MPA', (185, 207))	('use', 'MPA', (178, 181))	('disrupt', 'NegReg', (80, 87))	('splicing factor', 'Gene', (105, 120))	('interaction', 'Interaction', (88, 99))	('mutations', 'Var', (18, 27))
145564	31474574	This defect in splicing due to cancer-causing SF3B1 mutations is rescuable.	('mutations', 'Var', (52, 61))	('splicing', 'MPA', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('SF3B1', 'Gene', (46, 51))	('cancer', 'Disease', (31, 37))	('splicing', 'biological_process', 'GO:0045292', ('15', '23'))	('SF3B1', 'Gene', '23451', (46, 51))
145565	31474574	One of the most surprising and exciting findings from the sequencing of many cancer genomes in recent years has been the identification of frequent mutations in genes encoding splicing factors, such as SF3B1 (splicing factor 3b subunit 1), SRSF2 (serine and arginine rich splicing factor 2), and U2AF1 (U2 small nuclear RNA auxiliary factor 1).	('splicing factor', 'Gene', '10569', (209, 224))	('splicing factor', 'Gene', (176, 191))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('splicing factor', 'Gene', '10569', (272, 287))	('SF3B1', 'Gene', (202, 207))	('small nuclear RNA', 'molecular_function', 'GO:0005570', ('306', '323'))	('splicing', 'biological_process', 'GO:0045292', ('209', '217'))	('U2AF1', 'Gene', (296, 301))	('splicing', 'biological_process', 'GO:0045292', ('272', '280'))	('splicing factor 3b subunit 1', 'Gene', '23451', (209, 237))	('SF3B1', 'Gene', '23451', (202, 207))	('splicing factor', 'Gene', '10569', (176, 191))	('SRSF2', 'Gene', '6427', (240, 245))	('mutations', 'Var', (148, 157))	('U2AF1', 'Gene', '7307', (296, 301))	('cancer', 'Disease', (77, 83))	('SRSF2', 'Gene', (240, 245))	('RNA', 'cellular_component', 'GO:0005562', ('320', '323'))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('splicing', 'biological_process', 'GO:0045292', ('176', '184'))	('U2AF', 'cellular_component', 'GO:0089701', ('296', '300'))	('splicing factor', 'Gene', (272, 287))	('splicing factor 3b subunit 1', 'Gene', (209, 237))	('serine and arginine rich splicing factor 2', 'Gene', '6427', (247, 289))
145566	31474574	Despite rapid advances in research on their roles in misregulation of RNA splicing and in pathogenesis, no therapeutic interventions have been developed for any of the cancers harboring splicing factor mutations.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('RNA splicing', 'MPA', (70, 82))	('splicing factor', 'Gene', (186, 201))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('splicing', 'biological_process', 'GO:0045292', ('186', '194'))	('cancers', 'Disease', (168, 175))	('pathogenesis', 'biological_process', 'GO:0009405', ('90', '102'))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('RNA splicing', 'biological_process', 'GO:0008380', ('70', '82'))	('splicing factor', 'Gene', '10569', (186, 201))	('misregulation', 'Var', (53, 66))	('RNA', 'cellular_component', 'GO:0005562', ('70', '73'))
145568	31474574	Mutations in SF3B1 occur in about one third of patients with myelodysplastic syndromes (MDS) overall and in more than 80% of patients with the subtypes of MDS with ring sideroblasts.	('MDS', 'Disease', (155, 158))	('MDS', 'Disease', 'MESH:D009190', (155, 158))	('ring sideroblasts', 'Phenotype', 'HP:0004828', (164, 181))	('SF3B1', 'Gene', (13, 18))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (61, 86))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (61, 86))	('patients', 'Species', '9606', (47, 55))	('myelodysplastic syndromes', 'Disease', (61, 86))	('Mutations', 'Var', (0, 9))	('MDS', 'Disease', (88, 91))	('SF3B1', 'Gene', '23451', (13, 18))	('MDS', 'Disease', 'MESH:D009190', (88, 91))	('occur', 'Reg', (19, 24))	('patients', 'Species', '9606', (125, 133))
145569	31474574	SF3B1 mutations have been found also in chronic lymphocytic leukemia (CLL), uveal melanoma, as well as breast and many other cancers.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('chronic lymphocytic leukemia', 'Disease', (40, 68))	('leukemia', 'Phenotype', 'HP:0001909', (60, 68))	('SF3B1', 'Gene', (0, 5))	('cancers', 'Disease', (125, 132))	('uveal melanoma', 'Disease', 'MESH:C536494', (76, 90))	('uveal melanoma', 'Phenotype', 'HP:0007716', (76, 90))	('breast', 'Disease', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('uveal melanoma', 'Disease', (76, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('SF3B1', 'Gene', '23451', (0, 5))	('found', 'Reg', (26, 31))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (40, 68))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (40, 68))	('mutations', 'Var', (6, 15))
145570	31474574	Although there have been reports characterizing RNA missplicing induced by SF3B1 mutations, the defect of the mutant SF3B1 spliceosome is still unknown.	('RNA', 'cellular_component', 'GO:0005562', ('48', '51'))	('induced', 'Reg', (64, 71))	('spliceosome', 'cellular_component', 'GO:0005681', ('123', '134'))	('RNA missplicing', 'MPA', (48, 63))	('SF3B1', 'Gene', '23451', (75, 80))	('SF3B1', 'Gene', (117, 122))	('mutations', 'Var', (81, 90))	('SF3B1', 'Gene', '23451', (117, 122))	('SF3B1', 'Gene', (75, 80))
145573	31474574	The U2 snRNP complex is then recruited and its RNA component, U2 snRNA, interacts with the branchsite through base pairing in an ATP-dependent manner, leading to displacement of SF1 from the branchsite by p14, the branchsite binding protein in the U2 snRNP complex.	('p14', 'Gene', '51639', (205, 208))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('4', '12'))	('SF1', 'Gene', '7536', (178, 181))	('branchsite', 'Disease', 'None', (214, 224))	('snRNP', 'Gene', (251, 256))	('branchsite', 'Disease', 'None', (191, 201))	('RNA', 'cellular_component', 'GO:0005562', ('47', '50'))	('snRNP', 'Gene', '57819', (251, 256))	('branchsite', 'Disease', (191, 201))	('branchsite', 'Disease', (214, 224))	('ATP', 'Chemical', 'MESH:D000255', (129, 132))	('displacement', 'Var', (162, 174))	('protein', 'cellular_component', 'GO:0003675', ('233', '240'))	('branchsite', 'Disease', 'None', (91, 101))	('binding', 'molecular_function', 'GO:0005488', ('225', '232'))	('snRNP', 'molecular_function', 'GO:0003734', ('251', '256'))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('248', '256'))	('snRNP', 'molecular_function', 'GO:0003734', ('7', '12'))	('base pairing', 'molecular_function', 'GO:0003676', ('110', '122'))	('branchsite', 'Disease', (91, 101))	('p14', 'Gene', (205, 208))	('snRNP', 'Gene', (7, 12))	('SF1', 'Gene', (178, 181))	('snRNP', 'Gene', '57819', (7, 12))
145578	31474574	The C-terminal two-thirds consists largely of 20 tandem HEAT (Huntingtin, elongation factor 3, a subunit of protein phosphatase 2A, PI3 kinase target of rapamycin 1) repeats that form rod-like helical structures, providing a major scaffold within U2 snRNP for interactions with other SF3b subunits, including p14.	('interactions', 'Interaction', (260, 272))	('rapamycin', 'Chemical', 'MESH:D020123', (153, 162))	('snRNP', 'Gene', (250, 255))	('p14', 'Gene', (309, 312))	('snRNP', 'Gene', '57819', (250, 255))	('protein phosphatase 2A', 'molecular_function', 'GO:0050115', ('108', '130'))	('Huntingtin', 'Gene', '3064', (62, 72))	('Huntingtin', 'Gene', (62, 72))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('247', '255'))	('snRNP', 'molecular_function', 'GO:0003734', ('250', '255'))	('p14', 'Gene', '51639', (309, 312))	('repeats', 'Var', (166, 173))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
145579	31474574	Because of the complexity and highly dynamic nature of protein-protein, protein-RNA, and RNA-RNA interactions involved in spliceosome assembly, it has been a great challenge to identify the defect caused by SF3B1 mutations.	('SF3B1', 'Gene', (207, 212))	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('spliceosome', 'cellular_component', 'GO:0005681', ('122', '133'))	('spliceosome assembly', 'biological_process', 'GO:0000245', ('122', '142'))	('SF3B1', 'Gene', '23451', (207, 212))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('RNA', 'cellular_component', 'GO:0005562', ('89', '92'))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('RNA', 'cellular_component', 'GO:0005562', ('93', '96'))	('mutations', 'Var', (213, 222))	('RNA', 'cellular_component', 'GO:0005562', ('80', '83'))
145580	31474574	Almost all mutations in SF3B1 are located in the HEAT domain and are heterozygous missense substitutions with the absence of nonsense mutations, suggesting that the mutations likely affect specific function(s) related to this domain rather than cause a complete loss of SF3B1 function.	('mutations', 'Var', (11, 20))	('SF3B1', 'Gene', (270, 275))	('SF3B1', 'Gene', (24, 29))	('SF3B1', 'Gene', '23451', (270, 275))	('specific function', 'MPA', (189, 206))	('mutations', 'Var', (165, 174))	('function', 'MPA', (276, 284))	('SF3B1', 'Gene', '23451', (24, 29))	('affect', 'Reg', (182, 188))
145581	31474574	Nine residues in H4-H8 (including the most frequently mutated residue, K700) are clustered in a small area and are exposed to solvent, suggesting that the mutations may disrupt SF3B1 interactions with other spliceosomal protein(s) rather than with SF3b subunits.	('mutations', 'Var', (155, 164))	('disrupt', 'NegReg', (169, 176))	('SF3B1', 'Gene', '23451', (177, 182))	('protein', 'cellular_component', 'GO:0003675', ('220', '227'))	('interactions', 'Interaction', (183, 195))	('spliceosomal protein', 'Gene', (207, 227))	('spliceosomal protein', 'Gene', '10262', (207, 227))	('SF3B1', 'Gene', (177, 182))
145583	31474574	However, this region is not conserved in humans, and the human SF3B1 K700 residue is not conserved in budding yeast.	('budding', 'biological_process', 'GO:0007114', ('102', '109'))	('K700', 'Var', (69, 73))	('SF3B1', 'Gene', (63, 68))	('human', 'Species', '9606', (57, 62))	('human', 'Species', '9606', (41, 46))	('SF3B1', 'Gene', '23451', (63, 68))	('humans', 'Species', '9606', (41, 47))	('yeast', 'Species', '4932', (110, 115))
145584	31474574	Therefore, it is still unknown how SF3B1 mutations affect protein interactions in the spliceosome in human diseases.	('protein', 'Protein', (58, 65))	('mutations', 'Var', (41, 50))	('SF3B1', 'Gene', '23451', (35, 40))	('affect', 'Reg', (51, 57))	('human', 'Species', '9606', (101, 106))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('SF3B1', 'Gene', (35, 40))	('spliceosome', 'cellular_component', 'GO:0005681', ('86', '97'))
145585	31474574	In this study, we identified the defect of the mutant SF3B1 spliceosome responsible for the errors in splicing.	('SF3B1', 'Gene', (54, 59))	('spliceosome', 'cellular_component', 'GO:0005681', ('60', '71'))	('splicing', 'MPA', (102, 110))	('SF3B1', 'Gene', '23451', (54, 59))	('splicing', 'biological_process', 'GO:0045292', ('102', '110'))	('mutant', 'Var', (47, 53))
145586	31474574	We used affinity purification to isolate spliceosomal complexes associated with either wild-type (WT) or the hotspot K700E mutant SF3B1.	('K700E', 'Mutation', 'rs559063155', (117, 122))	('SF3B1', 'Gene', (130, 135))	('SF3B1', 'Gene', '23451', (130, 135))	('K700E', 'Var', (117, 122))
145587	31474574	We identified the proteins by mass spectrometry and found that levels of the spliceosomal protein SUGP1 (SURP and G-patch domain containing 1) were greatly reduced in the mutant SF3B1 spliceosome.	('levels', 'MPA', (63, 69))	('SUGP1', 'Gene', (98, 103))	('spliceosomal protein', 'Gene', '10262', (77, 97))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('SF3B1', 'Gene', (178, 183))	('reduced', 'NegReg', (156, 163))	('SF3B1', 'Gene', '23451', (178, 183))	('mutant', 'Var', (171, 177))	('spliceosome', 'cellular_component', 'GO:0005681', ('184', '195'))	('spliceosomal protein', 'Gene', (77, 97))
145588	31474574	We then show that knockdown (KD) of SUGP1, but not a large number of other SF3B1-associated proteins, or overexpression of a specific dominant negative mutant of SUGP1 with a mutated G-patch domain, completely recapitulated the splicing errors induced by mutant SF3B1.	('splicing errors', 'MPA', (228, 243))	('negative', 'NegReg', (143, 151))	('mutant', 'Var', (255, 261))	('SF3B1', 'Gene', '23451', (262, 267))	('SF3B1', 'Gene', '23451', (75, 80))	('splicing', 'biological_process', 'GO:0045292', ('228', '236'))	('SF3B1', 'Gene', (262, 267))	('recapitulated', 'NegReg', (210, 223))	('SUGP1', 'Gene', (162, 167))	('mutated', 'Var', (175, 182))	('SF3B1', 'Gene', (75, 80))
145589	31474574	Finally, we show that several additional hotspot mutations in SF3B1 behave the same way as K700E.	('K700E', 'Mutation', 'rs559063155', (91, 96))	('SF3B1', 'Gene', (62, 67))	('SF3B1', 'Gene', '23451', (62, 67))	('K700E', 'Var', (91, 96))
145590	31474574	Our study thus establishes that loss of SUGP1 is a common defect of spliceosomes with cancer-associated SF3B1 mutations, that the loss solely accounts for the splicing errors caused by SF3B1 mutations, and that this defect is potentially amenable to rescue, providing a molecular basis for developing treatments for mutant SF3B1 cancers.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('SF3B1', 'Gene', (185, 190))	('defect', 'MPA', (58, 64))	('spliceosomes', 'MPA', (68, 80))	('mutations', 'Var', (191, 200))	('SUGP1', 'Gene', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('cancers', 'Disease', 'MESH:D009369', (329, 336))	('SF3B1', 'Gene', '23451', (185, 190))	('SF3B1', 'Gene', (104, 109))	('splicing errors', 'MPA', (159, 174))	('cancer', 'Disease', (86, 92))	('mutations', 'Var', (110, 119))	('loss', 'NegReg', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('SF3B1', 'Gene', (323, 328))	('SF3B1', 'Gene', '23451', (104, 109))	('splicing', 'biological_process', 'GO:0045292', ('159', '167'))	('cancers', 'Phenotype', 'HP:0002664', (329, 336))	('cancer', 'Disease', (329, 335))	('cancers', 'Disease', (329, 336))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('SF3B1', 'Gene', '23451', (323, 328))
145591	31474574	To gain insights into the splicing defect of the mutant SF3B1 spliceosome in cancer, we began by analyzing RNA-sequencing data from MDS patient samples.	('patient', 'Species', '9606', (136, 143))	('mutant', 'Var', (49, 55))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('MDS', 'Disease', (132, 135))	('MDS', 'Disease', 'MESH:D009190', (132, 135))	('spliceosome', 'cellular_component', 'GO:0005681', ('62', '73'))	('splicing', 'biological_process', 'GO:0045292', ('26', '34'))	('RNA', 'cellular_component', 'GO:0005562', ('107', '110'))	('SF3B1', 'Gene', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('SF3B1', 'Gene', '23451', (56, 61))
145593	31474574	The analysis was applied to six MDS patients harboring SF3B1 mutations in the HEAT domain (three K700E, two D781G, and one H662D) and nine MDS patients carrying WT SF3B1.	('SF3B1', 'Gene', '23451', (55, 60))	('K700E', 'Var', (97, 102))	('patients', 'Species', '9606', (36, 44))	('SF3B1', 'Gene', (164, 169))	('MDS', 'Disease', (32, 35))	('MDS', 'Disease', 'MESH:D009190', (32, 35))	('MDS', 'Disease', (139, 142))	('patients', 'Species', '9606', (143, 151))	('MDS', 'Disease', 'MESH:D009190', (139, 142))	('H662D', 'Mutation', 'p.H662D', (123, 128))	('SF3B1', 'Gene', '23451', (164, 169))	('SF3B1', 'Gene', (55, 60))	('D781G', 'Mutation', 'rs756424171', (108, 113))	('D781G', 'Var', (108, 113))	('K700E', 'Mutation', 'rs559063155', (97, 102))
145594	31474574	Using a cutoff q value less than 0.05, we identified 1,145 novel (i.e., not annotated previously) cryptic 3'ss more frequently used in mutant SF3B1 samples and 186 cryptic 3'ss in WT SF3B1 samples (Figure 1A).	('SF3B1', 'Gene', '23451', (183, 188))	('SF3B1', 'Gene', '23451', (142, 147))	('mutant', 'Var', (135, 141))	('cryptic', 'Gene', '55997', (98, 105))	('cryptic', 'Gene', (164, 171))	('cryptic', 'Gene', (98, 105))	('SF3B1', 'Gene', (142, 147))	('cryptic', 'Gene', '55997', (164, 171))	('SF3B1', 'Gene', (183, 188))
145595	31474574	The cryptic 3'ss used in WT SF3B1 samples are widely distributed around the corresponding canonical 3'ss, whereas the great majority of the cryptic 3'ss used in mutant SF3B1 samples are located ~10-30 nt upstream of canonical 3'ss (Figure 1A), consistent with previous observations in CLL, uveal melanoma, and breast cancer.	('mutant', 'Var', (161, 167))	('CLL', 'Disease', (285, 288))	('SF3B1', 'Gene', '23451', (168, 173))	('SF3B1', 'Gene', (28, 33))	('SF3B1', 'Gene', (168, 173))	('uveal melanoma', 'Disease', 'MESH:C536494', (290, 304))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('cryptic', 'Gene', '55997', (140, 147))	('cryptic', 'Gene', '55997', (4, 11))	('SF3B1', 'Gene', '23451', (28, 33))	('uveal melanoma', 'Disease', (290, 304))	('cryptic', 'Gene', (140, 147))	('cryptic', 'Gene', (4, 11))	('breast cancer', 'Disease', (310, 323))	('breast cancer', 'Disease', 'MESH:D001943', (310, 323))	('uveal melanoma', 'Phenotype', 'HP:0007716', (290, 304))	('breast cancer', 'Phenotype', 'HP:0003002', (310, 323))	('melanoma', 'Phenotype', 'HP:0002861', (296, 304))
145597	31474574	Unsupervised clustering of these 3'ss clearly separated SF3B1 mutants from WT SF3B1, suggesting that the different SF3B1 mutations all consistently led to missplicing involving aberrant 3'ss usage (Figure 1B).	('mutations', 'Var', (121, 130))	('SF3B1', 'Gene', '23451', (78, 83))	('led to', 'Reg', (148, 154))	('SF3B1', 'Gene', (56, 61))	('SF3B1', 'Gene', (115, 120))	('missplicing', 'MPA', (155, 166))	('SF3B1', 'Gene', '23451', (115, 120))	("3'ss usage", 'MPA', (186, 196))	('SF3B1', 'Gene', '23451', (56, 61))	('SF3B1', 'Gene', (78, 83))
145598	31474574	By setting three stringent threshold parameters (q value < 0.05, closer than 50 nt upstream of the canonical 3'ss, and more than 15 supporting read counts), we obtained 169 high-confidence cryptic 3'ss differentially used by mutant vs. WT SF3B1 (Figure 1C and Table S1).	('SF3B1', 'Gene', '23451', (239, 244))	('mutant', 'Var', (225, 231))	('cryptic', 'Gene', '55997', (189, 196))	('cryptic', 'Gene', (189, 196))	('SF3B1', 'Gene', (239, 244))
145599	31474574	We first verified the mutant SF3B1-specific splicing defects using MDS patient cells and control samples (Figure 1D).	('SF3B1', 'Gene', '23451', (29, 34))	('splicing', 'MPA', (44, 52))	('MDS', 'Disease', (67, 70))	('MDS', 'Disease', 'MESH:D009190', (67, 70))	('mutant', 'Var', (22, 28))	('SF3B1', 'Gene', (29, 34))	('patient', 'Species', '9606', (71, 78))	('splicing', 'biological_process', 'GO:0045292', ('44', '52'))
145600	31474574	To rule out the possibility that the RNA splicing defects were the result of patients' complex genetic backgrounds in addition to the mutational status of SF3B1, we transiently overexpressed K700E SF3B1 in HEK293T cells and found that the use of upstream cryptic 3'ss was recapitulated (Figures 1E and 1F).	('SF3B1', 'Gene', '23451', (155, 160))	('K700E', 'Mutation', 'rs559063155', (191, 196))	('RNA splicing', 'biological_process', 'GO:0008380', ('37', '49'))	('SF3B1', 'Gene', '23451', (197, 202))	('K700E', 'Var', (191, 196))	('patients', 'Species', '9606', (77, 85))	('HEK293T', 'CellLine', 'CVCL:0063', (206, 213))	('SF3B1', 'Gene', (155, 160))	('cryptic', 'Gene', '55997', (255, 262))	('RNA', 'cellular_component', 'GO:0005562', ('37', '40'))	('cryptic', 'Gene', (255, 262))	('SF3B1', 'Gene', (197, 202))
145601	31474574	Finally, we constructed minigene reporters from four of the target genes with the relevant introns and flanking exons, and used these in cotransfection experiments with K700E or WT SF3B1 expression vector.	('K700E', 'Var', (169, 174))	('SF3B1', 'Gene', (181, 186))	('K700E', 'Mutation', 'rs559063155', (169, 174))	('SF3B1', 'Gene', '23451', (181, 186))
145603	31474574	Together, these results confirm that mutant SF3B1 is by itself sufficient to induce the 3'ss switch.	('SF3B1', 'Gene', (44, 49))	('SF3B1', 'Gene', '23451', (44, 49))	('mutant', 'Var', (37, 43))	("3'ss switch", 'CPA', (88, 99))	('induce', 'Reg', (77, 83))
145604	31474574	We next wished to identify the defect of the mutant SF3B1 spliceosome that is responsible for the RNA missplicing.	('mutant', 'Var', (45, 51))	('RNA', 'cellular_component', 'GO:0005562', ('98', '101'))	('SF3B1', 'Gene', (52, 57))	('SF3B1', 'Gene', '23451', (52, 57))	('spliceosome', 'cellular_component', 'GO:0005681', ('58', '69'))
145605	31474574	We hypothesized that SF3B1 mutations disrupt interactions with other spliceosomal protein(s) during assembly of the spliceosome, because all the hotspot mutations are localized in the HEAT domain, which functions as a major scaffold within U2 snRNP that facilitates the early events of spliceosome assembly.	('mutations', 'Var', (27, 36))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('spliceosomal protein', 'Gene', (69, 89))	('SF3B1', 'Gene', '23451', (21, 26))	('mutations', 'Var', (153, 162))	('spliceosome', 'cellular_component', 'GO:0005681', ('286', '297'))	('facilitates', 'PosReg', (254, 265))	('snRNP', 'molecular_function', 'GO:0003734', ('243', '248'))	('interactions', 'Interaction', (45, 57))	('SF3B1', 'Gene', (21, 26))	('spliceosome assembly', 'biological_process', 'GO:0000245', ('286', '306'))	('snRNP', 'Gene', (243, 248))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('240', '248'))	('snRNP', 'Gene', '57819', (243, 248))	('spliceosomal protein', 'Gene', '10262', (69, 89))	('spliceosome assembly', 'MPA', (286, 306))	('disrupt', 'NegReg', (37, 44))	('spliceosome', 'cellular_component', 'GO:0005681', ('116', '127'))
145606	31474574	To identify proteins differentially associated with mutant and WT SF3B1, we wished to perform affinity purification using cells expressing either K700E or WT SF3B1 with affinity tags.	('K700E', 'Var', (146, 151))	('mutant', 'Var', (52, 58))	('SF3B1', 'Gene', (158, 163))	('SF3B1', 'Gene', (66, 71))	('SF3B1', 'Gene', '23451', (158, 163))	('SF3B1', 'Gene', '23451', (66, 71))	('K700E', 'Mutation', 'rs559063155', (146, 151))
145607	31474574	To this end, we engineered K562 myelogenous leukemia cells using CRISPR/Cas9 technology to knock in the hotspot K700E mutation (or synonymous mutations for the WT control), followed by addition of mono-allelic His6 (hexahistidine)-FLAG tandem tags at the N-terminus of the knock-in SF3B1 allele (see STAR METHODS).	('His6', 'Chemical', 'MESH:C471213', (210, 214))	('K562', 'CellLine', 'CVCL:0004', (27, 31))	('K700E', 'Var', (112, 117))	('K700E', 'Mutation', 'rs559063155', (112, 117))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (32, 52))	('SF3B1', 'Gene', (282, 287))	('STAR', 'Gene', (300, 304))	('STAR', 'Gene', '6770', (300, 304))	('Cas', 'cellular_component', 'GO:0005650', ('72', '75'))	('leukemia', 'Phenotype', 'HP:0001909', (44, 52))	('leukemia', 'Disease', 'MESH:D007938', (44, 52))	('hexahistidine', 'Chemical', 'MESH:C471213', (216, 229))	('SF3B1', 'Gene', '23451', (282, 287))	('leukemia', 'Disease', (44, 52))
145608	31474574	Using RT-PCR, we confirmed that cells expressing the tagged K700E SF3B1 recapitulated the 3'ss switch (Figure 2A).	("3'ss switch", 'MPA', (90, 101))	('K700E', 'Var', (60, 65))	('SF3B1', 'Gene', (66, 71))	('K700E', 'Mutation', 'rs559063155', (60, 65))	('SF3B1', 'Gene', '23451', (66, 71))
145609	31474574	We next purified SF3B1 and associated spliceosomal proteins from extracts of the engineered K562 cells using two rounds of affinity purification with anti-DYKDDDDK antibody (for FLAG-tag) and cobalt beads (for His6-tag).	('anti-DYKDDDDK', 'Var', (150, 163))	('antibody', 'cellular_component', 'GO:0019815', ('164', '172'))	('spliceosomal protein', 'Gene', (38, 58))	('His6', 'Chemical', 'MESH:C471213', (210, 214))	('antibody', 'cellular_component', 'GO:0019814', ('164', '172'))	('SF3B1', 'Gene', (17, 22))	('antibody', 'molecular_function', 'GO:0003823', ('164', '172'))	('spliceosomal protein', 'Gene', '10262', (38, 58))	('SF3B1', 'Gene', '23451', (17, 22))	('cobalt', 'Chemical', 'MESH:D003035', (192, 198))	('antibody', 'cellular_component', 'GO:0042571', ('164', '172'))	('K562', 'CellLine', 'CVCL:0004', (92, 96))
145610	31474574	After partially resolving the recovered proteins by SDS-PAGE to remove cobalt ions (Figure 2B), we excised the entire gel lanes of both WT and K700E SF3B1 samples for mass spectrometry (MS) to identify all SF3B1-associated proteins.	('SDS', 'Chemical', 'MESH:D012967', (52, 55))	('SF3B1', 'Gene', '23451', (149, 154))	('cobalt', 'Chemical', 'MESH:D003035', (71, 77))	('SF3B1', 'Gene', (206, 211))	('K700E', 'Mutation', 'rs559063155', (143, 148))	('K700E', 'Var', (143, 148))	('SF3B1', 'Gene', (149, 154))	('SF3B1', 'Gene', '23451', (206, 211))
145611	31474574	Table S2 shows the identities of the 606 proteins (including 10 protein isoforms or fragments), of which 503 were in WT and 533 in K700E SF3B1 samples.	('K700E', 'Mutation', 'rs559063155', (131, 136))	('K700E', 'Var', (131, 136))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('SF3B1', 'Gene', (137, 142))	('SF3B1', 'Gene', '23451', (137, 142))
145612	31474574	To identify proteins differentially associated with WT and K700E SF3B1, we used stringent filtering to minimize false positives.	('false', 'biological_process', 'GO:0071877', ('112', '117'))	('SF3B1', 'Gene', (65, 70))	('K700E', 'Mutation', 'rs559063155', (59, 64))	('SF3B1', 'Gene', '23451', (65, 70))	('K700E', 'Var', (59, 64))	('false', 'biological_process', 'GO:0071878', ('112', '117'))
145613	31474574	We selected top candidates from proteins with at least 10 unique peptides recovered in either WT or K700E SF3B1 purification, and found three with a peptide ratio (K700E/WT) of less than or equal to 0.7 (Figure 2C).	('SF3B1', 'Gene', (106, 111))	('SF3B1', 'Gene', '23451', (106, 111))	('K700E', 'Mutation', 'rs559063155', (164, 169))	('K700E', 'Var', (100, 105))	('K700E', 'Mutation', 'rs559063155', (100, 105))
145614	31474574	The most reduced protein in the K700E SF3B1 purification was SUGP1.	('protein', 'Protein', (17, 24))	('SF3B1', 'Gene', (38, 43))	('K700E', 'Mutation', 'rs559063155', (32, 37))	('K700E', 'Var', (32, 37))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('reduced', 'NegReg', (9, 16))	('SF3B1', 'Gene', '23451', (38, 43))
145616	31474574	It is noteworthy that the only protein in the silver-stained gel that appeared reduced in the K700E lane was the one with the predicted size of SUGP1.	('K700E', 'Var', (94, 99))	('K700E', 'Mutation', 'rs559063155', (94, 99))	('reduced', 'NegReg', (79, 86))	('silver', 'Chemical', 'MESH:D012834', (46, 52))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))
145617	31474574	Importantly, all SF3b subunits were recovered at essentially the same levels in both complexes (Figure 2F), consistent with a previous study indicating that the K700E mutation does not affect interactions of SF3B1 with other SF3b subunits.	('interactions', 'Interaction', (192, 204))	('SF3B1', 'Gene', '23451', (208, 213))	('K700E', 'Var', (161, 166))	('K700E', 'Mutation', 'rs559063155', (161, 166))	('SF3B1', 'Gene', (208, 213))
145618	31474574	We reasoned that if weakened association of SUGP1 with SF3B1 in the spliceosome is responsible for the K700E-induced splicing defects, then reducing SUGP1 levels in cells should recapitulate the 3'ss switch.	('splicing defects', 'MPA', (117, 133))	('K700E-induced', 'Var', (103, 116))	('SF3B1', 'Gene', '23451', (55, 60))	('SUGP1', 'Gene', (44, 49))	('splicing', 'biological_process', 'GO:0045292', ('117', '125'))	('SF3B1', 'Gene', (55, 60))	('K700E', 'Mutation', 'rs559063155', (103, 108))	('association', 'Interaction', (29, 40))	('spliceosome', 'cellular_component', 'GO:0005681', ('68', '79'))
145619	31474574	To test this, we knocked down SUGP1 in HEK293T cells using two independent small interfering RNAs (siRNAs).	('knocked', 'Var', (17, 24))	('SUGP1', 'Gene', (30, 35))	('HEK293T', 'CellLine', 'CVCL:0063', (39, 46))
145620	31474574	Strikingly, we observed by RT-PCR that SUGP1 KD indeed led to use of upstream cryptic 3'ss in all transcripts tested (Figures 3A and 3B).	('cryptic', 'Gene', (78, 85))	('cryptic', 'Gene', '55997', (78, 85))	('led', 'Reg', (55, 58))	('SUGP1 KD', 'Var', (39, 47))
145621	31474574	It is noteworthy that KD of RBM6, which also appeared slightly reduced in the K700E SF3B1 purification based on the MS analysis (Figure 2C), did not induce cryptic 3'ss usage (Figures S2A and S2B).	('SF3B1', 'Gene', '23451', (84, 89))	('RBM6', 'Gene', '10180', (28, 32))	('cryptic', 'Gene', '55997', (156, 163))	('reduced', 'NegReg', (63, 70))	('cryptic', 'Gene', (156, 163))	('K700E', 'Var', (78, 83))	('K700E', 'Mutation', 'rs559063155', (78, 83))	('RBM6', 'Gene', (28, 32))	('SF3B1', 'Gene', (84, 89))
145622	31474574	Two previous studies showed that mutant SF3B1 induces cryptic 3'ss usage by causing the spliceosome to use an upstream BP.	('SF3B1', 'Gene', (40, 45))	('cryptic', 'Gene', '55997', (54, 61))	('SF3B1', 'Gene', '23451', (40, 45))	('cryptic', 'Gene', (54, 61))	("3'ss usage", 'MPA', (62, 72))	('BP', 'Chemical', '-', (119, 121))	('causing', 'Reg', (76, 83))	('mutant', 'Var', (33, 39))	('use an upstream BP', 'MPA', (103, 121))	('induces', 'Reg', (46, 53))	('spliceosome', 'cellular_component', 'GO:0005681', ('88', '99'))
145623	31474574	Using nested RT-PCR followed by sequencing of intron-lariat intermediates, we mapped the BP on the endogenous transcripts of two target genes, ORAI2 and TTI1, in the engineered K562 cells, and indeed found a mutant SF3B1-specific BP at 13- or 11-nt upstream of the corresponding canonical BP, respectively (Figure S3).	('BP', 'Chemical', '-', (230, 232))	('ORAI2', 'Gene', (143, 148))	('TTI1', 'Gene', (153, 157))	('SF3B1', 'Gene', '23451', (215, 220))	('mutant', 'Var', (208, 214))	('BP', 'Chemical', '-', (289, 291))	('TTI1', 'Gene', '9675', (153, 157))	('K562', 'CellLine', 'CVCL:0004', (177, 181))	('BP', 'Chemical', '-', (89, 91))	('ORAI2', 'Gene', '80228', (143, 148))	('SF3B1', 'Gene', (215, 220))
145624	31474574	To examine whether loss of SUGP1 also led to use of upstream BPs, we utilized minigenes from ORAI2 and TTI1 and mutated both constructs by changing the nucleotide corresponding to the upstream BP from A to G, the least likely nucleotide to function as a BP.	('BP', 'Chemical', '-', (254, 256))	('ORAI2', 'Gene', '80228', (93, 98))	('ORAI2', 'Gene', (93, 98))	('changing', 'Reg', (139, 147))	('BP', 'Chemical', '-', (193, 195))	('TTI1', 'Gene', '9675', (103, 107))	('SUGP1', 'Gene', (27, 32))	('BP', 'Chemical', '-', (61, 63))	('mutated', 'Var', (112, 119))	('TTI1', 'Gene', (103, 107))
145625	31474574	Minigene reporter assays showed that the BP mutations abolished the 3'ss switch by K700E SF3B1, and this effect was recapitulated by SUGP1 KD (Figure 3C).	('SF3B1', 'Gene', (89, 94))	('BP', 'Chemical', '-', (41, 43))	('SF3B1', 'Gene', '23451', (89, 94))	('abolished', 'NegReg', (54, 63))	('K700E', 'Mutation', 'rs559063155', (83, 88))	("3'ss switch", 'MPA', (68, 79))	('K700E', 'Var', (83, 88))
145626	31474574	These results provide further evidence that loss of SUGP1 indeed accounts for the splicing defects of the mutant SF3B1 spliceosome.	('mutant', 'Var', (106, 112))	('spliceosome', 'cellular_component', 'GO:0005681', ('119', '130'))	('splicing', 'biological_process', 'GO:0045292', ('82', '90'))	('SF3B1', 'Gene', (113, 118))	('loss', 'NegReg', (44, 48))	('splicing defects', 'MPA', (82, 98))	('SF3B1', 'Gene', '23451', (113, 118))	('SUGP1', 'Gene', (52, 57))
145633	31474574	We found that U2AF2 indeed coimmunoprecipitated with this portion of SUGP1, whereas mutation of the most conserved amino acid residue of this binding site from W to A completely abolished coimmunoprecipitation (Figure S4B).	('U2AF', 'cellular_component', 'GO:0089701', ('14', '18'))	('U2AF2', 'Gene', (14, 19))	('abolished', 'NegReg', (178, 187))	('binding', 'molecular_function', 'GO:0005488', ('142', '149'))	('U2AF2', 'Gene', '11338', (14, 19))	('SUGP1', 'Gene', (69, 74))	('mutation', 'Var', (84, 92))
145636	31474574	Assuming that the most conserved amino acid residue(s) in each domain are important for its function, we mutated each domain of SUGP1 by changing the most conserved residues to alanine based on the sequence alignments of the domains.	('SUGP1', 'Gene', (128, 133))	('changing', 'Reg', (137, 145))	('alanine', 'Chemical', 'MESH:D000409', (177, 184))	('mutated', 'Var', (105, 112))	('most conserved residues', 'MPA', (150, 173))
145638	31474574	Strikingly, we found that expression of the G-patch domain mutant of SUGP1 robustly switched 3'ss usage, recapitulating the splicing defects of the mutant SF3B1 spliceosome (Figure 4C).	('SF3B1', 'Gene', '23451', (155, 160))	('splicing', 'biological_process', 'GO:0045292', ('124', '132'))	('G-patch domain mutant', 'Var', (44, 65))	('switched', 'Reg', (84, 92))	('spliceosome', 'cellular_component', 'GO:0005681', ('161', '172'))	('SF3B1', 'Gene', (155, 160))	('SUGP1', 'Gene', (69, 74))	("3'ss usage", 'MPA', (93, 103))
145639	31474574	In contrast, mutations in either or both of the two SURP domains, or in the U2AF2 motif, did not affect splicing.	('U2AF', 'cellular_component', 'GO:0089701', ('76', '80'))	('U2AF2', 'Gene', (76, 81))	('splicing', 'MPA', (104, 112))	('U2AF2', 'Gene', '11338', (76, 81))	('mutations', 'Var', (13, 22))	('splicing', 'biological_process', 'GO:0045292', ('104', '112'))
145641	31474574	An important question is whether the function of the mutant SF3B1 spliceosome can be rescued.	('SF3B1', 'Gene', (60, 65))	('SF3B1', 'Gene', '23451', (60, 65))	('spliceosome', 'cellular_component', 'GO:0005681', ('66', '77'))	('mutant', 'Var', (53, 59))
145643	31474574	We first tested whether exogenous expression of His6-FLAG-tagged WT or K700E SF3B1 could recapitulate the defective interaction of K700E SF3B1 with endogenous SUGP1.	('K700E', 'Mutation', 'rs559063155', (131, 136))	('SF3B1', 'Gene', (77, 82))	('K700E', 'Var', (131, 136))	('K700E', 'Mutation', 'rs559063155', (71, 76))	('SF3B1', 'Gene', (137, 142))	('His6', 'Chemical', 'MESH:C471213', (48, 52))	('K700E', 'Var', (71, 76))	('SF3B1', 'Gene', '23451', (77, 82))	('SF3B1', 'Gene', '23451', (137, 142))	('interaction', 'Interaction', (116, 127))
145644	31474574	Using the small-scale protocol, we purified the SF3B1-containing complexes from HEK293T cells, and found that SUGP1 associated with exogenously expressed WT SF3B1 but the interaction was defective with the mutant SF3B1 (Figures S5A and S5B).	('SF3B1', 'Gene', (157, 162))	('S5B', 'Gene', (236, 239))	('SUGP1', 'Gene', (110, 115))	('interaction', 'Interaction', (171, 182))	('defective', 'NegReg', (187, 196))	('SF3B1', 'Gene', (213, 218))	('mutant', 'Var', (206, 212))	('associated', 'Interaction', (116, 126))	('SF3B1', 'Gene', '23451', (157, 162))	('SF3B1', 'Gene', (48, 53))	('SF3B1', 'Gene', '23451', (213, 218))	('SF3B1', 'Gene', '23451', (48, 53))	('S5B', 'Gene', '5711', (236, 239))	('HEK293T', 'CellLine', 'CVCL:0063', (80, 87))
145645	31474574	Next, we co-expressed SUGP1 with either WT or K700E SF3B1 and then isolated SF3B1 complexes using affinity tags.	('K700E', 'Var', (46, 51))	('K700E', 'Mutation', 'rs559063155', (46, 51))	('SF3B1', 'Gene', (52, 57))	('SF3B1', 'Gene', (76, 81))	('SF3B1', 'Gene', '23451', (52, 57))	('SF3B1', 'Gene', '23451', (76, 81))
145646	31474574	We found that overexpression of SUGP1 indeed increased its association with the mutant SF3B1 complexes (Figures 5A and 5B), indicating that the K700E mutation does not entirely preclude SUGP1 association.	('association', 'Interaction', (59, 70))	('increased', 'PosReg', (45, 54))	('mutant', 'Var', (80, 86))	('SUGP1', 'Gene', (32, 37))	('SF3B1', 'Gene', (87, 92))	('SF3B1', 'Gene', '23451', (87, 92))	('K700E', 'Mutation', 'rs559063155', (144, 149))	('overexpression', 'PosReg', (14, 28))
145647	31474574	Importantly, RT-PCR showed that SUGP1 overexpression partially rescued the splicing errors of the K700E SF3B1 spliceosome (Figures 5C-5E).	('splicing errors', 'MPA', (75, 90))	('spliceosome', 'cellular_component', 'GO:0005681', ('110', '121'))	('K700E', 'Var', (98, 103))	('K700E', 'Mutation', 'rs559063155', (98, 103))	('SF3B1', 'Gene', (104, 109))	('rescued', 'PosReg', (63, 70))	('splicing', 'biological_process', 'GO:0045292', ('75', '83'))	('SF3B1', 'Gene', '23451', (104, 109))
145648	31474574	In addition to K700E, a number of other SF3B1 mutations are frequently found in MDS and certain cancers.	('SF3B1', 'Gene', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('mutations', 'Var', (46, 55))	('K700E', 'Var', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('K700E', 'Mutation', 'rs559063155', (15, 20))	('found', 'Reg', (71, 76))	('SF3B1', 'Gene', '23451', (40, 45))	('MDS', 'Disease', (80, 83))	('MDS', 'Disease', 'MESH:D009190', (80, 83))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))
145649	31474574	To examine whether other disease mutations also weaken the interaction of SF3B1 with SUGP1, we introduced each of four common mutations into our SF3B1 expression vector and exogenously expressed the mutant derivatives in HEK293T cells.	('SF3B1', 'Gene', '23451', (145, 150))	('HEK293T', 'CellLine', 'CVCL:0063', (221, 228))	('SF3B1', 'Gene', '23451', (74, 79))	('interaction', 'Interaction', (59, 70))	('mutations', 'Var', (33, 42))	('SF3B1', 'Gene', (145, 150))	('mutations', 'Var', (126, 135))	('SF3B1', 'Gene', (74, 79))	('mutant', 'Var', (199, 205))
145650	31474574	Affinity purification showed that all the mutations reduced SUGP1 association with SF3B1 (Figures 6A and 6B).	('reduced', 'NegReg', (52, 59))	('association', 'Interaction', (66, 77))	('SUGP1', 'Gene', (60, 65))	('SF3B1', 'Gene', (83, 88))	('SF3B1', 'Gene', '23451', (83, 88))	('mutations', 'Var', (42, 51))
145651	31474574	As with K700E, these other SF3B1 mutations also led to 3'ss switching (Figures 6C and 6D).	('K700E', 'Mutation', 'rs559063155', (8, 13))	('K700E', 'Var', (8, 13))	("3'ss switching", 'MPA', (55, 69))	('mutations', 'Var', (33, 42))	('SF3B1', 'Gene', (27, 32))	('SF3B1', 'Gene', '23451', (27, 32))	('led to', 'Reg', (48, 54))
145652	31474574	These results suggest that loss of SUGP1 during assembly of the mutant spliceosome is a common mechanism by which SF3B1 mutations result in splicing defects in MDS and cancer.	('loss', 'Var', (27, 31))	('SF3B1', 'Gene', '23451', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('splicing', 'biological_process', 'GO:0045292', ('140', '148'))	('SF3B1', 'Gene', (114, 119))	('result in', 'Reg', (130, 139))	('MDS', 'Disease', (160, 163))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('MDS', 'Disease', 'MESH:D009190', (160, 163))	('cancer', 'Disease', (168, 174))	('mutations', 'Var', (120, 129))	('splicing defects', 'MPA', (140, 156))	('spliceosome', 'cellular_component', 'GO:0005681', ('71', '82'))	('SUGP1', 'Gene', (35, 40))
145653	31474574	Since the discovery of high frequencies of splicing factor mutations in MDS and other cancers, considerable progress has been made towards understanding the role of several of these mutant proteins in misregulation of RNA splicing.	('splicing factor', 'Gene', '10569', (43, 58))	('MDS', 'Disease', (72, 75))	('MDS', 'Disease', 'MESH:D009190', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('splicing', 'biological_process', 'GO:0045292', ('43', '51'))	('RNA splicing', 'biological_process', 'GO:0008380', ('218', '230'))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('RNA', 'cellular_component', 'GO:0005562', ('218', '221'))	('mutations', 'Var', (59, 68))	('cancers', 'Disease', (86, 93))	('splicing factor', 'Gene', (43, 58))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
145654	31474574	However, nothing has been known about how SF3B1 mutations, which are the most common of the splicing factor gene mutations, affect the function of the protein in splicing.	('function of the protein in splicing', 'MPA', (135, 170))	('affect', 'Reg', (124, 130))	('splicing factor', 'Gene', '10569', (92, 107))	('SF3B1', 'Gene', (42, 47))	('splicing', 'biological_process', 'GO:0045292', ('162', '170'))	('splicing', 'biological_process', 'GO:0045292', ('92', '100'))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('SF3B1', 'Gene', '23451', (42, 47))	('splicing factor', 'Gene', (92, 107))	('mutations', 'Var', (48, 57))
145658	31474574	Therefore, for mutant SF3B1 cancers, the ideal strategy would be to specifically repair the mutant spliceosome and thereby rescue the diseased cells rather than kill them.	('cancers', 'Disease', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('SF3B1', 'Gene', '23451', (22, 27))	('spliceosome', 'MPA', (99, 110))	('repair', 'MPA', (81, 87))	('rescue', 'PosReg', (123, 129))	('spliceosome', 'cellular_component', 'GO:0005681', ('99', '110'))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('mutant', 'Var', (92, 98))	('mutant', 'Var', (15, 21))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('SF3B1', 'Gene', (22, 27))
145659	31474574	Nevertheless, we have elucidated here the defect of the mutant SF3B1 spliceosome.	('SF3B1', 'Gene', (63, 68))	('spliceosome', 'cellular_component', 'GO:0005681', ('69', '80'))	('mutant', 'Var', (56, 62))	('SF3B1', 'Gene', '23451', (63, 68))
145661	31474574	Below we present a detailed mechanistic model explaining how SUGP1 loss affects splicing in this way, and also discuss our results in the context of the insights they provide into how restoring SUGP1 assembly into the mutant spliceosome can be developed as a potential cure for mutant SF3B1 cancers.	('mutant', 'Var', (278, 284))	('SUGP1', 'Gene', (61, 66))	('cancers', 'Phenotype', 'HP:0002664', (291, 298))	('cancers', 'Disease', (291, 298))	('spliceosome', 'cellular_component', 'GO:0005681', ('225', '236'))	('cancers', 'Disease', 'MESH:D009369', (291, 298))	('loss', 'NegReg', (67, 71))	('SF3B1', 'Gene', (285, 290))	('affects', 'Reg', (72, 79))	('splicing', 'biological_process', 'GO:0045292', ('80', '88'))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('SF3B1', 'Gene', '23451', (285, 290))	('splicing', 'MPA', (80, 88))
145662	31474574	Based on our data, we propose the following model for SUGP1 function in facilitating BP recognition, and how SF3B1 mutations disrupt this process and force use of a cryptic 3'ss (Figure 7).	('mutations', 'Var', (115, 124))	('SF3B1', 'Gene', (109, 114))	('disrupt', 'NegReg', (125, 132))	('SUGP1', 'Gene', (54, 59))	('SF3B1', 'Gene', '23451', (109, 114))	('cryptic', 'Gene', '55997', (165, 172))	('cryptic', 'Gene', (165, 172))	('BP', 'Chemical', '-', (85, 87))	('facilitating BP recognition', 'MPA', (72, 99))
145667	31474574	When SUGP1 is depleted or mutated in the G-patch domain (Figures 7B and 7C), the coupling between SF1/U2AF2 binding and ATP hydrolysis is absent, such that SF1 is not displaced and thus blocks access to the canonical BP.	('SUGP1', 'Gene', (5, 10))	('BP', 'Chemical', '-', (217, 219))	('SF1', 'Gene', '7536', (98, 101))	('ATP hydrolysis', 'biological_process', 'GO:0006200', ('120', '134'))	('U2AF2', 'Gene', '11338', (102, 107))	('U2AF', 'cellular_component', 'GO:0089701', ('102', '106'))	('absent', 'NegReg', (138, 144))	('binding', 'Interaction', (108, 115))	('ATP', 'Chemical', 'MESH:D000255', (120, 123))	('SF1', 'Gene', (156, 159))	('SF1', 'Gene', '7536', (156, 159))	('binding', 'molecular_function', 'GO:0005488', ('108', '115'))	('mutated', 'Var', (26, 33))	('blocks', 'NegReg', (186, 192))	('U2AF2', 'Gene', (102, 107))	('coupling', 'MPA', (81, 89))	('SF1', 'Gene', (98, 101))	('access', 'MPA', (193, 199))
145669	31474574	Similarly, in patients carrying SF3B1 HEAT domain mutations, U2 snRNP is unable to recruit SUGP1, the RNA helicase is thus also not recruited and/or activated, SF1 is not displaced, and the mutant spliceosome must again scan for an upstream branchsite and utilize a cryptic 3'ss (Figure 7D).	('SF1', 'Gene', '7536', (160, 163))	('snRNP', 'molecular_function', 'GO:0003734', ('64', '69'))	('cryptic', 'Gene', (266, 273))	('cryptic', 'Gene', '55997', (266, 273))	('HEAT domain mutations', 'Var', (38, 59))	('SF3B1', 'Gene', '23451', (32, 37))	('unable', 'NegReg', (73, 79))	('snRNP', 'Gene', (64, 69))	('SF1', 'Gene', (160, 163))	('RNA helicase', 'Protein', (102, 114))	('snRNP', 'Gene', '57819', (64, 69))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('61', '69'))	('RNA', 'cellular_component', 'GO:0005562', ('102', '105'))	('spliceosome', 'cellular_component', 'GO:0005681', ('197', '208'))	('SF3B1', 'Gene', (32, 37))	('branchsite', 'Disease', 'None', (241, 251))	('branchsite', 'Disease', (241, 251))	('patients', 'Species', '9606', (14, 22))
145670	31474574	An interesting question is why only a relatively small number of introns are affected by SF3B1 mutations, given that SF3B1 is an essential splicing factor.	('splicing factor', 'Gene', '10569', (139, 154))	('SF3B1', 'Gene', (89, 94))	('affected', 'Reg', (77, 85))	('splicing', 'biological_process', 'GO:0045292', ('139', '147'))	('SF3B1', 'Gene', '23451', (89, 94))	('SF3B1', 'Gene', (117, 122))	('mutations', 'Var', (95, 104))	('splicing factor', 'Gene', (139, 154))	('SF3B1', 'Gene', '23451', (117, 122))
145671	31474574	In order for the mutant SF3B1 spliceosome to misregulate RNA splicing, both an upstream BP and a cryptic 3'ss within an appropriate distance of the canonical 3'ss are required.	('cryptic', 'Gene', (97, 104))	('SF3B1', 'Gene', (24, 29))	('RNA', 'cellular_component', 'GO:0005562', ('57', '60'))	('misregulate', 'Reg', (45, 56))	('spliceosome', 'cellular_component', 'GO:0005681', ('30', '41'))	('RNA splicing', 'MPA', (57, 69))	('SF3B1', 'Gene', '23451', (24, 29))	('BP', 'Chemical', '-', (88, 90))	('mutant', 'Var', (17, 23))	('cryptic', 'Gene', '55997', (97, 104))	('RNA splicing', 'biological_process', 'GO:0008380', ('57', '69'))
145672	31474574	These restrictions define a small number of introns in which mutant SF3B1 can induce splicing errors.	('induce', 'Reg', (78, 84))	('splicing', 'biological_process', 'GO:0045292', ('85', '93'))	('SF3B1', 'Gene', (68, 73))	('splicing errors', 'MPA', (85, 100))	('SF3B1', 'Gene', '23451', (68, 73))	('mutant', 'Var', (61, 67))
145673	31474574	For the large number of other introns that do not appear misspliced by mutant SF3B1, we envision two different scenarios.	('SF3B1', 'Gene', '23451', (78, 83))	('mutant', 'Var', (71, 77))	('SF3B1', 'Gene', (78, 83))
145674	31474574	In one, where the intron has an upstream cryptic BP but not a cryptic 3'ss, we suggest that the mutant SF3B1 spliceosome proceeds through the normal splicing pathway by utilizing the upstream BP for lariat formation and then uses the canonical 3'ss for exon-exon joining, but at a much reduced rate.	('formation', 'biological_process', 'GO:0009058', ('206', '215'))	('BP', 'Chemical', '-', (192, 194))	('mutant', 'Var', (96, 102))	('BP', 'Chemical', '-', (49, 51))	('splicing', 'biological_process', 'GO:0045292', ('149', '157'))	('SF3B1', 'Gene', (103, 108))	('cryptic', 'Gene', '55997', (62, 69))	('spliceosome', 'cellular_component', 'GO:0005681', ('109', '120'))	('cryptic', 'Gene', '55997', (41, 48))	('cryptic', 'Gene', (62, 69))	('cryptic', 'Gene', (41, 48))	('SF3B1', 'Gene', '23451', (103, 108))
145675	31474574	In the other scenario, where neither an upstream BP nor a cryptic 3'ss is present in the intron, we suggest that the mutant SF3B1 spliceosome is assembled to the stage of complex B without SUGP1 and then it stalls to wait for SUGP1 incorporation.	('BP', 'Chemical', '-', (49, 51))	('mutant', 'Var', (117, 123))	('spliceosome', 'cellular_component', 'GO:0005681', ('130', '141'))	('cryptic', 'Gene', '55997', (58, 65))	('SF3B1', 'Gene', (124, 129))	('cryptic', 'Gene', (58, 65))	('SF3B1', 'Gene', '23451', (124, 129))
145676	31474574	Because the mutant SF3B1 still has residual affinity for SUGP1 (likely with a slower on-rate), after a long lag SUGP1 will eventually be incorporated into the stalled complex B, allowing the mutant spliceosome to carry out the subsequent catalytic reactions with the canonical BP and 3'ss.	('BP', 'Chemical', '-', (277, 279))	('carry', 'Reg', (213, 218))	('SF3B1', 'Gene', '23451', (19, 24))	('mutant', 'Var', (12, 18))	('catalytic reactions', 'MPA', (238, 257))	('SF3B1', 'Gene', (19, 24))	('spliceosome', 'cellular_component', 'GO:0005681', ('198', '209'))
145677	31474574	First, we found that the effects of SF3B1 mutations on the function of the mutant spliceosome are subtle.	('SF3B1', 'Gene', (36, 41))	('function', 'MPA', (59, 67))	('SF3B1', 'Gene', '23451', (36, 41))	('mutations', 'Var', (42, 51))	('spliceosome', 'cellular_component', 'GO:0005681', ('82', '93'))
145678	31474574	The fact that the WT spliceosome, in the absence of SUGP1 or when SUGP1 is mutated in the G-patch domain, apparently functions identically to the mutant SF3B1 spliceosome indicates that the mutations lead to only a small change in a limited area of the SF3B1 protein, leaving the remaining scaffold intact and functional.	('SF3B1', 'Gene', '23451', (153, 158))	('protein', 'cellular_component', 'GO:0003675', ('259', '266'))	('SF3B1', 'Gene', '23451', (253, 258))	('mutations', 'Var', (190, 199))	('spliceosome', 'cellular_component', 'GO:0005681', ('21', '32'))	('mutant', 'Var', (146, 152))	('spliceosome', 'cellular_component', 'GO:0005681', ('159', '170'))	('SF3B1', 'Gene', (153, 158))	('SF3B1', 'Gene', (253, 258))
145679	31474574	This structural change in SF3B1 appears to only impair recruitment of SUGP1 to the U2 snRNP complex during BP recognition, and the subsequent assembly of the active spliceosome as well as the catalytic splicing reactions are not affected.	('SF3B1', 'Gene', (26, 31))	('recruitment', 'MPA', (55, 66))	('BP', 'Chemical', '-', (107, 109))	('splicing', 'biological_process', 'GO:0045292', ('202', '210'))	('snRNP', 'molecular_function', 'GO:0003734', ('86', '91'))	('structural change', 'Var', (5, 22))	('SF3B1', 'Gene', '23451', (26, 31))	('spliceosome', 'cellular_component', 'GO:0005681', ('165', '176'))	('impair', 'NegReg', (48, 54))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('83', '91'))	('assembly', 'MPA', (142, 150))	('snRNP', 'Gene', (86, 91))	('SUGP1', 'Gene', (70, 75))	('snRNP', 'Gene', '57819', (86, 91))
145680	31474574	Second, we found that the effects of SF3B1 mutations are reversible.	('SF3B1', 'Gene', (37, 42))	('mutations', 'Var', (43, 52))	('SF3B1', 'Gene', '23451', (37, 42))
145681	31474574	Our data show that the mutant spliceosome is partially rescued by SUGP1 overexpression, indicating that the assembly of SUGP1 into the spliceosome is concentration dependent and that SF3B1 mutations simply reduce affinity for SUGP1.	('SF3B1', 'Gene', '23451', (183, 188))	('spliceosome', 'cellular_component', 'GO:0005681', ('135', '146'))	('reduce', 'NegReg', (206, 212))	('SUGP1', 'Protein', (226, 231))	('spliceosome', 'cellular_component', 'GO:0005681', ('30', '41'))	('affinity', 'Interaction', (213, 221))	('mutations', 'Var', (189, 198))	('SF3B1', 'Gene', (183, 188))
145682	31474574	Therefore, a more robust rescue of the mutant spliceosome may in principle be achieved, either by identifying small molecules that stabilize SUGP1 interaction with mutant SF3B1, or by complementary mutations (or suppressor mutations) in SUGP1 that fully restore its affinity for mutant SF3B1.	('SF3B1', 'Gene', (171, 176))	('mutant', 'Var', (164, 170))	('interaction', 'Interaction', (147, 158))	('spliceosome', 'cellular_component', 'GO:0005681', ('46', '57'))	('SF3B1', 'Gene', '23451', (171, 176))	('SF3B1', 'Gene', (286, 291))	('mutations', 'Var', (198, 207))	('mutant', 'Var', (39, 45))	('SUGP1', 'Gene', (237, 242))	('SF3B1', 'Gene', '23451', (286, 291))	('SUGP1', 'Gene', (141, 146))	('affinity', 'MPA', (266, 274))	('stabilize', 'Reg', (131, 140))
145686	31474574	The presence of all these functions in the same protein streamlines the BP recognition process, as illustrated in Figure 7A.	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('BP recognition process', 'CPA', (72, 94))	('BP', 'Chemical', '-', (72, 74))	('presence', 'Var', (4, 12))	('streamlines', 'PosReg', (56, 67))
145687	31474574	In keeping with this, our mechanistic model is different from several proposed in previous studies that suggested that SF3B1 mutations might: 1) facilitate selection of cryptic 3'ss by overcoming certain steric hindrance within a region of RNA immediately downstream of a BP; 2) enhance direct interactions of SF3B1 with specific nucleotides flanking the upstream BP; 3) induce a conformational change in the U2 snRNP complex leading to selection of a stronger upstream BP; or 4) facilitate the recognition of inaccessible 3'ss buried in RNA secondary structures.	('facilitate', 'PosReg', (480, 490))	('steric', 'MPA', (204, 210))	('conformational change', 'MPA', (380, 401))	('snRNP', 'molecular_function', 'GO:0003734', ('412', '417'))	('overcoming', 'PosReg', (185, 195))	('BP', 'Chemical', '-', (364, 366))	('facilitate', 'PosReg', (145, 155))	('RNA', 'cellular_component', 'GO:0005562', ('240', '243'))	('SF3B1', 'Gene', (310, 315))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('409', '417'))	('interactions', 'Interaction', (294, 306))	('cryptic', 'Gene', '55997', (169, 176))	('mutations', 'Var', (125, 134))	('cryptic', 'Gene', (169, 176))	('BP', 'Chemical', '-', (272, 274))	('SF3B1', 'Gene', (119, 124))	('RNA', 'cellular_component', 'GO:0005562', ('538', '541'))	('SF3B1', 'Gene', '23451', (310, 315))	('induce', 'Reg', (371, 377))	('enhance', 'PosReg', (279, 286))	('BP', 'Chemical', '-', (470, 472))	('SF3B1', 'Gene', '23451', (119, 124))	('snRNP', 'Gene', (412, 417))	('snRNP', 'Gene', '57819', (412, 417))
145688	31474574	All these models imply that the structural changes to SF3B1 induced by disease mutations are substantial and not readily amenable to rescue by restoring interaction with a partner protein, as argued by our data.	('SF3B1', 'Gene', (54, 59))	('SF3B1', 'Gene', '23451', (54, 59))	('interaction', 'Interaction', (153, 164))	('protein', 'cellular_component', 'GO:0003675', ('180', '187'))	('mutations', 'Var', (79, 88))
145699	31474574	As mentioned in the INTRODUCTION, a previous study showed that SF3B1 mutations affect the interaction of SF3B1 with the N-terminus of Prp5.	('mutations', 'Var', (69, 78))	('SF3B1', 'Gene', (105, 110))	('affect', 'Reg', (79, 85))	('Prp5', 'Protein', (134, 138))	('SF3B1', 'Gene', (63, 68))	('interaction', 'Interaction', (90, 101))	('SF3B1', 'Gene', '23451', (105, 110))	('SF3B1', 'Gene', '23451', (63, 68))	('N-terminus', 'Protein', (120, 130))
145701	31474574	It is worth mentioning that the G-patch domain mutation is unlikely to affect the interaction of SUGP1 with SF3B1, as the mutant SUGP1 had a dominant-negative effect on splicing, indicating that it is assembled into the spliceosome to induce use of cryptic 3'ss.	('SF3B1', 'Gene', '23451', (108, 113))	('splicing', 'MPA', (169, 177))	('SUGP1', 'Gene', (129, 134))	('cryptic', 'Gene', '55997', (249, 256))	('cryptic', 'Gene', (249, 256))	('dominant-negative', 'NegReg', (141, 158))	('splicing', 'biological_process', 'GO:0045292', ('169', '177'))	('SF3B1', 'Gene', (108, 113))	('mutant', 'Var', (122, 128))	('spliceosome', 'cellular_component', 'GO:0005681', ('220', '231'))
145702	31474574	Despite frequent SF3B1 mutations in MDS and other cancers, no mutations in SUGP1 have been identified in these diseases.	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('SF3B1', 'Gene', (17, 22))	('cancers', 'Disease', (50, 57))	('MDS', 'Disease', (36, 39))	('MDS', 'Disease', 'MESH:D009190', (36, 39))	('mutations', 'Var', (23, 32))	('SF3B1', 'Gene', '23451', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
145703	31474574	Since loss of SUGP1 recapitulates the splicing errors of the mutant SF3B1 spliceosome, why are there no loss-of-function SUGP1 mutations?	('spliceosome', 'cellular_component', 'GO:0005681', ('74', '85'))	('SF3B1', 'Gene', (68, 73))	('splicing errors', 'MPA', (38, 53))	('splicing', 'biological_process', 'GO:0045292', ('38', '46'))	('SF3B1', 'Gene', '23451', (68, 73))	('mutant', 'Var', (61, 67))	('SUGP1', 'Gene', (14, 19))
145705	31474574	Interestingly, we found that SUGP1 mRNA levels were elevated by ~60-80% on average in 3'ss-switching mutant SF3B1 vs. WT samples (Figure S6), suggesting that the mutant cells attempt to compensate for the defective SUGP1 interaction by increasing SUGP1 levels.	('SUGP1', 'Gene', (29, 34))	('SF3B1', 'Gene', '23451', (108, 113))	('mRNA levels', 'MPA', (35, 46))	('increasing', 'PosReg', (236, 246))	('mutant', 'Var', (101, 107))	('SF3B1', 'Gene', (108, 113))	('elevated', 'PosReg', (52, 60))
145706	31474574	Although the modestly elevated SUGP1 levels are insufficient to rescue mutant SF3B1 splicing, this compensation mechanism may provide an explanation for why there are no loss-of-function SUGP1 mutations in cancer.	('splicing', 'MPA', (84, 92))	('SUGP1', 'Gene', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('SF3B1', 'Gene', '23451', (78, 83))	('elevated SUGP1', 'Phenotype', 'HP:0030269', (22, 36))	('mutations', 'Var', (193, 202))	('mutant', 'Var', (71, 77))	('splicing', 'biological_process', 'GO:0045292', ('84', '92'))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('SF3B1', 'Gene', (78, 83))
145707	31474574	Specifically, it seems likely that heterozygous loss-of-function mutations in SUGP1 would also induce this feedback mechanism to elevate SUGP1 mRNA levels, which in turn would be sufficient to compensate for SUGP1 haploinsufficiency, thereby preventing disease-driving splicing changes.	('SUGP1', 'Gene', (208, 213))	('splicing', 'biological_process', 'GO:0045292', ('269', '277'))	('SUGP1', 'Gene', (78, 83))	('haploinsufficiency', 'Disease', (214, 232))	('haploinsufficiency', 'Disease', 'MESH:D058495', (214, 232))	('elevate SUGP1', 'Phenotype', 'HP:0030269', (129, 142))	('loss-of-function', 'NegReg', (48, 64))	('splicing changes', 'MPA', (269, 285))	('induce', 'Reg', (95, 101))	('elevate', 'PosReg', (129, 136))	('mutations', 'Var', (65, 74))	('SUGP1 mRNA levels', 'MPA', (137, 154))
145708	31474574	The functional consequences of the splicing errors produced by the mutant SF3B1 spliceosome in pathogenesis remain to be understood.	('spliceosome', 'cellular_component', 'GO:0005681', ('80', '91'))	('SF3B1', 'Gene', '23451', (74, 79))	('splicing', 'biological_process', 'GO:0045292', ('35', '43'))	('mutant', 'Var', (67, 73))	('pathogenesis', 'biological_process', 'GO:0009405', ('95', '107'))	('SF3B1', 'Gene', (74, 79))
145710	31474574	Missplicing of transcripts from genes involved in "innate immune response" may contribute to the activation of innate immune signaling in mutant SF3B1 patients.	('SF3B1', 'Gene', '23451', (145, 150))	('activation', 'PosReg', (97, 107))	('mutant', 'Var', (138, 144))	('patients', 'Species', '9606', (151, 159))	('SF3B1', 'Gene', (145, 150))	('innate immune signaling', 'MPA', (111, 134))	('Missplicing', 'Var', (0, 11))
145712	31474574	For example, a splicing error in MAP3K7 (mitogen-activated protein kinase kinase kinase 7) transcripts may result in reduced activation of the MAPK pathway required for hematopoiesis.	('activation', 'PosReg', (125, 135))	('MAP3K7', 'Gene', (33, 39))	('mitogen-activated protein kinase kinase kinase 7', 'Gene', '6885', (41, 89))	('MAP3K', 'molecular_function', 'GO:0004709', ('33', '38'))	('MAPK', 'molecular_function', 'GO:0004707', ('143', '147'))	('hematopoiesis', 'Disease', 'MESH:C536227', (169, 182))	('reduced', 'NegReg', (117, 124))	('mitogen-activated protein kinase kinase kinase 7', 'Gene', (41, 89))	('splicing error', 'Var', (15, 29))	('hematopoiesis', 'biological_process', 'GO:0030097', ('169', '182'))	('MAP3K7', 'Gene', '6885', (33, 39))	('hematopoiesis', 'Disease', (169, 182))	('MAPK pathway required', 'Pathway', (143, 164))	('splicing', 'biological_process', 'GO:0045292', ('15', '23'))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
145713	31474574	A splicing error in intron 3 of ZNF91 (zinc finger protein 91) may lead to translation from a start codon in exon 4, producing a truncated ZNF91 protein that lacks the N-terminal KRAB (the Kruppel-associated box) domain.	('zinc finger protein 91', 'Gene', (39, 61))	('ZNF91', 'Gene', (139, 144))	('lead to', 'Reg', (67, 74))	('ZNF91', 'Gene', (32, 37))	('protein', 'Protein', (145, 152))	('lacks', 'NegReg', (158, 163))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('splicing error', 'Var', (2, 16))	('translation', 'MPA', (75, 86))	('ZNF91', 'Gene', '7644', (139, 144))	('splicing', 'biological_process', 'GO:0045292', ('2', '10'))	('ZNF91', 'Gene', '7644', (32, 37))	('zinc finger protein 91', 'Gene', '7644', (39, 61))	('translation', 'biological_process', 'GO:0006412', ('75', '86'))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
145714	31474574	The KRAB domain is important for nuclear localization, and its loss may allow the truncated ZNF91 to localize to the cytoplasm where it may interact with the IkappaB kinase complex, activating the NF-kappaB pathway, as demonstrated for another member of this family of zinc-finger proteins.	('ZNF91', 'Gene', (92, 97))	('activating', 'PosReg', (182, 192))	('NF-kappaB', 'Gene', (197, 206))	('IkappaB kinase complex', 'cellular_component', 'GO:0008385', ('158', '180'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('117', '126'))	('ZNF91', 'Gene', '7644', (92, 97))	('truncated', 'Var', (82, 91))	('localization', 'biological_process', 'GO:0051179', ('41', '53'))	('loss', 'NegReg', (63, 67))	('interact', 'Interaction', (140, 148))	('NF-kappaB', 'Gene', '4790', (197, 206))
145715	31474574	A splicing error in PPP2R5A (protein phosphatase 2 regulatory subunit B'alpha) transcripts may also contribute to cancer development.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('phosphatase', 'molecular_function', 'GO:0016791', ('37', '48'))	('splicing error', 'Var', (2, 16))	('splicing', 'biological_process', 'GO:0045292', ('2', '10'))	('PPP2R5A', 'Gene', '5525', (20, 27))	("protein phosphatase 2 regulatory subunit B'alpha", 'Gene', '5520', (29, 77))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	("protein phosphatase 2 regulatory subunit B'alpha", 'Gene', (29, 77))	('PPP2R5A', 'Gene', (20, 27))	('contribute to', 'Reg', (100, 113))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('cancer', 'Disease', (114, 120))
145717	31474574	In summary, we have elucidated the defect of the mutant SF3B1 spliceosome in MDS and cancer, and provided proof-of-principle evidence that the cancer-causing spliceosome is curable.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mutant', 'Var', (49, 55))	('defect', 'NegReg', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('spliceosome', 'cellular_component', 'GO:0005681', ('158', '169'))	('spliceosome', 'cellular_component', 'GO:0005681', ('62', '73'))	('MDS', 'Disease', (77, 80))	('MDS', 'Disease', 'MESH:D009190', (77, 80))	('cancer', 'Disease', (85, 91))	('SF3B1', 'Gene', (56, 61))	('spliceosome', 'MPA', (62, 73))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('SF3B1', 'Gene', '23451', (56, 61))
145718	31474574	This study not only advances our understanding of how SF3B1 mutations disrupt splicing, but also provides insights into novel strategies for developing treatments for MDS and other cancers caused by SF3B1 mutations.	('SF3B1', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('splicing', 'MPA', (78, 86))	('disrupt', 'NegReg', (70, 77))	('mutations', 'Var', (60, 69))	('SF3B1', 'Gene', (199, 204))	('caused', 'Reg', (189, 195))	('mutations', 'Var', (205, 214))	('SF3B1', 'Gene', '23451', (54, 59))	('splicing', 'biological_process', 'GO:0045292', ('78', '86'))	('SF3B1', 'Gene', '23451', (199, 204))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('MDS', 'Disease', (167, 170))	('MDS', 'Disease', 'MESH:D009190', (167, 170))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('cancers', 'Disease', (181, 188))
145727	31474574	We used t tests with PSI values (instead of read counts) to identify novel cryptic 3'ss between WT and mutant SF3B1 samples.	('cryptic', 'Gene', '55997', (75, 82))	('mutant', 'Var', (103, 109))	('cryptic', 'Gene', (75, 82))	('SF3B1', 'Gene', (110, 115))	('SF3B1', 'Gene', '23451', (110, 115))
145729	31474574	An unsupervised hierarchical clustering of the 627 splice junctions differentially used by mutant vs. WT SF3B1 (q value < 0.05, and cryptic 3'ss closer than 100 nt upstream of the associated canonical 3'ss) was performed using the command "heatmap.2" from the R software package "gplots", with (1 - Spearman's correlation/2) as the clustering distance.	('SF3B1', 'Gene', (105, 110))	('cryptic', 'Gene', '55997', (132, 139))	('cryptic', 'Gene', (132, 139))	('SF3B1', 'Gene', '23451', (105, 110))	('mutant', 'Var', (91, 97))
145730	31474574	A standard gene ontology (GO) analysis was performed to reveal enriched functional pathways affected by RNA missplicing by mutant SF3B1 using DAVID.	('SF3B1', 'Gene', (130, 135))	('affected', 'Reg', (92, 100))	('gene ontology', 'biological_process', 'GO:0003673', ('11', '24'))	('SF3B1', 'Gene', '23451', (130, 135))	('RNA', 'cellular_component', 'GO:0005562', ('104', '107'))	('mutant', 'Var', (123, 129))
145731	31474574	The input was a list of genes associated with the 169 cryptic 3'ss differentially used by mutant vs. WT SF3B1 (q value < 0.05, closer than 50 nt upstream of the associated canonical 3'ss, and more than 15 supporting reads averaged over mutant SF3B1 samples).	('SF3B1', 'Gene', (243, 248))	('cryptic', 'Gene', '55997', (54, 61))	('mutant', 'Var', (90, 96))	('cryptic', 'Gene', (54, 61))	('SF3B1', 'Gene', '23451', (243, 248))	('SF3B1', 'Gene', (104, 109))	('SF3B1', 'Gene', '23451', (104, 109))
145745	31474574	Then we used overlapping PCR to make a mosaic sequence, in which nt 2497-3132 of the 3'-end portion of the SF3B1 cDNA was replaced with a sequence harboring extensive synonymous mutations (derived from a DNA synthesized by Life Technologies).	('SF3B1', 'Gene', '23451', (107, 112))	('nt 2497-3132', 'Var', (65, 77))	('SF3B1', 'Gene', (107, 112))	('DNA', 'cellular_component', 'GO:0005574', ('204', '207'))
145748	31474574	The K700E, E622D, R625C, H662Q, and K666N mutant constructs were generated by site-directed mutagenesis.	('K666N', 'Mutation', 'rs377023736', (36, 41))	('E622D', 'Mutation', 'rs763149798', (11, 16))	('H662Q', 'Mutation', 'rs778467242', (25, 30))	('E622D', 'Var', (11, 16))	('K700E', 'Mutation', 'rs559063155', (4, 9))	('K666N', 'Var', (36, 41))	('K700E', 'Var', (4, 9))	('H662Q', 'Var', (25, 30))	('R625C', 'Mutation', 'rs775623976', (18, 23))	('R625C', 'Var', (18, 23))	('mutagenesis', 'biological_process', 'GO:0006280', ('92', '103'))
145750	31474574	The F222A, F297A, F222A-F297A, W387A, and G574A-G582A mutant SUGP1 constructs were generated by site-directed mutagenesis.	('G582A', 'Mutation', 'rs754116350', (48, 53))	('W387A', 'Var', (31, 36))	('F222A', 'Mutation', 'p.F222A', (18, 23))	('G574A', 'Mutation', 'rs1489114461', (42, 47))	('F222A-F297A', 'Var', (18, 29))	('F222A', 'Var', (4, 9))	('SUGP1', 'Gene', (61, 66))	('F297A', 'Var', (11, 16))	('W387A', 'SUBSTITUTION', 'None', (31, 36))	('mutagenesis', 'biological_process', 'GO:0006280', ('110', '121'))	('G574A-G582A', 'Var', (42, 53))	('F222A', 'Mutation', 'p.F222A', (4, 9))	('F297A', 'Mutation', 'p.F297A', (24, 29))	('F297A', 'Mutation', 'p.F297A', (11, 16))
145766	31474574	Primary antibodies were: anti-SF3B1 (Bethyl Laboratories, A300-996A, 1:1,000), anti-ACTIN (Sigma, A2066, 1:2,000), anti-HA rabbit polyclonal (Abm, G166, 1:1,000), anti-HA mouse monoclonal (Sigma, H3663, 1:1,000), anti-DYKDDDDK (GenScript, A00187, 1:1,000), anti-SUGP1 (Bethyl Laboratories, A304-675A-M, 1:1,000), anti-RBM6 (ABclonal, A10391, 1:1,000), anti-U2AF2 (Sigma, U4758, 1;10,000), and anti-GST (Invitrogen, A5800, 1:1,500).	('RBM6', 'Gene', (318, 322))	('U2AF2', 'Gene', (357, 362))	('SF3B1', 'Gene', (30, 35))	('GST', 'Gene', '373156', (398, 401))	('anti-DYKDDDDK', 'Var', (213, 226))	('A304-675A-M', 'Mutation', 'p.A,A304_675M', (290, 301))	('SF3B1', 'Gene', '23451', (30, 35))	('RBM6', 'Gene', '10180', (318, 322))	('U2AF2', 'Gene', '11338', (357, 362))	('U2AF', 'cellular_component', 'GO:0089701', ('357', '361'))	('GST', 'Gene', (398, 401))
145777	31474574	The SF3B1 K700E mutation (or synonymous mutations for the WT control) was knocked into K562 cells using CRISPR/Cas9 technology as previously described.	('Cas', 'cellular_component', 'GO:0005650', ('111', '114'))	('SF3B1', 'Gene', (4, 9))	('K562', 'CellLine', 'CVCL:0004', (87, 91))	('SF3B1', 'Gene', '23451', (4, 9))	('K700E', 'Mutation', 'rs559063155', (10, 15))	('K700E', 'Var', (10, 15))
145778	31474574	The human SF3B1 CRISPR guide RNA was 5'-TGGATGAGCAGCAGAAAGTTcgg-3', and the single-stranded oligodeoxynucleotides (ssODNs, Integrated DNA Technologies) for WT and K700E SF3B1 were 5'-AATGTTGGGGCATAGTTAAAACCTGTGTTTGGTTTTGTAGGTCTTGTGGATGAGCAGCAGAAAGTGCGCACCATCAGTGCTTTGGCCATTGCTGCCTTGGCTGAAGCAGCAACTCCTTATGGTATCGAAT-3' and 5'-AATGTTGGGGCATAGTTAAAACCTGTGTTTGGTTTTGTAGGTCTTGTGGATGAGCAGCAGGAAGTGCGCACCATCAGTGCTTTGGCCATTGCTGCCTTGGCTGAAGCAGCAACTCCTTATGGTATCGAAT-3', respectively.	('K700E', 'Mutation', 'rs559063155', (163, 168))	('human', 'Species', '9606', (4, 9))	('SF3B1', 'Gene', '23451', (169, 174))	('K700E', 'Var', (163, 168))	('SF3B1', 'Gene', (10, 15))	('RNA', 'cellular_component', 'GO:0005562', ('29', '32'))	('SF3B1', 'Gene', '23451', (10, 15))	('SF3B1', 'Gene', (169, 174))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))
145780	31474574	To select for clones that have the tags and the K700E mutation (or synonymous mutations for the WT control) on the same SF3B1 allele, total RNA was isolated from positive clones with tag knock-in using TRIzol (Thermo Fisher Scientific), and then reverse transcribed using Superscript III (Invitrogen), followed by PCR using Phusion DNA polymerase (New England Biolabs) with the following primer set: 5'-TCACGACTACAAGGACGACG-3' and 5'-ACCCTTTCCTCTGTGTTGGC-3'.	('TRIzol', 'Chemical', 'MESH:C411644', (202, 208))	('SF3B1', 'Gene', (120, 125))	('knock-in', 'Var', (187, 195))	('RNA', 'cellular_component', 'GO:0005562', ('140', '143'))	('DNA', 'cellular_component', 'GO:0005574', ('332', '335'))	('SF3B1', 'Gene', '23451', (120, 125))	('K700E', 'Var', (48, 53))	('K700E', 'Mutation', 'rs559063155', (48, 53))
145781	31474574	PCR products were sequenced to confirm the presence of the tags and the K700E mutation (or synonymous mutations for the WT control) on the same SF3B1 allele using sequencing primers 5'-CATAATAACCTGTAGAATCGAG-3' and 5'-GCTGTGTGCAAAAGCAAGAA-3', respectively.	('SF3B1', 'Gene', (144, 149))	('SF3B1', 'Gene', '23451', (144, 149))	('K700E', 'Var', (72, 77))	('K700E', 'Mutation', 'rs559063155', (72, 77))
145782	31474574	A total of 200 million CRISPR/Cas9 engineered K562 cells with His6-FLAG-tagged WT or K700E SF3B1 were harvested by centrifugation at 2,000 x g for 5 min.	('SF3B1', 'Gene', (91, 96))	('His6', 'Chemical', 'MESH:C471213', (62, 66))	('SF3B1', 'Gene', '23451', (91, 96))	('K700E', 'Mutation', 'rs559063155', (85, 90))	('Cas', 'cellular_component', 'GO:0005650', ('30', '33'))	('K700E', 'Var', (85, 90))	('K562', 'CellLine', 'CVCL:0004', (46, 50))
145790	31474574	For K562 cells, 20 million CRISPR/Cas9 engineered K562 cells with His6-FLAG-tagged WT or K700E SF3B1 were used to purify SF3B1-associated proteins.	('SF3B1', 'Gene', (95, 100))	('Cas', 'cellular_component', 'GO:0005650', ('34', '37'))	('K562', 'CellLine', 'CVCL:0004', (4, 8))	('His6', 'Chemical', 'MESH:C471213', (66, 70))	('SF3B1', 'Gene', '23451', (95, 100))	('K700E', 'Mutation', 'rs559063155', (89, 94))	('SF3B1', 'Gene', (121, 126))	('K700E', 'Var', (89, 94))	('K562', 'CellLine', 'CVCL:0004', (50, 54))	('SF3B1', 'Gene', '23451', (121, 126))
145798	31474574	GST, and GST-tagged SUGP1 (amino acids 366-401) were cloned into p3xFLAG-CMV-14 (Sigma), and the W387A mutant construct of GST-tagged SUGP1 (amino acids 366-401) was generated by site-directed mutagenesis.	('GST', 'Gene', (0, 3))	('W387A', 'Var', (97, 102))	('GST', 'Gene', '373156', (0, 3))	('GST', 'Gene', (9, 12))	('W387A', 'SUBSTITUTION', 'None', (97, 102))	('mutagenesis', 'biological_process', 'GO:0006280', ('193', '204'))	('GST', 'Gene', (123, 126))	('GST', 'Gene', '373156', (9, 12))	('amino acids 366-401', 'Var', (141, 160))	('GST', 'Gene', '373156', (123, 126))
145800	31474574	On the next day, the cells were transfected with 4 mug plasmid DNA expressing GST, GST-tagged SUGP1 (amino acids 366-401), or the W387A mutant of GST-tagged SUGP1 (amino acids 366-401).	('amino acids 366-401', 'Var', (101, 120))	('GST', 'Gene', (83, 86))	('GST', 'Gene', (146, 149))	('amino acids 366-401', 'Var', (164, 183))	('GST', 'Gene', '373156', (83, 86))	('W387A', 'SUBSTITUTION', 'None', (130, 135))	('W387A', 'Var', (130, 135))	('GST', 'Gene', '373156', (146, 149))	('GST', 'Gene', (78, 81))	('mug', 'molecular_function', 'GO:0043739', ('51', '54'))	('DNA', 'cellular_component', 'GO:0005574', ('63', '66'))	('GST', 'Gene', '373156', (78, 81))
145808	31474574	GST, and GST-tagged SUGP1 (amino acids 366-401) were cloned in pGEX-4T-3 (GE Healthcare), and the W387A mutant construct of GST-tagged SUGP1 (amino acids 366-401) was generated by site-directed mutagenesis.	('GST', 'Gene', (0, 3))	('amino acids 366-401', 'Var', (142, 161))	('GST', 'Gene', (124, 127))	('GST', 'Gene', '373156', (0, 3))	('GST', 'Gene', '373156', (124, 127))	('GST', 'Gene', (9, 12))	('W387A', 'Var', (98, 103))	('mutagenesis', 'biological_process', 'GO:0006280', ('194', '205'))	('GST', 'Gene', '373156', (9, 12))	('W387A', 'SUBSTITUTION', 'None', (98, 103))
145816	31474574	To characterize the interaction between SUGP1 and U2AF2, 100 pmol purified His6-FLAG-tagged U2AF2 (amino acids 367-475) was mixed with 100 pmol purified GST, GST-tagged SUGP1 (amino acids 366-401), or the W387A mutant of GST-tagged SUGP1 (amino acids 366-401) in a total volume of 650 mul with a binding buffer (50 mM Tris-Cl, pH 7.4, 150 mM NaCl, and 0.5% Triton X-100).	('U2AF2', 'Gene', '11338', (50, 55))	('GST', 'Gene', (153, 156))	('GST', 'Gene', (158, 161))	('GST', 'Gene', (221, 224))	('W387A', 'Var', (205, 210))	('U2AF2', 'Gene', (92, 97))	('Tris-Cl', 'Chemical', '-', (318, 325))	('His6', 'Chemical', 'MESH:C471213', (75, 79))	('GST', 'Gene', '373156', (153, 156))	('GST', 'Gene', '373156', (158, 161))	('U2AF2', 'Gene', '11338', (92, 97))	('Triton X-100', 'Chemical', 'MESH:D017830', (357, 369))	('NaCl', 'Chemical', 'MESH:D012965', (342, 346))	('interaction', 'Interaction', (20, 31))	('GST', 'Gene', '373156', (221, 224))	('U2AF', 'cellular_component', 'GO:0089701', ('92', '96'))	('W387A', 'SUBSTITUTION', 'None', (205, 210))	('amino acids 366-401', 'Var', (239, 258))	('binding', 'molecular_function', 'GO:0005488', ('296', '303'))	('U2AF', 'cellular_component', 'GO:0089701', ('50', '54'))	('U2AF2', 'Gene', (50, 55))
145819	31474574	SF3B1 disease mutations disrupt SF3B1 interaction with SUGP1 in the spliceosome SUGP1 depletion completely recapitulates mutant SF3B1 splicing defects SUGP1 G-patch domain mutant also reproduces mutant SF3B1 splicing defects SUGP1 overexpression partially rescues the mutant SF3B1 spliceosome	('mutant', 'Var', (172, 178))	('SF3B1', 'Gene', '23451', (128, 133))	('SF3B1', 'Gene', (0, 5))	('splicing', 'biological_process', 'GO:0045292', ('208', '216'))	('mutant', 'Var', (268, 274))	('SF3B1', 'Gene', '23451', (32, 37))	('splicing', 'biological_process', 'GO:0045292', ('134', '142'))	('SF3B1', 'Gene', (202, 207))	('SF3B1', 'Gene', (275, 280))	('SF3B1', 'Gene', '23451', (0, 5))	('spliceosome', 'cellular_component', 'GO:0005681', ('281', '292'))	('SF3B1', 'Gene', (128, 133))	('SF3B1', 'Gene', '23451', (202, 207))	('SF3B1', 'Gene', (32, 37))	('SF3B1', 'Gene', '23451', (275, 280))	('mutations', 'Var', (14, 23))	('spliceosome', 'cellular_component', 'GO:0005681', ('68', '79'))	('interaction', 'Interaction', (38, 49))
145843	32083172	Blockage of CXCR4 gene expression by transfection with CXCR4 small interfering RNA (siRNA) has been found to inhibit invasive properties of UM cells exposed to soluble factors produced by human livers.	('soluble', 'cellular_component', 'GO:0005625', ('160', '167'))	('invasive properties of UM cells exposed', 'CPA', (117, 156))	('human', 'Species', '9606', (188, 193))	('CXCR4', 'molecular_function', 'GO:0038147', ('12', '17'))	('inhibit', 'NegReg', (109, 116))	('CXCR4', 'molecular_function', 'GO:0038147', ('55', '60'))	('CXCR4', 'Var', (55, 60))	('RNA', 'cellular_component', 'GO:0005562', ('79', '82'))	('UM', 'Phenotype', 'HP:0007716', (140, 142))	('gene expression', 'biological_process', 'GO:0010467', ('18', '33'))	('Blockage', 'NegReg', (0, 8))
145850	32083172	Immunohistochemical (IHC) analysis of CXCR4 in UM patient liver tissue revealed that CXCR4 is highly expressed in liver metastases with both nodular and infiltrative growth patterns (Fig.	('CXCR4', 'Var', (85, 90))	('CXCR4', 'molecular_function', 'GO:0038147', ('85', '90'))	('CXCR4', 'molecular_function', 'GO:0038147', ('38', '43'))	('liver metastases', 'Disease', (114, 130))	('liver metastases', 'Disease', 'MESH:D009362', (114, 130))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('patient', 'Species', '9606', (50, 57))
145852	32083172	1, D and E), which have the BAP1 gene mutation that is often observed in aggressive UM liver metastases.	('BAP1', 'Gene', '104416', (28, 32))	('aggressive UM liver metastases', 'Disease', 'MESH:D009362', (73, 103))	('aggressive UM liver metastases', 'Disease', (73, 103))	('BAP1', 'Gene', (28, 32))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('observed', 'Reg', (61, 69))	('mutation', 'Var', (38, 46))
145853	32083172	In these M20-09-196 mice, the CXCR4 immunoreactive score (IRS) of UM metastases in the liver was significantly higher than in primary UM (P < 0.05, Fig.	('metastases', 'Disease', (69, 79))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('M20-09-196', 'Var', (9, 19))	('CXCR4', 'molecular_function', 'GO:0038147', ('30', '35'))	('mice', 'Species', '10090', (20, 24))	('metastases', 'Disease', 'MESH:D009362', (69, 79))	('UM', 'Phenotype', 'HP:0007716', (134, 136))	('higher', 'PosReg', (111, 117))	('CXCR4 immunoreactive score', 'MPA', (30, 56))
145875	32083172	For other physiological metal ions such as Ca2+, ProCA32.CXCR4 also exhibited better metal selectivity than small chelator GBCAs, such as Dotarem (gadoterate meglumine) and ProHance (gadoteridol) (Fig.	('metal', 'Chemical', 'MESH:D008670', (85, 90))	('better', 'PosReg', (78, 84))	('meglumine', 'Chemical', 'MESH:D008536', (158, 167))	('metal', 'Chemical', 'MESH:D008670', (24, 29))	('ProCA32.CXCR4', 'Var', (49, 62))	('CXCR4', 'molecular_function', 'GO:0038147', ('57', '62'))	('gadoteridol', 'Chemical', 'MESH:C062402', (183, 194))	('ProHance', 'Chemical', 'MESH:C062402', (173, 181))	('Ca2+', 'Chemical', 'MESH:D000069285', (43, 47))	('metal selectivity', 'MPA', (85, 102))
145885	32083172	Molecular dynamic contrast imaging (MDCI) was performed to display implanted UM tumor in mouse liver by administration of Cys-ProCA32.CXCR4 via intravenous injection, followed by the acquisition of T1-weighted gradient echo MRI as a function of time.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Cys-ProCA32.CXCR4', 'Var', (122, 139))	('MDCI', 'Chemical', '-', (36, 40))	('tumor', 'Disease', (80, 85))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('Cys', 'Chemical', 'MESH:D003545', (122, 125))	('CXCR4', 'molecular_function', 'GO:0038147', ('134', '139'))	('mouse', 'Species', '10090', (89, 94))
145891	32083172	On the other hand, MRI results of Mel290 mice with Cys-ProCA32.CXCR4 and Lys-ProCA32 injection exhibited similar patterns of SNR changes in the liver regions over time (Fig.	('SNR changes', 'MPA', (125, 136))	('CXCR4', 'molecular_function', 'GO:0038147', ('63', '68'))	('Lys', 'Chemical', 'MESH:D008239', (73, 76))	('mice', 'Species', '10090', (41, 45))	('Lys-ProCA32', 'Var', (73, 84))	('Cys', 'Chemical', 'MESH:D003545', (51, 54))
145892	32083172	The liver SNR of both mice with Cys-ProCA32.CXCR4 and Lys-ProCA32 injection increased drastically right after injection and up to 3 hours, with a percentage increase of SNR of approximately 45% at 3 hours after injection when compared with before injection.	('Cys-ProCA32.CXCR4', 'MPA', (32, 49))	('Cys', 'Chemical', 'MESH:D003545', (32, 35))	('CXCR4', 'molecular_function', 'GO:0038147', ('44', '49'))	('increased', 'PosReg', (76, 85))	('Lys', 'Chemical', 'MESH:D008239', (54, 57))	('Lys-ProCA32', 'Var', (54, 65))	('SNR', 'MPA', (169, 172))	('increase', 'PosReg', (157, 165))	('mice', 'Species', '10090', (22, 26))
145903	32083172	In contrast, injection of Cys-ProCA32.CXCR4 resulted in maximum SNR enhancement at 24 hours after injection and returned to the baseline at 48 hours.	('mum', 'Gene', '56925', (60, 63))	('Cys-ProCA32.CXCR4', 'Var', (26, 43))	('SNR', 'MPA', (64, 67))	('mum', 'Gene', (60, 63))	('Cys', 'Chemical', 'MESH:D003545', (26, 29))	('CXCR4', 'molecular_function', 'GO:0038147', ('38', '43'))	('enhancement', 'PosReg', (68, 79))
145916	32083172	One of the hypotheses in the field postulates that tumor cells that overly express CXCR4 hijack the CXCR4/CXCL12 axis during the metastatic process and spread to the liver.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('CXCR4', 'molecular_function', 'GO:0038147', ('83', '88'))	('CXCR4', 'molecular_function', 'GO:0038147', ('100', '105'))	('CXCR4', 'Var', (83, 88))	('tumor', 'Disease', (51, 56))	('hijack', 'PosReg', (89, 95))	('CXCL12', 'Gene', '20315', (106, 112))	('CXCL12', 'Gene', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
145936	32083172	In this study, we also demonstrated that ProCA32.CXCR4 exhibits excellent tumor permeability, which is very different from most nanoparticles or chelator-based targeting contrast agents that mostly enhance the tumor boundary.	('ProCA32.CXCR4', 'Var', (41, 54))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', (74, 79))	('CXCR4', 'molecular_function', 'GO:0038147', ('49', '54'))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
145945	32083172	Moreover, the improved relaxivity of ProCA32.CXCR4 enabled excellent contrast enhancement in vivo with 75% reduction of Gd3+ dosage compared with other GBCAs.	('contrast', 'MPA', (69, 77))	('Gd3', 'Gene', (120, 123))	('CXCR4', 'molecular_function', 'GO:0038147', ('45', '50'))	('enhancement', 'PosReg', (78, 89))	('ProCA32.CXCR4', 'Var', (37, 50))	('Gd3', 'Gene', '117189', (120, 123))
146013	32083172	The final mixture contained 0.026 M KH2PO4, 0.041 M Na2HPO4, 2.5 mM Gd3+ complex, and 2.5 mM ZnCl2.	('Na2HPO4', 'Chemical', 'MESH:C018279', (52, 59))	('KH2PO4', 'Var', (36, 42))	('ZnCl2', 'Chemical', 'MESH:C016837', (93, 98))	('Gd3', 'Gene', '117189', (68, 71))	('KH2PO4', 'Chemical', '-', (36, 42))	('Gd3', 'Gene', (68, 71))
146111	31523242	Indeed, bevacizumab injections have decreased macular edema, clinically evident radiation maculopathy, and vision loss in this population.	('vision loss', 'Disease', 'MESH:D014786', (107, 118))	('bevacizumab', 'Chemical', 'MESH:D000068258', (8, 19))	('vision loss', 'Disease', (107, 118))	('macular edema', 'Phenotype', 'HP:0040049', (46, 59))	('radiation maculopathy', 'Phenotype', 'HP:0031420', (80, 101))	('injections', 'Var', (20, 30))	('edema', 'Disease', 'MESH:D004487', (54, 59))	('radiation maculopathy', 'Disease', 'MESH:D004194', (80, 101))	('edema', 'Phenotype', 'HP:0000969', (54, 59))	('radiation maculopathy', 'Disease', (80, 101))	('vision loss', 'Phenotype', 'HP:0000572', (107, 118))	('decreased', 'NegReg', (36, 45))	('vision', 'biological_process', 'GO:0007601', ('107', '113'))	('edema', 'Disease', (54, 59))
146129	31523242	For smaller exudative retinal detachments, intraoperative triamcinolone acetonide induces regression in 69% of cases, but it is associated with a side effect of steroid-induced cataract in 12% of cases.	('exudative retinal detachments', 'Phenotype', 'HP:0012231', (12, 41))	('triamcinolone acetonide', 'Chemical', 'MESH:D014222', (58, 81))	('retinal detachment', 'Disease', (22, 40))	('cataract', 'Disease', 'MESH:D002386', (177, 185))	('cataract', 'Disease', (177, 185))	('cataract', 'Phenotype', 'HP:0000518', (177, 185))	('triamcinolone acetonide', 'Var', (58, 81))	('retinal detachment', 'Disease', 'MESH:D012163', (22, 40))	('regression', 'MPA', (90, 100))	('steroid', 'Chemical', 'MESH:D013256', (161, 168))	('retinal detachments', 'Phenotype', 'HP:0000541', (22, 41))	('smaller', 'Disease', (4, 11))	('retinal detachment', 'Phenotype', 'HP:0000541', (22, 40))	('exudative retinal detachment', 'Phenotype', 'HP:0012231', (12, 40))
146259	31357497	Both comparisons (Figure 4a,b) did not show any reduction of the viability of the cell lines incubated with fucoidans, leading to the conclusion that fucoidans are generally neither directly cytotoxic nor impair the cell viability.	('fucoidans', 'Var', (150, 159))	('cell viability', 'CPA', (216, 230))	('fucoidan', 'Chemical', 'MESH:C007789', (108, 116))	('impair', 'NegReg', (205, 211))	('fucoidan', 'Chemical', 'MESH:C007789', (150, 158))
146345	31357497	It was previously described, that fucoidan fed mice developed lower tumor volume and tumor weight than the control mice after injection of blood cancer cells.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (85, 90))	('blood cancer', 'Disease', 'MESH:D009369', (139, 151))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('blood cancer', 'Phenotype', 'HP:0001909', (139, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lower', 'NegReg', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('blood cancer', 'Disease', (139, 151))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mice', 'Species', '10090', (115, 119))	('fucoidan', 'Var', (34, 42))	('mice', 'Species', '10090', (47, 51))	('fucoidan', 'Chemical', 'MESH:C007789', (34, 42))
146356	31357497	showed a decrease in cell viability of hepatocellular cell lines Hep G2 and HuH7 incubated with a mutant glypican 3 (heparan sulfate proteoglycan) without its GPI anchor.	('glypican 3', 'Gene', '2719', (105, 115))	('cell viability', 'CPA', (21, 35))	('glypican 3', 'Gene', (105, 115))	('HuH7', 'Gene', (76, 80))	('heparan sulfate', 'Chemical', 'MESH:D006497', (117, 132))	('glypican', 'molecular_function', 'GO:0015017', ('105', '113'))	('proteoglycan', 'molecular_function', 'GO:0005203', ('133', '145'))	('HuH7', 'Gene', '284424', (76, 80))	('Hep G2', 'CellLine', 'CVCL:0027', (65, 71))	('glycan', 'Chemical', 'MESH:D011134', (139, 145))	('decrease', 'NegReg', (9, 17))	('mutant', 'Var', (98, 104))
146395	31357497	11995065, 25 mM D-glucose) after adding 10% FBS and 1% penicillin/streptomycin.	('streptomycin', 'Chemical', 'MESH:D013307', (66, 78))	('11995065', 'Var', (0, 8))	('D-glucose', 'Chemical', 'MESH:D005947', (16, 25))	('FBS', 'Disease', (44, 47))	('penicillin', 'Chemical', 'MESH:D010406', (55, 65))	('FBS', 'Disease', 'MESH:D005198', (44, 47))
146445	29614755	As a result, in a melanogenically active cell, every mutation in genes coding regulatory factors, such as the cAMP response element-binding protein (CREB), PI3K/p70, c-KIT, (neuroblastoma RAS viral oncogene homolog) (NRAS), or (serine/threonine-protein kinase B-raf) (BRAF), becomes automatically expressed, manifesting itself in the pigment phenotype, and in gaining neoplastic features at the same time.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('mutation', 'Var', (53, 61))	('cAMP response element-binding protein', 'Gene', '1385', (110, 147))	('neuroblastoma RAS viral', 'Disease', 'MESH:D009447', (174, 197))	('p70', 'Gene', '309', (161, 164))	('NRAS', 'Gene', (217, 221))	('cAMP response element-binding protein', 'Gene', (110, 147))	('B-raf', 'Gene', (260, 265))	('BRAF', 'Gene', '673', (268, 272))	('CREB', 'Gene', (149, 153))	('neuroblastoma', 'Phenotype', 'HP:0003006', (174, 187))	('BRAF', 'Gene', (268, 272))	('B-raf', 'Gene', '673', (260, 265))	('protein', 'cellular_component', 'GO:0003675', ('245', '252'))	('neoplastic features', 'CPA', (368, 387))	('neuroblastoma RAS viral', 'Disease', (174, 197))	('p70', 'Gene', (161, 164))	('KIT', 'molecular_function', 'GO:0005020', ('168', '171'))	('NRAS', 'Gene', '4893', (217, 221))	('CREB', 'Gene', '1385', (149, 153))	('c-KIT', 'Gene', (166, 171))	('gaining', 'PosReg', (360, 367))	('cAMP response element-binding', 'molecular_function', 'GO:0035497', ('110', '139'))	('PI3K', 'molecular_function', 'GO:0016303', ('156', '160'))	('c-KIT', 'Gene', '3815', (166, 171))
146483	29614755	Another important feature of the Syrian hamsters is the variability in hair-coat coloration phenotypes, with numerous color mutants, which makes them particularly interesting objects of genetic studies and studies on the influence of hair color phenotypes on melanoma development.	('mutants', 'Var', (124, 131))	('Syrian hamsters', 'Species', '10036', (33, 48))	('melanoma', 'Disease', 'MESH:D008545', (259, 267))	('melanoma', 'Phenotype', 'HP:0002861', (259, 267))	('melanoma', 'Disease', (259, 267))	('hair-coat', 'Disease', (71, 80))	('rat', 'Species', '10116', (85, 88))	('hair-coat', 'Disease', 'MESH:D058456', (71, 80))
146504	29614755	Apart from the higher proportion of cells in S/G2/M phases (Table 1), the Ab line also has a decreased ability to undergo spontaneous apoptosis in comparison to the Ma line.	('S/G2', 'SUBSTITUTION', 'None', (45, 49))	('apoptosis', 'biological_process', 'GO:0006915', ('134', '143'))	('spontaneous apoptosis', 'CPA', (122, 143))	('decreased', 'NegReg', (93, 102))	('S/G2', 'Var', (45, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('134', '143'))
146532	29614755	During the first 2 to 3 days, disappearance of the implants was observed, followed by the appearance of iris tumors after 4-6 days in the case of BHM Ab, and after 8-10 days in the case of BHM Ma.	('BHM', 'Var', (146, 149))	('iris tumors', 'Disease', (104, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('iris tumors', 'Disease', 'MESH:D015811', (104, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
146561	29614755	Combining PDT with a very low-dose rate of gamma-irradiation was found to lead to tumor inhibition.	('PDT', 'Var', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('rat', 'Species', '10116', (35, 38))	('tumor', 'Disease', (82, 87))
146564	29614755	The cumulative results indicate that MC540-mediated PDT in combination with ionizing radiation has significant effects on the rapidly growing melanoma in the eye.	('MC540-mediated', 'Var', (37, 51))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('PDT', 'Gene', (52, 55))	('MC540', 'Chemical', 'MESH:C003954', (37, 42))	('effects', 'Reg', (111, 118))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma', 'Disease', (142, 150))
146593	29614755	Selection of BHM MI for less and more pigmented variants generated sub-lines with significantly different levels of melanin and tyrosinase, but without any significant effect on growth rate.	('different', 'Reg', (96, 105))	('variants', 'Var', (48, 56))	('rat', 'Species', '10116', (61, 64))	('MI', 'Chemical', 'MESH:C011506', (17, 19))	('BHM MI', 'Gene', (13, 19))	('rat', 'Species', '10116', (185, 188))	('melanin and tyrosinase', 'Gene', '7299', (116, 138))
146611	29614755	The latter consideration is in agreement with recent clinical and pathological studies that have demonstrated that the presence of melanin in metastatic melanomas attenuated the positive outcome of radiotherapy.	('rat', 'Species', '10116', (18, 21))	('melanin', 'Chemical', 'MESH:D008543', (131, 138))	('melanomas', 'Phenotype', 'HP:0002861', (153, 162))	('melanomas attenuated', 'Disease', (153, 173))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('positive outcome of radiotherapy', 'CPA', (178, 210))	('presence', 'Var', (119, 127))	('melanomas attenuated', 'Disease', 'MESH:C538265', (153, 173))	('rat', 'Species', '10116', (104, 107))
146624	29614755	Additionally, Shields and co-authors observed that the presence of melanin was found to be an unfavorable marker of metastasis and death in a multivariable analysis of ciliary body and choroidal melanomas.	('presence', 'Var', (55, 63))	('melanin', 'Chemical', 'MESH:D008543', (67, 74))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (185, 203))	('choroidal melanomas', 'Disease', 'MESH:D008545', (185, 204))	('melanomas', 'Phenotype', 'HP:0002861', (195, 204))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (185, 204))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('death', 'Disease', 'MESH:D003643', (131, 136))	('death', 'Disease', (131, 136))	('choroidal melanomas', 'Disease', (185, 204))
146635	29614755	Within the eye, radiation can cause cataract, retinopathy, optic neuropathy, hemorrhage, retinal detachment, neovascularization, and secondary glaucoma.	('hemorrhage', 'Disease', 'MESH:D006470', (77, 87))	('cataract', 'Disease', (36, 44))	('retinopathy', 'Disease', (46, 57))	('neuropathy', 'Phenotype', 'HP:0009830', (65, 75))	('optic neuropathy', 'Phenotype', 'HP:0001138', (59, 75))	('neovascularization', 'Disease', (109, 127))	('cataract', 'Disease', 'MESH:D002386', (36, 44))	('retinal detachment', 'Phenotype', 'HP:0000541', (89, 107))	('retinopathy', 'Disease', 'MESH:D012164', (46, 57))	('optic neuropathy', 'Disease', 'MESH:D009901', (59, 75))	('retinopathy', 'Phenotype', 'HP:0000488', (46, 57))	('hemorrhage', 'Disease', (77, 87))	('radiation', 'Var', (16, 25))	('cause', 'Reg', (30, 35))	('glaucoma', 'Phenotype', 'HP:0000501', (143, 151))	('glaucoma', 'Disease', (143, 151))	('cataract', 'Phenotype', 'HP:0000518', (36, 44))	('glaucoma', 'Disease', 'MESH:D005901', (143, 151))	('retinal detachment', 'Disease', (89, 107))	('retinal detachment', 'Disease', 'MESH:D012163', (89, 107))	('optic neuropathy', 'Disease', (59, 75))
146655	29614755	Six months after the indocyanine-PDT treatment, changes in microcirculation were detected in all cases as well as a significant decrease in tumor thickness in ultrasonography (mean 38%).	('microcirculation', 'MPA', (59, 75))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('indocyanine', 'Chemical', '-', (21, 32))	('indocyanine-PDT', 'Var', (21, 36))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('changes', 'Reg', (48, 55))	('decrease', 'NegReg', (128, 136))	('tumor', 'Disease', (140, 145))
146681	28124977	The Long Non-Coding RNA RHPN1-AS1 Promotes Uveal Melanoma Progression Increasing evidence suggests that aberrant long non-coding RNAs (lncRNAs) are significantly correlated with the pathogenesis, development and metastasis of cancers.	('pathogenesis', 'biological_process', 'GO:0009405', ('182', '194'))	('Promotes', 'PosReg', (34, 42))	('Melanoma', 'Disease', 'MESH:D008545', (49, 57))	('metastasis of cancers', 'Disease', 'MESH:D009362', (212, 233))	('Melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('AS1', 'Gene', '5729', (30, 33))	('AS1', 'Gene', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('RHPN1', 'Gene', (24, 29))	('Melanoma', 'Disease', (49, 57))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('aberrant', 'Var', (104, 112))	('RNA', 'cellular_component', 'GO:0005562', ('20', '23'))	('RHPN1', 'Gene', '114822', (24, 29))	('correlated with', 'Reg', (162, 177))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('metastasis of cancers', 'Disease', (212, 233))
146690	28124977	Recent studies have shown that somatic mutations occur in a mutually exclusive pattern in Guanine Nucleotide-Binding Protein alpha-Q (GNAQ) or Guanine Nucleotide-Binding Protein G alpha-11 (GNA11) in ~83% of UM cases, and inactivating somatic mutations of BRCA associated protein-1 (BAP1) occur in ~84% of metastasizing tumors.	('GNA11', 'Gene', (190, 195))	('BRCA associated protein-1', 'Gene', '8314', (256, 281))	('GNAQ', 'Gene', (134, 138))	('tumors', 'Disease', 'MESH:D009369', (320, 326))	('Nucleotide-Binding', 'molecular_function', 'GO:0000166', ('151', '169'))	('Nucleotide-Binding', 'molecular_function', 'GO:0000166', ('98', '116'))	('Guanine Nucleotide-Binding Protein G alpha-11', 'Gene', (143, 188))	('UM', 'Phenotype', 'HP:0007716', (208, 210))	('Guanine Nucleotide-Binding Protein alpha-Q', 'Gene', '2776', (90, 132))	('mutations', 'Var', (39, 48))	('BAP1', 'Gene', '8314', (283, 287))	('Guanine Nucleotide-Binding Protein alpha-Q', 'Gene', (90, 132))	('GNA11', 'Gene', '2767', (190, 195))	('inactivating', 'Var', (222, 234))	('tumors', 'Phenotype', 'HP:0002664', (320, 326))	('protein', 'cellular_component', 'GO:0003675', ('272', '279'))	('BAP1', 'Gene', (283, 287))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('BRCA associated protein-1', 'Gene', (256, 281))	('tumors', 'Disease', (320, 326))	('Guanine Nucleotide-Binding Protein G alpha-11', 'Gene', '2767', (143, 188))	('GNAQ', 'Gene', '2776', (134, 138))
146694	28124977	Aberrant expression of lncRNAs has been shown to contribute to tumorigenesis in cancers such as prostate cancer, gastric cancer and leukemia, and we previously conducted a study of cDNA microarrays in UM samples and normal tissues (data unpublished).	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('lncRNAs', 'Gene', (23, 30))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('prostate cancer', 'Disease', 'MESH:D011471', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('UM', 'Phenotype', 'HP:0007716', (201, 203))	('prostate cancer', 'Disease', (96, 111))	('leukemia', 'Phenotype', 'HP:0001909', (132, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('tumor', 'Disease', (63, 68))	('Aberrant expression', 'Var', (0, 19))	('cancers', 'Disease', (80, 87))	('leukemia', 'Disease', 'MESH:D007938', (132, 140))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('contribute', 'Reg', (49, 59))	('leukemia', 'Disease', (132, 140))	('gastric cancer', 'Disease', (113, 127))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
146696	28124977	Down regulating RHPN1-AS1 in a variety of UM cells inhibitedcolony formation, migration and invasionin vitroand tumor growthin vivo.	('RHPN1-AS1', 'Gene', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('formation', 'biological_process', 'GO:0009058', ('67', '76'))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Down regulating', 'Var', (0, 15))	('migration', 'CPA', (78, 87))	('tumor', 'Disease', (112, 117))	('inhibitedcolony formation', 'CPA', (51, 76))	('UM', 'Phenotype', 'HP:0007716', (42, 44))
146703	28124977	Next, we investigated whether the characteristics of the tumor cells were altered after RHPN1-AS1 knockdown.	('RHPN1-AS1', 'Gene', (88, 97))	('knockdown', 'Var', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('altered', 'Reg', (74, 81))	('tumor', 'Disease', (57, 62))
146704	28124977	We first examined the colony formation ability of shRHPN1-AS1-OCM1 cells and shRHPN1-AS1-OM431 cells compared to the control and mock groups using the colony formation assay.	('formation', 'biological_process', 'GO:0009058', ('158', '167'))	('shRHPN1-AS1-OCM1', 'Var', (50, 66))	('OCM1', 'Species', '83984', (62, 66))	('AS1-OM431', 'CellLine', 'CVCL:J308', (85, 94))	('colony formation ability', 'CPA', (22, 46))	('formation', 'biological_process', 'GO:0009058', ('29', '38'))
146705	28124977	The results demonstrated that the RHPN1-AS1 knockdown inhibited UM cell migration by ~55% in OCM1 cells and by ~50% in OM431 cells, respectively (p < 0.05, Figure 3B) using trans-well assay.	('inhibited', 'NegReg', (54, 63))	('RHPN1-AS1', 'Gene', (34, 43))	('UM cell migration', 'CPA', (64, 81))	('knockdown', 'Var', (44, 53))	('cell migration', 'biological_process', 'GO:0016477', ('67', '81'))	('UM', 'Phenotype', 'HP:0007716', (64, 66))	('OCM1', 'Species', '83984', (93, 97))	('OM431', 'CellLine', 'CVCL:J308', (119, 124))
146709	28124977	Fourteen days after injection, the tumor growth of RHPN1-AS1-sh1OCM1 cells was significant slower than that of control cells (p < 0.05, Figure 4A).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('RHPN1-AS1-sh1OCM1', 'Var', (51, 68))	('slower', 'NegReg', (91, 97))	('OCM1', 'Species', '83984', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))
146711	28124977	The average tumor weight of RHPN1-AS1-sh1OCM1 cells was significantly lower than that of the control cells (p < 0.05, Figure 4C).	('RHPN1-AS1-sh1OCM1', 'Var', (28, 45))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('lower', 'NegReg', (70, 75))	('OCM1', 'Species', '83984', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
146712	28124977	These data indicate that the growth of the tumors was impaired after RHPN1-AS1 knockdown in vivo.	('impaired', 'NegReg', (54, 62))	('RHPN1-AS1', 'Gene', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('knockdown', 'Var', (79, 88))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
146719	28124977	However, BRAF mutations are rare in UM, and GNAQ and GNA11 are typically mutated in UM.	('GNAQ', 'Gene', (44, 48))	('BRAF', 'Gene', (9, 13))	('GNA11', 'Gene', (53, 58))	('GNA11', 'Gene', '2767', (53, 58))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('GNAQ', 'Gene', '2776', (44, 48))	('mutations', 'Var', (14, 23))	('BRAF', 'Gene', '673', (9, 13))
146721	28124977	GNAQ is inversely associated with chromosome 3 monosomy and metastasis; and BAP1 is significantly associated with chromosome 3 monosomy but not with relapse.	('GNAQ', 'Gene', '2776', (0, 4))	('chromosome', 'cellular_component', 'GO:0005694', ('114', '124'))	('associated', 'Interaction', (98, 108))	('chromosome', 'cellular_component', 'GO:0005694', ('34', '44'))	('BAP1', 'Gene', '8314', (76, 80))	('GNAQ', 'Gene', (0, 4))	('BAP1', 'Gene', (76, 80))	('chromosome', 'Var', (34, 44))	('metastasis', 'CPA', (60, 70))	('associated', 'Interaction', (18, 28))
146725	28124977	PCAT-1 knockdown increases cell proliferation, suggesting that PCAT-1 might contribute to prostate cancer progression.	('increases', 'PosReg', (17, 26))	('prostate cancer', 'Disease', 'MESH:D011471', (90, 105))	('PCAT-1', 'Gene', (0, 6))	('cell proliferation', 'CPA', (27, 45))	('prostate cancer', 'Disease', (90, 105))	('PCAT-1', 'Gene', (63, 69))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('PCAT-1', 'Gene', '100750225', (0, 6))	('PCAT-1', 'Gene', '100750225', (63, 69))	('knockdown', 'Var', (7, 16))	('contribute', 'Reg', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cell proliferation', 'biological_process', 'GO:0008283', ('27', '45'))
146730	28124977	To determine the relationship between RHPN1-AS1 and RHPN1, we examined the mRNA and protein level of RHPN1 after knocking down endogenous RHPN1-AS1 expression in OCM1 and OM431 cells using qPCR and western blot.	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('RHPN1', 'Gene', (101, 106))	('RHPN1-AS1', 'Gene', (138, 147))	('knocking', 'Var', (113, 121))	('expression', 'MPA', (148, 158))	('OCM1', 'Species', '83984', (162, 166))	('OM431', 'CellLine', 'CVCL:J308', (171, 176))
146732	28124977	It is noteworthy that TGF-beta signaling pathway, which has a tremendous impact on the regulation of EMT is significantly changed after RHPN1-AS1 knockdown.	('knockdown', 'Var', (146, 155))	('RHPN1-AS1', 'Gene', (136, 145))	('signaling pathway', 'biological_process', 'GO:0007165', ('31', '48'))	('TGF-beta', 'Gene', '7040', (22, 30))	('EMT', 'biological_process', 'GO:0001837', ('101', '104'))	('TGF-beta', 'Gene', (22, 30))	('regulation', 'biological_process', 'GO:0065007', ('87', '97'))	('changed', 'Reg', (122, 129))
146734	28124977	Therefore, we hypothesize that RHPN1-AS1 may promote UM progression at least partly through interplay with TGF-beta signaling pathway.	('RHPN1-AS1', 'Var', (31, 40))	('UM progression', 'CPA', (53, 67))	('TGF-beta', 'Gene', (107, 115))	('signaling pathway', 'biological_process', 'GO:0007165', ('116', '133'))	('UM', 'Phenotype', 'HP:0007716', (53, 55))	('promote', 'PosReg', (45, 52))	('TGF-beta', 'Gene', '7040', (107, 115))
146797	25947067	Immunohistochemistry showed positive staining for CD5, CD20, CD23, CD38, CD79a, CD45RO, Bcl-2, Kappa, Lambda, LCA, Vimentin and Ki-67 (5%-10% positive cells), whereas CD10, Bcl-6 and Cyclin D1 were negative (Figure 5A-H).	('CD23', 'Gene', (61, 65))	('Vimentin', 'cellular_component', 'GO:0045099', ('115', '123'))	('LCA', 'Gene', '1211', (110, 113))	('CD23', 'Gene', '2208', (61, 65))	('CD79a', 'Gene', (73, 78))	('LCA', 'Gene', (110, 113))	('Cyclin D1', 'Gene', '595', (183, 192))	('Bcl-2', 'molecular_function', 'GO:0015283', ('88', '93'))	('Cyclin D1', 'Gene', (183, 192))	('Bcl-6', 'Gene', (173, 178))	('Vimentin', 'cellular_component', 'GO:0045098', ('115', '123'))	('CD10', 'Gene', '4311', (167, 171))	('CD5', 'Gene', (50, 53))	('Cyclin', 'molecular_function', 'GO:0016538', ('183', '189'))	('Bcl-6', 'Gene', '604', (173, 178))	('CD38', 'Gene', '952', (67, 71))	('Bcl-2', 'Gene', (88, 93))	('CD20', 'Gene', (55, 59))	('Vimentin', 'Gene', '7431', (115, 123))	('CD10', 'Gene', (167, 171))	('CD5', 'Gene', '921', (50, 53))	('CD20', 'Gene', '54474', (55, 59))	('Vimentin', 'Gene', (115, 123))	('CD45RO', 'Var', (80, 86))	('Bcl-2', 'Gene', '596', (88, 93))	('CD10', 'molecular_function', 'GO:0004245', ('167', '171'))	('CD79a', 'Gene', '973', (73, 78))	('CD38', 'Gene', (67, 71))
146824	23226204	Phase II Trial of Sorafenib in Combination with Carboplatin and Paclitaxel in Patients with Metastatic Uveal Melanoma: SWOG S0512 Sorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, inhibits the mitogen-activated protein kinase pathway that is activated in most uveal melanoma tumors.	('Metastatic Uveal Melanoma', 'Disease', 'MESH:C536494', (92, 117))	('uveal melanoma', 'Phenotype', 'HP:0007716', (285, 299))	('SWOG', 'Var', (119, 123))	('cell proliferation', 'biological_process', 'GO:0008283', ('168', '186'))	('tumors', 'Phenotype', 'HP:0002664', (300, 306))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('inhibits', 'NegReg', (205, 213))	('protein', 'cellular_component', 'GO:0003675', ('236', '243'))	('angiogenesis', 'biological_process', 'GO:0001525', ('191', '203'))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (285, 306))	('uveal melanoma tumors', 'Disease', (285, 306))	('Sorafenib', 'Chemical', 'MESH:D000077157', (130, 139))	('Sorafenib', 'Chemical', 'MESH:D000077157', (18, 27))	('Metastatic Uveal Melanoma', 'Disease', (92, 117))	('Carboplatin', 'Chemical', 'MESH:D016190', (48, 59))	('Patients', 'Species', '9606', (78, 86))	('Melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (291, 299))	('Paclitaxel', 'Chemical', 'MESH:D017239', (64, 74))	('mitogen-activated protein kinase pathway', 'Pathway', (218, 258))
146836	23226204	Loco-regional therapies to the liver like radiofrequency ablation, cryoablation, chemoembolization or isolated hepatic perfusion therapy may delay the progression of hepatic metastases and may lead to palliation of cancer symptoms in selected patients.	('cancer', 'Disease', (215, 221))	('patients', 'Species', '9606', (243, 251))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('palliation', 'Disease', (201, 211))	('delay', 'NegReg', (141, 146))	('cryoablation', 'Var', (67, 79))	('hepatic metastases', 'Disease', (166, 184))	('radiofrequency', 'Var', (42, 56))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('hepatic metastases', 'Disease', 'MESH:D009362', (166, 184))	('lead to', 'Reg', (193, 200))
146902	23226204	Also, the mechanisms of activation of MAPK-pathway in uveal melanoma appear to be distinct from cutaneous melanoma, as mutations in NRAS or BRAF are rarely found.	('NRAS', 'Gene', '4893', (132, 136))	('MAPK', 'Gene', (38, 42))	('cutaneous melanoma', 'Disease', (96, 114))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (96, 114))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (96, 114))	('BRAF', 'Gene', '673', (140, 144))	('MAPK', 'Gene', '5594', (38, 42))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('uveal melanoma', 'Disease', (54, 68))	('BRAF', 'Gene', (140, 144))	('uveal melanoma', 'Disease', 'MESH:C536494', (54, 68))	('activation', 'PosReg', (24, 34))	('mutations', 'Var', (119, 128))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('NRAS', 'Gene', (132, 136))	('MAPK', 'molecular_function', 'GO:0004707', ('38', '42'))
146903	23226204	Instead, mutually exclusive mutations in GNAQ and GNA11 (genes encoding small GTPases, which usually mediate signals from G-coupled receptors) that lead to the constitutive activation of several downstream signaling pathways including the MAPK-pathway have been implicated in the pathogenesis of the majority (greater than 80%) of uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (331, 346))	('GNA11', 'Gene', '2767', (50, 55))	('uveal melanoma', 'Phenotype', 'HP:0007716', (331, 345))	('implicated', 'Reg', (262, 272))	('uveal melanomas', 'Disease', (331, 346))	('uveal melanomas', 'Phenotype', 'HP:0007716', (331, 346))	('melanomas', 'Phenotype', 'HP:0002861', (337, 346))	('MAPK', 'Gene', (239, 243))	('GNAQ', 'Gene', '2776', (41, 45))	('GNAQ', 'Gene', (41, 45))	('downstream signaling pathways', 'Pathway', (195, 224))	('MAPK', 'Gene', '5594', (239, 243))	('mutations', 'Var', (28, 37))	('melanoma', 'Phenotype', 'HP:0002861', (337, 345))	('signaling', 'biological_process', 'GO:0023052', ('206', '215'))	('pathogenesis', 'biological_process', 'GO:0009405', ('280', '292'))	('activation', 'PosReg', (173, 183))	('GNA11', 'Gene', (50, 55))	('MAPK', 'molecular_function', 'GO:0004707', ('239', '243'))
146904	23226204	The recent discovery of paradoxical activation of the MAPK-pathway with RAF inhibitors in BRAF-wild type tumors raises the possibility that the use of a RAF inhibitor (sorafenib) could even have been counter-productive in uveal melanoma with GNAQ/GNA11 mutations, and may have negated the potential therapeutic benefits of sorafenib through mechanisms other than MAPK-inhibition.	('BRAF', 'Gene', (90, 94))	('sorafenib', 'Chemical', 'MESH:D000077157', (323, 332))	('activation', 'PosReg', (36, 46))	('RAF', 'Gene', '22882', (153, 156))	('MAPK', 'molecular_function', 'GO:0004707', ('363', '367'))	('MAPK', 'molecular_function', 'GO:0004707', ('54', '58'))	('type tumors', 'Disease', (100, 111))	('RAF', 'Gene', '22882', (72, 75))	('mutations', 'Var', (253, 262))	('GNA11', 'Gene', '2767', (247, 252))	('GNAQ', 'Gene', '2776', (242, 246))	('RAF', 'Gene', (153, 156))	('MAPK', 'Gene', '5594', (54, 58))	('GNAQ', 'Gene', (242, 246))	('RAF', 'Gene', (72, 75))	('uveal melanoma', 'Disease', 'MESH:C536494', (222, 236))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('RAF', 'Gene', '22882', (91, 94))	('uveal melanoma', 'Disease', (222, 236))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('MAPK', 'Gene', (363, 367))	('MAPK', 'Gene', (54, 58))	('sorafenib', 'Chemical', 'MESH:D000077157', (168, 177))	('type tumors', 'Disease', 'MESH:D009369', (100, 111))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('uveal melanoma', 'Phenotype', 'HP:0007716', (222, 236))	('GNA11', 'Gene', (247, 252))	('RAF', 'Gene', (91, 94))	('MAPK', 'Gene', '5594', (363, 367))	('BRAF', 'Gene', '673', (90, 94))
146970	32894202	These include the tumor molecular features including T cell infiltrate, mutational load, gut microbiome, germline genetics, proteomic biomarkers and possibly ethnicity.	('tumor', 'Disease', (18, 23))	('mutational load', 'Var', (72, 87))	('gut microbiome', 'Species', '749906', (89, 103))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
146972	32894202	Two autoimmune germline variants as potential biomarkers of anti-CTLA4 or anti-PD1 immune checkpoint inhibitors (ICI) efficacy in melanoma were identified and suggests that underlying genetic susceptibility to autoimmunity may play an important role during ICI treatments.	('CTLA4', 'Gene', '1493', (65, 70))	('variants', 'Var', (24, 32))	('CTLA4', 'Gene', (65, 70))	('autoimmunity', 'Phenotype', 'HP:0002960', (210, 222))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Disease', (130, 138))	('if', 'Gene', '17319', (149, 151))
146973	32894202	rs1893217 in PTPN2, involved in cytokine signaling, has been associated with colitis, celiac disease, inflammatory bowel, rheumatoid arthritis and type 1 diabetes.	('diabetes', 'Disease', (154, 162))	('celiac disease', 'Disease', 'MESH:D002446', (86, 100))	('arthritis', 'Phenotype', 'HP:0001369', (133, 142))	('rs1893217', 'Var', (0, 9))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (122, 142))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (147, 162))	('rs1893217', 'Mutation', 'rs1893217', (0, 9))	('colitis', 'Disease', (77, 84))	('associated', 'Reg', (61, 71))	('rheumatoid arthritis', 'Disease', (122, 142))	('diabetes', 'Disease', 'MESH:D003920', (154, 162))	('inflammatory bowel', 'Disease', (102, 120))	('colitis', 'Disease', 'MESH:D003092', (77, 84))	('celiac disease', 'Disease', (86, 100))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('PTPN2', 'Gene', (13, 18))	('celiac disease', 'Phenotype', 'HP:0002608', (86, 100))	('PTPN2', 'Gene', '5771', (13, 18))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (122, 142))	('inflammatory bowel', 'Disease', 'MESH:D015212', (102, 120))	('colitis', 'Phenotype', 'HP:0002583', (77, 84))
146974	32894202	Similarly, rs17388568 was mapped to important immune-related genes (IL-2, IL-21 and ADAD1) and associated with allergy, colitis and type 1 diabetes.	('rs17388568', 'Var', (11, 21))	('IL-2', 'molecular_function', 'GO:0005134', ('68', '72'))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (132, 147))	('associated', 'Reg', (95, 105))	('IL-2', 'Gene', (74, 78))	('ADAD1', 'Gene', '132612', (84, 89))	('colitis', 'Disease', (120, 127))	('ADAD1', 'Gene', (84, 89))	('colitis', 'Disease', 'MESH:D003092', (120, 127))	('diabetes', 'Disease', 'MESH:D003920', (139, 147))	('IL-2', 'Gene', '3558', (68, 72))	('allergy', 'Disease', 'MESH:D004342', (111, 118))	('IL-21', 'molecular_function', 'GO:0001531', ('74', '79'))	('IL-2', 'Gene', '3558', (74, 78))	('IL-21', 'Gene', (74, 79))	('rs17388568', 'Mutation', 'rs17388568', (11, 21))	('allergy', 'Disease', (111, 118))	('IL-21', 'Gene', '59067', (74, 79))	('allergy', 'Phenotype', 'HP:0012393', (111, 118))	('colitis', 'Phenotype', 'HP:0002583', (120, 127))	('diabetes', 'Disease', (139, 147))	('IL-2', 'Gene', (68, 72))
146982	32894202	However, epigenetic downregulation of cGAs and/or STING in some tumors may preclude the activation of IFN type I by radiation therapy (REF: PMID: 29367762).	('IFN', 'Gene', '3439', (102, 105))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('preclude', 'NegReg', (75, 83))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('epigenetic', 'Var', (9, 19))	('IFN', 'Gene', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('cGAs', 'Protein', (38, 42))
146987	32894202	In the non-canonical pathway, CD38 catalyzes the conversion of NAD+ to ADPR and CD203a converts ADPR to AMP (PMID: 27209048).	('CD203a', 'Var', (80, 86))	('ADPR', 'Chemical', '-', (71, 75))	('AMP', 'Chemical', 'MESH:D000249', (104, 107))	('ADPR', 'Chemical', '-', (96, 100))	('CD38', 'Gene', '952', (30, 34))	('NAD+', 'Chemical', 'MESH:D009243', (63, 67))	('ADPR', 'MPA', (96, 100))	('CD38', 'Gene', (30, 34))
146988	32894202	Radiation-induced cell death is associated with release of ATP and NAD+ in the TME, but we found that radiation also induces the upregulation of CD38, CD203a and CD73 on cancer cells.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('NAD+', 'Chemical', 'MESH:D009243', (67, 71))	('death', 'Disease', (23, 28))	('cancer', 'Disease', (170, 176))	('cell death', 'biological_process', 'GO:0008219', ('18', '28'))	('ATP', 'Gene', (59, 62))	('upregulation', 'PosReg', (129, 141))	('CD38', 'Gene', (145, 149))	('CD73', 'Gene', '4907', (162, 166))	('ATP', 'Gene', '51761', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('CD73', 'Gene', (162, 166))	('CD38', 'Gene', '952', (145, 149))	('death', 'Disease', 'MESH:D003643', (23, 28))	('CD203a', 'Var', (151, 157))
147001	32894202	Correlation between increased CD8+ T cell IFN-gamma release and serum IgG binding was also demonstrated by a study in which female BALB/c mice were vaccinated with a combination of an autophagosome-enriched vaccine derived from 4T1 mammary carcinoma along with poly-I:C adjuvant where serum was screened for IgG binding to arrays of peptides containing known mutation sites in 4T1.	('mutation sites', 'Var', (359, 373))	('increased', 'PosReg', (20, 29))	('CD8', 'Gene', (30, 33))	('CD8', 'Gene', '925', (30, 33))	('carcinoma', 'Disease', (240, 249))	('carcinoma', 'Disease', 'MESH:D009369', (240, 249))	('mice', 'Species', '10090', (138, 142))	('autophagosome', 'cellular_component', 'GO:0005776', ('184', '197'))	('IgG binding', 'molecular_function', 'GO:0019864', ('308', '319'))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (232, 249))	('IgG binding', 'molecular_function', 'GO:0019864', ('70', '81'))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('poly-I', 'Chemical', 'MESH:D011069', (261, 267))	('4T1', 'Gene', (377, 380))
147037	32894202	BRAF mutation has been shown to downregulate HLA class I and tumor antigen expression on melanoma cells.	('downregulate', 'NegReg', (32, 44))	('HLA class I', 'Protein', (45, 56))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mutation', 'Var', (5, 13))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Disease', (89, 97))	('tumor', 'Disease', (61, 66))	('tumor antigen', 'molecular_function', 'GO:0008222', ('61', '74'))
147055	32894202	Studies examining possible predictive biomarkers of response to immunotherapy have reported a higher density of preexisting cytotoxic T lymphocytes in tumor biopsies of patients who displayed a greater response to anti-PD-1/PD-L1 immunotherapy, and more significantly, an increased influx of T cells and PD-L1 macrophages early during treatment.	('increased', 'PosReg', (272, 281))	('influx', 'MPA', (282, 288))	('patients', 'Species', '9606', (169, 177))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('increased influx of T cells', 'Phenotype', 'HP:0100828', (272, 299))	('tumor', 'Disease', (151, 156))	('anti-PD-1/PD-L1', 'Var', (214, 229))	('if', 'Gene', '17319', (258, 260))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
147070	32894202	JAK1/2 mutations have also recently been identified as genetic markers of acquired resistance to immunotherapy in melanoma that is responsible for cell proliferation, differentiation, cell migration, and apoptosis.	('if', 'Gene', '17319', (156, 158))	('JAK1/2', 'Gene', '3716;3717', (0, 6))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('melanoma', 'Disease', (114, 122))	('cell proliferation', 'biological_process', 'GO:0008283', ('147', '165'))	('cell migration', 'biological_process', 'GO:0016477', ('184', '198'))	('apoptosis', 'biological_process', 'GO:0097194', ('204', '213'))	('JAK1/2', 'Gene', (0, 6))	('if', 'Gene', '17319', (168, 170))	('apoptosis', 'biological_process', 'GO:0006915', ('204', '213'))	('JAK', 'molecular_function', 'GO:0004713', ('0', '3'))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('if', 'Gene', '17319', (46, 48))	('mutations', 'Var', (7, 16))
147096	32894202	A meta-analysis in patients with metastatic uveal melanoma treated with anti-PD-1/PD-L1s reported an ORR of only 3.6% and a median PFS of 2.6 months.	('patients', 'Species', '9606', (19, 27))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('anti-PD-1/PD-L1s', 'Var', (72, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('uveal melanoma', 'Disease', (44, 58))
147102	32894202	The vast majority (85-95%) of uveal melanoma is characterized by activating mutations in genes encoding the G-protein-alpha subunits GNAQ or GNA11, which lead to stimulation of the MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways.	('GNA11', 'Gene', '2767', (141, 146))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('mutations', 'Var', (76, 85))	('Akt', 'Gene', (227, 230))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('GNAQ', 'Gene', (133, 137))	('phosphatidylinositol 3-kinase', 'Gene', (190, 219))	('phosphatidylinositol 3-kinase', 'Gene', '5291', (190, 219))	('uveal melanoma', 'Disease', 'MESH:C536494', (30, 44))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('uveal melanoma', 'Disease', (30, 44))	('stimulation', 'PosReg', (162, 173))	('Akt', 'Gene', '207', (227, 230))	('GNA11', 'Gene', (141, 146))	('GNAQ', 'Gene', '2776', (133, 137))	('MAPK', 'molecular_function', 'GO:0004707', ('181', '185'))	('PI3K', 'molecular_function', 'GO:0016303', ('221', '225'))
147103	32894202	Several other genetic alterations have been implicated in the development of uveal melanoma.	('genetic alterations', 'Var', (14, 33))	('implicated', 'Reg', (44, 54))	('uveal melanoma', 'Disease', 'MESH:C536494', (77, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (77, 91))	('uveal melanoma', 'Disease', (77, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
147104	32894202	Inactivating mutations in BAP1, a tumor suppressor gene located on chromosome 3p, are found in approximately 47% of primary uveal melanoma and 84% of metastatic uveal melanoma cases, consistent with the association between BAP1 mutations and poor prognosis.	('BAP1', 'Gene', '8314', (223, 227))	('uveal melanoma', 'Disease', (124, 138))	('uveal melanoma', 'Disease', 'MESH:C536494', (124, 138))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('BAP1', 'Gene', (26, 30))	('tumor', 'Disease', (34, 39))	('uveal melanoma', 'Phenotype', 'HP:0007716', (124, 138))	('BAP1', 'Gene', (223, 227))	('Inactivating mutations', 'Var', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('uveal melanoma', 'Disease', 'MESH:C536494', (161, 175))	('uveal melanoma', 'Disease', (161, 175))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))	('found', 'Reg', (86, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (161, 175))	('chromosome', 'cellular_component', 'GO:0005694', ('67', '77'))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('BAP1', 'Gene', '8314', (26, 30))
147105	32894202	Mutations in splicing factor 3B subunit 1 (SF3B1), involved in pre-messenger RNA splicing, while associated with more favorable prognostic features than BAP1 mutations, are also found in cases of delayed metastasis, with a median of 8.2 years.	('SF3B1', 'Gene', (43, 48))	('BAP1', 'Gene', (153, 157))	('RNA splicing', 'biological_process', 'GO:0008380', ('77', '89'))	('SF3B1', 'Gene', '23451', (43, 48))	('BAP1', 'Gene', '8314', (153, 157))	('splicing factor 3B subunit 1', 'Gene', '23451', (13, 41))	('RNA', 'cellular_component', 'GO:0005562', ('77', '80'))	('Mutations', 'Var', (0, 9))	('found', 'Reg', (178, 183))	('pre', 'molecular_function', 'GO:0003904', ('63', '66'))	('delayed metastasis', 'CPA', (196, 214))	('splicing factor 3B subunit 1', 'Gene', (13, 41))	('splicing', 'biological_process', 'GO:0045292', ('13', '21'))
147107	32894202	These mutations are mutually exclusive from BAP1 and SF3B1 and are associated with a longer disease-free survival and a more favorable prognosis Furthermore, metastatic UM are characterized by the low mutational burden observed in uveal melanoma may partly account for the limited success of immune checkpoint blockade.	('SF3B1', 'Gene', (53, 58))	('SF3B1', 'Gene', '23451', (53, 58))	('metastatic', 'Disease', (158, 168))	('uveal melanoma', 'Disease', 'MESH:C536494', (231, 245))	('BAP1', 'Gene', '8314', (44, 48))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('uveal melanoma', 'Phenotype', 'HP:0007716', (231, 245))	('uveal melanoma', 'Disease', (231, 245))	('mutations', 'Var', (6, 15))	('BAP1', 'Gene', (44, 48))
147127	32894202	The most common acquired genetic change distinguishing precursor lesions, such as melanocytic nevi or melanoma in situ (MIS), from invasive melanomas is loss of the CDKN2A locus.	('invasive melanomas', 'Disease', 'MESH:D008545', (131, 149))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (82, 98))	('nevi', 'Phenotype', 'HP:0003764', (94, 98))	('melanocytic nevi', 'Disease', (82, 98))	('loss', 'Var', (153, 157))	('melanoma', 'Disease', (102, 110))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('CDKN2A', 'Gene', (165, 171))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('invasive melanomas', 'Disease', (131, 149))	('CDKN2A', 'Gene', '1029', (165, 171))
147129	32894202	The loss of p16INK4A promotes melanocyte motility and the invasive and metastatic capacity of melanoma cells through the transcriptional activation of BRN2, a transcription factor previously associated with melanocytic invasive programs during both development and disease was demonstrated.	('transcriptional', 'MPA', (121, 136))	('transcription factor', 'molecular_function', 'GO:0000981', ('159', '179'))	('BRN2', 'Gene', '5454', (151, 155))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('p16INK4A', 'Gene', '1029', (12, 20))	('melanoma', 'Disease', (94, 102))	('melanocyte motility', 'CPA', (30, 49))	('promotes', 'PosReg', (21, 29))	('transcription', 'biological_process', 'GO:0006351', ('159', '172'))	('BRN2', 'Gene', (151, 155))	('activation', 'PosReg', (137, 147))	('p16INK4A', 'Gene', (12, 20))	('loss', 'Var', (4, 8))
147130	32894202	Loss of p16INK4A promotes melanocyte motility and the invasive and metastatic capacity of melanoma cells through the transcriptional activation of BRN2, a transcription factor previously associated with melanocytic invasive programs during both development and disease.	('melanoma', 'Disease', (90, 98))	('BRN2', 'Gene', '5454', (147, 151))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('p16INK4A', 'Gene', '1029', (8, 16))	('melanocyte motility', 'CPA', (26, 45))	('promotes', 'PosReg', (17, 25))	('transcription factor', 'molecular_function', 'GO:0000981', ('155', '175'))	('transcription', 'biological_process', 'GO:0006351', ('155', '168'))	('activation', 'PosReg', (133, 143))	('BRN2', 'Gene', (147, 151))	('p16INK4A', 'Gene', (8, 16))	('Loss', 'Var', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
147142	32894202	We hypothesize that truncating the intracellular domain of the TGF-beta receptor will abrogate immunosuppressive signalling through this pathway, which may augment immunotherapy effectiveness.	('abrogate', 'NegReg', (86, 94))	('TGF-beta', 'Gene', (63, 71))	('signalling', 'biological_process', 'GO:0023052', ('113', '123'))	('truncating', 'Var', (20, 30))	('TGF-beta', 'Gene', '7039', (63, 71))	('augment', 'NegReg', (156, 163))	('immunosuppressive signalling', 'MPA', (95, 123))	('immunotherapy effectiveness', 'CPA', (164, 191))	('intracellular', 'cellular_component', 'GO:0005622', ('35', '48'))
147148	32894202	Genetic modification of TIL with TGF-DNRII is feasible to generate, safe to administer and has demonstrated efficacy in malignant melanoma.. Loss of the tumor suppressor gene phosphatase and tensin homolog (PTEN) inhibits T cell infiltration into tumors and has been found to correlate with resistance to anti-PD-1 in melanoma patients.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('Loss', 'Var', (141, 145))	('tumors', 'Disease', (247, 253))	('melanoma', 'Phenotype', 'HP:0002861', (318, 326))	('melanoma', 'Disease', (318, 326))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('175', '205'))	('malignant melanoma', 'Phenotype', 'HP:0002861', (120, 138))	('phosphatase and tensin homolog', 'Gene', '5728', (175, 205))	('inhibits', 'NegReg', (213, 221))	('malignant melanoma', 'Disease', 'MESH:D008545', (120, 138))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumor', 'Disease', (153, 158))	('DNR', 'Chemical', '-', (37, 40))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (247, 252))	('PTEN', 'Gene', (207, 211))	('phosphatase', 'molecular_function', 'GO:0016791', ('175', '186'))	('if', 'Gene', '17319', (11, 13))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('153', '169'))	('melanoma', 'Disease', 'MESH:D008545', (318, 326))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('patients', 'Species', '9606', (327, 335))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('tumor suppressor', 'biological_process', 'GO:0051726', ('153', '169'))	('malignant melanoma', 'Disease', (120, 138))	('PTEN', 'Gene', '5728', (207, 211))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Disease', (130, 138))
147149	32894202	We recently demonstrated that loss of PTEN impedes trafficking of effector T cells to tumors, reduces the sensitivity of melanoma cells to T cell mediated killing, and correlates with inferior outcomes in patients treated with immune checkpoint blockade.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('sensitivity', 'MPA', (106, 117))	('melanoma', 'Disease', (121, 129))	('PTEN', 'Gene', '5728', (38, 42))	('patients', 'Species', '9606', (205, 213))	('impedes', 'NegReg', (43, 50))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('ecto', 'Gene', (69, 73))	('tumors', 'Disease', (86, 92))	('reduces', 'NegReg', (94, 101))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('ecto', 'Gene', '51592', (69, 73))	('trafficking', 'CPA', (51, 62))	('loss', 'Var', (30, 34))	('PTEN', 'Gene', (38, 42))
147154	32894202	Overexpression of glycolysis-related enzymes impaired T cell killing of tumor cells, whereas inhibition of glycolysis enhanced T cell-mediated antitumor immunity in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('glycolysis', 'biological_process', 'GO:0006096', ('18', '28'))	('tumor', 'Disease', (72, 77))	('enhanced', 'PosReg', (118, 126))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cell killing', 'biological_process', 'GO:0001906', ('56', '68'))	('impaired T', 'Disease', (45, 55))	('impaired T', 'Disease', 'MESH:D060825', (45, 55))	('enhanced T cell', 'Phenotype', 'HP:0100828', (118, 133))	('inhibition of glycolysis', 'biological_process', 'GO:0045820', ('93', '117'))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('inhibition', 'Var', (93, 103))
147155	32894202	Inhibition of glycolysis enhanced efficacy of adoptive T-cell therapy (ACT) and increased glycolytic activity was detected in cell lines from melanoma patients non-responding to ACT.	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('enhanced', 'PosReg', (25, 33))	('Inhibition of glycolysis', 'biological_process', 'GO:0045820', ('0', '24'))	('increased', 'PosReg', (80, 89))	('glycolytic', 'MPA', (90, 100))	('patients', 'Species', '9606', (151, 159))	('Inhibition', 'Var', (0, 10))	('adoptive T-cell therapy', 'CPA', (46, 69))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('glycolysis', 'Enzyme', (14, 24))	('melanoma', 'Disease', (142, 150))
147164	32894202	The analysis of ctDNA provides three parameters that may be correlated with clinical outcome: (1) the total quantity of ctDNA in the sample, (2) the molecular fingerprint of the ctDNA by mutation detection, and (3) the quantification of mutant copy numbers.	('if', 'Gene', '17319', (224, 226))	('mutation', 'Var', (187, 195))	('mutant copy numbers', 'Var', (237, 256))
147171	32894202	OS was worse in patients with TMB <= 23.1 Mut/Mb and either ctDNA increase/detectable or ctDNA increase of > 50% at first follow-up.	('TMB <= 23.1 Mut/Mb', 'Var', (30, 48))	('patients', 'Species', '9606', (16, 24))	('ctDNA', 'Disease', (60, 65))	('increase/detectable', 'PosReg', (66, 85))	('TMB', 'Chemical', '-', (30, 33))
147197	32894202	Overall, tumor types with higher median mutation burden tend to be more responsive to checkpoint inhibitors than tumors that harbor few mutations.	('mutation', 'Var', (40, 48))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('more', 'PosReg', (67, 71))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('responsive to checkpoint inhibitors', 'MPA', (72, 107))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
147204	32894202	Beyond beta-catenin, gene deletions and loss-of-function mutations of the tumor suppressor phosphatase and tensin homolog (PTEN) have also been associated with poor T cell infiltration in the tumor microenvironment in metastatic melanoma.	('mutations', 'Var', (57, 66))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('91', '121'))	('tumor', 'Disease', (74, 79))	('PTEN', 'Gene', (123, 127))	('melanoma', 'Phenotype', 'HP:0002861', (229, 237))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('melanoma', 'Disease', (229, 237))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('PTEN', 'Gene', '5728', (123, 127))	('loss-of-function', 'NegReg', (40, 56))	('tumor', 'Disease', (192, 197))	('beta-catenin', 'Gene', (7, 19))	('beta-catenin', 'Gene', '1499', (7, 19))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('melanoma', 'Disease', 'MESH:D008545', (229, 237))	('phosphatase', 'molecular_function', 'GO:0016791', ('91', '102'))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('phosphatase and tensin homolog', 'Gene', '5728', (91, 121))
147205	32894202	Loss of PTEN, which leads to increased activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, has been associated with primary and secondary resistance to PD-1 blockade in melanoma.	('PD-1 blockade in melanoma', 'Disease', (168, 193))	('activation', 'PosReg', (39, 49))	('Akt', 'Gene', (94, 97))	('PTEN', 'Gene', (8, 12))	('PTEN', 'Gene', '5728', (8, 12))	('phosphatidylinositol 3-kinase', 'Gene', (57, 86))	('phosphatidylinositol 3-kinase', 'Gene', '5291', (57, 86))	('Akt', 'Gene', '207', (94, 97))	('PD-1 blockade in melanoma', 'Disease', 'MESH:D010300', (168, 193))	('PI3K', 'molecular_function', 'GO:0016303', ('88', '92'))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('Loss', 'Var', (0, 4))	('associated', 'Reg', (116, 126))
147208	32894202	Two oncogenic events linked to poor T cell infiltration and secondary immunotherapy resistance are tumor cell-intrinsic beta-catenin pathway activation and PTEN loss-of-function mutation or deletion.	('tumor', 'Disease', (99, 104))	('beta-catenin', 'Gene', '1499', (120, 132))	('PTEN loss', 'Disease', 'MESH:D006223', (156, 165))	('deletion', 'Var', (190, 198))	('mutation', 'Var', (178, 186))	('PTEN loss', 'Disease', (156, 165))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('beta-catenin', 'Gene', (120, 132))	('activation', 'PosReg', (141, 151))
147215	32894202	In cancer, PD-1+Tim-3+ CD8+ T cells are dysfunctional/exhausted.	('PD-1+Tim-3+', 'Var', (11, 22))	('CD8', 'Gene', (23, 26))	('CD8', 'Gene', '925', (23, 26))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('dysfunctional', 'Disease', 'MESH:D009461', (40, 53))	('cancer', 'Disease', (3, 9))	('dysfunctional', 'Disease', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
147223	32894202	They also support that dual blockade of PD-1 and TIM-3 reinvigorates effector T cell responses more potently than single blockade.	('reinvigorates', 'Reg', (55, 68))	('TIM-3', 'Gene', (49, 54))	('dual blockade', 'Var', (23, 36))	('ecto', 'Gene', (72, 76))	('ecto', 'Gene', '51592', (72, 76))	('PD-1', 'Gene', (40, 44))
147225	32894202	Anti-TIM-3 antibody indirectly enhanced a CD8+ T cell response during chemotherapy.	('enhanced', 'PosReg', (31, 39))	('antibody', 'cellular_component', 'GO:0042571', ('11', '19'))	('antibody', 'cellular_component', 'GO:0019815', ('11', '19'))	('CD8', 'Gene', (42, 45))	('antibody', 'cellular_component', 'GO:0019814', ('11', '19'))	('CD8', 'Gene', '925', (42, 45))	('antibody', 'molecular_function', 'GO:0003823', ('11', '19'))	('Anti-TIM-3', 'Var', (0, 10))
147249	32894202	Its dysregulation has been implicated in tumorigenesis and tumor progression, and its upregulation is thought to be associated with many tumors.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('upregulation', 'PosReg', (86, 98))	('tumors', 'Disease', (137, 143))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', (41, 46))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('dysregulation', 'Var', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('implicated', 'Reg', (27, 37))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
147258	32894202	The dose expansion phase of the trial will evaluate CAN04 as monotherapy as well as in combination with cisplatin/gemcitabine in NSCLC and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma.	('pancreatic ductal adenocarcinoma', 'Disease', (169, 201))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (169, 201))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (169, 201))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('paclitaxel', 'Chemical', 'MESH:D017239', (155, 165))	('gemcitabine', 'Chemical', 'MESH:C056507', (114, 125))	('nab', 'Chemical', '-', (151, 154))	('NSCLC', 'Disease', (129, 134))	('gemcitabine', 'Chemical', 'MESH:C056507', (139, 150))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('CAN04', 'Chemical', '-', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('CAN04', 'Var', (52, 57))
147262	32894202	MIW815 (ADU-S100) has shown efficacy in combination with PD-1 checkpoint inhibitors and elicited near complete clearance of injected and non-injected tumors in mice.	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Disease', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('clearance', 'CPA', (111, 120))	('MIW815', 'Chemical', '-', (0, 6))	('MIW815', 'Var', (0, 6))	('mice', 'Species', '10090', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))
147263	32894202	In a phase 1b combination trial of intratumorally administered MIW815, a novel synthetic cyclic dinucleotide that activates the STING pathway, and spartalizumab, a humanized IgG4 monoclonal antibody that blocks the binding of PD-1 to PD-L1/2.	('antibody', 'molecular_function', 'GO:0003823', ('190', '198'))	('antibody', 'cellular_component', 'GO:0042571', ('190', '198'))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('antibody', 'cellular_component', 'GO:0019815', ('190', '198'))	('spartalizumab', 'Chemical', '-', (147, 160))	('STING pathway', 'Pathway', (128, 141))	('binding', 'molecular_function', 'GO:0005488', ('215', '222'))	('MIW815', 'Chemical', '-', (63, 69))	('MIW815', 'Var', (63, 69))	('antibody', 'cellular_component', 'GO:0019814', ('190', '198'))	('tumor', 'Disease', (40, 45))	('binding', 'Interaction', (215, 222))	('activates', 'PosReg', (114, 123))	('human', 'Species', '9606', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('PD-L1/2', 'Gene', '29126;80380', (234, 241))	('IgG4', 'cellular_component', 'GO:0071735', ('174', '178'))	('PD-L1/2', 'Gene', (234, 241))	('cyclic dinucleotide', 'Chemical', '-', (89, 108))
147270	32894202	CD8 frequency as detected by IHC increased in responding patients with high PD-L1 at baseline.	('high', 'Var', (71, 75))	('IHC', 'Gene', '11797', (29, 32))	('patients', 'Species', '9606', (57, 65))	('CD8', 'Gene', (0, 3))	('increased', 'PosReg', (33, 42))	('CD8', 'Gene', '925', (0, 3))	('IHC', 'Gene', (29, 32))	('PD-L1', 'Gene', (76, 81))
147271	32894202	The combination of MIW815 and spartalizumab demonstrated antitumor activity in PD-1-naive patients with TNBC and patients with anti PD-1-relapsed/refractory melanoma.	('TNBC', 'Disease', (104, 108))	('MIW815', 'Var', (19, 25))	('spartalizumab', 'Chemical', '-', (30, 43))	('patients', 'Species', '9606', (113, 121))	('TNBC', 'Disease', 'None', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('MIW815', 'Chemical', '-', (19, 25))	('patients', 'Species', '9606', (90, 98))	('tumor', 'Disease', (61, 66))
147282	32894202	Targeted therapy with BRAF/MEK inhibitor combinations are also effective as adjuvant therapy, with an estimated three-year RFS rate of 58% observed with dabrafenib plus trametinib versus 39% with placebo (HR for relapse or death, 0.47; 95% CI 0.39-0.58; P < 0.001), and so represent a new standard of care for BRAF-positive patients.	('BRAF', 'Gene', (310, 314))	('BRAF', 'Gene', '673', (310, 314))	('dabrafenib', 'Chemical', 'MESH:C561627', (153, 163))	('patients', 'Species', '9606', (324, 332))	('MEK', 'Gene', (27, 30))	('RFS', 'Disease', (123, 126))	('MEK', 'Gene', '5609', (27, 30))	('BRAF', 'Gene', '673', (22, 26))	('RFS', 'Disease', 'MESH:D005198', (123, 126))	('combinations', 'Var', (41, 53))	('death', 'Disease', 'MESH:D003643', (223, 228))	('death', 'Disease', (223, 228))	('BRAF', 'Gene', (22, 26))	('trametinib', 'Chemical', 'MESH:C560077', (169, 179))
147335	32894202	There is large variability in TMB within tumor types, ranging from just a few to thousands of mutations.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('TMB', 'Chemical', '-', (30, 33))	('mutations', 'Var', (94, 103))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
147336	32894202	A high TMB load has been shown to be associated with better response rates to checkpoint inhibitors in melanoma, NSCLC, and urothelial carcinoma.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('TMB', 'Chemical', '-', (7, 10))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (124, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('high', 'Var', (2, 6))	('response', 'MPA', (60, 68))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))	('TMB', 'Protein', (7, 10))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('NSCLC', 'Disease', (113, 118))	('melanoma', 'Disease', (103, 111))	('better', 'PosReg', (53, 59))	('urothelial carcinoma', 'Disease', (124, 144))
147339	32894202	For example, mutations in the isocitrate dehydrogenase (IDH)-1 and IDH2 genes may facilitate escape from immune surveillance in a subset of malignant gliomas.	('facilitate', 'PosReg', (82, 92))	('malignant gliomas', 'Disease', (140, 157))	('malignant gliomas', 'Disease', 'MESH:D005910', (140, 157))	('IDH2', 'Gene', (67, 71))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('IDH2', 'Gene', '3418', (67, 71))	('isocitrate dehydrogenase (IDH)-1', 'Gene', '3417', (30, 62))	('mutations', 'Var', (13, 22))	('escape', 'MPA', (93, 99))
147341	32894202	Treatment with IDH-C35, a selective mutant IDH-1 inhibitor, restored chemokine expression, promoted T-cell infiltration, and increased the efficacy of therapeutic peptide vaccination against IDH-mutated gliomas in mice.	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('IDH-C35', 'Var', (15, 22))	('promoted', 'PosReg', (91, 99))	('IDH-1', 'Gene', '15926', (43, 48))	('increased', 'PosReg', (125, 134))	('gliomas', 'Disease', (203, 210))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('IDH-1', 'Gene', (43, 48))	('T-cell infiltration', 'CPA', (100, 119))	('restored', 'PosReg', (60, 68))	('mice', 'Species', '10090', (214, 218))	('chemokine expression', 'MPA', (69, 89))
147351	32894202	In a cohort of 150 melanoma patients receiving anti-PD-1 antibodies whole plasma was analyzed at baseline, and on-treatment at 6-week and 6-month timepoints.	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('anti-PD-1', 'Var', (47, 56))	('patients', 'Species', '9606', (28, 36))
147377	32751207	At the epigenetic level, miR-21 inhibits key tumor suppressors of the RAS-BRAF signaling pathway enhancing proliferation and MM progression.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('BRAF', 'Gene', (74, 78))	('proliferation', 'CPA', (107, 120))	('BRAF', 'Gene', '673', (74, 78))	('tumor', 'Disease', (45, 50))	('signaling pathway', 'biological_process', 'GO:0007165', ('79', '96'))	('miR-21', 'Var', (25, 31))	('enhancing', 'PosReg', (97, 106))	('MM progression', 'CPA', (125, 139))	('inhibits', 'NegReg', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
147384	32751207	However, not only genetic deviations promote MM initiation, proliferation and progression but also epigenetic mechanisms including aberrant DNA- methylations and changes in microRNA (miR) expression, extensively reviewed elsewhere.	('microRNA (miR)', 'Gene', '220972', (173, 187))	('promote', 'PosReg', (37, 44))	('progression', 'CPA', (78, 89))	('expression', 'MPA', (188, 198))	('microRNA (miR', 'Gene', (173, 186))	('genetic deviations', 'Var', (18, 36))	('DNA- methylations', 'MPA', (140, 157))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('aberrant', 'Var', (131, 139))	('MM initiation', 'CPA', (45, 58))	('proliferation', 'CPA', (60, 73))	('changes', 'Reg', (162, 169))
147397	32751207	Patients with high miR-21 expression show shorter five-year disease-free or overall survival than those with low miR-21 expression.	('shorter', 'NegReg', (42, 49))	('overall survival', 'CPA', (76, 92))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('disease-free', 'CPA', (60, 72))	('miR-21', 'Gene', (19, 25))
147398	32751207	In contrast, antisense-mediated miR-21 inhibition suppresses growth, increases apoptosis and enhances chemo- or radiosensitivity of human MM cells.	('enhances', 'PosReg', (93, 101))	('increases', 'PosReg', (69, 78))	('antisense-mediated', 'Var', (13, 31))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('apoptosis', 'CPA', (79, 88))	('miR-21', 'Gene', (32, 38))	('human', 'Species', '9606', (132, 137))	('inhibition suppresses', 'NegReg', (39, 60))	('growth', 'CPA', (61, 67))	('chemo- or radiosensitivity of human MM cells', 'CPA', (102, 146))
147402	32751207	Remarkably, BRAF or NRAS mutations in MM had no significant effect on miR-21 expression.	('mutations', 'Var', (25, 34))	('expression', 'MPA', (77, 87))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('miR-21', 'Gene', (70, 76))	('NRAS', 'Gene', (20, 24))	('NRAS', 'Gene', '4893', (20, 24))
147413	32751207	Accordingly, targeting STAT3 sensitizes human MM cells to the BRAF inhibitor vemurafenib.	('STAT3', 'Gene', '6774', (23, 28))	('sensitizes', 'Reg', (29, 39))	('STAT3', 'Gene', (23, 28))	('targeting', 'Var', (13, 22))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('vemurafenib', 'Chemical', 'MESH:D000077484', (77, 88))	('human', 'Species', '9606', (40, 45))
147420	32751207	Gains of copy numbers directly affect YAP and are in the range of 4-10%, and 62% of MMs had copy number alterations affecting Hippo pathway genes.	('affect', 'Reg', (31, 37))	('Gains', 'PosReg', (0, 5))	('copy numbers', 'Var', (9, 21))	('Hippo', 'Gene', (126, 131))	('YAP', 'Gene', (38, 41))	('YAP', 'Gene', '10413', (38, 41))	('copy number alterations', 'Var', (92, 115))
147427	32751207	A recent study showed that XIST is overexpressed in MM tissues and cell lines, whereas XIST knockdown inhibits proliferation and migration in MM cells and increases the oxaliplatin sensitivity of resistant MM cells.	('oxaliplatin sensitivity', 'MPA', (169, 192))	('increases', 'PosReg', (155, 164))	('knockdown', 'Var', (92, 101))	('MM cells', 'CPA', (142, 150))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (169, 180))	('XIST', 'Gene', '7503', (27, 31))	('XIST', 'Gene', (27, 31))	('XIST', 'Gene', (87, 91))	('XIST', 'Gene', '7503', (87, 91))	('inhibits', 'NegReg', (102, 110))
147450	32751207	Notwithstanding, copy numbers of plasma miR-21 correlate with tumor burden in MM patients.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('patients', 'Species', '9606', (81, 89))	('copy numbers', 'Var', (17, 29))	('miR-21', 'Gene', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
147463	32751207	MiR-21 expression in cells of the tumor immune infiltrate, particularly macrophages, is responsible for promoting tumor growth, whereas the absence of miR-21 in tumor-associated macrophages causes a global rewiring of their transcriptional regulatory network that is skewed toward a pro-inflammatory angiostatic phenotype.	('miR-21', 'Gene', (151, 157))	('rewiring', 'Reg', (206, 214))	('tumor', 'Disease', (161, 166))	('age', 'Gene', '5973', (79, 82))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('MiR-21', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('age', 'Gene', (185, 188))	('MiR-21', 'Gene', '406991', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('promoting', 'PosReg', (104, 113))	('transcriptional', 'Pathway', (224, 239))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('absence', 'Var', (140, 147))	('age', 'Gene', (79, 82))	('age', 'Gene', '5973', (185, 188))
147478	32751207	Exposure to UV radiation from sunlight or tanning beds contributes to UV-induced DNA damage, oxidative stress, and inflammation in the skin playing a dominant role in melanomagenesis and DNA mutations causing MM.	('inflammation', 'Disease', 'MESH:D007249', (115, 127))	('inflammation', 'biological_process', 'GO:0006954', ('115', '127'))	('age', 'Gene', (174, 177))	('inflammation', 'Disease', (115, 127))	('DNA', 'cellular_component', 'GO:0005574', ('187', '190'))	('mutations', 'Var', (191, 200))	('age', 'Gene', '5973', (88, 91))	('inflammation in the skin', 'Phenotype', 'HP:0011123', (115, 139))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('melanoma', 'Disease', (167, 175))	('age', 'Gene', '5973', (174, 177))	('DNA', 'Gene', (187, 190))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('oxidative stress', 'Phenotype', 'HP:0025464', (93, 109))	('age', 'Gene', (88, 91))
147479	32751207	However, key mutations in MM are not UV-signature mutations (C T) including the BRAFV600E mutation found in 60% of MMs and NRAS mutations detected in 15-20% of MMs, respectively.	('mutations', 'Var', (128, 137))	('BRAFV600E', 'Mutation', 'rs113488022', (80, 89))	('NRAS', 'Gene', (123, 127))	('C', 'Chemical', 'MESH:D002244', (61, 62))	('BRAFV600E', 'Gene', (80, 89))	('NRAS', 'Gene', '4893', (123, 127))
147484	32751207	Accordingly, SOX5 knockdown upregulates MITF in MM cells.	('knockdown', 'Var', (18, 27))	('MITF', 'Gene', '4286', (40, 44))	('MITF', 'Gene', (40, 44))	('SOX5', 'Gene', (13, 17))	('SOX5', 'Gene', '6660', (13, 17))	('upregulates', 'PosReg', (28, 39))
147485	32751207	Furthermore, miR-21 controls the DNA mismatch repair (MMR) protein MSH2, which is a crucial caretaker of the MMR including transcription-coupled repair.	('MSH2', 'Gene', (67, 71))	('controls', 'Reg', (20, 28))	('miR-21', 'Var', (13, 19))	('MSH2', 'Gene', '4436', (67, 71))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('MMR', 'biological_process', 'GO:0006298', ('54', '57'))	('mismatch repair', 'biological_process', 'GO:0006298', ('37', '52'))	('transcription-coupled repair', 'biological_process', 'GO:0006283', ('123', '151'))	('MMR', 'biological_process', 'GO:0006298', ('109', '112'))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
147487	32751207	Reduced or defective expression of MSH2 has been associated with high genomic instability, poor MM prognosis, and metastasis.	('metastasis', 'CPA', (114, 124))	('associated', 'Reg', (49, 59))	('poor MM prognosis', 'CPA', (91, 108))	('defective', 'Var', (11, 20))	('expression', 'MPA', (21, 31))	('MSH2', 'Gene', (35, 39))	('high genomic instability', 'MPA', (65, 89))	('MSH2', 'Gene', '4436', (35, 39))
147488	32751207	Decreased expression or function of MSH2 is either a result of mutation-derived dysfunction of MSH2 or miR-21-mediated downregulation of MSH2.	('MSH2', 'Gene', (95, 99))	('MSH2', 'Gene', (137, 141))	('MSH2', 'Gene', '4436', (137, 141))	('downregulation', 'NegReg', (119, 133))	('Decreased', 'NegReg', (0, 9))	('MSH2', 'Gene', '4436', (95, 99))	('expression', 'MPA', (10, 20))	('function', 'MPA', (24, 32))	('mutation-derived', 'Reg', (63, 79))	('dysfunction', 'Var', (80, 91))	('MSH2', 'Gene', (36, 40))	('MSH2', 'Gene', '4436', (36, 40))
147489	32751207	Thus, UV-induced generation of exosomal miR-21 with subsequent uptake of miR-21 by melanocytes may promote genetic instability and gene mutations driving melanomagenesis.	('uptake', 'biological_process', 'GO:0098657', ('63', '69'))	('age', 'Gene', (161, 164))	('promote', 'PosReg', (99, 106))	('gene mutations', 'Var', (131, 145))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('genetic instability', 'MPA', (107, 126))	('melanoma', 'Disease', (154, 162))	('age', 'Gene', '5973', (161, 164))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('uptake', 'biological_process', 'GO:0098739', ('63', '69'))
147508	32751207	A case-control study of 1396 cases of MM diagnosed before the age of 30 in 1988-2013 and 27,920 controls in California demonstrated that high BW (>4000 g) compared to normal BW is associated with a 19% higher risk for MM before the age of 30.	('high BW (>4000 g', 'Var', (137, 153))	('age', 'Gene', '5973', (232, 235))	('age', 'Gene', (62, 65))	('C', 'Chemical', 'MESH:D002244', (108, 109))	('age', 'Gene', '5973', (62, 65))	('MM before', 'Disease', (218, 227))	('age', 'Gene', (232, 235))
147527	32751207	Thus, epigenetic evidence indicates that exosomal transfer of miR-21 by adipocytes of obese individuals and CAAs may promote melanomagenesis.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('age', 'Gene', '5973', (132, 135))	('miR-21', 'Gene', (62, 68))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('exosomal transfer', 'Var', (41, 58))	('CAAs', 'Disease', (108, 112))	('CAAs', 'Disease', 'MESH:C564321', (108, 112))	('obese', 'Disease', 'MESH:D009765', (86, 91))	('promote', 'PosReg', (117, 124))	('age', 'Gene', (132, 135))	('obese', 'Disease', (86, 91))
147530	32751207	In a diabetic mouse model, the curcumin analog C66 inhibits diabetes-related induction of miR-21 in analogy to miR-21 reductions by locked nucleic acid-modified anti-miR-21 (LNA-21).	('diabetic', 'Disease', (5, 13))	('mouse', 'Species', '10090', (14, 19))	('inhibits', 'NegReg', (51, 59))	('miR-21', 'Gene', (90, 96))	('curcumin', 'Chemical', 'MESH:D003474', (31, 39))	('C66', 'Var', (47, 50))	('nucleic acid', 'cellular_component', 'GO:0005561', ('139', '151'))	('C', 'Chemical', 'MESH:D002244', (47, 48))	('diabetes', 'Disease', (60, 68))	('diabetic', 'Disease', 'MESH:D003920', (5, 13))	('diabetes', 'Disease', 'MESH:D003920', (60, 68))
147534	32751207	Suppression of miR-21 prevents hypertrophic stimulation-induced cardiac remodeling by regulating PDCD4, AP-1, and TGF-beta1 signaling pathways.	('cardiac remodeling', 'Disease', (64, 82))	('cardiac remodeling', 'Disease', 'MESH:D020257', (64, 82))	('AP-1', 'Gene', '2353', (104, 108))	('hypertrophic', 'Disease', (31, 43))	('Suppression', 'Var', (0, 11))	('signaling', 'biological_process', 'GO:0023052', ('124', '133'))	('TGF-beta1', 'Gene', '7040', (114, 123))	('AP-1', 'Gene', (104, 108))	('TGF-beta1', 'Gene', (114, 123))	('regulating', 'Reg', (86, 96))	('miR-21', 'Gene', (15, 21))	('PDCD4', 'Gene', (97, 102))	('AP-1', 'cellular_component', 'GO:0005907', ('104', '108'))	('hypertrophic', 'Disease', 'MESH:D006984', (31, 43))	('PDCD4', 'Gene', '27250', (97, 102))
147545	32751207	For instance, oncogenic BRAFV600E upregulates HMG-CoA lyase, which converts HMG-CoA to acetyl-CoA and the ketone body acetoacetate, that selectively enhances BRAFV600E-dependent MEK1 activation in MM.	('enhances', 'PosReg', (149, 157))	('MEK1', 'molecular_function', 'GO:0004708', ('178', '182'))	('acetoacetate', 'Chemical', 'MESH:C016635', (118, 130))	('BRAFV600E', 'Mutation', 'rs113488022', (24, 33))	('BRAFV600E', 'Gene', (24, 33))	('C', 'Chemical', 'MESH:D002244', (94, 95))	('C', 'Chemical', 'MESH:D002244', (80, 81))	('BRAFV600E-dependent', 'Var', (158, 177))	('MEK1', 'Gene', '5604', (178, 182))	('C', 'Chemical', 'MESH:D002244', (50, 51))	('upregulates', 'PosReg', (34, 45))	('MEK1', 'Gene', (178, 182))	('ketone body', 'Phenotype', 'HP:0001946', (106, 117))	('activation', 'MPA', (183, 193))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (87, 97))	('BRAFV600E', 'Mutation', 'rs113488022', (158, 167))
147548	32751207	It is thus conceivable that miR-21-mediated downregulation of Sprouty enhances BRAFV600E-driven MM growth (Figure 2).	('BRAFV600E-driven', 'Var', (79, 95))	('BRAFV600E', 'Mutation', 'rs113488022', (79, 88))	('Sprouty', 'Protein', (62, 69))	('downregulation', 'NegReg', (44, 58))	('miR-21-mediated', 'Gene', (28, 43))	('enhances', 'PosReg', (70, 78))
147551	32751207	Interestingly, miR-21 via inhibiting PTEN activates telomerase (hTERT), which is a further feature of MM.	('hTERT', 'Gene', (64, 69))	('inhibiting', 'NegReg', (26, 36))	('PTEN', 'Gene', (37, 41))	('PTEN', 'Gene', '5728', (37, 41))	('hTERT', 'Gene', '7015', (64, 69))	('activates', 'PosReg', (42, 51))	('miR-21', 'Var', (15, 21))	('telomerase', 'Enzyme', (52, 62))
147568	32751207	GH promotes, while GHR knockdown attenuates MM progression.	('MM progression', 'CPA', (44, 58))	('knockdown', 'Var', (23, 32))	('attenuates', 'NegReg', (33, 43))	('GHR', 'Gene', (19, 22))	('GHR', 'Gene', '2690', (19, 22))
147576	32751207	Vitamin D (VD) deficiency has been associated with a poorer outcome in MM, and has been correlated with BRAF-mutated MM.	('correlated', 'Reg', (88, 98))	('BRAF', 'Gene', '673', (104, 108))	('deficiency', 'Var', (15, 25))	('VD', 'Gene', (11, 13))	('BRAF', 'Gene', (104, 108))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))
147583	32751207	The recently observed correlation between BRAFV600E mutation status and VD deficiency may thus be explained by BRAFV600E mutation-induced overexpression of CYP24A1, encoding 24-hydroxylase, the mitochondrial enzyme responsible for inactivating VD metabolites through the C-24 oxidation pathway.	('mutation-induced', 'Var', (121, 137))	('C', 'Chemical', 'MESH:D002244', (271, 272))	('BRAFV600E', 'Mutation', 'rs113488022', (42, 51))	('BRAFV600E', 'Gene', (42, 51))	('CYP24A1', 'Gene', (156, 163))	('BRAFV600E', 'Mutation', 'rs113488022', (111, 120))	('CYP24A1', 'Gene', '1591', (156, 163))	('BRAFV600E', 'Gene', (111, 120))	('VD deficiency', 'Disease', 'MESH:D007153', (72, 85))	('C', 'Chemical', 'MESH:D002244', (156, 157))	('VD deficiency', 'Disease', (72, 85))	('overexpression', 'PosReg', (138, 152))
147591	32751207	Furthermore, miR-21 activates the NLRP3 inflammasome.	('NLRP3', 'Gene', '114548', (34, 39))	('NLRP3', 'Gene', (34, 39))	('miR-21', 'Var', (13, 19))	('activates', 'PosReg', (20, 29))
147592	32751207	Increased expression of miR-21 and exosomal miR-21 is associated with inflammation in various conditions, such as diabetes mellitus (type 1 and 2), chronic renal fibrosis, and atopic diseases.	('inflammation', 'Disease', 'MESH:D007249', (70, 82))	('exosomal', 'Var', (35, 43))	('miR-21', 'Gene', (24, 30))	('atopic diseases', 'Disease', (176, 191))	('atopic diseases', 'Phenotype', 'HP:0001047', (176, 191))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (114, 131))	('inflammation', 'Disease', (70, 82))	('diabetes mellitus', 'Disease', (114, 131))	('expression', 'MPA', (10, 20))	('renal fibrosis', 'Phenotype', 'HP:0030760', (156, 170))	('Increased', 'PosReg', (0, 9))	('inflammation', 'biological_process', 'GO:0006954', ('70', '82'))	('diabetes mellitus', 'Disease', 'MESH:D003920', (114, 131))	('renal fibrosis', 'Disease', 'MESH:D005355', (156, 170))	('renal fibrosis', 'Disease', (156, 170))	('atopic diseases', 'Disease', 'MESH:C566404', (176, 191))	('associated', 'Reg', (54, 64))	('miR-21', 'Gene', (44, 50))
147597	32751207	Thus, MEK-ERK kinase inhibition in MM may attenuate miR-21 expression.	('ERK', 'molecular_function', 'GO:0004707', ('10', '13'))	('attenuate', 'NegReg', (42, 51))	('miR-21', 'Gene', (52, 58))	('MEK', 'Gene', (6, 9))	('MEK', 'Gene', '5609', (6, 9))	('inhibition', 'Var', (21, 31))	('expression', 'MPA', (59, 69))	('ERK', 'Gene', '5594', (10, 13))	('ERK', 'Gene', (10, 13))
147613	32751207	Adeno-associated viral vectors that preferentially express antisense miR against miR-21 has therapeutic efficacy in vivo in various cancer including glioblastoma.	('glioblastoma', 'Disease', (149, 161))	('miR-21', 'Gene', (81, 87))	('cancer', 'Disease', (132, 138))	('glioblastoma', 'Disease', 'MESH:D005909', (149, 161))	('antisense miR', 'Var', (59, 72))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
147615	32751207	Of interest, miR-21 antisense oligonucleotide decreased IC50 and increased cisplatin sensitivity for A375 melanoma cells and A375/CDDP cells, which shows that miR-21 is a new target of MM treatment.	('cisplatin sensitivity', 'MPA', (75, 96))	('increased', 'PosReg', (65, 74))	('miR-21', 'Gene', (13, 19))	('IC50', 'MPA', (56, 60))	('men', 'Species', '9606', (193, 196))	('C', 'Chemical', 'MESH:D002244', (57, 58))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('A375', 'CellLine', 'CVCL:0132', (125, 129))	('A375', 'CellLine', 'CVCL:0132', (101, 105))	('decreased', 'NegReg', (46, 55))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))	('melanoma', 'Disease', (106, 114))	('oligonucleotide', 'Chemical', 'MESH:D009841', (30, 45))	('antisense oligonucleotide', 'Var', (20, 45))
147618	32751207	The combined delivery of miR-21i and 5-FU with engineered exosomes effectively reversed drug resistance and significantly enhanced the cytotoxicity in 5-FU-resistant colon cancer cells, compared with the single treatment with either miR-21i or 5-FU.	('5-FU', 'Chemical', 'MESH:D005472', (37, 41))	('enhanced', 'PosReg', (122, 130))	('colon cancer', 'Disease', (166, 178))	('men', 'Species', '9606', (216, 219))	('drug resistance', 'biological_process', 'GO:0009315', ('88', '103'))	('drug resistance', 'biological_process', 'GO:0042493', ('88', '103'))	('miR-21i', 'Chemical', '-', (233, 240))	('reversed', 'Reg', (79, 87))	('cytotoxicity', 'Disease', (135, 147))	('colon cancer', 'Phenotype', 'HP:0003003', (166, 178))	('5-FU', 'Chemical', 'MESH:D005472', (151, 155))	('cytotoxicity', 'Disease', 'MESH:D064420', (135, 147))	('drug resistance', 'MPA', (88, 103))	('miR-21i', 'Chemical', '-', (25, 32))	('miR-21i', 'Var', (25, 32))	('drug resistance', 'Phenotype', 'HP:0020174', (88, 103))	('colon cancer', 'Disease', 'MESH:D015179', (166, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('5-FU', 'Chemical', 'MESH:D005472', (244, 248))
147621	32751207	Pegylated interferon-alpha (IFNalpha), as studied in the European Organisation for Research and Treatment of Cancer (EORTC) 18991 trial, in patients with stage III MM significantly reduced the risk of relapse (HR 0.87), however showed no impact on overall survival.	('C', 'Chemical', 'MESH:D002244', (121, 122))	('reduced', 'NegReg', (181, 188))	('Cancer', 'Disease', (109, 115))	('relapse', 'CPA', (201, 208))	('Pegylated interferon-alpha', 'Chemical', '-', (0, 26))	('age', 'Gene', '5973', (156, 159))	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Cancer', 'Disease', 'MESH:D009369', (109, 115))	('men', 'Species', '9606', (101, 104))	('C', 'Chemical', 'MESH:D002244', (109, 110))	('patients', 'Species', '9606', (140, 148))	('Pegylated', 'Var', (0, 9))	('age', 'Gene', (156, 159))
147631	32751207	Low expression of lncRNA MEG3 was associated with imatinib resistance and high miR-21 expression in chronic myeloid leukemia.	('associated', 'Reg', (34, 44))	('high', 'Var', (74, 78))	('chronic myeloid leukemia', 'Disease', (100, 124))	('expression', 'MPA', (4, 14))	('imatinib resistance', 'MPA', (50, 69))	('miR-21', 'Gene', (79, 85))	('expression', 'MPA', (86, 96))	('imatinib', 'Chemical', 'MESH:D000068877', (50, 58))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (100, 124))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (100, 124))	('MEG3', 'Gene', (25, 29))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (108, 124))	('Low', 'NegReg', (0, 3))	('MEG3', 'Gene', '55384', (25, 29))	('leukemia', 'Phenotype', 'HP:0001909', (116, 124))
147636	32751207	In human MM cells, SFN causes cell cycle growth arrest and induces apoptosis.	('arrest', 'Disease', 'MESH:D006323', (48, 54))	('apoptosis', 'CPA', (67, 76))	('arrest', 'Disease', (48, 54))	('human', 'Species', '9606', (3, 8))	('induces', 'Reg', (59, 66))	('cell cycle', 'biological_process', 'GO:0007049', ('30', '40'))	('SFN', 'Var', (19, 22))	('apoptosis', 'biological_process', 'GO:0097194', ('67', '76'))	('SFN', 'Chemical', 'MESH:C016766', (19, 22))	('apoptosis', 'biological_process', 'GO:0006915', ('67', '76'))	('growth arrest', 'Phenotype', 'HP:0001510', (41, 54))
147646	32751207	Scientific interest in oncogenic dysregulation of MM focuses mainly on DNA base mutations, primarily driven by UV-induced DNA damage.	('age', 'Gene', (129, 132))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('mutations', 'Var', (80, 89))	('DNA base', 'Gene', (71, 79))	('age', 'Gene', '5973', (129, 132))	('DNA', 'cellular_component', 'GO:0005574', ('122', '125'))
147647	32751207	In this review, translational and epidemiological evidence underlines that not only DNA base mutations, but also miR-21-mediated epigenetic alterations enhance NRAS, BRAF and downstream MEK-ERK and AKT-mTORC1 signaling in MM (Figure 2).	('DNA base', 'Gene', (84, 92))	('mTORC1', 'Gene', (202, 208))	('BRAF', 'Gene', '673', (166, 170))	('BRAF', 'Gene', (166, 170))	('NRAS', 'Gene', (160, 164))	('mTORC1', 'Gene', '382056', (202, 208))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('mTORC1', 'cellular_component', 'GO:0031931', ('202', '208'))	('MEK', 'Gene', '5609', (186, 189))	('mutations', 'Var', (93, 102))	('ERK', 'Gene', '5594', (190, 193))	('miR-21-mediated', 'Gene', (113, 128))	('epigenetic alterations', 'Var', (129, 151))	('MEK', 'Gene', (186, 189))	('signaling', 'biological_process', 'GO:0023052', ('209', '218'))	('ERK', 'molecular_function', 'GO:0004707', ('190', '193'))	('NRAS', 'Gene', '4893', (160, 164))	('ERK', 'Gene', (190, 193))	('enhance', 'PosReg', (152, 159))
147648	32751207	Notably, miR-21 via targeting a variety of tumor suppressors activates proliferation pathways promoted by common MM gene mutations.	('mutations', 'Var', (121, 130))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('activates', 'PosReg', (61, 70))	('MM gene', 'Gene', (113, 120))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('miR-21', 'Gene', (9, 15))	('proliferation', 'CPA', (71, 84))	('tumor', 'Disease', (43, 48))
147653	32751207	The missing correlation between miR-21 levels and NRAS and BRAF mutations in MM cells points to a mutation-independent pathway of miR-21-mediated signal transduction.	('signal transduction', 'biological_process', 'GO:0007165', ('146', '165'))	('NRAS', 'Gene', (50, 54))	('NRAS', 'Gene', '4893', (50, 54))	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (59, 63))	('mutations', 'Var', (64, 73))	('miR-21', 'MPA', (32, 38))
147655	32751207	The anti-proliferative effects of miR-21-antagonizing agents, its catalytic knockdown of miR-21 by artificial ribonuclease, and miR-21 expression lowering agents may synergistically improve MM therapy.	('age', 'Gene', '5973', (155, 158))	('knockdown', 'Var', (76, 85))	('MM therapy', 'CPA', (190, 200))	('improve', 'PosReg', (182, 189))	('age', 'Gene', '5973', (54, 57))	('miR-21', 'Gene', (128, 134))	('age', 'Gene', (155, 158))	('expression', 'MPA', (135, 145))	('miR-21-antagonizing', 'Gene', (34, 53))	('anti-proliferative effects', 'CPA', (4, 30))	('lowering', 'NegReg', (146, 154))	('age', 'Gene', (54, 57))	('miR-21', 'Gene', (89, 95))
147662	32168916	Human Cancer-Associated Mutations of SF3B1 Lead to a Splicing Modification of Its Own RNA Deregulation of pre-mRNA splicing is observed in many cancers and hematological malignancies.	('Human', 'Species', '9606', (0, 5))	('SF3B1', 'Gene', '23451', (37, 42))	('pre', 'molecular_function', 'GO:0003904', ('106', '109'))	('Cancer', 'Disease', (6, 12))	('Lead to', 'Reg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('hematological malignancies', 'Disease', 'MESH:D019337', (156, 182))	('Splicing', 'biological_process', 'GO:0045292', ('53', '61'))	('RNA', 'cellular_component', 'GO:0005562', ('86', '89'))	('hematological malignancies', 'Phenotype', 'HP:0004377', (156, 182))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('Mutations', 'Var', (24, 33))	('Cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancers', 'Disease', (144, 151))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('106', '123'))	('SF3B1', 'Gene', (37, 42))	('hematological malignancies', 'Disease', (156, 182))	('Own RNA', 'MPA', (82, 89))	('Cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Splicing Modification of', 'MPA', (53, 77))	('cancers', 'Disease', 'MESH:D009369', (144, 151))
147663	32168916	Genes encoding splicing factors are frequently mutated in myelodysplastic syndromes, in which SF3B1 mutations are the most frequent.	('mutations', 'Var', (100, 109))	('frequent', 'Reg', (123, 131))	('splicing factor', 'Gene', (15, 30))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (58, 83))	('myelodysplastic syndromes', 'Disease', (58, 83))	('SF3B1', 'Gene', (94, 99))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (58, 83))	('splicing', 'biological_process', 'GO:0045292', ('15', '23'))	('splicing factor', 'Gene', '10569', (15, 30))
147664	32168916	We found that SF3B1 was aberrantly spliced in various neoplasms carrying an SF3B1 mutation, by exploring publicly available RNA sequencing raw data.	('neoplasms', 'Phenotype', 'HP:0002664', (54, 63))	('mutation', 'Var', (82, 90))	('neoplasms', 'Disease', 'MESH:D009369', (54, 63))	('neoplasms', 'Disease', (54, 63))	('SF3B1', 'Gene', (76, 81))	('RNA', 'cellular_component', 'GO:0005562', ('124', '127'))
147665	32168916	We investigated the splicing proficiency of this SF3B1 protein isoform, in association with the most frequent mutation (K700E), through functional complementation assays in two myeloid cell lines stably expressing distinct SF3B1 variants.	('SF3B1', 'Gene', (223, 228))	('splicing', 'biological_process', 'GO:0045292', ('20', '28'))	('K700E', 'Mutation', 'rs559063155', (120, 125))	('K700E', 'Var', (120, 125))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('variants', 'Var', (229, 237))
147667	32168916	Insertion of these eight amino acids in wild-type or mutant SF3B1 (K700E) abolished SF3B1 essential function, highlighting the crucial role of the H3 repeat in the splicing function of SF3B1.	('SF3B1', 'Gene', (60, 65))	('K700E', 'Var', (67, 72))	('K700E', 'Mutation', 'rs559063155', (67, 72))	('splicing', 'biological_process', 'GO:0045292', ('164', '172'))	('abolished', 'NegReg', (74, 83))	('mutant', 'Var', (53, 59))	('SF3B1', 'Gene', (84, 89))	('essential function', 'MPA', (90, 108))
147669	32168916	Deregulation of splicing is observed in many cancers and hematological diseases.	('splicing', 'MPA', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Deregulation', 'Var', (0, 12))	('splicing', 'biological_process', 'GO:0045292', ('16', '24'))	('hematological diseases', 'Disease', 'MESH:D006402', (57, 79))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))	('hematological diseases', 'Disease', (57, 79))	('observed', 'Reg', (28, 36))
147670	32168916	Recent massive sequencing of many cancer genomes allowed the identification of recurrent mutations in genes encoding splicing factors, including SF3B1 (Splicing Factor 3B subunit 1), SRFS2 (Serine and arginine rich splicing factor 2), U2AF1 (U2 small nuclear RNA auxiliary factor 1), and ZRSR2 (Zinc finger CCCH-type, RNA binding motif and Serine/Arginine Rich 2), suggesting that somatic alterations of genes involved in splicing are common in cancer.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Splicing', 'biological_process', 'GO:0045292', ('152', '160'))	('splicing', 'biological_process', 'GO:0045292', ('215', '223'))	('U2AF1', 'Gene', '7307', (235, 240))	('U2AF', 'cellular_component', 'GO:0089701', ('235', '239'))	('SF3B1', 'Gene', (145, 150))	('splicing factor', 'Gene', (215, 230))	('mutations', 'Var', (89, 98))	('splicing', 'biological_process', 'GO:0045292', ('422', '430'))	('RNA', 'cellular_component', 'GO:0005562', ('259', '262'))	('ZRSR2', 'Gene', '8233', (288, 293))	('splicing factor', 'Gene', (117, 132))	('cancer', 'Disease', (445, 451))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (445, 451))	('Splicing Factor 3B subunit 1', 'Gene', '23451', (152, 180))	('RNA binding', 'molecular_function', 'GO:0003723', ('318', '329'))	('RNA', 'cellular_component', 'GO:0005562', ('318', '321'))	('Splicing Factor 3B subunit 1', 'Gene', (152, 180))	('small nuclear RNA', 'molecular_function', 'GO:0005570', ('245', '262'))	('splicing factor', 'Gene', '10569', (215, 230))	('Zinc finger CCCH-type, RNA binding motif and Serine/Arginine Rich 2', 'Gene', '8233', (295, 362))	('splicing factor', 'Gene', '10569', (117, 132))	('splicing', 'biological_process', 'GO:0045292', ('117', '125'))	('ZRSR2', 'Gene', (288, 293))	('cancer', 'Disease', 'MESH:D009369', (445, 451))	('U2AF1', 'Gene', (235, 240))	('SRFS2', 'Gene', (183, 188))	('cancer', 'Disease', (34, 40))
147671	32168916	Strikingly, in myelodysplastic syndromes (MDS), over 50% of patients have acquired mutations that affect the splicing machinery.	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (15, 40))	('mutations', 'Var', (83, 92))	('MDS', 'Disease', (42, 45))	('MDS', 'Disease', 'MESH:D009190', (42, 45))	('MDS', 'Phenotype', 'HP:0002863', (42, 45))	('myelodysplastic syndromes', 'Disease', (15, 40))	('patients', 'Species', '9606', (60, 68))	('splicing', 'biological_process', 'GO:0045292', ('109', '117'))	('splicing machinery', 'MPA', (109, 127))	('affect', 'Reg', (98, 104))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (15, 40))
147673	32168916	Mutations in genes involved in epigenetic regulation are also frequently present in MDS.	('MDS', 'Disease', (84, 87))	('MDS', 'Disease', 'MESH:D009190', (84, 87))	('Mutations', 'Var', (0, 9))	('present', 'Reg', (73, 80))	('MDS', 'Phenotype', 'HP:0002863', (84, 87))	('regulation', 'biological_process', 'GO:0065007', ('42', '52'))
147674	32168916	While many mutations may coexist in MDS and other neoplasms, splice factor mutations occur in a mutually exclusive manner Remarkably, mutations in SF3B1 occur in up to 85% of sideroblastic MDS (MDS-RS), a subtype of MDS characterized by the presence of ring sideroblasts (RS) in the bone marrow, and associated with good prognosis.	('MDS', 'Disease', (189, 192))	('SF3B1', 'Gene', (147, 152))	('MDS', 'Disease', 'MESH:D009190', (194, 197))	('MDS', 'Disease', (36, 39))	('occur', 'Reg', (153, 158))	('MDS', 'Disease', 'MESH:D009190', (216, 219))	('neoplasms', 'Phenotype', 'HP:0002664', (50, 59))	('MDS', 'Disease', (194, 197))	('presence of ring sideroblasts', 'Phenotype', 'HP:0004828', (241, 270))	('mutations', 'Var', (134, 143))	('MDS', 'Phenotype', 'HP:0002863', (189, 192))	('MDS', 'Disease', (216, 219))	('MDS', 'Phenotype', 'HP:0002863', (36, 39))	('MDS-RS', 'Disease', 'MESH:D009190', (194, 200))	('MDS-RS', 'Disease', (194, 200))	('neoplasms', 'Disease', 'MESH:D009369', (50, 59))	('MDS', 'Disease', 'MESH:D009190', (189, 192))	('MDS', 'Phenotype', 'HP:0002863', (194, 197))	('MDS', 'Disease', 'MESH:D009190', (36, 39))	('neoplasms', 'Disease', (50, 59))	('MDS', 'Phenotype', 'HP:0002863', (216, 219))
147675	32168916	SF3B1 mutations are also found in chronic lymphoid leukemia (CLL), where they are associated with poor outcome, in uveal melanoma (20%) and to a lesser extent in breast and pancreatic cancers.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('uveal melanoma', 'Disease', (115, 129))	('uveal melanoma', 'Disease', 'MESH:C536494', (115, 129))	('chronic lymphoid leukemia', 'Phenotype', 'HP:0005550', (34, 59))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (173, 191))	('CLL', 'Phenotype', 'HP:0005550', (61, 64))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('SF3B1', 'Gene', (0, 5))	('uveal melanoma', 'Phenotype', 'HP:0007716', (115, 129))	('pancreatic cancers', 'Disease', (173, 191))	('lymphoid leukemia', 'Phenotype', 'HP:0005526', (42, 59))	('chronic lymphoid leukemia', 'Disease', 'MESH:D007945', (34, 59))	('found', 'Reg', (25, 30))	('mutations', 'Var', (6, 15))	('pancreatic cancers', 'Disease', 'MESH:D010190', (173, 191))	('leukemia', 'Phenotype', 'HP:0001909', (51, 59))	('breast', 'Disease', (162, 168))	('chronic lymphoid leukemia', 'Disease', (34, 59))
147679	32168916	Recent RNA-sequencing (RNA-seq) analyses in various malignancies, including CLL and breast cancer, uveal melanoma and MDS, indicate that the most common mutations of SF3B1 lead to a global splicing defect characterized by the production of aberrant transcripts through the use of cryptic 3' splice sites and alternative branch points.	('mutations', 'Var', (153, 162))	('lead to', 'Reg', (172, 179))	('uveal melanoma', 'Disease', 'MESH:C536494', (99, 113))	('uveal melanoma', 'Disease', (99, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('MDS', 'Phenotype', 'HP:0002863', (118, 121))	('CLL', 'Phenotype', 'HP:0005550', (76, 79))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('SF3B1', 'Gene', (166, 171))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('splicing', 'biological_process', 'GO:0045292', ('189', '197'))	('breast cancer', 'Disease', (84, 97))	('cryptic', 'Gene', '55997', (280, 287))	('cryptic', 'Gene', (280, 287))	('MDS', 'Disease', 'MESH:D009190', (118, 121))	('RNA', 'cellular_component', 'GO:0005562', ('23', '26'))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('RNA', 'cellular_component', 'GO:0005562', ('7', '10'))	('CLL', 'Disease', (76, 79))	('MDS', 'Disease', (118, 121))	('global splicing defect', 'MPA', (182, 204))	('malignancies', 'Disease', 'MESH:D009369', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('malignancies', 'Disease', (52, 64))
147680	32168916	recently reported that disease-causing mutations in SF3B1 alter splicing by disrupting interaction with the spliceosomal protein SUGP1, providing a possible mechanistic explanation for the phenotype of SF3B1 point mutants.	('disease-causing', 'Reg', (23, 38))	('SUGP1', 'Gene', (129, 134))	('splicing', 'MPA', (64, 72))	('splicing', 'biological_process', 'GO:0045292', ('64', '72'))	('mutations', 'Var', (39, 48))	('SF3B1', 'Gene', (52, 57))	('interaction', 'Interaction', (87, 98))	('disrupting', 'NegReg', (76, 86))	('alter', 'Reg', (58, 63))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('SUGP1', 'Gene', '57794', (129, 134))
147681	32168916	Moreover, silencing of SF3B1 by shRNA alters the proliferation of erythroid progenitors in vitro and in vivo in a mouse model, highlighting its essential role during erythropoiesis.	('proliferation of erythroid progenitors', 'CPA', (49, 87))	('alters', 'Reg', (38, 44))	('erythropoiesis', 'biological_process', 'GO:0030218', ('166', '180'))	('mouse', 'Species', '10090', (114, 119))	('shRNA', 'Gene', (32, 37))	('SF3B1', 'Gene', (23, 28))	('silencing', 'Var', (10, 19))
147682	32168916	Upon analyzing published RNA-seq raw data, we found that SF3B1 was aberrantly spliced in various neoplasms carrying an SF3B1 mutation, including in MDS-RS.	('SF3B1', 'Gene', (119, 124))	('MDS', 'Phenotype', 'HP:0002863', (148, 151))	('neoplasms', 'Disease', 'MESH:D009369', (97, 106))	('neoplasms', 'Disease', (97, 106))	('RNA', 'cellular_component', 'GO:0005562', ('25', '28'))	('MDS-RS', 'Disease', 'MESH:D009190', (148, 154))	('MDS-RS', 'Disease', (148, 154))	('neoplasms', 'Phenotype', 'HP:0002664', (97, 106))	('mutation', 'Var', (125, 133))
147683	32168916	Here, we show that cancer-associated SF3B1 point mutations drive the formation of this SF3B1 aberrant transcript in MDS-RS patients and in human myeloid cell lines.	('formation', 'biological_process', 'GO:0009058', ('69', '78'))	('point mutations', 'Var', (43, 58))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('SF3B1', 'Gene', (87, 92))	('patients', 'Species', '9606', (123, 131))	('formation', 'MPA', (69, 78))	('MDS-RS', 'Disease', 'MESH:D009190', (116, 122))	('human', 'Species', '9606', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('MDS-RS', 'Disease', (116, 122))	('SF3B1', 'Gene', (37, 42))	('MDS', 'Phenotype', 'HP:0002863', (116, 119))
147684	32168916	Using complementary approaches in both human and yeast cells, we show that insertion of these eight amino acids in wild-type or mutant SF3B1 protein abolished SF3B1 essential splicing activity, highlighting the crucial role of the H3 repeat in the splicing function of SF3B1.	('insertion', 'Var', (75, 84))	('protein', 'Protein', (141, 148))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('splicing', 'biological_process', 'GO:0045292', ('175', '183'))	('mutant', 'Var', (128, 134))	('SF3B1', 'Gene', (159, 164))	('SF3B1', 'Gene', (135, 140))	('abolished', 'NegReg', (149, 158))	('splicing', 'biological_process', 'GO:0045292', ('248', '256'))	('essential splicing activity', 'MPA', (165, 192))	('yeast', 'Species', '4932', (49, 54))	('human', 'Species', '9606', (39, 44))
147686	32168916	By exploring publicly available RNA-seq raw data obtained from patients with SF3B1 mutations, we identified a transcript of SF3B1 that was solely detected in SF3B1 mutated samples in various neoplasms, including breast cancer, uveal melanoma and recently in MDS.	('uveal melanoma', 'Disease', 'MESH:C536494', (227, 241))	('MDS', 'Disease', 'MESH:D009190', (258, 261))	('uveal melanoma', 'Disease', (227, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('mutated', 'Var', (164, 171))	('neoplasms', 'Disease', 'MESH:D009369', (191, 200))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))	('MDS', 'Disease', (258, 261))	('uveal melanoma', 'Phenotype', 'HP:0007716', (227, 241))	('breast cancer', 'Disease', (212, 225))	('neoplasms', 'Disease', (191, 200))	('SF3B1', 'Gene', (158, 163))	('MDS', 'Phenotype', 'HP:0002863', (258, 261))	('mutations', 'Var', (83, 92))	('SF3B1', 'Gene', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('neoplasms', 'Phenotype', 'HP:0002664', (191, 200))	('SF3B1', 'Gene', (124, 129))	('patients', 'Species', '9606', (63, 71))	('RNA', 'cellular_component', 'GO:0005562', ('32', '35'))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))
147692	32168916	The two SF3B1wt MDS-RS patients had mutations in the other splicing factor encoding genes ZRSR2 or SRSF2, and in TET2.	('splicing factor', 'Gene', (59, 74))	('MDS', 'Phenotype', 'HP:0002863', (16, 19))	('patients', 'Species', '9606', (23, 31))	('ZRSR2', 'Gene', (90, 95))	('SF3B1wt', 'Gene', (8, 15))	('SF3B1wt', 'Gene', '23451', (8, 15))	('SRSF2', 'Gene', (99, 104))	('TET2', 'Gene', '54790', (113, 117))	('mutations', 'Var', (36, 45))	('ZRSR2', 'Gene', '8233', (90, 95))	('TET2', 'Gene', (113, 117))	('splicing factor', 'Gene', '10569', (59, 74))	('splicing', 'biological_process', 'GO:0045292', ('59', '67'))	('MDS-RS', 'Disease', 'MESH:D009190', (16, 22))	('MDS-RS', 'Disease', (16, 22))	('SRSF2', 'Gene', '6427', (99, 104))
147694	32168916	As expected, aberrant transcripts of TMEM14C and ENOSF1 were exclusively detected in SF3B1-mutated MDS-RS patients.	('ENOSF1', 'Gene', '55556', (49, 55))	('SF3B1-mutated', 'Gene', (85, 98))	('detected', 'Reg', (73, 81))	('TMEM14C', 'Gene', (37, 44))	('ENOSF1', 'Gene', (49, 55))	('MDS', 'Phenotype', 'HP:0002863', (99, 102))	('patients', 'Species', '9606', (106, 114))	('MDS-RS', 'Disease', 'MESH:D009190', (99, 105))	('TMEM14C', 'Gene', '51522', (37, 44))	('MDS-RS', 'Disease', (99, 105))	('aberrant', 'Var', (13, 21))
147695	32168916	To investigate whether production of SF3B1ins transcript was indeed driven by SF3B1 hot spot mutations, we first generated human myeloid leukemic cell lines (K562 and UT-7) expressing SF3B1WTFLAG or SF3B1K700EFLAG under the control of a doxycycline inducible promoter.	('K700E', 'Mutation', 'rs559063155', (204, 209))	('SF3B1K700EFLAG', 'Var', (199, 213))	('mutations', 'Var', (93, 102))	('human', 'Species', '9606', (123, 128))	('K562', 'CellLine', 'CVCL:0004', (158, 162))	('SF3B1WT', 'Gene', '23451', (184, 191))	('UT-7', 'CellLine', 'CVCL:2233', (167, 171))	('SF3B1WT', 'Gene', (184, 191))	('doxycycline', 'Chemical', 'MESH:D004318', (237, 248))	('myeloid leukemic', 'Disease', (129, 145))	('SF3B1', 'Gene', (78, 83))	('myeloid leukemic', 'Disease', 'MESH:D007951', (129, 145))
147696	32168916	We chose to study the K700E substitution, which is the most common in MDS.	('MDS', 'Phenotype', 'HP:0002863', (70, 73))	('K700E', 'Var', (22, 27))	('MDS', 'Disease', 'MESH:D009190', (70, 73))	('K700E', 'Mutation', 'rs559063155', (22, 27))	('MDS', 'Disease', (70, 73))
147697	32168916	Importantly, the amount of recombinant SF3B1FLAG protein was similar to that of endogenous SF3B1 (Figure S1), mimicking a heterozygous SF3B1wt/K700E background.	('SF3B1wt', 'Gene', '23451', (135, 142))	('SF3B1wt', 'Gene', (135, 142))	('K700E', 'Mutation', 'rs559063155', (143, 148))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('SF3B1FLAG', 'Var', (39, 48))
147698	32168916	Aberrant splice variants of ENOSF1, TMEM14C, and DPH5 were exclusively found when SF3B1K700EFLAG was expressed, as shown in three K562 independent clones (Figure 1D) and two independent UT-7 cell populations (Figure 1E), validating the cell models used in this study.	('DPH5', 'Gene', '51611', (49, 53))	('SF3B1K700EFLAG', 'Var', (82, 96))	('TMEM14C', 'Gene', (36, 43))	('K562', 'CellLine', 'CVCL:0004', (130, 134))	('ENOSF1', 'Gene', (28, 34))	('found', 'Reg', (71, 76))	('UT-7', 'CellLine', 'CVCL:2233', (186, 190))	('DPH5', 'Gene', (49, 53))	('TMEM14C', 'Gene', '51522', (36, 43))	('ENOSF1', 'Gene', '55556', (28, 34))
147699	32168916	While only traces of SF3B1ins transcript were detected in SF3B1WTFLAG-transfected cells or in the absence of transgene induction, this alternative transcript was clearly produced when SF3B1K700EFLAG was expressed.	('SF3B1WT', 'Gene', (58, 65))	('SF3B1WT', 'Gene', '23451', (58, 65))	('SF3B1K700EFLAG', 'Var', (184, 198))
147700	32168916	Expression of SF3B1K700E was thus sufficient to promote the formation of SF3B1ins transcript, even in the presence of endogenous SF3B1WT, as observed in patient cells.	('formation', 'MPA', (60, 69))	('SF3B1K700E', 'Var', (14, 24))	('SF3B1ins', 'Gene', (73, 81))	('patient', 'Species', '9606', (153, 160))	('SF3B1WT', 'Gene', '23451', (129, 136))	('promote', 'PosReg', (48, 55))	('formation', 'biological_process', 'GO:0009058', ('60', '69'))	('SF3B1WT', 'Gene', (129, 136))
147701	32168916	To check whether the SF3B1ins transcript was also produced when other SF3B1 hot spot mutations were expressed, we transfected K562 cells with plasmids expressing SF3B1WT, SF3B1K700E, SF3B1E622D, SF3B1H662Q, or SF3B1K666E.	('K700E', 'Mutation', 'rs559063155', (176, 181))	('SF3B1H662Q', 'Var', (195, 205))	('K562', 'CellLine', 'CVCL:0004', (126, 130))	('SF3B1K666E', 'Var', (210, 220))	('SF3B1WT', 'Gene', '23451', (162, 169))	('SF3B1WT', 'Gene', (162, 169))	('SF3B1E622D', 'Var', (183, 193))	('SF3B1K700E', 'Var', (171, 181))
147702	32168916	Consequently, expression of the main disease-related SF3B1 mutations is sufficient to generate SF3B1ins transcripts, even in the presence of a functional SF3B1wt protein.	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('SF3B1wt', 'Gene', '23451', (154, 161))	('SF3B1wt', 'Gene', (154, 161))	('mutations', 'Var', (59, 68))	('SF3B1', 'Gene', (53, 58))	('SF3B1ins', 'Gene', (95, 103))
147703	32168916	To study the functionality of the SF3B1ins isoforms, we inserted the sequence encoding the LLLFSLFQ peptide into the plasmids expressing wild type SF3B1FLAG or SF3B1K700EFLAG.	('SF3B1FLAG', 'Var', (147, 156))	('K700E', 'Mutation', 'rs559063155', (165, 170))	('SF3B1K700EFLAG', 'Var', (160, 174))
147705	32168916	SF3B1wtINS and SF3B1K700EINS proteins were both correctly produced, although in somewhat lower abundance than SF3B1wt and SF3B1K700E proteins (Figure 2A), and were both properly addressed to the nucleus, as shown by immunofluorescence analysis (Figure S2).	('SF3B1wt', 'Gene', (110, 117))	('lower', 'NegReg', (89, 94))	('nucleus', 'cellular_component', 'GO:0005634', ('195', '202'))	('SF3B1K700EINS', 'Var', (15, 28))	('K700E', 'Mutation', 'rs559063155', (20, 25))	('K700E', 'Mutation', 'rs559063155', (127, 132))	('SF3B1wt', 'Gene', '23451', (0, 7))	('SF3B1wt', 'Gene', (0, 7))	('SF3B1wt', 'Gene', '23451', (110, 117))
147706	32168916	Remarkably, transient expression of SF3B1K700EINS did not lead to the production of aberrant ENOSF1 or TMEM14C transcripts, in contrast to transient expression of SF3B1K700E (Figure 2B).	('ENOSF1', 'Gene', '55556', (93, 99))	('TMEM14C', 'Gene', '51522', (103, 110))	('ENOSF1', 'Gene', (93, 99))	('TMEM14C', 'Gene', (103, 110))	('SF3B1K700EINS', 'Var', (36, 49))
147707	32168916	Thus, inserting the LLLFSLFQ sequence into the H3 repeat impeded the phenotypic expression of the K700E substitution.	('phenotypic expression', 'MPA', (69, 90))	('K700E', 'Var', (98, 103))	('impeded', 'NegReg', (57, 64))	('K700E', 'Mutation', 'rs559063155', (98, 103))
147708	32168916	This may have occurred either by a mechanism whereby the LLLFSLFQ insertion in cis would suppress SF3B1K700E-dependent splicing anomalies (potentially through conformational modifications), or by inactivation of SF3B1 protein function, leading to a loss-of-function phenotype.	('SF3B1K700E-dependent', 'Gene', (98, 118))	('SF3B1', 'Gene', (212, 217))	('function', 'MPA', (226, 234))	('LLLFSLFQ', 'Gene', (57, 65))	('K700E', 'Mutation', 'rs559063155', (103, 108))	('protein', 'cellular_component', 'GO:0003675', ('218', '225'))	('splicing', 'biological_process', 'GO:0045292', ('119', '127'))	('insertion', 'Var', (66, 75))	('suppress', 'NegReg', (89, 97))	('loss-of-function', 'NegReg', (249, 265))	('protein', 'Protein', (218, 225))	('inactivation', 'NegReg', (196, 208))
147710	32168916	We decided to study specific exon skipping events in RBM5, DUSP11, CCNA2, and STK6, the splicing of which was known to be modified upon either SF3B1 silencing or treatment by the spliceosome inhibitor spliceotastin A. Depletion of SF3B1 in siRNA-only transfected cells or in K562 cells co-transfected with the empty vector favored skipping of exon 6 in RBM5, of exon 6 in DUSP11, of exon 5 in CCNA2 and of exons 4-5-6 in STK6 (Figure 2D,E), as previously described.	('STK6', 'Gene', '6790', (78, 82))	('DUSP11', 'Gene', '8446', (59, 65))	('CCNA2', 'Gene', '890', (67, 72))	('splicing', 'biological_process', 'GO:0045292', ('88', '96'))	('STK6', 'Gene', (421, 425))	('DUSP11', 'Gene', (59, 65))	('RBM5', 'Gene', (53, 57))	('RBM5', 'Gene', '10181', (353, 357))	('RBM5', 'Gene', '10181', (53, 57))	('RBM5', 'Gene', (353, 357))	('K562', 'CellLine', 'CVCL:0004', (275, 279))	('skipping', 'Var', (331, 339))	('STK6', 'molecular_function', 'GO:0016905', ('421', '425'))	('STK6', 'molecular_function', 'GO:0016905', ('78', '82'))	('STK6', 'Gene', (78, 82))	('DUSP11', 'Gene', '8446', (372, 378))	('spliceosome', 'cellular_component', 'GO:0005681', ('179', '190'))	('CCNA2', 'Gene', (393, 398))	('CCNA2', 'Gene', (67, 72))	('DUSP11', 'Gene', (372, 378))	('STK6', 'Gene', '6790', (421, 425))	('CCNA2', 'Gene', '890', (393, 398))
147711	32168916	While expression of both SF3B1WT and SF3B1K700E partially prevented exon skipping, expression of both SF3B1wtins and SF3B1K700Eins did not.	('SF3B1WT', 'Gene', '23451', (25, 32))	('SF3B1WT', 'Gene', (25, 32))	('prevented', 'NegReg', (58, 67))	('SF3B1wt', 'Gene', '23451', (102, 109))	('SF3B1K700E', 'Var', (37, 47))	('SF3B1K700Eins', 'Var', (117, 130))	('SF3B1wt', 'Gene', (102, 109))	('exon skipping', 'MPA', (68, 81))
147712	32168916	The inability of SF3B1wtins and SF3B1K700Eins to restore the normal splicing of specific transcripts known to be altered upon silencing of SF3B1 implies that both SF3B1wtins and SF3B1K700Eins are inactive for splicing.	('K700E', 'Mutation', 'rs559063155', (183, 188))	('SF3B1wt', 'Gene', '23451', (163, 170))	('SF3B1wt', 'Gene', (163, 170))	('K700E', 'Mutation', 'rs559063155', (37, 42))	('splicing', 'biological_process', 'GO:0045292', ('68', '76'))	('splicing of specific transcripts', 'MPA', (68, 100))	('SF3B1wt', 'Gene', '23451', (17, 24))	('SF3B1', 'Gene', (139, 144))	('SF3B1wt', 'Gene', (17, 24))	('splicing', 'biological_process', 'GO:0045292', ('209', '217'))	('silencing', 'Var', (126, 135))
147713	32168916	To further address this question, we generated K562 cell lines that stably expressed SF3B1WTins or SF3B1K700Eins in combination with shSF3B1, both under the control of a doxycycline-inducible promoter.	('SF3B1WT', 'Gene', (85, 92))	('K700E', 'Mutation', 'rs559063155', (104, 109))	('doxycycline', 'Chemical', 'MESH:D004318', (170, 181))	('SF3B1K700Eins', 'Var', (99, 112))	('SF3B1WT', 'Gene', '23451', (85, 92))	('K562', 'CellLine', 'CVCL:0004', (47, 51))
147714	32168916	Here again, the splicing pattern of RBM5, DUSP11, CCNA2, and STK6 was not rescued by expression of SF3B1wtins or SF3B1K700Eins (Figure S3).	('STK6', 'Gene', (61, 65))	('CCNA2', 'Gene', '890', (50, 55))	('STK6', 'Gene', '6790', (61, 65))	('splicing', 'biological_process', 'GO:0045292', ('16', '24'))	('K700E', 'Mutation', 'rs559063155', (118, 123))	('SF3B1K700Eins', 'Var', (113, 126))	('DUSP11', 'Gene', (42, 48))	('SF3B1wt', 'Gene', '23451', (99, 106))	('SF3B1wt', 'Gene', (99, 106))	('CCNA2', 'Gene', (50, 55))	('STK6', 'molecular_function', 'GO:0016905', ('61', '65'))	('RBM5', 'Gene', '10181', (36, 40))	('DUSP11', 'Gene', '8446', (42, 48))	('RBM5', 'Gene', (36, 40))
147715	32168916	Silencing of SF3B1 by shSF3B1 affected cell growth, as previously reported in other cell lines or in CD34+ cells.	('cell growth', 'biological_process', 'GO:0016049', ('39', '50'))	('SF3B1', 'Gene', (13, 18))	('affected', 'Reg', (30, 38))	('shSF3B1', 'Gene', (22, 29))	('cell growth', 'CPA', (39, 50))	('Silencing', 'Var', (0, 9))	('CD34', 'Gene', '947', (101, 105))	('CD34', 'Gene', (101, 105))
147716	32168916	Notably, induction of SF3B1wtINS or SF3B1K700EINS did not complement the growth phenotype due to SF3B1 silencing (Figure 2F).	('SF3B1wt', 'Gene', '23451', (22, 29))	('SF3B1wt', 'Gene', (22, 29))	('SF3B1', 'Gene', (97, 102))	('SF3B1K700EINS', 'Var', (36, 49))	('silencing', 'NegReg', (103, 112))
147717	32168916	Moreover, the fact that splicing of RBM5 and DUSP11 was not affected when SF3B1wtins or SF3B1K700Eins was expressed in regular conditions (i.e., without siSF3B1) suggests that SF3B1ins proteins do not seem to exert a dominant negative effect (Figure 2B).	('DUSP11', 'Gene', '8446', (45, 51))	('SF3B1K700Eins', 'Var', (88, 101))	('DUSP11', 'Gene', (45, 51))	('splicing', 'biological_process', 'GO:0045292', ('24', '32'))	('K700E', 'Mutation', 'rs559063155', (93, 98))	('SF3B1wt', 'Gene', '23451', (74, 81))	('SF3B1wt', 'Gene', (74, 81))	('RBM5', 'Gene', '10181', (36, 40))	('SF3B1ins', 'Var', (176, 184))	('RBM5', 'Gene', (36, 40))
147719	32168916	Nevertheless, while cancer-associated SF3B1 substitutions lead to an improper recognition of the branch site and to the use of cryptic splice sites, it remains possible that a fraction of the SF3B1 pool, i.e., SF3B1wtins and SF3B1K700Eins, may drive improper U2 snRNP assembly in SF3B1+/K700E cells.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('SF3B1wt', 'Gene', (210, 217))	('snRNP', 'molecular_function', 'GO:0003734', ('262', '267'))	('SF3B1', 'Gene', (38, 43))	('drive', 'Reg', (244, 249))	('K700E', 'Mutation', 'rs559063155', (287, 292))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('K700E', 'Mutation', 'rs559063155', (230, 235))	('cryptic', 'Gene', '55997', (127, 134))	('cryptic', 'Gene', (127, 134))	('cancer', 'Disease', (20, 26))	('snRNP', 'Gene', (262, 267))	('substitutions', 'Var', (44, 57))	('snRNP', 'Gene', '57819', (262, 267))	('SF3B1wt', 'Gene', '23451', (210, 217))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('259', '267'))	('SF3B1K700Eins', 'Var', (225, 238))
147721	32168916	The H3 repeat seems also to be directly implicated in the interaction of the concave surface of SF3B1 with SF3b14b, a highly conserved protein required for proper assembly of yeast U2 snRNP and stability of the spliceosome.	('SF3b14b', 'Var', (107, 114))	('snRNP', 'Gene', '57819', (184, 189))	('interaction', 'Interaction', (58, 69))	('spliceosome', 'cellular_component', 'GO:0005681', ('211', '222'))	('SF3B1', 'Gene', (96, 101))	('yeast', 'Species', '4932', (175, 180))	('implicated', 'Reg', (40, 50))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('snRNP', 'molecular_function', 'GO:0003734', ('184', '189'))	('snRNP', 'Gene', (184, 189))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('181', '189'))
147725	32168916	Most substitutions found in MDS patients affect amino acids conserved between the two species, in the HEAT domain (Figure S4), including the K700 residue.	('MDS', 'Disease', (28, 31))	('patients', 'Species', '9606', (32, 40))	('MDS', 'Disease', 'MESH:D009190', (28, 31))	('MDS', 'Phenotype', 'HP:0002863', (28, 31))	('K700', 'Var', (141, 145))	('amino acids conserved', 'MPA', (48, 69))	('affect', 'Reg', (41, 47))
147726	32168916	We took advantage of the thermosensitive growth phenotype of the yeast prp10-1 mutant strain, which harbors two point mutations in SAP155, initially selected in a genetic screen, to study the ability of various Sap155 alleles to restore growth at restrictive temperature (37  C).	('Sap155', 'Gene', '850601', (211, 217))	('SAP155', 'Gene', (131, 137))	('mutations', 'Var', (118, 127))	('mutant', 'Var', (79, 85))	('SAP155', 'Gene', '850601', (131, 137))	('Sap155', 'Gene', (211, 217))	('yeast', 'Species', '4932', (65, 70))	('growth', 'MPA', (237, 243))	('prp10', 'Gene', '23451', (71, 76))	('prp10', 'Gene', (71, 76))
147727	32168916	We first introduced the counterparts of E622N, H662Q, K666N (R666N), and K700E substitutions into the S. pombe SAP155 sequence by site-directed mutagenesis.	('S. pombe', 'Species', '4896', (102, 110))	('K700E', 'Mutation', 'rs559063155', (73, 78))	('H662Q', 'Var', (47, 52))	('mutagenesis', 'biological_process', 'GO:0006280', ('144', '155'))	('E622N', 'Var', (40, 45))	('K700E', 'Var', (73, 78))	('K666N', 'Mutation', 'rs377023736', (54, 59))	('SAP155', 'Gene', '850601', (111, 117))	('E622N', 'SUBSTITUTION', 'None', (40, 45))	('K666N', 'Var', (54, 59))	('R666N', 'Mutation', 'p.R666N', (61, 66))	('H662Q', 'Chemical', '-', (47, 52))	('SAP155', 'Gene', (111, 117))
147728	32168916	The growth deficiency of the prp10-1 strain at 37  C was restored upon expression of wild-type SAP155 or the different mutated versions of SAP155 (Figure S4), indicating that the main counterparts of Sap155 pathogenic mutations do not affect the growth of S. pombe, as also observed in S. cerevisiae.	('Sap155', 'Gene', (200, 206))	('S. pombe', 'Species', '4896', (256, 264))	('SAP155', 'Gene', (139, 145))	('growth deficiency', 'Phenotype', 'HP:0001510', (4, 21))	('mutations', 'Var', (218, 227))	('SAP155', 'Gene', (95, 101))	('S. cerevisiae', 'Species', '4932', (286, 299))	('growth deficiency', 'Disease', 'MESH:D006130', (4, 21))	('SAP155', 'Gene', '850601', (139, 145))	('prp10', 'Gene', '23451', (29, 34))	('mutated', 'Var', (119, 126))	('Sap155', 'Gene', '850601', (200, 206))	('SAP155', 'Gene', '850601', (95, 101))	('growth deficiency', 'Disease', (4, 21))	('prp10', 'Gene', (29, 34))
147729	32168916	Thus, the various cancer-related SAP155 point mutations do not alter splicing of genes essential for yeast viability, in both S. pombe and S. cerevisiae.	('S. pombe', 'Species', '4896', (126, 134))	('point mutations', 'Var', (40, 55))	('SAP155', 'Gene', (33, 39))	('S. cerevisiae', 'Species', '4932', (139, 152))	('splicing', 'biological_process', 'GO:0045292', ('69', '77'))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('SAP155', 'Gene', '850601', (33, 39))	('splicing', 'MPA', (69, 77))	('yeast', 'Species', '4932', (101, 106))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
147732	32168916	Hence, yeast counterparts of disease-related SF3B1 mutants do not alter the splicing of these specific transcripts in S. pombe.	('mutants', 'Var', (51, 58))	('splicing', 'biological_process', 'GO:0045292', ('76', '84'))	('S. pombe', 'Species', '4896', (118, 126))	('yeast', 'Species', '4932', (7, 12))	('SF3B1', 'Gene', (45, 50))	('splicing', 'MPA', (76, 84))
147733	32168916	Nevertheless, given that disease-related mutations appear to alter the fidelity of branch site selection of a mini-gene construct in S. cerevisiae, it is likely that the K700E counterpart impacts other transcripts in S. pombe upon selection of cryptic splice sites.	('K700E', 'Mutation', 'rs559063155', (170, 175))	('fidelity', 'MPA', (71, 79))	('K700E', 'Var', (170, 175))	('transcripts', 'MPA', (202, 213))	('S. pombe', 'Species', '4896', (217, 225))	('alter', 'Reg', (61, 66))	('impacts', 'Reg', (188, 195))	('cryptic', 'Gene', '55997', (244, 251))	('S. cerevisiae', 'Species', '4932', (133, 146))	('cryptic', 'Gene', (244, 251))
147735	32168916	While the nature of splicing defects observed in a conditional knock-in Sf3b1K700E/+ mouse model mimicked that described in human MDS, with numerous aberrant 3' splice-site selections, only a few mis-spliced transcripts were found in common between mouse and human.	('mouse', 'Species', '10090', (85, 90))	('K700E', 'Mutation', 'rs559063155', (77, 82))	('MDS', 'Phenotype', 'HP:0002863', (130, 133))	('splicing', 'biological_process', 'GO:0045292', ('20', '28'))	('splicing', 'MPA', (20, 28))	('human', 'Species', '9606', (124, 129))	('Sf3b1K700E/+', 'Var', (72, 84))	('mouse', 'Species', '10090', (249, 254))	('human', 'Species', '9606', (259, 264))	('MDS', 'Disease', (130, 133))	('MDS', 'Disease', 'MESH:D009190', (130, 133))
147738	32168916	Wild-type and prp10-1 mutant strains were transformed with plasmids expressing SAP155WT, SAP155K700E, SAP155 WTins, or SAP155 K700Eins.	('SAP155', 'Gene', (79, 85))	('SAP155', 'Gene', '850601', (102, 108))	('prp10', 'Gene', '23451', (14, 19))	('prp10', 'Gene', (14, 19))	('K700E', 'Mutation', 'rs559063155', (95, 100))	('K700E', 'Mutation', 'rs559063155', (126, 131))	('SAP155', 'Gene', '850601', (79, 85))	('SAP155', 'Gene', (89, 95))	('mutant', 'Var', (22, 28))	('SAP155', 'Gene', (102, 108))	('SAP155', 'Gene', (119, 125))	('SAP155', 'Gene', '850601', (119, 125))	('SAP155', 'Gene', '850601', (89, 95))
147739	32168916	Growth of prp10-1 cells expressing SAP155 WTins or SAP155 K700Eins was affected at 25  C. The growth phenotype was even stronger when K700E was associated to the eight-amino-acid insertion.	('SAP155', 'Gene', (51, 57))	('SAP155', 'Gene', (35, 41))	('prp10', 'Gene', '23451', (10, 15))	('prp10', 'Gene', (10, 15))	('stronger', 'PosReg', (120, 128))	('SAP155', 'Gene', '850601', (35, 41))	('K700E', 'Mutation', 'rs559063155', (134, 139))	('SAP155', 'Gene', '850601', (51, 57))	('K700E', 'Var', (134, 139))	('K700E', 'Mutation', 'rs559063155', (58, 63))	('growth', 'MPA', (94, 100))
147740	32168916	Moreover, expression of SAP155WTins and SAP155K700Eins in prp10-1 mutant strain did not complement at all the defective growth of prp10-1 strain at restrictive temperature (Figure 3A), in contrast to insertion-less constructions.	('prp10', 'Gene', '23451', (58, 63))	('prp10', 'Gene', (130, 135))	('SAP155WTins', 'Chemical', '-', (24, 35))	('mutant', 'Var', (66, 72))	('SAP155K700Eins', 'Var', (40, 54))	('prp10', 'Gene', (58, 63))	('prp10', 'Gene', '23451', (130, 135))
147741	32168916	The splicing of TFIID, NDA3, and RPL7 was not restored upon expression of SAP155WTins or in prp10-1 strain (Figure 3B).	('RPL7', 'Gene', (33, 37))	('splicing', 'biological_process', 'GO:0045292', ('4', '12'))	('splicing', 'MPA', (4, 12))	('SAP155WTins', 'Chemical', '-', (74, 85))	('prp10', 'Gene', '23451', (92, 97))	('RPL7', 'Gene', '6129', (33, 37))	('SAP155WTins', 'Var', (74, 85))	('prp10', 'Gene', (92, 97))
147742	32168916	Due to the major growth defect of the prp10-1 mutant strain expressing SAP155K700Eins, we could not study the splicing in such a background.	('prp10', 'Gene', '23451', (38, 43))	('SAP155K700Eins', 'Var', (71, 85))	('prp10', 'Gene', (38, 43))	('growth', 'MPA', (17, 23))	('splicing', 'biological_process', 'GO:0045292', ('110', '118'))
147743	32168916	Altogether, these results indicate that insertion of LLLFSLFQ in the H3 repeat of S. pombe SAP155 alters its essential function, as observed in human cell lines.	('human', 'Species', '9606', (144, 149))	('insertion', 'Var', (40, 49))	('essential function', 'MPA', (109, 127))	('alters', 'Reg', (98, 104))	('LLLFSLFQ', 'Gene', (53, 61))	('SAP155', 'Gene', (91, 97))	('SAP155', 'Gene', '850601', (91, 97))	('S. pombe', 'Species', '4896', (82, 90))
147744	32168916	Modulation of splicing catalysis by small molecules was proposed for therapeutic targeting of cancer cells with mutations in genes encoding spliceosomal proteins.	('splicing', 'biological_process', 'GO:0045292', ('14', '22'))	('mutations', 'Var', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
147746	32168916	The pladienolide B E7107 derivative was tested in a phase 1 clinical trial in solid tumors but tests were suspended due to adverse events.	('E7107', 'Var', (19, 24))	('pladienolide B E7107', 'Chemical', '-', (4, 24))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
147748	32168916	To test whether it was actually possible to increase SF3B1ins formation, thereby increasing splicing dysfunction in target cells, we designed splice switching oligonucleotides (SSO) with the intention to favor use of the AG' cryptic site at the intron 12/exon 13 junction.	('cryptic', 'Gene', '55997', (225, 232))	('increasing', 'PosReg', (81, 91))	('cryptic', 'Gene', (225, 232))	('splicing dysfunction', 'MPA', (92, 112))	('formation', 'biological_process', 'GO:0009058', ('62', '71'))	('increase', 'PosReg', (44, 52))	('splicing', 'biological_process', 'GO:0045292', ('92', '100'))	('oligonucleotides', 'Chemical', 'MESH:D009841', (159, 175))	('SSO', 'Chemical', '-', (177, 180))	('SF3B1ins', 'Var', (53, 61))
147750	32168916	We introduced the SSO in readily transfectable HEK293T cells that were co-transfected with plasmids expressing either SF3B1WT or SF3B1K700E, in comparison to cells transfected with a control fluorescent SSO.	('SF3B1K700E', 'Var', (129, 139))	('SF3B1WT', 'Gene', '23451', (118, 125))	('HEK293T', 'CellLine', 'CVCL:0063', (47, 54))	('K700E', 'Mutation', 'rs559063155', (134, 139))	('SSO', 'Chemical', '-', (203, 206))	('SF3B1WT', 'Gene', (118, 125))	('SSO', 'Chemical', '-', (18, 21))
147751	32168916	SSO #1, the center of which masks the 3' AG canonical site, was able to increase SF3B1ins formation in cells expressing SF3B1K700E, but also in SF3B1WT cells (Figure 4B,C).	('SF3B1WT', 'Gene', '23451', (144, 151))	('increase', 'PosReg', (72, 80))	('SF3B1K700E', 'Var', (120, 130))	('SF3B1ins', 'Gene', (81, 89))	('SF3B1WT', 'Gene', (144, 151))	('SSO', 'Chemical', '-', (0, 3))	('formation', 'biological_process', 'GO:0009058', ('90', '99'))	('K700E', 'Mutation', 'rs559063155', (125, 130))
147759	32168916	Mutations were detected using the Variant Caller v4.2 plugin from Torrent Suite Software and IonReporter v5.2 (Life Technologies, Carlsbad, CA, USA).	('v5.2', 'Gene', '28773', (105, 109))	('v4.2', 'Gene', '28781', (49, 53))	('Mutations', 'Var', (0, 9))	('v4.2', 'Gene', (49, 53))	('v5.2', 'Gene', (105, 109))
147761	32168916	Plasmids encoding E622D, H662Q, and K666E variants of SF3B1 were obtained by site-directed mutagenesis from pCMV-3tag-SF3B1WT plasmid using the QuikChange II XL Site-Directed Mutagenesis Kit (Agilent).	('SF3B1', 'Gene', (54, 59))	('K666E', 'Mutation', 'rs754688962', (36, 41))	('mutagenesis', 'biological_process', 'GO:0006280', ('91', '102'))	('Kit', 'Gene', (187, 190))	('H662Q', 'Chemical', '-', (25, 30))	('Mutagenesis', 'biological_process', 'GO:0006280', ('175', '186'))	('E622D', 'Var', (18, 23))	('E622D', 'Mutation', 'rs763149798', (18, 23))	('SF3B1WT', 'Gene', '23451', (118, 125))	('K666E', 'Var', (36, 41))	('SF3B1WT', 'Gene', (118, 125))	('Kit', 'Gene', '3815', (187, 190))	('H662Q', 'Var', (25, 30))
147762	32168916	The same strategy was used to produce the counterparts of E622N, H662Q, K666N (R666N), and K700E substitutions into the S. pombe SAP155.	('R666N', 'Mutation', 'p.R666N', (79, 84))	('SAP155', 'Gene', '850601', (129, 135))	('S. pombe', 'Species', '4896', (120, 128))	('H662Q', 'Chemical', '-', (65, 70))	('K700E', 'Mutation', 'rs559063155', (91, 96))	('H662Q', 'Var', (65, 70))	('K700E', 'Var', (91, 96))	('E622N', 'Var', (58, 63))	('SAP155', 'Gene', (129, 135))	('K666N', 'Mutation', 'rs377023736', (72, 77))	('E622N', 'SUBSTITUTION', 'None', (58, 63))
147773	32168916	The optimized coding sequences of SF3B1WT and SF3B1K700E, amplified from pCMV-3tag-1A-SF3B1WT and pCMV-3tag-1A-SF3B1K700E plasmids, respectively, were introduced in the lentiviral plasmid pCW57.1 using In-Fusion  HD Cloning Plus kit (Takara).	('SF3B1WT', 'Gene', '23451', (86, 93))	('SF3B1WT', 'Gene', '23451', (34, 41))	('HD Cloning Plus kit', 'Disease', (213, 232))	('SF3B1WT', 'Gene', (86, 93))	('SF3B1WT', 'Gene', (34, 41))	('HD Cloning Plus kit', 'Disease', 'MESH:D006816', (213, 232))	('pCMV-3tag-1A-SF3B1K700E', 'Var', (98, 121))	('SF3B1K700E', 'Var', (46, 56))
147778	32168916	Transduction with the shSF3B1 construct was done on both K562 and K562 stable cell lines expressing SF3B1wt, SF3B1K700E, SF3B1wtins, and SF3B1K700Eins to obtain co-transduced stable cell lines.	('K700E', 'Mutation', 'rs559063155', (142, 147))	('K562', 'CellLine', 'CVCL:0004', (57, 61))	('SF3B1wt', 'Gene', '23451', (100, 107))	('SF3B1wt', 'Gene', (100, 107))	('SF3B1K700E', 'Var', (109, 119))	('SF3B1wt', 'Gene', '23451', (121, 128))	('SF3B1wt', 'Gene', (121, 128))	('SF3B1K700Eins', 'Var', (137, 150))	('K562', 'CellLine', 'CVCL:0004', (66, 70))	('Transduction', 'biological_process', 'GO:0009293', ('0', '12'))	('K700E', 'Mutation', 'rs559063155', (114, 119))
147791	32168916	We used the following primary antibodies: anti-SF3B1 (1:5000, #170854 Abcam), anti-FLAG (1:5000, #F3165, Sigma), anti-GAPDH (1:5000), and anti-b-actin (1:1000, #ab8226, Abcam).	('1:1000', 'Var', (152, 158))	('GAPDH', 'Gene', '2597', (118, 123))	('anti-SF3B1', 'Var', (42, 52))	('GAPDH', 'Gene', (118, 123))	('#170854', 'Var', (62, 69))
147800	32168916	RNA splicing was reported as a process significantly affected (i.e., numerous splicing genes with abnormal expression or splicing) in all MDS harboring mutations in splice factor genes.	('RNA splicing', 'MPA', (0, 12))	('splicing genes', 'Gene', (78, 92))	('affected', 'Reg', (53, 61))	('MDS', 'Disease', (138, 141))	('mutations', 'Var', (152, 161))	('MDS', 'Disease', 'MESH:D009190', (138, 141))	('splicing', 'biological_process', 'GO:0045292', ('121', '129'))	('splicing', 'biological_process', 'GO:0045292', ('78', '86'))	('RNA splicing', 'biological_process', 'GO:0008380', ('0', '12'))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('MDS', 'Phenotype', 'HP:0002863', (138, 141))
147801	32168916	In this study, we identified and characterized a novel SF3B1 transcript that is specifically produced in neoplasms carrying an SF3B1 mutation, including in myelodysplastic syndromes.	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (156, 181))	('mutation', 'Var', (133, 141))	('myelodysplastic syndromes', 'Disease', (156, 181))	('SF3B1', 'Gene', (127, 132))	('neoplasms', 'Phenotype', 'HP:0002664', (105, 114))	('SF3B1', 'Gene', (55, 60))	('neoplasms', 'Disease', 'MESH:D009369', (105, 114))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (156, 181))	('neoplasms', 'Disease', (105, 114))
147802	32168916	Using complementary approaches in both human and yeast cells, we showed that this insertion abolished SF3B1 splice function, highlighting the functional importance of the H3 repeat in SF3B1.	('insertion', 'Var', (82, 91))	('SF3B1', 'Gene', (102, 107))	('splice function', 'MPA', (108, 123))	('yeast', 'Species', '4932', (49, 54))	('abolished', 'NegReg', (92, 101))	('human', 'Species', '9606', (39, 44))
147803	32168916	SF3B1 mutant cells are expected to accumulate numerous other aberrant proteins, which could participate in carcinogenesis.	('mutant', 'Var', (6, 12))	('SF3B1', 'Gene', (0, 5))	('accumulate', 'PosReg', (35, 45))	('proteins', 'Protein', (70, 78))	('participate', 'Reg', (92, 103))	('aberrant proteins', 'Protein', (61, 78))	('carcinogenesis', 'Disease', 'MESH:D063646', (107, 121))	('carcinogenesis', 'Disease', (107, 121))
147805	32168916	Finally, splicing inhibitors were recently proposed for therapeutic targeting of cancer cells with mutations in genes encoding spliceosomal proteins.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('splicing', 'biological_process', 'GO:0045292', ('9', '17'))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
147806	32168916	As the selectivity still remains an important issue, increasing splicing alterations in SF3B1K700E/+ cells in a specific way, through preferential selection of splice sites by SSO, might represent a novel way to sensitize cells to splicing inhibitor-induced apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('258', '267'))	('splicing', 'biological_process', 'GO:0045292', ('231', '239'))	('apoptosis', 'biological_process', 'GO:0006915', ('258', '267'))	('splicing', 'MPA', (64, 72))	('splicing', 'biological_process', 'GO:0045292', ('64', '72'))	('SF3B1K700E/+', 'Var', (88, 100))	('SSO', 'Chemical', '-', (176, 179))	('preferential', 'PosReg', (134, 146))	('increasing', 'PosReg', (53, 63))
147807	32168916	The following are available online at , Figure S1: Complementary results obtained in K562 and UT-7 cells upon inducible expression of SF3B1K700E or upon transitory expression of other important SF3B1 variants; Figure S2: SF3B1insFLAG proteins are correctly addressed to the nucleus; Figure S3: Splicing analysis of RBM5, DUSP11, CCNA2 and STK6 in inducible K562 cell lines expressing shSF3B1 alone or in combination with various SF3B1 constructs; Figure S4: Expression of the main disease-related SF3B1 mutations does not affect growth of the Schizosaccharomyces pombe prp10-1 strain; Table S1: Features of the MDS patients included in this study; Table S2: Primers used in this study.	('K562', 'CellLine', 'CVCL:0004', (357, 361))	('DUSP11', 'Gene', (321, 327))	('CCNA2', 'Gene', '890', (329, 334))	('UT-7', 'CellLine', 'CVCL:2233', (94, 98))	('MDS', 'Phenotype', 'HP:0002863', (611, 614))	('nucleus', 'cellular_component', 'GO:0005634', ('274', '281'))	('RBM5', 'Gene', (315, 319))	('Schizosaccharomyces pombe', 'Species', '4896', (543, 568))	('RBM5', 'Gene', '10181', (315, 319))	('Splicing', 'biological_process', 'GO:0045292', ('294', '302'))	('patients', 'Species', '9606', (615, 623))	('STK6', 'Gene', '6790', (339, 343))	('STK6', 'molecular_function', 'GO:0016905', ('339', '343'))	('MDS', 'Disease', 'MESH:D009190', (611, 614))	('K562', 'CellLine', 'CVCL:0004', (85, 89))	('CCNA2', 'Gene', (329, 334))	('MDS', 'Disease', (611, 614))	('SF3B1', 'Gene', (497, 502))	('prp10', 'Gene', '23451', (569, 574))	('STK6', 'Gene', (339, 343))	('prp10', 'Gene', (569, 574))	('DUSP11', 'Gene', '8446', (321, 327))	('mutations', 'Var', (503, 512))
147880	31175402	Among the responding patients, chromosome 3 monosomy was found in association with 8q duplication in one of the patients.	('chromosome', 'cellular_component', 'GO:0005694', ('31', '41'))	('monosomy', 'Var', (44, 52))	('patients', 'Species', '9606', (112, 120))	('patients', 'Species', '9606', (21, 29))	('chromosome 3', 'Gene', (31, 43))
147909	31175402	It has recently been reported that a defect of MBD4, a transcriptional factor of gene promoters, is associated with a hypermutated CpG > TpG pattern which generates multiple subclones of the primary UM with more heterogeneous metastases.	('metastases', 'Disease', 'MESH:D009362', (226, 236))	('MBD4', 'Gene', '8930', (47, 51))	('MBD4', 'Gene', (47, 51))	('associated', 'Reg', (100, 110))	('defect', 'Var', (37, 43))	('metastases', 'Disease', (226, 236))
147921	29794999	Targeted Tumor Therapy Remixed:An Update on the Use of Small-Molecule Drugs in Combination Therapies Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies.	('small-molecule', 'Var', (260, 274))	('Tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('patients', 'Species', '9606', (146, 154))	('tumor', 'Disease', (140, 145))
147928	29794999	As per the model of multi-step tumorigenesis, mutations in oncogenes and in tumor suppressor genes as well as further genetic and epigenetic changes mediate this transformation process.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mutations', 'Var', (46, 55))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('oncogenes', 'Gene', (59, 68))	('tumor suppressor', 'biological_process', 'GO:0051726', ('76', '92'))	('mediate', 'Reg', (149, 156))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('76', '92'))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
147938	29794999	In melanoma, the most common driver mutation occurring in over 50% of patients affects the serine/threonine protein kinase BRAF (BRAFV600E), a downstream effector of growth factor receptor signaling, that can be therapeutically targeted by specific BRAFV600mut inhibitors (BRAFi).	('BRAFV600E', 'Gene', (129, 138))	('signaling', 'biological_process', 'GO:0023052', ('189', '198'))	('serine', 'Chemical', 'MESH:D012694', (91, 97))	('patients', 'Species', '9606', (70, 78))	('BRAFV600E', 'Gene', '673', (129, 138))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('affects', 'Reg', (79, 86))	('BRAF', 'Gene', '673', (249, 253))	('BRAF', 'Gene', '673', (273, 277))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', (249, 253))	('BRAF', 'Gene', '673', (129, 133))	('BRAF', 'Gene', (273, 277))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('mutation', 'Var', (36, 44))
147946	29794999	In other types of lung cancer with epidermal growth factor receptor (EGFR) mutations, commonly tyrosine kinase inhibitors (TKi) against the mutant EGFR or anti-EFGR antibodies are applied alone or in new combination therapy trials with other anti-cancer therapeutics.	('EGFR', 'Gene', (147, 151))	('EGFR', 'molecular_function', 'GO:0005006', ('147', '151'))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Disease', (247, 253))	('EGFR', 'Gene', '1956', (69, 73))	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('FGR', 'Gene', '2268', (161, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('EGFR', 'molecular_function', 'GO:0005006', ('69', '73'))	('EGFR', 'Gene', '1956', (147, 151))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('35', '58'))	('epidermal growth factor receptor', 'Gene', (35, 67))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('epidermal growth factor receptor', 'Gene', '1956', (35, 67))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('mutant', 'Var', (140, 146))	('FGR', 'Gene', (161, 164))	('EGFR', 'Gene', (69, 73))	('mutations', 'Var', (75, 84))	('lung cancer', 'Disease', (18, 29))
147947	29794999	Combination therapy is also key to the treatment of metastatic colorectal cancer (CRC)-most frequently bearing KRAS, NRAS, BRAF, EGFR, and MYC mutations, loss of functions, amplifications, and microsatellite instability (MSI)-as reflected by ongoing clinical trials (e.g., HERACLES trial, NCT03225937).	('MYC', 'Gene', (139, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('microsatellite', 'MPA', (193, 207))	('EGFR', 'Gene', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('129', '133'))	('NRAS', 'Gene', '4893', (117, 121))	('colorectal cancer', 'Disease', (63, 80))	('amplifications', 'Var', (173, 187))	('mutations', 'Var', (143, 152))	('loss of functions', 'NegReg', (154, 171))	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('MYC', 'Gene', '4609', (139, 142))	('KRAS', 'Gene', '3845', (111, 115))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('EGFR', 'Gene', '1956', (129, 133))	('NRAS', 'Gene', (117, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('KRAS', 'Gene', (111, 115))
147948	29794999	In general, mutations in key oncogenic kinase signaling pathways-including the RAS-RAF-MEK-ERK/MAPK, the PI3K/PTEN-AKT-mTOR, the JAK-STAT-or the WNT/beta-catenin/MYC pathways occur with high frequency in a variety of tumors.	('PTEN', 'Gene', '5728', (110, 114))	('AKT', 'Gene', '207', (115, 118))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('RAF', 'Gene', (83, 86))	('MYC', 'Gene', (162, 165))	('MEK', 'Gene', (87, 90))	('ERK', 'Gene', (91, 94))	('JAK-STAT-or', 'Pathway', (129, 140))	('oncogenic kinase signaling pathways-including', 'Pathway', (29, 74))	('PI3K', 'molecular_function', 'GO:0016303', ('105', '109'))	('ERK', 'molecular_function', 'GO:0004707', ('91', '94'))	('mTOR', 'Gene', (119, 123))	('JAK', 'molecular_function', 'GO:0004713', ('129', '132'))	('MYC', 'Gene', '4609', (162, 165))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('beta-catenin', 'Gene', (149, 161))	('MAPK', 'molecular_function', 'GO:0004707', ('95', '99'))	('AKT', 'Gene', (115, 118))	('beta-catenin', 'Gene', '1499', (149, 161))	('mTOR', 'Gene', '2475', (119, 123))	('PTEN', 'Gene', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('RAF', 'Gene', '22882', (83, 86))	('tumors', 'Disease', (217, 223))	('ERK', 'Gene', '5594', (91, 94))	('mutations', 'Var', (12, 21))	('MEK', 'Gene', '5609', (87, 90))
147954	29794999	Based on a proven principle the use of new kinase inhibitors and inhibitor combinations may enhance established first line medications-because additional mutations or activation of compensatory growth factor signaling pathways are frequently observed in response to cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('cancer', 'Disease', (266, 272))	('signaling', 'biological_process', 'GO:0023052', ('208', '217'))	('activation', 'PosReg', (167, 177))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('mutations', 'Var', (154, 163))	('enhance', 'PosReg', (92, 99))
147957	29794999	Whereas the rationale for use of PI3Ki, METi, or FGFRi lies in the potential parallel activation of respective growth factor signaling pathways, adding CDKi may be beneficial for the treatment of tumors with elevated CDK4/6 activity or genetic alterations in the Cyclin D-CDK4/6-p16INK4A-RB pathway.	('Cyclin', 'molecular_function', 'GO:0016538', ('263', '269'))	('CDK4/6', 'Enzyme', (217, 223))	('activity', 'MPA', (224, 232))	('CDK', 'molecular_function', 'GO:0004693', ('217', '220'))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('elevated', 'PosReg', (208, 216))	('CDK', 'molecular_function', 'GO:0004693', ('272', '275'))	('Cyclin', 'Gene', (263, 269))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('genetic alterations', 'Var', (236, 255))	('signaling', 'biological_process', 'GO:0023052', ('125', '134'))	('p16INK4A', 'Gene', (279, 287))	('activation', 'PosReg', (86, 96))	('Cyclin', 'Gene', '5111', (263, 269))	('growth factor signaling pathways', 'Pathway', (111, 143))	('p16INK4A', 'Gene', '1029', (279, 287))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
147960	29794999	In advanced squamous cell lung, pancreatic, head & neck and other solid tumors, combining the inhibition of CDK4/6 (palbociclib) and PI3K/mTOR (gedatolisib) may have advantage over the use of each drug alone or the Platinum-based chemotherapy (NCT03065062).	('neck', 'cellular_component', 'GO:0044326', ('51', '55'))	('mTOR', 'Gene', (138, 142))	('solid tumors', 'Disease', 'MESH:D009369', (66, 78))	('mTOR', 'Gene', '2475', (138, 142))	('pancreatic', 'Disease', 'MESH:D010195', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('and', 'Var', (129, 132))	('CDK', 'molecular_function', 'GO:0004693', ('108', '111'))	('the', 'NegReg', (90, 93))	('pancreatic', 'Disease', (32, 42))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('Platinum', 'Chemical', 'MESH:D010984', (215, 223))	('solid tumors', 'Disease', (66, 78))	('head &', 'Disease', (44, 50))	('PI3K', 'molecular_function', 'GO:0016303', ('133', '137'))	('squamous cell lung', 'Disease', (12, 30))	('gedatolisib', 'Chemical', 'MESH:C549060', (144, 155))
147962	29794999	To target the signaling of angiogenic factors that control tumor neovascularization, including vascular epithelial growth factor (VEGF), PDGF, and FGF receptor tyrosine kinase signaling, oral multi-kinase inhibitors, such as lucitanib, have been tested in certain forms of NSCLC and breast cancer with genetic FGR alterations.	('tested', 'Reg', (246, 252))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('FGR', 'Gene', (310, 313))	('breast cancer', 'Phenotype', 'HP:0003002', (283, 296))	('VEGF', 'Gene', '7422', (130, 134))	('signaling', 'biological_process', 'GO:0023052', ('14', '23'))	('vascular epithelial growth factor', 'Gene', (95, 128))	('signaling', 'biological_process', 'GO:0023052', ('176', '185'))	('alterations', 'Var', (314, 325))	('VEGF', 'Gene', (130, 134))	('breast cancer', 'Disease', 'MESH:D001943', (283, 296))	('NSCLC', 'Disease', 'MESH:D002289', (273, 278))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('breast cancer', 'Disease', (283, 296))	('NSCLC', 'Disease', (273, 278))	('FGR', 'Gene', '2268', (310, 313))	('PDGF', 'molecular_function', 'GO:0005161', ('137', '141'))	('NSCLC', 'Phenotype', 'HP:0030358', (273, 278))	('vascular epithelial growth factor', 'Gene', '7422', (95, 128))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('lucitanib', 'Chemical', 'MESH:C000595232', (225, 234))
147964	29794999	Similarly, inhibitors of focal adhesion kinase (FAK), a key regulator of integrin signaling, target tumor cell proliferation, invasion, metastasis, and angiogenesis and are promising drugs for combination therapy:in melanoma with BRAFi and in other tumors such as CRC with activated stroma:because of a limitation of tumor cell escape mechanisms.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('signaling', 'biological_process', 'GO:0023052', ('82', '91'))	('tumor', 'Disease', (100, 105))	('BRAF', 'Gene', '673', (230, 234))	('tumor', 'Disease', (249, 254))	('BRAF', 'Gene', (230, 234))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('focal adhesion kinase', 'Gene', '5747', (25, 46))	('melanoma', 'Disease', 'MESH:D008545', (216, 224))	('focal adhesion', 'cellular_component', 'GO:0005925', ('25', '39'))	('cell proliferation', 'biological_process', 'GO:0008283', ('106', '124'))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CRC', 'Phenotype', 'HP:0003003', (264, 267))	('tumor', 'Disease', (317, 322))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('focal adhesion kinase', 'Gene', (25, 46))	('FAK', 'Gene', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('FAK', 'molecular_function', 'GO:0004717', ('48', '51'))	('angiogenesis', 'biological_process', 'GO:0001525', ('152', '164'))	('inhibitors', 'Var', (11, 21))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('melanoma', 'Disease', (216, 224))	('FAK', 'Gene', '5747', (48, 51))	('tumors', 'Disease', (249, 255))
147970	29794999	In addition, inhibition of autophagy may enhance tumor cell apoptosis.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('autophagy', 'CPA', (27, 36))	('enhance', 'PosReg', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('autophagy', 'biological_process', 'GO:0016236', ('27', '36'))	('inhibition', 'Var', (13, 23))	('tumor', 'Disease', (49, 54))	('autophagy', 'biological_process', 'GO:0006914', ('27', '36'))	('apoptosis', 'biological_process', 'GO:0097194', ('60', '69'))	('apoptosis', 'biological_process', 'GO:0006915', ('60', '69'))
147974	29794999	Different classes of small-molecule drugs enforce the intrinsic mitochondrial pathway: On the one hand, by mimicking the natural antagonists of BCL-2 family survival proteins (so called BH3-mimetics or BCL-2 family inhibitors) or of the inhibitors of apoptosis (IAPs) (so called SMAC-mimetics); on the other hand, by directly targeting BCL-2 expression with antisense oligonucleotides:all sensitizing tumor cells to death.	('BCL-2', 'molecular_function', 'GO:0015283', ('336', '341'))	('BCL-2', 'Gene', '596', (336, 341))	('BCL-2', 'Gene', (336, 341))	('BCL-2', 'Gene', '596', (202, 207))	('expression', 'Protein', (342, 352))	('BCL-2', 'molecular_function', 'GO:0015283', ('202', '207'))	('tumor', 'Disease', 'MESH:D009369', (401, 406))	('BCL-2', 'Gene', (202, 207))	('SMAC', 'Gene', '56616', (279, 283))	('BCL-2', 'molecular_function', 'GO:0015283', ('144', '149'))	('BH3', 'Chemical', 'MESH:C006008', (186, 189))	('sensitizing', 'Reg', (389, 400))	('BCL-2', 'Gene', '596', (144, 149))	('BCL-2', 'Gene', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (401, 406))	('targeting', 'Reg', (326, 335))	('antisense', 'Var', (358, 367))	('SMAC', 'Gene', (279, 283))	('apoptosis', 'biological_process', 'GO:0097194', ('251', '260'))	('apoptosis', 'biological_process', 'GO:0006915', ('251', '260'))	('tumor', 'Disease', (401, 406))
147976	29794999	While melanoma and other solid tumor are mostly insensitive against mono-therapy with either BH3-or SMAC-mimetics, combination approaches of kinase inhibitors with apoptosis mimetics or epigenetic drugs inducing BH3-proteins (see Section 3.4) have the potential to override drug resistance.	('epigenetic drugs', 'Var', (186, 202))	('override', 'PosReg', (265, 273))	('drug resistance', 'MPA', (274, 289))	('drug resistance', 'Phenotype', 'HP:0020174', (274, 289))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('SMAC', 'Gene', (100, 104))	('apoptosis', 'biological_process', 'GO:0097194', ('164', '173'))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('apoptosis', 'biological_process', 'GO:0006915', ('164', '173'))	('melanoma', 'Disease', (6, 14))	('drug resistance', 'biological_process', 'GO:0009315', ('274', '289'))	('drug resistance', 'biological_process', 'GO:0042493', ('274', '289'))	('SMAC', 'Gene', '56616', (100, 104))	('inducing', 'Reg', (203, 211))	('BH3-proteins', 'Protein', (212, 224))	('tumor', 'Disease', (31, 36))	('BH3', 'Chemical', 'MESH:C006008', (212, 215))	('BH3', 'Chemical', 'MESH:C006008', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
147983	29794999	p53 reactivation may have synergistic effects with BRAFi potentially overcoming therapeutic resistances.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('therapeutic resistances', 'MPA', (80, 103))	('BRAF', 'Gene', '673', (51, 55))	('overcoming', 'NegReg', (69, 79))	('BRAF', 'Gene', (51, 55))	('reactivation', 'Var', (4, 16))
147992	29794999	In addition, inhibitors of poly(ADP-ribose) polymerase (PARP), an enzyme involved in base excision repair (BER) of single strand breaks (SSB), are clinically evaluated singly or in combination with chemotherapy.	('BER', 'biological_process', 'GO:0006284', ('107', '110'))	('base excision repair', 'biological_process', 'GO:0006284', ('85', '105'))	('PARP', 'Gene', '142', (56, 60))	('poly(ADP-ribose) polymerase', 'Gene', '142', (27, 54))	('inhibitors', 'Var', (13, 23))	('poly(ADP-ribose) polymerase', 'Gene', (27, 54))	('PARP', 'Gene', (56, 60))
147993	29794999	In brief, ATM kinase is activated in response to double strand breaks (DBS), initially recognized by the so called MRN-complex (composed of MRE11, RAD50, and NBS1).	('ATM', 'Gene', '472', (10, 13))	('NBS1', 'Gene', '4683', (158, 162))	('RAD50', 'Gene', (147, 152))	('RAD50', 'Gene', '10111', (147, 152))	('double strand breaks', 'Var', (49, 69))	('MRN-complex', 'Chemical', '-', (115, 126))	('NBS1', 'Gene', (158, 162))	('MRE11', 'Gene', '4361', (140, 145))	('DBS', 'Chemical', '-', (71, 74))	('ATM', 'Gene', (10, 13))	('MRN-complex', 'cellular_component', 'GO:0030870', ('115', '126'))	('MRE11', 'Gene', (140, 145))	('RAD', 'biological_process', 'GO:1990116', ('147', '150'))
147998	29794999	Despite some limitations in the use of DDR inhibitors due to lipophilicity and toxicity in proliferating normal cells, the concept of synthetic lethality based on mutations in DDR pathways in tumor cells can be exploited therapeutically.	('tumor', 'Disease', (192, 197))	('mutations', 'Var', (163, 172))	('toxicity', 'Disease', 'MESH:D064420', (79, 87))	('lipophilicity', 'MPA', (61, 74))	('toxicity', 'Disease', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('DDR', 'Gene', (176, 179))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
148000	29794999	Similarly, due to mutations in the p53/RB-pathway, a deregulated G1 cell cycle checkpoint, and increased replication stress tumor cells often fully depend on the S/G2 checkpoint.	('S/G2', 'Var', (162, 166))	('p53', 'Gene', (35, 38))	('deregulated', 'PosReg', (53, 64))	('S/G2', 'SUBSTITUTION', 'None', (162, 166))	('p53', 'Gene', '7157', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('68', '89'))	('stress tumor', 'Disease', (117, 129))	('stress tumor', 'Disease', 'MESH:D004194', (117, 129))	('replication', 'MPA', (105, 116))	('mutations', 'Var', (18, 27))
148006	29794999	Cellular transformation and tumor cell plasticity require specific epigenetic changes occurring in response to environmental and intrinsic stimuli.	('epigenetic changes', 'Var', (67, 85))	('tumor', 'Disease', (28, 33))	('Cellular transformation', 'CPA', (0, 23))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
148007	29794999	Often, epigenetic modifications in tumor cells are involved in the silencing of tumor suppressor genes:at different stages of cellular dedifferentiation, during epithelial-mesenchymal transition (EMT), and during drug resistance development (reviewed in).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('drug resistance', 'Phenotype', 'HP:0020174', (213, 228))	('epithelial-mesenchymal transition', 'CPA', (161, 194))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('epigenetic modifications', 'Var', (7, 31))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('161', '194'))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', (80, 85))	('involved', 'Reg', (51, 59))	('tumor suppressor', 'biological_process', 'GO:0051726', ('80', '96'))	('dedifferentiation', 'biological_process', 'GO:0043696', ('135', '152'))	('silencing', 'MPA', (67, 76))	('EMT', 'biological_process', 'GO:0001837', ('196', '199'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('80', '96'))	('drug resistance', 'biological_process', 'GO:0009315', ('213', '228'))	('drug resistance', 'biological_process', 'GO:0042493', ('213', '228'))
148014	29794999	The first HDACi, vorinostat, approved as third line therapy for cutaneous T-cell lymphoma (CTL), is currently clinically tested as adjuvant treatment of CRC in combination with hydroxychloroquine (see Section 3.3) against TKi regorafenib (NCT02316340) and in advanced solid tumors (NCT01023737).	('HDAC', 'Gene', '9734', (10, 14))	('NCT02316340', 'Var', (239, 250))	('vorinostat', 'Chemical', 'MESH:D000077337', (17, 27))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (74, 89))	('cutaneous T-cell lymphoma', 'Disease', 'MESH:D016410', (64, 89))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('NCT01023737', 'Var', (282, 293))	('regorafenib', 'Chemical', 'MESH:C559147', (226, 237))	('lymphoma', 'Phenotype', 'HP:0002665', (81, 89))	('cutaneous T-cell lymphoma', 'Phenotype', 'HP:0012192', (64, 89))	('cell lymphoma', 'Phenotype', 'HP:0012191', (76, 89))	('solid tumors', 'Disease', (268, 280))	('CRC', 'Phenotype', 'HP:0003003', (153, 156))	('cutaneous T-cell lymphoma', 'Disease', (64, 89))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('hydroxychloroquine', 'Chemical', 'MESH:D006886', (177, 195))	('HDAC', 'Gene', (10, 14))	('solid tumors', 'Disease', 'MESH:D009369', (268, 280))
148019	29794999	Consequently, safety and efficacy of HDACi will currently be evaluated in particular in "problem" melanoma and tumors, such as resistant BRAFV600mut advanced melanoma (vorinostat, NCT02836548), high risk uveal melanoma (NCT03022565), and in combination therapies with checkpoint inhibitor immunotherapy (PEMDAC, NCT02697630, NCT02032810 and NCT02437136):seeking to overcome therapy resistance.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (204, 218))	('NCT03022565', 'Var', (220, 231))	('melanoma', 'Disease', 'MESH:D008545', (210, 218))	('vorinostat', 'Chemical', 'MESH:D000077337', (168, 178))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (158, 166))	('melanoma and tumors', 'Disease', 'MESH:D008545', (98, 117))	('HDAC', 'Gene', '9734', (37, 41))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('melanoma', 'Disease', (210, 218))	('uveal melanoma', 'Disease', 'MESH:C536494', (204, 218))	('uveal melanoma', 'Disease', (204, 218))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('HDAC', 'Gene', (37, 41))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))
148022	29794999	Due to their potential to induce apoptosis in melanoma cells by increasing NOXA and AIF and decreasing MCL-1 levels, EZH2 inhibitors may enhance the sensitivity to MAPK inhibition in combination regimens with BRAFi and MEKi.	('MCL-1', 'Gene', '4170', (103, 108))	('decreasing', 'NegReg', (92, 102))	('AIF', 'MPA', (84, 87))	('increasing', 'PosReg', (64, 74))	('NOXA', 'Gene', '5366', (75, 79))	('MCL-1', 'Gene', (103, 108))	('apoptosis', 'biological_process', 'GO:0097194', ('33', '42'))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('apoptosis', 'biological_process', 'GO:0006915', ('33', '42'))	('MEK', 'Gene', '5609', (219, 222))	('NOXA', 'Gene', (75, 79))	('MEK', 'Gene', (219, 222))	('EZH2', 'Gene', (117, 121))	('sensitivity', 'MPA', (149, 160))	('EZH2', 'Gene', '2146', (117, 121))	('MAPK', 'molecular_function', 'GO:0004707', ('164', '168'))	('enhance', 'PosReg', (137, 144))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('inhibitors', 'Var', (122, 132))	('BRAF', 'Gene', (209, 213))	('BRAF', 'Gene', '673', (209, 213))	('decreasing MCL', 'Phenotype', 'HP:0025066', (92, 106))
148027	29794999	In additional ongoing phase I dose-escalation studies, other BETi are tested in advanced or recurrent solid malignancies (NCT02630251, and NCT02419417) and in hematologic malignancies (NCT02543879), as well as in a phase I/IIa study as monotherapy or in combination with nivolumab immunotherapy (NCT02419417).	('hematologic malignancies', 'Disease', (159, 183))	('NCT02543879', 'Var', (185, 196))	('NCT02419417', 'Var', (139, 150))	('advanced', 'Disease', (80, 88))	('NCT02630251', 'Var', (122, 133))	('solid malignancies', 'Disease', 'MESH:D009369', (102, 120))	('nivolumab', 'Chemical', 'MESH:D000077594', (271, 280))	('solid malignancies', 'Disease', (102, 120))	('BETi', 'Chemical', '-', (61, 65))	('hematologic malignancies', 'Disease', 'MESH:D019337', (159, 183))
148029	29794999	Moreover, in pre-clinical studies novel roles of enzymes, either affecting the ubiquitination of histone H2A K119, such as PCR1 factor BMI1, 2A-DUB/MYSM1, and RNF2 or the methylation of H3 K9, in progression and drug resistance of melanoma and other cancers are currently being investigated.	('2A-DUB', 'Gene', '114803', (141, 147))	('drug resistance', 'Phenotype', 'HP:0020174', (212, 227))	('RNF2', 'Gene', '6045', (159, 163))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('melanoma', 'Disease', (231, 239))	('pre', 'molecular_function', 'GO:0003904', ('13', '16'))	('2A-DUB', 'Gene', (141, 147))	('methylation', 'MPA', (171, 182))	('BMI1', 'Gene', (135, 139))	('cancers', 'Disease', 'MESH:D009369', (250, 257))	('ubiquitination', 'MPA', (79, 93))	('MYSM1', 'Gene', (148, 153))	('H3 K9', 'Protein', (186, 191))	('RNF2', 'Gene', (159, 163))	('histone H2A', 'Protein', (97, 108))	('drug resistance', 'biological_process', 'GO:0009315', ('212', '227'))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('drug resistance', 'biological_process', 'GO:0042493', ('212', '227'))	('affecting', 'Reg', (65, 74))	('K119', 'Var', (109, 113))	('BMI1', 'Gene', '648', (135, 139))	('MYSM1', 'Gene', '114803', (148, 153))	('cancers', 'Phenotype', 'HP:0002664', (250, 257))	('cancers', 'Disease', (250, 257))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('methylation', 'biological_process', 'GO:0032259', ('171', '182'))
148032	29794999	Consequently, genes involved in telomere maintenance:including telomerase reverse transcriptase (hTERT, the catalytic subunit of telomerase), shelterin complex proteins (TRF1, TRF2, POT1, TIN2, TPP1, and Rap1), and telomerase-associated proteins (such as hTEP, p23, HSP90 and dyskerin):are relatively frequently activated or mutated in tumors including both familial and acquired melanoma, often in context with BRAF mutations (recently reviewed in).	('telomere maintenance', 'biological_process', 'GO:0000723', ('32', '52'))	('HSP90', 'Gene', '3320', (266, 271))	('shelterin complex', 'cellular_component', 'GO:0070187', ('142', '159'))	('tumors', 'Disease', (336, 342))	('TPP', 'molecular_function', 'GO:0004294', ('194', '197'))	('hTERT', 'Gene', (97, 102))	('POT1', 'Gene', '25913', (182, 186))	('TIN2', 'Gene', (188, 192))	('transcriptase', 'molecular_function', 'GO:0003899', ('82', '95'))	('TPP1', 'Gene', (194, 198))	('tumors', 'Disease', 'MESH:D009369', (336, 342))	('TRF1', 'Gene', '7013', (170, 174))	('TRF2', 'Gene', (176, 180))	('melanoma', 'Phenotype', 'HP:0002861', (380, 388))	('melanoma', 'Disease', (380, 388))	('BRAF', 'Gene', '673', (412, 416))	('BRAF', 'Gene', (412, 416))	('POT1', 'Gene', (182, 186))	('p23', 'Gene', '8851', (261, 264))	('telomere', 'cellular_component', 'GO:0000781', ('32', '40'))	('TRF2', 'Gene', '7014', (176, 180))	('familial', 'Disease', (358, 366))	('telomere', 'cellular_component', 'GO:0005696', ('32', '40'))	('TPP1', 'Gene', '1200', (194, 198))	('Rap1', 'Gene', '5906', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('Rap1', 'Gene', (204, 208))	('transcriptase', 'molecular_function', 'GO:0003968', ('82', '95'))	('HSP90', 'Gene', (266, 271))	('hTERT', 'Gene', '7015', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (336, 342))	('TRF1', 'Gene', (170, 174))	('transcriptase', 'molecular_function', 'GO:0034062', ('82', '95'))	('mutated', 'Var', (325, 332))	('melanoma', 'Disease', 'MESH:D008545', (380, 388))	('p23', 'Gene', (261, 264))	('TIN2', 'Gene', '26277', (188, 192))
148033	29794999	Therapeutic inhibition of telomerase activity can be achieved on the one hand by targeting either the hTERT catalytic subunit:by nucleoside analoga such as 3'-azido-2',3'-dideoxythymine (AZT):or on the other hand, the telomerase RNA (hTR) component:via antisense oligonucleotides or the more specific telomerase template antagonists such as the 13-mer oligonucleotide N3'-P5'-thio-phosphoramidate (GRN163L, imetelstat).	('hTERT', 'Gene', (102, 107))	('telomerase RNA', 'molecular_function', 'GO:0000332', ('218', '232'))	('inhibition of telomerase activity', 'biological_process', 'GO:0051974', ('12', '45'))	('telomerase activity', 'molecular_function', 'GO:0003720', ('26', '45'))	('antisense oligonucleotides', 'Var', (253, 279))	('hTR', 'Gene', (234, 237))	('hTERT', 'Gene', '7015', (102, 107))	('telomerase template', 'molecular_function', 'GO:0000332', ('301', '320'))	('telomerase RNA', 'cellular_component', 'GO:0005573', ('218', '232'))	('hTR', 'Gene', '7012', (234, 237))
148034	29794999	Telomerase enzyme inhibition and targeting of hTR in cancer cells generally result in progressive telomere shortening and reduced cellular viability.	('hTR', 'Gene', (46, 49))	('inhibition', 'NegReg', (18, 28))	('targeting', 'Var', (33, 42))	('cellular viability', 'CPA', (130, 148))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('telomere shortening', 'Phenotype', 'HP:0031413', (98, 117))	('telomere', 'cellular_component', 'GO:0005696', ('98', '106'))	('telomere', 'CPA', (98, 106))	('shortening', 'NegReg', (107, 117))	('hTR', 'Gene', '7012', (46, 49))	('Telomerase enzyme', 'Enzyme', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('reduced', 'NegReg', (122, 129))	('telomere', 'cellular_component', 'GO:0000781', ('98', '106'))
148044	29794999	On the other hand, ROS may promote tumorigenesis through induction of DNA damage and mutations, as well as epithelial-mesenchymal transition (EMT) and metastasis by regulating extracellular matrix and cytoskeleton remodeling.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('metastasis', 'CPA', (151, 161))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('176', '196'))	('EMT', 'biological_process', 'GO:0001837', ('142', '145'))	('DNA damage', 'Gene', (70, 80))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('ROS', 'Gene', (19, 22))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('tumor', 'Disease', (35, 40))	('extracellular', 'MPA', (176, 189))	('promote', 'PosReg', (27, 34))	('mutations', 'Var', (85, 94))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('107', '140'))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('201', '213'))	('epithelial-mesenchymal transition', 'CPA', (107, 140))	('regulating', 'Reg', (165, 175))	('induction', 'Reg', (57, 66))	('ROS', 'Chemical', 'MESH:D017382', (19, 22))
148047	29794999	Current clinical trials therefore assess the safety and suitable dose of DMF to reduce cytotoxicity in combination with radiotherapy (RT) and temozolomide (TMZ) in glioblastoma multiforme (GBM) (NCT02337426) and in other cancers.	('cytotoxicity', 'Disease', 'MESH:D064420', (87, 99))	('glioblastoma', 'Phenotype', 'HP:0012174', (164, 176))	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('NCT02337426', 'Var', (195, 206))	('cancers', 'Disease', (221, 228))	('glioblastoma multiforme', 'Disease', (164, 187))	('TMZ', 'Chemical', 'MESH:D000077204', (156, 159))	('DMF', 'Chemical', 'MESH:D000069462', (73, 76))	('temozolomide', 'Chemical', 'MESH:D000077204', (142, 154))	('cytotoxicity', 'Disease', (87, 99))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('reduce', 'NegReg', (80, 86))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (164, 187))
148048	29794999	In addition, DMF has been shown to induce apoptosis in T cell lymphoma cells and is currently being tested in phase-I-clinical trials in refractory chronic lymphocytic leukemia (CLL) (NCT02784834).	('DMF', 'Chemical', 'MESH:D000069462', (13, 16))	('leukemia', 'Phenotype', 'HP:0001909', (168, 176))	('T cell lymphoma', 'Disease', 'MESH:D016399', (55, 70))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (148, 176))	('DMF', 'Var', (13, 16))	('lymphocytic leukemia', 'Disease', (156, 176))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (156, 176))	('apoptosis', 'CPA', (42, 51))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (55, 70))	('apoptosis', 'biological_process', 'GO:0097194', ('42', '51'))	('induce', 'PosReg', (35, 41))	('apoptosis', 'biological_process', 'GO:0006915', ('42', '51'))	('T cell lymphoma', 'Disease', (55, 70))	('cell lymphoma', 'Phenotype', 'HP:0012191', (57, 70))	('CLL', 'Phenotype', 'HP:0005550', (178, 181))	('lymphoma', 'Phenotype', 'HP:0002665', (62, 70))
148049	29794999	In melanoma, anti-proliferative and pro-apoptotic effects of DMF could be demonstrated leading to reduced growth and metastasis of melanoma in pre-clinical models.	('metastasis of melanoma', 'Disease', 'MESH:D009362', (117, 139))	('pre', 'molecular_function', 'GO:0003904', ('143', '146'))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (131, 139))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('metastasis of melanoma', 'Disease', (117, 139))	('DMF', 'Var', (61, 64))	('anti-proliferative', 'CPA', (13, 31))	('pro-apoptotic', 'CPA', (36, 49))	('reduced', 'NegReg', (98, 105))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('DMF', 'Chemical', 'MESH:D000069462', (61, 64))
148062	29794999	In melanoma cell cultures, phenformin reduced cellular viability and growth of both CSC and non-CSC and abrogated invasion more potently than metformin.	('abrogated', 'NegReg', (104, 113))	('reduced', 'NegReg', (38, 45))	('phenformin', 'Var', (27, 37))	('growth', 'CPA', (69, 75))	('phenformin', 'Chemical', 'MESH:D010629', (27, 37))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('metformin', 'Chemical', 'MESH:D008687', (142, 151))	('invasion', 'CPA', (114, 122))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('cellular viability', 'CPA', (46, 64))
148067	29794999	In pre-clinical studies, inhibition of glutamine transport and uptake were suggested as potential therapeutic strategies in multiple myeloma and both, BRAFWT and BRAFV600mut, melanoma.	('uptake', 'biological_process', 'GO:0098657', ('63', '69'))	('multiple myeloma', 'Phenotype', 'HP:0006775', (124, 140))	('glutamine transport', 'MPA', (39, 58))	('multiple myeloma', 'Disease', 'MESH:D009101', (124, 140))	('multiple myeloma', 'Disease', (124, 140))	('BRAF', 'Gene', '673', (151, 155))	('glutamine', 'Chemical', 'MESH:D005973', (39, 48))	('glutamine transport', 'biological_process', 'GO:0006868', ('39', '58'))	('BRAF', 'Gene', (151, 155))	('inhibition', 'Var', (25, 35))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('BRAF', 'Gene', '673', (162, 166))	('melanoma', 'Disease', (175, 183))	('pre', 'molecular_function', 'GO:0003904', ('3', '6'))	('uptake', 'MPA', (63, 69))	('uptake', 'biological_process', 'GO:0098739', ('63', '69'))	('BRAF', 'Gene', (162, 166))
148071	29794999	Clinical evaluation of the first-generation reversible small molecular (26S) PI bortezomib, already approved as second line treatment for multiple myeloma and for mantel cell lymphoma, may hold promise for therapeutic use in combination with HDAC inhibitor vorinostat or chemotherapy in NSCLC or with purine nucleoside metabolic inhibitor clofarabine in other refractory solid tumors (NCT02211755).	('vorinostat', 'Chemical', 'MESH:D000077337', (257, 267))	('solid tumors', 'Disease', (371, 383))	('NSCLC', 'Phenotype', 'HP:0030358', (287, 292))	('small molecular', 'Var', (55, 70))	('HDAC', 'Gene', (242, 246))	('bortezomib', 'Chemical', 'MESH:D000069286', (80, 90))	('clofarabine', 'Chemical', 'MESH:D000077866', (339, 350))	('multiple myeloma', 'Phenotype', 'HP:0006775', (138, 154))	('cell lymphoma', 'Phenotype', 'HP:0012191', (170, 183))	('solid tumors', 'Disease', 'MESH:D009369', (371, 383))	('lymphoma', 'Phenotype', 'HP:0002665', (175, 183))	('multiple myeloma', 'Disease', 'MESH:D009101', (138, 154))	('tumors', 'Phenotype', 'HP:0002664', (377, 383))	('bortezomib', 'Gene', (80, 90))	('NSCLC', 'Disease', 'MESH:D002289', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (377, 382))	('lymphoma', 'Disease', (175, 183))	('multiple myeloma', 'Disease', (138, 154))	('purine', 'Chemical', 'MESH:C030985', (301, 307))	('lymphoma', 'Disease', 'MESH:D008223', (175, 183))	('NSCLC', 'Disease', (287, 292))	('HDAC', 'Gene', '9734', (242, 246))
148086	29794999	Second, certain epigenetic drugs (see Section 3.4) have the potential to regulate tumor cell transdifferentation, in particular DNA demethylating agents and HDACi.	('HDAC', 'Gene', '9734', (157, 161))	('epigenetic drugs', 'Var', (16, 32))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('DNA', 'MPA', (128, 131))	('regulate', 'Reg', (73, 81))	('tumor', 'Disease', (82, 87))	('HDAC', 'Gene', (157, 161))
148092	29794999	HDAC inhibitors also inhibit the growth of uveal melanoma cells both in vitro and in vivo, and other problem melanoma types (see Section 3.4).	('HDAC', 'Gene', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('HDAC', 'Gene', '9734', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('inhibitors', 'Var', (5, 15))	('melanoma', 'Disease', (109, 117))	('uveal melanoma', 'Disease', 'MESH:C536494', (43, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('growth', 'CPA', (33, 39))	('inhibit', 'NegReg', (21, 28))	('uveal melanoma', 'Disease', (43, 57))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
148100	29794999	According to pre-clinical studies, avidity-tuning through manipulation of negative TCR regulation may also enhance target cell selectivity in adoptive chimeric antigen receptor (CAR) T cell cancer therapy.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('TCR regulation', 'Gene', (83, 97))	('TCR', 'biological_process', 'GO:0006283', ('83', '86'))	('CAR', 'cellular_component', 'GO:0005826', ('178', '181'))	('enhance', 'PosReg', (107, 114))	('target cell selectivity', 'CPA', (115, 138))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('manipulation', 'Var', (58, 70))	('regulation', 'biological_process', 'GO:0065007', ('87', '97'))	('pre', 'molecular_function', 'GO:0003904', ('13', '16'))	('TCR', 'cellular_component', 'GO:0042101', ('83', '86'))
148110	29794999	To follow up on an alternative strategy to destabilize survival proteins in cancer cells by interfering with cellular chaperones, a number of HSP90 inhibitors are tested in combination with BRAFi and MEKi in melanoma (NCT02721459), in NSCLC (NCT01784640), and in other cancers.	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma', 'Disease', (208, 216))	('HSP90', 'Gene', (142, 147))	('NSCLC', 'Disease', 'MESH:D002289', (235, 240))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('BRAF', 'Gene', '673', (190, 194))	('NCT02721459', 'Var', (218, 229))	('NCT01784640', 'Var', (242, 253))	('BRAF', 'Gene', (190, 194))	('NSCLC', 'Disease', (235, 240))	('HSP90', 'Gene', '3320', (142, 147))	('interfering', 'NegReg', (92, 103))	('cancers', 'Phenotype', 'HP:0002664', (269, 276))	('cancers', 'Disease', (269, 276))	('cancer', 'Disease', (269, 275))	('tested', 'Reg', (163, 169))	('NSCLC', 'Phenotype', 'HP:0030358', (235, 240))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('cellular chaperones', 'MPA', (109, 128))	('cancer', 'Disease', (76, 82))	('MEK', 'Gene', '5609', (200, 203))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('MEK', 'Gene', (200, 203))	('cancer', 'Disease', 'MESH:D009369', (269, 275))	('cancers', 'Disease', 'MESH:D009369', (269, 276))
148119	29794999	Importantly, several of the emerging small-molecule approaches reviewed here are not directed against tumor-specific mutant proteins, but instead rather target metabolic, gene expression, or epigenetic changes more commonly occurring across different tumor types.	('gene expression', 'biological_process', 'GO:0010467', ('171', '186'))	('tumor', 'Disease', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('metabolic', 'MPA', (160, 169))	('epigenetic', 'Var', (191, 201))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
148121	29794999	Accordingly, preliminary results of clinical studies of novel kinase inhibitor combinations containing CDKi suggest that presence of alterations in the Cyclin D-CDK4/6-p16INK4A-RB axis confers increased tumor cell responsiveness:which may lead to overall manageable safety profiles of these combinations and favorable efficacies.	('kinase inhibitor', 'biological_process', 'GO:0033673', ('62', '78'))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('presence', 'Var', (121, 129))	('Cyclin', 'Gene', (152, 158))	('CDK', 'molecular_function', 'GO:0004693', ('161', '164'))	('Cyclin', 'molecular_function', 'GO:0016538', ('152', '158'))	('increased', 'PosReg', (193, 202))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('p16INK4A', 'Gene', (168, 176))	('alterations', 'Var', (133, 144))	('Cyclin', 'Gene', '5111', (152, 158))	('p16INK4A', 'Gene', '1029', (168, 176))
148122	29794999	Similarly, adding retinoids or certain epigenetic drugs in combination regimens may have synergistic anti-tumor effects without increasing toxicity for the patient because of non-overlapping side effects.	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('epigenetic drugs', 'Var', (39, 55))	('retinoids', 'Chemical', 'MESH:D012176', (18, 27))	('patient', 'Species', '9606', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('toxicity', 'Disease', (139, 147))	('toxicity', 'Disease', 'MESH:D064420', (139, 147))	('tumor', 'Disease', (106, 111))
148124	29794999	Importantly, newer small-molecule targeted therapies may also help to enhance immunogenicity of tumors for immunotherapies or to reduce side effects of established chemo- and radiotherapy regimens.	('small-molecule', 'Var', (19, 33))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('reduce', 'NegReg', (129, 135))	('enhance', 'PosReg', (70, 77))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('immunogenicity', 'CPA', (78, 92))
148125	29794999	Because the combination of immunotherapy using checkpoint inhibitors with kinase inhibitors such as BRAFi for metastatic BRAFV600mut melanoma may be effective, clinical trials assessing the best sequence, dose, and duration of treatments to archive the highest response rates are currently underway (NCT02818023, NCT02130466).	('BRAF', 'Gene', (121, 125))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('BRAF', 'Gene', '673', (100, 104))	('NCT02818023', 'Var', (300, 311))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('BRAF', 'Gene', (100, 104))	('BRAF', 'Gene', '673', (121, 125))
148132	28391358	Loss of chromosome 3, bi-allelic loss of BAP1 expression, and gain in chromosome 8q have been associated with metastasis formation and death, while loss of chromosome 3 has been associated with the influx of macrophages and T cells.	('chromosome', 'cellular_component', 'GO:0005694', ('156', '166'))	('gain', 'PosReg', (62, 66))	('loss', 'NegReg', (33, 37))	('BAP1', 'Gene', (41, 45))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('formation', 'biological_process', 'GO:0009058', ('121', '130'))	('chromosome', 'cellular_component', 'GO:0005694', ('70', '80'))	('associated', 'Reg', (94, 104))	('death', 'Disease', 'MESH:D003643', (135, 140))	('metastasis formation', 'CPA', (110, 130))	('death', 'Disease', (135, 140))	('expression', 'MPA', (46, 56))	('Loss', 'Var', (0, 4))	('BAP1', 'Gene', '8314', (41, 45))
148140	28391358	Following an initiating mutation in either GNAQ or GNA11, gain of 8q is thought to be one of the earliest genetic aberrations, followed by loss of one chromosome 3.	('GNA11', 'Gene', '2767', (51, 56))	('GNAQ', 'Gene', (43, 47))	('gain', 'PosReg', (58, 62))	('mutation', 'Var', (24, 32))	('GNA11', 'Gene', (51, 56))	('GNAQ', 'Gene', '2776', (43, 47))	('chromosome', 'cellular_component', 'GO:0005694', ('151', '161'))
148141	28391358	Gain of 8q and monosomy 3 and are both associated with the development of UM metastases and a poor prognosis.	('metastases', 'Disease', (77, 87))	('Gain', 'PosReg', (0, 4))	('associated', 'Reg', (39, 49))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('monosomy 3', 'Var', (15, 25))	('metastases', 'Disease', 'MESH:D009362', (77, 87))
148145	28391358	In UM, inactivating hemizygous mutations in this gene have been found, which are associated with loss of BAP1 protein expression and a high metastatic risk.	('loss', 'NegReg', (97, 101))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('BAP1', 'Gene', '8314', (105, 109))	('expression', 'MPA', (118, 128))	('inactivating hemizygous mutations', 'Var', (7, 40))	('BAP1', 'Gene', (105, 109))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
148155	28391358	Our data show that loss of BAP1 protein expression is predominantly related to T cell infiltration in UM, while early gain of chromosome 8q is associated with macrophage infiltration.	('expression', 'MPA', (40, 50))	('BAP1', 'Gene', (27, 31))	('related', 'Reg', (68, 75))	('protein', 'Protein', (32, 39))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('loss', 'Var', (19, 23))	('chromosome', 'cellular_component', 'GO:0005694', ('126', '136'))	('UM', 'Phenotype', 'HP:0007716', (102, 104))	('T cell infiltration', 'Disease', (79, 98))	('BAP1', 'Gene', '8314', (27, 31))
148166	28391358	T cell types were detected by primary antibodies: anti-CD3 (ab828, rabbit polyclonal; Abcam, Cambridge, MA, United States of America) and anti-CD8 (4B11, mouse monoclonal IgG2b; Novocastra, Valkenswaard, The Netherlands).	('mouse', 'Species', '10090', (154, 159))	('CD8', 'Gene', (143, 146))	('rabbit', 'Species', '9986', (67, 73))	('CD8', 'Gene', '925', (143, 146))	('IgG2b', 'cellular_component', 'GO:0071735', ('171', '176'))	('anti-CD3', 'Var', (50, 58))
148186	28391358	Within the monosomy 3 tumors, we noticed that the expression of BAP1 protein was associated with significantly lower numbers of CD3+ T cells (P = 0.034) and CD8+ T cells (P = 0.034), but not of CD68+ macrophages (P = 0.11; Fig.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('CD8', 'Gene', (157, 160))	('expression', 'Var', (50, 60))	('CD68', 'Gene', (194, 198))	('protein', 'Protein', (69, 76))	('CD8', 'Gene', '925', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('BAP1', 'Gene', '8314', (64, 68))	('lower', 'NegReg', (111, 116))	('CD68', 'Gene', '968', (194, 198))	('CD3+ T cells', 'CPA', (128, 140))	('tumors', 'Disease', (22, 28))	('BAP1', 'Gene', (64, 68))
148190	28391358	3), which confirms our finding that loss of BAP1 is associated with a higher density of T cells in UM.	('loss', 'Var', (36, 40))	('BAP1', 'Gene', '8314', (44, 48))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('higher', 'PosReg', (70, 76))	('BAP1', 'Gene', (44, 48))
148197	28391358	BAP1-positive tumors with extra copies of 8q had an increased expression of CD68 (P < 0.001) (Fig.	('increased', 'PosReg', (52, 61))	('BAP1', 'Gene', (0, 4))	('CD68', 'Gene', (76, 80))	('expression', 'MPA', (62, 72))	('CD68', 'Gene', '968', (76, 80))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('extra copies of 8q', 'Var', (26, 44))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('BAP1', 'Gene', '8314', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
148200	28391358	In addition, we determined whether, in the disomy3/BAP1-positive tumors from the Leiden cohort, extra copies of chromosome 8q affect the expression of pro-inflammatory cytokines.	('expression', 'MPA', (137, 147))	('BAP1', 'Gene', (51, 55))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('affect', 'Reg', (126, 132))	('extra copies', 'Var', (96, 108))	('pro-inflammatory cytokines', 'MPA', (151, 177))	('BAP1', 'Gene', '8314', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('chromosome', 'cellular_component', 'GO:0005694', ('112', '122'))
148203	28391358	We show that the presence of extra copies of chromosome 8q in UM is associated with macrophage infiltration, while loss of BAP1 protein expression, with or without loss of chromosome 3, is associated with T cell infiltration in UM.	('BAP1', 'Gene', (123, 127))	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('associated', 'Reg', (68, 78))	('T cell infiltration', 'Disease', (205, 224))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('extra copies', 'Var', (29, 41))	('UM', 'Phenotype', 'HP:0007716', (228, 230))	('associated', 'Reg', (189, 199))	('protein', 'Protein', (128, 135))	('loss', 'Var', (115, 119))	('chromosome', 'cellular_component', 'GO:0005694', ('172', '182'))	('BAP1', 'Gene', '8314', (123, 127))	('chromosome', 'cellular_component', 'GO:0005694', ('45', '55'))	('macrophage infiltration', 'CPA', (84, 107))
148204	28391358	The chromosomal evolution of aggressive UM is thought to start with a mutation in GNAQ/GNA11, followed by gain of chromosome 8q that precedes a potential loss of one copy of chromosome 3 and/or mutation in the BAP1 gene.	('GNA11', 'Gene', '2767', (87, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('114', '124'))	('BAP1', 'Gene', (210, 214))	('GNAQ', 'Gene', (82, 86))	('chromosome', 'cellular_component', 'GO:0005694', ('174', '184'))	('UM', 'Phenotype', 'HP:0007716', (40, 42))	('mutation', 'Var', (70, 78))	('GNA11', 'Gene', (87, 92))	('GNAQ', 'Gene', '2776', (82, 86))	('aggressive UM', 'Disease', (29, 42))	('BAP1', 'Gene', '8314', (210, 214))	('gain', 'PosReg', (106, 110))
148205	28391358	We show that in UM with disomy 3 and expression of BAP1, the presence of additional copies of chromosome 8q is highly associated with the increased expression of macrophage-attracting chemokines and a stronger macrophage infiltration.	('expression', 'Var', (37, 47))	('increased', 'PosReg', (138, 147))	('BAP1', 'Gene', (51, 55))	('chromosome', 'cellular_component', 'GO:0005694', ('94', '104'))	('UM', 'Phenotype', 'HP:0007716', (16, 18))	('stronger', 'PosReg', (201, 209))	('expression', 'MPA', (148, 158))	('BAP1', 'Gene', '8314', (51, 55))
148210	28391358	Monosomy 3 and loss of BAP1-protein expression are strongly correlated in UM, but we observed several atypical cases which allowed us to separately assess the contribution of chromosome 3 and BAP1-protein expression on the magnitude and type of immune cell infiltration and to pinpoint that it was the loss of BAP1 which was associated with the higher expression of T cell-attracting chemokines and a stronger T cell infiltration in UM.	('BAP1', 'Gene', (23, 27))	('BAP1', 'Gene', (192, 196))	('stronger', 'PosReg', (401, 409))	('BAP1', 'Gene', '8314', (310, 314))	('chromosome', 'cellular_component', 'GO:0005694', ('175', '185'))	('loss', 'Var', (302, 306))	('BAP1', 'Gene', '8314', (192, 196))	('BAP1', 'Gene', '8314', (23, 27))	('UM', 'Phenotype', 'HP:0007716', (433, 435))	('BAP1', 'Gene', (310, 314))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('protein', 'cellular_component', 'GO:0003675', ('197', '204'))	('expression', 'MPA', (352, 362))	('higher', 'PosReg', (345, 351))	('T cell infiltration', 'CPA', (410, 429))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
148215	28391358	We, therefore, hypothesize that BAP1 may have a similar function as UCHL1 and that loss of BAP1 alleviates the suppression pathways leading to activation of NF-kappaB, resulting in the production of cytokines and chemokines that attract tumor-specific T cells into UM.	('NF-kappaB', 'Gene', '4790', (157, 166))	('BAP1', 'Gene', (91, 95))	('tumor', 'Disease', (237, 242))	('UM', 'Phenotype', 'HP:0007716', (265, 267))	('loss', 'Var', (83, 87))	('BAP1', 'Gene', '8314', (32, 36))	('NF-kappaB', 'Gene', (157, 166))	('UCHL1', 'Gene', '7345', (68, 73))	('suppression pathways', 'Pathway', (111, 131))	('BAP1', 'Gene', '8314', (91, 95))	('BAP1', 'Gene', (32, 36))	('activation', 'PosReg', (143, 153))	('UCHL1', 'Gene', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('alleviates', 'NegReg', (96, 106))	('production of cytokines', 'MPA', (185, 208))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('143', '166'))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
148216	28391358	Loss of function of several tumor suppressor genes (p53, PTEN) due to genetic aberrations is known to be associated with inflammation.	('genetic aberrations', 'Var', (70, 89))	('inflammation', 'Disease', 'MESH:D007249', (121, 133))	('tumor', 'Disease', (28, 33))	('inflammation', 'Disease', (121, 133))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('PTEN', 'Gene', (57, 61))	('Loss of function', 'NegReg', (0, 16))	('inflammation', 'biological_process', 'GO:0006954', ('121', '133'))	('PTEN', 'Gene', '5728', (57, 61))	('tumor suppressor', 'biological_process', 'GO:0051726', ('28', '44'))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('28', '44'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
148217	28391358	Interestingly, loss of BAP1 in an unusual cutaneous tumor, the atypical Spitz nevus, was associated with a higher presence of T cells.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('BAP1', 'Gene', (23, 27))	('cutaneous tumor', 'Phenotype', 'HP:0008069', (42, 57))	('atypical Spitz nevus', 'Phenotype', 'HP:0001062', (63, 83))	('cutaneous tumor', 'Disease', (42, 57))	('BAP1', 'Gene', '8314', (23, 27))	('nevus', 'Phenotype', 'HP:0003764', (78, 83))	('loss', 'Var', (15, 19))	('cutaneous tumor', 'Disease', 'MESH:D009369', (42, 57))
148227	28391358	Hence, loss of chromosome 3 may also reduce beta-catenin expression.	('reduce', 'NegReg', (37, 43))	('loss', 'Var', (7, 11))	('chromosome', 'cellular_component', 'GO:0005694', ('15', '25'))	('beta-catenin', 'Gene', (44, 56))	('beta-catenin', 'Gene', '1499', (44, 56))
148235	28391358	BAP1 BRCA1-associated protein 1 CCL2 Chemokine (C-C motif) ligand 2 (Monocyte chemoattractant protein-1) CCL3 Chemokine (C-C motif) ligand 3 (Macrophage inflammatory protein 1alpha) CCL5 Chemokine (C-C motif) ligand 5 (RANTES) CXCL10 Chemokine (C-X-C motif) ligand 10 (Interferon gamma-induced protein 10) CXCL12 Chemokine (C-X-C motif) ligand 12 (Stromal cell-derived factor 1) dPCR Digital polymerase chain reaction HLA Human leukocyte antigen IF Immunofluorescence IHC Immunohistochemistry NF-kappaB Nuclear factor kappaB SNP Single-nucleotide polymorphism TCGA The Cancer Genome Atlas UCH Ubiquitin-carboxy-terminal hydrolase UCHL1 Ubiquitin carboxyl-terminal hydrolase L1 UCHL2 Ubiquitin carboxyl-terminal hydrolase L2 UM Uveal melanoma VEGFA Vascular Endothelial Growth Factor A The authors declare that they have no conflict of interest.	('CCL5', 'Gene', (182, 186))	('Human', 'Species', '9606', (422, 427))	('NF-kappaB', 'Gene', (493, 502))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('CCL', 'molecular_function', 'GO:0044101', ('105', '108'))	('CCL2', 'Gene', '6347', (32, 36))	('CCL3', 'Gene', (105, 109))	('Chemokine (C-X-C motif) ligand 12 (Stromal cell-derived factor 1', 'Gene', '6387', (313, 377))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('CXCL12', 'Gene', '6387', (306, 312))	('VEGFA', 'Gene', '7422', (742, 747))	('Interferon gamma', 'molecular_function', 'GO:0005133', ('269', '285'))	('NF-kappaB', 'Gene', '4790', (493, 502))	('BRCA1-associated protein 1', 'Gene', '8314', (5, 31))	('CXCL10', 'Gene', (227, 233))	('Ubiquitin', 'molecular_function', 'GO:0031386', ('683', '692'))	('UCHL2', 'Gene', (677, 682))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))	('CXCL12', 'Gene', (306, 312))	('BAP1', 'Gene', (0, 4))	('ligand', 'molecular_function', 'GO:0005488', ('337', '343'))	('UCHL1', 'Gene', (630, 635))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (569, 588))	('melanoma', 'Disease', 'MESH:D008545', (733, 741))	('Monocyte chemoattractant protein-1', 'Gene', '6347', (69, 103))	('ligand', 'molecular_function', 'GO:0005488', ('59', '65'))	('UM', 'Phenotype', 'HP:0007716', (724, 726))	('Vascular Endothelial Growth Factor', 'Gene', '7422', (748, 782))	('BRCA1-associated protein 1', 'Gene', (5, 31))	('UCHL1', 'Gene', '7345', (630, 635))	('Single-nucleotide polymorphism', 'Var', (529, 559))	('Ubiquitin', 'molecular_function', 'GO:0031386', ('636', '645'))	('Cancer Genome Atlas', 'Disease', (569, 588))	('CCL', 'molecular_function', 'GO:0044101', ('182', '185'))	('Chemokine (C-C motif) ligand 2', 'Gene', '6347', (37, 67))	('CCL2', 'Gene', (32, 36))	('CCL5', 'Gene', '6352', (182, 186))	('CCL3', 'Gene', '6348', (105, 109))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (727, 741))	('Ubiquitin', 'molecular_function', 'GO:0031386', ('593', '602'))	('ligand', 'molecular_function', 'GO:0005488', ('209', '215'))	('VEGFA', 'Gene', (742, 747))	('UCHL2', 'Gene', '8314', (677, 682))	('Chemokine (C-C motif) ligand 5', 'Gene', '6352', (187, 217))	('Vascular Endothelial Growth Factor', 'Gene', (748, 782))	('RANTES', 'Gene', (219, 225))	('Chemokine (C-X-C motif) ligand 10', 'Gene', '3627', (234, 267))	('RANTES', 'Gene', '6352', (219, 225))	('Cancer', 'Phenotype', 'HP:0002664', (569, 575))	('ligand', 'molecular_function', 'GO:0005488', ('132', '138'))	('protein', 'cellular_component', 'GO:0003675', ('294', '301'))	('Monocyte chemoattractant protein-1', 'Gene', (69, 103))	('Macrophage inflammatory protein 1alpha', 'Gene', (142, 180))	('melanoma', 'Disease', (733, 741))	('CXCL10', 'Gene', '3627', (227, 233))	('Macrophage inflammatory protein 1alpha', 'Gene', '6348', (142, 180))	('melanoma', 'Phenotype', 'HP:0002861', (733, 741))	('Vascular Endothelial Growth Factor', 'molecular_function', 'GO:0005172', ('748', '782'))	('BAP1', 'Gene', '8314', (0, 4))	('ligand', 'molecular_function', 'GO:0005488', ('258', '264'))	('CCL', 'molecular_function', 'GO:0044101', ('32', '35'))
148268	27941674	Aberrant activation of this pathway by some of the mutations in components within the pathway is frequently seen in melanoma.	('activation', 'PosReg', (9, 19))	('mutations', 'Var', (51, 60))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))
148269	27941674	An example of this is a single-base missense transversion causes the replacement of valine with glutamic acid at amino acid residue 600 in BRAF that is detected in about 85% of nevi and melanoma.	('glutamic acid', 'MPA', (96, 109))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanoma', 'Disease', (186, 194))	('BRAF', 'Gene', (139, 143))	('valine with glutamic acid at amino acid residue 600', 'Mutation', 'rs113488022', (84, 135))	('melanoma', 'Disease', 'MESH:D008545', (186, 194))	('replacement', 'Var', (69, 80))	('valine', 'Protein', (84, 90))	('nevi', 'Phenotype', 'HP:0003764', (177, 181))	('missense transversion', 'Var', (36, 57))
148271	27941674	Mutated BRAF not only upregulates its own kinase activity, but also that of MEK and ERK, and promote cell proliferation.	('Mutated', 'Var', (0, 7))	('BRAF', 'Gene', (8, 12))	('cell proliferation', 'CPA', (101, 119))	('upregulates', 'PosReg', (22, 33))	('ERK', 'Gene', (84, 87))	('ERK', 'Gene', '2048', (84, 87))	('MEK', 'Gene', (76, 79))	('cell proliferation', 'biological_process', 'GO:0008283', ('101', '119'))	('kinase activity', 'MPA', (42, 57))	('promote', 'PosReg', (93, 100))	('ERK', 'molecular_function', 'GO:0004707', ('84', '87'))	('kinase activity', 'molecular_function', 'GO:0016301', ('42', '57'))	('MEK', 'Gene', '5609', (76, 79))
148272	27941674	In addition to mutated BRAF, mutated NRAS accounts for about 20% of melanoma cases.	('NRAS', 'Gene', (37, 41))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('mutated', 'Var', (29, 36))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('NRAS', 'Gene', '4893', (37, 41))
148273	27941674	In uveal melanoma it has been shown that a mutation in the GTP binding region of the Galpha subunit (Q209L) blocks the cleavage of GTP to GDP and deregulates both MAPK and PI3K/AKT pathways.	('cleavage of', 'MPA', (119, 130))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('GTP', 'Chemical', 'MESH:D006160', (59, 62))	('GTP', 'Chemical', 'MESH:D006160', (131, 134))	('blocks', 'NegReg', (108, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('uveal melanoma', 'Disease', (3, 17))	('GTP', 'Protein', (131, 134))	('Q209L', 'Gene', (101, 106))	('mutation', 'Var', (43, 51))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('GTP binding', 'molecular_function', 'GO:0005525', ('59', '70'))	('Q209L', 'Mutation', 'p.Q209L', (101, 106))	('Galpha', 'Gene', (85, 91))	('deregulates', 'Reg', (146, 157))	('GDP', 'Chemical', 'MESH:D006153', (138, 141))	('MAPK', 'molecular_function', 'GO:0004707', ('163', '167'))	('PI3K', 'molecular_function', 'GO:0016303', ('172', '176'))	('Galpha', 'Gene', '8802', (85, 91))
148274	27941674	Transgenic mice harboring this mutated Galpha subunit have increased skin lesions.	('skin lesions', 'Disease', (69, 81))	('skin lesions', 'Disease', 'MESH:D012871', (69, 81))	('Transgenic mice', 'Species', '10090', (0, 15))	('increased', 'PosReg', (59, 68))	('Galpha', 'Gene', '8802', (39, 45))	('mutated', 'Var', (31, 38))	('Galpha', 'Gene', (39, 45))
148286	27941674	Melan-A cells, normal immortalized mouse melanocytes, showed increased cellular proliferation upon introduction of exogenous mutated BRAF (V600E), however no tumor formed.	('tumor', 'Disease', (158, 163))	('V600E', 'Mutation', 'rs113488022', (139, 144))	('cellular proliferation', 'CPA', (71, 93))	('mouse', 'Species', '10090', (35, 40))	('BRAF', 'Gene', (133, 137))	('V600E', 'Var', (139, 144))	('increased', 'PosReg', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
148288	27941674	Recently we also showed that in an in vivo mouse model with conditioned mutated BRAF (V600E), GRM1 expression is detected after mutated BRAF expression is activated, however, no tumor was detected in these mice up to 17 months of age.	('expression', 'MPA', (99, 109))	('tumor', 'Disease', (178, 183))	('BRAF', 'Gene', (80, 84))	('mutated', 'Var', (128, 135))	('V600E', 'Var', (86, 91))	('mice', 'Species', '10090', (206, 210))	('BRAF', 'Gene', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('GRM1', 'Protein', (94, 98))	('mouse', 'Species', '10090', (43, 48))	('activated', 'PosReg', (155, 164))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('V600E', 'Mutation', 'rs113488022', (86, 91))
148289	27941674	These preliminary results suggest that the temporal expression of mutated BRAF and GRM1 is critical in the determination of future tumorigenesis.	('mutated', 'Var', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('BRAF', 'Gene', (74, 78))	('GRM1', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))
148291	27941674	In a mutated BRAF mouse model, ablation of PTEN led to melanoma development, suggesting the PI3K/AKT signaling cascade is one of the critical players in melanomagenesis.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('mouse', 'Species', '10090', (18, 23))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', (153, 161))	('PTEN', 'Gene', (43, 47))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('PI3K', 'molecular_function', 'GO:0016303', ('92', '96'))	('ablation', 'Var', (31, 39))	('AKT signaling cascade', 'biological_process', 'GO:0043491', ('97', '118'))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))	('led to', 'Reg', (48, 54))
148292	27941674	Mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A) is common among human cancers including melanoma.	('CDKN2A', 'Gene', '1029', (51, 57))	('human', 'Species', '9606', (75, 80))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('13', '46'))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('30', '46'))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (13, 49))	('Mutations', 'Var', (0, 9))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (13, 49))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('CDKN2A', 'Gene', (51, 57))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('common', 'Reg', (62, 68))
148296	27941674	Therefore, mutation(s) in ARF dysregulate p53 function and play a role in tumor immune evasion.	('p53', 'Gene', (42, 45))	('immune evasion', 'biological_process', 'GO:0042783', ('80', '94'))	('role', 'Reg', (66, 70))	('ARF', 'Disease', 'MESH:D058186', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('p53', 'Gene', '7157', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('immune evasion', 'biological_process', 'GO:0051842', ('80', '94'))	('ARF', 'Disease', (26, 29))	('tumor', 'Disease', (74, 79))	('function', 'MPA', (46, 54))	('play', 'Reg', (59, 63))	('mutation', 'Var', (11, 19))	('dysregulate', 'Reg', (30, 41))
148298	27941674	Mutations or deletions of PTEN are concurrent with mutations in BRAF but not in N-RAS.	('mutations', 'Var', (51, 60))	('N-RAS', 'Gene', (80, 85))	('N-RAS', 'Gene', '4893', (80, 85))	('deletions', 'Var', (13, 22))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', (26, 30))	('BRAF', 'Disease', (64, 68))
148302	27941674	miRNAs that have been shown to be upregulated in melanoma are: miR-101, -182, -221, -222, -106-363, -106a, -92, -196, -21, -156, -214, -30b, -30d and -532-5p.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('miR-101', 'Var', (63, 70))	('upregulated', 'PosReg', (34, 45))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
148303	27941674	Those shown to be downregulated or lost in melanoma are: Let7a and b, miR-31, -125b, -148a, -211, -193b, -196a-1, -196a-2, and -203.	('miR-31', 'Gene', (70, 76))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('downregulated', 'NegReg', (18, 31))	('melanoma', 'Disease', (43, 51))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('Let7a', 'Var', (57, 62))	('miR-31', 'Gene', '407035', (70, 76))
148323	27941674	There has been great success with vemurafenib in clinical trials, which showed a response (measured as more than 90% reduction in active ERK) in greater than 50% of BRAFV600E or V600K melanoma patients and the median overall survival rate was 16 months, however many of these patients can develop resistance to the inhibitor, likely due to the reactivation of the MAPK pathway or other mutations.	('patients', 'Species', '9606', (276, 284))	('reduction', 'NegReg', (117, 126))	('clinical', 'Species', '191496', (49, 57))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanoma', 'Disease', (184, 192))	('BRAFV600E', 'Mutation', 'rs113488022', (165, 174))	('resistance', 'MPA', (297, 307))	('ERK', 'Gene', (137, 140))	('patients', 'Species', '9606', (193, 201))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('ERK', 'molecular_function', 'GO:0004707', ('137', '140'))	('MAPK', 'molecular_function', 'GO:0004707', ('364', '368'))	('V600K', 'Mutation', 'p.V600K', (178, 183))	('ERK', 'Gene', '2048', (137, 140))	('MAPK pathway', 'Pathway', (364, 376))	('BRAFV600E', 'Var', (165, 174))	('develop', 'PosReg', (289, 296))	('V600K', 'Var', (178, 183))	('vemurafenib', 'Chemical', 'MESH:D000077484', (34, 45))
148325	27941674	Inhibitors of ERK have been shown to successfully inhibit the MAPK pathway in MEK-inhibitor resistant cells, since ERK is downstream of MEK.	('ERK', 'Gene', (14, 17))	('ERK', 'Gene', '2048', (14, 17))	('MEK', 'Gene', (78, 81))	('MEK', 'Gene', '5609', (78, 81))	('MEK', 'Gene', (136, 139))	('MAPK pathway', 'Pathway', (62, 74))	('ERK', 'Gene', (115, 118))	('inhibit', 'NegReg', (50, 57))	('MEK', 'Gene', '5609', (136, 139))	('ERK', 'Gene', '2048', (115, 118))	('Inhibitors', 'Var', (0, 10))	('ERK', 'molecular_function', 'GO:0004707', ('14', '17'))	('MAPK', 'molecular_function', 'GO:0004707', ('62', '66'))	('ERK', 'molecular_function', 'GO:0004707', ('115', '118'))
148333	27941674	These pre-clinical findings suggest that in a combination therapy, which inhibits both MAPK and NOTCH pathways, may improve the efficacy of melanoma patients who develop BRAF inhibitor-resistance but both inhibitors must be present to sustain the anti-tumor progression responses.	('clinical', 'Species', '191496', (10, 18))	('MAPK', 'Pathway', (87, 91))	('patients', 'Species', '9606', (149, 157))	('BRAF', 'Gene', (170, 174))	('improve', 'PosReg', (116, 123))	('MAPK', 'molecular_function', 'GO:0004707', ('87', '91'))	('pre', 'molecular_function', 'GO:0003904', ('6', '9'))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('inhibits', 'NegReg', (73, 81))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('melanoma', 'Disease', (140, 148))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('NOTCH pathways', 'Pathway', (96, 110))	('inhibitor-resistance', 'Var', (175, 195))	('efficacy', 'MPA', (128, 136))	('tumor', 'Disease', (252, 257))
148395	27941674	Exosomes that were prominin-1 positive were isolated and analyzed, and were found to contain, along with exosome-specific proteins, multiple pro-metastatic proteins, including CD44, MAPK4K, GTP-binding proteins, ADAM10 and Annexin A2.	('prominin-1', 'Gene', '8842', (19, 29))	('CD44', 'Gene', (176, 180))	('ADAM10', 'Gene', '102', (212, 218))	('MAPK', 'molecular_function', 'GO:0004707', ('182', '186'))	('exosome', 'cellular_component', 'GO:0070062', ('105', '112'))	('prominin-1', 'Gene', (19, 29))	('ADAM10', 'Gene', (212, 218))	('Annexin A2', 'Gene', (223, 233))	('GTP-binding', 'Protein', (190, 201))	('GTP', 'Chemical', 'MESH:D006160', (190, 193))	('CD44', 'Gene', '960', (176, 180))	('Annexin A2', 'Gene', '302', (223, 233))	('MAPK4K', 'Var', (182, 188))	('GTP-binding', 'molecular_function', 'GO:0005525', ('190', '201'))
148418	27941674	The pro-metastatic protein, Met72, was detected in the highly metastatic clone of B16 melanoma cells (B16-10).	('Met72', 'Var', (28, 33))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('protein', 'cellular_component', 'GO:0003675', ('19', '26'))
148477	24661650	Mice with melanomas treated with hypofractionated radiotherapy (32 Gy in 4 once weekly fractions) had superior survival, irradiated tumor control and fewer lung metastases than mice treated with conventionally fractionated radiotherapy (60 Gy in daily 30 fractions).	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('32 Gy', 'Var', (64, 69))	('melanomas', 'Disease', (10, 19))	('lung metastases', 'Disease', 'MESH:D009362', (156, 171))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('lung metastases', 'Disease', (156, 171))	('superior', 'PosReg', (102, 110))	('tumor', 'Disease', (132, 137))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('Mice', 'Species', '10090', (0, 4))	('fewer', 'NegReg', (150, 155))	('mice', 'Species', '10090', (177, 181))	('melanomas', 'Disease', 'MESH:D008545', (10, 19))
148516	24661650	In 2002, investigators at the University of Utah reported 10 patients with melanoma who underwent fractionated radiotherapy (45-52.5 Gy in conventional fractionation in 9 patients, or 36 Gy hypofractionated in 1 patient) and received varying doses of interferon alpha-2b concurrently, or within one month of radiotherapy.	('patient', 'Species', '9606', (61, 68))	('patient', 'Species', '9606', (171, 178))	('patient', 'Species', '9606', (212, 219))	('patients', 'Species', '9606', (61, 69))	('interferon alpha-2b', 'Gene', '3440', (251, 270))	('interferon alpha-2b', 'Gene', (251, 270))	('patients', 'Species', '9606', (171, 179))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('45-52.5 Gy', 'Var', (125, 135))
148589	24661650	Preclinical studies with non-melanoma cancer models have demonstrated that CTLA-4 blockade promotes the abscopal effect of radiotherapy.	('abscopal effect of radiotherapy', 'CPA', (104, 135))	('promotes', 'PosReg', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('blockade', 'Var', (82, 90))	('CTLA-4', 'Gene', (75, 81))	('non-melanoma cancer', 'Disease', (25, 44))	('non-melanoma cancer', 'Disease', 'MESH:D008545', (25, 44))
148593	24661650	Fewer lung metastases were noted in animals treated with radiation and CTLA-4 blockade, and that this effect appeared dependent on CD8+ cells.	('blockade', 'Var', (78, 86))	('Fewer', 'NegReg', (0, 5))	('CTLA-4', 'Gene', (71, 77))	('lung metastases', 'Disease', 'MESH:D009362', (6, 21))	('lung metastases', 'Disease', (6, 21))	('CD8', 'Gene', (131, 134))	('CD8', 'Gene', '925', (131, 134))
148636	24661650	Preclinical evidence suggests that PD-1 blockade may interact with radiation to improve local tumor control, survival, in a variety of radiation dose and fractionation schema.	('blockade', 'Var', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('schema', 'Disease', 'None', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('schema', 'Disease', (168, 174))	('PD-1', 'Gene', (35, 39))	('improve', 'PosReg', (80, 87))	('PD-1', 'Gene', '5133', (35, 39))	('survival', 'CPA', (109, 117))
148654	22863277	Regulation of the Hippo-YAP pathway by G-protein coupled receptor signaling The Hippo pathway is crucial in organ size control and its dysregulation contributes to tumorigenesis.	('tumor', 'Disease', (164, 169))	('G-protein coupled receptor', 'Gene', '9170', (39, 65))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('YAP', 'Gene', (24, 27))	('signaling', 'biological_process', 'GO:0023052', ('66', '75'))	('YAP', 'Gene', '10413', (24, 27))	('dysregulation', 'Var', (135, 148))	('G-protein coupled receptor', 'Gene', (39, 65))	('Hippo', 'Gene', (80, 85))	('contributes', 'Reg', (149, 160))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
148663	22863277	The Hippo pathway was initially defined by genetic studies in Drosophila, wherein mosaic mutations of Hippo pathway genes resulted in tissue overgrowth (reviewed in).	('tissue overgrowth', 'CPA', (134, 151))	('mosaic mutations', 'Var', (82, 98))	('resulted in', 'Reg', (122, 133))	('overgrowth', 'Phenotype', 'HP:0001548', (141, 151))	('Hippo pathway', 'Gene', (102, 115))	('Drosophila', 'Species', '7227', (62, 72))
148684	22863277	Further, inhibition of MEK by U0126, PI3K by wortmannin, mTOR by torin, and p38 by SB253580 had no effect on the ability of FBS to induce dephosphorylation of YAP/TAZ (Figure S1G, S1H).	('YAP/TAZ', 'Protein', (159, 166))	('torin', 'Gene', '7001', (65, 70))	('p38', 'Gene', (76, 79))	('torin', 'Gene', (65, 70))	('dephosphorylation', 'MPA', (138, 155))	('induce', 'Reg', (131, 137))	('U0126', 'Var', (30, 35))	('PI3K', 'molecular_function', 'GO:0016303', ('37', '41'))	('mTOR', 'Gene', (57, 61))	('dephosphorylation', 'biological_process', 'GO:0016311', ('138', '155'))	('mTOR', 'Gene', '2475', (57, 61))	('wortmannin', 'Chemical', 'MESH:D000077191', (45, 55))	('SB253580', 'Chemical', '-', (83, 91))	('U0126', 'Chemical', 'MESH:C113580', (30, 35))	('p38', 'Gene', '5594', (76, 79))
148703	22863277	Lats can phosphorylate YAP on 5 serine residues including S381, with phosphorylation at S381 priming S384 phosphorylation by casein kinase.	('S384 phosphorylation', 'MPA', (101, 121))	('phosphorylation', 'biological_process', 'GO:0016310', ('69', '84'))	('S381', 'Var', (88, 92))	('phosphorylation', 'biological_process', 'GO:0016310', ('106', '121'))	('serine', 'Chemical', 'MESH:D012694', (32, 38))	('phosphorylation', 'Var', (69, 84))
148704	22863277	Indeed, we found that phosphorylation of S381/384 was also decreased in response to LPA treatment (Figure S3A).	('decreased', 'NegReg', (59, 68))	('response to LPA', 'biological_process', 'GO:1904565', ('72', '87'))	('S381/384', 'Var', (41, 49))	('LPA', 'Chemical', 'MESH:C032881', (84, 87))	('LPA treatment', 'MPA', (84, 97))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('phosphorylation', 'MPA', (22, 37))
148707	22863277	LPA also enhanced the interaction between YAP and the nuclear-localized TEAD1, a transcription factor target of YAP/TAZ (Figure 3C).	('LPA', 'Var', (0, 3))	('transcription factor', 'molecular_function', 'GO:0000981', ('81', '101'))	('TEAD1', 'Gene', '7003', (72, 77))	('TEAD1', 'Gene', (72, 77))	('interaction', 'Interaction', (22, 33))	('transcription', 'biological_process', 'GO:0006351', ('81', '94'))	('enhanced', 'PosReg', (9, 17))	('LPA', 'Chemical', 'MESH:C032881', (0, 3))
148709	22863277	Similar to LPA, S1P potently induced YAP/TAZ dephosphorylation (Figure 3B, S2D).	('induced', 'Reg', (29, 36))	('dephosphorylation', 'biological_process', 'GO:0016311', ('45', '62'))	('S1P', 'Chemical', 'MESH:C060506', (16, 19))	('S1P', 'Var', (16, 19))	('YAP/TAZ dephosphorylation', 'MPA', (37, 62))	('LPA', 'Chemical', 'MESH:C032881', (11, 14))
148713	22863277	Further mRNA and/or protein levels of CTGF, Cyr61, and ANKRD1 were also increased in cells stably expressing ectopic LPA receptor (LPA1) and autotaxin (ATX, an LPA producing enzyme; Figure S4A and S4B).	('CTGF', 'Gene', (38, 42))	('LPA', 'Chemical', 'MESH:C032881', (117, 120))	('autotaxin', 'Gene', '5168', (141, 150))	('LPA1', 'Gene', '1902', (131, 135))	('mRNA and/or', 'MPA', (8, 19))	('ANKRD1', 'Gene', '27063', (55, 61))	('Cyr61', 'Gene', '3491', (44, 49))	('LPA', 'Chemical', 'MESH:C032881', (131, 134))	('autotaxin', 'Gene', (141, 150))	('ANKRD1', 'Gene', (55, 61))	('ATX', 'Gene', (152, 155))	('ectopic', 'Var', (109, 116))	('LPA', 'Chemical', 'MESH:C032881', (160, 163))	('ATX', 'Gene', '5168', (152, 155))	('Cyr61', 'Gene', (44, 49))	('CTGF', 'Gene', '1490', (38, 42))	('increased', 'PosReg', (72, 81))	('LPA1', 'Gene', (131, 135))	('LPA receptor', 'Protein', (117, 129))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))
148717	22863277	LPA is known to activate multiple signaling pathways, including ERK (Figure 3A).	('LPA', 'Var', (0, 3))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('ERK', 'Gene', '5594', (64, 67))	('ERK', 'Gene', (64, 67))	('LPA', 'Chemical', 'MESH:C032881', (0, 3))	('activate', 'PosReg', (16, 24))	('ERK', 'molecular_function', 'GO:0004707', ('64', '67'))
148722	22863277	In a wound-healing assay YAP/TAZ knockdown also blocked the effect of LPA on cell migration (Figure S4E).	('LPA', 'Chemical', 'MESH:C032881', (70, 73))	('knockdown', 'Var', (33, 42))	('cell migration', 'biological_process', 'GO:0016477', ('77', '91'))	('cell migration', 'CPA', (77, 91))	('wound-healing', 'biological_process', 'GO:0042060', ('5', '18'))	('blocked', 'NegReg', (48, 55))
148729	22863277	In contrast to the cytoplasmic localization of TAZ in control tissues, TAZ was enriched in the cell nucleus of LPA1 and LPA2 transgenic tissues (Figure 4E).	('transgenic', 'Var', (125, 135))	('LPA1', 'Gene', (111, 115))	('localization', 'biological_process', 'GO:0051179', ('31', '43'))	('LPA1', 'Gene', '1902', (111, 115))	('cell nucleus', 'cellular_component', 'GO:0005634', ('95', '107'))	('LPA2', 'Gene', '9170', (120, 124))	('LPA2', 'Gene', (120, 124))
148739	22863277	Consistent with the observed Lats inhibition, phosphorylation levels of Lats1 at activation loop (S909) and hydrophobic motif (T1079), both of which determine Lats activity, were decreased upon LPA treatment (Figure 5C).	('phosphorylation', 'biological_process', 'GO:0016310', ('46', '61'))	('decreased', 'NegReg', (179, 188))	('phosphorylation levels', 'MPA', (46, 68))	('Lats1', 'Gene', (72, 77))	('T1079', 'Var', (127, 132))	('LPA', 'Chemical', 'MESH:C032881', (194, 197))	('hydrophobic', 'MPA', (108, 119))	('Lats1', 'Gene', '9113', (72, 77))
148744	22863277	To determine if LPA receptors were required for LPA-induced YAP/TAZ activation, we treated HEK293A cells with Ki16425, which preferentially inhibits LPA1 and LPA3.	('inhibits', 'NegReg', (140, 148))	('LPA3', 'Gene', (158, 162))	('LPA', 'Chemical', 'MESH:C032881', (48, 51))	('LPA', 'Chemical', 'MESH:C032881', (16, 19))	('LPA1', 'Gene', (149, 153))	('Ki16425', 'Chemical', 'MESH:C477898', (110, 117))	('LPA1', 'Gene', '1902', (149, 153))	('HEK293A', 'CellLine', 'CVCL:6910', (91, 98))	('Ki16425', 'Var', (110, 117))	('LPA3', 'Gene', '23566', (158, 162))	('LPA', 'Chemical', 'MESH:C032881', (158, 161))	('LPA', 'Chemical', 'MESH:C032881', (149, 152))
148746	22863277	Consistently, LPA-induced YAP dephosphorylation was significantly blocked by stable knockdown of LPA1 and LPA3 (Figure S6B).	('LPA3', 'Gene', (106, 110))	('LPA', 'Chemical', 'MESH:C032881', (14, 17))	('LPA1', 'Gene', (97, 101))	('LPA', 'Chemical', 'MESH:C032881', (106, 109))	('LPA', 'Chemical', 'MESH:C032881', (97, 100))	('LPA1', 'Gene', '1902', (97, 101))	('dephosphorylation', 'biological_process', 'GO:0016311', ('30', '47'))	('knockdown', 'Var', (84, 93))	('LPA3', 'Gene', '23566', (106, 110))	('blocked', 'NegReg', (66, 73))	('YAP dephosphorylation', 'MPA', (26, 47))
148747	22863277	Furthermore, ectopic expression of LPA and S1P receptors was sufficient to induce YAP nuclear localization and dephosphorylation (Figure 6B, S6C).	('LPA', 'Chemical', 'MESH:C032881', (35, 38))	('dephosphorylation', 'biological_process', 'GO:0016311', ('111', '128'))	('LPA', 'Gene', (35, 38))	('localization', 'biological_process', 'GO:0051179', ('94', '106'))	('S1P', 'Gene', (43, 46))	('YAP nuclear localization', 'MPA', (82, 106))	('dephosphorylation', 'MPA', (111, 128))	('S1P', 'Chemical', 'MESH:C060506', (43, 46))	('ectopic expression', 'Var', (13, 31))	('induce', 'PosReg', (75, 81))
148749	22863277	Notably, Ki16425 partially inhibited the ability of serum to repress YAP/TAZ phosphorylation, particularly at low serum concentrations (0.2%) (Figure 6A).	('YAP/TAZ phosphorylation', 'MPA', (69, 92))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('inhibited', 'NegReg', (27, 36))	('Ki16425', 'Chemical', 'MESH:C477898', (9, 16))	('Ki16425', 'Var', (9, 16))	('repress', 'NegReg', (61, 68))
148750	22863277	The Ki16425-insensitive YAP-dephosphorylating activity in serum could be due to S1P or other factors.	('YAP-dephosphorylating activity', 'MPA', (24, 54))	('Ki16425-insensitive', 'Var', (4, 23))	('Ki16425', 'Chemical', 'MESH:C477898', (4, 11))	('S1P', 'Chemical', 'MESH:C060506', (80, 83))	('due', 'Reg', (73, 76))
148754	22863277	Indeed, knockdown of both G12 and G13 largely blocked LPA-induced YAP dephosphorylation (Figure 6C), suggesting that G12/13 play a major role in mediating LPA signaling to the Hippo pathway.	('LPA', 'Chemical', 'MESH:C032881', (155, 158))	('G12/13', 'Gene', '1388', (117, 123))	('blocked', 'NegReg', (46, 53))	('G13', 'Gene', (34, 37))	('knockdown', 'Var', (8, 17))	('dephosphorylation', 'biological_process', 'GO:0016311', ('70', '87'))	('LPA-induced YAP dephosphorylation', 'MPA', (54, 87))	('G12/13', 'Gene', (117, 123))	('LPA', 'Chemical', 'MESH:C032881', (54, 57))	('G12', 'Gene', (26, 29))	('signaling', 'biological_process', 'GO:0023052', ('159', '168'))
148756	22863277	We therefore expressed the RhoA-N19 dominant-negative mutant and found that it blocked serum-induced YAP dephosphorylation (Figure S6D).	('RhoA', 'Gene', '387', (27, 31))	('serum-induced YAP dephosphorylation', 'MPA', (87, 122))	('dephosphorylation', 'biological_process', 'GO:0016311', ('105', '122'))	('mutant', 'Var', (54, 60))	('blocked', 'NegReg', (79, 86))	('RhoA', 'Gene', (27, 31))
148757	22863277	Conversely, expression of the constitutively active RhoA-L63 mutant induced a robust YAP dephosphorylation even in the absence of serum (Figure S6D).	('RhoA', 'Gene', (52, 56))	('YAP dephosphorylation', 'MPA', (85, 106))	('RhoA', 'Gene', '387', (52, 56))	('mutant', 'Var', (61, 67))	('dephosphorylation', 'biological_process', 'GO:0016311', ('89', '106'))
148761	22863277	Moreover, inhibition of LPA1 and LPA3 by Ki16425 and inactivation of Rho GTPases by C3 treatment effectively blocked Lats1 inhibition by LPA, S1P, and serum (Figure S6F, S6G).	('LPA', 'Chemical', 'MESH:C032881', (24, 27))	('Lats1', 'Gene', (117, 122))	('LPA1', 'Gene', '1902', (24, 28))	('inhibition', 'NegReg', (10, 20))	('S1P', 'Chemical', 'MESH:C060506', (142, 145))	('Ki16425', 'Chemical', 'MESH:C477898', (41, 48))	('LPA3', 'Gene', '23566', (33, 37))	('blocked', 'NegReg', (109, 116))	('Ki16425', 'Var', (41, 48))	('LPA', 'Chemical', 'MESH:C032881', (33, 36))	('GTP', 'Chemical', 'MESH:D006160', (73, 76))	('inhibition', 'NegReg', (123, 133))	('Lats1', 'Gene', '9113', (117, 122))	('inactivation', 'NegReg', (53, 65))	('LPA', 'Chemical', 'MESH:C032881', (137, 140))	('LPA3', 'Gene', (33, 37))	('LPA1', 'Gene', (24, 28))
148776	22863277	Our data indicate that GPCRs that activate G12/13-, Gq/11, or Gi/o could repress YAP/TAZ phosphorylation.	('Gq/11', 'Var', (52, 57))	('G12/13', 'Gene', (43, 49))	('GPCR', 'Gene', (23, 27))	('repress', 'NegReg', (73, 80))	('YAP/TAZ phosphorylation', 'MPA', (81, 104))	('G12/13', 'Gene', '1388', (43, 49))	('GPCR', 'Gene', '9170', (23, 27))	('phosphorylation', 'biological_process', 'GO:0016310', ('89', '104'))	('Gi/o', 'Var', (62, 66))
148798	22863277	Because only the GTP-bound Galpha is active and directly participates in signaling, we expressed constitutively active mutants (GTP-bound form) of Galpha subunits.	('GTP', 'Chemical', 'MESH:D006160', (17, 20))	('Galpha', 'Gene', (147, 153))	('Galpha', 'Gene', '8802', (27, 33))	('Galpha', 'Gene', '8802', (147, 153))	('participates', 'Reg', (57, 69))	('signaling', 'biological_process', 'GO:0023052', ('73', '82'))	('Galpha', 'Gene', (27, 33))	('GTP', 'Chemical', 'MESH:D006160', (128, 131))	('mutants', 'Var', (119, 126))
148799	22863277	We found that active Galpha mutants decreased YAP phosphorylation to varying degrees with the exception of Gs and Gz.	('mutants', 'Var', (28, 35))	('YAP phosphorylation', 'MPA', (46, 65))	('Galpha', 'Gene', '8802', (21, 27))	('Galpha', 'Gene', (21, 27))	('Gz', 'Chemical', '-', (114, 116))	('phosphorylation', 'biological_process', 'GO:0016310', ('50', '65'))	('decreased', 'NegReg', (36, 45))
148800	22863277	Among the Galpha subunits that decreased YAP phosphorylation, G12, G13, Gq, G11, G14, and G15 were more potent than Gi, Gt, and Go in repressing YAP phosphorylation.	('YAP phosphorylation', 'MPA', (145, 164))	('G14', 'Var', (81, 84))	('decreased', 'NegReg', (31, 40))	('G13', 'Var', (67, 70))	('Galpha', 'Gene', (10, 16))	('G11', 'Var', (76, 79))	('G12', 'Var', (62, 65))	('Galpha', 'Gene', '8802', (10, 16))	('YAP phosphorylation', 'MPA', (41, 60))	('phosphorylation', 'biological_process', 'GO:0016310', ('149', '164'))	('phosphorylation', 'biological_process', 'GO:0016310', ('45', '60'))	('G15', 'Var', (90, 93))
148823	22863277	We reason that the high redundancy and complexity may hinder genetic efforts to isolate upstream signals and receptors for the Hippo-YAP pathway because knockout or knockdown of a single GPCR may not significantly affect the Hippo-YAP pathway.	('GPCR', 'Gene', (187, 191))	('knockdown', 'Var', (165, 174))	('Hippo-YAP pathway', 'Pathway', (225, 242))	('GPCR', 'Gene', '9170', (187, 191))
148827	22863277	Indeed, it has been shown that knockout of gprc6a in Leydig cells reduces testis size.	('reduces', 'NegReg', (66, 73))	('testis size', 'CPA', (74, 85))	('reduces testis size', 'Phenotype', 'HP:0008734', (66, 85))	('knockout', 'Var', (31, 39))	('gprc6a', 'Gene', '222545', (43, 49))	('gprc6a', 'Gene', (43, 49))
148828	22863277	Gprc6a is able to activate Gq, and it is possible that YAP/TAZ activity is compromised in gprc6a knockout cells and contributes to the small organ size phenotype.	('knockout', 'Var', (97, 105))	('Gprc6a', 'Gene', (0, 6))	('contributes', 'Reg', (116, 127))	('small organ size', 'CPA', (135, 151))	('gprc6a', 'Gene', (90, 96))	('activate', 'PosReg', (18, 26))	('gprc6a', 'Gene', '222545', (90, 96))	('YAP/TAZ', 'MPA', (55, 62))	('Gprc6a', 'Gene', '222545', (0, 6))
148832	22863277	GPCR signaling plays important roles in cancer development as both familial and somatic activating mutations of GPCRs have been linked to human cancer.	('GPCR', 'Gene', '9170', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('linked', 'Reg', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('human', 'Species', '9606', (138, 143))	('GPCR', 'Gene', (112, 116))	('cancer', 'Disease', (40, 46))	('signaling', 'biological_process', 'GO:0023052', ('5', '14'))	('cancer', 'Disease', (144, 150))	('mutations', 'Var', (99, 108))	('GPCR', 'Gene', (0, 4))	('activating', 'PosReg', (88, 98))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('GPCR', 'Gene', '9170', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
148833	22863277	Recently, GPCR mutations have been identified in a wide range of human cancer specimens.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('human', 'Species', '9606', (65, 70))	('GPCR', 'Gene', '9170', (10, 14))	('cancer', 'Disease', (71, 77))	('identified', 'Reg', (35, 45))	('mutations', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('GPCR', 'Gene', (10, 14))
148835	22863277	Mutations of G-proteins are also linked to cancer.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('G-proteins', 'Protein', (13, 23))	('cancer', 'Disease', (43, 49))	('linked', 'Reg', (33, 39))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
148840	22863277	We hypothesize that inhibition of YAP/TAZ will be a new approach to treat human cancers caused by dysregulated Rho GTPase, G-proteins, GPCRs or their agonists.	('GPCR', 'Gene', (135, 139))	('G-proteins', 'Protein', (123, 133))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('GPCR', 'Gene', '9170', (135, 139))	('caused', 'Reg', (88, 94))	('Rho GTPase', 'Protein', (111, 121))	('human', 'Species', '9606', (74, 79))	('GTP', 'Chemical', 'MESH:D006160', (115, 118))	('dysregulated', 'Var', (98, 110))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
148866	21949607	The recent identification of several clinically linked melanoma gene mutations involved in mitogen-activated protein kinase (MAPK) pathway such as BRAF, NRAS, and cKIT has breathed new life into the drive to develop more effective therapies.	('mutations', 'Var', (69, 78))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('NRAS', 'Gene', (153, 157))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('cKIT', 'Gene', '3815', (163, 167))	('NRAS', 'Gene', '4893', (153, 157))	('BRAF', 'Gene', (147, 151))	('involved', 'Reg', (79, 87))	('BRAF', 'Gene', '673', (147, 151))	('cKIT', 'Gene', (163, 167))	('MAPK', 'Gene', '5595;5594;5595', (125, 129))	('MAPK', 'Gene', (125, 129))	('MAPK', 'molecular_function', 'GO:0004707', ('125', '129'))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
148885	21949607	Patients considered most appropriate for sentinel node biopsy include stage IB, stage II with a <= 1 mm thick lesion and ulceration or mitotic rate >= 1/mm2, stage II with a > 1 mm thick lesion, and resectable stage III tumors with in transit metastases.	('mitotic rate', 'CPA', (135, 147))	('III tumors', 'Disease', 'MESH:D009369', (216, 226))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('thick lesion', 'Disease', (181, 193))	('thick lesion', 'Disease', (104, 116))	('<= 1', 'Var', (96, 100))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('thick lesion', 'Disease', 'MESH:C535655', (181, 193))	('III tumors', 'Disease', (216, 226))	('metastases', 'Disease', (243, 253))	('Patients', 'Species', '9606', (0, 8))	('metastases', 'Disease', 'MESH:D009362', (243, 253))	('thick lesion', 'Disease', 'MESH:C535655', (104, 116))	('>= 1/mm2', 'Var', (148, 156))
148886	21949607	A trial from France determined that for melanomas with Breslow depth < 2.1 mm, there was no difference in 10-year overall survival between a 2 cm and a 5 cm excision margin.	('melanomas', 'Disease', (40, 49))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Disease', 'MESH:D008545', (40, 49))	('< 2.1', 'Var', (69, 74))
148916	21949607	Instead of a BRAF, NRAS, or cKIT mutation, 83% of uveal melanomas have a mutation at the GNA11 or GNAQ loci.	('uveal melanomas', 'Disease', (50, 65))	('uveal melanomas', 'Phenotype', 'HP:0007716', (50, 65))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('NRAS', 'Gene', (19, 23))	('BRAF', 'Gene', '673', (13, 17))	('cKIT', 'Gene', (28, 32))	('uveal melanomas', 'Disease', 'MESH:C536494', (50, 65))	('GNAQ', 'Gene', (98, 102))	('BRAF', 'Gene', (13, 17))	('NRAS', 'Gene', '4893', (19, 23))	('GNA11', 'Gene', '2767', (89, 94))	('GNA11', 'Gene', (89, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('cKIT', 'Gene', '3815', (28, 32))	('GNAQ', 'Gene', '2776', (98, 102))	('mutation', 'Var', (73, 81))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
148920	21949607	Just as the BRAF inhibitor, PLX4032, successfully treated patients with cutaneous melanomas, a MEK inhibitor may produce similar tumor shrinkage and improve the survival of uveal melanoma patients.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (72, 91))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (72, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (173, 187))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (72, 90))	('patients', 'Species', '9606', (188, 196))	('PLX4032', 'Chemical', 'MESH:D000077484', (28, 35))	('improve', 'PosReg', (149, 156))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('cutaneous melanomas', 'Disease', (72, 91))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('patients', 'Species', '9606', (58, 66))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('MEK', 'Gene', '5609', (95, 98))	('inhibitor', 'Var', (99, 108))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('survival', 'CPA', (161, 169))	('uveal melanoma', 'Disease', (173, 187))	('uveal melanoma', 'Disease', 'MESH:C536494', (173, 187))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('shrinkage', 'NegReg', (135, 144))	('MEK', 'Gene', (95, 98))
148930	21949607	Patients with desmoplastic histology, positive margins, recurrent disease, and/or a > 4.0 mm Breslow lesion with ulceration or satellitosis are at high risk for local recurrence and may benefit from adjuvant radiotherapy to the local site.	('benefit', 'Reg', (186, 193))	('desmoplastic', 'Disease', (14, 26))	('local recurrence', 'CPA', (161, 177))	('ulceration or satellitosis', 'Disease', 'MESH:D014456', (113, 139))	('positive', 'Var', (38, 46))	('Patients', 'Species', '9606', (0, 8))	('desmoplastic', 'Disease', 'MESH:D018220', (14, 26))	('ulceration or satellitosis', 'Disease', (113, 139))	('> 4.0', 'Var', (84, 89))
148942	21949607	These complexes phosphorylate the retinoblastoma protein, which disassociates from E2F and allows E2F to activate transcription of critical DNA synthesis genes and cyclins, such as cyclin E, facilitating progression into the S phase of the cell cycle (Figure 3).	('cyclin', 'molecular_function', 'GO:0016538', ('181', '187'))	('progression', 'CPA', (204, 215))	('retinoblastoma', 'Disease', (34, 48))	('transcription', 'biological_process', 'GO:0006351', ('114', '127'))	('S phase', 'biological_process', 'GO:0051320', ('225', '232'))	('DNA synthesis', 'biological_process', 'GO:0071897', ('140', '153'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (34, 48))	('cyclin', 'Gene', '5111', (181, 187))	('cyclin', 'Gene', '5111', (164, 170))	('cell cycle', 'biological_process', 'GO:0007049', ('240', '250'))	('cyclin', 'Gene', (181, 187))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('transcription', 'MPA', (114, 127))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('cyclin', 'Gene', (164, 170))	('retinoblastoma', 'Disease', 'MESH:D012175', (34, 48))	('activate', 'PosReg', (105, 113))	('E2F', 'Var', (98, 101))
148945	21949607	The PI3K-AKT pathway is also critical, with more than 60% of human melanomas exhibiting activated AKT, and inactivation and/or deletion of the PI3K negative regulator (PTEN) occurring in 5%-15% of uncultured melanoma specimens and metastasis, 17% of short-term melanoma cultures, and 30%-40% of established melanoma cell lines.	('melanoma', 'Disease', 'MESH:D008545', (307, 315))	('PTEN', 'Gene', '5728', (168, 172))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma', 'Disease', (208, 216))	('AKT', 'Gene', '207', (98, 101))	('deletion', 'Var', (127, 135))	('melanomas', 'Disease', 'MESH:D008545', (67, 76))	('melanoma', 'Phenotype', 'HP:0002861', (261, 269))	('melanoma', 'Disease', (261, 269))	('melanomas', 'Disease', (67, 76))	('AKT', 'Gene', '207', (9, 12))	('PI3K', 'Gene', (143, 147))	('PI3K', 'molecular_function', 'GO:0016303', ('143', '147'))	('inactivation', 'Var', (107, 119))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('melanoma', 'Phenotype', 'HP:0002861', (307, 315))	('melanoma', 'Disease', (307, 315))	('activated', 'PosReg', (88, 97))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('men', 'Species', '9606', (222, 225))	('human', 'Species', '9606', (61, 66))	('melanoma', 'Disease', 'MESH:D008545', (261, 269))	('AKT', 'Gene', (98, 101))	('PTEN', 'Gene', (168, 172))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('AKT', 'Gene', (9, 12))
148950	21949607	p16 can initiate a cyclin-dependent kinase 4/6-dependent autonomous senescence program that is disabled by inherited melanoma-associated mutations.	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('senescence', 'biological_process', 'GO:0010149', ('68', '78'))	('p16', 'Gene', (0, 3))	('cyclin', 'molecular_function', 'GO:0016538', ('19', '25'))	('mutations', 'Var', (137, 146))	('p16', 'Gene', '1029', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('cyclin-dependent kinase 4/6-dependent', 'Enzyme', (19, 56))	('melanoma', 'Disease', (117, 125))
148951	21949607	As more knowledge is obtained regarding aberrant components of the cell cycle regulatory circuit leading to melanoma development, therapeutic trials targeting specific mutant proteins are getting underway.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('mutant', 'Var', (168, 174))	('men', 'Species', '9606', (124, 127))	('cell cycle', 'biological_process', 'GO:0007049', ('67', '77'))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))
148952	21949607	For example, one study using human melanoma cancer cell lines cultured in vitro and in mice in vivo showed that selective and structurally distinct small molecular inhibitors of cyclin-dependent kinase 4 and cyclin-dependent kinase 6 resulted in increased cellular radioresistance, especially in those cancer cell lines dependent on the cyclin-dependent kinase 4/6 pathway for proliferation.	('cyclin-dependent kinase 6', 'Gene', (208, 233))	('cancer', 'Disease', (302, 308))	('melanoma cancer', 'Disease', 'MESH:C563985', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('cyclin', 'molecular_function', 'GO:0016538', ('208', '214'))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cyclin', 'molecular_function', 'GO:0016538', ('178', '184'))	('cyclin', 'molecular_function', 'GO:0016538', ('337', '343'))	('cyclin-dependent kinase 4', 'Gene', (337, 362))	('inhibitors', 'Var', (164, 174))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('human', 'Species', '9606', (29, 34))	('cyclin-dependent kinase 6', 'Gene', '12571', (208, 233))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma cancer', 'Disease', (35, 50))	('cyclin-dependent kinase 4', 'Gene', (178, 203))	('cyclin-dependent kinase 4', 'Gene', '12567', (337, 362))	('cancer', 'Disease', (44, 50))	('mice', 'Species', '10090', (87, 91))	('cellular radioresistance', 'CPA', (256, 280))	('increased', 'PosReg', (246, 255))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cyclin-dependent kinase 4', 'Gene', '12567', (178, 203))
148954	21949607	It has antiangiogenic effects and has been effective in treating cancers with and without BRAF mutations, making it a promising adjuvant therapy for melanoma.	('BRAF', 'Gene', (90, 94))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('antiangiogenic effects', 'CPA', (7, 29))	('mutations', 'Var', (95, 104))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('BRAF', 'Gene', '673', (90, 94))	('cancers', 'Disease', (65, 72))
148955	21949607	Because the majority of melanomas harbor an activating missense mutation (V600E) in the BRAF oncogene, targeted inhibition of the V600E gene product is an important therapeutic goal.	('activating', 'PosReg', (44, 54))	('V600E', 'Mutation', 'rs113488022', (74, 79))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('melanomas', 'Disease', (24, 33))	('V600E', 'Mutation', 'rs113488022', (130, 135))	('V600E', 'Var', (74, 79))	('melanomas', 'Phenotype', 'HP:0002861', (24, 33))	('melanomas', 'Disease', 'MESH:D008545', (24, 33))	('V600E', 'Var', (130, 135))
148957	21949607	A Phase I trial of PLX4032, an oral inhibitor of V600E-mutated BRAF, demonstrated complete or partial tumor regression in 81% of patients and improved median progression-free survival from 2.0-6.2 months for patients with metastatic melanoma.	('V600E-mutated', 'Var', (49, 62))	('PLX4032', 'Chemical', 'MESH:D000077484', (19, 26))	('patients', 'Species', '9606', (208, 216))	('patients', 'Species', '9606', (129, 137))	('V600E', 'Mutation', 'rs113488022', (49, 54))	('partial', 'NegReg', (94, 101))	('improved', 'PosReg', (142, 150))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))	('BRAF', 'Gene', '673', (63, 67))	('melanoma', 'Disease', 'MESH:D008545', (233, 241))	('tumor', 'Disease', (102, 107))	('BRAF', 'Gene', (63, 67))	('melanoma', 'Disease', (233, 241))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
148961	21949607	It has been shown recently that Ink4a/Arf-/- mice with melanocyte-specific deletion of Ikkbeta were protected from H-RasV12-initiated melanoma when p53 was expressed, providing genetic and mechanistic evidence that mutant H-Ras initiation of tumorigenesis requires Ikkbeta-mediated NF-kappaB activity.	('Ikkbeta', 'Gene', '16150', (265, 272))	('H-Ras', 'Gene', (115, 120))	('H-Ras', 'Gene', '15461', (115, 120))	('mice', 'Species', '10090', (45, 49))	('Ikkbeta', 'Gene', (87, 94))	('tumor', 'Disease', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('mutant', 'Var', (215, 221))	('Ikkbeta', 'Gene', '16150', (87, 94))	('H-Ras', 'Gene', (222, 227))	('H-Ras', 'Gene', '15461', (222, 227))	('Ikkbeta', 'Gene', (265, 272))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('Ink4a', 'Gene', '12578', (32, 37))	('Ink4a', 'Gene', (32, 37))	('deletion', 'Var', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))
148963	21949607	One study compared the radiosensitivity of cells expressing wild-type p16 with those having the mutant p16 found in melanomas, and found that the melanoma cells were less sensitive to x-ray irradiation if they had a p16 mutation.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('less', 'NegReg', (166, 170))	('melanomas', 'Disease', (116, 125))	('p16', 'Gene', '1029', (103, 106))	('p16', 'Gene', '1029', (70, 73))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('p16', 'Gene', (216, 219))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('mutation', 'Var', (220, 228))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('melanomas', 'Disease', 'MESH:D008545', (116, 125))	('p16', 'Gene', (103, 106))	('p16', 'Gene', (70, 73))	('p16', 'Gene', '1029', (216, 219))
148964	21949607	Therefore, an adjuvant therapy targeting the expression of mutant p16 would not only lead to better cell cycle regulation, but render the melanoma cells more radiosensitive.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('mutant', 'Var', (59, 65))	('p16', 'Gene', (66, 69))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('100', '121'))	('cell cycle regulation', 'CPA', (100, 121))	('better', 'PosReg', (93, 99))	('p16', 'Gene', '1029', (66, 69))
148965	21949607	A recent randomized trial of ipilimumab evaluated the role of an antibody targeting CTLA-4 in HLA-A*0201-positive unresectable stage III/IV melanoma patients who progressed on chemotherapy, and showed a significant improvement in median overall survival (10.0 months versus 6.4 months, P < 0.0001).	('CTLA-4', 'Gene', '1493', (84, 90))	('antibody', 'cellular_component', 'GO:0042571', ('65', '73'))	('patients', 'Species', '9606', (149, 157))	('IV melanoma', 'Disease', (137, 148))	('IV melanoma', 'Disease', 'MESH:D008545', (137, 148))	('CTLA-4', 'Gene', (84, 90))	('antibody', 'cellular_component', 'GO:0019815', ('65', '73'))	('improvement', 'PosReg', (215, 226))	('ipilimumab', 'Chemical', 'MESH:D000074324', (29, 39))	('HLA-A', 'Gene', '3105', (94, 99))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('antibody', 'cellular_component', 'GO:0019814', ('65', '73'))	('men', 'Species', '9606', (222, 225))	('overall survival', 'MPA', (237, 253))	('antibody', 'molecular_function', 'GO:0003823', ('65', '73'))	('antibody', 'Var', (65, 73))	('HLA-A', 'Gene', (94, 99))
148978	21949607	Only one study of 287 patients with melanomas > 4.0 mm and/or one regional metastasis randomized to either adjuvant therapy with high-dose IFN-alpha 2b for 1 year or to observation, demonstrated an improvement in both disease-free survival (1.0 years versus 1.7 years P = 0.0023) and overall survival (2.8 years versus 3.8 years, one-sided P = 0.0237) at 6.9 years of follow-up.	('disease-free survival', 'CPA', (218, 239))	('IFN-alpha', 'Gene', (139, 148))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('IFN-alpha', 'Gene', '3440', (139, 148))	('> 4.0 mm', 'Var', (46, 54))	('patients', 'Species', '9606', (22, 30))	('men', 'Species', '9606', (205, 208))	('improvement', 'PosReg', (198, 209))	('overall survival', 'CPA', (284, 300))	('melanomas', 'Disease', 'MESH:D008545', (36, 45))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('melanomas', 'Disease', (36, 45))
148985	21949607	Several clinical advances in the past decade have led to new treatment strategies, including agents targeted against mutations in B-Raf (PLX4032 and sorafenib) and c-KIT (kinase inhibitors such as imatinib), T cell immunotherapy, removal of immunologic inhibition at checkpoints in T cell activation (anti-CTLA 4 antibody), and many others.	('KIT', 'molecular_function', 'GO:0005020', ('166', '169'))	('mutations', 'Var', (117, 126))	('men', 'Species', '9606', (66, 69))	('antibody', 'cellular_component', 'GO:0042571', ('313', '321'))	('c-KIT', 'Gene', (164, 169))	('T cell activation', 'biological_process', 'GO:0042110', ('282', '299'))	('B-Raf', 'Gene', (130, 135))	('c-KIT', 'Gene', '3815', (164, 169))	('imatinib', 'Chemical', 'MESH:D000068877', (197, 205))	('CTLA 4', 'Gene', (306, 312))	('sorafenib', 'Chemical', 'MESH:D000077157', (149, 158))	('B-Raf', 'Gene', '673', (130, 135))	('PLX4032', 'Chemical', 'MESH:D000077484', (137, 144))	('antibody', 'cellular_component', 'GO:0019815', ('313', '321'))	('antibody', 'cellular_component', 'GO:0019814', ('313', '321'))	('antibody', 'molecular_function', 'GO:0003823', ('313', '321'))	('CTLA 4', 'Gene', '1493', (306, 312))
148990	21949607	Lastly, a recent study by Khan et al demonstrated that riluzole, an inhibitor of glutamate release by human GRM1-expressing melanoma cells, enhanced radiosensitivity in melanoma cells in vitro and in vivo.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('glutamate', 'Chemical', 'MESH:D018698', (81, 90))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (140, 165))	('enhanced', 'PosReg', (140, 148))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('GRM1', 'Gene', (108, 112))	('melanoma', 'Disease', (169, 177))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('riluzole', 'Var', (55, 63))	('radiosensitivity', 'CPA', (149, 165))	('GRM1', 'Gene', '2911', (108, 112))	('riluzole', 'Chemical', 'MESH:D019782', (55, 63))	('human', 'Species', '9606', (102, 107))
148999	21949607	The reversal or slowing of some of these protective pathways via genetic modifications (eg, targeted mutations) or pharmacologic inhibitors (eg, p53 or p16 small molecule inhibitors) perhaps in combination with appropriately fractionated radiotherapy and perhaps immunotherapy and chemotherapy may finally transform melanoma from the most lethal to one of the most curable of the primary cutaneous malignancies.	('melanoma', 'Phenotype', 'HP:0002861', (316, 324))	('cutaneous malignancies', 'Phenotype', 'HP:0008069', (388, 410))	('cutaneous malignancies', 'Disease', (388, 410))	('melanoma', 'Disease', (316, 324))	('mutations', 'Var', (101, 110))	('melanoma', 'Disease', 'MESH:D008545', (316, 324))	('p16', 'Gene', '1029', (152, 155))	('slowing', 'NegReg', (16, 23))	('cutaneous malignancies', 'Disease', 'MESH:C562393', (388, 410))	('transform', 'Reg', (306, 315))	('p16', 'Gene', (152, 155))
149103	33724676	It is hypothesized that MUM is less responsive to ICI due to the presence of fewer somatic mutations, which results in fewer potential neoantigens that can be targeted by antitumor immunity.	('tumor', 'Disease', (175, 180))	('neoantigens', 'MPA', (135, 146))	('mutations', 'Var', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('fewer', 'NegReg', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('UM', 'Phenotype', 'HP:0007716', (25, 27))
149106	33724676	24  Rare marked response to immunotherapy has been reported in UM, and molecular investigation of these tumors revealed high tumor mutation burden (TMB) secondary to germline, loss-of function MBD4 mutations.	('MBD4', 'Gene', '8930', (193, 197))	('MBD4', 'Gene', (193, 197))	('loss-of function', 'NegReg', (176, 192))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('UM', 'Phenotype', 'HP:0007716', (63, 65))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('TMB', 'Chemical', '-', (148, 151))	('mutations', 'Var', (198, 207))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('high tumor', 'Disease', (120, 130))	('high tumor', 'Disease', 'MESH:D009369', (120, 130))
149127	33724676	34 ,  35  Finally, several retrospective analyses have demonstrated that tumor thickness and chromosome 3 alterations may be used as markers to identify MUM patients at high risk of rapid disease progression.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('patients', 'Species', '9606', (157, 165))	('tumor thickness', 'Disease', (73, 88))	('UM', 'Phenotype', 'HP:0007716', (154, 156))	('tumor thickness', 'Disease', 'MESH:C535655', (73, 88))	('alterations', 'Var', (106, 117))	('chromosome 3', 'Gene', (93, 105))
149131	33724676	A predictive marker gives information about the effect of a particular therapeutic intervention, such as high TMB in melanoma predicting response to immunotherapy.	('high', 'Var', (105, 109))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('TMB', 'Chemical', '-', (110, 113))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
149175	33257317	Some genetic mutations linked to worse prognosis, including BAP1 itself.	('mutations', 'Var', (13, 22))	('BAP1', 'Gene', '8314', (60, 64))	('BAP1', 'Gene', (60, 64))
149176	33257317	Moreover, UM familial predisposition syndrome is marked by BAP1 germline mutations, which in turn is associated with other cancers, including cutaneous melanoma, malignant mesothelioma and renal cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('germline', 'Var', (64, 72))	('cutaneous melanoma', 'Disease', (142, 160))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (142, 160))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (142, 160))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('BAP1', 'Gene', '8314', (59, 63))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (162, 184))	('UM familial predisposition syndrome', 'Disease', (10, 45))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (189, 209))	('associated', 'Reg', (101, 111))	('malignant mesothelioma', 'Disease', (162, 184))	('BAP1', 'Gene', (59, 63))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (162, 184))	('renal cell carcinoma', 'Disease', (189, 209))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (189, 209))
149212	33257317	After adjusting for sex, race, age at diagnosis of UM, site of UM, stage at diagnosis of UM, size at diagnosis of UM, and undergoing cancer-directed surgery for UM, multivariate Cox models showed a better overall survival for females, but worse outcomes for black patients, ciliary body UM, larger or more advanced UM (table 6).	('ciliary', 'Var', (274, 281))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('age', 'Gene', (31, 34))	('cancer', 'Disease', (133, 139))	('age', 'Gene', (69, 72))	('better', 'PosReg', (198, 204))	('patients', 'Species', '9606', (264, 272))	('age', 'Gene', '5973', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('age', 'Gene', '5973', (31, 34))
149223	33257317	Germline pathogenic variants in several cancer genes have been reported in patients with UM.	('variants', 'Var', (20, 28))	('reported', 'Reg', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
149227	33257317	CHEK2 mutations predispose to papillary thyroid, prostate and breast cancers.	('CHEK2', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('breast cancers', 'Phenotype', 'HP:0003002', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancers', 'Disease', 'MESH:D001943', (62, 76))	('breast cancers', 'Disease', (62, 76))	('predispose', 'Reg', (16, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('papillary thyroid', 'Disease', (30, 47))	('prostate', 'Disease', (49, 57))	('CHEK2', 'Gene', '11200', (0, 5))	('mutations', 'Var', (6, 15))
149228	33257317	PALB2 mutations show an association with breast, ovarian and pancreatic cancers.	('ovarian and pancreatic cancers', 'Disease', 'MESH:D010195', (49, 79))	('breast', 'Disease', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('PALB2', 'Gene', '79728', (0, 5))	('PALB2', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('association', 'Reg', (24, 35))	('mutations', 'Var', (6, 15))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (61, 79))
149229	33257317	Mutations of SMARCE1 results in spinal meningiomas and its high expression associate with poor prognosis of breast cancer.	('expression', 'MPA', (64, 74))	('spinal meningiomas', 'Disease', (32, 50))	('meningiomas', 'Phenotype', 'HP:0002858', (39, 50))	('spinal meningiomas', 'Disease', 'MESH:D008577', (32, 50))	('SMARCE1', 'Gene', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('SMARCE1', 'Gene', '6605', (13, 20))	('Mutations', 'Var', (0, 9))	('spinal meningiomas', 'Phenotype', 'HP:0100010', (32, 50))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('results in', 'Reg', (21, 31))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
149264	31848373	COSMIC mutational signature analysis identified that most of the mutations in UVM patients (>90%) were associated with spontaneous deamination of 5-methylcytosine or defective mismatch repair.	('mismatch repair', 'biological_process', 'GO:0006298', ('176', '191'))	('associated', 'Reg', (103, 113))	('patients', 'Species', '9606', (82, 90))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (146, 162))	('spontaneous deamination of 5-methylcytosine', 'MPA', (119, 162))	('UVM', 'Phenotype', 'HP:0007716', (78, 81))	('defective', 'NegReg', (166, 175))	('mutations', 'Var', (65, 74))
149273	31848373	The GNAQ/GNA11 mutations frequently observed in UVM patients have also been reported to activate the MAPK pathway, but clinical trials with the MEK1/2 inhibitor, selumetinib, have failed to improve survival.	('MEK1/2', 'Gene', (144, 150))	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (4, 8))	('MAPK', 'molecular_function', 'GO:0004707', ('101', '105'))	('MAPK pathway', 'Pathway', (101, 113))	('mutations', 'Var', (15, 24))	('selumetinib', 'Chemical', 'MESH:C517975', (162, 173))	('GNAQ', 'Gene', (4, 8))	('UVM', 'Phenotype', 'HP:0007716', (48, 51))	('MEK1', 'molecular_function', 'GO:0004708', ('144', '148'))	('activate', 'PosReg', (88, 96))	('MEK1/2', 'Gene', '5604;5605', (144, 150))	('patients', 'Species', '9606', (52, 60))	('GNA11', 'Gene', '2767', (9, 14))
149284	31848373	A total of 1,994 and 32,508 single nucleotide variants (SNVs) and DNVs were identified in 80 UVM and 67 SKCM patients, respectively, and were included in the COSMIC mutational signature analyses.	('DNV', 'Chemical', '-', (66, 69))	('UVM', 'Phenotype', 'HP:0007716', (93, 96))	('patients', 'Species', '9606', (109, 117))	('UVM', 'Disease', (93, 96))	('SNV', 'Chemical', '-', (56, 59))	('single nucleotide variants', 'Var', (28, 54))
149300	31848373	The MYC copy number gain was associated with UVM-specific survival (P = 0.028; Fig.	('MYC', 'Gene', (4, 7))	('copy number gain', 'Var', (8, 24))	('UVM-specific survival', 'Disease', (45, 66))	('MYC', 'Gene', '4609', (4, 7))	('UVM', 'Phenotype', 'HP:0007716', (45, 48))
149304	31848373	Notably, significantly more BAP1 mutations were observed in patients with high MYC copy number (P < 0.002).	('BAP1', 'Gene', '8314', (28, 32))	('MYC', 'Gene', (79, 82))	('more', 'PosReg', (23, 27))	('patients', 'Species', '9606', (60, 68))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('MYC', 'Gene', '4609', (79, 82))
149305	31848373	In multivariate cox proportional hazards model, hazard ratios were 2.27 (P = 0.201) and 5.45 (P = 0.001) for MYC copy number gain and BAP1 mutation, respectively.	('mutation', 'Var', (139, 147))	('BAP1', 'Gene', (134, 138))	('copy number', 'Var', (113, 124))	('gain', 'PosReg', (125, 129))	('MYC', 'Gene', '4609', (109, 112))	('BAP1', 'Gene', '8314', (134, 138))	('MYC', 'Gene', (109, 112))
149306	31848373	Harrell's C indices were 0.623 and 0.687 for for MYC copy number gain and BAP1 mutation, respectively.	('MYC', 'Gene', (49, 52))	('copy number gain', 'Var', (53, 69))	('BAP1', 'Gene', '8314', (74, 78))	('mutation', 'Var', (79, 87))	('MYC', 'Gene', '4609', (49, 52))	('BAP1', 'Gene', (74, 78))
149312	31848373	SNVs, small insertions/deletions, and copy number variations of the genome alter the function of oncogenes and tumor suppressor genes, and can cause cancer.	('SNV', 'Chemical', '-', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('cancer', 'Disease', (149, 155))	('oncogenes', 'Protein', (97, 106))	('function', 'MPA', (85, 93))	('alter', 'Reg', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cause', 'Reg', (143, 148))	('tumor', 'Disease', (111, 116))	('tumor suppressor', 'biological_process', 'GO:0051726', ('111', '127'))	('copy number variations', 'Var', (38, 60))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('111', '127'))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
149313	31848373	Intense research efforts regarding cancer genomes have identified several oncogenic pathways important in human cancers, and have led to improved therapeutic outcomes for tumors with EGFR, ALK, and BRAF mutations.	('human', 'Species', '9606', (106, 111))	('ALK', 'Gene', '238', (189, 192))	('cancer', 'Disease', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('ALK', 'Gene', (189, 192))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('BRAF', 'Gene', '673', (198, 202))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('EGFR', 'Gene', (183, 187))	('BRAF', 'Gene', (198, 202))	('cancers', 'Disease', (112, 119))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('EGFR', 'molecular_function', 'GO:0005006', ('183', '187'))	('tumors', 'Disease', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('oncogenic pathways', 'Pathway', (74, 92))	('mutations', 'Var', (203, 212))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('EGFR', 'Gene', '1956', (183, 187))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('improved', 'PosReg', (137, 145))	('cancer', 'Disease', (35, 41))
149314	31848373	Cancer genome sequencing studies using UVM have identified frequent mutations in GNAQ/GNA11.	('GNAQ', 'Gene', (81, 85))	('UVM', 'Phenotype', 'HP:0007716', (39, 42))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('GNA11', 'Gene', (86, 91))	('mutations', 'Var', (68, 77))	('GNA11', 'Gene', '2767', (86, 91))	('GNAQ', 'Gene', '2776', (81, 85))
149315	31848373	Mutant GNAQ/GNA11-induced activation of the MAPK and Hippo-YAP pathways has been reported in many basic and translational studies, and has suggested as essential for tumorigenesis of UVM.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('YAP', 'Gene', (59, 62))	('GNA11', 'Gene', '2767', (12, 17))	('GNA11', 'Gene', (12, 17))	('GNAQ', 'Gene', '2776', (7, 11))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('MAPK', 'Pathway', (44, 48))	('tumor', 'Disease', (166, 171))	('MAPK', 'molecular_function', 'GO:0004707', ('44', '48'))	('activation', 'PosReg', (26, 36))	('UVM', 'Disease', (183, 186))	('GNAQ', 'Gene', (7, 11))	('Mutant', 'Var', (0, 6))	('YAP', 'Gene', '10413', (59, 62))	('UVM', 'Phenotype', 'HP:0007716', (183, 186))
149325	31848373	In MYC-driven cancers, MYC deregulation affects gene expression, DNA replication, or repair processes, leading to oncogenic proliferation.	('cancers', 'Disease', (14, 21))	('oncogenic proliferation', 'CPA', (114, 137))	('MYC', 'Gene', (3, 6))	('deregulation', 'Var', (27, 39))	('repair processes', 'CPA', (85, 101))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('affects', 'Reg', (40, 47))	('gene expression', 'biological_process', 'GO:0010467', ('48', '63'))	('DNA replication', 'CPA', (65, 80))	('MYC', 'Gene', '4609', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('MYC', 'Gene', '4609', (3, 6))	('MYC', 'Gene', (23, 26))	('gene expression', 'MPA', (48, 63))	('leading to', 'Reg', (103, 113))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('DNA replication', 'biological_process', 'GO:0006260', ('65', '80'))
149327	31848373	Emerging data have shown that MYC activation confers chemoresistance to cancer cells treated with BRAF, MEK, KRAS, or BET inhibitors.	('BET', 'Gene', '92737', (118, 121))	('MYC', 'Gene', '4609', (30, 33))	('chemoresistance', 'CPA', (53, 68))	('BET', 'Gene', (118, 121))	('BRAF', 'Gene', (98, 102))	('inhibitors', 'Var', (122, 132))	('BRAF', 'Gene', '673', (98, 102))	('KRAS', 'Gene', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('MEK', 'Gene', (104, 107))	('MEK', 'Gene', '5609', (104, 107))	('KRAS', 'Gene', '3845', (109, 113))	('activation', 'PosReg', (34, 44))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('MYC', 'Gene', (30, 33))	('cancer', 'Disease', (72, 78))
149329	31848373	Importantly, MYC copy number gain was associated with aggressive pathological features and poor survival outcomes in UVM patients.	('UVM', 'Phenotype', 'HP:0007716', (117, 120))	('UVM', 'Disease', (117, 120))	('MYC', 'Gene', '4609', (13, 16))	('copy number gain', 'Var', (17, 33))	('patients', 'Species', '9606', (121, 129))	('MYC', 'Gene', (13, 16))
149330	31848373	Because MYC deregulation is observed in multiple human cancers and associated with poor prognoses, there have been intense research efforts to develop treatments that target MYC.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('cancers', 'Disease', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('human', 'Species', '9606', (49, 54))	('MYC', 'Gene', '4609', (174, 177))	('MYC', 'Gene', (8, 11))	('deregulation', 'Var', (12, 24))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('MYC', 'Gene', '4609', (8, 11))	('MYC', 'Gene', (174, 177))
149339	31848373	Considering the Harrell's C indices for MYC copy number gain and BAP1 mutation, we think that both factors affect survival outcomes of uveal melanoma patients independently.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('affect', 'Reg', (107, 113))	('BAP1', 'Gene', '8314', (65, 69))	('MYC', 'Gene', '4609', (40, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (135, 149))	('copy number', 'Var', (44, 55))	('gain', 'PosReg', (56, 60))	('uveal melanoma', 'Disease', (135, 149))	('BAP1', 'Gene', (65, 69))	('uveal melanoma', 'Phenotype', 'HP:0007716', (135, 149))	('patients', 'Species', '9606', (150, 158))	('MYC', 'Gene', (40, 43))	('mutation', 'Var', (70, 78))
149340	31848373	Interestingly, some cases showed BAP1 mutation in primary tumors, but not in metastases, while high 8q copy number was detected in these metastases.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('metastases', 'Disease', (77, 87))	('BAP1', 'Gene', '8314', (33, 37))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('BAP1', 'Gene', (33, 37))	('metastases', 'Disease', (137, 147))	('mutation', 'Var', (38, 46))	('metastases', 'Disease', 'MESH:D009362', (77, 87))
149341	31848373	Considering that MYC is located at the 8q24 locus, it is possible that the MYC copy number gain is associated with 8q gains in metastatic UVM.	('MYC', 'Gene', (17, 20))	('MYC', 'Gene', '4609', (75, 78))	('gains', 'PosReg', (118, 123))	('MYC', 'Gene', '4609', (17, 20))	('metastatic UVM', 'Disease', (127, 141))	('MYC', 'Gene', (75, 78))	('copy number', 'Var', (79, 90))	('gain', 'PosReg', (91, 95))	('UVM', 'Phenotype', 'HP:0007716', (138, 141))
149345	31848373	Based on the present study, we expect that WEE1 inhibition will ameliorate intrinsic chemoresistance and increase the survival of metastatic UVM patients.	('patients', 'Species', '9606', (145, 153))	('WEE1', 'Gene', '7465', (43, 47))	('inhibition', 'Var', (48, 58))	('increase', 'PosReg', (105, 113))	('ameliorate', 'PosReg', (64, 74))	('survival', 'CPA', (118, 126))	('WEE1', 'Gene', (43, 47))	('metastatic UVM', 'Disease', (130, 144))	('intrinsic chemoresistance', 'CPA', (75, 100))	('UVM', 'Phenotype', 'HP:0007716', (141, 144))
149349	31848373	Whole exome sequencing data (Mutation Packager Oncotated Calls; downloaded from https://gdac.broadinstitute.org) were used for identification of SNVs, DNVs, insertions, and deletions.	('insertions', 'Var', (157, 167))	('SNVs', 'Var', (145, 149))	('SNV', 'Chemical', '-', (145, 148))	('DNVs', 'Var', (151, 155))	('DNV', 'Chemical', '-', (151, 154))	('deletions', 'Var', (173, 182))
149365	31848373	performed the cell viability tests using multiple cancer cells; Y.J.K., S.C.L.	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('Y.J.K.', 'Var', (64, 70))
149366	31146482	PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma Uveal melanoma (UM) remains without effective therapy at the metastatic stage, which is associated with BAP-1 (BRCA1 associated protein) mutations.	('mutations', 'Var', (210, 219))	('BRCA1 associated protein', 'Gene', '8315', (184, 208))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('Melanoma', 'Disease', (64, 72))	('BRCA1 associated protein', 'Gene', (184, 208))	('Increases', 'PosReg', (16, 25))	('Melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (73, 87))	('Inhibition', 'NegReg', (5, 15))	('BAP-1', 'Gene', '8314', (177, 182))	('BAP-1', 'Gene', (177, 182))	('Response to Chemotherapy', 'MPA', (30, 54))	('PARP', 'Gene', '142', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))	('protein', 'cellular_component', 'GO:0003675', ('201', '208'))	('PARP', 'Gene', (0, 4))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('Melanoma', 'Disease', 'MESH:D008545', (64, 72))
149380	31146482	Another recurrent mutation in UM is the bap1 (BRCA1-associated protein 1) gene mutation, which is associated with a higher risk of metastases.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('metastases', 'Disease', (131, 141))	('bap1', 'Gene', '8314', (40, 44))	('metastases', 'Disease', 'MESH:D009362', (131, 141))	('mutation', 'Var', (79, 87))	('BRCA1-associated protein 1', 'Gene', '8314', (46, 72))	('bap1', 'Gene', (40, 44))	('associated', 'Reg', (98, 108))	('BRCA1-associated protein 1', 'Gene', (46, 72))
149381	31146482	Sporadic germline bap1 mutations confer a predisposition to several types of cancer, including UM, confirming its role in tumorigenesis.	('predisposition', 'Reg', (42, 56))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mutations', 'Var', (23, 32))	('bap1', 'Gene', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', (122, 127))	('bap1', 'Gene', '8314', (18, 22))
149390	31146482	PARPs play an important role in various cellular processes and notably in DNA repair by base-excision repair (BER) and nucleotide excision repair (NER).	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('DNA', 'Disease', (74, 77))	('nucleotide excision repair', 'MPA', (119, 145))	('PARP', 'Gene', (0, 4))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('119', '145'))	('base-excision', 'Var', (88, 101))	('DNA repair', 'biological_process', 'GO:0006281', ('74', '84'))	('NER', 'biological_process', 'GO:0006289', ('147', '150'))	('base-excision repair', 'biological_process', 'GO:0006284', ('88', '108'))	('BER', 'biological_process', 'GO:0006284', ('110', '113'))	('PARP', 'Gene', '142', (0, 4))
149404	31146482	Similarly, we studied protein expression of the p116 uncleaved PARP, the two p25 and p89 cleavage products of PARPs, and the two corresponding ratios cleaved/uncleaved PARPs, using RPPA.	('PARP', 'Gene', '142', (63, 67))	('p116 uncleaved', 'Var', (48, 62))	('p89', 'Gene', '10989', (85, 88))	('PARP', 'Gene', (63, 67))	('p25', 'Gene', '8851', (77, 80))	('PARP', 'Gene', (168, 172))	('PARP', 'Gene', (110, 114))	('p89', 'Gene', (85, 88))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('p25', 'Gene', (77, 80))	('PARP', 'Gene', '142', (168, 172))	('PARP', 'Gene', '142', (110, 114))
149405	31146482	Patient's tumors (P0) and corresponding PDXs at various in vivo passages (P1, P4, and P9) were studied (ten pairs P0-P1 or P0-P4, four pairs P0-P9, 13 pairs P1-P4, and six pairs P4-P9).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('P0-P4', 'Var', (123, 128))	('P0-P9', 'Var', (141, 146))	('tumors', 'Disease', (10, 16))	('P4, and P9', 'Gene', '201780;11340', (78, 88))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('P0-P1', 'Var', (114, 119))	('Patient', 'Species', '9606', (0, 7))	('P1-P4', 'Var', (157, 162))
149414	31146482	Six models (MP41, MP55, MP77, MM33, MM52, and MM66) were treated with the olaparib + DTIC combination (Figure 3).	('MM52', 'Var', (36, 40))	('MM33', 'Var', (30, 34))	('MP77', 'Var', (24, 28))	('MM66', 'CellLine', 'CVCL:4D17', (46, 50))	('DTIC', 'Chemical', 'MESH:D003606', (85, 89))	('MP55', 'Var', (18, 22))	('olaparib', 'Chemical', 'MESH:C531550', (74, 82))	('MM66', 'Var', (46, 50))
149420	31146482	Among the six PDXs that received the olaparib + DTIC combination, four of them were included in the RPPA study, i.e., MP55, MP77, MM33, and MM52.	('DTIC', 'Chemical', 'MESH:D003606', (48, 52))	('MP55', 'Var', (118, 122))	('MM33', 'Var', (130, 134))	('MP77', 'Var', (124, 128))	('MM52', 'Var', (140, 144))	('olaparib', 'Chemical', 'MESH:C531550', (37, 45))
149422	31146482	Overall, the combination of olaparib + DTIC showed an additive effect in three models (MP55, MP77, MM33), while the fourth did not (MM52), with a total number of 15 and seven tumors in the two respective groups.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('MM33', 'Var', (99, 103))	('olaparib', 'Chemical', 'MESH:C531550', (28, 36))	('DTIC', 'Chemical', 'MESH:D003606', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('MP77', 'Var', (93, 97))
149424	31146482	For this, we defined proteins whose expression are predictive for response to DTIC alone (MP55, MP77, and MM52), olaparib alone (MM33), and DTIC + olaparib (MP55, MP77, and MM33) in the untreated (control) mice.	('DTIC + olaparib', 'Chemical', '-', (140, 155))	('olaparib', 'Chemical', 'MESH:C531550', (147, 155))	('mice', 'Species', '10090', (206, 210))	('DTIC', 'Chemical', 'MESH:D003606', (78, 82))	('MM52', 'Var', (106, 110))	('MP77', 'Var', (96, 100))	('DTIC', 'Chemical', 'MESH:D003606', (140, 144))	('expression', 'MPA', (36, 46))	('olaparib', 'Chemical', 'MESH:C531550', (113, 121))
149437	31146482	This result suggests that DTIC does not only induce DNA damage but might also exert an antitumor effect through YAP phosphorylation.	('induce', 'Reg', (45, 51))	('phosphorylation', 'biological_process', 'GO:0016310', ('116', '131'))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('YAP', 'Gene', '10413', (112, 115))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('DTIC', 'Chemical', 'MESH:D003606', (26, 30))	('DTIC', 'Var', (26, 30))	('tumor', 'Disease', (91, 96))	('DNA damage', 'MPA', (52, 62))	('YAP', 'Gene', (112, 115))
149443	31146482	An additive activity of PARP inhibitor combined with chemotherapeutic agents has already been reported, even in the absence of BRCA1/2 mutation, for the isoquinoline alkylating agent trabectedin, camptothecins, and, of course, temozolomide/dacarbazine.	('BRCA1', 'Gene', '672', (127, 132))	('isoquinoline', 'Chemical', 'MESH:C039109', (153, 165))	('trabectedin', 'Chemical', 'MESH:D000077606', (183, 194))	('PARP', 'Gene', (24, 28))	('BRCA1', 'Gene', (127, 132))	('temozolomide', 'Chemical', 'MESH:D000077204', (227, 239))	('camptothecins', 'Chemical', 'MESH:D002166', (196, 209))	('isoquinoline', 'MPA', (153, 165))	('dacarbazine', 'Chemical', 'MESH:D003606', (240, 251))	('PARP', 'Gene', '142', (24, 28))	('mutation', 'Var', (135, 143))
149446	31146482	However, among our three models that show an additive effect between olaparib and DTIC, only one (MP55) had a detectable BAP1 mutation (Table S10).	('BAP1', 'Gene', '8314', (121, 125))	('olaparib', 'Chemical', 'MESH:C531550', (69, 77))	('mutation', 'Var', (126, 134))	('BAP1', 'Gene', (121, 125))	('DTIC', 'Chemical', 'MESH:D003606', (82, 86))
149449	31146482	Several studies have indeed reported the absence of nuclear BAP1 protein despite the presence of a wild-type gene and normal mRNA levels, suggesting that post-translational regulation, for example by miR31, can also induce functional BAP1 deficiency.	('BAP1', 'Gene', (234, 238))	('miR31', 'Gene', (200, 205))	('induce', 'Reg', (216, 222))	('functional BAP1 deficiency', 'Disease', 'OMIM:608852', (223, 249))	('regulation', 'biological_process', 'GO:0065007', ('173', '183'))	('BAP1', 'Gene', '8314', (60, 64))	('functional BAP1 deficiency', 'Disease', (223, 249))	('miR31', 'Gene', '407035', (200, 205))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('BAP1', 'Gene', '8314', (234, 238))	('BAP1', 'Gene', (60, 64))	('post-translational', 'Var', (154, 172))
149450	31146482	However, this type of regulation does not seem to be at play in our models, since BAP1 mutation status and IHC staining are concordant.	('mutation', 'Var', (87, 95))	('regulation', 'biological_process', 'GO:0065007', ('22', '32'))	('BAP1', 'Gene', '8314', (82, 86))	('BAP1', 'Gene', (82, 86))
149455	31146482	High PARP expression has already been identified as being predictive for the synergy between olaparib and the alkylating agent trabectedin.	('synergy', 'MPA', (77, 84))	('PARP', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('PARP', 'Gene', '142', (5, 9))	('olaparib', 'Chemical', 'MESH:C531550', (93, 101))	('trabectedin', 'Chemical', 'MESH:D000077606', (127, 138))
149460	31146482	It was previously reported that GNAQ/GNA11 mutations induce dephosphorylation and thus nuclear accumulation of the YAP protein, both through a Hippo-independent and a Hippo-dependent pathway.	('GNAQ', 'Gene', (32, 36))	('YAP', 'Gene', '10413', (115, 118))	('GNA11', 'Gene', '2767', (37, 42))	('nuclear accumulation', 'MPA', (87, 107))	('GNA11', 'Gene', (37, 42))	('GNAQ', 'Gene', '2776', (32, 36))	('mutations', 'Var', (43, 52))	('induce', 'Reg', (53, 59))	('YAP', 'Gene', (115, 118))	('dephosphorylation', 'MPA', (60, 77))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('dephosphorylation', 'biological_process', 'GO:0016311', ('60', '77'))
149465	31146482	Eleven PDXs representative of the UM disease were used, five obtained from primary intraocular tumors (MP34, MP41, MP42, MP55, and MP77), five from liver metastatic tumor samples (MM26, MM52, MM66, MM224, and MM252), and one from cutaneous metastasis (MM33).	('MM66', 'Var', (192, 196))	('MP34', 'Var', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('MP77', 'Var', (131, 135))	('MM66', 'CellLine', 'CVCL:4D17', (192, 196))	('MP42', 'Var', (115, 119))	('MP55', 'Var', (121, 125))	('MM26', 'CellLine', 'CVCL:L791', (180, 184))	('MM26', 'Var', (180, 184))	('MM252', 'Var', (209, 214))	('MM224', 'Var', (198, 203))	('primary intraocular tumors', 'Disease', 'MESH:D064090', (75, 101))	('primary intraocular tumors', 'Disease', (75, 101))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('MP41', 'Var', (109, 113))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
149468	31146482	Five different targeted therapies were used, the mTORC1 inhibitor everolimus (RAD001, Certican ) (Novartis, Basel, Switzerland), the pan-PKC inhibitor AEB071 (provided from Novartis), the MDM2 inhibitor CGM097 (provided from Novartis), the ATM inhibitor AZD0156 (provided from Astra-Zeneca), and the ATR inhibitor AZD6738 (provided from Astra-Zeneca).	('MDM2', 'Gene', '4193', (188, 192))	('PKC', 'molecular_function', 'GO:0004697', ('137', '140'))	('AEB071', 'Var', (151, 157))	('ATM', 'Gene', (240, 243))	('mTORC1', 'cellular_component', 'GO:0031931', ('49', '55'))	('everolimus', 'Chemical', 'MESH:D000068338', (66, 76))	('PKC', 'Gene', '112476', (137, 140))	('ATR', 'Gene', (300, 303))	('PKC', 'Gene', (137, 140))	('mTORC1', 'Gene', (49, 55))	('RAD', 'biological_process', 'GO:1990116', ('78', '81'))	('mTORC1', 'Gene', '382056', (49, 55))	('ATM', 'Gene', '472', (240, 243))	('MDM2', 'Gene', (188, 192))	('AZD6738', 'Chemical', 'MESH:C000611951', (314, 321))	('CGM097', 'Chemical', 'MESH:C000602644', (203, 209))	('ATR', 'Gene', '545', (300, 303))	('AEB071', 'Chemical', 'MESH:C543528', (151, 157))	('AZD0156', 'Chemical', '-', (254, 261))
149486	31146482	(ii) A second one on four to six tumors per group obtained at the end of four in vivo experiments evaluating the olaparib + DTIC combination (MP55, MP77, MM33, and MM52 PDXs).	('DTIC', 'Chemical', 'MESH:D003606', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('MM33', 'Var', (154, 158))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('MP55', 'Var', (142, 146))	('MP77', 'Var', (148, 152))	('olaparib', 'Chemical', 'MESH:C531550', (113, 121))
149494	31146482	Immunohistochemical analyses were performed for the following pathways: Apoptosis and cell proliferation (caspase 3, cleaved-caspase 3, PARP, cleaved PARP, p-H2AX, and Ki67), the MAPK pathway (MEK1/2, p-MEK1/2, ERK, and p-ERK), the Pi3K pathway (AKT, p-AKT, S6, and p-S6), and the Hippo-related pathway (YAP and TAZ proteins).	('PARP', 'Gene', (150, 154))	('YAP', 'Gene', '10413', (304, 307))	('ERK', 'Gene', (211, 214))	('AKT', 'Gene', (253, 256))	('AKT', 'Gene', '207', (246, 249))	('p-S6', 'Gene', '338413', (266, 270))	('p-S6', 'Gene', (266, 270))	('ERK', 'molecular_function', 'GO:0004707', ('211', '214'))	('p-H2AX', 'Var', (156, 162))	('MEK1', 'molecular_function', 'GO:0004708', ('203', '207'))	('Hippo-related pathway', 'Pathway', (281, 302))	('TAZ', 'Gene', '6901', (312, 315))	('caspase 3', 'Gene', (125, 134))	('TAZ', 'Gene', (312, 315))	('caspase 3', 'Gene', '836', (125, 134))	('cleaved', 'Var', (142, 149))	('AKT', 'Gene', '207', (253, 256))	('ERK', 'Gene', '5594', (222, 225))	('cell proliferation', 'biological_process', 'GO:0008283', ('86', '104'))	('cell proliferation', 'CPA', (86, 104))	('PARP', 'Gene', '142', (136, 140))	('YAP', 'Gene', (304, 307))	('ERK', 'molecular_function', 'GO:0004707', ('222', '225'))	('Pi3K', 'molecular_function', 'GO:0016303', ('232', '236'))	('MAPK', 'molecular_function', 'GO:0004707', ('179', '183'))	('p-MEK1/2', 'Var', (201, 209))	('Apoptosis', 'CPA', (72, 81))	('ERK', 'Gene', '5594', (211, 214))	('MEK1', 'molecular_function', 'GO:0004708', ('193', '197'))	('PARP', 'Gene', (136, 140))	('MEK1/2', 'Var', (193, 199))	('AKT', 'Gene', (246, 249))	('ERK', 'Gene', (222, 225))	('PARP', 'Gene', '142', (150, 154))	('Pi3K pathway', 'Pathway', (232, 244))	('caspase 3', 'Gene', (106, 115))	('MAPK pathway', 'Pathway', (179, 191))	('caspase 3', 'Gene', '836', (106, 115))
149503	31146482	P.M., N.C., S.P.-N. and S.P.-R. provided patient material for PDX development, clinical insight and critical feedback.	('S.P.-R.', 'Var', (24, 31))	('S.P.-N.', 'Var', (12, 19))	('patient', 'Species', '9606', (41, 48))
149516	31248118	The variance in melanin expressing uveal melanocytes is associated with the occurrence of various ocular diseases, including age-related macular degeneration and uveal melanoma.	('melanin', 'Chemical', 'MESH:D008543', (16, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (162, 176))	('uveal melanoma', 'Disease', (162, 176))	('uveal melanoma', 'Disease', 'MESH:C536494', (162, 176))	('ocular diseases', 'Disease', 'MESH:D005128', (98, 113))	('variance', 'Var', (4, 12))	('macular degeneration', 'Phenotype', 'HP:0000608', (137, 157))	('age-related macular degeneration', 'Disease', (125, 157))	('associated', 'Reg', (56, 66))	('ocular diseases', 'Disease', (98, 113))	('ocular diseases', 'Phenotype', 'HP:0000478', (98, 113))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))
149519	31248118	The majority of CM cases harbor mutations in proteins associated with the mitogen-activated protein kinase (MAPK) pathway.	('proteins', 'Protein', (45, 53))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('CM', 'Gene', '69865', (16, 18))	('mutations', 'Var', (32, 41))	('CM', 'Phenotype', 'HP:0012056', (16, 18))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))
149521	31248118	BRAF kinase mutations are present in 40-60% of the CM patients, 97% of which is located in codon 600.	('CM', 'Gene', '69865', (51, 53))	('patients', 'Species', '9606', (54, 62))	('mutations', 'Var', (12, 21))	('BRAF', 'Gene', '673', (0, 4))	('CM', 'Phenotype', 'HP:0012056', (51, 53))	('BRAF', 'Gene', (0, 4))
149524	31248118	The second most common MAPK pathway aberration in CM is mutated NRAS, occurring in 15-30% of patients (Figure 1).	('MAPK', 'molecular_function', 'GO:0004707', ('23', '27'))	('mutated', 'Var', (56, 63))	('NRAS', 'Gene', (64, 68))	('CM', 'Gene', '69865', (50, 52))	('MAPK pathway', 'Pathway', (23, 35))	('NRAS', 'Gene', '4893', (64, 68))	('CM', 'Phenotype', 'HP:0012056', (50, 52))	('patients', 'Species', '9606', (93, 101))
149525	31248118	Melanoma with mutations in the stem cell factor receptor tyrosine kinase gene (KIT) represents a relatively rare subset, seen in roughly 20% of mucosal, acral, and chronically sun-damaged skin.	('sun-damaged', 'Phenotype', 'HP:0000992', (176, 187))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('receptor tyrosine kinase', 'Gene', (48, 72))	('receptor tyrosine kinase', 'Gene', '5979', (48, 72))	('Melanoma', 'Disease', (0, 8))	('stem cell factor', 'molecular_function', 'GO:0005173', ('31', '47'))	('mutations', 'Var', (14, 23))	('KIT', 'Gene', (79, 82))	('KIT', 'molecular_function', 'GO:0005020', ('79', '82'))
149526	31248118	The discovery that many CM are caused by a mutation in BRAF kinase has led to the development of selective inhibitors of the BRAF V600-mutated kinase (vemurafenib, dabrafenib, and encorafenib) and inhibitors of the downstream MEK kinase (trametinib, cobimetinib, and binimetinib).	('trametinib', 'Chemical', 'MESH:C560077', (238, 248))	('encorafenib', 'Chemical', 'MESH:C000601108', (180, 191))	('CM', 'Gene', '69865', (24, 26))	('vemurafenib', 'Chemical', 'MESH:D000077484', (151, 162))	('mutation', 'Var', (43, 51))	('MEK', 'Gene', (226, 229))	('MEK', 'Gene', '5609', (226, 229))	('binimetinib', 'Chemical', 'MESH:C581313', (267, 278))	('CM', 'Phenotype', 'HP:0012056', (24, 26))	('BRAF', 'Gene', (55, 59))	('cobimetinib', 'Chemical', 'MESH:C574276', (250, 261))	('BRAF', 'Gene', '673', (125, 129))	('dabrafenib', 'Chemical', 'MESH:C561627', (164, 174))	('BRAF', 'Gene', '673', (55, 59))	('BRAF', 'Gene', (125, 129))	('caused by', 'Reg', (31, 40))
149527	31248118	BRAF inhibition results in high response rates in patients with a BRAF V600E or V600K mutation; however, most patients ultimately develop acquired resistance.	('acquired resistance', 'MPA', (138, 157))	('response', 'MPA', (32, 40))	('patients', 'Species', '9606', (50, 58))	('V600K', 'Var', (80, 85))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('BRAF', 'Gene', '673', (0, 4))	('V600K', 'Mutation', 'rs121913227', (80, 85))	('V600E', 'Var', (71, 76))	('BRAF', 'Gene', '673', (66, 70))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', (66, 70))	('patients', 'Species', '9606', (110, 118))	('develop', 'Reg', (130, 137))
149530	31248118	The treatment with KIT inhibitors improved the overall survival of patients with KIT-mutated gastro-intestinal stromal tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('improved', 'PosReg', (34, 42))	('KIT-mutated', 'Var', (81, 92))	('gastro-intestinal stromal tumors', 'Disease', 'MESH:D046152', (93, 125))	('patients', 'Species', '9606', (67, 75))	('KIT', 'molecular_function', 'GO:0005020', ('81', '84'))	('gastro-intestinal stromal tumors', 'Phenotype', 'HP:0100723', (93, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('gastro-intestinal stromal tumors', 'Disease', (93, 125))	('KIT', 'molecular_function', 'GO:0005020', ('19', '22'))
149531	31248118	Following this success, multiple trials have shown that patients with metastatic melanoma harboring a KIT mutation were responsive to therapy with KIT inhibitors imatinib, sunitinib, dasatinib, and nilotinib.	('patients', 'Species', '9606', (56, 64))	('sunitinib', 'Chemical', 'MESH:D000077210', (172, 181))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('imatinib', 'Chemical', 'MESH:D000068877', (162, 170))	('KIT', 'molecular_function', 'GO:0005020', ('147', '150'))	('mutation', 'Var', (106, 114))	('responsive', 'MPA', (120, 130))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('dasatinib', 'Chemical', 'MESH:D000069439', (183, 192))	('KIT', 'Gene', (102, 105))	('KIT', 'molecular_function', 'GO:0005020', ('102', '105'))	('nilotinib', 'Chemical', 'MESH:C498826', (198, 207))
149532	31248118	The response rates in patients with metastatic melanoma are around 20-25%, when all KIT genetic lesions are considered, and reach 35-50% in melanomas with a KIT mutation in exon 11 or 13.	('KIT', 'molecular_function', 'GO:0005020', ('84', '87'))	('melanomas', 'Disease', (140, 149))	('patients', 'Species', '9606', (22, 30))	('KIT', 'molecular_function', 'GO:0005020', ('157', '160'))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('mutation in', 'Var', (161, 172))	('melanomas', 'Disease', 'MESH:D008545', (140, 149))
149533	31248118	Mutations in BRAF V600E occur in 29-50% and mutations in NRAS occur in up to 18% of the patients with a conjunctival melanoma.	('V600E', 'Var', (18, 23))	('BRAF', 'Gene', '673', (13, 17))	('occur', 'Reg', (62, 67))	('NRAS', 'Gene', (57, 61))	('patients', 'Species', '9606', (88, 96))	('BRAF', 'Gene', (13, 17))	('mutations', 'Var', (44, 53))	('conjunctival melanoma', 'Disease', (104, 125))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (104, 125))	('NRAS', 'Gene', '4893', (57, 61))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (104, 125))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
149534	31248118	KIT mutations have only been reported in one conjunctival tumor.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('conjunctival tumor', 'Disease', (45, 63))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('conjunctival tumor', 'Disease', 'MESH:D003230', (45, 63))	('reported', 'Reg', (29, 37))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))
149538	31248118	More than 90% of the UM exhibit a mutation in GNA11 or GNAQ, which activate signaling between G-protein-coupled receptors and downstream effectors as well as upregulate signaling of the MAPK pathway (Figure 1).	('GNA11', 'Gene', '2767', (46, 51))	('MAPK', 'molecular_function', 'GO:0004707', ('186', '190'))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('signaling between', 'MPA', (76, 93))	('MAPK pathway', 'Pathway', (186, 198))	('mutation', 'Var', (34, 42))	('GNAQ', 'Gene', '2776', (55, 59))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('signaling', 'biological_process', 'GO:0023052', ('169', '178'))	('GNA11', 'Gene', (46, 51))	('upregulate', 'PosReg', (158, 168))	('UM', 'Phenotype', 'HP:0007716', (21, 23))	('GNAQ', 'Gene', (55, 59))	('signaling', 'MPA', (169, 178))	('G-protein-coupled receptors', 'Protein', (94, 121))	('activate', 'PosReg', (67, 75))
149539	31248118	These mutations occur mutually exclusive in the majority of uveal melanomas, and are considered an early event in the development of UM.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('uveal melanomas', 'Disease', (60, 75))	('uveal melanomas', 'Phenotype', 'HP:0007716', (60, 75))	('UM', 'Phenotype', 'HP:0007716', (133, 135))	('uveal melanomas', 'Disease', 'MESH:C536494', (60, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('mutations', 'Var', (6, 15))
149540	31248118	Mutations in GNAQ and GNA11 are not associated with a worse prognosis or with the development of metastatic disease.	('GNA11', 'Gene', (22, 27))	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (22, 27))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', '2776', (13, 17))
149543	31248118	They are further distinguished by alterations in either EIF1AX or SF3B1, respectively, with 1A having a lower metastatic rate when compared to 1B.	('metastatic rate', 'CPA', (110, 125))	('SF3B1', 'Gene', (66, 71))	('lower', 'NegReg', (104, 109))	('SF3B1', 'Gene', '23451', (66, 71))	('alterations', 'Var', (34, 45))	('EIF1AX', 'Gene', '1964', (56, 62))	('EIF1AX', 'Gene', (56, 62))
149544	31248118	Class 2 UM is associated with a high metastatic risk and is characterized by a monosomy of chromosome 3, followed by aberrancies in BAP1 expression and global DNA methylation.	('DNA', 'cellular_component', 'GO:0005574', ('159', '162'))	('BAP1', 'Gene', '8314', (132, 136))	('UM', 'Phenotype', 'HP:0007716', (8, 10))	('BAP1', 'Gene', (132, 136))	('metastatic', 'CPA', (37, 47))	('chromosome', 'cellular_component', 'GO:0005694', ('91', '101'))	('monosomy', 'Var', (79, 87))	('DNA methylation', 'biological_process', 'GO:0006306', ('159', '174'))
149545	31248118	As most UM are characterized by mutations in GNAQ or GNA11, therapies that target downstream effectors of these pathways such as MEK, Akt, and protein kinase C (PKC) are being investigated.	('PKC', 'molecular_function', 'GO:0004697', ('161', '164'))	('GNA11', 'Gene', (53, 58))	('MEK', 'Gene', '5609', (129, 132))	('UM', 'Phenotype', 'HP:0007716', (8, 10))	('Akt', 'Gene', '207', (134, 137))	('GNA11', 'Gene', '2767', (53, 58))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('mutations', 'Var', (32, 41))	('GNAQ', 'Gene', (45, 49))	('Akt', 'Gene', (134, 137))	('MEK', 'Gene', (129, 132))	('GNAQ', 'Gene', '2776', (45, 49))
149547	31248118	The loss of BAP1 seems to sensitize UM cell lines to treatment with histone deacetylase (HDAC) inhibitors.	('HDAC', 'Gene', (89, 93))	('histone deacetylase', 'Gene', '9734', (68, 87))	('HDAC', 'Gene', '9734', (89, 93))	('histone deacetylase', 'Gene', (68, 87))	('BAP1', 'Gene', '8314', (12, 16))	('sensitize', 'Reg', (26, 35))	('UM', 'Phenotype', 'HP:0007716', (36, 38))	('BAP1', 'Gene', (12, 16))	('loss', 'Var', (4, 8))
149551	31248118	Inhibition of HDAC was shown to block tumor cell proliferation and differentiation.	('HDAC', 'Gene', (14, 18))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('HDAC', 'Gene', '9734', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('Inhibition', 'Var', (0, 10))	('block', 'NegReg', (32, 37))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))
149589	31248118	Furthermore, chemotaxis of uveal melanoma cells could be inhibited by anti-CXCR4.	('uveal melanoma', 'Phenotype', 'HP:0007716', (27, 41))	('uveal melanoma', 'Disease', (27, 41))	('uveal melanoma', 'Disease', 'MESH:C536494', (27, 41))	('CXCR4', 'molecular_function', 'GO:0038147', ('75', '80'))	('inhibited', 'NegReg', (57, 66))	('anti-CXCR4', 'Var', (70, 80))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('chemotaxis', 'biological_process', 'GO:0006935', ('13', '23'))
149621	31248118	The Class 2B tumors that display a gain in the copy number of chromosome 8q are associated with the increased expression of macrophage-attracting chemokines and a stronger influx of myeloid cells, whereas additional aberrations in BAP1 expression seem to drive T cell infiltration, irrespective of the chromosome 3 status.	('expression of macrophage-attracting chemokines', 'MPA', (110, 156))	('influx of myeloid cells', 'MPA', (172, 195))	('increased', 'PosReg', (100, 109))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('copy number', 'Var', (47, 58))	('chromosome', 'cellular_component', 'GO:0005694', ('62', '72'))	('T cell infiltration', 'CPA', (261, 280))	('BAP1', 'Gene', '8314', (231, 235))	('gain', 'PosReg', (35, 39))	('stronger', 'PosReg', (163, 171))	('drive', 'PosReg', (255, 260))	('BAP1', 'Gene', (231, 235))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('chromosome', 'cellular_component', 'GO:0005694', ('302', '312'))	('aberrations', 'Var', (216, 227))
149638	31248118	This could explain why PD-1 inhibition shows fever side effects and greater antitumor activity than CTLA-4 inhibition.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('fever', 'Phenotype', 'HP:0001945', (45, 50))	('PD-1', 'Gene', (23, 27))	('CTLA-4', 'Gene', (100, 106))	('PD-1', 'Gene', '5133', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('inhibition', 'Var', (28, 38))	('tumor', 'Disease', (80, 85))	('CTLA-4', 'Gene', '1493', (100, 106))
149643	31248118	High mutational burden is predictive of the response to immune checkpoint inhibitors across multiple cancer types.	('multiple cancer', 'Disease', 'MESH:D009369', (92, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('multiple cancer', 'Disease', (92, 107))	('mutational burden', 'Var', (5, 22))
149644	31248118	The neoantigens that derive from these tumor-specific mutations are potential targets for anti-tumor immune responses, as they are foreign to the immune system.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (95, 100))
149665	31248118	One of the pilot trials currently recruiting melanoma patients uses c-Met as a target antigen (NCT03060356).	('c-Met', 'Protein', (68, 73))	('patients', 'Species', '9606', (54, 62))	('NCT03060356', 'Var', (95, 106))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
149672	31248118	Based on the pre-clinical work with anti-CXCR4 and anti-IGF-1R, as well as the first clinical results with a MET/VEGF receptor inhibitor, several treatment options are now (further) investigated in the clinic.	('MET', 'Gene', (109, 112))	('MET', 'Gene', '4233', (109, 112))	('pre', 'molecular_function', 'GO:0003904', ('13', '16'))	('CXCR4', 'molecular_function', 'GO:0038147', ('41', '46'))	('IGF-1R', 'Gene', '3480', (56, 62))	('VEGF', 'Gene', (113, 117))	('VEGF', 'Gene', '7422', (113, 117))	('clinical', 'Species', '191496', (85, 93))	('anti-CXCR4', 'Var', (36, 46))	('IGF-1R', 'Gene', (56, 62))	('clinical', 'Species', '191496', (17, 25))
149679	30816460	Prognostic significance of deregulated microRNAs in uveal melanomas Uveal melanoma (UM) represents the most frequent primary tumor of the eye.	('uveal melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('uveal melanomas', 'Disease', 'MESH:C536494', (52, 67))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (68, 82))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('melanoma', 'Disease', (74, 82))	('tumor', 'Disease', (125, 130))	('deregulated', 'Var', (27, 38))	('uveal melanomas', 'Disease', (52, 67))	('uveal melanomas', 'Phenotype', 'HP:0007716', (52, 67))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('tumor of the eye', 'Phenotype', 'HP:0100012', (125, 141))	('melanoma', 'Disease', (58, 66))
149694	30816460	It is known that light exposure plays an important role in UM development; however, UV-associated mutational spectrum for UM is different from that observed for cutaneous melanoma.	('cutaneous melanoma', 'Disease', (161, 179))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (161, 179))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (161, 179))	('mutational', 'Var', (98, 108))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('UM', 'Phenotype', 'HP:0007716', (122, 124))	('UM', 'Phenotype', 'HP:0007716', (59, 61))
149695	30816460	The molecular mechanisms responsible for the carcinogenesis of UM have been linked with oncogenic mutations involved in cell cycle and apoptosis.	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('cell cycle', 'biological_process', 'GO:0007049', ('120', '130'))	('UM', 'Phenotype', 'HP:0007716', (63, 65))	('mutations', 'Var', (98, 107))	('carcinogenesis', 'Disease', 'MESH:D063646', (45, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))	('carcinogenesis', 'Disease', (45, 59))
149698	30816460	Mutations of the genes GNAQ and GNA11, affecting the RAF/MEK/ERK pathway, have been detected in approximately 45 and 30% of UM cases, respectively.	('affecting', 'Reg', (39, 48))	('GNA11', 'Gene', '2767', (32, 37))	('GNAQ', 'Gene', (23, 27))	('GNA11', 'Gene', (32, 37))	('MEK', 'Gene', '5609', (57, 60))	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('ERK', 'Gene', '5594', (61, 64))	('Mutations', 'Var', (0, 9))	('detected', 'Reg', (84, 92))	('RAF', 'Gene', '22882', (53, 56))	('RAF', 'Gene', (53, 56))	('ERK', 'Gene', (61, 64))	('GNAQ', 'Gene', '2776', (23, 27))	('MEK', 'Gene', (57, 60))	('ERK', 'molecular_function', 'GO:0004707', ('61', '64'))
149700	30816460	The mutation of the BAP1 gene has been also identified in metastatic UM cases.	('BAP1', 'Gene', (20, 24))	('UM', 'Phenotype', 'HP:0007716', (69, 71))	('mutation', 'Var', (4, 12))	('identified', 'Reg', (44, 54))	('BAP1', 'Gene', '8314', (20, 24))	('metastatic UM', 'Disease', (58, 71))
149705	30816460	In particular, several studies have demonstrated that epigenetic modifications, such as miRNA de-regulation, methylation or microbiota composition, play a key role in the regulatory mechanisms of different cellular processes, as well as in the regulation of carcinogenic processes.	('epigenetic modifications', 'Var', (54, 78))	('miR', 'Gene', (88, 91))	('regulation', 'biological_process', 'GO:0065007', ('97', '107'))	('carcinogenic processes', 'Disease', 'MESH:D009385', (258, 280))	('miR', 'Gene', '29116', (88, 91))	('methylation', 'biological_process', 'GO:0032259', ('109', '120'))	('regulation', 'biological_process', 'GO:0065007', ('244', '254'))	('methylation', 'MPA', (109, 120))	('carcinogenic processes', 'Disease', (258, 280))
149746	30816460	The Kaplan-Meier estimate of the OS of the patients with UM revealed that the alterations of the expression levels of 12 miRNAs out of the 20 computationally selected miRNAs were associated with a worse prognosis.	('associated', 'Reg', (179, 189))	('miR', 'Gene', (167, 170))	('patients', 'Species', '9606', (43, 51))	('UM', 'Phenotype', 'HP:0007716', (57, 59))	('expression levels', 'MPA', (97, 114))	('alterations', 'Var', (78, 89))	('miR', 'Gene', '29116', (167, 170))	('miR', 'Gene', (121, 124))	('miR', 'Gene', '29116', (121, 124))
149769	30816460	Among these 25 pathways, the most affected pathways were the Proteoglycans in cancer (hsa05205), Adherens junction (hsa04520), FoxO signaling pathway (hsa04068), Pathways in cancer (hsa05200) and the PI3K-Akt signaling pathway (hsa04151) modulated by 17 miRNAs.	('Akt signaling', 'biological_process', 'GO:0043491', ('205', '218'))	('Akt', 'Gene', (205, 208))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('hsa04520', 'Var', (116, 124))	('PI3K', 'molecular_function', 'GO:0016303', ('200', '204'))	('Akt', 'Gene', '207', (205, 208))	('cancer', 'Disease', (174, 180))	('signaling pathway', 'biological_process', 'GO:0007165', ('132', '149'))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (78, 84))	('signaling pathway', 'biological_process', 'GO:0007165', ('209', '226'))	('hsa04068', 'Var', (151, 159))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('miR', 'Gene', '29116', (254, 257))	('FoxO signaling pathway', 'Pathway', (127, 149))	('hsa04151', 'Var', (228, 236))	('affected', 'Reg', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('miR', 'Gene', (254, 257))	('Adherens junction', 'cellular_component', 'GO:0005912', ('97', '114'))
149770	30816460	Furthermore, Pathways in cancer (hsa05200), the PI3K-Akt signaling pathway (hsa04151) and Proteoglycans in cancer (hsa05205) were the pathways with the highest number of modulated genes (Table III).	('hsa04151', 'Var', (76, 84))	('Akt signaling', 'biological_process', 'GO:0043491', ('53', '66'))	('Akt', 'Gene', '207', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('PI3K', 'molecular_function', 'GO:0016303', ('48', '52'))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('Akt', 'Gene', (53, 56))	('hsa05200', 'Var', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', (107, 113))	('signaling pathway', 'biological_process', 'GO:0007165', ('57', '74'))
149777	30816460	Several genetic and epigenetic alterations have been proposed as good diagnostic and prognostic markers for both cutaneous melanoma and UM; however, these studies were not conclusive in identifying effective biomarkers for all patients and studies on this matter are still ongoing.	('UM', 'Disease', (136, 138))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('epigenetic alterations', 'Var', (20, 42))	('UM', 'Phenotype', 'HP:0007716', (136, 138))	('cutaneous melanoma', 'Disease', (113, 131))	('patients', 'Species', '9606', (227, 235))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (113, 131))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (113, 131))
149784	30816460	These first data are relevant to those reported in literature as other research groups have well characterized the so-called miRNA-506-514 cluster whose alteration is associated with melanocyte transformation and promoting melanoma growth, however contrasting data were generated on this matter.	('alteration', 'Var', (153, 163))	('promoting', 'PosReg', (213, 222))	('associated with', 'Reg', (167, 182))	('miR', 'Gene', '29116', (125, 128))	('melanoma growth', 'Disease', (223, 238))	('melanoma growth', 'Disease', 'MESH:D008545', (223, 238))	('melanocyte transformation', 'CPA', (183, 208))	('miR', 'Gene', (125, 128))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))
149802	30816460	It is clear that the alterations of these pathways were associated with the development of UM, as well as that of other tumors, as demonstrated in other similar studies.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('associated', 'Reg', (56, 66))	('UM', 'Phenotype', 'HP:0007716', (91, 93))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('alterations', 'Var', (21, 32))
149806	30816460	All these data demonstrated that the data mining of the TCGA UVM dataset can provide useful information in order to identify specific miRNAs whose alterations may be predictive of a worse prognosis for patients with UM.	('miR', 'Gene', (134, 137))	('patients', 'Species', '9606', (202, 210))	('miR', 'Gene', '29116', (134, 137))	('UM', 'Phenotype', 'HP:0007716', (216, 218))	('alterations', 'Var', (147, 158))
149821	28823399	Additionally, tumors with a higher proportion of cells expressing nuclear BAP1 had decreased odds of developing metastatic disease in a multivariate model (P=0.042).	('decreased', 'NegReg', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('BAP1', 'Gene', '8314', (74, 78))	('nuclear', 'Var', (66, 73))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('BAP1', 'Gene', (74, 78))
149822	28823399	Metastasis-free survival was significantly longer in uveal melanoma patients with high nuclear BAP1 stain (P=0.004).	('longer', 'PosReg', (43, 49))	('BAP1', 'Gene', (95, 99))	('high nuclear', 'Var', (82, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('uveal melanoma', 'Disease', (53, 67))	('patients', 'Species', '9606', (68, 76))	('uveal melanoma', 'Disease', 'MESH:C536494', (53, 67))	('BAP1', 'Gene', '8314', (95, 99))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('Metastasis-free survival', 'CPA', (0, 24))
149830	28823399	Inactivating mutations in the tumor suppressor BAP1 are strongly associated with metastasis, suggesting that BAP1 may function as a metastasis suppressor in uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))	('Inactivating mutations', 'Var', (0, 22))	('BAP1', 'Gene', '8314', (109, 113))	('associated', 'Reg', (65, 75))	('metastasis', 'Disease', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('BAP1', 'Gene', '8314', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (157, 171))	('uveal melanoma', 'Disease', 'MESH:C536494', (157, 171))	('BAP1', 'Gene', (109, 113))	('tumor', 'Disease', (30, 35))	('BAP1', 'Gene', (47, 51))	('uveal melanoma', 'Disease', (157, 171))
149831	28823399	demonstrated a strong association between BAP1 immunostaining and BAP1 mutation status (sensitivity: 88% and specificity: 97%) in 74 patients with histologically proven uveal melanoma.	('BAP1', 'Gene', '8314', (42, 46))	('BAP1', 'Gene', '8314', (66, 70))	('uveal melanoma', 'Phenotype', 'HP:0007716', (169, 183))	('uveal melanoma', 'Disease', 'MESH:C536494', (169, 183))	('patients', 'Species', '9606', (133, 141))	('BAP1', 'Gene', (42, 46))	('mutation status', 'Var', (71, 86))	('uveal melanoma', 'Disease', (169, 183))	('BAP1', 'Gene', (66, 70))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))
149875	28823399	Significantly lower nuclear BAP1 expression was found in patients with class 2 gene expression profile when compared to those with class 1 tumor (P = 0.001).	('BAP1', 'Gene', '8314', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('gene expression', 'biological_process', 'GO:0010467', ('79', '94'))	('lower', 'NegReg', (14, 19))	('patients', 'Species', '9606', (57, 65))	('BAP1', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('expression', 'MPA', (33, 43))	('class 2 gene expression profile', 'Var', (71, 102))
149880	28823399	Patients with high nuclear BAP1 stain had longer metastasis-free survival than those with low BAP1 stain (P = 0.004, Figure 3).	('BAP1', 'Gene', '8314', (94, 98))	('BAP1', 'Gene', (27, 31))	('longer', 'PosReg', (42, 48))	('metastasis-free survival', 'CPA', (49, 73))	('Patients', 'Species', '9606', (0, 8))	('high nuclear', 'Var', (14, 26))	('BAP1', 'Gene', (94, 98))	('BAP1', 'Gene', '8314', (27, 31))
149881	28823399	The estimated mean time to metastasis was 39.06 +- 7.41 months for low nuclear BAP1 stain and 138.12 +- 16.22 months for high nuclear BAP1 stain.	('BAP1', 'Gene', '8314', (79, 83))	('BAP1', 'Gene', (134, 138))	('low nuclear', 'Var', (67, 78))	('BAP1', 'Gene', (79, 83))	('BAP1', 'Gene', '8314', (134, 138))	('metastasis', 'CPA', (27, 37))
149882	28823399	It has been reported that germline BAP1 mutations measured in peripheral blood are present in approximately 22% (range 8% to 50%) of familial uveal melanomas compared with 2-4% in spontaneously occurring uveal melanoma cases.	('uveal melanoma', 'Disease', 'MESH:C536494', (204, 218))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('familial uveal melanomas', 'Disease', 'MESH:C536494', (133, 157))	('uveal melanoma', 'Phenotype', 'HP:0007716', (142, 156))	('uveal melanoma', 'Disease', 'MESH:C536494', (142, 156))	('uveal melanoma', 'Phenotype', 'HP:0007716', (204, 218))	('uveal melanoma', 'Disease', (204, 218))	('BAP1', 'Gene', '8314', (35, 39))	('mutations', 'Var', (40, 49))	('uveal melanomas', 'Phenotype', 'HP:0007716', (142, 157))	('BAP1', 'Gene', (35, 39))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('familial uveal melanomas', 'Disease', (133, 157))	('melanomas', 'Phenotype', 'HP:0002861', (148, 157))
149883	28823399	However, a higher rate (approximately 47.4%) of somatic BAP1 mutations has been reported in primary uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('BAP1', 'Gene', '8314', (56, 60))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (92, 114))	('mutations', 'Var', (61, 70))	('primary uveal melanoma', 'Disease', (92, 114))	('BAP1', 'Gene', (56, 60))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
149885	28823399	Whole-exome sequencing of metastatic uveal melanoma identified inactivating somatic mutations in BAP1 in 81-84% of metastatic tumors.	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('BAP1', 'Gene', '8314', (97, 101))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('uveal melanoma', 'Disease', 'MESH:C536494', (37, 51))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('BAP1', 'Gene', (97, 101))	('uveal melanoma', 'Disease', (37, 51))	('uveal melanoma', 'Phenotype', 'HP:0007716', (37, 51))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('inactivating', 'Var', (63, 75))
149886	28823399	reported that 77% of uveal melanomas carrying BAP1 mutations developed metastasis.	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))	('mutations', 'Var', (51, 60))	('uveal melanomas', 'Disease', 'MESH:C536494', (21, 36))	('BAP1', 'Gene', '8314', (46, 50))	('uveal melanomas', 'Disease', (21, 36))	('uveal melanomas', 'Phenotype', 'HP:0007716', (21, 36))	('metastasis', 'CPA', (71, 81))	('BAP1', 'Gene', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('developed', 'Reg', (61, 70))	('uveal melanoma', 'Phenotype', 'HP:0007716', (21, 35))
149887	28823399	strongly implicated that progression to metastatic competence of uveal melanomat requires inactivation of BAP1 as a crucial event.	('metastatic competence', 'CPA', (40, 61))	('uveal melanomat', 'Disease', 'MESH:D014603', (65, 80))	('BAP1', 'Gene', (106, 110))	('uveal melanomat', 'Phenotype', 'HP:0007716', (65, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('uveal melanomat', 'Disease', (65, 80))	('BAP1', 'Gene', '8314', (106, 110))	('inactivation', 'Var', (90, 102))
149888	28823399	Patients with tumor predisposition syndrome (TPDS) associated with BAP1 mutation have been reported to have an increased risk for different malignancies, including uveal melanoma.	('malignancies', 'Disease', 'MESH:D009369', (140, 152))	('tumor', 'Disease', (14, 19))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('malignancies', 'Disease', (140, 152))	('Patients', 'Species', '9606', (0, 8))	('BAP1', 'Gene', '8314', (67, 71))	('uveal melanoma', 'Disease', 'MESH:C536494', (164, 178))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('mutation', 'Var', (72, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (164, 178))	('uveal melanoma', 'Disease', (164, 178))	('BAP1', 'Gene', (67, 71))
149890	28823399	TPDS associated with BAP1 mutation is inherited in an autosomal dominant pattern with a high penetrance.	('BAP1', 'Gene', (21, 25))	('BAP1', 'Gene', '8314', (21, 25))	('TPDS', 'Disease', (0, 4))	('mutation', 'Var', (26, 34))
149898	28823399	observed no detectable BAP1 mutations in melanomas with positive nuclear BAP1 staining.	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))	('BAP1', 'Gene', (23, 27))	('BAP1', 'Gene', '8314', (73, 77))	('melanomas', 'Disease', 'MESH:D008545', (41, 50))	('BAP1', 'Gene', (73, 77))	('BAP1', 'Gene', '8314', (23, 27))	('melanomas', 'Disease', (41, 50))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('mutations', 'Var', (28, 37))
149899	28823399	They found a loss of BAP1 immunoreactivity in all of their specimens with a BAP1 mutation regardless of the type of mutation measured with Sanger sequencing, gene dosage and methylation analysis.	('BAP1', 'Gene', (21, 25))	('immunoreactivity', 'MPA', (26, 42))	('BAP1', 'Gene', '8314', (76, 80))	('mutation', 'Var', (81, 89))	('BAP1', 'Gene', (76, 80))	('loss', 'NegReg', (13, 17))	('methylation', 'biological_process', 'GO:0032259', ('174', '185'))	('BAP1', 'Gene', '8314', (21, 25))
149901	28823399	Wild type BAP1 was shown to be preferentially found in the nucleus, whereas mutant BAP1 proteins showed impaired nuclear localization with increased cytoplasmic appearance.	('impaired', 'NegReg', (104, 112))	('nucleus', 'cellular_component', 'GO:0005634', ('59', '66'))	('localization', 'biological_process', 'GO:0051179', ('121', '133'))	('BAP1', 'Gene', (10, 14))	('BAP1', 'Gene', (83, 87))	('mutant', 'Var', (76, 82))	('increased', 'PosReg', (139, 148))	('nuclear localization', 'MPA', (113, 133))	('proteins', 'Protein', (88, 96))	('cytoplasmic', 'MPA', (149, 160))	('BAP1', 'Gene', '8314', (10, 14))	('BAP1', 'Gene', '8314', (83, 87))
149903	28823399	This corresponds to our study of uveal melanoma patients with low nuclear BAP1 immunoreactivity which showed an increased incidence of metastasis.	('metastasis', 'CPA', (135, 145))	('uveal melanoma', 'Disease', 'MESH:C536494', (33, 47))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('uveal melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('uveal melanoma', 'Disease', (33, 47))	('BAP1', 'Gene', '8314', (74, 78))	('low', 'Var', (62, 65))	('patients', 'Species', '9606', (48, 56))	('BAP1', 'Gene', (74, 78))
149907	28823399	demonstrate that BAP1 is necessary for maintenance of melanocyte identity in uveal melanoma cells, and that loss of BAP1 leads to a damaged cell identity and a gain in stem cell-like behavior.	('BAP1', 'Gene', (116, 120))	('loss', 'Var', (108, 112))	('stem cell-like behavior', 'CPA', (168, 191))	('gain', 'PosReg', (160, 164))	('uveal melanoma', 'Disease', 'MESH:C536494', (77, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (77, 91))	('uveal melanoma', 'Disease', (77, 91))	('BAP1', 'Gene', '8314', (17, 21))	('BAP1', 'Gene', '8314', (116, 120))	('damaged cell identity', 'CPA', (132, 153))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('BAP1', 'Gene', (17, 21))
149908	28823399	assumed that BAP1 mutation likely develops later in tumor progression and is of prognostic significance.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('BAP1', 'Gene', (13, 17))	('tumor', 'Disease', (52, 57))	('mutation', 'Var', (18, 26))	('BAP1', 'Gene', '8314', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
149909	28823399	They found BAP1 mutations to be associated with class 2 gene expression profile (P < 0.001), older patient age (P = 0.007) and high metastatic risk in their study population.	('patient', 'Species', '9606', (99, 106))	('BAP1', 'Gene', '8314', (11, 15))	('mutations', 'Var', (16, 25))	('BAP1', 'Gene', (11, 15))	('class 2 gene expression profile', 'MPA', (48, 79))	('associated', 'Reg', (32, 42))	('gene expression', 'biological_process', 'GO:0010467', ('56', '71'))
149915	28823399	Variable BAP1 expression was demonstrated in liver metastases of uveal melanomas, supporting the concept that although BAP1 mutations are important for promoting uveal melanoma metastasis, the BAP1 expression may or may not be lost in the metastases in the liver.	('metastases', 'Disease', 'MESH:D009362', (51, 61))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('BAP1', 'Gene', (9, 13))	('metastases', 'Disease', (51, 61))	('BAP1', 'Gene', (119, 123))	('uveal melanoma', 'Phenotype', 'HP:0007716', (162, 176))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('metastases', 'Disease', 'MESH:D009362', (239, 249))	('uveal melanoma metastasis', 'Disease', (162, 187))	('metastases of uveal melanomas', 'Disease', 'MESH:D009362', (51, 80))	('promoting', 'PosReg', (152, 161))	('BAP1', 'Gene', '8314', (193, 197))	('metastases', 'Disease', (239, 249))	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('mutations', 'Var', (124, 133))	('BAP1', 'Gene', '8314', (9, 13))	('metastases of uveal melanomas', 'Disease', (51, 80))	('BAP1', 'Gene', '8314', (119, 123))	('uveal melanomas', 'Phenotype', 'HP:0007716', (65, 80))	('BAP1', 'Gene', (193, 197))	('uveal melanoma metastasis', 'Disease', 'MESH:C536494', (162, 187))
149916	28823399	However, the present study confirms the importance of BAP1 mutation of the primary tumor cells in the development of metastatic disease.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('BAP1', 'Gene', '8314', (54, 58))	('metastatic disease', 'CPA', (117, 135))	('mutation', 'Var', (59, 67))	('BAP1', 'Gene', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
149920	28823399	Patients with low nuclear BAP1 stain showed an increased chance of metastasis.	('BAP1', 'Gene', (26, 30))	('metastasis', 'CPA', (67, 77))	('Patients', 'Species', '9606', (0, 8))	('BAP1', 'Gene', '8314', (26, 30))	('low', 'Var', (14, 17))
149929	29559831	For instance, L166P and M26I weaken its biological activity.	('M26I', 'Var', (24, 28))	('L166P', 'Var', (14, 19))	('M26I', 'Mutation', 'rs74315351', (24, 28))	('biological activity', 'MPA', (40, 59))	('weaken', 'NegReg', (29, 35))	('L166P', 'Mutation', 'rs28938172', (14, 19))
149933	29559831	DJ-1 may exhibit its anti-oxidative defence through oxidation of Cys-106 to regulate transcription factors instead of removing ROS directly.	('regulate transcription factors', 'MPA', (76, 106))	('anti-oxidative defence', 'MPA', (21, 43))	('ROS', 'Chemical', 'MESH:D017382', (127, 130))	('DJ-1', 'Gene', (0, 4))	('oxidation', 'Var', (52, 61))	('transcription', 'biological_process', 'GO:0006351', ('85', '98'))	('Cys-106', 'Gene', (65, 72))	('Cys', 'Chemical', 'MESH:D003545', (65, 68))
149949	29559831	DJ-1-deficient CECs exhibited a vulnerable response to UV-A irradiation, and the declined in DJ-1 led to activation of caspase-3 and phospho-p53 under the oxidative stress.	('phospho-p53', 'Var', (133, 144))	('activation', 'PosReg', (105, 115))	('caspase-3', 'Gene', '12367', (119, 128))	('oxidative stress', 'Phenotype', 'HP:0025464', (155, 171))	('declined', 'NegReg', (81, 89))	('caspase-3', 'Gene', (119, 128))	('DJ-1', 'Gene', (93, 97))	('response to UV-A', 'biological_process', 'GO:0070141', ('43', '59'))	('DJ-1-deficient', 'Gene', (0, 14))
149956	29559831	Moreover, a single tail vein injection of NaIO3 (an oxidizing reagent) significantly accelerated RPE degeneration in DJ-1 KO mice.	('NaIO3', 'Chemical', 'MESH:C032285', (42, 47))	('RPE degeneration', 'Disease', (97, 113))	('accelerated', 'PosReg', (85, 96))	('NaIO3', 'Var', (42, 47))	('mice', 'Species', '10090', (125, 129))	('RPE degeneration', 'Disease', 'MESH:D009410', (97, 113))	('single tail', 'Phenotype', 'HP:0002825', (12, 23))
149961	29559831	The experiment demonstrated that the cysteine residues of DJ-1, Cys46 and Cys53, were found to be oxidized in aged cataractous human lenses.	('Cys53', 'Var', (74, 79))	('human', 'Species', '9606', (127, 132))	('cataractous', 'Disease', 'MESH:D002386', (115, 126))	('Cys53', 'Chemical', '-', (74, 79))	('Cys46', 'Chemical', '-', (64, 69))	('Cys46', 'Var', (64, 69))	('cysteine', 'Chemical', 'MESH:D003545', (37, 45))	('DJ-1', 'Gene', (58, 62))	('cysteine residues', 'MPA', (37, 54))	('oxidized', 'MPA', (98, 106))	('cataractous', 'Disease', (115, 126))	('cataract', 'Phenotype', 'HP:0000518', (115, 123))
149965	29559831	The disulfide ratio of the Cys46 and Cys53 in an aged human lens is much higher than the controls.	('disulfide', 'Chemical', 'MESH:D004220', (4, 13))	('Cys53', 'Var', (37, 42))	('Cys53', 'Chemical', '-', (37, 42))	('Cys46', 'Chemical', '-', (27, 32))	('disulfide ratio', 'MPA', (4, 19))	('Cys46', 'Var', (27, 32))	('human', 'Species', '9606', (54, 59))	('higher', 'PosReg', (73, 79))
149978	29559831	Genetic ablation of Nrf2 can aggravate irreversible RGCs apoptosis and visual deficits in the murine model.Gene therapy with Nrf2 could reduce RGCs degeneration.	('visual deficits', 'Disease', 'MESH:D014786', (71, 86))	('apoptosis', 'biological_process', 'GO:0006915', ('57', '66'))	('model.Gene therapy', 'Var', (101, 119))	('visual deficits', 'Phenotype', 'HP:0000505', (71, 86))	('reduce', 'NegReg', (136, 142))	('RGCs degeneration', 'Disease', (143, 160))	('visual deficits', 'Disease', (71, 86))	('RGCs degeneration', 'Disease', 'MESH:D009410', (143, 160))	('Nrf2', 'Gene', (125, 129))	('apoptosis', 'biological_process', 'GO:0097194', ('57', '66'))	('murine', 'Species', '10090', (94, 100))
149987	29559831	ASK1 deletion reduced the oxidative stress level and the factors which cause oxidative stress, for instance, TNF-alpha.	('reduced', 'NegReg', (14, 21))	('deletion', 'Var', (5, 13))	('oxidative stress level', 'MPA', (26, 48))	('oxidative stress', 'Phenotype', 'HP:0025464', (77, 93))	('ASK1', 'Gene', '26408', (0, 4))	('ASK1', 'Gene', (0, 4))	('TNF-alpha', 'Gene', '21926', (109, 118))	('TNF-alpha', 'Gene', (109, 118))	('oxidative stress', 'Phenotype', 'HP:0025464', (26, 42))
149988	29559831	ASK1 deletion prevented RGC apoptosis and increased RGC survival in mice model of glaucoma.	('increased', 'PosReg', (42, 51))	('mice', 'Species', '10090', (68, 72))	('deletion', 'Var', (5, 13))	('glaucoma', 'Disease', 'MESH:D005901', (82, 90))	('apoptosis', 'biological_process', 'GO:0097194', ('28', '37'))	('ASK1', 'Gene', (0, 4))	('prevented', 'NegReg', (14, 23))	('apoptosis', 'biological_process', 'GO:0006915', ('28', '37'))	('glaucoma', 'Phenotype', 'HP:0000501', (82, 90))	('RGC survival', 'CPA', (52, 64))	('glaucoma', 'Disease', (82, 90))	('RGC apoptosis', 'CPA', (24, 37))	('ASK1', 'Gene', '26408', (0, 4))
149990	29559831	Under oxidative stress, DJ-1 binds with ASK1 via the Cys-106 and forms the mixed disulfide bonds, which provide cytoprotection in mouse embryonic fibroblast.	('Cys-106', 'Var', (53, 60))	('ASK1', 'Gene', '26408', (40, 44))	('Cys', 'Chemical', 'MESH:D003545', (53, 56))	('binds', 'Interaction', (29, 34))	('DJ-1', 'Gene', (24, 28))	('cytoprotection', 'CPA', (112, 126))	('mixed disulfide bonds', 'MPA', (75, 96))	('oxidative stress', 'Phenotype', 'HP:0025464', (6, 22))	('disulfide', 'Chemical', 'MESH:D004220', (81, 90))	('ASK1', 'Gene', (40, 44))	('mouse', 'Species', '10090', (130, 135))
150005	28665402	Germline BAP1 mutations induce a Warburg effect Carriers of heterozygous germline BAP1 mutations (BAP1+/-) develop cancer.	('BAP1', 'Gene', (98, 102))	('cancer', 'Disease', (115, 121))	('BAP1', 'Gene', (82, 86))	('Warburg', 'MPA', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('BAP1', 'Gene', '8314', (9, 13))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('develop', 'PosReg', (107, 114))	('BAP1', 'Gene', '8314', (98, 102))	('BAP1', 'Gene', '8314', (82, 86))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('mutations', 'Var', (87, 96))
150006	28665402	We studied plasma from 16 BAP1+/- individuals from 2 families carrying different germline BAP1 mutations and 30 BAP1 wild-type (BAP1WT) controls from these same families.	('BAP1', 'Gene', (112, 116))	('BAP1', 'Gene', (26, 30))	('BAP1', 'Gene', '8314', (128, 132))	('BAP1', 'Gene', '8314', (90, 94))	('BAP1', 'Gene', (128, 132))	('BAP1', 'Gene', (90, 94))	('BAP1', 'Gene', '8314', (112, 116))	('mutations', 'Var', (95, 104))	('BAP1', 'Gene', '8314', (26, 30))
150014	28665402	We discovered that inherited heterozygous germline mutations in the BRCA-associated protein 1 (BAP1) gene cause a high rate of mesothelioma and uveal melanoma.	('mesothelioma', 'Disease', (127, 139))	('BAP1', 'Gene', (95, 99))	('BRCA-associated protein 1', 'Gene', (68, 93))	('cause', 'Reg', (106, 111))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('mesothelioma', 'Disease', 'MESH:D008654', (127, 139))	('BAP1', 'Gene', '8314', (95, 99))	('uveal melanoma', 'Disease', 'MESH:C536494', (144, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('germline mutations', 'Var', (42, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (144, 158))	('uveal melanoma', 'Disease', (144, 158))	('BRCA-associated protein 1', 'Gene', '8314', (68, 93))
150015	28665402	Our data, confirmed and expanded by others in several BAP1+/- families across the world, revealed that germline BAP1 mutations in addition to mesothelioma and uveal melanoma, also cause other malignancies.	('BAP1', 'Gene', (112, 116))	('malignancies', 'Disease', 'MESH:D009369', (192, 204))	('mutations', 'Var', (117, 126))	('uveal melanoma', 'Disease', 'MESH:C536494', (159, 173))	('uveal melanoma', 'Phenotype', 'HP:0007716', (159, 173))	('uveal melanoma', 'Disease', (159, 173))	('malignancies', 'Disease', (192, 204))	('BAP1', 'Gene', '8314', (54, 58))	('mesothelioma', 'Disease', (142, 154))	('BAP1', 'Gene', '8314', (112, 116))	('cause', 'Reg', (180, 185))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('BAP1', 'Gene', (54, 58))	('mesothelioma', 'Disease', 'MESH:D008654', (142, 154))
150034	28665402	We analyzed the metabolite profiles of plasma samples from 46 members of two unrelated families carrying different germline BAP1 mutations - the Wisconsin (W) and the Louisiana (L) families - that we have been following and treating for mesothelioma and other malignancies for >10 years.	('malignancies', 'Disease', 'MESH:D009369', (260, 272))	('BAP1', 'Gene', '8314', (124, 128))	('mutations', 'Var', (129, 138))	('mesothelioma', 'Disease', (237, 249))	('BAP1', 'Gene', (124, 128))	('malignancies', 'Disease', (260, 272))	('mesothelioma', 'Disease', 'MESH:D008654', (237, 249))
150035	28665402	A multivariate statistical analysis of the identified metabolites (Table 1), orthogonal partial least squares discriminant analysis (OPLS-DA), revealed a clear and statistically significant separation between BAP1WT and BAP1+/- individuals, both in plasma (OPLS-DA model: R2X=0.208, R2Y(cum)=0.951, Q2(cum)=0.313) (Figure 1a) and in cell extracts (OPLS-DA model: R2X=0.321, R2Y(cum)=0.916, Q2(cum)=0.215) (Figure 1b).	('BAP1', 'Gene', (209, 213))	('R2Y', 'Var', (374, 377))	('BAP1', 'Gene', (220, 224))	('OPLS-', 'Chemical', '-', (257, 262))	('OPLS-', 'Chemical', '-', (348, 353))	('BAP1', 'Gene', '8314', (220, 224))	('BAP1', 'Gene', '8314', (209, 213))	('OPLS-', 'Chemical', '-', (133, 138))
150036	28665402	The OPLS-DA model was not influenced by the year of collection of the samples (Figure 2a) and the age (Figure 2b) or gender (Figure 2c) of the individuals, suggesting that the differences observed in Figure 1a were specifically related to BAP1 status (Figure 2 and Supplementary Figure S1).	('related', 'Reg', (228, 235))	('OPLS-', 'Chemical', '-', (4, 9))	('differences', 'Var', (176, 187))	('BAP1', 'Gene', '8314', (239, 243))	('BAP1', 'Gene', (239, 243))
150037	28665402	To test whether the OPLS-DA model established with the metabolomics data of human subjects with known BAP1 status was able to clearly discriminate among samples from individuals with or without heterozygous germline BAP1 mutations (Figure 2d), we analyzed blindly plasma samples from 76 individuals: 22 BAP1WT, 12 BAP1+/-, 1 individual of the W family with unknown BAP1 status at the time the analysis was performed, and 41 healthy controls not related to the W and L families.	('BAP1', 'Gene', (216, 220))	('BAP1', 'Gene', (102, 106))	('mutations', 'Var', (221, 230))	('OPLS-', 'Chemical', '-', (20, 25))	('BAP1', 'Gene', (303, 307))	('BAP1', 'Gene', '8314', (314, 318))	('BAP1', 'Gene', '8314', (365, 369))	('human', 'Species', '9606', (76, 81))	('BAP1', 'Gene', (314, 318))	('BAP1', 'Gene', '8314', (102, 106))	('BAP1', 'Gene', (365, 369))	('BAP1', 'Gene', '8314', (216, 220))	('BAP1', 'Gene', '8314', (303, 307))
150073	28665402	Next, we silenced BAP1 in wild-type control fibroblasts using siRNAs (siBAP1) to test whether we were able to mimic the same increases in glycolysis and glycolytic capacity.	('BAP1', 'Gene', '8314', (18, 22))	('BAP1', 'Gene', '8314', (72, 76))	('increases', 'PosReg', (125, 134))	('BAP1', 'Gene', (18, 22))	('BAP1', 'Gene', (72, 76))	('glycolytic capacity', 'MPA', (153, 172))	('silenced', 'Var', (9, 17))	('glycolysis', 'biological_process', 'GO:0006096', ('138', '148'))	('glycolysis', 'MPA', (138, 148))
150076	28665402	We also transduced BAP1 in BAP1+/- fibroblasts with adenoviruses for wild-type BAP1 (AdBAP1) or its catalytic inactive mutant carrying the C91S point mutation (AdC91S) or a control adenovirus (AdGFP).	('BAP1', 'Gene', '8314', (87, 91))	('BAP1', 'Gene', '8314', (79, 83))	('BAP1', 'Gene', (27, 31))	('C91S', 'Mutation', 'p.C91S', (139, 143))	('BAP1', 'Gene', '8314', (19, 23))	('BAP1', 'Gene', (87, 91))	('BAP1', 'Gene', (79, 83))	('C91S', 'Var', (139, 143))	('BAP1', 'Gene', (19, 23))	('C91S', 'Mutation', 'p.C91S', (162, 166))	('BAP1', 'Gene', '8314', (27, 31))
150082	28665402	As citrate, a key TCA cycle intermediate, was decreased in carriers of germline BAP1 mutations (Figures 3f and 4d), we sought to determine whether the boost in the glycolytic pathway of energy production observed in BAP1+/- cells was associated with changes in mitochondrial respiration.	('citrate', 'MPA', (3, 10))	('respiration', 'biological_process', 'GO:0045333', ('275', '286'))	('BAP1', 'Gene', (216, 220))	('boost', 'PosReg', (151, 156))	('mitochondrial respiration', 'MPA', (261, 286))	('BAP1', 'Gene', '8314', (80, 84))	('respiration', 'biological_process', 'GO:0007585', ('275', '286'))	('glycolytic pathway of energy production', 'MPA', (164, 203))	('TCA cycle', 'biological_process', 'GO:0006099', ('18', '27'))	('mutations', 'Var', (85, 94))	('TCA', 'Chemical', 'MESH:D014233', (18, 21))	('decreased', 'NegReg', (46, 55))	('BAP1', 'Gene', (80, 84))	('BAP1', 'Gene', '8314', (216, 220))	('citrate', 'Chemical', 'MESH:D019343', (3, 10))
150106	28665402	We discovered that normal primary cells carrying heterozygous germline BAP1 mutations have increased aerobic glycolysis and impaired mitochondrial respiration.	('mitochondrial respiration', 'MPA', (133, 158))	('glycolysis', 'biological_process', 'GO:0006096', ('109', '119'))	('impaired', 'NegReg', (124, 132))	('mutations', 'Var', (76, 85))	('aerobic glycolysis', 'MPA', (101, 119))	('respiration', 'biological_process', 'GO:0007585', ('147', '158'))	('BAP1', 'Gene', '8314', (71, 75))	('increased', 'PosReg', (91, 100))	('BAP1', 'Gene', (71, 75))	('respiration', 'biological_process', 'GO:0045333', ('147', '158'))
150113	28665402	Moreover, similarly altered ECAR and OCR parameters were observed in BAP1WT primary HM cells and fibroblasts silenced for BAP1, indicating that the effects observed are caused by the reduced BAP1 protein levels, independently of donor or cell type.	('OCR', 'Chemical', '-', (37, 40))	('BAP1', 'Gene', (122, 126))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))	('altered', 'Reg', (20, 27))	('BAP1', 'Gene', (69, 73))	('BAP1', 'Gene', '8314', (191, 195))	('donor', 'Species', '9606', (229, 234))	('reduced', 'NegReg', (183, 190))	('BAP1', 'Gene', '8314', (122, 126))	('BAP1', 'Gene', (191, 195))	('silenced', 'Var', (109, 117))	('ECAR', 'MPA', (28, 32))	('BAP1', 'Gene', '8314', (69, 73))
150114	28665402	Therefore, we anticipate that our results are also relevant to the numerous malignancies that carry somatic BAP1 mutations.	('numerous malignancies', 'Disease', 'MESH:D009369', (67, 88))	('BAP1', 'Gene', '8314', (108, 112))	('numerous malignancies', 'Disease', (67, 88))	('BAP1', 'Gene', (108, 112))	('mutations', 'Var', (113, 122))
150117	28665402	Ongoing studies in our laboratory will determine whether the deregulation of intracellular Ca2+ signaling is also responsible for the distinctive metabolic signature of BAP1 mutation carriers.	('intracellular', 'cellular_component', 'GO:0005622', ('77', '90'))	('intracellular Ca2+ signaling', 'MPA', (77, 105))	('signaling', 'biological_process', 'GO:0023052', ('96', '105'))	('mutation', 'Var', (174, 182))	('BAP1', 'Gene', '8314', (169, 173))	('BAP1', 'Gene', (169, 173))	('Ca2+', 'Chemical', 'MESH:D000069285', (91, 95))
150119	28665402	In carriers of germline BAP1 mutations, the presence of a Warburg effect in both the cells that undergo malignant transformation and in the surrounding stromal cells, creates an environment that promotes carcinogenesis and tumor growth.	('carcinogenesis', 'Disease', (204, 218))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('BAP1', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('promotes', 'PosReg', (195, 203))	('carcinogenesis', 'Disease', 'MESH:D063646', (204, 218))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('BAP1', 'Gene', '8314', (24, 28))
150120	28665402	Indeed, in all cell cultures from individuals carrying germline BAP1 mutations, we observed increased levels of extracellular lactate.	('mutations', 'Var', (69, 78))	('levels of extracellular lactate', 'MPA', (102, 133))	('increased levels of extracellular lactate', 'Phenotype', 'HP:0002151', (92, 133))	('germline', 'Var', (55, 63))	('lactate', 'Chemical', 'MESH:D019344', (126, 133))	('increased', 'PosReg', (92, 101))	('BAP1', 'Gene', '8314', (64, 68))	('extracellular', 'cellular_component', 'GO:0005576', ('112', '125'))	('BAP1', 'Gene', (64, 68))
150124	28665402	In summary, our data indicate that the Warburg effect, in addition to being a hallmark of cancer cells, is also found in normal cells from individuals carrying heterozygous germline BAP1 mutations and may contribute to the high incidence of cancer observed among them.	('contribute', 'Reg', (205, 215))	('BAP1', 'Gene', '8314', (182, 186))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('BAP1', 'Gene', (182, 186))	('mutations', 'Var', (187, 196))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('Warburg effect', 'Disease', (39, 53))
150221	27587955	Diffusion-weighted imaging can also be useful for diagnosis of endophthalmitis and typically demonstrates hyperintensity and corresponding reduced apparent diffusion coefficient values in the anterior chamber and/or vitreous.	('apparent diffusion coefficient values', 'MPA', (147, 184))	('endophthalmitis', 'Disease', 'MESH:D009877', (63, 78))	('hyperintensity', 'Var', (106, 120))	('endophthalmitis', 'Disease', (63, 78))	('reduced', 'NegReg', (139, 146))	('/or vitreous', 'Phenotype', 'HP:0100832', (212, 224))
150304	27255356	In the metastatic sub-group the presence of nested CD147 positive cells was correlated with ciliary body involvement (p = 0.042).	('presence', 'Var', (32, 40))	('CD147', 'Gene', '682', (51, 56))	('ciliary body involvement', 'Disease', (92, 116))	('correlated', 'Reg', (76, 86))	('CD147', 'Gene', (51, 56))
150348	27255356	HCC cells with silenced MMP-2 and MMP-9 genes were less invasive compared to MMP-2 and MMP-9 silenced fibroblasts or CD147-silenced HCC cells when co-cultured with fibroblasts.	('MMP-2', 'Gene', (24, 29))	('MMP-2', 'Gene', '4313', (77, 82))	('HCC', 'Phenotype', 'HP:0001402', (0, 3))	('MMP-2', 'molecular_function', 'GO:0004228', ('77', '82'))	('MMP-9', 'molecular_function', 'GO:0004229', ('87', '92'))	('invasive', 'CPA', (56, 64))	('MMP-9', 'Gene', '4318', (34, 39))	('MMP-2', 'Gene', (77, 82))	('MMP-9', 'Gene', (34, 39))	('HCC', 'Phenotype', 'HP:0001402', (132, 135))	('CD147', 'Gene', '682', (117, 122))	('silenced', 'Var', (15, 23))	('MMP-2', 'Gene', '4313', (24, 29))	('MMP-2', 'molecular_function', 'GO:0004228', ('24', '29'))	('MMP-9', 'Gene', '4318', (87, 92))	('MMP-9', 'Gene', (87, 92))	('less', 'NegReg', (51, 55))	('MMP-9', 'molecular_function', 'GO:0004229', ('34', '39'))	('CD147', 'Gene', (117, 122))
150371	27255356	The presence of clustered CD147 in uveal melanomas was significantly associated with tumor stage in the non-metastatic subgroup.	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))	('tumor', 'Disease', (85, 90))	('CD147', 'Gene', '682', (26, 31))	('clustered', 'Var', (16, 25))	('CD147', 'Gene', (26, 31))	('associated', 'Reg', (69, 79))	('uveal melanomas', 'Disease', (35, 50))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('uveal melanomas', 'Phenotype', 'HP:0007716', (35, 50))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('presence', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('uveal melanomas', 'Disease', 'MESH:C536494', (35, 50))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))
150374	25562798	In NSCLC activating somatic mutations in exons encoding the tyrosine kinase domain of the Epidermal Growth Factor Receptor (EGFR) gene have been found to be predictive of a response to treatment with tyrosine kinase inhibitors (TKI), erlotinib or gefitinib.	('NSCLC', 'Disease', (3, 8))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (90, 122))	('gefitinib', 'Chemical', 'MESH:D000077156', (247, 256))	('EGFR', 'Gene', '1956', (124, 128))	('Epidermal Growth Factor', 'molecular_function', 'GO:0005154', ('90', '113'))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('Epidermal Growth Factor Receptor', 'Gene', (90, 122))	('EGFR', 'Gene', (124, 128))	('EGFR', 'molecular_function', 'GO:0005006', ('124', '128'))	('men', 'Species', '9606', (190, 193))	('erlotinib', 'Chemical', 'MESH:D000069347', (234, 243))	('mutations', 'Var', (28, 37))
150376	25562798	Similarly in melanoma, 50% of cases have BRAF mutations in exon 15 mostly V600E and these cases are sensitive to the BRAF inhibitors vemurafenib or dabrafenib.	('V600E', 'Mutation', 'rs113488022', (74, 79))	('dabrafenib', 'Chemical', 'MESH:C561627', (148, 158))	('mutations', 'Var', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('BRAF', 'Gene', '673', (41, 45))	('melanoma', 'Disease', (13, 21))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('V600E', 'Var', (74, 79))	('BRAF', 'Gene', (41, 45))	('BRAF', 'Gene', '673', (117, 121))	('vemurafenib', 'Chemical', 'MESH:D000077484', (133, 144))	('BRAF', 'Gene', (117, 121))
150379	25562798	Resistance to the TKI's in NSCLC is most frequently due to acquisition of secondary mutations within the tyrosine kinase of the EGFR or alternatively activation of alternative tyrosine kinases such as C-MET.	('due', 'Reg', (52, 55))	('C-MET', 'Gene', '4233', (201, 206))	('EGFR', 'molecular_function', 'GO:0005006', ('128', '132'))	('NSCLC', 'Disease', (27, 32))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('activation', 'PosReg', (150, 160))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('mutations', 'Var', (84, 93))	('C-MET', 'Gene', (201, 206))
150380	25562798	Mechanisms of drug resistance in melanoma to vemurafenib do not involve mutations in BRAF itself but are associated with a variety of molecular changes including RAF1 or COT gene over expression, activating mutations in RAS or increased activation of the receptor tyrosine kinase PDGFRbeta.	('PDGFRbeta', 'Gene', (280, 289))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('drug resistance', 'Phenotype', 'HP:0020174', (14, 29))	('RAF1', 'Gene', '5894', (162, 166))	('PDGFRbeta', 'Gene', '5159', (280, 289))	('increased activation', 'PosReg', (227, 247))	('mutations', 'Var', (207, 216))	('RAF1', 'Gene', (162, 166))	('activating', 'PosReg', (196, 206))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('over expression', 'PosReg', (179, 194))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('COT', 'Gene', (170, 173))	('COT', 'Gene', '1326', (170, 173))	('vemurafenib', 'Chemical', 'MESH:D000077484', (45, 56))	('RAS', 'Protein', (220, 223))	('drug resistance', 'biological_process', 'GO:0009315', ('14', '29'))	('drug resistance', 'biological_process', 'GO:0042493', ('14', '29'))	('associated', 'Reg', (105, 115))
150384	25562798	In non-small cell lung cancer (NSCLC), tumors with activating mutations of the EGFR have proved to be exquisitely sensitive to treatment with the EGFR tyrosine kinase inhibitors gefitnib and erlotinib.	('sensitive', 'MPA', (114, 123))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('non-small cell lung cancer', 'Disease', (3, 29))	('tumors', 'Disease', (39, 45))	('NSCLC', 'Disease', (31, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('EGFR', 'molecular_function', 'GO:0005006', ('146', '150'))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('mutations', 'Var', (62, 71))	('EGFR', 'Gene', '1956', (146, 150))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('EGFR', 'Gene', (79, 83))	('erlotinib', 'Chemical', 'MESH:D000069347', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('gefitnib', 'Chemical', '-', (178, 186))	('men', 'Species', '9606', (132, 135))	('activating', 'PosReg', (51, 61))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
150385	25562798	Another subset of tumors molecularly defined by the presence of rearrangements in the anaplastic lymphoma kinase (ALK) gene is similarly susceptible to treatment with crizotinib an oral inhibitor of ALK.	('ALK', 'Gene', '238', (199, 202))	('ALK', 'Gene', '238', (114, 117))	('men', 'Species', '9606', (73, 76))	('crizotinib', 'Chemical', 'MESH:D000077547', (167, 177))	('susceptible', 'Reg', (137, 148))	('anaplastic lymphoma kinase', 'Gene', '238', (86, 112))	('ALK', 'Gene', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (86, 105))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('ALK', 'Gene', (114, 117))	('men', 'Species', '9606', (157, 160))	('anaplastic lymphoma kinase', 'Gene', (86, 112))	('lymphoma', 'Phenotype', 'HP:0002665', (97, 105))	('rearrangements', 'Var', (64, 78))
150395	25562798	Molecular characterization of lung adenocarcinoma have led to the correlation of activating mutations in the Epidermal Growth Factor Receptor (EGFR) with sensitivity to the EGFR tyrosine kinase inhibitors (TKI) gefitinib and erlotinib and also the identification of rearrangements of the ALK gene in distinct subsets of NSCLCs that are highly sensitive to the ALK inhibitor Crizotinib (Figure 1).	('NSCLCs', 'Disease', (320, 326))	('erlotinib', 'Chemical', 'MESH:D000069347', (225, 234))	('EGFR', 'molecular_function', 'GO:0005006', ('173', '177'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (30, 49))	('Crizotinib', 'Chemical', 'MESH:D000077547', (374, 384))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (30, 49))	('EGFR', 'Gene', '1956', (173, 177))	('NSCLCs', 'Disease', 'MESH:D002289', (320, 326))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('ALK', 'Gene', '238', (288, 291))	('EGFR', 'molecular_function', 'GO:0005006', ('143', '147'))	('ALK', 'Gene', (288, 291))	('EGFR', 'Gene', (143, 147))	('ALK', 'Gene', '238', (360, 363))	('ALK', 'Gene', (360, 363))	('mutations', 'Var', (92, 101))	('gefitinib', 'Chemical', 'MESH:D000077156', (211, 220))	('Epidermal Growth Factor Receptor', 'Gene', (109, 141))	('rearrangements', 'Var', (266, 280))	('men', 'Species', '9606', (275, 278))	('Epidermal Growth Factor', 'molecular_function', 'GO:0005154', ('109', '132'))	('lung adenocarcinoma', 'Disease', (30, 49))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (109, 141))	('EGFR', 'Gene', '1956', (143, 147))	('EGFR', 'Gene', (173, 177))	('activating', 'PosReg', (81, 91))
150397	25562798	The first selective orally available EGFR TKIs gefitinib and erlotinib were first used over 10 years ago prior to the discovery of EGFR mutations.	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (131, 135))	('erlotinib', 'Chemical', 'MESH:D000069347', (61, 70))	('mutations', 'Var', (136, 145))	('gefitinib', 'Chemical', 'MESH:D000077156', (47, 56))	('EGFR', 'molecular_function', 'GO:0005006', ('131', '135'))	('EGFR', 'Gene', (37, 41))
150401	25562798	The basis for the sensitivity of this subset of patients was revealed in 2004 when somatic mutations in the EGFR tyrosine kinase domain were described.	('EGFR', 'molecular_function', 'GO:0005006', ('108', '112'))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('mutations', 'Var', (91, 100))	('patients', 'Species', '9606', (48, 56))
150402	25562798	The most common activating mutations are deletions in exon 19 and the L858R point mutation in exon 21 that account for approximately 85% of all activating EGFR mutations.	('EGFR', 'molecular_function', 'GO:0005006', ('155', '159'))	('mutations', 'Var', (160, 169))	('EGFR', 'Gene', '1956', (155, 159))	('activating', 'PosReg', (144, 154))	('L858R', 'Var', (70, 75))	('EGFR', 'Gene', (155, 159))	('deletions', 'Var', (41, 50))	('L858R', 'Mutation', 'rs121434568', (70, 75))	('activating', 'PosReg', (16, 26))
150403	25562798	Less frequent activating mutations including G719S in exon 18 and L861Q in exon 21 have also been described.	('G719S', 'Var', (45, 50))	('L861Q', 'Var', (66, 71))	('G719S', 'Mutation', 'rs28929495', (45, 50))	('L861Q', 'Mutation', 'rs121913444', (66, 71))
150404	25562798	Prospective studies of EGFR TKIs in patients with EGFR mutations have consistently identified high response rates and prolonged progression free survival.	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('patients', 'Species', '9606', (36, 44))	('mutations', 'Var', (55, 64))	('EGFR', 'molecular_function', 'GO:0005006', ('23', '27'))	('EGFR', 'Gene', '1956', (50, 54))	('EGFR', 'Gene', '1956', (23, 27))	('response', 'CPA', (99, 107))	('EGFR', 'Gene', (50, 54))	('EGFR', 'Gene', (23, 27))
150405	25562798	The Spanish Lung Cancer Group screened 2105 patients, to identify 350 patients (15%) with exon 19 deletions and L858R of whom 250 patients went on to receive erlotinib in the first or second-line setting.	('patients', 'Species', '9606', (70, 78))	('Lung Cancer', 'Phenotype', 'HP:0100526', (12, 23))	('exon 19 deletions', 'Var', (90, 107))	('L858R', 'Mutation', 'rs121434568', (112, 117))	('patients', 'Species', '9606', (44, 52))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('patients', 'Species', '9606', (130, 138))	('erlotinib', 'Chemical', 'MESH:D000069347', (158, 167))	('L858R', 'Var', (112, 117))	('deletions', 'Var', (98, 107))
150406	25562798	Six randomized studies have now been reported that demonstrate the superiority of either gefitinib or erlotinib over chemotherapy in NSCLC patients with EGFR mutations.	('gefitinib', 'Chemical', 'MESH:D000077156', (89, 98))	('patients', 'Species', '9606', (139, 147))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))	('erlotinib', 'Chemical', 'MESH:D000069347', (102, 111))	('EGFR', 'Gene', '1956', (153, 157))	('NSCLC', 'Disease', (133, 138))	('EGFR', 'molecular_function', 'GO:0005006', ('153', '157'))	('EGFR', 'Gene', (153, 157))	('mutations', 'Var', (158, 167))
150407	25562798	In one of these studies, the IPASS study; patients with clinical features associated with EGFR mutations were randomized to receive either gefitinib or chemotherapy with carboplatin and paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (186, 196))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('90', '94'))	('EGFR', 'Gene', (90, 94))	('gefitinib', 'Chemical', 'MESH:D000077156', (139, 148))	('mutations', 'Var', (95, 104))	('patients', 'Species', '9606', (42, 50))	('carboplatin', 'Chemical', 'MESH:D016190', (170, 181))
150408	25562798	Those with EGFR mutations had a significantly increased response rate (71.2% vs. 47.3%) and progression free survival (HR = 0.48, 0.36-0.64, p < 0.001) with gefitinib compared with chemotherapy.	('progression free survival', 'CPA', (92, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('11', '15'))	('increased', 'PosReg', (46, 55))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('gefitinib', 'Chemical', 'MESH:D000077156', (157, 166))	('response', 'CPA', (56, 64))
150409	25562798	Notably, in this population with clinical features associated with response to EGFR TKIs, patients without EGFR mutations did significantly worse with geftinib than they did with chemotherapy (median PFS 1.6 months compared with 5.5 months, HR 2.85, p < 0.0001) confirming the importance of selecting therapy based on genotype rather than clinical features.	('EGFR', 'molecular_function', 'GO:0005006', ('107', '111'))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', '1956', (107, 111))	('EGFR', 'Gene', (79, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('EGFR', 'Gene', (107, 111))	('mutations', 'Var', (112, 121))	('geftinib', 'Chemical', '-', (151, 159))	('patients', 'Species', '9606', (90, 98))	('worse', 'NegReg', (140, 145))
150410	25562798	Together these six Phase III studies firmly establish a role for EGFR mutation testing in selecting optimal therapy for newly diagnosed patients with advanced NSCLC.	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('NSCLC', 'Disease', (159, 164))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('patients', 'Species', '9606', (136, 144))	('mutation', 'Var', (70, 78))	('EGFR', 'molecular_function', 'GO:0005006', ('65', '69'))
150412	25562798	Originally identified in an uncommon T-Cell lymphoma called anaplastic large cell lymphoma, rearrangements in the ALK gene were first identified in NSCLC in 2007.	('T-Cell lymphoma', 'Disease', (37, 52))	('T-Cell lymphoma', 'Disease', 'MESH:D016399', (37, 52))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (60, 90))	('ALK', 'Gene', '238', (114, 117))	('lymphoma', 'Phenotype', 'HP:0002665', (44, 52))	('lymphoma', 'Phenotype', 'HP:0002665', (82, 90))	('NSCLC', 'Disease', (148, 153))	('cell lymphoma', 'Disease', 'MESH:D016399', (77, 90))	('cell lymphoma', 'Disease', (77, 90))	('men', 'Species', '9606', (101, 104))	('T-Cell lymphoma', 'Phenotype', 'HP:0012190', (37, 52))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('Cell lymphoma', 'Phenotype', 'HP:0012191', (39, 52))	('ALK', 'Gene', (114, 117))	('rearrangements', 'Var', (92, 106))	('cell lymphoma', 'Phenotype', 'HP:0012191', (77, 90))
150414	25562798	Different EML4-ALK variants containing variable portions of the EML4 gene consistently fused to exon 20 of the ALK gene have been identified as have other rare fusion partners including TFG and KIF5B.	('KIF5B', 'Gene', '3799', (194, 199))	('ALK', 'Gene', (15, 18))	('EML4', 'Gene', (64, 68))	('EML4', 'Gene', '27436', (64, 68))	('ALK', 'Gene', '238', (111, 114))	('EML4', 'Gene', (10, 14))	('ALK', 'Gene', '238', (15, 18))	('TFG', 'Gene', '10342', (186, 189))	('KIF5B', 'Gene', (194, 199))	('EML4', 'Gene', '27436', (10, 14))	('TFG', 'Gene', (186, 189))	('variants', 'Var', (19, 27))	('ALK', 'Gene', (111, 114))
150415	25562798	Preclinical data indicate that ALK rearrangements were transforming both in vitro and in vivo and conferred sensitivity to ALK inhibitors indicating their potential as a therapeutic target.	('ALK', 'Gene', '238', (31, 34))	('ALK', 'Gene', (123, 126))	('rearrangements', 'Var', (35, 49))	('ALK', 'Gene', (31, 34))	('sensitivity', 'MPA', (108, 119))	('men', 'Species', '9606', (44, 47))	('ALK', 'Gene', '238', (123, 126))
150417	25562798	These rearrangements are almost always mutually exclusive with EGFR mutations or KRAS mutations.	('EGFR', 'Gene', '1956', (63, 67))	('KRAS', 'Gene', '3845', (81, 85))	('EGFR', 'Gene', (63, 67))	('men', 'Species', '9606', (15, 18))	('KRAS', 'Gene', (81, 85))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('mutations', 'Var', (68, 77))
150421	25562798	Two Phase III studies, in the first line and the second line comparing crizotinib to standard chemotherapy are ongoing ((NCT00932893 and NCT01154140).	('(NCT00932893', 'Var', (120, 132))	('NCT01154140', 'Var', (137, 148))	('crizotinib', 'Chemical', 'MESH:D000077547', (71, 81))
150422	25562798	While there are several methods that have been used to detect ALK rearrangements in tumor tissue including immunohistochemistry, fluorescent in-situ hybridization (FISH) and reverse transcriptase polymerase chain reaction, FISH testing was used as a companion diagnostic to identify patients for the crizotinib trials and has emerged as the gold standard method to identify ALK gene rearrangements and is the only FDA approved test for this purpose.	('ALK', 'Gene', '238', (374, 377))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('transcriptase', 'molecular_function', 'GO:0003968', ('182', '195'))	('men', 'Species', '9606', (392, 395))	('rearrangements', 'Var', (66, 80))	('patients', 'Species', '9606', (283, 291))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('ALK', 'Gene', (62, 65))	('transcriptase', 'molecular_function', 'GO:0034062', ('182', '195'))	('tumor', 'Disease', (84, 89))	('men', 'Species', '9606', (75, 78))	('ALK', 'Gene', (374, 377))	('ALK', 'Gene', '238', (62, 65))	('crizotinib', 'Chemical', 'MESH:D000077547', (300, 310))	('transcriptase', 'molecular_function', 'GO:0003899', ('182', '195'))
150423	25562798	In addition to EGFR mutations and ALK rearrangements, genomic studies have also identified frequent copy number changes and somatic mutations affecting components of key signaling pathways in adenocarcinoma of the lung including KRAS, Her2, BRAF, C-MET, MEK1 and PIK3CA (Table 1).	('PIK3CA', 'Gene', '5290', (263, 269))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (192, 218))	('EGFR', 'Gene', '1956', (15, 19))	('MEK1', 'Gene', (254, 258))	('MEK1', 'molecular_function', 'GO:0004708', ('254', '258'))	('Her2', 'Gene', '2064', (235, 239))	('C-MET', 'Gene', '4233', (247, 252))	('BRAF', 'Gene', (241, 245))	('key signaling pathways', 'Pathway', (166, 188))	('PIK3CA', 'Gene', (263, 269))	('ALK', 'Gene', '238', (34, 37))	('Her2', 'Gene', (235, 239))	('signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('MEK1', 'Gene', '5604', (254, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('adenocarcinoma of the lung', 'Disease', (192, 218))	('ALK', 'Gene', (34, 37))	('EGFR', 'Gene', (15, 19))	('KRAS', 'Gene', '3845', (229, 233))	('men', 'Species', '9606', (47, 50))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (197, 218))	('mutations', 'Var', (20, 29))	('copy number changes', 'Var', (100, 119))	('mutations', 'Var', (132, 141))	('C-MET', 'Gene', (247, 252))	('KRAS', 'Gene', (229, 233))	('affecting', 'Reg', (142, 151))	('EGFR', 'molecular_function', 'GO:0005006', ('15', '19'))	('BRAF', 'Gene', '673', (241, 245))
150425	25562798	BRAF mutations, for instance, are found in approximately 3% of adenocarcinoma of the lung.	('mutations', 'Var', (5, 14))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (63, 89))	('BRAF', 'Gene', '673', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('adenocarcinoma of the lung', 'Disease', (63, 89))	('found', 'Reg', (34, 39))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (68, 89))	('BRAF', 'Gene', (0, 4))
150426	25562798	They tend to occur in smokers with adenocarcinoma and in contrast to melanoma where over 90% of mutations are V600E, in lung cancer only about 50% are V600E (usually G469A and D594G).	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('V600E', 'Mutation', 'rs113488022', (110, 115))	('lung cancer', 'Disease', (120, 131))	('mutations', 'Var', (96, 105))	('V600E', 'Var', (151, 156))	('G469A', 'Mutation', 'rs121913355', (166, 171))	('V600E', 'Var', (110, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('G469A', 'Var', (166, 171))	('melanoma', 'Disease', (69, 77))	('D594G', 'Mutation', 'rs121913338', (176, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('adenocarcinoma', 'Disease', (35, 49))	('D594G', 'Var', (176, 181))	('occur', 'Reg', (13, 18))	('V600E', 'Mutation', 'rs113488022', (151, 156))	('adenocarcinoma', 'Disease', 'MESH:D000230', (35, 49))
150427	25562798	As has proven to be the case in V600E BRAF mutant melanoma there is a compelling rationale for targeting this population of patients with BRAF inhibitors.	('V600E', 'Mutation', 'rs113488022', (32, 37))	('BRAF', 'Gene', '673', (138, 142))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('BRAF', 'Gene', '673', (38, 42))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('V600E', 'Var', (32, 37))	('BRAF', 'Gene', (38, 42))	('BRAF', 'Gene', (138, 142))	('patients', 'Species', '9606', (124, 132))
150428	25562798	Mutations within exon 20 that encodes part of the kinase domain of Her2 have been reported with a frequency of approximately 2-4% and tend to occur in never smokers with adenocarcinoma.	('Her2', 'Gene', (67, 71))	('occur', 'Reg', (142, 147))	('Mutations', 'Var', (0, 9))	('Her2', 'Gene', '2064', (67, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('adenocarcinoma', 'Disease', (170, 184))	('adenocarcinoma', 'Disease', 'MESH:D000230', (170, 184))
150430	25562798	KRAS mutations are reported in 15-25% of patients with lung adenocarcinoma and are typically mutually exclusive with EGFR mutations or ALK gene rearrangements.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('ALK', 'Gene', (135, 138))	('EGFR', 'molecular_function', 'GO:0005006', ('117', '121'))	('lung adenocarcinoma', 'Disease', (55, 74))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (55, 74))	('mutations', 'Var', (5, 14))	('ALK', 'Gene', '238', (135, 138))	('patients', 'Species', '9606', (41, 49))	('men', 'Species', '9606', (153, 156))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (55, 74))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
150435	25562798	Focal amplification of the Fibroblast Growth Factor Receptor 1 (FGFR1) gene has recently been identified in up to 20% of squamous cell carcinomas.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))	('Focal amplification', 'Var', (0, 19))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (121, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('FGFR', 'molecular_function', 'GO:0005007', ('64', '68'))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('identified', 'Reg', (94, 104))	('FGFR1', 'Gene', (64, 69))	('Fibroblast Growth Factor', 'molecular_function', 'GO:0005104', ('27', '51'))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (121, 145))	('FGFR1', 'Gene', '2260', (64, 69))	('squamous cell carcinomas', 'Disease', (121, 145))	('Fibroblast Growth Factor Receptor 1', 'Gene', '2260', (27, 62))	('Fibroblast Growth Factor Receptor 1', 'Gene', (27, 62))
150436	25562798	Tumors with FGFR1 amplification may be dependent of fibroblast growth factor receptor (FGFR) signaling for survival and are sensitive to FGFR inhibitors.	('FGFR1', 'Gene', (12, 17))	('FGFR', 'molecular_function', 'GO:0005007', ('137', '141'))	('FGFR1', 'Gene', '2260', (12, 17))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('52', '76'))	('signaling', 'biological_process', 'GO:0023052', ('93', '102'))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('FGFR', 'molecular_function', 'GO:0005007', ('87', '91'))	('amplification', 'Var', (18, 31))	('FGFR', 'molecular_function', 'GO:0005007', ('12', '16'))
150438	25562798	Mutations have also been identified in the discoidin domain receptor 2 (DDR2) tyrosine kinase gene in 3.8% (11/290) of SCC samples which may potentially be sensitive to treatment with dasatinib.	('DDR2', 'Gene', '4921', (72, 76))	('DDR2', 'Gene', (72, 76))	('SCC', 'Disease', (119, 122))	('discoidin domain receptor 2', 'Gene', (43, 70))	('Mutations', 'Var', (0, 9))	('dasatinib', 'Chemical', 'MESH:D000069439', (184, 193))	('discoidin domain receptor 2', 'Gene', '4921', (43, 70))	('men', 'Species', '9606', (174, 177))	('discoidin domain receptor', 'molecular_function', 'GO:0038062', ('43', '68'))
150439	25562798	Other mutations such as those involving the extracellular domain of the EGFR (EGFRvIII) or PIK3CA have also been described in squamous cell carcinoma and are potentially amenable to therapeutic intervention.	('PIK3CA', 'Gene', (91, 97))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (126, 149))	('EGFR', 'molecular_function', 'GO:0005006', ('72', '76'))	('squamous cell carcinoma', 'Disease', (126, 149))	('EGFR', 'Gene', '1956', (72, 76))	('PIK3CA', 'Gene', '5290', (91, 97))	('extracellular', 'cellular_component', 'GO:0005576', ('44', '57'))	('EGFR', 'Gene', (72, 76))	('men', 'Species', '9606', (171, 174))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('described', 'Reg', (113, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('mutations', 'Var', (6, 15))
150443	25562798	Recent efforts to search for molecular drivers of melanoma have identified frequent aberrations in a number of well characterized oncogenes and tumor suppressor genes including: BRAF (50-60% mutated), NRAS (15-20% mutated), AKT3 over expression, CDKN2A (30-70% deleted, mutated, or silenced), PTEN (5-20% deleted or mutated), APAF1 (40% silenced), TP53 (10% lost or mutated) with amplification of genes such as CCND1 and MITF occurring at varying frequencies.	('NRAS', 'Gene', (201, 205))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('144', '160'))	('PTEN', 'Gene', '5728', (293, 297))	('TP53', 'Gene', (348, 352))	('over expression', 'PosReg', (229, 244))	('MITF', 'Gene', (421, 425))	('tumor suppressor', 'biological_process', 'GO:0051726', ('144', '160'))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('BRAF', 'Gene', '673', (178, 182))	('tumor', 'Disease', (144, 149))	('CCND1', 'Gene', '595', (411, 416))	('CDKN2A', 'Gene', (246, 252))	('AKT3', 'Gene', '10000', (224, 228))	('deleted', 'Var', (261, 268))	('NRAS', 'Gene', '4893', (201, 205))	('TP53', 'Gene', '7157', (348, 352))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('APAF1', 'Gene', '317', (326, 331))	('CCND1', 'Gene', (411, 416))	('AKT3', 'Gene', (224, 228))	('PTEN', 'Gene', (293, 297))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('CDKN2A', 'Gene', '1029', (246, 252))	('APAF1', 'Gene', (326, 331))	('mutated', 'Var', (270, 277))	('BRAF', 'Gene', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('MITF', 'Gene', '4286', (421, 425))
150444	25562798	The most frequently mutated genes in melanoma with their respective frequencies of mutation are listed in Table 2.	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('mutated', 'Var', (20, 27))	('melanoma', 'Disease', (37, 45))
150445	25562798	One study of 102 melanomas found mutations or increased copy number of KIT in 28% of primary melanomas arising from chronic sun damaged skin, 36% of acral and 38% of mucosal melanomas.	('mutations', 'Var', (33, 42))	('sun damaged skin', 'Phenotype', 'HP:0000992', (124, 140))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanomas', 'Phenotype', 'HP:0002861', (174, 183))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('melanomas', 'Disease', 'MESH:D008545', (17, 26))	('copy number', 'Var', (56, 67))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('sun damaged', 'Phenotype', 'HP:0000992', (124, 135))	('KIT', 'Gene', (71, 74))	('melanomas', 'Disease', (17, 26))	('melanomas', 'Disease', 'MESH:D008545', (174, 183))	('mucosal melanomas', 'Disease', 'MESH:D008545', (166, 183))	('KIT', 'molecular_function', 'GO:0005020', ('71', '74'))	('melanomas', 'Disease', 'MESH:D008545', (93, 102))	('melanomas', 'Disease', (174, 183))	('increased', 'PosReg', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('mucosal melanomas', 'Disease', (166, 183))	('melanomas', 'Disease', (93, 102))	('melanomas', 'Phenotype', 'HP:0002861', (17, 26))
150450	25562798	The high frequency of substitutions of glutamic acid for valine (V600E) was first recognized by work conducted at the Sanger Institute, in Cambridge, the United Kingdom.	('V600E', 'Var', (65, 70))	('valine', 'Chemical', 'MESH:D014633', (57, 63))	('glutamic acid', 'Chemical', 'MESH:D018698', (39, 52))	('V600E', 'Mutation', 'rs113488022', (65, 70))	('glutamic acid', 'Protein', (39, 52))
150452	25562798	There was a dose escalation phase (55 patients, 49 of whom had melanoma) and an extension phase (32 patients with V600E mutant melanoma).	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('V600E mutant', 'Var', (114, 126))	('patients', 'Species', '9606', (38, 46))	('patients', 'Species', '9606', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('V600E', 'Mutation', 'rs113488022', (114, 119))
150453	25562798	The recommended Phase II dose of vemurafenib that emerged was 960mg BD orally and the most frequent toxicities were rash, fatigue and arthralgia.	('arthralgia', 'Phenotype', 'HP:0002829', (134, 144))	('fatigue', 'Disease', (122, 129))	('toxicities', 'Disease', (100, 110))	('rash', 'Disease', 'MESH:D005076', (116, 120))	('arthralgia', 'Disease', 'MESH:D018771', (134, 144))	('fatigue', 'Phenotype', 'HP:0012378', (122, 129))	('men', 'Species', '9606', (9, 12))	('rash', 'Disease', (116, 120))	('toxicities', 'Disease', 'MESH:D064420', (100, 110))	('rash', 'Phenotype', 'HP:0000988', (116, 120))	('vemurafenib', 'Chemical', 'MESH:D000077484', (33, 44))	('960mg', 'Var', (62, 67))	('arthralgia', 'Disease', (134, 144))	('fatigue', 'Disease', 'MESH:D005221', (122, 129))
150454	25562798	In the dose escalation cohort of the 16 patients with melanoma with the V600E mutation that received 240mg of vemurafenib twice daily or more, 10 had a partial response with 1 complete response.	('patients', 'Species', '9606', (40, 48))	('V600E', 'Var', (72, 77))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('vemurafenib', 'Chemical', 'MESH:D000077484', (110, 121))	('melanoma', 'Disease', (54, 62))	('V600E', 'Mutation', 'rs113488022', (72, 77))
150467	25562798	HRAS mutations have been found in kerathoacanthomas and squamous cell carcinomas arising as an iatrogenic manifestation of treatment with vemurafenib.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('HRAS', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('HRAS', 'Gene', '3265', (0, 4))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('men', 'Species', '9606', (128, 131))	('mutations', 'Var', (5, 14))	('vemurafenib', 'Chemical', 'MESH:D000077484', (138, 149))	('kerathoacanthomas and squamous cell carcinomas', 'Disease', 'MESH:D002294', (34, 80))	('found', 'Reg', (25, 30))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (56, 80))
150468	25562798	This shows how vemurafenib can be beneficial for tumors of one molecular phenotype (V600E mutant) but potentially adverse for another (HRAS/NRAS mutant).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('V600E', 'Mutation', 'rs113488022', (84, 89))	('HRAS', 'Gene', '3265', (135, 139))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('NRAS', 'Gene', (140, 144))	('V600E', 'Var', (84, 89))	('HRAS', 'Gene', (135, 139))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('beneficial', 'PosReg', (34, 44))	('vemurafenib', 'Chemical', 'MESH:D000077484', (15, 26))	('NRAS', 'Gene', '4893', (140, 144))
150472	25562798	BRAF and NRAS mutations occur frequently in benign and malignant neoplasm's that arise from melanocytes in epithelial structures.	("malignant neoplasm'", 'Disease', 'MESH:D009369', (55, 74))	("malignant neoplasm'", 'Disease', (55, 74))	('neoplasm', 'Phenotype', 'HP:0002664', (65, 73))	("malignant neoplasm's that arise from melanocytes", 'Phenotype', 'HP:0002861', (55, 103))	('NRAS', 'Gene', (9, 13))	('NRAS', 'Gene', '4893', (9, 13))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))
150475	25562798	Investigations lead by Boris Bastian of the University of California San Francisco, assessed the frequency of GNAQ mutations in a variety of melanocytic neoplasms following the discovery of frequent GNAQ mutations in 'malignant blue nevi' which are intra-dermal proliferations of melanocytes.	('mutations', 'Var', (115, 124))	('neoplasms', 'Phenotype', 'HP:0002664', (153, 162))	('neoplasm', 'Phenotype', 'HP:0002664', (153, 161))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (141, 162))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (141, 162))	('blue nevi', 'Phenotype', 'HP:0100814', (228, 237))	('GNAQ', 'Gene', (110, 114))	("'malignant blue nevi'", 'Disease', (217, 238))	('melanocytic neoplasms', 'Disease', (141, 162))	('nevi', 'Phenotype', 'HP:0003764', (233, 237))
150476	25562798	Mutations in GNAQ were found in 46% of uveal melanomas and 27% of uveal melanoma cell lines.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('uveal melanoma', 'Disease', (66, 80))	('uveal melanomas', 'Disease', (39, 54))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('uveal melanomas', 'Phenotype', 'HP:0007716', (39, 54))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (39, 53))	('GNAQ', 'Gene', (13, 17))	('found', 'Reg', (23, 28))	('uveal melanoma', 'Phenotype', 'HP:0007716', (39, 53))	('Mutations', 'Var', (0, 9))	('uveal melanomas', 'Disease', 'MESH:C536494', (39, 54))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))
150477	25562798	Prompted by similar phenotypes in mice harboring germline mutations in GNAQ and GNA11, GNA11 was also evaluated in a series of uveal melanomas, blue nevi and other nevi.	('mice', 'Species', '10090', (34, 38))	('blue nevi', 'Disease', (144, 153))	('GNAQ', 'Gene', (71, 75))	('nevi', 'Phenotype', 'HP:0003764', (149, 153))	('uveal melanomas', 'Disease', (127, 142))	('uveal melanomas', 'Phenotype', 'HP:0007716', (127, 142))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('uveal melanomas', 'Disease', 'MESH:C536494', (127, 142))	('uveal melanoma', 'Phenotype', 'HP:0007716', (127, 141))	('germline mutations', 'Var', (49, 67))	('GNA11', 'Gene', (80, 85))	('blue nevi', 'Phenotype', 'HP:0100814', (144, 153))	('nevi', 'Phenotype', 'HP:0003764', (164, 168))
150478	25562798	GNA11 was mutated in 7% of blue nevi and 32% of primary uveal melanomas and 57% of metastasis arising from uveal melanomas.	('mutated', 'Var', (10, 17))	('uveal melanomas', 'Disease', 'MESH:C536494', (107, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('blue nevi', 'Phenotype', 'HP:0100814', (27, 36))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('uveal melanomas', 'Disease', 'MESH:C536494', (56, 71))	('GNA11', 'Gene', (0, 5))	('blue nevi', 'Disease', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('nevi', 'Phenotype', 'HP:0003764', (32, 36))	('uveal melanomas', 'Phenotype', 'HP:0007716', (56, 71))	('uveal melanomas', 'Disease', (107, 122))	('uveal melanomas', 'Phenotype', 'HP:0007716', (107, 122))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('uveal melanomas', 'Disease', (56, 71))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
150481	25562798	Genetic differences are frequently found between primary tumors and their arising secondary metastases and even within primary tumors molecular heterogeneity is often found.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('Genetic', 'Var', (0, 7))	('metastases', 'Disease', (92, 102))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('metastases', 'Disease', 'MESH:D009362', (92, 102))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('found', 'Reg', (35, 40))
150483	25562798	An illustrative historic example is that in chronic myelogenous leukemia which is initially sensitive to treatment with imatinib mesylate (targets the BCR-ABL) treatment resistance may emerge due to the acquisition of secondary mutations in BCR-ABL that are resistant to imatinib but that are sensitive to second generation BCR-ABL inhibitors such as dasatinib or nilotinib.	('nilotinib', 'Chemical', 'MESH:C498826', (364, 373))	('BCR-ABL', 'Gene', (241, 248))	('BCR-ABL', 'Gene', '25', (151, 158))	('BCR-ABL', 'Gene', '25', (324, 331))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (44, 72))	('chronic myelogenous leukemia', 'Disease', (44, 72))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (52, 72))	('men', 'Species', '9606', (110, 113))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (120, 137))	('mutations', 'Var', (228, 237))	('BCR-ABL', 'Gene', (151, 158))	('BCR-ABL', 'Gene', '25', (241, 248))	('BCR-ABL', 'Gene', (324, 331))	('imatinib', 'Chemical', 'MESH:D000068877', (271, 279))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (44, 72))	('men', 'Species', '9606', (165, 168))	('dasatinib', 'Chemical', 'MESH:D000069439', (351, 360))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('imatinib', 'Chemical', 'MESH:D000068877', (120, 128))
150485	25562798	Despite initial sensitivity and responses that in many cases can be maintained over periods of many months or even years, tumors with EGFR mutations or ALK gene rearrangements treated with specific inhibitors will ultimately progress:a process termed acquired resistance.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('EGFR', 'Gene', (134, 138))	('mutations', 'Var', (139, 148))	('ALK', 'Gene', '238', (152, 155))	('EGFR', 'molecular_function', 'GO:0005006', ('134', '138'))	('men', 'Species', '9606', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('progress', 'PosReg', (225, 233))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('ALK', 'Gene', (152, 155))	('EGFR', 'Gene', '1956', (134, 138))
150486	25562798	In the case of acquired resistance to gefitinib and erlotinib in EGFR mutant tumors two major mechanisms have been identified.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('EGFR', 'Gene', '1956', (65, 69))	('gefitinib', 'Chemical', 'MESH:D000077156', (38, 47))	('EGFR', 'Gene', (65, 69))	('mutant', 'Var', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('EGFR', 'molecular_function', 'GO:0005006', ('65', '69'))	('erlotinib', 'Chemical', 'MESH:D000069347', (52, 61))
150487	25562798	Firstly, a secondary mutation, the T790M mutation within exon 20 of EGFR, is responsible for about 50% of instances of acquired resistance.	('responsible', 'Reg', (77, 88))	('EGFR', 'Gene', '1956', (68, 72))	('acquired resistance', 'MPA', (119, 138))	('T790M', 'Mutation', 'rs121434569', (35, 40))	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('EGFR', 'Gene', (68, 72))	('T790M', 'Var', (35, 40))
150488	25562798	This mutation increases the affinity of the EGFR for ATP approximately 10-fold and allows ATP to competitively displace gefitinib and erlotinib from EGFR.	('EGFR', 'Gene', (44, 48))	('increases', 'PosReg', (14, 23))	('erlotinib', 'MPA', (134, 143))	('EGFR', 'Gene', '1956', (149, 153))	('EGFR', 'molecular_function', 'GO:0005006', ('149', '153'))	('erlotinib', 'Chemical', 'MESH:D000069347', (134, 143))	('ATP', 'Chemical', 'MESH:D000255', (90, 93))	('EGFR', 'Gene', (149, 153))	('affinity', 'MPA', (28, 36))	('gefitinib', 'MPA', (120, 129))	('displace', 'NegReg', (111, 119))	('EGFR', 'Gene', '1956', (44, 48))	('gefitinib', 'Chemical', 'MESH:D000077156', (120, 129))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))	('mutation', 'Var', (5, 13))	('ATP', 'Chemical', 'MESH:D000255', (53, 56))
150489	25562798	Other less common point mutations, such as D761Y, have also been reported which confer acquired resistance to EGFR TKIs.	('D761Y', 'Var', (43, 48))	('acquired resistance', 'MPA', (87, 106))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('D761Y', 'Mutation', 'rs121913418', (43, 48))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))
150490	25562798	Although irreversible inhibitors of the EGFR such as dacomitinib or afatinib inhibit T790M in vitro their clinical activity in the setting of tumors with T790M mutations remains to be demonstrated and novel mutation specific T790M inhibitors are in clinical development.	('T790M', 'Mutation', 'rs121434569', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('mutations', 'Var', (160, 169))	('men', 'Species', '9606', (265, 268))	('inhibit', 'NegReg', (77, 84))	('T790M', 'Mutation', 'rs121434569', (154, 159))	('T790M', 'Mutation', 'rs121434569', (85, 90))	('T790M', 'Gene', (154, 159))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('T790M', 'Gene', (85, 90))	('afatinib', 'Chemical', 'MESH:D000077716', (68, 76))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('dacomitinib', 'Chemical', 'MESH:C525726', (53, 64))
150491	25562798	A second mechanism for resistance which is seen in 5-20% of patients is amplification of CMET which causes resistance to EGFR TKIs by activating PI3 Kinase signaling through ERBB3.	('amplification', 'Var', (72, 85))	('EGFR', 'Gene', '1956', (121, 125))	('ERBB3', 'Gene', (174, 179))	('ERBB3', 'Gene', '2065', (174, 179))	('patients', 'Species', '9606', (60, 68))	('EGFR', 'Gene', (121, 125))	('resistance', 'MPA', (107, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('121', '125'))	('causes', 'Reg', (100, 106))	('CMET', 'Gene', '4233', (89, 93))	('PI3 Kinase signaling', 'Pathway', (145, 165))	('CMET', 'Gene', (89, 93))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))	('activating', 'PosReg', (134, 144))
150493	25562798	The mechanisms of acquired resistance to crizotinib are only just coming to light but, analogous to acquired resistance to EGFR inhibitors, secondary mutations in ALK that render the ALK kinase resistant to inhibition by crizotinib have been identified.	('EGFR', 'Gene', (123, 127))	('crizotinib', 'Chemical', 'MESH:D000077547', (221, 231))	('ALK', 'Gene', '238', (163, 166))	('ALK', 'Gene', '238', (183, 186))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('resistant', 'MPA', (194, 203))	('crizotinib', 'Chemical', 'MESH:D000077547', (41, 51))	('mutations', 'Var', (150, 159))	('EGFR', 'Gene', '1956', (123, 127))	('ALK', 'Gene', (163, 166))	('ALK', 'Gene', (183, 186))
150494	25562798	These mutations including L1196M in the ALK kinase domain may be susceptible to inhibition with novel ALK inhibitors e.g., LDK378, AP26113, or AF802.	('L1196M', 'Var', (26, 32))	('ALK', 'Gene', (40, 43))	('LDK378', 'Gene', (123, 129))	('AF802', 'Var', (143, 148))	('ALK', 'Gene', (102, 105))	('AP26113', 'Var', (131, 138))	('ALK', 'Gene', '238', (40, 43))	('ALK', 'Gene', '238', (102, 105))	('L1196M', 'Mutation', 'rs1057519784', (26, 32))
150499	25562798	In non-small cell lung cancers sensitive to EGFR tyrosine kinase inhibition is lost usually due to 'gatekeeper' mutation however surprisingly acquisition of BRAF gatekeeper 'mutations' do not account for secondary drug resistance in melanoma that acquire resistance to BRAF inhibitors.	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (3, 30))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))	('gatekeeper', 'Species', '111938', (100, 110))	('gatekeeper', 'Species', '111938', (162, 172))	('BRAF', 'Gene', '673', (157, 161))	('drug resistance', 'biological_process', 'GO:0009315', ('214', '229'))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('BRAF', 'Gene', (157, 161))	('EGFR', 'Gene', '1956', (44, 48))	('lung cancers', 'Phenotype', 'HP:0100526', (18, 30))	('non-small cell lung cancers', 'Disease', (3, 30))	('drug resistance', 'biological_process', 'GO:0042493', ('214', '229'))	('melanoma', 'Disease', 'MESH:D008545', (233, 241))	('BRAF', 'Gene', '673', (269, 273))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (3, 30))	('BRAF', 'Gene', (269, 273))	('mutation', 'Var', (112, 120))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('drug resistance', 'Phenotype', 'HP:0020174', (214, 229))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (7, 30))	('EGFR', 'Gene', (44, 48))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))	('melanoma', 'Disease', (233, 241))
150501	25562798	In one study it was shown that acquired resistance to Vemurafenib develops by mutually exclusive PDGFRB up regulation or by NRAS mutations.	('up regulation', 'PosReg', (104, 117))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (54, 65))	('NRAS', 'Gene', '4893', (124, 128))	('mutations', 'Var', (129, 138))	('regulation', 'biological_process', 'GO:0065007', ('107', '117'))	('PDGFRB', 'Gene', '5159', (97, 103))	('PDGFRB', 'Gene', (97, 103))	('NRAS', 'Gene', (124, 128))
150502	25562798	The second study identified that the gene encoding COT/TpI2 called MAP3K8 is a MAPK pathway activator and maybe responsible for the evolution of resistance to vemurafenib in some cases of V600E mutated melanoma Furthermore it subverts RAF signaling by activating ERK signaling by mechanisms downstream of BRAF that are not RAF dependent.	('RAF', 'Gene', (306, 309))	('ERK signaling', 'MPA', (263, 276))	('V600E', 'Mutation', 'rs113488022', (188, 193))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('MAPK', 'molecular_function', 'GO:0004707', ('79', '83'))	('vemurafenib', 'Chemical', 'MESH:D000077484', (159, 170))	('MAP3K8', 'Gene', '1326', (67, 73))	('activating', 'PosReg', (252, 262))	('subverts', 'NegReg', (226, 234))	('MAP3K', 'molecular_function', 'GO:0004709', ('67', '72'))	('RAF', 'Gene', '22882', (323, 326))	('COT', 'Gene', (51, 54))	('COT', 'Gene', '1326', (51, 54))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('signaling', 'biological_process', 'GO:0023052', ('239', '248'))	('melanoma', 'Disease', (202, 210))	('RAF', 'Gene', '22882', (235, 238))	('V600E mutated', 'Var', (188, 201))	('BRAF', 'Gene', '673', (305, 309))	('ERK', 'molecular_function', 'GO:0004707', ('263', '266'))	('RAF', 'Gene', (323, 326))	('RAF', 'Gene', '22882', (306, 309))	('BRAF', 'Gene', (305, 309))	('MAP3K8', 'Gene', (67, 73))	('signaling', 'biological_process', 'GO:0023052', ('267', '276'))	('RAF', 'Gene', (235, 238))
150506	25562798	It is interesting to speculate why gatekeeper mutations are not usually found as a cause of molecular drug resistance in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', (121, 129))	('drug resistance', 'Phenotype', 'HP:0020174', (102, 117))	('molecular drug resistance', 'MPA', (92, 117))	('mutations', 'Var', (46, 55))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('drug resistance', 'biological_process', 'GO:0042493', ('102', '117'))	('cause', 'Reg', (83, 88))	('gatekeeper', 'Species', '111938', (35, 45))	('drug resistance', 'biological_process', 'GO:0009315', ('102', '117'))
150507	25562798	A speculation is that gatekeeper mutations would most likely reduce the kinase activity of mutant BRAF negating its oncogenic potential.	('oncogenic potential', 'CPA', (116, 135))	('reduce', 'NegReg', (61, 67))	('kinase activity', 'molecular_function', 'GO:0016301', ('72', '87'))	('gatekeeper', 'Species', '111938', (22, 32))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))	('mutations', 'Var', (33, 42))	('mutant', 'Var', (91, 97))	('kinase activity', 'MPA', (72, 87))
150509	25562798	The rapid transition from scientific findings to clinical application is exemplified by both the finding of BRAF mutations in melanoma in 2002 and FDA approval of vemurafenib for this indication in 2011 and that of the initial finding of EML4-ALK in 2007 and FDA approval of crizotinib in 2011.	('EML4', 'Gene', '27436', (238, 242))	('ALK', 'Gene', (243, 246))	('vemurafenib', 'Chemical', 'MESH:D000077484', (163, 174))	('mutations', 'Var', (113, 122))	('ALK', 'Gene', '238', (243, 246))	('BRAF', 'Gene', '673', (108, 112))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('crizotinib', 'Chemical', 'MESH:D000077547', (275, 285))	('melanoma', 'Disease', (126, 134))	('BRAF', 'Gene', (108, 112))	('EML4', 'Gene', (238, 242))
150511	25562798	The emergent knowledge of molecular tumor profiles e.g., EGFR and KRAS mutations and ALK rearrangements for instance raises logistic and algorithmic considerations to approaching the molecular management of the adenocarcinoma subtype of NSCLC.	('men', 'Species', '9606', (199, 202))	('ALK', 'Gene', (85, 88))	('KRAS', 'Gene', '3845', (66, 70))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('adenocarcinoma subtype of NSCLC', 'Disease', (211, 242))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('mutations', 'Var', (71, 80))	('EGFR', 'Gene', '1956', (57, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('ALK', 'Gene', '238', (85, 88))	('adenocarcinoma subtype of NSCLC', 'Disease', 'MESH:D000230', (211, 242))	('men', 'Species', '9606', (98, 101))	('EGFR', 'Gene', (57, 61))	('tumor', 'Disease', (36, 41))	('KRAS', 'Gene', (66, 70))
150518	23709298	A Novel Germline Mutation in BAP1 Predisposes to Familial Clear-Cell Renal Cell Carcinoma Renal cell carcinoma (RCC) clusters in some families.	('Renal cell carcinoma', 'Disease', (90, 110))	('Clear-Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (58, 89))	('Familial Clear-Cell Renal Cell Carcinoma', 'Disease', (49, 89))	('Renal cell carcinoma', 'Disease', 'MESH:C538614', (90, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (69, 89))	('Carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('BAP1', 'Gene', '8314', (29, 33))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('Germline Mutation', 'Var', (8, 25))	('Familial Clear-Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (49, 89))	('BAP1', 'Gene', (29, 33))	('Predisposes', 'Reg', (34, 45))
150519	23709298	Familial RCC arises from mutations in several genes, including VHL, which is also mutated in sporadic RCC.	('mutations', 'Var', (25, 34))	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('RCC', 'Disease', (9, 12))	('RCC', 'Phenotype', 'HP:0005584', (9, 12))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('VHL', 'Gene', (63, 66))	('arises from', 'Reg', (13, 24))	('VHL', 'Gene', '7428', (63, 66))
150523	23709298	Somatic BAP1 mutations are associated with high-grade ccRCC and poor patient outcomes.	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('associated', 'Reg', (27, 37))	('BAP1', 'Gene', '8314', (8, 12))	('patient', 'Species', '9606', (69, 76))	('BAP1', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))
150525	23709298	We identified a novel variant (c.41T>A; p.L14H), which cosegregated with the RCC phenotype.	('c.41T>A', 'Mutation', 'rs1241704385', (31, 38))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('c.41T>A;', 'Var', (31, 39))	('p.L14H', 'Mutation', 'rs1241704385', (40, 46))
150526	23709298	The p.L14H variant disrupts a highly conserved residue in the catalytic domain, a domain frequently targeted by missense mutations.	('disrupts', 'NegReg', (19, 27))	('p.L14H', 'Var', (4, 10))	('p.L14H', 'Mutation', 'rs1241704385', (4, 10))	('highly conserved residue in the catalytic domain', 'MPA', (30, 78))
150527	23709298	The family with the BAP1 variant was characterized by early-onset clear cell RCC, occasionally of high Fuhrman grade, and lacked other features that characterize von Hippel-Lindau syndrome.	('von Hippel-Lindau syndrome', 'Disease', (162, 188))	('BAP1', 'Gene', (20, 24))	('von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (162, 188))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('variant', 'Var', (25, 32))	('BAP1', 'Gene', '8314', (20, 24))
150532	23709298	VHL) that are also mutated in the sporadic setting, and thus somatically mutated genes may explain familial RCC if mutated in the germline.	('familial RCC', 'Disease', 'MESH:C538614', (99, 111))	('familial RCC', 'Disease', (99, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('mutated', 'Var', (115, 122))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))
150536	23709298	We found that BAP1 is inactivated in approximately 15% of sporadic ccRCCs, and that BAP1 mutations are associated with high Fuhrman grade and poor patient survival.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('BAP1', 'Gene', '8314', (14, 18))	('RCC', 'Disease', (69, 72))	('associated', 'Reg', (103, 113))	('patient', 'Species', '9606', (147, 154))	('BAP1', 'Gene', (14, 18))	('BAP1', 'Gene', '8314', (84, 88))	('mutations', 'Var', (89, 98))	('BAP1', 'Gene', (84, 88))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
150547	23709298	During studies that led to the discovery of somatic BAP1 mutations in ccRCC, a germline variant (c.121G>A; p.G41S) was identified in one individual (II:1) that had two first-degree and a second-degree relative with RCC and who had previously tested negative for a VHL mutation (Supplementary Figure S1).	('Supplementary Figure S1', 'Disease', 'MESH:D017034', (278, 301))	('VHL', 'Gene', '7428', (264, 267))	('BAP1', 'Gene', '8314', (52, 56))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('Supplementary Figure S1', 'Disease', (278, 301))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (215, 218))	('RCC', 'Disease', (215, 218))	('c.121G>A', 'Mutation', 'rs372586694', (97, 105))	('RCC', 'Phenotype', 'HP:0005584', (215, 218))	('BAP1', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))	('p.G41S', 'Mutation', 'rs372586694', (107, 113))	('VHL', 'Gene', (264, 267))	('c.121G>A;', 'Var', (97, 106))
150550	23709298	Nevertheless, BAP1 mutations have been previously observed in the germline, where they predispose to uveal and cutaneous melanoma as well as mesothelioma .	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('BAP1', 'Gene', '8314', (14, 18))	('cutaneous melanoma', 'Disease', (111, 129))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (111, 129))	('uveal', 'Disease', (101, 106))	('BAP1', 'Gene', (14, 18))	('predispose', 'Reg', (87, 97))	('mutations', 'Var', (19, 28))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (111, 129))	('mesothelioma', 'Disease', (141, 153))	('mesothelioma', 'Disease', 'MESH:D008654', (141, 153))
150552	23709298	On the basis of the somatic and germline associations of BAP1 mutations and RCC, we sought to determine whether germline BAP1 mutations were associated with familial RCC.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('BAP1', 'Gene', '8314', (121, 125))	('RCC', 'Disease', (76, 79))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('familial RCC', 'Disease', (157, 169))	('RCC', 'Disease', (166, 169))	('familial RCC', 'Disease', 'MESH:C538614', (157, 169))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('BAP1', 'Gene', (121, 125))	('BAP1', 'Gene', '8314', (57, 61))	('associated', 'Reg', (141, 151))	('mutations', 'Var', (126, 135))	('BAP1', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
150561	23709298	Individuals in this cohort had been previously evaluated for mutations in other RCC predisposition genes.	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('mutations', 'Var', (61, 70))
150562	23709298	41% had been evaluated for germline VHL mutations and had tested negative.	('mutations', 'Var', (40, 49))	('VHL', 'Gene', '7428', (36, 39))	('VHL', 'Gene', (36, 39))
150563	23709298	31% of the individuals had tested negative for germline PTEN mutations.	('PTEN', 'Gene', (56, 60))	('PTEN', 'Gene', '5728', (56, 60))	('mutations', 'Var', (61, 70))
150567	23709298	A germline missense variant (c.869A>G; p.N290S) was found in a UTSW female with unilateral, unifocal, ccRCC diagnosed at age 24 who had previously tested negative for germline mutations in VHL and PTEN.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('c.869A>G', 'Mutation', 'rs551221430', (29, 37))	('c.869A>G;', 'Var', (29, 38))	('PTEN', 'Gene', (197, 201))	('PTEN', 'Gene', '5728', (197, 201))	('VHL', 'Gene', (189, 192))	('p.N290S', 'Mutation', 'rs551221430', (39, 46))	('VHL', 'Gene', '7428', (189, 192))	('RCC', 'Disease', (104, 107))
150568	23709298	The variant was predicted to be benign by PolyPhen-2 and conservation studies across species showed that the corresponding asparagine was replaced by a serine in some species.	('asparagine', 'MPA', (123, 133))	('asparagine', 'Chemical', 'MESH:D001216', (123, 133))	('serine', 'Chemical', 'MESH:D012694', (152, 158))	('variant', 'Var', (4, 11))	('serine', 'MPA', (152, 158))
150585	23709298	Given the finding of a BAP1 missense germline variant (c.41T>A, p.L14H) in individual IV:1, we performed cosegregation studies.	('BAP1', 'Gene', (23, 27))	('c.41T>A', 'Var', (55, 62))	('c.41T>A', 'Mutation', 'rs1241704385', (55, 62))	('BAP1', 'Gene', '8314', (23, 27))	('p.L14H', 'Mutation', 'rs1241704385', (64, 70))
150588	23709298	Thus, the BAP1 c.41T>A (p.L14H) variant cosegregated with the RCC predisposition in this family.	('p.L14H', 'Mutation', 'rs1241704385', (24, 30))	('BAP1', 'Gene', (10, 14))	('c.41T>A', 'Var', (15, 22))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('c.41T>A', 'Mutation', 'rs1241704385', (15, 22))	('BAP1', 'Gene', '8314', (10, 14))
150589	23709298	The BAP1 variant (p.L14H) maps to the catalytic domain, a domain that is a frequent site of pathogenic missense mutations.	('BAP1', 'Gene', (4, 8))	('p.L14H', 'Mutation', 'rs1241704385', (18, 24))	('p.L14H', 'Var', (18, 24))	('BAP1', 'Gene', '8314', (4, 8))
150590	23709298	Somatic mutations in the ubiquitin C-terminal hydrolase (UCH) domain have been reported in several RCC studies as well as in COSMIC and the Kidney Renal Cell Carcinoma (KIRC) dataset produced by The Cancer Genome Atlas (TCGA) (Figure 6A).	('UCH', 'Gene', '7345', (57, 60))	('reported', 'Reg', (79, 87))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (147, 167))	('UCH', 'Gene', (57, 60))	('ubiquitin C-terminal hydrolase', 'molecular_function', 'GO:0036459', ('25', '55'))	('Cancer Genome Atlas', 'Disease', (199, 218))	('Carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('Kidney Renal Cell Carcinoma', 'Disease', (140, 167))	('Cancer', 'Phenotype', 'HP:0002664', (199, 205))	('mutations', 'Var', (8, 17))	('ubiquitin C-terminal hydrolase', 'Gene', (25, 55))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (199, 218))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('Kidney Renal Cell Carcinoma', 'Disease', 'MESH:D007674', (140, 167))	('ubiquitin C-terminal hydrolase', 'Gene', '7345', (25, 55))
150591	23709298	Leucine 14 is highly conserved (Figure 6B) and along with previously reported RCC mutations in neighboring residues, L14H is predicted to be deleterious by PROVEAN, SIFT, and PolyPhen-2 prediction tools (Figure 6C) .	('SIFT', 'Disease', 'None', (165, 169))	('L14H', 'SUBSTITUTION', 'None', (117, 121))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('mutations', 'Var', (82, 91))	('L14H', 'Var', (117, 121))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('Leucine', 'Chemical', 'MESH:D007930', (0, 7))	('SIFT', 'Disease', (165, 169))
150593	23709298	Leucine 14 maps to the first helix of the UCH domain and is physically adjacent to two previously identified pathogenic RCC mutations, p.G13V and p.H144N (Figure 6D).	('p.H144N', 'Mutation', 'p.H144N', (146, 153))	('UCH', 'Gene', '7345', (42, 45))	('p.H144N', 'Var', (146, 153))	('UCH', 'Gene', (42, 45))	('p.G13V', 'Mutation', 'p.G13V', (135, 141))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('Leucine', 'Chemical', 'MESH:D007930', (0, 7))	('p.G13V', 'Var', (135, 141))
150595	23709298	Mutation of this residue to histidine is predicted to increase the effective volume of the side chain, possibly causing steric clashes with surrounding residues, and may prevent productive ubiquitin binding (Figure 6D).	('productive ubiquitin', 'MPA', (178, 198))	('Mutation', 'Var', (0, 8))	('increase', 'PosReg', (54, 62))	('histidine', 'Chemical', 'MESH:D006639', (28, 37))	('ubiquitin binding', 'molecular_function', 'GO:0043130', ('189', '206'))	('causing', 'Reg', (112, 119))	('steric clashes', 'MPA', (120, 134))	('effective volume of the side chain', 'MPA', (67, 101))	('prevent', 'NegReg', (170, 177))
150598	23709298	DNA was extracted from the different tumors and sequenced for the BAP1 variant (c.41T>A).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('BAP1', 'Gene', '8314', (66, 70))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('c.41T>A', 'Var', (80, 87))	('BAP1', 'Gene', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('c.41T>A', 'Mutation', 'rs1241704385', (80, 87))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
150602	23709298	Enrichment of the mutant allele relative to the wild-type allele was observed in the other tumor from the proband 2012 surgery (Figure 5B, Tumor 3).	('mutant', 'Var', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (91, 96))
150604	23709298	This tumor also showed enrichment of the mutant allele consistent with LOH (Figure 5B, IV:4 Tumor 1).	('LOH', 'Disease', (71, 74))	('mutant', 'Var', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('Tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (5, 10))
150611	23709298	These data are most consistent with the notion that (1) p.L14H is a causative mutation, (2) p.L14H abrogates protein expression in tumors, and (3) mutations abolishing expression of the second allele are uniformly present.	('expression', 'MPA', (168, 178))	('p.L14H', 'Mutation', 'rs1241704385', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('abolishing', 'NegReg', (157, 167))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('p.L14H', 'Var', (56, 62))	('abrogates', 'NegReg', (99, 108))	('p.L14H', 'Mutation', 'rs1241704385', (92, 98))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('protein', 'Protein', (109, 116))	('p.L14H', 'Var', (92, 98))
150612	23709298	Previous VHL mutation testing of germline DNA from the proband of family NCI-1326 was negative.	('mutation', 'Var', (13, 21))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('VHL', 'Gene', '7428', (9, 12))	('VHL', 'Gene', (9, 12))
150614	23709298	VHL mutation analysis (Supplementary Methods) showed VHL mutation in some tumors (IV:1, Tumor 1 and IV:4, Tumor 1), but not in others (IV:1, Tumors 3 and 4) (Supplementary Figure S2 and data not shown).	('mutation', 'Var', (57, 65))	('Tumor', 'Phenotype', 'HP:0002664', (106, 111))	('VHL', 'Gene', (53, 56))	('Tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Tumors', 'Phenotype', 'HP:0002664', (141, 147))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (53, 56))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('Tumors', 'Disease', (141, 147))	('Tumors', 'Disease', 'MESH:D009369', (141, 147))	('VHL', 'Gene', '7428', (0, 3))	('Tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
150615	23709298	Thus, mutations in VHL and BAP1 may cooperate in the development of at least some of the tumors.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('cooperate', 'Reg', (36, 45))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('BAP1', 'Gene', (27, 31))	('VHL', 'Gene', (19, 22))	('VHL', 'Gene', '7428', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mutations', 'Var', (6, 15))	('BAP1', 'Gene', '8314', (27, 31))
150616	23709298	Together, these data suggest that the novel BAP1 p.L14H missense variant is the cause of the underlying cancer phenotype in the family described.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('p.L14H', 'Mutation', 'rs1241704385', (49, 55))	('p.L14H missense', 'Var', (49, 64))	('BAP1', 'Gene', '8314', (44, 48))	('cause', 'Reg', (80, 85))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('BAP1', 'Gene', (44, 48))
150617	23709298	First, the variant cosegregated with the RCC phenotype.	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))	('variant', 'Var', (11, 18))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))
150618	23709298	Second, the variant targets the catalytic domain, which is a common site of missense mutations including pathogenic somatically-acquired mutations in neighboring residues pG13V and p.H144N.	('p.H144N', 'Mutation', 'p.H144N', (181, 188))	('pG13V', 'Chemical', '-', (171, 176))	('p.H144N', 'Var', (181, 188))	('pG13V', 'Gene', (171, 176))
150619	23709298	Third, L14 is highly conserved across species and in silico analyses suggest that a histidine substitution at this position precludes productive ubiquitin binding.	('precludes', 'NegReg', (124, 133))	('ubiquitin binding', 'molecular_function', 'GO:0043130', ('145', '162'))	('productive ubiquitin', 'MPA', (134, 154))	('L14', 'Gene', '28900', (7, 10))	('histidine substitution', 'Var', (84, 106))	('histidine', 'Chemical', 'MESH:D006639', (84, 93))	('L14', 'Gene', (7, 10))
150620	23709298	Fourth, consistent with BAP1 function as a two-hit tumor suppressor gene, the variant was associated with LOH in tumors from the proband and an affected sister by DNA sequence analysis.	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('BAP1', 'Gene', (24, 28))	('tumor', 'Disease', (51, 56))	('variant', 'Var', (78, 85))	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))	('LOH', 'Disease', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor suppressor', 'biological_process', 'GO:0051726', ('51', '67'))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('51', '67'))	('BAP1', 'Gene', '8314', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
150621	23709298	Finally, albeit indirectly, the absence of BAP1 protein, by immunohistochemistry, in all tumors examined suggests that the BAP1 p.L14H variant abrogates protein expression.	('BAP1', 'Gene', (123, 127))	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('tumors', 'Disease', (89, 95))	('BAP1', 'Gene', (43, 47))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('protein', 'cellular_component', 'GO:0003675', ('153', '160'))	('p.L14H', 'Mutation', 'rs1241704385', (128, 134))	('BAP1', 'Gene', '8314', (43, 47))	('protein expression', 'MPA', (153, 171))	('BAP1', 'Gene', '8314', (123, 127))	('abrogates', 'NegReg', (143, 152))	('p.L14H', 'Var', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
150623	23709298	Although it is not possible to generalize from a single kindred, our data suggest that BAP1 mutations will be found, albeit infrequently, in familial RCC, and thus, it seems fitting to comment on the phenotypic aspects of the family we report.	('BAP1', 'Gene', '8314', (87, 91))	('found', 'Reg', (110, 115))	('BAP1', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('familial RCC', 'Disease', 'MESH:C538614', (141, 153))	('familial RCC', 'Disease', (141, 153))
150624	23709298	The family in which the novel p.L14H variant cosegregated with RCC demonstrated a cancer phenotype characterized by an early-onset, aggressive form of ccRCC.	('RCC', 'Disease', (63, 66))	('p.L14H', 'Var', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('cancer', 'Disease', (82, 88))	('RCC', 'Disease', (153, 156))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('p.L14H', 'Mutation', 'rs1241704385', (30, 36))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
150627	23709298	Another family member, who inherited the p.L14H variant, developed early-onset ccRCC at age 40.	('developed', 'Reg', (57, 66))	('p.L14H', 'Mutation', 'rs1241704385', (41, 47))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('p.L14H', 'Var', (41, 47))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))
150630	23709298	Taken together, these observations support the idea that germline BAP1 mutations may be associated with aggressive familial ccRCC.	('germline', 'Var', (57, 65))	('BAP1', 'Gene', '8314', (66, 70))	('BAP1', 'Gene', (66, 70))	('RCC', 'Disease', (126, 129))	('associated', 'Reg', (88, 98))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
150636	23709298	Our findings and the fact that somatic BAP1 mutations are often associated with ccRCC of high grade may encourage clinicians to look for these features when deciding whether to proceed with germline BAP1 mutation analysis.	('associated', 'Reg', (64, 74))	('BAP1', 'Gene', (199, 203))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('mutations', 'Var', (44, 53))	('BAP1', 'Gene', '8314', (39, 43))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('BAP1', 'Gene', '8314', (199, 203))	('BAP1', 'Gene', (39, 43))
150637	23709298	Identifying cues associated with germline BAP1 mutation will be important as these mutations are rare.	('BAP1', 'Gene', '8314', (42, 46))	('mutation', 'Var', (47, 55))	('BAP1', 'Gene', (42, 46))	('germline', 'Var', (33, 41))
150639	23709298	Thus, clinicians may consider BAP1 analysis for individuals who test negative for germline VHL mutations and display a more "aggressive" phenotype that lacks other VHL hallmark findings such as hemangioblastomas, pancreatic cysts, and pheochromocytomas.	('BAP1', 'Gene', (30, 34))	('VHL', 'Gene', (91, 94))	('BAP1', 'Gene', '8314', (30, 34))	('hemangioblastomas', 'Disease', 'MESH:D018325', (194, 211))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (235, 252))	('hemangioblastomas', 'Disease', (194, 211))	('VHL', 'Gene', '7428', (91, 94))	('VHL', 'Gene', (164, 167))	('pancreatic cysts', 'Disease', (213, 229))	('mutations', 'Var', (95, 104))	('pancreatic cysts', 'Disease', 'MESH:D010181', (213, 229))	('VHL', 'Gene', '7428', (164, 167))	('pheochromocytomas', 'Disease', 'MESH:D010673', (235, 252))	('pancreatic cysts', 'Phenotype', 'HP:0001737', (213, 229))	('pheochromocytomas', 'Disease', (235, 252))
150640	23709298	Prior to this report, germline BAP1 mutations were reported to predispose to several additional cancers including uveal and cutaneous melanoma and mesothelioma.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('germline', 'Var', (22, 30))	('predispose', 'Reg', (63, 73))	('BAP1', 'Gene', '8314', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutations', 'Var', (36, 45))	('uveal', 'Disease', (114, 119))	('cutaneous melanoma and mesothelioma', 'Disease', 'MESH:C562393', (124, 159))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (124, 142))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('BAP1', 'Gene', (31, 35))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))
150645	23709298	As germline BAP1 mutation families continue to be described, the phenotype may be clarified.	('BAP1', 'Gene', (12, 16))	('mutation', 'Var', (17, 25))	('BAP1', 'Gene', '8314', (12, 16))
150646	23709298	No clear genotype/phenotype correlation has been observed, and familial mutations frequently result in early truncation of the BAP1 protein.	('BAP1', 'Gene', (127, 131))	('familial mutations', 'Var', (63, 81))	('early truncation', 'MPA', (103, 119))	('protein', 'Protein', (132, 139))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('BAP1', 'Gene', '8314', (127, 131))	('result in', 'Reg', (93, 102))
150647	23709298	It seems plausible that germline BAP1 mutations produce a cancer susceptibility syndrome in which the penetrance of each given feature (RCC, melanoma or mesothelioma) depends upon additional environmental or genetic factors.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('produce', 'Reg', (48, 55))	('BAP1', 'Gene', '8314', (33, 37))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('BAP1', 'Gene', (33, 37))	('cancer', 'Disease', (58, 64))	('mutations', 'Var', (38, 47))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('melanoma or mesothelioma', 'Disease', (141, 165))	('RCC', 'Disease', (136, 139))	('melanoma or mesothelioma', 'Disease', 'MESH:D008654', (141, 165))
150648	23709298	Nevertheless, the presence of other BAP1-associated malignancies in RCC families may increase suspicion for a germline BAP1 mutation.	('BAP1', 'Gene', '8314', (36, 40))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('malignancies', 'Disease', 'MESH:D009369', (52, 64))	('RCC', 'Disease', (68, 71))	('BAP1', 'Gene', '8314', (119, 123))	('mutation', 'Var', (124, 132))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('malignancies', 'Disease', (52, 64))	('BAP1', 'Gene', (36, 40))	('BAP1', 'Gene', (119, 123))
150649	23709298	Our overall germline BAP1 mutation frequency of 1.2% suggests that, although germline BAP1 mutations may predispose to RCC, the frequency of these mutations is low but in keeping with that of other studies.	('BAP1', 'Gene', '8314', (86, 90))	('BAP1', 'Gene', (21, 25))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('BAP1', 'Gene', (86, 90))	('mutations', 'Var', (91, 100))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('predispose', 'Reg', (105, 115))	('RCC', 'Disease', (119, 122))	('BAP1', 'Gene', '8314', (21, 25))
150650	23709298	For comparison, several other studies describing germline BAP1 mutations in a variety of cohorts describe an overall germline frequency of approximately 3.8% (range of 1.9% in a group of individuals with uveal melanoma to 8.0% in a subset of apparent sporadic mesotheliomas) .	('mutations', 'Var', (63, 72))	('uveal melanoma', 'Disease', 'MESH:C536494', (204, 218))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('BAP1', 'Gene', (58, 62))	('uveal melanoma', 'Disease', (204, 218))	('uveal melanoma', 'Phenotype', 'HP:0007716', (204, 218))	('mesotheliomas', 'Disease', (260, 273))	('mesotheliomas', 'Disease', 'MESH:D008654', (260, 273))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (251, 273))	('BAP1', 'Gene', '8314', (58, 62))
150651	23709298	Overall, these data show that germline BAP1 mutations predispose to several tumor types and the degree of tumor susceptibility conferred by BAP1 mutation may vary across tissues.	('BAP1', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('predispose', 'Reg', (54, 64))	('mutations', 'Var', (44, 53))	('BAP1', 'Gene', '8314', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('BAP1', 'Gene', '8314', (140, 144))	('tumor', 'Disease', (106, 111))	('BAP1', 'Gene', (39, 43))
150652	23709298	First, among the 82 probands successfully evaluated, only one possibly pathogenic BAP1 variant was found.	('BAP1', 'Gene', (82, 86))	('variant', 'Var', (87, 94))	('BAP1', 'Gene', '8314', (82, 86))
150654	23709298	However, given the loss of BAP1 proein by IHC in all tumors examined (n=3) and a probability that this finding would be from chance alone of 0.0034, our results strongly suggest that the variant identified is responsible for the RCC predisposition observed.	('variant', 'Var', (187, 194))	('RCC', 'Disease', 'MESH:C538614', (229, 232))	('BAP1', 'Gene', (27, 31))	('loss', 'NegReg', (19, 23))	('RCC', 'Disease', (229, 232))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('RCC', 'Phenotype', 'HP:0005584', (229, 232))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', (53, 59))	('BAP1', 'Gene', '8314', (27, 31))
150659	19718013	Although the reported prevalence of KIT mutations in acral lentiginous/ mucosal melanomas is relatively low, detection of mutations in KIT can have profound therapeutic implications.	('melanomas', 'Phenotype', 'HP:0002861', (80, 89))	('KIT', 'molecular_function', 'GO:0005020', ('135', '138'))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('mutations', 'Var', (40, 49))	('KIT', 'molecular_function', 'GO:0005020', ('36', '39'))	('mucosal melanomas', 'Disease', (72, 89))	('mucosal melanomas', 'Disease', 'MESH:D008545', (72, 89))	('acral lentiginous', 'Disease', 'MESH:D007911', (53, 70))	('acral lentiginous', 'Disease', (53, 70))
150663	19718013	The overall frequency of activating KIT gene mutations in acral lentiginous/ mucosal melanomas was 15% (14 out of 91 cases), being the L576P mutation in exon 11 the most frequently detected (4 of 14 cases).	('mucosal melanomas', 'Disease', (77, 94))	('mutations', 'Var', (45, 54))	('acral lentiginous', 'Disease', 'MESH:D007911', (58, 75))	('KIT gene', 'Gene', (36, 44))	('activating', 'PosReg', (25, 35))	('mucosal melanomas', 'Disease', 'MESH:D008545', (77, 94))	('acral lentiginous', 'Disease', (58, 75))	('L576P', 'Mutation', 'rs121913513', (135, 140))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('L576P', 'Var', (135, 140))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('KIT', 'molecular_function', 'GO:0005020', ('36', '39'))
150665	19718013	Immunohistochemical expression of KIT in less than 10% of the cells of the invasive component of acral lentiginous/mucosal melanomas appears to be a strong negative predictor of KIT mutation and therefore can potentially be used to triage cases for additional KIT genotyping.	('KIT', 'Disease', (178, 181))	('KIT', 'molecular_function', 'GO:0005020', ('260', '263'))	('KIT', 'molecular_function', 'GO:0005020', ('178', '181'))	('acral lentiginous/mucosal melanomas', 'Disease', (97, 132))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('mutation', 'Var', (182, 190))	('acral lentiginous/mucosal melanomas', 'Disease', 'MESH:D007911', (97, 132))	('negative', 'NegReg', (156, 164))	('KIT', 'molecular_function', 'GO:0005020', ('34', '37'))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))
150667	19718013	Whereas KIT activation mutations are known to be associated with a variety of malignant human tumors such as gastrointestinal stromal tumor (GIST), seminoma, and mastocytosis/mast cell leukemia, the introduction of a KIT-activating mutation into an immortalized murine melanocyte cell line was reported to result in a motogenic more than a mitogenic effect.	('associated', 'Reg', (49, 59))	('gastrointestinal stromal tumor', 'Disease', (109, 139))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('GIST', 'Phenotype', 'HP:0100723', (141, 145))	('human', 'Species', '9606', (88, 93))	('motogenic more', 'MPA', (318, 332))	('seminoma', 'Disease', (148, 156))	('murine', 'Species', '10090', (262, 268))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('seminoma', 'Disease', 'MESH:D018239', (148, 156))	('mutations', 'Var', (23, 32))	('tumors', 'Disease', (94, 100))	('mastocytosis/mast cell leukemia', 'Disease', (162, 193))	('KIT', 'molecular_function', 'GO:0005020', ('217', '220'))	('mutation', 'Var', (232, 240))	('mastocytosis/mast cell leukemia', 'Disease', 'MESH:D007946', (162, 193))	('KIT', 'molecular_function', 'GO:0005020', ('8', '11'))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('mitogenic effect', 'MPA', (340, 356))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (109, 139))	('mastocytosis', 'Phenotype', 'HP:0100495', (162, 174))	('leukemia', 'Phenotype', 'HP:0001909', (185, 193))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (109, 139))
150671	19718013	Sporadic reports of rare metastatic melanomas harboring the L576P KIT-activating mutation and displaying strong and diffuse KIT expression, suggested that in a subset of cases, melanoma progression would involve KIT activation rather than loss of KIT activity.	('L576P', 'Var', (60, 65))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('KIT', 'molecular_function', 'GO:0005020', ('212', '215'))	('KIT', 'molecular_function', 'GO:0005020', ('124', '127'))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('melanoma', 'Disease', (177, 185))	('melanomas', 'Disease', 'MESH:D008545', (36, 45))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('KIT', 'molecular_function', 'GO:0005020', ('247', '250'))	('KIT', 'molecular_function', 'GO:0005020', ('66', '69'))	('activation', 'PosReg', (216, 226))	('KIT-activating', 'Gene', (66, 80))	('L576P', 'Mutation', 'rs121913513', (60, 65))	('melanomas', 'Disease', (36, 45))
150673	19718013	Although a trial using imatinib mesylate in melanomas without KIT mutations showed no overall benefit, use of tyrosine kinase inhibitors in cases with documented mutations has shown dramatic results.- Subsequently, using array comparative genomic hybridization and mutation analysis, Curtin et al found that mucosal, acral, and sun-induced melanomas frequently show genetic amplification of the KIT locus and activating mutations of the gene.	('KIT', 'Gene', (395, 398))	('activating', 'PosReg', (409, 419))	('KIT', 'molecular_function', 'GO:0005020', ('395', '398'))	('melanomas', 'Disease', (44, 53))	('melanoma', 'Phenotype', 'HP:0002861', (340, 348))	('melanomas', 'Disease', (340, 349))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('tyrosine kinase', 'Gene', '7294', (110, 125))	('KIT', 'molecular_function', 'GO:0005020', ('62', '65'))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('melanomas', 'Phenotype', 'HP:0002861', (340, 349))	('melanomas', 'Disease', 'MESH:D008545', (44, 53))	('genetic amplification', 'Var', (366, 387))	('melanomas', 'Disease', 'MESH:D008545', (340, 349))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (23, 40))	('tyrosine kinase', 'Gene', (110, 125))
150674	19718013	Although most of the mutation-positive cases showed elevated KIT protein expression, some of the analyzed tumors required higher antibody concentrations for the immunohistochemical detection of KIT.	('antibody', 'cellular_component', 'GO:0019815', ('129', '137'))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('antibody', 'cellular_component', 'GO:0019814', ('129', '137'))	('KIT', 'molecular_function', 'GO:0005020', ('194', '197'))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('antibody', 'molecular_function', 'GO:0003823', ('129', '137'))	('KIT', 'molecular_function', 'GO:0005020', ('61', '64'))	('expression', 'MPA', (73, 83))	('mutation-positive', 'Var', (21, 38))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('antibody', 'cellular_component', 'GO:0042571', ('129', '137'))	('KIT protein', 'Protein', (61, 72))	('elevated', 'PosReg', (52, 60))
150677	19718013	The prevalence of KIT mutations in acral lentiginous/mucosal melanomas is relatively low (no more than 15-20%-) but can have profound therapeutic implications for localized high risk or metastatic disease.	('KIT', 'Gene', (18, 21))	('acral lentiginous/mucosal melanomas', 'Disease', (35, 70))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('acral lentiginous/mucosal melanomas', 'Disease', 'MESH:D007911', (35, 70))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('mutations', 'Var', (22, 31))	('KIT', 'molecular_function', 'GO:0005020', ('18', '21'))
150679	19718013	Our goal was to correlate the level of KIT expression and activating KIT gene mutations in these tumors to evaluate the efficacy of immunohistochemistry to discriminate potential candidates for targeted therapy.	('KIT', 'molecular_function', 'GO:0005020', ('69', '72'))	('KIT gene', 'Gene', (69, 77))	('KIT', 'molecular_function', 'GO:0005020', ('39', '42'))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('activating', 'PosReg', (58, 68))	('mutations', 'Var', (78, 87))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
150684	19718013	Our series was enriched with a large number of acral lentiginous/mucosal melanomas as these tumors were the most likely to harbor mutations in KIT.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('KIT', 'molecular_function', 'GO:0005020', ('143', '146'))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('harbor', 'Reg', (123, 129))	('mutations', 'Var', (130, 139))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('KIT', 'Gene', (143, 146))	('acral lentiginous/mucosal melanomas', 'Disease', (47, 82))	('tumors', 'Disease', (92, 98))	('acral lentiginous/mucosal melanomas', 'Disease', 'MESH:D007911', (47, 82))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
150722	19718013	In two of the cases (one mucosal and one acral lentiginous melanoma), mutations of the KIT gene were found (Figure 3).	('acral lentiginous melanoma', 'Disease', (41, 67))	('mutations', 'Var', (70, 79))	('acral lentiginous melanoma', 'Disease', 'MESH:D007911', (41, 67))	('found', 'Reg', (101, 106))	('KIT', 'Gene', (87, 90))	('KIT', 'molecular_function', 'GO:0005020', ('87', '90'))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('acral lentiginous melanoma', 'Phenotype', 'HP:0012060', (41, 67))
150725	19718013	The overall frequency of KIT gene mutation in the acral lentiginous/ mucosal melanoma group was 15% (14 out of 91 informative cases).	('mucosal melanoma', 'Disease', (69, 85))	('mutation', 'Var', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('mucosal melanoma', 'Disease', 'MESH:D008545', (69, 85))	('acral lentiginous', 'Disease', 'MESH:D007911', (50, 67))	('KIT', 'molecular_function', 'GO:0005020', ('25', '28'))	('acral lentiginous', 'Disease', (50, 67))	('KIT gene', 'Gene', (25, 33))
150729	19718013	Two cases displaying the L576P mutation in exon 11 were mucosal melanomas from the anor-ectal region.	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('L576P', 'Mutation', 'rs121913513', (25, 30))	('mucosal melanomas', 'Disease', (56, 73))	('L576P', 'Var', (25, 30))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('mucosal melanomas', 'Disease', 'MESH:D008545', (56, 73))
150731	19718013	Mutations in exons 11, 13, and 17 were detected in both acral lentiginous and mucosal subgroups.	('acral lentiginous', 'Disease', (56, 73))	('detected', 'Reg', (39, 47))	('Mutations in', 'Var', (0, 12))	('acral lentiginous', 'Disease', 'MESH:D007911', (56, 73))
150735	19718013	However, there is an obvious association between the acral lentiginous/mucosal group (considered as a whole) and KIT mutation, as all the positive cases were acral lentiginous/mucosal melanomas, and none of the 'non-acral lentiginous/ mucosal' cases was found to carry any mutation.	('acral lentiginous/mucosal melanomas', 'Disease', 'MESH:D007911', (158, 193))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanomas', 'Phenotype', 'HP:0002861', (184, 193))	('acral lentiginous', 'Disease', 'MESH:D007911', (216, 233))	('acral lentiginous', 'Disease', (216, 233))	('acral lentiginous', 'Disease', 'MESH:D007911', (158, 175))	('KIT', 'molecular_function', 'GO:0005020', ('113', '116'))	('KIT', 'Gene', (113, 116))	('mutation', 'Var', (117, 125))	('acral lentiginous', 'Disease', 'MESH:D007911', (53, 70))	('acral lentiginous', 'Disease', (53, 70))	('acral lentiginous/mucosal melanomas', 'Disease', (158, 193))
150736	19718013	None of the cases showing <5% positive tumor cells was found to harbor KIT mutations (0 of 32 cases), indicating a negative predictive value of 100% in this study.	('KIT', 'molecular_function', 'GO:0005020', ('71', '74'))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('mutations', 'Var', (75, 84))	('tumor', 'Disease', (39, 44))
150755	19718013	Fifteen of 135 (11%) cases analyzed for KIT mutations were non-informative because of low quality or insufficient DNA and possibly inhibition of PCR amplification by melanin pigment or other inhibiting substances.	('melanin pigment', 'Chemical', '-', (166, 181))	('PCR', 'Gene', (145, 148))	('KIT', 'Gene', (40, 43))	('KIT', 'molecular_function', 'GO:0005020', ('40', '43'))	('mutations', 'Var', (44, 53))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('inhibition', 'NegReg', (131, 141))
150757	19718013	The first case of a KIT mutation-positive melanoma (an L576P activation mutation in exon 11) was published in 2004 by Went et al Since then, two cases of metastatic melanoma from unknown primary and three primary anal melanomas have been reported to harbor the same mutation.	('melanoma', 'Disease', (42, 50))	('KIT', 'molecular_function', 'GO:0005020', ('20', '23'))	('L576P', 'Mutation', 'rs121913513', (55, 60))	('melanomas', 'Disease', 'MESH:D008545', (218, 227))	('melanoma', 'Disease', (218, 226))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanomas', 'Phenotype', 'HP:0002861', (218, 227))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('melanomas', 'Disease', (218, 227))	('L576P', 'Var', (55, 60))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
150758	19718013	In 2006, Curtin et al found mutations and/or copy number increases of KIT in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin; specific KIT mutations were shown in three out of 28 (11%) primary acral and 8 of 38 (21%) primary mucosal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanomas', 'Phenotype', 'HP:0002861', (268, 277))	('copy', 'MPA', (45, 49))	('mucosal melanomas', 'Disease', (260, 277))	('melanomas', 'Disease', 'MESH:D008545', (268, 277))	('melanomas', 'Phenotype', 'HP:0002861', (118, 127))	('KIT', 'Gene', (70, 73))	('KIT', 'molecular_function', 'GO:0005020', ('70', '73'))	('primary acral', 'Disease', (220, 233))	('melanomas', 'Disease', 'MESH:D008545', (118, 127))	('sun-damaged', 'Phenotype', 'HP:0000992', (143, 154))	('mucosal melanomas', 'Disease', 'MESH:D008545', (260, 277))	('melanomas', 'Disease', (268, 277))	('melanoma', 'Phenotype', 'HP:0002861', (268, 276))	('mutations', 'Var', (174, 183))	('melanomas', 'Disease', (118, 127))	('KIT', 'molecular_function', 'GO:0005020', ('170', '173'))	('mutations', 'Var', (28, 37))
150760	19718013	Mucosal melanomas from the oral cavity have been reported to demonstrate mutations in KIT in 4 out of 18 cases.	('KIT', 'Gene', (86, 89))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('Mucosal melanomas', 'Disease', (0, 17))	('KIT', 'molecular_function', 'GO:0005020', ('86', '89'))	('mutations', 'Var', (73, 82))	('Mucosal melanomas', 'Disease', 'MESH:D008545', (0, 17))
150761	19718013	In a recent study, Beadling et al reported 23 and 15.6% of acral lentiginous and mucosal melanomas to be positive for KIT mutations, respectively.	('mucosal melanomas', 'Disease', (81, 98))	('KIT', 'molecular_function', 'GO:0005020', ('118', '121'))	('acral lentiginous', 'Disease', 'MESH:D007911', (59, 76))	('KIT', 'Gene', (118, 121))	('acral lentiginous', 'Disease', (59, 76))	('mucosal melanomas', 'Disease', 'MESH:D008545', (81, 98))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('mutations', 'Var', (122, 131))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('positive', 'Reg', (105, 113))
150765	19718013	We were able to show the same activating mutations in primary tumors and their metastases in three patients (Table 4).	('mutations', 'Var', (41, 50))	('activating', 'PosReg', (30, 40))	('metastases', 'Disease', 'MESH:D009362', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('patients', 'Species', '9606', (99, 107))	('metastases', 'Disease', (79, 89))
150766	19718013	KIT mutations in acral lentiginous/mucosal melanomas most frequently occurred in exon 11 (9 out of 14 cases, 64%).	('acral lentiginous/mucosal melanomas', 'Disease', (17, 52))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('acral lentiginous/mucosal melanomas', 'Disease', 'MESH:D007911', (17, 52))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanomas', 'Phenotype', 'HP:0002861', (43, 52))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))	('occurred', 'Reg', (69, 77))
150768	19718013	One of our cases was found to carry the V559A mutation in exon 11 in both primary and metastatic tumors.	('metastatic', 'CPA', (86, 96))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('V559A', 'Var', (40, 45))	('V559A', 'Mutation', 'rs121913517', (40, 45))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
150769	19718013	This substitution, as L576P, constitutes a target for imatinib mesylate therapy., One of our cases, a primary anorectal mucosal melanoma harboring the V560D mutation, was previously reported.	('anorectal mucosal melanoma', 'Disease', (110, 136))	('V560D', 'Var', (151, 156))	('V560D', 'Mutation', 'rs121913521', (151, 156))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('anorectal mucosal melanoma', 'Disease', 'MESH:D008545', (110, 136))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (54, 71))	('L576P', 'Mutation', 'rs121913513', (22, 27))
150770	19718013	Other mutations in exon 11, not previously found in melanomas, were the V559G substitution and deletions of codons 566- 572 and 566-574.- Mutations found in exon 13 were K642E, which affects the first tyrosine kinase domain and has been reported in melanomas and GIST,,, and N655K, which has recently been identified in a case of GIST and found to be of gain-of-function and imatinib mesylate sensitive.	('melanomas', 'Disease', 'MESH:D008545', (52, 61))	('V559G', 'Mutation', 'rs121913517', (72, 77))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('GIST', 'Phenotype', 'HP:0100723', (263, 267))	('melanomas', 'Phenotype', 'HP:0002861', (249, 258))	('N655K', 'Mutation', 'rs1057519708', (275, 280))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))	('N655K', 'Var', (275, 280))	('melanomas', 'Disease', 'MESH:D008545', (249, 258))	('tyrosine kinase', 'Gene', '7294', (201, 216))	('melanoma', 'Phenotype', 'HP:0002861', (249, 257))	('melanomas', 'Disease', (52, 61))	('GIST', 'Phenotype', 'HP:0100723', (330, 334))	('K642E', 'Var', (170, 175))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (375, 392))	('tyrosine kinase', 'Gene', (201, 216))	('melanomas', 'Disease', (249, 258))	('K642E', 'Mutation', 'rs121913512', (170, 175))
150771	19718013	One case harboring the K642E mutation was identified to carry a second mutation, N822I in exon 17.	('N822I', 'Mutation', 'rs993022333', (81, 86))	('K642E', 'Var', (23, 28))	('N822I', 'Var', (81, 86))	('K642E', 'Mutation', 'rs121913512', (23, 28))
150772	19718013	Evidence exists that K642E is a weakly activating mutation that requires additional genetic alterations to be fully oncogenic.	('K642E', 'Var', (21, 26))	('K642E', 'Mutation', 'rs121913512', (21, 26))	('activating', 'PosReg', (39, 49))
150773	19718013	Mutations detected in exon 17, which encodes the second tyrosine kinase catalytic domain of KIT, were D816V and N822I.	('D816V', 'SUBSTITUTION', 'None', (102, 107))	('N822I', 'Mutation', 'rs993022333', (112, 117))	('tyrosine kinase', 'Gene', '7294', (56, 71))	('KIT', 'molecular_function', 'GO:0005020', ('92', '95'))	('tyrosine kinase', 'Gene', (56, 71))	('D816V', 'Var', (102, 107))	('N822I', 'Var', (112, 117))
150774	19718013	D816V has been previously reported to occur in acute myeloid leukemia and mastocytosis, but not in melanoma.	('mastocytosis', 'Disease', (74, 86))	('occur', 'Reg', (38, 43))	('acute myeloid leukemia', 'Disease', (47, 69))	('mastocytosis', 'Disease', 'MESH:D008415', (74, 86))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (53, 69))	('D816V', 'SUBSTITUTION', 'None', (0, 5))	('mastocytosis', 'Phenotype', 'HP:0100495', (74, 86))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (47, 69))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (47, 69))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('leukemia', 'Phenotype', 'HP:0001909', (61, 69))	('D816V', 'Var', (0, 5))
150776	19718013	A mutation in the same site, D816H, has been identified in imatinib mesylate-resistant GIST, germ-cell tumors, and two cases of mucosal and chronic sun-induced damage melanomas.	('damage melanomas', 'Disease', (160, 176))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('identified', 'Reg', (45, 55))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (59, 76))	('damage melanomas', 'Disease', 'MESH:D008545', (160, 176))	('D816H', 'Mutation', 'rs121913506', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanomas', 'Phenotype', 'HP:0002861', (167, 176))	('GIST', 'Phenotype', 'HP:0100723', (87, 91))	('D816H', 'Var', (29, 34))
150784	19718013	Complete and major clinical responses to imatinib mesylate have been reported in two cases of metastatic anorectal mucosal melanomas carrying the K642E mutation and a seven codon duplication in exon 11, both strongly expressing KIT by immunohistochemistry., We have reported a case of metastatic mucosal melanoma from the anus/rectum harboring the V560D mutation and diffusely immunoreactive for KIT that showed complete response for 5 months to sorafenib, another receptor tyrosine kinase inhibitor.	('anorectal mucosal melanomas', 'Disease', (105, 132))	('anorectal mucosal melanomas', 'Disease', 'MESH:D008545', (105, 132))	('mucosal melanoma', 'Disease', 'MESH:D008545', (296, 312))	('KIT', 'molecular_function', 'GO:0005020', ('396', '399'))	('tyrosine kinase', 'Gene', (474, 489))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('483', '499'))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (41, 58))	('KIT', 'molecular_function', 'GO:0005020', ('228', '231'))	('tyrosine kinase', 'Gene', '7294', (474, 489))	('mucosal melanoma', 'Disease', (296, 312))	('V560D', 'Var', (348, 353))	('V560D', 'Mutation', 'rs121913521', (348, 353))	('sorafenib', 'Chemical', 'MESH:D000077157', (446, 455))	('metastatic', 'Disease', (285, 295))	('K642E', 'Mutation', 'rs121913512', (146, 151))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('melanoma', 'Phenotype', 'HP:0002861', (304, 312))	('mucosal melanoma', 'Disease', 'MESH:D008545', (115, 131))
150810	24685257	Several studies have shown that monosomy 3 is also an important prognostic factor with regard to predicting death due to metastatic disease.	('death', 'Disease', 'MESH:D003643', (108, 113))	('metastatic disease', 'Disease', (121, 139))	('death', 'Disease', (108, 113))	('monosomy 3', 'Var', (32, 42))
150811	24685257	reported that the best predictive index can be obtained by using several parameters, including monosomy 3, basal tumour diameter, and epithelioid cellularity, creating a combined prognostic index.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('basal tumour', 'Disease', 'MESH:D002280', (107, 119))	('basal tumour', 'Disease', (107, 119))	('basal tumour', 'Phenotype', 'HP:0002671', (107, 119))	('monosomy 3', 'Var', (95, 105))
150825	24685257	Cases were defined as patients with uveal melanoma as identified by the International Classification of Diseases, Tenth Revision (ICD-10) as C69.3 (Choroid) or C69.4 (Ciliary body) and by International Classification of Diseases for Oncology morphology codes 8720/3 to 8774/3 (uveal melanoma).	('patients', 'Species', '9606', (22, 30))	('C69.3', 'Var', (141, 146))	('uveal melanoma', 'Disease', 'MESH:C536494', (277, 291))	('uveal melanoma', 'Disease', 'MESH:C536494', (36, 50))	('C69.4', 'Var', (160, 165))	('melanoma', 'Phenotype', 'HP:0002861', (283, 291))	('uveal melanoma', 'Phenotype', 'HP:0007716', (277, 291))	('uveal melanoma', 'Disease', (277, 291))	('uveal melanoma', 'Phenotype', 'HP:0007716', (36, 50))	('Oncology', 'Phenotype', 'HP:0002664', (233, 241))	('uveal melanoma', 'Disease', (36, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
150846	24685257	By ciliary body involvement, the adjusted 5-year probability of uveal melanoma death was nearly doubled compared with no ciliary body involvement (21.0% (95% CI: 11.4-29.5) versus 12.2% (95% CI: 8.5-15.7)) (Figure 2c).	('men', 'Species', '9606', (141, 144))	('uveal melanoma death', 'Disease', (64, 84))	('ciliary', 'Var', (3, 10))	('men', 'Species', '9606', (23, 26))	('uveal melanoma', 'Phenotype', 'HP:0007716', (64, 78))	('uveal melanoma death', 'Disease', 'MESH:C536494', (64, 84))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
150882	23799844	TERT promoter mutations in ocular melanoma distinguish between conjunctival and uveal tumours Recently, activating mutations in the TERT promoter were identified in cutaneous melanoma.	('cutaneous melanoma', 'Disease', (165, 183))	('ocular melanoma', 'Disease', (27, 42))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (165, 183))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (165, 183))	('mutations', 'Var', (115, 124))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('uveal tumours', 'Disease', (80, 93))	('ocular melanoma', 'Disease', 'MESH:D008545', (27, 42))	('ocular melanoma', 'Phenotype', 'HP:0007716', (27, 42))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('TERT', 'Gene', (132, 136))	('TERT', 'Gene', '7015', (132, 136))	('mutations', 'Var', (14, 23))	('uveal tumours', 'Disease', 'MESH:D014604', (80, 93))
150883	23799844	We tested a cohort of ocular melanoma samples for similar mutations.	('mutations', 'Var', (58, 67))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('tested', 'Reg', (3, 9))	('ocular melanoma', 'Disease', 'MESH:D008545', (22, 37))	('ocular melanoma', 'Disease', (22, 37))	('ocular melanoma', 'Phenotype', 'HP:0007716', (22, 37))
150885	23799844	Mutations of the TERT promoter were not identified in uveal melanomas, but were detected in 12 (32%) conjunctival melanomas.	('uveal melanomas', 'Disease', (54, 69))	('uveal melanomas', 'Phenotype', 'HP:0007716', (54, 69))	('melanomas', 'Phenotype', 'HP:0002861', (114, 123))	('TERT', 'Gene', (17, 21))	('TERT', 'Gene', '7015', (17, 21))	('uveal melanomas', 'Disease', 'MESH:C536494', (54, 69))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('detected', 'Reg', (80, 88))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (101, 122))	('conjunctival melanomas', 'Disease', (101, 123))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (101, 123))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
150886	23799844	Mutations had a UV signature and were identical to those found in cutaneous melanoma.	('cutaneous melanoma', 'Disease', (66, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (66, 84))	('Mutations', 'Var', (0, 9))	('UV signature', 'MPA', (16, 28))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
150887	23799844	Mutations of TERT promoter with UV signatures are frequent in conjunctival melanomas and favour a pathogenetic kinship with cutaneous melanomas.	('TERT', 'Gene', (13, 17))	('TERT', 'Gene', '7015', (13, 17))	('frequent', 'Reg', (50, 58))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (124, 143))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (124, 143))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('conjunctival melanomas', 'Disease', (62, 84))	('Mutations', 'Var', (0, 9))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (124, 142))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('cutaneous melanomas', 'Disease', (124, 143))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (62, 84))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('melanomas', 'Phenotype', 'HP:0002861', (134, 143))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (62, 83))
150888	23799844	Absence of these mutations in uveal melanomas emphasises their genetic distinction from cutaneous and conjunctival melanomas.	('uveal melanomas', 'Disease', (30, 45))	('uveal melanomas', 'Phenotype', 'HP:0007716', (30, 45))	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (102, 124))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (102, 123))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('conjunctival melanomas', 'Disease', (102, 124))	('uveal melanomas', 'Disease', 'MESH:C536494', (30, 45))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('mutations', 'Var', (17, 26))	('Absence', 'NegReg', (0, 7))
150891	23799844	Cutaneous melanoma is characterised by activating driver mutations in genes such as BRAF, NRAS, and KIT, and recurrent losses of specific tumour suppressors such as CDKN2A and PTEN.	('KIT', 'Gene', (100, 103))	('mutations', 'Var', (57, 66))	('activating', 'PosReg', (39, 49))	('CDKN2A', 'Gene', '1029', (165, 171))	('Cutaneous melanoma', 'Disease', (0, 18))	('NRAS', 'Gene', (90, 94))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('tumour', 'Disease', (138, 144))	('BRAF', 'Gene', '673', (84, 88))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('PTEN', 'Gene', (176, 180))	('BRAF', 'Gene', (84, 88))	('losses', 'NegReg', (119, 125))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('NRAS', 'Gene', '4893', (90, 94))	('PTEN', 'Gene', '5728', (176, 180))	('KIT', 'molecular_function', 'GO:0005020', ('100', '103'))	('CDKN2A', 'Gene', (165, 171))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))
150895	23799844	They are characterised by activating somatic mutations in either GNAQ or GNA11.	('activating', 'PosReg', (26, 36))	('GNA11', 'Gene', (73, 78))	('mutations', 'Var', (45, 54))	('GNA11', 'Gene', '2767', (73, 78))	('GNAQ', 'Gene', '2776', (65, 69))	('GNAQ', 'Gene', (65, 69))
150897	23799844	Class 1 tumours frequently harbour SF3B1 mutations, whereas class 2 tumours typically show chromosomal monosomy 3, as well as inactivating BAP1 mutations.	('mutations', 'Var', (41, 50))	('SF3B1', 'Gene', '23451', (35, 40))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('tumours', 'Disease', (8, 15))	('BAP1', 'Gene', '8314', (139, 143))	('tumours', 'Disease', 'MESH:D009369', (68, 75))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('tumours', 'Disease', (68, 75))	('SF3B1', 'Gene', (35, 40))	('inactivating', 'Var', (126, 138))	('BAP1', 'Gene', (139, 143))	('mutations', 'Var', (144, 153))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('tumours', 'Disease', 'MESH:D009369', (8, 15))
150898	23799844	Conjunctival melanomas, unlike uveal melanomas, frequently harbour BRAF and NRAS mutations and copy number alterations reminiscent of cutaneous and mucosal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (31, 45))	('NRAS', 'Gene', (76, 80))	('uveal melanomas', 'Disease', (31, 46))	('uveal melanomas', 'Phenotype', 'HP:0007716', (31, 46))	('mutations', 'Var', (81, 90))	('melanomas', 'Phenotype', 'HP:0002861', (37, 46))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('harbour', 'Reg', (59, 66))	('copy number alterations', 'Var', (95, 118))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('NRAS', 'Gene', '4893', (76, 80))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('mucosal melanoma', 'Disease', 'MESH:D008545', (148, 164))	('uveal melanomas', 'Disease', 'MESH:C536494', (31, 46))	('Conjunctival melanomas', 'Disease', (0, 22))	('BRAF', 'Gene', '673', (67, 71))	('BRAF', 'Gene', (67, 71))	('mucosal melanoma', 'Disease', (148, 164))	('Conjunctival melanomas', 'Disease', 'MESH:D003229', (0, 22))
150900	23799844	Recently two studies showed that up to 71% of cutaneous melanomas harboured novel mutations in the promoter region of TERT, coding for the catalytic subunit of the telomerase holoenzyme.	('TERT', 'Gene', '7015', (118, 122))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (46, 65))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (46, 65))	('mutations in', 'Var', (82, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('cutaneous melanomas', 'Disease', (46, 65))	('TERT', 'Gene', (118, 122))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
150901	23799844	These mutations were shown to lead to increased TERT expression, most likely by creating ETS transcription-factor-binding sites.	('transcription', 'biological_process', 'GO:0006351', ('93', '106'))	('transcription-factor-binding', 'Interaction', (93, 121))	('TERT', 'Gene', (48, 52))	('transcription-factor-binding', 'molecular_function', 'GO:0008134', ('93', '121'))	('TERT', 'Gene', '7015', (48, 52))	('ETS', 'MPA', (89, 92))	('increased', 'PosReg', (38, 47))	('mutations', 'Var', (6, 15))
150902	23799844	An additional study found TERT promoter mutations in a wide array of different human cancers, including bladder cancer, hepatocellular carcinoma, and different types of gliomas.	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (104, 118))	('bladder cancer', 'Disease', (104, 118))	('hepatocellular carcinoma', 'Disease', (120, 144))	('gliomas', 'Disease', (169, 176))	('human', 'Species', '9606', (79, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('mutations', 'Var', (40, 49))	('bladder cancer', 'Phenotype', 'HP:0009725', (104, 118))	('gliomas', 'Disease', 'MESH:D005910', (169, 176))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (120, 144))	('TERT', 'Gene', (26, 30))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('TERT', 'Gene', '7015', (26, 30))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (120, 144))
150903	23799844	They associated high frequencies of TERT promoter mutations, with tumours arising in tissues having low rates of self-renewal.	('TERT', 'Gene', '7015', (36, 40))	('mutations', 'Var', (50, 59))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('tumours', 'Disease', (66, 73))	('TERT', 'Gene', (36, 40))
150904	23799844	The frequency of TERT promoter mutations in ocular melanomas has not been analysed.	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('mutations', 'Var', (31, 40))	('ocular melanoma', 'Phenotype', 'HP:0007716', (44, 59))	('TERT', 'Gene', (17, 21))	('TERT', 'Gene', '7015', (17, 21))	('ocular melanomas', 'Phenotype', 'HP:0025534', (44, 60))	('ocular melanomas', 'Disease', 'MESH:D008545', (44, 60))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('ocular melanomas', 'Disease', (44, 60))
150905	23799844	Here, we investigated the presence of TERT promoter mutations in ocular melanomas including conjunctival and uveal melanomas.	('mutations', 'Var', (52, 61))	('ocular melanomas', 'Phenotype', 'HP:0025534', (65, 81))	('uveal melanomas', 'Disease', (109, 124))	('uveal melanomas', 'Phenotype', 'HP:0007716', (109, 124))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('ocular melanomas', 'Disease', 'MESH:D008545', (65, 81))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('TERT', 'Gene', (38, 42))	('ocular melanomas', 'Disease', (65, 81))	('uveal melanomas', 'Disease', 'MESH:C536494', (109, 124))	('ocular melanoma', 'Phenotype', 'HP:0007716', (65, 80))	('TERT', 'Gene', '7015', (38, 42))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('conjunctival', 'Disease', (92, 104))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))
150916	23799844	The study cohort consisted of 50 uveal melanoma samples (which included 22 tumours with chromosome 3 disomy, and 28 tumours with chromosome 3 monosomy) randomly selected from a cohort of 374 tumours described previously, and 43 conjunctival melanoma samples.	('conjunctival melanoma', 'Disease', 'MESH:D003229', (228, 249))	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (228, 249))	('tumours', 'Disease', 'MESH:D009369', (75, 82))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('tumours', 'Disease', 'MESH:D009369', (116, 123))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('129', '139'))	('tumours', 'Disease', (191, 198))	('uveal melanoma', 'Disease', 'MESH:C536494', (33, 47))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('uveal melanoma', 'Disease', (33, 47))	('chromosome', 'cellular_component', 'GO:0005694', ('88', '98'))	('tumours', 'Phenotype', 'HP:0002664', (191, 198))	('conjunctival melanoma', 'Disease', (228, 249))	('tumours', 'Disease', 'MESH:D009369', (191, 198))	('uveal melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('tumours', 'Disease', (75, 82))	('chromosome 3 disomy', 'Var', (88, 107))	('tumours', 'Disease', (116, 123))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
150921	23799844	Sequence analysis was successful in 38 of the 43 conjunctival melanomas, and TERT promoter mutations were identified in 12 (32%) tumours.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('TERT', 'Gene', (77, 81))	('tumours', 'Disease', 'MESH:D009369', (129, 136))	('TERT', 'Gene', '7015', (77, 81))	('tumours', 'Disease', (129, 136))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (49, 70))	('mutations', 'Var', (91, 100))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (49, 71))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('conjunctival melanomas', 'Disease', (49, 71))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
150924	23799844	All identified TERT promoter mutations had a UV signature (C>T and CC>TT).	('TERT', 'Gene', '7015', (15, 19))	('CC>TT', 'Var', (67, 72))	('C>T', 'Var', (59, 62))	('TERT', 'Gene', (15, 19))
150927	23799844	Ten of the thirty-eight tumours (26%) harboured BRAF mutations: nine p.V600E (c.1799T>A) and one p.G469A (c.1406G>C).	('tumours', 'Disease', (24, 31))	('p.V600E (c.1799T>A', 'Var', (69, 87))	('c.1406G>C', 'Mutation', 'rs121913355', (106, 115))	('p.G469A', 'Mutation', 'rs121913355', (97, 104))	('c.1799T>A', 'Mutation', 'rs113488022', (78, 87))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('tumours', 'Disease', 'MESH:D009369', (24, 31))	('p.G469A', 'Var', (97, 104))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('p.V600E', 'Mutation', 'rs113488022', (69, 76))	('c.1406G>C', 'Var', (106, 115))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
150928	23799844	Four (40%) BRAF-mutant samples had a concomitant TERT promoter mutation (250C>T, n=2 and 228C>T, n=2).	('228C>T', 'Mutation', 'rs876658729', (89, 95))	('228C>T', 'Var', (89, 95))	('TERT', 'Gene', (49, 53))	('250C>T', 'Mutation', 'rs1338231889', (73, 79))	('TERT', 'Gene', '7015', (49, 53))	('BRAF', 'Gene', '673', (11, 15))	('250C>T', 'Var', (73, 79))	('BRAF', 'Gene', (11, 15))
150929	23799844	Mutations of NRAS were present in five (13%) conjunctival melanomas, including three p.Q61R (c.182A>G) and two p.Q61K (c.181C>A) mutations.	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))	('p.Q61K (c.181C>A', 'Var', (111, 127))	('p.Q61R (c.182A>G', 'Var', (85, 101))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (45, 66))	('c.182A>G', 'Mutation', 'rs11554290', (93, 101))	('NRAS', 'Gene', (13, 17))	('conjunctival melanomas', 'Disease', (45, 67))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('NRAS', 'Gene', '4893', (13, 17))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (45, 67))	('p.Q61K', 'Mutation', 'rs121913254', (111, 117))	('present', 'Reg', (23, 30))	('c.181C>A', 'Mutation', 'rs121913254', (119, 127))	('p.Q61R', 'Mutation', 'rs11554290', (85, 91))
150930	23799844	Three (60%) NRAS-mutant samples had concomitant TERT promoter mutations (250C>T, n=3).	('NRAS', 'Gene', (12, 16))	('TERT', 'Gene', (48, 52))	('NRAS', 'Gene', '4893', (12, 16))	('250C>T', 'Mutation', 'rs1338231889', (73, 79))	('250C>T', 'Var', (73, 79))	('TERT', 'Gene', '7015', (48, 52))
150933	23799844	Mutations of the TERT promoter were quite frequent (32%) in conjunctival melanoma, but were not seen in uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (104, 119))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('uveal melanoma', 'Phenotype', 'HP:0007716', (104, 118))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (60, 81))	('TERT', 'Gene', (17, 21))	('TERT', 'Gene', '7015', (17, 21))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (60, 81))	('Mutations', 'Var', (0, 9))	('frequent', 'Reg', (42, 50))	('uveal melanomas', 'Disease', (104, 119))	('uveal melanomas', 'Phenotype', 'HP:0007716', (104, 119))	('conjunctival melanoma', 'Disease', (60, 81))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
150935	23799844	The frequencies of TERT promoter mutations reported in cutaneous melanoma vary significantly, probably in part due to varying sample selection (type of melanomas, primary or metastatic samples, and so on).	('TERT', 'Gene', (19, 23))	('melanomas', 'Disease', 'MESH:D008545', (152, 161))	('TERT', 'Gene', '7015', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanomas', 'Phenotype', 'HP:0002861', (152, 161))	('cutaneous melanoma', 'Disease', (55, 73))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (55, 73))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (55, 73))	('mutations', 'Var', (33, 42))	('melanomas', 'Disease', (152, 161))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))
150938	23799844	Further support for such a link derives from the frequency of BRAF and NRAS mutations, and similarity of clinical behaviour between these melanoma types.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('mutations', 'Var', (76, 85))	('NRAS', 'Gene', (71, 75))	('NRAS', 'Gene', '4893', (71, 75))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('behaviour', 'biological_process', 'GO:0007610', ('114', '123'))
150942	23799844	Mutations of the TERT promoter join the list of genetic events such as mutations in BRAF or NRAS and losses of PTEN or CDKN2A, which are very common in cutaneous melanoma but are virtually never seen in uveal melanoma.	('PTEN', 'Gene', '5728', (111, 115))	('losses', 'NegReg', (101, 107))	('cutaneous melanoma', 'Disease', (152, 170))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (152, 170))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (152, 170))	('uveal melanoma', 'Phenotype', 'HP:0007716', (203, 217))	('mutations', 'Var', (71, 80))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', '4893', (92, 96))	('uveal melanoma', 'Disease', (203, 217))	('BRAF', 'Gene', '673', (84, 88))	('TERT', 'Gene', (17, 21))	('TERT', 'Gene', '7015', (17, 21))	('BRAF', 'Gene', (84, 88))	('CDKN2A', 'Gene', (119, 125))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('PTEN', 'Gene', (111, 115))	('NRAS', 'Gene', (92, 96))	('CDKN2A', 'Gene', '1029', (119, 125))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('uveal melanoma', 'Disease', 'MESH:C536494', (203, 217))
150943	23799844	Considering that correspondingly, almost all genetic events identified in uveal melanoma, such as mutations in GNAQ, GNA11, BAP1, and SF3B1, are rarely seen in cutaneous or mucosal melanoma; uveal melanomas potentially will be found to harbour their own unique set of recurrent mutations in regulatory DNA regions (that is, promoters, enhancers, and so on).	('uveal melanomas', 'Phenotype', 'HP:0007716', (191, 206))	('GNA11', 'Gene', (117, 122))	('mutations', 'Var', (278, 287))	('BAP1', 'Gene', '8314', (124, 128))	('DNA', 'cellular_component', 'GO:0005574', ('302', '305'))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanomas', 'Phenotype', 'HP:0002861', (197, 206))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('uveal melanoma', 'Disease', (74, 88))	('mucosal melanoma', 'Disease', 'MESH:D008545', (173, 189))	('SF3B1', 'Gene', (134, 139))	('uveal melanomas', 'Disease', 'MESH:C536494', (191, 206))	('uveal melanoma', 'Disease', 'MESH:C536494', (191, 205))	('BAP1', 'Gene', (124, 128))	('mucosal melanoma', 'Disease', (173, 189))	('GNA11', 'Gene', '2767', (117, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('GNAQ', 'Gene', '2776', (111, 115))	('uveal melanoma', 'Phenotype', 'HP:0007716', (191, 205))	('SF3B1', 'Gene', '23451', (134, 139))	('GNAQ', 'Gene', (111, 115))	('uveal melanomas', 'Disease', (191, 206))
150944	23799844	found high frequencies (>15%) of TERT promoter mutations in tumours arising from tissues with low self-renewal capability.	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('tumours', 'Disease', (60, 67))	('mutations', 'Var', (47, 56))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
150946	23799844	In certain cancers, reported alternative lengthening of telomeres (ALT) with inactivating mutations in ATRX and DAXX as a mechanism for telomere maintenance in TERT promoter mutation-negative samples.	('TERT', 'Gene', '7015', (160, 164))	('DAXX', 'Gene', (112, 116))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ATRX', 'Gene', (103, 107))	('telomere', 'cellular_component', 'GO:0000781', ('136', '144'))	('ALT', 'molecular_function', 'GO:0004021', ('67', '70'))	('DAXX', 'Gene', '1616', (112, 116))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('telomere maintenance', 'biological_process', 'GO:0000723', ('136', '156'))	('TERT', 'Gene', (160, 164))	('cancers', 'Disease', (11, 18))	('ATRX', 'Gene', '546', (103, 107))	('inactivating mutations', 'Var', (77, 99))	('telomere', 'cellular_component', 'GO:0005696', ('136', '144'))
150948	23799844	Additionally, larger whole-exome sequencing studies both for cutaneous melanoma (, n>250) and uveal melanoma ( and our own unpublished data, n=40) did not find recurrent mutations in ATRX or DAXX.	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('uveal melanoma', 'Disease', (94, 108))	('mutations', 'Var', (170, 179))	('DAXX', 'Gene', '1616', (191, 195))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('ATRX', 'Gene', (183, 187))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('DAXX', 'Gene', (191, 195))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (61, 79))	('cutaneous melanoma', 'Disease', (61, 79))	('ATRX', 'Gene', '546', (183, 187))
150951	23799844	The UV signature in the mutations identified in the TERT promoter of conjunctival melanomas suggests a potential role for UV-induced genetic alterations in the pathogenesis of these tumours.	('pathogenesis', 'biological_process', 'GO:0009405', ('160', '172'))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (69, 91))	('tumours', 'Phenotype', 'HP:0002664', (182, 189))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('TERT', 'Gene', (52, 56))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (69, 90))	('TERT', 'Gene', '7015', (52, 56))	('tumours', 'Disease', 'MESH:D009369', (182, 189))	('tumours', 'Disease', (182, 189))	('mutations', 'Var', (24, 33))	('conjunctival melanomas', 'Disease', (69, 91))
150953	23799844	In summary, the distribution of TERT promoter mutations in ocular melanoma provides further evidence that ocular melanomas comprise genetically distinct tumour groups.	('tumour', 'Disease', (153, 159))	('TERT', 'Gene', '7015', (32, 36))	('ocular melanoma', 'Disease', 'MESH:D008545', (106, 121))	('ocular melanoma', 'Disease', (59, 74))	('mutations', 'Var', (46, 55))	('ocular melanomas', 'Disease', (106, 122))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('ocular melanoma', 'Disease', 'MESH:D008545', (59, 74))	('ocular melanoma', 'Phenotype', 'HP:0007716', (106, 121))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('ocular melanoma', 'Phenotype', 'HP:0007716', (59, 74))	('ocular melanomas', 'Phenotype', 'HP:0025534', (106, 122))	('tumour', 'Disease', 'MESH:D009369', (153, 159))	('ocular melanomas', 'Disease', 'MESH:D008545', (106, 122))	('TERT', 'Gene', (32, 36))
150954	23799844	The presence of TERT promoter mutations with UV signatures in conjunctival melanomas supports an UV-induced pathogenesis and a pathogenetic kinship with cutaneous melanomas.	('TERT', 'Gene', (16, 20))	('melanomas', 'Phenotype', 'HP:0002861', (163, 172))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('TERT', 'Gene', '7015', (16, 20))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (153, 172))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (153, 172))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (153, 171))	('pathogenesis', 'biological_process', 'GO:0009405', ('108', '120'))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('conjunctival melanomas', 'Disease', (62, 84))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('mutations', 'Var', (30, 39))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (62, 84))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (62, 83))	('cutaneous melanomas', 'Disease', (153, 172))
150957	22038994	We recently showed that inactivating mutations in the tumor suppressor gene BAP1 are closely associated with loss of melanocytic differentiation in uveal melanoma and metastasis (UM).	('UM', 'Phenotype', 'HP:0007716', (179, 181))	('inactivating mutations', 'Var', (24, 46))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('54', '70'))	('loss of melanocytic differentiation in uveal melanoma', 'Disease', 'MESH:C536494', (109, 162))	('BAP1', 'Gene', '8314', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (148, 162))	('associated', 'Reg', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('metastasis', 'CPA', (167, 177))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('BAP1', 'Gene', (76, 80))	('tumor', 'Disease', (54, 59))	('tumor suppressor', 'biological_process', 'GO:0051726', ('54', '70'))
150960	22038994	HDAC inhibitors induced morphologic differentiation, cell cycle exit, and a shift to a differentiated, melanocytic gene expression profile in cultured UM cells.	('HDAC', 'Gene', (0, 4))	('induced', 'Reg', (16, 23))	('UM', 'Phenotype', 'HP:0007716', (151, 153))	('HDAC', 'Gene', '9734', (0, 4))	('morphologic differentiation', 'CPA', (24, 51))	('gene expression', 'biological_process', 'GO:0010467', ('115', '130'))	('inhibitors', 'Var', (5, 15))	('cell cycle exit', 'CPA', (53, 68))	('cell cycle', 'biological_process', 'GO:0007049', ('53', '63'))	('shift', 'Reg', (76, 81))
150972	22038994	We recently showed that inactivating somatic mutations in the tumor suppressor gene BAP1, located at chromosome 3p21, and concomitant loss of the other copy of chromosome 3 are present in the vast majority of class 2 tumors but not class 1 tumors.	('chromosome', 'cellular_component', 'GO:0005694', ('101', '111'))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Disease', (240, 246))	('tumor', 'Disease', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (240, 245))	('chromosome', 'cellular_component', 'GO:0005694', ('160', '170'))	('BAP1', 'Gene', '8314', (84, 88))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('inactivating', 'Var', (24, 36))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('62', '78'))	('BAP1', 'Gene', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('mutations', 'Var', (45, 54))	('tumors', 'Disease', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('tumor', 'Disease', (62, 67))	('tumor suppressor', 'biological_process', 'GO:0051726', ('62', '78'))	('loss', 'NegReg', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
150973	22038994	Depletion of BAP1 in cultured class 1 UM cells induced a loss of melanocytic differentiation and acquisition of a class 2 gene expression profile, suggesting that the loss of BAP1 may be mechanistically linked to metastasis.	('acquisition', 'PosReg', (97, 108))	('BAP1', 'Gene', (175, 179))	('BAP1', 'Gene', (13, 17))	('loss of melanocytic differentiation', 'Disease', (57, 92))	('class 2 gene expression profile', 'MPA', (114, 145))	('loss of melanocytic differentiation', 'Disease', 'MESH:D009508', (57, 92))	('gene expression', 'biological_process', 'GO:0010467', ('122', '137'))	('Depletion', 'Var', (0, 9))	('metastasis', 'CPA', (213, 223))	('UM', 'Phenotype', 'HP:0007716', (38, 40))	('BAP1', 'Gene', '8314', (13, 17))	('BAP1', 'Gene', '8314', (175, 179))	('loss', 'Var', (167, 171))	('linked', 'Reg', (203, 209))
150974	22038994	Functional studies have confirmed the tumor suppressor activity of BAP1, and several recent reports have linked germline BAP1 mutations to a spectrum of familial cancers including uveal and cutaneous melanoma and mesothelioma.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('familial cancers', 'Disease', 'MESH:D009369', (153, 169))	('BAP1', 'Gene', '8314', (121, 125))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('familial cancers', 'Disease', (153, 169))	('BAP1', 'Gene', (121, 125))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (190, 208))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('BAP1', 'Gene', '8314', (67, 71))	('cutaneous melanoma and mesothelioma', 'Disease', 'MESH:C562393', (190, 225))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('mutations', 'Var', (126, 135))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('tumor suppressor', 'biological_process', 'GO:0051726', ('38', '54'))	('BAP1', 'Gene', (67, 71))
151007	22038994	Western blotting was performed as previously described using anti-BAP1 (1:250; Santa Cruz), anti-alpha-tubulin (loading control, 1:1000; Sigma), anti-acetyl-histone H3Lys9 (1:200; Cell signaling), anti-histone H3 (1:200; Cell signaling), anti-ubiquityl-histone H2A (1:100; Millipore), and anti-histone H2A (1:200; Millipore) antibodies.	('anti-ubiquityl-histone', 'Var', (238, 260))	('acetyl-histone', 'Chemical', '-', (150, 164))	('BAP1', 'Gene', '8314', (66, 70))	('signaling', 'biological_process', 'GO:0023052', ('226', '235'))	('signaling', 'biological_process', 'GO:0023052', ('185', '194'))	('BAP1', 'Gene', (66, 70))	('anti-histone', 'Var', (197, 209))	('anti-histone H2A', 'Protein', (289, 305))	('anti-acetyl-histone', 'Var', (145, 164))
151008	22038994	Immunofluorescence was performed by plating 5x103 92.1 cells on Lab-Tek 8-well Permanox chamber slides (Nunc) and using anti-BAP1, anti-acetyl-histone H3Lys9 and anti-ubiquityl-histone H2A antibodies.	('Tek', 'Gene', (68, 71))	('acetyl-histone', 'Chemical', '-', (136, 150))	('BAP1', 'Gene', '8314', (125, 129))	('BAP1', 'Gene', (125, 129))	('Tek', 'Gene', '7010', (68, 71))	('anti-ubiquityl-histone H2A antibodies', 'Protein', (162, 199))	('anti-acetyl-histone', 'Var', (131, 150))
151029	22038994	As expected, RNAi-mediated knock down of BAP1 in UM cells (Fig.	('UM', 'Phenotype', 'HP:0007716', (49, 51))	('BAP1', 'Gene', (41, 45))	('RNAi', 'biological_process', 'GO:0016246', ('13', '17'))	('knock down', 'Var', (27, 37))	('BAP1', 'Gene', '8314', (41, 45))
151036	22038994	Since UM cell lines undergo genetic and epigenetic artifacts in long term culture, for these experiments we used primary UM cells from five class 2 tumors (MM137, MM138, MM151, MM161 and MM162) and one class 1 tumor (MM131) which were obtained immediately after surgical resection and placed in short term culture.	('MM162', 'CellLine', 'CVCL:J920', (187, 192))	('UM', 'Phenotype', 'HP:0007716', (121, 123))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('UM', 'Phenotype', 'HP:0007716', (6, 8))	('MM151', 'Var', (170, 175))	('MM162', 'Var', (187, 192))	('MM137', 'Var', (156, 161))	('tumor', 'Disease', (148, 153))	('MM151', 'CellLine', 'CVCL:N751', (170, 175))	('tumor', 'Disease', (210, 215))	('MM161', 'Var', (177, 182))	('tumors', 'Disease', (148, 154))	('MM138', 'Var', (163, 168))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
151037	22038994	While only four of the class 2 samples contained detectable BAP1 mutations, all five showed low BAP1 RNA levels compared to the class 1 tumors (Supplementary Table S2 and Supplementary Fig.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('BAP1', 'Gene', (96, 100))	('low', 'NegReg', (92, 95))	('BAP1', 'Gene', '8314', (60, 64))	('RNA', 'cellular_component', 'GO:0005562', ('101', '104'))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('BAP1', 'Gene', (60, 64))	('BAP1', 'Gene', '8314', (96, 100))	('mutations', 'Var', (65, 74))
151040	22038994	VPA shifted all of the class 2 UM cells towards a class 1 profile, and it even shifted the class 1 UM cells towards a more class 1 profile (Fig.	('UM', 'Phenotype', 'HP:0007716', (31, 33))	('shifted', 'Reg', (4, 11))	('VPA', 'Chemical', 'MESH:D014635', (0, 3))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('VPA', 'Var', (0, 3))
151047	22038994	We have not yet found a UM cell line with naturally occurring BAP1 mutations (data not shown), despite many of these cell lines being derived from metastasizing UMs that likely contained cells with mutant BAP1.	('BAP1', 'Gene', '8314', (62, 66))	('UM', 'Phenotype', 'HP:0007716', (24, 26))	('BAP1', 'Gene', '8314', (205, 209))	('BAP1', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))	('BAP1', 'Gene', (205, 209))	('UM', 'Phenotype', 'HP:0007716', (161, 163))
151049	22038994	This has hindered our ability to study the effects of HDAC inhibitors on BAP1 mutant UM cells in vivo.	('BAP1', 'Gene', '8314', (73, 77))	('BAP1', 'Gene', (73, 77))	('HDAC', 'Gene', (54, 58))	('HDAC', 'Gene', '9734', (54, 58))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('mutant', 'Var', (78, 84))
151051	22038994	Knock down of BAP1 caused an increase in histone H2A ubiquitination, consistent with its H2A ubiquitin carboxy-terminal hydrolase activity, which is critical for its tumor suppressor function.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('BAP1', 'Gene', '8314', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('ubiquitin carboxy-terminal hydrolase activity', 'molecular_function', 'GO:0004221', ('93', '138'))	('histone H2A ubiquitination', 'biological_process', 'GO:0033522', ('41', '67'))	('BAP1', 'Gene', (14, 18))	('increase', 'PosReg', (29, 37))	('tumor', 'Disease', (166, 171))	('tumor suppressor', 'biological_process', 'GO:0051726', ('166', '182'))	('histone H2A', 'Protein', (41, 52))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('166', '182'))	('Knock down', 'Var', (0, 10))
151060	22038994	Further, inhibition of HDAC activity has been shown to decrease histone ubiquitination through transcriptional repression of the PRC1 component BMI1.	('BMI1', 'Gene', '648', (144, 148))	('HDAC', 'Gene', '9734', (23, 27))	('histone ubiquitination', 'MPA', (64, 86))	('transcriptional', 'MPA', (95, 110))	('decrease', 'NegReg', (55, 63))	('BMI1', 'Gene', (144, 148))	('HDAC', 'Gene', (23, 27))	('PRC1', 'Gene', (129, 133))	('histone ubiquitination', 'biological_process', 'GO:0016574', ('64', '86'))	('PRC1', 'Gene', '9055', (129, 133))	('inhibition', 'Var', (9, 19))
151071	22038994	Recently, we discovered that inactivating mutations in the histone H2A ubiquitin hydrolase BAP1 are strongly associated with metastasis in uveal melanoma.	('BAP1', 'Gene', (91, 95))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('metastasis', 'CPA', (125, 135))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('uveal melanoma', 'Disease', 'MESH:C536494', (139, 153))	('inactivating mutations', 'Var', (29, 51))	('uveal melanoma', 'Disease', (139, 153))	('BAP1', 'Gene', '8314', (91, 95))	('associated with', 'Reg', (109, 124))	('ubiquitin', 'molecular_function', 'GO:0031386', ('71', '80'))
151129	20631901	Monosomy 3 is observed in approximately 50% of cases and appears rather specific for UM as this chromosomal anomaly is rarely encountered in CM or other cancer types (Figure 2).	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('anomaly', 'Disease', (108, 115))	('cancer', 'Disease', (153, 159))	('as', 'Chemical', 'MESH:D001151', (88, 90))	('CM', 'Phenotype', 'HP:0012056', (141, 143))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('as', 'Chemical', 'MESH:D001151', (48, 50))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('anomaly', 'Disease', 'MESH:D000014', (108, 115))	('Monosomy 3', 'Var', (0, 10))
151130	20631901	Several groups have already shown that there is a strong correlation between monosomy 3 and the development of metastatic disease.	('as', 'Chemical', 'MESH:D001151', (114, 116))	('as', 'Chemical', 'MESH:D001151', (126, 128))	('metastatic disease', 'Disease', (111, 129))	('monosomy 3', 'Var', (77, 87))
151131	20631901	In addition, monosomy 3 strongly relates to several clinical and histopathological parameters such as epithelioid cytology, closed vascular patterns, large tumor diameter, and ciliary body involvement.	('monosomy 3', 'Var', (13, 23))	('as', 'Chemical', 'MESH:D001151', (99, 101))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('epithelioid cytology', 'Disease', (102, 122))	('ciliary body involvement', 'Disease', (176, 200))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('closed', 'Disease', (124, 130))	('relates', 'Reg', (33, 40))	('tumor', 'Disease', (156, 161))	('large', 'Disease', (150, 155))	('as', 'Chemical', 'MESH:D001151', (132, 134))
151132	20631901	Also, monosomy 3 is thought to represent an early event in tumorigenesis because the alteration is frequently seen in combination with all other known chromosomal abnormalities.	('chromosomal abnormalities', 'Disease', (151, 176))	('tumor', 'Disease', (59, 64))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (151, 176))	('monosomy 3', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
151144	20631901	However, in the study by Kilic et al., chromosome 8q abnormalities were shown to correlate with large tumor diameter but there was no significant relation found between gain of 8q and the metastatic phenotype by univariate analysis.	('as', 'Chemical', 'MESH:D001151', (191, 193))	('chromosome', 'Var', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('abnormalities', 'Var', (53, 66))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('as', 'Chemical', 'MESH:D001151', (128, 130))
151147	20631901	Several oncogenes on chromosome 8q were hinted as possible factors in UM pathogenesis; among these genes are MYC (on 8q24), NBS1 (on 8q21), and DDEF1(on 8q24).	('on', 'Var', (114, 116))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('NBS1', 'Gene', '4683', (124, 128))	('DDEF1', 'Gene', (144, 149))	('MYC', 'Gene', '4609', (109, 112))	('as', 'Chemical', 'MESH:D001151', (47, 49))	('on', 'Var', (130, 132))	('pathogenesis', 'biological_process', 'GO:0009405', ('73', '85'))	('chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))	('DDEF1', 'Gene', '50807', (144, 149))	('MYC', 'Gene', (109, 112))	('NBS1', 'Gene', (124, 128))
151151	20631901	Of these alterations, gain of DNA-material on the short arm of chromosome 6 (+6p) is found in 25%-29% of UM and relates to spindle cell cytology and low risk for development of metastasis.	('short arm', 'Phenotype', 'HP:0009824', (50, 59))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('spindle cell cytology', 'CPA', (123, 144))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('spindle', 'cellular_component', 'GO:0005819', ('123', '130'))	('alterations', 'Var', (9, 20))	('as', 'Chemical', 'MESH:D001151', (180, 182))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('as', 'Chemical', 'MESH:D001151', (183, 185))	('gain', 'PosReg', (22, 26))
151155	20631901	Infrequently, abnormalities of the other chromosomes such as loss of 9p, loss of chromosome 10, loss of 11q23-q25, and gain of chromosomes 7 and 10 have been reported but a possible role in tumorigenesis and/ or development of metastasis in UM has yet to be evaluated.	('UM', 'Phenotype', 'HP:0007716', (241, 243))	('loss', 'Var', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('loss', 'Var', (96, 100))	('as', 'Chemical', 'MESH:D001151', (245, 247))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('as', 'Chemical', 'MESH:D001151', (230, 232))	('as', 'Chemical', 'MESH:D001151', (233, 235))	('as', 'Chemical', 'MESH:D001151', (58, 60))	('tumor', 'Disease', (190, 195))	('loss', 'Var', (61, 65))	('gain', 'PosReg', (119, 123))
151162	20631901	Several groups have shown that approximately 46% of UMs carry mutations in the GNAQ gene (Table 2) turning GNAQ into an oncogene.	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('GNAQ', 'Gene', '2776', (79, 83))	('GNAQ', 'Gene', '2776', (107, 111))	('GNAQ', 'Gene', (79, 83))	('UMs', 'Disease', (52, 55))	('GNAQ', 'Gene', (107, 111))	('mutations', 'Var', (62, 71))
151166	20631901	High expression of DDEF1 was shown to result in more motile low-grade UM cells by Ehlers et al.	('High expression', 'Var', (0, 15))	('motile low-grade UM cells', 'CPA', (53, 78))	('DDEF1', 'Gene', '50807', (19, 24))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('as', 'Chemical', 'MESH:D001151', (26, 28))	('more', 'PosReg', (48, 52))	('DDEF1', 'Gene', (19, 24))
151169	20631901	It is theorized that overexpressed NBS1 could allow UM progression by promoting the repair of DNA damage which occurs more frequently in advanced tumors with increased genetic instability.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('overexpressed', 'Var', (21, 34))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('UM', 'Phenotype', 'HP:0007716', (52, 54))	('repair of DNA damage', 'MPA', (84, 104))	('promoting', 'PosReg', (70, 79))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('NBS1', 'Gene', '4683', (35, 39))	('tumors', 'Disease', (146, 152))	('as', 'Chemical', 'MESH:D001151', (163, 165))	('NBS1', 'Gene', (35, 39))
151177	20631901	Because monosomy 10 could include loss of tumor suppressor genes, much research has been aimed at identifying possible tumor suppressor genes involved.	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', (42, 47))	('as', 'Chemical', 'MESH:D001151', (81, 83))	('tumor suppressor', 'biological_process', 'GO:0051726', ('119', '135'))	('monosomy 10', 'Var', (8, 19))	('tumor suppressor', 'biological_process', 'GO:0051726', ('42', '58'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('119', '135'))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('42', '58'))	('loss', 'NegReg', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
151179	20631901	PTEN is thought to be inactivated by deletion or mutation and through loss of its negative regulatory effect on AKT, lead to activation of the AKT-pathway, and consequently prevent apoptosis.	('activation', 'PosReg', (125, 135))	('apoptosis', 'biological_process', 'GO:0097194', ('181', '190'))	('loss', 'NegReg', (70, 74))	('deletion', 'Var', (37, 45))	('negative regulatory effect', 'MPA', (82, 108))	('apoptosis', 'biological_process', 'GO:0006915', ('181', '190'))	('mutation', 'Var', (49, 57))	('AKT', 'Gene', '207', (112, 115))	('apoptosis', 'CPA', (181, 190))	('AKT', 'Gene', '207', (143, 146))	('prevent', 'NegReg', (173, 180))	('PTEN', 'Gene', (0, 4))	('AKT', 'Gene', (112, 115))	('AKT', 'Gene', (143, 146))	('PTEN', 'Gene', '5728', (0, 4))
151182	20631901	In UM, inactivation of PTEN is reported in 15% of cases and has been linked to an increase in aneuploidy but also poor clinical outcome.	('as', 'Chemical', 'MESH:D001151', (61, 63))	('inactivation', 'Var', (7, 19))	('aneuploidy', 'Disease', (94, 104))	('PTEN', 'Gene', (23, 27))	('PTEN', 'Gene', '5728', (23, 27))	('aneuploidy', 'Disease', 'MESH:D000782', (94, 104))	('as', 'Chemical', 'MESH:D001151', (51, 53))	('as', 'Chemical', 'MESH:D001151', (87, 89))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
151185	20631901	NRAS is located in the 1p13-region and shown to be activated by mutation in 15%-25% of CMs.	('mutation', 'Var', (64, 72))	('CM', 'Phenotype', 'HP:0012056', (87, 89))	('NRAS', 'Gene', (0, 4))	('activated', 'PosReg', (51, 60))	('NRAS', 'Gene', '4893', (0, 4))
151190	20631901	Overexpression of AKT3 renders cells less sensitive to apoptotic stimuli and as mentioned before; PTEN inactivation can lead to the selective activation of AKT in CMs.	('AKT', 'Gene', '207', (156, 159))	('AKT3', 'Gene', (18, 22))	('as', 'Chemical', 'MESH:D001151', (77, 79))	('AKT3', 'Gene', '10000', (18, 22))	('activation', 'PosReg', (142, 152))	('AKT', 'Gene', (18, 21))	('inactivation', 'Var', (103, 115))	('AKT', 'Gene', (156, 159))	('CM', 'Phenotype', 'HP:0012056', (163, 165))	('PTEN', 'Gene', (98, 102))	('PTEN', 'Gene', '5728', (98, 102))	('AKT', 'Gene', '207', (18, 21))
151191	20631901	Different groups have shown NRAS mutations to be very rare in UM.	('UM', 'Phenotype', 'HP:0007716', (62, 64))	('NRAS', 'Gene', '4893', (28, 32))	('NRAS', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
151192	20631901	Of these alterations, the 6q10-q27 region shows the highest frequency of rearrangements as a result of deletion, translocation, or due to the formation of an isochromosome of its short arm.	('translocation', 'CPA', (113, 126))	('as', 'Chemical', 'MESH:D001151', (88, 90))	('short arm', 'Phenotype', 'HP:0009824', (179, 188))	('formation', 'biological_process', 'GO:0009058', ('142', '151'))	('deletion', 'Var', (103, 111))
151193	20631901	The region on the short arm of chromosome 6 that frequently shows alterations spans from 6p21 to 6p25 and mainly results in gain of DNA material.	('chromosome', 'cellular_component', 'GO:0005694', ('31', '41'))	('gain', 'PosReg', (124, 128))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('p25', 'Gene', '8851', (98, 101))	('DNA material', 'MPA', (132, 144))	('short arm', 'Phenotype', 'HP:0009824', (18, 27))	('p25', 'Gene', (98, 101))	('alterations', 'Var', (66, 77))
151197	20631901	The BRAF-gene encodes a kinase involved in the MAP-kinase pathway which, by mutation, is thought to lead to constitutive activation of the aforementioned pathway and cell proliferation.	('as', 'Chemical', 'MESH:D001151', (54, 56))	('cell proliferation', 'CPA', (166, 184))	('MAP', 'molecular_function', 'GO:0004239', ('47', '50'))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('as', 'Chemical', 'MESH:D001151', (27, 29))	('cell proliferation', 'biological_process', 'GO:0008283', ('166', '184'))	('mutation', 'Var', (76, 84))	('activation', 'PosReg', (121, 131))
151198	20631901	A single substitution (p.V600E) appears to account for more than 90% of all BRAF mutations.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('p.V600E', 'Mutation', 'rs113488022', (23, 30))	('p.V600E', 'Var', (23, 30))
151201	20631901	Mutations of BRAF were shown to be absent in UMs.	('BRAF', 'Gene', '673', (13, 17))	('Mutations', 'Var', (0, 9))	('UM', 'Phenotype', 'HP:0007716', (45, 47))	('BRAF', 'Gene', (13, 17))
151202	20631901	But in a small study, BRAF mutations were shown to occur in 48% of UM of the iris.	('mutations', 'Var', (27, 36))	('BRAF', 'Gene', (22, 26))	('BRAF', 'Gene', '673', (22, 26))	('UM', 'Phenotype', 'HP:0007716', (67, 69))
151205	20631901	Inactivating mutations, or loss, results in inactivation of the two encoding tumor suppressor genes p16 and p14.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('77', '93'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('Inactivating mutations', 'Var', (0, 22))	('p14', 'Gene', (108, 111))	('p16', 'Gene', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('inactivation', 'NegReg', (44, 56))	('p14', 'Gene', '1029', (108, 111))	('tumor', 'Disease', (77, 82))	('tumor suppressor', 'biological_process', 'GO:0051726', ('77', '93'))	('p16', 'Gene', '1029', (100, 103))
151209	20631901	In UM, the studies regarding gene/promoter methylation status are still limited but CDKN2A is found to be methylated in 33% of cases.	('CDKN2A', 'Gene', (84, 90))	('CDKN2A', 'Gene', '1029', (84, 90))	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))	('methylated', 'Var', (106, 116))	('as', 'Chemical', 'MESH:D001151', (128, 130))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
151210	20631901	Similarly, RASSF1 appears to be methylated in 13%-70% and hTERT in up to 52%.	('hTERT', 'Gene', (58, 63))	('RASSF1', 'Gene', '11186', (11, 17))	('hTERT', 'Gene', '7015', (58, 63))	('RASSF1', 'Gene', (11, 17))	('methylated', 'Var', (32, 42))
151212	20631901	Although there are limited studies available on the role of miRNAs, several miRNAs have been marked as possibly involved in UM tumorigenesis and/or metastasis such as let-7b, miR18a, miR-199a, miR495, miR549, and more.	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('as', 'Chemical', 'MESH:D001151', (151, 153))	('let-7b', 'Gene', '406884', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('involved', 'Reg', (112, 120))	('miR18a', 'Gene', (175, 181))	('miR495', 'Gene', '574453', (193, 199))	('as', 'Chemical', 'MESH:D001151', (164, 166))	('as', 'Chemical', 'MESH:D001151', (100, 102))	('miR495', 'Gene', (193, 199))	('let-7b', 'Gene', (167, 173))	('as', 'Chemical', 'MESH:D001151', (154, 156))	('miR549', 'Gene', (201, 207))	('metastasis', 'CPA', (148, 158))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('miR-199a', 'Var', (183, 191))	('tumor', 'Disease', (127, 132))	('miR18a', 'Gene', '406953', (175, 181))	('miR549', 'Gene', '693132', (201, 207))
151214	20631901	These miRNAs were shown to bind to genes often found to be deleted in UM such as 8p22, but also 13q and 17p.	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('as', 'Chemical', 'MESH:D001151', (78, 80))	('8p22', 'Var', (81, 85))	('13q', 'Var', (96, 99))	('bind', 'Interaction', (27, 31))
151233	20631901	In CM, alterations of chromosomes 1, 6, 7, 9, 10, 14, 16, and 21 are frequently observed and already several candidate genes and proteins involved in the tumorigenesis of CM have been identified.	('CM', 'Phenotype', 'HP:0012056', (171, 173))	('CM', 'Phenotype', 'HP:0012056', (3, 5))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('alterations', 'Var', (7, 18))	('tumor', 'Disease', (154, 159))
151234	20631901	Of these, monosomy 3, gain of 8q, and the combination of loss of 1p36 and monosomy 3 appeared to be significant prognostic factors for decreased survival; There have not been identified genes yet that are prognostically active in UM, and at this point developments in UM lag behind compared to CM.	('CM', 'Phenotype', 'HP:0012056', (294, 296))	('survival', 'MPA', (145, 153))	('UM', 'Phenotype', 'HP:0007716', (268, 270))	('as', 'Chemical', 'MESH:D001151', (140, 142))	('gain', 'PosReg', (22, 26))	('monosomy 3', 'Var', (10, 20))	('p36', 'Gene', '51251', (66, 69))	('p36', 'Gene', (66, 69))	('decreased', 'NegReg', (135, 144))	('loss', 'Var', (57, 61))	('UM', 'Phenotype', 'HP:0007716', (230, 232))	('monosomy 3', 'Var', (74, 84))
151238	20631901	We do have to remind that we do not yet know whether monosomy 3 and classifier genes are truly involved in tumor progression and metastatic potential or that those are merely markers of the underlying cause.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('as', 'Chemical', 'MESH:D001151', (132, 134))	('metastatic potential', 'CPA', (129, 149))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('as', 'Chemical', 'MESH:D001151', (70, 72))	('monosomy 3', 'Var', (53, 63))	('involved', 'Reg', (95, 103))
151250	33682883	Survival and Receiver Operating Characteristic (ROC) Curve analysis in the TCGA and other four independent UM cohorts (GSE22138, GSE27831, GSE44295 and GSE84976) proved that the ARG-signature possessed robust and steady prognosis predictive ability.	('UM', 'Phenotype', 'HP:0007716', (107, 109))	('ARG', 'Gene', (178, 181))	('ARG', 'Gene', '27', (178, 181))	('GSE84976', 'Var', (152, 160))	('GSE27831', 'Var', (129, 137))	('GSE22138', 'Var', (119, 127))	('GSE44295', 'Var', (139, 147))
151271	33682883	RNA-seq profile and related clinical information of The Cancer Genome Atlas (TCGA) cohort were obtained from the TCGA website (https://portal.gdc.cancer.gov/), and the related RNA expression and clinical information files of the other four cohorts (including GSE22138, GSE27831, GSE44295 and GSE84976) were downloaded from the Gene Expression Omnibus (GEO) repository (https://www.ncbi.nlm.nih.gov/geo/) and previous published researches.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('GSE27831', 'Var', (269, 277))	('Gene Expression', 'biological_process', 'GO:0010467', ('327', '342'))	('GSE44295', 'Var', (279, 287))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('RNA', 'cellular_component', 'GO:0005562', ('176', '179'))	('Cancer', 'Disease', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('Cancer', 'Disease', 'MESH:D009369', (56, 62))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
151291	33682883	Then univariate Cox regression analysis showed that 133 of the 423 ARGs were associated with the OS of UM patients in the TCGA cohort (P<0.05), of which 39 ARGs were protective genes (HR < 1) and 94 ARGs were risky genes (HR > 1).	('UM', 'Phenotype', 'HP:0007716', (103, 105))	('ARGs', 'Chemical', '-', (156, 160))	('ARGs', 'Var', (156, 160))	('ARGs', 'Chemical', '-', (67, 71))	('patients', 'Species', '9606', (106, 114))	('ARGs', 'Chemical', '-', (199, 203))	('associated', 'Reg', (77, 87))
151300	33682883	In the GSE44295 cohort, 57 UM patients were divided into low- and high-risk UM groups by the median risk score and survival analysis showed that high-risk UMs were associated with lower OS rate and shorter OS time (Figure 3A), patients' distributions of OS time and status also proved this result (Figure 3B).	('OS rate', 'MPA', (186, 193))	('UM', 'Phenotype', 'HP:0007716', (155, 157))	('UM', 'Phenotype', 'HP:0007716', (27, 29))	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('high-risk', 'Var', (145, 154))	('patients', 'Species', '9606', (227, 235))	('patients', 'Species', '9606', (30, 38))	('lower', 'NegReg', (180, 185))	('UMs', 'Var', (155, 158))	('shorter', 'NegReg', (198, 205))
151306	33682883	UM patients with high expression levels of IKBKE, BNIP1, ITGA6 and FKBP1A showed worse clinical outcomes which means they might be risky ARGs in UM (Figure 4A-D).	('IKBKE', 'Gene', '9641', (43, 48))	('ITGA6', 'Gene', '3655', (57, 62))	('FKBP1A', 'Gene', (67, 73))	('BNIP1', 'Gene', '662', (50, 55))	('ITGA6', 'Gene', (57, 62))	('FKBP1A', 'Gene', '2280', (67, 73))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('high expression levels', 'Var', (17, 39))	('ARGs', 'Chemical', '-', (137, 141))	('patients', 'Species', '9606', (3, 11))	('IKBKE', 'Gene', (43, 48))	('BNIP1', 'Gene', (50, 55))	('FKBP', 'molecular_function', 'GO:0030051', ('67', '71'))	('UM', 'Phenotype', 'HP:0007716', (0, 2))
151331	33682883	On the contrary, there were 18, 9 and 17 UM patient lived longer than 5 years in GSE22138, GSE44295 and GSE84976 cohorts, respectively.	('GSE22138', 'Var', (81, 89))	('GSE44295', 'Var', (91, 99))	('UM', 'Phenotype', 'HP:0007716', (41, 43))	('patient', 'Species', '9606', (44, 51))
151353	33422090	Recent evidence have discovered that ET-1R/beta-arr1 axis instigates a transcriptional interplay involving YAP and mutant p53 proteins, which share a common gene signature and cooperate in a oncogenic signaling network.	('proteins', 'Protein', (126, 134))	('mutant', 'Var', (115, 121))	('YAP', 'Gene', (107, 110))	('instigates', 'Reg', (58, 68))	('arr', 'biological_process', 'GO:0090644', ('48', '51'))	('signaling', 'biological_process', 'GO:0023052', ('201', '210'))	('YAP', 'Gene', '10413', (107, 110))	('transcriptional interplay', 'MPA', (71, 96))	('p53', 'Gene', (122, 125))
151357	33422090	In particular, we debate the clinical implications regarding the use of dual ET-1R antagonists to blunt gain of function activity of mutant p53 proteins and thereby considering them as a potential therapeutic option for mutant p53 cancers.	('gain', 'PosReg', (104, 108))	('activity', 'MPA', (121, 129))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('cancers', 'Disease', (231, 238))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('mutant', 'Var', (133, 139))	('p53', 'Gene', (140, 143))	('proteins', 'Protein', (144, 152))
151360	33422090	As such, aberrant activation of GPCR can alter the signaling landscape and cellular fate in multiple pathophysiologic contexts including cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('GPCR', 'Gene', (32, 36))	('signaling landscape', 'MPA', (51, 70))	('cellular fate', 'CPA', (75, 88))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('GPCR', 'Gene', '23566', (32, 36))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('alter', 'Reg', (41, 46))	('cancer', 'Disease', (137, 143))	('aberrant', 'Var', (9, 17))	('activation', 'PosReg', (18, 28))
151374	33422090	In this landscape, growing evidence discloses how beta-arr1 connects the ETAR signaling with other pathways fostering ETAR-intertwined signalings critically involved in the metastatic progression and drug response in many tumor types, including ovarian cancer.	('involved', 'Reg', (157, 165))	('ETAR', 'Gene', '1909', (118, 122))	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('ovarian cancer', 'Disease', (245, 259))	('ETAR', 'Gene', (73, 77))	('arr', 'biological_process', 'GO:0090644', ('55', '58'))	('beta-arr1', 'Var', (50, 59))	('ETAR', 'Gene', '1909', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('ETAR', 'Gene', (118, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (245, 259))	('ovarian cancer', 'Disease', 'MESH:D010051', (245, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
151377	33422090	In particular, we focus on the YAP/TAZ nexus through which ET-1/beta-arr1 fosters chemotherapy escape and metastatization.	('YAP/TAZ', 'Gene', '10413;6901', (31, 38))	('fosters', 'PosReg', (74, 81))	('ET-1/beta-arr1', 'Var', (59, 73))	('arr', 'biological_process', 'GO:0090644', ('69', '72'))	('YAP/TAZ', 'Gene', (31, 38))
151381	33422090	Clinically relevant, in many tumor contexts high levels of ET-1R are associated with a worst prognosis, proving the unfavorable prognostic role of ET-1R.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('ET-1R', 'Protein', (59, 64))	('tumor', 'Disease', (29, 34))	('high levels', 'Var', (44, 55))
151435	33422090	In particular, it has been described how beta-arr1 bridges ET-1/ETAR axis to YAP signaling in high-grade serous ovarian cancer (HG-SOC) cells and in breast cancer cell lines harboring TP53 mutations, fostering the YAP/TAZ-dependent transcriptional program that confers upon tumor cells an invasive behavior.	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('ETAR', 'Gene', '1909', (64, 68))	('TP53', 'Gene', '7157', (184, 188))	('YAP/TAZ', 'Gene', (214, 221))	('YAP', 'Gene', (77, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('tumor', 'Disease', (274, 279))	('SOC', 'biological_process', 'GO:0031578', ('131', '134'))	('YAP', 'Gene', (214, 217))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (105, 126))	('mutations', 'Var', (189, 198))	('breast cancer', 'Disease', (149, 162))	('HG-SOC', 'CellLine', 'CVCL:Y547', (128, 134))	('YAP', 'Gene', '10413', (77, 80))	('YAP', 'Gene', '10413', (214, 217))	('TP53', 'Gene', (184, 188))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('ovarian cancer', 'Phenotype', 'HP:0100615', (112, 126))	('ETAR', 'Gene', (64, 68))	('serous ovarian cancer', 'Disease', (105, 126))	('arr', 'biological_process', 'GO:0090644', ('46', '49'))	('fostering', 'PosReg', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('YAP/TAZ', 'Gene', '10413;6901', (214, 221))
151440	33422090	Thus, the interaction with different transcription factors, tethering mutp53 to the DNA, can expand mutp53 agenda to orchestrate specific gene expression regulating tumor growth and progression.	('tumor', 'Disease', (165, 170))	('interaction', 'Interaction', (10, 21))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('orchestrate', 'MPA', (117, 128))	('transcription', 'biological_process', 'GO:0006351', ('37', '50'))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('gene expression', 'biological_process', 'GO:0010467', ('138', '153'))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('mutp53', 'Var', (100, 106))
151441	33422090	Of relevance, the beta-arr1/YAP/mutp53/TEAD target gene pool includes EDN1, indeed, the depletion of all the players of such active transcriptional complex, including mutp53, strongly reduces the EDN1 gene expression, as well as ET-1 promoter activity.	('depletion', 'Var', (88, 97))	('YAP', 'Gene', (28, 31))	('expression', 'MPA', (206, 216))	('mutp53', 'Var', (167, 173))	('ET-1 promoter activity', 'MPA', (229, 251))	('EDN1', 'Gene', '1906', (196, 200))	('EDN1', 'Gene', '1906', (70, 74))	('arr', 'biological_process', 'GO:0090644', ('23', '26'))	('EDN1', 'Gene', (196, 200))	('gene expression', 'biological_process', 'GO:0010467', ('201', '216'))	('reduces', 'NegReg', (184, 191))	('YAP', 'Gene', '10413', (28, 31))	('EDN1', 'Gene', (70, 74))
151445	33422090	In particular, it has been described that YAP and mutp53 share a common transcriptional program relevant for sustaining cell proliferation in different human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (158, 170))	('YAP', 'Gene', (42, 45))	('mutp53', 'Var', (50, 56))	('malignancies', 'Disease', (158, 170))	('human', 'Species', '9606', (152, 157))	('cell proliferation', 'biological_process', 'GO:0008283', ('120', '138'))	('YAP', 'Gene', '10413', (42, 45))
151447	33422090	Clinically relevant, HG-SOC patients carrying TP53 mutations and simultaneously expressing high levels of ETAR, beta-arr1 and YAP, face a poor prognosis compared to those patients lacking this molecular signature.	('mutations', 'Var', (51, 60))	('YAP', 'Gene', (126, 129))	('SOC', 'biological_process', 'GO:0031578', ('24', '27'))	('TP53', 'Gene', '7157', (46, 50))	('arr', 'biological_process', 'GO:0090644', ('117', '120'))	('patients', 'Species', '9606', (171, 179))	('ETAR', 'Gene', '1909', (106, 110))	('HG-SOC', 'CellLine', 'CVCL:Y547', (21, 27))	('TP53', 'Gene', (46, 50))	('YAP', 'Gene', '10413', (126, 129))	('patients', 'Species', '9606', (28, 36))	('ETAR', 'Gene', (106, 110))	('HG-SOC', 'Disease', (21, 27))
151468	33422090	These findings allow us to hypothesize that ET-1R may also initiate a mechanosignals flow that via ECM guides YAP/TAZ activation in both tumoral and stromal compartments.	('YAP/TAZ', 'Gene', (110, 117))	('ET-1R', 'Var', (44, 49))	('tumoral', 'Disease', (137, 144))	('tumoral', 'Disease', 'MESH:D009369', (137, 144))	('YAP/TAZ', 'Gene', '10413;6901', (110, 117))	('mechanosignals flow', 'MPA', (70, 89))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
151475	33422090	For instance, it has been observed that the antagonization or depletion of Galpha12/13- or Galphaq/11-mediated signaling by using phosphatase-resistant LPA analogues or antibodies specific for LPA or SP1 receptors may interfere with YAP/TAZ activation.	('interfere', 'NegReg', (218, 227))	('phosphatase', 'molecular_function', 'GO:0016791', ('130', '141'))	('LPA', 'Chemical', 'MESH:C032881', (152, 155))	('LPA', 'Chemical', 'MESH:C032881', (193, 196))	('signaling', 'biological_process', 'GO:0023052', ('111', '120'))	('depletion', 'NegReg', (62, 71))	('Galphaq/11-mediated signaling', 'MPA', (91, 120))	('antagonization', 'Var', (44, 58))	('Galpha12/13', 'Gene', (75, 86))	('YAP/TAZ', 'Gene', (233, 240))	('Galpha12/13', 'Gene', '2768;10672', (75, 86))	('YAP/TAZ', 'Gene', '10413;6901', (233, 240))
151476	33422090	Recently, it has been reported that a cyclic depsipeptide, FR900359, targeting Galphaq/11, interferes with YAP nuclear functions stimulating its inhibitory phosphorylation.	('depsipeptide', 'Disease', (45, 57))	('phosphorylation', 'biological_process', 'GO:0016310', ('156', '171'))	('YAP', 'Gene', (107, 110))	('interferes', 'NegReg', (91, 101))	('FR900359', 'Var', (59, 67))	('depsipeptide', 'Disease', 'None', (45, 57))	('inhibitory phosphorylation', 'MPA', (145, 171))	('FR900359', 'Chemical', 'MESH:C000607068', (59, 67))	('Galphaq/11', 'Gene', (79, 89))	('YAP', 'Gene', '10413', (107, 110))
151484	33422090	In patient-derived (PD) HG-SOC cells, harboring hot spot TP53 missense mutations and in PD xenografts, macitentan, preventing the beta-arr1-orchestrated signaling network, hampers YAP/TAZ cytoplasmic-nuclear shuttling, disrupts YAP/mutp53 transcriptional activity, inhibits metastatic spread and re-sensitizes chemoresistant HG-SOC cells to platinum-based therapy.	('beta-arr1-orchestrated signaling', 'MPA', (130, 162))	('YAP', 'Gene', (228, 231))	('YAP/TAZ', 'Gene', '10413;6901', (180, 187))	('arr', 'biological_process', 'GO:0090644', ('135', '138'))	('TP53', 'Gene', '7157', (57, 61))	('signaling', 'biological_process', 'GO:0023052', ('153', '162'))	('preventing', 'NegReg', (115, 125))	('YAP/TAZ', 'Gene', (180, 187))	('YAP', 'Gene', (180, 183))	('HG-SOC', 'CellLine', 'CVCL:Y547', (24, 30))	('missense mutations', 'Var', (62, 80))	('SOC', 'biological_process', 'GO:0031578', ('27', '30'))	('inhibits', 'NegReg', (265, 273))	('HG-SOC', 'CellLine', 'CVCL:Y547', (325, 331))	('YAP', 'Gene', '10413', (228, 231))	('platinum', 'Chemical', 'MESH:D010984', (341, 349))	('disrupts', 'NegReg', (219, 227))	('hampers', 'NegReg', (172, 179))	('TP53', 'Gene', (57, 61))	('YAP', 'Gene', '10413', (180, 183))	('SOC', 'biological_process', 'GO:0031578', ('328', '331'))	('patient', 'Species', '9606', (3, 10))	('macitentan', 'Chemical', 'MESH:C533860', (103, 113))	('metastatic spread', 'CPA', (274, 291))
151485	33422090	Of note such effects are due to macitentan ability to dismantle YAP and mutp53 oncogenic network (Table 1).	('oncogenic', 'CPA', (79, 88))	('YAP', 'Gene', '10413', (64, 67))	('dismantle', 'NegReg', (54, 63))	('YAP', 'Gene', (64, 67))	('macitentan', 'Chemical', 'MESH:C533860', (32, 42))	('mutp53', 'Var', (72, 78))
151486	33422090	Considering that TP53 is frequently mutated in many human malignancies, the use of dual ET-1R antagonists holds the potential for the treatment of TP53 mutant cancer patients.	('cancer', 'Disease', (159, 165))	('TP53', 'Gene', (147, 151))	('human', 'Species', '9606', (52, 57))	('malignancies', 'Disease', 'MESH:D009369', (58, 70))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('mutant', 'Var', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('malignancies', 'Disease', (58, 70))	('TP53', 'Gene', '7157', (147, 151))	('TP53', 'Gene', '7157', (17, 21))	('patients', 'Species', '9606', (166, 174))	('TP53', 'Gene', (17, 21))
151487	33422090	Taking into account that YAP and TAZ can orchestrate non overlapping transcriptional programs regulating cellular outcomes, future investigations are needed to uncover the different activities of YAP and TAZ downstream of GPCR, as ET-1R, including the oncogenic network with mutp53.	('TAZ', 'Gene', '6901', (33, 36))	('TAZ', 'Gene', (204, 207))	('YAP', 'Gene', (25, 28))	('TAZ', 'Gene', (33, 36))	('GPCR', 'Gene', (222, 226))	('YAP', 'Gene', '10413', (25, 28))	('YAP', 'Gene', '10413', (196, 199))	('GPCR', 'Gene', '23566', (222, 226))	('TAZ', 'Gene', '6901', (204, 207))	('mutp53', 'Var', (275, 281))	('YAP', 'Gene', (196, 199))
151498	33422090	alpha-SMA Alpha-smooth muscle actin beta-arr1 beta-arrestin1 beta-arr2 beta-arrestin2 CAF Cancer associated fibroblasts cAMP Cyclic AMP CYR61 Cysteine-rich protein 61 CTGF Connective tissue growth factor DC Dendritic cells EDN1 ET-1 gene ICAM1 Endothelial intercellular adhesion molecule 1 EC Endothelial cells ET Endothelins ET-1 Endothelin-1 ET-2 Endothelin-2 ET-3 Endothelin-3 ET-1R Endothelin receptors ETAR Endothelin A receptor ETBR Endothelin B receptor EGFR Epithelial growth factor receptor EMT Epithelial-to-mesenchymal transition ECM Extracellular matrix FFAR-1 Fatty acid receptor GPCR G protein-coupled receptors GPER G protein-coupled estrogen receptor GRKs G protein-coupled receptors kinases HG-SOC High-grade serous ovarian cancer HIF-1alpha Hypoxia-inducible factor-1 alpha HMGCR HMG-CoA reductase LEC Lymphatic endothelial cells LPA Lysophosphatidic acid receptor MAPK Mitogen-activated protein kinase mutp53 Mutant p53 NSCLS Non-small cell lung cancer NES Nuclear export signal PD Patient derived PI3K Phosphoinositide 3-kinase EP2 Prostaglandin E2 receptor PARs Protease-activated receptors PKA Protein kinase A AKT Protein kinase B PAH Pulmonary arterial hypertension SP1 Sphingosine-1-phosphate receptor TAZ Transcriptional coactivator with PDZ-binding motif TME Tumor microenvironment TAM Tumor-associated macrophages TIL Tumor-infiltrating lymphocytes RTK Tyrosine kinase receptors VEGF Vascular endothelial growth factor VEGFR-3 Vascular endothelial growth factor receptor YAP Yes-associated protein All authors listed have made a substantial, direct and intellectual contribution to the work.	('ET', 'Gene', '79157', (407, 409))	('PAH', 'Phenotype', 'HP:0002092', (1154, 1157))	('ETAR', 'Gene', '1909', (407, 411))	('ET', 'Gene', '79157', (311, 313))	('ET-3', 'Gene', (362, 366))	('CYR61', 'Gene', (136, 141))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (726, 747))	('TAZ', 'Gene', '6901', (1227, 1230))	('Tumor', 'Phenotype', 'HP:0002664', (1286, 1291))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (945, 971))	('PAH', 'molecular_function', 'GO:0033972', ('1154', '1157'))	('binding', 'molecular_function', 'GO:0005488', ('1268', '1275'))	('Epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('504', '540'))	('Cancer', 'Disease', (90, 96))	('Endothelin', 'Gene', (412, 422))	('HG-SOC', 'CellLine', 'CVCL:Y547', (708, 714))	('PI3K', 'molecular_function', 'GO:0016303', ('1017', '1021'))	('beta-arr2', 'Gene', (61, 70))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('Vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('1455', '1489'))	('PI3', 'Gene', (1017, 1020))	('hypertension', 'Phenotype', 'HP:0000822', (1177, 1189))	('alpha-SMA', 'Gene', (0, 9))	('EDN1', 'Gene', '1906', (223, 227))	('G protein-coupled estrogen receptor', 'Gene', (631, 666))	('Cancer', 'Disease', 'MESH:D009369', (90, 96))	('intercellular adhesion molecule 1', 'Gene', (256, 289))	('CAF', 'Gene', '8850', (86, 89))	('Cyclic AMP', 'Chemical', 'MESH:D000242', (125, 135))	('EMT', 'biological_process', 'GO:0001837', ('500', '503'))	('Mutant', 'Var', (928, 934))	('ET', 'Gene', '79157', (362, 364))	('Hypoxia', 'Disease', 'MESH:D000860', (759, 766))	('Endothelin', 'Gene', (331, 341))	('alpha-SMA', 'Gene', '58', (0, 9))	('Nuclear export', 'biological_process', 'GO:0051168', ('976', '990'))	('cancer', 'Phenotype', 'HP:0002664', (741, 747))	('ET-2', 'Gene', '1907', (344, 348))	('NSCLS', 'Disease', (939, 944))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (949, 971))	('SOC', 'biological_process', 'GO:0031578', ('711', '714'))	('YAP', 'Gene', (1499, 1502))	('Endothelin', 'Gene', (367, 377))	('Tyrosine kinase', 'Gene', (1381, 1396))	('GPER', 'Gene', (626, 630))	('NSCLS', 'Disease', 'None', (939, 944))	('Endothelin', 'Gene', '1906;13614;1907;1908', (412, 422))	('beta-arrestin1', 'Gene', (46, 60))	('ET', 'Gene', '79157', (380, 382))	('Endothelin', 'Gene', (349, 359))	('VEGF', 'Gene', (1407, 1411))	('Vascular endothelial growth factor', 'Gene', '7422', (1455, 1489))	('ET-3', 'Gene', '1908', (362, 366))	('Pulmonary arterial hypertension', 'Disease', (1158, 1189))	('EGFR', 'Gene', '1956', (1448, 1452))	('ETBR', 'Gene', (434, 438))	('YAP', 'Gene', '10413', (1499, 1502))	('Tumor', 'Phenotype', 'HP:0002664', (1346, 1351))	('MAPK', 'molecular_function', 'GO:0004707', ('883', '887'))	('VEGFR-3', 'Gene', '2324', (1447, 1454))	('beta-arrestin2', 'Gene', '409', (71, 85))	('Vascular endothelial growth factor', 'Gene', '7422', (1412, 1446))	('ETAR', 'Gene', (407, 411))	('HIF-1alpha', 'Gene', (748, 758))	('Endothelin', 'Gene', '1906;13614;1907;1908', (331, 341))	('Endothelin', 'Gene', '1906;13614;1907;1908', (386, 396))	('Vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('1412', '1446'))	('PKA', 'cellular_component', 'GO:0005952', ('1112', '1115'))	('CAF', 'Gene', (86, 89))	('VEGFR-3', 'Gene', (1447, 1454))	('protein', 'cellular_component', 'GO:0003675', ('906', '913'))	('G protein-coupled receptors', 'Gene', '23566', (672, 699))	('beta-arr2', 'Gene', '409', (61, 70))	('EGFR', 'Gene', (1448, 1452))	('ET', 'Gene', '79157', (344, 346))	('Pulmonary arterial hypertension', 'Phenotype', 'HP:0002092', (1158, 1189))	('Endothelin', 'Gene', '1906;13614;1907;1908', (367, 377))	('GPCR', 'Gene', (593, 597))	('ET-2', 'Gene', (344, 348))	('Cancer', 'Phenotype', 'HP:0002664', (90, 96))	('EGFR', 'molecular_function', 'GO:0005006', ('461', '465'))	('beta-arrestin2', 'Gene', (71, 85))	('Endothelin', 'Gene', '1906;13614;1907;1908', (349, 359))	('TAZ', 'Gene', (1227, 1230))	('VEGF', 'Gene', (1447, 1451))	('cAMP', 'Chemical', 'MESH:D000242', (120, 124))	('Extracellular matrix', 'cellular_component', 'GO:0031012', ('545', '565'))	('GPCR', 'Gene', '23566', (593, 597))	('G protein-coupled receptors', 'Gene', '23566', (598, 625))	('arr', 'biological_process', 'GO:0090644', ('66', '69'))	('lung cancer', 'Phenotype', 'HP:0100526', (960, 971))	('Non-small cell lung cancer', 'Disease', (945, 971))	('G protein-coupled estrogen receptor', 'Gene', '2852', (631, 666))	('protein', 'cellular_component', 'GO:0003675', ('600', '607'))	('ICAM1', 'Gene', (238, 243))	('serous ovarian cancer', 'Disease', (726, 747))	('GPER', 'Gene', '2852', (626, 630))	('CYR61', 'Gene', '3491', (136, 141))	('ICAM1', 'Gene', '3383', (238, 243))	('Endothelin', 'Gene', (314, 324))	('protein', 'cellular_component', 'GO:0003675', ('1518', '1525'))	('Patient', 'Species', '9606', (1001, 1008))	('FFAR-1', 'Gene', '2864', (566, 572))	('Endothelin', 'Gene', (439, 449))	('Hypoxia', 'Disease', (759, 766))	('TAM', 'Chemical', '-', (1309, 1312))	('intercellular adhesion molecule 1', 'Gene', '3383', (256, 289))	('ETBR', 'Gene', '1910', (434, 438))	('PKA', 'molecular_function', 'GO:0004691', ('1112', '1115'))	('EGFR', 'Gene', '1956', (461, 465))	('FFAR-1', 'Gene', (566, 572))	('VEGF', 'Gene', '7422', (1447, 1451))	('Pulmonary arterial hypertension', 'Disease', 'MESH:D000081029', (1158, 1189))	('G protein-coupled receptors', 'Gene', (598, 625))	('PI3', 'Gene', '5266', (1017, 1020))	('Vascular endothelial growth factor', 'Gene', (1455, 1489))	('arr', 'biological_process', 'GO:0090644', ('41', '44'))	('VEGF', 'Gene', '7422', (1407, 1411))	('HIF-1alpha', 'Gene', '3091', (748, 758))	('ET', 'Gene', '79157', (326, 328))	('protein', 'cellular_component', 'GO:0003675', ('674', '681'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (733, 747))	('Vascular endothelial growth factor', 'Gene', (1412, 1446))	('ET', 'Gene', '79157', (228, 230))	('ET', 'Gene', '79157', (434, 436))	('Endothelin', 'Gene', '1906;13614;1907;1908', (314, 324))	('EGFR', 'Gene', (461, 465))	('LPA', 'Chemical', 'MESH:C032881', (848, 851))	('EP2', 'Gene', (1048, 1051))	('protein', 'cellular_component', 'GO:0003675', ('633', '640'))	('EP2', 'Gene', '5732', (1048, 1051))	('Tumor', 'Phenotype', 'HP:0002664', (1313, 1318))	('beta-arrestin1', 'Gene', '408', (46, 60))	('G protein-coupled receptors', 'Gene', (672, 699))	('Endothelin', 'Gene', '1906;13614;1907;1908', (439, 449))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (945, 971))	('Endothelin', 'Gene', (386, 396))	('cancer', 'Phenotype', 'HP:0002664', (965, 971))	('EDN1', 'Gene', (223, 227))	('Tyrosine kinase', 'Gene', '7294', (1381, 1396))
151503	32797202	Small numbers of MB were present in the presumptive choroid at E15.5 and E18.5.	('E18.5', 'Var', (73, 78))	('MB', 'Chemical', '-', (17, 19))	('E15.5', 'Var', (63, 68))
151523	32797202	In a study examining mammalian MB differentiation and migration in the eye, ear and Harderian Gland, TRP2 (also known as Dopachrome Tautomerase), was expressed as early as E10 in migrating mouse MB, 4 days earlier than the other markers, TYR and TRP1.	('TRP1', 'molecular_function', 'GO:0004167', ('246', '250'))	('MB', 'Chemical', '-', (31, 33))	('mouse', 'Species', '10090', (189, 194))	('TRP1', 'Gene', '22178', (246, 250))	('TRP2', 'Gene', (101, 105))	('TRP1', 'Gene', (246, 250))	('TRP2', 'molecular_function', 'GO:0004167', ('101', '105'))	('E10', 'Var', (172, 175))	('mammalian', 'Species', '9606', (21, 30))	('MB', 'Chemical', '-', (195, 197))
151532	32797202	Timed matings between naive B6(Cg)-Tyrc-2J/J, C57BL/6J mice that carry a mutation in the tyrosinase gene, rendering them albino, were used to investigate the developing choroid in E15.5 (n = 2), E18.5 (n = 4), P0 (n = 7), P2 (n = 4), P4 (n = 4), P6 (n = 4), and P8 (n = 4) eyes.	('tyrosinase', 'Gene', (89, 99))	('mice', 'Species', '10090', (55, 59))	('Tyr', 'Gene', '7299', (35, 38))	('Tyr', 'Gene', (35, 38))	('mutation', 'Var', (73, 81))
151534	32797202	Adult B6(Cg)-Tyrc-2J/J, C57BL/6J mice were sacrificed via an intraperitoneal injection of sodium pentobarbital and enucleated eyes were immersion fixed in 4% paraformaldehyde.	('Tyr', 'Gene', '7299', (13, 16))	('sodium pentobarbital', 'Chemical', 'MESH:D010424', (90, 110))	('Tyr', 'Gene', (13, 16))	('C57BL/6J', 'Var', (24, 32))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (158, 174))	('mice', 'Species', '10090', (33, 37))
151541	32797202	1), adult choroid and iris controls (from B6(Cg)-Tyrc-2J/J, C57BL/6J) were processed in parallel with fetal/embryonic at the time points previously detailed.	('C57BL/6J', 'Var', (60, 68))	('Tyr', 'Gene', (49, 52))	('Tyr', 'Gene', '7299', (49, 52))
151550	32797202	Vasculogenic cords of Ib4+ vessels were evident at E15.5 (data not shown), E18.5, and P0 (Fig.	('E15.5', 'Var', (51, 56))	('Ib4', 'Chemical', '-', (22, 25))	('E18.5', 'Var', (75, 80))
151552	32797202	The MB identified at E15.5 and E18.5 were not closely associated with the larger vessels (Figs.	('MB', 'Chemical', '-', (4, 6))	('E15.5', 'Var', (21, 26))	('associated', 'Reg', (54, 64))	('larger vessels', 'CPA', (74, 88))	('E18.5', 'Var', (31, 36))
151565	32797202	We found TRP2+ MB in the presumptive choroid of mice at our earliest time point of E15.5, which is comparable with approximately 8 to 9 weeks of development in humans, and in increased numbers by E18.5, equivalent to weeks 15 and 16.	('humans', 'Species', '9606', (160, 166))	('mice', 'Species', '10090', (48, 52))	('TRP2', 'molecular_function', 'GO:0004167', ('9', '13'))	('E15.5', 'Var', (83, 88))	('MB', 'Chemical', '-', (15, 17))	('TRP2+ MB', 'Protein', (9, 17))
151572	32797202	The human equivalent disorder, oculocutaneous albinism type 1A, is caused by a mutation in TYR gene located on chromosome 11q14.2 encoding tyrosinase.	('human', 'Species', '9606', (4, 9))	('caused by', 'Reg', (67, 76))	('oculocutaneous albinism type 1A', 'Disease', (31, 62))	('TYR', 'Gene', (91, 94))	('mutation', 'Var', (79, 87))	('chromosome', 'cellular_component', 'GO:0005694', ('111', '121'))	('albinism', 'Phenotype', 'HP:0001022', (46, 54))
151603	32797202	Highly metastatic UM demonstrate an epithelioid cell morphology with complex connective tissue loops containing vascular structures, scattered immature vascular lakes, as well as genetic alterations including loss of one copy of chromosome 3, amplifications of chromosome 8 and mutations in BAP1.	('mutations', 'Var', (278, 287))	('BAP1', 'Gene', (291, 295))	('chromosome', 'cellular_component', 'GO:0005694', ('261', '271'))	('amplifications', 'Var', (243, 257))	('UM', 'Phenotype', 'HP:0007716', (18, 20))	('chromosome', 'cellular_component', 'GO:0005694', ('229', '239'))	('BAP1', 'Gene', '104416', (291, 295))	('loss', 'Var', (209, 213))
151706	31367256	In addition, the clone formation rate of the C918 cells in the CCo group was nearly 50% of that in the control group (Figure 2B, and Figure S3B).	('C918', 'Var', (45, 49))	('CCo', 'Gene', '6261', (63, 66))	('formation', 'biological_process', 'GO:0009058', ('23', '32'))	('CCo', 'Gene', (63, 66))	('C918', 'CellLine', 'CVCL:8471', (45, 49))	('clone formation rate', 'CPA', (17, 37))
151719	31367256	A histopathological assay revealed a lower nuclear-to-cytoplasmic (N:C) ratio in the CCo group than the control group (Figure S4F), indicating that tumors arising from C918 cells co-cultured with ESCs were less aggressive than those arising from C918 cells cultured alone.	('C918', 'CellLine', 'CVCL:8471', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CCo', 'Gene', (85, 88))	('aggressive', 'CPA', (211, 221))	('C918', 'Var', (168, 172))	('C918', 'CellLine', 'CVCL:8471', (246, 250))	('tumors', 'Disease', (148, 154))	('lower', 'NegReg', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('less', 'NegReg', (206, 210))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('CCo', 'Gene', '6261', (85, 88))
151741	31367256	Furthermore, ESC treatment prevented the expression of the senescence markers, p21 and p27, at both transcriptional and translational levels (Figure 5E and G, and Figure S5).	('senescence', 'biological_process', 'GO:0010149', ('59', '69'))	('expression', 'MPA', (41, 51))	('p27', 'Gene', '3429', (87, 90))	('prevented', 'NegReg', (27, 36))	('p27', 'Gene', (87, 90))	('p21', 'Var', (79, 82))
151743	31367256	Quantitative gene expression and western blot analysis revealed that KLF4 was barely detectable in the RPE cells in the control group, but was markedly upregulated in ESC-treated RPE cells (Figure 5E and G), indicating that ESCs enhanced the stem cell phenotype of RPE cells.	('upregulated', 'PosReg', (152, 163))	('gene expression', 'biological_process', 'GO:0010467', ('13', '28'))	('stem cell phenotype of', 'CPA', (242, 264))	('KLF4', 'Gene', '9314', (69, 73))	('ESCs', 'Var', (224, 228))	('KLF4', 'Gene', (69, 73))	('RPE', 'Disease', (265, 268))	('enhanced', 'PosReg', (229, 237))
151752	31367256	Proliferating cell nuclear antigen (PCNA) is an indicator of cell proliferation, and we found significantly fewer PCNA+ cells (Figure 7A) and more apoptotic cells (Figure 7B) in the tumors of mice treated with ESCs than in those of mice treated with PBS or ESC-CM.	('apoptotic cells', 'CPA', (147, 162))	('mice', 'Species', '10090', (192, 196))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('PBS', 'Chemical', '-', (250, 253))	('Proliferating cell nuclear antigen', 'Gene', '18538', (0, 34))	('fewer', 'NegReg', (108, 113))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('PCNA', 'molecular_function', 'GO:0003892', ('36', '40'))	('Proliferating cell nuclear antigen', 'Gene', (0, 34))	('ESCs', 'Var', (210, 214))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('Proliferating cell nuclear antigen', 'molecular_function', 'GO:0003892', ('0', '34'))	('PCNA', 'molecular_function', 'GO:0003892', ('114', '118'))	('PCNA+', 'Protein', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('mice', 'Species', '10090', (232, 236))
151757	31367256	Compared with that in the PBS or ESC-CM treatment groups, the surrounding skin tissue in the ESC treatment group had more PCNA+ cells (Figure 7A), which correlated with the in vitro experiments.	('PCNA+', 'MPA', (122, 127))	('PCNA', 'molecular_function', 'GO:0003892', ('122', '126'))	('PBS', 'Chemical', '-', (26, 29))	('more', 'PosReg', (117, 121))	('ESC', 'Var', (93, 96))
151778	31367256	In a previous study, we employed ESCs to a murine leukemia model and found that the proliferation of leukemic cells decreased and the survival of mice increased after injection of ESCs.	('ESCs', 'Var', (180, 184))	('increased', 'PosReg', (151, 160))	('leukemic', 'Disease', (101, 109))	('survival', 'CPA', (134, 142))	('murine', 'Species', '10090', (43, 49))	('leukemic', 'Disease', 'MESH:D007938', (101, 109))	('mice', 'Species', '10090', (146, 150))	('proliferation', 'CPA', (84, 97))	('leukemia', 'Disease', (50, 58))	('leukemia', 'Disease', 'MESH:D007938', (50, 58))	('leukemia', 'Phenotype', 'HP:0001909', (50, 58))	('decreased', 'NegReg', (116, 125))
151790	31367256	To further confirm the bidirectional function of the ESCMe (inhibiting the malignant cell proliferation, and senescence of normal cells) in vivo, we transplanted ESCs into tumor-bearing mice and found that ESCs could markedly suppress tumor growth and enhance the proliferation of the adjacent skin tissue.	('inhibiting', 'NegReg', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('malignant cell proliferation', 'CPA', (75, 103))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('cell proliferation', 'biological_process', 'GO:0008283', ('85', '103'))	('tumor', 'Disease', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('ESCs', 'Var', (206, 210))	('proliferation of the adjacent skin tissue', 'CPA', (264, 305))	('tumor', 'Disease', (235, 240))	('mice', 'Species', '10090', (186, 190))	('enhance', 'PosReg', (252, 259))	('senescence', 'biological_process', 'GO:0010149', ('109', '119'))	('suppress', 'NegReg', (226, 234))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
151795	31367256	Similarly, in vivo experiments also demonstrated that the PI3K pathway related- genes of tumors tissues were changed more significantly in the ESC-treated mice than in the ESC-CM-treated mice.	('ESC-treated', 'Var', (143, 154))	('PI3K', 'molecular_function', 'GO:0016303', ('58', '62'))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('PI3', 'Gene', '5266', (58, 61))	('changed', 'Reg', (109, 116))	('mice', 'Species', '10090', (187, 191))	('PI3', 'Gene', (58, 61))	('mice', 'Species', '10090', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
151801	31367256	Researchers have also found that PI3K, a downstream effector of F2RL1 activation, has a negative regulatory role in limiting the proinflammatory gene expression induced by F2RL1.	('PI3K', 'molecular_function', 'GO:0016303', ('33', '37'))	('proinflammatory gene expression', 'MPA', (129, 160))	('gene expression', 'biological_process', 'GO:0010467', ('145', '160'))	('PI3', 'Gene', (33, 36))	('F2RL1', 'Gene', (64, 69))	('negative regulatory', 'MPA', (88, 107))	('limiting', 'NegReg', (116, 124))	('F2RL1', 'Var', (172, 177))	('PI3', 'Gene', '5266', (33, 36))
151805	31367256	Our study provides several lines of evidence that ESCs can suppress the malignant phenotype of tumor cells while repressing the senescence of normal cells through the bidirectional regulation of the PI3K pathway.	('ESCs', 'Var', (50, 54))	('regulation', 'biological_process', 'GO:0065007', ('181', '191'))	('PI3', 'Gene', '5266', (199, 202))	('senescence', 'MPA', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('senescence', 'biological_process', 'GO:0010149', ('128', '138'))	('repressing', 'NegReg', (113, 123))	('PI3K', 'molecular_function', 'GO:0016303', ('199', '203'))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('PI3', 'Gene', (199, 202))	('suppress', 'NegReg', (59, 67))	('tumor', 'Disease', (95, 100))
151868	30195895	Subretinal fluid was detected in 136 (65.7%) cases, orange lipofuscin pigment in 121 (58.4%), low acoustic internal reflectivity in 60 (29.0%) cases, drusen in 44 (21.0%) cases, retinal pigment epithelial fibrosis in 25 (12.3%) cases, and retinal pigment epithelial atrophy in 44 (21.3%) cases.	('low', 'Var', (94, 97))	('retinal pigment epithelial fibrosis', 'Disease', (178, 213))	('retinal pigment epithelial atrophy', 'Phenotype', 'HP:0007722', (239, 273))	('retinal pigment epithelial atrophy', 'Disease', 'MESH:C537835', (239, 273))	('drusen', 'Phenotype', 'HP:0011510', (150, 156))	('retinal pigment epithelial fibrosis', 'Disease', 'MESH:C537835', (178, 213))	('retinal pigment epithelial atrophy', 'Disease', (239, 273))	('orange lipofuscin', 'Chemical', 'MESH:D008062', (52, 69))	('Subretinal fluid', 'Phenotype', 'HP:0031526', (0, 16))
151895	30195895	Thus, initial observation for growth would seem appropriate in most suspicious choroidal nevi <=2.25 mm thickness and in patients <=60 years old, since most will have the class 1 profile.	('nevi', 'Phenotype', 'HP:0003764', (89, 93))	('choroidal nevi', 'Phenotype', 'HP:0025314', (79, 93))	('<=2.25', 'Var', (94, 100))	('choroidal nevi', 'Disease', (79, 93))	('patients', 'Species', '9606', (121, 129))
151899	30195895	If the nascent lesion then acquires a mutation in EIF1AX (Eukaryotic Translation Initiation Factor 1A, X-Linked) or SF3B1 (Splicing Factor 3B Subunit 1), it may progress and grow, but it retains the class 1 profile (class 1A or class 1B, respectively).	('Splicing Factor 3B Subunit 1', 'Gene', (123, 151))	('SF3B1', 'Gene', (116, 121))	('progress', 'PosReg', (161, 169))	('Splicing Factor 3B Subunit 1', 'Gene', '23451', (123, 151))	('EIF1AX', 'Gene', (50, 56))	('grow', 'CPA', (174, 178))	('EIF1AX', 'Gene', '1964', (50, 56))	('SF3B1', 'Gene', '23451', (116, 121))	('Translation Initiation', 'biological_process', 'GO:0006413', ('69', '91'))	('Eukaryotic Translation Initiation Factor 1A, X-Linked)', 'Gene', '1964', (58, 112))	('mutation', 'Var', (38, 46))	('Splicing', 'biological_process', 'GO:0045292', ('123', '131'))	('Eukaryotic Translation Initiation Factor 1A, X-Linked', 'Gene', (58, 111))
151900	30195895	Alternatively, if the tumor undergoes biallelic mutational inactivation of BAP1 (BRCA1 Associated Protein 1), the class 1 profile is overtaken by the class 2 profile, which denotes a loss of melanocytic differentiation and replacement by a cancer stem cell-like state.	('biallelic mutational inactivation', 'Var', (38, 71))	('loss', 'NegReg', (183, 187))	('BAP1', 'Gene', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('BAP1', 'Gene', '8314', (75, 79))	('melanocytic differentiation', 'CPA', (191, 218))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('tumor', 'Disease', (22, 27))	('cancer', 'Disease', (240, 246))	('BRCA1 Associated Protein 1', 'Gene', (81, 107))	('BRCA1 Associated Protein 1', 'Gene', '8314', (81, 107))
151902	30195895	Further, the gene expression profile has prognostic accuracy that is superior to sequencing for BAP1 mutations because current sequencing methods cannot detect all BAP1 mutations.	('mutations', 'Var', (101, 110))	('BAP1', 'Gene', (96, 100))	('gene expression', 'biological_process', 'GO:0010467', ('13', '28'))	('BAP1', 'Gene', (164, 168))	('BAP1', 'Gene', '8314', (164, 168))	('BAP1', 'Gene', '8314', (96, 100))
151903	30195895	Recently, we showed that once a choroidal melanocytic tumor acquires a "BSE" ( BAP1, SF3B1 or EIF1AX) mutation, its evolutionary trajectory generally becomes fixed, such that it does not acquire another BSE mutation or switch gene expression profiles.	('EIF1AX', 'Gene', '1964', (94, 100))	('EIF1AX', 'Gene', (94, 100))	('BAP1', 'Gene', '8314', (79, 83))	('SF3B1', 'Gene', (85, 90))	('mutation', 'Var', (102, 110))	('BAP1', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('gene expression', 'biological_process', 'GO:0010467', ('224', '239'))	('SF3B1', 'Gene', '23451', (85, 90))	('choroidal melanocytic tumor', 'Disease', (32, 59))	('choroidal melanocytic tumor', 'Phenotype', 'HP:0012054', (32, 59))	('choroidal melanocytic tumor', 'Disease', 'MESH:D009508', (32, 59))
151904	30195895	Thus, it may be unnecessary to treat an EIF1AX-mutant class 1 tumor (regardless of the presence of risk factors for growth) since its metastatic risk is minimal and its likelihood of acquiring a BAP1 mutation and switching to the class 2 profile is exceedingly low.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('BAP1', 'Gene', (195, 199))	('tumor', 'Disease', (62, 67))	('EIF1AX', 'Gene', (40, 46))	('EIF1AX', 'Gene', '1964', (40, 46))	('BAP1', 'Gene', '8314', (195, 199))	('mutation', 'Var', (200, 208))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
151906	30195895	The growing class 1 tumors that are most likely to benefit from treatment are those that have neither a EIF1AX or SF3B1 mutation, as these tumors are not yet evolutionarily stabilized and may go on to acquire a BAP1 mutation.	('EIF1AX', 'Gene', (104, 110))	('SF3B1', 'Gene', '23451', (114, 119))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('BAP1', 'Gene', (211, 215))	('mutation', 'Var', (120, 128))	('BAP1', 'Gene', '8314', (211, 215))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('SF3B1', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('EIF1AX', 'Gene', '1964', (104, 110))
151910	30195895	The class 2 profile is strongly associated with inactivating mutations in the tumor suppressor BAP1.	('inactivating mutations', 'Var', (48, 70))	('BAP1', 'Gene', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor suppressor', 'biological_process', 'GO:0051726', ('78', '94'))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('78', '94'))	('BAP1', 'Gene', '8314', (95, 99))	('associated', 'Reg', (32, 42))
151911	30195895	Indeed, it is likely that loss of BAP1 is the trigger for development of the class 2 profile by causing a loss of melanocytic differentiation.	('BAP1', 'Gene', (34, 38))	('melanocytic differentiation', 'CPA', (114, 141))	('loss', 'Var', (26, 30))	('loss', 'NegReg', (106, 110))	('BAP1', 'Gene', '8314', (34, 38))
151912	30195895	These findings suggest that increased patient age is associated with an increased risk of BAP1 mutations in suspicious choroidal nevi, as it is in overt uveal melanomas.	('choroidal nevi', 'Phenotype', 'HP:0025314', (119, 133))	('uveal melanomas', 'Disease', 'MESH:C536494', (153, 168))	('melanomas', 'Phenotype', 'HP:0002861', (159, 168))	('uveal melanoma', 'Phenotype', 'HP:0007716', (153, 167))	('BAP1', 'Gene', '8314', (90, 94))	('patient', 'Species', '9606', (38, 45))	('nevi', 'Phenotype', 'HP:0003764', (129, 133))	('suspicious choroidal nevi', 'Disease', (108, 133))	('BAP1', 'Gene', (90, 94))	('mutations', 'Var', (95, 104))	('uveal melanomas', 'Disease', (153, 168))	('uveal melanomas', 'Phenotype', 'HP:0007716', (153, 168))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
151913	30195895	One possible explanation is that BAP1 mutations occur more commonly with increasing age, perhaps due to less efficient DNA damage repair.	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('mutations', 'Var', (38, 47))	('BAP1', 'Gene', '8314', (33, 37))	('BAP1', 'Gene', (33, 37))
151914	30195895	Although we cannot rule this out completely at the current time, our recent analysis of a large number of primary uveal melanomas using next generation sequencing did not find an aging signature associated with BAP1 mutations.	('uveal melanomas', 'Disease', 'MESH:C536494', (114, 129))	('aging', 'biological_process', 'GO:0007568', ('179', '184'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('BAP1', 'Gene', '8314', (211, 215))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanomas', 'Phenotype', 'HP:0002861', (120, 129))	('uveal melanomas', 'Disease', (114, 129))	('uveal melanomas', 'Phenotype', 'HP:0007716', (114, 129))	('BAP1', 'Gene', (211, 215))	('mutations', 'Var', (216, 225))
151915	30195895	Another possible explanation is that with increasing age, the cellular microenvironment of the uveal tract becomes less able to limit the growth of a uveal melanocyte that develops a BAP1 mutation.	('mutation', 'Var', (188, 196))	('BAP1', 'Gene', (183, 187))	('BAP1', 'Gene', '8314', (183, 187))
151936	30195895	The primary tumors undergo fine needle biopsy prior to treatment, and the biopsy sample is subjected to gene expression profiling (class 1A, 1B or 2), PRAME expression status, and mutation profiling for all common uveal melanoma driver mutations.	('PRAME', 'Gene', '23532', (151, 156))	('uveal melanoma', 'Disease', 'MESH:C536494', (214, 228))	('PRAME', 'Gene', (151, 156))	('uveal melanoma', 'Phenotype', 'HP:0007716', (214, 228))	('uveal melanoma', 'Disease', (214, 228))	('gene expression', 'biological_process', 'GO:0010467', ('104', '119'))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mutations', 'Var', (236, 245))	('tumors', 'Disease', (12, 18))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
151995	30541578	With more data from children treated with PBT, the proton beam model policy adopted by the American Society of Radiation Oncology in 2017 supports PBT in children with solid neoplasms, and it is now an option for many Children's Oncology Group (COG) protocols.	('Oncology', 'Phenotype', 'HP:0002664', (229, 237))	('solid neoplasms', 'Disease', (168, 183))	('solid neoplasms', 'Disease', 'MESH:D018250', (168, 183))	('neoplasms', 'Phenotype', 'HP:0002664', (174, 183))	('COG', 'Chemical', '-', (245, 248))	('Children', 'Species', '9606', (218, 226))	('Oncology', 'Phenotype', 'HP:0002664', (121, 129))	('PBT', 'Var', (147, 150))	('children', 'Species', '9606', (20, 28))	('children', 'Species', '9606', (154, 162))
152000	30541578	There were no late toxicities of the heart, lungs, and digestive tract side effects, and no second primary tumor occurred, which was significantly better than that of photon therapy; the notable finding was that the intelligence quotient (IQ) of patients using PBT decreased slower than that using photon therapy.	('PBT', 'Var', (261, 264))	('intelligence quotient', 'Phenotype', 'HP:0001249', (216, 237))	('toxicities', 'Disease', 'MESH:D064420', (19, 29))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('patients', 'Species', '9606', (246, 254))	('decreased', 'NegReg', (265, 274))	('intelligence quotient', 'MPA', (216, 237))	('toxicities', 'Disease', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('IQ', 'Phenotype', 'HP:0001249', (239, 241))
152014	30541578	first showed the improved long-term health-related quality of life (HRQoL) outcomes of children with brain tumors treated with PBT compared to photon RT.	('improved', 'PosReg', (17, 25))	('children', 'Species', '9606', (87, 95))	('brain tumors', 'Phenotype', 'HP:0030692', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('brain tumors', 'Disease', (101, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('PBT', 'Var', (127, 130))	('brain tumors', 'Disease', 'MESH:D001932', (101, 113))
152020	30541578	At a median follow-up of 13.1 years in the photon therapy group and 6.9 years in the PBT group, the cumulative incidence of second malignancies (radiation-induced or in-field) at 10 years was significantly higher in photon therapy group than that in PBT group (14% vs. 0%; P = 0.015).	('malignancies', 'Disease', (131, 143))	('malignancies', 'Disease', 'MESH:D009369', (131, 143))	('photon therapy', 'Var', (216, 230))	('higher', 'PosReg', (206, 212))
152041	30541578	However, PBT can increase the tumor dose and can better protect normal tissues.	('PBT', 'Var', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('increase', 'PosReg', (17, 25))	('tumor', 'Disease', (30, 35))
152043	30541578	The patients with low-grade chondrosarcoma usually have a better long-term survival than those with chordoma in PBT and can even achieve a curable effect.	('chordoma', 'Disease', 'MESH:D002817', (100, 108))	('chondrosarcoma', 'Disease', (28, 42))	('low-grade', 'Var', (18, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('chordoma', 'Phenotype', 'HP:0010762', (100, 108))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (28, 42))	('chordoma', 'Disease', (100, 108))	('patients', 'Species', '9606', (4, 12))	('chondrosarcoma', 'Disease', 'MESH:D002813', (28, 42))
152050	30541578	The estimated 10-year OS rates of the PBT group reached 60%, which was significantly higher than that of conventional photon therapy (21%) and SRT (40%).	('PBT', 'Var', (38, 41))	('OS', 'Chemical', '-', (22, 24))	('higher', 'PosReg', (85, 91))
152077	30541578	In a retrospective case-control study, IMPT-treated NPC patients (n = 10) had significantly lower rates of gastrostomy tube insertion compared to IMRT-treated patients (n = 20) (20% vs. 65%, P = 0.02).	('IMPT-treated', 'Var', (39, 51))	('patients', 'Species', '9606', (56, 64))	('NPC', 'Phenotype', 'HP:0100630', (52, 55))	('NPC', 'cellular_component', 'GO:0005643', ('52', '55'))	('NPC', 'Disease', 'MESH:D052556', (52, 55))	('NPC', 'Disease', (52, 55))	('IMRT', 'Chemical', '-', (146, 150))	('IMPT', 'Chemical', '-', (39, 43))	('gastrostomy', 'Disease', (107, 118))	('patients', 'Species', '9606', (159, 167))	('lower', 'NegReg', (92, 97))
152096	30541578	In a retrospective study that enrolled 336 patients with large choroidal melanomas, the rates of visual acuity retention at 10 years were 8.7% for >= 20/200 and 22.4% for at least counting fingers; neovascular glaucoma was found in 25.3% patients.	('choroidal melanomas', 'Disease', (63, 82))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('neovascular glaucoma', 'Disease', 'MESH:D015355', (198, 218))	('patients', 'Species', '9606', (43, 51))	('choroidal melanomas', 'Disease', 'MESH:D008545', (63, 82))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (63, 81))	('retention', 'biological_process', 'GO:0051235', ('111', '120'))	('>= 20/200', 'Var', (147, 156))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (63, 82))	('glaucoma', 'Phenotype', 'HP:0000501', (210, 218))	('neovascular glaucoma', 'Disease', (198, 218))	('patients', 'Species', '9606', (238, 246))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
152174	30541578	Recently, one notable study at MD Anderson was reported that grade 4 lymphopenia during chemo-radiotherapy for EC was associated with poor overall and disease-specific survival outcomes, and OS in this group was significantly worse than the grade 0-2 group, with a median OS 2.8 vs. 5.0 years (P = 0.027).	('OS', 'Chemical', '-', (272, 274))	('lymphopenia', 'Phenotype', 'HP:0001888', (69, 80))	('OS', 'Chemical', '-', (191, 193))	('lymphopenia', 'Disease', 'MESH:D008231', (69, 80))	('grade 4', 'Var', (61, 68))	('poor', 'NegReg', (134, 138))	('lymphopenia', 'Disease', (69, 80))
152175	30541578	The important finding in the study was that PBT could reduce the low dose area, and then resulted in less lymphopenia risk.	('less', 'NegReg', (101, 105))	('lymphopenia', 'Disease', 'MESH:D008231', (106, 117))	('reduce', 'NegReg', (54, 60))	('PBT', 'Var', (44, 47))	('lymphopenia', 'Disease', (106, 117))	('low dose area', 'MPA', (65, 78))	('lymphopenia', 'Phenotype', 'HP:0001888', (106, 117))
152206	30541578	evaluated long-term outcomes with a focus on sexual health for young patients treated with PSPT in a dose of 76-82 Gy (2 Gy/F) or 70-72.5 Gy (2.5 Gy/F).	('patients', 'Species', '9606', (69, 77))	('70-72.5 Gy', 'Var', (130, 140))	('PSPT', 'Gene', (91, 95))
152280	30122851	suggested several modifications with the intent to decrease risk of operative complications including retinal breaks, rhegmatogenous retinal detachment, and postoperative diplopia.	('rhegmatogenous retinal detachment', 'Phenotype', 'HP:0012230', (118, 151))	('retinal detachment', 'Phenotype', 'HP:0000541', (133, 151))	('rhegmatogenous retinal detachment', 'Disease', 'MESH:C563710', (118, 151))	('modifications', 'Var', (18, 31))	('rhegmatogenous retinal detachment', 'Disease', (118, 151))	('postoperative diplopia', 'Disease', (157, 179))	('retinal breaks', 'Disease', (102, 116))	('diplopia', 'Phenotype', 'HP:0000651', (171, 179))	('postoperative diplopia', 'Disease', 'MESH:D004172', (157, 179))
152282	30122851	suggested cauterization of the short posterior ciliary arteries around the tumor and claimed that this had markedly diminished the risk of bleeding.	('bleeding', 'Disease', 'MESH:D006470', (139, 147))	('diminished', 'NegReg', (116, 126))	('bleeding', 'Disease', (139, 147))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cauterization', 'Var', (10, 23))	('tumor', 'Disease', (75, 80))
152293	30122851	The rate of complications including macular edema, vitreous hemorrhage and cataract was higher in the brachytherapy group.	('edema', 'Disease', (44, 49))	('cataract', 'Disease', 'MESH:D002386', (75, 83))	('vitreous hemorrhage', 'Phenotype', 'HP:0007902', (51, 70))	('cataract', 'Disease', (75, 83))	('cataract', 'Phenotype', 'HP:0000518', (75, 83))	('vitreous hemorrhage', 'Disease', (51, 70))	('vitreous hemorrhage', 'Disease', 'MESH:D014823', (51, 70))	('macular edema', 'Phenotype', 'HP:0040049', (36, 49))	('edema', 'Disease', 'MESH:D004487', (44, 49))	('edema', 'Phenotype', 'HP:0000969', (44, 49))	('brachytherapy', 'Var', (102, 115))
152391	26769193	SF3B1 and EIF1AX mutations occur in primary leptomeningeal melanocytic neoplasms; yet another similarity to uveal melanomas Like uveal melanomas, primary leptomeningeal melanocytic neoplasms (LMNs) frequently carry GNAQ and GNA11 mutations.	('leptomeningeal melanocytic neoplasms', 'Disease', 'MESH:D008577', (44, 80))	('uveal melanomas', 'Disease', 'MESH:C536494', (108, 123))	('carry', 'Reg', (209, 214))	('leptomeningeal melanocytic neoplasms', 'Disease', 'MESH:D008577', (154, 190))	('EIF1AX', 'Gene', (10, 16))	('neoplasm', 'Phenotype', 'HP:0002664', (181, 189))	('melanomas', 'Phenotype', 'HP:0002861', (135, 144))	('mutations', 'Var', (230, 239))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (169, 190))	('EIF1AX', 'Gene', '1964', (10, 16))	('leptomeningeal melanocytic neoplasms', 'Disease', (44, 80))	('SF3B1', 'Gene', (0, 5))	('LMN', 'Chemical', '-', (192, 195))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('uveal melanomas', 'Disease', (108, 123))	('uveal melanomas', 'Disease', 'MESH:C536494', (129, 144))	('uveal melanomas', 'Phenotype', 'HP:0007716', (108, 123))	('GNA11', 'Gene', '2767', (224, 229))	('SF3B1', 'Gene', '23451', (0, 5))	('GNAQ', 'Gene', '2776', (215, 219))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('GNAQ', 'Gene', (215, 219))	('uveal melanomas', 'Disease', (129, 144))	('uveal melanomas', 'Phenotype', 'HP:0007716', (129, 144))	('melanomas', 'Phenotype', 'HP:0002861', (114, 123))	('neoplasms', 'Phenotype', 'HP:0002664', (71, 80))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (59, 80))	('neoplasms', 'Phenotype', 'HP:0002664', (181, 190))	('neoplasm', 'Phenotype', 'HP:0002664', (71, 79))	('GNA11', 'Gene', (224, 229))	('leptomeningeal melanocytic neoplasms', 'Disease', (154, 190))
152392	26769193	However, it is currently unknown whether these LMNs harbor mutations in BAP1, SF3B1 and/or EIF1AX like uveal melanomas as well.	('uveal melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('LMN', 'Chemical', '-', (47, 50))	('uveal melanomas', 'Disease', 'MESH:C536494', (103, 118))	('BAP1', 'Gene', '8314', (72, 76))	('SF3B1', 'Gene', '23451', (78, 83))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('EIF1AX', 'Gene', '1964', (91, 97))	('EIF1AX', 'Gene', (91, 97))	('BAP1', 'Gene', (72, 76))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('uveal melanomas', 'Disease', (103, 118))	('uveal melanomas', 'Phenotype', 'HP:0007716', (103, 118))	('mutations', 'Var', (59, 68))	('SF3B1', 'Gene', (78, 83))
152393	26769193	In this study, we used Sanger sequencing for the detection of mutations in SF3B1 (hotspots in exon 14 and 15) and EIF1AX (exon 1 and 2 and flanking intronic regions) in a series of 24 primary LMNs.	('EIF1AX', 'Gene', '1964', (114, 120))	('LMN', 'Chemical', '-', (192, 195))	('EIF1AX', 'Gene', (114, 120))	('mutations', 'Var', (62, 71))	('SF3B1', 'Gene', '23451', (75, 80))	('SF3B1', 'Gene', (75, 80))
152394	26769193	Additionally, BAP1 immunohistochemistry was used as a surrogate marker for the detection of inactivating mutations in the BAP1 gene.	('BAP1', 'Gene', '8314', (14, 18))	('BAP1', 'Gene', (122, 126))	('BAP1', 'Gene', (14, 18))	('inactivating mutations', 'Var', (92, 114))	('BAP1', 'Gene', '8314', (122, 126))
152395	26769193	Mutations in either SF3B1 or EIF1AX were identified in 8 out of 24 primary LMNs (33 %).	('identified', 'Reg', (41, 51))	('SF3B1', 'Gene', (20, 25))	('EIF1AX', 'Gene', '1964', (29, 35))	('EIF1AX', 'Gene', (29, 35))	('SF3B1', 'Gene', '23451', (20, 25))	('primary LMNs', 'Disease', (67, 79))	('Mutations', 'Var', (0, 9))	('LMN', 'Chemical', '-', (75, 78))
152396	26769193	The presence of these mutations was mutually exclusive and occurred in primary LMNs of different malignancy grades (melanocytomas, intermediate-grade melanocytic tumors, melanomas).	('melanocytic tumors', 'Disease', (150, 168))	('melanocytic tumors', 'Disease', 'MESH:D009508', (150, 168))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('melanomas', 'Disease', 'MESH:D008545', (170, 179))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanomas', 'Phenotype', 'HP:0002861', (170, 179))	('melanocytomas', 'Disease', (116, 129))	('LMN', 'Chemical', '-', (79, 82))	('malignancy', 'Disease', 'MESH:D009369', (97, 107))	('melanocytomas', 'Disease', 'None', (116, 129))	('mutations', 'Var', (22, 31))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('melanomas', 'Disease', (170, 179))	('occurred', 'Reg', (59, 67))	('malignancy', 'Disease', (97, 107))
152403	26769193	In contrast to cutaneous melanomas (CMs), both LMNs and UMs frequently carry mutations in the G protein encoding genes GNAQ and GNA11, whereas mutations in BRAF and in the TERT promoter are infrequent.	('CMs', 'Phenotype', 'HP:0012056', (36, 39))	('GNA11', 'Gene', (128, 133))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (15, 33))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('TERT', 'Gene', (172, 176))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (15, 34))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (15, 34))	('TERT', 'Gene', '7015', (172, 176))	('carry', 'Reg', (71, 76))	('BRAF', 'Gene', '673', (156, 160))	('GNA11', 'Gene', '2767', (128, 133))	('BRAF', 'Gene', (156, 160))	('mutations', 'Var', (77, 86))	('GNAQ', 'Gene', '2776', (119, 123))	('cutaneous melanomas', 'Disease', (15, 34))	('LMN', 'Chemical', '-', (47, 50))	('UMs', 'Phenotype', 'HP:0007716', (56, 59))	('GNAQ', 'Gene', (119, 123))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanomas', 'Phenotype', 'HP:0002861', (25, 34))
152405	26769193	In the past years, inactivating mutations in the tumor suppressor gene BAP1 (BRCA-associated protein 1) were shown to be implicated in UM.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('BRCA-associated protein 1', 'Gene', (77, 102))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('49', '65'))	('tumor', 'Disease', (49, 54))	('BAP1', 'Gene', '8314', (71, 75))	('inactivating mutations', 'Var', (19, 41))	('BAP1', 'Gene', (71, 75))	('implicated', 'Reg', (121, 131))	('BRCA-associated protein 1', 'Gene', '8314', (77, 102))	('tumor suppressor', 'biological_process', 'GO:0051726', ('49', '65'))
152406	26769193	Somatic BAP1 mutations are predominantly present in UMs with monosomy 3 (~85 %), the latter being a strong predictor for metastatic disease.	('monosomy 3', 'Var', (61, 71))	('present', 'Reg', (41, 48))	('BAP1', 'Gene', '8314', (8, 12))	('UMs', 'Phenotype', 'HP:0007716', (52, 55))	('BAP1', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))
152407	26769193	In this setting BAP1 functions as a tumor suppressor gene, with loss of one copy of chromosome 3 and mutation in the other BAP1 allele representing the two hits causing inactivation of this gene.	('BAP1', 'Gene', (123, 127))	('mutation', 'Var', (101, 109))	('tumor suppressor', 'biological_process', 'GO:0051726', ('36', '52'))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('36', '52'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('loss', 'NegReg', (64, 68))	('BAP1', 'Gene', '8314', (16, 20))	('BAP1', 'Gene', '8314', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('BAP1', 'Gene', (16, 20))
152408	26769193	Indeed, in UMs with disomy 3 (and a good prognosis), mutations in BAP1 are rare.	('UMs', 'Phenotype', 'HP:0007716', (11, 14))	('BAP1', 'Gene', '8314', (66, 70))	('mutations', 'Var', (53, 62))	('BAP1', 'Gene', (66, 70))	('disomy 3', 'Disease', (20, 28))
152409	26769193	A small proportion of patients with UM (~2-3 %) harbor a germline mutation in BAP1.	('patients', 'Species', '9606', (22, 30))	('BAP1', 'Gene', '8314', (78, 82))	('germline mutation', 'Var', (57, 74))	('BAP1', 'Gene', (78, 82))
152412	26769193	Furthermore, recurrent hotspot mutations in the SF3B1 gene (mainly at codon 625) and mutations of the EIF1AX gene (spread over exon 1 and 2) were recently reported in UMs, especially in tumors with disomy 3 (up to 30 and 50 % of disomy 3 tumors, respectively).	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumors', 'Disease', (238, 244))	('UMs', 'Disease', (167, 170))	('SF3B1', 'Gene', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('EIF1AX', 'Gene', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('mutations', 'Var', (31, 40))	('hotspot', 'PosReg', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('disomy 3', 'Disease', (198, 206))	('mutations', 'Var', (85, 94))	('tumors', 'Disease', (186, 192))	('EIF1AX', 'Gene', '1964', (102, 108))	('disomy 3 tumors', 'Disease', (229, 244))	('SF3B1', 'Gene', '23451', (48, 53))	('UMs', 'Phenotype', 'HP:0007716', (167, 170))	('reported', 'Reg', (155, 163))	('disomy 3 tumors', 'Disease', 'MESH:D024182', (229, 244))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('tumors', 'Disease', 'MESH:D009369', (186, 192))
152413	26769193	These mutations in UMs appeared to be largely mutually exclusively with BAP1 mutations, while in CMs these mutations were found to be very infrequent (~1 %).	('BAP1', 'Gene', '8314', (72, 76))	('BAP1', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))	('UMs', 'Phenotype', 'HP:0007716', (19, 22))	('CMs', 'Phenotype', 'HP:0012056', (97, 100))	('UMs', 'Disease', (19, 22))	('mutations', 'Var', (6, 15))
152414	26769193	It is currently unknown whether somatic mutations in BAP1, SF3B1 and EIF1AX also characterize primary LMNs.	('EIF1AX', 'Gene', '1964', (69, 75))	('EIF1AX', 'Gene', (69, 75))	('LMN', 'Chemical', '-', (102, 105))	('characterize', 'Reg', (81, 93))	('primary LMNs', 'Disease', (94, 106))	('SF3B1', 'Gene', (59, 64))	('mutations', 'Var', (40, 49))	('BAP1', 'Gene', '8314', (53, 57))	('SF3B1', 'Gene', '23451', (59, 64))	('BAP1', 'Gene', (53, 57))
152415	26769193	Using Sanger sequencing, we searched for mutations in hotspot regions of SF3B1 (exon 14 and 15) and exon 1 and 2 and flanking intronic regions of EIF1AX in a series of 24 primary LMNs.	('mutations', 'Var', (41, 50))	('SF3B1', 'Gene', '23451', (73, 78))	('EIF1AX', 'Gene', '1964', (146, 152))	('EIF1AX', 'Gene', (146, 152))	('LMN', 'Chemical', '-', (179, 182))	('SF3B1', 'Gene', (73, 78))
152416	26769193	Additionally, we performed immunohistochemistry for the detection of BAP1 protein loss as a surrogate marker for identification of inactivating BAP1 mutations.	('mutations', 'Var', (149, 158))	('BAP1', 'Gene', (69, 73))	('BAP1', 'Gene', (144, 148))	('BAP1', 'Gene', '8314', (144, 148))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('loss', 'NegReg', (82, 86))	('protein', 'Protein', (74, 81))	('BAP1', 'Gene', '8314', (69, 73))
152426	26769193	Sanger sequencing was used for analysis of mutations in hotspot areas of SF3B1 including codon 625 and codon 700 as well as for mutations in exon 1 and 2 and flanking intronic regions of EIF1AX.	('EIF1AX', 'Gene', '1964', (187, 193))	('EIF1AX', 'Gene', (187, 193))	('SF3B1', 'Gene', '23451', (73, 78))	('mutations', 'Var', (128, 137))	('codon 625', 'Var', (89, 98))	('codon 700', 'Var', (103, 112))	('mutations', 'Var', (43, 52))	('SF3B1', 'Gene', (73, 78))
152429	26769193	Information on BAP1 mutation status was available for three patients (#20, #23, #24) (obtained by Sanger sequencing as previously described) while the chromosome 3 status was in part obtained from a previous MLPA study.	('patients', 'Species', '9606', (60, 68))	('mutation', 'Var', (20, 28))	('BAP1', 'Gene', '8314', (15, 19))	('BAP1', 'Gene', (15, 19))	('chromosome', 'cellular_component', 'GO:0005694', ('151', '161'))
152430	26769193	For all cases, the mutation status of GNAQ and GNA11 (codons 209 and 183), BRAF (codon 600) and NRAS (codons 12, 13 and 61) was available, part of this information has been published previously.	('GNAQ', 'Gene', '2776', (38, 42))	('BRAF', 'Gene', '673', (75, 79))	('GNA11', 'Gene', (47, 52))	('GNA11', 'Gene', '2767', (47, 52))	('codon 600', 'Var', (81, 90))	('GNAQ', 'Gene', (38, 42))	('BRAF', 'Gene', (75, 79))	('NRAS', 'Gene', (96, 100))	('NRAS', 'Gene', '4893', (96, 100))
152444	26769193	We detected a total of three mutations in SF3B1 (13 %), including two hotspot mutations at codon 625 (R625C and R625H) and one mutation affecting codon 634 (V634I) (Table 2).	('V634I', 'Mutation', 'p.V634I', (157, 162))	('R625H', 'Mutation', 'rs1057519961', (112, 117))	('SF3B1', 'Gene', (42, 47))	('R625H', 'Var', (112, 117))	('R625C', 'Var', (102, 107))	('R625C', 'Mutation', 'rs775623976', (102, 107))	('SF3B1', 'Gene', '23451', (42, 47))
152446	26769193	In the cosmic database the V634I mutation in SF3B1 (c.1900G > A (p.(Val634Ile))) has not been reported in cancer before (http://cancer.sanger.ac.uk/cosmic).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('c.1900G > A', 'Var', (52, 63))	('V634I', 'Mutation', 'p.V634I', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('SF3B1', 'Gene', (45, 50))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('p.(Val634Ile)', 'Mutation', 'p.V634I', (65, 78))	('c.1900G > A', 'Mutation', 'c.1900G>A', (52, 63))	('V634I', 'Var', (27, 32))	('SF3B1', 'Gene', '23451', (45, 50))	('cancer', 'Disease', (128, 134))
152448	26769193	One case with mutation in codon 625 of SF3B1 (c.1873C > T (p.(Arg625Cys))) concerned an intermediate-grade melanocytic tumor showing aggressive behavior with leptomeningeal seeding (patient #18).	('c.1873C > T', 'Var', (46, 57))	('leptomeningeal seeding', 'Phenotype', 'HP:0032070', (158, 180))	('SF3B1', 'Gene', '23451', (39, 44))	('melanocytic tumor', 'Disease', (107, 124))	('patient', 'Species', '9606', (182, 189))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('aggressive behavior', 'biological_process', 'GO:0002118', ('133', '152'))	('aggressive behavior', 'Phenotype', 'HP:0000718', (133, 152))	('p.(Arg625Cys)', 'Mutation', 'rs775623976', (59, 72))	('c.1873C > T', 'Mutation', 'rs775623976', (46, 57))	('melanocytic tumor', 'Disease', 'MESH:D009508', (107, 124))	('SF3B1', 'Gene', (39, 44))
152449	26769193	A concomitant GNA11 mutation was present in this tumor while immunohistochemistry showed intact nuclear BAP1 expression (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('BAP1', 'Gene', '8314', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mutation', 'Var', (20, 28))	('BAP1', 'Gene', (104, 108))	('tumor', 'Disease', (49, 54))	('GNA11', 'Gene', (14, 19))	('GNA11', 'Gene', '2767', (14, 19))
152450	26769193	The other mutation in codon 625 of SF3B1 (c.1874G > A (p.(Arg625His))) was present in a CNS melanoma of a 31-year-old woman (patient #21).	('SF3B1', 'Gene', '23451', (35, 40))	('woman', 'Species', '9606', (118, 123))	('CNS melanoma', 'Disease', (88, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('c.1874G > A', 'Mutation', 'rs1057519961', (42, 53))	('c.1874G > A', 'Var', (42, 53))	('SF3B1', 'Gene', (35, 40))	('patient', 'Species', '9606', (125, 132))	('p.(Arg625His)', 'Mutation', 'rs1057519961', (55, 68))	('CNS melanoma', 'Disease', 'MESH:D008545', (88, 100))
152454	26769193	This was supported by the presence of an NRAS mutation in both the CNS melanoma and in a more recent biopsy of the melanocytic nevus (c.182A > G (p.(Gln61Arg))).	('c.182A > G', 'Var', (134, 144))	('NRAS', 'Gene', '4893', (41, 45))	('CNS melanoma', 'Disease', (67, 79))	('p.(Gln61Arg)', 'Mutation', 'rs11554290', (146, 158))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanocytic nevus', 'Phenotype', 'HP:0000995', (115, 132))	('NRAS', 'Gene', (41, 45))	('CNS melanoma', 'Disease', 'MESH:D008545', (67, 79))	('nevus', 'Phenotype', 'HP:0003764', (127, 132))	('c.182A > G', 'Mutation', 'rs11554290', (134, 144))
152455	26769193	In contrast, the SF3B1 mutation (c.1874G > A (p.(Arg625His))) was present in the CNS melanoma but not in the melanocytic nevus.	('c.1874G > A', 'Mutation', 'rs1057519961', (33, 44))	('melanocytic nevus', 'Phenotype', 'HP:0000995', (109, 126))	('CNS melanoma', 'Disease', (81, 93))	('SF3B1', 'Gene', (17, 22))	('c.1874G > A', 'Var', (33, 44))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('SF3B1', 'Gene', '23451', (17, 22))	('p.(Arg625His)', 'Mutation', 'rs1057519961', (46, 59))	('nevus', 'Phenotype', 'HP:0003764', (121, 126))	('CNS melanoma', 'Disease', 'MESH:D008545', (81, 93))
152457	26769193	A point mutation in EIF1AX was detected in five of the primary LMNs in this series (21 %), each leading to an amino acid substitution (at codons 3, 4, 9 or 10).	('amino acid', 'MPA', (110, 120))	('LMN', 'Chemical', '-', (63, 66))	('EIF1AX', 'Gene', '1964', (20, 26))	('EIF1AX', 'Gene', (20, 26))	('point mutation', 'Var', (2, 16))	('leading to', 'Reg', (96, 106))
152458	26769193	These mutations occurred in tumors diagnosed as melanocytomas, intermediate-grade tumors, and melanomas (Fig.	('melanocytomas', 'Disease', 'None', (48, 61))	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('melanomas', 'Disease', 'MESH:D008545', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('occurred', 'Reg', (16, 24))	('melanocytomas', 'Disease', (48, 61))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('melanomas', 'Disease', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('mutations', 'Var', (6, 15))
152459	26769193	In addition, one point mutation was detected in the Kozak consensus sequence of exon 1 (c.1-4C > T) which may have an influence on the start of translation (patient #1).	('c.1-4C > T', 'Mutation', 'c.1_4C>T', (88, 98))	('patient', 'Species', '9606', (157, 164))	('start', 'MPA', (135, 140))	('translation', 'biological_process', 'GO:0006412', ('144', '155'))	('c.1-4C > T', 'Var', (88, 98))	('influence', 'Reg', (118, 127))
152460	26769193	EIF1AX mutations were mutually exclusive with SF3B1 mutations and generally co-occurred with GNAQ or GNA11 mutations (Table 2).	('mutations', 'Var', (52, 61))	('GNA11', 'Gene', (101, 106))	('GNA11', 'Gene', '2767', (101, 106))	('SF3B1', 'Gene', '23451', (46, 51))	('GNAQ', 'Gene', '2776', (93, 97))	('co-occurred', 'Reg', (76, 87))	('SF3B1', 'Gene', (46, 51))	('GNAQ', 'Gene', (93, 97))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
152462	26769193	Recently, a role for BAP1 in primary melanoma of the CNS was suggested based on the identification of a BAP1 germline mutation in a patient with primary CNS melanoma with monosomy 3 and a family history of UM and meningioma.	('CNS melanoma', 'Disease', (153, 165))	('BAP1', 'Gene', (104, 108))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('primary CNS melanoma', 'Phenotype', 'HP:0030069', (145, 165))	('BAP1', 'Gene', '8314', (21, 25))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('CNS melanoma', 'Disease', 'MESH:D008545', (153, 165))	('BAP1', 'Gene', (21, 25))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('meningioma', 'Disease', (213, 223))	('melanoma', 'Disease', (37, 45))	('mutation', 'Var', (118, 126))	('meningioma', 'Phenotype', 'HP:0002858', (213, 223))	('patient', 'Species', '9606', (132, 139))	('melanoma of the CNS', 'Phenotype', 'HP:0100836', (37, 56))	('BAP1', 'Gene', '8314', (104, 108))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('meningioma', 'Disease', 'MESH:D008577', (213, 223))
152463	26769193	In our study, we chose for BAP1 immunohistochemistry as a surrogate marker for the identification of an underlying inactivating BAP1 mutation as it offers an economical and faster alternative to sequence analysis of all 17 exons of BAP1.	('BAP1', 'Gene', (232, 236))	('mutation', 'Var', (133, 141))	('BAP1', 'Gene', '8314', (128, 132))	('BAP1', 'Gene', (27, 31))	('BAP1', 'Gene', (128, 132))	('BAP1', 'Gene', '8314', (232, 236))	('BAP1', 'Gene', '8314', (27, 31))
152465	26769193	None of the samples in our series showed such complete loss of nuclear BAP1 staining, suggesting absence of underlying BAP1 mutations.	('mutations', 'Var', (124, 133))	('BAP1', 'Gene', '8314', (71, 75))	('BAP1', 'Gene', '8314', (119, 123))	('BAP1', 'Gene', (71, 75))	('BAP1', 'Gene', (119, 123))
152466	26769193	In three cases (including the single patient with monosomy 3 in the LMN and the patient with liver metastases but disomy 3 in the LMN), BAP1 mutation status was available through Sanger sequencing analyses and confirmed absence of mutations.	('monosomy 3', 'Var', (50, 60))	('LMN', 'Chemical', '-', (68, 71))	('LMN', 'Chemical', '-', (130, 133))	('BAP1', 'Gene', (136, 140))	('patient', 'Species', '9606', (37, 44))	('liver metastases', 'Disease', (93, 109))	('BAP1', 'Gene', '8314', (136, 140))	('disomy', 'Var', (114, 120))	('liver metastases', 'Disease', 'MESH:D009362', (93, 109))	('patient', 'Species', '9606', (80, 87))
152467	26769193	In some cases, BAP1 mutations may still have been missed as BAP1 immunohistochemistry was reported to have a sensitivity of ~ 88 %.	('BAP1', 'Gene', '8314', (15, 19))	('BAP1', 'Gene', '8314', (60, 64))	('BAP1', 'Gene', (15, 19))	('BAP1', 'Gene', (60, 64))	('mutations', 'Var', (20, 29))
152468	26769193	Also, very rarely, heterogeneous ('mosaic') BAP1 nuclear immunostaining has been described in UM cases with a BAP1 mutation showing loss of nuclear staining in only 20 % of nuclei.	('BAP1', 'Gene', '8314', (110, 114))	('BAP1', 'Gene', (110, 114))	('BAP1', 'Gene', '8314', (44, 48))	('mutation', 'Var', (115, 123))	('BAP1', 'Gene', (44, 48))
152470	26769193	Furthermore, as BAP1 is mainly implicated in metastatic UM with monosomy 3, there might be a selection bias in our patient group as it mainly concerns (relatively) low-grade tumors with disomy for chromosome 3.	('monosomy 3', 'Var', (64, 74))	('implicated', 'Reg', (31, 41))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('chromosome', 'cellular_component', 'GO:0005694', ('197', '207'))	('BAP1', 'Gene', '8314', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('patient', 'Species', '9606', (115, 122))	('BAP1', 'Gene', (16, 20))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
152471	26769193	A larger number of primary LMNs with monosomy 3 should thus be investigated to further explore the role of BAP1 in these neoplasms.	('BAP1', 'Gene', '8314', (107, 111))	('neoplasms', 'Disease', 'MESH:D009369', (121, 130))	('LMN', 'Chemical', '-', (27, 30))	('neoplasms', 'Disease', (121, 130))	('neoplasm', 'Phenotype', 'HP:0002664', (121, 129))	('BAP1', 'Gene', (107, 111))	('monosomy 3', 'Var', (37, 47))	('neoplasms', 'Phenotype', 'HP:0002664', (121, 130))
152472	26769193	This is also important for therapeutic reasons as epigenetic modulators such as histone deacetylase (HDAC) inhibitors were shown to reverse the biochemical effects of BAP1 mutations in UM cells by inducing growth arrest and differentiation.	('mutations', 'Var', (172, 181))	('differentiation', 'CPA', (224, 239))	('growth arrest', 'Phenotype', 'HP:0001510', (206, 219))	('HDAC', 'Gene', (101, 105))	('HDAC', 'Gene', '9734', (101, 105))	('histone deacetylase', 'Gene', '9734', (80, 99))	('inducing', 'PosReg', (197, 205))	('BAP1', 'Gene', '8314', (167, 171))	('growth arrest', 'Disease', 'MESH:D006323', (206, 219))	('growth arrest', 'Disease', (206, 219))	('histone deacetylase', 'Gene', (80, 99))	('BAP1', 'Gene', (167, 171))
152474	26769193	Recurrent mutations in the SF3B1 gene have been detected in several types of cancer such as UMs, breast and pancreatic carcinoma, and hematological diseases like CLL and MDS.	('hematological diseases', 'Disease', (134, 156))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('SF3B1', 'Gene', (27, 32))	('MDS', 'Disease', 'MESH:D009190', (170, 173))	('UMs', 'Phenotype', 'HP:0007716', (92, 95))	('CLL', 'Disease', 'MESH:D015451', (162, 165))	('MDS', 'Disease', (170, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('SF3B1', 'Gene', '23451', (27, 32))	('cancer', 'Disease', (77, 83))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (108, 128))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('UMs', 'Disease', (92, 95))	('pancreatic carcinoma', 'Disease', (108, 128))	('detected', 'Reg', (48, 56))	('breast', 'Disease', (97, 103))	('CLL', 'Disease', (162, 165))	('hematological diseases', 'Disease', 'MESH:D006402', (134, 156))	('mutations', 'Var', (10, 19))
152475	26769193	These mutations affect hotspot codons, the hotspot being associated with cancer type.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('hotspot codons', 'MPA', (23, 37))	('affect', 'Reg', (16, 22))	('mutations', 'Var', (6, 15))	('associated', 'Reg', (57, 67))
152476	26769193	For example, codon 700 mutations are frequently present in CLL and MDS, while in UMs codon 625 is much more frequently involved.	('CLL', 'Disease', (59, 62))	('MDS', 'Disease', (67, 70))	('MDS', 'Disease', 'MESH:D009190', (67, 70))	('present', 'Reg', (48, 55))	('codon 700 mutations', 'Var', (13, 32))	('CLL', 'Disease', 'MESH:D015451', (59, 62))	('UMs', 'Phenotype', 'HP:0007716', (81, 84))
152477	26769193	Especially in low-grade UMs with disomy for chromosome 3, heterozygous mutations in SF3B1 are present in 10 to 30 % of UM.	('chromosome', 'cellular_component', 'GO:0005694', ('44', '54'))	('SF3B1', 'Gene', '23451', (84, 89))	('UMs', 'Phenotype', 'HP:0007716', (24, 27))	('SF3B1', 'Gene', (84, 89))	('disomy', 'Var', (33, 39))
152478	26769193	The fact that in UMs these SF3B1 mutations are almost mutually exclusive with BAP1 mutations suggests different pathways in the oncogenesis and/or malignant progression of these neoplasms.	('neoplasms', 'Disease', (178, 187))	('mutations', 'Var', (83, 92))	('UMs', 'Disease', (17, 20))	('mutations', 'Var', (33, 42))	('SF3B1', 'Gene', (27, 32))	('neoplasms', 'Phenotype', 'HP:0002664', (178, 187))	('oncogenesis', 'biological_process', 'GO:0007048', ('128', '139'))	('BAP1', 'Gene', '8314', (78, 82))	('SF3B1', 'Gene', '23451', (27, 32))	('UMs', 'Phenotype', 'HP:0007716', (17, 20))	('neoplasm', 'Phenotype', 'HP:0002664', (178, 186))	('neoplasms', 'Disease', 'MESH:D009369', (178, 187))	('BAP1', 'Gene', (78, 82))
152480	26769193	It was shown that SF3B1 mutations are associated with differential alternative splicing of several protein encoding genes in UMs.	('associated', 'Reg', (38, 48))	('alternative splicing', 'MPA', (67, 87))	('UMs', 'Phenotype', 'HP:0007716', (125, 128))	('SF3B1', 'Gene', (18, 23))	('SF3B1', 'Gene', '23451', (18, 23))	('UMs', 'Disease', (125, 128))	('mutations', 'Var', (24, 33))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('splicing', 'biological_process', 'GO:0045292', ('79', '87'))
152481	26769193	Moreover, SF3B1 mutant cell lines were found to be sensitive to the SF3b complex inhibitor spliceostatin A, suggesting a new therapeutic target in tumors carrying this mutation.	('spliceostatin A', 'Chemical', 'MESH:C553684', (91, 106))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('SF3B1', 'Gene', (10, 15))	('mutant', 'Var', (16, 22))	('SF3B1', 'Gene', '23451', (10, 15))	('sensitive', 'MPA', (51, 60))	('spliceostatin A', 'MPA', (91, 106))
152482	26769193	Up to now, it was unknown whether SF3B1 mutations also occur in primary LMNs.	('SF3B1', 'Gene', (34, 39))	('occur', 'Reg', (55, 60))	('LMN', 'Chemical', '-', (72, 75))	('mutations', 'Var', (40, 49))	('primary LMNs', 'Disease', (64, 76))	('SF3B1', 'Gene', '23451', (34, 39))
152483	26769193	In our series, in three out of 24 cases (13 %) an SF3B1 mutation affecting codon 625 or 634 was detected, this is at the lower end of the range of the frequency of SF3B1 mutations reported in UMs (10-30 %) and in contrast to the very low frequency reported for CMs (~1 %).	('UMs', 'Disease', (192, 195))	('SF3B1', 'Gene', (50, 55))	('mutations', 'Var', (170, 179))	('SF3B1', 'Gene', (164, 169))	('SF3B1', 'Gene', '23451', (50, 55))	('SF3B1', 'Gene', '23451', (164, 169))	('CMs', 'Phenotype', 'HP:0012056', (261, 264))	('mutation', 'Var', (56, 64))	('UMs', 'Phenotype', 'HP:0007716', (192, 195))
152484	26769193	As far as could be assessed, all three LMNs showing an SF3B1 mutation were tumors with disomy for chromosome 3.	('SF3B1', 'Gene', '23451', (55, 60))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('98', '108'))	('mutation', 'Var', (61, 69))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('SF3B1', 'Gene', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('LMN', 'Chemical', '-', (39, 42))
152485	26769193	Furthermore, like in UMs, in two cases the SF3B1 mutation co-occurred with a GNAQ or GNA11 mutation, while in a third case (with neurocutaneous melanocytosis) an NRAS mutation was present.	('SF3B1', 'Gene', (43, 48))	('neurocutaneous melanocytosis', 'Disease', (129, 157))	('GNAQ', 'Gene', (77, 81))	('NRAS', 'Gene', '4893', (162, 166))	('SF3B1', 'Gene', '23451', (43, 48))	('GNA11', 'Gene', '2767', (85, 90))	('GNA11', 'Gene', (85, 90))	('co-occurred', 'Reg', (58, 69))	('mutation', 'Var', (49, 57))	('neurocutaneous melanocytosis', 'Disease', 'MESH:D020752', (129, 157))	('NRAS', 'Gene', (162, 166))	('GNAQ', 'Gene', '2776', (77, 81))	('UMs', 'Phenotype', 'HP:0007716', (21, 24))
152486	26769193	The GNAQ, GNA11 and NRAS genes are now thought to play a role in the initiation of tumorigenesis, while mutation in SF3B1 (or BAP1) would then occur in a later phase of the oncogenic process.	('GNAQ', 'Gene', '2776', (4, 8))	('SF3B1', 'Gene', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('BAP1', 'Gene', (126, 130))	('tumor', 'Disease', (83, 88))	('occur', 'Reg', (143, 148))	('SF3B1', 'Gene', '23451', (116, 121))	('GNAQ', 'Gene', (4, 8))	('mutation', 'Var', (104, 112))	('GNA11', 'Gene', '2767', (10, 15))	('NRAS', 'Gene', (20, 24))	('GNA11', 'Gene', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('BAP1', 'Gene', '8314', (126, 130))	('NRAS', 'Gene', '4893', (20, 24))
152487	26769193	The co-occurrence of an NRAS and an SF3B1 mutation in the CNS melanoma of the neurocutaneous melanocytosis patient in our study is interesting in this respect as the SF3B1 mutation was absent in the congenital melanocytic nevus of this patient.	('NRAS', 'Gene', '4893', (24, 28))	('SF3B1', 'Gene', '23451', (166, 171))	('SF3B1', 'Gene', (36, 41))	('CNS melanoma', 'Disease', 'MESH:D008545', (58, 70))	('congenital melanocytic nevus', 'Phenotype', 'HP:0100814', (199, 227))	('nevus', 'Phenotype', 'HP:0003764', (222, 227))	('congenital melanocytic nevus', 'Disease', (199, 227))	('NRAS', 'Gene', (24, 28))	('SF3B1', 'Gene', '23451', (36, 41))	('mutation', 'Var', (42, 50))	('melanoma of the neurocutaneous melanocytosis', 'Disease', 'MESH:D020752', (62, 106))	('CNS melanoma', 'Disease', (58, 70))	('SF3B1', 'Gene', (166, 171))	('melanocytic nevus', 'Phenotype', 'HP:0000995', (210, 227))	('melanoma of the neurocutaneous melanocytosis', 'Disease', (62, 106))	('patient', 'Species', '9606', (107, 114))	('patient', 'Species', '9606', (236, 243))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
152489	26769193	Instead of GNAQ or GNA11 mutations, these patients frequently demonstrate identical NRAS mutations in both the congenital melanocytic nevus and in the LMN.	('GNA11', 'Gene', (19, 24))	('LMN', 'Chemical', '-', (151, 154))	('NRAS', 'Gene', (84, 88))	('GNA11', 'Gene', '2767', (19, 24))	('GNAQ', 'Gene', '2776', (11, 15))	('melanocytic nevus', 'Phenotype', 'HP:0000995', (122, 139))	('nevus', 'Phenotype', 'HP:0003764', (134, 139))	('NRAS', 'Gene', '4893', (84, 88))	('congenital melanocytic nevus', 'Disease', (111, 139))	('congenital melanocytic nevus', 'Phenotype', 'HP:0100814', (111, 139))	('mutations', 'Var', (89, 98))	('GNAQ', 'Gene', (11, 15))	('patients', 'Species', '9606', (42, 50))
152492	26769193	In addition, all three mutations in SF3B1 in our study were found in tumors which clinically showed aggressive behavior.	('aggressive behavior', 'Phenotype', 'HP:0000718', (100, 119))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('SF3B1', 'Gene', (36, 41))	('aggressive behavior', 'biological_process', 'GO:0002118', ('100', '119'))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('SF3B1', 'Gene', '23451', (36, 41))	('mutations', 'Var', (23, 32))	('found', 'Reg', (60, 65))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('aggressive behavior', 'CPA', (100, 119))
152494	26769193	Of note, in one of the three patients the SF3B1 mutation (c.1900G > A (p.(Val634Ile))) was present in a neoplasm diagnosed as melanocytoma, suggesting that SF3B1 mutations are not necessarily associated with worrisome histology.	('melanocytoma', 'Disease', (126, 138))	('patients', 'Species', '9606', (29, 37))	('neoplasm', 'Disease', (104, 112))	('p.(Val634Ile)', 'Mutation', 'p.V634I', (71, 84))	('SF3B1', 'Gene', '23451', (156, 161))	('SF3B1', 'Gene', (42, 47))	('neoplasm', 'Disease', 'MESH:D009369', (104, 112))	('c.1900G > A', 'Mutation', 'c.1900G>A', (58, 69))	('melanocytoma', 'Disease', 'None', (126, 138))	('neoplasm', 'Phenotype', 'HP:0002664', (104, 112))	('SF3B1', 'Gene', '23451', (42, 47))	('c.1900G > A', 'Var', (58, 69))	('SF3B1', 'Gene', (156, 161))
152495	26769193	Several recent studies have reported mutations in EIF1AX in different cancer types, including melanoma and thyroid and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ovarian cancer', 'Phenotype', 'HP:0100615', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('melanoma and thyroid and ovarian cancer', 'Disease', 'MESH:D010049', (94, 133))	('EIF1AX', 'Gene', (50, 56))	('reported', 'Reg', (28, 36))	('EIF1AX', 'Gene', '1964', (50, 56))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
152496	26769193	In UMs, heterozygous mutations in exon 1 and 2 of EIF1AX have reported to occur especially in tumors with disomy for chromosome 3 (up to 48 % of these tumors).	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('chromosome', 'cellular_component', 'GO:0005694', ('117', '127'))	('heterozygous mutations in', 'Var', (8, 33))	('disomy', 'Var', (106, 112))	('EIF1AX', 'Gene', '1964', (50, 56))	('tumors', 'Disease', (151, 157))	('EIF1AX', 'Gene', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('occur', 'Reg', (74, 79))	('UMs', 'Phenotype', 'HP:0007716', (3, 6))
152498	26769193	The exact role of EIF1AX mutations in tumorigenesis is currently not well understood but it has been suggested that mutations in EIF1AX could diminish the rate of bulk translation.	('EIF1AX', 'Gene', '1964', (18, 24))	('diminish', 'NegReg', (142, 150))	('mutations', 'Var', (25, 34))	('tumor', 'Disease', (38, 43))	('EIF1AX', 'Gene', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('EIF1AX', 'Gene', '1964', (129, 135))	('rate', 'MPA', (155, 159))	('EIF1AX', 'Gene', (129, 135))	('mutations', 'Var', (116, 125))	('bulk translation', 'MPA', (163, 179))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('translation', 'biological_process', 'GO:0006412', ('168', '179'))
152499	26769193	In our series of primary LMNs we found a relatively high frequency of EIF1AX missense mutations (21 %) which is in the range reported for UM (19-48 %).	('missense mutations', 'Var', (77, 95))	('LMN', 'Chemical', '-', (25, 28))	('EIF1AX', 'Gene', '1964', (70, 76))	('EIF1AX', 'Gene', (70, 76))
152500	26769193	In contrast, EIF1AX mutations are very rare in CM (5/231, ~2 %).	('EIF1AX', 'Gene', '1964', (13, 19))	('mutations', 'Var', (20, 29))	('EIF1AX', 'Gene', (13, 19))
152501	26769193	As in UMs, as far as could be assessed in our series, these mutations occurred in primary LMNs with disomy for chromosome 3 and were mutually exclusive with SF3B1 mutations, but co-occurred with GNAQ or GNA11 mutations.	('SF3B1', 'Gene', (157, 162))	('occurred', 'Reg', (70, 78))	('UMs', 'Phenotype', 'HP:0007716', (6, 9))	('mutations', 'Var', (163, 172))	('co-occurred', 'Reg', (178, 189))	('SF3B1', 'Gene', '23451', (157, 162))	('GNAQ', 'Gene', (195, 199))	('LMN', 'Chemical', '-', (90, 93))	('chromosome', 'cellular_component', 'GO:0005694', ('111', '121'))	('GNA11', 'Gene', '2767', (203, 208))	('GNA11', 'Gene', (203, 208))	('mutations', 'Var', (60, 69))	('GNAQ', 'Gene', '2776', (195, 199))
152502	26769193	In addition (and like SF3B1 mutations), the EIF1AX mutations in our cases occurred both in melanocytomas as well as melanomas, suggesting that they are not necessarily associated with worrisome histology, but the prognostic implications of these mutations remain to be elucidated.	('melanomas', 'Disease', (116, 125))	('mutations', 'Var', (51, 60))	('melanocytomas', 'Disease', (91, 104))	('SF3B1', 'Gene', '23451', (22, 27))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('EIF1AX', 'Gene', '1964', (44, 50))	('EIF1AX', 'Gene', (44, 50))	('occurred', 'Reg', (74, 82))	('melanocytomas', 'Disease', 'None', (91, 104))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('melanomas', 'Disease', 'MESH:D008545', (116, 125))	('SF3B1', 'Gene', (22, 27))
152503	26769193	Finally, the EIF1AX and SF3B1 mutations in LMNs occurred in hotspot regions of these genes, and in UMs such mutations were shown to be somatic in origin.	('LMN', 'Chemical', '-', (43, 46))	('SF3B1', 'Gene', (24, 29))	('EIF1AX', 'Gene', '1964', (13, 19))	('mutations', 'Var', (30, 39))	('EIF1AX', 'Gene', (13, 19))	('UMs', 'Phenotype', 'HP:0007716', (99, 102))	('SF3B1', 'Gene', '23451', (24, 29))
152505	26769193	We report for the first time that a substantial subset of LMNs carries a mutation in SF3B1 or EIF1AX.	('EIF1AX', 'Gene', '1964', (94, 100))	('LMN', 'Chemical', '-', (58, 61))	('EIF1AX', 'Gene', (94, 100))	('SF3B1', 'Gene', (85, 90))	('SF3B1', 'Gene', '23451', (85, 90))	('mutation', 'Var', (73, 81))
152506	26769193	Like in UMs, SF3B1 or EIF1AX mutations are mutually exclusive and generally co-occur with either a GNAQ or GNA11 mutation (SF3B1 occasionally with NRAS mutation), suggesting that SF3B1 and EIF1AX mutations occur later on in the tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('SF3B1', 'Gene', (123, 128))	('SF3B1', 'Gene', '23451', (179, 184))	('SF3B1', 'Gene', '23451', (13, 18))	('EIF1AX', 'Gene', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('SF3B1', 'Gene', '23451', (123, 128))	('NRAS', 'Gene', '4893', (147, 151))	('GNAQ', 'Gene', '2776', (99, 103))	('GNA11', 'Gene', (107, 112))	('EIF1AX', 'Gene', (189, 195))	('UMs', 'Phenotype', 'HP:0007716', (8, 11))	('EIF1AX', 'Gene', '1964', (22, 28))	('mutations', 'Var', (29, 38))	('GNAQ', 'Gene', (99, 103))	('EIF1AX', 'Gene', '1964', (189, 195))	('SF3B1', 'Gene', (179, 184))	('SF3B1', 'Gene', (13, 18))	('NRAS', 'Gene', (147, 151))	('tumor', 'Disease', (228, 233))	('GNA11', 'Gene', '2767', (107, 112))
152508	26769193	The role of BAP1 in the pathogenesis of primary LMNs is less clear, immunohistochemistry suggests that BAP1 mutation is infrequent in tumors with disomy for chromosome 3.	('BAP1', 'Gene', '8314', (103, 107))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('BAP1', 'Gene', (103, 107))	('LMN', 'Chemical', '-', (48, 51))	('pathogenesis', 'biological_process', 'GO:0009405', ('24', '36'))	('BAP1', 'Gene', '8314', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('mutation', 'Var', (108, 116))	('BAP1', 'Gene', (12, 16))	('chromosome', 'cellular_component', 'GO:0005694', ('157', '167'))
152510	26769193	Demonstration of BAP1 mutations in primary LMNs would potentially have therapeutic relevance as well, as epigenetic modulators are now being evaluated in patients with BAP1-mutant UMs.	('LMN', 'Chemical', '-', (43, 46))	('BAP1', 'Gene', '8314', (168, 172))	('UMs', 'Phenotype', 'HP:0007716', (180, 183))	('BAP1', 'Gene', (168, 172))	('patients', 'Species', '9606', (154, 162))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('UMs', 'Disease', (180, 183))	('BAP1', 'Gene', (17, 21))
152518	25084771	Monosomy 3 was found in 35 melanomas, of which 94% had an SUVmax >2.5 and 80% had an SUVmax >4.	('Monosomy', 'Var', (0, 8))	('melanomas', 'Disease', 'MESH:D008545', (27, 36))	('SUVmax >2.5', 'MPA', (58, 69))	('found', 'Reg', (15, 20))	('melanomas', 'Disease', (27, 36))	('SUVmax', 'MPA', (85, 91))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))
152520	25084771	SUVmax was significantly increased in tumours with monosomy 3 (p=0.043) but not in tumours with chromosome 8 gain (p=0.49).	('tumours', 'Disease', (38, 45))	('tumours', 'Disease', (83, 90))	('SUVmax', 'MPA', (0, 6))	('increased', 'PosReg', (25, 34))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('monosomy 3', 'Var', (51, 61))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumours', 'Phenotype', 'HP:0002664', (38, 45))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('tumours', 'Disease', 'MESH:D009369', (38, 45))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('tumours', 'Disease', 'MESH:D009369', (83, 90))
152553	25084771	SUVmax values were significantly higher in monosomy 3 compared with disomy 3 tumours (p=0.043, Mann-Whitney test) (table 1, figure 4A).	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('disomy 3 tumours', 'Disease', (68, 84))	('higher', 'PosReg', (33, 39))	('SUVmax values', 'MPA', (0, 13))	('monosomy 3', 'Var', (43, 53))	('disomy 3 tumours', 'Disease', 'MESH:D024182', (68, 84))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
152554	25084771	A SUVmax of >2.5 was noted in 33/35 (94%) of tumours with monosomy 3 and 32/35 (91.5%) of tumours with disomy 3 (chi2, p=0.8).	('monosomy 3', 'Var', (58, 68))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('tumours', 'Disease', 'MESH:D009369', (45, 52))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('tumours', 'Disease', (45, 52))	('tumours', 'Disease', (90, 97))
152557	25084771	SUVmax >2.5 was noted in 51/55 (92.7%) of tumours with gains in chromosome 8 and 17/18 (94.4%) with the normal diploid component (chi2, p=0.6).	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('chromosome', 'cellular_component', 'GO:0005694', ('64', '74'))	('tumours', 'Phenotype', 'HP:0002664', (42, 49))	('gains', 'Var', (55, 60))	('tumours', 'Disease', 'MESH:D009369', (42, 49))	('tumours', 'Disease', (42, 49))
152558	25084771	When chromosome status was assessed collectively (table 1), the coexistence of monosomy 3 and gains in chromosome 8 was associated with significantly higher SUVmax when compared against tumours with disomy 3 and gains in chromosome 8 (p=0.015, Mann-Whitney test).	('chromosome', 'cellular_component', 'GO:0005694', ('5', '15'))	('chromosome', 'cellular_component', 'GO:0005694', ('103', '113'))	('tumours', 'Disease', 'MESH:D009369', (186, 193))	('tumours', 'Disease', (186, 193))	('higher', 'PosReg', (150, 156))	('monosomy 3', 'Var', (79, 89))	('chromosome', 'cellular_component', 'GO:0005694', ('221', '231'))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('gains', 'Var', (94, 99))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))	('SUVmax', 'MPA', (157, 163))
152559	25084771	SUVmax >2.5 was noted in 33/34 (97%) of tumours with monosomy 3/gain of chromosome 8 and 15/15 (100%) of tumours with normal diploid component (chi2, p=0.694).	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('tumours', 'Disease', 'MESH:D009369', (40, 47))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('tumours', 'Disease', (40, 47))	('tumours', 'Disease', (105, 112))	('monosomy 3/gain of chromosome', 'Var', (53, 82))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))
152567	25084771	Chromosome 3 monosomy in uveal melanoma is a commonly used predictor of mortality.	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('uveal melanoma', 'Disease', (25, 39))	('monosomy', 'Var', (13, 21))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('Chromosome 3 monosomy', 'Var', (0, 21))	('uveal melanoma', 'Disease', 'MESH:C536494', (25, 39))
152568	25084771	Disomy of chromosome 3 has a protective effect, but recent data indicate that the presence of the SF3B1 mutation on chromosome 3 might be associated with increased mortality.	('SF3B1', 'Gene', '23451', (98, 103))	('chromosome', 'cellular_component', 'GO:0005694', ('10', '20'))	('associated', 'Reg', (138, 148))	('chromosome', 'cellular_component', 'GO:0005694', ('116', '126'))	('presence', 'Var', (82, 90))	('mutation', 'Var', (104, 112))	('increased', 'PosReg', (154, 163))	('SF3B1', 'Gene', (98, 103))
152577	25084771	SUVmax was significantly higher in patients with monosomy 3.	('patients', 'Species', '9606', (35, 43))	('monosomy 3', 'Var', (49, 59))	('SUVmax', 'MPA', (0, 6))	('higher', 'PosReg', (25, 31))
152580	25084771	Gains in chromosome 8 are known to be associated with a poorer prognosis in uveal melanoma.	('Gains', 'Var', (0, 5))	('uveal melanoma', 'Phenotype', 'HP:0007716', (76, 90))	('uveal melanoma', 'Disease', 'MESH:C536494', (76, 90))	('chromosome', 'cellular_component', 'GO:0005694', ('9', '19'))	('uveal melanoma', 'Disease', (76, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))
152581	25084771	The presence of gains in chromosome 8 was seen in 55 of 73 uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (59, 74))	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('chromosome', 'cellular_component', 'GO:0005694', ('25', '35'))	('uveal melanomas', 'Disease', (59, 74))	('uveal melanomas', 'Phenotype', 'HP:0007716', (59, 74))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanomas', 'Phenotype', 'HP:0002861', (65, 74))	('gains', 'Var', (16, 21))
152582	25084771	Tumours with monosomy 3/gains in chromosome 8 had a significantly higher SUVmax than disomy 3/gains in 8 and a SUVmax >4 would be more helpful in identifying an association with high-risk melanomas for chromosome 3/8 status.	('chromosome', 'cellular_component', 'GO:0005694', ('33', '43'))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('melanomas', 'Disease', (188, 197))	('SUVmax', 'MPA', (73, 79))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('higher', 'PosReg', (66, 72))	('monosomy 3/gains in', 'Var', (13, 32))	('melanomas', 'Phenotype', 'HP:0002861', (188, 197))	('chromosome', 'cellular_component', 'GO:0005694', ('202', '212'))	('melanomas', 'Disease', 'MESH:D008545', (188, 197))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
152614	25084771	SUVmax was confirmed to have a significant positive correlation with tumour size and monosomy 3 but did not correlate with histological cell type or chromosome 8 status.	('tumour', 'Disease', (69, 75))	('monosomy 3', 'Var', (85, 95))	('positive', 'PosReg', (43, 51))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('chromosome', 'cellular_component', 'GO:0005694', ('149', '159'))
152617	25084771	SUVmax >4, though not an absolute indicator, might be more helpful in identifying monosomy 3 and gain of chromosome 8 tumours.	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('tumours', 'Disease', (118, 125))	('chromosome', 'cellular_component', 'GO:0005694', ('105', '115'))	('monosomy', 'Var', (82, 90))	('gain of', 'PosReg', (97, 104))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))
152618	25010863	Targeting SRPK1 to control VEGF-mediated tumour angiogenesis in metastatic melanoma Current therapies for metastatic melanoma are targeted either at cancer mutations driving growth (e.g., vemurafenib) or immune-based therapies (e.g., ipilimumab).	('ipilimumab', 'Chemical', 'MESH:D000074324', (234, 244))	('cancer', 'Disease', (149, 155))	('SRPK1', 'Gene', (10, 15))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('mutations', 'Var', (156, 165))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('angiogenesis', 'biological_process', 'GO:0001525', ('48', '60'))	('tumour', 'Disease', (41, 47))	('vemurafenib', 'Chemical', 'MESH:D000077484', (188, 199))	('SRPK1', 'Gene', '6732', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('melanoma', 'Disease', (117, 125))
152619	25010863	Metastatic melanoma is associated with a splicing switch to pro-angiogenic VEGF-A, previously shown to be regulated by SRSF1 phosphorylation by SRPK1.	('splicing', 'biological_process', 'GO:0045292', ('41', '49'))	('splicing switch', 'Var', (41, 56))	('SRSF1', 'Gene', (119, 124))	('phosphorylation', 'biological_process', 'GO:0016310', ('125', '140'))	('Metastatic melanoma', 'Disease', (0, 19))	('SRSF1', 'Gene', '6426', (119, 124))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('VEGF-A', 'Gene', (75, 81))	('Metastatic melanoma', 'Disease', 'MESH:D008545', (0, 19))
152622	25010863	In both uveal and cutaneous melanoma cell lines, SRPK1 was highly expressed, and inhibition of SRPK1 by knockdown or with pharmacological inhibitors reduced pro-angiogenic VEGF expression maintaining the production of anti-angiogenic VEGF isoforms.	('SRPK1', 'Gene', (95, 100))	('inhibition', 'Var', (81, 91))	('cutaneous melanoma', 'Disease', (18, 36))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (18, 36))	('reduced', 'NegReg', (149, 156))	('SRPK1', 'Gene', (49, 54))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (18, 36))	('pro-angiogenic VEGF expression', 'MPA', (157, 187))	('production', 'MPA', (204, 214))	('anti-angiogenic VEGF isoforms', 'MPA', (218, 247))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
152623	25010863	Both pharmacological SRPK1 inhibitors and SRPK1 knockdown reduced growth of human melanomas in vivo, but neither affected cell proliferation in vitro.	('melanomas', 'Disease', (82, 91))	('SRPK1', 'Gene', (42, 47))	('SRPK1', 'Gene', (21, 26))	('cell proliferation', 'biological_process', 'GO:0008283', ('122', '140'))	('melanomas', 'Disease', 'MESH:D008545', (82, 91))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('human', 'Species', '9606', (76, 81))	('inhibitors', 'Var', (27, 37))	('reduced', 'NegReg', (58, 65))	('knockdown', 'Var', (48, 57))
152635	25010863	Current FDA-approved therapies for the treatment of CM metastases following surgery of the primary tumour include the chemotherapeutic agent, dacarbazine, which shows a response rate in 7-12% of patients, vemurafenib specifically for the treatment of melanomas containing the BRAFV600E mutation present in 40-60% of melanomas; and the CTLA4 antibody ipilimumab.	('CTLA4', 'Gene', (335, 340))	('BRAFV600E', 'Mutation', 'rs113488022', (276, 285))	('melanomas', 'Disease', (251, 260))	('antibody', 'cellular_component', 'GO:0019815', ('341', '349'))	('ipilimumab', 'Chemical', 'MESH:D000074324', (350, 360))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('melanomas', 'Phenotype', 'HP:0002861', (316, 325))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('patients', 'Species', '9606', (195, 203))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('CM metastases', 'Disease', (52, 65))	('melanomas', 'Phenotype', 'HP:0002861', (251, 260))	('melanoma', 'Phenotype', 'HP:0002861', (316, 324))	('antibody', 'cellular_component', 'GO:0019814', ('341', '349'))	('BRAFV600E', 'Var', (276, 285))	('CM', 'Phenotype', 'HP:0012056', (52, 54))	('vemurafenib', 'Chemical', 'MESH:D000077484', (205, 216))	('dacarbazine', 'Chemical', 'MESH:D003606', (142, 153))	('CTLA4', 'Gene', '1493', (335, 340))	('melanomas', 'Disease', 'MESH:D008545', (316, 325))	('antibody', 'molecular_function', 'GO:0003823', ('341', '349'))	('antibody', 'cellular_component', 'GO:0042571', ('341', '349'))	('melanomas', 'Disease', (316, 325))	('CM metastases', 'Disease', 'MESH:D009362', (52, 65))	('melanomas', 'Disease', 'MESH:D008545', (251, 260))
152640	25010863	VEGF splicing is regulated by the SR protein kinase SRPK1, and it has been shown that in a carcinoma cell line (LS174t) the splicing of VEGF can be modulated to prevent the production of pro-angiogenic isoforms through the lentiviral knockdown of SRPK1.	('lentiviral', 'Var', (223, 233))	('splicing', 'MPA', (124, 132))	('SRPK1', 'Gene', (247, 252))	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('splicing', 'biological_process', 'GO:0045292', ('124', '132'))	('pro-angiogenic isoforms', 'MPA', (187, 210))	('splicing', 'biological_process', 'GO:0045292', ('5', '13'))	('prevent', 'NegReg', (161, 168))	('LS174', 'CellLine', 'CVCL:1384', (112, 117))	('VEGF', 'Gene', (136, 140))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('knockdown', 'Var', (234, 243))	('production', 'MPA', (173, 183))	('carcinoma', 'Disease', (91, 100))
152643	25010863	A375 melanoma cells were treated with culture medium plus 6 mug polybrene and 1 mul scrambled shRNA (T=2.25 x 104) or 5 mul SRPK1 shRNA (T=3.44 x 108; SMART Vector 2.0, Dharmacon, Thermo Scientific, Lafayette, LA, USA) per 200 000 cells.	('A375', 'CellLine', 'CVCL:0132', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('melanoma', 'Disease', (5, 13))	('mug', 'molecular_function', 'GO:0043739', ('60', '63'))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('polybrene', 'Chemical', 'MESH:D006583', (64, 73))	('polybrene', 'Var', (64, 73))
152649	25010863	Five percent of the cDNA was added to a reaction mixture containing: 2 x PCR Master Mix (Promega, Southampton, UK), primers (1 muM each) complementary to exon7b (5'-GGCAGCTTGAGTTAAACGAAC-3') and the 3'-UTR of VEGF (5'-ATGGATCCGTATCAGTCTTTCCTGG-3') and DNase-/RNase-free water.	('muM', 'Gene', (127, 130))	('water', 'Chemical', 'MESH:D014867', (270, 275))	('exon7b', 'Var', (154, 160))	('muM', 'Gene', '56925', (127, 130))
152680	25010863	A similar relative expression of VEGF165 expression at the RNA level was seen (i.e., expression in A375 and Omm2.5, but not Mel270 or 92.1 Figure 1C) and total (pan) VEGF was higher in A375, Omm2.5 and Mel270 than 92.1, whereas the anti-angiogenic VEGFxxxb isoforms appeared stronger in the primary (Mel270 and 92.1) compared with metastatic cell lines.	('expression', 'MPA', (85, 95))	('A375', 'CellLine', 'CVCL:0132', (99, 103))	('A375', 'CellLine', 'CVCL:0132', (185, 189))	('higher', 'PosReg', (175, 181))	('VEGF165', 'Gene', (33, 40))	('RNA', 'cellular_component', 'GO:0005562', ('59', '62'))	('A375', 'Var', (185, 189))
152688	25010863	In Mel270, IGF-1 increased nuclear localisation of SRSF1 compared with untreated cells, and SRPIN340 significantly reduced the proportion of nuclear SRSF1 compared with IGF-1 treatment alone (P=0.018).	('increased', 'PosReg', (17, 26))	('SRSF1', 'Gene', (51, 56))	('IGF-1', 'Gene', '3479', (169, 174))	('SRPIN340', 'Chemical', 'MESH:C584061', (92, 100))	('IGF-1', 'Gene', (169, 174))	('SRSF1', 'Gene', (149, 154))	('reduced', 'NegReg', (115, 122))	('SRPIN340', 'Var', (92, 100))	('SRSF1', 'Gene', '6426', (51, 56))	('SRSF1', 'Gene', '6426', (149, 154))	('localisation', 'biological_process', 'GO:0051179', ('35', '47'))	('nuclear localisation', 'MPA', (27, 47))	('IGF-1', 'Gene', '3479', (11, 16))	('IGF-1 increased', 'Phenotype', 'HP:0030269', (11, 26))	('IGF-1', 'Gene', (11, 16))
152693	25010863	To confirm that VEGF levels can be regulated by SRPK1, a lentiviral approach to knock down SRPK1 expression levels was used in the CM cell line A375.	('knock', 'Var', (80, 85))	('A375', 'CellLine', 'CVCL:0132', (144, 148))	('CM', 'Disease', 'MESH:D009202', (131, 133))	('CM', 'Phenotype', 'HP:0012056', (131, 133))	('SRPK1', 'Gene', (91, 96))
152696	25010863	Initially, we investigated the effect of SRPK1 knockdown on SRSF1 nuclear localisation as a measure of phosphorylation.	('localisation', 'biological_process', 'GO:0051179', ('74', '86'))	('SRPK1', 'Gene', (41, 46))	('knockdown', 'Var', (47, 56))	('SRSF1', 'Gene', (60, 65))	('phosphorylation', 'biological_process', 'GO:0016310', ('103', '118'))	('SRSF1', 'Gene', '6426', (60, 65))
152698	25010863	SRPK1 knockdown did not affect the level of SRSF1 mRNA, suggesting a potential role for SRPK1 in partially regulating SRSF1 stability.	('SRPK1', 'Gene', (0, 5))	('SRSF1', 'Gene', (118, 123))	('stability', 'MPA', (124, 133))	('SRSF1', 'Gene', (44, 49))	('SRSF1', 'Gene', '6426', (118, 123))	('knockdown', 'Var', (6, 15))	('SRSF1', 'Gene', '6426', (44, 49))
152700	25010863	The effect of SRPK1 knockdown upon VEGF165 mRNA was similar to the effect of SRPIN340 treatment:shRNA SRPK1 significantly reduced VEGF165 expression compared with shRNA control-transduced cells (P<0.01, Student's t-test; Figure 3G).	('shRNA', 'Var', (96, 101))	('SRPIN340', 'Chemical', 'MESH:C584061', (77, 85))	('expression', 'MPA', (138, 148))	('VEGF165', 'Gene', (130, 137))	('reduced', 'NegReg', (122, 129))	('SRPK1', 'Gene', (102, 107))
152704	25010863	A375 shRNA SRPK1 tumours grew significantly slower than controls (P<0.001; two-way ANOVA with repeated measures; Figure 4D).	('A375', 'CellLine', 'CVCL:0132', (0, 4))	('slower', 'NegReg', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('SRPK1 tumours', 'Disease', (11, 24))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('A375', 'Var', (0, 4))	('SRPK1 tumours', 'Disease', 'MESH:D009369', (11, 24))	('grew', 'MPA', (25, 29))
152706	25010863	Furthermore, the VEGF protein was reduced in knockdown tumours compared with controls but anti-angiogenic VEGFxxxb isoforms were unchanged (Figure 4F).	('tumours', 'Disease', (55, 62))	('reduced', 'NegReg', (34, 41))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('VEGF protein', 'Protein', (17, 29))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('knockdown', 'Var', (45, 54))	('tumours', 'Disease', 'MESH:D009369', (55, 62))
152707	25010863	Similar to SRPK1 knockdown, we saw no alteration in proliferation (Figure 5A) or migration (Figure 5B) of A375 cells when dose dependently treated with SRPIN340.	('SRPIN340', 'Var', (152, 160))	('proliferation', 'CPA', (52, 65))	('migration', 'CPA', (81, 90))	('A375', 'CellLine', 'CVCL:0132', (106, 110))	('SRPIN340', 'Chemical', 'MESH:C584061', (152, 160))
152719	25010863	SRPIN340 significantly reduced MVD compared with vehicle-treated tumours (Figure 5E).	('MVD', 'MPA', (31, 34))	('vehicle-treated tumours', 'Disease', (49, 72))	('vehicle-treated tumours', 'Disease', 'MESH:D019553', (49, 72))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('SRPIN340', 'Var', (0, 8))	('SRPIN340', 'Chemical', 'MESH:C584061', (0, 8))	('reduced', 'NegReg', (23, 30))
152728	25010863	What was clear, however, was the effect of SRPK1 inhibition on reducing splicing to the VEGF165 isoforms in melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('reducing', 'NegReg', (63, 71))	('VEGF165', 'Gene', (88, 95))	('inhibition', 'Var', (49, 59))	('splicing', 'MPA', (72, 80))	('splicing', 'biological_process', 'GO:0045292', ('72', '80'))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('SRPK1', 'Gene', (43, 48))	('melanoma', 'Disease', (108, 116))
152735	25010863	SRSF1 expression is essential, and depletion of SRSF1 has been reported to cause cell cycle arrest, genomic instability and apoptosis.	('cause', 'Reg', (75, 80))	('apoptosis', 'CPA', (124, 133))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('genomic instability', 'CPA', (100, 119))	('SRSF1', 'Gene', '6426', (48, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (81, 98))	('arrest', 'Disease', 'MESH:D006323', (92, 98))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('81', '98'))	('SRSF1', 'Gene', (0, 5))	('arrest', 'Disease', (92, 98))	('depletion', 'Var', (35, 44))	('SRSF1', 'Gene', (48, 53))	('SRSF1', 'Gene', '6426', (0, 5))
152741	25010863	In this study, we observed reduced expression of VEGF165 in SRPK1 knockdown cells relative to GAPDH and compared with shRNA control cells (P<0.01).	('reduced', 'NegReg', (27, 34))	('VEGF165', 'Gene', (49, 56))	('expression', 'MPA', (35, 45))	('GAPDH', 'Gene', '2597', (94, 99))	('GAPDH', 'Gene', (94, 99))	('knockdown', 'Var', (66, 75))	('SRPK1', 'Gene', (60, 65))
152743	25010863	SRPK1 lentiviral knockdown was not lethal to A375 cells and did not appear to affect cell morphology.	('SRPK1', 'Gene', (0, 5))	('A375', 'CellLine', 'CVCL:0132', (45, 49))	('knockdown', 'Var', (17, 26))
152746	25010863	As SRPK1 knockdown appeared to reduce the expression of pro-angiogenic VEGF isoforms, isoforms that are necessary for tumour progression, the effect of SRPK1 knockdown on A375 tumour growth in vivo was investigated.	('A375', 'CellLine', 'CVCL:0132', (171, 175))	('tumour', 'Disease', (118, 124))	('knockdown', 'Var', (9, 18))	('SRPK1', 'Gene', (3, 8))	('expression', 'MPA', (42, 52))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('tumour growth', 'Disease', (176, 189))	('reduce', 'NegReg', (31, 37))	('tumour growth', 'Disease', 'MESH:D006130', (176, 189))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (176, 182))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('tumour', 'Disease', (176, 182))
152748	25010863	In addition, panVEGF expression was downregulated in knockdown (KD) compared with control tumours (Ctrl), whereas VEGFxxxb remained unchanged (Figure 4D).	('knockdown', 'Var', (53, 62))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('panVEGF', 'Gene', (13, 20))	('expression', 'MPA', (21, 31))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('downregulated', 'NegReg', (36, 49))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('tumours', 'Disease', (90, 97))
152751	25010863	Like SRPK1 knockdown, SRPIN340 had no effect on A375 cell proliferation or migration and resulted in reduced panVEGF expression, but not VEGFxxxb in treated tumours.	('migration', 'CPA', (75, 84))	('cell proliferation', 'biological_process', 'GO:0008283', ('53', '71'))	('SRPIN340', 'Chemical', 'MESH:C584061', (22, 30))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('expression', 'MPA', (117, 127))	('SRPIN340', 'Var', (22, 30))	('A375', 'CellLine', 'CVCL:0132', (48, 52))	('tumours', 'Phenotype', 'HP:0002664', (157, 164))	('tumours', 'Disease', 'MESH:D009369', (157, 164))	('reduced', 'NegReg', (101, 108))	('tumours', 'Disease', (157, 164))	('SRPK1', 'Gene', (5, 10))	('panVEGF', 'Protein', (109, 116))
152755	25010863	SRPK1 inhibition acts mechanistically, at least in part, to reduce VEGF165 expression and prevent tumour angiogenesis.	('SRPK1', 'Gene', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('reduce', 'NegReg', (60, 66))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Disease', (98, 104))	('prevent', 'NegReg', (90, 97))	('VEGF165', 'Gene', (67, 74))	('angiogenesis', 'biological_process', 'GO:0001525', ('105', '117'))	('inhibition', 'Var', (6, 16))	('expression', 'MPA', (75, 85))
152759	24855403	The Importance of Multidisciplinary Approach in Early Detection of BAP1 Tumor Predisposition Syndrome: Clinical Management and Risk Assessment Germline BAP1 (BRCA1-associated protein-1) mutations are involved into a novel specific cancer syndrome and strictly associated with a high cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('cancer syndrome', 'Disease', 'MESH:D009369', (231, 246))	('Tumor', 'Phenotype', 'HP:0002664', (72, 77))	('BAP1', 'Gene', (152, 156))	('involved', 'Reg', (200, 208))	('cancer', 'Disease', (231, 237))	('cancer syndrome', 'Disease', (231, 246))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('protein', 'cellular_component', 'GO:0003675', ('175', '182'))	('associated', 'Reg', (260, 270))	('BRCA1-associated protein-1', 'Gene', '8314', (158, 184))	('cancer', 'Disease', (283, 289))	('BRCA1-associated protein-1', 'Gene', (158, 184))	('BAP1', 'Gene', '8314', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('mutations', 'Var', (186, 195))	('BAP1', 'Gene', '8314', (152, 156))	('BAP1', 'Gene', (67, 71))
152760	24855403	Recent data suggest that BAP1 has activity toward target substrates explaining why loss of BAP1 causes a pro-tumorigenic deregulation of gene expression.	('BAP1', 'Gene', (91, 95))	('loss', 'Var', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('gene expression', 'biological_process', 'GO:0010467', ('137', '152'))	('tumor', 'Disease', (109, 114))	('has activity', 'molecular_function', 'GO:0050501', ('30', '42'))
152762	24855403	The clinical phenotype of BAP1 alterations includes MBAITs (melanocytic BAP1-mutated atypical intradermal tumors), uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), mesothelioma (MM), and possibly several other tumors.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (161, 181))	('uveal melanoma', 'Disease', (115, 129))	('uveal melanoma', 'Disease', 'MESH:C536494', (115, 129))	('UM', 'Phenotype', 'HP:0007716', (131, 133))	('tumors', 'Disease', (106, 112))	('BAP1', 'Gene', (26, 30))	('uveal melanoma', 'Phenotype', 'HP:0007716', (115, 129))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('MBAITs', 'Disease', (52, 58))	('renal cell carcinoma', 'Disease', (161, 181))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (161, 181))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('RCC', 'Phenotype', 'HP:0005584', (183, 186))	('RCC', 'Disease', (183, 186))	('intradermal tumors', 'Disease', 'MESH:D018330', (94, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('intradermal tumors', 'Disease', (94, 112))	('CM', 'Phenotype', 'HP:0012056', (156, 158))	('tumors', 'Disease', (235, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('alterations', 'Var', (31, 42))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('mesothelioma', 'Disease', (189, 201))	('mesothelioma', 'Disease', 'MESH:D008654', (189, 201))	('cutaneous melanoma', 'Disease', (136, 154))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (136, 154))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (136, 154))	('tumors', 'Disease', 'MESH:D009369', (235, 241))
152764	24855403	The uniformed and unambiguous definition of MBAITs as clinical/pathological predictive markers could provide physicians means to identify patients who may carry germline BAP1 mutations and thus could be at high risk of developing CM, UM, MM, RCC, and possibly other tumors.	('developing', 'PosReg', (219, 229))	('UM', 'Phenotype', 'HP:0007716', (234, 236))	('RCC', 'Disease', 'MESH:C538614', (242, 245))	('RCC', 'Disease', (242, 245))	('RCC', 'Phenotype', 'HP:0005584', (242, 245))	('CM', 'Phenotype', 'HP:0012056', (230, 232))	('BAP1', 'Gene', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('mutations', 'Var', (175, 184))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('patients', 'Species', '9606', (138, 146))	('tumors', 'Disease', (266, 272))
152774	24855403	Given that BAP1 is a UCH strictly associated with the BRCA1 complex of proteins, its loss or inactivation may affect a variety of signaling pathways in the cell as discussed below.	('affect', 'Reg', (110, 116))	('inactivation', 'Var', (93, 105))	('BAP1', 'Gene', (11, 15))	('loss', 'NegReg', (85, 89))	('BRCA1', 'Gene', '672', (54, 59))	('signaling', 'biological_process', 'GO:0023052', ('130', '139'))	('BRCA1', 'Gene', (54, 59))
152791	24855403	BAP1 gene mutations, including rearrangements, homozygous deletions, and missense mutations, were initially described in lung and breast carcinomas.	('breast carcinomas', 'Disease', 'MESH:D001943', (130, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('breast carcinomas', 'Disease', (130, 147))	('BAP1', 'Gene', (0, 4))	('described', 'Reg', (108, 117))	('lung', 'Disease', (121, 125))	('rearrangements', 'Var', (31, 45))	('breast carcinomas', 'Phenotype', 'HP:0003002', (130, 147))	('breast carcinoma', 'Phenotype', 'HP:0003002', (130, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('homozygous deletions', 'Var', (47, 67))	('missense mutations', 'Var', (73, 91))
152792	24855403	This region undergoes frequent copy-number loss and loss-of-heterozygosis in 80% of breast carcinomas, 90% of lung carcinomas, and almost all renal carcinomas.	('breast carcinomas', 'Phenotype', 'HP:0003002', (84, 101))	('renal carcinoma', 'Phenotype', 'HP:0005584', (142, 157))	('loss-of-heterozygosis', 'Disease', (52, 73))	('breast carcinoma', 'Phenotype', 'HP:0003002', (84, 100))	('loss-of-heterozygosis', 'Disease', 'MESH:D015431', (52, 73))	('renal carcinomas', 'Disease', 'MESH:C538614', (142, 158))	('lung carcinomas', 'Disease', 'MESH:D008175', (110, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('copy-number loss', 'Var', (31, 47))	('lung carcinomas', 'Disease', (110, 125))	('breast carcinomas', 'Disease', 'MESH:D001943', (84, 101))	('breast carcinomas', 'Disease', (84, 101))	('renal carcinomas', 'Disease', (142, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('renal carcinomas', 'Phenotype', 'HP:0005584', (142, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))
152793	24855403	For example, the NCI-H226 non-small cell lung carcinoma line carries a homozygous BAP1 deletion (BAP1-/-), and recently a relevant suppression both in tumor formation in mice and growth in monolayer cultures using this cell line by lentiviral-based restoration of BAP1 was shown.	('BAP1', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (30, 55))	('tumor', 'Disease', (151, 156))	('suppression', 'NegReg', (131, 142))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (36, 55))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (26, 55))	('mice', 'Species', '10090', (170, 174))	('deletion', 'Var', (87, 95))	('formation', 'biological_process', 'GO:0009058', ('157', '166'))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('cell lung carcinoma', 'Disease', (36, 55))
152794	24855403	It is reasonable to speculate that these tumor suppressor properties are highly dependent on localization of BAP1 to the nucleus and aberrations affecting its active site, particularly cysteine residue.	('active site', 'MPA', (159, 170))	('cysteine', 'Chemical', 'MESH:D003545', (185, 193))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('cysteine residue', 'MPA', (185, 201))	('localization', 'biological_process', 'GO:0051179', ('93', '105'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('41', '57'))	('aberrations', 'Var', (133, 144))	('BAP1', 'Gene', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('41', '57'))	('nucleus', 'cellular_component', 'GO:0005634', ('121', '128'))
152795	24855403	As mentioned earlier, germline BAP1 mutations are associated to a novel cancer syndrome characterized, at least in the affected families so far studied, by benign melanocytic skin BAP1-mutated tumors with an early age of the onset, and later in life by a high incidence of mesothelioma (MM), uveal melanoma (UM), cutaneous melanoma (CM), clear cell renal carcinoma (RCC), and possibly additional cancers, as reported in recent findings.	('uveal melanoma', 'Phenotype', 'HP:0007716', (292, 306))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (338, 364))	('additional cancers', 'Disease', 'MESH:D009369', (385, 403))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('mesothelioma', 'Disease', (273, 285))	('cancer syndrome', 'Disease', (72, 87))	('CM', 'Phenotype', 'HP:0012056', (333, 335))	('mesothelioma', 'Disease', 'MESH:D008654', (273, 285))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('clear cell renal carcinoma', 'Disease', (338, 364))	('melanoma', 'Phenotype', 'HP:0002861', (323, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (355, 364))	('cutaneous melanoma', 'Disease', (313, 331))	('cancers', 'Phenotype', 'HP:0002664', (396, 403))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (313, 331))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (313, 331))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (338, 364))	('melanoma', 'Phenotype', 'HP:0002861', (298, 306))	('BAP1', 'Gene', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (396, 402))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('RCC', 'Disease', (366, 369))	('RCC', 'Phenotype', 'HP:0005584', (366, 369))	('uveal melanoma', 'Disease', 'MESH:C536494', (292, 306))	('uveal melanoma', 'Disease', (292, 306))	('additional cancers', 'Disease', (385, 403))	('tumors', 'Disease', (193, 199))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('renal carcinoma', 'Phenotype', 'HP:0005584', (349, 364))	('UM', 'Phenotype', 'HP:0007716', (308, 310))	('RCC', 'Disease', 'MESH:C538614', (366, 369))	('associated', 'Reg', (50, 60))	('cancer syndrome', 'Disease', 'MESH:D009369', (72, 87))
152798	24855403	Furthermore, BAP1 mutations, depending on the cell type in which they occur and/or the nature of other co-existing mutations, may harvest different tumor phenotypes.	('BAP1', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('harvest', 'Reg', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('mutations', 'Var', (18, 27))
152799	24855403	Related to BAP1 tumor suppressive function, loss-of-function BAP1 mutations in a diverse array of solid tumor types have been identified, including frequent somatic mutations in MM, UM, and RCC (see Tables 3 and 4).	('mutations', 'Var', (66, 75))	('UM', 'Phenotype', 'HP:0007716', (182, 184))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('BAP1', 'Gene', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Disease', (190, 193))	('solid tumor', 'Disease', (98, 109))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('solid tumor', 'Disease', 'MESH:D009369', (98, 109))	('RCC', 'Phenotype', 'HP:0005584', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('mutations', 'Var', (165, 174))	('loss-of-function', 'NegReg', (44, 60))
152800	24855403	Recently, Dey et al identified a somatic heterozygous BAP1 mutation in a patient with de novo myelodysplastic syndrome (MDS) and deletion of 20q as the sole additional somatic abnormality.	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (94, 118))	('myelodysplastic syndrome', 'Disease', (94, 118))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (94, 118))	('patient', 'Species', '9606', (73, 80))	('mutation', 'Var', (59, 67))	('deletion of 20q', 'Var', (129, 144))	('MDS', 'Phenotype', 'HP:0002863', (120, 123))	('somatic abnormality', 'Phenotype', 'HP:0410009', (168, 187))	('BAP1', 'Gene', (54, 58))	('MDS', 'Disease', (120, 123))	('MDS', 'Disease', 'MESH:D009190', (120, 123))
152801	24855403	Interestingly, although only a total cohort of 32 patients was sequenced for BAP1 mutations, down-regulation of BAP1 expression in CD34 th cells from patients with de novo MDS compared with age-matched counterparts was identified.	('BAP1', 'Gene', (112, 116))	('down-regulation', 'NegReg', (93, 108))	('CD34', 'Gene', (131, 135))	('CD34', 'Gene', '947', (131, 135))	('patients', 'Species', '9606', (50, 58))	('MDS', 'Phenotype', 'HP:0002863', (172, 175))	('expression', 'MPA', (117, 127))	('MDS', 'Disease', 'MESH:D009190', (172, 175))	('mutations', 'Var', (82, 91))	('patients', 'Species', '9606', (150, 158))	('MDS', 'Disease', (172, 175))	('BAP1', 'Gene', (77, 81))	('regulation', 'biological_process', 'GO:0065007', ('98', '108'))
152802	24855403	A high metastatic potential was observed in the vast majority of these tumors, many of which also showed monosomy of chromosome 3.	('monosomy', 'Var', (105, 113))	('chromosome', 'cellular_component', 'GO:0005694', ('117', '127'))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
152803	24855403	Up to date, a broad spectrum of other tumors associated with germline and somatic mutations in BAP1 has been described, and the biological and clinical significance of BAP1-associated tumors is the subject of intensive ongoing studies.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('germline', 'Var', (61, 69))	('BAP1', 'Gene', (95, 99))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('associated', 'Reg', (45, 55))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('mutations', 'Var', (82, 91))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))
152804	24855403	Carbone et al first investigated the presence of melanocytic tumors in two families, to verify if germline BAP1 mutations were associated with distinct syndromes or with a single syndrome exhibiting a wide phenotypic range.	('associated', 'Reg', (127, 137))	('melanocytic tumors', 'Disease', 'MESH:D009508', (49, 67))	('BAP1', 'Gene', (107, 111))	('mutations', 'Var', (112, 121))	('melanocytic tumors', 'Disease', (49, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
152810	24855403	Lumping different melanocytic lesions, such as MBAITs, under the nomenclature used to describe ASTs may hinder both pathologists to identify and classify this subgroup of lesions and clinicians in selecting patients who may benefit from testing for BAP1 mutations.	('patients', 'Species', '9606', (207, 215))	('hinder', 'NegReg', (104, 110))	('BAP1', 'Gene', (249, 253))	('melanocytic lesions', 'Disease', 'MESH:D009508', (18, 37))	('mutations', 'Var', (254, 263))	('melanocytic lesions', 'Disease', (18, 37))
152814	24855403	These lesions are molecularly characterized by BAP1 inactivation and almost always by concurrent BRAF mutation, features absent or rare in Spitz and/or ASTs.	('mutation', 'Var', (102, 110))	('inactivation', 'Var', (52, 64))	('BRAF', 'Gene', '673', (97, 101))	('BRAF', 'Gene', (97, 101))	('BAP1', 'Gene', (47, 51))
152815	24855403	BRAF analysis was performed on all the MBAITs diagnosed, and BRAF V600E mutations were identified in all of them, confirming the extremely high prevalence of this mutation as originally reported and subsequently confirmed.	('V600E', 'Var', (66, 71))	('BRAF', 'Gene', '673', (61, 65))	('BRAF', 'Gene', (61, 65))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('V600E', 'Mutation', 'rs113488022', (66, 71))
152818	24855403	All these findings revealed that germline BAP1 mutations cause a novel autosomal dominant hereditary cancer syndrome, characterized predominantly by MM, UM, and CM, by MBAITs, and possibly by other cancers.	('cause', 'Reg', (57, 62))	('autosomal dominant hereditary cancer syndrome', 'Disease', 'MESH:D009386', (71, 116))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('UM', 'Phenotype', 'HP:0007716', (153, 155))	('BAP1', 'Gene', (42, 46))	('cancers', 'Disease', (198, 205))	('mutations', 'Var', (47, 56))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('CM', 'Phenotype', 'HP:0012056', (161, 163))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('autosomal dominant hereditary cancer syndrome', 'Disease', (71, 116))
152819	24855403	Recently, some other studies extended the spectrum of tumors related to BAP1 germline mutations.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('germline mutations', 'Var', (77, 95))	('BAP1', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
152820	24855403	For example, a screening for germline BAP1 deleterious mutations in familial BAP1-associated syndromes, including UM, malignant pleural MM, and CM, 6 families with 9 RCC-affected individuals within 11 families screened confirmed a significantly increased risk for RCC.	('RCC', 'Disease', 'MESH:C538614', (264, 267))	('malignant pleural MM', 'Disease', 'MESH:D016066', (118, 138))	('RCC', 'Disease', (264, 267))	('RCC', 'Phenotype', 'HP:0005584', (264, 267))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('deleterious mutations', 'Var', (43, 64))	('RCC', 'Disease', (166, 169))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('BAP1', 'Gene', (38, 42))	('CM', 'Phenotype', 'HP:0012056', (144, 146))	('UM', 'Phenotype', 'HP:0007716', (114, 116))	('malignant pleural MM', 'Disease', (118, 138))	('familial BAP1-associated syndromes', 'Disease', (68, 102))
152822	24855403	In addition, also meningioma, lung adenocarcinoma, neuroendocrine carcinoma, and abdominal (suspected to be ovarian) adenocarcinoma were identified in a family with BAP1 germline mutations.	('neuroendocrine carcinoma', 'Disease', (51, 75))	('identified', 'Reg', (137, 147))	('meningioma', 'Phenotype', 'HP:0002858', (18, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('ovarian) adenocarcinoma', 'Disease', 'MESH:D010051', (108, 131))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (30, 49))	('BAP1', 'Gene', (165, 169))	('meningioma', 'Disease', 'MESH:D008577', (18, 28))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (51, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('lung adenocarcinoma', 'Disease', (30, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (30, 49))	('meningioma', 'Disease', (18, 28))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (51, 75))	('germline mutations', 'Var', (170, 188))
152823	24855403	Previous and recent data, together with the evidence of biallelic BAP1 inactivation, confirmed that several other tumors such as paraganglioma and neuroendocrine tumors could be part of the BAP1 tumor predisposition syndrome.	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (147, 168))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', (162, 167))	('BAP1', 'Gene', (66, 70))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('biallelic', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('paraganglioma', 'Disease', (129, 142))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (147, 168))	('tumor', 'Disease', (114, 119))	('paraganglioma', 'Disease', 'MESH:D010235', (129, 142))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('neuroendocrine tumors', 'Disease', (147, 168))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('paraganglioma', 'Phenotype', 'HP:0002668', (129, 142))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', (162, 168))	('inactivation', 'Var', (71, 83))
152824	24855403	Moreover, members of two families with germline BAP1 mutations, who developed MM and UM, also developed other tumors.	('developed', 'PosReg', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('BAP1', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('developed', 'Reg', (94, 103))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('germline', 'Var', (39, 47))
152825	24855403	A recent screening of 46 previously untested, unrelated UM patients and 4 additional patients with a personal or family history suggestive of BAP1 hereditary cancer syndrome identified 3 patients with germline pathogenic mutations in BAP1.	('patients', 'Species', '9606', (187, 195))	('BAP1 hereditary cancer syndrome', 'Disease', 'MESH:D009386', (142, 173))	('mutations', 'Var', (221, 230))	('BAP1', 'Gene', (234, 238))	('BAP1 hereditary cancer syndrome', 'Disease', (142, 173))	('patients', 'Species', '9606', (85, 93))	('patients', 'Species', '9606', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('UM', 'Phenotype', 'HP:0007716', (56, 58))
152828	24855403	The results of this study confirmed the association between germline BAP1 mutation and predisposition to UM, MM, CM, and RCC.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('mutation', 'Var', (74, 82))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('BAP1', 'Gene', (69, 73))	('association', 'Reg', (40, 51))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('germline', 'Var', (60, 68))	('CM', 'Phenotype', 'HP:0012056', (113, 115))
152832	24855403	Pathologically, appearance of the predominantly intradermal ASTs with characteristic epithelioid cells may offer the means to identify patients with a higher likelihood of harboring a BAP1 germline mutation.	('BAP1', 'Gene', (184, 188))	('patients', 'Species', '9606', (135, 143))	('germline mutation', 'Var', (189, 206))
152833	24855403	The screening of ASTs, particularly those with a prominent epithelioid cell component, should be performed for BAP1 and BRAF status by IHC and/or by mutation assay.	('BRAF', 'Gene', '673', (120, 124))	('BAP1', 'Gene', (111, 115))	('BRAF', 'Gene', (120, 124))	('mutation', 'Var', (149, 157))
152834	24855403	If BAP1 mutations are identified in the tumors, testing for germline BAP1 mutations should be considered, preferably in the context of a familial cancer genetic screening unit.	('familial cancer', 'Disease', (137, 152))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('BAP1', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('BAP1', 'Gene', (3, 7))	('mutations', 'Var', (8, 17))	('familial cancer', 'Disease', 'MESH:D009369', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))
152843	24855403	Removal and testing of suspicious lesions may identify patients with germline and/or somatic BAP1 mutations.	('mutations', 'Var', (98, 107))	('BAP1', 'Gene', (93, 97))	('patients', 'Species', '9606', (55, 63))
152844	24855403	For example, in a setting of CMs reported showing biallelic BAP1 inactivation, one of the tumors was associated with an epithelioid naevus.	('epithelioid naevus', 'Disease', (120, 138))	('biallelic', 'Var', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('epithelioid naevus', 'Phenotype', 'HP:0010816', (120, 138))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('associated', 'Reg', (101, 111))	('CM', 'Phenotype', 'HP:0012056', (29, 31))	('naevus', 'Phenotype', 'HP:0003764', (132, 138))	('BAP1', 'Gene', (60, 64))
152846	24855403	It is essential to broaden knowledge not only about BAP1 differential expression in mutated/wild-type tumor tissues and its biological and functional behaviors but also about tumors with BAP1 mutations.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Disease', (175, 180))	('mutations', 'Var', (192, 201))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('BAP1', 'Gene', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
152847	24855403	Optimally, a patient with a BAP1 mutation is closely followed from the first clinical visit, passing to the morphological diagnosis and molecular testing, the genetic counseling, the risk assessment, and the prognosis estimation, until the curative treatment or treatments.	('patient', 'Species', '9606', (13, 20))	('mutation', 'Var', (33, 41))	('BAP1', 'Gene', (28, 32))
152848	24855403	Awareness of detailed and correct anamnestic history, at least covering the spectrum of tumors that occur in the setting of germline BAP1 mutations, is crucial for pathologists and clinical geneticists.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('BAP1', 'Gene', (133, 137))	('mutations', 'Var', (138, 147))
152849	24855403	Considering the wide variability of clinical presentation in BAP1 germline-mutated patients, it is important to collect familial and pathological history information for family members.	('patients', 'Species', '9606', (83, 91))	('germline-mutated', 'Var', (66, 82))	('BAP1', 'Gene', (61, 65))
152850	24855403	It would be useful to know if they could be involved into other not cancer-related disease processes, and here we would like to stress the importance of collecting also a detailed non-oncological history to deepen the knowledge even on the plane of not cancer disease, from a medical point of view, and to define if BAP1 mutations could be also associated with specific metabolic disorders or other internal disease predispositions.	('internal disease', 'Disease', (399, 415))	('involved', 'Reg', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer disease', 'Disease', 'MESH:D009369', (253, 267))	('metabolic disorders', 'Disease', 'MESH:D008659', (370, 389))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('associated', 'Reg', (345, 355))	('mutations', 'Var', (321, 330))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (253, 259))	('metabolic disorders', 'Disease', (370, 389))	('BAP1', 'Gene', (316, 320))	('cancer', 'Disease', (68, 74))	('cancer disease', 'Disease', (253, 267))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
152853	24855403	If family members or an individual patient is suspected to carry a BAP1 germline mutation on the basis of their familial pedigree and/or clinical phenotype, following detailed genetic counseling, absence/presence of a mutation can be confirmed by direct (Sanger) sequencing using blood or salivary-derived DNA.	('DNA', 'cellular_component', 'GO:0005574', ('306', '309'))	('mutation', 'Var', (81, 89))	('patient', 'Species', '9606', (35, 42))	('BAP1', 'Gene', (67, 71))
152857	24855403	As part of a multidisciplinary model, pathologists have an important role in the identification of BAP1-associated tumors, most importantly in identification of BAP1 mutation/loss-related morphological markers.	('mutation/loss-related', 'Var', (166, 187))	('BAP1', 'Gene', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('BAP1-associated', 'Gene', (99, 114))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('mutation/loss-related', 'NegReg', (166, 187))
152859	24855403	These morphological features might help pathologists to identify tumors with a higher likelihood of harboring BAP1 mutation/loss and to initiate screening of the tumor with BAP1 IHC.	('mutation/loss', 'Var', (115, 128))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (162, 167))	('BAP1', 'Gene', (110, 114))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('mutation/loss', 'NegReg', (115, 128))
152861	24855403	As emphasized previously, early diagnosis and clinical monitoring of new patients suspected to carry BAP1 mutations or family members with inherited mutations of BAP1 is central (see Figure 2B).	('BAP1', 'Gene', (162, 166))	('BAP1', 'Gene', (101, 105))	('mutations', 'Var', (106, 115))	('patients', 'Species', '9606', (73, 81))
152866	24855403	Under a speculative molecular model profile, considering the UM management, it could reflect on the possibility of multi-gene screening, based on the detection of BAP1 mutations and other UM-associated susceptibility genes (ie GNAQ, c-KIT, etc.)	('KIT', 'molecular_function', 'GO:0005020', ('235', '238'))	('c-KIT', 'Gene', (233, 238))	('GNAQ', 'Gene', '2776', (227, 231))	('c-KIT', 'Gene', '3815', (233, 238))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('BAP1', 'Gene', (163, 167))	('GNAQ', 'Gene', (227, 231))	('UM', 'Phenotype', 'HP:0007716', (188, 190))	('mutations', 'Var', (168, 177))
152867	24855403	for all new UM cases or just for members of families with BAP1-inherited mutations, following the MammaPrint  model already used in breast cancers for prognostic and therapeutic purposes.	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('UM', 'Phenotype', 'HP:0007716', (12, 14))	('breast cancers', 'Phenotype', 'HP:0003002', (132, 146))	('breast cancers', 'Disease', 'MESH:D001943', (132, 146))	('breast cancers', 'Disease', (132, 146))	('mutations', 'Var', (73, 82))	('BAP1-inherited', 'Gene', (58, 72))
152868	24855403	Interestingly, sequencing efforts demonstrated worse outcomes in patients with BAP1-mutated colorectal cancer (CRC).	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BAP1-mutated', 'Var', (79, 91))	('colorectal cancer', 'Disease', 'MESH:D015179', (92, 109))	('CRC', 'Phenotype', 'HP:0003003', (111, 114))	('patients', 'Species', '9606', (65, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('colorectal cancer', 'Disease', (92, 109))
152869	24855403	These findings provide the first evidence that reduced BAP1 expression is associated with poor CRC patients prognosis and that BAP1 mutation could be used as a novel prognostic biomarker for CRC.	('expression', 'MPA', (60, 70))	('BAP1', 'Gene', (127, 131))	('CRC', 'Disease', (191, 194))	('BAP1', 'Gene', (55, 59))	('CRC', 'Disease', (95, 98))	('patients', 'Species', '9606', (99, 107))	('CRC', 'Phenotype', 'HP:0003003', (191, 194))	('CRC', 'Phenotype', 'HP:0003003', (95, 98))	('mutation', 'Var', (132, 140))	('reduced', 'NegReg', (47, 54))
152873	24855403	BAP1 mutations tended to occur in Fuhrman grades III-IV tumors (P = 0.052) and were associated with worse CSS (P = 0.01).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('BAP1', 'Gene', (0, 4))	('III-IV tumors', 'Disease', 'MESH:D009369', (49, 62))	('III-IV tumors', 'Disease', (49, 62))	('mutations', 'Var', (5, 14))	('occur', 'Reg', (25, 30))	('CSS', 'Disease', (106, 109))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('associated', 'Reg', (84, 94))
152876	24855403	Regarding future perspectives, the association of overexpression of BAP1 with tumor progression and prognosis in many other cancer types suggests that inhibition of BAP1 activity (like proteins involved in chromatin modifications such as BMI and EZH2) aberrantly expressed in several tumors may have a beneficial therapeutic effect.	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumors', 'Phenotype', 'HP:0002664', (284, 290))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('beneficial', 'PosReg', (302, 312))	('chromatin', 'cellular_component', 'GO:0000785', ('206', '215'))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('EZH2', 'Gene', (246, 250))	('EZH2', 'Gene', '2146', (246, 250))	('tumors', 'Disease', (284, 290))	('BAP1', 'Gene', (165, 169))	('inhibition', 'Var', (151, 161))	('tumor', 'Disease', (78, 83))	('tumors', 'Disease', 'MESH:D009369', (284, 290))	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('activity', 'MPA', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Disease', (284, 289))
152877	24855403	However, as previously reported, depletion of BAP1 in UM cells induced loss of melanocytic differentiation together with acquisition of a gene expression profile seen in advanced metastasizing tumors.	('depletion', 'Var', (33, 42))	('gene expression profile', 'MPA', (138, 161))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('loss of melanocytic', 'Disease', 'MESH:D009508', (71, 90))	('BAP1', 'Gene', (46, 50))	('UM', 'Phenotype', 'HP:0007716', (54, 56))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('gene expression', 'biological_process', 'GO:0010467', ('138', '153'))	('loss of melanocytic', 'Disease', (71, 90))
152881	24855403	If studies will define a therapeutically accessible synthetic lethal target in the setting of BAP1 loss, this could eventually benefit patients whose tumors have BAP1 loss or mutation, and more speculatively, the same synthetic lethal target could be studied as chemoprevention drug targets in individuals with germline BAP1 mutations that predispose to tumor development.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('patients', 'Species', '9606', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (354, 359))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('mutation', 'Var', (175, 183))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('loss', 'NegReg', (167, 171))	('BAP1', 'Gene', (320, 324))	('BAP1', 'Gene', (162, 166))	('mutations', 'Var', (325, 334))	('loss', 'NegReg', (99, 103))	('tumor', 'Disease', (354, 359))	('BAP1', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
152882	24855403	Germline BAP1 mutations are involved into a novel specific cancer syndrome and are strictly associated with high cancer susceptibility.	('cancer syndrome', 'Disease', (59, 74))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('BAP1', 'Gene', (9, 13))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('involved', 'Reg', (28, 36))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer syndrome', 'Disease', 'MESH:D009369', (59, 74))	('cancer', 'Disease', (59, 65))	('associated', 'Reg', (92, 102))	('mutations', 'Var', (14, 23))
152885	24855403	The uniform and shared definition of MBAITs/ASTs as clinical/pathological predictive markers could provide physicians markers to identify individuals who may carry germline BAP1 mutations and thus are at high risk of developing CM, UM, MM, RCC, and possibly other tumors.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('developing', 'PosReg', (217, 227))	('UM', 'Phenotype', 'HP:0007716', (232, 234))	('CM', 'Phenotype', 'HP:0012056', (228, 230))	('tumors', 'Disease', (264, 270))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('BAP1', 'Gene', (173, 177))	('mutations', 'Var', (178, 187))	('RCC', 'Disease', 'MESH:C538614', (240, 243))	('RCC', 'Disease', (240, 243))	('RCC', 'Phenotype', 'HP:0005584', (240, 243))
133815	24855403	Next, genetic counseling should be offered and germline DNA should be tested for BAP1 mutations to identify individuals and families at higher risk for one or more of the neoplasms associated with the BAP1 cancer syndrome.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('BAP1', 'Gene', (81, 85))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('neoplasms', 'Phenotype', 'HP:0002664', (171, 180))	('cancer syndrome', 'Disease', 'MESH:D009369', (206, 221))	('cancer syndrome', 'Disease', (206, 221))	('neoplasms', 'Disease', 'MESH:D009369', (171, 180))	('neoplasms', 'Disease', (171, 180))
152889	24855403	Agents directed at these targets may be useful for treatment of patients with BAP1-loss tumors, and potentially as part of chemo-preventive strategies in individuals with germline BAP1 mutations.	('BAP1-loss tumors', 'Disease', (78, 94))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('BAP1-loss tumors', 'Disease', 'MESH:D009369', (78, 94))	('BAP1', 'Gene', (180, 184))	('mutations', 'Var', (185, 194))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
152958	23152651	For patients with massive macular edema and cystic changes where bevacizumab does not lead to significant improvement, combination treatment with bevacizumab followed by supplemental triamcinolone may often stabilize the macular edema.	('combination', 'Var', (119, 130))	('bevacizumab', 'Chemical', 'MESH:D000068258', (65, 76))	('bevacizumab', 'Chemical', 'MESH:D000068258', (146, 157))	('macular edema', 'Phenotype', 'HP:0040049', (221, 234))	('macular edema', 'Disease', (221, 234))	('edema', 'Phenotype', 'HP:0000969', (229, 234))	('macular edema', 'Disease', (26, 39))	('edema', 'Phenotype', 'HP:0000969', (34, 39))	('triamcinolone', 'Chemical', 'MESH:D014221', (183, 196))	('macular edema', 'Phenotype', 'HP:0040049', (26, 39))	('patients', 'Species', '9606', (4, 12))	('macular edema', 'Disease', 'MESH:D008269', (221, 234))	('macular edema', 'Disease', 'MESH:D008269', (26, 39))
153062	23060881	While these data suggested that DTH responses were critical for ocular tumor elimination, additional experiments showed that administration of anti-CD4 antibodies, which abrogated DTH responses measured in the footpad, did not prevent rejection of intraocular P91 tumors (Niederkorn et al.,).	('DTH responses', 'MPA', (180, 193))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('antibodies', 'Var', (152, 162))	('abrogated', 'NegReg', (170, 179))	('intraocular P91 tumors', 'Disease', (248, 270))	('ocular tumor', 'Disease', 'MESH:D009369', (64, 76))	('CD4', 'Gene', (148, 151))	('intraocular P91 tumors', 'Disease', 'MESH:D064090', (248, 270))	('ocular tumor', 'Phenotype', 'HP:0100012', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('ocular tumor', 'Disease', (64, 76))	('CD4', 'Gene', '12504', (148, 151))
153073	23060881	TNFalpha expression was critical for inducing Ad5E1 tumor death in a manner which promoted differentiation of tumoricidal macrophages.	('TNFalpha', 'Gene', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('promoted', 'PosReg', (82, 90))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor death', 'Disease', 'MESH:D003643', (52, 63))	('differentiation', 'CPA', (91, 106))	('TNFalpha', 'Gene', '21926', (0, 8))	('inducing', 'PosReg', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor death', 'Disease', (52, 63))	('Ad5E1', 'Var', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
153083	23060881	Hence, IFNgamma is required for rejection of established Ad5E1 ocular tumors but not for protection from a subsequent ocular tumor challenge.	('ocular tumor', 'Phenotype', 'HP:0100012', (63, 75))	('ocular tumor', 'Disease', 'MESH:D009369', (118, 130))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('ocular tumors', 'Phenotype', 'HP:0100012', (63, 76))	('ocular tumor', 'Disease', (118, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Ad5E1', 'Var', (57, 62))	('ocular tumor', 'Phenotype', 'HP:0100012', (118, 130))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('ocular tumors', 'Disease', (63, 76))	('ocular tumor', 'Disease', 'MESH:D009369', (63, 75))	('ocular tumors', 'Disease', 'MESH:D009369', (63, 76))	('IFNgamma', 'Gene', (7, 15))	('IFNgamma', 'Gene', '15978', (7, 15))
153158	23060881	However, the presence of FOXP3+ Treg in cycloxygenase-2 (COX-2) positive tumors did predict poor survival of uveal melanoma patients (Mougiakakos et al.,).	('FOXP3+', 'Var', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('Treg', 'Chemical', '-', (32, 36))	('survival', 'MPA', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('poor', 'NegReg', (92, 96))	('uveal melanoma', 'Disease', 'MESH:C536494', (109, 123))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('presence', 'Var', (13, 21))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('uveal melanoma', 'Disease', (109, 123))	('patients', 'Species', '9606', (124, 132))
153228	33389937	have reported their current use of adjuvant Ru-106 plaque for deep invasion with a dose of 100 Gy at 2 mm until 2006 and 100 Gy at 1 mm since 2006, instead of sclerectomy or cryotherapy, resulting in improved local recurrence rates.	('improved', 'PosReg', (200, 208))	('Ru-106 plaque', 'Chemical', '-', (44, 57))	('local recurrence rates', 'CPA', (209, 231))	('Ru-106', 'Var', (44, 50))
153256	33389937	Vemurafenib is a V600E mutation-specific BRAF inhibitor that has been suggested as a treatment of metastatic disease.	('V600E', 'Mutation', 'rs113488022', (17, 22))	('metastatic disease', 'Disease', (98, 116))	('V600E', 'Var', (17, 22))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))
153274	33389937	Pharmacological inhibition of EZH2 with GSK503 and genetic knock-down resulted in diminished cell growth in vitro and zebrafish xenografts.	('cell growth', 'biological_process', 'GO:0016049', ('93', '104'))	('GSK', 'molecular_function', 'GO:0050321', ('40', '43'))	('EZH2', 'Gene', (30, 34))	('diminished', 'NegReg', (82, 92))	('knock-down', 'Var', (59, 69))	('zebrafish', 'Species', '7955', (118, 127))	('cell growth in vitro', 'CPA', (93, 113))	('GSK503', 'Gene', (40, 46))
153284	33389937	The cell lines differed in their mutational profile which included BRAF V600E mutation for CRMM1, NRAS Q61L mutation for CRMM2 and BRAF G466E mutation for T1527A.	('Q61L', 'Mutation', 'rs11554290', (103, 107))	('G466E', 'Mutation', 'rs121913351', (136, 141))	('T1527A', 'Mutation', 'rs1276829336', (155, 161))	('NRAS', 'Gene', (98, 102))	('BRAF V600E', 'Var', (67, 77))	('NRAS', 'Gene', '4893', (98, 102))	('BRAF G466E', 'Var', (131, 141))	('V600E', 'Mutation', 'rs113488022', (72, 77))
153285	33389937	As a result, CRMM1 was found to be sensitive to inhibitors of both MAPK (trametinib and only marginally to vemurafenib), CRMM2 was found to be moderately sensitive to pictilisib, and T1527A was resistant to all tested agents; vemurafenib sensitivity was only displayed by CRMM1.	('vemurafenib', 'Chemical', 'MESH:D000077484', (226, 237))	('T1527A', 'Mutation', 'rs1276829336', (183, 189))	('vemurafenib', 'Chemical', 'MESH:D000077484', (107, 118))	('MAPK', 'molecular_function', 'GO:0004707', ('67', '71'))	('MAPK', 'Enzyme', (67, 71))	('T1527A', 'Var', (183, 189))	('trametinib', 'Chemical', 'MESH:C560077', (73, 83))	('pictilisib', 'Chemical', 'MESH:C532162', (167, 177))
153286	33389937	Thus, 2 of 3 cell lines, CRMM1 and CRMM2, which harbored the most commonly encountered mutations, showed significant growth inhibition with pictilisib (PI3K inhibitor).	('growth', 'MPA', (117, 123))	('PI3K', 'molecular_function', 'GO:0016303', ('152', '156'))	('mutations', 'Var', (87, 96))	('pictilisib', 'Chemical', 'MESH:C532162', (140, 150))
153291	33389937	Activating BRAF mutations can be found in up to 50% of CM, and among BRAF mutation-bearing samples, the ratio of BRAF V600E to BRAF V600K is nearly 4:1.	('Activating', 'PosReg', (0, 10))	('V600E', 'Mutation', 'rs113488022', (118, 123))	('V600K', 'Var', (132, 137))	('CM', 'Chemical', '-', (55, 57))	('V600E', 'Var', (118, 123))	('V600K', 'Mutation', 'rs121913227', (132, 137))	('BRAF', 'Gene', (11, 15))	('CM', 'Phenotype', 'HP:0007716', (55, 57))
153292	33389937	It is debatable whether BRAF mutations are of prognostic significance, but a population-based study in Denmark has correlated BRAF mutation status with male gender, younger age, sun-exposed tumors (which included bulbar conjunctiva or caruncle), mixed or non-pigmented color, absence of PAM, and CM of nevi origin.	('pigmented', 'Disease', (259, 268))	('correlated', 'Reg', (115, 125))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('CM', 'Chemical', '-', (296, 298))	('nevi', 'Phenotype', 'HP:0003764', (302, 306))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('pigmented', 'Disease', 'MESH:D010859', (259, 268))	('BRAF', 'Gene', (126, 130))	('PAM', 'Disease', (287, 290))	('bulbar conjunctiva', 'Disease', 'MESH:C563620', (213, 231))	('CM', 'Phenotype', 'HP:0007716', (296, 298))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('bulbar conjunctiva', 'Disease', (213, 231))	('mutation', 'Var', (131, 139))
153294	33389937	Activating NRAS mutations can be found at up to 18% frequency and are mutually exclusive with BRAF mutations.	('NRAS', 'Gene', '4893', (11, 15))	('NRAS', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('Activating', 'Reg', (0, 10))
153295	33389937	Remarkably, GNAQ and GNA11 mutations are virtually nonexistent in CM, which differs from uveal melanoma.	('mutations', 'Var', (27, 36))	('GNAQ', 'Gene', (12, 16))	('CM', 'Chemical', '-', (66, 68))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('GNAQ', 'Gene', '2776', (12, 16))	('GNA11', 'Gene', (21, 26))	('uveal melanoma', 'Phenotype', 'HP:0007716', (89, 103))	('CM', 'Phenotype', 'HP:0007716', (66, 68))	('GNA11', 'Gene', '2767', (21, 26))
153299	33389937	A more recent large cohort of 63 CMs demonstrated NF1 mutations as the most frequent mutation in CM (33%), followed by activating mutations of BRAF and RAS genes, all of which induce activation of the MAPK pathway.	('MAPK', 'molecular_function', 'GO:0004707', ('201', '205'))	('activation', 'PosReg', (183, 193))	('CM', 'Phenotype', 'HP:0007716', (97, 99))	('NF1', 'Gene', (50, 53))	('mutations', 'Var', (54, 63))	('BRAF', 'Gene', (143, 147))	('RAS', 'Gene', (152, 155))	('MAPK pathway', 'Pathway', (201, 213))	('NF1', 'Gene', '4763', (50, 53))	('CM', 'Chemical', '-', (33, 35))	('CM', 'Chemical', '-', (97, 99))	('CM', 'Phenotype', 'HP:0007716', (33, 35))
153300	33389937	The authors proposed a genetic classification of CM similar to cutaneous melanoma, including BRAF-mutated, RAS-mutated, NF1-mutated and triple wild-type CMs, implying mutual exclusion of each entity.	('CM', 'Phenotype', 'HP:0007716', (153, 155))	('CM', 'Phenotype', 'HP:0007716', (49, 51))	('cutaneous melanoma', 'Disease', (63, 81))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (63, 81))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (63, 81))	('CM', 'Chemical', '-', (49, 51))	('NF1', 'Gene', (120, 123))	('CM', 'Chemical', '-', (153, 155))	('NF1', 'Gene', '4763', (120, 123))	('BRAF-mutated', 'Var', (93, 105))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
153301	33389937	As for other mutations that were detected in CM, whole exome sequencing in excised material of 5 CM patients showed that in addition to BRAF, NRAS, and NF1 mutations, CM harbors previously unreported mutations in EGFR, APC, TERT, and other cancer-associated genes and the C T mutation signature consistent with UV-induced DNA damage.	('NF1', 'Gene', (152, 155))	('mutations', 'Var', (200, 209))	('NRAS', 'Gene', '4893', (142, 146))	('CM', 'Chemical', '-', (45, 47))	('patients', 'Species', '9606', (100, 108))	('cancer', 'Disease', (240, 246))	('EGFR', 'Gene', '1956', (213, 217))	('CM', 'Phenotype', 'HP:0007716', (167, 169))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('CM', 'Chemical', '-', (167, 169))	('NRAS', 'Gene', (142, 146))	('CM', 'Phenotype', 'HP:0007716', (97, 99))	('mutations', 'Var', (156, 165))	('TERT', 'Gene', (224, 228))	('APC', 'Disease', 'MESH:D011125', (219, 222))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('TERT', 'Gene', '7015', (224, 228))	('CM', 'Chemical', '-', (97, 99))	('APC', 'Disease', (219, 222))	('APC', 'cellular_component', 'GO:0005680', ('219', '222'))	('EGFR', 'molecular_function', 'GO:0005006', ('213', '217'))	('NF1', 'Gene', '4763', (152, 155))	('EGFR', 'Gene', (213, 217))	('DNA', 'cellular_component', 'GO:0005574', ('322', '325'))	('CM', 'Phenotype', 'HP:0007716', (45, 47))
153304	33389937	Four tumor suppressor genes (NEURL1, SUFU, PDCD4, C10orf90) which were affected by deletions of chromosome 10q24.32-26.2 were found to be significantly related to CM metastasis.	('PDCD4', 'Gene', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('C10orf90', 'Gene', '118611', (50, 58))	('deletions', 'Var', (83, 92))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('5', '21'))	('SUFU', 'Gene', (37, 41))	('NEURL1', 'Gene', '9148', (29, 35))	('PDCD4', 'Gene', '27250', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor suppressor', 'biological_process', 'GO:0051726', ('5', '21'))	('CM metastasis', 'Disease', 'MESH:D009362', (163, 176))	('CM metastasis', 'Disease', (163, 176))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('C10orf90', 'Gene', (50, 58))	('SUFU', 'Gene', '51684', (37, 41))	('NEURL1', 'Gene', (29, 35))	('related', 'Reg', (152, 159))	('tumor', 'Disease', (5, 10))	('CM', 'Phenotype', 'HP:0007716', (163, 165))
153305	33389937	Deletions of 10q24.32-26.2 were also strongly associated with lymphatic invasion and increasing tumor thickness.	('lymphatic invasion', 'CPA', (62, 80))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('increasing', 'PosReg', (85, 95))	('10q24.32-26.2', 'Gene', (13, 26))	('tumor thickness', 'Disease', 'MESH:C535655', (96, 111))	('tumor thickness', 'Disease', (96, 111))	('associated with', 'Reg', (46, 61))	('Deletions', 'Var', (0, 9))
153322	33066024	Digital pathology analysis identified that high expression of CysLT1 in primary UM is associated with reduced disease-specific survival (p = 0.012; HR 2.76; 95% CI 1.21-6.3) and overall survival (p = 0.011; HR 1.46; 95% CI 0.67-3.17).	('high expression', 'Var', (43, 58))	('CysLT1', 'Gene', (62, 68))	('6.3', 'Gene', '55558', (169, 172))	('disease-specific survival', 'CPA', (110, 135))	('reduced', 'NegReg', (102, 109))	('overall survival', 'CPA', (178, 194))	('6.3', 'Gene', (169, 172))
153328	33066024	These preclinical data suggest that antagonism of CysLT1, but not CysLT2, may be of therapeutic interest in the treatment of UM.	('CysLT2', 'Gene', '57105', (66, 72))	('antagonism', 'Var', (36, 46))	('CysLT2', 'Gene', (66, 72))	('CysLT1', 'Gene', (50, 56))
153334	33066024	Activating mutations in GNAQ or GNA11 are found in >80% of all UMs, with mutations in CYSLTR2 or PLCB4 likely to account for an additional 8-10% of activating UM mutations.	('PLCB4', 'Gene', (97, 102))	('mutations', 'Var', (11, 20))	('CYSLTR2', 'Gene', '57105', (86, 93))	('GNAQ', 'Gene', '2776', (24, 28))	('GNA11', 'Gene', '2767', (32, 37))	('GNA11', 'Gene', (32, 37))	('CYSLTR2', 'Gene', (86, 93))	('UMs', 'Disease', (63, 66))	('GNAQ', 'Gene', (24, 28))	('PLCB4', 'Gene', '5332', (97, 102))	('mutations', 'Var', (73, 82))
153347	33066024	Interestingly, colorectal and breast cancer patients with high expression of CysLT1 have a poor prognosis and reduced survival, respectively.	('survival', 'MPA', (118, 126))	('patients', 'Species', '9606', (44, 52))	('reduced', 'NegReg', (110, 117))	('colorectal and breast cancer', 'Disease', 'MESH:D001943', (15, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('high expression', 'Var', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('CysLT1', 'Gene', (77, 83))
153348	33066024	In contrast, a recurrent, hotspot mutation in CYSLTR2 is a driver oncogene in a small subset of UM.	('CYSLTR2', 'Gene', '57105', (46, 53))	('CYSLTR2', 'Gene', (46, 53))	('mutation', 'Var', (34, 42))	('hotspot', 'PosReg', (26, 33))
153349	33066024	This mutation encodes a p.Leu129Gln substitution, which leads to constitutive activation of endogenous Galphaq signalling and promotes tumorigenesis in vivo.	('Galphaq', 'Gene', (103, 110))	('promotes', 'PosReg', (126, 134))	('p.Leu129Gln', 'Mutation', 'p.L129Q', (24, 35))	('Galphaq', 'Gene', '2776', (103, 110))	('activation', 'PosReg', (78, 88))	('p.Leu129Gln', 'Var', (24, 35))	('signalling', 'biological_process', 'GO:0023052', ('111', '121'))	('tumorigenesis', 'CPA', (135, 148))
153350	33066024	The same Leu129Gln hotspot mutation in CYSLTR2 has also been identified in blue nevi, and in leptomeningeal melanocytic tumours confirming the oncogenic properties of constitutively active signalling through this receptor.	('signalling', 'biological_process', 'GO:0023052', ('189', '199'))	('blue nevi', 'Disease', (75, 84))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('Leu129Gln', 'Var', (9, 18))	('Leu129Gln', 'Chemical', '-', (9, 18))	('blue nevi', 'Phenotype', 'HP:0100814', (75, 84))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('nevi', 'Phenotype', 'HP:0003764', (80, 84))	('leptomeningeal melanocytic tumours', 'Disease', 'MESH:D008577', (93, 127))	('CYSLTR2', 'Gene', '57105', (39, 46))	('identified', 'Reg', (61, 71))	('leptomeningeal melanocytic tumours', 'Disease', (93, 127))	('CYSLTR2', 'Gene', (39, 46))
153355	33066024	Additionally, high expression of CysLT1 in primary UM is significantly associated with reduced melanoma-specific survival and overall survival.	('overall survival', 'CPA', (126, 142))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('reduced', 'NegReg', (87, 94))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('high', 'Var', (14, 18))	('CysLT1', 'Gene', (33, 39))
153356	33066024	CysLT1 antagonists alter survival, long-term proliferation, metabolism, and the secretion of pro-inflammatory and pro-angiogenic factors in in vitro UM cell line models and can promote anti-cancer activity in in vivo zebrafish xenograft models of UM.	('secretion of pro-inflammatory', 'MPA', (80, 109))	('alter', 'Reg', (19, 24))	('promote', 'PosReg', (177, 184))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('zebrafish', 'Species', '7955', (217, 226))	('survival', 'CPA', (25, 33))	('CysLT1', 'Gene', (0, 6))	('long-term proliferation', 'CPA', (35, 58))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('secretion', 'biological_process', 'GO:0046903', ('80', '89'))	('metabolism', 'CPA', (60, 70))	('antagonists', 'Var', (7, 18))	('metabolism', 'biological_process', 'GO:0008152', ('60', '70'))
153364	33066024	Interestingly, the same profiles plus glycolysis showed an altered expression in samples with high expression of CYSLTR2 (Figure 1F).	('altered', 'Reg', (59, 66))	('CYSLTR2', 'Gene', (113, 120))	('expression', 'MPA', (67, 77))	('high expression', 'Var', (94, 109))	('CYSLTR2', 'Gene', '57105', (113, 120))	('glycolysis', 'biological_process', 'GO:0006096', ('38', '48'))
153366	33066024	When the models were adjusted by the stromal infiltration scores from ESTIMATE, there was no statistically significant relationship between high CYSLTR1 expression and disease-free survival (Figure S1A) or overall survival (Figure S1B) (p = 0.57 and p = 0.075, respectively).	('CYSLTR1', 'Gene', '10800', (145, 152))	('high', 'Var', (140, 144))	('disease-free survival', 'CPA', (168, 189))	('CYSLTR1', 'Gene', (145, 152))	('expression', 'MPA', (153, 163))	('overall survival', 'CPA', (206, 222))
153367	33066024	However, high expression of CYSLTR2 maintains a statistically significant relationship with disease-free survival (Figure S1C) and overall survival (Figure S1D) (p = 0.004 and p = 0.00027, respectively).	('high expression', 'Var', (9, 24))	('CYSLTR2', 'Gene', '57105', (28, 35))	('overall survival', 'CPA', (131, 147))	('CYSLTR2', 'Gene', (28, 35))	('disease-free survival', 'CPA', (92, 113))
153378	33066024	However, high CysLT1 expression showed a robust trend towards reduced patient survival (Figure 2B).	('CysLT1', 'Gene', (14, 20))	('patient', 'Species', '9606', (70, 77))	('expression', 'MPA', (21, 31))	('patient survival', 'CPA', (70, 86))	('reduced', 'NegReg', (62, 69))	('high', 'Var', (9, 13))
153379	33066024	In agreement with TCGA data, manual analysis of the UM TMA at the median cut-off revealed a statistically significant relationship between high CysLT1 expression and overall survival in UM patients (p = 0.034; HR 2.34; 95% CI 1.04-5.25) (Figure 2C).	('expression', 'MPA', (151, 161))	('overall survival', 'CPA', (166, 182))	('significant relationship', 'Reg', (106, 130))	('patients', 'Species', '9606', (189, 197))	('CysLT1', 'Gene', (144, 150))	('high', 'Var', (139, 143))
153380	33066024	High CysLT1 expression also had a statistically significant relationship with ciliary body involvement in the UM patient cohort (p = 0.041) (Figure S2D).	('significant relationship', 'Reg', (48, 72))	('patient', 'Species', '9606', (113, 120))	('High', 'Var', (0, 4))	('ciliary body involvement', 'Disease', (78, 102))	('expression', 'MPA', (12, 22))	('CysLT1', 'Gene', (5, 11))
153383	33066024	There was no statistically significant relationship between high or low CysLT1 expression and other clinical features of disease (extraocular extension, monosomy 3, periodic acid-Schiff positive loops, or epithelioid cell morphology) examined (Figure S2D).	('high', 'Var', (60, 64))	('CysLT1', 'Gene', (72, 78))	('low', 'NegReg', (68, 71))	('monosomy 3', 'Disease', (153, 163))	('periodic acid', 'Chemical', 'MESH:D010504', (165, 178))
153384	33066024	Manual analysis did not identify a statistically significant relationship between high or low CysLT2 expression and clinical features of the disease examined (Figure S2D).	('CysLT2', 'Gene', (94, 100))	('low', 'NegReg', (90, 93))	('CysLT2', 'Gene', '57105', (94, 100))	('high', 'Var', (82, 86))
153385	33066024	A wider scoring range achieved by digital pathology analysis of this TMA (Figure 3A) strengthened the relationship between high CysLT1 expression and patient survival.	('patient', 'Species', '9606', (150, 157))	('strengthened', 'PosReg', (85, 97))	('high', 'Var', (123, 127))	('CysLT1', 'Gene', (128, 134))	('patient survival', 'CPA', (150, 166))
153386	33066024	With a 3rd quartile segregation, high expression of CysLT1 is significantly associated with reduced melanoma-specific survival (p = 0.0012; HR 2.76; 95% CI 1.21-6.3) and reduced overall survival (p = 0.0011; HR 2.76; 95% CI 1.21-6.3) in this primary UM cohort (Figure 3B,C, respectively).	('6.3', 'Gene', '55558', (161, 164))	('high expression', 'Var', (33, 48))	('CysLT1', 'Gene', (52, 58))	('6.3', 'Gene', (161, 164))	('reduced', 'NegReg', (170, 177))	('6.3', 'Gene', '55558', (229, 232))	('reduced', 'NegReg', (92, 99))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('overall', 'MPA', (178, 185))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('6.3', 'Gene', (229, 232))
153388	33066024	Gene expression data from TCGA suggest that high expression of CYSLTR2 is significantly linked to overall survival in UM patients.	('high', 'Var', (44, 48))	('CYSLTR2', 'Gene', '57105', (63, 70))	('linked to', 'Reg', (88, 97))	('CYSLTR2', 'Gene', (63, 70))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('overall', 'MPA', (98, 105))	('patients', 'Species', '9606', (121, 129))
153390	33066024	Data from both TCGA and the UM patient TMA suggest a link between high CysLT1 expression and patient survival.	('expression', 'MPA', (78, 88))	('patient survival', 'CPA', (93, 109))	('patient', 'Species', '9606', (31, 38))	('patient', 'Species', '9606', (93, 100))	('CysLT1', 'Gene', (71, 77))	('high', 'Var', (66, 70))
153391	33066024	A significant relationship between high CysLT1 expression and melanoma-specific survival, as well as overall survival, was confirmed by this data.	('melanoma', 'Disease', (62, 70))	('CysLT1', 'Gene', (40, 46))	('high', 'Var', (35, 39))	('expression', 'MPA', (47, 57))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
153392	33066024	Interestingly, high expression of CysLT1 was significantly associated with ciliary body involvement, further suggesting a potential link between receptor expression and patient prognosis.	('high', 'Var', (15, 19))	('associated', 'Reg', (59, 69))	('patient', 'Species', '9606', (169, 176))	('ciliary body involvement', 'Disease', (75, 99))	('CysLT1', 'Gene', (34, 40))
153395	33066024	Both Mel270 and OMM2.5 are GNAQ Q209P positive cell lines, while Mel285 is negative for both GNAQ and GNA11 mutations (Figure 4E).	('Q209P', 'Var', (32, 37))	('GNAQ', 'Gene', '2776', (27, 31))	('Q209P', 'Mutation', 'rs121913492', (32, 37))	('GNA11', 'Gene', (102, 107))	('GNAQ', 'Gene', '2776', (93, 97))	('GNA11', 'Gene', '2767', (102, 107))	('GNAQ', 'Gene', (27, 31))	('Mel285', 'Chemical', '-', (65, 71))	('GNAQ', 'Gene', (93, 97))
153402	33066024	In contrast, quininib and 1,4-dihydroxy quininib resulted in a dose-dependent reduction in Mel285 cell number with 50 microM quininib resulting in a 70.8% reduction in cell number (p = 0.029) and 20 microM 1,4-dihydroxy quininib reducing cell number by 61.8% (p = 0.027) after 24 h (Figure 5A).	('Mel285 cell number', 'CPA', (91, 109))	('quininib', 'Chemical', 'MESH:C000620980', (220, 228))	('cell number', 'CPA', (168, 179))	('Mel285', 'Chemical', '-', (91, 97))	('1,4-dihydroxy quininib', 'Chemical', '-', (26, 48))	('quininib', 'Chemical', 'MESH:C000620980', (40, 48))	('reduction', 'NegReg', (78, 87))	('quininib', 'Chemical', 'MESH:C000620980', (125, 133))	('cell number', 'CPA', (238, 249))	('1,4-dihydroxy quininib', 'Chemical', '-', (206, 228))	('reducing', 'NegReg', (229, 237))	('quininib', 'Var', (13, 21))	('reduction', 'NegReg', (155, 164))	('quininib', 'Chemical', 'MESH:C000620980', (13, 21))
153408	33066024	In Mel270 cells, following 96 h of drug treatment, HAMI 3379 still failed to significantly reduce cell number (Figure 5G).	('cell number', 'CPA', (98, 109))	('HAMI 3379', 'Var', (51, 60))	('reduce', 'NegReg', (91, 97))	('HAMI 3379', 'Chemical', 'MESH:C549635', (51, 60))
153425	33066024	There was a statistically significant reduction in clone survival in Mel285 cells treated with quininib for 96 h compared to those treated for 24 h (p = 0.0064) (Figure S3A).	('Mel285', 'Chemical', '-', (69, 75))	('reduction', 'NegReg', (38, 47))	('quininib', 'Var', (95, 103))	('clone survival', 'CPA', (51, 65))	('quininib', 'Chemical', 'MESH:C000620980', (95, 103))
153445	33066024	For example, in Mel285 cells, quininib decreases the secretion of inflammatory factors (IL-2 and IL-6) and increases the secretion of angiogenic factors (bFGF and VEGF-C).	('quininib', 'Chemical', 'MESH:C000620980', (30, 38))	('bFGF', 'Gene', '2247', (154, 158))	('secretion', 'biological_process', 'GO:0046903', ('121', '130'))	('quininib', 'Var', (30, 38))	('Mel285', 'Chemical', '-', (16, 22))	('increases', 'PosReg', (107, 116))	('secretion of angiogenic factors', 'MPA', (121, 152))	('VEGF-C', 'Gene', '7424', (163, 169))	('VEGF-C', 'Gene', (163, 169))	('IL-6', 'Gene', '3569', (97, 101))	('bFGF', 'Gene', (154, 158))	('IL-6', 'molecular_function', 'GO:0005138', ('97', '101'))	('IL-2', 'Gene', '3558', (88, 92))	('decreases', 'NegReg', (39, 48))	('IL-2', 'molecular_function', 'GO:0005134', ('88', '92'))	('secretion', 'biological_process', 'GO:0046903', ('53', '62'))	('IL-2', 'Gene', (88, 92))	('IL-6', 'Gene', (97, 101))
153446	33066024	In OMM2.5 cells, a similar upregulation of angiogenic factors was observed following treatment with quininib (Flt-1 and VEGF-A), but in profound contrast quininib increased the secretion of 8 inflammatory factors (IL-10, IL-12p70, IL-13, IL-1beta, IL-2, IL-6, IL-8, TNF-alpha) in OMM2.5 cells.	('secretion', 'MPA', (177, 186))	('Flt-1', 'Gene', (110, 115))	('IL-1beta', 'Gene', '3552', (238, 246))	('IL-13', 'Gene', '3596', (231, 236))	('IL-10', 'Gene', '3586', (214, 219))	('quininib', 'Var', (154, 162))	('VEGF-A', 'Gene', (120, 126))	('IL-10', 'Gene', (214, 219))	('quininib', 'Chemical', 'MESH:C000620980', (100, 108))	('increased', 'PosReg', (163, 172))	('IL-12', 'molecular_function', 'GO:0005143', ('221', '226'))	('IL-2', 'Gene', (248, 252))	('IL-8', 'Gene', '3576', (260, 264))	('TNF-alpha', 'Gene', '7124', (266, 275))	('IL-2', 'molecular_function', 'GO:0005134', ('248', '252'))	('TNF-alpha', 'Gene', (266, 275))	('IL-13', 'molecular_function', 'GO:0005144', ('231', '236'))	('IL-13', 'Gene', (231, 236))	('IL-6', 'molecular_function', 'GO:0005138', ('254', '258'))	('IL-1', 'molecular_function', 'GO:0005149', ('238', '242'))	('IL-1beta', 'Gene', (238, 246))	('Flt-1', 'Gene', '2321', (110, 115))	('VEGF-A', 'Gene', '7422', (120, 126))	('IL-6', 'Gene', '3569', (254, 258))	('secretion', 'biological_process', 'GO:0046903', ('177', '186'))	('quininib', 'Chemical', 'MESH:C000620980', (154, 162))	('IL-2', 'Gene', '3558', (248, 252))	('IL-8', 'Gene', (260, 264))	('IL-6', 'Gene', (254, 258))	('IL-10', 'molecular_function', 'GO:0005141', ('214', '219'))	('IL-8', 'molecular_function', 'GO:0005153', ('260', '264'))
153453	33066024	In Mel285 cells, quininib and 1,4-dihydroxy quininib significantly alter the OCR:ECAR ratio (p = 0.01) (Figure 9C) and reduce basal respiration (p = 0.01 and p = 0.05, respectively) (Figure 9D).	('quininib', 'Chemical', 'MESH:C000620980', (17, 25))	('alter', 'Reg', (67, 72))	('respiration', 'biological_process', 'GO:0007585', ('132', '143'))	('reduce', 'NegReg', (119, 125))	('quininib', 'Chemical', 'MESH:C000620980', (44, 52))	('OCR:ECAR ratio', 'MPA', (77, 91))	('Mel285', 'Chemical', '-', (3, 9))	('1,4-dihydroxy quininib', 'Chemical', '-', (30, 52))	('respiration', 'biological_process', 'GO:0045333', ('132', '143'))	('quininib', 'Var', (44, 52))	('basal respiration', 'MPA', (126, 143))	('OCR', 'Chemical', '-', (77, 80))
153455	33066024	In Mel285 cells, quininib significantly reduces ATP production (p = 0.001) (Figure 9E) and maximal respiration (p = 0.001) (Figure 9F).	('quininib', 'Var', (17, 25))	('quininib', 'Chemical', 'MESH:C000620980', (17, 25))	('maximal respiration', 'MPA', (91, 110))	('ATP production', 'MPA', (48, 62))	('respiration', 'biological_process', 'GO:0045333', ('99', '110'))	('Mel285', 'Chemical', '-', (3, 9))	('ATP', 'Chemical', 'MESH:D000255', (48, 51))	('reduces', 'NegReg', (40, 47))	('respiration', 'biological_process', 'GO:0007585', ('99', '110'))
153474	33066024	We identified that high CysLT1 expression is associated with survival of primary UM patients and that antagonism of CysLT1 alters cancer hallmarks in UM cells in vitro and in vivo.	('CysLT1', 'Gene', (24, 30))	('patients', 'Species', '9606', (84, 92))	('alters', 'Reg', (123, 129))	('cancer hallmarks', 'Disease', 'MESH:D009369', (130, 146))	('antagonism', 'Var', (102, 112))	('associated', 'Reg', (45, 55))	('expression', 'MPA', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('CysLT1', 'Gene', (116, 122))	('cancer hallmarks', 'Disease', (130, 146))
153479	33066024	TCGA data suggest that high expression of CYSLTR1 is associated with a poor patient prognosis in UM.	('patient', 'Species', '9606', (76, 83))	('high expression', 'Var', (23, 38))	('CYSLTR1', 'Gene', (42, 49))	('CYSLTR1', 'Gene', '10800', (42, 49))
153480	33066024	This finding was supported by the data generated at the protein level using the patient UM TMA, whereby CysLT1 was significantly associated with reduced melanoma-specific survival and reduced overall survival in a primary UM patient cohort.	('CysLT1', 'Var', (104, 110))	('reduced', 'NegReg', (145, 152))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', (153, 161))	('reduced', 'NegReg', (184, 191))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('overall', 'MPA', (192, 199))	('patient', 'Species', '9606', (225, 232))	('patient', 'Species', '9606', (80, 87))
153483	33066024	Of note, high CysLT1 expression is associated with poor prognosis and reduced survival in both colorectal and breast cancer, while CysLT2 has been reported to have an anti-tumorigenic effect in colorectal cancer.	('survival', 'CPA', (78, 86))	('reduced', 'NegReg', (70, 77))	('anti-tumorigenic effect', 'CPA', (167, 190))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('CysLT1', 'Gene', (14, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (194, 211))	('colorectal and breast cancer', 'Disease', 'MESH:D001943', (95, 123))	('expression', 'MPA', (21, 31))	('colorectal cancer', 'Phenotype', 'HP:0003003', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('CysLT2', 'Gene', '57105', (131, 137))	('CysLT2', 'Gene', (131, 137))	('colorectal cancer', 'Disease', (194, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('high', 'Var', (9, 13))
153487	33066024	Thus, further investigation using additional UM patient samples is warranted to determine if high CysLT1 or CysLT2 expression can be statistically associated with patient prognosis and metastatic disease development.	('associated', 'Reg', (147, 157))	('metastatic disease', 'Disease', (185, 203))	('patient', 'Species', '9606', (48, 55))	('expression', 'MPA', (115, 125))	('patient', 'Species', '9606', (163, 170))	('CysLT2', 'Gene', (108, 114))	('high', 'Var', (93, 97))	('CysLT2', 'Gene', '57105', (108, 114))	('metastatic disease', 'Disease', 'MESH:C538445', (185, 203))	('CysLT1', 'Gene', (98, 104))
153490	33066024	The CysLT2 antagonist HAMI 3379 was previously tested in Leu129Gln CysLT2 UM oncogene models but showed limited activity as an inverse agonist in these models of constitutive CysLT2 activation.	('CysLT2', 'Gene', (175, 181))	('Leu129Gln', 'Chemical', '-', (57, 66))	('HAMI 3379', 'Chemical', 'MESH:C549635', (22, 31))	('CysLT2', 'Gene', '57105', (175, 181))	('Leu129Gln', 'Var', (57, 66))	('CysLT2', 'Gene', '57105', (4, 10))	('CysLT2', 'Gene', (4, 10))	('CysLT2', 'Gene', '57105', (67, 73))	('CysLT2', 'Gene', (67, 73))
153509	33066024	For example, quininib treatment was associated with a significant increase in VEGF-C secretion from Mel285 cells, but not from OMM2.5 cells.	('increase', 'PosReg', (66, 74))	('secretion', 'MPA', (85, 94))	('VEGF-C', 'Gene', '7424', (78, 84))	('VEGF-C', 'Gene', (78, 84))	('Mel285', 'Chemical', '-', (100, 106))	('secretion', 'biological_process', 'GO:0046903', ('85', '94'))	('quininib', 'Var', (13, 21))	('quininib', 'Chemical', 'MESH:C000620980', (13, 21))
153510	33066024	1,4-dihydroxy quininib had negligible effects on VEGF-C secretion, but significantly increased Flt-1 in Mel285 in contrast to quininib which had no effect.	('quininib', 'Chemical', 'MESH:C000620980', (126, 134))	('VEGF-C', 'Gene', (49, 55))	('quininib', 'Var', (14, 22))	('Flt-1', 'Gene', '2321', (95, 100))	('quininib', 'Chemical', 'MESH:C000620980', (14, 22))	('1,4-dihydroxy quininib', 'Chemical', '-', (0, 22))	('Flt-1', 'Gene', (95, 100))	('VEGF-C', 'Gene', '7424', (49, 55))	('increased', 'PosReg', (85, 94))	('Mel285', 'Chemical', '-', (104, 110))	('secretion', 'biological_process', 'GO:0046903', ('56', '65'))
153513	33066024	For example, quininib significantly reduced the secretion of IL-2 in Mel285 cells, but significantly increased IL-2 secretion from OMM2.5 cells, whereas 1,4 -dihydroxy quininib exerted negligible effects on IL-2 in OMM2.5 cells.	('IL-2', 'Gene', (61, 65))	('increased', 'PosReg', (101, 110))	('quininib', 'Chemical', 'MESH:C000620980', (168, 176))	('1,4 -dihydroxy quininib', 'Chemical', '-', (153, 176))	('IL-2', 'Gene', '3558', (111, 115))	('secretion', 'MPA', (48, 57))	('quininib', 'Chemical', 'MESH:C000620980', (13, 21))	('IL-2', 'Gene', (207, 211))	('IL-2', 'molecular_function', 'GO:0005134', ('207', '211'))	('IL-2', 'Gene', '3558', (61, 65))	('secretion', 'MPA', (116, 125))	('IL-2', 'Gene', (111, 115))	('IL-2', 'molecular_function', 'GO:0005134', ('111', '115'))	('IL-2 secretion', 'biological_process', 'GO:0070970', ('111', '125'))	('quininib', 'Var', (13, 21))	('secretion', 'biological_process', 'GO:0046903', ('48', '57'))	('IL-2', 'molecular_function', 'GO:0005134', ('61', '65'))	('IL-2', 'Gene', '3558', (207, 211))	('reduced', 'NegReg', (36, 43))	('Mel285', 'Chemical', '-', (69, 75))
153516	33066024	Indeed, the basal expression of IL-13 and IL-8 is much higher in OMM2.5 than Mel285 cells.	('IL-13', 'molecular_function', 'GO:0005144', ('32', '37'))	('IL-8', 'molecular_function', 'GO:0005153', ('42', '46'))	('Mel285', 'Chemical', '-', (77, 83))	('IL-8', 'Gene', '3576', (42, 46))	('higher', 'PosReg', (55, 61))	('IL-13', 'Gene', (32, 37))	('basal expression', 'MPA', (12, 28))	('OMM2.5', 'Var', (65, 71))	('IL-8', 'Gene', (42, 46))	('IL-13', 'Gene', '3596', (32, 37))
153518	33066024	UM cell lines express IL-2R, and production of the IL-2 ligand by tumour infiltrating lymphocytes and macrophages stimulates tumour cell proliferation.	('IL-2', 'Gene', '3558', (51, 55))	('ligand', 'molecular_function', 'GO:0005488', ('56', '62'))	('IL-2', 'Gene', (51, 55))	('production', 'Var', (33, 43))	('IL-2', 'molecular_function', 'GO:0005134', ('51', '55'))	('IL-2', 'Gene', (22, 26))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('IL-2R', 'molecular_function', 'GO:0004911', ('22', '27'))	('IL-2R', 'Gene', '3559', (22, 27))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('cell proliferation', 'biological_process', 'GO:0008283', ('132', '150'))	('IL-2', 'Gene', '3558', (22, 26))	('tumour', 'Disease', (66, 72))	('tumour', 'Disease', (125, 131))	('stimulates', 'PosReg', (114, 124))	('IL-2R', 'Gene', (22, 27))
153519	33066024	IL-6 stimulates tumour cell proliferation and survival through the inhibition of apoptosis and interference with IL-6R signalling leads to decreased UM cell viability.	('IL-6', 'molecular_function', 'GO:0005138', ('0', '4'))	('stimulates', 'PosReg', (5, 15))	('survival', 'CPA', (46, 54))	('IL-6R', 'Gene', (113, 118))	('signalling', 'biological_process', 'GO:0023052', ('119', '129'))	('IL-6', 'Gene', '3569', (113, 117))	('cell proliferation', 'biological_process', 'GO:0008283', ('23', '41'))	('IL-6R', 'Gene', '3570', (113, 118))	('inhibition', 'NegReg', (67, 77))	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('67', '90'))	('IL-6', 'Gene', (113, 117))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('IL-6', 'Gene', '3569', (0, 4))	('IL-6R', 'molecular_function', 'GO:0004915', ('113', '118'))	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('tumour', 'Disease', (16, 22))	('interference', 'Var', (95, 107))	('apoptosis', 'CPA', (81, 90))	('UM cell viability', 'CPA', (149, 166))	('decreased', 'NegReg', (139, 148))	('IL-6', 'Gene', (0, 4))
153526	33066024	LTD4 increases mitochondrial metabolic activity and mitochondrial gene transcription in human intestinal epithelial cells and colorectal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('LTD4', 'Var', (0, 4))	('colorectal cancer', 'Disease', (126, 143))	('LTD', 'biological_process', 'GO:0060292', ('0', '3'))	('mitochondrial metabolic activity', 'MPA', (15, 47))	('increases', 'PosReg', (5, 14))	('LTD4', 'Chemical', 'MESH:D017998', (0, 4))	('colorectal cancer', 'Disease', 'MESH:D015179', (126, 143))	('transcription', 'biological_process', 'GO:0006351', ('71', '84'))	('human', 'Species', '9606', (88, 93))	('mitochondrial', 'MPA', (52, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))
153527	33066024	Significantly decreased oxidative phosphorylation was observed in Mel285 and OMM2.5 cells with quininib or 1,4-dihydroxy quininib and OMM2.5 cells with montelukast.	('quininib', 'Chemical', 'MESH:C000620980', (95, 103))	('decreased', 'NegReg', (14, 23))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('24', '49'))	('montelukast', 'Chemical', 'MESH:C093875', (152, 163))	('quininib', 'Chemical', 'MESH:C000620980', (121, 129))	('Mel285', 'Chemical', '-', (66, 72))	('1,4-dihydroxy quininib', 'Chemical', '-', (107, 129))	('quininib', 'Var', (95, 103))	('oxidative phosphorylation', 'MPA', (24, 49))
153528	33066024	Modulation of oxidative phosphorylation controls proliferation of tumour cells which may explain the effect of CysLT1 antagonists on UM cells.	('Modulation', 'Var', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('proliferation', 'CPA', (49, 62))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (66, 72))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('14', '39'))	('oxidative phosphorylation', 'MPA', (14, 39))
153577	33066024	H-score was used as the image analysis output, which was calculated using the following formula: [1x (% of weakly positive cells) + 2x (% of moderately strong positive cells) + 3x (% strong positive cells)], where the H-score of 0-100 was generally categorized as low expression, 101-200 as intermediate expression, and 201-300 as high expression of CysLT1 and CysLT2 (Figure 3A).	('101-200', 'Var', (280, 287))	('CysLT2', 'Gene', '57105', (361, 367))	('CysLT1', 'Gene', (350, 356))	('CysLT2', 'Gene', (361, 367))
153590	33066024	Embryos with tumour cells erroneously implanted in the yolk, brain, or circulation were removed.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('erroneously', 'Var', (26, 37))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('yolk', 'cellular_component', 'GO:0060417', ('55', '59'))	('tumour', 'Disease', (13, 19))
153608	33066024	For the first time, we examine the clinical relevance of CysLT1 and CysLT2 expression and in primary UM samples and show a link between high CysLT1 expression and primary UM patient survival.	('patient', 'Species', '9606', (174, 181))	('CysLT1', 'Gene', (141, 147))	('high', 'Var', (136, 140))	('link', 'Reg', (123, 127))	('CysLT2', 'Gene', '57105', (68, 74))	('primary UM', 'Disease', (163, 173))	('CysLT2', 'Gene', (68, 74))	('CysLT1', 'Gene', (57, 63))	('expression', 'MPA', (148, 158))
153611	33066024	The importance of the cysteinyl leukotriene receptor signalling pathway, and antagonism of CysLT1, in UM should be further explored.	('cysteinyl leukotriene receptor signalling pathway', 'Pathway', (22, 71))	('antagonism', 'Var', (77, 87))	('cysteinyl leukotriene', 'Chemical', 'MESH:C112381', (22, 43))	('signalling pathway', 'biological_process', 'GO:0007165', ('53', '71'))	('CysLT1', 'Gene', (91, 97))
153622	32274887	The catalyst for the development of targeted therapy modalities was the identification of activating NRAS mutations and BRAF mutations in 1984 and 2002, respectively, which paved the way for molecular stratification of the melanoma patient population.	('melanoma', 'Disease', (223, 231))	('mutations', 'Var', (125, 134))	('NRAS', 'Gene', (101, 105))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('men', 'Species', '9606', (28, 31))	('BRAF', 'Gene', '673', (120, 124))	('NRAS', 'Gene', '4893', (101, 105))	('BRAF', 'Gene', (120, 124))	('activating', 'PosReg', (90, 100))	('mutations', 'Var', (106, 115))	('patient', 'Species', '9606', (232, 239))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))
153623	32274887	Approximately 45%-50% of non-acral lentiginous (AL) cutaneous melanoma patients have tumors that harbor activating BRAF mutations, with a single amino acid substitution of valine for glutamic acid at codon 600 (V600E) occurring in 90% of cases (Figure 1a).	('BRAF', 'Gene', '673', (115, 119))	('cutaneous melanoma', 'Disease', (52, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (52, 70))	('BRAF', 'Gene', (115, 119))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('patients', 'Species', '9606', (71, 79))	('valine for glutamic acid at codon 600', 'Mutation', 'rs113488022', (172, 209))	('V600E', 'Mutation', 'rs113488022', (211, 216))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('AL', 'Chemical', '-', (48, 50))	('activating', 'PosReg', (104, 114))	('mutations', 'Var', (120, 129))	('V600E', 'Var', (211, 216))	('non-acral lentiginous', 'Disease', (25, 46))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
153624	32274887	Activating NRAS mutations at codon 12, 13, or 61 are detectable in 15%-20% of non-AL cutaneous melanoma patients and serve as an independent predictor of worse patient overall survival.	('Activating', 'PosReg', (0, 10))	('NRAS', 'Gene', '4893', (11, 15))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('AL cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 103))	('AL cutaneous melanoma', 'Disease', (82, 103))	('mutations', 'Var', (16, 25))	('patient', 'Species', '9606', (104, 111))	('patient', 'Species', '9606', (160, 167))	('NRAS', 'Gene', (11, 15))	('patients', 'Species', '9606', (104, 112))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))
153626	32274887	To date, it remains unclear whether the same melanoma cell can harbor both a BRAF and an NRAS mutation, or at the single-cell level, these mutations are indeed mutually exclusive.	('NRAS', 'Gene', '4893', (89, 93))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (77, 81))	('NRAS', 'Gene', (89, 93))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('mutation', 'Var', (94, 102))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
153627	32274887	With discoveries revealing that ~70% of non-AL cutaneous melanomas contain mutations constitutively activating the mitogen-activated protein kinase (MAPK) pathway came intense development of inhibitors capable of targeting various nodes of the mitogen-activated protein kinase (MAPK) pathway (i.e., BRAF, MEK, and ERK inhibitors) that continues to date.	('ERK', 'Gene', '5594', (314, 317))	('ERK', 'molecular_function', 'GO:0004707', ('314', '317'))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (47, 65))	('MEK', 'Gene', '5609', (305, 308))	('men', 'Species', '9606', (183, 186))	('ERK', 'Gene', (314, 317))	('MAPK', 'molecular_function', 'GO:0004707', ('149', '153'))	('BRAF', 'Gene', '673', (299, 303))	('MEK', 'Gene', (305, 308))	('BRAF', 'Gene', (299, 303))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (47, 66))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (47, 66))	('AL cutaneous melanoma', 'Disease', 'MESH:C562393', (44, 65))	('AL cutaneous melanoma', 'Disease', (44, 65))	('activating', 'PosReg', (100, 110))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('protein', 'cellular_component', 'GO:0003675', ('262', '269'))	('MAPK', 'molecular_function', 'GO:0004707', ('278', '282'))	('cutaneous melanomas', 'Disease', (47, 66))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('mutations', 'Var', (75, 84))
153628	32274887	The first targeted therapy approved for the treatment of patients with BRAFV600E/K mutant melanoma was the small molecule inhibitor vemurafenib, an agent designed to have high specificity against the mutant V600E, V600K, V600D, and V600R forms of BRAF.	('melanoma', 'Disease', (90, 98))	('V600E', 'Var', (207, 212))	('V600D', 'Mutation', 'rs121913377', (221, 226))	('BRAFV600E', 'Mutation', 'rs113488022', (71, 80))	('men', 'Species', '9606', (49, 52))	('V600D', 'Var', (221, 226))	('BRAF', 'Gene', '673', (71, 75))	('V600R', 'Mutation', 'rs121913227', (232, 237))	('V600E', 'Mutation', 'rs113488022', (75, 80))	('BRAF', 'Gene', (71, 75))	('V600K', 'Var', (214, 219))	('V600E/K', 'Mutation', 'rs113488022', (75, 82))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('BRAF', 'Gene', '673', (247, 251))	('patients', 'Species', '9606', (57, 65))	('V600E', 'Mutation', 'rs113488022', (207, 212))	('vemurafenib', 'Chemical', 'MESH:D000077484', (132, 143))	('BRAF', 'Gene', (247, 251))	('V600R', 'Var', (232, 237))	('V600K', 'Mutation', 'rs121913227', (214, 219))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
153632	32274887	For patients with wild-type BRAF, treatment with BRAF inhibitors that specifically target V600E/K mutant BRAF may increase melanoma aggressiveness due to the paradoxical activation of wild-type BRAF and downstream MAPK pathway signaling.	('melanoma aggressiveness', 'Disease', (123, 146))	('aggressiveness', 'Phenotype', 'HP:0000718', (132, 146))	('signaling', 'biological_process', 'GO:0023052', ('227', '236'))	('MAPK', 'molecular_function', 'GO:0004707', ('214', '218'))	('V600E', 'SUBSTITUTION', 'None', (90, 95))	('activation', 'PosReg', (170, 180))	('patients', 'Species', '9606', (4, 12))	('increase', 'PosReg', (114, 122))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('men', 'Species', '9606', (39, 42))	('BRAF', 'Gene', '673', (28, 32))	('BRAF', 'Gene', (28, 32))	('BRAF', 'Gene', '673', (105, 109))	('BRAF', 'Gene', '673', (194, 198))	('BRAF', 'Gene', (194, 198))	('BRAF', 'Gene', (105, 109))	('V600E', 'Var', (90, 95))	('melanoma aggressiveness', 'Disease', 'MESH:D008545', (123, 146))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', (49, 53))
153661	32274887	A 2009 SEER study found the overall incidence rates of AL melanoma were similar between non-Hispanic Whites and Blacks; however, Hispanic Whites have statistically higher incidence rates relative to non-Hispanic Whites.	('AL melanoma', 'Disease', 'MESH:D009101', (55, 66))	('higher', 'PosReg', (164, 170))	('Hispanic Whites', 'Var', (129, 144))	('AL melanoma', 'Disease', (55, 66))	('incidence', 'MPA', (171, 180))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
153668	32274887	BRAF mutations in are found in 1 in every 5 Al melanoma patients, leaving ~80% ineligible to receive BRAF inhibitor and combination BRAF/MEK inhibitor strategies (; Figure 1b).	('BRAF', 'Gene', (101, 105))	('BRAF', 'Gene', (132, 136))	('patients', 'Species', '9606', (56, 64))	('MEK', 'Gene', (137, 140))	('MEK', 'Gene', '5609', (137, 140))	('mutations in', 'Var', (5, 17))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (101, 105))	('BRAF', 'Gene', '673', (132, 136))
153670	32274887	80% of AL melanomas display genetic aberrations of cyclin-dependent kinase 4/6 (CDK4/6) pathway-related genes (i.e., amplification of CDK4 and CCND1, and/or loss of CDK2NA), representing the most frequent copy number alteration detected.	('CDK4', 'Gene', (80, 84))	('CDK', 'molecular_function', 'GO:0004693', ('165', '168'))	('CDK', 'molecular_function', 'GO:0004693', ('134', '137'))	('CDK4', 'Gene', '1019', (80, 84))	('CCND1', 'Gene', '595', (143, 148))	('CDK2NA', 'Gene', '1017', (165, 171))	('CDK', 'molecular_function', 'GO:0004693', ('80', '83'))	('cyclin', 'molecular_function', 'GO:0016538', ('51', '57'))	('AL melanomas', 'Disease', (7, 19))	('CDK2NA', 'Gene', (165, 171))	('CDK4', 'Gene', '1019', (134, 138))	('CCND1', 'Gene', (143, 148))	('CDK4', 'Gene', (134, 138))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('loss', 'NegReg', (157, 161))	('AL melanomas', 'Disease', 'MESH:D009101', (7, 19))	('amplification', 'Var', (117, 130))
153671	32274887	Additionally, activating KIT mutations are present in ~6% of cases.	('KIT', 'Gene', (25, 28))	('mutations', 'Var', (29, 38))	('activating', 'PosReg', (14, 24))	('KIT', 'Gene', '3815', (25, 28))	('KIT', 'molecular_function', 'GO:0005020', ('25', '28'))
153672	32274887	AL melanoma displays similar incidence of NRAS mutations as non-AL cutaneous melanoma, detectable in 15%-28% of AL melanoma patients, and NRAS mutations are an independent prognostic factor of worse overall survival.	('NRAS', 'Gene', '4893', (42, 46))	('AL melanoma', 'Disease', 'MESH:D009101', (112, 123))	('NRAS', 'Gene', '4893', (138, 142))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('AL cutaneous melanoma', 'Disease', 'MESH:C562393', (64, 85))	('AL cutaneous melanoma', 'Disease', (64, 85))	('AL melanoma', 'Disease', 'MESH:D009101', (0, 11))	('mutations', 'Var', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('AL melanoma', 'Disease', (112, 123))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (67, 85))	('AL melanoma', 'Disease', (0, 11))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('NRAS', 'Gene', (42, 46))	('patients', 'Species', '9606', (124, 132))	('mutations', 'Var', (143, 152))	('NRAS', 'Gene', (138, 142))
153678	32274887	Although AL melanoma patients with Kit mutations can be treated with a KIT inhibitor per National Comprehensive Cancer Network (NCCN) guidelines, resistance mechanisms that reactivate downstream MAPK and PI3K pathway signaling have been suggested to blunt long-term durability (Table 1).	('KIT', 'Gene', '3815', (71, 74))	('patients', 'Species', '9606', (21, 29))	('AL melanoma', 'Disease', (9, 20))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('reactivate', 'NegReg', (173, 183))	('PI3K', 'molecular_function', 'GO:0016303', ('204', '208'))	('blunt', 'NegReg', (250, 255))	('mutations', 'Var', (39, 48))	('AL melanoma', 'Disease', 'MESH:D009101', (9, 20))	('MAPK', 'molecular_function', 'GO:0004707', ('195', '199'))	('Cancer', 'Disease', (112, 118))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('KIT', 'Gene', (71, 74))	('Kit', 'Gene', (35, 38))	('Cancer', 'Disease', 'MESH:D009369', (112, 118))	('KIT', 'molecular_function', 'GO:0005020', ('71', '74'))	('signaling', 'biological_process', 'GO:0023052', ('217', '226'))	('Kit', 'Gene', '3815', (35, 38))	('PI3K pathway signaling', 'Pathway', (204, 226))
153679	32274887	Due to the high percentage of AL melanoma tumors with CDK4/6-pathway aberrations, CDK4/6 inhibition represents one of the most promising targeted therapy strategies for AL melanomas clinically (NCT03454919).	('AL melanomas', 'Disease', (169, 181))	('AL melanoma tumors', 'Disease', (30, 48))	('aberrations', 'Var', (69, 80))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('AL melanomas', 'Disease', 'MESH:D009101', (169, 181))	('CDK4', 'Gene', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('CDK', 'molecular_function', 'GO:0004693', ('82', '85'))	('CDK4', 'Gene', '1019', (82, 86))	('CDK4', 'Gene', (82, 86))	('CDK4', 'Gene', '1019', (54, 58))	('CDK', 'molecular_function', 'GO:0004693', ('54', '57'))	('AL melanoma tumors', 'Disease', 'MESH:D009101', (30, 48))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanomas', 'Phenotype', 'HP:0002861', (172, 181))
153689	32274887	This is in contrast to non-AL cutaneous melanomas where <10% of BRAF mutations are outside of the V600 codon, and more closely resembles the high prevalence of non-V600 mutations found in 48% of lung adenocarcinomas.	('mutations', 'Var', (69, 78))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (195, 215))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (195, 215))	('cutaneous melanomas', 'Disease', (30, 49))	('BRAF', 'Gene', '673', (64, 68))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('BRAF', 'Gene', (64, 68))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (30, 49))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (30, 49))	('AL cutaneous melanoma', 'Disease', 'MESH:C562393', (27, 48))	('AL cutaneous melanoma', 'Disease', (27, 48))	('lung adenocarcinomas', 'Disease', (195, 215))
153690	32274887	A closer analysis of the most common non-V600 mutations reveals (a) a difference between the frequency of mutations on D594, G469, and K601 between non-AL cutaneous melanomas and MMs, and (b) convergence in the non-V600 mutational landscape between MM and lung cancers where mutations are often associated with genotoxic agents.	('AL cutaneous melanoma', 'Disease', 'MESH:C562393', (152, 173))	('AL cutaneous melanoma', 'Disease', (152, 173))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (155, 174))	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('lung cancers', 'Disease', 'MESH:D008175', (256, 268))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (155, 174))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (155, 173))	('lung cancers', 'Phenotype', 'HP:0100526', (256, 268))	('cutaneous melanomas', 'Disease', (155, 174))	('MMs', 'Disease', (179, 182))	('melanomas', 'Phenotype', 'HP:0002861', (165, 174))	('mutations', 'Var', (106, 115))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('lung cancers', 'Disease', (256, 268))	('D594', 'Var', (119, 123))	('G469', 'Var', (125, 129))	('K601', 'Var', (135, 139))
153692	32274887	There is also a divergence in the location of NRAS mutations between MM and cutaneous melanoma, with 54% located on codon 61 in MM versus 88% in cutaneous melanoma, and 46% located on codons 12 and 13 in MM versus 12% for cutaneous melanomas.	('mutations', 'Var', (51, 60))	('NRAS', 'Gene', '4893', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (222, 241))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (222, 240))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (222, 241))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (222, 240))	('located', 'Reg', (173, 180))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('cutaneous melanomas', 'Disease', (222, 241))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('NRAS', 'Gene', (46, 50))	('cutaneous melanoma', 'Disease', (76, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (76, 94))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (76, 94))	('cutaneous melanoma', 'Disease', (145, 163))	('melanomas', 'Phenotype', 'HP:0002861', (232, 241))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (145, 163))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (145, 163))	('located', 'Reg', (105, 112))
153693	32274887	Approximately 7%-22% of MMs have v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) somatic mutations or amplifications.	('amplifications', 'Var', (122, 136))	('kit', 'Gene', (35, 38))	('kit', 'Gene', '3815', (35, 38))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('KIT', 'molecular_function', 'GO:0005020', ('96', '99'))	('sarcoma', 'Disease', (64, 71))	('KIT', 'Gene', '3815', (96, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('MMs', 'Disease', (24, 27))	('KIT', 'Gene', (96, 99))
153694	32274887	MMs located in the genital area appear to be driven by mutations in SF3B1 which encodes the subunit 1 of splicing factor 3b, a component of the spliceosome that processes pre-mRNA into mature transcripts.	('splicing', 'biological_process', 'GO:0045292', ('105', '113'))	('mutations', 'Var', (55, 64))	('SF3B1', 'Gene', (68, 73))	('pre', 'molecular_function', 'GO:0003904', ('171', '174'))	('driven by', 'Reg', (45, 54))	('MMs', 'Disease', (0, 3))	('SF3B1', 'Gene', '23451', (68, 73))	('spliceosome', 'cellular_component', 'GO:0005681', ('144', '155'))
153695	32274887	A recent study analyzing the mutational landscape of MM identified IGF2R mutations in 31.7% of MM samples relative to 6.3% of SSM cases.	('mutations', 'Var', (73, 82))	('IGF2R', 'Gene', (67, 72))	('IGF2R', 'Gene', '3482', (67, 72))	('SSM', 'cellular_component', 'GO:1990843', ('126', '129'))
153701	32274887	Clinical trials targeting KIT with imatinib show no clear effect in unselected metastatic melanoma patient populations, but encouraging clinical benefit has been observed with KIT inhibition specifically in patients with melanomas harboring KIT mutations (not in patients whose melanoma harbor KIT amplification only; Table 1).	('KIT', 'Gene', '3815', (176, 179))	('melanoma', 'Disease', (90, 98))	('melanomas', 'Phenotype', 'HP:0002861', (221, 230))	('KIT', 'Gene', '3815', (294, 297))	('KIT', 'molecular_function', 'GO:0005020', ('294', '297'))	('patient', 'Species', '9606', (207, 214))	('inhibition', 'NegReg', (180, 190))	('melanoma', 'Phenotype', 'HP:0002861', (278, 286))	('melanoma', 'Disease', (278, 286))	('KIT', 'Gene', (241, 244))	('patient', 'Species', '9606', (263, 270))	('KIT', 'molecular_function', 'GO:0005020', ('241', '244'))	('melanoma', 'Phenotype', 'HP:0002861', (221, 229))	('mutations', 'Var', (245, 254))	('melanoma', 'Disease', (221, 229))	('melanoma harbor KIT', 'Disease', 'MESH:C537062', (278, 297))	('KIT', 'molecular_function', 'GO:0005020', ('26', '29'))	('KIT', 'Gene', (26, 29))	('imatinib', 'Chemical', 'MESH:D000068877', (35, 43))	('KIT', 'molecular_function', 'GO:0005020', ('176', '179'))	('melanoma harbor KIT', 'Disease', (278, 297))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('melanomas', 'Disease', 'MESH:D008545', (221, 230))	('KIT', 'Gene', (176, 179))	('KIT', 'Gene', (294, 297))	('melanomas', 'Disease', (221, 230))	('KIT', 'Gene', '3815', (241, 244))	('patient', 'Species', '9606', (99, 106))	('melanoma', 'Disease', 'MESH:D008545', (278, 286))	('patients', 'Species', '9606', (207, 215))	('KIT', 'Gene', '3815', (26, 29))	('patients', 'Species', '9606', (263, 271))	('melanoma', 'Disease', 'MESH:D008545', (221, 229))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
153702	32274887	These data support the practice of determining KIT mutational status for MM patients to have a higher chance of receiving additional clinical benefit.	('patients', 'Species', '9606', (76, 84))	('KIT', 'molecular_function', 'GO:0005020', ('47', '50'))	('mutational status', 'Var', (51, 68))	('KIT', 'Gene', '3815', (47, 50))	('KIT', 'Gene', (47, 50))
153704	32274887	For the relatively small number of MM patients whose tumors harbor BRAF mutations (relative to the ~50% in non-AL cutaneous melanoma patients), treatment with combination BRAF inhibitor and MEK inhibitor therapy is available.	('mutations', 'Var', (72, 81))	('AL cutaneous melanoma', 'Disease', 'MESH:C562393', (111, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('BRAF', 'Gene', '673', (67, 71))	('tumors harbor BRAF', 'Disease', (53, 71))	('men', 'Species', '9606', (149, 152))	('BRAF', 'Gene', (67, 71))	('patients', 'Species', '9606', (133, 141))	('BRAF', 'Gene', '673', (171, 175))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (114, 132))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors harbor BRAF', 'Disease', 'MESH:C537062', (53, 71))	('BRAF', 'Gene', (171, 175))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('MEK', 'Gene', (190, 193))	('patients', 'Species', '9606', (38, 46))	('AL cutaneous melanoma', 'Disease', (111, 132))	('MEK', 'Gene', '5609', (190, 193))
153720	32274887	In contrast, the main drivers for UM are activating mutations of guanine nucleotide-binding protein G (GNAQ/11), splicing factor 3B subunit 1 (SF3B1), eukaryotic translation initiation factor (EIF1AX), and inactivating mutations of the tumor suppressor BRCA-associated protein-1 (BAP1).	('translation initiation', 'biological_process', 'GO:0006413', ('162', '184'))	('EIF1AX', 'Gene', '1964', (193, 199))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('236', '252'))	('activating', 'PosReg', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('73', '91'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('236', '252'))	('splicing factor 3B subunit 1', 'Gene', '23451', (113, 141))	('BRCA-associated protein-1', 'Gene', '8314', (253, 278))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('splicing', 'biological_process', 'GO:0045292', ('113', '121'))	('BAP1', 'Gene', '8314', (280, 284))	('SF3B1', 'Gene', (143, 148))	('protein', 'cellular_component', 'GO:0003675', ('269', '276'))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('BRCA-associated protein-1', 'Gene', (253, 278))	('mutations', 'Var', (52, 61))	('inactivating mutations', 'Var', (206, 228))	('GNAQ', 'Gene', '2776', (103, 107))	('EIF1AX', 'Gene', (193, 199))	('splicing factor 3B subunit 1', 'Gene', (113, 141))	('BAP1', 'Gene', (280, 284))	('SF3B1', 'Gene', '23451', (143, 148))	('GNAQ', 'Gene', (103, 107))	('tumor', 'Disease', (236, 241))
153722	32274887	GNAQ and GNA11 mutations are mutually exclusive, and thus in total are detected in 85%-94% of UM across all stages of disease (Figure 1d).	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('GNAQ', 'Gene', (0, 4))	('detected', 'Reg', (71, 79))	('GNA11', 'Gene', '2767', (9, 14))
153723	32274887	Due to their detection in benign uveal nevi, GNAQ/11 mutations are thought to be early mutational events.	('GNAQ', 'Gene', '2776', (45, 49))	('nevi', 'Phenotype', 'HP:0003764', (39, 43))	('GNAQ', 'Gene', (45, 49))	('mutations', 'Var', (53, 62))
153724	32274887	BAP1 (located on the short arm of chromosome 3) loss-of-function mutations are posited to serve as a predisposing factor for diverse hereditary cancers including mesothelioma, cutaneous melanoma, renal cell carcinoma, and UM.	('mesothelioma', 'Disease', (162, 174))	('short arm', 'Phenotype', 'HP:0009824', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('mesothelioma', 'Disease', 'MESH:D008654', (162, 174))	('BAP1', 'Gene', (0, 4))	('chromosome', 'cellular_component', 'GO:0005694', ('34', '44'))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('hereditary cancers', 'Disease', (133, 151))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (196, 216))	('hereditary cancers', 'Disease', 'MESH:D009369', (133, 151))	('loss-of-function', 'NegReg', (48, 64))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('cutaneous melanoma', 'Disease', (176, 194))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (176, 194))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (176, 194))	('renal cell carcinoma', 'Disease', (196, 216))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (196, 216))	('BAP1', 'Gene', '8314', (0, 4))	('mutations', 'Var', (65, 74))
153725	32274887	A recent comprehensive review identified that among 174 patients harboring germline BAP1 mutations, 130 developed tumors that were either UM (31% of cases), cutaneous melanoma (13% of cases), renal cell carcinoma (10% of cases), or MM (22% of cases).	('cutaneous melanoma', 'Disease', (157, 175))	('patients', 'Species', '9606', (56, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (157, 175))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (157, 175))	('germline', 'Var', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('BAP1', 'Gene', '8314', (84, 88))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('developed', 'Reg', (104, 113))	('renal cell carcinoma', 'Disease', (192, 212))	('tumors', 'Disease', (114, 120))	('mutations', 'Var', (89, 98))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('BAP1', 'Gene', (84, 88))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (192, 212))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (192, 212))
153726	32274887	In UM, loss of BAP1 returns melanoma cells to a more stem cell-like state as BAP1 is involved in melanocyte differentiation.	('loss', 'Var', (7, 11))	('returns melanoma', 'Disease', 'MESH:D008545', (20, 36))	('returns melanoma', 'Disease', (20, 36))	('BAP1', 'Gene', '8314', (15, 19))	('BAP1', 'Gene', '8314', (77, 81))	('melanocyte differentiation', 'biological_process', 'GO:0030318', ('97', '123'))	('BAP1', 'Gene', (15, 19))	('BAP1', 'Gene', (77, 81))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
153727	32274887	BAP1 is frequently mutated in metastasizing uveal melanomas, which supports the growing evidence that stem-like melanoma cell states drive elements of the metastatic cascade.	('uveal melanomas', 'Phenotype', 'HP:0007716', (44, 59))	('men', 'Species', '9606', (142, 145))	('BAP1', 'Gene', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('metastasizing uveal melanomas', 'Disease', 'MESH:D009362', (30, 59))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('mutated', 'Var', (19, 26))	('metastasizing uveal melanomas', 'Disease', (30, 59))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('BAP1', 'Gene', '8314', (0, 4))
153731	32274887	UM patients that possess GNAQ or GNA11 mutations can be treated in clinical trials with targeted therapy approaches specific for the MAPK pathway (i.e., MEK inhibitor, ERK inhibitor) as these tumors display elevated MAPK activity.	('MAPK', 'molecular_function', 'GO:0004707', ('133', '137'))	('tumors', 'Disease', (192, 198))	('ERK', 'Gene', '5594', (168, 171))	('MAPK', 'molecular_function', 'GO:0004707', ('216', '220'))	('MEK', 'Gene', (153, 156))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('GNA11', 'Gene', '2767', (33, 38))	('mutations', 'Var', (39, 48))	('ERK', 'Gene', (168, 171))	('GNAQ', 'Gene', '2776', (25, 29))	('elevated', 'PosReg', (207, 215))	('ERK', 'molecular_function', 'GO:0004707', ('168', '171'))	('GNAQ', 'Gene', (25, 29))	('patients', 'Species', '9606', (3, 11))	('MEK', 'Gene', '5609', (153, 156))	('GNA11', 'Gene', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('MAPK', 'Enzyme', (216, 220))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
153734	32274887	Additionally, preclinical studies identified that targeting the PI3K/AKT pathway (in GNAQ and GNA11 mutant xenograft models) in combination with a MEK inhibitor may be an effective treatment strategy for patients with GNAQ or GNA11 mutations; however, clinical trials using this combination have stopped due to low response rates and high toxicity (; Table 1).	('men', 'Species', '9606', (186, 189))	('mutations', 'Var', (232, 241))	('GNAQ', 'Gene', '2776', (85, 89))	('GNA11', 'Gene', (94, 99))	('patients', 'Species', '9606', (204, 212))	('AKT', 'Gene', (69, 72))	('MEK', 'Gene', '5609', (147, 150))	('GNA11', 'Gene', (226, 231))	('GNAQ', 'Gene', (85, 89))	('GNAQ', 'Gene', '2776', (218, 222))	('PI3K', 'molecular_function', 'GO:0016303', ('64', '68'))	('MEK', 'Gene', (147, 150))	('GNAQ', 'Gene', (218, 222))	('toxicity', 'Disease', 'MESH:D064420', (339, 347))	('AKT', 'Gene', '207', (69, 72))	('GNA11', 'Gene', '2767', (94, 99))	('mutant', 'Var', (100, 106))	('toxicity', 'Disease', (339, 347))	('GNA11', 'Gene', '2767', (226, 231))
153736	32274887	For UM with BAP1 mutations, it has been shown preclinically that treatment with a histone deacetylase (HDAC) inhibitor could be beneficial.	('histone deacetylase', 'Gene', '9734', (82, 101))	('HDAC', 'Gene', '9734', (103, 107))	('histone deacetylase', 'Gene', (82, 101))	('men', 'Species', '9606', (70, 73))	('BAP1', 'Gene', '8314', (12, 16))	('BAP1', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('HDAC', 'Gene', (103, 107))
153737	32274887	Because BAP1 mutations are associated with loss of melanocytic differentiation, treatment with HDAC inhibitors (valproic acid) are postulated to inhibit the growth of uveal melanoma in vivo by inducing morphological differentiation.	('valproic acid', 'Chemical', 'MESH:D014635', (112, 125))	('inducing', 'PosReg', (193, 201))	('loss of melanocytic', 'Disease', (43, 62))	('loss of melanocytic', 'Disease', 'MESH:D009508', (43, 62))	('morphological differentiation', 'CPA', (202, 231))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('BAP1', 'Gene', '8314', (8, 12))	('HDAC', 'Gene', '9734', (95, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (167, 181))	('uveal melanoma', 'Disease', 'MESH:C536494', (167, 181))	('growth', 'MPA', (157, 163))	('men', 'Species', '9606', (85, 88))	('uveal melanoma', 'Disease', (167, 181))	('BAP1', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))	('HDAC', 'Gene', (95, 99))	('inhibit', 'NegReg', (145, 152))
153750	32274887	Activating BRAF mutations are detected in patients with NM at a slightly lower frequency relative to SSM, with 43%-47% of patients possessing mutations mostly (88% of cases) in V600E (; Figure 1e).	('Activating', 'PosReg', (0, 10))	('V600E', 'Mutation', 'rs113488022', (177, 182))	('patients', 'Species', '9606', (122, 130))	('V600E', 'Var', (177, 182))	('SSM', 'cellular_component', 'GO:1990843', ('101', '104'))	('BRAF', 'Gene', '673', (11, 15))	('patients', 'Species', '9606', (42, 50))	('BRAF', 'Gene', (11, 15))
153751	32274887	A recent study identified evidence that BRAFV600E expression may serve as a prognostic marker in primary NM associated with ulceration and reduced survival.	('primary NM associated', 'Disease', (97, 118))	('BRAFV600E', 'Mutation', 'rs113488022', (40, 49))	('reduced', 'NegReg', (139, 146))	('ulceration', 'Disease', (124, 134))	('survival', 'MPA', (147, 155))	('BRAFV600E', 'Var', (40, 49))
153753	32274887	Activating NRAS mutations are detected at a significantly elevated frequency in NM relative to SSM in 30%-33% vs. 19% of cases, respectively.	('Activating', 'PosReg', (0, 10))	('NRAS', 'Gene', '4893', (11, 15))	('mutations', 'Var', (16, 25))	('SSM', 'cellular_component', 'GO:1990843', ('95', '98'))	('NRAS', 'Gene', (11, 15))
153770	32274887	The frequency of activating BRAF mutations in LM is unclear, with reports finding 16.7%-53.4% of LM patients harboring BRAF mutations (; Figure 1f).	('BRAF', 'Gene', '673', (28, 32))	('mutations', 'Var', (124, 133))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', (119, 123))	('patients', 'Species', '9606', (100, 108))	('BRAF', 'Gene', (28, 32))
153772	32274887	In a Greek cohort, 16.7% of LM melanoma cases expressed BRAF mutations and 50% of LM cases in a Japanese cohort expressed BRAF mutations.	('LM melanoma', 'Disease', 'MESH:D008545', (28, 39))	('BRAF', 'Gene', (56, 60))	('BRAF', 'Gene', '673', (122, 126))	('mutations', 'Var', (61, 70))	('BRAF', 'Gene', (122, 126))	('LM melanoma', 'Disease', (28, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('BRAF', 'Gene', '673', (56, 60))
153773	32274887	When BRAF mutations are present, the V600K substitution is frequently observed (~77%) relative to the V600E (~23%) as observed in SSM, in this small set of 13 LM patient tumor samples.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('BRAF', 'Gene', '673', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('BRAF', 'Gene', (5, 9))	('V600K', 'Var', (37, 42))	('SSM', 'Disease', (130, 133))	('tumor', 'Disease', (170, 175))	('V600E', 'Mutation', 'rs113488022', (102, 107))	('SSM', 'cellular_component', 'GO:1990843', ('130', '133'))	('V600K', 'Mutation', 'rs121913227', (37, 42))	('patient', 'Species', '9606', (162, 169))
153775	32274887	Activating NRAS mutations have been reported to occur in ~8.1%-16% of LM cases.	('NRAS', 'Gene', '4893', (11, 15))	('Activating', 'PosReg', (0, 10))	('NRAS', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))
153790	32325837	Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, ATM, BAP1, and POT1 The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined.	('Melanoma', 'Disease', (40, 48))	('ACD', 'Gene', '65057', (105, 108))	('POT1', 'Gene', (125, 129))	('Pathogenic', 'Reg', (82, 92))	('ATM', 'Gene', '472', (110, 113))	('BAP1', 'Gene', '8314', (115, 119))	('melanoma', 'Disease', (208, 216))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('Variants', 'Var', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('Melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('BAP1', 'Gene', (115, 119))	('Melanoma', 'Disease', 'MESH:D008545', (40, 48))	('ATM', 'Gene', (110, 113))	('ACD', 'Gene', (105, 108))
153792	32325837	We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes (BAP1, POT1, ACD, MITF, and TERF2IP), including two novel variants in BAP1 and 4 in POT1.	('variants', 'Var', (202, 210))	('cutaneous melanoma', 'Disease', (104, 122))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (104, 122))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (104, 122))	('BAP1', 'Gene', '8314', (214, 218))	('POT1', 'Gene', (151, 155))	('BAP1', 'Gene', (145, 149))	('POT1', 'Gene', '25913', (228, 232))	('ACD', 'Gene', (157, 160))	('variants', 'Var', (57, 65))	('TERF2IP', 'Gene', (172, 179))	('BAP1', 'Gene', (214, 218))	('BAP1 and 4', 'Gene', '8314', (214, 224))	('POT1', 'Gene', (228, 232))	('TERF2IP', 'Gene', '54386', (172, 179))	('pathogenic', 'Reg', (24, 34))	('MITF', 'Gene', '4286', (162, 166))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('ACD', 'Gene', '65057', (157, 160))	('BAP1', 'Gene', '8314', (145, 149))	('POT1', 'Gene', '25913', (151, 155))	('MITF', 'Gene', (162, 166))
153793	32325837	We also found four deleterious and five likely deleterious variants in ATM (3.3%).	('ATM', 'Gene', (71, 74))	('variants', 'Var', (59, 67))	('ATM', 'Gene', '472', (71, 74))
153794	32325837	Thus, including potentially deleterious variants in ATM increased the diagnostic yield to about 9%.	('ATM', 'Gene', '472', (52, 55))	('variants', 'Var', (40, 48))	('ATM', 'Gene', (52, 55))	('increased', 'PosReg', (56, 65))
153796	32325837	To our knowledge, this is the highest frequency of putative ATM deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('ATM', 'Gene', (60, 63))	('variants', 'Var', (76, 84))	('ATM', 'Gene', '472', (60, 63))
153800	32325837	Germline pathogenic variants in CDKN2A/ARF have been found in 20-45% of familial CM cases and in 11-19% of multiple primary melanomas (MPM) from the Italian population, characterized by a high prevalence of CDKN2A pathogenetic variants often associated with pancreatic cancer (PC) and other cancers.	('variants', 'Var', (20, 28))	('melanomas', 'Disease', 'MESH:D008545', (124, 133))	('variants', 'Var', (227, 235))	('melanomas', 'Disease', (124, 133))	('CDKN2A/ARF', 'Gene', '1029', (32, 42))	('pancreatic cancer', 'Disease', 'MESH:D010190', (258, 275))	('cancers', 'Disease', 'MESH:D009369', (291, 298))	('pancreatic cancer', 'Disease', (258, 275))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanomas', 'Phenotype', 'HP:0002861', (124, 133))	('CDKN2A', 'Gene', (207, 213))	('CDKN2A', 'Gene', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('associated', 'Reg', (242, 252))	('CDKN2A/ARF', 'Gene', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('CDKN2A', 'Gene', '1029', (207, 213))	('found', 'Reg', (53, 58))	('cancers', 'Phenotype', 'HP:0002664', (291, 298))	('familial CM', 'Disease', (72, 83))	('cancers', 'Disease', (291, 298))	('CDKN2A', 'Gene', '1029', (32, 38))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (258, 275))	('familial CM', 'Disease', 'MESH:D020936', (72, 83))
153801	32325837	Conversely, a small number of families carrying pathogenic variants in CDK4 have been described worldwide, including some Italian families.	('variants', 'Var', (59, 67))	('CDK4', 'Gene', (71, 75))	('CDK4', 'Gene', '1019', (71, 75))	('pathogenic', 'Reg', (48, 58))	('CDK', 'molecular_function', 'GO:0004693', ('71', '74'))
153804	32325837	Recently, novel rare high-risk variants have been identified in BAP1 (BRCA1 associated protein 1), POT1 (protection of telomeres 1), ACD (adrenocortical dysplasia), TERF2IP (telomeric repeat-binding factor-2 interacting protein), and the TERT (telomerase reverse transcriptase) promoter primarily by whole exome sequencing (WES) studies, although differences in terms of prevalence have been reported across studies.	('TERT', 'Gene', '7015', (238, 242))	('transcriptase', 'molecular_function', 'GO:0034062', ('263', '276'))	('telomerase reverse transcriptase', 'Gene', '7015', (244, 276))	('BRCA1 associated protein 1', 'Gene', '8314', (70, 96))	('protein', 'cellular_component', 'GO:0003675', ('220', '227'))	('ACD', 'Gene', (133, 136))	('BAP1', 'Gene', (64, 68))	('TERF2IP', 'Gene', (165, 172))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('transcriptase', 'molecular_function', 'GO:0003899', ('263', '276'))	('variants', 'Var', (31, 39))	('POT1', 'Gene', '25913', (99, 103))	('TERF2IP', 'Gene', '54386', (165, 172))	('BRCA1 associated protein 1', 'Gene', (70, 96))	('adrenocortical dysplasia', 'Gene', (138, 162))	('ACD', 'Gene', '65057', (133, 136))	('telomerase reverse transcriptase', 'Gene', (244, 276))	('telomeric repeat-binding', 'molecular_function', 'GO:0042162', ('174', '198'))	('POT1', 'Gene', (99, 103))	('BAP1', 'Gene', '8314', (64, 68))	('adrenocortical dysplasia', 'Gene', '65057', (138, 162))	('transcriptase', 'molecular_function', 'GO:0003968', ('263', '276'))	('TERT', 'Gene', (238, 242))
153807	32325837	Namely, carriers of the MITF p.Glu318Lys variant have a greater than fivefold increased risk of developing melanoma, especially MPM, with specific dermatological and dermoscopic features and with renal cell carcinoma (RCC) or both compared with non-carriers.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (196, 216))	('p.Glu318Lys', 'Mutation', 'rs149617956', (29, 40))	('melanoma', 'Disease', (107, 115))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('renal cell carcinoma', 'Disease', (196, 216))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('MITF', 'Gene', '4286', (24, 28))	('RCC', 'Disease', (218, 221))	('MITF', 'Gene', (24, 28))	('p.Glu318Lys', 'Var', (29, 40))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (196, 216))	('MPM', 'Disease', (128, 131))
153810	32325837	Further, in families with pathogenic variants in novel susceptibility genes, CM is part of a broader multi-cancer syndrome.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('multi-cancer syndrome', 'Disease', (101, 122))	('multi-cancer syndrome', 'Disease', 'MESH:D009369', (101, 122))	('pathogenic', 'Reg', (26, 36))	('variants', 'Var', (37, 45))
153811	32325837	In addition to CM, the tumor spectrum of BAP1 pathogenic variants includes uveal melanoma (UM), mesothelioma, basal cell carcinoma (BCC), renal cell carcinoma (RCC), and BAP1-inactivated melanocytic tumors (BIMTs), which together constitute the BAP1-tumor predisposition syndrome (BAP1-TPDS).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('BAP1', 'Gene', (281, 285))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (110, 130))	('BAP1', 'Gene', (41, 45))	('BAP1-tumor predisposition syndrome', 'Disease', (245, 279))	('BAP1', 'Gene', '8314', (245, 249))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('melanoma', 'Disease', (81, 89))	('tumor', 'Disease', (250, 255))	('renal cell carcinoma', 'Disease', (138, 158))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (138, 158))	('basal cell carcinoma', 'Disease', (110, 130))	('mesothelioma', 'Disease', (96, 108))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('uveal melanoma', 'Phenotype', 'HP:0007716', (75, 89))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('BAP1', 'Gene', (245, 249))	('variants', 'Var', (57, 65))	('tumor', 'Disease', (199, 204))	('BAP1', 'Gene', '8314', (170, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('RCC', 'Disease', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('melanocytic tumors', 'Disease', (187, 205))	('melanocytic tumors', 'Disease', 'MESH:D009508', (187, 205))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('tumor', 'Disease', (23, 28))	('BAP1', 'Gene', '8314', (281, 285))	('BAP1', 'Gene', '8314', (41, 45))	('BAP1-tumor predisposition syndrome', 'Disease', 'OMIM:614327', (245, 279))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (138, 158))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (110, 130))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('BAP1', 'Gene', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
153812	32325837	Moreover, POT1 pathogenic variants predispose to glioma, thyroid cancer, cardiac angiosarcoma, and colorectal cancer.	('cardiac angiosarcoma', 'Disease', (73, 93))	('angiosarcoma', 'Phenotype', 'HP:0200058', (81, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))	('predispose', 'Reg', (35, 45))	('colorectal cancer', 'Disease', (99, 116))	('thyroid cancer', 'Phenotype', 'HP:0002890', (57, 71))	('thyroid cancer', 'Disease', (57, 71))	('cardiac angiosarcoma', 'Disease', 'MESH:D006338', (73, 93))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('thyroid cancer', 'Disease', 'MESH:D013964', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('POT1', 'Gene', '25913', (10, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('POT1', 'Gene', (10, 14))	('glioma', 'Disease', (49, 55))	('variants', 'Var', (26, 34))
153813	32325837	Lastly, ACD and TERF2IP, as well as TERT promoter variants, are associated not only with early onset and multiple CM, but also with other cancers, although these latter associations are not yet conclusively defined.	('associated', 'Reg', (64, 74))	('TERT', 'Gene', '7015', (36, 40))	('TERF2IP', 'Gene', '54386', (16, 23))	('TERF2IP', 'Gene', (16, 23))	('multiple CM', 'Disease', (105, 116))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('early onset', 'Disease', (89, 100))	('ACD', 'Gene', (8, 11))	('variants', 'Var', (50, 58))	('ACD', 'Gene', '65057', (8, 11))	('TERT', 'Gene', (36, 40))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
153814	32325837	Pathogenic variants in the above-mentioned genes appear to be extremely rare in the context of non-syndromic familial aggregation (i.e., a familial clustering of only one type of cancer, such as CM).	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('variants', 'Var', (11, 19))	('syndromic familial aggregation', 'Disease', 'MESH:D001791', (99, 129))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('syndromic familial aggregation', 'Disease', (99, 129))	('cancer', 'Disease', (179, 185))
153815	32325837	Conversely, recent exome sequencing studies on PC-only families identified pathogenic variants in the ATM (ataxia-telangiectasia mutated) and PALB2 (partner and localizer of BRCA2) genes.	('BRCA2', 'Gene', '675', (174, 179))	('telangiectasia', 'Phenotype', 'HP:0001009', (114, 128))	('pathogenic', 'Reg', (75, 85))	('ataxia', 'Phenotype', 'HP:0001251', (107, 113))	('variants', 'Var', (86, 94))	('ATM (ataxia-telangiectasia mutated', 'Gene', '472', (102, 136))	('BRCA2', 'Gene', (174, 179))	('PALB2', 'Gene', '79728', (142, 147))	('PALB2', 'Gene', (142, 147))
153816	32325837	ATM is a known intermediate penetrance cancer predisposition gene, as heterozygous carriers of ATM germline pathogenic variants are at increased risk of developing several types of malignancies, including breast cancer (BC) and PC.	('ATM', 'Gene', (95, 98))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('malignancies', 'Disease', 'MESH:D009369', (181, 193))	('ATM', 'Gene', (0, 3))	('ATM', 'Gene', '472', (95, 98))	('cancer', 'Disease', (212, 218))	('malignancies', 'Disease', (181, 193))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('breast cancer', 'Disease', 'MESH:D001943', (205, 218))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))	('variants', 'Var', (119, 127))	('breast cancer', 'Disease', (205, 218))	('ATM', 'Gene', '472', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
153818	32325837	In a recent WES study on PC cases from CDKN2A-positive and negative CM families, ATM loss-of-function (LOF) variants were mostly observed in CDKN2A-negative PC patients.	('CDKN2A', 'Gene', '1029', (141, 147))	('patients', 'Species', '9606', (160, 168))	('CDKN2A', 'Gene', (39, 45))	('ATM', 'Gene', (81, 84))	('loss-of-function', 'NegReg', (85, 101))	('CDKN2A', 'Gene', '1029', (39, 45))	('variants', 'Var', (108, 116))	('ATM', 'Gene', '472', (81, 84))	('CDKN2A', 'Gene', (141, 147))
153819	32325837	In another WES study, a potentially deleterious missense variant in ATM detected in a CM family co-segregated with CM in three affected members whose mother developed PC.	('ATM', 'Gene', '472', (68, 71))	('deleterious', 'Reg', (36, 47))	('ATM', 'Gene', (68, 71))	('missense variant', 'Var', (48, 64))
153823	32325837	Under the hypothesis that part of the aggregation of PC seen in our CM families could be ascribed to variants in ATM and PALB2, we decided to include these genes in our panel, with the purpose of investigating their potential role in CM predisposition.	('PALB2', 'Gene', (121, 126))	('ATM', 'Gene', (113, 116))	('variants', 'Var', (101, 109))	('ATM', 'Gene', '472', (113, 116))	('PALB2', 'Gene', '79728', (121, 126))
153824	32325837	To determine the sensitivity and specificity of our next-generation sequencing (NGS) platform and bioinformatics algorithm, we first sequenced 10 DNA samples with known CDKN2A/ARF, CDK4, and MC1R germline variants previously found through SS.	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('MC1R', 'Gene', '4157', (191, 195))	('CDKN2A/ARF', 'Gene', '1029', (169, 179))	('variants', 'Var', (205, 213))	('MC1R', 'Gene', (191, 195))	('CDK4', 'Gene', (181, 185))	('CDK4', 'Gene', '1019', (181, 185))	('CDK', 'molecular_function', 'GO:0004693', ('181', '184'))	('CDKN2A/ARF', 'Gene', (169, 179))
153826	32325837	A 100% concordance in single-nucleotide polymorphisms (SNPs) detection in CDKN2A/ARF and MC1R was observed.	('MC1R', 'Gene', '4157', (89, 93))	('CDKN2A/ARF', 'Gene', (74, 84))	('MC1R', 'Gene', (89, 93))	('single-nucleotide polymorphisms', 'Var', (22, 53))	('CDKN2A/ARF', 'Gene', '1029', (74, 84))
153827	32325837	Out of 273 probands who underwent gene panel testing, we identified 16 (5.9%) pathogenetic or likely pathogenic variants in established high/intermediate penetrance CM susceptibility genes such as BAP1 (2.2%; n = 6), POT1 (0.7%; n = 2), ACD (0.37%; n = 1), and MITF (2.6%; n = 7).	('ACD', 'Gene', (237, 240))	('ACD', 'Gene', '65057', (237, 240))	('BAP1', 'Gene', '8314', (197, 201))	('pathogenetic', 'Reg', (78, 90))	('POT1', 'Gene', (217, 221))	('POT1', 'Gene', '25913', (217, 221))	('MITF', 'Gene', '4286', (261, 265))	('MITF', 'Gene', (261, 265))	('BAP1', 'Gene', (197, 201))	('variants', 'Var', (112, 120))
153829	32325837	In addition, we found four deleterious variants and five potentially deleterious variants (3.3%) as well as six rare VUS in ATM, whereas no rare variants were found in PALB2.	('ATM', 'Gene', '472', (124, 127))	('PALB2', 'Gene', (168, 173))	('PALB2', 'Gene', '79728', (168, 173))	('ATM', 'Gene', (124, 127))	('variants', 'Var', (39, 47))
153830	32325837	Overall, we identified six variants, five frameshift and one non-sense, which were classified as pathogenic, as well as one VUS in the BAP1 gene.	('frameshift', 'Var', (42, 52))	('BAP1', 'Gene', (135, 139))	('BAP1', 'Gene', '8314', (135, 139))
153831	32325837	All families with LOF variants showed the typical features of the BAP1-TPDS (OMIM 614327) as well as multiple cases of CM (Table 1).	('BAP1', 'Gene', (66, 70))	('variants', 'Var', (22, 30))	('BAP1', 'Gene', '8314', (66, 70))
153832	32325837	The patient with the novel c.1337delA variant developed a spitzoid CM at the age of 41, as well as a further CM and two dysplastic nevi:one classified as spitzoid:at the age of 43.	('c.1337delA', 'Mutation', 'c.1337delA', (27, 37))	('spitzoid CM', 'Disease', (58, 69))	('patient', 'Species', '9606', (4, 11))	('developed', 'PosReg', (46, 55))	('nevi', 'Phenotype', 'HP:0003764', (131, 135))	('dysplastic nevi', 'Disease', (120, 135))	('dysplastic nevi', 'Disease', 'MESH:D004416', (120, 135))	('c.1337delA', 'Var', (27, 37))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (120, 135))
153833	32325837	The second novel variant, c.1777dupC, which is predicted to cause a truncated protein after 50 amino acids, was found in a young patient diagnosed with an atypical Spitz nevus/tumor with loss of BAP1 expression and with a second-degree relative deceased owing to RCC at the age of 46.	('atypical Spitz nevus', 'Phenotype', 'HP:0001062', (155, 175))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('BAP1', 'Gene', (195, 199))	('truncated', 'MPA', (68, 77))	('loss', 'NegReg', (187, 191))	('nevus', 'Phenotype', 'HP:0003764', (170, 175))	('tumor', 'Disease', (176, 181))	('c.1777dupC', 'Var', (26, 36))	('RCC', 'Disease', (263, 266))	('RCC', 'Disease', 'MESH:C538614', (263, 266))	('c.1777dupC', 'Mutation', 'c.1777dupC', (26, 36))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('expression', 'MPA', (200, 210))	('BAP1', 'Gene', '8314', (195, 199))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('patient', 'Species', '9606', (129, 136))
153834	32325837	The patient with c.799_800delCA developed CM and had a brother previously diagnosed with three CMs and a mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (105, 117))	('CMs', 'Disease', (95, 98))	('patient', 'Species', '9606', (4, 11))	('c.799_800delCA', 'Var', (17, 31))	('mesothelioma', 'Disease', (105, 117))	('developed', 'PosReg', (32, 41))	('CMs', 'Disease', 'MESH:C564254', (95, 98))	('c.799_800delCA', 'Mutation', 'c.799_800delCA', (17, 31))
153837	32325837	Additionally, in a patient diagnosed with CM at the age of 52, we identified a missense BAP1 variant, c.1507T>C p.(Phe503Leu), which was found in The Genome Aggregation Database (gnomAD) with a very low frequency in the non-Finnish European population (f = 3.99e-6).	('c.1507T>C', 'Mutation', 'rs745959970', (102, 111))	('patient', 'Species', '9606', (19, 26))	('BAP1', 'Gene', '8314', (88, 92))	('p.(Phe503Leu', 'Var', (112, 124))	('p.(Phe503Leu)', 'SUBSTITUTION', 'None', (112, 125))	('BAP1', 'Gene', (88, 92))
153838	32325837	The patient's sister developed CM at the age of 23, but segregation in the family could not be verified as BAP1 germline status was only available for the proband, the family history was not suggestive for a BAP1 mutation, and the variant was thus classified as VUS.	('BAP1', 'Gene', '8314', (107, 111))	('BAP1', 'Gene', '8314', (208, 212))	('patient', 'Species', '9606', (4, 11))	('BAP1', 'Gene', (107, 111))	('mutation', 'Var', (213, 221))	('BAP1', 'Gene', (208, 212))
153840	32325837	The c.255+1G>A novel variant, involving the same canonical splice site of a variant functionally described by Potrony et al., was found in a patient who developed three CMs and several dysplastic nevi, as well as in his unaffected mother and sister.	('dysplastic nevi', 'Phenotype', 'HP:0001062', (185, 200))	('dysplastic nevi', 'Disease', 'MESH:D004416', (185, 200))	('CMs', 'Disease', (169, 172))	('c.255+1G>A', 'Mutation', 'c.255+1G>A', (4, 14))	('c.255+1G>A', 'Var', (4, 14))	('patient', 'Species', '9606', (141, 148))	('CMs', 'Disease', 'MESH:C564254', (169, 172))	('dysplastic nevi', 'Disease', (185, 200))	('nevi', 'Phenotype', 'HP:0003764', (196, 200))
153841	32325837	The c.1687-1G>A variant, which was predicted to be pathogenic by the MaxEntScan algorithm, and was previously shown to affect transcript splicing by RT-PCR and sequencing by Robles-Espinoza et al., was found in a family with two CM cases and an RCC case.	('c.1687-1G>A', 'Mutation', 'rs587777473', (4, 15))	('RCC', 'Disease', (245, 248))	('transcript splicing', 'MPA', (126, 145))	('splicing', 'biological_process', 'GO:0045292', ('137', '145'))	('RCC', 'Disease', 'MESH:C538614', (245, 248))	('affect', 'Reg', (119, 125))	('c.1687-1G>A', 'Var', (4, 15))
153842	32325837	Three of the six POT1 missense variants (c.158C>T, c.280C>A, and c.314C>T) were located in the DNA binding domain (OB1).	('c.158C>T', 'Var', (41, 49))	('c.314C>T', 'Var', (65, 73))	('POT1', 'Gene', '25913', (17, 21))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('DNA binding', 'molecular_function', 'GO:0003677', ('95', '106'))	('POT1', 'Gene', (17, 21))	('c.314C>T', 'Mutation', 'rs754742811', (65, 73))	('c.158C>T', 'Mutation', 'c.158C>T', (41, 49))	('c.280C>A', 'Mutation', 'rs769908514', (51, 59))	('c.280C>A', 'Var', (51, 59))
153843	32325837	c.158C>T p.(Thr53Ile), predicted to be pathogenic by in silico analysis, was detected in two different CM families: one included individuals with glioblastoma and PC, while the second was a CM-only family, with two affected CM members.	('p.(Thr53Ile', 'Var', (9, 20))	('p.(Thr53Ile)', 'SUBSTITUTION', 'None', (9, 21))	('glioblastoma', 'Phenotype', 'HP:0012174', (146, 158))	('c.158C>T', 'Mutation', 'c.158C>T', (0, 8))	('glioblastoma', 'Disease', (146, 158))	('glioblastoma', 'Disease', 'MESH:D005909', (146, 158))
153844	32325837	The c.280C>A p.(Gln94Lys) variant, which, according to A.J.	('c.280C>A', 'Var', (4, 12))	('p.(Gln94Lys)', 'SUBSTITUTION', 'None', (13, 25))	('c.280C>A', 'Mutation', 'rs769908514', (4, 12))	('p.(Gln94Lys', 'Var', (13, 24))
153846	32325837	The third variant, c.314C>T p.(Thr105Met), is phylogenetically highly conserved (suggesting that this threonine has an essential role in protein function) and was found in a MPM proband who also developed a dysplastic nevus and whose nephew had an atypical Spitz lesion.	('c.314C>T', 'Mutation', 'rs754742811', (19, 27))	('p.(Thr105Met)', 'SUBSTITUTION', 'None', (28, 41))	('nevus', 'Phenotype', 'HP:0003764', (218, 223))	('p.(Thr105Met', 'Var', (28, 40))	('dysplastic nevus', 'Phenotype', 'HP:0001062', (207, 223))	('c.314C>T', 'Var', (19, 27))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('Spitz lesion', 'Disease', (257, 269))	('dysplastic', 'Disease', (207, 217))	('threonine', 'Chemical', 'MESH:D013912', (102, 111))	('dysplastic', 'Disease', 'MESH:D004416', (207, 217))	('developed', 'PosReg', (195, 204))
153847	32325837	Of the remaining missense variants, c.809G>A p.(Ser270Asn) was found in a patient with more than 50 melanocytic nevi who developed nine CMs and was diagnosed with multiple myeloma at the age of 54.	('patient', 'Species', '9606', (74, 81))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (100, 116))	('Ser', 'cellular_component', 'GO:0005790', ('48', '51'))	('CMs', 'Disease', 'MESH:C564254', (136, 139))	('p.(Ser270Asn', 'Var', (45, 57))	('multiple myeloma', 'Phenotype', 'HP:0006775', (163, 179))	('multiple myeloma', 'Disease', 'MESH:D009101', (163, 179))	('multiple myeloma', 'Disease', (163, 179))	('c.809G>A', 'Mutation', 'rs587777477', (36, 44))	('CMs', 'Disease', (136, 139))	('diagnosed', 'Reg', (148, 157))	('nevi', 'Phenotype', 'HP:0003764', (112, 116))	('c.809G>A', 'Var', (36, 44))	('p.(Ser270Asn)', 'SUBSTITUTION', 'None', (45, 58))
153850	32325837	The last missense variant, c.1400C> p.(Ser467Leu), was found in a patient who developed two CMs and whose mother developed a CM at the age of 50 and a glioblastoma at the age of 79.	('CMs', 'Disease', (92, 95))	('glioblastoma', 'Disease', (151, 163))	('patient', 'Species', '9606', (66, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (151, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('CMs', 'Disease', 'MESH:C564254', (92, 95))	('p.(Ser467Leu)', 'SUBSTITUTION', 'None', (36, 49))	('Ser', 'cellular_component', 'GO:0005790', ('39', '42'))	('p.(Ser467Leu', 'Var', (36, 48))
153851	32325837	We found the c.866_867delCT frameshift variant in ACD that leads to a premature truncating protein in a patient affected by multiple CM and with a family history of CM and a relative who died of PC at the age of 55.	('ACD', 'Gene', '65057', (50, 53))	('c.866_867delCT frameshift variant', 'Var', (13, 46))	('leads to', 'Reg', (59, 67))	('premature truncating protein', 'MPA', (70, 98))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('patient', 'Species', '9606', (104, 111))	('ACD', 'Gene', (50, 53))	('c.866_867delCT', 'Mutation', 'rs777476880', (13, 27))
153852	32325837	Additionally, an MPM patient, with no family history of CM, had a VUS in the TERF2IP gene, c.258C>G p.(Asp86Glu).	('patient', 'Species', '9606', (21, 28))	('p.(Asp86Glu)', 'SUBSTITUTION', 'None', (100, 112))	('TERF2IP', 'Gene', (77, 84))	('p.(Asp86Glu', 'Var', (100, 111))	('c.258C>G', 'Mutation', 'rs752446617', (91, 99))	('TERF2IP', 'Gene', '54386', (77, 84))
153853	32325837	None of the 273 probands carried the c.-57T>G or other germline pathogenic TERT promoter variants.	('c.-57T>G', 'Var', (37, 45))	('c.-57T>G', 'Mutation', 'c.-57T>G', (37, 45))	('TERT', 'Gene', '7015', (75, 79))	('TERT', 'Gene', (75, 79))
153854	32325837	The MITF c.952G>A p.(Glu318Lys) risk variant was detected in 7 out 273 probands, four of whom had a history of MPMs and dysplastic nevi, one was also affected by RCC, and another who had a second degree relative also diagnosed with CM.	('detected', 'Reg', (49, 57))	('RCC', 'Disease', (162, 165))	('p.(Glu318Lys)', 'SUBSTITUTION', 'None', (18, 31))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('nevi', 'Phenotype', 'HP:0003764', (131, 135))	('MITF', 'Gene', '4286', (4, 8))	('MITF', 'Gene', (4, 8))	('dysplastic nevi', 'Disease', (120, 135))	('c.952G>A', 'Mutation', 'rs149617956', (9, 17))	('MPMs', 'Disease', (111, 115))	('dysplastic nevi', 'Disease', 'MESH:D004416', (120, 135))	('p.(Glu318Lys', 'Var', (18, 30))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (120, 135))
153855	32325837	Nine potentially pathogenic (four deleterious and five potentially deleterious variants) and six VUS were found in ATM.	('ATM', 'Gene', (115, 118))	('pathogenic', 'Reg', (17, 27))	('variants', 'Var', (79, 87))	('ATM', 'Gene', '472', (115, 118))
153856	32325837	c.3275C>A p.(Ser1092Ter) was detected in a CM proband with a second degree relative affected by PC.	('c.3275C>A', 'Var', (0, 9))	('p.(Ser1092Ter)', 'SUBSTITUTION', 'None', (10, 24))	('p.(Ser1092Ter', 'Var', (10, 23))	('Ter', 'cellular_component', 'GO:0097047', ('20', '23'))	('Ser', 'cellular_component', 'GO:0005790', ('13', '16'))	('c.3275C>A', 'Mutation', 'c.3275C>A', (0, 9))
153857	32325837	Three frameshift variants, predicted to cause truncated proteins owing to premature stop codons, were detected in families with MPM, UM, and other cancers (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('frameshift variants', 'Var', (6, 25))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('detected', 'Reg', (102, 110))	('cancers', 'Disease', (147, 154))	('MPM', 'Disease', (128, 131))	('truncated', 'MPA', (46, 55))
153858	32325837	Of these, c.4451delT was found in a proband who was treated 10 years earlier with cyclosporine and radiotherapy for a Hodgkin's lymphoma, and subsequently developed three CMs, two at the age of 45 and one at age 46.	('c.4451delT', 'Mutation', 'c.4451delT', (10, 20))	('CMs', 'Disease', 'MESH:C564254', (171, 174))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (118, 136))	('CMs', 'Disease', (171, 174))	('lymphoma', 'Phenotype', 'HP:0002665', (128, 136))	('cyclosporine', 'Chemical', 'MESH:D016572', (82, 94))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (118, 136))	('c.4451delT', 'Var', (10, 20))	("Hodgkin's lymphoma", 'Disease', (118, 136))
153860	32325837	In consideration of personal and family history, the presence of the ATM variant was reported to the proband in a research context, with emphasis on the uncertainty about the role of ATM in melanoma and PC development and the absence of a standardized surveillance protocol.	('ATM', 'Gene', '472', (69, 72))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('ATM', 'Gene', '472', (183, 186))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('ATM', 'Gene', (69, 72))	('ATM', 'Gene', (183, 186))	('variant', 'Var', (73, 80))
153865	32325837	c.5979_5983delTAAAG, which causes a premature stop codon after 23 aa, was found in a proband who developed two Ums at the age of 41 and a CM 10 years later.	('causes', 'Reg', (27, 33))	('premature stop codon', 'MPA', (36, 56))	('c.5979_5983delTAAAG', 'Mutation', 'rs876660134', (0, 19))	('c.5979_5983delTAAAG', 'Var', (0, 19))
153866	32325837	The last frameshift variant, c.8319_8323dupTGTCC, was found in a woman who developed two CMs at the ages of 48 and one at 53, as well one BCC and a BC (at the ages of 49 and 53, respectively).	('c.8319_8323dupTGTCC', 'Var', (29, 48))	('CMs', 'Disease', (89, 92))	('woman', 'Species', '9606', (65, 70))	('c.8319_8323dupTGTCC', 'Mutation', 'rs1060501552', (29, 48))	('CMs', 'Disease', 'MESH:C564254', (89, 92))
153869	32325837	The first one, a CM patient diagnosed at the age of 47, belonged to a family in which the variant co-segregated with the sister (CM at the age of 43) and their father developed prostate, bladder, colon cancer, and UM (at the ages of 70, 71, 72, and 74, respectively).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('bladder', 'Disease', (187, 194))	('prostate', 'Disease', (177, 185))	('colon cancer', 'Phenotype', 'HP:0003003', (196, 208))	('colon cancer', 'Disease', 'MESH:D015179', (196, 208))	('patient', 'Species', '9606', (20, 27))	('colon cancer', 'Disease', (196, 208))	('variant', 'Var', (90, 97))
153870	32325837	The second proband harboring the p.(Arg1917Thr) variant was an apparently sporadic MPM patient, with no other tumor in the family.	('p.(Arg1917Thr)', 'SUBSTITUTION', 'None', (33, 47))	('p.(Arg1917Thr', 'Var', (33, 46))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('patient', 'Species', '9606', (87, 94))	('MPM', 'Disease', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
153871	32325837	This patient was also a carrier of a MITF p.(Glu318Lys) variant.	('patient', 'Species', '9606', (5, 12))	('p.(Glu318Lys)', 'SUBSTITUTION', 'None', (42, 55))	('carrier', 'molecular_function', 'GO:0005215', ('24', '31'))	('MITF', 'Gene', '4286', (37, 41))	('MITF', 'Gene', (37, 41))	('p.(Glu318Lys', 'Var', (42, 54))
153873	32325837	We did not find previously undetected pathogenic variants in CDK4 and CDKN2A/ARF, although we included regulatory regions, for example, the whole CDKN2A/ARF 5'UTR, as we recently showed that nearly half of the rare 5'UTR germline variants are potentially pathogenic, owing to their impact on CDKN2A/ARF internal ribosome entry site (IRES)-mediated translation.	("ARF 5'UTR", 'Gene', '381', (153, 162))	('ribosome', 'cellular_component', 'GO:0005840', ('312', '320'))	("5'UTR", 'Gene', (215, 220))	('variants', 'Var', (230, 238))	('CDKN2A/ARF', 'Gene', '1029', (292, 302))	('CDKN2A/ARF', 'Gene', '1029', (70, 80))	('CDK', 'molecular_function', 'GO:0004693', ('61', '64'))	('translation', 'biological_process', 'GO:0006412', ('348', '359'))	('CDK4', 'Gene', (61, 65))	('CDKN2A/ARF', 'Gene', (292, 302))	('CDKN2A/ARF', 'Gene', (70, 80))	('impact', 'Reg', (282, 288))	('CDK4', 'Gene', '1019', (61, 65))	('CDKN2A/ARF', 'Gene', '1029', (146, 156))	('internal ribosome entry site', 'MPA', (303, 331))	('CDKN2A/ARF', 'Gene', (146, 156))	('pathogenic', 'Reg', (255, 265))	("ARF 5'UTR", 'Gene', (153, 162))
153875	32325837	Initial findings of pathogenic variants in POT1, however, considered the second most frequently mutated high penetrance gene after CDKN2A/ARF, showed a higher frequency, probably owing to the presence of founders in the studied populations.	('variants', 'Var', (31, 39))	('POT1', 'Gene', '25913', (43, 47))	('POT1', 'Gene', (43, 47))	('CDKN2A/ARF', 'Gene', '1029', (131, 141))	('CDKN2A/ARF', 'Gene', (131, 141))	('pathogenic', 'Reg', (20, 30))
153876	32325837	Currently, pathogenic variants in recently identified CM predisposition genes are detected at a frequency similar to that of pathogenic CDK4 variants, which was routinely screened in familial and MPM patients together with CDKN2A/ARF.	('patients', 'Species', '9606', (200, 208))	('CDKN2A/ARF', 'Gene', '1029', (223, 233))	('CDKN2A/ARF', 'Gene', (223, 233))	('CDK4', 'Gene', (136, 140))	('CDK4', 'Gene', '1019', (136, 140))	('variants', 'Var', (141, 149))	('CDK', 'molecular_function', 'GO:0004693', ('136', '139'))	('variants', 'Var', (22, 30))
153880	32325837	We also included ATM and PALB2 for research purposes, excluding them from the clinical report, under the assumption that their variants could play a role in families with known cancer associations, that is, CM and PC.	('variants', 'Var', (127, 135))	('play', 'Reg', (142, 146))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('role', 'Reg', (149, 153))	('ATM', 'Gene', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('PALB2', 'Gene', '79728', (25, 30))	('PALB2', 'Gene', (25, 30))	('ATM', 'Gene', '472', (17, 20))
153881	32325837	Overall, the detection yield of pathogenic/likely pathogenic variants in established melanoma risk genes was 5.86%.	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('variants', 'Var', (61, 69))	('pathogenic/likely', 'Reg', (32, 49))
153882	32325837	When deleterious and potentially deleterious ATM variants were also included, the detection yield rose to 9.16%, the highest estimate described so far to our knowledge.	('ATM', 'Gene', (45, 48))	('rose', 'PosReg', (98, 102))	('ATM', 'Gene', '472', (45, 48))	('variants', 'Var', (49, 57))
153883	32325837	However, the association between variants in ATM, mostly known for being associated with a low-intermediate risk of other cancers, and CM risk is not yet clearly established.	('ATM', 'Gene', '472', (45, 48))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('ATM', 'Gene', (45, 48))	('variants', 'Var', (33, 41))
153884	32325837	Further, the detection of a pathogenic variant in a gene such as BAP1, which is related to a complex syndrome that includes several potentially lethal cancers, should be reported to aid clinical management, even though the complete tumor spectrum and related tumor-specific penetrance and surveillance recommendations are not definitively drawn.	('BAP1', 'Gene', '8314', (65, 69))	('aid', 'Gene', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('BAP1', 'Gene', (65, 69))	('variant', 'Var', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('aid', 'Gene', '57379', (182, 185))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('tumor', 'Disease', (259, 264))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('tumor', 'Disease', (232, 237))	('pathogenic', 'Reg', (28, 38))	('cancers', 'Disease', (151, 158))
153888	32325837	For patients with MITF p.(Glu318Lys), based on the association of a higher risk of MPM, dysplastic nevi, and RCC, and on the basis of our data, we propose the inclusion of this gene in clinical diagnostic testing and suggest that an annual abdominal ultrasound should be integrated with the dermatological surveillance for the carriers, even though tailored surveillance for cancers other than CM is not standardized.	('cancers', 'Phenotype', 'HP:0002664', (375, 382))	('dysplastic nevi', 'Disease', (88, 103))	('p.(Glu318Lys', 'Var', (23, 35))	('cancers', 'Disease', 'MESH:D009369', (375, 382))	('dysplastic nevi', 'Disease', 'MESH:D004416', (88, 103))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (88, 103))	('patients', 'Species', '9606', (4, 12))	('MITF', 'Gene', '4286', (18, 22))	('MITF', 'Gene', (18, 22))	('nevi', 'Phenotype', 'HP:0003764', (99, 103))	('p.(Glu318Lys)', 'SUBSTITUTION', 'None', (23, 36))	('cancers', 'Disease', (375, 382))	('MPM', 'Disease', (83, 86))
153889	32325837	Specific recommendations are not yet available for multiple variants/genes such as POT1 variants.	('variants', 'Var', (88, 96))	('POT1', 'Gene', (83, 87))	('POT1', 'Gene', '25913', (83, 87))
153894	32325837	The finding of ATM LOF variants in our study cohort is in line with previous findings on the association between ATM and CM/PC risk.	('ATM', 'Gene', (15, 18))	('ATM', 'Gene', (113, 116))	('LOF', 'NegReg', (19, 22))	('ATM', 'Gene', '472', (15, 18))	('variants', 'Var', (23, 31))	('ATM', 'Gene', '472', (113, 116))	('CM/PC', 'Disease', (121, 126))
153895	32325837	In fact, four deleterious and five potentially deleterious variants were found, three of them in melanoma-prone families that also included PC cases.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('variants', 'Var', (59, 67))	('melanoma', 'Disease', (97, 105))
153899	32325837	found no variants in POT1, and occurrence of UM and mesothelioma in three BAP1 positive families in a large multigene panel study of 451 Dutch families with an overall diagnostic yield of 4%, principally explained by the identification of 15 MITF positive families (3.3%).	('MITF', 'Gene', '4286', (242, 246))	('MITF', 'Gene', (242, 246))	('POT1', 'Gene', '25913', (21, 25))	('mesothelioma', 'Disease', (52, 64))	('BAP1', 'Gene', '8314', (74, 78))	('POT1', 'Gene', (21, 25))	('variants', 'Var', (9, 17))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))	('BAP1', 'Gene', (74, 78))
153900	32325837	Casula et al., in a cohort of Italian MPM patients, used a panel containing the same genes we tested (with the exception of MITF), and found a lower pathogenic variant rate, considering the American College of Medical Genetics on Genomics (ACMG) variant classification (3%).	('variant', 'Var', (160, 167))	('pathogenic', 'MPA', (149, 159))	('lower', 'NegReg', (143, 148))	('MITF', 'Gene', '4286', (124, 128))	('MITF', 'Gene', (124, 128))	('patients', 'Species', '9606', (42, 50))
153901	32325837	CDKN2A pathogenic variants were also less frequent (3.84%).	('variants', 'Var', (18, 26))	('CDKN2A', 'Gene', '1029', (0, 6))	('CDKN2A', 'Gene', (0, 6))
153911	32325837	Variants were classified as pathogenic, likely pathogenic, VUS, likely benign, or benign based on the published ACMG recommendations, for known melanoma genes.	('Variants', 'Var', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('pathogenic', 'Reg', (28, 38))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))
153917	32325837	To verify whether the variant c.255+1G>A alters splicing in POT1, as described in Potrony et al., in which they tested the variant c.255G>A, we isolated total RNA from lymphoblastoid cells with TRIzol (Invitrogen, Carlsbad, CA, USA) and cDNA synthesis was performed with the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystem, Foster City, CA, USA) using random primers.	('variant c.255+1G>A', 'Var', (22, 40))	('c.255+1G>A', 'Mutation', 'c.255+1G>A', (30, 40))	('c.255+1G>A', 'Var', (30, 40))	('c.255G>A', 'Mutation', 'rs747851551', (131, 139))	('splicing', 'biological_process', 'GO:0045292', ('48', '56'))	('POT1', 'Gene', '25913', (60, 64))	('Reverse Transcription', 'biological_process', 'GO:0001171', ('294', '315'))	('POT1', 'Gene', (60, 64))	('alters', 'Reg', (41, 47))	('TRIzol', 'Chemical', 'MESH:C411644', (194, 200))	('synthesis', 'biological_process', 'GO:0009058', ('242', '251'))	('RNA', 'cellular_component', 'GO:0005562', ('159', '162'))	('c.255G>A', 'Var', (131, 139))
153923	32325837	To the best of our knowledge, this is the first study to report a high percentage of deleterious ATM variants in melanoma families (3.3%).	('ATM', 'Gene', '472', (97, 100))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('variants', 'Var', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('ATM', 'Gene', (97, 100))
153924	32325837	In fact, the finding of ATM deleterious or potentially deleterious variants in nearly 3.3% of our families, and an additional 2.2% of rare VUS, has led to a multicenter international collaboration, currently ongoing, to define the role of ATM as a susceptibility gene to CM.	('ATM', 'Gene', '472', (24, 27))	('ATM', 'Gene', (239, 242))	('ATM', 'Gene', (24, 27))	('ATM', 'Gene', '472', (239, 242))	('variants', 'Var', (67, 75))
153926	32325837	The following are available online at , Figure S1: Pedigree diagrams from the families carrying loss of function variants in BAP1, POT1, ATM, ACD genes; Figure S2: Pedigree diagram from the family with the rare c.799_800delCA BAP1 germline variant.	('c.799_800delCA', 'Var', (211, 225))	('POT1', 'Gene', (131, 135))	('BAP1', 'Gene', (226, 230))	('BAP1', 'Gene', '8314', (125, 129))	('ATM', 'Gene', (137, 140))	('BAP1', 'Gene', (125, 129))	('ACD', 'Gene', (142, 145))	('c.799_800delCA', 'Mutation', 'c.799_800delCA', (211, 225))	('ACD', 'Gene', '65057', (142, 145))	('ATM', 'Gene', '472', (137, 140))	('variants', 'Var', (113, 121))	('BAP1', 'Gene', '8314', (226, 230))	('POT1', 'Gene', '25913', (131, 135))
153927	32325837	; writing:review and editing L.P., B.D., V.A., I.V., S.M., R.L.S., M.G., F.G., S.S. (Stefania Sciallero), M.A.G., W.B.	('F.G.', 'Var', (73, 77))	('Stefania Sciallero', 'Disease', (85, 103))	('Stefania Sciallero', 'Disease', 'None', (85, 103))	('M.G.', 'Var', (67, 71))	('M.A.G.', 'Var', (106, 112))	('S.S.', 'Var', (79, 83))
153928	32325837	; acquisition, analysis, and interpretation of data, L.P., V.A., B.D., I.V., G.C., M.M., G.S., M.A.P., G.P., M.G.T., E.S., M.G., P.C., G.M., S.M., S.S. (Serena Sestini), R.D., V.Z., R.L.S., I.S., A.B., L.M., F.G., S.S. (Stefania Sciallero), F.C., E.T.T., F.S., P.Q., A.M.G., W.B.	('F.S.', 'Var', (255, 259))	('P.Q.', 'Var', (261, 265))	('F.C.', 'Var', (241, 245))	('Stefania Sciallero', 'Disease', 'None', (220, 238))	('Stefania Sciallero', 'Disease', (220, 238))
154020	30653520	Unfavorable prognostic markers are the presence of epithelioid cells, large tumor diameter, anterior localization and chromosome 3 monosomy.	('chromosome', 'Var', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('118', '128'))	('localization', 'biological_process', 'GO:0051179', ('101', '113'))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
154037	30653520	Clinical data included metastasis free survival, overall survival, tumor diameters, BAP1 mutations and mitotic count.	('overall survival', 'CPA', (49, 65))	('mitotic count', 'CPA', (103, 116))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('BAP1', 'Gene', '8314', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mutations', 'Var', (89, 98))	('tumor', 'Disease', (67, 72))	('BAP1', 'Gene', (84, 88))	('metastasis free survival', 'CPA', (23, 47))
154038	30653520	Statistical correlation between two continuous variables was calculated by partial correlation accounting for disease status, histological type, BAP1 mutation and adjuvant therapy.	('BAP1', 'Gene', (145, 149))	('mutation', 'Var', (150, 158))	('BAP1', 'Gene', '8314', (145, 149))
154060	30653520	Among the immune checkpoints, low levels of CD47 expression resulted in higher disease free survival, while higher expression of TNFRSF6B and GAL9 resulted in longer disease free survival (Table 4; Fig 5).	('GAL9', 'Gene', '3965', (142, 146))	('TNFRSF6B', 'Gene', '8771', (129, 137))	('TNFRSF6B', 'Gene', (129, 137))	('disease free survival', 'CPA', (79, 100))	('longer disease', 'Disease', (159, 173))	('low', 'Var', (30, 33))	('GAL9', 'Gene', (142, 146))	('expression', 'MPA', (49, 59))	('CD47', 'Gene', '961', (44, 48))	('expression', 'MPA', (115, 125))	('longer disease', 'Disease', 'MESH:D004194', (159, 173))	('higher', 'PosReg', (72, 78))	('CD47', 'Gene', (44, 48))	('higher', 'PosReg', (108, 114))
154070	30653520	It is worth pointing out that our analysis of the TGCA data have been performed accounting for the presence of BAP1 mutation as confounding variable.	('mutation', 'Var', (116, 124))	('BAP1', 'Gene', '8314', (111, 115))	('BAP1', 'Gene', (111, 115))
154073	30653520	Notably, no significant differences could be found in the expression of the genes here analyzed between BAP1 mutated and wild type samples (data not shown).	('expression', 'MPA', (58, 68))	('mutated', 'Var', (109, 116))	('BAP1', 'Gene', '8314', (104, 108))	('BAP1', 'Gene', (104, 108))
154097	30653520	In fact, a meta-analysis of fourteen studies, involving 2326 solid cancer patients, has recently revealed that high GAL9 expression was associated to improved overall survival, and was significantly correlated with smaller depth of invasion, earlier histopathological stage, negative lymph node metastasis and negative distal tumor metastasis.	('tumor metastasis', 'Disease', 'MESH:D009362', (326, 342))	('smaller', 'NegReg', (215, 222))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('overall survival', 'CPA', (159, 175))	('cancer', 'Disease', (67, 73))	('depth of invasion', 'CPA', (223, 240))	('tumor metastasis', 'Disease', (326, 342))	('patients', 'Species', '9606', (74, 82))	('negative lymph node metastasis', 'CPA', (275, 305))	('expression', 'MPA', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('GAL9', 'Gene', '3965', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('high', 'Var', (111, 115))	('GAL9', 'Gene', (116, 120))	('improved', 'PosReg', (150, 158))
154105	30653520	Hu5F9-G4, CC-90002, TTI-621, NI-1701, NI-1801, SRF231) and some of them are already under clinical investigation in human solid and hematological cancers.	('NI-1701', 'Var', (29, 36))	('hematological cancers', 'Disease', 'MESH:D009369', (132, 153))	('Hu5F9-G4', 'Var', (0, 8))	('SRF231', 'Var', (47, 53))	('hematological cancers', 'Disease', (132, 153))	('NI-1801', 'Var', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('CC-90002', 'Var', (10, 18))	('Hu5F9', 'CellLine', 'CVCL:H354', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('human', 'Species', '9606', (116, 121))
154113	28529629	Matrix metalloproteinase 9 (MMP-9) knockdown by shRNA potentiated, while ectopic expression of MMP-9 rescued, the niclosamide-attenuated invasion, implying that MMP-9 is pivotal for invasion blockage by niclosamide in UM cells.	('MMP-9', 'Gene', (95, 100))	('knockdown', 'Var', (35, 44))	('Matrix metalloproteinase 9', 'Gene', (0, 26))	('niclosamide', 'Chemical', 'MESH:D009534', (203, 214))	('MMP-9', 'molecular_function', 'GO:0004229', ('161', '166'))	('MMP-9', 'Gene', (28, 33))	('MMP-9', 'molecular_function', 'GO:0004229', ('95', '100'))	('invasion', 'CPA', (137, 145))	('niclosamide', 'Chemical', 'MESH:D009534', (114, 125))	('potentiated', 'PosReg', (54, 65))	('Matrix metalloproteinase 9', 'Gene', '4318', (0, 26))	('UM', 'Phenotype', 'HP:0007716', (218, 220))	('MMP-9', 'molecular_function', 'GO:0004229', ('28', '33'))	('MMP-9', 'Gene', '4318', (161, 166))	('MMP-9', 'Gene', '4318', (95, 100))	('MMP-9', 'Gene', (161, 166))	('MMP-9', 'Gene', '4318', (28, 33))
154116	28529629	Additionally, niclosamide treatment in UM cells reduced ATP and cAMP contents, and decreased PKA-dependent phosphorylation of beta-catenin at S552 and S675 which determine the stability of beta-catenin protein, suggesting that niclosamide may work as a mitochondrial un-coupler.	('niclosamide', 'Chemical', 'MESH:D009534', (227, 238))	('PKA-dependent phosphorylation', 'MPA', (93, 122))	('PKA', 'cellular_component', 'GO:0005952', ('93', '96'))	('niclosamide', 'Chemical', 'MESH:D009534', (14, 25))	('reduced', 'NegReg', (48, 55))	('decreased', 'NegReg', (83, 92))	('cAMP', 'Chemical', 'MESH:D000242', (64, 68))	('UM', 'Phenotype', 'HP:0007716', (39, 41))	('phosphorylation', 'biological_process', 'GO:0016310', ('107', '122'))	('beta-catenin', 'Protein', (126, 138))	('ATP', 'Chemical', 'MESH:D000255', (56, 59))	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('PKA', 'molecular_function', 'GO:0004691', ('93', '96'))	('S675', 'Var', (151, 155))
154122	28529629	Although mutations in GNAQ and GNA11 were observed in ~80% of patients with UM, which may drive the growth of the primary lesion, little is known about drivers of UM metastasis.	('UM', 'Phenotype', 'HP:0007716', (76, 78))	('UM', 'Phenotype', 'HP:0007716', (163, 165))	('mutations', 'Var', (9, 18))	('GNAQ', 'Gene', (22, 26))	('GNAQ', 'Gene', '2776', (22, 26))	('GNA11', 'Gene', (31, 36))	('patients', 'Species', '9606', (62, 70))	('observed', 'Reg', (42, 50))	('GNA11', 'Gene', '2767', (31, 36))
154123	28529629	Furthermore, directly targeting mutant GNAQ and GNA11 has been demonstrated to be structurally challenging.	('GNAQ', 'Gene', (39, 43))	('mutant', 'Var', (32, 38))	('GNA11', 'Gene', (48, 53))	('GNAQ', 'Gene', '2776', (39, 43))	('GNA11', 'Gene', '2767', (48, 53))
154131	28529629	Recent studies from us and others have demonstrated that niclosamide has antitumor activity in multiple types of cancers (e.g., leukemia, colorectal and prostate cancer), and that the underlying mechanisms involve the inhibition of NF-kappaB pathway, the increase in reactive oxygen species (ROS) and the blockage of Wnt/beta-catenin pathway.	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('NF-kappaB pathway', 'Pathway', (232, 249))	('leukemia', 'Disease', 'MESH:D007938', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancers', 'Disease', (113, 120))	('leukemia', 'Disease', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('prostate cancer', 'Phenotype', 'HP:0012125', (153, 168))	('reactive oxygen species', 'MPA', (267, 290))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('ROS', 'Chemical', 'MESH:D017382', (292, 295))	('niclosamide', 'Chemical', 'MESH:D009534', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Wnt/beta-catenin pathway', 'Pathway', (317, 341))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (267, 290))	('inhibition', 'NegReg', (218, 228))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('colorectal and prostate cancer', 'Disease', 'MESH:D015179', (138, 168))	('increase', 'PosReg', (255, 263))	('niclosamide', 'Var', (57, 68))	('leukemia', 'Phenotype', 'HP:0001909', (128, 136))	('tumor', 'Disease', (77, 82))
154133	28529629	Our results showed that niclosamide potently inhibited cell proliferation, induced apoptosis in UM cells, reduced migration and invasion, and eradicated CSCs of UM.	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('niclosamide', 'Chemical', 'MESH:D009534', (24, 35))	('induced', 'Reg', (75, 82))	('UM', 'Phenotype', 'HP:0007716', (96, 98))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('CSCs of UM', 'CPA', (153, 163))	('UM', 'Phenotype', 'HP:0007716', (161, 163))	('cell proliferation', 'biological_process', 'GO:0008283', ('55', '73'))	('eradicated', 'NegReg', (142, 152))	('cell proliferation', 'CPA', (55, 73))	('niclosamide', 'Var', (24, 35))	('apoptosis', 'CPA', (83, 92))	('inhibited', 'NegReg', (45, 54))	('reduced', 'NegReg', (106, 113))
154154	28529629	Antibodies against caspase-3, PARP (clone 4C10-5), XIAP, Bcl-2, cytochrome c (clone 6H2.B4) and phospho-GSK3beta (Y216) were obtained from BD Biosciences (San Jose, CA).	('PARP', 'Gene', '1302', (30, 34))	('Y216', 'CellLine', 'CVCL:V757', (114, 118))	('XIAP', 'Gene', '331', (51, 55))	('PARP', 'Gene', (30, 34))	('cytochrome c', 'molecular_function', 'GO:0009461', ('64', '76'))	('caspase-3', 'Gene', (19, 28))	('GSK', 'molecular_function', 'GO:0050321', ('104', '107'))	('cytochrome c', 'molecular_function', 'GO:0045155', ('64', '76'))	('caspase-3', 'Gene', '836', (19, 28))	('cytochrome c', 'Gene', (64, 76))	('Bcl-2', 'molecular_function', 'GO:0015283', ('57', '62'))	('Bcl-2', 'Gene', (57, 62))	('Bcl-2', 'Gene', '596', (57, 62))	('Y216', 'Var', (114, 118))	('cytochrome c', 'Gene', '54205', (64, 76))	('XIAP', 'Gene', (51, 55))
154199	28529629	There was a significant difference in the tumor weights between the p-niclosamide-treated and vehicle-treated groups (Figure 1E).	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('p-niclosamide', 'Chemical', '-', (68, 81))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('p-niclosamide-treated', 'Var', (68, 89))
154201	28529629	The immunohistochemistry staining for Ki67, a cell proliferation marker, was also decreased in the tumor xenografts of the p-niclosamide-treated mice (Figure 1F).	('tumor', 'Disease', (99, 104))	('Ki67', 'Gene', '17345', (38, 42))	('p-niclosamide-treated', 'Var', (123, 144))	('p-niclosamide', 'Chemical', '-', (123, 136))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('Ki67', 'Gene', (38, 42))	('mice', 'Species', '10090', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('decreased', 'NegReg', (82, 91))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))
154218	28529629	After Mel270 cells were exposed to 4 mumol/L niclosamide, the intracellular ROS level based on CM-H2DCF-DA started to rise at 2 h, and peaked at 16 h following treatment (Figure 4A, top).	('CM-H2DCF-DA', 'Var', (95, 106))	('intracellular', 'cellular_component', 'GO:0005622', ('62', '75'))	('rise', 'PosReg', (118, 122))	('ROS', 'Chemical', 'MESH:D017382', (76, 79))	('niclosamide', 'Chemical', 'MESH:D009534', (45, 56))	('CM-H2DCF-DA', 'Chemical', '-', (95, 106))	('intracellular ROS level', 'MPA', (62, 85))
154234	28529629	Conversely, knockdown of MMP-9 by lentiviral shRNA significantly weakened the invasion capacity of UM cells compared with the cells transfected with Control shRNA (Figure 5D).	('invasion capacity of UM cells', 'CPA', (78, 107))	('MMP-9', 'Gene', '4318', (25, 30))	('knockdown', 'Var', (12, 21))	('MMP-9', 'Gene', (25, 30))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('MMP-9', 'molecular_function', 'GO:0004229', ('25', '30'))	('weakened', 'NegReg', (65, 73))
154235	28529629	Furthermore, the abrogation of invasion mediated by niclosamide was reversed by ectopic overexpression of MMP-9, but enhanced by knockdown of MMP-9-shRNA (Figure 5D).	('MMP-9', 'Gene', (106, 111))	('MMP-9', 'Gene', '4318', (142, 147))	('niclosamide', 'Chemical', 'MESH:D009534', (52, 63))	('knockdown', 'Var', (129, 138))	('MMP-9', 'Gene', (142, 147))	('MMP-9', 'molecular_function', 'GO:0004229', ('106', '111'))	('MMP-9', 'molecular_function', 'GO:0004229', ('142', '147'))	('enhanced', 'PosReg', (117, 125))	('MMP-9', 'Gene', '4318', (106, 111))
154251	28529629	Consistently, the protein kinase A (PKA)-dependent phosphorylation of beta-catenin at S552 and S675 which can facilitate stability of beta-catenin protein were reduced in niclosamide-treated UM cells (Figure 6C).	('niclosamide', 'Chemical', 'MESH:D009534', (171, 182))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('beta-catenin', 'Protein', (70, 82))	('facilitate', 'PosReg', (110, 120))	('stability', 'MPA', (121, 130))	('UM', 'Phenotype', 'HP:0007716', (191, 193))	('PKA', 'cellular_component', 'GO:0005952', ('36', '39'))	('PKA', 'molecular_function', 'GO:0004691', ('36', '39'))	('phosphorylation', 'MPA', (51, 66))	('reduced', 'NegReg', (160, 167))	('protein', 'cellular_component', 'GO:0003675', ('18', '25'))	('S675', 'Var', (95, 99))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))
154252	28529629	Likewise, addition of PKA activator dbcAMP into culture medium resulted in phosphorylation of beta-catenin at S552 and S675 in UM cells (Figure 6F).	('beta-catenin', 'Protein', (94, 106))	('PKA', 'molecular_function', 'GO:0004691', ('22', '25'))	('PKA', 'cellular_component', 'GO:0005952', ('22', '25'))	('dbcAMP', 'Chemical', 'MESH:D003994', (36, 42))	('phosphorylation', 'MPA', (75, 90))	('phosphorylation', 'biological_process', 'GO:0016310', ('75', '90'))	('S675', 'Var', (119, 123))	('UM', 'Phenotype', 'HP:0007716', (127, 129))
154253	28529629	The pre-treatment with dbcAMP abolished the effect of niclosamide-mediated down-regulation in phospho-beta-catenin (S552 and S675) and total level of beta-catenin (Figure 6F).	('S552', 'Var', (116, 120))	('regulation', 'biological_process', 'GO:0065007', ('80', '90'))	('down-regulation', 'NegReg', (75, 90))	('S675', 'Var', (125, 129))	('niclosamide', 'Chemical', 'MESH:D009534', (54, 65))	('dbcAMP', 'Chemical', 'MESH:D003994', (23, 29))	('pre', 'molecular_function', 'GO:0003904', ('4', '7'))	('phospho-beta-catenin', 'MPA', (94, 114))
154256	28529629	Importantly, p-niclosamide shows strong antitumor activity in a UM xenograft mice model.	('mice', 'Species', '10090', (77, 81))	('p-niclosamide', 'Chemical', '-', (13, 26))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('p-niclosamide', 'Var', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('UM', 'Phenotype', 'HP:0007716', (64, 66))	('tumor', 'Disease', (44, 49))
154276	28529629	Our results demonstrated here that niclosamide remarkably decreased the percentage of Aldefluor+ cells and the serially re-plating ability of UM cells to form melanospheres, indicating that niclosamide is capable of eliminating CSCs and impairing their self-renewal trait in UM.	('Aldefluor', 'Chemical', '-', (86, 95))	('impairing', 'NegReg', (237, 246))	('UM', 'Phenotype', 'HP:0007716', (275, 277))	('niclosamide', 'Chemical', 'MESH:D009534', (35, 46))	('decreased', 'NegReg', (58, 67))	('UM', 'Phenotype', 'HP:0007716', (142, 144))	('self-renewal trait', 'CPA', (253, 271))	('CSCs', 'Disease', (228, 232))	('niclosamide', 'Chemical', 'MESH:D009534', (190, 201))	('eliminating', 'NegReg', (216, 227))	('niclosamide', 'Var', (190, 201))
154280	28529629	Because GSK3beta phosphorylate beta-catenin at S33, S37 and T41 which results in its subsequent proteasome-ubiquitination, reduction in phospho-GSK3beta (S9) by niclosamide may be helpful in explaining the reduced beta-catenin.	('reduced', 'NegReg', (206, 213))	('proteasome-ubiquitination', 'MPA', (96, 121))	('proteasome', 'cellular_component', 'GO:0000502', ('96', '106'))	('proteasome', 'molecular_function', 'GO:0004299', ('96', '106'))	('GSK', 'molecular_function', 'GO:0050321', ('8', '11'))	('beta-catenin', 'Protein', (214, 226))	('GSK', 'molecular_function', 'GO:0050321', ('144', '147'))	('T41', 'Var', (60, 63))	('reduction', 'NegReg', (123, 132))	('niclosamide', 'Chemical', 'MESH:D009534', (161, 172))	('results in', 'Reg', (70, 80))	('S37', 'Var', (52, 55))
154283	28529629	Our results showed that the decreased levels of phospho-beta-catenin at S552 and S675 in the niclosamide-treated UM cells may reflect the repressed PKA activity because PKA is the major kinase that phosphorylate beta-catenin on the sites of S552 and S675 to maintain the stability of beta-catenin.	('PKA', 'cellular_component', 'GO:0005952', ('148', '151'))	('decreased', 'NegReg', (28, 37))	('S675', 'Var', (81, 85))	('stability', 'MPA', (271, 280))	('S552', 'Var', (241, 245))	('niclosamide', 'Chemical', 'MESH:D009534', (93, 104))	('PKA', 'molecular_function', 'GO:0004691', ('169', '172'))	('PKA', 'cellular_component', 'GO:0005952', ('169', '172'))	('UM', 'Phenotype', 'HP:0007716', (113, 115))	('S675', 'Var', (250, 254))	('levels', 'MPA', (38, 44))	('PKA', 'molecular_function', 'GO:0004691', ('148', '151'))
154285	28529629	Indeed, exogenous PKA activator dbcAMP abrogated the effect of niclosamide on phospho-beta-catenin (S552 and S675) and beta-catenin.	('niclosamide', 'Chemical', 'MESH:D009534', (63, 74))	('S552', 'Var', (100, 104))	('phospho-beta-catenin', 'MPA', (78, 98))	('abrogated', 'NegReg', (39, 48))	('dbcAMP', 'Chemical', 'MESH:D003994', (32, 38))	('PKA', 'molecular_function', 'GO:0004691', ('18', '21'))	('S675', 'Var', (109, 113))	('PKA', 'cellular_component', 'GO:0005952', ('18', '21'))	('beta-catenin', 'MPA', (119, 131))
154322	25856819	It has been previously shown that uveal melanomas with class 1 GEP have a 2-21% risk of metastasis at 5 years while those with class 2 profile have a 72% risk of metastasis at 5 years.	('uveal melanomas', 'Phenotype', 'HP:0007716', (34, 49))	('metastasis', 'CPA', (88, 98))	('uveal melanomas', 'Disease', (34, 49))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('uveal melanomas', 'Disease', 'MESH:C536494', (34, 49))	('class 1 GEP', 'Var', (55, 66))	('uveal melanoma', 'Phenotype', 'HP:0007716', (34, 48))	('GEP', 'Var', (63, 66))
154324	25856819	Although absolute decreases in tumor thickness were similar between the two groups, proportional decrease was greater in tumors with class 1 GEP (26.5% v. 13.0%, P = 0.01).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('GEP', 'Var', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('class 1 GEP', 'Var', (133, 144))	('tumor', 'Disease', (31, 36))	('tumors', 'Disease', (121, 127))	('tumor', 'Disease', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('decrease', 'NegReg', (97, 105))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
154329	25856819	Other studies have described enhanced regression of intraocular melanoma when melanoma cells are mutagenized in vitro prior to intraocular injection in a murine model of intraocular melanoma.	('regression', 'CPA', (38, 48))	('intraocular melanoma', 'Disease', 'MESH:C563596', (52, 72))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('intraocular melanoma when melanoma', 'Disease', (52, 86))	('murine', 'Species', '10090', (154, 160))	('intraocular melanoma', 'Disease', 'MESH:C563596', (170, 190))	('intraocular melanoma', 'Phenotype', 'HP:0007716', (52, 72))	('intraocular melanoma', 'Disease', (170, 190))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('mutagenized', 'Var', (97, 108))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('intraocular melanoma', 'Phenotype', 'HP:0007716', (170, 190))	('enhanced', 'PosReg', (29, 37))	('intraocular melanoma when melanoma', 'Disease', 'MESH:D008545', (52, 86))
154330	25856819	Mutagenesis enhanced expression of class I major histocompatibility complex, increased susceptibility of the tumor graft to CD8+ cytotoxic T lymphocyte-mediated killing, and to tumor necrosis factor-mediated cytolysis.	('class I major', 'Protein', (35, 48))	('Mutagenesis', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('increased', 'PosReg', (77, 86))	('necrosis', 'biological_process', 'GO:0008220', ('183', '191'))	('Mutagenesis', 'biological_process', 'GO:0006280', ('0', '11'))	('necrosis', 'biological_process', 'GO:0070265', ('183', '191'))	('CD8', 'Gene', '925', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('necrosis', 'biological_process', 'GO:0019835', ('183', '191'))	('tumor', 'Disease', (177, 182))	('necrosis', 'biological_process', 'GO:0001906', ('183', '191'))	('cytolysis', 'biological_process', 'GO:0019835', ('208', '217'))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('susceptibility', 'Reg', (87, 101))	('tumor necrosis', 'Disease', 'MESH:D009336', (177, 191))	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('43', '75'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('177', '198'))	('enhanced', 'PosReg', (12, 20))	('tumor necrosis', 'Disease', (177, 191))	('expression', 'MPA', (21, 31))	('CD8', 'Gene', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('necrosis', 'biological_process', 'GO:0008219', ('183', '191'))	('tumor', 'Disease', (109, 114))
154344	25856819	The reason for this may be because such pair-wise matching may disproportionately exclude tumors with distinct genetic features that tend to present with thicker initial tumor thicknesses, such as tumors with class 2 status, monosomy 3, or with otherwise high propensities to metastasize.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('metastasize', 'CPA', (276, 287))	('tumor', 'Disease', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Disease', (170, 175))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('class 2 status', 'Var', (209, 223))	('monosomy 3', 'Var', (225, 235))	('tumors', 'Disease', (197, 203))	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
154351	25856819	seemed to confirm these findings by assessing monosomy 3 status, a genetic feature of choroidal melanoma highly associated with metastasis and death, in patients with I-125 brachytherapy.	('metastasis', 'CPA', (128, 138))	('patients', 'Species', '9606', (153, 161))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (86, 104))	('death', 'Disease', 'MESH:D003643', (143, 148))	('death', 'Disease', (143, 148))	('monosomy 3 status', 'Var', (46, 63))	('choroidal melanoma', 'Disease', 'MESH:D008545', (86, 104))	('I-125', 'Chemical', 'MESH:C000614960', (167, 172))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('associated', 'Reg', (112, 122))	('choroidal melanoma', 'Disease', (86, 104))
154352	25856819	found that initial thickness, absolute and proportional reduction in thickness were greater among tumors with monosomy 3 (v. disomy 3, (a feature associated with increased metastasis-free survival) when measured 0.5 - 3.33 y after I-125 brachytherapy.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('thickness', 'MPA', (19, 28))	('I-125', 'Chemical', 'MESH:C000614960', (231, 236))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('monosomy 3', 'Var', (110, 120))	('greater', 'PosReg', (84, 91))	('thickness', 'MPA', (69, 78))	('reduction', 'NegReg', (56, 65))
154354	25856819	found that tumors with monosomy 3 did not have a significant difference in regression at six months when compared to tumors with disomy 3.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('monosomy 3', 'Var', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', (117, 123))
154365	21956388	BAP1 is a tumor suppressor gene located on chromosome 3p21 in a region that shows loss or deletions in numerous cancers, including lung and breast cancer, as well as uveal melanoma and mesothelioma.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('numerous cancers', 'Disease', (103, 119))	('BAP1', 'Gene', (0, 4))	('tumor', 'Disease', (10, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('10', '26'))	('loss', 'NegReg', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('deletions', 'Var', (90, 99))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('breast cancer', 'Disease', (140, 153))	('tumor suppressor', 'biological_process', 'GO:0051726', ('10', '26'))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('uveal melanoma and mesothelioma', 'Disease', 'MESH:C536494', (166, 197))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('uveal melanoma', 'Phenotype', 'HP:0007716', (166, 180))	('lung', 'Disease', (131, 135))	('numerous cancers', 'Disease', 'MESH:D009369', (103, 119))	('BAP1', 'Gene', '8314', (0, 4))
154367	21956388	Harbour et al found inactivating somatic mutations of BAP1 in 47% (28/60) (Table 1) of uveal melanoma with a much higher frequency of somatic mutations (27/34, 79%) in metastasizing uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('uveal melanoma', 'Disease', (87, 101))	('uveal melanoma', 'Phenotype', 'HP:0007716', (182, 196))	('BAP1', 'Gene', '8314', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('inactivating', 'Var', (20, 32))	('uveal melanoma', 'Disease', 'MESH:C536494', (87, 101))	('BAP1', 'Gene', (54, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (87, 101))	('uveal melanoma', 'Disease', (182, 196))	('uveal melanoma', 'Disease', 'MESH:C536494', (182, 196))
154370	21956388	In this issue, Wiesner, Bastian, Speicher and colleagues and Testa, Carbone, and colleagues provide further links between BAP1, uveal melanoma and mesothelioma by reporting on germline mutations of BAP1 in two putatively distinct cancer-related syndromes characterized predominantly by melanocytic tumors or mesothelioma, respectively, plus uveal melanoma in both disorders.	('mesothelioma', 'Disease', (147, 159))	('BAP1', 'Gene', (122, 126))	('melanocytic tumors', 'Disease', (286, 304))	('BAP1', 'Gene', '8314', (198, 202))	('mesothelioma', 'Disease', 'MESH:D008654', (147, 159))	('melanocytic tumors', 'Disease', 'MESH:D009508', (286, 304))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('cancer', 'Disease', (230, 236))	('uveal melanoma and mesothelioma', 'Disease', 'MESH:C536494', (128, 159))	('BAP1', 'Gene', (198, 202))	('uveal melanoma', 'Disease', 'MESH:C536494', (341, 355))	('melanoma', 'Phenotype', 'HP:0002861', (347, 355))	('tumors', 'Phenotype', 'HP:0002664', (298, 304))	('uveal melanoma', 'Disease', (341, 355))	('uveal melanoma', 'Disease', 'MESH:C536494', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('uveal melanoma', 'Disease', (128, 142))	('BAP1', 'Gene', '8314', (122, 126))	('mesothelioma', 'Disease', (308, 320))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('germline mutations', 'Var', (176, 194))	('uveal melanoma', 'Phenotype', 'HP:0007716', (341, 355))	('mesothelioma', 'Disease', 'MESH:D008654', (308, 320))	('uveal melanoma', 'Phenotype', 'HP:0007716', (128, 142))	('cancer', 'Disease', 'MESH:D009369', (230, 236))
154371	21956388	Wiesner et al identified co-segregating germline mutations of BAP1 in two families (1 and 2) with multiple members with melanocytic tumors that ranged histopathologically from epithelioid nevi to atypical melanocytic proliferations that had features that overlapped with cutaneous melanoma.	('cutaneous melanoma', 'Disease', (271, 289))	('BAP1', 'Gene', '8314', (62, 66))	('melanocytic tumors', 'Disease', (120, 138))	('melanocytic tumors', 'Disease', 'MESH:D009508', (120, 138))	('germline mutations', 'Var', (40, 58))	('nevi to atypical melanocytic proliferations', 'Phenotype', 'HP:0000995', (188, 231))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (271, 289))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (271, 289))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('BAP1', 'Gene', (62, 66))	('melanocytic proliferations', 'Disease', 'MESH:D059545', (205, 231))	('melanoma', 'Phenotype', 'HP:0002861', (281, 289))	('epithelioid nevi', 'Disease', (176, 192))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('nevi', 'Phenotype', 'HP:0003764', (188, 192))	('atypical melanocytic proliferations', 'Phenotype', 'HP:0001062', (196, 231))	('melanocytic proliferations', 'Disease', (205, 231))
154374	21956388	Examination of a subset of the familial melanocytic tumors revealed that the majority of tumors showed biallelic inactivation of BAP1 by various somatic alterations.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('biallelic inactivation', 'Var', (103, 125))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('BAP1', 'Gene', '8314', (129, 133))	('familial melanocytic tumors', 'Disease', 'MESH:C536819', (31, 58))	('BAP1', 'Gene', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('familial melanocytic tumors', 'Disease', (31, 58))
154375	21956388	Testa et al discovered co-segregating germline mutations in BAP1 in two families (L and W) with 5 or more members with mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (119, 131))	('mesothelioma', 'Disease', (119, 131))	('BAP1', 'Gene', '8314', (60, 64))	('germline mutations', 'Var', (38, 56))	('BAP1', 'Gene', (60, 64))
154377	21956388	The families also had multiple members with various malignancies including two members with uveal melanoma in family L. Somatic alterations of the familial mesothelioma tumors indicated biallelic inactivation of BAP1.	('familial mesothelioma tumors', 'Disease', (147, 175))	('BAP1', 'Gene', (212, 216))	('mesothelioma tumors', 'Phenotype', 'HP:0100001', (156, 175))	('biallelic inactivation', 'Var', (186, 208))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('uveal melanoma', 'Phenotype', 'HP:0007716', (92, 106))	('uveal melanoma', 'Disease', (92, 106))	('uveal melanoma', 'Disease', 'MESH:C536494', (92, 106))	('malignancies', 'Disease', 'MESH:D009369', (52, 64))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('malignancies', 'Disease', (52, 64))	('BAP1', 'Gene', '8314', (212, 216))	('familial mesothelioma tumors', 'Disease', 'MESH:D008654', (147, 175))
154381	21956388	Several cancers including cutaneous melanoma (n=3), non-melanoma skin (n=2), ovarian (n=1), breast (n=1), renal (n=1), and pancreatic (n=1) cancer occurred in family members who inherited their family's inactivating BAP1 mutation.	('inactivating', 'Var', (203, 215))	('BAP1', 'Gene', (216, 220))	('pancreatic', 'Disease', 'MESH:D010195', (123, 133))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('breast', 'Disease', (92, 98))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancer', 'Disease', (8, 14))	('cancers', 'Disease', (8, 15))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('non-melanoma skin', 'Disease', (52, 69))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('pancreatic', 'Disease', (123, 133))	('non-melanoma skin', 'Disease', 'MESH:D008545', (52, 69))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('ovarian', 'Disease', (77, 84))	('cancer', 'Disease', (140, 146))	('BAP1', 'Gene', '8314', (216, 220))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('mutation', 'Var', (221, 229))	('cutaneous melanoma', 'Disease', (26, 44))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (26, 44))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (26, 44))	('occurred', 'Reg', (147, 155))	('renal', 'Disease', (106, 111))
154382	21956388	Whether these cancers are part of the spectrum of tumors related to germline BAP1 mutations requires additional study.	('cancers', 'Disease', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('BAP1', 'Gene', '8314', (77, 81))	('mutations', 'Var', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('BAP1', 'Gene', (77, 81))
154383	21956388	Data from COSMIC (Catalogue Of Somatic Mutations In Cancer) showed low frequencies of somatic BAP1 mutations in several of the observed tumors including breast (0.4%), ovarian (3.4%), and pancreatic (0.0%) cancer (table 1).	('tumors', 'Disease', (136, 142))	('ovarian', 'Disease', (168, 175))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('BAP1', 'Gene', '8314', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('breast', 'Disease', (153, 159))	('pancreatic', 'Disease', 'MESH:D010195', (188, 198))	('mutations', 'Var', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('pancreatic', 'Disease', (188, 198))	('BAP1', 'Gene', (94, 98))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
154384	21956388	In addition, Wiesner et al showed that five percent (3/60) of primary melanomas originating from acral skin (n=15), mucosa (n=15), or skin with (n=15) or without chronic sun damage had somatic BAP1 mutations.	('melanomas', 'Disease', 'MESH:D008545', (70, 79))	('BAP1', 'Gene', '8314', (193, 197))	('mutations', 'Var', (198, 207))	('sun damage', 'Phenotype', 'HP:0000992', (170, 180))	('melanomas', 'Disease', (70, 79))	('BAP1', 'Gene', (193, 197))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))
154385	21956388	Finally, lung cancer, which was one of the first cancers originally reported to have BAP1 somatic mutations, also had very few somatic mutations (0.6%) suggesting that another gene in the 3p21 region may be implicated in some of the cancers that show loss/deletion in this region.	('BAP1', 'Gene', (85, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('implicated', 'Reg', (207, 217))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('lung cancer', 'Disease', 'MESH:D008175', (9, 20))	('mutations', 'Var', (98, 107))	('loss/deletion', 'NegReg', (251, 264))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('cancers', 'Disease', (233, 240))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('BAP1', 'Gene', '8314', (85, 89))	('lung cancer', 'Disease', (9, 20))	('cancers', 'Disease', (49, 56))
154389	21956388	Harbour et al hypothesized that biallelic loss of BAP1 was a key event in uveal melanoma metastasis.	('uveal melanoma metastasis', 'Disease', (74, 99))	('biallelic', 'Var', (32, 41))	('uveal melanoma metastasis', 'Disease', 'MESH:C536494', (74, 99))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('BAP1', 'Gene', '8314', (50, 54))	('BAP1', 'Gene', (50, 54))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('loss', 'NegReg', (42, 46))
154390	21956388	The current studies suggest a potentially more complex scenario that may depend on various combinations of the tissue of origin, environmental exposures, functional consequences of the BAP1 mutations, and mechanisms of inactivation of the second BAP1 allele.	('BAP1', 'Gene', (246, 250))	('BAP1', 'Gene', (185, 189))	('mutations', 'Var', (190, 199))	('BAP1', 'Gene', '8314', (246, 250))	('BAP1', 'Gene', '8314', (185, 189))
154394	21956388	Given its complexity, different germline mutations in BAP1 may predispose to divergent tumor types.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('germline mutations', 'Var', (32, 50))	('predispose', 'Reg', (63, 73))	('tumor', 'Disease', (87, 92))	('BAP1', 'Gene', '8314', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('BAP1', 'Gene', (54, 58))
154395	21956388	For what tumor types do germline mutations of BAP1 increase susceptibility?	('increase', 'PosReg', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('BAP1', 'Gene', '8314', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('germline mutations', 'Var', (24, 42))	('BAP1', 'Gene', (46, 50))	('susceptibility', 'MPA', (60, 74))